Enantioselective hydrogenation of α,β-disubstituted nitroalkenes

Article abstract of DOI:10.1039/c4cc03942d

The first highly chemo- and enantioselective hydrogenation of α,β-disubstituted nitroalkenes was accomplished with rhodium/JosiPhos-J₂ as a catalyst, with the yield and enantioselectivity of up to 95% and 94%, respectively. The α-chiral nitroalkanes will provide an entry to valuable chiral amphetamines which are otherwise not so easily accessed. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03942d

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Enantioselective hydrogenation of
a,b-disubstituted nitroalkenes†‡
Shengkun Li,*ab Kexuan Huangb and Xumu Zhang*b
Cite this: Chem. Commun., 2014,
50, 8878
Received 23rd May 2014,
Accepted 16th June 2014
DOI: 10.1039/c4cc03942d
www.rsc.org/chemcomm
The first highly chemo- and enantioselective hydrogenation of
a,b-disubstituted nitroalkenes was accomplished with rhodium/
JosiPhos-J2 as a catalyst, with the yield and enantioselectivity of
up to 95% and 94%, respectively. The a-chiral nitroalkanes will
provide an entry to valuable chiral amphetamines which are other-
wise not so easily accessed.
Scheme 1 Transformation of nitroalkenes to chiral nitroalkanes.
Enantioenriched nitroalkanes are valuable intermediates in syn-
thetic chemistry. It can be further converted to other versatile
building blocks through simple transformation.1 The ‘‘chameleon’’
property renders chiral nitroalkanes valuable to the synthesis of
pharmaceuticals, agrochemicals and biologically interesting natural
compounds. With nitroalkenes as starting materials, considerable
progress in biocatalysis,2 transfer hydrogenation,3 conjugate addi-
tions1a,4 as well as asymmetric hydrogenation5 has been made for
the synthesis of b-branched nitroalkanes. These tactics seem not to
be so efficient or were not reported for the synthesis of a-branched
nitroalkanes. In this protocol, synthesis of a-chiral nitroalkanes via
asymmetric hydrogenation will be disclosed (Scheme 1).
Fig. 1 Structures of drugs and natural products.
The development of reliable methodologies for the preparation
of enantiopure a-branched nitroalkanes is an attractive topic for
the synthesis of chiral b-arylisopropylamines(amphetamines), been devoted to develop biocatalytic systems to furnish a-branched
which is the core scaffold of many top best-selling drugs world- nitroalkanes.2a,d,10 Only until recently, Hummel and Groer disclosed
¨
wide6 or natural products7 (Fig. 1).
an elegant procedure catalyzed by an ene reductase, which
Chiral b-arylisopropylamines are conventionally produced produced the enantioenriched a-chiral nitroalkanes with the enan-
through laborious chiral resolution or stoichiometric chiral auxiliary tiomeric excesses of up to 95%.11
assisted transformation.8 Though great progress has been made
Considering the environmental compatibility and atom
in hydrogenation of b-arylenamides to b-aryl-isopropylamines, economy, direct asymmetric hydrogenation of a,b-disubstituted
these approaches suffer from metal-catalysis, multi-steps, and E/Z nitroalkenes with H2 will be a compelling method for the synthesis
isomeric mixtures in synthesis of substrates.9 Intensive efforts have of chiral b-arylisopropylamines. The trans-nitroalkenes are easily
accessible starting from readily available and economically attrac-
a College of Plant Protection, Nanjing Agricultural University, Nanjing 210095,
P.R. China. E-mail: saintkun001@njau.edu.cn; Tel: +86-025-84399753
b Department of Chemistry and Chemical Biology, and Department of
Pharmaceutical Chemistry, Rutgers, the State University of New Jersey,
Piscataway, New Jersey 08854, USA. E-mail: xumu@rci.rutgers.edu
† Dedicated to Professor Wenjun Wu on the occasion of his 70th birthday.
