Synthesis and Chemistry of Agrochemicals II - American Chemical

Chapter 20

Synthetic Transformations of Acylcyclohexanediones 1

1

2

James E. Oliver , William R. Lusby, and Rolland M. Waters Downloaded by UNIV OF CALIFORNIA SAN DIEGO on January 23, 2016 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch020

1

2

Insect Hormone Laboratory and Insect Chemical Ecology Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705

2-Acylcyclohexane-1,3-diones, which in fact exist as the enolic 2-acyl-3-hydroxycyclohex-2-en-1-ones, are easily prepared from readily available materials and serve as starting materials for a variety of derivatives. In this paper we review the synthesis of isomeric and hydroxylated systems, and also describe other selected transformations that may be generally useful. Interest in acylcyclohexanediones has been increasing because of their recently discovered occurrence as insect-derived natural products (1-4) and because they and their derivatives constitute a rapidly emerging class of herbicides (5). Unlike many exercises in organic synthesis, which focus on carbon-carbon bond formation, much of our synthetic work on these systems has involved the manipulation - both location and oxidation state - of oxygen substituents. This paper will review some of our efforts in that area. 2-Acylcyclohexane-l,3-diones 1 exist as the enols 2, so that the correct nomenclature is based on 2-acyl-3-hydroxycyclohex-2-en-l-ones. The system has been known for many years, but interest was revived by Mudd (2) who reported the occurrence of several examples of 2, and of the 6-hydroxy homologs 3, in mandibular glands of larvae of the moth Ephestia kuehniella Zeller (R=long, unsaturated chain). Mudd subsequently described syntheses of several analogs of general structure 2; this involved reaction of cyclohexane-l,3-dione with an acid chloride followed by rearrangement of the resulting enol ester 4 by boiling in toluene with a 4-dialkylaminopyridine to give 2 (6). Recent patent literature (1) has described alternative conditions for the 4 2 rearrangement that involves a source of CN" and a tertiary amine; under these conditions the rearrangement occurs smoothly at room temperature. Cyclohexane-l,3-dione is readily available, so general structure 2 is in most respects as available as the corresponding carboxylic acid. An exception occurs with α,β-unsaturated acids; we found that rearrangement of enol ester 5 under either of the conditions mentioned gave the enol lactone 7 instead of the dihydrochromanone 6. There is precedent for the 5 7 type rearrangement (8); it has also been reported that α,β-unsaturated acid chlorides react with cyclohexane-l,3-dione in the presence of TiCL to give 6 directly (2), although this reaction has not been successful in our attempts (RCOCl=(E)-2-decenoyl chloride). This chapter not subject to U.S. copyright Published 1991 American Chemical Society

In Synthesis and Chemistry of Agrochemicals II; Baker, Don R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on January 23, 2016 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch020

