Pd(II)-Catalyzed Directing-Group-Aided C–H Arylation, Alkylation, Benzylation, and Methoxylation of Carbazole-3-carboxamides toward C2,C3,C4-Functionalized Carbazoles

Abstract

We report the Pd(II)-catalyzed β-C–H arylation, alkylation, benzylation, and methoxylation of carbazole-3-carboxamide and carbazole-2-carboxamide substrates, assisted by the bidentate directing groups 8-aminoquinoline or 2-(methylthio)aniline, and construction of C2,C3,C4-functionalized carbazole motifs. The Pd(II)-catalyzed β-C–H arylation reaction was attempted using different directing groups such as 8-aminoquinoline, 2-(methylthio)aniline, 4-amino-2,1,3-benzothiadiazole, 4-methoxyquinolin-8-amine, and butan-1-amine. Through optimization of the reactions, 8-aminoquinoline and 2-(methylthio)aniline were found to be suitable directing groups and, especially, 2-(methylthio)aniline was found to be an efficient directing group in the Pd(II)-catalyzed β-C–H arylation, alkylation, and methoxylation of carbazole-3-carboxamide, carbazole-2-carboxamide substrates. An ample number of β-C–H arylated, alkylated, benzylated, and methoxylated carbazole-3-carboxamides were synthesized. The structures of representative β-C(2)–H arylated carbazole and β-C(2)–H methoxylated carbazole motifs were unequivocally confirmed by single-crystal X-ray structure analysis. Given the wide range of applications of carbazoles in chemistry, materials sciences, and medicinal chemistry and there have been constant efforts for developing new methods for synthesizing functionalized carbazoles. This work contributes to the expansion of the library of C2,C3,C4-functionalized carbazole motifs through a Pd(II)-catalyzed directing-group-aided site-selective β-C–H activation and functionalization of carbazole-3-carboxamides.

Transition-metal-catalyzed C–H functionalization has transpired to be a reliable synthetic method for installing functional groups in aromatic and aliphatic molecules.[1] [2] [3] In general, the C–H bond functionalization of organic molecules has surfaced as an alternative to the traditional cross-coupling reactions, which involve the use of organometallic reagents.[4] C–H functionalization can be effectively accomplished with or without using a directing group.[1–3] Effective and site-selective C–H activation and functionalization have been accomplished through chelation assistance by a directing group (DG).[3] Along this line, Pd(II)-catalyzed, site-selective activation and functionalization of C–H bonds of organic substrates, using removable bidentate directing groups [e.g., 8-aminoquinoline, 2-(methylthio)aniline, and picolinamide] has emerged as a dependable synthetic transformation.[3] [5] [6] Notably, the functionalization of the β-C–H bonds of aromatic and aliphatic carboxamides has been well explored via the Pd(II)-catalyzed, 8-aminoquinoline or 2-(methylthio)aniline DG-aided C–H functionalization tactic.[3] [5] [6]

Carbazole derivatives are an important class of nitrogen-containing heterocycles that are used as key units in various materials (including conducting polymers, organic dyes, and photorefractive and optoelectronic materials).[7] [8] Naturally occurring carbazole alkaloids and synthetically derived carbazole derivatives have found a wide range of applications in chemical sciences (Figure [1]).[7] Carbazole motifs are popular small organic molecules in medicinal chemistry and have been found to exhibit various biological activities (e.g., anticancer and antimicrobial activities).[7] [9] Owing to their importance, various protocols, including the recently emerged C–H functionalization and, in particular, the intramolecular C–H amination method involving 2-amino­biphenyls have been developed for synthesizing carbazole derivatives.[7] ^, [10] [11] [12] Markedly, there have been some reports describing the functionalization of the C–H bonds of the carbazole motif 1aa, affording substituted carbazoles 1k–w (Scheme [1]).[12] Yoo reported the C(3)–H functionalization of carbazole via a Rh-catalyzed carbenoid insertion affording 1k.[12a] Satoh/Miura reported a Pd-catalyzed C(3)–H alkenylation of carbazole affording 1l [12b] and a Ru-catalyzed pyridyl DG-aided C(1)–H/C(8)–H acetoxylation of carbazole affording 1n.[12c] Carretero reported a Pd-catalyzed pyridyl DG-aided C(1)–H/C(8)–H olefination of carbazole affording 1m.[12d] Wu reported a Pd-catalyzed pyridyl DG-aided C(1)–H/C(8)–H arylation of carbazole affording 1o.[12e] Sperry reported a Ir-catalyzed C(1)–H/C(8)–H borylation of carbazole affording 1p.[12f] Patureau reported a Ru/Cu co-catalyzed C(1)–H amination of carbazole affording 1q.[12g] Frost reported a Ru-catalyzed C(4)–H alkylation of carbazole via σ-activation affording 1r.[12h] Kambe disclosed a Rh-catalyzed, pyrimidyl DG-aided C(1)–H functionalization of carbazole affording 1s.[12i] [j] Nageswar reported a Ru-catalyzed pyrimidyl DG-aided C(1)–H arylation of carbazole affording 1t.[12k] Chatani­ has reported single examples of Ni-catalyzed 8-aminoquinoline DG-aided β-C–H methylation and butylation affording 1u,v.[12`] [m] [n] An example of Ru-catalyzed cross-dehydrogenative annulation affording 1w was reported by Baidya (Scheme [1]).[12o]

Despite the widespread applications of carbazoles in chemical sciences and the constant efforts in synthesizing new carbazole molecules via classical and C–H functionalization routes[7] [8] [9] [10] [11] [12] and despite the considerable number of reports dealing with the functionalization of C–H bonds of the carbazole motif, the Pd(II)-catalyzed, bidentate DG-aided­ β-C–H functionalization tactic[3] has not been explored well for the functionalization of C–H bonds of the carbazole motif. In particular, to the best of our knowledge, the bidentate DG-aided β-C–H arylation of carbazole-3-carboxamide using aryl iodides or benzyl bromides has not been reported. Thus, given the limited number of methylated/butylated examples (1u,v) obtained via Ni-catalyzed reactions (Scheme [1]), there is scope for expanding the library of carbazole-3-carboxamides, especially C2,C3,C4-functionalized carbazoles 2b–e via the Pd(II)-catalyzed, DG-aided β-C–H functionalization tactic. Accordingly, in continuation of our lab’s work on the Pd(II)-catalyzed C–H activation and functionalization reactions, we have become interested in using the Pd(II)-catalyzed, 8-aminoquinoline and 2-(methylthio)aniline DG-aided β-C–H functionalization method for the C–H functionalization of carbazole motif 2a. Results comprising of the Pd(II)-catalyzed, bidentate DG-aided β-C–H arylation, alkylation, benzylation, and alkoxylation of carbazole-3-carboxamides and an example of β-C–H arylation of carbazole-2-carboxamide are reported (Scheme [1]).

Table 1 Screening of Reaction Conditions for the Pd(II)-Catalyzed C–H Arylation of Carbazole-3-carboxamide 5a ^a

Entry	PdL2 (mol%)	Additive (equiv)	Solvent	Yield of 7a (%)b
1	Pd(OAc)2 (10)	AgOAc (2.5)	toluene	18
2	Pd(OAc)2 (3)	Ag2CO3 (2)	p-xylene	<5
3	Pd(OAc)2 (3)	Cs2CO3 (2)	p-xylene	20
4	Pd(OAc)2 (3)	Na2CO3 (2)	p-xylene	23
5	PdCl2(MeCN)2 (3)	K2CO3 (2)	p-xylene	0
6	PdCl2 (3)	K2CO3 (2)	p-xylene	<5
7	Pd(OAc)2 (5)	K2CO3 (2)	o-xylene	24
8	Pd(OAc)2 (3)	K2CO3 (2)	p-xylene	55
9	Pd(OAc)2 (5)	K2CO3 (2)	p-xylene	55
10	Pd(OAc)2 (5)	K2CO3 (1)	p-xylene	38
11	Pd(OAc)2 (5)	K2CO3 (6)	p-xylene	19
12	Pd(OAc)2 (3)	K2CO3 (5)	p-xylene	45
13	Pd(OAc)2 (10)	K2CO3 (3)	p-xylene	61
14	Pd(OAc)2 (3)	K2CO3 (3)	p-xylene	64

^a Reaction conditions: 5a (1 equiv), 6a (4 equiv), PdL₂, additive, solvent (1 mL), 130 °C, 36 h, sealed tube filled with ambient air.

^b Isolated yield.

To commence the investigation on the Pd(II)-catalyzed, bidentate DG-aided β-C–H functionalization of the carbazole motif, we first assembled the required carbazole-3-carboxamides containing the corresponding directing groups. Carbazole-3-carboxylic acids 4a,b were prepared from commercially available carbazole-3-carboxaldehydes 3a,b, respectively (Scheme [2]). Then, the carbazole-3-carboxylic acids 4a,b were linked with various commonly employed directing groups[3] [5] [6] via the standard amide coupling method. Accordingly, N-ethylcarbazole-3-carboxamides 5a–e possessing the corresponding directing groups [8-aminoquinoline (8-AQ), 2-(methylthio)aniline (MTA), 4-amino-2,1,3-benzothiadiazole (ABTD), 4-methoxyquinolin-8-amine (MQ), and butan-1-amine (a simple aliphatic amine)] were prepared. Next, we assembled N-benzylcarbazole-3-carboxamides 5f,g linked with the corresponding directing groups 8-AQ and MTA (Scheme [2]). We also prepared additional carbazole-3-carboxamides 5i,j and carbazole-2-carboxamides 5h,k from their corresponding carboxylic acids 4c–f, which were assembled using the procedures reported in the literature.[13] Accordingly, we prepared 6-bromocarbazole-3-carboxylic acid 4c from 3a via bromination and oxidation reactions. Then, 4c was linked with MTA to afford 5i. Subsequently, we assembled ethyl carbazole-3-carboxylate derivative 4da from 3aa via Pd-catalyzed C–N and oxidative coupling reactions. Compound 4da was then subjected to ester hydrolysis to afford the carbazole-3-carboxylic acid 4d, which was linked with MTA to afford 5j. Next, we aimed to synthesize carbazole-2-carboxamides possessing the MTA directing group. Towards this, we assembled methyl carbazole-2-carboxylate derivative 4ea from 3ae via the triphenylphosphine-mediated reductive cyclization method. Compound 4ea was subjected to ester hydrolysis to afford carbazole-2-carboxylic acid 4e, which was then linked with MTA to afford 5k. Furthermore, compound 4ea was subjected to N-methylation to afford 4fa. Then, 4fa was subjected to ester hydrolysis to afford N-methylcarbazole-2-carboxylic acid 4f, which was then linked with MTA to afford 5h (Scheme [2]).

Next, we performed a screening of the reaction conditions comprising the β-C–H arylation of carbazole-3-carboxamide 5a containing the 8-AQ DG with p-anisyl iodide (6a). Table [1] shows the arylation of carbazole substrate 5a in the presence of various Pd(II) catalysts, silver or alkali metal salt additives, and solvents. Apart from the Pd(II) catalyst, in general, an additive such as a silver salt (AgOAc or Ag₂CO₃) or an alkali metal-based salt/base (e.g., Cs₂CO₃, K₂CO_3­, KOAc) is required for accomplishing the Pd(II)-catalyzed­, 8-AQ DG-aided C–H arylation reactions.[3] [5r] The additive functions as a halide ion scavenger and helps in regenerating the Pd(II) catalyst in the proposed Pd^II–Pd^IV catalytic cycle.[3] [5a] [r]

The β-C–H arylation of the carbazole-3-carboxamide substrate 5a containing the 8-AQ DG was attempted using p-anisyl iodide (6a; 4 equiv) in the presence of the Pd(OAc)₂ catalyst (10 mol%) and AgOAc (2.5 equiv) as an additive in toluene at 130 °C for 36 hours in a sealed tube (Table [1], entry 1). This reaction afforded the β-C(2)–H arylated product 7a in 18% yield. Heating a mixture of 5a with 6a in the presence of the Pd(OAc)₂ catalyst (3 mol%) and Ag₂CO₃ as an additive in p-xylene afforded the product 7a in traces (entry 2). The same reaction was performed using Cs₂CO₃ or Na₂CO_3­ as an additive instead of Ag₂CO₃ and these reactions yielded product 7a in 20–23% yield (entries 3 and 4). Next, we performed the C–H arylation of 5a with 6a in the presence of PdCl₂(MeCN)₂ or PdCl₂ as the catalyst and K₂CO₃ as an additive in p-xylene, but these attempts did not provide the product 7a (entries 5 and 6). Heating a mixture of 5a with 6a in the presence of the Pd(OAc)₂ catalyst (5 mol%) and K₂CO₃ as an additive in o-xylene instead of p-xylene afforded the product 7a in 24% yield (entry 7).

Next, heating a mixture of 5a with 6a in the presence of the Pd(OAc)₂ catalyst (3 mol%) and K₂CO₃ additive (2 equiv) in p-xylene afforded the product 7a in an improved yield of 55% yield (Table [1], entry 8). Then, we attempted the C–H arylation of 5a with 6a in the presence of an increased amount of the Pd(OAc)₂ catalyst (5 mol%) and K₂CO₃ additive (2 equiv) additive in p-xylene. This attempt also gave the β-C(2)–H arylated product 7a in 55% yield (entry 9). The reaction of 5a with 6a in the presence of the Pd(OAc)₂ catalyst (5 mol%) and of K₂CO₃ (1 equiv) as additive in p-xylene afforded the product 7a in a reduced yield of 38% (entry 10). Heating a mixture of 5a with 6a in the presence of the Pd(OAc)₂ catalyst (5 mol%) and excess amounts of K₂CO₃ additive (6 equiv) in p-xylene also afforded the product 7a in a reduced yield of 19% (entry 11). Similarly, heating a mixture of 5a with 6a in the presence of the Pd(OAc)₂ catalyst (3 mol%) and excess amounts of K₂CO₃ additive (5 equiv) in p-xylene afforded the product 7a in a reduced yield of 45% (entry 12). While a clear cause is not known, the reason for the observed reduced yield of 7a in entries 11 and 12 may be due to some over- or side reaction.

We then attempted the C–H arylation of 5a with 6a in the presence of an increased amount of the Pd(OAc)₂ catalyst (10 mol%) and K₂CO₃ additive (3 equiv) in p-xylene. This attempt afforded the β-C(2)–H arylated product 7a in a slightly improved yield of 61% (Table [1], entry 13). Finally, heating a mixture of 5a with 6a in the presence of the Pd(OAc)₂ catalyst (3 mol%) and the K₂CO₃ additive (3 equiv) in p-xylene afforded the β-C(2)–H arylated product 7a in a marginally improved yield of 64% (entry 14). The carbazole-3-carboxamide substrate 5a contains two β-C–H bonds, namely the C(2)–H and C(4)–H bonds. In all these attempts, the Pd(II)-catalyzed 8-AQ DG-aided β-C–H arylation of the carbazole-3-carboxamide substrate 5a afforded the C(2)–H arylated product 7a as the major product; the corresponding C(4)–H arylated product was not obtained in a demonstrable amount. The C(4)–H bond in the carbazole-3-carboxamide substrate 5a seems to be relatively hindered. Accordingly, the arylation of the C(4)–H position of 5a may be a sluggish process compared to the arylation of the C(2)–H position of substrate 5a. The selective formation of the C(2)–H arylated product 7a from the Pd(II)-catalyzed 8-AQ DG-aided arylation of 5a can also be corroborated with the Ni(II)-catalyzed C–H methylation/butylation of carbazole-3-carboxamide. Chatani et al. observed that the Ni-catalyzed, 8-AQ DG-aided methylation or butylation of a carbazole-3-carboxamide afforded the corresponding C(2)–H methylated or C(2)–H alkylated products 1u and 1v (Scheme [1]).[12l] [m]

Having studied the C–H arylation of the carbazole-3-carboxamide substrate 5a containing the 8-AQ DG, we then intended to test the efficiency of different bidentate directing groups for accomplishing the β-C–H arylation of carbazole-3-carboxamide (Scheme [3]). Accordingly, the β-C–H arylation of carbazole-3-carboxamide 5b containing the 2-(methylthio)aniline (MTA) DG was attempted with 6a in the presence of the Pd(OAc)₂ catalyst (5 mol%) and K₂CO₃ additive in o-xylene at 130 °C for 36 hours. This reaction afforded the β-C(2)–H arylated product 8a in 63% yield (Scheme [3]). This yield was comparable to the yield of product 7a (61–64%, Table [1], entries 13 and 14), which was obtained using the 8-AQ DG. Next, we performed the β-C–H arylation of carbazole-3-carboxamides 5c and 5d containing the ABTD or MQ DG with 6a in the presence of the Pd(OAc)₂ catalyst (5 mol%) and K₂CO₃ additive in o-xylene at 130 °C for 36 hours. The ABTD DG-aided reaction gave an inseparable mixture and the MQ DG-aided reaction afforded the β-C(2)–H arylated product 9b in low yield (32%) (Scheme [3]). The Pd(II)-catalyzed β-C–H arylation of carbazole-3-carboxamide 5e containing a simple amide DG with 6a did not afford the expected β-C(2)–H arylated product 9c. This reaction indicated that the usage of a bidentate directing group is necessary and, accordingly, the substrates 5a,b,d containing the corresponding directing groups resulted in the formation of the corresponding β-C(2)–H arylated products 7a, 8a, and 9b in demonstrable yields. The corresponding 8-AQ, MTA, and MQ DGs provide the required chelation assistance for the β-C–H arylation of carbazole-3-carboxamides 5a,b,d during the β-C–H functionalization process in the proposed Pd^II–Pd^IV catalytic cycle.[3] [5a] [r]

Table 2 Pd(II)-Catalyzed C–H Arylation of Carbazole-3-carboxylic Acid 4a ^a

Entry	Catalyst (mol%)	Additives (equiv)	Solvent	Yield of 10a (%)b
1	Pd(OAc)2 (6)	NMe4Cl (1.3), KOAc (1.5)	AcOH (1.5 equiv)	45
2	Pd(OAc)2 (10)	NMe4Cl (2.2), KOAc (2.8)	AcOH (1.5 equiv)	43
3	Pd(OAc)2 (10)	NMe4Cl (2.2), KOAc (2.8)	TFA (1.5 equiv)	30
4	PEPPSI-iPr (6)	NMe4Cl (2.2), KOAc (2.8)	AcOH (1.5 equiv)	0

^a Reaction conditions: 4a (0.21 mmol), 6a (3 equiv), catalyst, additives, solvent (1.5 equiv), 120 °C for 24 h, sealed tube filled with ambient air.

^b Isolated yield.

Subsequently, we intended to explore the native carboxylic acid group aided C–H arylation[2p] [q] of carbazole-3-carboxylic acid 4a (Table [2]). Towards this end, we performed the β-C–H arylation of N-ethylcarbazole-3-carboxylic acid (4a) with 6a in the presence of Pd(OAc)₂ as catalyst (6–10 mol%) and NMe₄Cl and KOAc as additives in AcOH or TFA at 120 °C for 24 hours. These reactions afforded the β-C(2)–H arylated carbazole-3-carboxylic acid 10a in low to satisfactory yields (30–45%, entries 1–3). In another attempt, we performed the β-C–H arylation of N-ethyl-carbazole-3-carboxylic acid 4a with 6a in the presence of the PEPPSI-iPr catalyst (6 mol%) and NMe₄Cl and KOAc as additives in AcOH at 120 °C for 24 hours. This reaction did not yield the expected product 10a (entry 4).

Having found suitable conditions for accomplishing the β-C(2)–H arylation of carbazole-3-carboxamides 5a,b and having obtained the products 7a and 8a in reasonable yields using the corresponding bidentate DGs 8-AQ and MTA, we then wished to expand the scope and generality of this protocol. The β-C–H arylation of carbazole-3-carboxamide 5a containing the 8-AQ DG was attempted using para-substituted aryl iodides in the presence of the Pd(OAc)₂ catalyst (3–5 mol%) and K₂CO₃ (2–3 equiv) in p-xylene at 130 °C for 36 hours (Scheme [4]). These reactions afforded the corresponding β-C(2)–H arylated carbazole-3-carboxamides 7a,b in 55–64% yield. Then, we performed the Pd(II)-catalyzed, 8-AQ DG-aided β-C–H arylation of 5a with 2-iodothiophene. This reaction afforded the β-C(2)–H arylated carbazole-3-carboxamide 7c in a demonstrable yield (21%). Next, the Pd(II)-catalyzed, 8-AQ DG-aided β-C–H arylation of 5a was performed using meta-substituted aryl iodides. These reactions afforded the corresponding β-C(2)–H arylated carbazole-3-carboxamides 7d,e in 43–45% yield.

