N-heterocyclic carbene-catalyzed radical reactions for highly enantioselective β-hydroxylation of enals

Article abstract of DOI:10.1021/ja511371a

An N-heterocyclic carbene-catalyzed β-hydroxylation of enals is developed. The reaction goes through a pathway involving multiple radical intermediates, as supported by experimental observations. This oxidative single-electron-transfer reaction allows for highly enantioselective access to β-hydroxyl esters that are widely found in natural products and bioactive molecules.

Full text of DOI:10.1021/ja511371a

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Communication
N-Heterocyclic Carbene-Catalyzed Radical Reactions
for Highly Enantioselective #-Hydroxylation of Enals
yuexia zhang, Yu Du, Zhijian Huang, Jianfeng Xu, Xingxing Wu, Yuhuang
Wang, Ming Wang, Song Yang, Richard D. Webster, and Yonggui Robin Chi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja511371a • Publication Date (Web): 04 Feb 2015
Downloaded from http://pubs.acs.org on February 9, 2015
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N-Heterocyclic Carbene-Catalyzed Radical Reactions for
Highly Enantioselective -Hydroxylation of Enals
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β
Yuexia Zhang,‡,1 Yu Du,‡,1 Zhijian Huang,1 Jianfeng Xu,1 Xingxing Wu,1 Yuhuang Wang,1 Ming
Wang,1 Song Yang,2 Richard D. Webster,1* and Yonggui Robin Chi1,2*
1Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological Uni-
versity, Singapore 637371, Singapore
2Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Ag-
ricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
Supporting Information Placeholder
potential measured as Epred ~ -1.2 V vs. ferrocene/ferrocenium, see
ABSTRACT: An N-heterocyclic carbene-catalyzed β-
Supporting Information), an N-centered radical precursor pio-
neered by MacMillan,9 as an oxidant. Somewhat to our surprise,
β-hydroxylation product (3) was obtained and initially proposed
amination product (3') was not observed. It is important to note
that near the completion of our study, Rovis and co-workers re-
ported carbene-catalyzed β-hydroxylation of enals via SET pro-
cesses using nitropyridine N-oxide as an oxidant.3 In Rovis’s
reaction, a homoenolate radical cation intermediate was proposed;
and the β-hydroxyl ester products were obtained in moderate
yields and 63-92% ee. In our system, it appears a radical process
involving both N- and O-centered radicals occurred. On the appli-
cation side, our reaction affords products with excellent enantiose-
lectivities (~95% ee for most products).
hydroxylation of enals is developed. The reaction goes through a
pathway involving multiple radical intermediates, as supported by
experimental observations. This oxidative SET reaction allows for
highly enantioselective access to β-hydroxyl esters that are widely
found in natural products and bioactive molecules.
N-heterocyclic carbenes (NHCs) have been explored as or-
ganocatalysts to mediate a large range of reactions.1 The majority
of these reactions, however, involve electron pair transfer steps.
On the other side, it has been envisioned that NHCs might be used
to develop single-electron-transfer (SET) reactions.2-4 The SET
process5 can provide valuable opportunities not readily available
from electron pair chemistry for the activation of inert chemical
bonds or direct assembling of functional molecules. Indeed, radi-
cal processes enabled by NHC catalyst in the living systems have
been studied. For example, the thiamine pyrophosphate (TPP,
precursor of a NHC) mediated oxidative decarboxylation of py-
ruvate to form acetyl-CoA and CO2 is believed to proceed via
SET/radical processes.6 Despite of the significance and the in-
principle feasibility, the development of NHC-mediated radical
reactions in synthetic chemistry is still in its infancy. In 2008,
Studer reported NHC-catalyzed oxidation of aldehydes using
TEMPO.2 The authors proposed that the reaction went through a
radical cation formed via removal of one electron of the Breslow
intermediate. Recently, we developed NHC-catalyzed reductive
β,β-coupling reactions of nitroalkenes via SET processes.4 The
nitroalkene-derived radical anion was characterized using electron
paramagnetic resonance (EPR) spectroscopy. Here we report car-
bene-catalyzed generation of unsaturated Breslow intermediate-
derived radical cation for β-hydroxylation of enals (Scheme 1).
