Construction of 3-(Picolinoyl)indolizines: Rh(III)-Catalyzed Cascade

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Construction of 3-(Picolinoyl)indolizines: Rh(III)catalyzed Cascade Reactions of 2-Vinylpyridines Zhen Wang, and Tiantian Han J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502424u • Publication Date (Web): 03 Dec 2014 Downloaded from http://pubs.acs.org on December 4, 2014

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The Journal of Organic Chemistry

Construction of 3-(Picolinoyl)indolizines: Rh(III)-catalyzed Cascade Reactions of 2-Vinylpyridines Zhen Wang,* and Tiantian Han Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China. Email: [email protected]. RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

ABSTRACT An efficient strategy for the construction of 3-(picolinoyl)indolizines via Rh(III)-catalyzed

oxidative

olefination/intramolecular Michael

type

addition/oxygenation cascade reactions of 2-vinylpyridines has been developed. The mechanistic studies illustrate that both Rh(III) and Cu(II) play dual roles during the reaction process.

Indolizines are an important structure motif in a wide range of pharmaceuticals, dyes, biological markers, and electroluminescent materials due to their diverse biological activities1 and abnormal fluorescence properties.2 Accordingly, efficient constructions of various functionalized indolizines have attracted increased research interest in recent years.3 A significant effort has been made to develop transition metal-catalyzed more versatile and general routes to indolizines.4-8 Gevorgyan,4 Liu,5a,b Sarpong,6 and their coworkers have demonstrated the transition metal (Cu, Au, Pd, Pt) catalyzed cycloisomerization of alkynylpyridines or propargylpyridines via nucleophilic attack of pyridine nitrogen to allenyl (Scheme 1, path a), alkynyl (Scheme 1, path b) or

ACS Paragon Plus Environment


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gold-vinylidene group (path c). Liu's group has further developed an Au-catalyzed multicomponent sequence for the direct synthesis of substituted aminoindolizines, in which NR1R2-substituted propargylic pyridines was formed in situ (Scheme 1, path b).7 Moreover, Barluenga8 have disclosed an alternate pathway involving a Cu(I)-catalyzed [3+2] cyclization of pyridine rings with alkenyldiazoacetates (Scheme 1, path d). The Michael type addition of pyridine nitrogen to Cu(I) alkenylcarbenes followed by cyclization/reductive elimination/aromatization contributed to the high regioselectivity of this transformation. Scheme 1. Strategies toward Indolizines

On the other hand, as a step and atom economic strategy for C-C and C-X bond formation, transition metal-catalyzed C-H bond activation provides us lots of opportunities in organic synthesis.9 Among C-H activation catalyzed by various metals, Rhodium-catalyzed C-C bond and C-X bond formations offers great versatility in terms of achieving a broad range of transformations. Recently, heterocyclic synthesis via Rh(III)/Cu(II)-catalyzed heteroatom directed C-H bond activation approach receives intensive attention in the area of organic synthesis including the groups of Fagnou, Miura and Satoh, Jones, Glorius, Rovis, Cheng, Li and others.10 Moreover, a great progress in Rh(III) catalyzed oxidative olefination via chelation-assisted aromatic or vinylic C-H bond activation has been developed by Miura ＆ Satoh, Li, Chang, Shi, and Glorius.11,12 Of note, the participation of directing groups themselves to the subsequent transformations seems to be of much interest.13

Additionally,

Sanford’s

group

has

displayed

an

elegant

Pd/polyoxometalate-catalyzed aerobic olefination of 2-alkylpyridine with acrylate followed by intramolecular Michael addition to afford the dihydroindolizinium salt.14 Inspired by these investigations, we envisage that the oxidative olefination of


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2-vinylpyridines with alkenes might also be catalyzed by Rh(III)/Cu(II) to afford the N-containing conjugated dienes which would then undergo intramolecular Michael type addition and aromatization to afford the corresponding indolizines (Scheme 2). Scheme 2. Working Hypothesis

Initially, the reaction of 2-vinylpyridine 1a with styrene (1.2 equiv) was tested in the presence of [Cp*RhCl2]2 (2.5 mol %) and Cu(OAc)2·H2O (2.5 equiv) at 60 oC, referring to the oxidative olefination conditions employed by Miura.11b To our surprise, styrene was not involved in the reaction at all, while 23% yield of conjugated diene 2a was isolated instead. Then the reaction of 1a in the absence of other alkenes was

examined.

When

the

reaction

was

performed

at

80

o

C,

3-(pyridin-2-ylmethyl)indolizine 3a and 3-(picolinoyl)indolizine 4a were generated in 23% and 8% yield respectively, along with 2a in 27% yield (Table 1, entry 2). Further increasement of the temperature to 100 oC led to the formation of 4a in 33% yield (Table 1, entry 3), while the yield of 3a decreased to 2% suggesting the subsequent transformation from 3a to 4a at higher temperatures. Encouraged by this result, the reaction was performed at 135 oC. To our delight, 4a was selectively isolated in 70% yield (Table 1, entry 4). Control experiments showed that the reaction did not work in the absence of either [Cp*RhCl2]2 or Cu(OAc)2•H2O (Table 1, entry 5-6). The eﬃciency of the catalyst system remained less eﬀective in other solvents such as xylene, t-AmOH and DMF (Table 1, entry 7-9). Table 1. Screening of Reaction Conditionsa

entry

catalystb

temp.(oC)

solvent

product (% yield)c

1

A

60

toluene

2a (23), 3a (0), 4a (0)



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2

A

80

toluene

2a (27), 3a (23), 4a (8)

3

A

100

toluene

2a (30), 3a (2), 4a (33)

4

A

135

toluene

2a (0), 3a (0), 4a (70)

5

B

135

toluene

2a (0), 3a (0), 4a (0)

6

C

135

toluene

2a (0), 3a (0), 4a (0)

7

A

135

xylene

4a (60)

8

A

135

t-AmOH

4a (66)

9

A

135

DMF

4a (63)

a

All reactions were performed by employing 2 mmol 2-vinylpyridine in 10

mL solvent for 18 h.bCondition A: [Cp*RhCl2]2 (2.5 mol %), Cu(OAc)2·H 2O (2.5 equiv); condition B: Cu(OAc)2·H2O (2.5 equiv); condition C: [Cp*RhCl2]2 (2.5 mol %).cIsolated yields based on 1a.

