A Mild Photocatalytic Synthesis of Guanidine from Thiourea under Visible Light

Article abstract of DOI:10.1021/acs.orglett.0c02770

In this work, we developed the catalytic guanylation of thiourea using Ru(bpy)3Cl2 as a photocatalyst under irradiation by visible light. The conversion of various thioureas to the corresponding guanidines was achieved using 1-5 mol % of photocatalyst in a mixture of water and ethanol at room temperature. Key benefits of this reaction include the use of photoredox catalyst, low-toxicity solvents/base, ambient temperature, and an open-flask environment.

Full text of DOI:10.1021/acs.orglett.0c02770

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Letter
A Mild Photocatalytic Synthesis of Guanidine from Thiourea under
Visible Light
Trin Saetan, Mongkol Sukwattanasinitt, and Sumrit Wacharasindhu*
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ABSTRACT: In this work, we developed the catalytic guanylation
of thiourea using Ru(bpy)3Cl2 as a photocatalyst under irradiation
by visible light. The conversion of various thioureas to the
corresponding guanidines was achieved using 1−5 mol % of
photocatalyst in a mixture of water and ethanol at room
temperature. Key benefits of this reaction include the use of
photoredox catalyst, low-toxicity solvents/base, ambient temper-
ature, and an open-flask environment.
Scheme 1. Synthetic Approaches for The Preparation of
Guanidines
uanidine has been known as an important class of N-
Gcontaining compounds, which are important building
blocks for pharmaceutical and chemical industry, due to their
broad spectrum of bioactivities.1−6 Examples of important
commercialized compounds containing guanidine groups such
as Pinacidil used as a treatment drug for hypertension7 and
NC-174, a high potency synthetic sweetener,8 are shown in
Figure 1.
Figure 1. Important guanidine derivatives.
require the use of stochiometric toxic metals. On the other
hand, for nonmetal reagents, Burgess’s reagent,23 Mukaiyama’s
reagent,24 TCT (trichloro cyanuric acid)25 and I2/PPh3,26 and
hypervalent iodine27,28 were reported as guanylating agents.
Although these reagents produced high yields of guanidines,
the reaction usually required harsh reaction conditions,
Typically, guanidine is prepared from amines using various
guanylating agents9−11 such as isothioureas,12 cyanamide,13
amidine,9 carbodiimide,14 triflylguanidines,15 pyrazole-1-carbox
imidamides,16 and thiourea.17 However, the use of some
guanylating agents suffers from either multiple step synthesis of
starting materials or stoichiometric use of oxidants. Among
guanylating agents, thioureas are the most promising because
of their stability and ease of preparation.18−20 The conversion
of thiourea into guanidine involves the treatment of amine with
various desulfurizing agents (Scheme 1). For example, mercury
Received: August 19, 2020
22
chloride,21 copper chloride,17 and Bi(III)/BiO3 have been
extensively used. Even though such reagents are highly efficient
and compatible with wide variety of functional groups, they
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complex operating procedures, and stoichiometric amounts of
oxidants. Regarding the concept of green chemistry where
catalytic processes that improve the atom economy and reduce
waste are preferred, a catalytic preparation of guanidine would
be highly attractive for both academic and industrial adoption.
