1-amino-3-siloxy-1,3-butadienes: Highly reactive dienes for the Diels- Alder reaction

Article abstract of DOI:10.1021/jo981563k

1-Amino-3-siloxy-1,3-butadienes represent a novel class of heteroatom- containing dienes with several useful properties. These dienes can be prepared efficiently by deprotonation of readily available vinylogous amides with potassium hexamethylsilazide, followed by silylation of the corresponding potassium enolates. This protocol has been found to be quite general for the preparation of various dienes containing different silyl and amino groups. Amino siloxy dienes readily undergo [4 + 2] cycloadditions with a wide range of electron-deficient dienophiles. The reactions generally occur under very mild conditions to afford the corresponding [4 + 2] adducts in high yields and with complete regioselectivity. High endo selectivity is observed in the case of N-phenylmaleimide and methacrolein. Other cycloadducts are usually obtained as mixtures of endo/exo diastereomers. The cycloadducts are versatile synthetic intermediates. They can be subjected to deprotonation, reduction, and Wittig olefination without any hydrolysis or elimination. In addition, the elimination of the amino group can be cleanly accomplished under acidic conditions leading to the formation of enones. A variety of substituted cyclohexenones can be prepared by this procedure.

Full text of DOI:10.1021/jo981563k

J . Org. Chem. 1999, 64, 3039-3052
3039
1-Am in o-3-siloxy-1,3-bu ta d ien es: High ly Rea ctive Dien es for th e
Diels-Ald er Rea ction
Sergey A. Kozmin, J acob M. J aney,‡ and Viresh H. Rawal*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637
Received August 4, 1998 (Revised Manuscript Received February 2, 1999)
1-Amino-3-siloxy-1,3-butadienes represent a novel class of heteroatom-containing dienes with several
useful properties. These dienes can be prepared efficiently by deprotonation of readily available
vinylogous amides with potassium hexamethylsilazide, followed by silylation of the corresponding
potassium enolates. This protocol has been found to be quite general for the preparation of various
dienes containing different silyl and amino groups. Amino siloxy dienes readily undergo [4 + 2]
cycloadditions with a wide range of electron-deficient dienophiles. The reactions generally occur
under very mild conditions to afford the corresponding [4 + 2] adducts in high yields and with
complete regioselectivity. High endo selectivity is observed in the case of N-phenylmaleimide and
methacrolein. Other cycloadducts are usually obtained as mixtures of endo/ exo diastereomers. The
cycloadducts are versatile synthetic intermediates. They can be subjected to deprotonation,
reduction, and Wittig olefination without any hydrolysis or elimination. In addition, the elimination
of the amino group can be cleanly accomplished under acidic conditions leading to the formation of
enones. A variety of substituted cyclohexenones can be prepared by this procedure.
In tr od u ction
the difficulty of their preparation, which frequently
involved pyrolytic eliminations of the corresponding
acetals, synthetic applications of these dienes remained
limited for many years.
Over the 70 years since its report by Diels and Alder,
the synthetic potential of the Diels-Alder reaction has
been greatly expanded through modifications of the diene
and dienophile components.1 The initial empirical obser-
vations that introduction of lone-pair containing hetero-
atoms onto the diene structure leads to an increase in
the rate and regioselectivity of the cycloadditions proved
to be essential in designing more reactive and specifically
functionalized dienes.2 These experimental results were
further supported by theoretical and computational stud-
ies.3 Over the years, various elements of the periodic table
have been incorporated into the diene structures.2a
The simple monoalkoxy dienes 1 and 2 were among
the first examples of heteroatom-substituted dienes used
in [4 + 2] cycloadditions.4 Several dialkoxy dienes, such
as 3, 4, and 5, were reported soon after the discovery of
the Diels-Alder reaction.5 However, mainly because of
The discovery of efficient synthetic methods for the
conversion of carbonyl compounds into silyl enol ethers6
allowed the preparation of various siloxydienes, such as
6 and 7, which have become much more popular than
their alkoxy counterparts.7 The most significant advance
among siloxy dienes is the development of 1-methoxy-3-
trimethylsiloxy-1,3-butadiene (8) by Danishefsky,8 after
whom the diene is named. The enormous popularity of
this diene stems from its high reactivity toward a range
of dienophiles, including heterodienophiles, as well as the
ease of conversion of its cycloadducts to enones and to
aromatic and heterocyclic compounds.9 Among the other
siloxy dienes prepared over the years, one that merits
mention is the trioxygenated diene 9, in which the
‡ Recipient of the Pfizer Undergraduate Summer Research Fellow-
ship in Synthetic Organic Chemistry (1997).
(1) (a) Kloetzel, M. C. Org. React. 1948, 4, 1. (b) Holmes, H. C. Org.
React. 1948, 4, 60. (c) Butz, L. W.; Rytina, A. W. Org. React. 1949, 5,
136. (d) Onishenko, A. S. Diene Synthesis; Daniel Davy & Co.: New
York, 1964. (e) Oppolzer, W. In Comprehensive Organic Synthesis;
Pergamon Press: New York, 1991; Vol. 5.
(2) (a) Petrzilka, M.; Grayson, J . I. Synthesis 1981, 753. (b)
Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley:
New York, 1990.
(3) (a) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital
Symmetry; Verlag Chemie: Weinheim, 1970. (b) Fleming, I. Frontier
Orbitals and Organic Chemical Reactions; Wiley: London, 1976. (c)
Herndon, W. C. Chem. Rev. 1972, 72, 157. (d) Sauer, J .; Sustamnn, R.
Angew. Chem., Int. Ed. Engl. 1980, 19, 779. (e) Houk, K. N.; Li, Y.;
Evanseck, J . D. Angew. Chem., Int. Ed. Engl. 1992, 31, 682. (f) Houk,
K. N.; Gonzalez, J .; Li, Y. Acc. Chem. Res. 1995, 28, 81.
(4) (a) Petrov, A. A. Zh. Obshch. Khim. 1941, 11, 661. (b) Fiessel-
mann, H. Chem. Ber. 1942, 75, 881. (c) Wichterle, O. Collect. Czech.
Chem. Commun. 1938, 10, 497. (d) Flaig, W. Liebigs Ann. Chem. 1950,
568, 1.
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Chem. 1969, 34, 2324. (b) Stork, G.; Hudrlik, P. F. J . Am. Chem. Soc.
1968, 90, 4462.
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Girard, C.; Amice, P.; Barnier, J . P.; Conia, J . M. Tetrahedron Lett.
1974, 3329. (c) J ung, M. E.; McCombs, C. A. Tetrahedron Lett. 1976,
2935.
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Soc. 1941, 63, 131. (b) McElvain, S. M.; Morris, L. R. J . Am. Chem.
Soc. 1952, 74, 2657. (c) Shavrygina, O. A.; Makin, S. M. Khim. Farm.
Zh. 1969, 3, 17.
(8) Danishefsky, S.; Kitahara, T. J . Am. Chem. Soc. 1974, 96, 7807.
(9) Reviews: (a) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400. (b)
Danishefsky, S. J .; DeNinno, M. P. Angew. Chem., Int. Ed. Engl. 1987,
15. (c) Danishefsky, S. Chemtracts: Org. Chem. 1989, 2, 273.
10.1021/jo981563k CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/06/1999

3040 J . Org. Chem., Vol. 64, No. 9, 1999
Kozmin et al.
Sch em e 1
enhanced nucleophilic character overrides the steric
problems associated with the (Z)-methoxy group.10
Amino dienes have also played an important role in
the development of the Diels-Alder reaction. 1-Amino-
substituted diene 10 was first reported in 1936.11 Al-
though relatively unstable, it was later found to be highly
reactive toward several dienophiles.12 The corresponding
1-N-acylamino-1,3-butadienes (11) appeared to be much
more stable, and several convenient protocols for their
preparation were developed.13 The usefulness of N-
acylaminodienes was demonstrated through the synthe-
ses of several alkaloids.14 Curiously, 2-aminodienes (12)
were predicted, on the basis of theoretical considerations,
to be unable to undergo [4 + 2] cycloadditions.15 Never-
theless, the Diels-Alder reactions of 2-aminodienes have
been successfully performed with various dienophiles.16
Especially noteworthy is the recent application of these
dienes in asymmetric synthesis.17
1-(dimethylamino)-3-ethoxy-1,3-butadiene (16) was pre-
pared by Meerwein in 1961,23 there is no report of its
use in the Diels-Alder reaction.
Inspection of the structure of 1-amino-3-siloxy-1,3-
butadienes (I) reveals the synergetic arrangement of the
nitrogen and oxygen substituents, which are set up to
confer these dienes with high reactivity in the normal
electron demand Diels-Alder reaction (Scheme 1). Fur-
ther analysis shows that the initial cycloadducts (II) can
potentially be converted to substituted cyclohexenones
(III). Although this initially projected sequence of events
is similar to the methodology developed by Danishefsky,9
the presence of the amino group was expected to offer
several significant advantages. First, the cycloadditions
of amino siloxy dienes will provide access to nitrogen-
containing compounds such as II, which potentially can
be useful intermediates in alkaloid synthesis. Second, as
a result of the higher nucleophilicity of the nitrogen atom,
amino siloxy dienes were expected to display reactivity
higher than that of the corresponding alkoxy siloxy diene
8. Finally, the amino group in I provides an opportunity
for the introduction of chirality into the diene structure,
which would allow for an extension of this methodology
to asymmetric synthesis.
Indeed, in a recent communication we showed that the
parent 1-(dimethylamino)-3-siloxy-1,3-butadiene can be
efficiently made by the silylation of the corresponding
vinylogous amide and that it displays high reactivity in
[4 + 2] cycloadditions with several dienophiles.24a Another
attractive feature of amino siloxy dienes, the possibility
for asymmetric induction, was demonstrated by introduc-
ing a chiral, C2-symmetric amino group and using the
resulting dienes for the asymmetric synthesis of various
The incorporation of both siloxy (or alkoxy) and amino
substituents into the diene structure has received sur-
prisingly little attention. The only examples found in-
clude cyclopentene-containing diene 13,18 amino siloxy
furan 14,19 and N-acylamino siloxy dienes 15a 20 and
15b,21 and 15c.22 It is also very surprising that although
(10) (a) Banville, J .; Brassard, P. J . Chem. Soc., Perkin. Trans. 1
1976, 1853. (b) Danishefsky, S.; Etheridge, S. J . J . Org. Chem. 1978,
43, 4604. (c) Danishefsky, S.; Singh, R. K.; Gammil, R. B. J . Org. Chem.
1978, 43, 379.
(11) Mannich, C.; Handke, K.; Roth, K. Chem. Ber. 1936, 69, 2112.
(12) (a) Langebeck, W.; Godde, O.; Weschky, L.; Schaller, R. Chem.
Ber. 1942, 75, 232. (b) Hunig, S.; Kahanek, H. Chem. Ber. 1957, 90,
238.
(13) (a) Oppolzer, W.; Frostl, W. Helv. Chim. Acta 1975, 58, 590.
(b) Oppolzer, W.; Bieber, L.; Francotte, E. Tetrahedron Lett. 1979, 11,
981. (c) Oppolzer, W.; Bieber, L.; Francotte, E. Tetrahedron Lett. 1979,
47, 4537. (d) Overman, L. E.; Taylor, G. F.; J essup, P. J . Tetrahedron
Lett. 1976, 3089. (e) Overman, L. E.; Freerks, R. L.; Petty, C. B.; Clizbe,
L. A.; Ono, R. K.; Taylor, G. F.; J essup, P. J . J . Am. Chem. Soc. 1981,
103, 2817. (f) Overman, L. E.; Taylor, G. F.; Houk, K. N.; Domelsmith,
L. N. J . Am. Chem. Soc. 1978, 100, 3182.
(14) (a) Oppolzer, W.; Keller, K. J . Am. Chem. Soc. 1971, 93, 3836.
(b) Oppolzer, W.; Frostl, W. Helv. Chim. Acta 1975, 58, 593. (c)
Overman, L. E.; J essup, P. J . J . Am. Chem. Soc. 1978, 100, 5179. (d)
Overman, L., E.; Lesuisse, D.; Hashimoto, M. J . Am. Chem. Soc. 1983,
105, 5373. (e) Stork, G.; Morgans, D. J . J . Am. Chem. Soc. 1979, 101,
7110. (f) Rawal, V. H.; Michoud, C.; Monestel, R. F. J . Am. Chem. Soc.
1993, 115, 3030. (g) Rawal, V. H.; Iwasa, S. J . Org. Chem. 1994, 59,
2685.
(15) Koikov, L. N.; Terentev, P. B.; Gloriozov, I. P.; Bundal, Y. G. J .
Org. Chem. USSR (Engl. Transl.) 1984, 20, 832.
(16) Review: Enders, D.; Meyer, O. Liebigs Ann. Chem. 1996, 1023.
(17) (a) Review: Krohn, K. Angew. Chem., Int. Ed. Engl. 1993, 32,
1582. (b) Enders, D.; Meyer, O.; Raabe, G. Synthesis 1992, 1242. (c)
Barluenga, J .; Aznar, F.; Valdes, C.; Martin, A.; Garcia-Granda, S.;
Martin, E. J . Am. Chem. Soc. 1993, 115, 4403.
(18) Smith, A. B., III; Wexler, B. A.; Tu, C.-Y.; Konopelski, J . P. J .
Am. Chem. Soc. 1985, 107, 1308.
(20) Sundberg, R. J .; Amat, M.; Fernando, A. M. J . Org. Chem. 1987,
52, 3151.
(21) Comins, D. L.; Al-awar, R. S. J . Org. Chem. 1992, 57, 4098.
(22) Ludwig, C.; Wistrand, L.-G. Acta Chem. Scand. 1989, 43, 676.
(23) Meerwein, H.; Florian, W.; Schon, N.; Stopp, G. Liebigs Ann.
Chem. 1961, 641, 1.
(19) (a) Shlessinger, R. H.; Pettus, T. R. R. J . Org. Chem. 1994, 59,
3246. (b) Shlessinger, R. H.; Bergstrom, C. P. J . Org. Chem. 1995, 60,
16.
(24) (a) Kozmin, S. A.; Rawal, V. H. J . Org. Chem. 1997, 62, 5252.
(b) Kozmin, S. A.; Rawal, V. H. J . Am. Chem. Soc. 1997, 119, 7165. (c)
Kozmin, S. A.; Rawal, V. H. J . Am. Chem. Soc. 1998, 119, 113523.

