Synthesis of Polycyclic Imidazoles via α-C–H/N–H Annulation of Alicyclic Amines

Abstract

Secondary alicyclic amines are converted to their corresponding ring-fused imidazoles in a simple procedure consisting of oxidative imine formation followed by a van Leusen reaction. Amines with an existing α-substituent undergo regioselective ring-fusion at the α’-position. This method was utilized in a synthesis of fadrozole.

Graphical Abstract

Functionalized azacycles, particularly those incorporating a piperidine core, are of significant importance in drug discovery.¹ This has served as an inspiration to us and many others to develop methods for the synthesis of such heterocycles that are based on the C–H functionalization of readily available alicyclic amines.^2,3 In the course of our studies, we have recently identified a reliable method to access relatively unstable cyclic imines from their corresponding amines via the in situ oxidation of lithium amides with ketones (Scheme 1a).⁴ Inspiration for this work came from studies by Wittig and coworkers who established this general mode of reactivity.^5,6 In addition to utilizing in-situ-generated imines for the synthesis of α-substituted alicyclic amines,⁵ we developed several methods that lead to a net α-C–H/N–H annulation of the parent heterocycles. For instance, we have shown that polycyclic lactams can be obtained from lithiated ortho-methyl benzamides (Scheme 1b),^5f while polycyclic isoindolines are accessible from ortho-lithiated benzyl chlorides (Scheme 1c).^5h While contemplating the development of other annulation reactions using cyclic enolizable imines, our attention was drawn to the van Leusen imidazole synthesis (Scheme 1d).⁷ While this transformation is popular in medicinal chemistry and has been applied extensively to acyclic imines,⁸ examples that use cyclic imines have remained limited.⁹ This is particularly true for enolizable cyclic imines which have rarely been used, a fact that is likely due to the relative instability of these species. Here we report a simple one-pot procedure for the synthesis of ring-fused imidazoles from alicyclic amines.^10,11

Scheme 1.

Generation of cyclic enolizable imines and selected annulation reactions.

We began our exploration of the proposed amine annulation reaction utilizing piperidine and TosMIC (p-toluenesulfonylmethyl isocyanide) as the model substrates (Table 1). The requisite imine, 1-piperideine (2,3,4,5-tetrahydropyridine), was generated from N-lithiated piperidine and trifluoroacetophenone via our established procedure⁵ and was then added to TosMIC and allowed to warm to room temperature. While a base is typically required in the van Leusen imidazole synthesis, we rationalized that the alkoxide byproduct from the imine formation step may fulfill this role. Indeed, the desired imidazole 1a was obtained in 30% yield without the addition of external base (Table 1, entry 1). Addition of TosMIC in methanol led to an increase in yield (Table 1, entry 2) which was further enhanced to 44% upon increasing the amount of TosMIC to two equivalents (Table 1, entry 3). Different bases were then evaluated as additives in combination with different solvents. The highest yield of 1a (63%) was achieved with DBU and methanol following a reaction time of 24 hours (Table 1, entry 13), although the reaction appeared to be mostly complete after only 3.5 hours (Table 1, entry 10). When the optimized reaction conditions were applied to 2-phenylpiperidine, the resulting imidazole 1b was isolated in a disappointing 12% yield (Table 2, entry 1). Exchange of DBU for t-butylamine led to a doubling of the yield in the same reaction time (Table 2, entry 2) while an increase in the reaction time to 12 hours allowed for the isolation of 1b in 41% yield (Table 2, entry 3). Increasing the reaction temperature to 50 °C while reducing the reaction time to 3.5 hours furnished imidazole 1b in an acceptable yield of 45% (Table 2, entry 8).

Table 1.

Optimization of the annulation reaction with piperidine.^a

Entry	TosMIC (equiv)	Base (equiv)	Time [h]	Solvent	Yield (%)
1	1.2	none	3.5	THF	30
2	1.2	none	3.5	MeOH	38
3	2.0	none	3.5	MeOH	44
4	2.0	K2CO3 (2.1)	3.5	MeOH	52
5	2.0	t-BuNH2 (2.1)	3.5	MeOH	55
6	2.0	t-BuNH2 (2.1)	3.5	THF	34
7	2.0	t-BuNH2 (2.1)	3.5	TFE	40
8	2.0	t-BuNH2 (2.1)	3.5	MeCN	48
9	2.0	t-BuNH2 (2.1)	3.5	DME	48
10	2.0	DBU (2.1)	3.5	MeOH	61
11	2.0	DBU (2.1)	2	MeOH	42
12	2.0	DBU (2.1)	7	MeOH	61
13	2.0	DBU (2.1)	24	MeOH	63
14	1.5	DBU (1.6)	3.5	MeOH	43

^aReactions were performed on a 1 mmol scale.

Table 2.

Optimization of the annulation reaction with 2-phenylpiperidine.^a

Entry	TosMIC (equiv)	Base (equiv)	Final temp [°C]	Time [h]	Yield (%)
1	2.0	DBU (2.1)	rt	3.5	12
2	2.0	t-BuNH2 (2.1)	rt	3.5	25
3	2.0	t-BuNH2 (2.1)	rt	12	41
4	2.0	t-BuNH2 (2.1)	rt	24	35
5	2.0	t-BuNH2 (2.1)	50	12	38
6	2.0	t-BuNH2 (2.1)	50	7	38
7	2.0	t-BuNH2 (2.1)	50	5	40
8	2.0	t-BuNH2 (2.1)	50	3.5	45
9	2.0	t-BuNH2 (2.1)	50	2	24
10	1.5	t-BuNH2 (1.6)	50	3.5	30

^aReactions were performed on a 0.5 mmol scale.

