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Synthesis 2015; 47(16): 2457-2466
DOI: 10.1055/s-0034-1380865
paper
© Georg Thieme Verlag Stuttgart · New York

Palladium-Catalyzed Double C–H Arylation Reaction: Tandem Synthesis of Benzo[a]imidazo[5,1,2-cd]indolizines from Imidazo[1,2-a]pyridines and o-Dihaloarenes

Hanyang Wang
a   Department of Chemistry and Chemical Engineering, College of Science, Northeast Forestry University, Harbin, 150040, P. R. of China   Email: jspeng1998@nefu.edu.cn
,
Chunxia Chen
a   Department of Chemistry and Chemical Engineering, College of Science, Northeast Forestry University, Harbin, 150040, P. R. of China   Email: jspeng1998@nefu.edu.cn
,
Zhangjie Huang
a   Department of Chemistry and Chemical Engineering, College of Science, Northeast Forestry University, Harbin, 150040, P. R. of China   Email: jspeng1998@nefu.edu.cn
,
Liping Yao
b   Key Laboratory of Forest Plant Ecology, Northeast Forestry University, Harbin, 150040, P. R. of China
,
Bin Li
a   Department of Chemistry and Chemical Engineering, College of Science, Northeast Forestry University, Harbin, 150040, P. R. of China   Email: jspeng1998@nefu.edu.cn
,
Jinsong Peng*
a   Department of Chemistry and Chemical Engineering, College of Science, Northeast Forestry University, Harbin, 150040, P. R. of China   Email: jspeng1998@nefu.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 06 March 2015

Accepted after revision: 24 April 2015

Publication Date:
19 June 2015 (online)

 
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Abstract

A palladium-catalyzed direct arylation of 2-arylimidazo[1,2-a]pyridines with o-dihaloarenes via double C–H activation is described. The process comprises intermolecular C3-arylation of 2-arylimidazo[1,2-a]pyridines followed by an intramolecular C5-arylation in a highly regioselective fashion, affording benzo[a]imidazo[5,1,2-cd]indolizine derivatives in moderate to good yields.


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Key words

palladium - C–H activation - arylation - tandem synthesis - indolizine-fused polycyclics

In the past decades, considerable attention has been devoted to the development of novel aromatic heteropolycyclics as organic fluorophores for application in materials science and medicine.[1] Of these fluorophores, the isoindole or indolizine-fused polycyclic frameworks have attracted significant interest as drug candidates, organic electronic, and optical materials.[2] In particular, substituted imidazo[1,2-a]pyridine derivatives have been intensely explored in several areas, spanning biological activities,[3] fluorescent probes,[4] organic dyes,[5] chemosensors,[6] and luminescent materials.[7]

Given the importance of molecules containing this motif, much effort has been focused on the functionalization of imidazo[1,2-a]pyridine templates in recent years.[3] Among the various methods, transition-metal-catalyzed cross-coupling reactions, such as Heck,[8] Negishi,[9] Suzuki–Miyaura,[10] Stille,[11] Sonogashira,[12] and amination[13] were widely employed. Compared to the above classical palladium-catalyzed reactions, direct C–H bond functionalization of (hetero)arene[14] has recently become a more popular and valuable strategy in the decoration of imidazo[1,2-a]pyridine system, and direct C-arylation,[15] C-alkenylation,[16] and carbonylation processes[17] at various positions have been developed. However, a sequential C–H activation strategy for the double or multiple functionalization of (hetero)arenes in one-pot fashion is still a challenge,[18] due to the lack of practicability and regioselectivity[19] in the metal-catalyzed cross-coupling processes. Such reports on double-coupling approaches at two different positions of imidazo[1,2-a]pyridines are scarce, and often two separate steps through conventional cross-coupling reactions/C–H functionalization are used.[20] Metal-catalyzed direct arylation of heteroaromatics with aryl halides is the most developed type of C–H functionalization. However, regiocontrolled arylation remains problematic for heteroarenes with multiple closely related nucleophilic centers and/or acidic C–H bonds.[19b] For C–H arylation of fused imidazoheterocycles,[21] biaryl cross-coupling reaction can potentially occur at various different positions depending on distinct mechanisms [SEAr, Heck-like, and CMD (concerted metalation–deprotonation) mechanism],[14b] as illustrated in Figure [1]. We envisioned that the reaction of 2-arylimidazo[1,2-a]pyridines 1 with 1,2-dibromoarenes 2 might first occur at the C3 position via electrophilic aromatic substitution mechanism (SEAr) to give C3-arylated intermediates, which might then undergo intramolecular C–H arylation at the C2′ position (path A) or at the C5 position (path B) to provide the corresponding π-expanded benzimidazole-fused phenanthridines or indolizines, respectively, as shown in Scheme [1]. In parallel with our continuing efforts to develop new synthetic methods of nitrogen-containing heteropolycyclics through palladium-catalyzed C–H functionalization,[22] herein we report on a highly regiocontrolled Pd-catalyzed dual C–H arylation process (path B) as a new and convenient entry to benzo[a]imidazo[5,1,2-cd]indolizines, a novel type of fluorescent dyes, which usually were prepared through [8+2] cycloaddition of benzynes and imidazo[1,2-a]pyridines.[7c] [23]

