CuBr-Catalyzed Aerobic Decarboxylative Cycloaddition for the

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CuBr-Catalyzed Aerobic Decarboxylative Cycloaddition for the Synthesis of Indolizines Under Solvent-Free Conditions Wenhui Wang, Junwen Han, Jinwei Sun, and Yun Liu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02455 • Publication Date (Web): 22 Feb 2017 Downloaded from http://pubs.acs.org on February 23, 2017

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The Journal of Organic Chemistry

CuBr-Catalyzed Aerobic Decarboxylative Cycloaddition for the Synthesis of Indolizines Under Solvent-Free Conditions Wenhui Wang,a Junwen Han,a Jinwei Sun,a,b,* Yun Liua,* a

Jiangsu Key Laboratory of Green Synthesis for Functional Materials, School of Chemistry and

Chemical Engineering, Jiangsu Normal University, Xuzhou 221116, Jiangsu, P. R. China b

School of Environmental Science & Engineering, Nanjing University of Information Science &

Technology, Nanjing, 210044, P. R. China TOC

Abstract: An efficient synthesis of diversified indolizine derivatives was developed via CuBr-catalyzed reaction of pyridines, methyl ketones and alkenoic acids under solvent-free conditions in oxygen atmosphere. This synthesis involves cascade processes of copper-catalyzed bromination of the methyl ketone, 1,3-dipolar cycloaddition of the pyridinium ylide with the alkenoic acid followed by oxidative decarboxylation and dehydrogenative aromatization of the primary cycloadduct. By this protocol, a wide range of indoliznes with different substitution patterns were selectively prepared in one pot from simple substrates in good to excellent yields.

Introduction Indolizine is an important structural skeleton in many natural and synthetic bioactive molecules.1 It displays intriguing biological properties and is used as inhibitor of 5-hydroxytryptamine (5-HT3) receptor,2 phospholipase,3 aromatase,4 15-lipoxygenase,5 cancer cell,6 and topoisomerase I7 et al.8

ACS Paragon Plus Environment


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Furthermore, many indolizine derivatives have wide applications in material science field due to their strong fluorescence.9-10 As a result, much effort has been paid to develop efficient and versatile synthetic methods for indolizine derivatives.11 Pyridine annulation is an important strategy to indolizine synthesis and is mainly accomplished by four routes (Part A of Scheme 1): 1,3-dipolar cycloaddition of activated alkynes or alkenes with pyridinium salts derived from pyridines and organic halides;12 intramolecular or intermolecular cyclization of C2-substituted pyridines;13,14 transannulation reaction of pyridotriazoles with terminal alkynes;15 and cyclization of pyridines with three carbon fragments.16 Among these, 1,3-dipolar cycloaddition is very attractive because it can synthesize indolizines from simple substrates with high efficiency. However, this methodology usually uses activated alkynes or alkenes and can only synthesize indolizines bearing electron-deficient group at C-1 position. To overcome this limitation, Shang discovered the synthetic route to 2-phenylindolizines by the reaction of phenylacetylenes with pyridinium salts (route 1a in part B of Scheme 1).17 Lately, our group reported the synthesis of 1,2-unsubstituted indolizines via TPCD-promoted bisdecarboxylative cycloaddition reaction using maleic anhydride as the alkene species (route 1b in Scheme 1).18 More recently, Xiao uncovered the synthesis of 2,3-unsubstituted pyrrolo[2,1-a]isoquinolines through 1,3-dipolar cycloaddition of isoquinolinium N-ylides with vinyl sulfonium salts (route 1c in Scheme 1).19 Despite these progresses, the substrate scope in these syntheses is still very limited and each can only afford indolizines with specific substitution pattern on the ring. Also, the existing examples of 1,3-dipolar cycloaddition reaction require various organic halides or pyridinium salts and the reaction is not atom-economical. Hence, more simple and versatile dipolar cycloaddition protocols for the selective synthesis of diversified indolizine derivatives are highly desired. Following our continuous interest in heterocycle synthesis using copper catalyst under aerobic conditions20, we herein describe an efficient synthesis of indolizine derivatives via CuBr-catalyzed aerobic decarboxylative cycloaddition reaction of pyridines, methyl ketones and alkenoic acids (C in


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Scheme 1). By this protocol, a wide range of indolizine derivatives with different substitution patterns could be selectively synthesized from easily available substrates in one pot with high yields. A) Synthesis of indolizines via pyridine annulation R1 O

+ N

Br

R

+ EWG

OR1

ref. 12a 1

R

R

ref. 13a R2

CO2Et ref. 16a

+

N

N

N2

ref. 15a R N N

or 1 CO2R + R

N

1

R3

N

ref. 14a

R2

N + R

B) Dipolar cycloaddition to synthesize indolizines without C-1 electron-deficient group H O R1 base R N N R1 (a) BrR O O

H

O

O

O

R

N

N Br-

TPCD, base O

N

R

Ph S

+

(b)

R H

DABCO Ph

N

Br-

(c) R

C) This work R

2

R N

1

R

+ CH3COR3 + CO2H

CuBr (20 mol%) O2 (1 atm)

R1 R N

80 oC, 12 h

R2

COR3 R1=H, alkyl R =H, alkyl, aryl, heteroaryl 2

Scheme 1. Synthesis of Indolizines

Results and Discussion To begin our work, methyl isonicotinate 1a (2.0 mmol), acetophone 2a (1.0 mmol), and (E)-butenoic acid 3a (0.5 mmol) were employed as model reactants. Initially, heating the reactants in acetonitrile at 80 oC for 12 h in the air in the presence of 0.3 equiv of CuBr2, we did not detect the formation of indolizine product 4a (Table 1, entry 1). Changing solvent to dioxane, benzene, toluene,



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DMF or DCE still did not make any improvement (Table 1, entry 2-6). However, when the reaction was carried out at 80 oC under solvent-free condition, the desired product 4a was isolated in 35% yield (Table 1, entry 7). Encouraged by this result, various copper salts were screened under solvent-free condition and CuBr performed better than others, giving 4a in 51% yield (Table 1, entry 7-11). Subsequently, oxidants including O2, BQ (benzoquinone), TBHP (tert-butyl peroxide) or DTBP (Di-tert-butyl peroxide) were added into the reaction system respectively, and we found DTBP and oxygen worked most efficiently (Table 1, entry 12-15). Considering the economic efficiency and environmental benignancy of using oxygen, we chose it as the terminal oxidant. Further experiments indicated that 0.2 equiv of CuBr was enough to assure the high yield in the presence of oxygen, while no indolizine product was found without CuBr even in O2 atmosphere (Table 1, entry 16-18). Besides, utilizing 0.2 equiv of CuBr2 in combination with O2 as oxidant or decreasing the amount of 1a led to a declined yield of 4a (entry 19-20). Finally, we attempted to reduce reaction temperature, but the yield decreased correspondingly (Table 1, entry 21-22). Therefore, the optimal conditions were set for heating the reactants at 80 oC for 12 h in oxygen atmosphere using 0.2 equiv of CuBr as the catalyst. Table 1 Optimization of Reaction Conditionsa

