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Convenient Synthesis of Acyclic Guanidines from Isothiouronium Iodides and
Amines without Protection of the Amino Groups

Naoto Aoyagi, Yoshio Furusho, Takeshi Endo*
Convenient Synthesis of Acyclic Guanidines

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

Key words: guanidines, synthetic methods, amines, nucleophiles,

increasing interest in the efficient CO2-capture and activation ability of substituted guanidines. In this paper, we report an efficient one-step synthesis of acyclic guanidines
3 and 4 by equimolar reaction between amines and S-methylisothiouronium iodides 1 and 2 under ambient conditions without an N-protection/deprotection procedure
(Scheme 1).

Both acyclic and cyclic guanidines are used as important
key compounds for natural products and pharmaceutical
chemicals.1 Generally, guanidine derivatives are wellknown, strongly basic compounds2 that have been extensively used as organocatalysts for C–C and C–X bond formation 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 reactions,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.
Although various methods for the synthesis of guanidines
have already been reported, most approaches require multistep reactions and tedious procedures. For example, although 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 isothiouronium salts and alkyl(aryl)amines, the reactions
need to be conducted in water or alcohols for several
hours under reflux, which severely restricts their application.16 Therefore, the development of facile synthetic
methodologies for substituted guanidines under mild conditions is awaited, especially with respect to an everSYNLETT 2014, 25, 0983–0986
Advanced online publication: 18.03.20140936-52141437-2096
DOI: 10.1055/s-0033-1340904; Art ID: ST-2014-U0013-L
© Georg Thieme Verlag Stuttgart · New York





R1 I–


1 R1 = Me
2 R1 = H



(1.0 equiv)

25 °C, 6–24 h




R1 I–



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-methylisothiouronium iodide (1) as a guanidinylating reagent, because the reaction products are easier to
characterize by 1H NMR spectroscopic analysis than
those with unsubstituted S-methylisothiouronium iodide
(Table 1). The guanidinylation with 1 of 4-chlorobenzylamine 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 tetrahydrofuran (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 chloroform gave similar results to those using ethanol and water
(entries 6 and 7). Thus, THF gave the highest yield among
the solvents investigated.
The conformation of 1 in reaction solvents was investigated by 1H and 13C NMR spectroscopic analysis using various 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 appeared in the 1H and 13C NMR spectra of the THF-d8 soluble part under the same conditions (Scheme 2, see also

Downloaded by: Dot. Lib Information. Copyrighted material.

Abstract: 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.