With the optimized conditions in hand, a number of 2-vinylpyridine derivatives were screened to explore the substrates scope. The results were summarized in Scheme 3. The reaction of 2-vinylpyridines 1b-d containing a methyl group at C-3, C-4, or C-5 position of pyridine rings afforded the corresponding indolizines in good yields (58%, 64%, 60% respectively). However, the reaction of 1e bearing methyl group at C-6 position only yielded the oxidative olefination product 2e and 2e' in 42% yield as a mixture of two geometrical isomers (1E,3E/1E,3Z≈1:1) possibly due to the steric hindrance. Both electron-donating and electron-withdrawing substrates could be tolerated, and the corresponding 3-(picolinoyl)indolizines (4f-4h) were obtained in good yields (43-63%). A number of aryl 2-vinylpyridines also underwent the same transformation to give aryl indolizines (4i-4m) in moderate yields. Of note, the annulation of 2-vinylquinoline was observed under the same catalytic conditions leading to the formation of pyrrolo[1,2-a]quinoline 4n in 61% yield. Scheme 3. Substrate Scope of Indolizine Synthesesa


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R

R

2.5 mol% [Cp*RhCl2]2 2.5 eq Cu(OAc)2.H2O, Air

N N

R

N N

toluene,135 oC,18 h

1 Me

R

O 4

Me

Me N

N

N

N

N O

O

O

Me

N

Me

N

N

Me

b

Me 4b, 58%

2e, 2e', 42%

Me 4c, 64%

4d, 60% MeO2C

MeO

N

MeO2C

N N O

N

N

N

O

CO2Me

O

OMe CO2Me

4f, 43%

Ph

4h, 63%

4g, 55% Me

N

N N

N

Ph

O

Ph

N N

Ph O

4i, 56%

Me O 4k, 68%

4j, 65% N N

N

N MeO

N F

N

O

O

O

OMe F

4l, 54%

a

Standard

reaction

4m, 72%

conditions:

Substrate

4n, 61%

(2

mmol),

[Cp*RhCl2]2 (2.5 mol %), Cu(OAc)2·H2O (5 mmol), and toluene (10 mL) under air for 18 h at 135 oC. Isolated yields are reported. b2e and 2e' were isolated as the only products.

To gain some insight into the reaction process, several experiments were carried out (Scheme 4). As mentioned above, neither [Cp*RhCl2]2 nor Cu(OAc)2.H2O alone could catalyze the annulation of 1a. Further studies revealed that the conversion from 1a to 2a could be realized at a stoichiometric level in the presence of Cp*Rh(OAc)2 or [Cp*RhCl2]2/NaOAc (Table S1). Meanwhile, the stoichiometric reaction of [Cp*RhCl2]2 with 2-vinylpyridine 1a (4 equiv) in the presence of NaOAc (4.8 equiv) yielded a Rh(I)-diene complex 5, the structure of which was unambiguously confirmed by single-crystal X-ray diffraction analysis (see ESI for details). The catalytic activity of complex 5 under the standard conditions was also tested. However, diminished yield of 4a (20%) was observed owing to the strong coordination of the conjugated diene to the low-valent metal center. Then to realize the transformation from 2a to 3a, several possible catalytic systems were screened in d8-toluene and monitored by 1H NMR (Table S2). A complete conversion from 2a to 3a occurred in the presence of Cp*Rh(OAc)2 and excess HOAc, which demonstrated that, rather than Rh(I) and Cu(II), Rh(III) is responsible for the transformation. Of note, the HOAc generated in situ may also play a crucial role. The oxygenation from 3a to 4a could be



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realized via the treatment of 3a with 2.5 equiv. Cu(OAc)2.H2O in toluene under high temperature (Table S3). While, no reaction proceed in the absence of Cu(OAc)2.H2O (Table S3). In order to figure out the origin of oxygen atom in 4a, the reaction of 1a in the presence of H218O (10 equiv), [Cp*RhCl2]2 (2.5 mol%), and anhydrous Cu(OAc)2 (2.5 equiv) were performed in dry toluene [Eq. (1)]. After 3 h, 4a with more than 90% 18

O was isolated in 11% yield (see Table S4 for details). With time going on (18 h), 4a

with only approximate 50%

18

O was obtained in 57% yield. These results indicated

that the oxygen atom in 4a could be derived from water rather than molecular oxygen in air, which appeared to be different from the phenomena observed by Chiba and his coworkers during their research on copper-catalyzed benzylic C-H oxygenation.15 Notably, the reaction of 2-vinylpyridine 1a with methyl acrylate under the same reaction conditions could also yield the conjugated diene 6 (26%) and indolizine 7 (20%) [Eq. (2)]. However, no further oxygenation of the methylene group of 7 was achieved.16

Scheme 4. Study of Reaction Process

On the basis of the above experimental results, a plausible reaction cycle for this


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fascinating transformation is depicted in Scheme 5. Initially, the reaction of [Cp*RhCl2]2 with Cu(OAc)2 leads to formation of active metalating agent I. 2-Vinylpyridine 1a may chelate to complex I to generate intermediate II via coordination of pyridyl nitrogen and subsequent terminal alkenyl C-H activation. Coordination of another molecular of 1a to II followed by insertion of alkenyl group to Rh-C bond gives rise to IV, which undergoes β-H elimination and reductive elimination to afford intermediate V and diene 2a'. V could be oxidized by Cu(OAc)2•H2O to regenerate the active Rh(III) species I. Meanwhile, 2a' may isomerize to 2a as a thermodynamic stable isomer under high temperatures,17 and complex 5 may be obtained via coordination of 2a to Rh(I) in the absence of Cu(II) oxidant. Next, Rh(III) species could promote the intramolecular Michael-type addition of diene 2a' to afford 3a with the help of HOAc. Finally, the oxygenation of 3a mediated by Cu(II) afforded the desired product 4a, the oxygen atom of which could be derived from water.

