Photochemical arylation of alkenols: Role of intermediates and synthetic significance

Article abstract of DOI:10.1002/ejoc.200701177

A one-pot, tandem synthesis of cyclic ethers is obtained by addition of photogenerated phenyl cations to hydroxyalkenes. Thus, 2- (or 3-) phenyl-substituted tetrahydrofurans were prepared by irradiation of 4-chloro-N,N-dimethylaniline, -anisole, and -phenol with β-hydroxyalkenes and 2-benzyltetrahydrofurans with λ-hydroxyalkenes. With nonterminal alkenes [diastereomeric (E)- and (Z)-3-hexen-1-ols] trans-2-ethyl-3- aryltetrahydrofuran derivatives were stereoselectively formed from both isomers. The output of the photoreaction is structure and solvent dependent and is rationalized through the intermediacy of a phenonium ion from the addition of the primarily formed triplet phenyl cation to the alkenol double bond. Intramolecular addition of the OH group to form benzyl (aryl) tetrahydrofurans is favored in polar protic solvents, where hydride shifts to form aryltetrahydropyrans also occur, whereas in ethyl acetate, intermolecular addition of the chloride anion to the phenonium ion takes place. The mechanism of the above reactions is also discussed on the basis of computational data. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701177

FULL PAPER
DOI: 10.1002/ejoc.200701177
Photochemical Arylation of Alkenols: Role of Intermediates and Synthetic
Significance
Stefano Protti,*[a] Daniele Dondi,[b] Maurizio Fagnoni,[a] and Angelo Albini[a]
Keywords: Aromatic substitution / Cations / Oxygen heterocycles / Phenonium ion / Photochemistry
A one-pot, tandem synthesis of cyclic ethers is obtained by
addition of photogenerated phenyl cations to hydroxy-
alkenes. Thus, 2- (or 3-) phenyl-substituted tetrahydrofurans
were prepared by irradiation of 4-chloro-N,N-dimethyl-
aniline, -anisole, and -phenol with β-hydroxyalkenes and 2-
benzyltetrahydrofurans with γ-hydroxyalkenes. With non-
terminal alkenes [diastereomeric (E)- and (Z)-3-hexen-1-ols]
trans-2-ethyl-3-aryltetrahydrofuran derivatives were stereo-
selectively formed from both isomers. The output of the pho-
toreaction is structure and solvent dependent and is rational-
ized through the intermediacy of a phenonium ion from the
addition of the primarily formed triplet phenyl cation to the
alkenol double bond. Intramolecular addition of the OH
group to form benzyl (aryl) tetrahydrofurans is favored in
polar protic solvents, where hydride shifts to form aryltetra-
hydropyrans also occur, whereas in ethyl acetate, inter-
molecular addition of the chloride anion to the phenonium
ion takes place. The mechanism of the above reactions is also
discussed on the basis of computational data.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
a synthetic strategy based on 1,2-aryl migration via phe-
nonium ion was applied to the total synthesis of some phe-
nolic sesquiterpenes.[9]
Introduction
The steric course of the solvolysis of 2-phenylethyl-1-tos-
ylates and the rearrangements involved were rationalized
more than half a century ago by Cram[1] through the inter-
mediacy of a σ-bridged ethylenebenzenium cation (phe-
nonium ion). The formation of this intermediate was later
supported by NMR spectroscopic characterization in su-
peracidic media.[2] Further studies[3] on the acetolysis of
some β-arylethyltosylates demonstrated that both stereo-
selectivity and rate of the reaction were affected by ring
substituents.[4] In particular, electron-donating groups such
as the methoxy group induced complete stereoselectivity,
which supports the role of the phenonium ion.
Interest in this intermediate, from both a mechanistic
and a preparative point of view, has continued. Computa-
tional evidence for the role of the bridged cation and the
effect of substituents has been recently reported by Sordo
et al.[5] As for the synthetic applications of this carbocation,
recent examples are the ring-contraction reactions of 2-
phenyltetrahydropyrans to give 2-benzyltetrahydrofurans[6]
and the lactonization that occurs either upon solvolysis of
4-aryl-5-tosyloxypentanoates[7] or by treatment of 4-aryl-4-
pentenoic acid with hypervalent iodine reagents.[8] Recently,
An alternative access to this intermediate is possible
either by protonation of benzocyclobutene in superacidic
media[10] or by addition of a triplet phenyl cation to an
alkene.[11] The latter approach has been recently developed
by our group[11] and involves the photoheterolysis of either
a carbon–halogen bond in electron-rich aryl chlorides such
as 4-chlorophenol[12] and 4-chloroaniline[11] or of a carbon–
oxygen bond (in the corresponding aryl sulfonates and
phosphates).[13] Thus, irradiation of such precursors gave
the bridged cation II (in the singlet state, Scheme 1) by ad-
dition of triplet phenyl cation (I) to a double bond and
intersystem crossing (ISC).[11,14] The intermediacy of phe-
nonium II was confirmed by flash photolysis experiments,
which revealed the addition of photogenerated 4-hy-
droxyphenyl cation (EDG = OH, Scheme 1) to 2-prope-
nol.[12]
The structure of the end products depended on the com-
peting paths occurring at the phenonium ion level, such as
the addition of a nucleophile (the halide counterion[14–16] or
the solvent;[14,15,17] Scheme 1, paths a, b), the elimination of
a good electrofugal group[14,18,19] (H+ or Me3Si+; Scheme 1,
path c), and the possible occurrence of a Wagner–Meerwein
rearrangement[1,15,20,21] (Scheme 1, path d).
[a] Department of Organic Chemistry, University of Pavia,
Via Taramelli 10, 27100 Pavia, Italy
Fax: +39-0382-987323
E-mail: prottistefano@gmail.com
The method is appealing because the phenonium ion is
generated under mild neutral conditions and thus can be
more easily directed towards the desired preparative target.
However, in order to exploit the synthetic potential of the
reactions via phenonium ions, the rationalization and thus
[b] Department of General Chemistry, University of Pavia,
Via Taramelli 12, 27100 Pavia, Italy
Fax: +39-0382-528544
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Photochemical Arylation of Alkenols
reactions in solvents of different polarity [ethyl acetate,
MeCN/H2O (5:1), and 2,2,2-trifluoroethanol (TFE)].
