Tandem oxidation of allylic and benzylic alcohols to esters catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1021/ol062940f

(Chemical Equation Presented) N-Heterocyclic carbenes catalyze the oxidation of allylic, propargylic, and benzylic alcohols to esters with manganese(IV) oxide in excellent yields. A variety of ester derivatives can be synthesized, including protected carboxylates. This one-pot tandem oxidation represents the first organocatalytic oxidation of alcohols to esters. Saturated esters can also be accessed from aldehydes using this method. Through the utilization of a chiral catalyst, the acyl-heteroazolium intermediate becomes a chiral acylating agent, which can desymmetrize meso-1,2-diols.

Full text of DOI:10.1021/ol062940f

ORGANIC
LETTERS
2007
Vol. 9, No. 2
371-374
Tandem Oxidation of Allylic and
Benzylic Alcohols to Esters Catalyzed
by N-Heterocyclic Carbenes
Brooks E. Maki, Audrey Chan, Eric M. Phillips, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
scheidt@northwestern.edu
Received December 4, 2006
ABSTRACT
N-Heterocyclic carbenes catalyze the oxidation of allylic, propargylic, and benzylic alcohols to esters with manganese(IV) oxide in excellent
yields. A variety of ester derivatives can be synthesized, including protected carboxylates. This one-pot tandem oxidation represents the first
organocatalytic oxidation of alcohols to esters. Saturated esters can also be accessed from aldehydes using this method. Through the utilization
of a chiral catalyst, the acyl−heteroazolium intermediate becomes a chiral acylating agent, which can desymmetrize meso-1,2-diols.
The development of mild and efficient oxidation methods
remains an important goal in chemistry.1 Tandem oxidation
strategies hold particular interest2 due to their potential to
access higher oxidation states in one reaction flask and to
generate and functionalize challenging substrates in situ. A
seminal report by Corey detailed the two-step oxidation of
allylic alcohols to esters in the presence of sodium cyanide
and manganese(IV) oxide.3 Gilman4 and Taylor5 further
developed this process independently into one-pot tandem
oxidation reactions to generate esters and amides. Although
efficient, the major limitation of these oxidations is the large
excess of cyanide used in the reaction. Iodine has also been
reported to oxidize alcohols to esters,6 although this method
requires superstoichiometric amounts of a toxic oxidant. We
have been interested in utilizing N-heterocyclic carbenes
(NHCs) to promote the oxidation of aldehyde C-H bonds.7
Herein, we report the tandem oxidation of allylic alcohols
to esters with manganese(IV) oxide catalyzed by NHCs (eq
1). Importantly, the acyl heteroazolium intermediate presents
(1) (a) Tojo, G.; Ferna´ndez, M. Oxidation of Alcohols to Aldehydes and
Ketones; Springer: New York, 2006. (b) Adam, W.; Saha-Moller, C. R.;
Ganeshpure, P. A. Chem. ReV. 2001, 101, 3499-3548. (c) Sheldon, R. A.;
Arends, I.; Ten Brink, G. J.; Dijksman, A. Acc. Chem. Res. 2002, 35, 774-
781. (d) Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D.
H. B. Chem. ReV. 2006, 106, 2943-2989.
the opportunity to create a chiral environment around the
activated carbonyl, lending this method to asymmetric
applications.
Our proposed pathway for this tandem oxidation is
outlined below (Scheme 1). Initial oxidation of the alcohol
(2) For a review of tandem oxidation processes, see: Taylor, R. J. K.;
Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851-869.
(3) (a) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616-5617. (b) Corey, E. J.; Katzenellenbogen, J. A.; Gilman,
N. W.; Roman, S. A.; Erickson, B. W. J. Am. Chem. Soc. 1968, 90, 5618-
5620. (c) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096. (d) Davidsen, S. K.; Chumoyer, M. Y. J. Org. Chem. 1989,
54, 5558-5567. (e) Fisher, M. J.; Chow, K.; Villalobos, A.; Danishefsky,
S. J. J. Org. Chem. 1991, 56, 2900-2907.
(6) Mori, N.; Togo, H. Tetrahedron 2005, 61, 5915-5925.
(7) (a) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558-
4559. (b) Castells, J.; Llitjos, H.; Morenomanas, M. Tetrahedron Lett. 1977,
205-206. (c) Inoue, H.; Higashiura, K. J. Chem. Soc., Chem. Commun.
