Biomimetic carbene-catalyzed oxidations of aldehydes using TEMPO

Article abstract of DOI:10.1002/anie.200802735

(Chemical Equation Presented) Transition-metal-free organocatalytic oxidations of various aldehydes proceed with the TEMPO radical as a mild organic oxidant; the resulting TEMPO esters are formed in moderate to excellent yields (see scheme). N-Heterocyclic carbenes (NHCs) are efficient catalysts and activate aldehydes for electron-transfer reactions. The TEMPO esters are readily hydrolyzed and the nitroxide can be regenerated by aerobic oxidation.

Full text of DOI:10.1002/anie.200802735

Angewandte
Chemie
DOI: 10.1002/anie.200802735
Aldehyde Oxidation
Biomimetic Carbene-Catalyzed Oxidations of Aldehydes Using
TEMPO**
Joyram Guin, Suman De Sarkar, Stefan Grimme, and Armido Studer*
Pyruvate ferredoxin oxidoreductase (PFOR), which catalyzes
the oxidative decarboxylation of pyruvate to form acetyl-CoA
and CO2, belongs to the family of 2-keto acid oxidoreduc-
tases.[1] This CoA-dependent enzyme uses thiamine pyro-
phosphate (TPP) as an additional cofactor. The anaerobic
decarboxylation is a reversible process, and the two electrons
obtained during one turnover are transferred to ferredoxine
via [Fe4S4] clusters.[1]
The initial steps of the oxidative decarboxylation resem-
ble those of the aerobic TPP-dependent 2-oxoacid dehydro-
genases.[2] Pyruvate reacts with A to form B after proton
transfer, and B subsequently undergoes CO2 elimination to
generate C (Scheme 1). Electron transfer to a [Fe4S4] cluster
leads to radical cation D. Although intensive studies (X-ray
and EPR) have been conducted on D, the structure of the
radical cation is still under debate.[3] Renewed electron
transfer in the presence of CoASH eventually leads to
CoASAc.
In aerobic organisms lacking the [Fe4S4] clusters, C reacts
with the dithiolane ring of a lipoyl group in a formal two-
electron transfer to an acetyl lipoamide thioester intermedi-
ate, which is further transformed in the presence of CoASH
using another enzyme to CoASAc. The liberated dithiol is
eventually reoxidized to the cyclic disulfide by a FAD-
dependent dihydrolipoyl dehydrogenase.[2]
It is known in synthesis that reaction of aldehydes with
thiazolium carbenes leads to intermediates of type C which
react as “umpoled”[4] nucleophiles with aromatic aldehydes
(benzoin condensation)[5] or with electron-poor olefins (Stet-
ter reaction).[6] Recently, N-heterocyclic carbene (NHC)
catalyzed transformations have gained increasing attention.[7]
However, these investigations have focused on ionic process-
es.[8] Guided by PFOR we planned to oxidize enamines of
type C by organic single-electron transfer (SET) oxidants.[9]
The process would represent a biomimetic transition-metal-
free organocatalytic oxidation of an aldehyde. As the oxidant
we used 2,2,6,6-tetramethylpiperidine N-oxyl radical
(TEMPO), which has been used successfully by our group
in transition-metal-mediated reactions and in various radical
processes.[10] Hence, the oxidizing [Fe4S4] clusters in PFOR
can be replaced by two oxidizing TEMPO units [Eq. (1)].[11,12]
Scheme 1. TPP-mediated enzymatic transformation of pyruvate to
CoASAc.
Initial studies were performed in THF at room temper-
ature with the three carbene precursors 3–5.[13] Carbenes were
generated upon treatment with 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU). As a test substrate we chose trans-cinammal-
[*] Dr. J. Guin, S. De Sarkar, Prof. Dr. S. Grimme, Prof. Dr. A. Studer
NRW Graduate School of Chemistry
=
dehyde (1a, R = PhCH CH) to give acyl-TEMPO derivative
[14]
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstrasse 40, 48149, Münster (Germany)
Fax: (+49)251-833-6523
=
2a (R = PhCH CH, Table 1).
Pleasingly, the carbene
generated from 3 (10 mol%) was able to catalyze the
TEMPO-mediated oxidation of cinammaldehyde, and 2a
was isolated in 87% yield (entry 1, Table 1). Similar results
were achieved with carbenes derived from 4 and 5, showing
that the carbene structure does not influence oxidation to a
large extent (entries 2 and 3, Table 1). We performed the
following studies with readily available 5. Reducing catalyst
loading to 5 and 2 mol% led to improved yields, and even
E-mail: studer@uni-muenster.de
[**] A.S. thanks Novartis Pharma AG for financial support (Novartis
Young Investigator Award). We thank the NRW Graduate School of
Chemistry for supporting our work (stipend to S.D.S.).
TEMPO=2,2,6,6,-tetramethylpiperidine-N-oxyl radical.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802735.
