Efficient one-pot synthesis of S-triazolo[3,4-b]-[1,3,5]thiadiazines containing a chiral side chain by double Mannich type reaction

Article abstract of DOI:10.1002/jhet.5570380418

An efficient and convenience method has been developed via a one-pot double Mannich type reaction for the synthesis of the important chiral s-triazole derivatives: (S)-3-α-phenylethyl-2,4-dihydro-5-aryl-oxymethyl-1,2,4-triazolo [3,4-b]-1,3,5-thiadiazines.

Full text of DOI:10.1002/jhet.5570380418

Jul-Aug 2001
Efficient One-Pot Synthesis of S-Triazolo[3,4-b]-
[1,3,5]thiadiazines Containing a Chiral Side Chain
by Double Mannich Type Reaction
929
Haijian Shi [a], Haoxin Shi* [b] and Zhongyi Wang [b,c]
[a] Department of Chemistry, Nanjing University, Nanjing 210093, P. R. China
[b] Department of Chemistry, Anhui Normal University, Wuhu, Anhui 241000, P. R. China
[c] Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
Received November 15, 2000
An efficient and convenience method has been developed via a one-pot double Mannich type reaction for
the synthesis of the important chiral s-triazole derivatives: (S)-3-α-phenylethyl-2,4-dihydro-5-aryl-
oxymethyl-1,2,4-triazolo[3,4-b]-1,3,5-thiadiazines.
J. Heterocyclic Chem., 38, 929 (2001).
S-triazoles and their heterocyclic derivatives are very
new and have been characterized by elemental analysis,
IR, H NMR and MS. The data confirmed the structure
1
well known compounds which have been important in
medicinal chemistry as potential therapeutic agent [1-2]
and in agricultural chemistry etc. [3-6]. Derivatives of
phenothiazine [7] are also a group of valuable drugs.
Therefore, the apparently specific role for the triazolo-
thiadiazine derivatives [8-9] in medicinal chemistry
suggests they may be suitable targets for antibiotic
design. We present here the first report of a new and
efficient method for the synthesis of 7. The novel chiral
(S)-3-α-phenylethyl-2,4-dihydro-5-aryloxymethyl-
1,2,4-triazolo[3,4-b]-1,3,5-thiadiazines (7a-g) have
been synthesized by one-pot double Mannich type reac-
tion of 3-mercapto-5-aryloxymethyl-1,2,4-triazoles,
S-(-)-α-phenylethylamine and formaldehyde in the
presence of acid under mild condition. All products are
of the synthesized compounds as depicted in Scheme 1.
The Mannich reaction is one of the most important
reactions usually available for the aminoalkylation of
CH-acidic compounds. However, the hydrogen atoms of
N-H and S-H groups on the ring of 3-mercapto-1,2,4-
triazoles (6a-g) are the acidic hydrogen required for the
double Mannich-type reaction. We use this type of reaction
of a chiral α-phenylethylamine, formaldehyde and
s-triazoles (molar ratio 1:2:1) for a one-pot procedure.
Chiral fused heterocyclic compounds are also important
reagents and could have extensive application in
asymmetric synthesis. The starting 5-aryloxymethyl-3-
mercapto-1,2,4-triazoles (6) were prepared by employing
our published procedures [10-11].
Aryloxyacetic acids (2) were prepared by Williamson
reaction of phenols (1) and chloroacetic acid in the pres-
ence of sodium hydroxide. Compound 2 was esterified
with ethanol to give ethyl aryloxy acetate (3). The aryloxy
acetate was treated with 85% hydrazine to yield aryloxy
acylhydrazine (4), then mixed with potassium thiocyanate
and aqueous sulfuric acid and refluxed for 4 hours to give
aryloxyacylamino thiourea (5). Compound 5 was cyclized
by treated with 8% sodium hydroxide and refluxed for

930
H. Shi, H. Shi and Z. Wang
Vol. 38
4 hours to produce the 2-aryloxymethyl-5-mercapto-1,2,4-
triazoles (6). Compounds 6a-g are new and have not been
reported in the literature. The synthetic route to prepare
6a-g is described in Scheme 2.
