Domino 6-endo-dig Cyclization/Halogenation Reactions: Three-Component Synthesis of 1,3-Disubstituted 4-Haloimidazo[1,2-a:4,5-c′]dipyridines

Abstract

A regiocontrolled 6-endo-dig cyclization of 3-ethynylimidazo[1,2-a]pyridine-2-carbonitriles promoted by Grignard reagent in the presence of iodine has been developed. We optimized the reaction conditions to allow the straightforward synthesis of 1,3-disubstituted 4-iodoimidazo[1,2-a:4,5-c′]dipyridines. Finally, the reactivity of the 4-iodo position toward various metal-catalyzed coupling reactions (Suzuki–Miyaura­, Sonogashira, etc.) or cyanation was successfully evaluated.

Because of their interesting biological activities, imidazo[1,2-a]pyridine-derived compounds have been widely studied in various pharmacological areas over recent decades.[1] The development of new pathways to prepare and functionalize imidazo[1,2-a]pyridine analogues is still needed, especially for the synthesis of fused heterocyclic frameworks.[2] We have previously reported an efficient 6-endo-dig cyclization of a nitrile group with an alkyne group in the imidazo[1,2-a]pyridine series, leading to new imidazo[1,2-a:4,5-c′]dipyridine derivatives 4 (Scheme [1]).[3] The protocol requires mild conditions and allows the functionalization of positions 1 and 3 of tricyclic compounds 4 with alkyl or aryl groups. In the light of previous reports on anionic heterocyclization reactions,[4] we focused on the introduction of a halogen atom at the 4-position of the core in tandem with the cyclization step in a three-step one-pot sequence, with the aim of providing an additional functionalization position. Indeed the presence of a halogen atom allowed the rapid preparation of structural variants, in particular through metal-catalyzed coupling reactions.

This tricyclic imidazodipyridine system has rarely been reported. Only a few reports of its synthesis have been presented in the literature. The reported methods include classical­ heating of various highly fluorinated pyridines,[4] photocyclization of chlorinated aminopyridines,[5] and palladium-catalyzed iminoannulation on imidazo[1,2-a]pyridines.[6]

We report here a one-pot three-component synthesis of novel 1,3-disubstituted 4-haloimidazo[1,2-a:4,5-c′]dipyridines, as well as their reactivities toward the usual metal-catalyzed coupling reactions or cyanation.

The mechanism proposed for the 6-endo-dig cyclization of 3-ethynylimidazo[1,2-a]pyridine-2-carbonitriles 1 starts with the addition of a Grignard reagent (Scheme [1]). This mechanism probably involves attack by the imine salt intermediate 2 on the triple bond, leading to a magnesium reagent of type 3. On addition of aqueous acid, this intermediate is protonated to give the corresponding imidazo[1,2-a:4,5-c′]dipyridine derivative 4 with different substituents at positions 1 and 3. This heterocyclization is instantaneous at room temperature if methoxycyclopentane (CPME) is used as the solvent.[3] We therefore decided to test the reactivity of the magnesium intermediate 3 toward various halogenating agents.

Our first attempt was based on the method developed by Knochel and co-workers for the 3-alkynylbenzofuran 5 (Scheme [2]).[7]

In their protocol, Knochel and co-workers prepared the lithiated imine 6, an analogue of our intermediate 2, which after iodolysis provided 7 in 62% yield.

The heterocyclization reaction of 3-(cyclopropylethynyl)imidazo[1,2-a]pyridine-2-carbonitrile (1a; 1 equiv) in the presence of ethylmagnesium bromide (2 equiv) in methoxycyclopentane was chosen as a model reaction, on the basis of our previously developed protocol. (The use of less than two equivalents of the Grignard reagent decreases the yield.)[3] The mixture was stirred for 15 minutes under argon at room temperature and then various halogenating agents were added (Table [1]). In most cases, stirring was maintained overnight at room temperature.

Table 1 Optimization of the One-Pot Heterocyclization and Halogenation Reaction^a

Entry	Reagent	Temp (°C)	Time	Yieldc (%) of 8a	Yieldc (%) of 9
1	I2 (2 equiv)	r.t.	overnight	2	0
2	ICl (2 equiv)	r.t.	3 h	(6)	(24)
3	ICl (2 equiv)	r.t.	overnight	(15)	(44)
4	ICl (2 equiv)	r.t.b	overnight	(18)	(41)
5	ICl (2 equiv)	50	5 h	(16)	(18)
6	ICl (2 equiv)	50	overnight	(11)	(15)
7	NaI (1 equiv), I2 (3 equiv)	r.t.	overnight	(69)	(18)
8	NaI (1 equiv), ICl (2 equiv)	r.t.	overnight	(11)	(53)
9	ZnI2 (1 equiv), I2 (2 equiv)	r.t.	overnight	56	0
10	ZnI2 (1 equiv), I2 (3 equiv)	r.t.	overnight	71	0

^a Reaction conditions: 1a (1 mmol), EtMgBr (2 mmol), methoxycyclopentane (10 mL), 15 min, r.t., followed by addition of the halogenating agent.

^b ICl was added at –10 °C.

^c Isolated yield (¹H NMR yield).

