Intramolecular carbolithiation of allyl o-lithioaryl ethers: A new enantioselective synthesis of functionalized 2,3-dihydrobenzofurans

Article abstract of DOI:10.1002/chem.200500377

A new and easy method for the diastereoselective synthesis of 3-functionalized 2,3-dihydrobenzofuran derivatives from allyl 2-bromoaryl ethers is described. The key step of this transformation involves an intramolecular carbolithiation reaction of allyl 2-lithioaryl ethers. The substituents in both the allyl and the aryl moieties play an important and decisive role in stopping the reaction at the benzofuran thus avoiding a γ-elimination reaction. Finally, this process is amenable to the synthesis of enantiomerically enriched compounds by using ( - )-sparteine as a chiral inductor.

Full text of DOI:10.1002/chem.200500377

FULL PAPER
Intramolecular Carbolithiation of Allyl o-Lithioaryl Ethers: A New
Enantioselective Synthesis of Functionalized 2,3-Dihydrobenzofurans
JosØ Barluenga,*[a] Francisco J. FaÇanµs,[a] Roberto Sanz,[b] and CØsar Marcos[b]
Abstract: A new and easy method for the diastereoselective synthesis of 3-func-
tionalized 2,3-dihydrobenzofuran derivatives from allyl 2-bromoaryl ethers is de-
scribed. The key step of this transformation involves an intramolecular carbolithia-
tion reaction of allyl 2-lithioaryl ethers. The substituents in both the allyl and the
aryl moieties play an important and decisive role in stopping the reaction at the
benzofuran thus avoiding a g-elimination reaction. Finally, this process is amenable
to the synthesis of enantiomerically enriched compounds by using (À)-sparteine as
a chiral inductor.
Keywords: (À)-sparteine · 2,3-dihy-
drobenzofurans · allyl aryl ethers ·
enantioselectivity · intramolecular
carbolithiation · synthetic methods
Introduction
construction of dihydrobenzofurans involve the radical cycli-
zation of an aryl radical onto a double bond and so general
functionalization is not always possible and, more impor-
tantly, ring closure to afford 2,3-dihydrobenzofurans is not
enantioselective and not completely diastereoselective.[12]
Moreover, an interesting study of the intramolecular carbo-
lithiation of allyl 2-lithiophenyl ether (2a) has been publish-
ed by Bailey and Punzalan (Scheme 1).[13] The main product
of this reaction is 2-cyclopropylphenol (4) which is proposed
to be formed by an intramolecular 5-exo carbolithiation re-
action, which gives the lithiated dihydrobenzofuran (3a),
followed by an 1,3-elimination process.
Inspired by this work and in connection with our interest
in this field,[14] we have investigated the possibility of access-
ing dihydrobenzofuran derivatives through a carbolithiation
reaction analogous to that described in Scheme 1. To this
end, it was necessary to find the appropriate conditions to
avoid the g-elimination reaction referred to above. Hence,
we report herein the stereoselective carbolithiation of allyl
o-lithioaryl ethers to afford 2,3-dihydrobenzofuran deriva-
tives. This process is amenable to the synthesis of enantio-
merically enriched products.
À
The intramolecular carbolithiation of carbon carbon double
bonds is now a common process in the generation of cyclic
compounds, and it is particularly well suited for the creation
of five-membered rings through a 5-exo-trig cyclization pro-
cess.[1] In this context, unsaturated aryllithium compounds
undergo carbometalation reactions to yield indanes,[2] benzo-
furans,[3] indoles,[4] indolines,[5] and isoquinolines.[6] Enantio-
selective reactions of this kind[7] can be carried out by start-
ing with an enantiomerically enriched secondary lithium de-
rivative in those cases in which the cyclization reaction is
fast enough to avoid epimerization.[8] Moreover, enantiofa-
cially selective cycloisomerization of an achiral olefinic orga-
nolithium can be achieved by performing the carbolithiation
reaction in the presence of a bidentate chiral ligand like
(À)-sparteine.[9] On the other hand, 2,3-dihydrobenzofuran
(coumaran) is a basic skeleton found in a number of biologi-
cally interesting compounds. For example, one group of neo-
lignans[10] possesses the dihydrobenzofuran moiety with a
trans-stereochemistry.[11] Many of the procedures used in the
[a] Prof. Dr. J. Barluenga, Dr. F. J. FaÇanµs
Instituto Universitario de Química Organometµlica “Enrique Moles”
Unidad Asociada al C.S.I.C., Universidad de Oviedo
Juliµn Clavería 8, 33006-Oviedo (Spain)
Fax: ( +34)985-103-450
E-mail: barluenga@uniovi.es
[b] Dr. R. Sanz, C. Marcos
Departamento de Química. rea de Química Orgµnica
Facultad de Ciencias, Universidad de Burgos
Pza. Missael BaÇuelos s/n, 09001-Burgos (Spain)
Scheme 1. Tandem carbolithiation/1,3-elimination reactions of allyl 2-lith-
iophenyl ether 2a.
Chem. Eur. J. 2005, 11, 5397 – 5407
DOI: 10.1002/chem.200500377
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5397

Table 1. Synthesis of dihydrobenzofuran derivatives 5.
Results and Discussion
Entry Ether[a]
R
E+
Product
E
Yield
[%][b]
Intramolecular carbolithiation of allyl 2-lithiophenyl ether:
First, we treated allyl 2-bromophenyl ether 1a with tert-bu-
tyllithium (2 equiv) in diethyl ether at À788C to afford allyl
2-lithiophenyl ether 2a, which is stable at this temperature.
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1b
1b
1c
1c
H
H
PhNCO 5a
PhNHCO 34[c]
PhS
D
Ph2S2
5b
29[d]
70
c-C6H11 D2O
c-C6H11 TMSCl
c-C6H11 Ph2S2
c-C6H11 Et2CO
Me
Me
5c
5d
5e
5 f
TMS
PhS
64
80
Addition
of
N,N,N’,N’-tetramethylethylenediamine
(TMEDA) (2.2 equiv) to the solution of intermediate 2a,
followed by warming to À208C and reaction with different
electrophiles gave rise, after hydrolysis, to the functionalized
dihydrobenzofuran derivatives 5a,b in yields of around 30%
along with 2- cyclopropylphenol 4 (ca. 20%) (Scheme 2 and
Table 1, entries 1 and 2). Moreover, in these cases around
40% of phenol was generated as a result of a competitive
Et2COH
H
73
74
H2O
5g
Ph2CO
H2O
5h
Ph2COH
H
65
9
10
(R)-1c[e] Me
(R)-1c[e] Me
(2R,3S)-5g
77[f]
69[f]
Ph2CO
(2R,3S)-5h Ph2COH
[a] For the synthesis of the starting ethers, see the Experimental Section.