Entry

Solvent

Cat. (equiv)

Oxidant

Yield (%)b

1

CH3CN

CuBr2 (0.3)

Air

0

2

Dioxane

CuBr2 (0.3)

Air

0

3

C 6 H6

CuBr2 (0.3)

Air

0

4

Toluene

CuBr2 (0.3)

Air

0

5

DMF

CuBr2 (0.3)

Air

0


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a

6

DCE

CuBr2 (0.3)

Air

0

7

none

CuBr2 (0.3)

Air

35

8

none

CuCl2 (0.3)

Air

0

9

none

CuCl (0.3)

Air

0

10

none

CuBr (0.3)

Air

51

11

none

CuI (0.3)

Air

25

12

none

CuBr (0.3)

O2 (1 atm)

82

13

none

CuBr (0.3)

BQ (2 eq)

0

14

none

CuBr (0.3)

TBHP (2 eq)

69

15

none

CuBr (0.3)

DTBP (2 eq)

82

16

none

CuBr (0.2)

O2 (1 atm)

82

17

none

CuBr (0.1)

O2 (1 atm)

53

18

none

none

O2 (1 atm)

0

19

none

CuBr2 (0.2)

O2 (1 atm)

62

20c

none

CuBr (0.2)

O2 (1 atm)

76

21d

none

CuBr (0.2)

O2 (1 atm)

71

22e

none

CuBr (0.2)

O2 (1 atm)

58

Reaction conditions: 1a (2.0 mmol), 2a (1.0 mmol), 3a (0.5 mmol), copper catalyst, oxidant, sealed

tube, 80 oC, 12 h. bIsolated yields based on 3a. cUsing 1.5 mmol of 1a. dHeating at 70 oC. eHeating at 60 oC.

With the optimal conditions in hand, we began to expand the reactant scope as shown in Table 2. It showed that various alkenoic acids 3 reacted with methyl isonicotinate 1a and acetophenones 2 well. For examples, (E)-butenioc acid 3a resulted in 3-benzoyl 2-methylindolizines 4a-4d in 75% to 84% yields. Similarly, (E)-2-hexenoic acid 3b, cinnamic acid 3c and (E)-3-(pyridin-2-yl)acrylic acid



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3d also provided 2,3-disubstituted indolizines 4e–4i in 48% to 79% yields. In the cases of acrylic acid 3e, methacrylic acid 3f, (E)-2-methyl-2-butenoic acid 3g, (E)-2-methyl-2-pentenoic acid 3h and (E)-2-methyl-3-phenylacrylic acid 3i, we obtained 1,2-unsubstituted indolizine 4j, 1,3-disubstituted indolizines 4k-4q and 1,2,3-trisubstituted indolizine 4r-4u in good to excellent yields. Meanwhile, with methacrylic acid 3f as substrate, we investigated the scope of acetophenone thoroughly. It was found that either steric or electronic effect of different acetophenones is very little to this reaction.

Table 2 Scope of alkenoic acid 3 and acetophenone 2a

a

Reaction conditions: 1a (2.0 mmol), 2 (1.0 mmol), 3 (0.5 mmol), CuBr (0.1 mmol, 20 mol%),

heating at 80 oC for 12 h in oxygen atmosphere in sealed tube. bIsolated yields based on 3.


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Next, the scope of pyridine was examined under the optimal conditions, shown in Table 3. For pyridines 1b-1f with or without para-substituents, the corresponding indolizines 5a-5g were isolated in 51% to 76% yields. High regioselectivity was observed in the reaction of methyl nicotinate 1g with acrylic acid and acetophenone, and product 5h was given exclusively in 80% yield. Quinoline 1h and isoquinoline 1i was proved to be good substrates as well, and accomplished this reaction effectively (5i-5l, 55%-87%).

Table 3 Scope of pyridine 1a

a

Reaction conditions: 1 (2.0 mmol), 2 (1.0 mmol), 3 (0.5 mmol), CuBr (0.1 mmol, 20 mol%), heating

at 80 oC for 12 h in oxygen atmosphere in sealed tube. bIsolated yields based on 3.



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For enlarging the reaction scope further, aliphatic methyl ketones 6a-6d and heterocyclic methyl ketones 6e-6f were employed instead of acetophenones 2 to this reaction (Table 4). Pleasingly, in the presence of 20 mol% of CuBr under 1 atm of O2, by heating the mixtures of 1a, alkenoic acids 3 with various methyl ketones, including acetone 6a, 3-methyl 2-butanone 6b, pinacolone 6c, 1-cyclohexylethanone 6d, 1-(furan-2-yl)ethanone 6e and 1-(thiophen-2-yl)ethanone 6f, we got 7a-7h in good yields. Table 4 Scope of Other Methyl Ketone 6a

a

Reaction conditions: 1a (2.0 mmol), 6 (1.0 mmol), 3 (0.5 mmol), CuBr (0.1 mmol, 20 mol%),

heating at 80 oC for 12 h in oxygen atmosphere in sealed tube. bIsolated yields based on 3. cAdding 3.0 mmol of methyl ketone 6 due to its low boiling point.

To clarify the reaction mechanism, some control experiments were carried out (Scheme 2). Firstly, adding 1.0 equiv of 2,2,6,6-Tetramethyl-1-piperidinyloxy (TMEPO) into the model reaction, we did not detect the formation of 4a (eq. 1). This implied that radical process was probably involved in the reaction sequence. Secondly, the reaction of methyl isonicotinate 1a and acetophone


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2a with either styrene (eq. 2) or methyl acrylate (eq. 3) under the standard conditions did not generate any indolizine product. These facts showed that a carboxyl group in the alkene substrate is indispensable. Thirdly, by stirring acetophenone 2a with 0.5 equiv of CuBr2 at 30 oC for 3 hours under solvent-free conditions, we obtained 2-bromoacetophenone in 41% yield (eq. 4). Finally, product 4a could not be formed by heating methyl isonicotinate 1a and (E)-butenoic acid 3a with α-bromoacetophenone without CuBr (eq. 5). This indicates the necessity of the copper salt as an oxidant in the reaction.