The scope of the annulation reaction is summarized in Scheme 2. Amines of different ring sizes, including piperidine, azepane, azocane, along with 4-substituted piperidines engaged in imidazole formation with TosMIC (products 1a, 1c–1f). For reasons that remain unclear at present, imidazoles derived from pyrrolidine and substituted pyrrolidines as well as a piperazine (1v–1y) could not be obtained under various conditions, although we have previously shown that the corresponding imines are readily formed from their parent amines and engage a variety of other nucleophiles.⁵ Substituted TosMIC derivatives engaged a broader range of imines, including those derived from pyrrolidine substrates (products 1g–1l). Gratifyingly, α-substituted amines of different ring sizes containing alkyl or aryl groups readily underwent imidazole formation with TosMIC and substituted TosMIC derivatives (products 1b, 1m–1u). Imidazoles were typically obtained in acceptable to good yields. Except for compounds 1a,^9e 1b,¹² 1m,¹³ and 1r,¹² imidazoles shown in Scheme 2 have not previously been reported.

Scheme 2.

Scope of the annulation reaction. ^a Reaction performed on a 1 mmol scale with TosMIC (2 equiv), DBU (2.1 equiv), –78 °C to rt, 3.5 h. ^b Reaction performed on a 0.5 mmol scale with corresponding tosyl isocyanide (2 equiv), t-BuNH₂ (2.1 equiv), –78 °C to 50 °C, 3.5 h. ^c The yield in parentheses is for a reaction performed on a 5 mmol scale. ^d Reaction performed on a 0.5 mmol scale with corresponding tosyl isocyanide (2 equiv), t-BuNH₂ (2.1 equiv), –78 °C to rt, 48 h.

To gauge the potential impact of imine trimerization on the annulation reaction,¹⁴ the readily available trimers of 1-piperideine (2)¹⁵ and 1-pyrroline (3)¹⁶ were exposed to the optimized reaction conditions with TosMIC (Scheme 3). As anticipated, the outcomes of these reactions were unfavorable, with 1a being obtained in 8% yield and no 1v being observed. Remarkably, however, the corresponding reactions with Ph-TosMIC resulted in the formation of 1g and 1h in 78% and 82% yield respectively. Otherwise identical reactions in which starting materials were mixed at room temperature provided nearly identical yields of 1g and 1h (not shown). This stark difference in performance may be related to the increased acidity of Ph-TosMIC over TosMIC, enabling a more efficient de-trimerization of 2 and 3.

Scheme 3.

Imine trimers in van Leusen imidazole syntheses. Equivalents of reagents are shown with respect to imine monomers.

Finally, we sought to apply our method to the synthesis of fadrozole (4), a potent inhibitor of aromatase (Scheme 4).^12,17 Unfortunately, 2-(4-cyanophenyl)piperidine failed to undergo annulation under a variety of conditions. However, we found that fadrozole (4) could be obtained in moderate yield from product 1r via palladium catalyzed cyanation.¹⁸ The overall three-step approach from piperidine to 4 compares favorably to previous procedures.^12,17

Scheme 4.

Synthesis of fadrozole.

In summary, we have accomplished the synthesis of relatively complex polycyclic imidazoles from their parent amines via a single operation that amounts to an α-C–H/N–H annulation. This study further establishes Li-amide based imine generation as a valuable approach to rapidly access interesting new chemical space.

The experimental section has no title; please leave this line here.

Starting materials and reagents were purchased from commercial sources and used as received unless stated otherwise. Anhydrous diethyl ether was dried using a JC Meyer solvent system. All liquid amines, liquid bromobenzenes, thiophene, trifluoroacetophenone, and t-butyl phenyl ketone were distilled prior to use. n-Butyl lithium solution in hexanes and phenyl lithium solution in dibutyl ether were purchased from commercial sources and freshly titrated using N-pivaloyl-o-toluidine prior to use.¹⁹ Purification of reaction products was carried out by flash column chromatography using Sorbent Technologies Standard Grade silica gel (60 Å, 230–400 mesh). Analytical thin layer chromatography was performed on EM Reagent 0.25 mm silica gel 60 F254 plates. Visualization was accomplished with UV light and Dragendorff-Munier stains followed by heating. Melting points were recorded on an Electrothermal Digital Mel-Temp 3.0 melting point apparatus. Proton nuclear magnetic resonance spectra (¹H NMR) were recorded on a Bruker 400 MHz and Bruker 600 MHz instrument and chemical shifts are reported in ppm using the solvent as an internal standard (CDCl₃ at 7.26 ppm). Data are reported as app = apparent, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, comp = complex; coupling constant(s) in Hz. Proton-decoupled carbon nuclear magnetic resonance spectra (¹³C NMR) spectra were recorded on a Bruker 400 MHz and Bruker 600 MHz instrument and chemical shifts are reported in ppm using the solvent as an internal standard (CDCl₃ at 77.0 ppm). High resolution mass spectra (HRMS) were obtained from an Agilent 6230 ESI-TOF instrument. 2-Phenylpiperidine,^5a 2-phenylazepane,^5a 2-phenylazocane,^5a 2-(naphthalen-2-yl)piperidine,⁵ⁱ 2-(4-methoxyphenyl)piperidine,⁵ⁱ 2-(thiophen-2-yl)piperidine,⁵ⁱ and all TosMIC derivatives²⁰ were synthesized according to literature procedures.

