A concise synthesis of asymmetrical N,N′-disubstituted guanidines

Article abstract of DOI:10.1016/j.tetlet.2011.05.132

We present a new and concise method for the preparation of asymmetrical N,N′-disubstituted guanidines starting from thiourea via the reaction of N-Boc-protected N′-alkyl/aryl substituted thioureas with an amine in the presence of mercury(II) chloride and

Full text of DOI:10.1016/j.tetlet.2011.05.132

Tetrahedron Letters 52 (2011) 4117–4119
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Tetrahedron Letters
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A concise synthesis of asymmetrical N,N0-disubstituted guanidines
⇑
Daniel H. O’Donovan, Isabel Rozas
School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
We present a new and concise method for the preparation of asymmetrical N,N0-disubstituted guanidines
starting from thiourea via the reaction of N-Boc-protected N0-alkyl/aryl substituted thioureas with an
amine in the presence of mercury(II) chloride and triethylamine.
Article history:
Received 25 April 2011
Revised 17 May 2011
Accepted 27 May 2011
Available online 2 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Guanidine
Thiourea
One-pot synthesis
N,N0-Dialkyl/aryl guanidine
Guanidine is a very relevant functional group present in Nature
both in the common amino acid arginine and in a variety of natural
products. This group possesses unique electronic and steric charac-
corresponding isothiocyanate. Other methods for the preparation
of guanidines have also been developed,8 but many of these proce-
dures lack the generality of the original methodology utilizing a
thiourea in the presence of a heavy metal. Recently, a solid
support-linked guanidylating reagent was published by Goodman
and co-workers9 consisting of a urethane-protected trifyl guani-
dine attached to a solid support facilitating the synthesis of
N-alkyl/aryl- or N,N-dialkylguanidines. This reagent allows gua-
nidylation of secondary amines, but requires prior preparation
and attachment to the resin and, after the guanidylation reaction,
a cleavage process is necessary.
teristics (superbasicity, ability to undergo
p-cation interactions,
etc.) due to the planar arrangement of the central C atom and
the three N atoms attached to it. This important system is found
in molecules of biochemical and pharmacological interest ranging
from complex natural products such as saxitoxin (a potent neuro-
toxin acting as a sodium channel blocker1) to small molecule adre-
noceptor ligands such as clonidine (an anaesthetic a2 adrenoceptor
agonist). During the past 10 years, our group has been investigat-
ing the preparation of derivatives of guanidine and of 2-aminoim-
idazoline (a closely-related cyclic analogue) towards a variety of
therapeutic applications.2,3 Our standard synthetic approach is
based on the nucleophilic attack of a primary aryl amine on either
N,N0-bis-(tert-butoxycarbonyl)thiourea (for the preparation of gua-
nidine derivatives), or N,N0-di(tert-butoxycarbonyl)imidazoline-2-
thione (for the preparation of 2-aminoimidazoline derivatives) in
the presence of mercury(II) chloride and excess triethylamine.4
Generally, the preparation of guanidine derivatives via primary
amines is carried out using a thiourea bearing one or more elec-
tron-withdrawing groups in the presence of mercury(II) or cop-
per(II) salts and a base.5 Although more recent methods have
included the catalytic preparation of symmetrically substituted
N,N0-bis-arylguanidines6 and the use of isothiocyanates for the
preparation of sterically crowded and electron-deficient guani-
dines,7 such methods are limited to the preparation of symmetri-
cally substituted molecules or by the availability of the
We sought to prepare a library of asymmetrical N,N0-disubsti-
tuted guanidines with different aliphatic and/or aromatic substitu-
ents. Therefore, in the present work, we report a new and robust
procedure for their preparation via appropriately functionalised
thiourea derivatives.
Yin et al. have described the preparation of N-Boc-N0-substi-
tuted thioureas by treatment of N,N0-di-Boc-substituted thiourea
with sodium hydride and trifluoroacetic anhydride in the presence
of an amine (R1-NH2).10 Based in part on the mild conditions sug-
gested by Yin, and considering the high cost of commercial N,N0-di-
Boc-substituted thiourea, we have developed a simple one-pot
procedure for the preparation of these N-Boc-N0-alkyl/aryl thio-
ureas starting from inexpensive thiourea (Scheme 1).
First, 4.5 equiv of sodium hydride (60% suspension in mineral
oil) were added to a solution of thiourea in dry tetrahydrofuran un-
der argon at 0 °C. This mixture was stirred at room temperature for
45 minutes to allow for complete formation of the thiourea anion
and then cooled again to 0 °C. At this point, 2.2 equiv of di-tert-bu-
tyl dicarbonate were added and the mixture stirred at room tem-
perature for 8 h to form N,N0-di-Boc-protected thiourea, which
was not isolated but used in situ. The reaction mixture was again
⇑
Corresponding author. Tel.: +353 1 8963731; fax: +353 1 6712826.
E-mail address: rozasi@tcd.ie (I. Rozas).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.132

