6607
J. Am. Chem. SOC. 1991, 113, 6607-6617
+
[16] = Ae-Alr Be-Azf [ l a ] = C(e-AI' - e-W)
[9] = [9]oe-X~f [ 101 = [ 10]oe-xzr
[11] = [I110 - [9]ok~'(e-~~'-l ) / A l - [10]ok~'(e-~~'1)/A2 [12] = [I210 - [9]ok~'(e-~'' - l ) / l l - [ 1 0 ] o k ~ ~ ( e-- ~1)/12 ~'
+
+
[I51 = DePXIf EZXZr+ (F [lS]o)e-X~' [I71 = [16Iob/X,X2 [1510 Ge-XIf+ He-Azr+ (I - [15]o)e-A3f
+
+
where
where = kHC f kD' A2
= k$
+ kH'
This system of equations is underdetermined as the Simplex procedure converges to different sets of optimized variables, depending on the input set. The convergence is univocal when the number of variables is reduced by the substitutions kHC= ikDc and kHt= ikD1,where the KIE i is assumed to be the same for the cis and trans rearrangements. The differential equations describing kinetic Scheme V are as follows: d[l6]/dt = k ~ ' [ I 8 ]- (kAC+ k~')[16] d[l8]/dt = k~'[16] - (kHr
+ k~~)[l8]
d[l5]/dt = k ~ ' [ 1 8 ]- k~'[15] d[l7]/dt = k~'[15]
+ k~'[16]
The integrated equations are as follows:
Supplementary Material Available: Figures 4 and 5 graphically illustrating the presence of systematic errors when the rearrangements of ions 15, 16, 17, and 18 are fitted into the equations in the Appendix, constraining kTfto 0 or kHiand kHTto the same value (3 pages). Ordering information is given on any current masthead page.
Cyclizations of Unsaturated 'CR(COX)2 Radicals. Manganese( 111) Acetate Oxidative Cyclizations of Unsaturated Acetoacetates and Atom-Transfer Cyclizations of Unsaturated Haloacetoacetates Give the Same Radicals Dennis P. Curran,**'Tina M. Morgan, C. Eric Schwartz, Barry B. Snider,*it and Mark A. Dombroskit Contribution from the Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and Department of Chemistry, Brandeis University, Waltham, Massachusetts 02254-91 10. Received January 18, 1991
Abstract: Comparable regio- and stereochemical results were obtained when cyclizations of a series of 2-substituted 3-oxohept-6-enoate (or oct-7-enoate) esters (acetoacetates) were conducted by manganese(II1) acetate oxidation or by iodine or bromine atom transfer cyclization. The observed trends support the conclusion that free radicals 6b (rather than Mn(II1)complexed radicals Sb) are involved in the Mn(II1)-mediatedoxidative cyclization of tertiary malonates and acetoacetates. Most cyclizations proceeded under kinetic control, and several showed large temperature dependences on stereoselectivity. An apparent discrepancy was resolved by demonstrating that ring opening of radical 43 (a reverse 6-ex0 cyclization) was faster than bromine transfer, but slower than iodine transfer or Cu(I1) oxidation. In the process of ring closure/ring opening, a Z-alkene is converted to an E-alkene. Since the E- and Z-alkenes provide distinct stereochemical results on cyclization, the observed stereochemical ratio becomes a very sensitive probe for this radical ring opening. This observation presages the design and use of related probes for radical ring opening.
Introduction Radical cyclizations of alkenes have rapidly emerged as powerful reactions for ring construction.* The precursors and the products for such cyclizations can vary as a function of the method
chosen to conduct the cyclization, and methods based on reduction, isomerization, and oxidation are popular. Oxidative methods have ( I ) IC1 Awardee, 1990. NIH Research Career Development Awardee 1987-1992.
'Brandeis University. 0002-7863/9 1/ 15 13-6607$02.50/0
0 1991 American Chemical Society
6608 J . Am. Chem. SOC.,Vol. I 13, No. 17, I991
Curran et al.
