Convenient synthesis of acyclic guanidines from isothiouronium iodides and amines without protection of the amino groups

Article abstract of DOI:10.1055/s-0033-1340904

Acyclic guanidines were obtained in one step by reaction of isothiouronium iodides with an equimolar amount of various amines in tetrahydrofuran. The reactions proceeded under ambient conditions without N-protection/deprotection to afford the corresponding substituted guanidines in quantitative yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340904

LETTER
▌983
lCettoernvenient Synthesis of Acyclic Guanidines from Isothiouronium Iodides and
Amines without Protection of the Amino Groups
Convenient Synthesis of Acyclic Guanidines
Naoto Aoyagi, Yoshio Furusho, Takeshi Endo*
Molecular Engineering Institute, Kinki University, 11-6 Kayanomori, Iizuka, Fukuoka 820-8555, Japan
Fax +81(948)219132; E-mail: tendo@moleng.fuk.kindai.ac.jp
Received: 06.01.2014; Accepted after revision: 06.02.2014
increasing interest in the efficient CO2-capture and activa-
Abstract: Acyclic guanidines were obtained in one step by reaction
tion ability of substituted guanidines. In this paper, we re-
of isothiouronium iodides with an equimolar amount of various
port an efficient one-step synthesis of acyclic guanidines
amines in tetrahydrofuran. The reactions proceeded under ambient
3 and 4 by equimolar reaction between amines and S-me-
thylisothiouronium iodides 1 and 2 under ambient condi-
tions without an N-protection/deprotection procedure
(Scheme 1).
conditions without N-protection/deprotection to afford the corre-
sponding substituted guanidines in quantitative yields.
Key words: guanidines, synthetic methods, amines, nucleophiles,
substitution
R2
Me
S
NH
R2NH2 (1.0 equiv)
R1
R1
Both acyclic and cyclic guanidines are used as important
key compounds for natural products and pharmaceutical
chemicals.1 Generally, guanidine derivatives are well-
known, strongly basic compounds2 that have been exten-
sively used as organocatalysts for C–C and C–X bond for-
mation and polymerization reactions.1e,3–11 Recent
examples of organocatalytic reactions using guanidines
include Michael,3 aza-Michael,4 aldol,5 Strecker,6 and
Henry reactions,7 Claisen rearrangement,8 Mannich reac-
tions,9 ring-opening polymerizations,10 and various other
reactions.1e,11 In addition to organocatalysis, guanidine
derivatives have attracted increasing attention as reagents
for carbon dioxide (CO2) capture and activation.12–14
Cyclic and acyclic guanidines readily react with CO2 in the
presence of alcohol or amine to form the corresponding
carbonate or carbamate salts, which were demonstrated to
work as ionic liquids.12 Some guanidines are reported to
catalyze the formation of carbamates13 and carbonates14
from CO2 and amines and alcohols, respectively.
R1
R1
+
N
N
H
+
N
R1 I–
N
H
THF
25 °C, 6–24 h
R1 I–
1 R1 = Me
2 R1 = H
3 R1 = Me
4 R1 = H
Scheme 1 Guanidinylation under ambient conditions
Iodides 1 and 2 were prepared quantitatively from N,N,N′-
trimethylthiourea or thiourea with methyl iodide.17 First,
we investigated the reaction with N,N′,N′-trimethyl-S-me-
thylisothiouronium iodide (1) as a guanidinylating re-
agent, because the reaction products are easier to
1
characterize by H NMR spectroscopic analysis than
those with unsubstituted S-methylisothiouronium iodide
(Table 1). The guanidinylation with 1 of 4-chlorobenzyl-
amine as a model alkylamine (which is known as a weak
nucleophile) was optimized by conducting the reaction
with a range of solvents.16d In general, guanidinylation
with isothiouronium salts were carried out by using polar
protic solvents such as water and alcohols and an excess
of amines under reflux.16,18 As expected, the use of either
water or ethanol as solvent gave acyclic guanidine 3a in
only moderate yields at 25 °C after 12 hours (entries 1and
2). In contrast, the use of polar aprotic solvents such as
N,N-dimethylformamide (DMF), acetonitrile, or tetrahy-
drofuran (THF) resulted in increased yields of 87–94%
under the same, ambient conditions (entries 3–5). The use
of nonpolar solvents such as dichloromethane and chloro-
form gave similar results to those using ethanol and water
(entries 6 and 7). Thus, THF gave the highest yield among
the solvents investigated.
