Asymmetric synthesis of β-nitro ketones via Michael addition of lithiated α-amino nitriles to nitroalkenes

Article abstract of DOI:10.1021/jo8017318

(Chemical Equation Presented) α-Amino nitriles, easily prepared from aldehydes, KCN, and an enantiopure secondary amine auxiliary, are metalated and used as nucleophiles in asymmetric Michael additions to nitroalkenes to afford the Michael adducts in good

Full text of DOI:10.1021/jo8017318

Asymmetric Synthesis of ꢀ-Nitro Ketones via Michael Addition of
Lithiated r-Amino Nitriles to Nitroalkenes†
Dieter Enders,* Dominik Fo¨rster, Gerhard Raabe, and Jan W. Bats‡
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1, 52074 Aachen, Germany, and
Institute of Organic Chemistry, UniVersity of Frankfurt, Max-Von-Laue-Strasse 9,
60438 Frankfurt am Main, Germany
enders@rwth-aachen.de
ReceiVed August 07, 2008
R-Amino nitriles, easily prepared from aldehydes, KCN, and an enantiopure secondary amine auxiliary,
are metalated and used as nucleophiles in asymmetric Michael additions to nitroalkenes to afford the
Michael adducts in good yields and good to excellent diastereoselectivities. After chromatographic
purification, the diastereomerically pure 1,4-adducts are cleaved under acidic conditions to give the ꢀ-nitro
ketones in good yields and with two exceptions in good to excellent enantiomeric excesses (ee ) 86-99%).
The absolute configuration was determined by X-ray structure analysis.
Introduction
mained relatively low.6 Later, high levels of asymmetric
inductions were reached with (S,S)-2,2-dimethyl-5-methylamino-
4-phenyl-1,3-dioxane [(S,S)-1], a chiral secondary amine aux-
iliary easily prepared on a mole scale from a commercially
available pharmaceutical intermediate (wrong enantiomer in the
chloramphenicol synthesis),7 and a variety of electrophiles
including Michael acceptors could be used.8 Moreover, we
recently developed an asymmetric nucleophilic glyoxylation
method via metalated R-amino nitriles.9
R-Amino nitriles have played an important role as bifunctional
compounds in organic chemistry ever since the report on the
Strecker reaction in 1850.1 Among the various synthetic
applications, the use of metalated R-amino nitriles as masked
acyl anion equivalents is a powerful nucleophilic acylation
method.2 The most widely used method for the Umpolung of
the carbonyl reactivity is the Corey-Seebach reaction employ-
ing lithiated 1,3-dithianes.3 Other protocols include catalytic
conditions, such as the Stetter reaction,4 and even neutral
conditions employing aldehyde N,N-dialkylhydrazones.5
In early attempts to develop asymmetric nucleophilic acyla-
tions via metalated R-amino nitriles, we mainly used proline-
derived chiral auxiliaries, but the enantiomeric excesses re-
(6) Enders, D.; Lotter, H.; Maigrot, N.; Mazaleyrat, J.-P.; Welvart, Z. NouV.
J. Chim. 1984, 8, 747.
(7) Enders, D.; Gerdes, P.; Kipphardt, H. Angew. Chem., Int. Ed. Engl. 1990,
29, 179.
(8) (a) Enders, D.; Mannes, D.; Raabe, G. Synlett 1992, 837. (b) Enders, D.;
Kirchhoff, J.; Mannes, D.; Raabe, G. Synthesis 1995, 659. (c) Enders, D.;
Kirchhoff, J.; Lausberg, V. Liebigs. Ann. 1996, 1361. (d) Enders, D.; Kirchhoff,
J.; Gerdes, P.; Mannes, D.; Raabe, G.; Runsink, J.; Boche, G.; Marsch, M.;
Ahlbrecht, H.; Sommer, H. Eur. J. Org. Chem. 1998, 63. (e) Enders, D.; Shilvock,
J. P.; Raabe, G. J. Chem. Soc., Perkin Trans. 1 1999, 1617. (f) Pierre, F.; Enders,
D. Tetrahedron Lett. 1999, 40, 5301. (g) Enders, D.; Lausberg, V.; Del Signore,
G.; Berner, O. M. Synthesis 2002, 515. (h) Enders, D.; Del Signore, G.; Berner,
O. M. Chirality 2003, 15, 510. (i) Enders, D.; Milovanovic, M.; Voloshina, E.;
Raabe, G.; Fleischhauer, J. Eur. J. Org. Chem. 2005, 1984. (j) Enders, D.;
Milovanovic, M. Z. Naturforsch. B 2007, 62b, 117.
† Dedicated to the memory of Professor Albert I. Meyers, a pioneer of
asymmetric synthesis.
‡ University of Frankfurt.
(1) Strecker, A. Liebigs Ann. Chem. 1850, 75, 27.
(2) For a review, see: (a) Enders, D.; Shilvock, J. P. Chem. Soc. ReV. 2000,
29, 359.
(3) For reviews, see: (a) Seebach, D. Synthesis 1969, 17. (b) Gro¨bel, B. T.;
Seebach, D. Synthesis 1977, 357. (c) Seebach, D. Angew. Chem., Int. Ed. Engl.
1979, 18, 239.
(4) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407.
(5) Review: Brehme, R.; Enders, D.; Ferna´ndez, R.; Lassaletta, J. M. Eur. J.
Org. Chem. 2007, 5629.
(9) (a) Enders, D.; Bonten, M. H.; Raabe, G. Angew. Chem., Int. Ed. 2007,
46, 2314. (b) For an organocatalytic version, see: Enders, D.; Bonten, M. H.;
Raabe, G. Synlett 2007, 885.
10.1021/jo8017318 CCC: $40.75
Published on Web 10/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9641–9646 9641

Enders et al.
SCHEME 1. Preparation of the Chiral r-Amino Nitriles 3a-d
SCHEME 2. Asymmetric Synthesis of ꢀ-Nitro Ketones 6
Nitroalkenes are excellent Michael acceptors in asymmetric
conjugate additions10 and allow synthetic transformations of the
nitro group to many other functionalities.11 Based on our long
experience with various nitroalkene 1,4-additions,12 we envis-
aged the asymmetric synthesis of ꢀ-nitro ketones through a
conjugate nucleophilic acylation protocol.13
of KCN under acidic conditions (Scheme 1). A chromatographic
separation of the R-epimeric amino nitriles 3a-d obtained in
52-86% yield is not necessary because in the subsequent
metalation step the new stereogenic center is destroyed by
formation of the corresponding N-lithio ketene imine inter-
mediates.8d,15
As is depicted in Scheme 2, the conjugate addition of the
R-amino nitriles 3 to aliphatic and aromatic E-configured
nitroalkenes 4a-e16 was performed by lithiation of 3 for 1.5 h
with 1.2 equiv of lithium diisopropylamide (LDA) in tetrahy-
drofuran at -78 °C, followed by the addition of the nitroalkenes
4 at -100 °C. In the case of the amino nitrile 3d derived from
the aliphatic aldehyde (R1 ) i-Pr), LDA had to be replaced by
the stronger base potassium diisopropylamide (KDA) to reach
good yields. The resulting Michael adducts 5a-h were obtained
in very good yields (82-90%) and moderate to excellent
diastereoselectivities (ds ) 62 - 97%) (Table 1). In all cases,
a chromatographic purification gave the diastereomerically pure
adducts 5 (de >98%). The best stereoselectivities were observed
with sterically demanding groups R2 (5d,f).
