Practical regioselective bromination of azaindoles and diazaindoles

Article abstract of DOI:10.1055/s-2007-967998

A mild and efficient synthesis of various 3-brominated azaindoles and diazaindoles was developed by regioselective halogenation of the parent systems. This practical and high-yielding transformation was achieved with copper(II) bromide in acetonitrile at

Full text of DOI:10.1055/s-2007-967998

LETTER
211
Practical Regioselective Bromination of Azaindoles and Diazaindoles
a,1
a
a
a
a
b
H
F
alogenation
a
b
D
iazaindole
r
s
ice Gallou,* Jonathan T. Reeves, Zhulin Tan, Jinhua J. Song, Nathan K. Yee, Christian Harcken,
b
b
a
Pingrong Liu, David Thomson, Chris H. Senanayake
a
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, P.O. Box 368, Ridgefield, CT
6877-0368, USA
0
Fax +41(61)6962711; E-mail: fabrice.gallou@novartis.com
b
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, P.O. Box 368, Ridgefield, CT
06877-0368, USA
Received 31 October 2006
Br
Abstract: A mild and efficient synthesis of various 3-brominated
azaindoles and diazaindoles was developed by regioselective halo-
genation of the parent systems. This practical and high-yielding
transformation was achieved with copper(II) bromide in acetonitrile
at room temperature.
CuBr2(II) (3 equiv)
R
N,N
R
N,N
N
MeCN
r.t.
N
H
H
R = H, alkyl, aryl
Key words: 3-brominated azaindoles, regioselective halogenation,
copper(II) bromide
Figure 1
copper(II) bromide. We were particularly interested in the
readily available unsubstituted 4-, 5-, 6- and 7-azaindoles
The indole ring system has always attracted the attention
of the medicinal chemistry community due to its wide
range of biological activities and the numerous possible
structural variations. This in turn generated interest in
surrogates of this structural class with the introduction of
(
1a–d, see Table 1) and the outcome of the regioselectiv-
ity. The reactions were carried out in acetonitrile with 3
equivalents of copper(II) bromide at room temperature for
2
1
–2 hours. At completion, the mixture was quenched with
a 7 N solution of ammonia in methanol to decomplex the
copper from the substrate. This work-up was found to be
particularly suitable for this class of compounds and al-
lowed for a rapid and practical isolation. Water was then
added and the mixture was extracted with ethyl acetate.
The combined organic extracts were concentrated and the
product was conveniently isolated in pure form by precip-
itation from ethyl acetate–hexane. To our delight, a highly
additional basic nitrogen(s). The pyrrolopyridine
3
(
azaindole) core, for example, has been extensively
utilized and other cores such as the pyrrolopyrazine or
3
f,4
pyrrolopyridazine have also emerged as interesting an-
alogues.
While various syntheses of these pyrrole-containing
5
systems have been reported, they usually suffer from
limitations in their scope or the accessible substitution
patterns. To circumvent this problem, functionalization of
the heterocyclic core is required but even fewer methods Table 1 Synthesis of 3-Bromoazaindoles
of chemo- and/or regioselective functionalization are
reported.
Entry
1
Starting material Product
Yield (assay, %)
74 (96)
6
N
Br
In the present paper, we wish to report a highly regioselec-
tive and high-yielding halogenation of various azaindoles
and diazaindoles using copper(II) bromide in acetonitrile
at room temperature (see Figure 1). The methodology is a
direct extension of our previously published work for the
N
N
H
a8
N
H
1
2
a10
7
2
3
4
Br
80 (97)
60 (92)
67 (94)
synthesis of 3-halo-6-azaindoles. The resulting products
N
N
constitute valuable entries into highly functionalized pyr-
role-containing heterocyclic systems via cross-coupling
chemistry, for example.
N
H
1b8,9
N
H
2
b10
We decided to initiate our study with an evaluation of the
reactivity of various pyrrole-containing systems with
Br
N
N
H
N
N
H
c10,7
c8
1
2
Br
SYNLETT 2007, No. 2, pp 0211–0214
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-967998; Art ID: S16506ST
0
1.
0
2.