Having obtained low to satisfactory yields of the corresponding β-C(2)–H arylated carbazole carboxamides 7a–e from 5a containing the 8-AQ DG, we then decided to explore the substrate scope using carbazole-3-carboxamide 5b containing the MTA DG (Scheme [5]). Accordingly, the β-C–H arylation of N-ethyl-carbazole-3-carboxamide 5b containing the MTA DG was attempted using various aryl iodides. Carbazole-3-carboxamide 5b was treated with various aryl iodides containing an electron-donating or electron-withdrawing substituent at the para position (e.g., OMe, OEt, alkyl, Br, F, NO₂, COOMe) and PhI in the presence of the Pd(OAc)₂ catalyst (5 mol%) and K₂CO₃ (2 equiv) in o-xylene at 130 °C for 36 hours. These reactions afforded the corresponding β-C(2)–H arylated carbazole-3-carboxamides 8a–k in moderate to good yields (50–90%, Scheme [5]). Next, substrate 5b was treated with various aryl iodides containing an electron-donating or electron-withdrawing substituent at the meta position (e.g., Me, OMe, Cl, Br, F, CF₃, NHAc, Ac, NO₂) in the presence of the Pd(OAc)₂ catalyst (5 mol%) and K₂CO₃ (2 equiv) in o-xylene at 130 °C for 36 hours. These reactions afforded the corresponding β-C(2)–H arylated carbazole-3-carboxamides 8l–t in moderate to good yields (41–72%, Scheme [5]).

The Pd(II)-catalyzed C–H arylation of the carbazole-3-carboxamide substrate 5b was also performed using various heteroaryl iodides such as iodopyridyls and 2-iodothiophene. These reactions afforded the corresponding β-C(2)–H arylated­ carbazole-3-carboxamides 8u–x in 35–54% yield (Scheme [5]). Next, N-ethyl-carbazole-3-carboxamide 5b was treated with various disubstituted and trisubstituted aryl iodides in the presence of the Pd(OAc)₂ catalyst (5 mol%) and K₂CO₃ (2 equiv) in o-xylene at 130 °C for 36 hours. These reactions afforded the corresponding β-C(2)–H arylated carbazole-3-carboxamides 8y,z and 8aa–ac in moderate to good yields (50–83%, Scheme [5]). Then, we performed the Pd(II)-catalyzed C–H arylation of N-benzyl-carbazole-3-carboxamide substrate 5g containing the MTA DG using various para-substituted aryl iodides. These reactions afforded the corresponding β-C(2)–H arylated N-benzylcarbazole-3-carboxamides 8ad,ae in 63–67% yield (Scheme [5]). Then, we attempted the Pd(II)-catalyzed β-C(2)–H arylation of 6-bromo-N-ethylcarbazole-3-carboxamide (5i) containing the MTA DG using p-tolyl iodide and 3-chloroiodobenzene. These reactions afforded the corresponding β-C(2)–H arylated carbazole-3-carboxamides 8ag,ah in 47–70% yield (Scheme [5]). Next, we intended to perform the β-C(3)–H arylation of carbazole-2-carboxamides 5h,k possessing the MTA DG. In this regard, N-methylcarbazole-2-carboxamide 5h was subjected to the Pd(II)-catalyzed β-C(3)–H arylation with p-tolyl iodide. This reaction afforded the β-C(3)–H arylated carbazole-2-carboxamide 8af in 67% yield (Scheme [5]). Although substrate 5h contains two β-C–H bonds, namely C(3)–H and C(1)–H, due to steric hindrance the arylation is believed to be facile at C(3)–H rather than at C(1)–H in compound 5h. Subsequently, we attempted the Pd(II)-catalyzed C–H arylation of carbazole substrates 5j,k (with unprotected N–H) with p-tolyl iodide or p-anisyl iodide. These reactions did not yield the expected C–H arylated products 8ai,aj, respectively (Scheme [5]).

We then focused our attention on performing the Pd(II)-catalyzed bidentate directing group-aided C–H alkylation and benzylation of carbazole-3-carboxamide substrates. Toward this, we performed some optimization reactions to find suitable conditions for obtaining the corresponding β-C(2)–H alkylated/benzylated carbazole-3-carboxamides (Table [3]). First, carbazole-3-carboxamide substrate 5a containing the 8-AQ DG was treated with benzyl bromide (11a; 4 equiv) in the presence of the Pd(OAc)₂ catalyst (10 mol%) and K₂CO₃ (2 equiv) and NaOTf (3 equiv) as additives[14] in toluene at 130 °C for 36 hours in a sealed tube (entry 1). This reaction gave the C(2)–H and C(4)–H bis-benzylated carbazole-3-carboxamide 12a in 40% yield. The other expected C(2)–H mono-benzylated carbazole-3-carboxamide 13a was not obtained in characterizable amounts (entry 1). Similarly, the same reaction using only 5 mol% of the Pd(OAc)₂ catalyst gave the bis-benzylated carbazole-3-carboxamide 12a in 20% yield (entry 2).

Table 3 Screening of Reaction Conditions for the Pd(II)-Catalyzed C–H Benzylation and Alkylation of Carbazole-3-carboxamides 5a,b ^a

Entry	5	11	PdL2 (mol%)	Additives (equiv)	Solvent	Yield (%)b	Yield (%)b
1	5a	11a	Pd(OAc)2 (10)	K2CO3 (2), NaOTf (3)	toluene	12a (40)	13a (–)
2	5a	11a	Pd(OAc)2 (5)	K2CO3 (2), NaOTf (3)	toluene	12a (20)	13a (–)
3	5a	11a	Pd(OAc)2 (10)	K2CO3 (2), NaOTf (0)	toluene	12a (–)	13a (27)
4	5a	11a	Pd(OAc)2 (10)	AgOAc (2), NaOTf (0)	toluene	12a (39)	13a (–)
5	5a	11a	Pd(OAc)2 (10)	Cs2CO3 (2), NaOTf (3)	toluene	12a (40)	13a (–)
6	5a	11a	Pd(OAc)2 (10)	Ag2CO3 (2), NaOTf (3)	toluene	12a (<5)	13a (–)
7	5a	11a	PdCl2(MeCN)2 (10)	K2CO3 (2), NaOTf (3)	toluene	12a (19)	13a (11)
8	5a	11a	Pd(OAc)2 (10)	K2CO3 (2), NaOTf (3)	t-amyl alcohol	12a (<5)	13a (–)
9c	5a	11a	Pd(OAc)2 (10)	K2CO3 (2), NaOTf (3)	toluene	12a (28)	13a (–)
10c	5b	11a	Pd(OAc)2 (10)	K2CO3 (2), NaOTf (3)	toluene	14a (–)d	15a (–)d
11e	5a	11b	Pd(OAc)2 (10)	K2CO3 (2), NaOTf (3)	t-amyl alcohol	16a (–)	17a (54)
12	5b	11b	Pd(OAc)2 (10)	K2CO3 (2), NaOTf (3)	t-amyl alcohol	18a (–)	19a (58)

^a Reaction conditions: 5 (1 equiv), 11 (4 equiv), PdL₂, additives, solvent (1 mL), 130 °C, 36 h, sealed tube purged with nitrogen.

^b Isolated yield.

^c Compound 11a (6 equiv) was used.

^d Products 14a and 15a were obtained as an inseparable mixture.

^e Reaction time 48 h.

The C–H benzylation of 5a with 11a was performed using the Pd(OAc)₂ catalyst (10 mol%) and only K₂CO₃ as additive; this reaction afforded the mono C(2)-benzylated carbazole-3-carboxamide 13a in 27% yield (entry 3). This reaction indicated that the C–H benzylation of 5a with 11a in the absence of the additional additive NaOTf is relatively slow, affording only the mono-benzylated carbazole-3-carboxamide 13a. Subsequently, the C–H benzylation of 5a with 11a was performed using the Pd(OAc)₂ catalyst (10 mol%) and only the AgOAc additive and without the NaOTf additive. This reaction afforded the bis-benzylated carbazole-3-carboxamide 12a in 39% yield (entry 4). This reaction indicated that the C–H benzylation of 5a with 11a in the presence of only AgOAc is relatively efficient but directly affords the bis-benzylated carbazole-3-carboxamide 12a.

Then, the C–H benzylation of 5a with 11a was performed using the Pd(OAc)₂ catalyst (10 mol%) and Cs₂CO₃ as additive instead of K₂CO₃ in the presence of NaOTf as additive (Table [3], entry 5). This reaction was found to afford the bis-benzylated carbazole-3-carboxamide 12a in 40% yield. In this reaction, the mono-benzylated carbazole-3-carboxamide 13a was not obtained; this observation is similar to that made in entry 1. Then, the C–H benzylation of 5a with 11a was performed using the Pd(OAc)₂ catalyst (10 mol%) and Ag₂CO₃ additive instead of K₂CO₃ and in the presence of NaOTf additive. This reaction did not afford the expected products 12a/13a (entry 6). The C–H benzylation of 5a with 11a was performed using the PdCl₂(MeCN)₂ catalyst (10 mol%) and K₂CO₃ and NaOTf additives. This reaction afforded the bis-benzylated carbazole-3-carboxamide 12a in 19% yield and also the mono-benzylated carbazole-3-carboxamide 13a in 11% yield (entry 7). This reaction indicated that the C–H benzylation of 5a with 11a using PdCl₂(MeCN)₂ instead of Pd(OAc)₂ as the catalyst seems to be relatively slow, affording both the benzylated carbazole-3-carboxamides 12a and 13a, but in low yields (entry 7). The Pd(II)-catalyzed­ C–H benzylation of 5a with 11a in t-amylOH instead of toluene as solvent did not yield the products 12a/13a (entry 8).

The C–H benzylation of 5a was also performed using an excess amount of 11a (6 equiv) in the presence of the Pd(OAc)₂ catalyst (10 mol%) and K₂CO₃ (2 equiv) and NaOTf (3 equiv) additives (Table [3], entry 9). This reaction afforded the bis-benzylated carbazole-3-carboxamide 12a in 28% yield. This reaction indicated that there seems to be some over-reaction and, thus, the bis-benzylated product 12a was obtained in low yield. In general, the benzyl units including benzyl halides are relatively reactive motifs and there may be some side reactions occurring during the Pd(II)-catalyzed C–H benzylation of 5a and, thus, products 12a/13a were obtained in low to satisfactory yields. Next, the carbazole-3-carboxamide substrate 5b containing the MTA DG was treated with 11a in the presence of the Pd(OAc)₂ catalyst and K₂CO₃ and NaOTf additives in toluene at 130 °C for 36 hours. This reaction afforded an inseparable mixture (entry 10).

Having done the optimization reactions using benzyl bromide, we then attempted the Pd(II)-catalyzed bidentate DG-aided C–H alkylation of carbazole-3-carboxamide substrates using simple alkyl iodides. Accordingly, the carbazole-3-carboxamide 5a containing the 8-AQ DG was treated with butyl bromide (11b; 4 equiv) in the presence of the Pd(OAc)₂ catalyst (10 mol%) and K₂CO₃ (2 equiv) and NaOTf (3 equiv) additives in t-amylOH at 130 °C for 48 hours in a sealed tube (Table [3], entry 11).[14] This reaction afforded the C(2)–H mono-alkylated carbazole-3-carboxamide 17a in a reasonable yield of 54%. The other expected bis C(2) and C(4)–H alkylated carbazole-3-carboxamide 16a was not obtained in characterizable amounts (entry 11). Similarly, we treated the carbazole-3-carboxamide 5b containing the MTA DG with butyl bromide (11b; 4 equiv) in the presence of the Pd(OAc)₂ catalyst (10 mol%) and K₂CO₃ (2 equiv) and NaOTf (3 equiv) additives in t-amylOH at 130 °C for 36 hours in a sealed tube. This reaction also afforded the C(2)–H mono-alkylated carbazole-3-carboxamide 19a in a reasonable yield of 58% (entry 12). The other expected bis C(2) and C(4)–H alkylated carbazole-3-carboxamide 18a was not obtained in characterizable amounts (entry 12). These two reactions shown in entries 11 and 12 indicated that the C–H alkylation of 5a,b with 11b is relatively slower than the benzylation reaction (entry 1), therefore affording only the mono C(2)–H butylated carbazole-3-carboxamides 17a and 19a. This observation is also in line with the general trend of the low reactivity of alkyl iodides (compared to aryl iodides­/benzyl halides) in cross-coupling reactions.

Having completed the optimization reactions to find suitable conditions for obtaining the β-C–H alkylated/benzylated carbazole-3-carboxamides, we then explored the substrate scope of this method. The β-C–H benzylation of carbazole-3-carboxamide 5a containing the 8-AQ DG was attempted using simple benzyl bromide or ortho-, para-, or meta-substituted benzyl bromides in the presence of the Pd(OAc)₂ catalyst and K₂CO₃ and NaOTf additives in toluene at 130 °C for 36 hours (optimized conditions from Table [3], entry 1). These reactions afforded the corresponding bis C(2) and C(4)–H benzylated carbazole-3-carboxamides 12a–e in 29–40% yield (Scheme [6]).

Subsequently, the β-C–H alkylation of carbazole-3-carboxamide 5a containing the 8-AQ DG was attempted using various alkyl iodides in the presence of the Pd(OAc)₂ catalyst and K₂CO₃ and NaOTf additives in t-amyl alcohol at 130 °C for 48 hours (optimized conditions from Table [3], entry 11). These reactions afforded the corresponding mono C(2)–H alkylated carbazole-3-carboxamides 17a–d in 26–62% yield (Scheme [6]). Similarly, the β-C–H alkylation of carbazole-3-carboxamide 5b containing the MTA DG was performed using various primary alkyl iodides in the presence of the Pd(OAc)₂ catalyst and K₂CO₃ and NaOTf additives in t-amyl alcohol at 130 °C for 36 hours (optimized conditions from Table [3], entry 12). These reactions successfully afforded the corresponding mono C(2)–H alkylated carbazole-3-carboxamides 19a–i in 27–74% yield (Scheme [6]). Then, we attempted the Pd(II)-catalyzed β-C(2)–H alkylation of 6-bromo-N-ethylcarbazole-3-carboxamide (5i) containing the MTA DG using 1-iodononane. This reaction afforded the β-C(2)–H alkylated carbazole-3-carboxamide 19j in 62% yield (Scheme [6]). We found the limitation that the Pd(II)-catalyzed β-C–H alkylation of 5b with secondary alkyl iodides­ was not successful and, accordingly, the expected products 19k–m were not obtained from their corresponding substrates under the optimized experimental conditions (Scheme [6]).

Table 4 Screening of Reaction Conditions for the Pd(II)-Catalyzed C–H Methoxylation of Carbazole-3-carboxamide 5a ^a

Entry	Catalyst	Additive (equiv)	Solvent	Conditions	Yield of 21a (%)b
1	CuI	DBU (2)	–	100 °C, 18 hc	38
2	CuId	DBU (2)	–	100 °C, 16 hc	40
3	Cu(OAc)2	DBU (2)	–	100 °C, 24 hc	40
4	CuCl2	DBU(2)	–	100 °C, 36 hc	37
5	CuBr	DBU (3)	–	100 °C, 24 hc	44
6	CuI	DABCO (2)	–	100 °C, 24 hc	–
7	CuI	KOAc (2)	–	100 °C, 20 hc	–
8	CuI	KOt-Bu (2)	–	100 °C, 36 hc	40
9	CuI	Cs2CO3 (2)	–	100 °C, 20 hc	30
10	Pd(OAc)2	PhI(OAc)2 (2)	o-xylene	air, 110 °C, 30 mine	23
11	Pd(OAc)2	PhI(OAc)2 (2)	1,4-dioxane	air, 110 °C, 30 mine	44
12	Pd(OAc)2	PhI(OAc)2 (2)	THF	air, 110 °C, 30 mine	41
13	Pd(OAc)2	PhI(OAc)2 (2)	MeCN	air, 110 °C, 30 mine	21
14	Pd(OAc)2	PhI(OAc)2 (2)	1,2-DCE	air, 110 °C, 30 mine	10
15	Pd(OAc)2	PhI(OAc)2 (2)	toluene	air, rt, 30 mine	36
16	Pd(OAc)2	PhI(OAc)2 (2)	1,4-dioxane	30 minf	38

^a Reaction conditions: 5a, MeOH (1 mL), catalyst (10 mol%), additive, solvent (1 mL).

^b Isolated yield.

^c Reaction carried out in a sealed tube filled with nitrogen.

^d CuI (20 mol%) was used.

^e Reaction carried out in a sealed tube filled with ambient air.

^f Reaction carried out with AcOH (1 equiv), Ac₂O (1 equiv), 100 °C, in a round-bottom flask under a nitrogen atmosphere.

^g Reaction conditions: 5a, ROH (1 mL), CuBr (10 mol%), DBU (3 equiv), 100 °C, sealed tube filled with ambient air.

^h Reaction conditions: 5a, ROH/1,4-dioxane (1:1 mL), Pd(OAc)₂ (10 mol%), PhI(OAc)₂ (2 equiv), 110 °C, 30 min, sealed tube filled with ambient air.

ⁱ Reaction conditions: 5a, ROH/1,4-dioxane (1:1 mL), Pd(OAc)₂ (10 mol%), PhI(OAc)₂ (2 equiv), 110 °C, 24 h, sealed tube filled with ambient air.

^j Reaction conditions: 5f, ROH (1 mL), CuBr (10 mol%), DBU (3 equiv), 100 °C, sealed tube filled with ambient air.

To further extend the utility of this method for obtaining C–H oxygenated carbazole-3-carboxamide motifs, we attempted the C–H oxygenation/alkoxylation[15] [16] of these carbazole-3-carboxamide substrates. For this, we performed optimization studies to find suitable conditions for obtaining the β-C–H methoxylated carbazole-3-carboxamides 20a and 21a (Table [4]). First, carbazole-3-carboxamide 5a containing the 8-AQ DG was treated with MeOH in the presence of CuI as catalyst (10–20 mol%) and with DBU at 100 °C for 16–18 hours in a sealed tube (entries 1 and 2).[16] These reactions afforded the mono β-C(2)–H methoxylated carbazole-3-carboxamide 21a in 38–40% yield. The other expected bis C(2) and C(4)–H methoxylated carbazole-3-carboxamide 20a was not obtained in characterizable amounts.

We continued with the optimization reactions to find out whether product 21a can be obtained in an improved yield (Table [4]). The C–H methoxylation of 5a with MeOH was attempted using other copper catalysts including Cu(OAc)₂, CuCl₂, and CuBr and DBU as additive at 100 °C for 24–36 hours (entries 3–5). These reactions also afforded only the mono β-C(2)–H methoxylated carbazole-3-carboxamide 21a in 37–44% yield (entries 3–5). The C–H methoxylation of 5a with MeOH in the presence of CuI as the catalyst and DABCO or KOAc as an additive was carried out at 100 °C for 20–24 hours. These reactions did not afford the expected products 21a or 20a (entries 6 and 7). The C–H methoxylation of 5a with MeOH in the presence of CuI as the catalyst and KOt-Bu or Cs₂CO₃ as an additive was carried out at 100 °C for 20–36 hours. These reactions also afforded the mono β-C(2)–H methoxylated carbazole-3-carboxamide 21a in 30–40% yield (entries 8 and 9).

Given that product 21a could not be obtained in an improved yield, we attempted the C–H methoxylation of 5a using a Pd catalyst and PhI(OAc)₂ as an oxidant (Table [4], entries 10–16).[15] Carbazole-3-carboxamide 5a was treated with MeOH in the presence of the Pd(OAc)₂ catalyst (10 mol%) and PhI(OAc)₂ (2 equiv) in o-xylene (co-solvent) at 110 °C for 30 minutes in air. This reaction afforded the mono β-C(2)–H methoxylated carbazole-3-carboxamide 21a in 23% yield (entry 10). The Pd(II)-catalyzed methoxylation of 5a was attempted with MeOH using PhI(OAc)₂ in different co-solvents including 1,4-dioxane, THF, MeCN, 1,2-DCE, and toluene at 110 °C for 30 minutes in air. These reactions gave the mono β-C(2)–H methoxylated carbazole-3-carboxamide 21a in 10–44% yield (entries 11–15). Finally, we also tried the Pd(II)-catalyzed methoxylation of 5a with MeOH using PhI(OAc)₂ in a mixture of 1,4-dioxane, AcOH, and Ac₂O at 110 °C for 30 min. This reaction afforded the mono β-C(2)–H methoxylated carbazole-3-carboxamide 21a in 38% yield (entry 16). Thus, the reaction conditions of entry 5, comprising of the CuBr catalyst and DBU additive in MeOH at 100 °C, which gave product 21a with a maximum yield of 44% was found to be the satisfactory reaction condition. Given that all the conditions which were tried have given the mono β-C(2)–H methoxylated carbazole-3-carboxamide 21a in only low to satisfactory yields, the formation of other expected bis C(2) and C(4)–H methoxylated carbazole-3-carboxamide 20a seems to be an unfavored or a sluggish process, as in none of the reactions we obtained 20a in characterizable amounts.