Scheme 2 Control Experiments

On the basis of these experiment results, a plausible mechanism was suggested (Scheme 3). Firstly, (E)-butenoic acid 3a reacted with CuBr to form its copper salt I, dispelling HBr, which, with the aid of O2, transformed Cu(I) to Cu(II) species. Then bromide II, yielding in situ from acetophenone 2a and Cu(II) salt,21 reacted with 1a to give N-ylide III. After this, intermediate III



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underwent cycloaddition with I followed by oxidative decarboxylation, leading to radical intermediate IV. At last, product 4a was produced via further oxidation, deprotonation and aromatization.

Scheme 3 Plausible Reaction Mechanism Conclusions In conclusion, a convenient and efficient CuBr-catalyzed aerobic decarboxylative cycloaddition reaction was developed for the synthesis of diversified indolizine derivatives. By adjusting the alkenoic acid structure, 1,2-unsubstituted, 1,3- and 2,3-disubstituted, or 1,2,3-trisubstituted indolizines can be selectively synthesized. Besides this remarkable synthetic versatility, this protocol features many other advantages such as using simple substrates, atom-economical reactions as well as high product yields. We believe that this strategy of combining Cu-catalyzed in situ generation of α-bromocarbonyl compounds with post-cycloaddition decarboxylation can also be applied to prepare other types of heterocycles with a ring-junction nitrogen atom.


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Experimental General Melting points are uncorrected. 1H NMR spectra were measured at 400 MHz with CDCl3 as solvent. The chemical shifts (δ) are reported in parts per million relative to the residual deuterated solvent signal, and coupling constants (J) are given in Hertz. 13C NMR spectra were measured at 100 MHz with CDCl3 as solvent. HRMS data were recorded on a mass spectrometer with electrospray ionization and TOF mass analyzer. All reagents and solvents were commercially available and used without further purification. General Procedure for the preparation of 4 The mixture of methyl isonicotinate 1a (2.0 mmol), acetophenone 2 (1.0 mmol), alkenoic acid 3 (0.5 mmol), and CuBr (0.1 mmol) was heated at 80 oC for 12 h in a sealed tube under 1 atm of O2. After the reaction was completed, the resulting mixture was separated by flash chromatography on a silica gel column with ethyl acetate/petroleum (1:20–1:30) as eluent to give the product 4. Methyl 3-benzoyl-2-methylindolizine-7-carboxylate (4a) Yellow solid (82%, 120 mg), mp 134– 136 °C. 1H NMR (400 MHz, CDCl3): δ 1.96 (s, 3H), 3.96 (s, 3H), 6.55 (s, 1H), 7.32 (dd, J = 7.6, 1.6 Hz, 1H), 7.46–7.56 (m, 3H), 7.63 (dd, J = 7.2, 1.2 Hz, 2H), 8.17 (s, 1H), 9.54 (d, J = 7.2 Hz, 1H). 13

C NMR (100 MHz, CDCl3): δ 187.2, 165.7, 141.3, 136.3, 135.3, 131.3, 128.5, 128.3, 127.4, 124.5,

123.2, 120.6, 111.4, 108.3, 52.4, 15.4. HRMS (ESI) m/z calcd for C18H16NO3 [M+H]+ 294.1130, found 294.1137. Methyl 3-(4-chlorobenzoyl)-2-methylindolizine-7-carboxylate (4b) Yellow solid (84%, 137 mg), mp 184–186 °C. 1H NMR (400 MHz, CDCl3): δ 1.99 (s, 3H), 3.96 (s, 3H), 6.56 (s, 1H), 7.33 (dd, J = 7.6, 2.0 Hz, 1H), 7.45–7.47 (m, 2H), 7.58–7.60 (m, 2H), 8.18 (s, 1H), 9.52 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 185.7, 165.7, 139.6, 137.6, 136.5, 135.2, 129.9, 128.8, 127.5, 124.8, 122.9, 120.6, 111.6, 108.4, 52.5, 15.6. HRMS (ESI) m/z calcd for C18H15ClNO3 [M+H]+ 328.0740, found 328.0748.



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Methyl 3-(4-bromobenzoyl)-2-methylindolizine-7-carboxylate (4c) Yellow solid (81%, 151 mg), mp 199–201 °C. 1H NMR (400 MHz, CDCl3): δ 1.99 (s, 3H), 3.96 (s, 3H), 6.56 (s, 1H), 7.33 (dd, J = 7.6, 2.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 8.18 (s, 1H), 9.53 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 185.8, 165.6, 140.0, 136.5, 135.2, 131.8, 130.0, 127.5, 126.0, 124.8, 122.9, 120.5, 111.7, 108.4, 52.5, 15.7. HRMS (ESI) m/z calcd for C18H15BrNO3 [M+H]+ 372.0235, found 372.0245. Methyl 2-methyl-3-(4-methylbenzoyl)indolizine-7-carboxylate (4d) Yellow solid (75%, 115 mg), mp 146–148 °C. 1H NMR (400 MHz, CDCl3): δ 2.01 (s, 3H), 2.44 (s, 3H), 3.95 (s, 3H), 6.55 (s, 1H), 7.26–7.30 (m, 3H), 7.55 (d, J = 8.0 Hz, 2H), 8.16 (s, 1H), 9.44 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 187.2, 165.8, 142.0, 138.4, 136.0, 134.8, 129.2, 128.7, 127.3, 124.1, 123.4, 120.6, 111.2, 108.0, 52.4, 21.6, 15.4. HRMS (ESI) m/z calcd for C19H18NO3 [M+H]+ 308.1287, found 308.1293. Methyl 3-benzoyl-2-propylindolizine-7-carboxylate (4e) Yellow solid (74%, 118 mg), mp 141– 143 °C. 1H NMR (400 MHz, CDCl3): δ 0.69 (t, J = 7.2 Hz, 3H), 1.46 (q, J = 7.2 Hz, 2H), 2.45 (t, J = 7.2 Hz, 2H), 3.95 (s, 3H), 6.61 (s, 1H), 7.30 (dd, J = 7.6, 2,.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 7.2 H, 2H), 8.19 (s, 1H), 9.43 (d, J = 7.6 Hz, 1H).