We began our study with the addition of two equivalents of iodine to the reaction mixture, in accordance with Knochel’s method. After stirring the mixture overnight at room temperature, only traces of the desired iodinated compound 8a were observed in the NMR spectra (Table [1], entry 1). However, we noted the presence of 15% of the imine intermediate 10, along with 22% of ketone 11, formed by hydrolysis of 10 (Figure [1]). The structures of products 10 and 11 were in good agreement with the mechanism proposed in Scheme [1].

We then replaced the iodine with iodine monochloride (2 equiv). Surprisingly, after the mixture had been stirred for three hours at room temperature, we observed the formation of 24% of the brominated derivative 9 along with 6% of the iodinated product 8a (Table [1], entry 2). The only source of bromine available in the reaction mixture was the Grignard reactant. Up to 44% of the brominated product 9 was recovered after overnight stirring, together with 15% of the iodo compounds 8a (Table [1], entry 3).

We then decided to study the influence of the reaction temperature on the halogenation step, and we therefore cooled the mixture to –10 °C during the addition of the iodine monochloride. The mixture was then warmed to room temperature and stirred overnight. The major product was again the bromo compound 9, with an iodination/bromination ratio of 18:41 (Table [1], entry 4). The reaction was then performed at 50 °C for five hours or overnight (Table [1], entries 5 and 6, respectively). Extensive degradation was noted in both cases, with only about a 15% yield of each compound 8a and 9.

We then decided to combine sodium iodide (1 equiv) with diiodine or iodine monochloride, with the aim of inducing halogen exchange in bromo compound 9 to give the iodo compound 8a. In the presence of diiodine (3 equiv), the formation of iodo compound 8a was greatly enhanced (69% as estimated from the ¹H NMR spectrum), but 8a could not be isolated under these conditions because of the difficulties in separating the byproduct 9, present in 18% yield (Table [1], entry 7). As previously observed, in the presence of iodine monochloride (2 equiv), the bromination reaction predominated, leading to 53% bromo compound 9 along with 11% of the iodo compound 8a (Table [1], entry 8).

In a further attempt to introduce the iodine atom, we then decided to continue using iodine, adding zinc(II) iodide (1 equiv) to carbanion 3 to provide an iodozinc intermediate that would react with iodine (entries 9 and 10). Under these conditions, no brominated byproduct 9 was recovered, greatly facilitating the purification of the iodo compound 8a. By using two equivalents of iodine, we obtained the iodo compound in 56% yield (entry 9). This result was greatly improved by using three equivalents of iodine, yielding 71% of the expected compound 8a (entry 10). The structure of compound 8a was confirmed by X-ray crystal structure analysis (Figure [2]).

To confirm the origin of the bromine atom, we performed the reaction by using methylmagnesium iodide (2 equiv) and iodine monochloride (3 equiv) at 50 °C for five hours. Interestingly, when the reaction proceeded at room temperature overnight, 57% of 3-cyclopropyl-4-iodo-1-methylimidazo­[1,2-a:4,5-c′]dipyridine was recovered along with 15% of the chlorinated analogue. Because alkylmagnesium iodides are not always commercially available and are often more expensive than their bromide analogue, we proceeded to develop the domino 6-endo-dig cyclization/iodination reaction by using alkylmagnesium bromides.

Our optimized conditions were applied to various starting materials and organometallic reagents to explore the scope of the sequence (Table [2]). The reaction proved to be quite general, as both alkyl (entries 1, 3, and 4) or aryl (entry 2) Grignard reagents could be used. In the case of alkyl side-chains R³ (entries 1, 2, and 4), the yields were moderate to good (39–71%), considering that three new chemical bonds were created in a one-pot manner. With phenyl as the R³ substituent, the yield fell to 26%, which is consistent with our previous report.[3]

Table 2 6-Endo-dig Cyclization/Iodination Reactions of Yne Nitriles 1

Entry	R1	Substrate	R3	Product	Yielda (%)
1	Et	1a	c-Pr	8a	71
2	Ph	1b	Bu	8b	39
3	Me	1c	Ph	8c	26
4	Me	1a	c-Pr	8d	56

^a Yield of isolated compound.

Finally, we focused on the further functionalization at position 4. First, the reactivity of compounds 8a–d toward various metal-catalyzed reactions was evaluated (Table [3]). The Suzuki–Miyaura cross-coupling reaction of m-tolylboronic acid (1.2 equiv) was first attempted on 8a and 8c under the classical conditions [Pd(PPh₃)₄ (0.05 equiv), Na₂CO₃ (2.2 equiv), DME–H₂O, 100 °C, 1 h]. This reaction gave 12 in 98% yield from 8a and 13 in 80% yield from 8c (Table [3], entries 1 and 2, respectively). A Sonogashira coupling reaction of 8a was also effective, giving 14 with 50% yield [Reaction conditions (unoptimized): 4-TolC≡CH (3.3 equiv), CuI (0.09 equiv), Pd₂(dba)₃ (0.05 equiv), 1,4-dioxane–Et₃N, 120 °C, 5 h][3] (Table [3], entry 3). The iodinated compound 8a was also reactive toward copper-catalyzed cross-coupling with benzamide or thiophenol, giving 15 and 16 in 57% and 98% yields, respectively, under the previously described conditions (Table [3], entries 4 and 5, respectively).[8] Finally, a nitrile group was successfully introduced in the 4-position of compounds 8a and 8b by treatment with copper(I) cyanide (1.3 equiv) in N,N-dimethylformamide with microwave irradiation at 200 °C for 15 minutes, giving 90% and 94% yields, respectively, of the cyano derivatives 17 and 18 (Table [3], entries 6 and 7).