an important feature for synthetic applications: the level of functionality in the product is retained or increased relative to that in the starting material. Among the various oxidative methods available, the manganese(II1)-based oxidation of enolizable dicarbonyl compounds is an especially powerful option3 Such Mn(II1)-promoted cyclizations have broad generality, often proceed with very high degrees of both regio- and stereoselectivity, and produce attractive products for subsequent synthetic transformation~.~Further, cyclization precursors (even for sophisticated double and triple cyclizations5) are readily available by exploiting standard 6-dicarbonyl enolate (and dienolate) chemistry. The required manganese salts are inexpensive, and the experimental procedures are straightforward. The exact nature of the products (alkenes, lactones, acetates, phenols) is readily anticipated on the basis of the structure of the starting material and the reaction conditions. Although important mechanistic features have emerged,6v7a detailed understanding of the role of manganese in these oxidative cyclizations has lagged behind the synthetic advances. Specifically, it is not clear whether free radicals or manganese-complexed radicals are intermediates in these cyclizations. This situation is in direct contrast to typical radical chain reactions (tin hydride reductions, for example), where a solid mechanistic understanding preceded (and promoted) synthetic growth. We now report the results of a study that was undertaken to address this central mechanistic question: What is the nature of the reactive intermediate that cyclizes in a manganese(II1) oxidative cyclization? This study was prompted by the observation of two general trends in Mn(II1)-based cyclizations that, several years ago, did not seem to tit well with the expected behavior for free-radical intermediates. These trends were observed in the Mn(II1) oxidation of a large number of unsaturated acetoacetates. First, the level of stereocontrol in 6-endo and 6-ex0 cyclizations was much higher than Second, that of existing cyclizations of related radicals (eq I).5b a variety of substrates give good to excellent yields of products derived from 6-endo cyclizations (eq 2),5a while the vast majority of existing radical classes give major products derived from 5-exo cyclizations. Despite these apparent differences, we now find
(I) first (6.exo) and semM (€-endo)
cyclzations are completely sIerm6ekclive
alkyl group [*CR(COX),], whether they are generated by Mn(111)-based oxidative methods or by atom-transfer methods. This indicates that Mn-complexed radicals are not involved in the cyclization process, and that the regio- and stereoselectivities observed are inherent to the free-radical intermediates.* Equation 3 summarizes the current mechanistic picture of manganese(II1) acetate promoted oxidations of acetoacetates. Several groups have observed that the rate of oxidation of acetoacetates with two CY hydrogens (la) is significantly accelerated by the presence of an alkene.' Such observations are inconsistent with the simple oxidation of acetoacetates to free radicals (path B), and indicate that adduct 4a is formed without the intermediacy of radical 3a. In contrast, Snider and co-workers observed that R I H. Path A alkene
x' 4a
(3)
la R - H
-
l b R = alkyl
R = alkyl Path E
Sb
6b
acetoacetates with only one CY hydrogen (lb) are oxidized by Mn(II1) acetate at the same rate whether an alkene is present or not.7 They presented evidence that the rate-determining step in these oxidations was the loss of a proton to form the manganese(II1) enol 2b. Rapid oxidation of the enol ligand of 2b by Mn(II1) should produce 5b. Since Sb is an odd-electron species, it might be the intermediate that is responsible for the radical-like additions and cyclizations observed in these oxidations. However, it is also conceivable that the enol ligand dissociates from 5b to give free radical 6b, or that dissociation is coupled with electron transfer so that 6b is formed directly from 2b (without the intermediacy of 5b). To address the question of the nature of the reactive intermediate, we decided to generate free radicals by an unambiguous method, and to compare the chemistry of these free radicals to that observed in the Mn(II1) oxidations. To generate authentic free-radical intermediates, we selected the halogen atom transfer method9 (eq 4) for several reasons. First, the mechanisms of these reactions are well-understood. Free-radical intermediates are formed, and kinetic cyclization products are generally obtained because atom transfer to cyclized radicals is more rapid than ring opening.'O Second, the requisite
Iirst cyclization IS 6-en&, not 5-ex0 11 1 mixture 01 en63lexo methyl groups
that identical mixtures of products are obtained from the cyclization of radicals substituted with two carbonyl groups and one (2) Recent reviews: (a) Hart, D. J . Science 1984, 223, 883. (b) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986. (c) Ramaiah, M. Tetrahedron 1987, 43, 3541. (d) Curran, D. P. Synthesis 1988, Part I , p 417; Part 2, p 489. (e) Curran. D. P. Radical Addition Reactions and Radical Cyclization Reactions and Sequential Radical Reactions, In Compr. Org. Syn. Trost, B. M., Fleming, I., Eds.; Pergamon. in press. (f) C-Radikale. In Methoden der Organischen Chimie; Regitz, M., Giese, B., Eds.: Houben-Weyl, 1989; Vol. E19A. (3) (a) de Klein, W. J. In Organic Synthesis by Oxidation with Meral Compounds; Mijs, W. J., de Jonge, C. R. H., Us.Plenum ; Press: New York, 1986; p 261-314. (4) Kates, S.A.; Dombroski, M. A.; Snider, B. B. J . Org. Chem. 1990, 55,
90110
cyduaton
- &.
(4)
atom transfer
?A71 -.-..
( 5 ) (a) Dombroski, M. A.; Kates, S.A.; Snider, B. B. J . Am. Chem. Soc. 1990, 112, 2759. (b) Mohan, R.; Kates, S.A.; Dombroski, M. A.; Snider, B. B. Tetrahedron Lett. 1987, 28, 845. (6) (a) Fristad, W. E.; Peterson, J . R. J . Org. Chem. 1985, 50, IO. (b) Fristad, W. E.;Peterson, J. R.; Ernst, A. B.; Urbi, G. B. Terrahedron 1986, 42. 3429. (7) Snider, 8. 8.;Patricia, J. J.; Kates, S.A. J. Org. Chem. 1988, 53, 2137 and references therein.
(8) In a related study, it was recently shown by competitive rate measurements that free malonyl radical intermediates are generated when diethyl malonate is oxidized with cerium(1V) ammonium nitrate: Baciocchi, E.; Giese, B.; Farshchi, H.; Ruzziconi, R. J . Org. Chem. 1990, 55, 5688. (9) (a) Curran, D.P.; Chen, M.-H.;Kim, D. J . Am. Chem. Soc. 1989,111, 6265. (b) Curran, D.P. In Free Radicals in Synthesis and Biology; Minisci, F., Ed.; Kluwer: Dordrecht, The Netherlands, 1989; p 37. (IO) Curran. D. P.; Chang, C.-T. J . Org. Chem. 1989,54, 3140.
