TRƢƠ
̀
NG ĐA
̣
I HO
̣
C KHOA HO
̣
C TƢ
̣
NHIÊN
Bùi Thị Hồng Phƣơng
NGHIÊN CỨU TỔNG HỢP VÀ CHUYỂN HÓA
MỘT SỐ 4-ACETYLSYDNONE TETRA-O-
ACETYL-β-D-GALACTOPYRANOSYL
THIOSEMICARBAZON THẾ
: 60 44 27
2012
TRƢƠ
̀
NG ĐA
̣
I HO
̣
C KHOA HO
̣
C TƢ
̣
NHIÊN
Bùi Thị Hồng Phƣơng
NGHIÊN CỨU TỔNG HỢP VÀ CHUYỂN HÓA
MỘT SỐ 4-ACETYLSYDNONE TETRA-O-
ACETYL-β-D-GALACTOPYRANOSYL
THIOSEMICARBAZON THẾ
: 60 44 27
PGS. TS. Nguyễn Đình Thành
2012
i
MỤC LỤC
M U 1
NG QUAN 3
1.1. TNG QUAN V SYDNONE 3
1.1.1. C 3
ng hp sydnone 10
1.2.
1,3,4-thiadiazin 11
1.2.1. 1,3,4-thiadiazin 11
1.2.2.
1,3,4-thiadiazin 21
1.2.3. p cht quan trng dng ca 1,3,4-thiadiazin 25
1.3. TNG QUAN VTHIOSEMICARBAZID 26
1.3.1. Tng hpthiosemicarbazid 26
t cathiosemicarbazid 27
1.4. S DC CARBOHYDRATE 28
2.2. TNG HP THIOSEMICARBAZID 34
2.3. TNG HP 3-(R-PHENYL)-4-BROMOACETYLSYDNONE (6) 36
2.3.2. Tng hp 3-(R-phenyl)-4-acetylsydnone (5) 45
2.3.3. Tng hp 3-(R-phenyl)-4-bromoacetylsydnone (6) 48
2.4. TNG HP CHT 2--(TETRA-O-ACETYL--D-
GALACTOZOPYRANOSYLAMINO)-5--ARYLSYDNONE)-6H-1,3,4-thiadiazin (7) 50
2.4.1. Tng hp 2--(tetra-O-acetyl--D-galactopyranosylamino)]-5--
phenylsydnone)-6H-1,3,4-thiadiazin (7a) 51
2.4.2. Tng hp 2--(tetra-O-acetyl--D-galactopyranosylamino)-5---
methyl phenyl)sydnone]-6H-1,3,4-thiadiazin (7b) 51
2.4.3. Tng hp 2--(tetra-O-acetyl--D-galactopyranosylamino)-5---
methyl phenyl)sydnone]-6H-1,3,4-thiadiazin (7c) 52
2.4.4. Tng hp 2--(tetra-O-acetyl--D-galactopyranosylamino)-5---
metoxy phenyl)sydnone]-6H-1,3,4-thiadiazin (7d) 52
2.4.5. Tng hp 2--(tetra-O-acetyl--D-galactopyranosylamino)-5---
clorophenyl)sydnone]-6H-1,3,4-thiadiazin (7e) 52
2.4.6. Tng hp 2--(tetra-O-acetyl--D-galactopyranosylamino)-5---
bromophenyl)sydnone]-6H-1,3,4-thiadiazin (7f) 53
ii
3.1. V TNG HP 4-BROMOACETYL-3-(R-PHENYL)SYDNONE 54
3.1.1. Tng hp cht N-(R-phenyl)glycine 54
3.1.2. Tng hp p cht N-nitroso-N-(R-phenyl)glycine 56
3.1.3. Tng hp cht 3-(R-phenyl)sydnone 56
3.1.4. Tng hp 4-acetyl-3-(R-phenyl)sydnone. 58
3.1.5. V tng hp 4-bromoacetyl-3-(R-phenyl)sydnone 60
3.2. V TNG HP 4-(TETRA-O-ACETYL--D-GALACTOPYRANOSYL)-
THIOSEMICARBAZID 62
3.3. V TNG HP CHT 2--(tetra-O-ACETYL--D-
GLACTOPYRANOSYLAMINO)-5--ARYLSYDNONE)-6H-1,3,4-THIADIAZIN 63
3.5. HOM CA THIADIAZIN 76
--(tetra-O-ACETYL--D-
GALACTOPYRANOSYLAMINO)-5--ARYLSYDNONE)-6H-1,3,4-
THIADIAZIN 64
76
78
79
83
1
MỞ ĐẦU
monosaccaride
1,3,4-thiadiazin
-oxadiazoli-5-
thiadiazin
thiosemicarbazid
thiadiazin, “
2
-acetylsydnone tetra-O-acetyl--D- ”
+ 3-(R-phenyl)
N-(R-N-nitroso-N-(R-
-acetyl-3-(R- -
bromacetyl-3-(R-.