Because of the acidity of both the N-H and S-H groups,
1,2,4-s-triazoles can undergo a double Mannich reaction
with S-(-)-α-phenylethylamine and formaldehyde under
acid catalyst to give chiral condensed heterocyclic
compounds, (S)-3-α-phenylethyl-2,4-dihydro-5-aryloxy-
methyl-1,2,4-triazolo[3,4-b]-1,3,5-thiadiazines (7a-g).
Again these compounds have not been reported in
literature.
The Mannich reaction usually occurs under acidic
condition. We found that the pH of reaction system has a
large effect on the reaction. The research illustrates that the
reaction gives a good yield at pH 5-6, where a buffer
solution is produced. By adding a catalytic amount of
potassium fluoride to the reaction system and maintaining
the temperature at 30 °C for 6-8 hours gives products in
considerably high yields. The reaction mechanism is
shown in scheme 3.
methylene protons non-equivalent [12]. The observed
chemical shift differences and hence coupling can be
explained based on the similarity of the 2,4-dihydro-1,3,5-
thiadiazine moiety to the chair conformation of the
cyclohexane ring system, which causes the methylene
protons to be spatially near the stereocenter. This leads to
the observation of the coupling constant of J=12-14 Hz for
H and H at C-4. Hence protons of C-2 and C-4 methyl-
ene resonate as four groups of doublet signals. The mass
spectrum of 7c exhibiteds a molecular ion peak at m/z 366.
The cleavage processes of 7a-g are similar. All of them
generate fragment ions with m/z 105 and 91 due to
methylcycloheptatriene positive ion and cycloheptatriene
positive ion, respectively.
a
e
EXPERIMENTAL
Melting points were recorded on a micro melting point
apparatus X and are uncorrected. Elemental analyses were
4
recorded on a Pekin-Elmer 2400 element analyser. IR spectra
were measured as potassium bromide pellets on a BIO-RAD
1
FTS-40 spectrophotometer. H NMR spectra were recorded on a
Bruker AM-400 spectrometer using tetramethylsilane as an
internal reference. Mass spectra were performed on HP 5989A
mass spectrometer. The optical rotations were recorded on a
WZZ-1 automatic polarimeter. All chemicals were analytically
pure.
General Procedure for the Preparation of 2-Aryloxymethyl-5-
mercapto-1,2,4-triazoles (6a-g).
A mixture of aryloxyacetic acids (2) (0.2 mol), absolute
ethanol (0.4 mol) and 5 g of p-toluenesulfonic acid was refluxed
for 5 hours and then after cooling to room temperature, was
poured into water (100 ml). The organic layer was washed with
5% sodium bicarbonate solution and dried over anhydrous
sodium sulfate and evaporated to give ethyl aryloxy acetate (3)
(75-81%). To a solution of 3 (0.2 mol) in 20 ml of absolute
ethanol was added 85% hydrazine (0.4 mol) and the mixture was
heated under reflux for 3 hours. After cooling to room tempera-
ture, the resulting precipitates were filtered to yield aryloxy acyl-
hydrazine (4) (79.5-95%). To a stirred solution of 4 (0.02 mol),
5 ml of concentrated hydrochloric acid and 20 ml of water was
added potassium thiocyanate (0.071 mol). The mixture was
heated under reflux for 4 hours and allowed to stand overnight at
room temperature. Then the resulting precipitates were isolated
by filtration and recrystallized from water to obtain aryloxyacyl-
amino thiourea (5) (95.5-97%). A mixture of 5 (0.1 mol) and 8%
sodium hydroxide (120 ml) was heated at 95 °C for 4 hours. Then
the mixture was cooled to room temperature and acidified with
dilute hydrochloric acid. The precipitate was collected by filtra-
tion and washed with water. Recrystallization from ethanol
provided the 2-aryloxymethyl-5-mercapto-1, 2, 4-triazoles (6)
(78%).
