Pd-Catalyzed C-3 functionalization of indolizines via C-H bond cleavage

Article abstract of DOI:10.1039/c2ob25643f

New transition metal-catalyzed methods for the arylation of indolizines by the direct cleavage of C-H bonds have been developed. A wide range of aryltrifluoroborate salts react with indolizines in the presence of Pd(OAc) ₂ catalyst and AgOAc oxidant to give the arylated indolizines in high yields. Both electron-donating and electron-withdrawing groups perform smoothly while bromide and chlorine substituents are tolerated. In addition, the indolizines display similar reactivities in the Pd-catalyzed reaction with 3-phenylpropiolic acid to afford the corresponding C-3 alkynylated indolizines. These methods allow the direct functionalization of indolizines in one step.

Full text of DOI:10.1039/c2ob25643f

View Online / Journal Homepage
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This is an Accepted Manuscript, which has been through the RSC Publishing peer
Organic &
review process and has been accepted for publication.
Biomolecular
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
Chemistry
www.rsc.org/obc
Volume 8 | Number 3 | 7 February 2010 | Pages 481–716
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1477-0520
PERSPECTIVE
FULL PAPER
Laurel K. Mydock and
AlexeiV. Demchenko
Shuji Ikeda et al.
Hybridization-sensitive fluorescent
DNA probe with self-avoidance ability
Mechanism of chemical O-glycosylation:
from early studies to recent discoveries
1477-0520(2010)8:3;1-H
www.rsc.org/obc
Registered Charity Number 207890

View Online
Pd-Catalyzed C-3 Functionalization of Indolizines via
C-H Bond Cleavage
Baoli Zhao
Institute of Applied Chemistry and Department of Chemistry, University of Shaoxing, Shaoxing,
Zhejiang Province 312000, People’s Republic of China,
E-mail: babygarfield@126.com
Fax: + 86-575-88345682
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
New transition metal-catalyzed methods for the arylation of indolizines by the direct cleavage of C-H
bond have been developed. A wide range of aryltrifluoroborate salts react with indolizines in the
1

presence of Pd(OAc)2 catalyst and AgOAc oxidant to give the arylated indolizines in high yields. Both
View Online
electron-donating and electron-withdrawing groups perform smoothly while the bromide and chlorine
substituents are tolerate. In addition, the indolizines display similar reactivities in the Pd-catalyzed
reaction with 3-phenylpropiolic acid to afford the corresponding C-3 alkynylated indolizines. These
methods allow the direct functionalization of indolizines in one step.
Introduction
The functionalization of heteroaromatics, particularly arylation, alkynylation, via the catalytic
processes is of the great importance in the organic chemistry, and transition metal-catalyzed
transformations such as Suzuki coupling reaction1 and Sonogashira coupling reaction2 have emerged as
the powerful tools for accessing the arylation and alkynylation of heteroaromatics. Although these
coupling reactions provide the viable scaffolds for the functionalization of heteroaromatics, the
preactivation of heteroaromatic carbon fragments with metal-containing functionalities and halides may
involve several synthetic steps. Recently, the selective functionalization of C-H bond has attracted a
substantial interest because such C-H activations often significantly shorten the synthesis steps and
decrease the byproduct waste.3 The C-H functionalizations of heteroaromatics display even more
advantages since some important types of heteroaromatic organometallic compounds have proven
challenging to synthesize and may even be inadequately stable to participate in the cross-coupling
process.4
Indolizines are important heterocycles and can be found in motifs of a wide variety of natural
products with useful biological5 and pharmaceutical properties.6 Consequently, the functionalization of
indolizines have attracted considerable interest in the past decades, and metal-catalyzed direct
7
functionalization of indolizines was explored recently. For instance, Gevorgyan and coworkers
reported the palladium-catalyzed direct arylation of indolizines with aryl bromides.8 In their reaction,
the C-H bond of indolizines directly coupled with aryl bromides to selectively give the C-3 arylated
indolizines in good yields. More recently, the copper-mediated direct halogenation of indolizines is
developed by You,9 in which the 3-haloindolizines were selectively produced under mild reaction
2

conditions and were conveniently further transformed to 3-arylated indolizines by Suzuki rVeiaewctOionlnin.e
Subsequently, You reported a palladium/copper bimetallic catalytic system with the assistance of CuCl
and BQ to achieve the arylation of indolizine with aryl boronic acids in the yield of 63% in one step.10
In this work, we investigate the C-3 arylation of indolizines with aryltrifluoroborate salts in the presence
of a Pd(OAc)2-AgOAc-KOAc catalytic system to form 3-arylated indolizines derivatives. Furthermore,
we extend the indolizines’ C-3 functionalization to alkynylation in DMSO/1,4-dioxine to form 3-
alkynylindolizine derivatives under N2 atomsphere.
Results and Discussion
C-3 Arylation of Indolizines with Aryltrifluoroborate Salts
Organotrifluoroborates are considered as alternatives to organoboron coupling partners which can be
simply prepared in large quantities and, unlike most organoboronic compounds, are completely air-,
moisture-stable and stoichiometric determination highly reliable. To explore a high efficacy catalytic
system for C-3 arylation, indolizine-1-carbonitrile and phenyltrifluoroborate salt were chosen as the
benchmark substrates in the model reaction (Table 1). We obtained the deserved product in the yield of
ο
67 % (Table 1, entry 1) in the presence of 5 mol% Pd(OAc)2 in DMF at 90 C for 12 h in air. The
formation of the 3-phenylindolizine-1-carbonitrile was increased to 89 % under pure nitrogen (Table 1,
entry 2). Other palladium salts showed less activity, and several metals such as RhCl(PPh3)3, RuCl3 and
Cu(OAc)2 was found to be incompatible with the reaction (Table 1, entries 3-10). Many silver(I)
reagents such as Ag2CO3, Ag2O, AgTFA and AgOTf were found to be effective and AgOAc performs
the best (Table 1, entries 11-14). The screening of commonly used bases indicated that KOAc and
NaOAc were suitable bases for this arylation (Table 1, entries 15-20). The reaction in other solvents
tested, including 1,4-dioxane, DMSO, CH3CN, and toluene was sluggish. No side products such as 3,3'-
biindolizine-1,1'-dicarbonitrile was observed in arylation of indolizine with phenyltrifluoroborate salts.
Table1 The effect of metals, oxidants and bases on the reactiona
3

View Online
Entry
1
Catalyst
Pd(OAc)2
Pd(OAc)2
RhCl(PPh3)3
RuCl3
Oxidant
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2CO3
Ag2O
Base
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
Na2CO3
K3PO4
KOH
Yield %b
67c
89
2
3
trace
trace
trace
75
4
5
Cu(OAc)2
PdCl2
6
7
PdCl2(PPh3)2
Pd (PPh3)4
Pd(dba)2
69
8
60
9
66
10
11
12
13
14
15
16
17
18
19
20
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
69
86
80
AgTFA
AgOTf
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
74
81
33
30
19
14
KF
trace
85
NaOAc
a Reaction conditions: indolizines (0.3 mmol), potassium phenyltrifluoroborate salts (0.3 mmol), catalyst
o
b
(0.015 mmol), oxidant (0.3 mmol), base (0.3 mmol), DMF (2 mL), 90 C, 12 h, N2. Isolated yields of
arylation. cThe reaction performed under air.
The scope of this reaction was then investigated under the optimized conditions. A wide range of
aryltrifluoroborate salts were examined and the results are listed in Table 2. This system demonstrated a
good functional group tolerance on both electrophilic and nucleophilic partners. Aryltrifluoroborate
4