2--(tetra-O-acetyl--D-galactopyranosyl-
amino)]-5-(3-arylsydnone)-6H-1,3,4-thiadiazin.
+ 2--(tetra-O-acetyl--D-
galactopyranosylamino)]-5-(3-arylsydnone)-6H-1,3,4-thiadiazin.
thiadiazin
3
Chƣơng 1. TỔNG QUAN
1.1. TỔNG QUAN VỀ SYDNONE
1.1.1. Cấu trúc sydnone
Sydnone
N-
enolat
O
N
-
N
+
O
R
O
+
N
N
O
-
R
O
+
N
N
O
R
O
N
N
O
-
R
O
N
N
+
O
-
R
O
N
N
+
O
R
C
5
O
1
C
4
N
2
N
3
O
6
R
1
Hình 1.1. Sự phân bố electron trong phân tử sydnone.
H
enolat oxy
4
oxy -carbon(C
4
enolat
4
pKa~18- base carbon
1
carbonyl.
O
N
N
O
Ph
O
N
N
O
Ph
O
N
N
O
Ph
O
N
N
O
Ph
1.52
1.37
1.64
1.64
1.41
1.64
-0.88
+0.19
+0.03
+0.03
-0.34
+0.73
-0.71
+0.24
+0.11
+0.21
-0.43
+0.57
-0.35
+0.08
+0.01
+0.35
-0.14
+0.3
2 3
4
5
Hình 1.2. Biểu diễn điện tích trong vòng sydnone.
- ra rng N
3
nitrogen
d i
bu cng s. Gi thit cho
rng electron 𝜋 kt lun rng N
3
N
4
4,
O
1,
O
6
5
ru cng 𝜋
3
1.1.2. Tính chất của sydnone
5
1.1.2.1. Độ bền của sydnone
2
N
N
N
NH
2
N NH
2
pyrrolidinhydrazin
-bromo
N
N
O
+
O
-
Br
N
H
NH
N
N
O
R
R
1.1.2.2.Tính chất hóa học của sydnone
H
nucleophil
+ m
+ electrophil.
6
1. Phản ứng thế electrophil của vòng thơm
+ Acyl hóa trực tiếp
-Crafts
3
, Et
2
acetonng cao
oxCarbeni (2).
acyl
acid (4-(tetra-O-clori
electrophil
i clorosulfonyl
+ Halogen hóa
-halogen sydnoneacid acetic, CH
3
COONa
N
N
O
+
OH
O
-
Ar
aceton
BF
3
, Et
2
O
N
O
O
+
O
-
N
CH
3
CH
3
Ar
O
+
N
N
O
-
R
Ac
2
O, HClO
4
or K
10
Clay, Ac
2
O, 110 °C
O
+
N
N
O
-
R
O
CH
3
7
N-N-aryl sydnone
bromo
bromo
dimethoxyphenyl.