Zoom Image
Figure 1 Site-selectivity in the C–H arylation of fused imidazoheterocycles
Zoom Image
Scheme 1 Possible pathways for Pd-catalyzed sequential dual C–H arylation of imidazo[1,2-a]pyridines and o-dibromoarenes

First, 2-phenylimidazo[1,2-a]pyridine (1a) and o-dibromobenzene (2a) were selected as the coupling partners for a Pd-catalyzed tandem two-fold C–H activation/arylation sequence. Extensive experiments were conducted in the presence of different ligands for the Pd catalyst, bases, solvents, and temperature, and some relevant results are summarized in Table [1]. The blank experiment (without the catalyst) was examined in DMF at 160 °C for 24 hours using K2CO3­ as the base; here the reaction did not proceed (Table [1], entry 1). When the model reaction was performed in the presence of Pd(OAc)2 and Ph3P as the catalyst system, interestingly, the benzimidazole-fused indolizine product 3aa (Scheme [1], path B) was exclusively obtained in 44% yield (entry 2). 1H and 13C NMR spectroscopical data and melting point of 3aa were consistent with the values reported in the literature.[23] We then investigated the effect of various ligands (PCy3, TFP, Xphos, bidentate phosphorus ligands such as dppb, dppf, and DPEphos) on the reaction (entries 3–8). An enhancement or inhibition of reactivity was observed in this sequential C3 and C5 direct arylation reaction, and it was found that Buchwald-type ligand Xphos[24] performed better, and the yield was improved to 77% (entry 5). A brief screening of various palladium sources with Xphos as the supporting ligand resulted in no improvement of the reaction efficiency (entries 9–11). On examining the use of various bases such as K2CO3, Cs2CO3, KOt-Bu, and K3PO4 (entries 11–14), Cs2CO3 and K2CO3 were found to give better results (80% and 77% yield, entries 12 and 5). It is worth noting that the use of catalytic amount of pivalic acid as a proton shuttle, mostly employed in the CMD-mediated direct arylation process,[25] provided a similar yield to K2CO3 or Cs2CO3 (82% vs 77% or 80%, entries 5, 12, and 15). Finally, a survey of reaction media showed that nonpolar solvents THF and toluene afforded inferior results (entries 17 and 18) than the polar solvents DMA and DMF (entries 16 and 5), and DMF provided a better result (entry 5).

Table 1 Optimization of Pd-Catalyzed Tandem Annulation Reactiona

Entry

Catalyst

Ligandb

Base

Solvent

Temp (°C)