The structures of compounds have been confirmed by
elemental analysis, IR, H NMR, and MS. The IR spectra
1
of these compounds revealed in each case, absorption
-1
-1
bands in the regions 3019-3029 cm , 1610-1676 cm ,
-1
-1
1506-1592 cm and 1026-1088 cm corresponding
to =C-H, C=N, N=C-S and C-O-C, respectively. The H
1
NMR spectra of 7d for example, exhibited two doublets at
δ 5.13-5.06 ppm (J = 13.25 Hz) and δ 4.43-4.40 ppm (J =
13.15 Hz), due to C-4 two geminal methylene protons,
respectively; and the other two doublets at 4.11-4.09 ppm
(J = 7.10 Hz) and 4.00-3.97 ppm (J = 7.15 Hz), due to C-2
two geminal methylene protons, respectively. The geminal
coupling illustrate that the stereocenter renders the two
2-Phenyloxymethyl-5-mercapto-1,2,4-triazole (6a).
Compound 6a was obtained as a white powder, yield (86.5%);
mp 216-218 °C; ir (potassium bromide): ν 3435 (NH), 3035
(=C-H), 2985 (CH ), 2551 (SH), 1650, 1460 (C=C, C=N), 1245,
3
-1
1
1052 (C-O-C) cm ; H nmr (400 MHz; DMSO-d ): δ 8.28
6

Jul-Aug 2001
931
Efficient One-Pot Synthesis of Chiral S-Triazole Derivatives
(s, 1H, NH), 7.75-6.97 (m, 5H, PhH), 5.43 (s, 2H, OCH ), 3.34
(s, 1H, SH); ms: (EI) m/z 207 (M , 15.82), 133 (5.28), 131
Anal. Calcd. for C H N OS: C, 60.68; H, 4.31; N, 16.33.
13 11 3
Found: C, 60.59; H, 4.28; N, 16.26.
2
+
(6.67), 114 (25.36), 94 (100), 77 (38.51).
2-α−Naphthyloxymethyl-5-mercapto-1,2,4-triazole (6g).
Anal. Calcd. for C H N OS: C, 52.15; H, 4.38; N, 20.28.
9
9 3
Found: C, 52.26; H, 4.47; N, 20.11.
Compound 6g was obtained as a cream-colored powder in
80.8% yield; mp >220 °C; ir (potassium bromide): ν 3432 (NH),
2-(2-Methyloxyphenyl)oxymethyl-5-mercapto-1,2,4-triazole (6b).
3055 (=C-H), 2912 (CH ), 2550 (SH), 1744, 1587 (C=C, C=N),
2
Compound 6b was obtained as a pale yellow powder in 83.2%
yield; mp 220-222 °C; ir (potassium bromide): ν 3430 (NH), 3028
1
1212, 1080 (C-O-C); H nmr (400 MHz; DMSO-d ): δ 8.15
6
(s, 1H, NH), 7.70-6.73 (m, 7H, α−C H -), 5.47 (s, 2H, OCH ),
10
7
2
(=C-H), 2920 (CH ), 2550 (SH), 1740-1493 (C=C, C=N), 1241,
+
3
4.14 (s, 1H, SH); ms: (EI) m/z 257 (M , 9.25), 144 (100), 127
(18.52), 115 (58.13), 114 (20.38).
-1 1
1150 (C-O-C) cm ; H nmr (400 MHz; DMSO-d ): δ 8.08 (s, 1H,
6
NH), 7.03-6.65 (m, 4H, ArH), 5.22 (s, 2H, OCH ), 2.68 (s, 1H, SH),
2
Anal. Calcd. for C H N OS: C, 60.68; H, 4.31; N, 16.33.
