Acid-free aza Diels-Alder reaction of Danishefsky's diene with imines

Article abstract of DOI:10.1021/ol0265822

equation presented A highly efficient aza Diels-Alder reaction of Danishefsky's diene with imines was found to occur in methanol in the absence of any acids at room temperature to give corresponding 2-substituted dihydro-4-pyridone derivatives in high yie

Full text of DOI:10.1021/ol0265822

ORGANIC
LETTERS
2002
Vol. 4, No. 19
3309-3311
Acid-Free Aza Diels−Alder Reaction of
Danishefsky’s Diene with Imines
Yu Yuan, Xin Li, and Kuiling Ding*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China
kding@pub.sioc.ac.cn
Received July 23, 2002
ABSTRACT
A highly efficient aza Diels−Alder reaction of Danishefsky’s diene with imines was found to occur in methanol in the absence of any acids at
room temperature to give corresponding 2-substituted dihydro-4-pyridone derivatives in high yields. This reaction can be also carried out in
a three-component one-pot reaction manner. The reaction was found to proceed through a Mannich-type condensation mechanism.
The aza Diels-Alder reaction of Danishefsky’s diene 1 with
imine 2 provides a convenient protocol for the synthesis of
a type of heterocycles, 2-substituted 2,3-dihydro-4-pyridones
3, with important synthetic applications in natural or un-
natural products.1 Various Lewis acids such as BF3‚Et2O,2
ZnCl2,3 or lanthanide triflates4 and Bronsted acids, including
HBF4 or TsOH,5 have been utilized to promote this reaction.6
The employment of chiral Lewis acids such as BINOL-Zr7
or Bis-Oxa-Cu8 catalyst for this reaction results in the
formation of enantioenriched dihydro-4-pyridones with high
ee. In our efforts to develop chiral Bronsted acid catalysts
for enantioselective addition of imines to Danishefsky’s
diene, a study on the background reaction in the absence of
any acids demonstrated that the reaction proceeded smoothly
to give the desired product in good yield. In the present
communication, we will report our results on the acid-free
aza Diels-Alder reaction of Danishefsky’s diene 1 with
imines 2. The correct choice of reaction solvents was found
to be critical for affording high conversion of the reaction.
The research was initiated by the work of Akiyama on
the catalysis of aza Diels-Alder reaction of Danishefsky’s
diene 1 with imines 2 by the catalysis of Bronsted acids such
as HBF4, p-TsOH, and CF3CO2H in methanol or acetonitrile.5
Accordingly, a chiral carboxylic acid, (S)-naproxen, was
employed as a chiral Bronsted acid catalyst for developing
an asymmetric version of this reaction in methanol. Unfor-
tunately, the isolated adduct 3a was racemic. To our surprise,
an examination on the noncatalyzed background reaction
showed that the conversion of 2a was completed within 2 h
in the absence of any acids to give the desired product 3a in
quantitative yield (entry 1 in Table 1). This result allowed
us to understand that the reaction system is most probably
not catalyzed by a Bronsted acid. To rule out the possibility
of the catalysis by adventitious acid in the reaction system,
the control experiment was carried out for the reaction of 1
and 2a in methanol that was freshly distilled over CaH2 or
in the presence of 10 mol % 2,6-di-tert-butyl-4-methyl-
pyridine. It was found that the reaction proceeded smoothly
(1) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: Oxford, 1990. (b) Oppolazer, W. In ComperhensiVe Organic
Synthesis; Paquette, L. A.; Ed.; Pergamon: Oxford, 1991; Vol. 5, p 315.
(c) Weinreb, S. M. Hetero Dienophile Additions to Dienes. In ComprehesiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 5, p 401. (d) Waldmann, H. Synthesis 1994, 535-551.
(2) Hattori, K.; Yamamoto, H. Synlett 1993, 129-130.
(3) Kervin, J. F., Jr.; Danishefsky, S. Tetrahedron Lett. 1982, 23, 3739-
3742.
(4) Kobayashi, S.; Araki, M.; Ishitani, H.; Nagayama, S.; Hachiya, I.
Synlett 1995, 233-234.
(5) Akiyama, T.; Takaya, J.; Kagoshima, H. Tetrahedron Lett. 1999, 40,
7831-7834.
(6) For an example of uncatalyzed cycloaddition of Danishefsky’s diene
with sulfonylimines in boiling toluene where 45-80% yields were obtained,
see: Abramovitch, R. A.; Stomers, J. R. Heterocycles 1984, 22, 671-673.
(7) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int.
Ed. 1998, 37, 979-981. (b) Kobayashi, S.; Kusakabe, K.; Komiyama, S.;
Ishitani, H. J. Org. Chem. 1999, 64, 4220-4221.
(8) Yao, S.; Johannsen, M.; Hazell, R. G.; Jogensen, K. A. Angew. Chem.,
Int. Ed. 1998, 37, 3121-3124.
10.1021/ol0265822 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/29/2002

