V d . 17 No. 6 CHINESE JOURNAL OF CHEMISTRY 1999

Studies on organophosphorus compounds 104 Reaction of carbanions derived

from alkylphosphonates

Ahptract Structural effect of substituents directly bonded to carbanions beanng a phosphonate moiety is ex- amined. Nucleophhc addition of phasphonate carbanion to 1-nitdkene followed by subsequent reaction with

chlorohimethylsh leads to a series of 2-isoxamline based on the formation of an alkene and silyl nitronate as a

1,3-dipole. On the other hand, addition of carbanion derived h isocyanomethylphosphonate to nitroalkene with he formation of nitronate followed by inhwn~lecular cyclization pmvides substituted pha~phoryl pyrroles.

Keywords Phosphonate carbanion, 4,5-dihydroiixamle, 1,3-dipole

Introduction

Carbanions are a class of important reactive intermediates in organic chemistry. Phosphonate carban-

ion constitutes the well-known Homer-Emmons-Wadsworth reaction, a facile, stereospecific mute convert- ing &nyl function to alkenes. As far as we are aware of, chemical reaction of phosphonate carbanions are not well stud~ed. As reported by us,' nucleophilic addition of carbanion derived from diethyl methylphcsphonate to nitroethylene followed by treaiment with chlomtrimethylsilane gave the corresponding silyl nitmnate as a 1, 3-dipole which upon treatment with monosubstituted alkene af€oded 4'-( di- ethoxyphosphoryl) ethyl 4,5-dihydroisoxazole derivatives in a one-pot procedure. On the other hand, car- b o n derived from diethyl isocyanomethylphosphonate reacted smoothly with a-ni tdkene leading to the formation of 3, C&substituted 2-phosphorylpyrrole . These data demonstrated that the phosphonate car- banion-based reaction is the convenient synthetic method for the preparation of phosphoryl -pyrroles and/ or -isomles. Heterocycles bearing a phosphonate moiety comprise an important class of compounds with potential biological activities. Unfortunately, direct phosphorylation of heterocycles via P-C bond forma- tion on the carbon atom located in the heterocycle ring system seems impractical. The phosphonate car- banion pathway is therefore regarded as the building block in the formation of phosphorylated heterocy-

Received February 3, 1999; accepted April 22, 1999. h j e c t (No. 29672042, 29832050) supported by the National Natural Science Foundation of China.

LJ&WAN Phosphonate &on 685

cles .

R d t s and discussion

Electron-withdraw;ng p u p (EWG) substituted diethyl methylphosphonates (1) reacted with trm-

2-nitro-1-phenylpmpene in the p m n c e of one equivalent of BuLi as the base to give the anion 2, which rearranged to the more stable anion 3. Qlllte contrary to Tamura' s results, no cyclopmpane derivatives

4 5 6

7 Y = P(O)(OEt), (a). COOMe 0). S02Me (c), CN (d)

L BuLi/THF\or LDAITHF), -7OOC n PhwMe R COMe, C02Me

iii. TMSCI NO2

were detected even under prolonged reaction at room tempera- for 2-3 days. This result might be due to the poor leaving ability of the nitro p u p . On the other hand, an equilibrium between anion 3 and 4a/ nitroethane anion was observed in the reaction of la . Since the anion of l a showed inertness toward chlorotrimethylsilane , we observed that, with the addition of this silyhting agent to the reaction mixture,

4a and trimethylsilyl nitronate 5 were formed. By further regioselective 1,3-diplar cycloaddition of 4a to 5, 2-isoxazoline derivative 6a was isolated in high yield. 'Ihis situation encouraged us to investigate the reaction of 3 k 3 d with chlomtrimethylsilane. As for sulfonyl and carbony1 p u p , the corresponding in- termediate 8 and 9 would be produced. By quenching with an acid, only the n o d Michael addition product was isolated in the case of l b as a typical example. ?%en we added to the intermediate 8 or 9, however, a catalytic amount of base such as triethylamine or diisopropylamine , the corresponding com- pound 6 was then isolated in good yield after stimng at room temperature for about 2 days. 'Ihis result in- dicated that the intermediate 8 or 9 underwent base-catalyzed rearrangement in which the trimethlysilyl p u p was migrated to the oxygen atom of the nitm p u p via a transition state involving an eight-mem- b e d ring and an alkene 4 and silyl nimnate 5 were produced. Further regioselective 1,3-dipolar cy-