Lib Information.16d 1-(4chlorobenzyl)guanidine hydroiodide (4a) was isolated in high yield (99%. Figures S1 and S2). entries 1and 2). In particular. which shifted the peak of the methyl protons (2. 12 h.68 ppm (NH) I– doublet (3JHCNH = 4. see also Table 1. entries 1 and 4).and alkylamines were smoothly guanidinylated with 2 into the corresponding guanidine derivatives 4b–k in high yields (98–100%. the Supporting Information. entry 1).8 ppm) with respect to the quaternary carbon of 1 (168. amine (10 mmol). the guanidinylation of ethanolamine and 4-hydroxybutylamine in THF at 25 °C proceeded to afford the corresponding hydroxy-appended guanidines 4m and 4n in high yields (98–100%.8 ppm (N+CN) THF-d8 25 °C S O NH N 6.0 equiv) organic solvent 25 °C. It was assumed that 5 would be highly reactive towards amines. owing to the higher nucleophilicities due to the absence of the electronwithdrawing chloro group (Table 2. Figure S2). because the 13C NMR signal of the cationic carbon of 5 was shifted low field (184. 6–24 h. 25 °C. the use of the polar aprotic solvent such as THF resulted in increased yields to 99–100% yield in the reaction of iodide 2 with amines (Table 3. and all were isolated in high yields (≥ 98%).61 ppm 1 (NH+) 184. entry 5).LETTER N. Table 4. It should be noted here that all guanidines 3a–f were purified simply by washing with diethyl ether. In contrast to the guanidinylation of 4-chlorobenzylamine in water/ethanol mixture. The new signals observed for 5 were assumed to arise from localization of the proton on the nitrogen atom. Aoyagi et al. 984 .19 The guanidinylation of 4-chlorobenzylamine required a long reaction time to complete (Table 2.4 Hz) 5 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). As in the reactions using 1. Table 3. anhydrous THF(10 mL). Table 3. the for- © Georg Thieme Verlag Stuttgart · New York Downloaded by: Dot. entries 2–6). 983–986 Yield (%)b Entry 3 R Time (h) 1 3a 4-ClC6H4CH2 24 98 2 3b PhCH2 6 >99 3 3c 4-H2C=CHC6H4CH2 6 98 4 3d n-Bu 6 >99 5 3e CH2=CHCH2 6 >99 6 3f Me2NCH2CH2 6 >99 a Reaction conditions: 1 (10 mmol). S-Methylisothiouronium sulfate (6) is readily available as a commercial product. entries 13 and 14).6 ppm (NCN) singlet (CH3) N H – I 9. solvent (1 mL). entry 1.22 Under the conditions described here. 1b and 1d–f were quantitatively guanidinylated at 25 °C within 6 h. We also examined the guanidinylation of various amines with 2 in THF at 25 °C (Table 3). which was reported to give low yield. We then investigated the effect of the counter anions of Smethylisothiouronium salts on the guanidinylation of amines under ambient conditions (Table 4). In contrast.4 Hz). other benzyl. b Isolated yield. Hydroxyl-functionalized guanidines are an emerging class of interesting compounds that can be used as CO2-capturing agents20 and organocatalysts for the Henry reaction and the Knoevenagel condensation.0 equiv) Me Me THF 25 °C. 6–24 h N + R NH Me I– Me 3a–f 3a Solvent Yield (%)b 1 H 2O 74 2 EtOH 77 3 DMF 87 4 MeCN 92 5 THF 94 6 CH2Cl2 84 7 CHCl3 76 a Reaction conditions: 1 (1 mmol). 4-chlorobenzylamine (1 mmol).99 ppm) and led to a doublet multiplicity (3JHCNH = 4. Even a bulky secondary amine such as dicyclohexylamine was quantitatively guanidinylated to 4l under the ambient conditions (entry 12). 25. see the Supporting Information. entry 1. Other benzyl and alkyl amines were converted into the guanidines much faster than 4-chlorobenzylamine. 25 °C. N + – Cl Entry S N HN S 168. Table 1 Effect of Solvent on the Guanidinylation of 1a Table 2 Guanidinylation of Amines with 1a Me H2N Me Me N S + – Me I 1 N H Me (1. entries 2–11). thus the nature of the counter anions did not influence the reaction in polar protic solvent such as water. b Determined by 1H NMR spectroscopic analysis.21 The guanidinylation of ethanolamine in ethanol at reflux was reported to give hydroxyfunctionalized guanidine 4m in 70% yield. Both the iodide 1 and the sulfate 6 gave acyclic guanidines 3a.6 ppm. whereas when sulfate 6 was used as the guanidinylating reagent. Table 3. 7a and 7b in only moderate yields in water (Table 1. Copyrighted material. 12 h HN Cl Me N + – Me NH Me I 1 Me I Me N H RNH2 (1. Synlett 2014.