Solutions (0.05 ) of 1 in the presence of the chosen alk-
enol (0.5 ) were externally irradiated up to complete con-
sumption of the starting aromatic (except where indicated)
and the reaction course was monitored by GC analysis. Cy-
clic or open-chain arylated products obtained from alkenes
2 and 3 are reported in Tables 1 and 2 and Schemes 2 and
3. Not included are the photoreactions of 4-chlorophenol
(1-OH) in ethyl acetate (too slow) and that with 2 in TFE
(a complex mixture is formed). Thus, phenol 1-OH gave 2-
(4-hydroxyphenyl)tetrahydrofuran 5-OH as the only iso-
lated product in 67% yield in the reaction with 2 in MeCN/
H2O (5:1) and gave again a single product, 2-(4-hy-
droxybenzyl)tetrahydrofuran 6-OH, in the reaction with 3
both in TFE and MeCN/H2O (5:1). The preparative viabil-
ity of the method was checked by synthesizing compound
6-OH on a larger scale (4.5 mmol) by using an immersion-
well apparatus, and it was easily isolated in 84% yield by
bulb-to-bulb distillation (see Experimental Section).
Scheme 1. Photochemical generation and fate of a phenonium ion.
Table 1. Photolysis of aryl chlorides 1 in the presence of alkenol 2.
the control of the competition between the above paths is
required. A way to tackle this problem was by using a bi-
functional trap containing two different nucleophilic sites.
Previous work showed that triplet phenyl cations react with
π and not with n nucleophilic functionalities. Thus, by using
an alkene containing a nucleophile, for example, an alcohol
functionality, the reaction should afford a phenonium ion
that would then undergo intramolecular attack by the hy-
droxy group. We first explored this strategy by irradiating
phenyl cation precursors in the presence of alkenoic acids,
and indeed we obtained phenyl (benzyl) lactones in a tan-
dem reaction in a number of cases.[22] This result had some
synthetic appeal and understanding the scope of this ap-
proach seemed convenient. As a contribution towards this
target, we report here a study of the reaction of photo-
generated phenyl cations with selected alkenols under vari-
ous conditions. It was hoped that the cations would add
again to the C=C bond and intramolecular trap by the OH
group would then occur in competition with intermolecular
reactions. Accordingly, the chemistry observed and the me-
dium effect on it would give information about the behavior
of the phenonium ion.
[a] No significant reaction of 1-OH. [b] Complex mixture.
Table 2. Photolysis of aryl chlorides 1 in the presence of alkenol 3.
[a] No significant reaction of 1-OH. [b] Reaction carried out in an
immersion-well reactor.
Results
We chose, as phenyl cation precursors, some phenyl chlo-
rides, viz. 4-chlorophenol (1-OH), 4-chloroanisole (1-OMe),
4-Chloroanisole (1-OMe) and 4-chloro-N,N-dimethylani-
and 4-chloro-N,N-dimethylaniline (1-NMe2) and as traps line (1-NMe2) were found to react efficiently in all of the
two ω-alkenols, namely, 3-buten-1-ol (2) and 4-penten-1-ol solvents tested, but the products formed were dependent on
(3), and two 1,2-disubstituted derivatives, viz. stereoiso- the medium. Thus, irradiation of compound 1-OMe in the
meric (E)- and (Z)-3-hexen-1-ol [(E)-4 and (Z)-4, respec- presence of 2 gave 3-chloro-4-(4-methoxyphenyl)butan-1-ol
tively] in order to have information on the regio- and stereo- (7-OMe) in ethyl acetate, 2-(4-methoxyphenyl)tetrahydro-
chemical course of the reaction. In view of the ionic nature furan (5-OMe) in MeCN/H2O (5:1), and a mixture of 7-
of the intermediates, it appeared important to explore these OMe and 5-OMe (the latter being the main product) in
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S. Protti, D. Dondi, M. Fagnoni, A. Albini
FULL PAPER
trans-tetrahydrofurans 10-OH and 10-NMe2, respectively)
in the presence of both (E) and (Z)-4 in all of the solvents
tested. In the case of chloroanisole 1-OMe, however, trans
(10-OMe) and cis (11-OMe) tetrahydrofurans were ob-
tained as a equal-ratio mixture of (E) and (Z)-4 in TFE and
MeCN/H2O, whereas only the trans isomer 10-OMe was
obtained in ethyl acetate.
Table 3. Photolysis of aryl chlorides 1 in the presence of (Z)- or
(E)-3-hexen-1-ol (4).
Scheme 2. Irradiation of aryl chlorides 1 in the presence of 3-buten-
1-ol (2).
[a] No significant reaction of 1-OH.
Scheme 3. Irradiation of 1 in the presence of 4-penten-ol (3).
TFE. The reaction between 1-OMe and 3 gave 2-(4-meth-
oxybenzyl)tetrahydrofuran (6-OMe) and 2-(4-methoxy-
phenyl)tetrahydropyran (8-OMe) in MeCN/H2O and TFE,
as well as 6-OMe (43%) along with open-chain derivative
9-OMe (29%) in ethyl acetate.
Scheme 4. Irradiation of aryl chlorides 1 in the presence of alkenols
(E)-4 and (Z)-4.
The experiments were supplemented by computational
With alkenol 2, 2-(4-N,N-dimethylaminophenyl)tetra- work. The geometry and energy of some phenonium ions
hydrofuran (5-NMe2) and 3-chloro-4-phenylbutanol (7- modeling the putative intermediates in the above arylation
NMe2) were formed in each case; the latter was predomi- of alkenes by the addition of substituted phenyl cations
nant in ethyl acetate and the former was the almost-exclus- were calculated by the DFT method at the B3LYP 6-31G(d)
ive product in TFE. With 3, 2-(4-N,N-dimethylamino- level (see Supporting Information). The key geometric pa-
benzyl)tetrahydrofuran (6-NMe2) and 2-(4-N,N-dimethyl- rameters for the adducts formed by the 4-methoxyphenyl
aminophenyl)tetrahydropyran (8-NMe2) were found, and cation with ethylene and propene are reported in Table 4,
the former was consistently the predominating species.
as well as those from phenyl and 4-aminophenyl cation with
The explorative study was pursued by irradiating aryl propene and from phenyl, 4-methoxy-, and 4-aminophenyl
chlorides 1 in the presence of two diastereomeric alkenols, cation with 2-butene [in this case the bond length did not
viz. (E)- and (Z)-3-hexen-1-ols (4) as shown in Table 3 and differ when starting from either the (E) or the (Z) isomer].
Scheme 4. Thus, with 1-OH and 1-NMe2, the arylation oc- The substituent effect was evaluated by calculating the free
curred efficiently and afforded a single diastereoisomer (the energy associated with the isodesmic reaction shown in
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Photochemical Arylation of Alkenols
Table 4. C–C Distances for the phenonium ions formed by the addition of phenyl cations to olefins.
