Palladium-Catalyzed Oxidative Annulation of Pyrrolylalkyl-1H-azoles: Towards the Synthesis of Polyheterocyclic Arenes

Abstract

A highly efficient and regioselective palladium-catalyzed annulation protocol for a series of linear and terminally substituted 1,2- and 1,3-di(heteroaryl)alkanes to the corresponding polyheterocyclic arenes is reported. Herein, intramolecular oxidative coupling involving double C(sp²)–H bond functionalization provides a feasible access to biheteroaryl systems annulated to a six-membered ring. The methodology is not restricted to six-membered annulations and was extended to the synthesis of compounds with a seven-membered ring and biheteroaryl core.

Key words

C–H functionalization - pyrroles - oxidative coupling - palladium - imidazoles

Compounds containing pyrroloimidazoles,[1] pyrrolopyrazoles,[2] pyrrolopyrazines[3] and imidazopyrazoles[4] have garnered significant attention in the last two decades, not only because of their remarkable biological activities but also due to their use as essential synthons for natural and synthetic bioactive compounds through their isosterism with pyrrolizine and indolizine. Among these classes of compounds, pyrrolobis(imidazoles),[5] FM-381,[6] pyrrolo[1,2-c]imidazol-3(2H)-ones,[7] AG110[8] and related structures are the most extensively studied scaffolds (Figure [1]). While many of the pyrazines and their analogues have potential antiarrhythmic,[9a] antiamnestic, antihypoxic,[9b] psychotropic,[9c] antihypersensitive[9d] and aldose reductase inhibition activities,[9e] interestingly most of them have received relatively little attention.

Figure 1 Representative bioactive imidazopyrrole and imidazopyrrolopyridine compounds, and other synthetically evolved polyheterocycles

In this context, the development of novel types of polycyclic structures with a pyrrolopyrazine skeleton, which is of immense interest for biological screening, is becoming more expedient. In particular, for obtaining heterobiaryl-embedded rings, oxidative dehydrogenative coupling via transition-metal-catalyzed intramolecular cyclization has emerged as a potential route.[10] Interestingly, all the methodologies to date for obtaining six-membered rings utilize coupling reactions for joining two fragments followed by an addition or substitution reaction for the ring closure that usually requires prefunctionalized substrate.[11] Very few reports have described the formation of a six-membered ring via a direct cross-coupling reaction. Towards this, a more environmentally benign and sustainable alternative reaction can be a simple oxidative intramolecular dehydrogenative coupling (IDC) of two aryl/heteroaryl C(Ar)–H bonds yielding biaryls/heterobiaryls. Using this strategy, the synthesis of biaryls and heterobiaryls embedded in a ring, including, but not limited to, the synthesis of phenanthridin-6-ones,[12] carbazoles,[13] N-fused heterocycles[14] and other related biaryls,[15] has proved the wide applicability of IDC.

Amongst synthetically evolved polycyclic heteroaryl cores (I [3b] [16a] ^, [17] [18] [19], II [16b] and III [16c]; Figure [1]), the significant approaches to pyrrolopyrazines include intramolecular aza-Friedel–Crafts reaction of N-aminoethylpyrroles with aldehydes catalyzed by a chiral phosphoric acid,[17] palladium-catalyzed intramolecular direct arylation of pyrrole-2-carboxamides,[18] AuCl₃-catalyzed intramolecular addition of pyrazoles to N-propargylpyrroles,[19] intramolecular oxidative C–H amination of an elaborated precursor to the corresponding polyheterocyclic arenes,[3b] and many other synthetic methodologies. Recently, some palladium-[20a] and copper-catalyzed[20b] [c] syntheses of indole- and pyrrole-annulated heterocycles have been attempted. However, unactivated pyrrole annulation to a heterocycle remains a challenge. Herein, we describe a workable model for palladium-catalyzed dehydrogenative intramolecular oxidative coupling involving double C(sp²)–H bonds resulting in the six- and seven-membered heterocyclic rings, dihydropyrazine and dihydrodiazepine, from terminal 1,2- and 1,3-diheteroaryl-substituted alkanes. We demonstrate that IDC can provide direct access to annulated heterobiaryl cyclic compounds (Scheme [1]).

