A mild preparation of substituted indolizines and indole from simple aromatic precursors using (trimethylsilyl)diazomethane

Article abstract of DOI:10.1016/j.tetlet.2008.01.067

A mild and convenient synthesis of substituted indolizines from readily available 2-(pyridin-2-yl)acetyl derivatives using (trimethylsilyl)diazomethane is described. The extension of this methodology to the synthesis of indole from 2-aminobenzaldehyde is also reported.

Full text of DOI:10.1016/j.tetlet.2008.01.067

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Tetrahedron Letters 49 (2008) 1768–1770
A mild preparation of substituted indolizines and indole from
simple aromatic precursors using (trimethylsilyl)diazomethane
Liusheng Zhu, Marc Vimolratana, Sean P. Brown, Julio C. Medina *
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, United States
Received 24 October 2007; revised 5 January 2008; accepted 14 January 2008
Available online 19 January 2008
Abstract
A mild and convenient synthesis of substituted indolizines from readily available 2-(pyridin-2-yl)acetyl derivatives using (trimethyl-
silyl)diazomethane is described. The extension of this methodology to the synthesis of indole from 2-aminobenzaldehyde is also reported.
Ó 2008 Elsevier Ltd. All rights reserved.
The indolizine ring system is an important heterocycle
commonly used by medicinal chemists in their drug-design
efforts. Indolizine-derived compounds have been reported
to be L-type calcium channel blockers,1 leukotriene synthe-
sis inhibitors,2 histamine H3 receptor antagonists,3 5-HT1A
receptor ligands,4 and phosphodiesterase V inhibitors5
(Fig. 1).
The synthesis of indolizine compounds has recently been
reviewed.6 Currently, several condensation reactions, 1,3-
dipolar cycloadditions, and 1,5-dipolar cyclizations are
known to facilitate the formation of these heterocycles.6,7
Perhaps the most widely utilized method is the Tschitschi-
babin synthesis, in which a quaternary pyridinium halide,
resulting from the reaction of a 2-substituted pyridine with
an a-halo carbonyl compound, undergoes intramolecular
condensation to deliver an indolizine product.8 Unfortu-
nately, many classical methods for indolizine con-
struction, such as the Tschitschibabin reaction, require ele-
vated temperatures and/or extended reaction times and,
thus, may not be compatible with some functionality. In
this Letter, we report a mild synthesis of substituted indoli-
zines (2) from readily available 2-(pyridin-2-yl)acetyl
derivatives (1) using (trimethylsilyl)diazomethane (Scheme
1). Addition of the lithium salt of (trimethylsilyl)diazo-
methane to ketones and aldehydes to generate indoles
and cyclopentenes through carbene intermediates has been
previously described.9 However, to our knowledge this
Me
Me
Me
Me
S
Me Me
CO2H
O
N
N
N
Histamine H3 Receptor Antagonist
N
HN
O
N
N
NC
Leukotriene Synthesis Inhibitor
Me
N
MeO
5-HT1A Receptor Ligand
O
O
S
N
O
Me
N
O
Me
Me
N
O
OMe
N
N
O
OMe
L-Type Calcium Channel Blocker
O
TMSCHN2
(1.2 equiv)
N
O
N
PDE5A Inhibitor
R3
R1
R3
R1
Fig. 1.
R2
R2
1
2
*
Corresponding author. Tel.: +1 650 244 2425; fax: +1 650 244 2015.
Scheme 1.
E-mail address: medinaj@amgen.com (J. C. Medina).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.067