Entry
FG
R1
R2
d(C1–C2) [Å]
d(C1–C3) [Å]
Relative free energies[a] [kcal/mol]
1
2
3
4
5
6
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
1.63
1.59
1.58
1.58
1.58
1.58
1.67
1.67
1.63
1.63
1.61
1.61
1.63
1.59
1.58
1.76
1.65
1.62
1.67
1.67
1.63
1.63
1.61
1.61
0
OCH3
NH2
H
OCH3
NH2
H
–11.5
–14.2
0
–10.1
–12.3
0
–0.5
–9.61
–10.3
–11.4
–12.3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
7[b]
8[c]
9[b]
10[c]
11[b]
12[c]
H
OCH3
OCH3
NH2
NH2
[a] Evaluated in MeCN. [b] From (Z)-2-butene. [c] From (E)-2-butene.
Scheme 5 and is likewise reported in Table 4. The data show
that the phenonium ion was stabilized by ca. 10 kcal/mol
by a 4-OMe group and by a further 2–3 kcal/mol by a 4-
NH2 group both when the phenyl cation added to ethylene
and when it added to 2-butene,[23] as evidenced also by the
considerable shortening of the C1–C2 and C1–C3 bond
lengths in the adduct with butene when passing from FG =
H to FG = NH2.
Scheme 5.
The attack of the parent phenyl cation to propene gave
a highly asymmetric adduct, with a very weak C1–C3 bond.
However, an electron-donating group considerably short-
ened that bond and stabilized the phenonium structure
(Table 4).
Discussion
The photochemical generation of phenyl cations has
been discussed previously. With a chlorinated phenol, ani-
sole, or aniline, intersystem crossing to give the triplet is
known to be efficient (ΦISC Ͼ 0.8),[24] and heterolysis of the
aryl chloride bond in polar media[11] occurs from that state
forming the triplet cation (Scheme 6). With all of the pres-
ent derivatives, the phenyl cation was conveniently gener-
ated, except for the case of 4-chlorophenol, which under-
went photofragmentation in polar protic media[12,25a] but
was quite photostable in ethyl acetate.
Scheme 6. Mechanism of addition of phenyl cation to ω-alkenols 2
and 3.
acetate, fragmentation gives an intimate phenyl cation–chlo-
Addition to the alkenols occurs selectively at the C=C ride ion pair (12), and adduct 13 is formed when still closely
bond in a stepwise fashion, as expected because the triplet coupled with the chloride anion to give the corresponding
phenyl cation is the attacking species. From the single- chloroalcohol as the end product (Scheme 6, path a). In
bonded intermediate, intersystem crossing and formation of contrast, when the phenyl cation is generated in an ion-
a second C–C bond may then lead to a phenonium ion as stabilizing medium such as MeCN/H2O (5:1) or TFE, a sol-
a further intermediate,[25b] unless cyclization on the OH vent penetrated pair or free solvated ions (14) are formed,
group occurs first.
and the reaction of the phenyl cation with alkenols is fol-
Considering first the reaction with terminal alkenols, it lowed by intramolecular attack by the OH group. This in-
was noticed that the nucleophile that added was dependent volves exclusive attack at the methine group (Scheme 6,
on the medium. In a moderately polar solvent such as ethyl path b) and not at the methylene group (Scheme 6, path c);
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S. Protti, D. Dondi, M. Fagnoni, A. Albini
FULL PAPER
this is in competition with hydride shift to give the more
Thus, in the key step the C2–C3 bond can freely rotate
stable benzyl cation (16) before nucleophilic attack (Scheme 7), in accord with the idea that the first intermedi-
(Scheme 6, path d). ate from the triplet cation is single-bonded (formulae 17/
The result is both medium and structure dependent. 17Ј) and ISC and intramolecular cyclization on the OH
Thus, in the photoreaction between 4-chloroanisole and group follow. Should a doubly bonded (phenonium) cation
pentenol (n = 2 in Scheme 6) the products observed arise be the first intermediate, a stereospecific arylation would
from paths a and b in a ratio 40:60 in AcOEt, b/d (62:38) take place,[1,4] as equilibration of stereoisomeric phenonium
in MeCN/H2O, and b/d (44:56) in TFE, whereas the same ions over an open-chain isomer is too slow.[28] The exclusive
reaction with aniline 1-NMe2 yields only products from formation of the trans isomers is determined by the steric
paths b and d (95:5, 91:9, and 95:5 in ethyl acetate, MeCN/ hindering by the ethyl group. However, with 1-OMe, cis
H2O, and TFE, respectively). The role of path a from the tetrahydrofuran 11-OMe is also formed, at least in polar
caged pair is expected to diminish on going to more polar solvents (10-OMe/11-OMe, 100:0 in ethyl acetate, 61:39 in
solvents, whereas the other differences are informative TFE), but the trans–cis ratio is the same starting from either
about the role of the adduct ion. Two factors play a role alkene. Thus, the single-bonded adduct is again the first in-
in the determination: donation from the substituent on the termediate, but the less-donating methoxy group does not
aromatic ring and weakening of the C1–C3 cyclopropane sufficiently stabilize the cation to make attack by the OH
bond by alkyl substituents (see above). Table 4 shows that group occur at the less-hindered side (Scheme 7).
the cyclopropane ring in these phenonium ions is highly
asymmetric (structure 15), which is in accord with exclusive
cyclization at C3.
Furthermore, the more localized the charge at C3, the
more likely a hydride shift will occur (Scheme 6, path d).
This is minimal for the reactions of chloroaniline in an ion-
stabilizing solvent, in which the large donation by the ami-
nophenyl group strengthens the C1–C3 bond, and under
these conditions, path b (Scheme 6) is almost the only pro-
cess. However, when either the substituent is a less-donating
group, such as the methoxy group, or the medium is less
stabilizing, charge localization and thus the role of path d
(Scheme 6) increases. The polarity/nucleophilicity of the
solvent then determines whether it is path a or b that com-
petes with d (Scheme 6).
In contrast, the seemingly appealing formation of β-aryl-
tetrahydrofurans from butenol by attack at the methylene
group (Scheme 6, path c) does not take place, even though
path b is precluded, as it would lead to an unstable four-
membered ring. In this case, rearrangement to 16 is the only
process competing with the in-cage-occurring coupling
(with Cl–), which demonstrates once again that electrophilic
reactivity resides at C3. As above, the proportion between
paths b/d vs. a (Scheme 6) is tuned by the solvent: the first
Scheme 7. Proposed mechanism for the addition of phenyl cations
onto alkenols 4.