3aaYield (%)c

 1

–

–

K2CO3

DMF

160

 0

 2

Pd(OAc)2

Ph3P

K2CO3

DMF

160

44

 3

Pd(OAc)2

Cy3P

K2CO3

DMF

160

44

 4

Pd(OAc)2

TFP

K2CO3

DMF

160

55

 5

Pd(OAc)2

Xphos

K2CO3

DMF

160

77

 6

Pd(OAc)2

dppb

K2CO3

DMF

160

39

 7

Pd(OAc)2

dppf

K2CO3

DMF

160

53

 8

Pd(OAc)2

DPEphos

K2CO3

DMF

160

59

 9

Pd2(dba)3

Xphos

K2CO3

DMF

160

62

10

PdCl2

Xphos

K2CO3

DMF

160

68

11

PdCl2(MeCN)2

Xphos

K2CO3

DMF

160

74

12

Pd(OAc)2

Xphos

Cs2CO3

DMF

160

80

13

Pd(OAc)2

Xphos

KOt-Bu

DMF

160

43

14

Pd(OAc)2

Xphos

K3PO4

DMF

160

64

15

Pd(OAc)2

Xphos

Cs2CO3/t-BuCO2Hd

DMF

160

82

16

Pd(OAc)2

Xphos

K2CO3

DMA

160

59

17

Pd(OAc)2

Xphos

K2CO3

THF

120

13

18

Pd(OAc)2

Xphos

K2CO3

toluene

120

trace

19

Pd(OAc)2

Xphos

K2CO3

DMF

140

70

a Reaction conditions: Unless otherwise stated: 1a (0.2 mmol), 2a (0.3 mmol), base (0.6 mmol), Pd (10 mol%), ligand (20 mol%), and solvent (2.0 mL), 24 h.

b Xphos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; TFP: Tri(2-furyl)phosphine; DPEphos: 2,2′-Bis(diphenylphosphino)diphenyl ether.

c Yield of isolated product after chromatography.

d Reaction conducted in the presence of 20 mol% pivalic acid.

In addition, when decreasing the reaction temperature to 140 °C in DMF, the desired annulation product 3a was isolated in 70% yield (Table [1], entry 19). In general, the combination of Xphos and Pd(OAc)2 was an efficient catalyst system with K2CO3 or Cs2CO3 as the base in DMF at 160 °C to perform a sequential double C–H arylation of 2-arylimidazo[1,2-a]pyridines in highly regiocontrolled fashion.

With the optimized protocol in hand, the scope and generality of the present process were explored next. Initially, the reaction of various 2-arylimidazo[1,2-a]pyridine derivatives 1a–h with o-dibromobenzene was investigated to ascertain whether the regioselectivity can be tuned or not by the nature of aromatic C–H bond at the C2′ position (Scheme [2]). Although they are susceptible toward possible direct C2′-arylation facilitated by fused nitrogen coordination to the catalyst, remarkably, in all cases, the sequential double C–H arylation reactions uniformly proceeded at the C3 and C5 position to exclusively give the corresponding products 3aa–ha. These substrates with both electron-rich 1b, 1c, 1f, and 1g (Scheme [2]) and electron-poor 1d and 1e (Scheme [2]) groups on the 2-aryl moiety, can be smoothly transformed into benzimidazole-fused indolizine products in moderate to good yields. Extending the scope to α-naphthyl substrate 1h, the reaction can also proceed smoothly to give the corresponding product 3ha in 52% yield (Scheme [2]).

Zoom Image
Scheme 2 Annulation of 2-arylimidazo[1,2-a]pyridines with o-dibromobenzene. Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), K2CO3 (0.6 mmol), Pd(OAc)2 (0.02 mmol), Xphos (0.04 mmol), DMF (2.0 mL), 160 °C, 24 h. Yields of isolated products are shown. a 1-Bromo-2-chlorobenzene was used as the o-dihaloarene.

The influence of the pyridine moiety of imidazo[1,2-a]pyridine substrates on the reaction was then investigated under the optimized conditions (Table [2], entries 1–5). Substrates containing an electron-donating methyl group, such as 1i, 1j, and 1l were generally more reactive and provided higher yields (73–87%, entries 1, 2, and 4) than 1k bearing an electron-withdrawing chloro substituent (only 27%, entry 3). When extending the substrate scope to imidazo[1,2-a]pyrimidine 1m, as the best example, the reaction proceeded very smoothly to provide 3ma in 95% yield (entry 5), probably attributed to the increase of C–H acidity at the C5 position. In addition, the incorporation of the sterically hindering methyl group in the C6 position seemed not to affect the regioselectivity, the product 3la was exclusively obtained in 73% yield (entry 4). Finally, 1,2-dihaloarenes were then examined as another reaction partner in this process (entries 6–9). 1,2-Dihaloarene containing two different halogen atoms, such as 1-bromo-2-chlorobenzene (2b) (entry 6) and 1-bromo-2-iodobenzene (2c) (entry 7), worked well under the reported conditions and afforded the desired cyclized product in good yields. The use of symmetrically substituted 1,2-dibromoarene 2d can avoid the chemo- and regioselectivity in this double C–H arylation process (entry 8); however, such issues may potentially exist when asymmetrically substituted 1,2-dihaloarenes were used. The use of two different halogen atoms, such as 1-bromo-2-chloro- 4-methylbenzene (2e), seemed to ensure a regiospecific transformation under the present reaction conditions, and 3ae as the only product was isolated in 86% yield (entry 9). It showed that due to higher reactivity of aryl bromide than aryl chloride, the C3-arylation of imidazo[1,2-a]pyridine with C–Br might occur preferentially, followed by the intramolecular direct arylation of the C–H bond at the C5 position with C–Cl.

