Bismuth nitrate pentahydrate: A new and environmentally benign reagent for guanidylation of N-benzoylthioureas

Article abstract of DOI:10.1016/S0040-4039(01)02067-6

The bismuth nitrate-mediated guanidylation of N-benzoylthioureas was studied. This salt proved to be an effective guanylating reagent and allowed the obtention of N-benzoyl-guanidines in good yields. The methodology described is a promising alternative to the use of toxic HgCl₂ in the synthesis of polysubstituted guanidines.

Full text of DOI:10.1016/S0040-4039(01)02067-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 49–52
Bismuth nitrate pentahydrate: a new and environmentally benign
†
reagent for guanidylation of N-benzoylthioureas
Silvio Cunha,* Byanka R. de Lima and Aparecido R. de Souza
Instituto de Qu ´ı mica, Universidade Federal de Goi a´ s, CP 131, Goi aˆ nia, GO 74001-970, Brazil
Received 31 August 2001; revised 30 October 2001; accepted 31 October 2001
Abstract—The bismuth nitrate-mediated guanidylation of N-benzoylthioureas was studied. This salt proved to be an effective
guanylating reagent and allowed the obtention of N-benzoyl-guanidines in good yields. The methodology described is a promising
alternative to the use of toxic HgCl2 in the synthesis of polysubstituted guanidines. © 2001 Elsevier Science Ltd. All rights
reserved.
1
25–35
The broad spectrum of biological proprieties, mainly
out its use as being ecologically friendly.
In addi-
2
medicinal activity, of natural and synthetic guanidine
tion, bismuth derivatives have been widely used in
medicine. Most bismuth salts are commercially avail-
able, inexpensive and easy to handle. Among them,
bismuth nitrate pentahydrate has the extra advantage
of being a crystalline solid insensitive to water and air.
Moreover, to the best of our knowledge, this is the
unique bismuth salt used to date in transformations
involving sulfur-containing compounds as reagents.
3
–5
36
compounds
has motivated the development of new
6–12
methods for guanidine synthesis.
In solution phase
synthesis of this class of compounds, N,N%-bis-Boc-pro-
tected thioureas and S-alkyl isothioureas are starting
materials extensively used when polysubstituted
3
7
1
1,13–20
guanidine is the synthetic goal (Scheme 1).
3
8
In a recent work, one of us described N-benzoyl-
thioureas as being conveniently converted into guanidi-
This communication presents the first successful synthe-
sis of guanidines using Bi(NO ) ·5H O as a guanylating
21
nes with reasonable yields using the HgCl protocol.
2
3 3
2
In fact, HgCl2 has been extensively employed in
reagent for N-benzoylthioureas. Our strategy to test
this salt as a guanylating reagent utilizes the previously
reported acylguanidines 3a–e as model compounds,
Scheme 2. In this way, we can compare the efficiency of
11,13–20
guanidine synthesis.
However, the use of stoichio-
metric amounts of this toxic salt is a serious drawback
if medicinal compounds need be synthesized because
even backgrounds levels of toxic metals are not
desirable.
this method with the HgCl methodology.
2
When a solution of thioureas 1a–e was treated with
equimolar quantities of amines 2a–e in the presence of
Bi(NO ) ·5H O a slow reaction took place and guanidi-
nes 3a–e were observed by TLC and IR, but the
starting thioureas were also present even at prolonged
In a search for safer reagents for guanidylation reaction
of thioureas, the chemistry of bismuth caught our
3
3
2
2
2–24
attention.
Many recent papers describing the use of
bismuth compounds in organic transformation pointed
Scheme 1.
Keywords: bismuth; acylguanidines; thioureas.
*
Corresponding author. Tel.: +55-62-5211008; e-mail: silvio@quimica.ufg.br
Dedicated to Professor Dr. Albert James Kascheres, now retired from Instituto de Qu ´ı mica, Universidade Estadual de Campinas, for his
outstanding contribution to organic chemists’ education in Brazil.
†
0
040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02067-6

5
0
S. Cunha et al. / Tetrahedron Letters 43 (2002) 49–52
Scheme 2.
times. To increase the reaction rate, we used 2 equiv. of
amines in relation to thioureas. With this modification,
the thioureas were consumed and guanidines 3a–e were
mechanistic details of this reaction and define the scope,
limitations and synthetic applications of this new guany-
lating reagent.
isolated in almost the same yields as when HgCl was the
2
guanylating reagent. In addition, the use of triethylamine
proved to be crucial to reaction success, as observed in
The general experimental procedure is as follows: to a
solution of 0.5 mmol of thiourea in 3 mL of DMF was
the HgCl methodology. In its absence the thioureas were
added 1 mmol of amine and 2 mmol of Et N and then
2
3
quantitatively recovered. Also, the best yield was
obtained with thiourea 1e containing an electron with-
drawing substituent and amine 2e containing an electron
releasing one. The results are summarized in Table 1. The
yields were improved and/or reaction times diminished
when the reaction was carried out at 70–90°C (see Table
0.5 mmol of Bi(NO ) ·5H O was added to the solution
3
3
2
with vigorous magnetic stirring and ice-bath cooling. The
suspension became black after a few minutes and was left
stirring at the indicated temperature (see Table 1), while
the progress of the reaction was monitored by TLC.
