The Hemetsberger-Knittel synthesis of substituted 5-, 6-, and 7-azaindoles

Article abstract of DOI:10.1055/s-2005-872165

A series of substituted 5-, 6-, and 7-azaindoles were prepared via the Hemetsberger-Knittel reaction. In general, better yields were obtained at higher temperatures and shorter reaction times than required for the formation of the analogous indoles, and in some cases, only decomposition occurred below a minimum temperature. The resulting templates offer up to five sites for subsequent functionalization to allow a wide range of chemical diversity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872165

PAPER
2751
The Hemetsberger–Knittel Synthesis of Substituted 5-, 6-, and 7-Azaindoles
S
ynthesis of
S
a
ubstitute
d
5
t
-, 6-,
a
r
nd 7-Aza
i
indole
c
s
k J. Roy,* Claude Dufresne, Nicolas Lachance, Jean-Philippe Leclerc, Michel Boisvert, Zhaoyin Wang,
Yves Leblanc
Merck Frosst Centre for Therapeutic Research, C.P. 1005, Pointe Claire-Dorval, Québec H9R 4P8, Canada
Fax +1(514)4284900; E-mail: patrick_roy@merck.com
Received 3 May 2005
Therefore we were interested in studying the generality of
this reaction for the preparation of a series of substituted
5-, 6-, and 7-azaindoles.
Abstract: A series of substituted 5-, 6-, and 7-azaindoles were pre-
pared via the Hemetsberger–Knittel reaction. In general, better
yields were obtained at higher temperatures and shorter reaction
times than required for the formation of the analogous indoles, and
in some cases, only decomposition occurred below a minimum tem-
perature. The resulting templates offer up to five sites for subse-
quent functionalization to allow a wide range of chemical diversity.
The synthesis began with the preparation of the inter-
mediate 2-azido-3-pyridineacrylates 7 as shown in
Scheme 1. The corresponding pyridine carboxaldehydes 6
were prepared using known procedures6 or were commer-
cially available (6a, 6b). The methyl ether 6c and methyl
thioether 6d were prepared by treating 6a with NaOMe or
NaSMe, respectively.7 Treatment of 6e with NaOMe in
MeOH at room temperature gave 6f. Methylsulfone 7g
was obtained by MMPP oxidation of 7d in 73% yield.
Key words: Hemetsberger–Knittel reaction, azaindoles, thermoly-
sis, cyclization, template
Indoles are very important heterocycles omnipresent in a
large variety of natural products and pharmaceuticals, and
their synthesis is well documented.1 Lately, more atten-
tion has been paid to their isosteric analogues, the aza-
indoles.2 Recently, during the course of a medicinal
chemistry investigation, we sought to gain rapid access to
functionalized azaindole templates 1–3 (Figure 1) shown
below as replacements of the indole nucleus.
R2
R2
N3
CO2Me
CHO
CO2Me
N3
NaOMe–MeOH
N
N
55–83%
R1
R1
6
7
6a R1 = H, R2 = Cl
6b R1 = H, R2 = Br
6c R1 = H, R2 = OMe
6d R1 = H, R2 = SMe
6e R1, R2 = Cl
7d R1 = H, R2 = SMe
MMPP
7g R1 = H, R2 = SO2Me
Target molecules
NaOMe
MeOH
R
R
R
N
6f R1 = Cl, R2 = OMe
N
N
Scheme 1 Synthesis of 5-azaindole precursors
N
CO2Me
N
CO2Me
N
CO2Me
H
H
H
1
2
3
Scheme 2 shows the preparation of two alkyl substituted
azidopyridine acrylates via the construction of the pyri-
dine ring 10.8 Keto ester 8 was condensed with NH4OAc
to give enamine 9, which was treated with acrolein and
catalytic piperidine to give the partially saturated pyri-
dine. Oxidation with elemental sulfur then provided pyri-
dine ester 10. Reduction/oxidation gave the aldehyde 11
which was carried through to the azidopyridine acrylate
12.
R = alkyl, Cl, Br, SMe
Figure 1
Although numerous methods exist for the synthesis of 2-
ester substituted indoles, relatively little has been pub-
lished on the analogous azaindoles.3 One such route is the
Hemetsberger–Knittel reaction4 recently employed by
Fresneda and Molina5 (Equation 1) where they effected
thermolysis of the 2-azido-3-pyridine acrylate 4 in xylene
at reflux. To our knowledge, this is the only instance of its
application to the synthesis of azaindoles.
1)
cat. base
2) S8
reflux
R
CHO
NH4OAc
O
O
NH2 O
CO2Et
N
R
OEt
R
OEt
/ i-PrOH
98%
8a R = CF3
8b R = i-Pr
9
10a 26%
10b 17%
OMe
OMe
CO2Et
N3
o-xylene
reflux
R
R
67%
N3
CO2Me
N
N
CO2Et
N
1) LiAlH4
H
CHO
CO2Me
4
5
NaOMe
MeOH
N
N
N3
2) Dess–Martin
quant.