[b] Yield of isolated product based on the starting ether 1. [c] 2-Cyclopro-
pylphenol 4 (18%) and phenol (38%) were also obtained. [d] 2-Cyclo-
propylphenol 4 (20%) and phenol (40%) were also obtained. [e] An ee
of 96% was determined by HPLC. [f] An ee of 96% was determined by
HPLC.
the presence of a substituent in the a-position of the allyl
moiety and so the reactions of the readily available ethers
1b,c were investigated. Ether 1b was prepared by the Mitsu-
nobu reaction between 2-bromophenol and 1-cyclohexyl-2-
propyn-1-ol and subsequent partial hydrogenation, whilst 1c
was synthesized by a Williamson ether synthesis between 2-
bromophenol and ethyl 2-bromopropionate followed by dii-
sobutylaluminum hydride (DIBAL) reduction and Wittig
methylenation. Thus, treatment of ethers 1b,c with tBuLi in
diethyl ether at À788C, further addition of TMEDA at the
same temperature, and warming to 08C afforded, after reac-
tion with different electrophiles, the corresponding function-
alized trans-2,3-dihydrobenzofurans 5c–h in good yields and
with total diastereoselectivity[16] (Scheme 2 and Table 1, en-
tries 3–8).
It is very interesting to note that this carbolithiation reac-
tion is completely diastereoselective, since only the trans di-
astereoisomer was obtained. This fact can be explained by
assuming that the cyclization reaction takes place via a tran-
sition state with the same geometric disposition as inter-
mediate 2, which resembles a chair-like cyclohexane.[17] The
stereocontrol is attributed to steric interactions that favour a
geometry in which the substituent preferentially occupies a
pseudoequatorial position. And so, for the case shown in
Scheme 2, one would predict that the formation of the trans
isomer of 3-lithiomethyl-2-substituted-2,3-dihydrobenzofur-
an 3 would be predominant. In fact, it can be deduced from
the exclusive formation of functionalized heterocycles 5 that
this diastereoisomer was indeed formed (Scheme 2).
Scheme 2. trans-2,3-Dihydrobenzofuran derivatives 5 from allyl 2-bromo-
phenyl ethers 1 through intramolecular carbolithiation of organolithium
compounds 2.
SN2’ cleavage of the allyl moiety by the excess tBuLi used in
the bromine/lithium exchange reaction.[15] We concluded
that the 1,3-elimination process is not slow enough com-
pared with the carbolithiation reaction and therefore it is
not possible to obtain selectively the dihydrobenzofuran de-
rivatives 5.
2,3-Disubstituted-2,3-dihydrobenzofurans by intramolecular
carbolithiation of 1-substituted-2-propenyl 2-lithiophenyl
ethers: With the purpose of minimizing the g-elimination re-
action, we considered that this process could be avoided in
Abstract in Spanish: Se describe un mØtodo nuevo y sencillo
para la síntesis diastereoselectiva de derivados de 2,3-dihidro-
benzofurano funcionalizados en la posición 3 a partir de alil
2-bromoaril Øteres. El paso clave de esta transformación im-
plica una reacción de carbolitiación intramolecular de alil 2-
litioaril Øteres. La presencia de sustituyentes tanto en el resto
alílico como en el arílico desempeÇa un papel decisivo e im-
portante para poder detener la reacción en el estadio de ben-
zofurano, evitando así la reacción de g-eliminación. Final-
mente, este proceso puede ser aplicado a la síntesis de com-
puestos enantiomØricamente enriquecidos mediante el uso de
(À)-esparteína como inductor quiral.
With this result in mind, we reasoned that if the starting
ether was nonracemic the resulting dihydrobenzofuran de-
rivative would be obtained enantioselectively. So, when (R)-
1c, prepared by the condensation of 2-bromophenol with
(S)-ethyl lactate under Mitsunobu conditions[18] and subse-
quent DIBAL reduction and Wittig methylenation, was al-
lowed to react under the conditions indicated in Scheme 2,
trans-dihydrobenzofuran derivatives (2R,3S)-5g,h were ob-
tained in good yields and with total transference of chirality
5398
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Chem. Eur. J. 2005, 11, 5397 – 5407

Enantioselective Synthesis of Functionalized Dihydrobenzofurans
FULL PAPER
(Table 1, entries 9 and 10). It is remarkable that this is the
first enantioselective synthesis of trans-2,3-dimethyl-2,3-di-
hydrobenzofuran.
À408C) with R1 =Me, whereas the nonsubstituted ether 1a
cyclizes at an even higher temperature (over À208C). This
fact could be due to the steric effect of the substituent that
forces the allyl group to be close to the lithium atom in the
organolithium intermediates. A similar effect could also be
responsible for the inhibition of the subsequent 1,3-elimina-
tion process.
The different behavior of the regioisomeric allyl ethers 6 f
and 6g, in which the methyl and chlorine substituents at the
4- and 6-positions are interchanged, is remarkable. Whereas
6 f (R1 =Me, R2 =Cl) efficiently gave dihydrobenzofuran de-
rivative 7s in 59% yield (Table 2), the regioisomer 6g (R1 =
Cl, R2 =Me) led, under the same reaction conditions, exclu-
sively to o-cyclopropylphenol derivative 9 in 68% yield
(Scheme 4). Although the carbolithiation reactions of the or-
3-Functionalized-2,3-dihydrobenzofurans by intramolecular
carbolithiation of allyl 2-lithio-6-substituted phenyl ethers:
Owing to the effect of a substituent in the position adjacent
to the oxygen atom, we decided to study the outcomes of
this kind of carbometallation reaction with allyl aryl ethers
in which the aromatic ring possesses different substituents.
Surprisingly, we found that when simple 2-propenyl ethers 6,
substituted at the 6-position of the aryl moiety, were treated
under the same conditions as those shown in Scheme 2,
functionalized 2,3-dihydrobenzofurans 7 were generated in
moderate-to-good yields (Scheme 3 and Table 2). We tenta-
Scheme 4. Formation of o-cyclopropylphenol derivative 9 from 6-chloro-
substituted aryl ether 6g.
Scheme 3. Formation of dihydrobenzofuran derivatives 7 from 6-substi-
tuted aryl ethers 6.
ganolithium intermediates derived from 6 f and 6g are
slower at 08C than the cyclization reactions of the organo-
lithiums derived from 6a–e (1 h for 6 f and 3 h for 6g), the
different outcomes of these reactions could be attributed to
an increase in the electron-withdrawing effect of the chlor-
ine atom in intermediate 8g (Scheme 4) relative to 8 f,
which in turn would decrease the electron density on the
oxygen atom and thus favor the g-elimination process.
Interestingly, ethers 6c,d with trimethylsilyl groups at the
6-position behave as synthetic equivalents of the parent
ether 1a because the trimethylsilyl group can be removed
under mild conditions with HBF4 in dichloromethane at 08C
(Scheme 5). In this way, functionalized 2,3-dihydrobenzofur-
an derivatives 5i,j and 7t,u, which have no substituents at
the 2- and 7-positions of the benzofuran moiety, can be syn-
Table 2. Synthesis of dihydrobenzofuran derivatives 7.
