Regioselective halogenation of 6-azaindoles: Efficient synthesis of 3-halo-2,3-disubstituted-6-azaindole derivatives

Article abstract of DOI:10.1055/s-2005-872680

A mild and efficient synthesis of 3-halo-2-substituted-6-azaindoles was developed by regioselective halogenation of 6-azaindole systems. The transformation was achieved with copper(II) bromide in acetonitrile at room temperature. Georg Thieme Verlag Stutt

Full text of DOI:10.1055/s-2005-872680

2
400
LETTER
Regioselective Halogenation of 6-Azaindoles: Efficient Synthesis of
-Halo-2,3-disubstituted-6-azaindole Derivatives
3
a
a
a
a
a
b
R
F
egioselective
a
H
alogena
t
b
ion of 6-Aza
r
indoles ice Gallou,* Jonathan T. Reeves, Zhulin Tan, Jinhua J. Song, Nathan K. Yee, Scot Campbell,
b
a
Paul-James Jones, Chris H. Senanayake
a
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, P.O. Box 368, Ridgefield,
CT 06877-0368, USA
b
Department of Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, P.O. Box 368, Ridgefield,
CT 06877-0368, USA
Fax +1(203)7916130; E-mail: fgallou@rdg.boehringer-ingelheim.com
Received 2 June 2005
tions (Br , NaHCO , MeOH, 0 °C) provided a 4:1 mixture
2
3
Abstract: A mild and efficient synthesis of 3-halo-2-substituted-6-
azaindoles was developed by regioselective halogenation of 6-aza-
indole systems. The transformation was achieved with copper(II)
bromide in acetonitrile at room temperature.
of monobrominated species at C-3 and on position 1 of the
furan ring. Earlier literature reports of halogenation of
pyrrole derivatives with copper(II) halides encouraged us
to evaluate its selectivity in the halogenation of 6-azain-
dole.18 We were hoping similar reactivity would be ob-
served for the 6-azaindole systems and that side-reactions
would be minimized. Substrates 1a–f were prepared in
one step by condensation of the dianion of 3-amino-4-pi-
coline to the corresponding carboxylic esters which
cyclized spontaneously to the desired azaindoles.1
Key words: regioselective halogenation of 6-azaindoles, pyrrolo-
pyridine, copper (II) bromide
Azaindole systems (also called pyrrolopyridine) have
drawn much attention in medicinal chemistry as indole
1a
1
isosteres with remarkable electronic properties. While
numerous synthetic methodologies have been developed
2
Br
for the indole system, very few syntheses of azaindoles
CuBr2(II) (3 equiv)
3
–11
have been reported
and even fewer examples of their
N
N
O
N
MeCN
r.t.
O
N
regio- and chemoselective functionalization can be found.
In the case of the parent unsubstituted azaindole systems
earlier precedents indicate that electrophilic reagents add
preferentially at C-3 but the narrow scope of this
transformation has limited its applications.12 For
substituted systems, regioselective functionalizations
have been restricted to the synthesis of 1-protected 3-tri-
methylstannyl-7-azaindoles and their coupling with aryl
H
H
2a
1
a
90% yield
Cl
CuCl2(II) (3 equiv)
1
a
N
MeCN
r.t.
O
N
H
3a
1
3
85% yield
and heteroaryl halides, the selective functionalization of
-azaindole at the 6-position by Reissert–Henze type Scheme 1
reaction (incorporation of Cl, Br, I, cyano and thiocyanato
7
1
4
groups to the pyridine ring of the 7-azaindole), and the
The 2-(2-furyl)-6-azaindole (1a) in acetonitrile was
stirred with three equivalents of copper(II) bromide over-
1
5
selective acylation of azaindoles at C-3.
In the present paper, we wish to report a new and opera- night at room temperature and gave a single brominated
tionally simple method for the regioselective halogena- isomer 2a as an off-white solid in 90% yield (Scheme 1).
1
tion of 6-azaindole derivatives.
The H NMR spectrum of the product showed character-
istic signals for the furan ring with three vicinal protons
coupled to each other [d = 7.99 ppm (d, J = 1.3 Hz, 1 H),
7.28 ppm (d, J = 4.8 Hz, 1 H), 6.77 ppm (dd, J = 1.3, 4.8
Hz, 1 H)] as confirmed by the correlations observed in the
COSY experiment, therefore indicating that no bromina-
tion had taken place on the furan ring. The three protons
of the pyridine ring were also preserved as proven by the
two coupled signals at d = 8.21 ppm (d, J = 5.0 Hz, 1 H)
and 7.40 ppm (d, J = 5.0 Hz, 1 H), and the singlet at d =
8.77 ppm (s, 1 H). The structure was further unambigu-
ously elucidated by HMBC, COSY, and NOESY. The
scope of the method was then explored using phenyl-,
thienyl-, furyl-, phenylethyl-, and adamantyl-substituted
6-azaindoles (1b through 1e, Table 1).11 In all cases the
Several 6-azaindole derivatives have displayed remark-
able biological activity similar to benzodiazepine ana-
1
6
logues for a variety of biological targets. The common
,3-disubstituted pattern encountered in most of the syn-
2
thetic targets prompted us to explore the functionalization
of 2-substituted-6-azaindoles. The 2-(2-furyl)-6-azain-
1
1
dole (1a) was chosen since it was proven a challenging
substrate for selective halogenation. Indeed, conventional
1
2
bromination methods led to various mixtures of mono-
1
7
and dibrominated species in our hands. The best condi-