Equation 1 The Hemetsberger–Knittel reaction
12a 50%
12b 75%
11
SYNTHESIS 2005, No. 16, pp 2751–2757
Advanced online publication: 12.08.2005
x
x.
x
x
.
2
0
0
5
Scheme 2 Alkyl-substituted 5-azaindole precursors
DOI: 10.1055/s-2005-872165; Art ID: M03305SS
© Georg Thieme Verlag Stuttgart · New York

2752
P. J. Roy et al.
PAPER
The preparation of two precursors for the synthesis of 6- insertion to give the 6-azaindole nucleus. For instance, in
azaindoles is shown in Scheme 3.9 Yields for all steps the case of the SMe containing precursor 16, clean forma-
were lower compared to those for the analogous reactions tion of the intermediate aziridine 38 was noted by NMR at
in Scheme 1.
approximately 110 °C (see Equation 2). However, when
the solution of 38 was heated to 140 °C no azaindole for-
mation was seen by NMR, only gradual decomposition
with time. Separate experiments with increasingly higher
temperatures indicated that refluxing decalin (191 °C,
procedure C) was required to obtain an acceptable yield
(51%) of the desired product. A minimum temperature is
therefore required to effect the desired cyclization of the
intermediate, below which only side reactions occur.
Br
SMe
NaSMe
CHO
CHO
N
N
MeOH
38%
13
14
19% N3
CO2Me
N3
CO2Me 44%
Br
SMe
CO2Me
N3
CO2Me
N3
N
N
SMe
SMe
SMe
15
16
CO2Me
CO2Me
N3
N
N
N
N
38
110 °C
Scheme 3 Synthesis of 6-azaindole precursors
N
CO2Me
16
35 H
Equation 2
The 7-azaindole precursors 17 and 18 were prepared from
4-chloropyridine in a similar fashion to Scheme 3, and for
comparison purposes, the unsubstituted precursors 19–21
were prepared from the commercially available pyridine
carboxaldehydes (see Figure 2).
Standard procedure A was also applied to the synthesis of
two 4-substituted 7-azaindoles (36 and 37) in modest
yields (40% and 56%, respectively).
Our best results were obtained in the synthesis of 5-azain-
doles. Entries 4–12 in Table 1 show the outcomes for sub-
stituted 5-azaindole formation. In general, the thermolysis
reaction appears to proceed smoothly at 160 °C with halo-
gen, ether, thioether, methylsulfone, and alkyl substitu-
ents on the pyridine ring, giving good to very good yields
(66–93%) of the corresponding azaindoles with the ex-
ception of the methoxychloro-substituted entry 12 (32%).
Cl
SMe
CO2Me
CO2Me
N3
N3
N3
N
N
N
17
18
CO2Me
CO2Me
N3
CO2Me
N3
N
N
19
20
21
Also noteworthy is that the thermolysis reaction was tol-
erant of various solvents, and was carried out equally well
in refluxing diglyme, DMF (microwave conditions), and
o-dichlorobenzene. However, the resulting azaindoles are
soluble in these solvents and for ease of isolation on me-
dium scale, mesitylene allowed for a simple crystalliza-
tion and filtration.
Figure 2
The cyclization was initially studied with the unsubstitut-
ed azidopyridine acrylates, the results of which can be
seen in entries 1–3 of Table 1. Heating a solution of 19 in
xylene at 110 °C or 140 °C for 60 minutes led only to the
formation of methyl pyrazolo[1,5-a]pyridine-2-carboxy-
late (22), a known reaction.10 At 110 °C, substrate 20 gave
very little product whereas at 160 °C we obtained selec-
tively the 7-azaindole 23 in modest yield. The para-sub-
stituted substrate 21 gave only decomposition products at
110 °C or 140 °C. These results are not surprising in light
of the fact that the pyridine ring is electron poor with re-
spect to the phenyl analogues which react smoothly in re-
fluxing xylene.4 The electron poor nature of the ring could
therefore hinder insertion of the nitrene into the C–H
bond. Also, in 19 and 21, cyclization onto the position
meta to the ring nitrogen appears to be even further disfa-
vored. These results suggested that the choice of temper-
ature could be critical for the outcome of the thermolysis
reaction, as is further exemplified for the two substrates
leading to 6-azaindoles (entries 13 and 14). In these cases,
no product was obtained using the standard procedure A
(160 °C). Subsequent experiments led us to suspect that
this was below the temperature threshold for the nitrene
In summary, we have demonstrated a facile, general meth-
od for the synthesis of 2-ester substituted 5-, 6-, and 7-aza-
indole templates which offer up to five different sites for
functionalization with the potential to give a wide range of
chemical diversity. It has been shown that the temperature
is critical, and the use of refluxing mesitylene for the ther-
molysis of the azidopyridine acrylates attains or exceeds
the temperature threshold for cyclization for the majority
of the substrates, while also allowing for easy isolation of
the product by filtration.
Flash chromatography was carried out with EM Science Silica gel
60 (230–400 mesh). 1H and 13C NMR spectra were measured on a
Bruker Avance 500 or AMX 500 NMR Spectrometer, with chemi-
cal shifts reported in ppm relative to the residual deuterated solvent.
Analytical analyses were carried out by Prevalere Life Sciences Inc.
in Whitesboro, NY. HRMS analysis was carried out by the Biomed-
ical Mass Spectrometry Unit of McGill University under FAB+
conditions.
Synthesis 2005, No. 16, 2751–2757 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted 5-, 6-, and 7-Azaindoles
2753
Table 1 Thermolysis of 2-Azido-3-pyridine Acrylates
Entry
1
Azidopyridine acrylate
Yield (%)a
Product
Procedure
B
Yield (%)
67
N
CO2Me
CO2Me
CO2Me
52
N
N
22
N3
19
N
2
3
56
7
B
B
25
0
N3
N
23
N
CO2Me
CO2Me
20
H
CO2Me
N
N
N
N
N3
N
21
7a
7b
H
24
Cl
Cl
CO2Me
4
5
63
B
A
A
A
A
B
B
A
A
C
C
72
78
93
84
69
66
75
77
32
44
51
N3
N
H
CO2Me
CO2Me
25
Br
Br
CO2Me
N3
55
N
N
N
N
H
26
OMe
OMe
CO2Me
6
66
N
N
N
N
N
N3
N
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
7c
SMe
27
SMe
CO2Me
7
68
N
N
N
N
N3
N
H
7d
28
SO2Me
SO2Me
CO2Me
8
73 from 7d
N3
N
7g
29
H
CF3
CF3
CO2Me
CO2Me
9
26
53
64
83
19
44
N3
N
H
12a
30
iPr
iPr
10
11
12
13
14
N3
N
H
12b
31
Cl
Cl
N
CO2Me
N3
N
N
Cl
N
CO2Me
CO2Me
Cl
7e
32
H
OMe
OMe
CO2Me
N3
N
Cl
N
N
H
Cl
N
7f
33
Br
Br
CO2Me
N3
N
CO2Me
15
SMe
34
H
SMe
CO2Me
N
N
N3
N
H
CO2Me
16
35
Synthesis 2005, No. 16, 2751–2757 © Thieme Stuttgart · New York

2754
P. J. Roy et al.
PAPER
Table 1 Thermolysis of 2-Azido-3-pyridine Acrylates (continued)
Entry
15
Azidopyridine acrylate
Yield (%)a
41
Product
Procedure
A
Yield (%)
40
Cl
Cl
CO2Me
N3
N
N
CO2Me
CO2Me
N
17
36 H
SMe
SMe
CO2Me
N3
16
60
B
56
N
N
37
N
18
H
a Yields for the conversion of pyridine carboxaldehyde 6 to azidopyridineacrylate 7 with the exception of 7g.
Preparation of Azidopyridine Acrylates; General Procedure
(Figure 3)
Methyl (2Z)-2-Azido-3-(2-chloropyridin-3-yl)acrylate (7a)
Synthesized following the general procedure to give the product as
a pale yellow solid (yield: 63%).
1H NMR (500 MHz, acetone-d6): d = 8.61 (dd, J = 1.8, 7.9 Hz, 1 H),
8.34 (dd, J = 1.8, 4.7 Hz, 1 H), 7.47 (dd, J = 4.7, 7.9 Hz, 1 H), 7.12
(s, 1 H), 3.94 (s, 3 H).
N3
CO2Me
R
R
CHO
H
CO2Me
NaOMe–MeOH
–10 °C to 0 °C
N
N
N3
H
Methyl (2Z)-2-Azido-3-(2 bromopyridin-3-yl)acrylate (7b)
Synthesized following the general procedure to give the product as
a pale yellow solid (yield: 55%).
Figure 3
1H NMR (500 MHz, acetone-d6): d = 8.53 (m, 1 H), 8.31 (m, 1 H),
To a solution of the pyridine carboxaldehyde (41 mmol) and methyl
azidoacetate (9.4 mL, 102 mmol) in MeOH (65 mL) at –10 °C to –
15 °C (internal temperature probe) was added, over 30 min, a 25
weight% solution of NaOMe in MeOH (4.37 M, 23.4 mL, 102
mmol). The addition was (and must be) carried out slowly to allow
the resulting heat (from the exothermic reaction) to dissipate and
maintain the internal temperature at ca –10 °C. When the addition
was completed, the reaction was allowed to warm slowly to 0 °C,
where it was maintained for 2 h. During this time a fine precipitate
(the product) generally started to form and bubbles were often ob-
served. The flask was then fitted with a bubbler and the reaction was
stirred overnight in an ice bath in the cold-room. The suspension
was then poured onto a mixture of ice (ca 200 g) and solid NH4Cl,
stirred until all the ice had melted (pH should be neutral), and the
product was collected by filtration11 and was washed with cold wa-
ter. After vacuum drying, the solid was dissolved in CH2Cl2 and
MgSO4 was added. The suspension was filtered through a small
plug of silica gel, and washed with CH2Cl2. This process ensured
that no NH4Cl or water remained in the product. Removal of solvent
then yielded the desired azidopyridine acrylate.