With the available reaction conditions, substrates 5a and 5f were subjected to the Cu- or Pd-catalyzed C–H alkoxylation with methanol or ethanol to afford the corresponding mono β-C(2)–H methoxylated carbazole-3-carboxamides 21a,b,d in demonstrable yields (21–44%) (Table [4]). The C–H alkoxylation of 5a with propan-1-ol failed to afford the corresponding mono β-C(2)–H methoxylated carbazole-3-carboxamide 21c. While we have carried out a considerable number of optimization reactions to find out the best conditions for the C(2)–H methoxylation of carbazole-3-carboxamide 5a, at this stage we obtained only an encouraging yield (40–44%) of the C(2)–H methoxylation product 21a. Further trials involving different strategies may be needed for accomplishing the C–H alkoxylation of carbazole-3-carboxamide in good yield.

The structures of all the C–H functionalized carbazole-3-carboxamides (Schemes 3–6 and Tables 1–4) obtained were ascertained by NMR spectroscopy and HRMS data. Additionally, the structures of representative β-C(2)–H arylated carbazole motif 8b and β-C(2)–H methoxylated carbazole motif 21a were unequivocally confirmed by single-crystal X-ray structure analysis (Figure [2]).[17] These X-ray structures revealed that the Pd(II)-catalyzed directing group and chelation-assisted C–H functionalization has occurred at the β-C(2)–H bond in carbazole-3-carboxamides 5a,b,c,d,f,g,i, although the carbazole-3-carboxamide substrates, e.g., 5a,b contain two β-C–H bonds. Based on the observed trend in our work as well as by Chatani’s examples 1u,v,[12l] [n] obtained by Ni-catalyzed reactions, it seems that the functionalization of the relatively less hindered β-C(2)–H bond of 5a,b is a preferred process (affording mono-selective β-C(2)–H functionalized carbazole-3-carboxamides). In general, the bidentate directing group 8-aminoquinoline or 2-(methylthio)aniline assisted C–H activation and functionalization of organic molecules is proposed to proceed via the well-documented Pd(II)/Pd(IV) redox cycle mechanism.[3] [5] In concurrence with the proposed mechanism[3] [5] of the bidentate directing-group-assisted C–H functionalization reaction, a plausible mechanism for the 2-(methylthio)aniline directing group-assisted Pd(II)-catalyzed arylation of the β-C(sp²)–H bond of carbazole-3-carboxamide 5b is proposed in Scheme [7]. The coordination of the 2-(methylthio)aniline directing group in carbazole-3-carboxamide 5b to the Pd(II) metal center is followed by concerted metalation–deprotonation (CMD), generating the five-membered Pd(II) species 5bb. Oxidative addition of the Pd(II) species 5bb with an aryl iodide then generates the Pd(IV) species 5bc, which then undergoes reductive elimination to generate the new C–C bond in 5bd. Halide abstraction by a halide ion scavenger (e.g., AgOAc), followed by the protonolysis of the intermediate 5bd affords the β-C(2)–H arylated product 8 and the active Pd(II) species is regenerated in the catalytic cycle (Scheme [7]).

Finally, we also attempted the removal of the bidentate directing group after performing the Pd(II)-catalyzed β-C–H functionalization (arylation, alkylation, methoxylation) of carbazole-3-carboxamides. Of the various trials performed, we succeeded in removing the 2-(methylthio)aniline (MTA) DG via the BF₃·OEt₂-mediated direct amide-to-ester conversion method. Accordingly, the β-C–H arylated carbazole-3-carboxamides 8s,c containing the MTA DG were subjected to the BF₃·OEt₂-mediated direct amide-to-ester conversion in EtOH at 130 °C for 48 hours in a sealed tube. These reactions afforded the MTA-DG-removed β-C–H arylated ethyl carbazole-3-carboxylates 22a,b in 31–48% yield (Scheme [8]). Then, the β-C–H alkylated carbazole-3-carboxamide 19h containing the MTA DG was subjected to the BF₃·OEt₂-mediated direct amide-to-ester conversion in EtOH at 130 °C for 48 hours in a sealed tube. This reaction also gave the MTA-DG-removed β-C–H alkylated ethyl carbazole-3-carboxylate 22c in 85% yield (Scheme [8]). Finally, the β-C–H methoxylated carbazole-3-carboxamide 21a containing the 8-AQ DG was subjected to the BF₃·OEt₂-mediated direct amide-to-ester conversion in EtOH at 130 °C for 36 hours in a sealed tube. Noticeably, we observed a complete decarboxylation (including the 8-AQ DG removal followed by decarbonylating reaction) and obtained 2-methoxy-N-ethylcarbazole (22d) in 50% yield (Scheme [8]) instead of the expected ethyl 9-ethyl-2-methoxy-9H-carbazole-3-carboxylate. Additional amide hydrolysis conditions were tried to remove the 8-AQ DG from 21a to provide 23a (clausine analogue) (Scheme [8]). These conditions include HCl- or PTSA-mediated amide hydrolysis of 21a in MeOH. All these attempts gave 22d in demonstrable yields; the desired product 23a was not obtained in characterizable yield. Treatment of 21a with TfOH also yielded only 22d. Next, we attempted the NaOH-mediated amide hydrolysis of 21a, which gave the carboxylic acid 24a (isomukonidine analogue) in a demonstrable yield (30%) (Scheme [8]). Subsequently, compound 24a was subjected to esterification to afford the carbazole derivative 25a (clausine L analogue) in good yield (Scheme [8]).

In summary, we have shown the application of the Pd(II)-catalyzed, 8-aminoquinoline and 2-(methylthio)aniline DG-aided β-C–H functionalization tactic for the β-C–H activation and functionalization of carbazole-3-carboxamide and carbazole-2-carboxamide motifs. We have performed the Pd(II)-catalyzed, bidentate directing-group-aided β-C–H arylation, alkylation, benzylation and alkoxylation of carbazole-3-carboxamide and carbazole-2-carboxamide substrates. Through screening of reaction conditions, 8-aminoquinoline and 2-(methylthio)aniline were found to be suitable directing groups. Especially 2-(methylthio)aniline was found to be an efficient directing group in the Pd(II)-catalyzed β-C–H arylation, alkylation, and methoxylation of carbazole-3-carboxamides. We have also shown examples involving the removal of the bidentate directing group after performing the Pd(II)-catalyzed β-C–H functionalization (arylation, alkylation, methoxylation) of carbazole-3-carboxamides. Overall, in this paper, we have described the assembly of a library of C2,C3,C4-functionalized carbazole motifs. The carbazole derivatives are versatile building blocks in chemical/materials sciences and have been found to exhibit potent biological/medicinal properties. Consequently, there have been sustained endeavors for developing efficient methods and synthesizing carbazole motifs. On the other hand, the development of the substrate scope in the Pd(II)-catalyzed, directing-group-assisted site-selective β-C–H functionalization is still only emerging. Towards this end, this paper revealed the application of a Pd(II)-catalyzed, bidentate directing-group-aided β-C–H functionalization route toward enriching the library of carbazoles.

Reactions were carried out in oven-dried round-bottom flasks in anhydrous solvents under a N₂ atmosphere or in sealed (pressure) tubes (10–15 mL capacity) filled with N₂ or ambient air. TLC analyses were performed on silica gel or silica gel 60 F₂₅₄ pre-coated plates; components were visualized with exposure to iodine vapor or by irradiation under a UV lamp. Column chromatography purification was performed using silica gel (100–200 mesh) or neutral alumina, with EtOAc­/hexane used as eluent. ¹H NMR and ¹³C{¹H} spectra of samples were recorded on 400 and ~101 MHz spectrometers, respectively (using TMS as an internal standard) and ¹⁹F{¹H} NMR was recorded on a ~376 MHz spectrometer. The HRMS data were obtained from a QTOF mass analyzer using the ESI method. The IR spectra of samples were recorded either as neat samples or by using an appropriate solvent. All the yields of the compounds reported are isolated yields and not optimized.

9-Ethyl-6-bromo-9H-carbazole-3-carbaldehyde (3c);[13a] Typical Procedure

In a round-bottom flask, 3a (2 mmol) was dissolved in DMF (5 mL) under a N₂ atmosphere in an ice bath. To this solution, a solution of NBS (1 equiv) in anhydrous DMF (5 mL) was added dropwise. The resulting reaction mixture was stirred for 12 h at rt. Then, the mixture was diluted with EtOAc (10 mL) and washed with H₂O (2 × 10 mL). The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The resulting crude mixture was purified by column chromatography (silica gel, EtOAc/hexane) to give 3c.

Carbazole-3-carboxylic Acid 4c;[13b] Typical Procedure

In a round-bottom flask, KMnO₄ (2 equiv) was added in three portions to a solution of 3c (4.7 mmol) in acetone/H₂O (1:1, 20 mL). The resulting reaction mixture was stirred at rt for 5 h and subjected to filtration using acetone (10 mL). The filtrate was concentrated under vacuum and the resulting aqueous solution was acidified using dilute HCl to pH 2, resulting in the formation of a precipitate. After 1 h, the precipitate was collected via filtration and air-dried to give 4c.

Ethyl 4-(Phenylamino)benzoate (3ab);[13c] Typical Procedure

Pd₂(dba)₃ (1 mol%), Xanthphos (0.02 equiv), Cs₂CO₃ (1.4 equiv), 3aa (1.2 equiv), and PhI (1 equiv) were added to a 50 mL round-bottom flask under a N₂ atmosphere. To this mixture, anhydrous 1,4-dioxane and t-BuOH (2:1, 12 mL) were added and the mixture was stirred at 110 °C for 24 h. Then, the reaction mixture was cooled to rt, diluted with EtOAc (10 mL) and filtered through a Celite plug. The filtrate was concentrated under vacuum and the crude mixture was purified by column chromatography (silica gel, EtOAc/hexane) to afford 3ab.

Ethyl 9H-Carbazole-3-carboxylate (4da);[13d] Typical Procedure

Compound 3ab (0.62 mmol), Pd(OAc)₂ (3 mol%), K₂CO₃ (10 mol%), and AcOH (0.2 mL) were added to a round-bottom flask (fitted with a condenser). The mixture was stirred at 130 °C for 36 h in air. Then, the solution was cooled to rt, diluted with DCM (10 mL), and washed with aq NaHCO₃ (2 × 10 mL). The organic layers were collected, dried over anhydrous Na₂SO₄, and concentrated under vacuum and the residue was purified by column chromatography (silica gel, EtOAc/hexane) to afford 4da.

Methyl 9H-Carbazole-2-carboxylate (4ea);[13e] Typical Procedure

Compound 3ae (1.8 mmol) and PPh₃ (2.5 equiv) were suspended in o-DCB (2 mL) in a 10 mL (sealed/pressure) tube, sealed with a PTFE-lined cap. The tube was heated at 180 °C for 36 h. Then, the reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (silica gel, EtOAc/hexane) to furnish 4ea.

Methyl 9-Methyl-9H-carbazole-2-carboxylate (4fa);[13f] Typical Procedure

In a round-bottom flask 4ea (0.7 mmol) was dissolved in anhydrous DMF (4 mL) under a N₂ atmosphere. The round-bottom flask was immersed in an ice bath and NaH (1.6 equiv) was added to the reaction mixture, after which the mixture was stirred for 45 min. Then, MeI (1 equiv) was added and the reaction mixture was stirred for 16 h. Then, the mixture was diluted with EtOAc (10 mL) and washed with brine solution (2 × 5 mL). The resulting organic layers were dried over anhydrous Na₂SO₄, concentrated under vacuum, and purified by column chromatography (silica gel, EtOAc/hexane) to afford 4fa.

Compounds 4d,e,f by Ester Hydrolysis of 4da,ea,fa;[13g] General Procedure

In a round-bottom flask ester one of 4da,ea,fa (0.67–0.73 mmol) was dissolved in EtOH (15–18 mL, 20 mL/mmol) and H₂O (2–3 mL, 5 mL/mmol) and then to this solution NaOH (5 equiv) was added. The reaction mixture was refluxed at 100 °C for 16 h (in open air). Then, the reaction mixture was cooled to rt and the pH was adjusted to 4 using 6 N HCl. Then, the mixture was concentrated under vacuum and diluted with EtOAc (10 mL) and washed with H₂O (2 × 5 mL). The organic layers were collected, dried over anhydrous Na₂SO₄, and concentrated under vacuum to afford the corresponding 4d,e,f.

Carbazole-3-carboxamides and Carbazole-2-carboxamides 5a–k; General Procedure

In a round-bottom flask, containing the appropriate carbazole-3-carboxylic acid 4 (0.39–2.0 mmol, 1 equiv) dissolved in anhydrous DCM (10 mL), the corresponding amine compound DGNH₂ (1 equiv), and DMAP (10 mol%) were added. In the same reaction flask was then added a solution of EDC·HCl (2 equiv) and anhydrous DCM dropwise under a N₂ atmosphere at rt. The resulting reaction mixture was stirred at rt for 36 h. Then, the reaction mixture was diluted with DCM (10–15 mL) and washed with H₂O (10–15 mL) and sat. aq NaHCO₃ (15 mL). The organic layers were then dried over anhydrous Na₂SO_4­ and concentrated under vacuum; the resulting crude mixture was then purified by column chromatography (silica gel, EtOAc/hexane) to give the corresponding carbazole-3-carboxamide 5.

9-Ethyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (5a)

Compound 5a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 400 mg (55%, 2.0 mmol scale); brown solid; R_f = 0.4 (EtOAc/hexane 20:80); mp 138–140 °C.

IR (DCM): 3353, 1664, 1232, 755 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.80 (s, 1 H), 8.94 (dd, J ₁ = 7.6, J ₂ = 1.0 Hz, 1 H), 8.83 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.80 (d, J = 1.6 Hz, 1 H), 8.18–8.11 (m, 3 H), 7.57–7.53 (m, 1 H), 7.47–7.38 (m, 5 H), 7.27–7.23 (m, 1 H), 4.35 (q, J = 7.3 Hz, 2 H), 1.41 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 166.0, 148.1, 141.8, 140.4, 138.7, 136.2, 134.9, 127.9, 127.3, 126.3, 125.4, 124.7, 122.8, 122.8, 121.5, 121.1, 120.6, 120.3, 119.6, 116.2, 108.7, 108.2, 37.6, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₀N₃O: 366.1606; found: 366.1619.

9-Ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (5b)

Compound 5b was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 358 mg (55%, 1.82 mmol scale); yellow solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 142–144 °C.

IR (DCM): 3353, 1672, 1225, 760 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.39 (s, 1 H), 8.77 (d, J = 1.6 Hz, 1 H), 8.62 (dd, J ₁ = 8.2, J ₂ = 1.2 Hz, 1 H), 8.20 (d, J = 7.7 Hz, 1 H), 8.08 (dd, J ₁ = 8.6, J ₂ = 1.8 Hz, 1 H), 7.58 (dd, J ₁ = 7.8 , J ₂ = 1.4 Hz, 1 H), 7.56–7.52 (m, 1 H), 7.50–7.45 (m, 2 H), 7.42–7.38 (m, 1 H), 7.34–7.30 (m, 1 H), 7.11 (td, J ₁ = 7.6, J ₂ = 1.4 Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 2.45 (s, 3 H), 1.47 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 165.9, 142.0, 140.6, 139.1, 133.4, 129.3, 126.5, 125.3, 125.2, 124.6, 124.0, 123.0, 122.9, 120.7, 120.4, 120.3, 119.8, 108.9, 108.4, 37.8, 19.3, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₀N₂NaOS: 383.1194; found: 383.1175.

N-(Benzo[c][1,2,5]thiadiazol-4-yl)-9-ethyl-9H-carbazole-3-carboxamide (5c):

Compound 5c was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 150 mg (48%, 0.84 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3354, 1674, 1223, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.35 (s, 1 H), 8.73 (d, J = 1.6 Hz, 1 H), 8.65 (dd, J ₁ = 6.7, J ₂ = 1.5 Hz, 1 H), 8.16 (d, J = 7.7 Hz, 1 H), 8.08 (dd, J ₁ = 8.6, J ₂ = 1.8 Hz, 1 H), 7.66–7.60 (m, 2 H), 7.50–7.40 (m, 3 H), 7.28–7.24 (m, 1 H), 4.37 (q, J = 7.2 Hz, 2 H), 1.42 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 166.3, 154.8, 148.2, 142.2, 140.7, 131.4, 130.5, 126.6, 124.8, 124.6, 123.1, 122.9, 120.8, 120.4, 119.9, 115.4, 114.7, 109.0, 108.5, 37.9, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₇N₄OS: 373.1123; found: 373.1119.

9-Ethyl-N-(5-methoxyquinolin-8-yl)-9H-carbazole-3-carboxamide (5d)

Compound 5d was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 200 mg (60%, 0.84 mmol scale); brown solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 148–150 °C.

IR (DCM): 3385, 1724, 1230, 768 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.52 (s, 1 H), 8.83 (d, J = 8.6 Hz, 1 H), 8.81 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.77 (d, J = 1.5 Hz, 1 H), 8.51 (dd, J ₁ = 8.4, J ₂ = 1.6 Hz, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 8.11 (dd, J ₁ = 8.6, J ₂ = 1.7 Hz, 1 H), 7.45–7.43 (m, 2 H), 7.41–7.34 (m, 2 H), 7.24–7.20 (m, 1 H), 6.82 (d, J = 8.6 Hz, 1 H), 4.30 (q, J = 7.4 Hz, 2 H), 3.92 (s, 3 H), 1.37 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 165.9, 150.1, 148.6, 141.8, 140.5, 139.4, 131.3, 128.4, 126.3, 125.9, 124.8, 123.0, 122.9, 120.8, 120.7, 120.5, 120.3, 119.6, 116.7, 108.8, 108.2, 104.5, 55.7, 37.8, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₂N₃O₂: 396.1712; found: 396.1718.

N-Butyl-9-ethyl-9H-carbazole-3-carboxamide (5e)

Compound 5e was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 40:60); yield: 127 mg (69%, 0.62 mmol scale); colorless solid; R_f = 0.3 (EtOAc/hexane 30:70); mp 116–118 °C.

IR (DCM): 3326, 2949, 1628, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.55 (d, J = 1.5 Hz, 1 H), 8.12 (d, J = 7.2 Hz, 1 H), 7.90 (dd, J ₁ = 8.6, J ₂ = 1.8 Hz, 1 H), 7.52–7.48 (m, 1 H), 7.43–7.41 (m, 1 H), 7.39–7.37 (m, 1 H), 7.28–7.24 (m, 1 H), 6.32 (br s, 1 H), 4.39–4.32 (m, 2 H), 3.53 (q, J = 7.0 Hz, 2 H), 1.69–1.62 (m, 2 H), 1.50- 1.41 (m, 5 H), 0.98 (t, J = 7.4 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.1, 141.6, 140.5, 126.2, 125.4, 124.6, 122.9, 122.6, 120.6, 119.7, 119.5, 108.8, 108.0, 39.9, 37.7, 31.9, 20.2, 13.8, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₃N₂O: 295.1810; found: 295.1806.

9-Benzyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (5f)

Compound 5f was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 100 mg (47%, 0.5 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 200–202 °C.

IR (DCM): 3178, 1670, 1534, 766 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.77 (s, 1 H), 8.93 (dd, J ₁ = 7.6, J ₂ = 1.0 Hz, 1 H), 8.82 (d, J = 1.4 Hz, 1 H), 8.80 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.18 (d, J = 7.7 Hz, 1 H), 8.12–8.07 (m, 2 H), 7.56–7.52 (m, 1 H), 7.46–7.43 (m, 1 H), 7.41–7.38 (m, 3 H), 7.33 (d, J = 8.1 Hz, 1 H), 7.27–7.24 (m, 1 H), 7.22–7.17 (m, 3 H), 7.08–7.06 (m, 2 H), 5.48 (s, 2 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 166.1, 148.2, 142.6, 141.3, 138.8, 136.5, 136.4, 135.0, 128.9, 128.0, 127.7, 127.5, 126.6, 126.4, 126.2, 125.1, 123.1, 123.1, 121.6, 121.3, 120.8, 120.5, 120.1, 116.4, 109.3, 108.8, 46.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₂N₃O: 428.1763; found: 428.1770.

9-Benzyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (5g)

Compound 5g was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 205 mg (37%, 1.32 mmol scale); colorless solid; R_f = 0.3 (EtOAc/hexane 20:80); mp 110–112 °C.

IR (DCM): 3344, 1669, 1504, 751 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.28 (s, 1 H), 8.71 (d, J = 1.6 Hz, 1 H), 8.52 (dd, J ₁ = 8.2, J ₂ = 1.0 Hz, 1 H), 8.13 (d, J = 7.7 Hz, 1 H), 7.94 (dd, J ₁ = 8.6, J ₂ = 1.8 Hz, 1 H), 7.48 (dd, J ₁ = 7.8 , J ₂ = 1.4 Hz, 1 H), 7.42–7.28 (m, 4 H), 7.26–7.22 (m, 1 H), 7.20–7.16 (m, 3 H), 7.07–7.04 (m, 2 H), 7.02–7.00 (m, 1 H), 5.46 (s, 2 H), 2.35 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 165.8, 142.7, 141.3, 139.1, 136.5, 133.4, 129.2, 128.9, 127.7, 126.7, 126.3, 125.8, 125.2, 124.7, 124.1, 123.2, 122.9, 120.7, 120.4, 120.3, 120.2, 109.3, 108.9, 46.7, 19.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₃N₂OS: 423.1531; found: 423.1540.

9-Methyl-N-[2-(methylthio)phenyl]-9H-carbazole-2-carboxamide (5h)

Compound 5h was obtained after purification by column chromatography (silica gel, EtOAc/hexane 30:70); yield: 72 mg (53%, 0.39 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3348, 1664, 1238 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.40 (s, 1 H), 8.60 (dd, J ₁ = 8.2, J ₂ = 1.1 Hz, 1 H), 8.15–8.10 (m, 3 H), 7.72 (dd, J ₁ = 8.1, J ₂ = 1.5 Hz, 1 H), 7.56–7.51 (m, 2 H), 7.43–7.36 (m, 2 H), 7.29–7.25 (m, 1 H), 7.10 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 3.88 (s, 3 H), 2.42 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 165.8, 142.1, 140.7, 138.8, 133.3, 131.8, 129.2, 126.9, 125.6, 125.4, 124.3, 121.9, 120.9, 120.4, 120.3, 119.4, 116.6, 108.8, 108.7, 29.1, 19.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₁₈N₂NaOS: 369.1038; found: 369.1045.

6-Bromo-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (5i)

Compound 5i was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 30:70); yield: 59 mg (20%, 0.70 mmol scale); yellow solid; R_f = 0.4 (EtOAc/hexane 20:80); mp 132–134 °C.

IR (DCM): 3355, 1671, 1225, 755 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.33 (s, 1 H), 8.65 (d, J = 1.5 Hz, 1 H), 8.58 (d, J = 8.2 Hz, 1 H), 8.25 (d, J = 1.8 Hz, 1 H), 8.09 (dd, J ₁ = 8.6, J ₂ = 1.7 Hz, 1 H), 7.59–7.55 (m, 2 H), 7.47 (d, J = 8.6 Hz, 1 H), 7.40–7.36 (m, 1 H), 7.30 (d, J = 8.7 Hz, 1 H), 7.11 (td, J ₁ = 7.6, J ₂ = 1.1 Hz, 1 H), 4.36 (q, J = 7.2 Hz, 2 H), 2.45 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 165.6, 142.2, 139.3, 139.0, 133.4, 129.3, 129.2, 125.9, 125.5, 125.3, 124.6, 124.2, 123.5, 121.9, 120.4, 120.3, 112.6, 110.4, 108.8, 38.0, 19.3, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₀BrN₂OS: 439.0480; found: 439.0478.

N-[2-(Methylthio)phenyl]-9H-carbazole-3-carboxamide (5j)

Compound 5j was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 30:70); yield: 34 mg (14%, 0.71 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 200–202 °C.

IR (DCM): 3254, 1672, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.36 (s, 1 H), 8.74 (d, J = 1.7 Hz, 1 H), 8.60 (dd, J ₁ = 8.2, J ₂ = 1.2 Hz, 1 H), 8.56 (br. s, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 8.02 (dd, J ₁ = 8.5, J ₂ = 1.8 Hz, 1 H), 7.57 (dd, J ₁ = 7.8, J ₂ = 1.5 Hz, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 7.47–7.46 (m, 2 H), 7.41–7.37 (m, 1 H), 7.33–7.29 (m, 1 H), 7.11 (td, J ₁ = 7.6, J ₂ = 1.4 Hz, 1 H), 2.44 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 166.0, 141.7, 140.1, 139.0, 133.4, 129.2, 126.7, 126.0, 125.4, 124.8, 124.2, 123.5, 123.1, 120.6, 120.5, 120.3, 120.2, 111.0, 110.7, 19.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₁₆N₂NaOS: 355.0881; found: 355.0884.

N-[2-(Methylthio)phenyl]-9H-carbazole-2-carboxamide (5k)

Compound 5k was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 30:70); yield: 66 mg (31%, 0.64 mmol scale); colorless solid; R_f = 0.4 (EtOAc/hexane 20:80); mp 134–136 °C.

IR (DCM): 3343, 1671, 1220 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.41 (s, 1 H), 8.71 (br. s, 1 H), 8.62–8.60 (m, 1 H), 8.21 (s, 1 H), 8.18 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 7.77 (dd, J ₁ = 8.2, J ₂ = 1.2 Hz, 1 H), 7.57 (dd, J ₁ = 7.8, J ₂ = 1.3 Hz, 1 H), 7.49–7.48 (m, 2 H), 7.43–7.38 (m, 1 H), 7.29 (dd, J ₁ = 7.9, J ₂ = 1.2 Hz, 1 H), 7.13 (td, J ₁ = 7.6, J ₂ = 1.1 Hz, 1 H), 2.43 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 165.9, 140.8, 139.4, 138.8, 133.4, 131.9, 129.2, 127.1, 126.4, 125.5, 124.4, 122.5, 121.0, 120.5, 120.4, 119.9, 117.4, 111.0, 110.7, 19.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₇N₂OS: 333.1062; found: 333.1063.

Pd(II)-Catalyzed C–H Arylation of Carbazole-3-carboxamides 5a–e,g,i,j and Carbazole-2-carboxamides 5h,k To Prepare Substituted Carbazolecarboxamides 7a–e,8a–z,aa–aj,9a–c; General Procedure

A mixture of the appropriate carbazole-3-carboxamide or carbazole-2-carboxamide 5 (1 equiv), the appropriate ArI (4 equiv), Pd(OAc)₂ (5 mol%), and K₂CO₃ (2 equiv) in o-xylene (1 mL) was added in a sealable 10 mL tube filled with ambient air; the tube was capped with a silicone septum and was then heated at 130 °C for 36 h. After completion of the reaction, the mixture was concentrated under vacuum and purified by column chromatography (silica gel, EtOAc/hexane) to afford the corresponding C–H arylated carboxamide (see the respective Table or Scheme for specific entry).

9-Ethyl-2-(4-methoxyphenyl)-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8a)

Compound 8a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 41 mg (63%, 0.14 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 174–176 °C.

IR (DCM): 3333, 1668, 1508, 756 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (s, 1 H), 8.53 (d, J = 7.9 Hz, 1 H), 8.39 (br s, 1 H), 8.14 (d, J = 7.7 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.52–7.48 (m, 1 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.38–7.35 (m, 2 H), 7.31–7.24 (m, 2 H), 7.00 (td, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 6.94 (d, J = 8.7 Hz, 2 H), 4.38 (q, J = 7.2 Hz, 2 H), 3.78 (s, 3 H), 2.07 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.7, 159.3, 141.0, 140.8, 138.9, 137.4, 133.4, 133.1, 130.4, 128.7, 127.1, 126.3, 125.1, 123.9, 122.7, 122.3, 121.8, 120.8, 120.0, 119.6, 114.2, 110.0, 108.7, 55.3, 37.7, 19.2, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₇N₂O₂S: 467.1793; found: 467.1800.

9-Ethyl-2-(4-methoxyphenyl)-N-(5-methoxyquinolin-8-yl)-9H-carbazole-3-carboxamide (9b)

Compound 9b was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 21 mg (32%, 0.126 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 202–204 °C.

IR (DCM): 3334, 1653, 1515, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.66 (s, 1 H), 8.82 (d, J = 8.5 Hz, 1 H), 8.72 (s, 1 H), 8.53 (dd, J ₁ = 4.2, J ₂ = 1.7 Hz, 1 H), 8.49 (dd, J ₁ = 8.4, J ₂ = 1.6 Hz, 1 H), 8.17 (d, J = 7.7 Hz, 1 H), 7.56 (d, J = 8.6 Hz, 2 H), 7.53–7.49 (m, 1 H), 7.44 (d, J = 8.1 Hz, 1 H), 7.39 (s, 1 H), 7.33 (dd, J ₁ = 8.4, J ₂ = 4.2 Hz, 1 H), 7.30–7.27 (m, 1 H), 6.88–6.84 (m, 3 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.98 (s, 3 H), 3.66 (s, 3 H), 1.47 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.2, 159.2, 150.0, 148.0, 141.0, 140.8, 139.2, 138.1, 133.8, 130.8, 130.6, 128.6, 127.4, 126.1, 122.9, 122.4, 121.8, 120.8, 120.4, 120.2, 119.6, 116.2, 113.9, 110.0, 108.7, 104.3, 55.7, 55.1, 37.7, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₈N₃O₃: 502.2131; found: 502.2133.

9-Ethyl-2-(4-methoxyphenyl)-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (7a)

Compound 7a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 36 mg (55%, 0.14 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 190–192 °C.

IR (DCM): 3324, 1663, 1524, 758 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.82 (s, 1 H), 8.83 (d, J = 7.5 Hz, 1 H), 8.65 (s, 1 H), 8.44 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.09 (d, J = 7.7 Hz, 1 H), 8.00 (dd, J ₁ = 8.3, J ₂ = 1.6 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 2 H), 7.46–7.41 (m, 2 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.32 (s, 1 H), 7.26 (dd, J ₁ = 8.2, J ₂ = 4.2 Hz, 1 H), 7.23–7.19 (m, 1 H), 6.79 (d, J = 8.7 Hz, 2 H), 4.33 (q, J = 7.2 Hz, 2 H), 3.58 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.6, 159.2, 147.5, 141.0, 140.8, 138.5, 138.2, 135.9, 135.0, 133.7, 130.6, 127.7, 127.3, 127.2, 126.2, 122.9, 122.6, 121.8, 121.2, 121.1, 120.8, 119.6, 116.1, 113.9, 110.1, 108.7, 55.2, 37.7, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₂₆N₃O₂: 472.2025; found: 472.2036.

2-(4-Acetylphenyl)-9-ethyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (7b)

Compound 7b was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 40 mg (60%, 0.14 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 175–177 °C.

IR (DCM): 3335, 1670, 1522, 756 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.91 (s, 1 H), 8.86 (d, J = 7.5 Hz, 1 H), 8.73 (s, 1 H), 8.51 (dd, J ₁ = 4.1, J ₂ = 1.6 Hz, 1 H), 8.19 (d, J = 7.7 Hz, 1 H), 8.09–8.07 (m, 1 H), 7.92 (d, J = 8.2 Hz, 2 H), 7.73 (d, J = 8.2 Hz, 2 H), 7.57–7.52 (m, 2 H), 7.49–7.46 (m, 2 H), 7.44 (s, 1 H), 7.36–7.30 (m, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 2.46 (s, 3 H), 1.49 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.8, 168.1, 147.7, 146.4, 140.9, 140.8, 138.4, 137.3, 136.0, 135.8, 134.7, 129.6, 128.4, 127.7, 127.3, 127.3, 126.6, 122.6, 122.5, 122.4, 121.4, 121.0, 119.8, 116.2, 110.1, 108.9, 37.8, 26.5, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₆N₃O₂: 484.2025; found: 484.2025.

9-Ethyl-N-(quinolin-8-yl)-2-(thiophen-2-yl)-9H-carbazole-3-carboxamide (7c)

Compound 7c was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 13 mg (21%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 160–162 °C.

IR (DCM): 3341, 1672, 1529, 768 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.0 (s, 1 H), 8.86 (d, J = 7.5 Hz, 1 H), 8.57 (s, 1 H), 8.53 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.08 (d, J = 7.7 Hz, 1 H), 8.02 (dd, J ₁ = 8.3, J ₂ = 1.6 Hz, 1 H), 7.51–7.47 (m, 1 H), 7.47 (s, 1 H), 7.45–7.37 (m, 3 H), 7.29 (dd, J ₁ = 8.2, J ₂ = 4.2 Hz, 1 H), 7.24–7.20 (m, 2 H), 7.18–7.16 (m, 1 H), 6.85 (dd, J ₁ = 5.1, J ₂ = 3.6 Hz, 1 H), 4.35 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.4, 147.8, 142.5, 140.9, 140.7, 138.5, 136.0, 135.0, 130.3, 127.9, 127.8, 127.5, 127.4, 127.3, 126.5, 126.1, 122.7, 122.4, 122.1, 121.4, 121.3, 120.9, 119.7, 116.2, 110.6, 108.8, 37.8, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₂N₃OS: 448.1484; found: 448.1495.

2-(3-Acetylphenyl)-9-ethyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (7d)

Compound 7d was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 30 mg (45%, 0.14 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 92–94 °C.

IR (DCM): 2933, 1679, 1527, 769 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.86 (s, 1 H), 8.85 (d, J = 7.2 Hz, 1 H), 8.73 (s, 1 H), 8.46 (d, J = 3.0 Hz, 1 H), 8.28 (s, 1 H), 8.19 (d, J = 7.7 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.80–7.75 (m, 2 H), 7.56–7.50 (m, 2 H), 7.48–7.43 (m, 3 H), 7.38–7.29 (m, 3 H), 4.43 (q, J = 7.1 Hz, 2 H), 2.52 (s, 3 H), 1.48 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 198.1, 168.2, 147.6, 141.8, 140.9, 140.9, 138.3, 137.4, 137.2, 136.0, 134.7, 134.2, 129.2, 128.5, 127.7, 127.3, 127.3, 127.1, 126.5, 122.7, 122.3, 121.4, 121.3, 120.9, 119.8, 116.0, 110.2, 108.9, 37.8, 26.7, 13.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₆N₃O₂: 484.2025; found: 484.2024.

2-(3-Chlorophenyl)-9-ethyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (7e)

Compound 7e was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 20 mg (43%, 0.10 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 2939, 1668, 1529, 761 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.75 (s, 1 H), 8.80 (d, J = 7.5 Hz, 1 H), 8.67 (s, 1 H), 8.53 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.11 (d, J = 7.8 Hz, 1 H), 7.99 (dd, J ₁ = 8.3, J ₂ = 1.6 Hz, 1 H), 7.67 (s, 1 H), 7.47–7.44 (m, 2 H), 7.39–7.37 (m, 2 H), 7.36–7.32 (m, 1 H), 7.31 (s, 1 H), 7.27 (dd, J ₁ = 8.2, J ₂ = 4.2 Hz, 1 H), 7.25–7.21 (m, 1 H), 7.08–7.02 (m, 2 H), 4.34 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.0, 147.8, 143.2, 140.9, 138.4, 137.0, 135.9, 134.8, 134.3, 129.4, 129.3, 128.0, 127.7, 127.4, 127.3, 127.2, 126.5, 122.7, 122.7, 122.4, 121.4, 121.2, 121.0, 119.8, 116.0, 110.1, 108.9, 37.8, 13.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₃ClN₃O₂: 476.1530; found: 476.1526.

2-(4-Ethoxyphenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8b)

Compound 8b was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 30 mg (57%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 184–186 °C.

IR (DCM): 3334, 1669, 1508, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 8.45 (d, J = 7.9 Hz, 1 H), 8.30 (br s, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.47 (d, J = 8.6 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 1 H), 7.31–7.29 (m, 2 H), 7.24–7.19 (m, 2 H), 6.93 (td, J ₁ = 7.6, J ₂ = 1.0 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 2 H), 4.33 (q, J = 7.2 Hz, 2 H), 3.95 (q, J = 7.0 Hz, 2 H), 2.00 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H), 1.32 (t, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.8, 158.7, 141.0, 140.8, 139.0, 137.5, 133.3, 133.2, 130.5, 128.8, 127.1, 126.3, 125.2, 123.9, 122.8, 122.3, 121.8, 120.8, 120.0, 119.7, 114.8, 110.0, 108.7, 63.5, 37.7, 19.2, 14.8, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₂S: 481.1950; found: 481.1952.

9-Ethyl-2-(4-hexylphenyl)-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8c)

Compound 8c was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 45 mg (73%, 0.12 mmol scale); colorless liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3336, 1672, 1509, 760 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 8.43 (d, J = 9.2 Hz, 1 H), 8.26 (br s, 1 H), 8.05 (d, J = 7.7 Hz, 1 H), 7.45 (d, J = 7.9 Hz, 2 H), 7.43–7.39 (m, 1 H), 7.33 (d, J = 8.2 Hz, 1 H), 7.30 (s, 1 H), 7.27 (dd, J ₁ = 7.7, J ₂ = 1.2 Hz, 1 H), 7.22–7.17 (m, 2 H), 7.14–7.11 (m, 2 H), 6.90 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 2.49 (t, J = 7.6 Hz, 2 H), 1.92 (s, 3 H), 1.51–1.44 (m, 2 H), 1.36 (t, J = 7.2 Hz, 3 H), 1.19–1.17 (m, 6 H), 0.79 (t, J = 6.8 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.8, 142.4, 141.0, 140.8, 139.0, 138.3, 137.8, 133.2, 129.2, 128.8, 128.7, 127.2, 126.3, 125.1, 123.8, 122.7, 122.3, 121.9, 120.8, 119.9, 119.6, 110.1, 108.7, 37.7, 35.6, 31.7, 31.3, 28.9, 22.5, 19.2, 14.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₄H₃₇N₂OS: 521.2627; found: 521.2626.

9-Ethyl-N-[2-(methylthio)phenyl]-2-(4-pentylphenyl)-9H-carbazole-3-carboxamide (8d)

Compound 8d was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 37 mg (67%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 117–119 °C.

IR (DCM): 3334, 1671, 1508, 760 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 8.44 (d, J = 8.2 Hz, 1 H), 8.26 (br s, 1 H), 8.06 (d, J = 7.7 Hz, 1 H), 7.46 (d, J = 7.9 Hz, 2 H), 7.41 (dd, J ₁ = 7.2, J ₂ = 1.0 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.31 (s, 1 H), 7.27 (dd, J ₁ = 7.7, J ₂ = 1.2 Hz, 1 H), 7.22–7.18 (m, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.92–6.89 (m, 1 H), 4.30 (q, J = 7.2 Hz, 2 H), 2.50 (t, J = 7.8 Hz, 2 H), 1.93 (s, 3 H), 1.53–1.45 (m, 2 H), 1.37 (t, J = 7.2 Hz, 3 H), 1.26–1.17 (m, 4 H), 0.79 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.8, 142.4, 141.0, 140.8, 139.0, 138.3, 137.8, 133.2, 129.2, 128.8, 128.8, 127.2, 126.3, 125.1, 123.8, 122.7, 122.3, 121.9, 120.8, 119.9, 119.6, 110.1, 108.7, 37.7, 35.5, 31.4, 31.0, 22.5, 19.2, 14.0, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₃H₃₅N₂OS: 507.2470; found: 507.2711.

9-Ethyl-N-[2-(methylthio)phenyl]-2-(4-propylphenyl)-9H-carbazole-3-carboxamide (8e)

Compound 8e was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 47 mg (90%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 144–146 °C.