Scheme 1 Previous attempt and current dehydrogenative intramolecular oxidative coupling approach towards pyrrole-annulated hetero­cycles

Optimization of the reaction conditions commenced with an initial screening of the transition-metal catalyst under various reaction conditions (Table [1]). At first, the reaction was explored under acidic conditions in the presence of excess oxidant to identify the optimal conditions. The substrate for the reaction was chosen keeping in mind that it should be easy to synthesize and can be easily diversified for the synthesis of related analogues. The reaction of 1a (1 equiv), Cu(OAc)₂ (10 mol%), benzoic acid (5 equiv) and AgOAc (2 equiv) in DMF at 120 °C was found ineffective, even after 12 hours, in affording the desired cyclized product (Table [1], entry 1). Next, we replaced Cu(OAc)₂ with PdCl₂­, and found that with oxidant AgOAc and additive benzoic acid the reaction did not yield the desired product (Table [1], entry 2). Delightfully, variation in the protic acid additive, from benzoic acid to acetic acid, while keeping the loading of catalytic Pd and Ag salts the same as stated in entry 2, gave the desired cyclized product 2a in 65% isolated yield (Table [1], entry 3). An increase in the yield (65% to 75%) was noticed when 10 mol% Pd(TFA)₂ was used with 2 equivalents of AgOAc and 5 equivalents of AcOH. A change in the Pd salt from Pd(TFA)₂ to Pd(OAc)₂ yielded 84% of desired product 2a (Table [1], entry 5). These findings confirmed the efficacy of Pd(OAc)₂ over other Pd salts. Use of O₂ as an oxidant had no effect on the reactivity and there was no improvement in the yield (Table [1], entries 6 and 7). Oxidants other than AgOAc were tested; Ag₂CO₃ yielded 74% cyclized product whereas Cu(OAc)₂ afforded 51% isolated yield of 2a (Table [1], entries 8 and 9).

Table 1 Optimization of the Reaction Conditions^a

Entry	Catalyst (equiv)	Oxidant (equiv)	Additive (equiv)	Yieldb (%) of 2a
1	Cu(OAc)2 (0.1)	AgOAc (2)	C6H5COOH (5)	nd
2	PdCl2 (0.1)	AgOAc (2)	C6H5COOH (5)	nd
3	PdCl2 (0.1)	AgOAc (2)	AcOH (5)	65
4	Pd(TFA)2 (0.1)	AgOAc (2)	AcOH (5)	75
5	Pd(OAc)2 (0.1)	AgOAc (2)	AcOH (5)	84
6	Pd(OAc)2 (0.1)	AgOAc (2)	AcOH (5) + O2 (1 atm)	60
7	Pd(OAc)2 (0.1)	AgOAc (2)	O2 (1 atm)	71
8	Pd(OAc)2 (0.1)	Ag2CO3 (2)	AcOH (5)	74
9	Pd(OAc)2 (0.1)	Cu(OAc)2 (2)	AcOH (5)	51
10	Pd(OAc)2 (0.1)	–	AcOH (5)	nd
11	–	AgOAc (2)	AcOH (5)	nd
12	Pd(OAc)2 (0.1)	AgOAc (2)	–	52
13	Pd(OAc)2 (0.1)	AgOAc (1)	AcOH (5)	48
14	Pd(OAc)2 (0.1)	AgOAc (2)	AcOH (2.5)	28
15	Pd(OAc)2 (0.05)	AgOAc (2)	AcOH (5)	46

^a Reaction conditions: 1a (0.2 mmol), catalyst, oxidant, additive, DMF (1 mL), 120 °C, 12 h.

^b Isolated yields; nd = not detected.

Control experiments were performed to assess the importance of each reagent in the optimized reaction conditions. In the absence of either Pd catalyst or oxidant, the reaction­ failed to initiate (Table [1], entries 10 and 11); hence, it was concluded that Pd catalyst and oxidant are essential for the reaction to proceed. A decreased yield of 2a was observed when the entire set of optimized reaction conditions were imposed in the absence of acid additive AcOH (Table [1], entry 12).

To check stoichiometric dependency, we lowered the amount of Ag salt to half of its initial loading, which resulted in a decreased yield of 2a (Table [1], entry 13). Further, reducing the amount of acid to 2.5 equivalents gave a poor yield (Table [1], entry 14). An attempt to reduce the catalytic loading of Pd(OAc)₂, to 5 mol%, gave 2a in a lower 46% yield (Table [1], entry 15). Based on these studies, finally it was concluded that 10 mol% Pd(OAc)₂, 2 equivalents of AgOAc and 5 equivalents of protic additive AcOH in DMF at 120 °C for 12 hours were the best optimized reaction conditions for the synthesis of 2a.

With these optimized reaction conditions in hand, we ventured into establishing a broad spectrum of substrate scope for this reaction and to get insight into the effect of various functionalities on this intramolecular C–H activation. We also studied the effect of the length of the alkyl loop linking the nitrogens of the azole and pyrrole on the yields. With these aims, we synthesized novel heterobiaryl systems with a six- or seven-membered ring, and the results are summarized in Table [2].