4118
D. H. O’Donovan, I. Rozas / Tetrahedron Letters 52 (2011) 4117–4119
1. NaH, Boc2O
2. NaH, TFAA
3. R1-NH2
HgCl2, Et3N
R2-NH2
R2
S
S
S
N
R1
Boc
R1
Boc
R1
Boc
N
H
N
H
H2N
NH2
N
H
N
H
CH2Cl2
0 °C to rt
16 h
N
H
N
H
THF, 0 °C to rt
1-6
28-91%
one-pot
8-16
49 - 91%
Scheme 1. R1 = Pr (1), (CH2)2OH (2), (CH2)2OAc (3), Ph (4), 4-Me2NC6H4 (5), 4-
EtOC6H4 (6).
Scheme 2. R1, R2 = Pr, (CH2)2OH, (CH2)2OAc, Ph, 4-Me2NC6H4, 4-EtOC6H4, 6-
(1,2,3,4-tetrahydronaphthalene).
cooled to 0 °C and a second portion of 60% sodium hydride
(1.68 equiv) added. One hour later, 1.54 equiv of trifluoroacetic
anhydride were added and the mixture stirred for 1 h at 0 °C. Next,
1.54 equiv of the appropriate amine (propylamine, hydroxyethyl-
amine, acetoxyethylamine, aniline, p-ethoxyaniline or p-dim-
ethylaminoaniline) were added and the reaction stirred at room
temperature for 18 h. The mixture was again cooled to 0 °C and
carefully quenched with H2O followed by extraction with EtOAc.
The organic phase was dried over MgSO4, the solvents were re-
moved under vacuum, and the residue purified by silica gel chro-
matography (hexane:EtOAc). Removal of solvents followed by
recrystallisation from hexane afforded the product. The N-Boc-N0-
substituted thioureas prepared in this work (see Table 1) were
characterized by means of 1H and 13C NMR, IR and HRMS, and their
purity assessed by HPLC (see Supplementary data).
Our one-pot procedure provided good results not only for ali-
phatic amines, but also for anilines which are less nucleophilic.
Good yields were obtained (Table 1) and, in general, they were bet-
ter for aliphatic than for aromatic amines. Moreover, the thioureas
thus obtained provide an ideal substrate for guanidylation using
our standard conditions in the presence of mercury(II) chloride
and triethylamine and a second primary amine (R2-NH2), resulting
in expedient access to asymmetrical N,N0-disubstituted guanidines
(Scheme 2).
avoid this unwanted reaction, two possible approaches were con-
sidered. In one approach, the corresponding N-Boc-N0-acetoxyethyl
thiourea (3) was prepared instead of the hydroxyethyl derivative in
order to avoid cyclization. In the second approach, we considered
the preparation of the asymmetric N,N0-substituted guanidine
derivatives 9, 11, 12 and 15 from the corresponding N-Boc-N0-aryl-
thioureas 5 and 6 by reaction with propylamine, ethanolamine and
aniline, respectively, under the conditions shown in Scheme 2.
Introducing first an aliphatic or an aromatic amine in the thio-
urea system did not seem to affect the overall yield of the synthesis
after treatment with the second primary amine. In all cases, the
yields of this second nucleophilic attack ranged from good to excel-
lent (49–91%), as can be seen in Table 1.
Previously, we have carried out the deprotection of N-Boc-pro-
tected guanidines and 2-aminoimidazolines by treatment with tri-
fluoroacetic acid at room temperature overnight, later obtaining
the hydrochloride salts by treatment with a basic anion-exchange
resin (Amberlite) in its chloride form. This lengthy procedure
proved necessary following our previous experience, in which
deprotection of N,N0-bis-Boc-protected guanidines with a solution
of hydrochloric acid often led to hydrolysis of the guanidine moi-
ety. However, in the case of our present N-Boc-protected N0-substi-
tuted derivatives 8–16, deprotection using a 1.25 M solution of HCl
in methanol proceeded readily and without hydrolysis, affording
the corresponding guanidine hydrochloride salts in good to excel-
lent yields (see Table 1) in less than 4 h at 35 °C (Scheme 3).
Our approach providing guanidines substituted with two dif-
ferent amino groups depends only on the availability of primary
amines, whereas the Goodman approach yields guanidines
doubly substituted at one of the amino groups depending on
Notably, during the attempted guanidylation of N-Boc-N0-
hydroxyethyl thiourea (2) with p-ethoxyaniline, we found that this
reaction failed to produce the intended guanidine derivative. In-
stead, the hydroxyethyl moiety of thiourea 2 cyclised in the pres-
ence of mercury(II) chloride and Et3N to produce (E)-oxazolidin-
2-(N-tert-butoxycarbonyl)imine (7) (see Supplementary data). To
Table 1
N-Boc-N0-alkyl/aryl substituted thioureas 1–6, N,N0-disubstituted guanidines 8–16 and the corresponding hydrochloride salts 17–25 produced via Schemes 1–3.
Product
Thiourea/guanidine
R1
R2
Yield (%)
NHBoc/NHꢀHCl
Yield (%)
Overall yield (%)
1
2
3
4
5
6
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
–
–
–
–
–
–
1
5
1
6
5
3
4
5
4
8
–(CH2)2CH3
–(CH2)2OH
–(CH2)2OAca
–C6H5
–C6H4(p-NMe2)
–C6H4(p-OEt)
–(CH2)2CH3
–C6H4(p-NMe2)
–(CH2)2CH3
–C6H4(p-OEt)
–C6H4(p-NMe2)
–(CH2)2OAc
–C6H5
–
–
–
–
–
–
–
–
–
–
–
–
91
82
78
49
67
75
53
88
84
–
–
–
–
–
–
–
–
–
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHꢀHCl
NHꢀHCl
NHꢀHCl
NHꢀHCl
NHꢀHCl
NHꢀHCl
NHꢀHCl
NHꢀHCl
NHꢀHCl
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
83
65
73
94
80
87
87
70
88
71
43
91
46
28
49
65
23
55
24
19
68
24
25
37
54
15
40
23
15
59
21
18
33
–C6H5
–(CH2)2CH3
—C6H3½—ðCH2Þ4ꢁꢂ
–(CH2)2OH
–(CH2)2OH
—C6H3½—ðCH2Þ4ꢁꢂ
–C6H4(p-OEt)
–C6H5
–C6H4(p-NMe2)
–C6H5
—C6H3½—ðCH2Þ4ꢁꢂ
–(CH2)2CH3
–C6H4(p-NMe2)
–(CH2)2CH3
–C6H4(p-OEt)
–C6H4(p-NMe2)
–(CH2)2OAc
–C6H5
–C6H5
9
–(CH2)2CH3
—C6H3½—ðCH2Þ4ꢁꢂ
–(CH2)2OH
–(CH2)2OH
—C6H3½—ðCH2Þ4ꢁꢂ
–C6H4(p-OEt)
–C6H5
10
11
12
13
14
15
16
–C6H4(p-NMe2)
–C6H5
—C6H3½—ðCH2Þ4ꢁꢂ
a
Prepared from 2 using acetic anhydride (1.5 equiv), pyridine (3.0 equiv), DMAP (0.05 equiv) in CH2Cl2 over 2 h, 0 °C to rt.

