N-heterocyclic carbene-catalyzed α-alkylation of ketones with primary alcohols

Article abstract of DOI:10.1002/hlca.201400076

Several N-heterocyclic carbene precursors are synthesized and used in the α-alkylations of ketones with primary alcohols. With the assistance of a base, these N-heterocyclic carbenes can catalyze the reaction smoothly to furnish dialkylated ketones in good-to-excellent yields.

Full text of DOI:10.1002/hlca.201400076

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Helvetica Chimica Acta – Vol. 97 (2014)
N-Heterocyclic Carbene-Catalyzed a-Alkylation of Ketones with Primary
Alcohols
by Yanfang Zhu, Chun Cai*, and Guoping Lu
Chemical Engineering College, Nanjing University of Science & Technology, 200 Xiaolingwei,
Nanjing 210094, P. R. China
(phone: þ 86-25-84315514; fax: þ 86-25-84315030; e-mail: c.cai@mail.njust.edu.cn)
Several N-heterocyclic carbene precursors are synthesized and used in the a-alkylations of ketones
with primary alcohols. With the assistance of a base, these N-heterocyclic carbenes can catalyze the
reaction smoothly to furnish dialkylated ketones in good-to-excellent yields.
Introduction. – The alkylation of ketones is a pivotal method to increase the
molecular complexity of simple organic substrates [1][2], and a-alkylation of ketones
with electrophiles such as alcohols has become a novel and efficient tool to form CꢀC
bonds. Since the pioneering work of Cho et al. [3], many catalytic systems for the a-
alkylation of ketones have been screened. For example, [Ru(DMSO)4]Cl2 [4],
[Ir(cod)Cl]2/PPh3 [5][6], [Cp*IrCl2]2 [7][8], Pd/AlO(OH) [9], Pd-NPs(nanoparti-
cles)/Ba(OH)2 · H2O [10][11], Ni-NPs [12],TiO2 [13], Ag/Mo [14], [Os(h6-p-cyme-
ne)(OH)(Ipr)]Otf [15] and RuHCl(CO)/(PPh3)3 [16] were reported as catalytic
systems to achieve this kind of alkylation. Metal-based catalytic systems play a
dominant role in this field since the yields are high, and the only by-product is H2O.
However, ligands are always used in these catalytic systems, and the catalysts are hard
to be reused. Very recently, Liang et al. Reported the a-alkylation of ketones with
t
alcohols by a catalyst-free reaction [17]. However, this reaction needs excess BuOLi,
long reaction time, and an Ar atmosphere. This prompted us to achieve a more efficient
approach using metal-free catalysts for the a-alkylation of ketones.
Recently, organocatalysis has attracted considerable attention because of its facile
reaction course, selectivity, and environmental friendliness. The application of organo-
catalysts made many new synthetic pathways possible. N-Heterocyclic carbenes (NHC)
as organocatalysts have been applied in numerous organic reactions [18 – 23]. In many
cases, NHCs were used for the ꢀumpolungꢁ of the C¼O group, serving as a kind of Lewis
base organocatalysts [18]. Since they are strong bases [24], we concluded NHCs
catalyst could be used for the a-alkylation of ketones.
With these considerations in mind, we synthesized several known N-heterocyclic
carbene precursors (Scheme 1) and applied them in a-alkylation reactions of ketones
with alcohols (Scheme 2). To our delight, these reactions proceeded very smoothly to
afforded the corresponding products in good-to-excellent yields with satisfactory
selectivity.
ꢂ 2014 Verlag Helvetica Chimica Acta AG, Zꢃrich

