Formaldehyde dialkylhydrazones as neutral formyl anion and cyanide equivalents: Nucleophilic addition to conjugated enones

Article abstract of DOI:10.1021/jo970481d

A versatile methodology for the nucleophihc formylation and cyanation of conjugated enones is reported. The procedure is based on the use of formaldehyde dimethylhydrazone, which, acting as a neutral formyl anion equivalent, adds to preformed trialkylsilyl-enone complexes. Both 4-(silyl- oxy)-3-enal hydrazones 3 or deprotected 4-oxo aldehyde monohydrazones 4 can be obtained at products depending on quenching conditions. In full analogy, an asymmetric version of the reaction using chiral formaldehyde SAMP- hydrazone as a neutral synthon of the chiral formyl anion has been developed, giving rise to the corresponding adducts 5 and 6 in good yields and with excellent diastereoselectivities (de 85-≤98%). Ozonolysis or HCl-mediated hydrolysis of adducts 4 and 6 readily affords racemic and optically enriched 4-oxo aldehydes 7, respectively. Additionally, high-yielding MMPP-oxidative cleavage of 4-oxo hydrazones 4 and 6 has been performed to obtain 4-oxo nitriles 8 in racemic and optically enriched forms, respectively. In this way, interesting chiral bifunctional building blocks, some of them bearing newly created stereogenic quaternary centers, have been efficiently synthesized.

Full text of DOI:10.1021/jo970481d

5144
J . Org. Chem. 1997, 62, 5144-5155
F or m a ld eh yd e Dia lk ylh yd r a zon es a s Neu tr a l F or m yl An ion a n d
Cya n id e Equ iva len ts: Nu cleop h ilic Ad d ition to Con ju ga ted
En on es
Elena D´ıez,† Rosario Ferna´ndez,† Consolacio´n Gasch,† J ose´ M. Lassaletta,*,‡ J ose´ M. Llera,§
Elo´ısa Mart´ın-Zamora,† and J uan Va´zquez†
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de Sevilla,
Apartado de Correos No. 553, E-41071 Seville, Spain, Instituto de Investigaciones Qu´ımicas,
CSIC-USe, c/ Americo Vespuccio s/ n, Isla de la Cartuja, E-41092 Seville, Spain, and
Departamento de Quı´mica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad de Sevilla,
Apartado de Correos No. 874, E-41080, Seville, Spain
Received March 17, 1997X
A versatile methodology for the nucleophilic formylation and cyanation of conjugated enones is
reported. The procedure is based on the use of formaldehyde dimethylhydrazone, which, acting as
a neutral formyl anion equivalent, adds to preformed trialkylsilyl-enone complexes. Both 4-(silyl-
oxy)-3-enal hydrazones 3 or deprotected 4-oxo aldehyde monohydrazones 4 can be obtained as
products depending on quenching conditions. In full analogy, an asymmetric version of the reaction
using chiral formaldehyde SAMP-hydrazone as a neutral synthon of the chiral formyl anion has
been developed, giving rise to the corresponding adducts 5 and 6 in good yields and with excellent
diastereoselectivities (de 85-g98%). Ozonolysis or HCl-mediated hydrolysis of adducts 4 and 6
readily affords racemic and optically enriched 4-oxo aldehydes 7, respectively. Additionally, high-
yielding MMPP-oxidative cleavage of 4-oxo hydrazones 4 and 6 has been performed to obtain 4-oxo
nitriles 8 in racemic and optically enriched forms, respectively. In this way, interesting chiral
bifunctional building blocks, some of them bearing newly created stereogenic quaternary centers,
have been efficiently synthesized.
In tr od u ction
eton (f higher ketones) has been satisfactorily accom-
plished by addition of several kinds of organometallics,5
using both chiral ligands or catalysts as the source of
chirality. Likewise, many optically enriched 1,5-bifunc-
tionalized compounds have been synthesized from enones
by asymmetric addition of silyl enol ethers,6 enamines,7
imines,8 malonates,9 aminocarbene complex anions,10 and
other enolate and aza enolate equivalents. For the
asymmetric Michael addition of acyl anion equivalents
to prochiral enones (f 1,4 dicarbonyl compounds), the
number of possibilities available is rather limited.11
As a particular case, the conjugate nucleophilic formy-
lation (f 4-oxo aldehydes) is of special significance due
to the synthetic versatility of the formyl group. There-
The Michael addition of carbon nucleophiles to conju-
gated enones is one of the most powerful methods for
carbon-carbon bond formation.1 Depending on the
functionality present on the nucleophile, many different
families of compounds have been synthesized using this
tool. Thus, the introduction of nonfunctionalized frag-
ments yielding higher ketones involves the addition of
organometallics (most usually cuprates) and has been
optimized in order to minimize competing side reactions,
such as 1,2-addition to the carbonyl group. Likewise,
efficient methodologies for the introduction of enolates
and aza enolates have been reported for the synthesis of
several kinds of 5-oxo carbonyl compounds. There is also
literature on the conjugate addition of acyl anion equiva-
lents as nucleophiles,2,3 leading, after release of the
masked carbonyl group, to 1,4-diketones. During the last
few years, the need for optically pure compounds has
invoked considerable activity directed toward the devel-
opment of methodologies for carrying out all these
reactions in an enantioselective way.4 Thus, the asym-
metric introduction of alkyl chains into the enone skel-
(3) Particularly related to this work is the ene-type thermal addition
of certain aldehyde monoalkylhydrazones with unhindered acceptors
such as methyl acrylate and acrylonitrile: (a) Baldwin, J . E.; Adlington,
R. M.; Bottaro, J . C.; J ain, A. U.; Kolhe, J . N.; Perry, M. W. D.;
Newington, I. M. J . Chem. Soc., Chem. Commun. 1984, 1095. (b)
Baldwin, J . E.; Adlington, R. M.; J ain, A. U.; Kolhe, J . N.; Perry, M.
W.D. Tetrahedron 1986, 42, 4247. The reaction with more-substituted
substrates and with conjugated enones, however, has not been
reported.
(4) Recent reviews: (a) Oare, D. A.; Heathcock, C. H. Top. Stereo-
chemi. 1989, 20, 87. (b) Oare, D. A.; Heathcock, C. H. Top. Stereochem.
1989, 20, 227.
* To whom correspondence should be addressed. Phone: +34-5-
4489560. Fax: +34-5-4460565. E-mail: jmlassa@cica.es.
† Facultad de Qu´ımica.
(5) Review: Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92,
771. Recent examples: Wang, Y.; Gladysz, J . A. J . Org. Chem. 1995,
60, 903 and references cited therein.
‡ Instituto de Investigaciones Qu´ımicas.
(6) Lohray, B. B.; Zimbiniski, R. Tetrahedron Lett. 1990, 31, 7273.
(7) Hickmott, P. W. In The Chemistry of Enamines; Patai, S.,
Rappoport, Z., Eds.; J ohn Wiley & Sons: New York, 1994; p 727.
(8) (a) Desmae¨le, D.; Pain, G.; d’Angelo, J . Tetrahedron: Asymmetry
1992, 3, 863. (b) For a review, see: d’Angelo, J .; Desmae¨le, D.; Dumas,
F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459.
(9) (a) Sasai, H.; Arai, T.; Shibasaki, M. J . Am. Chem. Soc. 1994,
116, 1571. (b) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1176. (c) Kawara, A.; Taguchi, T. Tetrahedron
Lett. 1994, 35, 8805.
(10) Anderson, B. A.; Wulff, W. D.; Rahm, A. J . Am. Chem. Soc.
1993, 115, 4602.
(11) For a leading reference see: Enders, D.; Kirchhoff, J .; Mannes,
D.; Raabe, G. Synthesis 1995, 659.
§ Facultad de Farmacia.
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, 1992. (b) Lee, V. J . In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 4, Chapters 1.2 and 1.3. (c) Kozlowski, J . A. Ibid. Vol. 4,
Chapter 1.4.
(2) (a) Ager, D. J . In Umpoled Synthons: A Survey of Sources and
Uses in Synthesis; Hase, T. A., Ed.; Wiley: New York, 1987; pp 19-
72. (b) Dondoni, A. Advances in the Use of Synthons in Organic
Chemistry; J AI Press Ltd.: London, 1993; pp 2-28. (c) Katritzky, A.
R.; Yang, Z.; Lam, J . N. J . Org. Chem. 1991, 56, 2143. See also
references cited therein.
S0022-3263(97)00481-7 CCC: $14.00 © 1997 American Chemical Society

Nucleophilic Addition to Conjugated Enones
J . Org. Chem., Vol. 62, No. 15, 1997 5145
fore, much effort has been focused on the development
of appropriate umpoled reagents, which are based almost
exclusively on the anionic12 forms derived from two types
of compounds: (i) those of the general structure XCH2Y,
where X and/or Y are anion-stabilizing functions, and (ii)
those derived from X(Y))CH structures, which require
a subsequent reduction step for the regeneration of the
carbonyl function. These approaches, however, gave
satisfactory solutions only in a limited number of cases
and are in general subject to various limitations. Among
these, the most common are the need for strong bases
for generating the actual anionic formyl equivalent, the
lack of selectivity observed for substrates containing
multiple electrophilic centers, the lack of reactivity
toward â,â-disubstituted substrates, and the difficulties
encountered in many cases regarding the release of X and
Y to regenerate the carbonyl function, in particular the
need to use environmentally undesirable mercury salts
or strongly acidic conditions. A survey of the literature
reveals that no efficient enantioselective formylating
protocols have been described up to now.13 This surpris-
ing finding reflects in most cases the unavailability of
chiral forms of the formylating reagents referred to above
and sometimes the inefficiency and/or lack of selectivity
of the process. Thus, an efficient general method for the
nucleophilic formylation of enones is still a challenge,
particularly if an enantioselective version (a practically
unprecedented reaction) is to be developed.
F igu r e 1.
fully gave rise, after release of the masked carbonyl
function, to the corresponding formylated products. We
now wish to report in full the trialkylsilyl triflate-
promoted conjugate addition of formaldehyde dimethyl-
hydrazone (1a , Figure 1) to R,â-unsaturated ketones, the
asymmetric version of this reaction using the SAMP-
derived hydrazone (1b) as an efficient chiral, neutral
formyl anion equivalent,21 and the synthesis of racemic
and optically enriched 4-oxo aldehydes and 4-oxo nitriles
from the obtained adducts.
In this context, we have explored the synthetic pos-
sibilities of dialkylhydrazones, whose aza enamine char-
acter should theoretically make them behave as nucleo-
philic acylating reagents in the same way as enamines
do.7 Such reactivity has been exhibited in the reactions
of aldehyde dialkylhydrazones with strong electrophiles
such as the Vilsmeier reagent,14 sulfonyl isocyanates,15
highly reactive Mannich bases,16 and trifluoroacetic
anhydride,17 but it is in fact too low for the reaction with
weaker electrophiles such as carbonyl compounds18 or
Michael-type acceptors. On the other hand, we have
recently reported some results on the use of formaldehyde
dialkylhydrazones (FDAH’s) as neutral formyl anion
equivalents, which have proved to be a good alternative
to the existing methodologies. Thus, their addition
reaction to compounds containing reactive double bonds
such as conjugated nitroalkenes19 and to activated car-
bonyl compounds such as R-alkoxy aldehydes20 success-
Resu lts a n d Discu ssion
Ad d ition of F or m a ld eh yd e Dim eth ylh yd r a zon e to
Con ju ga ted En on es. The preliminary experiments
carried out using readily available17a formaldehyde di-
methylhydrazone (FDMH, 1a ) indicated that, in contrast
to the related addition to the more electrophilic nitroal-
kenes19 or activated aldehydes,20 the reactivity of hydra-
zone 1a was not high enough to generate spontaneous
addition to a variety of conjugated enones (2a -i, Chart
1). Therefore, the presence of a catalyst or promoter was
suggested, and several Lewis acids of different strengths
(TiCl4, BF3‚Et2O, ZnCl2, etc.), in both catalytic and
stoichiometric amounts, were unsuccessfully tested for
the activation of the conjugate acceptor. As could be
anticipated, the competing irreversible formation of hy-
drazone-Lewis acid complexes, which readily decom-
posed as demonstrated in blank experiments, was ob-
served even at low temperatures and constituted a major
point of difficulty. Fortunately, this problem could be
finally solved by using bulky trialkylsilyl [TBDMS or
dimethyl(1,1,2-trimethylpropyl)silyl (TDS)] triflates as
promoters,22 giving rise to the formation of the desired
adducts trapped as their corresponding silyl enol ethers
3 (Scheme 1). This strategy even allowed the direct
addition of the promoter to the mixture of reactants
(method B for the synthesis of compounds 3, see Experi-
mental Section), since the decomposition of the hydrazone
1a in the presence of the promoter seems to take place
(12) (Trimethylsilyl)thiazole, a formyl anion equivalent belonging
to a different class of formyl anion equivalents due to its neutral
character, has never been reported to behave as such an equivalent in
Michael-type reactions.
(13) Some chiral formyl anion equivalents have been tested in their
reactions with aldehydes: Colombo, L.;. Di Giacomo, M.; Brusotti, G.;
Delugu, G. Tetrahedron Lett. 1994, 35, 2063 and references cited
therein. See also ref 2. However, the only attempt described for the
addition to enones was using a mono-S-oxidized dithioacetal derived
reagent and resulted, after
a complicated two-step deprotection
sequence, in poor yields and low ee values of the corresponding adducts.
(a) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico, C. Synthesis 1981,
74. (b) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico, C. J . Chem.
Soc., Perkin Trans. 1 1981, 1284.
(14) Brehme, R. Chem. Ber. 1990, 123, 2039.
(15) Brehme, R.; Nikolajewski, H. E. Tetrahedron Lett. 1982, 23,
1131.
(16) Brehme, R.; Nikolajewski, H. E. Tetrahedron 1976, 32, 731.
(17) (a) Kamitori,Y.; Hojo, M.; Masuda, R.; Fujitani, T.; Ohara, S.;
Yokohama, T. J . Org. Chem. 1988, 53, 129. (b) Kamitori, Y.; Hojo, M.;
Masuda, R.; Yoshida, T.; Ohara, S.; Yamada, K.; Yoshikawa, N. J . Org.
Chem. 1988, 53, 519.
(19) (a) Lassaletta, J . M.; Ferna´ndez, R. Tetrahedron Lett. 1992, 33,
3691. (b) Lassaletta, J . M.; Ferna´ndez, R.; Gasch, C.; Va´zquez, J .
Tetrahedron 1996, 52, 9143. (c) Ferna´ndez, R.; Gasch, C.; Lassaletta,
J . M.; Llera, J . M. Tetrahedron Lett. 1994, 35, 471. (d) Enders, D.;
Syrig, R.; Raabe, G.; Ferna´ndez, R.; Gasch, C.; Lassaletta, J . M.; Llera,
J . M. Synthesis 1996, 48. (e) Ferna´ndez, R.; Gasch, C.; Lassaletta, J .
M.; Llera, J . M. Synthesis 1996, 627.
(18) The intramolecular addition of the azomethine carbon of
aromatic hydrazones to a neighbor carbonyl group has been reported:
Shen, J .-K.; Katayama, H.; Takatsu, N.; Shiro, I. J . Chem. Soc., Perkin
Trans. 1 1993, 2087. The authors also reported failed attempts to
perform the same reaction intermolecularly.
(20) Lassaletta, J . M.; Ferna´ndez, R.; Mart´ın-Zamora, E.; Pareja,
C. Tetrahedron Lett. 1996, 37, 5787.
(21) A preliminary account of this work has recently appeared:
Lassaletta, J . M.; Ferna´ndez, R.; Mart´ın-Zamora, E.; D´ıez, E. J . Am.
Chem. Soc. 1996, 118, 7002.

