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Synthesis 2024; 56(20): 3131-3141
DOI: 10.1055/a-2368-8500
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Lewis Acid Mediated Synthesis of 4-Aminoquinoline Derivatives from 2-Aminobenzonitriles and Activated Alkynes via Aza-Michael and Annulation Reactions

Bikoshita Porashar
,
Anil K. Saikia∗

The authors are grateful to the Science and Engineering Research Board (SERB), New Delhi (Grant No. CRG/2022/001028) for financial support.
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Abstract

An efficient methodology for the synthesis of highly diverse 4-aminoquinoline derivatives from activated alkynes and 2-aminobenzonitriles mediated by Lewis acid is described. The reaction proceeds via sequential aza-Michael addition/intramolecular annulation to afford highly substituted 4-aminoquinolines in good yields. The reaction is operationally simple and has high atom-economy with broad substrate scope. The post synthetic application of the reaction provides 4H-benzo[de][1,6]naphthyridines.


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Key words

N-heterocycles - 4-aminoquinoline - 2-aminobenzonitrile - propynoate - ynone - aza-Michael - benzannulation

Biographical Sketches

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Anil K. Saikia received his Ph.D. from the North East Institute of Science and Technology (NEIST), Jorhat, India under the guidance of Dr. Anil C. Ghosh, former director of NEIST. He subsequently worked at the Indian Institute of Chemical Biology, Kolkata, and Chembiotek Research International, Kolkata, India for a short period of time. He then undertook postdoctoral research at Okayama University, Japan with Prof. Sadao Tsuboi, and at Florida State University, Florida USA, with Prof. Robert A. Holton. He joined as an Assistant Professor in the Chemistry Department of the Indian Institute of Technology Guwahati in 2001 and became a full professor in 2011. His research interests include synthetic methodology, asymmetric, and natural product synthesis. He is the recipient of the Chemical Research Society of India (CRSI) Bronze Medal. He is also a fellow of the Royal Society of Chemistry (FRSC). Currently, Prof. Saikia is the Subject Editor of the Indian Journal of Chemistry (IJC).

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Bikoshita Porashar was born in 1994 in Assam, India. She received her Integrated M.Sc. in Chemistry from Tezpur University in 2018. She qualified for the CSIR National Eligibility Test (2017) & GATE (2018) and is currently pursuing her doctoral research under the supervision of Prof. Anil K. Saikia at the Indian Institute of Technology Guwahati­ India. Her research projects primarily focus on Lewis acid promoted synthesis of heterocycles.

Quinolines are important class of N-heterocycles which exhibit significant biological activity and are widely employed in the manufacture of pharmaceutical drugs, synthetic intermediates, and building blocks.[1] Among them, 4-aminoquinolines have gained extensive research interest as they serve as potent chemotherapeutic agents majorly treating erythrocytic plasmodial infections.[2] Marketed drugs like chloroquine (A),[3] discovered in 1934, and amodiaquine (B)[4] have been extensively utilized for the treatment of malaria for more than half century. However, complications associated with these drugs such as resistance and toxicity have led to the development of promising structural analogues such as isoquine (C).[5] Similarly, commercially available floctafenine (D),[6] a non-steroidal anti-inflammatory drug, tacrine (E),[7] a centrally acting acetylcholinesterase inhibitor drug for treatment of Alzheimer’s disease, and nerlynx (F),[8] a targeted breast cancer drug, all possess 4-aminoquinoline as the core unit (Figure [1]). Therefore, inarguably there is a great interest for the development of various cascade reactions over the years to access diversely functionalized 4-aminoquinolines from readily available starting materials.

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Figure 1 Some biologically active molecules containing 4-aminoquinoline core
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Scheme 1 Literature reports

One of the extensively used commercially available starting materials is 2-aminobenzonitrile, owing to its wide range of synthetic possibilities. Conventionally, it undergoes intermolecular cyclization with a coupling partner by concomitant attack as a nucleophile from the amine functionality as well as electrophilic attack on the unsaturated nitrile motif. Thus, utilizing 2-aminobenzonitrile as a synthetic precursor for heterocyclization reaction is a well-known concept. In this instance, our group has previously developed the Lewis acid mediated synthesis of dihydro-1H-benzo[b]azepines and methylene-substituted tetrahydroquinazolines from donor–acceptor cyclopropanes and activated alkenes, respectively, with 2-aminobenzonitrile as the synthetic precursor (Scheme [1]B).[9] Similarly, several synthetic approaches for the synthesis of 4-aminoquinolines from 2-aminobenzonitriles have been reported.[10] In 2018, Sahoo et al. demonstrated a Au(I)-catalyzed strategic route featuring direct coupling of ynamides and 2-aminobenzonitriles to access 2,4-diamino-substituted quinolines via nitrile activation (Scheme [1]A).[11] Other promising approaches include base-promoted synthesis of 2-perfluoroalkylated 4-aminoquinolines from 2-aminobenzonitriles by reaction with perfluoroalk-2-ynoates or fluorinated alkynyl phosphonates.[12] Very recently, the Verma lab also developed a base-mediated, one-pot annulation of ynones with 2-aminobenzonitriles to give substituted 2,3-disubstituted 4-aminoquinolines (Scheme [1]A).[13] Although the existing methods are unique and elegant, the limitations include requirement of an expensive catalyst, additives, inert atmospheric reaction conditions, and harsh reaction conditions. Thus, inspired by our previous works, herein we introduce a Lewis acid mediated convenient and simple protocol to access of 2,3-disubstituted 4-aminoquinolines from 2-aminobenzonitriles and activated alkynes as an alternative approach (Scheme [1]C). Notably, the reaction follows an aza-Michael reaction followed by annulation to give the N-heterocycles. The salient features of this protocol include the use of a minimally toxic, ecobenign, and less expensive iron(III) salt along with broad substrate scope and operational simplicity.

Table 1 Optimization of the Reaction

Entry

Reagent (equiv)

Solvent

Temp (°C)

Yieldb (%)

 1

In(OTf)3 (0.2)

DCE

 25

–

 2

In(OTf)3 (0.2)

DCE

 60

24

 3

In(OTf)3 (0.2)

DCE

 80

38

 4

In(OTf)3 (0.2)

toluene

110

40

 5

In(OTf)3 (0.2)

THF

 65

–

 6

In(OTf)3 (0.2)

CH3CN

 80

–

 7

In(OTf)3 (0.2)

DMF

100

–

 8

Bi(OTf)3 (0.2)

DCE

 80

17

 9

Cu(OTf)2 (0.2)

DCE

 80

20

10

Zn(OTf)2 (0.2)

DCE

 80

15

11

AgOTf (0.2)

DCE

 80

35

12

AlCl3 (0.5)

DCE

 80

–

13

FeCl3 (0.5)

DCE

 80

58

14

FeCl3 (1.2)

DCE

 80

82

15

FeCl3 (2.0)

DCE

 80

80

16

BF3·OEt2 (1.2)

DCE

 25

–

17

TfOH (2.0)

DCE

 25

–

18

p-TsOH (2.0)

DCE

 25

–

a Reaction conditions: 1a (0.4 mmol), 2a (0.48 mmol), solvent (2.0 mL).

b Isolated yields.

