Rapid and efficient microwave-assisted synthesis of 4-, 5-, 6- and 7-azaindoles

Article abstract of DOI:10.1055/s-2005-872100

Under microwave irradiation conditions, the imines/enamines formed between aminopyridines and ketones are converted in moderate to good yields to the corresponding 4-, 5-, 6- or 7-azaindoles via the Hegedus-Mori-Heck reaction (intramolecular Heck reaction

Full text of DOI:10.1055/s-2005-872100

PAPER
2571
Rapid and Efficient Microwave-Assisted Synthesis of 4-, 5-, 6- and
7-Azaindoles
Synthesisof
A
zain
i
dole
s
v
c
ia Microw
a
ve Irradiatio
l
n
as Lachance,* Myriam April, Marc-André Joly
Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Québec, H9R 4P8, Canada
Fax +1(514)4284900; E-mail: nicolas_lachance@merck.com
Received 28 February 2005; revised 18 April 2005
The essential aspects of our approach are shown in
Scheme 1. Haloaminopyridine A first reacts with ketone
B to afford enamine D, which subsequently undergoes an
intramolecular palladium-catalyzed Heck reaction to pro-
Abstract: Under microwave irradiation conditions, the imines/
enamines formed between aminopyridines and ketones are convert-
ed in moderate to good yields to the corresponding 4-, 5-, 6- or 7-
azaindoles via the Hegedus–Mori–Heck reaction (intramolecular
Heck reaction). A systematic examination of all isomeric azaindoles duce azaindole C.
synthesis revealed this one-pot procedure to be general in scope.
R2
1. Condensation
2. Heck reaction
microwave
Key words: microwave, azaindole, pyrrolopyridine, palladium,
Heck reaction
X
R2
R1
R1
+
N
N
N
H
NH2
O
A
B
C
The preparation of important heterocycles such as azain-
doles is of interest in synthetic organic and medicinal
chemistry due to their potential biological properties.1,2
Application of the Hegedus–Mori–Heck reaction (in-
tramolecular Heck reaction) to the synthesis of azaindoles
was first explored on enamines with NaHCO3 and
Pd(PPh3)4 in HMPA at 140 °C.3,4 Under these conditions,
the scope of this palladium-catalyzed cross-coupling was
limited to the preparation of 4-azaindoles and N-methyl 7-
azaindoles. In a recent paper, Nazaré published the syn-
thesis of substituted 4- and 7-azaindoles involving a pal-
ladium coupling reaction with Pd[P(t-Bu)3]2 between
chloroaminopyridines and ketones by thermal heating in a
sealed tube (4–16 h at 140 °C).5 In contrast to the well
documented Fischer indole reaction applied to the azain-
doles synthesis,6–8 the Hegedus–Mori–Heck reaction has
never been reported for the preparation of 5- and 6-azain-
doles.
X = Cl, Br, I
Heck reaction
Condensation
X
R2
R1
N
N
H
D
Scheme 1 One-pot, two-step synthesis of azaindoles
Preliminary studies focused on optimization of the in-
tramolecular Heck reaction (D → C). The enamine 13 was
selected as the model substrate to explore the palladium-
catalyzed coupling reaction (Scheme 2). Several palladi-
um catalysts {Pd(OAc)2, Pd2Br2[P(t-Bu)3]2, Pd(PPh3)4},
bases (i-Pr2NEt, Cy2NMe), solvents (DMF, DMA, 1,4-di-
oxane, toluene, pyridine) and temperatures (160–180 °C
for 10–20 min) under non-degassed microwave irradia-
tion were examined.13 Under these conditions, yields of
the desired 5,6,7,8-tetrahydro-9H-pyrido[3,2-b]indol-9-
one (2) ranged from 50–95%. Investigation of the palladi-
um source and the solvent effect revealed that Pd(PPh3)4
and pyridine are the most appropriate reagents to perform
this intramolecular Heck reaction under microwave irra-
diation. Also, heating the reaction at a higher temperature
than 160 °C led to lower yields of azaindole 2 with in-
creased decomposition.
Since its introduction in 1986,9 microwave irradiation has
found increasing application in organic synthesis.10 For
the more challenging synthesis of 5- and 6-azaindoles, we
envisioned that the use of microwave irradiation would
improve the corresponding Hegedus–Mori–Heck reac-
tion, as observed for the intermolecular Heck reaction.11
To the best of our knowledge, a rapid and general synthe-
sis of the four isomeric azaindoles from readily accessible
starting materials has not been described. As part of our
medicinal chemistry research program, we needed an ef-
ficient route to azaindoles compatible with sensitive
groups such as bromine, ketones and esters.12 We wish to
report herein a rapid, one-pot, two-step procedure em-
ploying microwave conditions allowing the synthesis of
4-, 5-, 6- and 7-azaindoles.
After the exploration of the reaction conditions, we fo-
cused our attention on optimizing the isolation of the re-
action product. It was noted that on using an aqueous
O
O
Pd(PPh3)4
Cy2NMe
N
Cl
N
Pyridine
microwave
160 °C
N
H
N
H
SYNTHESIS 2005, No. 15, pp 2571–2577
x
x.
x
x
.