Conclusions
The phenylation of alkenes by triplet phenyl cations was
process dominates in TFE and MeCN/H2O[26] and the lat- studied with regard to the possible role of a phenonium ion,
ter is by far the main path in ethyl acetate.
which is the intermediate previously invoked in the substitu-
As for 1,2-disubstituted alkenes, calculations show that tion of phenethyl derivatives. Evidence about this point was
bonds to the phenyl cation are weaker and the C1–C2 and obtained through the competition of different reactions that
C1–C3 distances are considerably lengthened with respect to act as “chemical clocks”, as indicated in formulae 18 (aris-
the unsubstituted ethylene [1.59 vs. 1.63 Å in the case of the ing from the attack of the phenyl cation on terminal olefins)
methoxyphenyl derivative; compare Entry 2 with 9(10) in and 19 (from 1,2-disubstituted alkenes). In the first case,
Table 4].[5] Again, a good electron-donating substituent sta- intramolecular nucleophile trapping, kOH (or, in less polar
bilizes the phenonium and shortens the bonds (1.67 Å for solvents, addition of paired chloride, kCl) is faster than hy-
FG = H, 1.61 Å for FG = NH2 for 2-butene). With alkenes dride shift, kH,[29] when the tether has the appropriate
(Z)- and (E)-4, the geometrically favored attack at C2 is the length (n = 2). The reverse is true when the tether is too
only process occurring and leads to 3-aryltetrahydrofurans. short (n = 1, kH Ͼ kOH) in protic solvents, whereas intermo-
In addition to the reaction being chemoselective, it is also lecular chloride attack (kCl) remains predominant in aprotic
fully stereoselective when phenol 1-OH and chloroaniline solvent. A stabilized phenonium (kPh, see formula 19) is not
1-NMe2 are used, and only the trans isomers 10-OH and the first intermediate and is preceded by a singly bonded
10-NMe2 are formed by starting from both (E)- and (Z)- triplet adduct cation where the C2–C3 bond can freely rotate
hexenols.[27]
(krot Ͼ kPh), as shown by the stereoselective addition to 4.
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Photochemical Arylation of Alkenols
and halides 1-OH and 1-OMe are commercially available and were
freshly distilled before use. Aryl chloride 1-NMe2 was obtained
from 4-chloroaniline as described previously.[37]
General Procedure for the Photochemical Arylation of Alkenols 2–4:
A solution of halides 1 (0.05 , 1.5 mmol) and alkenol 2–4 (0.5 ,
15 mmol) in the solvent chosen (30 mL) was poured into two
quartz tubes and purged for 10 min with nitrogen, serum capped,
and irradiated with six 15-W phosphor-coated lamps (emission
centered at 310 nm). The solvent was eliminated in vacuo, and the
residue was purified by column chromatography (cyclohexane/ethyl
acetate).
Irradiation of 4-Chlorophenol (1-OH) in MeCN/H2O (5:1) in the
Presence of 3-Buten-1-ol (2): A solution of 4-chlorophenol (1-OH;
193 mg, 1.5 mmol) and 3-buten-1-ol (2; 1.3 mL 15 mmol) in
MeCN/H2O (5:1, 30 mL) was irradiated for 14 h. Purification by
column chromatography (cyclohexane/ethyl acetate, 9:1) afforded
2-(4-hydroxyphenyl)tetrahydrofuran (5-OH;[38] 165 mg, 67%) as an
oil. 1H NMR (300 MHz, CDCl3): δ = 6.75–7.15 (AAЈBBЈ, 4 H),
5.00 (br. s, 1 H), 4.80–4.85 (t, J = 7.0 Hz, 1 H), 4.05–4.15 (q, J =
7.0 Hz, 1 H), 3.90–4.00 (q, J = 7.0 Hz, 1 H), 2.35–2.45 (m, 1 H),
1.90–2.10 (m, 2 H), 1.75–1.85 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 154.7, 135.1, 127.1 (CH), 115.0 (CH), 80.4 (CH), 68.4
This addition of a triplet phenyl cation to alkenes differs
from the thermal generation of the phenonium ion by het-
erolytic cleavage of phenethyl derivatives.
Apart from the mechanistic indications, the above reac-
tion of phenyl cations with alkenols is synthetically useful
as an alternate method for preparing 2- (or 3) phenyl-sub-
stituted tetrahydrofurans (from β-hydroxyalkenes) and 2-
benzyltetrahydrofurans (from γ-hydroxy alkenes). These
targets are obtained by means of a one-step, tandem Ar–C,
C–O bond reaction that has no close precedent and gives
access to a class of tetrahydrofuran derivatives having po-
tential biological interest.[30] As it appears from a recent
review,[31] benzyltetrahydrofurans have been obtained by re-
action of aryl bromides (and not of chlorides, as here) with
substituted γ-hydroxy alkenes only in the presence of a pal-
ladium-based catalyst and a phosphane derivative as cocat-
alyst[32] or by a nickel-catalyzed reaction of aryl boronic
acids with 2-bromomethyltetrahydrofuran.[33] As for aryl
tetrahydrofurans, these were synthesized by metal-catalyzed
arylation of cis-2-butene-1,4-diol by an aryl halide[34] or di-
rectly from tetrahydrofuran[35a] or its 2-benzenesulfonyl[35b]
or 2-(1-benzotriazol-1-yl)[35c] derivatives in the reaction
with aryl Grignard reagents.
In contrast to the drastic conditions of the thermal reac-
tions, the present synthesis is carried out at room tempera-
ture and makes no use of expensive and labile metal cata-
lysts; it also does not require strictly anhydrous conditions,
and water actually favors the initial heterolytic step. Indeed,
aqueous acetonitrile can be used as the reaction solvent in
the place of the more expensive TFE and, noteworthy, with
no competitive addition of nucleophilic water to the phe-
nonium ion intermediates.[36] The selectivity is also an im-
portant issue, as with terminal alkenols the overall process
of carboetherification is regio- and chemoselective (the lat-
ter can be tuned through the choice of the solvent). With
nonterminal alkenols, the process is chemo- and stereoselec-
tive and affords a phenyl tetrahydropyran as a single dia-
stereoisomer.
(CH ), 34.3 (CH ), 25.9 (CH ) ppm. IR (neat): ν = 3401, 2960,
˜
2
2
2
1617, 1234, 1041, 814 cm–1. C10H12O2 (164.08): calcd. C 73.15, H
7.37; found C 73.3, H 7.5.