Procedures

2-(4-Bromophenyl)piperidine –

To a solution of piperidine (142.2 mg, 2 mmol) in anhydrous ether (4 mL) cooled to –78 °C (dry ice-acetone bath) was slowly added n-BuLi in hexanes (2 mmol, 1 equiv) under the protection of nitrogen, and the resulting solution was allowed to stir at the same temperature for 10 min. To this was then slowly added via cannula a solution of 2,2,2-trifluoroacetophenone (309 μL, 2.2 mmol) in anhydrous ether (2 mL). The resulting mixture was allowed to continue stirring at –78 °C (dry ice-acetone bath) for 10 minutes followed by the dropwise addition of the (4-bromophenyl)lithium^5a (3 mmol, 1.5 equiv). The reaction mixture was then allowed to warm up to room temperature and stirring was continued for another two hours before quenching via the addition of methanol (2 mL) at 0 °C. The reaction mixture was diluted with ether (20 mL) and washed with water (50 mL). The aqueous layer was extracted with ether (3 × 20 mL) and the combined organic layers were washed with brine (30 mL) and dried over anhydrous Na₂SO₄. Solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain 2-(4-Bromophenyl)piperidine as a yellow oil in 38% yield (182.5 mg). Ethyl acetate containing methanol (0–10%) was used as the eluent for silica gel chromatography. 2-(4-Bromophenyl)piperidine is known, and the characterization data matched our own in all respects.²¹

R_f = 0.3 in EtOAc/MeOH 90:10 v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.45–7.38 (m, 2H), 7.25–7.20 (m, 2H), 3.54 (dd, J = 10.5, 2.7 Hz, 1H), 3.21–3.13 (m 1H), 2.77 (app td, J = 11.6, 2.9 Hz, 1H), 1.92–1.83 (m, 1H), 1.80–1.74 (m, 2H), 1.68–1.61 (m, 1H), 1.56–1.38 (comp, 3H).

¹³C-NMR (100 MHz, CDCl₃): δ = 144.6, 131.4, 128.4, 120.6, 61.7, 47.7, 35.0, 25.8, 25.3.

HRMS (ESI-TOF): Calculated for C₁₁H₁₅BrN [M + H]⁺: 240.0382, found: 240.0389

General Procedure A –

To a solution of the amine (1 mmol, 1 equiv) in anhydrous ether (2 mL) cooled to –78 °C (dry ice-acetone bath) was slowly added n-BuLi in hexanes (1 mmol, 1 equiv) under the protection of nitrogen, and the resulting solution was allowed to stir at the same temperature for 10 min. To this was then slowly added via cannula a solution of the corresponding ketone oxidant (1.1 mmol, 1.1 equiv) in anhydrous ether (1 mL) and stirred at –78 °C (dry ice-acetone bath) for 10 minutes. This resulting mixture was then taken up by syringe and added in one portion to a separate round bottom flask containing TosMIC (2 mmol, 2 equiv) and DBU (2.1 mmol, 2.1 equiv) in methanol (2 mL) at –78 °C (dry ice-acetone bath). The reaction mixture was then allowed to warm up to room temperature and stirring was continued for another 3.5 hours, before the addition of water (1 mL) at 0 °C. The reaction mixture was diluted with ether (10 mL) and washed with water (25 mL). The aqueous layer was extracted with ether (3 × 10 mL) and the combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. Solvent was removed under reduced pressure and the residue purified by silica gel chromatography.

5,6,7,8-Tetrahydroimidazo[1,5-a]pyridine (1a)

Following general procedure A, compound 1a was obtained from piperidine (85.2 mg, 1 mmol), 2,2,2-trifluoroacetophenone (155 μL, 1.1 mmol), TosMIC (390.5 mg, 2 mmol), and DBU (314 μL, 2.1 mmol) as a colorless oil in 61% yield (74.5 mg). Dichloromethane containing methanol (0–10%) was used as the eluent for silica gel chromatography. Compound 1a is known and the characterization data matched our own in all respects.^9e

R_f = 0.23 in DCM/MeOH 90:10 v/v.

¹H NMR (400 MHz, CDCl₃): δ = 7.32 (s, 1H), 6.69 (s, 1H), 3.94 (app t, J = 6.1 Hz, 2H), 2.72 (app t, J = 6.4 Hz, 2H), 1.94– 1.86 (m, 2H), 1.83–1.74 (m, 2H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.1, 127.5, 124.2, 43.1, 23.1, 20.9, 20.7.

HRMS (ESI-TOF): Calculated for C₇H₁₁N₂ [M + H]⁺: 123.0917, found: 123.0928.

6,7,8,9-Tetrahydro-5H-imidazo[1,5-a]azepine (1c)

Following general procedure A, compound 1c was obtained from hexamethyleneimine (99.2 mg, 1 mmol), 2,2,2-trifluoroacetophenone (155 μL, 1.1 mmol), TosMIC (390.5 mg, 2 mmol) and DBU (314 μL, 2.1 mmol) as a colorless oil in 45% yield (61.3 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.28 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.33 (s, 1H), 6.73 (s, 1H), 4.00–3.88 (m, 2H), 2.74–2.64 (m, 2H), 1.84–1.70 (comp, 4H), 1.68–1.60 (m, 2H).

¹³C-NMR (100 MHz, CDCl₃): δ = 137.0, 133.9, 126.3, 47.7, 30.8, 29.5, 27.9, 25.3.

HRMS (ESI-TOF): Calculated for C₈H₁₃N₂ [M + H]⁺: 137.1073, found: 137.1077.

5,6,7,8,9,10-Hexahydroimidazo[1,5-a]azocine (1d)

Following general procedure A, compound 1d was obtained from heptamethyleneimine (113.2 mg, 1 mmol), benzophenone (200 mg, 1.1 mmol), TosMIC (390.5 mg, 2 mmol) and DBU (314 μL, 2.1 mmol) as a colorless oil in 76% yield (114.2 mg). Dichloromethane containing methanol (0–10%) was used as the eluent for silica gel chromatography.

R_f = 0.28 in DCM/MeOH 90:10 v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.29 (s, 1H), 6.69 (s, 1H), 3.95–3.87 (m, 2H), 2.65–2.57 (m, 2H), 1.73– 1.65 (m, 2H), 1.64–1.57 (m, 2H), 1.42–1.33 (m, 2H), 1.33–1.24 (m, 2H).

¹³C-NMR (100 MHz, CDCl₃): δ = 136.1, 132.7, 125.5, 42.6, 32.2, 32.1, 25.1, 23.7, 22.3.

HRMS (ESI-TOF): Calculated for C₉H₁₅N₂ [M + H]⁺: 151.1230, found: 151.1236.

7-Methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1e)

Following general procedure A, compound (±)-1e was obtained from 4-methylpiperidine (99.2 mg, 1 mmol), 2,2,2-trifluoroacetophenone (239 μL, 1.7 mmol), TosMIC (390.5 mg, 2 mmol) and DBU (314 μL, 2.1 mmol) as a colorless oil in 53% yield (72.2 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.35 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.35 (s, 1H), 6.70 (s, 1H), 4.11 (ddd, J = 12.3, 5.5, 2.8 Hz, 1H), 3.85 (app td, J = 11.9, 4.6 Hz, 1H), 2.93–2.84 (m, 1H), 2.31–2.21 (m, 1H), 1.99–1.85 (comp, 2H), 1.66–1.54 (m, 1H), 1.09 (d, J = 6.5 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃): δ = 135.0, 127.8, 124.1, 42.4, 31.2, 29.1, 27.8, 21.1.

HRMS (ESI-TOF): Calculated for C₈H₁₃N₂ [M + H]⁺: 137.1073, found: 137.1084.

7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1f)

Following general procedure A, compound (±)-1f was obtained from 4-benzylpiperidine (175.2 mg, 1 mmol), 2,2,2-trifluoroacetophenone (239 μL, 1.7 mmol), TosMIC (390.5 mg, 2 mmol) and DBU (314 μL, 2.1 mmol) as a white solid in 80% yield (169.8 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.36 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.37–7.27 (comp, 3H), 7.25–7.20 (m, 1H), 7.20–7.15 (m, 2H), 6.72–6.67 (m, 1H), 4.12 (ddd, J = 12.3, 5.5, 3.0 Hz, 1H), 3.81 (app td, J = 11.9, 4.8 Hz, 1H), 2.92–2.82 (m, 1H), 2.74–2.63 (comp, 2H), 2.40–2.31 (m, 1H), 2.14–1.97 (comp, 2H), 1.71–1.59 (m, 1H).

¹³C-NMR (100 MHz, CDCl₃): δ = 139.4, 135.0, 129.0, 128.4, 127.5, 126.3, 124.3, 42.4, 42.0, 34.8, 28.9, 27.2.

HRMS (ESI-TOF): Calculated for C₁₄H₁₇N₂ [M + H]⁺: 213.1386, found: 213.1400.

m.p.: = 68–70 °C

General Procedure B –

To a solution of the amine (0.5 mmol, 1 equiv) in anhydrous ether (1 mL) cooled to –78 °C (dry ice-acetone bath) was slowly added n-BuLi in hexanes (0.5 mmol, 1 equiv) under the protection of nitrogen, and the resulting solution was allowed to stir at the same temperature for 10 min. To this was then slowly added via cannula a solution of the corresponding ketone oxidant (0.55 mmol, 1.1 equiv) in anhydrous ether (0.5 mL) and stirred at –78 °C (dry ice-acetone bath) for 10 minutes. This resulting mixture was then taken up by syringe and added in one portion to a separate round bottom flask containing TosMIC derivative (1 mmol, 2 equiv), t-BuNH₂ (1.1 mmol, 2.1 equiv) in methanol (1 mL) at –78 °C (dry ice-acetone bath). The reaction mixture was then allowed to warm up to room temperature and stirring was continued at 50 °C for another 3.5 hours, before the addition of water (0.5 mL) at 0 °C. The reaction mixture was diluted with ether (5 mL) and washed with water (10 mL). The aqueous layer was extracted with ether (3 × 5 mL) and the combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. Solvent was removed under reduced pressure and the residue purified by silica gel chromatography.

