A regioselective route to 5- and 6-azaindoles

Article abstract of DOI:10.1055/s-2005-871946

The synthesis of 4,7-dimethoxy 5- and 6-azaindoles, a structural unit that is present in recently developed anti-HIV-1 agents, was achieved in a regioselective manner. The developed strategy is based on the appropriate choice of a protecting group during a lithium-mediated formylation step, followed by thermal cyclization of azidoacrylates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871946

2080
LETTER
A Regioselective Route to 5- and 6-Azaindoles
A
R
egioselectiv
h
e
R
oute to 5
i
-
and 6
e
Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie EA 3741, Ecosystèmes et Molécules Bioactives,
Université Claude Bernard Lyon 1, 8, Avenue Rockefeller, 69373 Lyon Cedex 08, France
Fax +33(4)78777549; E-mail: barret@sante.univ-lyon1.fr
Received 28 April 2005
OMe
OMe
OMe
OMe
Abstract: The synthesis of 4,7-dimethoxy 5- and 6-azaindoles, a
structural unit that is present in recently developed anti-HIV-1
agents, was achieved in a regioselective manner. The developed
strategy is based on the appropriate choice of a protecting group
during a lithium-mediated formylation step, followed by thermal
cyclization of azidoacrylates.
N
CO2Me
CO2Me
N
N
N
H
H
5-azaindole 1a
6-azaindole 1b
Key words: 5- and 6-azaindoles, pyridines, metalations, azides,
regioselectivity
OMe
OMe
CO2Me
CHO
X
Y
X
Y
N3
The indole nucleus is a prominent structural unit frequent-
ly found in numerous natural products and pharmaceuti-
cally active coumpounds.1 Even if a wide variety of
methodologies is known for the preparation of indoles,2 a
relatively small number of methods describes the prepara-
tion of azaindoles.3 Furthermore, most of these approach-
es deals with the preparation of 7-azaindoles.3b,d Recently,
5- and 6-azaindoles have drawn considerable attention
since 3-oxoacetyl-piperazino 6-aza derivatives (such as
BMS-488043, Figure 1) have shown promising antiviral
activities against HIV-1.4 However, there is a lack of a
general methodology for preparing 5- and 6-azaindoles:
this prompted us to develop a new route to these nitrogen-
containing rings.
OMe
OMe
3
X = N, Y = CH: 3-formylpyridine 2a
X = CH, Y = N: 4-formylpyridine 2b
Figure 2
metalation procedure developed by Quéguiner and co-
workers:7 lithiation of 5 was performed at 0 °C by using
methyllithium and a catalytic amount of diisopropylamine
(DIPA), followed by electrophilic quench with N-
formylpiperidine.8 Although this method led to exclusive
metalation at the 3-position on 2-methoxypyridine, with
substrate 5 it gives a 81:19 mixture (determined from the
1H NMR of the crude product) of 4- and 3-formyl deriva-
tives in the favor of 2b (55% isolated yield after flash
chromatography, Scheme 1).
O
OMe
OMe
O
N
N
MeO
HO
N
O
a
N
H
86%
N
OMe
N
OMe
BMS-488043
4
5
Figure 1
CHO
MeO
MeO
CHO
OMe
2a, 15%
b
+
Looking for a regioselective access to dimethoxy 5- and
6-azaindoles 1, we were interested in the preparation of
both 3- and 4-formylpyridines 2 (Figure 2). Indeed, such
compounds could be useful substrates for the preparation
of the corresponding azidoacrylates 3, precursors of the
desired structures 1 via a Hemetsberger–Knittel reaction.5
N
OMe
N
2b, 55%
Scheme 1 Reagents and conditions: a) MeI 1.0 equiv, K2CO3 1.5
equiv, DMF, 50 °C, 3 h; b) 1) MeLi 1.8 equiv, DIPA 2 mol%, THF,
0 °C, 3 h; 2) N-formylpiperidine 1.8 equiv, –40 °C, 2 h.