Initially, we commenced our preliminary investigation by treating diethyl but-2-ynedioate (2a) with 2-aminobenzonitrile (1a) in the presence of 0.2 equiv of In(OTf)3 in 1,2-dichloroethane (DCE) at room temperature (Table [1], entry 1). However, no product was obtained even after continuing it for up to 24 h. To our delight, the reaction occurred to deliver the product diethyl 4-aminoquinoline-2,3-dicarboxylate (3aa) in 24% yield when the temperature was raised to 60 °C (Table [1], entry 2). Further elevation of temperature to 80 °C led to comparative increase of yield to 38% (Table [1], entry 3). Encouraged by the results, the reaction was performed in a series of non-polar as well as polar solvents like toluene, THF, acetonitrile, and DMF. While toluene produced a similar yield of 40% (Table [1], entry 4), the reaction did not proceed at all with moderately and highly polar solvents (Table [1], entries 5–7). The reaction was then screened with a set of different Lewis and Brønsted acids. Metal triflates like AgOTf (Table [1], entry 11) gave the desired product with 35% yield, whereas other metal triflates, i.e. Bi(OTf)3, Cu(OTf)2, and Zn(OTf)2, produced inferior yields (Table [1], entries 8–10). Lewis acid, AlCl3 also failed to give any product (Table [1], entry 12). Gratifyingly, when the reaction was performed with 0.5 equiv of FeCl3 in DCE at 80 °C, the desired product was obtained with a better yield of 58% (Table [1], entry 13). Increasing the reagent to a stoichiometric amount of 1.2 equiv furnished 3aa with an optimum yield of 82% (Table [1], entry 14). However, further increasing the reagent loading to 2.0 equiv did not lead to any significant improvement in the yield (Table [1], entry 15). On the other hand, the use of other non–metal Lewis acids, like BF3·OEt2, and Brønsted acids, such as TfOH and p-TsOH, in DCE at room temperature was also found to be ineffective (Table [1], entries 16–18). Therefore, 1.2 equiv FeCl3 in DCE at 80 °C are the optimum conditions for the reaction.

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Scheme 2 Substrate scope. Reagents and conditions: 1 (0.4 mmol), 2 (0.48 mmol), FeCl3 (0.48 mmol), DCE (2 mL).

With the optimized reaction conditions in hand, we set out to explore the compatibility and scope of the reaction with different activated alkynes and 2-aminobenzonitrile substrates as depicted in Schemes 2 and 3. Initially, the influence of R1 substituents on the 2-aminobenzonitriles were investigated with the introduction of various electron-donating as well as electron-withdrawing groups (Scheme [2]). The reaction was not significantly affected by electronic effects, steric effects, and position of the substituent groups on the benzene ring of 2-aminobenzonitriles. The reaction of 2-aminobenzonitriles 1b–1d having moderately electron-withdrawing halo substituents, such as 5-Cl, 5-Br, and 6-F, with diethyl but-2-ynedioate furnished the corresponding products 3ba, 3ca, and 3da in good yields up to 84%. On the other hand, 2-aminobenzonitriles with strongly electron-withdrawing groups at the 5-position, such as 5-CF3 and 5-NO2, were well tolerated providing the desired products 3fa and 3ea with 60% and 78% yields, respectively. 2-Aminobenzonitriles 1g and 1h with electron-donating substituents, such as 4-Me and 4,5-(MeO)2, gave the corresponding products 3ga and 3ha with good yields. The reaction of 2-amino-4-chlorobenzonitrile with dimethyl but-2-ynedioate furnished the expected product 3ib with an excellent yield of 85%.

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Scheme 3 Substrate scope. Reagents and conditions: 1 (0.4 mmol), 2 (0.48 mmol), FeCl3 (0.48 mmol), DCE (2 mL).

Further, to demonstrate the substrate scope of this method, activated alkynes with aryl/alkyl and keto/ester groups were also employed in the reaction (Scheme [3]). The reaction of ethyl 3-phenylpropiolate (1c) with 1a under the optimized condition yielded the expected product ethyl 4-amino-2-phenylquinoline-3-carboxylate (3ac) with 62% yield. Decoration of the aryl group with various substituents led to the desired 2,3-disubstituted 4-aminoquinolines in moderate to good yields. A variety of ethyl 3-phenylpropiolates 2b–2g with moderately electron-withdrawing halo groups as well as strongly electron-withdrawing -CO2Me and -CF3 substituents at the para-position on phenyl ring underwent reaction with 2-aminobenzonitrile 1a, providing the corresponding products 3ad–3ah in 54–71% yields. Likewise, installing electron-donating substituents, such as -Me and -OMe, at the para-, meta-, and ortho-positions resulted in the expected products 3ai–3al and 3cm in 64–81% yields. The reaction was also tested with bulky polyaromatic substituted propiolate 2n, which produced the corresponding product 3an, in a low yield of 50%. Intriguingly, heteroaromatic, i.e. thiophen-2-yl-substituted propiolate, when treated with 2-amino-4-chlorobenzonitrile furnished the respective product 3io in 65% isolated yield. Subsequently, the protocol also exhibited compatibility with 3-alkylpropiolates like ethyl 4,4,4-trifluorobut-2-ynoate (2p) and ethyl hep-2-ynoate (2q) resulting in the alkyl-substituted 4-aminoquinolines 3gp and 3dq with 87% and 43% yields, respectively. The low yield in the case of ethyl hept-2-ynoate (2q) was attributed to deactivation of alkyne group. The reaction was also screened with ynones and gave corresponding 4-aminoquinolines 3ar, 3hr, and 3gs with moderate yields. It was evident from Schemes 2 and 3 that electron-withdrawing groups in the side chain of alkynes provided better yield (3ab–3ib, Scheme [2]), (3gp, Scheme [3]) compared to electron-donating groups (3ac–3io, 3dq, Scheme [3]). This is attributed to the increase in electrophilicity of activated alkyne in case of electron-withdrawing groups in the side chain of the alkyne. The present Lewis acid protocol has advantages over the conventional basic conditions as base-mediated protocol is strictly limited to ynones,[13] whereas in Lewis acidic conditions both ynones 2r and 2s and propiolates can be carried out.

The structure of the compounds was determined by 1H and 13C{1H} NMR spectroscopy and mass spectrometry, and the structure of compound 3io was determined by X-ray crystallographic analysis. To gain insight of the reaction pathway, two control experiments were performed. The substrate 1a when reacted with diphenylacetylene (2a′) under the standard conditions failed to give the desired product 3a′ which indicates that the alkyne group is not activated by FeCl3 to facilitate the hydroamination reaction followed by cyclization reaction. On the other hand, when the reaction of 1a with 2a under the standard reaction conditions was quenched after 15 minutes, the aza-Michael product 3a′′ was isolated with 10% yield as the Z-isomer. The Z-configuration of 3a′′ was determined from NOE experiment as there was no interaction between NH and olefinic CH protons. The intermediate 3a′′ was subjected to standard reaction conditions and it was observed that it provided desired product 3aa with 90% yield. This indicates that the reaction proceeds via aza-Michael reaction followed by annulation (Scheme [4]).