686 Chinese Journal of Chemistry Vol. 17 No. 6 1999

cloaddition of 4 and 5 gave the corresponding 4,5-dihydroisoxazole 6 . Compounds 4 and 6 could be both isolated if we quenched the reaction with an acid before cycloaddition was complete. This is the additional evidence supporting the proposed reaction mechanism. The rearrangement also indicated that the 0-Si bond in silyl nitronate might be more stable than that in 8 or 9, and the difference serves as the driving force in the rearrangement.

8 9 10

As for anion 3d beanng a cyano p u p , silylation should occur at the nitrogen atom of the cyano p u p to give the intermediate 10. Since the bond energy of 0-Si is much higher than that of N-Si bond, transfer of the trimethylsilyl group from the nitrogen atom to the oxygen atom of the nitro p u p is much easier and the corresponding alkene 4 and 5 were also formed via the rearrangement. Further reac- tion between 4 and 5 also gave the 4,5-dihydroisomle derivative 6d substantially.

Based on the above discussion, Michael addition of compound 5 to a - n i d k e n e in the presence of an equivalent LDA as the base followed by the i n d u c t i o n of chlorotrimethylsilane led to a one-pot syn- thesis of 4,5-hydmisoxazole derivatives 6. This reaction pmvided a novel and convenient synthesis of 4,5- dihyhisoxazoles . It should be noted that in this reaction diisopmpylamine played two important roles-to promote the rearrangement of interndates 8, 9, 10 and to stabilize the trimethylsilyl nitronate 5 formed in the rearrangement.’

Me

6c

6d 11

11

HCN M e d P h

12

It should also be noted that, since Y is not identical with phosphoryl p u p in 6, the latter was ob- tained as the mixture of two stereoisomers which could not be separated by column chromatography on sili- ca gel. In some cases, however, the ratio of the stereoisomers could be evaluated by the relative intensi- ties of the proton chemical shifts of the 2-methyl p u p . ‘ H NMR spectrum of 6b showed two singlets in-

Lr&YuAN Phosphonate carbanion 687

dicating that the two isomers were present in equal amounts. Tne 3'P NMR spectrum was also in agree- ment with this conclusion.

The chemical behaviours of compound 6 were very interesting. Deliberate addition of base induced decomposition of 6c and gave the componding 2-phosphoryl isoxaz.de 11 by the elimination of the sul- fonyl p u p ( Eq . 1 ) . The addition reaction of 11 and HCN, which were both fomed via the elimination reaction of 6d, could afford 12. The reaction was actually an eqdibrium among 6d, 11 and 12, on our trials, the pu&cation of 12 were unsuccessful.

In conclusion, condensation of various compounds bearing an active methylene p u p with a-ni-

troalkene followed by the addition of chlorotrimethylsilane provided a facile synthesis of 4,5-dihydroisoxa- zoles .

In addition to EWG, methylphosphonate (1, Y = H) behaves similarly. Nucleophilic addition of phosphonate carbanion to a-nitroethylene followed by reaction with chlomtrimethylsihe and an activated alkene provide a one-pot synthesis of phosphoryl methyl 4,5-dihydroisoxazole derivatives 7. ' By further reactions, these cxmpounds may be used as promising preclllsors in natural product synthesis.

