Synthesis of 2-aryl-1-hydroxyazaindoles and 2-arylazaindoles via oxidation of o-hydroxyaminostyrylpyridines

Article abstract of DOI:10.1055/s-2003-40884

2-Aryl-1-hydroxyazaindoles (pyrrolopyridin-1-ols) are prepared via an oxidation/cyclization of o-hydroxyaminostyrylpyridines with DDQ. Reduction of the N-OH bond affords the corresponding 2-arylazaindoles (1H-pyrrolopyridines). The scope of the cyclization is explored via (i) the condensation of 4-methyl-3-nitropyridine with various aryl aldehydes to afford 2-aryl substituted 6-azaindoles and, (ii) the synthesis of 2-phenyl-4-, 5- and 7-azaindoles.

Full text of DOI:10.1055/s-2003-40884

PAPER
1671
Synthesis of 2-Aryl-1-hydroxyazaindoles and 2-Arylazaindoles via Oxidation
of o-Hydroxyaminostyrylpyridines
S
ynthesis of 2-Ary
a
l
Substitute
n
d 4-, 5-, 6,
a
i
nd 7-A
e
zaindoles l Kuzmich,* Carol Mulrooney
Boehringer-Ingelheim Pharmaceuticals, Inc., Department of Medicinal Chemistry, Ridgefield, Connecticut 06877-0368, USA
Fax +1(203)7916072; E-mail: dkuzmich@rdg.boehringer-ingelheim.com
Received 22 May 2003
flux, surprisingly, gave a mixture of aniline 2 and 4-
Abstract: 2-Aryl-1-hydroxyazaindoles (pyrrolopyridin-1-ols) are
bromo-2-phenyl-6-azaindole (3) in 27% and 30% yield,
respectively (Scheme 1). On the contrary, reduction of the
desbromo compound 4a gave aniline 5 in 84% yield and
prepared via an oxidation/cyclization of o-hydroxyaminostyrylpy-
ridines with DDQ. Reduction of the N–OH bond affords the corre-
sponding 2-arylazaindoles (1H-pyrrolopyridines). The scope of the
cyclization is explored via (i) the condensation of 4-methyl-3-nitro- the formation of 2-phenyl-6-azaindole (6a) was not ob-
pyridine with various aryl aldehydes to afford 2-aryl substituted 6-
azaindoles and, (ii) the synthesis of 2-phenyl-4-, 5- and 7-azain-
doles.
served. Although, the difference in reactivity between 1
and 4a is intriguing, it was clear that optimization of re-
ductive conditions in favor of azaindole formation would
be highly substrate dependent. Thus, we considered the
Key words: azaindoles, 1N-hydroxy azaindoles, cyclization, oxi-
dation, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), pyrrol-
mechanism of cyclization.
opyridines
The reduction of nitro compounds to amines is presumed
to proceed through intermediate stages involving first
conversion to the nitroso compound followed by forma-
The indole ring system is a common substructure of many
tion of the hydroxylamine.10 Initially, we considered that
natural products and pharmaceutical agents and various
the hydroxylamine intermediate cyclized to afford azain-
methods have been developed for the synthesis of in-
dole 3 in a Michael type addition. It is known that 2- and
doles.1 A structure-activity relationship (SAR) study of an
4-vinylpyridines can undergo conjugate addition reac-
indole pharmacophore often involves the preparation of
tions with amines and hydroxylamines.11 Intramolecular
synthetically challenging substituted azaindoles.2 For ex-
addition of an intermediate o-arylhydroxylamine to a vi-
nylpyridine followed by proton transfer, loss of water and
tautomerization could account for azaindole 3.
ample, the deoxygenation of 2-nitrostilbene in the pres-
ence of triethyl phosphite affords 2-phenylindole in 58%
yield;3 similar treatment of 3-nitro-4-[(E)-phenylethe-
Alternatively, it is known that arylnitroso compounds can
cyclize to afford 1-hydroxyindoles which can be reduced
to the corresponding indoles. Hazard has reported a one-
pot procedure for the preparation of 1-hydroxyindoles via
an electrochemical reduction of o-nitrostyrenes to the cor-
responding hydroxylamines followed by an anodic oxida-
tion in situ presumably to afford the arylnitroso
compounds which cyclizes to the nitrones and then rear-
ranges to the corresponding 1-hydroxyindoles.12 Makosza
has also reported the base-catalyzed cyclization of , -
disubstituted o-nitroarylethanes to 2,3-disubstituted 1-hy-
droxindoles and has proposed that the cyclization occurs
via a nitroso intermediate.7 To identify which of these two
cyclization precursors were responsible for azaindole for-
mation we prepared the corresponding arylhydroxylamine
of nitropyridine 1 (Scheme 2).
nyl]pyridine (4a) affords 2-phenyl-6-azaindole (6a) in
only 14% yield.4 Recently, acetylenic aminopyridines
have proven useful for the synthesis of substituted azain-
doles.5 We now report the oxidation/cyclization of o-hy-
droxyaminostyrylpyridines with DDQ to afford 2-aryl
substituted 1-hydroxyazaindoles6 which can be readily re-
duced to the corresponding azaindoles.7
Our work in this area began with the observation shown in
Scheme 1.
Treatment of 3-bromo-5-nitro-4[(E)-2-phenylethenyl]py-
ridine (1)8,9 with iron filings in acetic acid–ethanol at re-
Ph
Ph
R
N
R
NH2
R
NO2
a
Ph
+
N
H
Ph
Ph
Br
N
N
2 R=Br (27%)
5 R=H (84%)
3
R=Br (30%)
1
R=Br
H
6a R=H (0%)
4a R=H
N
N
Br
Br
NO2
a
OH
Ph
+
N
Scheme 1 Reagents and conditions: (a) Fe, HOAc–EtOH,
N
N
OH
7 (77%)
8 (17%)
1
Synthesis 2003, No. 11, Print: 05 08 2003.
Art Id.1437-210X,E;2003,0,11,1671,1678,ftx,en;C03503SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Reagents and conditions: (a) SnCl2·2H2O, NaOAc·3H2O,
THF–MeOH, 0 °C

1672
D. Kuzmich, C. Mulrooney
PAPER
A
partial reduction of
1
with SnCl2·2H2O and acid–ethanol at reflux gave 2-aryl substituted 6-azain-
NaOAc·3H2O in THF–MeOH at 0 °C gave arylhydroxyl- doles 6a–f in good to excellent yields (Table 1). For the
amine 7 and 4-bromo-1-hydroxy-2-phenyl-6-azaindole oxidation/cyclization step, the addition of HOAc resulted
(8) in 77% and 17% yield, respectively.13
in a substantial improvement in yield while use of excess
DDQ resulted in lower yields. Also of interest, entry 9d
cyclized to 10d upon stirring in MeCN–H2O for 36 hours,
presumably, via autoxidation of 9d to the corresponding
nitroso compound.15 Finally, the hydroxyazaindoles 10a–
f and the corresponding azaindoles 6a–f have quite similar
1H and 13C NMR spectra, however, a significant upfield
shift is noted for the H-3 proton and the C-3 carbon in the
oxygenated compounds.6
Formation of 1-hydroxyazaindole 8 suggests that the cy-
clization occurs via nitroso compound 1a (Scheme 3).
