Tandem nitroaldol-dehydration reactions employing the dianion of phenylsulfonylnitromethane

Article abstract of DOI:10.1021/jo0000170

Reaction of phenylsulfonylnitromethane (1) with more than 2 molar equiv of LDA afforded the dilithium salt of phenylsulfonylnitromethane. Condensation of this dilithium salt with unbranched aldehydes occurred readily, but the initial nitroaldols dehydrate

Full text of DOI:10.1021/jo0000170

J . Org. Chem. 2000, 65, 7723-7730
7723
Ta n d em Nitr oa ld ol-Deh yd r a tion Rea ction s Em p loyin g th e
Dia n ion of P h en ylsu lfon yln itr om eth a n e1
Peter A. Wade,*,† J ames K. Murray, J r.,† Sharmila Shah-Patel,† Bruce A. Palfey,† and
Patrick J . Carroll‡
Department of Chemistry, Drexel University, Philadelphia, Pennsylvania 19104, and Department of
Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
wadepa@drexel.edu
Received J anuary 8, 2000
Reaction of phenylsulfonylnitromethane (1) with more than 2 molar equiv of LDA afforded the
dilithium salt of phenylsulfonylnitromethane. Condensation of this dilithium salt with unbranched
aldehydes occurred readily, but the initial nitroaldols dehydrated to afford unconjugated â,γ-
unsaturated R-nitrosulfones in 52-88% yield. Evidence is presented that the â,γ-unsaturated
R-nitrosulfones can equilibrate with the conjugated R,â-unsaturated R-nitrosulfones at neutral pH.
The normally disfavored R,â-unsaturated R-nitrosulfones have been implicated in the formation of
bis(R-nitrosulfones), Michael adducts of phenylsulfonylnitromethane. Three diastereomers (1R,2s,3S,
1R,2r,3S, and 1R,3R/ 1S,3S) have been identified for the bis(R-nitrosulfones) obtained in these
reactions. In the case of acetaldehyde, condensation with the dilithium salt of phenylsulfonyl-
nitromethane afforded only bis(R-nitrosulfones). The main product (three diastereomers) was the
bis(R-nitrosulfone) derived from Michael addition of phenylsulfonylnitromethane and a minor
product was tentatively identified as the bis(R-nitrosulfone) derived from dimerization. Also formed
in the reaction of propanal with the dilithium salt of phenylsulfonylnitromethane was an unstable
â-amine, the formal conjugate addition product of diisopropylamine to the R,â-unsaturated
R-nitrosulfone. When tandem nitroaldol/dehydration reactions were carried out in the presence of
thiols, the R,â-unsaturated R-nitrosulfones were intercepted to provide â-sulfides, the products of
conjugate addition, in 61-83% yield.
In tr od u ction
Seebach et al.6 have prepared a series of nitroalkane
dianions by R,R-doubly deprotonating primary nitro
compounds and have shown that these dianions undergo
nitroaldol condensation with aldehydes. Simple nitro-
alkanes, aromatic substituted nitroalkanes, and phen-
ylthionitromethane have been reported to undergo this
interesting double deprotonation-nitroaldol sequence.
Formation of the dianions was performed using a very
strong base (butyllithium) and extremely cold reaction
temperature (-90 °C). The questions then arise: Might
the dianion of a very acidic nitro compound such as
phenylsulfonylnitromethane be more readily formed and,
if so, would it then undergo useful nitroaldol transforma-
tions?
Arenesulfonylnitromethanes are quite acidic: Bordwell
and Bartmess2 have reported a pKa of 5.7 for phenylsul-
fonylnitromethane (1). This, coupled with the relatively
congested carbon site, causes the monoanions of arene-
sulfonylnitromethanes to be poor nucleophiles. In ac-
cordance with this fact, Zeilstra and Engberts have
reported3 an unsuccessful attempt to condense p-tolyl-
sulfonylnitromethane with aldehydes under basic condi-
tions,4 although they were able to condense p-tolylsulfo-
nylnitromethane with aldehydes and benzenesulfinic acid
in aqueous formic acid. In contrast to the monoanions
derived from arenesulfonylnitromethanes, the more nu-
cleophilic anion derived from phenylthionitromethane
has been reported5 to add smoothly to a number of
aldehydes.
Resu lts a n d Discu ssion
† Drexel University.
Reaction of phenylsulfonylnitromethane with 2.3 molar
equiv of lithium diisopropylamide (LDA) in tetrahydro-
furan at -78 °C followed by sequential addition of
propanal and glacial acetic acid led to the formation of
the â,γ-unsaturated R-nitrosulfone 7a in 88% yield after
optimization (Scheme 1). Here the crude product was
extracted into base to remove neutral side products
followed by reacidification. A small amount, typically
‡ University of Pennsylvania.
(1) R-Nitrosulfones. 3. For part 2, see: Wade, P. A.; Hinney, H. R.;
Amin, N. V.; Vail, P. D.; Morrow, S. D.; Hardinger, S. A.; Saft, M. S.
J . Org. Chem. 1981, 46, 765.
(2) Bordwell, F. G.; Bartmess, J . E. J . Org. Chem. 1978, 43, 3101.
(3) Zeilstra, J . J .; Engberts, J . B. F. N. J . Org. Chem. 1974, 39, 3215.
Zeilstra, J . J . Ph.D. thesis, Verenigde Reproductie Bedrijven, Gronin-
gen, The Netherlands, 1975.
(4) Rosini et al. have recently shown that certain aldehydes pos-
sessing an R-leaving group can undergo base-promoted reaction with
1 to afford 4-hydroxy-2-isoxazoline-N-oxides. The 4-hydroxy-2-isox-
azoline N-oxides were not isolated but, rather, were allowed to react
further with activated olefins (e.g., chlorodimethylvinylsilane). The
authors postulate an initial nitroaldol reaction of the aldehyde with 1
and subsequent intramolecular O-alkylation of the resulting nitronate
to give the 4-hydroxy-2-isoxazoline-N-oxide: Marotta, E.; Righi, P.;
Rosini, G.Tetrahedron Lett. 1998, 39, 1041; Marotta, E.; Righi, P.;
Rosini, G. Chem.-Eur. J . 1998, 4, 2501.
(5) Barrett, A. G. M.; Graboski, G. G.; Russell, M. A. J . Org. Chem.
1986, 51, 1012.
(6) (a) Seebach, D.; Beck, A. K.; Triptikumar, M.; Thomas, E. Helv.
Chim. Acta 1982, 65, 1109. (b) Eyer, M.; Seebach, D. J . Am. Chem.
Soc. 1985, 107, 3601. (c) For R,â-doubly deprotonated nitro compounds,
see: Henning, R.; Lehr, F.; Seebach, D. Helv. Chim. Acta 1976, 59,
2213.
10.1021/jo0000170 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/25/2000

7724 J . Org. Chem., Vol. 65, No. 23, 2000
Wade et al.
Sch em e 1
Two unstable intermediates were observed in the
condensation of dilithium salt 2 with propanal. The first
of these was the intermediate nitroaldol 9a . Nitroaldol
9a (50% of the crude products) was observed, accompa-
nied by â,γ-unsaturated R-nitrosulfone 7a , when the
reaction products were examined directly after addition
1
of glacial acetic acid. The H NMR signals attributed to
9a gradually disappeared on standing for a day in contact
with traces of acid, more rapidly in the presence of excess
acetic acid or when warmed. Two diastereomers of the
1
nitoaldol (60:40 ratio by H NMR) were apparent. The
low diastereioselectivity is consistent with observations
made by Seebach et al.6a for acidification of dianions
under conditions similar to those we employed, namely
in the absence of HMPA or DMPU. Presumably, the first
protonation of 3a occurred preferentially at the more
basic alkoxide site (pKa ) 16.488 for 2-propanol, a
representative secondary alcohol) rather than at the less
basic nitronate site (pKa ) 5.7 for 1,2 a representative
R-nitrosulfone). A subsequent protonation of 6a afforded
the nitroaldol 9a : here the aci-nitro tautomer was also
possible, indeed likely, but was not observed.
