Micelle-Enabled One-Pot Guanidine Synthesis in Water Directly from Isothiocyanate using Hypervalent Iodine(III) Reagents under Mild Conditions

Article abstract of DOI:10.1002/asia.201900982

In this work, we developed a one-pot synthesis of guanidine directly from isothiocyanate using DIB (diacetoxyiodobenzene) as a desulfurizing agent under micellar conditions in water. Our optimization study revealed that the use of 1 % TPGS-750-M as a surfactant with NaOH as an additive base at room temperature can convert a variety of isothiocyanates and amines into corresponding guanidines in excellent yields (69–95 %). This synthetic process in water can be applied to prepare guanidine at gram-scale quantity. Our aqueous micellar medium also demonstrated high reusability as the reaction can be performed for several cycles without losing its efficiency. The reaction is metal-free, utilizes water as solvent and practical (room temperature and open flask).

Full text of DOI:10.1002/asia.201900982

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Micelle-enabled one pot guanidine synthesis in water directly
from isothiocyanate using hypervalent iodine(III) reagents under
mild condition
Authors: Jakkrit Srisa, Theeranon Tankam, Mongkol Sukwattanasinitt,
and Sumrit Wacharasindhu
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10.1002/asia.201900982
Chemistry - An Asian Journal
FULL PAPER
Micelle-enabled one pot guanidine synthesis in water directly from
isothiocyanate using hypervalent iodine(III) reagents under mild
condition
Jakkrit Srisa,[a,b] Theeranon Tankam,[a] Mongkol Sukwattanasinitt,[a,c] and Sumrit Wacharasindhu*[b,c]
Abstract: In this work, we developed a one-pot synthesis of
guanidine directly from isothiocyanate using DIB
guanylating agents such as isothioureas38-40, carbodiimide41-44
,
amidine45, cyanamide46-49, pyrrazole50, triflylguanidines51 and
thiourea52-54. Among them, thiourea are the most promising
guanylating agent because of their stability and ease of
preparation. The two-step synthesis of guanidine from thiourea
begins with the formation of thiourea (4) from isothiocyanate (3)
and the corresponding amine (Scheme 1). The second step
involves the coupling reaction between thiourea and amine using
desulfurizing agents such as metals or non-metal mediators
(Scheme 1). For metal mediators, oxidizing agent such as
mercury chloride55 and copper chloride56 have been employed.
Even though such reagents are highly efficient and compatible
with wide verity of functional groups but the use of toxic metal and
organic solvent are unavoidable. On the other hands, for non-
metal mediators, ethyl-3-aminopropyl carbodiimide hydrochloride
(EDCI)57 and Mukaiyama’s reagent 58 and TCT (trichloro cyanuric
acid)59 and I2/PPh360 have been used in a metal-free process.
(diacetoxyiodobenzene) as a desulfurizing agent under micellar
condition in water. Our optimization study revealed that the use of
1% TPGS-750-M as a surfactant with NaOH as an additive base
at room temperature can convert a variety of isothiocyanates and
amines into corresponding guanidines in excellent yields (69 -
95%). This synthetic process in water can be applied to prepare
guanidine at gram-scale quantity. Our aqueous micellar medium
also demonstrated high reusability as the reaction can be
performed for several cycles without losing its efficiency. The
reaction is metal-free, utilize water as solvent and practical (room
temperature and open flask).
Introduction
Organic solvents are the most widely used reaction medium
in both academic and industry. However, its uses contribute to
environmental pollution. In recent years, water has gained
popularity as an alternative medium as it is safe, affordable and
has low environmental footprint. Neat water or so called “on-water”
reaction was first introduced by Sharpless.1-3 Since then many
elegant reactions have been reported.4-12 Although on-water
reactions offer much benefits, wide-spread adoption has been
limited by inability of on-water reaction to be adapted to all
CN
N
N
HN
N
NH
S
CH3
N
N
H
H
HN
N
H3C
CN
Cimetidine (H2 blocker drug)
Pinacidil drug
1
2
H
R3
N
R4
Previous work
metal
; HgCl2, CuCl2
R3
R4
N
or non-metal ; EDCI, TCT, IBX
mukaiyama's reagent, I2/PPh3
R2
S
N
H2NR2
R1
R1
R2
R1
N
C S
N
H
N
H
N
H
in organic solvent
traditional
chemical
transformation
reactions
due
to
3
4
5
heterogeneous behaviour. In recent years, new developments in
surfactant technology created by Lipshutz13-18 and others19-34 have
significantly made an improvement for aqueous reactions
allowing reaction to occur “in-water” via the formation of micelles,
thereby providing high reproducibility and reactivity.
1) H2N R2 TPGS-750-M/H2O
H
This work
(one-pot in water)
3
N
R4 DIB, rt.
2)
R
Guanidines are important moieties that attract many
interests in agricultural and pharmaceutical industry due to their
broad spectrum of biological activities.35-37 Many therapeutic
agents have been constructed from this scaffold such as
Cimetidine 1 (treatment of heartburn and peptic ulcers) and
Pinacidil 2 (treatment of hypertension) (Scheme 1). Typical
synthesis of guanidine involves reaction between an amine and
Scheme 1. Guanidines with biological activities and synthetic approaches
Recently, hypervalent iodine have received much attention
as oxidants due to their environmentally friendly character, ease
of handling, selectivity and reasonable cost.61-62 Because of the
broad synthetic potential of hypervalent iodine, IBX (2-
Iodoxybenzoic acid) have been reported as desulfurization agents
for guanidine synthesis from thiourea.63 However, for non-metal
mediated guanidine synthesis including IBX, requires a two-step
process from isocyanate (3) and the use of organic solvent as
medium in combination with stoichiometric organic amine base
are required. From green chemistry perspective, the use of
harmful organic solvent/base and multiple-step process would
increase the operating cost and risk in large scale production.