7.49 (m, 1 H), 7.08 (s, 1 H), 3.94 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 168.03, 154.86, 148.75,
144.32, 135.60, 134.63, 128.19, 125.16, 58.00.
Methyl (2Z)-2-Azido-3-(2-methoxypyridin-3-yl)acrylate (7c)
Synthesized following the general procedure to give the product as
a pale yellow solid (yield: 55%). Note: after stirring overnight at
0 °C the reaction mixture turned into a thick paste.
1H NMR (500 MHz, acetone-d6): d = 8.54 (m, 1 H), 8.13 (m, 1 H),
7.17 (s, 1 H), 7.02 (m, 1 H), 3.95 (s, 3 H), 3.90 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 168.48, 166.24, 152.76,
143.70, 132.13, 122.07, 122.02, 121.32, 58.32, 57.66.
Methyl (2Z)-2-Azido-3-[2-(methylthio)pyridin-3-yl]acrylate
(7d)
Synthesized following the general procedure to give the product as
a pale yellow solid (yield: 68%). Note: after stirring overnight at
0 °C the reaction mixture turned into a thick paste.
1H NMR (500 MHz, acetone-d6): d = 8.40 (m, 1 H), 8.28 (m, 1 H),
7.16 (m, 1 H), 7.02 (s, 1 H), 3.93 (s, 3 H), 2.55 (s, 3 H).
Methyl (2Z)-2-Azido-3-pyridin-3-ylacrylate (20)
Synthesized following the general procedure to give the product as
a pale brown solid (yield: 56%).
1H NMR (500 MHz, acetone-d6): d = 8.91 (d, J = 2.1 Hz, 1 H), 8.52
(dd, J = 1.6, 4.8 Hz, 1 H), 8.39 (m, 1 H), 7.41 (dd, J = 4.8, 8.1 Hz,
1 H), 6.94 (s, 1 H), 3.91 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 164.70, 160.38, 150.76,
138.20, 130.26, 128.30, 120.54, 119.65, 54.38, 14.00.
Methyl (2Z)-2-Azido-3-[2-(methylsulfonyl)pyridin-3-yl]acry-
late (7g)
To a solution of 7d (76 mg, 0.305 mmol) in MeOH (2 mL) and
CH2Cl2 (5 mL) at 0 °C was added MMPP (377 mg, 0.61 mmol). The
mixture was stirred at 0 °C for 1 h, followed by 4 h at r.t. The solvent
was then removed under vacuum, and the residue was partitioned
between EtOAc and sat. Na2CO3 solution. The organic layer was
washed with H2O and brine, and then dried (MgSO4), filtered, and
evaporated. The crude was purified by preparative TLC, eluting
with EtOAc–hexane (2:1) to give the title compound as an off-white
solid (yield: 63 mg, 73%).
13C NMR (500 MHz, acetone-d6): d = 164.82, 153.19, 151.45,
138.10, 130.96, 129.25, 124.99, 122.65, 54.24.
Methyl (2Z)-2-Azido-3-pyridin-4-ylacrylate (21)
Synthesized following the general procedure to give the product as
a pale brown solid (yield: 56%).
1H NMR (500 MHz, acetone-d6): d = 8.61–8.66 (m, 2 H), 7.75–7.80
(m, 2 H), 6.89 (s, 1 H), 3.95 (s, 3 H).
1H NMR (500 MHz, acetone-d6): d = 8.70 (dd, J = 0.88, 8.07 Hz, 1
H), 8.60 (m, 1 H), 7.74 (m, 1 H), 7.70 (s, 1 H), 3.92 (s, 3 H), 3.37 (s,
3 H).
Synthesis 2005, No. 16, 2751–2757 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted 5-, 6-, and 7-Azaindoles
2755
13C NMR (125 MHz, acetone-d6): d = 164.54, 158.01, 149.59,
141.94, 131.56, 128.51, 128.43, 118.03, 54.52, 41.42.
Methyl (2Z)-2-Azido-3-[4-(methylthio)pyridin-3-yl]acrylate
(18)
Synthesized following the general procedure to give the product as
an off-white solid (yield: 60%).
1H NMR (500 MHz, acetone-d6): d = 8.95 (s, 1 H), 8.39 (m, 1 H),
7.31 (m, 1 H), 7.00 (s, 1 H), 3.95 (s, 3 H), 2.60 (s, 3 H).