13

C NMR (100

MHz, CDCl3): δ 187.5, 165.8, 141.1, 140.2, 136.2, 131.4, 128.5, 128.4, 127.3, 124.1, 122.8, 120.8, 111.3, 106.7, 52.4, 30.4, 24.2, 13.9. HRMS (ESI) m/z calcd for C20H20NO3 [M+H]+ 322.1443, found 322.1437. Methyl 3-(4-chlorobenzoyl)-2-propylindolizine-7-carboxylate (4f) Yellow solid (79%, 141 mg), mp 123–125 °C.

1

H NMR (400 MHz, CDCl3): δ 0.72 (t, J = 7.6 Hz, 3H), 1.45–1.51 (m, 2H), 2.28

(t, J = 7.6 Hz, 2H), 3.96 (s, 3H), 6.61 (s, 1H), 7.31 (dd, J = 7.6, 1.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 8.19 (s, 1H), 9.41 (d, J = 7.6 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ

186.0, 165.7, 140.0, 139.4, 137.7, 136.4, 130.0, 128.7, 127.3, 124.4, 122.5, 120.8, 111.5, 106.8, 52.4, 30.5, 24.1, 13.9. HRMS (ESI) m/z calcd for C20H19ClNO3 [M+H]+ 356.1053, found 356.1059.


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Methyl 3-(4-bromobenzoyl)-2-propylindolizine-7-carboxylate (4g) Yellow solid (77%, 153 mg), mp 126–128 °C. 1H NMR (400 MHz, CDCl3): δ 0.72 (t, J = 7.6 Hz, 3H), 1.45–1.51 (m, 2H), 2.28 (t, J = 7.6 Hz, 2H), 3.96 (s, 3H), 6.61 (s, 1H), 7.31 (dd, J = 7.6, 1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 0.8 Hz, 1H), 9.42 (d, J = 7.6 Hz, 1H).

13

C NMR (100 MHz,

CDCl3): δ 186.1, 165.7, 140.0, 139.9, 136.5, 131.7, 130.2, 127.3, 126.2, 124.5, 122.5, 120.8, 111.5, 106.8, 52.4, 30.5, 24.1, 13.9. HRMS (ESI) m/z calcd for C20H19BrNO3 [M+H]+ 400.0548, found 400.0543. Methyl 3-benzoyl-2-phenylindolizine-7-carboxylate (4h) Yellow solid (66%, 117 mg), mp 130– 132 °C. 1H NMR (400 MHz, CDCl3): δ 3.98 (s, 3H), 6.83 (s, 1H), 7.02–7.11 (m, 7H), 7.19 (t, J = 7.2 Hz, 1H), 7.40 (dd, J = 7.6, 2.0 Hz, 1H), 7.45 (d, J = 7.2 Hz, 2H), 8.31 (s, 1H), 9.61 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 187.5, 165.7, 139.7, 139.4, 135.8, 135.2, 131.3, 130.1, 129.7, 127.9, 127.8, 127.6, 127.2, 127.0, 124.5, 121.6, 121.5, 112.1, 107.2, 52.5. HRMS (ESI) m/z calcd for C23H18NO3 [M+H]+ 356.1287, found 356.1283. Methyl 3-benzoyl-2-(pyridin-2-yl)indolizine-7-carboxylate (4i) Yellow solid (48%, 85 mg), mp 169–171 °C. 1H NMR (400 MHz, CDCl3): δ 1H NMR (400 MHz, CDCl3): δ 4.00 (s, 3H), 7.18 (t, J = 7.2 Hz, 1H), 7.52–7.64 (m, 5H), 7.72 (t, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 8.72 (d, J = 4.4 Hz, 1H), 9.41 (s, 1H), 9.95 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 185.5, 165.7, 153.4, 149.6, 140.1, 136.6, 135.9, 131.5, 129.1, 128.4, 128.0, 126.4, 125.2, 123.7, 123.0, 121.1, 120.9, 118.7, 118.6, 113.5, 52.6. HRMS (ESI) m/z calcd for C22H17N2O3 [M+H]+ 357.1239, found 357.1244. Methyl 3-benzoylindolizine-7-carboxylate (4j)22 Yellow solid (75%, 105 mg), mp 132–134 °C. 1H NMR (400 MHz, CDCl3): δ 3.97 (s, 3H), 6.76 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 4.4 Hz, 1H), 7.45– 7.58 (m, 4H), 7.81 (dt, J = 7.2, 1.6 Hz, 2H), 8.32 (s, 1H), 9.89 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 185.3, 165.6, 140.2, 137.8, 131.3, 129.0, 128.3, 127.9, 126.9, 124.8, 124.1, 121.6, 112.5, 105.9, 52.5. HRMS (ESI) m/z calcd for C17H14NO3 [M+H]+ 280.0974, found 280.0975.



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

Methyl 3-benzoyl-1-methylindolizine-7-carboxylate (4k) Yellow solid (82%, 120 mg), mp 155– 157 °C. 1H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 3.98 (s, 3H), 7.20 (s, 1H), 7.42 (dd, J = 7.6, 2.0 Hz, 1H), 7.48–7.56 (m, 3H), 7.79–7.81 (m, 2H), 8.27 (s, 1H), 9.85 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 184.9, 165.7, 140.4, 136.3, 131.1, 128.9, 128.2, 127.8, 126.6, 123.8, 122.8, 119.8, 115.5, 112.2, 52.4, 10.6. HRMS (ESI) m/z calcd for C18H16NO3 [M+H]+ 294.1130, found 294.1127. Methyl 3-(4-fluorobenzoyl)-1-methylindolizine-7-carboxylate (4l) Yellow solid (88%, 137 mg), mp 157–159 °C. 1H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 3.98 (s, 3H), 7.16–7.20 (m, 3H), 7.42 (d, J = 7.6 Hz, 1H), 7.81–7.84 (m, 2H), 8.27 (s, 1H), 9.81 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 183.3, 165.7, 164.5 (d, J = 250 Hz), 136.6, 136.5, 136.3, 131.2 (d, J = 8.8 Hz), 127.7, 126.3, 123.9, 122.6, 119.8, 115.5, 115.3 (d, J = 22 Hz), 112.3, 52.4, 10.6. HRMS (ESI) m/z calcd for C18H15FNO3 [M+H]+ 312.1036, found 312.1030. Methyl 3-(4-chlorobenzoyl)-1-methylindolizine-7-carboxylate (4m) Yellow solid (85%, 139 mg), mp 183–185 °C. 1H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 3.98 (s, 3H), 7.16 (s, 1H), 7.43 (dd, J = 7.2, 1.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 8.27 (s, 1H), 9.82 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 183.3, 165.6, 138.7, 137.4, 136.5, 130.3, 128.5, 127.8, 126.4, 124.1, 122.5, 119.8, 115.7, 112.4, 52.5, 10.6. HRMS (ESI) m/z calcd for C18H15ClNO3 [M+H]+ 328.0740, found 328.0749. Methyl 3-(4-methoxybenzoyl)-1-methylindolizine-7-carboxylate (4n) Yellow solid (80%, 129 mg), mp 163–165 °C. 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H), 3.90 (s, 3H), 3.97 (s, 3H), 7.00 (dd, J = 6.8, 2.0 Hz, 2H), 7.21 (s, 1H), 7.38 (dd, J = 7.6, 2.0 Hz, 1H), 7.82 (dd, J = 6.8, 2.0 Hz, 2H), 8.26 (t, J = 0.8 Hz, 1H), 9.78 (d, J = 7.6 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 184.0, 165.8,