2
0
0
5
1
2
Advanced online publication: 29.07.2005
DOI: 10.1055/s-2005-872100; Art ID: M01205SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Hegedus–Mori–Heck reaction

2572
N. Lachance et al.
PAPER
work-up for the isolation of azaindole 2, a lower yield Having established rapid and high yielding conditions for
than the conversion determined by HPLC was obtained. the palladium cross-coupling of enamine 1 to azaindole 2,
Therefore, we sought non-aqueous workup conditions we wanted to examine the scope of this method. Table 1
since we suspected 2 to be water-soluble. The optimized summarizes the results of azaindole syntheses starting
purification protocol involves a direct flash chromatogra- from imines/enamines. Most of these condensed starting
phy over silica gel (5–15% MeOH in CHCl3) of the reac- materials required for our studies were prepared following
tion mixture followed by trituration with CH2Cl2. By literature procedures.3,4,15,16 Surprisingly under these con-
doing so, the desired azaindole 2 was now prepared from ditions and with higher temperatures or longer reaction
enamine 1 in 95% isolated yield. Under thermal heating, time, 4-amino-3-bromopyridine remains unreacted in the
a yield of 39% for the synthesis of azaindole 2 from 1 has presence of 1,3-cyclohexanedione. As highlighted in
been reported.3 More recently, the same heterocycle 2 has Table 1, the use of microwave irradiation allows for easy
been prepared in 54% yield under Stille cross-coupling access to various isomeric azaindoles. The syntheses of 7-
conditions.14
azaindole 9 and 6-azaindole 11 were accomplished in ex-
cellent yields (Table 1, entries 2 and 4). For comparison,
9 and 11 have been previously prepared in 10% and 22%
yields, respectively, under photocyclization conditions.3,4
Also, this method gives access to substituted heterocycles
such as the bromoazaindole 10 in good yields (Table 1,
entry 3, condition B).
Table 1 Synthesis of Azaindoles from Imines/Enamines
Entry
1
Substrate
Product
Reaction Yield
conditionsa (%)b
1
2
A
95
We next investigated the reaction of cyclic imines under
the above reaction conditions (Table 1, entries 5–7, condi-
tions A and B). After submitting compounds 6–816 to the
microwave-assisted Hegedus–Mori–Heck reaction, aza-
indoles 12–14 were isolated in high yields (Table 1, en-
tries 5–7). Exploration of time and temperature effects
(Table 1, entries 5–7, conditions A–C) on the formation of
cycloalkanoazaindoles 12–14 established the reactivity of
ring size: the 5-membered ring compound 12 was the eas-
iest to form and the 6-membered ring compound 13 was
the most difficult. Finally to accomplish the purification
of these non-polar azaindoles 12–14, a better eluent (10–
50% EtOAc in hexane containing 10% Et3N) and solvent
(ClCH2CH2Cl or heptane) were required than in the previ-
ously described protocol.
O
O
Br
2
3
4
A
89
N
N
H
N
H
N
3
4
9
O
O
Br
Br
Br
A
B
43
57
N
N
H
N
H
N
10
O
O
Cl
A
95
N
N
N
H
N
H
During the course of this study, we discovered that the
presence of a strong base such as Cy2NMe was not always
necessary for the palladium cross-coupling reaction to oc-
cur. As an example, the Hegedus–Mori–Heck reaction of
enamine 1 (2.25 mmol) with 5 mol% of Pd(PPh3)4 and py-
ridine (1.5 mL) under microwave irradiation at 160 °C for
20 minutes delivered azaindole 2 in 97% isolated yield.17
However, exposure of the enamine 4 under the same reac-
tion conditions only led to recovery of starting material af-
ter 40 minutes at 160 °C.
5
11
N
Cl
N
A
C
87
89
5
6
N
H
N
6
12
N
Cl
N
A
B
47
83
N
N
H
Since azaindole 2 could be prepared under mild basic con-
ditions favorable for the condensation step, we were inter-
ested in determining if we could develop a one-step
procedure to prepare these azaindoles (Table 2).5,18 Under
microwave irradiation, the synthesis of 4-azaindoles 13
and 14 (Table 2, entries 1–3) was achieved in good yields
in 20–40 minutes by direct reaction of 3-amino-2-chloro-
pyridine (15) with cyclic ketals 1719 and 18 or ketone 19.
When the reaction was performed with a ketone (Table 2,
entry 3), PPTS and a dehydrating agent such as Si(OEt)4
were required.20 However, the reaction with ketals did not
need the dehydrating agent. Using these conditions adapt-
ed for ketals and monitoring the consumption of 4-amino-
3-bromopyridine (16), the synthesis of 5-azaindole 20
7
13
N
Cl
N
A
C
85
12
7
N
N
H
8
14
a Reaction conditions: Substrate (2.25 mmol) was allowed to react
with Pd(PPh3)4 (5 mol%) and Cy2NMe (1.2 equiv) in pyridine (1.5
mL). A: Heated under microwave irradiation for 20 min at 160 °C; B:
40 min at 160 °C; C: 20 min at 140 °C.
b Isolated yield.
Synthesis 2005, No. 15, 2571–2577 © Thieme Stuttgart · New York

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Synthesis of Azaindoles via Microwave Irradiation
2573
Table 2 One-Step Synthesis of Azaindoles
Entry
Substrate
Ketal/ketone
Product
Reaction
conditionsa
Yield
(%)b
OEt
OEt
N
Cl
1
14
A
81
NH2
15
15
17
OEt
2
3
13
13
Ac
83
87
OEt
18
15
B
O
19
Br
N
N
4
18
Ad
27
N
H
NH2
16
20
a Reaction conditions under microwave irradiation at 160 °C: Substrate (2.25 mmol) was allowed to react with ketal/ketone (2.0 equiv),
Pd(PPh3)4 (5 mol%); A: In pyridine (1.5 mL) for 20 min; B: PPTS (0.25 equiv), Si(OEt)4 (1.0 equiv) in pyridine (0.75 mL) for 40 min.
b Isolated yield.
c 40 min.
d PPTS (0.1 equiv) and 35 h.