Results and Discussion
ꢀ-Nitroketones constitute important bifunctional compounds,
which may be transformed into other synthetic building blocks,
such as ꢀ-aminoketones or 1,3-amino alcohols. Employing a
well-established procedure,8,14 we first synthesized four different
R-amino nitriles 3a-d derived from aromatic and an aliphatic
aldehyde (2a-d) and the chiral auxiliary (S,S)-1 in the presence
(10) For a review, see: Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877.
(11) (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979, 33,
1. (b) Calderari, G.; Seebach, D. HelV. Chim. Acta 1995, 78, 1592.
(12) For selected examples, see: (a) Enders, D.; Syrig, R.; Raabe, G.;
Ferna´ndez, R.; Gasch, C.; Lassaletta, J. M.; Llera, J. M. Synthesis 1996, 48. (b)
Enders, D.; Wiedemann, J. Synthesis 1996, 1443. (c) Enders, D.; Haertwig, A.;
Raabe, G.; Runsink, J. Angew. Chem., Int. Ed. Engl. 1996, 35, 2388. (d) Enders,
D.; Haertwig, A.; Runsink, J. Eur. J. Org. Chem. 1998, 1793. (e) Enders, D.;
Otten, T. Synlett 1999, 747. (f) Enders, D.; Teschner, P.; Raabe, G. Synlett 2000,
637. (g) Enders, D.; Tedeschi, L.; Bats, J. W. Angew. Chem., Int. Ed. 2000, 39,
4605. (h) Enders, D.; Seki, A. Synlett 2002, 26. (i) Enders, D.; Chow, S. Eur. J.
Org. Chem. 2006, 4578. (j) See also: Okino, T.; Hoashi, Y.; Furukawa, T.; Xu,
X. N.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (k) McCooey, S. H.;
Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (l) Herrera, R. P.; Sgarzani,
V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576.
(13) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am.
Chem. Soc. 2006, 128, 4932.
Finally, for the amino nitrile cleavage the standard protocols
were tested using CuSO4,17 AgNO3,18 or HCl, respectively. The
best results were obtained with 1.5 N HCl in refluxing THF for
(15) Raabe, G.; Zobel, E.; Fleischhauer, J.; Gerdes, P.; Mannes, D.; Mu¨ller,
E.; Enders, D. Z. Naturforsch. 1991, 46a, 275.
(16) (a) Knochel, P.; Seebach, D. Synthesis 1982, 1017. (b) Worral, D. E.
J. Am. Chem. Soc. 1934, 56, 1556. (c) McCarthy, A.; Kahl, W. J. Org. Chem.
1956, 21, 1118. (d) Shiga, M.; Konto, H.; Motoyama, I.; Hata, K. Bull. Chem.
Soc. Jpn. 1968, 41, 1897.
(17) Stork, G.; Ozonio, A. A.; Leong, A. Y. W. Tetrahedron Lett. 1978, 19,
5175.
(18) Herbert, E.; Maigrot, N.; Welvart, Z. Tetrahedron. Lett. 1983, 24, 4683.
(14) Weinges, K.; Brachmann, H.; Stahnecker, P.; Rodewald, H.; Nixdorf,
M.; Irngartinger, H. Liebigs Ann. Chem. 1985, 566.
9642 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Synthesis of ꢀ-Nitro Ketones
TABLE 1. Asymmetric Michael Addition of Lithiated Amino
hydrolysis. After chromatographic purification of the intermedi-
ate Michael adducts, high enantiomeric excesses (ee ) 86-99%)
of the title compounds could be obtained. In the case of an
aromatic nitroolefin and an aliphatic aldehyde, however, a
substantial racemization during the amino nitrile cleavage was
observed. The absolute configuration of the ꢀ-nitro ketones could
be determined as S by X-ray crystallography.
Nitriles 3a-d to Nitroalkenes 4a-e To Afford the 1,4-Adducts 5a-h
[R]2D6
5
R1
R2
Et
yielda (%) dsb (de) (%)c (CHCl3)
a
b
c
d
e
f
piperonyl
piperonyl
piperonyl
piperonyl
piperonyl
90
89
90
82
87
82
84
90
63 (>98)
88 (>98)
74 (>98)
95 (>98)
72 (>98)
97 (>98)
66 (>98)
62 (>98)
+73
-19
i-Pr
c-Hex
t-Bu
tolyl
-39.5
-37
+141
-7
p-methoxyphenyl t-Bu
Experimental Section
g
h
p-bromphenyl
i-Pr
t-Bu
i-Pr
-9.5
-28.5
(4S,5S,2R/S)-Benzo[1,3]dioxol-5-yl[N-(2,2-dimethyl-4-
phenyl-1,3-dioxan-5yl)methylamino]acetonitrile (3a). Prepared
from 33.40 g (150 mmol) of (S,S)-1, 22.50 g (150 mmol) of
piperonal, and 9.80 g (150 mmol) of KCN. After crystallization
from EtOH, 3a was obtained as a diastereomeric mixture of
colorless crystals (41.40 g, 73% yield): mp 118 °C; [R]26D ) +108.8
(c ) 1.16, CHCl3); IR (KBr) ν ) 1483, 1237, 1204, 1087, 1039,
733 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.53, 1.57 (s, 3H), 1.55,
1.57 (s, 3H), 2.27, 2.40 (s, 3H), 2.85, 2,88 (td, J ) 3.4, 1.4 Hz,
1H), 4.20, 4.32 (dd, J ) 12.9, 3.3 Hz, 1H), 4,53,4.59 (dd, J )
12.9, 1.4 Hz, 1H), 5.24, 5.27 (d, J ) 3.6 Hz, 1H), 5.40, 5.50 (s,
1H), 5.86 (d, J ) 1.4 Hz, 1H), 5.87 (d, J ) 1.4 Hz, 1H), 5.94-7.39
(m, 8H) ppm; 13C NMR (75 MHz, CDCl3) δ 19.1, 19.4, 30.1, 30.3,
33.8, 38.1, 57.6, 61.2, 58.0, 63.1, 59.7, 60.8, 74.1, 75.2, 99.6, 99.9,
101.8, 101.9, 108.0, 108.4, 108.2, 118.3, 118.6, 121.1, 121.2, 126.1,
126.3, 127.7, 128.6, 128.8, 129.5, 139.8, 140.9, 148.0, 148.3, 148.4,
148.6 ppm; MS (EI) m/z 380 (0.4 M+), 216 (77), 215 (22), 176
(46), 175 (41), 161 (13), 160 (100), 91 (9), 77 (11), 41 (22). Anal.
