A new regio- and stereoselective intermolecular Friedel-Crafts alkylation of phenolic substrates with aryl epoxides

Article abstract of DOI:10.1016/j.tetlet.2005.10.138

A conceptually new regioselective and highly syn-stereoselective intermolecular Friedel-Crafts-type O-alkylation of phenols with aryl epoxides by the use of appropriately substituted aryl borates is reported. The carbon-carbon bond formation occurs in neutral and mild conditions without the need for external Lewis acids or transition metal catalysts.

Full text of DOI:10.1016/j.tetlet.2005.10.138

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 61–64
A new regio- and stereoselective intermolecular
Friedel–Crafts alkylation of phenolic substrates with aryl epoxides
Ferruccio Bertolini, Paolo Crotti, Franco Macchia and Mauro Pineschi*
`
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita di Pisa, Via Bonanno 33, 56126 Pisa, Italy
Received 12 October 2005; revised 26 October 2005; accepted 26 October 2005
Available online 14 November 2005
Abstract—A conceptually new regioselective and highly syn-stereoselective intermolecular Friedel–Crafts-type O-alkylation of phe-
nols with aryl epoxides by the use of appropriately substituted aryl borates is reported. The carbon–carbon bond formation occurs
in neutral and mild conditions without the need for external Lewis acids or transition metal catalysts.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tive Friedel–Crafts alkylation of arenes with aromatic
epoxides is particularly attractive both because aromatic
epoxides are readily available in an enantioenriched
form,7 and because the product contains a benzylic car-
bon stereocenter.
The functionalization of relatively unreactive arene C–H
bonds with electrophiles is an area of current interest.1
Although the Friedel–Crafts alkylation is one of the old-
est and most intensively studied organic reactions, epox-
ides have rarely been used as the electrophilic partner.2
Strong Lewis acids, such as Et2AlCl, SnCl4, BF3–Et2O,
or protic additives, are often chosen for use with epox-
ides when the goal is an intramolecular addition to an
alkene or aromatic systems, and several elegant
biomimetic arene-epoxide cyclizations based on this
concept have been reported.3 On the other hand, inter-
molecular Friedel–Crafts alkylations of aromatics with
epoxides have only sparingly been reported, and these
reactions are often accompanied by various side reac-
tions.4 Often intractable mixtures of regioisomers have
been obtained,5 and only electron-rich nitrogen-based
heterocycles, such as indoles, are able to react with epox-
ides in the presence of metal catalysts in a regioselective
fashion.6
Recently, we have reported a new syn-stereoselective
ring opening of aryl epoxides and aziridines with aryl
borates.8 This reaction protocol allowed a smooth reac-
tion of poorly nucleophilic phenols with three-mem-
bered heterocyclic rings in neutral condition to give
phenoxy alcohols in a syn-stereoselective fashion (O-
alkylation). For example, the reaction of styrene oxide
with triphenylborate (1a, R1 = H) afforded a good yield
of the O-alkylated product 2a along with a smaller
amount (ca. 5%) of the corresponding o-(2-hydroxy-
alkyl) phenol 3a deriving from an intermolecular Fri-
edel–Crafts-type C-alkylation process (Scheme 1).
2. Results and discussion
We here report, a new cross-coupling reaction of aryl
borates with aryl epoxides under mild and neutral con-
ditions without the need for transition metal catalysts.
To the best of our knowledge, both intra- and intermo-
lecular Friedel–Crafts reactions of aromatic compounds
with epoxides invariably occur with inversion of configu-
ration at the cleaved center. The regio- and stereoselec-
We reasoned that increasing the nucleophilic contribu-
tion of the attacking aromatic function might bring
the C-alkylation process up to synthetically useful levels.
For this purpose, arylborates 1a–j, substituted in differ-
ent position with groups having different electronic and
steric properties were prepared and tested in our reac-
tion conditions (Scheme 1).9
Keywords: Friedel–Crafts alkylation; Epoxides; Regioselectivity;
Stereoselectivity.
*
Corresponding author. Tel.: +39 0502219668; fax: +39 0502219660;
e-mail: pineschi@farm.unipi.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.138