13 11
3
+
2.16 (s, 3H, CH ); ms: (EI) m/z 221 (M , 21.47), 207 (1.61), 147
3
Found: C, 60.61; H, 4.29; N, 16.27.
(5.68), 133 (3.73), 114 (100), 108 (54.28), 91 (11.88), 76 (38.75).
General procedure for Preparing (S)-3-α-phenylethyl-2,4-dihydro-
5-aryloxymethyl-1,2,4-triazolo[3,4-b]-1,3,5-thiadiazines (7a-g).
Anal. Calcd. for C H N OS: C, 54.28; H, 5.01; N, 18.99.
10 11
3
Found: C, 54.36; H, 5.05; N, 18.88.
To a solution of absolute ethanol (5 mL), polyformaldehyde
(6 mmol) and S-(-)-α-phenylethylamine (3 mmol), was added (6)
(3 mmol). The mixture was acidified with hydrochloric acid to
pH 4-5, followed by addition of potassium fluoride (0.1 g). After
the mixture was stirred at 30 °C for 30 minutes, the solution was
heated up to 55 °C for 6-8 hours, and then left to stand overnight.
The solvent was then removed by distillation to leave a solid that
was washed with water and 8% sodium hydroxide, then washed
again with water to neutrality. The solid was recrystallized from
absolute ethanol and purified by column chromatography to
obtain the products 7.
2-(3-Methylphenyl)oxymethyl-5-mercapto-1,2,4-triazole (6c).
Compound 6c was obtained as a pale yellow needle crystals in
85.3% yield; mp 208-210 ºC; ir (potassium bromide): ν 3426
(NH), 3037 (=C-H), 2985 (CH ), 2553 (SH), 1604, 1450 (C=C,
3
-1 1
C=N), 1245, 1042 (C-O-C) cm ; H nmr (400 MHz; DMSO-d ):
6
δ 8.01 (s, 1H, NH), 7.21-6.80 (m, 4H, ArH), 5.26 (s, 2H, OCH ),
2
+
2.69 (s, 1H, SH); 2.10 (s, 3H, CH ); ms: (EI) m/z 221 (M ,
3
26.15), 207 (3.52), 147 (6.88), 133 (5.62), 114 (100), 108 (58.38),
91 (15.23), 76 (35.21).
Anal. Calcd. for C H N OS: C, 54.28; H, 5.01; N, 18.99.
10 11
3
Found: C, 54.22; H, 5.03; N, 18.91.
(S)-3-α-Phenylethyl-2,4-dihydro-5-phenyloxymethyl-1,2,4-tria-
zolo[3,4-b]-1,3,5-thiadiazine (7a).
2-(4-Methylphenyl)oxymethyl-5-mercapto-1,2,4-triazole (6d).
Compound 6d was obtained as a pale yellow powder in 86.5%
yield; mp 205-207 °C; ir (potassium bromide): ν 3384 (NH),
This compound was prepared as a pale yellow powder in
20
-4
75.6% yield, mp 80-82 °C; [α]
-166.6° (c = 1.2 x 10 ,
D
3031 (=C-H), 2921 (CH ), 2550 (SH), 1617, 1514 (C=C, C=N),
3
DMSO); ir (potassium bromide): ν 3029 (=C-H), 2980 (CH -H),
-1 1
2
1236, 1063 (C-O-C) cm ; H nmr (400 MHz; DMSO-d ): δ 8.01
6
1676 (C=N), 1591 (N=C-S), 1275, 1029 (C-O-C) and 688
(s, 1H, NH), 7.01-6.90 (m, 4H, ArH), 5.15 (s, 2H, OCH ), 2.59
(s, 1H, SH), 2.08 (s, 3H, CH ); ms: (EI) m/z 221 (M , 41.26), 147
2
-1
1
(C-S-C) cm ; H nmr (400 MHz; DMSO-d ): δ 7.39-7.28
+
6
3
(m, 10H, Ph-H), 7.11-7.09 (q, 1H, CH, J = 6.73 Hz), 5.45 (s, 1H,
(4.09), 131 (5.58), 114 (19.72), 108 (100), 91 (23.66), 77 (22.40).