Thus, reduction of 1 affords nitroso intermediate 1a which
cyclizes to 1b followed by rearrangement to 1-hy-
droxyazaindole 8. Treatment of 8 with iron in acetic acid
at reflux gave 3 in 98% yield. Furthermore, a proton NMR
revealed a mixture of azaindoles 3 and 8 if the iron reduc-
tion of 1 was interrupted before completion.
Application of this methodology to the synthesis of 2-phe-
nyl-4-azaindole (14), 2-phenyl-5-azaindole (18) and 2-
We then concluded that compounds of type 7, if treated
with a suitable oxidant, could afford the indole nucleus.
Except for the aforementioned electrochemical process to
prepare 1-hydroxy-2-phenylindole reported by Hazard 30
years ago, there are no known examples of a chemical ox-
idation of either o-hydroxyaminostilbenes to afford in-
doles or o-hydroxyaminostyrylpyridines to afford
azaindoles.12 To explore this transformation 9a 10a we
optimized conditions for the preparation of arylhydroxyl-
amine 9a. Thus, condensation of 4-methyl-3-nitropyri-
dine with benzaldehyde using catalytic piperidine in
methanol at reflux gave trans-olefin 4a in 66% yield.9a
Reduction of the nitro group using SnCl2·2H2O and
NaOAc·3H2O in MeOH–THF at 0 °C gave arylhydroxyl-
amine 9a in 93% yield. Formation of 1-hydroxy-2-phe-
nyl-6-azaindole (10a) was not observed here, which is
consistent with our earlier observation (Scheme 1, 4a
5).
phenyl-7-azaindole
(21)
has
been
successful
(Schemes 4, 5 and 6). Styrylpyridine 11 was prepared by
known methods.16 Stannous chloride reduction of 11 gave
hydroxylamine 12 in 98% yield. Oxidation of 12 with
DDQ furnished 1-hydroxy-2-phenyl-4-azaindole (13) in
93% yield and reduction of 13 afforded 2-phenyl-4-azain-
dole (14) in 75% yield.
Ph
Ph
N
H
NO2
N
a
b
OH
N
N
Ph
N
R
12 (98%)
11
13 R = OH (93%)
14 R = H (75%)
c
Scheme 4 Synthesis of 2-phenyl-4-azaindole. Reagents and condi-
tions: (a) SnCl2·2H2O, NaOAc·3H2O, THF–MeOH, 0 °C (b) DDQ,
MeCN–H2O–HOAc, 0 °C (c) Fe, HOAc–EtOH,
There are a number of reagents known to oxidize arylhy-
droxylamines to nitroso compounds, however many of
these same oxidants are known to cause the decomposi-
tion of 1-hydroxyindoles.10,14 In our hands oxidations with
FeCl3, MnO2, DEAD, CAN, and CrO2 gave complex mix-
tures of 1-hydroxyazaindoles and azaindoles in poor to
moderate yields. To our knowledge DDQ has not been re-
ported to convert arylhydroxylamines to arylnitroso com-
pounds, however, it proved to be very useful for the
conversion of pyridylhydroxylamine 9a to 1-hydroxyaza-
indole 10a (Table 1).
A synthesis of 2-phenyl-5-azaindole (18) began with
styrylpyridine 15 which was prepared from commercially
available 3-methyl-4-nitropyridine N-oxide by known
methods.17 Reduction of 15 gave the hydroxylamine 16
which was shown to exist as a mixture of tautomers by 1H
NMR (DMSO-d6) spectroscopy. Fortunately, the major
tautomer could be characterized by 1H NMR spectroscopy
in CD3CO2D. Treatment of 16 with DDQ gave an insepa-
rable 2:1 mixture of 1-hydroxyazaindole 17 and azaindole
18 in 75% yield as shown by 1H NMR spectroscopy. Re-
duction of the mixture gave 2-phenyl-5-azaindole18 (18)
in 60% overall yield from 16.
The scope of the cyclization was explored by treatment of
hydroxylamines 9b–f with DDQ (1 equiv) in MeCN–
H2O–HOAc to afford the corresponding 1-hydroxyazain-
doles 10b–f in good to excellent yields. Subsequent, re-
duction of the N–OH bond using iron filings in acetic
Ph
Ph
Br
Br
H
N
N
Br
NO2
N
-H+
Br
+H+
Fe
O
Ph
N
N
Ph
N
OH
N
OH
1a
1b
8
Scheme 3 Proposed mechanism: cyclization occurs via the nitroso intermediate 1a
Synthesis 2003, No. 11, 1671–1678 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aryl Substituted 4-, 5-, 6, and 7-Azaindoles
1673
Table 1 Preparation of 2-Aryl-6-azaindolesa
R
R
H
N
N
N
NO2
b
c
a
OH
R
N
R
N
N
OH
10a-f
H
N
9a-f
6a-f
4a-f
Entry
R
Yield (%)
Yield (%)
Yield (%)
9
10
6
4a
93
83
92
91
97
94
85
80
99
4b
4c
4d
F3C
Br
91
96
85
OCH3
H3CO
4e
4f
90
85
88
93
98
97
S
O
a Reagents and conditions: (a) SnCl2·2H2O, NaOAc·3H2O, THF–MeOH, 0 °C (b) DDQ, MeCN–H2O–HOAc, 0 °C (c) Fe, HOAc–EtOH,
Ph
Ph
In conclusion, we have described a general method for
preparing 2-aryl substituted 4-, 5-, 6-, and 7-azaindoles
via an oxidation/cyclization of o-hydroxyaminostyrylpy-
ridines with DDQ. The cyclization provides access to 1-
hydroxyazaindoles compounds for which there are few
synthetic methods known. Extension of this methodology
to other heterocycles and indoles is under investigation.
N
H
NO2
N
a
b
OH
Ph
N
R
N
N
16 (97%)
15
17 R = OH
18 R = H (60% from 16)
c
Scheme 5 Synthesis of 2-phenyl-5-azaindole. Reagents and condi-
tions: (a) SnCl2·2H2O, NaOAc·3H2O, THF–MeOH, 0 °C (b) DDQ,
MeCN–H2O–HOAc, 0 °C (c) Fe, HOAc–EtOH,
Melting points (uncorrected) were measured with a Büchi 510 ap-
paratus. NMR spectra were recorded using a Bruker 400 spectrom-
eter in ppm from internal CHCl3, DMSO or HOAc on the scale
and coupling constants J are given in Hz. Column chromatography
was carried out on silica gel (70–230 mesh, E. Merck). Low resolu-
tion mass spectra were recorded using a Finnigan-SSQ7000 or a
Micromass platform LCZ instrument. IR spectra were recorded on
a Nicolet Impact 410 spectrometer.
Finally, 2-phenyl-7-azaindole4,19 (21) was prepared from
styrylpyridine 19.20 Reduction of 19 gave hydroxylamine
20 in 64% yield. Treatment of 20 with DDQ afforded 1-
hydroxy-2-phenyl-7-azaindole which was reduced with-
out purification to afford 21 in good yield (51% from 20).
4-Methyl-3-nitropyridine and 3-methyl-4-nitropyridine 1-oxide
were obtained from Lancaster. o-Nitrostyrylpyridines 4a, 4d, 4e
and 11 are known compounds. Compounds 1, 4b, 4c were prepared
according to literature procedures by reaction of 4-methyl-3-nitro-
pyridine with the appropriate aldehyde and 0.5 equivalent of piperi-
dine in MeOH at reflux or in Ac2O (for 4f) at reflux. Compound 15
was obtained from 3-methyl-4-nitropyridine 1-oxide via condensa-
tion with benzaldehyde followed by deoxygenation with PCl3 in
CH2Cl2. Compound 19 was prepared from 3-hydroxy-2-nitropyri-
dine via conversion to its triflate derivative followed by a Suzuki
coupling with trans-4-vinylphenylboronic acid. The analytical and
spectral data of the starting materials synthesized are given below.
