HETEROCYCLES

Note | Special issue | Vol. 80, No. 1, 2010, pp. 593-600
Received, 19th December, 2008, Accepted, 13th April, 2009, Published online, 21st April, 2009.
DOI: 10.3987/COM-08-S(S)4

■ Nickel–Promoted Favorskii Type Rearrangement of Cyclic α-Bromoketones

Vishnu K. Tandon,* Anoop K. Awasthi, Kunwar A. Singh, Hardesh K. Maurya, and Sanjay K. Gautam

Department of Chemistry, University of Lucknow, Lucknow, U.P. 226007, India

Abstract

Favorskii type rearrangement of cyclic α-bromo ketones 2 is promoted by NiCl2 in refluxing methanol, giving the rearranged carboxylic acid ester 3 in excellent yields. The reaction of 4-bromo-2,3,4,5-tetrahydronaphth [2,1-b]oxepin-5-one (5) and its regioisomer 8 with NiCl2 in MeOH resulted in Favorskii rearranged carboxylic acid esters 6 and 9 respectively.

The rearrangement of α-haloketones to the carboxylic acids, esters, salts or amides is a powerful method in organic synthesis1 and is known as Favorskii rearrangement. This reaction, however, is promoted by a strong base such as alkalies alkoxides or amines.2 Development of this important rearrangement promoted by a catalytic amount of active species has been strongly desired since long time. Favorskii rearrangement in presence of metal hydride and aromatic amines is also reported.3 DBU in DMSO has been used for Favorskii rearrangement of trichlorothioacetamides.4 Aq. KCN in presence of α- or β-cyclodextrin was reported to catalyze the reaction of 6,7-dibromo derivative of zerumbone.5 Lithium aluminium hydride has recently been used to catalyze the rearrangement of tricyclic α-bromoketone.6 The efficiency of the catalyst used in recent years is generally not very high based on the yields reported in literature. As an extension of our recent investigations on the use of transition metal, alkaline earth metal and Lewis acids in organic synthesis,7-10 we examined the Favorskii type rearrangement of cyclic α-haloketones 2. NiCl2 was found to promote the reaction of cyclic α-bromoketone 2 in presence of MeOH as shown in Scheme 1. When cyclic α-bromoketones 2 in methanol were treated with NiCl2 and the mixture was refluxed for 36 h, rearranged carboxylic acid methyl esters 3 were obtained in excellent yield (Table 1). Analogous reaction of 2 with CuCl2 resulted in formation of 3 albeit in comparatively lesser yields.

The NiCl2 promoted Favorskii type rearrangement of several cyclic α-bromoketones 2 is summarized in Table 1. We have compared results using NiCl2 as a promoter, with those by conventional Favorskii rearrangement using NaOMe as a base in MeOH (Table 1) and found that NiCl2 acts as a better promoter for Favorskii type rearrangement. NiCl2 was taken in excess (3 equivalent) because the reactant was not completely converted into the product. Using 1 or 2 equivalent NiCl2, long time (50-60 h) refluxing was required and hence an excess of NiCl2 was required to facilitate the reaction.

The reaction with NiCl2 to effect Favorskii type rearrangement was also applied to 4-bromo-2,3,4,5- tetrahydronaphth[2,1-b]oxepin-5-one (5) and its regioisomer 4-bromo-2,3,4,5-tetrahydronaphth[1,2-b]oxepin-5-one (8) resulting in the formation of rearranged carboxylic acid esters 6 and 9 in 92 and 95% yield respectively as shown in Scheme 2. Our method using NiCl2 for synthesis of these derivatives demonstrates a new useful and convenient route. However, Maiti et al.21 used ZnCl2 for the synthesis of a number of cyclic α-bromo ketones and their acetals from α-bromocycloalkyl aryl ketone and corresponding acetals in 22-91% yields while our method using NiCl2 leads to 86-97% yields of the rearranged products.

Although the mechanism of the present reaction is not clear, the first step is presumably the complexation of bromine atom of ketone carbonyl with nickel chloride 10, followed by the attack of methoxy group and the elimination of bromide anion taking place simultaneously to form 11. 11 undergoes ring contraction to form 12 which on deprotonation gave desired product 13 as shown in Figure 1.