5146 J . Org. Chem., Vol. 62, No. 15, 1997
D´ıez et al.
Ch a r t 1
Sch em e 2
indicated total consumption of the starting enone in most
cases, but relatively high amounts of unreacted material
were recovered when sterically hindered substrates, such
as 4-tert-butylcyclohexenone (2g) (33% unreacted) and
4,4-dimethyl-3-cyclohexenone (2f) (4% unreacted), were
used as substrates. As the quantitative formation of the
enone-promoter complexes is assumed under conditions
A, its recovery may well be attributed to a partial
irreversible transfer of the trialkylsilyl group from the
complex to the amino nitrogen atom in the hydrazone
(Scheme 2). The reaction proceeded cleanly in all cases,
and the 1H NMR analysis of the crude indicated the
absence of 1,2 adducts, as was expected taking into
account the neutral and extremely soft character of the
nucleophile, on one hand, and the great steric hindrance
around the carbonyl group due to chelation with bulky
trialkylsilyl groups, on the other. In addition to the
already mentioned survival of the hydrazone, the antici-
pated regioselectivity constitutes a second reason for the
choice of such sterically demanding reagents. The rich
chemistry of silyl enol ethers makes the primary adducts
3 appear to be promising synthetic intermediates that
can be used not only as protected forms of the corre-
sponding ketones but also for further transformations as
the regioselective introduction of diverse functionalities
at C-2.23 Although the low boiling points of compounds
3 made their isolation in good yields from small-scale
reactions difficult in some cases, they were mostly stable
compounds and could be purified by column chromatog-
raphy and used for further reactions. Moreover, the
corresponding deprotected adducts 4 could also be alter-
natively obtained in a “one pot” operation by simply
quenching the reaction mixtures with tetrabutylammo-
nium fluoride (TBAF), which, in order to avoid an excess
of triflic acid, must equal the initial amount of promoter
added to the reaction mixture. Verifying the generality
of the addition reaction, many different kinds of enone
were successfully examined as substrates. Thus, five-
(entries a and b) and six-membered (entries d , f, and g)
cyclic enones, as well as acyclic ones (entries h and i),
afforded the corresponding adducts 3 and 4 in moderate-
to-good yields. The results for the synthesis of com-
pounds 3 and 4 are collected in Table 1.
Sch em e 1
at a slower rate than the fast addition reaction. Presum-
ably, the great steric hindrance around the chosen
promoter makes the complexation of the small carbonylic
oxygen on ketone 2 much easier than that of the dialkyl-
substituted nitrogen on the hydrazone moiety. Condi-
tions B were used in some cases to avoid the competing
spontaneous silylation of the enolic forms of some of the
starting enones. Nevertheless, consumption of the start-
ing enone 2 because of this side reaction was insignificant
in most cases, and better results were generally observed
when the hydrazone 1a was added slowly to a solution
of preformed trialkylsilyl enone complexes (method A for
the synthesis of compounds 3, see Experimental Section).
A screening of reaction conditions revealed little influence
of the solvent, while optimal yields were observed for
reactions carried out at temperatures around 0 °C using
a 1:1.1:1.5 enone:promoter:hydrazone ratio. TLC control
Ad d ition of SAMP -Der ived F or m a ld eh yd e Hy-
d r a zon e 1b to P r och ir a l Con ju ga ted En on es. Hav-
ing the optimal conditions for the addition reaction in
the racemic series established, studies were directed
toward an asymmetric version of the reaction based on
the use of a chiral formaldehyde hydrazone. To this end,
(23) Following well-established procedures, this position could be
alkylated, used as nucleophile in the Mukaiyama aldol reaction, or
hydroxylated (the Rubottom reaction). Additionally, a recently reported
reaction describes the introduction of a nitrogenated function in this
position: Du Bois, J .; Hong, J .; Carreira, E. M.; Day, M. W. J . Am.
Chem. Soc. 1996, 118, 915.
(22) For other trialkylsilyl-promoted conjugated additions of soft
carbon nucleophiles to enones see: (a) Kim, S.; Park, J . H. Synlett 1995,
163. (b) Eriksson, M.; Iliefski, T.; Nilsson, M.; Olsson, T. J . Org. Chem.
1997, 62, 182. (c) Katritzky, A. R.; Soloducho, J .; Musgrave, R. P.;
Breytenbach, J . C. Tetrahedron Lett. 1995, 31, 5491.

Nucleophilic Addition to Conjugated Enones
J . Org. Chem., Vol. 62, No. 15, 1997 5147
Ta ble 1. Syn th esis of 4-(Silyloxy) 3-En a l
Dim eth ylh yd r a zon es 3 a n d 4-Oxo Dim eth ylh yd r a zon es 4
Ta ble 2. Syn th esis of 4-(Silyloxy) 3-En a l SAMP
Hyd r a zon es 5 a n d 4-Oxo Dim eth ylh yd r a zon es 6
enone 2
promoter
method workup product yield (%)
enone
2
product product dea
R1
R3
R2 R4
5 (%)
6 (%) (%) confgn
2a
2a
2a
2b
2d
2d
2d
2f
TDSOTf
TDSOTf
TBDMSOTf
TDSOTf
TDSOTf
TBDMSOTf
TDSOTf
TDSOTf
TDSOTf
TDSOTf
A
A
A
A
A
A
A
A
A
B
B
B
B
B
A
TBAF
4a
3a
3a ′
4b
3d
3d ′
4d
3f
72
a
a
91
a
a
75
60
65b
52c
55d
50
58
68
55
NaHCO3
NaHCO3
TBAF
NaHCO3
NaHCO3
TBAF
NaHCO3
TBAF
NaHCO3
TBAF
2a
2b
2c
2e
2f
2h
2i
-(CH2)2-
-(CH2)2-
H
H
64
76
77
82
74
75
c
69
80
83b
86
79
76
60
95 R,S
g98 R,S
97 R,R,S
85 R,S
94 S,S
g98 R,S
95 R,S
H
Me
H
Me
H
Me
H
-(CH2)2-
-(CH2)3-
-(CH2)2CMe2-
H
Ph
H
H
H
H
Ph
Ph
Me
2f
4f
a
b
See ref 25. 95:5 mixture of cis and trans isomers. c Unstable
2g
2g
2h
2h
2h
2i
cis-3g
cis-4g
3h
3h ′
4h
compound.
TBDMSOTf
TDSOTf
TBDMSOTf
TDSOTf
NaHCO3
NaHCO3
TBAF
reactions were observed even at temperatures as low as
-78 °C, provided that the choice of THF as solvent avoids
the solubility problems observed when ether or dichlo-
romethane was used instead. As a consequence, the
diastereoselectivity of the reaction, which during pre-
liminary experiments proved to be strongly dependent
on the temperature, could be improved to excellent levels.
As an illustrative example, the diastereoselectivity ob-
served for the synthesis of compound 6b rose from de 50%
when the reaction was carried out at 0 °C to de 73% at
-20 °C and finally to de >98% at -78 °C. As the
observed diastereoselectivities were not greatly affected
by the temperature of quenching (i.e., identical de values
were measured for a reaction performed and quenched
at -78 °C and for a parallel reaction allowed to warm
before quenching), it may be deduced that the reaction
is essentially irreversible and that kinetically controlled
products are obtained. Interestingly, the reaction also
proceeded with similar results in the presence of equimo-
lecular amounts of triethylamine. Under these condi-
tions, any trace of triflic acid eventually formed in the
reaction mixture would be neutralized, and theoretically
the use of acid-sensitive starting materials should be
allowed.
TDSOTf
TBAF
4i
a
b
Not determined (see text). 4% of 2f recovered. c 30% of 2g
recovered. 33c% of 2g recovered.
d
Sch em e 3
(-)-(S)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)
was chosen as a convenient, inexpensive chiral hydrazine
for the preparation of the reagent. Thus, SAMP-derived
formaldehyde hydrazone 1b19c,d was made to react with
a variety of prochiral enones 2 previously activated by
means of TDSOTf; this procedure gave rise, in full
analogy to the foregoing FDMH reaction, to the corre-
sponding diastereomeric silyl enol ethers 5, which, in
contrast to the FDMH-derived adducts, could be easily
isolated.24 Likewise, the SAMP-derived 4-oxohydrazones
6 were isolated in “one pot” by quenching in the presence
of TBAF (Scheme 3). Thus, both classes of adduct could
be obtained in satisfactory yields and with an excellent
degree of stereoselectivity.25 Representative experiments
for the synthesis of compounds 5 and 6 are collected in
Table 2.
It should be stressed that the reactivity exhibited by
the SAMP-derived formaldehyde hydrazone 1b was
clearly higher than that of the acyclic dimethylhydrazone
1a . This effect can be explained considering the presence
of the pyrrolidine ring in the reagent, which, as occurs
for the related enamines,26 confers higher π-donor capac-
ity to the aminic lone pair and, therefore, higher nucleo-
philicity to the azomethine carbon atom. Hence, very fast
As illustrated in the additions to â,â-disubstituted
enones 2b and 2e, the possibility of synthesizing com-
pounds containing all-carbon, quaternary carbon atoms
(bearing four differently functionalized alkyl chains),
maintaining a high degree of diastereoselectivity, en-
hances the synthetic value of this reaction, since such
centers are commonly encountered in a variety of natural
products, and the range of methodologies for their
generation is one of the most restricted in organic
synthesis.27 It should also be mentioned that the proline-
derived chiral auxiliary used is available in both enan-
tiomeric forms,19e thereby opening access to any desired
configuration.
Clea va ge of th e Hyd r a zon e Moiety. In order to
demonstrate the announced synthetic equivalence of
FDAHs with the formyl anion, the optimization of the
cleavage of the hydrazones to aldehydes was considered
a priority. Again, FDMH-derived adducts 4 were first
used as a useful model for this transformation, and as
expected, they could be easily deprotected by ozonolysis
(method A, see Experimental Section) and/or HCl-medi-
ated hydrolysis in a two-phase system (method B),
affording the 4-oxo aldehydes 7 in excellent yields
(Scheme 4, Table 3). Alternative methods, such as the
copper-assisted hydrolysis28 or other described oxidative
(24) These silyl enol ethers containing the SAMP moiety had much
higher boiling points than the parent FDMH-derived adducts, and their
stability was adequate for chromatographic purification except for the
4-phenylbutenone-derived compound 5i (see Experimental Section).
(25) The diastereomeric ratio was determined by 13C and 1H NMR
spectroscopy. The de values obtained before chromatography were
identical with those for the isolated diastereomeric mixtures.
(26) Ha¨felinger, G.; Mack, H.-G. In The Chemistry of Enamines;
Patai, S., Rappoport, Z., Eds.; J ohn Wiley & Sons: New York, 1994;
pp 1-85.
(27) The asymmetric creation of quaternary carbon centers has
recently been reviewed: Fuji, K. Chem. Rev. 1993, 93, 2037.