Methyl (2Z)-2-Azido-3-[2-(trifluoromethyl)pyridin-3-yl]acry-
late (12a)
Synthesized following the general procedure to give the product as
a pale yellow solid (yield: 26%).
1H NMR (500 MHz, acetone-d6): d = 8.67 (d, J = 4.3 Hz, 1 H), 8.63
(d, J = 8.1 Hz, 1 H), 7.77 (dd, J = 4.7, 8.1 Hz, 1 H), 7.14 (d, J = 2.0
Hz, 1 H), 3.97 (s, 3 H).
Small-Scale Thermolysis; Standard Procedure A (Figure 4)
R
R
13C NMR (125 MHz, acetone-d6): d = 163.58, 149.40 145.48 (q, J =
32.4 Hz), 140.34, 131.31, 128.79, 127.44, 123.03 (q, J = 274.8 Hz),
117.33 (d, J = 2.1 Hz), 53.79.
CO2Me
mesitylene
reflux
N
N
N3
H
N
CO2Me
H
Figure 4
Methyl (2Z)-2-Azido-3-(2-isopropylpyridin-3-yl)acrylate (12b)
Prepared according to the general procedure except that the reaction
was stirred for 3.5 h at 0 °C before being poured onto NH4Cl–ice
mixture. The product was then extracted with hexane–EtOAc (1:1),
and the organic layer was dried (Na2SO4), filtered, evaporated, and
co-evaporated with toluene to give the product as a yellow oil
(yield: 53%). The crude material was used as such for the thermo-
lysis.
A 0.1 M solution of the azidopyridine acrylate in mesytilene was
brought to reflux under N2 for 1 h. The solvent was then removed
by bulb-to-bulb distillation, and the azaindole was purified by flash
chromatography, eluting with EtOAc–hexane.
Medium-Scale Thermolysis (> 0.5 g); Standard Procedure B
A 0.1 M solution of the azidopyridine acrylate in mesytilene was
brought to reflux for 1 h, and was then allowed to cool to r.t., and
finally to 0 °C for 1 h. The crystalline product was collected by fil-
tration, and was then stirred overnight with EtOAc–hexane (1:20) to
give the final product.
Methyl (2Z)-2-Azido-3-(2,6-dichloropyridin-3-yl)acrylate (7e)
Synthesized following the general procedure to give the product as
a pale yellow solid (yield: 64%).
1H NMR (500 MHz, acetone-d6): d = 8.69 (d, J = 8.3 Hz, 1 H), 7.56
(d, J = 8.3 Hz, 1 H), 7.06 (s, 1 H), 3.94 (s, 3 H).
Synthesis of 6-Azaindoles; Standard Procedure C
To a refluxing solution of decalin was added the azidopyridine acry-
late (2 g/500 mL). After 10 min at reflux, the mixture was allowed
to cool to r.t., and then to 0 °C. The product was then collected by
filtration and washed with hexane to give the corresponding 6-aza-
indole.
13C NMR (125 MHz, acetone-d6): d = 164.38, 150.86, 150.60,
143.47, 131.79, 128.81, 124.99, 117.81, 54.58.
Methyl (2Z)-2-Azido-3-(6-chloro-2-methoxypyridin-3-yl)acry-
late (7f)
Synthesized following the general procedure to give the product as
a pale yellow solid (yield: 83%).
1H NMR (500 MHz, acetone-d6): d = 8.60 (d, J = 8.6 Hz, 1 H), 7.11
(s, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 3.92 (s, 3 H), 3.91 (s, 3 H).
Methyl 1H-Pyrrolo[2,3-b]pyridine-2-carboxylate (23)
Prepared following the standard thermolysis procedure A to give
the product as an off-white solid (yield: 25%); mp 200–201 °C.
13C NMR (125 MHz, acetone-d6): d = 164.82, 164.81, 149.93,
143.40, 128.59, 122.13, 119.82, 111.17, 55.39, 54.33.
1H NMR (500 MHz, CD3OD): d = 8.38 (m, 1 H), 8.12 (dd, J = 1.5,
8.0 Hz, 1 H), 7.19 (s, 1 H), 7.17 (m, 1 H), 3.94 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 161.44, 148.81, 146.76,
Methyl (2Z)-2-Azido-3-(3-bromopyridin-4-yl)acrylate (15)
Prepared following the general procedure except that the reaction
mixture was stirred at 0 °C for 40 h since little precipitate had
formed after 16 h, and mini-workup/NMR indicated incomplete re-
action. A pale yellow solid was obtained (yield: 19%).
130.78, 127.52, 118.99, 116.84, 106.62, 52.00.
Anal. Calcd for C9H8N2O2: C, 61.36; H, 4.58; N, 15.90. Found: C,
61.33; H, 4.38; N, 15.67.
Methyl 4-Chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (25)
Prepared following the standard thermolysis procedure B to give the
product as an off-white solid (yield: 72%); mp 213–216 °C (dec.).