(Table 2, entry 4) was realized in only 27% yield after 35 reaction (Table 3, entries 3–5). This method gives access
hours under microwave irradiation at 160 °C. The major to 2-ethyl carboxylate azaindoles 28 and 29 (Table 3, en-
side product was the reduction of 4-amino-3-bromopyri- tries 4 and 5), which are not always accessible by the
dine (16) into 4-aminopyridine in a 47% isolated yield. Hemetsberger synthesis.24 Finally, performing the reac-
Based on the large amount of this side product recovered tion with aromatic ketone 26 (Table 3, entry 6) has led to
and the unsuccessful reaction of 16 with 1,3-cyclohex- a 2-phenylazaindole 30, which constitutes an alternative
anedione, we concluded that the condensation with a 4- procedure to the Larock indole synthesis.25
aminopyridine was a more difficult step compared with a
In summary, the intramolecular Heck reaction of imines/
2- or 3-aminopyridine (Scheme 1).
enamines under microwave conditions provides good
To circumvent the reduction of the halogen bond observed yields of azaindoles. Under our optimized conditions, we
during slow reaction (Table 2, entry 4), we evaluated a have demonstrated that this reaction can be performed
two-step synthesis as a solution to prepare rapidly all the with chloro-, bromo- and iodoaminopyridines and toler-
isomeric azaindoles.21 A range of temperatures and times ates sensitive groups such as bromine, ketones and esters
for the condensation step between ketals or ketones with to deliver functionalized azaindoles. In addition, our
haloaminopyridines were examined (Table 3). As an ex- method is general and uses microwave irradiation to re-
ample, 3-halo-4-aminopyridines 16 and 2122 were con- duce the reaction time and promote the palladium cou-
densed with ketal 18 or ketone 24 under microwave pling with more traditional palladium catalyst. Finally,
irradiation at 220 °C (Table 3, entries 1–3), whereas this this paper is the first to describe the synthesis of 5- and 6-
step was performed at room temperature with ethyl pyru- azaindoles via an intramolecular Heck reaction.
vate 25 (Table 3, entries 4 and 5).23
Following the condensation step, the intramolecular Heck
reaction was realized in the same flask with Pd(PPh3)4 (5
mol%) and Cy2NMe (1.3 equiv) under microwave condi-
tions. Using this one-pot, two-step procedure, 5-azaindole
20 could now be obtained in 48% yield in less than three
hours (Table 3, entry 1). This compares favourably to the
27% yield obtained under the one-step synthesis (Table 2,
Melting points were determined on a Mettler apparatus and are un-
corrected. 1H and 13C NMR spectra were recorded in DMSO-d6 so-
lution at room temperature on a Bruker Avance 500 MHz or AMX
500 MHz spectrometer. ESI mass spectra were obtained on a PE
SCIEX/API 2000 instrument. TLC analyses were performed on
Merck Kieselgel 60 F254 plates. Neutralization of TLC plates was
performed by first eluting with 10–50% EtOAc in hexane contain-
ing 10% Et3N. Haloaminopyridines and compounds 18 and 25 were
entry 4). However, it is worth noting that the yield went obtained from Lancaster. Compounds 19 and 26 were purchased
from Aldrich and compound 24 from Acros. Pd(PPh3)4 was ac-
quired from Strem. HCl salts of haloaminopyridines were neutral-
up from 48% to 66% on changing from the bromopyridine
16 to the iodopyridine 21 (Table 3, entries 1 and 2). In ad-
ized by using aq NaHCO3. Column chromatography was conducted
dition, the presence of ester groups is well tolerated in this
with silica gel 230–400 mesh. Elemental analyses were determined
Synthesis 2005, No. 15, 2571–2577 © Thieme Stuttgart · New York

2574
N. Lachance et al.
PAPER
Table 3 One-Pot, Two-Step Synthesis of Azaindoles
Entry
1
Substrate
Ketal/ketone
Product
Reaction
conditionsa
Yield
(%)b
16
18
20
A
48
I
N
2
3
18
20
Ac
66
NH2
21
21
O
N
Ad
46
N
H
COOEt
COOEt
27
24
N
O
COOEt
COOEt
4
5
15
B
80
63
N
COOEt
H
25
28
Cl
25
Bd
N
N
N
H
NH2
22
23
29
O
Br
SO2Me
6
C
41
N
H
N
N
NH2
30
SO2Me
26
a Reaction conditions under microwave irradiation. A: [Condensation (Step 1): Substrate (2.25 mmol) was allowed to react with ketal/ketone
(2.0 equiv), Si(OEt)4 (1.0 equiv) if required and PPTS (0.10–0.25 equiv) in pyridine (0.75–1.5 mL), heated successively for 20 min at 160 °C,
180 °C, 200 °C and 220 °C; Heck reaction (Step 2): Pd(PPh3)4 (5 mol%) and Cy2NMe (1.3 equiv) were added and reaction was heated for 80
min at 160 °C]; B: [Step 1: 48 h at r.t.; Step 2: 20 min]; C: [Step 1: 160 °C, 180 °C, 200 °C; Step 2: 2 h].
b Isolated yield.
c Step 2: 20 min.
d Step 2: 40 min.
by Prevalere Life Science, Inc., Whitesboro, NY. Reactions under
microwave conditions were performed on a Smith CreatorTM micro-
wave reactor purchased from Biotage/Personal Chemistry.
Anal. Calcd for C11H11ClN2O: C, 59.33; H, 4.98; N, 12.58. Found:
C, 59.28; H, 4.84; N, 12.61.
Synthesis of Azaindoles from Imines/Enamines (Table 1); Gen-
eral Procedure I
3-[(4-Chloropyridin-3-yl)amino]cyclohex-2-en-1-one (5)
A solution of 22 (1.00 g, 7.78 mmol), 1,3-cyclohexanedione (2.28
g, 20.3 mmol) and p-TsOH·H2O (76 mg, 0.40 mmol) in benzene
(100 mL) was refluxed in a Dean–Stark apparatus for 2.5 h. After
cooling, the reaction mixture was concentrated in vacuo. The resi-
due was diluted with CH2Cl2, basified with aq NaHCO3 and extract-
ed with CH2Cl2 (2 ×). The organic layers were combined, dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(EtOAc–MeOH–Et3N, 9:0:1 → 8:1:1) followed by trituration with
toluene to afford 5 as a white solid (950 mg, 55%); mp 137–138 °C
(toluene).
