Alkylation of Ketene Silyl Acetals with Nitroolefins Mediated by Sterically Encumbered Lewis Acids

Article abstract of DOI:10.1021/jo9624004

The utility of nitroolefins as "⁺C-C-NH₂" and "⁺C(C=O)R" synthons is limited by their facile polymerization in the presence of nucleophiles. Although a number of procedures have been developed for the successful alkylation of ketones with nitroolefins, currently available procedures for the corresponding reaction of esters suffer from important limitations such as modest yields, lack of demonstrated generality, inconveniently low reaction temperatures, and/or the use of a large excess of one of the two reactants. In the present work, we examined the efficacy of a series of Lewis acid catalysts for the alkylation of ketene silyl acetals with nitroolefins. Previously reported conditions using diisopropoxytitanium dichloride failed to give satisfactory results with nitroolefins lacking a substituent α to the NO₂ group. In contrast, good to excellent results were obtained using sterically congested Lewis acids of the type pioneered by Yamamoto. The successful use of nitroethylene in this reaction represents a significant extension of the utility of this relatively unused "⁺CH₂CH₂NH₂" synthon.

Full text of DOI:10.1021/jo9624004

4370
J . Org. Chem. 1997, 62, 4370-4375
Alk yla tion of Keten e Silyl Aceta ls w ith Nitr oolefin s Med ia ted by
Ster ica lly En cu m ber ed Lew is Acid s
J ohn A. Tucker,*,† Terrance L. Clayton,† and Donald M. Mordas‡
Medicinal Chemistry Research and Pharmaceutical Development Assay Services, Pharmacia & Upjohn,
Kalamazoo, Michigan 49001
Received December 30, 1996X
The utility of nitroolefins as “+C-C-NH2” and “+C(CdO)R” synthons is limited by their facile
polymerization in the presence of nucleophiles. Although a number of procedures have been
developed for the successful alkylation of ketones with nitroolefins, currently available procedures
for the corresponding reaction of esters suffer from important limitations such as modest yields,
lack of demonstrated generality, inconveniently low reaction temperatures, and/or the use of a
large excess of one of the two reactants. In the present work, we examined the efficacy of a series
of Lewis acid catalysts for the alkylation of ketene silyl acetals with nitroolefins. Previously reported
conditions using diisopropoxytitanium dichloride failed to give satisfactory results with nitroolefins
lacking a substituent R to the NO2 group. In contrast, good to excellent results were obtained
using sterically congested Lewis acids of the type pioneered by Yamamoto. The successful use of
nitroethylene in this reaction represents a significant extension of the utility of this relatively unused
“+CH2CH2NH2” synthon.
Nitroolefins are powerful Michael acceptors which can
bach,6 Denmark,7 and others8 have reported a variety of
procedures for the successful addition of simple ketones
to nitroolefins via their lithium enolates, enol silanes,
enol ethers, or enamines. Limited success has also been
reported in the addition of simple esters to nitroolefins
via their lithium enolates or ketene silyl acetals.9 None
of the previously reported procedures for the addition of
esters to nitroolefins is completely satisfactory; however,
as all suffer from modest yields, lack of demonstrated
generality, inconveniently low reaction temperatures,
and/or the use of a large excess of one of the two react-
ants. In the present work, we describe a procedure for
the addition of esters to nitroolefins via their ketene silyl
acetals which avoids many of the disadvantages of previ-
ously reported methods. A particularly significant aspect
of this work is the successful extension of this procedure
to the highly reactive substrate nitroethylene, which
serves as a useful “+CH2CH2NH2” synthon in this pro-
cedure.
serve as synthons of the types “+C-C-NH2” and “+C-
(CdO)R”.1 Many nitroolefins are readily accessible via
the Henry (nitroaldol) reaction, and others are easily
prepared by a variety of more recently developed tech-
niques.2 In spite of their potential utility and ease of
synthesis, the synthetic applications of nitroolefins have
historically been limited by the great ease with which
they polymerize in the presence of nucleophiles. This
ease of polymerization can be understood in terms of the
high reactivity of nitroolefins and their rather modest
ability to discriminate between the intended nucleophile
and nucleophile-nitroolefin adducts (nitronates) as reac-
tion partners. As might be expected from this analysis,
only a handful of reports exist concerning synthetically
useful nucleophilic addition reactions of the most reactive
simple nitroolefin, nitroethylene.3
Classically, the reactions of nitroolefins with carbon-
centered nucleophiles have been limited to reactions
carried out under mildly basic conditions using relatively
acidic reaction partners such as malonate derivatives and
1,3-diketones.4 In more recent years, Yoshikoshi,5 See-
Our initial efforts in this area involved an examination
of a procedure for the addition of ketene silyl acetals to
nitroolefins reported previously by Yoshikoshi et al.10
These workers found that a variety of ketene silyl acetals
* Phone: (616) 833-1062. Fax: (616) 833-2516. E-Mail: john.a.tucker
@am.pnu.com.
(5) Yoshihiko, A.; Mayashita, M. Acc. Chem. Res. 1985, 18, 284.
(6) (a) Brook, M. A.; Seebach, D. Can. J . Chem. 1987, 65, 836. (b)
Seebach, D.; Brook, M. A. Helv. Chim. Acta 1985, 68, 319. (c) Seebach,
D.; Leitz, H. F.; Ehrig, V. Chem. Ber. 1975, 108, 1924. (d) Ha¨ner, R.;
Laube, T.; Seebach, D. Chimia 1984, 38, 255. (e) Seebach, D.; Golinski,
J . Helv. Chim. Acta 1981, 64, 1413. (f) Blarer, S. J .; Schweizer, W. B.;
Seebach, D. Helv. Chim. Acta 1982, 65, 1637.
(7) (a) Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1993, 58, 3857.
(b) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J . Org. Chem.
1993, 58, 1859. (c) Denmark, S. E.; Senanayake, C. B. W. J . Org. Chem.
1993, 58, 1853.
(8) (a) Cory, R. M.; Anderson, P. C.; Bailey, M. D.; McLaren, F. R.;
Renneboog, R. M.; Yamamoto, B. R. Can. J . Chem. 1985, 63, 2618. (b)
Cory, R. M.; Anderson, P. C.; McLaren, F. R.; Yamamoto, B. R. J . Chem.
Soc., Chem. Commun. 1981, 73. (c) Bradamente, P.; Pitacco, G.; Risaliti,
A.; Valentin, E. Tetrahedron Lett. 1982, 23, 2683.
(9) (a) Yoshikoshi, A. Miyashita, M. Acc. Chem. Res. 1985, 18, 284.
(b) Miyashita, M.; Yamaguchi, R.; Yoshikoshi, A. J . Org. Chem. 1984,
49, 2857. (c) Ha¨ner, R.; Laube, T.; Seebach, D. Chimia 1984, 38, 255.
(d) Zu¨ger, M.; Weller, T.; Seebach, D. Helv. Chim. Acta 1980, 63, 2005.
(e) Seebach, D.; Leitz, H. F.; Ehrig, V. Chem. Ber. 1975, 108, 1924. (f)
Curran, D. P.; J acobs, P. B.; Elliot, R. L.; Kim, B. H.; J . Am. Chem.
Soc. 1987, 109, 5280. (g) Hyean, K. B.; J acobs, P. B.; Elliot, R. L.
Curran, D. P. Tetrahedron 1988, 11, 3079. (h) Posner, G. H.; Crouch,
R. D. Tetrahedron 1990, 46, 7509.
† Medicinal Chemistry Research.
‡ Pharmaceutical Development Assay Services.
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 751.
(2) (a) Gairaud, C. B.; Lappin, G. R. J . Org. Chem. 1953, 18, 1. (b)
Buckley, G. D.; Scaife, C. W. J . Chem. Soc. 1947, 1471. (c) Knochel,
P.; Seebach, D. Synthesis 1982, 1018. (d) Corey, E. J .; Estreicher, H.
Tetrahedron Lett. 1980, 21, 1113. (e) Retherford, C.; Knochel, P.
Tetrahedron Lett. 1991, 441. (f) Denmark, S. E.; Marcin, L. R. J . Org.
Chem. 1993, 58, 3850. (g) Sakakibara, T.; Takai, I.; Ohara, E.; Sudoh,
R. J . Chem. Soc., Chem. Commun. 1981, 261.
(3) (a) Posner, G. H.; Crouch, R. D. Tetrahedron 1990, 46, 7509. (b)
Curran, D. P.; J acobs, P. B.; Elliot, R. L.; Kim, B. H.; J . Am. Chem.
Soc. 1987, 109, 5280. (c) Hyean, K. B.; J acobs, P. B.; Elliot, R. L.
Curran, D. P. Tetrahedron 1988, 11, 3079. (d) Seebach, D.; Leitz, H.
F.; Ehrig, V. Chem. Ber. 1975, 108, 1924. (e) Ranganathan, D.; Rao,
C. B.; Ranganathan, S.; Mehrotra, A. K.; Iyengar, R. J . Org. Chem.
1980, 45, 1185. (f) Noland, W. E.; Hartman, P. J . J . Am. Chem. Soc.
1954, 76, 3227. (g) Zueger, M.; Weller, T.; Seebach, D. Helv. Chim.
Acta 1980, 63, 2005. (h) Benchekroun-Mounir, N.; Dugat, D.; Gramain,
J . C.; Husson, H. P. J . Org. Chem. 1993, 58, 6457. (i) de Laszlo, S. E.;
Ley, S. V.; Porter, R. A. J . Chem. Soc., Chem. Commun. 1986, 344.
(4) Bauer, H. H.; Urbas, L. In The Chemistry of the Nitro and Nitroso
Groups; Feur, H., Ed.; Interscience: New York, 1970; Part 2, pp 136-
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(10) Miyashita, M.; Yanami, T.; Kumazawa, T.; Yoshikoshi, A. J .
Am. Chem. Soc. 1984, 106, 2149.
S0022-3263(96)02400-0 CCC: $14.00 © 1997 American Chemical Society

Alkylation of Ketene Silyl Acetals With Nitroolefins
J . Org. Chem., Vol. 62, No. 13, 1997 4371
Ta ble 1. Op tim iza tion of Rea ction Con d ition s
entry
Lewis acida
solvent
CH2Cl2
xylenes
THF
Et2O
Et2O
CH2Cl2
THF/CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
toluene
tolu en e
toluene
M
temp
yield, %
diastereomer ratio
1
2
3
4
5
6
7
8
9
10
11
12
13
TiCl2(OiPr)2
none
none
MgBr2‚OEt2
MgBr2 (s)
Mg(OTf)2
Eu(fod)3
TMSOTf
BF3‚OEt2
ZnI2
TBS
TBS
-78 °C
100 °C
-30 °C to -15 °C
25 °C
-78 to 25 °C
-78 to 25 °C
25 °C
<25
<25
80
5:1
1:1
1:1
2.2:1
2:1
not det
not det
not det
not det
3:1
not det
6.3:1
not det
SnMe3
TMS
TMS
TBS
TMS
TMS
TMS
TMS
TMS
TBS
TBS
90
slow/stopsb
slow/stopsb
slow/stopsb
slow/stopsb
slow/stopsb
slow/stopsb
slow/stopsb
90% (ver y fa st)
slow/stopsb
-78 to 25 °C
-78 to 25 °C
-20 to 25 °C
-78 to 25 °C
-78 °C
EtAlCl2
MAD
MAD (0.2 eq.)
-78 to 25 °C
a
b
1-1.5 equivalent of Lewis Acid was used except where noted. Analysis by 1H-NMR and/or thin layer chromatography indicated
very modest conversions which were not improved upon extended stirring at 25 °C.
In order to discover alternative reaction conditions
which would permit the use of a wider range of nitroolefin
substrates, we have examined a variety of catalysts for
the addition of ketene silyl acetals to â-nitrostyrene 6.
The results of these studies are summarized in Table 1.
The very modest reaction rates which were observed in
most of these reactions may result from an insufficient
affinity of the very weakly coordinating nitro group for
the Lewis acid employed. As described previously, the
use of diisopropoxytitanium dichloride as catalyst (entry
1) gave highly colored mixtures of apparently oligomeric
products. The reaction of ethylene bromide with mag-
nesium turnings in ether as solvent gave a two-phase
mixture of ether and magnesium bromide etherate which
exhibited good catalytic activity at 25 °C (entry 4). An
attempt to perform this reaction at lower temperatures
led to the precipitation of magnesium bromide as a solid.
This latter material was not an effective catalyst for the
reaction (entry 5). The trimethylstannyl enolate pre-
pared in situ from the lithium enolate of ethyl propanoate
and trimethylstannyl chloride reacted cleanly with â-ni-
trostyrene 6 at relatively low temperatures (entry 3). The
most effective procedure involved the use of Yamamoto’s
sterically encumbered Lewis acid MAD,11 which gave a
very rapid and clean reaction at -78 °C (entry 12).
As part of preliminary efforts to determine the scope
of the MAD-catalyzed addition of ketene silyl acetals to
nitroolefins, we examined the reaction of ketene silyl
acetal 5 with 1-nitropropene 7. Unexpectedly, the sole
product isolated from this reaction was the ligand-
nitroolefin adduct 10 (Scheme 1). Reasoning that an
increase in steric hinderance about the nucleophilic
4-position of the phenolate ligand would reduce the rate
of this side reaction, we prepared the modified catalyst
“MABu” from trimethylaluminum and commercially
available 2,4,6- tri-tert-butylphenol. As seen in Scheme
1, the use of this modified catalyst eliminated the
formation of ligand-nitroolefin adducts as side-products.
The results of a series of experiments designed to probe
the generality of MAD- and MABu-catalyzed additions
of ketene silyl acetals to nitroolefins are summarized in
can be successfully added to the R-substituted nitroolefins
1-4 using diisopropoxytitanium dichloride as catalyst.
The use of tin tetrachloride as catalyst was reported to
give poorer results. In order to determine whether this
procedure could be extended to the reactions of nitroole-
fins lacking an R substituent, we examined the diisopro-
poxytitanium dichloride-catalyzed reaction of ketene silyl
acetal 5 with the nitroolefins â-nitrostyrene 6 and 1-ni-
tropropene 7. In each case highly colored, complex
mixtures were obtained which contained little or none
of the desired 4-nitrobutyrate product. The salutory
effect of an R substituent (R6) on the nitroolefin in this
reaction can be understood in terms of the relative
nucleophilicities of the intermediate silyl nitronates III
(eq 1). Presumably the greater steric hinderance associ-
ated with nitronates in which R6 * H decreases their
ability to compete with the ketene silyl acetal for addition
to the unreacted nitroolefin.
(11) (a) Maruoka, K.; Itoh, T.; Yamamoto, H. J . Am. Chem. Soc.
1985, 107, 4573. (b) Maruoka, K.; Araki, Y.; Yamamoto, H. J . Am.
Chem. Soc. 1988, 110, 2650. Maruoka, K.; Saito, S.; Yamamoto, H. J .
Am. Chem. Soc. 1992, 114, 1089.

4372 J . Org. Chem., Vol. 62, No. 13, 1997
Tucker et al.
Sch em e 1. Mod ifica tion of th e Ca ta lyst for Use
w ith Mor e Rea ctive Nitr oolefin s
tion was observed in the reactions of the sterically
hindered ketene silyl acetal 23 (entries 8 and 9). In these
cases only very modest yields of difficultly purified
product were obtained. Satisfactory yields were obtained,
however, with the more reactive disubstituted ketene
silyl acetal 26 (entries 10 and 11).