1-Amino-3-siloxy-1,3-butadienes
J . Org. Chem., Vol. 64, No. 9, 1999 3041
Ta ble 1. P r ep a r a tion of Vin ylogou s Am id es
Sch em e 2
Sch em e 3
substituted cyclohexenones, as well as the terpene (-)-
R-elemene.24b We have also demonstrated the usefulness
of modified amino siloxy dienes in alkaloid synthesis
through an efficient, stereocontrolled synthesis of taber-
sonine.24c
The present paper provides a full account of our work
on the achiral amino siloxy dienes, including the details
of their preparation and their reactivity and stereo-
selectivity in [4 + 2] cycloadditions with numerous mono-
and diactivated dienophiles.
Several different procedures were evaluated to find the
most effective one for the conversion of the vinylogous
amides (17) into the corresponding 1-amino-3-siloxy-1,3-
butadienes (19). The use of a triethylamine-TMSCl
protocol6 resulted only in recovery of the starting mate-
rial. Deprotonation of the vinylogous amide with LDA
followed by addition of the silylating agent was also
unsuccessful, as silylation of the lithium enolate was
found to be slow at low temperature. Whereas addition
of DMPU did accelerate the silylation, removal of this
high-boiling polar additive proved impractical. The solu-
tion to the problem lay in the use of the more reactive
potassium or sodium enolates.
The best set of conditions for enolate formation in-
volved the addition of a solution of the vinylogous amide
in THF to 1.05 equiv of potassium hexamethyldisilazide
(KHMDS) dissolved in a 1:1 toluene/THF solution. The
completion of enolate formation was ensured by allowing
the temperature of the cooling bath to rise to -40 °C over
a 2 h period. Addition of 1.1 equiv of the silylating agent
to a cold solution of the enolate (-70 °C) followed by
warming of the reaction mixture to ambient temperature
resulted in the clean formation of the desired amino
siloxy dienes (19).
The procedure described above was found to be con-
venient and quite general, allowing the preparation of a
range of dienes (Table 2). In general, the 1-amino-3-
siloxy-1,3-dienes (19) are obtained in very high yields and
in essentially pure form. Simple filtration of the reaction
mixture, to remove the potassium chloride formed, and
evaporation of the volatile reagents under reduced pres-
sure afforded the dienes in quantitative yields. If neces-
sary, the crude dienes can be further purified by bulb-
to-bulb distillation. The amino siloxy dienes prepared by
this method were found to be quite stable to normal
Resu lts a n d Discu ssion
P r ep a r a tion of 1-Am in o-3-siloxy-1,3-d ien es. The
simplest, most direct route to 1-amino-3-siloxy-dienes (I)
was through silylation of the corresponding vinylogous
amides (IV), which in turn could be prepared in one of
two ways, as shown in a retrosynthetic sense in Scheme
2.
The first method represents the well-documented
Eschenmoser sulfide contraction procedure.25 N,N-Di-
methylthioformamide was first reacted with bromo-
acetone, followed by treatment with PPh3 and Et3N to
promote the sulfide contraction, which afforded the
desired vinylogous amide 17a in 76% yield after distil-
lation (Scheme 3). Although this reaction is preparatively
simple and was usually carried out in one pot, the
difficulty experienced with removing the large quantities
of triphenylphosphine sulfide produced made this pro-
cedure inconvenient, especially with preparative scale
reactions.
Alternatively, the required vinylogous amides (17) can
be efficiently prepared by the addition-elimination reac-
tion of secondary amines with vinylogous esters,26 such
as 4-methoxy-3-buten-2-one (18),27 as shown in Table 1.
This method was found to be much more convenient and
flexible and was utilized for the preparation of several
structurally and electronically varied vinylogous amides.
These reactions were quite facileseven moderately exo-
thermic with unhindered aminessbut required more
vigorous conditions with hindered amines (entry 3). In
all cases, however, the products were obtained in high
yield.
(27) Although 4-methoxy-3-buten-2-one (18) is commercially avail-
able, it can be more economically and conveniently obtained by heating
acetylacetaldehyde dimethyl acetal in the presence of NaOAc and
distilling the product out of the reaction mixture (see ref 26a). The
vinylogous amide (17a ) can also be obtained directly from acetyl-
acetaldehyde dimethyl acetal: Maggiulli, C. A.; Tang, P. W. Org. Prep.
Proc. Int. 1984, 16, 31.
(25) Review: Shiosaki, K. In Comprehensive Organic Synthesis;
Pergamon Press: New York, 1991; Vol. 2.
(26) (a) Lienhard, U.; Fahrni, H.-P.; Neuenschwander, M. Helv.
Chem. Acta 1978, 61, 1609. (b) Markova, N. K.; Zaichenko, Y. A.;
Tsil’ko, A. E.; Maretina, I. A. J . Org. Chem. USSR (Engl. Transl.) 1984,
20, 876.

3042 J . Org. Chem., Vol. 64, No. 9, 1999
Kozmin et al.
Ta ble 2. P r ep a r a tion of Am in o Siloxy Dien es
F igu r e 1. The extended boat conformation of cycloadduct 20.
Sch em e 5
Sch em e 4
Sch em e 6
handling and could be conveniently stored for several
months at low temperature. They do, however, hydrolyze
in water and in the presence of common Lewis acids.
Generally, TBSCl was used as the silylating reagent,
although silylation of the enolate with TIPSCl gave the
corresponding TIPS-protected diene 19b in similarly high
yield (entry 2). The parent TBDPS-protected diene was
synthesized using the standard procedure, but it could
not be further purified by Kugelrohr distillation. Dienes
protected with the TMS group were too labile to be
isolated in pure form and were always contaminated with
the starting vinylogous amide.
The standard protocol was also applied to the prepara-
tion of the dienes 19c-f containing sterically and elec-
tronically different amino groups (entries 3-6). Having
established an efficient access to various 1-amino-3-
siloxy-1,3-dienes, the stage was now set for probing their
behavior in [4 + 2] cycloadditions.
Cycloa d d ition s w ith Dou bly Activa ted Dien o-
p h iles. The initial Diels-Alder experiments were con-
ducted with 1-(dimethylamino)-3-siloxy-1,3-butadiene,
19a . Diene 19a reacted rapidly with N-phenylmaleimide,
even at -70 °C, and gave exclusively the endo adduct 20
in 96% yield after chromatography (Scheme 4). This and
the other cycloadducts described below are stable to
chromatography, provided the silica gel is pretreated with
triethylamine.
The structure of 20 was rigorously established by
means of 2D NMR spectroscopy. Figure 1 shows what
we believe to be the preferred conformation of this
cycloadduct. A COSY experiment allowed the unambigu-
ous assignment of all the signals in the 500 MHz 1H NMR
spectrum of 20. Proton H2 appeared at 3.39 ppm as a
doublet of doublets (J 1,2 ) 5.1 Hz, J 2,3 ) 6.3 Hz). The
methylene protons H5 and H6 were found at 2.43 and 2.76
ppm, respectively (J 5,6 ) 17.3 Hz). The large coupling
constant of 9.6 Hz between H5 and H4 indicated that
these protons are almost coplanar. On the other hand,
much smaller coupling was observed between H6 and H4
(J 4,6 ) 3.0 Hz). Combined with known literature prece-
dents,28 this initial analysis suggested that 20 exists in
a slightly distorted “extended”28a boat conformation, in
which the dimethylamino group occupies an axial posi-
tion. Further support for the assigned structure was
obtained from a NOESY29 experiment. The NOE cross-
peaks observed between H1 and H2, H2 and H3, and H4
and H,5 combined with the absence of cross-peaks be-
tween H4 and H6 or H2 and H6 provided additional
verification of the assignments shown.
The cycloaddition of 19a with diethyl acetylenedicar-
boxylate proceeded efficiently at 5 °C and directly gave
the aromatized product 21 (Scheme 5), presumably by
elimination of dimethylamine from the initially formed
cycloadduct under the reaction conditions. The reaction
of dimethylfumarate was complete after 15 h at 20 °C
and afforded in quantitative yield a 1.4:1 mixture of the
endo and exo cycloadducts (22a ), which were readily
separable by column chromatography (Scheme 5).
Initially, the reaction of amino siloxy diene 19a with
dimethyl maleate appeared not to be straightforward
(Scheme 6). When an excess of the dienophile was used,
the desired cycloadduct 23a was obtained in a modest
yield, accompanied by two other products, which were
identified as the endo and exo adducts (22b) of 19a with
dimethyl fumarate. The yield of 23a could be improved
(28) (a) Danishefsky, S.; Yan, C. F.; Singh, R.; Gammill, R.; McCurry,
P.; Fritsch, N.; Clardy, J . J . Am. Chem. Soc. 1979, 101, 7001-7007.
(b) Maddaluno, J .; Gaonach, O.; Marcual, A.; Toupet, L.; Giessner-
Prettre, C. J . Org. Chem. 1996, 61, 5290.
(29) States, D. J .; Haberkorn, R. A.; Ruben, D. J . J . Magn. Reson.
1982, 48, 286.

1-Amino-3-siloxy-1,3-butadienes
J . Org. Chem., Vol. 64, No. 9, 1999 3043
F igu r e 2. Conformational analysis of 23 and 24.
significantly by using an excess of diene 19a (2 equiv),
but even in this case the fumarate-derived products were
observed. We resisted the temptation to quickly rational-
ize this result by invoking a stepwise process for the
cycloaddition30 and decided to carry out additional ex-
periments to obtain support for or against a stepwise
process. In principle, the byproducts could form if the
expected Diels-Alder product (23a ), which contains a
tertiary amine unit, was catalyzing the isomerization of
dimethyl maleate to the fumarate, the latter being
thermodynamically more stable and significantly more
reactive. Support for this hypothesis was obtained through
an NMR experiment in which pure cycloadduct 23a was
mixed with dimethyl maleate in toluene-d8 and the
reaction was monitored for 8 days at 20 °C. At the end
of this period approximately 30% of the maleate was
converted into the fumarate. Additional support for the
isomerization hypothesis was obtained from the reaction
of dimethyl maleate with diene 19c, which gave the
expected Diels-Alder adduct 23b in 94% yield, with
complete stereospecificity (Scheme 6). The presence of the
more hindered amino groupsdiethyl instead of dimethyls
evidently slows down the conjugate addition-elimination
necessary to isomerize maleate to fumarate. Consistent
with this, when a mixture of cycloadduct 23b and
dimethyl maleate were observed by NMR, as described
above, less than 10% of the maleate was isomerized to
the fumarate after 8 days.
F igu r e 3. Conformational analysis of endo and exo cyclo-
adducts.
Ta ble 3. Cycloa d d ition s of Dien e 19a w ith
Mon oa ctiva ted Dien op h iles
The conformational analysis of the maleate cyclo-
adducts (23) proved to be nontrivial (Figure 2). On the
basis of the coupling constants between protons H1 and
H2, H2 and H3, and H3 and H4 (J 1,2 ) 5.0 Hz, J 2,3 ) 2.9
Hz, J 3,4 ) 3.6 Hz), it appeared that two out of the three
substituents in this cyclohexene ring were occupying
axial positions, a rather unusual situation. To more
rigorously establish the relative stereochemistry in the
proposed structures, the initial adducts 23 were subjected
to reduction with lithium aluminum hydride, which gave
the corresponding diols 24. The reduction was accompa-
nied by a change in preferred conformation of the
cyclohexene ring, as evidenced by the NMR coupling
constants (Figure 2). The pseudoequatorial orientation
of the dimethylamino group in 24 was evident from the
small coupling constant of 1.5 Hz between H1 and H2.
The cis relationship of the hydroxymethyl groups was
confirmed by the expected 3.5 Hz coupling constant
observed between H3 and H.4 Finally, the large coupling
constant of 10.0 Hz between H2 and H3 was diagnostic
of the trans diequatorial arrangement of the adjacent
amino and hydroxymethyl groups.
philes containing only one electron-withdrawing group.
The results of their cycloadditions with 1-(dimethyl-
amino)-3-siloxy-1,3-butadiene are summarized in Table
3. These reactions generally proceeded under relatively
mild conditions and afforded the cycloadducts in good
yields, with complete regioselectivity. The cycloadducts
in most cases are stable to flash chromatography, which
allowed the separation and spectroscopic characterization
of the endo and exo adducts.
The structures of these diastereomers were assigned
from their characteristic 1H NMR spectra. The endo
adducts (V) generally exist in the conformation in which
the amino group is pseudoaxial and the electron-
withdrawing group (E) is equatorial (Figure 3). The
preferred pseudoaxial orientation of the amino group is
presumably for stereoelectronic reasons. This arrange-
ment allows overlap between the occupied π-orbital of the
enol ether and σ* of the C-N bond.31 This arrangement
leads to diagnostic coupling constants between H1 and
Cycloa d d ition s w ith Mon oa ctiva ted Dien op h iles.
Next, we turned our attention to simple acyclic dieno-
(30) A stepwise mechnism was previously suggested to rationalize
a similar outcome of the reaction of 1-(dimethylamino)-1,3-butadiene
with dimethyl maleate: Sustmann, R.; Rogge, M.; Nuchter, U.;
Bandmann, H. Chem. Ber. 1992, 125, 1647.

3044 J . Org. Chem., Vol. 64, No. 9, 1999
Kozmin et al.
Ta ble 4. Cyloa d d ition of Meth yl Acr yla te w ith
H2, with J 1,2 ) 5 Hz. For the case when R3 ) H3, an
additional coupling is observed between H2 and H3, on
the order of 5-6 Hz. Conformational analysis of the exo
adducts (VI) follows the same logic as the endo adduct.
The only difference is that the nitrogen substituent now
becomes pseudoequatorial, and very small coupling is
observed between H1 and H2 (J 1,2 ) 1.5-2.0 Hz). For
cases where R3 ) H3, the additional diaxial coupling
constant, J 2,3 ) 10 Hz, further confirms the assignment.
Dia lk yla m in o Siloxy Dien es
The reaction of diene 19a with methacrolein was
determined to be complete in less than 5 h at 20 °C and
was highly stereoselective, affording exclusively the endo
adduct 25 in 87% isolated yield (entry 1, Table 3).
Cycloadditions with methyl acrylate, methyl vinyl ketone,
and acrylonitrile also proceeded at room temperature and
afforded the corresponding cycloadducts 26-28 in good
overall yields (entries 2-4). However, in contrast to the
high endo selectivity observed with methacrolein, the
other cycloadditions were less selective and gave signifi-
cant amounts of exo isomers. The cycloaddition with
methyl vinyl ketone was conducted in toluene at 20 °C
and was found to give a 1.1:1 ratio of endo/ exo isomers.
The isomer ratio was not affected significantly either by
using a more polar solvent (THF, CHCl3, or CH3CN) or
by starting the reaction at lower temperatures. Simple
steric effects also did not give a predictable outcome.
Compared to methyl acrylate, the sterically more
demanding tert-butyl acrylate was expected to be less
reactive and therefore more selective in disfavoring the
endo approach of the diene. The reaction was indeed
slower, requiring 3 days at 20 °C to reach completion,
but the stereoselectivity was surprisingly similar (entry
5). Higher temperatures were required for the cyclo-
additions of dienophiles containing additional substitu-
ents at either the R or â position. The reaction with
methyl methacrylate (entry 6) was carried out at 70 °C
and gave a 2:1 mixture of the endo/ exo adducts in 74%
yield. Methyl crotonate and methyl cinnamate exhibited
very similar behavior (entries 7 and 8). Both cycloaddi-
tions required heating the reaction mixture to 90 °C and
yielded a 3:1 mixtures of cycloadducts, with the exo
adducts predominating.
amino siloxy dienes, we examined the reaction of methyl
acrylate with dienes containing a few different amino
groups. The results of this study are presented in Table
4.
It was found that although dienes possessing the
diethylamino and pyrrolidinyl groups (19c and 19e;
entries 1 and 3) displayed reactivity similar to that of
the parent diene 19a , the sterically more encumbered
diisopropylamino-substituted diene (19d ) was less reac-
tive (entry 2). The less electron-rich indoline-substituted
diene (19f) exhibited reactivity markedly lower than that
of the dialkyl-substituted dienes and required that the
reaction be carried out at 60 °C (entry 4). It may appear
intuitive that the steric bulkiness of the dialkylamino
group should influence the diastereoselectivity of the [4
+ 2] cycloadditions. This assumption turns out to not be
supported by facts. Whereas the observed exo selectivity
was higher in the case of the diethylamino-substituted
diene (19c) than for the dimethylamino diene (19a ),
suggesting that the bulkier nitrogen substituent disfavors
the endo approach of the dienophile (entry 1), the opposite
effect was found in the case of the diisopropylamino diene
(19d , entry 2). This and the other results in Table 4
indicate that although the reactivity of the diene follows
logical trends, the factors influencing the stereoselectivity
of these cycloadditions are not obvious and involve a
complex combination of steric and electronic effects of the
dienes and dienophiles.
Ep im er iza tion a n d Alk yla tion of Cycloa d d u cts.
In general, the low endo/ exo selectivity of the [4 + 2]
cycloaddition step is not of concern, because acid-
catalyzed hydrolysis of the â-aminoenolsilyl ether elimi-
nates the amino group (vide infra). If control of the
relative stereochemistry of the cycloadduct is important,
then it can potentially be improved by epimerization at
the acidic R-position to the electron-withdrawing group
in the cycloadduct mixture (VIIa /VIIb). This process
would allow the preferential formation of the thermody-
namically more stable trans isomer VIIb, in which both
of the substituents would occupy equatorial positions in
the cyclohexene ring (Scheme 7).
A comparison of the reaction conditions required for
the cycloadditions with amino siloxy diene 19 with those
reported for Danishefsky’s diene (8) revealed that the
reactions with the former were taking place at much
lower temperatures, as anticipated. For example, the
Diels-Alder reactions between Danishefsky’s diene and
several dienophiles, such as maleimide,32a dimethyl
acetylenedicarboxylate,32b methacrolein,32b and methyl
crotonate,32c were reported to occur at a 30-70 °C higher
temperature. The higher reactivity of dimethylamino-
siloxy diene 16a compared to that of methoxysiloxy diene
8 was unambiguously established through a study of
their kinetics.33
Rea ctivity of Differ en t Dia lk yla m in o Siloxy Di-
en es. In an effort to better understand the factors
influencing the reactivity and endo/ exo selectivity of
(31) Lessard, J .; Tan, P. V. M.; Martino, R.; Saunders, J . K. Can. J .
Chem. 1977, 55, 1015.
(32) (a) Baldwin, S. W.; Greenspan, P.; Alaimo, C.; McPhail, A. T.
Tetrahedron Lett. 1991, 32, 5877. (b) Danishefsky, S.; Kitahara, T.;
Yan, C. F.; Morris, J . J . Am. Chem. Soc. 1979, 101, 6996-7000. (c)
Vorndam, P. E. J . Org. Chem. 1990, 55, 3693.
The methyl acrylate adduct 26 was examined to
address this question. Although no reaction was observed
when the initial 1.5:1 mixture of isomers was treated
with t-BuOK in t-BuOH at room temperature, it was
(33) The results of this study have been submitted for publication:
Kozmin, S. A.; Green, M. T.; Rawal, V. H., submitted for publication.

1-Amino-3-siloxy-1,3-butadienes
J . Org. Chem., Vol. 64, No. 9, 1999 3045
Sch em e 7
Sch em e 8
F igu r e 4. Outcome of protonation and alkylation.
Sch em e 9
Sch em e 10
found that deprotonation with a stronger base followed
by aqueous quench led to the desired trans isomer (26b)
as the preponderant product. The best selectivity (94:6)
was obtained when the potassium enolate, formed by
deprotonation with KHMDS, was quenched at -78 °C
with water in THF (Scheme 8). The major product, 26b,
was isolated in 78% yield. Treatment of the same enolate
with an excess of methyl iodide was found to produce
cleanly the corresponding methylated product, 30a , as a
single diastereomer. Because the NMR spectra of the
product obtained were identical with the endo adduct of
methyl methacrylate (30a ) the cis relationship between
the amine and the ester unit was firmly assigned. It is
especially noteworthy that no products resulting from the
elimination of the amino group were observed in either
of these cases.
The opposite stereochemical outcome of protonation
and alkylation of 26 may be understood by considering
steric and stereoelectronic influences.34 On the basis of
an examination of molecular models, the most reasonable
low-energy conformation of the enolate is that shown in
Figure 4, in which the potassium may be further bound
by coordination with the basic amine. The reaction of the
strongly nucleophilic ester enolate 37 is expected to
involve an early transition state, in which approach by
a bulky electrophile, such as methyl iodide, is expected
to be controlled by steric factors.35 Alkylation would then
be favored from the equatorial face, so as to avoid steric
interactions with both the adjacent dimethylamino group
and the pseudoaxial hydrogen. The preferred axial pro-
tonation of enolate 37 can be rationalized by considering
initial protonation of the enolate oxygen. Subsequent
protonation (tautomerization) of the enol should be much
less exothermic and, on the basis of the Hammond
postulate, involve a late, product-like transition state,
favoring formation of the trans product.36 The possibility
cannot be ruled out that the protonated form of the amine
is responsible for the selective protonation of the enol
intermediate, an example of neighboring group participa-
tion.
F u r th er Tr a n sfor m a tion s of th e Cycloa d d u cts.
The products of the Diels-Alder reactions of amino siloxy
dienes are potentially versatile synthetic intermediates.
As anticipated, the â-amino enol silyl ether portion of the
cycloadduct VIII can be converted to the corresponding
enone X under acidic conditions, which promote the
hydrolysis of the silyl enol ether as well as â-elimination
of the amino group (Scheme 9).
In the case of the methacrolein adduct (25), two
different sets of conditions were developed. Subjection of
25 to 1.2 M aqueous HCl in THF cleanly afforded
4-formyl-4-methylcyclohexenone (38) in 96% yield (Scheme
10). Close monitoring of this reaction revealed that under
these conditions full consumption of the starting material
(25) requires from 15 to 24 h. The use of a 10% solution
of HF in CH3CN promotes this transformation even more
rapidly, and the reaction is usually complete within 1-2
h.
The Diels-Alder adducts are sufficiently stable that
certain chemical transformations can be carried out prior
to the hydrolysis step. For example, with cycloadduct 25,
the formyl group can be subjected to Wittig olefination
and the resulting product can be hydrolyzed to afford the
corresponding enone 39.
The hydrolysis and reactivity of the methyl acrylate
adduct (26) was examined next. Acid-mediated hydrolysis
of this compound was complicated by the formation of
the ester-conjugated enone 41 (Scheme 11). Typically,
direct exposure of 26 to either 10% solution of HF or HF-
pyridine complex in CH3CN led to a mixture of isomeric
enones 40 and 41 in 1:1-2:1 ratio. The way around this
complication was to first reduce the ester group with
lithium aluminum hydride, followed by HF-mediated
elimination, which gave exclusively 4-hydroxymethyl
(34) Evans, D. A. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic: Orlando, FL, 1984; Vol. 3, p 1.
(35) (a) House, H. O.; Bare, T. M. J . Org. Chem. 1968, 33, 943. (b)
Krapcho, A. P.; Dundulis, E. A. J . Org. Chem. 1980, 45, 3236. (c) Hogg,
J . A. J . Am. Chem. Soc. 1948, 70, 161.
(36) Formation of the trans product has also been reported during
the epimerization of a related, albeit simpler, enolate. Davies, S. G.;
Ichihara, O.; Lenoir, I.; Walters, I. A. S. J . Chem. Soc., Perkin Trans.
1 1994, 1411.

3046 J . Org. Chem., Vol. 64, No. 9, 1999
Kozmin et al.
Ta ble 5. P r ep a r a tion of Su bstitu ted Cycloh exen on es
Sch em e 12
Sch em e 13
Sch em e 11
that exposure of 20 to silica gel that was not pretreated
with triethylamine caused a very clean formation of the
dihydrophthalimide, 47. The acidity of the silica gel was
evidently sufficient to promote the elimination of the
amino group without hydrolysis of the silyl enol ether
moiety. Treatment of 47 with 10% HF solution for a
period of 5 h gave a mixture of enones 48 and 49 in a 3:1
ratio. Additionally, DDQ oxidation of 47 provided simple
conversion to the corresponding siloxy phthalimide (50),
obtained in 86% yield.
cyclohexenone (42) in 83% overall yield. Although this
longer sequence contains an additional reduction step,
it is very efficient and preparatively simple. In addition,
the hydroxyl group in the product can be potentially used
as a handle for further functionalization.
Cycloa d d ition s w ith Oth er Cyclic Dien op h iles.
Having established the conditions for hydrolysis/elimina-
tion of the cycloadducts, we examined the cycloaddition
reactions of several monoactivated cyclic dienophiles,
which were capable of providing access to different
bicyclic systems (Scheme 13). The Diels-Alder reaction
of diene 19a with cyclohexenone was performed in
toluene at 80 °C and afforded dienone 51 in 66% yield.
The amino group was eliminated under the reaction
conditions, presumably as a result of the increased acidity
of the hydrogen R to the ketone. Attempts to either isolate
the cycloadduct prior to elimination of the amino group
or convert 51 to the corresponding enone were unsuc-
cessful. Dihydropyrone 52 underwent the cycloaddition
at 80 °C and afforded the corresponding adduct, which
was not isolated but was converted to bicyclic lactone 53
as the sole product, isolated in 76% overall yield. Amino
siloxy diene 19a even reacts with trisubstituted dieno-
philes, which are known to be particularly unreactive in
Diels-Alder reactions. The reaction between 19a and (+)-
carvone (54) was carried out at 110 °C for 48 h and, after
The versatility of this reduction-hydrolysis protocol
for the preparation of different cyclohexenones is evident
from the different examples shown in Table 5. A wide
range of cyclohexenones substituted at the 4- and 5-posi-
tions are available by selecting the appropriate substi-
tution pattern in the dienophile component. Further
transformations of the cyclohexenone, using well prece-
dented conjugate addition, alkylation, and carbonyl
chemistry, could allow the synthesis of cyclohexanes
substituted at every position. As mentioned above, the
variable endo/ exo selectivity of the Diels-Alder reaction
does not diminish the usefulness of this approach to
cyclohexenones, because the amino group is eliminated
in the last step.
Tr a n sfor m a tion s of N-P h en ylm a leim id e Ad d u ct.
The conversion of the N-phenylmaleimide adduct 20 to
the corresponding enone 48 proved difficult (Scheme 12).
The use of either HCl or HF-mediated hydrolysis proce-
dures gave only mixtures of unidentified products, among
which 48 could not be detected. Fortunately, it was found