With regard to dehydration, there is ample evidence
that the R,â-unsaturated R-nitrosulfone 8a was formed
prior to the â,γ-unsaturated R-nitrosulfone 7a . In all
runs, 10a , the Michael adduct of 7a and phenylsulfon-
ylnitromethane (1) was formed as a side product. The
amount of bis(R-nitrosulfone) 10a was variable, but in
certain cases where substantial amounts of 1 remained,
10a constituted more than 25% of the crude product.
about 2-5% yield, of the bis(R-nitrosulfone) 10a was also
obtained in the crude products. On the other hand,
attempts to condense lithium phenylsulfonylnitrometha-
nate (4)1 with propanal were unsuccessful: the reaction
products after 24 h at room temperature consisted of a
93:3:3 mixture of starting phenylsulfonylnitromethane,
alkene 7a , and the bis(R-nitrosulfone) 10a , respectively,
following acidification. Apparently, efficient formation of
7a requires formation of the dilithium salt 3a prior to
acidification.
A second unstable intermediate, â-amine 11 (25% of
the crude product), accompanied by â,γ-unsaturated
R-nitrosulfone 7a , was obtained in certain runs when the
reaction was examined directly after addition of glacial
acetic acid. Here, the nitroaldol had completely dehy-
drated and free diisopropylamine (possibly excess LDA)
had undergone conjugate addition to the intermediate
R,â-unsaturated R-nitrosulfone 8a affording the â-amine
Two alternative routes for the formation of 3a were
thought possible. In the first route, LDA, if sufficiently
basic, could doubly deprotonate phenylsulfonylnitro-
methane to form the dilithium salt 2. Condensation of
the dilithium salt 2 with propanal would lead directly to
3a , the apparent precursor to the â,γ-unsaturated R-ni-
trosulfone 7a . Alternatively, LDA might only be capable
of singly deprotonating phenylsulfonylnitromethane to
afford the lithium salt 4. Reaction of 4 with propanal
might occur to form the lithium alkoxide 5a in low
concentration. Deprotonation of 5a by excess LDA could
then afford the dilithium salt 3a driving condensation
toward completion.
1
11, present as two diastereomers (65:35 ratio). The H
NMR signals attributed to 11 disappeared from the crude
products during the usual base-acid workup and an
attempt to obtain pure 11 by preparative TLC led to
complete decomposition of 11. On protracted standing in
the freezer, signals attributed to 11 disappeared while
signals for 10a and phenylsulfonylnitromethane in-
creased: presumably 11 readily eliminates diisopropyl-
amine to afford R,â-unsaturated R-nitrosulfone 8a , which
in turn affords 7a , phenylsufonylnitromethane, and 10a .
An E1cb pathway for the formation of the R,â-unsatur-
ated R-nitrosulfone has been considered, but no support-
ing evidence has been obtained for it. In the case of the
nitroaldol 9a , a likely pathway would involve deproto-
nation to 6a , and subsequent loss of the hydroxyl group
furnishing the R,â-unsaturated R-nitrosulfone 8a . It is
reasonable that, even in the presence of excess acetic acid
(pKa 4.76), the acidic 9a could ionize to provide 6a in
sufficient concentration for dehydration. Thus, the pro-
pensity for dehydration observed here, in contrast to the
studies of Seebach et al. where the nitroaldols do not
readily dehydrate, is likely a consequence of the high
acidity of 9a . A similar process likely operates with the
To distinguish between the two mechanistic possibili-
ties, the stoichiometry for reaction of LDA with phenyl-
sulfonylnitromethane was established. A THF solution
of LDA containing triphenylmethane was titrated with
a THF solution of phenylsulfonylnitromethane. Dissipa-
tion of the blood-red color of lithium triphenylmethide
occurred after addition of only 0.5 molar equiv of phen-
ylsulfonylnitromethane. It is therefore concluded that
dilithium salt 2 was formed from reaction of excess LDA
with phenylsulfonylnitromethane and that 2 must be the
actual species condensing with propanal to furnish 7a .
Apparently the second pKa of phenylsulfonylnitromethane
in THF is less than 31 (i.e., the lithium salt 4 of
phenylsulfonylnitromethane is a stronger acid than
triphenylmethane, pKa 31.487).
(7) pKa of triphenylmethane in cyclohexylamine: Streitwieser, A.,
J r.; Ciuffarin, E.; Hammons, J . H. J . Am. Chem. Soc. 1967, 89, 63.
(8) pKa of 2-propanol in alcoholic media: Reeve, W.; Erikson, C. M.;
Aluotto, P. F. Can. J . Chem. 1979, 57, 2747.

Tandem Nitroaldol-Dehydration Reactions
J . Org. Chem., Vol. 65, No. 23, 2000 7725
Ta ble 1. P r od u cts Obta in ed fr om Rea ction of
LiC(dNO2Li)SO2P h (2) w ith Un br a n ch ed Ald eh yd es
F igu r e 1. Bis(R-nitrosulfone) 10 diastereomers.
Second, the conjugated lithium â,γ-unsaturated nitronate
12 is present and, quite likely, the conjugated nitronic
acid also. Protonation of nitronate 12 on the carbon
bearing the nitro group would then afford the â,γ-
unsaturated R-nitrosulfone. Indeed, the R-proton of 7a
can be readily deuterium exchanged (occasional shaking
over 45 min of a CDCl3 solution layered with D2O),
consistent with anion formation and reprotonation at the
R-carbon.
There is evidence that the R,â-unsaturated R-nitrosul-
fones are intermediates in the formation of the â,γ-
unsaturated R-nitrosulfones 7b-e as in the case of 7a .
Side products 10b-d derived from Michael addition of
phenylsulfonylnitromethane to the R,â-unsaturated R-ni-
trosulfones were obtained similar to 10a . Only in the case
of â,γ-unsaturated R-nitrosulfone 7e was no Michael
adduct detectable. Since the phenyl group of 7e would
be in conjugation with the C,C double bond, 7e would be
strongly favored at the expense of the R,â-unsaturated
R-nitrosulfone 8e. Nevertheless, trapping evidence was
obtained for the intermediacy of the R,â-unsaturated
R-nitrosulfones even in the case of 7e (vide infra).
a
Also obtained was bis(R-nitrosulfone) 13 in 6% yield.
â-amine 11, which is, however, somewhat more stable
than the nitoaldol 9a . Substantial reversion to propanal
and phenylsulfonylnitromethane did not normally occur
during acidification, although some of the starting phen-
ylsulfonylnitromethane could always be isolated from the
crude products. Under conditions optimized for formation
of 7a , the amount of remaining phenylsulfonylnitro-
methane was 2-5% of the product. On the other hand,
immediate treatment of the crude products containing
nitroaldol 9a with aqueous sodium hydroxide followed
by reacidification resulted in a substantially increased
formation of starting phenylsulfonylnitromethane: rapid
hydroxyl deprotonation and fragmentation of the ensuing
sodium alkoxide (analogous to the lithium alkoxide 5a )
would be the cause.
The scope of the tandem nitroaldol-elimination se-
quence was next investigated by examining a series of
aldehydes. Successful reactions to produce â,γ-unsatur-
ated R-nitrosulfones 7b-e in 52-77% yield were carried
out using butanal, pentanal, 3-phenylpropanal, and
phenylacetaldehyde (Table 1). The bis(R-nitrosulfones)
10b-d were obtained as incompletely purified side
products in yields ranging from 2 to 10%. Diphenyl-
acetaldehyde and isobutyraldehyde failed to give the
corresponding â,γ-unsaturated R-nitrosulfones: appar-
ently nitroaldol dianion formation (or the stability of the
dianion) is adversely affected by moderate steric bulk at
the R-carbon atom of the aldehyde. In the case of
acetaldehyde, too, none of the usual â,γ-unsaturated
R-nitrosulfone was obtained: instead, the main product
was the bis(R-nitrosulfone) 10f, obtained in 80% yield.