Irradiation of 1-OH in MeCN/H2O (5:1) in the Presence of 4-
Penten-1-ol (3): A solution of 1-OH (193 mg, 1.5 mmol) and 4-
penten-1-ol (3; 1.53 mL, 15 mmol) in MeCN/H2O (5:1, 30 mL) was
irradiated for 14 h. Purification by column chromatography af-
forded 4-(4-hydroxybenzyl)tetrahydrofuran (6-OH;[38] 210 mg,
79%) as an oil. Product 6-OH was synthesized on a larger scale
starting from a solution of 1-OH (580 mg, 4.5 mmol) and 3 (0.3 ,
2.76 mL, 27 mmol) in MeCN/H2O (5:1, 90 mL) by irradiation for
6 h in an immersion-well apparatus. The photolyzed solution was
evaporated, and the residue was purified by bulb-to-bulb distil-
1
lation to give 6-OH (666 mg, 84%). H NMR (300 MHz, CDCl3):
δ = 6.70–7.15 (AAЈBBЈ, 4 H), 6.50 (br. s, 1 H), 4.05–4.15 (quint.,
J = 7 Hz, 1 H), 3.90–4.00 (m, 1 H), 3.75–3.80 (m, 1 H), 2.75–2.90
(dd, J = 7 and 13 Hz, 1 H), 2.65–2.70 (dd, J = 7 and 13 Hz, 1 H),
1.80–2.00 (m, 3 H), 1.50–1.70 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 154.4, 130.2, 130.1 (CH), 115.2 (CH), 80.4 (CH), 67.7
(CH ), 40.8 (CH ), 30.8 (CH ), 25.4 (CH ) ppm. IR (neat): ν =
˜
2
2
2
2
3338, 2956, 1517, 1240, 822 cm–1. C11H14O2 (178.1): calcd. C 74.13,
H 7.92; found C 74.3, H 7.8.
Irradiation of 4-Chloroanisole (1-OMe) in Ethyl Acetate in the Pres-
ence of 3-Buten-1-ol (2): A solution of 4-chloroanisole (1-OMe;
200 µL, 1.5 mmol) and 3-buten-1-ol (2; 1.28 mL, 15 mmol) in ethyl
acetate (30 mL) was irradiated for 36 h. Purification by column
chromatography (cyclohexane/ethyl acetate, 99:1) afforded 3-
chloro-4-(4-methoxyphenyl)-butan-1-ol (7-OMe;[39] 222 mg, 59%)
1
as an oil. H NMR (300 MHz, CDCl3): δ = 6.75–7.15 (AAЈBB, 4
H), 4.20–4.30 (m, 1 H), 3.80–3.95 (t, J = 8 Hz, 2 H), 3.80 (s, 3 H),
2.95–3.00 (dd, J = 8 and 2 Hz, 2 H), 2.05–2.15 (m, 1 H), 1.80–1.95
(m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.3, 129.9 (CH),
128.8, 113.1 (CH), 59.9 (CH), 59.0 (CH2), 54.4 (CH3), 43.5 (CH2),
Experimental Section
39.0 (CH ) ppm. IR (neat): ν = 3369, 2924, 1614, 1223, 1058,
˜
2
General: NMR spectra were recorded with a 300 MHz spectrome-
821 cm–1. C11H15ClO2 (214.08): calcd. C 61.54, H 7.04; found C
1
ter. The attributions were made on the basis of H and 13C NMR,
61.4, H 7.2.
as well as DEPT-135 and NOESY experiments; chemical shifts are
reported downfield from TMS. The photochemical reactions were
performed by using nitrogen-purged solutions in quartz tubes and
a multilamp reactor fitted with six 15-W phosphor coated lamps
(maximum emission of 310 nm) for the irradiation. Alcohols 2–4
Irradiation of 4-Chloroanisole (1-OMe) in MeCN/H2O (5:1) in the
Presence of 2: A solution of 4-chloroanisole (1-OMe; 200 µL,
1.5 mmol) and 3-buten-1-ol (2; 1.28 mL, 15 mmol) in MeCN/H2O
(5:1, 30 mL) was irradiated for 24 h. Purification by column
Eur. J. Org. Chem. 2008, 2240–2247
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2245

S. Protti, D. Dondi, M. Fagnoni, A. Albini
FULL PAPER
chromatography (cyclohexane/ethyl acetate, 99:1) afforded 2-(4-
for 10 h. Purification by column chromatography (cyclohexane/
methoxyphenyl)tetrahydrofuran (5-OMe; 122 mg, 46%) as an oil.
ethyl acetate, 9:1) afforded 5-NMe2 (123 mg, 43%). 1H NMR
1H NMR[40] (300 MHz, CDCl3): δ = 6.80–7.30 (AAЈBBЈ, 4 H), (300 MHz, CDCl3): δ = 6.80–7.20 (AAЈBBЈ, 4 H), 4.80–4.90 (t, J
4.80–4.90 (t, J = 7 Hz, 1 H), 4.05–4.15 (q, J = 7 Hz, 1 H), 3.85–
3.95 (m, 1 H), 3.80 (s, 3 H), 2.10–2.20 (m, 1 H), 2.00–2.05 (m, 2
= 7 Hz, 1 H), 4.00–4.10 (m, 1 H), 3.90–3.95 (m, 1 H), 2.95 (s, 6
H), 2.20–2.25 (m, 1 H), 2.00–2.15 (m, 2 H), 1.80–1.90 (m, 1 H)
H), 1.90–1.95 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = ppm. 13C NMR (75 MHz, CDCl3): δ = 150.0, 130.8, 126.7 (CH),
158.7, 135.2, 126.8 (CH), 113.6 (CH), 80.3 (CH), 68.3 (CH2), 55.1
112.5 (CH), 80.6 (CH), 68.2 (CH2), 40.7 (CH3), 34.1 (CH2), 26.0
(CH ), 34.3 (CH ), 25.9 (CH ) ppm. IR (neat): ν = 2933, 1488,
(CH ) ppm. IR (neat): ν = 3300, 2930, 1772, 1167, 819 cm–1.
˜
˜
3
2
2
2
1246, 1039, 843 cm–1. C11H14O2 (178.1): calcd. C 74.13, H 7.92;
C12H17NO (191.13): calcd. C 75.35, H 8.96; found C 75.2, H 8.8.
found C 74.2, H 7.8.