salts with electron-withdrawing groups like 4-trifluoromethyl and 3-fluoro afforded better yields (Table
View Online
2, entries 7 and 10) than aryltrifluoroborate salts with electron-donating group such as 4-methoxy, 4-
tert-butyl, and 4-methyl (Table 2, entries 1, 3 and 4). Methyl, chloro, trifluoromethyl
phenyltrifluoroborate salt react similarly to provide the corresponding 3-arylindolizines which shows
that there is not much effect of meta- and para-substitution on phenyltrifluoroborate salts (Table 2,
entries 4, 5, 7, 8, 9 and 12). Ortho-substitution like methyl and bromo decrease the yield of products
obviously (Table 2, entries 13 and 14). α-Naphthalene and β-naphthalene show diversity in yield which
reveals steric effect exert action on the formation of the products (Table 2, entries 15 and 16). Notably,
other function groups like methylthio, trifluoromethoxy and formyl are bearing in this catalyst system
(Table 2, entries 2, 6 and 11). It is noteworthy to observe that when phenyltrifluoroborate salts are
replaced by iodobenzene, C-3 arylation products can be accomplished in good yields in the same way
(Table 2, entries 17). Nevertheless, it should be pointed out that the carbon-halogen bonds tolerated the
reaction conditions and the halogen-containing products were afforded smoothly without by-product
observed which shows high functional group tolerance and selectivity.
Table 2 The reaction of indolizine with aryltrifluoroborate saltsa
Entry
1
Product
Yield(%)b
80
Aryltrifluoroborate salts
2
78
5

View Online
3
4
81
86
77
66
91
75
79
92
81
5
6
7
8
9
10
11
6

View Online
12
13
14
93
44
40
15
16
17
46
86
83c
a Reaction conditions: indolizine-1-carbonitrile (0.3 mmol), potassium aryltrifluoroborate salts (0.3 mmol),
Pd(OAc)2 (5 mol%), AgOAc (0.3 mmol), KOAc (0.3 mmol), DMF (2 mL), 90 oC, 12 h, N2. b Isolated yields
of arylation. c Iodobenzene in place of phenyltrifluoroborate salt.
We examined a variety of structurally divergent indolizines to understand the scope and the
generality of the C-3 arylation and the results are summarized in Table 3. Indolizine-1-carbonitrile,
methyl indolizine-1-carboxylate, ethyl indolizine-1-carboxylate, and n-butylindolizine-1-carboxylate
afforded the desired products in good yield (Table 3, entries 1-4). When 2-methylindolizine-1-
carbonitrile coupled with phenyltrifluoroborate salt, a 88 % yield was obtained (Table 3, entry 5), which
showed steric effect didn’t restrain the formation of desired product. 7-Methyl-indolizine-1-carbonitrile
also proceeding smoothly under model reaction system (Table 3, entry 6).
7

Table 3 The reaction of phenyltrifluoroborate salt with various indolizinesa
View Online
Entry
1
Indolizines
Products
Yield %b
93
2
3
85
86
4
5
6
84
88
73
a Reaction conditions: indolizines (0.3 mmol), potassium aryltrifluoroborate salts (0.3 mmol), Pd(OAc)2 (0.015
mmol), AgOAc (0.3 mmol), KOAc (0.3 mmol), DMF (2 mL), 90 oC, 12 h, N2. b Isolated yields of arylation.
8

Indolizines are classified as electron-rich aromatic heterocycles, and their transformations catalyzed
View Online
by palladium show strong electrophilic character with reactions occurring at the most electron-rich C3-
position.11 In our experiment about electrophiles, the electron-deficient aryltrifluoroborate salts are
more reactive than the electron-rich aryltrifluoroborate salts, which is consistent with the electrophilic
substitution mechanism. On the basis of the previous chemistry and our results, we propose a plausible
mechanism for this arylation reaction, as shown in Scheme 1. Arylpalladium intermediate A was
generated by transmetalation between Pd(II) with aryltrifluoroborate salts in first step. The electrophilic
palladation first occurs preferentially at the C3-position of indolizine, and the subsequent deprotonation
leads to the formation of intermediate B with the assistance of KOAc. Followed by reductive
elimination to produce the desired product, the Pd(0) species are generated, which are reoxidized to
Pd(II) species by Ag(I) to complete the catalytic cycle.
Scheme 1 The arylation mechanism proposed
Direct Alkynylation of Indolizines with Phenylpropiolic Acid
Arylacetylenes are among the most fundamental and important π-conjugated systems in the various
fields of organic chemistry. A powerful and reliable approach to these molecules is Sonogashira
coupling reaction. On the other hand, the metal-catalyzed direct alkynylation of arene C-H bonds with
alkynyl halides has recently been receiving much attention as a complementary process to Sonogashira
9

coupling. The pioneering work in this field was performed by Gevorgyan11 in 2007, who reported
View Online
indolizines’ alkynylation applying alkynyl halides as electrophiles.
Carboxylic acids have been considered candidates for the coupling partner in the transition metal
catalyzed coupling reactions due to their environmental friendliness as leaving groups.12 Several groups
have employed the alkynyl carboxylic acids as the coupling substrates in a variety of coupling
reactions.13 The direct alknylation of heterocycles with phenylpropiolic acids would be an attractive
approach which can be easily prepared by corresponding aldehydes. It offers a novel method to obtain
alkynylation of heterocycles using aldehyde as precursor. Further more, phenylpropiolic acids are more
accessible and cheaper than alkynyl bromides which derived from alkynes related. At the outset of our
studies, there was few literature precedent for the direct C-H functionalization of (hetero)aromatics with
phenylpropiolic acids. Here, we provide a new approach straightforward and efficient access to diverse
alkynyl heterocycles conceptually via decarboxylative couplings.
Initially, we optimized the reaction conditions using 3-phenylpropiolic acid and indolizine-1-
o
carbonitrile as model substrate in DMSO with Ag2CO3 and Pd(OAc)2 at 80 C for 12 h under N2
atomosphere. Only 37 % yield of desired product was isolated (Table 4, entry 1). When other solvents
was introduced, the mixed solvents give increasing yields (Table 4, entries 2-5). The DMSO/1.4-
dioxane afforded the desired product in the yield of 83 % which performed the best (Table 4, entry 6).
The oxidant also played an important role in the procedure, many silver salts such as AgOAc, Ag2O and
AgOTf also presented high activity (Table 4, entries 7-10). During the screening of catalysts, we found
that palladium sources had a dramatic effect on the reaction. Among the Pd species tested,
PdCl2(PPh3)2, PdCl2(CH3CN)2, Pd2(dba)3, PdCl2 were not successful, and Pd(TFA)2 were ineffective
for this transformation. (Table 4, entries 11-15).
Table 4 Optimization of reaction conditions about alkynylationa
10

