Rh(III)-catalyzed C–H oxidative ortho-olefination of arenes using 7-azaindole as a directing group and utilization in the construction of new tetracyclic heterocycles containing a 7-azaindole skeleton

Abstract

A Rh(III)-catalyzed C–H ortho-mono-olefination of aryls directed by 7-azaindoles was reported. This method opens up a novel pathway to synthesize complex 7-azaindole derivatives and interestingly, we observed an intramolecular cascade annulation via unexpected double directing groups (7-azaindole and carbonyl).

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Introduction

The 7-azaindole skeleton, widely used as key scaffolds, has been found in various pharmaceutical molecules and drug candidates (Fig. 1).¹ More important, the two nitrogen atoms in 7-azaindole scaffolds could serve as both hydrogen-bond donors and acceptors to form bidentate hydrogen bonds leading to the enhanced activity in the binding site.^1b However, up to now, direct modifications of 7-azaindoles are still rare.² In 2009, Fagnou reported a Pd(II)-catalyzed arylation of 7-azaindoles via N-oxide activation.^3a Later, a direct C–H arylation of N-methyl-7-azaindole at the C-2 position by diverse arylboronic acids was also realized by Das and co-workers.^3b Very recently, Das et al. developed a Pd-catalyzed oxidative C-3 alkenylation of 7-azaindoles.⁴ Moreover, 7-azaindole also has an inherent property in C–H activation. Recently, Xu and Dong independently reported the Rh(III)-catalyzed 7-azaindole directed C–H activation of arenes forming novel complex derivatives.⁵ Despite this progress, the 7-azaindole directed C_sp²–C_sp² coupling/addition reaction has not been studied yet.

Fig. 1 Examples of 7-azaindoles as potent biological activities.

Since 1967, the report of the pioneering work by Fujiwara and Moritani, oxidative olefination of C–H bonds has attracted increasing attention.⁶ This strategy has been applied to the synthesis of many useful complex structures owing to its step-economic and waste-reducing process. Indeed, although various directing groups (e.g., pyrazole, pyridine, imine, amide, carboxylic acid and N-nitroso) have been identified as effective tools for selective C–C couplings,⁷ further development is still in strong demand regarding high ortho-monoselectivity and wide substrate scope. Thus based on the previous reports and as well as our own interest in developing novel complex 7-azaindole derivatives,^1b,5c herein we reported an efficient method for the 7-azaindole directed C–H oxidative ortho-olefination of arenes catalyzed by rhodium and its utilization in the construction of tetracyclic heterocycles containing 7-azaindole skeleton. Though the Dong group reported a novel Rh(III)-catalyzed C–H activation of 7-azaindoles with electron-rich alkenyl esters while our paper was in preparation,⁸ there is obvious difference between their work and our work.

Results and discussion

At the outset, the alkenylation of 1-phenyl-7-azaindole (1a) with styrene (2a) was used as model to optimize the reaction conditions (Table 1). First, four kinds of commonly used metal catalysts, Pd(II), Ru(II), Rh(III) and Ir(III), were examined in the in the presence of KOAc and AgOAc in toluene at 120 °C for 14 h (entries 1–5). The best result is the [RhCp*Cl₂]₂ as catalyst to afford the desired product 3a in 18% yield (entry 4). Then, different oxidants were screened using [RhCp*Cl₂]₂ as catalyst. To our delight, the use of Cu(OAc)₂ proved to be a superior oxidant and product 3a was isolated in 66% yield (entries 6–8). Subsequently, the effect of solvents were examined and it was found that 1,4-dioxane as solvent could improve the yield from 66% to 76% (entries 8–13). Finally, different additives were also screened and KOAc was still the most effective (entries 13–16). Interestingly, when excess styrene was added, bis-olefinated product was not observed, suggesting a high ortho-mono-selectivity (entry 17).

Table 1 Optimization of reaction conditions^a,b

Entry	Cat.	Oxidant	Solvent	Yield 3a (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (5 mol%), additive (0.2 mmol) and oxidant (0.4 mmol) in solvent (3.0 mL), stirred in a sealed tube at 120 °C for 14 h. b Isolated yields. c NaOAc as the additives. d CsOAc as the additives. e No additives were added. f 2a in large excess (1.2 mmol).
1	—	AgOAc	Toluene	n.r.
2	Pd(OAc)2	AgOAc	Toluene	n.r.
3	[RuCl2(p-cymene)]2	AgOAc	Toluene	n.r.
4	[RhCp*Cl2]2	AgOAc	Toluene	18
5	[IrCp*Cl2]2	AgOAc	Toluene	n.r.
6	[RhCp*Cl2]2	AgO	Toluene	14
7	[RhCp*Cl2]2	Ag2CO3	Toluene	12
8	[RhCp*Cl2]2	Cu(OAc)2	Toluene	66
9	[RhCp*Cl2]2	Cu(OAc)2	p-Xylene	16
10	[RhCp*Cl2]2	Cu(OAc)2	CH3CN	59
11	[RhCp*Cl2]2	Cu(OAc)2	DMF	32
12	[RhCp*Cl2]2	Cu(OAc)2	^tAmOH	n.r.
13	[RhCp*Cl 2 ] 2	Cu(OAc) 2	1,4-Dioxane	76
14^c	[RhCp*Cl2]2	Cu(OAc)2	1,4-Dioxane	74
15^d	[RhCp*Cl2]2	Cu(OAc)2	1,4-Dioxane	54
16^e	[RhCp*Cl2]2	Cu(OAc)2	1,4-Dioxane	12
17^f	[RhCp*Cl2]2	Cu(OAc)2	1,4-Dioxane	75