Table 3 Reactivity of the 4-Position toward Various Metal-Catalyzed Reactions

Entry	R1	R3	R4	Product	Yielda (%)
1b	Et	c-Pr	3-Tol	12	98
2b	Me	Ph	3-Tol	13	80
3c	Et	c-Pr	4-Tol-C≡C	14	50
4d	Et	c-Pr	NHBz	15	57
5e	Et	c-Pr	4-ClC6H4S	16	98
6f	Et	c-Pr	CN	17	90
7f	Ph	Bu	CN	18	94

^a Yield of isolated compound.

^b Reaction conditions: 3-TolB(OH)₂, Pd(PPh₃)₄, Na₂CO₃, DME–H₂O, 100 °C, 1 h.

^c 4-TolC≡CH, CuI, Pd₂(dba)₃, Et₃N, 1,4-dioxane, 120 °C, 5 h.

^d BzNH₂, CuI, K₃PO₄, (1R,2R)-N,N′-dimethylcyclohexane-1,2-diamine, toluene, 130 °C, 5 h.

^e 4-ClC₆H₄SH, CuI, K₂CO₃, HO(CH₂)₂OH–i-PrOH, 100 °C, 45 min.

^f CuCN, DMF, MW, 200 °C, 15 min.

In conclusion, we successfully developed an original three-step sequence for the synthesis of 1,3-disubstituted 4-haloimidazo[1,2-a:4,5-c′]dipyridines in a one-pot fashion. These molecules can easily be further functionalized to provide highly substituted tricycles through cross-coupling reactions.

All reagents were used directly as obtained from commercial sources. Melting points were determined on a capillary apparatus (Stuart Equipment, Stone, UK) and are uncorrected. IR spectra were recorded on a Bruker ALPHA-T FT-IR spectrometer equipped with an ATR crystal. NMR experiments were performed at 300 MHz (¹H) or 75 MHz (¹³C) on a Bruker-Avance 300 MHz spectrometer. Assignment of carbons denoted C* are interchangeable. Mass spectra were determined on a Hewlett Packard 5988A spectrometer or on a Shimadzu QP 2010 spectrometer by direct inlet at 70 eV. Compounds 1a–c were prepared according to a previously described procedure.[3]

Imidazo[1,2-a:4,5-c′]dipyridines 8a–d; General Procedure

A suspension of nitrile 1 (0.483 mmol) in methoxycyclopentane (5 mL) was introduced into a dry, single-necked, round-bottomed flask under argon. The suspension was vigorously stirred and Grignard reagent R¹MgBr (0.966 mmol) was added at r.t. The mixture was stirred magnetically under argon for 15 min, ZnI₂ (0.154 g, 0.483 mmol) was added, and the mixture was stirred at r.t. under argon for 5 h. I₂ (0.368 g, 1.449 mmol) was then added, and the suspension was stirred overnight under argon at r.t. The mixture was basified with 2 N aq NaOH (10 mL), extracted with EtOAc (10 mL), and washed with 5% aq Na₂S₂O₃ (10 mL). The organic layer was dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel).

3-Cyclopropyl-1-ethyl-4-iodoimidazo[1,2-a:4,5-c′]dipyridine (8a)

Eluent: CH₂Cl₂–MeOH (99.5:0.5); yellow solid; yield: 124 mg (0.34 mmol, 71%); mp 206 °C.

IR (neat): 3117, 2961, 2929, 1637, 1553, 1500, 1424, 1369, 1358, 1241, 903, 743, 730 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.99–1.06 (m, 2 H, CH₂ c-Pr), 1.12–1.18 (m, 2 H, CH₂ c-Pr), 1.42 (t, J = 7.5 Hz, 3 H, CH₃ Et), 2.64 (m, 1 H, CH c-Pr), 3.31 (q, J = 7.5 Hz, 2 H, CH₂ Et), 6.96 (td, J = 6.6, 1.2 Hz, 1 H, H-7), 7.50 (ddd, J = 9.3, 6.6, 1.2 Hz, 1 H, H-8), 7.78 (d, J = 9.3 Hz, 1 H, H-9), 9.95 (dt, J = 7.2, 0.9 Hz, 1 H, H-6).

¹³C NMR (75 MHz, CDCl₃): δ = 10.5 (2 C, CH₂ c-Pr), 12.7 (CH₃ Et), 20.1 (CH c-Pr), 26.5 (CH₂ Et), 73.0 (C-4), 110.4 (C-7), 118.7 (C-9), 126.3 (C-6), 130.7 (C-8), 132.8 (C-4a), 148.5 (C-9a), 153.3 (C-3), 155.4 (C-1); (C-10a was missing).

GC-MS (EI, 70 eV): m/z = 363 [M⁺].

Anal. Calcd for C₁₅H₁₄IN₃: C, 49.60; H, 3.89; I, 34.94; N, 11.57. Found: C, 49.51; H, 3.95; I, 34.87; N, 11.55.

3-Butyl-4-iodo-1-phenylimidazo[1,2-a:4,5-c′]dipyridine (8b)

Eluent: CH₂Cl₂; yellow solid; yield: 185 mg (0.43 mmol, 39%); mp 107 °C.