Calcd for C22H24N2O4 (380.44): C, 69.46; H, 6.36; N, 7.36. Found:
C, 69.53, H, 6.45; N, 7.21.
a Yield of the diastereomeric mixture. b Determined by HPLC.
c Determined by NMR spectroscopy after chromatographic purification
of the major diastereomer.
TABLE 2. Removal of the Chiral Auxiliary from the Michael
Adducts 5a-h To Yield the ꢀ-Nitroketones 6a-h
6
R1
R2
yield (%) eea (%) [R]D26 (CHCl3)
a
b
c
d
e
f
piperonyl
piperonyl
piperonyl
piperonyl
piperonyl
p-methoxyphenyl t-Bu
p-bromphenyl
i-Pr
Et
i-Pr
c-Hex
t-Bu
tolyl
73
68
70
71
64
70
71
72
86
99
95
99
44
99
86
25
-68
-83
-22
-81
-8.5
-138
-100
-1.5
g
h
t-Bu
i-Pr
a Determined by HPLC on
a chiral stationary phase (6a,b,g,h:
Chiralpac OD, 250 mm × 4,6 mm, flow 0.5-1 mL/min, n-heptane/
2-propanol 90:10-95:5; 6c,d-f: Chiralpac AD, 250 mm × 4,6 mm,
flow 0.5-1 mL/min, n-heptane/2-propanol 90:10-95:5).
(4S,5S,2R/S)-[N-(2,2-Dimethyl-4-phenyl-1,3-dioxan-5-
yl)methylamino](4-methoxyphenyl)acetonitrile (3b). Prepared
from 5.50 g (25 mmol) of (S,S)-1, 3.40 g (25 mmol) of p-
methoxybenzaldehyde, and 1.63 g (25 mmol) of KCN. After
crystallization from MeOH, 3b was obtained as a diastereomeric
mixture of colorless crystals (4.80 g, 52% yield): mp 128 °C; [R]26D
) + 104.07 (c ) 1.43, CHCl3); IR (KBr) ν 2947, 1610, 1509,
1
1382, 1253, 1200, 1175, 1121, 1079, 1045, 740 cm-1; H NMR
(300 MHz, CDCl3) δ 1.53, 1.58 (s, 6H), 2.39 (s, 3H), 2.92 (m,
1H), 3.75 (s, 3H), 4.31, 4.35 (dd, J ) 13.1, 3.4 Hz, 1H), 4.45 (s,
1H), 4.52, 4.57 (dd, J ) 13.1, 1.5 Hz, 1H), 5.24 (d, J ) 3.2 Hz,
1H), 6.60-7.40 (m, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 18.8,
29.4, 33.1, 55.2, 60.2, 60.6, 62.3, 74.6, 99.1, 113.6, 117.8, 125.8,
126.0, 126.9, 128.1, 128.5, 140.1, 159.6 ppm; MS (EI) m/z 351 (3,
M+), 202 (52), 201 36), 162 (15), 161 (7), 147 (10), 146 (100), 91
(5). Anal. Calcd for C22H26N2O3 (366.45): C, 72.11; H, 7.15; N, 7,
64. Found: C, 72.42, H, 7.17; N, 7.73.
FIGURE 1. Proposed transition state.
15-30 min, and the ꢀ-nitro ketones 6a-h could be isolated in
good yields (64-73%) and high to excellent enantiomeric
excesses (ee ) 86-99%) (Table 2). However, in the case of an
aromatic substituent R2 (6e) and an aliphatic group R1 (6h) a
substantial racemization during the acidic nitrile cleavage could
not be avoided.
The absolute configuration of the Michael adduct 5g could
be determined by X-ray structure analysis. In addition, suitable
crystals of 6d for X-ray analysis were obtained by slow
crystallization from benzene.19 Assuming a uniform reaction
mechanism for all the Michael additions reported, the ꢀ-nitro
ketone title compounds should all be S-configured.
It is interesting to note that the stereochemical outcome of
the amino nitrile 1.4-additions to nitroalkenes is different from
the relative topicity previously observed for other Michael
acceptors.8d To explain the S-configuration, we propose the
transition state given in Figure 1, which includes an N-lithio
ketene imine to nitroalkene Si-Si attack and an attractive
interaction via the lithium cation.
(4S,5S,2R/S)-2-(4-Bromophenyl)-2-[N-(2,2-dimethyl-4-
phenyl-1.3-dioxan-5-yl)methylamino]acetonitrile (3c). Prepared
from 11.06 g (50 mmol) of (S,S)-1, 9.25 g (50 mmol) of
p-bromobenzaldehyde, and 2.70 g (5.4 mmol) of NaCN. After
crystallization from MeOH, 3c was obtained as a diastereomeric
mixture of a colorless solid (16.10 g, 78% yield): mp 83 °C; [R]26
D
) + 94.17 (c ) 1.00, CHCl3); IR (KBr) ν 2986, 2939, 2869, 1479,
1383, 1197, 1074, 1046, 1002, 847, 741, 700 cm-1; 1H NMR (300
MHz, CDCl3) major diastereomer δ 1.54, 1.59 (s, 6H), 2.39 (s,
3H), 2.90 (m, 1H), 4.21, 4.25 (dd, J ) 13.1, 3.4 Hz, 1H), 4.45 (s,
1H), 4.52, 4.57 (dd, J ) 13.1, 1.7 Hz, 1H), 5.29 (d, J ) 3.3 Hz,
1H), 5.66 (s, 1H), 6.56-7.40 (m, 9H) ppm; 13C NMR (75 MHz,
CDCl3) major diastereomer δ 18.7, 29.7, 37.3, 57.6, 60.3, 74.5,
99.4, 117.1, 122.5, 125.6, 127.1, 128.2, 133.1, 134.2, 139.1, 140.1
ppm; MS (EI) m/z 401, 399 (4, M+ - CH3), 252 (99), 251 (80),
250 (100), 249 (67), 212 (18), 211 (25), 210 (19), 209 (25), 196
(19) CCDC 281281 (5g) and CCDC 696682 (6d) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
In conclusion, we have developed an efficient asymmetric
synthesis of ꢀ-nitro ketones through the Michael addition of
metalated R-amino nitriles to nitroalkenes and subsequent acidic
J. Org. Chem. Vol. 73, No. 24, 2008 9643

Enders et al.
(30), 194 (28), 171 (28), 131 (60). Anal. Calcd for C21H23N2O2Br
(415.32): C, 60.73; H, 5.58; N, 6.74. Found: C, 61.02, H, 5.44; N,
6.06.