Based on the previous reports[13] and above observation a plausible mechanism is postulated as shown in Scheme [5]. The Lewis acid activates the carbonyl group of the alkyne 2 for aza-Michael reaction with 2-aminobenzonitrile to form enolic allene intermediate A. The intermediate A after nucleophilic attack to activated nitrile forms unstable quinolin-4(1H)-imine B which after aromatization forms stable product 3.

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Scheme 4 Control experiments
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Scheme 5 Plausible reaction mechanism

To demonstrate the synthetic utility of the products, a few synthetic transformations were performed (Scheme [6]). For instance, functionalization in the backbone of product 3ca with pyrene moiety was accomplished by using palladium catalysis (Suzuki cross-coupling reaction), delivering 4 in 96% yield.

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Scheme 6 Post-synthetic modifications

The product 3ib was transformed into annulated product 5 in the presence of a Ru(II) catalyst via selective C–H, N annulation at the phenyl ring with diphenylacetylene. Additionally, selective reduction of the C–N bond of the pyridine ring of 3ib was also achieved using the NiCl2–NaBH4 combination to give 6 with 52% yield. Subsequently, a scale up experiment was also performed using 2-aminobenzonitrile (1a; 810 mg, 6.78 mmol) and diethyl but-2-ynedioate (2a; 1.3 mL, 8.14 mmol) under the standard conditions to provide 73% (1.4 g) yield of the corresponding product 3aa (Scheme [7]).

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Scheme 7 Gram-scale experiment of the reaction

In conclusion, we have developed an efficient Lewis acid promoted annulation of alkynyl esters or ynones with 2-aminobenzonitrile for the synthesis of multisubstituted 4-aminoquinolines in good to excellent yields. The reaction proceeds via aza-Michael addition and intramolecular annulation reaction. The present strategy is inexpensive, and highly atom-economical with broad substrate scope. Additionally, 4H-benzo[de][1,6]naphthyridine was obtained as a post-synthetic modification of 4-aminoquinoline. Similarly, 1,2-dihydroquinolin-4-amine was also synthesized from 4-aminoquinoline by selective reduction with NiCl2–NaBH4.

All reagents were of reagent grade (AR grade) and were used as purchased without further purification. Silica gel (60–120 mesh) was used for column chromatography. Reactions were monitored by TLC on silica gel GF254 (0.25 mm). Melting points were recorded in an open capillary tube and are uncorrected. Fourier transform-infra red (FT-IR) spectra were recorded as neat liquid or KBr pellets. NMR spectra were recorded in CDCl3 with TMS as the internal standard for 1H (600 MHz, 500 MHz, and 400 MHz) or 13C{1H} (150 MHz and 125 MHz) NMR. 19F{1H} NMR spectra were recorded at 470 MHz and chemical shifts are relative to hexafluorobenzene in CDCl3 at δ = –164.9 (external reference). HRMS spectra were recorded using Q-TOF and microTOF-Q II mass spectrometer.

Propiolate derivatives 2c–2o, and 2q were synthesized according to literature reports[14] and confirmed by comparison to the reported characterization data. Ynones 2r and 2s were also prepared using the standard reported procedure.[13]


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4-Aminoquinoline Derivatives 3; General Procedure

To a solution of 2-aminobenzonitrile 1 (0.4 mmol, 1 equiv) and activated alkyne 2 (0.48 mmol, 1.2 equiv) in DCE (2 mL) was added FeCl3 (0.48 mmol, 1.2 equiv). The mixture was then heated in an oil bath at 80 °C and the progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure and diluted with sat. NaHCO3 solution. Then the organic layer was extracted with EtOAc (3 × 10 mL). The combined organic extracts were further washed with brine solution 2–3 times, dried (Na2SO4­), and concentrated on a rotary evaporator. The crude was subjected to column chromatography (silica gel) to obtain the desired product.


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Diethyl 4-Aminoquinoline-2,3-dicarboxylate (3aa)

Light green oil; yield: 94 mg (82%); Rf (hexane/EtOAc, 4:1) = 0.40.

IR (KBr, neat): 3450, 3332, 2982, 1734, 1613, 1557, 1247, 1095, 1029, 766, 556 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.92 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.64 (t, J = 7.7 Hz, 1 H), 7.46 (bs, 2 H), 7.42–7.40 (m, 1 H), 4.41 (q, J = 7.1 Hz, 2 H), 4.32 (q, J = 7.1 Hz, 2 H), 1.39–1.33 (m, 6 H).

13C{1H} NMR (150 MHz, CDCl3): δ = 168.3, 167.2, 154.5, 153.7, 147.4, 132.0, 130.1, 126.6, 121.1, 118.0, 98.4, 62.1, 61.4, 14.2, 14.2.

HRMS (ESI): m/z [M + H]+ calcd for C15H17N2O4: 289.1183; found: 289.1187.


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Diethyl 4-Amino-6-chloroquinoline-2,3-dicarboxylate (3ba)

White solid; yield: 100 mg (78%); Rf (hexane/EtOAc, 4:1) = 0.40; mp 96–98 °C.

IR (KBr, neat): 3450, 3319, 2984, 1716, 1621, 1549, 1249, 1107, 1027, 831, 593 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.84–7.81 (m, 2 H), 7.54 (dd, J = 8.9, 2.2 Hz, 1 H), 7.44 (bs, 2 H), 4.41 (q, J = 7.2 Hz, 2 H), 4.31 (q, J = 7.2 Hz, 2 H), 1.38 (t, J = 7.2 Hz, 3 H), 1.33 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 168.1, 166.9, 153.8, 153.7, 145.8, 132.6, 132.4, 131.6, 120.8, 118.9, 99.0, 62.2, 61.6, 14.2, 14.2.

HRMS (ESI): m/z [M + H]+ calcd for C15H16ClN2O4: 323.0793; found: 323.0786.


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Diethyl 4-Amino-6-bromoquinoline-2,3-dicarboxylate (3ca)

White solid; yield: 123 mg (84%); Rf (hexane/EtOAc, 4:1) = 0.40; mp 100–102 °C.

IR (KBr, neat): 3450, 3326, 2980, 1719, 1621, 1545, 1257, 1101, 1029, 833, 591 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.74 (d, J = 8.9 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.46 (bs, 2 H), 4.41 (q, J = 7.2 Hz, 2 H), 4.31 (q, J = 7.1 Hz, 2 H), 1.37 (t, J = 7.2 Hz, 3 H), 1.32 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 168.1, 166.9, 153.9, 153.6, 146.1, 135.2, 131.7, 124.1, 120.4, 119.4, 99.0, 62.2, 61.6, 14.2, 14.2.