2. Phản ứng lithi hóa
lithi sydnone
electrophil lithi
Lithi
N-butyl lithi.
O
+
N
N
O
-
R
O
+
N
N
O
-
R
Li
n BuLi, -50 °C
3. Chuyển hóa C4-halogen sydnone
-bromo-N-
bromohydrazin monohydrate, NaHS,
O
+
N
N
O
-
R
AcOH, NaOAc
XY
XY= Cl
2
, Br
2
or ICl
O
+
N
N
O
-
R
X
O
+
N
N
O
-
R
AcOH, NaOAc
ICl
O
+
N
N
O
-
R
I
8
Na
2
-thiocresolat
N-phenyl sydnone 1.
bromo
sydnone:
O
+
N
N
O
-
R
Br
O
+
N
N
O
-
R
MeOH
Zn
bromobromo
cross-coupling
Suzuki--bromo-N-
bromo
c bromoalken
i cao.
4. Chuyển hóa C4 carbonyl sydnone
C4-carbonylsydnone
sydnone-
CH
3
COONH
4
3
COOH
O
+
N
N
O
-
R
1
NH
4
OAc/AcOH
N
N
H
N
O
+
N
O
-
Ar
Ar1
Ar2
amin
9
aldehyd clorooxim
-
nucleophil.
5. Phản ứng cộng đóng vòng với alkyl
sydnone
alkyl -
2
-
ocalkyn
ester
sydnone
alkyn
ba carboN-
N
S
N
O
+
O
-
benzen, reflux, 6h
CO
2
Me
CO
2
Me
N
S
N
CO
2
Me
CO
2
Me
O
+
N
N
O
-
R
I
benzen, reflux, 6h
CO
2
Me
CO
2
Me
N
N
MeO
2
C
CO
2
Me
I
R
Alkynyl ester
ortho
sydnone
N- pyrazole
10
1.1.3. Các phƣơng pháp tổng hợp sydnone
Theo phương pháp cổ điển N-
aminoacid:
N
H
R
1
R
2
CO
2
H
NaNO
2,
H
2
O
HCl
N
N
R
1
R
2
CO
2
H
O
c
2
O,
O
+
N
N
O
-
R
1
R
2
acid trifluoroacetic (TFAA)
3
CO)
2
O
isoamyl nitrit (IAN) acid
g
N-phenyl
N
H
R
1
R
2
CO
2
H
IAN
DME
N
N
R
1
R
2
CO
2
H
O
TFAA
O
+
N
N
O
-
R
1
R
2
romo-dimethylhydantoin DBH:
11
R
1
NH
CO
2
H
DBH, NaNO
2
Ac
2
O, DCM, 0
-
5 °C
O
+
N
N
O
-
R
1
.
1.2. TÔ
̉
NG QUAN VÊ
̀
1,3,4-thiadiazin
1.2.1. Tính chất của 1,3,4-thiadiazin
1.2.1.1. Phản ứng nhiệt và quang hoá
5-Aryl-1,3,4-thiadiazin
toluen 6
-thiadiazin 7
toluen
NH
N
S
N
NH
S
Ar
Ar
R
R
N
H
N
CH
3
Ph
Ph
6
7
2-Morpholino-5-phenyl-6H-1,3,4-thiadiazin
-thiadiazinium
tetrafluoroborate -
tetrafluoroborate
dipyrazolyldisulfide 8.
