Fe-Catalyzed Reductive Coupling of Unactivated Alkenes with β-Nitroalkenes

Article abstract of DOI:10.1021/acs.orglett.5b02294

An Fe-catalyzed reductive coupling of unactivated alkenes with β-nitroalkenes has been developed. The reaction proceeds through a radical pathway, with β-nitroalkenes serving as the vinylating reagents and the nitro group being cleaved in the process. The

Full text of DOI:10.1021/acs.orglett.5b02294

Letter
pubs.acs.org/OrgLett
Fe-Catalyzed Reductive Coupling of Unactivated Alkenes with
β‑Nitroalkenes
Jing Zheng,† Dahai Wang,† and Sunliang Cui*
Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou
310058, China
S
* Supporting Information
ABSTRACT: An Fe-catalyzed reductive coupling of unactivated
alkenes with β-nitroalkenes has been developed. The reaction proceeds
through a radical pathway, with β-nitroalkenes serving as the vinylating
reagents and the nitro group being cleaved in the process. Therefore,
this method provides a viable synthetic approach to valuable secondary- and tertiary-alkylated styrene derivatives. Furthermore,
control experiments were conducted and a plausible mechanism is proposed.
lkylated styrenes represent an important structure in
natural products and pharmaceuticals, such as Pitavastatin,
Recently, the Fe-catalyzed coupling of unactivated alkenes
has emerged as a powerful and distinct method for the facile
construction of C−C, C−N, and C−X (X = F, Cl, S) bonds
that allows divergent functionalization. These transformations
revealed that unactivated alkenes could be converted to
putative radical species which can be trapped by various
acceptors. For example, Boger demonstrated the hydro-
fluorination and hydroazidation of unactivated alkenes,6 while
Baran developed a practical olefin cross-coupling and hydro-
methylation of unactivated alkenes.7 These methods have
provided rapid access to many compounds that were difficult or
perhaps impossible to access using other methods. Recently,
Baran further invented a practical olefin hydroamination of
nitroarenes, in which the nitro group can be reduced in situ to
nitrosoamine and sequentially intercepted by the radical species
(Scheme 1).8
A
Vorapaxar, Metanicotine, Tamoxifen, and Zuclopenthixol
(Figure 1).1 Therefore, the development of facile syntheses of
In continuation of our research on the functionalization of
unactivated alkenes,9 herein we report an Fe-catalyzed
reductive coupling of unactivated alkenes with β-nitroalkenes
(Scheme 1). Interestingly, the nitro group is cleaved in this
Figure 1. Selected drugs with structure of alkylated alkenes.
Scheme 1. Fe-Catalyzed Coupling of Unactivated Alkenes
with Nitro Compounds
alkylated styrenes has attracted considerable attention. The
classical approaches include Wittig reaction and Julia
olefination,2 and these reactions rely on the requisite
phosphonium salts and sulfone starting materials. The Heck
reaction is another powerful method for access to styrenes, but
sometimes suffers from a limited substrate scope.3 Alternatively,
Oshima has developed a cobalt-catalyzed Heck-type reaction of
alkyl halides with styrenes that affords alkylated styrenes, and
this transformation proceeds through a radical pathway.4
Recently, Nishikata reported an efficient generation of a
functionalized tertiary-alkyl radical for a copper-catalyzed
tertiary-alkylative Heck-type reaction, via a similar type of
radical mechanism.5 Despite these advances, the development
of a mild and general method for the facile synthesis of
secondary- and tertiary-alkylated styrenes from simple starting
materials remains an important challenge.
Received: August 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02294
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
reductive coupling to furnish the valuable secondary- and
tertiary-alkylated styrene derivatives.
Table 2. Substrate Scope of Unactivated Alkenes
We commenced our study by investigating β-nitrostyrene 1a
and unactivated alkene 2a. When the reaction was subjected to
Boger’s Fe2(ox)3·6H2O and NaBH4 conditions in ethanol, at
either 0 or 60 °C, the reductive coupling product was not
observed (Table 1, entries 1−2). Variation of the reductant
a
Table 1. Optimization Experiments
b
entry
Fe(III) salt
reductant
solvent
t (°C)
yield (%)
1
2
3
4
5
6
7
8
9
Fe2(ox)3·6H2O
Fe2(ox)3·6H2O
Fe2(ox)3·6H2O
Fe2(ox)3·6H2O
Fe(acac)3
NaBH4
NaBH4
EtSiH3
PhSiH3
EtSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
0
<5
<5
<5
60
<5
60
60
60
60
60
0
c
Fe(acac)3
90 (82)
<5
Fe(acac)3
Fe(acac)3
25
60
75
Fe(acac)3
67
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Fe(III) salt (10
b
mol %), reductant (0.4 mmol), argon, 8 h. Yield of isolated product.