2
0
0
7
N
H
1d9
N
N
N
H
2d11
©
Georg Thieme Verlag Stuttgart · New York

2
12
F. Gallou et al.
LETTER
regioselective transformation was observed in all cases Table 2 Synthesis of 3-Bromo-2,3-disubstituted Azaindoles and
Diazaindoles (continued)
and the reaction proceeded in high yields. The structures
2
a–d were unequivocally proven by comparison with
Yield (%)a
Entry Starting material
Product
7
–11
known compounds and extensive NMR studies.
Particularly characteristic was the disappearance of the
deshielded aromatic singlet from H-3 at d = 6.5–7.0 ppm
by H NMR and the deshielding of C-3 from d = 97–90
ppm to d = 89.4–87.3 ppm after substitution with a bro-
mide. The assay yields were almost quantitative and the
previously described work-up protocol allowed for isola-
tion of the brominated products in 60% to 80% yield for
the first crop. In control experiments, alternative bromina-
tion conditions displayed at least 3–5% of other regio-
isomer(s) in all cases.
9
Br
74
Ph
N
N
Ph
N
N
1
N
H
N
H
1
m
2m
1
1
1
1
0
1
2
3
N
N
Br
Br
72
65
80
55
65
N
N
N
H
N
n5a
H
1
2n
N
N
Table 2 Synthesis of 3-Bromo-2,3-disubstituted Azaindoles and
Diazaindoles
N
N
H
N
N
H
Yield (%)a
62
1o5a
Ph
Entry Starting material
Product
2
o
N
Br
1
2
N
N
N
N
HO
N
Ph
N
N
H
N
H
N
H
N
H
e5a
1p
1
2e
2
p
q
N
Br
80
66
72
64
74
77
69
N
Br
Br
HO
N
N
H
HO
N
O
A
N
H
N
O
N
1
f
1q
H
2
f
2
3
4
5
6
7
8
Br
N
14
N
N
N
N
H
N
S
N
N
N
H
N
H
g5a
S
1
H
1
r
2
g
2r
Br
a
N
Yields reported are isolated and for the first crop using the general
procedure.
Ph
N
N
Ph
H
N
1
h5b
H
Encouraged by these results, we decided to turn our atten-
tion to 2-substituted 4-, 5-, and 7-azaindoles (1e–j),
pyrrolopyridazines (1k–m), pyrrolopyrazine (1n), and
pyrrolopyrimidines (1o–r, see Table 2). The starting
materials were prepared via a palladium-mediated Sono-
2
h
Br
N
N
H
N
N
H
1
1
i7
5a
gashira coupling followed by cyclization and reacted as
2
i7
previously described. High regioselectivities and high
yields were observed for all azaindole substrates (2e–j).
The method was also proven tolerant to a free hydroxyl
group on the alkyl substituent (2f). Bromination of 2-
phenyl-5-azaindole also proved uneventful (2h) and
resulted in a high yield of the desired brominated species.
The bromination of other 2-alkyl- and 2-aryl-substituted
pyrrolo[3,2]pyridazines, pyrrolo[2,3]pyridazines, pyr-
rolo[2,3]-pyrazine, and pyrrolo[3,2]pyrimidines gave
analogous results. The propensity of an aryl substituent to
undergo bromination demonstrates here the robustness of
the methodology and reinforces the prominent role of the
pyrrole moiety. Interestingly, the same regiocontrol was
observed independent of the nature of the aromatic
substituent (thiophene, furan, phenyl, benzyl, phenethyl;
Br
N
H
N
N
H
j5a
N
2
2
2
j
N
Br
Br
N
N
N
N
H
N
H
k5a
1
1
k
l
N
N
N
N
N
H
N
H
l5a
2
o–r) and the length of the linker (0, 1, or 2 methylene
spacers; 2h,m,p).
Synlett 2007, No. 2, 211–214 © Thieme Stuttgart · New York

LETTER
Halogenation of Aza- and Diazaindoles
213
In conclusion, we have demonstrated the high regioselec- 3-Bromo-2-methyl-1H-pyrrolo[3,2-c]pyridine (2g)
1
H NMR (500 MHz, DMSO-d ): d = 11.86 (br s, 1 H), 8.56 (s, 1 H),
tivity of halogenation at C-3 of various pyrrole-containing
heterocycles with copper(II) bromide. The method is
practical and allows for the rapid functionalization of the
corresponding halogenated species. We believe this selec-
tive transformation should prove useful for the rapid
elaboration of 2,3-disubstituted aza- and diazaindoles.
