This article was downloaded by: [McGill University Library] On: 14 October 2012, At: 22:39 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Phosphorus, Sulfur, and Silicon and the Related Elements Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/gpss20 ONE-FLASK SYNTHESES OF SOME NEW SPIROTHIAZOLOPYRANOPYRAZOLE, SPIROTHIAZOLODIHYDROPYRIDI- NOPYRAZOLE AND SPIROTHIAZOLOTHIOPY- RANOPYRAZOLE DERIVATIVES AS ANTIMICROBIAL AGENTS Abdullah A. Al-ahmadi a a Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University, Makkah Almukarramah, P.O. Box 5576, Saudi Arabia Version of record first published: 04 Oct 2006. To cite this article: Abdullah A. Al-ahmadi (1997): ONE-FLASK SYNTHESES OF SOME NEW SPIROTHIAZOLOPYRANOPYRAZOLE, SPIROTHIAZOLODIHYDROPYRIDI-NOPYRAZOLE AND SPIROTHIAZOLOTHIOPY-RANOPYRAZOLE DERIVATIVES AS ANTIMICROBIAL AGENTS, Phosphorus, Sulfur, and Silicon and the Related Elements, 122:1, 121-132 To link to this article: http://dx.doi.org/10.1080/10426509708043500 PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: http://www.tandfonline.com/page/terms-and- conditions This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden.
Transcript
This article was downloaded by: [McGill University Library]On: 14 October 2012, At: 22:39Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon andthe Related ElementsPublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/gpss20
ONE-FLASK SYNTHESESOF SOME NEWSPIROTHIAZOLOPYRANOPYRAZOLE,SPIROTHIAZOLODIHYDROPYRIDI-NOPYRAZOLE ANDSPIROTHIAZOLOTHIOPY-RANOPYRAZOLE DERIVATIVES ASANTIMICROBIAL AGENTSAbdullah A. Al-ahmadi aa Department of Chemistry, Faculty of Applied Sciences,Umm Al-Qura University, Makkah Almukarramah, P.O. Box5576, Saudi Arabia
Version of record first published: 04 Oct 2006.
To cite this article: Abdullah A. Al-ahmadi (1997): ONE-FLASK SYNTHESES OF SOME NEWSPIROTHIAZOLOPYRANOPYRAZOLE, SPIROTHIAZOLODIHYDROPYRIDI-NOPYRAZOLE ANDSPIROTHIAZOLOTHIOPY-RANOPYRAZOLE DERIVATIVES AS ANTIMICROBIAL AGENTS, Phosphorus,Sulfur, and Silicon and the Related Elements, 122:1, 121-132
To link to this article: http://dx.doi.org/10.1080/10426509708043500
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Anysubstantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make anyrepresentation that the contents will be complete or accurate or up to date. Theaccuracy of any instructions, formulae, and drug doses should be independentlyverified with primary sources. The publisher shall not be liable for any loss, actions,claims, proceedings, demand, or costs or damages whatsoever or howsoevercaused arising directly or indirectly in connection with or arising out of the use ofthis material.
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
Phosphorus. Sulfur, and Silicon. 1997. Vol. 122. pp. 121-132 Reprints available dinctly from the publisher Photocopying permitted by licenx only
8 1997 OPA (Overwas Publishers Assmiation) Amsterdam B.V. Published in The Netherlandq
under license by Gonlon a d Breach Science Publishers Printed in Malaysia
ONE-FLASK SYNTHESES OF SOME NEW SPIROTHIAZOLOPYRANOPYRAZOLE, SPIROTHIAZOLODIHYDROPYRIDI-
NOPYRAZOLE AND SPIROTHIAZOLOTHIOPY- RANOPYRAZOLE DERIVATIVES AS ANTIMI-
CROBIAL AGENTS
ABDULLAH A. AL-AHMADI
Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University, Makkah Almukarramah, P.O. Box 5576, Saudi Arabia
(Received 22 August I996; In final form 2 December 1996)
1 -'lhia-4-benzyl-4-azspiro[4.4]nonan-3-one (2a) and/or I -thia-4-benzyl-4-azaspiro[4.5]decan-3-one (2b) reacted with 4-arylidene-3-rnethylpyrazolin-5-ones (la-f) in a mixture of ethanoVpyridine at reflux temperature to give spirothiazolopyranopymoles (3a-I) in one flask. The fusion of com- pounds la-f with 2a and/or 2b in the presence of ammonium acetate afforded spirothiazolodihydro- pyridinopyrazole derivatives ( 4 4 ) in good yields. Also the reaction of compounds la-f with 2a and/or 2b with phosphorus pentasulfide in pyridine at reflux temperature yielded the spirothiazo- lothiopyranopyrazoles (5a-I). All the synthesized spirohetenxyclic derivatives were identified by conventional methods (IR, 'H-NMR) and elemenhl analyses. All the prepared compounds were tested for their antimicrobial activities in comparison with tetracycline as a reference compound.