Scheme 5. Postulated Catalytic Cycle

In summary, we have presented an efficient approach for the direct synthesis of 3-(picolinoyl)indolizine from 2-vinylpyridine derivatives. Preliminary mechanism studies illustrate that a Rh(III)/Cu(II) relay catalysis is responsible for the high efficiency of the process. Both Rh(III) and Cu(II) play dual roles during this multistep sequence, including the role of Rh(III) to promote both the oxidative olefination and intramolecular Michael addition, and the contribution of Cu(II) to both the regeneration of active Rh(III) species and the oxygenation of the diarylmethane to



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ketone.

Experimental Section General Remarks: Commercially available reagents and solvents were used without further purification except as noted. Products were purified by column chromatography on 200-300 mesh silica gels. All melting points were determined without correction. 1H NMR and

13

C NMR spectra were recorded at 500 and 125

MHz, respectively, in CDCl3. All chemical shifts are given as δ values (in ppm) with reference to tetramethylsilane (TMS) as an internal standard. HRMS was performed on

an FT-MS instrument using electrospray ionization (APCI or ESI).

Crystallographic

data

were

recorded

on

a

diffractometer

using

graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). Copies of the 1H NMR and 13CNMR spectra and crystallographic data in CIF are provided in the Supporting Information. General procedure of Suzuki cross-coupling reactions for the synthesis of functionalized

2-chloropyridine:

To

a

Schlenk

tube

was

added

4-

or

5-bromo-2-chloropyridine (8 mmol), aryl-boronic acid (8.5 mmol), Pd(OAc)2 (5.0 mol%), triphenylphosphine (20 mol%) and sodium carbonate (20 mmol), THF (20 mL) and water (10 mL) was added to the mixture under N2, then the mixture was stirred at 100℃ for desired time until complete consumption of starting materials judged by TLC. Water (30 mL) was added to the mixture and the resulting residue was extracted three times with ethyl acetate. The combined organic portions were dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to afford the desired products. General procedure of Stille cross-coupling reactions for the synthesis of 2-vinylpyridine derivatives: A mixture of 2-chloropyridine or 2-bromopyridine derivatives (8 mmol), tributyl(vinyl)tin (8.5 mmol), Pd(OAc)2 (5.0 mol%), triphenylphosphine (20 mol%) and DMF (10 mL) was added to a dry Schlenk tube. Then the mixture was stirred at 120℃ under N2 for desired time until complete


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consumption of starting materials judged by TLC. After cooling, the mixture was treated with saturated aqueous KF (50 mL) for 2 hours and extracted with ethyl acetate, and the organic phase were further washed with brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by chromatography (hexane/ethyl acetate) to afford the desired products. General procedure for Rh(III)-catalyzed indolizines synthesis: A mixture of 2-vinylpyridine derivatives 1a-n (2 mmol), [Cp*RhCl2]2 (2.5 mol%), Cu(OAc)2.H2O (5 mmol), and toluene (10 mL) was added to a Schlenk tube. Then the mixture was stirred at 135 oC under air for desired time (usually 18 h) until complete consumption of starting materials judged by TLC. Then the reaction mixture was filtered through a short plug of silica gel, washed with ethyl acetate and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to afford the desired products 4a-n. 2-chloro-5-phenylpyridine (s1i): white solid (786mg, 52% yield), mp. 51-52 °C. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J = 2.4 Hz, 1 H), 7.86 (d, J =2.4 Hz, 1 H), 7.57 (m, 2 H), 7.51 (m, 2 H), 7.46-7.41 (m, 2 H).

13

C NMR (125 MHz, CDCl3) δ 150.4,

148.0, 137.1, 136.5, 135.7, 129.2, 128.5, 127.1, 124.2. IR (KBr) 1452, 1098, 760, 693 cm-1. HRMS (ESI) Calcd for C11H8ClNNa [M+Na+] 212.0237, found 212.0244. 2-chloro-4-phenylpyridine (s1j): white solid (1.29g, 85% yield), mp. 68-69 °C. 1H NMR (500 MHz, CDCl3) δ 8.44 (d, J = 5.2 Hz, 1 H), 7.62 (m, 2 H), 7.55 (d, J = 1.0 Hz, 1 H), 7.53-7.48 (m, 3 H), 7.44 (q, J = 5.2 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 152.2, 151.5, 150.0, 136.9, 129.6, 129.3, 127.0, 122.1, 120.5. IR (KBr) 1588, 1534, 1373, 1080, 857, 758, 681 cm-1. HRMS (APCI-TOF) Calcd for C11H9ClN [M+H+] 190.0418, found 190.0415. 2-chloro-4-(m-tolyl)pyridine (s1k): white solid (1.38g, 85% yield), mp. 66-67 °C. 1H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 5.2 Hz, 1 H), 7.55 (d, J = 1.0 Hz, 1 H), 7.38-7.43 (m, 4 H), 7.29 (m, 1 H), 2.45 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ 152.2, 151.7, 149.9, 139.0, 136.8, 130.4, 129.2, 127.7, 124.2, 122.0, 120.5, 21.5. IR (KBr) 1649, 1588, 1366, 765 cm-1. HRMS (APCI-TOF) Calcd for C12H11ClN [M+H+] 204.0575, found 204.0574.