In recent years, photochemical reactions mediated by visible
light have drawn significant attention in the organic synthesis
community.29−39 The process allows utilization of low energy
and highly abundant visible light in the solar spectrum to
perform chemical reactions via the utilization of photocatalyst
creating a new paradigm of environmentally friendly processes
in organic transformation. Among them,29 photocatalytic
oxidation of various organosulfur compounds under visible
light has been established40−57 and, more recently, visible-
light-induced desulfurization of organosulfur followed by
amination has been applied in C−N bond construction. Tan
and co-workers demonstrated a visible-light-promoted amide
formation from the reaction between amines and potassium
salts of thioacids.53 Recently, our group also reported direct
amination of 2-mecaptobenzoxazole with amines using Rose
Bengal as a photocatalyst to prepare the corresponding
aminobenzoxazoles.58 As part of our continuing studies on
the oxidation of organosulfur,27,58−61 we plan to apply the
concept of photomediated desulfurization to guanidine syn-
thesis. Herein, we reported a new visible light promoted
process to prepare guanidines from thioureas and amines. To
the best of our knowledge, this is the first catalytic process for
guanylation of thiourea
For the optimization study, we used diphenyl thiourea (1a)
and morpholine as a model substrate for guanylation reaction
as shown in Table 1. Initially, the reaction was carried out in
the presence of 5% mol of catalysts under the household 42 W
CFL at room temperature under an open-air atmosphere
(Figure S2). Using an organic dye such as Eosin Y, Rose
Bengal, and Safranin O, guanidine 2a were isolated in 3−72%
yield (Table 1, entries 1−5) after 24 h irradiation. By switching
the organic dyes to a transition-metal photoredox catalyst,
Ru(bpy)3Cl2, the reaction was improved and 2a was isolated in
81% yield (Table 1, entry 7). With this result, we then selected
Ru(bpy)3Cl2 as a photocatalyst for further study. Importantly,
we also ran a control experiment in parallel. All conditions
were replicated except the reaction tube was covered with
aluminum foil. Only, ca. 10% of 2a was observed, suggesting
the reaction is mediated by the visible light (Table 1, entry 6).
With the promising results in hand, base, solvent, light sources,
and the amount of Ru(bpy)3Cl2 were optimized. Among the
bases tested, K2CO3, DBU, and CsCO3 gave 2a in excellent
yields (Table 1, entries 7−9) while significantly lower yields
were obtained in the case of TEA and DIPEA (Table 1, entries
10 and 11). Considering the toxicity and cost, we decided to
use K2CO3 as our choice of base for the photoreaction. When
the light source was replaced with a 19 W LED which
consumes less energy and produces less heat, the reaction still
maintained its effectiveness (Table 1, entry 12). Bearing the
concept of green chemistry in mind, we replaced acetonitrile
with a mixture of ethanol and water due to their low toxicity.62
To our surprise, the reaction occurred smoothly in a
homogeneous fashion and 2a was obtained in good yield
(Table 1, entry 13). Importantly, under 19 W LED irradiation
in a mixture of ethanol and water as a solvent, visible-light-
mediated guanylation could proceed even with only 1% of
catalyst loading to provide the product 2a in excellent yield
(Table 1, entry 14). Moreover, in the absence of catalyst, the
Table 1. Optimization Studies on Guanylation Reaction
b
entry
photocatalyst
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
base
yield (%)
1
2
3
4
5
pyrene
Phenazine
Eosin Y
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DBU
3
50
50
62
72
10
81
80
83
26
18
90
90
91
−
Rose Bengal
Safranin O
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
−
c
6
7
8
9
Cs2CO3
TEA
10
11
DIPEA
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
d
12
d
13
e
14
f
15
g
16
Ru(bpy)3Cl2
22
a
Reaction conditions: 1a (0.5 mmol), morpholine (2.0 mmol),
catalysts (0.025 mmol), bases (1.0 mmol), solvents (5.0 mL).
b
c
d
Isolated yield. Reaction tube was covered with aluminum foil. 19
e
W white LED as light source. 19 W white LED as light source and
0.005 mmol of catalyst. Room light. The reaction was conducted
f
g
under a N2 atmosphere.
reaction did not proceed (Table 1, entry 15) and only starting
material 1a was detected suggesting that the photoredox
catalyst is essential for guanylation reaction. Finally, when this
photoreaction was conducted under a nitrogen atmosphere,
the product 2a was isolated in 22% yield (Table 1, entry 16).
This low yield indicated that oxygen plays an essential role in
this reaction. However, the product yield did not drop to zero
with several rigorous attempts that may be due to the trace
amount of oxygen which still cannot be completely removed or
there might be a minor alternative pathway removing the sulfur
atom without involvement of oxygen gas.