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Table 1: NHC-catalyzed oxidation of various aldehydes with TEMPO
(2 equiv) and DBU in THF at room temperature for 6–12 h.
(entries 20 and 21, Table 1). Double bonds were not oxidized
under the applied conditions. Thus, 4-vinylbenzaldehyde and
=
4-(CH3OCH CH)C6H5CHO bearing the electron-rich vinyl
Entry
Catalyst
(mol%)
Product
R
Yield [%]
ether were chemoselectively oxidized (entries 22 and 23,
Table 1). Moreover, S oxidation was not a problem, as the
transformation of a dithiolanyl-substituted aldehyde to ester
2q demonstrates (92% yield, entry 24, Table 1). Importantly,
oxidation occurs under neutral conditions. Hence, acid-labile
enol ethers (see entry 23, Table 1) and acetals were tolerated
(entry 25, Table 1). Aliphatic aldehydes such as 3-phenyl-
propanal reacted more slowly. Carbene catalyst loading had
to be increased to 10 mol%, and ester 2 s was isolated in 44%
yield (entry 26, Table 1). When 14 mol% of 5 was employed
in the presence of 10 mol% DBU, the yield was improved to
51% (entry 27, Table 1).
It is important to note that TEMPOH [see Eq. (1)], which
can be quantitatively oxidized to TEMPO by O2 or air, was
formed in these reactions as a stoichiometric byproduct.[16]
However, owing to the volatility of TEMPO its recovery was
difficult. Therefore, oxidation of 1a was repeated with less
volatile HO-TEMPO (6). After completion of the oxidation
the reaction mixture was purged with O2 to recover 6. Ester 7
was isolated in 92% yield along with 6 (93% yield,
Scheme 2). To further improve the economy of the process
1[a]
2[a]
3 (10)
4 (10)
5 (10)
5 (5)
5 (2)
5 (1)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (0.5)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (10)
5 (14)
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
C6H5CH CH
C6H5CH CH
C6H5CH CH
C6H5CH CH
C6H5CH CH
C6H5CH CH
C6H5CH CH
C6H5
4-NO2C6H4
4-CH3OC6H4
4-BrC6H4
4-CH3OC(O)C6H4
2-FC6H4
2-CF3C6H4
3-ClC6H4
3-ClC6H4
b-naphthyl
2-thienyl
2-pyridyl
C6H5C(O)CO
CH3CH CH
87
86
85
91
94
92
94
95
92
91
93
96
91
89
98
97
94
98
94
54
83
95
87
92
89
44
51
=
=
=
=
3[a]
4[a]
5[a]
=
=
6[a]
7[b]
=
8[b]
9[b]
10[b]
11[b]
12[b]
13[b]
14[b]
15[b]
16[b]
17[b]
18[b]
19[b]
20[b]
21[b]
22[b]
23[b]
24[b]
25[b]
26[c]
27[c]
=
4-(CH2 =CH)C6H4
4-(CH3OCH CH)C6H4
4-([1,3]dithiolan-2-yl)C6H4
4-([EtO]2CH)C6H4
PhCH2CH2
=
2s
2s
PhCH2CH2
[a] Conducted with 1–1.1 equiv DBU. [b] Conducted with 3 mol% DBU.
[c] Conducted with 10 mol% DBU.
1 mol% of 5 provided an excellent yield (entries 4–6,
Table 1). Oxidation did not proceed without 5. As the
reaction can be conducted with 3 mol% DBU, the base
serves only for carbene generation (entry 7, Table 1).[15]
To study the scope we tested other aldehydes. Benzalde-
hyde (!2b, 95%; entry 8, Table 1) and electron-rich and
electron-poor para-substituted benzaldehyde derivatives
were oxidized to the corresponding esters 2c–f in excellent
yields (91–96%, entries 9–12, Table 1). ortho-Substituted
aromatic aldehydes also underwent clean oxidation
(entries 13 and 14, Table 1). Excellent yields were obtained
for the oxidation of m-chlorobenzaldehyde (98%, entry 15,
Table 1). With this reactive aldehyde, catalyst loading could
be reduced to 0.5 mol% without affecting the yield (entry 16,
Table 1). b-Naphthaldehyde and heteroarenes such as 2-
thiophenecarboxaldehyde and 2-pyridinecarboxaldehyde
also underwent clean oxidation to give the corresponding
TEMPO esters in excellent yields (entries 17–19, Table 1).
Oxidation of phenylglyoxal monohydrate and crotonal
afforded the esters 2m and 2n in moderate to good yields
Scheme 2. Regeneration of the nitroxide.
we treated the reaction mixture after completed oxidation
with aqueous HCl to transform the TEMPO ester into the
corresponding acid. This was shown for meta-chlorobenzal-
dehyde. After oxidation and hydrolysis, acid 8 and HO-
TEMPOH formed were readily separated by simple liquid/
liquid extraction. The organic layer obtained by basic workup
was purged with O2 to regenerate 6. Thus, O2 formally acts as
a terminal oxidant and the nitroxide was readily recovered in
high yield rendering this protocol attractive for industrial-
scale synthesis. It was also possible to transfer TEMPO esters
with methanolic HCl to the corresponding methyl esters (!9,
96%, recovered 6: 94%).
