Organocatalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated enones using novel imidazoline catalysts

Article abstract of DOI:10.1021/jo0261449

A new catalytic enantioselective conjugate addition of nitroalkanes to acyclic α,β-unsaturated enones catalyzed by novel organic catalysts has been developed. A series of chiral amines has been tested as catalysts for the addition of 2-nitropropane to benzylideneacetone, and it is found that a novel imidazoline catalyst, prepared from phenylalanine, can catalyze a highly enantioselective 1,4addition reaction. The reaction of various acyclic and cyclic nitroalkanes was found to proceed well with enantioselectivities up to 86% ee, and enantiopure products can be obtained by recrystallization. The potential of the reaction is documented by the reaction of a series of substituted α,β-unsaturated enones with different nitroalkanes. Furthermore, the synthetic applicability of the reaction is demonstrated by the formation of optically active functionalized pyrrolines and pyrrolidines by reductive amination of the products. On the basis of the absolute configuration of the conjugate addition products, the mechanism for the reaction is discussed and a transition state proposed.

Full text of DOI:10.1021/jo0261449

Or ga n oca ta lytic Asym m etr ic Con ju ga te Ad d ition of Nitr oa lk a n es
to r,â-Un sa tu r a ted En on es Usin g Novel Im id a zolin e Ca ta lysts
Nis Halland, Rita G. Hazell, and Karl Anker J ørgensen*
Danish National Research Foundation: Center for Catalysis, Department of Chemistry,
Aarhus University, DK-8000 Aarhus C, Denmark
kaj@chem.au.dk
Received J uly 5, 2002
A new catalytic enantioselective conjugate addition of nitroalkanes to acyclic R,â-unsaturated enones
catalyzed by novel organic catalysts has been developed. A series of chiral amines has been tested
as catalysts for the addition of 2-nitropropane to benzylideneacetone, and it is found that a novel
imidazoline catalyst, prepared from phenylalanine, can catalyze a highly enantioselective 1,4-
addition reaction. The reaction of various acyclic and cyclic nitroalkanes was found to proceed well
with enantioselectivities up to 86% ee, and enantiopure products can be obtained by recrystallization.
The potential of the reaction is documented by the reaction of a series of substituted R,â-unsaturated
enones with different nitroalkanes. Furthermore, the synthetic applicability of the reaction is
demonstrated by the formation of optically active functionalized pyrrolines and pyrrolidines by
reductive amination of the products. On the basis of the absolute configuration of the conjugate
addition products, the mechanism for the reaction is discussed and a transition state proposed.
In tr od u ction
chiral rubidium prolinate, proline and proline deriva-
tives,6,7 and chiral phase-transfer catalysts,8 but generally
only low to moderate enantioselectivities have been
obtained6a,b or the reaction has been limited to cyclic
enones.6c The best results obtained so far have been by
Bako´ et al. using a sugar-derived crown ether for the
addition of 2-nitropropane to chalcone in up to 89% ee9
and by Shibasaki et al. using a lanthanum tris-binaph-
thoxide catalyst in the addition of nitromethane to
chalcones in up to 97% ee;5a however, only nitromethane
was utilized and up to 60 mol % of the chiral ligand was
used.
The catalytic asymmetric conjugate additionsthe
Michael reactionsof stabilized carbanions to R,â-unsat-
urated enones is one of the fundamental C-C bond-
forming reactions in organic chemistry.1 This concept has
over the years been developed for the reaction of several
different stabilized carbanions with various types of R,â-
unsaturated enones1 and found use for the synthesis of
many important molecules by further reaction of the
Michael addition product.
For the Michael reaction of nitroalkanes2 with R,â-
unsaturated enones, the product of the 1,4-addition
reaction is a very useful precursor to different complex
organic molecules, such as aminocarbonyl, aminoalkanes,
and pyrrolidines by reduction of the nitro functionality,3
and to other functionalities that can be derived from the
nitro group.4
(4) Nef reaction: (a) Nef, J . U. J ustus Liebigs Ann. Chem. 1894,
280, 263. (b) Pinnick, H. W. Org. Reac. 1990, 38, 655. Nucleophilic
displacement: (c) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991,
423. Meyer reaction: (d) Meyer, V.; Wurster, C. Ber. Dtsch. Chem. Ges.
1873, 6, 1168. (e) Kamlet, M. J .; Kaplan, L. A.; Dacons, J . C. J . Org.
Chem. 1961, 26, 4371. Nitrile oxide: (f) Mukayama, T.; Hoshino, T. J .
Am. Chem. Soc. 1960, 82, 5339.
(5) Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shiba-
saki, M. Tetrahedron Lett. 1998, 39, 7557. See also: Keller, E.;
Veldman, N.; Spek, A. L.; Feringa, B. Tetrahedron: Asymmetry 1997,
8, 3403.
Several attempts have been performed toward achiev-
ing asymmetric conjugate addition of nitroalkanes to R,â-
unsaturated enones in the presence of chiral Lewis acids,5
(1) For recent reviews dealing with enantioselective conjugate
addition reactions, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033. (b) Yamaguchi, M. In Comprehensive Asymmetric Catalysis
I-III; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin-Heidelberg, 1999; Chapter 31.2. (c) Berner, O. E.;
Tedeschi, L.; Enders, D. Eur. J . Org. Chem. 2002, 1788. (d) Krause,
H.-R. A. Synthesis 2001, 171. (e) Leonard, J .; Diez-Barra, E.; Merino,
S. Eur. J . Org. Chem. 1998, 1, 2051. (f) Rossiter, B. E.; Swingle, M. N.
Chem. Rev. 1992, 92, 771.
(2) See, for example: Ono, N. The Nitro Group in Organic Synthesis;
Wiley-VCH: New York, 2001.
(3) See, for example: (a) Larock, R. C. Comprehensive Organic
Transformations; VCH: New York, 1989; p 411. (b) Beck, A. K.;
Seebach, D. Chem. Ber. 1991, 124, 2897. (c) Maeri, R. E.; Heinzer, J .;
Seebach, D. Liebigs Ann. 1995, 1193. (d) Poupart, M. A.; Fazal, G.;
Goulet, S.; Mar, L. T. I. Org. Chem. 1999, 64, 1356.
(6) (a) Yamaguchi, M.; Shiraishi, T.; Igarashi, Y.; Hirama, M.
Tetrahedron Lett. 1994, 35, 8233. (b) Yamaguchi, M.; Igarashi, Y.;
Reddy, R: S.; Shiraishi, T.; Hirama, M. Tetrahedron 1997, 53, 11223.
(c) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975.
(7) For organocatalytic enantioselective Michael addition of carbonyl
compounds to nitroalkenes, see: (a) List, B.; Pojarliev, P.; Martin, H.
J . Org. Lett. 2001, 3, 2423. (b) Betancort, J . M.; Barbas, C. F., III Org.
Lett. 2001, 3, 3737. (c) Enders, D.; Seki, A. Synlett 2002, 26.
(8) For phase-transfer catalysts, see: (a) Annunziata, R.; Cinquini,
M.; Colonna, S. J . Chem. Soc., Perkin Trans. 1 1980, 2422. (b) Colonna,
S.; Hiemstra, H.; Wynberg, H. J . Chem. Soc., Chem. Commun. 1978,
238. (c) Banfi, S.; Cinquini, M.; Colonna, S. Bull. Chem. Soc. J pn. 1981,
54, 1841.
(9) (a) Bako´, P.; Szo¨llo˜sy, A.; Bombicz, P.; To´ke, L. Synlett 1997,
291. (b) Bako´, P.; Bajor, Z.; To´ke, L. J . Chem. Soc., Perkin Trans 1
1999, 3651.
10.1021/jo0261449 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/31/2002
J . Org. Chem. 2002, 67, 8331-8338
8331

Halland et al.
In this paper, we disclose the organocatalyzed10 enan-
tioselective conjugate addition of nitroalkanes to acyclic
R,â-unsaturated enones using novel imidazoline cata-
lysts. The reaction has been developed for various types
of nitroalkanes 1 reacting with different acyclic R,â-
unsaturated enones 2 (eq 1). The scope of the catalytic
asymmetric conjugate addition will be presented by the
reaction of acyclic and cyclic nitroalkanes, as well as
functionalized nitroalkanes with various types of acyclic
R,â-unsaturated enones. The applicability of the reaction
will be demonstrated by the preparation of optically
active functionalized pyrrolines and pyrrolidines. Fur-
thermore, the mechanism for the reaction will be dis-
cussed.