1-Amino-3-siloxy-1,3-butadienes
J . Org. Chem., Vol. 64, No. 9, 1999 3047
Gen er a l P r oced u r e A: P r ep a r a tion of Vin ylogou s
Am id es (17) by Am in a tion of Meth oxybu ten on e (18). To
a solution of methoxybutenone (18) (1.00 g, 10 mmol) in CH2-
Cl2 or THF (7-10 mL) was slowly added secondary amine (15
mmol) at the temperature specified (Table 1). The resulting
light yellow solution was stirred for 1-8 h. Concentration in
vacuo, followed by bulb-to-bulb distillation afforded the cor-
responding vinylogous amides 17a -e.
4-(Dim eth yla m in o)-3-bu ten e-2-on e (17a ). The reaction
was performed as described in General Procedure A by
addition of the commercially available 2 M solution of dimeth-
ylamine in THF (25 mL, 50 mmol) to methoxybutenone (4.08
g, 40.8 mmol) at 5 °C. Bulb-to-bulb distillation (125 °C, 0.25
mmHg) afforded 4.41 g (95%) of the title compound as a
colorless oil.
4-(Dieth yla m in o)-3-bu ten e-2-on e (17b). The reaction was
performed as described in General Procedure A by addition of
diethylamine (2.20 mL, 21.2 mmol) to a solution of methoxy-
butenone (1.41 g, 14.1 mmol) in CH2Cl2 (7 mL) at 5 °C. Bulb-
to-bulb distillation (140 °C, 0.25 mmHg) afforded 1.74 g (89%)
of the title compound as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 1.19 (t, J ) 7 Hz, 6H), 2.10 (s, 3H), 3.34 (m, 4H),
5.12 (d, J ) 13 Hz, 1H), 7.49 (d, J ) 13 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 11.0, 14.0, 42.8, 49.6, 95.5, 150.6, 194.9.
1H and 13C NMR spectra of this sample were in good agree-
ment with those reported for this compound.26
treatment of the crude reaction mixture with an excess
of HF, afforded the bicyclic enone 55 as a 1:1 mixture of
diastereomers.37
Con clu sion s
1-Amino-3-siloxy-1,3-butadienes represent a novel class
of heteroatom-containing dienes with several properties
that make them synthetically useful. They are prepared
efficiently by silylation of the corresponding, readily
available vinylogous amides. Amino siloxy dienes are
highly reactive, considerably more so than the analogous
dialkoxy dienes, and undergo [4 + 2] cycloadditions under
mild conditions with a broad range of electron-deficient
dienophiles. In the case of monoactivated dienophiles,
these reactions are completely regioselective. The result-
ing cycloadducts are versatile synthetic intermediates,
as they can be subjected to deprotonation, reduction, and
Wittig olefination without any hydrolysis or elimination.
In addition, elimination of the amino group can be
accomplished cleanly under acidic conditions, leading to
the formation of enones. A variety of substituted cyclo-
hexenones can be prepared using the chemistry presented
above. We are currently investigating applications of
amino siloxy dienes to the synthesis of alkaloid natural
products.24c
4-(Diisop r op yla m in o)-3-bu ten e-2-on e (17c). The reac-
tion was performed as described in General Procedure A by
heating a solution of diisopropylamine (8.3 mL, 59 mmol) and
methoxybutenone (0.59 g, 5.9 mmol) to 84 °C for 8 h. Bulb-
to-bulb distillation (175 °C, 0.25 mmHg) afforded 0.92 g (92%)
of the title compound as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 1.19 (d, J ) 6.6 Hz, 12H), 2.10 (s, 3H), 3.6-3.9 (m,
2H), 5.23 (d, J ) 13 Hz, 1H), 7.64 (d, J ) 13 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 19.5, 44.7, 48.4, 96.0, 147.1, 194.9; IR (neat)
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under a
nitrogen atmosphere. Tetrahydrofuran and diethyl ether were
purified by distillation from potassium/benzophenone ketyl.
Dichloromethane, benzene, toluene, and triethylamine were
distilled from calcium hydride. All other reagents were reagent
grade and were purified where necessary. KHMDS was used
from newly opened 100 mL bottles and was purchased from
Aldrich, Inc. Reactions were monitored by thin-layer chroma-
tography (TLC) using 250 mm Whatman precoated silica gel
plates. Flash column chromatography was performed over EM
Science Laboratories silica gel (230-400 mesh). Melting points
are uncorrected. 1H and 13C NMR chemical shifts are reported
as δ values (ppm) relative to TMS, the internal standard. Mass
spectra were from The Ohio State University Campus Chemi-
cal Instrumentation Center.
P r epar ation of 4-(Dim eth ylam in o)-3-bu ten e-2-on e (17a)
by th e Esch en m oser Con tr a ction P r oced u r e. To a solu-
tion of N,N-dimethylthioformamide (8.92 g, 0.10 mol) in CH2-
Cl2 (100 mL) was added bromoacetone (15 g, 0.11 mol) at 5
°C, and stirring was continued for 2 h at room temperature.
The resulting clear solution was diluted with 250 mL of CH2-
Cl2 and cooled to 5 °C. Triphenylphosphine (29 g, 0.11 mol)
was added in one portion followed by a dropwise addition of
Et3N (20 mL, 0.14 mol). The reaction mixture was stirred for
19 h at room temperature, concentrated under reduced pres-
sure to an approximate volume of 150 mL, and diluted with
750 mL of ether under constant stirring. To facilitate precipi-
tation of triphenylphosphine sulfide, the mixture was kept for
20 h at -20 °C and then filtered and concentrated under
reduced pressure. The resulting dark oil was purified by a high
vacuum distillation (0.5 mmHg, bp 100-120 °C), which
afforded 8.6 g (76%) of vinylogous amide 17a as a light orange
oil: 1H NMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 2.88 (br s, 3H),
2.99 (br s, 3H), 5.05 (d, J ) 12.8 Hz, 1H), 7.47 (d, J ) 12.8 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 28.0, 36.9, 44.5, 96.6, 152.6,
195.2. 1H and 13C NMR spectra of this compound were in good
agreement with those reported in the literature.26
2974, 2934, 1646, 1551 cm-1
.
4-(P yr r olid in -1-yl)-3-bu ten e-2-on e (17d ). The reaction
was performed as described in General Procedure A by
addition of pyrrolidine (1.80 mL, 21.6 mmol) to a solution of
methoxybutenone (1.44 g, 14.4 mmol) in CH2Cl2 (7 mL) at 5
°C. Bulb-to-bulb distillation (140 °C, 0.25 mmHg) afforded 1.75
g (88%) of the title compound as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 1.96 (m, 4H), 2.10 (s, 3H), 3.15-3.49 (m, 4H),
5.01 (d, J ) 13 Hz, 1H), 7.68 (d, J ) 13 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 24.8, 44.2, 46.4, 51.8, 9.9, 148.2, 194.7. 1H and
13C NMR spectra of this sample were in good agreement with
those reported for this compound.33
4-(In d olin -1-yl)-3-bu ten e-2-on e (17e). The reaction was
performed as described in General Procedure A by addition of
indoline (1.88 mL, 16.8 mmol) to a solution of methoxybu-
tenone (2.02 g, 20.2 mmol) in CH2Cl2 (2 mL) at 20 °C. Bulb-
to-bulb distillation (215 °C, 0.1 mmHg) afforded 3.05 g (97%)
of the title compound as a pale yellow solid: mp 103-105 °C;
1H NMR (300 MHz, CDCl3) δ 2.22 (s, 3H), 3.23 (t, J ) 8.5 Hz,
2H), 3.82 (t, J ) 8.5 Hz, 2H), 5.36 (d, J ) 13 Hz, 1H), 6.93-
7.20 (m, 4H), 8.07 (d, J ) 13 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 27.5, 28.3, 48.0, 101.3, 108.6, 122.8, 125.6, 127.9,
130.9, 139.8, 143.8, 196.0; IR (neat) 3018, 1552, 1259, 1216,
755 cm-1
.
Gen er a l P r oced u r e B: P r ep a r a tion of 1-Am in o-3-
siloxy-1,3-bu ta d ien es (19). A solution of KHMDS in toluene
(0.5 M, 38.4 mL, 19.2 mmol) was diluted with THF (35 mL)
and cooled to -78 °C. To the resulting solution was added the
vinylogous amide 17 (18.3 mmol) in THF (17 mL) over a period
of 20 min. The reaction mixture was warmed to -30 °C over
a period of 3 h, cooled to -78 °C, and treated with trialkyl-
chlorosilane (20.1 mmol) dissolved in THF (15 mL). The
reaction mixture was allowed to reach room temperature,
diluted with ether (350 mL), filtered through dry Celite, and
concentrated in vacuo to give essentially pure amino siloxy
diene 19 as an oil which can be further purified by bulb-to-
bulb distillation.
(37) Harayama, T.; Cho, H.; Inubushi, Y. Chem. Pharm. Bull. 1978,
26, 1201.
(38) Marx, J . N.; Hahn, Y. S. J . Org. Chem. 1988, 53, 2866.
(39) Gloor, G.; Schaffner, K. Helv. Chim. Acta 1974, 57, 1815.
1-(Dim et h yla m in o)-3-(ter t-b u t yld im et h ylsiloxy)-1,3-
bu ta d ien e (19a ). The reaction was performed according to
General Procedure B. The title compound was obtained in 92%

