CONTROL OF REGIOSELECTIVITY IN THE DIELS-ALDER REACTIONS OF ALKYL-SUBSTITUTED 1,4-BENZOQUINONES BY BETA-CYCLODEXTRIN AND ITS DERIVATIVES

J. CHEM. SOC., CHEM. COMMUN., 1995 97 1

Control

of

Regioselectivity

in

the Diels-Alder Reactions of Alkyl-substituted

1,4-Benzoquinones by P-Cyclodextrin and its Derivatives

Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan 30050, ROC

The Diels-Alder reactions of benzoquinones 1-3 with penta-Ir3-diene 4 and isoprene 5 are studied i n aqueous cyclodextrin solutions, where highly enhanced ortho (6, 8 and 10) and meta (13, 15) regioselectivities are achieved. Quinones are widely employed as dienophiles in Diels-Alder

reactions. 1 The diverse biological activity of quinones has led to the development of several new synthetic methods for qui- nones.233 Much attention has been devoted to investigating the regio- and stereo-chemistry of Diels-Alder reactions by means of Lewis acid ~ a t a l y s i s ; ~ however, the acidic nature of the Lewis acid catalysts is not compatible with sensitive dienes or dienophiles prone to polymerization. The possibility of control- ling the course of Diels-Alder reactions by the use of aqueous solvents5.6 and by added cyclodextrins ( C D S ) ~ , ~ is also of considerable current interest. Although CDs have been known for several years to accelerate Diels-Alder reactions and enhance the endolexo stereo~electivity,~,~ surprisingly there have been few reports of their use in regio-selectivity control. As part of our continuing interest in using CDs to control diastereoselectivity in molecular reactions,x we report here a study in which aqueous CDs were applied to control the regioselectivity in Diels-Alder reactions of substituted 1,4-ben- zoquinones 1-3 with penta-1,3-diene 4 and isoprene 5.

ortho meta 0 0 0 ' 1 R' = Me, R2 = H 6 7 2 R1 = R2 = Me 8 9 3 R' = OMe, R2 = H 10 11 Scheme 1

The Diels-Alder reaction of methyl- 1,4-benzoquinone 1 with 4 in the presence and absence of Lewis acids in an organic solvent has been reported previously by Valenta.4" The reaction of 1 (0.2 mol dm-3) with 4 (0.2-0.35 mol dm-3) in acetone at room temp. leads sluggishly to a 64 : 36 mixture of ortho and

meta adducts, 6 and 7 (Scheme l), in 52% yield; however, 7 was

found to be the predominant product ( 6 : 7 = 31 :69) in BF3.0Et2 catalysed reactions (Table 1, entries 1, 5 ) . The regioselectivity of 6 : 7 was found to increase from 66:34 in water to 83 : 17 in aqueous CD solution. Products were formed less selectively with modified p-CDs, which may be due to unfavoured geometry in inclusion complexes (Table I, entries 3-4).* Table 1 summarizes some of our results in water and in (3-CDs, where the plateau value is reported; i.e. the relative yield

of ortho or metu products increased gradually with [p-CDs]

until a constant value was reached (Fig. 1). Product yields were also improved in the presence of P-CDs compared with those in water alone.

Similar results were observed for the addition of 2,6-di- methylbenzoquinone 2 and 2-methoxy-benzoquinone 3 with 4 (Table 1, entries 6-12). When p-CD solution was used, excellent ortho selectivities (8 and 10) with very good yields were achieved. Notice that this ortho selectivity is reversed from that of the Lewis acid-catalysed reaction, where metu was the only product formed (Table 1, entry 8 vs. 9). P-CDs also have a profound effect on the rate of the Diels-Alder reactions of 2 and 3; for example, less than 21% of adduct 10 was obtained in water compared to an 80% yield in (3-CD for the same reaction time (Table 1, entries 10-12).

The addition of isoprene 5 is usually regio non-selective in Diels-Alder reactions. For example, Houk9a and Chibagh independently reported that the Diels-Alder reaction of iso- Table 1 Diels-Alder reactions of isoprene 4 and penta-l,3-diene 5 with quinones 1-3 in different media

Entry Diene Dienophile Conditions" tlhh Product ratio' Yield(%)( Ref.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 1 1 1 1 1 2 2 2 2 3 3 3 1 1 1 1 1 2 2 2 2 2 Acetone Water (3-CD-Water 7-13-CD-Water BF3.0Et2-Toluene Benzene Water P-CD-Water Benzene Water P-CD-Water Acetone Water (3-CD-Water 7-p-CD-Water Benzene Water (3-CD-Water 7-(3-CD-Water BF3.OEt2-CH2C12 BF3.0Et2-CH2C12 BF3.OEt2-CH2C12 48 6 : 7 = 64:36 6 66 : 34 6 83: 17 6 70 : 30 31:69 47 8 : 9 = 90:10 9 d > 9 9 : I 40 > 9 9 : 1 5 0 : 100 48 1O:ll = 100:o 18 > 9 9 : 1 18 > 9 9 : 1 l l d 12:13 = 53:47 24 56 : 44 12 14:86 12 45 : 55 4.5 69:31 2 . 5 d 14:15 = 55:45 8 d 65 : 35 48 12:88 48 65 : 35 7 16: 84 - 52 4c 73 82 70 > 75 4c 64" 4d 25" 74d 90d 4r, 4d 77d 4e, 10 21d 80" 23 30 86 88 96 6 4d 4@ 76f2 21C' 93'

a Reactions were run at room temp. except for those of BF3.0Et2 at 0 "C and benzene at 1 10-1 15 "C. 7-(3-CD is heptakis-(6-O-hydroxypropyl)-fl-CD, [B-CDs]