1H NMR (500 MHz, acetone-d6): d = 8.80 (s, 1 H), 8.60 (m, 1 H),
8.14 (m, 1 H), 7.07 (s, 1 H), 3.98 (s, 3 H).
1H NMR (500 MHz, DMSO-d6): d = 12.77 (s, 1 H), 8.09 (d, J = 5.8
Hz, 1 H), 7.42 (d, J = 5.7 Hz, 1 H), 7.17 (s, 1 H), 3.91 (s, 3 H).
Methyl (2Z)-2-Azido-3-[3-(methylthio)pyridin-4-yl]acrylate
(16)
Synthesized following the general procedure to give the product as
a pale yellow solid (yield: 44%).
1H NMR (500 MHz, acetone-d6): d = 8.61 (s, 1 H), 8.47 (m, 1 H),
7.93 (m, 1 H), 7.18 (s, 1 H), 3.97 (s, 3 H), 2.60 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 161.70, 145.12, 142.71,
142.38, 130.00, 122.95, 108.74, 106.84, 53.17, 40.88, 40.71, 40.55,
40.38, 40.21.
Anal. Calcd for C9H7ClN2O2: C, 51.32; H, 3.35; N, 13.30. Found:
C, 51.14; H, 3.19; N, 13.28.
Methyl (2Z)-2-Azido-3-(4-chloropyridin-3-yl)acrylate (17)
Synthesized following the general procedure to give the product as
a pale yellow solid (yield: 41%).
1H NMR (500 MHz, acetone-d6): d = 9.28 (s, 1 H), 8.47 (d, J = 5.3
Hz, 1 H), 7.54 (d, J = 5.3 Hz, 1 H), 7.09 (s, 1 H), 3.94 (s, 3 H).
Methyl 4-Bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (26)
Prepared following the standard thermolysis procedure A to give
the product as an off-white solid (yield: 78%); mp 197–200 °C
(dec.).
1H NMR (500 MHz, DMSO-d6): d = 12.80 (s, 1 H), 8.05 (d, J = 5.7
Hz, 1 H), 7.44 (d, J = 5.7 Hz, 1 H), 7.06 (s, 1 H), 3.89 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 164.52, 153.32, 151.93,
144.30, 131.01, 129.53, 126.04, 117.81, 54.51.
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13C NMR (125 MHz, DMSO-d6): d = 160.85, 142.32, 140.6,
135.90, 129.04, 124.88, 108.18, 107.24, 52.36.
13C NMR (125 MHz, acetone-d6): d = 162.92, 161.86, 142.98,
141.35, 128.15, 122.37, 107.10, 105.68, 51.77, 33.58, 21.83.
Anal. Calcd for C9H7BrN2O2: C, 42.38; H, 2.77; N, 10.98. Found:
C, 42.77; H, 2.72; N, 10.95.
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.02; H, 6.51; N, 13.11.
Methyl 4-Methoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylate
(27)
Methyl 4,6-Dichloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate
(32)
Prepared following the standard thermolysis procedure A to give
the product as an off-white solid (yield: 93%); mp 172–174 °C
(dec.).
Prepared following the standard thermolysis procedure A to give
the product as an off-white solid (yield: 69%); mp 216–220 °C
(dec.).
1H NMR (500 MHz, acetone-d6): d = 11.32 (br, 1 H, NH), 7.86 (d,
J = 6.0 Hz, 1 H), 7.18 (d, J = 1.2 Hz, 1 H), 7.08 (m, 1 H), 4.01 (s, 3
H), 3.88 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 165.89, 160.67, 144.30,
142.35, 128.51, 113.96, 107.69, 104.30, 54.11, 52.97.
1H NMR (500 MHz, acetone-d6): d = 11.79 (br, 1 H, NH), 7.51 (s,
1 H), 7.22 (s, 1 H), 3.94 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 162.26, 145.13, 144.76,
144.34, 132.31, 124.03, 108.36, 107.85, 53.54.
HRMS (FAB+): m/z calcd for C9H6Cl2N2O2H+: 244.98838; found:
Anal. Calcd for C10H10N2O3: C, 58.25; H, 4.89; N, 13.59. Found: C,
58.09; H, 4.90; N, 13.40.
244.988458.
Methyl 6-Chloro-4-methoxy-1H-pyrrolo[3,2-c]pyridine-2-car-
boxylate (33)
Prepared following the standard thermolysis procedure A to give
the product as an off-white solid (yield: 32%); mp 196–208 °C
(dec.).
Methyl 4-(methylthio)-1H-pyrrolo[3,2-c]pyridine-2-carboxy-
late (28)
Prepared following the standard thermolysis procedure A to give
the product as an off-white solid (yield: 84%); mp 195–197 °C.
