Ruthenium-Catalyzed Urea Synthesis Using Methanol as the C1 Source

Article abstract of DOI:10.1021/acs.orglett.5b03328

An unprecedented protocol for urea synthesis directly from methanol and amine was accomplished. The reaction is highly atom-economical, producing hydrogen as the sole byproduct. Commercially available ruthenium pincer complexes were used as catalysts. In addition, no additive, such as a base, oxidant, or hydrogen acceptor, was required. Furthermore, unsymmetrical urea derivatives were successfully obtained via a one-pot, two-step reaction.

Full text of DOI:10.1021/acs.orglett.5b03328

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Urea Synthesis Using Methanol as the C1
Source
Seung Hyo Kim and Soon Hyeok Hong*
Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 151-742, Republic of Korea
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea
Korea Carbon Capture Sequestration R&D Center (KCRC), Daejeon 305-303, Republic of Korea
S
* Supporting Information
ABSTRACT: An unprecedented protocol for urea synthesis directly
from methanol and amine was accomplished. The reaction is highly
atom-economical, producing hydrogen as the sole byproduct.
Commercially available ruthenium pincer complexes were used as
catalysts. In addition, no additive, such as a base, oxidant, or hydrogen
acceptor, was required. Furthermore, unsymmetrical urea derivatives
were successfully obtained via a one-pot, two-step reaction.
renewable carbon resource.4 However, the required stoichio-
rea derivatives are commonly found in widespread
metric use of expensive and waste-producing dehydrating
Uapplications, such as biologically active compounds,
reagents, such as di-tert-butyl azodicarboxylate (DBAD), to
generate the isocyanate intermediates still limits the utility of
the reaction.4 Therefore, versatile urea synthesis under mild
conditions that avoids environmentally harmful reagents
remains a major challenge.
Recently, environmentally benign and atom-economical C−
N and C−C bond formation reactions utilizing alcohols,
generating water5 or hydrogen6,7 as the byproduct, have
attracted much attention. By applying the concept of
acceptorless dehydrogenative activation of alcohols,7 and
based on the thermodynamic feasibility for the formation of
pharmaceuticals, agricultural pesticides, dyes for cellulose fibers,
and antioxidants in gasoline.1 Many classical protocols and
catalytic transformations have been developed for urea
synthesis. Traditional syntheses of urea derivatives use
phosgene and isocyanates, which cause tremendous toxico-
logical and environmental problems (Scheme 1).2 Alternative
routes using carbon monoxide (CO) as the source of the
carbonyl moiety have been developed;3 these carbonylation
reactions are generally carried out at high temperatures under
high CO pressure with oxidants. In recent years, the utilization
of CO2 has attracted significant attention because it is a
1,3-dimethyl urea from methylamine and methanol (ΔH°298
=
−66.2 kJ/mol, ΔG°298 = −268.8 kJ/mol),8 we envisioned an
unprecedented strategy to synthesize urea derivatives directly
from amines utilizing methanol as the C1 source.
Scheme 1. Synthesis of Urea Derivatives
Utilization of methanol as the C1 feedstock could be an ideal
solution to reduce the predominant dependence on conven-
tional toxic C1 sources, such as phosgene and isocyanates, for
urea synthesis.9 For intermolecular coupling of alcohols and
amines, three pathways, i.e., imination,10 alkylation,7e and
amidation,11 have been well reported. Recently, formylation of
amines using methanol as the C1 source has been developed.12
Inspired by previous works, we devised a possible strategy to
synthesize urea utilizing methanol as follows: (1) Generation of
formamide in situ and (2) coupling of the formamide with
amine using an active catalyst that can mediate activation of
formamide followed by dehydrogenation of the resultant
hemiaminal intermediate.
To identify an active catalyst for the proposed urea synthesis,
we investigated complex 4, which was recently used for the
Received: November 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03328
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formylation of amine and nitrile with excess methanol.12a The
reaction of benzylamine (8a) and methanol under modified
conditions with less methanol (1.0 equiv vs amine) generated a
trace amount of 1,3-dibenzyl urea (9aa, 5%) (Table 1, entry 5).
Scheme 2. Symmetrical Urea Synthesis from Methanol and
Amine
a
Table 1. Urea Synthesis from Methanol and Benzylamine
a
Using Various Catalysts
entry
1
Ru complex (0.5 mol %)
solvent
yield (%)
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
hexane
THF
97
93
88
0
b
2
2
b
3
c
3
4
[Ru(cod)(2-methylallyl)2]
5
6
4
5
6
7
1
1
1
1
5
0
b
7
b
0
8
0
9
81
80
60
87
10
11
12
dioxane
p-xylene
a
Reaction conditions: amine (2 mmol, 1.0 equiv), 1 (0.5 mol %),
a
Reaction conditions: benzylamine (2 mmol, 1.0 equiv), [Ru] (0.5
methanol (2 mmol), toluene (1.5 mL), 140 °C, 24 h in a closed vessel;
isolated yield. Amine (10 mmol, 1.0 equiv), 1 (0.5 mol %), 1 (2 mol
%), methanol (4 mmol), KOH (15 mol %). Amine (1 mmol, 1.0
equiv), 1 (1 mol %), methanol (2 mmol).