Ph
Ph
H
N
NO2
a
b,c
OH
Ph
N
N
H
N
N
19
20 (64%)
21 (51% from 20)
Scheme 6 Synthesis of 2-phenyl-7-azaindole. Reagents and condi-
tions: (a) SnCl2·2H2O, NaOAc·3H2O, THF–MeOH, 0 °C (b) DDQ,
MeCN–H2O–HOAc, 0 °C (c) Fe, HOAc–EtOH,
Synthesis 2003, No. 11, 1671–1678 © Thieme Stuttgart · New York

1674
D. Kuzmich, C. Mulrooney
PAPER
3-Bromo-5-nitro-4-[(E)-2-phenylethenyl]pyridine (1)
4-[(E)-2-(3-Furyl)ethenyl]-3-nitropyridine (4f)
Yield: 80%; mp 74–78 °C.
Yield: 22%; mp 77–79 °C.
1H NMR (400 MHz, CDCl3): = 8.95 (s, 1 H), 8.92 (s, 1 H), 7.55
(m, 2 H), 7.46–7.38 (m, 3 H), 7.12 (d, J = 16.6 Hz, 1 H, C=CH),
6.98 (d, J = 16.6 Hz, 1 H, C=CH).
1H NMR (400 MHz, CDCl3): = 9.19 (s, 1 H), 8.75 (d, J = 5.3 Hz,
1 H), 7.71 (s, 1 H), 7.67 (d, J = 5.3 Hz, 1 H), 7.51 (s, 1 H), 7.39 (d,
J = 16.0 Hz, 1 H), 7.30 (d, J = 16.0 Hz, 1 H), 6.75 (s, 1 H).
13C NMR (100 MHz, CDCl3): = 155.0 (d), 143.4 (d), 139.9 (s),
139.4 (d), 129.7 (d), 128.9 (d), 127.3 (d), 122.4 (s), 119.6 (d), one
aromatic singlet was not resolved.
13C NMR (100 MHz, DMSO-d6): = 153.4, 146.2, 145.44, 144.9,
144.0, 139.7, 128.7, 124.1, 121.2, 119.9, 108.1.
3-Nitro-2-[(E)-2-phenylethenyl]pyridine (11)
3-Nitro-4-[(E)-2-phenylethenyl]pyridine (4a)
Yield: 35%; mp 104–106 °C (Lit.16 mp 107–108 °C).
Yield: 67%; mp 111–113 °C (Lit.9a mp 114–116 °C).
1H NMR (400 MHz, CDCl3): = 8.83 (dd, J = 4.5, 1.4 Hz, 1 H),
8.27 (dd, J = 8.3 Hz, 1 H), 8.09 (d, J = 15.5 Hz, 1 H), 7.78 (d,
J = 15.5 Hz, 1 H), 7.66 (m, 2 H), 7.45–7.33 (m, 4 H).
1H NMR (400 MHz, DMSO-d6): = 9.14 (s, 1 H), 8.82 (d, J = 5.3
Hz, 1 H), 8.02 (d, J = 5.3 Hz, 1 H), 7.67 (m, 3 H), 7.54 (d, J = 16.3
Hz, 1 H), 7.47–7.38 (m, 3 H).
4-Nitro-3-[(E)-2-phenylethenyl]pyridine (15)
3-Nitro-4-{[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}pyridine
2-Steps from 3-methyl-4-nitropyridine 1-oxide; overall yield: 44%.
(4b)
Mp 84–85 °C.
Yield: 24%; mp 102–104 °C.
1H NMR (400 MHz, CDCl3): = 9.12 (s, 1 H), 8.73 (d, J = 5.4 Hz,
1 H), 7.77 (d, J = 5.3 Hz, 1 H), 7.57 (m, 2 H), 7.52 (d, J = 16.3 Hz,
HC=C), 7.39 (m, 3 H), 7.21 (d, J = 16.3 Hz, CH=C).
13C NMR (100 MHz, CDCl3): = 150.7 (d), 149.6 (d), 135.9 (d),
135.8, 129.2 (d), 128.9 (d), 127.3 (d), 126.6, 119.7 (d), 116.7 (d),
one aromatic singlet was not resolved.
1H NMR (400 MHz, CDCl3): = 9.27 (s, 1 H), 8.84 (d, J = 5.3 Hz,
1 H), 7.78 (d, J = 16.2 Hz, 1 H, C=CH), 7.73 (d, coupling obscured
by singlet at 7.72, 1 H), 7.72 (s, 4 H).
13C NMR (100 MHz, CDCl3): = 153.8 (d), 146.9 (d), 144.1 (s),
2
140.2 (s), 139.2 (s), 136.3 (d), 131.7 (q, JCF = 32 Hz), 128.2 (d),
124.3 (q, 1JCF = 270 Hz), 123.8 (d), 121.6 (d).
MS: m/z (%) = 295 (MH+, 100).
2-Nitro-3-[(E)-2-phenylethenyl]pyridine (19)
Mp 76–77 °C.
Anal. Calcd for C14H9F3N2O2: C, 57.15; H, 3.08; N, 9.52. Found: C,
56.89; H, 3.24; N, 9.42.
1H NMR (400 MHz, CDCl3): = 8.44 (dd, J = 4.5, 1.3 Hz, 1 H),
8.22 (dd, J = 7.9, 0.8 Hz, 1 H), 7.59 (dd, J = 7.9, 4.5 Hz, 1 H), 7.53
(m, 2 H), 7.41–7.32 (m, 4 H), 7.16 (d, J = 16.2 Hz, CH=C).
4-[(E)-2-(4-Bromophenyl)ethenyl]-3-nitropyridine (4c)
Yield: 53%; mp 115–119 °C.
13C NMR (100 MHz, CDCl3): = 146.9 (d), 137.1 (d), 135.9 (d),
135.7 (s), 129.2 (d), 128.9 (d), 127.8 (d), 127.2 (d), 126.9 (s), 119.9
(d), one aromatic singlet was not resolved.
1H NMR (400 MHz, CDCl3): = 9.23 (s, 1 H), 8.80 (d, J = 5.3 Hz,
1 H), 7.71 (d, J = 4.7 Hz, 1 H), 7.68 (d, J = 15.4 Hz, 1 H), 7.59 (d,
J = 8.4 Hz, 2 H), 7.48 (d, J = 8.4 Hz, 2 H), 7.29 (d, J = 16.1 Hz, 1
H).
13C NMR (100 MHz, CDCl3): = 153.6 (d), 146.9 (d), 144.0 (s),
140.4 (s), 136.9 (d), 134.8 (s), 132.6 (d), 129.4 (d), 124.4 (s), 121.7
(d), 121.4 (d).
