Synthesis of (5R)-4-Methyl-5-phenyl-1,3,4-oxadiazinan-2-one and Some N-Acyl Derivatives from (R)-Phenylglycine

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1 C R R C R =, R = a: R =, R = b: CDI TF 78 PAPER Synthesis of (R)--Methyl--phenyl-,,-oxadiazinan--one and Some -Acyl Derivatives from (R)-enylglycine Synthesis Alessandro of,,-xadiazinan--ones Rodrigues,* a Paulo Roberto livato,* a Roberto Rittner b a Conformational Analysis and Electronic Interactions Laboratory, Instituto de Química, Universidade de São Paulo, C.P. 077, São Paulo, SP 0-970, Brazil Fax +()879; alessand@iq.usp.br; prolivat@iq.usp.br b ysical rganic Chemistry Laboratory, Chemistry Institute, State University of Campinas, C.P., Campinas, SP 08-97, Brazil Received 0 March 00; revised May 00 Abstract: (R)--Methyl--phenyl-,,-oxadiazinan--one was synthesized from (R)-phenylglycine in five steps and in % overall yield. In addition, a convenient and practical method for -acylation of,,-oxadiazinan--one directly with acids in the presence of DCC and catalytic quantities of DMAP is described. The acylated products were obtained in excellent yields. Key words: (R)-phenylglycine,,,-oxadiazinan--ones, heterocycles, acylation, carboxylic acids In 98, Trepanier and co-workers reported the first synthesis of the,,,-tetrahydro--,,-oxadiazin-- ones as candidates for central nervous system stimulant activity. The synthesis of substituted,,-oxadiazinan-- ones has attracted attention because of their promising general application as chiral auxiliaries in asymmetric aldol addition reactions. eterocycles (Figure ) were synthesized by itchcock and co-workers from (R,S)-ephedrine and (S,S)- pseudoephedrine, which have limited utility in creating diverse,,-oxadiazinan--ones, because the -position is substituted with a methyl group and both the C- and C- substituents are fixed (methyl and phenyl groups, respectively). chiral starting materials. Therefore, we present in this paper the synthesis of the heterocycle (Scheme ) and a simple method to prepare the -acylated-,,-oxadiazinan--ones (Scheme ). The synthesis of heterocycle was readily performed in five steps from (R)-phenylglycine () on a multigram scale without chromatographic purification in % overall yield. The starting point was the synthesis of -formyl-(r)-phenylglycine (), which was obtained in quantitative yield by the treatment of (R)-phenylglycine () with formic acid and acetic anhydride (Scheme ). C a /Cl TF C C 7 C, Ac C ab /I TF LiAl TF Scheme C Figure,,-xadiazinan--ones ( and ) We have developed another,,-oxadiazinan--one framework the (R)--methyl--phenyl-,,-oxadiazinan--one () starting from (R)-phenylglycine (), which can be replaced by other amino acids; these are excellent templates for the creation of new,,-oxadiazinan--ones due to the wide range and diversity of these SYTESIS 00, o., pp 78 8xx.xx.00 Advanced online publication: DI: 0.0/s ; Art ID: M00SS Georg Thieme Verlag Stuttgart ew York Compound was cleanly reduced to -methyl-(r)-phenylglycinol () with ab /I in TF in 9% yield. Compound was treated with a in the presence of aqueous Cl and TF to conveniently give the desired - methyl--nitrosamine () in 9% yield. -itrosamine was reduced 7 with LiAl in TF leading to hydrazine 7. 8 Subsequent treatment 9 with carbonyldiimidazole (CDI) furnished the cyclic diazacarbamate in 7% yield. DCC and DMAP are known as synthetically useful and mild reagents for the preparation of esters and amides. 0, This chemistry was used to prepare (in one step) the - acylated,,-oxadiazinan--ones 8a j using carboxylic acids, DCC, and DMAP (cat., mol%) in C Cl, at room temperature (Scheme ). The -acylated products 8a j were obtained in excellent yields (Table ).

