Synthesis and spectroscopic properties of 15n-labelled 1,2,4-thiadiazoles

Article abstract of DOI:10.1002/jhet.5570390135

5-Phenyl-1,2,4-thiadiazole-4-¹⁵N and 3-methyl-5-phenyl-1,2,4-thiadiazole-4-¹⁵N were synthesized from commercially available benazmide-¹⁵N. The mass spectra and the ¹H, ¹³C, and ¹⁵N-nmr spec

Full text of DOI:10.1002/jhet.5570390135

Jan-Feb 2002
Synthesis and Spectroscopic Properties of
237
15
N-Labelled 1,2,4-Thiadiazoles
James W. Pavlik [a], Chutchawin Changtong [a] and Supawan Tantayanon [b]
[a] Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA 01609
[b] Department of Chemistry, Chulalongkorn University, Bangkok, 10330, Thailand
Received July 24, 2001
15
15
5-Phenyl-1,2,4-thiadiazole-4- N and 3-methyl-5-phenyl-1,2,4-thiadiazole-4- N were synthesized from
15
1
13
15
commercially available benazmide- N. The mass spectra and the H, C, and N-nmr spectra of these
compounds, which show various long-range heteronuclear coupling with the N-nucleus, are discussed.
15
J. Heterocyclic Chem., 39, 237 (2002).
As part of our interest in the chemistry of phenyl
substituted 1,2,4-thiadiazoles, we found it necessary to
distinguish between the two nitrogen atoms in the 1,2,4-
thiadiazole ring. To accomplish this we have synthesized
14
molecular ion or from the presence of thiobenzamide- N
14
in the sample. The mass spectrum of thiobenzamide- N
also exhibited a molecular ion at m/z 137 and an M-1 peak
at m/z 136 with an intensity of 18% of the molecular ion.
This confirms that loss of hydrogen is a normal fragmen-
tation pathway for thiobenzamide- N and therefore will
also be a normal fragmentation pathway for thio-
15
5-phenyl-1,2,4-thiadiazole-4- N (1) and 3-methyl-5-
15
phenyl-1,2,4-thiadiazole-4- N (2). In this paper we report
14
the syntheses of these compounds and their spectroscopic
properties.
15
benzamide- N (4). The peak at m/z 137 in the mass
spectrum of thiobenzamide- N (4) is therefore not due to
15
Results and Discussion.
14
the presence of thiobenzamide- N in the sample.
15
N-labelled thiadiazoles 1 and 2 were synthesized from
1
15
The H-nmr spectrum of thiobenzamide- N (4) is more
complicated than the H-nmr spectrum of unlabelled
thiobenzamide [4] due to the heteronuclear coupling
between the H and N nuclei. As a result of this coupling
the two non-equivalent amide protons appear as double
15
commercially available benzamide- N (3) [1] according
1
to the procedure shown in Scheme 1 developed by Lin and
colleagues for the synthesis of unlabelled thiadiazole 1 [2].
1
15
doublets at δ 7.24 and 7.82 (J
= 89.5 Hz,
1
15
15
-
H
N
1
J
1
= 4.2 Hz). As a result of this H- N coupling, the
1
-
H
H
15
15
N nucleus of 4 appeared in the N-nmr spectrum at
δ 134.8 as a triplet (J = 91.2 Hz), which is within experi-
mental error of the coupling constant observed in the
1
13
H-nmr spectrum [5]. The C-nmr spectrum of 4 exhib-
ited signals for the thiocarbonyl carbon at δ 203.3 and for
the carbons of the phenyl ring at δ 127.3, 128.9, 132.5, and
139.5. The absence of the latter signal in the DEPT-135
spectrum confirmed that this signal is due to C-1 of the
phenyl ring. Interestingly, although all of these signals
appear as sharp singlets in the proton decoupled spectrum
of unlabelled 4, the signals due to the thiocarbonyl carbon
at δ 203.3 and the C-1 carbon of the phenyl ring at δ 139.5
of labelled 4 appeared as doublets with J = 13.3 and 3.1 Hz
15
respectively due to their coupling with the N nucleus.
