N. Koay et al. / Tetrahedron Letters 52 (2011) 122–124
123
TsO
H
H
EWG
a or b
X
N
OH
H
3a; EWG = CN, X = Br, R = H, 22%
3b; EWG = NO2, X = Br, R = H, 84%
3c; EWG = NO2, X = Cl, R = H, 85%
3d; EWG = NO2, X = Br, R = OMe, 21%
3e; EWG = NO2, X = Cl, R = OMe, 40%
EWG
X
F
N
N
OH
OH
or
+
R
1a; EWG = CN, X = Br
1b; EWG = NO2, X = Br
1c; EWG = NO2, X = Cl
2a
2b; R = OMe
R
OMe
O
X
OMe
O
EWG
X
N
O
EWG
EWG
6a, 67%
6b, 76%
6c, 73%
6d, 55%
6e, 62%
c
d
e
N
N
R
R
R
4a-e
5a, 80%; 5b, 45%
5c, 55%; 5d, 54%
5e, 79%
Scheme 2. Reagents and conditions: (a) 1a–c (1.0 equiv), 2a (1 equiv) in DMSO at 100 °C; (b) 1b–c (2.0 equiv), 2b (1.0 equiv), N-methyldicyclohexylamine (2.0 equiv) in NMP
at 120 °C; (c) (CO)2Cl2 (1.2 equiv), DMSO (3.0 equiv), CH2Cl2, À78 °C to À40 °C, then Et3N (5.0 equiv), À78 °C to 0 °C; (d) methyl (triphenylphosphoranylidene)acetate
(1.5 equiv), THF, rt, except for 4a at 40 °C; (e) N-methyldicyclohexylamine (2.6 equiv), Bu4NBr (1 equiv), Pd(OAc)2 (0.2 equiv), DMF, 120 °C.
used. Using nitro as electron-withdrawing group on the benzene
ring 1b–c gave high isolated yields of 3b and 3c (84 and 85% yield,
respectively). Interestingly, the SNAr reaction was more efficient
with nitro group on the benzene ring. N-arylated piperidinemeth-
anols 3b and 3c were subsequently converted into the correspond-
ing N-fused tricyclic indoles 6b using the same Swern, Wittig, and
Heck reaction sequence.
Next, we examined the effect of amines on the SNAr reaction by
using (5-methoxypiperidin-2-yl)methanol 2b. A methoxy group
was introduced to the piperidine to act as a masked ketone in cases
of further functionalization.
As 2b is not commercially available, we needed to design a syn-
thetic method for the preparation of this key intermediate. The
reaction sequence is shown in Scheme 3. One-pot esterification
and etherification of 5-hydroxypicolinic acid 7 using silver carbon-
ate and methyl iodide in acetonitrile afforded ester 8. Treatment of
8 with 3.5 equiv of Dibal-H converted the methyl ester into the
corresponding alcohol 9 in 78% yield. Hydrogenation using 5% rho-
dium on alumina in methanol under 50 psi pressure of hydrogen
yielded (5-methoxypiperidin-2-yl)methanol 10 as an oil.9 To ease
the handling, the crude (5-methoxypiperidin-2-yl)methanol 10
was converted into the corresponding tosylate salt 2b in 75% yield.
With tosylate salt 2b in hand, it was allowed to react with
2-bromo-1-fluoro-4-nitrobenzene 1b and 2-chloro-1-fluoro-4-
nitrobenzene 1c under SNAr conditions. It was found that NMP at
120 °C was the best condition for the preparation of 3d and 3e.
Following the same Swern, Wittig, and Heck reaction sequence,
we successfully prepared 6d.
So far, only a,b-unsaturated methyl ester partner was explored
in the intramolecular Heck coupling which allowed direct access to
C-3 methyl acetate. We believe that such strategy will have useful
application in the synthesis of CRTH2 antagonists which are com-
monly constituted of acetic acid functional group at C-3.1
In conclusion, we have developed a novel and practical meth-
od for the preparation of methyl 6,7,8,9-tetrahydropyrido[1,2-
a]indol-10-ylacetate analogues. The efficient synthesis of piperi-
dinemethanol, the convenient four step sequence, and the various
aryl fluorides commercially available make this methodology a
very attractive alternative for the synthesis of methyl 6,7,8,9-tet-
rahydropyrido[1,2-a]indol-10-ylacetate analogues. Application of
Buchwald–Hartwig amination or Ullmann N-arylation for the
preparation of analogues 3 to expand the scope of N-arylation,
and ultimately this methodology, are underway, and will be re-
ported in due course.
Acknowledgment
We thank Ms. Stéphanie Lessard (Merck Frosst) for her help in
the manuscript preparation.
Supplementary data
Supplementary data (experimental details for all reactions and
spectral data for new compounds) associated with this article
HO
MeO
MeO
b
a
OH
OH
OMe
N
N
N
References and notes
O
O
7
8
9
1. (a) Wang, Z. PCT International Patent Application WO 2010031182, 2010.; (b)
Colucci, J.; Boyd, M.; Zaghdane, M. H. PCT International Patent Application WO
2010031183, 2010.; (c) Stearns, B. A.; Baccei, C.; Bain, G.; Broadhead, A.; Clark, R.
C.; Coate, H.; Evans, J. F.; Fagan, P.; Hutchinson, J. H.; King, C.; Lee, C.; Lorrain, D.
S.; Prasit, P.; Prodanovich, P.; Santini, A.; Scott, J. M.; Stock, N. S.; Truong, Y. P.
Bioorg. Med. Chem. Lett. 2009, 19, 4647–4651.
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Med. Chem. 1993, 36, 21–29; (b) Davis, P. D.; Hallam, T. J.; Harris, W.; Hill, C. H.;
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Chem. Lett. 1994, 4, 1303–1308; (c) Tanaka, M.; Sagawa, S.; Hoshi, J.-I.; Shimoma,
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MeO
MeO
c
d
OH
TsO
OH
N
N
H
H
H
10
2b
Scheme 3. Reagents and conditions: (a) Ag2CO3 (4.0 equiv), MeI (4.0 equiv),
CH3CN; (b) Dibal-H (3.5 equiv), toluene, À78 °C to 0 °C; (c) 5% Rh/Al2O3 (0.12 equiv),
H2 (50 psi), MeOH; (d) TsOH (1.0 equiv), EtOAc.