Entry
1
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
PdCl2(CH3CN)2
Pd(TFA)2
PdCl2
Oxidant
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
Ag2O
Solvent
Yield %b
37
View Online
DMSO
2
DMSO/t-BuOH
DMSO/ i-PivOH
DMSO/DMF
45
3
57
4
33
5
DMSO/THF
70
6
DMSO/1.4-dioxane
DMSO/1.4-dioxane
DMSO/1.4-dioxane
DMSO/1.4-dioxane
DMSO/1.4-dioxane
DMSO/1.4-dioxane
DMSO/1.4-dioxane
DMSO/1.4-dioxane
DMSO/1.4-dioxane
DMSO/1.4-dioxane
83
7
80
8
76
9
AgTFA
AgOTf
56
10
11
12
13
14
15
77
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
64
66
41
79
Pd2(dba)3
70
a Reaction conditions: indolizine-1-carbonitrile (0.3 mmol), 3-phenylpropiolic acid (0.3 mmol), catalyst
o
(0.015 mmol), oxidant (0.3 mmol), solvent (2 mL, v/v=1:1), 80 C, 12 h, N2. b Isolated yields of
alkynylation.
We test a series of indolizines react with 3-arylpropiolic acid in moderate to good yields (Table 5).
Methyl indolizine-1-carboxylate, ethyl indolizine-1-carboxylate, and n-butyl indolizine-1-carboxylate
are cooperate with the reaction conditions (Table 5, entries 2-4). 7-Methyl-indolizine-1-carbonitrile is a
good substrate for the reaction to give deserved products in 76 % yields (Table 5, entry 5). The catalytic
system could tolerate many functional groups, such as OMe and Cl. Electronwithdrawing or
electrondonating groups on the aryl propiolic acids didn’t show significant regularities (Table 5, entries
6-8).
Table 5 The reaction of phenylpropiolic acid with various indolizinesa
11

Entry
1
Indolizines
Products
Yield %b
81
View Online
2
3
4
79
75
78
5
6
7
76
81c
83d
8
77e
a
Reaction conditions: indolizines (0.3 mmol), 3-phenylpropiolic acid (0.3 mmol), Pd(OAc)2 (0.015
o
b
mmol), Ag2CO3 (0.3mmol), DMSO/1,4-dioxane (1:1, 2 mL), 80 C, 12 h, N2. Isolated yields of
alkynylation. C Using 3-(4-methoxyphenyl)propiolic acid as alkynyl reagent. d Using 3-(p-tolyl)propiolic
acid as alkynyl reagent. e Using 3-(4-chlorophenyl)propiolic acid as alkynyl reagent.
The reaction mechanism is not clear currently. We propose that the transformation undergo the direct
Pd-catalyzed C-H alkynylation of electron-rich heterocycles operates via an electrophilic substitution
pathway, analogous to our previously postulated for the Pd(II)-catalyzed C-3 arylation of indolizines
with aryltrifluoroborate salts.11 The Ag(I)-catalyzed decarboxylation of phenylpropiolic acid to form
12

alkynylsilver(0) intermediate A by releasing CO2 (Scheme 2, cycle 1). These processes are initViaietwedOnbliyne
transmetallation of alkynylsilver(0) intermediate A with Pd(II) species to form alkynylpalladium(II)
intermediate B, followed by the electrophilic attack of the generated Pd(II) species B to indolizine
groups to form intermediate C. Carbonate which was derived from Ag2CO3 played the role of
deprotonation in this stage. Reductive elimination of the latter furnishes alkynylpalladium intermediate
C to release desired products and Pd(0) species are regenerated and oxidized to Pd(II) to complete the
catalytic cycle (Scheme 2, cycle 2).
Scheme 2 The alkynylation mechanism proposed
Conclusion
In conclusion, we report here our results concerning the systematic study of indolizines’ C-3
functionalization involving C-H activation afford a diversity of C-3 substitution via arylation and
alkynylation. We discovered a well-precedented palladium-catalyzed regioselective direct C-3 arylation
reaction with phenyltrifluoroborate salts. The mild reaction conditions enabled these transformations to
tolerate different functional groups very well. Our studies also resulted in the direct alkynylation of
indolizines with phenylpropiolic acid which can be performed as substitute of alkynyl halides via
13

decarboxylative couplings. Undoubtedly, as part of the continuing exploration of new chemistrVyieowfOtnhlinee
indolizine core, these reactions have great prospects of applications in organic syntheses and industrial
processes.
Experimental Section
Preparation of C-3 arylation indolizines: A mixture of indolizines (0.3 mmol), potassium
phenyltrifluoroborate salts (0.3 mmol), Pd(OAc)2 (3 mg, 5 mol%), AgOAc (50 mg, 0.3 mmol), KOAc
(59 mg, 0.6 mmol) in DMF (2 mL) was stirred at 90 oC under N2 for 12 h. Afterward, the mixture was
cooled to room temperature, filtered through a pad of celite. The crude product was dissolved in Et2O
(20 mL), washed with water (2×10 mL), brine (10 mL), then dried over MgSO4. The solvent was
evaporated under reduced pressure, and the residue was subjected to flash column chromatography to
obtain the desired product.
3-(4-Methoxyphenyl)indolizine-1-carbonitrile (T 2-1) White solid. m.p. 241-242 oC. 1H NMR ( 400
MHz, CDCl3, TMS ) δ 8.19 ( d, J = 6.8 Hz, 1 H ), 7.67 ( d, J = 8.4 Hz, 1 H ), 7.41 ( d, J = 8.4 Hz, 2 H ),
7.02-7.08 ( m, 3 H ), 6.98 ( s, 1 H ), 6.72 ( t, J = 7.2 Hz, 1 H ), 3.88 ( s, 3 H ). 13C NMR (100MHz,
CDCl3 ) δ 159.8, 138.2, 130.2, 126.8, 123.7, 122.4, 122.0, 118.1, 115.6, 114.7, 112.9, 81.8, 55.4.
HRMS (EI) Calcd for C16H12N2O (M+) 248.0950, Found 248.0957. Elem. Anal.: C, 77.40; H, 4.87; N,
11.29; O, 6.44.
3-(4-(Methylthio)phenyl)indolizine-1-carbonitrile (T 2-2) Yellow solid. m.p. 250-252 oC. 1H NMR (
400 MHz, CDCl3, TMS ) 8.25 ( d, J = 7.2 Hz, 1 H ), 7.71 ( t, J = 9.6 Hz, 1 H ), 7.38-7.45 ( m, 4 H ),
7.09 ( t, J = 7.6 Hz, 1 H ), 7.04 ( s, 1 H ), 6.76 ( t, J = 6.8 Hz, 1 H ), 2.56 ( s, 3 H ). 13C NMR (
100MHz, CDCl3 ) δ 139.6, 138.4, 129.0, 126.8, 126.6, 126.5, 123.7, 122.3, 118.2, 116.7, 116.1, 113.1,
82.2, 15.5. HRMS (EI) Calcd for C16H12N2S (M+) 264.0721, Found 264.0725. Elem. Anal.: C, 72.70;
H, 4.58; N, 10.60; S, 12.12.
o
1
3-(4-Tert-butylphenyl)indolizine-1-carbonitrile (T 2-3) White solid. m.p. 236-238 C. H NMR (
400 MHz, CDCl3, TMS ) δ 8.29 ( d, J = 7.6 Hz, 1 H ), 7.68 ( d, J = 8.8 Hz, 1 H ), 7.54 ( d, J = 8.0 Hz, 2
H ), 7.44 ( d, J = 8.0 Hz, 2 H ), 7.06 ( t, J = 7.6 Hz, 1 H ), 7.02 ( s, 1 H ), 6.72 ( t, J = 6.8 Hz, 1 H ), 1.39
( s, 9 H ). 13C NMR ( 100 MHz, CDCl3 ) δ 151.8, 138.3, 130.6, 129.1, 128.4, 127.2, 127.0, 126.2, 125.4,
123.9, 122.2, 118.1, 116.0, 113.0, 82.0, 34.8, 31.3. HRMS (ESI) Calcd for C19H18N2 (M+) 274.1470,
Found 274.1479. Elem. Anal.: C, 83.18; H, 6.61; N, 10.21.
o
1
3-p-Tolylindolizine-1-carbonitrile (T 2-4) White solid. m.p. 232-233 C. H NMR ( 400 MHz,
CDCl3, TMS ) δ 8.24 ( d, J = 6.8 Hz, 1 H ), 7.67 ( d, J = 9.2 Hz, 1 H ), 7.38 ( d, J = 8.0 Hz, 2 H ), 7.31 (
14

