J. Org. Chem. 1990,55,5894-5900
5894
synthetic route for triazole preparation.
Experimental Section Melting points were determined on a Thomas-Hoover capillary melting point apparatus and were not corrected. NMR spectra were run on a Varian XL-300 300 MHz spectrometer in CDC13 solutions with TMS as internal standard. C, H, and N elemental analyses were performed by Galbraith Laboratories, Knoxville, TN. Nickel Peroxide (NiO,) Oxidation of 1,2,3-Triazolines: Synthesis of lH-1,2,3-Triazoles. To a solution of the 1,2,3triazolineHag*m (0.005 mol) in reagent-grade benzene (100 mL) was added dried, finely powdered NiOzl" (0.060 mol), and the mixtire was refluxed with vigorous magnetic stirring for 3-4 h. The reaction mixture was then allowed to cool to room temperature and filtered under gravity to remove the spent NiOz. The residual NiO, was washed with hot CHCI,, and the combined filtrates were subjected to rotary evaporation. The resulting oily residue was cooled and triturated with petroleum ether or an ether-petroleum ether mixture, when it solidified to a clean crystalline mass, and the colored impurities remained in solution. Many of the triazoles a t this point were quite pure, giving reasonably sharp melting points and little, if any, N, gas evolution, which is indicative of the presence of appreciable amounts of unreacted triazoline.28 Recrystallization from acetone-petroleum ether gave analytically pure samples, with only slight changes in the previously determined melting points. Triazoles 1, 2, and 26, however, showed wide melting point ranges with significant gas evolution; N M R analysis indicated 28% unreacted triazoline 26 and 12-13% 1 and 2. Two crystallizations from acetone-petroleum ether mixture were required before the characteristic ABC multiplet of the 4CH2-5CHtriazoline protonsa in the 6 4-6 region disappeared from the NMR spectrum. Triazole 26, prepared by permanganate oxidation, resulted in 34% yield, of which almost 30% was unchanged triazoline, as revealed by NMR. Synthesis of 1,2,3-Triazolines. The 1,2,3-triazolines were synthesized according to the Kadaba procedure by the cycloaddition of diazomethane to Schiff bases in a dioxane-water mixture, utilizing the catalytic effect of water on the addition (eq 1).3~4-23*2*30 Triazolines 4, 14, 20, 22, 25, 28, 29, 31, and 33 were newly synthesized and gave satisfactory elemental analysis for C, H and N; compound numbers, melting points, and percent yields of pure compounds were as follows: 4, 151-152 dec, 69; 14,13!3-140 dec, 78; 20,127-128 dec, 65; 22,67-70,45; 25,150-153 dec, 83; 28 133-136 dec, 48; 29, 130-132 dec, 80; 31,146-148 dec, 70; 33, 84-88, 73.
Acknowledgment. This work was supported in part by research grants NS-16843 and NS24750 from the National Institute of Neurological and Communicative Dis-
orders and Stroke (NINCDS) of the National Institutes of Health and a pilot grant from the University of Kentucky Medical Center Research Fund. The technical assistance of undergraduate laboratory assistants Bruce Polly, Linda McGlone, and David Wright from the College of Pharmacy is also acknowledged. Registry No. 1, 68090-19-7; 2, 68090-21-1; 3, 68090-20-0; 4, 129239-50-5; 5, 68090-18-6; 6, 129239-51-6; 7, 110684-22-5; 8, 129239-52-7; 9,31802-50-3; io, 18250-08-3; 11,110684-40-7; 12, 110684-41-8; 13,110684-21-4; i4,i29239-53-a; 15,12a229-10-7; 16,84817-40-3; 17,128229-11-8; 18, i2a229-12-9; 19,128229-13-0; 20,128252-72-2;21,129239-54-9; 22, 128229-14-1; 23,128229-15-2; 24,128229-16-3; 25,128229-17-4; 26, 128229-18-5; 27,84817-41-4; 28,129239-55-0; 29,129239-56-1; 30, i29239-57-2;31, 129239-58-3; 32, 129239-59-4; 33, 129239-60-7; NiO,, 12035-36-8; 1-(4methylphenyl)-5-(4-pyridyl)-l,2,3-triazoline, 55643-89-5; 1-(4methoxyphenyl)-5-(4-pyridyl)-1,2,3-triazoline, 55643-90-8; 1-(4chlorophenyl)-5-(4-pyridyl)-l,2,3-triazoline,55643-87-3; 144nitrophenyl)-5-(4-pyridyl)-1,2,3-triazoline, 129239-61-8; 1phenyl-5-(4-pyridyl)-1,2,3-triazoline, 55643-88-4; 1-(4-fluorophenyl)-5-(4-pyridyl)-1,2,3-triazoline,97230-32-5; 1-(4-nitrophenyl)-5-(2-pyridyl)-1,2,3-triazoline, 110684-20-3; l-phenyl-5(4-nitrophenyl)-1,2,3-triazoline,10445-18-8; 1-(4-bromophenyl)-5-phenyl-1,2,3-triazoline, 10480-35-0; l-(4-bromophenyl)-5-(2-pyridyl)-1,2,3-triazoline, 17843-17-3; 1-(3,4-difluorophenyl)-5-(2-pyridyl)-1,2,3-triazoline, 110684-19-0;1-(3,4dichlorophenyl)-5-(4-pyridyl)-1,2,3-triazoline, 106878-43-7;1-(4methoxyphenyl)-5-(2-quinolyl)-1,2,3-triazoline, 129239-62-9; 1(4-methoxyphenyl)-5-(2-chlorophenyl)-1,2,3-tri~ol~e, 91283-09-9; l-(3,4-dichlorophenyl)-5-(2-chlorophenyl)-l,2,3-triazo~ine, 14717-17-0; l-phenyl-5-(2,4-dichlorophenyl)-1,2,3-triazoline, 14632-41-8;l-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-l,2,3-triazoline, 91283-12-4; 1-(3-chlorophenyl)-5-(2,4-dichlorophenyl)1,2,3-triazoline, 14632-43-0; 1-(4-fluorophenyl)-5-(2,4-dichlorophenyl)-1,2,3-triazoline, 128229-07-2; 1-(4-bromophenyl)-5-(2,4dichlorophenyl)-1,2,3-triazoline,14632-44-1; 1-(4-(trifluoromethyl)phenyl)-5-(2,4-dichlorophenyl)-l,2,3-triazo~ine, 12822908-3; l-(3-(trifluoromethyl)phenyl)-5-(2,4-dich~oropheny~)-l,2,3triazoline, 91283-11-3; l-phenyl-5-(2,6-dichlorophenyl)-1,2,3-triazoline, 91283-13-5; l-(4-chlorophenyl)-5-(2,6-dichlorophenyl)1,2,3-triazoline, 128229-09-4;l-(3-chlorophenyl)-5-(2,6-dichlorophenyl)-1,2,3-triazoline, 91283-14-6; 1-(4-bromophenyl)-5-(2,6dichlorophenyl)-1,2,3-triazoline,84817-34-5; 1-(4-(trifluoromethyl)phenyl)-5-(2,6-dichlorophenyl)-1,2,3-triazoline, 12923963-0; l-(3-(trifluoromethyl)phenyl)-5-(2,6-dichlorophenyl)-l,2,3triazoline, 129239-64-1; l-(3,4-dichloropheny1)-5-(2,4-dichlorophenyl)-1,2,3-triazoline,14632-48-5; 1-(4-~hloropheny1)-5-(2nitrophenyl)-1,2,3-triazoline,129239-65-2; l-(3,4-dichlorophenyl)-5-(2-nitrophenyl)-l,2,3-triazoline, 14717-16-9; 1-(3-(trifluoromethyl)phenyl)-5-(2-nitrophenyl)-l,2,3-triazoline, 12923966-3.
Synthesis of Spiroketals: A General Approach Michael T. Crimmins*J and Rosemary O'Mahony Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599-3290 Received March 28, 1989 (Revised Manuscript Received J u n e 6, 1990) A general procedure for the synthesis of functionalized spiroketals from lactones is described. Addition of to lactones followed by a hydration of the acetylene, hydrolysis the lithium acetylide of cis-1-methoxy-1-buten-3-yne of the enol ether and cyclization gives excellent yields of spiroketals containing a useful enone functionality.
The presence of highly substituted and functionalized spiroketals in many biologically significant natural products has stimulated a great d e d of synthetic work directed toward the synthesis of these systems.2 These include (1) Fellow of the Alfred P. Sloan Foundation, 1986-90.
0022- 3 263 /go/ 1955-5894$02.50/
o
complex molecules such as calcimycin (A-23187), okadaic acid,4 m o n e n ~ i n aplysiatoxin,6 ,~ phyllanth~cin,~ and the (2) Boivin, T. L. B. Tetrahedron 1987, 43, 3309-62. (3) Chaney, M. 0.;Demarco, P. V.; Jones, N. D.; Occolowitz, J. L. J. Am. Chem. SOC.1974, 96,1932.
Q 1990 American Chemical Society
J. Org. Chem., Vol. 55, No. 23, 1990 5895
Synthesis of Spiroketals: A General Approach milbemycins* and avermectin~.~While the majority of synthetic approaches rely heavily on acyclic stereocontrol to establish relative and absolute stereochemistry about the periphery of the spirocyclic system, some approaches have utilized the spiroketal as a template for stereochemical control.2J0 The former approach can be a very useful and successful one, but usually requires that a different basic strategy be invoked for each individual molecule. The latter approach can in principal be more general if the initial spiroketal contains a sufficient useful functionality for further elaboration of the spirocyclic template. We report here our studies directed toward the construction of spiroketal systems which contain a versatile enone functionality. If one examines many of the known spiroketal containing natural products, two features are immediately obvious. Many contain hydroxyl substituents on the carbon @ to the spiroketal center as well as a substituent on the carbon bearing the spiroketal oxygen in that same ring. A potentially useful approach to construction of these types of systems would be to utilize an a,@-unsaturatedsystem such as 1 which contains an oxygen a t a suitable position and presents the opportunity for introduction of substituents @ to that oxygen as well. Additionally, the multitude of reactions which can be carried out on a,@-unsaturated enone systems could allow the incorporation of a wide variety of substituents and functionality into these systems.
rification, a modest yield (29%) of the desired spiroketal 1.
'' 0
1
Results and Discussion The simplest approach to systems of this type might be to utilize the addition of the dianion" of formyl acetone 2 to lactones followed by acid-catalyzed cyclization to the spiroketals. Barrett has used an analogous procedure involving the dianions of P-diketones to prepare substituted systems such as 3." In an attempt to execute this plan, addition of 2 equiv of n-butyllithium to a suspension of sodioformyl acetone in tetrahydrofuran followed by addition of 6-valerolactone gave, after acidification and pu(4) Tachibana, K.; Scheur, P. J.; Tsukitani, Y.; Kikuchi, H.; Engen, D. V.; Clardy, J.; Gopichand, Y.; Schmitz, F. J. Am. Chem. SOC.1981,103, 2469. (5) Chamberlin, J. W.; Agtarap, A.; Steinrauf, L.; Pinkerton, M. J.Am. Chem. SOC.1967,89, 5737. (6)Kato, Y.; Scheuer, P. T. J. Am. Chem. SOC.1974,96,2248. Moore, R. E.; Blackman, A. J.; Chenk, C. E.; Mynderse, J. S.; Mahumoto, G. K.; Clardy, J.; Woodard, R. W.; Craig, J. C. J. Org. Chem. 1984, 49, 2484. (7) Kupchan, S. M.; LaVoie, E. J.; Branfman, A. R.; Fei, B. Y.; Bright, W. M.; Bryan, R. F. J. Am. Chem. SOC.1977, 99, 3199. Pettit, G. R.; Cragg, G. M.; Suffness, M. J. Org. Chem. 1985,50, 5060. (8) Miehima, H.; Kurabayashi, M.; Tamura, C.; Sato, S.; Kuwano, H.; Saito, A. Tetrahedron Lett. 1975 711. Mishima, H.; Junya, I.; Muramahu, S.; Ono, M. J. Antibiot. 1983, 36, 980. Ono, M.; Mishima, H.; Takiguchi, Y.; Terao, M. J. Antibiot. 1983, 36, 991.. (9) Albers-Schonberg, G.;Arison, B. H.; Chabala, J. C.;Douglas, A. W.; Eskola, P.; Fisher, M. H.; Jusi, A,; Mrozik, H.; Smith, L. J.; Tolman, R. L. J. Am. Chem. SOC.1981, 103, 4216. Springer, J. P.; Arison, J. P.; Hirschfield, J. M.; Hoogsten, K. J. Am. Chem. SOC.1981, 103, 4221. (IO)(a) DeShong, P. E.; Waltermire, R. E.; Ammon, H. L. J. Am. Chem. SOC. 1988, 110, 1901-10. (b) Deslongchamps, P.; Ruest, L.; Schwartz,D. A.; Sauve, G.Can. J.Chem. 1984,62,2929. Deslongchamps, P. Can. J. Chem. 1985, 63, 2810. 2814, 2818. (c) Ireland, R. E.; Daub, J. P. J. Org. Chem. 1983,48, 1312. (d) Barrett, A. G. M.; Carr, R. A. E. J. Org. Chem. 1986, 51, 4254. Barrett, A. G. M. J. Chem. Soc., Chem. Comm. 1981,556. (11) Harris, T. M.; Harris, C. M. Org. React. 1969, 17, 155.
H
A
2
2. then 18.5% HCI
0
1
While this procedure is very direct and works with a variety of substituted lactones (Table I), the low yields (due primarily to the difficulties encountered with the preparation, storage and metallation of sodioformylacetone) led us to search for a more suitable equivalent to formylacetone dianion. The obvious first alternative, 4-methoxy-3-buten-2-one, underwent smooth metalation but failed to react with 6-valerolactone to any appreciable extent. Another alternative was the lithium acetylide 8 of 1-methoxy-1-buten-3-ynewherein the enol ether serves as the formylacetone aldehyde and the acetylene is a latent
OLi
0
U
ONa OLi
M
0
OCH3
No Readion
carbonyl. This acetylide proved to be an extraordinary nucleophile for the addition to lactone carbonyls. Addition of 6-valerolactone to a solution of acetylide 8 in T H F at -78 "C produced the acetylenic ketone 9 in >95% yield after workup. A variety of acids and solvent systems were investigated in an attempt to effect direct hydrolysis and cyclization of the acetylenic ketone 9 to the desired spiroketal 1 (Scheme I). The best combination of acid and solvent was found to be 30% perchloric acid-dichloromethane. This biphase system gave yields of up to 5040% for spiroketals derived from simple lactones (Table 11),12 although the results were not always reproducible and the conditions failed when substitution on the lactones was increased. If the acetylenic ketone 9 was subjected to potassium carbonate in methanol, the enol ether-acetal 15 was produced in near quantitative yield. Acid hydrolysis of this acetal as before gave fairly consistent good yields of the spiroketals if the rate of stirring of the biphase system was rapid (Table 111). Insufficient mixing of the two phases results in production of significant amounts (up to 50%) of the 0-methoxy derivatives such as 16. While elimination of methanol from 16 to produce 1 could be accomplished with BF,-EhO in dichloromethane at -78 "C or with wet Amberlyst 15 in dichloromethane at 40 "C, the consistent presence of even small amounts of this contaminant was troublesome. The main problem with this procedure for the preparation of spiroketals such as 1 was again the reduced yields which resulted from the use of more highly substituted lactones. For example 5,6-dimethylvalerolactone 18 underwent smooth addition with acetylide 8 and the resultant acetylenic ketone gave a nearly quantitative yield of the acetal 19, but only trace amounts of the spiroketal4 were produced under the biphase conditions (Scheme 11). This problem was attributed to the decreased hydrophilicity of (12) Crimmins, M. T.; Bankaitis, D. M. Tetrahedron Lett.1983, 24, 5303.
5896
Crimmins and O'Mahony
J. Org. Chem., Vol. 55, No. 23, 1990
Table I. Addition of Sodiolithioformylacetone to Lactones lactone
spiroketal (yield)
Table 11. Direct Hydrolysis of Hydroxyacetylenic Ketones to Spiroketals lactone
0
acetylenic ketone (yield)
0 'OH
g (98%)
spiroketal (yield)
p
0 1 (58%)
0 O
H OH
10 (69%)
0
QT 0
f& & I
0
6
5 (