Therefore, a mild, scalable, metal-free and more practical
approach for guanidine synthesis in a greener medium would be
highly desirable for both academia and industry. In view of this
new development, herein we report an efficient one-pot synthesis
[a]
Department of Chemistry, Faculty of Science, Chulalongkorn
University, Bangkok 10330, Thailand
[b]
[c]
Center of Excellence on Petrochemical and Materials Technology,
Chulalongkorn University, Bangkok, Thailand
Nanotec-CU Center of Excellence on Food and Agriculture,
Department of Chemistry, Faculty of Science, Chulalongkorn
University, Bangkok 10330, Thailand. E-mail: sumrit.w@chula.ac.th
Supporting information for this article is given via a link at the
end of the document.((Please delete this text if not
appropriate))
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10.1002/asia.201900982
Chemistry - An Asian Journal
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of guanidine directing from isothiocyanate (3) mediated by DIB
(diacetoxyiodobenzene) as oxidant in water. The reaction was
performed in a micellar system, TPGS-750-M/H2O, in the
presence of non-hazardous and inexpensive sodium hydroxide as
base at room temperature under open-flask condition (Scheme 1).
Table 1. Optimization of the reaction conditiona
1)
H2N
H
N
H
N
H
N
N
2) H2
N
NCS
HN
S
solvent.1h., rt.
DIB, 1h., rt.
5a
3a
4a
Result and discussion
Yield (%)b
Entry
Reaction medium
Additive
4a
28
71
51
42
20
15
10
15
17
5
5a
50
19
35
39
60
52
54
61
67
75
69
70
40
83
We selected phenyl isothiocyanate (3a) as a starting material to
perform
a two-step sequence guanidine synthesis using
1
2
MeCN
H2O
None
None
benzylamine as nucleophile for the formation of thiourea 4a and
subsequently added butylamine and hypervalent iodine (III), DIB,
to facilitate guanidine formation. This is used as a representative
one-pot reaction for the optimization investigation (table 1). We
would like to note here that although related hypervalent (V) IBX
were used in guanidine synthesis as mentioned above, the
reagent poses serious drawback because of its potential shock
sensitive nature.64 Thus, we decided to use a non-explosive
hypervalent iodine(III) such as DIB as oxidant instead. Initially, the
reaction was conducted in acetonitrile. Resulting guanidine
products 5a were isolated in 50% yield along with unreacted
intermediate thiourea 4a in 28% yield (Table 1, entry1). Switching
from traditional organic solvent to neat water, as expected,
reduced guanidine 5a to 19% yield along with increasing
unreacted intermediate thiourea 4a to 71% yield (Table 1, entry
2). Poor conversion is caused by heterogeneous nature of the on-
water reaction. Next, efficiency of selected surfactants was
examined in a model reaction in order to improve the in-water
reaction. Among three surfactants, TPGS-750-M gave the best
result, providing guanidine 5a in 60% yield (Table 1, entry 3-5) .
The superiority of this surfactant over the other could be explained
by highly stable and suitable size of particle formed in water,
which could accelerate the reaction.15 Changing to more
3
2WT%SDS
2wt%TritonX-100
None
4
None
5
2wt%TPGS-750-M
2wt%TPGS-750-M
2wt%TPGS-750-M
2wt%TPGS-750-M
2wt%TPGS-750-M
2wt%TPGS-750-M
2wt%TPGS-750-M
1wt%TPGS-750-M
0.1wt%TPGS-750-M
1wt%TPGS-750-M
None
6c
None
7
1.0 eq. TEA
1.0 eq. KOH
1.0 eq. NaOH
1.5 eq. NaOH
1.5 eq. NaOH
1.5 eq. NaOH
1.5 eq. NaOH
1.5 eq. NaOH
8
9
10
11d
12d
13d
14d,e
14
10
41
-
aReaction conditions: 3a (1.0 equiv. 0.37 mmol) and benzylamine (1.0
equiv.) butylamine (3.0 equiv.) DIB (1.2 equiv.) in water (0.5 M) under room
temperature for 1 h.
hydrophobic
hypervalent
iodine
(III),
BTB
(Bis(tert-
butylcarbonyloxy)iodobenzene) resulted in slightly lower yield of
5a (Table 1, entry 6). We next surveyed the effect of base (Table
1, entry 7-9). To out delight, yield of guanidine 5a increased to
75% along with only small amount of unreacted intermediate
thiourea 4a when 1.5 eq of NaOH was used (Table 1, entry 10).
As we set the goal to create an atom-economy guanidine
synthesis, large excess of reagents must be reduced as much as
possible. In the guanidine formation step, amount of butylamine
were then reduced from 3 to 1.5 equivalent. Fortunately, there
was negligible effect on product 5a yield (69%, Table 1, entry 11).
Lowering TPGS-750-M from 2% to 1% w/w still provided a
comparable yield but when 0.1% w/w were employed, only 40%
yield of 5a were isolated along with large amount of unreacted 4a
(41% yield) (Table 1, entry 12-13). This was likely because the
reaction was carried near the critical micelle concentration of
TPGS-750-M.65 At such concentration, the micelle may not be
formed effectively. Finally, we discovered that upon increasing the
reaction concentration to 1.0 M, the reaction rate was enhanced,
and it was completed within 30 min providing target compound 5a
in 83% yield (Table 1, entry 14).
bIsolated yield cBTB instead of DIB
dn-buthylamine (1.5 equiv.) eReaction concentration = 1.0 M and stirred for
30 min after addition of DIB
O
O
H
n
O
O
O
O
17
O
O
3
TPGS-750-M
Triton X-100
O
OAc
O
I
O
I
O
O
O
O
OAc
O
H3C
6
S
I
O
Na
O
O
HO
SDS
BTB
DIB
IBX
Figure 1. Structure of surfactants and hypervalent iodines used in this work
We would like to emphasize here that the newly developed “in
water” reaction is very convenient and practical. The reaction was
performed in an open test-tube and after the reaction was
completed, crude products could be separated using only a small
amount of ethyl acetate and transferred by a Pasteur pipet for
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10.1002/asia.201900982
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further purification (Figure S1). Having established an optimized
reaction condition (Table 1, entry 14), we then explored the
A panel of phenyl isothiocyanates (3b-3e) were reacted with
benzylamine to form corresponding thioureas which were further
coupled with n-butyl amine to generate desired guanidines (5b-
5e) in good to excellent yields. Here, we demonstrated that phenyl
isothiocyanates containing electron withdrawing group (nitro (3b)
and fluorine groups (3c) and electron donating group (p-
methyl(3c), m-methyl(3e) has no effect on the reaction efficiency.
We next explored the scope of amine in the formation of thiourea.