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With the optimized reaction conditions in hand, the scope of the current method was investigated. We tested various substituted 7-azaindoles as well as styrenes and acrylates under the optimized reaction conditions (Table 2). Gratifyingly, the reaction condition was compatible with a variety of common functional groups substituted on 1-phenyl ring of 7-azaindole and aryl ring of styrene to afford the corresponding products in good to excellent yields (3a–k). For the 7-azaindoles, both the electron-deficient and electron-rich 1-aryls showed good reactivity (3b–e). For the coupling partners, even instead of styrene with 2-vinylnaphthalene, the product 3k was still obtained in 80% yield. When treating 1a with acrylates, the oxidative coupling reaction also proceeded well to afford the desired products in high yields (3l–o, 77–86%). However, phenyl-acrylate and benzyl-acrylate gave lower yields, presumably due to steric hindrance (3p, q). Varying the coupling partner with acrylamide and vinyl phosphonate, it was found that the reaction could be readily transformed without loss of reactivity (3r, s). Moreover, aryl, heteroaryl and alkyl substituents on the 7-azaindole core were all well tolerated to give the desired products in moderate to good yields (3t–v). Unfortunately, 3-halo substituted 7-azaindoles did not afford the expected products which need further explanation (3w).

Table 2 Substrate scope of 7-azaindole directed olefination^a,b

a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [RhCp*Cl₂]₂ (5 mol%), KOAc (0.2 mmol) and Cu(OAc)₂ (0.4 mmol) in solvent (3.0 mL), stirred in a sealed tube at 120 °C for 14 h. b Isolated yields.

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Interestingly, when 3-acetyl-1-phenyl-7-azaindole 1j was subjected to the reaction with styrene 2a under standard conditions, an unexpected intramolecular cascade annulation took place to afford the tetracyclic compound 4a in 45% yield (see ESI for characterization†). According to the literature,⁹ the 3-acetyl group of 1j should be a directing group, which could trigger the intramolecular annulation (Table 3). It has to be pointed out, unfortunately, the intermediates 4aa could not be detected in the process of the reaction. Gladly, when replacing the 3-acetyl group with other similar directing groups, the corresponding tetracycles 4b–d were also smoothly obtained, further demonstrating the directing function of the 3-acyl moiety and oxalyl amide/DG (4d, 51%) proved to be the most efficient. To the best of our knowledge, we are the first to synthesize this new kind of azaindole fused heterocyclic derivatives via Rh(III)-catalyzed cascade C–H alkenylation/intramolecular carbonyl directed annulation. Despite the modest yield, while in these cases, the majority of the starting materials were recovered.

Table 3 Substrate scope of 7-azaindoles for annulation^a,b

a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [RhCp*Cl₂]₂ (5 mol%), KOAc (0.2 mmol) and Cu(OAc)₂ (0.4 mmol) in solvent (3.0 mL), stirred in a sealed tube at 120 °C for 20 h. b Isolated yields.

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To explore the reaction pathway, the deuterium-labeling experiments were also carried out (Scheme 1). With the excess introduction of CD₃OD, the H/D exchange was clearly observed (20% D incorporation), which illustrates that the C–H cleavage step occurs and is reversible. A mixture of 1a and d₅-1a was also allowed to react with 2a, which demonstrated an intermolecular kinetic isotope effect (KIE) of 2.3, thus suggesting that the C–H bond cleavage of the arenes might be involved in the rate-limiting step.

Scheme 1 Deuterium-labeling result and kinetic isotope effect.

On the basis of the above results and recent achievements in Rh(III)-catalyzed oxidative C–H olefination,^7,10 a plausible mechanism is proposed (Scheme 2). First, monomeric RhCp*(OAc)₂ reacted with 7-azaindole to form rhodacycle species A. Subsequently, olefin 2a inserted into the C–Rh bond to give an intermediate B which undergo β-H elimination to afford products 3a. When 3-acetyl existed,⁹ rhodacycle species C appeared from the second C–H activation of the ortho C–H bond, followed by C–Rh addition giving the cyclometalated complex D, which undergo protonation giving the alkylation product 4a.

Scheme 2 Proposed mechanism.

