Cycloaromatization approach to polysubstituted indolizines from 2-acetylpyrroles: Decoration of the pyridine unit

Article abstract of DOI:10.1021/jo302590a

A new synthetic route to indolizines with various substituents on the pyridine moiety was developed by utilizing a facile cycloaromatization of 2-acetylpyrrole derivatives. Without isolation, the resulting intermediates were allowed to react with various electrophiles to afford a range of indolizines. In particular, Suzuki-Miyaura cross-coupling of O-triflates with (hetero)arylboronic acids permitted introduction of diverse substituents at the C8 position of an indolizine skeleton.

Full text of DOI:10.1021/jo302590a

Note
pubs.acs.org/joc
Cycloaromatization Approach to Polysubstituted Indolizines from
2‑Acetylpyrroles: Decoration of the Pyridine Unit
Jin Ho Lee and Ikyon Kim*
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 162-1 Songdo-dong, Yeonsu-gu, Incheon
406-840, Republic of Korea
S
* Supporting Information
ABSTRACT: A new synthetic route to indolizines with
various substituents on the pyridine moiety was developed
by utilizing a facile cycloaromatization of 2-acetylpyrrole
derivatives. Without isolation, the resulting intermediates
were allowed to react with various electrophiles to afford a
range of indolizines. In particular, Suzuki−Miyaura cross-
coupling of O-triflates with (hetero)arylboronic acids
permitted introduction of diverse substituents at the C8
position of an indolizine skeleton.
trategic introduction of functional substituents at various
positions of core chemical skeletons at will is very
detected on TLC. Without isolation of this intermediate, acetic
anhydride was added to the reaction mixture, which resulted in
8-acetoxyindolizine 6a in 90% yield (Table 1, entry 1).
Subsequent treatment of the cyclized intermediate with tosyl
chloride gave the corresponding O-tosylate 6b (entry 2).
Since (hetero)aryl O-triflates are valuable substrates for a
number of metal-catalyzed cross-coupling reactions, we decided
to prepare the O-triflate from this reaction. Thus, the
intermediate was allowed to react with N-phenyl-bis-
(trifluoromethanesulfonimide) to provide 6c in an excellent
yield (entry 3). Similarly, the intermediates derived from 4b
and 4c were isolated as O-acetates, O-tosylates, and O-triflates
in good yields (entries 4−9).
In the mean time, similar efforts with substrate 4d were
attempted (Scheme 3). In this case, the intermediate formed by
base-mediated intramolecular Claisen-type cyclization was
isolated as bis-O-acetates 6j or bis-O-mesylates 6k upon
subsequent exposure to acetic anhydride or mesyl chloride,
respectively.
Having secured a facile sequential one-pot route to
functionalized indolizines in hand, we next directed our
attention to Pd-catalyzed Suzuki−Miyaura coupling reactions
of O-triflates, 6c and 6f. After brief screening of the reaction
conditions, we found that the reaction of 6c with 4-
acetylphenylboronic acid (1.5 equiv) in the presence of
Pd(PPh3)4 (5 mol %) and K3PO4 (3 equiv)8 in THF at 90
°C afforded the coupled product 7a in 69% yield (Table 2,
entry 1).9 Under these conditions, several boronic acids were
successfully employed to furnish the corresponding coupled
products in good yields. In the case of 4-pyridineboronic acid,
higher reaction temperature and use of 1,4-dioxane as solvent
were required (entry 5).
S
important in medicinal chemistry with respect to drug
discovery. For instance, as illustrated in Figure 1, several
indolizines were reported to exhibit different biological
activities with therapeutic potential depending on the
substitution patterns of the core structure.1 Therefore,
development of new synthetic methods to install diverse
functional groups at suitable positions around an indolizine2
core should further extend versatility of this scaffold in many
different medicinal areas.
In contrast to most synthetic approaches toward this skeleton
where pyrrole rings were formed from pyridines (from 1 to 2,
Scheme 1),3 construction of pyridine rings from pyrroles has
been rare (from 3 to 1).4
As part of our research interest on nitrogen-fused bicycles,
we have recently reported mild and facile syntheses of
indolizines and indolizinones, employing a strategy where
activation of alkene or alkyne allows for subsequent intra-
molecular ring closure by nucleophilic attack of a tethered
pyridine in a highly efficient manner.5 While these approaches
enable us to easily decorate the pyrrole ring with various
functional groups, we also hope to design new methods to gain
access to indolizines with diverse functionalities incorporated
on the pyridine moiety. In this context, here we report a novel
synthesis of indolizines from 2-acetylpyrrole based on a facile
cycloaromatization strategy.6
As outlined in Scheme 2, we reasoned that 4 would undergo
intramolecular aldol-type cyclization in the presence of base
followed by tautomerization to afford 5, which can be trapped
with various electrophiles to give 6,8-disubstituted indolizines 6.
To the best of our knowledge, indolizines with this type of
substitution have not been disclosed yet.
To test this idea, 4a was used as a substrate for optimization
study.7 When 4a was treated with NaH (2.5 equiv) in THF at
room temperature, the presumed 8-hydroxyindolizine was
Received: November 30, 2012
© XXXX American Chemical Society
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dx.doi.org/10.1021/jo302590a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 1. Some representative biological modulators containing an indolizine core.