IR (DCM): 3333, 1669, 1505, 754 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 8.43 (d, J = 7.9 Hz, 1 H), 8.26 (s, 1 H), 8.06 (d, J = 7.7 Hz, 1 H), 7.46 (d, J = 7.9 Hz, 2 H), 7.42–7.40 (m, 1 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.31 (s, 1 H), 7.27 (dd, J ₁ = 7.7, J ₂ = 1.2 Hz, 1 H), 7.22–7.18 (m, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 6.91 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.31 (q, J = 7.2 Hz, 2 H), 2.49 (t, J = 7.8 Hz, 2 H), 1.94 (s, 3 H), 1.57–1.47 (m, 2 H), 1.37 (t, J = 7.2 Hz, 3 H), 0.81 (t, J = 7.4 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.8, 142.2, 141.0, 140.8, 139.0, 138.3, 137.8, 133.2, 129.2, 128.8, 127.2, 126.3, 125.1, 123.8, 122.7, 122.3, 121.9, 120.8, 119.9, 119.6, 110.1, 108.7, 37.7, 37.7, 24.4, 19.2, 13.8, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₁N₂OS: 479.2157; found: 479.2156.

9-Ethyl-2-(4-isopropylphenyl)-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8f)

Compound 8f was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 40 mg (70%, 0.12 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 129–131 °C.

IR (DCM): 3332, 1669, 1507, 758 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 8.45 (d, J = 7.8 Hz, 1 H), 8.27 (br s, 1 H), 8.05 (d, J = 7.7 Hz, 1 H), 7.47 (d, J = 7.9 Hz, 2 H), 7.43–7.39 (m, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 7.30 (s, 1 H), 7.27–7.25 (m, 1 H), 7.22–7.16 (m, 4 H), 6.90 (td, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 2.84–2.77 (m, 1 H), 1.89 (s, 3 H), 1.36 (t, J = 7.2 Hz, 3 H), 1.13 (d, J = 6.9 Hz, 6 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.8, 148.3, 141.0, 140.8, 139.1, 138.4, 137.7, 133.3, 129.3, 128.8, 127.2, 126.8, 126.3, 125.1, 123.8, 122.7, 122.3, 121.9, 120.8, 119.8, 119.6, 110.1, 108.7, 37.7, 33.8, 23.9, 19.2, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₁N₂OS: 479.2157; found: 479.2144.

9-Ethyl-N-[2-(methylthio)phenyl]-2-phenyl-9H-carbazole-3-carboxamide (8g)

Compound 8g was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 27 mg (63%, 0.10 mmol scale); yellow solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 93–95 °C.

IR (DCM): 3335, 1669, 1506, 760 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.61 (s, 1 H), 8.50 (d, J = 7.6 Hz, 1 H), 8.34 (br s, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.64 (d, J = 7.3 Hz, 2 H), 7.54–7.50 (m, 1 H), 7.45 (s, 1 H), 7.43–7.39 (m, 3 H), 7.36 (dd, J ₁ = 7.8, J ₂ = 1.2 Hz, 1 H), 7.34–7.27 (m, 3 H), 7.00 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 2.05 (s, 3 H), 1.46 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.6, 141.1, 140.9, 140.8, 138.9, 137.8, 133.1, 129.3, 128.8, 128.7, 127.6, 127.2, 126.4, 125.1, 123.9, 122.7, 122.2, 122.1, 120.9, 119.9, 119.7, 110.2, 108.8, 37.7, 19.2, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₅N₂OS: 437.1688; found: 437.1672.

2-(4-Bromophenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8h)

Compound 8h was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 38 mg (53%, 0.14 mmol scale); brown solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 100–102 °C.

IR (DCM): 3335, 1670, 1505, 761, 653 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.50 (d, J = 7.5 Hz, 1 H), 8.40 (br s, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.55–7.48 (m, 5 H), 7.45 (d, J = 8.2 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.35 (s, 1 H), 7.32–7.28 (m, 2 H), 7.04 (td, J ₁ = 7.6, J ₂ = 1.0 Hz, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 2.14 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.3, 140.9, 140.9, 140.1, 138.6, 136.5, 133.0, 131.7, 130.9, 128.8, 127.0, 126.6, 125.2, 124.2, 122.6, 122.3, 122.2, 122.0, 120.9, 120.0, 119.8, 110.1, 108.9, 37.8, 19.2, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₄BrN₂OS: 515.0793; found: 515.0801.

9-Ethyl-2-(4-fluorophenyl)-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8i)

Compound 8i was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 32 mg (51%, 0.14 mmol scale); brown solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 125–127 °C.

IR (DCM): 2936, 1677, 1513, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.49 (d, J = 9.0 Hz, 1 H), 8.35 (br s, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.61–7.57 (m, 2 H), 7.55–7.51 (m, 1 H), 7.45 (d, J = 8.2 Hz, 1 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.36 (s, 1 H), 7.32–7.28 (m, 2 H), 7.12–7.08 (m, 2 H), 7.03 (td, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 2.13 (s, 3 H), 1.47 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.4, 162.5 (d, J _C-F = 245 Hz), 140.9, 140.8, 138.7, 137.1 (d, J _C-F = 3.1 Hz), 136.7, 133.0, 130.9 (d, J _C-F = 8.1 Hz), 128.8, 127.2, 126.5, 125.1, 124.1, 122.6, 122.1, 120.9, 119.9, 119.8, 115.6 (d, J _C-F = 21.4 Hz), 110.1, 108.8, 37.8, 19.1, 13.8.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –114.82.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₄FN₂OS: 455.1593; found: 455.1607.

9-Ethyl-N-[2-(methylthio)phenyl]-2-(4-nitrophenyl)-9H-carbazole-3-carboxamide (8j)

Compound 8j was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 36 mg (50%, 0.15 mmol scale); yellow solid; R_f = 0.3 (EtOAc/hexane 30:70); mp 200–202 °C.

IR (DCM): 3335, 1669, 1344, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.57 (s, 1 H), 8.49 (br s, 1 H), 8.40 (d, J = 5.2 Hz, 1 H), 8.26 (d, J = 8.6 Hz, 2 H), 8.17 (d, J = 7.7 Hz, 1 H), 7.75 (d, J = 7.2 Hz, 2 H), 7.59–7.55 (m, 1 H), 7.49 (d, J = 8.2 Hz, 1 H), 7.40–7.39 (m, 2 H), 7.35–7.27 (m, 2 H), 7.08–7.04 (m, 1 H), 4.44 (q, J = 7.2 Hz, 2 H), 2.22 (s, 3 H), 1.49 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 167.8, 148.2, 147.1, 141.0, 140.7, 138.2, 135.9, 132.6, 130.0, 128.7, 127.1, 127.0, 125.4, 124.5, 123.7, 122.8, 122.4, 121.7, 121.0, 120.2, 120.1, 110.3, 109.0, 37.8, 18.9, 13.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₄N₃O₃S: 482.1538; found: 482.1556.

Methyl 4-(9-Ethyl-3-{[2-(methylthio)phenyl]carbamoyl}-9H-carbazole-2-yl)benzoate (8k)

Compound 8k was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 47 mg (68%, 0.14 mmol scale); brown solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 188–190 °C.

IR (DCM): 3335, 1669, 1509, 1344, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (s, 1 H), 8.46 (d, J = 6.5 Hz, 1 H), 8.39 (s, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 8.08 (d, J = 8.3 Hz, 2 H), 7.70 (d, J = 7.9 Hz, 2 H), 7.56–7.52 (m, 1 H), 7.47 (d, J = 8.2 Hz, 1 H), 7.41 (s, 1 H), 7.38 (d, J = 7.8 Hz, 1 H), 7.33–7.28 (m, 2 H), 7.04–7.01 (m, 1 H), 4.43 (q, J = 7.2 Hz, 2 H), 3.91 (s, 3 H), 2.10 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.2, 166.8, 145.9, 140.9, 140.9, 138.6, 136.7, 132.9, 129.9, 129.2, 129.1, 128.8, 127.2, 126.7, 125.2, 124.1, 122.5, 122.4, 122.0, 120.9, 120.0, 119.9, 110.2, 108.9, 52.1, 37.8, 19.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₇N₂O₃S: 495.1742; found: 495.1757.

9-Ethyl-N-[2-(methylthio)phenyl]-2-(m-tolyl)-9H-carbazole-3-carboxamide (8l)

Compound 8l was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 26 mg (41%, 0.14 mmol scale); yellow solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 164–166 °C.

IR (DCM): 3335, 1672, 1509, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.61 (s, 1 H), 8.48 (d, J = 6.2 Hz, 1 H), 8.30 (s, 1 H), 8.16 (d, J = 7.7 Hz, 1 H), 7.53–7.50 (m, 1 H), 7.46–7.36 (m, 5 H), 7.31–7.25 (m, 3 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.00 (td, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 2.36 (s, 3 H), 2.07 (s, 3 H), 1.47 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.7, 141.0, 140.9, 140.8, 138.9, 138.3, 138.0, 133.1, 129.9, 128.8, 128.5, 128.4, 127.2, 126.4, 126.4, 125.2, 123.9, 122.7, 122.3, 122.0, 120.9, 120.0, 119.7, 110.1, 108.8, 37.7, 21.4, 19.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₇N₂OS: 451.1844; found: 451.1863.

9-Ethyl-2-(3-methoxyphenyl)-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8m)

Compound 8m was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 40 mg (62%, 0.11 mmol scale); colorless liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3327, 1677, 1511, 766 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (s, 1 H), 8.51 (d, J = 8.9 Hz, 1 H), 8.35 (s, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.53–7.50 (m, 1 H), 7.44 (d, J = 8.2 Hz, 1 H), 7.41 (s, 1 H), 7.37 (dd, J ₁ = 7.7, J ₂ = 1.0 Hz, 1 H), 7.32–7.27 (m, 3 H), 7.21–7.18 (m, 2 H), 7.00 (td, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 6.88–6.85 (m, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 3.78 (s, 3 H), 2.08 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.6, 159.7, 142.5, 140.9, 140.8, 138.9, 137.6, 133.1, 129.7, 128.8, 127.2, 126.4, 125.2, 123.9, 122.7, 122.2, 122.2, 121.8, 120.9, 119.9, 119.7, 114.6, 113.5, 110.0, 108.8, 55.3, 37.7, 19.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆N₂NaO₂S: 489.1613; found: 489.1626.

2-(3-Chlorophenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8n)

Compound 8n was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 37 mg (56%, 0.14 mmol scale); brown liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3059, 1673, 1510, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.49–8.46 (m, 1 H), 8.35 (br s, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.67 (s, 1 H), 7.55–7.51 (m, 1 H), 7.46–7.44 (m, 2 H), 7.39–7.36 (m, 2 H), 7.32–7.28 (m, 4 H), 7.02 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 2.14 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.2, 143.0, 140.9, 140.8, 138.6, 136.3, 134.5, 132.9, 129.7, 129.0, 128.7, 127.7, 127.6, 127.1, 126.6, 125.3, 124.1, 122.5, 122.4, 122.1, 120.9, 120.0, 119.8, 110.1, 108.9, 37.8, 19.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₄ClN₂OS: 471.1298; found: 471.1311.

2-(3-Bromophenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8o)

Compound 8o was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 57 mg (65%, 0.17 mmol scale); brown solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 140–142 °C.

IR (DCM): 3336, 1670, 1507, 761 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.48 (d, J = 8.5 Hz, 1 H), 8.33 (br s, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 7.82 (s, 1 H), 7.55–7.51 (m, 2 H), 7.47–7.44 (m, 2 H), 7.40–7.37 (m, 2 H), 7.32–7.29 (m, 2 H), 7.22 (d, J = 7.8 Hz, 1 H), 7.02 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.42 (q, J = 7.2 Hz, 2 H), 2.14 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.2, 143.3, 140.9, 140.8, 136.2, 132.9, 132.9, 131.9, 130.1, 130.0, 128.8, 128.2, 127.2, 126.6, 125.3, 124.1, 122.8, 122.6, 122.4, 121.2, 120.9, 120.1, 119.9, 110.1, 108.9, 37.8, 19.1, 13.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₄BrN₂OS: 515.0793; found: 515.0810.

9-Ethyl-2-(3-fluorophenyl)-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8p)

Compound 8p was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 44 mg (69%, 0.11 mmol scale); yellow solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 110–112 °C.

IR (DCM): 2931, 1672, 1507, 760 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.48 (d, J = 7.1 Hz, 1 H), 8.37 (br s, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 7.56–7.52 (m, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.40–7.35 (m, 5 H), 7.33–7.29 (m, 3 H), 7.03 (td, J ₁ = 7.8, J ₂ = 1.3 Hz, 1 H), 4.42 (q, J = 7.2 Hz, 2 H), 2.14 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.3, 162.8 (d, J _C-F = 245 Hz), 143.4 (d, J _C-F = 7.8 Hz), 140.9, 140.8, 138.7, 136.5 (d, J _C-F = 1.8 Hz), 133.0, 130.1, 130.0, 128.8, 127.2, 126.6, 125.2 (d, J _C-F = 2.3 Hz), 124.1, 122.5, 122.3, 122.1, 120.9, 120.0, 119.8, 116.1 (d, J _C-F = 21.9 Hz), 114.4 (d, J _C-F = 20.7 Hz), 110.1, 108.9, 37.8, 19.1, 13.8.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –112.74.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₄FN₂OS: 455.1593; found: 455.1608.

9-Ethyl-N-[2-(methylthio)phenyl]-2-(3-trifluoromethylphenyl)-9H-carbazole-3-carboxamide (8q)

Compound 8q was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 25 mg (50%, 0.10 mmol scale); yellow solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 135–137 °C.

IR (DCM): 2934, 1679, 1512, 768 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.61 (s, 1 H), 8.45 (d, J = 7.1 Hz, 1 H), 8.32 (br s, 1 H), 8.17 (d, J = 7.8 Hz, 1 H), 7.93 (s, 1 H), 7.77 (d, J = 7.6 Hz, 1 H), 7.60–7.57 (m, 1 H), 7.54 (d, J = 7.2 Hz, 1 H), 7.51–7.47 (m, 2 H), 7.39–7.36 (m, 2 H), 7.34–7.29 (m, 2 H), 7.05–7.01 (m, 1 H), 4.44 (q, J = 7.2 Hz, 2 H), 2.12 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.1, 142.0, 140.9, 140.9, 138.4, 136.3, 132.9, 132.7, 131.1 (q, J _C-F = 32 Hz), 128.9, 128.7, 127.2, 126.7, 125.7 (q, J _C-F = 3.5 Hz), 125.2, 124.2 (q, J _C-F = 4.0 Hz), 124.2, 124.1 (q, J _C-F = 271.1 Hz), 122.5, 122.5, 122.2, 121.0, 120.0, 119.9, 110.2, 108.9, 37.8, 18.9, 13.9.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –62.41

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₄F₃N₂OS: 505.1561; found: 505.1580.

2-(3-Acetamidophenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8r)

Compound 8r was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 30:70); yield: 37 mg (56%, 0.13 mmol scale); brown solid; R_f = 0.2 (EtOAc/hexane 30:70); mp 100–102 °C.

IR (DCM): 3315, 1663, 1497, 751 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.51 (s, 1 H), 8.48 (s, 1 H), 8.37 (d, J = 7.9 Hz, 1 H), 8.20 (s, 1 H), 8.10 (d, J = 7.7 Hz, 1 H), 7.60–7.58 (m, 2 H), 7.50–7.47 (m, 1 H), 7.38 (d, J = 7.3 Hz, 1 H), 7.32–7.29 (m, 1 H), 7.27–7.19 (m, 5 H), 7.03 (td, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 2.18 (s, 3 H), 2.02 (s, 3 H), 1.33 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.9, 168.8, 141.5, 140.7, 140.7, 138.8, 138.3, 137.7, 132.4, 128.9, 128.4, 126.9, 126.4, 126.2, 124.6, 124.4, 122.4, 121.7, 121.4, 120.6, 120.5, 120.4, 119.6, 118.9, 110.3, 108.9, 37.5, 24.4, 18.8, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₇N₃NaO₂S: 516.1722; found: 516.1709.

2-(3-Acetylphenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8s)

Compound 8s was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 51 mg (72%, 0.15 mmol scale); brown liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3337, 1676, 1598, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (s, 1 H), 8.45 (d, J = 9.0 Hz, 1 H), 8.38 (br s, 1 H), 8.23 (s, 1 H), 8.16 (d, J = 7.7 Hz, 1 H), 7.91 (d, J = 7.9 Hz, 1 H), 7.80 (d, J = 7.4 Hz, 1 H), 7.56–7.50 (m, 1 H), 7.48–7.46 (m, 2 H), 7.42 (s, 1 H), 7.36 (d, J = 7.6 Hz, 1 H), 7.33–7.27 (m, 2 H), 7.01 (td, J ₁ = 7.6, J ₂ = 1.0 Hz, 1 H), 4.42 (q, J = 7.2 Hz, 2 H), 2.59 (s, 3 H), 2.11 (s, 3 H), 1.47 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 198.0, 168.3, 141.7, 140.9, 140.9, 138.5, 137.4, 136.8, 133.9, 132.9, 128.9, 128.8, 127.4, 127.2, 126.6, 125.1, 124.1, 122.5, 122.3, 122.0, 120.9, 119.9, 119.8, 110.2, 108.9, 37.8, 26.8, 19.0, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₆N₂NaO₂S: 501.1613; found: 501.1636.

9-Ethyl-N-[2-(methylthio)phenyl]-2-(3-nitrophenyl)-9H-carbazole-3-carboxamide (8t)

Compound 8t was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 30:70); yield: 35 mg (61%, 0.12 mmol scale); colorless solid; R_f = 0.3 (EtOAc/hexane 30:70); mp 107–109 °C.

IR (DCM): 3336, 1668, 1513, 756 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.45 (s, 1 H), 8.40 (d, J = 15.3 Hz, 2 H), 8.28 (br s, 1 H), 8.11–8.07 (m, 2 H), 7.79 (d, J = 7.5 Hz, 1 H), 7.49–7.43 (m, 2 H), 7.41–7.38 (m, 1 H), 7.32–7.29 (m, 2 H), 7.25–7.22 (m, 1 H), 7.20–7.16 (m, 1 H), 6.95 (td, J ₁ = 7.6, J ₂ = 1.1 Hz, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 2.13 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 167.8, 148.3, 143.1, 140.9, 140.8, 138.2, 135.7, 135.5, 132.5, 129.2, 128.7, 127.0, 126.8, 125.4, 124.4, 123.7, 122.6, 122.4, 122.3, 121.7, 120.9, 120.2, 120.0, 110.4, 109.0, 37.8, 18.9, 13.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₄N₃O₃S: 482.1538; found: 482.1530.

2-(6-Chloropyridin-3-yl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8u)

Compound 8u was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 32 mg (52%, 0.13 mmol scale); yellow solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 147–149 °C.

IR (DCM): 3334, 1668, 1506, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.65 (br s, 1 H), 8.59 (s, 1 H), 8.50–8.42 (m, 2 H), 8.17 (d, J = 7.7 Hz, 1 H), 7.85 (d, J = 8.1 Hz, 1 H), 7.58–7.54 (m, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 7.43 (d, J = 7.6 Hz, 1 H), 7.36–7.34 (m, 2 H), 7.33–7.31 (m, 2 H), 7.07 (td, J ₁ = 7.8, J ₂ = 1.2 Hz, 1 H), 4.43 (q, J = 7.2 Hz, 2 H), 2.25 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 167.6, 150.6, 149.1, 140.9, 140.8, 139.5, 138.2, 136.1, 133.0, 132.6, 128.7, 127.0, 126.9, 125.5, 124.5, 123.8, 122.7, 122.4, 121.9, 121.0, 120.3, 120.0, 110.4, 109.0, 37.9, 19.0 13.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₂₂ClN₃NaOS: 494.1070; found: 494.1064.

9-Ethyl-2-(6-fluoropyridin-3-yl)-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8v)

Compound 8v was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 30 mg (51%, 0.13 mmol scale); yellow solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 134–136 °C.

IR (DCM): 3075, 1678, 1503, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.48–8.42 (m, 3 H), 8.17 (d, J = 7.7 Hz, 1 H), 8.00–7.95 (m, 1 H), 7.58–7.54 (m, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 7.42 (d, J = 7.6 Hz, 1 H), 7.37 (s, 1 H), 7.34–7.30 (m, 2 H), 7.08–7.04 (m, 1 H), 6.95 (dd, J ₁ = 8.4, J ₂ = 2.8 Hz, 1 H), 4.43 (q, J = 7.2 Hz, 2 H), 2.24 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 167.8, 163.1 (d, J _C-F = 238.6 Hz), 147.0 (d, J _C-F = 15 Hz), 142.0 (d, J _C-F = 8.1 Hz), 140.9, 140.8, 138.2, 135.1 (d, J _C-F = 4.4 Hz), 133.0, 132.6, 128.7, 127.1, 126.8, 125.4, 124.4, 122.6, 122.4, 121.8, 120.9, 120.2, 120.0, 110.4, 109.2 (d, J _C-F = 37.2 Hz), 109.0, 37.8, 18.9, 13.8.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –69.71.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₂FN₃NaOS: 478.1365; found: 478.1375.

