Oxidative esterification of aldehydes using a recyclable oxoammonium salt

Article abstract of DOI:10.1021/ol400785d

A simple, high yielding, rapid route for the oxidative esterification of a wide range aldehydes to hexafluoroisopropyl (HFIP) esters using the oxoammonium salt 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1a) is reported. These esters can be readily transformed into a variety of other functional groups. The spent oxidant (1b) can be recovered and conveniently reoxidized to regenerate the oxoammonium salt, 1a.

Full text of DOI:10.1021/ol400785d

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Oxidative Esterification of Aldehydes
Using a Recyclable Oxoammonium Salt
Christopher B. Kelly,† Michael A. Mercadante,† Rebecca J. Wiles,† and
Nicholas E. Leadbeater*,†,‡
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs,
Connecticut 06269-3060, United States, and Department of Community Medicine &
Health Care, University of Connecticut Health Center, The Exchange,
263 Farmington Avenue, Farmington, Connecticut 06030, United States
nicholas.leadbeater@uconn.edu
Received March 22, 2013
ABSTRACT
A simple, high yielding, rapid route for the oxidative esterification of a wide range aldehydes to hexafluoroisopropyl (HFIP) esters using the
oxoammonium salt 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1a) is reported. These esters can be readily
transformed into a variety of other functional groups. The spent oxidant (1b) can be recovered and conveniently reoxidized to regenerate the
oxoammonium salt, 1a.
Esters are highly attractive building blocks to the syn-
thetic organic chemist. This functionality can readily be
interconverted into a number of other functional groups,
and theyare frequently employed inindustryasfragrances,
medicines, or in polymer construction.1 The classical route
to ester preparation exploits reagent-based activation of
carboxylic acids and subsequent treatment with the desired
alcohol coupling partner.1a This activation can be per-
formed in situ (e.g., using strong acids, SOCl2, CDI,2
DEAD/PPh3,3 DCC,4 etc.) or in a stepwise fashion (e.g.,
carboxylic acid to acid chloride to ester).5 Many of these
processes employ reagents that can lack broad functional
group tolerance as well as being toxic or hazardous to the
user. Moreover, the byproducts that accompany these
reactions are often difficult to separate from the desired
ester.
An emerging alternative to ester synthesis is a tandem
oxidationÀesterification approach which offers greater
flexibility in the requisite starting materials.6 The most
successful of these oxidative esterification methods is the
conversion of an aldehyde to an ester. Several routes have
been utilized to date such as those exploiting N-hetero-
cyclic carbene activation,7 transition metal-mediated pro-
cesses,8 and those simply using a stoichiometric oxidant9 in
the presence of the alcohol coupling partner. Of note is a
recent report by Molander and co-workers that employs
Pd(OAc)2/XPhos with acetone as a terminal oxidant to
accomplish oxidative esterification.10
† University of Connecticut.
‡ University of Connecticut Health Center.
Oxoammonium salts such as 4-acetylamino-2,2,6,6-tetra-
methylpiperidine-1-oxoammonium tetrafluoroborate (1a)
are environmentally benign, recyclable, metal-free species
(1) (a) Otera, J. Esterification: Methods, Reaction and Application,
2nd ed.; Wiley-VCH: Weinheim, 2010. (b) Riemenschneider, W., Bolt, H. M.
Esters, Organic. Ullmann’s Encyclopedia of Industrial Chemistry: Wiley-
VCH: Weinheim, 2005. (c) Rosato, D. V.; Rosato, D. V.; Rosato, M. V.
Plastic Product Material and Process Selection Handbook: Elesevier Inc.:
New York, 2004.
(2) Staab, H. A.; Mannschreck, A. Chem. Ber. 1962, 95, 1284.
(3) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Dembinski, R. Eur. J.
Org. Chem. 2004, 2763.
(6) Ekoue-Kovi, K.; Wolf, C. Chem.;Eur. J. 2008, 14, 6302.
