Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides: Access to highly substituted aromatic guanidines

Article abstract of DOI:10.1055/s-2003-40844

The reaction of bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides with primary aromatic amines in CHCl₃/Et₃N yields new highly substituted aromatic guanidines (up to 90% yield).

Full text of DOI:10.1055/s-2003-40844

LETTER
1459
Bis(1,3,4-Thiadiazolo)-1,3,5-triazinium Halides: Access to Highly Substituted
Aromatic Guanidines1
Access to
Highly
S
u
ubstitute
d
A
r
romatic
tG
uanidines Wermann,a Martin Walther,a Helmar Görls,b Ernst Anders*a
a
Institut für Organische Chemie und Makromolekulare Chemie der Friedrich-Schiller-Universität, Lessingstrasse 8, 07743 Jena, Germany
b
Institut für Anorganische und Analytische Chemie der Friedrich-Schiller-Universität, Lessingstrasse 8, 07743 Jena, Germany
Fax +49(3641)948212; E-mail: Ernst.Anders@uni-jena.de
Received 22 May 2003
However, under the same reactions conditions primary
aromatic amines 2a,b, 2l, 2n (cf. Table 1) induced an
competing reaction channel, i. e. the formation of ring
cleavage products 7a,b, 7d,13 7h,14 7l,15 and 7n in yields
up to 80%, accompanied by formation of very hygroscop-
ic iminium intermediates 816 which are hydrolyzed almost
immediately (air moisture is sufficient) to yield thiadi-
azoles 917 and aldehydes 10.18 The aldehydes 10 are iden-
tical with those used for the synthesis of the 5/6/5-
heterocycles 1.10a,11
Abstract: The reaction of bis(1,3,4-thiadiazolo)-1,3,5-triazinium
halides with primary aromatic amines in CHCl3/Et3N yields new
highly substituted aromatic guanidines (up to 90% yield).
Key words: guanidinylation, nitrogen heterocycles, nucleophilic
addition, rearrangements, sulfur heterocycles
The guanidine unit is an important structural key compo-
nent both for biologically active natural compounds2 and
for potential chiral auxiliaries in asymmetric syntheses.3
Moreover, due to their strong basic character guanidines
can be considered as superbases catalyzing for example
oxazolidine ring formation from carbon dioxide and
amines.4 Consequently, syntheses that allow for the easy
access to modified guanidines with high yield under mild
conditions are of great interest.5–8 Typically, many synthe-
ses achieve guanidinylation by the addition of a nucleo-
philic amine to cyanamides or carbodiimides.9
The formation of zwitterion 5 depends on a preceding
deprotonation step of 3.1b The resulting structure (not
shown) allows a strong negative hyperconjugation of the
exocyclic nitrogen lone pair into the s* orbital of the
C(4a)-S(5) bond. This facilitates the cleavage of the bond
under mild conditions (CHCl3/Et3N, r.t. for 24 h) thus
forming 5.1b Under less basic conditions (pyridine, r.t.), a
proton shift to give 4a opens an alternative reaction path-
way. Now, the N-(exocyclic)-lone pair is delocalized into
the C(4a)-N(4) s* orbital. This effect weakens the bond
and causes the formation of cation 4b. The reactivity of
cation 4b is controlled by the influence of the negative hy-
perconjugation, in this case by the delocalization of the
N(10) lone pair into the s* orbital of the C(9)-N(8) bond.
Thus, cleavage of the bond affords compounds 7 and 8.