L. Zhu et al. / Tetrahedron Letters 49 (2008) 1768–1770
1769
Table 2
Substituents tolerability
Letter represents the first report of the addition of (trimethyl-
silyl)diazomethane to carbonyl compounds to generate
indolizines.
TMSCHN2
(1.2 equiv)
N
O
N
R3
R1
R3
Typical reaction conditions involve the treatment of a
0.1 M solution of the 2-(pyridin-2-yl)acetyl substrate
(1 equiv) with (trimethylsilyl)diazomethane (1.2 equiv) at
room temperature in a vial open to air. The effects of sol-
vent on the rate and yield of the reaction were evaluated
using ketoester 3 as a model substrate, and the results are
summarized in Table 1. Aprotic solvents of different polar-
ities, such as CH2Cl2, CH3CN, THF, DMF, and DMSO,
and protic solvents, such as MeOH, EtOH, and i-PrOH,
were examined. In general, the reactions were clean, and
no products other than unreacted starting material were
identified. It was noted that protic solvents were signifi-
cantly preferred over aprotic solvents and that the reaction
was fastest in MeOH. When carried out in EtOH and
i-PrOH, the reaction afforded some transesterified
indolizine byproducts, the yields of which are given in
parentheses below.
R1
R2
R2
Entry
Product
Yielda,b (%)
N
5
67
Me
Ph
N
N
6
7
4
8
9
57
41
84
81
64
N
N
CO2Me
N
MeO
CO2Me
BnO
N
CO2Me
The versatility of the reaction was evaluated using
2-(pyridin-2-yl)acetyl derivatives with modifications at the
pyridyl ring and at the acetyl moiety (Table 2). Substrates
with ester (4, 8, and 9), alkyl (5, 10), aryl (6), and heteroaryl
(7) substituents at R1 afforded indolizine products in mod-
erate to good yields (41–84%).10–12 Compound 10 demon-
strates that alkyl substitution is also tolerated at R2 and
that R2 and R1 can be linked to efficiently furnish a tricyclic
ring system (72%). 2-(Pyridin-2-yl)acetyl derivatives bear-
ing methoxy (8) and benzyloxy (9) substituents on the
pyridyl ring were also smoothly converted to indolizine
products (81% and 64%, respectively), demonstrating
further that substitutions at the pyridyl ring are tolerated.
In fact, the pyridyl moiety can be replaced by quinoline
(11) without significantly affecting the reaction yield
(Scheme 2).
N
10
63
a
Reactions were carried out at 1 mmol substrate in 10 mL of methanol
with 1.2 equiv of TMSCHN2 (2 M in Et2O) at ambient temperature.
b
Yields are for isolated product after a reaction time of 24 h and are
unoptimized.14
TMSCHN2
(1.2 equiv)
N
O
O
N
CO2Et
EtOH
CO2Et
11
NH2
12 (72%)
H
N
TMSCHN2
(4 equiv)
H
MeOH, 60 °C
Cs2CO3
Table 1
Solvent effects
13
14 (53%)
N
O
TMSCHN2
(1.2 equiv)
N
Scheme 2.
CO2Me
CO2Me
3
4
In light of the mild conditions and operational simplicity
of our indolizine synthesis, we sought to extend the
described protocol to the preparation of other heterocycles.
Having noted both the presence and proximity of nucleo-
philic and electrophilic moieties in the 2-(pyridin-2-yl)-
acetyl derivatives discussed above, we hypothesized that
similarly disposed bifunctional molecules might also prove
amenable substrates for heterocycle formation. We were,
thus, pleased to discover that 2-aminobenzaldehyde (13),
a bifunctional substrate, could be converted to indole (14,
Scheme 2) in moderate yield. While the rate of indole
formation was slower than that typically observed for the
indolizine derivatives described in this Letter, efficient
conversion was achieved at 60 °C using 4 equiv of
Solvent
% Yielda,b of 4
0.5 h
2 h
6 h
24 h
CH2Cl2
CH3CN
THF
DMF
DMSO
MeOH
EtOH
i-PrOH
a
0
1
0
0
0
2
1
4
0
93
0
2
2
6
0
92
0
10
2
6
0
94
46(44)
83(11)
0
94
11(22)
8(2)
34(34)
19(4)
37(41)
47(9)
Reactions were carried out at 0.3 mmol substrate in 5 mL solvent with
1.2 equiv of TMSCHN2 (2 M in Et2O) at ambient temperature.
Yields are based on reverse-phase HPLC analysis compared to an
analytical sample.
b

