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Z. Rappoport, Apeloig, Y. The Chemistry of Organic Silicon Compounds, pp.39-43, 1998.

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. Un-accès-régiosélectif, -trisubstitués faisant intervenir l'addition conjuguée d'organolithiens à des acides 1-et 2-naphtoïques suivi par un piégeage par divers électrophiles: ref 54, 2002.

S. Un-mécanisme-de-type, semble peu plausible dans la mesure où l'addition de pièges à radicaux (tétraphénylhydrazine ou dimère du 2-méthyl-2-nitrosopropane) à un mélange d'acide 2-fluorobenzoïque et LiNEt 2 conduit seulement à une faible réduction du produit de réaction

H. J. Reich and W. H. Sikorski, 97 (a) Mortier, J. Org. Chem. J.; Castanet, A.-S, vol.64, issue.14, pp.2011101599-2011101600, 1999.

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M. In, 0 mL, 6.6 mmol) Standard workup followed by recrystallization (cyclohexane/ethylacetate 1:3) afforded 5d as a white solid (560 mg, 93%): mp 147?149 °C (lit, pp.150-151

. Mhz, 71 (s, 1H), 27 (d, J = 9.0 Hz, 1H), 7.93?7.90 (m, 2H), 7.80 (d, J = 8.7 Hz, 1H), 7.62?7.55 (m, 2H), 3.49 (q, J = 7

. Hz, 4 Hz, 3H); 13 C NMR (100 MHz, acetone-d 6 ) ? 170, pp.37-1244

H. Calcd-for, C. , and J. , 0843. 1-Vinyl-2-naphthoic acid (5e) Table 1, entry 11 (2 + H 2 C? CHMgBr) According to the general procedure, vinyl magnesium bromide (0.75 M in THF, 8.8 mL, 6.6 mmol) was added dropwise to a solution of 1-methoxy-2-naphthoic acid (2) (606 mg, 3.0 mmol) at rt. The mixture was then refluxed for 2 h. Standard workup followed by recrystallization (cyclohexane/ether 1:3) afforded 5e as a white solid (505 mg, 85%): mp 144?146 °C, H NMR (400 MHz, CDCl 3 ) ? 8.38 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), pp.83-90

1. Hz, 78 (dd, J = 11, Hz, vol.55, issue.58, p.41

J. =. Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) ? 173, Hz, issue.1

. Phli, According to the general procedure6 mL, 6.6 mmol) was added dropwise to a solution of 1-fluoro-2-naphthoic acid (1) (570 mg, 3.0 mmol) or 1-methoxy-2- naphthoic acid (2) (606 mg, 3.0 mmol) in THF at ?30 °C. Stirring was maintained at this temperature for 2 h. Standard workup followed by recrystallization (n-hexane/ethylacetate 1:3) afforded 5f as a pale yellow solid (560 mg, 75% from 1, 597 mg, pp.145-147

. Mhz, 125.9; IR (KBr, cm ?1 ) 30000837, found 248.0869. Anal. Calcd for C 17 H 12 O 2 : C, 82.24; H, 4.87. Found: C, 82.03; H, 4.85 Table 2, entry 3 (2 + PhMgBr) According to the general procedure, phenylmagnesium bromide (2.16 M in THF, 3.1 mL, 6.6 mmol) was added dropwise to a solution of 1-methoxy-2-naphthoic acid (2) (606 mg, 3.0 mmol) in THF at 0 °C. Stirring was maintained this temperature for 2 h. Standard workup followed by recrystallization (nhexane/ethylacetate 1:3) gave 5f as a pale yellow solid (630 mg, 84%). 1-(2-Methoxyphenyl)-2-naphthoic acid (5g) Table According to the general procedure-methoxyphenyl)lithium (8.0 mmol) was added dropwise to a solution of 1-fluoro-2-naphthoic acid (1) (380 mg, 2.0 mmol) or 1- methoxy-2-naphthoic acid (2) (404 mg, 2.0 mmol) in THF at ?30 °C. The reaction mixture was stirred at ?30 °C for 2 h, H NMR (400 MHz, acetone-d 6 ) ? 8.00?7.94 (m, 3H), pp.127-135, 1284.

H. Calcd, 0943, found 278.0956. 1-(2-Methylphenyl)-2-naphthoic acid (5h) Table 2 According to the general procedure

. Mhz, CDCl 3 ) ? 10, 90 (br, 1H), 8.03 (d, J = 8.6 Hz, 1H)

2. Hz, 1H), 1.92 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) ? 173, )-2-naphthoic acid (5i). Table 2, pp.7-36, 0942.

