N. Selvakumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4416–4419
4417
O2N
F
Cl
NO2
F
NO2
NH
+
+
NH
a
NO
2b,c
NO2
b
N
N
a
O2N
F
OH
OH
OH
F
OH
4
13
F
Cbz-HN
N
Cbz-HN
N
c
NO2
N
NO2
N
d
NH-Cbz
O
NH-Cbz
d
e
SAc
Br
F
Br
6
OH
15
14
5
NO2
N
N
NO2
O
N
f,g
N
NH-Cbz
N
N
Cbz
8: R = OH
e
N
f
R
SH
S
N
Cbz
17
16
g,h,i
O
7
9: R = NHAc
NH-Cbz
h,i,j
k
O
N
N
j
k
N3
O
S
O
S
18
19
O
N
N
O
N
N
H
l,m,n
S
H
N
O
O
N
N
CHO
N
R
O
O
H
N
N
O
N
N
O
N
O
H
10
N
OMe
11: R = COCH3
R
12: R = COCH2Cl
O
S
21
3: R = S
20: R = SO2
Scheme 1. Reagents and conditions: (a) Et3N, CH3CN, rt, 4 h, 94%;
(b) 10% Pd on C, H2, THF, 14 h; (c) Cbz-Cl, aq Na2CO3, acetone, rt,
2 h, 75% for two steps; (d) CBr4, PPh3, CH2Cl2, rt, 48 h, 70%; (e)
K2CO3, DMF, rt, 28 h, 62%; (f) BuLi, (R)-glycidyl butyrate, THF,
À78 °C to rt, 14 h, 58%; (g) MsCl, Et3N, CH2Cl2, 0 °C, 4 h, 96%; (h)
NaN3, DMF, 80 °C, 1 h, 91%; (i) MeCOSH, rt, 14 h, 68%; (j) 10% Pd
on C, H2 then HCOOEt, 41%; (k) 10% Pd on C, H2 then AcCl (62%)
or chloroacetyl chloride, Et3N (55%).
Scheme 2. Reagents and conditions: (a) Hunig’s base, CH3CN, rt, 5 h,
86%; (b) CBr4, PPh3, CH2Cl2, 0 to 45 °C, 5 h, 93%; (c) MeCOSH,
NaH, THF, 8 h, 100%; (d) K2CO3, MeOH, reflux, 3 h, 66%; (e) NaH,
DMF, 60 °C, 1 h, 46%; (f) Fe, HCl, EtOH, 0 °C to rt, 45 min.; (g) Cbz-
Cl, aq Na2CO3, acetone, 0 °C to rt, 5 h, 81% for two steps; (h) BuLi,
(R)-glycidyl butyrate, THF, À78 °C, 4 h, 56%; (i) MsCl, Et3N,
CH2Cl2, 0 °C to rt, 2 h, 90%; (j) NaN3, DMF, 80 °C, 2 h, 91%; (k)
MeCOSH, rt, 15 h, 65%; (l) PPh3, H2O, THF, 68%; (m) CSCl2, Et3N;
(n) MeOH, reflux, 56% for two steps; (o) NaIO4, CH2Cl2, 50%.
culty for isolation due to its instability and thus was
directly treated with Cbz chloride in situ to produce
the di-Cbz compound 5. The compound 5 was converted
into its bromo derivative 6 with CBr4 and PPh3, which
was cyclised with K2CO3 in DMF to result in the tricy-
clic Cbz compound 7. After this point, the compound 7
was converted into the acetamide 9 as per the usual
literature procedures.9 The attempts to deprotect the
Cbz group to the corresponding free amine or as a salt
failed to give the required material because of the insta-
bility of the product. Thus, we resorted to installing
smaller groups such as formate, acetate and chloroace-
tate employing usual procedures of treating the amine
in situ with the appropriate reagents to give the com-
pounds 10, 11 and 12, respectively.
the protocol described in Scheme 1.11 The acetamide 3
was further converted to the sulfone 20 with sodium
metaperiodate. The intermediate azide 19 could be
converted to the thiocarbamate 21 following usual
reaction conditions.
Synthesis of fluorine containing hexahydroazolo-quinox-
aline and tetrahydroazolo-benzothiazine compounds:
A new methodology was developed for the prepara-
tion of title compounds involving a tandem SN2 and
a SNAr reaction. The nitro-alcohol 22 (Scheme 3),
obtained as per our earlier method,10 was converted
to the bromo compound 23 as usual. The analogous
bromo compound 14 in Scheme 2 was initially con-
verted to the thiol 16, by a SN2 reaction of the anion
of thioacetic acid followed by basic hydrolysis, before
inducing the cyclisation by a SNAr reaction to result
in the tricyclic nitro compound 17. Instead of this
usual three-step protocol, we envisioned a single pot
tandem SN2 and a SNAr reaction involving thioacetic
acid and a base as it was anticipated that the anion
addition onto bromide followed by the hydrolysis
and the subsequent cyclisation should occur
Synthesis of tetrahydroazolo-benzothiazine compounds:
Addition of L-prolinol onto 3,4-difluoronitrobenzene
resulted in the nitro-alcohol 13 (Scheme 2). The bromo
compound 14, obtained from the nitro-alcohol 13 as
above, was converted to the thioacetate 15 with
thioacetic acid. The treatment of the thioacetate 15
with K2CO3 in MeOH resulted in the thiol 16 that
was cyclised with NaH in DMF to yield the tricyclic
nitro compound 17. The nitro compound 17 was
converted into the acetamide 3 by essentially following