Conclusions

In summary, we have developed a useful method for the synthesis of a wide range of ortho-olefinated 7-azaindole derivatives. Moreover, we are the first to realize the cascade reaction of Rh(III)-catalyzed C–H alkenylation/intramolecular carbonyl directed C–C annulation for 1-phenyl-3-acyl-7-azaindoles, which lead to new azaindole fused heterocyclic derivatives. Further applications of these synthesized molecules as well as their biological activities are currently under investigation in our laboratory.

Experimental section

Unless otherwise noted, starting materials were purchased from J&K, TCI, Sigma, Arcos, Alfa and used without purification. Catalysts and additives were purchased from TCI, solvents were used without pre-purification. All of the reactions were monitored by thin layer chromatography (TLC) on GF₂₅₄ silica gel plates. ¹H NMR spectra and ¹³C NMR spectra were recorded on a Bruker AVANCE III 400 (400 MHz) spectrometer in needful d-reagents (CDCl₃) with tetramethylsilane (TMS) as an internal reference. HRMS of additional products were carried out on Bruker Apex IV FTMS. Melting points were determined on X5A made by Beijing Fukai Company as uncorrected values. All manipulations were conducted with a standard sealed tube.

General procedure for Rh(III)-catalyzed oxidative olefination and annulation via double DGs

To a 15 mL sealed tube was added 1 (0.2 mmol), styrene (0.3 mmol, 31 mg), [RhCp*Cl₂]₂ (5%, 6.1 mg), KOAc (0.2 mmol, 20 mg), Cu(OAc)₂ (0.4 mmol, 72 mg) and 1,4-dioxane (3 mL). The reaction mixture was vigorously stirred at 120 °C under air for 14–20 h. And then the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel to afford the desired products 3 or 4 (PET : EtOAc = 8 : 1).

(E)-1-(2-Styrylphenyl)-1H-pyrrolo[2,3-b]pyridine (3a)

Light yellow oil, (yield, 76%), ¹H NMR (400 MHz, CDCl₃) δ 8.35 (dd, J = 4.7, 1.5 Hz, 1H), 8.01 (dd, J = 7.8, 1.5 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.54–7.38 (m, 3H), 7.33 (d, J = 3.5 Hz, 1H), 7.24 (d, J = 4.4 Hz, 4H), 7.22–7.17 (m, 1H), 7.13 (dd, J = 7.8, 4.7 Hz, 1H), 7.06 (d, J = 16.3 Hz, 1H), 6.71 (d, J = 16.3 Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 148.6, 144.0, 137.1, 136.1, 134.8, 130.9, 130.2, 129.1, 128.6, 128.4, 128.3, 127.8, 126.6, 126.5, 124.0, 120.7, 116.5, 101.0. HRMS m/z (ESI) calcd for C₂₁H₁₇N₂ (M + H)⁺: 297.1386, found 297.1382.

(E)-1-(4-Chloro-2-styrylphenyl)-1H-pyrrolo[2,3-b]pyridine (3b)

White solid, (yield, 83%), mp 96.3–98.2 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (dd, J = 4.7, 1.3 Hz, 1H), 8.01 (dd, J = 7.8, 1.4 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.39 (dt, J = 8.4, 5.2 Hz, 3H), 7.30 (d, J = 3.6 Hz, 1H), 7.27–7.21 (m, 4H), 7.14 (dd, J = 7.8, 4.7 Hz, 1H), 7.06 (d, J = 16.3 Hz, 1H), 6.64 (dd, J = 12.6, 9.9 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 148.6, 144.1, 136.6, 136.4, 134.5, 134.3, 132.2, 129.9, 129.8, 129.2, 128.7, 128.2, 128.2, 126.8, 126.3, 122.8, 120.7, 116.7, 101.4. HRMS m/z (ESI) calcd for C₂₁H₁₆ClN₂ (M + H)⁺: 331.0997, found 331.0993.

(E)-1-(4-Methoxy-2-styrylphenyl)-1H-pyrrolo[2,3-b]pyridine (3c)

Light yellow solid, (yield, 54%), mp 34.4–36.8 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (dd, J = 4.7, 1.3 Hz, 1H), 8.04–7.97 (m, 1H), 7.35 (dd, J = 8.4, 5.7 Hz, 2H), 7.29 (d, J = 3.5 Hz, 1H), 7.27–7.19 (m, 5H), 7.11 (dd, J = 7.8, 4.7 Hz, 1H), 7.02 (d, J = 16.3 Hz, 1H), 6.97 (dd, J = 8.6, 2.8 Hz, 1H), 6.66–6.57 (m, 2H), 3.92 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 159.5, 148.9, 144.0, 137.0, 136.1, 131.1, 130.4, 129.8, 129.4, 129.0, 128.6, 127.9, 126.7, 123.9, 120.5, 116.3, 114.2, 111.0, 100.7, 55.7. HRMS m/z (ESI) calcd for C₂₂H₁₉N₂O (M + H)⁺: 327.1492, found 327.1488.