J . Am. Chem. SOC.,Vol. 113, NO. 17, 1991 6609
Cyclizations of Unsaturated T R ( C O X J 2Radicals precursors would be readily available from the substrates previously used for Mn(II1) cyclizations, and the interconversion of the halides produced in atom-transfer cyclizations with the alkenes produced in Mn(1II) cyclizations was expected to be. easy. Third, although there were as yet no examples of bromine- or iodinetransfer cyclizations of acetoacetates, an in-depth study of halomalonates'O augured well for the success of the proposed atomtransfer cyclizations. And finally, the validity of the basic mechanistic approach has recently been demonstrated-a series of atom-transfer cyclization reactions provided evidence that palladium-promoted "enehalogenocyclization reactions" occur by a radical chain mechanism."
Results and Discussion The type of mechanistic test that we propose cannot rely on comparison of a single substrate, but instead requires a series of substrates that incorporates as much diversity as possible. The substrates that we have selected fall into two broad classes: substituted hexenyl radicals (S-exo/dendo cyclizations possible) and substituted heptenyl radicals (6-exo/7-endo cyclizations possible). At the outset of this project, there were no examples of Mn(II1) oxidations and atom-transfer cyclizations on substrates that would generate the same radical. To begin, we conducted a manganese(Il1) oxidation with a simple substrate whose atom-transfer chemistry was already established, and we continued by conducting atom-transfer cyclizations on a series of substrates whose Mn(111)-oxidation chemistry was established. We have assumed in this study that, if radical intermediates are involved, isomer ratios will be sensitive neither to small variations in temperature (atom-transfer cyclizations are conducted at 70-80 OC, Mn(II1) oxidations at 25-55 0C)4*snor to large variations in solvent polarity (atom-transfer cyclizations are conducted in benzene, Mn(ll1) oxidations in acetic acid). Insensitivity to solvent effects is a standard characteristic of many radical reactions, so this should be a valid assumption. When temperature effects appeared to be important, we conducted the atom-transfer cyclizations and the Mn(II1) oxidations at comparable temperatures. We have also assumed that the isolated product ratios are representative of the possible competing cyclization rates. In other words, we assume that all cyclic radicals are converted to final products with equal efticiency and that these final products are stable to the reaction conditions. This is probably a good assumption for the atom-transfer reactions, where high mass balances are the norm. We were less certain about this assumption for the Mn(II1) oxidations. Mass balances are sometimes moderate, and cyclic radicals can be converted to stable products with differing efficiencies depending on their oxidation potentials. Therefore, we selected for comparison Mn(lI1) oxidations conducted in the presence of Cu(II), which is a more efficient oxidizer of alkyl radicals than Mn(II1). That comparable mixtures of products were obtained in all cases ultimately validates this assumption. Equation 5 contains the results of Mn(II1) oxidative cyclization of 7; the parallel atom-transfer chemistry is presented in eq 4. Standard oxidation of 7 with 2 equiv of M ~ ( O A C(1) ~equiv of Cu(OAc)z, HOAc, 5 5 OC, 43 h)435resulted in the formation of 5-ex0 products 8 and 9, and 6-endo product 10 in a combined yield of 75%. Unreacted 7 was also recovered in 12% yield. Cyclization
by Cu(I1) to the lactone 8 and the methylenecyclopentane 9, or the cyclohexyl radical, which is oxidized to give the cyclohexene 10. The ratio of 5-exo/6-endo products was 90/10, which is identical with the ratio of regioisomers obtained in the atomtransfer cyclization of eq 4. That the ratios were identical despite differences in solvent polarity provided the first clue that freeradical intermediates might be involved in Mn(II1)-promoted cyclizations. We next investigated regio- and stereoselectivity in an atomtransfer cyclization of an acetoacetate. On the basis of the Mn(II1)-mediated oxidations of more complex substrate^,^ we anticipated that atom-transfer cyclization of iodoacetoacetate 11 (eq 6) should show a slight bias for the formation of 6-endo products over 5-exo (typical ratios in Mn cyclizations are 70/30).
XRu.. 11
1ZaR-I 1ZbR-H
14a,b
13a,b
(6)
Isomerization of 11 by the standard ditin procedure (10% Me3SnSnMe3,sunlamp irradiation in benzene) produced a mixture of four products, 12a-l4a, which was not easy to analyze. Direct reduction of the mixture with tributyltin hydride gave the 6-endo product 12bIZalong with the 5-exo products 13b and 14bI3 (91% combined yield). The ratio of 12b/(13b 14b) was 55/45. Although this ratio is slightly lower than the manganese precedents would indicate, we do not believe it is inconsistent with free-radical intermediates given the differences in the substrates. The modest stereoselectivity in favor of 13b over 14b (2.5/1) is in line with related Mn(II1) oxidation^.^ To provide a better comparison, we advanced to substrates whose Mn( 111) oxidation products had already been established (eq 7). Oxidation of 15 with Mn(OAc), and Cu(OAc), gave 20 in 86% yield.sa Oxidation of 15 with Mn(OAc), and LiCl gave stereoisomeric chlorides 16a and 17a in a 67/33 ratio (SO%, eq 7). Iodination of 15 by the standard procedure (NaH, NIS) gave
+
0
0
0
w 20
t
130'c
?\
21 7
130'C
$ -
ia X = I 19 X = B r 8 (48%)
7E-COOMe
x u.- x bJ
9 (20%)
R
#'-
Ibb, X = Br 16c. X = I
X
l7b, X = Br 17c. X = I
iodoacetoacetate 18 in good yield; however, initial attempts to cyclize 18 were frustrated by its ionic reactivity. This led to some interesting discoveries that are presented at the end of this paper. To circumvent this problem we prepared bromide 19, and it isomerized smoothly to a mixture of stereoisomers 16b and 17b
10 (7%)
occurs to give the cyclopentylmethyl radical, which is oxidized ( 1 I ) Curran, D. P.; Chang, C.-T. Tetrahedron Lotr. 1990, 31, 933.