A variety of primary amines such as 4-chlorobenzylamine, n-
buthylamine, cyclohexylamine, aniline, 4-mtoxyaniline and 2-
aminopyridine were reacted smoothly with phenyl isothiocyanates
3a which subsequently underwent guanidine formation with either
benzyl or n-butyl amines to provide products 5f-5j in satisfactory
yields. Interestingly, bulky amine such as tert-butylamine also
proceeded successfully, offering 5k in excellent yield. Next, a
variety of amines such as cyclohexylamine, morpholine and
diethylamine were tested in the guanidine formation step. Under
the optimized condition, products 5l-n were isolated in high yields.
Importantly, amine containing acid sensitive protecting group
such as BOC protected piperazine were tolerated in our micellar
in water system, and yielded product 5o in 82% yield without any
deprotected by-product. Unfortunately, reaction failed with
aromatic amine (5p) and only corresponding thiourea
intermediate was observed. This is probably due to the poor
nucleophilic property of aniline. We also applied our micellar
coupling reaction in water method to the synthesis of symmetrical
guanidines. For symmetric guanidine, we were able to add an
excess amount of amine (2.5 equivalents) at the first step. After
stirring for 1 hour to ensure complete formation of thiourea, DIB
was added to facilitate the guanidine formation with the remaining
amine from the first step. As shown in Scheme 3, both electron-
withdrawing and electron-donating group substituted on phenyl
isothiocyanates (3a-3e) have almost no effect in thiourea and
guanidine formation as they can react smoothly with butylamine,
cyclohexylamine and benzylamine to provide the desired
guanidines 6a-e, 7a-e and 8a-e, respectively in excellent yields.
To demonstrate the recyclability of the waste water
containing surfactant TPGS-750-M, we reacted phenyl
generality and scope of the reaction across
a series of
isothiocyanate and amine nucleophiles (Scheme 2).
Scheme 2. Substrate scopea
H
H NR1 1wt%TPGS-750-M/H2O, NaOH 1h. rt.
N
N
NCS 1)
2
R1
R
N
2) NHR2R3 DIB 30min. rt.
R2
R3
3a-e
5a-p
Cl
H
H
N
N
N
H
N
N
N
HN
R
HN
HN
5b
5d
5f
5g
;R = p-NO2, 94%
5c;R = p-F, 89%
;R = p-CH3, 92%
75%
89%
5e;R = m-CH3, 91%
H
H
N
H
N
N
N
N
N
CH3
HN
HN
HN
N
O
5h 90%
5i 78%
5j 69%
H
N
N
H
H
N
N
N
N
HN
HN
N
O
5k
5l
5m
90%
78%
72%
H
N
N
H
N
H
N
N
N
NH
N
N
N
Boc
5n 86%
5o 82%
5p 0%
aReaction condition: 3 (1.0 equiv. 0.37 mmol) and H2NR1 (1.0 equiv.), HNR2R3
(1.5 equiv.), DIB (1.2 equiv.) in water (1.0 M)
Scheme 3. Symmetric Guanidine Synthesisa
isothiocyanate
(3a)
with
benzylamine
followed
by
cyclohexylamine (Scheme 4) under the optimized condition.
After each reaction, small amount of ethyl acetate was added, and
this organic layer containing product 5l was collected and purified.
The aqueous layer containing TPGS-750-M was then reused for
three subsequent fresh reaction batches. Excellent results were
obtained without any significant loss in product yields. Importantly,
after 3 recycles, E-factor of 8.3 was found, indicating the low
waste process of this protocol.
H
1) H2NR1 1wt%TPGS-750-M/H2O, NaOH, 1h. rt.
N
N
NCS
R1
R
R
HN
R1
2)
DIB, 30min. rt.
3a-e
6a-e, 7a-e, 8a-e
H
H
N
N
N
NH
N
N
R
R
R
HN
HN
HN
6a; R = H, 89%
6b
7a; R = H, 95%
8a; R = H, 84%
7b
8b
; R = p-NO2, 75%
; R = p-NO2, 92%
; R = p-F, 92%
; R = p-NO2, 95%
8c
; R = p-CH3, 78%
6c
7c
; R = p-F, 80%
6d; R = p-CH3, 86%
6e
7d; R = p-CH3, 89%
7e
8d; R = p-F, 73%
8e
; R = m-CH3, 70%
; R = m-CH3, 81%
; R = m-CH3,91%
aReaction conditions:3 (1.0 equiv. 0.37 mmol) and H2NR1 (2.5 equiv.) DIB
(1.2 equiv.) in water (1.0 M).
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1)
H2N
Visualization was performed with a 254 nm ultraviolet lamp.
Column chromatography was performed by using Merck and
1wt%TPGS-750-M/H2O,
NaOH 1 h. rt.
H
1
N
N
silica gel (60,230–400 mesh) from ICN Silitech. The H and
NCS
13C NMR spectra were recorded on a Varian Mercury 400 or
BrukerAvance 400 for 1H (400 MHz) and Bruker Avance 400
for 13C (100 MHz) in CDCl3 solution. Mass spectrometry was
performed with a MicroTOF Bruker mass spectrometer and
triple quadrupole GC/MS from Agilent Technologies.
HN
5l
2)
H2N
3a
DIB 30 min. rt.
0th
1st
2nd
3rd
cycle
E Factor = 8.3
%Yield of 5l 78% 69%
69%
70%
General experimental procedure A: asymmetry guanidines
5a-5p
Scheme 4. Recycle Studies
In a 5.0 mL reaction vial containing a magnetic stir bar,
isothiocyanate (1.0 equivalent), amine (1.0 equivalent), NaOH
(1.5 equivalent) and TPGS-750-M/H2O (1wt%, 0.4 mL, 1.0 M)
were sequentially added. The reaction mixture was stirred at
room temperature for 1h. After starting material was completely
consumed, as monitored by TLC, amine (1.5 equivalent) and DIB
(1.2 equivalent) were sequentially added and stirring continued
for 30 minutes. Then ethyl acetate (2x1mL) was added to the
reaction mixture, which was stirred for 2 minutes. The organic
layer was transferred using a Pasteur pipet and evaporated
under reduced pressure to give the crude product. The residue
was purified by column chromatography over silica gel by using
25%ethyl acetate in hexane to 100%ethyl acetate as eluent to
obtain guanidine derivative.