Based on our recently reported cyclization reaction of 2-
amino-1,3,4-thiadiazoles and N-alkylpyridinium halides
to the novel bis(1,3,4-thiadiazolo)-1,3,5-triazinium ha-
lides 1 (cationic ‘5/6/5 heterocycles’, Scheme 1),10 we
have developed a rearrangement protocol, that may be
complementary to previously described guanidine synthe-
ses.5–8 The C(3a) and C(4a) positions of the central di-
hydrotriazinium ring in
1 possess a remarkable
In order to suppress this pathway and to favour the forma-
tion of zwitterion 5, we therefore increased the basicity of
the medium by adding triethylamine to the 1:1 mixture of
1 and 2 in CHCl3. This allows circumventing the pathway
1+2→4a→4b→7+8 and, furthermore, the protonation of
the thiolate moiety of 5, which would reduce the forma-
tion of 6, too. Interestingly and in agreement with this
mechanistic interpretation, no reaction of 1a and 2c
(R3 = 3-NO2Ph) in pyridine was observed whereas guani-
dine 6c is formed by using the triethylamine/chloroform
mixture. Thus, under these conditions the reaction path-
way 1+2→3→5→6 turns out to be predominant as it is
demonstrated by the excellent yields of guanidines 6 (up
to 92%, Table 1).
electrophilicity and can be easily attacked by a nucleo-
philic amine 2 under formation of intermediate 3. After
deprotonation, compound 3 is transformed into the zwit-
terion 5,1b which is the key intermediate for the consecu-
tive reaction cascade to give the novel highly substituted
guanidines 6.11 This pathway can be classified as a novel
example of the SN(ANRORC) concept.12 The ring-clo-
sure/ring-opening step which is initiated by the nucleo-
philic attack of the thiolate sulfur in 5 at the C(9) center is
remarkable. The activation barrier for that step can easily
be surmounted as it has been estimated by DFT calcula-
tions to be about 17 kcal/mol.1b A series of 6 was prepared
by reaction of primary/secondary aliphatic amines 2 and a
variety of salts 1 in yields up to 90% according to the pub-
lished general procedure (pyridine or MeCN, r.t., 24 h, 2
equiv amine 2).11a
Structural assignments of the new heterocyclic com-
pounds 6a–m and 7n are based on 1H, and 13C NMR data,
MS spectra as well as elemental analyses,19 and in the cas-
es of guanidine 6b and the novel 2-pyridyl-thiadiazole
compound 7n, also by X-ray analysis.20
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1459,1462,ftx,en;G11503ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1460
K. Wermann et al.
LETTER
References
(1) (a) Part 7 in the series ‘Bis(1,3,4-Thiadiazolo)-1,3,5-
triazinium Halides’. Part 6, see: Nilson Lill, St. O.; Rauhut,
G.; Anders, E. Chem.–Eur. J. 2003, in press. (b) Part 5,
see: Wermann, K.; Walther, M.; Günther, W.; Görls, H.;
Anders, E. Eur. J. Org. Chem. 2003, 1389. (c) Part 4, see:
Wermann, K.; Walther, M.; Anders, E. ARKIVOC 2002, 10,
24.
(2) (a) Berlinck, R. G. S. Nat. Prod. Rep. 2002, 19, 617.
(b) Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339.
(c) Hannon, C. L.; Anslyn, E. V. Bioorg. Chem. Front. 1993,
3, 193.
(3) Ishikawa, T.; Isobe, T. Chem.–Eur. J. 2002, 8, 553.
(4) Costa, M.; Chiusoli, G. P.; Taffurelli, D.; Dalmonego, G. J.
Chem. Soc., Perkin Trans. 1 1998, 1541.
(5) Heinisch, G.; Matuszak, B.; Rakowitz, D.; Mereiter, K. J.
Heterocycl. Chem. 2002, 39, 695.
(6) (a) Isobe, T.; Fukuda, K.; Ishikawa, T. J. Org. Chem. 2000,
65, 7770. (b) Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.;
Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2000, 65, 7774.
(c) Isobe, T.; Fukuda, K.; Yamaguchi, K.; Seki, H.;
Tokunaga, T.; Ishikawa, T. J. Org. Chem. 2000, 65, 7779.
(7) (a) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J.
Org. Chem. 1998, 63, 3804. (b) Feichtinger, K.; Sings, H.
L.; Baker, T. J.; Matthews, K.; Goodman, M. J. Org. Chem.
1998, 63, 8432.
