Benzyl (phenyl) γ- and δ-lactones via photoinduced tandem Ar-C, C-O bond formation

Article abstract of DOI:10.1021/ja0627287

A convenient metal-free procedure for the preparation of benzyl (phenyl) γ- and δ-lactones is illustrated. This method is based on the photochemical generation of phenyl cations and their reaction with 3, 4, or 5-alkenoic acids. This leads to a phenyl- or benzyl-substituted lactone by tandem formation of an aryl-C and C-O bond. The intermediacy of a phenonium ion imparts a full regio- and stereoselectivity to the reaction. Copyright

Full text of DOI:10.1021/ja0627287

Published on Web 07/28/2006
Benzyl (Phenyl) γ- and δ-lactones via Photoinduced Tandem Ar-C, C-O
Bond Formation
Stefano Protti, Maurizio Fagnoni,* and Angelo Albini
Department of Organic Chemistry, The UniVersity, V. Taramelli 10, 27100 PaVia, Italy
Received April 19, 2006; E-mail: fagnoni@unipv.it
Scheme 1. Photochemical Synthesis of Benzyl(phenyl) Lactones
The γ-lactone moiety is present in many biologically active
natural compounds.1 In particular, some benzyl- and aryl-substituted
γ-lactones have shown cancer preventive and anti-inflammatory
activity2a or are used as intermediates for the synthesis of antibiotic
antitumor agents.2b This notwithstanding, the synthesis of such
derivatives has received only sparse attention. Thus, aryl γ-lactones
have been obtained by Baeyer-Villiger reaction of aryl cyclobu-
tanones,3 or by reaction of 2-phenyloxirane with the malonate
anion,4 while benzyl lactones have been formed by arylation of a
substituted epoxide by means of an aryl cyanocuprate.2b The
arylation of unsaturated lactones has been exploited in the Rh(I)-
catalyzed conjugate addition of aryl boronic acids5a or of
aryltrimethylstannanes.5b Recently, it has been reported that aryl
δ-lactones (I, Scheme 1) rearrange to benzyl γ-lactones under acidic
conditions6 via a phenonium ion (II). We reasoned that generating
directly the phenonium ion by addition of a phenyl cation (III) onto
an unsaturated acid would offer a novel entry to these lactones via
Scheme 2. Possible Pathways in the Reaction between Phenyl
tandem formation of an aryl-C and a C-O bond. There is hardly
Cations and Unsaturated Acids 4 and 5
a precedent for this strategy.7 However, we recently showed that
phenyl cations (III) are smoothly generated by photoheterolysis of
electron-rich aromatic chlorides, fluorides, or esters (IV)8 and add
to alkenes forming phenonium ions. We first tested this idea by
generating phenyl cations in the presence of some terminal alkenoic
acids, namely, 3-butenoic (1), 4-pentenoic (2), and 5-hexenoic (3)
acid. Electron-donating substituted phenyl halides and esters 6-13
were used as precursors of the cations. Because photoheterolysis
is favored by polar (protic) solvents, the irradiation (310 nm, 254
nm for 13)9a was carried out in acetonitrile-water 5:1.9b
Indeed, irradiation of 4-chlorophenol (6) in the presence of 1
under these conditions (see Supporting Information for details) gave
the desired phenyl-γ-lactone 14 in a moderate yield (52%, Table
1), arising via path R, Scheme 1. On the other hand, irradiation of
aniline 7a and anisole 10a under the same conditions gave only a
30% of the corresponding lactone (not reported in the Table).
Satisfactory results were obtained in the arylation of 4-pentenoic
acid (2). Thus, when using 4-chlorophenol, lactone 15 was formed
in nearly quantitative yield and with complete regioselectivity (in
this case path â was followed, see Scheme 1). This result fostered
a more extensive exploration of the reaction, which showed that
benzyl γ-lactones were consistently the only products. Phenyl
chlorides could be substituted by other halides or esters. Thus,
aminobenzyl lactone 16 was formed in more than 70% yield when
starting both from 4-chloro- (7a)11 and from 4-fluoro-N,N-dim-
ethylaniline (7b, same irradiation time, 6 h) and in a lower yield
(50%) from phosphate 7c. Analogously, aminobenzyl lactone 17
was prepared by irradiating both 4-chloro and 4-fluoroaniline.
