One-pot carbonyl reduction and carbonate formation using sodium borohydride in dialkyl carbonate solvents

Article abstract of DOI:10.1016/j.tetlet.2019.151203

Preparation of mixed carbonates proceeded in one step from ketones and aldehydes via treatment with NaBH₄ in dimethyl or diethyl carbonate solvent at elevated temperatures. This is an efficient and convenient alternative to the traditional two-step sequence of carbonyl reduction to alcohol and subsequent carbonate formation by treatment with an alkyl chloroformate. 25 examples are presented from 49 to 92% yield, highlighting the versatility of this reaction.

Full text of DOI:10.1016/j.tetlet.2019.151203

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One-pot carbonyl reduction and carbonate formation using sodium borohydride
in dialkyl carbonate solvents
Abdulakeem Osumah, Jakob Magolan, Kristopher V. Waynant
PII:
S0040-4039(19)30983-9
DOI:
https://doi.org/10.1016/j.tetlet.2019.151203
TETL 151203
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
20 August 2019
19 September 2019
23 September 2019
Please cite this article as: Osumah, A., Magolan, J., Waynant, K.V., One-pot carbonyl reduction and carbonate
formation using sodium borohydride in dialkyl carbonate solvents, Tetrahedron Letters (2019), doi: https://doi.org/
10.1016/j.tetlet.2019.151203
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One-pot carbonyl reduction and carbonate
formation using Sodium Borohydride in
dialkyl carbonate solvents
Leave this area blank for abstract info.
Abdulakeem Osumah, Jakob Magolan, and Kristopher V. Waynant
O
O
NaBH4
O
OR
H(R2)
R1
H(R2)
CO(OR)2 reflux
R = Me, Et
R1
25 examples
(49 - 92% yield)
R1, R2 = Aryl, Alkyl

1
Tetrahedron Letters
journal homepage: www.elsevier.com
One-pot carbonyl reduction and carbonate formation using sodium borohydride in
dialkyl carbonate solvents
Abdulakeem Osumaha , Jakob Magolanb,  and Kristopher V. Waynanta
aDepartment of Chemistry, University of Idaho, 875 Perimeter Dr. Moscow, ID 83844-2343
bDepartment of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. West, Hamilton, ON, L8N 3Z5 Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Preparation of mixed carbonates proceeded in one step from ketones and aldehydes via
treatment with NaBH4 in dimethyl or diethyl carbonate solvent at elevated temperatures. This is
an efficient and convenient alternative to the traditional two-step sequence of carbonyl reduction
to alcohol and subsequent carbonate formation by treatment with an alkyl chloroformate. 25
examples are presented from 49-92% yield, highlighting the versatility of this reaction.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbonate formation
One-pot synthesis
Mixed carbonates
Tandem reactions
———
 Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
1
Concerns of step economy and synthetic efficiency
have long been ubiquitous in multi-step, target-directed organic
reaction by H NMR showed 43% unreacted acetophenone, 31%
reduced alcohol 2, and none of the desired mixed carbonate 3.
However, when the reaction was heated to 90 °C for 6 hours,
alcohol 2 was no longer observed and carbonate 3 was found in
38 % (entry 2). Complete conversion of acetophenone to
carbonate 3 occurred in 17 hours at 90 °C (entry 3). However,
when the reaction was performed at reflux temperature, complete
consumption of the substrate occurred within 6 hours and the
