Alkyl transfer from C-C cleavage: Replacing the nitro group of nitro-olefins

Article abstract of DOI:10.1039/c4cc01119h

Alkyl substituted Hantzsch esters are rationally used as alkylation reagents to replace the nitro groups of nitro olefins to give excellent yields of trans-olefins. The reaction mechanism is considered to proceed through a free radical mechanism, which is different from the corresponding transfer alkylation of imines. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01119h

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Alkyl transfer from C–C cleavage: replacing the
nitro group of nitro-olefins†
Cite this: Chem. Commun., 2014,
50, 6246
Guangxun Li,a Lei Wu,a Gang Lv,a Hongxin Liu,a Qingquan Fu,a Xiaomei Zhangb
and Zhuo Tang*a
Received 12th February 2014,
Accepted 17th March 2014
DOI: 10.1039/c4cc01119h
www.rsc.org/chemcomm
Alkyl substituted Hantzsch esters are rationally used as alkylation
reagents to replace the nitro groups of nitro olefins to give excel-
lent yields of trans-olefins. The reaction mechanism is considered
to proceed through a free radical mechanism, which is different
from the corresponding transfer alkylation of imines.
Methods for C–C bond formation are basic tools for synthetic
chemists. In spite of the myriad methods available,1 alternative
metal-free green chemistry routes for C–C bond formation, in
terms of operational simplicity and functional-group tolerance,
are in constant demand.2 The highly efficient natural bio-
chemical pathways to produce complex molecules are a good
source of inspiration for chemists.3 Examination of the chemical
building blocks, modes of substrate activation, and biosynthetic
Scheme 1 Alkyl transfer with alkyl substituted DHPs.
pathways in nature provide much insight to achieve many (Scheme 1, eqn (2)). In fact, 1,4-cyclohexadiene derivatives have
biomimetic organocatalytic C–C bond formations.4
already been used as all sorts of radical precursors including alkyl
Hantzsch esters (HEH) are bio-inspired hydride donors, com- radicals.7 However, the efficiency of alkyl radicals provided by direct
monly known as synthetic analogues of reduced nicotinamide splitting of C–C bonds was very low.7i
adenine dinucleotide (NADH). Taking advantage of their special
It has been proved that b-nitrostyrenes are versatile building
hydrogen transfer properties, a broad range of transfer hydrogena- blocks which could be selectively reduced by HEH through hydrogen
tions can be conducted.5 However, the study of alkyl transfer in this transfer.8 Based on this information we have tried the corresponding
way has never been addressed until recent work by our group.6 alkylation at the beginning of reaction (Scheme 1, eqn (3)). Appar-
Similar to the corresponding transfer hydrogenation, high efficiency ently, this alkyl transfer reaction was difficult to anticipate for the
C-4 alkyl substituted DHPs were rationally designed for the alkylation following reasons: (1) the competitive hydrogen transfer reaction
of imines (Scheme 1, eqn (1)). Meanwhile, we put forward a reason- (Scheme 1, eqn (4)), (2) the transfer mechanism was unknown which
able stepwise concerted reaction mechanism. However, the transfer may proceed through a concerted process9 or a free radical process.10
scope was limited to benzyls, secondary alkyl groups and tertiary alkyl For example, DHP analogue 1-benzyl-1,4-dihydronicotinamide
groups. Here, we give another type of alkyl transfer in which alkyl (BNAH) was used as a reagent for replacing aliphatic nitro groups
substituted Hantzsch esters could effectively cleave the C–C bond to by hydrogen through a single electron transfer chain process. More-
provide alkyl radicals that replace the nitro groups of nitro olefins over, it was also discovered that substitution of b-nitrostyrenes to
generate corresponding alkenes was facilitated by an electrophilic
carbon-centered radical process.11
a Natural Products Research Center, Chengdu Institution of Biology,
Chinese Academy of Science, Chengdu, Sichuan, 610041, China.
