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Involvement of Azomethine Ylides in the Thermal Rearrangement of Aziridinyl Ketones to Pyrroles Albert Padwa,* David Dean, and Toyonari Oine Contribution from the Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 1421 4. Received July 3, 1974
Abstract: Thermolysis of a number of N-alkyl-2-aroyl-3-methylaziridines has been found to afford N-alkyl-3-arylpyrrolesin high yield. Kinetic studies show that trans-N-tert-butyl-2-benzoyl-3-methylaziridine rearranges 40 times more rapidly than the corresponding cis isomer at 70°.A mechanism involving conrotatory opening of the aziridine ring to an azomethine ylide is proposed to account for the observed rearrangement patterns. The higher energy requirement for rearrangement of the cis isomer was attributed to the stereochemicalconsequences of orbital symmetry control. Support for the proposed mechanism was obtained by trapping the 1,3 dipoles with dimethyl acetylenedicarboxylate.The thermal rearrangement of 2-tert-butyl3-methyl-5-phenyl-4-isoxazolinewas shown to involve an aroylaziridine as a transient intermediate. The excited state behavior of a set of stereoisomeric aziridinyl ketones was also studied.
The thermal “ene reaction” of three-membered rings, Results and Discussion which takes place with a sigmatropic 1,s-hydrogen shift and cis- and trans-N-tert-butyl-2-benzoyl-3-methylaziriconcomitant ring cleavage, is a well-documented reaction dines (5 and 6) were conveniently prepared from a-bro(eq l).’-27A cis relationship between the R system and the 0 alkyl group on the vicinal ring carbon has been proposed as being necessary for these rearrangements to p r ~ c e e d . ~ - ~ LH t-BuNH, The lack of reaction of the corresponding trans isomer Ph n Br CH3 under similar reaction conditions and the low energy and large negative entropy of activation for the cis isomer constitute compelling support for the concertedness of the react i ~ n . ~Much - ~ higher temperatures are required to effect the rearrangement of trans- l-alkyl-2-vinylcyclopropanes.24 The reason for this is evident from an examination of molecular models. The trans isomer would require severe dist-Bu t-Bu tortions to achieve a geometry where hydrogen transfer 6 5 might become possible. The transition state for the homodimoethylideneacetophenone and tert-butylamine according enyl 1,Shydrogen shift has been rationalized in terms of a to established p r o c e d ~ r e s .Stereochemical ~~ assignments nonplanar conformation (Le., 1) in which the migrating hywere made on the basis of uv and N M R spectroscopy. Evidrogen and the methylene group of the cyclopropane ring dence has been obtained demonstrating that in a given pair are anti, with the plane of the ring parallel to that of the R of @-substitutedaziridinyl ketone stereoisomers, the isomer bond.3 Models indicate that this conformation is the most possessing the trans structure exhibits an absorption maxiR R mum in the R-R* transition at longer wavelengths than
+
1 X=CH2
4,
x=o
3, x - 0
favorable for overlap of the developing p orbitals derived from the cyclopropane ring bond with the olefinic group and also the developing p orbital derived from the C-H bond. The selection rules for these homodienyl [ 1,5]-hydrogen shifts are similar to those for 1,S-dienyl shifts and predict that suprafacial migration of the hydrogen atom is a thermally allowed process. We recently found an unusual variation in an apparent homodienyl “ene” reaction while examining the thermal rearrangement of N-alkyl-2-aroyl-3-methylaziridinesto N-alkyl-3-arylpyrr0les.~~ Our observations indicated that this system differed dramatically from heretofore observed three-membered ring “ene” reactions, in that the trans isomer reacted at a faster rate than the corresponding cis form. The present publication describes our preliminary findings in detail and delineates the significant role played by azomethine yields in the overall thermal chemistry of this ring system. Journal of the American Chemical Society
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does the cis isomer.30 This difference was attributed to the nature of the electrical interaction between the three ring As expected, the uv spectrum of and the $arbonyl cis-aziridine 5 exhibited a maximum at 245 nm (e 13,200) while the maximum for the corresponding trans isomer (6) was shifted to slightly longer wavelength (247 nm, 13,500) and had a slightly greater intensity, Structural assignments were further strengthened by N M R measurements. The ring protons of the cis isomer are known to absorb at higher field than those of the trans form.31 The chemical shift of the aziridine ring protons of 5 appeared at 6 2.22-2.48 (m) and 3.12 (d, J = 7.0 Hz), while the corresponding trans isomer 6 exhibited signals a t 6 2.64-2.88 (m) and 3.16 (d, J = 3.0 Hz). Finally, isomerization of 6 to the thermodynamically more stable cis form (5) could be readily effected with methanolic sodium m e t h ~ x i d eproviding ~~ additional support for the structural assignments. A number of related N-alkyl-2-aroyl-3-methylaziridines (1 1-16) were also prepared by similar procedures and their stereochemistry was assigned by similar spectroscopic arguments (see Experimental Section). With the stereochemistry of the isomeric cis- and transN-alkyl-2-aroyl-3-methylaziridines firmly established, a detailed study of their thermal behavior was undertaken. Thermolysis of 140 mg of cis-aziridine 5 in methanol at 120’ for 3 hr afforded 110 mg (80%) of N-tert-butyl-3-