12
N
N
S
Ph
O
N
N
N
S
Ph
O
N
BF
4
N
N
NH
2
Ph
S
N
N
NH
2
Ph
S
N
O
N
O
EtOBF
3
, ClCH
2
CH
2
Cl
t°, 7h
8
-dimethylamino-5-phenyl-6H-1,3,4-
thiadiazin-6-on
N,N-dimethyl-5-phenyl-1,3,4-thiadiazol-2-
nitril:
N
N
S
Ph
O
N
S
N
NMe
2
Ph
550 °C, 0.008 Torr
-CO
+ +
Me
2
N-CN
PhCN
9
1-(Benzensulfonyl)-3-phenylnaphtho[2,3-e]1,3,4-thiadiazin-5,10-dion (10)
-(benzensulfonyl)-3-phenyl-1H-benzo[f]indazole-4,9-dion (11)
:
N
N
S
O
O
SO
2
Ph
Ph
O
O
N
N
SO
2
Ph
Ph
t°, toluen
-S
10
11
1.2.1.2. Sự tấn công của electrophil vào nguyên tử nitrogen
Trong anhydrid aceti-thiadiazin(12)
13
etylpyrazole (13)-(14)
N
N
S
MeO
2
C
Ph
NH
2
N
H
N
MeO
2
C
Ph
NHAc
12
13
N
H
N
MeO
2
C
CH
3
NH
CH
3
N
N
MeO
2
C
Ac
CH
3
NH
2
14
15
- -dialkylamino-5-aryl-6H-1,3,4-thiadiazin
(R=NMe
2
, piperidino, morpholino, pyrrolidino, 1-anhydrid acetic
(16)
(16) -mercaptopyrazole(17)
pyrazole (18) (19) oxy
thiadiazin anhydrid - -
trifluoroacetylsulfanyl-5-arylpyrazole:
N
N
S
Ar
R
N
N
Ar
R
Ac
AcS
N
N
Ar
R
Ac
AcS
N
N
Ar
R
Ac
AcS
NH
N
Ar
R
S
N
NH
Ar
R
S
t°, Ac
2
O
HCl
-S
16
17
18
19
1,3,4-thiadiazin (20) (R
1
=H, MeEt, Ar, COOEt, Ac; R
2
=H, Alk,Ar;
R
3
=NHAlk, NHAr, NMe
2
(21)
-thiadiazinpyrazole
1,3,4-thiadiazin
-thiadiazin
14
.
N
N
S
R
1
R
2
R
3
N
H
N
R
1
R
2
R
3
H
+
-S
20
21
sulfur - -3-methyl-2,3-dihydro-6H-1,3,4-
thiadiazin(22) (23).
-phenyl- -ethoxycarbonyl-6H-
1,3,4-thiadiazin(20) (R
2
pyrazole
(22) H-1,3,4-
thiadiazin(24) -40% 5-imino-1,2-
N
N
S
Ph
NR
Me N
N
Ph
NHR
Me
H
+
-S
22
23
N
N
S
Ph
NMe
Me
Me
N
N
Ph
NMe
Me
Me
H
+
-S
24
25
-carboxy6-phenyl-2-phenylimino-
6H-1,3,4-thiadiazin(26)
gian (27)-diphenyl-2,7-diphenylimino-1H,6H-dipyrazolo[1,5--
d]pyrazin (28).
15
-thiadiazin -
-thiadiazin
-imino- -alkylimino-5-methyl-6H-1,3,4-
thiadiazin(29) -amino- -[alkyl(aryl)amino]-4-methyl-
2,3-dihydro-1,3-thiazole (30).
NH
N
S
R
1
NH
2
+
R
2
H
29
N
S
R
1
NH
2
NH
2
+
R
2
30
5-Methyl-6H-1,3,4-thiadiazin(31) (R
1
=H, Me,
aldehyd -nitrobenzaldehyd (R
2
=H, NO
2
-(benzylideN- -[(4-
nitrobenzylidene)hydrazino]thiazole (32).