(dd, J ) 12.7, 3.7 Hz, 1H), 3.96 (dd, J ) 13.5, 4.1 Hz, 1H), 4.20
(d, br, J ) 12.7 Hz, 1H), 4.66 (dd, J ) 13.5, 1.9 Hz, 1H), 5.01 (d,
J ) 4.4 Hz, 1H), 5.98 (s, 2H), 6.84-7.44 (m, 8H.) ppm; 13C NMR
(100 MHz, CDCl3) δ 18.9, 19.1, 23.4, 27.2, 28.4, 31.1, 48.6, 53.8,
58.5, 71.0, 72.5, 75.4, 99.3, 101.6, 108.1, 108.4, 118.8, 125.7, 126.5,
127.2, 127.8, 128.0, 139.2, 148.0, 148.1 ppm; MS (EI) m/z 480 (2,
M+ - CH3), 331 (46), 314 (48), 288 (14), 276 (16), 275 (100),
228 (33), 215 (12), 198 (21), 187 (20), 186 (26), 156 (26), 83 (14),
72 (11). Anal. Calcd for C27H33N3O6 (495.57): C, 65.44; H, 6.71;
N, 8.48. Found: C, 65.31; H, 6.56; N, 8.61.
(4S,5S,2R/S)-2-[N-(2.2-Dimethyl-4-phenyl-1,3-dioxan-5-
yl)methylamino]-3-methylbutanenitrile (3d). Prepared from 22.10
g (100 mmol) of (S,S)-1, 7.20 g (100 mmol) of 2-methylpropanal,
and 6.5 g (100 mmol) of KCN. After crystallization from EtOH,
3d was obtained as a diastereomeric mixture of a colorless solid
(26.10 g, 86% yield): mp 58 °C; [R]26 ) + 110.84 (c ) 1.00,
D
CHCl3); IR (KBr) ν 2805, 1605, 1500, 1465, 1450, 1285 cm-1; 1H
NMR (300 MHz, CDCl3) δ 0.15, 0.30 (d, J ) 6.6 Hz, 3H), 0.86,
0.94 (d, J ) 6.6 Hz, 3H), 1.5-1.75 (m, 7H), 2.23, 2.53 (s, 3H),
2.66, 2.74 (m, 1H), 3.75, 4.55 (m, 3H), 5.15 (m, 1H), 7.28 (m, 5H)
ppm; 13C NMR (75 MHz, CDCl3 δ 17.6, 18.1, 18.5, 18.9, 19.7,
20.0, 29.2, 29.4, 29.6, 30.4, 32.8, 37.9, 58.2, 60.6, 59.7, 60.1, 61.8,
65.8, 73.6, 74.4, 99.0, 99.1, 119.2, 119.2, 119.5, 125.6, 125.7, 126.7,
126.9, 127.8, 127.9, 139.3, 139.9 ppm; MS (EI) m/z 302 (0.5, M+),
287 (5), 244 (5), 227 (19), 138 (99), 123 (26), 105 (15), 98 (73),
96 (66), 95 (71), 91 (13), 77 (17), 57 (100), 43 (24), 42 (51), 41
(11), 28 (12), 27 (13). Anal. Calcd for C18H26N2O2 (302.42): C,
71.48; H, 8.66; N, 9.26. Found: C, 71.96, H, 8.67; N, 9.38.
General Procedure A. Diisopropylamine (1.2 equiv) was placed
in a dry Schlenk flask, and absolute THF (10 mL per mmol
diisopropylamine) was added. The reaction mixture was cooled to
-78 °C, and n-BuLi (1.2 equiv) was added dropwise. The mixture
was stirred at 0 °C for 30 min and cooled to -78 °C, and then the
amino nitrile 3 (1.0 equiv) was added. After 1.5 h at -78 °C, the
reaction mixture was cooled to -100 °C followed by addition of
the Michael acceptor 4 (1.0 equiv) in THF (10 mL per mmol) via
a syringe pump. The reaction mixture was stirred for 5 h and
allowed to warm to -60 °C. After quenching by addition of satd
NH4Cl solution under vigorous stirring, H2O was added and the
organic phase was separated. The aqueous phase was extracted with
Et2O, and the combined organic layers were washed with brine,
dried with MgSO4, and evaporated in vacuo. The crude product 5
was purified by flash chromatography.
Amino Nitrile 5c. According to the general procedure A, the
R-amino nitrile 3a (1.14 g, 3.0 mmol), diisopropylamine (0.51 mL,
3.6 mmol), and n-BuLi (2.25 mL, 3.6 mmol) were dissolved in
dry THF (30 mL). The nitroalkene 4c (0.56 g, 3.6 mmol) was added
immediately. The crude product was purified by flash chromatog-
raphy (silica gel, pentane/diethyl ether 2:1 with 3% triethylamine)
to afford the Michael adduct 5c (1.45 g, 90% yield): mp 102 °C;
[R]26 ) -39.5 (c ) 1.0, CHCl3); IR (KBr) ν 2930, 2857, 1554,
D
1
1489, 1443, 1379, 1243, 1203, 1035 cm-1; H NMR (300 MHz,
CDCl3) δ 1.2-1.6 (m, 11H), 1.45 (s, 3H), 1.55 (s, 3H), 2.95 (m,
1H), 3.15 (s, 3H), 3.42 (m, 1H), 3.78 (dd, J ) 12.9, 2.0 Hz, 1H),
3.96 (dd, J ) 13.1, 4.2 Hz, 1H), 4.15 (d, br, J ) 12.9 Hz, 1H),
4.67 (dd, J ) 13.1, 2.0 Hz, 1H), 5.02 (d, J ) 4.2 Hz, 1H), 5.98 (s,
2H), 6.84-7.44 (m, 8H) ppm; 13C NMR (75 MHz, CDCl3) δ 19.2,
25.7, 26.1, 26.3, 26.9, 27.5, 28.9, 35.0, 38.7, 49.0, 53.9, 58.6, 71.2,
72.7, 75.6, 99.5, 101.8, 108.1, 108.5, 119.6, 125.8, 126.9, 127.4,
127.8, 128.1, 139.5, 148.1, 148.3 ppm; MS (EI) m/z 520 (3, M+ -
•
CH3 ), 371 (59), 354 (100), 315 (81), 311 (10), 288 (13), 268 (20),
215 (25), 187 (23), 186 (73), 156 (21), 83 (48), 72 (10), 55 (27).
Anal. Calcd for C30H37N3O6 (535.64): C, 67.27; H, 6.96; N, 7.85.
Found: C, 67.43; H, 6.87; N, 7.48.