Ether R1
R2
E+
Product
E
Yield [%][a]
6a
6a
6a
6a
6b
6b
6b
6b
6c
6c
6c
6c
6d
6d
6d
6d
6d
6e
6 f
tBu
Me D2O
Me Ph2CO
Me Br(CH2)2Br 7c
Me PhNCO
Me D2O
Me Ph2CO
Me Ph2S2
Me Br(CH2)2Br 7h
7a
7b
D
73
73
63
tBu
tBu
tBu
Me
Me
Me
Me
Ph2COH
Br
PhNHCO 61
7d
7e
7 f
7g
D
62
66
65
66
75
Ph2COH
PhS
Br
TMS Me D2O
TMS Me PhNCO
TMS Me Bu3SnCl
7i
7j
7k
D
PhNHCO 75
Bu3Sn
Br
69
75
70
TMS Me Br(CH2)2Br 7l
TMS
TMS
TMS
TMS
TMS
i-Pr
H
H
H
H
H
H
Cl
H2O
7m
7n
7o
7p
7q
7r
H
PhNCO
Bu3SnCl
Ph2S2
Me2SO4
Ph2CO
Ph2S2
PhNHCO 70
Bu3Sn
PhS
Me
Ph2COH
PhS
73
79
67
78
59
Me
7 s
[a] Yield of isolated product based on starting ether 6.
tively proposed that the substituent at the 6-position could
exert a stereoelectronic effect that inhibits the 1,3-elimina-
tion process in the intermediate organolithium 8. Although
we carried out all the reactions in the temperature range of
À78 to 08C, we also observed that ether 6a, with the bulky
tert-butyl group as R1, undergoes the carbolithiation reaction
at a lower temperature (over À608C) than ether 6b (over
Scheme 5. Protodesilylation of 7-trimethylsilyl-substituted 2,3-dihydro-
benzofurans 7i,k,m,o.
Chem. Eur. J. 2005, 11, 5397 – 5407
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5399

J. Barluenga et al.
thesized in good yields, avoiding the careful control of the
temperature and the low yields obtained with ether 1a.
Enantioselective synthesis of 3-functionalized-2,3-dihydro-
benzofurans: Having developed an efficient methodology
for the diastereoselective synthesis of 2,3-dihydrobenzofuran
derivatives we next turned our attention to the possibility of
carrying out this reaction enantioselectively by conducting
the carbolithiation reaction in the presence of a bidentate
chiral ligand such as (À)-sparteine.[9] First, we carried out
several experiments with ether 6b and determined that,
under the same reaction conditions, diisopropyl ether was
the most effective solvent with which to obtain high enantio-
selectivity and chemical yield. We did not observe significant
change in the ee values when a less polar solvent such as
hexane was used, but lower chemical yields were obtained.
Accordingly, we carried out a set of experiments with ethers
6a–e in diisopropyl ether using (À)-sparteine in the second
step and at the lowest temperature at which the carbolithia-
tion reaction proceeds to obtain the best enantioselectivity
possible. The results of these experiments are summarized
in Table 3.
Scheme 6. Chemical correlation of 3-ethyl-7-trimethylsilyl-2,3-dihydro-
benzofuran 7q with (À)-(R)-2-sec-butylphenol.
facial selectivity in these cyclization reactions is the same as
that reported for the asymmetric carbolithiation of N-allyl-
2-lithioanilines, which affords (R)-lithiomethylindolines.[9a,b]
Conclusions
In summary, we have developed an effective and general
method for the synthesis of 2,3-dihydrobenzofuran deriva-
tives based on an intramolecular carbolithiation reaction of
o-lithioaryl ethers. Note that this process supposes the first
example in which the carbolithiation reaction can be stop-
ped at the 2,3-dihydrobenzofuran stage by appropriate selec-
tion of the ether moiety. Moreover, and in marked contrast
to the previously published synthesis of dihydrobenzofuran
derivatives by radical cyclization reactions, the strategy de-
scribed herein allows the enantioselective and totally dia-
stereoselective preparation of this kind of heterocycle. Cur-
rent investigations are focused on the application of this
methodology to the preparation of biologically active com-
pounds in which 2,3-dihydrobenzofuran is the basic molecu-
lar framework.
Table 3. Enantioselective synthesis of dihydrobenzofurans 7.
Ether R1
R2
T
[8C]
E+
Product
E
Yield
[%][a]
ee
[%][b]
6a
6a
6b
6b
6b
6c
6d
6d
6e
tBu Me À65 Ph2CO 7b
tBu Me À65 PhNCO 7d
Ph2COH 64
PhNHCO 58
84
86
79
77
80
80
82
81[c]
87
Me
Me
Me
Me À40 D2O
7e
D
47
Ph2COH 60
PhS 61
Me À40 Ph2CO 7 f
Me À40 Ph2S2 7g
Experimental Section
TMS Me À50 PhNCO 7j
PhNHCO 56
PhNHCO 68
General: All reactions were carried out under nitrogen in oven-dried
glassware with magnetic stirring. Temperatures are reported as bath tem-
peratures. Diethyl ether, diisopropyl ether, and THF were continuously
refluxed and freshly distilled from sodium under nitrogen. TMEDA and
(À)-sparteine were refluxed over potassium under nitrogen using benzo-
phenone as indicator and distilled at reduced pressure. Solvents used in
extraction and purification were distilled prior to use. TLC was per-
formed on aluminum-backed plates coated with silica gel 60 with F254 in-
dicator (Merck) and compounds were visualized with UV light (254 nm)
or iodine. Flash column chromatography was carried out on silica gel 60,
230–400 mesh (Merck). Melting points were obtained on a Büchi-Tottoli
apparatus using open capillary tubes and are uncorrected. 1H and 13C
TMS
TMS
i-Pr
H
H
H
À50 PhNCO 7n
À50 Me2SO4 7q
À60 Ph2CO 7r
Me
76
Ph2COH 66
[a] Yield of isolated product based on starting ether 6. [b] The ee values
were assayed by HPLC using mixtures of hexane/2-propanol. [c] The ee
value was determined from the specific rotation of the transformed (À)-
2-sec-butylphenol compared with the literature value.[19]
The absolute configuration of the stereogenic center of
the major enantiomer was unequivocally determined by
chemical correlation of the 2,3-dihydrobenzofuran 7q with
the known (À)-(R)-2-sec-butylphenol 10.[19] Thus, protodesi-
lylation of 2,3-dihydrobenzofuran 7q with HBF4 followed
by reductive ring opening with Li/4,4’-di-tert-butylbiphenyl
(DTBB)[20] afforded, after hydrolysis, 2-sec-butylphenol 10
in 64% yield (Scheme 6). The measure of the specific rota-
tion of 10 {[a]D23 =À15.1; [a]2D3(lit.)[19] =À18.6} allowed the
unequivocal assignment of the absolute configuration of the
stereogenic center as R. We assume the same configuration
for all the examples shown in Table 3. Note that the enantio-
NMR spectra were recorded on
a Varian Inova-400 (400 MHz;
101 MHz), Varian Mercury-plus 300 (300 MHz; 75 MHz) or Varian
Gemini VXR-200 (200 MHz; 50 MHz) spectrometer. Chemical shifts are
reported in ppm relative to tetramethylsilane with the residual solvent
resonance used as the internal standard (CHCl3: dH =7.26 ppm; dC =
76.95 ppm; [D6]DMSO: dH =2.54 ppm; dC =40.15 ppm). 1H NMR data
are reported as follows: chemical shift, multiplicity (s: singlet, d: doublet,
dd: double doublet, td: triplet of doublets, t: triplet, q: quartet, dq:
double quartet, m: multiplet), coupling constants (J in Hz), and integra-
tion. Low-resolution electron-impact mass spectra (EI-LRMS) were ob-
tained at 70 eV on a HP 5987A or Micromass Autospec spectrometer
and only the molecular ions and/or base peaks in the spectra are given.