NH
N
S NH
2
+
R
1
H
CH
3
31
N
S
CH
3
NH
2
NH
R
1
N
CH
C
6
H
4
-4-R
2
32
2-Amino- -alkylamino-5-phenyl-6H-1,3,4-thiadiazin(33)
-alkylimino-3-methyl-4-phenyl-2,3-dihydro-6H-1,3,4-
thiadiazin(34) --2-imino-5-methyl-2,3-dihydro-6H-1,3,4-thiadiazin
NH
N
H
S
HOOC
NPh
Ph
N
H
N
HOOC
NHPh
26
27
PPA
-S
N
N
N
H
N
H
O
O
Ph
PhN NPh
Ph
28
16
-amino-5-methyl-6H-1,3,4-thiadiazin
N
N
S NHR
2
R
1
Ph
33
N
N
S
Ph
CH
3
NR
2
R
1
34
Mel, Me
2
CO
t°, 10h
2-Dialkylamino-5-aryl-6H-1,3,4-thiadiazin
iodide. 1,3,4-thiadiazin hydroiodid-dialkylamino-6H-1,3,4-
thiadiazin
-pyrrolidino- -cyclohexylamino-5-phenyl-6H-1,3,4-
thiadiazin -
dialkylamino-5-phenyl-6H-1,3,4-thiadiazin(35)
N
N
S
Ph
R
1
N
N
+
S
Ph
R
1
R
2
35
X
-
Me
2
CO
MeSO
3
F or
EtOBF
4
t°, 0.5-6h
6H-1,3,4-thiadiazin-2(3H)-on
2
-thiadiazoles (36).
+
N-
2
.
NH
N
S
R
2
O
R
1
N
N
S
R
2
R
1
36
ButOCl,DMF, 0 °C
-CO
2
a 6H-1,3,4-thiadiazin-2-amin (37) -halogen keton cho
2H-imidazo[2,1-b]6H-1,3,4-thiadiazin(38) (R
1
=Ar; R
2
=H).
N
N
S
Ph
NH
2
+
R
2
Br
O
R
1
-HBr, -H
2
O
N
N
S
N
Ph
R
2
R
1
37
38
17
1.2.1.3. Sự tấn công của electrophil vào nguyên tử Carbon
-amino- -alkyl(aryl)amino-5-phenyl-6H-1,3,4-
thiadiazin(39) -nitrobenzaldehyd, s
icarbazon (42). 6-(4-Nitrobenzyliden)-6H-
1,3,4-thiadiazin(40)
thiadiazin -(4-nitrobenzyliden).
(40) -nucleophil
imid carbazon(41),
2
(42).
-dialkylamino-5-phenyl-6H-1,3,4-thiadiazin(43)
-(4-nitrobenzyliden) (44)
imid -dialkylamino.
N
N
S
Ph
NHR
1
39
R
2
CHO
N
N
S
Ph
R
2
NHR
1
N
N
SH
Ph
R
2
NR
1
40
+H
2
O
NH
N
SH
Ph
R
2
O
NHR
1
+2H
-H
2
S
NH
NPh
R
2
O
NHR
1
41
42
N
N
S
Ph
R
1
43
R
2
CHO
N
N
S
Ph
R
2
R
1
44
18
1.2.1.4. Sự tấn công của nucleophil vào nguyên tử lưu huỳnh
- 6H-1,3,4-thiadiazin(45)
cho pyrazole
mercapto
6--thiadiazin-thiadiazin(45)
pyrazole(46)
N
N
S
Ph
R
1
NHR
2
N
H
N
Ph
R
1
NHR
2
Ph
3
P or EtO
3
P, EtOH
t°, 3
-
10 h
45
46
1.2.1.5. Sự tấn công của Nucleophil vào nguyên tử hydro
1,3,4-Thiadiazin(47) (48)
t- d -
-thiadiazin
t-butoxide.
N
N
S
Ph
R
1
R
2
N
H
N
Ph
R
1
R
2
47
48
t-BuLi, NaOEt or NaOH
-S
R
1
= Ph, Me, Et
R
2
= NH
2
, NH-NH
2
-methylsulfanyl-5,6-dihydro-1,3,4-thiadiazin anhydrid
trifluoroacetic N-trilfluoroacetyl (49) (49)
benzen
t
C cho S-alkenyl hydrazinecarbodithiolat
ester(50)(51) (52)
-(49)
-methysulfanyl-6-alkylidene-4H-1,3,4-thiadiazin-5-on.
