DABCO- and DBU-accelerated green chemistry for N-, O-, and S-benzylation with dibenzyl carbonate

Article abstract of DOI:10.1016/S0040-4039(03)00992-4

An environmentally friendly process for the benzylation of nitrogen, oxygen, or sulfur atoms with dibenzyl carbonate has been developed. Catalytic amounts of DABCO or DBU can accelerate this 'green' alkylation.

Full text of DOI:10.1016/S0040-4039(03)00992-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4563–4565
DABCO- and DBU-accelerated green chemistry for N-, O-, and
S-benzylation with dibenzyl carbonate
Wen-Chung Shieh,* Mario Lozanov, Mauricio Loo, Oljan Repi cˇ and Thomas J. Blacklock
Chemical and Analytical Development, Novartis Institute for Biomedical Research, One Health Plaza, East Hanover, NJ 07936,
USA
Received 27 March 2003; revised 16 April 2003; accepted 16 April 2003
Abstract—An environmentally friendly process for the benzylation of nitrogen, oxygen, or sulfur atoms with dibenzyl carbonate
has been developed. Catalytic amounts of DABCO or DBU can accelerate this ‘green’ alkylation. © 2003 Elsevier Science Ltd.
All rights reserved.
Benzylation of nitrogen, oxygen, or sulfur atoms is an
important and frequently utilized protection strategy in
organic synthesis. The most commonly used benzyla-
tion methodology employs a toxic and carcinogenic
reagent benzyl chloride or a lachrymose compound
practical application of DABCO and DBU to the ben-
zylation of N-, O-, or S-atoms with non-toxic dibenzyl
carbonate (DBC).
DBC is an excellent acylating agent as demonstrated in
a high yielding process for the preparation of Cbz-ser-
1
benzyl bromide. Our lab has been engaged in the
5
exploration of practical green chemistry that eliminates
the use of substances hazardous to human health and
the environment. In our recent study we reported that
the green reagent dimethyl carbonate (DMC) can func-
tion effectively as a methylating reagent for N- and
O-methylations under mild conditions if DBU is
ine methyl ester under room temperature conditions. It
is relatively less active when used as an alkylating
reagent. This has been shown in the reported benzyla-
6
7
tion reactions for anilines and active methylenes,
where high energy (130–180°C) and stoichiometric
amounts of bases were required to facilitate the benzyl-
ation. We were pleased to discover that both DABCO
and DBU serve as efficient nucleophilic catalysts in
promoting DMC as an effective alkylating reagent. Due
2
,3
employed as a catalyst. We also developed the first
catalytic process for the N-methylation of indoles using
4
DABCO as the catalyst. We report herein another
a
Table 1. Effect of DABCO on the benzylation rate of 5-bromoindole
b
b
Entry
DABCO [mol%]
Temp. [°C]
Time [h]
1 [%]
3
[%]
4
[%]
1
2
3
4
None
10
None
10
95
95
135
135
96
96
24
24
84
20
53
12
11
0
4
5
80
43
82
6
a
All reactions were conducted with 1 (2.0 mmol), DBC (3.0 mmol) in 4.0 mL of DMA. The product distributions were determined by HPLC
analysis of reaction mixture at the end of the reaction time indicated.
The identity of product was confirmed by H and C NMR and MS.
b
1
13
Keywords: nucleophilic catalyst; DABCO; DBU; benzylation; dibenzyl carbonate; green chemistry.
*
0
Corresponding author. E-mail: wen.shieh@pharma.novartis.com
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00992-4