SYNLETT 2005, No. 15, pp 2400–2402
1
9
.0
9
.2
0
0
5
Advanced online publication: 07.09.2005
DOI: 10.1055/s-2005-872680; Art ID: S05805ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Halogenation of 6-Azaindoles
2401
bromination was observed to be regioselective and high the methodology and looking at streamlining the condi-
yielding (entries 3–6, yields ranging from 74–90%). The tions for further cross-coupling reactions. We believe this
reactions were complete after overnight stirring and yield- selective transformation should prove useful for the rapid
ed off-white crystalline material after work up. The alkyl- elaboration of 2,3-disubstituted 6-azaindoles.
ated 2-methyl-6-azaindole and the parent unsubstituted 6-
azaindole displayed similar reactivity and regioselectivity
but isolation proved more troublesome due to the high sol-
ubility of the products in aqueous medium (entries 7 and 3-Bromo-2-furan-2-yl-1H-pyrrolo[2,3-c]pyridine (2a)
General Procedure
8
, 64% and 60% yield, respectively). Interestingly, chlori- The azaindole (1 mmol) was dissolved into MeCN (10 mL) and
CuBr (3 mmol, 3 equiv) was added at r.t. The resulting mixture was
nation of 1a performed under the same reaction conditions
with three equivalents of copper(II) chloride resulted in
the regioselective formation of 3-chloro-2-furan-2-yl-1H-
pyrrolo[2,3-c]pyridine (3a) in 85% isolated yield.
2
stirred at r.t. until completion. The heterogeneous reaction mixture
was quenched with NH in MeOH (5 mL, 7 M solution). The mix-
ture was stirred vigorously for 30 min. Then, H O (10 mL) and IPAc
10 mL) were added. The layers were separated and the aqueous
3
2
(
In conclusion, we have developed conditions for the layer was extracted with IPAc. The combined organic extracts were
washed with sodium metabisulfite, then brine and dried over
regioselective halogenation of 6-azaindoles. The halide
introduced allows for further functionalization of the aza-
indole core and we are currently evaluating the scope of
MgSO . Concentration provided a solid, which could be filtered
4
through silica if necessary (EtOAc–MeOH 5%).
3
-Bromo-2-furan-2-yl-1H-pyrrolo[2,3-c]pyridine (2a)
1
H NMR (500 MHz, DMSO-d ): d = 12.50 (br s, 1 H), 8.76 (s, 1 H),
8
6
Table 1 Synthesis of 3-Halo-2,3-disubstituted-6-azaindole
.21 (d, J = 5.0 Hz, 1 H), 7.99 (d, J = 1.3 Hz, 1 H), 7.40 (d, J = 5.0
Hz, 1 H), 7.29 (d, J = 4.8 Hz, 1 H), 6.77 (dd, J = 1.3, 4.8 Hz, 1 H).
Entry Reactant
Product
Yield (%)
90
1
3
C NMR (125 MHz, DMSO-d ): d = 144.8, 144.0, 138.9, 134.8,
6
1
2
32.5, 131.8, 129.5, 112.3, 110.6, 83.5. HRMS: m/z calcd:
1
Br
62.9801; found: 262.9814. Mp 228–230 °C.
N
N
O
N
H
N
N
O
N
H
3
-Chloro-2-furan-2-yl-1H-pyrrolo[2,3-c]pyridine (3a)
1
1
a
a
1
H NMR (500 MHz, DMSO-d ): d = 12.10 (br s, 1 H), 8.77 (s, 1 H),
8
6
2
3
a
.12 (d, J = 4.8 Hz, 1 H), 7.87 (d, J = 1.6 Hz, 1 H), 7.56 (d, J = 4.8
2
3
4
Cl
85
85
74
Hz, 1 H), 7.08 (d, J = 3.8 Hz, 1 H), 6.78 (d, J = 1.3 Hz, 1 H), 6.69
1
3
(dd, J = 1.3, 4.8 Hz, 1 H). C NMR (125 MHz, DMSO-d ): d =
O
N
H
6
O
N
H
147.0, 144.4, 139.2, 137.9, 135.2, 133.8, 133.6, 133.3, 112.6, 109.8,
9
2
7.3. HRMS: m/z calcd: 219.0310; found: 219.0319. Mp 216–
26 °C.
a
Br
Ph
3
-Bromo-2-phenyl-1H-pyrrolo[2,3-c]pyridine (2b)
N
N
Ph
1
H
N
H NMR (500 MHz, DMSO-d ): d = 9.18 (s, 1 H), 8.40 (d, J = 6.3
6
13
N
H
Hz, 1 H), 8.02–7.97 (m, 3 H), 7.65–7.61 (m, 3 H). C NMR (125
1
b
2
b
MHz, DMSO-d ): d = 145.5, 136.3, 131.4, 130.9, 129.7, 129.4,
6
129.2, 129.1, 127.4, 100.5, 86.6. HRMS: m/z calcd: 273.0021;
Br
S
found: 273.0029. Mp 268–272 °C.
N
S
N
H
N
N
3
-Bromo-2-thiophen-2-yl-1H-pyrrolo[2,3-c]pyridine (2c)
1c
H
1
H NMR (500 MHz, DMSO-d ): d = 12.5 (br s, 1 H), 8.81 (s, 1 H),
8
6
2
c
.37 (dd, J = 1.2, 2.9 Hz, 1 H), 8.22 (d, J = 5.5 Hz, 1 H), 7.91 (dd,
5
6
7
8
Br
80
90
64
60
J = 1.2, 4.9 Hz, 1 H), 7.79 (dd, J = 2.9, 4.9 Hz, 1 H), 7.45 (d, J = 5.5
N
13
Ph
N
Hz, 1 H). C NMR (125 MHz, DMSO-d ): d = 138.9, 134.9, 133.9,
6
H
N
Ph
N
131.2, 130.5, 130.4, 128.1, 127.7, 127.1, 114.9, 87.4. HRMS: m/z
H
1d
calcd: 278.9591; found: 278.9586. Mp >296 °C.
2
2
2
d
Br
3
-Bromo-2-phenethyl-1H-pyrrolo[2,3-c]pyridine (2d)
1
N
H NMR (500 MHz, DMSO-d ): d = 13.63 (s, 1 H), 9.16 (s, 1 H),
8.34 (d, J = 5.4 Hz, 1 H), 7.85 (d, J = 5.4 Hz, 1 H), 7.27–7.16 (m, 5
H), 3.26–3.23 (m, 2 H), 3.09–3.06 (m, 2 H). C NMR (125 MHz,
6
N
N
H
N
H
13
1
1
e
f
e
Br
DMSO-d ): d = 150.5, 139.1, 134.9, 129.5, 128.7, 128.6, 127.6,
6
127.4, 126.5, 125.5, 113.3, 89.3, 32.7, 27.8. HRMS: m/z calcd:
N
301.0329; found: 301.0334. Mp 215–222 °C.
N
H
N
N
H
2-Adamantan-1-yl-3-bromo-1H-pyrrolo[2,3-c]pyridine (2e)
1
H NMR (500 MHz, DMSO-d ): d = 12.89 (s, 1 H), 9.05 (s, 1 H),
f
6
8.35 (d, J = 5.9 Hz, 1 H), 7.88 (d, J = 6.0 Hz, 1 H), 2.25 (s, 6 H),
2
156.3, 140.0, 129.6, 129.4, 127.5, 115.2, 86.9, 41.1, 36.2, 35.9,
Br
1
3
.13 (s, 3 H), 1.80 (s, 6 H). C NMR (125 MHz, DMSO-d ): d =
6
N
N
H
N
N
2
2
7.7. HRMS: m/z calcd: 331.0804, found: 331.0777. Mp 276–
79 °C.
H
1g
2
g
Synlett 2005, No. 15, 2400–2402 © Thieme Stuttgart · New York