A pyrex cylindrical reaction tube adapted to the Smith CreatorTM
was charged with the imine/enamine (2.25 mmol), Pd(PPh3)4 (5
mol%), Cy2NMe (1.2 equiv), pyridine (1.5 mL), and a magnetic
stirrer bar. The tube was septum-sealed and irradiated with micro-
waves at the set temperature and reaction time given in Table 1. The
reaction mixture was cooled to r.t., and purified by column chroma-
tography on silica gel with the suitable CHCl3–MeOH mixture (or
hexane–EtOAc–Et3N mixture) followed by trituration with CH2Cl2
(or ClCH2CH2Cl or heptane) to give the corresponding azaindole.
One-Step Synthesis of Azaindoles (Table 2); General Procedure
II
1H NMR: d = 8.84 (s, 1 H), 8.51 (s, 1 H), 8.43 (d, J = 5.3 Hz, 1 H),
7.67 (d, J = 5.3 Hz, 1 H), 4.63 (s, 1 H), 2.52 (t, J = 6.1 Hz, 2 H), 2.14
(t, J = 6.4 Hz, 2 H), 1.92–1.86 (m, 2 H).
A pyrex cylindrical reaction tube adapted to the Smith CreatorTM
was charged with haloaminopyridine (2.25 mmol), ketal or ketone
(2.0 equiv), Si(OEt)4 (0–1.0 equiv), PPTS (10–25 mol%), Pd(PPh3)4
(5 mol%), pyridine (0.75–1.5 mL), and a magnetic stirrer bar. The
tube was septum-sealed and irradiated with microwaves at the set
temperature and reaction time given in Table 2. The reaction mix-
ture was cooled to r.t., treated with Cy2NMe (1.2 equiv), and puri-
13C NMR: d = 195.6, 163.2, 149.6, 148.4, 139.7, 132.9, 125.1, 99.0,
36.3, 27.8, 21.5
MS (ESI): m/z = 225, 223 [M + 1].
Synthesis 2005, No. 15, 2571–2577 © Thieme Stuttgart · New York

PAPER
Synthesis of Azaindoles via Microwave Irradiation
2575
fied by column chromatography on silica gel with the suitable
CHCl3–MeOH mixture (or CH2Cl2–MeOH–NH4OH mixture or
hexane–EtOAc–Et3N mixture) followed by trituration with CH2Cl2
(or 50% CH2Cl2 in heptane, or heptane) to give the corresponding
azaindole.
3-Bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (10)
Following the General Procedure I, the reaction of 44 (781 mg, 2.26
mmol), Pd(PPh3)4 (132 mg, 0.12 mmol), Cy2NMe (0.58 mL, 2.73
mmol) and pyridine (1.5 mL), heated for 40 min at 160 °C and after
purification (column chromatography: 0–5% MeOH in CHCl3; trit-
uration: CH2Cl2), afforded 10 as an off-white solid (341 mg, 57%);
mp > 280 °C (acetone).
One-Pot, Two-Step Synthesis of Azaindoles (Table 3); General
Procedure III
1H NMR: d = 12.60 (s, 1 H), 8.31 (d, J = 2.1 Hz, 1 H), 8.29 (d, J =
2.1 Hz, 1 H), 2.98 (t, J = 6.1 Hz, 2 H), 2.45 (t, J = 6.3 Hz, 2 H), 2.16–
2.10 (m, 2 H).
A pyrex cylindrical reaction tube adapted to the Smith CreatorTM
was charged with haloaminopyridine (2.25 mmol), ketal or ketone
(1.5–2.0 equiv), Si(OEt)4 (0–1.0 equiv), PPTS (10–25 mol%), pyri-
dine (0.75–1.5 mL), and a magnetic stirrer bar. The tube was sep-
tum-sealed and irradiated with microwaves (or not) at the set
temperature and reaction time given in Table 3 for the condensation
step. Then, Pd(PPh3)4 (5 mol%) and Cy2NMe (1.3 equiv) were add-
ed before the tube was septum-sealed and irradiated again with mi-
crowaves at the set temperature and reaction time given in Table 3
for the palladium cross-coupling. The reaction mixture was cooled
to r.t. and purified by column chromatography on silica gel with the
suitable CHCl3–MeOH mixture (or CH2Cl2–MeOH–NH4OH mix-
ture or hexane–EtOAc–Et3N mixture) followed by trituration with
1–50% CH2Cl2 in heptane (or 60% ClCH2CH2Cl in heptane) to give
the corresponding azaindole.
13C NMR: d = 193.1, 155.0, 147.4, 143.6, 129.8, 118.6, 113.4,
110.0, 37.6, 23.1, 22.7.
MS (ESI): m/z = 267, 265 [M + 1].
Anal. Calcd for C11H9BrN2O: C, 49.84; H, 3.42; N, 10.57. Found:
C, 49.84; H, 3.21; N, 10.59.
6,7,8,9-Tetrahydro-5H-b-carbolin-5-one (11)
Following the General Procedure I, the reaction of 5 (496 mg, 2.23
mmol), Pd(PPh3)4 (133 mg, 0.12 mmol), Cy2NMe (0.58 mL, 2.73
mmol) and pyridine (1.5 mL), heated for 20 min at 160 °C and after
purification [column chromatography: 0–5% MeOH in CHCl3; trit-
uration: CH2Cl2], afforded 11 as a white solid (396 mg, 95%); mp
275–277 °C (EtOAc–heptane) (Lit.3 mp > 260 °C).
5,6,7,8-Tetrahydro-9H-pyrido[3,2-b]indol-9-one (2)
Method 1: Following the General Procedure I, the reaction of 13
(502 mg, 2.25 mmol), Pd(PPh3)4 (133 mg, 0.12 mmol), Cy2NMe
(0.58 mL, 2.73 mmol) and pyridine (1.5 mL), heated for 20 min at
160 °C and after purification [column chromatography: 0–15%
MeOH in CHCl3; trituration: CH2Cl2], afforded 2 as a white solid
(398 mg, 95%).