5148 J . Org. Chem., Vol. 62, No. 15, 1997
D´ıez et al.
Sch em e 4
equivalence with the cyano group. For this transforma-
tion, our recently reported oxidative cleavage of aldehyde
dimethylhydrazones 4 by means of magnesium mono-
peroxyphthalate hexahydrate (MMPP‚6H2O)32 again
proved to be an efficient method, affording racemic ni-
triles 8 in essentially quantitative yields. Comparable
yields of the optically enriched nitriles 8 were obtained
when the SAMP-derived hydrazones 6 were exposed to
the same treatment. In order to confirm the already re-
ported19d,e absence of racemization during this process,
independent ee measurements were carried out in some
cases. Thus, the optical purity of compounds 8h and 8i
1
was verified by H NMR analysis using Eu(hfc)3 as the
chiral lanthanide shift reagent. To this aim, the corre-
sponding racemic compounds, obtained from dimethyl-
hydrazones 4h and 4i, were used as references. Addi-
tionally, the optical purities of compounds 8a , 8e, and
8f were indirectly established using (2R,3R)-2,3-butane-
diol as a chiral derivatizating reagent. Therefore, the
corresponding diastereomeric ketals 10 were easily pre-
pared under established conditions (Scheme 5), and their
optical purities were determined by 13C NMR. The re-
sults for the synthesis of derivatives 7-9 are summarized
in Table 3.
cleavages of the CdN bond,29 gave no positive results in
our hands. Although ozonolysis of the more complex
SAMP-derived hydrazones is known to be a rather
unpredictable reaction,30 it proved to be suitable also for
compounds 6, and the desired aldehydes were obtained
after the usual workup in good-to-excellent yields. Hy-
drolysis by HCl, however, led to slightly higher yields of
aldehydes 7 from both dimethyl- and SAMP-hydrazones
4 and 6, as illustrated in several examples (Table 3,
entries 9, 10, and 14). Hence, ozonolysis remains as an
appropriate alternative for acid-sensitive or racemizable
substrates. The rather unstable and volatile aldehyde
7a was best oxidized in situ by treatment of the resulting
crude ozonolyzate or hydrolyzate with the J ones reagent
to afford the known carboxylic acid 9a 31 (93% from 4a
via ozonolysis; 84% from 6a via HCl-mediated hydroly-
sis). Compounds 6c, 4d , 6e, 6f, and 6h were treated a
similar way, affording the corresponding carboxylic acids
9c-f, h (Scheme 4, Table 3). Although the absence of
racemization under the conditions used for the ozonolysis
of similar compounds is a well-documented fact, inde-
pendent evidence for it was obtained in some cases.
Thus, the optical purity of compound 7f was determined
by 1H NMR shift experiments using (R)-1-(9-anthryl)-
2,2,2-trifluoroethanol as cosolvent and with the help of
the racemic form obtained from 4f and proved to be
comparable (ee 95%) with that of the parent adduct 6f
(de 94%). Additionally, two samples of compound 7f,
obtained from compound 6f by ozonolysis and HCl-
mediated hydrolysis, respectively, showed matching [R]D
values, suggesting both reactions to be racemization-free
processes. A second piece of evidence was indirectly
deduced from the optical rotation data observed for
derivative 9a (obtained by tandem ozonolysis-oxidation
of adduct 6a ), which indicated a high optical purity by
comparison with literature data.31
Det er m in a t ion of Ab solu t e Con figu r a t ion s a n d
Ster eoch em ica l Asp ects. The assignment of the con-
figuration of the newly created stereogenic centers was
made in several cases. First, the absolute configuration
of the crystalline (R,S)-6h (an open-chain compound) was
unequivocally determined by X-ray structure analysis,33
while that corresponding to 6i was assigned by analogy,
taking into account the close relationship between the
two structures. A chemical correlation allowed the
assignment of the absolute configuration corresponding
to 6a : comparison of the optical rotation of the derived
(+)-(R)-3-oxocyclopentanecarboxylic acid [(R)-9a ] with
literature data31 led to the assigned R,S configuration.
Again, structurally related cyclopentenone-derived ad-
ducts 6b and 6c were deduced to be 3R by analogy. For
the determination of the absolute configuration of the six-
membered adduct 6f, a well-established empirical rule
developed by Lemie`re et al.34 was the method of choice.
Hence, the mixture of (2R,3R)-2,3-butanediol-derived
ketals 10f (Figure 2) showed in its 13C NMR spectrum
two sets of peaks in a 97:3 ratio (selected shifts shown
in Table 4). These two sets of peaks were confirmed as
corresponding to the two diastereoisomers, since they
were also found in a 1:1 ratio when racemic 8f was used
for the synthesis of ketal 10f. According to the rule, the
3S configuration was then assigned to the major isomer
10f.35 For the determination of the absolute configura-
tion of compound 6e, a similar analysis was made for the
corresponding ketal 10e. The conformational requisite
(31) (R)-9a had [R]21D +21.8° (c 1.9, CH3OH). The maximum reported
value for this compound is [R]21 +22.1° (c 1.9, CH3OH): (a) Toki, K.
D
The synthetic versatility of the dialkylhydrazone moi-
ety could be additionally exploited by demonstrating its
Bull. Chem. Soc. J pn. 1958, 31, 333. (b) Sato, Y.; Nishioka, S.;
Yonemitsu, O.; Ban, T. Chem. Pharm. Bull. 1963, 11, 829.
(32) Ferna´ndez, R.; Gasch, C.; Lassaletta, J . M.; Llera, J . M.;
Va´zquez, J . Tetrahedron Lett. 1993, 34, 141.
(28) Corey, E. J .; Knapp, S. Tetrahedron Lett. 1976, 41, 3667.
(29) (a) Corey, E. J .; Enders, D. Tetrahedron Lett. 1976, 3; (b) 1976,
11. (c) Corey, E. J .; Enders, D.; Bock, M. G. Tetrahedron Lett. 1976, 7.
(30) Failure of the ozonolysis of SAMP-derived hydrazones in other
systems has forced the synthesis of the aldehydes via reduction of the
easily available nitriles: (a) Enders, D.; Backhaus, D.; Runsink, J .
Tetrahedron 1996, 52, 1503. (b) Ferna´ndez, R.; Mart´ın-Zamora, E.;
Pareja, C.; Va´zquez, J .; Lassaletta, J . M. Unpublished results. How-
ever, ozonolysis is particularly convenient since the chiral auxiliary
(SAMP) can be recycled: Enders, D.; Eichenauer, H. Chem. Ber. 1979,
112, 2933.
(33) Complete crystallographic details for this compound will be
published separately: Dia´nez, M. J .; Estrada, M. D.; Lo´pez-Castro,
A.; Pe´rez-Garrido, S., Dpto. F´ısica Materia Condensada, Apartado de
Correos 1065, E-41080 Seville, Spain.
(34) Lemie`re, G. L.; Dommisse, R. A.; Lepoivre, F. C.; Alderweireldt,
F. C.; Hiemstra, H.; Wynberg, H.; J ones, J . B.; Toone, E. J . J . Am.
Chem. Soc. 1987, 107, 1363.
(35) The S configuration at the newly created center in this case is
simply the result of a change in CIP priorities; the stereochemistry,
however, is homogeneous with that observed for the rest of the
additions and in accordance with a uniform reaction pathway.

Nucleophilic Addition to Conjugated Enones
J . Org. Chem., Vol. 62, No. 15, 1997 5149
product 9
Ta ble 3. Syn th esis of 4-Oxo Ald eh yd es 7, 4-Oxo Nitr iles 8, a n d 4-Oxo Ca r boxylic Acid s 9
product 7
product 8
starting
compd
entry
% yield
[R]22
ee
% yield
[R]22
ee
% yield
[R]22
ee
confgn
D
D
D
1
2
3
4
5
6
7
8
9
4a
6a
4b
6b
6c
4d
6e
4f
6f
6f
4g
4g
4h
6h
4i
a
a
91
90
86
98
70
91
87
91
83
93
84
+35.3
93b
-21.8c
99d
R
85e
87e
94g
a
-22.0
+82.3
>98f
-54.2
+63.6
>98f
R
R,R
97f
97f
28
92
46
+66.6
-14.0
+18.8
97f
85f
94f
69e
71e
69g
78e
75g
81e
88e
79g
75e
72g
88e
+5.5
85f
95h
-24.3
-11.7
84b
94b
R
S
+34.1
+34.3
64
10
86
11
12
13
14
90
95
91
91
-55.6i
j
j
+15.3
+8.1
>98k
31
-92.9
>98
R
R
6i
6i
-39.7i
-41.6i
96k
Unstable compound. Determined as de of its (2R,3R)-2,3-butanediol derived ketal 10. c See ref 31. Determined by comparison with
a
b
d
the reported data. e Obtained by HCl-mediated hydrolysis. f Given as diasteromeric excess of compounds 6. Obtained by ozonolysis.
Determined by shift experiments using (R)-1-(9-anthryl)-2,2,2-trifluoroethanol as cosolvent. Maximum values measured for freshly
obtained products. Racemization occurs during ee determination with Eu(hfc)3. Determined by shift experiments using Eu(hfc)3 in
CDCl3.
g
h
i
j
k
Sch em e 5
F igu r e 3.
methyl group at C-3 (hence, the assignment of the 3R-
configuration to this compound) was then demonstrated
by means of a NOE difference experiment, which showed
the specific enhancement depicted for isomer C (Figure
3). Additionally, a gated 13C NMR spectrum was re-
F igu r e 2.
Ta ble 4. Selected 13C NMR Ch em ica l Sh ifts Used for th e
Assign m en t of th e Absolu te Con figu r a tion of f- a n d
e-Ser ies Com p ou n d s
3
corded, which showed no estimable anti J C,H coupling
constants for the methyl carbon atom, while the peak
corresponding to the axial CN carbon was clearly broad-
ened because of these couplings. Assuming retention of
configuration at the new chiral center along the route 6
f 10, the S and R configurations can be assigned to any
compound belonging to series f and e, respectively. The
C-2/C-3 relative stereochemistry of c-series compounds
has been assigned to be cis by comparison of the physical
data of both the racemic derived nitrile (()-8c and its
optically enriched form (R)-8c with those previously
reported for the racemic form.36 Finally, it is noteworthy
that the addition of hydrazone 1a to the sterically-
hindered, 4-substituted enone 2g yielded a single product,
whose stereochemistry, as for all g-series compounds, was
assigned cis by comparison of the derived nitrile 8g with
reported data.37
compd
isomer
δC-2
δC-3
δC-5
δC-6
assigned to
10f
10f
10e
10e
major
minor
major
minor
35.2
36.1
45.9
44.8
37.8
37.4
33.5
33.8
35.7
36.2
20.6
20.4
32.5
31.7
35.4
36.1
3Sa
3Ra
B or Cb
A or Db
a
b
See Figure 2. See Figure 3.
for the application of the rule, i.e., a chairlike geometry
of the ring, was first confirmed by means of two “W”
coupling constants [4J H-2eq,H-6eq = 4J H-2eq,H-4eq = 1.9 Hz]
observed in its 1H NMR spectrum. As the axial-
equatorial disposition of the methyl and cyano groups
cannot be assumed considering steric factors as in the
preceding case, two different conformers for each dias-
tereoisomer should be considered (Figure 3, forms A-D).
Consequently, the use of the rule indicated only that the
position of the C-3 quaternary center relative to the
dioxolane moiety was that of forms B or C, according to
the analysis of the selected 13C NMR chemical shifts
shown in Table 4. The equatorial orientation of the
Interestingly, the results outlined above indicate that
the nucleophilic attack always occurs on the same face
(36) Cocker, W.; Grayson, D. H.; Shannon, P. V. R. J . Chem. Soc.,
Perkin Trans. 1 1995, 1153.

5150 J . Org. Chem., Vol. 62, No. 15, 1997
D´ıez et al.
care. FDAHs are actually formyl anion equivalents; no
strong bases are needed.
(ii) The range of electrophilic substrates (nitroalkenes,
carbonyl compounds, conjugated enones) efficiently formy-
lated up to now opens access to a wide variety of
compounds.
(iii) The regeneration of the carbonyl function is an
easy and clean operation. Alternatively, dialkylhydra-
zones can be considered as precursors of nitriles.
(iv) A chiral version of the reaction, which allows access
to both enantiomers of each synthesized compound, has
also been developed.
F igu r e 4.
of the enone, irrespective of its structure and the geom-
etry of the double-bond. As a direct consequence, the
stereochemistry of the obtained products can be predicted
for additions to any enone not having structural features
different from those studied here. As an explanation of
these findings, a cyclic, compact, chairlike geometry for
the approach of the reactants is proposed (Figure 4).
Thus, the steric repulsion between the CH2OMe group
in the pyrrolidine ring and both the highly demanding
TDS+-chelated oxygen atom and the substituent R1
should result in a much higher energy for II than for I,
according to the absolute configuration and the high
induction observed. This compact geometry, stabilized
by secondary orbital interactions, has been proposed for
the closely related reaction of enamines with R,â-
unsaturated systems.38
The extension of this methodology to dialkylhydrazones
different to those derived from formaldehyde (i.e., the
development of a more general nucleophilic acylation
protocol) as well as the reactivity toward other electro-
philic substrates, is currently under study in our labora-
tory.
Exp er im en ta l Section
Gen er a l Exp er im en ta l Da ta . Melting points were de-
termined using a metal block and are uncorrected. Optical
rotations were measured at room temperature. 1H and 13C
NMR spectra were obtained in CDCl3 with either TMS (0.00
1
1
ppm H, 0.00 ppm 13C) or CDCl3 (7.26 ppm H, 77.00 ppm 13C)
as an internal reference. Quantitative 1H NMR measurements
were carried out at 298 K at 500 and 300 MHz in 5-mm NMR
tubes using a 90° pulse angle and a pulse delay of 1.5 s.
Quantitative 13C NMR measurements were carried out at 298
K at 125 and 75 MHz in 5-mm NMR tubes. The spectra were
completely proton decoupled; a 90° pulse angle and a pulse
delay of 2 s were used. The data were processed three times,
and the average value is reported. The sensitivity of the
method was examined by adding increasing amounts of 8i to
a sample solution containing known amounts of 8h . This
assay was able to detect 8i at a concentration equal to 0.5 mol
% of the major component 8h . FT-IR spectra were recorded
for KBr pellets or films. EI-mass spectra were obtained at 70
eV, using an ionizing current of 100 µA, an accelerating voltage
of 4 kV, and a resolution of 1000 or 10 000 (10% valley
definition). The reactions were monitored by TLC. Purifica-
tion of the products was carried out by flash chromatography
(silica gel, 0.063-0.200 nm). The light petroleum ether (PE)
used had boiling range 40-65 °C. Tetrahydrofuran (THF) was
distilled from sodium-benzophenone ketyl immediately prior
to use. Elemental analyses were carried out at the Instituto
Qu´ımico de Sarria´ (Barcelona, Spain) and the Departamento
de Qu´ımica Anal´ıtica, Universidad de Sevilla (Seville, Spain).
Formaldehyde dimethylhydrazone (1a )17a and (-)-(S)-2-(meth-
oxymethyl)-1-(methyleneamino)pyrrolidine (1b)19d were pre-
pared according to the literature. Enones 2, TBDMSOTf, and
TDSOTf were obtained from commercial suppliers.
Con clu sion s
In summary, an efficient protocol for the nucleophilic
formylation of conjugated enones has been developed,
based on the use of bulky trialkylsilyl triflates as promot-
ers. This strategy simultaneously provides the necessary
activation of the conjugated enone and conditions for
trapping the enolates actually generated during the
Michael reaction. In addition, the reaction specifically
gives rise to 1,4-adducts, and the stereoselectivity for the
addition of SAMP-derived formaldehyde hydrazones is
shown to be excellent. The overall formylation and
cyanation protocols take advantage of the efficiency and
mildness of the dialkylhydrazone cleavage reactions to
afford both aldehydes and nitriles.
In terms of the obtained products, the process described
in this paper offers a new route to racemic and optically
enriched 4-oxo aldehydes and 4-oxo nitriles, some of them
bearing new stereogenic quaternary centers. Many other
synthetic possibilities may be envisaged for the interme-
diates 3-6. For instance, the same azomethinic carbon
atom of hydrazones that served as nucleophile may now,
exhibiting its versatility, be used as an electrophile and
suffer addition of organometallic compounds.39
Syn th esis of Silyl En ol Eth er s 3. Meth od A. To a cooled
(0 °C) solution of enone 2 (2 mmol) in dry ether (10 mL) were
added dropwise trialkylsilyl (TBDMS or TDS) triflate (2.5
mmol) followed by a solution of 1a (0.34 mL, 4 mmol) in dry
ether (4 mL) over 10 min under an argon atmosphere. The
mixture was stirred for 15 min, quenched with saturated
NaHCO3 solution, and purified by column chromatography.
Meth od B. To a cooled (0 °C) solution of enone 2 (1 mmol)
in dry ether (5 mL) were added 1a (0.17 mL, 2 mmol) and then
dropwise TDSOTf (0.32 mL, 1.25 mmol) under an argon
atmosphere. The mixture was stirred at 0 °C until TLC
indicated no further change and then quenched with saturated
NaHCO3 and the product purified by column chromatography.
Methods followed for synthesis, chromatography solvents,
yields, and spectral and analytical data for compounds 3 are
as follows:
From a more general point of view, a comparison
between FDAHs as formyl anion equivalents and other
available methodologies should consider many different
aspects. In our opinion, the following points are remark-
able advantages of the FDAH methodology:
(i) The reagents can be easily and economically gener-
ated; they can be stored and handled without particular
(37) Agami, C.; Fadlallah, M.; Levisalles, J . Tetrahedron 1981, 37,
903.
(38) Pfau, M.; Tomas, A.; Lim, S.; Revial, G. J . Org. Chem. 1995,
60, 1143. See also: Cave´, C.; Desmae¨le, D.; d’Angelo, J .; Riche, C.;
Chiaroni, A. J . Org. Chem. 1996, 61, 4361 and references cited therein.
(39) Mart´ın-Zamora, E.; D´ıez, E.; Ferna´ndez, R.; Lassaletta, J . M.
Unpublished results.
3-[(Dim eth ylth exylsilyl)oxy]-2-cyclop en ten e-1-ca r box-
a ld eh yd e Dim eth ylh yd r a zon e (3a ). Following method A
from 2a and TDSOTf, flash chromatography (1:6 Et2O-PE)
gave 3a as an oil: 1H NMR (500 MHz, CDCl3) δ 0.20 (s, 6H),