N-CH -N), 5.08 (s, 1H, N-CH -N), 4.68 (s, 1H, N-CH -S), 4.40
2
2
2
Anal. Calcd. for C H N OS: C, 54.28; H, 5.01; N, 18.99.
10 11
3
(s, 1H, N-CH -S), 1.46-1.44 (d, 3H, CH , J = 6.48 Hz); ms: (EI)
2
3
Found: C, 54.23; H, 5.10; N, 18.86.
+
m/z 352 (M , 1.13), 260 (0.51), 259 (2.00), 156 (1.65), 147
(1.67), 128 (1.41), 115 (4.03), 107 (2.75), 105 (100), 91 (13.29),
90 (2.20).
2-(2-Chlorophenyl)oxymethyl-5-mercapto-1,2,4-triazole (6e).
Compound 6e was obtained as pale yellow prism crystals in
87.1% yield; mp 153-154 °C; ir (potassium bromide): ν 3383
Anal. Calcd. for C H N OS: C, 64.75; H, 5.72; N, 15.90.
19 20
4
Found: C, 64.39; H, 5.58; N, 15.61.
(NH), 3187 (=C-H), 2980 (CH ), 2553 (SH), 1628, 1488 (C=C,
2
1
C=N), 1239, 1015 (C-O-C), 648 (C-Cl); H nmr (400 MHz;
(S)-3-α-Phenylethyl-2,4-dihydro-5-(2-methyloxyphenyl)-
oxymethyl-1,2,4-triazolo[3,4-b]-1,3,5-thiadiazine (7b).
DMSO-d ): δ 7.41-6.88 (m, 4H, ArH), 5.43 (s, 1H, NH), 5.14
6
(s, 2H, OCH ), 4.20 (s, 1H, SH); ms: (EI) m/z 243 (M+2, 15.47),
2
+
This compound was prepared as a yellow powder in 55.5%
241 (M , 38.93), 206 (0.77), 182 (0.72), 169 (0.87), 167 (1.98),
20
-4
yield, mp 174-176 °C; [α]
–50° (c = 2 x 10 , DMSO); IR
131 (2.91), 130 (32.54), 128 (95.13), 114 (100), 59 (15.54).
D
(potassium bromide) ν 3019 (=C-H), 2931 (CH -H), 1670
(C=N), 1585 (N=C-S), 1234, 1042 (C-O-C) and 696 (C-S-C)
cm ; H NMR (400 MHz; DMSO-d ): δ 7.97-7.27 (m, 9H,
Ar-H), 7.15-7.09 (q, 1H, CH, J = 6.62 Hz), 5.59 (s, 2H, CH -O),
Anal. Calcd. for C H N OClS: C, 44.72; H, 3.34; N, 17.39.
2
9
8 3
Found: C, 44.63; H, 3.31; N, 17.32.
-1
1
6
2-β−Naphthyloxymethyl-5-mercapto-1,2,4-triazole (6f).
2
5.36 (s, 1H, N-CH -N), 4.81 (s, 1H, N-CH -N), 4.69 (s, 1H,
Compound 6f was obtained as a pale yellow powder in 81.2%
yield; mp 216-218 °C; ir (potassium bromide): ν 3428 (NH),
2
2
N-CH -S), 4.59 (s, 1H, N-CH -S), 2.18 (s, 3H, CH -Ph),
2
2
3
1.56-1.54 (d, 3H, CH , J = 6.72 Hz); MS (EI) m/z 259 (7.36), 156
3055 (=C-H), 2980 (CH ), 2553 (SH), 1628, 1513 (C=C, C=N),
3
2
1
(21.83), 147 (10.68), 128 (8.36), 115 (17.46), 114 (100), 108
(67.85), 105 (36.61), 91 (33.92), 90 (11.20).