In order to examine the stereoselectivity of this trans-
formation, the experiments described in Scheme 2 were
carried out. The MAD-catalyzed reactions of the E- and
Z-ketene silyl acetals of ethyl propionate each gave a
6.3:1 ratio of stereoisomeric 4-nitrobutyrates 9, with the
same stereoisomer of the product predominating in both
reactions. Hydrogenation of this mixture of stereoiso-
mers gave a 6.3:1 mixture of stereoisomeric lactams. The
close match between observed and predicted (MM2/
Karplus) coupling constants and the upfield chemical
shift of the methyl hydrogens of the minor isomer led us
to tentatively assign the trans and cis arrangements to
the major and minor isomers respectively. This tentative
assignment was later confirmed in an equilibration
experiment in which a 64:36 mixture of 30 and 31 was
converted to a 90:10 mixture by stirring three days in
tetrahydrofuran solution in the presence of 3.0 equiv of
potassium tert-butoxide. Overall, these experiments
demonstrate that the alkylation of the E- and Z-ketene
silyl acetals 5 and 29 with â-nitrostyrene 6 is stereocon-
vergent and the major 4-nitrobutyrate product in each
case has the syn geometry.
Overall, the research described in this paper demon-
strates that synthetically useful yields can be obtained
in the alkylation of ketene silyl acetals with nitroolefins
of widely varying structure including nitroethylene. The
success of this procedure is based on the use of a Lewis
acid catalyst prepared by the reaction of trimethylalu-
minum with 2 equiv of commercially available 2,4,6-tri-
tert-butylphenol. This catalyst is structurally related to
Lewis acids which have been reported previously by
Yamamoto,11 but incorporates greater steric hinderance
Table 2. The generality of the reaction is fairly good,
acceptable yields being obtained with ketene silyl acetals
and nitroolefins of a variety of substitution patterns. Most
notable is the successful application of nitroethylene in
this procedure (entries 6, 7, and 11). One major limita-
Sch em e 2. Ster eoselectivity a n d Str u ctu r a l Assign m en ts

Alkylation of Ketene Silyl Acetals With Nitroolefins
J . Org. Chem., Vol. 62, No. 13, 1997 4373
Ta ble 2. Rep r esen ta tive MAD- a n d MABu -Ca ta lyzed Tr a n sfor m a tion s

4374 J . Org. Chem., Vol. 62, No. 13, 1997
Tucker et al.
minor diastereomer), 2.68 (dq, J ) 9.8, 7.1 Hz, 1 H, major
diastereomer), 1.21 (t, J ) 7.1 Hz, 3 H, major diastereomer),
1.16 (d, J ) 7.1 Hz, 3H, minor diastereomer), 1.00 (t, J ) 7.1
Hz, 3H, minor diastereomer), 0.96 (d, J ) 7.1 Hz, 3 H, major
diastereomer). 13C-NMR (75 MHz, CDCl3): The major isomer
(in full): δ 174.34, 136.99, 128.90, 128.80, 127.84, 78.43, 60.86,
in the 4-position of the ligand to inhibit reaction of the
ligand with the nitroolefin substrate.
Exp er im en ta l Section
Gen er a l Exp er im en ta l. All reactions were performed in
oven-dried (200 °C, 2 h) glassware which was flushed with
nitrogen prior to cooling. It was found particularly important
to rigorously remove the air from reaction vessels in which
trimethylaluminum was to be used. Methylene chloride,
toluene, and diisopropylamine were distilled from calcium
hydride immediately prior to use. Tetrahydrofuran was
distilled from sodium benzophenone ketyl immediately before
use. The nitroolefins 7, 13, 15, and 19 were prepared accord-
ing to literature procedures12 and stored neat in the dark at
-15 °C until use. All of the nitroolefins used in this work,
including nitroethylene, retained satisfactory purity after
several months of storage under these conditions. Ketene silyl
acetals were prepared according to reference 13 and purified
by Kugelrohr distillation prior to use.
Gen er a l P r oced u r e for Alk yla tion of Keten e Silyl
Acet a ls w it h Nit r oolefin s Ot h er Th a n Nit r oet h ylen e.
P r oced u r e A. A solution of 1.57 g (6.00 mmol) of 2,4,6-tri-
tert-butylphenol (Aldrich) in 4.5 mL of anhydrous methylene
chloride was prepared in an oven-dried 15 mL round bottom
flask. (When MAD is used as the catalyst, 2,6-di-tert-butyl-
4-methylphenol is used in place of 2,4,6-tri-tert-butylphenol,
and toluene is used in place of methylene chloride as the
reaction solvent.) The solution was deoxygenated with a
stream of dry nitrogen and cooled to 0 °C. Neat trimethyl-
aluminum (0.288 mL, 3.00 mmol, extremely pyrophoric!) was
added to the solution dropwise over 2-3 min via syringe.