Reduction of 1 with Iron Filings; 5-Bromo-4-[(E)-2-phenylethe-
nyl]pyridin-3-ylamine (2) and 4-Bromo-2-phenyl-1H-pyrro-
lo[2,3-c]pyridine (3); Typical Procedure
A mixture of 1 (305 mg, 1.0 mmol) and iron filings (336 mg, 6.0
mmol) in HOAc (5 mL) was refluxed for 40 min. The mixture was
diluted with EtOAc (20 mL) and made basic with sat. aq NaHCO3
(50 mL). The aqueous layer was separated and extracted with
EtOAc (3 × 10 mL). The aqueous layer was filtered and extracted
again with EtOAc (2 × 20 mL). The combined organic layers were
washed with sat. aq NaHCO3 (2 × 20 mL), brine (2 × 20 mL), dried
(Na2SO4), filtered and concentrated in vacuo. The residue was ad-
sorbed onto silica gel and chromatographed on silica gel using
MeOH–CH2Cl2 (0:100, then 0.5:99.5, then 2:98) to afford 110 mg
of 2 which was recrystallized from Et2O–hexane to afford 75 mg
(27%) of aniline 2 and 81 mg (30%) of azaindole 3.
4-[(E)-2-(2,4-Dimethoxyphenyl)ethenyl]-3-nitropyridine (4d)
Yield: 56%; mp 85–86 °C (Lit.9b mp 98–99 °C).
1H NMR (400 MHz, CDCl3): = 9.16 (s, 1 H), 8.71 (d, J = 5.4 Hz,
1 H) 7.75 (d, J = 5.0 Hz, 1 H), 7.72 (d, J = 15.6 Hz, 1 H, C=CH),
7.62 (d, J = 16.2 Hz, 1 H, C=CH), 7.60 (d, J = 8.6 Hz, 1 H), 6.60
(dd, J = 8.6, 2.2 Hz, 1 H), 6.52 (d, J = 2.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): = 162.9, 159.6, 153.0, 146.8, 144.0,
141.6, 133.5, 129.5, 120.9, 118.3, 118.1, 105.9, 98.9, 56.0, 55.9.
3-Nitro-4-[(E)-2-(2-thienyl)ethenyl]pyridine (4e)
Yield: 84%; mp 103–105 °C (Lit.4 mp 108–109 °C).
2
Mp 86–88 °C.
1H NMR (400 MHz, CDCl3): = 9.21 (s, 1 H), 8.75 (d, J = 5.3 Hz,
1 H), 7.68 (d, J = 5.3 Hz, 1 H), 7.54 (d, J = 15.9 Hz, 1 H, C=CH),
7.50 (d, J = 16.1 Hz, 1 H, C=CH), 7.44 (d, J = 5.0 Hz, 1 H), 7.31 (d,
coupling obscured by CDCl3 peak, 1 H), 7.12 (dd, J = 4.9, 3.9 Hz,
1 H).
1H NMR (400 MHz, DMSO-d6): = 7.99 (s, 1 H), 7.89 (s, 1 H), 7.61
(d, J = 7.4 Hz, 1 H), 7.38 (dt, J = 7.1 Hz, 2 H), 7.31 (dt, J = 7.4 Hz,
1 H), 7.12 (d, J = 16.7 Hz, 1 H), 7.01 (d, J = 16.7 Hz, 1 H), 5.68 (s,
2 H, NH2).
13C (100 MHz, DMSO-d6): = 144.2 (s), 138.9 (d), 137.0 (d), 136.9
(s), 136.2 (d), 129.1 (d), 128.8 (d), 127.3 (d), 126.9 (s), 123.0 (d),
121.6 (s).
13C NMR (100 MHz, CDCl3): = 153.3 (d), 147.0 (d), 143.8 (s),
141.3 (s), 140.3 (s), 131.1 (d), 130.0 (d), 128.5 (d), 128.4 (d), 120.8
(d), 119.7 (d).
MS: m/z (%) = 275/277 (MH+, 100/85).
MS: m/z (%) = 295 (MH+, 100).
Synthesis 2003, No. 11, 1671–1678 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aryl Substituted 4-, 5-, 6, and 7-Azaindoles
1675
3
N-{4-[(E)-2-Phenylethenyl]pyridin-3-yl}hydroxylamine (9a)
Mp 234–238 °C (dec.).
Yellow solid; mp 158–162 °C.
1H NMR (400 MHz, DMSO-d6): = 12.4 (s, 1 H, NH), 8.70 (s, 1
H), 8.21 (s, 1 H), 7.98 (d, J = 7.2 Hz, 2 H), 7.51 (m, 2 H), 7.42 (m,
1 H), 6.96 (s, 1 H, H-3).
13C NMR (100 MHz, DMSO-d6): = 142.9 (s), 139.2 (d), 134.7 (s),
133.9 (s), 133.6 (d), 131.0 (s), 129.5 (d), 126.5 (d), 111.4 (s), 98.2
(d), one aromatic doublet was obscured.
1H NMR (400 MHz, DMSO-d6): = 8.67 (s, 1 H, D2O exchange-
able), 8.53 (d, J = 1.8 Hz, 1 H), 8.38 (s, 1 H, D2O exchangeable),
8.01 (d, J = 5.0 Hz, 1 H), 7.67 (d, J = 7.2 Hz, 2 H), 7.45 (d, J = 5.1
Hz, 1 H), 7.38 (m, 2 H), 7.31–7.29 (m, 3 H).
13C NMR (100 MHz, DMSO-d6): = 144.1 (s), 141.4 (d), 137.2 (s),
136.8 (d), 132.4 (d), 129.1 (d), 128.7 (d), 127.4 (d), 121.9 (d), 118.6
(d), one aromatic singlet was not resolved.
MS: m/z (%) = 273/275 (MH+, 100/97).
MS: m/z (%) = 213 (MH+, 100).
4-[(E)-2-Phenylethenyl]pyridin-3-ylamine (5)
Mp 185–188 °C.
N-(4-{(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl}pyridine-3-
yl)hydroxylamine (9b)
Mp 143–146 °C.
1H NMR (400 MHz, CDCl3): = 8.14 (s, 1 H), 8.07 (d, J = 4.9 Hz,
1 H), 7.55 (d, J = 7.4 Hz, 2 H), 7.41 (t, J = 7.2 Hz, 2 H), 7.34 (t,
J = 7.3 Hz, 1 H), 7.25 (1 H, partially obscured by CDCl3), 7.18 (d,
J = 16.2 Hz, 1 H), 7.08 (d, J = 16.2 Hz, 1 H), 3.83 (br s, 2 H, NH2).
1H NMR (400 MHz, DMSO-d6): = 8.79 (s, 1 H, D2O exchange-
able), 8.63 (s, 1 H, D2O, exchangeable), 8.43 (s, 1 H), 8.05 (d,
J = 5.1 Hz, 1 H), 7.86 (d, J = 8.2 Hz, 2 H), 7.77 (d, J = 8.3 Hz, 2 H),
7.52 (d, J = 4.9 Hz, 1 H), 7.49 (d, coupling obscured by doublet at
7.52, 2 H), 7.42 (d, J = 16.2 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): = 144.8 (s), 141.7 (s), 141.6 (d),
137.2 (d), 131.2 (d), 128.9, 128.3 (d), 126.4 (d), 125.1 (d), 123.8,
119.4 (d), one peak was not resolved.
MS: m/z (%) = 197 (MH+, 100).
