Synthesis of five- and six-membered cyclic guanidines by guanylation with isothiouronium iodides and amines under mild conditions

Article abstract of DOI:10.1080/00397911.2016.1269927

Cyclic guanidine hydroiodides were obtained in one step by the reactions of isothiouronium iodides with an equimolar amount of various amines in tetrahydrofuran. The obtained hydroiodides were neutralized with sodium hydroxide or anionic exchange resin to afford the corresponding substituted cyclic guanidines in quantitative yields.

Full text of DOI:10.1080/00397911.2016.1269927

Synthesis of five- and six-membered cyclic guanidines by guanylation with
isothiouronium iodides and amines under mild conditions
Naoto Aoyagi1, Takeshi Endo1
1Molecular Engineering Institute, Kindai University, Iizuka, Fukuoka
Address correspondence to Takeshi Endo, Molecular Engineering Institute, Kindai
University, 11-6 Kayanomori, Iizuka, Fukuoka 820-8555. E-mail:
tendo@moleng.fuk.kindai.ac.jp
Supplemental data (experimental detail and 1H and 13C NMR spectra) can be accessed on
the publisher’s website.
Abstract
Cyclic guanidine hydroiodides were obtained in one step by the reactions of
isothiouronium iodides with an equimolar amount of various amines in tetrahydrofuran.
The obtained hydroiodides were neutralized with sodium hydroxide or anionic exchange
resin to afford the corresponding substituted cyclic guanidines in quantitative yields.
GRAPHICAL ABSTRACT

KEYWORDS: Cyclic guanidine; Five-membered; Six-membered; Hydroiodide;
Isothiouronium iodide
INTRODUCTION
The guanidine group is an important structural component in a number of natural
products and pharmaceutical chemicals, playing important roles in many biochemical and
physiochemical events.[1] In addition, guanidines are well known strongly basic
compounds that have been extensively used as organocatalysts for C-C and C-X bond
formation reactions and polymerization reactions.[1e,2–11] In most cases, cyclic guanidines
give better results than acyclic counterparts. Among them, the cyclic guanidine, 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD), is one of the most versatile organocatalysts. Recent
examples of the organocatalytic reactions using cyclic guanidines include Michael,[2]
oxa-Michael,[3] Aldol,[4] Henry,[5] Wittig,[6] and 1,4-addition reactions of 5H-oxazol-4-
ones to alkynones,[7] amidations,[8] esterifications,[9] ring-opening polymerizations[10] and
other various reactions.[1e,11] Moreover, guanidine derivatives have attracted increasing
attention as reagents for carbon dioxide (CO2) capture and activation.[12–14]

The synthetic utility of cyclic guanidines as well as the widespread occurrence in nature
has inspired considerable development of synthetic methodology. Although various
synthetic methods for cyclic guanidines have been already reported, most of the efficient
methods require multi-step reactions including introduction and removal of protecting
groups.[15] For example, N-Boc protected guanylating reagents give various cyclic
guanidines in moderate to high yields. However, these guanylating reagents themselves
have to be prepared in two to three steps in moderate yields. One of the simplest methods
for the synthesis of cyclic guanidines is the direct reaction of isothiouronium salts and
alkyl(aryl)amines, although the reactions need to be conducted in water or alcohols under
refluxing conditions.[16] In particular, six-membered cyclic guanidines are difficult to
obtain quantitatively even at microwave irradiation (160 °C).[17] Therefore, the
development of facile synthetic methodologies for cyclic guanidines under mild
conditions is demanding. Recently, we have reported that acyclic guanidines are obtained
in one step by guanylation of various amines with an equimolar amount of
isothiouronium iodides in high yields under mild conditions.[18] It should be of great
interest to establish the synthetic method for cyclic guanidines based on the one for
acyclic guanidines. In this paper, we report an efficient synthesis of cyclic guanidines (3

and 4) by equimolar reaction between amines and S-methylisothiouronium iodides (1•HI
and 2•HI) under ambient conditions (Scheme 1).
RESULTS AND DISCUSSION
Iodides 1•HI and 2•HI were prepared quantitatively from ethylenethiourea or
trimethylenethiourea with methyl iodide.[16d,19] First, we investigated the reaction with 2-
(methylthio)-4,5-dihydro-1H-imidazole hydroiodide (1•HI) as a guanylating reagent,
since it is highly reactive with amines than 2-(methylthio)-1,4,5,6-tetrahydropyrimidine
hydroiodide (2•HI) (Table 1). The guanylation with 1•HI was optimized by various
solvents using n-butylamine as a model alkylamine. In general, guanylation with
isothiouronium salts is carried out using polar protic solvents such as alcohols under
refluxing conditions.[16] As expected, the use of either water or ethanol as solvent gave
the cyclic guanidine 3a•HI in only moderate yields at 25 °C after 24 hours (entries 1 and
2). The protic solvents can interact with the amine groups via hydrogen bonds formed
between the hydroxyl and the lone pair electrons on the nitrogen atom, which decrease
the ability of nucleophilic attack from the amine group to the cationic carbon of 1•HI. In
contrast, the use of the polar aprotic solvents such as N,N-dimethylformamide (DMF),