We first investigated the formylation of 2,5-dimethoxypy-
ridine 5, a substrate which was easily prepared by methyl-
ation of 5-hydroxypyridine 4 under basic conditions
(Scheme 1).6 For this purpose, we used the lithium-based
To enhance the proportion of the 4-isomer further, we be-
lieved that the ortho-directing methoxymethyl (MOM)
group would be of prime interest.9 To this end, the MOM-
protected pyridine 6 was synthesized by trapping the phe-
nolate of 4 with MOM chloride (CAUTION: MOMCl is
known to be a powerful carcinogenic alkylating reagent!
Scheme 2). Metalation under the above conditions on
SYNLETT 2005, No. 13, pp 2080–2082
1
9
.0
8
.2
0
0
5
Advanced online publication: 12.07.2005
DOI: 10.1055/s-2005-871946; Art ID: D11705ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Regioselective Route to 5- and 6-Azaindoles
2081
CHO
MOMO
TIPSO
MOMO
TIPSO
e, a
b
2b
c
N
OMe
N
OMe
OMe
85%
over 2 steps
7, 62%
4
6
d
CHO
OMe
f, a
b
2a
84%
over 2 steps
N
N
9, 64%
8
Scheme 2 Reagents and conditions: a) MeI 1.0 equiv, K2CO3 1.5 equiv, DMF, 50 °C, 3 h; b) 1) MeLi 1.8 equiv, DIPA 2 mol%, THF, 0 °C,
3 h; 2) N-formylpiperidine 1.8 equiv, –40 °C, 2 h; c) NaH 1.2 equiv, MOMCl 1.15 equiv, DMF, r.t., 3 h, 92%; d) TIPSCl 1.2 equiv, imidazole
2.1 equiv, DMF, r.t., 24 h, quantitative; e) 3 N aq HCl, THF, 50 °C, 3 h, 95%; f) TBAF 1.5 equiv, THF, 0 °C to r.t., 2 h, 87%.
OMe
substrate 6 led to the regioselective formation of 4-
formylpyridine 7 with a 62% isolated yield.10 Acidic
cleavage of the MOM group followed by methylation
afforded the 4-formylpyridine 2b.
OMe
CO2Me
xylene
X
Y
X
Y
CO2Me
N3
140 °C, 1 h
N
H
OMe
OMe
At the same time, we designed a selective synthesis of the
other regioisomer 2a using the sterically hindered triiso-
propylsilyl (TIPS) ether of common substrate 4. Com-
pound 8 was first prepared by silylation of 4 under
classical conditions (TIPSCl, imidazole in DMF) and then
submitted to the same metalation–electrophilic quench se-
quence. This resulted in the exclusive formation of the 3-
formylpyridine 8 with a good 64% yield,11 showing the
utility of the bulky ‘ortho-repulsing’ TIPS group. The
dimethoxy compound 2a was then obtained after de-
protection of the silyl group with a fluoride source and
subsequent methylation (Scheme 2).
5-aza: 1a, 82%
6-aza: 1b, 52%
X = N, Y = CH: 3a
X = CH, Y = N: 3b
Scheme 4
In conclusion, we have described a regioselective synthe-
sis of 4,7-dimethoxy 5- and 6-azaindoles 1 starting from
5-hydroxy 2-methoxypyridine 4. Our strategy was based
on the judicious choice of the protecting group (ortho-
directing vs. ortho-repulsing) of this common substrate 4
during the formylation step. The reactivity of 5- and 6-
azaindoles 1 is under investigation and will be reported in
due course.
With both regioisomers 2a and 2b in hand, we decided to
prepare acrylates 3a and 3b by condensation of the latter
with methyl azidoacetate12 in the presence of sodium
methoxide as a base. When the reaction was carried out at
30 °C, we observed the exclusive formation of the desired
acrylates 3 albeit in moderate yields (Scheme 3).13
References
(1) (a) Sundberg, R. J. In Comprehensive Heterocyclic
Chemistry, Vol. 4; Katritzki, A. R.; Rees, C. W., Eds.;
Pergamon: Oxford, 1984, 313–376. (b) For a recent review
of indole-containing natural products, see: Lounasmaa, M.;
Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175.