desired carbonate was isolated in 89% yield (entry 4). Reducing
the amount of NaBH4
synthesis.1,
From the perspective of efficiency, it is
2
advantageous whenever more than one sequential chemical
transformation can be achieved in one pot without isolation or
purification of intermediates.3-5 We recently noticed that a
particular two-step sequence, the reduction of a carbonyl with
sodium borohydride followed by conversion to its corresponding
ethyl or methyl carbonate, is reported a number of times in the
context of natural products synthesis,6-9 synthetic methods
development,10-12 and medicinal chemistry.13-15 The second step
of this sequence is typically the treatment of the alcohol with
methyl or ethyl chloroformate16, 17 in the presence of an amine
base. Many “greener” methods are now available for the
preparation of mixed carbonates from alcohols using dialkyl
carbonate solvents rather than chloroformate reagents.18-25
Therefore, we wondered whether this overall two-step process of
reduction and carbonate formation could be adequately
accomplished simply by using diethyl or dimethyl carbonate as
the solvent during the borohydride reduction. Herein are the
results of a brief investigation of this idea which has yielded a
simple one-pot procedure for the reduction of a ketone or
aldehyde and conversion to its corresponding mixed carbonate.
Table 1: Various conditions for testing carbonate formation from
acetophenone.
Entry
Equiv.
NaBH4
Temp
(° C)
Time
(h)
aUnreacted
(1)%
Yield
(2) %
Yield
(3) %
1
2
3
4
5
6
1.0
1.0
1.0
1.0
0.5
0
25
24
6
43
45
0
31
0
0
90
38
90
17
6
0
99
128
128
128
0
0
99(89)b
6
5
0
84
0
Beginning with acetophenone 1, treatment with NaBH4 in
diethyl carbonate at room temperature for 24 hours (Table 1,
entry 1) produced a mixture of products. Analysis of the crude
6
100
0
aYield determined by NMR with 1-methylnapthalene internal standard
OCO2Et
OCO2Et
OCO2Et
Me OCO2Et
OCO2Et
NO2 OCO2Et
Me
Cl
Br
8
(75%)
4
(61%)
5
(80%)
3
6
(82%)
(89%)
7
(78%)
OCO2Et
OCO2Et
OMe OCO2Et
OCO2Et
OCO2Et
OCO2Et
NaBH4
(1 equiv.)
Cl
O
R1
R2
(EtO)2CO
reflux, 6 h
Br
MeO
Cl
Cl
12
13
14
(69%)
(58%)
(65%)
11
(51%)
9
10
(76%)
(80%)
O
O
OCO2Et
O
OH
OCO Et
OEt
2
OCO2Et
OCO2Et
O
NaBH4
OCO2Et
+
OCO2Et
(EtO)2CO
S
1
2
3
17
(43%)
15
16
(70%)
(92%)
18
19
(89%)
(72%)
20
(70%)
OCO2Me
OCO2Me
OCO2Me
(83%)
OCO2Me
OCO2Me
(49%)
OCO2Me
NaBH4
(1 equiv.)
OCO2Me
3
25
(MeO)2CO
reflux, 6 h
Br
23
21
(70%)
24
26
(59%)
22
(76%)
(68%)
27
(83%)
bIsolated Yield after chromatography
Figure 1. Scope of representative examples of mixed carbonates formation from refluxing diethyl carbonate and those for refluxing
dimethyl carbonate condition
borohydride (1 equiv.) and the reaction was stirred at reflux for
six hours. The reactions were cooled to room temperature,
diluted with diethyl ether, filtered through a fritted funnel
containing a sequential layer of celite and silica, and concentrated
under reduced pressure to give carbonate products in high
purity.26 The reaction did not require stringent conditions and
could be performed open to the atmosphere.
from 1 to 0.5 equivalents slowed the reaction slightly (entry 5)
and, as expected, removing the reducing reagent entirely led to
unreacted substrate (entry 6).
Satisfied with these conditions, here are presented
twenty-five examples of this reaction (Figure 1). In each case, a
ketone or aldehyde substrate was dissolved in diethyl or dimethyl
carbonate (10 or more equiv.) followed by addition of sodium