(12) Compared with an authentic sample prepared by methylation of the anion derived from 2-carbomethoxycyclohexanone. ( f 3 ) Compared with an authentic sample: Narasaka, K.;Sakakura, T.; Uchimaru, T.; Gui5din-Vuong, D. J . Am. Chem. Soc. 1984, 106, 2954.
Curran et al.
6610 J . Am. Chem. SOC.,Vol. 113, No. 17, 1991
(65/35, 74% yield). We were later able to isomerize iodide 18, and it gave 16c and 17c in the same ratio (64% yield). The spectra of all the halides 16a-c and 17a-c were very similar, and stereochemistry was assigned accordingly. Bromides 16b and 17b were converted to iodides 16c and 17c, respectively, by a standard Finkelstein reaction. Treatment of this mixture of 16c and 17c (72/28) with DBU (benzene, 130 "C) provided the products of elimination 2Oc (from 16c) and intramolecular alkylation 21 (from 17c) in a ratio of 75/25. The structure assignment of 21 is tentative because we could not separate it from 20 by liquid chromatography. The results of the atom-transfer cyclization mesh nicely with those of the M ~ ( O A Coxidations )~ (eq 7). Only products derived from sequential 6-endo and 5-exo cyclizations are formed, and the ratio of stereoisomers is the same in all the cases. Interestingly, we isolate only the products derived from tandem cyclizations in both the bromine and iodine atom-transfer experiments. It was already known that the second cyclization was faster than Cu(I1) oxidation at 0.1 M ( k = (1-3) X IO6 mol-' ~ - l ) , ~ and * our new results indicate that the second radical cyclization is faster than both bromine- and iodine-transfer reactions at 0.3 M. On the basis of known rate constants, we anticipate that a primary radical would abstract iodine from 18 with a rate constant 11 X IO9 M-' s-I at 50 0C.14 Unfortunately, there are no known rate constants for the reactions of secondary or tertiary radicals with such iodides; however, these rate constants must still be very high. One cannot escape the conclusion that the second cyclization has a very high rate constant for a radical cyclization to form a bridged ring (probably >5 X IO7 s-l). That the regio- and stereochemistry of the second radical cyclization is the same in the M ~ ( O A Coxidations )~ and the atomtransfer reactions is reassuring, but it is not especially informative. It is already generally assumed that free radicals are produced after cyclization in the Mn(OAc), oxidations. The identical regiochemical result in the first cyclization is informative, and is consistent with the intermediacy of a free acetoacetate radical in both reactions. Substrates that produce new stereocenters in the first (rather than the second) cyclization provide more information about the role of Mn in the first cyclization, and eqs 8-10 present such comparisons. M ~ ( O A Coxidation )~ of 22 (30/1 E / Z mixture) provided 23 as an 11/1 mixture of stereoisomers in 67% yield (eq 8).5a Atom-transfer cyclization of bromide 24
23
n X.H 24 X - b
Mn(OAc)&u(ll)
87%(11l1mixlure)
l)lO%dlinmV 12o'c
@/* ( S W I J D W
2)
provided a mixture of two stereoisomeric bromides (65/35, 75% yield). Alkene 23 was isolated in 40% yield upon treatment of this bromide mixture with DBU at 120 "C. This shows that the diastereomers are bromomethyl rather than methyl epimers. We did not observe any monocyclic products, nor were there products in which the second cyclization was 6-endo, nor was the diastereomer of 23 present in detectable quantities. At this point, we do not know if the failure to detect the diastereomer of 23 in the atom-transfer reaction is due to solvent effects (higher stereoselectivity in benzene than in acetic acid), to analytical technique (authentic samples of this trace product were not available), or to loss of the product in the DBU elimination (for example, by intramolecular alkylation as in eq 7). Equations 9 and 10 present the comparison of the last of the hexenyl radical substrates. In addition to the primary goal of comparing regio- and stereoselectivity in the first cyclization, a secondary goal was to learn something about the rate of a second cyclization to an aromatic ring. In the absence of Cu(Il), cy(14) Curran, 1989, 54, 1826.
D.P.;Bosch, E.; Kaplan, J.; Newcomb, M. J . Org. Chem.
clization of 25 with M ~ ( O A Cgave ) ~ 46% of 26a, 16% of 26b, and 9% of 27.5b When Cu(I1) was present, only 5% of 26a and 15% of 26b were formed, and 27 (38%) was the major product.
