Synthesis of 5,7-dichloro-6-azaindoles and functionalization via a highly selective lithium-chlorine exchange

Article abstract of DOI:10.1055/s-0028-1083354

The synthesis of a range of novel 5,7-dichloro-6-azain- doles through the use of a Fischer cyclization with pyridine hydro- chloride in N-methylpyrrolidin-2-one is described. Dichloro-6- azaindoles are versatile compounds that can be selectively substitut

Full text of DOI:10.1055/s-0028-1083354

PAPER
721
Synthesis of 5,7-Dichloro-6-azaindoles and Functionalization via a Highly
Selective Lithium–Chlorine Exchange
S
ynthesis and Fun
i
c
tionali
c
z
ation of
5
o
6
l
-azain
a
doles s Lachance,* Louis-Philippe Bonhomme-Beaulieu, Pascal Joly
Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, QC, H9R 4P8, Canada
Fax +1(514)4284900; E-mail: nicolas_lachance@merck.com
Received 8 October 2008; revised 11 November 2008
undocumented.4b We elected the Fischer indole reaction
as a route of choice for the synthesis of the desired 5,7-
dichloro-6-azaindoles 5, since the palladium-catalyzed
cross-coupling reaction between ketones and 3-amino-
Abstract: The synthesis of a range of novel 5,7-dichloro-6-azain-
doles through the use of a Fischer cyclization with pyridine hydro-
chloride in N-methylpyrrolidin-2-one is described. Dichloro-6-
azaindoles are versatile compounds that can be selectively substitut-
ed through a palladium-catalyzed cross-coupling reaction or a high- 2,4-dichloropyridines is known to lead to 7-chloro-4-
azaindoles.10 Our approach relies on access to the
yielding lithium–chlorine exchange.
corresponding 2,6-dichloro-3-hydrazinopyridine (2) in-
termediate. Following established literature conditions,11b
the requisite hydrazine precursor 2 was synthesized in
80% yield from commercially available 3-amino-2,6-
dichloropyridine (1) on a 120 mmol scale (20 g)
(Scheme 1).
Key words: azaindole, pyrrolopyridine, Fischer cyclizations, meta-
lations, palladium
The chemistry of indole heterocycles is of great interest to
the pharmaceutical industry as a result of the diverse bio-
logical properties observed for this core.1–3 More recently,
interest has increased around the use of azaindoles as in-
doles surrogates, as a consequence of the differential ac-
tivity and in vivo properties these basic indoles often
display.4,5 As part of our research program on azain-
doles,6,7 we required an efficient route to access 5,7-disub-
stituted 6-azaindoles. Although numerous methods are
available for the preparation of 6-azaindoles,5a,b,d these
methods suffer from lengthy synthesis, low compatibility
to labile functional groups, and difficulty in the synthesis
of complex starting materials. A better approach for our
purposes would be to avoid a de novo synthesis for each
substrate and to rather synthesize a common functional-
ized 5,7-disubstituted 6-azaindole which could readily be
diversified to yield different analogues. We envisioned
that a common 5,7-dichloro-6-azaindole would allow en-
try into more functionalized molecules, through halogen
substitution or cross-coupling reactions.8,9 Critical to the
realization of this approach would be the discovery of
conditions that enable the selective functionalization of
the 5,7-dichloro-6-azaindole template.
R2
4
3
Cl
Cl
5
2
R1
N
6 N
N1
H
NH2
7
Cl
Cl
1
5a–e
1) NaNO2, HCl (concd)
2) SnCl2, –10 °C
3) NaOH (10 N)
Py⋅HCl
NMP
160 °C
O
R2
Cl
Cl
R1
R1
R2
3a–e
N
NH2
N
N
N
N
H
H
Cl
Cl
2
4a–e
Scheme 1 Synthesis of 5,7-dichloro-6-azaindoles
Having in hand this starting material 2, preliminary stud-
ies focused on optimization of the Fischer cyclization.11
We selected the hydrazone 4a, easily prepared from
cyclohexanone 3a and hydrazine 2, to screen a variety of
acids (Py·HCl, ZnCl2, NH4Cl, AcOH) and solvents (neat,
Ph2O, 1,2-dichlorobenzene, NMP, pyridine). By submit-
ting the hydrazone 4a under the combination of pyridine
hydrochloride in N-methylpyrrolidin-2-one at 160 °C for
30 minutes, a 57% isolated yield of the azaindole 5a was
obtained. The optimal conditions that we found, starting
from the hydrazine 2, are as follows: step 1: hydrazine 2
(9.27 mmol), ketone (1.1 equiv), NMP (1.2 M), r.t., 1 h;
step 2: Py·HCl (3.0 equiv), 160 °C, 1 h. As we evaluated
the effects of solvent, it was noted that the presence of py-
ridine completely inhibited the reaction. This fact high-
lights the need to keep the system open to the air, or in a
similar way, to allow free pyridine liberated from pyridine
hydrochloride to be removed.12 We noted that purification
Herein, we report the preparation and further transforma-
tion of 5,7-dichloro-6-azaindoles. These compounds can
be converted into diverse 6-azaindole derivatives via a
highly selective lithium–chlorine exchange that allows for
the functionalization of 6-azaindoles in the 7-position. In
addition, we have discovered suitable conditions for the
selective arylation of 6-azaindoles in the 7-position under
Suzuki–Miyaura cross-coupling conditions.
To the best of our knowledge, the synthesis of 5,7-dichlo-
ro-6-azaindoles and their synthetic utility appears to be
SYNTHESIS 2009, No. 5, pp 0721–0730
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Advanced online publication: 02.02.2009
DOI: 10.1055/s-0028-1083354; Art ID: M05808SS
© Georg Thieme Verlag Stuttgart · New York

722
N. Lachance et al.
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Table 1 Synthesis of 5,7-Dichloro-6-azaindolesa
of the preformed hydrazone 4a had no impact on the out-
come of the reaction.
Entry Ketone
Product
Time Yieldb
(h) (%)
Using the Fischer cyclizations conditions developed with
pyridine hydrochloride at 160 °C, a range of 5,7-dichloro-
6-azaindoles 5a–e were prepared in good to moderate
yields (Table 1). Regiochemistry of 6-azaindoles 5a–e
has been confirmed with NOE experiments (Figure 1).
Better yields were obtained with the larger ring cyclohex-
anone (3a) and cycloheptanone (3b) than with the smaller
ring cyclopentanone (3c) (Table 1, entries 1–3). For the
latter, the low yield may be ascribed to the Fischer cy-
clization step where extensive decomposition occurred
and the starting aminopyridine 1 was isolated in 28%
yield.13 Considering the Fischer indolization, the 29–63%
yields obtained for the 6-azaindoles 5a–e still compares
favorably with formation of the corresponding dehaloge-
nated 6-azaindoles for which the yields vary between 3–
10%.11c Also, for comparison, a 7-chloro-6-azaindole has
been previously prepared by Tacconi with zinc chloride/
sodium chloride at 165–170 °C in 27% isolated yield.14
Cl
1
2
3a
3b
5a
1
63
O
N
N
H
Cl
Cl
Cl
Cl
Cl
5b
2.5 55
O
O
N
N
N
N
N
H
Cl
Cl
Cl
Cl
3
4
5
3c
3d
3e
5c
5d
5e
2.5 37
N
H
2.5 39
O
O
Having established conditions suitable for the synthesis of
the 5,7-dichloro-6-azaindole templates 5a–e, our efforts
turned to finding methods that would allow selective func-
tionalization of the chlorine atoms, in order to gain access
to substituted 6-azaindoles. We initially investigated the
reduction of the chlorine atoms present on 5,7-dichloro-6-
azaindoles 5a–e (Scheme 2). After methylating the indole
nitrogen, both chlorine atoms on the azaindole 6 could be
removed by catalytic hydrogenation with Pearlman’s cat-
alyst to give a 92% isolated yield of 6-azaindole 7.