(8) (a) Katritzky, A. R.; Rogovoy, B. V.; Chassaing, C.;
Vvedensky, V. J. Org. Chem. 2000, 65, 8080. (b) Kim, H.-
O.; Mathew, F.; Ogbu, C. Synlett 1999, 193. (c) Guo, Z.-X.;
Cammidge, A. N.; Horwell, D. C. Synth. Commun. 2000, 30,
2933.
(9) See ref.5,7a,8 and literature cited therein.
(10) (a) Anders, E.; Wermann, K.; Wiedel, B.; Günther, W.;
Görls, H. Eur. J. Org. Chem. 1998, 2923. (b) Anders, E.;
Vanden Eynde, J.-J.; Wermann, K. In Advances in
Heterocyclic Chemistry, Vol. 77; Katritzky, A. R., Ed.;
Academic Press: New York, 2000, 183.
(11) (a) Wermann, K.; Walther, M.; Günther, W.; Görls, H.;
Anders, E. J. Org. Chem. 2001, 66, 720. (b) Walther, M.;
Wermann, K.; Görls, H.; Anders, E. Synthesis 2001, 1327.
(12) Van der Plas, H. C. In Advances in Heterocyclic Chemistry,
Vol. 74; Katritzky, A. R., Ed.; Academic Press: New York,
1999, 87.
(13) Besides 7b, N-(4-methylphenyl)-N-[(1E)-(4-methyl-phenyl)
methylene]amine was isolated in almost quantitative yield
by the reaction of 2b and 4-methyl benzaldehyde formed in
situ, see: Bolognese, A.; Diumo, M. V.; Mazzoni, O.;
Giordano, F. Tetrahedron 1991, 47, 7417.
(14) Tripathy, P. B.; Rout, M. R. J. Indian Chem. Soc. 1960, 37,
414.
(15) Dubenko, R. G.; Benzina, I. N.; Pel’kis, P. S. Zh. Obshch.
Khim. 1963, 33, 274.
Scheme 1
In conclusion, highly substituted aromatic guanidines can
easily be obtained from bis(1,3,4-thiadiazolo)1,3,5-triaz-
inium halides 1 via intermediate formation of triazinium–
imidothioate zwitterions 5. This new synthetic procedure
appears to be applicable to a surprisingly wide manifold
of primary and secondary aliphatic and aromatic amines.
(16) The iminium salt 8a (R1 = 4-MePh; R2 = Me): Identification
by HMQC experiments showing a CH correlation between d
= 160.7 and 8.45 ppm. 1H NMR (400 MHz, CDCl3): d = 2.34
(s, 3 H, CH3), 2.46 (s, 3 H, CH3), 7.79 (d, 2 H, aryl-CH), 7.25
(d, 2 H, aryl-CH), 7.31 (br s, 1 H, NH), 8.45 (s, 1 H, imine-
CH). 13C NMR (100.6 MHz, CDCl3): d = 17.5, 21.7, 129.2,
129.3, 132.8, 142.6, 150.9, 160.7 (imine-CH, broad), 170.0.
(17) Chubb, F. C.; Nissenbaum, J. Can. J. Chem. 1959, 37, 1121.
(18) The hydrolysis products 9 and 10 were unambiguously
identified by TLC (EtOAc), GC, derivatization with 2,4-
dinitrophenylhydrazine, and 1H and 13C NMR spectroscopy
in DMSO-d6.
Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft (Colla-
borative Research Center 436, University of Jena, Germany), the
Fonds der Chemischen Industrie (Germany), and the Thüringer
Ministerium für Wissenschaft, Forschung und Kultur (Erfurt,
Germany) is gratefully acknowledged. We thank Dr. W. Guenther
(Institut für Organische Chemie und Makromolekulare Chemie der
Friedrich-Schiller-Universität Jena) for valuable assistance in NMR
analyses.