1H NMR (500 MHz, acetone-d6): d = 11.35 (br, 1 H, NH), 8.18 (d,
J = 5.9 Hz, 1 H), 7.21 (m, 1 H), 7.16 (d, J = 1.1 Hz, 1 H), 3.90 (s, 3
H), 2.64 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 162.79, 155.96, 144.25,
141.26, 129.27, 123.33, 107.47, 105.72, 53.11.
1H NMR (400 MHz, acetone-d6): d = 11.24 (br, 1 H, NH), 7.16 (m,
1 H), 6.75 (m, 1 H), 3.933 (s, 3 H), 3.929 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 162.57, 162.45, 146.84,
143.27, 130.96, 120.82, 107.88, 90.75, 55.48, 53.21.
Anal. Calcd for C10H9ClN2O3: C, 49.91; H, 3.77; N, 11.64. Found:
C, 49.97; H, 3.78; N, 11.30.
Anal. Calcd for C10H10N2O2S: C, 54.04; H, 4.53; N, 12.60. Found:
C, 53.93; H, 4.69; N, 12.57.
Methyl 4-Bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (34)
Prepared following the standard thermolysis procedure C to give the
product as an off-white solid (yield: 44%); mp 222–224 °C.
Methyl 4-(Methylsulfonyl)-1H-pyrrolo[3,2-c]pyridine-2-car-
boxylate (29)
Prepared following the standard thermolysis procedure A to give
the product as an off-white solid (yield: 69%).
1H NMR (500 MHz, acetone-d6): d = 11.81 (br, 1 H, NH), 8.44 (d,
J = 5.7 Hz, 1 H), 7.79 (m, 1 H), 7.68 (d, J = 1.0 Hz, 1 H), 3.96 (s, 3
H), 3.33 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 162.58, 154.23, 144.40,
143.13, 132.71, 121.36, 112.77, 108.12, 53.54, 41.10.
1H NMR (500 MHz, DMSO-d6): d = 12.93 (br s, 1 H), 8.83 (s, 1 H),
8.34 (s, 1 H), 7.09 (s, 1 H), 3.94 (s, 3 H).
13C NMR (125 MHz, DMSO): d = 161.77, 139.85, 136.38, 134.82,
132.31, 132.04, 113.36, 106.37, 53.39.
Anal. Calcd for C9H7BrN2O2: C, 42.38; H, 2.77; N, 10.98. Found:
C, 42.29; H, 2.69; N, 10.92.
Anal. Calcd for C10H10N2O4S: C, 47.24; H, 3.96; N, 11.02; S, 12.61.
Found: C, 47.42; H, 4.14; N, 10.91; S, 12.42.
Methyl 4-(Methylthio)-1H-pyrrolo[2,3-c]pyridine-2-carboxy-
late (35)
Prepared following the standard thermolysis procedure C to give the
product as an off-white solid (yield: 51%).
1H NMR (500 MHz, acetone-d6): d = 11.55 (br s, 1 H), 8.78 (s, 1 H),
8.13 (s, 1 H), 7.20 (s, 1 H), 3.97 (s, 3 H), 2.66 (s, 3 H).
Methyl 4-(Trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine-2-car-
boxylate (30)
Prepared following the standard thermolysis procedure B to give the
product as an off-white solid (yield: 66%); mp 204–205 °C.
1H NMR (500 MHz, acetone-d6): d = 11.81 (br s, 1 H), 8.48 (d, J =
5.7 Hz, 1 H), 7.78 (d, J = 5.7 Hz, 1 H), 7.37 (s, 1 H), 3.98 (s, 3 H).
13C NMR (125 MHz, acetone-d6): d = 161.29, 142.49, 142.28 (q, J =
34.8 Hz), 142.26, 131.30, 122.87 (q, J = 273.6 Hz), 120.77, 110.99,
105.63 (d, J = 1.75 Hz), 52.25.
Methyl 4-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (36)
Prepared following the standard thermolysis procedure A to give
the product as an off-white solid (yield: 40%); mp 217–218 °C
(dec.).
1H NMR (500 MHz, DMSO-d6): d = 8.36 (d, J = 5.1 Hz, 1 H), 7.31
(d, J = 5.1 Hz, 1 H), 7.13 (s, 1 H), 3.88 (s, 3 H).
Anal. Calcd for C10H7F3N2O2: C, 49.19; H, 2.89; N, 11.47. Found:
C, 49.52; H, 2.97; N, 11.29.
13C NMR (125 MHz, DMSO-d6): d = 161.00, 149.24, 147.35,
136.41, 128.46, 118.14, 116.68, 104.01, 52.27.
Methyl 4-Isopropyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylate
(31)
Prepared following the standard thermolysis procedure B to give the
product as a pale yellow solid (yield: 75%); mp 129–130 °C.
1H NMR (500 MHz, acetone-d6): d = 11.36 (s, 1 H), 8.27 (d, J = 5.8
Hz, 1 H), 7.41 (s, 1 H), 7.30 (d, J = 5.8 Hz, 1 H), 3.93 (s, 3 H), 3.59
(m, 1 H), 1.39 (d, J = 6.8 Hz, 6 H).