N
H
6
29c
N
H
a Reaction conditions: step 1: hydrazine 2 (9.27 mmol), ketones 3a–e
(1.1 equiv), NMP (1.2 M), r.t., 30–60 min; step 2: Py·HCl (3.0 equiv),
160 °C, 1–6 h.
b Isolated yield.
We next explored a lithium–chlorine exchange on azain-
dole 6 as a means to selectively functionalize one of the
chlorinated positions of the 5,7-dichloro-6-azaindole
(Scheme 2).15,16 Treatment of azaindole 6 with tert-butyl-
lithium and quenching the resultant anion with water af-
forded 5-chloro-6-azaindole 8 in 95% yield. Surprisingly,
this compound 8 remains unreacted after being submitted
again to the lithium–chlorine exchange conditions. More-
over, when the medium was quenched with deuterium ox-
ide in the metalation experiments with azaindoles 6 and 8,
it produced, counterintuitively, the same deuterated azain-
c Step 1: 15 min at 160 °C.
dole 9. Indeed, the lithiation occurs favorably at the 7-po-
sition and 1H NMR of the unpurified reaction mixture did
not show any incorporation of deuterium on the 2-alkyl
substituent, or at the 4-position, as expected.17 These
results are in contrast to literature ortho-lithiations direct-
ed by the chlorine atom on 4-chloro-7-azaindoles or with
halogenated pyridines.18,19
Cl
Cl
5
1. NaH
H2, Pd(OH)2/C
92%
N
2. MeI
DMF
N
N
N
N
N
7
H
Me
Me
Cl
Cl
97%
5a
6
7
1. t-BuLi
2. D2O
1. t-BuLi
2. H2O
1. t-BuLi
2. H2O
95%
94%
1. t-BuLi
2. D2O
Cl
Cl
N
N
quantitative
N
N
Me
Me
D
H
9
8
Scheme 2 Reactivity of chlorine atoms on azaindole 6
Synthesis 2009, No. 5, 721–730 © Thieme Stuttgart · New York

PAPER
Synthesis and Functionalization of 5,7-Dichloro-6-azaindoles
723
We sought to take advantage of this remarkably selective ing N,N-dimethylformamide as the electrophile, the 7-
lithium–chlorine exchange at the 7-position of 5,7-dichlo- formyl derivative 11 was isolated in 96% yield (Table 2,
ro-6-azaindole as a means to prepare a series of 5,7-disub- entry 2). In addition, an acrylic ethyl ester group could be
stituted 6-azaindoles. We further explored the metalation introduced in 83–84% yield after in situ Wadsworth–Hor-
with tert-butyllithium using a series of 6-azaindoles and ner–Emmons reaction by the sequential addition of N,N-
selected electrophiles. Table 2 presents our results in in- dimethylformamide and triethyl phosphonoacetate
troducing several functional groups to the azaindole core (Table 2, entries 3 and 7). The tert-butyl ester group can
via a metalation strategy. For example, the 7-chlorine be introduced directly at the 7-position in 61% yield by
atom can be replaced by the more reactive bromine in using di-tert-butyl dicarbonate as the electrophile
95% yield by using 1,2-dibromo-1,1,2,2-tetrafluoroet- (Table 2, entry 4), and tertiary alcohols 14 and 16 were
hane as the bromine source (Table 2, entry 1).20 Employ- synthesized from 6-azaindoles 6 and 15 using acetone as
Table 2 Synthesis of 7-Substituted 6-Azaindolesa
Entry
Substrate
Electrophile
Product
Yieldb (%)
95
Cl
1
6
CF2BrCF2Br
10
11
N
N
N
N
Me
Br
Cl
Cl
2
3
DMF
96
84
6
6
N
Me
CHO
1. DMF
2. (EtO)2P(O)CH2CO2Et
12
N
Me
CO2Et
Cl
4
5
Boc2O
13
14
61
75
6
6
N
t-BuO2C
Cl
N
Me
acetone
N
N
Me
OH
Cl
Cl
6
acetone
16
69
15
N
N
N
N
N
Me
Me
Cl
Cl
OH
Cl
Cl
1. DMF
2. (EtO)2P(O)CH2CO2Et
N
7
8
18
6
83
94
N
17
N
SEM
SEM
CO2Et
8
CCl3CCl3
a Reaction conditions: step 1: substrate (0.5 mmol), t-BuLi (1.7 equiv), –78 °C, 2 h; step 2: electrophile (2.0 equiv), –78 °C, 1 h.
b Isolated yield.
Synthesis 2009, No. 5, 721–730 © Thieme Stuttgart · New York

724
N. Lachance et al.
PAPER
an electrophile (Table 2, entries 5 and 6). Moreover, As a further demonstration of the differential reactivity of
groups easier to remove than the methyl on the indole ni- the chlorine atoms in the 5,7-dichloro-6-azaindole 6, we
trogen could be used, such as 2-(trimethylsi- performed a palladium-catalyzed cross-coupling reaction
lyl)ethoxy]methyl (SEM), to perform the highly selective with 5,7-dichloro-6-azaindole 6 and 1.1 equivalent of the
lithium–chlorine exchange (Table 2, entry 7). Finally, a boronic acid 19 (Equation 1). Here, the 7-aryl-6-azaindole
complementary method to the Fischer cyclization for the 22 and the 5,7-diaryl-6-azaindoles 23 were isolated in
preparation of a 5,7-dichloro-6-azaindole could start from 82% and 12% respectively; regiochemistry of 22 has been
the corresponding 5-chloro-6-azaindole (Table 2, entry confirmed with NOE experiments (Figure 1).22 This result
8).4c
demonstrates once again the greater reactivity of the chlo-
rine at the 7-position of azaindole 6.
While chlorine at the 5-position of the azaindole 6 is un-
reactive under lithium–chlorine exchange conditions, it Interestingly, as documented for pyridines,23 the basic ni-
can be converted into new functional groups using trogen in the 6-azaindole core directs an ortho-lithiation
Suzuki–Miyaura cross-coupling chemistry (Scheme 3). onto an aromatic ring resulting in further elaboration of 21
Under Guram’s conditions,21 the coupling of azaindole 8 and 22 into 24 and 25 (Equations 2 and 3). Regiochemis-
(0.5 mmol scale) with boronic acid 19 could be realized try of 6-azaindoles 24 and 25 has been confirmed with
by employing only 3 mol% of the highly active palladium NOESY and gHSQCAD experiments (Figure 2).
catalyst 20. After purification, the 5-aryl-6-azaindole 21
was obtained in 91% yield.
HO
OH
F
B
F
20 (3 mol%)
Cl
+
K2CO3 (2.0 equiv)
toluene/H2O (9:1)
100 °C, 1 h
N
N
N
N
Me
Me
8
19
21
91%
Catalyst:
Me
Cl
Me
Me
Pd
N
P
P
N
Me
Cl
20
Scheme 3 Suzuki–Miyaura coupling of 5-chloro-6-azaindole 8
F
HO
OH
B
Cl
Cl
5
20 (3 mol%)
+
+
N
N
N
K2CO3 (2.0 equiv)
toluene/H2O (9:1)
100 °C, 1 h
N
N
N
7
Me
Me
Me
Cl
F
19 (1.1 equiv)
22, 82%
6
23, 12%
F
F
Equation 1 Selective Suzuki–Miyaura coupling of 5-chloro-6-azaindole 6
NOE
H
NOE
H
Cl
H
H
H
NOE
H
H
H
H
N
H
n
N
Cl
Cl
H
H
NOE
H
H
H
N
N
H
H
N
N
H
H
H
NOE
NOE
Cl
Cl
NOE
22
5a–d: n = 0,1,2,3
5e
F
Figure 1 NOE experiments
Synthesis 2009, No. 5, 721–730 © Thieme Stuttgart · New York

PAPER
Synthesis and Functionalization of 5,7-Dichloro-6-azaindoles
725
scopic electrophiles (Table 2) were placed under high vacuum for
drying, prior to use. Column chromatography was conducted with
silica gel 230–400 mesh. Elemental analyses were determined by
Prevalere Life Science, Inc., Whitesboro, NY.
