402
L. Tenora et al. / Tetrahedron Letters 52 (2011) 401–403
H
N
3 (75%)
+
i
N
O
N
Cl
N
ii
ii, iii
N
N
iii
5
(70%)
O
4 (78 %)
O
6
HS
v
O
iv
6
N
N
O
N
NH2
CH3OH
OH
O
O
S
O
S
vi
- H2O
- CH3OH
S
S
O
O
O
1b
(80%)
8 (69 %)
7
9 (72%)
O
Scheme 3. Reagents and conditions: (i) p-toluenesulfonic acid, benzene, reflux; (ii) Et3N, toluene, 4 °C, then rt for 18 h; (iii) 10% HCl, H2O, rt; (iv) HCl (g), Et2O, molecular
sieves (5 Å), MeOH, rt; (v) base, MeOH, rt; or p-toluenesulfonic acid, EtOH, rt; (vi) t-BuOK, THF, reflux.
obtained when the reaction was performed under solvent-free
conditions with an excess of compound 6 (8 equiv).
In the final step, base-promoted cyclization of compound 9 was
realized (Scheme 3). The reaction was accomplished either at room
temperature in 24 h or in 15–30 min in boiling THF. The target
molecule 1b was obtained in pure form without any other purifica-
tion necessary (see Supplementary data for analytical data).
In conclusion, we have developed a new means of access to
methyl 3-amino-4,5,6,7-tetrahydrobenzo[b]-thiophene-2-carbox-
ylate (1b) as an important intermediate in the synthesis of hista-
mine H4 receptor modulators. Our synthesis consists of four
steps leading to compound 1b in 34% overall yield without any col-
umn chromatography required. The method is based on simple and
Figure 1. ORTEP representation9 of compound 8 (major diastereomer).
industrially accessible chemicals with yields comparable to those
obtained by other research groups.
Acknowledgement
Thus, we tested the analogous treatment of ketone 4 with sulfa-
nylacetate 6 according to a procedure carried out on similar struc-
tures.8 To our surprise, we were only able to obtain a mixture of
diastereomeric lactones 8 in the ratio 2:1 (Scheme 3). The major
diastereomer was isolated by fractional crystallization from meth-
anol. The stereochemistry was determined by X-ray analysis9
(Fig. 1). Most attempts to transform lactones 8 into compound 9
by ring-opening resulted in recovery of ketone 4 (Scheme 3). How-
ever, passing anhydrous hydrogen chloride through a methanolic
solution of lactones 8 finally yielded the desired product 9.
ˇ
The authors thank Marek Necas for X-ray analysis.
Supplementary data
Supplementary data (experimental procedures) associated with
this article can be found, in the online version, at doi:10.1016/
References and notes
On this basis we developed a new reaction protocol for the reac-
tion of ketone 4 with acetate 6. Both reactants were mixed in
diethyl ether and gaseous HCl was bubbled through the reaction
mixture for a few minutes. It was shown that at the moment when
compound 4 was consumed, the reaction mixture contained, be-
side lactone 8 (85%), a small amount of product 9 (15%, monitored
by GC–MS). Subsequently, methanol and an additional portion of
gaseous HCl were added. The reaction was stopped when complete
conversion of lactones 8 into product 9 was registered by GC–MS.
During this transformation, intermediate 7 was also detected.
However, its isolation was not attempted. Comparable results were
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Tenora, Luká?