248

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

The 6-hydroxy compounds 3 (R=saturated or unsaturated C,« or chains) became of interest when they were identified as the major components of retal exudates of immature lace bugs of the genus Corythucha (12). We recently completed the first synthesis of this class of compounds (10); this work will be discussed in more detail elsewhere in this volume, but one of its key features included converting die easily available 2 to its dihydrobenzisoxazolone derivative 8. This proceduretiedup two of die three oxygens of 2, circumventing competitive enolizations and insuring regioselectivity in die hydroxylation to 9, which was in turn converted, via 10, to 3. (Scheme 1). In contrast to the readily available 3, the isomeric 2-acylcyclohexane-l,4-dione (actually a 3-acyl-4-hydroxycyclohex-3-en-l-one) 11 had not been reported. We have recently completed a synthesis of 11 (R=n-C«« H^), again utilizing the dihydrobenzisoxazolone 8 (11). Lithium aluminum hydride reduction of 8 gave the alcohol 12 (Scheme 2) which readily eliminated water to give the dihydrobenzisoxazole 13. Hydroboration/oxidation of 13 primarily regenerated 12; however LiAlH* reduction of epoxide 14 gave the desired alcohol 15 with very litde of the unwanteaisomer 12. Oxidation of 15 with pyridinium chlorochromate gave ketone 16 which is the isoxazole derivative (i.e. a masked form) of target ketone 11. Conversion of an isoxazole to a 1,3-diketone simply requires reductive cleavage of the N-O bond followed by hydrolysis of the resulting enaminoketone. For the conversion of 9 to 3 (Scheme 1), catalytic hydrogénation (or NaBHJNiCWDMF) had achieved thefirsthalf of the sequence (9 - 10), and aqueous NaOH had effected the hydrolysis of 10 (in this case an iminoenol instead of an enaminoketone) QQ). The transformation 16 11 proceeded differently in each step: reduction of the carbonyl of 16 tended to compete with reduction of die N-O bond, and the reduction product 17 was stable to aqueous base. The latter problem was not really a problem because treatment of 17 with aqueous acid achieved the desired hydrolysis. This contrast in reactivities between 17 and 10 reflects the structural difference, enaminoketone vs. iminoenol, respectively; the distinction can also be inferred from their H-NMR spectra (10.11). We briefly explored alternative methodology for the conversion of 16 to 17 including NaBH./NiCWMeOH and also Mo(CO) in moist acetonitrile (12), and although improvement/in selectivity were achieved, recoveries tended to be somewhat unsatisfactory. To circumvent die problem of carbonyl reduction during the 16 -> 11 conversion, 16 was converted to its ethylene ketal 16a (Scheme 3). Mild acid hydrolysis of 17a achieved hydrolysis of the enamine, but not of the ketal, and, in fact, hydrolysis of the product 11a required such forcing conditions that aromatization became a competing reaction, producing the hydroquinone derivative 18. In contrast, both the enamine and ketal functionalities of the propylene ketal 17b were smoothly hydrolyzed with mild acid to provide the target ketone 11. At this point we briefly reinvestigated hydroxylations. Our purpose in the original synthesis of 3 had been twofold: to obtain material to work with, but also to confirm the structural assignment. The hydroxylation procedure we used was that developed by Rubottom (12); it depends, like so many important reactions, on the enolization of a ketone, and by converting 2, which has four potentially enolizable positions (two of them equivalent), to 8, we produced a system with a single enolizable position and thereby ensured the required regioselectivity in the 8 •+ 9 conversion (see the companion paper, Lusby and Oliver, elsewhere in this volume). Although conditions have not been optimized, we have recendy observed that it is possible to convert 2 to 3 in a single step. Treatment of 2 with two equivalents of strong base afforded dianion 19 (Scheme 4) which, when reacted with oxaziridine 20 6


20.

OLIVER ET AL.

Synthetic Transformations ofAcykyclohexanediones

ai" ai" Ο

O


1

OH

OH

O

2

O

OH

3

o I 2

7 Ο

Ν

8

10

f

>

O

N

OH

OH

OH

9

10

NH

3

a . 4-(dialkylamino)pyrkJine, Δ . 2) T M S C I , 3) A r C 0 3 H , 4) F'.

b. acetone cyanohydrin, E L N . θ. H 2 , Pt. f. N a O H .

c. Ν Η , Ο Η .

Scheme 1


d . 1 ) LDA,

249

250



OH

Ο

ο 11

16 g. LAH.

h. TsOH.

i. ArC0 H. 3

j . B H , H202. 2

e

k. PCC.

Scheme 2


OLIVER ET AL.

Synthetic Transformations of Acylcyclohexanediones


O

NH

O

2

NHg

OH

O

17 16

O

NH,

NCH,),/

16a 16b OH

it

17a

n=2 n=3

17a 17b

n=2 n=3

O

OH

->

11 •

ί OH

18

111

17 b H , Pt. 2

->

O

11

I. aqueous oxalic acid.

n. HO(CH ) OH, Η . 2

n

+

ο.