Scheme 1. Two Approaches to the Indolizine Scaffold
Scheme 3. Cycloaromatization of 4d Followed by Reactions
with Electrophiles
Scheme 2. Synthesis of 6,8-Disubstituted Indolizines
a
Table 2. Suzuki−Miyaura Reaction of 6
Table 1. Cycloaromatization of 4 Followed by Reactions
a
with Electrophiles
b
entry
6
R2B(OH)2
7
yield
1
2
3
4
6c
6c
6c
6c
6c
6c
6c
6c
6c
6f
4-acetylphenylboronic acid
3-acetylphenylboronic acid
5-acetylthiopheneboronic acid
3-cyanophenylboronic acid
4-pyridineboronic acid
7a
7b
7c
7d
7e
7f
69
60
79
85
42
82
59
65
88
82
40
60
c
5
6
3-methoxycarbonylphenylboronic acid
4-methoxycarbonylphenylboronic acid
3-nitrophenylboronic acid
b
entry
4
electrophile
6
yield (%)
7
7g
7h
7i
1
2
3
4
5
6
7
8
9
4a (R1 = Ph)
Ac2O
6a (E = Ac)
6b (E = Ts)
6c (E = Tf)
6d (E = Ac)
6e (E = Ts)
6f (E = Tf)
6g (E = Ac)
6h (E = Ts)
6i (E = Tf)
90
92
95
97
89
67
88
85
74
8
4a
TsCl
9
4-nitrophenylboronic acid
4a
PhNTf2
Ac2O
10
11
12
4-nitrophenylboronic acid
7j
4b (R1 = 4-MeOPh)
6f
3-cyanophenylboronic acid
4-methoxycarbonylphenylboronic acid
7k
7l
4b
TsCl
6f
a
4b
PhNTf2
Ac2O
A mixture of 6 (0.161 mmol), arylboronic acid (1.5 equiv),
4c (R1 = 4-ClPh)
Pd(PPh3)4 (5 mol %), and K3PO4 (3 equiv) in THF (2 mL) was
b
4c
4c
TsCl
heated at 90 °C for 2 h unless otherwise noted. Isolated yield (%)
c
1,4-Dioxane was used as solvent, and the reaction mixture was heated
PhNTf2
a
at 120 °C.
To a stirred solution of 4 (0.132 mmol) in THF (2 mL) was added
60% NaH (13.2 mg, 2.5 equiv) at 0 °C. After being stirred at rt for 1 h,
the reaction mixture was treated with appropriate electrophile (1.5
b
equiv). Isolated yields (%).
unstable; in some cases, pure NMR data could not be obtained
even after flash column chromatography due to rapid
decomposition. For example, it was found that indolizine
bearing 4-methoxyphenyl group at the C8 position initially
Notably, cross-coupled products from the reactions with
boronic acids having electron-donating groups seemed to be
B
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Note
isolated in 82% yield was quickly decomposed to give impure
NMR spectra (data not shown).
Heck coupling of 6c with ethyl acrylate was also attempted
under Jeffery’s phosphine-free conditions10 as shown in Scheme
4. When 4 equiv of ethyl acrylate was used, the expected
product 9 was obtained along with 8.11
As new substitution patterns on the pyridine unit of an
indolizine core were made possible, this chemistry should
further extend the utility of this skeleton.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of 4. A mixture of 2-
acetylpyrrole (2.749 mmol), K2CO3 (6.873 mmol, 2.5 equiv), and 2-
bromoacetophenone (3.024 mmol, 1.1 equiv) in CH3CN (9 mL) was
stirred at 40 °C. After being stirred for 24 h, the reaction mixture was
concentrated under reduced pressure, diluted with ethyl acetate (12
mL), and washed with H2O (12 mL). The water layer was extracted
with ethyl acetate (12 mL) one more time. The organic layer was dried
over MgSO4 and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexanes/ethyl
acetate/dichloromethane = 30:1:2 to 10:1:2) to give 4.
Scheme 4. Heck Reaction of 6c
2-(2-Acetyl-1H-pyrrol-1-yl)-1-phenylethanone (4a). White
powder, mp 127.3−127.6 °C (468.6 mg, 75%); 1H NMR (400
MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.51
(t, J = 7.6 Hz, 2H), 7.07 (d, J = 2.4 Hz, 1H), 6.87 (s, 1H), 6.28 (s,
1H), 5.75 (s, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
193.6, 188.9, 135.2, 133.8, 131.6, 130.5, 129.0, 128.2, 120.5, 109.0,
55.8, 27.0; HRMS (ESI-QTOF) calcd for C14H14NO2 228.1019 ([M +
H]+), found 228.1015.
Finally, introduction of additional functional groups at the
C3 site of the indolizines prepared by this route was
demonstrated in Scheme 5, thereby increasing diversity of
Scheme 5. Further Elaboration of the Suzuki−Miyaura
Products
2-(2-Acetyl-1H-pyrrol-1-yl)-1-(4-methoxyphenyl)ethanone
(4b). White powder, mp 123.5−123.9 °C (587.0 mg, 83%); 1H NMR
(400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.97 (d, J
= 8.4 Hz, 2H), 6.86 (s, 1H), 6.27 (s, 1H), 5.72 (s, 2H), 3.88 (s, 3H),
2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.0, 188.9, 164.0,
131.6, 130.5, 128.2, 120.4, 114.1, 108.9, 55.7, 55.3, 27.0; HRMS (ESI-
QTOF) calcd for C15H16NO3 258.1125 ([M + H]+), found 258.1121.
2-(2-Acetyl-1H-pyrrol-1-yl)-1-(4-chlorophenyl)ethanone
1
(4c). White powder, mp 116.7−117.0 °C (489.2 mg, 68%); H NMR
(400 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.6 Hz,
2H), 7.07 (s, 1H), 6.87 (s, 1H), 6.28 (s, 1H), 5.69 (s, 2H), 2.40 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 192.5, 189.0, 140.3, 133.6,
131.6, 130.4, 129.6, 129.3, 120.6, 109.1, 55.6, 27.0; HRMS (ESI-
QTOF) calcd for C14H13ClNO2 262.0629 ([M + H]+), found
262.0626.