When the gas evolution became slow (5 min), the solution was
warmed to 25 °C and stirred for 1 h (solution A). In a separate
50 mL oven-dried round bottom flask, a solution of the ketene
silyl acetal (3.0 mmol) in 6 mL of methylene chloride was
cooled to -78 °C and treated with a solution of the nitroolefin
(2.73 mmol) in 6 mL of methylene chloride. (In some cases
precipitation of the nitroolefin was observed.) After stirring
this solution 5 min at -78 °C, solution A was added dropwise
over 2 min. The resulting mixture was stirred an additional
30 min at -78 °C, and then 0.32 g of anhydrous sodium sulfate
was added followed by 0.32 g of sodium sulfate decahydrate.
The mixture was allowed to warm to 25 °C and stirred 30 min
at this temperature. The solution was diluted with 50 mL of
chloroform (this is important in order to minimize solvent
evaporation and consequent crystallization of the tri-tert-
butylphenol within the frit during filtration) and filtered
through Celite. Evaporation of the filtrate at reduced pressure
gave a white solid which was chromatographed on 100 mL of
silica gel eluting with 10% methylene chloride in pentanes
until the tri-tert-butylphenol was completely removed from the
column and then with a more polar mixture of methylene
chloride/pentanes to elute the product. Yields are given in
Table 2.
46.59, 42.63, 15.84, 13.97. The minor isomer (in part):
δ
173.40, 136.99, 128.90, 128.80, 127.84, 77.53, 60.54, 46.42,
42.95, 14.62, 13.74. IR (neat) 2983, 2464 (w), 1957 (w), 1729
(s), 1556 (s), 1497, 1455, 1434, 1380, 1344, 1248, 1180 (s), 1130,
1097, 702, cm-1
. MS (EI) m/ z (rel intensity) 251 (M +, 1),
206 (24), 205 (25), 204 (55), 189 (98), 132 (29), 131 (95), 117
(33), 104 (91), 103 (23), 91 (100). Anal. Calcd for C13H17NO4:
C, 62.14; H, 6.82; N, 5.57. Found: C, 62.11; H, 6.86; N, 5.60.
E t h yl 2,3-Dim et h yl-4-n it r obu t yr a t e (11). Rf 0.35 (1:1
dichloromethane/hexanes). 1H NMR (300 MHz, CDCl3) δ 4.54
(dd, J ) 12.3, 5.3 Hz, 1 H, major diastereomer), 4.43 (dd, J )
12.1, 5.5 Hz, 1 H, minor diastereomer), 4.29 (dd, J ) 12.1, 8.4
Hz, 1 H, major diastereomer), 4.28 (dd, J ) 12.3, 8.2 Hz, 1 H,
minor diastereomer), 4.15 (overlapping q, J ) 7.1 Hz, 2 H, both
diastereomers), 2.70-2.40 (m, 2 H, both diastereomers), 1.21
(overlapping t, J ) 7.1 Hz, 3 H, both diastereomers), 1.14 (d,
J ) 7.1 Hz, 3 H, minor diastereomer), 1.13 (d, J ) 7.1 Hz, 3
H, major diastereomer), 0.98 (d, J ) 7.1 Hz, 3 H, minor
diastereomer), 0.97 (d, J ) 7.1 Hz, 3 H, major diastereomer).
13C-NMR (75 MHz, CDCl3) δ 174.29, 173.90, 79.19, 79.11,
60.62, 41.70, 41.62, 35.09, 34.64, 26.74, 14.35, 14.04, 13.99,
13.18. Consideration of relative peak intensities suggests that
the peaks at δ 14.35 and 14.04 each correspond to two
unresolved resonances. IR (neat) 2982, 2941, 2459 (w), 1731
(s), 1555 (s), 1460, 1381, 1261, 1226, 1189, 1164, 1126, 1097,
1079, 1032, cm-1. MS (FAB) m/ z (rel intensity) 190 (M + H,
21), 123 (34), 103 (37), 75 (39), 73 (100), 69 (43), 57 (71), 55
(31), 43 (30). HRMS (FAB) calcd for C8H15NO4 + H 190.1079,
found 190.1076. Anal. Calcd for C8H15NO4: C, 50.78; H, 7.99;
N, 7.40. Found: C, 50.52; H, 8.07; N, 7.04.
Bu tyl 4-n itr o-3-(4-ch lor op h en yl)bu tyr a te (14). Rf 0.20
(3:2 dichloromethane/hexanes). 1H NMR (300 MHz, CDCl3) δ
7.32 (d, J ) 6.5 Hz, 2 H), 7.17 (d, J ) 6.5 Hz, 2 H), 4.71 (dd,
J ) 6.8, 12.6 Hz, 1 H), 4.60 (dd, J ) 8.1, 12.6 Hz, 1 H), 4.03 (t,
J ) 7.3 Hz, 2 H), 3.97 (ddt, J ) 6.8, 8.1, 7 Hz, 1 H), 2.82-2.63
(AB, 2 H), 1.60-1.45 (m, 2 H), 1.35-1.17 (m, 2 H), 0.89 (t, J
) 7.3 Hz, 3 H). 13C-NMR (75 MHz, CDCl3) δ 170.35, 136.75,
133.88, 129.19, 128.72, 79.15, 64.86, 39.62, 37.57, 30.44, 18.95,
13.55. IR (neat) 2962, 2935, 1902 (w), 1732 (s), 1556 (s), 1495,
1379, 1269, 1249, 1226, 1190, 1175, 1096, 1016, 830, cm-1. MS
(FAB) m/ z (rel intensity) 300 (M + H, 45), 226 (25), 197 (52),
75 (25), 73 (46), 57 (100), 55 (43), 43 (35), 41 (49), 29 (46). Anal.
Calcd for C14H18ClNO4: C, 56.10; H, 6.05; N, 4.67. Found: C,
56.25; H, 5.94; N, 4.56.
1-(Nitr om eth yl)-1-[(bu toxyca r bon yl)m eth yl]cycloh ex-
a n e (16). Rf 0.22 (38% dichloromethane in hexanes). 1H NMR
(300 MHz, CDCl3) δ 4.68 (s, 2 H), 4.07 (t, J ) 6.6 Hz, 2 H),
2.51 (s, 2 H), 1.55-1.27 (m, 14 H), 0.93 (t, J ) 6.6 Hz, 3 H).
13C-NMR (75 MHz, CDCl3) δ 171.21, 81.25, 64.26, 39.04, 36.89,
33.51, 30.56, 25.41, 21.10, 19.10, 13.55. IR (neat) 2959 (s),
2935 (s,b), 2868 (s), 2453 (w), 2338 (w), 1732 (s), 1549 (s), 1458
Eth yl 2-Meth yl-4-n itr o-3-p h en ylbu tyr a te (9). Rf 0.29
(7% MTBE in dichloromethane). 1H NMR (300 MHz, CDCl3)
δ 7.30-7.14 (m, 3 H, both diastereomers), 7.10 (dd, J ) 1.7,
8.1 Hz, 2 H, both diastereomers), 4.78 (dd, J ) 5.8, 12.9 Hz, 1
H, minor diastereoisomer), 4.67 (dd, J ) 9.3, 12.9 Hz, 1 H,
minor diastereomer), 4.63 (d, J ) 7.4 Hz, 2 H, major diaste-
reomer), 4.11 (q, J ) 7.1 Hz, 2 H, major diastereomer), 3.91
(q, J ) 7.1 Hz, 2 H, minor diastereomer), 3.63 (dt, J ) 9.8, 7.4
Hz, 1 H, both diastereomers), 2.79 (dq, J ) 7.1, 7.1 Hz, 1 H,
(s), 1434, 1380 (s), 1364, 1243, 1202 (s), 1178 (s), 1135, cm-1
.
MS (FAB) m/ z (rel intensity) 258 (M + H, 95), 256 (22), 184
(100), 95 (50), 93 (20), 67 (20), 57 (25), 55 (25), 41 (41), 29 (24).
Anal. Calcd for C13H23NO4: C, 60.68; H, 9.01; N, 5.44.
Found: C, 61.08; H, 8.97; N, 5.26.
1-(Nitr om eth yl)-1-[(1-bu toxyca r bon yl)eth yl]cycloh ex-
a n e (17). Rf 0.29 (1:1 dichloromethane/hexanes). 1H NMR
(300 MHz, CDCl3) δ 4.72 (d, J ) 11.0 Hz, 1 H), 4.49 (d, J )
11.0 Hz, 1 H), 4.20-4.05 (m, 2 H), 2.89 (q, J ) 7.2 Hz, 1 H),
1.73-1.37 (m, 10 H), 1.26 (t, J ) 7.1 Hz, 3 H), 1.14 (d, J ) 7.2
Hz, 3 H). 13C-NMR (75 MHz, CDCl3) δ 174.53, 79.65, 60.27,
42.47, 39.39, 30.43, 30.17, 25.08, 20.93, 13.99, 11.39. Consid-
eration of relative peak intensities suggests that the peak at
δ 20.93 corresponds to two unresolved resonances. MS (FAB)
m/ z (rel intensity) 244 (M + H, 100), 198 (34), 123 (25), 109
(12), 95 (16), 81 (21), 55 (13). Anal. Calcd for C12H21NO4: C,
59.24; H, 8.70; N, 5.76. Found: C, 59.10; H, 8.96; N, 5.61.
Meth yl 1-(2-Nitr o-1-p h en yleth yl)cycloh exa n eca r box-
yla te (27). Mp 89-91 °C. Rf 0.20 (7% MTBE in dichlo-
(12) (a) Nitroethylene 19 and 1-nitropropene 7: Buckley, G. D.;
Scaife, C. W. J . Chem. Soc. 1947, 1471. Grob, C. A.; von Sprecher, H.
Helv. Chim. Acta 1952, 35, 902. Hurd, C. D.; Nilson, M. E. J . Org.
Chem. 1955, 20, 927. (b) (Nitromethylidene)cyclohexane (15): Cunico,
R. F. J . Org. Chem. 1990, 55, 4474. Dauben, H. J ., J r.; Ringold, H. J .;
Wade, R. H.; Pearson, D. L.; Anderson, A. G., J r.; Cope, A. G.; Baxter,
W. N.; Cotter, R. J . Organic Syntheses; Wiley: New York, 1963; Coll.
Vol. IV, p 221. 1-(Nitromethyl)cyclohexanone was converted to its
acetate by refluxing it with excess actetyl chloride in chloroform for
20 h. (c) Huitric, A. C.; Kumler, W. D. J . Am. Chem. Soc. 1956, 78,
614.