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2-chloro-4-(4-fluorophenyl)pyridine (s1l): white solid (1.37g, 83% yield), mp. 143-144 °C. 1H NMR (500 MHz, CDCl3) δ 8.44 (d, J = 5.2 Hz, 1 H), 7.62 (m, 2 H), 7.52 (d, J = 1.0 Hz, 1 H), 7.40 (m, 1 H), 7.21 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ 163.8 (d, JC-F = 250.2 Hz), 152.3, 150.5, 150.1, 133.0, 133.0, 128.9 (d, JC-F =8.2 Hz), 121.9, 120.3, 116.4 (d, JC-F = 21.8 Hz). IR (KBr) 1596, 1511, 1457, 1219, 819, 550 cm-1. HRMS (APCI-TOF) Calcd for C11H8ClFN [M+H+] 208.0324, found 208.0321. 2-chloro-4-(4-methoxyphenyl)pyridine (s1m): white solid (1.45g, 83% yield), mp. 69-70 °C. 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J = 5.2 Hz, 1 H), 7.58 (m, 2 H), 7.51 (d, J = 1.0 Hz, 1 H), 7.40 (m, 1 H), 7.02 (m, 2 H), 3.90 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ 161.0, 152.2, 151.0, 149.9, 129.0, 128.3, 121.3, 119.9, 114.7, 55.4. IR (KBr) 1596, 1526, 1249, 1019, 811, 581 cm-1. HRMS (APCI-TOF) Calcd for C12H11ClNO [M+H+] 220.0524, found 220.0525. methyl 6-vinylnicotinate (1g): colorless oil (990mg, 76% yield). 1H NMR (500 MHz, CDCl3) δ 9.16 (d, J = 1.7 Hz, 1 H), 8.24 (m, 1 H), 7.39 (d, J = 8.2 Hz, 1 H), 6.86 (dd, J = 17.6 Hz, J = 10.7 Hz, 1 H), 6.34 (dd, J = 17.6 Hz, J = 0.9 Hz, 1 H), 5.62 (dd, J = 10.7 Hz, J = 0.9 Hz, 1 H) , 3.94 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ 165.7, 159.2, 150.8, 137.6, 136.2, 124.5, 121.0, 120.7, 52.3. IR (thin film) 1719, 1588, 1434, 1273, 1119, 1010, 796, 581 cm-1. HRMS (APCI-TOF) Calcd for C9H10NO2 [M+H+] 164.0706, found 164.0704. methyl 2-vinylisonicotinate (1h): colorless oil (938mg, 72% yield). 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J = 4.8 Hz, 1 H), 7.91 (s, 1 H), 7.71 (m, 1 H), 6.89 (dd, J = 17.6 Hz, J = 10.7 Hz, 1 H), 6.30 (dd, J = 17.6 Hz, J = 0.9 Hz, 1 H), 5.58 (dd, J = 10.7 Hz, J = 0.9 Hz, 1 H), 3.98 (s, 3 H).

13

C NMR (125 MHz, CDCl3) δ 165.7, 156.8,

150.3, 137.9, 136.3, 121.4, 120.4, 119.4, 52.7. IR (thin film) 1734, 1626, 1430, 1291, 1203, 1111, 758 cm-1. HRMS (APCI-TOF) Calcd for C9H10NO2 [M+H+] 164.0706, found 164.0702. 5-phenyl-2-vinylpyridine (1i): colorless oil (724mg, 50% yield). 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1 H), 7.88 (d, J = 7.5 Hz, 1 H), 7.62 (d, J = 7.5 Hz, 1 H), 7.53-7.40 (m, 5 H), 6.90 (dd, J = 17.6 Hz, J = 10.7 Hz, 1 H), 6.26 (dd, J = 17.6 Hz, J = 0.9 Hz, 1 H), 5.54 (dd, J = 10.7 Hz, J = 0.9 Hz, 1 H).

13

C NMR (125 MHz, CDCl3) δ 154.6,


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148.0, 137.7, 136.6, 135.3, 134.8, 129.1, 128.0, 127.0, 121.1, 118.1. IR (thin film) 1472, 1370, 849, 754, 693 cm-1. HRMS (APCI-TOF) Calcd for C13H12N [M+H+] 182.0964, found 182.0958. 4-phenyl-2-vinylpyridine (1j): colorless oil (1.09g, 75% yield). 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J = 5.2 Hz, 1 H), 7.67 (m, 2 H), 7.56 (s, 1 H), 7.50-7.53 (m, 3 H), 7.40 (m, 1 H), 6.92 (dd, J = 17.6 Hz, J = 10.7 Hz, 1 H), 6.31 (dd, J = 17.6 Hz, J = 0.9 Hz, 1 H), 5.55 (dd, J = 10.7 Hz, J = 0.9 Hz, 1 H).

13

C NMR (125 MHz, CDCl3) δ

156.2, 150.0, 149.0, 138.3, 137.0, 129.1, 129.0, 127.0, 120.6, 119.4, 118.5. IR (thin film) 1595, 1549, 995, 749, 695 cm-1. HRMS (APCI-TOF) Calcd for C13H12N [M+H+] 182.0964, found 182.0960. 4-(m-tolyl)-2-vinylpyridine (1k): colorless oil (1.12g, 72% yield). 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J = 5.2 Hz, 1 H), 7.55 (s, 1 H), 7.38-7.47 (m, 4 H), 7.27 (d, J = 5.8 Hz, 1 H), 6.92 (dd, J = 17.6 Hz, J = 10.7 Hz, 1 H), 6.31 (dd, J = 10.7 Hz, J = 0.9 Hz, 1 H), 5.55 (dd, J = 10.7 Hz, J = 0.9 Hz, 1 H) , 2.46 (s, 3 H).

13

C NMR (125 MHz,

CDCl3) δ 156.2, 149.9, 149.2, 138.8, 138.3, 137.0, 129.8, 129.0, 127.7, 124.1, 120.6, 119.4, 118.3, 21.5. IR (thin film) 1595, 1511, 1426, 1257, 1037, 819, 550 cm-1. HRMS (APCI-TOF) Calcd for C14H14N [M+H+] 196.1121, found 196.1122. 4-(4-fluorophenyl)-2-vinylpyridine (1l): colorless oil (1.24g, 78% yield). 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J = 5.2 Hz, 1 H), 7.63 (m, 1 H), 7.34 (m, 1 H), 7.19 (t, J = 8.6 Hz, 1 H), 6.90 (dd, J = 17.6 Hz, J = 10.7 Hz, 1 H), 6.31 (dd, J = 17.6 Hz, J = 0.9 Hz, 1 H), 5.55 (dd, J = 10.7 Hz, J = 0.9 Hz, 1 H).