Due to the marked pharmacological and biological activities11-20 of benzopyran and 1-benzoxepine derivatives, our method provides a convenient and useful route to synthesis of different benzopyran and benzoxepine derivative. Further work to synthesize saturated α-halo alkanones viz. cyclopropanone-type intermediate is in progress.

EXPERIMENTAL
Melting points are uncorrected. IR spectra were recorded on a Perkin-Elmer model 137 spectrometer. 1H NMR (200 MHz) spectra were recorded on a Perkin-Elmer model R-32 spectrometer in CDCl3 using TMS as internal standard and mass spectra on Joel-JMS-D-300 spectrometer.
General procedure for the synthesis of α-bromoketones 2(a-h): Br2 (1.60g, 10 mmol) was added to a stirred solution of ketone 1(a-h) (10 mmol) in dry Et2O at 0 oC. The reaction mixture was further stirred at rt for 3 h. The resulting solution was washed with 10 mL 10% aq. NaHCO3 solution and 10 mL of brine. The ether extract was dried (Na2SO4) and concentrated in vacuo to give crude product. The crude product was purified by column chromatography using silica gel G and hexane and CHCl3 as eluant.
2-Bromo-indanone (2a):
Pale yellow solid; mp 39-40 oC (lit.,22 mp 37-38.5 oC); yield 78%; IR (KBr): 1723 (C=O) cm-1; 1H NMR (CDCl3): δ 3.45 (m, 1H, CH2), 3.88 (m, 1H, CH2), 4.65 (m, 1H, CH–Br), 7.39-7.91 (m, 4H, phenyl-H); MS (m/z): 211 (M+); Anal. Calcd for C9H7BrO: C, 51.18; H, 3.31. Found: C, 51.32; H, 3.40.
3-Bromo-chroman-4-one (2b):
Pale yellow solid; mp 96-98 oC; yield 98%; IR (KBr): 1705 (C=O) cm-1; 1H NMR (CDCl3): δ 4.72 (m, 3H, OCH2 & CHBr), 6.95-7.26 (m, 2H, ArH), 7.59-7.68 (m, 1H, Ar-H), 8.00-8.12 (m, 1H, Ar-H); MS (m/z): 227 (M+); Anal. Calcd for C9H7BrO2: C, 47.61; H, 3.11. Found: C, 47.54; H, 3.06.
4-Bromo-3, 4-dihydro-1 (2H)-benzoxepin-5-one (2c):
Yellow oil; yield 70%; IR (Neat): 1693 (C=O) cm-1; 1H NMR (CDCl3): δ 2.75 (m, 2H, CH2), 4.35 (m, 2H, OCH2), 4.95 (dd, 1H, CHBr), 7.45 (m, 4H, phenyl-H); MS (m/z): 244 (M++3), 242 (M++1), 241 (M+); Anal. Calcd for C10H9BrO2: C, 49.79; H, 3.73. Found: C, 49.92; H, 3.85.
3-Bromo-6-methyl-chroman-4-one (2d):
Yellow solid; mp 75o C (lit.,23 mp 74 oC); yield 85%; IR (KBr): 1696 (C=O) cm-1; 1H NMR (CDCl3): δ 2.47 (s, 3H, CH3); 4.61 (m, 3H, CHBr and OCH2), 7.26-8.01 (m, 3H, phenyl-H); MS (m/z): 242 (M++1); Anal. Calcd for C10H9BrO2: C, 49.79; H, 3.73. Found: C, 50.02; H, 3.94.
4-Bromo-7-methyl-3,4-dihydro-1(2H)-benzoxepin-5-one (2e):