26b
Cyclization gives mainly the cyclic radical with the alkyl and benzyl groups transsb This radical cyclizes primarily to the trans-fused hydrindan 26a in the absence of Cu(I1) and is oxidized primarily to 27 in the presence of Cu(I1). The minor radical cyclizes to the cis-fused hydrindan 26b in the absence or presence of Cu(I1). These results were interpreted to mean that Cu(I1) oxidation of the monocyclic radical (at 0.1 M) was faster than cyclization to the aromatic ring to give trans-fused 26a. Cyclization to give 26b, which is less strained than 26a, occurs in the absence or presence of Cu(I1). A Friedel-Crafts type cyclization to give 26 was discounted because Mn(II1) does not rapidly oxidize secondary radicals to cations. The required bromide 28 was prepared by standard bromination of 25, and was isomerized in the usual manner. In contrast to most other atom-transfer reactions, the resulting crude reaction mixture was not especially clean. Two major products were evident in the 'HNMR spectra of this mixture, but GC analysis indicated the presence of several minor products. Direct reduction of the crude reaction mixture with tributyltin hydride produced 29 as the single major product in 60% yield. Compound 29 also formed
28
29
on catalytic hydrogenation of 27 (Pd, H2), thus confirming its structure. We did not attempt to isolate or identify any of the minor products; however, we did determine (NMR, GC) that neither 26a nor 26b was present in significant amounts. Once again, the results of the atom-transfer cyclization are generally consistent with the M ~ ( O A Coxidation. )~ Product 29 has the expected stereo- and regiochemistry. In contrast to the rapid cyclizations to alkenes, the second cyclization to the aromatic ring is now slower than bromine transfer (at 0.3 M). We selected substrate 30 to initiate studies of substituted heptenyl radicals (eq 11). Oxidation of 30 with Mn(OAc)3 gave tricyclic ketone 31 whether Cu(I1) was present or not.5b These results indicated that the second cyclization in this substrate was considerably faster than that in eq 9, and we were interested to learn its efficiency relative to bromine transfer. Unfortunately,
\ 31
when bromide 32 was treated under the normal atom-transfer conditions, a very complex mixture of products formed. We could not discern any peaks in the crude 'HNMR spectrum that could be assigned to the expected products, and further characterization was not attempted. At this point, we do not understand why there are problems in the atom-transfer reactions of benzylic acetoacetates 28 and 32.
J . Am. Chem.Soc., Vol. 113, No. 17, 1991 6611
Cyclizations of Unsaturated ‘CR(COX), Radicals We next moved to the methyl-substituted acetoacetates (eqs 12 and 13), and these substrates yielded the most interesting and informative results. Mn(OAc)3 cyclizations of 33E and 332 had
been shown to give mixtures of products that depended on the geometry of the starting alkene. Cyclization of 33E gave 34/35/36 in a ratio of 4.5/ 1 / 1 .4 In contrast, cyclization of 332 gave the same three products in a ratio of 18/4.6/Ie4 Defining the stereoselectivity in these experiments is complicated by the presence of trisubstituted olefin 35, which could have resulted from either stereoisomer of the initial cyclization product. However, an inspection of the products implies that most of 35 must come from the same radical that leads to 34.4915 Thus, the cyclization of the radical derived from 33E is moderately stereoselective (-3/l) and that derived from 332 is highly stereoselective (-20/1).
radical 43 with excellent stereoselectivity (195/5).16 The features that dictate this stereochemistry have been previously discussed for the Mn(II1) cy~lization:~,~ the enol radical 422 adopts a geometry with the ketone and the ester carbonyl groups trans, and cyclization occurs through a chairlike transition state (see 422). The atom-transfer experiments presented above demonstrate that the trans geometry of the enol radical 42 is not imposed in any way by the manganese salts. It is simply the preferred geometry of the enol radical in the transition state, and probably also in the ground state. A trans orientation of the two carbonyls should minimize unfavorable dipolar interactions.
Ap
34 and 35, wllh Cull11 40b wilh -or. 39bZ
x.
0 11
COrEl ‘”I,
It
\ 422
33E
43
(14)
epimer 441
332
37
38
The atom-transfer method is well suited for a direct analysis of stereochemistry. We prepared bromide 39aE, and upon standard irradiation with ditin, it produced a clean mixture of four stereoisomeric bromides (4.1 / 1.8/ 1.4/ 1) in essentially quantitative yield (eq 13). The two major diastereomers 40a were isolated
2) B&SnH
--
k
E
1
+ 42E
0
39a ER X 39b EIZ X
-
slowlrap
\
Br
4Oa X - B r
I
4ObX.I 37 X - H
-
418 X Er 41bX-I 38 X - H
in pure form free of the two minor isomers 41a. Tin hydride reduction of this mixture of 40a produced only 37, proving that 40a and 41a differed in configuration on the ring. Thus, the &/trans (40a/41a) ratio in the cyclization of 39a is 2.4/1, and this compares favorably to the estimated ratio (3/1) from the Mn(OAc)3 cyclization of 33E. However, unlike the Mn(OAc), oxidations, the isomer 39aZ behaved essentially the same as 39aE. Upon isomerization, four isomers (two epimers of 40a and two epimers of 41a) formed in a ratio of 4.4/2.5/1.3/1. Direct tin hydride reduction of the mixture gave 37 and 38 in a ratio of 2.8/ 1. The key to resolving this apparent discrepancy came when we prepared the iodide 39b2, and isomerized it according to the standard procedure. In this case, only two diastereomeric iodides formed (not four). Direct tin hydride reduction of this mixture gave only 37 (65% overall yield), demonstrating that these two iodides were epimers of 40b. The different behaviors of bromide 39aZ and iodide 39bZ indicate that radical ring-opening reactions (reverse cyclizations) are important in the case of the bromide (see below). Thus, the kinetic cyclizations of the radicals derived from the Z-alkene precursors are indeed highly stereoselective. We propose the kinetic scenario outlined in eq 14 to explain these results. Radical 422 is formed from all the Z olefin precursors (332, 39a2, 39bZ), and it cyclizes kinetically to give (IS) Cyclization of 332 gives a 4.1/1 mixture of (34+ 36)/35. Cyclization of 33E gives much more 36 but gives a SS/l mixture of (34+ 36)/35. Since the ratios are similar it is likely that each radical gives a ‘=4-5/ 1 mixture of disubstituted/trisubstituted double bonds as has been observed for the parent I-cyclohexylhexyl radical. (See:Snider, B. B.; Kwon, T.J . Org. Chem. 1990.55, 1965.) The formation of a 1 / 1 mixture of 35/36from 33E and a 4.6/1 mixture from 332 indicates that most of the 35 formed from 332 comes from the radical precursor to 34 since the radical precursor to 36 must give a SI / I ratio of 35/36.This can account for, at most, 22% of the 35 formed from 332.
