Hetero Diels-Alder reactions of 1-amino-3-siloxy-1,3-butadienes under strictly thermal conditions

Article abstract of DOI:10.1021/ol006404d

(matrix presented) The hetero Diels-Alder reaction of 1-amino-3-siloxy-1,3-butadiene (1a) with a range of unactivated aldehydes proceeds readily under remarkably mild conditions: at room temperature and in the absence of Lewis acid catalysts. The cycloadd

Full text of DOI:10.1021/ol006404d

ORGANIC
LETTERS
2000
Vol. 2, No. 21
3321-3323
Hetero Diels−Alder Reactions of
1-Amino-3-siloxy-1,3-butadienes under
Strictly Thermal Conditions
Yong Huang and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
V-rawal@uchicago.edu
Received August 1, 2000
ABSTRACT
The hetero Diels−Alder reaction of 1-amino-3-siloxy-1,3-butadiene (1a) with a range of unactivated aldehydes proceeds readily under remarkably
mild conditions: at room temperature and in the absence of Lewis acid catalysts. The cycloadducts are formed in good yields and can be
converted directly to the corresponding dihydro-4-pyrones using acetyl chloride. Ketones and imines are also reactive in hetero Diels−Alder
reactions with this diene.
The hetero Diels-Alder reaction has emerged as the method
of choice for the stereocontrolled synthesis of six-membered
heterocycles such as dihydropyrones and dihydropyridones,
building blocks to a wide range of natural products of
interest.1 The cycloaddition of electron-rich dienes with
aldehydes and ketones, for example, provides de novo
syntheses of biologically significant carbohydrates.2 Its clear
importance to organic synthesis notwithstanding, the hetero
Diels-Alder is a sluggish reaction. Only highly reactive
carbonyls, such as that in formaldehyde or in aldehydes
bearing electron-withdrawing groups (e.g., glyoxylates), are
reported to react with dienes.3 The hetero Diels-Alder
reactions of less reactive carbonyl groups necessitate either
very high pressure (15-25 kbar)4 or the use of Lewis acid
catalysts.5,6 We report here the first hetero Diels-Alder
reactions between a stable diene and an unactivated carbonyl
group under atmospheric pressure and in the absence of
Lewis acids.7 The cycloadditions are carried out at room
temperature or lower and afford upon workup dihydro-4-
pyrones in good yields.
We recently reported on the synthesis and Diels-Alder
reactivity of a new family of highly reactive dienes possess-
(4) Jurczak, J.; Chmielewski, M.; Filipek, S. Synthesis 1979, 41-42.
(5) Reviews: (a) Santelli, M.; Pons, J, -M. Lewis Acids and SelectiVity
in Organic Synthesis; CRC Press: Boca Raton, FL, 1996. See also refs 1
and 2.
(6) (a) Molander, G. A.; Rzasa, R. M. J. Org. Chem. 2000, 65, 1215-
1217 and references therein. For recent examples of chiral Lewis acid-
catalyzed hetero Diels-Alder reactions, see: (b) Ghosh, A. K.; Mathivanan,
P.; Cappiello, J. Tetrahedron Lett. 1997, 38, 2427-2430. (c) Schaus, S.
E.; Brånalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 403-406. (d) Yao,
S.; Johannsen, M.; Audrain, H.; Hazell, R. G.; Jørgensen, K. A. J. Am.
Chem. Soc. 1998, 120, 8599-8605, and references therein.
(7) This work was presented at the 219th National Meeting of the
American Chemical Society: Huang, Y.; Rawal, V. H. Abstr. Pap. Am.
Chem. Soc. 2000, 219, 527-ORGN. After this manuscript was completed
and being readied for submission, a paper appeared describing the thermal
hetero Diels-Alder reactions of in situ generated ortho-quinodimethanes
with carbonyl and imino hetero dienophiles: Hentemann, M. F.; Allen, J.
G.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2000, 39, 1937-1940.
(1) For excellent general reviews, see: (a) Tietze, L. F.; Kettschau, G.
In Topics in Current Chemistry; Metz, P., Ed.; Springer-Verlag: Berlin,
1997; Vol. 189, pp 1-120, and references therein. (b) Boger, D. L.; Weinreb,
S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Wasserman,
H. H., Ed; Academic Press: San Diego, CA, 1987; Vol. 47.
(2) Reviews: (a) Schmidt, R. R. Acc. Chem. Res. 1986, 19, 250-259.
(b) Danishefsky, S. J.; DeNinno, M. P. Angew. Chem., Int. Ed. Engl. 1987,
15, 5-23. (c) Kametani, T.; Hibino, S. AdV. Heterocycl. Chem. 1987, 42,
245-333. (d) Bednarski, M. D.; Lyssikatos, J. P. In ComprehensiVe Organic
Synthesis; Trost, B. M., Heathcock, C. H., Eds.; Pergamon Press: New
York, 1991; Vol. 2, pp 661-706.
(3) (a) Gresham, T. L.; Steadman, T. R. J. Am. Chem. Soc. 1949, 71,
737-738. (b) Dale, W. J.; Sisti, A. J. J. Am. Chem. Soc. 1954, 76, 81-82.
(c) Jung, M. E.; Shishido, K.; Light, L.; Davis, L. Tetrahedron. Lett. 1981,
22, 4607-4610.
10.1021/ol006404d CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/23/2000