When the length of the linked alkyl chain was fixed at two carbons (n = 1), the desired imidazopyrrolodihydropyrazines 2a–2h were successfully obtained in 48–83% isolated yield. Unsubstituted benzimidazole 1a and benzimidazoles installed with electron-donating groups (1b) or electron-withdrawing groups (1c and 1d) were successfully coupled at their C2 position with pyrrole, and resulted in the corresponding imidazopyrrolodihydropyrazines 2a–2d in 83%, 76%, 77% and 72% isolated yield, respectively. Pyrrole N-ethyl-linked with imidazoles [imidazoles 4,5-disubstituted with Cl (1e), CN (1f) or Ph (1g) groups] and unsubstituted triazole 1h were successfully coupled to give the six-membered­ cyclized products 2e–2h in 48–73% isolated yield. Thus, the results were promising both when electron-donating groups or electron-withdrawing groups were installed on benzimidazoles and imidazoles. Next, we extended the linked alkyl chain between pyrrole and the azoles to three carbons (n = 2). Using our reaction conditions, we successfully synthesized imidazopyrrolodiazepines 2i–2o from the corresponding lengthened pyrrolopropylazoles 1i–1o. Unsubstituted (1i) and electron-donating (Me, 1j) or electron-withdrawing [Cl (1k), Br (1l)] functional groups on the benzimidazole of pyrrolopropylbenzimidazoles were well tolerated under these reaction conditions, giving diazepines 2i–2l in 62–71% isolated yield. Pyrrolopropylimidazoles substituted with electron-withdrawing substituents [Cl (1m), CN (1n), Ph (1o)] at the imidazole also led to the corresponding imidazopyrrolodiazepines 2m–2o in good yields (52%, 58% and 46%, respectively).

Table 2 Substrate Scope for the Cross-Coupling Reaction^a

^a Reaction conditions: 1 (0.2 mmol), Pd(OAc)₂ (10 mol%), AgOAc (2.0 equiv), AcOH (5.0 equiv), DMF (1 mL), 120 °C, 12 h.

To gain mechanistic insight into this intramolecular oxidative cross-coupling, we explored the optimized cyclization in the presence of TEMPO (Scheme [2]). While no TEMPO-coupled side product was observed, a slight loss in product yield was noted. This observation rules out the possibility of a radical pathway for the cyclization. Also, intermolecular coupling of ethyl acrylate in a mixture of N-methylbenzimidazole and 1a was studied (Scheme [2]). Here, the intramolecular cyclization appeared to predominate over the intermolecular, leaving the added other coupling partners intact in the reaction mixture. The quest was to identify the preferred activation site for the intermolecular reactions and then extend the insight into the developed intramolecular oxidative C–C bond formation. Based on our recent reports,[20] we expected the C-2 position of benzimidazole to be more reactive than the C-2 of pyrrole. This was indeed observed in our competition studies, too. Thus, it indicates that the reaction is probably initiated by metalation at the azole. Palladation of the benzimidazole at C-2 forms complex A with the loss of one molecule of AcOH (Scheme [3]). Further, electrophilic C-2 carbometalation of pyrrole proceeds via transition state B in a concerted metalation–deprotonation (CMD) step to form complex C. Finally, the desired product is formed along with expulsion of Pd(0) from complex C through a reductive elimination process. The Pd(0) is re-oxidized to Pd(II) with the Ag(I) oxidant and re-enters the catalytic cycle.

Scheme 2 Cyclization in the presence of TEMPO and other controlled conditions

Scheme 3 Proposed mechanism for the intramolecular dehydrogenative coupling

In accordance with the information obtained from ¹H and ¹³C NMR spectroscopy, the structure of cyclized product 2a was also unequivocally confirmed by X-ray crystallography (Figure [2]).

Figure 2 X-ray crystal structure of 2a [21]

In conclusion, we have developed an efficient method for synthesizing polyheteroarenes, via palladium-catalyzed intramolecular oxidative cross-coupling, which involves dual C(sp²)–H bond functionalization. Moreover, this reaction accesses the synthesis of the six- and seven-membered rings of pyrazine and diazepine annulated with pyrrole–azole systems.

NMR spectra were recorded in deuterated solvents with the residual protonated solvent signal as internal reference on a Bruker Ava-300 or Bruker Ava-400 spectrometer. Chemical shifts are reported in parts per million using the solvent resonance as internal standard (chloroform, 7.26 and 77.0 ppm; DMSO, 2.50 and 40.0 ppm). Data are reported as follows: chemical shift, multiplicity (standard abbreviations), coupling constant(s), and integration. Electrospray ionization (ESI) high-resolution mass spectrometry was performed on a Bruker micro­OTOF-Q II mass spectrometer. Solvents for starting material preparation and coupling reactions were dried following the literature procedures before use.