High-resolution mass spectrometry was carried out on a Micromass Au-
5400
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Chem. Eur. J. 2005, 11, 5397 – 5407

Enantioselective Synthesis of Functionalized Dihydrobenzofurans
FULL PAPER
tospec spectrometer. Elemental analyses were performed with Perkin
Elmer and LECO elemental analysers. Enantiomer ratios were deter-
mined by chiral HPLC analysis using a Hewlett Packard Series 1100 with
G1315A detector and a Chiralcel OD-H column (25”0.46 cm, Daicel
Chem. Ind.) in comparison with the authentic racemic products. Optical
rotations were measured on a Perkin Elmer 241 polarimeter (c=1,
10 mgmLÀ1); [a]D values are given in units of 10À1 degcm2 gÀ1. All com-
mercially available reagents were used without further purification unless
otherwise indicated and were purchased from Aldrich Chemical Co. and
Acros Organics. tBuLi was used as a 1.5m solution in pentane. Ether 1a
was prepared as described in our previous report.[14c]
added to the solution and the resulting mixture was refluxed for 24 h.
Then the mixture was cooled to room temperature and concentrated to
about 5 mL. Water was added and the mixture was extracted with ethyl
acetate (3”15 mL). The combined organic layers were dried with anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure to
afford the corresponding ester (4.80 g, 88%) which was used in the next
reaction step without further purification. 1H NMR (CDCl3, 400 MHz):
d=7.52 (dd, J=7.9, 1.6 Hz, 1H), 7.21–7.15 (m, 1H), 6.86–6.81 (m, 1H),
6.79 (dd J=8.2, 1.3 Hz, 1H), 4.73 (q, J=6.9 Hz, 1H), 4.24–4.14 (m, 2H),
1.66 (d, J=6.9 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H) ppm; 13C NMR (CDCl3,
101 MHz): d=171.4, 154.1, 133.4, 128.2, 122.8, 114.7, 112.8, 73.9, 61.2,
18.3, 13.9 ppm; LRMS (70 eV, EI): m/z (%): 274 (38) [M+2]+, 272 (38)
[M]+, 199 (100).
Procedure for the synthesis of 2-bromophenyl 1-cyclohexyl-2-propenyl
ether (1b)
Preparation of 2-(2-bromophenoxy)propanal: A solution of DIBAL-H
(15 mL of a 1.0m solution in hexane, 15 mmol) was added dropwise
through a syringe to a solution of ethyl 2-(2-bromophenoxy)propanoate
(4.10 g, 15 mmol) in CH2Cl2 (40 mL) at À788C. The resulting solution
was stirred for an additional 3 h at this temperature prior to quenching
with MeOH and the mixture was allowed to warm to room temperature.
Water was then added and the reaction mixture was filtered through a
pad of Celite and extracted with CH2Cl2 (3”20 mL). The combined or-
ganic layers were dried with anhydrous Na2SO4, filtered, concentrated
under reduced pressure, and purified by silica gel column chromatogra-
phy (hexane/ethyl acetate, 7:1) to give the title compound (2.92 g, 85%)
as a colorless oil. Rf =0.29 (hexane/ethyl acetate, 3:1); 1H NMR (CDCl3,
400 MHz): d=9.76 (d, J=1.8 Hz, 1H), 7.56 (dd, J=7.9, 1.6 Hz, 1H),
7.25–7.19 (m, 1H), 6.91–6.86 (m, 1H), 6.80 (dd, J=8.2, 1.4 Hz, 1H), 4.62
(dq, J=6.9, 1.8 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H) ppm; 13C NMR (CDCl3,
101 MHz): d=201.6, 153.8, 133.7, 128.4, 123.2, 115.1, 113.1, 79.4,
15.4 ppm; LRMS (70 eV, EI): m/z (%): 230 (86) [M+2]+, 228 (87) [M]+,
63 (100).
Preparation of 1-cyclohexyl-2-propynol: A solution of cyclohexanecar-
boxaldehyde (5.60 g, 50 mmol) in THF (20 mL) was added dropwise to a
solution of 0.5m ethynylmagnesium bromide in THF (100 mL, 50 mmol)
at 08C. After stirring for an additional 1 h at room temperature, the reac-
tion mixture was quenched with saturated aqueous NH4Cl. The aqueous
layer was extracted with ethyl acetate (3”30 mL) and the combined or-
ganic layers were dried with anhydrous Na2SO4, filtered, and concentrat-
ed under reduced pressure. Purification of the residue by column chro-
matography (hexane/ethyl acetate, 7:1) afforded 1-cyclohexyl-2-propynol
(6.42 g, 93%) as a colorless oil. Rf =0.17 (hexane/ethyl acetate, 7:1); 1H
NMR (CDCl3, 400 MHz): d=4.13–4.08 (m, 1H), 2.48 (s, 1H), 2.42 (d, J=
2.2 Hz, 1H), 1.85–1.59 (m, 5H), 1.56–1.46 (m, 1H), 1.27–0.96 (m,
5H) ppm; 13C NMR (CDCl3, 101 MHz): d=83.9, 73.3, 66.7, 43.7, 28.3,
27.8, 26.2, 25.7, 25.6 ppm ppm; LRMS (70 eV, EI): m/z (%): 138 (1) [M]+
, 55 (100).
Preparation of 2-bromophenyl 1-cyclohexyl-2-propynyl ether: A solution
of diisopropyl azodicarboxylate (6.06 g, 30 mmol) in THF (10 mL) was
added dropwise to a solution of 2-bromophenol (5.19 g, 30 mmol), 1-cy-
clohexyl-2-propynol (4.14 g, 30 mmol), and PPh3 (7.86 g, 30 mmol) in
THF (40 mL) at 08C. After stirring for 12 h at room temperature, the re-
action mixture was quenched with water and extracted with ethyl acetate
(3”15 mL). The combined organic layers were dried with anhydrous
Na2SO4, filtered, concentrated under reduced pressure, and purified by
silica gel column chromatography (hexane/ethyl acetate, 40:1) to afford
2-bromophenyl 1-cyclohexyl-2-propynyl ether (5.63 g, 64%) as a pale
yellow solid. M.p. 34–368C; 1H NMR (CDCl3, 400 MHz): d=7.54 (dd,
J=7.9, 1.6 Hz, 1H), 7.29–7.23 (m, 1H), 7.13 (dd, J=8.3, 1.4 Hz, 1H),
6.88–6.83 (m, 1H), 4.54 (dd, J=5.8, 2.1 Hz, 1H), 2.50 (d, J=2.1 Hz, 1H),
2.09–1.78 (m, 5H), 1.76–1.68 (m, 1H), 1.41–1.15 (m, 5H) ppm; 13C NMR
(CDCl3, 101 MHz): d=154.0, 133.2, 128.1, 122.3, 115.0, 112.7, 80.5, 75.7,
73.3, 42.6, 28.4, 28.2, 26.2, 25.8, 25.7 ppm; LRMS (70 eV, EI): m/z (%):
294 (4) [M+2]+, 292 (4) [M]+, 209 (100).