To gain insight into the mechanism of the reaction, a direct palladium-catalyzed monoarylation of 2-phenylimidazo[1,2-a]pyridine (1a) and iodobenzene or bromobenzene was conducted under the present conditions. As a result, the regioselective C3-arylated product[15c] was exclusively isolated and no traces of the regioisomeric C5 or C2′-arylated product was detected. On the basis of the above results, a reaction mechanism is proposed as shown in Scheme [3]. The initial step involves an electrophilic attack by the arylpalladium halide species, derived from oxidative addition of o-dibromobenzene (2a) to Pd(0) at the 3-position of the imidazopyridine 1 to give 4, then followed by deprotonation to form the aryl(imidazopyridyl)palladium(II) intermediate 5.

Table 2 Synthesis of Benzo[a]imidazo[5,1,2-cd]indolizines with Diverse Substitutionsa

Entry

2-Arylimidazo[1,2-a]pyridine 1

o-Dihaloarene 2

Product 3

Yield (%)b

1

1i

2a

3ia

83

2

1j

2a

3ja

87

3

1k

2a

3ka

27

4

1l

2a

3la

73

5

1m

2a

3ma

95

6

1a

2b

3aa

80

7

1a

2c

3aa

69

8

1a

2d

3ad

82

9

1a

2e

3ae

86

a Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), K2CO3 (0.6 mmol), Pd(OAc)2 (0.02 mmol), Xphos (0.04 mmol), DMF (2.0 mL), 160 °C, 24 h.

b Yields of isolated products.

Subsequent reductive elimination gives the C3-arylated intermediate 6 and regenerates the palladium(0) catalyst (SEAr mechanism, Scheme [3]).[21a] [26] Next, oxidative addition of intermediate 6 to Pd(0) followed by the approach of the aromatic C–H bond at the 5-position leads to a concerted metalation deprotonation transition state to form a six-membered palladacycle 8 (CMD mechanism, Scheme [3]).[25] The palladacycle 8 undergoes a C–C reductive elimination to afford the desired product 3 and Pd(0) species for the next catalytic cycle.

Zoom Image
Scheme 3 Proposed mechanism for sequential Pd-catalyzed twofold C–H arylation

In conclusion, we have developed a palladium-catalyzed protocol for the tandem synthesis of benzo[a]imidazo[5,1,2-cd]indolizines from 2-arylimidazo[1,2-a]pyridines and 1,2-dihaloarenes. The process is based on the highly regiocontrolled intermolecular C3-arylation and subsequent intramolecular C5-arylation to form the desired products in moderate to good yields. This Pd-catalyzed double arylation reaction will provide a useful tool for the discovery of fluorescent materials.

All chemicals were purchased from commercial suppliers and used without further purification. Solvents were dried and purified according to the standard procedures before use. 2-Arylimidazo[1,2-a]pyridines were prepared according to the literature methods.[27] All reactions were carried out in dried glassware and monitored by TLC. Melting points were determined on a melting point apparatus in open capillaries and are uncorrected. 1H NMR spectra were recorded on a 400 or 600 MHz spectrometer, 13C NMR spectra were recorded at 100 or 150 MHz. CDCl3 was used as solvent for recording the spectra, unless otherwise stated. Chemical shifts (δ) are given in ppm downfield relative to TMS (0.00 ppm). Standard abbreviations were used to report the splitting patterns. Coupling constants are given in hertz (Hz). High-resolution mass spectra were recorded on a BIO TOF Q mass spectrometer.


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Tandem Synthesis of Benzo[a]imidazo[5,1,2-cd]indolizines; General Procedure

A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with 2-arylimidazo[1,2-a]pyridine 1 (0.2 mmol, 1.0 equiv), o-dihaloarene 2 (0.3 mmol, 1.5 equiv), and K2CO3 (82.9 mg, 0.6 mmol, 3.0 equiv). To this mixture were added Pd(OAc)2 (0.02 mmol, 4.5 mg) and Xphos (0.04 mmol, 19.1 mg), followed by DMF (2.0 mL) via a syringe at r.t. The tube was sealed and kept in a preheated oil bath at 160 °C for 24 h. The mixture was cooled to r.t., quenched with H2O (5 mL), and diluted with CH2Cl2 (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel (H), eluting with 5–20% EtOAc–petroleum ether.


