Highly diastereo- and enantioselective formal conjugate addition of nitroalkanes to nitroalkenes by chiral ammonium bifluoride catalysis

Article abstract of DOI:10.1002/anie.200602787

(Chemical Equation Presented) A matter of control: A chiral quaternary ammonium bifluoride catalyst in combination with silyl nitronates results in the highly diastereo- and enantioselective formal conjugate addition of nitroalkanes to nitroalkenes (see s

Full text of DOI:10.1002/anie.200602787

Communications
anions of nitroalkanes (nitronates) as prominent Michael
donors.[3] Surprisingly, however, despite its potential use for
the synthesis of optically active 1,3-diamines, carbon–carbon
coupling between nitroalkanes and nitroalkenes is extremely
rare,[4] and catalytic enantioselective systems have so far been
limited to the recent contribution reported by Du and co-
workers[5]. This is partly because of the inherent difficulty of
controlling the addition of nitronate 3 to nitroalkene 4. The
initial product formed is the nitronate 5, which is sufficiently
reactive to also undergo conjugate addition to 4, thus
resulting in a mixture of oligomerization products [Eq. 1].
Asymmetric Catalysis
Our strategy toward overcoming this methodological
deficiency involves the use of chiral ammonium bifluoride
catalysis in combination with silyl nitronates (6, Scheme 1).[6]
The chiral ammonium nitronate 8, generated in situ from 6,
and chiral ammonium bifluoride of type 1[7] or 2 would be
responsible for controlling the relative and absolute stereo-
chemistry in the addition to the nitroalkene 4, to afford the
corresponding chiral nitronate 9 of the stereochemically
defined conjugate adduct. If the reaction of 9 with residual 6 is
DOI: 10.1002/anie.200602787
Highly Diastereo- and Enantioselective Formal
Conjugate Addition of Nitroalkanes to
Nitroalkenes by Chiral Ammonium Bifluoride
Catalysis**
Takashi Ooi, Saki Takada, Kanae Doda, and
Keiji Maruoka*
The conjugate addition of reactive nucleophiles to electron-
deficient alkenes (the Michael addition reaction) is an
important and reliable tool for the construction of highly
functionalized carbon skeletons. Among the various candi-
dates for this bond-forming process, nitro compounds are
particularly attractive because of the strong electron-with-
drawing property of the nitro group and their versatility as a
masked functionality.[1] Indeed, it is well documented that
nitroalkenes serve as excellent Michael acceptors[2] and the
[*] Dr. T. Ooi,[+] S. Takada, K. Doda, Prof. K. Maruoka
Department of Chemistry
Graduate School of Science
Kyoto University
Sakyo, Kyoto, 606-8502 (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[+] Current address:
Department of Applied Chemistry
Graduate School of Engineering
Nagoya University
Chikusa, Nagoya, 464-8603 (Japan)
[**] This workwas partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transformation of
Carbon Resources” from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Selective conjugate addition of silyl nitronates to nitro-
alkenes under chiral ammonium bifluoride catalysis.
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Chemie
Table 1: Screening of the reaction variables in the conjugate addition
faster than its further addition to 4, the requisite chiral
nucleophile 8 would be regenerated along with derivatization
of the desired product 7 as the silyl nitronate 10. This process
would thereby allow the asymmetric formal conjugate
addition of nitroalkanes to nitroalkenes with ideal stoichi-
ometry. Herein, we describe the realization of this hypothesis
by using the N-spiro C2-symmetric chiral quaternary ammo-
nium bifluoride 2b.