(E)-1-(4-(1H-Pyrrolo[2,3-b]pyridin-1-yl)-3-styrylphenyl)ethan-1-one (3d)

Yellow solid, (yield, 81%), mp 40.0–41.7 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.48–8.41 (m, 1H), 8.38–8.31 (m, 1H), 8.08–7.95 (m, 2H), 7.68–7.57 (m, 1H), 7.38–7.33 (m, 1H), 7.31–7.13 (m, 7H), 6.84–6.75 (m, 1H), 6.72–6.63 (m, 1H), 2.70 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 197.4, 148.5, 144.1, 139.9, 136.7, 136.5, 134.7, 132.1, 129.6, 129.3, 128.7, 128.6, 128.2, 128.0, 126.8, 126.8, 123.4, 120.9, 117.0, 101.9, 26.9. HRMS m/z (ESI) calcd for C₂₃H₁₉N₂O (M + H)⁺: 339.1492, found 339.1484.

(E)-1-(5-Fluoro-2-styrylphenyl)-1H-pyrrolo[2,3-b]pyridine (3e)

Colorless oil, (yield, 65%), ¹H NMR (400 MHz, CDCl₃) δ 8.34 (dd, J = 4.7, 1.5 Hz, 1H), 8.01 (dd, J = 7.8, 1.6 Hz, 1H), 7.38–7.28 (m, 3H), 7.25–7.15 (m, 6H), 7.15–7.11 (m, 1H), 7.04 (d, J = 16.7 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 6.53 (d, J = 16.7 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 162.6, 148.5, 144.1, 137.6, 137.4, 135.4 (d, J_C–F = 11 Hz), 129.8, 129.2, 128.5, 128.1, 128.0, 126.5, 124.6 (d, J_C–F = 4 Hz), 123.6 (d, J_C–F = 13 Hz), 120.65, 118.35, 116.71, 116.0 (d, J_C–F = 24 Hz), 101.47. HRMS m/z (ESI) calcd for C₂₁H₁₆FN₂ (M + H)⁺: 315.1292, found 315.1290.

(E)-1-(2-(4-Chlorostyryl)phenyl)-1H-pyrrolo[2,3-b]pyridine (3f)

Yellow solid, (yield, 68%), mp 39.9–41.9 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (dd, J = 4.7, 1.5 Hz, 1H), 8.01 (dd, J = 7.8, 1.5 Hz, 1H), 7.90–7.77 (m, 1H), 7.52–7.42 (m, 3H), 7.32 (d, J = 3.5 Hz, 1H), 7.22–7.17 (m, 2H), 7.13 (dd, J = 7.9, 4.6 Hz, 3H), 6.99 (d, J = 16.3 Hz, 1H), 6.66 (dd, J = 9.9, 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 148.6, 144.0, 136.2, 135.6, 134.4, 133.4, 130.1, 129.5, 129.1, 128.8, 128.6, 128.6, 128.5, 127.8, 126.5, 124.7, 120.6, 116.6, 101.2. HRMS m/z (ESI) calcd for C₂₁H₁₆ClN₂ (M + H)⁺: 331.0997, found 331.0990.

(E)-1-(2-(4-(Trifluoromethyl)styryl)phenyl)-1H-pyrrolo[2,3-b]pyridine (3g)

Light red oil, (yield, 72%), ¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, J = 4.6 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.56–7.38 (m, 5H), 7.30 (dd, J = 11.4, 5.8 Hz, 3H), 7.13 (dd, J = 7.8, 4.7 Hz, 1H), 7.05 (d, J = 16.3 Hz, 1H), 6.78 (d, J = 16.3 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 148.7, 144.1, 140.6, 136.5, 134.1, 130.0, 129.6, 129.5, 129.2, 129.1, 129.0, 128.7, 128.5, 126.7, 126.6, 125.5 (CF₃, q, J_C–F = 11 Hz), 122.8, 120.7, 116.6, 101.3. HRMS m/z (ESI) calcd for C₂₂H₁₆F₃N₂ (M + H)⁺: 365.1260, found 365.1268.

(E)-1-(2-(4-Nitrostyryl)phenyl)-1H-pyrrolo[2,3-b]pyridine (3h)

Yellow oil, (yield, 31%), ¹H NMR (400 MHz, CDCl₃) δ 8.34 (dd, J = 4.7, 1.3 Hz, 1H), 8.09 (d, J = 8.8 Hz, 2H), 8.04 (dd, J = 7.9, 1.4 Hz, 1H), 7.92–7.84 (m, 1H), 7.56–7.46 (m, 3H), 7.37–7.30 (m, 3H), 7.16 (dd, J = 7.8, 4.7 Hz, 1H), 7.09 (d, J = 16.3 Hz, 1H), 6.86 (d, J = 16.3 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 148.6, 146.9, 144.1, 143.6, 136.8, 133.6, 129.9, 129.5, 129.3, 129.2, 128.8, 128.6, 128.3, 127.0, 126.7, 124.0, 120.7, 116.7, 101.5. HRMS m/z (ESI) calcd for C₂₁H₁₆N₃O₂ (M + H)⁺: 342.1237, found 342.1238.

