Photoinduced three-component reaction: A convenient access to 3-arylacetals or 3-arylketals

Article abstract of DOI:10.1021/ol802560t

(Chemical Equation Presented) A mild and versatile method for the photoinduced three-component synthesis of 3-arylacetals and ketals is presented. Desired targets are smoothly obtained by irradiating aromatic halides or esters in alcohols, in the presence

Full text of DOI:10.1021/ol802560t

ORGANIC
LETTERS
2009
Vol. 11, No. 2
349-352
Photoinduced Three-Component
Reaction: A Convenient Access to
3-Arylacetals or 3-Arylketals
Simone Lazzaroni, Stefano Protti, Maurizio Fagnoni,* and Angelo Albini
Department of Organic Chemistry, The UniVersity of PaVia, V. Taramelli 10,
27100 PaVia, Italy
fagnoni@unipV.it
Received November 6, 2008
ABSTRACT
A mild and versatile method for the photoinduced three-component synthesis of 3-arylacetals and ketals is presented. Desired targets are
smoothly obtained by irradiating aromatic halides or esters in alcohols, in the presence of vinyl ethers.
Multicomponent reactions (MCRs) are used in modern
organic chemistry for the preparation of functionalized
molecules by a cascade of chemical reactions.1 Photoinduced
MCRs are not common; one of the most representative
examples is the nucleophile-olefin-combination-aromatic-
substitution (NOCAS) process.2a This leads to a ꢀ-arylethyl
ether starting from an arylnitrile, an olefin, and an alcohol
(the solvent of the reaction). The key intermediates in this
process are radical ions and further variations based again
on such intermediates have been recently devised,2b but
photochemistry makes accessible further highly activated
intermediates potentially useful for three-component reac-
tions.
synthesis via a phenonium ion intermediate (I, Scheme 1,
path a). Unfortunately, product mixtures are obtained because
other processes compete efficiently with the desired reaction,
namely, solvent addition onto I (path a′).5 These are proton
Scheme 1. Competing Paths in the Arylation of Olefins
Phenyl cations are electrophilic intermediates that are
smoothly generated by photoinduced heterolytic cleavage of
phenyl halides and esters.3,4 We previously found that
irradiation of these aromatics in the presence of alkenes and
alcohols gave phenyl alkyl ethers through a three-component
(1) For an overview, see: Multicomponent Reactions; Zhu, J., Bienayme´,
H., Eds.; Wiley-VCH: Weinheim, 2005.
(2) (a) Mangion, D.; Arnold, D. R. Acc. Chem. Res. 2002, 35, 297–
304. (b) Lu, Z.-F.; Shen, Y.-M.; Yue, J.-J.; Hu, H.-W.; Xu, J.-H. J. Org.
Chem. 2008, 73, 8010–8015.
(3) Fagnoni, M.; Albini, A. Acc. Chem. Res. 2005, 38, 713–721
.
(4) Dichiarante, V.; Fagnoni, M. Synlett 2008, 787–800
.
10.1021/ol802560t CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society