6
1
3
8
.19 (d, J = 5.7 Hz, 1 H), 7.33 (d, J = 5.7 Hz, 1 H), 2.39 (s, 3 H).
C
NMR (125 MHz, DMSO-d ): d = 140.7, 140.0, 139.4, 135.1, 124.2,
1
Mp 213 °C.
6
07.2, 86.6, 11.7. HRMS: m/z calcd 210.9865; found: 210.9870.
2-Phenyl-1H-pyrrolo[3,2-c]pyridine (2h)
1
H NMR (500 MHz, DMSO-d ): d = 11.98 (br s, 1 H), 8.83 (br s, 1
6
H), 8.17 (d, J = 5.6 Hz, 1 H), 7.90 (dd, J = 8.5, 1.2 Hz, 2 H), 7.51
1
3
(
dd, J = 7.5, 1.6 Hz, 2 H), 7.30–7.35 (m, 2 H), 7.06 (s, 1 H).
C
General Procedure
NMR (125 MHz, DMSO-d ): d = 142.8, 140.3, 138.8, 131.3, 128.9,
6
3
-Bromo-2-furan-2-yl-1H-pyrrolo[2,3-c]pyridine (2a)
The azaindole (1 mmol) was dissolved in MeCN (10 mL) and CuBr2
3 mmol, 3 equiv) was added at r.t. The resulting mixture was stirred
1
28.0, 125.3, 106.5, 97.5. HRMS: m/z calcd 273.0021; found:
273.0025. Mp 247–260 °C.
(
at r.t. until completion. The heterogeneous reaction mixture was
3
-Bromo-2-propyl-1H-pyrrolo[2,3-b]pyridine (2j)
quenched with NH in MeOH (5 mL, 7 M solution). The mixture
1
3
H NMR (500 MHz, DMSO-d ): d = 12.28 (br s, 1 H), 8.24 (dd,
J = 4.7, 1.5 Hz, 1 H), 7.86 (dd, J = 7.8, 0.9 Hz, 1 H), 7.22 (dd,
J = 7.8, 4.7 Hz, 1 H), 2.75 (t, J = 7.4 Hz, 2 H), 1.73–1.68 (m, 2 H),
0
146.9, 142.7, 138.2, 125.3, 119.3, 116.1, 85.8, 27.9, 21.6, 13.4.
HRMS: m/z calcd 239.0178; found: 239.0171. Mp 145–152 °C.
6
was stirred vigorously for 30 min. Then, H O (10 mL) and i-PrOAc
2
(
10 mL) were added. The layers were separated and the aqueous
layer was extracted with i-PrOAc. The combined organic extracts
13
.91 (t, J = 6.5 Hz, 3 H). C NMR (125 MHz, DMSO-d ): d =
6
were washed with brine and dried over MgSO . Concentration pro-
4
vided a solid which could be filtered through silica gel if necessary
(EtOAc–5% MeOH).
7
-Bromo-6-propyl-5H-pyrrolo[3,2-c]pyridazine (2k)
3
-Bromo-1H-pyrrolo[3,2-b]pyridine (2a)
1
H NMR (400 MHz, DMSO-d ): d = 13.28 (br s, 1 H), 9.78 (br s, 1
H), 9.69 (br s, 1 H), 2.95 (t, J = 7.4 Hz, 2 H), 1.82–1.74 (m, 2 H),
0
143.6, 87.2, 28.0, 21.6, 13.3. HRMS: m/z calcd: 240.0130; found:
2
6
1
H NMR (500 MHz, DMSO-d ): d = 11.69 (br s, 1 H), 8.41 (s, 1 H),
7
NMR (125 MHz, DMSO-d ): d = 143.1, 142.3, 128.2, 128.1, 119.2,
1
2
6
1
3
.84–7.82 (m, 2 H), 7.69 (s, 1 H), 7.20 (dd, J = 4.5, 4.1 Hz, 1 H).
C
13
.93 (t, J = 7.4 Hz, 3 H). C NMR (100 MHz, DMSO-d ): d =
6
6
17.2, 89.4. HRMS: m/z calcd: 196.9708; found: 196.9701. Mp
32–238 °C.