To demonstrate the scalability of this protocol, the reaction
was also performed on gram scale (Scheme 5). Treatment of 3a
(1.12 g.) with cyclohexylamine (2.05 g.) under optimized
conditions. It resulted in the formation of 7a in nearly excellent
yield. Importantly, in large scale experiment, resulting product 7a
gradually underwent precipitation out of the reaction medium.
Therefore, we were able to perform the simple filtration and then
wash the solid with hexane/water without further purification by
column chromatography. This suggested the possibility of
reducing the use of organic solvent in extraction and purification
process for large scale reaction. Notably, 1H NMR of 7a is clean
showing no signal of surfactant, by-product iodobenzene or
remaining amine (Figure S43).
NH2
1wt%TPGS-750-M/H2O,
filtration
NCS
NaOH, 1h. rt.
General experimental procedure B: symmetry guanidines
6a-8e
(no extraction)
2)
DIB, 30min. rt.
3a; 1.12 g
2.05 g.
In a 5.0 mL reaction vial containing a magnetic stir bar, isothiocyanate
(1.0 equivalent), amine (2.5 equivalent), NaOH (1.5 equivalent) and
TPGS-750-M/H2O (1wt%, 0.4 mL, 1.0 M) were sequentially added.
The reaction mixture was stirred at room temperature for 1h. after
starting material was completely consumed, as monitored by TLC,
DIB (1.2 equivalent) was sequentially added and stirring continued for
30 minutes. Then ethyl acetate (1 mL x 2) was added to the reaction
mixture, which was stirred for 2 minutes. The organic layer was
transferred using a Pasteur pipet and evaporated under reduced
pressure to give the crude product. The residue was purified by
column chromatography over silica gel by using 25%ethyl acetate in
hexane to 100%ethyl acetate as eluent to obtain guanidine derivative.
after reaction completion
7a; 2.15 g (87%)
Scheme 5. Gram scale synthesis of 7a
Conclusions
In summary, we developed synthesis method for guanidine
directly from isothiocyanate using DIB as desulfurizing reagent
under aqueous micellar medium. The protocol has high selectivity
and high functional group compatibility providing guanidines in
high yields under mild reaction condition. The reactions are
operationally very simple performing at room temperature in an
open-air system. Importantly, micellar medium can be reused,
providing a green and low waste process. Our methodology offers
an alternative route for large-scale synthesis of guanidine for the
chemical industries.
Synthesis of guanidines
1-benzyl-3-butyl-2-phenylguanidine (5a)
General procedure A was followed, using phenyl isothiocyanate
3a (51.1 mg, 0.3780 mmol), benzylamine (40.5 mg, 0.3780
mmol) and butylamine (41.4 mg, 0.5671 mmol). The compound
1
was obtained in yellow oil (0.9489 g, 83% yield.); H NMR (400
Experimental Section
MHz, CDCl3) δ 7.39-7.27 (m, 7H), 6.99 (t, J = 7.6 Hz, 1H), 6.95
(d, J = 7.6 Hz, 2H), 4.39 (s, 2H), 3.12 (t, J = 7.2 Hz, 2H), 1.48-
1.41 (m, 2H), 1.31-1.22 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 151.8, 148.8, 138.9, 129.3, 128.7,
127.5, 127.3, 123.5, 122.0, 46.0, 41.8, 31.7, 19.9, 13.7 [M+H]+ :
calcd 282.1970, found 282.1983.
All chemicals were obtained from commercial suppliers
(Sigma Aldrich), Fluka (Switzerland) or Merck (Germany)
and were used without further purification. All solvents were
used directly without drying. Analytical thin-layer
chromatography (TLC) was performed on Kieselgel F254
pre-coated plastic TLC plates from EM Science.
1-benzyl-3-butyl-2-(4-nitrophenyl)guanidine (5b)
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General
procedure
A
was
followed,
using
4-
133.1, 129.5, 128.8, 128.8, 128.6, 127.6, 127.2, 123.5, 122.3,
46.1, 45.2. [M+H]+ : calcd 350.1424, found 350.1430
nitrophenylisothiocyanate 3a (52.0 mg, 0.2886 mmol),
benzylamine (31.5 mg, 0.2886 mmol) and butylamine (31.6 mg,
0.4329 mmol). The compound was obtained in yellow solid
(0.0855 g, 94% yield.); 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J =
7.6 Hz, 2H), 7.38-7.29 (m, 5H), 6.94 (d, J = 7.6 Hz, 2H), 4.41 (s,
2H), 3.14 (t, J = 7.2 Hz, 2H), 1.50-1.43 (m, 2H), 1.32-1.23 (m,
2H), 0.88 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 156.8,
152.5, 141.1, 138.1, 128.8, 127.7, 127.3, 125.5, 122.6, 46.1,
41.9, 31.5, 19.9, 13.6. [M+H]+ : calcd 327.1821, found 327.1849
1-butyl-3-cyclohexyl-2-phenylguanidine (5g)
General procedure A was followed, using phenylisothiocyanate
3a (50 mg, 0.3734 mmol), butylamine (27 mg, 0.3734 mmol) and
cyclohexylamine (55 mg, 0.5601 mmol) The compound was
obtained in yellow solid (0.0908 g, 89% yield.); 1H NMR (400
MHz, CDCl3) δ 7.17 (t, J = 7.6 Hz, 2H), 6.87 (t, J = 7.6 Hz, 1H),
6.81 (d, J = 7.6 Hz, 2H), 3.34-3.29 (m, 1H), 3.07 (t, J = 7.2 Hz,
2H), 1.92-1.89 (m, 2H), 1.68-0.93 (m, 12H), 0.85 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 151.2, 129.2, 123.5, 121.6,
50.4, 41.9, 33.7, 31.9, 25.6, 24.8, 20.1, 13.8. [M+H]+ : calcd
274.2283, found 274.2284
1-benzyl-3-butyl-2-(4-fluorophenyl)guanidine
General procedure was followed,
(5c)
A
using
4-
fluorophenylisothiocyanate 3a (51.0 mg, 0.3330 mmol),
benzylamine (36.0 mg, 0.3330 mmol) and butylamine (36.1 mg,
0.4995 mmol). The compound was obtained in colorless oil
1-benzyl-2,3-diphenylguanidine (5h)
General procedure A was followed, using phenylisothiocyanate
3a (50.5 mg, 0.3746 mmol), aniline (35.5 mg, 0.3746 mmol) and
benzylamine (60.1 mg, 0.5620 mmol) The compound was
obtained in yellow solid (0.1016 g, 90% yield.); 1H NMR (400
MHz, CDCl3) δ 7.23-7.12 (m, 9H), 6.94-6.90 (m, 6H), 4.38 (s,
2H). 13C NMR (100 MHz, CDCl3) δ 148.8, 138.8, 129.5, 128.7,
127.6, 127.4, 123.5, 123.0, 46.0. [M+H]+ : calcd 302.1657, found
302.1652.
