786
J. Org. Chem. 1982,47, 786-791
On the Problem of Regioselectivity in the 1,3-Dipolar Cycloaddition Reaction of Munchnones and Sydnones with Acetylenic Dipolarophiles Albert Padwa*+ Department of Chemistry, Emory University, Atlanta, Georgia 30322
Edward M. Burgess* School of Chemistry, Georgia Institute of Technology, Atlanta, Georgia 30332
Henry L. Gingrich* and David M. Roush Agricultural Chemical Research Group, FMC Corporation, Princeton, New Jersey 08540 Received S e p t e m b e r 22, 1981
The l,3-dipolar cycloaddition reaction of several unsymmetrically substituted munchnones and sydnones with methyl propiolate has been examined. The initially formed cycloadducts readily extrude carbon dioxide to produce five-membered heteroaromatic ring compounds. The reaction of sydnones with methyl propiolate produced a mixture of regioisomeric pyrazoles. The analogous [3 + 21 cycloaddition reaction of munchnones with methyl propiolate proceeds with formation of mixtures of both possible regioisomeric pyrroles. The structural assignment of the isolated adducts is based on spectroscopicdata. The distribution of products depends on the nature and location of the substituent groups present on the heterocyclic ring. The observed regioselectivity is discussed on the basis of MO-perturbation theory.
During the last decade a new impulse has been given to research in the field of heterocyclic chemistry when it was found that various mesoionic compounds undergo 1,3-dipolar cycloaddition with different dipolar~philes.'-~~ Of the known mesoionic heterocycles, the structure, physical properties, and reactions of sydnones have drawn the closest scrutiny.20 These mesoionic compounds can be readily prepared by cyclodehydration of N-nitroso-a-alkyl amino acids (1) with reagents such as acetic anhydride. The resulting compounds contain a mesoionic aromatic system (2) which can only be depicted with polar resonance structures.21 Sydnones undergo smooth cycloaddition with acetylenes to give pyrazoles (4) in high yield.22-24 The reaction involves a 1,3-dipolar cycloaddition of the sydnones, behaving like a cyclic azomethine imine, to the corresponding acetylene followed by carbon dioxide evolution and aromatization.
R3> C02H
r
R2
a
'John Simon Guggenheim Memorial Fellow, 1981-1982.
L
Apart from the obvious synthetic value associated with the 1,3-dipolar cycloaddition reaction of mesoionic com(1)R. Huisgen, Angew. Chem., Int. Ed. Engl., 2, 565 (1963). (2)R. Huisgen, Angew. Chem., Int. Ed. Engl., 2,633 (1963). (3)R. Huisgen, R. Grashey, and J. Sauer in "The Chemistry of Alkenes", S. Patai, Ed., Interscience, New York, 1964,pp 806-878. (4)R. Huisgen, G. Szeimies, and L. Mobius, Chem. Ber., 100,2494 (1967). - -, (5)R. Huisgen, H. Stangl, H. J. Stern, and H. Wagenhofer, Angew. Chem., 73, 170 (1961). (6)R. Huisnen. L.Mobius, G. Muller, H. Stand, G. Szeimies, and J. M. Vernon, C6em. Ber., 98,3992 (1965). (7)R. Huisgen, J. Org. Chem., 33, 2291 (1968);41,403 (1976). (8)K. Fukui, Fortschr. Chem. Forsch., 15,l (1970);Acc. Chem. Res., 4,57 (1971). (9)M. J. S. Dewar, "The Molecular Orbital Theory of Organic Chemistry", McGraw-Hill, New York, 1969. (10)J. Klopman, Ed., "Chemical Reactivity and Reaction Paths", Wiley-Interscience, New York, 1974. (11)W. C.Herndon, Fortschr. Chem. Forsch., 46,141 (1974). (12)L.Salem, J. Am. Chem. SOC.,90,543,553 (1968). (13)A. Devaquet and L. Salem, J. Am. Chem. Soc., 91,3793(1969). (14)R.Sustmann and G. Binsch, Mol. Phys., 20,9 (1971). (15)N. D. Epiotis, Angew. Chem., Int. Ed. Engl., 13, 751 (1974). (16)R. Sustmann, Tetrahedron Lett., 2717 (1971). (17)K. N. Houk, Acc. Chem. Res., 8,361 (1975). (18)I. Fleming "Frontier Orbitals and Organic Chemical Reactions", Wiley, New York, 1976. (19)For a recent review of mesoionic heterocycles,see W. D. Ollis and C. A. Ramsden, Adu. Heterocycl. Chem., 19,1 (1976). (20)J. C.Earl and A. W. Mackney, J . Chem. SOC.,899 (1935). (21) W. Baker and W. D. Ollis, Q.Reo., Chem. Soc., 11, 15 (1957). (22)R. Huisgen, Bull. SOC.Chim. Fr., 3431 (1965). (23)R.Huisgen and H. Gotthardt, Chem. Ber., 101,1059 (1968). \--
L Huisgen and co-workers have also described the cycloaddition behavior of the "munchnones", unstable mesoionic A2-oxazolium5-oxides of type 6 with azomethine ylide structures.%29 Their reactions closely parallel those of the related sydnones. The reaction of munchnones with acetylenic dipolarophiles constitutes a pyrrole synthesis of broad scope.w36 1,3-Dipolarcycloaddition of acetylene to the A2-oxazolium5-oxide (6) followed by cycloreversion of carbon dioxide from the initially formed adduct 7 gives pyrrole derivatives 8 in good yield.