1980, 549-550. (d) Miyashita, A.; Suzuki, Y.; Nagasaki, I.; Ishiguro, C.;
Iwamoto, K.; Higashino, T. Chem. Pharm. Bull. 1997, 45, 1254-1258.
(4) Gilman, N. W. J. Chem. Soc. 1971, 733-734.
(5) Foot, J. S.; Kanno, H.; Giblin, G. M. P.; Taylor, R. J. K. Synthesis
2003, 1055-1064 and references cited therein.
10.1021/ol062940f CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/20/2006

Table 1. Survey of Heteroazolium Saltsa
Scheme 1. Proposed Mechanistic Pathway for Tandem
Oxidation
entry
azolium
mol %
time, h
yield, %
1
2
3
4
5
6
7
20 mol % DBU only
24
24
24
24
24
12
48
0
0
0
A
B
C
D
E
E
20
20
20
20
10
2
0
40
93
83
aAll reactions were performed with 1:1 NHC/DBU, 15 equiv of MnO2, 0.2
M in MeOH at 23 °C.
(1) by manganese(IV) oxide provides in situ generation of
aldehyde 2. The deprotonation of the heteroazolium salt
generates the N-heterocyclic carbene (I), which then adds
to the carbonyl to yield tetrahedral intermediate II. This
secondary alcohol is rapidly oxidized to acyl heteroazolium
III by manganese(IV) oxide.8 It should be noted that no
generation of homoenolate equivalents9 (IV) is observed. The
implication from these observations is that the secondary
alcohol generated in situ (II) presumably undergoes oxidation
faster than deprotonation of the carbinol carbon to afford
IV. Acylation10 of the nucleophilic alcohol (3) by activated
ester III completes the oxidation to an unsaturated ester (4)
and regenerates the NHC catalyst in the presence of base.
Our investigation began by surveying heteroazolium salts
as potential catalysts. Cinnamyl alcohol was used as the
initial substrate with methanol as the nucleophile and solvent
(Table 1, eq 2). The two alcohols were stirred in the presence
of DBU, manganese(IV) oxide, and catalytic quantities of
the NHC precursor. This oxidation sequence is particularly
sensitive to azolium structure. In our hands, thiazolium,
benzimidazolium and imidazolium salts A-D gave no
product or incomplete conversion (entries 2-5).11 However,
with simple triazolium salt E,12 we were delighted to isolate
methyl cinnamate (5) in a 93% yield (entry 6) with no dimer
product. Reducing the catalyst loading (2 mol %) resulted
in good yields but longer reaction times (entry 7).
With heteroazolium salt E identified as an effective
precatalyst, we surveyed potential substrates using 1-butanol
as the nucleophile (Table 2). A variety of activated alcohols
are smoothly oxidized to the respective unsaturated esters
in excellent yields.13 The use of R-substituted allylic alcohols
gave comparable yields (entry 2) but required longer reaction
times and increased catalyst loading. Propargyl substrates
afford the ynoate ester without complications resulting from
undesired conjugate addition reactions (entry 5). These
conditions also accommodate heteroaromatic systems (entry
6) as well as alkyl (entry 7) and ester (entry 8) functional
groups. It is interesting to note that the ethyl ester of 12 does
not undergo NHC-catalyzed transesterification in the protic
media of the reaction.14 Substituted benzylic alcohols were
the most reticent to undergo oxidation (entries 9 and 10),
and electron-rich alcohols such as 4-methoxybenzyl alcohol
showed no reactivity in this system, yielding only p-
anisaldehyde. The slow rate of the second oxidation step with
benzylic systems (i.e., II-III, Scheme 1) may be due to the
destabilizing interaction between the aromatic ring and the
heteroazolium core that would be generated if the acyl
heteroazolium species were formed. However, the success
with naphthyl systems (entries 3 and 4) should suffer similar
(8) In the absence of manganese(IV) oxide, the combination of aldehydes
with triazolium salt E and DBU yielded only benzoin products. See: (a)
Breslow, R.; Schmuck, C. Tetrahedron Lett. 1996, 37, 8241-8242. (b)
White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124-5131.
(9) (a) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905-908. (b) Sohn,
S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370-
14371. (c) Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org.
Lett. 2006, 8, 507-509. (d) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7,
3873-3876. (e) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131-3134. (f)
Nair, V.; Poonoth, M.; Vellalath, S.; Suresh, E.; Thirumalai, R. J. Org.
Chem. 2006, 71, 8964-8965.