Ethyl 2-(2-Acetyl-1H-pyrrol-1-yl)acetate (4d). White powder,
1
mp 66.2−66.9 °C (456.2 mg, 85%); H NMR (400 MHz, CDCl3) δ
7.01 (d, J = 2.0 Hz, 1H), 6.83 (s, 1H), 6.22 (s, 1H), 5.00 (s, 2H), 4.23
(q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 188.8, 168.9, 131.1, 130.6, 120.4, 108.9, 61.6,
51.4, 26.9, 14.3; HRMS (ESI-QTOF) calcd for C10H14NO3 196.0968
([M + H]+), found 196.0964.
General Procedure for the Synthesis of 6. To a stirred solution
of 4 (0.132 mmol) in THF (2 mL) was added 60% NaH (13.2 mg, 2.5
equiv) at 0 °C. After being stirred at rt for 1 h, the reaction mixture
was treated with the appropriate electrophile (1.5 equiv.). After an
additional 1 h at rt, the mixture was quenched with H2O (2 mL) and
extracted with ethyl acetate (2 mL) two times. The organic layer was
dried over MgSO4 and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography (hexanes/
ethyl acetate/dichloromethane = 50:1:2 to 30:1:2) to give 6.
6-Phenylindolizin-8-yl Acetate (6a). Yellowish oil (29.9 mg,
this skeleton. For this purpose, Friedel−Crafts acylation of 7g
and 7h with 3,4,5-trimethoxybenzoyl chloride and acetyl
chloride was undertaken, delivering 10 and 11, respectively
(unoptimized yields).12 Vilsmeier−Haack formylation13 of
indolizine 7i proceeded to give 12 in 62% yield.14
In summary, we have described a novel synthetic approach to
indolizines in which pyridine parts with unique substitution
patterns were constructed from acetylpyrroles. In particular, the
resulting O-triflates from a sequential one-pot cycloaromatiza-
tion/O-sulfonylation process were employed in palladium-
catalyzed Suzuki−Miyaura cross-coupling reactions, allowing
easy access to indolizines with various substituents at the C6
and C8 positions. Subsequent elaboration of the resulting
Suzuki−Miyaura products at the C3 position by additional
functionalization was also demonstrated to maximize diversity.
1
90%); H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.52 (d, J = 7.2
Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.38 (dd, J = 1.6, 2.8 Hz, 1H), 7.33
(t, J = 7.2 Hz, 1H), 6.80 (d, J = 0.8 Hz, 1H), 6.78 (dd, J = 2.8, 4.0 Hz,
1H), 6.39 (d, J = 4.0 Hz, 1H), 2.40 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 168.8, 142.2, 137.9, 129.1, 127.6, 127.0, 126.9, 124.2, 120.7,
114.7, 114.4, 109.4, 97.1, 21.2; IR (ATR) 3057, 1766, 1599, 1469,
1186 cm−1; HRMS (ESI-QTOF) calcd for C16H14NO2 252.1019 ([M
+ H]+), found 252.1021.
6-Phenylindolizin-8-yl 4-Methylbenzenesulfonate (6b).
1
Brownish oil (44.1 mg, 92%); H NMR (500 MHz, CDCl3) δ 7.98
(s, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.42−7.39 (m, 4H), 7.35−7.30 (m,
4H), 6.73 (s, 1H), 6.69 (d, J = 1.5 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H),
2.43 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 145.7, 141.4, 137.4,
132.9, 129.9, 129.1, 128.7, 127.7, 126.8, 126.7, 123.8, 121.3, 114.8,
C
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Note
114.6, 109.9, 98.3, 21.8; IR (ATR) 3059, 2920, 1596, 1455, 1376,
1175, 1088, 759 cm−1; HRMS (ESI-QTOF) calcd for C21H18NO3S
364.1002 ([M + H]+), found 364.1002.
Indolizine-6,8-diyl Diacetate (6j). Yellowish oil (28.7 mg, 80%);
1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.32 (dd, J = 1.5, 2.5 Hz
1H), 6.76 (dd, J = 3.0, 4.0 Hz, 1H), 6.49 (d, J = 1.5 Hz, 1H), 6.42 (d, J
= 4.0 Hz, 1H), 2.37 (s, 3H), 2.28 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.4, 168.3, 141.8, 137.5, 126.3, 115.6, 115.2, 114.3, 105.9,
97.9, 21.2, 21.1; IR (ATR) 3074, 1764, 1545, 1467, 1181 cm−1; HRMS
(ESI-QTOF) calcd for C12H12NO4 234.0761 ([M + H]+), found
234.0767.
6-Phenylindolizin-8-yl Trifluoromethanesulfonate (6c). Light
brownish oil (42.8 mg, 95%); 1H NMR (500 MHz, CDCl3) δ 8.07 (s,
1H), 7.50 (d, J = 7.0 Hz, 2H), 7.46−7.43 (m, 3H), 7.37 (t, J = 7.0 Hz,
1H), 6.93 (s, 1H), 6.86 (dd, J = 2.5, 4.0 Hz, 1H), 6.64 (d, J = 4.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 141.2, 136.9, 129.3, 128.1,
126.8, 125.6, 123.7, 122.4, 118.9 (q, JC,F = 318.9 Hz), 115.7, 115.4,
109.6, 98.4; IR (ATR) 3061, 1601, 1466, 1346, 1208 cm−1; HRMS
(ESI-QTOF) calcd for C15H11F3NO3S 342.0406 ([M + H]+), found
342.0402.