162.2, 135.8, 132.9, 131.2, 127.6, 126.1, 123.3, 123.0, 119.9, 115.2, 113.5, 111.9, 55.5, 52.4, 10.6. HRMS (ESI) m/z calcd for C19H18NO4 [M+H]+ 324.1236, found 324.1233.


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Methyl 1-methyl-3-(4-methylbenzoyl)indolizine-7-carboxylate (4o) Yellow solid (81%, 124 mg), mp 185–187 °C. 1H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 2.45 (s, 3H), 3.97 (s, 3H), 7.21 (s, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 2H), 8.26 (s, 1H), 9.83 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 184.8, 165.8, 141.7, 137.7, 136.0, 129.1, 128.9, 127.7, 126.5, 123.5, 123.0, 119.9, 115.3, 112.1, 52.4, 21.6, 10.6. HRMS (ESI) m/z calcd for C19H18NO3 [M+H]+ 308.1287, found 308.1295. Methyl 3-(3,4-dichlorobenzoyl)-1-methylindolizine-7-carboxylate (4p) Yellow solid (86%, 155 mg), mp 174–176 °C. 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H), 3.99 (s, 3H), 7.16 (s, 1H), 7.45 (dd, J = 7.2, 1.6 Hz, 1H), 7.57–7.63 (m, 2H), 7.88 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 9.81 (d, J = 7.6 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 181.7, 165.6, 140.1, 136.9, 135.4, 132.7, 130.8, 130.3,

128.0, 127.9, 126.3, 124.5, 122.1, 119.8, 116.0, 112.7, 52.5, 10.6. HRMS (ESI) m/z calcd for C18H14Cl2NO3 [M+H]+ 362.0351, found 362.0362. Methyl 3-(2-chlorobenzoyl)-1-methylindolizine-7-carboxylate (4q) Yellow solid (83%, 136 mg), mp 136–138 °C. 1H NMR (400 MHz, CDCl3): δ 2.36 (s, 3H), 3.98 (s, 3H), 6.87 (s, 1H), 7.36–7.49 (m, 5H), 8.27 (s, 1H), 9.91 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 182.7, 165.6, 139.7, 137.1, 131.3, 130.6, 130.0, 129.1, 128.1, 126.8, 126.4, 124.6, 122.9, 119.8, 116.0, 112.7, 52.5, 10.5. HRMS (ESI) m/z calcd for C18H15ClNO3 [M+H]+ 328.0740, found 328.0747. Methyl 3-benzoyl-1,2-dimethylindolizine-7-carboxylate (4r) Yellow solid (70%, 107 mg), mp 174–176 °C. 1H NMR (400 MHz, CDCl3): δ 1.88 (s, 3H), 2.28 (s, 3H), 3.96 (s, 3H), 7.27 (dd, J = 8.0, 1.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 8.19 (s, 1H), 9.49 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 187.0, 165.9, 141.4, 135.0, 132.7, 131..2, 128.5, 128.4, 127.1, 123.2, 122.8, 119.1, 114.9, 111.1, 52.4, 12.9, 8.7. HRMS (ESI) m/z calcd for C19H18NO3 [M+H]+ 308.1287, found 308.1293. Methyl 3-(4-chlorobenzoyl)-1,2-dimethylindolizine-7-carboxylate (4s) Yellow solid (68%, 116 mg), mp 192–194 °C. 1H NMR (400 MHz, CDCl3): δ 1.90 (d, J = 1.6 Hz, 3H), 2.28 (d, J = 2.4 Hz,



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3H), 3.96 (s, 3H), 7.28–7.30 (m, 1H), 7.45 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 8.18 (d, J = 2.4 Hz, 1H), 9.48 (dd, J = 7.2, 2.8 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 185.4, 165.8, 139.7,

137.5, 135.2, 132.5, 130.0, 128.8, 127.1, 123.7, 122.5, 119.1, 115.1, 111.3, 52.4, 13.1, 8.7. HRMS (ESI) m/z calcd for C19H17ClNO3 [M+H]+ 342.0897, found 342.0886. Methyl 3-benzoyl-2-ethyl-1-methylindolizine-7-carboxylate (4t) Yellow solid (65%, 104 mg), mp 139–141 °C. 1H NMR (400 MHz, CDCl3): δ 0.91 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 2.34 (q, J = 7.2, 2H), 3.96 (s, 3H), 7.24 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.55 (td, J = 7.6, 0.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 8.20 (s, 1H), 9.35 (d, J = 7.2 Hz, 1H).

13


187.3, 166.0, 141.3, 139.0, 135.1, 131.3, 128.6, 128.4, 128.3, 128.2, 127.1, 123.1, 122.1, 119.3, 114.1, 111.0, 52.3, 19.1, 15.3, 8.6. HRMS (ESI) m/z calcd for C20H20NO3 [M+H]+ 322.1443, found 322.1438. Methyl 3-benzoyl-1-methyl-2-phenylindolizine-7-carboxylate (4u) Yellow solid (60%, 110 mg), mp 134–136 oC. 1H NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 3.99 (s, 3H), 6.97–7.03 (m, 6H), 7.14 (t, J = 7.6 Hz, 1H), 7.36–7.43 (m, 4H), 8.31 (s, 1H), 9.65 (d, J = 7.6 Hz, 1H).