Procedure for the synthesis of 2-bromophenyl 3-buten-2-yl ether (1c): A
solution of LDA, obtained by addition of nBuLi (6.0 mL of a 2.5m solu-
tion in hexane, 15 mmol) to a solution of diisopropylamine (2.10 mL,
15 mmol) in THF (5 mL), was added dropwise to a stirred suspension of
methyltriphenylphosphonium bromide (5.36 g, 15 mmol) in THF (10 mL)
at 08C. The mixture was stirred for an additional 1.5 h at 08C and a solu-
tion of 2-(2-bromophenoxy)propanal (2.29 g, 10 mmol) in THF (10 mL)
was added dropwise at 08C. The suspension was then allowed to warm to
room temperature and stirred for an additional 10 h. Water was added
and the mixture was extracted with ethyl acetate (3”15 mL). The com-
bined organic layers were dried with anhydrous Na2SO4, filtered, concen-
trated under reduced pressure, and purified by silica gel column chroma-
tography (hexane/ethyl acetate, 100:1) to give 1c (1.27 g, 56%) as a col-
orless oil. Rf =0.43 (hexane/ethyl acetate, 10:1); 1H NMR (CDCl3,
400 MHz): d=7.53 (d, J=8.0 Hz, 1H), 7.24–7.18 (m, 1H), 6.92 (d, J=
8.3 Hz, 1H), 6.84–6.79 (m, 1H), 5.99–5.88 (m, 1H), 5.29 (dd, J=17.2,
1.2 Hz, 1H), 5.18 (dd, J=10.5, 1.2 Hz, 1H), 4.81 (quintet, J=6.3 Hz,
1H), 1.50 (d, J=6.3 Hz, 3H) ppm; 13C NMR (CDCl3, 101 MHz): d=
154.3, 138.5, 133.2, 128.0, 121.9, 115.9, 115.8, 113.2, 76.3, 21.2 ppm; LRMS
(70 eV, EI): m/z (%): 228 (7) [M+2]+, 226 (7) [M]+, 172 (100); elemen-
tal analysis calcd (%) for C10H11BrO: C 52.89, H 4.88; found: C 52.86, H
4.90.
Preparation of 2-bromophenyl 1-cyclohexyl-2-propenyl ether (1b): A sus-
pension of palladium (5% on calcium carbonate, 0.39 g) in hexane
(3 mL) was added to a solution of 2-bromophenyl 1-cyclohexyl-2-propyn-
yl ether (4.40 g, 15 mmol) and quinoline (0.56 mL, 3.89 mmol) in hexane
(20 mL). The mixture was stirred under hydrogen (1 atm) at room tem-
perature until the reaction had gone to completion, which was monitored
by GC–MS. The mixture was filtered through a pad of Celite to remove
the catalyst and then hexane was removed under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(hexane/ethyl acetate, 100:1) to afford 1b (3.45 g, 78%) as a colorless oil.
Rf =0.48 (hexane/ethyl acetate, 10:1); 1H NMR (CDCl3, 400 MHz): d=
7.51 (dd, J=7.9, 1.6 Hz, 1H), 7.20–7.14 (m, 1H), 6.86 (dd, J=8.3, 1.3 Hz,
1H), 6.81–6.75 (m, 1H), 5.89–5.79 (m, 1H), 5.27–5.17 (m, 2H), 4.40 (t,
J=6.1 Hz, 1H), 2.02–1.94 (m, 1H), 1.86–1.63 (m, 5H), 1.35–1.10 (m,
5H) ppm; 13C NMR (CDCl3, 101 MHz): d=154.8, 135.9, 133.1, 127.9,
121.4, 117.5, 115.2, 112.9, 84.6, 42.6, 28.7, 28.2, 26.4, 26.1, 26.0 ppm;
LRMS (70 eV, EI): m/z (%): 296 (1) [M+2]+, 294 (1) [M]+, 81 (100); el-
emental analysis calcd (%) for C15H19BrO: C 61.03, H 6.49; found: C
61.09, H 6.46.
Procedure for the synthesis of the starting ether (R)-1c
Preparation of (R)-ethyl 2-(2-bromophenoxy)propanoate: The title com-
pound was prepared from 2-bromophenol and (S)-ethyl lactate under
Mitsunobu conditions following the procedure described in the litera-
ture.[18] HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=90:10, flow
rate=0.8 mLminÀ1, l=210 nm): tR =5.84 (minor), 7.06 (major) min.
Procedure for the synthesis of (R)-2-bromophenyl 3-buten-2-yl ether [(R)-
1c]: The title compound was prepared from (R)-ethyl 2-(2-bromophenox-
y)propanoate by the same procedure (DIBAL reduction and Wittig olefi-
nation) as described above for the synthesis of the racemic ether. HPLC
(Daicel Chiralcel OD-H, hexane/2-PrOH=99.5:0.5, flow rate=
0.8 mLminÀ1, l=210 nm): tR =16.45 (minor), 21.68 (major) min.
Procedure for the synthesis of 2-bromophenyl 3-buten-2-yl ether (1c)
Preparation of ethyl 2-(2-bromophenoxy)propanoate: 2-Bromophenol
(3.46 g, 20 mmol) and ethyl 2-bromopropanoate (3.62 g, 10 mmol) were
dissolved in acetone (50 mL). Potassium carbonate (2.76 g, 20 mmol) was
General procedure for the synthesis of starting ethers 6a–g: 2-Bromo-6-
tert-butyl-4-methylphenol,
2-bromo-4,6-dimethylphenol,
2-bromo-4-
chloro-6-methylphenol, and 2-bromo-6-chloro-4-methylphenol were pre-
Chem. Eur. J. 2005, 11, 5397 – 5407
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5401

J. Barluenga et al.
pared by bromination of commercially available 2-tert-butyl-4-methylphe-
nol, 2,4-dimethylphenol, 4-chloro-2-methylphenol, and 2-chloro-4-methyl-
phenol with bromine in CH2Cl2. 2-Bromo-6-isopropylphenol was pre-
pared by bromination of 2-isopropylphenol with Br2/tBuNH2.[21] 2-
Bromo-4-methyl-6-trimethylsilylphenol and 2-bromo-6-trimethylsilylphe-
nol were prepared by treatment of the corresponding O-trimethylsilyl
ether of 2,6-dibromo-4-methylphenol and 2,6-dibromophenol with
nBuLi.[22] The corresponding 2-bromophenol (25 mmol) and allyl bro-
mide (4.24 g, 35 mmol) were dissolved in acetone (50 mL), potassium car-
bonate (3.46 g, 25 mmol) was added to the solution, and the resulting
mixture was refluxed for 24 h. Then the mixture was cooled to room tem-
perature and concentrated to about 5 mL. Water was added and the mix-
ture was extracted with ethyl acetate (3”15 mL). The combined organic
layers were dried with anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatogra-
phy (hexane/ethyl acetate, 100:1) to afford the corresponding ethers 6.