40.0126. Mp 198 °C.
3
-Bromo-2-propyl-1H-pyrrolo[2,3-d]pyridazine (2l)
3
-Bromo-1H-pyrrolo[3,2-c]pyridine (2b)
1
H NMR (500 MHz, DMSO-d ): d = 12.14 (br s, 1 H), 8.93 (d,
J = 5.7 Hz, 1 H), 7.58 (d, J = 5.7 Hz, 1 H), 2.83 (t, J = 7.4 Hz, 2 H),
1
DMSO-d ): d = 144.7, 136.6, 128.9, 107.7, 87.3, 28.2, 21.4, 13.5.
HRMS: m/z calcd 240.0130; found: 240.0121. Mp 201.5 °C.
6
1
H NMR (500 MHz, DMSO-d ): d = 11.90 (br s, 1 H), 8.70 (s, 1 H),
8
NMR (125 MHz, DMSO-d ): d = 141.1, 140.9, 139.2, 126.2, 123.4,
1
1
6
1
3
.25 (d, J = 5.7 Hz, 1 H), 7.69 (s, 1 H), 7.43 (d, J = 5.7 Hz, 1 H).
C
13
.76–1.72 (m, 2 H), 0.93 (t, J = 7.4 Hz, 3 H). C NMR (125 MHz,
6
6
07.0, 87.7. HRMS: m/z calcd: 196.9708; found: 196.9706. Mp
90–192 °C.
2
-Benzyl-1H-pyrrolo[2,3-d]pyridazine (1m)
3
-Bromo-1H-pyrrolo[2,3-b]pyridine (2d)
1
H NMR (400 MHz, DMSO-d ): d = 12.02 (br s, 1 H), 9.22 (br s, 1
6
1
H NMR (500 MHz, DMSO-d ): d = 12.07 (br s, 1 H), 8.30 (dd,
J = 4.6, 1.3 Hz, 1 H), 7.85 (dd, J = 7.9, 1.3 Hz, 1 H), 7.72 (d, J = 2.4
Hz, 1 H), 7.18 (dd, J = 7.9, 4.6 Hz, 1 H). C NMR (125 MHz,
DMSO-d ): d = 147.3, 145.9, 128.5, 127.6, 118.0, 102.6, 87.3.
6
H), 9.15 (br s, 1 H), 7.48–7.17 (m, 5 H), 6.34 (s, 1 H), 4.14 (s, 2 H).
13
C NMR (125 MHz, DMSO-d ): d = 138.4, 137.0, 128.6, 128.5,
6
1
3
1
26.5, 98.5, 33.5. HRMS: m/z calcd 210.1025; found: 210.1026.
6
Mp 227–229 °C.
HRMS: m/z calcd: 196.9708; found: 196.9706. Mp 210 °C.
2
-Benzyl-3-bromo-1H-pyrrolo[2,3-d]pyridazine (2m)
3
-Bromo-2-propyl-1H-pyrrolo[3,2-b]pyridine (2e)
1
H NMR (400 MHz, DMSO-d ): d = 9.34 (br s, 1 H), 9.25 (br s, 1
H), 7.34–7.24 (m, 5 H), 4.20 (s, 2 H). C NMR (125 MHz, DMSO-
d6): d = 137.4, 128.8, 128.7, 128.5, 126.9, 126.7, 87.5, 32.1. HRMS:
m/z calcd 288.0130; found: 288.0106. Mp 228–230 °C.
6
1
H NMR (500 MHz, DMSO-d ): d = 11.68 (br s, 1 H), 8.36 (br s, 1
H), 7.73 (d, J = 8.0 Hz, 1 H), 7.16 (br s, 1 H), 6.27 (s, 1 H), 3.33 (t,
J = 6.4 Hz, 3 H), 2.84 (t, J = 7.7 Hz, 2 H), 1.87–1.80 (m, 2 H).
NMR (125 MHz, DMSO-d ): d = 143.2, 142.8, 141.3, 128.0, 118.4,
13
6
1
3
C
6
1
2
16.9, 88.5, 28.4, 21.7, 13.5. HRMS: m/z calcd: 239.0178; found:
39.0169. Mp 176–177 °C.
7
-Bromo-6-propyl-5H-pyrrolo[2,3-b]pyrazine (2n)
1
H NMR (500 MHz, DMSO-d ): d = 8.37 (d, J = 2.5 Hz, 1 H), 8.22
6
(
0
d, J = 2.5 Hz, 1 H), 2.80 (t, J = 7.5 Hz, 2 H), 1.76–1.71 (m, 2 H),
3
-{1H-Pyrrolo[3,2-b]pyridin-2-yl}-propan-1-ol (1f)
13
.91 (t, J = 7.4 Hz, 2 H). C NMR (125 MHz, DMSO-d ): d =
6
1
H NMR (400 MHz, DMSO-d ): d = 8.19 (dd, J = 4.6, 1.3 Hz, 1 H),
7
H), 4.69 (t, J = 5.1 Hz, 1 H), 3.47–3.41 (m, 2 H), 2.79 (t, J = 7.6 Hz,
2
1
6
144.1, 140.9, 138.7, 137.4, 87.2, 28.8, 21.8, 13.7. HRMS: m/z calcd
40.0130; found: 240.0142. Mp 280 °C.
.58 (d, J = 8.0 Hz, 1 H), 7.00 (dd, J = 8.0, 4.6 Hz, 1 H), 6.27 (s, 1
2
1
3
H), 1.88–1.81 (m, 2 H). C NMR (125 MHz, DMSO-d ): d =
6
7-Bromo-6-propyl-5H-pyrrolo[3,2-d]pyrimidine (2o)
47.0, 144.7, 141.8, 128.8, 117.5, 115.5, 99.0, 60.3, 31.9, 24.5.
1
H NMR (500 MHz, DMSO-d ): d = 12.24 (br s, 1 H), 8.80 (br s, 2
6
HRMS: m/z calcd 177.1022; found: 177.1024. Mp 120 °C.
H), 2.84 (t, J = 7.4 Hz, 2 H), 1.76–1.71 (m, 2 H), 0.92 (t, J = 7.4 Hz,
3
1
1
3
H). C NMR (125 MHz, DMSO-d ): d = 150.5, 147.0, 146.5,
6
3
-{3-Bromo-1H-pyrrolo[3,2-b]pyridin-2-yl}-propan-1-ol (2f)
39.2, 126.5, 87.8, 28.5, 21.4, 13.5. HRMS: m/z calcd 240.0130;
1
H NMR (400 MHz, DMSO-d ): d = 11.70 (br s, 1 H), 8.35 (br s, 1
6
found: 240.0139. Mp 268 °C.
H), 7.71 (d, J = 8.1 Hz, 2 H), 7.10 (br s, 1 H), 4.71 (br s, 1 H), 2.83
1
3
(
t, J = 7.6 Hz, 2 H), 1.85–1.81 (m, 2 H). C NMR (125 MHz,
6
-Phenethyl-5H-pyrrolo[3,2-d]pyrimidine (1p)
DMSO-d ): d = 143.0, 141.3, 118.4, 117.5, 87.8, 60.0, 31.4, 23.3.
HRMS: m/z calcd 255.0127; found: 255.0122. Mp 160–165 °C.
1
6
H NMR (500 MHz, DMSO-d ): d = 11.85 (br s, 1 H), 8.85 (s, 1 H),
6
8
.82 (s, 1 H), 7.29–7.20 (m, 5 H), 6.32 (s, 1 H), 3.20–3.05 (m, 4 H).
Synlett 2007, No. 2, 211–214 © Thieme Stuttgart · New York

2
14
F. Gallou et al.
LETTER
1
3
C NMR (125 MHz, DMSO-d ): d = 150.2, 149.9, 148.4, 140.8,
4236. (c) Marminon, C.; Pierré, A.; Pfeiffer, B.; Pérez, V.;
Léonce, S.; Prudhomme, M. J. Med. Chem. 2003, 46, 609.
(d) Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett. 2001, 42,
6
1
38.1, 128.3, 128.2, 127.1, 126.0, 98.8, 34.0, 29.7. HRMS: m/z cal-
cd 224.1182; found: 224.1183. Mp 172 °C.
6441. (e) Cooper, L. C.; Chicchi, G. G.; Dinnell, K.; Elliott,
7
-Bromo-6-phenethyl-5H-pyrrolo[3,2-d]pyrimidine (2p)
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. (f) Minakata, S.; Hamada, T.; Komatsu, M.;
Tsuboi, H.; Kikuta, H.; Ohshiro, Y. J. Agric. Food Chem.