H S0 2

4

Scheme 3


in Me CO. 2

251


252

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II

Scheme 4



20. OLIVER ET AL.

253 Synthetic Transformations ofAcylcyclohexanediones

(14), gave 3 directly. The dihydrobenzisoxazolone 8 was also hydroxylated under similar conditions (one equivalent of base) to give 19, the same product obtained from the Rubottom (13) procedure. In contrast, none of the anticipated 22 was observed when the isomer 16 was subjected to identical conditions; instead, 9 was again obtained. This unexpected reaction has not been further investigated, but may proceed through an enediolate. The formation of 3, and not 21, from 2 via this hydroxylation sequence indicates that the dianion formed from 3 has structure 19 and results from abstraction of a hydrogen from position 6 of 2 instead of from position 2' of the side chain (in which case 21 should have resulted). In contrast, in three examples of dianion formationfrom2-acetylcyclohexanone 23 cited in a review (15), the second hydrogen was abstractedfromthe 2' position (23 •+ 24 products, Scheme 5). We have one further experience that suggests that deprotonation occurs preferentially from the 6-position instead of from fie 2'-position of 2-acyl-3-hydroxycyclohex-2-en-l-ones: treatment of the 2-acetyl compound 25 with two equivalents of lithium diisopropylamide followed by decanal gave an aldol product that, although not completely characterized, consisted of a pair of poorly separated (by GLC) isomers with essentially identical mass spectra believed to be the pair of diastereomers 26. In contrast, had reaction occurred at the methyl group, diastereomers would not have been produced (structure 27). Thus dienolate ions from 2 may represent untapped resources with respect toringsubstitution and elaboration. We recently identified 2,6-(dihydroxy)undecanophenone 28fromthe andromeda lace bug Stephanitis takeyai (16), and our interest in this compound was stimulated when it was found to possess high prostaglandin synthase inhibition activity (12). Although 2,6-dihydroxyacetophenone homologs like 28 are not particularly complicated molecules, there is no really simple general method for their synthesis. 2,6-Dimethoxybenzaldehyde and 2,6-dimethoxybenzoic acid are commercially available as potential precursors, but the former is expensive and in any event the vigorous conditions required for removal of the methoxyl groups make ο

23

24

OH

25

ο

CH~OH C

O

OH

27

H

9 19

26

Scheme 5


254


alternatives attractive. The easy availability of 2 makes it attractive as a potential precursor, and since it is only one oxidation state removed from the aromatic 28, we assumed that the required dehydrogenation/aromatization (2 28 Scheme 6) would be relatively easy to achieve. Contrary to these expectations, and in contrast to the unwelcome ease of the 11a •+ 18 oxidation (Scheme 3) the 2 28 conversion has been particularly difficult, and we have tried with little or no success the following reagents or conditions: CuBr^/LiBr/MeCN, DDQ/dioxane, D D Q / D M F , DDQ/collidine, C^H^N-HBr^, PdCli/f-BuOH, PdCWAc^O, Pd on C/l-decene/tetralin, Pb(OAc) ?. Some success has been achieved with Hg(OAc) + NaOAc in HOAc, and we are currendy optimizing conditions to develop a procedure for the convenient synthesis of 2,6-dihydroxyacetophenone derivatives of type 28.


2

Scheme 6 Acknowledgments We appreciate the assistance of K. R. Wilzer and D. J. Harrison. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Lusby, W. R.; Oliver, J. E . ; Neal, J. W. Jr.; Heath, R. R. J. Nat. Prod. 1987, 50, 1126. Lusby, W. R.; Oliver, J. E . ; Neal, J. W. Jr.; Heath, R. R. J. Chem. Ecol. 1989, 15, 2369. Mudd, A . J. Chem. Soc. Perkin Trans. I 1981, 2357. Nemoto, T.; Shibuya, M . ; Kuwahara, Y.; Suzuki, T. Agric. Biol. Chem. 1987, 51, 1805. Sato, N.; Uchiyama, Y.; Asada, M . ; Iwataki, I.; Takematsu, T. C H E M T E C H 1988, 430. Mudd, A . J. Chem. Ecol. 1985, 11, 51. Knudsen, C . Eur. Pat. Appl. EP 249, 150, 16 Dec. 1987; Chem. Abstr. 1988, 109, 6219u. Gelin, S.; Chantegrel, B. C. R. Acad. Sc. Paris C 1971, 273, 635. Arnoldi, A . Synthesis, 1984, 856. Oliver, J. E . ; Lusby, W. R. Tetrahedron 1988, 44, 1591. Oliver, J. E . ; Lusby, W. R.; Waters, R. M . J. Agric. Food Chem., in press. Nitta, M . ; Kobayashi, T. J. Chem. Soc. Chem. Commun., 1982, 877. Rubottom, G. M . ; Gruber, J. M . ; Juve, H . D. Jr.; Charleson, D . A . Org. Syn. 1985, 64, 118. Davis, F. Α.; Vishwakarma, L. C.; Billmers, J. M . ; Finn, J. J. Org. Chem. 1984, 49, 3243. Kaiser, Ε . M . ; Petty, J. D.; Knutson, P. L. A . Synthesis 1977, 509. Oliver, J. E.; Lusby, W. R.; Neal, J. W., Jr. J. Chem. Ecol. Submitted. Jurenka, R. Α.; Neal, J. W., Jr.; Howard, R.; Oliver, J. E . ; Blomquist, G. J. Comp. Biochem. Physiol. 1989. In press.

RECEIVED November 21, 1989


Synthesis and Chemistry of Agrochemicals II - American Chemical

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