(2) For reviews on indole syntheses, see: (a) ref. 1a.
(b) Sundberg, R. J. Indoles; Academic: London, 1996.
(c) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045.
(3) (a) Zhang, Z.; Yang, Z.; Meanwell, N. A.; Kadow, J. F.;
Wang, T. J. Org. Chem. 2002, 67, 2345; and references cited
therein. (b) Cottineau, B.; O’Shea, D. F. Tetrahedron Lett.
2005, 46, 1935; and references cited therein. (c)Debenham,
S. R.; Chan, A.; Liu, K.; Price, K.; Wood, H. B. Tetrahedron
Lett. 2005, 46, 2283; and references cited therein. (d) For a
review on 7-azaindoles, see: Mérour, J.-Y.; Joseph, B. Curr.
Org. Chem. 2001, 5, 471.
(4) (a) De Clercq, E. J. Med. Chem. 2005, 48, 1297. (b)Yeung,
K.-S.; Farkas, M.; Kadow, J. F.; Meanwell, N. A.; Taylor,
M.; Johnston, D.; Coulter, T. S.; Wright, J. J. K. PCT Int.
Appl. WO 2005/004801, 2005.
OMe
OMe
CO2Me
N3
CO2Me
CHO
X
Y
X
Y
N3
MeONa
MeOH, 30 °C
2 h
OMe
OMe
3a, 57%
3b, 51%
X = N, Y = CH: 2a
X = CH, Y = N: 2b
Scheme 3
The desired 5- and 6-azaindoles 1 were finally synthe-
sized in moderate to good yields as solids by simply
refluxing suspensions of the corresponding acrylates 3 in
xylene during one hour followed by a slow cooling of the
reaction mixture (Scheme 4).14
(5) (a) Hemetsberger, H.; Knittel, D.; Weidmann, H. Monatsh.
Chem. 1969, 100, 1599. (b) For a review, see: Moody, C. J.
In Comprehensive Organic Synthesis, Vol. 7; Trost, B. M.;
Fleming, I.; Ley, S. V., Eds.; Pergamon Press: Oxford, 1991,
21–38. (c) For a recent application of the Hemetsberger
reaction directed towards the total synthesis of Variolin B,
see: Molina, P.; Fresneda, P. M.; Delgado, S. J. Org. Chem.
2003, 68, 489.
Synlett 2005, No. 13, 2080–2082 © Thieme Stuttgart · New York

2082
T. Lomberget et al.
LETTER
(6) Compound 4 was prepared in two steps from commercially
available 2-methoxypyridine, following a literature
procedure: Van de Poël, H.; Guillaumet, G.; Viaud-
Massuard, M.-C. Heterocycles 2002, 57, 55.
(7) Trécourt, F.; Mallet, M.; Marsais, F.; Quéguiner, G. J. Org.
Chem. 1988, 53, 1367.
ppm. HRMS (CI): m/z calcd for C11H13N4O4: 265.0937
[MH+]; found: 265.0938.
Acrylate 3b (yellow powder, 268 mg, 51%): mp 117–118 °C
(dec.). 1H NMR (300 MHz, acetone-d6): d = 3.84 (3 H, s),
3.91 (3 H, s), 3.92 (3 H, s), 7.12 (1 H, s), 7.50 (1 H, s), 7.90
(1 H, s) ppm. 13C NMR (75 MHz, acetone-d6): d = 53.6,
53.6, 57.2, 111.1, 116.1, 130.3, 130.5, 133.3, 149.3, 159.4,
164.0 ppm. HRMS (EI): m/z calcd for C11H12N4O4:
264.0859 [M+•]; found: 264.0856.
(8) After trying DMF as the electrophilic agent, we found that
this reagent gave better results.
(9) For a precedent on the ortho-directing properties of the
MOM ether group on a pyridine ring, see: (a)Ronald, R. C.;
Winkle, M. R. Tetrahedron 1983, 39, 2031. (b) See ref. 6.