ing an amine at the 1-position and a siloxy substituent at
the 3-position (1).8-12 Such amino-siloxy dienes are conve-
niently prepared on a large scale (up to 20 g)12 and are highly
reactive in conventional Diels-Alder reactions, providing
quick access to a wide range of 4- and 4,5-disubstituted
cyclohexenones,8,9 even in enantiomerically enriched10 form
(Scheme 1).
The presence of the labile amino-glycoside linkage in
cycloadduct 3 precluded the use of standard workup and
purification procedures. However, the adduct could easily
be transformed to a stable product. Interestingly, depending
on the workup conditions, it was possible to obtain alcohol
4, TBS-ether 5, or dihydro-4-pyrone 7a as the major product
(Table 1). Thus, direct subjection of the reaction mixture to
Scheme 1
Table 1. Direct Transformations of Cycloadduct 3
entry hydrolysis conditions
time
4a,b
5
6
7a
1
2
3
4
5
6
silica gel or alumina
TFA-THF
HF-CH3CN
HCl-THF
ClCO2Me, -78 °C
78%
24 h
20 h
24 h
30 min
72%
42% 17%
19% 40%
66%
The exceptional reactivity11 of amino-siloxy dienes was
clearly evident from its hetero Diels-Alder reaction with
benzaldehyde (Scheme 2). Upon addition of benzaldehyde
acetyl chloride, -78 °C 30 min
86%
a Yields refer to isolated, chromatographically purified products. b Prod-
ucts constituting <10% of the product mixture were not isolated.
either silica gel or alumina column chromatography afforded
primarily alcohol 4 (entry 1). TBS-ether 5, the Mukaiyama-
aldol type product,13 was the major product using trifluoro-
acetic acid in THF (entry 2). Aqueous acidic conditions did
afford the desired dihydro-4-pyrone (7), but it was ac-
companied by appreciable quantities of the hydrolysis
product, lactol 6. To circumvent the concomitant hydrolysis
to 6, nonaqueous eliminative workup conditions were
explored. After completion of the cycloaddition, the reaction
solution was chilled (-78 °C) and then treated with a slight
excess of an acylating agent (entries 5 and 6). Presumably,
under these conditions the amino group is acylated, making
it a good leaving group, followed by attack of the silyl group
by the chloride ion, triggering a â-elimination to reveal the
dihydroprone product.
We have examined the hetero Diels-Alder/hydrolysis
sequence using a variety of aldehydes as hetero dienophiles
and have found this methodology to be quite general and
reliable. The reactions proceed at room temperature and
afford, after quenching with acetyl chloride, the dihydro-4-
pyrone products in good to high yields (Table 2). The
cycloadditions between diene 1a and aromatic aldehydes
were quite fast, and the reaction rates appeared to correlate
with the electrophilicities of the respective carbonyl groups
(entries 1-4). The cycloadditions with primary aliphatic
aldehydes were complete within ∼2-3 h (entries 5 and 6)
and required 6-8 h with secondary aldehydes (entries 7 and
8). Even less reactive was the tertiary aldehyde, pivaldehyde,
Scheme 2
to a solution of diene 1a in CDCl3, a rapid cycloaddition
ensued, as monitored by NMR. The reaction was complete
in only ca. 30 min, resulting in clean, quantitative formation
of the expected cycloadducts (3, ca. 3:1 ratio). The high rate
of the reaction cannot simply be explained by invoking
catalysis by the trace amounts of HCl present in chloroform,
since comparable results were obtained even when iPr2NEt
or K2CO3 was added to the reaction mixture. The facility of
this cycloaddition is noteworthy in light of the high-pressure
conditions reportedly required for an analogous uncatalyzed
reaction of 2a and 1-methoxy-1,3-butadiene (19.5 kbar, 50
°C).4
(8) (a) Kozmin, S. A.; Rawal, V. H. J. Org. Chem. 1997, 62, 5252-
5253. (b) Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J. Org. Chem. 1999,
64, 3039-3052.
(9) Application to tabersonine synthesis: Kozmin, S. A.; Rawal, V. H.
J. Am. Chem. Soc. 1998, 120, 13523-13524.
(10) (a) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119,
7165-7166. (b) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1999,
121, 9562-9573.
(11) Kozmin, S. A.; Green, M. T.; Rawal, V. H. J. Org. Chem. 1999,
64, 8045-8047.
(12) Two preparative procedures have been accepted for publication in
Organic Syntheses, one for the synthesis of amino-siloxy diene 1a, and the
other for the use of this diene in a Diels-Alder reaction: Kozmin, S. A.;
He, S.; Rawal, V. H. Org. Synth. 2000, 78, in press.
(13) Cf.: (a) Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron. Lett.
1992, 46, 6907-6910. (b) Keck, G. E.; Li, X.; Krishnamurthy, D. J. Org.
Chem. 1995, 60, 5998-5999.
3322
Org. Lett., Vol. 2, No. 21, 2000