Stannous Chloride Reduction of Nitrostyrylpyridines 1, 4a–f,
11, 15 and 19; N-{4-[(E)-2-(4-Bromophenyl)ethenyl]pyridin-3-
yl}hydroxylamine (9c); Typical Procedure
To a solution of 4c (1.0 g, 3.28 mmol) in THF–MeOH (1:1, 80 mL)
cooled to 0 °C was added NaOAc·3H2O (4.5 g, 33.08 mmol) fol-
lowed by SnCl2·2H2O (3.7 g, 16.44 mmol). The reaction was mon-
itored by TLC (MeOH–CH2Cl2, 5:95). After 5 h, the mixture was
poured into ice cold sat. aq NaHCO3 (pH 9), and extracted with
EtOAc (3 × 80 mL). The combined organic layers were washed with
sat. aq NaHCO3 (2 × 80 mL), brine (3 × 80 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo to afford 963 mg of crude hydrox-
ylamine 9c, which was triturated with Et2O to give 885 mg (92%)
of 9c as a yellow solid; mp 153–155 °C (dec.).
1H NMR (400 MHz, DMSO-d6): = 8.70 (br s, 1 H), 8.58 (d, J = 1.5
Hz, 1 H), 8.41 (s, 1 H), 8.03 (d, J = 5.0 Hz, 1 H), 7.60 (s, 4 H), 7.47
(d, J = 5.0 Hz, 1 H), 7.36 (d, J = 16.3 Hz, 1 H), 7.30 (d, J = 16.2 Hz,
1 H).
MS: m/z (%) = 281 (MH+, 100).
N-{4-[(E)-2-(2,4-Dimethoxyphenyl)ethenyl]pyridin-3-yl}hy-
droxylamine (9d)
Mp 121–125 °C.
1H NMR (400 MHz, DMSO-d6): = 8.60 (s, 1 H, D2O exchange-
able), 8.50 (s, 1 H, D2O exchangeable), 8.38 (s, 1 H), 8.00 (d, J = 5.1
Hz, 1 H), 7.66 (d, J = 9.2 Hz, 1 H), 7.41 (d, J = 16.3 Hz, 1 H), 7.36
(d, J = 5.1 Hz, 1 H), 7.12 (d, J = 16.3 Hz, 1 H), 6.60 (m, 2 H), 3.86
(s, 3 H, OCH3), 3.82 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): = 161.8 (s), 158.8 (s), 144.3 (s),
141.8 (d), 136.9 (d), 130.7 (s), 128.6 (d), 127.1 (d), 119.9 (d), 118.9
(s), 118.8 (d), 106.7 (d), 99.1 (d), 56.5 (q), 56.2 (q).
13C NMR (100 MHz, DMSO-d6): = 144.6 (d), 141.8 (s), 137.3 (d),
136.9 (s), 132.5 (d), 131.5 (d), 129.7 (d), 129.2 (s), 123.2 (d), 122.1
(s), 119.2 (d).
MS: m/z (%) = 271 (MH+, 100).
N-{4-[(E)-2-(2-Thienyl)ethenyl]pyridin-3-yl}hydroxylamine
(9e)
MS: m/z (%) = 291/293 (MH+, 100).
Mp 131–134 °C.
N-{5-Bromo-4-[(E)-2-phenylethenyl]pyridin-3-yl}hydroxyl-
1H NMR (400 MHz, DMSO-d6): = 8.69 (s, 1 H, D2O exchange-
able), 8.49 (br s, 1 H, D2O exchangeable), 8.40 (s, 1 H), 8.01 (d,
J = 5.0 Hz, 1 H), 7.54 (d, J = 4.5 Hz, 1 H), 7.51 (d, J = 15.8 Hz, 1
H), 7.43 (d, J = 5.0 Hz, 1 H), 7.29 (d, J = 3.3 Hz, 1 H), 7.09 (dd,
J = 4.8, 3.7 Hz, 1 H), 7.02 (d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): = 144.3 (s), 142.9 (s), 141.9 (d),
137.2 (d), 129.5 (s), 128.9 (d), 128.6 (d), 127.4 (d), 126.1 (d), 121.5
(d), 119.0 (d).
amine (7)
Mp 125–129 °C (dec.).
1H NMR (400 MHz, DMSO-d6): = 8.78 (s, 1 H, D2O exchange-
able), 8.67 (br s, 1 H, D2O exchangeable), 8.38 (s, 1 H), 8.19 (s, 1
H), 7.60–7.58 (d, 2 H), 7.40 (t, 2 H), 7.34 (d, J = 7.2 Hz, 1 H), 7.13
(d, J = 16.8 Hz, 1 H, CH=C), 7.00 (d, J = 16.7 Hz, 1 H, CH=C).
MS: m/z (%) = 291/293 (MH+, 100).
MS: m/z (%) = 219 (MH+, 10), 203 (100), 201 (40).
4-Bromo-2-phenyl-1H-pyrrolo[2,3-c]pyridin-1-ol (8)
Mp 230–233 °C (dec.).
N-{4-[(E)-2-(3-Furyl)ethenyl]pyridin-3-yl}hydroxylamine (9f)
Mp 136–139 °C.
1H NMR (400 MHz, DMSO-d6): = 11.99 (s, 1 H, D2O exchange-
able), 8.78 (s, 1 H), 8.27 (s, 1 H), 7.96 (d, 2 H, J = 7.1 Hz), 7.55–
7.51 (m, 3 H), 6.68 (s, 1 H, H-3).
13C NMR (100 MHz, DMSO-d6): = 141.2 (s), 139.4 (d), 132.5 (s),
131.6 (d), 129.7 (d), 129.6 (s), 129.3 (d), 128.9 (d), 127.8 (s), 111.7
(s), 95.5 (d).
1H NMR (400 MHz, DMSO-d6): = 8.56 (s, 1 H), 8.55 (s, 1 H), 8.38
(s, 1 H), 7.99 (d, J = 5.0 Hz, 1 H), 7.88 (s, 1 H), 7.71 (s, 1 H), 7.38
(d, J = 5.0 Hz, 1 H), 7.20 (d, J = 16.1 Hz, 1 H), 7.01 (d, J = 16.1 Hz,
1 H), 6.89 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): = 145.2 (d), 144.2 (s), 143.2 (d),
141.9 (d), 137.6 (d), 129.8 (s), 125.3 (s), 123.0 (d), 121.8 (d), 118.8
(d), 108.6 (d).
MS: m/z (%) = 289/291 (MH+, 100).
Synthesis 2003, No. 11, 1671–1678 © Thieme Stuttgart · New York

1676
D. Kuzmich, C. Mulrooney
PAPER
N-{2-[(E)-2-Phenylethenyl]pyridin-3-yl}hydroxylamine (12)
2-Phenyl-1H-pyrrolo[2,3-c]pyridin-1-ol (10a)
Mp 159–162 °C.
Mp 172–175 °C (dec.).
1H NMR (400 MHz, DMSO-d6): = 8.80 (s, 1 H), 8.53 (s, 1 H), 8.02
(d, J = 4.4 Hz, 1 H), 7.66 (d, J = 7.7 Hz, 2 H), 7.62 (d, J = 15.6 Hz,
1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 14.5 Hz, 1 H), 7.40 (dd,
J = 7.3, 7.3 Hz, 2 H), 7.30 (t, J = 7.3 Hz, 1 H), 7.17 (d, J = 8.1, 4.5
Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): = 11.79 (br s, 1 H), 8.75 (br, 1
H), 8.12 (br, 1 H), 7.91 (d, J = 7.1 Hz, 2 H), 7.53–7.40 (m, 4 H),
6.69 (s, 1 H, H-3).
MS: m/z (%) = 211 (MH+, 100).