Pyrrolylalkyl-1H-azoles 1; General Procedure for the N-Alkylation of Azoles

To a suspension of NaH (1.0 equiv) in anhydrous DMF at 0 °C was dropwise added a solution of the appropriate 5,6-disubstituted benzimidazole, 4,5-disubstituted imidazole or triazole (1.0 mmol, 1.0 equiv) in anhydrous DMF, and the reaction mixture was allowed to stir at rt for 30 min. Then, a solution of 2-(1H-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate or 3-(1H-pyrrol-1-yl)propyl 4-methylbenzenesulfonate (1.2 equiv) in DMF was added, and the resulting solution was heated at 80 °C for 16 h. Once the reaction was completed (monitored by TLC), the mixture was allowed to cool and saturated brine solution was added. The mixture was extracted with EtOAc (3 ×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The organic residue was purified by silica gel column chromatography (EtOAc/hexane, 2:3 to 4:1) to provide the desired product 1.

1-(2-(1H-Pyrrol-1-yl)ethyl)-1H-benzo[d]imidazole (1a)

Brown solid; yield: 184 mg (87%).

¹H NMR (300 MHz, CDCl₃): δ = 7.82 (d, J = 2.9 Hz, 1 H), 7.31 (d, J = 2.5 Hz, 4 H), 6.37 (d, J = 2.5 Hz, 2 H), 6.13 (d, J = 1.7 Hz, 2 H), 4.43 (br s, 2 H), 4.25 (br s, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 143.4, 142.9, 132.9, 122.8, 122.0, 120.1, 109.1, 108.9, 108.8, 48.4, 46.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₄N₃: 212.1182; found: 212.1189.

5,6-Dimethyl-1-(2-(1H-pyrrol-1-yl)ethyl)-1H-benzo[d]imidazole (1b)

White solid; yield: 201 mg (84%).

¹H NMR (300 MHz, CDCl₃): δ = 7.59 (s, 1 H), 7.29 (dd, J = 2.2, 3.9 Hz, 1 H), 7.04 (s, 1 H), 6.41 (dd, J = 2.1, 4.2 Hz, 2 H), 6.15 (dd, J = 2.1, 4.2 Hz, 2 H), 4.44–4.40 (m, 2 H), 4.29–4.25 (m, 2 H), 2.42 (s, 3 H), 2.41 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 142.2, 141.7, 132.4, 131.5, 131.3, 120.3, 120.1, 109.3, 48.7, 46.5, 20.4, 20.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₈N₃: 240.1495; found: 240.1491.

5,6-Dichloro-1-(2-(1H-pyrrol-1-yl)ethyl)-1H-benzo[d]imidazole (1c)

Brown powder; yield: 200 mg (71%).

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.86 (d, J = 2.3 Hz, 2 H), 7.73 (s, 1 H), 6.55 (s, 2 H), 5.93 (d, J = 1.8 Hz, 2 H), 4.58 (t, J = 5.6 Hz, 2 H), 4.29 (t, J = 5.6 Hz, 2 H).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 146.3, 142.5, 133.2, 124.9, 124.1, 120.6, 120.3, 112.1, 108.1, 48.2, 45.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₂Cl₂N₃: 280.0402; found: 280.0409.

5,6-Dibromo-1-(2-(1H-pyrrol-1-yl)ethyl)-1H-benzo[d]imidazole (1d)

Brown solid; yield: 283 mg (77%).

¹H NMR (400 MHz, CDCl₃): δ = 8.05 (s, 1 H), 7.40 (s, 1 H), 7.27 (d, J = 4.8 Hz, 1 H), 6.35 (s, 2 H), 6.13 (s, 2 H), 4.45–4.31 (m, 2 H), 4.26–4.14 (m, 2 H).

¹³C NMR (101 MHz, CDCl₃): δ = 144.8, 144.0, 133.6, 125.0, 120.4, 118.8, 117.9, 130.8, 110.1, 49.1, 47.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₂Br₂N₃: 367.9392; found: 367.9395.

4,5-Dichloro-1-(2-(1H-pyrrol-1-yl)ethyl)-1H-imidazole (1e)

Brown sticky solid; yield: 170 mg (74%).

¹H NMR (300 MHz, CDCl₃): δ = 6.71 (s, 1 H), 6.43 (d, J = 1.4 Hz, 2 H), 6.12 (d, J = 1.6 Hz, 2 H), 4.17–4.13 (m, 4 H).

¹³C NMR (75 MHz, CDCl₃): δ = 134.7, 125.7, 120.1, 112.3, 109.2, 48.4, 47.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₀Cl₂N₃: 230.0246; found: 230.0246.