D. H. O’Donovan, I. Rozas / Tetrahedron Letters 52 (2011) 4117–4119
4119
R2
R2
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.05.132.
N
HN
1.25 M HCl
R1
Boc
R1
Cl
N
H
N
H
N
NH2
H
References and notes
MeOH,
35 °C
3.5 h
1. (a) Nagle, P. S.; Quinn, S. J.; Kelly, J. M.; Rodriguez, F.; Rozas, I. J. Med. Chem.
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17-25
65-94%
Scheme 3. R1, R2 = Pr, (CH2)2OH, (CH2)2OAc, Ph, 4-Me2NC6H4, 4-EtOC6H4, 6-
(1,2,3,4-tetrahydronaphthalene).
the availability of the corresponding secondary amines. Thus, our
new and simple route to the N,N0-asymmetrical disubstituted
guanidines is straightforward, affordable and shows the addi-
tional advantage of allowing the preparation of asymmetrical
substituted bis-aryl guanidine derivatives, which have proven dif-
ficult to prepare in the past.6,11
Acknowledgements
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8. Katritzky, A. R.; Rogovoy, B. V. ARKIVOC 2005, iv, 49–87.
9. Zapf, C. W.; Creighton, C. J.; Tomioka, M.; Goodman, M. Org. Lett. 2001, 3, 1133–
1136.
The authors are grateful to the IRCSET for financial support
(D.H.O’D.) and are indebted to Dr. John O’Brien for NMR studies.
10. Yin, B.; Zhaogui, L.; Mingjun, Y.; Jiancun, Z. Tetrahedron Lett. 2008, 49, 3687–
3690.
11. Barvian, M. R.; Hollis Showalter, H. D.; Doherty, A. M. Tetrahedron Lett. 1997,
6799–6802.
Supplementary data
Supplementary data (synthesis and spectroscopic data of all
compounds prepared, and HPLC information of target compounds)