Enantioselective aza-Henry reaction using cinchona organocatalysts

Article abstract of DOI:10.1016/j.tet.2005.09.076

The aza-Henry reaction of imines with nitromethane was promoted by cinchona alkaloids and modified cinchona bases to give optically active β-nitroamines. Various N-protected imines were examined as substrates. N-Boc, N-Cbz, and N-Fmoc protected imines gav

Full text of DOI:10.1016/j.tet.2005.09.076

Tetrahedron 62 (2006) 375–380
Enantioselective aza-Henry reaction using
cinchona organocatalysts
a
Luca Bernardi,a Francesco Fini,a Raquel P. Herrera,b Alfredo Riccia, and Valentina Sgarzani
*
aDepartment of Organic Chemistry ‘A. Mangini’, University of Bologna, Viale Risorgimento No 4, I-40136 Bologna, Italy
bUniversidad de Alicante, Dpto. Quimica Organica, Apdo. 99, 03080-Alicante, Spain
Received 5 July 2005; revised 9 September 2005; accepted 16 September 2005
Available online 19 October 2005
Abstract—The aza-Henry reaction of imines with nitromethane was promoted by cinchona alkaloids and modified cinchona bases to give
optically active b-nitroamines. Various N-protected imines were examined as substrates. N-Boc, N-Cbz, and N-Fmoc protected imines gave
the best results in terms of chemical yields and enantioselectivities. After a careful screening of a series of chiral bases, very good
enantioselectivities up to 94% ee were obtained using a cinchona-based thiourea organocatalyst under the optimized reaction conditions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives,9 while Johnston et al. have developed a chiral
bisamidine triflate salt that effects the enantio- and
diastereoselective addition of nitroethane to a range of
electron deficient N-Boc imines.10 More recently Jacobsen
using a new thiourea based bifunctional catalyst was able to
promote the highly stereoselective addition of a range of
nitroalkanes to aromatic N-Boc imines.11
The aza-Henry reaction is a carbon–carbon bond-forming
process, which allows a straightforward entry to a variety of
nitrogen-containing chiral building blocks. Among them
1,2-diamines, a structural motif present in biologically
active natural products, in medicinal chemistry, and as a
core unit in chiral ligands for asymmetric catalysis, can be
obtained by reduction of the nitro group in the b-nitroamine
derivatives,1 whereas a-amino carbonyl compounds can be
generated by means of the Nef reaction.2 As a result of the
importance of this reaction, a considerable effort has been
directed over the last years toward the development of the
catalytic asymmetric version of the aza-Henry reaction.3
Shibasaki et al. have described the enantioselective addition
of nitroalkanes to N-phosphinoyl imines using chiral
ytterbium,4 and aluminum catalysts,5 while Jørgensen
et al. have reported the asymmetric copper-catalyzed
addition to a-iminoesters.6–8 Several drawbacks of the
reactions catalyzed or promoted by metal salts may lie in the
cost and the toxicity of the metal species. To face these
problems, beyond these metal-catalyzed variants, the first
reports of enantioselective organocatalytic aza-Henry
reaction have recently appeared. Takemoto et al. have
reported that the aza-Henry reaction of N-phosphinoyl
imines with nitroalkanes can be promoted by chiral
thiourea bearing an N,N-dimethylamino group leading
with moderate enantioselectivities to b-nitroamine
In a recent paper, we described a new metal- and solvent-
free procedure for the aza-Henry reaction organocatalyzed
by a nitrogen-contaning superbase such as 1,1,3,3-tetra-
methyl guanidine (TMG).12 Herein, we present an extensive
investigation on the effectiveness of chiral nitrogen-
containing bases as organocatalysts in promoting reactivity
and asymmetric induction in the aza-Henry reaction of
differently N-protected imines.
2. Results and discussion
The groups bound at nitrogen of imines are not fully
innocent groups since besides protecting the C]N moiety
they can greatly affect its stability and electrophilicity.