Although various methods for the synthesis of guanidines
have already been reported, most approaches require mul-
tistep reactions and tedious procedures. For example, al-
though N-Boc protected amidine (or guanidine) reagents
give various acyclic guanidines in high yields under mild
conditions,15 these guanidinylation reagents themselves
are prepared in one to three steps in moderate yields. In
addition, it is necessary to deprotect the N-Boc or N-Cbz
groups from the guanidine products. Although substituted
guanidines can be prepared directly by the reaction of iso-
thiouronium salts and alkyl(aryl)amines, the reactions
need to be conducted in water or alcohols for several
hours under reflux, which severely restricts their applica-
tion.16 Therefore, the development of facile synthetic
methodologies for substituted guanidines under mild con-
ditions is awaited, especially with respect to an ever-
The conformation of 1 in reaction solvents was investigat-
ed by 1H and 13C NMR spectroscopic analysis using vari-
ous deuterated solvents. 1H and 13C NMR spectra of 1 in
DMF-d7, CD3CN or CDCl3 showed no change during 6 h
at 25 °C. However, by using THF-d8, four new signals ap-
peared in the 1H and 13C NMR spectra of the THF-d8 sol-
uble part under the same conditions (Scheme 2, see also
SYNLETT 2014, 25, 0983–0986
Advanced online publication: 18.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340904; Art ID: ST-2014-U0013-L
© Georg Thieme Verlag Stuttgart · New York

984
N. Aoyagi et al.
LETTER
Table 1 Effect of Solvent on the Guanidinylation of 1a
Table 2 Guanidinylation of Amines with 1a
Me
S
R
H2N
HN
Me
RNH2 (1.0 equiv)
S
HN
Me
Me
Me
Cl
+
N
N
H
N
NH
Me
+
(1.0 equiv)
THF
25 °C, 6–24 h
Me
Me
Me
+
N
N
H
organic solvent
25 °C, 12 h
N
NH
Me
Cl
I–
1
–
+
Me
Me
I
I–
I–
1
3a–f
Me
Me
3a
Entry
3
R
Time (h) Yield (%)b
Entry
Solvent
Yield (%)b
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
4-ClC6H4CH2
PhCH2
24
6
98
>99
98
1
2
3
4
5
6
7
H2O
74
77
87
92
94
84
76
EtOH
DMF
MeCN
THF
4-H2C=CHC6H4CH2
n-Bu
6
6
>99
>99
>99
CH2=CHCH2
Me2NCH2CH2
6
6
CH2Cl2
CHCl3
a Reaction conditions: 1 (10 mmol), amine (10 mmol), anhydrous
THF(10 mL), 25 °C, 6–24 h.
b Isolated yield.
a Reaction conditions: 1 (1 mmol), 4-chlorobenzylamine (1 mmol),
solvent (1 mL), 25 °C, 12 h.
b Determined by 1H NMR spectroscopic analysis.
We also examined the guanidinylation of various amines
with 2 in THF at 25 °C (Table 3). In contrast to the gua-
nidinylation of 4-chlorobenzylamine in water/ethanol
mixture, which was reported to give low yield,16d 1-(4-
chlorobenzyl)guanidine hydroiodide (4a) was isolated in
high yield (99%; Table 3, entry 1). As in the reactions us-
ing 1, other benzyl- and alkylamines were smoothly gua-
nidinylated with 2 into the corresponding guanidine
derivatives 4b–k in high yields (98–100%; Table 3, en-
tries 2–11). Even a bulky secondary amine such as dicy-
clohexylamine was quantitatively guanidinylated to 4l
under the ambient conditions (entry 12). Hydroxyl-func-
tionalized guanidines are an emerging class of interesting
compounds that can be used as CO2-capturing agents20
and organocatalysts for the Henry reaction and the Kno-
evenagel condensation.21 The guanidinylation of ethanol-
amine in ethanol at reflux was reported to give hydroxy-
functionalized guanidine 4m in 70% yield.22 Under the
conditions described here, the guanidinylation of ethanol-
amine and 4-hydroxybutylamine in THF at 25 °C pro-
ceeded to afford the corresponding hydroxy-appended
guanidines 4m and 4n in high yields (98–100%; Table 3,
entries 13 and 14).