E-mail: tangzhuo@cib.ac.cn
Our study of alkyl transfer started with the hypothesis that DHPs
with two alkyl groups at the C4 position should only transfer the alkyl
groups due to the lack of competition in transfer hydrogenation. DHP
2a bearing cyano groups was the only C4 dialkyl substituted DHP
which could be obtained. However, the designed reaction didn’t take
place. Moreover, the corresponding C4 single benzyl substituted DHP
b Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu,
Sichuan, 610041, China
† Electronic supplementary information (ESI) available: Experimental procedures
include the synthetic protocol of the alkyl transfer reaction as well as full
spectroscopic data of the related products. See DOI: 10.1039/c4cc01119h
6246 | Chem. Commun., 2014, 50, 6246--6248
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Scheme 2 Screening of alkyl donors for alkyl transfer.
2b couldn’t transfer alkyl as well. Surprisingly, it was found that DHPs
with ester substituents could transfer the benzyl group with high
efficiency (Scheme 2, 2c–2e). Even more interesting was the alkyl
transfer product, which was exclusively trans-olefin. Moreover, we
found that DHP 2d with an ethyl ester substituent transferred the
benzyl group more efficiently than the corresponding methyl ester
substituted DHP 2c and tert-butyl ester substituted DHP 2e.
Meanwhile, alkyl substituted benzothiazoles, already
applied for transfer alkylation of imines,6 were synthesized
and used in our alkyl transfer reaction. C-2 single benzyl
substituted benzothiazole 5b or disubstituted benzothiazoles
5b–5d, were screened, however, the expected alkyl transfer
reaction did not take place.
Next we turned our attention to ascertain the initial scope for this
unexpected alkylation reaction. Reaction conditions were optimized
by using 2d as an alkyl transfer donor and nitro-olefin 1a as the
acceptor. It was found that the alkylation reaction could not take
place at the low temperature of 60 1C (Table 1, entry 2). Considering
that the reaction may proceed through a free radical mechanism, we
used the radical initiator AIBN to promote the reaction at 60 1C
without a Brønsted acid catalyst. To our delight, the alkylation
reaction proceeded with higher efficiency compared with TsOH at
80 1C (Table 1, entry 3). Meanwhile, the radical scavenger TEMPO
inhibited the alkylation reaction (Table 1, entry 4). Therefore, we
speculated that the reaction may proceed through a radical
Scheme 3 Screening of nitro-olefins for alkyl transfer.
mechanism. Further screening of the appropriate reaction solvent
revealed that n-butyl ether was better to use for higher alkyl transfer
efficiency (Table 1, entries 5–7). Finally, the ratio of the reaction
material was standardized and the optimal ratio for 1a/2d was found
to be 1/2 (Table 1, entry 8).
Further we explored the scope of the nitro-olefin acceptors in the
alkyl-transfer reactions using benzyl substituted DHP 2d as a repre-
sentative donor (Scheme 3). Nitro-olefins bearing electron withdraw-
ing groups or electron donating groups on the aromatic rings were
readily used in the alkyl transfer reactions with high efficiency (3a–3e,
3g–3j). Trans-olefins were obtained exclusively with up to 90% yield
except for 3j which was obtained as a mixture of the trans- and cis-
olefins. Meanwhile, the results revealed that nitro-olefins with electron
withdrawing groups could readily be use in the alkyl transfer reaction
with higher efficiency compared to nitro-olefins with electron donat-
ing groups. However, nitro-olefins with a p-nitro group substituted on
the phenyl ring could not form the alkyl transfer product 3f, which
was ascribed to inhibition of the nitro group.10 Interestingly, tri-
substituted olefin 3k could not be prepared through the alkyl transfer
reaction, which was attributed to its slightly higher steric hindrance.