(E)-1-(2-(4-Methoxystyryl)phenyl)-1H-pyrrolo[2,3-b]pyridine (3i)

Light yellow solid, (yield, 63%), mp 36.5–37.6 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (dd, J = 4.7, 1.3 Hz, 1H), 8.01 (dd, J = 7.8, 1.4 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.50–7.37 (m, 3H), 7.33 (d, J = 3.5 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.13 (dd, J = 7.8, 4.7 Hz, 1H), 7.01 (d, J = 16.3 Hz, 1H), 6.78 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 3.5 Hz, 1H), 6.56 (d, J = 16.2 Hz, 1H), 3.76 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 159.4, 148.6, 143.9, 135.9, 135.1, 130.4, 130.2, 130.0, 129.0, 128.6, 128.4, 127.9, 127.9, 126.2, 121.8, 120.6, 116.5, 114.0, 100.9, 55.3. HRMS m/z (ESI) calcd for C₂₂H₁₉N₂O (M + H)⁺: 327.1492, found 327.1486.

(E)-1-(2-(2-Methoxystyryl)phenyl)-1H-pyrrolo[2,3-b]pyridine (3j)

Colorless oil, (yield, 50%), ¹H NMR (400 MHz, CDCl₃) δ 8.35 (dd, J = 4.7, 1.5 Hz, 1H), 8.00 (dd, J = 7.8, 1.5 Hz, 1H), 7.93–7.87 (m, 1H), 7.51–7.36 (m, 4H), 7.34 (d, J = 3.5 Hz, 1H), 7.20–7.08 (m, 3H), 6.81 (dd, J = 12.1, 4.3 Hz, 2H), 6.73 (d, J = 16.4 Hz, 1H), 6.63 (d, J = 3.5 Hz, 1H), 3.76 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 157.0, 148.7, 143.9, 136.1, 135.4, 130.3, 129.0, 128.8, 128.49, 128.4, 128.0, 126.8, 126.5, 126.2, 125.8, 124.4, 120.6, 116.4, 110.9, 100.8, 55.4. HRMS m/z (ESI) calcd for C₂₂H₁₉N₂O (M + H)⁺: 327.1492, found: 327.1497.

(E)-1-(2-(2-(Naphthalen-2-yl)vinyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (3k)

Light yellow solid, (yield, 80%), mp 156.2–156.7 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (dd, J = 4.7, 1.3 Hz, 1H), 8.03 (dd, J = 7.8, 1.5 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.80–7.70 (m, 2H), 7.66 (d, J = 5.8 Hz, 2H), 7.55–7.30 (m, 7H), 7.24 (d, J = 2.7 Hz, 1H), 7.14 (dd, J = 7.8, 4.7 Hz, 1H), 6.82 (d, J = 16.3 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 148.7, 144.0, 136.2, 134.8, 134.7, 133.5, 133.1, 131.0, 130.2, 129.1, 128.6, 128.4, 128.4, 128.2, 128.0, 127.6, 126.9, 126.5, 126.3, 126.0, 124.4, 123.4, 120.7, 116.5, 101.1. HRMS m/z (ESI) calcd for C₂₅H₁₉N₂ (M + H)⁺: 347.1543, found 347.1539.

Methyl (E)-3-(2-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylate (3l)

Light yellow oil, (yield, 81%), ¹H NMR (400 MHz, CDCl₃) δ 8.32 (dd, J = 4.7, 1.5 Hz, 1H), 8.00 (dd, J = 7.8, 1.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.59–7.43 (m, 3H), 7.38 (d, J = 16.0 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 7.18–7.09 (m, 1H), 6.67 (d, J = 3.6 Hz, 1H), 6.37 (d, J = 16.0 Hz, 1H), 3.68 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 167.0, 148.6, 144.0, 140.3, 137.6, 131.8, 130.9, 129.7, 129.3, 128.9, 128.5, 127.6, 120.8, 120.0, 116.8, 101.8, 51.7. HRMS m/z (ESI) calcd for C₁₇H₁₅N₂O₂ (M + H)⁺: 279.1128, found 279.1132.

Ethyl (E)-3-(2-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylate (3m)

Light yellow oil, (yield, 77%), ¹H NMR (400 MHz, CDCl₃) δ 8.32 (dd, J = 4.7, 1.4 Hz, 1H), 8.00 (dd, J = 7.8, 1.4 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.57–7.42 (m, 3H), 7.37 (d, J = 16.0 Hz, 1H), 7.31–7.24 (m, 1H), 7.13 (dd, J = 7.8, 4.7 Hz, 1H), 6.67 (d, J = 3.6 Hz, 1H), 6.38 (d, J = 16.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 148.6, 144.0, 140.0, 137.6, 131.9, 130.8, 129.8, 129.2, 128.8, 128.4, 127.5, 120.8, 120.4, 116.8, 101.8, 60.5, 14.2. HRMS m/z (ESI) calcd for C₁₈H₁₇N₂O₂ (M + H)⁺: 293.1285, found 293.1287.