(10) The ratio 4-formyl pyridine/3-formyl pyridine derivatives
was determined by 1H NMR on the crude product and
estimated to be 95:5, respectively.
(14) Typical Experimental Procedure for the Preparation of
Azaindoles 1.
To 13 mL of hot xylene (140 °C) was slowly added under
vigorous stirring a suspension of acrylate 3a (423 mg, 1.6
mmol) in 27 mL xylene. After addition, the mixture was
stirred for 1 h at 140 °C and then slowly cooled down to r.t.
overnight without stirring. Once the solid crystallized, the
supernatant was removed and the solid dried under high
vacuum to give 5-azaindole 1a as pale pink crystals (310 mg,
82%). For the synthesis of 6-azaindole 1b starting from
acrylate 3b, the crystallization occurred only at –20 °C.
Additional purification of the supernatant by flash
chromatography (silica gel, petroleum ether–EtOAc, 50:50)
was necessary to recover all of 1b, which is more soluble in
xylene than its 5-aza analogue (compound 1a is
quantitatively recovered after crystallization at r.t.).
5-Azaindole 1a: mp 192–193 °C. 1H NMR (300 MHz,
DMSO-d6): d = 3.84 (3 H, s), 3.90 (3 H, s), 3.92 (3 H, s),
7.10 (1 H, s), 7.47 (1 H, s), 12.57 (1 H, br s) ppm. 13C NMR
(75 MHz, DMSO-d6): d = 51.9, 52.8, 56.4, 106.5, 113.0,
120.4, 127.5, 134.2, 140.0, 152.8, 160.9 ppm. HRMS (CI):
m/z calcd for C11H13N2O4: 237.0875 [MH+]; found:
237.0874.
(11) No trace of the 4-formyl derivative was detected by 1H NMR
on the crude product. In this case, a small amount (less than
10%) of the starting material 8 was detected and separated
from the desired product 9 by flash chromatography on silica
gel.
(12) Methyl azidoacetate was prepared from methyl
bromoacetate and sodium azide according to the following
procedure: Moore, A. T.; Rydon, H. N. Org. Synth. 1965, 45,
47.
(13) Typical Experimental Procedure for the Preparation of
Acrylates 3.
To dry MeOH (4 mL) at 0 °C was added Na (189 mg, 8.2
mmol) portionwise and the resulting mixture was stirred
until complete consumption of the metal. The temperature
was then raised to 30 °C and a solution of aldehyde 2a (335
mg, 2.0 mmol) and methyl azidoacetate (875 mg, 7.6 mmol)
in dry MeOH (6 mL) was added in one portion. After stirring
during 2 h, the mixture was poured on ice (40 g) and placed
at 4 °C during 1 h. The solid was then filtered on a sintered-
glass funnel to afford acrylate 3a as an off-white fine powder
(299 mg, 57%); mp 123–124 °C (dec.). 1H NMR (300 MHz,
DMSO-d6): d = 3.81 (3 H, s), 3.86 (3 H, s), 3.87 (3 H, s),
7.02 (1 H, s), 7.89 (1 H, d, J = 3.0 Hz), 8.12 (1 H, d, J = 3.0
Hz) ppm. 13C NMR (75 MHz, DMSO-d6): d = 53.3, 53.8,
56.2, 115.7, 116.0, 125.3, 127.3, 132.7, 150.4, 155.2, 163.0
6-Azaindole 1b (pale yellow powder, 123 mg, 52%): mp
169–170 °C. 1H NMR (300 MHz, DMSO-d6): d = 3.86 (3
H, s), 3.88 (3 H, s), 3.96 (3 H, s), 7.07 (1 H, s), 7.27 (1 H, s),
12.63 (1 H, br s) ppm. 13C NMR (75 MHz, DMSO-d6):
d = 52.0, 52.8, 55.9, 104.9, 114.7, 123.0, 124.8, 129.0,
145.7, 146.4, 161.0 ppm. HRMS (EI): m/z calcd for
C11H12N2O4: 236.0797 [M+•]; found: 236.0798.
Synlett 2005, No. 13, 2080–2082 © Thieme Stuttgart · New York