TABLE 1. Scr een in g of Differ en t Ch ir a l Am in es 4a -h
a s Ca ta lysts for th e En a n tioselective Ad d ition of
2-Nitr op r op a n e 1a to Ben zylid en ea ceton e 2a (eq 2)a
catalyst
(mol %)
Et3N
(mol %)
reaction
time (h)
conversionb
(%)
Resu lts a n d Discu ssion
entry
eec (%)
The initial studies of the organocatalytic enantioselec-
tive addition of nitroalkanes to the R,â-unsaturated
enones focused on the screening of different chiral amines
as the catalyst for the reaction of 2-nitropropane 1a with
benzylideneacetone 2a (eq 2). The results from these
investigations are presented in Table 1.
In the absence of a base, 2-nitropropane 1a did not
react with benzylideneacetone 2a . L-Proline turned out
to be a poor catalyst in terms of enantioselectivity for
the reaction (Table 1, entry 2), a result which is in
accordance with the general observations from literature
on proline-catalyzed Michael additions to acyclic enones.6a,b
Surprisingly, the organocatalyst developed by MacMillan
et al. (4b)10k gave no conversion for the Michael reaction
of 1a with 2a , under the present reaction conditions, not
even in the presence of Et3N (Table 1, entry 3). However,
catalyst 4c, which can easily be prepared from phenyla-
lanine by reaction with first thionyl chloride in MeOH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
24
50
60
4a (10)
4b (20)
4c (20)
4c (10)
4c (10)
4d (10)
4e (20)
4f (20)
4g (20)
4h (20)
4i (20)
4j (20)
4k (20)
50
20
37
<5
180
180
150
180
150
130
130
200
80
87
57
68
33
11
<5
33
83
74
3
79
80
78
59
56
10
20
20
60
13
43
<5
40
20
68
a
b
Reaction performed as neat reactions. Determined by GC;
the isolated yields are generally about 5% lower. c Determined by
chiral GC using a Chirasil Dex-CΒ chiral stationary phase.
SCHEME 1. Syn th esis of Ca ta lyst 4c
(10) For chiral amines as catalysts, see the following. Aldol reac-
tion: (a) Co´rdova, A.; Notz, W.; Barbas, C. F., III J . Org. Chem. 2002,
67, 301. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J . Am.
Chem. Soc. 2001, 123, 5260. (c) List, B.; Lerner, R. A.; Barbas, C. F.,
III J . Am. Chem. Soc. 2000, 122, 2395. (d) Bøgevig, A.; Kumaragu-
rubaran, N.; J ørgensen, K. A. Chem. Commun. 2002, 620. (e) Northrup,
A. B.; MacMillan, D. W. C. J . Am. Chem. Soc. 2002, 124, 6798. Friedel-
Crafts alkylation: (f) Austin, J . F.; MacMillan, D. W. C. J . Am. Chem.
Soc. 2002, 124, 1172. (g) Paras, N. A.; MacMillan, D. W. C. J . Am.
Chem. Soc. 2001, 123, 4370. (h) Paras, N. A.; MacMillan, D. W. C. J .
Am. Chem. Soc. 2002, ASAP. Diels-Alder: (i) Northrup, A. B.;
MacMillan, D. W. C. J . Am. Chem. Soc. 2002, 124, 2458. (j) Ahrendt,
K. A.; Borths, C. J .; MacMillan, D. W. C. J . Am. Chem. Soc. 2000,
122, 4243. 1,3-Dipolar cycloaddition: (k) J en, W. S.; Wiener, J . J . M.;
MacMillan, D. W. C. J . Am. Chem. Soc. 2000, 122, 9874. (l) Karlsson,
S.; Ho¨gberg, H. Tetrahedron: Asymmetry 2002, 13, 923; Michael
addition: ref 7 and (m) Betancort, J . M.; Barbas, C. F., III Org. Lett.
2001, 3, 3737. (n) Betancort, J . M.; Sakthivel, K.; Thayumanavan, R.;
Barbas, C. F., III Tetrahedron Lett. 2001, 42, 4441. (o) Horstmann, T.
E.; Guerin, D. J .; Miller, S. J . Angew. Chem., Int. Ed. 2000, 39, 3635.
R-Amination: (p) List, B. J . Am. Chem. Soc. 2002, 124, 5656. (q)
Bøgevig, A.; J uhl, K.; Kumaragurubaran, N.; Zhuang, W.; J ørgensen,
K. A. Angew. Chem., Int. Ed. 2002, 41, 1790. (r) Kumaragurubaran,
N.; J uhl, K.; Zhuang, W.; Bøgevig, A.; J ørgensen, K. A. J . Am. Chem.
Soc. 2002, 124, 6254. Mannich reaction: (s) Co´rdova, A.; Watanabe,
S.; Tanaka, F. Notz, W.; Barbas, C. F., III J . Am. Chem. Soc. 2002,
124, 1842. (t) Co´rdova, A.; Notz, W.; Zhong, G.; Betancort, J . M.;
Barbas, C. F., III J . Am. Chem. Soc. 2002, 124, 1866. (u) Castello, C.;
List, B. Synlett 2001, 1687. (v) List, B.; Pojarliev, P.; Biller, W. T.;
Martin, H. J . J . Am. Chem. Soc. 2002, 124, 827.
and methylamine followed by reduction of the carbonyl
functionality and ring closure with glyoxalic acid (Scheme
1), turned out to be an excellent catalyst for the reaction
of 1a with 2a . The catalyst 4c was obtained as a
configurationally stable 2:1 mixture of diastereomers and
used as such. Attempts to separate the diastereomers by
chromatographic methods were not successful. In the
presence of 20 mol % of 4c, the Michael adduct 3a was
formed in high yield and with 79% ee (Table 1, entry 4).
The reaction also proceeds well with 10 mol % of catalyst
4a (Table 1, entry 5), as well as with 10 mol % of Et3N
as a base (Table 1, entry 6). However, it should be noted
8332 J . Org. Chem., Vol. 67, No. 24, 2002

Addition of Nitroalkanes to R,â-Unsaturated Enones
TABLE 2. Ca ta lytic En a n tioselective Ad d ition of
Nitr oa lk a n es 1a -f to Ben zylid en ea ceton e 2a Ca ta lyzed
by 4c (20 m ol %) a n d 4e (20 m ol %) (eq 2)
that an increase in the amount of base leads to a lower
conversion, presumably due to salt formation with the
catalyst. The phenyl analogue (4d ) gave moderate con-
version and enantioselectivity (Table 1, entry 7). We have
also prepared a series of chiral organocatalysts based on
optically active 1,2-diphenyl-1,2-diamine as the chiral
backbone (4e-i), and of these, only catalysts 4h and 4i
gave satisfactory conversion, and only the former catalyst
provided a moderate enantioselectivity (entry 11). The
C2-symmetric catalyst 4j and the chiral diamine 4k
turned out to be less effective catalysts for the addition
of 1a to 2a (Table 1, entries 13 and 14). The simplicity
of the nitroalkane Michael reaction should be empha-
sized: The bench-stable catalyst is added to a mixture
of the nitroalkane and R,â-unsaturated enone under an
aerobic atmosphere, taking no precautions to exclude
water, and the mixture stirred for the time indicated.
Addition of 5 or 10 equiv of water was not found to
increase the reaction rate as observed by MacMillan et
al.,10j but was found to produce identical results to
reactions without added water both in terms of yield and
enantioselectivity. After evaporation of the reaction
mixture to remove excess nitroalkane, purification by
flash chromatography yielded the pure product. It should
also be noted that the reactions are very clean and that
no byproducts are observed. Therefore, the reported
yields are a consequence of the reaction time, as demon-
strated by the addition of 2-nitropropane 1a to benzyli-
deneacetone 2a (Table 2, entry 1), where the reaction has
been allowed to go to completion. If the reaction between
2-nitropropane 1a and benzylideneacetone 2a proceeds
at higher temperatures (50 °C) using 10 mol % of catalyst
4c, the yield of 3a was increased to 83%; however, the
enantioselectivity was reduced to 59% ee. To demonstrate
the preparative utility of the organocatalyzed reactions,
a similar reaction was run on a kilogram scale using
catalyst 4c with recovery and reuse of the catalyst,
without any observed decrease in catalytic activity or
enantioselectivity.
reaction
entry nitroalkane catalyst time (h) conversionb (%) eec (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1f
1g
1g
4c
4c
4c
4c
4c
4c
4e
4c
4e
240
150
130
100
275
110
110
170
170
3a , 100 (52)d 79 (99)d
3b, 52
3c, 80
3d , 100
3e, 64
3f, 89e
3f, 70e
3g, 71g
3g, 61h
73
71/73
77
71
79f
60f
58/72
58/63
a
Reactions in entries 1-5 were performed under neat condi-
tions, while reactions in entry 6-9 were performed in THF using
b
1.1 equiv of the nitroalkanes. Determined by GC; the isolated
yields are generally about 5% lower. c Determined by chiral
d
stationary phase GC or HPLC. Run on a 10 mmol scale; yield
and ee after a single recrystallization in EtOH. e Diastereomeric
ratio 1:1. f Measured after decarboxylation. g Diastereomeric ratio
h
2.2:1. Diastereomeric ratio 1.7:1.
TABLE 3. Ca ta lytic En a n tioselective Ad d ition of
2-Nitr op r op a n e 1a to Differ en t r,â-Un sa tu r a ted En on es
2a -i Ca ta lyzed by 4c (20 m ol %) (eq 4)a
R,â-unsatd
enone
reaction
entry
R1
R2 time (h)
yieldb (%)
eec (%)
1
2
2a
2b
Ph
Ph
Me
Et
240
300
130
110
130
130
180
200
200
80
3a , 100 (52)d 79 (99)d
3h , 69
3h , 33
3I, <5
3j, 87
3k , 95
3l, 86
83
86
3
4
5
6
7
8
9
10
11
12
13
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
Ph
p-ClC6H4
p-NO2C6H4 Me
p-HOC6H4 Me
i-Pr
Me
75 (94)d
65 (98)d
75
2-thienyl
Me
Me
3m , 87
3n , 69
3o, 60
3p , 50
3q, <10
3r , 84
3s, 78
73
70
52
73
73
49
34
2-furyle
2-pyridyle Me
n-Bu
i-Pr
Me
Me
150
160
130
110
A series of different nitroalkanes 1a -g has been
reacted with benzylideneacetone 1a in the presence of
4c or 4e as the catalyst, as shown in eq 3 and Table 2.
-(CH2)3-
2m
CO2Me
Me
a
b
Reaction conditions. Determined by GC; the isolated yields
are generally about 5% lower. c Determined by chiral stationary
phase GC or HPLC. After a single recrystallization. e Mixture
d
of E-and Z-isomers.
entries 4 and 5). Nitrocyclopentane 1d and nitrocyclo-
hexane 1e also react well with 2a , and 3d and 3e are
formed with 77% ee and 71% ee, respectively (Table 2,
entries 5 and 6). Nitroacetate 1f gives a 1:1 mixture of
diastereomers using both 4c and 4e as the catalysts and
with up to 79% ee (Table 2, entries 7 and 8) (vide supra).
The reaction of phenylnitromethane 1g with 2a is slightly
more diastereoselective than 1f, as a 2:1 mixture of
diastereomers are obtained with up to 72% ee of one of
the diastereomers (Table 2, entries 9 and 10); however,
it should be noted that 3g racemizes upon prolonged
standing.
The results for the catalytic enantioselective conjugate
addition of the nitroalkanes to benzylideneacetone show
that both the yield and enantioselectivity of the reaction
are very similar for the different nitroalkanes investi-
gated, which demonstrates that the reaction is very
The different nitroalkanes 1a -g react well with benz-
ylideneacetone 2a in an enantioselective fashion, giving
the Michael adducts 3a -g in good yields and with very
similar enantioselectivities for the various nitroalkanes
studied. For all the acyclic nitroalkanes 1a -c (Table 2,
entries 1-3), the enantioselectivities of the Michael
adducts 3a -c are in the range 71-79% ee. The enantio-
selectivities of the Michael adducts can be improved by
recrystallization to enantiopure products (99% ee), as
shown for compound 3a ,j,k (Table 2, entry 1; Table 3,
J . Org. Chem, Vol. 67, No. 24, 2002 8333

Halland et al.
tolerant to changes in the nitroalkane used. Therefore,
2-nitropropane 1a was selected as the nitroalkane for the
1,4-addition to a series of different R,â-unsaturated
enones in order to further expand the scope of the
reaction, and the results are presented in Table 3.
It appears from the two first entries in Table 3 that
an exchange of the methyl substituent in 2a to an ethyl
substituent in 2b improves the enantioselectivity of the
reaction, and the Michael adduct is formed with 83% ee.
However, further increase of the steric bulk at R2-position
to an isopropyl substituent slows down the reaction and
a very low conversion is observed (Table 3, entry 3). The
Michael addition of 2-nitropropane 1a to the other
aromatic enones 2d -f also proceeds well, and good
enantioselectivities are obtained (entries 4-6). Further-
more, it is also demonstrated that the enantioselectivity
of the products can be improved to be 94% ee and 98%
ee for 3j and 3k by a single recrystallization (Table 3,
entries 4 and 5). The heteroaromatic R,â-unsaturated
enones 2g-i also reacts well with 1a in the presence of
4a as the catalyst, and good enantioselectivities of the
Michael adducts 3m -o are obtained (Table 3, entries
7-9). The Michael addition of 2a to the R,â-unsaturated
enones substituted with an alkyl group is very dependent
on the R1-substituent: substrate 2j, which has a butyl
substituent as R1, gives a moderate yield of 3p having
73% ee (Table 3, entry 10), while 2k , having an isopropyl
substituent, gives less than 10% yield of 3q, but with the
same good enantioselectivity (Table 3, entry 11). The
cyclic enone 2l reacts also well with 1a ; however, the
enantioselectivity of 3r is moderate (Table 3, entry 12).
P r od u ct Mod ifica tion . The Michael adducts obtained
from the present catalytic enantioselective addition of
nitroalkanes to the R,â-unsaturated enones opens up for
a simple approach to optically active pyrrolidines by
reductive amination (eq 5). Nitro ketones 3a and 3m were
conditions (MeOH, 40 bar), the two diastereomeric pyr-
rolidines 5d ,e were obtained in quantitative yield, but if
the reduction was conducted at an atmospheric pressure,
the main product obtained was the 2,3-trans-pyrroline
5f and the 2,3,5-cis-pyrrolidine 5d arising from the two
diastereomers of nitro ketone 3f.
Absolu te Con figu r a tion a n d Mech a n istic Asp ects.
The absolute configuration of the Michael adduct 3j
obtained from the reaction of 2-nitropropane 1a with
p-chlorobenzylideneacetone 2d in the presence of catalyst
4c has been assigned by X-ray analysis (see Supporting
Information).
The configuration of the chiral center formed in the
Michael addition reaction could be determined to have
the (S)-configuration.
The observed stereochemistry of the product can be
explained by formation of the catalyst-substrate imi-
nium intermediate 6a in which the benzyl group of the
catalyst shields the re-face of the enone, leaving the si-
face open for attack. Figure 1 shows the energy mini-
mized (PM3)16 structure of 6a .
Obviously, there are several other possible conforma-
tions and isomers of the catalyst-substrate iminium
intermediate (6b-d ) than 6a (Scheme 2). However, the
catalyst-substrate iminium intermediates 6b,c arising
from the trans diastereomer of the catalyst are calculated
to be considerably higher in energy (>3 kcal/mol) than
6a and 6d , due to steric interactions. The two catalyst-
substrate iminium intermediates 6a and 6d obtained
from the cis diastereomer of the catalyst are of similar
energy, but conformation 6a is slightly favored over 6d .