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L. Zhu et al. / Tetrahedron Letters 49 (2008) 1768–1770
10. Substrate 5 (1-pyridin-2-yl-propan-2-one) was purchased from Chem-
Bridge Corp., San Diego, CA, USA. Substrates 10 (2-(2-pyridin-
yl)cyclohexanone) and 11 (2-oxo-3-quinolin-2-yl-propionic acid ethyl
ester) was purchased from Ryan Scientific Inc., Isle of Palms, SC,
USA.
(trimethylsilyl)diazomethane and 2 equiv of Cs2CO3 as an
alkaline additive.13 The utility of this method for the syn-
thesis of functionalized indoles is currently under investiga-
tion and will be reported in due course.
In conclusion, we have developed a mild and convenient
method for the synthesis of substituted indolizines from
readily available 2-(pyridin-2-yl)acetyl derivatives using
(trimethylsilyl)diazomethane in moderate to good yields
(41–84%). We have further demonstrated that this reaction
can be applied to the synthesis of indole from 2-amino-
benzaldehyde and are currently evaluating the feasibility
of this synthetic construct for the preparation of substi-
tuted indoles and other heterocycles.
11. Substrate 6 (1-phenyl-2-(pyridin-2-yl)ethanone) was prepared in a
manner similar to: Goldberg, N. N.; Barkley, L. B.; Levine, R. J. Am.
Chem. Soc. 1951, 73, 4301–4303; Substrate
7 (2-(pyridin-2-yl)-
1-(pyridin-4-yl)ethanone) was prepared in a manner similar to:
Goldberg, N. N.; Levine, R. J. Am. Chem. Soc. 1952, 74, 5217–
5219.
12. Typical procedure for the preparation of substrates 4 (methyl 2-oxo-
3-(pyridin-2-yl)propanoate), 8 (methyl 3-(6-methoxypyridin-2-yl)-2-
oxopropanoate), and 9 (methyl 3-(6-(benzyloxy)pyridin-2-yl)-2-oxo-
propanoate): Lithium diisopropylamide (33.5 mL of 1.5 M in
heptane/tetrahydronfuran/ethylbenzene, 50.2 mmol) was added
dropwise at À78 °C under nitrogen to a solution of 2-picoline
(2.33 g, 25.1 mmol) in THF (100 mL). The mixture was stirred for
15 min and methyl 2,2,2-trimethoxyacetate (4.56 g, 27.6 mmol) was
added in 5 mL of THF. The mixture was stirred at À78 °C for 60 min.
The mixture was then allowed to warm to room temperature and stir
for another 60 min. The mixture was poured into 1 M HCl (200 mL)
and stirred at room temperature for 45 min. The reaction mixture was
neutralized with saturated NaHCO3 solution and extracted with Et2O
(200 mL). The organic phase was washed with brine and dried over
anhydrous MgSO4. After removal of solvent, the residue was purified
by flash chromatography (silica gel, 1:3 EtOAc/hexane) to obtain
3.67 g of substrate 4, 82%. Substrates 8 and 9 were obtained in 58%
and 37%, respectively.
References and notes
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2-indolizinecarboxamides and related compounds as central nervous
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13. Procedure for the synthesis of indole (14) from 2-aminobenzaldehyde:
To
a homogeneous solution of 2-aminobenzaldehyde (0.200 g,
5. Orme, M. W.; Sawyer, J. S.; Schultze, L. M. Preparation of
1.65 mmol) and cesium carbonate (1.08 g, 3.30 mmol) in MeOH
(8.5 mL) was added (trimethylsilyl)diazomethane (2.0 M in ether,
3.30 mL, 6.60 mmol) dropwise over 10 min at 60 °C. The mixture was
stirred for 30 min at 60 °C, cooled to room temperature, quenched
with saturated aqueous NH4Cl, and diluted with EtOAc. The
organics were washed with water and brine, dried (MgSO4), and
concentrated. The crude product was purified by silica gel flash
chromatography (0–15% EtOAc/hexane) to afford indole (0.102 g,
53%) as a crystalline solid. Spectroscopic properties of the synthetic
material matched those of an authentic sample.
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14. Procedure for the synthesis of methyl indolizine-2-carboxylate (4) from
methyl 2-oxo-3-(pyridin-2-yl)propanoate. Trimethylsilyldiazomethane
(2.0 M in diethyl ether, 0.6 mL, 1.2 mmol) was added slowly to a
solution of methyl 2-oxo-3-(pyridin-2-yl)propanoate (0.179 g, 1.0 mmol)
in methanol (10 mL). The reaction was stirred at room temperature
for 24 h. The solvent was removed under reduced pressure and the
residue purified by flash column chromatography (silica gel, 1:2
EtOAc/hexane) to afford 4 as a white solid (0.147 g, 84%). 1H NMR,
MS, and CHN-analysis were consistent with the structure, mp:
96–97 °C (recrystallized from 10% v/v EtOAc/hexane, uncorrected;
lit. 99–100 °C from hexane).