c
The value in parentheses refers to 5 mmol scale.
revealed that EtSiH3 also was not effective (entry 3), but
gratifyingly, the utilization of PhSiH3 at 60 °C gave a product
3a in 60% yield (entry 4). Standard methods of identification
showed that the nitro-group had been cleaved and the product
was a tertiary-alkylated styrene derivative. This promising result
encouraged us to further optimize the reaction conditions, and
we next switched the Fe(III) salt to Fe(acac)3. The
combination of Fe(acac)3/EtSiH3 was inferior, and 3a was
not detected (entry 5). Replacement of EtSiH3 with PhSiH3 led
to the formation of 3a in a significant 90% yield (entry 6). To
unravel the synthetic potential, a 5 mmol scale reaction was
carried out and the reaction was still efficient, affording the
product in 82% yield. Decreasing the temperature to 0 °C
completely suppressed the reactivity (entry 7). When the
reaction was carried out at rt, 3a was formed in 75% yield
(entry 8). Moreover, shifting the solvent to THF at 60 °C led
to a decreased yield (entry 9). Since the β-nitrostyrene 1a
served as a vinylation reagent in this process,10 other vinylation
reagents such as (E)-(2-(phenylsulfonyl)vinyl)benzene 4 and
cinnamonitrile 5 were tested and found not applicable in this
protocol (Figure 2).11
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Fe(acac)3 (10
b
mol %), PhSiH3 (0.4 mmol), in EtOH at 60 °C for 8 h, argon. Yield
of isolated product. PMP = para-methoxyphenyl.
c
thus offering opportunities for further derivatizaiton. Trisub-
stituted alkenes were also applicable furnishing the product 3f
in good yield (entry 5). Additionally, when monosubstituted
terminal alkenes with valuable cyano, para-methoxyphenyl, and
trimethylsilyl functional groups were subjected to this process,
the reaction proceeded smoothly to enable access to secondary-
alkylated styrenes in moderate to good yields (entries 6−8).
Moreover, cyclic alkenes such as cyclohexene and 1-methyl-
cyclohexene were amenable to this transformation delivering
the corresponding products in moderate yields (entries 9−10).
Interestingly, when the more hindered norbornene was used in
this protocol, the reaction furnished the endocyclic tethered
styrene 3l in moderate yield (entry 11), which is difficult to
access with conventional methods.
Next, a variety of nitroalkenes were utilized as vinylation
reagents to react with unactivated alkene 2a to construct
diverse alkylated styrenes (Table 3). Gratifyingly, many
substituents, such as fluoro, chloro, bromo, methyl, methoxy,
dimethylamino, and hydroxy, were well tolerated in this
reductive coupling to provide the functionalized alkylated
Figure 2. Other vinylation reagents unsuccessfully screened.
With the optimized conditions in hand, we next investigated
the scope with various unactivated alkenes (Table 2).
Disubstituted terminal alkenes served as viable donor substrates
in this reductive coupling providing tertiary alkylated styrenes
(3b−3e) in good to excellent yields (Table 2, entries 1−4),
with exclusive bond formation occurring at the most substituted
side of the alkenes. Notably, ether, hydroxy, and even
piperidine ring functionality were well tolerated in this process,
B
DOI: 10.1021/acs.orglett.5b02294
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Organic Letters
Letter
a
To gain insight into the possible reaction mechanism, control
experiments were carried out (Scheme 3). Omission of
Table 3. Substrate Scope of Nitroalkenes
Scheme 3. Control Experiments
Fe(acac)3 completely shut down the reactivity and the starting
materials were recovered, demonstrating the necessity for the
Fe catalyst. Moreover, when a radical scavenger such as Tempo
was added, the reductive coupling product 3a was not observed,
indicating a radical-mediated reaction pathway.