The suggested mechanism is depicted in Scheme 3.
Reaction of the carbene with RCHO provides enamine F
via E.[7] SET to TEMPO would lead to radical cation G and
TEMPOꢀ.[17] Deprotonation of G by TEMPOꢀ should
generate radical H and TEMPOH.[18] Direct hydrogen trans-
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20.4 kcalmolꢀ1 at the PBEh/TZVP level between OH and C
=
O forms) were obtained for the two tautomers with X = N,
which indicates that the electronic structure of this system is
not very sensitive with respect to substituents or structural
changes of the carbene. This is in agreement with the
experimental results (Table 1).
In conclusion, we have developed NHC-catalyzed oxida-
tions of aldehydes by using TEMPO as an oxidant. Inspired
by nature, we report that NHCs can be applied in synthesis to
activate aldehydes to react as organic electron-transfer
reagents.[17] This type of NHC catalysis is not well explored.
Importantly, the oxidant identified does not destroy the NHC
catalyst. We believe that this type of aldehyde activation will
open new avenues in the field of organocatalysis by NHCs.[20]
The TEMPO esters can be hydrolyzed and the nitroxide be
regenerated by O2 which formally acts as terminal oxidant
rendering these processes economic.[21]
Scheme 3. Suggested mechanism (X=N, CH).
Received: June 10, 2008
Revised: August 25, 2008
Published online: October 9, 2008
fer from F to TEMPO to give H and TEMPOH cannot be
ruled out. Renewed SET from H to TEMPO might provide
activated ester I, which can react further with TEMPOꢀ to
give 2 and the corresponding carbene.
Keywords: carbenes · density functional calculations ·
The structure of the intermediate radical cation D in the
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DFT calculations were performed on the two tautomeric
radical cations G and G’ (for X = CH and N, R = Ph).[19] We
found that for the phenyl-substituted system in the gas phase
without environmental effects the OH tautomer G (X = CH)
is about 11 kcalmolꢀ1 lower in energy than G’ (X = CH). The
spin-density distributions are in agreement with the given
Lewis structures: G corresponds to a mainly carbon-centered
radical with a partial double bond (1.43 Š) between the
carbonyl and carbene C atoms. In G’ the spin density is
delocalized mostly in the carbene fragment, which forms a
weakened s bond (1.58 Š) with an acyl-type cation (Figure 1).
Similar results (but with an even increased energy gap of
.
organocatalysis · oxidations · synthetic methods
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trapping reaction were not identified. Moreover, when oxidation
of 1a was conducted in MeOH, methyl cinnamate was formed as
a side product along with 2a. This experiment clearly shows that
reaction occurred via I.
[19] The DFT calculations were performed unrestricted using triple-
zeta Gaussian AO basis sets (TZVP and TZVPP, see Ref. [19a])
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larger fraction of exact Hartree–Fock exchange (i.e., 53% and
further a nonlocal perturbation term for correlation). For the
energy differences between G and G’ (R = Ph, X = CH) we
obtained 12.8 (PBEh/TZVP), 9.6 (B2PLYP/TZVP), and
11.4 kcalmolꢀ1 (B2PLYP/TZVPP). These values are all in a
rather narrow energy range and prove an energetic preference
for the OH tautomer under gas-phase conditions; a) A. Schꢂfer,
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sets are available from the TURBOMOLE homepage via the
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[15] Oxidation of 3-Cl-C6H4CHO with DBU (3 mol%) and
5
(2 mol%) gave 2i in 98% yield (entry 15, Table 1); with DBU
(2 mol%) and 5 (2 mol%) 2i was isolated in 98% yield, and with
DBU (2 mol%) and 5 (3 mol%) ester 2i was formed in 97%
yield, clearly proving that DBU is only acting as base to liberate
the carbene catalyst.
[16] During chromatography TEMPOH was partially oxidized by air
as indicated by the red color of the solution. In situ oxidation of
TEMPOH by dioxygen during the reaction did not work.
Dioxygen itself is a better oxidant than TEMPO and is able to
oxidize intermediates of type C to the corresponding radical
cations. However, dioxygen is known to oxidize carbenes.
[17] SET by organic electron donors: a) J. A. Murphy, T. A. Khan, S.-
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[18] Trapping of H with TEMPO is unlikely since in the case of
[21] Preliminary studies showed that NHC-catalyzed aerobic oxida-
tion of aldehydes in MeOH affords the corresponding methyl
esters in up to 50% yield.
cinnamaldehyde, TEMPO trapping of the delocalized radical
=
cation G (R = PhCH CH) should occur at least in part at the
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