‡ Electronic supplementary information (ESI) available: Experimental procedures
and analytical data. See DOI: 10.1039/c4cc03942d
tive aldehydes and nitroalkanes through the Henry reaction
followed by dehydration in one pot with high yields.2d,10c The
asymmetric hydrogenation of a,b-disubstituted nitroalkenes have
met limited progress so far, to the best of our knowledge, only
asymmetric hydrogenation of (E)-(2-nitroprop-1-en-1-yl)benzene
1a was reported with the maximum enantioselectivity of 58%
under rather harsh conditions.12 Herein, we will document that
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Table 1 Optimization for asymmetric hydrogenation of nitroalkene 1aa
Product distributioni
Entry
Ligand
Conv.i
1a
2a
3
ee of 2a j
1
2
3
4
5
6
7
8
TangPhos
Ph-BPE
BDPP
Phanephos
Binap
MeO-Biphep
C3-tunephos
Et-f-ketalphos
Josiphos-J1
Walphos
Mandyphos
TaniaPhos
Chenphos
Josiphos-J1
Josiphos-J2
Josiphos-J3
Josiphos-J4
Josiphos-J2
Josiphos-J2
Josiphos-J2
Josiphos-J2
Josiphos-J2
Josiphos-J2
Josiphos-J2
95
92
6
32
84
15
5
495
495
7
12
59
29
42
24
21
0
8.5
100
63.8
5.5
0
27.7
0
0
15.9
0
7
35
40
33
18
7
NA
8
30
42
21
59
4
35
70
33
NA
87
44
NA
NA
49
86
86
94.5
67.7
15.9
84.7
495
0
32.3
68.2
15.3
o5
Scheme 2 Challenges of hydrogenation of a,b-disubstituted nitroalkenes.
100
100
7.3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
the Rh/JosiPhos-J2 catalyst enables the first highly enantioselective
hydrogenation of a,b-disubstituted nitroalkenes, providing a-chiral
nitroalkanes with good enantioselectivity of up to 94%.
9
0
10
11
12
13
14
15
16
17
18b
19b,c
20b,d
21b,e
22b,f
23g
24h
92.6
88.1
40.8
71.2
57.7
76.2
79.6
495
62.3
56.5
495
495
68.3
41.9
0
11.9
59.2
28.8
42.3
23.8
20.4
o5
In our continuing efforts on the transition-metal-catalyzed
asymmetric hydrogenation of nitroalkenes, our group reported
the first asymmetric hydrogenation of b,b-disubstituted
nitroalkenes with a rhodium catalyst and a base assisted
practical asymmetric reduction (eqn (1), Scheme 2).5 However,
these established methodologies were not readily translated
from b,b-disubstituted nitroalkenes to a,b-disubstituted
nitroalkenes, with poor enantioselectivity or low reactivity even
at elevated temperature and higher catalyst loading (see ESI‡).
Several critical concerns have been postulated or recognized
that have thus far hindered the overall efficiency in asymmetric
hydrogenation of a,b-disubstituted nitroalkenes (eqn (2), Scheme 2).
(1) The high acidity of the CH adjacent to the nitro group will make
the resulting products to racemize easily.10b (2) The protonation
step of a-carbon is necessary for building up the stereocenter,
while it is postulated to proceed in a non-chiral environment
o5
38
37.7
43.5
o5
43
o5
o5
32
58
495
o5
31.7
58.1
100
a
Unless otherwise mentioned, all reactions were carried out with a
Rh(nbd)2BF4/ligand/substrate ratio of 1 : 1.1 : 20, under 80 atm H2 in
b
DCM, at 50 1C for 24 h; 14–22: 60 atm, 40 1C, 36 h. Rh(nbd)2SbF6 as a
c
d
metal precursor. With 10% NEt3 as an additive. With 10% PTSA as
following chiral catalyst adduct elimination.3a (3) Binding of an additive. With 10% L-CSA as an additive. With 50% CH3NO2 as
e
f
g
h
an additive. 60 atm, 60 1C, 24 h, 5% Rh(nbd)2SbF6. 50 atm, 70 1C,
coordinating groups to metals will synergize with catalysts to
enhance the activity and stereocontrol, while the four-membered
i
36 h, 2.5% Rh(nbd)2SbF6. The conversion and the molar ratio of
product distribution were determined by 1H NMR of the crude product
j
ring chelates from the a,b-disubstituted nitroalkenes are presum- of hydrogenation. Enantiomeric excess was determined by HPLC on
ably less stable because of ring strain.13 (4) Nef reaction, over
a chiral phase. NA: not available; Cy: cyclohexyl; tBu: tert-butyl; DCM:
dichloromethane.
reduction and isomerization of nitroalkenes will compete with the
desired stereogenic transformation.12,14
Hence, exploration and progress of the asymmetric hydro- the a-chiral nitroalkane in moderate yield and enantioselec-
genation of a,b-disubstituted nitroalkenes will be of both tivity (entry 4, Table 1). Besides the negative effect of electron-
fundamental and practical importance. With nitroalkene 1a donating substituents of the atropisomeric biaryl-bisphosphine
as a model substrate, our initial attempts with the previous ligands, the decrease in dihedral angle will lead to similar
catalysts were not so satisfying. In an effort to settle this results on both reactivity and selectivity (entries 5–7, Table 1).
