P ht halimide - Induced Rearrangement
J . Org. Chem., Vol. 43, No. 21, 1978 4143
P. W. R. Corfield, bid., 92, 2581 (1970);F. G.Bordwell and E. Doomes, J. Org. Chem., 39, 2526 (1974):L. Ramberg and B. Backlund, Arkiu Kemi Mineral Geol., 13A, No. 27 (1940);Chem. Abstr., 34,4725 (1940). (2)N. P. Neureiter, J. Am. Cbern. SOC.,88, 558 (1966). (3)C. R. Johnson and H. G. Corkins, J. Org. Chem., companion paper in this issue. (4)L. A. Paquette, "Advances in Organic Chemistry", Vol 6,E. C. Taylor and H. Wynberg, Eds., interscience. New York, N.Y., 1969. (5) The protons and the carbon atom which do not carry the halogen will be referred to as the a' position, while the protons and the carbon atom bearing
the halogen will be called the (Y protons or a carbon: F. G. Bordwell, E. Doomes, and P. W. Corfield, J. Am. Chem. SOC., 92, 2591 (1970);F. G. Bordwell and B. B. Jarvis, ibid., 95, 3585 (1973). (6) F. G.Bordwell and G. D. Cooper, J. Am. Chem. SOC.,73, 5187 (1951). (7) In an experiment performed by Dr. Susan O f f it was found that S-(bromomethyl)-Smethyl-Ktosylsulfoxirnine was reduced to S,Sdimethyl-K tosylsulfoxirnine by potassium sulfite in refluxing methanol. (8) Y. Tamura, K. Sumoto, J. Minamikawa, and M. Ikeda, TetrahedronLen., 4137 ( 1972). (9)C. R. Johnson and C. W. Schroeck, J. Am. Chem. SOC.,95, 7418 (1973).
Rearrangement Reaction of l-Chloro-4-[p-(carbomethoxy) thiophenoxyl-2-butanone with Potassium Pht halimide Shiang-Yuan Chen and M. G. Nair* Department of Biochemistry, College of Medicine, Unioersity of South Alabama, Mobile, Alabama 36688 Received June 5, 1078 Treatment of l-chloro-4-[p-(carbomethoxy)thiophenoxy]-2-butanone with potassium phthalimide in acetonitrile resulted in skeletal rearrangement with t h e formation of 1-phthalimido-4- [ p-(carbomethoxy)thiophenoxq.]-3butanone. T h e structure of the rearrangement product was established by independent synthesis and mass spectrometry. T h e isolation of some intermediates from t h e reaction mixture gave evidence for t h e mechanism of this reaction; these mechanistic considerations guided t h e successful synthesis of 1-phthalimido-4- [p-icarbomethoxy)thiophenoxyl-2-butanone.
As part of a continuing program1-6 aimed a t developing folate analogues that are altered a t the C9-N10 bridge region for possible use as anticancer agents,7 we were interested in the synthesis of 11-thiohomofolicacid, which is an analogue of homofolic acid.8 A t the outset, we explored methods for the construction of the partial side chain 2, which could eventually be elaborated to the title compound 1. In this regard, we investigated the reaction between chloro ketone 5 and potassium phthalimide. Chloro ketone 5 was conveniently prepared by the nucleophilic addition of p -carbomethoxythiopheno14 to hydroxymethyl vinyl ketone9 and subsequent treatment of the resulting addition product with thionyl chloride. Treatment of 1 equiv of chloro ketone 5 with a solution of 2 equiv of potassium phthalimide in acetonitrile containing crown ether for 4 h a t ambient temperature and subsequent workup of the reaction mixture gave a product that displayed NMR resonances a t 7.9 (d, J = 9 Hz, 2 H), 7.8 (c, 4 H), 7.3 (d, J = 9, 2 H), 3.97 (t, J = 7 , 2 H), 3.9 (s, 3 H ) , 3.8 (s, 2 H), and 3.09 (t, J = 7, 2 H) ppm. These resonances, although they appeared to be consistent with the expected structure 3a, were proved to be due to the alternate structure 4a. This compound, on reaction with hydroxylamine, gave an oxime and on ketalization with ethylene glycol gave a crystalline ketal. Treatment of the oxime with hydrazine, in a standard hydrazinolysis reaction, liberated an aminoacetonyl oxime, which was different from 2a, but reacted with 2-amino-6chloro-4-hydroxy-5-nitr~pyrimidine~ to obtain an intermediate (7a).This reaction product, possessing spectral characteristics and giving analytical data consistent with either structure 7a or 8a, was deprotected a t the carbonyl function using trifluoroacetic acid and 1 N HCl, as previously described.j The deprotected nitro ketone thus obtained was subjected to the dithionite reduction and one-step cyclization oxidation technique to generate the homopteroic acid analogue 9,4,5J0 Although the dithionite reduction of the nitro group t o the amino group worked well, the subsequent cyclization of the pyrimidine to the dihydropteridine did not occur.