1-Phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (1g)

Following general procedure B, compound 1g was obtained from piperidine (42.6 mg, 0.5 mmol), 2,2,2-trifluoroacetophenone (78 μL, 0.55 mmol), 1-((isocyano(phenyl)methyl)sulfonyl)-4-methylbenzene (271.3 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a colorless oil in 65% yield (64.4 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.41 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.72–7.66 (m, 2H), 7.50 (s, 1H), 7.40–7.33 (m, 2H), 7.23–7.17 (m, 1H), 4.02 (app t, J = 6.0 Hz, 2H), 2.98 (app t, J = 6.4 Hz, 2H), 1.99–1.92 (m, 2H), 1.91–1.83 (m, 2H).

¹³C-NMR (100 MHz, CDCl₃): δ = 135.1, 135.0(1), 134.9(8), 128.3, 125.9, 125.8, 124.2, 43.6, 22.7, 22.6, 21.0.

HRMS (ESI-TOF): Calculated for C₁₃H₁₅N₂ [M + H]⁺: 199.1230, found: 199.1246.

1-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole (1h)

Following general procedure B, compound 1h was obtained from pyrrolidine (35.6 mg, 0.5 mmol), benzophenone (100.2 mg, 0.55 mmol), 1-((isocyano(phenyl)methyl)sulfonyl)-4-methylbenzene (271.3 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a white solid in 60% yield (55.3 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.42 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.75–7.68 (m, 2H), 7.47 (s, 1H), 7.39–7.32 (m, 2H), 7.21–7.14 (m, 1H), 4.00 (app t, J = 7.2 Hz, 2H), 3.07–3.00 (comp, 2H), 2.74–2.64 (m, 2H).

¹³C-NMR (100 MHz, CDCl₃): δ = 135.0, 133.5, 131.4, 130.2, 128.5, 125.7, 124.5, 44.0, 29.4, 23.2.

HRMS (ESI-TOF): Calculated for C₁₂H₁₃N₂ [M + H]⁺: 185.1073, found 185.1087.

m.p.: = 101–103 °C

(5aR*,8aS*)-1-Phenyl-5,5a,6,7,8,8a-hexahydrocyclopenta[3,4]pyrrolo[1,2-c]imidazole ((±)-1i)

Following general procedure B, compound (±)-1i was obtained from octahydrocyclopenta[c]pyrrole (55.6 mg, 0.5 mmol), 2,2,2-trifluoroaceto phenone (78 μL, 0.55 mmol), 1-((isocyano(phenyl)methyl)sulfonyl)-4-methylbenzene (271.3 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a white solid in 59% yield (66.2 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.46 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.80–7.70 (m, 2H), 7.41–7.31 (comp, 3H), 7.21–7.13 (m, 1H), 4.17 (dd, J = 11.0, 8.8 Hz, 1H), 3.77 (app td, J = 8.6, 3.9 Hz, 1H), 3.67 (dd, J = 11.0, 4.4 Hz, 1H), 3.57–3.47 (m, 1H), 2.11–2.00 (m, 1H), 1.96–1.80 (comp, 2H), 1.73–1.51 (comp, 3H).

¹³C-NMR (100 MHz, CDCl₃): δ = 137.7, 134.8, 130.9, 129.6, 128.4, 125.6, 124.7, 50.3, 48.6, 40.9, 33.9, 31.9, 26.3.

HRMS (ESI-TOF): Calculated for C₁₅H₁₇N₂ [M + H]⁺: 225.1386, found: 225.1401.

m.p.: = 112–114 °C

1-(4-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (1j)

Following general procedure B, compound 1j was obtained from piperidine (42.6 mg, 0.5 mmol), 2,2,2-trifluoroacetophenone (78 μL, 0.55 mmol), 1-((isocyano(4-methoxyphenyl)methyl)sulfonyl)-4-methylbenzene (301.4 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a white solid in 70% yield (79.9 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.4 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.64–7.59 (m, 2H), 7.42 (s, 1H), 6.95–6.90 (m, 2H), 4.01 (app t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 2.96 (app t, J = 6.3 Hz, 2H), 1.99–1.91 (m, 2H), 1.91–1.83 (m, 2H).

¹³C-NMR (100 MHz, CDCl₃): δ = 157.8, 135.2, 134.8, 128.2, 127.1, 123.0, 113.8, 55.2, 43.5, 22.7(0), 22.6(7), 21.1.

HRMS (ESI-TOF): Calculated for C₁₄H₁₇N₂O [M + H]⁺: 229.1335, found: 229.1354.

m.p.: = 100–102 °C

1-(4-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (1k)

Following general procedure B, compound 1k was obtained from piperidine (42.6 mg, 0.5 mmol), 2,2,2-trifluoroacetophenone (78 μL, 0.55 mmol), 1-fluoro-4-(isocyano(tosyl)methyl)benzene (289.3 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a white solid in 64% yield (69.2 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.39 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.67–7.59 (m, 2H), 7.41 (s, 1H), 7.08–7.00 (m, 2H), 3.99 (app t, J = 6.0 Hz, 2H), 2.92 (app t, J = 6.3 Hz, 2H), 1.97–1.81 (comp, 4H).

¹³C-NMR (100 MHz, CDCl₃): δ = 161.1 (d, J = 245.4 Hz), 135.0, 134.5, 131.5 (d, J = 3.0 Hz), 127.3 (d, J = 8.0 Hz), 123.7, 115.1 (d, J = 21.2 Hz), 43.5, 22.6, 22.5, 20.9.

¹⁹F-NMR (377 MHz, CDCl₃): δ = –117.18.