May 14, 1975
co;w
Table I. Rates of Thermal Rearrangement of N-Alkyl-2-benzoyl3-methylaziridines and Related Systems
co2c+y CH3
H
I
I
I
I
CH3 11
CH, I
5
6 15
16 I I1
k. sec-'
1.18 x 1 0 - ~ 3.23 x 1.05 x 1 0 - ~ 1.52 X 4.54 X 2.16 x 1 0 - ~ 3.2 X 4.8 x 1 0 - ~ 7.0X lo4 2.1 x 1 0 - ~ 3.2 X 4.3 x 2.0 x 1 0 - ~ 1.46 X
100 110 120 70 80 90 100 io5 110 100 105 110 70 70
26.4 f 0.5 kcal/mol, and log A = 13.0). These data correspond to A H t = 25.4 f 0.5 kcal/mol and AS+ = -1.7 eu. Extrapolation of the data for the cis isomer to 70' indicates that the trans-aziridine 6 rearranges 40 times more rapidly than the corresponding cis isomer. In order to help elucidate the mechanism for the trans-6 cis-5 aziridine epimerization, we studied the thermal rearrangement of both aziridines in deuteriomethanol a t 77O for 15 hr. Recovered starting material (80%) from the cis-aziridine 5 run was found to have incorporated one deuterium atom into the 2 position of the aziridine ring. The fact that addition of an excess of dimethyl fumarate to a solution of 5 did not significantly affect either the rate of disappearance of starting ketone or the amount of pyrrole formed strongly argues against the involvement of azomethine ylides in the transcis-aziridine isomerization. This conclusion was reached by knowing that azomethine ylides can be readily trapped in the presence of d i p ~ l a r o p h i l e s . ~ ~ Consequently, one would have anticipated a marked diminution in the yield of the pyrrole if an azomethine ylide were involved in the trans cis isomerization. Similar results were obtained with trans-aziridine 6, except that in
-
N
N
Comoda T. "C
2823
Re1 rate (70")
kcal/ mol
ASt,
1
27.7
-2.3
40
25.4
-1.7
6.1
21.5
-17.2
4.7
19.7
-22.9
AHi,
eu
-
-
5.2 3.8
aSee ref 19 for rates of last two aziridines.
phenylpyrrole (7). This compound was identified by comparison with an authentic sample.33 Similar reactions were observed with trans-aziridine 6 as well as with aziridines
t-Bu
t-Bu
8
6
0
11-16.
The rate data for the thermolysis of aziridines 5 and 6 together with those of related compounds are summarized in Table I. The disappearance of cis-aziridine 5 and the appearance of pyrrole 7 in methanol was followed simulta-
t-Bu
n
5
I
R
5 (cis), 6 (trans), R = t-Bu; Ar = Ph ll (cis), 12 (trans), R = t-Bu; Ar = BiPh 13 (cis), 14 (trans), R = C,H,G Ar = BiPh 15 (cis), 16 (trans), R = CH,; Ar = Ph
I
R 7, R = t-Bu
Ar = Ph
neously by N M R spectroscopy. The reaction followed firstorder kinetics, and rate constants were determined a t three different temperatures constant to f0.5', 100' ( k = 1.18 X sec-'), 1 loo ( k = 3.23 X sec-'), and 120' ( k = 1.05 X sec-I). An Arrhenius plot gives E , = 28.6 f 0.5kcal/mol and log A = 12.8 from which values of A H ? = 27.7 kcal and A S t = -2.3 eu can be calculated. The reaction kinetics encountered with trans-aziridine 6 were more complicated since the thermolysis of 6 in methanol a t 80' produced cis-aziridine 5 as well as pyrrole 7. It should be pointed out, however, that with the lower temperature and short reaction times used for the thermolysis of trans-aziridine 6, the cis isomer ( 5 ) did not appreciably rearrange to pyrrole 7. The concentration of all three compounds was followed simultaneously by N M R spectroscopy. By using steady state approximations and by numerical integration of the resultant differential equations with the program KINET,34 an analytical function was obtained for the concentration of the trans isomer. The results indicate that trans-aziridine 6 also proceeds on to pyrrole by a first-order rate process (Le., k = 1.52 X sec-l (70°), k = 4.54 X sec-' (SO'), and k = 2.16 X loV3 sec-' (go'), E , =
this case the recovered aziridine was mostly the epimerized cis 2-dl isomer. The most direct interpretation of the above data involves enol 8 as the reactive intermediate responsible for the epimerization. This suggestion is quite reasonable since enolization has been implicated in the cis-trans interconverson of other a r ~ y l a z i r i d i n e sas ~ ~well , ~ ~as with the related dypnone oxide system.37 It is especially interesting to note that the pyrrole isolated from the thermolysis of the cis-aziridine in CH30D contained deuterium atoms in both the 2 and 4 positions of the pyrrole ring. A control experiment indicated that pyrrole 7 only incorporates deuterium into the 2 position of the ring 0
I
t-Bu
t-Bu
6
7
0
Ph Ph &7?-L
wH \
t-Bu 9
H
I
t -Bu
7
under the reaction conditions used. A further experiment utilizing cis-N-tert-butyl-2-benzoyl-3-methylaziridine-.?methyl-d3 (9) and methanol confirmed this intermolecular
Padwa, Dean, Oine / Thermal Rearrangement of Aziridinyl Ketones to Pyrroles
2824 hydrogen exchange. No detectable deuterium was found in the final product (7) when deuterated cis-aziridine 9 was heated at 120' in methanol for 2.5 hr. Similar results were obtained with the corresponding trans-aziridines. These observations may be explained in terms of a rapid intermolecular exchange of the vinyl hydrogens of the initially formed enamine (10) with the solvent prior to cyclization to the 0
CH,
II
II
P..
