N-heterocyclic carbene-catalyzed oxidation of unactivated aldehydes to esters

Article abstract of DOI:10.1021/ol8018488

(Chemical Equation Presented) N-Heterocyclic carbenes catalyze the oxidation of unactivated aldehydes to esters with manganese(IV) oxide in excellent yield. The reaction proceeds through a transient activated alcohol, which when generated in situ allows for the selective oxidation of the aldehyde under mild conditions. These conditions successfully oxidize potentially epimerizable aldehydes and alcohols while preserving stereochemical integrity. A variety of ester derivatives can be synthesized with variation of the acylated alcohol as well as the unactivated aldehyde.

Full text of DOI:10.1021/ol8018488

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Org Lett. Author manuscript; available in PMC 2009 October 2.
Published in final edited form as:
Org Lett. 2008 October 2; 10(19): 4331–4334. doi:10.1021/ol8018488.
N-Heterocyclic Carbene-Catalyzed Oxidation of Unactivated
Aldehydes to Esters
Brooks E. Maki and Karl A. Scheidt
Department of Chemistry, Northwestern University, Evanston, IL 60208
Abstract
N-Heterocyclic carbenes catalyze the oxidation of unactivated aldehydes to esters with manganese
(IV) oxide in excellent yield. The reaction proceeds through a transient activated alcohol, which,
when generated in situ allows for the selective oxidation of the aldehyde under mild conditions. These
conditions successfully oxidize potentially epimerizable aldehydes and alcohols while preserving
stereochemical integrity. A variety of ester derivatives can be synthesized with variation of the
acylated alcohol as well as the unactivated aldehyde.
Efficient oxidations carried out under mild conditions are important organic transformations.
1
Of particular interest are processes that achieve multiple oxidations and/or functionalization
2
in a single procedural step. Transformations of this type have several attractive attributes
including their potential to generate and/or transform challenging products in situ. These
advantages have inspired numerous investigations into the direct oxidation of aldehydes to
3
4
5
esters. Recent methods have employed Oxone, pyridinium hydrobromide perbromide, or
6
peroxides as oxidants, but these approaches can suffer from toxic or expensive reagents or
competing oxidation of the alcohol nucleophile. The less efficient two-step process involving
the oxidation of the aldehyde to a carboxylic acid and subsequent alkylation can be significantly
complicated by over-oxidation of electron-rich aromatic rings and chemoselectivity issues
during the alkylation step. Lastly, the use of saturated aldehydes in either approach can be
problematic due to enolization/aldol issues.
7
While N-heterocyclic carbenes (NHCs) are known to catalyze interesting redox processes,
8
the potential and synthetic utility of these reactions are far from being fully realized. During
9
10
our recent investigations of carbene-catalyzed redox reactions and related process, we
recognized that a transient benzylic alcohol intermediate should be accessible through addition
of an NHC to any aldehyde (Figure 1). This process fundamentally diverges from previous
reports since the aromatic nature of the NHC catalyst imparts unique reactivity in the presence
scheidt@northwestern.edu.

