4322 Inorg. Chem. 1984, 23, zyxwvu 4322-4324 Contribution from the Paul M. Gross Chemical Laboratory, Duke University, Durham, North Carolina 27706 Boron Analogues of Amino Acids. 4.’ Synthesis of Glycine and N-Methylated Glycine Ester Analogues BERNARD F. SPIELVOGEL,* FAHIM U. AHMED,+ GARY L. SILVEY, PATTY WISIAN-NEILSON, and ANDREW T. McPHAIL* Received March 29, I984 Selected representatives of a series of esters derived from boron analogues of amino acids and having the general formulation amine.BHzCOOR (amine zyxwvutsrq = (CH3)3N, (CH3)zNH, CH3NHz, NH,; R = CH,, CHzCH3, CHzCH2CI) were prepared in good to excellent yields by condensing the corresponding acids and alcohols with dicyclohexylcarbodiimide (DCC) at room temperature in CHzCl2. (CH3)zNH-BH2COOCH, and H3N.BHzCOOCH3 were prepared in 67% and 49% yields, respectively, by amine-exchange reactions of (CH3),N-BHZCOOCH3 with (CH3)zNH and NH,. (CH,),N.BH,COOSi(CH,), was obtained by reacting (CH,),N.BH,COOLi and (CH,),SiCI. Introduction Isoelectronic and isosteric boron analogues of the amino acids glycine and betaine (H3N.BH2COOHZ and (CH3),N. BH2COOH,, respectively) and t ~ e i r derivatives and precursors have been shown to possess interesting biological activities, in particular, significant antitumor, antiarthritic, and hypo- lipidemic activities in rodentsM For example, (CH3),N.B- H2COOH afforded 82% inhibition of tumor growth in the Ehrlich Ascites screen4 and lowered serum cholesterol levels by 49% at low dosages.6 An ester, trimethylamine-carbeth- oxyborane, (CH3),N.BH2COOC2HS (l), produced 74% in- hibition of the induced arthritic states and lowered serum cholesterol levels6 by 36% in animal model studies. In view of their potential biological activities, we have therefore pre- pared selected representative members of a series of alkyl esters having the general formulation aminpBH2COOR (amine = CH2CH2Cl, Si(CH3),) for structure-activity relationship studies. These compounds may also prove to be useful in boron neutron capture therapy for the treatment of cancer.’ Results and Discussion Trimethylamine-carbethoxyborane, (CH3),N-BH2COO- C2H5 (l), was prepared as described previously5by refluxing a solution of (CH,),N.BH2CN8 in CH2C12 with 2 equiv of (C2H5)30BF49 under dry N2 for 24 h. The resulting N- (CH3)SN, (CH3)2NH, CH,NH2, NH3; R = CH,, CH2CH3, H+ (CH3) ~N-BH~CENC~HS’B F4- (CH3)3N*BH2COOC2Hs 1 ethylnitrilium salt (not isolated) was alcoholized at reflux temperature for 48 h with 95% ethanol and concentrated HCl. After neutralization, workup resulted in a yellow liquid, which was either crystallized or sublimed to give a 34% yield of the ethyl ester. This ester (1) was also made by an alternative method in 45% yield by dehydrating a solution of (CH,),- N.BH2COOH3 and absolute ethanol with dicyclohexyl- carbodiimide (DCC) at room temperature for 6 days. The relatively high volatility and solubility in water of this sweet-smelling ester probably contributed to its low yield by either of these procedures. Trimethylamine-carbomethoxyborane, (CH3),N.BH2C0- OCH, (2), was prepared in 82% yield by condensing (C- H,),N.BH,COOH and CH,OH with DCC at room temper- ature for 1 week; extension of the reaction period to 2 weeks ‘Present address: Research and Development Division, Colgate-Palmolive Co., 909 River Road, Piscataway, N J 08854. led to an increase in the yield of 2 to 98%. DCC (CH,),N*BH,COOH + CH30H Dimethylamine-carbomethoxyborane, (CH3),NH.BH2CO- OCH, (3), was prepared in 67% yield by an amine-exchange reaction of (CH3),N.BH2COOCH3 (2) with an %fold excess (CH3)3N.BH2COOCH3 + (CH3)ZNH ---* 2 (CH,),NH*BH2COOCH, + (CH3)3N 3 (by weight) of (CH3)2NH in a glass pressure reaction vessel for 2 weeks at room temperature. Ca. 8% unreacted 2 in the product mixture was readily removed by washing with H 2 0 and vacuum pumping. The ester linkages in the starting material and product were not cleaved by the excess amine. The amine-exchange process is the preferred route as the alternative preparation of 3 by condensation of (CH3),NH- BH2COOH and CH,OH with DCC at room temperature for 4 days gave only a very low yield (8%). Methylamine-carbomethoxyborane, CH3NH2.BH2COOC- H3 (4), was prepared in 21% yield of condensing CH,NH2- BH2COOH and CH30H with DCC at room temperature for 6 days. DCC CH,NH,.BH,COOH + CH3OH - 4 CH,NHZ*BH,COOCH3 + DCU Trimethylamine-(carbo-2-chloroethoxy)borane, (CH,),- N.BH2COOCH2CH2C1 zyxw (5), was prepared in 61% yield in a manner similar to the preparation of 4 by condensing (C- H3),N.BH2COOH and HOCH2CHzClwith DCC at room temperature for 1 week. DCC (CH3)3N*BH,COOH + HOCH2CH2Cl- (CH3)3N*BH2COOCH2CH2Cl + DCU 5 (1) Part 3: Spielvogel, B. F.; Ahmed, F. U.; Morse, K. W.; McPhail, A. T. Inorg. Chem. 1984, 23, 1776. (2) Spielvogel, B. F.; Das, M. K.; McPhail, A. T.; Onan, K. D.; Hall, I. H. zy J. Am. Chem. SOC. 1980, 102, 6343. (3) Spielvogel, B. F.; Wojnowich, L.; Das, M. K.; McPhail, A. T.; Hargrave, K. D. J. Am. Chem. SOC. 1976, 98, 5702. (4) Hall, I. H.; Starnes, C. 0.; Spielvogel, B. F.; Wisian-Neilson, P.; Das, M. K.; Wojnowich, L. J. Pharm. Sci. 1979, 68, 685. (5) Hall, I. H.; Starnes, C. 0.; McPhail, A. T.;Wisian-Eilson, P.; Das, M. K.; Harchelroad, F., Jr.; Spielvogel, B. F. J. Pharm. Sci. 1980, 69, 1025. (6) Hall, I. H.; Das, M. K.; Harchelroad, F., Jr.; Wisian-Neilson, P.; McPhail, A. T.; Spielvogel, B. F. J. Pharm. Sci. 1981, 70, 339. (7) Spielvogel, B. F. “Boron Chemistry 4”; Parry, R. W., Kodama, G., Eds.; Pergamon Press: New York, 1980; pp 119-129. (8) Wisian-Neilson, P.; Das, M. K.; Spielvogel, B. F. Inorg. Chem. 1978, 17, 2327. (9) Meerwein, H. Org. Synfh. 1966, 46, 113 0020-1669/84/ 1323-4322$01 zyxwvuts SO/O 0 1984 American Chemical Society