13


163.5 (d, JC-F = 250.2 Hz), 152.3, 150.5, 150.1, 133.0, 133.0, 128.9 (d, JC-F =8.2 Hz), 121.9, 120.3, 116.4 (d, JC-F = 21.8 Hz). IR (thin film) 1595, 1511, 1234, 1157, 826, 550 cm-1. HRMS (APCI-TOF) Calcd for C13H11FN [M+H+] 200.0870, found 200.0867. 4-(4-methoxyphenyl)-2-vinylpyridine (1m): colorless oil (1.22g, 72% yield). 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J = 5.2 Hz, 1 H), 7.55 (s, 1 H), 7.38-7.47 (m, 4 H), 7.27 (d, J = 5.8 Hz, 1 H), 6.92 (dd, J = 17.6 Hz, J = 10.7 Hz, 1 H), 6.31 (dd, J = 17.6 Hz, J = 0.9 Hz, 1 H), 5.55 (dd, J = 10.7 Hz, J = 0.9 Hz, 1 H), 2.46 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ 156.2, 149.9, 149.2, 138.8, 138.3, 137.0, 129.8, 129.0, 127.7, 124.1,



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

120.6, 119.4, 118.3, 21.5. IR (thin film) 1588, 1519, 1249, 826 cm-1. HRMS (APCI-TOF) Calcd for C14H14NO [M+H+] 212.1070, found: 212.1073. (1E,3E)-1,4-di(pyridin-2-yl)buta-1,3-diene (2a): white solid, mp. 124-125 °C. 1H NMR (500 MHz, C6D6) δ 8.50 (d, J = 3.9 Hz, 1 H), 7.86-7.80 (m, 1 H), 7.01-6.98 (m, 1 H), 6.74-6.68 (m, 2 H), 6.56-6.54 (m, 1 H).

13

C NMR (125 MHz, C6D6) δ 155.6,

149.8, 135.5, 134.4, 132.8, 122.1, 121.6. IR (KBr) 1571, 1443, 1250, 999, 779 cm-1. HRMS (ESI-TOF) Calcd for C14H13N2 [M+H+] 209.1073, found 209.1080. (1E,3E)-1,4-bis(6-methylpyridin-2-yl)buta-1,3-diene (2e): yellow solid (49 mg, 21% yield), mp. 127-128 °C. 1H NMR (500 MHz, CDCl3) δ 7.53 (t, J = 7.7 Hz, 2 H), 7.49-7.43 (m, 2 H), 7.16 (d, J = 7.7 Hz, 2 H), 7.00 (d, J = 7.7 Hz, 2 H), 6.86-6.81 (m, 2 H), 2.58 (s, 6 H). 13C NMR (125 MHz, CDCl3) δ 158.4, 154.9, 136.6, 134.4, 132.3, 121.8, 119.2, 24.7. IR (KBr) 1573, 1449, 1254, 1009, 773 cm-1. HRMS (APCI-TOF) Calcd for C16H17N2 [M+H+] 237.1386, found 237.1388. (1Z,3E)-1,4-bis(6-methylpyridin-2-yl)buta-1,3-diene (2e'): yellow solid (49 mg, 21% yield), mp. 118-119 °C. 1H NMR (500 MHz, CDCl3) δ 8.68 (m, 1 H), 7.58-7.52 (m, 2 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.12 (d, J = 7.8 Hz, 1 H), 7.01 (m, 2 H), 6.83 (d, J = 15.7 Hz, 1 H), 6.58 (t, J = 11.4 Hz, 1 H), 6.50 (d, J = 11.4 Hz, 1 H), 2.65 (s, 3 H) 2.57 (s, 3 H).

13

C NMR (125 MHz, CDCl3) δ 158.2, 158.1, 155.9, 155.6, 136.5, 136.5,

136.4, 136.3, 134.4, 132.9, 132.3, 130.2, 130.2, 121.8, 121.6, 121.1, 119.2, 118.3, 24.8, 24.6. IR (KBr) 1587, 1420, 1109, 785 cm-1. HRMS (APCI-TOF) Calcd for C16H17N2 [M+H+] 237.1386, found 237.1391. 3-(pyridin-2-ylmethyl)indolizine (3a): unstable yellow to black oil. 1H NMR (500 MHz, CDCl3) δ 8.59 (d, J = 4.7 Hz, 1 H), 7.80 (d, J = 7.1 Hz, 1 H), 7.55 (m, 1 H), 7.40 (d, J = 8.9 Hz, 1 H), 7.14 (m, 1 H), 6.98 (d, J = 7.9 Hz, 1 H), 6.73 (d, J = 4.7 Hz, 1 H), 6.65 (m, 1 H), 6.48-6.44 (m, 2 H), 4.46 (s, 2 H). 13C NMR (125 MHz, CDCl3) δ 158.6, 149.2, 136.8, 133.1, 122.5, 122.3, 121.6, 120.9, 119.3, 116.0, 113.8, 110.2, 98.3, 35.6. IR (thin film) 1590, 1470, 1436, 1361, 752 cm-1. HRMS (ESI-TOF) Calcd for C14H13N2 [M+H+] 209.1073, found 209.1078. indolizin-3-yl(pyridin-2-yl)methanone (4a): yellow solid (155 mg, 70% yield), mp. 125-126 °C. 1H NMR (500 MHz, CDCl3) δ 10.11 (d, J = 7.1 Hz, 1 H), 8.75 (d, J = 4.3