Irradiation of 1-NMe2 in MeCN/H2O (5:1) in the Presence of 3: A
solution of 4-chloro-N,N-dimethylaniline (1-NMe2; 233 mg,
1.5 mmol) and 4-penten-1-ol (3; 1.53 mL, 15 mmol) in MeCN/H2O
(5:1, 30 mL) was irradiated for 6 h. Purification by column
chromatography (cyclohexane/ethyl acetate, 9:1) afforded a mixture
Irradiation of 1-OMe in Ethyl Acetate in the Presence of 4-Penten-
1-ol (3): A solution of 4-chloroanisole (1-OMe; 200 µL, 1.5 mmol)
and 4-penten-1-ol (3; 1.53 mL, 15 mmol) in ethyl acetate (30 mL)
was irradiated for 36 h. Purification by column chromatography
(cyclohexane/ethyl acetate, 99:1) afforded 4-(4-methoxybenzyl)- of
tetrahydrofuran (6-OMe;[41] 124 mg, 43%) and 4-chloro-5-(4-meth-
oxyphenyl)pentan-1-ol (9-OMe; 99 mg, 29%) as an oil. Data for 6-
OMe: 1H NMR (300 MHz, CDCl3): δ = 6.80–7.20 (AAЈBBЈ, 4 H),
3.85–4.15 (m, 2 H), 3.80 (s, 3 H), 3.70–3.75 (m, 1 H), 2.85–2.90
(dd, J = 6 and 13 Hz, 1 H), 2.70–2.75 (dd, J = 6 and 13 Hz, 1 H),
2.05–2.10 (m, 1 H), 1.65–1.95 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 157.9, 131.0, 130.0 (CH), 113.6 (CH), 80.1 (CH), 67.8
(CH2), 55.1 (CH3), 40.9 (CH2), 30.8 (CH2), 25.5 (CH2) ppm. IR
2-(4-N,N-dimethylaminobenzyl)tetrahydrofuran
(6-NMe2,
169 mg, 50%) and 2-(4-N,N-dimethylaminophenyl)tetrahydropyran
(8-NMe2, 5%). Spectroscopic data of compounds 6-NMe2 and 8-
NMe2 are in accordance with the literature data.[43]
Irradiation of 1-OH in MeCN/H2O (5:1) in the Presence of (E)-3-
Hexen-1-ol (4): A solution of 4-chlorophenol (1-OH; 0.05 ,
193 mg, 1.5 mmol) and (E)-3-hexen-1-ol (4; 0.5 , 1.78 mL,
15 mmol) in MeCN/H2O (5:1, 30 mL) was irradiated for 14 h to
give trans-2-ethyl-3-(4-hidroxyphenyl)tetrahydrofuran (10-OH,
161 mg, 0.84 mmol, 56%) as a colorless solid. M.p. 81–82 °C. The
same reaction carried out in the presence of (Z)-3-hexen-1-ol (4;
0.5 ) gave again compound 10-OH (53%). 1H NMR (300 MHz,
CDCl3): δ = 6.80–7.10 (AAЈBBЈ, 4 H), 5.50 (br. s, 1 H), 4.00–4.10
(m, 2 H), 3.70–3.75 (m, 1 H), 2.95–3.00 (q, J = 8 Hz, 1 H), 2.35–
2.40 (m, 1 H), 2.05–2.10 (m, 1 H), 1.50–1.60 (m, 2 H), 0.95–1.00
(t, J = 8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.3,
133.8, 128.6 (CH), 115.3 (CH), 87.4 (CH), 67.3 (CH2), 49.9 (CH),
(neat): ν = 2933, 1513, 1242, 1037, 826 cm–1. C H O (192.12):
˜
12 16
2
1
calcd. C 74.97, H 8.39; found C 74.8, H 8.3. Data for 9-OMe: H
NMR (300 MHz, CDCl3): δ = 6.85–7.10 (AAЈBBЈ, 4 H), 4.00–4.20
(t, J = 6 Hz, 2 H), 3.80 (s, 3 H), 3.00–3.10 (m, 1 H), 1.60–2.00 (m,
6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.4, 130.2 (CH),
129.6, 113.7 (CH), 64.0 (CH), 63.4 (CH2), 55.1 (CH3), 44.0 (CH2),
33.7 (CH), 25.6 (CH ) ppm. IR (neat): ν = 3340, 2927, 1250 1026,
˜
2
817 cm–1. C12H17ClO2 (228.09): calcd. C 63.02, H 7.49; found C
63.1, H 7.3.
35.6 (CH ), 26.7 (CH ), 10.5 (CH ) ppm. IR (neat): ν = 3272, 2967,
˜
2
2
3
Irradiation of 1-OMe in MeCN/H2O (5:1) in the Presence of 3: A
solution of 4-chloroanisole (1-OMe; 200 µL, 1.5 mmol) and 4-
penten-1-ol (3; 1.53 mL, 15 mmol) in MeCN/H2O (5:1; 30 mL) was
irradiated for 24 h. Purification by column chromatography (cyclo-
hexane/ethyl acetate, 99:1) afforded a mixture of 6-OMe (152 mg,
33%) and 2-(4-methoxyphenyl)tetrahydropyran (8-OMe, 20%, oil).
Data for 8-OMe: 1H NMR[42] (300 MHz, CDCl3, from the mix-
ture): δ = 6.80–7.10 (AAЈBBЈ, 4 H), 4.15–4.30 (m, 2 H), 3.80 (s, 3
H), 3.70–3.75 (m, 2 H), 2.05–2.10 (m, 1 H), 1.60–1.90 (m, 4 H)
ppm. 13C NMR (75 MHz, CDCl3, from the mixture): δ = 158.7,
135.5, 127.0 (CH), 113.5 (CH), 79.9 (CH), 68.9 (CH2), 55.1 (CH3),
33.7 (CH2), 25.5 (CH2), 23.8 (CH2) ppm. IR (neat, from the mix-
1517, 1230, 1018, 830 cm–1. C12H16O2 (192.12): calcd. C 74.97, H
8.39; found C 75.1, H 8.3
Irradiation of 1-OMe in MeCN/H2O (5:1) in the Presence of (Z)-
3-Hexen-1-ol (4): A solution of 4-chloroanisole (1-OMe; 200 µL,
1.5 mmol) and (Z)-3-hexen-1-ol (4; 1.78 mL, 15 mmol) in MeCN/
H2O (5:1, 30 mL) was irradiated for 30 h. Purification by column
chromatography (cyclohexane/ethyl acetate, 99:1) afforded trans-2-
ethyl-3-(4-methoxyphenyl)tetrahydrofuran (10-OMe; 111 mg) as an
oil and a mixture containing 10-OMe (93 mg, overall yield 52%)
and cis-2-ethyl-3-(4-methoxyphenyl)tetrahydrofuran (11-OMe;
1
43 mg, 14%). Data for 10-OMe: H NMR (300 MHz, CDCl3): δ =
6.80–7.15 (AAЈBB, 4 H), 4.20–4.30 (m, 1 H), 3.95–4.05 (m, 2 H),
3.80 (s, 3 H), 3.55–3.65 (dt, J = 8 and 4 Hz, 1 H), 2.80–2.95 (q, J
= 8 Hz, 1 H), 2.15–2.35 (m, 1 H), 2.00–2.10 (m, 1 H), 1.50–1.60
(m, 2 H), 0.90–1.00 (t, J = 7 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.5, 134.0, 128.4 (CH), 113.9 (CH), 87.3 (CH), 67.3
(CH2), 55.1 (CH3), 49.9 (CH), 35.7 (CH2), 26.7 (CH2), 10.5 (CH3)
ture): ν = 2933, 1513, 1242, 1037, 826 cm–1.