6-(4-Methoxyphenyl)indolizin-8-yl Acetate (6d). Yellowish oil
(36.0 mg, 97%); 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.44 (d,
J = 8.4 Hz, 2H), 7.36, (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6. 76 (s, 2H),
6.37 (d, J = 3.2 Hz, 1H), 3.83 (s, 3H), 2.39 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 168.8, 159.2, 142.1, 130.3, 127.8, 126.8, 123.8, 120.0,
114.4, 114.4, 114.1, 109.3, 96.9, 55.5, 21.2; IR (ATR) 3035, 1765,
1608, 1464, 1244, 1180 cm−1; HRMS (ESI-QTOF) calcd for
C17H16NO3 282.1125 ([M + H]+), found 282.1128.
6-(4-Methoxyphenyl)indolizin-8-yl 4-Methylbenzenesulfo-
nate (6e). Greenish oil (46.2 mg, 89%); 1H NMR (400 MHz,
CDCl3) δ 7.92 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.35, (d, J = 8.8 Hz,
2H), 7.31−7.29 (m, 3H), 6.94 (d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 6.68
(dd, J = 2.4, 4.0 Hz, 1H), 6.27 (d, J = 2.8 Hz, 1H), 3.84 (s, 3H), 2.43
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 145.6, 141.3, 133.0,
129.9, 129.9, 128.7, 127.8, 126.7, 123.5, 120.6, 114.6, 114.5, 114.4,
110.0, 98.2, 55.5, 21.9; HRMS (ESI-QTOF) calcd for C22H20NO4S
394.1108 ([M + H]+), found 394.1111.
Indolizine-6,8-diyl Dimethanesulfonate (6k). Colorless oil
1
(17.4 mg, 37%); H NMR (500 MHz, CDCl3) δ 8.04 (dd, J = 1.0,
1.5 Hz, 1H), 7.45 (dd, J = 1.5, 2.5 Hz, 1H), 6.89 (dd, J = 3.0, 4.0 Hz,
1H), 6.76 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 4.0 Hz, 1H), 3.25 (s, 3H),
3.21 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 140.5, 135.4, 126.1,
118.5, 116.5, 115.8, 106.2, 99.7, 38.6, 37.7; IR (ATR) 3030, 1540,
1465, 1360, 962 cm−1; HRMS (ESI-QTOF) calcd for C10H12NO6S2
306.0101 ([M + H]+), found 306.0104.
General Procedure for the Synthesis of 7. A mixture of 6
(0.161 mmol), arylboronic acid (1.5 equiv), Pd(PPh3)4 (5 mol %), and
K3PO4 (3 equiv) in THF (2 mL) was heated at 90 °C for 2 h. After
being cooled to rt, the reaction mixture was concentrated, diluted with
ethyl acetate (2 mL), and washed with H2O (2 mL). The water layer
was extracted with ethyl acetate (2 mL) one more time. The organic
layer was dried over MgSO4 and concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography
(hexanes/ethyl acetate/dichloromethane = 50:1:2 to 30:1:2) to give 7.
1-(4-(6-Phenylindolizin-8-yl)phenyl)ethanone (7a). Brownish
oil (34.6 mg, 69%); 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 8.08
(d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H),
7.46−7.44 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 7.01 (s, 1H), 6.86 (s,
1H), 6.57 (d, J = 2.4 Hz, 1H), 2.67 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.9, 144.0, 138.3, 136.7, 131.9, 130.9, 129.1, 128.9, 128.6,
127.6, 126.8, 124.9, 122.7, 118.2, 114.7, 114.2, 99.5, 26.9; IR (ATR)
3056, 1724, 1602, 1450, 1263 cm−1; HRMS (ESI-QTOF) calcd for
C22H18NO 312.1383 ([M + H]+), found 312.1383.
1-(3-(6-Phenylindolizin-8-yl)phenyl)ethanone (7b). Brownish
oil (30.1 mg, 60%); 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.17
(s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.62−7.57
(m, 3H), 7.48−7.44 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 6.99 (s, 1H),
6.85 (dd, J = 3.2, 3.6 Hz, 1H), 6.54 (d, J = 3.6 Hz, 1H), 2.63 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 198.1, 139.7, 138.3, 137.7, 133.0,
132.0, 131.2, 129.1, 129.1, 128.4, 128.0, 127.5, 126.8, 125.0, 122.4,
117.9, 114.6, 114.2, 99.3, 27.0; IR (ATR) 3058, 1727, 1598, 1465,
1207 cm−1; HRMS (ESI-QTOF) calcd for C22H18NO 312.1383 ([M +
H]+), found 312.1383.
6-(4-Methoxyphenyl)indolizin-8-yl Trifluoromethanesulfo-
1
nate (6f). Light brownish oil (32.8 mg, 67%); H NMR (500 MHz,
CDCl3) δ 8.04 (s, 1H), 7.46−7.45 (m, 1H), 7.44 (d, J = 8.5 Hz, 2H),
6.99 (d, J = 9.0 Hz, 2H), 6. 90 (s, 1H), 6.86 (dd, J = 2.5, 4.0 Hz, 1H),
6.63 (d, J = 4.0 Hz, 1H), 3.86 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
159.7, 141.2, 129.4, 128.0, 125.5, 123.4, 121.7, 118.9 (q, JC,F = 318.9
Hz), 115.5, 115.2, 114.7, 109.7, 98.3, 55.6; IR (ATR) 3063, 1607,
1461, 1332, 1245, 1210, 756 cm−1; HRMS (ESI-QTOF) calcd for
C16H13F3NO4S 372.0512 ([M + H]+), found 372.0510.
6-(4-Chlorophenyl)indolizin-8-yl Acetate (6g). Yellowish oil
(33.2 mg, 88%); 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.45 (d,
J = 8.4 Hz, 2H), 7.40−7.38 (m, 3H), 6.79 (dd, J = 2.8, 3.6 Hz, 1H),
6.75 (s, 1H), 6.40 (d, J = 3.6 Hz, 1H), 2.41 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 168.7, 142.3, 136.4, 133.6, 129.2, 128.1, 126.9, 123.1,
120.6, 114.8, 114.6, 108.9, 97.4, 21.2; HRMS (ESI-QTOF) calcd for
C16H13ClNO2 286.0629 ([M + H]+), found 286.0626.