2 PAPER Synthesis of,,-xadiazinan--ones 79 C 8a j Scheme Table Synthesis of -Acyl-(R)--methyl--phenyl-,,-oxadiazinan--ones 8a j from Carboxylic Acids and,,-xadiazinan- -one Using DCC and DMAP Entry Product RC Time (h) Yield (%) a 8a. 90 8b 9 8c 90 8d 87 8e 8 8f 8 7 8g h 8 S Et 9 8i j 8 80 a Isolated yields after chromatography. R DCC, DMAP (cat.) C Cl The reaction does not require rigorously dried solvents or reagents, and eliminates the need for strong bases, such as BuLi or Li. In addition, arylacetic acids and conjugated enoic acids can be employed to provide the desired - acyl-oxadiazinan--ones free of by-products. In conclusion, we have prepared (R)--methyl--phenyl-,,-oxadiazinan--one in a five-step reaction and % overall yield. In addition, the method described provides a mild and efficient process for -acylation mediated by DCC/DMAP, resulting in a large variety of -acylatedoxadiazinan--ones and this method should be easily extend to acylations with more complex substrates. The initial reaction can also be extended to other amino acids besides (R)-phenylglycine described in this paper. R C MR spectra were recorded on a Varian Unity Inova and on a Bruker DRX 00 spectrometer operating at Mz or 00. Mz ( MR), and 7.9 Mz or.77 Mz ( C MR). and C chemical shifts (d) are reported in ppm relative to TMS as internal standard. Coupling constants (J) are given in z. IR spectra were measured on a MB-00 Michelson-Bomem FTIR instrument. Elemental analyses were carried out on a Perkin Elmer 00 C-standard analyzer. Low resolution mass spectra were recorded on a SIMADZU QP00A GC-MS spectrometer (DB column, EI). Mps were measured on a Büchi melting point apparatus. ptical rotations were determined at C with a JASC DIP- 70 polarimeter ( dm cell). Column chromatography was performed on Merck silica gel 0 (0 00 mesh). All reactions were conducted with magnetic stirring in oven-dried glassware under anhyd. Solvents were purified and dried according to standard procedures. ther reagents were commercially available. (R)--(-Formyl)amino--phenylacetic Acid () Ac (8 ml) was added dropwise to a mixture of (R)-phenylglycine (; 0.00 g, mmol) in formic acid (0 ml, 99%) at such a rate that the temperature of the reaction mixture was maintained between C. After the addition was complete the mixture was stirred at r.t. for h; iced-water (00 ml) was introduced and the mixture was concentrated at reduced pressure to give as white crystals in 00% yield (7. g); mp C (dec.) (Lit. 78 C); [a] D 7.0 (c.00, Me); {Lit. [a] D 0.0 (c.00, Me)}. MR (00 Mz, DMS-d ): d = 8.9 (d,, J = 7.7 z), 8.08 (s, ), (m, ),.9 (d,, J = 7.7 z). (R)--(-Methyl)amino--phenylethanol () To a stirred solution of amino acid (8.00 g, 80 mmol), ab (9.8 g, 0 mmol), and anhyd TF (00 ml) cooled to 0 C