corresponding adducts 3 in good to excellent yields. The
electron-withdrawing group at the para-position of aldimine
slightly decreases the yield of the reaction (entry 4). An R,â-
unsaturated aldimine furnished the corresponding cycload-
duct in excellent yield (entry 5). An aldimine derived from
4-anisidine also worked very well as a substrate (entry 7).
Because imines, particularly those derived from aliphatic
aldehydes, are not always stable, it is synthetically useful if
aldimines are generated in situ and allowed to react under
one-pot reaction conditions. Accordingly, three-component
synthesis starting from aldehyde and amine was thus
investigated under the experimental conditions mentioned
above. The aldehyde was first allowed to react with amine
in methanol at room temperature, and Danishefsky’s diene
1 was introduced successively. As shown in Table 3, the
Table 1. Solvent Effect on the Reaction
entry
solvent
yield (%) entry
solvent
THF
toluene
ethyl ether
DCMc
yield (%)
1
2
3
4
5
6
methanol
methanola
methanolb
acetonitrile
ethanol
>99
>99
>99
>99
32
7
8
9
10
11
12
47
<5
0
<5
<5
0
chloroform
d
DMF
54
a Methanol was distilled over CaH2. b Reaction was carried out in
methanol in the presence of 10 mol % 2,6-di-tert-butyl-4-methylpyridine.
c Dichloromethane. d (S)-(-)-1-phenyl ethanol.
Table 3. Three-Component Synthesis of Dihydro-4-pyridone
Derivatives by One-Pot Aza Diels-Alder Reaction
to give the cycloadduct 3a in the same yields (entries 2-3).
With this result in hand, we further examined the solvent
effect on the reaction in the absence of acids. Various
solvents, including polar and nonpolar ones, were employed
for the reaction. Indeed, the solvent effect was found to be
evident. As shown in Table 1, the reactions can occur in
more polar solvents such as methanol, acetonitrile, ethanol,
DMF, and THF (entries 4-7). However, the reaction in a
nonpolar solvent such as toluene, diethyl ether, chloroform,
or dichloromethane was very sluggish with less than 5% yield
(entries 8-11). An attempt to carry out the reaction in a
chiral solvent, (S)-(-)-1-phenyl ethanol, proved that no
reaction occurred at all (entry 12). The significant solvent
effect on the reaction suggested that the addition of Dan-
ishefsky’s diene 1 with imines 2 probably proceeds via a
stepwise mechanism rather than a concerted one, which will
entry
R
Ar
C6H5
yield (%)
1
2
C6H5
>99
91
80
67
91
93
89
76
74
91
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
C6H5
PhCHdCH
PhCH2CH2
(CH3)2CH
2-furyl
C6H5
C6H5
C6H5
4-MeOC6H4
C6H5
C6H5
C6H5
C6H5
3
4
5
6
7
8
9
10
2-pyridyl
C6H5
1
be further illustrated by H NMR spectroscopic evidence.
The aza Diels-Alder reaction of Danishefsky’s diene 1
with a variety of imines 2 were then investigated in methanol
at room temperature. The reactions of the all of the imines
2 shown in Table 2 with 1 take place smoothly to afford the
three components condensation reaction proceeded smoothly
to afford the corresponding dihydro-4-pyridone derivatives
in good to excellent yields. The yields of the reaction were
comparable to those obtained by the reaction of isolated
aldimines. The reaction was able to tolerate various alde-
hydes, including aromatic, olefinic and aliphatic derivatives.
Particularly, the reactions of heteroaromatic aldehydes,
2-pyridylaldehyde, and 2-furylaldehyde afforded the corre-
sponding heteroaromatic-substituted dihydro-4-pyridone de-
rivatives in high yields, which may be interesting in the
synthesis of some biologically important compounds.
The development of methods to effect the hetero Diels-
Alder asymmetrically in this field has been the subject of
intense activity during the past decade. The diastereoselec-
tivity of this reaction has been investigated with chiral
C-acylimine,9 chiral alkoxy imines,10 chiral aliphatic,11 imines
derived from chiral amino sugars,12 chiral amino esters,13 or
chiral amino alcohols.14 Enantioselective methods employing
chiral Lewis acids have also emerged.7,8,15 We chose to utilize
(R)-2,3-di-O-isopropylideneglyceraldehyde 6 as the chiral
auxiliary due to its low cost and easy availability in organic
Table 2. Aza Diels-Alder Reaction of Danishefsky’s Diene
(1) with Imines (2) in Methanol
entry
R
Ar
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
4-MeOC6H4
yield (%)
1
2
3
4
5
6
7
C6H5
>99
95
89
63
97
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
PhCHdCH
C6H5
96
95
C6H5
3310
Org. Lett., Vol. 4, No. 19, 2002