1-(5-(6-Phenylindolizin-8-yl)thiophen-2-yl)ethanone (7c).
6-(4-Chlorophenyl)indolizin-8-yl 4-Methylbenzenesulfonate
1
1
Orange oil (40.4 mg, 79%); H NMR (500 MHz, CDCl3) δ 8.15 (s,
(6h). Colorless oil (44.6 mg, 85%); H NMR (400 MHz, CDCl3) δ
1H), 7.73 (d. J = 4.0 Hz, 1H), 7.58−7.56 (m, 3H), 7.47−7.44 (m,
3H), 7.37 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 1.5 Hz, 1H), 6.89−6.85 (m,
2H), 2.60 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 190.8, 149.5,
143.2, 137.9, 132.9, 129.5, 129.2, 127.7, 126.8, 126.3, 124.9, 124.5,
123.3, 118.5, 115.0, 114.6, 100.2, 26.8; IR (ATR) 3057, 1727, 1654,
1445, 1270 cm−1; HRMS (ESI-QTOF) calcd for C20H16NOS
318.0947 ([M + H]+), found 318.0947.
3-(6-Phenylindolizin-8-yl)benzonitrile (7d). Yellow gum (40.3
mg, 85%); 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.02 (s, 1H),
7.97 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.59−7.58 (m, 3H),
7.48−7.44 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 6.94 (s, 1H), 6.86 (dd, J
= 2.8, 3.6 Hz, 1H), 6.50 (d, J = 3.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 140.5, 138.1, 132.8, 131.9, 131.6, 130.7, 129.7, 129.2, 127.6,
126.8, 124.9, 122.8, 118.9, 118.2, 114,8, 114.5, 113.0, 99.2; IR (ATR)
3060, 2228, 1598, 1478 cm−1; HRMS (ESI-QTOF) calcd for
C21H15N2 295.1230 ([M + H]+), found 295.1232.
7.96 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.38−7.31 (m, 7H), 6.70−6.69
(m, 2H), 6.29 (d, J = 2.8 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 145.8, 141.5, 135.9, 133.8, 132.9, 130.0, 129.3, 128.7, 127.9,
126.8, 122.7, 121.3, 114.9, 114.9, 109.5, 98.6, 21.9; HRMS (ESI-
QTOF) calcd for C21H17ClNO3S 398.0612 ([M + H]+), found
398.0615.
6-(4-Chlorophenyl)indolizin-8-yl Trifluoromethanesulfonate
(6i). Light brownish oil (36.7 mg, 74%); 1H NMR (500 MHz, CDCl3)
δ 8.08 (s, 1H), 7.48 (dd, J = 1.5, 2.5 Hz, 1H), 7.46−7.42 (m, 4H), 6.89
(d, J = 4.0 Hz, 2H), 6.66 (d, J = 4.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 141.3, 135.4, 134.2, 129.5, 128.1, 125.5, 122.6, 122.4, 118.8
(q, JC,F = 319.0 Hz), 115.8, 115.6, 109.2, 98.7; IR (ATR) 3065, 1596,
1463, 1327, 1300, 762 cm−1; HRMS (ESI-QTOF) calcd for
C15H10ClF3NO3S 376.0017 ([M + H]+), found 376.0016.
Synthesis of 6j and 6k. To a stirred solution of 4d (0.154 mmol)
in THF (2 mL) was added 60% NaH (27.7 mg, 4.5 equiv) at 0 °C.
After being stirred at 90 °C for 1 h, the reaction mixture was treated
with acetic anhydride or mesyl chloride (5 equiv) at rt. After an
additional 1 h at rt, the mixture was quenched with H2O (2 mL) and
extracted with ethyl acetate (2 mL) two times. The organic layer was
dried over MgSO4 and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography (hexanes/
ethyl acetate/dichloromethane = 10:1:2 to 5:1:2) to give 6j or 6k.
6-Phenyl-8-(pyridin-4-yl)indolizine (7e). Brownish gum (18.3
1
mg, 42%); H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 5.6 Hz, 2H),
8.18 (s, 1H), 7.65 (d, J = 6.0 Hz, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.48−
7.44 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 7.02 (s, 1H), 6.87 (dd, J = 2.8,
3.2 Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
150.3, 146.9, 138.1, 130.3, 130.3, 129.2, 127.7, 126.8, 124.8, 123.2,
123.1, 118.3, 114.9, 114.4, 99.4; IR (ATR) 3053, 1596, 1448 cm−1;
D
dx.doi.org/10.1021/jo302590a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
HRMS (ESI-QTOF) calcd for C19H15N2 271.1230 ([M + H]+), found
271.1237.
heated at 100 °C for 1 h. Then the mixture was evaporated, diluted
with ethyl acetate (2 mL), and washed with H2O (2 mL). The water
layer was extracted with ethyl acetate (2 mL) one more time. The
organic layer was dried over MgSO4 and concentrated under reduced
pressure. The resulting residue was purified by silica gel chromatog-
raphy (hexanes/ethyl acetate/dichloromethane = 30:1:2) to give 8 and
9.
