5273
Heterodienophiles. I. Stereoselectivity in the 1,4 Addition of Iminocarbamates to Cyclohexa- 1,3-diene1 Grant Krow,* Ron Rodebaugh, R. Carmosin, W. Figures, H. Pannella, G. DeVicaris, and M. Grippi Contribution from the Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122. Received October 14, 1972 Abstract: The acid-catalyzed 1,4 addition of iminourethanes to cyclohexa-l,3-dienehas been investigated in several
solvents in order to determine reaction stereochemistry. “r analysis of 3-substituted-N-carbethoxy-2-azabicyclo[2.2.2]oct-5-enes(5,6-dehydroisoquinuclidines)utilizing long-range W-plan coupling and shift effects has indicated preferential formation of 3-ex0 adducts from acetyl and several aryl bisurethanes (Table I). Methyl, ethyl, benzyl, and phenyl benzalbiscarbamatesalso affordedmajor amounts of 3-ex0 adducts (Table 11). Analysis of the stereochemistry of iminourethane cycloadditions suggests that a stepwise cyclic process involving protonated (E)iminourethanes best explains the observed structural and stereochemical data. The mass spectral fragmentation patterns of N-carbethoxy-5,6-dehydroisoquinuclidines have been found to differ from previously reported patterns for ring cleavage of N-methyl-5,6-dehydroisoquinuclidines.
T
he Diels-Alder reaction, one of the most fundamental and useful reactions of the synthetic organic chemist, provides ready access to six-membered rings, especially bridged ones. Adding to the utility of this reaction is its remarkable stereoselectivity. Among the several stereochemical aspects of this reaction, 20, two principles derived from numerous studies are here worthy of note: (1) it has been observed that the geometric arrangement of substituents on the olefinic bond of the dienophile is preserved in the cyclic product; this has been generalized as the “principle of cis addition”; and (2) it has been noted that in the reaction of a cyclic diene and a substituted olefin, where the substituent of the dienophile can in principle enter either an exo (anti to the olefinic bond of the bicyclic product) or an endo position, there is a general kinetic preference arising from electronic and/or steric factors for endo a d d i t i ~ n . Although ~ a number of exceptions are known, 2 a , 3 , 4 this stereoselective observation has been generalized as the “Alder endo-rule.” While the six atoms involved in the formation of a ring are commonly all carbon atoms, it has been possible t o synthesize heterocycles by inclusion of a heteroatom into either the diene or dienophilic components of the cyc1oaddition.j Consideration of the stereoselectivity noted in the all carbon Diels-Alder reaction renders it somewhat surprising, however, that little is known concerning the stereochemical outcome of 1,4 additions involving heterodienophiles. Biehler and Fleury‘j have synthesized a number of 2-azanor(1) Presented in part at the 164th National Meeting of the American Chemical Society, New York, N. Y., Aug 1972. (2) For general discussions of the Diels-Alder reaction, see (a) A. Wasserman, “Diels-Alder Reactions,” Elsevier, Amsterdam, 1965 ; (b) J. Sauer, Angew. Chem., Znt. Ed. Engl., 5,211 (1966); 6, 16 (1967); (c) A. S. Onishchenko, Diene Synthesis, D. Davey, New York, N. Y., 1964. (3) For a discussion of the stereochemistry of the Diels-Alder reaction, see J. Martin and R. Hill, Chem. Rev., 61, 537 (1961). (4) See, for example: (a) K. Alder and Gunzl, Chem. Ber., 93, 809 (1960); (b) H. Stockman, J . Org. Chem., 26, 2025 (1961); (c) J. A. Berson, Z. Hamlet, and W. A. Mueller, J. Amer. Chem. SOC.,84, 297 (1962); (d) Y. Kobuke, T. Sugimoto, J. Furukawa, and T. Fueno, ibid., 94,3633 (1972). ( 5 ) Reactions of dienes with dienophiles containing heteroatoms have been reviewed by (a) S. Needleman and M. C. Kuo, Chem. Rev., 62, 405 (1962); (b) Y. Arbuzov, Russ, Chem. Reu., 33, 407 (1964); (c) Y. Titov, ibid., 31,267 (1962). (6) J. Biehler and J. Fleury, J. Heterocycl. Chem., 8,431 (1971).
U
1
2
3
bornene derivatives 1 (R = COOEt, COOMe, CONHz; R’ = SOZPhCH3-p, SOZCHz, COPhNOz-p, COPh) via cycloaddition of sulfonyl or acyl isonitrosomalonoimines with cyclopentadiene. In all cases the evidence, mainly adduced from nmr shift parameters of the 7-syn and 7-anti hydrogens, has indicated kinetically controlled stereospecific formation of 3-ex0 cyano adducts 1.
The reaction of N-arylsulfonylimines of chloral with several dienes has recently been utilized in the synthesis of a number of functionally substituted tetrahydropyridines and piperidines.’ X-Ray study of the adduct 2 has shown the trichloromethyl group to occupy a position trans t o the bridge hydrogen. Cyclohexadiene has been reacted with the imine formed upon acid-catalyzed decomposition of 5methoxy-3-phenylhydantointo form an adduct 3 which has been assigned the C-3 endo configuration on the basis of a 6-Hz deshielding of the phenyl group upon hydrogenation of the double bond of From analysis of the stereochemistry of imine cyclo(7) P. Rijsenbrij, R. Loven, J. Wijnberg, W. Speckamp, and H. Huisman, TetrahedronLett., 1425 (1972). (8) (a) D. Ben-Ishai and E. Goldstein, Tetrahedron, 27, 3119 (1971). (b) E. Goldstein and D. Ben-Ishai, Tetrahedron Lett., 2631 (1969). (c) We have obtained 3 as a single stereoisomer in which the C-3 proton does not exhibit long-range W-plan coupling.9 This proton is likely exo and the C-3 substituent is thus endo oriented. (9) (a) A. Rassat, C. W. Jefford, J. M. Lehn, and B. Waegell, Tetrahedron Lett., 233 (1964); (b) M. Barfield and B. Chakrabarti, Chem. Reu., 69, 757 (1969); (c) S. Sternhell, Rev. Pure Appl. Chem., 14, 15 (1964); (d) A. Rassat and P. Rey, Tetrahedron, 28,741 (1972).