elimination and Wagner-Meerwein rearrangements (path a′′)
driving the adduct cation I to more stabilized intermediates
(or products). On the other hand, it was demonstrated that
when an n nucleophile such as an OH or COOH group is
tethered to the alkene, a fast intramolecular attack onto
carbocationic intermediate I is highly favored and a clean
C-C, C-O tandem bond formation occurs. In this way,
ꢀ-benzyl-lactones and tetrahydrofurans have been prepared.4
This suggests that a selective three-component reaction could
be obtained also in an intermolecular fashion, provided that
the first formed adduct cation was stabilized in such a way
that other competing reactions were disfavored and addition
of the solvent predominated. It appeared reasonable that an
oxonium ion6 intermediate satisfied these requirements, and
we surmised that addition of a phenyl cation onto a vinyl
ether followed by alcohol trapping may lead to 3-arylacetals
or 3-arylketals by the tandem formation of two new bonds,
C-C and C-O (Scheme 1, path b).
Table 1. Synthesis of 3-Arylacetals 15-22 by Irradiation of
Aromatics 1-8 in the Presence of Ethyl Vinyl Ether (12)a
It should be noted that under these conditions O,O-mixed
acetals may be obtained depending on the solvent chosen.
This is an added bonus, because these derivatives have been
exploited for preferential activation of the less hindered OR
group (generally OMe) under Lewis acid catalysis. Examples
are substitution by an alkynyl group in the synthesis of
propargylic ethers7 or by a 5-fluorouracil in the preparation
of prodrugs.8
An explorative study was carried out to test the viability
and the scope of the method. The results obtained by
irradiating nitrogen flushed solutions of phenyl halides and
esters 1-8 (0.05 M) in methanol in the presence of ethyl
vinyl ether (12, 0.05 M) are reported in Table 1. Because of
the liberation of mineral acids4 in the photofragmentation
and of the limited stability of acetals under such conditions,
Cs2CO3 was added to the solution in an equimolar amount
with respect to the aromatic substrates. This protocol allowed
us to obtain good yields of the 3-aryl mixed acetals 15-22.
In Table 1 the results obtained are grouped according to
the target product. Thus, for the synthesis of 4-methoxyphe-
nyl acetaldehyde ethyl, methyl acetal (15), three aromatic
starting compounds were compared. 4-Chloroanisole (1a)
turned out to be the most effective reagent and gave the acetal
in 70% yield, whereas with 4-fluoroanisole (1b) and 4-meth-
oxyphenyl diethyl phosphate (1c), the yields were lower and
a longer irradiation time was required. With a lower amount
of the trap (0.2 M), the arylacetal was obtained in a somewhat
lower yield (53% vs 70%).
a Reaction conditions: ArX (0.05 M), 12 (0.5 M), and Cs2CO3 (0.025
M) irradiated in MeOH. b 12 (0.2 M). c 12 (1.0 M). d ArX (0.1 M).
able result also because it was obtained starting directly from
the phenols and skipping protection of the acidic OH group.
Furthermore, compound 16 was formed from 2b in a higher
yield (85%) by using 1 M 12. Compound 17, containing two
different acetal moieties, was prepared from chloride 3a and,
less satisfactorly, from phosphate 3b.
It is noteworthy that the hydroxyphenyl derivative 16 was
obtained in a good yield from both 4-chlorophenol (2a) and
4-fluorophenol (2b) under comparable conditions, a remark-
(5) See for instance: Protti, S.; Fagnoni, M.; Mella, M.; Albini, A. J.
Org. Chem. 2004, 69, 3465–3473. Lazzaroni, S.; Dondi, D.; Fagnoni, M.;
Albini, A. Eur. J. Org. Chem. 2007, 4360–4365.
N,N-Dimethylanilines 4a and 4b and aniline 5 likewise
gave mixed acetals 18 and 19 in comparable yields and in a
shorter irradiation time. Doubling the scale by using 0.1 M
chloroaniline 4a was possible with only a slight decrease of
the yield of formation of arylacetal 18. The scope of this
procedure as far as the substituents were concerned was
tested by the synthesis in reasonable yields of a 4-methylth-
(6) These intermediates have been successfully used in total organic
synthesis, e.g., for the preparation of cytotoxic Amphidinolides; see: Aı¨ssa,
C.; Riveiros, R.; Ragos, J.; Fu¨rstner, A. J. Am. Chem. Soc. 2003, 125, 15512–
15520. Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374–2375.
(7) Linderman, R. J.; Chen, S. Tetrahedron Lett. 1996, 37, 3819–3822.
(8) Saniger, E.; Campos, J. M.; Entrena, A.; Marchal, J. A.; Boulaiz,
H.; Ara´nega, A.; Gallo, M. A.; Espinosa, A. Tetrahedron 2003, 59, 8017–
8026.
350
Org. Lett., Vol. 11, No. 2, 2009

iophenyl (20) and a 4-butylphenyl (21) derivative. Dimethy-
lated chlorophenol 8 likewise gave the O,O-mixed acetal 22.
However, steric hindrance had some effect. Thus, a single
methyl group in ortho with respect to the leaving group had
no effect on the arylation, as shown by the efficient synthesis
of acetal 19 from halide 5 in methanol. With O,O′-dimethyl
phenyl chlorides such as 9 and 11, as well as the 2,4-
dimethoxyphenyl chloride 10, poor arylation yields were
obtained. In fact, under the above conditions the main process
was reduction. However, the desired arylation was obtained
when the reaction was carried out in 2,2,2-trifluoroethanol
(TFE) rather than in methanol. In this case, mixed acetals
were again obtained in yields comparable to those from
nonhindered precursors (see Table 2). The use of such an
oxypropene (13). The result was positive, and desired
dimethyl ketals 26 and 27 were obtained when using 0.5 M
of 13, although a slight excess of base (0.03 M, Cs2CO3)
was found to be required due to the lower stability of ketals
with respect to acetals. Finally, the reaction of chlorophenol
1a with 2,3-dihydrofuran (14) was explored. A fully regio-
and stereoselective arylation occurred and afforded com-
pound 28 as the cis diastereoisomer (de >98%).
The generation of triplet phenyl cations by photolysis of
electron-rich aryl halides has been previously documented,
both by experimental3,4 and by computational9,10 studies, as
has the selective reaction of these intermediates with π
nucleophiles.
The adduct cation undergoes intersystem crossing to the
singlet state, making addition of the solvent (an n nucleo-
phile) possible. The adduct is an oxonium ion, a relatively
stabilized intermediate (see structure of 29). The localization
of the charge in 29 makes attack of the solvent at the
ꢀ-carbon exclusive, in contrast to the two possible alterna-
tives in phenonium intermediate I formed from simple
alkenes (Scheme 1). Thus, in the present case attack by the
solvent yields a single product, the desired 3-arylacetal (see
Scheme 2).
Table 2. Photoinduced Synthesis of 3-Arylacetals and
3-Arylketals 23-28a
Scheme 2
.
Proposed Mechanism of the Photoinduced Formation
of 3-Arylacetals
The high 1,2-cis diastereoselectivity observed in the
formation of compound 28 reasonably results from the
preferred conformation of the intermediate tetrahydrofuran-
derived oxonium ion 30. The stereochemical outcome of the
attack of a nucleophile onto this type of intermediates has
been thoroughly studied by Woerpel and co-workers.11 In
our case, the selectivity appears to come from the “inside”
attack11 of the solvent onto conformer 30 where the aryl
group is present in equatorial position.
a Reaction conditions: ArX (0.05 M), 12-14 (0.5 M), Cs2CO3 (0.025
M) or TEA (0.05 M) irradiated in the chosen solvent. b Cs2CO3 (0.03 M).
(9) Lazzaroni, S.; Dondi, D.; Fagnoni, M.; Albini, A. J. Org. Chem.
2008, 73, 206–211
.
(10) See for example: Protti, S.; Dondi, D.; Fagnoni, M.; Albini, A.
Eur. J. Org. Chem. 2008, 2240–2247. Manet, I.; Monti, S.; Grabner, G.;
Protti, S.; Dondi, D.; Dichiarante, V.; Fagnoni, M.; Albini, A. Chem. Eur.
ion stabilizing solvent allows the use of an easy removable
base such as triethylamine (TEA). A more elaborated
molecule such as 25, where two functional groups are
protected in an orthogonal manner, was smoothly synthe-
sized. The extension of the method to the synthesis of
R-arylacetone ketals was likewise tested by using 2-meth-
J. 2008, 14, 1029–1039
.
(11) See for instance: Shaw, J. T.; Woerpel, K. A. Tetrahedron 1999,
55, 8747–8756. Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A.
J. Am. Chem. Soc. 1999, 121, 12208–12209. Bear, T. J.; Shaw, J. T.;
Woerpel, K. A. J. Org. Chem. 2002, 67, 2056–2064. Smith, D. M.; Woerpel,
K. A. Org. Lett. 2004, 6, 2063–2066.
Org. Lett., Vol. 11, No. 2, 2009
351