in an ice bath, was slowly added dropwise a solution of I (.8 g, mmol) in TF (00 ml). Upon addition of I gas evolution occurred, once this had ceased the flask was heated at reflux for 8 h and then cooled to r.t.; Me was added cautiously until the mixture became clear. After stirring for 0 min, the solvent was removed by rotary evaporator leaving a white paste, which was dissolved by the addition of K (0% aq, 00 ml). The resulting solution was stirred for h and extracted with C Cl ( 0 ml). The organic extracts were dried over a S and concentrated under vacuum, affording as a colorless liquid in 9% yield (0. g, 00 mmol); [a] D 8. (c.08, CCl ). IR (film): 0, 0, 8, 798,, 00, 0, 7, 70 cm. MR (00 Mz, CDCl ): d = (m, ),.7. (m, ),.07 (br s, ),.9 (s, ). C MR (7 Mz, CDCl ): d = 0., 8.7, 7., 7.9,.8,.,.. (R)--(-Methylnitroso)amino--phenylethanol () To a solution of (.0 g, 7 mmol) in TF (7 ml) was added an aq solution of Cl ( M, 7 ml, mmol) followed by the addition of a (.9 g, 0 mmol); the resulting mixture was stirred for h. The mixture was then diluted with a sat. aq solution of ac until its p was >7. The reaction mixture was extracted with EtAc ( 00 ml), washed with a sat. solution of brine (80 ml), dried (a S ), and the solvent was removed by rotary evaporation to give as an orange oil (0.0 g, 9%); [a] D.0 (c.7, CCl ) IR (film): 90, 0, 0, 9, 88, 9,, 9, 09, 0, 70 cm. MR (00 Mz, CDCl ): d = (m, ),. (dd, J = 9.0 z, J =. z, ),. (dd, J =. z, J = 9.0 z, Synthesis 00, o., 78 8 Thieme Stuttgart ew York

3 80 A. Rodrigues et al. PAPER ),.7 (dd, J =. z, J =. z, ),.8 (s, ),.9 (s, ). C MR (7 Mz, CDCl ): d =.7, 9.0, 8.78, 7.8, 9.87,.9,.7. (R)--Methyl--phenyl-,,-oxadiazinan--one () To a stirred suspension of LiAl (0.0 g, 9 mmol) in TF (00 ml) was added dropwise a solution of (0.0 g, 70 mmol) in TF (0 ml) at r.t. The mixture was then heated at reflux for h. The cooled and stirred mixture was quenched with (0 ml), % aq a (0 ml), (0 ml), filtered, dried (a S ), and the solvent was removed by rotary evaporation. This process afforded 7 as a viscous yellow oil (7. g, 98%), which was >9% pure, as determined by MR spectroscopy. The hydrazine 7 was directly converted into the corresponding oxadiazinone derivative due to its facile decomposition. CDI (.0 g, mmol) was added to a solution of 7 (7. g, mmol) in TF (80 ml). The mixture was stirred for h at r.t., concentrated, dissolved in (70 ml), and extracted with C Cl ( ml). The organic extracts were washed with brine (0 ml), dried (a S ), and evaporated. This process yielded a yellow solid, which was purified by recrystallization (EtAc hexane) to give heterocycle as white crystals (.9 g, 7%); [a] D 00. (c.08, CCl ); mp 0 0 C. IR (KBr):, 08, 090, 97, 790, 7, 77,, 0,, 08, 90, 88, 79, 7, 98 cm. MR (00 Mz, CDCl ): d = 