(2E,2′E)-Diethyl 3,3′-(6-Phenylindolizine-3,8-diyl)diacrylate
(8). Brown solid, mp 158.7−159.6 °C (20.9 mg, 46%); 1H NMR
(500 MHz, CDCl3) δ 8.39 (s, 1H), 8.00 (d, J = 15.5 Hz, 1H), 7.92 (d,
J = 16.5 Hz, 1H), 7.59 (d, J = 7.0 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H),
7.42 (t, J = 7.5 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J = 4.5 Hz, 1H), 6.85 (d,
J = 4.5 Hz, 1H), 6.67 (d, J = 16.0 Hz, 1H), 6.33 (d, J = 15.5 Hz, 1H),
4.33−4.26 (m, 4H), 1.37 (t, J = 7.0 Hz, 3H), 1.35 (t, J = 7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 168.9, 166.8, 140.2, 137.4, 134.0,
Methyl 3-(6-Phenylindolizin-8-yl)benzoate (7f). Brownish
1
gum (43.2 mg, 82%); H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H),
8.16 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.61
(d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.6 HZ, 1H), 7.46−7.44 (m, 3H), 7.36
(t, J = 7.2 Hz, 1H), 6.99 (s, 1H), 6.85 (s, 1H), 6.54 (d, J = 3.2 Hz,
1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 139.5,
138.4, 132.8, 132.0, 131.2, 130.8, 129.6, 129.3, 129.1, 128.8, 127.5,
126.8, 124.9, 122.3, 117.9, 114.6, 114.2, 99.4, 52.4; IR (ATR) 3058,
1719, 1600, 1486, 1286, 1106 cm−1; HRMS (ESI-QTOF) calcd for
C22H18NO2 328.1332 ([M + H]+), found 328.1334.
Methyl 4-(6-Phenylindolizin-8-yl)benzoate (7g). Yellow oil
1
(31.1 mg, 59%); H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.6 Hz,
3H), 7.81 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.47−7.43 (m,
3H), 7.35 (t, J = 7.2 Hz, 1H), 6.99 (s, 1H), 6.85 (s, 1H), 6.56 (d, J =
3.2 Hz, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0,
143.8, 138.3, 131.9, 130.9, 130.1, 129.7, 129.1, 128.4, 127.5, 126.8,
124.8, 122.6, 118.1, 114.6, 114.2, 99.5, 52.3; HRMS (ESI-QTOF)
calcd for C22H18NO2 328.1332 ([M + H]+), found 328.1333.
130.0, 129.3, 128.2, 127.1, 126.7, 126.2, 122.8, 121.8, 121.4, 121.2,
117.3, 112.5, 102.1, 60.9, 60.5, 14.6, 14.5; IR (ATR) 3078, 3062, 2985,
2852, 1717, 1691, 1636, 1610, 1469 cm−1; HRMS (ESI-QTOF) calcd
for C24H24NO4 390.1700 ([M + H]+), found 390.1700.
(E)-Ethyl 3-(6-Phenylindolizin-8-yl)acrylate (9). Brown oil (9.5
1
8-(3-Nitrophenyl)-6-phenylindolizine (7h). Orange oil (32.9
mg, 28%); H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.90 (d, J =
1
mg, 65%); H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.26 (d, J =
16.0 Hz, 1H), 7.57−7.55 (m, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.43 (dd, J
= 1.5, 3.0 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.23 (s, 1H), 6.89 (dd, J =
3.0, 4.0 Hz, 1H), 6.75 (d, J = 4.0 Hz, 1H), 6.68 (d, J = 16.0 Hz, 1H),
4.30 (q, J = 7.5 Hz, 2H), 1.37 (t, J = 7.5 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 167.3, 141.6, 137.8, 129.2, 127.7, 126.8, 125.8, 124.5,
124.4, 121.1, 120.2, 115.0, 114.3, 99.3, 60.8, 14.5; IR (ATR) 3058,
3031, 2854, 1703, 1635, 1612, 1464 cm−1; HRMS (ESI-QTOF) calcd
for C19H18NO2 292.1332 ([M + H]+), found 292.1333.
8.0 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz,
1H), 7.59 (d, J = 7.2 Hz, 2H), 7.48−7.44 (m, 3H), 7.37 (t, J = 7.2 Hz,
1H), 7.00 (s, 1H), 6.87 (s, 1H), 6.53 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 148.7, 140.8, 138.0, 134.4, 130.6, 130.5, 129.7, 129.2, 127.6,
126.8, 124.8, 123.3, 122.9, 122.9, 118.3, 114.9, 114.5, 99.2; HRMS
(ESI-QTOF) calcd for C20H15N2O2 315.1128 ([M + H]+), found
315.1130.
8-(4-Nitrophenyl)-6-phenylindolizine (7i). Reddish solid, mp
110.0−110.5 °C (44.5 mg, 88%); 1H NMR (400 MHz, CDCl3) δ 8.36
(d, J = 8.4 Hz, 2H), 8.20 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.60 (d, J =
8.0 Hz, 2H), 7.50−7.46 (m, 3H), 7.39 (t, J = 8.0 Hz, 1H), 7.02 (s,
1H), 6.88 (dd, J = 2.8, 3.6 Hz, 1H), 6.55 (d, J = 3.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 147.5, 145.8, 138.0, 130.7, 130.4, 129.2,
129.1, 127.7, 126.8, 124.8, 124.1, 123.2, 118.7, 114.9, 114.5, 99.4; IR
(ATR) 3064, 1593, 1509, 1437, 1338 cm−1; HRMS (ESI-QTOF)
calcd for C20H15N2O2 315.1128 ([M + H]+), found 315.1130.
6-(4-Methoxyphenyl)-8-(4-nitrophenyl)indolizine (7j). Or-
Synthesis of 10. A mixture of 7g (0.0916 mmol), 3,4,5-
trimethoxybenzoyl chloride (2 equiv), and Et3N (5 equiv) in dried
CH2Cl2 (2 mL) was heated at 80 °C for 24 h. Then the mixture was
evaporated, diluted with ethyl acetate (2 mL), and washed with
saturated NaHCO3 solution (2 mL). The water layer was extracted
with ethyl acetate (2 mL) one more time. The organic layer was dried
over MgSO4 and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexanes/ethyl
acetate/dichloromethane = 10:1:2) to give 10.