reaction of silyl nitronate 6a to b-nitrostyrene (4a), catalyzed by chiral
quaternary ammonium bifluoride.[a]
Entry 6a
(equiv)
Catalyst mol% Solvent Conc. Yield [%] ee[c]
[M]
[%][b]
We began our studies by examining the reaction of
nitropropane-derived silyl nitronate 6a with b-nitrostyrene
(4a) using the chiral quaternary ammonium bifluoride 1a.[7b,c]
When 4a was treated with 6a (1.2 equiv) in the presence of 1a
(2 mol%) in toluene (0.1m substrate concentration) at
À788C, an almost instantaneous consumption of 4a was
observed along with the formation of totally insoluble white
precipitate, and the one-to-one adduct 7a was isolated in only
7% yield. This finding implied the predominant intervention
of the rapid oligomerization process under the reaction
conditions. However, we were encouraged by the fact that 7a
thus obtained was diastereomerically homogeneous and it
was determined to have 58% ee (entry 1, Table 1). We next
screened reaction variables and found initially that switching
the solvent to THF under otherwise similar conditions
significantly augmented the desired pathway to furnish 7a
in 73% yield, although the enantioselectivity decreased to
29% ee (entry 2, Table 1). On the basis of this result, we
evaluated the effect of the catalyst structure mainly on the
enantioselectivity. Although the electron-withdrawing 3,5-
bis(trifluoromethyl)phenyl-substituted 1b[7a,b] exhibited com-
parable chiral efficiency to that of 1a, modification of the 3,3’-
aromatic substituent to the meta-terphenyl-type structure
1c[7] led to a dramatic improvement in selectivity (entries 3
and 4, Table 1). Furthermore, we assembled the chiral
ammonium bifluoride 2a, which consisted of a chiral octahy-
drobinaphthyl subunit, with the expectation that its steric and
electronic effects would help control ste-
1
2
3
4
5
6
7
8
9
1.2
(R,R)-1a
(R,R)-1a
(R,R)-1b
(R,R)-1c
(R,R)-2a
(R,R)-2b
(R,R)-2b
(R,R)-2b
(R,R)-2b
2
toluene 0.1
THF
7
58
29
32
80
89
91
85
91
90
90
73
67
80
78
85
97
97
99
86
2.0
0.04
1
10
(R,R)-2b 0.5
[a] The reaction was carried out at À788C for 1 h using (R,R)-1 or (R,R)-2
as catalyst. [b] Yield of isolated product. The ratio syn/anti was
determined by 1H NMR analysis to be >95:5, which means that the
minor isomer could not be detected by NMR analysis (the authentic
sample of anti isomer was prepared by a literature procedure[4a]). [c] The
enantiopurity of 7a was determined by HPLC analysis on a chiral
stationary phase using hexane-2-propanol as the solvent. The relative
and absolute configurations were assigned by 1H NMR analysis after
derivatization to the corresponding cyclic thiourea and diamide
compounds. For further details, see the Supporting Information.
aromatic nitroalkenes, the reaction efficiency and diastereo-
selectivity were relatively insensitive to the electronic proper-
ties of the aromatic ring, although the presence of electron-
withdrawing substituents seemed to be associated with
slightly lower enantioselectivity (entries 1–4, Table 2). This
protocol proved to be compatible with heteroaromatic nitro-
reoselectivity. Fortunately, the conjugate
Table 2: Stereoselective conjugate addition of silyl nitronates 6 to nitroalkenes 4 catalyzed by chiral
quaternary ammonium bifluoride (R,R)-2b.[a]
addition of 6a to 4a proceeded smoothly
under the influence of 2a in a highly
diastereoselective manner, affording syn-
7a in 78% yield with 89% ee (entry 5,
Table 1). Moreover, introduction of a tri-
fluoromethyl group in the 6,6’ position of
the binaphthyl core of 2b delivered even
higher enantioselectivity (91% ee, entry 6,
Table 1).[8] Here, the use of two equivalents
of silyl nitronate 6a allowed near quantita-
tive production of 7a, and the slight erosion
in enantiomeric excess was recovered by
performing the reaction at a lower substrate
concentration (entries 7 and 8, Table 1). It
should be noted that the catalyst loading
can be reduced to 0.5 mol% without sub-
stantial loss of reactivity and stereoselec-
tivity (entries 9 and 10, Table 1).
Entry R1 (6)
R2 (4)
(R,R)-2b [mol%] Yield [%][b] syn/anti[c] ee [%] [d] Prod.
1
2
3
Et (6a)
p-MeO-C6H4
o-MeO-C6H4 0.5
o-Cl-C6H4
1
99
99
98
>95:5
>95:5
>95:5
91
87
80
7b
7c
7d
0.5
4
0.5
95
>95:5
89
7e
5
6
2
2
92
85
>95:5
>95:5
93
91
7 f
7g
7
8
9
10
c-Hex
CH3(CH2)5
Ph
1
1
1
1
99
93
99
99
>95:5
>95:5
>95:5
82:18
92
76
91
83
7h
7i
7j
Pr (6b)
MeOCH2 (6c) Ph
7k
Having established the optimized con-
ditions,[9] the scope of the reaction was
investigated using silyl nitronate 6a and a
variety of nitroalkenes (Table 2). With
[a] The reaction was carried out using 2 equiv of silyl nitronate 6 in the presence of (R,R)-2b in THF
(0.04m substrate concentration) at À788C for 1 h. [b] Yield of isolated product. [c] Determined by
1H NMR analysis. [d] The enantiopurity of major product syn-7 was determined by HPLC analysis on a
chiral stationary phase using hexane-2-propanol or ethanol as the solvent. c-Hex=cyclohexyl.
Angew. Chem. Int. Ed. 2006, 45, 7606 –7608
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Communications
[3] a) M. Yamaguchi in Comprehensive Asymmetric Catalysis, Vol.3
(Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, chap. 31.2; b) M. Yamaguchi in Comprehensive
Asymmetric Catalysis Supplement 1 (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, Berlin, 2004, p. 151; c) R.
Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini, Chem.Rev.
2005, 105, 933.
alkenes and the corresponding 1,3-dinitro compounds were
obtained in high yield with excellent diastereo- and enantio-
selectivities by employing 2 mol% of 2b (entries 5 and 6,
Table 2). Aliphatic nitroalkenes also appeared to be good
acceptors, further expanding the generality of the substrates
(entries 7 and 8, Table 2). The present method was applicable
to other silyl nitronates derived from simple nitroalkanes,
where eminent catalytic activity and a high level of stereo-
selectivity were attained (entries 9 and 10, Table 2).
The resulting 1,3-dinitro compounds with two consecutive
stereochemically defined stereocenters can be readily con-
verted into the corresponding 1,3-diamines, which are versa-
tile chiral building blocks from synthetic as well as pharma-
ceutical viewpoints.[10] For example, exposure of a mixture of
7a in THF to a hydrogen atmosphere in the presence of a
catalytic amount of Raney Nickel at 458C for 36 h resulted in
the formation of 11 in 75% yield with complete preservation
of the stereochemical integrity (Scheme 2).[11]
[4] For
a fewexamples of non-stereoselective reactions, see:
a) M. D. Alcµntara, F. C. Escribano, A. Gómez-Sµnchez, M. J.
Diµnez, M. D. Estrada, A. López-Castro, S. PØrez-Garrido,
Synthesis 1996, 64; b) R. Ballini, G. Bosica, D. Fiorini, A.
Palmieri, Synthesis 2004, 1938.
[5] S.-F. Lu, D.-M. Du, J. Xu, S.-W. Zhang, J.Am.Chem.Soc. 2006,
128, 7418.
[6] For an account of chiral ammonium fluoride catalysis, see: T.
Ooi, K. Maruoka, Acc.Chem.Res. 2004, 37, 526.
[7] a) T. Ooi, K. Doda, K. Maruoka, J.Am.Chem.Soc. 2003, 125,
2054; b) T. Ooi, K. Doda, K. Maruoka, J.Am.Chem.Soc. 2003,
125, 9022; c) T. Ooi, K. Doda, S. Takada, K. Maruoka,
Tetrahedron Lett. 2006, 47, 145.
[8] When the reaction was quenched with an excess amount of D2O,
approximately 60% of deuterium incorporation was observed at
the C1 methylene center of syn-7a, thereby suggesting the
intervention of a silyl nitronate intermediate of type 10. We
assume that the lowdeuterium incorporation could be ascribed
to the high susceptibility of the silyl nitronate, generated in situ,
to protonation from a small amount of water or methanol.
[9] Although 1.2 equiv of silyl nitronate 6 seemed to be sufficient,
we decided to use 2 equiv of 6 at 0.04m substrate concentration
for further investigations to constantly attain excellent yields.
[10] For selected examples, see: a) C. F. Bigge, J.-P. Wu, J. T.
Drummond, Bioorg.Med.Chem.Lett. 1992, 2, 207; b) G. H. P.
Roos, A. R. Donovan, Tetrahedron: Asymmetry 1999, 10, 991;
Scheme 2. Derivatization of 1,3-dinitroalkane syn-7a into the corre-
sponding 1,3-diamine syn-11.
c) S. E. Denmark, J.-H. Kim, Can.J.Chem.
2000, 78, 673;
d) M. M. Kabat, Tetrahedron Lett. 2001, 42, 7521; e) F. Cohen,
L. E. Overman, J.Am.Chem.Soc. 2001, 123, 10782.
[11] The ee value of syn-11 was confirmed by HPLC analysis after
derivatization to the corresponding cyclic thiourea. See the
Supporting Information.
In conclusion, we have achieved an efficient, highly
diastereo- and enantioselective formal conjugate addition of
nitroalkanes to nitroalkenes by the catalysis with the novel
chiral quaternary ammonium bifluoride 2b in combination
with silyl nitronates. This strategy greatly expands the use of
conjugate addition chemistry involving organonitro com-
pounds and provides a reliable route to optically active 1,3-
dinitro compounds, which are synthetically useful intermedi-
ates for a wide range of valuable 1,3-difunctionalized organic
molecules.
Received: July 13, 2006
Published online: October 18, 2006
Keywords: 1,3-dinitro compounds · asymmetric catalysis ·
.
À
C C coupling · conjugate addition · homogeneous catalysis
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Angew.Chem.Int.Ed. 2005, 44, 612.
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1451; d) M. Terada, H. Ube, Y. Yaguchi, J.Am.Chem.Soc. 2006,
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