1.2.3.4- Tetrahydroquinoline-8-carboxylic

Treatment of 8-hydroxymethyl-l,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroquinoline-8-carboxylic acid, or l-(2-hydroxyethyl)-l,2,3,4-tetrahydroisoquinolines with COCI2 in the presence of a base furnished... 

Treatment of 8-hydroxymethyl-l,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroquinoline-8-carboxylic acid, or l-(2-hydroxyethyl)-l,2,3,4-tetrahydroisoquinolines with COCI2 in the presence of a base furnished l,5,6,7-tetrahydro-3//-pyrido[3,2,l-(/ ][3,l]benzoxazin-3-one (92JMC1076), the -1,3-dione (102) (78JHC645), and l,2,4,6,7,llft-hexahydro[l,3]oxazino[4, 3-a]isoquinolin-4-ones (92T4937), respectively. 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

BJ Marsden, TM Nguyen, PW Schiller. Spontaneous degradation via diketopiperazine formation of peptides containing a tetrahydroquinoline-3-carboxylic acid residue in the 2-position of the peptide sequence. Int J Pept Prot Res 41, 313, 1993. 

Optically active benzo[y]quinolizine-2-carboxylic acid (716, R = R2 = H, R1 = Me, R3 = F, R4 = Br) was prepared in the reaction of optically active 2-metyl-5-bromo-6-fluoro-l, 2,3,4-tetrahydroquinoline and EMME in polyphosphoric acid [88JAP(K)192753]. 

Ethyl cyanoacetate reacts with 1,3-diketones to give 4,6-disubstituted 2-oxopyridine-3-carboxylates such as compound (483) (15JCS792), and with hydroxymethylenecyclohexanone to give a mixture of tetrahydroquinolines (484) and (485) (55AP174). 

Fmoc-amino acids used as building blocks of testing compounds are as follows Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Met-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Ile-OH, Fmoc-His(Trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Pro-OH, Fmoc-Trp(Boc)-OH, Fmoc-D-Ala-OH, Fmoc-D-Arg(Pmc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Glu(OtBu)-OH, Fmoc-D-His(Trt)-OH, Fmoc-D-Gln(Trt)-OH, Fmoc-D-Leu-OH, Fmoc-D-Met-OH, Fmoc-D-Pro-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-D-Lys(Boc)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-D-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-D-Asn(Trt)-OH, Fmoc-3-(4-pyridyl)alanine, Fmoc-D-3-(3-pyridyl)alanine, Fmoc-4-tert-butoxyproline, Fmoc-3-chlorophenylalanine, Fmoc-norleucine, Fmoc-2-cyclohexylglycine, Fmoc-2-aminoisobutyric acid, Fmoc-tranexamic acid, Fmoc-(i ,S)-3-amino-3-(2-furyl)propionic acid, Fmoc-(i ,S)-(6,7-di-methoxy)-l,2,3,4-tetrahydroquinoline-3-carboxylic acid, Fmoc- (R, S)-3-amino-3-(4-hydroxyphenyl)propionic acid, Fmoc-(i ,S)-3-aminovaleric acid, Fmoc-(i ,5 )-3-amino-3-(3,4-dichlorophenyl)propionic acid, Fmoc-isonipecotic acid, Fmoc-(i ,S)-3-amino-3-(3,4-methylenedioxyphenyl)... 

Reaction of methyl 5-fluoro-l,2,3,4-tetrahydroquinoline-8-carboxylate and (3-Cl-Ph)NCO in PhMe at 90 °C for 20 h afforded 2-(3-chlorophenyl)-8-fluoro-2,3,6,7-tetrahydro-l H,5H-pyrido [3,2,1 -ij] quinazoline-1,3-dione in 35% yield (07WOP2007/028789). 

Reaction of 5-bromo-l,2,3,4-tetrahydroquinoline-8-carboxylic acid with COCl2 in THF at room temperature for 16 h gave 8-bromo-6,7-dihy-dro-lH,3H,5H-pyrido[3,2,l-//J[3,lJbenzoxazine-l,3-dione in 80% yield (07WOP2007/028789). 8-Bromo-2-aryl-2,3,6,7-tetrahydro-lH,5H-pyrido [3,2,1-zy]quinazoline-l,3-diones were also prepared in the reaction of N-aryl-5-bromo-l, 2,3,4-tetrahydroquinoline-8-carboxamides and ClC02Ph in boiling 1,2-dichloroethane for 30 min. 