Therefore, despite the considerable advances made in the
field of the aza-Henry reaction there remain limitations to its
general applicability. To tackle the goal of envisaging the
optimized reaction conditions under which differently
protected imines can undergo the aza-Henry reaction in
the presence of chiral bases and to prepare the ground for the
asymmetric version of this reaction, a range of possible
benzaldehyde imine candidates 1a–f were synthesized and
screened (Scheme 1).
Keywords: Organocatalysis; Imines; Nitromethane; b-Nitroamines; Aza-
Henry reaction; Cinchona alkaloids; Enantioselectivity.
Corresponding author. Tel.: C39 51 2093635; fax: C39 51 2093654;
e-mail: ricci@ms.fci.unibo.it
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.076

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L. Bernardi et al. / Tetrahedron 62 (2006) 375–380
and ee (entry 8). We speculated that the reaction on an
electron rich imine can proceed efficiently only if the imine
is activated by protonation with a Brønsted acid such as
TFA.15
On changing the nature of the organocatalysts, cinchona
alkaloids CD and CN0 not bearing any oxygen-based
substituent at position 6 in the quinoline ring were found
to afford (entries 12 and 13) the desired adduct 2a in poor
yields and with enantioselectivities significantly lower than
those bearing a 60-methoxyquinoline moiety. Next, the
influence of modifications on the natural cinchona bases
reported in Figure 1 was studied using Cbz-, Boc-, and
Fmoc- imines 1a–c, which had shown the most promising
results in the previous screening.
Scheme 1.
Inspired by previous work,13 we focused at first on the use of
chiral bases directly accessible from the chiral pool such as
cinchona alkaloids, as organocatalysts for this reaction.14
The b-nitroamines 2a–g were obtained (Table 1) in fairly
good yields with moderate enantioselectivities from Cbz-,
Boc-, and Fmoc- N-protected benzaldehyde imines 1a–c in
the presence of quinine (QN) (entries 1–4) and of quinidine
(QD) (entries 10 and 11). In the case of the (diphenylphos-
phinoyl) DPP-, Ts-, and t-BuCO- benzaldehyde imines
1d,e,g a drop of the ee was noticed (entries 5, 6, and 9)
accompanied in the case of the former by a sizeable
decrease in the chemical yield. Even more disappointing
were the results with (p-methoxyphenyl) PMP imine 1f,
which gave even under forcing conditions (entry 7) poor
conversion and no ee at all. However, by running the
reaction in the presence of 20% TFA a significant
improvement was observed in terms both of conversion
As shown in Table 2, unlike the catalytic efficiency shown
by QN catalyst (entry 1), derivatives II and V, in which the
OH of the quinine moiety has been protected via acetylation
or carbamate formation, and derivative III with the
alcoholic function replaced by a benzamido moiety, did
not give rise to the formation of the desired adducts in
significant yields (entries 2, 3, and 9). Neither the presence
of a newly formed NH bond in III and V seemed to convey
to these modified cinchona alkaloids any catalytic activity.
Modest catalytic efficiency, accompanied by moderate
enantioselectivity, was observed (entry 4) on the other
hand in the case of the conformationally more rigid catalyst
Table 1. Results from the screening of various imines 1a–g using unmodified cinchona alkaloids as catalystsa
Entry
Imine
PG
Adduct
Catalyst
Conversion (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1d
1e
1f
Cbz
Cbz
Boc
2a
2a
2b
2c
2d
2e
2f
QN
QN
QN
QN
QN
QN
QN
QN
QN
QD
QD
CN
CD
O95
90
O95
O95
50
53
61d
51
48
12
30
rac
40
27
52
55
25
40
Fmoc
DPP
Ts
PMP
PMP
t-BuCO
Fmoc
Cbz
O95
10e
1f
2f
O95e,f
O95
O95
80
9
1g
1c
1a
1a
1a
2g
2c
2a
2a
2a
10
11
12
13
Cbz
Cbz
15
15
a Unless noted, reactions were run at 20 8C, for 18 h in toluene (0.1 M).
b Determined by 1H NMR spectroscopy.
c Determined by chiral stationary phase HPLC.
d Reaction performed in mesitylene as the solvent.
e Reaction performed in CH3NO2 (0.25 M).
f
Reaction performed in the presence of TFA (20 mol%).