Maki and Scheidt
Page 2
of a selective oxidant upon addition to a saturated (unactivated) aldehyde. Connon and
9
coworkers have very recently reported an extension of our 2007 report using a thiazolium
11
catalyst. However, their method was low yielding when attempts were made with saturated
12
9
aldehydes as substrates. In our 2007 paper, we reported a single example of the oxidation
of a saturated aldehyde (91% yield for the oxidation of hydrocinnamaldehyde). Given the
potential of this mild oxidative transformation, we engaged in a full exploration of this process
which has taken us well beyond our recent NHC-catalyzed tandem oxidations of allylic or
benzylic alcohols. Herein, we report the general oxidation of saturated aldehydes (1) to esters
(4) via activated alcohol intermediates (2) using carbene catalysis.
Initial efforts were directed toward finding the optimal oxidizing agent for the activated alcohol
13
intermediate. Metal-free oxidation conditions were investigated for the conversion of
,
14
aldehyde 5 to the methyl ester (6 Table 1, entries 1-4). A screen of azolium salts (not shown)
indicated that the simple dimethyl triazolium iodide (A) was the optimal pre-catalyst in terms
of conversion. These preliminary reactions showed promise, but decomposition was evident
before complete consumption of the aldehyde starting material. Fortunately, manganese(IV)
oxide proved to be an ideal oxidant for this process, efficiently providing the methyl ester in
less than three hours in excellent yields with 10 mol % of azolium A. The reaction can be
carried out either in methanol (entry 5) or with 5 equivalents of the alcohol in dichloromethane
(entry 6). On a multi-gram scale, the optimized reaction provides nearly quantitative conversion
15
to the ester (entry 7).
This new carbene-catalyzed transformation is remarkable when compared to the cyanide-
16
promoted Corey-Gilman oxidation of allylic alcohols. In distinct contrast to the
transformation in Table 1, a full equivalent of NaCN with MnO and aldehyde 5 does not
2
17
provide any saturated ester. Furthermore, no oxidation is observed when A is omitted,
highlighting the unique ability of the NHC catalyst to generate activated alcohols in situ.
A key feature of this process is that a wide variety of saturated aldehydes and alcohols can be
employed (Table 2). For example, methanol as the nucleophile affords the fastest reactions,
but other primary (entries 2, 4, 5), and secondary alcohols (Table 2, entries 3, 6) afford the
desired esters. With this process, direct access to protected carboxylate derivatives (TMSE and
18
trichloroethyl) from the corresponding aldehydes is high yielding.
Most importantly, this new oxidation is successful with electron-rich aromatic rings present
(entries 16, 17, 18). These results are distinct from established chlorine-based oxidation
19
conditions which can promote significant electrophilic aromatic chlorination. Substitution
at the α-(entries 8, 9) or β-position (entry 10) has little effect on the yield, although moderate
yields are observed with more congested aldehydes such as pivalaldehyde (entry 11). This
decrease in efficiency is most likely due to the slow formation of the activated alcohol resulting
from the difficult addition of the carbene catalyst to the hindered aldehyde.
The oxidation is compatible with a range of functional groups, including potentially
epimerizable substrates. The acylation of methyl lactate occurs with minimal loss of
stereochemical information (entry 6). An aldehyde with a stereogenic center at the α-position
undergoes a minor amount of epimerization (from 99% ee to 92% ee), with 25 mol% catalyst
to increase the rate of oxidation (entry 9) so that the reaction was complete in 30 to 45 minutes.
20
Despite previous reports of silicon activation by NHCs, aldehydes containing silyl ethers
are stable to these conditions (entries 9, 12, 13) and smoothly undergo oxidation. Multiple
nitrogen-containing heterocycles are compatible, yielding the indolyl-substituted ester and the
pyridyl-substituted ester in high yields (entries 14, 15). Electron-rich oxygen and sulfur-
containing heterocycles (entries 16, 17) give similarly excellent results.
Org Lett. Author manuscript; available in PMC 2009 October 2.

Maki and Scheidt
Page 3
In summary, saturated esters are produced in a single flask from a wide variety of aldehydes
by a carbene-catalyzed oxidation. In this process, the N-heterocyclic carbene catalyst formed
in situ undergoes addition to a saturated aldehyde and the aromatic framework of the catalyst
activates the carbinol intermediate generated in situ for a mild manganese(IV) oxidation. The
scope of the reaction includes electron-rich heterocyclic aldehydes and substrates containing
potentially sensitive stereochemistry. Further investigations capitalizing on the unique aspects
of carbene catalysis for oxidations and reductions are underway and will be reported in due
course.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgment
Research support was generously provided by NIH/NIGMS (GM73072), Abbott Laboratories, Amgen, AstraZeneca,
GlaxoSmithKline, the Sloan Foundation, and Boehringer-Ingelheim. B. E. M. was supported by a GAANN Fellowship.
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2
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Figure 1.
Oxidation of Unactivated Aldehydes
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Table 1
Oxidation Optimization
b
entry
oxidant
solvent
yield
1
2
o-chloranil (2 equiv)
THF
(<10)
0
TEMPO (1 mol %), NaOCl (aq.) (2 equiv)
TEMPO (1 mol %), Oxone (4 equiv)
CH2Cl2/H2O
3
4
CH2Cl2
CH2Cl2
(52)
(59)
c
TEMPO (1 mol %), n-Bu4NSO5 (2 equiv)
5
6
7
MnO2 (5 equiv)
MnO2
MeOH
CH2Cl2
CH2Cl2
99
d
98
d
MnO2 19 mmol scale
98
a
20 mol% A, 1.2 equiv DBU, 2-5 equiv methanol, 0.2 M in solvent.
b
c
Isolated yields (yields in parentheses calculated by GC with dodecane as an internal standard).
Prepared from commercial Oxone (see Supporting Information).
d
10 mol% A, 1.1 equiv DBU, 5 equiv methanol, 5 equiv MnO , 0.2 M in CH Cl .
2
2 2
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Table 2
NHC-Catalyzed Oxidation Scope
a
entry
substrate
product
yield
1
2
3
R1OH = MeOH
= n-PrOH
98 (6)
82 (7)
88 (8)
= CyOH
4
5
6
85 (9)
87 (10)
b
74 (11)
7
8
91 (12)
96 (13)
c
9
91 (14)
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a
entry
substrate
product
yield
10
93 (15)
11
56 (16)
12
13
94 (17)
95 (18)
14
90 (19)
15
88 (20)
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a
entry
substrate
product
yield
16
92 (21)
96 (22)
17
18
99 (23)
a
b
c
Isolated yield. See Table 1 for general procedure.
Methyl (S)-(-)-lactate (97% ee) yields the ester in 93% ee.
25 mol % triazolium salt A yields the methyl ester in 92% ee from enantiopure aldehyde.
Org Lett. Author manuscript; available in PMC 2009 October 2.