(7) Example: Maki, B. E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331.
(8) Example: Kiyooka, S.; Wada, Y.; Ueno, M.; Yokoyama, T.;
Yokoyama, R. Tetrahedron 2007, 63, 12695.
(4) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(9) Example: Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B.
Org. Lett. 2003, 5, 1031.
(5) Larock, R. C. Comprehensive Organic Transformations; VCH:
New York, 1999.
(10) Tschaen, B. A.; Schmink, J. R.; Molander, G. A. Org. Lett. 2013,
15, 500.
r
10.1021/ol400785d
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that can facilitate oxidation under extremely mild condi-
tions. As such, they have gained recent popularity as
alternativesto moretraditionaloxidizingreagents.11 Much
of the literature involving oxoammonium salts centers
around the conversion of alcohols to corresponding car-
bonyl species.12 As part of a broad program to enhance the
profile of oxoammonium salt-based transformations,13 we
became interested in the possibility of synthesizing esters
by means of oxidative esterification utilizing 1a as the
oxidant. Currently, there is little precedence for oxoam-
monium salt-mediated oxidative esterification.14 Bobbitt
and co-workers recently reported that alcohols could be
converted into their dimeric esters under basic oxidative
conditions (Scheme 1).12 However, the reaction was lim-
ited in that the dimerization process was unique to alcohols
bearing β-oxygen substituents.12 At high concentrations in
dichloromethane as solvent, dimeric esters of non-β-oxy-
gen alcohols could be observed, albeit in suboptimal
conversion.12
wondered if perfluoroesters could be synthesized from
aldehydes and an excess of the requisite perfluoroalcohol.
If successful, such a methodology would have several
advantages. Fluorinated esters are valuable synthons that
can easily be converted to other types of esters or to amides
under mild conditions. Additionally, they are themselves
more lipophilic than their nonfluorinated analogs16 and
have other unique properties (e.g., they can be readily
reduced17 with NaBH4). Perfluoroalcohols are very easy to
remove, thus facilitating product isolation (e.g., hexafluoro-
isopropanol, HFIP, has a boiling point of 57 °C). Despite
these advantages, limited examples exist for the prepara-
tion of this type of ester and those that are known either
require large excesses of the oxidant18 or report poor
yields.6
Initially, we investigated whether hexafluoroisopropyl
(HFIP) esters could be synthesized by way of oxidative
esterification. Using 2a as a model aldehyde, 2.2 equiv of
pyridine as the base, 2.5 equiv of 1a as the oxidant, and
1.5 equiv of HFIP in CH2Cl2 (0.5 M), we obtained 70%
conversion by GC/MS to the desired ester 3a in 12 h.
To improveboththe conversion and reaction time, we then
increased the loading of HFIP (3 equiv) and utilized
pyridine as both the base and solvent (12.75 equiv).
Gratifyingly we were able to achieve complete conversion
to 3a in 1 h (Scheme 2). Isolation proved facile, giving an
excellent yield of 3a (96%). Reducing the HFIP loading led
to extended reaction times being required to obtain com-
parable product conversion. We therefore opted to use
3 equiv. We also screened 4-picoline and 2,6-lutidine as
potential solvents and bases for the reaction, but these
pyridyl systems failed to affect appreciable oxidative ester-
ification of 2a.
Scheme 1. Dimeric Ester Synthesis by Oxidative Esterification
Seeking to expand the utility of this process, we posited
that a coupling reaction in which an aldehyde and an
alcohol partner could be joined to form an ester in the
presence of 1a could be possible. However, because of the
propensity for alcohols to undergo oxidation themselves
when exposed to 1a under basic conditions,15 it would be
very unlikely that the oxidative esterification pathway
would predominate. One solution would be to use as a
coupling partnera tertiary alcohol which could not itselfbe
oxidized. However, previous methods have shown this to
be very difficult, likely because of the steric bulk of these
species.10,14b We had previously shown that, in the pre-
sence of pyridyl bases, aliphatic R-trifluoromethyl alcohols
fail to oxidize when exposed to 1a.13a With this finding we
Following reaction optimization, we next subjected a
variety of aldehydes to our oxidative esterification condi-
tions. Both electron-rich (Table 1, entries 1À2, 4, 6À7) and
electron-poor (entries 3, 5, 8 and 9) functionalized deriva-
tives of benzaldehyde all underwent rapid oxidation and
gave excellent yields of their corresponding HFIP esters.