1-(2-(1H-Pyrrol-1-yl)ethyl)-1H-imidazole-4,5-dicarbonitrile (1f)

Brown sticky solid; yield: 165 mg (78%).

¹H NMR (300 MHz, CDCl₃): δ = 6.85 (s, 1 H), 6.44 (d, J = 1.1 Hz, 2 H), 6.18 (d, J = 1.0 Hz, 2 H), 4.43 (t, J = 6.0 Hz, 2 H), 4.28–4.23 (t, J = 6.0 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 141.7, 123.1, 120.2, 111.8, 111.5, 110.7, 107.6, 49.2, 49.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₀N₅: 212.0930; found: 212.0938.

4,5-Diphenyl-1-(2-(1H-pyrrol-1-yl)ethyl)-1H-imidazole (1g)

Brown solid; yield: 295 mg (94%).

¹H NMR (300 MHz, CDCl₃): δ = 7.51–7.48 (m, 5 H), 7.28–7.17 (m, 6 H), 6.40–6.38 (m, 2 H), 6.16–6.15 (m, 2 H), 4.10 (t, J = 6.0 Hz, 2 H), 3.96 (t, J = 6.0 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 137.9, 136.8, 134.1, 130.7, 130.1, 129.2, 128.9, 128.0, 126.4, 126.4, 120.3, 109.1, 49.4, 49.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₀N₃: 314.1652; found: 314.1665.

1-(2-(1H-Pyrrol-1-yl)ethyl)-1H-1,2,4-triazole (1h)

Red oily liquid; yield: 122 mg (75%).

¹H NMR (300 MHz, CDCl₃): δ = 7.98 (s, 1 H), 7.52 (s, 1 H), 6.39 (dd, J = 4.3, 6.2 Hz, 2 H), 6.11 (dd, J = 4.3, 6.3 Hz, 2 H), 4.45–4.42 (m, 2 H), 4.30 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 152.4, 143.9, 120.3, 109.3, 51.1, 48.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₁₁N₄: 163.0978; found: 163.0980.

1-(3-(1H-Pyrrol-1-yl)propyl)-1H-benzo[d]imidazole (1i)

Brown solid; yield: 210 mg (93%).

¹H NMR (400 MHz, CDCl₃): δ = 7.84–7.81 (m, 2 H), 7.31–7.30 (m, 3 H), 6.64 (s, 2 H), 6.22 (s, 2 H), 4.05 (t, J = 6.8 Hz, 2 H), 3.85 (t, J = 6.4 Hz, 2 H), 2.31 (t, J = 6.4 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 143.6, 142.8, 133.4, 123.0, 122.2, 120.3, 120.2, 109.5, 108.7, 45.9, 41.6, 30.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₆N₃: 226.1338; found: 226.1343.

5,6-Dimethyl-1-(3-(1H-pyrrol-1-yl)propyl)-1H-benzo[d]imidazole (1j)

White solid; yield: 218 mg (86%).

¹H NMR (300 MHz, CDCl₃): δ = 7.69 (s, 1 H), 7.61 (s, 1 H), 7.07 (s, 1 H), 6.65 (s, 2 H), 6.24 (s, 2 H), 4.00 (t, J = 6.8 Hz, 2 H), 3.84 (t, J = 6.4 Hz, 2 H), 2.41 (s, 3 H), 2.41 (s, 3 H), 2.32–2.28 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 142.3, 142.0, 132.0, 131.9, 130.9, 120.2, 120.1, 109.6, 108.5, 45.8, 41.4, 30.7, 20.3, 20.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₀N₃: 254.1652; found: 254.1651.

5,6-Dichloro-1-(3-(1H-pyrrol-1-yl)propyl)-1H-benzo[d]imidazole (1k)

Brown sticky solid; yield: 256 mg (87%).

¹H NMR (300 MHz, CDCl₃): δ = 7.68 (s, 1 H), 7.62 (s, 1 H), 7.16 (s, 1 H), 6.49 (s, 2 H), 6.07 (d, J = 1.3 Hz, 2 H), 3.85 (t, J = 6.8 Hz, 2 H), 3.73 (t, J = 6.3 Hz, 2 H), 2.20–2.14 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 144.5, 142.8, 132.5, 126.7, 126.0, 121.2, 120.2, 110.8, 108.8, 45.7, 41.8, 30.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₄Cl₂N₃: 294.0559; found: 294.0556.

5,6-Dibromo-1-(3-(1H-pyrrol-1-yl)propyl)-1H-benzo[d]imidazole (1l)

Brown solid; yield: 305 mg (80%).