Formation of the â,γ-unsaturated R-nitrosulfones 7a -e
was highly stereoselective. All products obtained were
> 97% pure E-isomers: no trace of the Z-isomer was
detected in any of the examples studied. The stereochem-
ical assignment is based on 1H NMR and 13C NMR
spectra. The 15.3-15.5 Hz coupling constants for the
olefinic protons are only consistent with a 180° dihedral
angle.9
All of the bis(R-nitrosulfones), products of Michael
addition, were obtained as mixtures of diastereomers:
three diastereomers are possible and all were readily
apparent for 10a -f. All of the bis(R-nitrosulfones) were
somewhat sensitive and difficult to purify by chromatog-
raphy: indeed, 10c, the most sensitive, could only be
obtained in 80% purity. Structure assignment for 10b is
typical: diastereomer i (Figure 1) was assigned the
structure of the racemate 1R,3R/ 1S,3S based on the
observation of two equal intensity 1H NMR doublets with
chemical shifts of δ 6.67 and 6.08. The more downfield
of these doublets exhibited a large coupling constant (J 1,2
) 5.7 Hz) and the more upfield a small coupling constant
(J 2,3 ) 1.9 Hz). The remaining two diastereomers ii-iii
were assigned the structures of the meso diastereomers
1R,2s,3S and 1R,2r,3S based on the presence of only one
1H NMR doublet each at δ 6.19 (major) and 6.14 (minor).
The isomer ratio was 62:25:13 i, ii, and iii, respectively.
It is not possible, on the basis of the data accumulated,
to provide an unambiguous assignment of the individual
meso isomers. However, if it is assumed that these
compounds adopt an extended conformation (Figure 1)
where the large sulfone groups avoid each other, then
the isomer with the larger coupling constant J 1,2 should
correspond to the 1R,2s,3S isomer: thus, ii is probably
the 1R,2s,3S isomer. In the case of 1,3-propanediol
derivatives where a conformational preference exists
owing to intramolecular H-bonding, similar, but more
The isolated alkene products were the nonconjugated
â,γ-unsaturated R-nitrosulfones in all cases. Initially this
seemed surprising, especially in light of the reported5
formation of conjugated R,â-unsaturated R-nitrosulfides.
Formation of the â,γ-unsaturated R-nitrosulfones can be
rationalized on two counts. First, sulfones often prefer
to be nonconjugated under equilibrating conditions.10
(9) The typical trans-coupling constant is 12-18 Hz and the typical
cis-coupling constant is 6-12 Hz: Silverstein, R. M.; Webster, F. X.
Spectrometric Identification of Organic Compounds; 6th ed.; Wiley:
New York, 1998; p 212.
(10) Meagher, T. P.; Yet, L.; Hsiao, C.-N.; Shechter, H. J . Org. Chem.
1998, 63, 4181.

7726 J . Org. Chem., Vol. 65, No. 23, 2000
Wade et al.
Ta ble 2. P r od u cts Obta in ed fr om Th iol Tr a p p in g of
r,â-Un sa tu r a ted r-Nitr osu lfon e In ter m ed ia tes Der ived
fr om th e Rea ction of 2 w ith Ald eh yd es
definite, assignments have been made based upon cou-
pling constants.11
Reaction of phenylsulfonylnitromethane with 2.3 molar
equiv of LDA in tetrahydrofuran at -78 °C followed by
sequential addition of acetaldehyde and glacial acetic acid
led to the formation of the bis(R-nitrosulfone) 10f in 80%
yield. The bis(R-nitrosulfone) 10f was obtained in ap-
proximately 95% purity as a 54:40:6 mixture of three
diastereomers, i, ii, and iii, respectively. Also present in
the crude products was a small amount of material
tentatively identified as the â,γ-unsaturated bis(R-nitro-
sulfone) 13, apparently formed via Michael addition of
the nitronate 12f to 8f followed by deconjugation of the
double bond. None of the simple â,γ-unsaturated R-ni-
R*,S*/R*,R*
isomer ratio
â,γ-unsaturated
R-nitrosulfone
yield, %
RCH2CHdO
R )
R′SH
R′ )
â-sulfide
yield,a
%
(crude) (purea)n
CH3
Ph
PhCH2
CH3CH2 14c, 63
Ph 14d , 61
14a , 83
(67:33) (100:0)
7a , 0
7b, 0
7c, 18
7d , 19
CH3CH2
PhCH2
Ph
14b, 72b (65:35) (65:35b)
(75:25) (100:0)
(57:43) (100:0)
a
After chromatographyand subsequent crystallization. b Remained
an oil.
dergoes Michael addition. Similarly, a pure sample of 7d
afforded a mixture of products containing bis(R-nitrosul-
fone) 10d , 7d , and phenylsulfonylnitromethane in a
27:34:40 mole ratio. Apparently, isomerization of 7d is
somewhat more facile than isomerization of 7a .
It has not been established whether a single isomer or
both possible isomers of the R,â-unsaturated R-nitrosul-
fone are present in the above reactions. However, mo-
lecular mechanics calculations suggest a 1.1 kcal/mol
lower steric strain energy for the Z-isomer of 8f compared
to the E-isomer. A similar 1.0 kcal/mol lower steric strain
energy was calculated for the Z-isomer of 8a compared
to the E-isomer. Also, by analogy to R,â-unsaturated
R-nitrosulfides,5 the Z-isomer of the R,â-unsaturated
R-nitrosulfones would seem to be the preferred isomer.
The R,â-unsaturated R-nitrosulfone intermediate present
in the tandem nitroaldol/dehydration reactions was
purposefully intercepted to provide products of conjugate
addition. Thus, various thiols were added to the dianion
reaction mixture prior to the addition of aldehyde. In all
four of the cases examined, the R,â-unsaturated R-nitro-
sulfone intermediate was intercepted by the thiol and
little if any of the normal â,γ-unsaturated R-nitrosulfone
was formed (Table 2). Thus, reaction of phenylsulfonylni-
tromethane with excess LDA in tetrahydrofuran at -78
°C followed by sequential addition of thiophenol, propanal
and glacial acetic acid led to the formation of â-sulfide
14a in 83% yield. The initial product was a mixture of
diastereomers that was converted to a single diastere-
omer on crystallization, presumably the isomer with the
stronger crystal lattice. The diastereomer with the larger
coupling constant (J 1,2 ) 11.2 Hz) observable for the
R-proton was formed preferentially. Based on X-ray
crystallographic data obtained for a single enantiomor-
phic crystal (pure 1R,2R-enantiomer) of the major isomer
of 14a , the R*,R* configuration was assigned whereas
the isomer with the smaller coupling constant (J 1,2 ) 5.5
Hz) was assigned the R*,S* configuration. The R*,R* and
R*,S* diastereomers must interconvert in the liquid
state, presumably via the nitronate intermediate, with
the R*,R* isomer crystallizing preferentially from solu-
tion to afford a conglomerate: perhaps the driving force
for the isomerization is the preference of R,R and S,S
isomers to crystallize separately.
trosulfone 7f was detected in this reaction. It seems that
here the R,â-unsaturated R-nitrosulfone was present at
significantly higher equilibrium concentration than in the
cases of 8a -e. Perhaps the lack of a stabilizing alkyl
group on the double bond of â,γ-unsaturated R-nitrosul-
fone 7f might disfavor its formation. Typical monosub-
stituted alkenes (e.g., 1-butene) are approximately 2.5
kcal/mol less stable than trans-disubstituted alkenes.
In several cases, as little as 1.2 molar equiv of LDA
led after acidification to formation of a mixture rich in 7
and 10 with varying amounts of remaining phenylsul-
fonylnitromethane. Thus, after formation of lithium salt
4, its condensation with the aldehyde must have been
occurring and required only a catalytic portion of strong
base (i.e., the alternate condensation pathway not involv-
ing dianion 2 must have occurred). It is concluded that a
low equilibrium concentration of the lithium alkoxide 5
must have been present and that deprotonation of 5 was
occurring to afford the dilithium salt 3. Perhaps further
reaction was self-catalytic: dilithium salt 3, likely the
strongest base present during most of the reaction, could
deprotonate more 5 affording 6 and another molecule of
3. We were able to make use of this result since increased
amounts (more than 50% of the crude product) of the bis-
(R-nitrosulfones) 10b-c became available. Nevertheless,
although the dianion 2 was not required for condensation,
cleaner condensation to the â,γ-unsaturated R-nitro-
sulfone was observed when more than 2 molar equiv of
LDA was employed, implicating the dianion 2 as the
preferred intermediate.