'R
H'
I
t-Bu 5 (or 6) CD,
10
isomer ( 5 ) (see Table I) can be attributed to the stereochemical consequences of orbital-symmetry control. Conrotatory rotation in either direction for the cis isomer causes one of the rotating groups to encounter a large steric interaction with the adjacent tert-butyl group. With the trans isomer, however, conrotation will result in a smaller steric interaction since neither the methyl nor benzoyl group needs to rotate toward the large tert-butyl group. Since no adduct was formed when the thermolyses were carried out in methanol in the presence of a potent dipolarophile, it would appear that the initially formed azomethine ylides have very short lifetimes in methanol and undergo rapid exchange with the protic solvent. Further support for the above mechanism was obtained by carrying out the thermolysis of the aziridine ( 5 or 6) in a nonprotic solvent. Under these conditions, the azomethine ylides could be trapped by 1,3-dipolar cycloaddition with an added dipolarophile prior to the formation of pyrrole 7.38 Thus, heating cis-5 or trans-6 aziridine with dimethyl
t-Bu 7
pyrrole. It should also be pointed out that recovered cis-aziridine 5 did not incorporate deuterium into the methyl group when 5 was heated in deuteriomethanol. A similar set of results was obtained when deuterated cis-aziridine 9 was heated in methanol. The recovered ketone did not exchange hydrogen for deuterium. The lack of deuterium incorporation on the methyl group of aziridine 5 argues against the "enolene" for rearrangement of these aziridines. Also noteworthy is the absence of a primary deuterium isotope effect on the rate of rearrangement of cis-aziridine 9. These observations coupled with the fact that transaziridine 6 rearranges at a faster rate than the cis isomer ( 5 ) mitigate against a homodienyl 1,s shift as the mechanism responsible for the formation of enol 10. The simplest mechanism consistent with the observed rearrangement patterns of the substituted aziridines examined is the one outlined below. It is based on the knowledge 0
I
t-Bu
t-Bu
5
6
"J
1"
Ph
x + A "x:X
H
,O
I"H
CHB
CH3
I
H
H
I
0
t-Bu
CH3
t-iU
/&.OH
I
t-Bu
t-Bu 10
7
that aziridines readily undergo thermal cleavage to azomethine ylides by conrotation of the substituent groups.35 The higher energy requirement for rearrangement of the cis Journal of the American Chemical Society
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H
I
I
t-Bu
t.Bu 17
5 (or 6)
+c
CH302C
H ~ 2 ~ ~ c o 2 c H 3 CH,
ph) t-Bu 18
t-Bu 19
acetylenedicarboxylate in chloroform at 120' gave an excellent yield of the crystalline N-tert- butyl-2-benzoyl-3,4dicarbomethoxy-5-methyl-2,5-dihydropyrrole (17), mp 129-139'. The structure of the cycloadduct (17) was confirmed by oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to N-tert-butyl-2-benzoyl-3,4-dicarbomethoxy-5-methylpyrrole (18) and N-tert-butyl-2-methyl3,4-dicarbomethoxypyrrole (19). Most importantly, no detectable quantities of pyrrole 7 were observed in this trapping experiment. A control reaction demonstrated that the aziridines were smoothly converted into pyrrole 7 in chloroform at 120' in the absence of the dipolarophile. The trapping experiments clearly indicate that the aziridines open to a 1,3 dipole prior to the transfer of a hydrogen atom. Both