2-(5-Bromopyridin-2-yl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8w):

Compound 8w was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 30 mg (54%, 0.11 mmol scale); brown solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 110–112 °C.

IR (DCM): 3076, 1678, 1503, 767 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.66 (d, J = 7.7 Hz, 1 H), 8.52 (br s, 1 H), 8.45 (s, 1 H), 8.36–8.35 (m, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.73 (dd, J ₁ = 8.4, J ₂ = 2.4 Hz, 1 H), 7.59 (s, 1 H), 7.48–7.45 (m, 2 H), 7.40–7.36 (m, 2 H), 7.25–7.21 (m, 2 H), 6.99 (td, J ₁ = 7.7, J ₂ = 1.0 Hz, 1 H), 4.36 (q, J = 7.2 Hz, 2 H), 2.18 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.5, 157.2, 150.5, 141.0, 140.7, 138.9, 138.6, 135.7, 132.8, 128.7, 127.4, 126.8, 125.3, 124.3, 122.8, 122.5, 121.4, 121.0, 120.4, 120.4, 119.8, 119.6, 110.2, 109.0, 37.8, 18.9, 13.9.

HRMS (ESI): m/z [M-H]⁺ calcd for C₂₇H₂₁BrN₃OS: 514.0589; found: 514.0583.

9-Ethyl-N-[2-(methylthio)phenyl]-2-(thiophen-2-yl)-9H-carbazole-3-carboxamide (8x)

Compound 8x was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 17 mg (35%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 140–142 °C.

IR (DCM): 3332, 1671, 1508, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.49–8.45 (m, 2 H), 8.45 (s, 1 H), 8.06 (d, J = 7.7 Hz, 1 H), 7.47–7.43 (m, 1 H), 7.42 (s, 1 H), 7.38–7.34 (m, 2 H), 7.26–7.23 (m, 2 H), 7.21–7.20 (m, 2 H), 6.99–6.95 (m, 2 H), 4.33 (q, J = 7.2 Hz, 2 H), 2.06 (s, 3 H), 1.40 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.4, 142.5, 140.9, 140.7, 139.0, 133.3, 129.7, 128.9, 127.9, 127.6, 127.2, 126.6, 126.4, 125.2, 124.1, 122.6, 122.5, 122.0, 120.9, 120.1, 119.8, 110.4, 108.8, 37.8, 19.2, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₂N₂NaOS₂: 465.1071; found: 465.1063.

2-(3,4-Dimethylphenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8y)

Compound 8y was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 35 mg (50%, 0.15 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3335, 1670, 1509, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (s, 1 H), 8.50 (d, J = 7.2 Hz, 1 H), 8.36 (br s, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.53–7.49 (m, 1 H), 7.44 (s, 1 H), 7.42–7.41 (m, 1 H), 7.38–7.33 (m, 3 H), 7.30–7.26 (m, 2 H), 7.15 (d, J = 7.7 Hz, 1 H), 7.00 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.39 (q, J = 7.2 Hz, 2 H), 2.27 (s, 3 H), 2.25 (s, 3 H), 2.05 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.8, 141.1, 140.9, 139.1, 138.7, 138.1, 137.0, 136.1, 133.2, 130.5, 130.0, 128.9, 127.2, 126.8, 126.4, 125.3, 123.9, 122.8, 122.3, 121.9, 120.9, 120.2, 119.7, 110.2, 108.8, 37.8, 19.9, 19.5, 19.1, 13.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂OS: 465.2001; found: 465.2014.

9-Ethyl-N-[2-(methylthio)phenyl]-2-(3,4,5-trimethoxyphenyl)-9H-carbazole-3-carboxamide (8z)

Compound 8z was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 48 mg (83%, 0.11 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3333, 1667, 1505, 754 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.53 (s, 1 H), 8.44 (d, J = 8.0 Hz, 1 H), 8.22 (br s, 1 H), 8.08 (d, J = 7.7 Hz, 1 H), 7.47–7.43 (m, 1 H), 7.38 (d, J = 8.2 Hz, 1 H), 7.33 (s, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.24–7.17 (m, 2 H), 6.93 (td, J ₁ = 7.7, J ₂ = 1.2 Hz, 1 H), 6.75 (s, 2 H), 4.34 (q, J = 7.2 Hz, 2 H), 3.75 (s, 6 H), 3.72 (s, 3 H), 2.03 (s, 3 H), 1.40 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.6, 153.3, 140.9, 140.8, 138.9, 137.6, 137.6, 136.7, 133.1, 128.8, 127.2, 126.4, 124.9, 124.0, 122.7, 122.4, 122.2, 120.9, 119.7, 119.5, 109.5, 108.8, 106.5, 60.8, 56.2, 37.4, 19.2, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₁N₂O₄S: 527.2005; found: 527.2003.

2-(4-Bromo-3-fluorophenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8aa)

Compound 8aa was obtained after purification by column chromatography (silica gel, EtOAc/hexane 20:80); yield: 41 mg (64%, 0.12 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 129–131 °C.

IR (DCM): 2938, 1672. 1505, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.48 (s, 1 H), 8.39–8.34 (m, 2 H), 8.07 (d, J = 7.7 Hz, 1 H), 7.48–7.44 (m, 2 H), 7.38 (d, J = 8.2 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.27 (s, 1 H), 7.25–7.21 (m, 2 H), 7.18–7.15 (m, 1 H), 6.97 (td, J ₁ = 7.6, J ₂ = 1.1 Hz, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 2.12 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.0, 159.0 (d, J _C-F = 246.3 Hz), 142.7 (d, J _C-F = 7.0 Hz), 140.9, 140.7, 138.4, 135.6 (d, J _C-F = 1.4 Hz), 133.4, 132.7, 128.7, 126.9, 126.7, 126.2 (d, J _C-F = 2.97 Hz), 125.4, 124.3, 122.5, 122.4, 121.9, 120.9, 120.2, 119.9, 117.1 (d, J _C-F = 22.2 Hz), 110.0, 108.9, 108.3 (d, J _C-F = 20.6 Hz), 37.8, 19.0, 13.8.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –107.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃BrFN₂OS: 533.0698; found: 533.0699.

2-(3,5-Dimethylphenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8ab)

Compound 8ab was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 41 mg (72%, 0.12 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 179–181 °C.

IR (DCM): 3336, 1668, 1503, 756 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.61 (s, 1 H), 8.45 (d, J = 7.6 Hz, 1 H), 8.26 (br s, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.53–7.49 (m, 1 H), 7.44 (d, J = 8.2 Hz, 1 H), 7.37–7.35 (m, 2 H), 7.30–7.27 (m, 2 H), 7.23 (s, 2 H), 7.00 (td, J ₁ = 7.6, J ₂ = 1.1 Hz, 1 H), 6.94 (s, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 2.30 (s, 6 H), 2.08 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.7, 141.0, 140.9, 140.8, 138.9, 138.2, 132.9, 129.3, 128.7, 127.2, 127.1, 126.3, 125.4, 123.9, 122.8, 122.3, 121.9, 120.8, 120.1, 119.6, 110.0, 108.7, 37.7, 21.3, 19.0, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₈N₂NaOS: 487.1820; found: 487.1834.

2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8ac)

Compound 8ac was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 44 mg (64%, 0.14 mmol scale); brown solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 147–149 °C.

IR (DCM): 3332, 1667, 1503, 751 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.53 (d, J = 7.5 Hz, 1 H), 8.39 (br s, 1 H), 8.13 (d, J = 7.7 Hz, 1 H), 7.52–7.48 (m, 1 H), 7.43–7.38 (m, 2 H), 7.35 (s, 1 H), 7.32–7.26 (m, 2 H), 7.18 (s, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 7.01 (td, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 6.86 (d, J = 8.3 Hz, 1 H), 4.37 (q, J = 7.2 Hz, 2 H), 4.24 (s, 4 H), 2.13 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.6, 143.6, 143.3, 140.9, 140.8, 139.0, 137.2, 134.4, 133.1, 128.8, 127.0, 126.3, 125.2, 123.9, 122.7, 122.6, 122.2, 121.8, 120.8, 120.1, 119.6, 118.0, 117.5, 110.0, 108.7, 64.3, 37.7, 19.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₇N₂O₃S: 495.1742; found: 495.1726.

9-Benzyl-2-(4-methoxyphenyl)-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8ad)

Compound 8ad was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 40 mg (63%, 0.12 mmol scale); brown liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3333, 1667, 1505, 744 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.61 (s, 1 H), 8.53 (d, J = 8.0 Hz, 1 H), 8.37 (br s, 1 H), 8.16 (d, J = 7.7 Hz, 1 H), 7.49–7.44 (m, 3 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.33–7.24 (m, 6 H), 7.15–7.13 (m, 2 H), 7.01 (td, J ₁ = 7.6, J ₂ = 1.1 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 2 H), 5.54 (s, 2 H), 3.77 (s, 3 H), 2.07 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.7, 159.3, 141.8, 141.5, 138.9, 137.6, 136.6, 133.2, 133.1, 130.4, 128.9, 128.8, 127.6, 126.5, 126.3, 125.2, 123.9, 122.8, 122.2, 121.9, 120.8, 120.1, 120.0, 114.2, 110.4, 109.2, 55.3, 46.6, 19.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₄H₂₉N₂O₂S: 529.1950; found: 529.1958.

9-Benzyl-N-[2-(methylthio)phenyl]-2-(p-tolyl)-9H-carbazole-3-carboxamide (8ae)

Compound 8ae was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 41 mg (67%, 0.12 mmol scale); yellow solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 74–76 °C.

IR (DCM): 3333, 1670, 1505, 753 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.62 (s, 1 H), 8.52 (d, J = 8.0 Hz, 1 H), 8.38 (br s, 1 H), 8.17 (d, J = 7.7 Hz, 1 H), 7.49–7.44 (m, 3 H), 7.39–7.35 (m, 3 H), 7.32–7.25 (m, 5 H), 7.18–7.14 (m, 4 H), 7.03–6.99 (m, 1 H), 5.56 (s, 2 H), 2.32 (s, 3 H), 2.05 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.7, 141.7, 141.5, 138.9, 138.0, 137.9, 137.4, 136.5, 133.2, 129.4, 129.1, 128.9, 128.9, 127.7, 127.6, 126.6, 126.3, 125.2, 123.9, 122.8, 122.2, 122.0, 120.8, 120.1, 120.0, 110.5, 109.3, 46.6, 21.1, 19.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₄H₂₉N₂OS: 513.2001; found: 513.1995.

9-Methyl-N-[2-(methylthio)phenyl]-3-(p-tolyl)-9H-carbazole-2-carboxamide (8af)

Compound 8af was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 30:70); yield: 40 mg (67%, 0.14 mmol scale); colorless liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3332, 1664, 1232 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.53 (d, J = 8.2 Hz, 1 H), 8.41 (s, 1 H), 8.13–8.11 (m, 2 H), 7.90 (s, 1 H), 7.56–7.51 (m, 4 H), 7.44 (d, J = 8.2 Hz, 1 H), 7.38 (d, J = 7.7 Hz, 1 H), 7.33–7.21 (m, 2 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.02 (td, J ₁ = 7.6, J ₂ = 0.8 Hz, 1 H), 3.91 (s, 3 H), 2.33 (s, 3 H), 2.00 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.8, 142.2, 139.8, 138.8, 137.8, 136.8, 133.4, 133.3, 130.5, 129.4, 129.3, 128.8, 126.8, 125.3, 124.6, 124.1, 122.4, 122.2, 120.8, 120.0, 119.4, 109.8, 108.8, 29.3, 21.1, 19.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₂₄N₂NaOS: 459.1507; found: 459.1511.

6-Bromo-9-ethyl-N-[2-(methylthio)phenyl]-2-(p-tolyl)-9H-carbazole-3-carboxamide (8ag)

Compound 8ag was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 34 mg (70%, 0.09 mmol scale); colorless liquid; R_f = 0.6 (EtOAc/hexane 20:80).

IR (DCM): 3333, 1667, 1507, 749 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 8.50 (d, J =8.2 Hz, 1 H), 8.38 (br. s, 1 H), 8.23 (d, J = 1.8 Hz, 1 H), 7.58 (dd, J ₁ = 8.6, J ₂ = 1.9 Hz, 1 H), 7.51 (d, J =7.9 Hz, 2 H), 7.40–7.37 (m, 2 H), 7.31–7.29 (m, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.01 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.36 (q, J = 7.3 Hz, 2 H), 2.35 (s, 3 H), 2.07 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.4, 141.2, 139.4, 138.8, 138.6, 137.9, 137.6, 133.1, 129.4, 129.1, 129.0, 128.8, 127.7, 125.2, 124.4, 124.0, 123.5, 122.4, 120.8, 120.1, 112.5, 110.4, 110.2, 37.9, 21.1, 19.2, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆BrN₂OS: 529.0949; found: 529.0960.

6-Bromo-2-(3-chlorophenyl)-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (8ah)

Compound 8ah was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 21 mg (47%, 0.08 mmol scale); colorless solid; R_f = 0.6 (EtOAc/hexane 20:80); mp 185–187 °C.

IR (DCM): 3341, 1669, 1508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 8.45 (d, J = 7.8 Hz, 1 H), 8.33 (br. s, 1 H), 8.25 (d, J = 1.8 Hz, 1 H), 7.65 (br. s, 1 H), 7.61 (dd, J ₁ = 8.7, J ₂ = 1.9 Hz, 1 H), 7.45–7.35 (m, 4 H), 7.32–7.26 (m, 3 H), 7.04 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.39 (q, J = 7.3 Hz, 2 H), 2.16 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 167.9, 142.8, 141.1, 139.5, 138.5, 137.1, 134.6, 132.8, 132.8, 129.8, 129.3, 129.0, 128.8, 127.8, 127.7, 127.7, 125.4, 124.3, 123.6, 122.3, 121.3, 120.1, 112.7, 110.4, 110.4, 38.0, 19.1, 13.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₂₂BrClN₂NaOS: 571.0222; found: 571.0222.

9-Ethyl-2-(4-methoxyphenyl)-9H-carbazole-3-carboxylic acid (10a)

Compound 10a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 30:70); yield: 33 mg (45%, 0.21 mmol scale); brown liquid; R_f = 0.5 (EtOAc/hexane 20:80).

IR (DCM): 3224, 1678, 760 cm^–1.

¹H NMR (400 MHz, DMSO-d₆): δ = 8.63 (s, 1 H), 8.27 (d, J = 7.7 Hz, 1 H), 7.65 (d, J = 8.2 Hz, 1 H), 7.51–7.48 (m, 2 H), 7.38 (d, J = 8.6 Hz, 2 H), 7.28–7.24 (m, 1 H), 7.00 (d, J = 8.6 Hz, 2 H), 4.49 (q, J = 7.1 Hz, 2 H), 3.81 (s, 3 H), 1.32 (t, J = 7.0 Hz, 3 H). (The signal corresponding to COOH was not ascertained).

¹³C{¹H} NMR (~101 MHz, DMSO-d₆): δ = 170.5, 158.8, 141.2, 140.9, 140.1, 135.1, 130.8, 130.4, 126.7, 123.1, 122.5, 121.2, 120.8, 120.0, 113.8, 111.2, 109.9, 55.6, 37.6, 14.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₀NO₃: 346.1443; found: 346. 1432.

Disubstituted Carbazole-3-carboxamides 12a–e by Pd(II)-Catalyzed C–H Benzylation of Carbazole-3-carboxamide 5a; General Procedure

A mixture of carboxamide 5a (0.14 mmol, 1 equiv), the appropriate benzyl bromide (0.56 mmol, 4 equiv), Pd(OAc)₂ (10 mol%), K₂CO₃ (0.22 mmol, 2 equiv), and NaOTf (0.42 mmol, 3 equiv), was suspended in anhydrous toluene (1 mL) in a 10 mL sealed pressure tube. The tube was flushed with N₂ for 2 min, and sealed with a PTFE-lined cap, and then the tube was heated at 130 °C for 36 h. After completion of the reaction, the resulting mixture was concentrated under vacuum and purified by column chromatography (silica gel, EtOAc/hexane), to afford the corresponding C–H benzylated carboxamide 12.

2,4-Dibenzyl-9-ethyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (12a)

Compound 12a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 34 mg (40%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 196–198 °C.

IR (DCM): 3337, 1668, 1519, 751 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.63 (s, 1 H), 8.87 (d, J = 7.6 Hz, 1 H), 8.31 (dd, J ₁ = 4.2, J ₂ = 1.4 Hz, 1 H), 7.99 (dd, J ₁ = 8.3, J ₂ = 1.2 Hz, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.49–7.46 (m, 1 H), 7.40 (d, J = 8.2 Hz, 1 H), 7.34–7.33 (m, 2 H), 7.23 (dd, J ₁ = 8.2, J ₂ = 4.2 Hz, 1 H), 7.20–7.17 (m, 2 H), 7.08–6.98 (m, 6 H), 6.95–6.90 (m, 3 H), 6.87–6.84 (m, 1 H), 4.69 (s, 2 H), 4.27–4.24 (m, 4 H), 1.33 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.1, 147.7, 140.7, 140.5, 140.5, 139.3, 138.3, 136.3, 135.8, 134.4, 131.8, 131.2, 129.2, 128.3, 128.2, 127.7, 127.2, 125.9, 125.7, 125.3, 122.8, 122.7, 121.6, 121.2, 120.3, 119.2, 116.4, 108.3, 108.3, 108.3, 40.0, 37.4, 37.0, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₈H₃₂N₃O: 546.2545; found: 546.2542.

2-Benzyl-9-ethyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (13a)

Compound 13a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 12 mg (27%, 0.10 mmol scale); colorless liquid; R_f = 0.5 (EtOAc/hexane 10:90).

IR (DCM): 3334, 1725, 1503, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.18 (s, 1 H), 8.88 (dd, J ₁ = 7.6, J ₂ = 1.0 Hz, 1 H), 8.65 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.39 (s, 1 H), 8.10 (dd, J ₁ = 8.3, J ₂ = 1.6 Hz, 1 H), 8.05 (d, J = 7.7 Hz, 1 H), 7.55–7.51 (m, 1 H), 7.47 (dd, J ₁ = 8.3, J ₂ = 1.3 Hz, 1 H), 7.44–7.40 (m, 1 H), 7.38–7.34 (m, 1 H), 7.20–7.17 (m, 5 H), 7.13–7.09 (m, 2 H), 7.03–6.99 (m, 1 H), 4.50 (s, 2 H), 4.25 (q, J = 7.2 Hz, 2 H), 1.32 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.0, 148.1, 141.4, 141.0, 140.5, 138.6, 138.1, 136.3, 135.1, 129.1, 128.3, 127.9, 127.4, 126.0, 125.8, 122.8, 121.5, 121.4, 120.9, 120.5, 120.1, 119.4, 116.4, 110.7, 108.7, 39.7, 37.6, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₂₆N₃O: 456.2076; found: 456.2074.

9-Ethyl-2,4-bis(2-methylbenzyl)-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (12b)

Compound 12b was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 31 mg (39%, 0.14 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 200–202 °C.

IR (DCM): 2931, 1674, 1524, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.80 (s, 1 H), 8.93 (dd, J ₁ = 7.5, J ₂ = 1.4 Hz, 1 H), 8.41 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.07 (dd, J ₁ = 8.3, J ₂ = 1.6 Hz, 1 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.55–7.51 (m, 1 H), 7.48 (dd, J ₁ = 8.3, J ₂ = 1.4 Hz, 1 H), 7.39 (d, J = 3.8 Hz, 2 H), 7.31 (dd, J ₁ = 8.3, J ₂ = 4.2 Hz, 1 H), 7.19 (d, J = 7.4 Hz, 1 H), 7.14–7.10 (m, 1 H), 7.06–7.05 (m, 2 H), 7.04–7.01 (m, 1 H), 6.95 (s, 1 H), 6.92–6.87 (m, 4 H), 4.62 (s, 2 H), 4.36 (s, 2 H), 4.27 (q, J = 7.2 Hz, 2 H), 2.27 (s, 3 H), 2.24 (s, 3 H), 1.36 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.2, 147.8, 140.4, 140.4, 138.6, 138.3, 137.4, 136.8, 135.9, 135.8, 135.7, 134.4, 131.6, 131.2, 130.2, 130.1, 129.5, 127.6, 127.3, 127.1, 126.3, 126.3, 126.0, 125.7, 125.2, 122.7, 122.5, 121.6, 121.2, 120.4, 119.2, 116.3, 108.3, 107.6, 37.4, 37.3, 34.5, 19.8, 19.7, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₄₀H₃₆N₃O: 574.2858; found: 574.2865.