(19) General Procedure for the Preparation of Guanidines 6:
To a well-stirred mixture of the corresponding bis-(1,3,4-
thiadiazolo)-1,3,5-triazinium halide 1 (5 mmol) and amine 2
Synlett 2003, No. 10, 1459–1462 © Thieme Stuttgart · New York

LETTER
Access to Highly Substituted Aromatic Guanidines
1461
Table 1 Synthesis of Highly Substituted Aromatic Guanidines and Ring Cleavage Reactions of 5/6/5-Heterocycles 1 with Primary Aromatic
Amines 219
R1
R2
X
R3
Yield (%) Mp (°C)
Yield (%) Mp (°C)
1a
4-MePh
Me
Br
2a
2b
2c
2d
2e
2f
Ph
6a
6b
6c
6d
6e
6f
73
84
64
84
92
158
134
174
140
125
143
7a
7b
7c
80
19114
19414
4-MePh
3-NO2Ph
4-t-BuPh
4-MeOPh
2-MeOPh
2-pyridyl
Ph
7213
7d
80
20215
90
b
2g
2a
2h
2a
2d
2e
2h
2d
7e
7f
75
63
274
1b
1c
1-Bu
Me
Br
Br
6g
6h
6i
55
65
74
79
81
77
34
93
73
19114
2-HOPh
Ph
1-Naphthyl Me
147
89
7a
80
19114
4-t-BuPh
4-MeO Ph
2-HOPh
4-t-BuPh
6j
6k
6l
175
142
222
1d
2-HOPh
t-Bu
Cl
6m
a No reaction.
b Inseparable product mixture.
(5 mmol) in 30 mL CHCl3, Et3N (30 mL) was added
gradually at r.t. After stirring over a period of 24 h, the
resulting suspension was concentrated in vacuo. The residue
was washed with cold water and extracted three times with
CHCl3. The combined extracts were dried with Na2SO4 and
concentrated in vacuo. The residues were purified by column
chromatography (silicagel 60; eluting with EtOAc; pentane/
EtOAc; Et2O/EtOAc) or by fractional crystallization from
EtOH, MeCN, EtOAc.
59.58; H, 5.33; N, 20.28; S, 15.05.
5-Methyl-2-(4-methylphenyl)-N¢-(5-methyl-1,3,4-
thiadiazol-2-yl)-N-(3-nitrophenyl)-1,3,4-thiadiazole-
3(2H)-carboximidamide (6c): Purified by column
chromatography. 1H NMR (250 MHz, CDCl3): d = 1.99 (s, 3
H, CH3), 2.23 (s, 3 H, CH3), 2.49 (s, 3 H, CH3), 6.96 (s, 1 H,
2-CH), 7.19–7.87 (m, 8 H, CHph), 10.59 (s, 1 H, NH). 13
C
NMR (62.9 MHz, CDCl3): d = 16.5, 16.9, 21.6, 72.2, 117.4,
118.9, 125.5, 127.7, 127.9, 129.5, 137.6, 138.4, 141.0,
148.4, 148.6, 149.5, 159.7, 173.7. MS (DCI/H2O): m/z
(%) = 454 (81) [C20H20N7O2S2]+. Anal. Calcd for
All new compounds 6 were fully characterized. Selected
analytical data:
5-Methyl-2-(4-methylphenyl)-N¢-(5-methyl-1,3,4-
thiadiazol-2-yl)-N-phenyl-1,3,4-thiadiazole-3(2H)-
carboximidamide (6a): Recrystallized from EtOH. 1H
NMR (250 MHz, CDCl3): d = 2.00 (s, 3 H, CH3), 2.26 (s, 3
H, CH3), 2.44 (s, 3 H, CH3), 7.19 (s, 1 H, 2-CH), 6.96–7.22
(m, 9 H, CHph), 10.04 (s, 1 H, NH). 13C NMR (62.9 MHz,
CDCl3): d = 16.1, 16.6, 21.2, 72.0, 122.4, 124.3, 126.6,
128.6, 129.4, 137.7, 138.6, 139.1, 147.9, 149.0, 158.5,
173.1. MS (DCI/H2O): m/z (%) = 409 (100) [C20H21N6S2]+.
Anal. Calcd for C20H20N6S2 (408.53): C, 58.80; H, 4.93; N,
20.57; S, 15.69. Found: C, 58.54; H, 5.08; N, 20.62; S,
15.53.