Experimental

Infrared spectra were obtained on an IR-440 i n f d spectrometer. 'H NMR spectra were recoded on a XL-200 spectrometer. 31P and 13C NMR spectra were taken with broad band decoupling on a FX- 9OQ spectrometer using TMS as the internal standard and 85% phosphoric acid as the external standad for 3'P NMR spectra. Mass spectra were recorded on a Finnigan 4021 mass spectrometer. Butyllithium (2.5 moVL solution in hexanes) was purchased from Aldrich Chemical Co. Other reagents were obtained from local commerical source ( Sh& Chemical Co . ) . Trans-2-nitro-l-phenylpropene was prepad according to the Diisopmpylamine was treated with CaH2 and distilled under nitrogen. Chlorotrimethylsilane was distilled prior to use.

Diethy1 4,5 -dihyab 5 -methmycarbonyl- 3 -methyl-4-phenylisoxazole-5-yl-phosphonate ( 6b)

&nerd Procedwe Butyllithium (2 .0 mL, 5 mmol, 2.5 moVL solution in h e m e ) was added to diisopropylamine (0.8 mL, 5.5 mmol) in dry, freshly distilled THF (25 mL) at -20°C and the so- lution was s t i d for 5 min under nitrogen in a 100 mL 3-necked flask fitted with a drylng tube and a rub- ber septum. The solution was cooled down to - 70°C and methyl diethoxyphosphonoacetate ( lb, 1.05 g, 5 mmol) was added dropwise. After the addition was complete, the solution was stirred for 30 min and tram-2-methyl-1-phenylpropene (0.82 g, 5.25 mmol) was added. The reaction mixture was then al- lowed to warm up to r. t. and stirred for 5 h. The solution was cooled down to - 40°C and chlorotrimethylsilane (0.70 mL, 5.5 mmol) was added. The solution was allowed to warm up to r . t . and stirred for 60 h. The resulting mixture was concentrated under vacuum and the residue was p o d into water. Hydrochloric acid (1 moVL) was added to the solution until the pH value was slightly acidic. The mivture was extracted with CH2CI2 (4 x 30 mL) and the combined organic layer was dried over anhy- drous Na2SO4. After removal of the solvent, the crude product was puriGed by column chromatography on

688 Chinese Journal of Chemistry Vol. 17 No. 6 1999

silica gel with ethyl acetatelacetone (511, v l v ) as the eluent to give the pure product 6b as a colorless oil. Yield: 1.45 g (82%). u,(film): 3050, 1740, 1450, 1240, 1025, 960, 730, 700. GH(CD-

(s, 3H, CH3O), 3.72(m, lH, CH) , 4.15(m, 4H, CHZO), 7.24(m, 5H, GHS). Gp(CDC13): 21.51, 21.76 ( l l l ) . Gc(CDC13): 13.28(C- C = N ) , 16.10, 16.20(CH3CH20), 30.39(CH-Ph), 48.37(d, = 97 Hz, C-P), 51.79, 52.04(CH30), 62.86, 62.90(CH20), 127.15, 128.4,

Cl3): 1.29, 1.32(2t, J = 8 , 2 ~ 3 H , CH3CHzO), 1.80, 2 . 1 4 ( 2 ~ ( l l l ) , 3H, CH,C=N), 3.40

128.6, 128.8, 129.7, 138.1, 138.8(Ph), 156.6(C=N), 168.3 ( c = o ) . A d . C~~HZ-NO~P. Calcd: C , 54.09; H, 6.24; N , 3.94. Found: C, 54.20; H, 6.07; N, 3.88.

Tetraethyl 4,5- dihydo -3- methyl 4 p h e n y l i s ~ l e -5 ,5- diylbisphosphonate ( 6a )

The spectra were identical with those reported in the literam.