ⁿ Butyl (E)-3-(2-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylate (3n)

Light yellow oil, (yield, 82%), ¹H NMR (400 MHz, CDCl₃) δ 8.32 (dd, J = 4.7, 1.5 Hz, 1H), 8.00 (dd, J = 7.8, 1.5 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.57–7.43 (m, 3H), 7.34 (d, J = 16.0 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 7.13 (dd, J = 7.8, 4.7 Hz, 1H), 6.67 (d, J = 3.6 Hz, 1H), 6.38 (d, J = 16.0 Hz, 1H), 4.07 (t, J = 6.6 Hz, 2H), 1.55 (dt, J = 14.5, 6.6 Hz, 2H), 1.33–1.26 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.6, 148.6, 144.0, 139.9, 137.6, 131.9, 130.8, 129.8, 129.2, 128.8, 128.4, 127.4, 120.8, 120.4, 116.7, 101.7, 64.3, 30.6, 19.1, 13.7. HRMS m/z (ESI) calcd for C₂₀H₂₁N₂O₂ (M + H)⁺: 321.1598, found 321.1596.

^t Butyl (E)-3-(2-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylate (3o)

Light yellow oil, (yield, 86%), ¹H NMR (400 MHz, CDCl₃) δ 8.32 (dd, J = 4.7, 1.4 Hz, 1H), 7.99 (dd, J = 7.8, 1.5 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.62–7.43 (m, 3H), 7.26 (dd, J = 12.8, 7.0 Hz, 2H), 7.13 (dd, J = 7.8, 4.7 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 6.33 (d, J = 15.9 Hz, 1H), 1.40 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 165.8, 148.7, 143.9, 138.8, 137.5, 132.0, 130.6, 129.8, 129.2, 128.8, 128.4, 127.3, 122.2, 120.8, 116.7, 101.6, 80.5, 28.1. HRMS m/z (ESI) calcd for C₂₀H₂₁N₂O₂ (M + H)⁺: 321.1598, found 321.1601.

Phenyl (E)-3-(2-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylate (3p)

Yellow solid, (yield, 52%), mp 102.5–104.2 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (dd, J = 4.7, 1.4 Hz, 1H), 7.99 (dd, J = 7.8, 1.5 Hz, 1H), 7.95–7.85 (m, 1H), 7.64–7.48 (m, 4H), 7.40–7.29 (m, 3H), 7.19 (t, J = 7.4 Hz, 1H), 7.13 (dd, J = 7.9, 4.7 Hz, 1H), 7.05 (d, J = 7.6 Hz, 2H), 6.68 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 16.0 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 164.9, 150.7, 148.7, 144.1, 142.0, 137.9, 131.6, 131.3, 129.7, 129.4, 129.3, 128.9, 128.5, 127.7, 125.7, 121.5, 120.8, 119.3, 116.9, 102.0. HRMS m/z (ESI) calcd for C₂₂H₁₇N₂O₂ (M + H)⁺: 341.1285, found 341.1282.

Benzyl (E)-3-(2-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylate (3q)

Colorless oil, (yield, 54%), ¹H NMR (400 MHz, CDCl₃) δ 8.32 (dd, J = 4.7, 1.5 Hz, 1H), 8.00 (dd, J = 7.8, 1.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.57–7.44 (m, 3H), 7.41 (d, J = 16.0 Hz, 1H), 7.37–7.29 (m, 3H), 7.29–7.23 (m, 3H), 7.14 (dd, J = 7.8, 4.7 Hz, 1H), 6.67 (d, J = 3.6 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 5.12 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 166.3, 148.7, 144.0, 140.6, 137.7, 136.0, 131.8, 131.0, 129.7, 129.3, 128.8, 128.5, 128.5, 128.1, 127.9, 127.5, 120.8, 119.9, 116.8, 101.8, 66.2. HRMS m/z (ESI) calcd for C₂₃H₁₉N₂O₂ (M + H)⁺: 355.1441, found 355.1436.

(E)-3-(2-(1H-Pyrrolo[2,3-b]pyridin-1-yl)phenyl)-N,N-dimethylacrylamide (3r)

Red solid, (yield, 70%), mp 91.7–93.9 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dd, J = 4.7, 1.4 Hz, 1H), 7.97 (dd, J = 7.8, 1.5 Hz, 1H), 7.82–7.70 (m, 1H), 7.55–7.42 (m, 3H), 7.37–7.24 (m, 2H), 7.11 (dd, J = 7.8, 4.7 Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H), 6.54 (d, J = 15.6 Hz, 1H), 2.93 (s, 3H), 2.91 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.3, 148.6, 144.0, 137.4, 137.1, 133.1, 130.1, 129.6, 129.2, 129.1, 128.5, 128.3, 120.8, 120.2, 116.6, 101.6, 37.2, 35.7. HRMS m/z (ESI) calcd for C₁₈H₁₈N₃O (M + H)⁺: 292.1444, found 292.1441.