1212, 1006 (C-O-C); H nmr (400 MHz; DMSO-d ): δ 8.13
6
(s, 1H, NH), 8.05-6.90 (m, 7H, β−C H -), 5.58 (s, 2H, OCH ),
10
7
2
+
4.25 (s, 1H, SH); ms: (EI) m/z 257 (M , 8.37), 144 (100), 130
(1.60), 127 (14.07), 115 (62.87), 114 (17.67).
Anal. Calcd. for C H N OS, C, 65.54; H, 6.05; N, 15.29.
20 22 4
Found: C, 65.36; H, 6.17; N, 15.01.

932
H. Shi, H. Shi and Z. Wang
Vol. 38
(S)-3-α-Phenylethyl-2,4-dihydro-5-(3-methylphenyl)oxymethyl-
1,2,4-triazolo[3,4-b]-1,3,5-thiadiazine (7c).
5.20-5.18 (d, 1H, N-CH -N, J = 10.20 Hz), 4.96-4.93 (d, 1H,
2
N-CH -N, J = 10.11 Hz), 4.46-4.42 (d, 1H, N-CH -S, J = 16.91
2
2
Hz), 4.18-4.13 (d, 1H, N-CH -S, J = 16.99 Hz), 1.50-1.48 (d, 3H,
2
This compound was prepared as a pale yellow powder in
CH , J = 6.35 Hz); ms (EI) m/z 275 (2.69), 170 (4.42), 156
3
20
-4
95.6% yield, mp 75-77 °C; [α]
+ 46.6º (c = 2 x 10 , DMSO);
D
(49.95), 144 (15.73), 142 (0.81), 128 (100), 115 (15.12), 105
(98.38), 91 (12.20), 90 (2.34).
ir (potassium bromide) ν 3028 (=C-H), 2975 (CH -H), 1620
2
(C=N), 1592 (N=C-S), 1261, 1057 (C-O-C) and 698 (C-S-C)
Anal. Calcd. for C H N OS, C, 68.63; H, 5.51; N, 13.92.
23 22
4
-1 1
cm ; H nmr (400 MHz; DMSO-d ): δ 7.38-7.13 (m, 9H, Ar-H),
6
Found: C, 68.31; H, 5.70; N, 13.65.
6.92-6.84 (q, 1H, CH, J = 8.90 Hz), 6.79 (s, 2H, CH -O), 5.52
2
(s, 1H, N-CH -N), 5.33 (s, 1H, N-CH -N), 4.79 (s, 1H,
(S)-3-α-Phenylethyl-2,4-dihydro-5-α-naphthyloxymethyl-1,2,4-
triazolo[3,4-b]-1,3,5-thiadiazine (7g).
2
2
N-CH -S), 4.67 (s, 1H, N-CH -S), 2.27 (s, 3H, CH -Ph),
2
2
3
+
1.45-1.43 (d, 3H, CH , J = 6.27 Hz); ms (EI) m/z 366 (M , 3.39),
3
This compound was prepared as a pale yellow powder in
260 (2.62), 259 (10.01), 156 (4.38), 147 (6.79), 128 (3.97), 115
(10.14), 114 (34.88), 105 (100), 91 (17.31), 90 (4.27);
20
-4
90.4% yield, mp 122-124 °C; [α]
-53° (c = 2.0 x 10 ,
D
DMSO); ir (potassium bromide): ν 3065, 3038 (naphthyl =C-H),
2985 (CH -H), 1615 (C=N), 1514 (N=C-S), 1213, 1010 (C-O-C),
Anal. Calcd. for C H N OS, C, 65.54; H, 6.05; N, 15.29.