15
N-[(Dimethylamino)methylene]thiobenzamide- N (7) or
15
N-[(Dimethylamino)ethylidene]thiobenzamide- N (8), the
This sequence began with the reaction of benzamide-
precursors of 1 or 2, were synthesized in 60% or 82%
15
15
N (3) with P S in benzene to provide thiobenzamide-
respectively by the condensation of thiobenzamide- N (4)
2 5
15
N (4) in 60% yield [3]. The mass spectrum of 4 exhibited
with N,N-dimethylformamide dimethyl acetal (5) or N,N-
dimethylacetamide dimethyl acetal (6) at room temperature.
a molecular ion as the base peak at m/z 138 which
corresponds to the molecular weight of 4. The spectrum
also exhibited a peak at m/z 137 with an intensity of 18%
of the peak at m/z 138. This peak at m/z 137 could be due
to an M-1 peak resulting from loss of hydrogen from the
1
The H-nmr spectrum of 7 exhibited a singlet a δ 8.78
due to the imine proton. Although no coupling of this
15
1
proton with the N nucleus was observed in the H-nmr
15
spectrum, coupling was observed in the N-nmr spectrum

238
J. W. Pavlik, C. Changtong and S. Tantayanon
Vol. 39
interchange during fragmentation. The signal at m/z 105
was assigned to the [Ph-C≡ N-H] fragment formed by
which exhibited a doublet (J = 2.0 Hz) at δ 268.7 due to
15
+•
15
coupling of the N-nucleus with the imine proton. The
1
elimination of CNS from the molecular ion while the
H-nmr spectrum of 7 also exhibited two 3H singlets at δ
15 +•
13
peak at m/z 104 was assigned to the [Ph-C≡ N]
3.24 and 3.25 which correlated with signals in the C-nmr
14
fragment formed by the elimination of HC NS. No
spectrum at δ 36.4 and 41.9. The phenyl protons of 7
1
signal was observed at m/z 103 which would be expected
if nitrogen interchange led to the formation of
appeared as a 3H multiplet in the H-nmr spectrum at δ
7.29-7.52 due to the meta and para protons, which
14
+•
13
[Ph-C≡ N] . The mass spectrum of unlabelled 1
showed an analogous fragmentation pattern. Thus, in
addition to an intense peak at m/z 135 due to the
correlated with signals in the C-nmr spectrum at δ 127.7
and 131.9, and a 2H multiplet at δ 8.36-8.41 due to the
ortho protons, which correlated with a doublet (J = 2.6 Hz)
14
+•
13
[PhC NS] fragment formed by elimination of
in the C-nmr spectrum at δ 128.8 due to the ortho ring
14
H-C≡ N, the spectrum also had signals at m/z 104 due to
carbons. This is presumably due to the long-range
14
+•
15
the [Ph-C≡ N-H] fragment and a smaller signal at m/z
103 (26% of 104 peak) due to [Ph-C≡ N] . The spectra
coupling of the ortho carbons with the N nucleus since
14 +•
no analogous coupling was observed in the unlabelled
13
of 1 and unlabelled 1 both exhibited intense peaks at m/z
compound. The C-nmr spectrum of 7 also shows that
+•
77 (58% of base peak) due to [C H ] and at m/z 59
although the imine carbon of 7 appears as a doublet
6
5
+•
15
(57% of base peak) due to the formation of [HCNS] .
As expected, the mass spectrum of 3-methyl-5-phenyl-
1,2,4-thiadiazole-4- N (2) exhibited a molecular ion at
(J = 9.6 Hz) at δ 159.0 due to its coupling with the
N
nucleus, the thiocarbonyl carbon appears as a sharp singlet
15
15
at δ 216.1. Lack of coupling of this carbon with the
nucleus is surprising since coupling between the
N
N
15
m/z 177 and a base peak at m/z 136 again assigned to the
15
+•
[Ph-C NS] fragment formed in this case by elimination
nucleus and the carbonyl carbon was observed in
14
15
15
of CH C≡ N. Again, no signal at m/z 135 was observed
benzamide- N (3) and thiobenzamide- N (4).
3
14
1
showing that only CH -C≡ N was eliminated confirming
The H-nmr spectrum of 8 exhibited 3H singlets at δ 3.91,
3
that nitrogen scrambling does not occur during the
fragmentation process. The spectrum also showed an
intense signal at m/z 73 (77% of base) assigned to the
3.21, and 2.47 due to the two non-equivalent N-methyl
groups and the allyl methyl group, respectively, which
13
correlated with signals in the C-nmr spectrum at δ 39.6,
14
+•
CH -C NS) fragment formed by elimination of
3
39.7, and 18.4 respectively. The phenyl protons appeared in
15
Ph-C≡ N and a small peak at m/z 104 (12% of base) due
1
the H-nmr as a 3H multiplet due to the meta and para
15 +•
to the formation of a small amount of [Ph-C≡ N] .
hydrogens at δ 7.29-7.42, which correlated with singlets in
1
The H-nmr spectrum of 1 exhibited a doublet (J =
13
the C nmr spectrum at δ 128.0 and 131.3 due to the meta
13.9 Hz) at δ 8.84 due to the proton at position 3 of the
and para carbons respectively, whereas the ortho hydrogens
appeared as a 2H multiplet at δ 8.22-8.24, which correlated
15
thiadiazole ring coupling with the N nucleus at ring
15
position 4. Furthermore, the N-nmr spectrum showed a
13
with a doublet in the C-nmr spectrum at δ 128.8 (J = 2.1
doublet (J = 13.9 Hz) at δ 304.2 confirming this coupling.