F
F
1. t-BuLi
2. CCl3CCl3
87%
H
N
Cl
N
N
N
2,6-Dichloro-3-hydrazinopyridine (2)
Me
Me
Into a 2-L Erlenmeyer flask equipped with a large magnetic stirrer
bar, 3-amino-2,6-dichloropyridine (1, 20.00 g, 123 mmol) was
mixed with concd HCl (37%, 180 mL) and stirred at r.t. for 30 min
and then it was cooled to –20 °C. Then, a soln of NaNO2 (10.58 g,
153 mmol) dissolved in H2O (50 mL) was added to the suspension
over 15 min, keeping the internal temperature between –20 to –10
°C. After completion of the addition, the mixture was slowly
warmed to 0 °C over 20 min and maintained at this temperature for
an additional 1.5 h with continuous stirring. Finally, the suspension
was cooled again to –10 °C before a soln of SnCl2 (70.05 g, 369
mmol) in concd HCl (37%, 180 mL) was added over 40 min, keep-
ing the internal temperature below 0 °C. The final mixture was
slowly warmed to r.t. over 1 h and kept at this temperature for 2 h
with continuous stirring. The acidic soln was basified with 10 M
NaOH (700 mL), without exceeding an internal temperature of 20
°C. The suspension was extracted with CHCl3 (2 L) and the organic
phase was separated. The aqueous phase was extracted again with
CHCl3 (2 × 500 mL). All the organic phases were combined, dried
(MgSO4), and filtered and the filtrate was concentrated in vacuo.
The residue was purified by overnight trituration (15% CHCl3–hex-
anes, 1 L) to afford 2 as a tan solid (80%); mp 153–154 °C (toluene).
21
24
Equation 2 ortho-Lithiation of 5-aryl-6-azaindole 21
Cl
Cl
N
N
N
N
1. t-BuLi
2. DMF
Me
Me
EtO2C
H
3. (EtO)2P(O)CH2CO2Et
22
25
97%
F
F
Equation 3 ortho-Lithiation of 7-aryl-6-azaindole 22
Cl
NOE
F
H
H
N
N
H
NOE
H
H
H
H
Cl
1H NMR (DMSO-d6): d = 7.56 (d, J = 8.5 Hz, 1 H), 7.34 (d, J = 8.5
Hz, 1 H), 7.08 (br s, 1 H), 4.32 (br s, 2 H).
13C NMR (DMSO-d6): d = 143.9, 133.3, 131.1, 123.7, 122.6.
HRMS (ESI): m/z [M + H]+ calcd for C5H6Cl2N3: 177.9933; found:
EtO2C
N
N
NOE
25
Me
24
F
Figure 2 NOESY experiments
177.9933.
Anal. Calcd for C5H5Cl2N3: C, 33.73; H, 2.83; N, 23.60. Found: C,
33.97; H, 2.72; N, 24.02.
Cyclohexanone (2,6-Dichloropyridin-3-yl)hydrazone (4a)
A neat mixture of cyclohexanone (3a, 6.00 mL, 57.9 mmol) and 2
(4.55 g, 25.6 mmol) was stirred at r.t. for 30 min. Then, excess of 3a
was distilled off by gentle heating under high vacuum. The residue
was purified by column chromatography (silica gel, 0–30% EtOAc–
hexanes) followed by trituration (heptane, –78 °C) to give 4a (86%)
as a yellow solid; mp 50–52 °C.
1H NMR (DMSO-d6): d = 8.35 (s, 1 H), 7.74 (d, J = 8.5 Hz, 1 H),
7.37 (d, J = 8.5 Hz, 1 H), 2.44–2.38 (m, 2 H), 2.32–2.26 (m, 2 H),
1.74–1.50 (m, 6 H).
13C NMR (DMSO-d6): d = 158.1, 139.4, 136.0, 132.5, 124.5, 124.0,
34.9, 26.71, 26.66, 25.3, 25.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H14Cl2N3: 258.0559;
found: 258.0559.
In summary, we have described the first synthesis of 5,7-
dichloro-6-azaindoles by use of a Fischer indole reaction
with pyridine hydrochloride in N-methylpyrrolidin-2-one
at 160 °C. These 5,7-dichloro-6-azaindoles are versatile
templates that can be selectively functionalized via a
lithium–chlorine exchange or Suzuki–Miyaura cross-
coupling reaction. The efficiency of this method, which
relies on an unprecedented lithium–chlorine exchange on
azaindoles (instead of an expected ortho-lithiation),
makes this an important addition to the synthetic method-
ology for 5,7-disubstituted 6-azaindole analogues. Further
efforts to improve the synthesis and selective functional-
ization of 5,7-dichloro-6-azaindoles are currently being
investigated within our laboratory.
5,7-Dichloro-6-azaindoles 5a–e; General Procedure for Fischer
Cyclizations
Melting points were determined on a Mettler FP61 apparatus and
are uncorrected. 1H and 13C NMR spectra were recorded in acetone-
d6 or DMSO-d6 at room temperature on a Bruker Avance II 400
MHz spectrometer. Additional 2D experiments were conducted on
Varian Inova 600 MHz spectrometer equipped with a cryogenic
probe. The spectra were referenced to residual protons in the NMR
solvent [acetone-d6: 1H NMR d = 2.04 (quintet), 13C NMR d = 29.8
The reactions were performed under the ambient atmosphere: i.e. no
septum, no cap, no reflux condenser, and no N2 flow were used (ex-
cept 5e: a flow of N2 was placed for the last 5 h of heating). All
Fischer cyclizations (Table 1) were typically performed on an 8.43
mmol scale. Into a 25-mL round bottom flask, ketone 3 (1.1 equiv)
was added to a soln of 2 (1.50 g, 8.43 mmol) in NMP (7.50 mL) and
the mixture was stirred at r.t. for 30–60 min (except 5e: additional
15 min at 160 °C). Anhyd Py·HCl (2.92 g, 25.3 mmol) was added
to the mixture at r.t., then immersed into a preheated oil bath at 160
°C. After heating for 1–6 h (see Table 1; the reaction progresses by
removal of free pyridine), the reaction was cooled to r.t., neutralized
with aq NaHCO3 and extracted with EtOAc. When necessary, the
phases were filtered through a Celite pad before their separation.
(heptet), 206.0 (singlet); DMSO-d6: 1H NMR d = 2.49 (quintet); 13
C
NMR d = 39.5 (heptet)]. HRMS (ESI) data were acquired on an
Agilent LC/MSD TOF high-resolution mass spectrometer. TLC
analyses were performed on Merck Kieselgel 60 F254 plates. 3-Ami-
no-2,6-dichloropyridine (1) was obtained from Acros. 1.7 M t-BuLi
in pentane and Pd catalyst 20 were purchased from Aldrich. Hygro-
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726
N. Lachance et al.
PAPER
The aqueous phase was further extracted with EtOAc. The organic
layers were combined, washed with water and brine, dried
(Na2SO4), and filtered and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography (silica gel, 0–
50% EtOAc–hexanes) to give the corresponding azaindoles 5a–e.
1H NMR (DMSO-d6): d = 11.79 (br s, 1 H), 7.50 (s, 1 H), 2.37 (s, 3
H), 2.13 (s, 3 H).
13C NMR (DMSO-d6): d = 140.9, 137.9, 135.9, 130.1, 127.8, 111.5,
107.3, 11.4, 8.1.