Several authors have reported the synthesis and applications of spirocyclic de- rivatives.l-'O The synthesis of spirocycles as class 111 antiarrhythmic agent was done.18. Synthesis of spiro[3H-indole-3,4(4H)pyran]-2-( lH)-ones having central nervous system activities were carried out.'* Spirocycloalkylsubstituted azetidi- nones were used as hypocholesterolemic agents.13 Spiro compounds showed photochromic proper tie^.'^ The preparation of fluoran derivatives as
121
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
122 A. AL-AHMADI
coloring agents for recording materials was carried out." Also the preparation of spiroazafuranone derivatives to be used for the treatment of neurodegenerative disorders and as anxiolytics was achieved.16 Spiro derivatives were used as herbicides, insecticides, acaricides and antivirals." It is of interest to note that pyrazole derivatives are reported as well known pharmaceuticals.'8-u) From all of the forgoing facts and as a continuation of our previous we report herein the synthesis and application of some new spirothiazolopyrazole deriva- tives.
RESULTS AND DISCUSSION
Syntheses started with the reaction of 1 -thia-4-benzyl-4-apiro[4.4]nonan-3- one (2a) and l-thia-4-benzyl-4-azaspiro[4.5]decan-3-one (2b) with 4-arylidene- 3-methylpyrazolin-5-ones (la-f) in a mixture of ethanoVpyridine to yield spirothiazolopyranopyrazole derivatives (3a-1) in good yields in one flask and one step. The structures of compounds 3a-1 were established from their elemen- tal analyses and spectroscopic data (Table I).The IR spectrum of 3a showed characteristic strong absorption bands at 3150 cm-' corresponding to the stretching vibration of NH group of the pyrazoline ring, 3050 cm-' for aromatic carbon-hydrogen stretching, 2870 cm-' for aliphatic carbon-hydrogen, 1600 cm-' for the C=N bond of the pyrazoline moiety and 710 cm-' for the C-S bond and no absorption bands for any carbonyl groups. The 'H-NMR spectrum of 3a (DMSO-4) showed the following signals: 6 1.30-1.70 (4H, m, two me- thylene groups of cyclopentane ring), 1.90-2.20 (4H, m, two methylene groups of cyclopentane ring), 2.78(3H, s, for the methyl protons of the pyrazoline ring), 3.20(2H, s, the methylene of benzyl group), 3.40 (lH, s, the proton at C4 of the pyran ring), 7.0&7.80(10H, m, for the aromatic protons) and 8.20 ppm (lH, s, the NH proton of the pyrazole ring). The fusion of the spiro derivatives 2a,b with la-f in the presence of ammonium acetate yielded the spirothiazolodihy- dropyridinopyrazole derivatives 4a-1 in good yields (Scheme 1). The structures of compounds 4a-1 were confirmed on the basis of their elemental analyses and spectroscopic data (Table I). Reactions of compounds 2a,b with la-f in the presence of phosphorus pentasulfide in pyridine afforded the spirothiazolo- thiopyranopyrazole derivatives 5a-1 in good yields (Scheme 1, Table I). The structure assignment of the prepared spirwycles 5a-1 were based on elemental and spectral analyses (Table I). The 'H-NMR spectrum of 5a (DMSO-4) showed the following signals: 6 1.30-1.70 (4H. m, two methylene groups of the cyclopentane ring), 1.90-2.10 (4H. m, two methylene groups of the cyclopen-
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
TABL
E I
Physical Data o
f Sp
irot
hiaz
o Lop
yran
opyr
azol
es (
3~
0, Spirothiazolodihydropyridinopyrazoles (
4~
1) and Spirothiazolothiopyranopyrazoles (5
~1
).
Com
poun
d Yw
ld
MP
. M
olec
ular
fonn
uln
MicrwMtyses-CalcukuedFound (%
) IR
(K
Br)
(m-'
) 'H
-NM
R (D
MSO
-dd
No.
(96)
("C)
(Solvent o
f 8 (WS) pp
m
CH
NS
Cl
cr
ysta
lliza
tion)
3a
60
160-
162
(&H
,ON
,S 72
.28
6.02
10
.12
7.71
-
3150
(NH
). 30
5O(C
H a
rom
). 1.
30-1
.7q4
H.m
). 1.
90-2
.20(
4H.m
), (e
than
ol)
72.1
0 6.
00
10.0
0 7.