13C NMR (100 MHz, DMSO-d6): = 145.8 (s), 140.8 (d), 140.4 (s),
137.9 (s), 131.8 (d), 129.6 (d), 128.8 (d), 127.9 (d), 123.8 (d), 123.5
(d), 121.0 (d).
2-(4-Trifluoromethylphenyl)-1H-pyrrolo[2,3-c]pyridin-1-ol
(10b)
Mp 192–198 °C (dec.).
MS: m/z (%) = 213 (MH+, 5), 197 (100), 195 (50).
1H NMR (400 MHz, DMSO-d6): = 12.01 (br, 1 H), 8.81 (br, 1 H),
8.13 (d, J = 8.2 Hz, 3 H), 7.85 (d, J = 8.3 Hz, 2 H), 7.52 (br, 1 H),
6.83 (s, 1 H, H-3).
N-{3-[(E)-2-Phenylethenyl]pyridin-4-yl}hydroxylamine (16)
Yellow oil.
MS: m/z (%) = 278 (M+, 34), 262 (100).
1H NMR (400 MHz, CD3CO2D, major tautomer): = 9.06 (br, par-
tially CD3CO2D exchanged), 8.51 (br, partially CD3CO2D ex-
changed), 8.37 (s, 1 H), 8.24 (d, J = 7.0 Hz, 1 H) 7.66 (d, J = 7.2 Hz,
1 H), 7.60 (d, J = 7.3 Hz, 2 H), 7.48–7.31 (m, 5 H), 7.19 (d, J = 16.0
Hz, 1 H), 7.02 (d, J = 16.1 Hz, 1 H).
2-(2,4-Dimethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-1-ol (10d)
Mp 95–100 °C.
1H NMR (400 MHz, DMSO-d6): = 11.18 (br s, 1 H, OH), 8.72 (s,
1 H), 8.10 (d, J = 5.4 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.47 (d,
J = 5.4 Hz, 1 H), 6.73 (d, J = 2.0 Hz, 1 H), 6.68 (dd, J = 8.5, 2.1 Hz,
1 H), 6.46 (s, 1 H), 3.86 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): = 162.2 (s), 159.4 (s), 138.7 (d),
138.3 (s), 133.0 (d), 132.2 (d), 127.9 (s), 115.0 (d), 111.9 (s), 105.9
(d), 99.6 (d), 97.8 (d), 56.5 (q), 56.3 (q), one aromatic doublet was
not resolved.
N-{3-[(E)-2-Phenylethenyl]pyridin-2-yl}hydroxylamine (20)
Orange solid; mp 141–146 °C (dec.).
1H NMR (400 MHz, CD3CO2D, single tautomer): = 8.11 (d,
J = 7.3 Hz, 1 H), 8.00 (d, J = 6.1 Hz, 1 H), 7.59 (d, J = 7.3 Hz, 2 H),
7.40–7.31 (m, 3 H), 7.23 (d, J = 16.0 Hz, CH=C), 7.06 (d, J = 16.0
Hz, 1 H), 7.00 (t, J = 6.9 Hz, 1 H).
13C NMR (100 MHz, CD3CO2D): = 151.26 (s), 137.85 (d), 135.96
(s), 135.25 (d), 133.39 (d), 128.93 (d), 128.70 (d), 127.17 (d),
121.46 (s), 117.25 (d), 113.79 (d).
2-(2-Thienyl)-1H-pyrrolo[2,3-c]pyridin-1-ol (10e)
Mp 190–195 °C.
1H NMR (400 MHz, DMSO-d6): = 12.04 (br, 1 H), 8.72 (s, 1 H),
8.10 (d, J = 5.4 Hz, 1 H), 7.82 (d, J = 3.6 Hz, 1 H), 7.73 (d, J = 5.0
Hz, 1 H), 7.47 (d, J = 5.4 Hz, 1 H), 7.23 (dd, J = 4.9, 3.8 Hz, 1 H),
6.77 (s, 1H, H-3).
13C NMR (100 MHz, DMSO-d6): = 138.5 (d), 135.5 (s), 132.1 (d),
131.5 (s), 129.0 (d), 128.5 (d), 128.4 (d), 128.0 (s), 115.0 (d), 94.1
(d), one aromatic singlet was not resolved.
MS: m/z (%) = 213 (MH+, 100).
DDQ Oxidation/Cyclization; 2-(4-Bromophenyl)-1H-pyrro-
lo[2,3-c]pyridin-1-ol (10c); Typical Procedure
To a solution of arylhydroxylamine 9c (145 mg, 0.50 mmol) in a
mixture of MeCN–H2O–HOAc (10:2:1, 19.5 mL) cooled to –10 °C
was added DDQ (110 mg, 0.48 mmol) in one portion. The mixture
turned a deep red and the reaction was monitored by TLC (MeOH–
CH2Cl2, 1:9). After 20 min, the yellow reaction mixture was diluted
with 1 N aq HCl (10 mL) and Et2O (20 mL). The acidic aqueous
phase was separated and the organic layer extracted with 1 N aq HCl
(3 × 5 mL). The combined acidic aqueous layers were washed with
1:1 Et2O–hexane (3 × 5 mL), made basic with NaHCO3 and extract-
ed with EtOAc (3 × 15 mL). The combined organic layers were
dried (Na2SO4), filtered and concentrated in vacuo to afford 136 mg
(94%) of 1-hydroxy-6-azaindole 10c as a yellow solid; mp 184–188
°C.
1H NMR (400 MHz, DMSO-d6): = 11.84 (br, 1 H, OH), 8.82 (s, 1
H, H-7), 8.16 (d, J = 5.5 Hz, 1 H, H-5), 7.90 (d, J = 8.5 Hz, 2 H,
ArH), 7.74 (d, J = 8.5 Hz, 2 H, ArH), 7.56 (d, J = 5.5 Hz, 1 H, H-
4), 6.79 (s, 1 H, H-3).
13C NMR (100 MHz, DMSO-d6): = 139.5 (s), 139.1 (d), 132.9 (s),
132.8 (d), 132.6 (d), 130.9 (d), 129.9 (s), 127.8 (s), 123.1 (s), 115.4
(d), 96.7 (d).
MS: m/z (%) = 216 (M+, 60), 200 (100).
2-(3-Furyl)-1H-pyrrolo[2,3-c]pyridin-1-ol (10f)
Mp 194–197 °C.
1H NMR (400 MHz, DMSO-d6): = 11.80 (br s, 1 H), 8.73 (s, 1 H),
8.35 (s, 1 H), 8.10 (d, J = 5.2 Hz, 1 H), 7.85 (s, 1 H), 7.47 (d, J = 5.2
Hz, 1 H), 7.09 (d, J = 1.8 Hz, 1 H), 6.67 (s, 1 H, H-3).
13C NMR (100 MHz, DMSO-d6): = 144.8 (d), 142.2 (d), 138.8 (d),
134.1 (s), 132.1 (d), 128.2 (s), 116.5 (s), 115.1 (d), 110.5 (d), 94.4
(d), one aromatic doublet was not resolved.
MS: m/z (%) = 201 (MH+, 25), 185 (100).
2-Phenyl-1H-pyrrolo[3,2-b]pyridin-1-ol (13)
Mp 194–196 °C (dec.).