(10) Acyl heteroazolium species have been proposed as acylating agents
in several NHC-catalyzed processes. See: (a) Suzuki, Y.; Yamauchi, K.;
Muramatsu, K.; Sato, M. Chem. Commun. 2004, 2770-2771. (b) Reynolds,
N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518-
9519. (c) Chow, K. Y. K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-
8127.
(11) In a related, but strongly discouraging result, Taylor reported that
2 full equiv of a thiazolium salt in the presence of 20 equiv of manganese-
1
(IV) oxide only afforded 4% yield (calculated by H NMR) of methylcin-
namate from cinnamyl alcohol (see ref 5).
(12) Mirzaei, Y. R.; Twamley, B.; Shreeve, J. M. J. Org. Chem. 2002,
67, 9340-9345.
(13) The use of cis-allylic alcohols in this reaction leads to slower reaction
times and partial isomerization of the double bond (1:5 E/Z mixture). n-Butyl
cis-cinnamate can be isolated in moderate yield (62%).
(14) (a) Connor, E. F.; Nyce, G. W.; Myers, M.; Mock, A.; Hedrick, J.
L. J. Am. Chem. Soc. 2002, 124, 914-915. (b) Grasa, G. A.; Guveli, T.;
Singh, R.; Nolan, S. P. J. Org. Chem. 2003, 68, 2812-2819. (c) Movassaghi,
M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453-2456.
372
Org. Lett., Vol. 9, No. 2, 2007

A modification of the reaction conditions allows the use
of the nucleophilic alcohol as a reagent rather than as a
solvent. With 5 equiv of the nucleophilic alcohol in toluene,
a full equivalent of DBU is added to aid proton transfer
during acylation because using catalytic amounts of DBU
results in reduced yields. A variety of alcohols can be
employed to trap the acyl triazolium intermediate (Table 3,
Table 2. Examination of Activated Alcohol Scopea
Table 3. Variation of Nucleophilic Alcohola
entry
nucleophile
methanol
2-propanol
tert-butanol
2,2,2-trichloroethanol
2-methoxyethanol
2-(trimethylsilyl)ethanol
product
yield, %
1
2
3
4
5
6
5
15
-
16
17
18
95
89
0
82
82
74
a Reactions run at a 1 mmol scale using 15 mol % of NHC, 1.15 equiv
of DBU, 5 equiv of ROH, 15 equiv of MnO2, 0.2 M in toluene at 23 °C.
eq 4). The hindered nature of the acylating agent is evidenced
by the fact that primary alcohols were the most reactive as
nucleophiles, with the use of methanol resulting in the highest
yield (entry 1). Secondary alcohols such as 2-propanol (entry
2) are effective nucleophiles in the reaction, and tert-butanol
(entry 3) affords no product.15 This approach allows for the
efficient synthesis of carboxylate derivatives such as 2,2,2-
trichloroethyl (Troc),16 2-methoxyethyl (ME),17 and 2-(tri-
methylsilyl)ethyl (TMSE)18 cinnamyl esters (entries 4-6).
A promising feature of this tandem oxidation reaction is
the in situ generation of a chiral activated ester, presumably
in the form of the acyl heteroazolium intermediate III. An
application for this chiral acylating agent is the desymme-
trization of meso-diols. Initial results for the selective
acylation of cis-1,2-cyclohexane diol (Table 4, eq 5) yielded
modest levels of enantioselectivity that decreased with time,
presumably due to base-catalyzed acyl transfer19 of the
product (Table 4, entries 1 and 2). The use of a milder base
such as a proton sponge (entries 3 and 4) supresses acyl
transfer and allows for the isolation of 21 in >60% yield
with ∼60% ee.
a See Table 1 for reaction conditions. b25 mol % of NHC/DBU. c50 mol
% of NHC/DBU.
unfavorable interactions and provide high yields of the
desired esters. Experiments to investigate this divergence in
reactivity are currently ongoing.
In addition to allylic and benzylic substrates, hydrocin-
namaldehyde was oxidized to the corresponding methyl ester
19 using catalytic amounts of the NHC precursor and DBU
(Scheme 2). The alcohol resulting from addition of the NHC
Scheme 2. Oxidation of Hydrocinnamaldehyde
A survey of solvents for this desymmetrization indicates
that methylene chloride provides the best combination of
(15) See Supporting Information for details.