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1-Phenylbenzo[a]imidazo[5,1,2-cd]indolizine (3aa)

Yield: 41.5 mg (77%); yellow solid; mp 115–116 °C (Lit.[23] mp 114–115 °C).

1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J = 8.0 Hz, 1 H), 8.41–8.38 (m, 3 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.95 (dd, J = 8.0, 8.0 Hz, 1 H), 7.79 (dd, J = 8.0, 8.0 Hz, 1 H), 7.61 (m, 3 H), 7.51 (dd, J = 8.0, 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 146.4, 139.6, 134.6, 131.5, 130.6, 129.4, 129.3, 129.2, 128.5, 126.8, 125.1, 123.3, 121.1, 121.0, 113.4, 109.0.


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1-(p-Tolyl)benzo[a]imidazo[5,1,2-cd]indolizine (3ba)

Yield: 66.7 mg (79%); yellow solid; mp 181–182 °C.

IR (KBr): 3042, 1609, 1497, 1463, 1412, 1396, 1342, 1288, 1182, 1094, 765, 751, 570 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J = 8.0 Hz, 1 H), 8.39 (d, J = 8.0 Hz, 1 H), 8.31 (d, J = 8.0 Hz, 2 H), 8.07–8.02 (m, 2 H), 7.93 (dd, J = 8.0, 8.0 Hz, 1 H), 7.78 (dd, J = 8.0, 8.0 Hz, 1 H), 7.61 (dd, J = 8.0, 8.0 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 2 H), 2.49 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.0, 139.8, 139.3, 132.0, 131.4, 130.5, 130.0, 129.3, 129.2, 128.5, 126.5, 124.9, 123.3, 121.1, 120.8, 113.2, 108.8, 21.7.

ESI-MS: m/z = 282 [M+], 283 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C20H14N2Na: 305.1055; found: 305.1059.


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1-(4-Methoxyphenyl)benzo[a]imidazo[5,1,2-cd]indolizine (3ca)

Yield: 32.2 mg (54%); yellow solid; mp 164–165 °C (Lit.[23] mp 161–162 °C).

1H NMR (400 MHz, CDCl3): δ = 8.42–8.34 (m, 4 H), 8.01 (dd, J = 8.0, 8.0 Hz, 2 H), 7.91 (dd, J = 8.0, 8.0 Hz, 1 H), 7.76 (dd, J = 8.0, 8.0 Hz, 1 H), 7.59 (dd, J = 8.0, 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 2 H), 3.94 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 160.7, 146.9, 139.9, 131.3, 130.3, 129.9, 129.2, 129.1, 127.5, 126.4, 124.7, 123.3, 120.8, 120.4, 114.7, 112.9, 108.6, 55.6.


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1-(4-Chlorophenyl)benzo[a]imidazo[5,1,2-cd]indolizine (3da)

Yield: 27.2 mg (45%); yellow solid; mp 174–175 °C.

IR (KBr): 3043, 2923, 1620, 1497, 1463, 1411, 1393, 1337, 1290, 1249, 1191, 1090, 1012, 830, 784, 760, 743, 596 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.39 (m, 2 H), 8.32 (d, J = 8.0 Hz, 2 H), 8.05 (dd, J = 8.0, 8.0 Hz, 2 H), 7.95 (dd, J = 8.0, 8.0 Hz, 1 H), 7.79 (dd, J = 8.0, 8.0 Hz, 1 H), 7.64–7.59 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 145.3, 139.8, 135.0, 133.4, 131.6, 130.6, 129.6, 129.5, 129.4, 129.0, 126.8, 125.2, 123.4, 121.0, 120.9, 113.5, 109.0.

ESI-MS: m/z = 302 [M+], 303 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C19H11ClN2Na: 325.0508; found: 325.0511.


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1-[4-(Trifluoromethyl)phenyl]benzo[a]imidazo[5,1,2-cd]indolizine (3ea)

Yield: 49.9 mg (74%); yellow solid; mp 176–177 °C.

