Accelerated benzylation reaction utilizing dibenzyl carbonate as an alkylating reagent

Article abstract of DOI:10.1016/S0040-4039(03)01711-8

Ionic liquids can effectively accelerate slow N-benzylation reactions utilizing dibenzyl carbonate as an alkylating reagent. By applying microwave irradiation in the presence of the same ionic liquid, additional rate enhancement was accomplished.

Full text of DOI:10.1016/S0040-4039(03)01711-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6943–6945
Accelerated benzylation reaction utilizing dibenzyl carbonate as
an alkylating reagent
Wen-Chung Shieh,* Mario Lozanov and Oljan Repicˇ
Chemical and Analytical Development, Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA
Received 18 June 2003; revised 30 June 2003; accepted 2 July 2003
Abstract—Ionic liquids can effectively accelerate slow N-benzylation reactions utilizing dibenzyl carbonate as an alkylating
reagent. By applying microwave irradiation in the presence of the same ionic liquid, additional rate enhancement was
accomplished.
© 2003 Elsevier Ltd. All rights reserved.
Table 1. Effect of ionic liquids as additives or solvents on
Recently our laboratory reported a novel DABCO-cat-
alyzed benzylation methodology for a variety of N-, O-,
and S-containing compounds utilizing dibenzyl carbon-
ate (DBC) as a replacement for hazardous reagents
such as carcinogenic benzyl chloride and lachrymose
benzyl bromide.1 We demonstrated that DABCO, act-
ing as a nucleophilic catalyst, could effectively promote
DBC to behave as an alkylating reagent. From our
observation, this benzylation protocol seemed to work
efficiently (within hours) with several soft nucleophiles.
On the other hand, for some nitrogen-containing nucle-
ophiles, such as amide, indole, and aniline derivatives,
the benzylation was extremely slow (1–4 days) even at
an elevated temperature (135°C). Hence, we had a need
to develop a more efficient and expeditious methodol-
ogy for broader and more practical applications.
Herein, we report that by employing an ionic liquid as
either a solvent or an additive, significant rate enhance-
ment of the benzylation reaction can be accomplished.
the benzylation rate of benzimidazolea
Entry
Ionic liquidb
% 3c
1
2
3
4
5
6
7
8
Noned
64
77
84
77
92
90
90
85
74
82
95
88
90
[emim]+Cl−
[emim]+PF6
−
[hmim]+Cl−
Bu4N+Cl−
Bu4N+Br−
Bu4N+I−
Bu4N+OTf−
−
9
Bu4N+BF4
−
10
11
12
13
Bu4N+PF6
Oct4N+Br−
Octadecyl4N+Br−
[hmim]+Cl− as solvente
Ionic liquids have been shown to promote a variety of
organic transformations effectively. In most of these
reported applications, an ionic liquid was employed as
a reaction medium in a solvent-free fashion so that
volatile organic solvents can be eliminated.2,3 It has also
been reported that ionic liquids can be utilized as
catalysts or as additives to enhance the rates of reac-
tions in organic solvents.4,5 Based on these precedents,
a All reactions, except entries 1 and 13, were conducted with 1 (2
mmol), DBC (3 mmol), DABCO (0.2 mmol, 10 mol%), and an ionic
liquid (2 mmol) in 4 mL of CH3CN at 85°C for 23 h.
b [emim]=1-ethyl-3-methylimidazolium; [hmim]=1-n-hexyl-3-methyl-
imidazolium.
c The yields were determined by HPLC analysis of the reaction
mixture at the end of the reaction time indicated.
d Same as procedure in footnote a, except no ionic liquid was present.
e This reaction was conducted with 1 (2 mmol), DBC (3 mmol),
DABCO (0.2 mmol, 10 mol%) in [hmim]+ Cl− (4 mL) at 85°C for 11
h.
Keywords: nucleophilic catalyst; DABCO; N-benzylation; dibenzyl
carbonate; ionic liquid; microwave-assisted reactions.
* Corresponding author. E-mail: wen.shieh@pharma.novartis.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01711-8