3
Substituted acetophenones (3-8) were converted in high
yields (75-89%) with the exception of ortho-nitro-substituted
derivative yielding carbonate 4 in a moderate 61% yield. High
yields (76-80%) were also observed for the chloro- and bromo-
para-substituted benzaldehyde-derived carbonates 9 and 10 with
lower yields in the ortho and meta derivatives (11, 12) showing
preference to electron-rich substituted arenes. Reactions with
napthaldehyde, benzophenone, and heteroaromatic benzo-[b]-
thiophene-3-carboxaldehyde formed 14, 15, and 16 respectively,
in good yields while 17, from furfural, proceeded in lower yield.
All reactions proceeded with minimal byproducts. Representative
examples of carbonate formation from aliphatic aldehydes and
ketones also gave carbonates 18-20 in good yields. Substrate
scope for mixed methyl carbonate formation from exchanging
solvent to dimethyl carbonate provided moderate to good yields
of acetophenone (21), substituted benzaldehyde (22),
benzophenone (23), and aliphatic aldehydes and ketones (24-27).
This reaction was not compatible with substrates containing
acidic protons such as phenols and carboxylic acids.
4.
D. Enders, M. R. M. Huettl, C. Grondal and G. Raabe, Nature,
2006, 441, 861.
5.
Z. Li, B. Hu, Y. W. Wu, C. Fei and L. Deng, P Natl Acad Sci USA,
2018, 115, 1730-1735.
6.
D. C. Blakemore and L. A. Marples, Tetrahedron letters, 2011,
52, 4192-4195.
7.
A. Endo and S. J. Danishefsky, Journal of the American Chemical
Society, 2005, 127, 8298-8299.
8.
M. D. Ganton and M. A. Kerr, Organic letters, 2005, 7, 4777-
4779.
9.
Y. Ueda, T. Furuta and T. Kawabata, Angewandte Chemie
International Edition, 2015, 54, 11966-11970.
D. L. J. Clive, W. Yang, A. C. MacDonald, Z. Wang and M. Cantin,
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organic chemistry, 2011, 76, 10099-10113.
10.
11.
12.
13.
B. M. Trost and L. C. Czabaniuk, Chemistry–A European Journal,
2013, 19, 15210-15218.
Mechanistically, following borohydride reduction of the
carbonyl, the reaction requires a catalytic amount of base to form
a nucleophilic alkoxide intermediate that attacks the dialkyl
carbonate solvent. It is suggested that the decreased
electrophilicity of the dialkyl carbonate increases the activation
energy of the nucleophilic attack which correlates with the
reaction proceeding faster at elevated temperatures and with
higher yields. Lower yields from substrates with electron
withdrawing substituents indicates that these groups inhibit the
nucleophilicity of the alkoxide species.
S. Usui, H. Fujieda, T. Suzuki, N. Yoshida, H. Nakagawa and N.
Miyata, Bioorganic & medicinal chemistry letters, 2006, 16,
3249-3254.
14.
E. Van Quaquebeke, G. Simon, A. André, J. Dewelle, M. E. Yazidi,
F. Bruyneel, J. Tuti, O. Nacoulma, P. Guissou and C.
Decaestecker, Journal of medicinal chemistry, 2005, 48, 849-
856.
15.
16.
J. A. Campbell, V. Bordunov, C. A. Broka, J. Dankwardt, R. T.
Hendricks, J. M. Kress, K. A. M. Walker and J.-H. Wang,
Tetrahedron letters, 2004, 45, 3793-3796.
Attempts to form mixed carbonates from alcohol
substrates at elevated temperatures using carbonate solvents
without the addition of sodium borohydride did not proceed.
However, when benzyl alcohol was reacted with 10 mol % of
NaBH4 in refluxing diethyl carbonate, the mixed carbonate was
obtained in 91% yield. Similarly, reaction of benzyl alcohol with
10 mol % of NaH with dimethyl carbonate as solvent at reflux for
6 h resulted in 85% yield of mixed carbonate signifying the
necessity of substoichiometric base and heat to complete the
tandem reaction. No reaction was observed when reducing agent
BH3•THF was substituted for sodium borohydride.
A. Böttcher, H. Becker, M. Brunner, T. Preiss, J. Henkelmann, C.
De Bakker and R. Gleiter, Journal of the Chemical Society,
Perkin Transactions 1, 1999, 3555-3556.
17.
18.
19.
B. Husar and R. Liska, Chemical Society Reviews, 2012, 41,
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D. Nakatake, R. Yazaki, Y. Matsushima and T. Ohshima,
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D. Nakatake, Y. Yokote, Y. Matsushima, R. Yazaki and T.
Ohshima, Green Chemistry, 2016, 18, 1524-1530.
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M. Hatano, S. Kamiya and K. Ishihara, Chemical
Communications, 2012, 48, 9465-9467.
In conclusion, an efficient one-pot reaction for the
formation of carbonates from a variety of aromatic and aliphatic
ketones and aldehydes has been shown to proceed at elevated
temperatures in the presence of NaBH4 and dialkyl carbonate
solvents with most substrates resulting in good yields and high
purity. The conversion of carbonyls directly to carbonates allows
for fewer synthetic steps and without need for toxic
alkylchloroformate reagents.
20.
21.
22.
23.
24.
25.
26.
M. Hatano, S. Kamiya, K. Moriyama and K. Ishihara, Organic
Letters, 2011, 13, 430-433.
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Biomolecular Chemistry, 2012, 10, 6569-6578.
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Acknowledgments
M. L. Kantam, U. Pal, B. Sreedhar and B. e. M. Choudary,
Advanced Synthesis & Catalysis, 2007, 349, 1671-1675.
The M. J. Murdock Charitable Trust, Vancouver, WA, Reference
No.: 2014120:MNL: 11/20/2014, provided funds supporting the
purchase of a 500 MHz NMR spectrometer. Thanks to Alex
Blumenfeld for NMR characterization.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
References and notes
1.
T. Newhouse, P. S. Baran and R. W. Hoffmann, Chemical Society
Reviews, 2009, 38, 3010-3021.
2.
3.
P. A. Wender, Natural product reports, 2014, 31, 433-440.
K. C. Nicolaou, T. Montagnon and S. A. Snyder, Chemical
Communications, 2003, 551-564.

4
Tetrahedron
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Highlights



Efficient one-pot carbonyl to carbonate conversion
Green dialkyl carbonate solvents as reagents
Multiple examples of aliphatic and aromatic ketones/aldehydes