¹H NMR (300 MHz, CDCl₃): δ = 8.01 (s, 1 H), 7.70 (s, 1 H), 7.48 (s, 1 H), 6.61 (s, 2 H), 6.20 (s, 2 H), 3.97 (t, J = 6.3 Hz, 2 H), 3.86 (d, J = 5.6 Hz, 2 H), 2.31–2.29 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 144.4, 144.0, 139.0, 133.5, 124.6, 120.2, 118.2, 117.4, 114.0, 113.9, 108.9, 45.8, 41.9, 30.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₄Br₂N₃: 381.9548; found: 381.9552.

4,5-Dichloro-1-(3-(1H-pyrrol-1-yl)propyl)-1H-imidazole (1m)

Brown sticky solid; yield: 212 mg (87%).

¹H NMR (300 MHz, CDCl₃): δ = 7.27 (d, J = 9.0 Hz 1 H), 6.64 (d, J = 3.0 Hz 1 H), 6.20 (s, 1 H), 3.92 (t, J = 6.0 Hz, 2 H), 3.84 (t, J = 6.0 Hz, 2 H), 2.31–2.24 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 134.5, 126.7, 120.4, 113.2, 109.1, 45.9, 43.4, 31.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₂Cl₂N₃: 244.0402; found: 244.0405.

1-(3-(1H-Pyrrol-1-yl)propyl)-1H-imidazole-4,5-dicarbonitrile (1n)

Brown sticky solid; yield: 171 mg (76%).

¹H NMR (300 MHz, CDCl₃): δ = 7.49 (s, 1 H), 6.62 (d, J = 1.8 Hz, 2 H), 6.20–6.18 (m, 2 H), 4.07–3.97 (m, 4 H), 2.44–2.37 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 141.4, 123.5, 120.3, 112.0, 111.5, 109.6, 107.8, 45.8, 45.2, 31.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₂N₅: 226.1087; found: 226.1091.

4,5-Diphenyl-1-(3-(1H-pyrrol-1-yl)propyl)-1H-imidazole (1o)

Brown sticky solid; yield: 275 mg (84%).

¹H NMR (300 MHz, CDCl₃): δ = 7.60 (s, 1 H), 7.54–7.48 (m, 5 H), 7.39–7.32 (m, 2 H), 7.26–7.15 (m, 3 H), 6.51 (d, J = 1.7 Hz, 2 H), 6.15 (d, J = 1.5 Hz, 2 H), 3.79–3.75 (m, 4 H), 1.99–1.95 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 138.4, 136.9, 134.2, 130.7, 130.5, 129.3, 128.9, 128.2, 126.7, 126.5, 120.2, 108.6, 46.1, 42.4, 32.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₂N₃: 328.1808; found: 328.1810.

Intramolecular Dehydrogenative Cross-Coupling of Pyrrolylalkyl-1H-azoles 1; General Procedure

A tube was loaded with N-alkylated azole 1 (0.2 mmol, 1 equiv), Pd(OAc)₂ (0.1 equiv), AgOAc (2 equiv) and AcOH (5 equiv) in DMF (1 mL), then sealed with a screw cap. The reaction mixture was stirred in a preheated silicone oil bath at 120 °C for 12 h. Once the reaction was completed, the mixture was allowed to cool and saturated brine solution was added. The mixture was extracted with EtOAc (3 ×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane, 3:7 to 3:2) to provide the desired product 2.

5,6-Dihydrobenzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazine (2a)

Brown solid; yield: 35 mg (83%).

¹H NMR (400 MHz, CDCl₃): δ = 7.74 (d, J = 8.7 Hz, 1 H), 7.26–7.22 (m, 3 H), 7.03–7.02 (m, 1 H), 6.79 (s, 1 H), 6.31–6.30 (m, 1 H), 4.32 (br s, 4 H).

¹³C NMR (101 MHz, CDCl₃): δ = 144.9, 143.9, 133.7, 123.1, 122.5, 122.3, 119.3, 119.2, 110.4, 109.7, 108.4, 43.7, 40.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₂N₃: 210.1026; found: 210.1028.

9,10-Dimethyl-5,6-dihydrobenzo[4,5]imidazo[1,2-a]pyrrolo-[2,1-c]pyrazine (2b)

White solid; yield: 36 mg (76%).

¹H NMR (300 MHz, CDCl₃): δ = 7.50 (s, 1 H), 7.07 (s, 1 H), 7.01 (d, J = 1.9 Hz, 1 H), 6.82 (s, 1 H), 6.32 (s, 1 H), 4.37 (br s, 4 H), 2.38 (s, 3 H), 2.37 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 144.1, 132.3, 131.5, 131.4, 122.8, 122.4, 119.6, 110.4, 109.4, 108.9, 43.9, 40.9, 20.6, 20.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₆N₃: 238.1339; found: 238.1339.