The reaction affords β-hydroxyl esters, including those bearing
quaternary β-carbon centers, in high enantioselectivities. Notably,
β-hydroxyl (α-unsubstituted) esters and their derivatives are im-
portant building blocks and ubiquitous subunits present in biolog-
ically active compounds and natural products.7,8 Our catalytic
approach provides a concise and highly enantioselective access to
this class of important compounds.
Scheme 1. NHC-Catalyzed β-Hydroxylation of Enals via
Radical Intermediates
X
EtO2C
N
R'
N
OH
O
N
O
R'
CHO
H3C
O2S
+
R
R
OCH3
+ CH3OH
NHC cat.
3
O2N
(oxidant)
2
1
91-98% ee
Me
CO2Et
O
R'
OH
N
O
N
CO2Et
N
R'
R
N
X
R
OMe
O
SO3
N
initially proposed prod.
3' (not observed)
proposed key radical intermediates in this reaction
Key results of condition optimization are briefed in Table 1.
The search for suitable conditions indicated that nitrobenzenesul-
fonic carbamate 2 was an effective oxidant and K2CO3 was a suit-
able base for this β-hydroxylation reaction. When imidazolium
NHC precursor 4a10 was used for the reaction carried out in THF
with degassing, the β-hydroxyl ester product 3a was obtained in
encouraging 32% yield (entry 1). We next moved to triazolium
NHCs and found that the use of amino indanol derived triazolium
4b11 as an NHC pre-catalyst led to 3a with 31% yield and excel-
lent 92% ee (entry 2). Switch of the NHC catalyst to 4c12 with a
bulkier N-mesityl substituent resulted in an improved ee (96%)
with similar yield (entry 3). NHC pre-catalysts with electron-
deficient N-aryl substituents (4d, 4e)13 led to no formation of 3a
(entries 4-5). This result is different from Rovis’s study3: in his
Our initial design was to achieve β-amination of enals (Scheme
1). We chose nitrobenzenesulfonic carbamate 2 (reductive peak
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system triazolium-based NHCs with electron-deficient N-aryl
quaternary carbon centers with moderate yields and excellent
substituents could mediate the reaction. The use of amino acid-
derived NHC catalyst 4f14 afforded 3a with an improved yield but
unfortunately unsatisfactory ee (entry 6). We next chose NHC
pre-catalyst 4c for further optimization, and found that toluene
was a better solvent than THF (entry 7). We finally found that
when methanol was added at the same time as other sub-
strates/reagents with the use of 150 mol% base (relative to oxidant
2), the product 3a could be obtained in excellent yield and ee
(entry 9). The use of 15 mol% NHC pre-catalyst could give satis-
factory results as well (entry 10). Notably, two equivalents of enal
1a (relative to oxidant 2) were used in this reaction. One equiva-
lent of the enal was exclusively oxidized to the corresponding α,β-
unsaturated ester. Mechanistic origins for this observed result are
illustrated in Scheme 2. As a technical note, it is essential to degas
the reaction mixture and perform the reaction under N2 protection.
When the reaction was conducted under open air, the product (3a)
was not detectable or observed in very low (< 5%) yield.
enantioselectivities. Notably, among these β-hydroxyl esters, 3e is
a natural product named pisoninol I that exhibits antitubercular
activity;7 and 3o was found to be a potent membrane-perturbing
agent on human erythrocytes.8
Table 2. Substrates Scope
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Table 1. Condition Optimizationa
entry Condition
Yield (%)b
ee (%)c
1
4a, K2CO3, THF
32
-
aIsolated yields. bDetermined via HPLC analysis on a chiral stationary
2
4b, K2CO3, THF
31
92
96
-
c
phase. Determined via HPLC analysis on a chiral stationary phase after
3
4c, K2CO3, THF
31
derivatization (see Supporting Information).