Nucleophilic Addition to Conjugated Enones
J . Org. Chem., Vol. 62, No. 15, 1997 5151
0.87-0.91 (m, 12H), 1.65 (m, 1H, J ) 6.7 Hz), 1.72 (dddd, 1H,
J ) 13.5, 8.9, 7.3, 5.7 Hz), 2.15 (dtd, 1H, J ) 13.5, 8.1, 6.1
Hz), 2.28-2.32 (m, 2H), 2.72 (s, 6H), 3.42-3.47 (m, 1H), 4.55
(br s, 1H), 6.48 (d, 1H, J ) 7.2 Hz); 13C NMR (75 MHz,
CDCl3): δ -2.9, -2.8, 18.3, 20.0, 24.8, 26.8, 33.2, 33.9, 43.2,
45.4, 103.8, 143.4, 156.6; IR (film, cm-1) 2868, 1642, 1466; mass
spectrum m/ z (rel intensity) 296 M+ (5), 224 (26), 73 (100);
m/ z calcd for C16H32N2OSi 296.2284, found 296.2285.
3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-cyclop en ten e-1-ca r -
boxa ld eh yd e Dim eth ylh yd r a zon e (3a ′). Following method
A from 2a and TBDMSOTf, flash chromatography (1:6 Et2O-
PE) gave 3a ′ as an oil: 1H NMR (500 MHz, CDCl3) δ 0.15 (s,
6H), 0.91 (s, 9H), 1.70 (dddd, 1H, J ) 13.1, 8.9, 7.4, 5.7 Hz),
2.16 (dtd, 1H, J ) 13.1, 8.2, 6.2 Hz), 2.27-2.30 (m, 2H), 2.70
(s, 6H), 3.40-3.45 (m, 1H), 4.55 (m, 1H, J ) 1.9 Hz), 6.46 (d,
1H, J ) 7.2 Hz); 13C NMR (125 MHz, CDCl3) δ -4.9, -4.8,
17.9, 25.5, 26.8, 33.1, 43.1, 45.4, 103.8, 143.1, 156.7; IR (film,
cm-1) 2853, 1643, 1468; mass spectrum m/ z (rel intensity) 268
M+ (10), 223 (61), 196 (54), 73 (100); m/ z calcd for C14H28N2-
OSi 268.1971, found 268.1963.
3-[(Dim eth ylth exylsilyl)oxy]-2-cycloh exen e-1-ca r box-
a ld eh yd e Dim eth ylh yd r a zon e (3d ). Following method A
from 2d and TDSOTf, flash chromatography (1:6 Et2O-PE)
gave 3d as an oil: 1H NMR (500 MHz, CDCl3) δ 0.14 (s, 3H),
0.15 (s, 3H), 0.88 (s, 6H), 0.90 (d, 3H, J ) 7.0 Hz), 0.91 (d, 3H,
J ) 7.0 Hz), 1.37-1.45 (m, 1H), 1.58-1.71 (m, 2H), 1.65 (m,
1H, J ) 7.0 Hz), 1.75-1.82 (m, 1H), 1.97-2.07 (m, 2H), 2.73
(s, 6H), 3.02-3.07 (m, 1H), 4.78-4.80 (m, 1H), 6.47 (d, 1H, J
) 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ -1.5, 18.5, 20.1, 21.2,
24.8, 27.7, 29.7, 34.1, 38.8, 43.3, 105.6, 142.8, 151.8; IR (film,
cm-1) 2866, 1663; mass spectrum m/ z (rel intensity) 310 M+
(13), 265 (34), 238 (52) 73 (100); m/ z calcd for C17H34N2OSi
310.2440, found 310.2444.
3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-cycloh exen e-1-ca r -
boxa ld eh yd e Dim eth ylh yd r a zon e (3d ′). Following method
A from 2d and TBDMSOTf, flash chromatography (1:6 Et2O-
PE) gave 3d ′ as an oil: 1H NMR (500 MHz, CDCl3) δ 0.11 (s,
6H), 0.93 (s, 9H), 1.61-1.66 (m, 1H), 1.76-1.81 (m, 3H), 2.01-
2.18 (m, 2H), 2.72 (s, 6H), 3.03-3.10 (m, 1H), 4.80 (br s, 1H),
6.45 (d, 1H, J ) 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ -3.7,
17.9, 20.3, 25.6, 27.5, 29.2, 38.7, 43.2, 105.5, 142.7, 151.8; IR
(film, cm-1) 2855, 1688; mass spectrum m/ z (rel intensity) 282
M+ (20), 237 (56), 210 (89) 73 (100); m/ z calcd for C15H30N2-
OSi 282.2127, found 282.2133.
6,6-Dim eth yl-3-[(d im eth ylth exylsilyl)oxy]-2-cycloh ex-
en e-1-ca r boxa ld eh yd e Dim eth ylh yd r a zon e (3f). Follow-
ing method A from 2f and TDSOTf, flash chromatography (1:
10 Et2O-PE) gave 405 mg (60%) of 3f as an oil: 1H NMR (500
MHz, CDCl3) δ 0.16 (s, 3H), 0.17 (s, 3H), 0.85 (s, 3H), 0.87 (s,
6H), 0.89 (d, 6H, J ) 6.9 Hz), 0.96 (s, 3H), 1.41 (dt, 1H, J )
13.2, 6.6 Hz), 1.51 (dt, 1H, J ) 13.2, 6.6 Hz), 1.66 (m, 1H, J )
6.9 Hz), 2.00-2.04 (m, 2H), 2.67 (ddt, 1H, J ) 7.9, 3.9, 1.9
Hz), 2.72 (s, 6H), 4.68 (dd, 1H, J ) 3.9, 1.3 Hz), 6.44 (d, 1H, J
) 7.9 Hz); 13C NMR (125 MHz, CDCl3) δ -2.6, -2.5, 18.4, 20.0,
24.4, 24.8, 27.4, 27.6, 31.3, 34.0, 34.9, 43.4, 48.7, 104.9, 141.1,
150.5; IR (film, cm-1) 2888, 1663, 1485; mass spectrum m/ z
(rel intensity) 338 M+ (19), 293 (50), 266 (17); m/ z calcd for
C19H38N2OSi 338.2753, found 338.2753.
flash chromatography [1:100 f 1:50 ethyl acetate-petroleum
ether (EA-PE)] gave 211 mg (50%) of 3h as an oil: 1H NMR
(500 MHz, CDCl3) δ -0.17 (s, 3H), 0.01 (s, 3H), 0.92-0.94 (m,
12H), 1.74 (m, 1H, J ) 6.8 Hz), 2.75 (s, 6H), 4.82 (dd, 1H, J )
9.9, 6.1 Hz), 5.39 (dd, 1H, J ) 9.9, 0.8 Hz), 6.67 (d, 1H, J )
6.1 Hz), 7.16-7.48 (m, 10H); 13C NMR (75 MHz, CDCl3) δ -2.0,
-1.9, 18.5, 18.6, 20.2, 20.3, 25.1, 33.8, 43.2, 44.8, 111.3, 126.0,
126.4, 127.6, 127.7, 127.8, 128.3, 138.8, 139.8, 142.9, 149.9;
IR (film, cm-1) 2868, 1601, 1489; mass spectrum m/ z (rel
intensity) 422 M+ (9), 378 (7) 75 (100); m/ z calcd for C26H38N2-
OSi 422.2753, found 422.2757.
4-[(ter t-Bu tyld im eth ylsilyl)oxy]-2,4-d ip h en yl-3-bu ten -
a l Dim eth ylh yd r a zon e (3h ′). Following method B from 2h ,
flash chromatography (1:100 f 1:50 EA-PE) gave 229 mg
(58%) of 3h ′ as an oil: 1H NMR (300 MHz, CDCl3) δ 0.00 (s,
3H), 0.15 (s, 3H), 1.13 (s, 9H), 2.90 (s, 6H), 4.98 (dd, 1H, J )
9.9, 6.1 Hz), 5.58 (d, 1H, J ) 9.9 Hz), 6.83 (d, 1H, J ) 6.1 Hz),
7.31-7.66 (m, 10H); 13C NMR (75 MHz, CDCl3) δ -4.0, 18.2,
25.8, 43.1, 44.8, 111.0, 126.0, 126.3, 127.6, 127.7, 128.3, 138.8,
139.8, 142.9, 149.9; IR (film, cm-1) 2857, 1652, 1599, 1489;
mass spectrum m/ z (rel intensity) 394 M+ (37), 350 (38), 323
(33) 73 (100); m/ z calcd for C24H34N2OSi 394.2440, found
394.2449.
Syn th esis of 4-Oxo Hyd r a zon es 4. Meth od A. This
method was described above for the synthesis of 3 (method A,
using TDSOTf). After stirring, TBAF (1M in THF, 2.5 mL)
was added and the mixture diluted with Et2
O (20 mL) and
washed with brine. The combined organic layer was concen-
trated, and the residue was purified by column chromatogra-
phy.
Meth od B. This method was described above for the
synthesis of 3 (method B). After stirring, TBAF (1 M in THF,
2.5 mL) was added and the mixture diluted with Et2O (20 mL)
and washed with brine. The combined organic layer was
concentrated, and the residue was purified by column chro-
matography.
The methods followed for synthesis, chromatography sol-
vents, yields, and spectral and analytical data for compounds
4 are as follows.
3-Oxocyclopen ta n e-1-ca r boxa ldeh yde Dim eth ylh yd r a -
zon e (4a ). Following method A from 2a , flash chromatogra-
phy (1:1 f 2:1 Et2O-PE) gave 222 mg (72%) of 4a as an oil:
1H NMR (500 MHz, CDCl3) δ 1.90 (dtd, 1H, J ) 13.6, 8.7, 3.5
Hz), 2.16-2.24 (m, 1H), 2.23- 2.25 (m, 1H), 2.29 (dd, 1H, J )
18.4, 8.2 Hz), 2.35 (td, 1H, J ) 13.9, 8.3 Hz), 2.43 (dd, 1H, J
) 18.4, 7.8 Hz), 2.76 (s, 6H), 3.03-3.11 (m, 1H), 6.58 (d, 1H,
J ) 5.3 Hz); 13C NMR (125 MHz, CDCl3) δ 28.1, 37.7, 39.7,
42.8, 42.9, 137.6, 218.5; IR (film, cm-1) 2863, 1740, 1649; mass
spectrum m/ z (rel intensity) 154 M+ (100), 83 (49); m/ z calcd
for C8H14N2O 154.1106, found 154.1111.
1-Met h yl-3-oxocyclop en t a n e-1-ca r b oxa ld eh yd e
Di-
m eth ylh yd r a zon e (4b). Following method A from 2b, flash
chromatography (1:1 Et2O-PE) gave 306 mg (91%) of 4b as
an oil: 1H NMR (500 MHz, CDCl3) δ 1.24 (s, 3H), 1.78 (dt,
1H, J ) 12.4, 8.5 Hz), 2.00 (d, 1H, J ) 1.78 Hz), 2.12 (dddd,
1H, J ) 12.7, 8.7, 5.2, 1.5 Hz), 2.22 (dddd, 1H, J ) 18.7, 8.4,
5.2, 1.1 Hz), 2.29 (dtd, 1H, J ) 18.7, 8.6, 1.0 Hz), 2.61 (d, 1H,
J ) 17.8 Hz), 2.69 (s, 6H), 6.50 (s, 1H);
13C NMR (125 MHz,
CDCl3) δ 25.5, 29.7, 34.6, 36.9, 43.8, 49.9, 141.3, 210.4; mass
spectrum m/ z (rel intensity) 168 M+ (28), 57 (100); m/ z calcd
for C9H16N2O 168.1263, found 168.1254.
cis-6-ter t-Bu t yl-3-[(d im et h ylt h exylsilyl)oxy]-2-cyclo-
h exen e-1-ca r boxa ld eh yd e Dim eth ylh yd r a zon e (3g). Fol-
lowing method B from 2g, flash chromatography (1:8 Et2O-
PE) afforded unreacted 2g (33%) and 190 mg (52%) of 3g as
3-Oxocycloh exa n e-1-ca r boxa ld eh yd e Dim eth ylh yd r a -
zon e (4d ). Following method A from 2d , flash chromatogra-
phy (1:1 f 2:1 Et2O-PE) gave 102 mg (75%) of 4d as an oil:
1
an oil: bp 120-125 °C; H NMR (500 MHz, CDCl3) δ 0.14 (s,
6H), 0.85 (s, 6H), 0.90 (d, 6H, J ) 6.9 Hz), 0.91 (s, 9H), 1.28
(ddd, 1H, J ) 10.9, 8.0, 3.8 Hz), 1.42 (dtd, 1H, J ) 12.9, 10.9,
5.1 Hz), 1.64 (m, 1H, J ) 6.9 Hz), 1.79 (ddt, 1H, J ) 12.9, 4.8,
3.8 Hz), 1.93 (dtd, 1H, J ) 17.0, 5.1, 1.4 Hz), 2.03 (dddd, 1H,
J ) 17.0, 10.2, 4.8, 2.5 Hz), 2.66 (s, 6H), 3.05-3.07 (m, 1H),
4.50-4.51 (m, 1H), 6.41 (d, 1H, J ) 7.4 Hz); 13C NMR (125
MHz, CDCl3) δ -2.7, -2.6, 18.3, 19.9, 23.9, 24.6, 28.9, 30.0,
1
bp 206 °C; H NMR (500 MHz, CDCl3) δ 1.62 (ddt, 1H, J )
12.4, 10.0, 3.1 Hz), 1.72 (dddt, 1H, J ) 13.5, 11.6, 4.9, 3.2 Hz),
1.97-2.03 (m, 1H), 2.04-2.10 (m, 1H), 2.29 (dddd, 1H, J )
14.4, 11.6, 6.0, 1.1 Hz), 2.35-2.40 (m, 1H), 2.37 (ddd, 1H, J )
14.3, 11.1, 1.1 Hz), 2.50 (ddt, 1H, J ) 14.3, 4.2, 1.8 Hz), 2.66-
2.73 (m, 1H), 2.74 (s, 6H), 6.51 (d, 1H, J ) 5.1 Hz); 13C NMR
(125 MHz, CDCl3) δ 24.5, 29.7, 41.1, 42.9, 45.4, 67.8, 138.2,
218.7; IR (film, cm-1) 2863, 1711; mass spectrum m/ z (rel
intensity) 168 M+ (100). Anal. Calcd for C9H16N2O: C, 64.25;
H, 9.58; N, 16.65. Found: C, 63.79; H, 9.40; N, 17.02.
2,2-Dim et h yl-5-oxocycloh exa n eca r b oxa ld eh yd e Di-
m eth ylh yd r a zon e (4f). Following method A from 2f, flash
33.7, 33.8, 41.0, 43.3, 46.7, 106.2, 146.7, 151.6; IR (film, cm-1
)
2868, 1669, 1466; mass spectrum m/ z (rel intensity) 366 M+
(26), 321 (24) 73 (100); m/ z calcd for C21H42N2OSi 366.3066,
found 366.3077.
4-[(Dim et h ylt h exylsilyl)oxy]-2,4-d ip h en yl-3-b u t en a l
Dim eth ylh yd r a zon e (3h ). Following method B from 2h ,