Repetition of the same reaction sequence using a ketal protective group also resulted in complete failure of its transformation to the pteridine. Since several analogous amino ketones were readily cyclized to the pteridines, and no failures were reported in literature in using such an approach to the general synthesis of pteridines, it became apparent that the crown ether reaction product between chloro ketone 5 and potassium phthalimide did not have the expected structure 3a. Since this product was a ketone, which could easily be converted to an oxime and an ethylene ketal, the alternate structure 4a was proposed for this product. Indeed, if this product had structure 4a rather than 3a, then the failure to construct the pteridine ring using this material can easily be understood. These expectations were proved correct (vide infra). The transformations are summarized in Scheme I. In order to prove that the crown ether reaction product has structure 4a, an unambiguous synthesis of this material was undertaken. Reaction of phthalic anhydride with d-alanine gave N-(3-~arboxypropyl)phthalirnide(131, which was converted to an acid chloride by reaction with thionyl chloride. Treatment of the acid chloride with ethereal diazomethane gave the diazo ketone 14, which was converted to the corresponding chloromethyl ketone 15 by standard procedures.11 Reaction of p-(carbomethoxy)thiopheno14with 15 was carried out in acetone using 1 molar equiv of anhydrous sodium carbonate; subsequent workup of the reaction mixture gave a product that was identical with the crown ether reaction product in all respects (TLC, NMR, mp). Thus, the structure of the product obtained by reaction of chloromethyl ketone 5 with potassium phthalimide was unequivocally established as 4a.
Mechanism of the Reaction When equimolar amounts of chloromethyl ketone 5 and potassium phthalimide were allowed to react in the presence of crown ether using acetonitrile as a solvent, it was observed by monitoring the reaction by TLC that a product was being
0022-3263/78/1943-4143$01.00/00 1978 American Chemical Society
4144 J. Org. Chem., Vol. 43, No. 21,1978
Chen and Nair Scheme I
$Ns-kW H
formed in the reaction mixture that was less polar than 4a. Under these conditions, this product predominates; only very little 4a is formed (-lo??). However, addition of 1equiv more of potassium phthalimide at this stage resulted in the complete disappearance of this material with the concomitant formation of 4a. Therefore, it became clear that this reaction occurred in a stepwise fashion; 4a is formed by reaction of potassium phthalimide with the less polar intermediate. In order to prove this assumption, conditions were optimized so that the less polar intermediate (hereto referred to as 11) could be isolated and characterized. Compound 11 had a molecular weight of 404, as determined by mass spectrometry, and showed NMR resonances in TFA at 7.95 (d, 4 H), 7.4,7.33 (d d, 4 H ) , 4.06 (s, 6 H), 3.93 (s, 2 H), and 3.25 (c, 4 H) ppm. The formation and isolation of 11 requires the formation of p (carbomethoxy)thiophenolateanion in the reaction mixture, which in turn should result from a reverse Michael addition to chloro ketone 5 by potassium phthalimide. If this assumption was correct, then we reasoned that weak nucleophiles, such as sodium acetate, might be used to generate a phenolate anion from 5 , which on reaction with chloro ketone 5 should yield intermediate 11 in quantitative yield. This is because we had prior knowledge that intermediate 11 is stable to sodium acetate in boiling methanol. Thus, treatment of a solution of 5 in boiling methanol with excess sodium acetate gave intermediate 11 in quantitative yield, as required by the proposed mechanism. Next, the fate of 4-chloro-3-butenone, which is a compulsory co-product of the reaction between 5 and sodium acetate, was investigated. Evaporation of the reaction mixture, after