HRMS (ESI): m/z [M + H]+ calcd for C15H16BrN2O4: 367.0288; found: 367.0292.


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Diethyl 4-Amino-5-fluoroquinoline-2,3-dicarboxylate (3da)

Colorless gum; yield: 93 mg (76%); Rf (hexane/EtOAc, 4:1) = 0.30.

IR (KBr, neat): 3520, 3305, 2991, 1742, 1687, 1603, 1557, 1250, 1045, 827, 537 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.67–7.65 (m, 1 H), 7.52–7.48 (m, 1 H), 7.02–6.98 (m, 1 H), 4.37 (q, J = 7.2 Hz, 2 H), 4.28 (q, J = 7.1 Hz, 2 H), 1.35 (t, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 167.6, 166.8, 160.3 (d, J = 251.0 Hz), 154.6, 154.5 (d, J = 2.9 Hz), 149.4, 131.6 (d, J = 11.5 Hz), 126.2 (d, J = 3.6 Hz), 111.6 (d, J = 23.9 Hz), 108.5 (d, J = 6.6 Hz), 98.4 (d, J = 1.8 Hz), 61.9, 61.4, 14.1, 14.0.

19F NMR (470 MHz, C6F6/CDCl3): δ = –116.96 (s, F).

HRMS (ESI): m/z [M + H]+ calcd for C15H16FN2O4: 307.1089; found: 307.1110.


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Diethyl 4-Amino-6-nitroquinoline-2,3-dicarboxylate (3ea)

Yellow solid; yield: 104 mg (78%); Rf (hexane/EtOAc, 4:1) = 0.40; mp 175–177 °C.

IR (KBr, neat): 3445, 3336, 2985, 1732, 1622, 1521, 1335, 1251, 1091, 1030, 847, 745 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.93 (d, J = 2.4 Hz, 1 H), 8.39 (dd, J = 9.2, 2.3 Hz, 1 H), 7.99 (d, J = 9.2 Hz, 1 H), 7.85 (bs, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 4.36 (q, J = 7.2 Hz, 2 H), 1.42–1.35 (m, 6 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 167.5, 166.6, 156.6, 155.6, 150.4, 145.1, 131.6, 125.5, 119.0, 117.4, 99.6, 62.5, 62.1, 14.2, 14.2.

HRMS (ESI): m/z [M + H]+ calcd for C15H16N3O6: 334.1034; found: 334.1039.


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Diethyl 4-Amino-6-(trifluoromethyl)quinoline-2,3-dicarboxylate (3fa)

White gum; yield: 85 mg (60%); Rf (hexane/EtOAc, 5:1) = 0.40.

IR (KBr, neat): 3463, 3334, 2988, 1724, 1613, 1521, 1319, 1246, 1161, 1091, 838, 515 cm–1.

1H NMR (600 MHz, CDCl3): δ = 8.22 (s, 1 H), 8.00 (d, J = 8.7 Hz, 1 H), 7.81 (dd, J = 8.8, 1.9 Hz, 1 H), 7.70 (bs, 2 H), 4.43 (q, J = 7.2 Hz, 2 H), 4.34 (q, J = 7.2 Hz, 2 H), 1.39 (t, J = 7.2 Hz, 3 H), 1.35 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (150 MHz, CDCl3): δ = 167.9, 166.9, 155.5, 155.0, 148.9, 131.1, 128.2 (q, J = 32.7 Hz), 127.8 (q, J = 3.2 Hz), 123.9 (q, J = 270.8 Hz), 119.6 (d, J = 4.4 Hz), 117.4, 99.3, 62.4, 61.8, 14.2, 14.1.

19F NMR (470 MHz, C6F6/CDCl3): δ = –65.37 (s, F).

HRMS (ESI): m/z [M + H]+ calcd for C16H16F3N2O4: 357.1057; found: 357.1061.


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Diethyl 4-Amino-7-methylquinoline-2,3-dicarboxylate (3ga)

Light brown gum; yield: 91 mg (75%); Rf (hexane/EtOAc, 5:1) = 0.40.

IR (KBr, neat): 3458, 3333, 2983, 1735, 1619, 1564, 1251, 1099, 1034, 795, 551 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.70–7.66 (m, 2 H), 7.41 (bs, 2 H), 7.20 (d, J = 8.2 Hz, 1 H), 4.39 (q, J = 7.2 Hz, 2 H), 4.31 (q, J = 7.1 Hz, 2 H), 2.41 (s, 3 H), 1.39–1.31 (m, 6 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 168.3, 167.1, 154.5, 153.6, 147.3, 142.5, 128.9, 128.3, 121.2, 115.7, 97.7, 61.9, 61.2, 21.6, 14.1.

HRMS (ESI): m/z [M + H]+ calcd for C16H19N2O4: 303.1339; found: 303.1337.


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Diethyl 4-Amino-6,7-dimethoxyquinoline-2,3-dicarboxylate (3ha)

Red solid; yield: 99 mg (71%); Rf (hexane/EtOAc, 1:1) = 0.40; mp 118–120 °C.

IR (KBr, neat): 3450, 3340, 2981, 1731, 1621, 1505, 1234, 1112, 1030, 857, 519 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.31 (s, 1 H), 7.13 (bs, 2 H), 6.98 (s, 1 H), 4.43 (q, J = 7.2 Hz, 2 H), 4.34 (q, J = 7.1 Hz, 2 H), 4.00 (s, 3 H), 3.96 (s, 3 H), 1.41 (t, J = 7.2 Hz, 3 H), 1.36 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 168.5, 167.2, 153.8, 153.2, 151.9, 149.5, 144.0, 112.0, 108.8, 100.3, 98.0, 62.0, 61.3, 56.3, 56.2, 14.18, 14.15.

HRMS (ESI): m/z [M + H]+ calcd for C17H21N2O6: 349.1394; found: 349.1390.


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Dimethyl 4-Amino-7-chloroquinoline-2,3-dicarboxylate (3ib)

Off-white solid; yield: 100 mg (85%); Rf (hexane/EtOAc, 3:1) = 0.40; mp 193–195 °C.

IR (KBr, neat): 3373, 3152, 2941, 1749, 1685, 1603, 1432, 1232, 1105, 911, 794, 557 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.77–7.75 (m, 1 H), 7.49–7.47 (m, 1 H), 7.29 (bs, 2 H), 4.01 (s, 3 H), 3.91 (s, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 168.3, 167.4, 154.6, 154.1, 148.3, 138.4, 129.6, 127.6, 122.4, 116.4, 99.0, 53.1, 52.6.

HRMS (ESI): m/z [M + H]+ calcd for C13H12ClN2O4: 295.0480; found: 295.0479.


#

Ethyl 4-Amino-2-phenylquinoline-3-carboxylate (3ac)

Off-white solid; yield: 72 mg (62%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 167–169 °C.

IR (KBr, neat): 3407, 3166, 2970, 1679, 1618, 1544, 1240, 1167, 1078, 767, 573 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 8.3 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 7.53 (d, J = 6.4 Hz, 2 H), 7.47 (t, J = 7.7 Hz, 1 H), 7.42–7.37 (m, 3 H), 6.75 (bs, 2 H), 3.95 (q, J = 7.1 Hz, 2 H), 0.74 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.8, 160.7, 153.0, 147.8, 143.5, 131.5, 130.3, 128.3, 128.2, 128.1, 125.7, 120.8, 117.2, 103.2, 60.8, 13.3.

HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O2: 293.1285; found: 293.1282.


#

Ethyl 4-Amino-2-(4-chlorophenyl)quinoline-3-carboxylate (3ad)

Off-white solid; yield: 83 mg (64%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 184–186 °C.

IR (KBr, neat): 3407, 3164, 2980, 1680, 1614, 1544, 1237, 1089, 1016, 769, 598 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.99 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.69 (t, J = 7.7 Hz, 1 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 2 H), 6.85 (bs, 2 H), 3.98 (q, J = 7.1 Hz, 2 H), 0.81 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (150 MHz, CDCl3): δ = 169.5, 159.6, 153.2, 147.7, 142.2, 134.0, 131.6, 130.2, 129.6, 128.2, 125.8, 120.8, 117.2, 102.6, 60.9, 13.4.

HRMS (ESI): m/z [M + H]+ calcd for C18H16ClN2O2: 327.0895; found: 327.0898.


#

Ethyl 4-Amino-2-(4-bromophenyl)quinoline-3-carboxylate (3ae)

Off-white solid; yield: 91 mg (61%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 153–155 °C.

IR (KBr, neat): 3406, 3164, 2980, 1678, 1616, 1542, 1236, 1068, 1011, 768, 585 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.00 (d, J = 8.4 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 2 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 2 H), 6.85 (bs, 2 H), 3.98 (q, J = 7.2 Hz, 2 H), 0.82 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.4, 159.6, 153.3, 147.7, 142.6, 131.7, 131.2, 130.2, 130.0, 125.8, 122.2, 120.8, 117.2, 102.6, 60.9, 13.4.

HRMS (ESI): m/z [M + H]+ calcd for C18H16BrN2O2: 371.0390; found: 371.0338.


#

Ethyl 4-Amino-2-(4-fluorophenyl)quinoline-3-carboxylate (3af)

Off-white solid; yield: 88 mg (71%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 215–217 °C.

IR (KBr, neat): 3405, 3166, 2982, 1679, 1618, 1546, 1219, 1155, 1080, 768, 557 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.01 (d, J = 8.4 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.72–7.69 (m, 1 H), 7.53–7.50 (m, 2 H), 7.48–7.44 (m, 1 H), 7.10 (t, J = 8.7 Hz, 2 H), 6.79 (bs, 2 H), 3.98 (q, J = 7.1 Hz, 2 H), 0.82 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.6, 163.0 (d, J = 245.3 Hz), 159.6, 153.1, 147.7, 139.7 (d, J = 3.2 Hz), 131.6, 130.2, 130.1 (d, J = 8.11 Hz), 125.7, 120.8, 117.2, 115.1 (d, J = 21.4 Hz), 102.9, 60.9, 13.5.

19F NMR (470 MHz, C6F6/CDCl3): δ = –117.65 (s, F).

HRMS (ESI): m/z [M + H]+ calcd for C18H16FN2O2: 311.1190; found: 311.1189.


#

Ethyl 4-Amino-2-(4-(methoxycarbonyl)phenyl)quinoline-3-carboxylate (3ag)

Off-white solid; yield: 76 mg (54%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 206–208 °C.

IR (KBr, neat): 3405, 3169, 2953, 1719, 1681, 1615, 1544, 1271, 1174, 1099, 771, 566 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 7.9 Hz, 2 H), 8.01 (d, J = 8.5 Hz, 1 H), 7.83 (d, J = 8.3 Hz, 1 H), 7.72 (t, J = 7.7 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 1 H), 6.89 (bs, 2 H), 3.97–3.92 (m, 5 H), 0.72 (t, J = 7.1 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.3, 167.3, 159.9, 153.4, 148.4, 147.8, 131.7, 130.4, 129.5, 129.4, 128.4, 126.0, 120.8, 117.3, 102.6, 60.9, 52.4, 13.4.

HRMS (ESI): m/z [M + H]+ calcd for C20H19N2O4: 351.1339; found: 351.1348.


#

Ethyl 4-Amino-2-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylate (3ah)

Off-white solid; yield: 80 mg (56%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 193–195 °C.

IR (KBr, neat): 3403, 3162, 2993, 1682, 1620, 1548, 1321, 1244, 1118, 1064, 772, 579 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.02 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.5 Hz, 1 H), 7.74 (t, J = 7.7 Hz, 1 H), 7.66 (dd, J = 23.4, 8.1 Hz, 4 H), 7.51 (t, J = 7.6 Hz, 1 H), 6.92 (bs, 2 H), 3.96 (q, J = 7.2 Hz, 2 H), 0.73 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.2, 159.6, 153.5, 147.8, 147.6, 131.8, 130.0 (q, J = 32.1 Hz), 128.6, 126.1, 125.1 (q, J = 3.8 Hz), 124.8 (q, J = 270.4 Hz), 120.8, 117.3, 102.43, 60.9, 13.2.

19F NMR (470 MHz, C6F6/CDCl3): δ = –65.58 (s, F).

HRMS (ESI): m/z [M + H]+ calcd for C19H16F3N2O2: 361.1158; found: 361.1110.


#

Ethyl 4-Amino-2-(p-tolyl)quinoline-3-carboxylate (3ai)

Off-white solid; yield: 82 mg (67%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 144–146 °C.

IR (KBr, neat): 3409, 3167, 2978, 1678, 1617, 1542, 1236, 1166, 1076, 770, 559 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.01 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8.3 Hz, 1 H), 7.70–7.66 (m, 1 H), 7.44–7.41 (m, 3 H), 7.20 (d, J = 7.7 Hz, 2 H), 6.70 (bs, 2 H), 3.97 (q, J = 7.1 Hz, 2 H), 2.38 (s, 3 H), 0.77 (t, J = 7.1 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.9, 160.7, 152.8, 147.8, 140.6, 137.9, 131.4, 130.2, 128.8, 128.2, 125.4, 120.8, 117.1, 103.3, 60.8, 21.5, 13.4.

HRMS (ESI): m/z [M + H]+ calcd for C19H18N2O2: 307.1441; found: 307.1451.


#

Ethyl 4-Amino-2-(3,5-dimethylphenyl)quinoline-3-carboxylate (3aj)

Off-white solid; yield: 83 mg (65%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 135–137 °C.