L. Bernardi et al. / Tetrahedron 62 (2006) 375–380
377
Figure 1. Modified cinchona bases screened for the aza-Henry reaction using imines 1a–c.
IV bearing a phenolic moiety, which could eventually
provide a site for hydrogen bonding.16 To explore the
influence, in terms of catalytic efficiency and enantioselec-
tivity, of the quinine-epiquinine change,17 epiquinine I
catalysed addition of nitromethane to the N-Boc protected
imine 1b was examined. Even though the conversion in the
reaction was lower, the comparable enantioselectivities
(compare entries 7 and 8) suggested that the proper
conformation of the cinchona derivatives as such may not
be crucial in the case for successful catalysis. Within the
range of enantioselectivities observed, the best results were
obtained with catalysts bearing methoxy and hydroxy
functionalities. These findings prompted us to apply to the
aza-Henry reaction under study the recently reported
bifunctional cinchona-based catalysts VI and VII bearing
a stronger Lewis acid thiourea moiety.18 By running the
reaction with quinine-derived catalyst VI under the standard
conditions adducts 2a and 2b were obtained (entries 5 and
11) in satisfactory isolated yields and with ee’s up to 76%,
whereas also in line with the findings regarding the
asymmetric addition of nitromethane to trans-chalcone,18
organocatalyst VII with the natural configuration, derived
from epiquinine turned out to be much less efficient (entry
10). Next, the influence of two experimental parameters
(temperature and concentration) was evaluated using the
most efficient catalyst VI. Very good levels of enantios-
electivity were observed on lowering the temperature
(entries 6, 11–13) and at K24 8C with an increase of the
imine concentration to 0.2 M, adducts 2b and 2c were
obtained (entries 15 and 16) with up to 90% ee. Adduct 2b
in Table 2 was determined to have the (S) configuration by
comparison with the literature data.10,11
Table 2. Effect of modified cinchona alkaloid catalysts I–VII and optimisation of reaction conditionsa
Entry
Imine
PG
Adduct
Catalyst
T (8C)
t (h)
Conversion
(%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Fmoc
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2c
QN
II
V
20
20
20
20
18
120
120
120
22
22
18
18
120
18
18
20
20
23
18
43
O95
!10
!10
20
53
—
—
37
61
84
51
56
—
19
76
81
86
85
88
90
IV
VI
VI
QN
I
III
VII
VI
VI
VI
VI
VI
VI
20
46d
K24
20
20
20
20
20
0
K24
K24
K24
K24
64d
O95
45
9
!10
30
10
11
12
13
14
15
16
60d
58d
52d
63d,e
72d,f
60d,f
a Unless noted, reactions were run 0.1 M in toluene.
1
b Determined by H NMR spectroscopy.
c Determined by chiral stationary phase HPLC.
d Yield of product isolated after silica gel chromatography.
e Reaction (0.05 M).
f
Reaction (0.2 M).

378
L. Bernardi et al. / Tetrahedron 62 (2006) 375–380
Table 3. Scope of the aza-Henry reaction using imines 1h–o and catalyst VI
Entry
Ar
PG
Imine
Adduct
t (h)
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
1-Napht
2-Napht
2-Napht
4-ClC6H4
4-ClC6H4
2-BrC6H4
2-BrC6H4
4-MeOC6H4
2-Thienyl
2-Furyl
Boc
Boc
Boc
Boc
Cbz
Boc
Boc
Boc
Boc
Boc
Boc
1h
1i
1i
1j
1k
1l
2h
2i
2i
2j
2k
2l
20
23
38
68
45
24
72
45
40
40
48
87
95
82
77
58
66
82
65
50
70
58
88
85
94c
94
90
80
88c
82
82
44
63c
1l
2l
1m
1n
1o
1o
2m
2n
2o
2o
9
10
11
2-Furyl
a Yield of product isolated after silica gel chromatography.
b Determined by chiral stationary phase HPLC.
c Reaction performed at K40 8C.