Notably, substrates bearing electron-deficient aryl systems
reached completion at a much faster rate than those bearing
electron-donating groups. In certain cases (entries 3, 4, 9,
16, 18, 23, and 24), we were unable to achieve complete
conversion using our optimized conditions. However, by
simply increasing loadings of both 1a and HFIP, we were
able to ensure that the starting material was completely
consumed.
(11) (a) Mercadante, M. A.; Kelly, C. B.; Bobbitt, J. M.; Tilley, L. J.;
Leadbeater, N. E. Nat. Protoc. 2013, 8, 666. (b) Kelly, C. B. Synlett 2013,
24, 527.
Scheme 2. Model Oxidative Esterification of Aldehydes
(12) Bobbitt, J. M.; Bruckner, C.; Merbouh, N. Org. React. 2010, 74,
103.
(13) (a) Kelly, C. B; Mercadante, M. A.; Hamlin, T. A.; Fletcher,
M. H.; Leadbeater, N. E. J. Org. Chem. 2012, 77, 8131. (b) Eddy, N. A.;
Kelly, C. B.; Mercadante, M. A.; Leadbeater, N. E.; Fenteany, G. Org.
Lett. 2012, 14, 498.
(14) (a) Merbouh, N.; Bobbitt, J. M.; Bruckner, C. J. Org. Chem.
2004, 69, 5116. (b) Bartelson, A. L. Novel Reactions of Oxoammonium
Salts in the Presence of Base, Graduate Thesis, University of Connecticut,
Storrs, CT, 2011.
(16) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
€
(15) (a) Merbouh, N.; Bobbitt, J. M.; Bruckner, C. Tetrahedron Lett.
2001, 42, 8793. (b) Bobbitt, J. M.; Merbouh, N. Org. Synth. 2005, 82, 80.
(17) Takahashi, S.; Cohen, L. A. J. Org. Chem. 1970, 35, 1505.
B
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We then probed whether polycyclic and heterocyclic
systems would be amenable to esterification. Furyl and
pyridylsubstitutedaldehydes(entries 11, 12, and 13respec-
tively) were compatible with our optimized conditions
giving their ester products in excellent yield. Our represen-
tative polycyclic species, 1-napthaldehyde (entry 10), simi-
larly tolerated our reaction conditions, the HFIP ester
being obtained in good yield.
Table 1. Scope of Oxidative Esterification of Various Aldehydes
with HFIPa
Wondering whetherthisoxidative esterification couldbe
extended to aliphatic aldehydes, we initially screened a
representative straight-chain system (entry 14). We were
delighted to find this system readily underwent oxidative
esterification in good yield. We next screened a variety of
aliphatic systems. Those with R-substitution (entries 16
and 23) proved to react slower and required additional 1a
and HFIP to achieve complete conversion. This retarda-
tion in rate is likely due to the steric encumbrance caused
by the R-substituents. Interestingly, 2o was not impeded by
R-substitution, likely due to the restricted rotation of the
cyclohexyl system (entry 15). By moving the substituent to
the β-position (entries 17À19 and 21), the reaction pro-
ceeds readily, giving good to excellent yields of the desired
esters. Of note is the R-diphenyl substituted substrate 2t
whose failure to react could be attributed to the enhanced
acidity of its R-proton (entry 20). When treated under the
optimized conditions, neither starting material nor pro-
duct was obtained, but rather a tar-likepolymeric material.
This could be the result of either an R-alkylation reaction
between an enol form of the aldehyde and 1a or a series of
aldol-like reactions.