62
F. Bertolini et al. / Tetrahedron Letters 47 (2006) 61–64
R1
Interestingly, the reaction with borate 1f can be carried
out also at low temperatures with a slight increase in the
C-alkylated product from 45% at rt to 58% at ꢀ78 °C
(Table 1, entry 5). Consistently with our expectations,
tris(m-methoxyphenyl)borate 1g was able to activate
both the ortho-position with respect to the phenolic oxy-
gen by a mesomeric effect, and a substantial amount of
the corresponding C-alkylated products 3g and 3g0,
albeit as a ca. 3:1 mixture of regioisomers was obtained
(Table 1, entry 6). The use of electron-rich substituted
aryl borates 1h–j gave a very fast reaction with (R)-
(+)-styrene oxide even at low temperature with the
obtainment in good yields of the corresponding C-alkyl-
ated products 3i–j with a high syn-stereoselectivity and a
complete regioselectivity (Table 1, entries 8–9).
O
OH
Ph
2a-j
O-alkylation
O
solvent
O
B
+
R1
+
Ph
R1
3
HO
Ph
*
OH
3a-j
C-alkylation
1a, R1=H, 1b, R1=o-Me, 1c, R1=o-t-Bu, 1d, R1=o-TIPS,
1e, R1=p-OMe, 1f, R1=p-Me, 1g, R1=m-OMe, 1h,
R1=2,3,5-tri-Me, 1i, R1=3,5-di-Me, 1j, R1=3,5-di-OMe.
To verify the scope of our new reaction protocol, some
substituted aryl epoxides were examined (Table 2). The
reactions of unsubstituted triphenylborate 1a with
trans-stilbene oxide and trans-glycidic ester 4, afforded
an increased amount of C-alkylated products (up to
27% of the crude mixture) with respect to the same reac-
tion performed with styrene oxide (data not shown in
Table 2). However, the use of the more electron-rich bo-
rates 1f,g, and 1i led to a significant but modest increase
in the C-alkylation pathway pointing to the incursion of
a more crowded transition state in the case of substi-
tuted epoxides (Table 2, entries 1–4). It is quite remark-
able that these reactions gave the corresponding
hydroxy phenols 5–8 with a complete retention of config-
uration at the cleaved benzylic center. Also cis-stilbene
oxide gave substantial amounts of C-alkylated hydroxy
phenol 9 with a good syn-stereoselectivity (Table 2,
entry 5).12
Scheme 1. Product distribution of the reaction of a generic triaryl-
borate with styrene oxide.
The use of borate 1b, derived from o-cresol gave a mod-
est but significant increase in the Friedel–Crafts type
product 3b, which was obtained as a single constitu-
tional isomer in the ortho-position with respect to the
phenolic oxygen (Table 1, entry 1).10 The use of the
more hindered tris-(o-tert-butyl phenyl)borate 1c gave
an almost equimolar mixture of products 3c and 2c
deriving from C- and O-alkylation pathways, respec-
tively (entry 2). As the nucleophilicity of the oxygen is
most probably reduced by the presence of the t-butyl
substituent, we also considered the use of more sterically
hindered o-TIPS borate 1d. The reaction of borate 1d
with styrene oxide was very fast, but the main reaction
product was phenylacetaldehyde, derived from a rear-
rangement reaction of styrene oxide catalyzed by the
Lewis acid (entry 3). The electron-donating mesomeric
effect of the p-OMe substituent of borate 1e increases
the electron density of the oxygen atom,11 whereas its
inductive electron-withdrawing effect hampers the alkyl-
ation in the ortho-position of the phenol with respect to
borate 1f, which bears a methyl group and in which both
effects go in the same sense (Table 1, cf. entries 4 and 5).
Although our procedure often gives mixtures of prod-
ucts, it should be stressed that all C-alkylated products
can easily be separated from the corresponding O-alkyl-
ated products and obtained in a pure state by simple
chromatographic purifications.
The good to high syn-stereoselectivity observed
throughout this work for C-alkylated products, as well
Table 1. Reaction of substituted arylborates 1b–j with styrene oxidea
Entry
R1 (borate)
Conditions
C-alk/O-alkb
Products [isolated yields (%)]
1
2
3
4
5
o-Me (1b)
o-t-Bu (1c)
o-TIPS (1d)
p-OMe (1e)
p-Me (1f)
2 h, rt
6 h, rt
2 h, rt
1 h, rt
20/80
48/52
70/30c
31/69
45/55
58/42
92/8d
87/13
90/10
>95/<5
3b/2b (10/45)
3c/2c (35/24)
3d/2dc
3e/2e (18/40)
4 h, rt
12 h, ꢀ78 °C
12 h, ꢀ78 °C
1 h, ꢀ60 °C
1.5 h, ꢀ78 °C
1 h, ꢀ78 °C
3f/2f (48/32)
6
7
8e
9e
m-OMe (1g)
3g+3g0/2g (35+11/4)
3h/2h (67/nd)
3i/2i (75/7)
2,3,5-Tri-Me (1h)
3,5-Di-Me (1i)
3,5-Di-OMe (1j)
3j/2j (77/nd)
a All reactions were carried out in accordance with the general procedure.9
b Determined by 1H NMR examination of the crude reaction mixture. Only the attack on the secondary benzylic position of the epoxide was
observed.
c Phenyl acetaldehyde was the main product. See Supplementary data.
d Determined by HPLC. Two C-alkylated products were obtained in a 3:1 ratio (see Supplementary data for details).
e Performed with (R)-(+)-styrene oxide. Retention versus inversion configuration ratio was >92/8 in both cases, as determined by chiral HPLC
analysis.