5152 J . Org. Chem., Vol. 62, No. 15, 1997
D´ıez et al.
1
chromatography (1:4 f 1:3 Et2O-PE) gave unreacted 2f (4%)
and 224 mg (65%) of 4f as an oil: 1H NMR (500 MHz, CDCl3)
δ 1.06 (s, 3H), 1.08 (s, 3H), 1.64 (td, 1H, J ) 12.5, 5.0 Hz),
1.74 (ddd, 1H, J ) 13.0, 5.8, 5.0 Hz), 2.31 (dtd, 1H, J ) 15.3,
5.0, 1.9 Hz), 2.35-2.50 (m, 4H), 2.73 (s, 6H), 6.52 (d, 1H, J )
5.3 Hz); 13C NMR (125 MHz, CDCl3) δ 20.0, 28.6, 32.8, 37.8,
39.1, 41.6, 43.0, 49.4, 136.5, 211.1; IR (film, cm-1) 2824, 1712;
mass spectrum m/ z (rel intensity) 196 M+ (100), 152 (38), 125
(13); m/ z calcd for C11H20N2O 196.1576, found 196.1578.
cis-2-ter t-Bu t yl-5-oxocycloh exa n e-1-ca r b oxa ld eh yd e
Dim eth ylh yd r a zon e (4g). Following method B from 2g,
flash chromatography (1:2 Et2O-PE) gave unreacted 2g (33%)
and 123 mg (55%) of 4g as an oil: 1H NMR (500 MHz, CDCl3)
δ 0.89 (s, 9H), 1.54 (dtd, 1H, J ) 15.5, 13.5, 3.6 Hz), 1.67 (dt,-
1H, J ) 12.0, 5.1 Hz), 1.91 (dtd, 1H, J ) 5.1, 4.8, 3.6 Hz), 2.14
(ddd, 1H, J ) 17.5, 15.5, 4.8 Hz), 2.28 (dt, 1H, J ) 17.5, 3.6
Hz), 2.35 (dd, 1H, J ) 15.6, 6.1 Hz), 2.40 (dd, 1H, J ) 15.6,
4.9 Hz), 2.62 (s, 6H), 2.75 (m, 1H), 6.45 (d, 1H, J ) 5.4 Hz);
13C NMR (125 MHz, CDCl3) δ 22.9, 27.5, 33.9, 37.9, 38.6, 42.3,
42.9, 46.7, 141.2, 212.4; IR (film, cm-1) 2868, 1717, 1468; mass
spectrum m/ z (rel intensity) 224 M+ (100). Anal. Calcd for
C13H24N2O: C, 69.60; H, 10.78; N, 12.49. Found: C, 69.32;
H, 10.78; N, 12.64.
1, CHCl3); H NMR (500 MHz, CDCl3) δ 0.19 (s, 3H), 0.19 (s,
3H), 0.87-0.90 (m, 12H), 1.18 (s, 3H), 1.62-1.68 (m, 2H),
1.75-1.97 (m, 4H), 2.04 (ddd, 1H, J ) 12.7, 8.6, 6.3 Hz), 2.25-
2.37 (m, 2H), 2.63-2.70 (m, 1H), 3.26-3.36 (m, 2H), 3.38 (s,
3H), 3.44 (dd, 1H, J ) 9.2, 7.0 Hz), 3.61 (dd, 1H, J ) 9.2,
3.6 Hz), 4.53 (t, 1H, J ) 1.6 Hz), 6.62 (s, 1H); 13C NMR (125
MHz, CDCl3) δ -2.8, 18.4, 20.0, 21.8, 24.9, 25.4, 26.4, 32.9,
34.0, 34.5, 48.2, 49.9, 59.0, 63.4, 74.6, 110.5, 145.5, 154.4; IR
(film, cm-1) 2870, 1643; mass spectrum m/ z (rel intensity) 380
M
+ (26), 335 (100); m/ z calcd for C21H40N2O2Si 380.2859, found
380.2857.
(2S)-1-[[(1R)-[3-[(Dim eth ylth exylsilyl)oxy]-2-m eth yl-2-
cyclop en t en yl]m et h ylen e]a m in o]-2-(m et h oxym et h yl)-
p yr r olid in e (5c). From 2c, flash chromatography (1:5 Et2O-
PE) gave 1.46 g (77%) of 5c as an oil: [R]22D +23.1° (c 1, CHCl3);
1H NMR (500 MHz, CDCl3) δ 0.13 (s, 3H), 0.16 (s, 3H), 0.87-
0.92 (m, 12H), 1.50 (td, 3H, J ) 2.0, 1.1 Hz), 1.64-1.71 (m,
1H), 1.68 (m, 1H, J ) 6.8 Hz), 1.78-1.96 (m, 4H), 2.11 (dtd,
1H, J ) 14.0, 9.0, 5.2 Hz), 2.26-2.33 (m, 2H), 2.72-2.77 (m,
1H), 3.17-3.23 (m, 1H), 3.30-3.34 (m, 1H), 3.37 (s, 3H), 3.38-
3.41 (m, 1H), 3.43 (dd, 1H, J ) 8.8, 6.8 Hz), 3.57 (dd, 1H, J )
8.8, 3.3 Hz), 6.45 (d, 1H, J ) 7.5 Hz); 13C NMR (125 MHz,
CDCl3) δ -2.0, 10.6, 18.5, 20.0, 22.0, 24.9, 26.0, 26.5, 32.7, 33.9,
48.8, 50.4, 59.1, 63.4, 74.6, 113.7, 142.8, 148.2; IR (film, cm-1
)
4-Oxo-2,4-d ip h en ylbu ta n a l Dim eth ylh yd r a zon e (4h ).
Following method B from 2h , flash chromatography (1:9 Et2O-
2875, 1685, 1466; mass spectrum m/ z (rel intensity) 380 M+
(16), 335 (41), 265 (100); m/ z calcd for C21H40N2O2Si 380.2859,
found 380.2859.
1
PE) gave 190 mg (68%) of crystalline 4h : mp 86-88 °C; H
NMR (500 MHz, CDCl3) δ 2.63 (s, 6H), 3.04 (dd, 1H, J ) 16.5,
5.6 Hz), 3.91 (dd, 1H, J ) 16.5, 8.5 Hz), 4.37 (ddd, 1H, J )
8.9, 5.7, 3.7 Hz), 6.73 (d, 1H, J ) 3.7 Hz), 7.21-7.98 (m, 10H);
13C NMR (125 MHz, CDCl3) δ 42.5, 44.3, 126.7, 128.1, 128.2,
(2S)-1-[[(1R)-[3-[(Dim eth ylth exylsilyl)oxy]-1-m eth yl-2-
cycloh exen yl]m eth ylen e]a m in o]-2-(m eth oxym eth yl)p yr -
r olid in e (5e). From 2e, flash chromatography (1:10 Et2O-
128.3, 128.6, 132.5, 137.1, 137.6, 142.4, 198.9; IR (KBr, cm-1
)
PE) gave 1.62 g (82%) of 5e as an oil: [R]22 -36.8° (c 1,
D
1678, 1595; mass spectrum m/ z (rel intensity) 280 M+ (20),
236 (100). Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N,
9.99. Found: C, 77.19; H, 7.18; N, 9.90.
CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.16 (s, 3H), 0.17 (s, 3H),
0.86-0.90 (m, 12H), 1.10 (s, 3H), 1.24-2.00 (m, 11H), 2.60-
2.69 (m, 1H), 3.24-3.34 (m, 2H), 3.36 (s, 3H), 3.43 (dd, 1H, J
) 9.2, 6.9 Hz), 3.59 (dd, 1H, J ) 9.2, 3.6 Hz), 4.70 (s, 1H), 6.53
(s, 1H); 13C NMR (75 MHz, CDCl3) δ -2.6, -2.5, 18.4, 19.4,
20.0, 21.8, 24.7, 26.3, 26.9, 29.7, 33.9, 34.3, 38.6, 49.8, 59.0,
63.4, 74.5, 111.8, 145.6, 150.1; IR (film, cm-1) 1657, 1458; mass
spectrum m/ z (rel intensity) 394 M+ (8), 349 (100). Anal.
Calcd for C22H42N2O2Si: C, 66.95; H, 10.73; N, 7.10. Found:
C, 66.89; H, 11.05; N, 7.00.
2-P h en yl-4-oxop en ta n a l Dim eth ylh yd r a zon e (4i). Fol-
lowing method A from 2i, flash chromatography (1:3 Et2O-
PE) gave 240 mg (55%) of 4i as an oil: 1H NMR (500 MHz,
CDCl3) δ 2.20 (s, 3H), 2.59 (dd, 1H, J ) 16.3, 5.5 Hz), 2.74 (s,
6H), 3.28 (dd, 1H, J ) 16.3, 9.0 Hz), 4.15 (ddd, 1H, J ) 9.0,
5.4, 3.8 Hz), 6.67 (d, 1H, J ) 3.7 Hz), 7.23-7.37 (m, 5H); 13C
NMR (125 MHz, CDCl3) δ 30.6, 42.9, 44.0, 47.1, 126.6, 127.9,
128.5, 137.2, 141.9, 207.5; IR (KBr, cm-1) 2850, 1707, 1558;
mass spectrum m/ z (rel intensity) 218 M+ (28), 200 (100).
Anal. Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83.
Found: C, 71.18; H, 8.15; N, 13.04.
(2S)-1-[[(1R)-[6,6-Dim et h yl-3-[(d im et h ylt h exylsilyl)-
oxy]-2-cycloh e xe n yl]m e t h yle n e ]a m in o]-2-(m e t h oxy-
m eth yl)p yr r olid in e (5f). From 2f, flash chromatography (1:
15 f 1:10 Et2O-PE) gave 1.51 g (74%) of 5f as an oil: [R]22
D
Syn th esis of Silyl En ol Eth er s 5. To a cooled (-78 °C)
solution of enone 2 (5 mmol) in dry THF (5 mL) were
sequentially added TDSOTf (1.41 mL, 5.5 mmol) and precooled
(-78 °C) 1b (0.89 mL, 6.25 mmol) under an argon atmosphere.
After 15 min, NaHCO3 (s, 0.5 g) was added, and the mixture
was allowed to warm to rt, diluted with Et2O (50 mL), and
washed with H2O (2 × 30 mL). The organic layer was dried
(Na2SO4) and concentrated, and the residue was purified by
flash chromatography (Et2O-PE) to yield pure compounds 5.
Compound 5i was detected, but it decomposed and could not
be characterized. Chromatography solvents, yields, and spec-
tral and analytical data for compounds 5 are as follows.
(2S)-1-[[(1R)-[3-[(Dim eth ylth exylsilyl)oxy]-2-cyclop en -
t e n yl]m e t h yle n e ]a m in o]-2-(m e t h oxym e t h yl)p yr r oli-
d in e (5a ). From 2a , flash chromatography (1:6 Et2O-PE)
+11.6° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.17 (s, 6H),
0.85-0.96 (m, 18H), 1.40-2.06 (m, 9H), 2.65-2.67 (m, 1H),
2.67-2.71 (m, 1H), 3.37-3.40 (m, 2H), 3.38 (s, 3H), 3.43 (dd,
1H, J ) 9.1, 6.9 Hz), 3.57 (dd, 1H, J ) 9.0, 3.8 Hz), 4.72 (d,
1H, J ) 3.6 Hz), 6.47 (d, 1H, J ) 7.7 Hz); 13C NMR (125 MHz,
CDCl3) δ -2.5, 18.4, 20.0, 22.0, 23.9, 24.7, 26.4, 27.4, 27.7, 31.3,
33.9, 35.3, 48.6, 50.8, 59.1, 63.5, 74.8, 104.9, 140.8, 150.2; IR
(film, cm-1) 2868, 1665, 1464; mass spectrum m/ z (rel inten-
sity) 408 M+ (22), 363 (56), 73 (100). Anal. Calcd for
C23H44N2O2Si: C, 67.59; H, 10.85; N, 6.85. Found: C, 67.66;
H, 10.90; N, 6.66.
(2S)-1-[[(1R)-4-[(Dim eth ylth exylsilyl)oxy]-2,4-diph en yl-
3-b u t en ylid en e]a m in o]-2-(m et h oxym et h yl)p yr r olid in e
(5h ). From 2h , flash chromatography (1:10 Et2O-PE) gave
1.85 g (75%) of 5h as an oil: [R]22 -49.6° (c 1, CHCl3); 1H
D
gave 1.17 g (64%) of 5a as an oil: [R]22 -13.2° (c 1, CHCl3);
NMR (300 MHz, CDCl3) δ 0.17 (s, 3H), 0.28 (s, 3H), 1.01-
1.11 (m, 13H), 1.75-2.14 (m, 4H), 2.88-2.93 (m, 1H), 3.43-
3.47 (m, 2H), 3.53 (s, 3H), 3.62-3.65 (m, 1H), 3.80 (dd, 1H, J
) 8.9, 3.2 Hz), 4.96 (dd, 1H, J ) 10.0, 5.9 Hz), 5.54 (d, 1H, J
) 10.0 Hz), 6.82 (d, 1H, J ) 5.9 Hz), 7.30-7.60 (m, 10H); 13C
NMR (75 MHz, CDCl3) δ -2.0, -1.9, 18.5, 18.6, 20.2, 20.3, 21.8,
25.1, 26.4, 33.8, 44.9, 49.6, 59.1, 63.3, 74.5, 111.6, 126.0, 126.3,
127.5, 127.7, 127.8, 128.8, 138.5, 139.8, 143.0, 149.7; IR (film,
cm-1) 2870, 1645, 1599; mass spectrum m/ z (rel intensity)
492 M+ (49), 447 (57), 73 (100). Anal. Calcd for C30H44N2O2-
Si: C, 73.12; H, 9.00; N, 5.68. Found: C, 73.24; H, 8.80; N,
5.45.
D
1H NMR (500 MHz, CDCl3) δ 0.14 (s, 3H), 0.21 (s, 3H), 0.87-
0.92 (m, 12H), 1.62-1.96 (m, 6H), 2.13-2.17 (m, 1H), 2.27-
2.31 (m, 2H), 2.68-2.73 (m, 1H), 3.35-3.43 (m, 3H), 3.39 (s,
3H), 3.43 (dd, 1H, J ) 9.1, 6.9 Hz), 3.58 (dd, 1H, J ) 9.1, 3.8
Hz), 4.56-4.58 (m, 1H), 6.49 (d, 1H, J ) 7.3 Hz); 13C NMR
(125 MHz, CDCl3) δ -2.7, -2.6, 18.5, 20.1, 22.1, 25.0, 26.6,
27.2, 33.3, 34.1, 45.7, 50.5, 59.2, 63.5, 74.9, 104.1, 143.4, 156.5;
IR (film, cm-1) 2872, 1641; mass spectrum m/ z (rel intensity)
366 M+ (12), 321 (53), 73 (100). Anal. Calcd for C20H38N2O2-
Si: C, 65.52; H, 10.45; N, 7.64. Found: C, 65.31; H, 10.80; N,
7.33.
(2S)-1-[[(1R)-[3-[(Dim eth ylth exylsilyl)oxy]-1-m eth yl-2-
cyclop en t en yl]m et h ylen e]a m in o]-2-(m et h oxym et h yl)-
p yr r olid in e (5b). From 2b, flash chromatography (1:15
Syn th esis of 4-Oxo Hyd r a zon es 6. To a cooled (-78 °C)
solution of enone 2 (5 mmol) in dry THF (5 mL) were
sequentially added TDSOTf (1.41 mL, 5.5 mmol) and precooled
(-78 °C) 1b (0.89 mL, 6.25 mmol) under an argon atmosphere.
Et2O-PE) gave 1.45 g (76%) of 5b as an oil: [R]22 -36.1° (c
D