IR (KBr, neat): 3400, 3158, 2981, 1681, 1615, 1550, 1249, 1170, 1094, 765, 576 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.02 (d, J = 8.3 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.70–7.66 (m, 1 H ), 7.42 (t, J = 7.6 Hz, 1 H), 7.14 (s, 2 H), 6.99 (s, 1 H), 6.67 (bs, 2 H), 4.00–3.95 (m, 2 H), 2.33 (s, 6 H), 0.78 (t, J = 7.1 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.9, 161.0, 152.7, 147.9, 143.3, 137.5, 131.3, 130.3, 129.6, 126.1, 125.4, 120.8, 117.1, 103.4, 60.7, 21.5, 13.3.

HRMS (ESI): m/z [M + H]+ calcd for C20H21N2O2: 321.1598; found: 321.1589.


#

Ethyl 4-Amino-2-(o-tolyl)quinoline-3-carboxylate (3ak)

Off-white solid; yield: 78 mg (64%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 97–99 °C.

IR (KBr, neat): 3408, 3168, 2978, 1679, 1616, 1542, 1234, 1168, 1076, 775, 559 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.01 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.3 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.22–7.16 (m, 4 H), 7.02 (bs, 2 H), 3.90 (q, J = 7.2 Hz, 2 H), 2.21 (s, 3 H), 0.70 (t, J = 7.1 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.4, 161.3, 153.5, 147.8, 143.7, 135.2, 131.5, 130.2, 129.9, 127.8, 127.5, 125.6, 125.5, 120.8, 117.2, 103.3, 60.6, 19.8, 13.2.

HRMS (ESI): m/z [M + H]+ calcd for C19H19N2O2: 307.1441; found: 307.1447.


#

Ethyl 4-Amino-2-(4-methoxyphenyl)quinoline-3-carboxylate (3al)

Off-white solid; yield: 104 mg (81%); Rf (hexane/EtOAc, 7:3) = 0.50; mp 128–130 °C.

IR (KBr, neat): 3404, 3161, 2927, 1676, 1608, 1541, 1244, 1166, 1074, 771, 560 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.01 (dd, J = 8.5, 1.3 Hz, 1 H), 7.79 (dd, J = 8.4, 1.3 Hz, 1 H), 7.70–7.67 (m, 1 H), 7.50 (d, J = 8.8 Hz, 2 H), 7.45–7.42 (m, 1 H), 6.94 (d, J = 8.7 Hz, 2 H), 6.66 (bs, 2 H), 4.00 (q, J = 7.1 Hz, 2 H), 3.84 (s, 3 H), 0.83 (t, J = 7.1 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 170.0, 160.1, 160.0, 152.7, 147.8, 136.0, 131.4, 130.2, 129.7, 125.4, 120.8, 117.0, 113.7, 103.3, 60.9, 55.7, 13.6.

HRMS (ESI): m/z [M + H]+ calcd for C19H19N2O3: 323.1390; found: 323.1395.


#

Ethyl 4-Amino-7-bromo-2-(3-methoxyphenyl)quinoline-3-carboxylate (3cm)

Off-white solid; yield: 115 mg (72%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 103–105 °C.

IR (KBr, neat): 3458, 3350, 2980, 1685, 1613, 1552, 1251, 1102, 1043, 755, 565 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.97 (d, J = 2.1 Hz, 1 H), 7.86 (d, J = 8.9 Hz, 1 H), 7.72 (dd, J = 8.9, 2.1 Hz, 1 H), 7.28 (t, J = 7.86 Hz, 1 H), 7.11 (s, 1 H), 7.06–7.04 (m, 1 H), 6.92–6.90 (m, 1 H), 6.72 (bs, 2 H), 3.97 (q, J = 7.2 Hz, 2 H), 3.82 (s, 3 H), 0.78 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (150 MHz, CDCl3): δ = 169.4, 160.8, 159.6, 151.9, 146.4, 144.4, 134.6, 131.9, 129.2, 123.7, 120.9, 119.2, 118.6, 114.4, 113.3, 103.8, 61.0, 55.6, 13.4.

HRMS (ESI): m/z [M + H]+ calcd for C19H18BrN2O3: 401.0495; found: 401.0483.


#

Ethyl 4-Amino-2-(naphthalen-1-yl)quinoline-3-carboxylate (3an)

Off-white solid; yield: 68 mg (50%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 140–142 °C.

IR (KBr, neat): 3410, 3169, 2977, 1675, 1608, 1542, 1244, 1167, 1075, 769, 565 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.05 (d, J = 8.4 Hz, 1 H), 7.89–7.85 (m, 3 H), 7.74 (t, J = 7.6 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.51 (q, J = 7.1 Hz, 2 H), 7.46–7.42 (m, 2 H), 7.38–7.35 (m, 1 H), 7.06 (bs, 2 H), 3.68–3.61 (m, 1 H), 3.57–3.50 (m, 1 H), 0.19 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.2, 160.2, 153.5, 148.0, 141.9, 133.7, 132.1, 131.6, 130.5, 128.2, 127.8, 126.2, 125.9, 125.73, 125.71, 125.49, 125.46, 120.8, 117.5, 104.2, 60.4, 12.6.

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O2: 343.1441; found: 343.1458.


#

Ethyl 4-Amino-7-chloro-2-(thiophen-2-yl)quinoline-3-carboxylate (3io)

Off-white solid; yield: 86 mg (65%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 121–123 °C.

IR (KBr, neat): 3471, 3367, 2978, 1686, 1606, 1554, 1437, 1241, 1096, 788, 707 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.63 (d, J = 8.9 Hz, 1 H), 7.40 (d, J = 5.0 Hz, 1 H), 7.30 (dd, J = 8.8, 2.1 Hz, 1 H), 7.18 (d, J = 3.6 Hz, 1 H), 7.05 (t, J = 4.4 Hz, 1 H), 6.47 (bs, 2 H), 4.12 (q, J = 7.1 Hz, 2 H), 0.99 (t, J = 7.1 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.4, 154.1, 152.0, 148.5, 144.8, 137.4, 129.0, 127.7, 127.3, 127.2, 126.2, 122.3, 115.6, 103.9, 61.3, 13.6.

HRMS (ESI): m/z [M + H]+ calcd for C16H14ClN2O2S: 333.0459; found: 333.0450.


#

Ethyl 4-Amino-7-methyl-2-(trifluoromethyl)quinoline-3-carboxylate (3gp)

Off-white solid; yield: 103 mg (87%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 142–144 °C.

IR (KBr, neat): 3478, 3367, 2987, 1696, 1619, 1454, 1259, 1182, 1018, 978, 796 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.81 (s, 1 H), 7.66 (d, J = 8.6 Hz, 1 H), 7.35 (dd, J = 8.5, 2.2 Hz, 1 H), 6.60 (bs, 2 H), 4.40 (q, J = 7.1 Hz, 2 H), 2.50 (d, J = 2.1 Hz, 3 H), 1.39 (t, J = 7.2 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 167.8, 152.8, 147.0 (q, J = 33.3 Hz), 146.6, 142.7, 130.1 (d, J = 2.7 Hz), 129.7, 121.8 (q, J = 274.4 Hz), 120.5, 116.1, 101.4, 62.1, 21.8, 13.9.