Interconversion of the â,γ-unsaturated R-nitrosulfones
7 and the R,â-unsaturated R-nitrosulfones 8 was dem-
onstrated under neutral buffered conditions. Thus, a pure
sample of 7a was allowed to react with phenylsulfonylni-
tromethane and lithium acetate/acetic acid in THF for
24 h affording conversion to a mixture of products
containing bis(R-nitrosulfone) 10a , 7a , and phenylsul-
fonylnitromethane in a 13:42:45 mole ratio. The bis(R-
nitrosulfone) 10a must be forming via Michael addition
to the R,â-unsaturated R-nitrosulfone 8a and hence the
presence of 8a is required: it is surmised that an
unfavorable equilibrium exists between the â,γ-unsatur-
ated R-nitrosulfone 7a , which is inert to Michael addition,
and the R,â-unsaturated R-nitrosulfone 8a , which un-
In analogous fashion, the â-sulfides 14b-d were
prepared as initial diatereomeric mixtures from the
appropriate thiols and aldehydes. In all cases the initial
(11) Barluenga, J .; Resa, J . G.; Olano. B.; Fustero, S. J . Org. Chem.
1987, 52, 1425.
major isomer exhibited a large coupling constant (J 1,2
)

Tandem Nitroaldol-Dehydration Reactions
J . Org. Chem., Vol. 65, No. 23, 2000 7727
Con clu sion s
A simple procedure employing excess LDA for the
formation of the dilithium salt of phenylsulfonylnitro-
methane has been developed. Condensation of this dil-
ithium salt with unbranched aldehydes occurs readily but
the resulting nitroaldols are sensitive and will rapidly
dehydrate to â,γ-unsaturated R-nitrosulfones. An inter-
esting tautomeric equilibration between â,γ-unsaturated
R-nitrosulfones and the corresponding R,â-unsaturated
R-nitrosulfones at or near pH 7 has been established. This
equilibration, reminiscent of the equilibration between
keto and enol tautomers, provides a low concentration
of the reactive Michael-acceptor, the R,â-unsaturated
R-nitrosulfone. The formation of bis(R-nitrosulfones) and
â-sulfides via conjugate addition to the intermediate R,â-
unsaturated R-nitrosulfones readily occurs, presaging
their general use as novel Michael acceptors.
F igu r e 2. Conformations of the C1-C2 bond of â-sulfides
14a -d .
9.2-11.2 Hz) for the R-proton while the minor isomer
exhibited a small coupling constant (J 1,2 ) 3.9-6 Hz).
By analogy with 14a , the isomer with the larger J 1,2 was
assigned the R*,R* configuration. â-Sulfide 14b did not
crystallize and remained a 65:35 diastereomer mixture.
However, â-sulfides 14c,d crystallized affording conver-
sion of the R*,S* isomer to the R*,R* isomer. In both
cases, initial crystallization afforded a 95:5 R*,R*/R*,S*
diastereomer ratio for the entire product which, with one
recrystallization, afforded pure R*,R* diastereomer.
It is noteworthy that even the R,â-unsaturated R-ni-
trosulfone 8e could be intercepted before isomerization
to 7e in which the double bond is in conjugation with
the benzene ring. Here, â-sulfide 14d was isolated as the
major product. However, the â-sulfide 14d was somewhat
thermally sensitive. On warming 14d to 50 °C, rapid
elimination occurred and the â,γ-unsaturated R-nitro-
sulfone 7e was formed.
Conformational isomers around the C1-C2 bond of the
â-sulfides 14a -d have been examined for the purpose of
defining substituent interactions (Figure 2). For the
R*,R*diastereomer, conformation B where protons are
located anti must be major owing to the large coupling
constants observed. Indeed, the crystallographic data
obtained for 14a clearly indicate conformation B as the
preferred conformation in the crystalline state. Confor-
mation A would be disfavored owing to steric hindrance
to placing the bulky sulfone group simultaneously gauche
to the thioether group and C3 of the extended chain.
Conformation C would be disfavored largely owing to an
unfavorable steric interaction between the thioether and
the sulfone groups.
For the R*,S*diastereomer, conformation A seems
unlikely as a preferred conformation owing to steric
hindrance from the thioether group and C3 of the
extended chain with the sulfone group. Conformation C
must then be a favored conformation in order to explain
the modest coupling constants observed. It is therefor
concluded that placing the nitro group gauche to the
thioether groups is favorable, strongly suggesting an
attractive interaction. This also explains the preference
for conformation B of the R*,R*diastereomer. Other
workers have noted a preference for gauche conforma-
tions and apparent dipolar attractive interaction between
the nitro and hydroxyl groups of nitro alcohols12 and the
nitro and alkoxyl groups of nitroethers.13
Exp er im en ta l Section
1
Gen er a l Meth od s. NMR spectra (250 MHz for H in CDCl3)
were obtained as previously described14 unless otherwise
noted. High-resolution mass spectra were obtained using a VG
ZAB-HS mass spectrometer.15 Diisopropylamine (from CaH2),
acetaldehyde, propanal, butanal, and pentanal were freshly
distilled just prior to use. Phenylsulfonylnitromethane was
prepared by a published procedure.1 All reactions were run
under a nitrogen atmosphere.
Ta n d em Nit r oa ld ol/Deh yd r a t ion R ea ct ion of 1 a n d
P r op a n a l. Butyllithium (1.9 mL of a 2.5 M solution in
hexanes, 4.7 mmol) was added to a cold (dry ice) solution of
diisopropylamine (0.49 g, 4.8 mmol) in THF (6 mL). The
resulting solution was allowed to warm to -20 °C and was
recooled (dry ice). A solution of phenylsulfonylnitromethane
(1) (0.40 g, 2.0 mmol) in THF (4 mL) was added dropwise over
a 10 min period to the first solution. The resulting yellow
solution of dianion 2 was stirred for 1 h, allowed to warm to
-40 °C, and recooled (dry ice). A solution of propanal (0.14 g,
2.4 mmol) in THF (10 mL) was added dropwise over 30 min
and the resulting solution was stirred for an additional 30 min.
Glacial acetic acid (5 mL) was added dropwise and the reaction
solution was allowed to warm to room temperature. The
reaction solution was poured into water that had been acidified
with a few drops of concentrated hydrochloric acid. The
resultant mixture was extracted with CH2Cl2. The combined
organic layers were washed with water, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was kept at room temp for 12-24 h and
was taken up in CH2Cl2 (50 mL). Alternatively, the crude
product was warmed at 40-50 °C for 2 h during concentration
and was taken up in CH2Cl2. Aqueous 5% NaOH (200 mL)
was added, the resulting mixture was stirred for 10 min, and
the CH2Cl2 layer containing propanal self-condensation prod-
ucts16 was removed. The basic aqueous layer was washed with
CH2Cl2 and acidified with concentrated aqueous HCl affording
a milky-white mixture. This mixture was extracted with CH2-
Cl2, and the combined extracts were washed with water, dried
over anhydrous Na2SO4, filtered, and concentrated. The crude
product at this stage typically consisted of 1 (2-5%), â,γ-
unsaturated R-nitrosulfone 7a (90-95%), and Michael adduct
10a (2-5%). Further purification was either by procedure A
or procedure B.
(13) Aebischer, B.; Hollenstein, R.; Vasella, A. Helv. Chim. Acta
1983, 66, 1748.
(14) Wade, P. A.; Kondracki, P. A.; Carroll, P. J . J . Am. Chem. Soc.
1991, 113, 8807.