HRMS (ESI-TOF): Calculated for C₁₃H₁₄N₂F [M + H]⁺: 217.1136, found: 217.1147.

m.p.: = 98–100 °C

1-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (1l)

Following general procedure B, (except reaction was stirred at rt for 48 hours) compound 1l was obtained from piperidine (42.6 mg, 0.5 mmol), 2,2,2-trifluoroacetophenone (78 μL, 0.55 mmol), 1-((1-isocyano-2-phenylethyl)sulfonyl)-4-methylbenzene (285.4 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a colorless oil in 52% yield (55.2 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.41 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.33 (s, 1H), 7.27–7.21 (comp, 4H), 7.18–7.12 (m, 1H), 3.93 (app t, J = 6.0 Hz, 2H), 3.85 (s, 2H), 2.60 (app t, J = 6.4 Hz, 2H), 1.91–1.84 (m, 2H), 1.83–1.74 (m, 2H).

¹³C-NMR (100 MHz, CDCl₃): δ = 140.8, 134.9, 134.1, 128.5, 128.2, 125.7, 123.2, 43.3, 33.6, 22.9, 20.9, 20.5.

HRMS (ESI-TOF): Calculated for C₁₄H₁₇N₂ [M + H]⁺: 213.1386, found: 213.1405.

5-Phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1b)

Following general procedure B, compound (±)-1b was obtained from 2-phenylpiperidine (80.6 mg, 0.5 mmol), 2,2,2-trifluoroacetophenone (120 μL, 0.85 mmol), TosMIC (195.3 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a yellow oil in 45% yield (44.6 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography. Compound (±)-1b is known and the characterization data matched our own in all respects.¹²

R_f = 0.43 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.36–7.26 (comp, 3H), 7.14 (s, 1H), 7.08–7.01 (m, 2H), 6.81 (s, 1H), 5.15 (dd, J = 7.9, 5.1 Hz, 1H), 2.92–2.75 (comp, 2H), 2.30–2.18 (m, 1H), 2.01–1.83 (comp, 2H), 1.79–1.65 (m, 1H).

¹³C-NMR (100 MHz, CDCl₃): δ = 141.6, 135.6, 128.7, 128.4, 127.9, 126.4, 123.8, 58.2, 33.0, 20.8, 18.8.

HRMS (ESI-TOF): Calculated for C₁₃H₁₅N₂ [M + H]⁺: 199.1230, found: 199.1246.

5-Methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1m)

Following general procedure B, compound (±)-1m was obtained from 2-methylpiperidine (58.8 μL, 0.5 mmol), 2,2,2-trifluoroacetophenone (120.0 μL, 0.85 mmol), TosMIC (195.2 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a white solid in 55% yield (37.5 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography. Compound (±)-1m is known and the characterization data matched our own in all respects.¹³

R_f = 0.33 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.51 (s, 1H), 6.73–6.67 (m, 1H), 4.16–4.05 (m, 1H), 2.84–2.74 (m, 1H), 2.69–2.59 (m, 1H), 2.08–1.98 (m, 1H), 1.97–1.87 (m, 1H), 1.71–1.52 (comp, 2H), 1.49 (d, J = 6.5 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃): δ = 133.9, 127.8, 123.8, 49.6, 31.5, 22.1, 20.9, 19.4.

HRMS (ESI-TOF): Calculated for C₈H₁₃N₂ [M + H]⁺: 137.1073, found: 137.1084.

m.p.: = 56–58 °C

5-(Naphthalen-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1n)

Following general procedure B, compound (±)-1n was obtained from 2-(naphthalen-2-yl)piperidine (105.7 mg, 0.5 mmol), 2,2,2- trifluoroacetophenone (120.0 μL, 0.85 mmol), TosMIC (195.3 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a yellow oil in 60% yield (74.5 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.39 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.86–7.81 (comp, 2H), 7.80–7.75 (m, 1H), 7.53–7.46 (comp, 3H), 7.22 (dd, J = 8.5, 1.9 Hz, 1H), 7.17 (s, 1H), 6.87 (s, 1H), 5.33 (dd, J = 8.0, 5.1 Hz, 1H), 2.97–2.82 (comp, 2H), 2.37–2.27 (m, 1H), 2.11–2.01 (m, 1H), 2.00–1.88 (m, 1H), 1.83–1.72 (m, 1H).

¹³C-NMR (150 MHz, CDCl₃): δ = 139.1, 135.9, 133.1, 133.0, 128.8, 128.5, 127.9, 127.7, 126.5, 126.3, 125.6, 124.3, 124.1, 58.4, 33.0, 21.0, 19.0.

HRMS (ESI-TOF): Calculated for C₁₇H₁₇N₂ [M + H]⁺: 249.1386, found: 249.1404.

5-Phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine ((±)-1o)

Following general procedure B, compound (±)-1o was obtained from 2-phenylazepane (87.7 mg, 0.5 mmol), t-butyl phenyl ketone (142 μL, 0.85 mmol), TosMIC (195.3 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a yellow oil in 45% yield (47.8 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.40 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.38–7.26 (comp, 3H), 7.21 (s, 1H), 7.04–6.97 (m, 2H), 6.83 (s, 1H), 5.46–5.39 (m, 1H), 2.85–2.75 (m, 1H), 2.55–2.42 (comp, 2H), 2.14–2.04 (m, 1H), 1.84–1.65 (comp, 3H), 1.61–1.49 (m, 1H).