IR (neat): 2953, 2923, 2857, 1640, 1536, 1494, 1359, 745, 725, 691, 471, 418 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.02 (t, J = 7.5 Hz, 3 H, CH₃ Bu), 1.47–1.59 (m, 2 H, CH₂ Bu), 1.82–1.93 (m, 2 H, CH₂ Bu), 3.31 (t, J = 7.8 Hz, 2 H, CH₂ Bu), 6.90 (td, J = 6.6, 1.2 Hz, 1 H, H-7), 7.42–7.49 (m, 2 H, CH Ph & H-8), 7.54–7.59 (m, 2 H, 2 CH Ph), 7.75 (dt, J = 9.3, 1.2 Hz, 1 H, H-9), 8.66–8.70 (m, 2 H, 2 CH Ph), 9.95 (dt, J = 7.2, 1.2 Hz, 1 H, H-6).

¹³C NMR (75 MHz, CDCl₃): δ = 14.2 (CH₃ Bu), 22.7 (CH₂ Bu), 31.9 (CH₂ Bu), 40.6 (CH₂ Bu), 73.7 (C-4), 110.0 (C-7), 119.0 (C-9), 126.3 (C-6), 128.5 (2 C, CH Ph), 129.3 (CH Ph), 129.7 (2 C, CH Ph), 130.4 (C-8), 134.5 (C-4a), 137.4 (Cq Ph), 138.4 (C-10a), 148.5 (C-1), 149.4 (C-9a), 154.1 (C-3).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₉IN₃: 428.06182; found: 428.06046.

4-Iodo-1-methyl-3-phenylimidazo[1,2-a:4,5-c′]dipyridine (8c)

Eluent: CH₂Cl₂–MeOH (99:1); pale-brown solid; yield: 180 mg (0.47 mmol, 26%); mp 226 °C.

IR (neat): 3051, 1640, 1414, 1258, 747, 731, 697 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 3.03 (s, 3 H, CH₃), 6.98 (td, J = 7.5, 1.2 Hz, 1 H, H-7), 7.40–7.57 (m, 6 H, 5 CH Ph & H-8), 7.81 (dt, J = 9.3, 1.2 Hz, 1 H, H-9), 9.95 (dt, J = 7.2, 1.2 Hz, 1 H, H-6).

¹³C NMR (75 MHz, CDCl₃): δ = 20.1 (CH₃), 71.9 (C-4), 110.4 (C-7), 118.9 (C-9), 126.5 (C-6), 128.2 (2 C, CH Ph), 128.3 (CH Ph), 130.0 (2 C, CH Ph), 130.9 (C-8), 133.1 (C-4a), 139.9 (C-10a), 143.1 (Cq Ph), 149.5 (C-9a), 151.5 (C-1), 153.5 (C-3).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₃IN₃: 386.01486; found: 386.01323.

3-Cyclopropyl-4-iodo-1-methylimidazo[1,2-a:4,5-c′]dipyridine (8d)

Eluent: CH₂Cl₂–MeOH (99:1); pale-brown solid; yield: 280 mg (0.80 mmol, 56%); mp 215 °C.

IR (neat): 3000, 1636, 1369, 1254, 970, 899, 742, 728, 416 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.00–1.08 (m, 2 H, CH₂ c-Pr), 1.10–1.14 (m, 2 H, CH₂ c-Pr), 2.55–2.63 (m, 1 H, CH c-Pr), 2.88 (s, 3 H, CH₃), 6.90 (td, J = 6.9, 1.5 Hz, 1 H, H-7), 7.44 (ddd, J = 9.3, 6.6, 1.2 Hz, 1 H, H-8), 7.70 (dt, J = 9.3, 1.2 Hz, 1 H, H-9), 9.89 (dt, J = 7.5, 0.9 Hz, 1 H, H-6).

¹³C NMR (75 MHz, CDCl₃): δ = 10.3 (2 C, CH₂ c-Pr), 20.1 (CH c-Pr), 20.2 (CH₃), 73.2 (C-4), 110.1 (C-7), 118.8 (C-9), 126.3 (C-6), 130.3 (C-8), 132.7 (C-4a), 139.3 (C-10a), 148.8 (C-9a), 151.1 (C-1), 153.0 (C-3).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₃IN₃: 350.01486; found: 350.01366.

4-(3-Tolyl)imidazo[1,2-a:4,5-c′]dipyridines 12 and 13; General Procedure

The appropriate iodo compound 8 (0.22 mmol), 3-tolylboronic acid (36 mg, 0.27 mmol), Na₂CO₃ (52 mg, 0.49 mmol), and (Ph₃P)₄Pd (13 mg, 0.01 mmol) were introduced into a screw-cap test tube. A Teflon septum was attached to the tube, which was then evacuated and backfilled with argon. The evacuating/backfilling sequence was repeated twice. DME (1 mL) and H₂O (0.5 mL) were subsequently added by syringe under argon. The test tube was sealed with a screw-cap, and the mixture was stirred magnetically at 100 °C for 1 h then cooled. CH₂Cl₂ was added, and the solution was washed with H₂O. The organic layers were dried (MgSO₄), filtered, and concentrated under reduced pressure. Finally, the residue was purified by chromatography (silica gel).

3-Cyclopropyl-1-ethyl-4-(3-tolyl)imidazo[1,2-a:4,5-c′]dipyridine (12)

Eluent: CH₂Cl₂ (100%) to CH₂Cl₂–MeOH (99:1); off-white solid; yield: 88 mg (0.27 mmol, 98%); mp 155 °C.