HRMS (ESI): m/z [M + H]+ calcd for C9H9Cl2N2: 215.0137; found:
215.0139.
1,3-Dichloro-6,7,8,9-tetrahydro-5H-b-carboline (5a)
Method 1: Into a 25-mL round-bottom flask open to the air, a mix-
ture of 4a (2.5 g, 9.68 mmol) and Py·HCl (3.36 g, 29.1 mmol) in
NMP (8.00 mL) was immersed into a preheated oil bath at 160 °C.
After 30 min, the reaction was cooled to r.t., neutralized with aq
NaHCO3 and extracted with EtOAc (2 ×). The organic layers were
combined, washed with H2O and brine, dried (Na2SO4), and filtered
and the filtrate was concentrated in vacuo. The residue was purified
by column chromatography (silica gel, 0–50% EtOAc–hexanes) to
afford 5a (57%) as a white solid.
Anal. Calcd for C9H8Cl2N2: C, 50.26; H, 3.75; N, 13.02. Found: C,
50.22; H, 3.72; N, 13.16.
5,7-Dichloro-3-methyl-2-phenyl-1H-pyrrolo[2,3-c]pyridine (5e)
Following the general procedure (Fischer cyclizations) using 2 and
3e (1.23 mL, 9.27 mmol) (step 1: 160 °C for an additional 15 min)
gave 5e (29%) as a beige solid; mp 129–131 °C.
1H NMR (DMSO-d6): d = 12.12 (br s, 1 H), 7.73–7.68 (m, 3 H),
7.55 (t, J = 7.5 Hz, 2 H), 7.48 (t, J = 7.3 Hz, 1 H), 2.34 (s, 3 H).
13C NMR (DMSO-d6): d = 141.9, 138.3, 136.3, 131.2, 130.8, 129.0
(2 C), 128.8, 128.7, 128.6 (2 C), 112.5, 108.4, 9.5.
HRMS (ESI): m/z [M + H]+ calcd for C14H11Cl2N2: 277.0294;
found: 277.0295.
Method 2: Following the general procedure (Fischer cyclizations)
using 2 and 3a (960 mL, 9.27 mmol) gave 5a (63%) as a white solid;
mp 192–193 °C.
1H NMR (DMSO-d6): d = 11.75 (br s, 1 H), 7.44 (s, 1 H), 2.74 (t,
J = 6.0 Hz, 2 H), 2.58 (t, J = 5.9 Hz, 2 H), 1.85–1.73 (m, 4 H).
Anal. Calcd for C14H10Cl2N2: C, 60.67; H, 3.64; N, 10.11. Found:
C, 60.76; H, 3.48; N, 10.07.
13C NMR (DMSO-d6): d = 143.4, 136.3, 135.9, 130.3, 128.3, 111.4,
110.0, 22.9, 22.3, 22.2, 20.3.
HRMS (ESI): m/z [M + H]+ calcd for C11H11Cl2N2: 241.0294;
found: 241.0293.
N-Alkyl-5,7-dichloro-6-azaindoles 6, 15, and 17; General Proce-
dure for N-Alkylations
To a stirred suspension (or soln) of dichloro-6-azaindole (1.0 equiv)
in DMF (0.4 M) at 0 °C, was added carefully NaH (60% w/w) (1.25
equiv). The mixture was stirred at 0 °C for 10 min, then, alkyl halide
(1.25 equiv) was added and the final suspension was warmed to r.t.
After 30 min, the suspension was poured into aq NaHCO3 and ex-
tracted with EtOAc (2 ×). The organic layers were combined,
washed with H2O (2 ×) and brine, dried (Na2SO4), and filtered and
the filtrate was concentrated in vacuo. The residue was purified by
column chromatography (silica gel, 0–30% EtOAc–hexanes), or by
trituration with heptane, to give the corresponding N-alkylated aza-
indoles 6, 15, and 17.
Anal. Calcd for C11H10Cl2N2: C, 54.79; H, 4.18; N, 11.62. Found:
C, 54.69; H, 3.97; N, 11.66.
1,3-Dichloro-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrro-
lo[2,3-c]pyridine (5b)
Following the general procedure (Fischer cyclizations) using 2 and
3b (1.09 mL, 9.27 mmol) gave 5b (55%) as a beige solid; mp 161–
163 °C.
1H NMR (DMSO-d6): d = 11.78 (br s, 1 H), 7.51 (s, 1 H), 2.92–2.86
(m, 2 H), 2.73–2.67 (m, 2 H), 1.86–1.78 (m, 2 H), 1.72–1.57 (m, 4
H).
13C NMR (DMSO-d6): d = 147.4, 137.4, 136.0, 130.3, 126.9, 114.1,
111.3, 31.2, 28.2, 28.0, 26.4, 24.0.
5-Chloro-6-azaindoles 6, 8–14, 16, 18, 24, and 25; General Pro-
cedure for Lithium–Chlorine Exchange
Crystalline 6-azaindole reagents were milled with a mortar and pes-
tle to a fine powder before use. All lithium–chlorine exchanges
(Table 2, Scheme 2, and Equations 2 and 3) were typically per-
formed on a 0.5 mmol scale based on the 6-azaindole. To a suspen-
sion (or soln) of 6-azaindole (0.5 mmol) in anhyd Et2O (7 mL)
under N2 at –78 °C, t-BuLi (500 mL, 0.85 mmol) was slowly added
dropwise over 5 min and the resulting mixture was stirred at –78 °C
for 2 h after the addition. Electrophile (3.0 equiv) was then added
rapidly, and the resulting mixture was stirred at –78 °C for 1 h.
[Only for in situ Wadsworth–Horner–Emmons reactions of the syn-
thesis of 12, 18, and 25: Prior to the quench, the mixture was treated
with triethyl phosphonoacetate (300 mL, 1.51 mmol) and was al-
lowed to warm to r.t. for 1 h.] The cold reaction mixture was then
quenched by the addition of aq NaHCO3 (3 mL). The suspension
was poured into aq NaHCO3 and extracted with EtOAc (2 ×). The
organic layers were combined, washed with brine, dried (Na2SO4),
and filtered and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography (silica gel, suitable
EtOAc–hexanes mixtures and/or CH2Cl2–hexanes mixture), or by
trituration (heptane), to give the corresponding azaindoles 6, 8–14,
16, 18, 24, and 25.
HRMS (ESI): m/z [M + H]+ calcd for C12H13Cl2N2: 255.0450;
found: 255.0450.
Anal. Calcd for C12H12Cl2N2: C, 56.49; H, 4.74; N, 10.98. Found:
C, 56.55; H, 4.67; N, 11.07.
1,3-Dichloro-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-
c]pyridine (5c)
Following the general procedure (Fischer cyclizations) using 2 and
3c (820 mL, 9.27 mmol) and after a second purification by column
chromatography (silica gel, 0–100% CH2Cl2–hexanes) gave 5c
(37%) as a white solid; mp 175–177 °C (toluene).
1H NMR (DMSO-d6): d = 11.96 (br s, 1 H), 7.43 (s, 1 H), 2.87 (t,
J = 7.3 Hz, 2 H), 2.72 (t, J = 7.0 Hz, 2 H), 2.51–2.43 (m, 2 H).
13C NMR (DMSO-d6): d = 153.4, 136.4, 133.1, 132.6, 130.6, 119.0,
111.9, 28.1, 25.2, 23.5.
HRMS (ESI): m/z [M + H]+ calcd for C10H9Cl2N2: 227.0137; found:
227.0140.
Anal. Calcd for C10H8Cl2N2: C, 52.89; H, 3.55; N, 12.34. Found: C,
52.92; H, 3.41; N, 12.44.
1,3-Dichloro-9-methyl-6,7,8,9-tetrahydro-5H-b-carboline (6)
Method 1: Following the general procedure (N-alkylations) using
5a (1.40 g, 5.81 mmol), DMF (14 mL), NaH (60% w/w) (290 mg,
7.25 mmol), and MeI (450 mL, 7.26 mmol) and after purification by
trituration (heptane) gave 6 (97%) as a white solid.
5,7-Dichloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (5d)
Following the general procedure (Fischer cyclizations) using 2 and
3d (830 mL, 9.27 mmol) gave 5d (39%) as a beige solid; mp 174–
175 °C (toluene).
Synthesis 2009, No. 5, 721–730 © Thieme Stuttgart · New York

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Synthesis and Functionalization of 5,7-Dichloro-6-azaindoles
727
Method 2: Following the general procedure (lithium–chlorine ex-
change) using 8 (110 mg, 0.50 mmol) and hexachloroethane (354
mg, 1.50 mmol) and after purification by column chromatography
(silica gel, 0–20% EtOAc–hexanes) gave 6 (94%) as a white solid;
mp 145–146 °C.
1H NMR (acetone-d6): d = 7.34 (s, 1 H), 3.97 (s, 3 H), 2.81–2.75 (m,
2 H), 2.63 (t, J = 6.2 Hz, 2 H), 1.96–1.89 (m, 2 H), 1.86–1.78 (m, 2
1H NMR (DMSO-d6): d = 7.38 (s, 1 H), 3.67 (s, 3 H), 2.72 (t, J = 6.1
Hz, 2 H), 2.58 (t, J = 6.0 Hz, 2 H), 1.89–1.80 (m, 2 H), 1.78–1.70
(m, 2 H).
13C NMR (DMSO-d6): d = 143.0, 138.6, 133.8, 132.8, 130.7 (t,
JCD = 27.4 Hz), 111.0, 108.1, 29.3, 22.3, 22.2, 21.4, 20.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H13DClN2: 222.0903;
found: 222.0902.
H).
13C NMR (acetone-d6): d = 145.7, 138.4, 137.3, 131.3, 129.3, 112.1,
110.7, 32.1, 23.4, 23.3, 22.9, 21.2.
1-Bromo-3-chloro-9-methyl-6,7,8,9-tetrahydro-5H-b-carboline
(10)
Following the general procedure (lithium–chlorine exchange) using
6 (128 mg, 0.50 mmol) and 1,2-dibromo-1,1,2,2-tetrafluoroethane
(180 mL, 1.50 mmol) and purification by trituration (heptane, 2–3
mL) gave 10 (95%) as a beige solid; mp 152–153 °C.
1H NMR (acetone-d6): d = 7.36 (s, 1 H), 3.99 (s, 3 H), 2.80–2.74 (m,
2 H), 2.63 (t, J = 6.1 Hz, 2 H), 1.98–1.87 (m, 2 H), 1.86–1.78 (m, 2
HRMS (ESI): m/z [M + H]+ calcd for C12H13Cl2N2: 255.0450;
found: 255.0450.
9-Methyl-6,7,8,9-tetrahydro-5H-b-carboline (7)
A suspension of 6 (128 mg, 0.50 mmol) and Pearlman’s catalyst
[20% Pd(OH)2 on carbon, 14 mg] in anhyd EtOH (5 mL) was de-
gassed by bubbling N2 for 10 min. Then, an atmosphere of H2 was
introduced via a balloon. After overnight stirring at r.t., the H2 at-
mosphere was replaced with N2. The medium was diluted with
CH2Cl2 (5 mL) and the HCl salt formed was neutralized with
Hünig’s base (260 mL, 1.51 mmol) and stirred for 30 min. The crude
mixture was filtered through a pad of Celite and rinsed with a mix-
ture of 50% EtOH–CH2Cl2 (2 ×). The filtrate was concentrated in
vacuo and the resulting material was diluted with CH2Cl2, washed
with aq NaHCO3 and the aqueous layer was further extracted with
CH2Cl2 (2 ×). The organic layers were combined, dried (MgSO4),
and filtered and the filtrate was concentrated in vacuo. The residue
was purified by trituration with heptane (2 × 1 mL) to give 7 (92%)
as a beige solid; mp 103–105 °C.
H).
13C NMR (acetone-d6): d = 145.8, 138.0, 137.5, 131.1, 120.5, 112.2,
110.5, 32.1, 23.4, 23.3, 23.0, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H13BrClN2: 298.9945;
found: 298.9944.
3-Chloro-9-methyl-6,7,8,9-tetrahydro-5H-b-carboline-1-carb-
aldehyde (11)
Following the general procedure (lithium–chlorine exchange) using
6 (128 mg, 0.50 mmol) and DMF (120 mL, 1.51 mmol) and purifi-
cation by column chromatography (silica gel, 0–70% EtOAc–hex-
anes) gave 11 (96%) as a yellow solid; mp 196–198 °C.
1H NMR (DMSO-d6): d = 10.00 (s, 1 H), 7.76 (s, 1 H), 3.86 (s, 3 H),
2.76 (t, J = 6.2 Hz, 2 H), 2.62 (t, J = 6.0 Hz, 2 H), 1.92–1.83 (m, 2
H), 1.79–1.71 (m, 2 H).
13C NMR (DMSO-d6): d = 191.9, 145.9, 138.4, 137.3, 136.3, 130.8,
116.3, 109.6, 33.8, 22.2, 22.0, 21.9, 20.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H14ClN2O: 249.0789;
found: 249.0789.
1H NMR (acetone-d6): d = 8.64 (s, 1 H), 8.08 (d, J = 5.4 Hz, 1 H),
7.29 (d, J = 5.4 Hz, 1 H), 3.72 (s, 3 H), 2.75 (t, J = 6.2 Hz, 2 H), 2.65
(t, J = 6.0 Hz, 2 H), 1.96–1.87 (m, 2 H), 1.85–1.77 (m, 2 H).
13C NMR (acetone-d6): d = 140.7, 138.7, 134.8, 132.5, 132.1, 112.6,
109.2, 29.3, 23.7, 23.6, 22.4, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C12H15N2: 187.1230; found:
187.1229.
Ethyl (2E)-3-(3-Chloro-9-methyl-6,7,8,9-tetrahydro-5H-b-car-
bolin-1-yl)acrylate (12)
Following the general procedure (lithium–chlorine exchange) using
6 (128 mg, 0.50 mmol), DMF (120 mL, 1.51 mmol), and triethyl
phosphonoacetate (300 mL, 1.51 mmol) and purification by column
chromatography (silica gel, 0–40% EtOAc–hexanes) gave 12
(84%) as a yellow solid; mp 163–165 °C.
1H NMR (acetone-d6): d = 8.34 (d, J = 14.9 Hz, 1 H), 7.36 (s, 1 H),
6.99 (d, J = 14.9 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.93 (s, 3 H),
2.83–2.76 (m, 2 H), 2.63 (t, J = 6.1 Hz, 2 H), 1.99–1.90 (m, 2 H),
1.86–1.78 (m, 2 H), 1.31 (t, J = 7.1 Hz, 3 H).
3-Chloro-9-methyl-6,7,8,9-tetrahydro-5H-b-carboline (8)
Following the general procedure (lithium–chlorine exchange) using
6 (128 mg, 0.50 mmol) and H2O (27 mL, 1.50 mmol) and after puri-
fication by column chromatography (silica gel, 0–60% EtOAc–hex-
anes) gave 8 (95%) as an off-white solid; mp 162–163 °C.
1H NMR (DMSO-d6): d = 8.51 (s, 1 H), 7.39 (s, 1 H), 3.68 (s, 3 H),
2.73 (t, J = 6.1 Hz, 2 H), 2.59 (t, J = 6.0 Hz, 2 H), 1.89–1.80 (m, 2
H), 1.79–1.71 (m, 2 H).