To expand the scope of reaction, various amines were tested
in the guanylation reaction with diphenyl thiourea (1a) under
the optimized conditions (Scheme 2). Primary amines such as
butylamine, benzylamine, cyclohexylamine, and β-Alanine
ethyl ester reacted smoothly under the optimized conditions
providing the corresponding guanidine 2b−2e respectively, in
excellent yields. For ethanolamine, which contains both O and
N nucleophilic atoms, the C−N bond formation occurred
selectively, giving product 2f in 80% yield. Then, we expanded
the amine substrate into secondary amines. When diethylamine
was used as a nucleophile, product 2g was obtained in 82%
yield after an extended reaction time of 3 days. Next, a variety
of cyclic amines such as 2-methylpiperidine, pyrrolidine,
azepine, and BOC-protected piperazine were tested and
products 2h−2k were isolated in moderate to high yields.
Unfortunately, a less nucleophilic amine such as aniline failed
to give the expected 2l and only the starting thiourea 1a was
observed.
B
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Scheme 2. Substrate Scope of Amine with 1,3-
Diphenylthioureaa
Scheme 3. Substrate Scope of Thiourea with Morpholine
a
a
Reaction conditions: 1b−1j (0.5 mmol), morpholine (2.0 mmol)
Ru(bpy)3Cl2 (0.005 mmol), K2CO3 (1.0 mmol), in EtOH/H2O (9:1)
5.0 mL, isolated yields. Ru(bpy)3Cl2 (0.025 mmol)
b
product 3i in 61% yield. Unfortunately, the benzyl thiourea
1j only provided the desired product 3j in 22% yield. This may
be caused by the low stability of the benzyl group in 1j under
the radical reaction, as there was no starting thiourea left in the
reaction. For other alkyl thioureas, the reaction was sluggish
and the starting thioureas were mostly recovered. Currently,
this new photoreaction is thus effective for the synthesis of
guanidines from aryl substituted thioureas but not from the
alkyl thioureas. Therefore, the photocatalytic conversion of
alkyl thioureas to the corresponding guanidines remains very
challenging.
To simplify the synthetic method, we combined the photo-
guanylation step with the thiourea formation step. Isocyanate
(4), para-toluidine, and morpholine were mixed with a
ruthenium catalyst and irradiated under white LED for 24 h
(Scheme 4). The reaction exclusively provided guanidine
product 3c in 68% yield. The process allows construction of
structurally diverse guanidines directly from commercially
available isothiocyanate in a one-pot fashion, and the process
may also be considered as multicomponent reactions (MCRs).
To propose a plausible reaction mechanism of this new
visible-light photoredox-catalyzed guanylation reaction, several
mechanistic studies were conducted. We irradiated 1a under a
19 W white LED light bulb for 24 h under optimized
conditions without the addition of amine. Although complex
mixtures were produced in the crude product, the
a
Reaction conditions: 1a (0.5 mmol), amines (2.0 mmol), Ru-
(bpy)3Cl2 (0.005 mmol), K2CO3 (1.0 mmol), in EtOH/H2O (9:1)
b
5.0 mL, isolated yields. Reaction was conducted using 1a in 1 mmol.
c
d
Ru(bpy)3Cl2 (0.025 mmol). Reaction was carried out for 3 days.
With successful guanylation of 1a, we extended the scope of
this reaction further to other thiourea substrates (Scheme 3).
Diphenyl thiourea containing an electron-donating group such
as methyl (1b−1c) and methoxy (1d) reacted with morpho-
line to provide guanidines 3b−3d in excellent yields.
Moreover, for halide-substituted thiourea with halides such
as the bromo (1e) and iodo group (1f), the expected products
3e and 3f were isolated in high yields. Thiourea carrying an
electron-deficient group such as a trifluoromethyl (1g) and
chloride/trifluoromethyl (1h) group had an effect on the
reaction, as low to moderate yields of target guanidines (3g−
3h) were obtained. This group may decrease electron density
that suppresses the oxidation of thiourea which will be further
discussed in the mechanistic investigation. N-Heterocycle
thioureas such as pyridine (1i) were also found to be
compatible with the optimized conditions delivering the
C
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Scheme 4. One-Pot Synthesis of Guanidine from
Isothiocyanate
Scheme 6. Proposed Mechanism
a
a
Reaction conditions: 4 (0.5 mmol), p-toluidine (0.75 mmol),
morpholine (2.0 mmol), Ru(bpy)3Cl2 (0.005 mmol), K2CO3(1.0
mmol), in EtOH/H2O (9:1) 5.0 mL. Isolated yields.
