Nitroolefins as a nucleophilic component for highly stereoselective aza Henry reaction under the catalysis of chiral ammonium betaines

Article abstract of DOI:10.1002/chem.201201259

Vinylogous nitronate was successfully generated from β,β- disubstituted nitroolefins for achieving a highly regio-, diastereo-, and enantioselective aza Henry reaction under the influence of chiral ammonium betaine of type 1 as an organic-base catalyst. The present approach greatly expands the synthetic utility of nitroolefins in the development of carbon-carbon bond-forming reactions (see scheme). Copyright

Full text of DOI:10.1002/chem.201201259

DOI: 10.1002/chem.201201259
Nitroolefins as a Nucleophilic Component for Highly Stereoselective Aza
Henry Reaction under the Catalysis of Chiral Ammonium Betaines
Daisuke Uraguchi, Keigo Oyaizu, and Takashi Ooi*[a]
Catalytic stereoselective syntheses of nitro compounds are
recognized as an important process to provide valuable
chiral-building blocks for the construction of biologically
relevant, complex organic molecules.[1] This is largely due to
the utility of the nitro group as a masked functionality to be
transformed to a variety of other useful functional groups,
which is well described by the term “synthetic chameleon”.[2]
Accordingly, numerous efforts have been devoted to devel-
op reliable methodologies for the catalytic stereocontrolled
assembly of nitro-containing carbon frameworks. In this en-
deavor, the addition of carbon or heteroatom nucleophiles
to nitroolefins featuring a highly electron-deficient conju-
gate system has been extensively studied, demonstrating the
versatility of nitroolefins as a reactive Michael acceptor.[3] In
sharp contrast, there are few known applications of nitroole-
fins as a nucleophilic component.[4–6] Although the Morita–
Baylis–Hillman (MBH) reaction is one of the representative
bond-forming processes for utilizing an electron-deficient
conjugate system as a nucleophile,[7] it is difficult to accom-
modate nitroolefins by avoiding concomitant polymerization
because of their extremely electrophilic character; hence,
only limited examples of nonstereoselective reactions have
appeared in literatures.[4] In 2007, Shi and co-workers re-
ported a new approach to overcome this problem by intro-
ducing b,b-disubstituted nitroolefins as a requisite nucleo-
phile.[5a] The steric hindrance created by the additional b-
alkyl substituent would be instrumental in suppressing unde-
sired homooligomerization. Thus, Lewis base (LB)-catalyzed
double Michael reaction between b,b-disubstituted nitroole-
fins and enones or enoates was realized in moderate-to-
good chemical yield albeit with poor diastereoselectivity.
Following this stimulating disclosure, b,b-disubstituted nitro-
olefins 2 have been used for achieving enantioselective aza
MBH-type reactions with bifunctional thiourea catalyst.[6]
This study by Xu et al. proposed that another role of a b-
alkyl substituent would be to effectively deliver a proton to
the intermediary amide ion II in an intramolecular fashion
to give the final product III with concurrent regeneration of
Scheme 1. Two possible reaction routes for the aza Henry reaction of b,b-
disubstituted nitroolefins 2 with N-protected imines.
the LB catalyst (Scheme 1, route A). Apart from these LB-
catalyzed protocols, which involve the generation of nitro-
nate I by virtue of the electrophilic character of nitroolefins,
there is another possible way of employing this class of ni-
troolefins as a nucleophile (Scheme 1, route B). Considering
the relatively high acidity of the g-proton of 2, treating 2
with an appropriate base would afford vinylogous nitronate
IV.[8,9] However, experimental and computational studies
conducted by Shiꢀs group suggested that the addition of ni-
tronate IV to enones would be energetically unfavorable,[5a]
and the synthetic potential of this approach has been largely
unexplored, leaving the intrinsic reactivity at a- and g-posi-
tion of the extended nitronate virtually unknown. Herein,
we communicate the first example of the latter reaction
system (Scheme 1, route B) by establishing an aza Henry re-
action[10] of nitronate IV with high regio-, enantio-, and dia-
stereoselectivity under the influence of the chiral ammoni-
um betaine of type 1 as a base catalyst.[11,12]
Initially, axially chiral ammonium betaine 1a was applied
as catalyst to the reaction of b,b-disubstituted nitroolefin 2a
with N-tert-butoxycarbonyl (N-Boc) imine 3a in toluene
containing molecular sieves (MS; 4 ꢁ) at À308C. After 24 h
of stirring, the expected aza Henry adduct 4aa was indeed
obtained in 77% isolated yield with almost complete regio-
and diastereoselectivities (Table 1, entry 1). Fortunately, the
enantiomeric excess (ee) of anti-4aa was determined to be
97%. When the more nucleophilic catalyst 1b,[13] which
lacks a substituent at the 3-position of the aryloxylate
[a] Dr. D. Uraguchi, K. Oyaizu, Prof. Dr. T. Ooi
Department of Applied Chemistry
Graduate School of Engineering, Nagoya University
Furo-cho B2-3ACHTUNGTRENNUNG(611), Chikusa, Nagoya 464-8603 (Japan)
Fax : (+81)52-789-3338
E-mail: tooi@apchem.nagoya-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201259.
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Chem. Eur. J. 2012, 18, 8306 – 8309