Scheme 1
Scheme 2
mechanism was identified in the present reaction system
1
(Scheme 2). In methanol-d4, the H NMR spectrum of the
crude product from the reaction of Danishefsky’s diene with
aldimine revealed the exclusive presence of a Mannich-type
condensation adduct.17
synthesis.16 An attempt to form the imine of 4-anisidine in
situ in the presence of Danishefsky’s diene in methanol at
room temperature afforded the expected cycloproduct with
two diastereomers 7a and 7b in moderate yield (66%) and
good stereoselectivity (80/20) (Scheme 1).
In conclusion, the aza Diels-Alder reaction of Danishef-
sky’s diene with imines has been found to proceed efficiently
in methanol in the absence of any acids at room temperature
to give corresponding 2-substituted dihydro-4-pyridone
derivatives in high yields. The further evolution of this
reaction to a three-component one-pot procedure and an
asymmetric version using a chiral auxiliary was also
achieved. The determination of the primary product formed
in the reaction system combined with the observed solvent
effect demonstrated that the reaction proceeded through a
stepwise Mannich-type condensation mechanism.
An important question arises regarding the mechanism of
the condensation of Danishefsky’s diene with aldimine in
methanol. A concerted [4 + 2] cycloaddition mechanism has
been suggested in the Lewis acid-catalyzed reaction reported
by Danishefsky3, whereas a Mannich-type condensation
(9) (a) Hamley, P.; Helmchen, G.; Holmes, A. B.; Marshall, D. R.;
Mackinnon, J. W. M.; Smith, D. F.; Ziller, J. W. J. Chem. Soc., Chem.
Commun. 1992, 786-788. (b) Abraham, H.; Stella, L. Tetrahedron 1992,
48, 9707-9718. (c) MacFalane, A. K.; Thomas, G.; Whiting, A. Tetrahe-
dron Lett. 1993, 34, 2379-2382. (d) Bailey, P. D.; Londesbrough, D. J.;
Hancox, T. C.; Heffernan, J. D.; Holmes, A. B. J. Chem. Soc., Chem.
Commun. 1994, 2543-2544. (e) Ager, D.; Cooper, N.; Cox, G. G.; Garro-
Helion, F.; Harwood, L. M. Tetrahedron: Asymmetry 1996, 7, 2563-2566.
(10) (a) Midland, M. M.; Koops, R. W. J. Org. Chem. 1992, 57, 1158-
1161. (b) Ishimaru, K.; Yamamoto, Y.; Akiba, K. Tetrahedron 1997, 53,
5423-5432. (c) Herczegh, P.; Kovacs, I.; Erdosi, G.; Varga, T.; Agocs,
A.; Szilagyi, L.; Staricskai, F.; Bereceibar, A.; Lukacs, G.; Olesker, A. Pure
Appl. Chem. 1997, 69, 519-524. (d) Yu, L.; Li, J.; Ramirez, J.; Chem, D.;
Wang, P. G. J. Org. Chem. 1997, 62, 903-907.
Acknowledgment. Financial support from the National
Natural Science Foundation of China, Chinese Academy of
Sciences, the Major Basic Research Development Program
of China (Grant G2000077506), and the Ministry of Science
and Technology of Commission of Shanghai Municipality
is gratefully acknowledged.
Supporting Information Available: Experimental details
(11) Kuethe, J. T.; Davies, I. W.; Dormer, P. G.; Reamer, R. A.; Mathre,
D. J.; Reider, P. J. Tetrahedron Lett. 2002, 43, 29-32.
1
and spectral data for the cycloadducts, H NMR spectra of
(12) (a) Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. 1989, 28, 1067-
1069. (b) Weymann, W.; Pfrengle, W.; Schollmeyer, D.; Kunz, H. Synthesis
1997, 1151-1160.
the crude condensation adduct of the reaction between 1 and
1
2a in methanol and diastereomers of 7, H-1H COSY
1
(13) (a) Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768-
1769. (b) Waldmann, H. Synlett 1995, 133-141.
spectrum of 7a, and H NMR spectra of products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Devine, P. N.; Reilly, M.; Oh, T. Tetrahedron Lett. 1993, 34, 5827-
5830.
(15) (a) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49, 1749-1760.
(b) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264-3265.
(16) Badorrey, R.; Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A.
Tetrahedron 1999, 55, 7601-7612.
OL0265822
(17) See Supporting Information.
Org. Lett., Vol. 4, No. 19, 2002
3311