9,10-Dichloro-5,6-dihydrobenzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazine (2c)

Brown solid; yield: 43 mg (77%).

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.92 (s, 1 H), 7.79 (s, 1 H), 7.15 (s, 1 H), 6.83–6.82 (m, 1 H), 6.29–6.27 (m, 1 H), 4.49–4.48 (m, 4 H).

¹³C NMR (101 MHz, DMSO-d ₆): δ = 146.8, 143.3, 133.7, 124.5, 124.0, 123.7, 120.8, 119.1, 111.3, 109.6, 109.4, 42.9, 40.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₀Cl₂N₃: 278.0246; found: 278.0258.

9,10-Dibromo-5,6-dihydrobenzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazine (2d)

Brown solid; yield: 52 mg (72%).

¹H NMR (300 MHz, CDCl₃): δ = 7.97 (s, 1 H), 7.57 (s, 1 H), 7.04 (s, 1 H), 6.86 (s, 1 H), 6.35 (s, 1 H), 4.42–4.35 (m, 4 H).

¹³C NMR (75 MHz, CDCl₃): δ = 146.7, 144.7, 134.2, 123.9, 123.7, 121.5, 117.7, 117.2, 113.1, 111.0, 111.0, 46.7, 41.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₀Br₂N₃: 365.9236; found: 365.9217.

2,3-Dichloro-5,6-dihydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazine (2e)

Brown sticky solid; yield: 31 mg (69%).

¹H NMR (300 MHz, CDCl₃): δ = 6.70 (d, J = 3.1 Hz, 2 H), 6.24–6.22 (m, 1 H), 4.30–4.26 (m, 2 H), 4.20–4.14 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 138.2, 126.2, 122.0, 121.5, 110.8, 110.2, 107.1, 43.4, 41.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₈Cl₂N₃: 228.0090; found: 228.0092.

5,6-Dihydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazine-2,3-dicarbonitrile (2f)

White powder; yield: 31 mg (73%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 7.16 (s, 1 H), 6.77 (dd, J = 2.1, 3.4 Hz, 1 H), 6.29–6.27 (m, 1 H), 4.48–4.42 (m, 4 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 143.9, 125.0, 120.6, 119.2, 112.6, 110.7, 109.7, 109.3, 108.9, 43.6, 42.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₈N₅: 210.0774; found: 210.0763.

2,3-Diphenyl-5,6-dihydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazine (2g)

Brown sticky solid; yield: 36 mg (58%).

¹H NMR (300 MHz, CDCl₃): δ = 7.54 (dd, J = 5.3, 3.1 Hz, 2 H), 7.44 (q, J = 4.8 Hz, 3 H), 7.35–7.33 (m, 2 H), 7.26–7.16 (m, 3 H), 6.89 (d, J = 3.6 Hz, 1 H), 6.72 (d, J = 1.4 Hz, 1 H), 6.29–6.27 (m, 1 H), 4.23–4.19 (m, 2 H), 4.08–4.05 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 140.0, 138.4, 134.5, 130.5, 130.3, 129.1, 128.5, 128.2, 127.4, 126.8, 126.6, 122.9, 121.3, 109.8, 106.7, 43.9, 42.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₈N₃: 312.1495; found: 312.1505.

5,6-Dihydropyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazine (2h)

Brown powder; yield: 15 mg (48%).

¹H NMR (300 MHz, CDCl₃): δ = 7.89 (d, J = 2.6 Hz, 1 H), 6.83 (d, J = 4.7 Hz, 2 H), 6.30 (d, J = 2.7 Hz, 1 H), 4.51–4.49 (m, 2 H), 4.40–4.38 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 151.6, 147.3, 123.3, 120.6, 110.6, 109.3, 45.4, 44.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₉N₄: 161.0827; found: 161.0823.

6,7-Dihydro-5H-benzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c][1,4]diazepine (2i)

Brown solid; yield: 32 mg (71%).

¹H NMR (300 MHz, CDCl₃): δ = 7.78 (dd, J = 1.7, 6.4 Hz, 1 H), 7.29–7.25 (m, 4 H), 6.80 (d, J = 1.8 Hz, 1 H), 6.28–6.26 (m, 1 H), 4.35–4.29 (m, 4 H), 2.57–2.51 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 147.4, 143.3, 135.7, 125.4, 124.2, 122.6, 122.1, 119.2, 114.9, 109.5, 108.9, 48.6, 44.5, 27.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₄N₃: 224.1182; found: 224.1188.

10,11-Dimethyl-6,7-dihydro-5H-benzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c][1,4]diazepine (2j)

White solid; yield: 31 mg (62%).