mol %), methanol (2 mmol), toluene (1.5 mL), 140 °C, 24 h in a
closed vessel; NMR yield; p-xylene was used as a standard. K2CO3
(0.5 mol %). [Ru(cod)(2-methylallyl)2] (0.5 mol %), KOtBu (1.5
mol %), and dicyclohexylimidazolium chloride (ICy-HCl, 1 mol %).
b
c
b
d
c
excellent yields. Electron-rich benzylamines (8a−e) produced
the corresponding ureas smoothly. The reaction worked
efficiently even in a gram-scale reaction (1.07 g of 8a, 91%).
The use of chloride- and bromide-substituted benzylamines
(8f−8h) required a higher catalyst loading (1, 2 mol %) and a
base additive (KOH, 15 mol %) to obtain the products in good
yields. Pyridine functional groups (8i and 8j) were tolerated
under the reaction conditions. Various kinds of aliphatic amines
afforded the desired urea products in very good to excellent
yields (8k−8o). In the case of 2-adamantyl amine (8p), a poor
yield of 9pp (31%) was observed and most of the 8p remained;
this was presumably due to high steric hindrance. Furthermore,
the use of diamines 8q and 8r in the reaction resulted in the
production of cyclic ureas. The yield of the product was
relatively decreased probably due to the coordination effect of
diamine. To our delight, subjection of chiral amine 8s to the
reaction generated urea product 9ss with no epimerization.
However, secondary amines, such as 8t, and electron-deficient
aryl amines, such as aniline, were not applicable under the
developed reaction conditions. In the case of 8t, the
corresponding formamide was formed as the major product,
which implies that the second nucleophilic addition of the
secondary amine to formamide could be the limiting step for
the urea synthesis. Aniline did not react at all under the reaction
conditions. Therefore, in the case of 4-aminobenzyl amine (8e),
selective urea formation on the aliphatic amine group was
achieved in an 84% yield.
Inspired by this result, other Ru-based complexes that had been
reported to catalyze acceptorless dehydrogenative coupling
reactions were screened to improve the reaction efficiency. The
N-formylation catalytic system developed by the Glorius group
was not active for urea synthesis (entry 4).12b Milstein’s catalyst
(5)11d also did not produce any urea under the reaction
conditions (entry 6). Complexes 6 and 7, which showed
excellent performance for hydrogenation of esters,13 were not
active for this reaction (entries 7 and 8). To our delight, Ru
complex 2, which is known as the Ru-MACHO catalyst,6b,14
afforded desired product 9aa in an excellent yield (93%) in the
presence of a catalytic amount of K2CO3 (entry 2). Analogous
complex 3 containing cyclohexyl groups on the phosphine
moiety gave a slightly lower yield (88%, entry 3). Finally, when
complex 1 (Ru-MACHO-BH) was used as a precatalyst, a
quantitative amount of 9aa was obtained under base-free
conditions (entry 1). The reaction was optimized in a closed
reaction vessel due to the low boiling point of methanol.
Toluene was the best solvent among those tested (entries 9−
12). Notably, the developed reaction is highly atom-
economical, produces hydrogen gas as the sole byproduct,
and is catalyzed by a low loading of the Ru catalyst (0.1 mol %,
TONs ≈ 295, Table S2) without any additive such as a base,
oxidant, or hydrogen acceptor.
Next, we turned our attention to the synthesis of
unsymmetrical urea derivatives. Traditionally, unsymmetrical
ureas are synthesized via nucleophilic attack of amines on
isocyanates. Recently, Buchwald and co-workers reported an
unsymmetrical urea synthesis using an arylisocyanate inter-
mediate synthesized by Pd-catalyzed cross-coupling of aryl
Using the optimized conditions, the scope of the reaction
was examined (Scheme 2). Various amines smoothly provided
the corresponding symmetrical urea products in good to
B
DOI: 10.1021/acs.orglett.5b03328
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
chlorides and triflates with sodium cyanate.15 Other efforts have
been devoted to achieve in situ generation of isocyanates from
different precursors, such as carboxylic acids, carbamic acids,4c
carbamates,16 acyl azides,17 hydroxamic acids,18 or acetoaceta-
nilide.19 They have also been prepared by functionalization of
mother ureas via N-alkylation20 or N-arylation.21 Despite the
significant advances in this field, many procedures still suffer
from a limited availability of starting materials and a restricted
substrate scope.