The favored intermediate 6a can be due to either steric
interactions between the methyl group of the ketone and
the benzyl group, as proposed by MacMillan et al.,10i who
have been using another phenylalanine-derived catalyst,
or the possibility of a positive interaction (π-stacking)
between the two π-systems. The latter argument is also
in agreement with the fact that the catalyst made from
D-phenylalanine produces the other enantiomer of the
Michael addition product.
reduced by H2/Ra-Ni in MeOH at 40 bar pressure to give
a quantitative yield of the corresponding pyrrolidines
5a ,c with remarkable diastereoselectivity, as only a
single diastereomer was obtained, with the enantiomeric
excess obtained in the Michael addition step being
maintained. For nitro ketone 3g, containing a benzylic
amine, much milder reduction conditions had to be
employed, and the reduction was performed in EtOH at
atmospheric pressure. Even then, under these mild
conditions, the 2,3-trans-substituted diastereomer was
unstable, and the only product obtained was the 2,3,5-
cis-substituted pyrrolidine 5b as a colorless solid. The
structure of 5b was confirmed by X-ray analysis (see
Supporting Information).
(11) Kelleher, R. G.; McKervey, M. A.; Vibuljan, Pongsak. Chem.
Commun. 1980, 486.
(12) Brophy, P. M.; Campbell, A. M.; Eldik, A. J . van; Teesdale-
Spittle, P. H.; Liebau, E.; Wang, M. F. Bioorg. Med. Chem. Lett. 2000,
979.
(13) Black, A. P.; Babers, F. H. Organic Syntheses; Wiley: New York,
1943, Collect. Vol. II, p 512.
(14) Robinson, C. N.; Wiseman, L. J ., J r.; Slater, C. D. Tetrahedron
1989, 45, 4103.
(15) Chong, J . M.; Clarke, I. S.; Koch, I.; Olbach, P. C.; Taylor, N. J .
Tetrahedron: Asymmetry 1995, 6, 409.
(16) Performed using the protonated carboxylic acid and a positive
charge on the nitrogen atom using the Chem3D program.
The more functionalized Michael adduct 3f was also
subjected to the reductive amination conditions to yield
optically active proline analogues 5d ,e or pyrroline 5f,
depending on the reaction conditions, as shown in eq 6.
If the reductive amination was performed under forcing
8334 J . Org. Chem., Vol. 67, No. 24, 2002

Addition of Nitroalkanes to R,â-Unsaturated Enones
4-methyl-1-phenylpent-1-en-3-one 2c,12 phenylnitromethane
1g,13 4-pyridin-2-ylbut-3-en-2-one 2i,14 and 2,5-diphenylpyr-
rolidine 4j15 were prepared according to literature procedures.
Gen er a l P r oced u r e for th e Ca ta lytic Asym m etr ic
Mich a el Ad d ition to r,â-Un sa tu r a ted En on es. In an
ordinary test tube equipped with a magnetic stirring bar, 0.5
mmol of the enone was added to 1.0 mL of the nitroalkane,
and then the catalyst (0.1 mmol) was added, the tube closed
with a rubber stopper, and the reaction mixture stirred at
ambient temperature for the time indicated in table. The crude
reaction mixture was purified by FC on silica gel after
evaporation of the nitroalkane.
5-Meth yl-5-n itr o-4-p h en ylh exa n -2-on e (3a ) was purified
by FC using Et2O/pentane and isolated as a colorless oil.
Enantiomers were separated by GC using a Chirasil Dex-CB
chiral stationary phase. A single recrystalization in EtOH
increased the enantioselectivity to 99% ee: [RrtD] ) -34.1° (c
1
) 1.0 g/100 mL, EtOH, 99% ee); H NMR (CDCl3) δ 1.47 (s,
3H), 1.55 (s, 3H), 2.03 (s, 3H), 2.71 (dd, J ) 16.8, 3.6 Hz, 1H),
3.09 (dd, J ) 16.8, 10.8 Hz, 1H), 3.92 (dd, J ) 10.8, 3.6 Hz,
1H), 7.16-7.21 (m, 2H), 7.24-7.33 (m, 3H); 13C NMR (CDCl3)
δ 22.3, 25.8, 30.3, 44.0, 48.8, 91.0, 127.9, 128.5, 129.1, 137.5,
205.2; HRMS m/z 258.1109 (M + Na+), calcd for C13H17O3NNa+
258.1106.
F IGURE 1. PM3-minimized structure of iminium ion 6a .
SCHEME 2. P ossible Ca ta lyst-Su bstr a te Im in iu m
In ter m ed ia tes, 6a -d
5-Nitr o-4-p h en ylp en tan -2-on e (3b) was purified by FC
using Et2O/pentane and isolated as a colorless solid. Enanti-
omers were separated by GC using an Chiraldex G-TA chiral
stationary phase: 1H NMR (CDCl3) δ 2.12 (s, 3H), 2.92 (d, J
) 6.8 Hz, 2H), 4.01 (q, J ) 6.8 Hz, 1H), 4.60 (dd, J ) 7.6, 12.4
Hz, 1H), 4.69 (dd, J ) 6.8, 12.4 Hz, 1H), 7.20-7.34 (m, 5H);
13C NMR (CDCl3) δ 30.3, 38.9, 46.0, 79.4, 127.3, 127.5, 129.0,
138.7, 205.4; HRMS m/z 230.0785 (M + Na+), calcd for
C
11H13O3NNa+ 230.0793.
5-Nitr o-4-p h en ylh exa n -2-on e (3c). Diastereomers were
separated by FC using Et2O/pentane and isolated as colorless
oils. Enantiomers were separated by GC using a Chirasil Dex-
CB chiral stationary phase. Diastereomer A: 1H NMR (CDCl3)
δ 1.32 (d, J ) 6.8 Hz, 3H), 2.00 (s, 3H), 2.73 (dd, J ) 4.0, 17.2
Hz, 1H), 2.99 (dd, J ) 9.6, 17.2 Hz, 1H), 3.70 (td, J ) 10.0, 4.0
Hz, 1H), 4.76 (dq, J ) 10.4, 6.8 Hz, 1H), 7.17-7.20 (m, 2H),
7.25-7.35 (m, 3H); 13C NMR (CDCl3) δ 17.7, 30.4, 45.2, 46.2,
87.0, 127.8, 128.1, 129.0, 138.2, 205.0; HRMS m/z 244.0951
(M + Na+), calcd for C12H15O3NNa+ 244.0950. Diastereomer
B: 1H NMR (CDCl3) δ 1.48 (d, J ) 6.4 Hz), 2.12 (s, 3H), 2.89
(dd, J ) 7.6, 17.6 Hz, 1H), 3.05 (dd, J ) 6.4, 17.6 Hz, 1H),
3.72 (q, J ) 6.8 Hz, 1H), 4.87 (quintet, J ) 6.4 Hz, 1H), 7.11-
7.15 (m. 2H), 7.25-7.33 (m. 3H); 13C NMR (CDCl3) δ 16.7, 30.5,
44.4, 44.6, 85.8, 127.8, 128.1, 128.7, 137.8, 205.9; HRMS m/z
244.0953 (M + Na+), calcd for C12H15O3NNa+ 244.0950.
In summary, we have developed a new organocatalytic
enantioselective Michael addition of nitroalkanes to R,â-
unsaturated enones using a new imidazoline catalyst,
easily prepared from phenylalanine. The Michael addi-
tion of both acyclic and cyclic nitroalkanes to a variety
of different R,â-unsaturated enones proceeds in high
yields and with up to 86% ee, and enantiopure products
are obtained by recrystallization. The optically active
nitro ketones formed undergo a reductive amination, and
functionalized pyrrolines and pyrrolidines are obtained
with very high diastereomeric excess and the enantio-
meric excess is maintained. To account for the absolute
configuration of the Michael addition adduct, a catalyst-
substrate iminium intermediate in which the benzyl
group of the catalyst (4c) shields the re-face of the R,â-
unsaturated enone leaving the si-face available for ap-
proach has been proposed.
4-(1-Nit r ocyclop en t yl)-4-p h en ylb u t a n -2-on e (3d ) was
purified by FC using Et2O/pentane and isolated as a colorless
oil. Enantiomers were separated by HPLC using a Chiralpak
AS chiral stationary phase in hexane/2-propanol 90/10: 1H
NMR (CDCl3) δ 1.51-1.68 (m, 4H), 1.75-1.84 (m, 2H), 2.01
(s, 3H), 2.41-2.57 (m, 2H), 2.90 (dd, J ) 17.2, 3.6 Hz, 1H),
3.11 (dd, J ) 17.2, 10.0 Hz, 1H), 3.84 (dd, J ) 10.0, 3.6 Hz,
1H), 7.08-7.14 (m, 2H), 7.22-7.29 (m, 3H); 13C NMR (CDCl3)
δ 22.9, 23.0, 30.4, 33.9, 36.3, 45.0, 47.2, 103.8, 127.7, 128.4,
128.6, 138.2, 205.6; HRMS m/z 284.1263 (M + Na+), calcd for
C
15H19O3NNa+ 284.1263.