Studies on further aromatic precursors and computational
analyses aimed at confirming the hypotheses are in progress.
Apart from this issue, the above method allows the direct
synthesis of 3-arylacetals and 3-arylketals, in turn useful
intermediates, e.g., for the preparation of pyroglutamic
acids12 and of the anticancer agent omuralide13 (by means
of the Ugi reaction) and in combinatorial chemistry.14
3-Arylacetals(ketals) are usually prepared from precursors
containing a preformed carbon skeleton by acid-catalyzed
acetalization of the corresponding aldehydes and imines14
or by the oxidation of styrenes catalyzed by Pd(II) com-
plexes.15 Recently, a Lewis acid mediated 1,2-migration of
aryl groups in (1-alkoxy-2-iodoethyl)benzenes was also
reported.16 The preparation of these acetals through the
formation of an aryl-C bond, however, is no trivial issue
and involves two steps, the Pd-catalyzed addition of trim-
ethylsilyl acetylene onto an aryl halide and the treatment with
KOH in MeOH.17
The present method is appealing from the synthetic point
of view, since it uses cheap starting compounds (aryl
chlorides and vinyl ethers) under mild conditions (room
temperature, no transition metal catalysis). In a single
operation an aryl-C and a C-O bond are consecutively
formed. Photohydrodehalogenation of the starting aromatic
usually favored in alcoholic solvent take place to a minimal
extent because vinyl ethers are excellent nucleophiles and
readily trap the phenyl cation formed. Furthermore, the
results show that aromatic derivatives not considered suitable
for cross-coupling arylations such as phosphate esters18 and
especially fluorides19 can be efficiently used. Finally, these
reactions occur in alcohols, which are considered to be good
solvents from a green synthetical chemistry point of view.20
Acknowledgment. Partial support of this work by MURST,
Rome is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and analytical data for compounds 3b and 15-28.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Isaacson, J.; Gilley, C. B.; Kobayashi, Y. J. Org. Chem. 2007, 72,
3913–3916. Vatmos, M.; Ozboya, K.; Kobayashi, Y. Synlett 2007, 1595–
1599.
(13) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631–
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OL802560T
(14) Todd, M. H.; Olivier, S. F.; Abell, C. Org. Lett. 1999, 1, 1149–
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(15) Hosokawa, T.; Ohta, T.; Kanayama, S.; Murahashi, S. J. Org. Chem.
1987, 52, 1758–1764. Jiang, H.-F.; Shen, Y.-X.; Wang, Z.-Y. Tetrahedron
2008, 64, 508–514.
(18) Protti, S.; Fagnoni, M. Chem. Commun. 2008, 3611–3621.
(19) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem.,
Int. Ed. 2005, 44, 7216–7219.
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(16) Fan˜ana´s, F. J.; Alvarez-Pe´rez, M.; Rodr´ıguez, F. Chem. Eur. J. 2005,
(20) Capello, C.; Fischer, U.; Hungerbu¨lher, K. Green Chem. 2007, 9,
927–937. Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.;
Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.;
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(17) See for example Tischler, A. N.; Lanza, T. J. Tetrahedron Lett.
1986, 27, 1653–1656.
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