1
OQ22-3263/82/19~1-Q786$01.25/0 0 1982 American Chemical Society
J. Org. Chem., Vol. 47, No. 5, 1982
Cycloaddition Reaction of Munchnones and Sydnones pounds, there has been considerable interest in the reaction mechanism and regioselectivity of the cycloaddition. The mechanism that has emerged from Huisgen's group is that of a single-step, four-center, %o-mechanism" cycloaddition, in which the two new bonds are both partially formed in the transition state, although not necessarily to the same extent.'-3 An alternative mechanism that has been proposed is a two-step process involving a spin-paired diradical intermediatea3' In order to predict regioselectivity, it becomes necessary to determine the relative magnitudes of the coefficients in the HOMO and LUMO of the l,&dipole and dipolarophile. According to simple FMO theory, bond formation is dictated primarily by the charge transfer interaction energy determined by overlap of the HOMO(dipo1e)-LUMO(o1efin) and the LUMO(dipole)-HOMO(o1efin) with the appropriate symmet r y . % ~ ~Which ~ of these interactions will dominate is sometimes determined by the relative energy differences of either pair of orbitals. The regioselectivity is then the result of best orbital overlap, i.e., the atoms with the largest orbital coefficients combine preferentially. When sydnones are used as 1,3-dipoles, the dipole LUMO and dipolarophile HOMO interaction has been suggested to be the controlling term.%*@Calculations by Houk indicate that the terminal coefficients of the azomethine imine system are almost identical in the LUM0.38*@Thus, although LUMO control of reactivity will obtain, a decrease in regioselectivity of sydnone cycloaddition with respect to that observed with simpler azomethine imines is expected. In fact, sydnones do undergo regioselective reactions, but the degree of regioselectivity appears to be smaller than is observed with simpler azomethine imines.@ For example, N-phenylsydnone is known to react with all three classes of dipolarophiles to give predominantly the products resulting from intermediate adduct 9.41 Methyl propiolate gives a 4 1 mixture of adducts arising from 9 and the other regioisomer 10, re~pectively.~' We have encountered similar resulta in our investigation with sydnones 14a-c. The conversion of the three amino acids 13a-c to a mixture of regioisomeric carbomethoxypyrazoles was accomplished by treating the acid with methyl propiolate in acetic anhydride at 100-120 "C. No (24)H. Gotthardt and R. Huisaen, Chem. Ber., 101,552 (1968). (25)R. Huisgen, H. Gotthardt, H. 0.Bayer, and F. C. Schaefer, Chem. Ber., 103, 2611 (1970). (26)R. Huisgen, H. Gotthardt, H. 0. Bayer, and F. C. Schaefer, Annew. Chem.. Znt. Ed. End.. 3. 136 (19641. (27)H. Gotthardt and R. Huisgen, Chem. Ber., 103,2625(1970). (28)H. Gotthardt,R. Huisgen, and F. C. Schaefer, Tetrahedron Lett., 487 (1964). (29)E.-Brunn, E. Funke, H. Gotthardt, and R. Huisgen, Chem. Ber., 104,1562 (1971). (30) K. T. Potta and U. P. Singh, Chem. Commun., 66 (1969);K.T. Potta and J. Baum. J. Chem. SOC..Chem. Commun.. 833 (1973). (31)G. V.Boyd A d P. H. Wright, J. Chem. Soc., Perkin 'kan~:1,909, 914 (1972). (32)G. Manecke and J. Klawitter, Makromol. Chem., 175,3383(1974). (33)L. M.Hershenson, J. Org. Chem., 40, 1260 (1975). (34)I. A. Benages and S. M. Albonico, J.Org. Chem., 43,4273(1978). (35)M.T.P h m o and S. M. Albonico, J. Org. Chem., 42,909(1977). (36)J. W. ApSimmon, D. G. Durham, and A. H. Rees, Chem. 2nd. (London),275 (1973). (37)R. A. Firestone, J.Org. Chem., 33,2285(1968);37,2181 (1972); J. Chem. SOC. A , 1570 (1970). (38)K.N.Houk, J. Sims,C. R. Watte, and L. J. L u s h , J. Am. Chem. SOC., 95,7301 (1973). (39)K.N.Houk,J. Sims, R. E. Duke, Jr., R. W. Strozier, and J. K. George, J. Am. Chem. SOC.,95,7287 (1973). (40)H.Gctthardt and F. Reiter, Chem. Ber., 112,1193 (1979). (41)R. Huisgen, H. Gotthardt, and R. Grashey, Chem. Ber., 101,536 (1968);101,829(1968);R.Huisgen and H. Gotthardt, ibid., 101,839,1059 (1968).
