Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides. 2. Intramolecular ring transformation and synthesis of novel highly substituted guanidines

Article abstract of DOI:10.1021/jo001016a

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides 6 can be easily attacked by nucleophiles at either the C(3a) or the C(4a) position of the central six-membered (cationic) ring. Nucleophilic attack leads to at least two reaction channels, one of which has been previously detected (pathway a) and leads to novel aminals 19. In this paper we report on a second channel (pathway b). Attack of primary or secondary amines 8 at C(3a) or C(4a) in 6 (and their analogues 7) leads to the weakly stabilized intermediates 14. A cascade of several proton shifts, ring openings, rearrangements, and ring closure processes is initiated which finally leads via 17 and 18 to novel highly substituted guanidines 9, 10, 12, and 13. Pathway b seems to be the result of well-balanced negative-hyperconjugative effects in 14 and/or 17 which control the highly selective opening of a relatively stable central 1,3,5-triazinium ring to yield the crucial intermediate 18. Some representatives of the guanidines have been characterized by X-ray analyses. Since some of the guanidines contain one or two chirality centers, an effort was made to investigate the stereochemistry of these compounds.

Full text of DOI:10.1021/jo001016a

720
J . Org. Chem. 2001, 66, 720-726
Bis(1,3,4-th ia d ia zolo)-1,3,5-tr ia zin iu m Ha lid es. 2.† In tr a m olecu la r
Rin g Tr a n sfor m a tion a n d Syn th esis of Novel High ly Su bstitu ted
Gu a n id in es|
Kurt Wermann,‡ Martin Walther,‡ Wolfgang Gu¨nther,‡ Helmar Go¨rls,§ and Ernst Anders*,‡
Institut fu¨r Organische Chemie und Makromolekulare Chemie der Friedrich-Schiller-Universita¨t,
Humboldtstrasse10, D-07743 J ena, Germany, and Institut fu¨r Anorganische und Analytische Chemie der
Friedrich-Schiller-Universita¨t, Lessingstrasse 8, D-07743 J ena, Germany
c5eran@rz.uni-jena.de.
Received J uly 6, 2000
Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides 6 can be easily attacked by nucleophiles at either
the C(3a) or the C(4a) position of the central six-membered (cationic) ring. Nucleophilic attack
leads to at least two reaction channels, one of which has been previously detected (pathway a) and
leads to novel aminals 19. In this paper we report on a second channel (pathway b). Attack of
primary or secondary amines 8 at C(3a) or C(4a) in 6 (and their analogues 7) leads to the weakly
stabilized intermediates 14. A cascade of several proton shifts, ring openings, rearrangements,
and ring closure processes is initiated which finally leads via 17 and 18 to novel highly substituted
guanidines 9, 10, 12, and 13. Pathway b seems to be the result of well-balanced negative-
hyperconjugative effects in 14 and/or 17 which control the highly selective opening of a relatively
stable central 1,3,5-triazinium ring to yield the crucial intermediate 18. Some representatives of
the guanidines have been characterized by X-ray analyses. Since some of the guanidines contain
one or two chirality centers, an effort was made to investigate the stereochemistry of these
compounds.
In tr od u ction
R1 ) CH3, R2 ) H; qC3a ) qC4a ) +0.40 e; HF/6-31G* opt.
+0.25 e; B3LYP/6-31G* opt.). All previously performed
as well as our ongoing studies demonstrate that the
instability of the initial intermediates 14 (Scheme 5)
shouldsdepending on the properties of the incoming
nucleophile 8sopen surprising reaction channels in ad-
dition to the “5/6/5 to aminal” transformation. We report
here on experimental investigations which support this
assumption since we succeeded in finding a novel pro-
cedure for the preparation of highly substituted guanidines
9, 10, 12, and 13 (Schemes 2-4).
All of the intermediate ring opening/ring closure reac-
tions are determined by the influence of well-balanced
stereoelectronic effects. Furthermore, reaction pathway
b for compounds 6 (or the benzofused derivatives 7) with
aliphatic amines are the first examples of a novel
heterocyclic ring transformation via an unexpected re-
arrangement process.
In the course of a three-component reaction of an
aldehyde 1, a thionyl halide 2 and a variety of hetarenes
(pyridine and pyridine derivatives, methylimidazole,
quinolines etc.), N-(1-haloalkyl)pyridinium halides 31,2
are readily accessible. As recently reported, these salts
3 react with 2-amino-1,3,4-thiadiazoles 4 to yield the
novel cationic 5/6/5-heterocycles, the bis(1,3,4-thiadia-
zolo)-1,3,5-triazinium halides 61,3 (Scheme 1). The prod-
ucts 6 are generated with almost 80% yields in the course
of a multistep cascade reaction of 3 with the heterocycles
4. The 5/6/5-heterocycles 6 can be transformed into novel
bis(thiadiazolyl)alkanes (“aminals”, Scheme 5)3 by em-
ploying an excess of 4 and slightly varying the reaction
conditions. This reaction indicates that both centers C(3a)
and C(4a) (Scheme 1) are suitable for nucleophilic reac-
tions which, in the case of 4a , yields the aminals via
another multistep reaction under extrusion of pyridine
and the corresponding ammonium halide. This assump-
tion is supported by calculating the charges at these
centers. Both ab initio and DFT-methods4-6 predict these
centers to be significantly positively charged (results of
natural population analyses7 for the model cation of 6:
Guanidines represent one of the most extensively
investigated class of carbonic acid derivatives.8 The
(4) GAUSSIAN 98, Revision A.5, Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.;
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* To whom correspondence should be addressed. Fax: +49(0)3641/
948212.