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Scheme 1. Synthesis of N-Heterocyclic Carbene Precursors
Scheme 2. NHC-Mediated a-Alkylations of Ketones with Primary Alcohols
Results and Discussion. – At the outset of our study, using precatalyst A, and 4-
bromoacetophenone (1a) and benzyl alcohol (BnOH; 2a) as model substrates, we
examined the a-alkylation under several conditions (Table 1). When 1a was reacted
with 2a in the presence of 0.2 mol-% of A and 1.0 equiv. of KOH at 1108 (bath temp.)
for 5 h, the desired a-alkylated ketone 3a was formed in 98% yield (Table 1, Entry 1).
As evident from Table 1, the NHC precursors A – D all facilitated the reaction to afford
the expected product 3a (Table 1, Entries 1 – 4), while precatalysts A and C provide
almost the same excellent yields of 3a (Table 1, Entries 1 and 3). After survey of several
bases, we found that KOH gave a good yield of 3a (Table 1, Entry 1). The influence of
the amount of the catalyst was also examined. When the amount of A was decreased to
0.1 mol-%, or no precatalyst was used in the reaction, the results were unsatisfactory
(Table 1, Entries 9 and 10). However, an increase in the amount of catalyst (Table 1,
Entries 11 and 13 – 15) had a negative effect. In addition, decreased base amount was

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Helvetica Chimica Acta – Vol. 97 (2014)
Table 1. Optimization of Reaction Conditionsa)
Entry
NHC · HX ([mol-%])
Base ([mol-%])
Yield [%]b)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
A (0.2)
B (0.2)
C (0.2)
D (0.2)
A (0.2)
A (0.2)
B (0.2)
B (0.2)
A (0.1)
–
A (1)
A (0.2)
A (1)
A (2)
A (5)
KOH (100)
KOH (100)
KOH (100)
KOH (100)
NaOH (100)
Cs2CO3 (100)
NaOH (100)
Et3N (100)
KOH (100)
KOH (100)
KOH (100)
KOH (50)
98
74
96
84
93
4
92
trace
74
58
54
63
70
62
58
KOH (50)
KOH (50)
KOH (50)
a) Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), and precatalyst (0.002 mmol) were mixed
together in 3 ml of toluene in air, and finally base (1 equiv.) was added; 1108; 5 h. b) Yield of isolated
1
product; product identified by H-NMR.
found to have a significantly negative effect (Table 1, Entry 12). It should be noted that
the modified a-alkylation of ketones using the NHC catalyst could proceed readily at a
shorter time, a lower base equivalent, and under an atmosphere of air, as compared to
t
that using BuOLi reported in the literature.
Having established the optimum reaction conditions for the NHC-mediated a-
alkylation of acetophenone with BnOH, we then examined the further scope and
general applicability of this process (Table 2). Thus, a range of acetophenones with
different substituents were employed which provided the desired products 3 in
excellent yields (i.e., 3a – 3e). At the same time, using benzyl alcohols with various
substituents gave the corresponding products 3f – 3k also in moderate-to-good yields.
Tetralone 1f and 2-acetylpyridine (1g) were alkylated by 2a to give 3l and 3m in good
and moderate yields, respectively. A hydroxymethyl heteroaryl such as pyridine-3-
methanol (2e) also reacted with acetophenone (1a) to give 3n in moderate yield.
Unfortunately, only when ketones contained an aromatic substituent in a-position
and alcohols also contained aromatics substituents, the reaction occurred smoothly. The
reaction of aliphatic ketones with BnOH was achieved in only 16% yield (3o) and the
reaction using EtOH (2f) gave an unsatisfactory result ( ! 3b) as well. These results
might be ascribed to the participation of the aromatic ring in conjugation.
In conclusion, we have synthesized several N-heterocyclic carbene precursors and
disclosed a simple and efficient NHCs-catalyzed reaction of a-aryl ketones with various