(15) We thank Dr. J effrey Honovich (Drexel University) for obtaining
the mass spectra.
(16) 1H NMR spectra of simple aldols from: Mahrwald, R.; Cos-
tisella, B.; Gundogan, B. Synthesis 1998, 262. Aldol condensation side
reactions under basic conditions are numerous; see: Nielsen, A. T.;
Houlihan, W. J . In Organic Reactions; Nielsen, A. T., Houlihan, W. J .,
Assoc. Eds.; Wiley: New York; Vol. 16, p 1.
(12) Kingsbury, C. A.; Sopchik, A. E.; Underwood, G.; Rajan, S. J .
Chem. Soc., Perkin Trans. 2 1982, 867.

7728 J . Org. Chem., Vol. 65, No. 23, 2000
Wade et al.
Procedure A was followed for crude product containing
2-3% 1: Preparative TLC (CH2Cl2-HOAc, 98:2) removed the
Michael adduct 10a (less mobile fraction) but not 1. In this
way, nearly pure 7a (0.43 g, 88% yield, 97% pure contaminated
with 3% of 1) was obtained as an oil from the more mobile
band. Further purification by preparative TLC (CH3CN-Et2O,
50:50) gave material free of 1 in the upper half of the main
band, providing the analytical sample: IR (film) 1562 (NO2),
(m) 5.76 (dd, J ) 9.2, 14.8 Hz), and 5.35-5.45 (m) (total 3H);
3.3-3.45 (m, major) and 3.2-3.3 (m, minor) total 1H, 1.42 (d,
J ) 6.8 Hz, isomer i), 1.20 (d, J ) 6.8 Hz, isomer ii), and 1.14
(d, J ) 6.7 Hz, isomer iii) (total 3H); HRMS (M + Na+, FAB,
NaBr) calcd for C18H18N2O8S2Na 477.0402, found 477.0410.
Ta n d em Nit r oa ld ol/Deh yd r a t ion R ea ct ion of 1 a n d
Bu ta n a l. The procedure employed for propanal was repeated
using butanal (0.17 g, 2.4 mmol) in place of propanal. Purifica-
tion (procedure B) as before gave 0.39 g (77% yield) of â,γ-
unsaturated R-nitrosulfone 7b from the most mobile chroma-
tography fraction (CH2Cl2-HOAc, 98:2) as an oil: IR (film)
1562 (NO2), 1336, 1156 (SO2) cm-1; 1H NMR δ 7.6-7.9 (m, 5H),
6.2 (dt, 1H, J ) 15.4, 6.2 Hz), 5.97 (d, 1H, J ) 9.6 Hz), 5.65
(ddt, 1H, J ) 15.4, 9.6, 1.6 Hz), 2.19 (m, 2H), 0.98 (t, 3H, J )
7.1 Hz); 13C NMR δ 148.4, 135.3, 134.0, 130.0, 129.1, 113.8,
103.2, 25.7, 12.1; HRMS (M + Na+, FAB, NaBr) calcd for
1
1335, 1156 (SO2) cm-1; H NMR δ 7.6-7.9 (m, 5H), 6.15 (dq,
1H, J ) 15.4, 6.7 Hz), 5.92 (d, 1H, J ) 9.2 Hz), 5.70 (ddq, 1H,
J ) 15.4, 9.6, 1.7 Hz), 1.84 (dd, 3H, J ) 6.7, 1.7 Hz); 13C NMR
(CDCl3) δ 142.3, 135.3, 134.0, 130.0, 129.2, 115.8, 103.1, 18.4;
HRMS (M + Na+, FAB, NaBr) calcd for C10H11NO4SNa
264.0306, found 264.0299.
The less mobile chromatography fraction afforded 12 mg (3%
yield) of a relatively pure sample of 10a consisting of three
diastereomers i, ii, and iii in a 60:25:15 ratio, respectively)
C
11H13NO4SNa 278.0463, found 278.0464.
Michael adduct 10b (2% yield) was observed in the crude
products (least mobile TLC fraction).
1
as an oil: H NMR δ 7.6-8.1 (m, 10H), 6.65 (d, due to i, J )
6.3 Hz), 6.19 (d, due to ii, J ) 6.5 Hz), 6.1 (d, 1H due to i, J )
2.0 Hz), 6.13 (d, 2H due to iii, J ) 2.1 Hz), 3.8-3.95 (m, 1H),
2.3-2.55 (m) and 2.05-2.25 (m) (total 2H), 1.03 (m, 3H);
HRMS (M + Na+, FAB, NaBr) calcd for C17H18N2O8S2Na
465.0402, found 465.0393.
Ta n d em Nit r oa ld ol/Deh yd r a t ion R ea ct ion of 1 a n d
P en ta n a l. The procedure employed for propanal was repeated
using pentanal (0.21 g, 2.4 mmol) in place of propanal.
Purification (procedure B) as before gave 0.38 g (70% yield) of
â,γ-unsaturated R-nitrosulfone 7c from the most mobile chro-
matography fraction (CH2Cl2-HOAc, 98:2) as an oil: IR (film)
1560 (NO2), 1344, 1157 (SO2) cm-1; 1H NMR δ 7.6-7.9 (m, 5H),
6.13 (dt, 1H, J ) 15.3, 6.8 Hz), 5.92 (d, 1H, J ) 9.7 Hz), 5.64
(ddt, 1H, J ) 15.3, 9.6, 1.5 Hz), 2.14 (m, 2H), 1.44 (app sx,
2H, J ) 7.4 Hz), 0.92 (t, 3H, J ) 7.3 Hz); 13C NMR δ 146.9,
135.1, 133.8, 129.8, 129.0, 114.6, 103.0, 34.3, 21.1, 13.3; HRMS
(M + Na+, FAB, NaBr) calcd for C12H15NO4SNa 292.0619,
found 292.0618.
Procedure B was followed in cases where significant quanti-
ties (>3%) of 1 were present. First 1 was removed from the
crude product by taking advantage of its more rapid rate of
deprotonation compared to the other acidic products. Repeti-
tive acid-base extractions afforded a slow acid fraction free
of 1 and a fast acid fraction which was predominantly 1. Thus,
product contaminated with 1 was dissolved in CH2Cl2 (50 mL),
and the solution was rapidly extracted with 5% sodium
hydroxide (200 mL; mixing in a separatory funnel involved
three quick inversions taking <20 s). The organic extracts were
washed successively with 10% aqueous HCl and distilled
water, dried over anhydrous Na2SO4, and concentrated to an
oil. This oil contained â,γ-unsaturated R-nitrosulfone 7a and
Michael adduct 10a but no 1. The basic aqueous layer was
acidified with concentrated HCl and extracted with CH2Cl2.
The combined CH2Cl2 extracts were washed with water, dried
over anhydrous Na2SO4, and concentrated to afford a mixture
enriched in 1 but containing some 7a . This mixture was
resubjected to the separation procedure: several (2-3) repeti-
tions on the mixed fractions afforded more material free of 1
which was combined with the first fraction. The product free
of 1 was then further purified by preparative TLC (CH2Cl2-
HOAc, 98:2) to remove Michael adduct 10a (less mobile
fraction). However, a trace (1-2%) of 1 reformed during the
final chromatographic purification. It was determined that
unidentified impurities formed from a small amount of base-
induced decomposition of 7a were the source of the newly
reformed 1.17 This procedure typically afforded 0.36-0.4 g (75-
83% yield) of 7a (98% pure, contaminated with 2% of 1).
Michael adduct 10c (1% yield) was observed in the crude
products (least mobile TLC fraction).