scribed above yielded 6e (5.23 g, 82%) as a colorless oil. Rf =0.57
(hexane/ethyl acetate, 5:1); H NMR (CDCl3, 400 MHz): d=7.38 (dd, J=
1
7.8, 1.6 Hz, 1H), 7.20 (dd, J=7.8, 1.6 Hz, 1H), 6.98 (t, J=7.8 Hz, 1H),
6.15 (ddt, J=17.2, 10.4, 5.6 Hz, 1H), 5.46 (dq, J=17.2, 1.5 Hz, 1H), 5.29
(dq, J=10.4, 1.5 Hz, 1H), 4.45 (dt, J=5.6, 1.5 Hz, 2H), 3.36 (sept., J=
7.0 Hz, 1H), 1.22 (d, J=7.0 Hz, 6H) ppm; 13C NMR (CDCl3, 101 MHz):
d=153.0, 144.2, 133.4, 130.7, 125.8, 125.5, 117.6, 117.5, 74.4, 27.1,
23.7 ppm; LRMS (70 eV, EI): m/z (%): 256 (73) [M+2]+, 254 (74) [M]+,
41 (100); HRMS (EI) calcd for C12H15BrO: 254.0306; found: 254.0308; el-
emental analysis calcd (%) for C12H15BrO: C 56.49, H 5.93; found: C
56.52, H 5.97.
2-Bromo-4-chloro-6-methylphenyl 2-propenyl ether (6 f): Reaction of 2-
bromo-4-chloro-6-methylphenol (5.54 g, 25 mmol), K2CO3 (3.46 g,
25 mmol), and allyl bromide (4.24 g, 35 mmol) in acetone (50 mL) fol-
lowed by workup as described above yielded 6 f (5.43 g, 83%) as a white
solid. M.p. 36–388C; 1H NMR (CDCl3, 400 MHz): d=7.37 (dq, J=2.6,
0.6 Hz, 1H), 7.09 (dq, J=2.6, 0.6 Hz, 1H), 6.11 (ddt, J=17.2, 10.4,
5.8 Hz, 1H), 5.42 (dq, J=17.2, 1.5 Hz, 1H), 5.28 (dq, J=10.4, 1.5 Hz,
1H), 4.40 (dt, J=5.8, 1.5 Hz, 2H), 2.28 (t, J=0.6 Hz, 3H) ppm; 13C NMR
(CDCl3, 101 MHz): d=153.0, 134.6, 133.1, 130.3, 130.0, 129.3, 118.2,
117.8, 73.7, 16.8 ppm; LRMS (70 eV, EI): m/z (%): 264 (8) [M+4]+, 262
(36) [M+2]+, 260 (28) [M]+, 221 (100); HRMS (EI) calcd for
C10H10BrClO: 259.9604; found: 259.9608.
2-Bromo-6-tert-butyl-4-methylphenyl 2-propenyl ether (6a): Reaction of
2-bromo-6-tert-butyl-4-methylphenol (6.09 g, 25 mmol), K2CO3 (3.46 g,
25 mmol), and allyl bromide (4.24 g, 35 mmol) in acetone (50 mL), fol-
lowed by workup as described above, yielded 6a (5.59 g, 79%) as a color-
less oil. Rf =0.59 (hexane/ethyl acetate, 10:1); 1H NMR (CDCl3,
400 MHz): d=7.25 (s, 1H), 7.07 (s, 1H), 6.19–6.08 (m, 1H), 5.50 (dq, J=
17.2, 1.6 Hz, 1H), 5.30 (dq, J=10.6, 1.6 Hz, 1H), 4.57 (dt, J=5.2, 1.6 Hz,
2H), 2.27 (s, 3H), 1.38 (s, 9H) ppm; 13C NMR (CDCl3, 101 MHz): d=
152.5, 144.7, 134.1, 133.4, 132.1, 127.4, 117.9, 117.0, 73.3, 35.4, 30.8,
20.7 ppm; LRMS (70 eV, EI): m/z (%): 284 (11) [M+2]+, 282 (11) [M]+,
162 (100); HRMS (EI): calcd for C14H19BrO: 282.0619; found: 282.0620;
elemental analysis calcd (%) for C14H19BrO: C 59.37, H 6.76; found: C
59.43, H 6.73.
2-Bromo-6-chloro-4-methylphenyl 2-propenyl ether (6g): Reaction of 2-
bromo-6-chloro-4-methylphenol (5.54 g, 25 mmol), K2CO3 (3.46 g,
25 mmol), and allyl bromide (4.24 g, 35 mmol) in acetone (50 mL) fol-
lowed by workup as described above yielded 6g (5.36 g, 82%) as a color-
less oil. Rf =0.37 (hexane/ethyl acetate, 30:1); 1H NMR (CDCl3,
400 MHz): d=7.25 (dq, J=2.1, 0.7 Hz, 1H), 7.12 (dq, J=2.1, 0.7 Hz,
1H), 6.15 (ddt, J=17.2, 10.4, 5.9 Hz, 1H), 5.43 (dq, J=17.2, 1.5 Hz, 1H),
5.27 (dq, J=10.4, 1.5 Hz, 1H), 4.51 (dt, J=5.9, 1.5 Hz, 2H), 2.26 (t, J=
0.7 Hz, 3H) ppm; 13C NMR (CDCl3, 101 MHz): d=149.7, 135.8, 133.0,
132.2, 130.0, 128.6, 118.5, 118.2, 74.1, 20.3 ppm; LRMS (70 eV, EI): m/z
(%): 264 (12) [M+4]+, 262 (55) [M+2]+, 260 (42) [M]+, 221 (100);
HRMS (EI) calcd for C10H10BrClO: 259.9604; found 259.9598.
2-Bromo-4,6-dimethylphenyl 2-propenyl ether (6b): Reaction of 2-
bromo-4,6-dimethylphenol (5.03 g, 25 mmol), K2CO3 (3.46 g, 25 mmol),
and allyl bromide (4.24 g, 35 mmol) in acetone (50 mL) followed by
workup as described above yielded 6b (4.88 g, 81%) as a colorless oil.
Rf =0.34 (hexane/ethyl acetate, 25:1); 1H NMR (CDCl3, 400 MHz): d=
7.19 (s, 1H), 6.91 (s, 1H), 6.13 (ddt, J=17.1, 10.4, 5.7 Hz, 1H), 5.43 (dq,
J=17.1, 1.4 Hz, 1H), 5.26 (dq, J=10.4, 1.4 Hz, 1H), 4.40 (dt, J=5.7,
1.4 Hz, 2H), 2.27 (s, 3H), 2.24 (s, 3H) ppm; 13C NMR (CDCl3,
101 MHz): d=151.9, 134.8, 133.6, 132.7, 131.2, 130.9, 117.7, 117.0, 73.5,
20.4, 17.0 ppm; LRMS (70 eV, EI): m/z (%): 242 (34) [M+2]+, 240 (34)
[M]+, 199 (100); HRMS (EI): calcd for C11H13BrO: 240.0150; found:
240.0148; elemental analysis calcd (%) for C11H13BrO: C 54.79, H 5.43;
found: C 54.75, H 5.41.
