4- Trifluoromethyl- -4,5,6,7-tetrahydro

The approach to 3-trifluoromethyl-tetrahydro-l,2,4-triazaolo-/4,3-a/-pyrazine (3-trifluoromethyl-l,2,4-triazaolo-piperazine), the heterocyclic portion of the sitagliptin molecule, requires construction of the annulated ring on 2-chloropyrazine 4 to yield the intermediate 7. The latter is selectively hydrogenated in step iv to 8, maintaining the five-membered heteroaromatic ring. 

Reduction. Quinoline may be reduced rather selectively, depending on the reaction conditions. Raney nickel at 70—100°C and 6—7 MPa (60—70 atm) results in a 70% yield of 1,2,3,4-tetrahydroquinoline (32). Temperatures of 210—270°C produce only a slightly lower yield of decahydroquinoline [2051-28-7]. Catalytic reduction with platinum oxide in strongly acidic solution at ambient temperature and moderate pressure also gives a 70% yield of 5,6,7,8-tetrahydroquinoline [10500-57-9] (33). Further reduction of this material with sodium—ethanol produces 90% of /ra/ j -decahydroquinoline [767-92-0] (34). Reductions of the quinoline heterocycHc ring accompanied by alkylation have been reported (35). Yields vary widely sodium borohydride—acetic acid gives 17% of l,2,3,4-tetrahydro-l-(trifluoromethyl)quinoline [57928-03-7] and 79% of 1,2,3,4-tetrahydro-l-isopropylquinoline [21863-25-2]. This latter compound is obtained in the presence of acetone the use of cyanoborohydride reduces the pyridine ring without alkylation. 

Coumarin, 5,6,7,8-tetrahydro-5-oxo-synthesis, 3, 790 Coumarin, 4-trifluoromethyl-synthesis, 3, 800... 

A sulfoxide was obtained by oxidation of 8-[(4-trifluoromethylmercapto-phenyl)methoxy] derivative 358 with 36% H2O2 in AcOH (98MIP7) and by oxidation of l-[2-(4-thiomorfolin-l-yl)acetyl]-7-(3-methoxyphenyl)-A-methyl-A- [3,5-bis(trifluoromethyl)phenyl]ethyl -5-oxo-1,2,3,5-tetrahydro-pyrido[l,2,3-i/ ]quinoxaline-6-carboxamide with 3-chloroperbenzoic acid (01MIP12). A 7-[(4-fluorophenylsulfonyl)methyl] derivative was obtained by oxidation of a 7-[(4-fluorophenylsulfanyl)methyl]perhydropyrido[l,2-u] prazine with 3-chloroperbenzoic acid in CHCI3 (01EUP1074257). 

Tiifluoromethyl derivatives of tetrahydrothiopyran-4-ols result from the Michael addition of hydrosulfide to a, -unsaturated trifluoromethyl ketones <96JOC1986> and tetrahydro-thiopyran-4-ones arise from the reaction of H2S with l,5-diaryl-2-chloropenta-l,4-dien-3-ones <96PS(108)93>. 

Cyclocondensation of 2-iminopiperidine and 3-aryl-2-propynylnitriles afforded 4-aryl-2-imino-6,7,8,9-tetrahydro-22/-pyrido[l,2- ]pyrimidines <20000L3389, 2002W002/00629>. The minor isomers, 2-aryl-4-imino-6,7,8,9-tetrahy-dro-4/7-pyrido[l,2- ]pyrimidines could also be isolated in 2-30% yields from the reaction mixtures <20000L3389>. When the reactions were carried out in the presence of 2 equiv of NaHMDS, the product ratio was reversed. From the reaction mixture of 2-aminopyridine and perfluoro-2-methylpent-2-ene in MeCN, a 9 1 mixture of 2,4-difluoro-2-pentafluoroethyl-3-trifluoromethyl-477- and the isomeric 2,4-difluoro-4-pentafluoroethyl-3-trifluoromethyl-277-pyr-ido[l,2- ]pyrimidine (64%), and 2-pentafluoroethyl-3-trifluoromethyl-47/-pyrido[l,2- ]-pyrimidine-4-one (20%) was isolated <2000JFC(103)105>. 

With a-trifluoromethyl oxiranes. cr-Opening oxirane ring of the 2-benzenesulfonyl-2-trifluoromethyl-oxirane 374 by nucleophilic attack with 2-aminothiazole followed by Mannich cyclocondensation of the intermediate trifluoroketone gave the 6-trifluoromethyl-imidazo[2,l-A]thiazole 375 (Equation 168) <1995JFC83>. The same transformation was conducted with 2-isopropoxy-2-trifluoromethyl-3-phenyloxirane 376 and 2-imidazolidinethione and furnished the 2,3,5,6-tetrahydro-imidazo[2,l-A]thiazole 377 in good yield (Equation 169) <1999RJ0741>. 

Methyl 5-(3-fluorophenyl)-7-methyl-l,2,3,4,5,8-hexahydropyrido[2,3-tetrahydro derivative 137 by the action of sodium nitrite in acetic acid <1994T8085>. Oxidation of 2,7-disubstituted-5-trifluoromethyl-l,2-dihydropyrido[2,3-r/]pyrimidin (3//)-ones using active Mn02 in CH2CI2 gave the corresponding pyridopyrimidin-4(3//)-ones 138 <1995IJB587>. 