The fate of radical 43 depends on the efficiency of the radical trap in the reaction. In the presence of stoichiometric quantities of C U ( O A C )(an ~ excellent radical trap), 43 is rapidly oxidized to 34 and 35. When iodide 39bZ is the precursor, radical 43 is also trapped very efficiently by irreversible iodine transfer (a chain propagation step) to give 40b. However, bromine transfer is typically about 1000 times slower than iodine t r a n ~ f e r ,and ’ ~ we postulate that bromide 39aZ is not a sufficiently good trap for 43. Instead, 43 suffers ring opening. Although 43 might open to reform 422, we postulate that most of the time it opens to form the more stable isomer 42E. Radical 42E then recloses to give 43 and its epimer 44 in a kinetic ratio of about 3/1. These radicals are then trapped by bromine transfer, and the result is that the E and 2 bromide precursors give the same product ratio because the same radical 42E is formed. We do not know the thermodynamic ratio of isomeric radicals 43 and 44; however, we doubt very much that radicals 43/44 live sufficiently long under these conditions to reach true equilibrium. In effect, the Z olefin precursors are exquisitely sensitive probes for reverse radical cyclizations since only one reverse cyclization is needed to transform the product ratio observed for the 2 olefin into that observed for the E olefin. The results fix the rate for reverse cyclization of 43 to 42E somewhere between the rate of bromine transfer (from 39a) and iodine transfer (from 39b) to 43. At present, the best we can do is define a rather large window for the rate constant for ring opening of 43. Equation 15 shows the closest known rate constants for bromine and iodine transfer.I4 We can assume that the CO,M C*H,,,
+
‘fC0,M
x
Br, I
50’c
C0,M
caH17x
+
.f-
C0,M.
haloacetoacetates 39a,b are roughly similar in atom-donor capabilities to the halomalonic esters. However, radical 43 is secondary, and all known rate constants have been measured with primary radicals. It is not clear whether secondary radicals will abstract halogen atoms slower (due to reduced exothermicity) or faster (due to favorable polar effects) than primary radicals. We estimate that the reverse cyclization must have a rate constant somewhere in the range of IO5to IO8 s-I. Since Cu(I1) also traps the radical before opening, it is more likely that the actual number (16) (a) It has been considered that such enol radicals may cyclize rapidly on oxygen, but that this cyclization may be reversible, with cyclization ultimately occurring on carbon. Our results rule out this possibility because radicals 42E and 422 would produce the same radical if they cyclized initially on oxygen. (b) See: Clive, D. L. J.; Cheshire, D. R. J . Chem. SOC.,Chem. Commun. 1987, 1520.
Curran et al.
6612 J . Am. Chem. Soc.. Vol. 113, No. 17, 1991
E = COR, CN, Ph
Figure 1. Ring opening of cyclopentylmethyl radicals.