1
(0.0917 g, 92% yield.); H NMR (400 MHz, CDCl3) δ 7.43-7.27
(m, 5H), 6.98 (t, J = 8.8 Hz, 2H), 6.84 (dd, J = 8.2, 5.2 Hz, 2H),
4.40 (s, 2H), 3.13 (t, J = 7.2 Hz, 2H), 1.54-1.37 (m, 2H), 1.35-
1.20 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 158.4 (d, JC-F = 237.7 Hz), 151.7, 145.9, 138.9, 128.7, 127.5,
127.3, 124.6 (d, JC-F = 7.7 Hz), 115.9 (d, JC-F = 21.8 Hz), 46.0,
41.6, 31.8, 19.9, 13.7. [M+H]+ : calcd 300.1876, found 300.1893
1-benzyl-3-butyl-2-(p-tolyl)guanidine
General procedure was
(
5d
)
1-benzyl-3-(4-methoxyphenyl)-2-phenylguanidine (5i)
A
followed,
using
p-
General procedure A was followed, using phenylisothiocyanate
3a (50.8 mg, 0.3764 mmol), 4-methoxyphenylisothiocyanate
(46.1 mg, 0.3764 mmol) and benzylamine (60.3 mg, 0.5646
mmol) The compound was obtained in yellow solid (0.0973 g,
78% yield.); 1H NMR (400 MHz, CDCl3) δ 7.33-7.25 (m, 7H), 7.05
(d, J = 7.6 Hz, 3H), 7.01 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz,
2H), 4.37 (s, 2H), 3.67 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
156.9, 138.6, 129.4, 128.6, 127.6, 127.4, 125.6, 123.4, 123.2,
114.8, 55.4, 46.1. [M+H]+ : calcd 332.1763, found 332.1757.
tolylphenylisothiocyanate 3a (50.0 mg, 0.3351 mmol),
benzylamine (36.1 mg, 0.3351 mmol) and butylamine (37.3 mg,
0.5027 mmol). The compound was obtained in yellow oil (0.0881
1
g, 89% yield.); H NMR (400 MHz, CDCl3) δ 7.29-7.22 (m, 3H),
7.17 (m, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 8.0 Hz, 2H),
4.28 (s, 2H), 3.01 (t, J = 7.2 Hz, 2H), 2.20 (s, 3H), 1.40-1.28 (m,
2H), 1.21-1.11 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 151.6, 146.9, 139.1, 130.9, 129.9, 128.7, 127.4,
127.3, 123.3, 46.0, 41.6, 31.8, 20.7, 20.0, 13.7. [M+H]+ : calcd
296.2127, found 296.2150
1-benzyl-3-(4-methylpyridin-2-yl)-2-phenylguanidine (5j)
General procedure A was followed, using phenylisothiocyanate
3a (52.1 mg, 0.3854 mmol), 2-amino-4-metylpyridine (42.3 mg,
0.3854 mmol) and benzylamine (62.1 mg, 0.5782 mmol) The
compound was obtained in yellow solid (0.0841 g, 69% yield.);
1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 5.2 Hz, 1H), 7.27-7.06
(m, 8H), 6.88 (m, 2H), 6.39 (d, J = 5.2 Hz, 1H), 6.22 (s, 1H), 4.26
(s, 2H), 2.13 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.5, 151.3,
148.8, 147.6, 138.7, 129.4, 128.7, 127.4, 127.2, 123.5, 122.0,
115.5, 108.9, 46.0, 20.9. [M+H]+ : calcd 317.1766, found
316.1808
1-benzyl-3-butyl-2-(m-tolyl)guanidine
(5e)
General procedure was followed,
A
using
m-
tolylphenylisothiocyanate 3a (52.2 mg, 0.3497 mmol),
benzylamine (37.3 mg, 0.3497 mmol) and butylamine (38.1 mg,
0.5246 mmol). The compound was obtained in yellow oil (0.0940
1
g, 91% yield.); H NMR (400 MHz, CDCl3) δ 7.43-7.27 (m, 5H),
7.18 (t, J = 7.6 Hz, 1H), 6.85-6.70 (m, 3H), 4.39 (s, 2H), 3.12 (t,
J = 7.2 Hz, 2H), 2.32 (s, 3H), 1.49-1.42 (m, 2H), 1.33-1.23 (m,
2H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 151.8,
148.8, 139.0, 129.1, 128.7, 127.4, 127.3, 124.2, 122.7, 120.3,
46.1, 41.8, 31.8, 21.4, 19.9, 13.7. [M+H]+ : calcd 296.2127, found
296.2158
1-benzyl-3-(tert-butyl)-2-phenylguanidine (5k)
General procedure A was followed, using phenylisothiocyanate
3a (53.0 mg, 0.3921 mmol), t-butylamine (27.3 mg, 0.3921
mmol) and benzylamine (63.2 mg, 0.5881 mmol) The compound
was obtained in yellow solid (0.0993 g, 90% yield.); 1H NMR
(400 MHz, CDCl3) δ 7.42-7.26 (m, 7H), 6.98 (t, J = 7.2 Hz, 1H),
6.91 (d, J = 7.2 Hz, 2H), 4.41 (s, 2H), 1.31 (s, 9H). 13C NMR (100
MHz, CDCl3) δ 151.1, 139.1, 129.3, 128.7, 127.4, 127.4, 123.2,
1-benzyl-3-(4-chlorobenzyl)-2-phenylguanidine (5f)
General procedure A was followed, using phenylisothiocyanate
3a (50.9 mg, 0.3771 mmol), 4-chlorobenzylamine (53.2 mg,
0.3771 mmol) and benzylamine (60.9 mg, 0.5657 mmol). The
compound was obtained in yellow oil (0.0989 g, 75% yield.); 1H
NMR (400 MHz, CDCl3) δ 7.44-7.18 (m, 9H), 7.15 (d, J = 8.2 Hz,
2H), 7.02 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 2H), 4.34 (s,
4H). 13C NMR (100 MHz, CDCl3) δ 151.2, 148.6, 138.6, 137.4,
121.6, 50.9, 46.4, 30.1. [M+H]+
:
calcd 282.1970, found
282.1964.