¹H NMR (300 MHz, CDCl₃): δ = 7.51 (s, 1 H), 7.14–7.13 (m, 1 H), 7.03 (s, 1 H), 6.73 (s, 1 H), 6.24–6.22 (m, 1 H), 4.25–4.20 (m, 4 H), 2.49–2.41 (m, 2 H), 2.38 (s, 3 H), 2.37 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 146.7, 141.9, 134.2, 131.2, 131.2, 124.9, 124.6, 119.4, 114.2, 109.3, 109.2, 48.5, 44.3, 28.0, 20.6, 20.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₈N₃: 252.1495; found: 252.1508.

10,11-Dichloro-6,7-dihydro-5H-benzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c][1,4]diazepine (2k)

Yellow solid; yield: 37 mg (64%).

¹H NMR (300 MHz, CDCl₃): δ = 7.73 (s, 1 H), 7.28–7.27 (d, J = 3.4 Hz, 1 H), 7.18–7.16 (m, 1 H), 6.75–6.74 (m, 1 H), 6.23–6.21 (m, 1 H), 4.29–4.18 (m, 4 H), 2.51–2.44 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 149.1, 142.8, 135.1, 126.4, 126.1, 125.6, 123.4, 119.9, 115.8, 110.3, 109.7, 48.9, 45.2, 27.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₂Cl₂N₃: 292.0403; found: 292.0403.

10,11-Dibromo-6,7-dihydro-5H-benzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c][1,4]diazepine (2l)

Brown solid; yield: 52 mg (69%).

¹H NMR (400 MHz, CDCl₃): δ = 7.92 (s, 1 H), 7.49 (s, 1 H), 7.18 (dd, J = 1.6, 3.7 Hz, 1 H), 6.76 (d, J = 1.8 Hz, 1 H), 6.24–6.22 (m, 1 H), 4.29–4.27 (m, 2 H), 4.23–4.20 (m, 2 H), 2.51–2.49 (m, 2 H).

¹³C NMR (101 MHz, CDCl₃): δ = 149.0, 143.8, 136.0, 126.2, 123.3, 123.1, 117.7, 116.8, 116.0, 113.5, 109.8, 49.02, 45.2, 27.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₂Br₂N₃: 379.9392; found: 379.9364.

2,3-Dichloro-6,7-dihydro-5H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]diazepine (2m)

Brown solid; yield: 25 mg (52%).

¹H NMR (300 MHz, CDCl₃): δ = 6.87 (dd, J = 1.7, 3.8 Hz, 1 H), 6.70–6.69 (m, 1 H), 6.19–6.17 (m, 1 H), 4.20 (t, J = 6.0 Hz, 2 H), 4.09 (t, J = 6.0 Hz, 2 H), 2.45–2.37 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 140.1, 126.1, 124.3, 123.8, 112.5, 112.0, 109.2, 47.9, 45.5, 27.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₀Cl₂N₃: 242.0246; found: 242.0254.

6,7-Dihydro-5H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]diazepine-2,3-dicarbonitrile (2n)

Brown solid; yield: 26 mg (58%).

¹H NMR (300 Hz, DMSO-d ₆): δ = 7.05 (m, 1 H), 6.96–6.94 (m, 1 H), 6.18–6.16 (m, 1 H), 4.39–4.33 (m, 4 H), 2.38–2.36 (m, 2 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 145.3, 127.3, 121.3, 120.9, 115.4, 112.6, 112.0, 109.3, 109.0, 49.1, 48.9, 25.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₀N₅: 224.0930; found: 224.0935.

2,3-Diphenyl-6,7-dihydro-5H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]diazepine (2o)

Brown solid; yield: 30 mg (46%).

¹H NMR (300 MHz, CDCl₃): δ = 7.56–7.52 (m, 2 H), 7.48–7.42 (m, 3 H), 7.38–7.34 (m, 2 H), 7.23–7.14 (m, 3 H), 6.92–6.90 (m, 1 H), 6.75–6.74 (m, 1 H), 6.24–6.22 (m, 1 H), 4.21 (t, J = 6.3 Hz, 2 H), 3.85 (t, J = 6.3 Hz, 2 H), 2.36–2.32 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 142.7, 134.7, 131.0, 130.8, 130.6, 129.3, 129.2, 128.6, 128.3, 128.1, 127.1, 126.4, 123.4, 111.4, 108.7, 46.5, 43.0, 29.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₀N₃: 326.1652; found: 326.1645.

Acknowledgment

K.N.T. and A.H.B. are grateful to the CSIR, New Delhi, India for research fellowships. We thank Ashima Chopra for helping in making starting materials.

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