¹³C-NMR (150 MHz, CDCl₃): δ = 138.8, 137.7, 133.7, 128.8, 127.6, 127.2, 126.5, 60.7, 34.0, 27.7, 26.1, 25.5.

HRMS (ESI-TOF): Calculated for C₁₄H₁₇N₂ [M + H]⁺: 213.1386, found: 213.1405.

5-Phenyl-5,6,7,8,9,10-hexahydroimidazo[1,5-a]azocine ((±)-1p)

Following general procedure B, compound (±)-1p was obtained from 2-phenylazocane (94.7 mg, 0.5 mmol), t-butyl phenyl ketone (142 μL, 0.85 mmol), TosMIC (195.2 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a yellow oil in 30% yield (34.0 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.36 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.41–7.31 (comp, 5H), 7.10 (s, 1H), 6.80 (s, 1H), 5.29 (dd, J = 12.4, 3.7 Hz, 1H), 3.03 (app dt, J = 12.8, 4.0 Hz, 1H), 2.68–2.57 (m, 1H), 2.35–2.25 (m, 1H), 2.16–1.97 (comp, 2H), 1.91–1.79 (comp, 2H), 1.53–1.29 (comp, 2H), 0.94–0.81 (m, 1H).

¹³C-NMR (100 MHz, CDCl₃): δ = 138.7, 134.9, 133.8, 128.9, 128.4, 127.8, 124.2, 55.7, 35.5, 33.0, 25.7, 23.6(4), 23.6(3).

HRMS (ESI-TOF): Calculated for C₁₅H₁₉N₂ [M + H]⁺: 227.1543, found: 227.1562.

5-(4-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1q)

Following general procedure B, compound (±)-1q was obtained from 2-(4-Methoxyphenyl)piperidine (95.6 mg, 0.5 mmol), 2,2,2- trifluoroacetophenone (120 μL, 0.85 mmol), TosMIC (195.2 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a yellow oil in 46% yield (52.5 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.4 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.15 (s, 1H), 7.05–7.00 (m, 2H), 6.89–6.84 (m, 2H), 6.83–6.80 (m, 1H), 5.08 (dd, J = 8.4, 4.8 Hz, 1H), 3.80 (s, 3H), 2.93–2.75 (comp, 2H), 2.27–2.18 (m, 1H), 1.98–1.87 (comp, 2H), 1.79–1.67 (m, 1H).

¹³C-NMR (150 MHz, CDCl₃): δ = 159.3, 135.8, 133.7, 128.4, 127.8, 124.1, 114.1, 57.9, 55.3, 33.2, 20.9, 19.2.

HRMS (ESI-TOF): Calculated for C₁₄H₁₇N₂O [M + H]⁺: 229.1335, Found: 229.1354.

5-(4-Bromophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1r)

Following general procedure B, compound (±)-1r was obtained from 2-(4-Bromophenyl)piperidine (120 mg, 0.5 mmol), 2,2,2-trifluoroaceto phenone (120 μL, 0.85 mmol), TosMIC (195.2 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a white solid in 44% yield (61 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.41 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.48–7.42 (m, 2H), 7.11 (s, 1H), 6.96–6.90 (m, 2H), 6.84–6.78 (m, 1H), 5.14 (dd, J = 7.6, 5.1 Hz, 1H), 2.91–2.77 (comp, 2H), 2.29–2.20 (m, 1H), 1.95–1.81 (comp, 2H), 1.78–1.66 (m, 1H).

¹³C-NMR (100 MHz, CDCl₃): δ = 140.9, 135.7, 131.9, 128.3, 128.2, 124.4, 121.9, 57.6, 33.0, 20.9, 18.7.

HRMS (ESI-TOF): Calculated for C₁₃H₁₄N₂Br [M + H]⁺: 277.0335, found: 277.0350.

m.p.: = 103–105 °C

5-(Thiophen-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1s)

Following general procedure B, compound (±)-1s was obtained from 2-(thiophen-2-yl)piperidine (83.6 mg, 0.5 mmol), 2,2,2-trifluoroacetophenone (120 μL, 0.85 mmol), TosMIC (195.2 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a white solid in 51% yield (52.1 mg). Ethyl acetate/hexanes 50:50 v/v (200 mL), followed by ethyl acetate containing methanol (1%) and isopropylamine (1%) was used as the eluent for silica gel chromatography.

R_f = 0.4 in EtOAc/MeOH/i-PrNH₂ 90:9:1 v/v/v.

¹H-NMR (400 MHz, CDCl₃): δ = 7.33–7.26 (comp, 2H), 7.02–6.96 (m, 1H), 6.96–6.90 (m, 1H), 6.82 (s, 1H), 5.44 (dd, J = 8.4, 4.8 Hz, 1H), 2.96–2.77 (comp, 2H), 2.40–2.30 (m, 1H), 2.13–1.99 (comp, 2H), 1.86–1.74 (m, 1H).

¹³C-NMR (100 MHz, CDCl₃): δ = 144.4, 135.6, 127.8, 126.7, 125.9, 125.5, 124.4, 54.0, 33.6, 20.8, 19.5.

HRMS (ESI-TOF): Calculated for C₁₁H₁₃N₂S [M + H]⁺: 205.0797, Found: 205.0806.

m.p.: = 77–79 °C

1-Phenyl-5-(thiophen-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1t)

Following general procedure B, compound (±)-1t was obtained from 2-(thiophen-2-yl)piperidine (83.6 mg, 0.5 mmol), 2,2,2-trifluoroaceto phenone (120 μL, 0.85 mmol), 1-((isocyano(phenyl)methyl)sulfonyl)-4-methylbenzene (271.1 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a white solid in 52% yield (72.8 mg). Hexanes containing ethyl acetate (40–50%) was used as the eluent for the silica gel chromatography.