4-(1-Nitr ocycloh exyl)-4-p h en ylbu ta n -2-on e (3e) was pu-
Exp er im en ta l Section
rified by preparative TLC using 10% Et2O/CH2Cl2 and isolated
as a colorless oil. Enantiomers were separated by HPLC using
a Chiralpak AS chiral stationary phase in hexane/2-propanol
90/10: 1H NMR (CDCl3) δ 1.04-1.69 (m, 8H), 2.02 (s, 3H), 2.32
(br dd, J ) 2.4, 14.4 Hz, 1HH), 2.52 (br dd, J ) 2.4, 14.4 Hz,
1H), 2.92 (dd, J ) 4.4, 17.6 Hz, 1H), 3.02 (dd, J ) 9.6, 17.6
Hz, 1H), 3.64 (dd, J ) 4.4, 9.6 Hz, 1H), 7.11 (dd, J ) 1.6, 7.6
Hz, 2H), 7.25-7.29 (m, 3H); 13C NMR (CDCl3) δ 22.0, 22.2,
24.4, 30.5, 31.3, 33.7, 43.6, 49.6, 94.1, 127.8, 128.4, 129.1, 137.8,
205.6; HRMS m/z 298.1416 (M + Na+), calcd for C16H21O3NNa+
298.1419.
Gen er a l Meth od s. The 1H NMR and 13C NMR were
recorded at 400 and 100 MHz, respectively. The chemical shifts
are reported in ppm downfield to TMS (δ ) 0) for 1H NMR
and relative to the to the central CDCl3 resonance (δ ) 77.0).
Flash chromatography (FC) was carried out using silica gel
60 (230-400 mesh). The enantiomeric excess (ee) of the
products were determined by chiral stationary phase GC or
HPLC, as indicated in the respective entries.
Ma ter ia ls. All solvents and commercially available chemi-
cals were used as received. 1-Phenylpent-1-en-3-one 2b ,11
J . Org. Chem, Vol. 67, No. 24, 2002 8335

Halland et al.
2-Nitr o-5-oxo-3-p h en ylh exa n oic Acid Eth yl Ester (3f)
was purified as a 1:1 diastereomeric mixture by FC using Et2O/
pentane and isolated as a colorless oil. Enantiomeric excess
was determined as for compound 3b after decarboxylation
(EtOH/H2O, Et3N, 50 °C overnight): 1H NMR (CDCl3, mixture
of diastereomers) δ 1.06 (t, J ) 6.8 Hz, 3H), 1.29 (t, J ) 7.6
Hz, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 2.92-3.14 (m, 4H, CH2 for
both diastereomers), 4.05 (q, J ) 7.2 Hz, 1H), 4.07 (q, J ) 6.8
Hz, 1H), 4.22-4.30 (m, 4H, CH2 for both diastereomers), 5.40
(d, J ) 8.8 Hz, 1H), 5.47 (d, J ) 9.6 Hz, 1H), 7.23-7.31 (m,
10H); 13C NMR (CDCl3, mixture of diastereomers) δ 13.4, 13.6,
30.0, 30.1, 41.1, 41.4, 45.0, 45.2, 62.7, 63.1, 91.1, 127.8, 127.9,
128.2, 128.7, 128.8, 136.7, 137.7, 163.1, 163.4, 204.7; HRMS
m/z 302.1004 (M + Na+), calcd for C14H17O5NNa+ 302.1004.
single recrystalization in hexane/2-propanol increased the
enantioselectivity to 98% ee: [RrtD] ) -56.4° (c ) 1.0 g/100
1
mL, EtOH, 98% ee); H NMR (CDCl3) δ 1.50 (s, 3H), 1.55 (s,
3H), 2.06 (s, 3H), 2.85 (dd, J ) 3.2, 17.6 Hz, 1H), 3.11 (dd, J
) 10.4, 17.6 Hz, 1H), 4.01 (dd, J ) 3.2, 10.4 Hz, 1H), 7.36 (d,
J ) 8.8 Hz, 2 H), 8.14 (d, J ) 8.8 Hz, 2 H); 13C NMR (CDCl3)
δ 23.1, 25.1, 30.2, 43.7, 48.2, 90.3, 123.5, 130.0, 145.5, 147.3,
204.2; HRMS m/z 303.0952 (M + Na+), calcd for C13H16O5N2-
Na+ 303.0957.
4-(4-Hyd r oxyp h en yl)-5-m eth yl-5-n itr oh exa n -2-on e (3l)
was purified by FC using Et2O/CH2Cl2 and isolated as a
colorless solid. Enantiomers were separated by HPLC using a
Chiralpak AD chiral stationary phase in hexane/2-propanol
90/10: 1H NMR (CDCl3) δ 1.47 (s, 3H), 1.53 (s, 3H), 2.04 (s,
3H), 2.67 (dd, J ) 3.2, 16.4 Hz, 1H), 3.04 (dd, J ) 10.8, 16.4
Hz, 1H), 3.84 (dd, J ) 3.2, 10.8 Hz, 1H), 5.57 (br s, 1H), 6.68
(d, J ) 8.4 Hz, 2 H), 7.02 (d, J ) 8.4 Hz, 2 H); 13C NMR (CDCl3
+ CD3OD) δ 22.0, 25.3, 30.0, 43.9, 48.1, 91.3, 115.1, 127.9,
130.0, 156.3, 206.7; HRMS m/z 254.1053 (M + Na+), calcd for
5-Nitr o-4,5-d ip h en ylp en ta n -2-on e (3g) was purified by
FC using Et2O/pentane, and the diastereomers were isolated
as colorless solids. Enantiomers were separated by HPLC
using a Chiralcel OB stationary phase in ethanol/hexane 50/
50 for the major diastereomer and a Chiralpak AS chiral
stationary phase in hexane/2-propanol 50/50 for the minor
diastereomer: 1H NMR (CDCl3, minor diastereomer) δ 1.71
(s, 3H), 2.28 (dd, J ) 3.6, 17.2 Hz, 1H), 2.61 (dd, J ) 10.0,
17.2 Hz, 1H), 4.25 (dt, J ) 3.6, 12.4 Hz, 1H), 5.69 (d, J ) 12.0
Hz, 1H), 7.11-7.28 (m, 5H), 7.32-7.35 (m, 3H), 7.50-7.53 (m,
2H); 13C NMR (CDCl3, minor diastereomer) δ 30.6, 44.6, 45.7,
95.5, 127.8, 128.2, 128.3, 128.4, 128.7, 128.9, 132.6, 138.6,
205.1; 1H NMR (CDCl3, major diastereomer) δ 2.01 (s, 3H),
2.78 (dd, J ) 3.2, 17.2 Hz, 1H), 3.11 (dd, J ) 10.4, 17.2 Hz,
1H), 4.32 (dt, J ) 3.2, 11.2 Hz, 1H), 5.69 (d, J ) 11.2 Hz, 1H),
C
13H17O4NNa+ 254.1055.
5-Meth yl-5-n itr o-4-th iop h en -2-ylh exa n -2-on e (3m ) was
purified by FC using Et2O/pentane and isolated as a colorless
oil. Enantiomers were separated by GC using a Chirasil Dex-
CB chiral stationary phase after reductive amination to 2,2,5-
trimethyl-3-(tetrahydrothiophen-2-yl)pyrrolidine 5c and TFA
protection of the amine (TFAA, CH2Cl2, 60 °C, 30 min): 1H
NMR δ 1.53 (s, 3H), 1.62 (s, 3H), 2.06 (s, 3H), 2.65 (dd, J )
3.2, 16.4 Hz, 1H), 3.01 (dd, J ) 10.8, 16.8 Hz, 1H), 4.30 (dd, J
) 3.2, 10.8 Hz, 1H), 6.90-6.95 (m, 2H), 7.20 (dd, J ) 1.2, 5.2
Hz, 1H); 13C NMR δ 22.4, 25.5, 30.3, 44.2, 45.5, 90.9, 124.8,
126.8, 127.4, 140.1, 204.4.