1-benzyl-3-cyclohexyl-2-phenylguanidine
(5l)
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10.1002/asia.201900982
Chemistry - An Asian Journal
FULL PAPER
General procedure A was followed, using phenylisothiocyanate
3a (50.0 mg, 0.3702 mmol), benzylamine (40.0 mg, 0.3702
mmol) and cyclohexylamine (55.1 mg, 0.5553 mmol) The
compound was obtained in yellow solid (0.0887 g, 78% yield.);
1H NMR (400 MHz, CDCl3) δ 7.41-7.25 (m, 7H), 6.99 (t, J = 7.6
Hz, 1H), 6.95 (d, J = 7.6 Hz, 2H), 4.41 (s, 2H), 3.42-3.38 (m, 1H),
1.95-1.92 (m, 2H), 1.69-1.51 (m, 3H), 1.39-0.99 (m, 5H). 13C
NMR (100 MHz, CDCl3) δ 150.8, 149.3, 139.1, 129.3, 128.7,
127.4, 127.4, 123.5, 121.8, 50.2, 46.0, 33.6, 25.5, 24.7. [M+H]+ :
calcd 308.2127, found 308.2120
General procedure B was followed, using 4-nitroaniline 3b (51.9
mg, 0.3481 mmol), butylamine (63.6 mg, 0.8704 mmol) The
1
compound was obtained in yellow oil (0.0632 g, 75% yield.); H
NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 2H), 6.90 (d, J =
8.8 Hz, 2H), 4.55 (s, 2H), 3.15 (t, J = 7.2 Hz, 4H), 1.61-1.42 (m,
4H), 1.36-1.29 (m, 4H), 0.90 (t, J = 7.2 Hz, 6H). 13C NMR (100
MHz, CDCl3) δ 158.0, 152.3, 141.2, 125.7, 123.0, 41.9, 31.9,
20.2, 13.9. [M+H]+ : calcd 293.1978, found 293.1972.
1,3-dibutyl-2-(4-fluorophenyl)guanidine
(6c)
General procedure was followed,
B
using
4-
N-benzyl-N'-phenylmorpholine-4-carboximidamide
(
5m
)
fluorophenylisothiocyanate 3c (50.1 mg, 0.3271 mmol) and
butylamine (59.8 mg, 0.8177 mmol). The compound was
obtained in yellow oil (0.0694 g, 80% yield.); 1H NMR (400 MHz,
CDCl3) δ 6.92 (t, J = 8.4 Hz, 2H), 6.78 (dd, J = 8.4, 4.8 Hz, 2H)
3.12 (t, J = 7.2 Hz, 4H), 1.48 (m, 4H), 1.32 (m, 4H), 0.90 (t, J =
7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 158.3 (d, JC-F = 237.6
Hz), 152.0, 145.8, 124.5 (d, JC-F= 7.7 Hz), 115.8 (d, JC-F = 21.8
Hz), 41.6, 31.8, 20.0, 13.7. [M+H]+ : calcd 266.2033, found
266.2044
General procedure A was followed, using phenylisothiocyanate
3a (51.0 mg, 0.3772 mmol), benzylamine (40.5 mg, 0.3772
mmol) and morpholine (49.4 mg, 0.5658 mmol) The compound
1
was obtained in yellow oil (0.0802 g, 72% yield.); H NMR (400
MHz, CDCl3) δ 7.33-7.17 (m, 7H), 6.96 (t, J = 7.6 Hz, 1H), 6.74
(d, J = 7.6 Hz, 2H), 4.32 (s, 2H), 3.73 (t, J = 4.4 Hz, 4H), 3.29 (t,
J = 4.4 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 156.1, 138.6,
129.4, 128.9, 127.7, 127.6, 122.8, 122.1, 66.7, 49.2, 48.5.
[M+H]+ : calcd 296.1763, found 296.1785
1,3-dibutyl-2-(p-tolyl)guanidine
(6d)
3-benzyl-1,1-diethyl-2-phenylguanidine
(
5n
)
General procedure was
B
followed,
using
p-
General procedure A was followed, using phenylisothiocyanate
3a (51.0 mg, 0.3775 mmol), benzylamine (40.4 mg, 0.3775
mmol) and diethylamine (41.2 mg, 0.5663 mmol) The compound
tolylphenylisothiocyanate 3d (51.0 mg, 0.3418 mmol) and
butylamine (62.5 mg, 0.8546 mmol). The compound was
obtained in yellow oil (0.0768 g, 86% yield); 1H NMR (400 MHz,
CDCl3) δ 7.04 (d, J = 8 Hz, 2H), 6.75 (d, J = 8 Hz, 2H), 3.14 (t, J
= 7.2 Hz, 4H), 2.27 (s, 3H), 1.53-1.45 (m, 4H), 1.39-1.29 (m, 4H),
0.91 (t, J = 7.2 Hz, 6H).13C NMR (100 MHz, CDCl3) δ 151.7,
147.3, 130.6, 129.8, 123.4, 41.7, 31.9, 20.7, 20.1, 13.8. [M+H]+ :
calcd 262.2283, found 262.2277
1
was obtained in yellow oil (0.0913 g, 86% yield.); H NMR (400
MHz, CDCl3) δ 7.35-7.19 (m, 7H), 6.91 (t, J = 7.6 Hz, 1H), 6.77
(d, J = 7.6 Hz, 2H), 4.20 (s, 2H), 3.30 (q, J = 7.2 Hz, 4H), 1.18 (t,
J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 155.1, 150.3,
139.2, 129.0, 128.5, 127.5, 127.3, 122.1, 121.1, 49.3, 42.7, 13.1.