60
- 28
7qC
H a
liph)
. 16
OO
(C=N
), 2.
78(3
H.s)
3.2
q2H
.s).
3.4q
IH.s
). 71
qc-s
) 7.
00-7
.80(
10H
.m),
8.2q
IH.s
). 3b
57
16
4-16
6 %
H,O
N,SC
I 66
.81
5.34
9.
35
7.12
7.
79
31
~.3
05
O(C
Hm
m),
(e
than
ol)
66.7
0 5.
25
9.20
7.
00
7.60
28
90(C
H a
liph)
, 16
oo(N
=C).
1.30
-1.7
0(4H
Jn).
1,
s
720(
C-S
). 2.
20(4
H.m
). 2.
80 (3
H.s)
. 3.
2q2H
.s).
3.4q
lH.s)
. 7.
00-
v)
7.80
(9H
.m).
8.2q
lH.s
).
z i; i3 ;;I
3c
55
180-
182
&H
mO
,N,S
65
.21
5.21
12
.17
6.95
-
31
50
0, 307qCH ar~m),
1.30
-1.7
0(4H
,1~)
. 1.90
-2.2
0(4H
~11)
, (m
etha
nol)
65.1
0 5.
10
12.1
0 6.
80
- 28
80(C
H a
liph)
. 16
OO
(C=N
). 2.
80(3
H.s)
. 3.
20(2
H.s)
, 3.
40(1
H.s)
15
1qN
O~
. 73O
(C-S
). 7.
00-7
.80(
9H~n
). 8.20(1H.s).
M
56
170-
172
C,,H
&,O
S 75
.76
5.90
8.
55
6.51
-
3050
(CH
arom).
2870
(CH
1.
30-1
.70(
4H.m
). 1.
90-2
.20(
4H.m
). $ rn
3e
55
17
6178
C
,,H,N
,OSC
I 70
.85
5.33
8.
00
6.09
6.
66
3050
(CH
arom). 2899O(CH
1.30
-1.7
0(4H
Jn),
1.90
-2.2
0(4H
~n),
v)
(met
hano
l) 75
.50
5.80
8.
40
6.40
-
alip
h),
16O
O(C
=N). 7
3O(C
-S)
2.80
(3H
.s),
3.2q
2H.s)
. 3.
wlH
.s).
7.
00-7
.90(
15H
.m).
(eth
anol
) 70
.70
5.20
7.
90
6.00
6.
50
alip
h),
16O
O(C
=N). 7
2qC
-S)
2.8Q
3H.s)
. 3.
2q2H
.s).
3.40
(1H
.s).
7.00
-7.9
0( l4
H.m
). 3f
58
185-
187
C,,H
,N,O
,S 69
.40
5.22
10
.44
5.97
-
3050
(CH
ar~m), 28
90(C
H
1.30
-1.7
q4H
~n).
1.90
-2.2
0(4H
.m),
(-1) 69
.30
5.10
10
.30
5.80
-
alip
h).
16O
O(C
=N).
1510
2.
80(3
H~)
. 3.2q
2H.s
). 3.
40(1
H.s)
. N
od. 7
30(C
-S)
7.00
-8.2
0(14
H~~
).
3g
60
190-
192
f&H
nN30
S 72
.72
6.29
9.
79
7.45
-
315o
(NH
),305
0(C
H m
m).
1.
40-1
.80(
6H.m
). 1.
90-2
.10(
4H.m
), (m
etha
nol)
72.6
0 6.
20
9.60
7.
10
- 29
00(C
H a
liph)
. 16
OO
(C=N
), 2.
75(3
H,s)
, 3.2
0(2R
s), 3
.40(
1H.s)
, 73
O(c
-S).
(eth
anol
) 67
.20
5.40
9.
00
6.70
7.
40
2890
(CH
alip
h),
16O
O(C
=N).
2.75
(3H
,s). 3
.2q2
H.s)
. 3.
70(1
H.s)
,
7.C
KM
.Iq 1 OH@).
8.30
( 1H
.s).
3h
55
163-
165
f&H
a,O
SC
I 67
.38
5.61
9.
07
6.91
7.
55
31
50
0, 3
07qC
H arum),
1.40
-1.8
5(6H
Jn).
1.90
-2.2
0(4H
.m).
w t4
W
71qc
-s)
7.00
-8.1
q9H
~n).
8.30
(1H
.s).
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
TA
BL
EI
(continued)
e
3i
3J 3k
31
'la
4b
4c
4d
60
172-
175
57
180-
182
55
187-
189
56
194-
1%
65.8
2 5.
48
65.7
0 5.
30
76.0
3 6.
13
76.0
0 6.
00
71.2
4 5.
56
71.1
0 5.