R_f = 0.5 in EtOAc.

¹H-NMR (400 MHz, CDCl₃): δ = 7.77–7.68 (m, 2H), 7.39 (app t, J = 7.7 Hz, 2H), 7.36 (s, 1H), 7.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.25–7.20 (m, 1H), 7.01–6.97 (m, 1H), 6.97–6.94 (m, 1H), 5.47 (dd, J = 8.3, 4.8 Hz, 1H), 3.17–2.99 (comp, 2H), 2.41–2.31 (m, 1H), 2.18–2.02 (comp, 2H), 1.89–1.76 (m, 1H).

¹³C-NMR (100 MHz, CDCl₃): δ = 144.2, 135.5, 135.4, 135.2, 128.4, 126.8, 126.0(3), 125.9(8), 125.9, 125.6, 124.2, 54.3, 33.0, 22.7, 19.5.

HRMS (ESI-TOF): Calculated for C₁₇H₁₇N₂S [M + H]⁺: 281.1107, Found: 281.1119.

m.p.: = 143–145 °C

5-Methyl-1-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ((±)-1u)

Following general procedure B, compound (±)-1u was obtained from 2-methylpiperidine (59 μL, 0.5 mmol), 2,2,2-trifluoroacetophenone (120 μL, 0.85 mmol), 1-((isocyano(phenyl)methyl)sulfonyl)-4-methylbenzene (271.1 mg, 1 mmol) and t-BuNH₂ (110 μL, 1.05 mmol) as a white solid in 54% yield (57.3 mg). Hexanes containing ethyl acetate (40–50%) was used as the eluent for the silica gel chromatography

R_f = 0.46 in EtOAc.

¹H-NMR (400 MHz, CDCl₃): δ = 7.73–7.66 (m, 2H), 7.57 (s, 1H), 7.41–7.34 (m, 2H), 7.24–7.17 (m, 1H), 4.23–4.13 (m, 1H), 3.08–2.98 (m, 1H), 2.95–2.84 (m, 1H), 2.12 – 1.96 (comp, 2H), 1.78 – 1.62 (comp, 2H), 1.55 (d, J = 6.5 Hz, 3H).

¹³C-NMR (100 MHz, CDCl₃): δ = 135.4, 135.2, 133.8, 128.3, 126.0, 125.8, 124.3, 49.8, 31.0, 22.9, 22.2, 19.5.

HRMS (ESI-TOF): Calculated for C₁₄H₁₇N₂ [M + H]⁺: 213.1386, Found: 213.1396.

m.p.: = 86–88 °C

General procedure for the preparation of 1-Phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (1g) and 1-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole (1h) from 1-piperideine (2) and 1-pyrroline (3) respectively

To a solution of 1-((isocyano(phenyl)methyl)sulfonyl)-4-methylbenzene (135.5 mg, 0.5 mmol) and t-BuNH₂ (55 μL, 1.05 mmol) in MeOH (0.5 mL) cooled to –78 °C (dry ice-acetone bath) was slowly added the solution of corresponding imine trimer (0.25 mmol) in anhydrous ether (0.75 mL). The reaction mixture was then allowed to warm up to room temperature and stirring was continued at 50 °C for another 3.5 hours before the addition of water (0.5 mL) at 0 °C. The reaction mixture was diluted with ether (5 mL) and washed with water (10 mL). The aqueous layer was extracted with ether (3 × 5 mL) and the combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. Solvent was removed under reduced pressure and the residue purified by silica gel chromatography. Characterization data for 1g and 1h matched those reported above.

4-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile ((±)-4)

A flame dried reaction vial was charged with 5-(4-bromophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (±)-1r (41.6 mg, 0.15 mmol), Zn(CN)₂ (35.2 mg, 0.3 mmol), Pd(PPh₃)₄ (26 mg, 0.02 mmol) and DMF (1 mL). The mixture was purged with nitrogen for 5 min, sealed and heated to 125 °C overnight. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (3 × 10 mL). The combined extracts were washed with water (10 mL) and brine (10 mL) and dried over Na₂SO₄. Solvent was removed under reduced pressure and the residue purified via silica gel chromatography using ethyl acetate containing isopropylamine (0–1% v/v) to give compound (±)-4 as a colorless oil in 52% yield (17.4 mg). Compound (±)-4 is known and the characterization data matched our own in all respects.^12,17

R_f = 0.23 in EtOAc.

¹H-NMR (400 MHz, CDCl₃): δ = 7.67–7.59 (m, 2H), 7.15–7.09 (comp, 3H), 6.83 (s, 1H), 5.32–5.25 (m, 1H), 2.84 (app t, J = 8.0 Hz, 2H), 2.34–2.25 (m, 1H), 1.98–1.87 (m, 1H), 1.84–1.68 (comp, 2H).

¹³C-NMR (100 MHz, CDCl₃): δ = 147.3, 135.5, 132.6, 128.2, 127.1, 124.6, 118.3, 111.9, 57.4, 32.6, 20.7, 18.2.

HRMS (ESI-TOF): Calculated for C₁₄H₁₄N₃ [M + H]⁺: 224.1182, Found: 224.1191.