1H NMR (400 MHz, DMSO-d6): = 11.48 (s, 1 H, OH), 8.36 (dd,
J = 4.5, 1.1 Hz, 1 H), 7.93 (d, J = 7.2 Hz, 2 H), 7.83 (d, J = 8.2 Hz,
1 H), 7.52 (td, J = 7.5, 7.3 Hz, 2 H), 7.43 (td, J = 7.3, 7.3 Hz, 1 H),
7.18 (dd, J = 8.1, 4.6 Hz, 1 H), 6.79 (s, 1 H, H-3).
13C NMR (100 MHz, DMSO-d6): = 143.7 (d), 141.2 (s), 140.4 (s),
130.6 (s), 129.1 (d), 128.9 (d), 128.6 (d), 117.3 (d), 116.5 (d), 97.3
(d), one aromatic singlet was not resolved.
MS: m/z (%) = 291/289 (MH+, 42/42), 274 (100), 272 (88), 194
(50).
Anal. Calcd for C13H9BrN2O: C, 54.00; H, 3.14; N, 9.69. Found: C,
53.85; H, 3.02; N, 9.45.
MS: m/z (%) = 211 (MH+, 20), 209 (32), 195 (100).
Synthesis 2003, No. 11, 1671–1678 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aryl Substituted 4-, 5-, 6, and 7-Azaindoles
1677
Iron Reduction of 1-Hydroxyazaindoles; 2-(4-Bromophenyl)-
1H-pyrrolo[2,3-c]pyridine (6c); Typical Procedure
2-(3-Furyl)-1H-pyrrolo[2,3-c]pyridine (6f)
Mp 218–220 °C.
A mixture of hydroxyindole 10c (52 mg, 0.180 mmol) and iron fil-
ings (200 mg, 3.58 mmol) was refluxed in HOAc–EtOH (1:2, 12
mL). The reaction was monitored by TLC in MeOH–CH2Cl2 (5:95)
for disappearance of the yellow starting material to afford a slightly
less polar product, which has a blue fluorescence under UV light.
After 45 min, the excess iron was removed with a magnetic bar.
The mixture was made basic with sat. aq NaHCO3 (25 mL) and ex-
tracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with sat. aq NaHCO3 (20 mL), brine (3 × 20 mL), dried
(Na2SO4), filtered, and concentrated in vacuo to afford the crude
product in quantative yield; mp 264–266 °C. Chromatography on
silica gel using MeOH–CH2Cl2 (1:9, then 2:98, then 3:97, then 4:96,
then 5:95, then 6:94) gave 40.1 mg (81%); mp 264–266 °C.
1H NMR (400 MHz, DMSO-d6): = 11.88 (br s, 1 H, NH), 8.70 (s,
1 H), 8.28 (s, 1 H), 8.07 (d, J = 5.4 MHz, 1 H), 7.82 (br s, 1 H), 7.47
(d, J = 5.4 Hz, 1 H), 7.05 (br s, 1 H), 6.73 (s, 1 H).
2-Phenyl-1H-pyrrolo[3,2-b]pyridine (14)
Mp 235–242 °C (Lit.4 mp 255–256 °C).
1H NMR (400 MHz, DMSO-d6): = 11.80 (s, 1 H, NH), 8.31 (d,
J = 4.1 Hz, 1 H), 7.93 (d, J = 7.6 Hz, 2 H), 7.75 (d, J = 8.1 Hz, 1 H),
7.50 (m, 2 H), 7.38 (m, 1 H), 7.10 (dd, J = 8.1, 4.6 Hz, 1 H), 7.06 (s,
1 H, H-3).
2-Phenyl-1H-pyrrolo[3,2-c]pyridine (18)4
Mp 271–274 °C (dec.) (Lit.19 mp 274–276 °C).
1H NMR (400 MHz, DMSO-d6): = 12.13 (br s, 1 H), 8.76 (s, 1 H,
H-7), 8.10 (d, J = 5.5 Hz, 1 H, H-5), 7.90 (d, J = 8.5 Hz, 2 H), 7.73
(d, J = 8.5 Hz, 2 H), 7.53 (d, J = 5.5 Hz, 1 H, H-4), 7.03 (s, 1 H, H-
3).
1H NMR (400 MHz, DMSO-d6): = 11.97 (s, 1 H, NH), 8.82 (s, 1
H), 8.17 (d, J = 5.5 Hz, 1 H), 7.90 (d, J = 7.8 Hz, 2 H), 7.49 (t,
J = 7.4 Hz, 2 H), 7.38 (m, 2 H), 7.05 (s, 1H, H-3).
13C NMR (100 MHz, DMSO-d6): = 143.8 (d), 141.3 (d), 141.2 (s),
139.7 (s), 132.3 (s), 129.9 (d), 129.0 (d), 126.6 (s), 126.2 (d), 107.5
(d), 98.5 (d).
13C NMR (100 MHz, DMSO-d6): = 141.0 (s), 139.1 (d), 135.2 (d),
133.6 (s), 132.9 (d), 131.4 (s), 128.6 (d), 122.6 (s), 115.4 (d), 99.4
(d).
MS: m/z (%) = 194 (M+, 100).
MS: m/z (%) = 273/275 (MH+, 100/100).
2-Phenyl-1H-pyrrolo[2,3-b]pyridine (21)19
2-Phenyl-1H-pyrrolo[2,3-c]pyridine (6a)
Mp 195–198 °C (Lit.4 mp 204–205 °C).
Mp 222–224 °C (Lit.4 mp 223–225 °C).
1H NMR (400 MHz, DMSO-d6): = 12.20 (br s, 1 H, NH), 8.19 (dd,
J = 4.7, 1.57 Hz, 1 H), 7.93–7.90 (m, 3 H), 7.45 (‘t’, J = 7.7 Hz, 2
H), 7.33 (t, J = 7.4 Hz, 1 H), 7.04 (dd, J = 7.8, 4.68 Hz, 1 H), 6.91
(d, J = 2.1 Hz, H-3).
1H NMR (400 MHz, DMSO-d6): = 12.03 (s, 1 H, NH), 8.76 (s, 1
H), 8.10 (d, J = 5.3 Hz, 1 H), 7.94 (d, J = 7.6 Hz, 2 H), 7.51 (m, 3
H), 7.41 (m, 1 H), 6.98 (s, 1 H, H-3).
2-(4-Trifluoromethylphenyl)-1H-pyrrolo[2,3-c]pyridine (6c)
Mp 239–242 °C.
Acknowledgement
1H NMR (400 MHz, DMSO-d6): = 12.23 (s, 1 H), 8.80 (s, 1 H),
8.16 (d, J = 8.2 Hz, 2 H), 8.13 (d, J = 5.5 Hz, 1 H), 7.88 (d, J = 8.3
Hz, 2 H), 7.56 (d, J = 5.4 Hz, 1 H), 7.15 (s, 1 H, H-3).
The authors wish to thank Ed Harris for recording mass spectra and
Scott Campbell for NMR support.
13C NMR (100 MHz, DMSO-d6): = 140.3 (s), 139.2 (d), 136.0 (s),
2
135.5 (d), 129.9 (q, JCF = 31 Hz), 127.2 (d), 126.8 (d), 125.0 (q,
References
1JCF = 270 Hz), 100.6 (d), one aromatic doublet and one aromatic
(1) (a) Sunberg, R. J. The Chemistry of Indoles; Academic
Press: New York, 1970. (b) Pindur, U.; Adam, R. J.
Heterocycl. Chem. 1988, 25, 1.
singlet was not resolved.
MS: m/z (%) = 263 (MH+, 100).