40
69.8
1 5.
45
69.7
0 5.
30
72.4
6 6.
28
6.10
13
.40
&.%
5.
58
5.30
12
.40
65.3
5 5.
44
5.20
15
.10
75.9
1 6.
12
6.00
11
.20
11.8
1 6.
75
- 11
.70
6.60
-
831
633
- 8
20
6.
20
-
7.79
5.
93
6.49
7.
60
5.70
6.
30
10.1
8 5.
81
-
10.0
0 5.
60
-
13.5
2 7.
72
- 7.
50
-
12.5
0 7.
14
7.81
7.
00
7.60
15.25
6.
97
- 6.
70
-
11.4
2 6.
53
- 6.
40
-
318o
(NH
. 305
O(c
H arom).
1.3S
l.75(
6H.m
). 1.
90-2
.20(
4H.m
), 2870(cH
alip
h), 1
6OO
(C=N
), 2.
70(3
9s).
4.W
2H.s)
. 3.
60(1
H.s)
, 15
1qN
OJ.
72q
C-S
). 7.
00-8
.1q9
H.m
). 8.
2qlH
.s).
30
7qC
H arom). 2
890(
cH
1.40
-1.W
6H.m
). 1.
90-2
.10(
4H.m
).
7.00
-8.1
0(1S
H~n
). 30
5O(c
H 81
0111
). 28
75(c
H
1.@
1.80
(6H
.m).
1.90
-2.2
0(4H
.m).
7.00
-8.1
0(14
H,m
). 3080(CH
-1. 28
7qcH
1.
35-1
.75(
6H.m
). 1.
90-2
.20(
4H.m
). W
h),
16o
o(C
=N),
7WC
-S)
2.W
3H.s
), 3.
20(2
H,~
), 3.4
qlH
.s).
15lO
(NO
&
7.00
-8.1
0(14
H.m
). 31
5O(N
H, W
qcH
arom).
1.30
-1.7
0(4H
.m),
1.90
-2.1
0(4H
.m).
287O
(CH
alip
h), 1
6OO
(C=N
) 2.
W3H
.s).
3.2y
W.s
). 3.
40(1
H.s)
. 7.
00-8
.10(
10H
.m),
8.3q
2H.s)
. 72
qc-S
).
31
80
0, 3
07qC
H arom).
1.30
-1.7
0(4H
.m),
1.9&
2.10
(4H
.m).
289O
(CH
alip
h). 1
6OO
(C=N
), 2.
W3H
.s).
3.2q
W.s
). 3.
60(lH
.s).
71qc
-s).
7.
00-8
.1q9
H.m
). 8.
3q2H
.s).
315O
@W
, 3060(CH arom).
1.3C
L1.7
q4H
.m).
1.90
-2.2
0(4H
.m),
ISlO
(N0~
. 72qC
-S).
7.00
-8.1
q9H
.s).
8.2q
W.s
) 31
700.
3080
(cH
arom).
130-
1.70
(4H
.m).
1.W
2.2q
4H~1
1).
29oo(cH
aliph)
. 16
OO
(C=N
). 2.
W3H
.s).
3.2q
2H.s)
. 3.
50(1
H.s)
, 7W
C-S
).
aliph).
16oo
(C=N
). 7W
C-S
) 2.
7W3H
.s). 3
.2X
2H.s)
. 3.4
0(1&
),
F al
iph)
, 16o
o(C
=N).
72qC
-S)
2.80
(38~
), 3.
2qW
.s).
3.60
(lH
,~),
aliph).
16oo
(C=N
). 2.
W3K
.9.
3.2q
2H.s)
. 3.4
5(lH
.s).
7.00
-8.1
q 1 W
). 8.3q
19s
).
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
TA
BL
EI
(con
tinue
d)
Com
uow
d Y
ield
MJ?
Mol
ecul
ar tb
rmuk
i~ MicroaMlyses-CalculatedlFound (%
) 'H
-NM
R (D
MS0
-d.J
4e
4f
4g
4h
4i
4J 4k
41
62
2142
16
(eth
anol
) 70
.99
5.30
5.
53
10.5
0 10
.68
6.00
6.
10
650
6.67
31
ElM
PH). 3060(CH arom),
1.35
-1.7
5(4H
.m).
1.90
-2.2
0(4H
.m).
mm alip
h).
16oo
(C=N
). 2.
80(3
Ils)
,3.2
0(W
s).
3.50
(lH.s)
. 73
qc-S
).
7.00
-8.1
0(4H
.m).
8.30
(1H
.s).
29
00
(a a
liph)
. 16o
o(C
=N).
2.W
3H.s
). 3.