IR (KBr): 1621, 1322, 1291, 1250, 1192, 1159, 1107, 1072, 1061, 840, 792, 763, 748, 730 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.46 (d, J = 8.0 Hz, 2 H), 8.35 (dd, J = 8.0, 2.4 Hz, 2 H), 8.05 (d, J = 8.0 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.96–7.92 (m, 1 H), 7.86 (d, J = 8.0 Hz, 2 H), 7.76 (dd, J = 8.0, 8.0 Hz, 1 H), 7.61 (dd, J = 8.0, 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 144.4, 139.6, 138.1, 131.5, 130.6, 130.5 (q, J C,F = 21 Hz), 129.4, 128.7, 128.4, 126.9, 126.0 (q, J C,F = 2 Hz), 125.2, 124.2 (q, J C,F = 180 Hz), 123.3, 121.4, 120.8, 113.7, 109.1.

ESI-MS: m/z = 336 [M+], 337 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C20H11F3N2Na: 359.0772; found: 359.0776.


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1-(3-Methoxyphenyl)benzo[a]imidazo[5,1,2-cd]indolizine (3fa)

Yield: 50.1 mg (83%); orange solid; mp 120–121 °C.

IR (KBr): 3063, 2992, 2939, 2833, 1620, 1611, 1579, 1556, 1536, 1496, 1460, 1429, 1393, 1336, 1283, 1292, 1227, 1188, 1130, 1095, 1064, 1051, 783, 763, 751, 681 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.47 (d, J = 8.0 Hz, 1 H), 8.40 (d, J = 8.0 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 8.00–7.93 (m, 3 H), 7.79 (dd, J = 8.0, 8.0 Hz, 1 H), 7.62 (dd, J = 8.0, 8.0 Hz, 1 H), 7.55 (dd, J = 8.0, 8.0 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 4.00 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 160.3, 146.5, 139.6, 136.1, 131.4, 130.5, 130.1, 129.2, 129.0, 126.4, 124.9, 123.2, 121.0, 115.5, 113.3, 113.0, 108.7, 100.0, 55.6.

ESI-MS: m/z = 298 [M+], 299 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C20H14N2ONa: 321.1004; found: 321.1007.


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1-(o-Tolyl)benzo[a]imidazo[5,1,2-cd]indolizine (3ga)

Yield: 34.4 mg (60%); yellow solid; mp 108–109 °C.

IR (KBr): 3055, 2920, 1610, 1531, 1495, 1462, 1402, 1331, 1303, 1187, 1118, 967, 748, 725, 650, 574 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.39 (d, J = 8.0 Hz, 1 H), 8.13–8.06 (m, 3 H), 7.98–7.92 (m, 2 H), 7.71 (dd, J = 7.6, 7.6 Hz, 1 H), 7.59 (dd, J = 8.0, 8.0 Hz, 1 H), 7.43 (m, 3 H), 2.72 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.8, 139.3, 137.5, 134.0, 131.3, 131.2, 131.0, 130.4, 129.1, 129.0, 128.7, 126.1, 126.0, 124.7, 123.1, 121.9, 120.8, 113.4, 108.7, 20.6.

ESI-MS: m/z = 282 [M+], 283 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C20H14N2Na: 305.1055; found: 305.1059.


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1-(Naphthalen-1-yl)benzo[a]imidazo[5,1,2-cd]indolizine (3ha)

Yield: 58.4 mg (52%); yellow solid; mp 138–139 °C.

IR (KBr): 3043, 1620, 1533, 1514, 1498, 1346, 1290, 1244, 1195, 1185, 1161, 1290, 1244, 1195, 1185, 1075, 1029, 958, 793, 784, 767, 750 cm–1.

1H NMR (400 MHz CDCl3): δ = 8.80 (d, J = 8.0 Hz, 1 H), 8.41 (d, J = 8.0 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.04–7.99 (m, 3 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.71 (dd, J = 8.0, 8.0 Hz, 1 H), 7.65–7.55 (m, 4 H).

13C NMR (100 MHz CDCl3): δ = 145.3, 139.7, 134.1, 132.2, 131.4, 131.2, 130.6, 129.5, 129.2, 129.0, 128.5, 127.0, 126.4, 126.2, 126.1, 125.6, 124.8, 123.0, 122.4, 121.5, 113.6, 108.8, 106.9.

ESI-MS: m/z = 318 [M+], 319 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C23H14N2Na: 341.1055; found: 341.1058.


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3-Methyl-1-phenylbenzo[a]imidazo[5,1,2-cd]indolizine (3ia)

Yield: 47.1 mg (83%); yellow solid; mp 140–141 °C.

