J. Org. Chem., Vol.40,No.21, 1975 3079
Cleavage of a Cyclopropane Ring by Singlet Oxygen
Cleavage of a Cyclopropane Ring by Singlet Oxygen Ronald H. Rynbrandt* and Fred E. Dutton Diabetes and Atherosclerosis Research, The Upjohn Company, Kalamazoo, Michigan 49001 Received April 3,1975 The photooxygenation of the aminocyclopropyl sulfide cis-2- [(p-chlorophenyl)thio]-N,N,3,3-tetramethylcyclopropylamine (2) afforded mainly ring opened products which can be accounted for by the formation of and subsequent cleavage of a 1,2-dioxolaneintermediate. It is believed that this is the first reported singlet oxygen cleavage of a cyclopropane ring to occur via a 1,2-dioxolaneintermediate.
There is currently only one reported example of the cleavage of a cyclopropane ring during the photooxygenation of a cyclopropane. This occurred during the photooxygenation of the sesquiterpene gurjunene.l The authors attributed this cyclopropane cleavage to the presence of the transoid vinylcyclopropane system and proposed a mechanism which was based upon this structural feature. In the course of work directed toward the synthesis of cis-2-[(pchlorophenyl)sulfiny1]-N,N, 3,3-tetramethylcyclopropylamine ( 1),293 it was decided that a reasonable approach to this
sens
CHS'
" 2
N(CHJ2
l
o
I
CH, CH,
/
\
3 32 %
H
0
molecule would be by the singlet oxygen oxidation of the corresponding sulfide, cis-2-[(p-chlorophenyl)thio]-N,N,3,3-tetramethylcyclopropylamine(2).394 Foote and Peters5 have reported the photooxygenation of sulfides to afford the corresponding sulfoxides. However, application of their method to sulfide 2, while affording some oxidation at the sulfur atom, afforded mainly ring opened products which can be accounted for by the formation of and subsequent cleavage of a 1,2-dioxolane intermediate. It is believed that this is the first reported singlet oxygen cleavage of a cyclopropane to occur via a 1,2-dioxolane intermediate.
Results and Discussion Photooxygenation of a methanol solution of 2 using Rose Bengal as a sensitizer afforded the products shown in Scheme I. The products, with the exception of dimethylamine (9), were isolated by column chromatography and the yields are shown in Scheme I. The reaction mixture was also examined by GLC (see Experimental Section). The yields follow: 3 (29%),4 (30%),5 (6%), 6 (5%),7 (12%), and 8 (39%).These yields are in good agreement with the isolated yields (Scheme I). Five of the seven products, 3, 5, 7, 8, and 9, have been previously reported and were identified by comparisons of their physical constants and/or spectral data with those of the known compounds. The structure of compound 4 was assigned on the basis of elemental analysis and mass, ir, and 'H NMR spectra (see Experimental Section). The structure of 6 was identified as N,N,2,2-tetramethylmalonaldehydamide by comparison with an authentic sample. Compound 6 was independently synthesized by the reaction of N,N, 2-trimethylpropenylamine and phosgene to afford an iminiurn salt intermediate which was subgequently treated with dimethylamine and hydrolyzed. Halleux and Viehe6 have prepared the pyrrolidine analog in a similar manner. That the above reaction is indeed a singlet oxygen oxy-
CHj
II I
1
p-C1CGH4-S-C-C-H
I
CHJ 6
5 7%
3% 0
II + HC-N(CH,), + 8 44 %
HN(CHJ2 9"
nIdentified via GLC; yield not determined.
genation was shown by the following control reactions. When 2 was irradiated in the presence of Rose Bengal with molecular nitrogen being bubbled through the solution, in place of molecular oxygen, no reaction occurred. Nor did any appreciable reaction occur during irradiation of a solution of 2 continuously purged with molecular oxygen but in the absence of sensitizer. 1,4-Diazabicyclo[2.2.2]octane (Dabco) has been shown to inhibit singlet oxygen reactions but has little effect on free-radical reactions.' When an equimolar amount of Dabco was added the reaction rate was dramatically inhibited (21% completion in 14.5 hr vs. complete reaction without Dabco) with essentially no change in the product ratio (see Experimental Section). It was also shown that the two major products 3 and 4 were relatively stable to the phooxygenation conditions. None of the other products originated from these compounds. The photooxygenation reaction was found to be solvent dependent in that little reaction occurred in methylene chloride owing to the insolubility of Rose Bengal in this solvent. Also, little reaction occurred in acetone as a result of the rapid bleaching of the Rose Bengal. However, the use of tetrahydrofuran as the reaction solvent afforded the same products in essentially the same relative abundances as with methanol.