Nucleophilic Addition to Conjugated Enones
J . Org. Chem., Vol. 62, No. 15, 1997 5153
After 15 min, TBAF (1 M in THF, 5.5 mL, 5.5 mmol) was
added, and the mixture was allowed to warm to rt and stirred
until TLC indicated total consumption of the silyl enol ether
5. The mixture was then diluted with Et2O (50 mL) and
washed with H2O (2 × 30 mL). The organic layer was dried
(Na2SO4) and concentrated, and the residue was purified by
flash chromatography. Eluants, yields, and spectral and
analytical data for compounds 6 are as follows.
(2S)-2-(Met h oxym et h yl)-1-[[(1R)-(3-oxocyclop en t yl)-
m eth ylen e]a m in o]p yr r olid in e (6a ). From 2a , flash chro-
matography (1:4 f 1:1 Et2O-PE) gave 0.72 g (69%) of 6a as
an oil: [R]22D -112.5° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 1.75-2.00 (m, 5H), 2.14-2.34 (m, 4H), 2.39 (dd, 1H, J ) 18.4,
7.8 Hz), 2.72-2.77 (m, 1H), 3.04-3.08 (m, 1H), 3.33-3.41 (m,
2H), 3.37 (s, 3H), 3.44 (dd, 1H, J ) 9.2, 6.4 Hz), 3.54 (dd, 1H,
J ) 9.2, 3.8 Hz), 6.59 (d, 1H, J ) 5.1 Hz); 13C NMR (125 MHz,
CDCl3) δ 22.0, 26.4, 28.1, 37.4, 39.6, 42.7, 49.7, 59.1, 63.2, 74.4,
137.4, 218.7; IR (film, cm-1) 2880, 1742; mass spectrum m/ z
(rel intensity) 224 M+ (5), 179 (100); m/ z calcd for C12H20N2O2
224.1525, found 224.1524.
C15H26N2O2: C, 67.63; H, 9.84; N, 10.52. Found: C, 67.39; H,
9.99; N, 10.40.
(2S)-1-[[(1R)-4-Oxo-2,4-d ip h en ylbu tylid en e]a m in o]-2-
(m eth oxym eth yl)p yr r olid in e (6h ). From 2h , flash chro-
matography (1:20 f 1:4 Et2O-PE) gave 1.33 g (76%) of
1
crystalline 6h : mp 71-72 °C; [R]22 -203.7° (c 1, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 1.69-1.92 (m, 4H), 2.67-2.72 (m,
1H), 2.94 (dd, 1H, J ) 16.4, 5.0 Hz), 3.09-3.10 (m, 1H), 3.12
(s, 3H), 3.20 (dd, 1H, J ) 9.3, 3.7 Hz), 3.23-3.30 (m, 2H), 3.92
(dd, 1H, J ) 16.4, 9.1 Hz), 4.39 (m, 1H), 6.71 (d, 1H, J ) 3.6
Hz), 7.22-8.01 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 21.8,
26.6, 42.4, 44.2, 49.4, 58.8, 62.9, 74.4, 126.6, 128.1, 128.3, 128.5,
132.5, 136.7, 137.5, 142.6, 198.7; IR (KBr, cm-1) 2826, 1665,
1597; mass spectrum m/ z (rel intensity) 350 M+ (9), 305 (18),
70 (100). Anal. Calcd for C22H26N2O2: C, 76.27; H, 6.40; N,
8.09. Found: C, 76.11; H, 6.24; N, 7.74.
(2S)-2-(Meth oxym eth yl)-1-[[(1R)-4-oxo-2-p h en yl-3-p en -
tylid en e]a m in o]p yr r olid in e (6i). From 2i, flash chroma-
tography (1:4 f 1:2 Et2O-PE) gave 0.86 g (60%) of 6i as an
oil: [R]22 -179.0° (c 1, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
1.73-2.02 (m, 4H), 2.18 (s, 3H), 2.56 (dd, 1H, J ) 16.3, 5.4
Hz), 2.69-2.77 (m, 1H), 3.21 (dd, 1H, J ) 16.3, 9.2 Hz), 3.24-
3.30 (m, 1H), 3.34-3.50 (m, 2H), 3.37 (s, 3H), 3.54 (dd, 1H, J
) 8.5, 3.2 Hz), 4.13 (ddd, 1H, J ) 9.0, 5.2, 3.7 Hz), 6.64 (d,
1H, J ) 3.6 Hz), 7.19-7.34 (m, 5H); 13C NMR (125 MHz,
CDCl3) δ 21.9, 26.6, 30.5, 44.1, 47.4, 49.6, 59.1, 63.1, 74.7,
126.6, 127.9, 128.5, 137.0, 142.3, 207.4; IR (film, cm-1) 2878,
1715, 1601; mass spectrum m/ z (rel intensity) 288 M+ (20),
243 (100). Anal. Calcd for C17H24N2O2: C, 70.80; H, 8.39; N,
9.71. Found: C, 70.64; H, 8.17; N, 9.33.
Syn th esis of 4-Oxo Ald eh yd es 7. Meth od A. Dry ozone
was bubbled through a cooled (-78 °C) solution of hydrazone
4 or 6 (1 mmol) in CH2Cl2 (6 mL) until appearance of a
permanent blue color. After addition of Me2S (1 mL, 13.6
mmol), the mixture was allowed to reach rt and concentrated,
and the residue was purified by flash chromatography.
Meth od B. To a cooled (0 °C) solution of hydrazone 4 or 6
(1 mmol) in Et2O (30 mL) was added 5 N HCl (10 mL), and
the mixture was vigorously stirred until TLC indicated total
consumption of the starting material (ca. 10 min). The
aqueous layer was extracted with Et2O several times (each
10 mL) until the product could no longer be detected (TLC).
The combined organic layers were neutralized (NaHCO3, s, 0.1
g), dried (MgSO4), and concentrated. The resulting residue
was purified by flash chromatography.
(2S)-2-(Meth oxym eth yl)-1-[[(1R)-(1-m eth yl-3-oxocyclo-
p en tyl)m eth ylen e]a m in o]p yr r olid in e (6b). From 2b, flash
chromatography (1:2 Et2O-PE) gave 0.95 g (80%) of 6b as an
oil: [R]22 -210.4° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
1.27 (s, 3H), 1.79-1.98 (m, 5H), 1.99 (d, 1H, J ) 17.6 Hz),
2.12 (dddd, 1H, J ) 13.0, 8.7, 4.4, 1.8 Hz), 2.22 (ddd, 1H, J )
18.8, 8.4, 4.4 Hz), 2.24-2.34 (m, 1H), 2.63 (d, 1H, J ) 17.6
Hz), 2.67-2.72 (m, 1H), 3.27-3.33 (m, 2H), 3.36 (s, 3H), 3.45
(dd, 1H, J ) 9.4, 6.1 Hz), 3.52 (dd, 1H, J ) 9.4, 3.6 Hz), 6.52
(s, 1H); 13C NMR (125 MHz, CDCl3) δ 21.7, 25.4, 26.1, 34.6,
36.7, 42.8, 49.3, 49.6, 58.9, 63.2, 74.0, 141.0, 219.0; IR (film,
cm-1) 2876, 1742; mass spectrum m/ z (rel intensity) 238 M+
(8), 193 (100). Anal. Calcd for C13H22N2O2: C, 65.51; H, 9.30;
N, 11.75. Found: C, 65.49; H, 9.56; N, 11.42.
(2S)-2-(Meth oxym eth yl)-1-[[(1R,2R)-(2-m eth yl-3-oxocy-
clop en tyl)m eth ylen e]a m in o]p yr r olid in e (6c). From 2c,
flash chromatography (1:3 Et2O-PE) gave 0.98 g (82%) of 6c
as an oil: [R]22 -69.9° (c 1, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 1.10 (d, 3H, J ) 7.0 Hz), 1.72-1.82 (m, 2H), 1.88-
1.99 (m, 3H), 2.08-2.11 (m, 1H), 2.13-2.20 (m, 2H), 2.40 (ddd,
1H, J ) 17.3, 8.5, 1.4 Hz), 2.47-2.52 (m, 1H), 2.75-2.80 (m,
1H), 3.32-3.36 (m, 1H), 3.37 (s, 3H), 3.40-3.42 (m, 1H), 3.45
(dd, 1H, J ) 8.6, 6.5 Hz), 3.55 (dd, 1H, J ) 8.6, 3.1 Hz), 6.56
(d, 1H, J ) 5.9 Hz); 13C NMR (125 MHz, CDCl3) δ 12.4, 22.0,
26.2, 26.4, 36.9, 48.0, 48.6, 49.8, 59.1, 63.2, 74.4, 137.6, 219.9;
IR (film, cm-1) 2875, 1740; mass spectrum m/ z (rel intensity)
238 M+ (4), 193 (100). Anal. Calcd for C13H22N2O2: C, 65.51;
H, 9.30; N, 11.75. Found: C, 65.71; H, 9.58; N, 12.02.
The methods followed for deprotection, chromatography
eluants, yields, and spectral and analytical data for compounds
7b,c,e-i are as follows.
1-Met h yl-3-oxocyclop en t a n eca r b a ld eh yd e (r a c-7b ).
From 4b, following method B, flash chromatography (1:1
Et2O-PE) gave 107 mg (85%) of 7b as an oil: 1H NMR (300
MHz, CDCl3) δ 1.33 (s, 3H), 1.78-1.88 (m, 1H), 2.03 (d, 1H, J
) 18.3 Hz), 2.25-2.40 (m, 3H), 2.67 (d, 1H, J ) 18.3 Hz), 9.58
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.2, 30.0, 36.1, 45.2, 50.6,
202.4, 215.8; IR (film, cm-1) 2724, 1742; mass spectrum m/ z
(rel intensity) 126 M+ (8), 98 (100). Anal. Calcd for C7H10O2:
C, 66.64; H, 7.99. Found: C, 66.55; H, 8.06.
(R)-1-Meth yl-3-oxocyclop en ta n eca r ba ld eh yd e [(R)-7b].
From 6b, following method B, flash chromatography (1:1
Et2O-PE) gave 110 mg (87%) of (R)-7b as an oil: [R]22D -22.0°
(c 1, CHCl3). Spectral and analytical data were as for the
racemic 7b described above.
(2S)-2-(Meth oxym eth yl)-1-[[(1R)-(1-m eth yl-3-oxocyclo-
h exyl)m eth ylen e]a m in o]p yr r olid in e (6e). From 2e, flash
chromatography (1:4 Et2O-PE) gave 1.09 g (86%) of 6e as an
oil: [R]22 -164.5° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
1.12 (s, 3H), 1.59-1.66 (m, 1H), 1.75-2.00 (m, 7H), 2.09 (dd,
1H, J ) 14.3, 1.2 Hz), 2.19 (dt, 1H, J ) 13.6, 7.7 Hz), 2.31
(dtt, 1H, J ) 13.2, 6.7, 1.35 Hz), 2.58 (dt, 1H, J ) 14.3, 1.5
Hz), 2.65-2.71 (m, 1H), 3.25-3.32 (m, 2H), 3.37 (s, 3H), 3.47
(dd, 1H, J ) 9.5, 5.9 Hz), 3.52 (dd, 1H, J ) 9.5, 3.5 Hz), 6.39
(s, 1H); 13C NMR (125 MHz, CDCl3) δ 21.5, 21.7, 25.7, 26.6,
35.3, 40.4, 41.8, 49.2, 51.1, 59.1, 63.2, 73.9, 141.6, 210.7; IR
(film, cm-1) 2876, 1711; mass spectrum m/ z (rel intensity) 252
M+ (4), 207 (100). Anal. Calcd for C14H24N2O2: C, 66.66; H,
9.58; N, 11.10. Found: C, 66.65; H, 9.84; N, 11.36.
(1R ,2R )-2-Me t h yl-3-oxocyclop e n t a n e ca r b a ld e h yd e
[(R,R)-7c]. From 6c, following method A, flash chromatog-
(2S)-1-[[(1R)-(2,2-Dim eth yl-5-oxocycloh exyl)m eth ylen e]-
a m in o]-2-(m eth oxym eth yl)p yr r olid in e (6f). From 2f, flash
chromatography (1:4 f 1:1 Et2O-PE) gave 1.05 g (79%) of 6f
raphy (1:2 Et2O-PE) gave 118 mg (94%) of (R,R)-7c as an oil:
1
[R]22 +82.3° (c 1, CHCl3); H NMR (500 MHz, CDCl3) δ 1.17
as an oil: [R]22 -76.3° (c 1, CHCl3); 1H NMR (500 MHz,
D
D
(d, 3H, J ) 7.0 Hz), 1.93-2.01 (m, 1H), 2.21-2.33 (m, 2H),
2.39-2.52 (m, 2H), 2.68-2.75 (m, 1H), 9.78 (d, 1H, J ) 2.3
Hz); 13C NMR (75 MHz, CDCl3) δ 13.1, 21.1, 36.1, 44.4, 56.2,
201.0, 217.1; IR (film, cm-1) 2882, 1744, 1657; mass spectrum
m/ z (rel intensity) 126 M+ (19), 98 (55), 69 (100). Anal. Calcd
for C7H10O2: C, 66.64; H, 7.99. Found: C, 66.30; H, 8.11.
(R)-1-Meth yl-3-oxocycloh exa n eca r ba ld eh yd e [(R)-7e].
From 6e, following method B, flash chromatography (4:1
CDCl3) δ 1.06 (s, 3H), 1.08 (s, 3H), 1.61 (ddd, 1H, J ) 13.6,
11.5, 5.3 Hz), 1.74 (ddd, 1H, J ) 13.6, 6.0, 4.9 Hz), 1.77-1.98
(m, 4H), 2.29 (dtd, 1H, J ) 15.3, 5.1, 1.9 Hz), 2.37-2.52 (m,
4H), 2.70-2.75 (m, 1H), 3.31-3.38 (m, 2H), 3.36 (s, 3H), 3.44
(dd, 1H, J ) 9.3, 6.3 Hz), 3.52 (dd, 1H, J ) 9.3, 3.8 Hz), 6.55
(d, 1H, J ) 5.6 Hz); 13C NMR (125 MHz, CDCl3) δ 21.1, 21.9,
26.3, 28.5, 32.9, 37.8, 38.9, 41.7, 49.5, 49.9, 59.1, 63.3, 74.3,
136.4, 211.2; IR (film, cm-1) 1713, 1597; mass spectrum m/ z
(rel intensity) 266 M+ (4), 221 (100). Anal. Calcd for
Et2O-PE) gave 97 mg (69%) of (R)-7e as an oil: [R]22 +5.5°
D