When thiourea was consumed, 10 mL of CH Cl was
2
2
1). We also attempted the reaction with lower amounts
added and the suspension was filtered through a pad of
Celite. The filtrate was concentrated and the residue (ꢀ3
mL) was dissolved in 15 mL of CH Cl and extracted
of bismuth nitrate. Thus, when N-benzoylthiourea 1a
was treated with amine 2a in the presence of 10 mol%
of Bi(NO ) ·5H O guanidine 3a was not formed, but with
2
2
with water (4×15 mL) and dried over anhydrous MgSO4.
After filtration the solvent was evaporated and the crude
3
3
2
5
0 mol% it was isolated in 54% yield. In this way, the
39
best yields are obtained with stoichiometric amounts of
bismuth nitrate.
residue was treated as indicated in each case.
In
conclusion,
we
have
demonstrated
that
Acknowledgements
Bi(NO ) ·5H O is a novel guanylating reagent of N-ben-
3
3
2
zoylthioureas. Additionally, the yields and spectrum of
guanidines synthesized are comparable with those of the
The authors thank the Brazilian Agency CAPES for a
studentship to B.R.L.
HgCl protocol. Efforts are underway to elucidate the
2
a
Table 1. Isolated guanidine yields produced via Scheme 2

S. Cunha et al. / Tetrahedron Letters 43 (2002) 49–52
51
References
31. Mashraqui, S. H.; Karnik, M. A. Synthesis 1998, 713–
14.
7
1
2
. Hannon, C. L.; Anslyn, E. V. In Bioorganic Chemistry
Frontiers; Dugas, H., Ed.; Springer-Verlag: Berlin,
Heidelberg, 1993; Vol. 3, pp. 193–247.
. Greenhill, J. V.; Lee, L. In Progress in Medicinal Chem-
istry; Ellis, G. P.; Luscombe, D. K., Eds.; Elsevier: New
York, 1993; Vol. 30, pp. 203–326.
32. Laurent-Robert, H.; Garrigues, B.; Dubac, J. Synlett
2000, 1160–1162.
33. Laurent-Robert, H.; Dubac, J. Synlett 1998, 1138–1140.
34. Roux, C. L.; Ciliberti, L.; Laurent-Robert, H.; Dubac, J.
Synlett 1998, 1249–1251.
35. Komatsu, N.; Uda, M.; Suzuki, H. Synlett 1995, 984–
986.
3
4
. Berlinck, R. G. S. Nat. Prod. Rep. 1996, 13, 337–407.
. Berlinck, R. G. S. Fortschr. Chem. Org. Naturst. 1995, 66,
3
3
6. Comprehensive Coordination Chemistry; Wilkinson, G.;
Gillard, R. D.; McCleverty, J. A., Eds.; Pergamon Press:
London, 1987; Vol. 3, pp. 292–313.
7. Kr u¨ ger, J.; Winkler, P.; L u¨ deritz, E.; L u¨ ck, M.; Wolf, H.
V. In Ullman’s Encyclopedia of Industrial Chemistry; Ger-
hartz, W., Ed.; VCH: Weinheim, 1985; Vol. A4, pp.
1
19–295.
5
6
. Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339–365.
. Dodd, D. S.; Zhao, Y. Tetrahedron Lett. 2001, 42, 1259–
1
262.
7
8
9
. Zapf, C. W.; Creighton, C. J.; Tomioka, M.; Goodman,
171–189.
M. Org. Lett. 2001, 3, 1133–1136.
. Ghosh, A. K.; Hol, W. G. J.; Fan, E. J. Org. Chem. 2001,
6
3
3
8. Komatsu, N.; Taniguchi, A.; Uda, M.; Suzuki, H. J.
Chem. Soc., Chem. Commun. 1996, 1847–1848.
9. N1-Di(cyclohexylamino)methylenebenzamide (3a): recrys-
6, 2161–2164.
. Overman, L. E.; Wolfe, J. P. J. Org. Chem. 2001, 66,
167–3175.
0. Tamaki, M.; Han, G.; Hruby, V. J. Org. Chem. 2001, 66,
038–1042.
tallization from ethyl ether/petroleum ether. w
(KBr)
max
3
−
1
1
3
1
3
289, 1605, 1572 cm . l H (CDCl ) 1.19–1.48 (8H, m);
3
1
1
1
1
1
.52–1.70 (4H, m); 1.78–1.80 (4H, m); 1.95–2.15 (4H, m);
.50 (1H, sl); 4.20 (1H, m); 7.37–7.48 (3H, m); 8.21 (2H,
1
1. Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D.
J. Org. Chem. 2000, 65, 1566–1568.
2. Katritzky, A. R.; Rogovoy, B. V.; Chassainy, C.; Vve-
densky, V. J. Org. Chem. 2000, 65, 8080–8082.
13
d, J=7.2 Hz); 10.35 (1H, sl). l C (CDCl ) 24.6 (CH );
3
2
2
5.5 (CH ); 33.1 (CH ); 49.9 (CH ), 127.7 (CH); 128.9
2 2 2
(
CH); 130.7 (CH); 139.2 (C ); 158.3 (C ); 176.9 (C ). MS
0 0 0
+
+
m/z (%): 328 (12) [M +1], 327 (47) [M ], 245 (26),164
3. Srinivasan, N.; Ramadas, K. Tetrahedron Lett. 2001, 42,
(
46), 105 (100), 77 (57). Anal. calcd for C H N O: C,
20 29 3
3
43–346.
7
9
1
3.39%; H, 8.87%; N, 12.84%. Found: C, 73.57%; H,
.01%; N, 13.11%.
-Cyclohexylamino(phenylcarbonylimino)methylamino-4-
4. Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.;
Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2000, 65,
7
774–7778.
5. Isobe, T.; Fukuda, K.; Ishikawa, T. J. Org. Chem. 2000,
5, 7770–7773.
6. Ramadas, K.; Janarthanan, N.; Pritha, R. Synlett 1997,
053–1054.
7. Jeong, J.-H.; Murray, B. W.; Takayama, S.; Wong, C.-H.
J. Am. Chem. Soc. 1996, 118, 4227–4234.
8. Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997,
3, 5291–5304.
9. Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677–
680.
0. Poss, M. A.; Ivanowick, E.; Reid, J. A.; Lin, J.; Gu, Z.
Tetrahedron Lett. 1992, 33, 5933–5936.
1. Cunha, S.; Costa, M. B.; Napolitano, H. B.; Lariucci, C.;
Vencato, I. Tetrahedron 2001, 57, 1671–1675.
2. Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57,
methoxybenzene (3b): recrystallization from ethyl ether/
1
1
1
1
1
2
2
2
2
−
1
1
petroleum ether. wmax (KBr) 3356, 1594, 1570 cm . l H
6
(
(
CDCl ) 1.10–1.26 (3H, m); 1.30–1.51 (2H, m); 1.61–1.73
3H, m); 2.02–2.05 (2H, m); 3.84 (3H, s); 4.14 (1H, l);
3
1
4.64 (1H, sl); 6.95 (2H, d, J=4.8 Hz); 7.19 (2H, d, J=9.0
Hz); 7.40–7.57 (3H, m); 8.26 (2H, d, J=6.6 Hz); 11.86
13
(
1H, sl). l C (CDCl ) 24.6 (CH ); 25.4 (CH ); 33.0
3 2 2
(
CH ); 50,0 (CH); 55.4 (CH ); 115.2 (CH); 127.5 (CH);
2
2
5
1
27.9 (CH); 128.6 (C ); 129.1 (2×CH); 131.1 (CH); 138.9
0
+
(
C ); 158.6 (C ); 177.6 (C ). MS m/z (%): 353 (5) [M +2],
0 0 0
+
7
+
3
52 (29) [M +1], 351 (64) [M ], 269 (41), 123 (47), 105
(
100), 77 (35). Anal. calcd for C H N O : C, 71.79%; H,
21 25 3 2
7
1
2
.12%; N, 11.97%. Found: C, 71.68%; H, 7.28%; N,
2.12%.
-Cyclohexylamino(phenylcarbonylimino)methylamino-pyr-
idine (3c): recrystallization from ethyl ether/petroleum
5
683–5705.
3. Suzuki, H.; Ikegami, T.; Matano, Y. Synthesis 1997,
49–267.
4. Marshall, J. A. Chemtracts 1997, 1064–1075.
5. Keramane, E.-M.; Boyer, B.; Roque, J.-P. Tetrahedron
−1
1
ether. wmax (KBr) 1622, 1592, 1564 cm . l H (CDCl )
3
1.33–1.56 (4H, m); 1.65 (2H, m); 1.76–1.82 (2H, m); 2.11
2
(
2H, m); 4.31 (1H, m); 6.90 (1H, d, J=8.2 Hz); 6.97 (1H,
2
2
dd, J=7.3 Hz, 5.2 Hz); 7.37–7.50 (3H, m); 7.66 (1H, dt,
J=7.5 Hz, 1.8 Hz); 8.26 (3H, m); 10.42 (1H, s); 13.35
13
2
001, 57, 1909–1916.
(
1H, s). l C (CDCl ) 24.5 (CH ); 25.7 (CH ); 32.8
3 2 2
2
2
2
2
3
6. Keramane, E.-M.; Boyer, B.; Roque, J.-P. Tetrahedron
(
CH ); 49.8 (CH); 113.7 (CH); 117.8 (CH); 127.8 (CH);
2
Lett. 2001, 42, 855–857.
129.0 (CH); 131.1 (CH); 138.5 (CH); 138.6 (C ); 146.0
0
7. Mohammadpoor-Baltork, I.; Aliyan, H.; Khosropour, A.
R. Tetrahedron 2001, 57, 5851–5854.
8. Anderson, A. M.; Blazek, J. M.; Garg, P.; Payne, B. J.;
Mohan, R. S. Tetrahedron Lett. 2000, 41, 1527–1530.
9. Tymonko, S. A.; Nattier, B. A.; Mohan, R. S. Tetra-
hedron Lett. 1999, 40, 7657–7659.
(CH); 153.2 (C ); 156.4 (C ); 176.9 (C ). MS m/z (%): 324
0
0
0
+
+
+
(23) [M +2], 323 (100) [M +1], 322 (96) [M ], 239 (42),
212 (28), 120 (40), 105 (96), 77 (57). Anal. calcd for
C H N O: C, 70.81%; H, 6.83%; N, 17.39%. Found: C,
19
22
4
70.89%; H, 6.73%; N, 17.63%.
4-Methoxy-1-[4-methoxyanilino(phenylcarbonylimino)-
methylamino]benzene (3d): recrystallization from CH Cl /
0. Eash, K. J.; Pulia, M. S.; Wieland, L. C.; Mohan, R. S.
J. Org. Chem. 2000, 65, 8399–8401.
2
2
−
1
petroleum ether. wmax (KBr) 3373, 1606, 1568, 1506 cm .

5
2
S. Cunha et al. / Tetrahedron Letters 43 (2002) 49–52
1
l H (CDCl ) 3.82 (6H, s); 6.94 (4H, d, J=8.8 Hz); 7.33
1.63 (9H, s); 6.95 (1H, d, J=8.4 Hz); 7.07 (1H, ddd, J=8.4
Hz, 7.4 Hz, 1.9 Hz); 7.41–7.46 (2H, m); 7.48–7.52 (1H, m);
7.78 (1H, ddd, J=7.4 Hz, 5.0 Hz, 1.0 Hz); 8.21 (2H, m);
3
(
4H, d, J=8.8 Hz); 7.53–7.46 (3H, m); 8.18 (2H, d, J=7.0
Hz). l C (CDCl ) 55.7 (CH ); 115.1 (CH); 126.8 (C and
13
3
3
0
CH); 128.4 (CH); 129.8 (CH); 131.8 (CH); 139.0 (C ); 158.3
8.27 (1H, ddd, J=5.0 Hz, 1.9 Hz, 1.0 Hz); 10.74 (1H, s);
0
+
13
(
3
C ); 158.4 (C ); 178.8 (C ). MS m/z (%): 376 (13) [M +1],
75 (50) [M ], 123 (100), 105 (75), 77 (38). Anal. calcd for
13.09 (1H, s). l C (CD OD) 29.7 (CH ); 53.4 (C ); 114.7
3 3 0
0
0
0
+
(CH); 119.6 (CH); 129.0 (CH); 130.0 (CH); 132.5 (CH);
139.7 (C ); 140.3 (CH); 147.2 (CH); 154.1 (C ); 158.0 (C );
177.9 (C
239 (62), 212 (27), 120 (31), 105 (100), 77 (66). Anal. calcd
for C17 O: C, 68.92%; H, 6.76%; N, 18.92%. Found:
C, 68.17%; H, 6.96%; N, 18.60%.
C H N O : C, 70.40%; H, 5.60%; N, 11.20%. Found: C,
0
0
0
22
21
3
3
+
+
7
0.49%; H, 5.58%; N, 11.21%.
). MS m/z (%): 297 (13) [M +1], 296 (64) [M ],
0
2
-[tert-Butylamino(phenylcarbonylimino)methylamino]-pyr-
idine (3e): recrystallization from ethyl acetate/petroleum
H N
20 4
−
1
1
ether. wmax (KBr) 1618, 1594, 1568 cm . l H (CD OD)
3
.