Synthesis of ~~-2-(2,,1~,6-Cycloheptatrien-l-yl)glycine STI:PHENHAR.ESSI.IX~ AR'D
G C N T H E R SCHCTZE
Research Laboratories, Parke, Davis and Co., Ann Arbor, Michigan 48106 Receizjed September 11 1968
We report herein the synthesis of the title compound 4 which can be considered to be a nonbenzenoid isomer
of the biologically important amino acid &phenylalanine. The preparative route is b a ~ e d on ~ . ~the condensation of tropylium tetraflu~roborate~with dimethyl formamidomalonate .5
4
Experimental Section Melting points are uncorrected. Optical rotations were measured in water with a Perkin-Elmer photoelectric polarimeter a t 25". Dimethyl a-Formamido-2,4,6-cycloheptatriene-l-malonate (1). -A solution of Na (2.3 g) in 60 ml of EtOH was added dropwise and with st,irring to a finely powdered mixture of dimethyl formamidomalonate5 (17.5 g, 0.1 mole) and tropylium tet.raf l ~ o r o b o r a t e(17.8 ~ g, 0.1 mole). H2O (150 ml) was added, the solution was extracted (CH2Cls) and the extracts were dried and evaporated t o a pale yellow oil (20.5 g). A portion (14 g) was dissolved in boiling HL;the solution was filtered through charcoal and allowed to cool giving 12.7 g of the crystalline product, mp 107-108". Anal. (C13HlaNO;) C, H, N. ~ ~ - N - F o r m y l - 22,4,6-cycloheptatrien-l-yl)glycine -( (2).-A solution of 1 (2.63 g, 0.01 mole) in 60 ml of MeOH containing 8 g of NaOH was alloxed to stir overnight at room temperature. After 20 min a precipitate was formed. The heterogeneous solution was evaporated to dryness at low temperature, the residue was dissolved (HzO), and the p H was adjusted to 5-5.3 by the addition of Uowex-50 ( H + ) . Filtration and concentration of the filtrate afforded the crystalline product; yield 0&0.7 g. Hecrystallization was effected by dissolving in AIeOH-H& arid removing most of the lIeOII under reduced preswre; mp 183", [ a ]0' ~ (c 2.18, AIeOH). (CI~H~~PYIO~) C, 13, N. Dimethyl a-acetamido-2,4,6-cycIoheptatriene-l-malonate(3) was prepared essentially as described for 1, biit using dimethyl acetamidomalonate.5 The produat crystallized upon adding H,O and it was recrystallized from MeOH ti, give pure material ( 5 4 5j, mp 16t5-1670. Anal. IC14Hj;NOa) C, H, K. ~~-2-(2,4,6-Cycloheptatrien-l-yl)glycine (4).-To a suirpension of 2 ( 3 g) in 40 ml of 3 -YHCI were added 25 ml of D31F and 10 ml of XIeOH with brief heating. The resiiltiiig sulrition was then treated dropwise with 1 ml of concentrated I1C1 and stiri,ed a t room temperature overnight. Solvelit was removed by addition of n-BuOH and evaporation at ca. 60" to give a dark crysta!line reiidne. The latter was dissolved i n the minimum volume of H2O and added t o a column ( 2 . 5 X 30 cm) containiiig Ilowex-50 ( H + ) and the column was washed (H,Oj until the effliient was faintly acidic. Elution with 2 -Y NI-IdOH (300 ml total) afforded a pale yellow soltilion which was evaporated to dryneas leaving a crystalline cream-colored d i d . The latter was SIUS(1) T o v h o m correspondence should he addressed: Department of Chemistry, University of Montreal. Montreal, Quebec, Canada. (2) For reviews, see G. Alaier, Angew. Chem. I n t e r n . Ed. Enol., 6 , 402 (1967); 0. A. Reutov, "Fundamentals of Theoretical Organic Chemistry," T . J. Katz, Ed., Appleton-Century-Crofts, N e x York, N. P.,1967, p 445. ( 3 ) F. Korte, K.-H. Buchel, and F. F. Kiese, Ann. Chem., 664, 114 (1963). ( 4 ) H. J. Dauben, J r . , L. R. Honnen, and K. AI. Harmon, J. Org. Chem., 86, 1442 (1960). (5) H . Hellmann and F. Lingens, 2. Phgsiol. Chem., 297, 283 (1954).