COMMUNICATION
Table 1. Optimization of catalyst structure and determination of the re-
action pathway for the ammonium-betaine-catalyzed stereoselective aza
Henry reaction.[a]
2a’ in the crude residue was determined to be 6.4:1
(Table 1, entry 3), 5.8:1 (Table 1, entry 4), and 4.0:1
(Table 1, entry 5). Consequently, the aza Henry reaction
proceeded via vinylogous nitronate IV, through which com-
petitive isomerization of the starting nitroolefins took place.
Furthermore, because the treatment of the b-monosubstitut-
ed nitroolefin, such as 1-nitrohept-1-ene, with 3a under the
influence of 1a or 1b in a similar manner led to the forma-
tion of neither an aza MBH adduct nor a polymer of the ni-
troolefin. The possibility of route A involving the initial con-
jugate addition of 1 to 2 could be ruled out, and the pres-
ence of the two b-substituents in 2 appeared to be crucial
for the generation of the requisite nitronate IV. We then
turned our attention to the structural modification of chiral
ammonium betaine 1 for improving the reactivity and selec-
tivity profiles. Although the structures of the aromatic
groups attached to the binaphthyl backbone (Ar1 and Ar2)
had marginal effects on stereoselectivity, 1e possessing two
para-trifluoromethylphenyl substitutions at the 3-positions
of both naphthyl units was identified as an optimal catalyst
in terms of catalytic efficiency (Table 1, entries 1 and 6–8).
Experiments to evaluate the substrate scope of this
unique asymmetric aza Henry protocol revealed the excel-
lent stereocontrolling ability of the chiral ammonium be-
taine 1e (Table 2). With regard to the aromatic imine elec-
trophiles 3, the incorporation of ortho-, meta-, and para-sub-
stituents of different electronic properties was tolerated
(Table 2, entries 1–6), and the heteroaromatic imine 3h de-
rived from 2-furylaldehyde also appeared to be a good can-
didate (Table 2, entry 7). The b-aromatic substituent (R1) of
the nitroolefin nucleophiles 2 could be variable with rigor-
1
t [h]
Yield[b] [%]
dr[c] [anti/syn]
ee[d] [%]
1
2
3
1a
1b
1a
1a
1a
1c
1d
1e
24
24
1
1
1
24
24
24
77
20
38
40
57
87
70
90
>20:1
1:1
97/–
32/26
96/–
96/–
96/–
95/–
96/95
99/–
>20:1
>20:1
>20:1
>20:1
17:1
4[e]
5[f]
6
7
8
>20:1
[a] Unless otherwise noted, reactions were performed with 2a
(0.11 mmol) and 3a (0.10 mmol) in the presence of 1 (2 mol%) in tolu-
ene (0.5 mL) with MS (4 ꢁ) at À308C. See the Supporting Information
for further details. [b] The isolated yields were reported. [c] Diastereo-
meric ratios (dr) were determined by 1H NMR (400 MHz) analysis of
crude aliquot. [d] ee were analyzed by chiral stationary-phase HPLC. Ab-
solute and relative configuration was determined by X-ray crystallo-
graphic analysis after derivatization. See the Supporting Information.
[e] An equimolar mixture of 2a and 2a’ was used instead of pure 2a.
[f] b,g-Unsaturated nitroolefin 2a’ was used instead of 2a.
moiety (Ar2), was used as a catalyst under other-
wise identical conditions, the bond formation oc-
Table 2. Scope of nitroolefins 2 and N-Boc imines 3.[a]
curred sluggishly to afford 4aa in only 20% yield
with low stereoselectivity (Table 1, entry 2).[14] This
intriguing result strongly suggests that 1 functions
as an organic base to catalyze the reaction through
route B and also reveals the importance of Ar2 for
attaining high reactivity and stereoselectivity.
1
R1[2]
Ar[3]
t [h] Yield[b] [%] ee[c] [%] Product[4]
Meanwhile, the H NMR (400 MHz) analysis of the
crude mixture obtained from the initial attempt
with 1a showed that the remaining nitroolefin was
substantially contaminated by nonconjugated 2a’
(2a/2a’ 3.3:1).[15] This observation prompted us to
separately prepare the b,g-unsaturated nitroolefin
2a’ for comparing the initial rate of reactions with
2a, an equimolar mixture of both nitroolefins, and
2a’ as a substrate (Table 1, entries 3–5, respective-
ly). The isolated yield of 4aa, which was deter-