IR (KBr): 3057, 2922, 1612, 1497, 1464, 1448, 1430, 1413, 1345, 1309, 1255, 1183, 1069, 1057, 811, 763, 738, 695 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.38–8.37 (m, 3 H), 8.30–8.27 (m, 1 H), 7.87–7.82 (m, 1 H), 7.70–7.60 (m, 4 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.48 (dd, J = 8.0, 8.0 Hz, 1 H), 2.99 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 145.5, 139.5, 134.9, 131.4, 129.1, 129.0, 128.9, 128.8, 128.5, 128.4, 126.5, 124.7, 124.6, 122.7, 121.1, 120.8, 108.8, 16.5.

ESI-MS: m/z = 282 [M+], 283 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C20H14N2Na: 305.1055; found: 305.1058.


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4-Methyl-1-phenylbenzo[a]imidazo[5,1,2-cd]indolizine (3ja)

Yield: 49.4 mg (87%); yellow solid; mp 187–188 ° C.

IR (KBr): 3044, 2918, 1623, 1611, 1530, 1491, 1464, 1447, 1385, 1339, 1252, 1186, 1114, 966, 846, 753, 738, 685, 585 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 8.0 Hz, 3 H), 8.29 (d, J = 8.0 Hz, 1 H), 7.81 (s, 2 H), 7.73 (dd, J = 8.0, 8.0 Hz, 1 H), 7.62 (dd, J = 8.0, 8.0 Hz, 2 H), 7.55 (dd, J = 8.0, 8.0 Hz, 1 H), 7.48 (dd, J = 8.0, 8.0 Hz, 1 H), 2.81 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.1, 139.6, 138.0, 134.8, 131.0, 129.7, 129.3, 129.0, 128.9, 128.3, 124.6, 123.1, 120.8, 120.4, 112.9, 110.4, 22.9.

ESI-MS: m/z = 282 [M+], 283 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C20H14N2Na: 305.1055; found: 305.1059.


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4-Chloro-1-phenylbenzo[a]imidazo[5,1,2-cd]indolizine (3ka)

Yield: 16.1 mg (27%); yellow solid; mp 200–201 °C.

IR (KBr): 3046, 2973, 2925, 1618, 1528, 1460, 1446, 1387, 1340, 1248, 1180, 1166, 1053, 883, 842, 759, 733, 685, 586 cm–1.

1H NMR (600 MHz, CDCl3): δ = 8.41 (d, J = 12.0 Hz, 1 H), 8.35 (d, J = 9.0 Hz, 2 H), 8.33 (d, J = 9.0 Hz, 1 H), 8.04 (s, 1 H), 8.00 (s, 1 H), 7.80 (dd, J = 9.0, 9.0 Hz, 1 H), 7.65-7.61 (m, 3 H), 7.52 (dd, J = 9.0, 9.0 Hz, 1 H).

13C NMR (150 MHz, CDCl3): δ = 147.7, 139.2, 134.2, 133.0, 130.8, 130.1, 130.0, 129.6, 129.4, 129.2, 128.4, 125.3, 123.5, 121.1, 121.0, 113.0, 109.9.

ESI-MS: m/z = 302 [M+], 303 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C19H11ClN2Na: 325.0508; found: 325.0510.


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5-Methyl-1-phenylbenzo[a]imidazo[5,1,2-cd]indolizine (3la)

Yield: 41.2 mg (73%); yellow solid; mp 148–149 °C.

IR (KBr): 3051, 2921, 1611, 1559, 1498, 1463, 1447, 1430, 1403, 1338, 1301, 1277, 1190, 1097, 1068, 810, 764, 755, 695, 637, 573 cm–1.

1H NMR (600 MHz, CDCl3): δ = 8.45 (d, J = 6.0 Hz, 1 H), 8.39 (d, J = 6.0 Hz, 3 H), 7.94 (d, J = 6.0 Hz, 1 H), 7.75 (dd, J = 6.0, 6.0 Hz, 1 H), 7.70 (d, J = 6.0 Hz, 1 H), 7.64–7.60 (m, 3 H), 7.49 (t, J = 6.0 Hz, 1 H), 3.03 (s, 3 H).

13C NMR (150 MHz, CDCl3): δ = 146.0, 138.5, 134.9, 131.6, 129.6, 129.1, 128.9, 128.5, 128.3, 128.2, 127.9, 124.7, 124.1, 121.9, 120.8, 120.7, 112.9, 17.6.