1H NMR: d = 12.29 (s, 1 H), 8.73 (s, 1 H), 8.24 (d, J = 5.2 Hz, 1 H),
7.82 (d, J = 5.2 Hz, 1 H), 3.00 (t, J = 6.2 Hz, 2 H), 2.45 (t, J = 6.4
Hz, 2 H), 2.16–2.10 (m, 2 H).
13C NMR: d = 193.1, 155.2, 140.9, 134.1, 133.0, 129.2, 114.6,
111.2, 37.7, 23.1, 22.8.
MS (ESI): m/z = 187 [M + 1].
Method 2: Following the General Procedure II, the reaction of 13
(498 mg, 2.24 mmol), Pd(PPh3)4 (131 mg, 0.11 mmol), and pyridine
(1.5 mL), heated for 20 min at 160 °C and after purification
[Cy2NMe (0.58 mL); column chromatography: 0–15% MeOH in
CHCl3; trituration: CH2Cl2], afforded 2 as a white solid (404 mg,
97%); mp 268–270 °C (H2O) (Lit.3 mp 272–274 °C).
Anal. Calcd for C11H10N2O: C, 70.95; H, 5.41; N, 15.04. Found: C,
70.71; H, 5.37; N, 14.85.
5,6,7,8-Tetrahydrocyclopenta[4,5]pyrrolo[3,2-b]pyridine (12)
Following the General Procedure I, the reaction of 616 (440 mg, 2.26
mmol), Pd(PPh3)4 (137 mg, 0.12 mmol), Cy2NMe (0.58 mL, 2.73
mmol) and pyridine (1.5 mL), heated for 20 min at 160 °C and after
purification [column chromatography: hexane–EtOAc–Et3N, 9:1:1
→ 5:4:1; trituration: ClCH2CH2Cl], afforded 12 as a white solid
(312 mg, 87%); mp 258–260 °C (acetone) (Lit.7 mp 258–260 °C).
1H NMR: d = 12.06 (s, 1 H), 8.38 (dd, J = 1.4, 4.7 Hz, 1 H), 7.76
(dd, J = 1.4, 8.1 Hz, 1 H), 7.15 (dd, J = 4.7, 8.1 Hz, 1 H), 3.00 (t,
J = 6.2 Hz, 2 H), 2.43 (t, J = 6.4 Hz, 2 H), 2.14–2.08 (m, 2 H).
13C NMR: d = 191.4, 154.8, 144.0, 143.0, 128.7, 118.5, 117.3,
111.3, 38.5, 23.2, 23.0.
1H NMR: d = 11.03 (s, 1 H), 8.16 (d, J = 4.6 Hz, 1 H), 7.59 (d, J =
8.1 Hz, 1 H), 6.94 (dd, J = 4.6, 8.1 Hz, 1 H), 2.85 (t, J = 7.2 Hz, 2
H), 2.77 (t, J = 6.9 Hz, 2 H), 2.47–2.43 (m, 2 H).
MS (ESI): m/z = 187 [M + 1].
Anal. Calcd for C11H10N2O·1/2H2O: C, 67.68; H, 5.68; N, 14.35.
Found: C, 67.67; H, 5.60; N, 14.38.
13C NMR: d = 148.9, 142.2, 141.2, 133.6, 118.0, 117.4, 114.7, 28.1,
25.6, 23.7.
3-Methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (9)
Following the General Procedure I, the reaction of 34 (638 mg, 2.27
mmol), Pd(PPh3)4 (138 mg, 0.12 mmol), Cy2NMe (0.58 mL, 2.73
mmol) and pyridine (1.5 mL), heated for 20 min at 160 °C and after
purification [column chromatography: 0–5% MeOH in CHCl3; trit-
uration: CH2Cl2], afforded 9 as a white solid (404 mg, 89%); mp >
280 °C (ClCH2CH2Cl).
MS (ESI): m/z = 159 [M + 1].
Anal. Calcd for C10H10N2: C, 75.92; H, 6.37; N, 17.71. Found: C,
75.88; H, 6.50; N, 17.75.
6,7,8,9-Tetrahydro-5H-pyrido[3,2-b]indole (13)
Method 1: Following the General Procedure I, the reaction of 716
(480 mg, 2.30 mmol), Pd(PPh3)4 (130 mg, 0.11 mmol), Cy2NMe
(0.58 mL, 2.73 mmol) and pyridine (1.5 mL), heated for 40 min at
160 °C and after purification [column chromatography: hexane–
EtOAc–Et3N, 9:1:1 → 5:4:1; trituration: heptane], afforded 13 as a
white solid (327 mg, 83%).
1H NMR: d = 12.22 (s, 1 H), 8.06 (s, 1 H), 8.04 (s, 1 H), 2.94 (t, J =
6.1 Hz, 2 H), 2.42 (t, J = 6.3 Hz, 2 H), 2.36 (s, 3 H), 2.14–2.08 (m,
2 H).
13C NMR: d = 192.8, 153.2, 147.3, 143.9, 128.0, 126.6, 116.6,
109.9, 37.6, 23.2, 22.6, 18.0.
Method 2: Following the General Procedure II, the reaction of 15
(291 mg, 2.26 mmol), 18 (0.54 mL, 4.50 mmol), Pd(PPh3)4 (136
mg, 0.12 mmol) and pyridine (1.5 mL), heated for 40 min at 160 °C
and after purification [Cy2NMe (0.58 mL); column chromatogra-
phy: hexane–EtOAc–Et3N, 9:1:1 → 5:4:1; trituration: heptane], af-
forded 13 as a white solid (323 mg, 83%).
MS (ESI): m/z = 201 [M + 1].
Anal. Calcd for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C,
72.01; H, 6.03; N, 13.94.
