4
Tetrahedron
Interestingly, the isomer arising from benzoyl migration 3b
(45%) was the main product; therefore Route A was more
favored than Route B. These data clearly indicate that the O-
The present work was partially supported by FIR (Fondo
Integrativo per la Ricerca – annualità 2018) - University of
Cagliari.
acylated phosphorane
I spontaneously cyclizes into II,
References and notes
presumably because intramolecular attack of the ylide carbanion
to the ortho carbonyl group is favoured by their proximity
(Scheme 5 and Table 1, entry 1).
[1] Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC,
Massie BM, Colling C, Layyeri D. N. Eng. J. Med. 1995;333:77-82; (b)
Kálai T, Várbió G, Bognár Z, Pálfi A, Hantó K, Bognár B, Ősz E, Smegi
B, Hideg K. Bioorg. Med. Chem. 2005;13:2629-2636; (c) Hartong R,
Wiersinga WM, Plomp TA. Horm. Metab. Res. 1990;22:85-89; (d)
Basaria S, Cooper DS. Am. J. Med. 2005;118:706-714.
[2] Felder CC, Joyce KE, Briley EM, Glass M, Mackie KP, Fahey KJ,
Cullian GJ, Hunden DC, Johnson DW, Chaney MO, Koppel GA,
Brownstein M J. Pharmacol Exp Ther. 1998;284(1):291-297.
[3] Heel RC, Brogden RN, Speight TM, Avery GS. Drugs 1977;14:349-366.
[4] (a) Brenner LM, Brush CK. US Pat. 4.001.426 (1997); (b) Howlett DR,
Perry AE, Godfrey F, Swatton JE, Jennings KH, Spitzfaden C,
Wadsworth H, Wood SE, Markwell RE. Biochem. J. 1999;340:283-289.
[5] Gong W, Liu D, Li F, Gao J, Li H, Lang J. Tetrahedron 2015;71:1269-
1275.
This behaviour was even more pronounced when 4-
nitrobenzoyl chloride was replaced by 4-methoxybenzoyl
chloride (Table 1, entry 2). In the latter case, the reaction of I
with the less electrophilic 4-methoxybenzoyl chloride (Route B)
was suppressed (4c, 3%) in favour of Route A (1a, 20%; 5c,
15%). These results clearly indicate that deactivated benzoyl
chlorides allow the formation of both isomeric 3-acyl derivatives,
most likely because I and III rapidly attack the highly
electrophilic carbonyl of the 4-nitrobenzoyl chloride.
Accordingly, analogous trends were also observed with 4-bromo
and 4-cyanobenzoyl chlorides (Table 1, entries 3 and 4).
[6] (a) Nakamura M, Ilies L, Otsubo S, Nakamura E. Org Lett. 2006;8:2803-
2805; (b) Zhao J, Fang H, Xie C, et al. Org Chem. 2013;2:1044-1047; (c)
Farrar MW, Levine R. J Am Chem Soc. 1950;72:4433-4436.
[7] (a) Oda K, Machida M. Chem. Pharm. Bull. 1993;41:1299-1301; (b) Yuan
H, Bi K, Li B, Yue R, Ye J, Shen Y, Shan L, Jin H, Sun Q, Zhang W.
Org. Lett. 2013;15:4742-4745; (c) Arcadi A, Cacchi S, Del Rosario M,
Fabrizi G, Marinelli F. J. Org. Chem. 1996;61:9280-9288. (d) Jason H,
Chaplin JH, Flynn BL. Chem. Commun. 2001;1594-1595; (e) Mothe SR,
Susanti D, Hong Chan PW. Tetrahedron Lett. 2010;51:2136-2140.
[8] Begala M, Caboni P, Matos MJ, Delogu GL. Tetrahedron Lett.
2018;59:1711-1714.
[9] Begala M, Delogu GL. J. Mass Spectrom. 2019;54(9):750-760.
[10] (a) Hercouet A, Le Corre M. Tetrahedron Lett. 1979;23:2145-2148; (b)
Hercouet A, Le Corre M. Tetrahedron 1981;37(16):2867-2873.
[11] (a) Kabalka GW, Varma RS. Comprehensive Organic Synthesis; Trost
BM, Fleming I, eds, 8. Oxford: Pergamon Press; 1991:363–379; (b)
Rappoport Z, ed. Chemistry of the Cyano Group. London: John Wiley &
Sons; 1970.
When
substituted
o-[(benzoyloxy)benzyl]-triphenyl-
phosphoranes were used (R = NO2, OCH3, entries 5 and 6), we
observed that the electron withdrawing group further suppressed
Route B in favour of cyclization to II (Route A), as reflected by
the higher yield of 2-(4-nitrophenyl)benzofuran 1b (42%) and the
absence of 3-benzoyl-2-(4-nitrophenyl)benzofuran 3b (Table 1,
entry 5). This behaviour could be rationalized by the fact that the
4-nitro group increases the electrophilicity of the carbonyl group
of I (R = NO2), making it easier for the ylide carbanion to attack
this electrophilic centre. Accordingly, o-[(benzoyloxy)benzyl]-
triphenyl-phosphorane bearing an electron donating group (R =
OCH3) still resulted in the formation of isomer 5c; albeit in low
yield (4%) (Table 1, entry 6).
The reaction of substituted o-[(benzoyloxy)benzyl]-triphenyl-
phosphoranes I (R = OCH3) with 4-nitrobenzoyl chloride (Table
1, entry 7) again leads predominantly to 2-(4-
methoxyphenyl)benzofuran 1c (12%) and isomer 11 (15 %) via
Route A.
[12] (a) Twyman LJ, Allsop D. Tetrahedron Lett. 1999;40:9383-9384; (b)
Thévenin M, Thoret S, Grellier P, Dubois J. Bioorg. Med. Chem.
2013;21(17):4885-4892.
[13] Ghosh S, Das J. Tetrahedron Lett. 2011;52:1112-1116.
[14] Routasalo T, Helaja J, Kavakka J, Koskinen AMP. Eur. J. Org. Chem.
2008;18:3190-3199.
Conclusion
[15] Ledoussal B, Gorgues A, Le Coq A. Tetrahedron 1987;43:5841-5852.
Our previous results demonstrated that under aprotic
conditions 3-acylbenzofurans can be obtained from the reaction
of o-[(benzoyloxy)benzyl]-triphenyl-phosphoranes with benzoyl
chlorides. We have also demonstrated that under these conditions
phosphoranes preferentially undergo intramolecular migration of
the benzoyl group via cyclization and ring opening. This
behaviour clarifies the unexpected formation of two sets of 3-
acylbenzofuran isomers when phosphoranes react with benzoyl
chlorides.
Supporting Information
Details of the experimental procedures and spectroscopic data
for new compounds. This material is available free of charge in
the online version [http://].
Declaration of interests
In particular, we found that the isomer arising from benzoyl
migration is further favoured by the use of deactivated benzoyl
chlorides or by phosphoranes I with a 4-methoxy group. This
finding is of considerable interest as it allows preparation of a
wide variety of 3-acylbenzofuran derivatives which are difficult
to obtain using alternative methods.
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments