Organic Letters
Letter
substrates are 2-vinylbenzyl alcohols and benzoic acids 1,
whose application in metal-catalyzed alkene cyclization/
difunctionalization is less common, possibly due to loss of
conjugation in the exo-cyclization transition state. The
envisioned reaction sequence for phthalan formation, analo-
gous to our prior tetrahydrofuran synthesis method,9a is
illustrated in Scheme 2. The benzylalcohol 1 is proposed to
diphenylethylene (3 equiv) in PhCF3 at 120 °C in the presence
of K2CO3 (1 equiv)9 provided phthalan 2a in 90% yield and
97% ee (Table 1, entry 1). An attempt to reduce loading of the
Cu(OTf)2 and (S,S)-t-Bu-Box to 15 and 18 mol %,
respectively, decreased the isolated yield to 74% (Table 1,
entry 2). Reducing the reaction temperature to 100 °C resulted
in reduced isolated yield (Table 1, entry 3). The reaction of 1a
under optimal conditions (Table 1, entry 1) was performed on
1 mmol scale and resulted in 70% isolated yield of 2a (>99%
ee, Table 1, entry 4). 2-Vinylbenzyl alcohol 1b, a primary
benzyl alcohol, was next investigated. Under the conditions
deemed optimal for 1a (Table 1, entry 1), cycloetherification
occurred to provide a 2:2:1 ratio (crude 1H NMR) of phthalan
2b, the benzaldehyde derived from 1b, and benzyl alcohol 1b,
respectively (Table 1, entry 5). The competitive oxidation of
the primary benzyl alcohol under these conditions, which
employ MnO2 as the stoichiometric oxidant, was not
surprising. Fortunately, upon changing to a milder oxidant,
Ag2CO3 (200 mol %), 71% of phthalan 2b could be obtained
in 80% ee (Table 1, entry 6). Reducing the amount of Ag2CO3
to 100 mol % provided 2b in even higher yield (93%, Table 1,
entry 7). Reducing the reaction temperature to 100 °C resulted
in lower conversion (Table 1, entry 8). It should be noted that
no reaction was observed when Cu(OTf)2 was omitted and
minimal reaction (ca. 5% conversion) was detected when
MnO2 was omitted in the reaction of 1a (not shown). Thus,
with the optimal conditions in hand (Table 1, entries 1 and 7),
the 2-vinylbenzyl alcohol scope was further explored (Scheme
3).
A number of substrate functionalities including Cl, Me,
OMe, CF3, and a tertiary amine were tolerated under the
reaction conditions (Scheme 3). Tertiary alcohol substrates
uniformly provided higher levels of enantioselectivity than
primary benzyl alcohol substrates (e.g., compare 2a and 2h to
2b and 2c). A benzoic acid was able to cyclize to give phthalide
2e, albeit with low enantioselectivity. In this case, the soluble
base 2,6-di-tert-butyl-4-methylpyridine provided higher con-
version than when K2CO3 was used, possibly due to the
difference in solubility of the intermediate corresponding
benzoate salt. (2-(1-Phenylvinyl)phenyl)methanol provided
phthalan 2d, but the enantioselectivity was greatly diminished.
The absolute stereochemistry of the products was assigned by
conversion of phthalan 2c to its known corresponding primary
alcohol (using OsO4 and PhI(OAc)2, then NaBH4) and optical
Scheme 2. Proposed Copper-Catalyzed Carboetherification
Mechanism
coordinate to the copper(II) center followed by intramolecular
cis-oxycupration. Homolysis of the resulting alkyl-Cu(II) bond
provides a methyl radical that can add to vinyl arenes.
Oxidation of the resulting benzylic radical then results in
formation of the higher substituted vinyl arene 2.
We investigated the optimal conditions for enantioselective
carboetherification of 2-vinylbenzyl alcohols 1a and 1b with
1,1-diphenylethylene, as shown in Table 1. Subjecting 1a to
Cu(OTf)2 (20 mol %), (S,S)-t-Bu-Box (25 mol %), and 1,1-
a
Table 1. Reaction Optimization
b
c
d
entry
1
substrate
oxidant (mol %)
yield (%)
ee (%)
1a
1a
1a
1a
1b
1b
1b
1b
MnO2 (260)
MnO2 (260)
MnO2 (260)
MnO2 (260)
MnO2 (260)
Ag2CO3 (200)
Ag2CO3 (100)
Ag2CO3 (100)
90
74
78
70
ca. 40
71
97
98
e
2
A survey of vinylarene coupling partners was also
investigated (Scheme 4). While 1,1-disubstituted vinyl arenes
are generally the best partners due to their greater ability to
react with the presumed carbon radical intermediates, 4-
methylstyrene also provided phthalan 2k in 99% yield and 96%
ee. Similarly, reaction with 4-methoxystyrene and unsubsti-
tuted styrene (5 equiv) provided 65% and 95% yields of
adducts 2l and 2m in 99% ee each. The less electron-rich 4-
chlorostyrene (5 equiv) underwent the reaction with alcohol
1a in 55% yield and 99% ee, while the 4-cyanostyrene was
unreactive under these conditions. Reaction of 1a with 2-
methoxystyrene provided 2p in 52% yield and 99% ee, while
reaction with 2-bromostyrene provided 2q in 33% yield and
99% ee. In these reactions with styrenes, use of the soluble 2,6-
di-tert-butyl-4-methylpyridine instead of K2CO3 significantly
reduced styrene polymerization. Reaction of 1a with 1,1-(4-
chlorophenyl)ethylene provided phthalan 2r in 90% yield and
f
3
g
4
h
>99
5
6
7
80
81
93
ca. 56
fh
8 ,
a
Reaction conditions: Cu(OTf)2 (0.037 mmol, 20 mol %) and (S,S)-
t-Bu-Box (25 mol %) were complexed in PhCF3 (1 mL) at 60 °C.
After 2 h, oxidant, alcohol 1 (0.185 mmol) in PhCF3 (1 mL), K2CO3
(1 equiv), 1,1-diphenylethylene (3 equiv), and 4 Å mol. sieves were
added at rt and the mixture was heated and stirred for 24 h at 120 °C
b
c
in a sealed tube. MnO2 (85%, <5 μ was used). Isolated yield unless
d
otherwise noted. Enantioselectivity determined by chiral HPLC.
Reaction run with 15 mol % Cu(OTf)2 and 18 mol % (S,S)-t-Bu-Box.
e
f
g
Reaction run at 100 °C. This reaction used substrate 1a at 1 mmol
h
scale. Yield estimated by crude 1H NMR. Ca. 40% of the
benzaldehyde derived from 1b was also formed.
B
Org. Lett. XXXX, XXX, XXX−XXX