Page 12 of 20

Page 13 of 20

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Hz, 1 H), 8.11 (d, J = 4.7 Hz, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.89 (m, 1 H), 7.60 (d, J = 8.7 Hz, 1 H), 7.45 (m, 1 H), 7.24 (t, J = 7.8 Hz, 1 H), 6.98 (t, J = 6.9 Hz, 1 H), 6.61 (d, J = 4.7 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 180.3, 157.6, 148.3, 139.9, 136.9, 129.2, 128.4, 125.1, 124.7, 123.8, 122.2, 118.6, 114.0, 103.5. IR (KBr) 1598, 1576, 1463, 1386, 1359, 1229, 879, 769 cm-1. HRMS (APCI-TOF) Calcd for C14H11N2O [M+H+] 223.0866, found 223.0865. (8-methylindolizin-3-yl)(3-methylpyridin-2-yl)methanone (4b): yellow solid (145 mg, 58% yield), mp. 103-104 °C. 1H NMR (500 MHz, CDCl3) δ 9.93 (d, J = 7.0 Hz, 1 H), 8.51 (d, J = 4.7 Hz, 1 H), 7.65 (d, J = 7.0 Hz, 1 H), 7.32 (q, 1 H), 7.15 (d, J = 4.7 Hz, 1 H), 7.06 (m, 1 H), 6.92 (t, J = 7.0 Hz, 1 H), 6.52 (d, J = 4.7 Hz, 1 H), 2.53 (s, 3 H), 2.45 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ 183.0, 157.0, 145.9, 140.5, 138.6, 131.9, 127.8, 126.9, 124.2, 123.9, 123.1, 114.1, 101.7, 18.4, 18.1. IR (KBr) 1593, 1568, 1468, 1361, 1051, 803, 771 cm-1 HRMS (APCI-TOF): Calcd for C16H15N2O [M+H+] 251.1179, found 251.1172. (7-methylindolizin-3-yl)(4-methylpyridin-2-yl)methanone (4c): yellow solid (160 mg, 64% yield), mp. 98-99 °C. 1H NMR (500 MHz, CDCl3) δ 9.98 (d, J = 7.2 Hz, 1 H), 8.57 (d, J = 4.8 Hz, 1 H), 8.04 (d, J = 4.8 Hz, 1 H), 7.87 (s, 1 H), 7.34 (s, 1 H), 7.24 (d, J = 4.8 Hz, 1 H), 6.81 (dd, J = 7.2 Hz, J = 1.7 Hz, 1 H), 6.46 (d, J = 4.8 Hz, 1 H), 2.46 (s, 3 H), 2.43 (s, 3 H).

13

C NMR (125 MHz, CDCl3) δ 178.0, 157.6, 148.1, 148.0,

140.4, 135.8, 128.7 ,128.7, 125.9, 124.5, 122.0, 117.3, 116.4, 102.5, 21.3, 21.2. IR (KBr) 1573, 1459, 1315, 1235, 1041, 823, 649 cm-1. HRMS (APCI-TOF) Calcd for C16H15N2O [M+H+] 251.1179, found 251.1171. (6-methylindolizin-3-yl)(5-methylpyridin-2-yl)methanone (4d): yellow solid (150mg, 60% yield), mp. 108-109 °C. 1H NMR (500 MHz, CDCl3) δ 9.95 (s, 1 H), 8.55 (m, 1 H), 8.06 (d, J = 4.7 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.67 (m, 1 H), 7.48 (d, J = 8.8 Hz, 1 H), 7.07 (dd, J = 8.8 Hz, J = 1.4 Hz, 1 H), 6.53 (d, J = 4.7 Hz, 1 H), 2.44 (s, 3 H), 2.41 (s, 3 H).

13

C NMR (125 MHz, CDCl3) δ 180.1, 155.2, 148.7, 138.6, 137.2,

135.1, 127.8, 127.6, 127.3, 123.7, 123.4, 122.1, 117.9, 103.2, 18.6, 18.5. IR (KBr) 1590, 1561, 1459, 1349, 1240, 1051, 882, 806, 711 cm-1. HRMS (APCI-TOF) Calcd for C16H15N2O [M+H+] 251.1179, found 251.1171.



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(6-methoxyindolizin-3-yl)(5-methoxypyridin-2-yl)methanone

Page 14 of 20

(4f):