Diethyl (E)-(2-(1H-pyrrolo[2,3-b]pyridin-1-yl)styryl)phosphonate (3s)

Colorless oil, (yield, 71%), ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J = 3.9 Hz, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 7.3 Hz, 1H), 7.49 (ddd, J = 25.0, 15.8, 7.4 Hz, 3H), 7.30 (d, J = 3.5 Hz, 1H), 7.13 (dd, J = 7.7, 4.8 Hz, 1H), 7.01 (dd, J = 22.2, 17.5 Hz, 1H), 6.68 (d, J = 3.4 Hz, 1H), 6.14 (t, J = 17.6 Hz, 1H), 4.06–3.83 (m, 4H), 1.18 (t, J = 7.1 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 148.5, 144.0, 137.0, 132.6, 132.4, 130.8, 129.6, 129.5, 128.7, 128.6, 127.4, 121.0, 116.8, 101.9, 61.9, 61.9, 16.3, 16.2. HRMS m/z (ESI) calcd for C₁₉H₂₂N₂O₃P (M + H)⁺: 357.1363, found: 357.1350.

ⁿ Butyl (E)-3-(2-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylate (3t)

White solid, (yield, 78%), mp 79.2–80.9 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (dd, J = 4.7, 1.4 Hz, 1H), 8.30 (dd, J = 8.0, 1.5 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.71–7.63 (m, 2H), 7.60–7.39 (m, 7H), 7.34 (t, J = 7.4 Hz, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 4.07 (t, J = 6.6 Hz, 2H), 1.53 (dt, J = 14.5, 6.6 Hz, 2H), 1.30–1.23 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 149.1, 144.4, 139.8, 137.3, 134.3, 131.9, 130.9, 129.0, 128.8, 128.6, 128.6, 127.5, 127.3, 126.7, 126.6, 120.6, 119.1, 117.3, 117.2, 64.4, 30.6, 19.1, 13.7. HRMS m/z (ESI) calcd for C₂₆H₂₅N₂O₂ (M + H)⁺: 397.1911, found 397.1911.

ⁿ Butyl (E)-3-(2-(4-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylate (3u)

Colorless oil, (yield, 65%), ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J = 5.0 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.58–7.41 (m, 3H), 7.37 (d, J = 16.0 Hz, 1H), 7.23 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 5.1 Hz, 1H), 6.39 (d, J = 16.0 Hz, 1H), 4.08 (t, J = 6.6 Hz, 2H), 2.36–2.22 (m, 1H), 1.56 (dt, J = 14.5, 6.6 Hz, 2H), 1.30 (dd, J = 15.0, 7.5 Hz, 2H), 1.22–1.15 (m, 2H), 1.02 (dt, J = 6.2, 4.3 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.6, 148.4, 146.8, 144.3, 140.1, 137.8, 131.9, 130.8, 128.8, 128.7, 128.3, 127.4, 120.4, 120.3, 111.3, 100.1, 64.3, 30.6, 19.1, 13.7, 13.0, 9.7. HRMS m/z (ESI) calcd for C₂₃H₂₅N₂O₂ (M + H)⁺: 361.1911, found 361.1914.

ⁿ Butyl (E)-3-(2-(5-(furan-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylate (3v)

Yellow oil, (yield 26%), ¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.60–7.47 (m, 4H), 7.36 (d, J = 16.0 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 6.70 (d, J = 3.6 Hz, 1H), 6.66 (d, J = 3.2 Hz, 1H), 6.50 (dd, J = 3.3, 1.8 Hz, 1H), 6.39 (d, J = 16.0 Hz, 1H), 4.07 (t, J = 6.6 Hz, 2H), 1.59–1.52 (m, 2H), 1.29 (d, J = 7.6 Hz, 2H), 0.88–0.84 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 152.8, 147.9, 142.0, 140.9, 139.8, 137.4, 131.9, 130.9, 130.6, 128.7, 128.6, 127.5, 124.4, 121.0, 120.5, 120.5, 111.6, 104.3, 102.1, 64.4, 30.6, 19.1, 13.6. HRMS m/z (ESI) calcd for C₂₄H₂₃N₂O₃ (M + H)⁺: 387.1703, found 387.1706.