Methyl 4-(6-Phenyl-3-(3,4,5-trimethoxybenzoyl)indolizin-8-
1
yl)benzoate (10). Light green solid, mp 230.2−230.7 °C (26.8 mg,
ange gum (45.5 mg, 82%); H NMR (400 MHz, CDCl3) δ 8.33 (d,
1
56%); H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.21 (d, J = 8.4
J = 8.4 Hz, 2H), 8.12 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4
Hz, 2H), 7.46 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.97 (s, 1H), 6.86 (dd,
J = 3.2, 3.6 Hz, 1H), 6.52 (d, J = 4.0 Hz, 1H), 3.86 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.4, 147.5, 145.9, 130.6, 130.5, 130.3, 129.1,
127.9, 124.5, 124.1, 122.5, 118.8, 114.7, 114.6, 114.3, 99.3, 55.6; IR
(ATR) 3078, 1594, 1505, 1462, 1338, 1248 cm−1; HRMS (ESI-
QTOF) calcd for C21H17N2O3 345.1234 ([M + H]+), found 345.1237.
3-(6-(4-Methoxyphenyl)indolizin-8-yl)benzonitrile (7k).
Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 7.6 Hz, 2H), 7.53−7.48
(m, 4H), 7.42 (t, J = 7.2 Hz, 1H), 7.13 (s, 2H), 6.67 (d, J = 4.4 Hz,
1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.93 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 183.9, 166.8, 153.0, 142.6, 140.8, 137.4, 137.3, 135.9, 131.6,
130.3, 130.2, 129.3, 128.8, 128.4, 128.1, 127.2, 127.1, 125.8, 124.4,
123.4, 106.6, 102.4, 61.1, 56.4, 52.5; IR (ATR) 3055, 1719, 1609,
1456, 1234, 1180, 1130 m−1; HRMS (ESI-QTOF) calcd for
C32H28NO6 522.1911 ([M + H]+), found 522.1913.
1
Brown oil (20.9 mg, 40%); H NMR (400 MHz, CDCl3) δ 8.11 (s,
Synthesis of 11. To a stirred solution of 7h (0.0954 mmol) in
CHCl3 (1 mL) were added pyridine (76.9 μg, 10 equiv) and acetyl
chloride (30.5 μg, 4.5 equiv). After being stirred at rt for 3 h, the
mixture was evaporated, diluted with ethyl acetate (2 mL), and washed
with saturated NaHCO3 solution (2 mL). The water layer was
extracted with ethyl acetate (2 mL) one more time. The organic layer
was dried over MgSO4 and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography (hexanes/
ethyl acetate/dichloromethane = 10:1:2) to give 11.
1H), 8.02 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H),
7.59 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.46 (m, 1H), 7.00
(d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 6.85 (dd, J = 2.8, 3.6 Hz, 1H), 6.49
(d, J = 4.0 Hz, 1H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
159.3, 140.5, 132.8, 131.9, 131.6, 130.6, 130.5, 130.2, 129.6, 127.8,
124.5, 122.1, 118.9, 118.3, 114.6, 114.6, 114.3, 113.0, 99.0, 55.5; IR
(ATR) 3060, 2228, 1067, 1463, 1242 cm−1; HRMS (ESI-QTOF)
calcd for C22H17N2O 325.1335 ([M + H]+), found 325.1337.
Methyl 4-(6-(4-Methoxyphenyl)indolizin-8-yl)benzoate (7l).
Yellow oil (34.5 mg, 60%); 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J =
8.4 Hz, 2H), 8.09 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.8 Hz,
2H), 7.44 (s, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 6.84−6.83
(m, 1H), 6.54 (d, J = 3.6 Hz, 1H), 3.96 (s, 3H), 3.85 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.0, 159.3, 143.9, 131.8, 130.8, 130.7,
130.0, 129.6, 128.4, 127.9, 124.5, 121.9, 118.2, 114.5, 114.4, 114.0,
99.3, 55.5, 52.3; IR (ATR) 3036, 1716, 1608, 1462, 1274, 1178 cm−1;
HRMS (ESI-QTOF) calcd for C23H20NO3 358.1438 ([M + H]+),
found 358.1437.
1-(8-(3-Nitrophenyl)-6-phenylindolizin-3-yl)ethanone (11).
1
Orange oil (10.5 mg, 31%); H NMR (400 MHz, CDCl3) δ 10.24
(s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.02 (d, J =
7.6 Hz, 1H), 7.74−7.68 (m, 3H), 7.58 (d, J = 4.8 Hz, 1H), 7.50 (t, J =
7.2 Hz, 2H) 7.45 (s, 1H), 7.41 (t, J = 7.2 Hz, 1H), 6.60 (d, J = 4.4 Hz,
1H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.3, 148.8,
139.9, 137.3, 136.2, 134.7, 130.1, 130.0, 129.3, 128.2, 128.2, 127.2,
126.0, 124.6, 124.0, 123.7, 123.4, 101.5, 27.6; IR (ATR) 3080, 1737,
1624, 1575, 1477, 1324, 1299 cm−1; HRMS (ESI-QTOF) calcd for
C22H17N2O3 357.1234 ([M + H]+), found 357.1233.