carbodiimide 5 (Scheme 5 eq 1) intermediate was observed in
the mass spectrum of the crude product (Figure S43). This
suggested that 5 could serve as a key intermediate in our
photoreaction.
ruthenium(II) via a single-electron transfer process followed by
reaction with an oxygen species to generate a peroxysulfur
intermediate which rapidly desulfurizes to a carbodiimide
intermediate. The reaction is relatively green and convenient to
conduct, as it can be performed in safe solvent (ethanol/water)
at ambient temperature in an open flask without additional
oxidant. This reaction should provide an environmentally
friendly synthetic route to various guanidines useful for
medicinal chemistry.
Scheme 5. Mechanistic Investigation Experiment
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02770.
General procedure, materials and methods, copies of 1H
and 13C NMR and HRMS spectra of compounds 2a−3j,
and EDX-SEM spectrum of PbSO4 (PDF)
Moreover, we successfully trapped the sulfur-containing
byproduct as a precipitate by the addition of Pb(OAc)2
(Scheme 5. eq 2). It is important to note that the trapping
experiment was conducted by using DBU as a base and MeCN
as a solvent (Table 1, entry 8) to avoid the solid interference
from potassium carbonate salt. The yellow precipitate was
filtered and characterized with SEM/EDX, revealing that the
byproduct was lead sulfate (Figure S63 and Table S1).
Based on the results of the mechanistic studies, we proposed
a visible-light-catalyzed guanylation reaction as shown in
Scheme 6. First, the reaction starts with tautomerization of
1a to the 1ab intermediate. Then, the 1ab intermediate is
deprotonated by a base and transformed into radical
intermediate 1ad via photo-single-electron transfer (SET) to
the ruthenium(II) catalyst. Oxidative coupling between radical
intermediate 1ad and superoxide produce a peroxysulfur
intermediate 1ae. Then, sulfate was released to form a
carbodiimide as key intermediate 5 which was consequently
attacked by the morpholine at the carbon atom to produce
guanidine product 2a.63 In this proposed mechanism, the
oxygen molecule serves as the terminal oxidant and catalyst
regenerator that allows the reaction to proceed without
additional oxidants.
AUTHOR INFORMATION
■
Corresponding Author
Sumrit Wacharasindhu − Nanotec-CU Center of Excellence on
Food and Agriculture, Department of Chemistry, Faculty of
Science and Green Chemistry for Fine Chemical Productions
STAR, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Bangkok 10330, Thailand;
orcid.org/0000-0001-6940-1329; Email: Sumrit.w@
chula.ac.th
Authors
Trin Saetan − Nanotec-CU Center of Excellence on Food and
Agriculture, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Bangkok 10330, Thailand
Mongkol Sukwattanasinitt − Nanotec-CU Center of Excellence
on Food and Agriculture, Department of Chemistry, Faculty of
Science, Chulalongkorn University, Bangkok 10330, Thailand;
orcid.org/0000-0002-8315-9679
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02770
In summary, a mild photocatalytic guanylation of thiourea
has been developed for the synthesis of guanidines. The
reaction showed good compatibility with several reactive
functional groups such as alcohol, halides, and ester. The
mechanistic study suggested a photooxidation of thiourea by
Notes
The authors declare no competing financial interest.
D
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ethane-Protected Guanidines: New Reagents for Guanidinylation
Reactions. J. Org. Chem. 1998, 63 (23), 8432−8439.
ACKNOWLEDGMENTS
■
This study was financially supported by National Research
Council of Thailand (NRCT): NRCT5-RSA63001-16, Thai-
land Research Fund (RTA6180007) and National Nano-
technology Centre (NANOTEC), NSTDA, Ministry of
Science and Technology, Thailand, through its program of
the Centre of Excellence Network. T.S. was supported by a
Science Achievement Scholarship of Thailand.
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Org. Lett. XXXX, XXX, XXX−XXX