-
787
N.Ph
J-co'
Ph
12
= II
attempt was made to isolate the intermediate sydnones 14a-c. The progress of the reaction was monitored by carbon dioxide evolution. Workup procedures consist of addition of water, extraction with ether, and silica gel chromatographic separation of the mixture of regioisomen. Identification of each isomer was made on the basis of its characteristic NMR spectrum. Particular attention was given to the chemical shift of the pyrazole proton. The ring proton in the 3-carbomethoxy-substituted isomer appeared 1.2-1.3 ppm upfield relative to the 4-carbomethoxy-substituted isomer. In all cases, a mixture of two regioisomeric cycloadducts was obtained. The major product (i.e., 15) always corresponded to the 3-carbomethoxy-substituted isomer (15/16 3:l).
-
0-
2. AC20
== 16
15 =
The 1,3-cycloaddition of A2-oxazolium5-oxides (munchnones) with dipolarophiles has frequently been utilized in the synthesis of a variety of heterocyclic The reaction pathway involves a cycloaddition to an azomethine ylide to give a N-bridged intermediate that loses carbon dioxide and forms a heterocycle. HoukS has suggested that unsymmetrically substituted azomethine ylides such as munchnones will react readily with both electron-deficient and electron-rich dipolarophiles due to the narrow frontier orbital separation (i.e., S ~ s t m a n type n~~ I1 classification). The regiochemistry of the cycloaddition should be controlled by asymmetry in the dipole frontier orbitals caused by the substituent groups. When electron-deficient dipolarophiles such as unsymmetrically substituted acetylenes are used, the cycloaddition reaction of a number of munchnones has been reported to produce a single cycloadduct. Two typical examples are outlined below.25P43~
" 7 phGo
CH3 t
CH3
+
17 O-
20
PhCEC-R
= IS
-Cop
Ph
p
CH3 CH3
(R=H or COpC&)
21 -
During the course of a study dealing with the 1,3-dipolar cycloaddition behavior of mesoionic compounds,43we in(42)R.Sustmann, Tetrahedron Lett., 2721 (1971);Pure Appl. Chem., 40,569 (1974);J. Geittner, R.Huisgen, and R. Sustmann, Tetraedron Lett., 881 (1977).
788
J. Org. Chem., Vol. 47, No. 5, 1982
Padwa et al.
Table I value for compd Darameter Eh(n)
Ei(n*)
Ed.*) 4i 4i Cui( 7r 1 Cjh(n)
Cil(n*) Cjdn * 1
26
27
28
-7.794 0.960 1.614 t 0.298 -0.458 0.419 0.737 0.738 0.260 0.060 0.393
-8.490 1.176 2.153 -0.164 -0.018 0.656 0.645 0.369 0.555 0.159 0.229
-11.233 0.345 0.882 +0.073 -0.393 0.657 0.587 0.434 0.563 0.079 0.170
values shown in Table I where the subscripts h and 1 refer to the highest occupied and lowest unoccupied orbitals of energy, E (in eV) and subscripts i, j to the orbitals on the indicated atomic center with total charge density, q, and coefficients, c. The interaction energy between two
2
9
2
reactants, A and B, at some distance R may be assumed to be the sum of terms representing the covalent or in*1 termolecular charge transfer energy, All,,; the van der Cjl(.*) Waals or ionic (ion pairs without any charge transfer) vestigated the cycloaddition of several unsymmetrically energy, mi;and solvation energy which is neglected here.* substituted munchnones and have found that the reaction This interaction energy is expressed in first and second leads to a mixture of regioisomeric cycloadducta. This order by Rayleigh-Schrodinger perturbation treatment stands in marked contrast to the situation encountered given the zeroth order energies and associated wave with the munchnones outlined above. Munchnones 23a-c functions. The usual assumptions of separability of the were obtained by treating the appropriate a-amino acid interacting electronic systems, zero overlap between with acetic anhydride at 100-130 "C. No attempt was reactants, and neglect of multicenter integrals allow convenient estimates to be made of the relative interaction R 2 - N 4 0R l A R2
