Polyhalides as Efficient and Mild Oxidants for Oxidative Carbene Organocatalysis by Radical Processes

Article abstract of DOI:10.1002/anie.201611692

Simple and inexpensive polyhalides (CCl₄ and C₂Cl₆) have been found to be effective and versatile oxidants in removing electrons from Breslow intermediates under N-heterocyclic carbene (NHC) catalysis. This oxidative react

Full text of DOI:10.1002/anie.201611692

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611692
German Edition: DOI: 10.1002/ange.201611692
Carbenes
Polyhalides as Efficient and Mild Oxidants for Oxidative Carbene
Organocatalysis by Radical Processes
Xingxing Wu, Yuexia Zhang, Yuhuang Wang, Jie Ke, Martin Jeret, Rambabu N. Reddi,
Song Yang, Bao-An Song,* and Yonggui Robin Chi*
Abstract: Simple and inexpensive polyhalides (CCl4 and
C2Cl6) have been found to be effective and versatile oxidants
in removing electrons from Breslow intermediates under N-
heterocyclic carbene (NHC) catalysis. This oxidative reaction
involves multiple single-electron-transfer (SET) processes and
several radical intermediates. The a, b, and g-carbon atoms of
aldehydes and enals could be readily functionalized. Given the
low cost of the oxidants and the broad applicability of the
reactions, this study is expected to greatly enhance the
feasibility of oxidative NHC catalysis for large-scale applica-
tions. Also this new SET radical process with polyhalides as
single-electron oxidants will open a new avenue in the
development of NHC-catalyzed radical reactions.
O
xidation is nearly an unavoidable process in chemical
synthesis. In the thiamine pyrophosphate (TPP; Vitamin B1)
mediated reactions in the biological systems, pyruvate
ferredoxin oxidoreductase (PFOR) is believed to enable
two single-electron-transfer (SET) processes which oxidize
the Breslow intermediate to an acyl azolium intermediate for
further transformations.[1] In synthetic chemistry with N-
heterocyclic carbenes (NHCs) as organic catalysts, oxidation
of NHC/aldehyde-derived Breslow intermediates to the
corresponding acyl azoliums has led to development of
numerous useful reactions (Figure 1a).[2] To date, dipheno-
quinone (DQ), pioneered by Studer and co-workers,[3a,b] has
become a most popular oxidant in NHC catalysis.[3] This
quinone oxidant likely behaves as an electron pair acceptor
which converts the Breslow intermediate into an acyl azolium
intermediate.[3b] Despite the amazing success, some of the
drawbacks in using the DQ oxidant include relatively high
cost and inconvenience in separating the stoichiometric
amount of reduced DQ adduct (hydroquinone) from the
Figure 1. Representative oxidants used in oxidative NHC catalysis and
our proposed oxidative pathway using simple polyhalides as oxidants.
SET=single-electron transfer.
reaction mixture (Figure 1b). Other common oxidants have
also been reported, such as nitrobenzene,[4] N-oxyl radical
(e.g., TEMPO),[5] azabenzene,[6] MnO2,[7] riboflavin, phena-
zine,[8] a catalytic transition metal (TM) in combination with
O2 as a terminal oxidant[9] or atmospheric O2,[10] NFSI,[11] and
electrochemistry.[12] However, these oxidants are found to
have fewer applications because of the various limitations.
For example, while O2 (and air) is in principle an excellent
choice as oxidant, its application in NHC catalysis is mostly
limited to the conversion of aldehydes into the corresponding
carboxylic acids and esters.[9,10] When O2 was used as the
oxidant for functionalization of the a, b, or g-carbon of
aldehydes, they are unproductively consumed to form simple
carboxylic acids or esters as the side products.[10e]
Our group is interested in the oxidation of Breslow
intermediates, through an SET process, for the development
of new activation modes and reactions.[13] In 2013, we
reported that a,b-unsaturated nitroalkenes could oxidize
aldehydes into the corresponding esters by an SET proc-
ess.[13a] Indeed, the nitro groups (NO2) in several different
reagents could behave as SET oxidants in a number of
reactions, as independently disclosed by the group of Rovis[14]
and our own group.[13] Very recently, we found that nitro-
benzyl bromide could oxidize aldehydes into esters.[13c] This
[*] X. Wu, Y. Zhang, Y. Wang, J. Ke, M. Jeret, R. N. Reddi,
Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry
School of Physical & Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: robinchi@ntu.edu.sg
Prof. Dr. S. Yang, Prof. Dr. B.-A. Song, Prof. Dr. Y. R. Chi
Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering
Ministry of Education, Guizhou University
Huaxi District, Guiyang 550025 (China)
E-mail: basong@gzu.edu.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611692.