d, J = 8.4 Hz, 2 H ), 7.06 ( t, J = 8.0 Hz, 1 H ), 7.00 ( s, 1 H ), 6.72 ( t, J = 6.8 Hz, 1 H ), 2.43 ( Vs,ie3w OHnli)n.e
13C NMR ( 100 MHz, CDCl3 ) δ 138.6, 138.3, 129.9, 128.6, 127.2, 127.0, 123.8, 122.1, 118.1, 117.0,
115.9, 113.0, 82.0, 21.3. HRMS (EI) Calcd for C16H12N2 (M+) 232.1000, Found 232.1001. Elem. Anal.:
C, 82.73; H, 5.21; N, 12.06.
3-(4-Chlorophenyl)indolizine-1-carbonitrile (T 2-5) Light yellow solid. m.p. 244-246 oC. 1H NMR (
400 MHz, CDCl3, TMS ) δ8.17 ( d, J = 7.2 Hz, 1 H ), 7.65 ( d, J = 8.8 Hz, 1 H ), 7.40-7.46 ( m, 4 H ),
7.06 ( t, J = 8.0 Hz, 1 H ), 7.00 ( s, 1 H ), 6.73 ( t, J = 6.8 Hz, 1 H ). 13C NMR ( 100 MHz, CDCl3 ) δ
138.6, 138.3, 129.9, 128.6, 127.2, 127.0, 123.8, 122.1, 118.1, 117.0, 115.9, 113.0, 82.0. HRMS (EI)
Calcd for C15H9N2Cl (M+) 252.0454, Found 252.0452. Elem. Anal.: C, 71.29; H, 3.59; Cl, 14.03, N,
11.09.
o
1
3-(4-(Trifluoromethoxy)phenyl)indolizine-1-carbonitrile (T 2-6) White solid. m.p. 276-277 C. H
NMR ( 400 MHz, CDCl3, TMS ) δ 8.26 ( d, J = 6.8 Hz, 1 H ), 7.69 ( d, J = 9.6 Hz, 1 H ), 7.55 ( t, J =
8.4 Hz, 1 H ), 7.46 ( d, J = 7.6 Hz, 1 H ), 7.37 ( s, 1 H ), 7.28 ( t, J = 8.8 Hz, 1 H ), 7.12 ( t, J = 8.0 Hz, 1
H ), 7.08 ( s, 1 H ), 7.80 ( t, J = 6.8 Hz, 1 H ). 13C NMR ( 100MHz, CDCl3 ) δ 149.81, 149.79, 138.7,
132.1, 131.8, 126.8, 125.2, 123.4, 122.8, 120.9, 120.8, 118.3, 116.9, 113.6, 82.7. HRMS (EI) Calcd for
C16H9N2OF3 (M+) 302.0667, Found 302.0664. Elem. Anal.: C, 63.58; H, 3.00; F, 18.86, N, 9.27, O,
5.29.
o
1
3-(4-(Trifluoromethyl)phenyl)indolizine-1-carbonitrile (T 2-7) White solid. m.p. 269-270 C. H
NMR ( 400 MHz, CDCl3, TMS ) δ 8.29 ( d, J = 6.8 Hz, 1 H ), 7.77 ( d, J = 8.4 Hz, 2 H ), 7.68 ( d, J =
8.8 Hz, 1 H ), 7.65 ( d, J = 8.4 Hz, 2 H ), 7.13 ( t, J = 6.4 Hz, 1 H ), 7.10 ( s, 1 H ), 6.81 ( t, J = 6.8 Hz, 1
H ). 13C NMR ( 100 MHz, CDCl3 ) δ 138.8, 133.8, 130.3 ( q, J = 32 Hz ), 128.6, 126.3( q, J = 4.0 Hz ),
125.3, 125.2, 123.5, 122.9, 122.5, 118.4, 117.1, 116.4, 113.7, 82.9. HRMS (EI) Calcd for C16H9N2F3
(M+) 286.0718, Found 286.0713. Elem. Anal.: C, 67.13; H, 3.17; F, 19.91, N, 9.79.
o
1
3-m-Tolylindolizine-1-carbonitrile (T 2-8) White solid. m.p. 239-241 C. H NMR ( 400 MHz,
CDCl3, TMS ) δ 8.34 ( d, J = 7.2 Hz, 1 H ), 7.74 ( d, J = 9.2 Hz, 1 H ), 7.46 ( d, J = 7.6 Hz, 1 H ), 7.31-
7.38 ( m, 3 H ), 7.14 ( t, J = 8.0 Hz, 1 H ), 7.09 ( s, 1 H ), 6.80 ( d, J = 6.8 Hz, 1 H ), 2.50 ( s, 3 H ). 13C
NMR (100MHz, CDCl3 ) δ 139.1, 138.3, 130.1, 129.4, 129.3, 129.1, 127.1, 125.6, 123.8, 118.1, 116.1,
113.0, 82.1, 21.4. HRMS (EI) Calcd for C16H12N2 (M+) 232.1000, Found 232.0998. Elem. Anal.: C,
82.73; H, 5.21; N, 12.06.
o
1
3-(3-Chlorophenyl)indolizine-1-carbonitrile (T 2-9) Yellow solid. m.p. 245-246 C. H NMR ( 400
MHz, CDCl3, TMS ) δ 8.21 ( d, J = 7.2 Hz, 1 H ), 7.64 ( d, J = 8.8 Hz, 1 H ), 7.15 ( s, 1 H ), 7.06 ( t, J =
8.0 Hz, 1 H ), 7.01 ( s, 1 H ), 6.74 ( t, J = 7.2 Hz, 1 H ). 13C NMR ( 100MHz, CDCl3 ) δ 138.6, 135.2,
15

