Hydrogen-bond-promoted hetero-Diels-Alder reactions of unactivated ketones

Article abstract of DOI:10.1021/ja0267627

We report the first examples of hydrogen-bond-promoted acceleration of hetero-Diels-Alder reactions and the use of such catalysis for the hetero-Diels-Alder reactions of simple, unactivated ketones. Several spiro-fused dihydropyans were synthesized in good yields using this procedure. This activation protocol represents an attractive and operationally simple alternative to conventional, Lewis acid catalysis. Copyright

Full text of DOI:10.1021/ja0267627

Published on Web 07/30/2002
Hydrogen-Bond-Promoted Hetero-Diels-Alder Reactions of Unactivated
Ketones
Yong Huang and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received May 2, 2002
The [4 + 2] cycloaddition reaction between dienes and carbonyl-
group-containing compounds provides one of the most direct
methods for the synthesis of six-membered oxygen heterocycles.
Although these hetero-Diels-Alder reactions have been studied
Figure 1.
extensively,1 due to the prevalence and biological importance of
oxygen heterocycles,2 their scope is limited. Nearly all such
Table 1. Rates of HDA Reactions in Different Solvents
cycloadditions have been reported with aldehydes, and, even then,
they require special reaction conditions, such as high temperature,
high pressure, or Lewis acid catalysis.1a,3 For steric and electronic
reasons, the ketone carbonyl group is a much poorer heterodieno-
phile than the aldehyde carbonyl group, such that there are very
few reports of successful hetero-Diels-Alder reactions of simple
ketones.1,4,5a We report here the first examples of hydrogen-bond-
promoted acceleration of hetero-Diels-Alder reactions and the use
of such catalysis to carry out the hetero-Diels-Alder reactions of
simple, unactivated ketones.
While investigating the solvent effect for the hetero-Diels-Alder
reaction between aldehydes and 1-amino-3-siloxybuadiene,5 we
observed a significantly higher reaction rate in chloroform than in
other aprotic organic solvents. To more precisely assess the solvent
effect, we examined the rate of the hetero-Diels-Alder reaction
between diene 1 and p-anisaldehyde (2) in several different solvents
(Table 1). It is clear from the data that the rate differences do not
correlate with the solvent’s dielectric constant: the reaction in
chloroform was 10 times faster than that in the more polar solvent,
acetonitrile. The higher rate in chloroform cannot simply be
explained by invoking catalysis from trace amounts of acid in
chloroform, since the same rate was observed even after rigorous
purification of the solvent. Moreover, the addition of triethylamine
or a catalytic amount of HCl did not affect the rate one way or
another.6 The increased reaction rate in chloroform, we concluded,
could arise from a CsH‚‚‚O hydrogen bond between chloroform
and the carbonyl oxygen,7,8 which would render the carbonyl group
a stronger heterodienophile (Figure 1).
As the data show, the cycloadditions are accelerated to a much
greater extent in protic solvents, in which the OH group is expected
to form a strong hydrogen bond to the aldehyde oxygen.9,10 Thus,
the hetero-Diels-Alder reaction of 1 and anisaldehyde is 630 times
faster in deuterated 2-propanol than in deuterated THF, which
corresponds to a ∆∆Gq of -3.77 kcal/mol.
Importantly, the activation provided by hydrogen-bonding sol-
vents is sufficient that even simple ketones, generally considered
unreactive,1 undergo the hetero-Diels-Alder reaction. We initially
examined the hetero-Diels-Alder reaction of cyclohexanone (4a)
and diene 1 in chloroform (Table 2). Remarkably, although slow,
the cycloaddition with this unactivated ketone proceeded cleanly
and gave, upon acetyl chloride-mediated elimination of the amino
group, the desired spiro-fused dihydropyrone in 45% yield, along
dielectric
constanta
rate constant
relative
rate
entry
solvent
(k)b
1
2
3
4
5
6
THF-d8
7.6
2.3
37.5
4.8
10.9
18.3
1.0 × 10-5
1.3 × 10-5
3.0 × 10-5
3.0 × 10-4
2.8 × 10-3
6.3 × 10-3
1
1.3
3.0
30
280
630
benzene-d6
acetonitrile-d3
chloroform-d
tert-butyl alcohol-d10
isopropyl alcohol- d8
a For the corresponding undeuterated solvent, at 25 ( 5 °C . b Kinetics
measured by NMR integration using internal standard.
Table 2. Reactions of Cyclohexanone and 1 in H-Bonding
Solvents
entry
solvent
time (h)
solvolysis (%)a
yield (%)c
1
2
3
4
5
6
chloroform
tert-butyl alcohol
isopropyl alcohol
ethanol
methanol
2-butanol
48
24
3
0.5
0.5
5
20-25
<5
10-15
∼50b
∼40b
<5
45
71
60
30
0
78
a Percentage of hydrolysis was calculated by NMR integration. b Sig-
nificant amount of other type of decomposition took place as well as
hydrolysis. c Yields refer to isolated, chromatographically purified products,
except for entries 4 and 5, where the yield was based on NMR integration
of cycloadduct.
with E-4-(N,N-dimethylamino)-3-buten-2-one (5).11 As anticipated,
the cycloaddition was considerably faster in protic solvents. The
reaction went to completion in 1 day in t-BuOH and, upon acetyl
chloride workup, afforded the expected spiro product in 71% yield.
Solvents with less shielded hydroxyl groups were more effective
at accelerating the hetero-Diels-Alder reaction.
The reaction went to completion in just 3 h in 2-propanol, but