20(W
). 3
.40(
1H.s)
. 15
lO(N
OJ,
72qC
-S).
7.
00-8
.1q1
4H.m
). 8.
3qlH
.s).
v1
29oo
(cH
alip
h). 1
6oo(
C=N
). 2.
8W3H
.s). 3
.2q
W).
3.5
0(1H
.s),
73o(
c-S)
. 7.
CG
8.10
(1O
H.m
). 8.
3qX
s).
7.57
31
7qN
H).
305q
CH
arom).
1.30
-1.7
q6H
.m).
1.90
-2.2
0(4H
.m).
29
00
(a a
liph)
. 16o
o(C
=N).
2.8CN
3H.s)
. 3.2
0(W
s).3
.60(
1H.s)
. 73
0(C
-S).
7.00
-8.1
0(9H
.m).
8.40
(2H
.s).
- 31
800.
3050
(CH
ar~m).
1.4&
1.75
(4H
~t1)
. 1.9
0-2q
4H.m
).
z i;
- 3
18
00
. 305
qC
H ar~m).
1.30
-1.7
0(6H
.1~)
, 1.90
-2.2
0(4H
.1~)
.
B 8 -
3180
WH
). U
nO(C
H ~
rom
),
1.40
-1.8
0(6H
,!~).
1.90
-2.2
q4H
.m).
2900
(CH
alip
h). 1
6oo(
C=N
). 2.
8q2H
.s).
3.60
(1H
s). 7
.00-
el
lSlO
(N0J
. 71
qc-s
).
8.1q
9H.m
). 8.
40(2
H.s)
. -
31
70
0, 3060(CH m
),
1.30
-1.7
0(6H
~). 1
.90-
2.10
(4H
.m).
alip
h).
16oo
(C=N
). 2.
80(3
H.s)
. 3.
20(W
). 3.
60(1
H.s)
. 71
qc-s
).
7.00
-8.1
0(15
H.m
). 8.
40(1
H.s)
. 6.
50
317o
(NH
). 3050(CH arom),
1.40
-1.8
0(6H
.m).
1.90
-2.2
0(4H
.m).
71qc
-s).
7
.W. l
o( 14
H.m
). 8.
5qlH
.s).
2900
(CH
alip
h).
16oo
(C=N
). 2.
W3H
.s).
3.20
(W~)
. 3.40
(1H
.s),
lSlO
(N0J
. 73
qC-S
). 7.
00-8
.10(
14H
.m).
8.3x
lH.s
).
alip
h). 1
6oo(
C=N
). 2.
80(3
H.s)
. 3.
2O(W
s). 3
.40(
1H.s)
.
- 3
18
00
. 3060(CH m
).
1.40
-1.8
0(6H
.m).
1.90
-2.1
0(4H
.m),
-
e
h)
m
69.5
3 5.
30
5.42
13
.00
13.0
8 5.
80
5.98
-
55
170-
172
(met
hano
l) W
mN
4S
72
.70
72.8
9 6.
30
6.54
13
.00
13.0
8 7.
30
7.47
-
67.5
3 5.
60
5.84
12
.00
12.1
2 6.
60
6.92
7.
50
65%
5.
50
5.70
14
.60
14.7
9 6.
50
6.76
-
G2H
32N
4S
76.0
0 76
.19
6.20
6.
34
11.0
0 11
.11
6.20
6.
34
-
M
194-
1%
(eth
anol
) %
2H31
N4s
a 71
.20
71.3
7 5.
60
5.76
10
.30
10.4
0 5.
70
5.94
6.
20
55
194-
1%
69.9
4 69
.70
5.64
5.
50
12.7
5 12
.50
5.82
5.
60
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
5c
60
240-
242
C&H,
N&&
5f
62
210-
212
G,H
,N4W
(-01)
67
.10
69.6
0 5.
80
5.60
9.
48
64.5
1 5.
16
5.00
9.
00
63.0
2 5.
04
73.3
7 5.
71
73.1
0 5.
60
68.7
6 5.
17
68.5
0 5.
00
67.3
9 5.
07
5.00
10
.00
70.1
1 6.
06
70.0
0 6.
00
65.1
3 5.
42
65.0
0 5.
20
9.74
14
.84
14.7
0 -
9.03
13
.76
13.5
0 7.
30
11.7
6 13
.44
828
12.6
0 8.
10
12.4
0
7.76
11
.82
7.50
11
.60
10.1
4 11
.59
11.2
0 -
9.43
9.
20
14.1
0
8.76
13
.36
8.60
13
.20
~~
- 3
15
00
. u)5
0(C
H m). 1
.30-
1.7q
4H.m
). 1.
90-2
.10(
4H.m
), 28
90(C
H a
liph)
. 16O
O(C
=N).