removal of 11 by filtration, extraction of the residue with ether, and evaporation of the ether layer, yielded an oil that gave an NMR spectrum that was identical with 4-chloro-3-butenone. This compound, a sample of which was available, was found to be stable to sodium acetate under conditions of the above reaction. These experimental results clearly demonstrated the mechanism by which 11 was generated from 5 on treatment with potassium phthalimide. Next, we examined the mechanism of the subsequent steps by which 11 was converted to 4a. Treatment of 11 with potassium phthalimide in acetonitrile, with or without the
s presence of crown ether, resulted in the formation of two products, one of which was identical with 4a. The other product, which was less polar than 4a, was identified as 16 by isolation after workup and chromatography of the reaction mixture. This material was identical in all respects with an authentic sample4 of 16. On the other hand, by monitoring the reaction by TLC until all 11 had disappeared, evaporation and ether extraction of the reaction mixture resulted in the isolation of p-(carbomethoxy)thiophenoL4The isolation of p (carbomethoxy)thiophenol and dimer 16 from the reaction mixture gave evidence for the mechanism of formation of 4a from 11. It is postulated that attack of potassium phthalimide on 11 resulted in the formation of an enolate that collapsed to an intermediate 12; a retro Michael reaction and subsequent addition of phthalimide to 12 in a Michael addition resulted in the formation of 4a with the liberation of the resonancestabilized thiophenolate anion. The enhanced stability of 4a toward potassium phthalimide, compared to 11, together with the formation of a thermodynamically more stable intermediate (12) from 11 facilitates the formation of 4a. A direct nucleophilic attack of phthalimide anion on 11 with concurrent displacement of the thiophenolate anion is unlikely because one would anticipate the production of both 4a and 3a by this mechanism. From the preceding discussion, it is apparent that the initial formation of the enolate from 5 leads to the formation of 11. Due to the ease of formation of 12, nucleophillic displacement reactions on 5 results in the formation of rearranged products. Therefore, any attempt involving direct displacement of chlorine of 5 by a nucleophile should be carried out under conditions which avoid enolate formation. On reaction of 5 with HzNOH, chloro ketone 5 could be converted to the chloroacetonyl oxime 6 under carefully controlled conditions. Reaction of 6 with potassium phthalimide in acetonitrile or DMF resulted in the formation of an oxime 3b, which was not identical with 4b. Deprotection of the carbonyl group of 3b with aqueous TFA resulted in the formation of a ketone, which was an isomer of 4a but was not identical with it. The compound showed relevant NMR signals at 7.98 (m, phthalimido, 4 H), 7.84,7.35 (d, d, arom, 4 H), 4.53 (s,methylene, 2 H), 3.93
J. Org. Chern., Vol. 43, No. 21, 1978 4145
Phthalimide-Induced Rearrangement Scheme I1
C H30-@S-S@-0
I
CH3
Y'
-",!
(s, carbomethoxy, 3 H), and a t 3.29 and 2.93 (t, t, ethylene, 4 H) ppm and had a different R f value and melting point. Structure 3a was assigned to this product after comparing its mass spectral fragmentation pattern with that of 4a. The relevant fragments and their respective mle values are presented in Table I. The presence of fragments representing mle values of 188,195, and 223 in the mass spectrum of 3a and the total absence of these fragments in the spectrum of 4a establishes the structure of 3a as written. The mass spectrum of 4a shows a fragment representing an mle value of 174, which is completely absent in the spectrum of 3a. Since this value of 174 represents the N-ethylphthalimide fragment, the Table
fragment
I
mass to charge ratio ( d e ) 4a 3a 404 174
404 absent
181
181
absent
195
absent
223
160
160
absent
188
0
-
~-CH2