IR (neat): 2964, 2927, 1638, 1576, 1377, 1357, 926, 749, 540, 424 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.74–084 (m, 2 H, CH₂ c-Pr), 1.13–1.23 (m, 2 H, CH₂ c-Pr), 1.47 (t, J = 7.5 Hz, 3 H, CH₃ Et), 1.85–1.93 (m, 1 H, CH c-Pr), 2.45 (s, 3 H, CH₃ 3-Tol), 3.36 (q, J = 7.5 Hz, 2 H, CH₂ Et), 6.44 (t, J = 6.9 Hz, 1 H, H-7), 7.25–7.36 (m, 5 H, 3 CH 3-Tol, H-8 & H-6), 7.46 (t, J = 7.5 Hz, 1 H, 1 CH 3-Tol), 7.67 (d, J = 9.3 Hz, 1 H, H-9).

¹³C NMR (75 MHz, CDCl₃): δ = 9.8 (CH₂ c-Pr), 9.9 (CH₂ c-Pr), 12.9 (CH₃ Et), 14.0 (CH c-Pr), 21.7 (CH₃ 3-Tol), 26.9 (CH₂ Et), 110.5 (C-7), 118.5 (C-4), 118.7 (C-9), 127.2 (C-6), 127.4 (CH 3-Tol), 129.2 (CH 3-Tol), 129.3 (CH 3-Tol), 129.5 (C-8), 130.9 (CH 3-Tol), 131.2 (C-4a), 135.3 (Cq 3-Tol), 136.8 (C-10a), 139.2 (Cq 3-Tol), 148.3 (C-9a), 149.7 (C-3), 155.1 (C-1).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₂N₃: 328.18082; found: 328.17963.

1-Methyl-3-phenyl-4-(3-tolyl)imidazo[1,2-a:4,5-c′]dipyridine (13)

Eluent: CH₂Cl₂ (100%) to CH₂Cl₂–MeOH (99:1); yellow solid; yield: 87 mg (0.25 mmol, 80%); mp 215 °C.

IR (neat): 2918, 1639, 1356, 1139, 756, 695, 431 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 2.35 (s, 3 H, CH₃ 3-Tol), 3.15 (s, 3 H, C-1CH₃), 6.53 (td, J = 7.2, 1.2 Hz, 1 H, H-7), 7.12–7.44 (m, 11 H, 4CH 3-Tol, 5CH Ph, H-8 & H-6), 7.75 (d, J = 9.3 Hz, 1 H, H-9).

¹³C NMR (75 MHz, CDCl₃): δ = 20.5 (C-1 CH₃), 21.6 (CH₃ 3-Tol), 110.9 (C-7), 118.8 (C-9), 119.9 (C-4), 127.0 (CH 3-Tol), 127.6 (C-6), 127.7 (2 C, CH Ph), 127.8 (CH 3-Tol), 129.0 (CH 3-Tol), 129.2 (CH 3-Tol), 130.2 (C-8), 130.4 (2 C, CH Ph), 131.2 (CH Ph), 131.4 (C-4a), 134.8 (Cq 3-Tol), 138.8 (C-10a), 138.9 (Cq 3-Tol), 140.1 (Cq Ph), 147.8 (C-3), 149.3 (C-9a), 151.1 (C-1).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₀N₃: 350.16517; found: 350.16399.

3-Cyclopropyl-1-ethyl-4-(4-tolylethynyl)imidazo[1,2-a:4,5-c′]di­pyridine (14)

Iodo compound 8a (80 mg, 0.22 mmol), CuI (4 mg, 0.02 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were introduced into a screw-cap test tube. A Teflon septum was attached to the tube, which was then evacuated and backfilled with argon. This sequence was repeated twice. Then, 4-TolCH≡CH (85 mg, 0.73 mmol), 1,4-dioxane (240 µL), and Et₃N (240 µL) were added by syringe under argon, and the mixture was stirred magnetically at 120 °C for 5 h. The suspension was diluted with sat. aq NH₄Cl and extracted with CH₂Cl₂. The organic layers were dried (MgSO₄), filtered, and concentrated under vacuum. The residue was purified by column chromatography [silica gel, PE–Et₂O (50:50 to 0:100)] to give a yellow solid; yield: 39 mg (50%); mp 148 °C.

IR (neat): 3077, 2962, 2924, 2209, 1638, 1567, 1509, 1408, 1386, 1359, 1346, 1276, 1166, 1052, 928, 810, 746, 736 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.04–1.11 (m, 2 H, CH₂ c-Pr), 1.25–1.31 (m, 2 H, CH₂ c-Pr), 1.42 (t, J = 7.5 Hz, 3 H, CH₃ Et), 2.41 (s, 3 H, CH₃ 4-Tol), 2.83 (m, 1 H, CH c-Pr), 3.31 (q, J = 7.5 Hz, 2 H, CH₂ Et), 6.81 (td, J = 6.6, 0.9 Hz, 1 H, H-7), 7.23 (d, J = 8.1 Hz, 2 H, 2 CH 4-Tol), 7.40 (ddd, J = 9.3, 6.6, 1.5 Hz, 1 H, H-8), 7.53 (d, J = 8.1 Hz, 2 H, 2 CH 4-Tol), 7.69 (dt, J = 9.3, 0.9 Hz, 1 H, H-9), 9.42 (dt, J = 6.6, 1.5 Hz, 1 H, H-6).