Amino Nitrile 5d. According to the general procedure A, the
R-amino nitrile 3a (1.14 g, 3.0 mmol), diisopropylamine (0.51 mL,
3.6 mmol), and n-BuLi (2.25 mL, 3.6 mmol) were dissolved in
dry THF (30 mL). The nitroalkene 4d (0.46 g, 3.6 mmol) was added
immediately. The crude product was purified by flash chromatog-
raphy (silica gel, pentane/diethyl ether 3:1 with 3% triethylamine)
to afford the Michael adduct 5d (1.25 g, 82% yield): mp 79 °C;
[R]26D ) -36.9 (c ) 1.0, CHCl3); IR (KBr) ν 2988, 1552, 1488,
Amino Nitrile 5a. According to the general procedure A, the
R-amino nitrile 3a (1.14 g, 3.0 mmol), diisopropylamine (0.51 mL,
3.6 mmol) and n-BuLi (2.25 mL, 3.6 mmol) were dissolved in dry
THF (30 mL). The nitroalkene 4a (0.36 g, 3.6 mmol) was added
immediately. The crude product was purified by flash chromatog-
raphy (silica gel, pentane/diethyl ether 2: 1 with 3% triethylamine)
to afford the Michael adduct 5a (1.29 g, 89% yield): mp 99 °C;
1
1440, 1377, 1241, 1203, 1038, 744 cm-1; H NMR (400 MHz,
CDCl3) δ 0.68 (s, 9H), 1.42 (s, 6H), 2.76 (s, 3H), 2.80 (dd, J )
13.5, 3.0 Hz, 1H), 3.22 (d, J ) 8.51 Hz, 1H), 3.42 (m, 1H), 3.72
(dd, J ) 13.46, 4.4 Hz, 1H), 3.8 (dd, J ) 15.4, 4.4 Hz, 1H), 3.98
(dd, J ) 15.4, 8.5 Hz, 1H), 5.24 (d, J ) 4.4 Hz, 1H), 6.00 (s, 2H),
6.82-7.4 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3) δ 18.9, 28.9,
29.7, 31.7, 35.1, 48.3, 55.0, 60.4, 69.2, 73.8, 74.3, 98.6, 101.6,
107.1, 107.7, 108.2, 119.2, 120.4, 125.6, 127.4, 127.8, 139.1, 147.3,
148.3 ppm; MS (EI) m/z 509 (0.4, M+), 346 (10), 345 (61), 290
(18), 289 (100), 187 (14), 186 (87), 114 (51), 83 (48), 72 (30).
Anal. Calcd for C28H35N3O6 (509.60): C, 65.99; H, 6.92; N, 8.25.
Found: C, 65.68; H, 6.74; N, 8.58.
[R]26 ) +72.8 (c ) 1.0, CHCl3); IR (KBr) ν 2988, 1555, 1488,
D
1441, 1380, 1243, 1035, 934, 739 cm-1
;
1H NMR (400 MHz,
CDCl3) δ 0.55 (m, 2H), 0.70 (t, J ) 7.4 Hz, 3H), 1.46 (s, 3H),
1.52 (s, 3H), 2.71 (m, 1H), 3.04 (m, 1H), 3.14 (s, 3H.), 3.55 (dd,
J ) 13.7, 4.1 Hz, 1H.), 3.97 (dd,, J ) 13.4, 4.1 Hz, 1H), 4.30 (d,
br, J ) 13.7 Hz, 1H), 4.66 (dd, J ) 13.4, 1.3 Hz, 1H), 5.02 (d, J
) 3.8 Hz, 1H), 5.96 (s, 2H), 6.64-7.44 (m, 8H) ppm; 13C NMR
(100 MHz, CDCl3) δ 11.3, 19.0, 25.6, 29.0, 35.0, 45.1, 54.0, 58.6,
72.3, 74.7, 75.4, 99.2, 101.7, 107.5, 108.4, 119.5, 125.7, 126.8,
127.6, 127.8, 127.9, 138.9, 148.0, 148.2 ppm; MS (EI) m/z 466 (6,
Amino Nitrile 5e. According to the general procedure A, the
R-amino nitrile 3a (1.14 g, 3.0 mmol), diisopropylamine (0.51 mL,
3.6 mmol), and n-BuLi (2.25 mL, 3.6 mmol) were dissolved in
dry THF (30 mL). The nitroalkene 4e (0.59 g, 3.6 mmol) was added
immediately. The crude product was purified by flash chromatog-
raphy (silica gel, pentane/diethyl ether 3:1 with 3% triethylamine)
to afford the Michael adduct 5e (1.41 g, 87% yield): mp 122 °C;
[R]26D ) +140.9 (c ) 1.0, CHCl3); IR (KBr) ν 2987, 1555, 1487,
•
M+ - CH3 ), 317 (77), 301 (17), 300 (95), 271 (13), 261 (100),
257 (17), 231 (11), 215 (28), 214 (62), 185 (14), 184 (93), 177
(10), 156 (29), 128 (11), 105 (14), 91 (14), 83 (13), 72 (12).
Anal.Calcd for C26H31N3O6 (481,55): C, 64.85; H, 6.49; N, 8.73.
Found: C, 64.78; H, 6.26; N, 8.83.
Amino Nitrile 5b. According to the general procedure A, the
R-amino nitrile 3a (1.14 g, 3.0 mmol), diisopropylamine (0.51 mL,
3.6 mmol), and n-BuLi (2.25 mL, 3.6 mmol) were dissolved in
dry THF (30 mL). The nitroalkene 4b (0.41 g, 3.6 mmol) was added
immediately. The crude product was purified by flash chromatog-
raphy (silica gel, pentane/diethyl ether 2:1 with 3% triethylamine)
to afford the Michael adduct 5b (1.33 g, 90% yield): mp 90 °C;
[R]26D ) -19.1 (c ) 1.0, CHCl3); IR (KBr) ν 3460, 2974, 1554,
1492, 1380, 1243, 1035, 734 cm-1; 1H NMR (400 MHz, CDCl3) δ
0.05 (d, J ) 7.1 Hz, 3H), 0.86 (d, J ) 7.1 Hz, 3H), 1.45, 1.53 (2s,
6H), 1.70 (m, 1H), 2.64 (s, 3H), 2.74 (m, 1H), 3.04 (m, 1H), 3.78
1
1442, 1379, 1242, 1202, 1121, 1037, 747 cm-1; H NMR (300
MHz, CDCl3) δ 1.52 (s, 3H), 1.58 (s, 3H), 2.2 (s, 3H), 2.78 (s,
3H), 3.54 (m, 1H), 3.9 (dd, J ) 13.1, 3.5 Hz, 1H), 4.1 (d, br, J )
13.1 Hz, 1H), 4.26 (dd, br, J ) 3.2, Hz, 1H), 4.42 (dd, J ) 13.4,
3.2 Hz, 1H), 5.00 (dd, J ) 13.4, 3.5 Hz, 1H), 5.4 (d, J ) 3.5 Hz,
1H), 5.9 (s, 2H), 6.8-7.5 (m, 12H) ppm; 13C NMR (75 MHz,
CDCl3) δ 19.0, 21.00, 29.3, 37.8, 48.5, 52.6, 58.9, 72.1, 73.5, 76.0,
99.5, 101.6, 107.0, 108.1, 118.9, 120.5, 125.9, 127.2, 128.1, 128.6,
129.2, 129.5, 130.2, 138.0, 139.0, 148.0, 148.2 ppm; MS (EI) m/z
•
528 (2, M+ - CH3 ), 379 (94), 276 (11), 215 (100). Anal. Calcd
9644 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Synthesis of ꢀ-Nitro Ketones
for C31H33N3O6 (543.62): C, 68.49; H, 6.12; N, 7.73. Found: C,
68.27; H, 6.40; N, 7.63.