Heating 1,3,4,6,7,1 lb-hexahydro[l,4]oxazino[4,3-aJquinoline-l,4-diones 186 in the presence of cone. HC1 in EtOH (method a) and DME (method b) at reflux yielded tetrahydroquinoline-2-carboxylic acids 187 (08T2321). Methyl derivative 187 (R = Me) was accompanied with the ethyl ester 188, when EtOH was the solvent (method a). 

The action of concentrated sulfuric acid at 0 °C on the geminal diazide 2 gives in high yield (> 90 %) the N-oxamoyl anthranilic acid 14 [72TH000], This compound can be further hydrolyzed to anthranilic acid 15 or converted into the ester 16. N-Alkyl derivatives of 2 behave in a similar manner cf. the conversion of 18 to 19. The latter compound may be easily degradated to 1,2,3,4-tetrahydroquinoline-l-carboxylic acid in the same way. Only the biphenyl derivative of 2 reacts differently and affords acridone 17 in 65 % yield. The cleavage of the C-3 - C-4 bond in these reactions is again noteworthy. 

Sodium cyanide in DMF at 120 °C has been used for the decarboxylation of 1-substituted-4-oxoquinoline-3-carboxylic acids <94TL(35)8303>. Quinoline Reissert adducts have been epoxidized at the 3,4-bond. Its reaction with amine nucleophiles gave regiospecifically substituted 1,2,3,4-tetrahydroquinolines <95H(41)897>. Successive Claissen rearrangements of 2-(8-quinolinoxymethyl)-3-(8-quinolinoxy)-l-propene gave a product which shows excellent ability to extract heavy metal ions <95TL(36)5567>. An Eschenmoser approach has been used in a facile synthesis of monofunctional and difunctional A -substituted-4-alkylidenequinolines (54) (Scheme 39) <95S(St)56>. 

Heald repeated the same reduction of 6-nitroquinoline (147) at a higher temperature and isolated 1-ethyl-l,2-dihydro-6-nitroquinoline (148), the product of reductive alkylation. With quinoline and NBH in carboxylic acids the Aralkyl-1,2,3,4-tetrahydroquinoline 149 is obtained. Use of sodium cyanoborohydride gives reduction but no alkylation (150). In the presence of acetone, l-isopropyl-l,2,3,4-tetrahydroquinoline (151) is the predominant compound. Quinoline W-oxides undergo deoxygenation, and some ring reduction with NBH. ... 

Usually, N-substituted IA s are synthesized by the action of phosgene on the corresponding N-substituted anthranilic adds, for example, the tricyclic derivative (26) was recently prepared in high yield from tetrahydroquinoline-8-carboxylic add (25).19 An earlier preparation of 26 required a five-step synthesis via 2752 (Eq. 2). (For the analogous synthesis of IA itself via the corresponding chloronitroquinoline derivative see Ref. 53). 

A-Acylated indolines and 1,2,3,4-tetrahydroquinolines free of osubstituent to the heteroatom are arylated by reaction with ArB(OH)2. Besides Pd(OAc)2, the catalyst system also contains equivalents of Cu(OTf )2 and Ag20 Similarly, a protocol for the Pd-catalyzed o-arylation of acetanilides employs Cu(OTf)2 and AgF, with ArSi(OR)3 as aryl group donors. Further variants of couphng conditions involving oxygen in a carboxylic acid solvent enable the use of ArH as reaction partners. Cyclization of A-aroylindoles proceeds via double C—H activation. ... 

Pictet-Spengler cyclization. Ethyl tetrahydroquinoline-l-carboxylates are readily prepared from a reaction (catalyzed by SnCl4) of phenethylamines and the ester. 

Rearrangements. A variety of reactions catalyzed by Rh(ll) carboxylates, including Wolff rearrangement of 3-diazo-2,4-dioxo-l,2,3,4-tetrahydroquinolines leading to oxindoles due to in situ decarboxylation, insertion followed by [2,3]sigmatropic rearrangement and Claisen rearrangement," serve to affirm their synthetic potential. 

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