13

C NMR (100 MHz,

CDCl3): δ 187.3, 165.9, 139.6, 137.7, 134.7, 134.2, 130.9, 130.8, 129.8, 129.3, 127.5, 127.3, 127.1, 126.7, 123.6, 121.9, 120.0, 114.4, 112.0, 52.4, 9.3. HRMS (ESI) m/z calcd for C24H20NO3 [M+H]+ 370.1443, found 370.1448. General Procedure for the preparation of 5 The mixture of pyridine 1b-1i (2.0 mmol), acetophenone 2 (1.0 mmol), alkenoic acid 3 (0.5 mmol), and CuBr (0.1 mmol) was heated at 80 oC for 12 h in a sealed tube under 1 atm of O2. After the reaction was completed, the resulting mixture was separated by flash chromatography on a silica gel column with ethyl acetate/petroleum (1:20–1:30) as eluent to give the product 5. (2-Methylindolizin-3-yl)phenylmethanone (5a)23 Yellow solid (71%, 84 mg), mp 62-63 oC. 1H NMR (400 MHz, CDCl3): δ 1.91 (s, 3H), 6.32 (s, 1H), 6.82 (td, J = 6.8, 0.8 H, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.41‒7.50 (m, 4H), 7.59 (dd, J = 8.0, 1.6 Hz, 2H), 9.74 (d, J = 7.2 Hz, 1H). 13C NMR (100


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MHz, CDCl3): δ 186.3, 142.2, 138.3, 135.5, 130.5, 128.6, 128.4, 128.1, 124.3, 121.6, 117.5, 112.9, 105.2, 15.6. HRMS (ESI) m/z calcd for C16H14NO [M+H]+ 236.1075, found 236.1068. (1-Methylindolizin-3-yl)phenylmethanone (5b)24 Yellow oil (73%, 86 mg). 1H NMR (400 MHz, CDCl3): δ 2.34 (s, 3H), 6.92 (td, J = 6.8, 1.2 Hz, 1H), 7.15 (s, 1H), 7.16‒7.20 (m, 1H), 7.45‒7.52 (m, 4H), 7.77‒7.80 (m, 2H), 9.96 (d, J = 7.2 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 183.8, 141.2,

138.0, 130.6, 128.9, 128.8, 128.1, 126.6, 123.6, 121.2, 116.8, 113.7, 111.7, 10.5. HRMS (ESI) m/z calcd for C16H14NO [M+H]+ 236.1075, found 236.1063. (4-Chlorophenyl)(indolizin-3-yl)methanone (5c)18 Yellow solid (65%, 83 mg), mp 120–122 oC. 1H NMR (400 MHz, CDCl3): δ 6.54 (d, J = 4.8 Hz, 1H), 6.97 (td, J = 7.2, 0.8 Hz, 1H), 7.21 (td, J = 7.6, 1.2 Hz, 1H), 7.30 (d, J = 4.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 9.94 (d, J = 7.2 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 182.9, 139.7, 139.1, 137.0,

130.3, 128.8, 128.4, 126.6, 124.6, 122.3, 118.7, 114.0, 102.8. HRMS (ESI) m/z calcd for C15H11ClNO [M+H]+ 256.0529, found 256.0522. Indolizine-3,7-diylbis(phenylmethanone) (5d)22 Yellow solid (73%, 118 mg), mp 143–145 °C. 1H NMR (400 MHz, CDCl3): δ 6.77 (d, J = 4.8 Hz, 1H), 7.42 (dd, J = 7.2, 2.0 Hz, 2H), 7.49–7.64 (m, 6H), 7.82–7.85 (m, 4H), 8.02 (s, 1H), 9.94 (d, J = 7.6 Hz, 1H).

13


194.3, 185.4, 140.1, 137.4, 137.1, 132.6, 131.7, 131.4, 129.8, 129.0, 128.5, 128.3, 128.1, 127.0, 124.1, 122.6, 113.1, 106.4. HRMS (ESI) m/z [M+H]+ calcd for C22H16NO2 [M+H]+ 326.1181, found 326.1193. (1,7-Dimethylindolizin-3-yl)phenylmethanone (5e) Yellow solid (51%, 63 mg), mp 118–120 °C. 1

H NMR (400 MHz, CDCl3): δ 2.29 (s, 3H), 2.44 (s, 3H), 6.77 (dd, J = 7.2, 0.8 Hz, 1H), 7.10 (s, 1H),

7.26 (s, 1H), 7.44–7.50 (m, 3H), 7.77 (d, J = 6.8 Hz, 2H), 9.87 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 183.1, 141.3, 138.6, 134.8, 130.3, 128.8, 128.4, 128.0, 126.9, 120.8, 116.2, 115.4, 110.6, 21.4, 10.5. HRMS (ESI) m/z [M+H]+ calcd for C17H16NO [M+H]+ 250.1232, found 250.1225.



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(7-tert-Butyl-1-methylindolizin-3-yl)phenylmethanone (5f) Yellow solid (76%, 111 mg), mp 141– 143 °C. 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H), 2.33 (s, 3H), 6.99 (dd, J = 7.6, 2.0 Hz, 1H), 7.11 (s, 1H), 7.36 (t, J = 1.2 Hz, 1H), 7.44–7.51 (m, 3H), 7.77 (dd, J = 7.6, 1.2 Hz, 2H), 9.88 (d, J = 7.2 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 183.1, 147.8, 141.3, 138.4, 130.4, 128.8, 128.4, 128.0,

126.8, 120.6, 113.0, 111.2, 111.1, 34.9, 30.5, 10.6. HRMS (ESI) m/z calcd for C20H22NO [M+H]+ 292.1701, found 292.1700. (7-Methoxy-1-methylindolizin-3-yl)phenylmethanone (5g) Yellow solid (56%, 74 mg), mp 152-154 °C. 1H NMR (400 MHz, CDCl3): δ 2.27 (s, 3H), 3.92 (s, 3H), 6.63 (dd, J = 7.6, 2.4 Hz, 1H), 6.70 (d, J = 1.6 Hz, 1H), 7.09 (s, 1H), 7.46–7.50 (m, 3H), 7.76 (d, J = 6.4 Hz, 2H), 9.87 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 182.4, 156.9, 141.3, 140.1, 130.5, 130.3, 128.8, 128.0, 127.9, 120.3, 110.1, 107.5, 94.5, 55.4, 10.6. HRMS (ESI) m/z calcd for C17H16NO2 [M+H]+ 266.1181, found 266.1172. Methyl 3-benzoylindolizine-6-carboxylate (5h)22 Yellow solid (80%, 112 mg), mp 118–120 °C. 1H NMR (400 MHz, CDCl3): δ 3.97 (s, 3H), 6.59 (d, J = 4.4 Hz, 1H), 7.45–7.52 (m, 3H), 7.55–7.59 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.81–7.83 (m, 2H), 10.62 (s, 1H).