acetonitrile, or tetrahydrofuran (THF) resulted in increased yields of 85-90% under the
same ambient conditions (entries 3-5). The use of non-polar solvents such as
dichloromethane, chloroform and diethyl ether showed similar results to those using polar
aprotic solvents (entries 6-8). The yield of 3a•HI in THF increased when the reaction
temperature was raised from 25 to 45 °C (entry 9). Thus, THF gave the highest yield
among the solvents investigated here.
Next, we investigated the effect of the counter anions of the salts of 1 on the guanylation
of n-butylamine under ambient conditions (Table 2). It has been reported that the
guanylation of amines with isothioureas such as 2-methylthio-2-imidazoline 1 required
long reaction time and/or high temperature under alkaline or acidic conditions.[20] The
isothiourea 1 gave no cyclic guanidine 3a by using THF in the absence of alkaline or
acidic reagent (entry 1). In contrast, the use of the chloride (1•HCl) and the bromide
(1•HBr) resulted in increased yields of 68% and 81%, respectively (entries 2 and 3),
when the iodide salt (1•HI) was used as the guanylating reagent, the yield was further
increased up to 90% (entry 4). The order of reactivity of 1 and 1•HX was 1•HI > 1•HBr >
1•HCl >> 1, which indicates that the reactivity of 1•HX with amine is highly affected by

the counter anion of 1•HX; The electrophilicity of the cation moiety of 1•HX was more
enhanced by the “soft” iodide anion than the bromide anion and the “hard” chloride anion.
Furthermore, we examined the guanylation of various amines with 1•HI in THF at 40 °C,
followed by neutralization with aqueous sodium hydroxide solution (Table 3). Alkyl,
heterocyclic-methyl and arylmethyl amines were smoothly guanylated within 24 h to the
corresponding guanidine derivatives 3a-j•HI in high yields (entries 1-10). The 4-
chlorobenzylamine was converted to the guanidine hydroiodide much slower than other
amines, owing to the lower nucleophilicity due to the electron withdrawing chloro group
(entry 11). It should be noted here that all the guanidine hydroiodides (3a-f•HI) were
purified simply by washing with ether, and were isolated in quantitative yields. Then, the
hydroiodides were neutralized by 40% sodium hydroxide solution, and were isolated in
high yields (≥ 98%) without hydrolysis of the cyclic guanidine structure.
We also examined the guanylation of various amines with 2•HI in THF at 40 °C,
followed by neutralization with aqueous sodium hydroxide solution (Table 4). As in the
reactions using 1•HI, alkylamines were smoothly guanylated with 2•HI into the

corresponding guanidine derivatives 4a-c•HI in high yields (entries 1-3). Although (2-
pyridylmethyl)amine or benzylamine was quantitatively converted to the guanidine
hydroiodide (4d•HI or 4e•HI), it took a very long time to complete (entries 4, 5). The
hydroiodides of six-membered cyclic guanidines were also neutralized by 40% sodium
hydroxide solution, and were isolated in high yields (≥ 98%) without hydrolysis of the
cyclic guanidine structure as with five-membered cyclic guanidines.
Finally, our synthetic method was applied to the synthesis of hydroxyl-functionalized
cyclic guanidines, which are an emerging class of interesting compounds that can be used
as CO2-capturing agents[21] and organocatalysts for the Henry reaction and Knoevenagel
condensation.[22] The hydroxyl-functionalized cyclic guanidines also used as
intermediates for the synthesis of bicyclic guanidines.[23] The guanylation of
ethanolamine in acetonitrile at reflux was reported to give hydroxyl-functionalized
guanidine hydroiodide in 71% yield.[23] Under the conditions described here, the
guanylation of ethanolamine with 1•HI and 2•HI in THF at 40 °C readily proceeded to
afford the corresponding hydroxyl-appended guanidines 3l•HI and 4f•HI in quantitative
yields (Scheme 2). The hydroiodides (3l•HI and 4f•HI) were neutralized by anion-

exchange resin such as amberlyst A-26 (OH) instead of 40% sodium hydroxide solution,
because hydroxyl-functionalized free guanidines are difficult to isolate from alkaline
aqueous solution. Both 3l and 4f were purified simply by filtration, and were isolated in
quantitative yields.
CONCLUSION
In summary, we have found that amines are guanylated by the reaction with
isothiouronium iodides to give five- and six-membered cyclic guanidine hydroiodides
under mild conditions. The hydroiodides are neutralized with sodium hydroxide or
anionic exchange resin to afford the corresponding substituted cyclic guanidines in
quantitative yields without hydrolysis of the cyclic guanidine structure. We believe that
this method will find use in the development of guanidine-based organocatalysts for the
synthesis of cyclic carbonates from epoxides with CO2 under the ambient conditions, and
studies toward this end are ongoing in our group.
EXPERIMENTAL