= 0.14-0.28 mol dm-?. Reaction time in hours unless stated otherwise. Satisfactory spectral data and elemental analysis were obtained. Yields and ratios were determined by GC analysis (ca. +2%) unless otherwise specified. Isolated yields. Yields and ratios were determined by lH NMR.

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972 J. CHEM. SOC., CHEM. COMMUN., 1995

prene with 2,5-dimethyl benzoquinone shows a 1 : 1 ratio of para and rnetu adducts. Addition of isoprene to both 1 and 2 in the presence of 1-2 equiv. of (3-CD resulted in a large increase in the amount of nietu adducts (Scheme 2; Table 1, entries 13-15, 18-20). Note that the rnetu-selectivity in 1 with CDs is opposite to that with Lewis acid-catalysis10 (Table 1, entry 15 vs. 17); also, it would be difficult to achieve such a synthesis by other methods.? In the reaction of 2 with 5, both 6-CD and BF,.0Et2 reversed the normal para selectivity with excellent yield (Table 1, entries 19-22). Interestingly, such processes in CDs are often carried out in suspensions, and in these cases, the reaction proceeds via small amounts of dissolved reactants.

The observed preference for the ortho (reactions with penta-

1,3-diene 4) or meta (reactions with isoprene 5) regioselectivity in aqueous (3-CDs may be interpreted in terms of a 'cavity control' in the transition state for adduct formation. The

loo

1

I I I

0 1 2 3

[p-CD] I [Quinones]

Fig. 1 % meta-Adducts (13 and 15) from the Diels-Alder reactions of isoprene with toluquinone 1 and 2,6-dimethyl-1 ,4-benzoquinone 2 as a function of the ratio [p-CD]: [Quinones].

para meta n 0 0 0 1 R1 = Me, R2 = H 12 13 2 R1 = R2 = Me 14 15 Scheme 2

Table 2 'H NMR chemical shifts1 for protons of fi-CD and its complex with 13 ii H-1 H-2 H-3 H-4 13-5 H-6 (3-CD 1526.8 1095. I 1185.7 1074.3 1 154.7 1163.2 p-CD

+

(I Measured in a Varian Unity 300 MHz NMR at 24 k 0.5 "C in D 2 0 with

MeAi as an external standard.

occurrence of deep binding of the reaction products, naphthohy- droquinones, by CDs is supported by a report of Tabushi et a1.12 based on their study of the electronic and fluorescence spectra of complexes of CDs with substituted naphthohydroquinones or benzoquinones. Further support concerning the inclusion com- plexes comes from a lH NMR titration study, where the upfield shifts of H-3 and H-5 of (3-CD in D 2 0 can be attributed to the diamagnetic anisotropic shielding effect of the benzoquinone ring of adduct 13 (Table 2). The results for modified B-CDs also support the notion that inclusion complexes are needed, otherwise no reversal in selectivity can be achieved (Table 1, entries 21 vs. 19).

We thank the National Science Council of the Republic of China for financial support.

Received, 20th February 1995; Corn. 5101015B

Footnote

? Adducts 6,12 73"and 10'0 have been reported in the literature, our samples correspond in all respects with the reported properties. Compound 13 has been postulated but was not isolated before. Pure 13 (mp 76-77 "C) can be obtained by recrystallization from light petroleum (bp 35-60 "C) (Table 1, entry 15) 'H NMR (300 MHz, CDC13)O b 1.66 (3 H, br s), 1.99 (3H, d, J 1.5 Hz), 1.99-2.22 (2 H, m); 2.32-2.47 (2 H, m), 3.11 (1 H, t d , J 8.8, 5.9 Hz), 3.23 (1 H, td, J 8.8,5.9 Hz), 5.33-5.40 (1 H, m) and 6.5 1 (1 H, m). liC NMR 131.64, 136.08, 148.96, 200.40 and 200.53; IR (KBr) v/cm - I 2894, 2914, 1670, 1637 and 1621. (75.4 MHz, CDC11) b 16.31, 23.36, 24.79, 28.80, 46.25, 46.77, 118.40, References 1 2 3 4 5 6 7 8 9 10 11 12

R. H. Thomson, Naturally Occurring Quirzones, Chapman and Hall, New York, 1987.

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