19
N
N
S
COCF
3
SMe
EtO
2
C
R
1
R
2
N
R
2
S
R
1
EtO
2
C
SMe
NH
COCF
3
R
1
EtO
2
C
R
2
R
1
EtO
2
C
R
2
KOBut
0 °C, 30 min
49
50
51
52
1.2.1.6. Khả năng phản ứng của các nhóm thế gắn với nguyên tử Carbon của vng
+ Nhóm Amino
3-Alkyl-5-aryl-2,3-dihydro-6H -1,3,4-thiadiazin(53) nitrogen acid
-(nitrosoimino)-3-alkyl-5-aryl-2,3-dihydro-6H-1,3,4-
thiadiazin(54)
Nitrogen -oxo-3-alkyl-5-aryl-2,3-dihydro-6H-1,3,4-thiadiazin(55).
N
N
S
R
1
R
2
NH
HNO
2
, AcOH
N
N
S
R
1
R
2
N
NO
-N
2
N
N
S
R
1
R
2
O
53
54
55
-amino-5-(2,4-dicloro-5-fluorophenyl)-6H-1,3,4-thiadiazin(56)
aldehyd -arylideneamino-6H-1,3,4-
thiadiazin(57)(57) acetyl clororide
-oxazetidin (58)
20
Cl
Cl
F
N
N
S
NH
2
Cl
Cl
F
N
N
S
N
N Ar
ClCH
2
COCl
MW
HSCH
2
COCl
MW
Cl
Cl
F
N
N
S
N
O
Ar
Cl
Cl
F
N
N
S
N
Ar
O
56
57
58
+ Nhóm hidrazino
2-Hydrazino-1,3,4-thiadiazin aldehyd cho 2-alkyl(aryl)idenehydra-
zino-6H-1,3,4-thiadiazin(59)
H-triazolo[3,4-b][6H-1,3,4]thiadiazin. 2-Hydrazino-6H-1,3,4-thiadiazin
clororide
3
4
O
10
7H-triazolo[3,4-b][6H-1,3,4]thiadiazin.
N
N
S
R
1
CH
3
N
N
S
R
1
NH
N
R
2
R
2
CHO
R
1
=R
2
=Alk, Ar
59
+ Nhóm hydroxy
de-amino-5carboxymethyl-5-hydroxy-6-phenyl-2,3,4,5-
6H-1,3,4-thiadiazin hydroclororide(60) ,3,4-thiadiazin hydroclororide (61)
nitril -
21
N
N
H
S CH
3
Ph
CH
3
MeCOOC
N
S
HOOC
Ph
NH
NHAc
N
S
MeCOOC
Ph
NH
NH
2
N
S
MeCOOC
Ph
NH
N
CH
3
CH
3
N
N
S
MeOOC
Ph
NH
2
HCl
Me
2
CO
CF
3
CO
2
H
55
-
60 °C
60
61
1.2.2.Các phƣơng pha
́
p tô
̉
ng hơ
̣
p 1,3,4-thiadiazin
1.2.2.1. Sự tổng hợp vng từ các hợp chất acyclic
+ Bằng sự hình thành liên kết giữa carbon và lưu huỳnh
g vinylsulfonylfluorobenzen (62) )thiosemicarbazid -
amin cho 5,6-dihydro[h,i]-1,4-thiazino[4,3-d]1,3,4-
thiadiazin-7,7-dioxide (63).
F
O
2
S
F
SO
2
F
F
NH
2
NH
NH
2
S
+
F
O
2
S
F
O
2
S
F
F
NH
NH NH
S
NH
2
NH
2
S
F
O
2
S
O
2
S
F
NH
NH
2
S
N
N
S NH
2
62
63
DMF,Bu
3
N
75
-
80 °C
16h
81%