¹³C NMR (75 MHz, CDCl₃): δ = 10.2 (2 C, CH₂ c-Pr), 12.7 (CH₃ Et), 15.1 (CH c-Pr), 21.7 (CH₃ 4-Tol), 27.1 (CH₂ Et), 83.0 (C≡C), 99.6 (C≡C), 100.0 (C-4), 110.9 (C-7), 118.5 (C-9), 119.8 (Cq 4-Tol), 126.9 (C-6), 129.5 (2 C, CH 4-Tol), 130.0 (C-8), 131.4 (2 C, CH 4-Tol), 136.6 (C-10a), 139.4 (Cq 4-Tol), 148.2 (C-9a), 155.4 (C-3), 156.0 (C-1). (C-4a is missing).

GC-MS (EI, 70 eV): m/z = 351 [M⁺].

Anal. Calcd for C₂₄H₂₁N₃: C, 82.02; H, 6.02; N, 11.96. Found: C, 82.11; H, 6.07; N, 11.89.

N-(3-Cyclopropyl-1-ethylimidazo[1,2-a:4,5-c′]dipyridin-4-yl)benzamide (15)

Iodo compound 8a (80 mg, 0.22 mmol), BzNH₂ (53 mg, 0.44 mmol), CuI (4 mg, 0.02 mmol), and K₃PO₄ (94 mg, 0.44 mmol) were introduced into a microwave vial. The tube was evacuated and backfilled with argon three times. Then, (1R,2R)-N,N′-dimethylcyclohexane-1,2-diamine (3 mg, 0.02 mmol) and toluene (240 µL) were added by syringe under argon, and the mixture was stirred magnetically at 130 °C for 5 h. The solvent was evaporated to dryness, and the residue was purified by column chromatography (neutral alumina, CH₂Cl₂) to give a white solid; yield: 45 mg (57%); mp 280 °C.

IR (neat): 3003, 2962, 2928, 2315, 1635, 1579, 1479, 1449, 1396, 1271, 1057, 932, 745, 731, 716 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 0.90–1.09 (m, 4 H, 2 CH₂ c-Pr), 1.36 (t, J = 7.5 Hz, 3 H, CH₃ Et), 2.36 (m, 1 H, CH c-Pr), 3.21 (q, J = 7.5 Hz, 2 H, CH₂ Et), 7.00 (t, J = 6.6 Hz, 1 H, H-7), 7.60–7.70 (m, 4 H, 3 CH Ph & H-8), 7.78 (d, J = 9.0 Hz, 1 H, H-9), 8.17 (d, J = 7.2 Hz, 2 H, 2 CH Ph), 8.50 (d, J = 6.6 Hz, 1 H, H-6), 10.82 (br s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 9.2 (CH₂ c-Pr), 9.4 (CH₂ c-Pr), 11.7 (CH c-Pr), 12.7 (CH₃ Et), 26.2 (CH₂ Et), 112.0 (C-7), 115.9 (C-4), 117.7 (C-9), 127.6 (C-6), 128.0 (CH₂ Ph), 128.8 (CH₂ Ph), 129.7 (Cq Ph*), 131.2 (C-4a*), 132.3 (CH Ph*), 133.2 (C-8*), 136.7 (C-10a), 147.6 (C-9a), 148.4 (C-3), 153.2 (C-1), 166.8 (CO).

GC-MS (EI, 70 eV): m/z = 356 [M⁺].

Anal. Calcd for C₂₂H₂₀N₄O: C, 74.14; H, 5.66; N, 15.72; O, 4.49. Found: C, 74.09; H, 5.75; N, 15.60; O, 4.56.

4-[(4-Chlorophenyl)sulfanyl]-3-cyclopropyl-1-ethylimidazo[1,2-a:4,5-c′]dipyridine (16)

Iodo compound 8a (100 mg, 0.28 mmol), 4-ClC₆H₄SH (60 mg, 0.42 mmol), CuI (3 mg, 0.01 mmol), and K₂CO₃ (80 mg, 0.58 mmol) were introduced into a microwave vial. The tube was evacuated and backfilled with argon. This sequence was repeated twice. HO(CH₂)₂OH (31 µL, 0.55 mmol) and i-PrOH (300 µL) were added by syringe under argon, and the mixture was stirred magnetically at 100 °C for 45 min in a microwave apparatus (CEM Discover). The suspension was diluted with EtOAc and washed with 10 M aq NaOH. The organic layers were dried (MgSO₄), filtered, and concentrated under reduced pressure. Finally, the residue was purified by column chromatography (silica gel, CH₂Cl₂) to give an off-white solid; yield: 103 mg (98%); mp 173 °C.

IR (neat): 3003, 2966, 2927, 1640, 1562, 1474, 1422, 1356, 1086, 1006, 920, 807, 751 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.92–0.99 (m, 2 H, CH₂ c-Pr), 1.18–1.24 (m, 2 H, CH₂ c-Pr), 1.46 (t, J = 7.5 Hz, 3 H, CH₃ Et), 2.93 (m, 1 H, CH c-Pr), 3.36 (q, J = 7.5 Hz, 2 H, CH₂ Et), 6.73 (t, J = 6.6 Hz, 1 H, H-7), 6.97 (d, J = 8.7 Hz, 2 H, 2 CH Ph), 7.17 (d, J = 8.7 Hz, 2 H, 2 CH Ph), 7.38 (ddd, J = 9.3, 6.6, 1.2 Hz, 1 H, H-8), 7.70 (d, J = 9.3 Hz, 1 H, H-9), 9.53 (d, J = 6.6 Hz, 1 H, H-6).