1997, 45, 2345. (g) Kunick, C.; Lauenroth, K.; Leost, M.;
Meijer, L.; Lemcke, T. Bioorg. Med. Chem. Lett. 2004, 14,
413. (h) Trejo, A.; Arzeno, H.; Browner, M.; Chanda, S.;
Cheng, S.; Comer, D. D.; Dalrymple, S. A.; Dunten, P.;
Lafargue, J.; Lovejoy, B.; Freire-Moar, J.; Lim, J.; Mcintosh,
J.; Miller, J.; Papp, E.; Reuter, D.; Roberts, R.; Sanpablo, F.;
Saunders, J.; Song, K.; Villasenor, A.; Warren, S. D.; Welch,
M.; Weller, P.; Whiteley, P. E.; Zeng, L.; Goldstein, D. M.
J. Med. Chem. 2003, 46, 4702. (i) Fisher, M.;
1
H NMR (500 MHz, DMSO-d ): d = 12.33 (br s, 1 H), 8.85 (s, 1 H),
8
J = 7.1 Hz, 2 H). C NMR (125 MHz, DMSO-d ): d = 146.3, 145.1,
1
6
.82 (s, 1 H), 7.29–7.20 (m, 5 H), 3.14 (t, J = 7.1 Hz, 2 H), 3.14 (t,
13
6
40.1, 128.3, 128.1, 128.0, 126.1, 88.3, 33.4, 28.6. HRMS: m/z cal-
cd 302.0287; found: 302.0283. Mp 155 °C.
6
-Furan-3-yl-5H-pyrrolo[3,2-d]pyrimidine (1q)
1
H NMR (500 MHz, CDCl ): d = 12.30 (br s, 1 H), 9.10 (s, 1 H),
3
8
.88 (s, 1 H), 8.27 (br s, 1 H), 7.60 (br s, 1 H), 6.99 (s, 1 H), 6.91 (s,
1
1
1
H). 13C NMR (125 MHz, CDCl ): d = 150.1, 144.4, 141.4, 138.4,
3
28.9, 118.0, 108.8, 97.9. HRMS: m/z calcd: 186.0661; found:
86.0659. Mp 268–270 °C.
7
-Bromo-6-furan-3-yl-5H-pyrrolo[3,2-d]pyrimidine (2q)
Schwartzkopf, G.; Hoff, D. R. J. Med. Chem. 1972, 15,
1168.
1
H NMR (500 MHz, CDCl ): d = 9.06 (s, 1 H), 8.99 (s, 1 H), 8.71
3
1
3
(br s, 1 H), 7.97 (br s, 1 H), 7.27 (s, 1 H). C NMR (125 MHz,
(4) (a) Mettey, Y.; Gompel, M.; Thomas, V.; Garnier, M.; Leost,
M.; Ceballos-Picot, I.; Noble, M.; Endicott, J.; Vierfond, J.-
M.; Meijer, L. J. Med. Chem. 2003, 46, 222. (b) Meade, E.
A.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med.
Chem. 1997, 40, 794.
CDCl ): d = 148.5, 147.3, 145.0, 145.0, 144.1, 135.8, 126.0, 116.0,
1
3
08.8, 87.2. HRMS: m/z calcd: 263.9766; found: 263.9779. Mp 164
°C.
6
-Thiophen-2-yl-5H-pyrrolo[3,2-d]pyrimidine (1r)
(5) (a) Harcken, C.; Ward, Y.; Thomson, D.; Riether, D. Synlett
2005, 3121. (b) Kuzmich, D.; Mulrooney, C. Synthesis
2003, 1671. (c) Lachance, N.; April, M.; Joly, M.-A.
Synthesis 2005, 2571. (d) Roy, P. J.; Dufresne, C.;
Lachance, N.; Leclerc, J.-P.; Boisvert, M.; Wang, Z.;
Leblanc, Y. Synthesis 2005, 2751. (e) Lefoix, M.; Daillant,
J.-P.; Routier, S.; Mérour, J.-Y.; Cillaizeau, I.; Coudert, G.
Synthesis 2005, 3581. (f) Schirok, H. Synlett 2005, 1255.
(g) Lomberget, T.; Radix, S.; Barret, R. Synlett 2005, 2080.