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À
study encouraged us to evaluate structurally simple and
inexpensive polyhalides as oxidants for NHC catalysis.[15]
Herein we report that readily available CCl4 and C2Cl6 can
effectively oxidize aldehyde-derived Breslow intermediates
to acyl azolium intermediates. In addition to simple carbox-
ylic ester formation, these polyhalides as oxidants allow
effective and asymmetric functionalization of the a,b, and g-
carbon atoms of aldehydes and enals. The reactions are very
during the redox process. It is known that CCl3 and
aldehydes can undergo multiple side reactions to give
complex mixtures.[19] We hypothesized that this problem
might be solved if the reactive carbanion intermediate could
be rapidly quenched. In this regard, hexachloroethane (C2Cl6;
À
or viewed as CCl3 CCl3) might be a good choice as release of
a ClÀ from the pentachloroethyl anion ( CCl2 CCl3) would
À
À
=
furnish tetrachloride ethylene (CCl2 CCl2), which is inert in
=
À
clean as the reduced oxidant (e.g., CCl2 CCl2 from CCl3
CCl3) is essentially a hydroponic volatile solvent which does
not require separation. Our oxidation is proposed to go
through two SET processes and several radical intermediates
(Figure 1c). It provides a practical and inexpensive method
amenable for large-scale applications. Additionally, the
polyhalo-carbon radicals and NHC-bound radical intermedi-
ates generated in our process may find applications in new
reaction development.
the reaction mixture (see Scheme 1a). Fortunately, C2Cl6
behaved better than CCl4, thus affording 3a in 61% yield
(Table 1, entry 6). It is worth mentioning that hexachloro-
ethane is a byproduct of many industrial chlorination
processes and hence available at very low cost (Figure 1c).
Further optimization of the reaction conditions revealed that
the reaction proceeded effectively at room temperature by
using 1.2 equivalents. C2Cl6 as the oxidant (Table 1, entry 7).
The reaction yield could be improved from 72% (entry 7) to
83% (entry 8) by using a mixture of Cs2CO3 and DABCO as
the bases. Last, we found that using THF/tBuOH (20:1, v/v) as
the solvent could provide 3a with 89% yield upon isolation
(entry 9).
We began our investigation by choosing the formal [3+3]
annulation of the enal 1a and acetoacetate (2a) as the model
reaction (Table 1).[16a] We first chose CCl4 as a potential
oxidant owing to its low cost.[17] To our delight, with the
triazolium salt A[18] as an NHC precatalyst, THF as a solvent,
and Cs2CO3 as a base at 408C, the desired [3+3] lactone
product (3a) was obtained in 41% yield (entry 1). A switch of
CCl4 to either CHCl3, CH2ClCH2Cl (DCE), or CHCl2CHCl2
(TCE) as the oxidant did not lead to the formation of 3a
(entry 2). Replacing Cs2CO3 with either K2CO3 (entry 3) or
DABCO (entry 4) as the base gave lower yields of the
product. No apparent improvement was observed when other
solvents and NHCs were used (entry 5).