5154 J . Org. Chem., Vol. 62, No. 15, 1997
D´ıez et al.
(c 1, CHCl3). Spectral and analytical data were in good
and analytical data were in good agreement with those
reported for the racemic form.45
agreement with those reported for the racemic form.40
(1R,2R)-2-Meth yl-3-oxocyclopen tan ecar bon itr ile [(R,R)-
8c]. From 6c, flash chromatography (1:2 Et2O-PE) gave 86
mg (70%) of crystalline (R,R)-8c: mp 55-57 °C (lit.36 mp 55
2,2-Dim eth yl-5-oxocycloh exa n eca r ba ld eh yd e (r a c-7f).
From 4f, following method B, flash chromatography (1:3 Et2O-
PE) gave 109 mg (71%) of known41 crystalline 7f.
°C); [R]22 +63.6° (c 1, CHCl3). Spectral and analytical data
D
(R)-2,2-Dim eth yl-5-oxocycloh exa n eca r ba ld eh yd e [(R)-
7f]. From 6f, following method B, flash chromatography (1:6
Et2O-PE) gave 120 mg (78%) of crystalline (R)-7f: mp 86-
were in good agreement with those reported for the racemic
compound.36 The minor isomer was not isolated.
3-Oxocycloh exa n eca r bon itr ile [(r a c)-8d ]. From 4d ,
flash chromatography (3:1 Et2O-PE) gave 116 mg (94%) of
known 8d 46 as an oil.
87 °C; [R]22 +34.3° (c 1, CHCl3). Following method A, flash
D
chromatography (1:6 Et2O-PE) gave 106 mg (69%) of crystal-
line (R)-7f: mp 86-88 °C; [R]22D +34.1° (c 1, CHCl3). Spectral
and analytical data were in good agreement with those
reported for the racemic form.41
(R)-1-Met h yl-3-oxocycloh exa n eca r b on it r ile [(R)-8e].
From 6e, flash chromatography (1:1 Et2O-PE) gave 119 mg
(87%) of (R)-8e as an oil: [R]22 -24.3° (c 1, CHCl3). Spectral
D
cis-2-ter t-Bu tyl-5-oxocycloh exa n eca r ba ld eh yd e [(r a c)-
7g]. From 4g, following method A, flash chromatography (1:1
Et2O-PE) gave 137 mg (75%) and, following method B, flash
chromatography (2:1 Et2O-PE) gave 147 mg (81%) of 7g as
an oil: 1H NMR (500 MHz, CDCl3) δ 0.98 (s, 9H), 1.58-1.68
(m, 1H), 1.98-2.06 (m, 3H), 2.34-2.39 (m, 1H), 2.36 (dd, 1H,
J ) 16.5, 6.5 Hz), 2.63 (dd, 1H, J ) 16.4, 3.8 Hz), 2.84-2.87
(m, 1H), 9.63 (d, 1H, J ) 1.2 Hz); 13C NMR (125 MHz, CDCl3)
δ 21.9, 27.0, 33.8, 36.8, 38.1, 41.9, 46.8, 201.7, 210.1; IR (film,
cm-1) 2891, 1726; mass spectrum m/ z (rel intensity) 182 M+
(1), 57 (100); m/ z calcd for C11H18O2 182.1307, found 182.1304.
4-Oxo-2,4-d ip h en ylbu ta n a l [(r a c)-7h ]. From 4h , follow-
ing method B, flash chromatography (1:10 Et2O-PE) gave 210
mg (88%) of known42 crystalline 7h .
(R)-4-Oxo-2,4-d ip h en ylbu ta n a l [(R)-7h ]. From 6h , fol-
lowing method A, flash chromatography (1:20 Et2O-PE) gave
186 mg (78%) of crystalline (R)-7h : mp 59-60 °C; [R]22D -55.6°
(c 1, CHCl3). Spectral and analytical data were in good
agreement with those reported for the racemic form.42
and analytical data were in good agreement with those
reported for the racemic compound.47
2,2-Dim eth yl-5-oxocycloh exa n eca r bon itr ile [(r a c)-8f].
From 4f, flash chromatography (1:2 Et2O-PE) gave 138 mg
(91%) of known41 crystalline 8f.
(S)-2,2-Dim et h yl-5-oxocycloh exa n eca r b on it r ile [(S)-
8f]. From 6f, flash chromatography (1:6 Et2O-PE) gave 126
mg (83%) of crystalline (S)-8f: mp 63-64 °C; [R]22 -11.7° (c
D
1, CHCl3). Spectral and analytical data were in good agree-
ment with those reported for the racemic compound.41
cis-2-ter t-Bu tyl-5-oxocycloh exa n eca r bon itr ile [(r a c)-
8g]. From 4g, flash chromatography (1:1 Et2O-PE) gave 154
mg (86%) of known cis-8g37 as an oil.
4-Oxo-2,4-d ip h en ylbu ta n en itr ile [(r a c)-8h ]. From 4h ,
flash chromatography (1:20 Et2O-PE) gave 212 mg (90%) of
known48 crystalline 8h .
(R)-4-Oxo-2,4-d ip h en ylbu ta n en itr ile [(R)-8h ]. From 6h ,
flash chromatography (1:20 Et2O-PE) gave 223 mg (95%) of
crystalline (R)-8h : mp 64-65 °C; [R]22 +16.2° (c 1, CHCl3).
D
2-P h en yl-4-oxop en t a n a l [(r a c)-7i]. From 4i, following
method B but with 3 mmol of 5 N HCl (0.6 mL), flash
chromatography (1:5 Et2O-PE) gave 132 mg (75%) of known43
7i as an oil.
Spectral and analytical data were in good agreement with
those reported for the racemic compound.48
2-P h en yl-4-oxop en ta n en itr ile [(r a c)-8i]. From 4i, flash
chromatography (1:3 Et2O-PE) gave 158 mg (91%) of crystal-
(R)-2-P h en yl-4-oxop en ta n a l [(R)-7i]. From 6i, following
method B, flash chromatography (1:6 f 1:4 Et2O-PE) gave
1
line 8i: mp 63-64 °C; H NMR (300 MHz, CDCl3) δ 2.24 (s,
3H), 3.03 (dd, 1H, J ) 18.0, 6.2 Hz), 3.25 (dd, 1H, J ) 18.0,
155 mg (88%) of (R)-7i as an oil: [R]22 -41.6° (c 1, CHCl3).
D
7.9 Hz), 4.40 (dd, 1H, J ) 7.9, 6.2 Hz), 7.38-7.47 (m, 5H); 13
C
Following method A, flash chromatography (1:6 Et2O-PE)
NMR (75 MHz, CDCl3) δ 29.8, 31.4, 48.6, 120.3, 127.2, 128.3,
129.2, 134.9, 203.0; IR (KBr, cm-1) 2236, 1704; mass spectrum
m/ z (rel intensity) 173 M+ (43), 130 (100). Anal. Calcd for
C11H11NO: C, 76.27; H, 6.40; N, 8.09. Found: C, 76.11; H,
6.24; N, 7.74.
gave 127 mg (72%) of (R)-7i: [R]22 -39.5° (c 1, CHCl3).
D
Spectral and analytical data were in good agreement with
those reported for the racemic form.43
Syn th esis of 4-Oxo Nitr iles 8. To a cooled (0 °C) solution
of 4-oxo hydrazone 4 or 6 (1 mmol) in CH3OH (10 mL) was
added dropwise a suspension of MMPP‚6 H2O (1.24 g, 2.50
mmol), and the mixture was stirred until consumption of the
starting material (ca. 5 min). The mixture was then diluted
with H2O (20 mL) and extracted with CH2Cl2 (20 mL). The
organic layer was washed with brine (2 × 20 mL) and H2O
(20 mL), dried (MgSO4), and concentrated, and the residue
purified by flash chromatography. Eluants, yields, and spec-
tral and analytical data for compounds 8a -i are as follows.
3-Oxocyclop en ta n eca r bon itr ile [(r a c)-8a ]. From 4a ,
flash chromatography (1:1 Et2O-PE) gave 99 mg (91%) of
known44 8a as an oil.
(R)-3-Oxocyclop en ta n eca r bon itr ile [(R)-8a ]. From 6a ,
flash chromatography (1:1 Et2O-PE) gave 98 mg (90%) of (R)-
8a as an oil: [R]22D +35.3° (c 1, CHCl3). Spectral and analytical
data were in good agreement with those reported for the
racemic form.44
(R)-2-P h en yl-4-oxop en t a n en it r ile [(R)-8i]. From 6i,
flash chromatography (1:4 f 1:2 Et2O-PE) gave 157 mg (91%)
of crystalline (R)-8i: mp 63-64 °C; [R]22 +8.1° (c 1, CHCl3).
D
Spectral and analytical data were as for the racemic 8i
described above.
Syn th esis of 4-Oxo Ca r boxylic Acid s 9. Meth od A.
Hydrazone 4 or 6 (1 mmol) was treated with HCl as for
aldehydes 7. After neutralization, the combined organic layers
were concentrated to a volume of ca. 10 mL. The solution
was then cooled to -30 °C and treated with a solution of the
J ones reagent (10 mL, 6.7 mmol). The reaction mixture was
allowed to warm to rt and then stirred for 10 min. The
mixture was filtered through a short silica gel column and
eluted with Et2O until the product could no longer be detected
(TLC). The filtrate was then concentrated in vacuo and the
residue dissolved in 1 M NaOH (10 mL) and washed with Et2O
(2 × 10 mL). The aqueous phase was acidified with 2 N H2-
SO4 and extracted with ethyl acetate (7 × 10 mL). The
combined organic layers were dried (MgSO4) and concentrated,
and the residue was purified by flash chromatography.
1-Met h yl-3-oxocyclop en t a n eca r b on it r ile [(r a c)-8b ].
From 4b, flash chromatography (1:1 Et2O-PE) gave 106 mg
(86%) of known45 8b as an oil.
(R)-1-Meth yl-3-oxocyclop en ta n eca r bon itr ile [(R)-8b].
From 6b, flash chromatography (1:1 Et2O-PE) gave 120 mg
(44) Farcasiu, D.; Schleyer, P. v. R.; Ledlie, D. B. J . Org. Chem. 1973,
38, 3455.
(45) Froissant. J .; Vidal, J .; Guibe´-J ampel, E.; Huet, F. Tetrahedron
1987, 47, 317.
(98%) of (R)-8b as an oil: [R]22 -54.2° (c 1, CHCl3). Spectral
D
(40) Kulinkovich, O. G.; Tishchenko, I. G.; Romashin, Y. U. Zh. Org.
Khim. 1985, 21, 90.
(41) Goodyear, G.; Waring, A. J . J . Chem. Res., Synop. 1991, 307;
J . Chem. Res., Miniprint 1991, 2937.
(42) Araki, S.; Butsugan, Y. Bull. Soc. Chem. J pn. 1991, 64, 727.
(43) Yasuda, M.; Nishio, M.; Shibata, I.; Baba, A.; Matsuda, H. J .
Org. Chem. 1994, 59, 486.
(46) Willaert, J . J .; Lemie`re, G. L.; Domisse, R. A.; Lepoivre, J . A.:
Alderweireldt, F. C. J . Chem. Res., Synop. 1985, 222; J . Chem. Res.,
Miniprint 1985, 2401.
(47) Shibuya, H.; Tsuyii, S.; Yamamoto, Y.; Miura, H.; Kitagawa, I.
Chem. Pharm. Bull. 1984, 32, 3417.
(48) Ciller, J . A.; Seoane, C.; Soto, J . L. Liebigs Ann. Chem. 1985,
51.