4
4d, K2CO3, THF
0
The proposed reaction pathway is illustrated in Scheme 2. The
Breslow intermediate A formed between NHC catalyst and enal
1a undergoes an oxidative SET process with oxidant 2 to generate
three intermediates: N-centered radical B1,9 nitroaryl molecule B2
5
4e, K2CO3, THF
0
-
6
4f, K2CO3, THF
46
88
96
96
97
97
red
7
4c, K2CO3, toluene
61
(reductive peak potential measured as Ep ~ -1.8 V vs. ferro-
cene/ferrocenium, see Supporting Information), and Breslow in-
termediate-derived radical cation B3. The radical cation B3 un-
dergoes a deprotonation to form a neutral radical intermediate B3'
that goes through a subsequent oxidation by nitroaryl compound
B2 to provide an nitro radical anion C and an α,β-unsaturated
azolium ester intermediate F. The resulting intermediate F is
trapped by CH3OH to yield ester 5a as a side product (see Scheme
3a) with the regeneration of NHC catalyst. In the productive
pathway leading to β-hydroxylation of enal, the N-centered radi-
cal B1 undergoes a SET process to abstract one electron from
another equivalent of Breslow intermediate A to form anther
Breslow intermediate-derived radical cation B3 and a carbamate
anion G. The carbamate anion intermediate G is then protonated
to generate carbamate 6 (confirmed by GC-MS). We propose a
pathway similar to that of Rovis3 for the conversion of radical
intermediates B3 and C to yield the final product 3a. Specifically,
a reaction between two radical intermediates B3 and C affords
adduct D with the creation of a new C-O bond on the formal enal
β-carbon. Subsequent N-O bond cleavage of D gives a nitroso
compound 73 and intermediate E. A reaction of intermediate E
with CH3OH (proton transfers followed by ester formation) yields
desired product 3a with the regeneration of the NHC catalyst.
8
4c, 150 mol% K2CO3, toluene
4c, 150 mol% K2CO3, toluene
4c, 150 mol% K2CO3, toluene
79
9d
10d,e
98 (95)
89 (87)
aUnless otherwise noted, reactions were carried out at RT using 1a (0.1
mmol), 2 (0.05 mmol), catalyst (20 mol%), base (100 mol%), and 1.5 mL
of solvent, MeOH was added via a needle 30 minutes later after the reac-
tion started. bEstimated via 1H NMR analysis using 1,3,5-
trimethoxybenzene as an internal standard; isolated yields are in parenthe-
sis. cDetermined via HPLC analysis on a chiral stationary phase; the abso-
lute configuration was determined by comparing the optical rotation of 3a
(and products in Table 2) with literature values (see Supporting Infor-
mation). dThe methanol was added at the same time as other substrates and
reagents (see Supporting Information). e15 mol% catalyst was used.
The scope of this reaction is quite general (Table 2). We first
evaluated β-(hetero)aryl enals and found that placing various sub-
stituents on the aryls have little effect on the reaction outcomes
(3a-g). Essentially all products (3a-j) were obtained with excel-
lent yields and ee. Enals with a β-alkyl substituent reacted excep-
tionally well too, providing products 3k-o with 81-99% yields and
96-97% ee. Enals with two substituents at the β-carbon were also
excellent substrates, leading to products (3p-v) bearing β-
Scheme 2. Proposed Reaction Pathway
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CHO
Ph
1a
OH
O
SO2
N
CO2Et
N
4
5
6
7
OH
O
Ph
X
N
N
N
X
NO2
2 (oxidant)
Ph
OMe
A
3a
NHC
SET
8
9
MeOH
OH
CO2Et
10
11
12
13
N
N
Ph
B1
X
CO2Et
H+
N
H
CO2Et
N
B3
-H+
(observed via EPR,
Figure 1)
N
6
O
OH
SO3
O
SET
observed by
GC-MS
N
N
G
Ph
O
X
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O
N
B2
(isolated in ~5% yield,
structure confirmed by X-ray)
SET
N
E
Ph
X
N
B3'
O
O
N
SO3
Ph
MeOH
Ph
OMe
SO3
OH
X
O
F
NO
N
5a
N
N
O
HO
O
O
(main side product,
see Scheme 3a)
SO3
N
N
Ph
Ph
X
X
C
7
N
N
B3
(see Scheme 3b)
D
The mechanistic pathway proposed above is supported by sev-
eral experimental studies. The existence of the N-centered radical
B1 was first supported by the observation of carbomate 6 (GC-
MS). Much clearer evidence came from EPR spin trapping exper-
iments using DMPO.15 The EPR spectrum of the DMPO trapped
radical is shown in Figure 1a. A simulated spectrum could be
matched to the experimental data by assuming that the major hy-
perfine coupling occurred to two non-equivalent nitrogen atoms
and one hydrogen atom (Figure 1b).