Procedure for the carbolithiation of ether 1a: Preparation of 2-cyclopro-
pylphenol (4) and 2,3-dihydrobenzofuran derivatives 5a and 5b: A solu-
tion of ether 1a (213 mg, 1 mmol) in diethyl ether (10 mL) cooled in a
dry ice/acetone bath at À788C was treated with tBuLi (1.33 mL, 2 mmol)
and the reaction mixture was stirred for 15 min at this temperature.
TMEDA (0.33 mL, 2.2 mmol) was added to the resulting solution at
À788C and the reaction mixture was stirred for an additional 30 min at
this temperature. The resulting mixture was allowed to warm to À208C
and stirred overnight at this temperature. Then the corresponding elec-
trophile (PhNCO or Ph2S2, 1.1 mmol) was added at À788C. Stirring was
continued for 30 min at this temperature and then for 5 h at room tem-
perature before the hydrolysis with water. The mixture was extracted
with ethyl acetate (3”10 mL) and the combined organic layers were
washed with 1m HCl (2”10 mL), dried with anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate).
2-Bromo-4-methyl-6-trimethylsilylphenyl 2-propenyl ether (6c): Reaction
of 2-bromo-4-methyl-6-trimethylsilylphenol (6.48 g, 25 mmol), K2CO3
(3.46 g, 25 mmol), and allyl bromide (4.24 g, 35 mmol) in acetone
(50 mL) followed by workup as described above yielded 6c (5.54 g, 74%)
1
as a colorless oil. Rf =0.49 (hexane/ethyl acetate, 30:1); H NMR (CDCl3,
400 MHz): d=7.39 (s, 1H), 7.13 (s, 1H), 6.17–6.06 (m, 1H), 5.47 (dq, J=
17.3, 1.6 Hz, 1H), 5.29 (dq, J=10.6, 1.6 Hz, 1H), 4.50 (dt, J=5.3, 1.6 Hz,
2H), 2.29 (s, 3H), 0.30 (s, 9H) ppm; 13C NMR (CDCl3, 101 MHz): d=
157.8, 135.3, 135.0, 134.8, 133.4, 117.2, 116.4, 73.9, 20.4, À0.3 ppm; LRMS
(70 eV, EI): m/z (%): 300 (14) [M+2]+, 298 (14) [M]+, 177 (100); HRMS
(EI) calcd for C13H19BrOSi: 298.0389; found: 298.0393.
2-Cyclopropylphenol (4): The spectral data of 4 were in total agreement
with those previously reported.[14c]
2-Bromo-6-trimethylsilylphenyl 2-propenyl ether (6d): Reaction of 2-
bromo-6-trimethylsilylphenol (6.13 g, 25 mmol), K2CO3 (3.46 g,
25 mmol), and allyl bromide (4.24 g, 35 mmol) in acetone (50 mL) fol-
lowed by workup as described above yielded 6d (5.49 g, 77%) as a color-
less oil. Rf =0.57 (hexane/ethyl acetate, 10:1); 1H NMR (CDCl3,
400 MHz): d=7.56 (dd, J=7.9, 1.6 Hz, 1H), 7.35 (dd, J=7.5, 1.6 Hz,
1H), 6.98 (dd, J=7.9, 7.5 Hz, 1H), 6.17–6.06 (m, 1H), 5.48 (dq, J=17.3,
1.6 Hz, 1H), 5.30 (dq, J=10.6, 1.6 Hz, 1H), 4.53 (dt, J=5.3, 1.6 Hz, 1H),
0.30 (s. 9H) ppm; 13C NMR (CDCl3, 101 MHz): d=160.1, 135.6, 135.1,
134.4, 133.3, 125.2, 117.2, 116.8, 73.8, À0.3 ppm; LRMS (70 eV, EI): m/z
(%): 286 (4) [M+2]+, 284 (3) [M]+, 269 (100); elemental analysis calcd
(%) for C12H17BrOSi: C 50.53, H 6.01; found: C 50.59, H 5.98.
(2,3-Dihydrobenzofuran-3-yl)-N-phenylacetamide
(5a):
Ether
1a
(213 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and
TMEDA (0.33 mL, 2.2 mmol). Addition of phenyl isocyanate (131 mg,
1.1 mmol) and workup as described above yielded 5a (86 mg, 34%) as a
pale yellow solid. M.p. 128–1308C (lit.[23] 132–1338C); 1H NMR
([D6]DMSO, 400 MHz): d=10.02 (s, 1H), 7.65–7.56 (m, 2H), 7.33–7.17
(m, 3H), 7.13–6.98 (m, 2H), 6.85–6.72 (m, 2H), 4.68 (t, J=9.0 Hz, 1H),
4.24 (dd, J=9.0, 6.6 Hz, 1H), 3.92–3.81 (m, 1H), 2.83 (dd, J=15.2,
5.9 Hz, 1H), 2.61 (dd, J=15.2, 8.8 Hz, 1H) ppm; 13C NMR ([D6]DMSO,
101 MHz): d=170.1, 160.1, 139.7, 130.8, 129.4, 128.9, 125.2, 123.9, 121.0,
119.8, 109.9, 76.9, 42.1, 38.7 ppm; LRMS (70 eV, EI): m/z (%): 253 (88)
[M]+, 134 (100); HRMS (EI) calcd for C15H15NO2: 253.1102; found:
253.1099.
2-Bromo-6-isopropylphenyl 2-propenyl ether (6e): Reaction of 2-bromo-
6-isopropylphenol (5.38 g, 25 mmol), K2CO3 (3.46 g, 25 mmol), and allyl
bromide (4.24 g, 35 mmol) in acetone (50 mL) followed by workup as de-
3-Phenylthiomethyl-2,3-dihydrobenzofuran (5b):[12f] Ether 1a (213 mg,
1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and TMEDA
5402
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 5397 – 5407

Enantioselective Synthesis of Functionalized Dihydrobenzofurans
FULL PAPER
(0.33 mL, 2.2 mmol). Addition of diphenyl disulfide (237 mg, 1.1 mmol)
and workup as described above yielded 5b (70 mg, 29%) as a colorless
oil. Rf =0.40 (hexane/ethyl acetate, 5:1); 1H NMR (CDCl3, 400 MHz):
d=7.42–7.37 (m, 2H), 7.34–7.29 (m, 2H), 7.27–7.20 (m, 2H), 7.18–7.13
(m, 1H), 6.90–6.84 (m, 1H), 6.82–6.79 (m, 1H), 4.62 (t, J=9.1 Hz, 1H),
4.45 (dd, J=9.1, 5.5 Hz, 1H), 3.68–3.57 (m, 1H), 3.32 (dd, J=13.0,
5.0 Hz, 1H), 3.01 (dd, J=13.0, 9.7 Hz, 1H) ppm; 13C NMR (CDCl3,
101 MHz): d=159.9, 135.4, 129.8, 129.0, 128.8, 126.5, 124.5, 120.4, 109.7,
76.0, 41.5, 38.8 ppm; LRMS (70 eV, EI): m/z (%): 242 (95) [M]+, 77
(100); HRMS (EI) calcd for C15H14OS: 242.0765; found: 242.0766.