Cycloaddition of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 321 with l-methyl(acetyl)-l,2,5,6-tetrahydro-4-pyrrolidinopyridine 322 led to the formation of A -methyl(acetyl)pyridopyridazine 323 (Equation 26) <1994H(38)1845>. 

A range of 2,2-bis(trifluoromethyl)-l,3-oxazepin-5-ones (334) has been prepared by the reaction of oxazolidin-5-ones with 1-diethylamino-l-propyne (75TL3223). l,3-Oxazepan-2-one has been prepared by the Beckmann rearrangement of tetrahydro-2-pyranone oxime. 

Soviet chemists have used the Diels-Alder reaction of acetone azine (309) with azotrifluoromethane (310) for the preparation of 3,3,6,6-tetramethyl-l,2-bis(trifluoromethyl)-l,2,3,6-tetrahydro-l,2,4,5-tetrazine (311) (62DOK(i42)354>. 

JA11707), 4-cyano-3-phenyl-3-trifluoromethyl-2,3-dihydro-lH-pyrido [l,2-c]pyrimidin-l-one (05MI1), and 10-(ferf-butyl)-3-methylene-3,4,4fl,5-tetrahydro-3H-[l,3]oxazino[3,4-b]isoquinolin-l-one (07EJ02015) under either acidic or basic conditions. 

The treatment of 6(S)-(iodomethyl)-4(R)-phenyl-l(R)-(trifluoromethyl)-3,4,7,8-tetrahydro-lH,6H-pyrido[2,l-c][l,4]oxazin-l-ol with NaH and I2 under microwave irradiation in CHC13 gave 6(S)-(iodomethyl-4(R)-phe-nyl-9a-(trifluoromethyl)-9-iodoperhydropyrido[2,l-c][l,4]oxazin-l-one in 90% yield (080L605). 

A, 1,1,1 -Tetrafluoro-/V- (trifluoromethyl)sulfonyl methanesulfonamide, see lV-Fluorobis(trifluoromethanesulfonyl)imide, 0640b 1.3a, 4,6a-Tetrahydro-lV,lV -dinitroimidazo[4,5-ii]imidazole-2,5-diamine, see Octahydro-2,5-bis(nitroimino)imidazo[4,5-(i]imidazole, 1511... 

Chemical Name 2-(3-Trifluoromethyl)phenyl-4-isopropyl-tetrahydro-l,4-oxazine hydrochloride... 

Trifluoromethyl)phenyl-4-isopropyl tetrahydro-l,4-oxazine hydrochloride The following mixture is heated in an autoclave at 100°C 2-(3-trifluoromethyl)-2-(2-chloro)-ethoxy-l-bromoethane 33.15 g (0.1 mol) isopropylamine 20 g (0.34 mol) toluene 100 ml. 

Chemical Name Pyridine, l,2,3,6-tetrahydro-l-(2-(2-naphthalenyl)ethyl)-4-(3-(trifluoromethyl)phenyl)- hydrochloride... 

Pent-4-ynylamino)-6-trifluoromethyl-l,2,4-triazine (79) underwent thermal cyclization to give 3-trifluoromethyl-5,6,7,8-tetrahydro-l,8-naphthyridine... 

Reaction of 8-amino-2,5,6,7-tetrahydro-3//-pyrido[l,2,3-de]-l, 4-benzox-azin-3-one with tetrahydrophthalic anhydride gave 100 (91EUP406993). The hydroxy group of 9-[2,2,2-trifluoro-l-hydroxy-l-(trifluoromethyl)-ethyl]-2,3-dihydro-5//-pyrido-[l, 2,3-de]-l,4-benzoxazin-5-ones was acy-lated (79GEP2854727). Treatment of 9-fluoro-10-phenyl-3-methyl-7-oxo-2,3-dihydro-7//-pyrido-[l,2,3-de]-l,4-benzoxazine-6-carboxylate with CISO3H afforded the 10-(p-chlorosulphonylphenyl) derivative, which was converted to the 10-(p-aminosulphonylphenyl) derivative with NH3 (86EUP184384). 

Pteridine also adds ammonia at low temperature to form 4-amino-3,4-dihydropteridine (42) which is transformed in a slower reaction into 6,7-diamino-5,6,7,8-tetrahydropteridine (43) (Scheme 5). 2-Chloropteridine (36) shows the same behavior, whereas 2-chloro-4-phenylpteridine (37) and 2-methylthiopteridine (38) lead directly to the corresponding 6,7-diamino-5,6,7,8-tetrahydro derivatives (43) (Scheme 5). The 4-amino-3,4-dihydropteridines can easily be oxidized to the 4-aminopteridines <75RTC45>. Covalent hydrations with various 6,7-bis-trifluoromethyl-pteridine derivatives were studied showing that 6,7-bis-trifluoromethylpteridine (40) itself and the cor-... 

Bis[trifluoromethyl]phosphino methyl tellurium replaced tetrahydrofuran in tetrahydro-furan(pentacarbonyl)chromium when the reagents were combined at —196° under an atmosphere of nitrogen in tetrahydrofuran as the reaction medium. Warming the mixture to room temperature, removing the solvent under a vacuum, and distilling or subliming the residue yielded analytically pure complexes2. The entire procedure must be carried out in the dark. 

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