The proposed reaction pathway[20] is illustrated in Sche-
me 1a. One electron of the Breslow intermediate I (formed
between NHC and aldehyde) is removed by the polyhalide
(C2Cl6) by an SET process to form the radical cation
À
intermediate I’ and perchloroethane radical anion ([CCl3
CCl3]ÀC). Release of a ClÀ from radical anion forms a neutral
À
radical intermediate (·CCl2 CCl3) which could remove one
additional electron from the radical cation I’ to give the
unsaturated acyl azolium intermediate II. In this process,
À
À
À
The low yields obtained when using CCl4 as the oxidant
·CCl2 CCl3 is reduced to CCl2 CCl3, which undergoes the
was mainly caused by side reactions from CCl3À, generated
elimination of a ClÀ to form an unreactive CCl2 CCl2. The
=
formation of tetrachloroethylene (TCE) was confirmed by
gas chromatography (GC) and 13C NMR analysis (see the
Supporting Information). The presence of the NHC-bound
enal-derived radical cation intermediate I’ was evidenced by
Table 1: Screening of polyhalide oxidants for the annulation of 1a with
2a.[a]
Entry Halide (4 equiv)
Base (2 equiv)
Cs2CO3
T
Yield [%][b]
1
2
CCl4
40
40
41
N.R.
(HCCl3, CH2ClCH2Cl, Cs2CO3
or CHCl2CHCl2)
3
4
5
6
7
8
CCl4
CCl4
K2CO3
DABCO
(other solvents, NHCs, see SI)
Cs2CO3
40
40
30
7
<46
61
72
83
C2Cl6
C2Cl6
C2Cl6
40
RT
RT
[c]
[c]
Cs2CO3
Cs2CO3/
DABCO[d]
9[e]
C2Cl6
Cs2CO3/
RT
93 (89)[f]
[c]
DABCO[d]
[a] Reaction conditions: The NHC A (10 mol%), 1a (0.05 mmol,
1.0 equiv), 2a (0.075 mmol), base (2.0 equiv), halide (4.0 equiv), THF
(1.0 mL), 4 ꢀ M.S., 12 h. [b] Yield determined by NMR spectroscopy
based on 1a by using 1,3,5-trimethoxybenzene as an internal standard.
[c] 1.2 equiv of C2Cl6 was used. [d] Cs2CO3 (1.2 equiv) and DABCO
(1.2 equiv) were used. [e] THF/tBuOH (20:1, 1 mL) as the solvent.
[f] Yield of isolated product given within parentheses. DABCO=1,4-
diazabicyclo[2.2.2]octane.
Scheme 1. Proposed reaction pathway (a) and experiment indicating
the presence of radical intermediates (b).
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Table 3: g-Carbon atom reaction:[a] Examples for the reactions of enals
the formation of cyclopentanone (4), when 1a was subjected
to the reaction conditions in the absence of a nucleophilic
substrate (e.g., 2a; Scheme 1b). This dimer-forming reaction
of an enal through a radical process was reported by Rovis
and co-workers.[14b]
(7) with either hydrazones (8)[b] or activated ketones (10).[c]
To demonstrate the generality of our oxidation approach
using C2Cl6 as the oxidant, we studied carbon–carbon bond-
forming reactions involving a-, b-, and g-carbon atoms of
aldehydes and enals. In each type of reaction with different
substrates, only a slight change of the reaction conditions was
necessary (Tables 2, 3, and 4), and clearly indicates the
versatile features of the polyhalide oxidants.
Exemplified in Table 2 is the b-carbon reaction of enals
under oxidative NHC catalysis. Various enals and 1,3-
dicarbonyls reacted effectively to give the lactone products
(3a–g) with 73–89% yields. The imine 5 (precursor of
enamide) could also be used as a nucleophile to react with
enals to form lactam products (6a–c) in 70–75% yields.[16b,c]
Table 2: b-Carbon atom reaction:[a] Examples for the reactions of enals
(1) with either 1,3-dicarbonyls (2)[b] or imines 5.[c]
[a] For details, see the Supporting Information. [b] Enal 7 (0.13 mmol), 8
(0.10 mmol, 1.0 equiv.), RT for 12 h. Yields of the isolated products
based on 8. [c] Enal 7 (0.13 mmol), 10 (0.10 mmol, 1.0 equiv.), RT for
12 h. Yields of the isolated products based on 10. Bz=benzoyl.