3048 J . Org. Chem., Vol. 64, No. 9, 1999
Kozmin et al.
yield after bulb-to-bulb distillation (100 °C, 0.25 mmHg): 1H
NMR (500 MHz, CDCl3) δ 0.19 (s, 6H), 0.98 (s, 9H), 2.70 (s,
6H), 3.84 (s, 1H), 3.92 (s, 1H), 4.78 (d, J ) 13.2 Hz, 1H), 6.57
(d, J ) 13.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -4.6, 18.3,
25.9, 40.5, 85.8, 95.9, 140.9, 156.4; IR (neat) 2930, 1647, 1333,
Rea ction of Dien e 19a w ith Dieth yla cetylen ed ica r -
boxyla te. To a solution of diene 19a (350 mg, 1.54 mmol) in
benzene (10 mL) was added diethylacetylenedicarboxylate (187
mg, 1.10 mmol) at 5 °C. The reaction mixture was warmed to
room temperature, stirred overnight, and concentrated in
vacuo. The 1H NMR analysis of the crude reaction mixture
showed the formation of the aromatic product 21, which was
purified by flash chromatography on silica gel (elution with
14% EtOAc in hexanes) to afford 320 mg (84%) of a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 0.22 (s, 6H), 0.98 (s, 9H),
1.35 (t, J ) 7.1 Hz, 3H), 1.37 (t, J ) 7.1 Hz, 3H), 4.33 (q, J )
7.1 Hz, 2H), 4.35 (q, J ) 7.1 Hz, 2H), 6.91 (dd, J ) 8.3, 2.8 Hz,
1H), 7.02 (d, J ) 2.8 Hz, 1H), 7.74 (d, J ) 8.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ -4.5, 14.0, 14.1, 18.1, 25.5, 61.2, 61.6,
119.9, 121.4, 123.4, 131.3, 135.7, 158.5, 166.5, 168.1; IR (neat)
2931, 1725, 1602, 1302, 1120, 844 cm-1; HRMS m/z [M+] calcd
for C18H28O5Si 352.1706, found 352.1711.
1253, 1095, 828 cm-1
.
1-(Dim et h yla m in o)-3-(t r iisop r op ylsiloxy)-1,3-b u t a d i-
en e (19b). The reaction was performed according to General
Procedure B. The title compound was obtained in 90% yield
after bulb-to-bulb distillation (100 °C, 0.25 mmHg): 1H NMR
(300 MHz, CDCl3) δ 1.12 (d, 18H, J ) 6.8 Hz), 1.25 (m, 3H),
2.70 (s, 6H), 3.85 (s, 1H), 3.89 (s, 1H), 4.78 (d, J ) 13.2 Hz,
1H), 6.65 (d, J ) 13.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
12.9, 18.2, 40.6, 85.2, 96.0, 140.9, 156.6; IR (neat) 2944, 1647,
1334, 1094, 1022 cm-1
.
1-(Dieth ylam in o)-3-(ter t-bu tyldim eth ylsiloxy)-1,3-bu ta-
d ien e (19c). The reaction was performed according to General
Procedure B. The title compound was obtained in 95% yield
after bulb-to-bulb distillation (130 °C, 0.25 mmHg): 1H NMR
(300 MHz, CDCl3) δ 0.21 (s, 6H), 1.00 (s, 9H), 1.11 (t, J ) 7
Hz, 6H), 3.07 (q, J ) 7 Hz, 4H), 3.81 (s, 9H), 3.89 (s, 1H), 4.81
(d, J ) 13 Hz, 1H), 6.62 (d, J ) 13 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ -4.6, 13.1, 18.3, 25.9, 45.3, 84.7, 93.7, 138.3, 156.9;
Rea ction of Dien e 19a w ith Dieth yl F u m a r a te. To a
solution of diene 19a (340 mg, 1.50 mmol) in toluene (3.5 mL)
was added diethyl fumarate (180 mg, 1.02 mmol). The reaction
mixture was stirred for 15 h at room temperature and
concentrated in vacuo. The 1H NMR analysis of the crude
product mixture showed the formation of cycloadduct 22 as a
mixture of endo and exo isomers (406 mg, 100%, dr 1.4:1.0),
separated by flash chromatography on silica gel (elution with
33% ether in hexanes). Less polar endo adduct 22a : 1H NMR
(300 MHz, CDCl3) δ 0.15 (s, 3H), 0.16 (s, 3H), 0.92 (s, 9H),
1.24 (t, J ) 7.1 Hz, 3H), 1.25 (t, J ) 7.1 Hz, 3H), 2.06 (dddd,
J ) 17.1, 12.0, 1.8, 1.8 Hz, 1H), 2.23 (s, 6H), 2.33 (dd, J )
17.1, 6.0 Hz, 1H), 2.93 (dd, J ) 12.6, 6.9 Hz, 1H), 3.19 (ddd, J
) 12.6, 12.0, 6.0 Hz, 1H), 3.67 (ddd, J ) 6.0, 5.0, 1.8 Hz, 1H),
4.13 (q, J ) 7.1 Hz, 2H), 4.15 (m, 2H), 4.93 (dd, J ) 5.1, 1.8
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -4.5, 14.0, 17.9, 25.5,
32.5, 38.4, 43.3, 47.0, 58.7, 60.0, 60.6, 99.4, 151.3, 172.7, 174.7;
IR (neat) 2934, 2859, 1740, 1669, 1182, 838 cm-1. More polar
exo adduct 22b: 1H NMR (300 MHz, CDCl3) δ 0.15 (s, 3H),
0.16 (s, 3H), 0.92 (s, 9H), 1.24 (t, J ) 7.3 Hz, 3H), 1.25 (t, J )
7.3 Hz, 3H), 2.25 (s, 6H), 2.30 (m, 2H), 2.70 (dd, J ) 11.4, 10.0
Hz, 1H), 2.98 (ddd, J ) 11.4, 8.7, 8.1 Hz, 1H), 3.50 (dddd, J )
10.0, 2.0, 2.0, 2.0 Hz, 1H), 4.13 (m, 4H), 4.84 (br d, J ) 2.0
1H); 13C NMR (75 MHz, CDCl3) δ -4.7, -4.3, 14.0, 17.9, 25.5,
32.3, 40.4, 42.4, 45.5, 60.4, 60.8, 63.0, 102.0, 150.3, 173.0, 174.2;
IR (neat) 2959, 2859, 1645, 1251, 1113, 1022, 830, 781 cm-1
.
1-(Diisop r op yla m in o)-3-(ter t-bu tyld im eth ylsiloxy)-1,3-
bu ta d ien e (19d ). The reaction was performed according to
General Procedure B. The title compound was obtained in 85%
yield after bulb-to-bulb distillation (150 °C, 0.25 mmHg): 1H
NMR (300 MHz, CDCl3) δ 0.21 (s, 6H), 1.00 (s, 9H), 1.13 (d, J
) 6.6 Hz, 12H), 3.56 (sept, J ) 6.7 Hz, 2H), 3.76 (s, 1H), 3.83
(s, 1H), 4.86 (d, J ) 13.5 Hz, 1H), 6.78 (d, J ) 13.5 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ -4.6, 18.2, 21.7, 25.9, 46.1, 83.8,
92.5, 133.9, 157.3; IR (neat) 2960, 2920, 2850, 1640, 1601,
1305, 1245, 1022, 810, 760 cm-1
.
1-(P yr r olidin -1-yl)-3-(ter t-bu tyldim eth ylsiloxy)-1,3-bu ta-
d ien e (19e). The reaction was performed according to General
Procedure B. The title compound was obtained in 89% yield
after bulb-to-bulb distillation (130 °C, 0.25 mmHg): 1H NMR
(300 MHz, CDCl3) δ 0.196 (s, 6H), 0.975 (s, 9H), 1.86 (m, 2H),
3.12 (m, 2H), 3.80 (s, 1H), 3.89 (s, 1H), 4.73 (d, J ) 13 Hz,
1H), 6.82 (d, J ) 13 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
-4.5, 18.3, 25.2, 25.9, 48.8, 85.0, 95.1, 136.6, 156.7; IR (neat)
3026, 2920, 2850, 1601, 1492, 1451, 1372, 1328, 1312, 1028,
IR (neat) 2932, 1740, 1668, 1464, 1197, 840 cm-1
.
842, 758 cm-1
.
R ea ct ion of Dien e 19c w it h Dim et h yl Ma lea t e. To a
solution of diene 19c (510 mg, 2 mmol) in toluene (1 mL) was
added dimethyl maleate (375 mg, 3 mmol). The reaction
mixture was stirred for 3 days at room temperature and
concentrated in vacuo. The 1H NMR analysis of the crude
reaction mixture showed the formation of a single cycloadduct
(exo), which was isolated by flash chromatography on silica
gel (elution with 50% EtOAc in hexanes containing 1% Et3N)
to give 751 mg of cycloadduct 23b (94%) as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 0.13 (s, 3H), 0.14 (s, 3H), 0.92 (s,
9H), 1.03 (t, 6H, J ) 7.0 Hz), 2.31 (dd, J ) 17.6, 6.4 Hz, 1H),
2.55 (m, 3H), 2.70 (dq, 2H, J ) 14.0, 7.0 Hz), 3.07 (ddd, J )
10.4, 6.4, 4.0 Hz, 1H), 3.24 (dd, J ) 4.0, 3.4 Hz, 1H), 3.64 (s,
3H), 3.71 (s, 3H), 3.76 (m, 1H), 4.82 (d, J ) 5.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ -4.6, -4.4, 13.1, 17.9, 25.6, 29.0,
37.7, 42.4, 43.6, 51.7, 51.9, 56.5, 103.9, 152.2, 172.9, 174.1; IR
1-(In d olin -1-yl)-3-(ter t-bu tyld im eth ylsiloxy)-1,3-bu ta -
d ien e (19f). The reaction was performed according to General
Procedure B. The title compound was obtained in 90% yield
after bulb-to-bulb distillation (200 °C, 0.25 mmHg): 1H NMR
(300 MHz, CDCl3) δ 0.23 (s, 6H), 1.04 (s, 9H), 3.14 (t, J ) 8.7
Hz, 1H), 3.72 (t, J ) 8.7 Hz, 1H), 4.03 (s, 1H), 4.09 (s, 1H),
5.14 (d, J ) 13 Hz, 1H), 6.6-7.2 (m, 4H), 7.27 (d, J ) 13 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ -4.6, 18.3, 26.0, 27.5, 47.8,
88.8, 100.6, 106.2, 119.4, 125.0, 127.6, 128.1, 129.8, 146.0,
155.6; IR (CHCl3) 2955, 2929, 2857, 1644, 1596, 1491, 1319,
1276, 1023, 839, 780, 741 cm-1
.
Rea ction of Dien e 19a w ith N-P h en ylm a leim id e. To a
solution of diene 19a (407 mg, 1.80 mmol) in toluene (1 mL)
was added N-phenylmaleimide (208 mg, 1.20 mmol) in toluene
(2 mL) at -70 °C. The reaction mixture was stirred for 2 h at
-70 °C, allowed to reach room temperature, and concentrated
in vacuo. The NMR analysis of the crude reaction mixture
showed the formation of the single endo cycloadduct 20, which
was purified by flash chromatography on silica gel (elution
with 50% EtOAc in hexanes containing 5% Et3N) to afford 460
mg (96%) of a yellow oil: 1H NMR (500 MHz, CDCl3) δ 0.15
(s, 3H), 0.18 (s, 3H), 0.92 (s, 9H), 2.31 (s, 6H), 2.43 (dd, J )
17.3, 9.6 Hz, 1H), 2.76 (dd, J ) 17.3, 3.0 Hz, 1H), 3.31 (dd, J
) 9.5, 6.3 Hz, 1H), 3.36 (ddd, J ) 9.6, 9.5, 3.0 Hz, 1H), 3.39
(dd, J ) 6.3, 5.1 Hz, 1H), 5.01 (d, J ) 5.1 Hz, 1H), 7.27 (d, J
) 7.6 Hz, 2H), 7.36 (t, J ) 7.6 Hz, 1H), 7.44 (t, J ) 7.6 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ -4.7, -4.4, 17.9, 25.5, 27.3,
39.3, 43.4, 44.3, 61.2, 100.7, 126.3, 128.3, 129.0, 132.2, 152.2,
176.1, 178.5; IR (neat) 2930, 1714, 1659, 1363, 1202, 840, 754
cm-1; HRMS m/z [M+] calcd for C22H32N2O3Si 400.2182, found
400.2182.
(neat) 2931, 2858, 1734, 1668, 1259, 1173, 836 cm-1
.
Diol 24b . To a suspension of lithium aluminum hydride
(100 mg, 2.6 mmol) in ether (3 mL) was added at 0 °C diester
23b (265 mg, 0.66 mmol) dissolved in ether (4 mL). The
reaction mixture was allowed to reach room temperature,
stirred for 2.5 h, diluted with ether (20 mL), and quenched by
addition of a minimum amount of water. Anhydrous Na2SO4
was then added, and the organic layer was carefully decanted
from the solid, which was washed with ether (2 × 15 mL). The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo to give 210 mg (93%) of
diol 24b: 1H NMR (500 MHz, CDCl3) δ 0.10 (s, 3H), 0.11 (s,
3H), 0.89 (s, 9H), 1.05 (t, J ) 7.2 Hz, 6H), 1.91 (tt, J ) 10.0,
3.0 Hz, 1H), 2.06 (m, 1H), 2.13 (br d, J ) 17.5 Hz, 1H), 2.22
(m, 1H), 2.31 (dq, 2H, J ) 14.4, 7.2 Hz), 2.62 (dq, J ) 14.4, 7.2
Hz, 2H), 2.8 (br s, 1H), 3.41 (m, 1H), 3.55 (dd, J ) 10.3, 4.8