Scheme 3. Unsymmetrical Urea Synthesis from Methanol
and Amine
a
To elucidate the viability of the optimized reaction
conditions for the synthesis of unsymmetrical urea, two
different aliphatic amines, i.e., 8a and 8k, were reacted in a
reaction vessel (Scheme S1). This reaction produced three of
the corresponding urea derivatives with a statistical distribution:
Symmetrical 9aa (21%) and 9kk (25%), and unsymmetrical
9ak (48%). The reaction of 4-aminobenzyl amine (8e) with
benzylamine resulted in a similar distribution of products. To
improve the selectivity toward the unsymmetrical ureas, we
devised a strategy comprising a sequential two-step reaction in
one pot by first generating formamide from an amine and
methanol, and then reacting the formamide with the second
amine. This reaction strategy was proven to be viable by the
reaction of 10 and 8k to produce 9ak in an excellent yield
(94%) under the catalytic conditions of 1. Recently, Reddy and
co-workers reported Cu-catalyzed unsymmetrical urea synthesis
from formamide and amines using tert-butylhydroperoxide
(TBHP) as a stoichiometric oxidant at a relatively low
efficiency (mostly <50% yields).22 Here, an unsymmetrical
urea synthesis from formamide and amine was achieved under
oxidant-free conditions with high efficiency.
Combining the current strategy and the previous report of
formamide synthesis using methanol,12 we attempted selective
unsymmetrical urea synthesis in one pot. After first generating
benzyl formamide from 8 using methanol as the solvent, the
methanol was removed in vacuum. Then, n-hexyl amine and
toluene were added to the reaction tube with an additional
loading of Ru complex 1 under inert conditions. After further
reaction for 16 h at 120 °C, desired 1-benzyl-3-hexyl urea 9ak
was obtained in a good yield (79%).
a
Reaction conditions: (1) amine (0.5 mmol, 1.2 equiv), 1 (2 mol %),
methanol (2 mL), 150 °C, 12 h in a closed vessel; (2) amine (0.42
mmol, 1 equiv), toluene (1.5 mL), 1 (4 mol %), 120 °C, 16 h in a
closed vessel; isolated yield. m-Xylylenediamine (0.21 mmol) in the
b
second step.
excluded, as we could not observe the formation of amidine
under our reaction conditions even in the presence of
molecular sieves to remove water. Based on the results, the
formation of urea is proposed to follow the pathway shown in
Scheme 4. The primary amine is oxidatively coupled with
Scheme 4. Proposed Mechanism
The scope of the reaction was expanded to include a variety
of coupling partners, and various unsymmetrical ureas were
synthesized in good to excellent yields (Scheme 3). Reactions
with amines containing heterocycles provided the correspond-
ing ureas, i.e., 9aj and 9av, in very good yields. Notably, using
secondary amines as the second cross partners was successful
(9at and 9au) although symmetrical urea synthesis of
secondary amines was not possible; this implies that tertiary
formamides are not reactive for further urea functionalization
because of steric congestion. Unfortunately, the use of aniline in
the reaction did not generate a urea derivative, as in the case of
symmetrical urea synthesis. It is worthwhile to note that a
diamine reacted with in situ generated formamide to afford a
diurea compound (9aw).
An independent reaction with paraformaldehyde and benzyl-
amine under our reaction conditions gave 1,3-dibenzylurea
(Scheme S3a). To investigate the possibility of an isocyanate
mediated mechanism, N-benzyl formamide was treated with
aniline utilizing complex 1, but no reaction occurred (Scheme
S3b). Since benzyl isocyanate is easily reacted with aniline to
form the corresponding urea,23 the isocyanate mediated urea
formation pathway was ruled out. In addition, isocyanate was
not observed from N-benzyl formamide under our reaction
conditions (Scheme S3b). Involvement of amidine was also
formaldehyde, which is formed from dehydrogenation of
methanol, to generate the formamide. Subsequent nucleophilic
attack of an amine on the formamide generates the hemiaminal
analogue, which is further dehydrogenated to the urea.
In conclusion, we reported a novel urea synthetic method
directly from methanol and amines catalyzed by a readily
available ruthenium PNP catalyst with hydrogen as the sole
byproduct. No additive, such as a base, oxidant, or hydrogen
acceptor, was required. Symmetrical and unsymmetrical urea
derivatives were successfully obtained using methanol as the C1
feedstock by applying a dehydrogenative condensation strategy.
C
DOI: 10.1021/acs.orglett.5b03328
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03328.
■
S
Experimental procedures and characterization data
(PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: soonhong@snu.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Byungjoon Kang in our group for helpful discussions.
This research was supported by the National Research
Foundation of Korea (NRF-2014R1A2A1A11050028; NRF-
2014S1A2A2028156; NRF-2015M1A8A1048891) and the
Institute for Basic Science (IBS-R006-D1), funded by the
Korean Government. S.H.K. was supported by the NRF
Fostering Core Leaders of the Future Basic Science Program.
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DOI: 10.1021/acs.orglett.5b03328
Org. Lett. XXXX, XXX, XXX−XXX