4
564
W.-C. Shieh et al. / Tetrahedron Letters 44 (2003) 4563–4565
to structural similarity of DBC to DMC, we decided to
investigate if these catalysts may also be effective in
activating DBC as a more useful benzylating reagent.
Our catalytic benzylation strategy was first evaluated by
treating 5-bromoindole (1) with DBC (2) at 95°C in
For the benzylation of a carboxylic acid with DBC, rate
enhancement by DBU is also evident. For example,
benzylation of 2,6-dimethoxybenzoic acid (7) with DBC
employing Bu N as a proton scavenger is slow and
3
afforded 36% of the benzyl ester after 24 h (Table 2,
entry 1). When an additional 0.1 equiv. of DBU was
employed for the same reaction, the yield of benzyla-
tion was almost tripled (95%) over the same period of
time (entry 2). Near quantitative (99%) conversion to
the benzyl ester was achieved in 2 h when 1.1 equiv. of
DBU was employed as both proton scavenger and
catalyst (entry 3). The rate acceleration is presumably
attributed to the reaction of DBU with DBC forming a
more active benzylating agent (9) as shown in Scheme
N,N-dimethylacetamide
(DMA)
using
catalytic
amounts (10 mol%) of DABCO. As revealed in Table 1,
this reaction successfully afforded the desired 5-bromo-
N-benzylindole (4) in 80% yield (Table 1, entry 2).
Without DABCO, the same reaction generated only 5%
of 4 over the same period of time (entry 1).
Although this initial result demonstrates the feasibility
of the DABCO-catalyzed benzylation reaction, the rate
at 95°C was quite slow. We decided to probe the same
reaction at higher temperature (135°C). In the absence
of DABCO, benzylation of 4-bromoindole gave 43% of
the desired product in 24 h (entry 3). The rate was
increased by about twofold when a catalytic amount
2
.
To investigate the scope and synthetic utility of the
DABCO- and DBU-catalyzed benzylation reactions, a
variety of compounds were examined at 135°C (Table
3
). Employing this protocol, the reaction appears ver-
(
0.1 equiv.) of DABCO was employed (entry 4).
satile and applicable to several classes of substrates.
Excellent to good yields were obtained for the indole
compounds (entries 1–3). Presence of an electron-with-
We believe that the DABCO-catalyzed indole benzyla-
tion proceeds through the pathways illustrated in
Scheme 1. DABCO could function as a nucleophilic
catalyst and react with DBC to generate an ion pair 5.
drawing group (NO ) in the aromatic ring seems to
2
enhance the benzylation rate (entry 3). In comparison,
benzylation for the unsubstituted indole was very slow
Deprotonation of indole 1 with phenylmethoxide
(
entry 2). The protocol is highly efficient for benzimida-
−
(
PhCH O ) would lead to an ion pair 6, which could
2
zole (entry 4). Introducing a phenyl group at the 2-posi-
tion slows down the reaction significantly due to
increased steric hindrance around the nitrogen. Benzyl-
ation for a cyclic carbamate 20 (2-benzoxazolinone)
and a mercaptan 24 (2-mercaptobenzothiazole) are fast
undergo alkylation affording the N-benzylated indole 4.
Alternatively, ion-pair 6 could proceed through an
acylation pathway yielding indole carbamate 3, which
was isolated from the reaction mixture and supported
1
13
by H and C NMR, MS, and elemental analysis. It
was experimentally verified that pure 3 can convert
efficiently (96% conversion) into 4 at 95°C within 47 h
in the presence of DBC when catalytic amount (0.1
equiv.) of DABCO was employed. Without DABCO,
the conversion of 3 into 4 was not facile (only 5%
conversion) under the same conditions. Transformation
of 3 to 4 became more effective at higher temperature
Table 2. Effect of DBU on benzylation rate of 2,6-
a
dimethoxybenzoic acid at 135°C
(
e.g. 135°C) in the absence of DABCO.
b
Entry
Bu N
DBU
Time [h]
Yield of 8
3
[
equiv.]
[equiv.]
[%]
1
2
3
1.0
1.0
None
None
0.1
1.1
24
24
2
36
96
99
a
All reactions were conducted with 7 (2.0 mmol), DBC (3.0 mmol) in
.0 mL of DMA.
4
b
Yield was determined by HPLC analysis of reaction mixture at the
end of the reaction time indicated. The identity of product was
1
13
confirmed by H and C NMR and MS.
Scheme 1. Plausible mechanism for the indole benzylation.
Scheme 2.

W.-C. Shieh et al. / Tetrahedron Letters 44 (2003) 4563–4565
4565
Table 3. Catalytic N-, O-, and S-benzylation with DBC
and high yielding (entries 7 and 9). For a succinimide
2 (phthalimide), the benzylation was extremely slow
2
with moderate yield (entry 8). In a couple of cases, the
benzylation reaction had been extremely slow and more
DABCO was employed to further accelerate the rate
(
30 mol% DABCO was used in entries 2 and 6). For the
benzylation of aromatic acids, we found DBU a supe-
rior catalyst to DABCO. The isolated yields for the two
benzyl benzoates are excellent (entries 10 and 11).
In conclusion, we have established a novel, DABCO-
catalyzed benzylation methodology for a variety of
N-containing compounds and a mercaptan utilizing
DBC as the benzylating reagent. Benzylation reactions
for carboxylic acids are also effective when DBU is
employed as the catalyst. To the best of our knowledge,
this is the first reported method of preparing benzyl
carboxylates employing DBC. These protocols avoid
the use of toxic benzyl halides, eliminate the need of
stoichiometric amount of base, and provide green pro-
cesses for several important chemical transformations.
Acknowledgements
We thank Dr. Ernst Kuesters, Dr. Gerhard Penn, Dr.
Daniel Monti, and Dr. Ching-Pong Mak for their
encouragement in pursuing this study.
References
1. Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 2nd ed.; John Wiley & Sons: New York,
1991; Chapters 2 and 5–7.
2. Shieh, W.-C.; Dell, S.; Repi cˇ , O. Org. Lett. 2001, 3, 4279.
3. Shieh, W.; Dell, S.; Repi cˇ , O. J. Org. Chem. 2002, 67, 2188.
4. Shieh, W.; Dell, S.; Bach, A.; Repi cˇ , O.; Blacklock, T. J.
J. Org. Chem. 2003, 68, 1954.
5
6
7
8
9
. Monache, G. D.; Di Giovanni, M. C.; Maggio, F.; Misiti,
D.; Zappia, G. Synthesis 1995, 1155.
. Selva, M.; Tundo, P.; Perosa, A. J. Org. Chem. 2001, 66,
677.
. Selva, M.; Marques, C. A.; Tundo, P. J. Chem. Soc., Perkin
Trans. 1 1995, 1889.
. Katritzky, A.; Lang, H.; Lan, X. Tetrahedron 1993, 49,
2
829.
. Ucar, H.; Van Derpoorten, K.; Poupaert, J. Heterocycles
997, 45, 805.
0. Arnold, L.; Assil, H.; Vederas, J. J. Am. Chem. Soc. 1989,
11, 3973.
1
1
1
1
1
1
1. Baudin, J.; Hareau, G.; Julia, S.; Lorne, R.; Ruel, O. Bull.
Soc. Chim. Fr. 1993, 130, 856.
2. Ooi, T.; Miura, T.; Itagaki, Y.; Ichikawa, H.; Maruoka,
K. Synthesis 2002, 2, 279.
3. Lu, T.; Vargas, D.; Fischer, N. Phytochemistry 1993, 34,
737.