9-Ethyl-2,4-bis(3-methylbenzyl)-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (12c)

Compound 12c was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 30 mg (38%, 0.14 mmol scale); yellow solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 148–150 °C.

IR (DCM): 3337, 1667, 1503, 755 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.53 (s, 1 H), 8.89 (dd, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 8.30 (dd, J ₁ = 4.2, J ₂ = 1.7 Hz, 1 H), 7.99 (dd, J ₁ = 8.3, J ₂ = 2.0 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.51–7.47 (m, 1 H), 7.41 (dd, J ₁ = 8.3, J ₂ = 1.2 Hz, 1 H), 7.35–7.34 (m, 2 H), 7.24 (dd, J ₁ = 8.3, J ₂ = 4.2 Hz, 1 H), 7.13 (s, 1 H), 7.05–7.01 (m, 1 H), 6.99–6.98 (m, 1 H), 6.94 (d, J = 7.6 Hz, 2 H), 6.91–6.87 (m, 1 H) 6.84–6.80 (m, 2 H), 6.68 (d, J = 6.9 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 4.64 (br s, 2 H), 4.27 (q, J = 7.2 Hz, 2 H), 4.22 (s, 2 H), 1.95 (s, 3 H), 1.83 (s, 3 H), 1.35 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.1, 147.8, 140.6, 140.5, 140.5, 139.3, 138.2, 137.8, 137.7, 136. 3, 135.7, 134.4, 132.1, 131.2, 129.9, 129.0, 128.1, 128.1, 127.6, 127.2, 126.6, 126.4, 126.1, 125.2, 125.2, 122.8, 121.5, 121.2, 120.3, 119.2, 116.3, 108.3, 108.2, 40.0, 37.4, 36.9, 21.1, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₄₀H₃₆N₃O: 574.2858; found: 574.2863.

2,4-Bis(3-chlorobenzyl)-9-ethyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (12d)

Compound 12d was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 20 mg (29%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 202–204 °C.

IR (DCM): 3331, 1728, 1522, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.54 (s, 1 H), 8.84 (dd, J ₁ = 7.5, J ₂ = 1.3 Hz, 1 H), 8.37 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.01 (dd, J ₁ = 8.3, J ₂ = 1.6 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.50–7.46 (m, 1 H), 7.42 (dd, J ₁ = 8.3, J ₂ = 1.4 Hz, 1 H), 7.38–7.37 (m, 2 H), 7.26 (dd, J ₁ = 8.2, J ₂ = 4.2 Hz, 1 H), 7.14–7.14 (m, 2 H), 7.07–7.01 (m, 3 H), 6.94 (d, J = 7.0 Hz, 1 H), 6.91–6.87 (m, 1 H), 6.85–6.81 (m, 3 H), 4.64 (br s, 2 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.23 (s, 2 H), 1.38 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.7, 147.8, 142.7, 141.4, 140.6, 140.5, 138.2, 135.9, 135.4, 134.2, 134.1, 134.1, 131.1, 131.0, 129.5, 129.4, 129.0, 128.1, 127.7, 127.3, 127.2, 126.4, 126.1, 126.1, 125.6, 122.6, 122.5, 121.8, 121.4, 120.4, 119.4, 116.3, 108.7, 108.6, 39.8, 37.6, 36.6, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₈H₃₀Cl₂N₃O: 614.1766; found: 614.1773.

9-Ethyl-2,4-bis(4-methylbenzyl)-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (12e)

Compound 12e was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 30 mg (38%, 0.14 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 204–206 °C.

IR (DCM): 3337, 1668, 1522, 757 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.55 (s, 1 H), 8.87 (dd, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 8.30 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 7.99 (dd, J ₁ = 8.3, J ₂ = 1.6 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.49–7.45 (m, 1 H), 7.40 (dd, J ₁ = 8.3, J ₂ = 1.2 Hz, 1 H), 7.34–7.33 (m, 2 H), 7.23 (dd, J ₁ = 8.3, J ₂ = 4.2 Hz, 1 H), 7.10 (s, 1 H), 7.05 (d, J = 7.9 Hz, 2 H), 7.03–6.99 (m, 1 H), 6.92 (d, J = 8.0 Hz, 2 H), 6.81 (d, J = 7.8 Hz, 2 H), 6.74 (d, J = 7.9 Hz, 2 H), 4.60 (br s, 2 H), 4.28–4.23 (m, 2 H), 4.22 (s, 2 H), 2.02 (s, 3 H), 2.00 (s, 3 H), 1.33 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.2, 147.5, 140.5, 140.4, 138.2, 137.6, 136.6, 136.3, 135.8, 135.2, 134.9, 134.5, 132.1, 131.1, 129.0, 129.0, 128.9, 128.0, 127.6, 127.2, 125.2, 122.8, 122.8, 121.4, 121.1, 120.2, 119.2, 116.3, 108.3, 108.1, 39.6, 37.4, 36.6, 20.8, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₄₀H₃₆N₃O: 574.2858; found: 574.2859.

Alkyl-Substituted Carbazolecarboxamides 17a–d and 19a–j by Pd(II)-Catalyzed C–H Alkylation of Carbazolecarboxamides 5a,b,i; General Procedure

A mixture of the appropriate carboxamide 5 (0.11–0.14 mmol, 1 equiv), the appropriate alkyl iodide (0.4 mmol, 4 equiv), Pd(OAc)₂ (10 mol%), K₂CO₃ (0.22–0.28 mmol, 2 equiv), NaOTf (0.33–0.42 mmol, 3 equiv), and anhydrous t-amylOH (1 mL) was placed in a microwave tube. The tube was flushed with N₂ for 2 min, capped with a silicone septum, and then the tube was subjected to heating at 130 °C for 36 h. After completion of the reaction, the resulting mixture was concentrated under vacuum and purified by column chromatography (silica gel, EtOAc/hexane), furnishing the corresponding C–H alkylated carboxamide.

2-Butyl-9-ethyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (17a)

Compound 17a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 32 mg (54%, 0.14 mmol scale); brown liquid; R_f = 0.5 (EtOAc/hexane 10:90).

IR (DCM): 3354, 2944. 1671, 758 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.24 (s, 1 H), 8.92 (dd, J ₁ = 7.6, J ₂ = 0.9 Hz, 1 H), 8.69 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.35 (s, 1 H), 8.10 (dd, J ₁ = 8.3, J ₂ = 1.6 Hz, 1 H), 8.02 (d, J = 7.7 Hz, 1 H), 7.56–7.52 (m, 1 H), 7.47 (dd, J ₁ = 8.3, J ₂ = 1.2 Hz, 1 H), 7.42–7.33 (m, 3 H), 7.23 (s, 1 H), 7.19–7.15 (m, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 3.08 (t, J = 8.0 Hz, 2 H), 1.75–1.67 (m, 2 H), 1.40–1.33 (m, 5 H), 0.83 (t, J = 7.4 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.2, 148.2, 141.0, 140.5, 140.1, 138.7, 136.3, 135.2, 128.0, 128.0, 127.5, 125.8, 122.9, 121.6, 121.4, 120.6, 120.4, 120.2, 119.3, 116.4, 109.7, 108.7, 37.6, 34.5, 34.1, 22.8, 14.0, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₈N₃O: 422.2232; found: 422.2246.

9-Ethyl-2-propyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (17b)

Compound 17b was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 15 mg (26%, 0.14 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 10:90).

IR (DCM): 3355, 2938, 1673, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.25 (s, 1 H), 8.93 (d, J = 7.5 Hz, 1 H), 8.71 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.36 (s, 1 H), 8.12 (dd, J ₁ = 8.3, J ₂ = 1.6 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.58–7.54 (m, 1 H), 7.48 (dd, J ₁ = 8.3, J ₂ = 1.2 Hz, 1 H), 7.43–7.41 (m, 1 H), 7.40–7.39 (m, 1 H), 7.38–7.35 (m, 1 H), 7.25 (s, 1 H), 7.20–7.16 (m, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 3.08 (t, J = 7.9 Hz, 2 H), 1.81–1.71 (m, 2 H), 1.40 (t, J = 7.2 Hz, 3 H), 0.93 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.3, 148.2, 141.0, 140.5, 139.9, 138.7, 138.2, 136.3, 135.2, 128.0, 127.5, 125.8, 122.9, 121.6, 121.4, 120.6, 120.4, 120.2, 119.3, 116.4, 109.8, 108.7, 37.6, 36.5, 25.4, 14.2, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₆N₃O: 408.2076; found: 408.2076.

9-Ethyl-2-heptyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (17c)

Compound 17c was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 34 mg (62%, 0.12 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 10:90).

IR (DCM): 3352, 2937, 1676, 769 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.32 (s, 1 H), 9.00 (d, J = 7.6 Hz, 1 H), 8.78 (dd, J ₁ = 4.2, J ₂ = 1.6 Hz, 1 H), 8.42–8.42 (m, 1 H), 8.20–8.18 (m, 1 H), 8.11 (d, J = 7.7 Hz, 1 H), 7.65–7.61 (m, 1 H), 7.56 (dd, J ₁ = 8.3, J ₂ = 1.2 Hz, 1 H), 7.51–7.42 (m, 3 H), 7.32 (s, 1 H), 7.27–7.24 (m, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.16 (t, J = 7.2 Hz, 2 H), 1.83–1.76 (m, 2 H), 1.47 (t, J = 7.2 Hz, 3 H), 1.43–1.34 (m, 2 H), 1.30–1.26 (m, 3 H), 1.20–1.19 (m, 3 H), 0.80–0.77 (t, J = 6.9 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.3, 148.2, 141.0, 140.5, 140.1, 138.7, 136.3, 135.2, 128.1, 128.0, 127.5, 125.8, 122.9, 121.6, 121.4, 120.6, 120.4, 120.1, 119.3, 116.4, 109.7, 108.7, 37.6, 34.4, 32.3, 31.8, 29.6, 29.2, 22.6, 14.0, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₄N₃O: 464.2702; found: 464.2693.

9-Ethyl-2-octyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (17d)

Compound 17d was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 35 mg (53%, 0.14 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 148–150 °C.

IR (DCM): 3353, 2933, 1675, 766, cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.31 (s, 1 H), 9.00 (d, J = 7.4 Hz, 1 H), 8.78 (dd, J ₁ = 4.2, J ₂ = 1.5 Hz, 1 H), 8.42 (s, 1 H), 8.19 (dd, J ₁ = 8.3, J ₂ = 1.4 Hz, 1 H), 8.11 (d, J = 7.7 Hz, 1 H), 7.65–7.61 (m, 1 H), 7.56 (dd, J ₁ = 8.2, J ₂ = 0.9 Hz, 1 H), 7.51–7.42 (m, 3 H), 7.31 (s, 1 H), 7.27–7.24 (m, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.15 (t, J = 7.9 Hz, 2 H), 1.83–1.75 (m, 2 H), 1.47 (t, J = 7.2 Hz, 3 H), 1.41–1.33 (m, 2 H), 1.29–1.25 (m, 3 H), 1.21–1.15 (m, 5 H), 0.80 (t, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.3, 148.2, 141.0, 140.5, 140.1, 138.7, 136.3, 135.2, 128.1, 128.0, 127.5, 125.8, 123.0, 121.6, 121.4, 120.6, 120.4, 120.1, 119.3, 116.4, 109.7, 108.7, 37.6, 34.4, 32.3, 31.8, 29.7, 29.4, 29.2, 22.6, 14.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₃₆N₃O: 478.2858; found: 478.2871.

2-Butyl-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (19a)

Compound 19a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 29 mg (58%, 0.12 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 80–82 °C.

IR (DCM): 3344, 2938, 1674, 758 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.66 (s, 1 H), 8.44 (d, J = 8.1 Hz, 1 H), 8.23 (s, 1 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.45 (dd, J ₁ = 7.8, J ₂ = 1.4 Hz, 1 H), 7.41–7.37 (m, 1 H), 7.34–7.28 (m, 2 H), 7.21 (s, 1 H), 7.19–7.15 (m, 1 H), 7.06–7.02 (m, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 3.04 (t, J = 7.9 Hz, 2 H), 2.31 (s, 3 H), 1.70–1.63 (m, 2 H), 1.38–1.32 (m, 5 H), 0.85 (t, J = 7.4 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.9, 141.0, 140.4, 140.2, 138.8, 132.8, 128.8, 127.5, 125.9, 125.7, 124.3, 122.8, 120.8, 120.5, 120.2, 119.7, 119.3, 109.8, 108.7, 37.6, 34.5, 34.1, 22.8, 18.9, 14.0, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₉N₂OS: 417.2001; found: 417.2016.

9-Ethyl-N-[2-(methylthio)phenyl]-2-propyl-9H-carbazole-3-carboxamide (19b)

Compound 19b was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 12 mg (27%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 115–117 °C.

IR (DCM): 3343, 2939, 1676, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.68 (s, 1 H), 8.45 (d, J = 8.1 Hz, 1 H), 8.24 (s, 1 H), 8.00 (d, J = 7.7 Hz, 1 H), 7.46 (dd, J ₁ = 7.8, J ₂ = 1.4 Hz, 1 H), 7.43–7.39 (m, 1 H), 7.36–7.29 (m, 2 H), 7.23 (s, 1 H), 7.20–7.17 (m, 1 H), 7.07–7.03 (m, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 3.05–3.01 (m, 2 H), 2.33 (s, 3 H), 1.75–1.69 (m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H), 0.93 (t, J = 7.4 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.0, 141.1, 140.5, 140.0, 138.9, 132.8, 128.9, 127.5, 125.9, 125.6, 124.3, 122.8, 120.7, 120.5, 120.3, 119.7, 119.4, 110.0, 108.7, 37.6, 36.4, 25.4, 18.9, 14.2, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₇N₂OS: 403.1844; found: 403.1842.

9-Ethyl-N-[2-(methylthio)phenyl]-2-pentyl-9H-carbazole-3-carboxamide (19c)

Compound 19c was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 14 mg (30%, 0.11 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 10:90).

IR (DCM): 3347, 2936, 1677, 763 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.67 (s, 1 H), 8.44 (d, J = 8.1 Hz, 1 H), 8.24 (s, 1 H), 8.00 (d, J = 7.7 Hz, 1 H), 7.45 (dd, J ₁ = 7.8, J ₂ = 1.3 Hz, 1 H), 7.43–7.39 (m, 1 H), 7.36–7.28 (m, 2 H), 7.22 (s, 1 H), 7.20–7.16 (m, 1 H), 7.05 (td, J ₁ = 7.6, J ₂ = 1.2 Hz, 1 H), 4.31 (q, J = 7.2 Hz, 2 H), 3.04 (t, J = 7.9 Hz, 2 H), 2.32 (s, 3 H), 1.73–1.65 (m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H), 1.35–1.26 (m, 4 H), 0.80 (t, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.0, 141.1, 140.5, 140.2, 138.9, 132.8, 128.9, 127.5, 125.9, 125.7, 124.3, 122.8, 120.8, 120.5, 120.3, 119.7, 119.4, 109.9, 108.7, 37.6, 34.3, 32.0, 31.9, 22.6, 18.9, 14.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₃₁N₂OS: 431.2157; found: 431.2159.

9-Ethyl-2-heptyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (19d)

Compound 19d was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 24 mg (47%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 87–89 °C.

IR (DCM): 3340, 2930, 1678, 761 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.67 (s, 1 H), 8.46 (d, J = 8.2 Hz, 1 H), 8.24 (s, 1 H), 8.01 (d, J = 7.7 Hz, 1 H), 7.46 (dd, J ₁ = 7.8, J ₂ = 1.4 Hz, 1 H), 7.43–7.39 (m, 1 H), 7.36–7.29 (m, 2 H), 7.22 (s, 1 H), 7.20–7.16 (m, 1 H), 7.07–7.03 (m, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 3.04 (t, J = 8.0 Hz, 2 H), 2.32 (s, 3 H), 1.72–1.64 (m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H), 1.34–1.28 (m, 2 H), 1.26–1.21 (m, 3 H), 1.18–1.16 (m, 3 H), 0.77 (t, J = 6.9 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.0, 141.1, 140.5, 140.2, 138.9, 132.8, 128.9, 127.5, 125.9, 125.6, 124.3, 122.8, 120.8, 120.5, 120.3, 119.7, 119.4, 109.9, 108.7, 37.6, 34.4, 32.4, 31.8, 29.7, 29.2, 22.6, 18.9, 14.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₃₅N₂OS: 459.2470; found: 459.2470.

9-Ethyl-N-[2-(methylthio)phenyl]-2-octyl-9H-carbazole-3-carboxamide (19e)

Compound 19e was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 26 mg (51%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 87–89 °C.

IR (DCM): 3346, 2929, 1678, 763 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.66 (s, 1 H), 8.44 (d, J = 8.1 Hz, 1 H), 8.23 (s, 1 H), 8.00 (d, J = 7.7 Hz, 1 H), 7.45 (dd, J ₁ = 7.8, J ₂ = 1.4 Hz, 1 H), 7.42–7.38 (m, 1 H), 7.35–7.28 (m, 2 H), 7.21 (s, 1 H), 7.19–7.15 (m, 1 H), 7.04 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.30 (q, J = 7.2 Hz, 2 H), 3.04 (t, J = 7.9 Hz, 2 H), 2.31 (s, 3 H), 1.71–1.64 (m, 2 H), 1.37 (t, J = 7.2 Hz, 3 H), 1.33–1.27 (m, 2 H), 1.23–1.15 (m, 8 H), 0.77 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.9, 141.0, 140.4, 140.2, 138.9, 132.8, 128.9, 127.5, 125.9, 125.6, 124.3, 122.8, 120.8, 120.5, 120.3, 119.7, 119.3, 109.9, 108.7, 37.6, 34.3, 32.4, 31.9, 29.7, 29.5, 29.3, 22.6, 18.9, 14.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₇N₂OS: 473.2627; found: 473.2639.

9-Ethyl-N-[2-(methylthio)phenyl]-2-nonyl-9H-carbazole-3-carboxamide (19f)

Compound 19f was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 39 mg (74%, 0.11 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 10:90).

IR (DCM): 3327, 2930, 1681, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.66 (s, 1 H), 8.44 (d, J = 8.1 Hz, 1 H), 8.22 (s, 1 H), 7.98 (d, J = 7.7 Hz, 1 H), 7.44 (dd, J ₁ = 7.8, J ₂ = 1.4 Hz, 1 H), 7.40–7.36 (m, 1 H), 7.32 (d, J = 8.2 Hz, 1 H), 7.29–7.27 (m, 1 H), 7.20 (s, 1 H), 7.18–7.14 (m, 1 H), 7.03 (td, J ₁ = 7.7, J ₂ = 1.3 Hz, 1 H), 4.27 (q, J = 7.2 Hz, 2 H), 3.03 (t, J = 7.9 Hz, 2 H), 2.30 (s, 3 H), 1.70–1.63 (m, 2 H), 1.35 (t, J = 7.2 Hz, 3 H), 1.31–1.28 (m, 2 H), 1.27–1.13 (m, 10 H), 0.77 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.9, 141.0, 140.4, 1402, 138.8, 132.7, 128.8, 127.5, 125.8, 125.6, 124.3, 122.8, 120.7, 120.5, 120.2, 119.7, 119.3, 109.8, 108.7, 37.5, 34.3, 32.3, 31.8, 29.7, 29.6, 29.5, 29.3, 22.6, 18.8, 14.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₉N₂OS: 487.2783; found: 487.2786.

9-Ethyl-N-[2-(methylthio)phenyl]-2-undecyl-9H-carbazole-3-carboxamide (19g)

Compound 19g was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 37 mg (66%, 0.11 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 10:90); mp 58–60 °C.