2. Hz and . Nmr, 90 (s, 3H); 13 C NMR (50 MHz, CDCl 3 ) ? 173 HRMS calcd for C 18 H 14 O 3 ([M] + ) 278.0943, found 278.0940. 1-(2,5-Dimethylphenyl)-2-naphthoic acid (5j) Table 2, entry 15 (2 + 2,5-diMeC 6 H 4 MgBr) According to the general procedure5-dimethylphenyl)magnesium bromide (0.50 M in THF, 13.2 mL, 6.6 mmol) was allowed to react with 1-methoxy-2-naphthoic acid (2) (606 mg, 3.0 mmol) in THF at rt. The reaction mixture was refluxed for 2 h. Standard workup followed by recrystallization (cyclohexane) afforded 5j as a white solid (600 mg, 72%): mp 165-°C According to the general procedure, 55.3; IR (ATR, cm ?1 ) 1698 2H), 7.53 (m, 1H), 7.37?7.36 (m, 2H), 7.22?7.13 (m, 2H), 6.89 (s, 1H), 2.32 (s, 3H), 1.88 (s, 3H); 13 C NMR (100 MHz THF. After 2 h refluxing, standard workup followed by chromatography on silica gel (cyclohexane/ethylacetate 9:1 ? 0:1) gave 5l as a pale yellow solid, pp.61-68, 0200.

. Mhz, IR (ATR, cm ?1 ) 759, 724; HRMS calcd for C 19Binaphthalene]-2-carboxylic acid (5m) Table 3, entries 1 and 2 (1,2 + 1-naphthyllithium) According to the general procedure, p.1, 0910.

I. Atr, 795, 768; HRMS calcd for C 21, 0913.

J. =. Hz, 70 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) ? 168.2, 1531; IR (ATR, cm ?1 ), pp.90-765, 0913.

J. =. Buli, According to the general procedure0 mmol) was allowed to react with s-BuLi (0.90 M in hexane, 7.3 mL, 6.6 mmol) at ?78 °C Standard workup followed by recrystallization (cyclohexane/ethylacetate 1:3) afforded 6b as a white solid (650 mg, 95%): mp 168?170 °C (lit. 31 166?168 °C); 1 H NMR (400 MHz, CDCl 3 ) ? 11.93 (s, 1H), 1H), 7.50?7.43 (m, 2H), 3.12 (m, 1H)), 0.88 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, pp.2-3, 1253.

. Buli, According to the general procedure, 2-methoxy-1-naphthoic acid (3) (606 mg, 3.0 mmol) was reacted with t-BuLi (1.70 M in pentane, 3.9 mL, 6.6 mmol) at ?78 °C. Standard workup followed by recrystallization (cyclohexane/ethylacetate 1:3) afforded 6c as a white solid (600 mg, 87%): mp 120?123 °C, H NMR (400 MHz, CDCl 3 ) ? 10.75 (s, 1H), 7.93 (d, J = 8.4 Hz 1H), 7.89 (d, J = 8.8 Hz, 1H), p.83

. Hz, m, 4H, pp.7-48

+. Phmgbr and J. =. , According to the general procedure64 mmol) in THF (4.5 mL) was treated with phenyl magnesium bromide (3 M in THF, 0.47 mL, 1.41 mmol) at rt for 2 h Standard workup followed by chromatography on silica gel (DCM/MeOH/AcOH 10:0.2:0.05) afforded 7f as a beige solid (145 mg, 81%): mp 196?197 °C; 1 H NMR (270 MHz (s, 3H), C NMR (67.5 MHzOCH 2 O)C 6 H 4 MgBr), pp.279-10214, 1989.

C. Nmr, CDCl 3 ) ? 171, 1039.

H. Calcd-for and C. , + ) 323.0919, found 323.0911. 2-Methoxy-3-methyl-1-naphthoic acid (8) Table 2

+. Phli and /. Mei, According to the general procedure with 2-methoxy-1- naphthoic acid (3) (606 mg, 3.0 mmol) and phenyllithium (1.80 M in dibutylether, 3.7 mL, 6.6 mmol) in THF at ?30 °C. Stirring was maintained at at ?30 °C for 2 h after which iodomethane (1.0 mL, 16.1 mmol) was added. Stirring was then maintained for 30 min. Standard workup followed by recrystallization (cyclohexane/ethylacetate 1:3) gave 8 as a yellow solid (897 mg, 86%): mp 84?86 °C, H NMR (400 MHz, CDCl 3 ) ? 10.50 (s, 1H), p.12

J. Mmol, The mixture was refluxed for 1 day Standard workup followed by chromatography on silica gel (cyclohexane/ethylacetate 95:5 ? 0:1) afforded 12 as a white solid (295 mg, 75% from 1, pp.191-193

?. Associated, Supporting Information Details of compound characterization. This material is available free of charge via the Internet at http

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A. G. Livingston, R. C. Org-fuson, F. W. Wassmundt, and D. J. Carini, Nucleophilic Aromatic Substitution Review: Mortier, Process Res. Dev 8732?8733. (15) Snieckus, V The requisite naphthoic acids 1 and 2 were prepared by lithiation of 1-fluoronaphthalene using s-BuLi in THF at ?75 °C followed by quench with CO 2, pp.5409-5413, 1956.