† Part 1: Reference 3.
‡ Institut fu¨r Organische Chemie und Makromolekulare Chemie.
§ Institut fu¨r Anorganische und Analytische Chemie.
| Dedicated to Professor Ernst-Gottfried J a¨ger (J ena, Germany) on
the occasion of his 65th birthday.
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10.1021/jo001016a CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/09/2001

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium Halides
J . Org. Chem., Vol. 66, No. 3, 2001 721
Sch em e 1. “5/6/5” Ha logen id es 6 a n d 7 fr om N-(1-Ha loa lk yl)p yr id in iu m Sa lts 3 a n d Heter ocyclic
Com p ou n d s 4 a n d 5
various synthetic procedures which yield such compounds
employ amines and various carbonic acid derivatives as
reactants.9 However, only a few guanidines, in which A,
B, and C represent nitrogen heterocycles, have been
reported (Figure 1). Such compounds were prepared, for
example, from appropriate dithiocarbonimidates and
corresponding heterocyclic amines,10 or from halo sub-
stituted heterocycles and guanidines, or from amino
heterocycles and isothioureas.11
Resu lts a n d Discu ssion
Starting from N-(1-haloalkyl)pyridinium halides 3 and
aminothiadiazoles 4, the bis[1,3,4-]thiadiazolo[3,2-a: 3′,2′-
d]-[1,3,5]-triazin-8-ium halides 6 were synthesized1,3
(Scheme 1). Salts 3 were prepared from a 1:1:1 molar
(8) Ku¨hle E. Methoden Org. Chem. (Houben-Weyl), Vol. E4, 4th ed.;
Georg-Thieme-Verlag: Stuttgart, New York, 1983; p 608.
(9) Ried, W.; Woithe, H. Helv. Chim. Acta 1989, 72, 1860. Ried, W.;
Ku¨mbel, B.; Tauer, M.-L. Liebigs Ann. Chem. 1984, 564. Ried, W.; Erle,
H.-E. Chem. Ber. 1979, 112, 640. W. Ried, R. Christ, Liebigs Ann.
F igu r e 1. Heterocyclic moieties of previously prepared
Chem. 1980, 699. Ried, W.; Kothe, N. Chem. Ber. 1976, 109, 2706. Ried,
W.; Kothe, N.; Merkel, W. Chem. Ber. 1975, 108, 181. Liebscher, J .;
Mitzner, E.; Radies, U.; Klempke, S. Z. Chem. 1985, 25, 362. Rasmus-
sen, C. R.; Villani, J r., F. J .; Reynolds, B. E.; Plampin, J . N.; Hood, A.
R.;. Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J .; Howse,
J r., R.; Molinari, M. A. J . Synthesis 1988, 460. Schramm, H. W.;
Schubert - Zsilavecz, M.; Saracoglu, A. J .; Kratky, Ch. Monatsh. Chem.
1991, 122, 1063. Bansfield, J . E. J . Chem. Soc. 1960, 2108. LaMattina,
J . L.; McCarthy, P. A.; Reiter, L. A.; Holt, W. F.; Yeh, L.-A. J . Med.
Chem. 1990, 33, 543. Quintela, J . M.; Alvarez-Serandes, R.; Carmen,
M.; Peinador, C. Heterocycles 1997, 45, 1319. Quintela, J . M.; Peinador,
C.; Botana, L.; Estevez, M.; Riguera, R. Bioorg. Med. Chem. 1997, 5,
1543. Rasmussen, C. R. Ger. Offen. 2,711,757, 1977. Chem. Abstr. 1978,
88, 37603s. Hough, T. L.; J ones, G. P. J . Heterocycl. Chem. 1984, 21,
1377. Abraham, W.; Barnikow, G. Tetrahedron 1973, 29, 691. Mazum-
dar, S. N.; Mahajan, M. P. Tetrahedron 1991, 47, 1473. Turner, S.;
Myers, M.; Gadie, B.; Hale, S. A.; Horsley, A.; Nelson, A. J .; Pape, R.;
Saville, J . F.; Doxey, J . C.; Berridge, T. L. J . Med. Chem. 1988, 31,
906. Kantlehner, W.; Haug, E.; Mergen, W. W.; Speh, P.; Maier, T.;
Kapassakalidis, J . J .; Bra¨uner, H.-J .; Hagen, H. Liebigs Ann. Chem.
1984, 108. J ochims, J . C.; Abu-El-Halawa, R.; Zsolnai, L.; Huttner, G.
Chem. Ber. 1984, 117, 1161. Mull, R. P.; Egbert, M. E.; Dapero, M. R.
J . Org. Chem. 1960, 25, 1953.
guanidines, cf. refs 10, 11.
ratio of reactants 1, 2, and pyridine. For the synthesis of
3b (which has not yet been described in the literature),
the presence of 2 equivof 2a is required due to the
presence of an reactive OH group in the aldehyde
component. The regeneration of the OH function was
performed by methanolysis. The molecular structure of
3b was studied by X-ray analysis,12 it is structurally quite
similar to the corresponding methoxy derivative 3f13
when one compares the most important bond lengths and
bond angles. The 5/6/5 heterocycles 6b, e, and f were
obtained in yields up to 82% by procedures analogous to
those described previously for 6a , c, d , and g.3 The novel
bis-benzothiazolo-1,3,5-triazinium bromides 7a -d were
(12) Crystallographic data (excluding structure factors) for the
structures 3b, 9a , 9n , and 12a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos. CCDC
146230 (3b), 146150 (9a ), 146149 (9n ), 146151 (12a , racem.), 146152
(12a , meso). Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (Fax:
(+44)1223-336-033; E-mail: deposite@ccdc.cam.ac.uk).
(10) Bogdanowicz-Szwed, K.; Krasodomska, M. Monatsh. Chem.
1996, 12, 1273. Otto-J aworska, T. Acta Pol. Pharm. 1992, 49, 77. Chem.
Abstr. 1994, 120, 323173. Mizuyama, K.; Tominaga, Y.; Matsuda, Y.;
Kobayashi, G. Chem. Pharm. Bull. 1979, 27, 2879. Merkel, W.; Ried,
W. Chem. Ber. 1973, 106, 471. Kodoma et al. Yuki Gosei Kagaku
Kyokaishi 1964, 22, 749. Chem. Abstr. 1964, 61, 12002h.
(11) Reuter, W.; Alexander,A. Ger. Offen. 1,944,049, 1971; Chem.
Abstr. 1971, 74, 141758.
(13) Kataeva, O. N.; Litvinov, I. A.; Kataev, V. E.; Vanden Eynde,
J .-J .; Mayence, A.; Anders, E. Mol. Struct. 1998, 442, 55.

722 J . Org. Chem., Vol. 66, No. 3, 2001
Wermann et al.
Sch em e 2. Gu a n id in es 9 fr om th e Th ia d ia zolo “5/6/5” Sa lts 6 a n d P r im a r y a n d Secon d a r y Am in es 8
Sch em e 3. Ben zo-F u sed Exa m p les: Gu a n id in es
10 fr om th e Ben zoth ia zolo “5/6/5” Sa lt 7a a n d
P r im a r y a n d Secon d a r y Am in es 8
Sch em e 4 Bis-gu a n id in es (12, 13) fr om 6 or 7a a n d
P ip er a zin e
analogously synthesized by the cyclization reaction of
1,1′-[(4-methoxyphenyl)methylene]-bis-pyridinium dibro-
mide3 with 2-aminobenzothiazoles 5a -c (ca. 40% yield)
and were characterized by NMR, MS, UV spectra, and
elemental analyses. The potential of our 5/6/5 heterocycle
synthesis is, thus, not restricted to the sole use of
aminothiadiazoles 4. Interestingly enough, these com-
pounds 7 possess intensive fluorescence properties.
Whereas the reaction of 6 with an amine 4 yields the
compound 19 (pathway a, Scheme 5), a complete different
reaction pathway b for 6 (and 7) was observed after
exchanging 4 for primary and secondary amines 8 or 11.
The novel guanidines 9 (from 6a -f, Scheme 2), 10 (from
7a , Scheme 3), 12 (from 6a -e, Scheme 4), and 13 (from
7a , Scheme 4), could be obtained with very good yields.
The best results (9a -p , 10a -d , 12a -e, and 13: 80-
90%) are obtained in pyridine solution at room temper-
ature and employing 2 equiv of the amines 8a -f.14 The
excess of amine is required to bind the HX formed in the
course of the reaction.
transformed in the course of the reaction into the
exocyclic C(1) of the guanidine unit. This transformation
causes a shift in the 13C signals toward higher fields (ca.
15 ppm) as compared with the parent compounds 6 and
7. The reaction causes a similar shift toward higher fields
for the HC(9) and C(9) (1H ≈ 1 ppm; 13C ≈ 7 ppm) since
C(9) in the cationic system has been converted into the
C(2) atom of the new dihydrothiadiazole ring. All of the
1H and 13C NMR signals of the rearrangement products
have been unambiguously assigned to the dihydrothia-
diazole, the aromatic thiadiazole ring, and guanidine unit
via HMQC, HMBC, COSY, TOCSY, and NOESY correla-
tions. These spectra are in agreement with the postulated
structures (cf. Supporting Information). Noteworthy is
an NOE experiment on compound 9a which shows a
correlation between the HC(2) signal of the dihydrothia-
diazole ring (δ ) 6.91) and the HC(2′) (or HC(6′)) protons
of the piperidyl moiety (δ ) 3.02/3.23). In addition, a
correlation is observed between the HC(2′′)/HC(6′′) pro-
Str u ctu r a l Assign m en ts. Structural assignments of
the guanidines 9, 10, 12, and 13 were based on NMR
data, mass spectra (CI), IR spectra (ATR), and elemental
analyses. As already mentioned, the cyclic carbon atom
(C(3a) or C(4a)) that undergoes nucleophilic attack is
(14) The reaction can be also proceed with one equivalent amine
and triethylamine as solvent.

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium Halides
J . Org. Chem., Vol. 66, No. 3, 2001 723
F igu r e 2. NOE correlations in the guanidine 9a .
F igu r e 4. 1H NMR investigation of 9a (racemate; 30 mg,
0.074 mmol, in CDCl3); shift reagent: (S)-(+)2,2,2-trifluoro-
1-(9-anthryl)ethanol. (a) without shift reagent; (b) addition of
0.036 mmol; (c) addition of (total) 0.072 mmol.
F igu r e 3. Crystal structure of the (R,S) meso isomer of 12a ,
a representative of the novel guanidines. For further crystal
structures cf. Supporting Information. Selected bond lengths
[pm] and bond angles [deg]: C(1)-N(1) 138.6(3), C(1)-N(3)
130.6(3), C(1)-N(6) 136.7(3), C(2)-N(1) 149.1(3), C(2)-S(1)
183.8(3), C(5)-N(3) 137.3(3), C(5)-S(2) 176.0(3), C(3)-N(2)
128.5(3); N(1)-C(1)-N(3) 116.1(2), N(1)-C(1)-N(6) 116.8(2),
N(3)-C(1)-N(6) 127.1(2), N(1)-C(2)-H(2) 108.7(18), C(8)-
C(2)-H(2) 109.7(18), N(1)-C(2)-S(1) 102.56(18), C(8)-C(2)-
S(1) 112.26(19), N(1)-C(2)-C(8) 113.4(2), S(1)-C(2)-H(2)
110.0(18).
achiral diastereomer (the meso isomer, Figure 3) which
possesses an inversion center.
Furthermore, it is noteworthy that this rearrangement
gives rise to a new chiral center at the 2,3-dihydro-
thiadiazole ring. As expected, the products 9 and 10 were
obtained as racemic mixtures. This was confirmed by the
analysis of the 1H NMR spectra of 9a obtained in the
presence of the shift reagent (S)-(+)-2,2,2-trifluoro-1-(9-
anthryl)ethanol.15 For example, the Me signals both of
the dihydrothiadiazole unit at 2.21 and the 4-tolyl Me at
2.27, and the Me group of the aromatic thiadiazole ring
at 2.53 ppm, show a significant shift toward higher fields
after addition of the above-mentioned reagent (Figure 4).
If R1 is a butyl group (9i, 9j, 9o), the protons in the
methylene group in the neighborhood of the new chiral
center are diastereotopic. Compounds 12 and 13 contain
two chiral centers. In the case of 12a , the corresponding
racemic mixture and the meso structures could be easily
isolated by crystallization from MeOH.
Som e Mech a n istic Con sid er a tion s. The overall
results of these reactions can be summarized as follows:
The attack of amine nitrogen occurs, as expected, at the
electrophilic carbon atom C(3a) or C(4a) which initiates
an unexpected reaction cascade. The most important
steps are the cleavage of both the S(5)-C(4a) bond in the
thiadiazole and of the C(9)-N(10) bond in the triazinium
ring. This initiates an interesting rearrangement. The
sp3-C(9) atom in the triazinium system becomes a sp3-
center in the newly formed 2,3-dihydro-thiadiazole ring
in the course of the cascade whereas C(9)-N(10) bond
cleavage leads to the final guanidine moiety (Schemes
2-4). The C(4a) ring atom of the 5/6/5 cation becomes
the central guanidine C atom which also bears the NR4R5
moiety of the (former) nucleophilic primary and or
secondary amine component. This rearrangement process
tons of the phenyl group (δ ) 7.18 ppm) with the same
piperidyl protons (Figure 2).
These findings indicate that, in solution, the NR4R5
moiety (cf. Scheme 2) of the original nucleophile and the
substituent at C(2) of the newly generated dihydrothia-
diazole ring can approach each other due to relatively
unhindered rotations around the corresponding C-N
bonds. Steric effects apparently do not play an important
role.
The structures of compounds 9a , 9n , and 12a (racemic
mixtures and the meso compound) were confirmed by
X-ray analyses (Figure 3, vide infra, and Figures 5 - 7,
cf. Supporting Information). The arrangement of the
aromatic thiadiazole and the dihydrothiadiazole ring
shows the expected E-stereochemistry at the imine
double bond. Important bond lengths and bond angles
are in agreement with the expected properties of a
guanidine unit which has been substituted by moieties
stemming from the nucleophiles 8 and 11. These data
show the existence of an unconjugated (shorter) C ) N
bond (≈128 pm) and a somewhat longer CdN bond (≈131
pm) which conjugates with the heteroaromatic ring Cd
N bonds. This corresponds, for example, with the IR
spectrum of 9a which shows a sharp absorption signal
(1573 cm-1) due to the guanidine CdN bond and a
weaker absorption peak (1614 cm-1) due to the isolated
dihydrothiadiazole CdN bond. Significant differences in
bond lengths and angles are not observed in the guani-
dine structure moieties of 9a , 9n , and 12a . The racemic
12a (Figure 7, cf. Supporting Information) possesses C2v
symmetry in the solid state. This contrasts with the
(15) Pirkle, W. H.; Sikkenga, D. L.; Pavlin, M. S. J . Org. Chem. 1977,
42, 382.

724 J . Org. Chem., Vol. 66, No. 3, 2001
Wermann et al.
Sch em e 5. P r op osed Rea ction P a th w a ys a a n d b
for th e Tr a n sfor m a tion of 6 or 7 by Nu cleop h ilic
Atta ck of Am in es a t th e C(4a ) P osition
completely destroys the central 1,3,5-triazinium ring of
6 and 7.
It is difficult to find at least slightly analogous re-
arrangement reactions in the literature.16-20 For example,
our results cannot be directly compared with either the
classical Dimroth-16 or with the related Angeli-rearrange-
ment21 or with other so-called “ring-degenerate rearrage-
ments” of heterocylic systems.18
On the basis of initial calculations (vide supra) and the
knowledge of the final structures (compounds 9, 10, 12
and 13), the key step in the reaction sequence is most
probably an equilibrium reaction resulting from the
nucleophilic attack of the primary or secondary amine
at the most electrophilic ring position (C(3a) and C(4a))
under formation of a very weakly stabilized intermediate
14 (Scheme 5).
This structure is of interest since the C(4a) atom
involved is surrounded by four heteroatoms (three dif-
ferent nitrogens and a sulfur) and might therefore open
a variety of different reaction channels. Most importantly,
the ammonium (N(+)HR4R5) moiety in 14 is situated in
the neighborhood of several internal proton acceptors, i.e.,
at least two nitrogens and the sulfur center. We believe
that the following mechanistic considerations are plau-
sible: A proton shift resulting in 15 or 17 (other pos-
sibilities are conceivable) allows the delocalization of the
lone pair (n) of the exocyclic N atom into the antibonding
C-NH or C-SH bonding orbital (σC-NH* or σC-SH*). This
negative hyperconjugation causes a lengthening (weak-
ening) of the C-NH or C-SH and a shortening (strength-
ening) of the exocyclic N-C bond.22 Further progress of
the reaction, i.e., the preferential formation of 16 or 18,
then depends on the well-balanced stereoelectronic prop-
erties of these structures and their relative amounts in
several equilibrium reactions. Weakening of the cyclic
C-N+ bond will cause the dihydrotriazinium ring to open,
yielding 16, the precursor of the so-called “aminals” 19.
This route has already been detected.3 Although the
basicity of the nitrogen N(4) is presumably significantly
higher than that of the sulfur atom S(5), formation of a
small amount of 17 (resulting from an equilibrium
between 15 and 17) could induce the second reaction
channel, i.e., the opening of the fused thiadiazole ring to
yield 18.23 The N atom of the C(9)-N(10) bond in 18 is
part of a conjugated [-N(10)-C(3a)-N(4)-C(4a)-NR4R5]+-
cationic moiety. Nucleophilic attack of the sulfur center
of 18 (probably after deprotonation of the SH group thus
creating a more nucleophilic thiolate) and the displace-
ment of the uncharged N(10)-C(3a)-N(4)-C(4a)-NR4R5-
moiety (which is part of a heteroaromatic ring and is
therefore an excellent leaving group)24 causes the forma-
tion of the dihydrothiadiazole ring and finally the gen-
eration of the guanidine structures. Interestingly enough,
the overall reaction can be understood as a novel example
of an SN(ANRORC) mechanism.25
(16) Wahren, M. Z. Chem. 1969, 9, 241. Fischer, G. In Advances in
Heterocyclic Chemistry; Katritzky, A. R.; Boulton, A.-J ., Eds.; Academic
Press: NewYork, 1993; Vol. 57, pp 94. Sandstro¨m, J . In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Boulton, A.-J ., Eds.; Academic
Press: NewYork, 1968; Vol. 9, p 194. Gilchrist, T. L.; Gymer, G. E. In
Advances in Heterocyclic Chemistry; Katritzky, A. R.; Boulton, A.-J .,
Eds.; Academic Press: NewYork, 1974; Vol. 16, p 78.
(17) Ruccia, M.; Vivona, N.; Spinelle, D. In Advances in Heterocyclic
Chemistry; Katritzky, A. R.; Boulton, A.-J ., Eds.; Academic Press:
NewYork, 1981; Vol. 29, p 142. Vivona, N.; Buscemi, S.; Frenna, V.;
Cusmano, G. In Advances in Heterocyclic Chemistry; Katritzky, A. R.;
Boulton, A.-J ., Eds.; Academic Press: NewYork, 1993; Vol. 56, p 49.
(18) L’abbe’, G.; Dekerk, J .-P.; Deketele, M. J . Chem. Soc., Chem.
Commun. 1983, 588. L’abbe’, G. J . Heterocycl. Chem. 1984, 24, 627.
L’abbe’, G.; D’hooge, B.; Dehaen, W. Molecules 1996, 190.
(19) van der Plas, H. C.; J ongejan, H. Tetrahedron Lett. 1967, 4385.
Hetzheim, A.; Ko¨hler, G.; Beyer, H. Z. Chem. 1967, 7, 186.
(20) Bakulev, V. A.; Tarasov, E. V.; Morzherin, Y. Y.; Luyten, I.;
Toppet, S.; Dehaen, W. Tetrahedron 1998, 54, 8501.
Some mechanistic questions remain open, for example,
whether a fast initial deprotonation of 14 yielding an
(21) Angeli, A. Ber. 1892, 25, 1956. Boulton, A. J .; Coe, D. E.;
Tsoungas, P. S. Gazz. Chim. Ital. 1981, 111, 167. Boulton, A. J . Bull.
Chim. Belg. 1981, 90, 645.
(22) Nordhoff, K.; Anders, E. J . Org. Chem. 1999, 64, 7485. J uaristi,
E.; Introduction to Stereochemistry and Conformational Analysis; J ohn
Wiley & Sons: New York, 1991; Chapter 17, p 286. Deslongchamps,
P. Stereoelectronic Effects in Organic Chemistry; Pergamon Press:
Oxford, 1984.
(23) Cf. the Curtin-Hammet Priciple: Curtin, D. Y., Rec. Chem. Prog.
1954, 15, 111. Eliel, E. L. Stereochemistry of Carbon Compounds;
McGraw-Hill Book Co.: NewYork, 1962; pp 151, 152, 237, 238. Seeman,
J . I., Chem. Rev. 1983, 83, 83.
(24) The C(9)-N(10) bond of the dihydrotriazinium ring is generally
subjected to ring cleavages under the influence of nucleophilic reagents,
cf. Grundmann, Ch. Angew. Chem. 1963, 75, 393. van der Plas, H. C.
Lect. Heterocycl. Chem. 1982, 6, S-1.

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium Halides
J . Org. Chem., Vol. 66, No. 3, 2001 725
13H-3,9-Dim eth oxy-13-(4-m eth oxyph en yl)-bis-ben zoth i-
a zolo[3,2-a :3′,2′-d ]-[1,3,5]tr ia - zin -12-iu m br om id e (7c):
39% from 3g and 5c, mp 266 °C (dec).
13H -3-Met h yl-9-m et h oxy-13-(4-m et h oxyp h en yl)-b is-
b en zot h ia zolo[3,2-a :3′,2′-d ]-[1,3, 5]t r ia zin -12-iu m b r o-
m id e (7d ): 22% from 3g, 5b, and 5c, together with 7b (ca.
10%) and 7c (ca. 10%) separated by crystallization, mp 253
°C (dec).
uncharged reactive carbon center with four heteroatoms
dominates the reaction pathway. High level ab initio and
DFT calculations under inclusion of solvent effects as well
as further detailed experimental mechanistic studies
addressing this questions are presently underway.
Con clu sion
Gen er a l P r oced u r e for th e Syn th esis of Gu a n id in es
9, 10, 12, a n d 13 fr om 5/6/5-Heter ocycles (6 or 7) a n d
Am in es (8 or 11). To a stirred suspension of 5 mmol of 6 or
7 in pyridine (60 mL)26 was added 10.1 mmol of 8a -f or 11 at
room temperature. After stirring of this mixture at room
temperature (24 h), the nearly clear solution was concd to
dryness under vacuum. From the residue the amine HX
byproduct and some pyridine were washed off with water. The
solid products were recrystallized from MeOH/tert-butyl meth-
yl ether. Oily products were dissolved in CHCl3 and purified
by column chromatography (silica gel 60, 0.063-0.2 mm, ethyl
acetate).
(E)-1-[(5-Met h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(4-
m eth ylp h en yl)-5-m eth yl-1,3,4-th ia d ia zol-3-yl]m eth ylp i-
p er id in e (9a ): 85%, mp 142-143 °C.
(E)-4-[(5-Met h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(4-
m eth ylph en yl)-5-m eth yl-1,3,4-th iadiazol-3-yl]m eth ylm or -
p h olin e (9b): 68%, mp 84 °C.
(E)-1-[(5-Met h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(4-
m eth ylp h en yl)-5-m eth yl-1,3,4-th ia d ia zol-3-yl]m eth ylp yr -
r olid in e (9c): 70%; 83% (rough), mp 74 °C (dec); 9c •2 HBF4
salt mp 135 °C (dec).
(E)-[(5-Meth yl-1,3,4-th iadiazol-2-yl)im in o]-[2H-2-(4-m eth -
ylphenyl)-5-methyl-1,3,4-thiadiazol-3-yl]methyl-diethylamine
(9d ): 70%, oil.
(E)-1-[(5-Met h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(2-
h ydr oxyph en yl)-5-m eth yl-1,3,4-th iadiazol-3-yl]m eth ylpyr -
r olid in e (9e): 87%, mp 148 °C.
(E)-4-[(5-Met h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(2-
h yd r oxyp h en yl)-5m et h yl-1,3,4-t h ia d ia zol-3-yl]m et h yl-
m or p h olin e (9f): 85%, mp 124 °C.
(E)-1-[(5-Met h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(1-
n a p h t h yl)-5-m et h yl-1,3,4-t h ia d ia zol-3-yl]m et h ylp ip er i-
d in e (9g): 68%, mp 149-150 °C.
(E)-4-[(5-Met h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(1-
n a p h th yl)-5-m eth yl-1,3,4-th ia d ia zol-3-yl]m eth ylm or p h o-
lin e (9h ): 90%, mp 152-153 °C.
(E)-1-[(5-Met h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(1-
bu tyl)-5-m eth yl-1,3,4-th iadiazol-3-yl]m eth ylpiper idin e (9i):
95%, oil.
(E)-4-[(5-Met h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(1-
bu tyl)-5-m eth yl-1,3,4-th ia d ia - zol-3-yl]m eth ylm or p h olin e
(9j): 90%, oil.
(E)-1-[(5-Eth yl-1,3,4-th ia d ia zol-2-yl)im in o]-[2H-2-(2-h y-
d r oxyp h en yl)-5-eth yl-1,3,4-th ia d ia zol-3-yl]m eth ylp yr r o-
lid in e (9k ): 84%, mp 127 °C.
(E)-4-[(5-Eth yl-1,3,4-th ia d ia zol-2-yl)im in o]-[2H-2-(2-h y-
d r oxyp h en yl)-5-et h yl-1,3,4-t h ia d ia zol-3-yl]m et h ylm or -
p h olin e (9l): 89%, mp 144 °C (dec).
(E)-[(5-Meth yl-1,3,4-th iadiazol-2-yl)im in o]-[2H-2-(4-m eth -
ylphenyl)-5-methyl-1,3,4-thiadiazol-3-yl]methyl-butylamine
(9m ): 74%, mp 97 °C.
(E )-[(5-Me t h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(1-
n a p h t h yl)-5m et h yl-1,3,4-t h ia d ia zol-3-yl]m et h yl-b u t yl-
a m in e (9n ): 77%, mp 134-135 °C.
The new tricyclic bis(1,3,4-thiadiazolo)-1,3,5-dihydro-
triazinium halides 6 and their analogues 7 are suitable
precursors for the synthesis of novel guanidine deriva-
tives. In this investigation we concentrated on the
reaction behavior of some primary and secondary ali-
phatic amines 8 and 11 with 6 and 7. The initial attack
of nucleophiles at the C(3a) or C(4a) positions of the fused
5/6/5 heterocyclic cations are, with great certainty, not
restricted to such nucleophiles. A manifold of further
interesting structures resulting from 6 (and 7) after
reaction with carbon, phosphorus, or sulfur nucleophiles
appears to be accessible. Theoretical ab initio and DFT
investigations will allow the estimation and control of the
structural and electronic properties of the crucial inter-
mediates which determine the alternative reaction path-
ways a and b.
Exp er im en ta l Section
Gen er a l Meth od s. Cf. Supporting Information.
1-[Ch lor o-(2-h yd r oxyp h en yl)m eth yl]p yr id in iu m Ch lo-
r id e (3b). To a stirred solution of 0.2 mol of 2a in MeCN (150
mL) was added 0.2 mol of pyridine under an atmosphere of
argon at 0 °C followed by aldehyde 1g (0.1 mol). The mixture
was kept at 0 °C for 1 h and then allowed to warm to room
temperature. After cooling to 0 °C, again 0.1 mol of MeOH
was added. After heating to room temperature, the solution
was concd under vacuum to 1/3 of its initial volume. The
crystallization of the product 3b was completed at 4 °C and
then filtered off. The so separated crystalline pyridinium salt
3b was pure enough for the further reactions. 68%, mp 169-
172 °C.
Bis[1,3,4]th ia d ia zolo[3,2-a :3′,2′-d ]-[1,3,5]tr ia zin iu m h a -
lid es 6 a n d 7 were prepared in MeCN from salts 3 and the
heterocyclic compounds 4 and 5 according to the procedure
reported in the literature.3
9H -2,6-Dim et h yl-9-(2-h yd r oxyp h en yl)-b is-[1,3,4]t h ia -
d ia zolo[3,2-a :3′,2′-d ]-[1,3,5] tr ia zin -8-iu m Ch lor id e (6b).
Heating 3b and 4a for only 5 h at 75 °C and washing the
crystalline product with a little amount cold water yields 6b:
72%, mp 214 °C.
9H-2,6-Dieth yl-9-(2-h yd r oxyp h en yl)-bis-[1,3,4]th ia d ia -
zolo[3,2-a :3′,2′-d ]-[1,3,5]tr ia zin -8-iu m ch lor id e (6e): analo-
gous to 6b from 3e and 4b. The solvent was removed
completely under vacuum after the reaction time of 5 h. The
solid residue was extracted with CHCl3. The CHCl3 solution
was concentrated in the rotary evaporator to 1/3 of its volume.
6e, which crystallizes from that solution within 12 h at 4 °C,
was filtered off and dried under vacuum at room tempera-
ture: 82%, mp 182 °C.
9H -2,6-Dim et h yl-9-(2-m et h oxyp h en yl)-b is-[1,3,4]t h ia -
diazolo[3,2-a :3′,2′-d]-[1,3,5]tr iazin -8-iu m ch lor ide (6f): 47%
from 6f and 4a , mp 208-211 °C.
13H-13-(4-Meth oxyph en yl)-bis-ben zoth iazolo[3,2-a :3′,2′-
d ]-[1,3,5]tr ia zin -12-iu m br om id e (7a ): 43% from 3g and 5a ,
mp 288 °C (dec).
(E)-[(5-Meth yl-1,3,4-th ia d ia zol-2-yl)im in o]-[2H-2-(1-bu -
tyl)-5-m eth yl-1,3,4-th iadiazol-3-yl]m eth yl-bu tylam in e (9o):
80%, oil.
(E)-[(5-E t h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-[2H -2-(2-h y-
d r oxyp h en yl)-5-eth yl-1,3,4-th ia d ia zol-3-yl]m eth yl-(2-p y-
r id in -2-yl-eth yl)a m in e (9p ): 81%, mp 150 °C.
13H-3,9-Dim eth yl-13-(4-m eth oxyp h en yl)-bis-ben zoth i-
a zolo[3,2-a :3′,2′-d ]-[1,3,5]tr ia z-in -12-iu m br om id e (7b):
37% from 3g and 5b, mp 264 °C (dec).
(25) Van der Plas, H. C.; de Valk, J . Rec. Trav. Chim. 1972, 91, 1414.
Van der Plas, H. C. Acc. Chem. Res. 1978, 11, 462. Van der Olas, H.
C. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.;
Academic Press: New York, 1999; Vol. 74, p 1.
(26) Instead of pyridine, triethylamine, THF, and tert-butyl methyl
ether can be used as solvents as well.

726 J . Org. Chem., Vol. 66, No. 3, 2001
Wermann et al.
(E)-1-[(Ben zoth iazol-2-yl)im in o]-[2H-2-(4-m eth oxyph en -
yl)ben zoth ia zol-3-yl]m eth yl-p ip er id in e (10a ): 90%, mp
147-149 °C.
(E)-4-[(Ben zoth iazol-2-yl)im in o]-[2H-2-(4-m eth oxyph en -
yl)ben zoth ia zol-3-yl]m eth yl-m or p h olin e (10b): 91%, mp
176 °C.
(E)-1-[(Ben zoth iazol-2-yl)im in o]-[2H-2-(4-m eth oxyph en -
yl)ben zoth ia zol-3-yl]m eth yl-p yr r olid in e (10c): 90%, mp
177-180 °C (dec).
(E,E)-1,4-Bis-[[(5-m et h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-
[2H-2-(2-m eth oxyp h en yl)-5-m eth yl-1,3,4-th ia d ia zol-3-yl]-
m eth ylp ip er a zin e (12e): 82%, mp 178-180 °C (isomeric
mixture).
(E,E)-1,4-Bis[(Ben zoth ia zol-2-yl)im in o]-[2H-2-(4-m eth -
oxyph en yl)ben zoth iazol-3-yl] m eth ylpiper azin e (13): 90%,
mp 237 °C (isomeric mixture).
Ack n ow led gm en t. Financial support by the Deut-
sche Forschungsgemeinschaft (Sonderforschungsbereich
436), the Fonds der Chemischen Industrie and by the
Thu¨ringer Ministerium fu¨r Wissenschaft, Forschung
und Kultur (Erfurt, Germany) is gratefully acknowl-
edged.
(E)-[(Ben zoth iazol-2-yl)im in o]-[2H-2-(4-m eth oxyph en yl)-
ben zoth iazol-3-yl]m eth yl-(2-pyr idin -2-yl-eth yl)am in e (10d):
86%, mp 90 °C (dec).
(E,E)-1,4-Bis-[[(5-m et h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-
[2H -2-(4-m et h ylp h en yl)-5-m et h yl-1,3,4-t h ia d ia zol-3-yl]-
m eth ylp ip er a zin e (12a ): 79%, mp 192 °C (MeOH) (meso
form 2R,2′S), mp 177 °C (racemic 2R,2′R and 2S,2′S).
(E,E)-1,4-Bis-[[(5-m et h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-
[2H -2-(1-n a p h t h yl)-5m et h yl-1,3,4-t h ia d ia zol-3-yl]m et h -
ylp ip er a zin e (12b): 94%, mp 242 °C (MeOH), (meso form
2R,2′S), mp 157 °C (MeOH), (racemic 2R,2′R and 2S,2′S).
(E,E)-1,4-Bis-[[(5-m et h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-
[2H-2-(1-bu tyl)-5-m eth yl-1,3,4-th ia d ia zol-3-yl]m eth ylp ip -
er a zin e (12c): 88%, mp 108-109 °C (isomeric mixture).
(E,E)-1,4-Bis-[[(5-m et h yl-1,3,4-t h ia d ia zol-2-yl)im in o]-
[2H-2-(2-h yd r oxyp h en yl)-5-m eth yl-1,3,4-th ia d ia zol-3-yl]-
m eth ylp ip er a zin e (12d ): 85%, mp 168-169 °C (isomeric
mixture).
Su p p or tin g In for m a tion Ava ila ble: General methods;
data of 1H NMR, 13C NMR, MS, elemental analyses for the
compounds 3b, 6b, 6e, 6f, 7a -d , 9a -p , 10a -d , 12a -e, 13;
crystal structure determination and crystal data for 9a , 9n ,
12a (R,R)-isomer, 12a ‚2MeOH (meso isomer) as well as the
corresponding crystal structures (Figure 5: 9a ; Figure 6: 9n ;
Figure 7: (R,R)-isomer of 12a ). This material is available free
of charge at http://pubs.acs.org.
J O001016A