73qc
-S).
7.
00-8
.10(
10H
.m),
8.3q
lH.s
). 7.
52
317O
(NH
). 3050(CH arom).
1.30
-1.7
0(4H
.111
). 1.
90-2
.10(
4H~n
). 29
00(C
H a@). 1W
C=
N).
72
qc-S
).
7.00
-8.1
0(9H
.m).
8.50
(1H
.s).
2900
(CH
alip
h). 1
6OO
(C=N
). 73
qc-S
).
2.W
3H.s)
. 3.
2qW
.s).
3.40
(1H
.s).
2.W
3H.s)
. 3.
2qW
.s).
3.40
(lH.s)
.
- 3
16
00
. 3050(CH m). 1
.30-
1.70
(4H
.m).
1.90
-2.1
0(4H
~~),
2.
8q3H
.s).
3.2q
2H.s)
. 3.
40(1
&).
7.00
-8.1
0(9I
lm).
8.50
(1H
.s).
ii - uno(cH -1
. 29
00(c
H
1.30
-1.7
0(4H
.m).
I .90-
2.20
(4H
.m).
- lW
C=
N).
71q
c-s)
2.
7Y3h
s).
3.2q
2H.s)
. 3.
50(1
H.s)
.
G 7.
00-8
.10(
15H
.m).
6.46
U
)60(
CH
arom
).289
0(C
H
1.30
-1.7
q4H
.m).
1.90
-2.2
q4H
.m).
6.20
&@
). 16
2qC
= N).
72qC
-S)
2.7X
3H.s)
. 3.
30(2
H,~
), 3.5
0(1H
.s).
7.00
-8.1
0(14
H.m
).
2.7Y
3H.s)
. 3.3
O(W
s), 3
.60(
lH.s)
. -
3050
(CH
a~11
~).2
890(
CH
1.
30-1
.70(
4Ilm
), 1.
90-2
.20(
4H.m
). al
iph)
. lW
C=
N).
151O
(NO
J. 7m
C-S
) 7.
00-8
.00(
14H
.m).
14.3
8 -3
18
00
. m
),
1.40
-1.8
q6H
Sn).
1.90
-2.2
0(4H
.m).
- 2
WC
H al
iph)
. 1W
C=
N).
2.7q
3H.s)
. 3.
3q2H
.s).
3.60
(1H
,~).
7-30
3
17
0.
3050(CH m). 1
.40-
1.70
(6H
&
1.8&
2.20
(4H
~~),
7.
10
2W
CH
alif
i). 1
WC
= N
). 2.
7q3H
.s).
3.W
2H.s)
. 3.
50(lH
.s).
73qc
-S).
7.
00-8
.10(
9H.m
). 8.
6qlH
.s).
7.00
-8.0
0(10
H.m
), 8.
50(lH
.s).
73qc
-S).
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
TA
BIE
I (continued)
63.6
7 5.
30
63.5
0 5.
16
73.7
0 5.
95
5.70
8.
00
69.1
8 5.
40
5.30
7.
30
67.8
4 5.
30
5.20
9.
70
11.4
2 11
.20
8.06
12
.10
7.56
1.
30
9.89
11
.10
13.0
6 13
.00
12.2
8 -
1153
6.
10
11.3
0 -
- 3
18
00
. 30
6o(C
H ar~m).
1.40
-1.7
0(6H
~n). 1
.90-
2.10
(4H
~n),
- 2
WC
H al
iph)
, 1W
C=
N),
27x3
H.Q
. 3.2
q2H
.s).
3.W
lH.s
). 15
2O(N
09.7
30(C
-S).
7.00
-8.1
0(9H
.m).
8.W
lH.s)
. -
307q
cH m).
29O
O(C
H
1.40-
1.70(
6H.11
1).
1.90
-2.W
4€hl
), al
iph)
. 16
20(C
=N).
7WC
-S)
2.7q
3H.s)
. 3.
30(2
8,~)
, 3.60
(1H
.s).
7.00
-8.0
0(15
H.m
). 6.
30
307q
CH
anw). 2
9OO
(cH
1.
40-1
.75(
6H.m
). 1.
90-2
.2q4
H.m
). al
iph)
. 16
2O(C
=N). 7
1qC
-S)
2.7X
3H.s)
. 3.
30(2
H,~
). 3.6
0(lH
,~),
7.
00-8
.00(
14H
.m).
alip
h).
160o
(C=N
). 15
10
(Nod
. 71q
c-s)
. 7.
00-8
.1q1
4H.m
).
- 3050(CH m
).
29O
O(c
H
1.40
-l~0
(6H
~1l)
. 1.90
-2.2
q4H
.m).