1-(Benzo[d][1,3]dioxol-6-yl)-2-(nitromethyl)butan-1-one (6a)
. Following general procedure B, the Michael adduct 5a (500 mg,
1.04 mmol) was dissolved in THF (20 mL), 1.5 M hydrochloric
acid (20 mL) was added, and the reaction mixture was refluxed for
30 min. The crude product was purified by flash chromatography
(silica gel, pentane/diethyl ether 3: 1) to afford 6a as a colorless
solid (190 mg, 73% yield): mp 69 °C; ee g 86%; [R]26D ) -67.7
(c ) 1.0, CHCl3); IR (KBr) ν 3442, 1659, 1607, 1554, 1448, 1255,
Amino Nitrile 5f. According to the general procedure A, the
R-amino nitrile 3b (1.10 g, 3.0 mmol), diisopropylamine (0.51 mL,
3.6 mmol), and n-BuLi (2.25 mL, 3.6 mmol) were dissolved in
dry THF (30 mL). The nitroalkene 4d (0.46 g, 3.6 mmol) was added
immediately. The crude product was purified by flash chromatog-
raphy (silica gel, pentane/diethyl ether 3:1 with 3% triethylamine)
to afford the Michael adduct 5f (1.22 g, 82% yield): mp 69 °C;
1
1031, 927, 885 cm-1; H NMR (400 MHz, CDCl3) δ 0.92 (t, J )
[R]26 ) -6.7 (c ) 1.0, CHCl3); IR (KBr) ν 3679, 3451, 2962,
7.4, 3H), 1.62 (m, 1H), 1.78 (m, 1H), 4.13 (m, 1H), 4.49 (dd, J )
14.3, 4.4 Hz, 1H), 5.00 (dd, J ) 14.3, 9.3 Hz, 1H), 6.06 (s, 2H),
6.90 (d, J ) 8.2 Hz, 1H), 7.45 (d, J ) 1.7 Hz, 1H), 7.60 (dd, J )
8.2, 1.9, Hz, 1H.) ppm; 13C NMR (100 MHz, CDCl3) δ 11.0, 23.5,
44.6, 74.8, 102.0, 108.0, 108.1, 124.7, 130.3, 148.3, 152.2, 197.2
ppm; MS (EI) m/z 251 (23, M+), 149 (100), 121 (12), 65 (6). Anal.
Calcd for C12H13NO5 (251.24): C, 57.37; H, 5.22; N, 5.58. Found:
C, 57.05; H, 5.59; N, 5.50.
D
1609, 1552, 1511, 1377, 1260, 1187, 1028, 840, 746 cm-1; 1H NMR
(400 MHz, CDCl3) δ 0.66 (s, 9H), 1.40 (s, 6H), 2.66 (dd, J )
12.9, 1.7 Hz, 1H) 2.73 (s, 3H), 3.30 (dd, br, J ) 7.7 Hz, 1H), 3.43
(m, 1H), 3.65 (dd, J ) 12.9, 4.4 Hz, 1H), 3.82 (s, 3H), 3.84 (dd,
J ) 15.7, 7.7 Hz, 1H), 4.00 (dd, J ) 15.7, 8.5 Hz, 1H), 5.24 (d, J
) 4.4 Hz, 1H), 6.90-7.85 (m, 9H.) ppm; 13C NMR (100 MHz,
CDCl3) δ 18.9, 28.9, 29.8, 31.5, 35.1, 48.3, 55.1, 55.2, 60.1, 69.0,
73.9, 74.4, 98.6, 113.5, 119.2, 125.7, 127.0, 127.8, 128.2, 131.8,
139.1, 159.8 ppm; MS (EI) m/z 495 (1, M+·), 331 (39), 275 (100),
172 (60), 114 (29), 83 (23), 72 (12), 57 (92). Anal. Calcd for
C28H37N3O5 (495.62): C, 67.86; H, 7.52; N, 8.48. Found: C, 67.59;
H, 7.87; N, 8.21.
1-(Benzo[d][1,3]dioxol-6-yl)-3-methyl-2-(nitromethyl)butan-
1-one (6b). Following general procedure B, the Michael adduct
5b (500 mg, 1.01 mmol) was dissolved in THF (20 mL), 1.5 M
hydrochloric acid (20 mL) was added, and the reaction mixture
was refluxed for 30 min. The crude product was purified by flash
chromatography (silica gel, pentane/diethyl ether 3:1) to afford 6b
as a colorless solid (182 mg, 68% yield): mp 126 °C; ee g 99%;
Amino Nitrile 5g. According to the general procedure A, the
R-amino nitrile 3c (1.25 g, 3.0 mmol), diisopropylamine (0.51 mL,
3.6 mmol), and n-BuLi (2.25 mL, 3.6 mmol) were dissolved in
dry THF (30 mL). The nitroalkene 4d (0.46 g, 3.6 mmol) was added
immediately. The crude product was purified by flash chromatog-
raphy (silica gel, pentane/diethyl ether 5:1 with 3% triethylamine)
to afford the Michael adduct 5g (1.37 g, 84% yield): mp 151 °C;
[R]26 ) -83.0 (c ) 1.0, CHCl3); IR (KBr) ν 1655, 1555, 1446,
D
1372, 1255, 1034 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.88 (d, J
) 6.9 Hz, 3H), 1.03 (d, J ) 6.9 Hz, 3H), 2.13 (m, 1H.), 4.06 (m,
1H), 4.49 (dd, J ) 14.6, 3.3 Hz, 1H), 5.05 (dd, J ) 14.6, 10.2 Hz,
1H), 6.06 (s, 2H), 6.90 (d, J ) 8.2 Hz, 1H), 7.46 (d, J ) 1.7, Hz,
1H), 7.60 (dd, J ) 8.2, 1.7, Hz, 1H.) ppm; 13C NMR (100 MHz,
CDCl3) δ 18.8, 20.9, 29.5, 49.1, 73.2, 101.9, 107.9, 108.1, 124.7,
131.0, 148.2, 152.1, 197.2 ppm; MS (EI); m/z 265 (17, M+), 149
(100), 121 (8). Anal. Calcd for C13H15NO5 (265.27): C, 58.86; H,
5.70; N, 5.28. Found: C, 58.53; H, 5.67; N, 5.17.