[M+H]+ : calcd 282.1970, found 282.1977
1,3-dibutyl-2-(m-tolyl)guanidine
(6e)
tert-butyl-4-(N-benzyl-N'-phenylcarbamimidoyl)piperazine-
General procedure was
B
followed,
using
m-
1-carboxylate
(
5o
)
tolylphenylisothiocyanate 3e (52.1 mg, 0.3491 mmol) and
butylamine (64.4 mg, 0.8728 mmol). The compound was
obtained in yellow oil (0.0739 g, 81% yield.); 1H NMR (400 MHz,
CDCl3) δ 7.11 (td, J = 7.6, 1.2 Hz, 1H), 6.73(d, J =7.6 Hz, 1H),
6.69(s, 1H), 6.66(d, J = 7.6 Hz, 1H), 3.12 (t, J = 7.2 Hz, 4H), 2.27
(s, 3H), 1.54-1.44 (m, 4H), 1.39-1.27 (m, 4H), 0.91 (t, J = 7.2 Hz,
6H). 13C NMR (100 MHz, CDCl3) δ 151.6, 150.0, 138.9, 129.0,
124.4, 122.3, 120.4, 41.7, 31.9, 21.3, 20.1, 13.8. [M+H]+ : calcd
262.2283, found 262.2295
General procedure A was followed, using phenylisothiocyanate
3a (50.1 mg, 0.3705 mmol), benzylamine (40.4 mg, 0.3705
mmol) and tert-Butyl-piperazine-1-carboxylate (103.2 mg,
0.5558 mmol) The compound was obtained in yellow oil (0.1198
1
g, 82% yield.); H NMR (400 MHz, CDCl3) δ 7.34-7.11 (m, 7H),
6.99-6.90 (m, 1H), 6.70 (d, J = 8.4 Hz, 2H), 4.20 (s, 2H), 3.45 (s,
4H), 3.21 (s, 4H), 1.46 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
155.9, 154.7, 148.4, 138.7, 129.2, 128.7, 127.5, 127.4, 127.2,
122.2, 122.2, 79.9, 49.1, 47.6, 46.1, 28.4. [M+H]+ : calcd
395.2447, found 395.2433
1,3-dicyclohexyl-2-phenylguanidine (7a)
General procedure B was followed, using phenylisothiocyanate
3a (52.5 mg, 0.3887 mmol) and cyclohexylamine (96.3 mg,
0.9717 mmol). The compound was obtained in yellow solid
(0.1015 g, 95% yield.);1H NMR (400 MHz, CDCl3) δ 7.22 (t, J =
7.6 Hz, 2H), 6.92 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz 2H),
3.37-3.32 (m, 2H), 1.94-1.92 (m, 4H), 1.67-1.53 (m, 6H), 1.29-
1.06 (m, 10H). 13C NMR (100 MHz, CDCl3) δ 150.93, 129.29,
123.47, 122.01, 50.62, 33.67, 25.61, 24.93. [M+H]+ : calcd
300.2440, found 300.2447
1,3-dibutyl-2-phenylguanidine (6a)
General procedure B was followed, using phenylisothiocyanate
3a (51.7 mg, 0.3748 mmol) and butylamine (68.1 mg, 0.9370
mmol). The compound was obtained in yellow oil (0.082.5 g, 89%
yield.); 1H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 8.0 Hz, 2H), 6.95
(t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 3.13 (t, J = 8.0 Hz,
4H), 1.53-1.46 (m, 4H), 1.37-1.28 (m, 4H), 0.90 (t, J = 8.0 Hz,
6H). 13C NMR (100 MHz, CDCl3) δ 152.3, 148.2, 129.2, 123.4,
122.0, 42.0, 31.8, 20.0, 13.7. [M+H]+ : calcd 248.2127, found
248.2127
1,3-dicyclohexyl-2-(4-nitrophenyl)guanidine
(7b)
General procedure was followed,
B
using
4-
1,3-dibutyl-2-(4-nitrophenyl)guanidine
(
6b
)
nitrophenylisothiocyanate 3b (50.1 mg, 0.2782 mmol) and
cyclohexylamine (69.2 mg, 0.6955 mmol). The compound was
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10.1002/asia.201900982
Chemistry - An Asian Journal
FULL PAPER
obtained in yellow solid (0.0881 g, 92% yield.); 1H NMR (400
MHz, CDCl3) δ 8.08 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H),
3.40-3.33 (m, 2H), 1.98-1.90 (m, 4H), 1.72-1.53 (m, 6H), 1.33-
1.12 (m, 10H). 13C NMR (100 MHz, CDCl3) δ 156.2, 151.2, 141.1,
125.5, 122.1, 50.9, 33.4, 25.3, 24.7. [M+H]+ : calcd 345.2291,
found 3345.2294
1,3-dibenzyl-2-(4-fluorophenyl)guanidine
(8c)
General procedure was followed,
B
using
4-
fluorophenylisothiocyanate 3c (50.9 mg, 0.3328 mmol) and
benzylamine (89.1 mg, 0.8320 mmol). The compound was
obtained in yellow oil (0.086.5 g, 78% yield.); 1H NMR (400 MHz,
CDCl3) δ 7.36-7.23 (m, 10H), 7.00 (t, J = 8.4 Hz, 4H), 6.90 (dd,
J = 8.4, 5.2 Hz), 4.37 (s, 4H). 13C NMR (100 MHz, CDCl3) δ 158.7
(d, JC-F = 238.2 Hz), 151.7, 145.0, 138.5, 128.7, 127.5, 127.2,
124.6 (d, JC-F = 7.7 Hz), 116.0 (d, JC-F = 11.8 Hz), 46.0. [M+H]+ :
calcd 3334.17206, found 334.1719
1,3-dicyclohexyl-2-(4-fluorophenyl)guanidine
General procedure was followed,
(7c)
B
using
4-
fluorophenylisothiocyanate 3c (51.1 mg, 0.3337 mmol) and
cyclohexylamine (82.7 mg, 0.8343 mmol). The compound was
obtained in colorless solid (0.0974 g, 92% yield.); 1H NMR (400
MHz, CDCl3) δ 6.90 (t, J = 8.0 Hz, 2H), 6.77 (dd, J = 8.0, 4.0 Hz,
2H), 3.35 (s, 2H), 1.95-1.92 (m, 4H), 1.66-1.54 (m, 6H), 1.37-
1,3-dibenzyl-2-(p-tolyl)guanidine
(8d)
General procedure was
B
followed,
using
p-
tolylphenylisothiocyanate 3d (53.9 mg, 0.3615 mmol) and
benzylamine (96.8 mg, 0.9039 mmol). The compound was
obtained in yellow oil (0.0869 g, 73% yield.); 1H NMR (400 MHz,
CDCl3) δ 7.46-7.17 (m, 10H), 7.13 (d, J = 8.0 Hz, 2H), 6.88 (d, J
= 8.0 Hz, 2H), 4.38 (s, 4H), 2.34 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 151.4, 146.3, 138.8, 131.3, 130.0, 128.7, 127.4, 127.2,
123.3, 46.0, 20.8. [M+H]+ : calcd 330.1970, found 330.1977
0.96 (m, 10H). 13C NMR (100 MHz, CDCl3) δ 159.6, (d, JC-F
=
237.6 Hz), 150.7, 124.5 (d, JC-F = 7.7 Hz), 115.7 (d, JC-F = 21.8
Hz), 50.3, 33.7, 25.6, 24.9. [M+H]+ : calcd 318.2346, found
318.2363
1,3-dicyclohexyl-2-(p-tolyl)guanidine
General procedure was
(
7d
)
B
followed,
using
p-
tolylphenylisothiocyanate 3d (50.2 mg, 0.3364 mmol) and
cyclohexylamine (73.5 mg, 0.8410 mmol). The compound was
obtained in 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 7.6 Hz, 2H),
6.76 (d, J = 7.6 Hz, 2H), 3.36 (s, 2H), 2.26 (s, 3H), 1.96-1.94 (m,
4H), 1.67-1.54 (m, 6H), 1.35-1.02 (m, 10H). 13C NMR (100 MHz,
CDCl3) δ 150.8, 131.1, 129.8, 123.2, 50.4, 33.6, 25.5, 24.8, 20.7.