2.75
(3H
.s).
3.20
(2H
.s).
3.W
IH.s)
.
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
128 A. AL-AHMADI
I 1 0 2
h 2 I 2 I 2 k 2 1 2
SCHEME 1
tane ring), 2.80 (3H, s, the methyl group protons of the pyrazole ring), 3.20 (2H, s, the methylene protons of the benzyl group), 3.40 (lH, s, the proton at C, of the thiopyran ring), 7.00-8.10 (lOH, m, the aromatic protons) and 8.30 (lH, s, the NH proton of the pyrazole ring).
Antimicrobial Activity
The antimicrobial activity of the newly synthesized compounds were tested against representative organisms of the different categories of -pathogenic mi- croorganisms such as Escherichia coli, Pseudomonas aeruginosa as Gram- negative bacteria, Staphylococcus aureus, Bacillus cereus as Gram-positive bac- teria, Aspergillus nigar, Aspergillus clavatus, Aspergillus fumigatus from the moulds, and Candida albicans as yeast organism using the agar cup diffusion techniq~e.~' Each compound was tested on the various organisms and the inhi- bition of growth observed against controls.
Tested Minmrganisms
Aspergillus Spps: representative of the moulds that cause generalized toxicosis and pulmonary aspergillosis.
Candida albicans: representive yeast that causes thrush (oral candidosis), infection of the esophagus, intestine, vagina, skin, nails and other sites and organs of the body.
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
SPIROHETEROCYCLES 129
Culture medium
1-Nutrient agar medium used for bacteria. 2-Sabaurounds dextrose agar medium for moulds. 3-Sabourauds maltose agar medium for yeast.
Environmental conditions for optimal growth were as follows: 1) 35-37°C incubation temperature for both Gram-negative and Gram-
positive bacteria and the incubation period was 48 hrs., 28°C incubation tem- perature was used for moulds and yeast. The incubation period for moulds was 4-6 days, while 2-3 days for yeast.
Results of antimicrobial activity
The biological activities of the synthesized compounds were studied at two different concentrations A: 50 ~ g / c m - ~ , B: 100 ~ g / c m - ~ . Results of the biologi- cal activities are shown in Table (10.
The data showed that all the synthesized compounds have a remarkable effect against the tested microorganisms (both Gram-negative and Gram-positive bac- teria as well as moulds and yeast. Compounds 5c, 5d, 5f, 5i and 51 (at the concentrations A and B) showed highly significant effects against bacteria, moulds and yeast as indicated from the inhibition zones of 21 mm up to 27 nun range. Aspergillus niger has a resistant effect against compounds 3c, 3e, 3k, 31 (at the concentration A). The same compounds (at the concentration B) gave promising results against Aspergillus niger as well as moderate effect against bacteria.
EXPERIMENTAL
The time required for completion of the reaction was monitored by thin layer chromatography (TLC). Melting points were determined in open glass capillar- ies and are uncorrected. IR spectra were recorded on a Pye-Unicam Sp2OOG spectrophotometer. 'H-NMR spectra were measured on an EM 360 90 MHz NMR spectrophotometer. Microanalyses were determined on a Perkin-Elmer 240 C microanalyser.
Preparation of 3-methyl-4-arylidine-2-pyrazoline-5sne Mvatives (lt+f).
These compounds were prepared according to the reported procedure.25
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
3c
3e
3b
3k
31
4i
k
5c
5d
5f
5i
51
mli-
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
SPIROHETEROCYCLES 131
Preparation of l-thia-4-benzyl-4-azaspiro[4.4] nonan-3-one (2a) and l-thia-4-benzyl-4-azaspiro[4.SJdecan-3-one (2b):
These compounds were prepared according to the reported procedure.26
Synthesis of Spiroheterocycles Derivatives 3a-1-5a-1:
General Procedure
A mixture of 1 -thia-4-benzyl-4-azaspiro[4.4]nonan-3-one (2a) andor 1 -thia-4- benzyl-4-azaspiro[4.5]decan-3-one (2b) (0.001 mole) and 4-aryl- methylpyrazolin-5-ones ( I a-f) was refluxed in 25 cm3 of ethanoVpyridine mix- ture ( 1 : 1) or fused with 0.0012 mole of ammonium acetate and/or refluxed with 0.001 mole of phosphorus pentasultide in 25 cm3 of pyridine. The reaction was heated at reflux temperature for 10 h, then cooled to room temperature and poured in 50 ml of dilute HCI (10%) whereby the target products were precipitated, fil- tered off and crystallized from the appropriate solvent (Table I).