the desired cycloadduct was accompanied by a significant amount
(10-15%) of the solvolysis byproduct, 5. Diene solvolysis pre-
dominated in ethanol and methanol. The results show that although
better hydrogen-bonding alcohols promote faster reactions, they also
* Author for correspondence. E-mail: vrawal@uchicago.edu.
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J. AM. CHEM. SOC. 2002, 124, 9662-9663
10.1021/ja0267627 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Cycloaddition Reactions of Diene 1 and Unactivated
Ketones
Figure 2.
and 4). In general, six-membered-ring ketones were more effective
as heterodienophiles than other ketones (cf. entries 8-10). Finally,
the hetero-Diels-Alder reaction of the hindered aldehyde, pival-
dehyde, is greatly accelerated in a hydrogen-bonding solvent (entry
11).12
The results above demonstrate that the hetero-Diels-Alder
reactions are greatly accelerated in hydrogen-bonding solvents. This
activation protocol represents an attractive and operationally simple
alternative to conventional Lewis acid catalysis. The extension of
this hydrogen bond acceleration concept to asymmetric synthesis
remains to be explored.
Acknowledgment. This work was supported by the National
Institutes of Health (R01-GM-55998). Generous financial support
from Abbott Laboratories (Graduate Fellowship to Y.H.) and Merck
Research Laboratories is gratefully acknowledged.
Supporting Information Available: General experimental proce-
dures for the HDA reactions shown and spectroscopic data for the
products (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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Top. Curr. Chem. 1997, 189, 1 and references therein. For earlier work,
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CA, 1987; Vol. 47.
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a All reactions were carried out 0.5 mmol scale in 0.5 mL of 2-butanol,
using 2 equiv of the ketone. b The ketone was dissolved in 0.2 mL of
benzene. c Yields refer to chromatographically purified products. d An equal
amount of the Mukaiyama aldol side product was formed. See ref 5a.
(4) Cf., inter alia: (a) Guay, V.; Brassard, P. Tetrahedron 1984, 40, 5039.
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3047.
solvolyze the diene. The use of 2-butanol (entry 6) provided a good
compromise: the reaction was reasonably fast and was accompanied
by little of the solvolysis byproduct.
This hydrogen-bond-promoted protocol represents the first
general method for achieving the hetero-Diels-Alder reactions of
unactivated ketones (Table 3). The reactions were carried out
conveniently by mixing the diene and the ketone in 2-butanol and
letting the resulting solution stir at room temperature for the
indicated time. The alcohol was removed in vacuo and replaced
with dichloromethane. After the solution was cooled to -78 °C,
acetyl chloride was added, and the resulting solution was subjected
to an aqueous workup and chromatographic purification. This
simple, one-pot procedure allowed the preparation of a variety of
structurally novel spiro-dihydropyrones in good yields.
(5) (a) Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321. See also: (b)
Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J. Org. Chem. 1999, 64, 3039.
(c) Kozmin, S. A.; Green, M. T.; Rawal, V. H. J. Org. Chem. 1999, 64,
8045. (d) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1999, 121,
9562. (e) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000,
122, 7843.
(6) Even if there were a trace amount of acid in the solvent, it would be
neutralized by the basic nitrogen in the cycloadduct.
(7) The rate of the hetero-Diels-Alder reaction in deuteriochloroform was
the same (within experimetal error) as that in chloroform.
(8) (a) Green, R. D. Hydrogen Bonding by C-H Groups; Wiley: New York,
1974. (b) Steiner, T. New J. Chem. 1998, 1099. (c) Kryachko, E. S.;
Zeegers-Huyskens, Z. J. Phys. Chem. A 2001, 105, 7118 and references
therein.
(9) Acceleration of Diels-Alder reactions in water is well established. See:
(a) Breslow, R. Acc. Chem. Res. 1991, 24, 159 (b) Grieco, P. A.
Aldrichimica Acta 1991, 24, 59. (c) Labineau, A.; Auge´, J. Top. Curr.
Chem. 1999, 206, 2.
(10) Hydrogen bond activation of dienophiles in standard DA reactions: (a)
Kelly, T. R.; Meghani, P.; Ekkundi, V. S. Tetrahedron Lett. 1990, 31,
3381. (b) Schuster, T.; Kurz, M.; Go¨bel, M. W. J. Org. Chem. 2000, 65,
1697. (c) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
(11) Diene 1 is readily hydrolyzed or solvolyzed, affording 5.
(12) The corresponding reaction in chloroform was considerably slower and
afforded the product in 54% product after 2 days (ref 5a).
These hetero-Diels-Alder reactions are sensitive to steric and
electronic variations in the ketone. Whereas the reaction of diene
1 and cyclohexanone went to completion in just 5 h, the reaction
with 2-methylcyclohexanone was only ca. 50% complete after 4 d
(entry 2). By contrast, 2-methoxycyclohexanone was comparable
in reactivity to cyclohexanone (entry 6). Evidently, the inductive
effect of the methoxy group and its capacity to hydrogen bond
override the steric effect (Figure 2). Substituents at the 3 or 4
positions of cyclohexanones do not retard the reaction (entries 3
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