2
402
F. Gallou et al.
LETTER
2
-Methyl-3-Bromo-1H-pyrrolo[2,3-c]pyridine (2f)
(5) (a) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39,
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1
H NMR (500 MHz, DMSO-d ): d = 12.05 (s, 1 H), 8.59 (s, 1 H),
8
6
1
3
.08 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.0, 1H), 2.44 (s, 3 H).
C
NMR (125 MHz, DMSO-d ): d = 138.6, 137.9, 133.8, 132.0, 131.3,
(6) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.;
Cottrell, I. F.; Wright, S. H. B. Synthesis 1996, 877.
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6
1
11.7, 87.1, 12.0. HRMS: m/z calcd: 210.9865; found: 210.9862.
Mp 227–230 °C.
2740.
3
-Bromo-1H-pyrrolo[2,3-c]pyridine (2g)
(8) Kuzmich, D.; Mulrooney, C. Synthesis 2003, 1671.
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1
H NMR (500 MHz. DMSO-d ): d = 12.1 (s, 1 H), 7.95 (s, 1 H), 7.88
6
1
3
(
(
d, J = 5.7 Hz, 1 H), 7.70 (s, 1H), 7.25 (d, J = 5.7 Hz, 1 H). C NMR
125 MHz, DMSO-d ): d = 147.5, 143.9, 126.6, 125.9, 116.7, 107.1,
6
8
2
7.8. HRMS: m/z calcd: 196.9703; found: 196.9708. Mp 199–
02 °C.
(
(
10) Dormoy, J. R.; Heymes, A. Tetrahedron 1993, 49, 2885.
11) (a) Song, J. J.; Tan, Z.; Gallou, F.; Xu, J.; Yee, N. K.;
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Synlett 2005, No. 15, 2400–2402 © Thieme Stuttgart · New York