Based on these results and past literatures, a plausible
mechanism is proposed in Scheme 4.7,10,12Initially, the Fe(III)-
Scheme 4. Proposed Mechanism
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Fe(acac)3 (10
mol %), PhSiH3 (0.4 mmol), in EtOH at 60 °C for 8 h, argon; yields
refer to isolated products.
styrenes in good yields (6a−6g). And the electron properties
did not show significant effects on the reactivity. Additionally,
polysubstitution in the aromatic ring of the nitroalkenes was
also compatible with this process generating the corresponding
product in moderate yield (6h, 53%). Interestingly, when
heterocyclic nitroalkenes containing the furan, thiophene,
pyridine, and indole moieties were utilized in this reductive
coupling, the process delivered the desired alkenes in moderate
to good yields (6i−6l). Considering the wealth of alkylated
alkenes accessible, this process represents a powerful and
distinct approach toward their construction under mild reaction
conditions and with readily available starting materials.
Furthermore, the synthetic utility of this reductive coupling
protocol was demonstrated by vinylation of alkenes with a
natural product derivative (Scheme 2). For example, the (S)-
Scheme 2. Scope of Alkenes with Natural Products
Derivatives
catalyst is converted to Fe hydride species A in the presence of
phenylsilane and ethanol.13,14 Then A regioselectively adds to
alkene 2 to form B, placing the Fe atom on the more
substituted carbon atom. The dissociation of B delivers Fe(II)
species C and alkyl radical D, which is trapped by nitroalkene 1
to generate the β-nitro radical E. The sequential elimination of
E would furnish the alkylated styrene products (3 or 6) and a
nitro radical,15,16which would reoxidize C to an Fe(III) species
to enable the catalytic cycle.
In summary, we have developed an Fe-catalyzed reductive
coupling of unactivated alkenes with nitroalkenes. The
unactivated alkenes are converted to alkyl radicals which are
trapped by the nitroalkene, while the nitro group is cleaved in
the sequential elimination to furnish the products to enable the
catalytic cycle. Therefore, this method provides a rapid and
efficient access to alkylated styrene derivatives, with simple and
readily available starting materials.
(−)-β-citronellol 2m could be easily coupled with nitroalkene
1i for access to alkylated styrene derivative 6m in 54% yield
under standard conditions. Meanwhile, the L-menthol derived
alkene 2n could be converted to corresponding vinylpyridine
derivative 6n in 63% yield upon coupling with nitroalkene 1l.
Therefore, this protocol can provide an expedient approach to
those olefins with natural product moieties.
C
DOI: 10.1021/acs.orglett.5b02294
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Organic Letters
Letter
(12) For selected Fe-catalyzed reduction using silane, see: (a) Zhou,
S.; Junge, K.; Addis, D.; Das, S.; Beller, M. Angew. Chem., Int. Ed. 2009,
48, 9507. (b) Wu, J. Y.; Stanzl, B. N.; Ritter, T. J. Am. Chem. Soc. 2010,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02294.
■
S
132, 13214. (c) Das, S.; Wendt, B.; Moller, K.; Junge, K.; Beller, M.
̈
Angew. Chem., Int. Ed. 2012, 51, 1662.
(13) Wang, L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.;
Wang, X.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448.
(14) For Co-catalyzed tranformation of alkene to alkyl radical using
silane, see: (a) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 18, 1071.
(b) Waser, J.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 5676.
(c) Waser, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 4099.
(d) Waser, J.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127,
8294. (e) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am.
Chem. Soc. 2006, 128, 11693. (f) Gaspar, B.; Carreira, E. M. Angew.
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Full experimental procedures and spectra data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: slcui@zju.edu.cn.
Author Contributions
†J.Z. and D.W. contributed equally
Notes
(15) (a) Russell, G. A.; Tashtoush, H.; Ngoviwatchai, P. J. Am. Chem.
Soc. 1984, 106, 4622. (b) Ouvry, G.; Quiclet-Sire, B.; Zard, S. Z. Org.
Lett. 2003, 5, 2907.
The authors declare no competing financial interest.
(16) For similar radical addition−elimination for alkynylation, see:
(a) Liu, X.; Wang, Z.; Cheng, X.; Li, C. J. Am. Chem. Soc. 2012, 134,
14330. (b) Huang, H.; Zhang, G.; Chen, Y. Angew. Chem., Int. Ed.
2015, 54, 7872.
ACKNOWLEDGMENTS
We are grateful for the financial support from National Natural
Science Foundation of China (Nos. 21202143 and 21472163).
■
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DOI: 10.1021/acs.orglett.5b02294
Org. Lett. XXXX, XXX, XXX−XXX