3080 J . Org. Chem., Vol. 40, No. 21,1975
It was found that Rose Bengal was a more efficient sensitizer in methanol than either Eosin Yellow or Methylene Blue. With Eosin Yellow the reaction was much slower, requiring 41 hr for completion, as opposed to 17 hr or less with Rose Bengal. The product ratio was essentially the same (see Experimental Section). With Methylene Blue the reaction was very slow as a result of the bleaching out of the sensitizer. Additional sensitizer was added; however, the reaction was only 20% complete in 22 hr. The product ratio was the same as with Rose Bengal (lH NMR). The formation of 3 as the major product quite likely arose from the formation and subsequent hydrolysis of 1. Indeed, examination of the reaction mixture (lH NMR) before completeness of reaction showed the presence of a small amount of 1. We have previously reported that 1 is rapidly hydrolyzed to 3 and dimethylamine.2 The formation of the remaining reaction products can be best rationalized in terms of the 1,2-dioxolane intermediate A* (Scheme 11). The formation of A can be accounted for by the trapping of a 1,3 diradical generated from 2 or by attack of singlet oxygen across the electron-rich Cl-Cz bond of 2 as in the case of electron-rich o l e f i n ~ . ~Whether ,l~ the fragmentation of A proceeds via diradical intermediates B and/or C1' or an ionic mechanism cannot be answered with certainty a t this time. However, the migration of the p chlorophenylmercapto group to afford 4 can be best explained on the basis of a radical fragmentation. The vicinal migration of arylmercapto groups in radical reactions is well documented.12J3J4 Adam and Durln have recently studied the photolysis of 1,2-dioxolanes and have observed an analogous migration of the phenyl group.sb Fragmentation of B at point a (Scheme 11) would lead to, after requisite hydrogen atom rearrangement, 6 and p chlorothiophenol which would subsequently be oxidized to disulfide 7. It was demonstrated that p-chlorophenol is rapidly oxidized to disulfide 7 under the reaction conditions. Fragmentation of B at point b would afford C, which with hydrogen rearrangement would afford 5 and with p chlorophenylmercapto migration would afford 4. Experimental Section Ail melting points were determined on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Ir spectra were
Rynbrandt and Dutton
obtained on a Perkin-Elmer Model 421 recording spectrometer, the IH NMR spectra were recorded on a Varian A-60A spectrometer, and the mass spectra were determined on an Atlas CH-4 spectrometer. GLC analyses were performed on a Hewlett-Packard dual flame gas chromatograph Model 402 using a 6-ft HIEFF-8BP Gas-Chrom-Q 100/120 (3%) column.15 The internal standard method was used for yield determinations. Photooxygenation of cis-3-[(p-Chlorophenyl)thio]-N,N,3,3-tetramethylcyclopropylamine(2). A solution of z2p3(8.0 g, 0.031 mol, 0.2 M ) and Rose Bengal (50 mg) in anhydrous methanol (150 ml) was irradiated with 16 8-W, cool-white fluorescent lamps in a Rayonet photochemical reactor while oxygen was bubbled into the solution. The solution was maintained at 25 i 2' by means of a cold finger. Irradiation was discontinued after 17 hr, at which time no starting material remained (TLC). The reaction was repeated twice more and the crude reaction mixtures were combined and concentrated in vacuo to afford a viscous brown oil (25 9). The oil was subjected to adsorption chromatography on silica gel (4 kg). The fractions (300 ml) and eluents were 1-27 (benzene); 28-57 (5-10% ethyl acetate in benzene, gradient elution); 58-80 (20% ethyl acetate in benzene); 81-119 (50% ethyl acetate in benzene); 120-180 (5% methanol in chloroform); and 181-200 (50% methanol in chloroform). Concentration of fractions 18-23 afforded 1.43 g (11%yield) of bis(p-chlorophenyl) disulfide (7). The structure of 7 was determined by comparison of its ir, IH NMR, melting point, and mass spectra with those of an authentic sample.16 Concentration of fractions 25-30 afforded 1.4 g (7% yield) of p chlorophenyl isothiobutyrate ( 5 ) : bp 105-107O (4 mm) [lit.17 bp 147-148' (13 mm)]; ir (CHC13) 1710 cm-' (C=O); IH NMR (CDC13) 6 1.26 (d, 6 H, J = 6.5 Hz), 2.77 (sextet, 1 H, J = 6.5 Hz), 7.32 (9, 4 H); mass spectrum m/e 214,216 (M+). Anal, Calcd for CloH11ClOS: C, 55.93; H, 5.16; C1, 16.51; S, 14.94. Found: C, 55.79; H, 4.90; C1, 16.61; S, 15.15. Concentration of fractions 33-44 afforded 4.9 g (25% yield) of 2[(p-chlorophenyl)thio]-2-methylpropionaldehyde(4):bp 114-115' (4 mm); ir (CHC13) 1720 (C=O) and 2720 cm-' (aldehyde C-H); IH NMR (CDC13) 6 1.32 (s, 6 H), 7.30 (s, 4 H), 9.32 (s, 1 H); mass spectrum mle 214,216 (M+). Anal. Calcd for CloHI1ClOS: C, 55.93; H, 5.16; C1, 16.51; S, 14.94. Found: C, 56.01; H, 5.30; C1, 16.79; S, 14.92. Concentrations of fractions 109-125 afforded 7.2 g (32%yield) of 3-[(p-chlorophenyl)sulfinyl]-2,2-dimethylpropionaldehyde (3)? mp 61-62O (hexane); the ir, 'H NMR, and mass spectra were identical with those of 3 prepared below. Concentrations of fractions 166-180 afforded 3.0 g (44%yield) of dimethylformamide (8) which was identified by comparison of its ir, IH NMR, and mass spectra with those of an authentic sample. Concentrations of fractions 186-200 afforded 0.4 g (3% yield) of
J.Org. Chem., Vol. 40, No. 21,1975
Cleavage of a Cyclopropane Ring by Singlet Oxygen N,N,2,2-tetramethylmalonaldehydamide(6). The ir, 'H NMR, and mass spectra were identical with those of 6 prepared below. GLC Analysis of the Photooxygenation of 2 Using Rose Bengal in Methanol. The photooxygenation of 2 was carried out in the above described manner. The reaction was monitored by GLC and shown to be complete in 14.5 hr. The yields follow: 3 (29%),4 (30%),5 (6%),6 (5%),7 (12%),and 8 (39%).Several minor products (