P r ep a r a tion of Mich a el Ad d u ct 10b. To obtain a work-
able quantity of the Michael adduct 10b, a modified tandem
nitroaldol dehydration procedure was followed. Less base (2.4
mmol of LDA) was employed keeping the amount of phenyl-
sulfonylnitromethane (1) (0.40 g, 2.0 mmol) and butanal (0.17
g, 2.4 mmol) as before. Further reaction and workup as before
gave variable amounts of 7b, 1, and Michael adduct 10b:
however, much more Michael adduct was noted than when 4
mmol of base was employed. Indeed, the crude products
routinely consisted of more 10b than 7b. Purification (proce-
dure B) as before followed by preparative TLC afforded a
1
purified sample of 10b (0.20 g, 22% yield: >95% pure by H
NMR; least mobile fraction) consisting of three diastereomers
i, ii, and iii in a 62:25:13 ratio, respectively: IR (film) 1565
-1
(NO2), 1341, 1153 (SO2) cm
;
1H NMR δ 7.5-8.1 (m, 5H),
6.67 (d, 1H of i, J ) 5.7 Hz), 6.19 (d, 2H of ii, J ) 6.4 Hz), 6.14
(d, 2H of iii, J ) 1.8 Hz), 6.08 (d, 1H of i, J ) 1.9 Hz), 3.95-
4.05 (m, 1H), 2.3-2.5 (m) and 1.95-2.1 (m) (total 2H), 1.2-
1.55 (m, 2H), 0.8-1.0 (m, 3H); HRMS (M + Na+, FAB, NaBr)
calcd for C18H20N2O8S2Na 479.0559, found 479.0578.
Ta n d em Nit r oa ld ol/Deh yd r a t ion R ea ct ion of 1 a n d
Aceta ld eh yd e. The procedure employed for propanal was
repeated using acetaldehyde (0.11 g, 2.4 mmol) in place of
propanal. Purification (procedure B) as before gave only
Michael adducts. The main product, obtained as an oil, was
7f (0.69 g, 80% yield, 52:39:08 mixture of diastereomers i, ii,
and iii, respectively): 1H NMR δ 7.61-8.01 (m, 10H), 6.54 (d,
1H of i, J ) 2.7 Hz), 6.36 (d, 1H of i, J ) 10.0 Hz), 6.19 (d, 2H
of ii, J ) 6.6 Hz), 5.79 (d, 2H of iii, J ) 6.0 Hz), 3.9-4.1 (m,
1H of i-iii), 1.97 (d, 3H of iii, J ) 6.9 Hz), 1.68 (d, 3H of i, J
) 6.8 Hz), 1.52 (d, 3H of ii, J ) 6.7 Hz); 13C NMR δ 137.05,
136.29, 135.99, 135.61, 134.75, 133.37, 129.84, 129.78, 129.63,
129.58, 101.61, 99.67, 97.0, 34.68, 32.65, 12.16, 11.83; HRMS
(M + Na+, FAB, NaBr) calcd for C16H16N2O8S2Na 451.0246,
found 451.0244.
P r ep a r a tion of Mich a el Ad d u ct 10c. The procedure for
preparing 10b was followed substituting pentanal (0.21 g, 2.4
mmol) for butanal. Further reaction and workup as before gave
a mixture of 7c, 1, and 10c. Here the crude product ratios were
quite variable from run to run. In some cases â,γ-unsaturated
R-nitrosulfone 7c was the major product but in other cases
the crude product consisted of more Michael adduct than 7c.
Purification (procedure B) of crude product rich in 10c followed
by preparative TLC afforded 94 mg of a partially purified
sample of 10c (least mobile fraction; 10% isolated yield, 80%
pure contaminated predominantly by 1) consisting of three
diastereomers i, ii, and iii in a 67:23:10 ratio, respectively:
IR (film) 1565 (NO2), 1341, 1154 (SO2) cm -1; 1H NMR δ 7.5-
8.1 (m, 5H), 6.67 (d, 1H of i, J ) 5.6 Hz), 6.19 (d, 2H of ii, J )
Obtained as an oil (55 mg, 6% yield) from a more mobile
chromatography fraction was a compound which appears to
be Michael adduct 13 (predominantly 3 of the 4 possible
diastereomers: i, ii, and iii in a 2:1:1 ratio): 1H NMR (500
MHz)18 δ 7.53-7.96 (m, 5H); 6.30 (dd, J ) 14.8, 8.4 Hz), 6.05-
6.15 (m), 6.03 (d, J ) 9.5 Hz), 5.98 (d, J ) 9.6 Hz), 5.8-5.9
(17) This matter is under investigation. The fate of the 3-carbon
side-chain is not known when 1 is regenerated. However, it is known
that repetitive chromatography does not increase the amount of 1 (i.e.,
â,γ-unsaturated R-nitrosulfone 7a is not reverting to 1 on silica gel).
(18) We thank Dr. Hu Liu (University of Pennsylvania) for obtaining
the spectra.

Tandem Nitroaldol-Dehydration Reactions
J . Org. Chem., Vol. 65, No. 23, 2000 7729
6.2 Hz), 6.14 (d, 2H of iii, J ) 1.9 Hz), 6.07 (d, 1H of i, J ) 1.9
Hz), 3.9-4.0 (m, 1H), 2.0-2.5 (m, 2H), 1.2-1.55 (m, 4H), 0.8-
1.0 (m, 3H); HRMS (M + Na+, FAB, NaBr) calcd for
m/z 260 (m + 1 for 9a ) was observed which decreased on aging
of the sample compared to an ion m/z 242 (m + 1 for 7a ).
Rever sion of Nitr oa ld ol 9a to 1. A solution of crude
nitroaldol (155 mg; 9a , 7a , and 1 57:32:10, respectively) in CH2-
Cl2 was rapidly extracted with 5% aqueous NaOH. Acidifica-
tion (con HCl to pH 1-3) of the aqueous layer and extraction
with CH2Cl2 afforded, after workup, a mixture (125 mg; 1 and
7a , 59:41) free of nitoaldol 9a and enriched in phenylsulfo-
nylnitromethane. The original CH2Cl2 layer was washed with
10% aqueous HCl and water and was dried. Concentration
afforded 23 mg of alkene contaminated with several unidenti-
fied products, in part those derived from simple aldol conden-
sation of propanal.
Rea ction of 1 a n d P r op a n a l. Obser va tion of â-Am in e
11. The first procedure employed for propanal was repeated
except the products were examined immediately after removal
of CH2Cl2, prior to sitting and without warming. Crude
products consisted of 11 (25%), 7a (70%), and Michael adduct
10a (5%) as well as small amounts of propanal self-condensa-
tion products and acetic acid. Acetic acid was removed by
entrainment with CCl4 (three 10-mL portions, sequentially
evaporated in vacuo at 20 °C). Two diastereomers i and ii of
11 (65:35 ratio, respectively) were apparent by 1H NMR: δ
6.69 (d, 1H of ii, J ) 10.4 Hz), 6.56 (d, 1H of i, J ) 10.5 Hz),
4.1-4.25 (m, 1H of ii), 3.97 (app dt, 1H of i, J ) 3.8, 10.4 Hz),
3.2-3.4 (broad s, 2H of i,ii), 2.1-2.5 (m, 2H of i,ii), 1.20 (d,
6H of i,ii, J ) 6.5 Hz), 0.9-1.05 (m, 3H of i,ii). Other
overlapping bands and bands attributable solely to 7a , 10a ,
and propanal self-condensation were also apparent.
St oich iom et r y of LDA R ea ct ion w it h P h en ylsu lfon -
yln itr om eth a n e (1). Two 3.0-mL aliquots of LDA solution
(approximately 0.8 M) were prepared as described under
“Tandem nitroaldol/dehydration reaction of 1 and propanal”
and were kept cold (dry ice). Triphenylmethane (2 mg) was
added to each, and an intense red color rapidly developed. The
first aliquot was titrated with a solution of benzoic acid (0.305
g) in THF (2 mL) to disappearance of the red color. The
remaining portion of solution containing benzoic acid was
concentrated and the unused amount of benzoic acid was
weighed and subtracted from the total amount. In this way,
it was determined that 0.269 g (2.20 mmol) of benzoic acid
had been consumed and that the titrated solution was 0.73 M
in LDA. The second aliquot was titrated with a solution of 1
(0.503 g) in THF (2 mL) to disappearance of red color (light
yellow end point). The unused portion of solution containing
1 was concentrated and the amount of the recovered 1 was
subtracted from the total to determine the amount con-
sumed: 0.190 g (0.95 mmol). A duplicate run gave similar
results.