Krow, et ai.
Addition of Iminocarbamates to Cyclohexa-1,3-diene
5274
additions, it is obvious that nitrogen inversion introduces a number of parameters not found in the allcarbon Diels-Alder reaction. Firstly, the principle of cis addition cannot be confirmed by inspection of the configurations of starting imine and product bicyclic amine since the nitrogen lone pair may be free t o invert in both instances. Secondly, since in considering the imine component only the configuration at the imine carbon becomes configurationally fixed in product, it is difficult in many instances to determine if addition to dienes has occurred via the 2 or E form of the imine. In the absence of this knowledge, it is difficult to apply the Alder endo-rule to predict the preferred stereochemistry at carbon in imine cycloadditions. Thirdly, the polarity of the imine bond may increase the likelihood of stepwise rather than concerted cycloadditions. Certain stereochemical predictions for heterodienophilic cycloadditions might be made, however, by making reasonable assumptions based on the allcarbon Diels-Alder reaction. As applied to imines the principle of cis addition implies that in a Diels-Alder transition state Z ( E ) imine initially leads to product with the same Z ( E ) orientation of substituents. It can be further assumed that the steric course of kinetically controlled dienophilic imine cycloadditions is governed by steric and electronic factors qualitatively similar to those found for dienophilic olefins. The cisendo principle can then be applied in the following manner as shown in Scheme I. For a cycloaddition of
would be speculative at this time since it is possible that small amounts of minor exo isomer were undetected due t o the nmr method6 of analysis of 1 or by isomeric enrichment of 2 before X-ray structure determination.' Although a rigorous stereochemical assignments to 3 has not been made, the adduct 3 was obviously formed from an imine locked into the 2 configuration as part of a ring. With this historical background in mind, we decided to investigate the stereochemistry of 3-substituted-Ncarbethoxy-5,6-dehydroisoquinuclidine10 formation via the acid-catalyzed reaction of iminourethanes with cyclohexa-1,3-diene. The rigid nature of the azabicyclic system promised to be most suitable for stereochemical determinations because of the relative ease of determining nmr shift parameters. l 1 Further, the ease of formation of 5,6-dehydroisoquinuclidines by this route indicated that our results could be of some synthetic utility. l 2 Assignment of Stereochemistry by Nmr Methods. In order to determine if nmr coupling parameters would enable a distinction to be made between the 3-ex0 and 3-endo positions of a 5,6-dehydroisoquinuclidine, the nmr spectrum of N-carbethoxy-2-azabicyclo[2.2.2]oct5-ene (7) was analyzed. Of special interest to the
Scheme I H3"
7
k R
H 6a
5a
ti
I
P I
R 5b(C-3 endo)
6b (C-3 exo)
a hypothetical imine 4 with cyclohexadiene, cycloaddition via either the Z form, E form, or via both forms concurrently might occur. For cycloaddition via the Z form, the cis-endo rule predicts predominant kinetic formation of product 5 with the endo configuration at (2-3, and only minor amounts of exo C-3 isomer 6. However, if cycloaddition via the E form of 4 occurs, a competition between the substituent on imine carbon and the substituent on imine nitrogen for the endo position can result in a continuum of possibilities at C-3 from total endo adduct 5 to total exo adduct 6. If adducts 1-3 are formed via cyclic transition states the stereospecific introduction of the bulkier substituent of the imine carbon into the endo position indicates one or a combination of two possibilities: (1) addition occurs endo via the Z configuration of the imine, or (2) addition occurs from the E configuration of an imine in which the bulkier substituent on carbon is favored endo over the substituent on nitrogen. A complete analysis of the additions to form 1 and 2 Journal of the American Chemical Society
present study were the nmr (CDC13)resonances (Figure = 1) for Hsx at 6 3.26 (sharp doublet of doublets, J3n,3x 10.5 Hz, JaX,4= 2.2 Hz) and for Hanat 6 3.04 (doublet of triplets, J3n,*a = J3n,4= 2.2 Hz). A long-range Wplang coupling between Hsa and Ha,, was confirmed by irradiation of Hsa (6 1.15) whereupon HBncollapsed to a doublet of doublets. The olefinic region of 7 centered at 6 6.32 consisted of a narrow (11-Hz peak width at half-height) pattern for H5and Hg. The similar environment for the olefinic hydrogens indicating a lack of unequal anisotropic shift contributions to these hydrogens is consistent with the carbethoxyl in other than an endo configuration.13 To apply the W-plan coupling phenomena t o stereochemical determination of a 3-substituted 5,6-dehydroisoquinuclidine an exo-endo mixture of 3-acetyl-Ncarbethoxy-2-azabicyclo[2.2.2]oct-5-ene(8a,b) was synthesized. lob The major em-acetyl isomer 8a was identified by the nmr (CDC13) resonance for H3n at 6 3.83 (quartet, J3n,4 = 2.8 Hz, = 1.5 Hz). The couplings were confirmed by irradiation at H 4 (6 2.96) which col(10) (a) M. P. Quan, T. I