[R]26 ) -9.6 (c ) 1.0, CHCl3); IR (KBr) ν 2931, 1731, 1544,
D
1483, 1376, 1285, 1124, 1078, 1015, 850, 704 cm-1; 1H NMR (300
MHz, CDCl3) δ 0.52 (s, 9H), 1.42 (s, 3H), 1.52 (s, 3H), 2.56 (m,
1H), 3.10 (s, 3H), 3.20 (d, J ) 8.5 Hz, 1H) 3.84 (dd, J ) 8.5, 1.9
Hz, 1H), 4.55 (dd, J ) 8.5, 2.2 Hz, 1H), 4.95 (d, J ) 4.4 Hz, 1H),
5.67 (dd, J ) 8.5, 2.2 Hz, 1H), 7.20-7.65 (m, 9H) ppm; 13C NMR
(100 MHz, CDCl3) δ 19.3, 28.6, 29.9, 34.9, 35.3, 51.9, 53.7, 58.4,
69.4, 71.7, 75.1, 99.5, 120.2, 123.9, 126.9, 127.9, 128.3, 130.5,
132.5, 133.2, 139.2 ppm; MS (EI) m/z 529 (2, M+ - CH3), 381
(64), 379 (73), 323 (23), 276 (8), 249 (28), 149 (15), 57 (100).
Anal. Calcd for C27H34N3O4Br (544.48): C, 59.56; H, 6.29; N, 7.72.
Found: C, 59.87; H, 6.54; N, 7.39.
1-(Benzo[d][1,3]dioxol-6-yl)-2-cyclohexyl-3-nitropropan-1-
one (6c). Following general procedure B, the Michael adduct 5c
(1 g, 1.86 mmol) was dissolved in THF (37 mL), 1.5 M
hydrochloric acid (37 mL) was added, and the reaction mixture
was refluxed for 30 min. The crude product was purified by flash
chromatography (silica gel, pentane/diethyl ether 3:1) to afford 6c
as a colorless oil (396 mg, 70% yield): ee g 95%; [R]26D ) -22.2
(c ) 1.0, CHCl3); IR (KBr) ν 2929, 2855, 1670, 1554, 1490, 1444,
1374, 1255, 1096, 1039, 758 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.03-1.77 (m, 11H), 4.08 (m, 1H), 4.54 (dd, J ) 14.6, 3.6 Hz,
1H), 5.06 (dd, J ) 14.6, 10.4 Hz, 1H), 6.04 (s, 2H), 6.87 (d, J )
8.2 Hz, 1H), 7.45 (d, J ) 1.7 Hz, 1H), 7.60 (dd, J ) 8.2, 1.9 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 25.9, 26.2, 26.4, 29.6,
31.4, 39.4, 48.7, 73.8, 102.0, 107.9, 108.0, 124.8, 131.2, 148.2,
152.1, 197.4 ppm; MS (EI) m/z 305 (2, M+), 216 (9), 176 (31),
148 (100), 120 (13), 90 (68), 72 (22). Anal. Calcd for C16H19NO5
(305.33): C, 62.94; H, 6.27; N, 4.59. Found: C, 63.11; H, 6.51; N,
4.68.
1-(Benzo[d][1,3]dioxol-6-yl)-3,3-dimethyl-2-(nitromethyl)-
butan-1-one (6d). Following general procedure B, the Michael
adduct 5d (470 mg, 0.92 mmol) was dissolved in THF (20 mL),
1.5 M hydrochloric acid (20 mL) was added, and the reaction
mixture was refluxed for 30 min. The crude product was purified
by flash chromatography (silica gel, pentane/diethyl ether 3:1) to
afford 6d as a colorless solid (183 mg, 71% yield): mp 130 °C; ee
g 99%; [R]26D ) -81.0 (c ) 1.0, CHCl3); IR (KBr) ν 2363, 1653,
1555, 1495, 1369, 1252, 1034, 927, 881 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.96 (s, 9H), 4.06 (dd, J ) 11.0, 2.7 Hz, 1H), 4.57 (dd,
J ) 14.6, 2.8 Hz, 1H), 5.10 (dd, J ) 14.6, 11.0 Hz, 1H), 6.04 (s,
2H), 6.87 (d, J ) 8.2 Hz, 1H), 7.46 (d, J ) 1.6, Hz, 1H.), 7.62 (dd,
J ) 8.2, 1.7, Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 28.5,
33.9, 51.4, 74.9, 102.1, 108.0, 108.1, 125.0, 133.3, 148.3, 152.0,
198.3 ppm; MS (EI) m/z 279 (20, M•+), 177 (15), 149 (100), 121
(7). Anal. Calcd for C14H17NO5 (279.29): C, 60.20; H, 6.14; N,
5.02. Found: C, 60.37; H, 6.23; N, 5.22.
Amino Nitrile 5h. According to the general procedure A, the
R-amino nitrile 3d (0.91 g, 3.0 mmol), diisopropylamine (0.51 mL,
3.6 mmol), and n-BuLi (2.25 mL, 3.6 mmol) were dissolved in
dry THF (30 mL). The nitroalkene 4b (0.41 g, 3.6 mmol) was added
immediately. The crude product was purified by flash chromatog-
raphy (silica gel, pentane/diethyl ether 3:1 with 3% triethylamine)
to afford the Michael adduct 5h (1.12 g, 90% yield): colorless oil;
[R]26 ) -28.4 (c ) 1.0, CHCl3); IR (KBr) ν 2987, 1456, 1379,
D
1201, 1080, 754 cm-1; H NMR (300 MHz, CDCl3) δ 0.92 (d, J
1
) 6.9 Hz, 6H), 1.12 (d, J ) 6.7 Hz, 6H), 1.17/1.20 (2s, 6H), 1.68/
1.8 (2m, 1H), 2.27 (s, 3H), 2.59 (m, 1H), 2.92 (m, 1H), 3.55 (dd,
J ) 11.3, 1.7 Hz, 1H), 3.84 (dd, J ) 11.3, 3.3 Hz, 1H), 4.13 (dd,
J ) 13.2, 9.1 Hz, 1H), 4.77 (dd, J ) 13.2, 1.4 Hz, 1H), 5.19 (d, J
) 9.4 Hz 1H), 7.30-7.47 (m, 5H.) ppm; 13C NMR (75 MHz,
CDCl3) δ 17.7, 18.8, 19.8, 23.1, 26.7, 31.7, 35.6, 48.5, 56.9, 69.1,
72.2, 74.1, 79.5, 100.7, 119.1, 126.7, 127.9, 128.5, 139.3 ppm; MS
(EI) m/z 417 (1, M+), 253 (22), 210 (31), 207 (13), 137 (30), 136
(88), 135 (51), 122 (16), 121 (100). Anal. Calcd for C23H35N3O4
(417.55): C, 66.16; H, 8.45; N, 10.06. Found: C, 66.42; H, 8.57;
N, 9.89.
General Procedure B. The Michael adduct 5 was dissolved in
THF (20 mL per mmol), 1.5 M hydrochloric acid (20 mL per mmol
amino nitrile) was added, and the reaction mixture was refluxed
for 30 min. The phases were separated, and the water phase was
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, and the solvent was removed under reduced pressure.