Yellow solid; mp 66-67 oC (lit.,24 mp 66-67 oC); yield 60%; IR (KBr): 1694 (C=O) cm-1; 1H NMR (CDCl3): δ 2.25 (s, 3H, CH3), 2.36 (m, 1H, CH), 2.43 (m, 1H, CH), 4.06 (m, 1H, OCH), 4.34 (m, 1H, OCH), 4.90 (dd, 1H, CHBr), 6.89 (d, 1H, phenyl-H), 7.18 (dd, 1H, phenyl-H), 7.47 (d, 1H, phenyl-H). MS (m/z): 256 (M++1), 255 (M+); Anal. Calcd for C11H11BrO2: C, 51.76; H, 4.31. Found: C, 51.88; H, 4.40.
3-Bromo-6,7-dimethyl-chroman-4-one (2f):
Yellow brown solid; mp 95 oC, yield 81%; IR (KBr): 1697 (C=O) cm-1; 1H NMR (CDCl3): δ 2.35 (s, 3H, CH3), 2.38 (s, 3H, CH3), 4.62 (m, 3H, CHBr and OCH2), 7.23 (s, 1H, phenyl-H), 7.94 (s, 1H, phenyl-H); MS (m/z): 255 (M+); Anal. Calcd for C11H11BrO2: C, 51.76; H, 4.31. Found: C, 51.96; H, 4.48.
4-Bromo-7,8-dimethyl-3,4-dihydro-1(2H)-benzoxepin-5-one (2g):
Pale yellow solid; mp 81 oC (lit.,25 83-85 oC) yield 75%; IR (KBr): 1689 (C=O) cm-1; 1H NMR (CDCl3): δ 2.15 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.41 (m, 1H, CH2), 2.79 (m, 1H, CH2), 4.08 (m, 1H, OCH2), 4.49 (m, 1H, OCH2), 4.89 (m, 1H CHBr), 6.78 (s, 1H, phenyl-H), 7.47 (s, 1H, phenyl-H); MS (m/z): 269 (M+); Anal. Calcd for C12H13BrO2: C, 53.53; H, 4.83. Found: C, 53.78; H, 5.02.
4-Bromo-7-methoxy-3,4-dihydro-1(2H)-benzoxepin-5-one (2h):
Yellow oil; yield 60%; IR (Neat): 1685 (C=O) cm-1; 1H NMR (CDCl3): δ 2.22-2.53 (m, 1H, CH2), 2.89 (m, 1H, CH2) 3.81 (s, 3H, OCH3), 4.14 (m, 1H, OCH2), 4.40 (m, 1H, OCH2), 4.99 (m, 1H, CHBr), 7.02 (m, 2H, phenyl-H), 7.23 (m, 1H, phenyl-H). MS (m/z): 272 (M++1), 271 (M+); Anal. Calcd for C11H11BrO3: C, 48.70; H, 4.05. Found: C, 48.94; H, 4.18.
General procedure for base catalyzed Favorskii type rearrangement of 2(a-h): Synthesis of carboxylic acid esters 3(a-h):
a) General procedure for NiCl2 promoted Favorskii type rearrangement of cyclic α-bromo ketones 2(a-h): NiCl2 (390 mg; 3mmol) was added to a stirred solution of α-bromo ketones 2(a-h) (1 mmol) in MeOH (10 mL) under N2. The reaction mixture was refluxed for 36 h and MeOH distilled off from the reaction mixture. The residue was concentrated in vacuo and 10 mL of H2O was added to the reaction mixture. The reaction mixtrure was extracted with CHCl3 (15 mL) and extract was washed with 10 mL of brine, dried (Na2SO4) and concentrated in vacuo to yield product 3(a-h).
b) CuCl2 was used in place of NiCl2 to effect Favorskii type rearrangement of 2 (a-h): analogous reaction takes place and 3(a-h) were formed in 70-90% yields (Table 1).