(2) (a) Wilette, R. E. Adv. Heterocycl. Chem. 1968, 9, 27.
(b) Yakhontov, L. N. Russ. Chem. Rev. 1968, 37, 551.
(c) Yakhontov, L. N.; Prokopov, A. A. Russ. Chem. Rev.
1980, 49, 428. (d) Greenhill, J. V. In Comprehensive
Heterocyclic Chemistry, Vol. 4; Katritzky, A. R.; Rees, C.
W.; Bird, C. W.; Cheeseman, G. W. H., Eds.; Pergamon:
Oxford, 1984, 497.
2-(2,4-Dimethoxyphenyl)-1H-pyrrolo[2,3-c]pyridine (6d)
Yield: 85%; mp 142–145 °C (Lit.9b mp 150–152 °C).
1H NMR (400 MHz, DMSO-d6): = 11.51 (br s, 1 H, NH), 8.73 (s,
1 H), 8.05 (d, J = 5.4 Hz, 1 H), 7.78 (d, J = 8.6 Hz, 1 H), 7.45 (d,
J = 5.4 Hz, 1 H), 6.85 (s, 1 H), 6.74 (d, J = 2.2 Hz, 1 H), 6.69 (dd,
J = 8.6, 2.3 Hz, 1 H), 3.95 (s, 3H, OCH3), 3.85 (s, 3H, OCH3).
13C NMR (100 MHz, DMSO-d6): = 161.4 (s), 158.2 (s), 139.3 (s),
138.1 (d), 134.2 (d), 132.9 (s), 129.9 (d), 112.9 (s), 106.3 (d), 99.5
(d), 56.2 (q), 55.9 (q), two aromatic doublets and one aromatic sin-
glet was not resolved.
(3) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.;
Searle, R. J. G. J. Chem. Soc. 1965, 4831.
(4) Fisher, M. H.; Schwartzkopf, G. Jr.; Hoff, D. R. J. Med.
Chem. 1972, 15, 1168.
(5) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B.
Tetrahedron Lett. 1998, 39, 5159.
MS: m/z (%) 254 (M+, 100), 253 (68).
(6) For a review of 1-hydroxyindoles, see: Acheson, R. M.
Advan. Heterocycl. Chem. 1990, 51, 119.
2-(2-Thienyl)-1H-pyrrolo[2,3-c]pyridine (6e)
Mp 208–211 °C (dec.) (Lit.4 mp 235–236 °C).
(7) Wrobel, Z.; Makosza, M. Tetrahedron 1997, 53, 5501.
(8) For a synthesis of 3-bromo-5-nitro-4-methylpyridine, see:
Prokopov, A. A.; Yakhontov, L. N. Khim. Geterotsikl.
Soedin. 1979, 15, 86; Chem. Heterocycl. Compd. (Engl.
Transl.) 1979, 15: 76.
1H NMR (400 MHz, DMSO-d6): = 12.08 (s, 1 H), 8.71 (s, 1 H),
8.09 (d, J = 5.4 Hz, 1 H), 7.65 (m, 2 H), 7.48 (d, J = 5.4 Hz, 1 H),
7.20 (dd, J = 4.0, 4.6 Hz, 1 H), 6.75 (s, 1 H, H-3).
13C NMR (100 MHz, DMSO-d6): = 139.1 (d), 136.9 (s), 135.2 (s),
134.7 (d), 133.7 (s), 129.2 (d), 127.7 (d), 126.2 (d), 98.7 (d), one ar-
omatic doublet and one aromatic singlet was not resolved.
(9) For condensation conditions, see Ref. 4 and: (a) Herz, W.;
Murty, D. R. K. J. Org. Chem. 1961, 26, 418.
(b) Barraclough, P.; Beams, R. M.; Black, J. W.; Cambridge,
D.; Collard, D.; Demaine, D. A.; Firmin, D.; Gerskowitch,
MS: m/z (%) = 201 (M+, 100).
Synthesis 2003, No. 11, 1671–1678 © Thieme Stuttgart · New York

1678
D. Kuzmich, C. Mulrooney
PAPER
V. P.; Glen, R. C.; Giles, H.; Hill, A. P.; Hull, R. A. D.; Iyer,
R.; King, W. R.; Livingstone, D. J.; Nobbs, M. S.; Randall,
P.; Shah, G.; Vine, S. J.; Whiting, M. V. Eur. J. Med. Chem.
1990, 25, 467; Chem. Abstr. 1991, 114, 17097.
(16) (a) Hooper, M.; Patterson, D. A.; Wibberley, D. G. J. Pharm.
Pharmacol. 1965, 17, 734. (b) Alternatively, 2-methyl-3-
nitropyridine was prepared from 2-chloro-3-nitropyridine in
66% yield via displacement of the chloride with the sodium
salt of diethyl malonate in DMF at 0 °C followed by
hydrolysis and decarboxylation in 6 N aq HCl for 4 h at
reflux
(17) (a) For condensation, see: Jerchel, D.; Heck, H. E. Liebigs
Ann. Chem. 1958, 613, 171. (b) Followed by Essaery, J. M.;
Schofield, K. J. Chem. Soc. 1960, 4953.
(18) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.;
Cottrell, I. F.; Wright, S. H. B. Synthesis 1996, 877.
(19) Davis, M. L.; Wakefield, B. J.; Wardell, J. A. Tetrahedron
1992, 48, 939.
(20) (a) Compound 19 was prepared from 3-hydroxy-2-
nitropyridine via formation of the triflate followed by a
Suzuki coupling with trans-4-vinylphenylboronic acid
(b) For a general procedure, see: Friesen, R. W.; Brideau, C.;
Chan, C. C.; Charleson, S.; Deschenes, D.; Dube, D.; Ethier,
D.; Rortin, R.; Gauthier, J. Y.; Gordon, R.; Greig, G. M.;
Riendeau, D.; Savoie, C.; Wang, Z.; Wong, E.; Visco, D.;
Xu, L. J.; Young, R. Bioorg. Med. Chem. Lett. 1998, 8, 2777.
(10) Entwistle, I. D.; Gilkerson, T. Tetrahedron 1978, 34, 213.
(11) (a) Doering, W. E.; Weil, R. A. N. J. Am. Chem. Soc. 1947,
69, 2461. (b) Cliffe, I. A.; Ifill, A. D.; Mansell, H. L.; Todd,
R. S.; White, A. C. Tetrahedron Lett. 1991, 32, 6789.
(12) Hazard, R.; Tallec, A. Bull. Soc. Chim.Fr. 1974, 121.
(13) (a) Walkser, A.; Zenchoff, G.; Fryer, R. I. J. Med. Chem.
1976, 19, 1378. (b) We found compounds 9a–f, 12, and 16
to be sensitive to strong base (for example: K2CO3/MeOH or
NaOH). During work-up our reaction was made basic with
sat. aq NaHCO3 rather than 1 N aq NaOH as described by the
authors
(14) (a) Taylor, E. C.; Yoneda, F. J. Chem. Soc., Chem. Commun.
1967, 199. (b) Coleman, G. H.; McCloskey, C. M.; Stuart, F.
A. Org. Synth. Coll. Vol. 3; Wiley: New York, 1955, 668.
(15) Ogata, Y.; Sawaki, Y.; Mibae, J.; Morimoto, T. J. Am. Chem.
Soc. 1964, 86, 3854.
Synthesis 2003, No. 11, 1671–1678 © Thieme Stuttgart · New York