7.04-7.14 (m, 5H), 7.20-7.24 (m, 3H), 7.31-7.34 (m, 2H); 13
C
NMR (CDCl3, major diastereomer) δ 30.6, 44.5, 46.5, 95.1,
127.4, 128.2, 128.3, 128.6, 128.7, 129.6, 132.5, 137.4, 205.0;
HRMS m/z 306.1111 (M + Na+), calcd for C17H17O3NNa+
306.1106.
4-F u r a n -2-yl-5-m eth yl-5-n itr oh exa n -2-on e (3n ) was pu-
rified by FC using Et2O/pentane and isolated as a colorless
oil. Enantiomers were separated by GC using an Chiraldex
G-TA chiral stationary phase: 1H NMR δ 1.49 (s, 3H), 1.56 (s,
3H), 2.07 (s, 3H), 2.52 (dd, J ) 3.2, 17.2 Hz, 1H), 3.07 (dd, J
) 10.8, 17.2 Hz, 1H), 4.10 (dd, J ) 3.2, 10.8 Hz, 1H), 6.17 (d,
J ) 3.6 Hz, 1H), 6.29 (dd, J ) 1.6, 3.2 Hz, 1H), 7.31 (m, 1H);
13C NMR δ 22.3, 25.7, 30.0, 42.0, 42.4, 90.4, 109.1, 110.4, 142.1,
151.1, 204.6; HRMS m/z 248.0898 (M + Na+), calcd for
6-Meth yl-6-n itr o-5-p h en ylh ep ta n -3-on e (3h ) was puri-
fied by FC using Et2O/pentane and isolated as a colorless oil.
Enantiomers were separated by GC using a Chirasil Dex-CB
chiral stationary phase: 1H NMR (CDCl3) δ 0.90 (t, J ) 7.2
Hz, 3H), 1.48 (s, 3H), 1.55 (s, 3H), 2.22 (dq, J ) 18.0, 7.6 Hz,
1H), 2.37 (dq, J ) 18.0, 7.6 Hz, 1H), 2.67 (dd, J ) 3.6, 16.8
Hz, 1H), 3.07 (dd, J ) 10.8, 16.8 Hz, 1H), 3.94 (dd, J ) 3.6,
10.8 Hz, 1H), 7.16-7.19 (m, 2H), 7.23-7.31 (m, 3H); 13C NMR
(CDCl3) δ 7.5, 22.4, 25.9, 36.4, 42.8, 48.8, 91.0, 127.8, 128.5,
129.1, 137.7, 207.8; HRMS m/z 272.1263 (M + Na+), calcd for
C
11H15O4NNa+ 248.0899.
5-Meth yl-5-n itr o-4-p yr id in -2-ylh exa n -2-on e (3o) was
purified by FC using Et2O/pentane and isolated as a colorless
oil. Enantiomers were separated by HPLC using a Chiralcel
OJ chiral stationary phase in hexane/2-propanol 92/8; 1H NMR
(CDCl3) δ 1.43 (s, 3H), 1.62 (s, 3H), 2.03 (s, 3H), 2.56 (dd, J )
2.8, 17.6 Hz, 1H), 3.58 (dd, J ) 10.8, 17.6 Hz, 1H), 4.07 (dd, J
) 2.8, 10.8 Hz, 1H), 7.14 (dd, J ) 5.2, 8.0 Hz, 1H), 7.25 (d, J
) 7.2 Hz, 1H), 7.59 (dt, J ) 1.6, 8.0 Hz, 1H), 8.48 (d, J ) 5.2
Hz, 1H); 13C NMR (CDCl3) δ 22.5, 25.2, 30.2, 43.0, 49.3, 91.1,
122.5, 126.2, 136.3, 148.9, 157.5, 205.8; HRMS m/z 237.1241
(M + Na+), calcd for C12H17O3N2Na+ 237.1239.
4-(1-Meth yl-1-n itr oeth yl)octa n -2-on e (3p ) was purified
by FC using Et2O/pentane and isolated as a colorless oil.
Enantiomers were separated by GC using a Chirasil Dex-CB
chiral stationary phase: 1H NMR (CDCl3) δ 0.86 (t, J ) 6.8
Hz, 3H), 1.03-1.44 (m, 6H), 1.51 (s, 3H), 1.52 (s, 3H), 2.17 (s,
3H), 2.34 (dd, J ) 6.0, 18.4 Hz, 1H), 2.52 (dd, J ) 4.4, 18.4
Hz, 1H), 2.75 (m, 1H); 13C NMR (CDCl3) δ 13.6, 22.5, 23.4,
23.5, 29.7, 30.7, 41.0, 44.7, 91.5, 205.9; HRMS m/z 238.1420
(M + Na+), calcd for C11H21O3NNa+ 238.1419.
4-Isop r op yl-5-m eth yl-5-n itr oh exa n -2-on e (3q) was puri-
fied by FC using Et2O/pentane and isolated as a colorless oil.
Enantiomers were separated by GC using a Chirasil Dex-CB
chiral stationary phase: 1H NMR (CDCl3) δ 0.75 (d, J ) 7.2
Hz, 3H), 0.87 (d, J ) 7.2 Hz, 3H), 1.51 (s, 6H), 1.87 (d septet,
J ) 2.4, 6.8 Hz, 1H), 2.18 (s, 3H), 2.39-2.57 (m, 2H), 2.76 (dt,
J ) 2.4, 6.8 Hz, 1H); 13C NMR (CDCl3) δ 17.6, 23.8, 24.5, 24.8,
27.4, 29.8, 39.8, 45.9, 91.4, 206.6; HRMS m/z 224.1258 (M +
Na+), calcd for C10H19O3NNa+ 224.1258.
C
14H19O3NNa+ 272.1263.
2,6-Dim eth yl-6-n itr o-5-p h en ylh ep ta n -3-on e (3i) was pu-
rified by FC using Et2O/pentane and isolated as a colorless
solid: 1H NMR (CDCl3) δ 0.90 (d, J ) 6.8 Hz, 3H), 0.98 (d, J
) 6.8 Hz, 3H), 1.49 (s, 3H), 1.56 (s, 3H), 2.48 (septet, J ) 6.8
Hz, 1H), 2.71 (dd, J ) 3.2, 17.2 Hz, 1H), 3.14 (dd, J ) 10.4,
17.2 Hz, 1H), 3.94 (dd, J ) 3.2, 10.4 Hz, 1H), 7.16-7.19 (m,
2H), 7.24-7.29 (m, 3H); 13C NMR (CDCl3) δ 17.8, 17.9, 18.5,
22.6, 26.0, 41.0, 48.7, 91.0, 127.7, 128.4, 129.2, 137.9, 211.0;
HRMS m/z 286.1416 (M + Na+), calcd for C15H21O3NNa+
286.1419.
4-(4-Ch lor op h en yl)-5-m eth yl-5-n itr oh exa n -2-on e (3j)
was purified by FC using Et2O/pentane and isolated as a
colorless oil. Enantiomers were separated by GC using an
Chiraldex G-TA chiral stationary phase. A single recrystal-
ization in EtOH increased the enantioselectivity to 94% ee:
[RrtD] ) -38.0° (c ) 1.0 g/100 mL, EtOH, 94% ee). For details
on the X-ray analysis, see the Supporting Information. 1H
NMR (CDCl3) δ 1.47 (s, 3H), 1.53 (s, 3H), 2.04 (s, 3H), 2.73
(dd, J ) 3.2, 17.2 Hz, 1H), 3.03 (dd, J ) 10.8, 17.2 Hz, 1H),
3.89 (dd, J ) 3.2, 10.8 Hz, 1H), 7.12 (d, J ) 8.4 Hz, 2 H), 7.28
(d, J ) 8.4 Hz, 2 H); 13C NMR (CDCl3) δ 22.5, 25.4, 30.3, 43.8,
48.1, 90.7, 128.7, 130.3, 133.7, 136.1, 204.8; HRMS m/z
292.0719 (M + Na+), calcd for C13H16O3NClNa+ 292.0716.