challenging problem, a large and diverse set of chiral ligands The illuminating results were achieved when ferrocene-based
were evaluated through a chiral toolbox approach, including ligands were chosen, careful screening protrudes the JosiPhos
both monodentate and bidentate ligands and multitudinous type ligands (entry 9, Table 1). The reactivity and enantioselec-
subspecies thereof. With the conversion o5%, the catalysts of tivity showed distinct variation with the steric and electronic
rhodium with monodentate phosphine ligands seemed not to factors of the substituents on the phosphorus atom of the
be so efficient (see ESI‡). Some representative results for JosiPhos ligands, while no clear trends could be concluded
bidentate phosphorus ligands of structure-diversity are shown (entries 9–17, Table 1, for more information see ESI‡). Con-
in Table 1. The rigid P-chiral TangPhos only demonstrated poor sidering enantioselectivity and reaction efficiency, JosiPhos-J2
enantioselectivity (7%), albeit with full conversion (entry 1, was chosen as the optimal ligand for further optimizÀation of
Table 1). 30% of the Nef product was detected in the Ph-BPE other parameters. Replacement of the counterion BF4 by the
reaction system (entry 2, Table 1), and the conversion dropped bulky and weak coordinating SbF6À improved the enantioselec-
dramatically when it was replaced by BDPP (6% conversion, tivity to 87%, which is already high for this type of reaction
entry 3, Table 1). The planar chiral ligand PhanePhos furnished (entry 18, Table 1).
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Since the efficiency was still not so satisfying (38% conver-
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sion), a diverse set of additives, including bases, acids and
nitroethane, were evaluated. Unfortunately, no promising results
were achieved; the acids can deactivate the catalyst thoroughly
(entries 20–23, Table 1). After fine tuning and systematic opti-
mization of reaction parameters, the nitroalkene 1a was hydro-
genated with 86% ee in full conversion (entry 25, Table 1).
To establish the scope and limitations of this novel catalytic
system, a broad range of a,b-disubstituted nitroalkenes were
tested under the optimized reaction conditions. Notably, an
array of meta and para substituted nitroalkenes (monosubsti-
tuted or disubstituted with electron-withdrawing or electron-
donating groups) are amenable to this catalytic system to furnish
the optically active nitroalkanes in useful enantioselectivities
(2a–2k, Scheme 3). Most of the nitroalkenes were hydrogenated
enantioselectively independent of the type of substituent. The
sharp deterioration in the ee value was detected in the hydro-
genation of 1h, may be due to the distinctive physicochemical
properties of fluorine. This process can proceed smoothly keep-
ing the nitro group on the phenyl ring intact (2k, Scheme 3).
A dramatic drop in both yield and ee occurs when the ortho-
chloro nitroalkene was used (2l, Scheme 3). This may be
ascribed to the competing Nef reaction and the unstable
coplanar arrangement of electron delocalized nitro groups,
the CQC bond and the aromatic p-system.
Scheme 4 Synthesis of chiral amphetamines.
and 85% ee, respectively (2m, Scheme 3). Though the a,b-
dialkyl-substituted nitroalkene demonstrated low reactivity, it
can also furnish chiral nitroalkane in useful enantioselectivity
(2n, Scheme 3). With the more hindered ethyl group at the
a-position of the a,b-disubstituted nitroalkenes, the substrates
can also be hydrogenated with moderate to good enantioselec-
tivities (2o–2r, Scheme 3).
A wide array of heterocyclic substrates are also tolerated
(2s–2u, Scheme 3). Notably, the furyl, thiophenyl-nitroalkenes
were successfully hydrogenated with the enantioselectivity of
up to 94% (2t) and 92% (2u), respectively.
To further demonstrate the utility of this hydrogenation
procedure, we turned our attention to scale-up hydrogenation
(1.63 g scale for 1a) and drug synthesis. Valuable chiral amphe-
tamine can be accessed from 2a directly with a good ee value
and excellent yield (84% ee and 90% yield, Scheme 4). It can
also be further converted to other drugs easily through simple
transformation,15 for example, the condensation of ampheta-
mine with Boc-Lys(2-Cl-Z)-OH will give the N-protected Vyvanse
in high yield.
It should be noted that 2-naphthylnitroalkene 1m will
furnish the enantioenriched nitroalkane with 86% conversion
In conclusion, we have accomplished the first rhodium
catalyzed highly chemo- and enantioselective hydrogenation
of a variety of a,b-disubstituted nitroalkenes. The nitroalkane
products provide entry to valuable chiral amphetamine and its
derivatives, which are otherwise not so easily accessed in a few
steps in view of atom economy and cost-efficiency. Given the
relatively high catalyst loading, further work should be carried
out with the aim of better understanding the hydrogenation
mechanism of this substrate, and ultimately developing cata-
lytic systems that can lead to further improvement in reactivity
as well as enantioselectivity.
This research was financially supported by National Insti-
tutes of Health (GM58832) and the Scientific Research Founda-
tion for introduced talent of Nanjing Agricultural University for
S. Li (020-80900205).
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