131.9, 130.5, 128.6, 128.5, 126.6, 125.4, 123.5, 122.7, 118.3, 116.7, 113.5, 82.6. HRMS (EI) CVailecwdOnfloinre
C15H9N2Cl (M+) 252.0454, Found 252.0448. Elem. Anal.: C, 71.29; H, 3.59; Cl, 14.03, N, 11.09.
o
1
3-(3-Fluorophenyl)indolizine-1-carbonitrile (T 2-10) White solid. m.p. 261-262 C. H NMR ( 400
MHz, CDCl3, TMS ) δ 8.35 ( d, J = 6.8 Hz, 1 H ), 7.75 ( d, J = 9.2 Hz, 1 H ), 7.52-7.58 ( m, 1 H ), 7.37
( d, J = 7.6 Hz, 1 H ), 7.28 ( d, J = 9.6 Hz, 1 H ),7.15-7.22 ( m, 2 H ), 7.12 ( s, 1 H ), 6.85 ( t, J = 6.8 Hz,
1 H ). 13C NMR ( 100MHz, CDCl3 ) δ 164.3, 161.9, 138.6, 132.2 ( d, J = 7.7 Hz ), 130.9( d, J = 8.0 Hz
), 125.6, 124.2( d, J = 3.2 Hz ), 123.6, 122.7, 118.3, 116.7, 115.6( d, J = 8.9 Hz ),115.3( d, J = 9.0 Hz ),
113.4, 82.5. HRMS (EI) Calcd for C15H9N2F (M+) 236.0750, Found 236.0745. Elem. Anal.: C, 76.26;
H, 3.84; Cl, 8.04, N, 11.86.
o
1
3-(3-Formylphenyl)indolizine-1-carbonitrile (T 2-11) White solid. m.p. 183-186 C. H NMR ( 400
MHz, CDCl3, TMS ) δ10.04 ( s, 1 H ), 8.01 ( s, 1 H ),7.95 ( d, J = 6.8 Hz, 1 H ), 7.82-7.85 ( m, 3 H ),
7.26-7.29 ( m, 2 H ), 7.52-7.61 ( m, 2 H ), 7.18 ( d, J = 6.8 Hz, 1 H ), 6.93-6.99 ( m, 1 H ). 13C NMR (
100MHz, CDCl3 ) δ 192.0, 140.6, 137.0, 132.9, 129.7, 129.4, 127.9, 126.4, 122.3, 117.8, 116.8, 113.9,
112.9, 82.8. HRMS (EI) Calcd for C16H10N2O (M+) 246.0793, Found 246.0796. Elem. Anal.: C, 78. 03;
H, 4.09; N, 11.38; O, 6.50.
o
1
3-(3-(Trifluoromethyl)phenyl)indolizine-1-carbonitrile (T 2-12) White solid. m.p. 262-264 C. H
NMR ( 400 MHz, CDCl3, TMS ) δ 8.22 ( d, J = 6.8 Hz, 1 H ), 7.72 ( s, 1 H ), 7.63-7.72 ( m, 4 H ), 7.13
( t, J = 6.4 Hz, 1 H ), 7.10 ( s, 1 H ), 6.80 ( t, J = 6.8 Hz, 1 H ). 13C NMR ( 100MHz, CDCl3 ) δ 138.7,
131.8, 131.0, 129.9, 125.3( q, J = 4.6 Hz ), 123.3, 122.8, 118.4, 117.0, 116.5, 113.7, 82.8. HRMS (EI)
Calcd for C16H9N2F3 (M+) 286.0718, Found 286.0721. Elem. Anal.: C, 67.13; H, 3.17; F, 19.91, N,
9.79.
o
1
3-o-Tolylindolizine-1-carbonitrile (T 2-13) White solid. m.p. 209-210 C. H NMR ( 400 MHz,
CDCl3, TMS ) δ 7.77 ( d, J = 9.2 Hz, 1 H ), 7.70 ( d, J = 6.8 Hz, 1 H ), 7.37-7.50 ( m, 4 H ), 7.15 ( t, J =
8.0 Hz, 1 H ), 7.05 ( s, 1 H ), 6.78 ( t, J = 6.8 Hz, 1 H ), 2.17 ( s, 3 H ). 13C NMR ( 100MHz, CDCl3 ) δ
138.4, 137.4, 131.3, 130.7, 129.5, 129.2, 126.3, 125.9, 124.0, 122.0, 118.0, 116.5, 112.9, 81.4, 19.5.
HRMS (EI) Calcd for C16H12N2 (M+) 232.1000, Found 232.0999. Elem. Anal.: C, 82.73; H, 5.21; N,
12.06.
3-(2-Bromophenyl)indolizine-1-carbonitrile (T 2-14) Yellow solid. m.p. 278-279 oC. 1H NMR ( 400
MHz, CDCl3, TMS ) δ 7.77 ( d, J = 9.2 Hz, 1 H ), 7.70 ( d, J = 6.8 Hz, 1 H ), 7.37-7.50 ( m, 4 H ), 7.15
( t, J = 8.0 Hz, 1 H ), 7.05 ( s, 1 H ), 6.78 ( t, J = 6.8 Hz, 1 H ). 13C NMR ( 100MHz, CDCl3 ) δ 138.4,
137.4, 131.3, 130.7, 129.5, 129.2, 126.3, 125.9, 124.0, 122.0, 118.0, 116.5, 112.9, 120.0, 81.4. HRMS
16

(EI) Calcd for C15H9N2Br (M+) 295.9949, Found 295.9944. Elem. Anal.: C, 60.63; H, 3.05; Br, 26.89;
View Online
N, 9.43.
3-(Naphthalen-1-yl)indolizine-1-carbonitrile (T 2-15) White solid. m.p. 303-305 oC. 1H NMR ( 400
MHz, CDCl3, TMS ) δ 8.03-8.09 ( m, 2 H ), 7.83 ( d, J = 8.8 Hz, 1 H ), 7.60-7.69 ( m, 4 H ), 7.45-7.53 (
m, 2 H ), 7.24 ( s, 1 H ), 7.18 ( t, J = 8.0 Hz, 1 H ), 6.71 ( t, J = 6.8 Hz, 1 H ). 13C NMR ( 100MHz,
CDCl3 ) δ 138.2, 133.8, 132.1, 129.9, 129.5, 128.8, 127.3, 127.1, 126.5, 125.6, 125.0, 124.8, 124.5,
122.3, 118.0, 117.7, 112.8, 81.9. HRMS (ESI) Calcd for C19H12N2 (M+) 268.1000, Found 268.0992.
Elem. Anal.: C, 85.05; H, 4.51; N, 10.44.
3-(Naphthalen-2-yl)indolizine-1-carbonitrile (T 2-16) White solid. m.p. 311-312 oC. 1H NMR ( 400
MHz, CDCl3, TMS ) δ 8.35 ( d, J = 7.2 Hz, 1 H ), 7.95-7.98 ( m, 2 H ), 7.86-7.91 ( m, 2 H ), 7.71 ( d, J
= 8.4 Hz, 1 H ), 7.54-7.59 ( m, 3 H ), 7.12 ( s, 1 H ), 7.10 ( t, J = 8.0 Hz, 1 H ), 6.75 ( t, J = 6.8 Hz, 1 H
). 13C NMR ( 100MHz, CDCl3 ) δ 138.5, 133.5, 133.0, 129.0, 128.0, 127.8, 127.7, 126.9, 126.8, 126.0,
123.7, 122.5, 118.2, 116.6, 113.2, 82.4. HRMS (ESI) Calcd for C19H12N2 (M+) 268.1000, Found
268.1002. Elem. Anal.: C, 85.05; H, 4.51; N, 10.44.
3-Phenylindolizine-1-carbonitrile (T 3-1) 1H NMR ( 400 MHz, CDCl3, TMS ) δ 8.30 ( d, J = 7.2 Hz,
1 H ), 7.71 ( d, J = 8.8 Hz, 1 H ), 7.53-7.55 ( m, 4 H ), 7.46-7.49 ( m, 1 H ), 7.10 ( t, J = 8.0 Hz, 1 H ),
7.06 ( s, 1 H ), 6.77 ( t, J = 6.8 Hz, 1 H ). 13C NMR ( 100MHz, CDCl3 ) δ 138.4, 137.7, 131.4, 130.7,
129.5, 129.2, 126.3, 125.9, 124.0, 122.0, 117.9, 116.5, 112.8, 81.4. HRMS (EI) Calcd for C15H10N2
(M+) 218.0844, Found 218.0839.
Methyl 3-phenylindolizine-1-carboxylate (T 3-2) 1H NMR ( 400 MHz, CDCl3, TMS ) δ 8.27 ( t, J =
8.8 Hz, 2 H ), 7.50 (m, 4 H ), 7.39 ( t, J = 7.2 Hz, 1 H ), 7.28 ( s, 1 H ), 7.06 ( t, J = 8.0 Hz, 1 H ), 6.69 (
t, J = 7.6 Hz, 1 H ), 3.91 ( s, 3 H ),. 13C NMR ( 100 MHz, CDCl3 ) δ 165.4, 136.4, 131.2, 129.1, 128.6,
128.0, 126.4, 123.3, 122.3, 120.7, 112.6, 103.9, 50.9. HRMS (EI) Calcd for C16H13NO2 (M+) 251.0946,
Found 251.0951.
Ethyl 3-(1-p-tolylvinyl)indolizine-1-carboxylate(T 3-3) 1H NMR ( 400 MHz, CDCl3, TMS ) δ 8.28 (
t, J = 7.6 Hz, 2 H ), 7.54 ( d, J = 8.0 Hz, 2 H ), 7.49 ( t, J = 7.6 Hz, 2 H ), 7.39 ( t, J = 7.2 Hz, 1 H ), 7.31
(s, 1 H ), 7.06 ( d, J = 7.6 Hz, 1 H ), 6.69 ( t, J = 6.8 Hz, 1 H ), 4.40 ( m, 2 H ), 1.42 ( t, J = 7.2 Hz, 3 H
). 13C NMR ( 100MHz, CDCl3 ) δ 165.0, 136.3, 131.2, 129.0, 128.6, 128.0, 126.4, 123.3, 122.2, 120.1,
116.0, 112.5, 104.2, 59.5, 14.6. HRMS (EI) Calcd for C17H15NO2 (M+) 265.1103, Found 265.1104.
1
Butyl 3-phenylindolizine-1-carboxylate (T 3-4) Brown oil. H NMR ( 400 MHz, CDCl3, TMS ) δ
8.28 ( t, J = 7.2 Hz, 2 H ), 7.55 ( d, J = 8.0 Hz, 2 H ), 7.50 ( t, J = 7.6 Hz, 2 H ), 7.40 ( t, J = 7.2 Hz, 1 H
), 7.32 ( s, 1 H ), 7.07 ( m,1 H ), 6.70 ( t, J = 7.6 Hz, 1 H ), 4.36 ( t, J = 6.8 Hz, 2 H ), 1.80 ( m,2 H ),
17