8.7 (s, ), (m, ),.. (m, ),.8 (dd, J =8. z, J =. z, ),. (s, ). C MR (7 Mz, CDCl ): d =.9,.0, 8.98, 8.7, 7.78, 8.,.70,.00. MS (EI): m/z (%) = 9 (), 8 (), 0 (8), 0 (8), 0 (9), 9 (), 78 (7), 77 (), 0 (00). Anal. Calcd for C 0 (9.): C,.9;,.9;,.7. Found: C,.;,.;,.77. -Acylation; General Procedure To a mixture of,,-oxadiazinan--one (; 00 mg,.0 mmol), DMAP ( mg, 0. mmol) and the corresponding carboxylic acid (.8 mmol) in C Cl ( ml) at 0 C, under a nitrogen atmosphere, DCC was added in one portion (90 mg,.8 mmol). The temperature of the resulting suspension was allowed to reach r.t. Stirring was continued until no starting material was left, as confirmed by TLC. The dicyclohexylurea formed was filtered and the precipitate washed with C Cl (0 ml). The filtrate was washed with a sat. aq solution of ac ( ml) and dried over a S. Filtration and evaporation yielded the crude compounds 8a j, which were purified by flash chromatography on silica gel (hexane EtAc, :). (R)--Acetyl--methyl--phenyl-,,-oxadiazinan--one (8a) Yield: 90%; white crystals; mp 0 0 C; [a] D +. (c.00, CCl ). IR (CCl ): 08, 9, 9, 770, 77,, 7,, 7, 070 cm. MR (00 Mz, CDCl ): d = (m, ),.8 (dd, J =.7 z, J =.7 z, ),. (dd, J =.7 z, J = 7.8 z, ),. (dd, J = 7.8 z, J =.7 z, ),.80 (s, ),.8 (s, ). C MR (7 Mz, CDCl ): d = 9.8, 0.7,., 9.0, 8., 7.0, 7.8,.07,.7,.80. MS (EI): m/z (%) = (), 9 (90), 8 (0), 0 (), 0 (00), 0 (), 0 (8), 9 (), 78 (), 77 (8). Anal. Calcd for C (.): C,.;,.0;,.9. Found: C,.;,.8;.. (R)--Methyl--phenyl--propionyl-,,-oxadiazinan--one (8b) Yield: 9%; white crystals; mp 0 0 C; [a] D +. (c.0, CCl ). IR (CCl ): 07, 98, 9, 80, 79, 70, 8, 7, 8, 89 cm. MR (00 Mz, CDCl ): d = (m, ),.8 (dd, J =. z, J =. z, ),. (dd, J =. z, J = 7.8 z, ),. (dd, J = 7.8 z, J =. z, ),.8.9 (m, ),.78 (s, ),.08 (t, J = 7. z, ). C MR (7 Mz, CDCl ): d = 7.70, 0.,.9, 8.97, 8.8, 7.0, 7.7,.98,., 9.88, 8.8. MS (EI): m/z (%) = 9 (9), 8 (), 0 (7), 0 (00), 0 (), 0 (0), 9 (), 78 (), 77 (). Anal. Calcd for C (8.8): C,.89;,.0;,.8. Found: C,.7;,.;.. (R)--(Cyclopropylcarbonyl)--methyl--phenyl-,,-oxadiazinan--one (8c) Yield: 90%; white crystals; mp 89 9 C; [a] D +7. (c 0.9, CCl ). IR (CCl ): 07, 0, 9, 80, 7, 79, 7,, 89, 9, 88 cm. MR (00 Mz, CDCl ): d = (m, ),.77 (dd, J =. z, J =.8 z, ),.7 (dd, J =. z, J = 8. z, ),. (dd, J =8. z, J =.8 z, ),.8 (s, ),.9. (m, ),.0.07 (m, ), (m, ). C MR (7 Mz, CDCl ): d = 7.0, 0.8,.79, 8.98, 8., 7.07, 8.7,.07,.,., 0. ( C). MS (EI): m/z (%) = 9 (9), 8 (), 0 (9), 0 (7), 78 (8), 77 (8), 9 (8), (), (00), 9 (7). Anal. Calcd for C (0.9): C,.0;,.0;, 0.7. Found: C,.0;,.;, 0.9. (R)--Benzoyl--methyl--phenyl-,,-oxadiazinan--one (8d) Yield: 87%; white crystals; mp 9 9 C; [a] D +0.0 (c.0, CCl ). IR (CCl ): 07, 0, 00, 800, 777, 7, 709, 0,, 78, cm. MR (00 Mz, CDCl ): d = (m, 0 ),.9 (dd, J =.7 z, J =.7 z, ),.7 (dd, J =.7 z, J = 7.0 z, ),. (m, ),.00 (s, ). C MR (7 Mz, CDCl ): d = 9.9,.08,.98,.,.97, 9., 8., 8., 7.9,.89, 7.7,.,.9. MS (EI): m/z (%) = 9 (), (), 0 (00), 77 (8), (7). Anal. Calcd for C 7 (9.): C, 8.9;,.;, 9.. Found: C, 8.;,.9;, 9.. (R)--Methyl--phenyl--(phenylacetyl)-,,-oxadiazinan-- one (8e) Yield: 8%; colorless viscous oil; [a] D +88. (c.09, CCl ). IR (CCl ): 0, 0, 00, 80, 770, 7, 0, 97,, cm. MR (00 Mz, CDCl ): d = (m, 0 ),.70 (dd, J =. z, J =. z, ),. (m, ),. (dd, J =8.0 z, Synthesis 00, o., 78 8 Thieme Stuttgart ew York

4 PAPER Synthesis of,,-xadiazinan--ones 8 J =. z, ),.0 (AB system, Dn =. z, J =. z, ),.7 (s, ). C MR (7 Mz, CDCl ): d = 70.8, 0.,.,.9, 9.8, 9.0, 8., 8., 7.09, 7.0, 7.98,.8,.,.9. MS (EI): m/z (%) = (), 9 (), 9 (00), 0 (), 9 (), (7), (). Anal. Calcd for C 8 8 (0.): C, 9.;,.8;, 9.0. Found: C, 9.98;,.9;, 8.9. (R)--(Methoxyacetyl)--methyl--phenyl-,,-oxadiazinan- -one (8f) Yield: 8%; white crystals; mp 7 C; [a] D +.9 (c.00, CCl ). IR (CCl ): 08, 0, 9, 8, 77, 70,, 7,, 90 cm. MR (00 Mz, CDCl ): d = (m, ),.90 (dd, J =. z, J =. z, ),.78 (dd, J =. z, J =. z, ),. (AB system, Dn = 0. z, J = 7. z, ),. (dd, J =. z, J =. z, ),. (s, ),.8 (s, ). C MR ( Mz, CDCl ): d = 9.7, 9.9,.99, 9.0, 8.7, 7.0, 7.09, 7., 0.9, 9.,.. MS (EI): m/z (%) = 77 (), 8 (), 0 (), 0 (9), 9 (), 89 (), 78 (), 77 (), (8), (), (), (0), (7), 0 (), (00), (8), (0), 9 (9). Anal. Calcd for C (.8): C, 9.08;,.0;, 0.0. Found: C, 8.7;,.90;, 0.. (R)--Methyl--(phenoxyacetyl)--phenyl-,,-oxadiazinan- -one (8g) Yield: 90%; white crystals; mp C; [a] D +7.7 (c.00, CCl ). IR (CCl ): 08, 0, 9, 799, 777, 7, 00, 9, 7, 9 cm. MR (00 Mz, CDCl ): d = (m, ), (m, ),.97.9 (m, ),.7. (m, ),.9 (AB system, Dn =.0 z, J = 7. z, ),.9 (dd, J =.7 z, J =. z, ),.7 (dd, J =.7 z, J =.7 z, ),. (dd, J =.7 z, J =. z, ),.8 (s, ). C MR (7 Mz, CDCl ): d = 8.0, 7.79, 9.8,.0, 9.7, 9.0, 8.7, 7.,.,.7, 8., 7.09, 0.8,.8. MS (EI): m/z (%) = (7), 0 (), 9 (), (0), (7), 8 (0), 7 (), 07 (), 0 (), 0 (), 9 (), 79 (), 78 (), 77 (00), (9), (), (8), (), 9 (). Anal. Calcd for C 8 8 (.): C,.;,.;, 8.8. Found: C,.9;,.;, 9.0. (R)--[(Ethylthio)acetyl]--methyl--phenyl-,,-oxadiazinan--one (8h) Yield: 8%; light-yellow oil; [a] D +.0 (c.09, CCl ). IR (CCl ): 08, 00, 99, 80, 770, 7,, 7, 7, cm. MR (00 Mz, CDCl ): d = (m, ),.79 (dd, J =. z, J =. z, ),. (m, ),. (dd, J =8. z, J =. z, ),.9 (AB system, Dn = 78.9 z, J =. z, ),.80 (s, ),.8.7 (m, ),. (t, J = 7. z, ). C MR (7 Mz, CDCl ): d = ,., 9., 8.9, 7., 8.0,.79,.0,.77,.7,.. MS (EI): m/z (%) = 9 (), (), 8 (7), 0 (00), 0 (), 9 (), 89 (), 78 (7), 77 (8), (7), (), (), (), (9), 0 (0), (), (9), 9 (). Anal. Calcd for C 8 S (9.7): C, 7.;,.;, 9.. Found: C,.70;,.0;, 9.9. (R)--(-Furoyl)--methyl--phenyl-,,-oxadiazinan--one (8i) Yield: 90%; colorless viscous oil; [a] D +. (c.00, CCl ). IR (CCl ): 07, 0, 00, 80, 778, 700, 7, 7, 9, 8 cm. MR (00 Mz, CDCl ): d =7. (dd, J =.7 z, J =0.8 z, ), (m, ), 7.0 (dd, J =. z, J = 0.8 z, ),.0 (dd, J =. z, J =.7 z, ),.7 (dd, J =. z, J =.0 z, ),. (dd, J =. z, J = 9.7 z, ),.7 (dd, J = 9.7 z, J =.0 z, ),.9 (s, ). C MR (7 Mz, CDCl ): d = 8.,.,.8,.9,.9, 9.0, 8.,., 9.9,., 8.9,.80,.9. MS (EI): m/z (%) = 8 (), 9 (9), 7 (9), (), 8 (0), 0 (), 9 (00), 77 (0), (0), 9 (). Anal. Calcd for C (8.8): C,.9;,.9;, Found: C,.9;,.80;, 0.0. (R)--[(E)-Cinnamoyl]--methyl--phenyl-,,-oxadiazinan--one (8j) Yield: 80%; colorless viscous oil; [a] D +.0 (c.0, CCl ). IR (CCl ): 087, 0, 0, 80, 7, 77, 700,, 9,,, 88 cm. MR (00 Mz, CDCl ): d = 7.8 (d, J =. z, ), (m, 0 ), 7.0 (d, J =. z, ),.8 (dd, J =. z, J =.7 z, ),. (dd, J =. z, J = 8. z, ),.8 (dd, J = 8. z, J =.7 z, ),.87 (s, ). C MR ( Mz, CDCl ): d =., 0.,.7,.,., 0., 9.0, 8.8, 8., 8.7, 7.0, 7.98, 8.,.8,.. MS (EI): m/z (%) = (), (0), (00), 0 (0), 0 (0), 7 (), (). Anal. Calcd for C 9 8 (.): C, 70.79;,.. Found: C, 70.9;,.70;, 8.. Acknowledgment We thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for financial support of this research and a fellowship to A.R. We thank the Conselho acional de Desenvolvimento Científico e Tecnológico (CPq) for fellowships to. P.R.. and R.R. References () (a) Trepanier, D. L.; Elbe, J..; arris, G.. J. Med. Chem. 98,, 7. (b) Trepanier, D. L.; arris, G.. US Patent,77,, 98; Chem. Abstr. 99, 70, 780c. () (a) Casper, D. M.; Burgeson, J. R.; Esken, J. M.; Ferrence, G. M.; itchcock, S. R. rg. Lett. 00,, 79. (b) Casper, D. M.; itchcock, S. R. Tetrahedron: Asymmetry 00,, 7. (c) oover, T. R.; itchcock, S. R. Tetrahedron: Asymmetry 00,,. (d) Burgeson, J. R.; Renner, M. K.; aradt, I.; Ferrence, G. M.; Standard, J. M.; itchcock, S. R. J. rg. Chem. 00, 9, 77. Synthesis 00, o., 78 8 Thieme Stuttgart ew York

5 8 A. Rodrigues et al. PAPER () itchcock, S. R.; ora, G. P.; Casper, D. M.; Squire, M. D.; Maroules, C. D.; Ferrence, G. M.; Szczepura, L. F.; Standard, J. M. Tetrahedron 00, 7, () Sheehan, J. C.; Yang Ding-Djong,. J. Am. Chem. Soc. 98, 80,. () (a) Brown,. C.; Subba Rao, B. C. J. Am. Chem. Soc. 90, 8, 8. (b) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. rg. Chem. 99, 8, 8. () Corey, E. J.; McCaully, R. J.; Sachdev,. S. J. Am. Chem. Soc. 970, 9, 7. (7) Takahashi,.; Suzuki, Y. Chem. arm. Bull. 98,, 9. (8) This product was used without further purification, is quite sensitive, and had to be stored at 0 C to avoid decomposition. (9) achman, R. J. J. eterocycl. Chem. 98, 9,. (0) assner, A.; Alexanian, V. Tetrahedron Lett. 978, 7. () öfle, G.; Steglich, W.; Vorbrüggen,. Angew. Chem., Int. Ed. Engl. 978, 7, 9. () Shiraiwa, T.; Miyazaki,.; Imal, T.; Sunami, M.; Kurokawa,. Bull. Chem. Soc. Jpn. 987, 0,. Synthesis 00, o., 78 8 Thieme Stuttgart ew York