pended in H20-lleOH ( l : l ) , filtered] and washed with the same mixt,ure; yield 2 g of pure product: nip 246" dec; ir (KBr), 1590, 1525 (zwitterion), 2600, 2100 cm-l (acid dimer); hmax256 mfi (H20-MeOH). Anal. ( C ~ H I I N O C, ? ) H, N. ~~-N-2-(2,4,6-Cycloheptatrien-l -yl)trifluoroacetylglycine (5).To a suspension of 4 (0.2 g) in 7 ml of HzO was added 1.2 ml of 1 S NaOH. After warming briefly the homogeneous solution was cooled to room temperature and treated with 1.5 ml of ethylthio trifluoroacetate6 with vigorous stirring. After 30 niin, the solution was evaporated, and the residue was taken up in E t 2 0 and processed to a syrup which solidified in a small volume of cold HzO. The product was filtered and washed (H20) to give 0.227 g of colorless crystals. Recrystallization was effected by dissolving in Et20,adding petroleum ether (bp 30-60"), and allowing the solution t o evaporate slowly, mp 122-124'. Anal. (CLiHioFaNOZ)C, H, 5 . Fragmentation of Dimethyl a-Acetamido-2,4,6-cycloheptatriene-1-malonate.-An amount of 3 (1 g) was suspended in 10 ml of 2 .Y HC1 and the mixture was heated under reflux for 5 hr. The homogeneous solution was evaporated t o dryness and the resulting white solid was suspended in ether and filtered; yield 0.16 g C6070), mp 230-233". This product was identical with glycine (mixture melting point and ir spectra). (6) E. E . Schallenberg and AI. Calvin, J . B m . Chem. Soc., 77, 2779 (1955).
Preparation of 3-Fluoropropane-1,2-diol from Glycidol (Hydroxymethyloxirarie)la ROBERT J. DVMVEL I Z ~ DE. Kus'b Department of Pharinaceutical Chemzstiy, School of Pharmacy, Departments of Pharmacology and Bzochentistry and the Cardzovascitlar Research Instztute of The School of Jfediczne, the Cnzverszty of California Medical Center, S a n Franczsco, Californta 941%' Received October 25, 1968
3-Fluoropropane-1,2-diolis an int'ermediate in t'he synthesis of fluorolactic acid2which is a specific inhibitor of lactate dehydrogena~e.~I n contrast, t o previous lengthy procedure^*^^^^ the present' paper describes a one-step synthesis, suit'able for large-scale preparat'ion of 3-fluoropropane-1 ,%diol. Experimental Section
2-Fluoropropane-l,2-diol.-A mixture of glycidol (100 g, 1.33 moles) and KHF2 ( 106 g, 1.35 moles) in 200 ml of D l I F was refluxed overnight. Solid K F was filtered off and the solvent was vacuum evaporated. The product (34.3 g, 0.37 mole, 27y0 yield) had bp 74-79' (4mm). Anal. ( C B H ~ F O C~, H. ) 2-Ethyl-4-fluoromethyl-Z-methyl-l,3-dioxolane.-Asample of 3-fluoropropane-1,2-diol ( 2 g) was refluxed overnight with 2biitanone (20 ml) in the presence of toluenesulfonic acid (0.05 9). ITYO was removed from the azeotrope by refluxing in a Soxhlet extractor, charged in the cup with 10 g of Linde Molecular Sieve. After removal of the unreacted solvent under vacuum, the product was obtained by distillatmion( 2 g), bp 145-150' (lit.5 146-147'). A mixture of 1,2-propanediol and 1,3-propanediol was separated into two distinct peaks at 80" on a 4 m X 3.2 mm column, packed with 12% DEGS on Chromosorb W, indicat,ing that, this column separates isomeric diols. Both 3-fluoropropane-1,2-diol and t.he ketal prepared from it gave single distinct peaks. (1) (a) Supported b y research grants from t h e Sational Institute of Child Health and Development (HD-01239), National Cancer Institute (CA079.551, Life Insurance Medical Research Fund (GB-5749), and t h e American Cancer Society (E-493). (b) Research Career Awardee of t h e U. S. Public Health Service, t o whom correspondence should be addressed. (2) L. K. Gottvald and E. Kun, J . Org. Chem., 30, 877 (1965); E. K u n and R . J. Dummel, M e t h o d s Enzymol., in press. (3) J. C . dyling and E. K u n , M o l . Pharmacol., 1, 256 (lY65). ( 4 ) N. F. Taylor and P. W. Kent, J. Chem. Sac., 2150 (1956). ( 5 ) F. L. 31. Pattison and J. J. S o r m a n , J . Am. Chem. S'oc., 79, 2311 (1957).