mined after 1 h of stirring, gradually increased as
the content of 2a’ increased, whereas the stereose-
lectivity was retained at the same level. Therefore,
2a’ with acidic a-protons is more frequently con-
verted to the product 4aa, confirming the operation
of base catalysis in the present system. It should be
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
o-F-C6H5
2a o-F-C6H5
3b 24
93
93
99
99
91
99
92
87
96
93
91
90
90
98
96
98
98
98
99
96
98
98
98
98
99
95
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ba
4ca
4da
4ea
4 fa
4ga
2a o-MeO-C6H5 3c 27
2a m-MeO-C6H5 3d 24
2a p-MeO-C6H5 3e 29
2a p-Me-C6H5
2a p-Br-C6H5
2a 2-furyl
2b Ph
3 f 30
3g 23
3h 24
3a 24
3a 18
3a 15
3a 22
3a 25
3a 28
8
9[d]
m-Cl-C6H5 2c Ph
10[d] p-Br-C6H5 2d Ph
11
12
p-Me-C6H5 2e Ph
2-naphthyl 2 f Ph
13[e] Me
2g Ph
[a] Unless otherwise noted, reactions were performed with 2 and/or 2’ (0.11 mmol)
and 3 (0.10 mmol) in the presence of 1 (2 mol%) in toluene (0.5 mL) with MS (4 ꢁ)
at À308C. See the Supporting Information for further details. [b] The isolated yields
were reported. [c] ee were analyzed by chiral stationary-phase HPLC. Absolute and
relative configurations of 4 were assigned by analogy to 4aa. [d] Reaction was con-
ducted with 0.12 mmol of 2. [e] Reaction was performed at À408C. A diastereomeric
noted that isomerization of the nitroACTHNUTRGNEoNUG lefin was
again observed in this trial, and the ratio of 2a to mixture of 4ga was obtained in the anti/syn ratio of 10:1.
Chem. Eur. J. 2012, 18, 8306 – 8309
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T. Ooi et al.
ous relative and absolute stereocontrols (Table 2, entries 8–
12). Moreover, aliphatic nitroolefin, such as 2g, was employ-
able as a nucleophilic component and underwent smooth ad-
dition to 3a at À408C to give 4ga in 90% yield with 95%
ee albeit with a slight loss of the diastereoselectivity
(Table 2, entry 13).
The generality of the present system was further demon-
strated through the application to g-substituted nitroolefins.
For example, reaction of an isomeric mixture of nitroolefin
5 with 3a in the presence of 1e proceeded with similar effi-
ciency to afford the corresponding adduct 6 in an almost ste-
reochemically pure form in 90% yield (Scheme 2). In addi-
tion, excellent levels of diastereo- and enantioselectivity
were also attained with carbocyclic nitroolefin 7 as a sub-
strate.
simple hydrogenation produced a diastereomeric mixture of
the saturated 1,2-diamine derivative 11 containing three
consecutive stereogenic carbon centers without the loss of
enantiomeric excess.
In conclusion, we successfully utilized b,b-disubstituted ni-
troolefins as a synthetically relevant nucleophile through the
generation of the corresponding chiral vinylogous nitronate
under the base catalysis of chiral ammonium betaines. The
reactivity and selectivity of this key intermediate have been
clearly visualized for the first time by achieving a highly
regio-, diastereo-, and enantioselective aza Henry reaction
with N-Boc imines under mild conditions. The present ap-
proach greatly expands the scope of the carbon–carbon
bond-forming processes involving nitroolefins.
Acknowledgements
This work was supported by NEXT program, the Global COE program
in Chemistry of Nagoya University, Program for Leading Graduate
Schools “Integrative Graduate Education and Research Program in
Green Natural Sciences” in Nagoya University, Grants of JSPS for Scien-
tific Research, the Sumitomo Foundation, and the Tatematsu Founda-
tion.
Keywords: asymmetric synthesis
betaine · nitroolefin · organocatalysis
·
azo compounds
·
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Nitroolefins as a Nucleophilic Component for Aza Henry Reaction
COMMUNICATION
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Received: April 13, 2012
Published online: June 1, 2012
Chem. Eur. J. 2012, 18, 8306 – 8309
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8309