13


184.8, 165.8, 140.1, 139.6, 132.7, 131.3, 129.0, 128.7, 128.3, 123.5, 123.4, 118.1, 117.5, 112.5, 104.3, 103.2, 52.4. HRMS (ESI) m/z calcd for C17H14NO3 [M+H]+ 280.0974, found 280.0980. (4-Chlorophenyl)(pyrrolo[1,2-a]quinolin-1-yl)methanone (5i)18 Yellow solid (55%, 84 mg), mp 108–110 °C. 1H NMR (400 MHz, CDCl3): δ 6.54 (d, J = 4.4 Hz, 1H), 7.18 (d, J = 4.4 Hz, 1H), 7.41– 7.43 (m, 3H), 7.48–7.53 (m, 3H), 7.72 (dd, J = 8.0, 1.6 Hz, 1H), 8.00 (dd, J = 6.8, 2.0 Hz, 2H), 8.14 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 182.8, 139.7, 138.5, 137.9, 133.7, 131.4, 128.9, 128.7, 128.5, 128.1, 128.0, 126.0, 125.0, 124.8, 120.0, 117.8, 104.3. HRMS (ESI) m/z calcd for C19H13ClNO [M+H]+ 306.0686, found 306.0687. (2-Methylpyrrolo[2,1-a]isoquinolin-3-yl)phenylmethanone (5j) Yellow solid (82%, 117 mg), mp 143–145 °C. 1H NMR (400 MHz, CDCl3): δ 1.97 (s, 3H), 6.84 (s, 1H), 6.98 (d, J = 7.6 Hz, 1H),


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7.43–7.53 (m, 5H), 7.65–7.69 (m, 3H), 8.09 (dd, J = 8.4, 1.6 Hz, 1H), 9.23 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 187.2, 141.6, 135.3, 133.8, 131.1, 129.0, 128.5, 128.4, 127.8, 127.4, 126.8, 125.7, 124.2, 123.5, 112.2, 104.8, 15.4. HRMS (ESI) m/z calcd for C20H16NO [M+H]+ 286.1232, found 286.1236. (1-Methylpyrrolo[2,1-a]isoquinolin-3-yl)phenylmethanone (5k) Yellow solid (87%, 124 mg), mp 160–162 °C. 1H NMR (400 MHz, CDCl3): δ 2.67 (s, 3H), 7.05–7.08 (m, 1H), 7.10 (s, 1H), 7.47– 7.58 (m, 5H), 7.72 (dd, J = 7.6, 2.8 Hz, 1H), 7.83 (d, J = 7.2 Hz, 2H), 8.36–8.39 (m, 1H), 9.63 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 185.0, 140.9, 133.0, 130.9, 129.5, 129.1, 128.1, 128.0, 127.4, 127.2, 126.9, 126.3, 125.9, 124.0, 122.3, 114.8, 113.2, 15.5. HRMS (ESI) m/z calcd for C20H16NO [M+H]+ 286.1232, found 286.1229. (1,2-Dimethylpyrrolo[2,1-a]isoquinolin-3-yl)phenylmethanone (5l) Yellow solid (78%, 117 mg), mp 177–179 °C. 1H NMR (400 MHz, CDCl3): δ 1.91 (s, 3H), 2.56 (s, 3H), 6.90 (d, J = 7.2 Hz, 1H), 7.44–7.56 (m, 5H), 7.65–7.70 (m, 3H), 8.39 (d, J = 8.0 Hz, 1H), 9.14 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 187.2, 141.7, 131.7, 131.6, 131.3, 129.7, 128.9, 128.4, 127.1, 126.8, 126.7, 126.0, 125.3, 124.1, 122.6, 114.3, 111.8, 12.8, 12.4. HRMS (ESI) m/z calcd for C21H18NO [M+H]+ 300.1388, found 300.1386. General Procedure for the preparation of 7 The mixture of methyl isonicotinate 1a (2.0 mmol), methyl ketone 6 (1.0 mmol), alkenoic acid 3 (0.5 mmol), and CuBr (0.1 mmol) was heated at 80 oC for 12 h in a sealed tube under 1 atm of O2. After the reaction was completed, the resulting mixture was separated by flash chromatography on a silica gel column with ethyl acetate/petroleum (1:20–1:30) as eluent to give the product 7. Methyl 3-acetyl-1-methylindolizine-7-carboxylate (7a) Yellow solid (51%, 59 mg), mp 156–158 °C. 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H), 2.56 (s, 3H), 3.96 (s, 3H), 7.33–7.35 (m, 2H), 8.23 (s, 1H), 9.74 (d, J = 7.2 Hz, 1H).13C NMR (125 MHz, CDCl3): δ 187.1, 165.8, 135.4, 127.5, 123.8,



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123.1, 119.8, 115.1, 112.0, 52.4, 27.4, 10.6. HRMS (ESI) m/z calcd for C13H14NO3 [M+H]+ 232.0974, found 232.0982. Methyl 3-isobutyryl-1-methylindolizine-7-carboxylate (7b) Yellow solid (70%, 91 mg), mp 134– 136 °C. 1H NMR (400 MHz, CDCl3): δ 1.26 (d, J = 6.8 Hz, 6H), 2.43 (s, 3H), 3.39–3.46 (m, 1H), 3.96 (s, 3H), 7.35 (d, J = 7.6 Hz, 1H), 7.39 (s, 1H), 8.24 (s, 1H), 9.81 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 194.6, 165.9, 135.6, 127.7, 123.0, 122.1, 119.8, 115.1, 112.0, 52.4, 36.8, 19.8, 10.6. HRMS (ESI) m/z calcd for C15H18NO3 [M+H]+ 260.1287, found 260.1276. Methyl 3-isobutyryl-1,2-dimethylindolizine-7-carboxylate (7c) Yellow solid (67%, 91 mg), mp 106–108 °C. 1H NMR (400 MHz, CDCl3): δ 1.25 (d, J = 6.4 Hz, 6H), 2.33 (s, 3H), 2.58 (s, 3H), 3.45–3.51 (m, 1H), 3.95 (s, 3H), 7.24–7.26 (m, 1H), 8.17 (s, 1H), 9.90 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 195.8, 166.0, 134.7, 130.8, 127.9, 123.1, 122.2, 118.9, 114.8, 111.3, 52.3, 37.2, 19.4, 13.1, 8.8. HRMS (ESI) m/z calcd for C16H20NO3 [M+H]+ 274.1443, found 274.1448. Methyl 1-methyl-3-pivaloylindolizine-7-carboxylate (7d) Yellow solid (72%, 98 mg), mp 134– 136 °C. 1H NMR (400 MHz, CDCl3): δ 1.15 (s, 9H), 2.44 (s, 3H), 3.95 (s, 3H), 7.32 (dd, J = 7.6, 1.2 Hz, 1H), 7.51 (s, 1H), 8.22 (s, 1H), 9.86 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 196.6, 165.9, 134.4, 128.0, 123.7, 122.8, 121.0, 119.6, 114.7, 111.9, 52.3, 43.9, 29.0, 10.7. HRMS (ESI) m/z calcd for C16H20NO3 [M+H]+ 274.1443, found 274.1445. Methyl 1,2-dimethyl-3-pivaloylindolizine-7-carboxylate (7e) Yellow solid (66%, 95 mg), mp 115–117 °C. 1H NMR (400 MHz, CDCl3): δ 1.35 (s, 9H), 2.29 (s, 3H), 2.36 (s, 3H), 3.92 (s, 3H), 7.02 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 205.5, 166.3, 131.4, 125.8, 124.6, 120.2, 119.5, 113.9, 109.5, 52.1, 45.0, 27.5, 12.9, 8.7. HRMS (ESI) m/z calcd for C17H22NO3 [M+H]+ 288.1600, found 288.1599. Methyl 3-(cyclohexanecarbonyl)-2-methylindolizine-7-carboxylate (7f) Yellow solid (59%, 88 mg), mp 114–116 °C. 1H NMR (400 MHz, CDCl3): δ 1.29–1.43 (m, 3H), 1.56–1.65 (m, 2H), 1,75– 1.77 (m, 1H), 1.87–1.90 (m, 4H), 2.66 (s, 3H), 3.12 (t, J = 11.6 Hz, 1H), 3.94 (s, 3H), 6.56 (s, 1H),