20 22
4
2
Found: C, 65.31; H, 6.18; N, 15.66.
-1
815, 782 (α-substituted naphthyl =C-H), and 695 (C-S-C) cm ;
1
(S)-3-α-Phenylethyl-2,4-dihydro-5-(4-methylphenyl)oxymethyl-
1,2,4-triazolo[3,4-b]-1,3,5-thiadiazine (7d).
H nmr (400 MHz; DMSO-d ): δ 8.16-7.29 (m, 12H, Ar-H),
6
7.09-7.07 (q, 1H, CH, J = 9.20 Hz), 5.66 (s, 2H, CH -O),
2
5.27-5.25 (d, 1H, N-CH -N, J = 10.07 Hz), 5.04-5.02 (d, 1H,
2
This compound was prepared as a yellow powder in 79.2%
N-CH -N, J = 10.20 Hz), 4.24-4.21 (d, 1H, N-CH -S, J = 10.28
2
2
20
-4
yield, mp 77-79 °C; [α]
+75º (c = 2 x 10 , DMSO); ir (potas-
D
Hz), 4.06-4.03 (d, 1H, N-CH -S, J = 10.25 Hz), 1.51-1.49 (d, 3H,
2
sium bromide) ν 3028 (=C-H), 2950 (CH -H), 1610 (C=N), 1506
2
CH , J = 6.50 Hz); ms (EI) m/z 260 (3.44), 156 (5.31), 147
3
-1
1
(N=C-S), 1222, 1026 (C-O-C) and 699 (C-S-C) cm ; H nmr
(12.32), 144 (100), 128 (14.87), 115 (71.89), 105 (83.65), 91
(5.91), 89 (8.65).
(400 MHz; DMSO-d ): δ 7.28-7.00 (m, 9H, Ar-H), 6.90-6.85
6
(q, 1H, CH, J = 8.5Hz), 5.33 (s, 2H, CH -O), 5.13-5.06 (d, 1H,
2
Anal. Calcd. for C H N OS, C, 68.63; H, 5.51; N, 13.92.
23 22
4
N-CH -N, J = 13.25 Hz), 4.43-4.40 (d, 1H, N-CH -N, J = 13.15
2
2
Found: C, 68.35; H, 5.71; N, 13.61.
Hz), 4.11-4.09 (d, 1H, N-CH -S, J = 7.10Hz), 4.00-3.97 (d, 1H,
2
N-CH -S, J = 7.15 Hz), 2.27 (s, 3H, CH -Ph), 1.43-1.42 (d, 3H,
Acknowledgements.
2
3
+
CH , J = 6.39 Hz); ms (EI) m/z 366 (M , 7.01), 260 (11.92), 156
3
This work has been financially supported by Natural Science
Foundation and Educational Committee Foundation of Anhui
Province in P. R. China.
(9.16), 147 (9.36), 128 (4.16), 115 (10.43), 108 (76.79), 105
(100), 91 (19.98), 90 (6.36).
Anal. Calcd. for C H N OS, C, 65.54; H, 6.05; N, 15.29.
20 22
4
Found: C, 65.19; H, 6.30; N, 15.68.
REFERENCES AND NOTES
(S)-3-α-Phenylethyl-2,4-dihydro-5-(2-chlorophenyl)oxymethyl-
1,2,4-triazolo[3,4-b]-1,3,5-thiadiazine (7e).
[*] E-mail: shihx@yahoo.com.
This compound was prepared as a dark yellow powder in
[1] G. W. Miller and F. L. Rose, J. Chem. Soc., 5642 (1963).
[2] J. J. Wades, US Patent 4,528,288, (1985); Chem. Abstr., 104,
5889x (1986).
[3] J. C. Van Heertum, B. C. Gerwick and W. A. Kleschick,
European Patent 343,752, (1989); Chem. Abstr., 112, 198409n (1990).