1.53 ( m,2 H ), 1.01 ( t, J = 7.6 Hz, 3 H ). 13C NMR ( 100 MHz, CDCl3 ) δ 165.1, 136.3, 131.2, 129.1,
View Online
128.6, 128.0, 126.4, 123.3, 122.2, 120.1, 116.1, 114.9, 112.6, 104.3, 63.5, 31.1, 19.4, 13.8. HRMS (EI)
Calcd for C19H19NO2 (M+) 293.1416, Found 293.1424. Elem. Anal.: C, 77.79; H, 6.53; N, 4.77, O,
10.91.
o
1
2-Methyl-3-phenylindolizine-1-carbonitrile (T 3-5) White solid. m.p. 253-254 C. H NMR ( 400
MHz, CDCl3, TMS ) δ 8.03 ( d, J = 7.2 Hz, 1 H ), 7.62 ( d, J = 9.2 Hz, 1 H ), 7.56 ( t, J = 7.6 Hz, 2 H ),
7.48 ( t, J = 8.0 Hz, 1 H ), 7.43 ( d, J = 8.0 Hz, 2 H ), 7.05 ( t, J = 8.0 Hz, 1 H ), 6.67 ( t, J = 6.8 Hz, 1 H
13
), 2.39 ( s, 3 H ). C NMR ( 100 MHz, CDCl3 ) δ 137.1, 130.1, 129.5, 129.2, 128.6, 126.1, 123.8,
122.1, 117.3, 116.8, 112.5, 83.4, 10.9. HRMS (EI) Calcd for C16H12N2 (M+) 232.1000, Found
232.0998. Elem. Anal.: C, 82.73; H, 5.21; N, 12.06.
o
1
7-Methyl-3-phenylindolizine-1-carbonitrile (T 3-6) White solid. m.p. 237-238 C. H NMR ( 400
MHz, CDCl3, TMS ) δ 8.17 ( d, J = 7.2 Hz, 1 H ), 7.85 ( d, J = 7.2 Hz, 1 H ), 7.22 ( d, J = 8.0 Hz, 2 H ),
7.47-7.52 ( m, 4 H ), 7.41-7.45 ( m, 2 H ), 6.97 ( s, 1 H ),6.57 ( d, J = 7.2 Hz, 1 H ), 2.39 ( s, 3 H ),. 13C
NMR ( 100 MHz, CDCl3 ) δ 139.1, 133.4, 130.4, 129.2, 128.5, 128.3, 127.1, 126.2, 123.2, 116.5, 115.9,
115.7, 80.5, 21.1. HRMS (EI) Calcd for C16H12N2 (M+) 232.1000, Found 232.0996. Elem. Anal.: C,
82.73; H, 5.21; N, 12.06.
Preparation of C-3 alkynylation indolizines: A mixture of indolizines (0.3 mmol), 3-
phenylpropiolic acid (0.3 mmol), Pd(OAc)2 (3 mg, 5 mol%), Ag2CO3 (83 mg, 0.3 mmol) in
o
DMSO/1,4-dioxane (1:1, 2 mL) was stirred at 80 C under N2 for 12 h. Afterward, the mixture was
cooled to room temperature, filtered through a pad of celite. The crude product was dissolved in Et2O
(10 mL), washed with water (2×10 mL), brine (10 mL), then dried over MgSO4. The solvent was
evaporated under reduced pressure, and the residue was subjected to flash column chromatography to
obtain the desired product.
o
1
3-(Phenylethynyl)indolizine-1-carbonitrile (T 5-1) White solid. m.p. 276-278 C. H NMR ( 400
MHz, CDCl3, TMS ) δ 8.37 ( d, J = 6.8 Hz, 1 H ), 7.67 ( d, J = 8.8 Hz, 1 H ), 7.56-7.58 ( m, 2 H ), 7.38-
13
7.39 ( m, 3 H ), 7.28 ( s, 1 H ),7.19 ( t, J = 7.6 Hz, 1 H ), 6.92 ( t, J = 6.4 Hz, 1 H ). C NMR ( 100
MHz, CDCl3 ) δ 138.0, 131.4, 128.9, 128.5, 125.7, 124.0, 122.1, 121.4, 117.9, 113.8, 97.2, 82.3. HRMS
(EI) Calcd for C17H10N2 (M+) 242.0844, Found 242.0851. Elem. Anal.: C, 84.28; H, 4.16; N, 11.56.
1
Methyl 3-(phenylethynyl)indolizine-1-carboxylate (T 5-2) H NMR ( 400 MHz, CDCl3, TMS ) δ
8.36 ( d, J = 6.8 Hz, 1 H ), 8.23 ( d, J = 9.2 Hz, 1 H ), 7.56-7.58 ( m, 2 H ), 7.52 ( s, 1 H ), 7.37-7.39 ( m,
3 H ), 7.17 ( t, J = 8.0 Hz, 1 H ), 6.88 ( t, J = 6.8 Hz, 1 H ), 3.91 ( s, 3 H ). 13C NMR ( 100 MHz, CDCl3
18

