5223
J. Org. Chem. 1985,50, 5223-5230
Intramolecular N-H, 0-H, and S-H Insertion Reactions. Synthesis of Heterocycles from a-Diazo P-Keto Esters Mike1 P. Moyer, Paul L. Feldman, and Henry Rapoport* Department of Chemistry, University of California, Berkeley, California 94720 Received J u n e 7, 1985
Several aspects of the Rh2(OAc)4-catalyzedintramolecular N-H, 0-H, and S-H insertion reactions have been studied. Examination of the effect of ring size revealed that four-, five- and six-membered nitrogen heterocycles can be efficiently prepared from the corresponding a-diazo @-ketoester precursors (ga-c), whereas competing C-Hinsertion prevented formation of the seven-membered heterocycle. Variations in solvent, temperature, and catalyst concentration were found to play an important role in determining the product distribution in the cyclization of the 6-carbamoyl 2-diazo 3-keto ester 9c. The intramolecular X-H insertion reaction has also been successful in the synthesis of oxygen (39) and sulfur (49) heterocycles as well as a heterocycle containing two (N, 0)heteroatoms (34).
Transition-metal-mediated carbon-carbon bond-forming reactions from various diazo precursors have been extensively utilized in carbocycle synthesis. The intramolecular versions of cyclopropanation and C-H insertion reactions have been used in the synthesis of both theoretically interesting compounds and natural products. A general review of intramolecular diazo carbonyl reactions appeared in 1979,l and since then many further publications on the transition-metal-catalyzed reactions have extended the scope of this meth~dology.~-~ Recently, Rh2(OAc)(has been used to catalyze intramolecular C-H insertion reactions of a-diazo @-ketoesters into freely rotating aliphatic side chains.3b This work was significant because the regioselectivity of C-H insertion was determined on a conformationally mobile side chain rather than on a constrained system in which ring size is determined by the proximity of the diazo function to the C-H bond. The results demonstrated that (a) there is a kinetic preference for five-membered ring formation and (b) C-H insertion into a more substituted carbon is faster than into a less substituted one for the same ring size. Even though five-membered ring formation is favored with conformationally mobile side chains, there are many examples of C-H insertion giving both four- and six-membered rings depending upon the ~ u b s t r a t e . l *The ~ ~ regioselectivity one obtains in a particular molecule depends upon the type of diazo function, substitution of the carbon where insertion takes place, steric factors, and the reagent (1)Burke, S. D.; Grieco, P. A. Org. React. 1979, 26, 361. (2) A general review on carbenoid reactions is presented in: Wulfman, D. S.; Poling, B. "Reactive Intermediates"; Abramovitch, R. A., Ed.; Plenum Press: New York, 1980, Vol. 1, p 321. (3) Recent studies on carbenoid C-H insertion are given in: (a) Cane, D. E.; Thomas, P. J. J. Am. Chem. SOC.1984,106,5295. (b) Taber, D. F.; Petty, E. H. J. Org. Chem. 1982,47,4808. (c) Taber, D. F.; Raman, K. J. Am. Chem. SOC.1983, 105, 5935. (d) Taber, D. F.; Petty, E. H.; Raman, K. J. Am. Chem. SOC.1985,107,196. ( e )Demonceau, A.; Noels, A. F.; Hubert, A. J.; Teyasie, P. J . Chem. Soc., Chem. Commun. 1981,688. (fj Taber, D. F.; Ruckle, R. E.; Jr. Tetrahedron Lett. 1985, 26, 3059. (4) Recent studies on carbenoid cyclopropanation are found in: (a) Doyle, M. P.; Dorow, R. L.; Buhro, W. E.; Griffin, J. H.; Tamblyn, W. H.; Trudell, M. L. Organometallics 1984,3,44. (b) Doyle, M. P.; van Leusen, D.; Tamblyn, W. H. Synthesis 1981, 787. (c) Anciaux, A. J.; Hubert, A. J.; Noels, A. F.; Petiniot, N.; Teyssie, P. J. Org. Chem. 1980, 45, 695. (5) Carbenoids have been used for intramolecular X-H insertion: (a) Cama, L. D.; Christensen, B. G. Tetrahedron Lett. 1978, 4233. (b) Ratcliffe, R. W.; Salzmann, T. N.; Christensen, B. G . Tetrahedron Lett. 1980, 21, 31. ( c ) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G. Tetrahedron Lett. 1980,21, 1193. (d) Melillo, D. G.; Shinkai, I.; Liu, T.; Ryan, K.; Sletzinger, M. Tetrahedron Lett. 1980,21,2783. ( e ) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G. Bouffard, F. A. J. Am. Chem. SOC.1980,102, 6163. (fj Yamamoto, S.; Itani, H.; Takahashi, H.; Tsuji, T.; Nagata, W. Tetrahedron Lett. 1984, 25,4545. (g) Campbell, M. M.; Jasys, V. J. Heterocycles 1981, 16, 1487. (h) Moody, C. J.; Pearson, C. J.; Lawton, G . Tetrahedron Lett. 1985, 26, 3171.