To establish the generality of this reaction in substrate scope
we finally examined the aza-Henry reaction with represen-
tative N-Boc imines under catalysis by VI and the results are
reported in Table 3. The reaction appears tolerant with
respect to the nature of the imine and the benefits of catalyst
VI extend over a wide range of substrates. The desired
adducts were isolated in satisfactory to good yields
and synthetically useful levels of enantioselectivity, with
1- and 2-naphthaldehyde-derived imines 1h–i (entries 1–3)
and with benzaldimine derivatives 1j–m bearing both
electron donating and electron withdrawing substituents
(entries 4–8). The good results obtained using the Cbz-
protected imine 1k further confirm the tolerance of this
catalytic reaction to different N-acyl protecting groups
(entry 5). Among the aromatic heterocyclic aldimines, the
2-thiophenecarboxyaldehyde derived imine 1n (entry 9)
gave better results with respect to the oxygenated analogue
1o (entry 10 and 11).
4. Experimental
4.1. General methods
All reactions were carried out in test tubes. 1H and 13C NMR
spectra were measured on a Varian AS 400 spectrometer
running at 400 and 100 MHz, respectively, in CDCl3 as the
solvent. Chemical shifts were reported in the d scale relative
to residual CHCl3 (7.26 ppm) for 1H NMR and to the central
line of CDCl3 (77.0 ppm) for 13C NMR. Mass spectra were
recorded on a micromass LCT spectrometer using electro-
spray (ESC) ionisation techniques. Flash column chroma-
tography (FC) was carried out using Merck silica gel 60
(230–400 mesh). Optical rotations were measured on a
Perkin-Elmer 241 polarimeter at 22 8C. The enantiomeric
excess (ee) of the products was determined by chiral
stationary phase HPLC (Daicel Chiralpak AD-H). Melting
points are uncorrected. Imines 1a,c,k,19 1b,h–j,l–o,20 as
well as catalyst VI18 were prepared following literature
procedures.
Any insight about the exact nature of the stereochemical-
determining catalyst-substrate complex would be premature
at this time and different mechanistic scenarios can be
considered for this catalytic transformation. However, it is
clear from these experiments that cinchona-bases herein
studied and particularly thiourea derivatives, which are
known to bind to and modulate the reactivity of nitronate
anions,9,18 are likely to act as bifunctional organocatalysts,
but the role in activating the nitroalkane or in the dual
activation of both reaction partners still remains obscure.
4.2. Optimized general procedure for the catalytic
enantioselective aza-Henry reaction
In a test tube, to a cooled (K24 8C) solution of the imine 1
(0.1 mmol) and catalyst VI (11.9 mg, 0.02 mmol) in toluene
(500 mL), nitromethane (27 mL, 0.5 mmol) was added in one
portion. The test tube was placed in a freezer at K24 8C for
the time reported in Tables 2 and 3, then the products 2 were
obtained by FC on silica gel (CH2Cl2).
3. Conclusion
4.2.1. 2-Nitro-1-phenylethyl carbamic acid benzyl ester
(2a). Following the general procedure, compound 2a was
obtained as a yellow solid in 64% yield. The ee of the
product was determined by HPLC using a Daicel Chiralpak
AD-H column (n-hexane/i-PrOHZ80:20, flow rate
0.75 mL/min, tmajorZ17.1 min; tminorZ24.9 min). Rf 0.41
(n-hexane/EtOAc, 7:3); mp 67–70 8C; 1H NMR d 4.65 (dd,
JZ4.6, 12.6 Hz, 1H), 4.72–4.88 (br s, 1H), 5.04 (s, 2H),
5.33–5.42 (br s, 1H), 5.46–5.57 (br s, 1H), 7.17–7.35 (m,
10H); 13C NMR d 53.2, 67.4, 78.6, 126.3, 128.2, 128.4,
In summary, we have developed a highly enantioselective
organocatalyzed aza-Henry reaction using nitromethane and
a range of aromatic and heteroaromatic differently protected
imines. This new system will nicely complement the very
few examples of organocatalyzed aza-Henry reactions
reported to date. Further investigations into the mechanism
and use of new organocatalysts for this reaction are
underway and will be reported in due course.