of enal substrate used, one equivalent is converted to unsaturated
ester 5, as illustrated in Scheme 2. This pathway is also supported
by results from our initial condition optimizations when excess
amount of oxidant was used (Scheme 3a). The use of excess oxi-
dant did not improve the yield of 3a. For example, when enal 1a
(0.05 mmol) was exposed to 1.5 equivalents of oxidant 2 (0.075
mmol), 48% yield (relative to 1a) of β-hydroxyl ester and 46%
yield of α,β-unsaturated ester were isolated (Scheme 3a). Results
similar to those using β-aryl enal 3a were obtained when β-alkyl
enals (e.g., 3n, 3o) were used (see Supporting Information). The
results support that our system is different from that of Rovis3.
Under our condition, half of the enal is converted to α,β-
unsaturated ester, as proposed in our mechanism. Thus, for prepa-
ration applications (Table 2), enals and the oxidant were used in
2:1 molar ratio to ensure effective use of the oxidant.
The structural characteristics of α,β-unsaturated Breslow inter-
mediate-derived radical cation B3 (Scheme 2) was studied by
“radical clock” experiments (Scheme 3b). When the cis-
cyclopropyl-substituted enal 9 was used in our reaction system,
the relative configurations of the cyclopropyl in the final ester
products (cis-10 and cis-10') were retained (Scheme 3b). This
observation suggested that prior to the desired C-O bond for-
mation (from B3 and C to D, Scheme 2) of the enal β-carbon, a β-
carbon-centered radical is unlikely dominated. Because a β-
carbon-centered radical (e.g, cis-9A, Scheme 3b) will likely lead
to stereorandom radical rearrangement that results in isomeriza-
tion of the cis-cyclopropyl unit to the trans-isomer. Such a rear-
rangement was not observed under our reaction condition. These
results suggested that the radical spin is more likely delocalized
between the enal formal carbonyl carbon and the triazolium NHC
unit, supporting the structure of intermediate B3 as proposed in
Scheme 2. Related radical cation intermediate derived from alde-
hyde under NHC catalysis using TEMPO as an oxidant was pro-
posed by Studer and co-workers in their aldehyde oxidation reac-
tions.2
Figure 1. (Black line) EPR spectra of the radical derived from
trapping B1 with DMPO at 22( 2) oC in toluene according to the
reaction in Scheme 2. (Red line) Simulated EPR spectrum based
on hyperfine coupling constants of 1N = 13.55 G, 1N = 2.53 G,
1H = 20.10 G, and with a linewidth of 0.75 G.
The generation of intermediate B2 was confirmed experimen-
tally. This anion B2 was obtained in its potassium salt form with
around 5% yield, and its structure was confirmed via X-ray dif-
fraction (see Supporting Information).
In our catalytic reaction, the α,β-unsaturated ester 5a (Scheme
2) was obtained as the major side product with yield similar to the
desired β-hydroxylation product 3a. Among the two equivalents
The oxygen ends up in the β-hydroxylation product 3a likely
come from the NO2 unit of oxidant 2 (Scheme 2, reaction between
B3 and C to form the C-O bond on the enal β-carbon). When a
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similar oxidant with the “NO2” group removed is used, no β-
hydroxylation product 3a is formed (see Supporting Information).
tance with X-ray structure analysis; Linyi Bai and Prof. Yanli
Zhao (NTU) for help with preliminary CV studies..
4
5
Scheme 3. Experiments to Probe Reaction Mechanism
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
robinchi@ntu.edu.sg, webster@ntu.edu.sg
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Generous financial support for this work is provided by Singapore
National Research Foundation, Nanyang Technological Universi-
ty (NTU), China’s Thousand Talent Plan, National Natural Sci-
ence Foundation of China (No. 21132003; No. 21472028), and
Guizhou University. We thank Dr. Yongxin Li (NTU) for assis-
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