5-Meth yl-5-n itr o-4-(4-n itr oph en yl)h exan -2-on e (3k) was
purified by FC using Et2O/pentane and isolated as a colorless
oil. Enantiomers were separated by HPLC using a Chiralpak
AD chiral stationary phase in hexane/2-propanol 90/10. A
2-(1-Meth yl-1-n itr oeth yl)-4-oxop en ta n oic a cid m eth yl
ester (3s) was purified by FC using Et2O/pentane and isolated
8336 J . Org. Chem., Vol. 67, No. 24, 2002

Addition of Nitroalkanes to R,â-Unsaturated Enones
as a colorless solid. Enantiomers were separated by GC using
a Chirasil Dex-CB chiral stationary phase: 1H NMR (CDCl3)
δ 1.58 (s, 3H), 1.61 (s, 3H), 2.16 (s, 3H), 2.40 (dd, J ) 2.8, 18.0
Hz, 1H), 3.04 (dd, J ) 11.2, 18.0 Hz, 1H), 3.67 (dd, J ) 2.8,
11.2 Hz, 1H), 3.71 (s, 3H): 13C NMR (CDCl3) δ 22.9, 25.6, 29.8,
41.4, 48.2, 52.5, 88.2, 171.4, 205.0; HRMS m/z 240.0844 (M +
Na+), calcd for C9H15O5NNa+ 240.0848.
2,4,5-Tr ip h en ylim id a zolid in e (4g) was isolated as a
colorless solid: 1H NMR (CDCl3) δ 2.35 (br s, 2H), 4.36 (s, 2H),
5.50 (s, 1H), 7.18-7.46 (m, 13H), 7.72 (d, J ) 7.6 Hz, 2H); 13
C
NMR (CDCl3) δ 69.5, 71.4, 76.8, 126.6, 126.8, 126.9, 127.1,
127.6, 127.7, 127.8, 128.0, 128.1, 128.3, 128.4, 128.5, 140.7,
+
142.4; HRMS m/z 302.1703 (M + H+), calcd for C21H21N2
302.1705.
2,2-Dim eth yl-4,5-d ip h en ylim id a zolid in e (4h ) was iso-
lated as a colorless solid: 1H NMR (CDCl3) δ 1.54 (s, 6H), 1.79
(br s, 2H), 4.10 (s, 1H), 4.25 (s, 1H), 7.25-7.28 (m, 10H); 13C
NMR (CDCl3) δ 30.3, 61.6, 70.0, 75.6, 126.6, 126.7, 126.8, 127.1,
127.9, 128.1, 140.4, 143.2; HRMS m/z 275.1491 (M + Na+),
calcd for C17H20N2Na+ 275.1524.
4,5-Dip h en ylim id a zolid in e (4i) was isolated as a colorless
solid after purification by FC on silica using 2-propanol/CH2-
Cl2: 1H NMR (CDCl3) δ 2.80-3.30 (br, 2H), 4.25 (s, 2H), 4.32
(s, 2H), 7.20-7.33 (m, 10H); 13C NMR (CDCl3 + CD3OD) δ 60.5,
64.1, 69.0, 126.6, 126.7, 127.7, 127.8, 128.2, 128.5, 137.9, 139.0.
Gen er a l P r oced u r e for th e Red u ctive Am in a tion of
Nitr o Keton es. To a suspension of Raney-nickel in MeOH or
EtOH in an appropriate vessel was added nitro ketone and
H2 at the indicated pressure, and the reaction mixture was
stirred at ambient temperature overnight (12-16 h). After
reaction the Raney-nickel catalyst was filtered off using a fine
filter (0.45 µm), to give quantitative yields of the analytically
pure pyrrolidine.
P r oced u r e for th e Syn th esis 4-Ben zyl- a n d 4-P h en yl-
1-m eth ylim id a zolid in e-2-ca r boxylic Acid (4c,d ). Syn th e-
sized Accor d in g to Sch em e 1. (S)-Phenylalanine-N-meth-
ylamide was prepared by the method of Macmillan et al.10j in
quantitative yield followed by reduction of the amide by LiAlH4
in refluxing THF for 12 h or until all starting material was
consumed (TLC). After quenching with a minimal amount of
H2O, filtration, and extraction with CH2Cl2, N1-methyl-3-
phenylpropane-1,2-diamine was obtained as a colorless oil in
92% yield. If necessary, the N1-methyl-3-phenylpropane-1,2-
diamine could be further purified by distillation (bp 120 °C,
0.4 mbar). Condensation with an equimolar amount of gly-
oxylic acid monohydrate was performed in CH2Cl2 at ambient
temperature for 15 h, after which the solvent was evaporated
to give 4-benzyl-1-methylimidazolidine-2-carboxylic acid (4c)
as a slightly hygroscopic colorless solid that could be stored
for months after drying under vacuum. The 1-methyl-4-
phenylimidazolidine-2-carboxylic acid (4d ) was prepared simi-
larly.
3,5-cis-2,2,5-Tr im eth yl-3-p h en ylp yr r olid in e (5a ). After
reductive amination, the Raney-nickel catalyst was filtered off
to yield 5a as an analytically pure compound. The diastereo-
meric ratio was determined by GC. Enantiomers were sepa-
rated by GC using a Chirasil Dex-CB chiral stationary phase:
1H NMR (CDCl3) δ 0.73 (s, 3H), 1.24 (s, 3H), 1.26 (d, J ) 6.4
Hz, 3H), 1.84 (dt, J ) 9.6, 12.0 Hz, 1H), 2.21 (quintet, J ) 6.4
Hz), 3.03 (dd, J ) 6.4, 12.0 Hz, 1H), 3.36 (dq, J ) 16.4, 5.6
Hz, 1H), 7.18-7.22 (m, 3H), 7.26-7.30 (m, 2H); 13C NMR
(CDCl3) δ 22.1, 27.1, 30.1, 40.6, 51.7, 56.6, 61.6, 126.2, 127.9,
128.2, 141.3; HRMS m/z 190.1592 (M + H+), calcd for C13H20N+
190.1596.
4-Ben zyl-1-m eth ylim id a zolid in e-2-ca r boxylic a cid (4c)
was isolated as a colorless solid in a 2:1 mixture of diastere-
omers: 1H NMR (CDCl3, major diastereomer) δ 2.52-2.93 (m,
2H), 2.89 (s, 3H), 3.21 (dd, J ) 5.8, 13.4 Hz, 1H), 3.41-3.48
(m, 1H), 3.74 (quintet, J ) 6.8 Hz, 1H), 4.19 (s, 1H), 7.20-
7.31 (m, 5H); 13C NMR (CDCl3, major diastereomer) δ 38.4,
40.6, 58.1, 58.8, 85.6, 126.9, 128.8, 128.7, 137.4, 168.8; 1H NMR
(CDCl3, minor diastereomer) δ 2.52-2.93 (m, 2H), 2.84 (s, 2H),
3.01 (dd, J ) 6.3, 13.4 Hz, 1H), 3.64-3.71 (m, 1H), 4.01
(quintet, J ) 6.7 Hz, 1H), 4.12 (s 1H), 7.20-7.31 (m, 5H); 13
C
NMR (CDCl3, minor diastereomer) δ 39.3, 40.3, 57.3, 58.9, 82.3,
126.8, 128.6, 129.2, 137.3, 169.4; HRMS m/z 243.1100 (M +
Na+), calcd for C12H16O2N2Na+ 243.1109.
2,3,5-cis-5-Met h yl-2,3-d ip h en ylp yr r olid in e (5b ). After
reductive amination, the Raney-nickel catalyst was filtered off
to yield 5b as an analytically pure compound. The diastereo-
meric ratio was determined by GC. Enantiomers were sepa-
rated by GC using a Chirasil Dex-CB chiral stationary phase.
For details on the X-ray analysis, see the Supporting Informa-
tion: 1H NMR (CDCl3) δ 1.43 (d, J ) 6.4 Hz, 3H), 1.79 (dt, J
) 12.4, 9.0 Hz, 1H), 1.94 (br, 1H), 2.36 (ddd, J ) 6.8, 8.0, 12.4
Hz, 1H), 3.51 (ddq, J ) 6.4, 12.4, 9.2 Hz, 1H), 3.65 (q, J ) 8.4
Hz, 1H), 4.57 (d, J ) 8.0 Hz, 1H), 6.90-6.93 (m, 2H), 6.97-
7.05 (m, 8H); 13C NMR (CDCl3) δ 21.1, 40.2, 50.8, 53.5, 67.2,
125.6, 126.1, 127.3, 127.4, 127.5, 128.7, 142.0, 142.3; HRMS
m/z 238.1588 (M + H+), calcd for C17H20N+ 238.1596.