Anal. Calcd for C9H7ClN2O2: C, 51.32; H, 3.35; N, 13.30. Found:
C, 51.04; H, 3.20; N, 13.13.
Methyl 4-(Methylthio)-1H-pyrrolo[2,3-b]pyridine-2-carboxy-
late (37)
Prepared following the standard thermolysis procedure B to give the
product as an off-white solid (yield: 56%); mp 213–216 °C (dec.).
Synthesis 2005, No. 16, 2751–2757 © Thieme Stuttgart · New York

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Synthesis of Substituted 5-, 6-, and 7-Azaindoles
2757
1H NMR (500 MHz, DMSO-d6): d = 12.65 (s, 1 H), 8.29 (d, J = 5.0
Hz, 1 H), 7.07 (s, 1 H), 7.00 (d, J = 5.1 Hz, 1 H), 3.88 (s, 3 H), 2.61
(s, 3 H).
13C NMR (125 MHz, DMSO): d = 162.06, 148.42, 147.59, 144.95,
127.46, 117.43, 111.82, 105.19, 52.86, 13.73.
(3) (a) Yakovlev, M. Y.; Kadushin, A. V.; Granik, V. G. Khim.-
Farm. Zh. 1996, 30, 36. (b) Dodd, R. H.; Doisy, X.; Potier,
P.; Potier, M.-C.; Rossier, J. Heterocycles 1989, 28, 1101.
(c) Scott, A. I.; Okada, K.; Kajiwara, M.; Townsend, C. A. J.
Am. Chem. Soc. 1974, 96, 8054. (d) Frydman, B.; Buldain,
G.; Repetto, J. C. J. Org. Chem. 1973, 38, 1824. (e) Fisher,
M. H.; Matzuk, A. R. J. Heterocycl. Chem. 1969, 6, 775.
(4) Hemetsberger, H.; Knittel, D.; Wiedmann, H. Monatsh.
Chem. 1970, 101, 161.
(5) Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A.
Tetrahedron Lett. 2000, 41, 4777.
(6) (a) Bracher, F. J. Heterocycl. Chem. 1993, 30, 157. (b) For
6e and 6f, also see: Mallet, M. J. Organomet. Chem. 1991,
406, 49.
(7) (a) Trécourt, F.; Marsais, F.; Güngör, T.; Quéguiner, G. J.
Chem. Soc., Perkin Trans. 1 1990, 9, 2409. (b) For an
alternative synthesis of 6d, see: Salvino, J. M.; Mervic, M.;
Mason, H. J.; Kiesow, T.; Teager, D.; Airey, J.;
Labaudiniere, R. J. Org. Chem. 1999, 64, 1823.
(8) Kao, B. C.; Doshi, H.; Reyes-Rivera, H.; Titus, D. D.; Yin,
M.; Dalton, D. J. Heterocycl. Chem. 1991, 28, 1315.
(9) (a) For 13, see: Jones, K.; Fiumana, A.; Escuerdo-
Hernandez, M. L. Tetrahedron 2000, 56, 397. (b) For 14,
see: Leblanc, Y.; Dufresne, C.; Roy, P. World Patent, WO
2004/039807, 2004.
References
(1) For reviews on indole ring synthesis methodology, see:
Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045;
and references therein.
(2) (a) Trejo, A.; Arzeno, H.; Browner, M.; Chanda, S.; Cheng,
S.; Comer, D. D.; Dalrymple, S. A.; Dunten, P.; Lafargue, J.;
Lovejoy, B.; Freire-Moar, J.; Lim, J.; Mcintosh, J.; Miller, J.;
Papp, E.; Reuter, D.; Roberts, R.; Sanpablo, F.; Saunders, J.;
Song, K.; Villasenor, A.; Warren, S. D.; Welch, M.; Weller,
P.; Whiteley, P. E.; Zeng, L.; Goldstein, D. M. J. Med.
Chem. 2003, 46, 4702. (b) Chi, S. M.; Choi, J.-K.; Yum, E.
K.; Chi, D. Y. Tetrahedron Lett. 2000, 41, 919. (c) Xu, L.;
Lewis, I. R.; Davidsen, S. K.; Summers, J. B. Tetrahedron
Lett. 1998, 39, 5159. (d) Desarbre, E.; Coudret, S.; Meheust,
C.; Mérour, J.-Y. Tetrahedron 1997, 53, 3637.
(10) Hickey, D. M. B.; Moody, C. J.; Rees, C. W. J. Chem. Soc.,
Perkin Trans. 1 1986, 1119.
(11) Azidopyridine acrylate 12b was isolated by extraction with
EtOAc–hexane (1:1) since it is an oil.
Synthesis 2005, No. 16, 2751–2757 © Thieme Stuttgart · New York