ESI-MS: m/z = 282 [M+], 283 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C20H14N2Na: 305.1055; found: 305.1059.


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1-Phenyl-2,2a1,3-triazacyclopenta[jk]fluorene (3ma)

Yield: 51.3 mg (95%); orange solid; mp 178–180 °C (Lit.[23] mp 177–178 °C).

1H NMR (400 MHz, CDCl3): δ = 9.12 (d, J = 4.0 Hz, 1 H), 8.40 (d, J = 8.0 Hz, 2 H), 8.34 (d, J = 8.0 Hz, 2 H), 7.88 (d, J = 4.0 Hz, 1 H), 7.82 (dd, J = 7.6, 7.6 Hz, 1 H), 7.64–7.56 (m, 3 H), 7.52 (dd, J = 8.0, 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 150.3, 148.7, 146.0, 135.0, 133.8, 131.6, 130.6, 130.5, 129.9, 129.1, 128.7, 125.4, 124.8, 121.2, 118.8, 104.5.


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7,8-Dimethyl-1-phenylbenzo[a]imidazo[5,1,2-cd]indolizine (3ad)

Yield: 48.6 mg (82%); orange solid; mp 126–127 °C.

IR (KBr): 3051, 2853, 1623, 1547, 1497, 1443, 1415, 1330, 1296, 1251, 1184, 1095, 1048, 774, 736, 690 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.39 (d, J = 8.0 Hz, 2 H), 8.17 (s, 1 H), 8.12 (s, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.93–7.86 (m, 2 H), 7.64 (dd, J = 8.0, 8.0 Hz, 2 H), 7.49 (dd, J = 8.0, 8.0 Hz, 1 H), 2.57 (s, 3 H), 2.53 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 145.6, 139.6, 138.9, 134.8, 134.2, 130.6, 129.8, 129.0, 128.8, 128.3, 127.6, 126.3, 123.4, 121.4, 120.8, 112.6, 108.0, 21.2, 20.5.

ESI-MS: m/z = 296 [M+], 297 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C21H16N2Na: 319.1211; found: 319.1215.


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7-Methyl-1-phenylbenzo[a]imidazo[5,1,2-cd]indolizine (3ae)

Yield: 48.7 mg (86%); yellow solid; mp 113–114 °C.

IR (KBr): 3053, 2917, 1620, 1559, 1536, 1497, 1459, 1394, 1336, 1290, 1250, 1209, 1170, 1094, 1066, 769, 690, 549 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.39 (d, J = 8.0 Hz, 2 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.21 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.98–7.90 (m, 2 H), 7.65 (dd, J = 8.0, 8.0 Hz, 2 H), 7.51 (dd, J = 8.0, 8.0 Hz, 1 H), 7.43 (dd, J = 8.0, 8.0 Hz, 1 H), 2.68 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.3, 139.7, 134.7, 130.6, 129.4, 129.2, 129.1, 129.0, 128.4, 126.5, 126.4, 122.8, 121.0, 120.7, 112.8, 108.2, 22.5.

ESI-MS: m/z = 282 [M+], 283 [(M + 1)+].

HRMS-ESI: m/z [M + Na]+ calcd for C20H14N2Na: 305.1055; found: 305.1058.


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Acknowledgment

We are grateful for the financial support from the Fundamental Research Funds for the Central Universities (2572014DB04), the National Natural Science Foundation of China (31300286, 31400294), China Postdoctoral Science Foundation (20110491013, 2012T50319), and Heilongjiang Postdoctoral Grant (LBH-Z11251).

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0034-1380865.
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Figure 1 Site-selectivity in the C–H arylation of fused imidazoheterocycles
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Scheme 1 Possible pathways for Pd-catalyzed sequential dual C–H arylation of imidazo[1,2-a]pyridines and o-dibromoarenes
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Scheme 2 Annulation of 2-arylimidazo[1,2-a]pyridines with o-dibromobenzene. Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), K2CO3 (0.6 mmol), Pd(OAc)2 (0.02 mmol), Xphos (0.04 mmol), DMF (2.0 mL), 160 °C, 24 h. Yields of isolated products are shown. a 1-Bromo-2-chlorobenzene was used as the o-dihaloarene.
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Scheme 3 Proposed mechanism for sequential Pd-catalyzed twofold C–H arylation