c) General procedure for MeONa catalyzed Favorskii type rearrangement of cyclic α-bromoketones 2(a-h): α-bromo ketones 2(a-h) (5 mmol) was added to a stirred solution of MeONa [prepared from 230 mg (0.01g atom) of Na in 10 mL of MeOH] and the mixture was stirred with refluxing for 2 h at 80oC. The resulting solution was concentrated in vacuo, H2O (15 mL) added and the mixture was extracted with CHCl3 (20 mL), dried (Na2SO4) and concentrated in vacuo to give 3(a-h).
Methyl 1,2-dihydrocyclobutabenzene-1-carboxylate (3a): 26
Oil; IR (neat): 1739 (C=O) cm-1; 1H NMR (CDCl3): δ 3.40 (m, 2H, CH2), 3.67 (s, 3H, OCH3) 4.10 (t, 1H, CH), 7.15- 7.32 (m, 4H, phenyl-H); MS (m/z): 162 (M+); Anal. Calcd for C10H10O2: C, 74.06; H, 6.21. Found: C, 73.98; H, 6.17.
Methyl 2,3-dihydrobenzofuran-3-carboxylate (3b):27
For spectral and physical data of 3b refer to http://pubs.acs.org.OL0157858
Methyl chroman-4-carboxylate (3c):21
For spectral and physical data of 3b refer to reference 21.
Methyl 5-methyl-2,3-dihydrobenzofuran-3-carboxylate (3d):28
Pale yellow oil; IR (neat): 1737 (C=O) cm-1; 1H NMR (CDCl3): δ 2.33 (s, 3H, Me), 3.06 (m, 2H, OCH2), 3.85 (s, 3H, OMe), 4.33 (m, 1H, CH), 6.92 (m, 1H, phenyl-H), 7.36 (m, 2H, phenyl-H); MS (m/z): 193 (M++1); Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.57; H, 6.23.
Methyl 6-methylchroman-4-carboxylate (3e):
Oil, IR (neat): 1723 cm-1; 1H NMR (CDCl3): δ 1.91 (m, 2H, CH2), 2.32 (s, 3H, CH3), 3.70 (s, 3H, OCH3), 3.97 (t, J=4.0 Hz, 1H, CH), 4.19 (t, J=4.0 Hz, 2H, OCH2), 6.87-7.08 (m, 2H, phenyl-H), 7.55 (s, 1H, phenyl-H); MS (m/z): 193 (M++1); Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 69.78; H, 6.80.
Methyl 5,6-dimethyl-2,3-dihydrobenzofuran-3-carboxylate (3f):
Oil; IR (neat): 1739 (C=O) cm-1; 1H NMR (CDCl3); δ 2.35 (s, 3H, CH3), 2.38 (s, 3H, CH3), 3.90 (t, 3H, CH3), 4.20 (t, 1H, CH), 4.58 (m, 2H, OCH2), 7.23 (s, 1H, phenyl-H), 7.44 (s, 1H, phenyl-H); MS (m/z): 207 (M++1); Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 69.72; H, 6.88.
Methyl 6,7-dimethylchroman-4-carboxylate (3g):
Brown oil; IR (neat): 1726 cm-1; 1H NMR (CDCl3): 2.14 (m, 2H, CH2), 2.22 (s, 3H, CH3), 2.23 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 3.88 (t, J=4.0 Hz, 1H, CH), 4.10 (t, J=4.0 Hz, 2H, OCH2), 6.72 (s, 1H, phenyl-H), 7.41 (s, 1H, phenyl-H); MS (m/z) 220 (M++1); Anal. Calcd for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.79; H, 7.28.