Synthesis 2005, No. 15, 2571–2577 © Thieme Stuttgart · New York

2576
N. Lachance et al.
PAPER
Method 3: Following the General Procedure II, the reaction of 15
(295 mg, 2.29 mmol), 19 (0.47 mL, 4.53 mmol), PPTS (140 mg,
0.56 mmol), Si(OEt)4 (0.51 mL, 2.28 mmol), Pd(PPh3)4 (139 mg,
0.12 mmol) and pyridine (0.75 mL), heated for 40 min at 160 °C and
after purification [Cy2NMe (0.58 mL); column chromatography:
hexane–EtOAc–Et3N, 9:1:1 → 5:4:1; trituration: heptane], afforded
13 as a white solid (344 mg, 87%); mp 206–208 °C (EtOAc–hep-
tane) (Lit.7 mp 202–203 °C).
at 160 °C, and after purification [column chromatography: CH2Cl2–
MeOH–NH4OH, 99:1:0 → 87:10:3; trituration: 50% CH2Cl2 in hep-
tane], afforded 20 as a white solid (257 mg, 66%); mp 272–274 °C
(acetone) (Lit.8 mp 270–272 °C).
1H NMR: d = 11.11 (s, 1 H), 8.60 (s, 1 H), 8.06 (d, J = 5.5 Hz, 1 H),
7.20 (d, J = 5.5 Hz, 1 H), 2.70–2.64 (m, 4 H), 1.83–1.77 (m, 4 H).
13C NMR: d = 140.0, 139.5, 139.0, 135.6, 124.2, 107.7, 106.0, 22.7,
22.57, 22.55, 20.4.
1H NMR: d = 10.87 (s, 1 H), 8.17 (dd, J = 1.4, 4.6 Hz, 1 H), 7.55
(dd, J = 1.4, 8.0 Hz, 1 H), 6.95 (dd, J = 4.6, 8.0 Hz, 1 H), 2.72 (t,
J = 6.1 Hz, 2 H), 2.67 (t, J = 6.0 Hz, 2 H), 1.86–1.76 (m, 4 H).
MS (ESI): m/z = 173 [M + 1].
Anal. Calcd for C11H12N2: C, 76.71; H, 7.02; N, 16.26. Found: C,
76.61; H, 6.99; N, 16.30.
13C NMR: d = 145.2, 140.9, 138.8, 128.3, 116.8, 115.1, 108.7, 23.0,
22.8, 22.7, 20.0.
Ethyl 5,6,7,8-Tetrahydrocyclopenta[4,5]pyrrolo[3,2-c]pyridin-
6-ylacetate (27)
MS (ESI): m/z = 173 [M + 1].
Anal. Calcd for C11H12N2: C, 76.71; H, 7.02; N, 16.26. Found: C,
76.95; H, 6.76; N, 16.21.
Following the General Procedure III, the reaction of 2126 (496 mg,
2.25 mmol), 24 (786 mg, 4.62 mmol), PPTS (141 mg, 0.56 mmol),
Si(OEt)4 (0.51 mL, 2.28 mmol), and pyridine (0.75 mL) heated suc-
cessively for 20 min at 160 °C, 180 °C, 200 °C and 220 °C, treated
with Pd(PPh3)4 (136 mg, 0.12 mmol) and Cy2NMe (0.62 mL, 2.92
mmol), heated successively for 2 × 20 min (40 min) at 160 °C, and
after purification [column chromatography: hexane–EtOAc–Et3N,
9:1:1 → 0:9:1; trituration: 1% CH2Cl2 in heptane], afforded 27 as a
tan solid (252 mg, 46%); mp 123–124 °C (CH2Cl2–heptane).
5,6,7,8,9,10-Hexahydrocyclohepta[4,5]pyrrolo[3,2-b]pyridine
(14)
Method 1: Following the General Procedure I, the reaction of 816
(509 mg, 2.29 mmol), Pd(PPh3)4 (134 mg, 0.12 mmol), Cy2NMe
(0.58 mL, 2.73 mmol) and pyridine (1.5 mL), heated for 20 min at
160 °C and after purification [column chromatography: hexane–
EtOAc–Et3N, 9:1:1 → 5:4:1; trituration: heptane], afforded 14 as a
white solid (363 mg, 85%).
1H NMR: d = 11.10 (s, 1 H), 8.59 (s, 1 H), 8.06 (d, J = 5.6 Hz, 1 H),
7.29 (d, J = 5.6 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 2 H), 3.56–3.50 (m, 1
H), 2.84–2.68 (m, 4 H), 2.52–2.46 (m, 1 H), 2.16–2.09 (m, 1 H),
1.17 (t, J = 7.1 Hz, 3 H).
Method 2: Following the General Procedure II, the reaction of 15
(299 mg, 2.33 mmol), 1719 (841 mg, 4.51 mmol), Pd(PPh3)4 (141
mg, 0.12 mmol) and pyridine (1.5 mL), heated for 20 min at 160 °C
and after purification [Cy2NMe (0.58 mL); column chromatogra-
phy: hexane–EtOAc–Et3N, 9:1:1 → 5:4:1; trituration: heptane], af-
forded 14 as a white solid (351 mg, 81%); mp 236–238 °C (EtOAc–
heptane).
13C NMR: d = 171.7, 147.0, 144.1, 140.7, 139.3, 120.9, 116.7,
107.4, 60.0, 38.7, 35.5, 34.9, 22.9, 14.1.
MS (ESI): m/z = 245 [M + 1].
Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C,
68.56; H, 6.32; N, 11.29.
1H NMR: d = 10.88 (s, 1 H), 8.18 (d, J = 4.6 Hz, 1 H), 7.54 (d, J =
8.1 Hz, 1 H), 6.93 (dd, J = 4.6, 8.1 Hz, 1 H), 2.85–2.82 (m, 4 H),
1.87–1.83 (m, 2 H), 1.72–1.62 (m, 4 H).