the Supporting Information, Figures S1 and S2). The new
signals observed for 5 were assumed to arise from local-
ization of the proton on the nitrogen atom, which shifted
the peak of the methyl protons (2.99 ppm) and led to a
doublet multiplicity (3JHCNH = 4.4 Hz). It was assumed
that 5 would be highly reactive towards amines, because
the 13C NMR signal of the cationic carbon of 5 was shifted
low field (184.8 ppm) with respect to the quaternary car-
bon of 1 (168.6 ppm; see the Supporting Information,
Figure S2).
168.6 ppm
(NCN)
184.8 ppm
(N+CN)
S
O
S
6.68 ppm
(NH)
singlet
(CH3)
N
N
H
N
NH
THF-d8
25 °C
I–
I–
doublet
9.61 ppm
(NH+)
(3JHCNH = 4.4 Hz)
5
1
possible structure
Scheme 2 1H (400 MHz) and 13C (100 MHz) spectra of a mixture of
1 and 5 in THF-d8
We then examined the guanidinylation of various amines
with 1 in THF at 25 °C (Table 2).19 The guanidinylation of
4-chlorobenzylamine required a long reaction time to
complete (Table 2, entry 1; see also Table 1, entry 5). Oth-
er benzyl and alkyl amines were converted into the guani-
dines much faster than 4-chlorobenzylamine, owing to the
higher nucleophilicities due to the absence of the electron-
withdrawing chloro group (Table 2, entries 2–6). In par-
ticular, 1b and 1d–f were quantitatively guanidinylated at
25 °C within 6 h. It should be noted here that all guani-
dines 3a–f were purified simply by washing with diethyl
ether, and all were isolated in high yields (≥ 98%).
We then investigated the effect of the counter anions of S-
methylisothiouronium salts on the guanidinylation of
amines under ambient conditions (Table 4). S-Methyliso-
thiouronium sulfate (6) is readily available as a commer-
cial product. Both the iodide 1 and the sulfate 6 gave
acyclic guanidines 3a, 7a and 7b in only moderate yields
in water (Table 1, entry 1; Table 4, entries 1and 2), thus
the nature of the counter anions did not influence the reac-
tion in polar protic solvent such as water. In contrast, the
use of the polar aprotic solvent such as THF resulted in in-
creased yields to 99–100% yield in the reaction of iodide
2 with amines (Table 3, entries 1 and 4), whereas when
sulfate 6 was used as the guanidinylating reagent, the for-
Synlett 2014, 25, 983–986
© Georg Thieme Verlag Stuttgart · New York

LETTER
Convenient Synthesis of Acyclic Guanidines
985
Table 3 Guanidinylation of Amines with 2a
Finally, our synthetic method was applied to the synthesis
of acyclic bisguanidines, which are compounds of phar-
maceutical interest that show a blocking ability for neural
nicotinic acetylcholine receptors16b and some antibiotic
activity.23 Bisguanidines were also used as ligands for
some transition-metal complexes.24 Bisguanidines with
di-, tri-, and tetramethylene spacers 4o–q were synthe-
sized by nucleophilic substitutions on 2 with 1,2-diamino-
ethane, 1.3-diaminopropane, and 1,4-diaminobutane,
respectively, in THF at 25 °C for 6 h (Scheme 3). Bisgua-
nidines 4o–q were isolated in high yields (98–100%) by
simple purification, in contrast to the previous report that
the guanidinylation of these diamines in ethanol–water at
reflux gave the corresponding bisguanidines in moderate
yields.16b,d
Me
R2
R1
S
N
R1R2NH (1.0 equiv)
THF
25 °C, 6–12 h
H2N
NH2
H2N
NH2
+
I–
+
I–
2
4a–n
Entry
4
R1
R2
Time
(h)
Yield
(%)b
1
2
4a
4b
4c
4d
4e
4f
4-ClC6H4CH2
PhCH2
H
H
H
H
H
H
H
H
H
H
H
Cy
H
H
12
6
6
6