13C NMR (DMSO-d6): d = 143.0, 138.6, 133.8, 132.9, 131.0, 111.1,
108.1, 29.3, 22.3, 22.2, 21.4, 20.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H14ClN2: 221.0840; found:
221.0841.
13C NMR (acetone-d6): d = 166.9, 145.3, 139.9, 139.2, 138.6, 136.0,
132.7, 123.6, 113.4, 109.9, 61.0, 33.3, 23.5, 23.3, 23.0, 21.1, 14.6.
HRMS (ESI): m/z [M + H]+ calcd for C17H20ClN2O2: 319.1208;
found: 319.1209.
3-Chloro-1-deuterio-9-methyl-6,7,8,9-tetrahydro-5H-b-carbo-
line (9)
Method 1: Following the general procedure (lithium–chlorine ex-
change) using 6 (128 mg, 0.50 mmol) and D2O (800 mL, 44.2 mmol)
and purification by column chromatography (silica gel, 0–60%
EtOAc in hexanes) gave 9 (95% D, 94%) as a beige solid.
tert-Butyl 3-Chloro-9-methyl-6,7,8,9-tetrahydro-5H-b-carbo-
line-1-carboxylate (13)
Following the general procedure (lithium–chlorine exchange) using
6 (128 mg, 0.50 mmol) and Boc2O (350 mL, 1.51 mmol) and purifi-
cations by column chromatography (silica gel, 1st purification: 0–
20% EtOAc–hexanes; 2nd: 0–100% CH2Cl2–hexanes) gave 13
(61%) as a white solid; mp 148–150 °C.
1H NMR (acetone-d6): d = 7.43 (s, 1 H), 3.69 (s, 3 H), 2.75 (t,
J = 6.3 Hz, 2 H), 2.62 (t, J = 6.1 Hz, 2 H), 1.97–1.89 (m, 2 H), 1.83–
1.77 (m, 2 H), 1.64 (s, 9 H).
Method 2: Following the general procedure (lithium–chlorine ex-
change) using 8 (110 mg, 0.50 mmol) and D2O (800 mL, 44.2 mmol)
and purification by column chromatography (silica gel, 0–60%
EtOAc–hexanes) gave 9 (95% D, quant.) as a beige solid; mp 161–
163 °C.
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N. Lachance et al.
PAPER
13C NMR (acetone-d6): d = 166.2, 145.4, 138.4, 138.1, 135.7, 130.1,
113.8, 110.1, 83.4, 32.0, 28.1 (3 C), 23.4, 23.2, 22.8, 21.1.
13C NMR (acetone-d6): d = 143.2, 140.9, 138.2, 131.2, 129.1, 112.6,
109.6, 73.2, 65.7, 18.4, 10.6, 8.4, –1.4 (3 C).
HRMS (ESI): m/z [M + H]+ calcd for C17H22ClN2O2: 321.1364;
HRMS (ESI): m/z [M + H]+ calcd for C15H23Cl2N2OSi: 345.0951;
found: 321.1365.
found: 345.0951.
2-(3-Chloro-9-methyl-6,7,8,9-tetrahydro-5H-b-carbolin-1-
yl)propan-2-ol (14)
Following the general procedure (lithium–chlorine exchange) using
6 (128 mg, 0.50 mmol) and acetone (110 mL, 1.50 mmol) and puri-
fication by column chromatography (silica gel, 0–40% EtOAc–hex-
anes) gave 14 (75%) as an off-white solid; mp 126–127 °C.
1H NMR (acetone-d6): d = 7.24 (s, 1 H), 4.61 (s, 1 H), 4.12 (s, 3 H),
2.75 (t, J = 6.3 Hz, 2 H), 2.63 (t, J = 6.2 Hz, 2 H), 1.98–1.87 (m, 2
H), 1.86–1.78 (m, 2 H), 1.70 (s, 6 H).
13C NMR (acetone-d6): d = 150.8, 144.2, 138.6, 136.9, 131.5, 111.1,
109.8, 74.5, 35.2, 31.5 (2 C), 23.8, 23.5, 23.3, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C15H20ClN2O: 279.1259;
found: 279.1258.
Ethyl (2E)-3-(5-Chloro-2,3-dimethyl-1-{[2-(trimethylsi-
lyl)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridin-7-yl)acrylate (18)
Following the general procedure (lithium–chlorine exchange) using
17 (173 mg, 0.50 mmol), DMF (120 mL, 1.51 mmol), and triethyl
phosphonoacetate (300 mL, 1.51 mmol) and purification by column
chromatography (silica gel, 0–50% EtOAc–hexanes) gave 18
(83%) as a yellow solid; mp 85–87 °C.
1H NMR (acetone-d6): d = 8.35 (d, J = 15.0 Hz, 1 H), 7.43 (s, 1 H),
6.99 (d, J = 15.0 Hz, 1 H), 5.57 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H),
3.74 (t, J = 8.0 Hz, 2 H), 2.48 (s, 3 H), 2.20 (s, 3 H), 1.32 (t, J = 7.1
Hz, 3 H), 1.00 (t, J = 8.0 Hz, 2 H), –0.01 (s, 9 H).
13C NMR (acetone-d6): d = 166.8, 141.9, 140.8, 140.5, 140.0, 136.4,
132.2, 124.3, 113.7, 108.4, 74.2, 65.8, 60.9, 18.4, 14.6, 10.6, 8.4, –
1.3 (3 C).
1,3-Dichloro-10-methyl-5,6,7,8,9,10-hexahydrocyclohep-
ta[4,5]pyrrolo[2,3-c]pyridine (15)
HRMS (ESI): m/z [M + H]+ calcd for C20H30ClN2O3Si: 409.1709;
found: 409.1709.
Following the general procedure (N-alkylations) using 5b (383 mg,
1.50 mmol), DMF (4 mL), NaH (60% w/w) (75 mg, 1.88 mmol),
and MeI (120 mL, 1.87 mmol) and purification by trituration (hep-
tane) gave 15 (95%) as a white solid; mp 138–139 °C (toluene–hep-
tane).
1H NMR (DMSO-d6): d = 7.56 (s, 1 H), 3.99 (s, 3 H), 2.93–2.88 (m,
2 H), 2.75–2.70 (m, 2 H), 1.85–1.80 (m, 2 H), 1.77–1.71 (m, 2 H),
1.68–1.62 (m, 2 H).
13C NMR (DMSO-d6): d = 148.7, 137.5, 135.7, 130.1, 127.0, 114.0,
111.4, 32.0, 30.4, 27.4, 25.7, 25.6, 23.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H15Cl2N2: 269.0607;
found: 269.0608.
Substituted 6-Azaindoles 21–23; General Procedure for
Suzuki–Miyaura Coupling Reactions
The Suzuki–Miyaura coupling reactions (Scheme 3 and
Equation 1) were typically performed on a 0.5 mmol scale of the
azaindoles 6 and 8 following the procedure of Guram.21 A mixture
of 6-azaindole (1.0 equiv), boronic acid 19 (1.1–1.2 equiv), K2CO3
(139 mg, 1.00 mmol), and Pd catalyst 20 (11 mg, 0.015 mmol) in
H2O–toluene (1:9, 2 mL) was stirred at 100 °C in screw-capped
glass vial for 1 h. The mixture was cooled to r.t. and extracted with
MTBE (3 ×). The organic layers were combined, washed with brine,
dried (Na2SO4), and filtered and the filtrate was concentrated in
vacuo. The residue was purified by column chromatography (silica
gel) to give the corresponding azaindoles 21–23.
Anal. Calcd for C13H14Cl2N2: C, 58.01; H, 5.24; N, 10.41. Found:
C, 58.00; H, 5.19; N, 10.48.