L. Bernardi et al. / Tetrahedron 62 (2006) 375–380
379
1
128.6, 128.9, 129.2, 135.8, 136.4, 155.4; ESIMS m/z 323
[MCNaC]; [a]D22 C5 (c 0.348, CHCl3), 84% ee.
0.68 (n-hexane/EtOAc, 7:3); mp 128–131 8C; H NMR d
1.44 (s, 9H), 4.68 (dd, JZ5.0, 12.6 Hz, 1H), 4.76–4.9 (br s,
1H), 5.28–5.40 (br s, 2H), 7.23–7.27 (m, 2H), 7.34–7.37 (m,
2H); 13C NMR d 28.2, 52.2, 78.6, 80.9, 127.7, 129.4, 134.6,
135.4, 154.6; ESIMS m/z 323 [MCNaC]; [a]D22 C20
(c 0.790, CHCl3), 94% ee.
4.2.2. (S)-2-Nitro-1-phenylethyl carbamic acid t-butyl
ester (2b). Following the general procedure, compound 2b
was obtained as a white solid in 72% yield. The ee of the
product was determined by HPLC using a Daicel Chiralpak
AD-H column (n-hexane/i-PrOHZ95:5, flow rate 0.75 mL/
min, tmajorZ36.0 min; tminorZ38.2 min). [a]2D2 C14
4.2.7. 1-(p-Chlorophenyl)-2-nitroethyl carbamic acid
benzyl ester (2k). Following the general procedure,
compound 2k was obtained as a yellow oil in 58% yield.
The ee of the product was determined by HPLC using a
Daicel Chiralpak AD-H column (n-hexane/i-PrOHZ90:10,
1
(c 0.578, CHCl3), 88% ee. The H and 13C NMR spectra
and mp are consistent with values previously reported in the
literature.10
flow rate 0.75 mL/min, tmajorZ36.7 min; tminor
Z
59.0 min). Rf 0.45 (n-hexane/EtOAc, 7:3); 1H NMR d
4.68 (dd, JZ5.1, 12.7 Hz, 1H), 4.76–4.89 (br s, 1H), 5.10 (s,
2H), 5.36–5.45 (br s, 1H), 5.63–5.71 (br s, 1H), 7.20–7.41
(m, 9H); 13C NMR d 52.6, 67.5, 78.3, 127.7, 128.4, 128.6,
128.9, 129.4, 129.9, 134.8, 135.7, 155.3; ESIMS m/z 357
[MCNaC]; [a]D22 C8 (c 0.160, CHCl3), 90% ee.
4.2.3. (9-H-Fluoren-9-yl)methyl 2-nitro-1-phenylethyl-
carbamate (2c). Following the general procedure, com-
pound 2c was obtained as a white solid in 60% yield. The ee
of the product was determined by HPLC using a Daicel
Chiralpak AD-H column (n-hexane/i-PrOHZ80:20, flow
rate 0.75 mL/min, tmajorZ23.7 min; tminorZ42.3 min). Rf
1
0.51 (n-hexane/EtOAc, 7:3); mp 148–150 8C; H NMR d
4.20 (t, JZ6.6 Hz, 1H), 4.38–4.62 (br s, 2H), 4.62–4.94 (br
s, 2H), 5.36–5.60 (br s, 2H), 7.22–7.64 (m, 11H), 7.66 (d,
JZ7.6 Hz, 2H); 13C NMR d 47.1, 53.1, 67.1, 78.4, 120.0,
124.9, 126.3, 127.1, 127.8, 128.8, 129.3, 136.4, 141.3,
143.6, 155.4; ESIMS m/z 411 [MCNaC]; [a]D22 C11 (c
0.675, CHCl3), 90% ee.