1-Amino-3-siloxy-1,3-butadienes
J . Org. Chem., Vol. 64, No. 9, 1999 3049
Hz, 1H), 3.66 (dd, J ) 10.0, 3.0 Hz, 1H), 3.84 (dd, J ) 10.0,
10.0 Hz, 1H), 4.77 (s, 1H), 6.5 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ -4.6, -4.3, 13.8, 17.9, 25.5, 32.4, 38.8, 39.2, 43.9,
59.8, 61.1, 67.9, 101.1, 151.8; IR (neat) 3300, 2830, 1662, 1463,
25.5, 27.7, 27.9, 41.1, 62.5, 101.9, 121.8, 152.8; IR (neat) 2929,
2240, 1652, 1456, 1253, 1204, 833 cm-1; HRMS m/z [M+] calcd
for C15H28N2OSi 280.1971, found 280.1958. More polar endo
adduct 28a : 1H NMR (300 MHz, CDCl3) δ 0.19 (s, 3H), 0.19
(s, 3H), 0.94 (s, 9H), 1.85 (m, 1H), 2.1 (m, 2H), 2.38 (m, 1H),
2.46 (s, 6H), 3.06 (ddd, J ) 5.3, 5.0, 3.3 Hz, 1H), 3.33 (m, 1H),
4.89 (m, 1H); 13C NMR (75 MHz, CDCl3) δ -4.6, -4.3, 17.9,
24.3, 25.6, 26.9, 28.5, 42.1, 61.3, 103.2, 120.8, 152.2; IR (neat)
2930, 2238, 1653, 1456, 1253, 1205, 839 cm-1; HRMS m/z [M+]
calcd for C15H28N2OSi 280.1971, found 280.1969.
1369, 1179, 839, 733 cm-1
.
Rea ction of Dien e 19a w ith Meth a cr olein . A solution
of diene 19a (1.14 g, 5.0 mmol) in toluene (3 mL) at 0 °C was
treated with methacrolein (294 mg, 0.35 mL, 4.2 mmol). The
reaction mixture was allowed to reach room temperature,
stirred for 3 h, and concentrated in vacuo. The 1H NMR
analysis of the crude reaction mixture showed the formation
of the single endo cycloadduct 25, which was purified by flash
chromatography on silica gel (elution with 33% ether in
hexanes containing 3% Et3N) to afford 1.08 g (87%) of a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.16 (s, 6H), 0.93
(s, 9H), 1.06 (s, 3H), 1.50 (m, 1H), 2.0-2.2 (m, 3H), 2.20 (s,
6H), 3.28 (d, J ) 5.0 Hz, 1H), 4.84 (d, J ) 5.0 Hz, 1H), 9.58 (s,
1H); 13C NMR (75 MHz, CDCl3) δ -4.4, 18.0, 20.4, 24.7, 25.6,
25.9, 43.1, 47.5, 65.4, 97.3, 153.6, 204.0; IR (neat) 2930, 1725,
1661, 1252, 1204, 838, 778 cm-1; HRMS m/z [M+] calcd for
Rea ction of Dien e 19a w ith ter t-Bu tyl Acr yla te. To a
solution of diene 19a (312 mg, 1.37 mmol) in toluene (1 mL)
was added tert-butyl acrylate (0.60 mL, 4.1 mmol) at 20 °C.
The reaction mixture was stirred for 64 h at room temperature
1
and concentrated in vacuo. The H NMR analysis of the crude
product mixture showed the formation of cycloadduct 29 as a
mixture of endo and exo isomers (437 mg, 90%, dr 1.0:1.4),
which were separated by flash chromatography on silica gel
(elution with 12% ether in hexanes containing 2% Et3N). Less
polar endo adduct 29a : 1H NMR (300 MHz, CDCl3) δ 0.15 (s,
3H), 0.16 (s, 3H), 0.93 (s, 9H), 1.46 (s, 9H), 1.80 (m, 1H),2.0
(m, 3H), 2.26 (s, 6H), 2.51 (ddd, J ) 12.7, 6.5, 4.2 Hz, 1H),
3.52 (dd, J ) 6.5, 5.0 Hz, 1H), 4.35 (d, J ) 5.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ -4.4 (2 carbons), 17.9, 20.9, 25.6,
28.1, 29.0, 43.7, 45.6, 59.1, 79.5, 100.3, 153.6, 173.3; IR (neat)
2930, 2859, 1734, 1662, 1365, 1150, 887, 858 cm-1. More polar
exo adduct 29b: 1H NMR (300 MHz, CDCl3) δ 0.14 (s, 3H),
0.15 (s, 3H), 0.92 (s, 9H), 1.45 (s, 9H), 1.9 (m, 2H), 2.1 (m,
2H), 2.26 (s, 6H), 2.41 (ddd, J ) 10.4, 8.4, 3.6 Hz, 1H), 3.64
(m, 1H), 4.81 (t, J ) 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ -4.5, -4.3, 17.9, 25.4, 25.6, 28.0, 28.9, 40.7, 42.4, 61.9, 79.9,
103.8, 152.2, 174.9; IR (neat) 2931, 2859, 1729, 1662, 1366,
C
16H31NO2Si 297.2124, found 297.2110.
Rea ction of Dien e 19a w ith Meth yl Acr yla te. A solution
of diene 19a (377 mg, 1.66 mmol) in toluene (2 mL) at 0 °C
was treated with methyl acrylate (0.134 mL, 1.5 mmol). The
reaction mixture was stirred for 14 h at room temperature and
concentrated in vacuo. The 1H NMR analysis of the crude
product mixture showed the formation of cycloadduct 26 as a
mixture of endo and exo isomers (380 mg, 92%, dr 1.0:1.5),
which were separated by flash chromatography on silica gel
(elution with 12% ether in hexanes containing 2% Et3N). Less
polar endo adduct 26a : 1H NMR (300 MHz, CDCl3) δ 0.16 (s,
6H), 0.93 (s, 9H), 1.83 (m, 1H), 2.0-2.2 (m, 3H), 2.27 (s, 6H),
2.62 (m, 1H), 3.56 (dd, J ) 5.0, 5.0 Hz, 1H), 3.70 (s, 3H), 4.95
(d, J ) 5.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -4.4, 18.0,
20.9, 25.6, 28.9, 43.5, 44.8, 51.3, 59.2 100.7, 153.7, 174.6; IR
(neat) 2980, 1743, 1662, 1253, 1196, 839, 780 cm-1; HRMS m/z
[M+] calcd for C16H31NO3Si 313.2073, found 313.2074. More
polar exo adduct 26b: 1H NMR (300 MHz, CDCl3) δ 0.14 (s,
3H), 0.15 (s, 3H), 0.92 (s, 9H), 1.7-2.0 (m, 2H), 2.0-2.2 (m,
2H), 2.24 (s, 6H), 2.52 (ddd, J ) 12.7, 9.2, 3.8 Hz, 1H), 3.66
(m, 1H), 3.70 (s, 3H), 4.84 (dd, J ) 2.0, 1.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ -4.5, -4.3, 18.0, 25.5, 25.6, 29.0, 40.6, 42.3,
51.7, 61.9, 102.6, 152.4, 176.0; IR (neat) 2980, 1734, 1662, 1253,
1193, 839, 779 cm-1; HRMS m/z [M+] calcd for C16H31NO3Si
313.2073, found 313.2068.
1147, 839 cm-1
.
Rea ction of Dien e 19a w ith Meth yl Meth a cr yla te. To
a solution of diene 19a (200 mg, 0.88 mmol) in toluene (1 mL)
was added methyl methacrylate (0.14 mL, 1.3 mmol). The
reaction mixture was stirred for 15 h at 70 °C and concentrated
1
in vacuo. The H NMR analysis of the crude product mixture
showed the formation of cycloadduct 30 as a mixture of endo
and exo isomers (215 mg, 74%, dr 2:1), which were separated
by flash chromatography on silica gel (elution with 9% ether
in hexanes containing 2% Et3N). Less polar endo adduct 30a :
1H NMR (300 MHz, CDCl3) δ 0.15 (s, 6H), 0.92 (s, 9H), 1.16
(s, 3H), 1.57 (ddd, J ) 13.5, 4.4, 1.2 Hz, 1H), 2.04 (m, 2H),
2.20 (m, 1H), 2.23 (s, 6H), 3.09 (dd, J ) 5.5, 1.0 Hz, 1H), 3.68
(s, 3H), 4.83 (dt, J ) 5.5, 1.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ -4.4, 18.0, 21.9, 25.6, 26.0, 26.4, 43.9, 46.5, 51.2, 65.8
98.6, 152.4, 177.2; IR (neat) 2931, 1734, 1652, 1456, 1252,
1179, 838, 778 cm-1; HRMS m/z [M+] calcd for C17H33NO3Si
327.2229, found 327.2206. More polar exo adduct 30b: 1H
NMR (300 MHz, CDCl3) δ 0.15 (s, 6H), 0.93 (s, 9H), 1.23 (s,
3H), 1.62 (ddd, J ) 13.0, 6.2, 6.2 Hz, 1H), 1.95 (m, 1H), 2.05
(m, 2H), 2.32 (s, 6H), 3.68 (s, 3H), 3.78 (m, 1H), 4.90 (m, 1H);
13C NMR (75 MHz, CDCl3) δ -4.4, -4.3, 18.0, 18.8, 25.6, 26.9,
30.9, 43.8, 46.9, 51.8, 63.2, 102.0, 151.6, 178.0; IR (neat) 2931,
1733, 1663, 1457, 1252, 1179, 838, 778 cm-1; HRMS m/z [M+]
calcd for C17H33NO3Si 327.2229, found 327.2222.
Rea ction of Dien e 19a w ith Meth ylcr oton a te. To a
solution of diene 19a (293 mg, 1.29 mmol) in toluene (1 mL)
was added methylcrotonate (0.41 mL, 3.9 mmol). The reaction
mixture was stirred for 7 h at 90 °C, concentrated in vacuo,
and purified by bulb-to-bulb distillation (160-200 °C, 0.25
mmHg). The 1H NMR analysis showed the formation of
cycloadduct 31 as a mixture of endo and exo isomers (368 mg,
87%, dr 1:3), which were separated by flash chromatography
on silica gel (elution with 15% ether in hexanes containing
2% Et3N). Less polar endo adduct 31a : 1H NMR (300 MHz,
CDCl3) δ 0.17 (s, 6H), 0.94 (s, 9H), 0.98 (d, J ) 5.6 Hz, 3H),
1.71 (ddt, J ) 17.0, 10.5, 3.1 Hz, 1H), 2.14 (dd, J ) 17.0, 5.0
Hz, 1H), 2.24 (s, 6H), 2.35 (m, 2H), 3.58 (m, 1H), 3.71 (s, 3H),
4.91 (dd, 1H, J ) 4.6, 1.7 Hz); 13C NMR (75 MHz, CDCl3) δ
-4.4, -4.3, 18.0, 20.9, 25.6, 26.9, 37.5, 42.9, 51.1, 52.3, 60.2,
99.0, 152.9, 173.7; IR (neat) 2931, 1745, 1669, 1365, 1197, 838,
779 cm-1; HRMS m/z [M+] calcd for C17H33NO3Si 327.2230,
found 327.2243. More polar exo adduct 31b: 1H NMR (300
Rea ction of Dien e 19a w ith Meth yl Vin yl Keton e. A
solution of diene 19a (220 mg, 0.97 mmol) in toluene (1 mL)
was treated with methyl vinyl ketone (0.15 mL, 2.0 mmol).
The reaction mixture was stirred for 3 h at room temperature,
1
and concentrated in vacuo. The H NMR analysis of the crude
product mixture showed the formation of cycloadduct 27 as a
mixture of endo and exo isomers (280 mg, 97%, dr 1.1:1.0): 1H
NMR (500 MHz, CDCl3) δ 0.14 (s, 3H, exo), 0.15 (s, 3H, exo),
0.17 (s, 3H, endo), 0.17 (s, 3H, endo), 0.92 (s, 9H, exo), 0.94 (s,
9H, endo), 1.72 (m, 2H), 1.81 (m, 1H), 2.05 (m, 5H), 2.19 (s,
6H, endo), 2.21 (s, 3H, exo), 2.22 (s, 3H, endo), 2.64 (m, 2H,
endo,exo), 3.64 (br d, J ) 10.7 Hz, 1H, exo), 3.76 (dd, J ) 6.5,
5.0 Hz, 1H, endo), 4.87 (t, J ) 2.0 Hz, 1H, exo), 4.96 (d, J )
5.0 Hz, 1H, endo); 13C NMR (125 MHz, CDCl3) δ -4.5, -4.4,
-4.3, -4.2, 17.9, 18.0, 20.3, 24.9, 25.6, 28.7, 29.0, 29.3, 40.7,
42.8, 49.7, 51.5, 58.8, 62.0, 98.3, 101.8, 152.4, 154.7, 209.3,
212.0.
Rea ction of Dien e 19a w ith Acr ylon itr ile. A solution of
diene 19a (219 mg, 0.96 mmol) in toluene (1 mL) at 0 °C was
treated with acrylonitrile (0.13 mL, 2.0 mmol). The reaction
mixture was allowed to reach room temperature, stirred for
1
15 h, and concentrated in vacuo. The H NMR analysis of the
crude product mixture showed the formation of cycloadduct
28 as a mixture of endo and exo isomers (231 mg, 85%, dr 1:4),
which were separated by flash chromatography on silica gel
(elution with 50% ether in hexanes containing 4% Et3N). Less
polar exo adduct 28b: 1H NMR (300 MHz, CDCl3) δ 0.15 (s,
3H), 0.17 (s, 3H), 0.92 (s, 9H), 1.90 (m, 1H), 2.15 (m, 3H), 2.32
(s, 6H), 2.68 (ddd, J ) 9.7, 7.6, 3.0 Hz, 1H), 3.47 (m, 1H), 4.80
(m, 1H); 13C NMR (75 MHz, CDCl3) δ -4.5, -4.4, 17.9, 24.4,