yellow

solid

(121mg, 43% yield), mp. 93-94 °C. 1H NMR (500 MHz, CDCl3) δ 9.88 (s, 1 H), 8.41 (d, J = 2.4 Hz, 1 H), 8.12 (m, 2 H), 7.47 (d, J = 9.4 Hz, 1 H), 7.35(dd, J = 8.4 Hz, J = 2.8 Hz, 1 H), 7.02 (dd, J = 9.4 Hz, J = 2.1 Hz, 1 H), 6.55 (d, J = 4.7 Hz, 1 H), 3.96 (s, 3 H), 3.94 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ 179.4, 157.0, 150.2, 136.1, 127.1, 124.9, 122.9, 120.4, 122.1, 119.2, 118.5, 111.6, 103.5, 56.0, 55.7. IR (KBr) 1596, 1470, 1360, 1229, 1029, 819, cm-1. HRMS (ESI-TOF) Calcd for C16H15N2O3 [M+H+] 283.1077, found 283.1073. methyl 3-(5-(methoxycarbonyl)picolinoyl)indolizine-6-carboxylate (4g): yellow solid (186mg, 55% yield), mp. 209-210 °C. 1H NMR (500 MHz, CDCl3) δ 10.79 (s, 1 H), 9.34 (m, 1 H), 8.51 (dd, J = 8.2 Hz, J = 2.1 Hz, 1 H), 8.36 (d, J = 4.7 Hz, 1 H), 8.21 (d, J = 8.2 Hz, 1 H), 7.80 (dd, J = 9.1 Hz, J = 1.4 Hz, 1 H), 7.64 (d, J = 9.1 Hz, 1 H), 6.69 (d, J = 4.7 Hz, 1 H), 4.03 (s, 3 H), 4.01 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ 179.3, 165.7, 165.3, 159.8, 149.6, 140.3, 138.1, 133.1, 130.8, 127.2, 124.3, 123.5, 123.1, 118.1, 117.9, 104.5, 52.6, 52.4. IR (KBr) 1731, 1608, 1418, 1297, 1119, 741 cm-1. HRMS (ESI-TOF) Calcd for C18H15N2O5 [M+H+] 339.0975, found 339.0985. methyl 3-(4-(methoxycarbonyl)picolinoyl)indolizine-7-carboxylate (4h): yellow solid (213mg, 63% yield), mp 185-186 °C. 1H NMR (500 MHz, CDCl3) δ 10.59 (d, J = 7.4 Hz, 1 H), 8.91 (d, J = 4.9 Hz, 1 H), 8.65 (s, 1 H), 8.36 (s, 1 H), 8.22 (d, J = 4.9 Hz, 1 H), 8.04 (dd, J = 4.9 Hz, J = 1.5 Hz, 1 H), 7.53 (dd, J = 7.4 Hz, J = 1.9 Hz, 1 H), 6.84 (d, J = 4.9 Hz, 1 H), 4.03 (s, 3 H), 4.00 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ 178.0, 157.6, 148.1, 148.0, 140.4, 135.8, 128.7, 128.7, 125.9, 124.5, 122.0, 117.3, 116.4, 102.5, 21.3, 21.2. IR (KBr) 1729, 1610, 1580, 1459, 1329, 1256, 755 cm-1. HRMS (ESI-TOF) Calcd for C18H15N2O5 [M+H+] 339.0975, found 339.0979. (6-phenylindolizin-3-yl)(5-phenylpyridin-2-yl)methanone (4i): yellow solid (209mg, 56% yield), mp. 133-134 °C. 1H NMR (500 MHz, CDCl3) δ 10.47 (s, 1 H), 9.00 (s, 1 H), 8.31 (d, J = 4.7 Hz, 1 H), 8.21 (s, 1 H), 8.11 (d, J = 7.6 Hz, 1 H), 7.74-7.68 (m, 5 H), 7.57-7.41 (m, 7 H), 6.66 (d, J = 4.7 Hz, 1 H) 13C NMR (125 MHz, CDCl3) δ 179.8, 156.1, 146.8, 138.9, 138.0, 137.8, 137.3, 135.1, 129.2, 129.1, 128.8, 128.6, 128.3, 127.8, 127.3, 127.1, 127.0, 125.0, 123.9, 122.8, 118.5, 103.5. IR (KBr) 1581, 1472,


Page 15 of 20

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1242, 1057, 881, 690 cm-1. HRMS (ESI-TOF) Calcd for C26H19N2O [M+H+] 375.1492, found 375.1495. (7-phenylindolizin-3-yl)(4-phenylpyridin-2-yl)methanone (4j): yellow solid (243mg, 65% yield), mp. 135-136 °C. 1H NMR (500 MHz, CDCl3) δ 10.18 (d, J = 7.4 Hz, 1 H), 8.80 (d, J = 5.0 Hz, 1 H), 8.35 (d, J = 1.3 Hz, 1 H), 8.22 (d, J = 4.7 Hz, 1 H), 7.83 (d, J = 1.3 Hz, 1 H), 7.78-7.74 (m, 4 H), 7.68 (m, 1 H), 7.56-7.43 (m, 6 H), 7.30 (dd, J = 7.4 Hz, J = 2.0 Hz, 1 H), 6.69 (d, J = 4.7 Hz, 1 H).

13


180.0, 158.1, 149.4, 148.9, 140.3, 138.5, 137.9, 137.4, 129.3, 129.3, 129.2, 129.1, 129.1, 128.4, 127.1, 126.8, 122.9, 122.3, 121.7, 115.5, 113.5, 104.3. IR (KBr) 1583, 1473, 1328, 753, 693 cm-1. HRMS (ESI-TOF) Calcd for C26H19N2O [M+H+] 375.1492, found 375.1497. (7-(m-tolyl)indolizin-3-yl)(4-(m-tolyl)pyridin-2-yl)methanone

(4k):

yellow

solid

(273mg, 68% yield), mp. 132-133 °C. 1H NMR (500 MHz, CDCl3) δ 10.17 (d, J = 7.4 Hz, 1 H), 8.78 (d, J = 5.0 Hz, 1 H), 8.35 (s, 1 H), 8.23 (d, J = 4.7 Hz, 1 H), 7.81 (s, 1 H), 7.67 (dd, J = 5.0 Hz, J = 1.7 Hz,1 H), 7.59-7.53 (m, 4 H), 7.44-7.39 (m, 2 H), 7.31-7.25 (m, 3 H), 6.68 (d, J = 4.7 Hz, 1 H), 2.48 (s, 6 H).

13

C NMR (125 MHz,

CDCl3) δ 180.0, 158.0, 149.4, 148.8, 140.4, 138.9, 138.8, 138.5, 137.8, 137.6, 130.0, 129.2, 129.2, 129.1, 129.1, 129.0, 127.9, 127.5, 124.2, 123.9, 122.9, 122.3, 121.7, 115.4, 113.5, 104.3, 21.6, 21.5. IR (KBr) 1581, 1459, 1329, 1238, 1051, 777 cm-1. HRMS (ESI-TOF) Calcd for C28H23N2O [M+H+] 403.1805, found 403.1801. (7-(4-fluorophenyl)indolizin-3-yl)(4-(4-fluorophenyl)pyridin-2-yl)methanone

(4l):

yellow solid (221mg, 54% yield), mp. 230-231 °C. 1H NMR (500 MHz, CDCl3) δ 10.16 (d, J = 7.4 Hz, 1 H), 8.79 (d, J = 5.0 Hz, 1 H), 8.30 (s, 1 H), 8.23 (d, J = 4.7 Hz, 1 H), 7.77-7.63 (m, 6 H), 7.28-7.19 (m, 5 H), 6.68 (d, J = 4.7 Hz, 1 H), 3.91 (s, 6 H). 13