6
6
6
6
6
6
6
6
6
6
99
>99
>99
>99
>99
>99
98
3
4-H2C=CHC6H4CH2
n-Bu
4
5
n-Oct
NH2
Me
H2N
I–
NH2
6
Cy
n
S
H
N
+
(1.0 equiv)
2
H2N
NH2
I–
H2N
N
H
7
4g
4h
4i
i-Pr
n
+
+
I–
NH2
THF
25 °C, 6 h
NH2
8
CH2=CHCH2
propargyl
Me2NCH2CH2
MeOCH2CH2
Cy
>99
>99
>99
>99
>99
98
2
4o (n = 1), >99%
4p (n = 2), 98%
4q (n = 3), >99%
9
10
11
12
13
14
4j
Scheme 3 Guanidinylation of α,ω-diamines with 2
4k
4l
In summary, we have found that amines are guanidinylat-
ed by reaction with isothiouronium salts to give acyclic
guanidines in a single step without an N-protection/depro-
tection procedure. This mild method can be applied to var-
ious amines to afford the corresponding acyclic
guanidines, including bioactive bisguanidines, in excel-
lent yields under ambient conditions. We believe that this
method will find use in the development of guanidine-
based organocatalysts for the synthesis of cyclic carbon-
ates from epoxides with CO2 under ambient conditions,
and studies toward this end are ongoing in our group.
4m
4n
HOCH2CH2
HO(CH2)4
>99
a Reaction conditions: 2 (10 mmol), amine (10 mmol), anhydrous (10
mL), THF, 25 °C, 6–12 h.
b Isolated yield.
mation of 7a and 7b was almost completely abolished
(<1%; Table 4, entries 3 and 4). The counter anion of the
S-methylisothiouronium salt in THF is thus a critical pa-
rameter for the guanidinylation of amines.
Supporting Information for this article is available online at
Table 4 Guanidinylation of Amines with 6a
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Me
R
S
HN
2–
2–
1/2
1/2
SO4
SO4
RNH2 (1.0 equiv)
References and Notes
H2O or THF
25 °C, 6–12 h
+
H2N
NH2
H2N
NH2
+
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7
R
Solvent
Time
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2
3
4
7a
7b
7a
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4-ClC6H4CH2
n-Bu
H2O
H2O
THF
THF
12
6
67
81
4-ClC6H4CH2
n-Bu
12
6
1
N.D.c
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b Determined by 1H NMR spectroscopic analysis.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 983–986

986
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LETTER
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portion, amine (10 mmol) or α,ω-diamine (5 mmol) was
added to a stirring suspension of S-methylisothiouronium
iodide 1 or 2 (10 mmol) in anhydrous THF (10 mL) at 25 °C.
The mixture was stirred at 25 °C for 6–24 h, then evaporated
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precipitate was dried in vacuo for 12 h at 40 °C to give the
corresponding guanidine hydroiodide.
1-Butyl-2,3,3-trimethylguanidine Hydroiodide (3d):
Yield: 2.85 g (>99%); pale-yellow oil. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.94 (t, J = 7.2 Hz, 3 H, CH3), 1.38 (sext,
J = 7.2 Hz, 2 H, CH2CH3), 1.71 (quint, J = 7.2 Hz, 2 H,
NCH2CH2), 3.04 (d, J = 4.8 Hz, 3 H, NHCH3), 3.13 [s, 6 H,
N(CH3)2], 3.35 (q, J = 6.8 Hz, 2 H, NCH2CH2), 6.72 (br s,
1 H, CH2NH), 7.10 (br s, 1 H, NHCH3). 13C NMR (100
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(NHCH3), 31.8 (NCH2CH2), 40.6 [N(CH3)2], 44.5
(NCH2CH2), 159.5 (N=CN).
n-Butylguanidine Hydroiodide (4d): Yield: 2.44 g
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NCH2CH2), 3.08 (q, J = 7.2 Hz, 2 H, NCH2CH2), 6.51–7.49
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Synlett 2014, 25, 983–986
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