The first bismuth(III)-catalyzed guanylation of thioureas

Article abstract of DOI:10.1016/j.tetlet.2006.07.138

This work describes the first catalytic bismuth-promoted synthesis of polysubstituted guanidines in good yields through the guanylation reaction of N-benzoyl or N-phenylthioureas with primary and secondary amines, but now employing equimolar amounts of ea

Full text of DOI:10.1016/j.tetlet.2006.07.138

Tetrahedron Letters 47 (2006) 6955–6956
The first bismuth(III)-catalyzed guanylation of thioureas
Silvio Cunha* and Manoel T. Rodrigues, Jr.
Instituto de Qu´ımica, Universidade Federal da Bahia, Campus de Ondina, Salvador-BA 40170-290, Brazil
Received 10 February 2006; accepted 26 July 2006
Abstract—This work describes the first catalytic bismuth-promoted synthesis of polysubstituted guanidines in good yields through
the guanylation reaction of N-benzoyl or N-phenylthioureas with primary and secondary amines, but now employing equimolar
amounts of each organic reagent. Both bismuth iodine and bismuth nitrate were efficient as inorganic thiophiles at only 5 mol %
in relation to substrates, being the first example of inorganic thiophiles acting in guanylation at catalytic levels.
Ó 2006 Elsevier Ltd. All rights reserved.
Despite of the variety of guanylating reagents to solu-
tion synthesis of guanidines, the most used guanylation
protocols employ protected thiourea as guanylating re-
agents and stoichiometric amounts of heavy metal salts
as guanylating agent, HgCl2 being the toxic and the
most popular.1
because (SOx)yÀ-derivatives of Bi(III) are more soluble
than Bi2S3.1a To test this hypothesis we reacted thiourea
2a with amine 3a in the presence of diverse Bi(III) salts
and oxidants. After experimentation, 4a was obtained in
15% yield after 5 days when BiI3 5 mol % was used in the
presence of K2S2O8. The oxidant was thus screened.
Changing the oxidant to sodium bismuthate, NaBiO3,
guanidine 4a was isolated in 92% yield and 10 h, Table 1.
The use of cheap NaBiO3 is noteworthy because both
thiophile and oxidant are now environmental friendly.2,5
This protocol could be extended to less activated N-
phenylthioureas, and primary and secondary amines
were tolerated as the nucleophilic component using both
Bismuth is the least toxic of the heavy metals and their
salts have been intensively used in organic transforma-
tions.2,3 We have reported guanylation of N-benzoyl-
thioureas using stoichiometric amounts of Bi(NO3)3
as thiophile, but the use of 2 equiv of the amine was
required to achieve an yield comparable to the HgCl2
method.4 This is a serious drawback when expensive
or no commercial amines are necessary. Herein, we
describe the first successful catalytic Bi(III)-mediated
synthesis of functionalized guanidines. Besides, no
excess of nucleophilic amine was needed.
N-substituted thioureas, affording
a representative
spectrum of guanidines through this new catalytic
guanylation (Table 1). Bi(NO3)3 5 mol % was also
effective but BiI3 afforded better yield and shorter
reaction time. For instance, guanylation of 2a with
cyclohexylamine and Bi(NO3)3 5 mol % afforded 4c in
69% yield (21 h).
In the previously stoichiometric bismuth-promoted
guanylation, we identified Bi2S3 as byproduct. Here we
hypothesized that stoichiometric amount of Bi(NO3)3
was necessary because the low solubility of Bi2S3 in
the reaction medium precluded the continuous thiourea
activation, that is, necessary to the guanylation. Thus,
we reason that a catalytic cycle could operate if Bi2S3
could be in situ transformed into a more soluble Bi(III)
derivative, affording guanidines in good yields. To this
end, an oxidant agent as co-reagent could be useful
The proposed catalytic cycle for this guanylation is indi-
cated in Figure 1. In analogy to the HgCl2-promoted
guanylation,1 we assumed that a carbodiimide is the
key intermediate. In this way, Bi(III) should behave as
a thiophilic soft Lewis acid that coordinated to the thio-
urea followed by reaction with Et3N and form the car-
bodiimide by thiourea desulfurization, which is
trapped by the amine affording the guanidine, and the
insoluble Bi2S3 is oxidized to a more soluble Bi(III)
derivative.
Keywords: Thioureas; Guanidines; Bismuth.
*
In conclusion, we have developed the first catalytic
Bi(III) guanylation of thioureas, wherein only 5 mol %
Corresponding author. Tel.: +55 71 32375784; fax: +55 71
32374117; e-mail: silviodc@ufba.br
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.138

6956
S. Cunha, M. T. Rodrigues, Jr. / Tetrahedron Letters 47 (2006) 6955–6956
Table 1. Isolated guanidine yields
References and notes
R2
S
H
N
R3
H
1. Review on synthesis: Manimala, J. C.; Anslyn, E. Eur. J.
Org. Chem. 2002, 3909–3922; Representative papers: (a)
Katritzky, A.; Rogovoy, B. V.; Cai, X.; Kirichenko, N.;
Kovalenko, K. V. J. Org. Chem. 2004, 69, 309–313; (b)
Gers, T.; Kunce, D.; Markowski, P.; Izdebski, J. Synthesis
2004, 37–42; (c) Miller, C. A.; Batey, R. A. Org. Lett. 2004,
6, 699–702; (d) Bowser, A. M.; Madalengoitia, J. S. Org.
Lett. 2004, 6, 3409–3412; (e) Porcheddu, A.; Giacomelli, G.;
Chighine, A.; Masala, S. Org. Lett. 2004, 6, 4925–4927.
2. (a) Organobismuth Chemistry; Suzuki, H., Matano, Y., Eds.;
Elsevier: Amsterdam, 2001; (b) Leonard, N. M.; Wieland, L.
C.; Mohan, R. S. Tetrahedron 2002, 58, 8373–8397.
3. (a) Evans, P. A.; Andrews, W. J. Tetrahedron Lett. 2005, 46,
5625–5627; (b) Srivastava, N.; Banik, B. K. J. Org. Chem.
2003, 68, 2109–2114.
4. (a) Cunha, S.; Lima, B. R.; Souza, A. R. Tetrahedron Lett.
2002, 43, 49–52; (b) Cunha, S.; Rodrigues, M. T., Jr.; Silva,
C. C.; Napolitano, H. B.; Vencato, I.; Lariucci, C.
Tetrahedron 2005, 61, 10536–10540.
R1
R2
BiI3 (5mol%)
N
N
R1
R3
N
H
N
H
+
R4
N
R4
NaBiO3, Et3N
CH3CN, reflux
2a-j
4a-j
3a-d
Guanidine Thiourea R1/R2 Amine R3/R4
Yield Time
(%)
(h)
4a
4b
4c
4d
4e
4f
Bz/p-CH3OPh
Bz/Ph
Bz/p-CH3OPh
Bz/p-CH3Ph
Bz/Ph
Bz/c-C6H11
Bz/o-ClPh
Bz/p-CH3OPh
Ph/p-CH3OPh
Ph/c-C6H11
p-CH3OPh/H
p-CH3OPh/H
c-C6H11/H
c-C6H11/H
c-C6H11/H
92
75
86
65
77
69
91
10
12
3
8
3
21
11
5
3
7
c-C6H11/H
c-C6H11/c-C6H11
4g
4h
4i
CH2CH2OCH2CH2 97
CH2CH2OCH2CH2 95
4j
c-C6H11/H
95
5. The use of NaBiO3 in organic transformations is scarcely
reported. For reviews, see Refs. 2a,2b.
6. The general synthetic procedure is as follows: to a solution
of 0.5 mmol of thiourea in 7 mL of CH3CN were added
0.5 mmol of amine and 1 mmol of Et3N, and then 0.5 mmol
of NaBiO3 and 0.025 mmol of BiI3 were added to the
solution with vigorous magnetic stirring. The suspension
was left stirring for 10 min at room temperature and
became black. After this time, it was heated at reflux at the
indicated time in Table 1. The solvent was evaporated and
20 mL of CH2Cl2 was added. The suspension was filtered
through a pad of Celite and the pad washed with 10 mL of
CH2Cl2. The filtrate was dried over anhydrous MgSO4,
filtrated and the solvent was evaporated. The crude residue
was recrystallized from Et2O/petroleum ether affording a
solid or a viscous oleo as indicated in each case.
BiX3
X = I, NO3
S
(SOx) y-
2
1
R
R
Bi3+
N
H
N
H
[O]
Bi3+
S
Bi2S3
2
1
R
R
N
H
N
H
+
Et3NH
R
Compound 4d: Mp 100–103 °C. IR (KBr): 3287, 1570 cmÀ1
.
1
Et3N
1H NMR (CDCl3): 1.10–2.10 (10H, m); 2.34 (3H, s); 4.15
(1H, m); 4.80 (1H, br); 7.13 (2H, d, J = 8.0 Hz); 7.21 (2H, d,
J = 8.0 Hz); 7.38–7.45 (3H, m); 8.24 (2H, d, J = 6.3 Hz);
11.97 (1H, br). 13C NMR (CDCl3): 20.9 (CH3); 24.7 (CH2);
25.5 (CH2); 33.1 (CH2) 50.0 (CH); 125.3 (CH); 127.7 (CH);
129.0 (CH); 130.9 (CH); 133.4 (C); 136.6 (C); 138.8 (C);
158.0 (C); 177.3 (C).
N
C N
2
R
3
R3NH2
R
N
2
1
R
R
N
H
N
H
Compound 4e: Mp 107–110 °C. IR (KBr): 3250, 1570 cmÀ1
.
1H NMR (CDCl3): 1.10–2.15 (10H, m); 4.18 (1H, m); 4.84
(1H, br); 7.20–7.30 (3H, m); 7.35–7.50 (5H, m); 8.26 (2H, d,
J = 6.6 Hz); 12.97 (1H, br). 13C NMR (CDCl3): 24.7 (CH2);
25.4 (CH2). 33.0 (CH2); 50.1 (CH); 125.0 (CH): 126.5 (CH);
127.8 (CH); 128.9 (CH); 129.9 (CH); 131.03 (CH); 136.2 (C);
138.6 (C); 157.7 (C); 177.4 (C).
Figure 1. Proposed catalytic cycle for the Bi(III)-promoted guanyl-
ation of thioureas.
of inorganic thiophiles and no excess of amine was
required, with yields and scope comparable with the
stoichiometric HgCl2 protocol.6 Efforts are underway
to elucidate the mechanistic details of this reaction and
define the scope, limitations and synthetic applications
to natural and unnatural bioactive guanidines.
Compound 4g: Mp 125–127 °C; IR (KBr): 3065, 1610, 1544,
1
1366 cmÀ1. H NMR (CDCl3): 1.00–2.25 (20H, m); 3.25–
3.40 (2H, m); 7.00–7.20 (2H, m); 7.30–7.50 (2H, m); 8.26 (1H,
d, J = 6.6 Hz); 11.07 (1H, br). 13C NMR (CDCl3): 25.5
(CH2); 26.3 (CH2); 31.1 (CH2); 58.6 (CH); 125.2 (CH); 126.0
(CH); 127.2 (CH); 127.2 (CH); 127.8 (CH); 128.7 (C); 129.0
(CH); 130.0 (CH); 130.9 (CH); 138.5 (C); 160.7 (C); 175.4 (C).
Compound 4h: oil. IR (film): 3013, 1600, 1575 cmÀ1 1H
.
NMR (CDCl3): 3.55 (4H, m); 3.67 (4H, m); 3.78 (3H, s); 6.85
(2H, d, J = 8.8 Hz); 7.06 (2H, d, J = 8.8 Hz); 7.40–7.55 (3H,
m); 8.22 (2H, d, J = 6.9 Hz); 11.85 (1H, br). 13C
NMR(CDCl3): 46.9 (CH2); 55.4 (CH3); 66.3 (CH2); 114.8
(CH); 123.4 (CH); 127.9 (CH); 129.2 (CH); 131.5 (CH); 132.3
(C); 138.2 (C); 156.9 (C); 160.2 (C); 177.1 (C).
Acknowledgements
The authors thank CNPq and FAPESB for support and
fellowships, and Professor A.C.S. Costa for donation of
BiI3.