C20H19N7O2S2 (453.53): C, 52.97; H, 4.22; N, 21.62; O,
7.06; S, 14.14. Found: C, 52.80; H, 4.38; N, 21.57; S, 13.83.
5-Methyl-2-(4-methylphenyl)-N¢-(5-methyl-1,3,4-
thiadiazol-2-yl)-N-(4-t-butylphenyl)-1,3,4-thiadiazole-
3(2H)-carboximidamide (6d): Purified by column
chromatography and recrystallized from Et2O. 1H NMR
(250 MHz, CDCl3): d = 1.32 (s, 9 H, CH3), 2.11 (s, 3 H,
CH3), 2.36 (s, 3 H, CH3), 2.53 (s, 3 H, CH3), 7.01–7.16 (AA¢/
XX¢, 4 H, CHph), 7.13 (s, 1 H, 2-CH), 7.27–7.29 (AA¢/XX¢,
4 H, CHph), 10.02 (br s, 1 H, NH). 13C NMR (62.9 MHz,
CDCl3): d = 16.1, 16.6, 21.2, 31.3, 34.4, 72.0, 122.1, 125.5,
126.4, 129.4, 136.3, 137.8, 138.6, 147.4, 147.8, 149.2,
158.7, 173.0. MS (DCI/H2O): m/z (%) = 465(100)
5-Methyl-2-(4-methylphenyl)-N¢-(5-methyl-1,3,4-
thiadiazol-2-yl)-N-(4-methylphenyl)-1,3,4-thiadiazole-
3(2H)-carboximidamide (6b): Recrystallized from MeCN.
1H NMR (250 MHz, CDCl3): d = 2.12 (s, 3 H, CH3), 2.26 (s,
3 H, CH3), 2.32 (s, 3 H, CH3), 2.49 (s, 3 H, CH3), 7.12 (s, 1
[C24H29N6S2]+. Anal. Calcd for C24H28N6S2 (464.65): C,
62.04; H, 6.07; N, 18.09; S, 13.80. Found: C, 61.98; H, 6.47;
N, 18.40; S, 13.93.
5-Methyl-2-(4-methylphenyl)-N¢-(5-methyl-1,3,4-
thiadiazol-2-yl)-N-(4-methoxyphenyl)-1,3,4-thiadiazole-
3(2H)-carboximidamide (6e): Recrystallized from EtOAc.
1H NMR (250 MHz, CDCl3): d = 2.10 (s, 3 H, CH3), 2.32 (s,
3 H, CH3), 2.54 (s, 3 H, CH3), 3.81 (s, 3 H, OCH3), 6.78–7.00
(AA¢/XX¢, 4 H, CHph), 7.11 (s, 1 H, 2-CH), 7.15–7.26 (AA¢/
XX¢, 4 H, CH), 10.08 (br s, 1 H, NH). 13C NMR (62.9 MHz,
H, 2-CH), 6.95–7.26 (m, 8 H, CHph), 10.03 (s, 1 H, NH). 13
C
NMR (62.9 MHz, CDCl3): d = 16.8, 17.0, 21.3, 21.6, 72.3,
122.8, 126.9, 129.6, 129.7, 134.4, 136.8, 138.2, 139.0,
148.1, 148.7, 155.2, 173.5. MS (DCI/H2O): m/z
(%) = 423(100) [C21H23N6S2]+. Anal. Calcd for C21H22N6S2
(422.56): C, 59.69; H, 5.25; N, 19.89; S, 15.17. Found: C,
Synlett 2003, No. 10, 1459–1462 © Thieme Stuttgart · New York

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K. Wermann et al.
LETTER
CDCl3): d = 16.5, 17.0, 21.5, 55.8, 72.4, 114.2, 124.9, 126.9,
129.7, 132.5, 138.3, 139.0, 147.9, 150.0, 157.1, 159.1,
173.7. MS (DCI/H2O): m/z (%) = 439 (439)
Found: C, 64.53; H, 6.14; N, 16.51; S, 12.39.