References
A.A. Abdel-Hafez. A.M.A. Awad. R.A. Ahmed and K.M. Hassan Afinidad, 5x455). 59, (1995). U. Diefenbach and U. Engelhardt, Phosphorus, Sulfur. Silicon, Relur. Elem., 65( la), 107. (1992). A. Wulferding. J:H. Jankowshi. M.R. Hoffman. Chem. Ber., 127(7). 1275, (1994). S. Stverkova, Z. Zak and J. Jonas, Liebigs Ann.. 3, 477. (1995). T.V. Lee and J.R. Porter, Org. Synrh., 72, 189, ( 1995). C.M.R. Ribeiro. S.T. ReMelo, M. Bonin, J.C. Quirion and H.P. Husson, Tetrahedron Len., 35(39), 722, (1994). S.P. Watson, G.R. Knox and N.M. Heron, Terruhedmn Left., 35(52). 9763. (1994). L. Fitjer. A. Kanschik and M. Majewski, Terruhedron, 50(37), 10867. (1994). M.S. Malamas. J. Hererocycl. Chem., 31(2), 565, (1994). T. Naito, H. Tanada, Y. Suzuki, H. Saito, 1. Ninomiya and T. Kiguchi, Nur. Prod. Left., 2(4), 309. (1993). E. Fanghanel, T. Palmer, J. Kersten, R. Ludwigs, K. Peters and H.G. Von Schnering, Synthe- sis. 10, 1067, (1994). R. Jain and M. Bansel. Pbarmazie, 50(3), 224, (1995). S. Dugar. J.W. Clader, D.A. Burnett, M.E. Browne and H.R. Davis. PCTInr. Appl Wo 94 17, 038. (1995) (CI. CO 7D205/12) 04 Aug, 1994, USAppl. 6. 439, 21 Jan., 1993.45 pp,; Cbern. Absrr. 123, 8322Od. K. Tsujita, Y. Suzuki and A. Myashita. Jpn. Kokui Tokkyo Koho J p 06. 263, 767. (1995). [94. 263. 7671 (CI. CO 7D517/10), 20 Sep. 1994, Appl9Y77, 542, I 1 Mar. 1993; 7 pp.; Chern. Absrr., 122, 105902m. A. Takeda and M. Satomura, Jpn. Kokui Tokkyo Kobo J p 06,271,579 [94.271, 5791 (CI. Co 7D494/10), 27 Sep. 1994, Appl. 93/60, 509. 19 Mar. 1993; 13 pp.; Chern. Abstr., 122, 105858b. (1995). 1. Gacsalyi. 2. Budai. K. Reiter. T. Mezei, G . Blasko. G. Simig, M. Fekete, K. Szemeredi. A. Egyed et al.. Eur. Puf. Appl. Ep 623,616. (1995) (CI. Co 7D413/12) 09 Nov. 1994, Hu Appl. 9319. 301. 284. 04 May, 1993, 14pp.; Chern. Ahsrr.. 122. 8 1 4 0 5 ~ .
Dow
nloa
ded
by [
McG
ill U
nive
rsity
Lib
rary
] at
22:
39 1
4 O
ctob
er 2
012
132 A. AL-AHMADI
[I71 N. Kolocouris. G.B. Foscolos. A. Kolocouris. P. Marnkos, N. Pouli. G. Fytas, S. Ikeda. and E. Declereq. J . Mecl. Chrm., 37( 18). 28%. ( 1994).
[I81 0. Bruno, F. Bondavalli, A. Ranise. P. Schenone, C. Losasso, L. Cilenti, C. Matera and E. Marmo. Furmuco, 45(2), 147. (1990).
[ 191 S. Mitkidou, S. Papadopoulos, J. Stephnidou Stephnatou, A. Terzis and D. Mentzafos, J . Chem. Soc., Perkin Trans. 1(4), 1025, (1990).
[20] P. Sharan, S. Nizamuddin and J. Gin. J . Indian Client. Soc., 66(6). 393. (1989). [21] A.A. Al-Ahmadi and M.F. El-Zohry, Phosphorus, Sulfir and Silicon. 97, 35, (1994). [22] A.A. Al-Ahmaddi and M.F. El-Zohry, J . Chem. Tech. Biotechnol., 62, 366. (1995). [23] A.A. Al-Ahmadi. J . Chem. Tech. Biotechnol. 65,200, (1996). [24] A.A. Al-Ahmadi and M.F. El-Zohry, Hereroutom Chemistry, 7(3). 171. (1996). [25] A.M. Nor, M.Sc. Thesis, Assiut University, Qena Branch, P 136. (1995). [26] M.F. El-Zohry, I.M.A. Awad and A.A. Abdel-HafeZ Arch. fharm. (Weinheim). 326, 115,