(13) Ireland, E. E.; Wipf, P.; Armstrong, J . D., III. J . Org. Chem.
1991, 56, 650.

Alkylation of Ketene Silyl Acetals With Nitroolefins
J . Org. Chem., Vol. 62, No. 13, 1997 4375
romethane). 1H NMR (300 MHz, CDCl3) δ 7.25- 7.12 (m, 3
H), 7.02-6.93 (m, 2 H), 4.87-4.70 (m, 2 H), 3.59 (s, 3 H), 3.49
(dd, J ) 5.4, 10.1 Hz, 1 H), 2.20-2.07 (m, 1 H), 1.83-1.73 (m,
1 H), 1.62-1.39 (m, 4 H), 1.23-0.97 (m, 4 H). 13C-NMR (75
MHz, CDCl3) δ 174.75, 135.68, 128.76, 128.26, 128.06, 76.57,
52.33, 51.69, 50.27, 33.63, 31.86, 25.56, 23.34, 22.93. IR (Nujol
mull) 2463 (w), 2313 (w), 2043 (w), 1995 (w), 1982 (w), 1714
(s), 1557 (s), 1429, 1226 (s), 1214 (s), 1150, 1137, 998, 758,
707 (s), cm-1. MS (FAB) m/ z (rel intensity) 292 (M + H, 99),
260 (29), 245 (73), 185 (52), 105 (33), 91 (72), 81 (45), 79 (22),
77 (23). Anal. Calcd for C16H21NO4: C, 65.96; H, 7.26; N, 4.81.
Found: C, 66.04; H, 7.29; N, 4.75.
136.88, 129.12, 128.03, 127.79, 72.99, 52.38, 47.91, 30.46. IR
(Nujol mull) 2417 (w), 2364 (w), 2100 (w), 1979 (w), 1960 (w),
1731 (s), 1548 (s), 1436 (s), 1316, 1272 (s), 1233 (s), 1196, 1170
(s), 1160 (s), 734, cm-1. MS (FAB) m/ z (rel intensity) 224 (M
+ H, 100), 221 (51), 177 (35), 121 (42), 117 (82), 91(43), 77
(37), 75 (34), 73 (59), 57 (78). Anal. Calcd for C11H13NO4: C,
59.19; H, 5.87; N, 6.27. Found: C, 59.42; H, 5.87; N, 6.03.
Meth yl 1-(2-Nitr oeth yl)cycloh exa n eca r boxyla te (28).
Rf 0.32 (1:1 dichloromethane/hexanes). 1H NMR (300 MHz,
CDCl3) δ 4.40-4.28 (m, 2 H), 3.69 (s, 3 H), 2.28-2.16 (m, 2
H), 2.12-1.99 (m, 2 H), 1.65-1.47 (m, 2 H), 1.42-1.17 (m, 6
H). 13C-NMR (75 MHz, CDCl3) δ 175.57, 71.64, 51.86, 45.41,
36.18, 33.70, 25.40, 22.72. IR (neat) 2938 (s), 2859, 1728 (s),
1556 (s), 1454, 1434, 1385, 1365, 1331, 1276, 1231, 1213, 1155,
1137, 1103, cm-1. MS (FAB) m/ z (rel intensity) 216 (M + H,
99), 184 (39), 169 (76), 109 (73), 81 (38), 73 (39), 67 (32), 57
(23), 55 (23), 41 (30). Anal. Calcd for C10H17NO4: C, 55.80;
H, 7.96; N, 6.51. Found: C, 55.80; H, 7.92; N, 6.29.
Gen er a l P r oced u r e for Alk yla tion of Keten e Silyl
Aceta ls w ith Nitr oeth ylen e. P r oced u r e B. This procedure
differs from procedure A primarily because nitroethylene/
ketene silyl acetal mixtures and nitroethylene/MABu mixtures
have very limited stability even at -78 °C. An oven dried 50
mL three-neck round bottom flask was equipped with a 10 mL
addition funnel having an external cooling jacket capable of
maintaining the addition funnel contents at -78 °C. The flask
was loaded with a solution of 1.57 g (6.00 mol) of 2,4,6-tri-
tert-butylphenol in 16 mL of anhydrous methylene chloride.
The solution was degassed in a stream of nitrogen and then
cooled to 0 °C. Neat trimethylaluminum (0.288 mL, 3.00
mmol, extremely pyrophoric!) was added to the solution drop-
wise over 2-3 min via syringe. When the gas evolution
became slow (5 min), the solution was warmed to 25 °C and
stirred 1 h. The solution was then cooled to -78 °C (some
precipitate may form), and a -78 °C solution of the ketene
silyl acetal (2.73 mmol) in 5 mL of methylene chloride was
added all at once via the addition funnel. The -78 °C addition
funnel was immediately loaded with a solution of nitroethylene
(2.73 mmol) in 5 mL of methylene chloride. After 2 min, the
cold nitroolefin solution was added to the reaction mixture
dropwise over 1 min. The mixture was stirred an additional
20 min at -78 °C and then it was allowed to warm to 25 °C.