to serve as enolate precursors by oxidative NHC catalysis. Not
surprisingly, our method utilizing C2Cl6 as the oxidant has the
capacity to generate the NHC-bound enolates directly from
simple aldehydes. The results in Table 4 illustrate a formal
[4+2] cycloaddition of aliphatic aldehydes with a,b-unsatu-
rated imines and ketones to afford six-membered lactams and
lactones in good yields.[22]
Table 4: a-Carbon atom reaction:[a] Examples for the reactions of
aliphatic aldehydes (11) with either chalcone imines (13)[b] or enones
(15).[c]
[a] For details, see the Supporting Information. [b] Enal 1 (0.10 mmol,
1.0 equiv), 2 (0.15 mmol), RT for 12 h. Yields of isolated product based
on 1. [c] Enal 1 (0.10 mmol, 1.0 equiv.), 5 (0.15 mmol), RT for 12 h. Yields
of isolated products based on 1. Ts=4-toluenesulfonyl.
We next evaluated our approach for the oxidative g-
carbon atom reaction of enals (Table 3).[21] Under reaction
conditions which were more or less the same as used above for
the [3+3] annulations, the g-carbon atom of the enals (7)
reacted smoothly with hydrazones (8) to provide lactam
adducts (9a–e) in 75–85% yields.[21a,b] Activated trifluoro-
methyl ketones (10) could also be used as effective electro-
philes in this reaction under similar reaction conditions, thus
affording the corresponding unsaturated d-lactones (11a–d)
in 72–76% yields.[21c]
[a] For details, see the Supporting Information. [b] Aldehyde 12
(0.22 mmol), 13 (0.10 mmol, 1.0 equiv), RT for 18 h. Yields of combined
isolated products based on 13. [c] 12 (0.30 mmol), 15 (0.10 mmol,
1.0 equiv), RT for 18 h. Yields of combined isolated products based on
15.
We then studied oxidative a-carbon atom functionaliza-
tion of aldehydes. The group of Rovis[8d] and ours[22a]
previously, and independently, employed aliphatic aldehydes
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Apparently, our approach with C2Cl6 as an oxidant could
be directly used in asymmetric catalysis when chiral NHC
catalysts are applied (Scheme 2). For example, in the formal
[3+3] reactions of enals and 1,3-dicarbonyl compounds, the
use of the amino-indanol-derived triazolium NHC catalyst
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Scheme 2. Asymmetric reactions using polyhalides as oxidants.
In conclusion, polyhalides, such as C2Cl6, can be used as
effective oxidants in NHC organic catalysis. This approach
allows oxidation of an aldehyde-derived Breslow intermedi-
ate into an acyl azolium intermediate. The a-, b-, and g-
carbon atoms of aldehydes and enals could be readily
functionalized with our method. On the practical application
side, the low cost of the oxidants, the mild reaction conditions,
and the simplicity in product purification shall make this
method an attractive choice for both small- and large-scale
synthesis. On the fundamental side, our oxidation process
involves multiple SET processes and radical intermediates,
and therefore provides an opportunity for developing new
reactions.
Acknowledgments
We acknowledge financial support from the National Natural
Science Foundation of China (No. 21132003; No. 21472028),
Singapore National Research Foundation (NRF-NRFI2016-
06), the Ministry of Education of Singapore (MOE2013-T2-2–
003), Nanyang Technological University (NTU, Singapore),
Chinaꢀs Ministry of Education, Thousand Talent Plan,
Guizhou Province Returned Oversea Student Science and
Technology Activity Program, Science and Technology of
Guizhou Province, and Guizhou University.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: aldehydes · electron transfer ·
N-heterocyclic carbenes · organocatalysis · oxidation
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Manuscript received: November 30, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Carbenes
X. Wu, Y. Zhang, Y. Wang, J. Ke, M. Jeret,
R. N. Reddi, S. Yang, B.-A. Song,*
Y. R. Chi*
&&& — &&&
Polyhalides as Efficient and Mild
Oxidants for Oxidative Carbene
Organocatalysis by Radical Processes
Simple and inexpensive polyhalides (e.g.,
C2Cl6) can be used as effective oxidants in
N-heterocyclic carbene (NHC) organoca-
talysis. This approach allows oxidation of
an aldehyde-derived Breslow intermedi-
ate into an acyl azolium intermediate
involving multiple single-electron-trans-
fer (SET) processes. The a-, b-, and g-
carbon atoms of aldehydes could be
readily functionalized with this method.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!