15
Hz) due to long-range coupling with the N nucleus. The
1
This doublet in the H-nmr spectrum correlated with a
C-1 carbon of the phenyl ring, the imine carbon, and the
13
doublet at δ 164.6 (J = 3.8 Hz) in the C-nmr spectrum
15
thiocarbonyl carbon also exhibited coupling with the
N
that was therefore assigned to the carbon at ring position 3
13
nucleus and appeared as doublets in the C-nmr spectrum
15
which is also coupled to the N nucleus of 1. In contrast,
at δ 142.9 (J = 8.2 Hz), 168.3 (J = 12.3 Hz), and 202.7 (J =
1
both of these signals appeared as singlets in the H and
15
6.8 Hz) respectively. The N nucleus appeared as a sharp
13
C-spectra of unlabelled 1. Interestingly, the C-5 carbon
15
singlet at δ 291.4 in the N-nmr spectrum.
15
of the thiadiazole ring exhibited no coupling with the
nucleus but appeared as a sharp singlet in the C-nmr
N
15
5-Phenyl-1,2,4-thiadiazole-4- N (1) or 3-methyl-5-
13
phenyl-1,2,4-thiadiazole (2) were each prepared in 80%
yield by reaction of 7 or 8 with hydroxylamine-O-sulfonic
acid at room temperature.
spectrum at δ 188.9.
1
In addition, the H-nmr spectrum of 1 exhibited a 3H
multiplet at δ 7.59-7.61 due to the para and meta phenyl
The mass spectrum of 5-phenyl-1,2,4-thiadiazole-4-
N (1) exhibited a molecular ion at m/z 163 with no
13
protons, which correlated with signals in the C-nmr spec-
15
trum at δ 130.3 and 133.0 assigned to the meta and para
carbons respectively, and a 2H multiplet at δ 8.05-8.08 due to
the ortho phenyl protons, which correlated with the signal in
signal at m/z 162 indicating the absence of unlabelled 1
in the sample. The spectrum also exhibited a base peak at
m/z 136 and an intense peak (92% of the base peak) at
m/z 105 and a smaller peak (27% of 105 peak) at m/z
104. The signal at m/z 136 was assigned to the
13
the C-nmr spectrum at δ 128.2 assigned to the two equiva-
lent ortho phenyl ring carbons. Furthermore, the doublet
13
(J = 6.3 Hz) in the C-nmr spectrum at δ 131.1 was assigned
15
+•
[PhC NS] fragment formed by elimination of
to the quaternary C-1 carbon of the phenyl ring since this
14
1
13
H-C≡ N from the molecular ion. No signal was
signal was not observed in the H- C correlation or
DEPT-135 spectra. The signal again shows long-range
14
observed at m/z 135 showing that only H-C≡ N was
15
coupling between the C-1 phenyl carbon and the N nucleus.
eliminated indicating that the two ring nitrogens do not

15
Jan-Feb 2002
Synthesis and Spectroscopic Properties of N-Labelled 1,2,4-Thiadiazoles
239
dichloromethane. Elution of the column with dichloromethane
gave a homogeneous yellow solid, which was recrystallized
from chloroform:hexane to yield 0.6 g (60%), mp 113-115°.
1
In the H-nmr spectrum of 2 the signal due to the C-3
ring proton was replaced by a 3H doublet at δ 2.71 (J =
2.3 Hz) showing long range coupling of the methyl protons
15
15
N-[(Dimethylamino)methylene]thiobenzamide- N (7) and
with the N nucleus. As expected by this coupling, the
15
15
N-[(Dimethylamino)ethylidene]thiobenzamide- N (8).
N nucleus appeared as a quartet (J = 2.7 Hz) at δ 303.6 in
15
1
the N-nmr spectrum. The H-nmr spectrum of 2 also
exhibited 3H and 2H multiplets at δ 7.46-7.50 and at δ
7.90-7.92 due to the para-meta and ortho phenyl ring
protons respectively. The H- C correlation and
DEPT-135 spectra allowed the signals in the C-NMR
spectrum at δ 127.8 (d, J = 1.9 Hz), 129.7, 130.9 (d, J = 6.1
Hz), and 132.3 to be assigned to the ortho, meta, C-1, and
para carbons, respectively. Thus, both the C-1 and ortho
ring carbons exhibit long-range coupling with the
nucleus. As in the case of 1, the C-3 and C-5 carbons of the
thiadiazole ring were observed in the C-nmr spectrum as
a doublet (J = 2.3 Hz) at δ 174.5 and as a singlet at δ 188.5.