Methyl 6-methoxychroman-4-carboxylate (3h):
Yellow oil; IR (Neat): 1726 (C=O) cm-1; 1H NMR (CDCl3): 2.15 (m, 2H, CH2), 3.70 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 4.04 (t, J=4.01 Hz, 1H, CH), 4.45 (t, J=4.0 Hz, 2H, OCH2), 6.92-7.26 (m, 3H, phenyl-H); MS (m/z): 223 (M++1); Anal. Calcd for C12H14O4: C, 64.85; H, 6.35. Found: C, 64.76; H, 6.31.
2-Bromo-3,4-dihydronaphtho[2,1-b]oxepin-1(2H)-one (5):
3,4-dihydronaphtho[2,1-b]oxepin-1(2H)-one (4) on reaction with Br2 in Et2O, according to the procedure followed for 2(a-h) yielded dull colored solid; mp 93 oC; yield 78%; IR (KBr): 1685 (C=O) cm-1; 1H NMR (CDCl3): δ 3.43 (m, 2H, CH2), 4.22 (t, J=7.0 Hz, 2H, OCH2), 5.85 (m, 1H, CHBr), 7.5-8.27 (m, 6H, naphth-H); MS (m/z): 292 (M++1), 291 (M+); Anal. Calcd for C14H11BrO2: C, 57.76; H, 3.81. Found: C, 57.94; H, 3.86.
Methyl 2,3-dihydro-1H-benzo[f]chromene-1-carboxylate (6):
2-Bromo-3,4-dihydronaphtho[2,1-b]oxepin-1(2H)-one (5) on reaction with NiCl2 in MeOH according to the procedure followed for 2(a-h) yielded methyl 2,3-dihydro-1H-benzo[f]chromene-1-carboxylate (6) as an oil; IR (neat): 1738 (C=O) cm-1; 1H NMR (CDCl3): 1.65 (m, 2H, CH2), 3.50 (t, J=4.0 Hz, 2H, OCH2), 3.85 (s, 3H, OMe), 4.02 (t, J=4.0 Hz, 1H, CH), 7.10-8.0 (m, 6H, naphth-H); MS (m/z): 243 (M++1); Anal. Calcd for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.25; H, 5.80.
4-Bromo-3,4-dihydronaphtho[1,2-b]oxepin-5(2H)-one (8):
3,4-dihydronaphtho[1,2-b]oxepin-5(2H)-one (7) on reaction with Br2 in Et2O, according to the procedure followed for 2(a-h) yielded light brown colored solid; mp 106 oC; yield 84%; IR (KBr): 1680 cm-1; 1H NMR (CDCl3): δ 3.39-3.47 (m, 2H, CH2), 4.20 (t, J=7 Hz, 2H, OCH2), 5.67 (m, 1H, CHBr), 7.56-8.20 (m, 6H, naphth-H); MS (m/z): 292 (M++1), 291 (M+); Anal. Calcd for C14H11BrO2: C, 57.76; H, 3.81. Found: C, 57.66; H, 3.79.
Methyl 3,4-dihydro-2H-benzo[h]chromene-4-carboxylate (9):
4-Bromo-3,4-dihydronaphtho[1,2-b]oxepin-5(2H)-one (8) on reaction with NiCl2 in MeOH according to the procedure followed for 2(a-h) yielded methyl 3,4-dihydro-2H-benzo[h]chromene-4-carboxylate (9) as an oil; IR (neat): 1734 cm-1; 1H NMR (CDCl3): 1.59 (m, 2H, CH2), 3.46 (t, J=4.0 Hz, 2H, OCH2), 3.79 (s, 3H, OMe), 3.92 (t, J=4.0 Hz, 1H, CH), 6.80-7.84 (m, 6H, naphth-H); Anal. Calcd for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.24; H, 5.78.