C. Gant, T. G. Meyers, A. I. Jane, R. Pathak, T. P. Sigman et al., 2-Methoxy-1- naphthoic acid (3) and 2,3-dimethoxy-1-naphthoic acid (4) were synthesized from 2-methoxynaphthalene and 2,3-dimethoxynaphtha- lene, respectively, by bromination followed by Br-Li permutation and CO 2 quench (19) The Chemistry of Organomagnesium Compounds, Chem. Eur. J. J. Am. Chem. Soc. Chem. Rev. 1417?1492. J. Org. React, vol.11421, issue.18, pp.1-97, 1970.

K. P. Nguyen, J. Mortier, . Org, B. Lett-plunian, J. Mortier et al., In earlier studies, we described a stereospecific route to 1,1,2- and 1,2,2-trisubstituted 1,2-dihydronaphthalenes that involves the nucleophilic conjugate addition of organolithium reagents to unprotected 1-and 2-naphthalenecarboxylic acids followed by trapping of the intermediate carboxylic acid dilithium enolates with several electrophiles: (a), The S R N l mechanism seems less plausible because the addition of radical scavengers (tetraphenylhydrazine or 2-methyl-2-nitro- sopropane dimer) to a mixture of 2-fluorobenzoic acid and NEt, pp.446-447, 1996.

M. N. Whisler and S. Macneil, gave only a slight lowering of the yield of the substitution product. See ref 21

. Chem, . E. Int, K. Tomioka, Y. Shioya, Y. Nagaoka et al., (b) See also: The Chemistry of Organomagnesium Compounds, Organometallics in Synthesis. A Manual 1438?1452. (31) Mortier 98?112. (32) Gabard 105?107. (34) Shindo, M.; Yamamoto, pp.5279-5282, 1958.

K. Prasad, T. J. Blacklock, and . Org, Note for guidance on specification limits for residues of metal catalysts The European Agency for the Evaluation of Medicinal Products Web site). (6) See, for instance, 2002.

C. Gohier, F. Castanet, A. Mortier, J. Org, K. P. Mortier et al., The reaction of 2-fluorobenzoic acid with s-BuLi and t-BuLi affords the the ipso-attack product arising out of substitution of the fluorine atom by the alkyl group: (a) Metalation reactions, recent references, J. Org. Lett, vol.42, issue.8, pp.2653-2654, 1919.

M. Alessi, A. Castanet, V. Snieckus, J. Mortier, . Org et al., (12) Two recent papers described LiHMDS-promoted coupling of primary and N-substituted anilines with 2-fluorobenzoic acid (or amide) to give N-arylanthranilic acids and N-arylanthranilamides, pp.68-71, 2010.

C. Davis, E. M. Nanninga, T. N. Tjiong, H. I. Winkle, D. D. Smith et al., Nucleophilic displacements of 2-fluorobenzoic acid derivatives are well known to occur readily in the presence of strong electron-withdrawing substituents Lithium arylamides have weaker nucleophilic strengths than lithium dialkylamines but are more stable at higher temperature (50-60 °C). (15) The synthesis of anthranilic acids using sterically hindered amines via a three-component coupling with arynes and CO 2 has been reported, Org. Process Res. DeV. J. Org. Lett. J. AdVanced Organic Chemistry, vol.32, issue.1016, pp.411-417, 2002.

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M. N. Whisler and S. Macneil, Beyond Thermodynamic Acidity: A Perspective on the Complex-Induced Proximity Effect (CIPE) in Deprotonation Reactions, Angewandte Chemie International Edition, vol.43, issue.17, pp.2206-2225, 2004.
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D. Tilly, S. S. Samanta, A. De, A. Castanet, J. Mortier et al., (22) Rappoport, Z. The Chemistry of Peroxides (24) Observations of a similar rearrangement, leading to dioxindoles, have been reported It is assumed that the reduction step leading to 25 is the first irreversible step in the pathway. (26) All new compounds gave correct analytical data. See Supporting Information, 25) In deoxygenated medium, the reaction of 2 with LiNMeBn (5 equiv) led to 5 (> 90%)29) A patent application was filed: Mortier, J.; Castanet, A.-S.; Belaud- Rotureau, M. patent pending, pp.827-830, 1956.