6944
W.-C. Shieh et al. / Tetrahedron Letters 44 (2003) 6943–6945
we decided to investigate if the rate of the DABCO-cat-
alyzed benzylation reaction can be enhanced with an
ionic liquid. We were particularly interested in examin-
ing the advantages of employing stoichiometric
amounts of ionic liquid for the benzylation, since most
of the imidazolium or pyridinium type ionic liquids are
expensive when used as solvents. This study was first
conducted by treating benzimidazole 1 with DBC in the
presence of 1 equiv. of a variety of ionic liquids at 85°C
for 23 h. As shown in Table 1, both imidazolium- and
ammonium-type ionic liquids did enhance the rate of
reactions moderately. Employing [hmim]+Cl− as the
solvent, the rate was found to be slightly (however not
significantly) faster than when [hmim]+Cl− was used as
an additive (entries 4 and 13).
to 135°C and monitored by HPLC until a trace or no
starting material was detected. As promoted by TBAC,
the benzylation rates for both 5-bromoindole and the
unsubstituted indole were significantly improved as
shown by impressive reductions in reaction times to 0.5
(entry 1) and 2 h (entry 2), respectively. In the absence
of TBAC, the same reactions took 24 and 45 h under
the same conditions of solvent, temperature, concentra-
tion, and DABCO loading. A dramatic rate enhance-
ment was observed for the benzylation of
a
succinimide. In this example, the benzylation time of
phthalimide was reduced from 96 to 1 h, which corre-
sponds to a rate increase of more than 96-fold (entry 4).
Microwave irradiation has been employed for the pro-
motion of a variety of organic transformations leading
to faster and cleaner reactions when compared to con-
Acceleration of the benzylation reaction for carbazole 4
in N,N-dimethylacetamide (DMA) involving various
ionic liquids as an additive at a higher temperature
(135°C) was then investigated. Excellent conversion
(93%) in 3 h was observed when 1 equiv. of tetra-
butylammonium chloride (TBAC) (Table 2, entry 9)
was used. In comparison, the imidazolium-series of
ionic liquids that we screened were found to be less
effective. Ionic liquids that contain a chloride anion
consistently out-performed the ones containing differ-
ent anions (entries 7–9).
Table 3. Rate enhancement with Bu4N+Cl− for slow benz-
ylation reactions utilizing DBC
Since tetrabutylammonium chloride (TBAC) not only
performed well in both cases but also was readily
available, we decided to probe the potential of utilizing
TBAC as an additive to enhance the rates of several
slow benzylation reactions. The results of this study are
summarized in Table 3. In a typical experiment, a
substrate (2 mmol), DABCO (10–30 mol%), DBC (3
mmol), TBAC (2 mmol) in DMA (4 mL) were heated
Table 2. Effect of ionic liquids as an additive on the benz-
ylation rate of carbazolea
a
The identity of the benzylated products was confirmed by 1H and
Entry
Ionic liquidb
% 5c
13C NMR and MS.
b General procedure using conventional thermal heating: a reaction
flask was charged with substrate (2 mmol), DABCO (10–30 mol%),
DMA (4 mL), and DBC (3 mmol). The mixture was heated to
135°C, and the reaction was monitored by HPLC until trace or no
starting substrate was detected (reaction time).
1
2
3
4
5
6
7
8
9
Noned
59
28
34
28
65
28
66
79
93
[bmim]+OTf−
−
[bmim]+BF4
−
[bmim]+PF6
[bmim]+Cl−
c Isolated yield based on starting substrate.
−
[emim]+BF4
d Same as procedure b, except 1 equiv. of Bu4N+Cl− was charged to
the reaction mixture.
[emim]+Cl−
[hmim]+Cl−
Bu4N+Cl−
e General procedure using microwave heating: A solution of substrate
(20 mmol), DBC (60 mmol), DABCO (10–30 mol%), Bu4N+Cl− (20
a All reactions, except entry 1, were conducted with 4 (2 mmol), DBC
(3 mmol), DABCO (0.6 mmol, 30 mol%), and an ionic liquid (2
mmol) in 4 mL of DMA at 135°C for 3 h.
mmol) in CH3CN (80 mL) was passed through
a Milestone
ETHOS-CFR continuous-flow reactor preheated to 160°C at 20
bar. The reaction products were analyzed by HPLC after each pass
(6 min).
b [bmim]=1-n-butyl-3-methylimidazolium [emim]=1-ethyl-3-methyl-
imidazolium; [hmim]=1-n-hexyl-3-methylimidazolium.
f 10 mol% DABCO used.
g 30 mol% DABCO used.
c The yields were determined by HPLC analysis of the reaction
mixture at the end of the reaction time indicated.
h 31% of the starting material was recovered.
i 21% of the starting material was recovered.
d Same as procedure in footnote a, except no ionic liquid was present.

W.-C. Shieh et al. / Tetrahedron Letters 44 (2003) 6943–6945
6945
ventional heating.6 A few laboratories have reported
Acknowledgements
that improvement in yields or reaction times could be
achieved for alkylation reactions by combining
microwave irradiation with tetraalkylammonium halide
either in the absence7,8 or presence9–11 of solvents. Since
use of both ionic liquid and microwave for organic
transformations is still not a widely applied strategy, we
decided to probe whether there is any advantage for
this approach. By circulating the solution containing a
substrate (20 mmol), DBC (60 mmol), DABCO (10–30
mmol), Bu4N+Cl− (20 mmol) in CH3CN (0.25 M)
through a continuous-flow microwave reactor set at
160°C, we observed further rate enhancement for all
but one example that we studied (Table 3, entries 1–4).
Synthesizing 10 under microwave conditions was fast,
however, it led to several by-products as indicated by
HPLC, which explained the lower isolated yield. Repro-
ducibility was confirmed for the preparation of 6 at 5
and 25 g scales, which afforded consistent yield of 76
and 74%, respectively.
We thank Dr. Thomas Blacklock, Dr. Ernst Kuesters,
Dr. Gerhard Penn, Dr. Daniel Monti, and Dr. Ching-
Pong Mak for their encouragement in pursuing this
study.
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We have demonstrated that by employing stoichiomet-
ric amounts (1 equiv.) of ionic liquids, slow N-benzyla-
tion reactions that utilize dibenzyl carbonate as the
alkylating reagent can be effectively accelerated. The
recently developed imidazolium-type ionic liquids have
no advantage over the ammonium-type ones such as
TBAC, which effectively reduced the benzylation times
from several days to hours. A mechanistic study to
elucidate the role of TBAC is on going in our lab. By
applying microwave irradiation in the presence of the
same ionic liquid, further rate enhancements were
accomplished from hours to minutes. Preliminary
experimental data imply that it is the temperature (ther-
mal heat generated by the microwave), instead of a
special microwave effect, that contributes to the rate
enhancement of the benzylation reaction. More kinetic
studies are underway to verify this account. The new
methodology has the advantages of rapid reaction
times, ease of operation, use of readily available ionic
liquids, and avoiding toxic benzylating reagents. This
could make this newly developed chemistry of general
interest to organic chemists.
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Tetrahedron 1999, 55, 10851.
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