F. Bertolini et al. / Tetrahedron Letters 47 (2006) 61–64
63
Table 2. Product distribution and stereoselectivity of the reaction of arylborates with substituted aromatic epoxidesa
Entry
Epoxide
Conditions
Borate
C-alk/O-alkb
C-alkylated productc
syn/anti d
O
1
3 h, rt
R1 = 3,5-Di-Me 1i
40/60
>95/<5
Ph
HO
Ph
Ph
Ph
OH
5 (38)
6 (30)
Me
O
HO
2
3
18 h, rt
R1 = p-Me 1f
40/60
50/50
>95/<5
>95/<5
Ph
O
Ph
Ph
OH
Me
Ph
COOMe
COOMe
HO
4 h, rt
R1 = p-Me 1f
COOMe
OH
OMe
4
4
7 (38)
O
4
5
4 h, ꢀ40 °C
R1 = m-OMe 1g
75/25e
>95/<5
HO
HO
COOMe
OH
8 (27)
O
3 h, rt
R1 = 3,5-Di-Me 1i
55/45
82/18
Ph
Ph
Ph
OH
Ph
9 (33)
a,b See corresponding notes of Table 1.
c Isolated yields of the indicated C-alkylated product after chromatographic purification.
d Determined by 1H NMR examination of the crude reaction mixture.
e See footnote d of Table 1.
for O-alkylated products13 (Tables 1 and 2), points to an
advanced carbocationic intermediate, such as A (Fig. 1).
Nucleophilic attack would preferentially occur for
entropic reasons by the internal nucleophile, with reten-
tion of configuration, to afford the corresponding syn-
adducts (C-alkylated products from B and O-alkylated
products from C), as experimentally found. In the inter-
molecular Friedel–Crafts alkylation, it is reasonable to
hypothesize the formation of a chelated seven-mem-
bered transition state in which the new benzylic car-
bon–carbon bond is preferentially formed from the
same side of the oxygen atom as the former epoxide ring
(Fig. 1, path b).
R1
OAr
O
O B OAr
(ArO)3B
b
a
O
δ+
3. Conclusions
δ+
A
In summary, considering the importance of the stereo-
selective construction of benzylic carbon stereocenters,
our new reaction protocol offers a simple route for
stereodefined polyfunctional compounds, otherwise very
difficult to obtain, in neutral conditions and without the
need for transition metal catalysts.
R1
O
b
a
R1
OAr
OAr
O
δ-
B
δ+
δ+
O
B
O
OAr
OAr
δ+
C
B
Acknowledgements
syn-C-alkylation process
syn-O-alkylation process (ref. 8)
This work was supported by P.R.I.N. (M.I.U.R., Rome)
and by the University of Pisa.
Figure 1. Competition between plausible chelated transition states of
the syn-stereoselective pathways.

64
F. Bertolini et al. / Tetrahedron Letters 47 (2006) 61–64
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43,
Supplementary data
550.
7. Katsuki, T. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; Wiley-VCH, 2000; p 287.
8. Pineschi, M.; Bertolini, F.; Haak, R. M.; Crotti, P.;
Macchia, F. Chem. Commun. 2005, 1426.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.10.138.
9. General procedure as follows: A solution of aryl borate 1a–
j (1.5 mmol) in CH2Cl2 (1.0 mL) was added to a solution
of epoxide (1.0 mmol) in CH2Cl2 (0.5 mL) under magnetic
stirring. The reaction was followed by TLC and was
quenched with brine (2.0 mL) after the times indicated in
Tables 1 and 2. The solution was diluted with Et2O or
CH2Cl2 (20 mL) and washed with brine. Evaporation of
the dried organic solution afforded a crude reaction
mixture that was purified by silica gel chromatography
to give the corresponding pure compounds. See Supple-
mentary data for details.
References and notes
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11. In substituted triarylborates there is
a competition
between the phenyl ring and the boron atom for the
electron density of the oxygen atom, the latter occurring
by a pp–pp mechanism. For a study of the Lewis acidity of
the boron atom in triarylborates, see: Fenwick, J. T. F.;
Wilson, J. W. Inorg. Chem. 1975, 14, 1602.
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Bull. Chem. Soc. Jpn. 1980, 53, 458.
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12. The relative stereochemistry of C-alkylated adducts 5–9
1
was determined by H NMR examination of the J values
of the corresponding benzylic protons and comparison
with the literature data. For example, see: Varela, J. A.;
Pena, D.; Goldfuss, B.; Polborn, K.; Knochel, P. Org.
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opening of aryl epoxides, see: Crotti, P.; Di Bussolo, V.;
Macchia, F.; Favero, L.; Pineschi, M.; Lucarelli, L.;
Roselli, G.; Renzi, G. J. Phys. Org. Chem. 2005, 18, 321,
and references cited therein.