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Table 2. a-Alkylation of Ketones with Alcohols Catalyzed by NHCsa)
Entry
Ketone
(1)
R1
Alcohol
(2)
R2
Product
(3)
Time [h]
Yield
[%]b)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1b
1b
1b
1e
1e
1e
Ph
2a
2a
2a
2a
2a
2b
2c
2d
2c
2d
2b
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
5
5
5
5
5
5
1
5
5
1
5
83
98
85
86
87
95
88
94
76
85
86
2-BrꢀC6H4
2-ClꢀC6H4
2-MeOꢀC6H4
2-MeꢀC6H4
2-BrꢀC6H4
2-BrꢀC6H4
2-BrꢀC6H4
2-MeꢀC6H4
2-MeꢀC6H4
2-MeꢀC6H4
Ph
2-MeOꢀC6H4
4-BrꢀC6H4
4-ClꢀC6H4
4-BrꢀC6H4
4-ClꢀC6H4
2-MeOꢀC6H4
10
11
3j
3k
12
13
14
15
16
1f
1g
1a
1h
1b
2a
2a
2e
2a
2f
Ph
Ph
3l
3
5
1
5
5
81
60
69
16
3
Pyridin-2-yl
Ph
Me
2-BrꢀC6H4
3m
3n
3o
3p
Pyridin-3-yl
Ph
Me
a) The reaction was carried out with ketone (1 mmol), alcohol (1.2 mmol), precatalyst A (0.2 mol-%),
and KOH (1 equiv.) in toluene (3 ml) at 1108. b) Yield of isolated product.
benzyl alcohols in high yields. This procedure constitutes an excellent example of very
high atom efficiency reaction. The advantages of these catalyst precursors such as being
air-stable and easy to handle and to prepare render the NHCs-catalyzed alkylation as a
significant development compared to the established alkylation protocols. A detailed
mechanistic study involving the precise role of N-heterocyclic carbenes in the
promotion of a-aryl ketones with primary alcohols, as well as synthetic applications
of the present reactions, is currently underway in our laboratory.
Experimental Part
General. All chemicals were commercially available and used without further purification. GC:
Agilent 7890A instrument. 1H- and 13C-NMR spectra: Bruker DRX 500; d in ppm rel. to Me4Si as internal
1
standard, J in Hz. The H-NMR data of the precatalysts are in agreement with those reported in the
literature [25 – 28].
Synthesis of 1,3-Dibenzyl-1H-benzimidazol-3-ium Chloride (A). To a 100-ml three-necked round-
bottomed flask charged with 1H-benzimidazole (5.90 g, 50 mmol) was added K2CO3 (75 mmol),
followed by MeCN (40 ml) at reflux (808) for 30 min. Then BnCl (50 mmol) was added slowly over
30 min, and the mixture was refluxed at 808 for 24 h. After cooling to r.t., the mixture was concentrated in