(h) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino,
G. Tetrahedron 2005, 61, 1077. (i) Koradin, C.; Dohle, W.;
Rodriguez, A. L.; Schmid, B.; Knochel, P. Tetrahedron
2003, 59, 1571. (j) Hopkins, C. R.; Collar, N. Tetrahedron
Lett. 2005, 46, 1845. (k) Cottineau, B.; O’Shea, D. F.
Tetrahedron Lett. 2005, 46, 1935. (l) Debenham, S. D.;
Chan, A.; Liu, K.; Price, K.; Wood, H. B. Tetrahedron Lett.
1
H NMR (500 MHz, DMSO-d ): d = 11.80 (br s, 1 H), 8.82 (s, 1 H),
8
H). C NMR (125 MHz, DMSO-d ): d = 150.4, 139.0, 128.0, 126.3,
1
2
6
.75 (d, J = 1.0 Hz, 1 H), 8.16 (s, 1 H), 7.73 (br s, 2 H), 6.98 (s, 1
1
3
6
23.9, 98.2. HRMS: m/z calcd 202.0433; found: 202.0432. Mp
60–263 °C.
7
-Bromo-6-thiophen-2-yl-5H-pyrrolo[3,2-d]pyrimidine (2r)
1
H NMR (500 MHz, DMSO-d ): d = 11.86 (br s, 1 H), 8.98 (s, 1 H),
6
1
3
8
.95 (s, 1 H), 8.45 (d, J = 0.7 Hz, 1 H), 7.86–7.84 (m, 2 H).
C
NMR (125 MHz, DMSO-d ): d = 149.0, 148.1, 137.8, 130.0, 127.9,
1
2
6
27.7, 126.5, 114.0, 86.8. HRMS: m/z calcd: 279.9538; found:
79.9555. Mp 245–248 °C.
Acknowledgment
2
005, 46, 2283.
We are grateful to Dr. Heewon Lee and Ms. Sherry Shen for provi-
ding mass spectral analyses.
(
6) (a) Prokopov, A. A.; Yakhontov, L. N. Khim. Geterotsikl.
Soedin. 1978, 496. (b) Yakhontov, L. N.; Azimov, V. A.;
Lapan, E. I. Tetrahedron Lett. 1969, 10, 1909. (c) Alvarez,
M.; Fernandez, D.; Joule, J. A. Synthesis 1999, 615.
References and Notes
(
d) Minakata, S.; Komatsu, M.; Ohshiro, Y. Synthesis 1992,
(
1) Current address: Novartis Pharma AG, Chemical and
Analytical Development, Werk Klybeck, Postfach, 4002
Basel, Switzerland. This address should be used for
correspondence.
661. (e) Zhang, Z.; Yang, Z.; Wong, H.; Zhu, J.; Meanwell,
N. A.; Kadow, J. F.; Wang, T. J. Org. Chem. 2002, 67, 6226.
(7) Gallou, F.; Reeves, J. T.; Tan, Z.; Song, J. J.; Yee, N. K.;
Campbell, S.; Jones, P.-J.; Senanayake, C. H. Synlett 2005,
2400.
(8) Sloan, M. J.; Phillips, R. S. Bioorg. Med. Chem. Lett. 1992,
2, 1053.
(9) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.;
Cottrell, I. F.; Wright, S. H. B. Synthesis 1996, 877.
(10) Kelly, T. A.; McNeil, D. W.; Rose, J. M.; David, E.; Shih,
C.-K.; Grob, P. M. J. Med. Chem. 1997, 40, 2430.
(11) Alvarez, M.; Fernández, D.; Joule, J. A. Synthesis 1999, 615.
(
2) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045;
and references therein.
(
3) (a) Messaoudi, S.; Anizon, F.; Pfeiffer, B.; Golsteyn, R.;
Prudhomme, M. Tetrahedron Lett. 2004, 45, 4643.
(b) Wang, T.; Zhang, Z.; Wallace, O. B.; Deshpande, M.;
Fang, H.; Yang, Z.; Zadjura, L. M.; Tweedie, D. L.; Haung,
S.; Zhao, F.; Ranadive, S.; Robinson, B. S.; Gong, Y.-F.;
Ricarrdi, K.; Spicer, T. P.; Deminie, C.; Rose, R.; Wang, H.-
G. H.; Blair, W. S.; Shi, P.-Y. J. Med. Chem. 2003, 46,
Synlett 2007, No. 2, 211–214 © Thieme Stuttgart · New York

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