IR (DCM): 3346, 2922, 1675, 749 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.67 (s, 1 H), 8.45 (d, J = 8.2 Hz, 1 H), 8.24 (s, 1 H), 8.00 (d, J = 7.7 Hz, 1 H), 7.46 (dd, J ₁ = 7.8, J ₂ = 1.4 Hz, 1 H), 7.43–7.39 (m, 1 H), 7.36–7.29 (m, 2 H), 7.22 (s, 1 H), 7.20–7.17 (m, 1 H), 7.07–7.03 (m, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 3.04 (t, J = 8.0 Hz, 2 H), 2.33 (s, 3 H), 1.71–1.64 (m, 2 H), 1.39 (t, J = 7.2 Hz, 3 H), 1.34–1.28 (m, 2 H), 1.25–1.15 (m, 14 H), 0.80 (t, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.9, 141.0, 140.4, 140.2, 138.9, 132.8, 128.8, 127.5, 125.9, 125.6, 124.3, 122.8, 120.7, 120.5, 120.2, 119.7, 119.3, 109.8, 108.7, 37.6, 34.3, 32.3, 31.9, 30.0, 29.6, 29.6, 29.6, 29.5, 29.3, 22.7, 18.8, 14.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₃H₄₃N₂OS: 515.3096; found: 515.3108.

2-Dodecyl-9-ethyl-N-[2-(methylthio)phenyl]-9H-carbazole-3-carboxamide (19h)

Compound 19h was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 38 mg (65%, 0.11 mmol scale); brown liquid; R_f = 0.5 (EtOAc/hexane 10:90).

IR (DCM): 3342, 2928, 1507, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.67 (s, 1 H), 8.44 (d, J = 8.1 Hz, 1 H), 8.23 (s, 1 H), 8.00 (d, J = 7.7 Hz, 1 H), 7.45 (dd, J ₁ = 7.8, J ₂ = 1.4 Hz, 1 H), 7.42–7.38 (m, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.32–7.28 (m, 1 H), 7.21 (s, 1 H), 7.19–7.15 (m, 1 H), 7.04 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.30 (q, J = 7.2 Hz, 2 H), 3.04 (t, J = 7.9 Hz, 2 H), 2.32 (s, 3 H), 1.72–1.64 (m, 2 H), 1.37 (t, J = 7.3 Hz, 3 H), 1.33–1.28 (m, 2 H), 1.21–1.14 (m, 16 H), 0.79 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.9, 141.0, 140.5, 140.2, 138.9, 132.8, 128.9, 127.5, 125.9, 125.6, 124.3, 122.8, 120.8, 120.5, 120.3, 119.7, 119.4, 109.9, 108.7, 37.6, 34.3, 32.4, 31.9, 29.7, 29.7, 29.6, 29.5, 29.3, 22.7, 18.9, 18.9, 14.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₄H₄₅N₂OS: 529.3253; found: 529.3268.

4-(9-Ethyl-3-{[2-(methylthio)phenyl]carbamoyl}-9H-carbazol-2-yl)butyl Acetate (19i)

Compound 19i was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 21 mg (40%, 0.11 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 10:90).

IR (DCM): 3342, 2937, 1733, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.67 (s, 1 H), 8.41 (d, J = 8.1 Hz, 1 H), 8.25 (s, 1 H), 8.00 (d, J = 7.6 Hz, 1 H), 7.45 (dd, J ₁ = 7.8, J ₂ = 1.5 Hz, 1 H), 7.43–7.39 (m, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.32–7.28 (m, 1 H), 7.22 (s, 1 H), 7.20–7.17 (m, 1 H), 7.05 (td, J ₁ = 7.6, J ₂ = 1.4 Hz, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 4.02 (t, J = 6.6 Hz, 2 H), 3.10–3.06 (m, 2 H), 2.33 (s, 3 H), 1.91 (s, 3 H), 1.80–1.71 (m, 2 H), 1.69–1.63 (m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.2, 168.8, 141.0, 140.5, 139.6, 138.7, 132.6, 128.8, 127.3, 126.0, 125.8, 124.4, 122.7, 120.8, 120.7, 120.3, 119.7, 119.4, 110.0, 108.8, 64.4, 37.6, 33.9, 28.6, 28.5, 20.9, 18.8, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₃₁N₂O₃S: 475.2055; found: 475.2059.

6-Bromo-9-ethyl-N-[2-(methylthio)phenyl]-2-nonyl-9H-carbazole-3-carboxamide (19j)

Compound 19j was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 28 mg (62%, 0.08 mmol scale); colorless solid; R_f = 0.7 (EtOAc/hexane 20:80); mp 98–100 °C.

IR (DCM): 3345, 2925, 1673 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.70 (s, 1 H), 8.49 (d, J = 8.1 Hz, 1 H), 8.24 (s, 1 H), 8.17 (d, J = 1.8 Hz, 1 H), 7.56–7.52 (m, 2 H), 7.40–7.36 (m, 1 H), 7.30–7.27 (m, 2 H), 7.14 (td, J ₁ = 7.6, J ₂ = 1.3 Hz, 1 H), 4.35 (q, J = 7.3 Hz, 2 H), 3.10 (t, J = 8.0 Hz, 2 H), 2.41 (s, 3 H), 1.78–1.70 (m, 2 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.39–1.31 (m, 2 H), 1.29–1.22 (m, 10 H), 0.85 (t, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.6, 141.3, 141.1, 139.1, 138.6, 132.6, 128.8, 128.5, 128.1, 125.8, 124.5, 124.5, 123.0, 120.8, 119.8, 119.5, 112.2, 110.1, 110.1, 37.7, 34.3, 32.3, 31.9, 29.7, 29.6, 29.5, 29.3, 22.6, 18.8, 14.1, 13.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₃₇BrN₂NaOS: 587.1708; found: 587.1704.

Carbazole-3-carboxamides 21a,b,d by Cu(I)-Catalyzed C–H Alkoxylation of Carbazole-3-carboxamides 5a,f; General Procedure

The appropriate carboxamide 5 (0.14–0.16 mmol), CuI (10 mol%), and DBU (0.42–0.48 mmol, 3 equiv) were suspended in anhydrous MeOH (1 mL) in a 10 mL pressure tube, sealed with a PTFE-lined cap. The tube was subjected to heating at 110 °C for 24–48 h. After completion of the reaction, the reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (silica gel, EtOAc/hexane), to furnish the corresponding alkoxylated carboxamide.

Carbazole-3-carboxamides 21a,b by Pd(II)-Catalyzed C–H Alkoxylation of Carbazole-3-carboxamide 5a; General Procedure

Carboxamide 5a (0.14 mmol), Pd(OAc)₂ (10 mol%), and PIDA (0.28 mmol, 2 equiv) were suspended in a solvent mixture of 1,4-dioxane/MeOH (1:1, 2 mL) in a 10 mL pressure tube, sealed with a PTFE-lined cap. The tube was subjected to heating at 110 °C for 30 min. After completion of the reaction, the reaction mixture was concentrated under vacuum and the residue was purified by column chromato­graphy (silica gel, EtOAc/hexane), to furnish the corresponding alkoxylated carboxamide.

9-Ethyl-2-methoxy-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (21a)

Compound 21a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 21 mg (38%, 0.14 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 190–192 °C.

IR (DCM): 3275, 1645, 1536, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 12.46 (s, 1 H), 9.12–9.10 (m, 2 H), 8.84 (dd, J ₁ = 4.2, J ₂ = 1.7 Hz, 1 H), 8.14–8.10 (m, 2 H), 7.62–7.58 (m, 1 H), 7.49 (dd, J ₁ = 8.2, J ₂ = 1.1 Hz, 1 H), 7.42–7.39 (m, 2 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.28–7.24 (m, 1 H), 6.83 (s, 1 H), 4.29–4.23 (m, 5 H), 1.43 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 164.5, 157.5, 148.0, 143.1, 140.4, 139.2, 136.1, 136.1, 128.0, 127.6, 125.2, 125.1, 123.4, 121.3, 121.0, 120.2, 119.8, 117.1, 117.0, 114.6, 108.5, 90.6, 56.3, 37.6, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₂N₃O₂: 396.1712; found: 396.1714.

2-Ethoxy-9-ethyl-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (21b)

Compound 21b was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:80); yield: 12 mg (21%, 0.14 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 60–62 °C.

IR (DCM): 3292, 1642, 1530, 766 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 12.13 (s, 1 H), 9.19 (d, J = 7.6 Hz, 1 H), 9.13 (s, 1 H), 8.82 (dd, J ₁ = 4.1, J ₂ = 1.3 Hz, 1 H), 8.16 (dd, J ₁ = 8.2, J ₂ = 1.3 Hz, 1 H), 8.11 (d, J = 7.7 Hz, 1 H), 7.63–7.60 (m, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.45–7.40 (m, 2 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.26–7.26 (m, 1 H), 6.87 (s, 1 H), 4.46 (q, J = 7.0 Hz, 2 H), 4.29 (q, J = 7.2 Hz, 2 H), 1.82 (t, J = 7.0 Hz, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 164.9, 157.0, 147.6, 143.2, 140.5, 139.3, 136.4, 136.2, 128.1, 127.7, 125.6, 125.1, 123.5, 121.3, 121.1, 120.2, 119.9, 117.7, 117.0, 114.9, 108.4, 91.4, 65.6, 37.7, 15.1, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₄N₃O₂: 410.1869; found: 410.1875.

9-Benzyl-2-methoxy-N-(quinolin-8-yl)-9H-carbazole-3-carboxamide (21d)

Compound 21d was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 20:90); yield: 12 mg (22%, 0.12 mmol scale); colorless solid; R_f = 0.5 (EtOAc/hexane 20:80); mp 90–92 °C.

IR (DCM): 3294, 1642, 1535, 764 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 12.37 (s, 1 H), 9.08 (s, 1 H), 9.04 (d, J = 7.8 Hz, 1 H), 8.79–8.78 (m, 1 H), 8.10–8.07 (m, 2 H), 7.56–7.52 (m, 1 H), 7.44 (d, J = 7.5 Hz, 1 H), 7.37 (dd, J ₁ = 8.2, J ₂ = 4.2 Hz, 1 H), 7.32–7.30 (m, 1 H), 7.24–7.20 (m, 5 H), 7.08 (d, J = 6.4 Hz, 2 H), 6.78 (s, 1 H), 5.41 (s, 2 H), 4.13 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 164.5, 157.6, 148.1, 143.9, 141.2, 139.3, 136.5, 136.2, 136.1, 128.9, 128.1, 127.7, 126.3, 125.4, 125.3, 123.5, 121.3, 121.1, 120.3, 120.2, 117.2, 115.2, 109.0, 91.3, 56.3, 46.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₄N₃O₂: 458.1869; found: 458.1866.

Ester Derivatives 22a–d by Removal of the 2-(Methylthio)aniline and 8-Aminoquinoline Directing Groups from 8c,s, 19h, and 21a; General Procedures

Procedure A: A mixture of the appropriate carboxamide (0.06–0.08 mmol, 1 equiv), BF₃·OEt₂ (20 equiv), and anhydrous EtOH (2 mL) was suspended in a 10 mL pressure tube, sealed with a PTFE-lined cap. The pressure tube was flushed with N₂ and then stirred at 130 °C for 48 h. After completion of the reaction, the resulting mixture was diluted with EtOAc (5 mL), and Et₃N (1 mL) was added dropwise, until the fumes subsided. The reaction mixture was concentrated under vacuum and further diluted with EtOAc (5 mL) and washed with H₂O (2 × 5 mL). The resulting organic layer was dried over anhydrous Na₂SO₄­, concentrated under vacuum, and purified by column chromato­graphy (silica gel, EtOAc/hexane), to furnish the corresponding ester.

Procedure B: A mixture of 21a (0.18 mmol), p-TSA (5 equiv), and anhydrous MeOH (2 mL) were suspended in a 10 mL pressure tube, sealed with a PTFE-lined cap. The pressure tube was flushed with N₂ and stirred at 100 °C for 36 h. The resulting reaction mixture was concentrated under vacuum and purified by column chromatography (silica gel, EtOAc/hexane) to furnish 22d. The other expected product 23a was not obtained in characterizable amounts.

Procedure C: In a 10 mL sealed pressure tube, carboxamide 21a and 1.25 M HCl in MeOH (2 mL) were added. The pressure tube was flushed with N₂ and sealed with a PTFE-lined caped. The reaction mixture was stirred at 80 °C for 36 h and then cooled to rt. The mixture was concentrated under vacuum and diluted with EtOAc (10 mL) and sat. aq NaHCO₃ (10 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL) and the combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromato­graphy (silica gel, EtOAc/hexane) to afford 22d. The other expected product 23a was not obtained in characterizable amounts.

Procedure D: A mixture of carboxamide 21a (0.10 mmol), TfOH (0.2 mL), and toluene/H₂O (1:0.1, 1.1 mL) was suspended in a 10 mL pressure tube, sealed with a PTFE-lined cap. The pressure tube was flushed with N₂ and stirred at 100 °C for 36 h, after which it was cooled to rt. Then, the reaction mixture was diluted with EtOAc (10 mL) and washed with aq Na₂CO₃ (2 × 5 mL). The organic layers were collected, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude mixture was then purified by column chromato­graphy (silica gel, EtOAc/hexane) to furnish 22d. The other expected product 23a was not obtained in characterizable amounts.

Ethyl 2-(3-Acetylphenyl)-9-ethyl-9H-carbazole-3-carboxylate (22a)

Compound 22a was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 11 mg (48%, 0.06 mmol scale); yellow liquid; R_f = 0.7 (EtOAc/hexane 10:90).

IR (DCM): 2975, 1697, 1253, 752 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.70 (s, 1 H), 8.11 (d, J = 7.7 Hz, 1 H), 7.96–7.96 (m, 1 H), 7.93–7.90 (m, 1 H), 7.56–7.53 (m, 1 H), 7.49–7.43 (m, 2 H), 7.39 (d, J = 8.2 Hz, 1 H), 7.27–7.22 (m, 2 H), 4.32 (q, J = 7.3 Hz, 2 H), 4.08 (q, J = 7.2 Hz, 2 H), 2.58 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H), 1.00 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 198.2, 168.3, 143.8, 141.4, 140.8, 140.2, 136.7, 133.7, 128.5, 127.9, 126.8, 126.5, 123.9, 122.8, 122.0, 121.1, 120.9, 120.0, 110.5, 109.0, 60.6, 37.8, 26.8, 13.9, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₄NO₃: 386.1756; found: 386.1743.

Ethyl 9-Ethyl-2-(4-hexylphenyl)-9H-carbazole-3-carboxylate (22b)

Compound 22b was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 10 mg (31%, 0.07 mmol scale); yellow liquid; R_f = 0.7 (EtOAc/hexane 10:90).

IR (DCM): 2933, 1712, 1244, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (s, 1 H), 8.08 (d, J = 7.7 Hz, 1 H), 7.46–7.42 (m, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.28–7.24 (m, 2 H), 7.22–7.20 (m, 1 H), 7.19–7.16 (m, 3 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.06 (q, J = 7.1 Hz, 2 H), 2.61 (t, J = 7.8 Hz, 2 H), 1.63–1.56 (m, 2 H), 1.38–1.34 (m, 4 H), 1.28–1.22 (m, 5 H), 0.96 (t, J = 7.2 Hz, 3 H), 0.84 (t, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 169.3, 141.6, 141.4, 141.1, 140.8, 140.4, 128.6, 127.9, 126.2, 123.4, 122.9, 121.9, 121.5, 120.8, 119.7, 110.4, 108.7, 60.6, 37.7, 35.7, 31.8, 31.6, 29.1, 22.7, 14.1, 13.8, 13.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₃₄NO₂: 428.2590; found: 428.2599.

Ethyl 2-Dodecyl-9-ethyl-9H-carbazole-3-carboxylate (22c)

Compound 22c was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 22 mg (85%, 0.06 mmol scale); yellow liquid; R_f = 0.5 (EtOAc/hexane 10:90).

IR (DCM): 2933, 1711, 1230, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.64 (s, 1 H), 8.03 (d, J = 7.7 Hz, 1 H), 7.41–7.37 (m, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.19–7.16 (m, 1 H), 7.12 (s, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 4.28 (q, J = 7.2 Hz, 2 H), 3.10 (t, J = 8.0 Hz, 2 H), 1.65–1.57 (m, 2 H), 1.40–1.35 (m, 8 H), 1.28–1.19 (m, 16 H), 0.79 (t, J = 6.5 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 168.3, 143.3, 142.0, 140.6, 125.8, 124.2, 123.2, 120.7, 120.5, 119.5, 109.9, 108.7, 60.5, 37.6, 35.9, 32.5, 31.9, 29.9, 29.7, 29.6, 29.4, 22.7, 14.5, 14.1, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₄₂NO₂: 436.3216; found: 436.3218.

9-Ethyl-2-methoxy-9H-carbazole (22d)[9o]

Compound 22d was obtained after purification by column chromato­graphy (silica gel, EtOAc/hexane 10:90); yield: 36 mg (50%, 0.32 mmol scale); brown liquid; R_f = 0.7 (EtOAc/hexane 10:90).

IR (DCM): 2963, 1613, 749 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.98 (d, J = 7.7 Hz, 1 H), 7.94 (dd, J ₁ = 8.0, J ₂ = 0.9 Hz, 1 H), 7.40–7.36 (m, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 7.21–7.17 (m, 1 H), 6.84–6.82 (m, 2 H), 4.27 (q, J = 7.2 Hz, 2 H), 3.91 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 159.0, 141.2, 140.0, 124.3, 123.1, 121.1, 119.5, 118.8, 116.8, 108.1, 107.0, 92.8, 55.7, 37.4, 13.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₆NO: 226.1232; found: 226.1218.

9-Ethyl-2-methoxy-9H-carbazole-3-carboxylic acid (24a)

A solution of carboxamide 21a (0.16 mmol) and NaOH (40 equiv) in EtOH (2 mL) was heated in a 10 mL pressure tube, sealed with a PTFE-lined cap, at 130 °C for 36 h. Then, the reaction mixture was cooled and diluted with H₂O and washed with EtOAc (2 × 10 mL). The aqueous layer was acidified with 1 N aq HCl and extracted with EtOAc (2 × 10 mL). The organic layers were dried over anhydrous Na₂SO₄, concentrated under vacuum to obtain a crude mixture, and purified by column chromatography (silica gel, EtOAc/hexane) to furnish 24a (in this reaction, some unknown byproduct also was obtained in 25% yield). Compound 24a was obtained after purification by column chromatography (silica gel, EtOAc/hexane 80:20); yield: 12 mg (30%, 0.16 mmol scale); brown liquid; R_f = 0.2 (EtOAc/hexane 8.2).

IR (DCM): 2927, 1617, 1234 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.89 (s, 1 H), 8.03 (d, J =7.7 Hz, 1 H), 7.48–7.44 (m, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.29–7.26 (m, 1 H), 6.81 (s, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 4.15 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H) (the signal corresponding to COOH is not detected clearly).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 166.5, 157.4, 143.8, 140.6, 126.7, 125.8, 122.9, 120.4, 120.3, 117.8, 109.1, 108.8, 90.7, 56.8, 37.8, 13.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₆NO₃: 270.1130; found: 270.1130.

Methyl 9-Ethyl-2-methoxy-9H-carbazole-3-carboxylate (25a)

Carboxylic acid 24a (0.04 mmol) was dissolved in MeOH (5 mL), and H₂SO₄ (1.5 equiv) was added dropwise. The mixture was refluxed for 16 h (in the open air) and cooled to rt. The reaction mixture was diluted with EtOAc (5 mL) and washed with sat. aq NaHCO₃ (2 × 5 mL). The combined organic layers were collected, dried over anhydrous Na₂SO_4­, and concentrated under vacuum to furnish 25a. Compound 25a was obtained after purification by column chromatography (silica gel, EtOAc/hexane 20:80); yield: 10 mg (90%, 0.04 mmol scale); brown liquid; R_f = 0.7 (EtOAc/hexane 8.2).

IR (DCM): 2932, 1619, 1239 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.63 (s, 1 H), 8.03 (d, J =7.7 Hz, 1 H), 7.45–7.37 (m, 2 H), 7.27–7.23 (m, 1 H), 6.84 (s, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 4.04 (s, 3 H), 3.95 (s, 3 H), 1.45 (t, J = 7.4 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 167.0, 159.4, 143.6, 140.5, 125.1, 125.1, 123.2, 119.9, 116.0, 111.7, 108.6, 91.3, 56.4, 51.8, 37.7, 13.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₈NO₃: 284.1287; found: 284.1294.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank the NMR, HRMS, and X-ray facilities of IISER Mohali.

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Corresponding Author

Publication History

Received: 30 December 2022

Accepted after revision: 16 March 2023

Accepted Manuscript online:
16 March 2023

Article published online:
08 May 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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• 17 CCDC 2233500 (8b) and CCDC 2233501 (21a) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures