A versatile one-pot synthesis of 1,3-substituted guanidines from carbamoyl isothiocyanates

Full text of DOI:10.1021/jo991458q

1566
J . Org. Chem. 2000, 65, 1566-1568
Ta ble 1. Rea ction of Eth oxyca r bon yl Isoth iocya n a te
A Ver sa tile On e-P ot Syn th esis of
1,3-Su bstitu ted Gu a n id in es fr om
Ca r ba m oyl Isoth iocya n a tes
w ith Va r iou s Am in es To F or m Th iou r ea 2 a n d
Gu a n id in e 3
Brian R. Linton,† Andrew J . Carr,‡
Brendan P. Orner,‡ and Andrew D. Hamilton*,‡,§
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, and Sterling Chemistry
Laboratory, Box 208107, Yale University,
New Haven, Connecticut 06520
Received September 15, 1999
Recent advances have demonstrated the importance
of the guanidine group in receptors capable of binding
molecular anions.1,2 The need for more complex receptors
required a new protocol for creating highly substituted
guanidines under mild conditions. Several new methods
have been developed that use carbamate protection to
reduce the basicity of guanidines, simplifying purifica-
tion.3-8 While these methods permit the mild guanidi-
nylation of amines to form monosubstituted guanidines,
most do not allow the formation of highly functionalized
guanidines. Synthesis of multisubstituted guanidines has
been accomplished primarily with unprotected isothio-
uronium salts9 or imino carbonates10 or using protocols
requiring treatment with strong base.11-13 We wished to
take advantage of the benefits of carbamate-protected
guanidines, but with a protocol that allowed the forma-
tion of 1,3-multisubstituted guanidines from two separate
amines.
% yield of guanidine 3
% yield
of thiourea 2
amine
A
B
C
D
E
F
G
A
B
C
D
E
F
99
99
99
99
92
77
72
99
99
0
99
74
0
95
59
0
76
55
0
92
99
0
82
99
0
85
65
0
0
0
0
0
0
0
0
99
96
85
87
99
76
99
61
99
81
84
42
95
98
35
97
67
34
34
39
0
G
provide a protecting group throughout the synthesis,
making purification trivial, without the later inclusion
of a protection step. The carbamate increases the reactiv-
ity of the isothiocyanate, permitting formation of thiourea
2 even with hindered amines. A second amine can be
coupled to the carbamoyl thiourea 2 using EDCI,4 form-
ing 1,3-disubstituted and 1,1,3-trisubstituted guanidines
through either stepwise or one-pot synthesis.
To gauge the steric and electronic limitations of this
procedure, amines of varying reactivity (A-G) were
investigated for their ability to form protected thiourea
2 and guanidine 3. The synthetic yields for this series of
reactions with ethoxycarbonyl isothiocyanate and amines
A-G are shown in Table 1. Formation of thiourea 2
proceeded in near quantitative yields for alkylamines (A-
D), while aromatic amines (E-G) produced slightly lower
yields. Each amine has a dual effect on guanidine
synthesis: reactivity of the amine with various thioureas
as well as coupling efficiency of the thiourea formed from
that amine. Both showed a steric effect as yields de-
creased with bulkier substituents. Most noticeably, both
thioureas formed from secondary amines (2C and 2D)
failed to form guanidines in detectable yields. It is
unclear if this results from increased steric bulk limiting
nucleophile attack or from the removal of a reactive
proton. Trisubstituted guanidines can be formed, how-
ever, through the coupling of unencumbered thioureas
with secondary amines, albeit in lower yields than with
primary amines. Aromatic amines were also successful
in both aspects of guanidinylation, with both phenyl-
amine and the more sterically hindered 2-methoxy-
phenylamine producing guanidinium in good yields. The
electronic nature of the 4-nitrophenylamine reduces the
efficiency of the reaction of this amine to form guanidine
as well as the coupling with the corresponding thiourea,
producing lower yields in each case.
This procedure, shown in eq 1, exploits several advan-
tages of carbamoyl isothiocyanates 1. These reagents
(1)
† University of Pittsburgh.
‡ Sterling Chemistry Laboratory.
§ Phone: (203)432-5570.Fax: (203)432-6144.Email: Andrew.Hamilton@
yale.edu.
(1) Linton, B.; Hamilton, A. D. Tetrahedron 1999, 55, 6027-6038.
(2) Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997, 97, 1609-1646.
(3) Yong, Y. F.; Kowalski, J . A.; Lipton, M. A. J . Org. Chem. 1997,
62, 1540-1542. Employing Mukaiyama’s reagent in this protocol was
unsuccessful, suggesting the singly protected thioureas are less reactive
than the bis-carbamoyl thioureas used in the Lipton study.
(4) Poss, M. A.; Iwanowicz, E.; Reid, J . A.; Lin, J .; Gu, Z. Tetrahedron
Lett. 1992, 33, 5933-5936.
(5) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron Lett.
1993, 34, 3389-3392.
(6) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677-7680.
(7) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977-
980.
(8) Robinson, S.; Roskamp, E. J . Tetrahedron 1997, 53, 6697-6705.
(9) Rasmussen, C. R.; Villani, F. J .; Weaner, L. E.; Reynolds, B. E.;
Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J .;
Powell, E. T.; Molinari, A. J . Synthesis 1988, 460-466. Wilson, L. J .;
Klopfenstein, S. R.; Li, M. Tetrahedron Lett. 1999, 40, 3999-4002.
(10) Schlama, T.; Gouerneur, V.; Valleix, A.; Greiner, A.; Toupet,
L.; Mioskowski, C. J . Org. Chem. 1997, 62, 4200-4202.
(11) Knieps, S.; Michel, M. C.; Dove, S.; Buschauer, A. Bioorg. Med.
Chem. Lett. 1995, 5, 2065-2070.
The generality of this procedure for other carbamoyl
isothiocyanates allows synthetic flexibility in the final
(12) Corelli, F.; Dei, D.; Monache, G. D.; Botta, B.; DeLuca, C.;
Carmignani, M.; Volpe, A. R.; Botta, M. Bioorg. Med. Chem. Lett. 1996,
6, 653-658.
(13) Of notable exception is the method of Dodd and Wallace (Dodd,
D.; Wallace, O. B. Tetrahedron Lett. 1998, 39, 5701-5704) which
permits the solid-phase synthesis of N,N′-disubstituted guanidines.
10.1021/jo991458q CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/17/2000

Notes
Ta ble 2. Yield s of Rea ction P r od u cts for Va r iou s
J . Org. Chem., Vol. 65, No. 5, 2000 1567
Highly reactive carbamoyl isothiocyanates reacted
smoothly with equimolar amounts of amine to form
thioureas in high yield and purity. Addition of a second
amine, base, and the coupling reagent resulted in the
formation of the protected guanidine 3, without purifica-
tion of the initial thiourea 2. Dibenzylethoxycarbon-
ylguanidine 3AA was formed in 98% yield through a one-
pot reaction starting from ethoxycarbonyl isothiocyanate,
while asymmetric N-benzyl-N′-butyl-N′′-ethoxycarbon-
ylguanidine 3AB was formed in 80% yield. It is recom-
mended that carbamoylguanidines be purified prior to
deprotection due to the polarity of the guanidinium
product.
P r otectin g Gr ou p s (R2 ) R4 ) Bn , R3 ) R5 ) H)
Synthetic difficulty increases with molecules contain-
ing more than one guanidine due to the accumulation of
charge, making purification more challenging. Using this
protocol, there are no highly polar or charged intermedi-
ates which may be formed using existing methods. The
constant presence of a carbamoyl group in this protocol
permits all intermediates to be purified through standard
organic chromatography. As an example, bis-guanidine
5 (eq 2) was synthesized in a 79% overall yield from the
two-step reaction of benzyloxycarbonyl isothiocyanate [1,
R1 ) Bn] with xylylenediamine to form bis-carbamoyl
thiourea 4, and subsequent coupling with benzylamine.
deprotection step. In addition to the ethyl carbamate
employed above, benzyl carbamate (Cbz), 2,2,2-trichloro-
1,1-dimethylethyl carbamate, fluorenylmethyl carbamate
(Fmoc), and phenyl carbamate were investigated for their
potential to participate in the guanidine synthesis as in
eq 1. In each case, carbamoyl isothiocyanate 1 was
converted to thiourea 2 with benzylamine and coupled
with a second equivalent of benzylamine to form guani-
dine 3. These yields are listed in Table 2.
While ethoxycarbonyl isothiocyanate was commercially
available, all other carbamoyl isothiocyanates 1 were
synthesized from the corresponding chloroformate and
potassium thiocyanate. Several reports list acetonitrile
or ethyl acetate as reaction solvents,14-16 however yields
of benzyloxycarbonyl isothiocyanate [1, R1 ) Bn] and
fluorenylmethoxycarbonyl isothiocyanate [1, R1 ) (C13H9)-
CH2] were maximized using 20% acetonitrile/toluene,
which reduced the production of alternate products
formed by the ambident thiocyanate nucleophile.17 Other
carbamoyl isothiocyanates 1 were synthesized using this
same procedure and are stable in the refrigerator for
months. Reaction of carbamoyl isothiocyanate 1 with
benzylamine to form thiourea 2 proved trivial, with high
yields being observed in every case. Coupling of thiourea
with amine was limited, however, by the stability of the
carbamate under the reaction conditions. While benzyl-
oxycarbonyl thiourea [2, R1 ) Bn] and 2,2,2-tricloro-1,1-
dimethylethyl thiourea [2, R1 ) Cl3CC(CH3)2] efficiently
formed guanidine 3, Fmoc and phenyl carbamate failed
to produce guanidine in appreciable yields. In these cases
the carbamates were not stable to the basic reaction
conditions and resulted in protecting group cleavage. It
appears that any carbamate capable of withstanding the
coupling conditions will be applicable to this protocol.
An additional advantage of this method is the creation
of multisubstituted guanidines using a one-pot synthesis.
Carbamoyl isothiocyanates are ideal starting materials
for the synthesis of multisubstituted guanidines. The
electron-withdrawing protecting groups reduce the basic-
ity of guanidines, making them more easily handled
through standard organic techniques. The coupling of
amine to protected thiourea occurs under mild conditions
and without producing unpleasant side products. The
nature of these carbamoyl thioureas permits creation of
disubstituted and trisubstituted guanidines, as well as
aromatic guanidines. The success of this protocol in a one-
pot synthesis of guanidines further underscores the ease
and efficiency of this protocol.
Exp er im en ta l Section
(14) Doran, R. E. J . Chem. Soc. 1901, 79, 906-915. Dixon, A. E.;
Taylor, J . J . Chem. Soc. 1908, 93, 684-700.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca r -
ba m oyl Isoth iocya n a tes (1). A saturated solution of
potassium thiocyanate (40 g) in boiling ethanol (300 mL)
was poured into 1.5 L of ethyl ether, forming a fine, white
powder. The solid was collected by filtration and washed
(15) Esmail, R.; Kurzer, F. Synthesis 1975, 301-312.
(16) Kearney, P. C.; Fernandez, M.; Flygare, J . A. J . Org. Chem.
1998, 63, 196-200.
(17) Elmore, D. T.; Ogle, J . R.; Fletcher, W.; Toseland, P. A. J . Chem.
Soc. 1956, 4458-4463.

1568 J . Org. Chem., Vol. 65, No. 5, 2000
Notes
with 300 mL of ethyl ether, before being dried in vacuo
over P2O5. Finely powdered potassium thiocyanate was
isolated (33 g, 82%).
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca r -
b a m oyl Gu a n id in es (3). Carbamoyl thiourea 2 (1.0
mmol), alkylamines A-G (1.5 mmol), and diisopropyl-
ethylamine (1.0 mmol) were added to 10 mL of anhydrous
dichloromethane and cooled to 0 °C. EDCI (1.5-2.0
mmol) was added, and the solution was stirred under
nitrogen. After 1 h the ice bath was removed and the
solution was stirred for an additional 10 h at room
temperature. In cases where TLC indicated unreacted
starting material, addition of more amine and EDCI
resulted in increased yields. The reaction mixture was
washed with 1% HCl, water, and brine and dried with
Na2SO4. The residue that remained after removal of
solvent under reduced pressure was purified by silica
chromatography.
Alkyl chloroformate (20 mmol) was slowly added to a
well-stirred suspension of freshly powdered potassium
thiocyanate (10 g, 110 mmol) in 250 mL of 20% toluene/
acetonitrile. After 2 days of stirring, no chloroformate was
detectable by TLC (silica, 20% dichloromethane/hexanes).
The reaction mixture was filtered through Celite, and the
solid was washed twice with toluene (50 mL). Solvent
was removed in vacuo with mild heating, before isolating
the carbamoyl isothiocyanate by distillation or silica gel
chromatography.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca r -
ba m oyl Th iou r ea s (2). A solution of carbamoyl isothio-
cyanate 1 (1.0 mmol) in 50 mL of dichloromethane was
cooled to 0 °C before adding alkylamines A-G (1.0
mmol). The ice bath was removed, and the solution was
stirred for 4 h under nitrogen. The solution was washed
with 1% HCl, water, and brine and dried with Na2SO4.
Solvent was removed under reduced pressure, yielding
a white solid. As an alternative to extractive workup, the
reaction mixture can be poured into 50 mL of pentane.
The white solid that formed was collected by filtration
and dried in vacuo.
Ack n ow led gm en t. The authors wish to thank the
National Science Foundation for financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
HRMS, and elemental analyses for all compounds discussed
herein. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O991458Q