Scheme 3
Table 2. Hetero Diels-Alder Reactions of Various Aldehydes
glyoxylate (13) was equally effective and afforded the
expected dihydropyridone (14) in good yield.
Scheme 4
In summary, the present work demonstrates another facet
of the remarkable utility of 1-amino-3-siloxy-1,3-butadienes.
These dienes are easily prepared and stable, and yet are so
reactive that they readily undergo hetero Diels-Alder
reactions with a wide range of heterodienophiles, including
various aldehydes and activated ketones and imines. The
cycloadditions proceed under mild, strictly thermal conditions
(i.e., without the assistance of Lewis acid catalysis) and the
adducts can be hydrolyzed in the same flask. The one-pot
sequence proceeds in good yields and provides a simple
synthesis of many useful dihydro-4-pyrone and dihydro-4-
pyridone derivatives.
a Yield of chromatographically purified product. b Obtained as an
inseparable mixture of diastereomers.
the cycloaddition with which required over 1 day to go to
completion (entry 9). Aldehydes with a chiral center adjacent
to the carbonyl group afforded a mixture of diastereomers,
with only moderate diastereoselectivity (entries 7 and 8, ratios
of 1.3/1 and 1.2/1, respectively).
Acknowledgment. This work was supported by the
National Institutes of Health (R01-GM-55998). Pfizer Inc.
and Merck Research Laboratories are also thanked for
generous financial assistance.
Initial examination showed that diene 1a was considerably
less reactive with simple ketones (e.g., cyclohexanone) than
aldehydes. On the other hand, the hetero Diels-Alder
reaction with methyl pyruvate (8) proceeded nicely even at
-40 °C and gave, after acetyl chloride workup, the car-
boxylated dihydroprone 10 in 77% yield (Scheme 3). The
cycloaddition of 1a with activated imines also proceeded
well.14 The reaction of 1a and the N-carbomethoxy imine of
benzaldehyde (11) went to completion in 3 h at -78 °C and
gave, upon aqueous acidic hydrolysis of the intermediate
cycloadduct, dihydro-4-pyridone 12 in 77% yield (Scheme
4). The corresponding reaction of N-phenyl imine of methyl
Supporting Information Available: General experimen-
tal procedures for the cycloadditions shown and spectroscopic
data for the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL006404D
(14) Thermal hetero Diels-Alder reactions of doubly activated imines
have been reported: (a) Birkinshaw, T. N.; Tabor, A. B.; Holmes, A. B.;
Kaye, P.; Mayne, P. M.; Raithby, P. R. J. Chem. Soc., Chem. Commun.
1988, 1599-1601. (b) Birkinshaw, T. N.; Tabor, A. B.; Holmes, A. B.;
Raithby, P. R. J. Chem. Soc., Chem. Commun. 1988, 1601-1602.
Org. Lett., Vol. 2, No. 21, 2000
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