Nucleophilic Addition to Conjugated Enones
J . Org. Chem., Vol. 62, No. 15, 1997 5155
Meth od B. A solution of hydrazone 6 (1 mmol) in Et2O
(10 mL) cooled to -30 °C was treated with a solution of the
J ones reagent (15 mL, 10 mmol). The reaction mixture was
allowed to warm to rt and then stirred for 10 min. The
mixture was filtered through a short silica gel column and
eluted with Et2O until the product could no longer be de-
tected (TLC). The filtrate was then concentrated in vacuo and
the residue dissolved in 1 M NaOH (10 mL) and washed
with Et2O (2 × 10 mL). The aqueous phase was acidified
with 2 N H2SO4 and extracted with ethyl acetate (7 × 10 mL).
The combined organic layers were dried (MgSO4) and con-
centrated, and the residue was purified by flash chromatog-
raphy.
Meth od C. Dry ozone was bubbled through a cooled (-78
°C) solution of hydrazone 4 (1 mmol) in acetone (25 mL) until
appearance of a permanent blue color. The solution was then
treated with a solution of the J ones reagent (15 mL, 10 mmol),
and the reaction mixture was allowed to warm to rt and
concentrated. The residue was dissolved in 1 M NaOH (10
mL) and washed with Et2O (2 × 10 mL). The aqueous phase
was acidified with 2 N H2SO4 and extracted with ethyl acetate
(7 × 10 mL). The combined organic layers were dried (MgSO4)
and concentrated, giving the pure product. Eluants, yields,
and spectral and analytical data for compounds 9 are as
follows:
(R)-4-Oxo-2,4-d ip h en ylbu tyr ic Acid [(R)-9h ]. Following
method B from 6h , flash chromatography (1:4 f 1:1 Et2O-
PE) gave 79 mg (31%) of crystalline (R)-9h : mp 161-162 °C;
[R]22D -92.9° (c 1.2, CHCl3). Spectral and analytical data were
in good agreement with those reported for the racemic form.50
Syn th esis of (2R,3R)-2,3-Bu ta n ed iol-Der ived Keta ls 10.
To a solution of ketone 8 (1 mmol) and (2R,3R)-2,3-butanediol
(0.18 mL, 2 mmol) in dry benzene (25 mL) was added p-TsOH
(cat.), and the mixture was refluxed with azeotropic removal
of water until TLC indicated total consumption of the starting
material (ca. 1 h). The mixture was then neutralized (NaH-
CO3, solid), concentrated, and purified by flash chromatogra-
phy. Eluants, yields, and spectral and analytical data for
compounds 10 are as follows:
10a . By use of 8a , flash chromatography (1:6 f 1:1 Et2O-
PE) gave 154 mg (85%) of crystalline 10a : mp 34-35 °C; [R]22
D
1
-18.2° (c 1, CHCl3); H NMR (500 MHz, CDCl3) δ 1.23-1.26
(m, 6H), 1.81-1.87 (m, 1H), 1.95-2.03 (m, 2H), 2.09 (dd, 1H,
J ) 13.5, 9.8 Hz), 2.16-2.25 (m, 1H), 2.23 (ddd, 1H, J ) 13.5,
8.2, 1.0 Hz), 2.81-2.88 (m, 1H), 3.53-3.61 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 16.4, 16.5, 25.2, 28.0, 36.3, 41.4, 78.3, 78.5,
114.8, 121.9; IR (KBr, cm-1) 2239; mass spectrum m/ z (rel
intensity) 181 M+ (11), 153 (100). Anal. Calcd for C10H15
-
NO2: C, 66.27; H, 8.34; N, 7.73. Found: C, 65.96; H, 8.46, N,
7.63.
3-Oxocyclop en ta n eca r boxylic Acid (r a c-9a ). Following
method C, use of 4a yielded pure 9a (119 mg, 93%). Spectral
and analytical data were in good agreement with those
reported.31
10e. By use of 8e, flash chromatography (1:4 Et2O-PE)
gave 184 mg (88%) of 10e as an oil: [R]22D -45.1° (c 1, CHCl3);
1H NMR (500 MHz, CDCl3) δ 1.23 (d, 3H, J ) 5.5 Hz), 1.25-
1.32 (m, 1H), 1.28 (d, 3H, J ) 5.6 Hz), 1.40 (s, 3H), 1.43-1.48
(m, 1H), 1.50 (d, 1H, J ) 13.5 Hz), 1.70-1.77 (m, 2H), 1.85-
1.92 (m, 1H), 1.93-1.98 (m, 1H), 2.05 (dt, 1H, J ) 13.5, 1.9
Hz), 3.58-3.72 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 16.8,
20.6, 27.7, 33.5, 35.4, 36.4, 45.9, 78.0, 78.7, 106.1, 124.3; IR
(film, cm-1) 2236; mass spectrum m/ z (rel intensity) 209 M+
(23), 127 (100). Anal. Calcd for C12H19NO2: C, 68.87; H, 9.15;
N, 6.69. Found: C, 68.57; H, 9.17, N, 6.73.
(R)-3-Oxocyclop en ta n eca r boxylic Acid [(R)-9a ]. Fol-
lowing method A from 6a , flash chromatography (1:4 Et2O-
PE) gave 108 mg of (R)-9a (84%) as an oil: [R]22 +21.8° (c
D
1.9, CH3OH) [lit.31 [R]21D +22.1° (c 1.9, CH3OH)]. Spectral data
were in good agreement with those previously reported.31
(1R,2R)-2-Met h yl-3-oxocyclop en t a n eca r b oxylic Acid
[(R,R)-9c]. Following method B from 6c, flash chromatogra-
phy (1:1 Et2O-PE) gave 39 mg (28%) of crystalline (R,R)-9c:
10f. By use of 8f, flash chromatography (1:20 f 1:6 Et2O-
1
mp 84-86 °C; [R]22 +66.6° (c 1, CHCl3); H NMR (500 MHz,
PE) gave 172 mg (77%) of 10f as an oil: [R]22 -38.1° (c 1,
D
D
CDCl3) δ 1.19 (d, 3H, J ) 7.0 Hz), 2.04 (dtd, 1H, J ) 12.5,
10.9, 8.7 Hz), 2.23 (ddd, 1H, J ) 19.0, 11.0, 9.0 Hz), 2.36 (dddd,
1H, J ) 12.5, 8.7, 6.7, 1.9 Hz), 2.42-2.50 (m, 1H), 2.51 (ddt,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.09 (s, 3H), 1.12 (s, 3H),
1.20-1.24 (m, 6H), 1.47 (ddd, 1H, J ) 13.7, 4.7, 3.4 Hz), 1.54
(td, 1H, J ) 13.6, 3.9 Hz), 1.58-1.62 (m, 1H), 1.71 (td, 1H, J
) 13.4, 4.7 Hz), 1.87-1.92 (m, 2H), 2.68 (dd, 1H, J ) 9.9, 7.0
Hz), 3.57-3.65 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 16.4,
16.7, 20.0, 29.6, 31.9, 32.4, 35.2, 35.6, 37.7, 78.0, 78.2, 105.8,
120.4; IR (film, cm-1) 2236; mass spectrum m/ z (rel intensity)
223 M+ (4), 127 (100) Anal. Calcd for C13H21NO2: C, 69.92;
H, 9.48; N, 6.27. Found: C, 70.16; H, 9.59, N, 6.17
1H, J ) 18.8, 8.8, 1.7 Hz), 2.70 (td, 1H, J ) 11.0, 6.7 Hz); 13
C
NMR (125 MHz, CDCl3) δ 13.1, 24.2, 36.6, 47.3, 48.7, 179.6,
217.4; IR (KBr, cm-1) 3380-2810, 1734, 1717; mass spec-
trum m/ z (rel intensity) 142 M+ (68), 97 (58), 69 (100).
Anal. Calcd for C7H10O3: C, 59.14; H, 7.09. Found: C, 59.08;
H, 7.22.
3-Oxocycloh exa n eca r boxylic Acid (r a c-9d ). Following
method C, use of 4d yielded pure 9d (131 mg, 92%). Spectral
and analytical data were in good agreement with those
previously reported.49
Ack n ow led gm en t. We thank the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica for financial sup-
port (Grant No. PB 94/1429). We also thank the Min-
isterio de Educacio´n y Ciencia for a doctoral fellowship
to E.D. and a postdoctoral fellowship to E.M.-Z.
(R)-1-Meth yl-3-oxocycloh exa n eca r boxylic Acid [(R)-
9e]. Following method B from 6e, flash chromatography (1:1
Et2O-PE) gave 72 mg (46%) of (R)-9e as an oil: [R]22 -14.0°
D
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 3a , 3a ′, 3d , 3d ′, 3f, 3g, 3h , 3h ′, 4a ,
4b, 4f, 5b, 5c, 6a , and 7g (35 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(c 1, CHCl3). Spectral and analytical data were in good
agreement with those reported for the racemic form.47
(S)-2,2-Dim eth yl-5-oxocycloh exan ecar boxylic Acid [(S)-
9f]. Following method B from 6f, flash chromatography (1:2
Et2O-PE) gave 109 mg (64%) of crystalline (S)-9f: mp 103-
104 °C; [R]22 +18.8° (c 0.8, CHCl3). Spectral and analytical
D
data were in good agreement with those reported for the
racemic form.41
J O970481D
(49) Marchand, A. P.; Sharma, R.; Zope, U. R.; Watson, W. H.;
Kashyap, R. P. J . Org. Chem. 1993, 58, 759.
(50) Hussain, S. A. M. T.; Ollis, W. D.; Smith, C.; Stoddart, J . F. J .
Chem. Soc., Perkin Trans. 1 1975, 1480.