ACKNOWLEDGMENTS
A.K.A. thanks, C.S.T., Lucknow, India for Junior Research Fellowship, K.A.S. thanks U.G.C., New Delhi, India for award of a Junior Research Fellowship and H.K.M. thanks U.G.C., New Delhi, India for Senior Research Fellowship.

References

1. P. J. Chenier, J. Chem. Edu., 1978, 55, 286 and references therein.
2. L. F. Silva Jr., Tetrahedron, 2002, 58, 9137. CrossRef
3. (a) T. Satoh, K. Oguro, J. Shishikura, N. Kanetaka, R. Okada, and K. Yamakawa, Tetrahedron Lett., 1992, 33, 1455; CrossRef (b) T. Satoh, S. Motohashi, S. Kimura, S. Kimura, N. Tokutake, and K. Yamakawa, Tetrahedron Lett., 1993, 34, 4823. CrossRef
4. S. Braverman, M. Cherkinsky, E. V. K. S. Kumar, and H. E. Gottlieb, Tetrahedron, 2000, 56, 4521. CrossRef
5. T. Kitayama and T. Okamoto, J. Org. Chem., 1999, 64, 2667. CrossRef
6. M. Harmata, G. Bohnert, L. Kurti, and C. L. Barnes, Tetrahedron Lett., 2002, 43, 2347. CrossRef
7. V. K. Tandon and R. B. Chhor, Lett. in Org. Chem., 2004, 1, 40. CrossRef
8. V. K. Tandon and M. Kumar, Tetrahedron Lett., 2004, 45, 4185. CrossRef
9. V. K. Tandon and R. B. Chhor, Synth. Commun., 2001, 31, 1727. CrossRef
10. V. K. Tandon, A. Sharon, R. Bandichhor, and P. R. Maulik, Acta Cryst., 2002, E58, 869.
11. M. Shiraishi, Y. Aramaki, M. Seto, H. Imoto, Y. Nishikawa, N. Kanzaki, M. Okamoto, H. Sawada, O. Nishimura, M. Baba, and M. Fujino, J. Med. Chem., 2000, 43, 2049. CrossRef
12. P. D. Gupta, A. Pal, A. Roy, and D. Mukherjee, Tetrahedron Lett., 2000, 41, 7563. CrossRef
13. (a) M. Shiraishi, M. Baba, M. Seto, N. Kanzaki, and O. Nishimura, Japanese Pat. Appl. 1999/127, 724, 1999 (Chem. Abstr., 2000, 133, 362714q); (b) K. Takashima, Y. Iizawa, M. Shiraishi, Y. Sugihara, and M. Baba, Japanese Pat. Appl. 2002/141, 657, 2002 (Chem. Abstr., 2003, 139, 341780s).
14. S. Kloubert, M. Mathé-Allainmat, J. Andrieux, and M. Langlois, Synth. Commun., 2000, 30, 2873. CrossRef
15. (a) M. Brunet, J. J. Zeilter, J. J. Berthelon, F. Contard, G. Augert, and D. Guerrier, French Pat. Appl. 1998/16, 574, 1998 (Chem. Abstr., 2000, 133, 89445j); (b) Y. Auberson, C. Betschart, S. Flohr, R. Glalthar, O. Simic M. Tintelnot-Blomly, T. J. Troxler, E. Vangrevelinghe, and S. J. Veenstra, British Pat. Appl. 2003/17, 491, 2003 (Chem. Abstr., 2005, 142, 240329h).
16. V. K. Tandon, M. Kumar, A. K. Awasthi, H. O. Saxena, and G. K. Goswamy, Bioorg. Med. Chem. Lett., 2004, 14, 3177. CrossRef
17. V. K. Tandon, K. A. Singh, A. K. Awasthi, J. M. Khanna, B. Lal, and N. Anand, Bioorg. Med. Chem. Lett., 2004, 14, 2867. CrossRef
18. V. K. Tandon and A. Chandra, Tetrahedron Lett., 1993, 34, 4403. CrossRef
19. V. K. Tandon, J. M. Khanna, A. Chandra, and N. Anand, Tetrahedron, 1990, 46, 2871. CrossRef
20. V. K. Tandon, A. Chandra, P. R. Dua, and R. C. Srimal, Arch. Pharm., 1993, 326, 221. CrossRef
21. S. B. Maiti, S. R. R. Chaudhuri, and A. Chatterjee, Synthesis, 1987, 9, 806. CrossRef
22. H. O. House, V. Paragamian, R. S. Ro, and D. J. Wluka, J. Am. Chem. Soc., 1960, 82, 1452. CrossRef
23. J. Colonge and A. Guyol, Bull. Soc. Chim. France., 1958, 329.
24. V. K. Tandon, J. M. Khanna, N. Anand, R. C. Srimal, C. R. Prasad, and K. Kar, Ind. J. Chem., 1975, 13, 1.
25. G. Fontaine, Ann. Chim. (Paris)., 1968, 3, 179.
26. a) F. M. Nongrum and B. Myrboh, Synthesis, 1987, 9, 845; CrossRef b) H. Tomioka and K. Taketsuji, J. Org. Chem., 1993, 58, 4196. CrossRef
27. H. M. L. Davies, M. V. A. Grazini, and E. Aouad, Org. Lett., 2001, 3, 1475. CrossRef
28. E. A. Boyle, F. R. Mangan, R. E. Markwell, S. A. Smith, M. J. Thomson, R. W. Ward, and P. A. Wyman, J. Med. Chem., 1986, 29, 894. CrossRef