Further derivatives bearing O- or S-bonded electron-donating
groups in position 4 reacted similarly. In particular, the photolysis
of 4-chloroanisole 10a or of the triflate or phosphate esters (10b,c)
afforded dihydrofuranone 19 in moderate to excellent yield (48 to
87%). 4-Chloro-1,2-benzodioxole and 4-chlorothioanisole gave
lactones 20 and 21, respectively (>50% yield). Interestingly, a
phenyl cation could be generated and trapped also when using an
alkyl-substituted phenyl halide. Thus, lactone 22 was formed from
4-butylchlorobenzene (13) and 2 upon 254 nm irradiation. Fur-
thermore, we recently demonstrated that ortho-substituted phenyl
cations were obtained just as the para-analogues,13 and this
suggested a further extension of the study. Thus, 2-chlorophenol
(9) was irradiated in the presence of acid 2 and found to give lactone
18. Noteworthy, the alternative cyclization of the phenolic OH group
onto the phenonium ion did not take place.14 As for the hexenoic
acid 3, this gave, regioselectively, the hydroxyphenyl and ami-
nophenyl tetrahydropyranones 23 and 24 (following again path â
in Scheme 1). In these cases the yields were slightly lower with
respect to the previous cases (53 and 37%).
In the second part of our work, we explored the scope and the
selectivity of the reaction by using nonterminal alkenoic acids.
Irradiation of 4-chlorophenol in the presence of (E)-3-hexenoic acid
9
10670
J. AM. CHEM. SOC. 2006, 128, 10670-10671
10.1021/ja0627287 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Photoinduced Synthesis of Phenyl(benzyl) Lactones10
Table 1 and Scheme 2). In these compounds, three stereogenic
centers were simultaneously generated and the phenyl group laid
on the same side of the hydrogens of the cis ring junction, again
due to the backside attack in the ring-closure step. To the best of
our knowledge, only a single synthesis of a bicyclic aryllactone
has been previously reported and was based on a nickel-catalyzed
phenylation reaction (via trifluoroarylsilanes) of the corresponding
iodide as the final step.17
In conclusion, the electrophilic addition of a phenyl cation onto
alkenoic acids occurs efficiently and is followed by an intramo-
lecular attack by the carboxylic group. This tandem reaction has
no close precedent and results in the one-step synthesis of 4- (or,
respectively, 5-) benzyl γ- and δ-lactones from 4-pentenoic and
5-hexenoic acids, as well as (although in a lower yield) of 4-phenyl-
γ-lactones from 3-butenoic acids. Such compounds are otherwise
obtained in several steps by thermal reactions. The photoinduced
method avoids the use of expensive and labile metal catalysts, of
a high temperature,14b or of anhydrous conditions (actually water
favors the initial heterolytic step), making this an experimentally
convenient procedure. Furthermore, the intermediacy of a phe-
nonium ion imparts a strict stereoselectivity to the reaction,
supporting the synthetic significance of the proposed method.
1
Supporting Information Available: Experimental details and H
and 13C NMR spectra of compounds 14-27. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) See for example: Brown, H. C.; Kulkarni, S. V.; Racherla U. S. J. Org.
Chem. 1994, 59, 365-369 and references therein.
(2) (a) Lambert, J. D.; Rice, J. E.; Hong, J.; Hou, Z.; Yang, C. S. Bioorg.
Med. Chem. Lett. 2005, 15, 873-876. (b) Asano, M.; Inoue, M.; Katoh,
T. Synlett 2005, 2599-2602.
(3) Murahashi, S.-I.; Ono, S.; Imada, Y. Angew. Chem., Int. Ed. 2002, 41,
2366-2368.
(4) Sato, M.; Kosasayama, A.; Uchimaru, F. Chem. Pharm. Bull. 1981, 29,
2885-2892.
(5) (a) Defieber, C.; Paquin, J.-F.; Serna, S.; Carriera, E. M. Org. Lett. 2004,
6, 3873-3876. (b) Oi, S.; Moro, M.; Ito, H.; Honma, Y.; Miyano, S.;
Inoue, Y. Tetrahedron 2002, 58, 91-97.
(6) Nagumo, S.; Ishii, Y.; Kakimoto, Y.; Kawahara, N. Tetrahedron Lett.
2002, 43, 5333-5337.
(7) A related process is the Pd-catalyzed reaction of aryl bromides with
γ-hydroxy alkenes, see: Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc.
2004, 126, 1620-1621.
(8) Fagnoni, M.; Albini, A. Acc. Chem. Res. 2005, 38, 713-721.
(9) (a) Chlorides 9, 10b, and 13 did not significantly absorb at >300 nm.
Acetone sensitization was effective for 9 and 10b. (b) A convenient
medium such as 2,2,2-trifluoroethanol could not be used in this case
because it formed the corresponding trifluoroethyl esters and precluded
the formation of the lactones.
(10) General procedure: A solution of the carboxylic acid 1-5 (15 mmol, 0.5
M) and halides or esters 6-12 (1.5 mmol, 0.05 M) in MeCN-water 5:1
(30 mL) was irradiated at 310 nm (unless when otherwise stated). The
photolyzed mixture was neutralized and extracted with CH2Cl2, and the
residue was purified by column chromatography.
(11) The same reaction carried out in acetonitrile gave 5-(4-(dimethylamino)-
benzyl)-dihydro-furan-2-one in about the same yield (70%, see ref 12).
a Isolated yields. b 0.9 M acetone added. c Irradiation at 254 nm. d Halide
0.025 M. e Phenol (6%) as a byproduct. f N,N-Dimethylaniline (9%) also
formed.
(12) Mella, M.; Coppo, P.; Guizzardi, B.; Fagnoni, M.; Freccero, M.; Albini,
(E-4) gave exclusively (E)-arylethyllactone 25 (Table 1). As a
matter of fact, the process was fully stereoselective, because 25
was likewise obtained by using Z-4 in the place of E-4.
A. J. Org. Chem. 2001, 66, 6344-6352.
(13) Dichiarante, V.; Fagnoni, M.; Mella, M.; Albini, A. Chem.sEur. J. 2006,
12, 3905-3915.
The selectivity results from the facile ring closure by backside
attack in ion E+ (path a), a process that is sterically hindered in
isomeric ion Z+ from Z-4, where preliminary bond rotation is
required (see Scheme 2).15 The analogy between this finding and
the selectivity observed in the solvolysis of phenethyl derivatives,
at the time the basis for the phenonium ion proposal, is apparent.16
With 2-cyclopentenacetic acid 5, arylation and ring closure
likewise took place with full regio- and stereoselectivity, affording
hexahydrocyclopenta[b]furan-2-ones 26 (from 6) and 27 (from 7a;
(14) (a) The formation of an oxonium ion has been invoked in related cases.
See: (b) Nagumo, S.; Ono, M.; Kakimoto, Y.-I.; Furukawa, T.; Hisano,
T.; Mizukami, M.; Kawahara, N. Akita, H. J. Org. Chem. 2002, 67, 6618-
6622. (c) Manner, J. A.; Cook, J. A., Jr.; Ramsey, B. G. J. Org. Chem.
1974, 39, 1199-1203.
(15) The orthogonal staggered and planar perpendicular open-chain forms of
these cations are known to equilibrate with negligible activation energy,
see: Hehre, W. J. J. Am. Chem. Soc. 1972, 94, 5919-5920.
(16) Kirmse, W. Top. Curr. Chem. 1979, 80, 125-311.
(17) Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788-7789.
JA0627287
9
J. AM. CHEM. SOC. VOL. 128, NO. 33, 2006 10671