Heck Reaction of 6c. A mixture of 6c (0.117 mmol), ethyl
acrylate (4 equiv), Pd(OAc)2 (10 mol %), tetrabutylammonium
bromide (1 equiv), and NaHCO3 (2 equiv) in DMF (1 mL) was
Synthesis of 12. A solution of POCl3 (13.7 μL, 0.147 mmol, 3.3
equiv) in DMF (0.5 mL) was stirred at 0 °C for 1 h. To a stirred
E
dx.doi.org/10.1021/jo302590a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
solution of 7i (0.0445 mmol) in dried CH2Cl2 (1 mL) was added 1/3
of POCl3 (1.1 equiv) and DMF mixture at 0 °C. After being stirred at
rt for 1 h, the reaction mixture was quenched by saturated NaHCO3
solution (2 mL), diluted with CH2Cl2 (2 mL), and washed with H2O
(2 mL). The water layer was extracted with ethyl acetate (2 mL) one
more time. The organic layer was dried over MgSO4 and concentrated
under reduced pressure. The resulting residue was purified by silica gel
chromatography (hexanes/ethyl acetate/dichloromethane =20:1:2 to
10:1:2) to give 12.
Commun. 2010, 46, 6341. (j) Barluenga, J.; Lonzi, G.; Riesgo, L.;
Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2010, 132, 13200.
́
́
(k) Ziyaadini, M.; Hazeri, N.; Maghsoodlou, M. T.; Habibi-Khorassani,
S. M.; Willis, A. C. Tetrahedron Lett. 2011, 52, 5774. (l) Mao, Z.; Li,
X.; Lin, X.; Lu, P.; Wang, Y. Tetrahedron 2012, 68, 85. (m) Kucukdisli,
M.; Opatz, T. Eur. J. Org. Chem. 2012, 4555.
(4) (a) Cheeseman, G. W. H.; Eccleshall, S. A.; Thornton, T. J.
Heterocycl. Chem. 1985, 809. (b) Ohier, P.; Daïch, A.; Decroix, B.
Tetrahedron 1996, 52, 13547. (c) Mamane, V.; Hannen, P.; Furstner,
̈
8-(4-Nitrophenyl)-6-phenylindolizine-3-carbaldehyde (12).
Yellow solid, mp 218.3−218.5 °C (9.4 mg, 62%); 1H NMR (400
MHz, CDCl3) δ 10.05 (s, 1H) 9.81 (s, 1H), 8.40 (d, J = 8.4 Hz, 2H),
7.87 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 7.6 Hz, 2H), 7.53−7.49 (m, 4H),
7.43 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 4.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 178.1, 147.9, 144.4, 137.1, 136.8, 130.4, 129.6, 129.4,
128.7, 128.4, 127.8, 127.2, 126.0, 125.4, 125.2, 124.4, 103.0; HRMS
(ESI-QTOF) calcd for C21H15N2O3 343.1077 ([M + H]+), found
343.1077.
A. Chem.Eur. J. 2004, 10, 4556. (d) Kim, M.; Vedejs, E. J. Org.
Chem. 2004, 69, 6945. (e) Virieux, D.; Guillouzic, A.-F.; Cristau, H.-J.
Tetrahedron 2006, 62, 3710. (f) Chai, D. I.; Lautens, M. J. Org. Chem.
2009, 74, 3054. (g) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2010, 12, 2068. (h) Zhu, H.; Stockigt, J.; Yu, Y.; Zou, H. Org.
̈
Lett. 2011, 13, 2792.
(5) (a) Kim, I.; Choi, J.; Won, H. K.; Lee, G. H. Tetrahedron Lett.
2007, 48, 6863. (b) Kim, I.; Won, H. K.; Choi, J.; Lee, G. H.
Tetrahedron 2007, 63, 12954. (c) Kim, I.; Kim, S. G.; Kim, J. Y.; Lee,
G. H. Tetrahedron Lett. 2007, 48, 8976. (d) Choi, J.; Lee, G. H.; Kim, I.
Synlett 2008, 1243. (e) Kim, I.; Choi, J.; Lee, S.; Lee, G. H. Synlett
2008, 2334. (f) Kim, K.; Kim, I. J. Comb. Chem. 2010, 12, 379.
(g) Kim, I.; Kim, K. Org. Lett. 2010, 12, 2500. (h) Cho, H.; Kim, I.
Tetrahedron 2012, 68, 5464. (i) Jung, Y.; Kim, I. Tetrahedron 2012, 68,
8198.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 4−12. This material is
available free of charge via the Internet at http://pubs.acs.org.
(6) For recent papers on cycloaromatization-based synthesis of
(hetero)aromatic cycles, see: (a) García-García, P.; Fernandez-
́
Rodríguez, M.; Aguilar, E. Angew. Chem., Int. Ed. 2009, 48, 5534.
(b) Poloukhtine, A.; Rassadin, V.; Kuzmin, A.; Popik, V. V. J. Org.
Chem. 2010, 75, 5953. (c) Kuninobu, Y.; Tatsuzaki, T.; Matsuki, T.;
Takai, K. J. Org. Chem. 2011, 76, 7005. (d) Spencer, W. T.; Frontier, A.
J. J. Org. Chem. 2012, 77, 7730.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ikyonkim@yonsei.ac.kr.
Notes
■
The authors declare no competing financial interest.
(7) For the synthesis of 4, see the Experimental Section.
(8) Nawaz, M.; Adeel, M.; Ibad, M. F.; Langer, P. Synlett 2009, 2154.
(9) One-pot preparation of Suzuki−Miyaura product from 4a was
also examined. Thus, direct Suzuki−Miyaura coupling of the triflate 6c
with 3-cyanophenylboronic acid without further purification was
attempted after the formation of 6c was confirmed by TLC, but the
yield of 7c was inferior to the case with purified 6c.
(10) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(11) For Heck-type coupling of indolizine at the C3 site via C-H
activation, see: Hu, H.; Liu, Y.; Zhong, H.; Zhu, Y.; Wang, C.; Ji, M.
Chem. Asian J. 2012, 7, 884.
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ACKNOWLEDGMENTS
■
This research was supported by Nano·Material Technology
Development Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
Education, Science and Technology (2012M3A7B4049656).
We thank Ms. Kyungsun Kim for carrying out preliminary
experiments of this study.
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