3050 J . Org. Chem., Vol. 64, No. 9, 1999
Kozmin et al.
MHz, CDCl3) δ 0.15 (s, 3H), 0.17 (s, 3H), 0.92 (m, 3H), 0.93 (s,
9H), 1.81 (m, 3H), 1.9-2.1 (m, 3H), 2.23 (s, 6H), 3.60 (m, 1H),
3.72 (s, 3H), 4.85 (t, J ) 2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ -4.6, -4.2 17.9, 19.3, 25.6, 31.6, 38.3, 40.4, 50.7, 51.4, 63.3,
101.9, 151.6, 175.9; IR (neat) 2931, 1739, 1663, 1369, 1194,
839 779 cm-1; HRMS m/z [M+] calcd for C17H33NO3Si 327.2230,
found 327.2229.
Rea ction of Dien e 19e w ith Meth yl Acr yla te. To a
solution of diene 19e (253 mg, 1.0 mmol) in toluene (1 mL)
was added methyl acrylate (0.14 mL, 1.5 mmol). The reaction
mixture was stirred for 37 h at 20 °C and concentrated in
vacuo. The 1H NMR analysis of the crude product mixture
showed the formation of cycloadduct 35 as a mixture of endo
and exo isomers (299 mg, 88%, dr 1:1), separated by flash
chromatography on silica gel (elution with 10% ether in
hexanes containing 2-5% Et3N). Less polar endo adduct 35a :
1H NMR (300 MHz, CDCl3) δ 0.149 (s, 6H), 0.923 (s, 9H), 1.64
(m, 4H), 1.83-2.09 (m, 4H), 2.61 (m, 5H), 3.67 (s, 3H), 3.7 (m,
1H), 4.93 (d, J ) 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
-4.4, 18.0, 20.8, 24.1, 25.6, 29.1, 45.1, 50.9, 51.2, 56.7, 101.1,
153.5, 174.7; IR (neat) 2932, 2857, 1743, 1662, 1364, 1253,
1187, 877, 839, 780 cm-1. More polar exo adduct 35b: 1H NMR
(300 MHz, CDCl3) δ 0.137 (s, 6H), 0.915 (s, 9H), 1.72 (m, 4H),
1.94-2.08 (m, 4H), 2.55-2.63 (m, 5H), 3.68 (s, 3H), 3.7 (m,
1H), 4.88 (t, J ) 1.35 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
-4.5, -4.4, 17.9, 23.8, 24.4, 25.6, 28.7, 43.8, 48.9, 51.6, 58.5,
103.2, 152.4, 175.7; IR (neat) 3097, 2802, 1743, 1661, 1364,
Rea ction of Dien e 19a w ith Meth yl Cin n a m a te. To a
solution of diene 19a (292 mg, 1.28 mmol) in toluene (1 mL)
was added methyl cinnamate (622 mg, 3.8 mmol). The reaction
mixture was stirred for 18 h at 90 °C and then concentrated
1
in vacuo. The H NMR analysis of the crude product mixture
showed the formation of cycloadduct 32 as a mixture of endo
and exo isomers (448 mg, 90%, dr 1:3), which were separated
by flash chromatography on silica gel (elution with 20% ether
in hexanes containing 1% Et3N). Less polar endo adduct 32a :
1H NMR (300 MHz, CDCl3) δ 0.18 (s, 6H), 0.92 (s, 9H), 2.18
(m, 1H), 2.30 (m, 1H), 2.32 (s, 6H), 3.08 (dd, J ) 12.6, 6.9 Hz,
1H), 3.45 (ddd, J ) 12.6, 11.4, 6.3 Hz, 1H), 3.50 (s, 3H), 3.72
(dd, J ) 6.9, 4.5 Hz, 1H), 5.01 (dd, J ) 4.5, 1.2 Hz, 1H), 7.3
(m, 5H); 13C NMR (75 MHz, CDCl3) δ -4.4, -4.3, 17.9, 25.6,
38.6, 38.7, 43.1, 50.7, 51.1, 60.1, 99.3, 126.3, 127.2, 128.4, 144.8,
152.6, 172.8; IR (neat) 2930, 2858, 1748, 1668, 1362, 1191, 838
cm-1; HRMS m/z [M+] calcd for C22H35O3NSi 389.2386, found
389.2385. More polar exo adduct 32b : 1H NMR (300 MHz,
CDCl3) δ 0.17 (s, 3H), 0.18 (s, 3H), 0.93 (s, 9H), 2.30 (m, 2H),
2.29 (s, 6H), 2.79 (dd, J ) 11.4, 10.2 Hz, 1H), 3.12 (ddd, J )
11.4, 11.4, 5.4 Hz, 1H), 3.86 (m, 1H), 4.94 (t, J ) 1.8 Hz, 1H),
7.3 (m, 5H); 13C NMR (75 MHz, CDCl3) δ -4.6, -4.3, 17.9,
25.5, 38.1, 40.5, 43.7, 49.8, 51.2, 63.6, 102.1, 126.8, 127.5, 128.3,
141.8, 151.6, 174.8; IR (neat) 2934, 2858, 1737, 1663, 1361,
1179, 833 cm-1; HRMS m/z [M+] calcd for C22H35O3NSi
389.2386, found 389.2373.
1255, 1194, 1040, 877, 835 cm-1
.
Rea ction of Dien e 19f w ith Meth yl Acr yla te. To a
solution of diene 19f (603 mg, 2.0 mmol) in toluene (1 mL)
was added methyl acrylate (0.9 mL, 10 mmol). The reaction
mixture was stirred for 3 h at 60 °C and concentrated in vacuo.
The 1H NMR analysis of the crude product mixture showed
the formation of cycloadduct 36 as a mixture of endo and exo
isomers (662 mg, 85%, dr 1.0:1.5). The crude product was
purified by flash chromatography on silica gel (elution with
10% ether in hexanes containing 2-5% Et3N), which did not
separate the two diastereomers: 1H NMR (300 MHz, CDCl3)
δ 0.10 (s, 6H, exo), 0.12 (s, 6H, endo), 0.91 (s, 9H, exo), 0.92 (s,
9H, endo), 1.94-2.16 (m, 8H, endo,exo), 2.70 (ddd, 1H, J )
11.0, 10.0, 3.5 Hz, exo), 2.80 (ddd, 1H, J ) 10.0, 6.0, 4.0 Hz,
endo), 2.8-3.0 (m, 4H, endo,exo), 3.30 (q, 1H, J ) 9.0 Hz),
3.42-3.51 (m, 3H, endo,exo), 3.52 (s, 3H, endo), 3.60 (s, 3H,
exo), 4.6-4.7 (m, 2H, endo,exo), 4.68 (br s, 1H, exo), 4.73 (d,
1H, J ) 5.5 Hz), 6.5-6.6 (m, 4H, endo,exo), 7.0-7.1 (m, 4H,
endo,exo); 13C NMR (75 MHz, CDCl3) δ -4.4, -4.5, 17.9, 21.3,
25.1, 25.6, 28.2, 28.5, 29.0, 43.4, 44.5, 47.0, 49.1, 51.4, 51.7,
51.8, 54.3, 101.2, 103.7, 106.5, 107.3, 116.8, 117.2, 124.2, 124.4,
127.0, 127.2, 129.1, 130.0, 150.8, 151.8, 153.2, 154.8, 173.8,
175.2; IR (neat) 2955, 2858, 1738, 1664, 1365, 1199, 868, 780,
Rea ction of Dien e 19c w ith Meth yl Acr yla te. To a
solution of diene 19c (511 mg, 2.0 mmol) in toluene (2 mL)
was added methyl acrylate (0.27 mL, 3.0 mmol). The reaction
mixture was stirred for 20 h at 20 °C and concentrated in
vacuo. The 1H NMR analysis of the crude product mixture
showed the formation of cycloadduct 33 as a mixture of endo
and exo isomers (584 mg, 86%, dr 1.0:2.5), which were
separated by flash chromatography on silica gel (elution with
10% ether in hexanes containing 2-5% Et3N). Less polar endo
adduct 33a : 1H NMR (300 MHz, CDCl3) δ 0.20 (s, 6H), 0.98
(s, 9H), 0.99(t, J ) 7.0 Hz, 6H), 1.90 (m, 1H), 2.11 (m, 3H),
2.45-2.66 (m, 5H), 3.77 (s, 3H), 4.9 (d, J ) 4.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ -4.4, 13.9, 17.5, 20.6, 25.6, 28.7, 45.5,
45.9, 51.0, 56.2, 102.9, 152.9, 174.3; IR (neat) 2931, 2859, 1743,
1633, 1364, 1259, 1194, 874, 839 cm-1. More polar exo adduct
33b: 1H NMR (300 MHz, CDCl3) δ 0.12 (s, 3H), 0.13 (s, 3H),
0.91(s, 9H), 0.99 (t, J ) 7 Hz, 6H), 1.90 (m, 1H), 2.10 (m, 3H),
2.37-2.47 (m, 5H), 3.67 (s, 3H), 3.77 (m, 1H), 4.8 (br s, 1H);
13C NMR (75 MHz, CDCl3) δ -4.6 (2 carbons), 14.7, 17.9, 25.3,
25.6, 29.2, 44.3, 44.7, 51.3, 58.6, 104.1, 151.7, 176.1; IR (neat)
742 cm-1
.
Ep im er iza tion of Ad d u ct 26. A solution of KHMDS in
toluene (0.5 M, 1.4 mL, 0.7 mmol) was diluted with THF (1.5
mL) and cooled to -78 °C. A solution of adduct 26 (174 mg,
0.55 mmol, 1:1.5 mixture of diastereomers) in THF (1 mL) was
added over a period of 5 min. The reaction mixture was
warmed to 0 °C over a period of 3 h, cooled to -78 °C, and
treated slowly with a 10:1 solution of THF-H2O (1.1 mL). The
reaction mixture was allowed to reach room temperature and
quenched by addition of 10 mL of water. The aqueous layer
was extracted with ether (2 × 30 mL), and the combined
organic extracts were dried over anhydrous MgSO4, filtered,
2935, 2897, 1740, 1654, 1363, 1179, 875, 837 cm-1
.
1
Rea ction of Dien e 19d w ith Meth yl Acr yla te. To a
solution of diene 19d (273 mg, 1.0 mmol) in toluene (1 mL)
was added methyl acrylate (0.14 mL, 1.5 mmol). The reaction
mixture was stirred for 37 h at 20 °C and concentrated in
vacuo. The 1H NMR analysis of the crude product mixture
showed the formation of cycloadduct 34 as a mixture of endo
and exo isomers (240 mg, 67%, dr 1.4:1.0). The crude product
was purified by flash chromatography on silica gel (elution
with 10% ether in hexanes containing 2-5% Et3N), which did
not separate the two diastereomers: 1H NMR (300 MHz,
CDCl3) δ 0.13 (s, 6H, exo), 0.15 (s, 6H, endo), 0.91(s, 9H, exo),
0.92(s, 9H, endo), 1.93-1.03 (m, 24H, endo, exo), 1.86-2.11
(m, 8H, endo, exo), 2.50 (m, 1H, exo), 2.61 (m, 1H, endo), 3.08
(m, 4H, endo, exo), 3.63 (s, 3H, endo), 3.64 (s, 3H, exo), 3.82
(m, 2H), 4.82 (br s, 1H, exo), 4.88 (d, 1H, J ) 5.0 Hz); 13C NMR
(75 MHz, CDCl3) δ -4.2, -4.3, -4.4, -4.5, 31.4, 21.5, 21.6,
23.7, 24.1, 25.3, 25.6, 28.5, 29.0, 45.0, 46.5, 46.7, 47.0, 50.3,
50.9, 51.1, 54.0, 106.7, 109.4, 126.9, 128.2, 151.1, 151.8, 174.5,
176.3; IR (neat) 2959, 2859, 1740, 1660, 1366, 1189, 880, 840
and concentrated. The H NMR analysis of the crude product
mixture showed the formation of a 94:6 mixture of trans/cis
diastereomers. Flash chromatography on silica gel (elution
with 33% hexanes in EtOAc containing 2% of Et3N) afforded
137 mg (78%) of the trans isomer 26b as a clear oil. 1H and
13C NMR spectra were identical to the same compound
described above.
Alk yla tion of Ad d u ct 26 w ith Iod om eth a n e. A solution
of KHMDS in toluene (0.5 M, 2.2 mL, 1.1 mmol) was diluted
with THF (2.5 mL) and cooled to -78 °C. A solution of adduct
26 (315 mg, 1.00 mmol, 1:1.5 mixture of diastereomers) in THF
(1.5 mL) was then added over a period of 5 min. The reaction
was allowed to warm to 0 °C and kept at this temperature for
15 min. The resulting solution of the enolate was added slowly
via cannula to iodomethane (0.62 mL, 10 mmol) dissolved in
THF (0.5 mL). Immediately after the addition was complete,
the reaction mixture was diluted with ether (50 mL) and
washed with water (10 mL). The organic layer was dried over
1
anhydrous MgSO4, filtered, and concentrated. H NMR analy-
cm-1
.
sis of the crude product mixture showed the formation of a

1-Amino-3-siloxy-1,3-butadienes
J . Org. Chem., Vol. 64, No. 9, 1999 3051
single diastereomeric product 30a , which was purified by flash
chromatography on silica gel (elution with 33% EtOAc in
hexanes containing 1% of Et3N) to afford 248 mg (76%) of a
colorless oil. 1H and 13C NMR spectra were identical to the
same compound described above.
Procedure C: 1H NMR (300 MHz, CDCl3) δ 1.60 (m, 1H), 1.82
(dddd, J ) 12.6, 12.6, 9.8, 5.0 Hz, 1H), 2.14 (dddd, J ) 12.6,
9.7, 5.0, 1.3 Hz, 1H), 2.42 (ddd, J ) 16.8, 12.6, 5.0, Hz, 1H),
2.56 (ddd, J ) 16.8, 5.0, 5.0 Hz, 1H), 2.65 (m, 1H), 3.71 (m,
2H), 6.08 (dd, J ) 10.0, 2.2 Hz, 1H), 6.96 (ddd, J ) 10.0, 2.7,
1.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 25.3, 36.6, 38.9, 65.1,
130.2, 151.5, 199.9; IR (neat) 3370, 2924, 2871, 1669, 1050,
845 cm-1; HRMS m/z [M+] calcd for C7H10O2 126.0681, found
126.0687.
4-F or m yl-4-m eth yl-2-cycloh exen e-1-on e (38). To a solu-
tion of 25 (130 mg, 0.44 mmol) in THF (3 mL) was added 1.2
M aqueous solution of HCl (1 mL). The reaction mixture was
stirred at room temperature for 24 h, diluted with water, and
extracted with ether. The combined organic layers were dried
over anhydrous MgSO4, concentrated, and purified by flash
chromatography on silica gel (elution with 50% ether in
hexane) to afford 58 mg (96%) of 38 as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 1.35 (s, 3H), 1.97 (m, 1H), 2.35 (m, 1H),
2.49 (m, 2H), 6.12 (d, J ) 9.6 Hz, 1H), 6.76 (d, J ) 9.6 Hz,
1H), 9.58 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 21.0, 29.5, 33.8,
48.4, 130.8, 149.0, 197.8, 199.9; IR (neat) 2930, 1726, 1679,
1457, 1230, 1117, 801 cm-1. The 1H NMR spectrum of this
compound was in agreement with that reported in the
literature.32b
4-Meth yl-4-vin yl-2-cycloh exen e-1-on e (39). A suspension
of methyl triphenylphosphonium bromide (3.00 g, 8.3 mmol)
in THF (15 mL) at 0 °C was treated with 2.17 M solution of
n-butyllithium in hexane (3.6 mL, 7.8 mmol). The resulting
yellow solution of the ylide was stirred for 30 min and then
cooled to -78 °C. A solution of cycloadduct 25 (1.64 g, 5.5 mmol)
in THF (10 mL) was added. The reaction mixture was allowed
to warm to room temperature and stirred for 16 h. Water (10
mL) was added, and the aqueous phase was extracted with
ether. The combined organic layers were washed with brine
and dried over anhydrous Na2SO4. Concentration in vacuo
afforded the expected olefinated product, which was carried
on to the hydrolysis step.
4-(Hyd r oxym eth yl)-4-m eth yl-2-cycloh exen e-1-on e (43).
The title compound was prepared in 85% yield according to
General Procedure C: 1H NMR (300 MHz, CDCl3) δ 1.17 (s,
3H), 1.56 (dd, J ) 6.0, 5.0 Hz, 1H), 1.78 (dddd, J ) 13.2, 5.7,
5.7, 1.0 Hz, 1H), 2.10 (ddd, J ) 13.2, 8.2, 6.8 Hz, 1H), 2.51 (m,
2H), 3.53 (dd, J ) 10.4, 6.0 Hz, 1H), 3.59 (dd, J ) 10.4, 5.0
Hz, 1H), 5.99 (d, J ) 10.0 Hz, 1H), 6.73 (d, J ) 10.0 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 21.9, 30.8, 33.9, 38.2, 69.8, 129.1,
155.9, 199.6; IR (neat) 3360, 2924, 1670, 1049, 804 cm-1
;
HRMS m/z [M+] calcd for C8H12O2 140.0837, found 140.0838.
The 1H NMR spectrum of this compound was in agreement
with that reported in the literature.39
tr a n s-4-(H yd r oxym et h yl)-5-p h en yl-2-cycloh exen e-1-
on e (44). The title compound was prepared in 86% yield
according to General Procedure C: 1H NMR (400 MHz, CDCl3)
δ 2.32 (m, 1H), 2.61 (dd, J ) 16.4, 4.8 Hz, 1H), 2.70 (dd, J )
16.4, 13.6 Hz, 1H), 2.80 (m, 1H), 3.23 (ddd, J ) 13.6, 10.8, 4.8
Hz, 1H), 3.43 (m, 1H), 3.68 (m, 1H), 6.15 (dd, J ) 10.0, 2.0
Hz, 1H), 7.12 (dd, J ) 10.0, 2.1 Hz, 1H), 7.20-7.30 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 42.9, 44.8, 45.1, 62.6, 127.2,
127.3, 128.8, 129.8, 141.6, 152.2, 199.2; IR (neat) 3430, 2884,
1676, 1388, 1253, 1073, 701 cm-1; HRMS m/z [M+] calcd for
C
13H14O2 202.0993, found 202.1006.
tr a n s-4,5-Bis(h ydr oxym eth yl)-2-cycloh exen e-1-on e (45).
The crude Wittig product was dissolved in acetonitrile (4
mL) and treated with a 10% solution of HF in acetonitrile (3
mL). After the resulting mixture stirred for 5 h at room
temperature, it was diluted with ether (100 mL) and washed
with a saturated solution of NaHCO3 (20 mL). The combined
organic layers were dried over anhydrous Na2SO4, concen-
trated in vacuo, and purified by flash chromatography on silica
gel (elution with pentane, followed by 50% ether in pentane)
The title compound was prepared in 82% yield according to
General Procedure C: 1H NMR (500 MHz, CDCl3) δ 2.25 (m,
1H), 2.37 (dd, J ) 16.5, 12.0 Hz, 1H), 2.50 (dd, J ) 16.5, 4.5
Hz, 1H), 2.61 (m, 1H), 3.26 (br s, 1H), 3.65 (dd, J ) 11.0, 6.5
Hz, 1H), 3.73 (dd, J ) 11.0, 4.5 Hz, 1H), 3.81 (dd, J ) 11.0,
6.5 Hz, 1H), 3.86 (dd, J ) 11.0, 5.0 Hz, 1H), 6.07 (dd, J ) 10.2,
2.4 Hz, 1H), 6.96 (dd, J ) 10.2, 2.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 39.8, 40.2, 42.2, 64.3,64.9, 130.1, 151.8, 199.6; IR
(neat) 3370, 2884, 1669, 1394, 1075 cm-1; HRMS m/z [M+]
calcd for C8H12O3 156.0787, found 156.0800.
cis-4,5-Bis(h yd r oxym eth yl)-2-cycloh exen e-1-on e (46).
The title compound was prepared in 85% yield according to
General Procedure C: 1H NMR (500 MHz, CDCl3) δ 2.40 (m,
1H), 2.55 (m, 2H), 2.87 (m, 1H), 3.21 (br s, 1H), 3.56 (br s,
1H), 3.80 (m, 4H), 6.06 (d, J ) 10.2 Hz, 1H), 6.89 (dd, J )
10.2, 5.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 38.1, 38.6,
41.03, 60.55, 63.53, 130.3, 149.8, 199.3; IR (neat) 3330, 2886,
1669, 1031 cm-1; HRMS m/z [M+] calcd for C8H12O3 156.0787,
found 156.0775.
1
to afford 630 mg (84%) of 39 as a colorless oil: H NMR (300
MHz, CDCl3) δ 1.25 (s, 3H), 1.95 (m, 2H), 2.37 (ddd, J ) 16.6,
4.8, 4.8 Hz, 1H), 2.46 (ddd, J ) 16.6, 8.7, 7.6 Hz, 1H), 5.03
(dd, J ) 17.5, 0.8 Hz, 1H), 5.12 (dd, J ) 10.4, 0.8 Hz, 1H),
5.80 (dd, J ) 17.5, 10.4 Hz, 1H), 6.00 (d, J ) 9.6 Hz, 1H), 6.63
(d, J ) 9.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 27.0, 34.2,
34.7, 39.3, 114.2, 128.5, 142.5, 155.9, 199.6; IR (neat) 2962,
2869, 1681, 1455, 1201, 922, 801 cm-1; HRMS m/z [M+] calcd
1
for C9H12O 136.0888, found 136.0897. The H NMR spectrum
of this compound was in agreement with that reported in the
literature.38
Gen er a l P r oced u r e C: P r ep a r a tion of Su bstitu ted
Cycloh exen on es 42-46. To a suspension of lithium alumi-
num hydride (1-2 mmol) in ether (4 mL) at -78 °C was added
a solution of a cycloadduct (1 mmol) in ether (2 mL). The
reaction mixture was stirred for 3 h at -78 °C, warmed to
room temperature, and stirred until the starting material had
completely disappeared (by TLC). The resulting mixture was
diluted with ether (10 mL) and quenched by dropwise addition
of water (0.3 mL). After vigorous stirring of the suspension
for an additional 30 min, anhydrous Na2SO4 was added. The
organic layer was carefully decanted from the solid, which was
washed twice with ether (15 mL each). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo to give the expected alcohol, which was
sufficiently pure for the hydrolysis step.
Im id e 47. To a solution of diene 19a (300 mg, 1.32 mmol)
in toluene (1 mL) was added N-phenylmaleimide (173 mg, 1.00
mmol) in toluene (2 mL) at -20 °C. The reaction mixture was
allowed to reach room temperature. Concentration in vacuo,
followed by flash chromatography on silica gel that was not
pretreated with Et3N (elution with 20% EtOAc in hexanes),
afforded 294 mg (83%) of 47 as a white solid: mp 114-116
°C; 1H NMR (300 MHz, CDCl3) δ 0.24 (s, 3H), 0.27 (s, 3H),
0.96 (s, 9H), 2.65 (m, 2H), 3.80 (ddd, 1H, J ) 13.2, 10.8, 2.7
Hz), 5.45 (dd, 1H, J ) 6.0, 1.5 Hz), 7.07 (dd, 1H, J ) 6.0, 2.7
Hz), 7.35 (m, 3H), 7.47 (t, 2H, J ) 6.5 Hz); 13C NMR (75 MHz,
CDCl3) δ -4.6, -4.4, 18.0, 25.4, 29.8, 39.4, 103.2, 116.9, 126.4,
128.2, 128.9, 131.3, 132.1, 161.8, 166.3, 174.6; IR (CHCl3) 3019,
2932, 1767, 1706, 1549, 1215, 833 cm-1; HRMS m/z [M+] calcd
for C20H25NO3Si 355.1604, found 355.1599.
A solution of the above alcohol in acetonitrile (1-2 mL) was
treated with 10% solution of HF in acetonitrile (0.50 mL). The
reaction mixture was stirred for 2 h at room temperature and
purified directly by flash chromatography on silica gel (elution
with ethyl acetate), which afforded the corresponding enones
42-46.
En on es 48 a n d 49. A solution of bicyclic imide 47 (294 mg,
0.83 mmol) in acetonitrile (1.5 mL) was treated with 10%
solution of HF in acetonitrile (0.50 mL). The reaction mixture
was stirred for 5 h at room temperature and purified directly
by flash chromatography on silica gel (elution with 30%
hexanes in EtOAc), which afforded an inseparable mixture of
isomeric enones 48 and 49 in a 3:1 ratio: 1H NMR (500 MHz,
CDCl3) δ 2.47 (dd, 1H, J ) 16.0, 12.8 Hz, 49), 2.75 (dd, 1H, J
4-(Hyd r oxym eth yl)-2-cycloh exen e-1-on e (42). The title
compound was prepared in 90% yield according to General