C NMR (125 MHz, CDCl3) δ 179.9, 163.6 (d, JC-F =250.2 Hz), 163.0 (d, JC-F =250.2

Hz), 158.1, 148.9, 148.3, 140.2, 136.5, 134.7, 134.0, 129.4, 129.1, 128.9 (d, JC-F =8.2 Hz), 128.5 (d, JC-F =8.2 Hz), 122.8, 122.3, 121.5, 116.3 (d, JC-F =21.8 Hz), 116.1 (d, JC-F =21.8 Hz), 115.4, 113.3, 104.3. IR (KBr) 1581, 1510, 1461, 1408, 1240, 827 cm-1. HRMS (ESI-TOF) Calcd for C26H17F2N2O [M+H+] 411.1303, found 411.1310. (7-(4-methoxyphenyl)indolizin-3-yl)(4-(4-methoxyphenyl)pyridin-2-yl)methanone



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Page 16 of 20

(4m): yellow solid (312mg, 72% yield), mp. 179-180 °C. 1H NMR (500 MHz, CDCl3) δ 10.15 (d, J = 7.4 Hz, 1 H), 8.74 (d, J = 5.0 Hz, 1 H), 8.30 (s, 1 H), 8.18 (d, J = 4.7 Hz, 1 H), 7.77-7.63 (m, 6 H), 7.26 (d, J = 7.4 Hz, 1 H), 7.07-7.04 (m, 4 H), 6.64 (d, J = 4.7 Hz, 1 H), 3.91 (s, 6 H).

13

C NMR (125 MHz, CDCl3) δ 180.0, 160.7, 160.0,

158.1, 148.8, 148.8, 140.5, 137.1, 130.9, 130.1, 129.3, 129.1, 128.3, 127.9, 122.2, 122.2, 121.1, 114.6, 114.6, 114.5, 113.2, 104.0, 55.4. IR (KBr) 1610, 1579, 1460, 1324, 1249, 1181, 822 cm-1. HRMS (ESI-TOF) Calcd for C28H23N2O3 [M+H+] 435.1703, found 435.1700. pyrrolo[1,2-a]quinolin-1-yl(quinolin-2-yl)methanone (4n): yellow solid (196mg, 61% yield), mp. 149-150 °C. 1H NMR (500 MHz, CDCl3) δ 8.40-8.38 (q, 2 H), 8.30 (d, J = 8.4 Hz, 1 H), 8.24 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.85-7.81 (m, 1 H), 7.76 (dd, J = 8.0 Hz, J = 1.2 Hz, 1 H), 7.71-7.68 (m, 2 H), 7.58 (m, 1 H), 7.51-7.44 (m, 3 H), 6.63 (d, J = 4.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 180.8, 156.6, 146.9, 140.5, 137.0, 134.0, 131.5, 130.5, 130.0, 129.0, 128.5, 128.4, 128.1, 127.9, 127.7, 126.6, 125.2, 124.8, 121.0, 120.9, 117.7, 105.2. IR (KBr) 1619, 1449, 1347, 896, 825, 803, 762 cm-1. HRMS (ESI-TOF) Calcd for C22H15N2O [M+H+] 323.1179, found: 323.1185. Complex (5): red solid. 1H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 4.8 Hz, 2 H), 7.49 (td, J = 7.5 Hz, J = 1.7 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 6.90 (m, 2 H), 5.65 (d, J = 6.1 Hz, 2 H), 2.32 (d, J = 6.6 Hz, 2 H), 1.33 (s, 15 H). 13C NMR (125 MHz, CDCl3) δ 162.3, 149.2, 135.6, 121.3, 118.4, 95.0 (d, J 54.7 (d, J

Rh-C

Rh-C

= 6.4 Hz), 77.2 (d, J

Rh-C

= 7.2 Hz),

= 14.4 Hz), 9.0. HRMS (ESI-TOF) Calcd for C24H28N2Rh [M+H+]

447.1302, found 447.1305. (2E,4E)-methyl 5-(pyridin-2-yl)penta-2,4-dienoate (6): white solid (98mg, 26% yield), mp. 64-66 °C. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J = 4.5 Hz, 1 H), 7.69 (td, J = 8.0 Hz, J = 1.8 Hz, 1 H), 7.52-7.47 (dd, J = 11.8 Hz, J = 15.1 Hz, 1 H), 7.42-7.35 (m, 2 H), 7.21 (m, 1 H), 6.96 (d, J = 15.1 Hz, 1 H), 6.13 (d, J = 15.1 Hz, 1 H), 3.80 (s, 3 H).

13

C NMR (125 MHz, CDCl3) δ 167.2, 154.3, 149.9, 143.8, 139.0, 136.7, 130.1,

123.2, 123.2, 123.1, 51.6. IR (KBr) 1715, 1634, 1432, 1246, 1137, 1001 cm-1. HRMS (ESI-TOF) Calcd for C11H11NNaO2 [M+Na+] 212.0682, found 212.0679.


Page 17 of 20

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methyl 2-(indolizin-3-yl)acetate (7): colorless oil (76mg, 20% yield). 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 7.0 Hz, 1 H), 7.41 (d, J = 9.0 Hz, 1 H), 6.74 (d, J = 3.8 Hz, 1 H), 6.70 (dd, J = 9.0 Hz, J = 7.0 Hz, 1 H), 6.57 (t, J = 7.0 Hz, 1 H), 6.46 (d, J = 3.8 Hz, 1 H), 3.95 (s, 2 H), 3.72 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ 170.3, 133.4, 122.1, 119.4, 116.3, 115.8, 114.3, 110.5, 98.6, 52.2, 32.5. IR (KBr) 2950, 1743, 1436, 1316, 1167, 756 cm-1. HRMS (ESI-TOF) Calcd for C11H11NNaO2 [M+Na+] 212.0682, found 212.0686.

Acknowledgment. This work was supported by the Program for New Century Excellent Talents in University of China (NCET-08-0472).

Supporting Information Available: Copies of 1H and

13

C NMR spectra for the

products and substrates, crystallographic data in CIF of 4a (CCDC 922879) and 5 (CCDC 922880). This material is available free of charge via the Internet at http://pubs.acs.org.

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Construction of 3-(Picolinoyl)indolizines: Rh(III)-Catalyzed Cascade

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