˜
Irradiation of 4-Chloro-N,N-dimethylaniline (1-NMe2) in Ethyl Ace-
tate in the Presence of 3-Buten-1ol (2): A solution of 1-NMe2
(233 mg, 1.5 mmol) and 2 (1.28 mL, 15 mmol) in ethyl acetate
(30 mL) was irradiated for 14 h. Purification by column chromatog-
raphy (cyclohexane/ethyl acetate, 9:1) afforded 3-chloro-4-(4-N,N-
dimethylamino)butan-1-ol (7-NMe2; 133 mg, 39%) and 2-(N,N-di-
methylamino)tetrahydropyran (5-NMe2; 23 mg, 8%) both as oils.
ppm. IR (neat): ν = 3401, 2930, 1510, 1247, 1034, 807 cm–1.
˜
C13H18O2 (206.13): calcd. C 75.69, H 8.80; found C 75.7, H 9.0.
Data for 11-OMe: 1H NMR (300 MHz, CDCl3, from the mixture):
Data for 7-NMe2: 1H NMR (300 MHz, CDCl3): δ = 6.75–7.10 δ = 6.80–7.00 (AAЈBBЈ, 4 H), 4.30–4.35 (d, J = 8 Hz, 1 H), 4.00–
(AAЈBB, 4 H), 4.15–4.25 (m, 1 H), 3.80–3.90 (t, J = 7 Hz, 1 H), 4.20 (m, 2 H), 3.85–3.90 (m, 1 H), 3.80 (s, 3 H), 2.10–2.20 (m, 1
2.95–3.05 (m, 2 H), 2.95 (s, 6 H), 2.00–2.15 (m, 1 H), 1.80–1.90 (m,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.3, 130.0 (CH),
128.3, 112.7 (CH), 61.3 (CH), 59.8 (CH2), 44.2 (CH3), 40.5 (CH2),
H), 1.90–2.00 (m, 1 H), 1.30–1.45 (m, 2 H), 0.90–1.00 (t, J = 7 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3, from the mixture): δ =
158.0, 134.1, 127.4 (CH), 113.6 (CH), 86.1 (CH), 66.7 (CH2), 55.1
(CH3), 49.6 (CH), 32.3 (CH2), 24.7 (CH2), 12.6 (CH3) ppm. IR
39.7 (CH ) ppm. IR (neat): ν = 3369, 2924, 1342, 1058, 821 cm–1.
˜
2
C12H18ClNO (227.11): calcd. C 63.29, H 7.97; found C 63.1, H 8.0.
(neat, from the mixture): ν = 3401, 2930, 1510, 1247, 1034,
˜
807 cm–1.
Irradiation of 1-NMe2 in TFE in the Presence of 2: A solution of
4-chloro-N,N-dimethylaniline (1-NMe2; 233 mg, 1.5 mmol) and 3-
buten-1-ol (2; 1.28 mL, 15 mmol) in TFE (30 mL) was irradiated
Irradiation of 1-NMe2 in TFE in the Presence of (E)-4: A solution
of 4-chloro-N,N-dimethylaniline (1-NMe2; 233 mg, 1.5 mmol) and
2246
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2240–2247

Photochemical Arylation of Alkenols
[19] S. Milanesi, M. Fagnoni, A. Albini, J. Org. Chem. 2005, 70,
603–610.
[20] B. Guizzardi, M. Mella, M. Fagnoni, A. Albini, J. Org. Chem.
2003, 68, 1067–1074.
[21] D. J. Cram, J. Am. Chem. Soc. 1964, 86, 3767–3772.
[22] S. Protti, M. Fagnoni, A. Albini, J. Am. Chem. Soc. 2006, 128,
10670–10671.
[23] The hydroxyphenyl cation was not considered because of the
possible deprotonation of the OH group.
(E)-3-hexen-1-ol (4; 1.78 mL, 15 mmol) in TFE (30 mL) was irradi-
ated for 8 h. Purification by column chromatography (cyclohexane/
ethyl acetate, 9:1) afforded 10-NMe2 (191 mg, 58%) as a pale-yel-
low oil. 1H NMR (300 MHz, CDCl3): δ = 6.75–7.20 (AAЈBBЈ, 4
H), 3.95–4.10 (m, 2 H), 3.60–3.75 (dt, J = 4 and 8 Hz, 1 H), 2.95
(s, 6 H), 2.75–2.85 (q, J = 9 Hz, 1 H), 2.35–2.45 (m, 1 H), 2.00–
2.15 (m, 1 H), 1.50–1.60 (m, 2 H), 0.90–1.00 (t, J = 8 Hz, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 149.3, 129.7, 128.1 (CH),
112.8 (CH), 87.3 (CH), 63.2 (CH2), 49.8 (CH), 40.6 (CH3), 35.6 [24] a) H. Lemmettyimen, J. Konijneberg, J. Cornellisse, C. A. G. O.
Varma, J. Photochem. 1985, 30, 315–338; b) M. Freccero, M.
Fagnoni, A. Albini, J. Am. Chem. Soc. 2003, 125, 13182–13190.
[25] a) G. Grabner, C. Richard, G. Köhler, J. Am. Chem. Soc. 1994,
116, 11470–11480; b) triplet phenyl cations have a triplet car-
bene character and the first-formed adduct to alkenes has a
diradicalic character; such a transient was recently detected,
see: I. Manet, S. Monti, G. Grabner, S. Protti, D. Dondi, V.
Dichiarante, M. Fagnoni, A. Albini, Chem. Eur. J. 2008, 14,
1029–1039.
[26] The mixture MeCN/H2O (5:1) was conveniently used in place
of TFE especially in the reaction of 1 with 2 where, in this
alcoholic solvent, a complex mixture rather than compound 5-
OH was obtained. In the last case, a possible competitive reac-
tion of the 4-oxocyclohexa-2,5-dienylidene carbene formed by
deprotonation of the 4-hydroxyphenyl cation intermediate
could take place as previously reported (See refs.[12,25a]).
[27] The same selectivity was previously found in the reaction of 4-
hydroxyphenyl cation with (E or Z)-3-hexenoic acid that gave
exclusively a trans-aryl ethyl lactone (See ref.[22]).