[M+H]+ : calcd 314.2596, found 314.2604
1,3-dibenzyl-2-(m-tolyl)guanidine
General procedure was
(
8e
)
B
followed,
using
m-
tolylphenylisothiocyanate 3e (52.9 mg, 0.3548 mmol) and
benzylamine (95.0 mg, 0.8870 mmol). The compound was
obtained in yellow oil (0.0818 g, 70% yield.) ;1H NMR (400 MHz,
CDCl3) δ 7.59-7.15 (m, 11H), 6.85-6.79 (m, 3H), 4.39 (s, 4H),
2.35 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 151.2, 149.2, 139.1,
138.9, 129.2, 128.7, 127.4, 127.3, 124.3, 122.9, 120.4, 46.0,
21.5. [M+H]+ : calcd 330.1970, found 330.1975
1,3-dicyclohexyl-2-(m-tolyl)guanidine
(7e)
General procedure was followed,
B
using
m-
tolylphenylisothiocyanate 3e (50.2 mg, 0.3364 mmol) and
cyclohexylamine (83.4 mg, 0.8410 mmol). The compound was
obtained in colorless solid (0.0959 g, 91% yield.); 1H NMR (400
MHz, CDCl3) δ 7.12 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H),
6.69 (s, 1H), 6.65 (d, J = 7.6 Hz), 3.41-3.36 (m, 2H), 2.27 (s, 3H),
2.06-1.87 (m, 4H), 1.73-1.54 (m, 6H), 1.39-1.03 (m, 10H). 13C
NMR (100 MHz, CDCl3) δ 150.2, 138.8, 128.9, 124.3, 122.3,
120.3, 50.2, 33.7, 25.6, 24.9, 21.3. [M+H]+ : calcd 314.2596,
found 314.2611
Acknowledgements
This study was financially supported by the Thailand Research
Fund (RSA6080018 and RTA6180007) and the National
Nanotechnology Center, NSTDA, Ministry of Science and
Technology, Thailand, through its program of Research Network
NANOTEC (RNN). This work was also partially supported by a
Grant for International Research Integration: Chula Research
Scholar and Center of Excellence on Petrochemical and Materials
Technology (PETROMAT), Thailand.
1,3-dibenzyl-2-phenylguanidine (8a)
General procedure B was followed, using phenylisothiocyanate
3a (51.4 mg, 0.3802 mmol) and benzylamine (101.8 mg, 0.9505
mmol). The compound was obtained in yellow oil (0.1008 g, 84%
1
Keywords: reaction in water • surfactant • one-pot synthesis •
yield.) H NMR (400 MHz, CDCl3) δ 7.22-7.00 (m, 12H), 6.91-
6.85 (m, 3H), 4.23 (s, 4H). 13C NMR (100 MHz, CDCl3) δ 151.7,
148.3, 138.6, 129.4, 128.7, 127.4, 127.2, 123.4, 122.2, 46.1.
[M+H]+ : calcd 316.1814, found 316.1839
guanidine • hypervalent iodine
1.
2.
3.
4.
Q. Zheng, J.Dong, K.B. Sharpless, J. Org. Chem., 2016, 81, 11360-
11362.
1,3-dibenzyl-2-(4-nitrophenyl)guanidine
(8b)
Q. Liang, P. Xing, Z. Huang, J. Dong, K.B. Sharpless, X. Li, B. Jiang, Org.
Lett., 2015, 17, 1942-1945.
General procedure was followed,
B
using
4-
S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb and K. B.
Sharpless, Angew. Chem. Int. Ed. Engl., 2005, 44, 3275-3279.
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nitrophenylisothiocyanate 3b (52.0 mg, 0.2886 mmol) and
benzylamine (77.3 mg, 0.7216 mmol). The compound was
obtained in yellow solid (0.0998 g, 95% yield.);1H NMR (400
MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 2H), 7.53-7.06 (m, 10H), 7.00
(d, J = 8.0 Hz, 2H), 4.41 (s, 4H). 13C NMR (100 MHz, CDCl3) δ
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A new one-pot synthesis of guanidine
directly from isothiocyanates is
developed using mild oxidizing agent,
hypervalent iodine (III), in green
medium TPGS-750-M/H2O. Waste
medium from the reaction can be
reused up to 3 time providing E-factor
of 8.3 which indicates the low waste
process of this protocol.
Jakkrit Srisa,Theeranon Tankam,
Mongkol Sukwattanasinitt, Sumrit
Wacharasindhu*
Page No. – Page No.
Micelle-enabled one pot guanidine
synthesis in water directly from
isothiocyanate using hypervalent
iodine(III) reagents under mild
condition
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm))
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