The unexpectedly high efficiency of alkyl transfer with
benzyl substituted DHPs drove us to determine whether other
alkyls could efficiently be transferred as well. Firstly, we
screened benzyl groups with different substituents. The results
revealed that the substituents performed well, regardless of
being either electron-withdrawing (Scheme 4, 3m, 3n, 3q) or
electron-donating (Scheme 4, 3l, 3o, 3p), delivering the desired
E-olefin in good isolated yields (most > 80%). We further
determined that secondary alkyl groups, whether open-chain
(Scheme 4, 3r) or cyclic (Scheme 4, 3s–3t) could transfer with
high efficiency. Finally, we screened primary alkyl groups,
which were unable to transfer in our previous work.6 The
results revealed that all of the primary alkyl groups could
transfer efficiently, except the methyl group which was ascribed
to the transience of the methyl radical (Scheme 4, 3u–3y).
Previous discussion about the mechanism of the transfer
alkylation of imines with C-4 substituted DHPs focused on the
two step concerted alkyl transfer process.6 However, we propose
here that the C-4 substituted DHPs could replace the nitro
groups of the nitro-olefins with alkyl groups via a single
Table 1 Standardization of the alkyl transfer reaction conditionsa
Entry
Catalyst
Solvent
T (1C)
Yieldb (%)
1
2
3
4
5
6
7
8c
TsOH 30%
TsOH 30%
AIBN 50%
AIBN/TEMPO
AIBN 1 eq.
AIBN 1 eq.
AIBN 1 eq.
AIBN 1 eq.
Toluene
Toluene
Toluene
Toluene
Toluene
AcOH
n-Butyl ether
n-Butyl ether
80
60
60
60
80
80
80
80
60
—
62
—
70
65
73
80
a
Reaction conditions: 1 eq. nitro-olefin 1a (0.2 M in solvent), DHP 2d
(1.5 eq.), catalyst or additives were stirred in a nitrogen environment at
b
the given temperature. Yields are calculated after purification from
c
silica column depending on 1a. The ratio of 1a/2d is 1/2.
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Meanwhile, the reaction conditions are mild and have been
able to site selectively and stereoselectively prepare a range of
trans-olefins. The scope of the transferred alkyls included
benzyls, secondary alkyls and especially primary alkyls which
were unable to transfer in our previous work. This study paves
the way for the use of alkyl substituted Hantzsch esters to
provide alkyl radicals, which are traditionally produced by
splitting of C–X bonds rather than C–C bond cleavage. Further
alkyl transfer experiments, as well as investigations into the
reaction mechanisms, are underway in our lab.
We are grateful for the financial support from Chinese
Academy of Science (Hundreds of Talents Program) and
National Sciences Foundation of China (Grant No. 21102139)
and Innovation Program of the Chinese Academy of Sciences
(Grant No. KSCX2-EW-J-22).
Scheme 4 Screening of the DHP donors for alkyl transfer.
Notes and references
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Scheme 5 Proposed reaction mechanism.
electron transfer chain process (Scheme 5). Firstly, the free
radical initiator AIBN decomposes to form 2-cyanoprop-2-yl
radicals, which then initiate the alkyl transfer reaction. Then
the DHP radical (Scheme 5, Im1) forms by extracting a hydro-
gen radical. The resultant DHP radical transfers the alkyl
radical and adds to the nitro olefin due to the aromatization
of the DHP ring. The resulting radical interconverts by internal
rotation (Scheme 5, Im2 and Im3), and then produces the
thermodynamically controlled product – the trans-olefin – via
b-elimination. Finally the resulting nitro radical will initiate
further reaction cycles.
The reported results support this novel mechanistic assign-
ment: (1) the alkylation reaction could be initiated with AIBN
and quenched with TEMPO; (2) the alkylation product 3f could
not be prepared due to the presence of a p-nitro group; (3)
special DHPs with N-methyl substitutents were intentionally
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6248 | Chem. Commun., 2014, 50, 6246--6248
This journal is ©The Royal Society of Chemistry 2014