) δ 164.7, 136.3, 131.2, 128.5, 125.4, 123.8, 122.7, 121.1, 119.8, 117.9, 113.3, 108.2, 104.0, 97.0, 78.9,
View Online
51.1. HRMS (EI) Calcd for C18H13NO2 (M+) 275.0946, Found 275.0941.
o
1
Ethyl 3-(phenylethynyl)indolizine-1-carboxylate (T 5-3) White solid. m.p. 247-248 C. H NMR (
400 MHz, CDCl3, TMS ) δ 8.37 ( d, J = 6.8 Hz, 1 H ), 8.24 ( d, J = 8.8 Hz, 1 H ), 7.56-7.58 ( m, 2 H ),
7.55 ( s, 1 H ), 7.36-7.39 ( m, 3 H ), 7.17 ( t, J = 8.0 Hz, 1 H ), 6.88 ( t, J = 7.2 Hz, 1 H ), 4.36-4.41 ( m,
13
2 H ), 1.42 ( t, J = 7.2 Hz, 3 H ). C NMR ( 100 MHz, CDCl3 ) δ 164.3, 136.2, 131.2, 128.5, 128.4,
125.3, 123.8, 122.7, 121.2, 119.8, 113.3, 108.1, 104.4, 97.0, 79.0, 59.7, 14.6. HRMS (EI) Calcd for
C19H15NO2 (M+) 289.1103, Found 289.1106. Elem. Anal.: C, 78.87; H, 5.23; N, 4.84; O, 11.06.
o
1
Butyl 3-(phenylethynyl)indolizine-1-carboxylate (T 5-4) Brown solid. m.p. 260-262 C. H NMR (
400 MHz, CDCl3, TMS ) δ 8.36 ( d, J = 6.8 Hz, 1 H ), 8.23 ( d, J = 9.6 Hz, 1 H ), 7.55-7.58 ( m, 2 H ),
7.54 ( s, 1 H ), 7.36-7.38 ( m, 3 H ), 7.14-7.18 ( m, 1 H ), 6.87 ( t, J = 7.6 Hz, 1 H ), 4.33 ( t, J = 6.4 Hz,
13
2 H ), 1.74-1.79 ( m, 2 H ), 1.48-1.54 ( m, 2 H ), 1.00 ( t, J = 7.6 Hz, 3 H ). C NMR ( 100 MHz,
CDCl3 ) δ 164.4, 136.2, 131.2, 128.5, 128.4, 125.3, 123.7, 122.7, 121.2, 119.8, 113.2, 108.1, 104.4,
97.0, 78.9, 63.6, 31.0, 19.4, 13.8. HRMS (EI) Calcd for C21H19NO2 (M+) 317.1416, Found 317.1422.
Elem. Anal.: C, 79.47; H, 6.03; N, 4.41; O, 10.08.
2-Methyl-3-(phenylethynyl)indolizine-1-carbonitrile (T 5-5) White solid. m.p. 293-294 oC. 1H NMR
( 400 MHz, CDCl3, TMS ) δ 8.27 ( d, J = 7.2 Hz, 1 H ), 7.54-7.58 ( m, 3 H ), 7.39-7.40 ( m, 3 H ), 7.13
( t, J = 7.6 Hz, 1 H ), 6.86 ( t, J = 7.6 Hz, 1 H ), 2.52 ( s, 3 H ). 13C NMR ( 100 MHz, CDCl3 ) δ 137.4,
133.5, 131.2, 128.7, 128.5, 125.5, 123.8, 122.4, 117.1, 116.0, 113.3, 107.7, 99.6, 83.4, 77.3, 11.4.
HRMS (EI) Calcd for C18H12N2 (M+) 256.1000, Found 256.1001. Elem. Anal.: C, 84.35; H, 4.72; N,
10.93.
o
1
3-((4-methoxyphenyl)ethynyl)indolizine-1-carbonitrile (T 5-6) White solid. m.p. 296-297 C. H
NMR ( 400 MHz, CDCl3, TMS ) δ 8.18 ( d, J = 6.8 Hz, 1 H ), 7.67 ( d, J = 8.4 Hz, 1 H ), 7.42 ( d, J =
8.8 Hz, 2 H ), 7.02-7.07 ( m, 3 H ), 6.98 ( s, 1 H ), 6.71 ( t, J = 7.2 Hz, 1 H ), 3.87 ( s, 3 H ). 13C NMR
(100MHz, CDCl3 ) δ 159.9, 138.2, 130.2, 126.8, 123.7, 122.4, 122.0, 118.1, 115.8, 114.6, 112.9, 104.0,
97.0, 81.8, 55.4. HRMS (EI) Calcd for C18H12N2O (M+) 272.0950, Found 272.0952. Elem. Anal.: C,
79.39; H, 4.44; N, 10.29; O, 5.88.
o
1
3-(p-tolylethynyl)indolizine-1-carbonitrile (T 5-7) White solid. m.p. 279-280 C. H NMR ( 400
MHz, CDCl3, TMS ) δ 8.24 ( d, J = 6.8 Hz, 1 H ), 7.67 ( d, J = 8.8 Hz, 1 H ), 7.39 ( d, J = 8.0 Hz, 2 H ),
7.31 ( d, J = 8.4 Hz, 2 H ), 7.07 ( t, J = 7.6 Hz, 1 H ), 7.00 ( s, 1 H ), 6.73 ( t, J = 6.8 Hz, 1 H ), 2.43 ( s,
13
3 H ). C NMR ( 100 MHz, CDCl3 ) δ 138.6, 138.2, 129.9, 128.6, 127.2, 127.0, 123.7, 122.2, 118.1,
19

117.0, 115.9, 112.9, 104.0, 96.9, 82.0, 21.3. HRMS (EI) Calcd for C18H12N2 (M+) 256.1000, Found
View Online
256.0999. Elem. Anal.: C, 84.35; H, 4.72; N, 10.93.
o
1
3-((4-chlorophenyl)ethynyl)indolizine-1-carbonitrile (T 5-8) Yellow solid. m.p. 317-318 C. H
NMR ( 400 MHz, CDCl3, TMS ) δ 8.36 ( d, J = 7.2 Hz, 1 H ), 7.69( d, J = 8.8 Hz, 1 H ), 7.49 ( d, J =
8.0 Hz, 2 H ), 7.36 ( d, J = 8.4 Hz, 2 H ), 7.28 ( s, 1 H ), 7.21 ( t, J = 8.0 Hz, 1 H ), 6.95 ( t, J = 6.8 Hz, 1
13
H ). C NMR ( 100 MHz, CDCl3 ) δ 138.0, 134.9, 132.5, 128.9, 125.7, 124.1, 121.7, 120.6, 117.9,
115.9, 113.9, 108.5, 96.2, 82.5, 78.7. HRMS (EI) Calcd for C17H9ClN2 (M+) 276.0454, Found
276.0457. Elem. Anal.: C, 73.79; H, 3.28; Cl, 12.81, N, 10.12.
Acknowledgements
This study was supported by the Science Technology Department of Zhejiang Province (Grant #
2012R10014-15).
Notes and Reference
1. (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483; (b) S. Kotha, K. Lahiri and D.
Kashinath, Tetrahedron, 2002, 58, 9633–9695; (c) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew.
Chem., Int. Ed., 2005, 44, 4442–4489; (d) A. Zapf and M. Beller, Chem. Commun., 2005, 431–440; (e)
N. Miyaura, Bull. Chem. Soc. Jpn., 2008, 81, 1535–1553; (f) R. Martin and S. L. Buchwald, Acc. Chem.
Res., 2008, 41, 1461–1473.
2. (a) B. M. Trost, Science, 1991, 254, 1471–1477; (b) B. M. Trost, Angew.Chem., Int. Ed. Engl., 1995,
34, 259–281; (c) B. M. Trost, Acc. Chem. Res., 2002, 35, 695–705; (d) M. Eissen, R. Mazur, H. G.
Quebbemann and K. H. Pennemann, Helv. Chim. Acta, 2004, 87, 524–535.
3. For reviews, see: (a) A. E. Shilov and G. B. Shul’pin, Chem. Rev. 1997, 97, 2879–2932; (b) G.
Dyker, Angew. Chem., Int. Ed., 1999, 38, 1699–1712; (c) Y. Guari, S. Sabo-Etienne and B. Chaudret,
Eur. J. Inorg. Chem., 1999, 1047–1055; (d) C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001,
34, 633–639; (e) V. Ritleng, C. Sirlin and M. Pfeffer, Chem. Rev., 2002, 102, 1731–1769; (f) F.
Kakiuchi and N. Chatani, Adv. Synth. Catal., 2003, 345, 1077–1101; (g) A. R. Dick and M. S. Sanford,
Tetrahedron, 2006, 62, 2439–2463; (h) C. I. Herrerías, X. Yao, Z. Li and C. J. Li, Chem. Rev. 2007,
107, 2546–2562; (i) L. C. Campeau, D. R. Stuart and K. Fagnou, Aldrichimica Acta, 2007, 40, 35–41;
(j) F. Kakiuchi, Top. Organomet. Chem., 2008, 24, 1–33; (k) B. J. Li, S. D. Yang and Z. J. Shi, Synlett,
20