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7.29 (dd, J = 7.6, 1.6 Hz, 1H), 8.13 (s, 1H), 9.93 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 195.1, 185.8, 135.7, 133.5, 128.2, 124.1, 122.7, 120.2, 111.5, 108.9, 52.3, 47.9, 29.7, 29.6, 26.3, 26.2, 26.0, 16.4. HRMS (ESI) m/z calcd for C18H22NO3 [M+H]+ 300.1600, found 300.1607. Methyl 3-(furan-2-carbonyl)-2-methylindolizine-7-carboxylate (7g) Yellow solid (76%, 107 mg), mp 125–127 °C. 1H NMR (400 MHz, CDCl3): δ 2.28 (s, 3H), 3.94 (s, 3H), 6.58 (s, 1H), 6.60‒6.62 (m, 1H), 7.16 (d, J = 3.6 Hz, 1H), 7.26 (m, 1H), 7.64 (s, 1H), 8.15 (s, 1H), 9.21 (d, J = 7.6 Hz, 1H). 13

C NMR (100 MHz, CDCl3): δ 173.8, 165.8, 153.2, 145.6, 136.1, 134.2, 126.9, 124.1, 123.0, 120.8,

117.5, 112.3, 111.1, 108.1, 52.4, 14.5. HRMS (ESI) m/z calcd for C16H14NO4 [M+H]+ 284.0923, found 284.0912. Methyl 2-methyl-3-(thiophene-2-carbonyl)indolizine-7-carboxylate (7h) Yellow solid (75%, 112 mg), mp 143–145 °C. 1H NMR (400 MHz, CDCl3): δ 2.27 (s, 3H), 3.94 (s, 3H), 6.57 (s, 1H), 7.14 (t, J = 4.4 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 3.6 Hz, 1H), 7.67 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 9.17 (d, J = 7.2 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 178.8, 165.8, 144.9, 135.8, 133.6,

132.8, 132.5, 127.5, 126.9, 123.9, 123.4, 120.8, 111.0, 108.0, 52.4, 15.3. HRMS (ESI) m/z calcd for C16H14NO3S [M+H]+ 300.0694, found 300.0690. ASSOCIATED CONTENT Supporting Information NMR spectra of all compounds (PDF) X-ray structures and data of compound 4m (CIF) AUTHOR INFORMATION Corresponding Authors E-mail: [email protected] E-mail: [email protected] ACKNOWLEDGMENTS



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The authors gratefully acknowledge National Natural Science Foundation of China and Jiangsu Province (21202058, BK20161307), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Foundation of Jiangsu Normal University (15XLA06) for financial support of this work. REFERENCES (1) (a) Michael, J. P. Alkaloids 2001, 55, 91. (b) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191. (c) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. (2) Bermudez, J.; Fake, C. S.; Joiner, G. F.; Joiner, K. A.; King, F. D.; Miner, W. D.; Sanger, G. J. J. Med. Chem. 1990, 33, 1924. (3) (a) Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.; Murakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.; Ueno, M.; Chikazawa, Y.; Yamada, K.; Ono, T.; Teshirogi, I.; Ohtani, M. J. Med. Chem. 1996, 39, 3636. (b) Weide, T.; Arve, L.; Prinz, H.; Waldmann, H.; Kessler, H. Bioorg. Med. Chem. Lett. 2006, 16, 59. (4) Sonnet, P.; Dallemagne, P.; Guillon, J.; Enguehard, C.; Stiebing, S.; Tanguy, J.; Bureau, R.; Rault, S.; Auvray, P.; Moslemi, S.; Sourdaine, P.; Séralini, G. E. Bioorg. Med. Chem. 2000, 8, 945. (5) Teklu, S.; Gundersen, L. L.; Larsen, T.; Malterud, K. E.; Rise, F. Bioorg. Med. Chem. 2005, 13, 3127. (6) (a) James, D. A.; Koya, K.; Li, H.; Liang, G.-Q.; Xia, Z.-Q.; Ying, W.-W.; Wu, Y.-M.; Sun, L.-J. Bioorg. Med. Chem. Lett. 2008, 18, 1784. (b) Shen, Y.-M.; Lv, P.-C.; Chen, W.; Liu, P.-G.; Zhang, M.-Z.; Zhu, H.-L. Eur. J. Med. Chem. 2010, 45, 3184. (7) Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi, F.; Bailly, C.; Gago, F. J. Med. Chem. 2005, 48, 3796. (8) (a) Zhou, H.-Q.; Danger, D. P.; Dock, S. T.; Hawley, L.; Roller, S. G.; Smith, C. D.; Handlon, A. L. ACS. Med. Chem. Lett. 2010, 1, 19. (b) Hazra, A.; Mondal, S.; Maity, A.; Naskar,


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CuBr-Catalyzed Aerobic Decarboxylative Cycloaddition for the

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