is near the lower end of this range. Even if this rate constant is at the lower end of this range, it is surprisingly high. As far as we are aware, no ring openings of cyclohexylmethyl radicals (reverse 6-ex0 cyclization) are known. Excluding strained cyclopropylmethyl and cyclobutylmethyl radicals, most known radical ring openings to form alkenes are of the type outlined in Figure 1. Ring opening of cyclopentylmethyl radicals to give stabilized radicals was extensively studied by Julia." Typically, two stabilizing groups are present (E = carbonyl, cyano, phenyl), and both are exocyclic substituents. No accurate rate constants for such ring openings are known, but there is no reason to believe that these ring openings are relatively fast. For example, it has been estimated that the rate constant for ring opening to give a malonyl radical (Figure 1, E = C02R) is < 1O4 s-l I 1
In a more related observation, Clive and Cheshire generated radical i by standard tin hydride reduction and found that it opened with C-0 bond cleavage very slowly to give ii (Figure 2).16 Radical ii is an isomer of an acetoacetate radical (the radical is only conjugated to the ketone), and we can estimate that its rate constant for formation is very slow ( k < io4 s-l). Although the rapidity of the ring opening of 43 is surprising, it is even more surprising that none of the related 5-exo cyclizations of the lower homologues have yet shown any clear-cut evidence for reversibility. Because of higher ring strain, it is generally expected that ring openings of cyclopentylmethyl radicals (reverse 5-ex0 cyclizations) will be more rapid than those of cyclohexylmethyl radicals (reverse 6-ex0 cyclizations).18 Thus, both 5-ex0 and 6-ex0 cyclizations of acetoacetates of this type should be carefully scrutinized for reversibility. To garner further evidence for reversibility, we investigated the concentration dependence of the 37/38 ratio in the reduction of 40b. The results of initial experiments with tin hydride were di~appointing;'~ however, switching to the Mn(OAc), oxidations of 33 proved very profitable. Oxidative cyclization of 332 with Mn(IIl), but without Cu(II), afforded a complex mixture of 34-38 (eq 12) since the secondary alkyl radicals produced in the cyclization are not oxidized rapidly by Mn(II1). Oxidation of the cyclized secondary radical gives 34-36, while competing abstraction of a hydrogen atom gives 37 and 38. The mixture was most efficiently analyzed by hydrogenation (Pd/H2), which gave an 8/1 mixture of 37 and 38. This result contrasts to a 25/1 mixture of 34 and 36 obtained from 33 by oxidation with both Mn(II1) and Cu(11). Since it is known that Cu(I1) oxidizes radicals 300 times faster than Mn(lII),Zothe most likely explanation for this observation is that the cyclization is partially reversible in the absence of Cu(I1). For comparison with atom-transfer cyclizations, we examined the cyclization of 332 at higher temperatures. Oxidative cyclization with Mn(II1) and Cu(I1) at 90 OC gave a 6.3/1 mixture Ph3SnH
Figure 2. A reverse 6-ex0 cyclization.
of 34 and 36. Oxidative cyclization with Mn(II1) followed by hydrogenation gave a 2.7/1 mixture of 37 and 38.2i The selectivity of the cyclization at 90 OC is also lower in the absence of Cu(I1). In both cases, the selectivity of the cyclization is decreased, as expected, at higher temperature.22 From this example, it is not clear whether this is due entirely to the normal decrease in selectivity with increase in temperature or whether the cyclization is more reversible at higher temperature. The last pair of comparison substrates is described in eqs 16 and 17. The ratio of tandem cyclization products 46 and 47 produced in the Mn(OAc), oxidation of 45 depended on temperature. At 25 OC, the ratio of 46/47 was 20/1, but this ratio was reduced to 8/1 at 90 OC. These product ratios are very similar to the ratios obtained in the oxidative cyclization of 332 with Mn(II1) and Cu(I1) at both 25 and 90 "C. Is this variation due to temperature effects in a kinetic cyclization, or does reverse cyclization compete more effectively with the second cyclization at 90 OC than at 25 OC? The monocyclic radical obtained from 332 is oxidized by Cu(II), and the monocyclic radical obtained from 45 cyclizes to give a bicyclic system. Since the same ratios of stereoisomers are obtained in both cases, these cyclizations are probably kinetically controlled. This conclusion was confirmed by examination of the atom-transfer cyclization of 48a and 48b.
%- 6 Mn(OAc),
+ (16)
CU(OAC12
n r
tl
\
\
45
20/1 ai 2sc 811at90'c
46
f
DEU/lPO'C
47
f
10% dilinihv __t
H
B
\
&, X = E r 48b, x - l
-
49a. X Er 49b. X i I
ma, X = Br
m,X = I
Bromide 48a was prepared and isomerized at 80 O C to give a 9/1 mixture of stereoisomers 49a and 5Oa in 68% yield (the configuration of one stereocenter of 50 is not assigned). Treatment of this mixture with DBU at 120 OC gave a 10/1 mixture of 46 and 47. Similarly, iodide 48b gave a 10/1 mixture of 49b and 5Ob after isomerization, and a 10/1 mixture of 46/47 after DBU treatment. When bromide 48a was isomerized at 5 OC, the ratio of 49a/SOa was now >20/1. We know from eq 15 that ring opening of the first-formed cyclic radical is faster than bromine transfer but slower than iodine transfer. That iodide 48b and bromide 48a gave the same bicyclic products at 80 OC (with no monocyclic product) tells us that the second cyclization in this system is faster than both bromine and iodine transfer (at 0.3 M). Thus, the second cyclization must be much faster than the reverse of the first cyclization at 80 O C . Taken together, the results indicate that the improved stereoselectivity at 5-25 OC reflects the kinetic temperature dependence of the first radical cyclization. At present, there are only a few examples where stereoselectivities in radical cyclizations exhibit significant temperature dependences.22 Since there are good methods to initiate radical
J . Am. Chem. Soc.. Vol. 113, No. 17, 1991 6613
Cyclizations of Unsaturated 'CR(COXJ2Radicals reactions at 25 O C or lower, reduction of temperature is a simple method to increase the stereoselectivity in a radical reaction. Conclusions The primary goal of this work was to establish the nature of the reactive intermediate in the manganese(II1) oxidations of tertiary acetoacetates and malonates. We can now safely conclude that free radicals such as 6b are produced in the Mn(II1) oxidations because all Mn(l1I) oxidative cyclizations and atomtransfer cyclizations gave comparable regie and stereoselectivity. If Mn-complexed radicals such as 5b are produced, they must dissociate rapidly, before cyclizations occur. We have also learned that the atom-transfer method is highly suitable for conducting cyclization reactions of acetoacetates, and that the primary products formed (halides) are often structurally complementary to those formed in Mn(I1I) oxidations (alkenes, lactones). Further, the tandem cyclizations to alkenes are so fast that atom transfer cannot compete, and thus the sequences are not interrupted prior to completion. An unexpected observation in this work was the rapid ring opening of cyclohexylmethyl radical 43. This opening, a reverse 6-ex0 cyclization, is considerably faster ( k > lo5 s-l) than the sparse literature precedent would lead one to believe, and it points to a need for better understanding of the factors affecting the rates of such ring openings. A practical consequence of this rapid opening is that the radical derived from 332 is a very sensitive probe for reversible radical cyclizations; it takes only one ring opening to convert the stereoisomer ratio observed for 332 to that observed for 33E. This stereochemical approach to the detection of reverse radical cyclizations should be general. Finally, we have learned that the stereoselectivity of these radical cyclizations is strongly influenced by temperature. Although this point seems intuitively obvious, it is only recently that temperature effects have been harnessed to insure highly stereoselective radical reactions. Ionic Reactions of lodoacetoacetates As mentioned earlier, the atom-transfer cyclization of iodide 18 was initially complicated by a competing rearrangement. We observed that samples of crude, freshly prepared 18 (which contained about 5% 15) spontaneously isomerized (CDC13or C6D6, dark, 25 "C) to tetrahydrofuran 51a, which could be isolated in yields ranging from 30 to 60% (eq 18). Tin hydride reduction l2 CH,I 0
f-
R = Me, X = H
b3 R
R = Me, x = I
15 R - M e , X = H 18 R = M e , X = I 11 R = H , X = I
Experimental Section Manganese(II1)Cyclizations. General Methods. All reactions were carried out in flame-dried glassware unless otherwise noted. Diethyl ether was distilled from sodium/benzophenonebefore use. Manganese triacetate dihydrate (M~(OAC)~-~H,O) was purchased from Aldrich Chemical Co. and was used without further purification. All oxidative free-radical cyclizations were carried out under nitrogen and monitored by TLC or capillary GC for the disappearance of starting material. Nuclear magnetic resonance spectra were recorded on either a Varian EM-390 or a Varian XL-300 spectrometer. All NMR spectra were recorded in CDCI, with tetramethylsilane as an internal reference. Chemical shifts are reported in parts per million downfield from (CH,),Si (6). Coupling constants are reported in hertz. IR spectra were recorded on a Perkin-Elmer 683 and are reported in cm-I. Analytical GC was performed on a Perkin-Elmer 8310 fitted with a flame-ionization detector. A 25 m X 0.25 mm fused silica column containing OV-225B was used at a helium flow rate of 25 mL/min. A temperature program starting at 60 OC, increasing to 100 OC at a rate of 5 OC/min, holding at 100 OC for IO min, increasing to 120 OC at a rate of 5 OC/min, and holding at 120 OC for 1 min was used. Elemental analyses were performed by Spang Microanalytical Laboratories, Eagle Harbor, MI. Column chromatography was carried out on Baker silica gel deactivated with methanol. Ethyl 2-methyl-3-oxodec-(Z)-7-enoate(332). ethyl 6a-(E)-(1-propenyl)-1/3-methyl-2-oxocyclohexane-l a-carboxylate (M), ethyl 6-(E)-propylidene-1~-methyl-2-oxocyclohexane-la-carboxylate (35), and ethyl 6/3-(E)-(I-propenyl)-1~-methyI-2-oxocyclohexane-lacarboxylate (36) were prepared as described.' Oxidative Free-Radical Cyclization of 7. Reaction of 7 (300 mg, 1 .SO mmol), Mn(OAc),~2H20(803 mg, 3.00 mmol), and Cu(OAc),.HzO (299 mg, 1.50 mmol) in glacial acetic acid (15 mL) at 55 OC for 43 h gave 279 mg of crude product. Flash chromatography of 243 mg (9/1 hexane/EtOAc followed by 5/ 1 hexane/EtOAc, deactivated silica gel) gave 100 mg of a 2/3/1 mixture of recovered 7, 9, and 10 (39%), followed by 124 mg of 8 (48%). The spectral data for 9 were determined from the mixture: 'H NMR 6 5.30 (t, 1, J = 2.3, =CHI), 5.27 (t, 1, J = 2.3, =CH2), 3.74 (s, 3, OCHI), 2.46 (tt, 2, J = 2.3, 7.3, H4), 2.35 (t, 2, J 6.7, H2), 1.74 (tt, 2, J = 6.7, 7.3, H3). The diethyl ester has been rep~rted.~' The spectral data for 10: 'H NMR 8 5.67 (br t, 2, J = 2.0, H3 and H4), 3.72 (s, 6, OCH]), 2.57 (br s, 2, H2), 2.20-2.00 (m, 4, HS and H6); ',C NMR 6 172.0 (OC=O X 2), 126.1 (CH=), 123.9 (=CH), 52.6 (OCH, X 2), 30.5 (C2), 27.5 (CS), 22.3 (C6), CI was not observed; IR (neat) 3080, 1760, 1737, 1641 cm-I. The spectral data are identical with those previously described.25
mo2c CHIX
CH,
52
Photolysis of this sample provided the atom-transfer cyclization products (see eq 7) contaminated with only a trace (