19F NMR (470 MHz, C6F6/CDCl3): δ = –66.38 (s, F).

HRMS (ESI): m/z [M + H]+ calcd for C14H14F3N2O2: 299.1002; found: 299.1005.


#

Ethyl 4-Amino-2-butyl-5-fluoroquinoline-3-carboxylate (3dq)

Yellow oil; yield: 50 mg (43%); Rf (hexane/EtOAc, 9:1) = 0.30.

IR (KBr, neat): 3468, 3338, 2985, 1691, 1619, 1459, 1259, 1152, 1040, 796 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.65 (d, J = 8.4 Hz, 1 H), 7.52 (q, J = 8.0 Hz, 1 H), 7.43 (bs, 2 H), 6.99 (dd, J = 14.2, 7.8 Hz, 1 H), 4.41 (q, J = 7.1 Hz, 2 H), 3.09–3.06 (m, 2 H), 1.72–1.66 (m, 2 H), 1.45–1.39 (m, 5 H), 0.94 (t, J = 7.3 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.4, 164.3, 160.5 (d, J = 251.0 Hz), 153.6 (d, J = 3.1 Hz), 149.9, 130.8 (d, J = 11.8 Hz), 125.4 (d, J = 3.4 Hz), 110.0 (d, J = 24.1 Hz), 107.9 (d, J = 6.4 Hz), 103.1 (d, J = 1.9 Hz), 61.3, 39.8, 32.6, 23.4, 14.4, 14.3.

19F NMR (470 MHz, C6F6/CDCl3): δ = –118.03 (s, F).

HRMS (ESI): m/z [M + H]+ calcd for C16H20FN2O2: 291.1503; found: 291.1502.


#

(4-Amino-2-phenylquinolin-3-yl)(phenyl)methanone (3ar)

Light yellow solid; yield: 74 mg (57%); Rf (hexane/EtOAc, 4:1) = 0.30; mp 222–224 °C.

IR (KBr, neat): 3464, 3364, 3055, 1612, 1547, 1256, 762, 695 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.11 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.2 Hz, 1 H), 7.75 (t, J = 7.7 Hz, 1 H), 7.52–7.48 (m, 3 H), 7.39 (d, J = 7.6 Hz, 2 H), 7.21 (t, J = 7.4 Hz, 1 H), 7.13–7.07 (m, 5 H), 6.43 (s, 2 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 199.7, 160.2, 151.6, 148.3, 141.9, 140.2, 132.2, 131.4, 130.4, 129.9, 129.4, 128.7, 128.3, 128.0, 125.7, 121.0, 117.3, 111.0.

HRMS (ESI): m/z [M + H]+ calcd for C22H17N2O: 325.1336; found: 325.1331.


#

(4-Amino-6,7-dimethoxy-2-phenylquinolin-3-yl)(phenyl)methanone (3hr)

Light yellow solid; yield: 91 mg (59%); Rf (hexane/EtOAc, 2:1) = 0.30; mp 220–222 °C.

IR (KBr, neat): 3459, 3370, 2933, 1619, 1503, 1232, 1001, 919, 728 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.47 (s, 1 H), 7.44 (d, J = 7.3 Hz, 2 H), 7.38 (d, J = 7.7 Hz, 2 H), 7.20 (t, J = 7.4 Hz, 1 H), 7.11–7.05 (m, 6 H), 6.32 (s, 2 H), 4.03 (s, 3 H), 4.00 (s, 3 H).

13C{1H} NMR (150 MHz, CDCl3): δ = 199.8, 158.5, 153.8, 150.6, 149.2, 145.0, 141.5, 140.4, 132.1, 129.9, 129.4, 128.5, 128.2, 127.9, 111.3, 110.8, 109.2, 99.9, 56.5, 56.4.

HRMS (ESI): m/z [M + H]+ calcd for C24H21N2O3: 385.1547; found: 385.1536.


#

(4-Amino-7-methyl-2-(thiophen-2-yl)quinolin-3-yl)(phenyl)methanone (3gs)

Yellow solid; yield: 76 mg (55%); Rf (hexane/EtOAc, 5:1) = 0.30; mp 240–242 °C.

IR (KBr, neat): 3373, 3075, 3055, 1618, 1550, 1437, 1253, 886, 699 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.84 (s, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 7.7 Hz, 2 H), 7.30 (q, J = 7.5 Hz, 2 H), 7.20–7.15 (m, 3 H), 6.98 (d, J = 3.7 Hz, 1 H), 6.70 (s, 1 H), 6.23 (s, 2 H), 2.54 (s, 3 H).

13C{1H} NMR (150 MHz, CDCl3): δ = 198.9, 152.9, 151.1, 148.5, 144.8, 142.0, 139.6, 132.5, 130.3, 129.4, 129.3, 128.4, 128.2, 127.7, 127.4, 120.8, 115.0, 110.1, 21.9.

HRMS (ESI): m/z [M + H]+ calcd for C21H17N2OS: 345.1057; found: 345.1059.


#

Diethyl (Z)-2-((2-Cyanophenyl)amino)but-2-enedioate (3a′′)

Yellow oil; yield: 12 mg (10%); Rf (hexane/EtOAc, 9:1) = 0.30.

IR (KBr, neat): 3473, 3379, 2984, 2217, 1730, 1620, 1265, 1209, 1030, 756 cm–1.

1H NMR (500 MHz, CDCl3): δ = 9.90 (s, 1 H), 7.58 (d, J = 7.7 Hz, 1 H), 7.44 (t, J = 7.9 Hz, 1 H), 7.12 (t, J = 7.6 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 5.71 (s, 1 H), 4.26–4.17 (m, 4 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.15 (t, J = 7.1 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 169.1, 163.6, 145.8, 143.9, 133.4, 133.3, 123.9, 121.3, 116.7, 105.1, 99.5, 62.6, 60.8, 14.5, 13.9.

HRMS (ESI): m/z [M + H]+ calcd for C15H17N2O4: 289.1183; found: 289.1192.


#

Diethyl 4-Amino-6-(pyren-1-yl)quinoline-2,3-dicarboxylate (4) from 3ca

To an oven-dried Schlenk Tube containing a magnetic bar, 3ca (50 mg, 0.14 mmol, 1.0 equiv), pyrene-1-boronic acid (52 mg, 0.21 mmol, 1.5 equiv), anhyd K2CO3 (93 mg, 2.7 mmol, 5.0 equiv), Pd(PPh3)4 (8 mg, 0.007 mmol, 5 mol%), H2O (1.0 mL), EtOH (0.5 mL), and toluene (2.0 mL) were added. The reaction vessel was charged with N2 and sealed. The mixture was heated to 95 °C using and oil bath and stirred for 8 h. The mixture was filtered over a small pad of Celite and diluted with CH2Cl2 and H2O and extracted with CH2Cl2. The combined organic layers were washed with brine solution, dried (anhyd MgSO4), concentrated, and then the residue was purified by column chromatography (silica gel, EtOAc/hexane) to afford the desired product 4 as an off white solid; yield: 66 mg (96%); Rf (hexane/EtOAc, 5:1) = 0.40; mp 170–172 °C.