3-Bu tyl-2,2,5-tr im eth ylp yr r olid in e (5c). After reductive
amination, the Raney-nickel catalyst was filtered off to yield
5c as an analytically pure compound. The diastereomeric ratio
was determined by GC. Enantiomers were separated by GC
using a Chirasil Dex-CB chiral stationary phase after TFA
protection of the amine (TFAA, CH2Cl2, 60 °C, 30 min): 1H
NMR (CDCl3) δ 0.85-0.89 (m, 3H), 1.12-1.61 (m, 8H), 1.37
(s, 3H), 1.52 (d, J ) 3.2 Hz, 3H), 1.55 (s, 3H), 1.91-2.01 (m,
1H), 2.28-2.37 (m, 1H), 3.84 (ddq, J ) 7.2, 14.4, 10.4 Hz, 1H);
13C NMR (CDCl3) δ 13.9, 19.8, 21.1, 22.7, 25.7, 28.5, 30.4, 37.9,
48.5, 52.7, 66.0.
2,3,5-cis-5-Meth yl-3-ph en ylpyr r olidin e-2-car boxylic acid
eth yl ester (5d ) was separated from 5e by FC on silica gel
using MeOH/CH2Cl2. The diastereomeric ratio was determined
by GC. Enantiomers were separated by GC using a Chirasil
Dex-CB chiral stationary phase: 1H NMR (CDCl3) δ 0.73 (t, J
) 7.2 Hz, 3H), 1.37 (d, J ) 6.4 Hz, 3H), 1.37 (q, J ) 10.4 Hz,
1H), 2.00-2.18 (br, 1H), 2.21-2.27 (m, 1H), 3.27 (septet, J )
5.2 Hz, 1H), 3.49 (dq, J ) 10.4, 7.2 Hz, 1H), 3.64-3.74 (m,
2H), 4.03 (d, J ) 10.0 Hz, 1H), 7.16-7.27 (m, 5H); 13C NMR
(CDCl3) δ 13.4, 20.0, 41.2, 50.0, 54.0, 60.4, 66.1, 126.7, 127.9,
1-Meth yl-4-p h en ylim id a zolid in e-2-ca r boxylic a cid (4d )
was isolated as a colorless solid in a 1.5:1 mixture of diaster-
eomers; 1H NMR (CDCl3, major diastereomer) δ 2.78-2.83 (dd,
J ) 7.6, 11.2 Hz, 2H), 2.93 (s, 3H), 4.27 (s, 1H), 4.90 (t, J )
7.6 Hz, 1H), 7.24-7.50 (m, 5H); 13C NMR (CDCl3, major
diastereomer) δ 38.8, 58.6, 61.1, 83.1, 126.1, 127.3, 128.6,
136.5, 169.5; 1H NMR (CDCl3, minor diastereomer) δ_2.99 (s,
3H), 3.20 (dd, J ) 7.2, 11.2 Hz, 2H), 4.39 (s, 1H), 4.61 (t, J )
7.6 Hz, 1H), 7.24-7.50 (m, 5H); 13C NMR (CDCl3, minor
diastereomer) δ 40.6, 59.4, 59.8, 83.8, 126.4, 127.2, 128.4,
140.0, 169.4; HRMS m/z 229.0952 (M + Na+), calcd for
C
12H16O2N2Na+ 229.0953.
Gen er a l P r oced u r e for t h e Syn t h esis of (4R,5R)-
Dip h en ylim id a zolid in e Ca ta lysts (4e-i). To a solution of
(R,R)-diphenylethanediamine in CH2Cl2 was added an equimo-
lar amount of glyoxylic acid monohydrate 4e, or diethyl
ketomalonate 4f, or benzaldehyde 4g, or 2 equiv of acetone
4h , or paraformaldehyde 4i, and the reaction mixture was
stirred at ambient temperature for 15 h. The solvent was
removed by rotary evaporation to yield the catalyst as a
colorless solid, which was further dried under vacuum.
4,5-Dip h en ylim id a zolid in e-2-ca r boxylic a cid (4e) was
1
isolated as a colorless solid. H NMR ((CD3)2CO) δ 4.01 (d, J
) 9.0 Hz, 1H), 4.30 (d, J ) 9.0 Hz, 1H), 5.29 (s, 1H), 7.09 (m,
3H), 7.21-7.28 (m, 10H); 13C NMR ((CD3)2SO) δ 68.1, 69.2,
74.6, 127.5, 127.7, 127.9, 128.4, 128.5, 137.9, 138.5, 171.4.
4,5-Dip h en ylim id a zolid in e-2,2-d ica r boxylic a cid d i-
eth yl ester (4f) was isolated as a colorless solid: 1H NMR
(CDCl3) δ 1.39 (t, J ) 7.2 Hz, 6H), 4.39 (q, J ) 7.2 Hz, 4H),
4.67 (s, 1H), 4.69 (s, 1H), 7.00-7.26 (m, 10H); 13C NMR (CDCl3)
δ 13.9, 59.9, 62.8, 64.7, 84.1, 127.4, 127.8, 127.9, 128.0, 128.2,
128.3, 137.2, 137.6, 166.9, 170.2.
J . Org. Chem, Vol. 67, No. 24, 2002 8337

Halland et al.
128.0, 140.5, 173.2; HRMS m/z 256.1313 (M + Na+), calcd for
by GC using a Chirasil Dex-CB chiral stationary phase: 1H
NMR (CDCl3) δ 1.25 (t, J ) 7.6 Hz, 3H), 2.14 (d, J ) 2.0 Hz,
3H), 2.70 (dd, J ) 6.8, 17.2 Hz, 1H), 3.15 (ddd, J ) 2.0, 10.0,
17.2 Hz, 1H), 3.73 (dt, J ) 10.0, 6.8 Hz, 1H), 4.15-4.23 (m,
2H), 4.65-4.68 (m, 1H), 7.16-7.31 (m, 5H); 13C NMR (CDCl3)
δ 14.1, 19.7, 46.6, 48.3, 61.1, 82.2, 126.7, 126.9, 128.7, 143.0,
C
14H19NO2Na+ 256.1313.
2,3-tr a n s-5-Met h yl-3-p h en ylp yr r olid in e-2-ca r b oxylic
a cid eth yl ester (5e) was separated from 5d by FC on silica
gel using MeOH/CH2Cl2. The diastereomeric ratio was deter-
mined by GC. Enantiomers were separated by GC using a
Chirasil Dex-CB chiral stationary phase: 1H NMR (CDCl3,
major diastereomer) δ 1.18 (t, J ) 6.8 Hz, 3H), 1.25 (d, J )
6.4 Hz, 3H), 1.62 (dt, J ) 11.6, 10.8 Hz, 1H), 2.29-2.35 (m,
1H), 3.36 (dt, J ) 10.8, 7.6 Hz, 1H), 3.47 (septet, J ) 6.0 Hz,
1H), 3.84 (d, J ) 7.6 Hz, 1H), 4.05-4.23 (m, 2H), 7.30-7.33
(m, 5H); 13C NMR (CDCl3, major diastereomer) δ 14.1, 21.1,
44.0, 50.7, 54.5, 60.9, 67.1, 126.6, 127.3, 128.5, 142.9, 175.2;
HRMS m/z 256.1313 (M + Na+), calcd for C14H19NO2Na+
256.1314.
172.3, 177.3; HRMS m/z 254.1154 (M + Na+), calcd for C14H17
-
NO2Na+ 254.1157.
Ack n ow led gm en t. This work was made possible by
a grant from The Danish National Research Foundation.
Su p p or tin g In for m a tion Ava ila ble: Complete X-ray
data for compounds 3j and 5b. This material is available free
of charge via the Internet at http.//pubs.acs.org.
tr a n s-5-Meth yl-3-p h en yl-3,4-d ih yd r o-2H-p yr r ole-2-ca r -
boxylic a cid eth yl ester (5f) was separated from 5e,f by FC
on silica gel using MeOH/CH2Cl2. Enantiomers were separated
J O0261449
8338 J . Org. Chem., Vol. 67, No. 24, 2002