1886
E. Duval et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1885–1889
R2
O
R2
S
R2
R1
O
N
R2
CO2Et
NH2
R2
S
O
R3
R3
X
Method
b
R3
Cl
N
a
b,c
O
N
R1
N
R1
H
N
4b
R1
A, B or C
R1
S
S
N
XH
NH2
N
2
3a : R1=H
4a : X=S
4b : X=O
O
a
18a : X=O
3b : R1=Cl
17
18b : X=NH
18c : X=NMe
Scheme 1. Reagents and conditions: Method A: (i) EtO2CCH2CN,
AcOH, AcONH4, C6H6, Dean–Stark, D; (ii) sulfur, Et2NH, EtOH,
50 °C; Method B: EtO2CCH2CN, sulfur, morpholine, EtOH, 50 °C;
Method C: EtO2CCH2CN, sulfur, DBU, toluene, MW, 120 °C, 20min;
(a) TFAA, Et3N, CH2Cl2 then SO2Cl2, CH2Cl2 then NaBH4, EtOH;
(b) R3NCX (X = S or O), pyridine, 50 °C then MeONa, MeOH, rt.
Scheme 3. Reagents and conditions: (a) POCl3, MW, 150 °C, 1 h; (b)
18a: EtO2CCH2OH, NaH, THF, D; 18b: MeO2CCH2NH2ÆHCl, Et3N,
EtOH/MeCN, 60 °C; 18c: EtO2CCH2NHMeÆHCl, Et3N, EtOH/
MeCN, 60 °C; (c) NH2NH2, EtOH, rt.
from 19 and 21 using the same procedures that were em-
ployed for the thiophene series (Scheme 4).
3a–b with alkyl or aryl isothiocyanates (or isocyanates)
in basic conditions afforded compounds 4a (or 4b).10
The N-Boc-protected thiophene derivative 23 (Scheme
5), prepared from N-Boc-4-piperidone, 22, utilizing
methodology described in Scheme 1/Method B, was
alkylated with ethyl bromoacetate to afford 24a. The
amine was de-protected to give 24b, which in turn was
alkylated to afford 24c and 24d. Each of these deriva-
tives (24a–d) was subsequently converted into acylhydr-
azines 25a–d.
Alkylation of thiol 4a with ethyl bromoacetate followed
by aminolysis of the resulting ester 5 with hydrazine led
to acylhydrazine 6 (Scheme 2). Compound 5 was also
converted into amides 7 and 8, acid 9 and hydroxamic
acid 10. Reaction of 5 with methylhydrazine led to a sep-
arable mixture of regioisomers 11 and 12. Similarly,
reaction of 4a to methyl chloropropionate followed by
aminolysis led to the acylhydrazine 13. The homolo-
gated analog 14 was accessible by a Michael addition
of 4a with methylacrylate followed by aminolysis of
the ester with hydrazine. Alternatively, alkylation of
4a with the a-bromoketone BrCH2C(O)CH2NHBoc,
16,11 followed by de-protection of the amine led to the
a-aminoketone 15.
O
R1
R2
S
Ph
CO2Me
NH2
a,b,c
N
H
N
N
NH2
O
19
20a : R1=Ph, R2=3-F-Ph
The oxygen and nitrogen analogs 18a–c (Scheme 3) were
obtained in three steps from 4b. First, 4b was converted
to chloride 17 by treatment with POCl3 under micro-
wave (MW) irradiation. Addition of the requisite nucle-
ophile to 17 followed by aminolysis of the ester gave
18a–c.
O
O
R1
R2
b,c
Ph
N
H
N
N
N
S
NH2
N
SH
O
20b : R1=H, R2=Ph
21
Scheme 4. Reagents and conditions: (a) 3-F-Ph-NCS, pyridine, 50 °C
then MeONa, MeOH, rt; (b) BrCH2CO2Et, K2CO3, DMF, rt;
(c) NH2NH2, EtOH, rt.
Compounds 20a and 20b, in which the thiophene moiety
has been replaced with a benzene ring, were prepared
R2
R2
S
O
N
O
N
R3
R3
S
N
a
N
R1
R1
F
Y
Z
S
SH
O
O
N
a
O
BocN
Z
OEt
NHNH2
NHMe
NH2
OH
NHOH
NHNHMe
Y
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH(Me)
C2H4
CH2
BocN
N
Scheme 1
Method B
4a
5
6
b
c
d
e
S
SH
O
7
22
8
9
23
F
F
f
10
11
12
13
14
15
O
g
RN
RN
b
e
N
N
N(Me)NH2
NHNH2
H
N
h,b
i,b
j,k
4a
4a
4a
OEt
O
S
S
N
S
NH2
N
S
NHNH2
CH2NH2
O
24a : R = Boc
24b : R = H
24c : R = Me
24d : R = n-Pr
25a : R = Boc
25b : R = H
25c : R = Me
25d : R = n-Pr
c
d
Scheme 2. Reagents and conditions: (a) BrCH2CO2Et, K2CO3, DMF,
rt; (b) NH2NH2, EtOH, rt; (c) MeNH2, MeOH, rt; (d) NH3, MeOH, rt;
(e) 10N NaOH, THF/MeOH, 0 °C; (f) (ClCO)2, DMF cat, CH2Cl2,
then NH2OHÆHCl, Et3N, THF/water, rt; (g) MeNHNH2, EtOH,
80 °C; (h) methyl 2-chloropropionate, K2CO3, THF, D; (i) methylac-
rylate, Et3N, MeOH, 60 °C then rt; (j) 16, K2CO3, DMF, rt; (k) HCl,
Et2O, rt.
Scheme 5. Reagents and conditions: (a) BrCH2CO2Et, K2CO3, DMF,
rt; (b) TFA, CH2Cl2, rt; (c) H2C@O 37%, NaBH(OAc)3, AcOH,
MeOH, CH2Cl2; (d) C2H5CHO, NaBH(OAc)3, AcOH, MeOH,
CH2Cl2; (e) NH2NH2, EtOH, rt.