IR (KBr, neat): 3374, 3278, 2981, 1741, 1686, 1616, 1557, 1246, 1100, 1028, 844, 763, 553 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.16 (d, J = 7.6 Hz, 2 H), 8.09 (d, J = 8.1 Hz, 2 H), 8.05 (s, 2 H), 8.00–7.95 (m, 2 H), 7.94–7.92 (m, 2 H), 7.90–7.86 (m, 2 H), 7.35 (bs, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 4.33 (q, J = 7.1 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H), 1.36 (t, J = 7.1 Hz, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 168.2, 167.3, 154.5, 153.9, 146.6, 139.5, 136.3, 134.6, 131.6, 131.1, 131.0, 130.0, 128.6, 128.2, 127.9, 127.8, 127.5, 126.4, 125.6, 125.3, 125.0, 124.9, 124.8, 124.7, 122.8, 118.0, 98.9, 62.1, 61.5, 14.3, 14.2.

HRMS (ESI): m/z [M + H]+ calcd for C31H25N2O4: 489.1809; found: 489.1812.


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Dimethyl 8-Chloro-5,6-diphenyl-4H-benzo[de][1,6]naphthyridine-2,3-dicarboxylate (5) from 3ib

To an oven-dried pressure tube containing a magnetic bar was added 3ib (50 mg, 0.17 mmol, 1.0 equiv), diphenylacetylene (68 mg, 0.38 mmol, 2.0 equiv), [Ru(p-cymene)Cl2]2 (5 mg, 0.009 mmol, 5 mol%), Cu(OAc)2·H2O (3 mg, 0.017 mmol, 10 mol%), and t AmOH (2 mL). The mixture was stirred in an oil bath preheated at 120 °C for 24 h. After completion of the reaction (monitored by TLC analysis), the mixture was cooled to rt, filtered through a small plug of Celite and then washed with EtOAc (3 × 10 mL). The solvents were evaporated under reduced pressure and the crude material was purified using column chromatography (silica gel, n-hexane/EtOAc) to give 5 as a light green solid; yield: 50 mg (62%); Rf (hexane/EtOAc, 5:1) = 0.40; mp 208–210 °C.

IR (KBr, neat): 3172, 2946, 1754, 1671, 1593, 1441, 1255, 1213, 1081, 998, 701, 561 cm–1.

1H NMR (500 MHz, CDCl3): δ = 11.94 (s, 1 H), 7.58 (d, J = 1.9 Hz, 1 H), 7.41–7.35 (q, J = 6.0, 5.4 Hz, 3 H), 7.32–7.28 (m, 5 H), 7.20 (d, J = 7.0 Hz, 2 H), 6.85 (d, J = 1.8 Hz, 1 H), 4.00 (s, 3 H), 3.89 (s, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 168.0, 167.4, 155.9, 149.8, 148.7, 140.6, 138.4, 137.6, 134.8, 134.7, 131.0, 129.5, 129.4, 129.0, 128.9, 128.3, 122.2, 121.6, 118.4, 117.0, 94.2, 53.0, 52.5.

HRMS (ESI): m/z [M + H]+ calcd for C27H20ClN2O4: 471.1106; found: 471.1106.


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Dimethyl 4-Amino-7-chloro-1,2-dihydroquinoline-2,3-dicarboxylate (6) from 3ib

In an oven-dried round-bottomed flask, 3ib (50 mg, 0.17 mmol, 1.0 equiv) was taken with NiCl2·6H2O (81 mg, 0.34 mmol, 2.0 equiv) in MeOH and stirred at rt for 5 min. To this mixture NaBH4 (25 mg, 0.68 mmol, 4.0 equiv) was added in portions at 0 °C and the mixture was stirred at rt for 8 h. After completion of the reaction as confirmed by TLC, the solvent was removed under vacuum. The residue was extracted with EtOAc and the combined extracts were washed with brine solution. The organic layer was dried (anhyd Na2SO4­), concentrated, and the residue was purified by column chromatography (EtOAc­/hexane) to afford 6 as a light green gum; yield: 30 mg (60%); Rf (hexane/EtOAc, 4:1) = 0.40.

IR (KBr, neat): 3454, 3332, 2953, 1734, 1607, 1439, 1242, 1082, 792 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 8.3 Hz, 1 H), 6.76–6.72 (m, 2 H), 5.00 (d, J = 2.3 Hz, 1 H), 4.90 (s, 1 H), 3.77 (s, 3 H), 3.63 (s, 3 H).

13C{1H} NMR (125 MHz, CDCl3): δ = 174.0, 168.8, 150.2, 147.3, 137.9, 124.4, 119.3, 115.3, 115.0, 88.3, 52.73, 52.71, 51.4.

HRMS (ESI): m/z [M + H]+ calcd for C13H14ClN2O4: 297.0637; found: 297.0636.


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Experimental Procedure for the Gram-Scale Reaction

To a solution of 2-aminobenzonitrile (1a; 810 mg, 6.78 mmol, 1 equiv) and diethyl but-2-ynedioate (2a; 1.3 mL, 8.14 mmol, 1.2 equiv) in DCE (10 mL) was added FeCl3 (1.3 g, 8.14 mmol, 1.2 equiv). The reaction was then heated in an oil bath at 80 °C. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure and diluted with sat. NaHCO3 solution. Then the organic layer was extracted with EtOAc (3 × 30 mL). The combined organic extracts were further washed with brine solution 2–3 times, dried (Na2SO4), and concentrated on rotary evaporator. The crude was subjected to column chromatography (silica gel, hexane/EtOAc 3:2) to give 3aa as a green gum; yield: 1.4 g (73%).


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgement

Authors are grateful to Central Instrument Facility (CIF) and Department of Chemistry IIT Guwahati for analytical facilities.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2368-8500.
  • Supporting Information

Corresponding Author

Anil K. Saikia
Department of Chemistry, Indian Institute of Technology Guwahati
Guwahati 781039, Assam
India   

Publication History

Received: 11 June 2024

Accepted after revision: 17 July 2024

Accepted Manuscript online:
18 July 2024

Article published online:
08 August 2024

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Figure 1 Some biologically active molecules containing 4-aminoquinoline core
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Scheme 1 Literature reports
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Scheme 2 Substrate scope. Reagents and conditions: 1 (0.4 mmol), 2 (0.48 mmol), FeCl3 (0.48 mmol), DCE (2 mL).
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Scheme 3 Substrate scope. Reagents and conditions: 1 (0.4 mmol), 2 (0.48 mmol), FeCl3 (0.48 mmol), DCE (2 mL).
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Scheme 4 Control experiments
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Scheme 5 Plausible reaction mechanism
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Scheme 6 Post-synthetic modifications
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Scheme 7 Gram-scale experiment of the reaction