4.2.8. 1-(o-Bromophenyl)-2-nitroethyl carbamic acid
t-butyl ester (2l). Following the general procedure,
performing the reaction at K40 8C, compound 2l was
obtained as a white solid in 82% yield. The ee of the product
was determined by HPLC using a Daicel Chiralpak AD-H
column (n-hexane/i-PrOHZ90:10, flow rate 1 mL/min,
tmajorZ18.4 min; tminorZ12.9 min). Rf 0.60 (n-hexane/
EtOAc, 7:3); mp 130–133 8C; 1H NMR d 1.43 (s, 9H), 4.72–
4.92 (br s, 2H), 5.64–5.76 (br s, 2H), 7.20 (dt, JdZ8.0 Hz,
JtZ4.5 1H), 7.34 (d, JZ4.2 Hz, 2H), 7.59 (dt, JdZ7.9 Hz,
JtZ0.9 Hz, 1H); 13C NMR d 28.2, 52.4, 77.5, 80.8, 122.7,
127.9, 128.1, 130.1, 133.6, 135.9, 154.5; ESIMS m/z 367
[MCNaC]; [a]D22 K8 (c 0.402, CHCl3), 88% ee.
4.2.4. 1-(1-Naphthyl)-2-nitroethyl carbamic acid t-butyl
ester (2h). Following the general procedure, compound 2h
was obtained as a white solid in 87% yield. The ee of the
product was determined by HPLC using a Daicel Chiralpak
AD-H column (n-hexane/i-PrOHZ90:10, flow rate 1 mL/
min, tmajorZ17.0 min; tminorZ25.7 min). Rf 0.64
1
(n-hexane/EtOAc, 7:3); mp 174–177 8C; H NMR d 1.43
(s, 9H), 4.80–4.98 (br s, 2H), 5.24–5,38 (br s, 1H),
6.22–6.34 (br s, 1H), 7.44–7.48 (m, 2H), 7.52–7.58 (m,
1H), 7.60–7.64 (m, 1H), 7.84–7.86 (m, 1H), 7.88–7.92 (m,
1H), 8.11–8.13 (m, 1H); 13C NMR d 28.2, 49.2, 78.2, 80.8,
122.2, 123,2, 125.2, 126.3, 127.3, 129.2, 129.5, 130.3,
132.6, 134.1, 154.7; ESIMS m/z 339 [MCNaC]; [a]D22 C7
(c 0.498, CHCl3), 88% ee.
4.2.9. 1-(p-Methoxyphenyl)-2-nitroethyl carbamic acid
t-butyl ester (2m). Following the general procedure,
compound 2m was obtained as a white solid in 65% yield.
The ee of the product was determined by HPLC using a
Daicel Chiralpak AD-H column (n-hexane/i-PrOHZ98:2,
flow rate 1 mL/min, tmajorZ91.6 min; tminorZ97.5 min). Rf
1
0.53 (n-hexane/EtOAc, 7:3); mp 141–144 8C; H NMR d
1.44 (s, 9H), 3.80 (s, 3H), 4.66 (dd, JZ5.9, 12.4 Hz, 1H),
4.75–4.9 (br s, 1H), 5.14–5.24 (br s, 1H), 5.25–5.35 (br s,
1H), 6.89 (d, JZ8.8 Hz, 2H), 7.22 (d, JZ8.8 Hz, 2H); 13C
NMR d 28.2, 52.4, 55.3, 78.9, 80.6, 114.5, 127.6, 128.8,
154.7, 159.8; ESIMS m/z 319 [MCNaC]; [a]D22 C28 (c
0.693, CHCl3), 82% ee.
4.2.5. 1-(2-Naphthyl)-2-nitroethyl carbamic acid t-butyl
ester (2i). Following the general procedure, performing the
reaction at K40 8C, compound 2i was obtained as a white
solid in 82% yield. The ee of the product was determined by
HPLC using a Daicel Chiralpak AD-H column (n-hexane/
i-PrOHZ90:10, flow rate 1 mL/min, tmajorZ17.8 min;
tminorZ21.5 min). Rf 0.79 (n-hexane/EtOAc, 7:3); mp
4.2.10. 2-Nitro-1-(thiophen-2-yl)ethyl carbamic acid
t-butyl ester (2n). Following the general procedure,
compound 2n was obtained as a yellow oil in 50% yield.