Lhethyl 4,5-dihydro-5-met~dfonyl-3-methyZ4-phenylisoxazole-5- ylphosphonate (6c)

Eluent : petroleum etherlacetone ( 1.5/1 , v l v ) . Yellowish oil. v, ( film) : 1720, 1560, 1450, 1260, 1020, 980. &(CDCl3): 1.35(m, 9H, C H 3 a + CH3CHzO>, 1.60-2.40(m, 3H, CH3C = N ) , 3.80(m, 1H, CH), 4.20(m, 4H, CHzO), 7.37(m, 5H, G,H5). Gp(CDC13): 21.64. Gc(CD- Cl3 ) : 1 1 . 2 1 , 1 1 .56( CH3 C = N ) , 16.06, 16.85 ( CH3 CHzO) ,22.11,22.35 ( CH3Sq) ,30.10,30.89 (CH) , 49.20(d, J ( c p ) = 95 Hz, C-P), 62.50, 62. 80(CHzO), 127.8, 127.9, 128.2, 128.4, 128.7, 129.0, 129.9(Ph), 156.4, 156.7(C=N). Anal. Calcd: C, 48.00; H, 5.91; N , 3.73. Found: C, 48.16; H, 6.20; N, 3.78.

c 1 5 H ~ N o 6 ~ .

Diethy1 4,5-~y~-5-cyano-3-methyl4phenylisowzzole-5-ylphosphonate (6d)

Eluent: petroleum etherlacetone (211, v / v ) . Yellowish oil. u, (film) : 2200, 1555, 1450,

CH3C = N ) , 3.50(m, l H , CH), 4.16(m, 4H, 2 x CHZO), Gp(CDCl3): 21.70. aC(CDCl3): 10.68, 11.64(CH3C=N), 16.19, 16.73(CH3CH20), 29.27, 30.92(CH),

1260, 1025, 970, 700. a~(CDc13): 1.27, 1.34(2t, . /=7 Hz, 2 ~ 3 H , CH3CHzO), 2 . 1 8 ( ~ , 3H, 7.20(m, 5H, G,H5).

61.63(CHzO), 65.01(d, J ( G P ) = 100 Hz, C-P), 115.O(CN), 128.4, 129.0, 129.2,129.8,130.7 (Ph), 158.5(C=N). Anal. CpjHigN204P. Calcd: C, 55.90; H, 5.94; N , 8.69. Found: C , 55.72; H , 5.97; N, 8.98.

Lhthyl 3-methyl4-phenylisoxuzole-5- y l p h p b n a t e (11)

Triethylamine(O.l6mL, 1.1 m l ) wasaddedto6~(0.375g, 1 mmol) inTHF(l0mL) and the solution was stirred for 2 h at r . t . The resulting mixture was concentrated in uacuo and the residue was purified by column chromatography on silica gel using petroleum etherlacetone ( 1.511, v / v ) as the eluent to give pure 12 as a yellowish oil. u - ( f i h ) : 1540, 1250, 1020, 970, 700. G~(cDc13): 1.30 ( t , 5 = 7 Hz, 6H, CH~CHZO), 1.85(s, 3H, CH,C=N), 4.18(m, 4H, CH*O), 7.28(m, 5H,

Ll&YuAN Phosphonate carbanion 689

SHs) . BH(CDC13): 10.69. Anal. C14Hl~N04P. Calcd: C , 56.95; H , 6.15; N , 4.75. Found: C , 57.00; H , 6.23; N , 4.57.

Referem

1. 2. 3. 4.

5 . 6. 7.

Li, C . ; Yuan, C . , SptJwk , 471(1993). Yuan, C; Huang, W . , synthesis, 473(1993). Tamura, R.; Kamimura, A . ; Cmo, N . , spfh~k, 423(1991). Li, C . , Ph. D Dissertation, Shar&ai Institute of 0I.ganic Chemistry, Chinese Academy of Sciences, 1993. JorseU, K.; Zeuthen, O . , A d a C h . &and., B32, 118(198). Gairaud, C.B.; Lappin, G . R . , 1. Org. Chem., 18, l(1953). Yuan, C. ; Li, C . , P h p h o m , S@, Silicon, R$oted Elanentc, 69, 75(1992).

(SONG, J . P . ; LING, J.)

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