Thus, as was observed in the spectrum of 1, coupling was
observed between the N nucleus and the carbon at ring
position 3 but not with the carbon at ring position 5 of the
thiadiazole ring.
A mixture of 4 (0.50 g, 2.60 mmoles) and N,N-dimethyl-
formamide dimethyl acetal (5) (0.50 g, 4.2 mmoles) or
N,N-dimethylacetamide dimethyl acetal (6) (0.44 g, 3.3 mmoles)
was stirred in an argon atmosphere while several addition drops
of 5 or 6 was added to completely dissolve any remaining 4. The
resulting red mixture was allowed to stir at room temperature
under argon for 30 minutes. Removal of volatile materials in
vacuo gave a red-orange or orange solid that was recrystallized
from ethanol to give orange crystals of 7 (0.61 g, 60%), mp
52-54° or orange crystals of 8 (0.70 g, 82%), mp 110-113°.
1
13
13
15
N
15
13
5-Phenyl-1,2,4-thiadiazole-4- N (1) or 3-Methyl-5-phenyl-
15
1,2,4-thiadiazole-4 N (2).
A solution of hydroxylamine-O-sulfonic acid (0.34 g,
3.0 mmoles) in absolute methanol (10 ml) was added to a
solution of 7 (0.48 g, 2.50 mmoles) in absolute ethanol (10 ml)
containing pyridine (0.50 ml, 6.2 mmoles) in an argon
atmosphere or to a solution of 8 (0.52 g, 2.50 mmoles) in absolute
ethanol (15 ml) containing pyridine (0.50 ml, 6.2 mmoles) in an
argon atmosphere. The reaction mixture was stirred at room
temperature for 1 hour. Evaporation in vacuo gave a yellow
viscous residue that was dissolved in dichloromethane (50 ml),
washed with water (15 ml), 0.1 N aqueous sodium hydroxide
(15 ml), and water (15 ml) and then dried over anhydrous sodium
sulfate. Evaporation gave 1 as a yellow oil (0.48 g) which was
purified by distillation (Kugelrohr, oven temperature 40-50°,
0.4 Torr) to give 1 as a colorless oil (0.34 g, 84%) or 2 as a light
yellow solid (0.42 g) that was recrystallized from hexane to give
a yellow solid which was sublimed (60°, 20 Torr) to give 2
(0.35 g, 80%) as white crystals, mp 50-52°.
15
EXPERIMENTAL
1
13
H, and C spectra were recorded at 400.1 and 100.6, MHz in
1
13
deuteriochloroform on a Bruker FT-NMR system. H and
chemical shifts were measured relative to internal tetramethyl-
silane and chloroform, respectively. H- C correlation spectra
were recorded using the HETCOR (HCCOSW) experiment in the
Bruker system. N-nmr spectra were recorded at 40.5 Mhz in
C
1
13
15
15
acetone-d . The N chemical shifts are reported in ppm down-
6
field from NH (δNH = 0.0) and were measured relative to
aqueous Na NO which was used as an external standard and
taken to absorb at 378.4 ppm downfield from NH
3(l)
3(l)
15
3
[6]. Mass
3(l)
spectra were recorded with an HP 5970B mass selective detector
interfaced to an HP 588 capillary gas chromatograph.
REFERENCES AND NOTES
15
Throbenzamide- N (4).
[1] Cambridge Isotope laboratories, Inc.
[2] Y. Lin, S. A. Lang, Jr., S. R. Petty, J. Org. Chem., 45, 3750
(1980).
[3] L. C. King and F. M. Miller, J. Am. Chem. Soc, 71, 367 (1949).
[4] P. Lin, W. Ku, M. Shiao, Synthesis, 1219 (1992).
[5] R. T. C. Brownlee and M. Sadek, Mag. Reson. Chem., 24, 821
(1986).
[6] M. Witanowski, L. Stefaniak, and G. A. Webb, in Annual
Reports on NMR Spectroscopy, Vol 11B, G. A. Webb, ed, Academic
Press, New York, 1981, pp 2 – 494.
15
A solution of 1.0 g (8.2 mmoles) of benzamide- N (3) and
0.36 g of phosphorous pentasulfide (1.6 mmoles) in 6 ml of
benzene was magnetically stirred and heated at reflux for
50 minutes. The hot yellow benzene solution was decanted and
the residual red solid was extracted with four 3 ml portions of
hot benzene. The combined benzene solution was concentrated
and allowed to cool to yield a yellow crystalline solid which was
purified on a silica gel column (3.5 x 22 cm), prepacked in