3-(4-Fluorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-b-carbo-
line (21)
Following the general procedure (Suzuki–Miyaura coupling) using
8 (110 mg, 0.50 mmol) and 19 (84 mg, 0.60 mmol) and purification
by column chromatography (silica gel, 0–70% EtOAc–hexanes)
gave 21 (91%) as an off-white solid; mp 145–146 °C.
1H NMR (acetone-d6): d = 8.71 (s, 1 H), 8.17 (dd, J = 8.5, 5.6 Hz, 2
H), 7.87 (s, 1 H), 7.17 (t, J = 8.7 Hz, 2 H), 3.75 (s, 3 H), 2.79–2.72
(m, 2 H), 2.75–2.68 (m, 2 H), 1.97–1.88 (m, 2 H), 1.88–1.80 (m, 2
H).
13C NMR (acetone-d6): d = 163.2 (d, JCF = 244 Hz), 145.6, 141.6,
138.7 (d, JCF = 2.9 Hz), 134.3, 133.5, 132.0, 128.9 (d, JCF = 8.0 Hz,
2 C), 115.8 (d, JCF = 21.3 Hz, 2 C), 110.0, 108.9, 29.5, 23.64, 23.62,
22.5, 21.5.
2-(3-Chloro-10-methyl-5,6,7,8,9,10-hexahydrocyclohep-
ta[4,5]pyrrolo[2,3-c]pyridin-1-yl)propan-2-ol (16)
The 6-azaindole reagent 15 was milled with a mortar and pestle to
a fine powder before use. Following the general procedure (lithi-
um–chlorine exchange) using 15 (135 mg, 0.50 mmol) and acetone
(110 mL, 1.50 mmol) and purification by column chromatography
(silica gel, 0–30% EtOAc–hexanes) gave 16 (69%) as a white solid;
mp 103–104 °C.
1H NMR (acetone-d6): d = 7.28 (s, 1 H), 4.69 (s, 1 H), 4.21 (s, 3 H),
2.98–2.92 (m, 2 H), 2.78–2.72 (m, 2 H), 1.90–1.85 (m, 2 H), 1.83–
1.78 (m, 2 H), 1.81–1.62 (m, 2 H), 1.70 (s, 6 H).
13C NMR (acetone-d6): d = 150.7, 147.8, 139.0, 137.0, 131.1, 114.3,
111.0, 74.6, 35.9, 31.8, 31.6 (2 C), 28.7, 27.4, 26.9, 24.2.
HRMS (ESI): m/z [M + H]+ calcd for C16H22ClN2O: 293.1415;
found: 293.1414.
HRMS (ESI): m/z [M + H]+ calcd for C18H18FN2: 281.1449; found:
281.1449.
3-Chloro-1-(4-fluorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-
b-carboline (22)
Following the general procedure (Suzuki–Miyaura coupling) using
6 (128 mg, 0.50 mmol) and 19 (77 mg, 0.55 mmol) and purification
by column chromatography (silica gel, 0–20% EtOAc–hexanes)
gave 22 (82%) as a white solid; mp 161–163 °C.
1H NMR (acetone-d6): d = 7.59 (dd, J = 8.4, 5.5 Hz, 2 H), 7.36 (s, 1
H), 7.27 (t, J = 8.7 Hz, 2 H), 3.26 (s, 3 H), 2.77–2.65 (m, 4 H), 1.97–
1.88 (m, 2 H), 1.87–1.79 (m, 2 H).
13C NMR (acetone-d6): d = 163.7 (d, JCF = 245 Hz), 144.8, 142.7,
139.2, 137.5, 136.5 (d, JCF = 3.7 Hz), 132.6 (d, JCF = 8.2 Hz, 2 C),
5,7-Dichloro-2,3-dimethyl-1-{[2-(trimethylsilyl)ethoxy]meth-
yl}-1H-pyrrolo[2,3-c]pyridine (17)
Following the general procedure (N-alkylations) using 5d (323 mg,
1.50 mmol), DMF (4 mL), NaH (60% w/w) (75 mg, 1.88 mmol) and
SEMCl (330 mL, 1.88 mmol) and purification by column chroma-
tography (silica gel, 0–30% EtOAc–hexanes) gave 17 (92%) as a
white solid; mp 52–53 °C.
1H NMR (acetone-d6): d = 7.45 (s, 1 H), 5.86 (s, 2 H), 3.62 (t,
J = 7.9 Hz, 2 H), 2.48 (s, 3 H), 2.21 (s, 3 H), 0.88 (t, J = 7.9 Hz, 2
H), –0.07 (s, 9 H).
Synthesis 2009, No. 5, 721–730 © Thieme Stuttgart · New York

PAPER
Synthesis and Functionalization of 5,7-Dichloro-6-azaindoles
729
131.8, 115.6 (d, JCF = 21.8 Hz, 2 C), 111.2, 110.0, 32.9, 23.6, 23.4,
stance on NOE, NOESY, and gHSQCAD experiments and David
23.0, 21.3.
A. Powell for proofreading the manuscript and useful comments.
HRMS (ESI): m/z [M + H]+ calcd for C18H17ClFN2: 315.1059;
found: 315.1059.
References
1,3-Bis(4-fluorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-b-car-
boline (23)
This side product was isolated as a white solid (12%) from the prep-
(1) For leading references to the physiological activity of indole
derivatives, see: (a) Sturino, C. F.; O’Neill, G. P.; Lachance,
N.; Boyd, M. J.; Berthelette, C.; Labelle, M.; Li, L. H.; Roy,
B.; Scheigetz, J.; Tsou, N. N.; Bateman, K. P.; Day, S. H.;
Levesque, J. F.; Seto, C.; Silva, J. M.; Carriere, M.; Denis,
D.; Greig, G. M.; Kargman, S. L.; Lamontagne, S.; Mathieu,
M.; Sawyer, N.; Slipetz, D. M.; Jones, T. R.; Mcauliffe, M.;
Piechuta, H.; Nicoll-Griffith, D. A.; Wang, Z.; Zamboni, R.
J.; Young, R. N.; Metters, K. M. J. Med. Chem. 2007, 50,
794. (b) Van Zandt, M. C.; Jones, M. L.; Gunn, D. E.;
Geraci, L. S.; Jones, J. H.; Sawicki, D. R.; Sredy, J.; Jacot, J.
L.; DiCioccio, A. T.; Petrova, T.; Mitschler, A.; Podjarny, A.
D. J. Med. Chem. 2005, 48, 3141. (c) Kuethe, J. T.; Wong,
A.; Qu, C.; Smitrovich, J.; Davies, I. W.; Hughes, D. L.
J. Org. Chem. 2005, 70, 2555.
aration of 22; mp 165–166 °C.
1H NMR (acetone-d6): d = 8.18 (dd, J = 8.5, 5.5 Hz, 2 H), 7.91 (s, 1
H), 7.66 (dd, J = 8.2, 5.5 Hz, 2 H), 7.27 (t, J = 8.6 Hz, 2 H), 7.15 (t,
J = 8.7 Hz, 2 H), 3.27 (s, 3 H), 2.76 (t, J = 6.0 Hz, 2 H), 2.70 (t,
J = 6.0 Hz, 2 H), 1.99–1.90 (m, 2 H), 1.88–1.82 (m, 2 H).
13C NMR (acetone-d6): d = 163.5 (d, JCF = 246 Hz), 163.3 (d,
JCF = 243 Hz), 144.8, 142.8, 142.7, 138.2 (d, JCF = 2.9 Hz), 138.0
(d, JCF = 3.7 Hz), 135.7, 132.5 (d, JCF = 8.2 Hz, 2 C), 132.0, 129.0
(d, JCF = 8.0 Hz, 2 C), 115.7 (d, JCF = 21.4 Hz, 2 C), 115.4 (d,
JCF = 21.4 Hz, 2 C), 110.6, 108.2, 32.9, 23.8, 23.6, 22.9, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C24H21F2N2: 375.1667; found:
(2) For review on indoles synthesis, see: Gribble, G. W.