¹³C NMR (75 MHz, CDCl₃): δ = 10.7 (2 C, CH₂ c-Pr), 12.5 (CH₃ Et), 14.0 (CH c-Pr), 27.1 (CH₂ Et), 105.6 (C-4), 111.4 (C-7), 118.7 (C-9), 127.3 (2 C, CH Ph), 128.1 (C-6), 129.7 (2 C, CH Ph), 130.1 (C-8), 131.8 (Cq Ph), 133.6 (C-4a), 135.1 (Cq Ph), 137.6 (C-10a), 148.4 (C-9a), 158.0 (C-3), 158.3 (C-1).

GC-MS (EI, 70 eV): m/z = 379 [M⁺].

Anal. Calcd for C₂₁H₁₈ClN₃S: C, 66.39; H, 4.78; Cl, 9.33; N, 11.06; S, 8.44. Found: C, 66.47; H, 4.63; Cl, 9.39; N, 11.12; S, 8.59.

Imidazo[1,2-a:4,5-c′]dipyridine-4-carbonitriles 17 and 18; General Procedure

The appropriate iodo compound 8 (0.28 mmol) and CuCN (32 mg, 0.36 mmol) were introduced into a microwave vial. The tube was evacuated and backfilled with argon. The evacuating/backfilling sequence was repeated twice. DMF (200 µL) was added by syringe under argon, and the mixture was stirred magnetically at 200 °C for 15 min in a microwave apparatus (CEM Discover). The solvent was removed under reduced pressure, and the residue was diluted with CH₂Cl₂ and washed with 10% aq NH₃ (3 ×). The organic layers were then dried (MgSO₄), filtered, and concentrated under vacuum. The residue was finally purified by column chromatography (silica gel).

3-Cyclopropyl-1-ethylimidazo[1,2-a:4,5-c′]dipyridine-4-carbonitrile (17)

Eluent: CH₂Cl₂; brown solid; yield: 65 mg (0.25 mmol, 90%); mp 159 °C.

IR (neat): 3037, 2965, 2930, 2217, 1642, 1572, 1448, 1431, 1407, 1359, 1274, 1149, 1055, 926, 752 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.11–1.18 (m, 2 H, CH₂ c-Pr), 1.28–1.34 (m, 2 H, CH₂ c-Pr), 1.40 (t, J = 7.5 Hz, 3 H, CH₃ Et), 2.60 (m, 1 H, CH c-Pr), 3.32 (q, J = 7.5 Hz, 2 H, CH₂ Et), 6.96 (td, J = 6.9, 0.9 Hz, 1 H, H-7), 7.49 (ddd, J = 9.6, 6.9, 1.2 Hz, 1 H, H-8), 7.74 (dd, J = 9.6, 0.9 Hz, 1 H, H-9), 9.04 (dt, J = 6.9, 1.2 Hz, 1 H, H-6).

¹³C NMR (75 MHz, CDCl₃): δ = 11.4 (2 C, CH₂ c-Pr), 12.3 (CH₃ Et), 16.2 (CH c-Pr), 27.5 (CH₂ Et), 88.6 (C-4), 112.6 (C-7), 116.3 (C≡N), 118.9 (C-9), 126.0 (C-6), 130.9 (C-4a), 131.1 (C-8), 136.2 (C-10a), 148.4 (C-9a), 158.7 (C-3), 161.4 (C-1).

GC-MS (EI, 70 eV): m/z = 262 [M⁺].

Anal. Calcd for C₁₆H₁₄N₄: C, 73.26; H, 5.38; N, 21.36. Found: C, 73.18; H, 5.43; N, 21.40.

3-Butyl-1-phenylimidazo[1,2-a:4,5-c′]dipyridine-4-carbonitrile (18)

Eluent: CH₂Cl₂; yellow solid; yield: 30 mg (0.092 mmol, 94%); mp 172 °C.

IR (neat): 2958, 2928, 2857, 2216, 1638, 1554, 1354, 754 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.01 (t, J = 7.5 Hz, 3 H, CH₃ Bu), 1.44–1.57 (m, 2 H, CH₂ Bu), 1.89–1.99 (m, 2 H, CH₂ Bu), 3.27 (t, J = 7.5 Hz, 2 H, CH₂ Bu), 6.97 (td, J = 7.2, 1.2 Hz, 1 H, H-7), 7.48–7.61 (m, 4 H, 3 CH Ph & H-8), 7.79 (dt, J = 9.6, 1.2 Hz, 1 H, H-9), 8.80–8.83 (m, 2 H, 2 CH Ph), 9.11 (dt, J = 6.9, 0.9 Hz, 1 H, H-6).

¹³C NMR (75 MHz, CDCl₃): δ = 14.1 (CH₃ Bu), 22.6 (CH₂ Bu), 32.2 (CH₂ Bu), 36.8 (CH₂ Bu), 89.9 (C-4), 112.5 (C-7), 116.0 (C≡N), 119.2 (C-9), 125.9 (C-6), 128.7 (2 C, CH Ph), 130.3 (2 C, CH Ph), 130.6 (C-8), 131.2 (CH Ph), 133.1 (C-4a), 136.6 (Cq Ph*), 136.9 (C-10a*), 149.3 (C-9a), 152.4 (C-1), 157.7 (C-3).