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Helvetica Chimica Acta – Vol. 97 (2014)
vacuo, and the residue was dissolved in CH2Cl2 (20 ml) and washed with H2O (20 ml). The aq. layer was
extracted with CH2Cl2 (3 ꢁ 30 ml), and the combined org. phase was dried (anh. Na2SO4), filtered, and
concentrated in vacuo to afford 1-benzyl-1H-benzimidazole (95%).
In a 50-ml three-necked round-bottomed flask, 1-benzyl-1H-benzimidazole (10 mmol) was dissolved
in toluene (20 ml), and BnCl (10 mmol) was added dropwise, and the mixture was refluxed for 24 h.
Upon completion of the reaction, the solvent was evaporated in vacuo. The residue was washed with
1
AcOEt and dried in vacuo to afford the product (92%). M.p. 210 – 2128. H-NMR ((D6)DMSO, 258):
10.21 (s, 1 H); 7.98 – 8.01 (m, 2 H); 7.63 – 7.65 (m, 2 H); 7.56 (d, J ¼ 7.2, 4 H); 7.35 – 7.45 (m, 6 H); 5.81 (s,
4 H).
Synthesis of 1,3-Di(propan-2-yl)-1H-benzimidazol-3-ium Bromide (B). A mixture of 1H-benzimi-
dazole (591 mg, 5 mmol) and K2CO3 (760 mg, 5.5 mmol) was suspended in MeCN (3 ml) and stirred at
r.t. for 1 h. To the suspension was added iPrBr (1.40 ml, 15 mmol). The mixture was stirred under reflux
conditions for 24 h, followed by a second addition of iPrBr (1.40 ml, 15 mmol). Stirring under reflux was
continued for an additional 72 h. After removing the volatiles in vacuo, CH2Cl2 (50 ml) was added to the
residue, and the resulting suspension was filtered over Celite. The filter cake was washed with CH2Cl2
(5 ꢁ 20 ml), and the solvent was removed in vacuo to give a spongy solid, then this solid was washed with
AcOEt to afford B (88%). White powder. M.p. 136 – 1388. 1H-NMR (500 MHz, CDCl3): 11.26 (s, 1 H);
7.83 (m, 2 H); 7.63 (m, 2 H); 5.20 (m, 2 H); 1.84 (d, J ¼ 6.5, 12 H).
Synthesis of 1,3-Dibenzyl-4,5-dihydro-1H-imidazol-3-ium Bromide (C).
A mixture of
NH2CH2CH2NH2 (1.0 ml, 14.8 mmol) and PhCHO (3.32 ml, 32.5 mmol) was stirred in toluene (10 ml)
at r.t. for 6 h. The solvent was then removed in vacuo to give the diimine as a yellow liquid. NaBH4 (3.4 g,
77.3 mmol), dissolved in MeOH (10 ml), was slowly added to the diimine in MeOH (10 ml) at 08. The
mixture was allowed to stir overnight at r.t. MeOH was then removed in vacuo, and the residue was
dissolved in Et2O (30 ml) and washed with H2O (2 ꢁ 20 ml) and brine (20 ml). Drying of the Et2O layer
gave the diamine as a yellow liquid. To the diamine, CH(OEt)3 (7.4 ml, 44.4 mmol) and NH4Br (1.45 g,
14.8 mmol) were added, and the mixture was stirred for 4 h at 1008. The mixture was cooled to r.t., and
excess CH(OEt)3 was removed in vacuo at 608. The residue was dissolved in a minimal amount of
CH2Cl2, and the soln. was added dropwise to the mixed soln. of Et2O and THF. Filtration gave C (3.04 g,
1
62%). White solid. M.p. 163 – 1658. H-NMR (500 MHz, CDCl3): 10.36 (s, 1 H); 7.37 – 7.43 (m, 10 H);
4.90 (s, 4 H); 3.77 (s, 4 H).
Synthesis of 1,3-Di(propan-2-yl)-1H-imidazol-3-ium Bromide (D). Compound D was prepared as
described for B. The product was collected as a white solid after washing with AcOEt (84%). M.p. 132.08.
1H-NMR (500 MHz, CDCl3): 10.84 (s, 1 H); 7.43(d, 2 H); 5.00 (m, 2 H), 1.64 (d, J ¼ 6.5, 12 H).
General Procedure for the Reaction of Ketones with Alcohols. To a soln. of catalyst precursor (0.6 mg,
0.002 mmol) and KOH (0.056 g, 1 mmol) in toluene (3 ml) was added the corresponding ketone
(1 mmol), followed by the corresponding alcohol (1.2 mmol). The mixture was stirred and heated at 1108
for an appropriate time. Then, the reaction was quenched by the addition of a sat. NH4Cl soln. (20 ml),
and the mixture was extracted with AcOEt (3 ꢁ 15 ml). The combined org. layers were dried (Na2SO4),
filtered, and the solvents were removed under reduced pressure. The resulting residue was purified by
flash chromatography to afford the corresponding products. All the products were known compounds
and were characterized by comparison of their physical and spectroscopic data with those described in
the literature.
We are grateful to the Province Natural Science Foundation of Jiangsu for financial support
(BK20131346).
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Received March 4, 2014