0022-3263/85/1950-5223$01.50/0
Scheme I 0
0
"8
COeR
-ti
e
I
4
3
5
used to promote the reaction. The use of diazo carbonyl precursors to prepare heterocycles has been limited. Cyclopropanation6 and C-H i n ~ e r t i o n lhave , ~ ~ been used to synthesize lactones, and C-H insertions employing a-diazoamides have served extensively to synthesize lacta tam^.'^^ Intermolecular examples of 0-H insertion reactions have shown Rh2(OAc), to be the most efficient catalyst for intermolecular insertion between ethyl diazoacetate and a variety of alcoholsa and C-H insertion not to be competitive with ether f~rmation.~ The Rh,(OA~)~-mediated X-H insertion was extended to include N-H and S-H insertions by coupling ethyl diazoacetate with aniline and thiophenol.'O Subsequently, the S-H insertion reaction was used as an efficient means of synthesizing a-(phenylthio) ketones from the corresponding a-diazoketones.'l There have been a number of examples of Rh2(OAc)4-catalyzedintramolecular N-H insertions as a key step in the synthesis of various P-la~tams.~ With one exception, all intramolecular X-H insertion reactions catalyzed by R ~ , ( O A Cinvolve )~ insertion into amide N-H bonds.12 This methodology has also been used (6) A leading reference on intramolecular cyclopropanation with diazo esters is: Hudlicky, T.; Reddy, D. B.; Govindan, S. V.; Kulp, T.; Still, B.; Sheth, J. P. J. Org. Chem. 1983, 48, 3422. (7) Bright, G. M.; Dee, M. F.; Kellogg, M. S. Heterocycles 1980, 14, 1251.
(8) Paulissen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett. 1973, 2233. (9) Noels, A. F.; Demonceau, A,; Petiniot, N.; Hubert, A. J.; Teyssie, P. Tetrahedron 1982, 38, 2733. (10) Paulissen, R.; Hayez, E.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett. 1974, 607. (11) McKervey, M. A.; Ratananukul, P. Tetrahedron Lett. 1982,23, 2509. (12) A Rh,(OAc),-catalyzed intramolecular OH insertion has been
reported in the synthesis of oxazinones; however, stoichiometric quantities of BF3-Et20were found to be better in promoting the insertion. McClure, D. E.; Lumma, P. K.; Arison, B. H.; Jones, J. H.; Baldwin, J. J. J. Org. Chem. 1983, 48, 2675.
0 1985 American Chemical Society
5224 J. Org. Chem., Vol. 50, No. 25, 1985
with two heteroatoms in the ring to synthesize oxapenams* and o~acephams~**~ and has led to anomalous results when applied to aza ana10gues.l~ We have examined several aspects of the intramolecular X-H insertion reaction in order to increase its utility and now present our results. By determining the effect of ring size on the N-H insertion reaction we have shown that intramolecular N-H insertion reactions can provide good yields of various sized aza rings. Also, the versatility of the reaction has been demonstrated by synthesizing heterocycles containing one (N, 0, S ) and two (0,N) heteroatoms in the ring. Finally, the effect of solvent, temperature, and catalyst stoichiometry on the outcome of one N-H insertion reaction has been studied. Results and Discussion To facilitate investigation of the fundamental aspects of the carbenoid insertion reaction we utilized substrates devoid of unnecessary functionality. Thus, the synthetic objective was to construct substrates of general type 1 (Scheme I) in which the heteroatom to undergo insertion is tethered to the a-diazo P-keto ester with carbon chains of various lengths to allow investigation of the effect of ring size. The products that would result from successful X-H insertion are functionalized heterocycles of type 2. The potential synthetic applicability of these compounds prompted a literature review to determine whether heterocycles of this type are known and, if so, how efficient has been their construction. Heterocycles of general structure 2 in the past have been almost invariably prepared via Dieckmann cyclization of the appropriate diester. Their construction suffers the same limitations present in any unsymmetrical Dieckmann cyclization, namely the difficulty in obtaining regiochemical control and the need for strongly basic conditions. The problem of regiocontrol has been resolved to some extent by manipulation of reaction conditions to give either kinetic or thermodynamic control or by differentiation of the esters to make one carbonyl more susceptible to nucleophilic attack. The strongly basic conditions cannot be avoided. By judicious choice of reaction conditions it was dem(type 2) could onstrated that 2-carboxy-3-oxopyrrolidines14 be obtained via Dieckmann condensation. Previously, the thermodynamically more stable 4-carboxy-3-oxopyrrolidines (type 3) had been the exclusive products because the reaction had been conducted under equilibrating conditions (sodium ethoxide in ethanol at reflux). Upon utilization of nonequilibrating conditions (potassium tert-butoxide in toluene at 0 "C), the kinetic isomer became the preponderant product; however, the 4-carboxy isomer was still formed in significant amounts (40%). A similar kinetically controlled Dieckmann cyclization was used in the preparation of a 2-carboxy-3-0xopiperidine'~ derivative but only in very poor yield (25%). Also, a kinetically controlled Dieckmann condensation was utilized in the synthesis of a 2-carboxy-3-oxotetrahydrothiophene.16 In this case, the pure product could not be isolated free of contamination with the isomeric 4-carboxy compound. Thus, although some degree of regiochemical selectivity is possible through control of reaction parameters, the (13) An attempt to accomplish an intramolecular N-H insertion on 2-substituted 1,2-diazetidin-3-ones is described by: Taylor, E. C.; Davies, H. M. L. J. Org. Chem. 1984,49, 113. (14) Blake, J.; Willson, C. D.; Rapoport, H. J. Am. Chem. SOC.1964, 86, 5293. (15) Plieninger, H.; Leonhauser, S. Chem. Ber. 1959, 92, 1579. (16) Woodward, R. B.; Eastman, R. H. J. Am. Chem. SOC.1946, 68, 2229.
Moyer et al. Scheme I1
6
7
8 2=CeHSCHz0C;
8
s
a,nsl, b,n=Z,c,n:3,d,n=4
classical Dieckmann condensation often produces a regioisomeric mixture and frequently gives low yields of the desired product when applied to the construction of heterocycles of type 2. A more successful approach to the problem of regiochemical control has been to differentiate the two carboxyl functions such that one mode of Dieckmann closure is favored over the other. A direction-controlled Dieckmann type cyclization using half-thiol diesters has been successfully employed in the synthesis of both carbocycles and heterocyc1es.l' For example, the tetrahydrothiophene 5 was prepared from half-thiol diester 4 in 74% yield by treatment with sodium hydride in THF. An analogous N-protected 2-carboxy-3-oxopyrrolidine derivative has also been prepared by using this methodology. In spite of this progress in obtaining regioselective syntheses of heterocycles of type 2, a need still remains for a general, mild, and regiospecific method for constructing such heterocycles. The discussion that follows describes such a method. Information is also presented that will facilitate extension of this methodology to more complicated heterocyclic compounds. N-H Insertion Reactions. A general and efficient synthetic route to N-H insertion substrates 9a-d, potential precursors of four-, five-, six- and seven-membered nitrogen-containing heterocycles, is outlined in Scheme 11. The readily available amino acids 6a-d were first converted to the corresponding benzyl carbamates 7a-d by a modified Schotten-Baumann procedure. Initial attempts at conversion of the protected amino acids to P-keto esters 8a-d involved Claisen condensations on the corresponding methyl esters of 7a-d. The harsh conditions and low yields (10-40%) made this method synthetically unacceptable. A far more satisfactory method involved activation of the carboxyl by treatment with N,N'-carbonyldiimidazole, followed by treating the resulting imidazolide with the dianion of hydrogen methyl malonate.18 Good yields (70-95%) and mild reaction conditions make this the method of choice for forming P-keto esters 8a-d. The diazo group was introduced by diazo transfer from (pcarboxypheny1)sulfonyl azidelg since the p-carboxybenzenesulfonamide that results from the diazo transfer can be removed via a simple alkaline wash. Although all of the diazo compounds (sa-d) were stable to purification by silica gel chromatography, in most cases this was unnecessary due to the absence of byproducts, and yields were generally 80-95%. Initially, P-keto ester 8c presented difficulties in the diazo transfer reaction. When (p-carboxyphenyl) sulfonyl azide was added to a solution of 8c in acetonitrile, the diazo transfer reagent remained insoluble until dropwise addition of triethylamine formed its triethylammonium salt. Although the desired diazo compound was formed to some extent, a less polar material was the major component. (17) Yamada, Y.; Ishii, T.; Kimura, M.; Hosaka, K. Tetrahedron Lett. 1981,22, 1353. (18) (a) Cox, M. T.; Jackson, A. H.; Kenner, G. W.; McCombie, S. W.; Smith, K. M. J. Chem. SOC.Perkin Trans. 1 1974, 516. (b) Bram, G.; Vilkas, M. Bull. SOC.Chim. Fr. 1964,945. ( c ) Bates, H. A.; Rapoport, H. J. Am. Chem. SOC.1979, 101,1259. (19) Hendrickson, J. B.; Wolf, W. A. J. Org. Chem. 1968, 33, 3610.
J. Org. Chem., Vol. 50, No. 25, 1985 5225
Heterocycle Synthesis from a-Diazo @-KetoEsters Scheme I11 -NS02Ar
I
HNS02A, N A
Table I. Effect of Solvent, Temperature, and Amount of Rh2(OAc), on the Cyclization of 9c temp, Rh2(oAc)4, product distribn," % entry
solvent C6H6
C6H6 C6H6
4
5 14
IS
I
Ib
10
IS
The infrared spectrum of this material contained no diazo or N-H stretch, while mass spectral evidence indicated a molecular weight of 275, which is 16 mass units less than the starting material, @-ketoester 8c. The lH NMR also indicated the absence of an N-H and contained one vinylic hydrogen coupled (J= 1.9 Hz) to a two-proton absorbance at 3.16 ppm. These data are consistent with pyrrolidine 10 (Scheme 111), whose structure was further supported by fully proton decoupled 13C NMR and 13C NMR using a distortionless enhancement by polarization transfer (DEPT) pulse sequence to allow complete assignment of carbon resonances.20 The structure was unambiguously established by hydrogenolysis of the benzyl carbamate to give methyl 2-pyrrolidinylidene acetate, which was spectrally identical (except for the ester resonances) with the analogous ethyl ester prepared via a different route.21 With the structure of 10 established, the remaining question was the route by which it was formed. Formally, 10 arises by condensation of the carbamate with the ketone of the @-ketoester followed by elimination of water. To test whether we were observing simply a base-catalyzed reaction, @-ketoester 8c was treated with triethylamine but no reaction occurred. Similarly, when 8c was treated with triethylamine and p-carboxybenzenesulfonamide,the other component of the reaction mixture, we recovered only starting material. Extended reaction time did not change the product ratio, indicating that 10 does not come from further reaction of 9c. These limited data suggest that the 10 was formed from a diazo intermediate. The proposed mechanism for diazo transfer is shown in Scheme I11 (8c 11 12 9c). The path to 10 must branch at intermediate 11, since proton transfer to give 12 would effectively protect the carbonyl from nucleophilic attack. Two possible routes from 11 to 10 are shown in Scheme 111. A seemingly minor change in conditions allowed formation of the desired diazo compound 9c in good yield. By adding the triethylamine all in one portion, instead of dropwise, 9c can be reproducibly isolated in 81390% yield. Even under our best conditions, 10 is still formed in small amounts (5-10%). We have seen no previous mention of this type of reaction and have not observed it with any of the other substrates. Dissolution of a-diazo @-ketoester 9a in benzene fol) ~ immelowed by addition of 0.6 mol % of R ~ , ( O A Cand diate immersion of the reaction vessel into a preheated oil
- - -
(20) Doddrell, D. M.; Pegg, D. T.; Bendall, M. R. J. Mugn. Reson. 1982,48,323. The DEPT pulse sequence we used inverted the CHp and
left the CHe and CH3e upright. Quaternary carbons are not seen with this technique. (21) (a) Pinnick, H. W.; Chang, Y.-H. J.Org. Chem. 1978,43,4662. (b) Luly, J. R.; Rapoport, H. J. Am. Chem. SOC. 1983, 105, 2869.
6 7
CeH5CHS CHzClz ClCHpCH2Cl
THF
OC
mol %
80 80 20
5 1.5 1.5 1.5 1.5 1.5 1.5
111
20 83 66
21 10