3052 J . Org. Chem., Vol. 64, No. 9, 1999
Kozmin et al.
) 17.7, 8.8 Hz, 48), 3.10-3.25 (m, 3H, 49), 3.15 (dd, 1H, J )
17.7, 3.0 Hz, 48), 3.64 (ddd, 1H, J ) 8.8, 8.8, 3.0 Hz, 48), 3.92
(ddd, 1H, J ) 8.8, 3.6, 2.7 Hz, 48), 6.26 (dd, 1H, J ) 10.2, 2.7
Hz, 48), 6.93, (dd, 1H, J ) 10.2, 3.6 Hz, 48), 7.09 (m, 1H, 49),
7.2-7.5 (m, 10H, 48,49); 13C NMR (125 MHz, CDCl3) δ 33.1,
37.6, 37.8, 39.6, 41.7, 126.11, 126.2, 128.7, 128.9, 129.1, 129.2,
129.3, 130.7, 131.1, 131.4, 131.6, 141.6, 173.2, 173.6, 176.0,
193.4, 204.4; IR (CHCl3) 3016, 1776, 1714, 1682, 1499, 1382,
1H), 3.05 (dt, J ) 23.5, 3.0 Hz, 1H), 3.24 (ddd, J ) 23.5, 4.8,
2.8 Hz, 1H), 4.39 (ddd, J ) 23.3, 11.6, 2.3 Hz, 1H), 4.51 (ddd,
J ) 23.3, 4.6, 2.8 Hz, 1H), 7.35 (ddd, J ) 4.8, 3.0, 2.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 29.7, 33.7, 40.5, 44.5, 68.1, 129.3,
139.3, 163.5, 206.0; IR (CHCl3) 3019, 1717, 1642, 1400, 1255,
1216, 668 cm-1; HRMS m/z [M+] calcd for C9H10O3 166.0630,
found 166.0633.
Rea ction of Dien e 19a w ith (+)-Ca r von e (54). To a
solution of diene 19a (305 mg, 1.34 mmol) in toluene (1 mL)
was added (+)-carvone (0.10 mL, 0.7 mmol). The reaction
mixture was stirred for 48 h at 110 °C, concentrated in vacuo,
and diluted with 2 mL of acetonitrile. The resulting mixture
was treated with 10% solution of HF in acetonitrile (0.5 mL,
1.9 mmol). The reaction mixture was stirred for 12 h, diluted
with ether, and washed with a saturated solution of NaHCO3.
The combined organic layers were dried over anhydrous Na2-
SO4, concentrated, and purified by flash chromatography on
silica gel (elution with 20% EtOAc in hexanes, followed by 40%
EtOAc in hexanes) to afford 91 mg (60%) of bicyclic enone 55
as a 1:1 mixture of diastereomers that were separated by
MPLC. Less polar diastereomer 55a : 1H NMR (500 MHz,
CDCl3) δ 1.41 (s, 3H), 1.71 (s, 3H), 1.95 (m, 1H), 1.80 (m, 1H),
2.35 (m, 4H), 2.50 (m, 1H), 2.85 dd, J ) 17.0, 5.0 Hz, 1H),
4.70 (s, 1H), 4.77 (s, 1H), 6.06 (d, J ) 10.0, Hz, 1H) 6.44 (dd,
J ) 10.0, 2.0 Hz, 13C NMR (125 MHz, CDCl3) δ 20.3, 20.9,
33.6, 40.7, 42.8, 43.8, 44.8, 50.6, 110.3, 128.8, 149.6, 197.1,
1176 cm-1
.
Siloxy P h th a lim id e (50). To a solution of the imide 47
(80 mg, 0.23 mmol) in CH2Cl2 (2 mL) was added DDQ (136
mg, 0.6 mmol). The resulting solution was stirred for 16 h at
room temperature, concentrated, and purified by flash chro-
matography on silica gel (elution with 15% EtOAc in hexanes)
to afford 69 mg (86%) of the siloxy phthalimide (50) as a white
1
solid: mp 106-108 °C; H NMR (500 MHz, CDCl3) δ 0.28 (s,
6H), 1.01 (s, 9H), 7.16 (dd, 1H, J ) 8.0, 2.2 Hz), 7.34 (d, 1H, J
) 2.2 Hz), 7.38 (t, 1H, J ) 7.4 Hz), 7.42 (d, 2H, J ) 7.4 Hz),
7.49 (t, 2H, J ) 7.4 Hz), 7.82 (d, 1H, J ) 8.0 Hz); 13C NMR
(125 MHz, CDCl3) δ -4.4, 18.1, 25.4, 114.9, 124.1, 125.5, 125.6,
126.5, 127.9, 128.9, 131.8, 134.2, 161.6, 166.9, 167.0; IR
(CHCl3) 3019, 1774, 1723, 1613, 1486, 1377, 1215, 875 cm-1
.
Rea ction of Dien e 19a w ith Cycloh exen on e. To a
solution of diene 19a (310 mg, 1.36 mmol) in toluene (1.5 mL)
was added cyclohexenone (0.3 mL, 3.11 mmol). The reaction
mixture was stirred for 2.5 h at 80 °C, concentrated in vacuo,
and purified by flash chromatography on silica gel (elution
with 20% EtOAc in hexanes), which afforded 249 mg (66%) of
210.7; IR (neat) 2919, 1713, 1681, 1645, 1242, 894, 774 cm-1
;
HRMS m/z [M+] calcd for C14H18O2 218.1307, found 218.1295.
More polar diastereomer 55b: 1H NMR (500 MHz, CDCl3) δ
1.48 (s, 3H), 1.76 (m, 1H), 1.77 (s, 3H), 2.38 (m, 1H), 2.4 (m,
3H), 2.53 (m, 1H), 2.64 (m, 1H), 2.67 (m, 1H), 4.77 (s, 1H),
4.86 (s, 1H) 6.06 (d, J ) 10.5, Hz, 1H), 6.75 (d, J ) 10.5 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 20.8, 24.2, 31.2, 40.7, 41.5,
42.7, 50.9, 110.9, 128.4, 146.3, 153.4, 198.5, 212.6; IR (neat)
2900, 1704, 1680, 1644, 1375, 894, 774 cm-1; HRMS m/z [M+]
calcd for C14H18O2 218.1307, found 218.1303.
1
the bicyclic dienone 51: H NMR (500 MHz, CDCl3) δ 0.19 (s,
3H), 0.20 (s, 3H), 0.97 (s, 9H), 1.25 (m, 1H), 1.60 (m, 1H), 1.91
(m, 2H), 2.16 (dd, 1H, J ) 15.3, 15.3 Hz), 2.20 (m, 1H), 2.47
(dd, 1H, J ) 15.3, 4.7 Hz), 2.72 (m, 1H), 5.77 (d, 1H, J ) 9.8
Hz), 7.57 (d, 1H, J ) 9.8 Hz); 13C NMR (125 MHz, CDCl3) δ
-3.7, -3.6, 18.3, 21.7, 25.7, 30.0, 31.1, 34.2, 44.7, 115.1, 123.1,
142.2, 155.1, 199.8; IR (neat) 2931, 2858, 1669, 1617, 1404,
1254, 1043, 914, 780 cm-1
.
Rea ction of Dien e 19a w ith Un sa tu r a ted La cton e 52.
To a solution of diene 19a (390 mg, 1.71 mmol) in toluene (1
mL) was added lactone 52 (0.10 mL, 1.16 mmol). The reaction
mixture was stirred for 9 h at 80 °C, concentrated in vacuo,
and diluted with 6 mL of acetonitrile. The resulting mixture
was treated with 10% solution of HF in acetonitrile (0.46 mL,
1.7 mmol). The reaction mixture was immediately passed
through a plug of silica gel using EtOAc as an eluent. The
crude product obtained upon evaporation of the solvent was
further purified by flash chromatography on silica gel (elution
with EtOAc) to afford 145 mg (76%) of the bicyclic lactone 53
as a pale-yellow solid: mp 122 °C; 1H NMR (300 MHz, CDCl3)
δ 1.86 (m, 1H), 2.09 (dq, J ) 13.9, 2.3 Hz, 1H), 2.31 (dd, J )
15.0, 12.4 Hz, 1H), 2.69 (dd, J ) 15.0, 4.6 Hz, 1H), 2.99 (m,
The 1H and 13C NMR spectra of both diastereomers 59a and
59b were in good agreement with those reported in the
literature.37
Ack n ow led gm en t. This work was supported in part
by the National Institutes of Health (R01-GM-55998).
Pfizer Inc. and Merck Research Laboratories are also
thanked for generous financial assistance.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR of
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O981563K