J. Chem. Soc., Perkin Trans. 1 2000, 1045; and references
therein.
(3) For recent reviews on palladium-catalyzed synthesis of
indoles, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875; and references therein. (b) Cacchi, S.;
Fabrizi, G. Chem. Rev. 2005, 105, 2873; and references
therein.
375.1667.
3-(2-Chloro-4-fluorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-
b-carboline (24)
Following the general procedure (lithium–chlorine exchange) using
21 (140 mg, 0.50 mmol) and hexachloroethane (354 mg, 1.50
mmol) and purification by column chromatography (silica gel, 0–
75% EtOAc–hexanes) gave 24 (87%) as an off-white solid; mp
133–135 °C.
1H NMR (acetone-d6): d = 8.73 (s, 1 H), 7.68 (dd, J = 8.6, 6.4 Hz, 1
H), 7.62 (s, 1 H), 7.32 (dd, J = 8.9, 2.6 Hz, 1 H), 7.19 (td, J = 8.5,
2.6 Hz, 1 H), 3.78 (s, 3 H), 2.78 (t, J = 6.2 Hz, 2 H), 2.69 (t, J = 6.0
Hz, 2 H), 1.98–1.90 (m, 2 H), 1.87–1.79 (m, 2 H).
13C NMR (acetone-d6): d = 162.3 (d, JCF = 247 Hz), 145.1, 141.7,
138.9 (d, JCF = 3.7 Hz), 134.4 (d, JCF = 8.8 Hz), 134.0, 133.5 (d,
JCF = 10.2 Hz), 132.5, 132.0, 117.4 (d, JCF = 24.9 Hz), 114.7 (d,
JCF = 20.9 Hz), 113.7, 109.8, 29.5, 23.62, 23.60, 22.5, 21.4.
(4) For leading reference to the physiological activity of
azaindole derivatives, see: (a) Kim, K. S.; Zhang, L.;
Schmidt, R.; Cai, Z.-W.; Wei, D.; Williams, D. K.;
Lombardo, L. J.; Trainor, G. L.; Xie, D.; Zhang, Y.; An, Y.;
Sack, J. S.; Tokarski, J. S.; Darienzo, C.; Kamath, A.;
Marathe, P.; Zhang, Y.; Lippy, J.; Jeyaseelan, R. Sr.;
Wautlet, B.; Henley, B.; Gullo-Brown, J.; Manne, V.; Hunt,
J. T.; Fargnoli, J.; Borzilleri, R. M. J. Med. Chem. 2008, 51,
5330. (b) Lu, R.-J.; Tucker, J. A.; Zinevitch, T.; Kirichenko,
O.; Konoplev, V.; Kuznetsova, S.; Sviridov, S.; Pickens, J.;
Tandel, S.; Brahmachary, E.; Yang, Y.; Wang, J.; Freel, S.;
Fisher, S.; Sullivan, A.; Zhou, J.; Stanfield-Oakley, S.;
Greenberg, M.; Bolognesi, D.; Bray, B.; Koszalka, B.; Jeffs,
P.; Khasanov, A.; Ma, Y.-A.; Jeffries, C.; Liu, C.;
Proskurina, T.; Zhu, T.; Chucholowski, A.; Li, R.; Sexton, C.
J. Med. Chem. 2007, 50, 6535. (c) Cooper, L. C.; Chicchi,
G. G.; Dinnell, K.; Elliott, J. M.; Hollingworth, G. J.; Kurtz,
M. M.; Locker, K. L.; Morrison, D.; Shaw, D. E.; Tsao, K.-
L.; Watt, A. P.; Williams, A. R.; Swain, C. J. Bioorg. Med.
Chem. Lett. 2001, 11, 1233.
HRMS (ESI): m/z [M + H]+ calcd for C18H17ClFN2: 315.1059;
found: 315.1058.
Ethyl (2E)-3-[2-(3-Chloro-9-methyl-6,7,8,9-tetrahydro-5H-b-
carbolin-1-yl)-5-fluorophenyl]acrylate (25)
Following the general procedure (lithium–chlorine exchange) using
22 (157 mg, 0.50 mmol), DMF (120 mL, 1.51 mmol), and triethyl
phosphonoacetate (300 mL, 1.51 mmol) and purification by column
chromatography (silica gel, 0–50% EtOAc–hexanes) gave 25
(97%) as a white solid; mp 131–133 °C.
(5) For reviews on azaindoles synthesis, see: (a) Popowycz, F.;
Mérour, J.-Y.; Joseph, B. Tetrahedron 2007, 63, 8689.
(b) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120.
(c) Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y.
Tetrahedron 2007, 63, 1031. (d) Le Hyaric, M.;
1H NMR (600 MHz, acetone-d6): d = 7.79 (dd, J = 10.2, 2.6 Hz, 1
H), 7.51 (dd, J = 8.5, 5.8 Hz, 1 H), 7.44 (s, 1 H), 7.34 (td, J = 8.4,
2.6 Hz, 1 H), 7.31 (dd, J = 16.0, 1.7 Hz, 1 H), 6.57 (d, J = 16.0 Hz,
1 H), 4.08 (q, J = 7.1 Hz, 2 H), 3.12 (s, 3 H), 2.70 (t, J = 6.1 Hz, 4
H), 1.95–1.89 (m, 2 H), 1.85–1.80 (m, 2 H), 1.17 (t, J = 7.1 Hz, 3
H).
13C NMR (acetone-d6): d = 166.5, 163.8 (d, JCF = 246 Hz), 145.0,
141.3 (d, JCF = 2.9 Hz), 140.6, 139.1, 137.1, 136.8 (d, JCF = 8.1 Hz),
136.7 (d, JCF = 2.9 Hz), 133.8 (d, JCF = 8.0 Hz), 132.7, 121.9, 117.3
(d, JCF = 22.0 Hz), 113.3 (d, JCF = 22.7 Hz), 111.9, 110.0, 60.9,
31.9, 23.5, 23.3, 22.9, 21.2, 14.4.
Vieira de Almeida, M.; Nora de Souza, M. V. Quim. Nova
2002, 25, 1165. (e) Mérour, J.-Y.; Joseph, B. Curr. Org.
Chem. 2001, 5, 471; and references therein.
(6) Lachance, N.; April, M.; Joly, M.-A. Synthesis 2005, 2571.
(7) Roy, P. J.; Dufresne, C.; Lachance, N.; Leclerc, J.-P.;
Boisvert, M.; Wang, Z.; Leblanc, Y. Synthesis 2005, 2751.
(8) Seela, F.; Bourgeois, W. Synthesis 1988, 938.
(9) (a) Charrier, N.; Demont, E.; Dunsdon, R.; Maile, G.;
Naylor, A.; O’Brien, A.; Redshaw, S.; Theobald, P.; Vesey,
D.; Walter, D. Synthesis 2006, 3467. (b) Allegretti, M.;
Arcadi, A.; Marinelli, F.; Nicolini, L. Synlett 2001, 609.
(10) Nazaré, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W.
Angew. Chem. Int. Ed. 2004, 43, 4526.
Acknowledgment
The authors thank Claudio F. Sturino for his helpful suggestions,
Laird A. Trimble and Dan Sørensen for NMR spectroscopic assi-
Synthesis 2009, No. 5, 721–730 © Thieme Stuttgart · New York

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N. Lachance et al.
PAPER
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(13) Typically, aminopyridine 1 was isolated in less than 5%.
(14) Tacconi, G.; Perotti, A. Ann. Chim. (Rome) 1965, 55, 1223.
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(a) Li, L.; Martins, A. Tetrahedron Lett. 2003, 44, 5987.
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Synthesis 2009, No. 5, 721–730 © Thieme Stuttgart · New York