The ee of the product was determined by HPLC using a
Daicel Chiralpak AD-H column (n-hexane/i-PrOHZ98:2,
flow rate 1 mL/min, tmajorZ54.0 min; tminorZ57.4 min). Rf
1
144–146 8C; H NMR d 1.45 (s, 9H), 4.80 (dd, JZ5.5,
12.6 Hz, 1H), 4.88–5.00 (br s, 1H), 5.34–5.46 (br s, 1H),
5.50–5.60 (br s, 1H), 7.40 (dd, JZ1.8, 8.5 Hz, 1H), 7.48–
7.54 (m, 2H), 7.76 (m, 1H), 7.82–7.88 (m, 3H); 13C NMR d
28.3, 53.0, 78.8, 80.8, 123.7, 125.6, 126.7, 126.7, 127.7,
128.0, 129.2, 133.2, 133.2, 134.2, 154.8; ESIMS m/z 339
[MC NaC]; [a]D22 C38 (c 0.505, CHCl3), 94% ee.
1
0.52 (n-hexane/EtOAc, 7:3); H NMR d 1.46 (s, 9H), 4.75
(dd, JZ5.6, 12.9 Hz, 1H), 4.84–4.98 (br s, 1H), 5.22–5.36
(br s, 1H), 5.56–5.70 (br s, 1H), 6.97–7.02 (m, 2H), 7.27–
7.29 (m, 1H); 13C NMR d 28.2, 48.9, 77.3, 78.6, 81.0, 125.7,
127.3, 140.0, 154.4; ESIMS m/z 295 [MCNaC]; [a]D22 C12
(c 0.445, CHCl3), 82% ee.
4.2.6. 1-(p-Chlorophenyl)-2-nitroethyl carbamic acid
t-butyl ester (2j). Following the general procedure,
compound 2j was obtained as a white solid in 77% yield.
The ee of the product was determined by HPLC using a
Daicel Chiralpak AD-H column (n-hexane/i-PrOHZ90:10,
flow rate 1 mL/min, tmajorZ12.8 min; tminorZ16.1 min). Rf
4.2.11. 1-(Furan-2-yl)-2-nitro-ethyl carbamic acid
t-butyl ester (2o). Following the general procedure,

380
L. Bernardi et al. / Tetrahedron 62 (2006) 375–380
5. Yamada, K.; Moll, G.; Shibasaki, M. Synlett 2001, 980–982.
6. Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.;
Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843–5844.
7. Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen,
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8. Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005,
1362–1364.
performing the reaction at K40 8C, compound 2o was
obtained as a yellow oil in 58% yield. The ee of the product
was determined by HPLC using a Daicel Chiralpak AD-H
column (n-hexane/i-PrOHZ97:3, flow rate 0.75 mL/min,
tmajorZ33.8 min; tminorZ31.2 min). Rf 0.67 (n-hexane/
1
EtOAc, 7:3); H NMR d 1.46 (s, 9H), 4.72 (dd, JZ6.0,
12.9 Hz, 1H), 4.84 (dd, JZ6.0, 12.9 Hz, 1H), 5.08–5.26 (br
s, 1H), 5.38–5.50 (br s, 1H), 6.28–6.36 (m, 2H), 7.34–7.40
(m, 1H); 13C NMR d 28.2, 47.2, 80.9, 88.1, 107.8, 110.7,
142.9, 149.4, 154.6; ESIMS m/z 279 [MCNaC]; [a]D22 C11
(c 0.305, CHCl3), 63% ee.
9. Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org.
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Acknowledgements
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8168–8171.
We gratefully acknowledge financial support by the
National Project ‘Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni, 2003’, by the RTN project
‘Design, Analysis and Computation for Catalytic Organic
Reactions’, contract HPRN-CT-2001-00172, and by the
ex-60% MURST-funds 2004. R.P.H. thanks the European
Union for a post-doctoral fellowship.
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¨
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