All starting materials and dehydrated solvents were purchased from Aldrich, Wako Pure
Chemical Industries (Osaka, Japan), Tokyo Kasei Kogyo (Tokyo, Japan) and Kanto
Chemical (Tokyo, Japan), and were used without further purification.
1H (400 MHz) and 13C (100 MHz) nuclear magnetic resonance (NMR) spectroscopy
measurements were performed on a JEOL ECS-400/SS instrument using
tetramethylsilane as an internal standard at ambient temperatures. EI- and FI-HRMS were
obtained on a JEOL JMS-T100GCV. ESI-HRMS was obtained on a JEOL AccuTOF
JMS-T100LP.
Synthesis Of 3a-K And 4a-E; General Procedure
In one portion, amine (11 mmol) was added to a stirring suspension of S-
methylisothiouronium iodide 1•HI or 2•HI (10 mmol) in anhydrous THF (10 mL) at
room temperature. The mixture was stirred at 40 °C for 24-120 h, then evaporated under
reduced pressure. The residue was washed with Et2O, and the precipitate was dried in
vacuo for 12 h at 40 °C to give quantitatively the corresponding guanidine hydroiodide.
The hydroiodide was added to a 40% NaOHaq (10 mL). To the mixture was added

CH2Cl2 or acetonitrile (20 mL), and was vigorously stirred at room temperature for 5-10
minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2 or
acetonitrile (10 mL × 2). The combined organic phase was dried with Na2SO4, then
evaporated under reduced pressure. The residue was dried in vacuo for 12 h at 40 °C to
give the corresponding cyclic guanidine in high yield (≥ 98%).
Neutralization Of 3l•HI And 4f•HI
Hydroiodides 3l•HI and 4f•HI were obtained by general procedure in ref. 20. The
amberlyst A-26 (OH) (10 g) was added to the mixture of hydroiodide (10 mmol) in
methanol (10 mL) at room temperature. After the mixture was stirred at room
temperature for 12 h, the heterogeneous mixture was filtered and the residue was washed
with methanol (10 mL × 2). The filtrate was evaporated under reduced pressure, and the
residue was dried in vacuo for 12 h at 40 °C to give the corresponding cyclic guanidine in
high yield (>99%).
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Table 1. Effect of solvent on the synthesis of the five-membered cyclic guanidine 3a•HI
from 1•HI and n-butylamine.a
Entry
Solvent
H2O
Temp./°C
Yield/%b
69
1
2
3
4
5
6
7
8
9
25
25
25
25
25
25
25
25
40
EtOH
DMF
73
85
CH3CN
THF
87
90
CH2Cl2
CHCl3
Et2O
86
84
87
THF
97
aReaction conditions: 1 mmol of 1•HI, 1 mmol of n-butylamine, 1 mL of solvent, 25 or
40 °C for 24 h. bDetermined by 1H NMR.

Table 2. Effect of anion moiety of 1•HX on the synthesis of the five-membered cyclic
guanidine under ambient conditions.a
Entry
Reagent
1
Yield/%b
1
2
3
4
Not detected
1·HCl
1·HBr
1·HI
68
81
90
aReaction conditions: 1 mmol of 1 or 1•HX, 1 mmol of n-butylamine, 1 mL of anhydrous
THF, 25 °C for 24 h. bDetermined by 1H NMR.

Table 3. Synthesis of various five-membered cyclic guanidines 3a-k from 1•HI and
amines.a
Entry
R
Time/h
24
Yield/%b
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
3
1
n-Bu
3a
3b
3c
3d
3e
3f
2
CH2=CHCH2
MeOCH2CH2
Me2NCH2CH2
i-Pr2NCH2CH2
Furfuryl
24
3
24
4
24
5
24
6
24
7
Thienyl
24
3g
3h
3i
8
2-PyCH2
24
9
PhCH2
24
10
11
4-CH2=CHC6H4CH2
4-ClC6H4CH2
24
3j
72
98
3k
aReaction conditions: 10 mmol of 1•HI, 11 mmol of amine, 10 mL of anhydrous THF,
40 °C for 24-72 h. bIsolated yields as free guanidines 3a-k.

Table 4. Synthesis of various six-membered cyclic guanidines 4a-e from 2•HI and
amines.a
Entry
R
Time/h
24
Yield/%b
>99
4
1
2
3
4
5
n-Bu
4a
4b
4c
4d
4e
CH2=CHCH2
MeOCH2CH2
2-PyCH2
PhCH2
24
>99
24
>99
120
120
98
98
aReaction conditions: 10 mmol of 2•HI, 11 mmol of amine, 10 mL of anhydrous THF,
40 °C for 24-120 h. bIsolated yields as free guanidines 4a-e.

Scheme 1. Guanylation under ambient conditions.

Scheme 2. Synthesis of hydroxyl-functionalized cyclic guanidines.