1-(6-Phenyl-5,6-dihydro-6l3-pyrido[3′,2′:4,5]pyrrolo[1,2-a]quinolin-7-yl)ethan-1-one (4a)

Yellow solid, (yield 45%), racemic, ¹H NMR (400 MHz, CDCl₃) δ 9.10 (d, J = 8.2 Hz, 1H), 8.58–8.41 (m, 2H), 7.46–7.37 (m, 1H), 7.31 (dd, J = 7.9, 4.8 Hz, 1H), 7.20–7.07 (m, 5H), 6.98 (dd, J = 7.5, 1.6 Hz, 2H), 5.51 (dd, J = 5.9, 1.5 Hz, 1H), 3.46 (dd, J = 15.4, 6.0 Hz, 1H), 3.18 (dd, J = 15.5, 1.7 Hz, 1H), 2.60 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 193.7, 147.3, 145.9, 143.7, 140.0, 135.1, 129.7, 129.2, 128.5, 127.8, 127.4, 126.9, 126.3, 125.7, 120.4, 120.2, 119.0, 112.0, 37.9, 33.9, 31.5. HRMS m/z (ESI) calcd for C₂₃H₁₉N₂O (M + H)⁺: 339.1492, found 339.1493.

Phenyl(6-phenyl-5,6-dihydro-6l3-pyrido[3′,2′:4,5]pyrrolo[1,2-a]quinolin-7-yl)methanone (4b)

Light yellow solid, (yield 15%), racemic, ¹H NMR (400 MHz, CDCl₃) δ 9.13 (d, J = 8.1 Hz, 1H), 8.46 (dd, J = 4.7, 1.6 Hz, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.70–7.61 (m, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.48–7.41 (m, 1H), 7.42–7.32 (m, 2H), 7.21–7.05 (m, 6H), 6.91 (dd, J = 7.0, 2.3 Hz, 2H), 5.12 (dd, J = 5.7, 2.5 Hz, 1H), 3.45 (dd, J = 15.5, 5.8 Hz, 1H), 3.15 (dd, J = 15.5, 2.6 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 192.0, 147.2, 145.7, 143.7, 140.9, 140.5, 135.3, 131.9, 129.6, 129.2, 128.9, 128.4, 128.3, 127.8, 127.3, 126.7, 126.6, 125.6, 121.0, 120.1, 118.5, 111.4, 37.6, 34.2. HRMS m/z (ESI) calcd for C₂₈H₂₁N₂O (M + H)⁺: 401.1648, found 401.1655.

Methyl 2-oxo-2-(6-phenyl-5,6-dihydro-6l3-pyrido[3′,2′:4,5]pyrrolo[1,2-a]quinolin-7-yl)acetate (4c)

Yellow solid, (yield 32%), racemic, ¹H NMR (400 MHz, CDCl₃) δ 9.10 (d, J = 8.2 Hz, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.38 (dd, J = 8.0, 1.6 Hz, 1H), 7.43 (dt, J = 8.4, 4.2 Hz, 1H), 7.34 (dd, J = 8.0, 4.7 Hz, 1H), 7.21–7.07 (m, 5H), 6.97 (dd, J = 7.4, 1.8 Hz, 2H), 5.35 (dd, J = 5.9, 1.9 Hz, 1H), 3.75 (s, 3H), 3.48 (dd, J = 15.5, 6.0 Hz, 1H), 3.19 (dd, J = 15.6, 2.0 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 181.0, 165.6, 148.8, 147.6, 144.5, 139.5, 134.7, 129.6, 129.2, 128.6, 127.9, 127.3, 127.0, 126.4, 126.3, 120.4, 119.9, 119.7, 107.5, 52.6, 37.4, 33.8. HRMS m/z (ESI) calcd for C₂₄H₁₉N₂O₃ (M + H)⁺: 383.1390, found 383.1394.

N,N-Diisopropyl-2-oxo-2-(6-phenyl-5,6-dihydro-6l3-pyrido[3′,2′:4,5]pyrrolo[1,2-a]quinolin-7-yl)acetamide (4d)

Yellow solid, (yield 51%), racemic, ¹H NMR (400 MHz, CDCl₃) δ 9.12 (d, J = 8.2 Hz, 1H), 8.50 (dd, J = 6.5, 5.0 Hz, 2H), 7.44–7.36 (m, 1H), 7.32 (dd, J = 7.9, 4.8 Hz, 1H), 7.18–7.04 (m, 5H), 6.99–6.87 (m, 2H), 5.62 (d, J = 4.8 Hz, 1H), 3.62–3.49 (m, 2H), 3.44 (dd, J = 13.6, 6.8 Hz, 1H), 3.19 (dd, J = 15.6, 1.5 Hz, 1H), 1.53 (dd, J = 13.9, 6.8 Hz, 6H), 1.05 (d, J = 6.6 Hz, 3H), 0.66 (d, J = 5.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 186.3, 167.8, 147.6, 144.2, 139.9, 134.9, 129.9, 129.2, 128.5, 127.8, 127.3, 126.8, 126.4, 126.0, 120.3, 120.2, 119.4, 108.0, 50.4, 45.9, 36.8, 33.8, 20.6, 20.2, 20.2, 19.8. HRMS m/z (ESI) calcd for C₂₉H₃₀N₃O₂ (M + H)⁺: 452.2332, found 452.2328.

Acknowledgements

We gratefully acknowledge the financial support from National Science Foundation of China (No. 21172011).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra07478b

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