Ethyl 1H-Pyrrolo[3,2-b]pyridine-2-carboxylate (28)
Following the General Procedure III, the reaction of 15 (291 mg,
2.26 mmol), 25 (0.50 mL, 4.52 mmol), PPTS (141 mg, 0.56 mmol),
Si(OEt)4 (0.51 mL, 2.28 mmol), and pyridine (0.75 mL) stirred for
48 h at r.t., treated with Pd(PPh3)4 (136 mg, 0.12 mmol) and
Cy2NMe (0.62 mL, 2.92 mmol), heated for 20 min at 160 °C, and
after purification [column chromatography: hexane–EtOAc–Et3N,
9:1:1 → 0:9:1; trituration: 10% CH2Cl2 in heptane], afforded 28 as
a white solid (343 mg, 80%); mp 179–181 °C (CH2Cl2–hexane)
(Lit.27 mp 179 °C).
13C NMR: d = 146.1, 142.4, 141.2, 127.0, 117.0, 115.1, 112.9, 31.8,
29.2, 28.6, 27.2, 23.2.
MS (ESI): m/z = 187 [M + 1].
Anal. Calcd for C12H14N2: C, 77.38; H, 7.58; N, 15.04. Found: C,
77.20; H, 7.65; N, 14.95.
6,7,8,9-Tetrahydro-5H-pyrido[4,3-b]indole (20)
Method 1: Following the General Procedure II, the reaction of 16
(391 mg, 2.25 mmol), 18 (0.55 mL, 4.58 mmol), PPTS (61 mg, 0.24
mmol), Pd(PPh3)4 (136 mg, 0.12 mmol) and pyridine (1.5 mL),
heated for 35 h at 160 °C and after purification [Cy2NMe (0.58 mL);
1H NMR: d = 12.14 (s, 1 H), 8.45 (dd, J = 1.3, 4.4 Hz, 1 H), 7.83 (d,
J = 8.3 Hz, 1 H), 7.26 (dd, J = 4.4, 8.3 Hz, 1 H), 7.20 (d, J = 1.3 Hz,
1 H), 4.36 (q, J = 7.1 Hz, 2 H), 1.34 (t, J = 7.1 Hz, 3 H).
column chromatography: CH2Cl2–MeOH–NH4OH, 99:1:0
87:10:3; trituration: 50% CH2Cl2 in heptane], afforded 20 as a pale
yellow solid (104 mg, 27%) and 4-aminopyridine (99 mg, 47%).
→
13C NMR: d = 161.1, 144.6, 144.3, 130.3, 129.8, 120.1, 119.5,
107.2, 60.8, 14.2.
MS (ESI): m/z = 191 [M + 1].
Method 2: Following the General Procedure III, the reaction of 16
(390 mg, 2.25 mmol), 18 (0.55 mL, 4.58 mmol), PPTS (61 mg, 0.24
mmol), and pyridine (1.5 mL) heated successively for 20 min at 160
°C, 180 °C, 200 °C and 220 °C, treated with Pd(PPh3)4 (137 mg,
0.12 mmol) and Cy2NMe (0.62 mL, 2.92 mmol), heated successive-
ly for 4 × 20 min (80 min) at 160 °C, and after purification [column
chromatography: CH2Cl2–MeOH–NH4OH, 99:1:0 → 87:10:3; trit-
uration: 50% CH2Cl2 in heptane], afforded 20 as a white solid (187
mg, 48%).
Anal. Calcd for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C,
63.02; H, 5.33; N, 14.42.
Ethyl 1H-Pyrrolo[2,3-c]pyridine-2-carboxylate (29)
Following the General Procedure III, the reaction of 22 (291 mg,
2.26 mmol), 25 (0.50 mL, 4.52 mmol), PPTS (140 mg, 0.56 mmol),
Si(OEt)4 (0.51 mL, 2.28 mmol), and pyridine (0.75 mL) stirred for
48 h at r.t., treated with Pd(PPh3)4 (136 mg, 0.12 mmol) and
Cy2NMe (0.62 mL, 2.92 mmol), heated successively for 2 × 20 min
(40 min) at 160 °C, and after purification [column chromatography:
hexane–EtOAc–Et3N, 9:1:1 → 0:9:1; trituration: 10% CH2Cl2 in
heptane], afforded 29 as a white solid (272 mg, 63%); mp 212–214
°C (toluene) (Lit.28 mp 212–214 °C).
Method 3: Following the General Procedure III, the reaction of 2126
(495 mg, 2.25 mmol), 18 (0.55 mL, 4.58 mmol), PPTS (61 mg, 0.24
mmol), and pyridine (1.5 mL) heated successively for 20 min at 160
°C, 180 °C, 200 °C and 220 °C, treated with Pd(PPh3)4 (137 mg,
0.12 mmol) and Cy2NMe (0.62 mL, 2.92 mmol), heated for 20 min
Synthesis 2005, No. 15, 2571–2577 © Thieme Stuttgart · New York

PAPER
Synthesis of Azaindoles via Microwave Irradiation
2577
1H NMR: d = 12.39 (s, 1 H), 8.84 (s, 1 H), 8.16 (d, J = 5.5 Hz, 1 H),
7.62 (d, J = 5.5 Hz, 1 H), 7.16 (s, 1 H), 4.37 (q, J = 7.1 Hz, 2 H),
1.34 (t, J = 7.1 Hz, 3 H).
(4) Blache, Y.; Sinibaldi-Troin, M.-E.; Hichour, M.; Benezech,
V.; Chavignon, O.; Gramain, J.-C.; Teulade, J.-C.; Chapat,
J.-P. Tetrahedron 1999, 55, 1959.
(5) Nazaré, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W.
Angew. Chem. Int. Ed. 2004, 43, 4526.
(6) Abramovitch, R. A.; Adams, K. A. H. Can. J. Chem. 1962,
40, 864.
13C NMR: d = 160.9, 138.3, 136.4, 134.0, 130.6, 130.5, 116.0,
106.2, 61.0, 14.2.
MS (ESI): m/z = 191 [M + 1].
(7) Kelly, A. H.; Parrick, J. J. Chem. Soc. C 1970, 303.
(8) Mann, F. G.; Prior, A. F.; Willcox, T. J. J. Chem. Soc. 1959,
3830.
Anal. Calcd for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C,
63.09; H, 5.32; N, 14.66.
(9) (a) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera,
L.; Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279.
(b) Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G.
Tetrahedron Lett. 1986, 27, 4945.
(10) For reviews on microwave irradiation, see: (a) Kappe, C. O.
Angew. Chem. Int. Ed. 2004, 43, 6250; and references
therein. (b) Hayes, B. L. Aldrichimica Acta 2004, 37, 66; and
references therein. (c) Perreux, L.; Loupy, A. Tetrahedron
2001, 57, 9199.
(11) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582.
(12) Lachance, N.; Sturino, C. F. WO Patent, 111047/A2, 2004.
(13) Pyrex cylindrical reaction tubes adapted to the Smith
CreatorTM (Biotage/Personal Chemistry) were used. The
temperature was measured by IR detection and maintained
constant by modulated irradiation of 8–300 W.
(14) Scott, T. L.; Söderberg, B. C. G. Tetrahedron 2003, 59,
6323.
2-[4-(Methylsulfonyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (30)
Following the General Procedure III, the reaction of 23 (392 mg,
2.27 mmol), 26 (666 mg, 3.36 mmol), PPTS (141 mg, 0.56 mmol),
Si(OEt)4 (0.51 mL, 2.28 mmol), and pyridine (0.75 mL) heated suc-
cessively for 20 min at 160 °C, 180 °C and 200 °C, treated with
Pd(PPh3)4 (136 mg, 0.12 mmol) and Cy2NMe (0.62 mL, 2.92
mmol), heated successively for 6 × 20 min (2 h) at 160 °C, and after
purification [column chromatography: 0–10% MeOH in CHCl3;
trituration: 60% ClCH2CH2Cl in heptane], afforded 30 as a white
solid (251 mg, 41%); mp >280 °C (acetone).
1H NMR: d = 12.36 (s, 1 H), 8.27 (dd, J = 1.5, 4.6 Hz, 1 H), 8.19 (d,
J = 8.5 Hz, 2 H), 8.01–7.97 (m, 3 H), 7.15 (d, J = 2.0 Hz, 1 H), 7.10
(dd, J = 4.6, 7.8 Hz, 1 H), 3.25 (s, 3 H).
13C NMR: d = 149.9, 144.0, 139.5, 136.4, 136.1, 128.6, 127.6 (2 C),
125.8 (2 C), 120.6, 116.4, 99.8, 43.5.
MS (ESI): m/z = 273 [M + 1].
(15) Condensation of 3-amino-4-chloropyridine (22) with 1,3-
cyclohexanedione (2.6 equiv) and PTSA (0.05 equiv) in
refluxing benzene for 2.5 h delivered 5 (55%).
(16) Compounds 6–8, see: Couture, A.; Deniau, E.;
Grandclaudon, P.; Simion, C. Synthesis 1993, 1227.
(17) Absence of Pd(PPh3)4 resulted in the recovery of starting
enamine 1.
(18) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676.
(19) Napieraj, A.; Zawadzki, S.; Zwierzak, A. Tetrahedron 2000,
56, 6299.
Anal. Calcd for C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29. Found:
C, 61.63; H, 4.41; N, 10.20.
Acknowledgment
We are grateful to NSERC for a scholarship to Myriam April. We
thank Yves Leblanc, Carl Berthelette, Lianhai Li and Claudio Stu-
rino for their helpful discussion and suggestions.
References
(20) Love, B. E.; Ren, J. J. Org. Chem. 1993, 58, 5556.
(21) Lachance, N.; Chan, W. Y. J. Heterocycl. Chem. 2003, 40,
289.
(22) Mazéas, D.; Guillaumet, G.; Viaud, M.-C. Heterocycles
1999, 50, 1065.
(23) For comparison, we have repeated the condensation step at
160 °C for 20 min with PPTS (0.05 equiv) for entries 4 and
5 from Table 3. Azaindole 28 has been obtained in 62%
isolated yield whereas only decomposition was observed
when 22 and 25 were submitted to the same conditions.
(24) Roy, P. J.; Dufresne, C.; Lachance, N.; Leclerc, J.-P.;
Boisvert, M.; Wang, Z.; Leblanc, Y. Synthesis 2005, in
press.
(25) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39,
5355; and references therein.
(26) Mazéas, D.; Guillaumet, G.; Viaud, M.-C. Heterocycles
1999, 50, 1065.
(27) Frydman, B.; Reil, S. J.; Boned, J.; Rapoport, H. J. Org.
Chem. 1968, 3762.
(28) Fisher, M. H.; Matzuk, A. R. J. Heterocycl. Chem. 1969,
775.
(1) For reviews on indoles and azaindoles synthesis, see:
(a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045. (b) Mérour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001,
5, 471.
(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,
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Chem. 2003, 46, 4702. (b) Sanderson, P. E. J.; Stanton, M.
G.; Dorsey, B. D.; Lyle, T. A.; McDonough, C.; Sanders, W.
M.; Savage, K. L.; Naylor-Olsen, A. M.; Krueger, J. A.;
Lewis, S. D.; Lucas, B. J.; Lynch, J. J.; Yan, Y. Bioorg. Med.
Chem. Lett. 2003, 13, 795. (c) Ujjainwalla, F.; Walsh, T. F.
Tetrahedron Lett. 2001, 42, 6441.
(3) Blache, Y.; Sinibaldi-Troin, M.-E.; Voldoire, A.;
Chavignon, O.; Gramain, J.-C.; Teulade, J.-C.; Chapat, J.-P.
J. Org. Chem. 1997, 62, 8553.
Synthesis 2005, No. 15, 2571–2577 © Thieme Stuttgart · New York