[28] Parent phenonium ion lies 18.7 kcal/mol below the phenethyl
cation, see: E. del Rio, M. I. Menéndez, R. Lopez, T. L. Sordo,
J. Am. Chem. Soc. 2001, 123, 5064–5068.
[29] a) S. Winstein, K. C. Schreiber, J. Am. Chem. Soc. 1952, 74,
2171–2178; b) A. F. Diaz, S. Winstein, J. Am. Chem. Soc. 1969,
91, 4300–4302; c) W. Kirmse, W. Gruber, Chem. Ber. 1971, 104,
1795–1799.
[30] See, for example: F. Q. Alali, X.-X. Liu, J. L. McLaughlin, J.
Nat. Prod. 1999, 62, 504–540; E. J. Kang, E. Lee, Chem. Rev.
2005, 105, 4348–4378.
[31] J. P. Wolfe, Eur. J. Org. Chem. 2007, 571–582.
[32] J. P. Wolfe, M. A. Rossi, J. Am. Chem. Soc. 2004, 126, 1620–
1621.
(CH ), 26.8 (CH ), 10.5 (CH ) ppm. IR (neat): ν = 3310, 2937,
˜
2
2
3
1780, 1172, 808 cm–1. C14H21NO (219.16): calcd. C 76.67, H 9.65;
found C 76.5, H 9.5.
Computational Study: Structure and energy were optimized at the
UB3LYP/6-31G(d) level by using the Gaussian 03W package (see
Supporting Information).
Supporting Information (see footnote on the first page of this arti-
cle): Cartesian coordinates and energies for the adducts cited in the
text.
Acknowledgments
Support of this work by CILEA for free access to their supercom-
puter facility is gratefully acknowledged.
[1] D. J. Cram, J. Am. Chem. Soc. 1949, 71, 3863–3870.
[2] a) J. A. Manner, J. A. Cook, B. G. Ramsey, J. Org. Chem. 1974,
39, 1199–1203; b) G. A. Olah, R. D. Porter, J. Am. Chem. Soc.
1971, 93, 6877–6887.
[3] a) J. M. Harris, F. L. Schadt, P. R. von Schleyer, J. Am. Chem.
Soc. 1969, 91, 7508–7510; b) H. C. Brown, C. J. Kim, C. J. Lan-
celot, P. R. von Schleyer, J. Am. Chem. Soc. 1970, 92, 5244–
5245.
[4] W. Kirmse, Top. Curr. Chem. 1979, 80, 125–311.
[5] E. del Rio, M. I. Menéndez, R. Lopez, T. L. Sordo, J. Phys.
Chem. A 2000, 104, 5568–5571.
[6] S. Nagumo, Y. Ishii, Y. Kakimoto, N. Kawahara, Tetrahedron
Lett. 2002, 43, 5333–5337.
[7] a) S. Nagumo, M. Ono, Y. Kakimoto, T. Furukawa, T. Hisano,
M. Mizukami, N. Kawahara, H. Akita, J. Org. Chem. 2002,
67, 6618–6622; b) S. Nagumo, T. Hisano, Y. Kakimoto, N. Ka-
wahara, M. Ono, T. Furukawa, S. Takeda, H. Akita, Tetrahe-
[33] F. González-Bobes, G. C. Fu, J. Am. Chem. Soc. 2006, 128,
5360–5361.
dron Lett. 1998, 39, 8109–8112; c) S. Nagumo, T. Furukawa, [34] M. D. Wendt, A. Geyer, W. J. McClellan, T. W. Rockway, M.
M. Ono, H. Akita, Tetrahedron Lett. 1997, 38, 2849–2852.
[8] A. C. Boye, D. Meyer, C. K. Ingison, A. N. French, T. Wirth,
Org. Lett. 2003, 5, 2157–2159.
[9] T. Ehara, H. Yokoyama, M. Ono, H. Akita, Heterocycles 2007,
71, 627–634.
[10] G. A. Olah, N. J. Head, G. Rasul, G. K. S. Prakash, J. Am.
Chem. Soc. 1995, 117, 875–882.
[11] a) M. Fagnoni, A. Albini, Acc. Chem. Res. 2005, 38, 713–721;
b) M. Fagnoni, Lett. Org. Chem. 2006, 3, 253–259.
[12] I. Manet, S. Monti, P. Bortolus, M. Fagnoni, A. Albini, Chem.
Eur. J. 2005, 11, 140–151.
Weitzberg, X. Zhao, R. Mantei, K. Stewart, V. Nienaber, V.
Klinghofera, V. L. Giranda, Bioorg. Med. Chem. Lett. 2004, 14,
3063–3068.
[35] a) A. Inoue, H. Shinokubo, K. Oshima, Synlett 1999, 1582–
1584; b) D. S. Brown, S. V. Ley, Tetrahedron Lett. 1988, 29,
4869–4872; c) A. R. Katrizky, S. Rachwal, B. Rachwal, J.
Chem. Soc. Perkin Trans. 1 1990, 1717–1725.
[36] Addition of hydrophilic solvents to phenonium ion was pre-
viously reported, see, for example, ref.[15]
[37] A. G. Giumanini, G. Chiavari, M. M. Musiani, P. Rossi, Syn-
thesis 1980, 743–746.
[13] M. De Carolis, S. Protti, M. Fagnoni, A. Albini, Angew. Chem.
Int. Ed. 2005, 44, 1232–1236.
[14] M. Mella, P. Coppo, B. Guizzardi, M. Fagnoni, M. Freccero,
A. Albini, J. Org. Chem. 2001, 66, 6344–6352.
[15] S. Protti, M. Mella, M. Fagnoni, A. Albini, J. Org. Chem. 2004,
69, 3465–3473.
[16] For halide-anion addition to phenonium ions, see also: D.
Fain, J.-E. Dubois, J. Org. Chem. 1987, 52, 260–267.
[17] F. Formarini, C. Sparapani, M. Speranza, J. Am. Chem. Soc.
1988, 110, 34–41.
[18] S. Protti, M. Fagnoni, A. Albini, Org. Biomol. Chem. 2005, 3,
2868–2871.
[38] J. M. Teulon (Ger. Offen.), DE 2733305, 1978 [Chem. Abs.
1978, 89, 43095].
[39] Y. Tamaru, M. Hojo, H. Higashimura, Z. Yoshida, Angew.
Chem. Int. Ed. Engl. 1986, 25, 735–737.
[40] A. Inoue, H. Shinokubo, K. Ochima, Synlett 1999, 1582–1584.
[41] H. Normant, Ann. Chim. Appl. 1942, 335–346.
[42] Y. Senda, H. Kanto, H. Itoh, J. Chem. Soc. Perkin Trans. 2
1997, 1143–1146.
[43] V. Dichiarante, C. Betti, M. Fagnoni, A. Maia, D. Landini, A.
Albini, Chem. Eur. J. 2007, 13, 1834–1841.
Received: December 12, 2007
Published Online: March 11, 2008
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