The crude product 6 was purified by flash chromatography.
J. Org. Chem. Vol. 73, No. 24, 2008 9645

Enders et al.
1-(Benzo[d][1,3]dioxol-6yl)-3-nitro-2-p-tolylpropan-1-one (6e)
. Following general procedure B, the Michael adduct 5e (500 mg,
0.92 mmol) was dissolved in THF (20 mL), 1.5 M hydrochloric
acid (20 mL) was added, and the reaction mixture was refluxed for
30 min. The crude product was purified by flash chromatography
(silica gel, pentane/diethyl ether 4:1) to afford 6e as a colorless oil
(184 mg, 64% yield): ee g 44%; [R]26D ) -8.4 (c ) 1.0, CHCl3);
IR (KBr) ν 1673, 1554, 1506, 1489, 1443, 1374, 1258, 1218, 1039,
as a colorless solid (134 mg, 71% yield): mp 52 °C; ee ) 86%;
[R]26D ) -100.1 (c ) 1.0, CHCl3); IR (KBr) ν 1677, 1560, 1371,
1214 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.95 (s, 9H), 4.10 (dd,
J ) 11.1, 2.9 Hz, 1H), 4.59 (dd, J ) 14.8, 2.7 Hz, 1H), 5.11 (dd,
J ) 14.8, 3.7 Hz, 1H), 5.13 (dd, J ) 14.3, 11.0 Hz, 1H), 7.60 (dm,
J ) 8.8 Hz, 2H), 7.85 (dm, J ) 8.8, Hz, 2H) ppm; 13C NMR (100
MHz, CDCl3) δ 28.4, 33.9, 51.5, 74.7, 128.6, 129.9, 132.1, 137.3,
199.8 ppm; MS (EI) m/z 314 (1, M+), 211 (21), 183 (100), 155
(13), 132 (11), 57 (13). Anal. Calcd for C13H16NO3Br (314.17): C,
49.69; H, 5.13; N, 4.46. Found: C, 49.91; H, 5.30; N, 4.56.
2,5-Dimethyl-4-(nitromethyl)hexan-3-one (6h). Following gen-
eral procedure B, the Michael adduct 5h (200 mg, 0.48 mmol) was
dissolved in THF (10 mL), 1.5 M hydrochloric acid (10 mL) was
added, and the reaction mixture was refluxed for 30 min. The crude
product was purified by flash chromatography (silica gel, pentane/
diethyl ether 3:1) to afford 6h as a colorless oil (64 mg, 72% yield):
1
758 cm-1; H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H), 4.54 (dd,
J ) 13.2, 3.9 Hz, 1H), 5.22 (dd, J ) 13.2, 9.3 Hz, 1H), 5.27 (dd,
br, J ) 3.8 Hz, 1H), 5.97 (s, 2H), 6.77-7.57 (m, 7H) ppm; 13C
NMR (100 MHz, CDCl3) δ 21.0, 50.4, 76.2, 101.8, 107.9, 108.4,
125.4, 127.8, 128.7, 129.7, 130.6, 138.2, 148.0, 152.0, 193.6 ppm;
MS (EI) m/z 313 (5, M+), 195 (6), 149 (100), 121 (8), 118 (6).
Anal. Calcd for C17H15NO5 (313.31): C, 65.17; H, 4.83; N, 4.47.
Found: C, 65.29; H, 4.59; N, 4.77.
ee g 25%; [R]26 ) -1.8 (c ) 1.0, CHCl3); IR (KBr) ν 2970,
1-(4-Methoxyphenyl)-3,3-dimethyl-2-(nitromethyl)butan-
1-one (6f). Following general procedure B, the Michael adduct 5f
(300 mg, 0.6 mmol) was dissolved in THF (12 mL), 1.5 M
hydrochloric acid (12 mL) was added, and the reaction mixture
was refluxed for 30 min. The crude product was purified by flash
chromatography (silica gel, pentane/diethyl ether 3:1) to afford 6f
as a colorless solid (111 mg, 70% yield): mp 74 °C; ee g 99%;
[R]26D ) -138.2 (c ) 1.0, CHCl3); IR (KBr) ν 3426, 2963, 1667,
1604, 1550, 1422, 1376, 1258, 1220, 1172, 1025, 957, 847, 799,
D
1710, 1557, 1378 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.85 (d, J
) 7.14 Hz, 3H), 1.07 (d, J ) 6.9 Hz, 3H), 1.10 (d, J ) 6.6 Hz,
3H), 1.17 (d, J ) 7.15 Hz, 3H), 2.15 (m, 1H), 2.83 (m, 1H), 3.46
(m, 1H), 4.31 (dd, J ) 14.28, 3.3 Hz, 1H), 4.89 (dd, J ) 14.28,
10.43 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 17.5, 18.2,
19.0, 21.0, 28.1, 39.9, 52.9, 71.9, 212.7 ppm; MS (EI) m/z 187
(0.4, M+), 141 (5), 97 (31), 73 (5), 71 (100), 69 (25), 55 (23).
Anal. Calcd for C9H17NO3 (187.24): C, 57.73; H, 9.15; N, 7.48.
Found: C, 57.45; H, 8.89; N, 7.32.
1
525 cm-1; H NMR (300 MHz, CDCl3) δ 0.97 (s, 9H), 3.87 (s,
3H), 4.13 (dd, J ) 11.1, 2.8 Hz, 1H), 4.58 (dd, J ) 14.3, 2.8 Hz,
1H), 5.13 (dd, J ) 14.3, 11.0 Hz, 1H), 6.96 (dm, J ) 8.8 Hz, 2H),
8.00 (dm, J ) 8.8 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ
28.4, 33.7, 51.0, 55.5, 74.9, 113.9, 130.8, 131.5, 163.7, 198.9 ppm;
MS (EI) m/z 265 (14, M+), 219 (5), 163 (19), 134 (100), 77 (5).
Anal. Calcd for C14H19NO4 (265.31): C, 63.38; H, 7.22; N, 5.28.
Found: C, 63.24; H, 7.39; N, 5.03.
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie. We thank BASF AG, Bayer AG, and
the former Boehringer Mannheim GmbH for the donation of
chemicals.
Supporting Information Available: Proton and carbon NMR
spectra of new compounds. Crystallographic information files
(CIF) for 5g and 6d. This material is available free of charge
via the Internet at http://pubs.acs.org.
1-(4-Bromophenyl)-3,3-dimethyl-2-(nitromethyl)butan-1-
one (6g). Following general procedure B, the Michael adduct 5g
(327 mg, 0.6 mmol) was dissolved in THF (12 mL), 1.5 M
hydrochloric acid (12 mL) was added, and the reaction mixture
was refluxed for 30 min. The crude product was purified by flash
chromatography (silica gel, pentane/diethyl ether 5:1) to afford 6g
JO8017318
9646 J. Org. Chem. Vol. 73, No. 24, 2008