2008, 949–957; (l) A. Mori and A. Sugie, Bull. Chem. Soc. Jpn., 2008, 81, 548–561. (m) J. Wencel-
View Online
Delord, T. Dröge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740–4761.
4. Recent reviews: (a) D.Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174–238; (b) T.
Satoh and M. Miura, Chem. Lett., 2007, 36, 200–205; (c) G. P. McGlacken and L. M. Bateman, Chem.
Soc. Rev., 2009, 38, 2447–2464; (d) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 1173–
1193; (e) Y. J. Park, J.–W. Park and C.–H. Jun, Acc. Chem. Res., 2008, 41, 222–234; (f) L. C. Lewis, R.
G. Bergman and J. A. Ellman, Acc. Chem. Res., 2008, 41, 1013–1025; (g) F. Kakiuchi and T. Kochi,
Synthesis, 2008, 3013–3039; (h) O. Daugulis, H.–Q. Do and D. Shabashov, Acc. Chem. Res., 2009, 42,
1074–1086; (i) A. A. Kulkarni and O.Daugulis, Synthesis, 2009, 4087–4109; (j) L. Ackermann, R.
Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792-9826; (k) C.–L. Sun, B.–J. Li and Z.–
J. Shi, Chem. Commun., 2010, 46, 677–685; (l) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110,
1147–1169.
5. (a) F. T. Swinbourne, J. Hunt and K. Klinkert, Adv. Heterocycl. Chem., 1978, 23, 103–170; (b) W.
Flitsch, In Comprehensive Heterocyclic Chemistry; A. R.Katrizky and C. W. Rees, Eds, Pergamon:
Oxford, 1984, Vol. 4, 476; (b) J. P. Michael, Nat. Prod. Rep., 1995, 12, 535–552; (c) J. Mahon, L. K.
Mehta, R. W. Middleton, J. Parrick and H. K. Rami, J. Chem. Res. (S), 1992, 362–363; (d) J. P.
Michael, Nat. Prod. Rep., 2002, 19, 742–760.
6. (a) J. Bermudez, C. S. Fake, G. F. Joiner, K. A. Joiner, F. D. King, W. D. Miner and G. J. Sanger, J.
Med. Chem. 1990, 33, 1924–1929; (b) S. Okada, K. Sawada, A. Kozo, S. Watarabe and H. Tanaka, Brit.
UK Pat. Appl. GB 2287706, 1995; Chem. Abstr. 1995, 124, 175847; (c) S. Hagishita, M. Yamada,
K.Shirahase, T. Okada, Y. Murakami, Y. Ito, T. Matsuura, M. Wada, T. Kato, M. Ueno, Y. Chikazawa,
K. Yamada, T. Ono, I. Teshirogi and M. Ohtani, J. Med. Chem., 1996, 39, 3636–3658; (d) O. B. Ostby,
B. Dalhus, L.–L. Gundersen, F. Rise, A. Bast and G. R. M. M. Haenen, Eur. J. Org. Chem., 2000,
3763–3770; (e) L. Halab, J. A. J. Becker, Z. Darula, D. Tourwe, B. L. Kieffer, F. Simonin and W. D.
Lubell, J. Med. Chem., 2002, 45, 5353–5357; (f) W. H. Pearson and E. J. Hembre, J. Org. Chem., 1996,
61, 5546–5556.
7. (a) B. Liu, X. Qin, K. Li, X. Li, Q. Guo, J. Lan and J. You, Chem. Eur. J., 2010, 16, 11836–11839;
(b) D. Lapointe, T. Markiewicz, C. J. Whipp, A. Toderian and K. Fagnou, J. Org. Chem., 2011, 76,
749–759; (c) T. P. Pathak and M. S. Sigman, Org. Lett. 2011, 13, 2774–2777; (d) L. Huang, T. Niu, J.
Wu and Y. Zhang, J. Org. Chem., 2011, 76, 1759–1766; (e) Y. Yang, L. Chen, Z. Zhang and Y. Zhang,
Org. Lett., 2011, 13, 1342–1345; (f) Y. Yang, K. Cheng and Y. Zhang, Org. Lett. 2009, 11, 5606–5609.
8. C.–H. Park, V. Ryabova, I. V. Seregin, A. W. Sromek and V. Gevorgyan, Org. Lett., 2004, 6, 1159–
1162.
21

9. J.–B. Xia and S.–L. You, Org. Lett. 2009, 11, 1187–1190.
View Online
10. P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu and J. You, J. Am. Chem. Soc. 2010, 132,
1822–1824.
11. I. V. Seregin, V.Ryabova, V.Gevorgyan, J. Am. Chem. Soc. 2007, 129, 7742–7743.
12. N. Rodríguez and L. J. Goossen, Chem. Soc. Rev., 2011, 40, 5030–5048.
13. (a) J. Park, E. Park, A. Kim, S.-A. Park, Y. Lee, K.-W. Chi, Y. H. Jung and I. S. Kim, J. Org.
Chem., 2011, 76, 2214–2219; (b) A. Park, K. Park, Y. Kim and S. Lee, Org. Lett., 2011, 13, 944–947; (c)
H. Zhao, Y. Wei, J. Xu, J. Kan, W. Su and M. Hong, J. Org. Chem., 2011, 76, 882–893; (d) C. Feng and
T.-P. Loh, Chem. Commun., 2010, 46, 4779–4781; (e) W.-W. Zhang, X.-G. Zhang and J.-H. Li, J. Org.
Chem., 2010, 75, 5259–5264; (f) H. Kim and P. H. Lee, Adv. Syn. Catal., 2009, 351, 2827–2832; (g) J.
Moon, M. Jang and S. Lee, J. Org. Chem., 2009, 74, 1403–1406; (h) D. K. Rayabarapu and J. A. Tunge,
J. Am. Chem. Soc., 2005, 127, 13510–13511.
22