[4] M. J. Costales, J. C. Van Heertum, W. A. Kleschick, R. J. Ehr,
and P. G. Ray, US Patent 5, 201,938 (1993); Chem. Abstr., 119, 180806z
(1993).
[5] F. Clemence, C. Joliveau and R. Fournex, Fr. Demande FR
Patent 2,539,127 (1984); Chem. Abstr., 102, 95677n (1985).
[6] A-M. M. E. Omar and O. M. Aboul Wafa, J. Heterocyclic
Chem., 21, 1415 (1984).
[7] C. Bidea and I. S. Adv, Heterocycl. Chem., 9, 321 (1968).
[8] S. P. Singh, R. Naithani, R. Aggarwal and O. Prakash, Synth.
Commun. 28 , 3133 (1998).
20
-4
56.1% yield, mp 127-129 °C; [α]
-54° (c = 3.24 x 10 ,
D
DMSO); ir (potassium bromide) ν 3029 (=C-H), 2970 (CH -H),
2
1626 (C=N), 1586 (N=C-S), 1229, 1088 (C-O-C) and 629
-1
1
(C-S-C) cm ; H nmr (400 MHz; DMSO-d ): δ 7.39-7.28
6
(m, 9H, Ar-H), 7.14-7.12 (q, 1H, CH, J = 8.97 Hz), 5.67-5.63
(d, 1H, N-CH -N, J = 12.93 Hz), 5.46 (s, 2H, -CH -O), 5.25-5.22
2
2
(d, 1H, N-CH -N, J = 13.25 Hz), 4.63-4.60 (d, 1H, N-CH -S, J =
2
2
12.91 Hz), 4.33-4.30 (d, 1H, N-CH -S, J = 13.12 Hz), 1.47-1.46
2
(d, 3H, CH , J = 6.80 Hz); ms (EI) m/z 260 (2.17), 156 (7.44),
3
148 (4.54), 128 (44.56), 115 (20.76), 114 (100), 105 (75.10), 91
(7.05), 90 (2.24).
Anal. Calcd. for C H N OS, C, 58.98; H, 4.95; N, 14.48.
19 19
4
Found: C, 58.65; H, 4.77; N, 14.09.
[9] Z. A. Hozien, A. O. S. Abd EI-Wareth, H. A. H. EI-Sherief
and A. M. Mahmould, Z. Naturforsch., B. Chem. Sci. 52 (11), 1401
(1997); Chem. Abstr., 128, 88906v (1998).
[10] H. J. Shi, Z. Y. Wang and H. X. Shi, Youji Huaxue, 16, 242
(1996); Chem. Abstr., 125, 142224z (1996).
[11] Z. Y. Wang, H. J. Shi and H. X. Shi, Youji Huaxue, 17(3), 271
(1997); Chem. Abstr., 127, 65726b (1997).
[12] R. M. Silverstein, G. C. Bassier and T. C. Morrill,
Spectrometric Identification of Organic Compounds, 4th Ed; John Wiley,
New York, 1981; p 183 (Chinese).
(S)-3-α-Phenylethyl-2,4-dihydro-5-β−naphthyloxymethyl-1,2,4-
triazolo[3,4-b]-1,3,5-thiadiazine (7f).
This compound was prepared as a dark yellow powder in 50%
20
-4
yield, mp 87-89 °C; [α]
-50° (c = 2.0 x 10 , DMSO); ir
D
(potassium bromide): ν 3085, 3035 (naphthyl =C-H), 2982
(CH -H), 1625 (C=N), 1515 (N=C-S), 1213, 1011 (C-O-C), 844,
2
-1
816, 735 (β-substituted naphthyl =C-H) and 692 (C-S-C) cm ;
1
H nmr (400 MHz; DMSO-d ): δ 7.86-7.27 (m, 12H, Ar-H),
6
7.09-7.03 (q, 1H, CH, J = 9.09 Hz), 5.97 (s, 2H, CH -O),
2