Moving to R,β-unsaturated and propargylic systems, we
explored several olefinic species (entries 22 and 24À26).
While cinnamyl (entry 22) and furylacryl (entry 24) alde-
hydes were successfully oxidized in good yield, R-methyl
cinnamylaldehyde failed to go to complete conversion (not
shown), despite increased addition of both 1a and HFIP.
Interestingly, a nonconjugated R,β-unsaturated aldehyde
and a representative alkynyl aldehyde both afforded no
product (entries 25 and 26 respectively). Only polymeric
material and a trace amount of starting material were
recovered each time.
In an attempt to expand the utility of this transforma-
tion, we investigated whether trifluoroethanol (TFE)-
based esters could be prepared using our oxidative ester-
ification. We chose three representative benzaldehyde
derivatives (2b, 2c, 2d) to probe the efficacy of this trans-
formation as compared to the preparation of the HFIP
analogs. Unfortunately, even at the higher loadings of 1a
and trifluoroethanol, wefailedtoachievegreater than30%
conversion with any of these aldehydes.
a Reaction conditions unless otherwise noted: Aldehyde (1 equiv), 1a
(2.5 equiv), HFIP (3 equiv), pyridine (12.75 equiv). b Required 3 equiv of
1a and 3.5 equiv of HFIP.
To further demonstrate the utility of the HFIP esters
synthesized in this study, we conducted several subsequent
reactions using 3q as a representative ester (Scheme 3). To
investigate the reported propensity toward reduction,16 we
treated 3q with sodium borohydride. We found that it
could indeed be reduced quite readily, giving the corre-
sponding alcohol in excellent yield. We next explored
amidation, finding that the desired benzylamide could be
readily synthesized. In contrast to the traditional amida-
tion of esters,1 no strong base was required in our case. Of
additional note is that, unlike a previous report by Studer19
in which HFIP esters were made from aldehydes in situ
prior to amidation, using our protocol, aliphatic systems
(18) Mori, N.; Togo, H. Tetrahedron 2005, 61, 5915.
Org. Lett., Vol. XX, No. XX, XXXX
(19) Sarkar, S. D.; Studer, A. Org. Lett. 2010, 12, 1992.
C

can be utilized without competitive aldol processes. We
also conducted a transesterification of 3q, again under
very mild conditions, giving a good yield of the desired
methyl ester 6q. Finally, hydrolysis of 3q proceeded
quite rapidly giving the carboxylic acid 7q in excellent
yield.
range of functionalities, and the byproducts of the reaction
can be removed with ease. Moreover, the spent oxidant,
4-acetylamino-2,2,6,6-tetramethyl-1-piperidinyloxy (1b), can
be recovered and recycled (see Supporting Information).
Finally, HFIP esters can be easily converted to other valuable
products under very mild reaction conditions. Further
oxoammonium-mediated oxidative functionalization re-
actions are currently being investigated as is a mechanistic
study on this transformation.
Scheme 3. Applications of HFIP Esters
Acknowledgment. This work was supported by the
National Science Foundation (CAREER Award CHE-
0847262). We especially acknowledge Dr. James Bobbitt
of the University of Connecticut for helpful discussions,
troubleshooting assistance, and aid in the preparation of
1a. We thank Dr. You-Jun Fu of the University of Con-
necticut for his assistance in obtaining HRMS of novel
compounds. We also acknowledge Trevor Hamlin and
Timothy Monos of the University of Connecticut and
Dr. Leon Tilley at Stonehill College for useful discussions
and technical assistance.
In summary, we have disclosed a methodology for the
oxoammonium salt-mediated oxidative esterification of
aldehydes in the presence of HFIP to furnish a range of
HFIP esters. Using pyridine as the solvent and 1a as the
oxidant, the ester products can be obtained in good to
near-quantitative yields. The reaction is compatible with a
Supporting Information Available. Experimental pro-
cedures, characterization data, and spectra of the com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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