C
19H22N2O8S2Na 493.0715, found 493.0705.
Three attempts to further purify 10c by additional prepara-
tive TLC led to less pure samples in each case. The 1 present
could be removed but an increased amount of unidentified
materials was obtained.
Ta n d em Nit r oa ld ol/Deh yd r a t ion R ea ct ion of 1 a n d
3-P h en ylp r op a n a l. The procedure employed for propanal was
repeated using 3-phenylpropanal (0.32 g, 2.4 mmol) in place
of propanal. Purification (procedure B) as before gave â,γ-
unsaturated R-nitrosulfone 7d (0.33 g, 52% yield) as an oil:
IR (film) 1562 (NO2), 1337, 1156 (SO2) cm-1; 1H NMR δ 7.06-
8.0 (m, 10H), 6.28 (dt, 1H, J ) 15.3, 6.7 Hz), 5.92 (d, 1H, J )
9.6 Hz), 5.68 (ddt, 1H, J ) 15.3, 9.6, 1.5 Hz), 3.4-3.6 (m, 2H);
13C NMR δ 145.1, 137.1, 135.2, 133.8, 130.0, 129.2, 128.6,
128.5, 126.7, 115.9, 103.0, 38.8; HRMS (M + Na+, FAB, NaBr)
calcd for C16H15NO4SNa 340.0619, found 340.0610.
Preparative TLC (least mobile fraction) afforded 0.10 g (10%
yield) of a purified sample of 10d consisting of three diaster-
eomers i, ii, and iii in a 65:25:10 ratio, respectively: IR (film)
1
1559 (NO2), 1341, 1154 (SO2) cm -1; H NMR δ 7.55-8.0 (m,
5H), 7.1-7.4 (m, 5H), 6.67 (d, 1H of i, J ) 5.7 Hz), 6.21 (d, 2H
of ii, J ) 6.4 Hz), 6.10 (d, 2H of iii, J ) 2.2 Hz), 6.03 (d, 1H of
i, J ) 2.2 Hz), 4.0-4.08 (m, 1H), 2.3-3.0 (m, 4H); HRMS (M
+ Na+, FAB, NaBr) calcd for C23H22N2O8S2Na 541.0712, found
541.0715.
Ta n d em Nit r oa ld ol/Deh yd r a t ion R ea ct ion of 1 a n d
P h en yla ceta ld eh yd e. The procedure employed for propanal
was repeated using phenylacetaldehyde (0.29 g, 2.4 mmol) in
place of propanal. Purification (procedure B) as before gave
â,γ-unsaturated R-nitrosulfone 7e (0.45 g, 75% yield) as an
oil that crystallized from benzene/hexanes (33:67): mp 120.5-
1
121.5 °C; IR (film) 1560, 1340, 1152 cm-1; H NMR δ 7.55-
7.95 (m, 5H), 7.35-7.45 (m, 5H), 6.92 (d, 1H, J ) 15.5 Hz),
6.23 (dd, 1H, J ) 15.5, 9.6 Hz), 6.10 (d, 1H, J ) 9.7 Hz); 13C
NMR δ 142.9, 135.4, 134.0, 133.8, 130.1, 129.9, 129.1, 128.8,
127.3, 112.3, 103.6. Anal. Calcd for C15H13NO4S: C, 59.39; H,
4.32; N, 4.62. Found: C, 59.43; H, 4.32; N, 4.51.
None of the Michael adduct 10e could be detected in the
crude reaction products.
Rea ction of P h en ylsu lfon yln itr om eth a n e w ith â,γ-
Un sa t u r a t ed r-Nit r osu lfon e 7a . A solution containing
phenylsulfonylnitromethane (63 mg, 0.31 mmol), alkene 7a (73
mg, 0.30 mmol), LiOAc‚H2O (150 mg, 1.47 mmol), and glacial
HOAc (0.78 g, 13 mmol) in THF (7 mL) was stirred at rt for
24 h. Volatiles were removed in vacuo, and the residue was
partitioned between water and CH2Cl2. The layers were
separated, and the CH2Cl2 layer was washed with water, dried,
and concentrated at reduced pressure to afford an oil (124 mg,
91% recovery of material). This oil by 1H NMR consisted of
7a , 1, and 10a in a 42:45:13 mole ratio, respectively. Longer
reaction times resulted in an increased percentage of 10a but
a much reduced material balance.
Ta n d em Nitr oa ld ol/Deh yd r a tion Rea ction of 1 a n d
P r op a n a l in th e P r esen ce of Th iop h en ol: Isola tion of
â-Su lfid e 14a . A cold (dry ice) THF solution of dianion 2 was
prepared from butyllithium (7.0 mL of a 2.0 M solution in
cyclohexane, 14 mmol), diisopropylamine (1.67 g, 16.5 mmol),
phenylsulfonylnitromethane (1) (0.50 g, 2.5 mmol), and THF
(15 mL) as described previously. Thiophenol (0.42 g, 3.8 mmol)
was added dropwise over 1 min followed by a solution of
propanal (0.22 g, 3.7 mmol) in THF (15 mL) added dropwise
over 30 min. The resulting solution was stirred for an ad-
ditional 30 min. Glacial acetic acid (20 mL) was added
dropwise, and the reaction solution was allowed to warm to
room temperature. Workup as previously described afforded
the crude product which was kept at room temp for 12-18 h.
Examination of the crude product by 1H NMR indicated
â-sulfide 14a (67:33, diastereomer ratio) and diphenyl disulfide
as the major products present. Diphenyl disulfide was removed
by rapid chromatography on silica gel (CH2Cl2-hexanes, 50:
50 elution) without noticeable change in the diastereomer ratio
for 14a (0.73 g, 83% yield) obtained as an oil. However, the
entire portion of purified oil crystallized to afford the R*,R*
isomer exclusively. The analytical sample of 14a was recrys-
tallized from benzene/hexanes: mp 96-97 °C; IR (KBr) 1551
Rea ction of P h en ylsu lfon yln itr om eth a n e w ith â,γ-
Un sa tu r a ted r-Nitr osu lfon e 7d . The procedure employed
for 7a was repeated using alkene 7d (95 mg, 0.30 mmol)
instead. An oil (138 mg, 87% recovery of material) was
1
obtained. This oil by H NMR consisted of 7d , 1, and 10d in a
34:40:27 mole ratio, respectively.
Rea ction of 1 a n d P r op a n a l. Obser va tion of Nitr oa ld ol
9a . The first procedure employed for propanal was repeated
except more butyllithium (7.0 mmol), diisopropylamine (0.74
g, 7.3 mmol), and propanal (0.42 g, 7.2 mmol) were employed
and the products were examined immediately after removal
of CH2Cl2, prior to sitting and without warming. Two diaster-
1
eomers of nitroaldol 9a (60:40 ratio, i/ii) were apparent by H
NMR: δ 5.56 (d, 1H of ii, J ) 8.6 Hz) overlapping 5.54 (d, 1H
of i, J ) 6.2 Hz), 4.42 (ddd, 1H of i, J ) 8.6, 6.2, 4.0), 4.34 (1H
of ii, app td), 1.5-1.8 (m, 2H), 0.9-1.1 (m, 3H). These bands
decreased with time. Other bands attributable to 7a , 1, 10a ,
and propanal self-condensation were also observed. The IR
showed a broad band at 3100-3600 cm-1 (OH) which gradually
decreased with time. In the mass spectrum (CI, CH4), an ion
1
(NO2), 1338, 1316, 1158 (SO2) cm -1; H NMR δ 7.3-7.9 (m,
10H), 5.50 (d, 1H, J ) 11.2 Hz), 3.60 (app td, 1H, J ) 2.9,
10.9 Hz), 2.25-2.40 (m, 1H), 1.5-1.7 (m, 1H), 1.25 (t, 3H, J )

7730 J . Org. Chem., Vol. 65, No. 23, 2000
Wade et al.