5-Methyl-2-naphthyl-N¢-(5-methyl-1,3,4-thiadiazol-2-
yl)-N-(4-methoxyphenyl)-1,3,4-thiadiazole-3(2H)-
carboximidamide (6k): Recrystallized from EtOH. 1H
NMR (250 MHz, CDCl3): d = 2.10 (s, 3 H, CH3), 2.44 (s, 3
H, CH3), 3.83 (s, 3 H, OCH3), 6.81–7.08 (AA¢/XX¢, 4 H,
CHph), 7.48–7.93 (m, 7 H, CHnaphthyl), 7.89 (s, 1 H, 2-CH).
13C NMR (62.9 MHz, CDCl3): d = 16.3, 17.1, 55.9, 69.8,
114.2, 123.1, 124.2, 125.2, 126.0, 126.3, 126.8, 129.4,
129.5, 129.6, 132.4, 134.4, 136.3, 149.3, 150.0, 157.3,
159.2, 173.5. MS (DCI/H2O): m/z (%) = 475 (100)
[C24H23N6OS2]+. Anal. Calcd for C24H22N6OS2 (474.57): C,
60.74; H, 4.67; N, 17.71; O, 3.37; S, 13.51. Found: C, 60.57;
H, 4.87; N, 17.90; S, 13.20.
5-Methyl-2-naphthyl-N¢-(5-methyl-1,3,4-thiadiazol-2-
yl)-N-(2-hydroxyphenyl)-1,3,4-thiadiazole-3(2H)-
carboximidamide (6l): Recrystallized from EtOAc. 1H
NMR (250 MHz, CDCl3): d = 2.14 (s, 3 H, CH3), 2.28 (s, 3
H, CH3), 6.79–7.08 (m, 4 H, CHph), 7.49 (s, 1 H, NH), 7.38–
7.83 (m, 7 H, CHnaphthyl), 7.95 (s, 1 H, 2-CH), 9.13 (s, 1 H,
OH). 13C NMR (62.9 MHz, CDCl3): d = 16.2, 16.9, 69.1,
118.4, 120.4, 122.7, 123.7, 125.7, 126.1, 126.3, 126.9,
127.0, 128.0, 129.4, 129.9, 134.3, 2 × 135.3, 150.4, 150.6,
151.7, 160.0, 171.5. MS (DCI/H2O): m/z (%) = 461(94)
[C23H21N6OS2]+. Anal. Calcd for C17H22N6OS2 (460.57): C,
59.98; H, 4.38; N, 18.25; O, 3.47; S, 13.92. Found: C, 59.57;
H, 4.70; N, 18.09; S, 13.71.
5-t-Butyl-2-(2-hydroxyphenyl-N¢-(5-t-butyl-1,3,4-
thiadiazol-2-yl)-N-(4-t-butylphenyl)-1,3,4-thiadiazole-
3(2H)-carboximidamide (6m): Recrystallized from Et2O.
1H NMR (250 MHz, CDCl3): d = 0.99 (s, 9 H, CH3), 1.28 (s,
9 H, CH3), 1.42 (s, 9 H, CH3), 6.84–7.41 (m, 9 H, CHph, 2-
CH), 11.0 (s, br, 1 H, OH), 11.16 (br s, 1 H, NH). 13C NMR
(62.9 MHz, CDCl3): d = 28.8, 31.1, 31.7, 34.8, 36.6, 36.7,
66.4, 119.5, 121.3, 123.8, 125.7, 126.4, 129.4, 131.3, 137.0,
148.4, 150.8, 154.9, 163.8, 172.4, 174.3. MS (DCI/H2O):
m/z (%) = 551(20) [C29H39N6OS2]+. Anal. Calcd for
C29H38N6OS2 (550.78): C, 63.24; H, 6.95; N, 15.26; S,
11.64. Found: C, 63.03; H, 7.43; N, 15.37; S, 11.43.
General Procedure for the Formation of 2-
(Het)arylamino-5-methyl-1,3,4-thiadiazoles 7: The
suspension of 1 (5 mmol) and amine 2 (10.1 mmol) in
pyridine (60 mL) was stirred at r.t. for 24–60 h.11a The
reaction mixture, changing to a nearly clear solution, was
concentrated to dryness in vacuo. The solid residue was
washed off with water and recrystallized as described in the
literature.14,16 The novel compound 7e was purified by
column chromatography and fractional crystallization from
CHCl3/EtOAc to prepare crystalline material suitable for X-
ray investigation.
[C21H23N6OS2]+. Anal. Calcd for C21H22N6OS2 (438.56): C,
57.51; H, 5.06; N, 19.16; O, 3.65; S, 14.12. Found: C, 57.47;
H, 5.31; N, 19.10; S, 14.24.
5-Methyl-2-(4-methylphenyl)-N¢-(5-methyl-1,3,4-
thiadiazol-2-yl)-N-(2-methoxyphenyl)-1,3,4-thiadiazole-
3(2H)-carboximidamide (6f): Recrystallized from EtOAc.
1H NMR (250 MHz, CDCl3): d = 2.12 (s, 3 H, CH3), 2.38 (s,
3 H, CH3), 2.53 (s, 3 H, CH3), 3.88 (s, 3 H, OCH3), 6.76–7.29
(m, 8 H, CHph, 1 H, 2-CH), 9.71 (br s, 1 H, NH). 13C NMR
(62.9 MHz, CDCl3): d = 16.1, 16.5, 21.5, 56.1, 72.2, 110.9,
120.6, 122.9, 125.0, 126.7, 128.5, 129.7, 138.3, 138.9,
148.3, 149.2, 151.2, 159.2, 172.8. MS (DCI/H2O): m/z
(%) = 439 (100) [C21H23N6OS2]+. Anal. Calcd for
C21H22N6OS2 (438.56): C, 57.51; H, 5.06; N, 19.16; S,
14.12. Found: C, 56.91; H, 5.32; N, 18.67; S, 14.04.
2-Butyl-5-methyl-2-N¢-(5-methyl-1,3,4-thiadiazol-2-yl)-
N-phenyl-1,3,4-thiadiazole-3(2H)-carboximidamide
(6g): Purified by column chromatography. 1H NMR (250
MHz, CDCl3): d = 0.91 (t, 3 H, CH3), 1.21–1.40 (m, 4 H,
CH2), 1.89–2.21 (m, 2 H, CH2), 2.06 (s, 3 H, CH3), 2.57 (s,
3 H, CH3), 6.18–6.22 (t, 1 H, 2-CH), 7.02–7.29 (m, 5 H,
CHph), 9.86 (s, 1 H, NH). 13C NMR (62.9 MHz, CDCl3):
d = 14.3, 16.5, 17.2, 22.4, 27.1, 36.7, 71.7, 122.6, 124.7,
129.0, 139.5, 149.5, 150.1, 159.1, 173.4. MS (DCI/H2O): m/
z (%) = 375 (100) [C17H23N6S2]+. Anal. Calcd for
C17H22N6S2 (374.52): C, 54.52; H, 5.92; N, 22.44; S, 17.12.
Found: C, 54.59; H, 6.31; N 22.60; S, 16.75.
2-Butyl-5-methyl-2-N¢-(5-methyl-1,3,4-thiadiazol-2-yl)-
N-(2-hydroxyphenyl)-1,3,4-thiadiazole-3(2H)-
carboximidamide (6h): Purified by column
chromatography. 1H NMR (250 MHz, CDCl3): d = 0.91 (t, 3
H, CH3), 1.28–1.40 (m, 4 H, CH2), 2.07–2.21 (m, 2 H, CH2),
2.16 (s, 3 H, CH3), 2.56 (s, 3 H, CH3), 6.75–6.81 (t, 1 H, 2-
CH), 6.93-7.07 (m, 4 H, CHph), 6.17 (s, 1 H, NH), 8.94 (s, 1
H, OH). 13C NMR (62.9 MHz, CDCl3): d = 14.1, 16.5, 17.1,
22.7, 26.9, 36.4, 71.3, 117.6, 120.3, 125.3, 126.9, 127.5,
150.8, 151.2, 151.3, 159.6, 172.7. MS (DCI/H2O): m/z
(%) = 391(100) [C17H23N6OS2]+. Anal. Calcd for
C17H22N6OS2 (390.52): C, 52.29; H, 5.68; N, 21.52; O, 4.10;
S, 16.42. Found: C, 51.76; H, 5.88; N, 21.53; S, 16.29.