. Ed. A... Lib Information. Flores. 61.c a Reaction conditions: 6 (1 mmol). 6–12 h. anhydrous (10 mL). amine (1 mmol).. our synthetic method was applied to the synthesis of acyclic bisguanidines. © Georg Thieme Verlag Stuttgart · New York + I– I– http://www. The counter anion of the S-methylisothiouronium salt in THF is thus a critical parameter for the guanidinylation of amines.. Org.. Terada. (2) Ishikawa. 25 °C. Int. Biodiversity 2012. in excellent yields under ambient conditions. M. G. Int. 24. P. Burtoloso. De Vos. Bardeau.. D. D. K. Tarasyuk. Synlett 2013. Mizuno.LETTER R2 S H2N + R1R2NH (1. >99% Scheme 3 Guanidinylation of α. B. 100. E. L.. 2009. L.ω-diamines with 2 In summary. we have found that amines are guanidinylated by reaction with isothiouronium salts to give acyclic guanidines in a single step without an N-protection/deprotection procedure. Mioskowski. Baati. Harwood. c Not detected. K. 4104. Bisguanidines 4o–q were isolated in high yields (98–100%) by simple purification. Teng. Macro Lett. Y.-F. 6–12 h. (4) Pahadi. C. Supporting Information for this article is available online at References and Notes NH2 7a. 983–986 Downloaded by: Dot.. (5) Ghobril.0 equiv) S (1) (a) Rogalskyy. (d) Berlinck. V.. D. (b) Treat.. 686. A.4-diaminobutane. 25 °C. John Wiley & Sons. b Determined by 1H NMR spectroscopic analysis.. 27. 2008. 1871. 48. W. which are compounds of pharmaceutical interest that show a blocking ability for neural nicotinic acetylcholine receptors16b and some antibiotic activity..D. 9.23 Bisguanidines were also used as ligands for some transition-metal complexes. M. J.. Polym. Chem. 1997. N. F. M. 25. including bioactive bisguanidines. York. and studies toward this end are ongoing in our group. J. Ed. P. Chem. This mild method can be applied to various amines to afford the corresponding acyclic guanidines. A.d 4 R1 R2 Time (h) 1 4a 4-ClC6H4CH2 H 12 99 2 4b PhCH2 H 6 >99 3 4c 4-H2C=CHC6H4CH2 H 6 >99 4 4d n-Bu H 6 >99 5 4e n-Oct H 6 >99 6 4f Cy H 6 >99 Me 98 2 H2N Entry 7 4g i-Pr H 6 Yield (%)b 8 4h CH2=CHCH2 H 6 >99 9 4i propargyl H 6 >99 10 4j Me2NCH2CH2 H 6 >99 11 4k MeOCH2CH2 H 6 >99 12 4l Cy Cy 6 >99 13 4m HOCH2CH2 H 6 98 14 4n HO(CH2)4 H 6 >99 a Reaction conditions: 2 (10 mmol). N.. Abel. A. in contrast to the previous report that the guanidinylation of these diamines in ethanol–water at reflux gave the corresponding bisguanidines in moderate yields. Ube. Morais. (e) Ishikawa. Table 3 Guanidinylation of Amines with 2a Me 985 Convenient Synthesis of Acyclic Guanidines . We believe that this method will find use in the development of guanidinebased organocatalysts for the synthesis of cyclic carbonates from epoxides with CO2 under ambient conditions.. J. 6 h 2 NH2 H N + H2N N H NH2 n + NH2 I– 4o (n = 1). O. and tetramethylene spacers 4o–q were synthesized by nucleophilic substitutions on 2 with 1. H2N S + 1/2 SO42– HN RNH2 (1. J.com/ejournals/toc/synlett. 2010. C. In Superbases for Organic Synthesis: Guanidines. 1. 8700. 331.. E. Amidines.. R. Trinidade-Silva. T.. C. K. THF. mation of 7a and 7b was almost completely abolished (<1%.thieme-connect.3-diaminopropane. Eur. >99% 4p (n = 2). Copyrighted material. Smith. 2007. Fatyeyeva... C. 6–12 h NH2 I– 2 N H2N R1 + NH2 I– 4a–n Finally. McCormick. 98% 4q (n = 3).SonurmfIpgitSa Table 4 Guanidinylation of Amines with 6a Me NH2 H2N n (1. A.24 Bisguanidines with di-. T. 2661.2-diaminoethane. Angew. and 1. Bandeira. C.0 equiv) THF 25 °C. Sabot..b Entry 7 R Solvent Time (h) Yield (%)b 1 7a 4-ClC6H4CH2 H2 O 12 67 2 7b n-Bu H2 O 6 81 3 7a 4-ClC6H4CH2 THF 12 1 4 7b n-Bu THF 6 N. S. (3) Subba Rao. 1. Synlett 2014.. S. Ishikawa. Tetrahedron Lett. S.. entries 3 and 4). R. 36. Phosphazenes and Related Organocatalysts. respectively. Rep. R. 2012. Jacobs.. 6–12 h NH2 H2N 6 + R 1/2 SO42– NH2 THF 25 °C.. F. Romminger. H. 2012. b Isolated yield.0 equiv) H2O or THF 25 °C. Ltd: Chichester. in THF at 25 °C for 6 h (Scheme 3). Nat. Table 4. Huang. amine (10 mmol). C.16b. (c) Pietra. C. Chem. 2507. B. 1–326. tri-. Prod. solvent (1 mL). T.

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