Anhydrous sodium sulfate (0.50 g) was added, followed by 0.50
g of sodium sulfate decahydrate. The desired product was then
isolated as described in procedure A. In reactions involving
nitroethylene as the nitroolefin component, small quantities
of a tri-tert-butylphenol-nitroethylene adduct are typically
observed at Rf values intermediate between those of tri-tert-
butylphenol and the desired product. Yields are given in Table
2.
cis- a n d tr a n s-3-Meth yl-4-p h en yl-2-p yr olid in on e (30
a n d 31). To a mixture of 429 mg (1.71 mmol) of ethyl
2-methyl-4-nitro-3-phenylbutyrate diastereomers 9 (6.3:1 ratio)
dissolved in 2.5 mL of methanol were added 539 mg of
ammonium formate and 117 mg of 10% Pd/C. A mild exo-
therm was observed. After stirring overnight, the solution was
filtered and the solvent was removed from the filtrate by
evaporation at reduced pressure. The residue was partitioned
between 75 mL of dichloromethane and 20 mL of distilled
water. The aqueous phase was washed with two successive
15 mL portions of distilled water, and the combined organic
extracts were dried (MgSO4). The solvent was removed by
evaporation at reduced pressure. 1H-NMR analysis revealed
a 6.3:1 ratio of diastereomers. An analytical sample obtained
by repeated crystallization from cyclohexane contained a 19:1
ratio of diastereomers and had mp 102-103.5 °C. 1H NMR
(300 MHz, CDCl3): The major isomer gave (in full): δ 7.35-
6.99 (m, 5 H), 6.37 (bs, 1 H), 3.57 (dd, J ) 9.6, ca. 9 Hz, 1 H),
3.32 (dd, J ) 9.6, 9.6 Hz, 1 H), 3.10 (ddd, J ) 10.7, 9.6, ca. 9
Hz, 1 H), 2.49 (dq, J ) 10.7, 7.0 Hz, 1 H), 1.13 (d, J ) 7.0 Hz,
3 H). The minor isomer gave (in part): δ 3.73-3.62 (m, 2 H),
2.78-2.65 (dq, J ) 7.4, 7.0 Hz, 1 H), 0.75 (d, J ) 7.4 Hz, 3 H).
13C-NMR (MHz, CDCl3): The major isomer gave δ 179.89,
140.38, 128.85, 49.96, 47.71, 43.49, 13.98. The minor isomer
gave: δ 180.83, 139.81, 128.31, 127.86, 127.01, 46.35, 44.45,
40.61, 11.37. IR (Nujol mull) 3202 (b), 3152 (b), 3102, 3040,
3028, 2313 (w), 1957 (w), 1695 (s), 1497, 1484, 1359, 1249 (s),
Bu tyl 4-Nitr o-2-m eth ylbu tyr a te (20). 1H NMR (400
MHz, CDCl3) δ 4.52-4.40 (AB of ABX2 system, J AX ≈ J BX
)
756 (s), 701 (s), 605, cm-1
(M+, 40), 175 (40), 119 (10), 118 (99), 117 (43), 115 (10), 91
(21), 77 (10), 65 (10), 63 (7), 51 (17). Anal. Calcd for C11H13
. MS (EI) m/ z (rel intensity) 175
ca. 7 Hz, 2 H), 4.11 (t, J ) 6.6 Hz, 2 H), 2.57 (tq, J ) ca. 7, 7.1
Hz, 1 H), 2.37-2.25 (six line m, 1 H), 2.22-2.09 (six line m, 1
H), 1.64 (tt, J ) 6.6, 7.0 Hz, 2 H), 1.39 (tq, J ) 7.0, 7.3 Hz, 2
H), 1.25 (d, J ) 7.1 Hz, 3 H), 0.95 (t, J ) 7.3 Hz, 3 H). 13C-
NMR (75 MHz, CDCl3) δ 174.90, 73.39, 64.75, 36.53, 30.56,
30.51, 19.07, 17.22, 13.65. MS (FAB) m/ z (rel intensity) 204
(M + H, 42), 358 (29), 204 (42), 130 (40), 75 (33), 73 (38), 57
-
NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.02; H, 7.51; N,
7.90.
Ack n ow led gm en t. The authors gratefully acknowl-
edge Professors Scott Denmark and Edwin Vedejs for
their encouragement and helpful advice. We also thank
the workers of Pharmacia & Upjohn’s Structural, Ana-
lytical and Medicinal Chemistry Unit for providing
combustion analyses, infrared spectral data, and mass
spectral data.
(99), 55 (64), 43 (33), 41 (70), 29 (42). Anal. Calcd for C9H17
-
NO4: C, 53.19; H, 8.43; N, 6.89. Found: C, 53.25; H, 8.68; N,
6.55.
Meth yl 4-Nitr o-2-p h en ylbu tyr a te (22). Mp 30-32 °C.
Rf 0.23 (3:1 dichloromethane/hexanes). 1H NMR (300 MHz,
CDCl3) δ 7.35-7.13 (m, 5 H), 4.37-4.15 (m, 2 H), 3.65 (t, J )
8 Hz, 1 H), 3.62 (s, 3 H), 2.75-2.59 (six line m, 1 H), 2.47-
2.30 (six line m, 1 H). 13C-NMR (75 MHz, CDCl3) δ 172.93,
J O9624004