GC-MS (EI, 70 eV): m/z = 326.1 [M⁺].

Anal. Calcd for C₂₁H₁₈N₄: C, 77.28; H, 5.56; N, 17.17. Found: C, 77.21; H, 5.49; N, 17.24.

Acknowledgment

We thank the Département d’analyses chimiques et S.R.M. biologique et médicale (Tours, France) for chemical analyses.

• References

• 1a For a review on biological activities, see: Enguehard-Gueiffier C, Gueiffier A. Mini-Rev. Med. Chem. 2007; 7: 888
  CrossrefPubMedSearch in Google Scholar

For recent examples see:
• 1b Jose G, Kumara TH. S, Nagendrappa G, Sowmya HB. V, Sriram D, Yogeeswari P, Sridevi JP, Guru Row TN, Hosamani AA, Ganapathy PS. S, Chandrika N, Narendra LV. Eur. J. Med. Chem. 2015; 89: 616
  CrossrefSearch in Google Scholar
• 1c Moraski GC, Miller PA, Bailey MA, Ollinger J, Parish T, Boshoff HI, Cho S, Anderson JR, Mulugeta S, Franzblau SG, Miller MJ. ACS Infect. Dis. 2015; 1: 85
  CrossrefSearch in Google Scholar
• 1d Kamal A, Kumar GB, Nayak VL, Reddy VS, Shaik AB, Reddy R, Reddy MK. MedChemComm 2015; 6: 606
  CrossrefSearch in Google Scholar
• 2 For a review on functionalization of imidazo[1,2-a]pyridine, see: Koubachi J, El Kazzouli S, Bousmina M, Guillaumet G. Eur. J. Org. Chem. 2014; 5119
• 3 Oudot R, Costes P, Allouchi H, Pouvreau M, Abarbri M, Gueiffier A, Enguehard-Gueiffier C. Tetrahedron 2011; 67: 9576
  CrossrefSearch in Google Scholar
• 4 Cartwright MW, Convery L, Kraynck T, Sandford G, Yufit DS, Howard JA. K, Christopher JA, Miller DD. Tetrahedron 2010; 66: 519
  CrossrefSearch in Google Scholar
• 5 Frolov AN. Russ. J. Org. Chem. 2006; 883
• 6 Andaloussi M, Chezal JM, Moreau E, Lartigue C, El Laghdach A, Teulade JC, Chavignon O. Heterocycles 2005; 65: 1071
  CrossrefSearch in Google Scholar
• 7 Dubbaka SR, Kienle M, Mayr H, Knochel P. Angew. Chem. Int. Ed. 2007; 46: 9093
  CrossrefSearch in Google Scholar
• 8 Enguehard-Gueiffier C, Thery I, Gueiffier A, Buchwald SL. Tetrahedron 2006; 62: 6042
  CrossrefSearch in Google Scholar

• References

• 1a For a review on biological activities, see: Enguehard-Gueiffier C, Gueiffier A. Mini-Rev. Med. Chem. 2007; 7: 888
  CrossrefPubMedSearch in Google Scholar

For recent examples see:
• 1b Jose G, Kumara TH. S, Nagendrappa G, Sowmya HB. V, Sriram D, Yogeeswari P, Sridevi JP, Guru Row TN, Hosamani AA, Ganapathy PS. S, Chandrika N, Narendra LV. Eur. J. Med. Chem. 2015; 89: 616
  CrossrefSearch in Google Scholar
• 1c Moraski GC, Miller PA, Bailey MA, Ollinger J, Parish T, Boshoff HI, Cho S, Anderson JR, Mulugeta S, Franzblau SG, Miller MJ. ACS Infect. Dis. 2015; 1: 85
  CrossrefSearch in Google Scholar
• 1d Kamal A, Kumar GB, Nayak VL, Reddy VS, Shaik AB, Reddy R, Reddy MK. MedChemComm 2015; 6: 606
  CrossrefSearch in Google Scholar
• 2 For a review on functionalization of imidazo[1,2-a]pyridine, see: Koubachi J, El Kazzouli S, Bousmina M, Guillaumet G. Eur. J. Org. Chem. 2014; 5119
• 3 Oudot R, Costes P, Allouchi H, Pouvreau M, Abarbri M, Gueiffier A, Enguehard-Gueiffier C. Tetrahedron 2011; 67: 9576
  CrossrefSearch in Google Scholar
• 4 Cartwright MW, Convery L, Kraynck T, Sandford G, Yufit DS, Howard JA. K, Christopher JA, Miller DD. Tetrahedron 2010; 66: 519
  CrossrefSearch in Google Scholar
• 5 Frolov AN. Russ. J. Org. Chem. 2006; 883
• 6 Andaloussi M, Chezal JM, Moreau E, Lartigue C, El Laghdach A, Teulade JC, Chavignon O. Heterocycles 2005; 65: 1071
  CrossrefSearch in Google Scholar
• 7 Dubbaka SR, Kienle M, Mayr H, Knochel P. Angew. Chem. Int. Ed. 2007; 46: 9093
  CrossrefSearch in Google Scholar
• 8 Enguehard-Gueiffier C, Thery I, Gueiffier A, Buchwald SL. Tetrahedron 2006; 62: 6042
  CrossrefSearch in Google Scholar

• Supplementary Material