5-Methyl-2-naphthyl-N¢-(5-methyl-1,3,4-thiadiazol-2-
yl)-N-phenyl-1,3,4-thiadiazole-3(2H)-carboximidamide
(6i): Purified by column chromatography. 1H NMR (250
MHz, CDCl3): d = 2.10
(s, 3 H, CH3), 2.44 (s, 3 H, CH3), 7.09–7.95 (m, 12 H,
CHph;naphthyl), 7.95 (s, 1 H, 2-CH), 10.03 (s, 1 H, NH). 13
NMR (62.9 MHz, CDCl3): d = 16.4, 17.1, 69.8, 123.0,
123.1, 124.2, 124.8, 125.9, 126.3, 126.9, 129.0, 129.5,
129.6, 129.8, 134.4, 136.1, 139.5, 149.3, 149.8, 159.4,
C
N-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-amine (7e):
Purified by column chromatography and crystallized from
EtOAc. 1H NMR (250 MHz, DMSO-d6): d = 2.56 (s, 3 H,
CH3), 6.94 (t, 1 H, pyridine-5 H), 7.05 (d, 1 H, pyridine-3 H),
7.68 (dd, 1 H, pyridine-4 H), 8.24 (d, 1 H, pyridine-6 H),
11.44 (s, 1 H, NH). 13C NMR (62.9 MHz, DMSO-d6):
d = 14.6 (CH3), 111.0 (pyridine-5C), 116.5 (pyridine-4C),
138.3 (pyridine-3C), 146.5 (pyridine-6C), 150.9 (pyridine-
2C), 156.9 (thiadiazole-5C), 159.9 (thiadiazole-2C). MS
(DEI): m/z (%) = 192(100) [ C8H8N4S]+. Anal. Calcd for
C8H8N4S (192.2): C, 49.98; H, 4.19; N, 29.14; S, 16.68.
Found: C, 50.22; H, 4.18; N, 28.83; S, 16.47.
173.3. MS (DCI/H2O): m/z (%) = 445 (100) [C23H21N6S2]+.
Anal. Calcd for C23H20N6S2 (444.57): C, 62.14; H, 4.53; N,
18.90; S, 14.42. Found: C, 61.90; H, 4.60; N, 19.25; S,
14.32.
5-Methyl-2-naphthyl-N¢-(5-methyl-1,3,4-thiadiazol-2-
yl)-N-(4-t-butylphenyl)-1,3,4-thiadiazole-3(2H)-
carboximidamide (6j): Purified by column
chromatography. 1H NMR (250 MHz, CDCl3): d = 1.33 (s, 9
H, CH3), 2.09 (s, 3 H, CH3), 2.42 (s, 3 H, CH3), 7.08–7.29
(AA¢/XX¢, 4 H, CHph), 7.48–7.93 (m, 7 H, CHnaphthyl), 7.91
(s, 1 H, 2-CH), 9.98 (s, 1 H, NH). 13C NMR (62.9 MHz,
CDCl3): d = 16.2, 17.0, 31.8, 34.8, 69.7, 122.4, 122.7, 123.5,
125.5, 125.6, 125.9, 126.3, 126.8, 129.1, 129.2, 134.4,
136.1, 136.6, 147.9, 149.5, 149.8, 159.7, 173.2. MS (DCI/
H2O): m/z (%) = 501 (100) [C27H29N6S2]+. Anal. Calcd for
C27H28N6S2 (500.67): C, 64.77; H, 5.64; N, 16.79; S, 12.81.
(20) CCDC 210984 and 210985 contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK;
fax: +44(1223)336033; or deposit@ccdc.cam.ac.uk).
Synlett 2003, No. 10, 1459–1462 © Thieme Stuttgart · New York