(16) (a) Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer,
W.; Ramage, R.; Ranganat, S.; Vorbrugg, H. J. Am. Chem. Soc. 1966, 88,
852-853. (b) Pearson, A. J.; Lee, K. S. J. Org. Chem. 1994, 59, 2304-
2313.
(17) Gewehr, M.; Kunz, H. Synthesis 1997, 1499-1511.
(18) Sieber, P. HelV. Chim. Acta 1977, 60, 2711-2716.
is sufficiently activated to undergo oxidation to the acyl
triazolium intermediate. The excellent yield of this reaction
demonstrates the feasibility of this process as a method to
access not only unsaturated but also saturated esters.
(19) Resubjecting optically enriched acylated material to reaction condi-
tions led to complete racemization after 90 min. For examples of acyl
transfer of monoacylated 1,2-cyclohexane diols, see: Vedejs, E.; Daugulis,
O.; Diver, S. T. J. Org. Chem. 1996, 61, 430-431. Laumen, K.; Seemayer,
R.; Schneider, M. P. J. Chem. Soc., Chem. Commun. 1990, 49-51.
Org. Lett., Vol. 9, No. 2, 2007
373

provides the highest selectivity and reactivity with 20 and
cinnamaldehyde (entry 7). When this reaction is conducted
at -30 °C, chiral triazolium G catalyzes the oxidation of
cinnamaldehyde and subsequently selectively acylates cis-
1,2-cyclohexane diol in 58% yield and 80% ee (entry 12).21
This strategy of accessing activated acylating agents from
aldehydes and an oxidant only in the presence of an
N-heterocyclic carbene has potential applications with nu-
cleophiles that undergo fast background reactions with acid
chlorides or anhydrides.
In conclusion, a tandem oxidation of allylic and benzylic
alcohols to esters has been developed using N-heterocyclic
carbenes as catalysts. This operationally simple one-pot
process avoids the use of cyanide and delivers esters in good
to excellent yield using a simple triazolium salt as the
precatalyst. Saturated esters can also be prepared by the
oxidation of saturated aldehydes in the same manner. An
asymmetric desymmetrization can be achieved using a chiral
heteroazolium salt. Studies utilizing N-heterocyclic carbenes
as catalysts in oxidation reactions are ongoing.
Table 4. Desymmetrization of cis-1,2-Cyclohexane Diola
entry catalyst
conditions
toluene, 23 °C
yield, % ee, %
1b
2b
3
F
G
F
53
47
66
62
39
53
78
76
57
76
67
58
38
20
41
52
60
63
54
59
23
20
37
65
80
73
toluene, 23 °C
proton sponge, toluene, 23 °C
proton sponge, toluene, 23 °C
proton sponge, 4-CF3-Ph, 23 °C
proton sponge, THF, 23 °C
proton sponge, CH2CI2, 23 °C
proton sponge, CH2CI2, 23 °C
proton sponge, CH2CI2, 23 °C
proton sponge, CH2CI2, 23 °C
proton sponge, CH2CI2, 0 °C
proton sponge, CH2CI2, -30 °C
proton sponge, CH2CI2, -40 °C
4
5
6
7
8
9
10
11
12
13
G
G
G
G
H
J
K
G
G
G
Acknowledgment. Financial support was generously
provided by Northwestern University, the PRF (Type-G),
Abbott Laboratories, Amgen, 3M, and Boerhinger-Ingelheim
(New Investigator Awards). A.C. is the recipient of a Dow
Chemical Company Fellowship. We thank FMCLithium,
Sigma-Aldrich, and BASF for providing reagents used in
this research. The funding for the NU Analytical Services
Laboratory has been furnished in part by the NSF (CHE-
9871268).
aReactions performed with 30 mol % of K2CO3, 15 mol % of 18-crown-6,
1 equiv of proton sponge, and 0.25 M solvent. Reaction performed with
b
1.5 equiv of K2CO3, 20 mol % of 18-crown-6, and 0.25 M solvent. Proton
sponge ) N,N,N′,N′-tetramethyl-1,8-naphthalenediamine.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
yield and selectivity (entry 7). A variety of chiral triazolium
salts were screened in this reaction. Triazolium G20 in the
presence of both potassium carbonate and a proton sponge
OL062940F
(20) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
8418-8420.
(21) (a) Wills, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765-1784.
(b) Hoffmann, R. W. Angew. Chem., Int. Ed. 2003, 42, 1096-1109.
374
Org. Lett., Vol. 9, No. 2, 2007