7.2 Hz); 13C NMR δ 135.6, 135.2, 134.3, 129.9, 129.5, 129.4,
129.3, 105.1, 50.4, 22.7, 11.1; HRMS (M + Na+, FAB, NaBr)
calcd for C16H17NO4S2Na: 374.0497, found 374.0501. Anal.
Calcd for C16H17NO4S2: C, 54.68; H, 4.87; N, 3.98. Found: C,
54.76; H, 4.74; N, 3.95.
Independent spectral bands present for the mixture of
diastereomers attributed to the R*,S* isomer of 14a : 1H NMR
δ 5.48 (d, 1H, J ) 5.5 Hz), 3.6-3.7 (m, 1H), 2.1-2.25 (m, 1H),
1.22 (t, 3H J ) 7.2 Hz); 13C NMR δ 135.5, 135.4, 133.8, 129.8,
129.7, 102.5, 49.6, 22.7, 12.0.
(NO2), 1333, 1311, 1153 (SO2) cm -1; H NMR δ 7.5-7.9 (m,
5H), 7.2-7.4 (m, 5H), 5.59 (d, 1H, J ) 10.9 Hz), 3.39 (app td,
1H, J ) 3.2, 10.4 Hz), 3.0-3.15 (m, 1H), 2.75-2.9 (m, 1H),
2.55 (q, J ) 7.4 Hz) overlapping 2.55-2.7 (m)[3H total], 2.0-
2.15 (m, 1H), 1.21 (t, 3H, J ) 7.4 Hz); 13C NMR δ 140.3, 135.6,
134.5, 129.9, 129.5, 128.6, 126.3, 105.6, 44.6, 32.7, 32.1, 26.5,
14.4; HRMS (M + Na+, FAB, NaBr) calcd for C18H21NO4S2Na
402.0810, found 402.0814. Anal. Calcd for C18H21NO4S2: C,
56.97; H, 5.58; N, 3.69. Found: C, 57.37; H, 5.49; N, 3.91.
Independent spectral bands present for the mixture of
diastereomers attributed to the R*,S* isomer of 14c: 1H NMR
δ 5.63 (d [one band coincident with R*,R* isomer], 1H, J ) 6
Hz), 2.3-2.5 (m, 1H), 1.8-2.0 (m, 1H), 1.19 (t, 3H, J ) 7.3
Hz).
1
Ta n d em Nitr oa ld ol/Deh yd r a tion Rea ction of 1 a n d
Bu ta n a l in th e P r esen ce of r-Tolu en eth iol: Isola tion of
â-Su lfid e 14b. The procedure employed for the preparation
of 14a was repeated with R-toluenethiol (0.47 g, 3.8 mmol) in
place of thiophenol and butanal (0.53 g, 7.4 mmol) in place of
propanal. After chromatography, â-sulfide 14b (0.68 g, 72%
yield) was obtained as a noncrystallizable oil consisting of a
65:35 mixture of R*,R* and R*,S* diastereomers, respec-
tively: IR (film) 1562 (NO2), 1338, 1153 (SO2) cm -1; 1H NMR
δ 7.5-7.9 (m, 5H), 7.05-7.3 (m, 5H), 5.46 (d, 1H R*,R*, J )
10.7 Hz), 5.24 (d, 1H R*,S*, J ) 5.6 Hz), 3.72 (s, 2H, R*,S*)
3.57 (d, 1H R*,R*, J ) 13.0 Hz), 3.53 (d, 1H R*,R*, J ) 13.0
Hz), 3.31 (ddd, 1H R*,S*, J ) 2.5, 5.6, 10.4 Hz), 3.19 (app td,
1H R*,R*, J ) 2.9, 10.3 Hz), 1.9-2.05 (m, 1H R*,R*), 1.75-
1.9 (m, 1H R*,S*), 1.3-1.6 (m, 2H), 1.0-1.3 (m, 1H), 0.74 (t,
R*,S*, J ) 7.3 Hz) overlapping 0.70 (t, R*,R*, J ) 7.4 Hz) [3H
total]; 13C NMR δ 137.0, 136.7, 136.0, 135.5, 135.2, 134.6,
129.9, 129.5, 129.4, 129.3, 129.2, 129.1, 128.9, 128.6, 127.6,
127.5, 105.7, 103.9, 43.6, 43.5, 37.1, 36.7, 33.0, 32.1, 20.0, 18.9,
Chromatography also afforded the â,γ-unsaturated R-nitro-
sulfone 7d (0.14 g, 18% yield) as a less mobile fraction.
Ta n d em Nitr oa ld ol/Deh yd r a tion Rea ction of 1 a n d
P h en yla ceta ld eh yd e in th e P r esen ce of Th iop h en ol:
Isola tion of â-Su lfid e 14d . The procedure employed for the
preparation of 14a was repeated with phenylacetaldehyde
(0.44 g, 3.7 mmol) in place of propanal. Examination of the
crude product by 1H NMR indicated â-sulfide 14d (57:43,
diastereomer ratio) and â,γ-unsaturated R-nitrosulfone 7e as
the major products present. Thin-layer chromatography af-
forded 7e (0.14 g, 19% yield) as the less mobile fraction and
crystalline 14d (0.68 g, 61% yield, 95:5 R*,R*/ R*,S* ratio) as
the more mobile fraction. The analytical sample of 14d was
recrystallized from benzene-hexanes: mp 112-113 °C; IR
(KBr) 1551 (NO2), 1333, 1311, 1153 (SO2) cm -1; H NMR δ
1
13.4, 13.3; HRMS (M + Na+, FAB, NaBr) calcd for C18H21
NO4S2Na 402.0809, found 402.0809.
-
7.1-8.0 (m, 10H), 5.67 (d, 1H, J ) 9.9 Hz), 4.00 (app td, 1H,
J ) 3.6, 10.4l), 3.72 (dd, 1H, J ) 14.5, 3.6 Hz), 2.83 (dd, 1H,
J ) 14.5, 10.7 Hz); 13C NMR δ 135.7, 134.8, 134.5, 131.2, 130.0,
129.6, 129.5, 129.1, 129.0, 128.6, 127.2, 104.8, 50.5, 36.6;
HRMS (M + Na+, FAB, NaBr) calcd for C21H19NO4S2Na
436.0653, found 436.0645. Anal. Calcd for C21H19NO4S2: C,
60.99; H, 4.63; N, 3.38. Found: C, 60.90; H, 4.55; N, 3.15.
Independent spectral bands present for the mixture of
diastereomers attributed to the R*,S* isomer of 14d : 1H NMR
Ta n d em Nitr oa ld ol/Deh yd r a tion Rea ction of 1 a n d
3-P h en ylp r op a n a l in th e P r esen ce of Eth a n eth iol: Iso-
la tion of â-Su lfid e 14c. The procedure employed for the
preparation of 14a was repeated with ethanethiol (0.23 g, 3.8
mmol) in place of thiophenol and 3-phenylpropanal (0.51 g,
3.8 mmol) in place of propanal. After addition of the aldehyde,
more of the volatile ethanethiol (0.23 g, 3.8 mmol) and again
after addition of acetic acid still more ethanethiol (0.92 g, 14.9
mmol) was added. Volatiles were not stripped until after 12
h. Chromatography of the crude products afforded 14c (g 75:
25 R*,R*/R*,S* ratio, 0.60 g, 63% yield) as the more mobile
fraction. This purified material crystallized affording predomi-
nantly the R*,R* isomer (95:5 R*,R*/R*,S* ratio) of 14c as a
solid. The analytical sample of pure (R*,R*)-14c was recrystal-
lized from benzene/hexanes: mp 105-106.5 °C; IR (KBr) 1551
1
δ H NMR δ 5.55 (d, 1H, J ) 3.9 Hz), 4.0-4.1 (m, 1H), 3.87
(dd, 1H, J ) 14.8, 2.3 Hz), 2.89 (dd, 1H, J ) 11.1, 14.8 Hz).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
7a -d , 10a -d ,f, 11, 13, and 14a -c. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0000170