(CDCl3, 400 MHz): d=7.17–7.14 (m, 1H), 7.11–7.05 (m, 1H), 6.83–6.78
(m, 1H), 6.76–6.71 (m, 1H), 4.43 (t, J=4.4 Hz, 1H), 3.38–3.32 (m, 1H),
1.83–1.47 (m, 12H), 1.35–0.98 (m, 6H), 0.94–0.85 (m, 6H) ppm; 13C
NMR (CDCl3, 101 MHz): d=159.3, 132.1, 127.7, 124.3, 119.8, 108.7, 93.9,
74.9, 45.4, 42.2, 40.0, 31.6, 30.7, 29.8, 26.6, 26.3, 26.2, 25.9, 8.0, 7.6 ppm;
LRMS (70 eV, EI): m/z (%): 302 (12) [M]+, 161 (100); HRMS (EI) calcd
for C20H30O2: 302.2246; found: 302.2244.
(R*,S*)-2,3-Dimethyl-2,3-dihydrobenzofuran (5g):[16] Ether 1c (227 mg,
1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and TMEDA
(0.33 mL, 2.2 mmol). Addition of water (excess) and workup as described
above yielded 5g (110 mg, 74%) as a colorless oil. Rf =0.34 (hexane/
ethyl acetate, 10:1); 1H NMR (CDCl3, 400 MHz): d=7.15–7.09 (m, 2H),
6.89–6.84 (m, 1H), 6.79–6.75 (m, 1H), 4.35 (dq, J=8.4, 6.3 Hz, 1H),
3.11–3.02 (m, 1H), 1.49 (d, J=6.3 Hz, 3H), 1.32 (d, J=6.9 Hz, 3H) ppm;
13C NMR (CDCl3, 101 MHz): d=159.0, 132.4, 127.9, 123.6, 120.2, 109.3,
87.2, 43.8, 20.0, 17.9 ppm; LRMS (70 eV, EI): m/z (%): 148 (62) [M]+,
133 (100); HRMS (EI) calcd for C10H12O: 148.0888; found: 148.0891.
General procedure for the carbolithiation of ethers 1b,c and 6: Prepara-
tion of 2,3-dihydrobenzofuran derivatives 5c–h, 7a—s, and 2-chloro-6-cy-
clopropyl-4-methylphenol (9): A solution of the corresponding starting
ether 1b,c or 6 (1 mmol) in diethyl ether (10 mL) cooled in a dry ice/ace-
tone bath at À788C was treated with tBuLi (1.33 mL, 2 mmol) and the
reaction mixture was stirred for 15 min at this temperature. TMEDA
(0.33 mL, 2.2 mmol) was added to the resulting solution at À788C and
the reaction mixture was stirred for an additional 30 min at this tempera-
ture. The mixture was allowed to warm to 08C and then stirred for an ad-
ditional 15 min for ethers 1b,c and 6a–e, 1 h for ether 6 f, and 3 h for
ether 6g. The corresponding electrophile (1.1 mmol) was added to the so-
lution at À788C and stirring was continued for 30 min at this temperature
and then for 5 h at room temperature prior to the addition of water. The
mixture was extracted with ethyl acetate (3”10 mL) and the combined
organic layers were washed with 1m HCl (2”10 mL), dried with anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography.
(R*,S*)-2-(2-Methyl-2,3-dihydrobenzofuran-3-yl)-1,1-diphenylethanol
(5h): Ether 1c (227 mg, 1 mmol) was treated with tBuLi (1.33 mL,
2 mmol) and TMEDA (0.33 mL, 2.2 mmol). Addition of benzophenone
(200 mg, 1.1 mmol) and workup as described above yielded 5g (215 mg,
1
65%) as a white solid. M.p. 132–1348C; H NMR (CDCl3, 400 MHz): d=
7.51–7.23 (m, 10H), 7.13–7.07 (m, 1H), 7.04 (d, J=7.4 Hz, 1H), 6.85–6.79
(m, 1H), 7.23 (d, J=8.0 Hz, 1H), 4.61–4.54 (m, 1H), 3.10–3.04 (m, 1H),
2.75–2.65 (m, 2H), 2.21 (s, 1H), 1.16 (d, J=6.2 Hz, 3H) ppm; 13C NMR
(CDCl3, 101 MHz): d=158.7, 147.0, 146.4, 131.6, 128.3, 128.0, 127.3,
127.1, 126.1, 124.6, 120.1, 109.3, 86.5, 78.4, 48.6, 44.8, 20.6 ppm; LRMS
(70 eV, EI): m/z (%): 330 (75) [M]+, 75 (100); elemental analysis calcd
(%) for C23H22O2: C 83.60, H 6.71; found: C 83.54, H 6.72.
(R*,S*)-2-Cyclohexyl-3-deuteriomethyl-2,3-dihydrobenzofuran
(5c):
Ether 1b (295 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of deuterium oxide (excess)
and workup as described above yielded 5c (152 mg, 70%) as a white
(2R,3S)-5g: HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=99.8:0.2,
flow rate=0.8 mLminÀ1, l=290 nm): tR =8.94 (minor), 9.95 (major) min.
1
solid. M.p. 38–408C; H NMR (CDCl3, 400 MHz): d=7.17–7.10 (m, 2H),
(2R,3S)-5h: HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=90:10,
flow rate=0.8 mLminÀ1, l=210 nm): tR =11.37 (minor), 15.06 (major) -
min.
6.90–6.84 (m, 1H), 6.82–6.76 (m, 1H), 4.08 (t, J=6.9 Hz, 1H), 3.31 (q,
J=6.9 Hz, 1H), 2.02–1.94 (m, 1H), 1.88–1.61 (m, 5H), 1.38–1.09 (m,
7H) ppm; 13C NMR (CDCl3, 101 MHz): d=159.1, 132.3, 127.8, 123.6,
119.8, 108.9, 94.9, 42.5, 39.1, 28.4, 28.3, 26.4, 26.0, 25.8, 20.2 (t, J=
19.6 Hz) ppm; LRMS (70 eV, EI): m/z (%): 217 (14) [M]+, 122 (100);
HRMS (EI) calcd for C15H19DO: 217.1576; found: 217.1580.
7-tert-Butyl-3-deuteriomethyl-5-methyl-2,3-dihydrobenzofuran
(7a):
Ether 6a (283 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of deuterium oxide (excess)
and workup as described above yielded 7a (150 mg, 73%) as a colorless
oil. Rf =0.48 (hexane/ethyl acetate, 25:1); 1H NMR (CDCl3, 400 MHz):
d=6.97 (s, 1H), 6.93 (s, 1H), 4.73 (t, J=8.5 Hz, 1H), 4.10 (t, J=8.5 Hz,
1H), 3.58–3.48 (m, 1H), 2.39 (s, 3H), 1.45 (s, 9H), 1.39–1.35 (m,
2H) ppm; 13C NMR (CDCl3, 101 MHz): d=155.5, 132.7, 132.5, 129.1,
125.2, 121.9, 77.8, 36.2, 33.9, 29.3, 21.0, 18.7 (t, J=19.5 Hz) ppm; LRMS
(70 eV, EI): m/z (%): 205 (28) [M]+, 190 (100); HRMS (EI) calcd for
C14H19DO: 205.1576; found: 205.1573.
(R*,S*)-2-Cyclohexyl-3-trimethylsilylmethyl-2,3-dihydrobenzofuran (5d):
Ether 1b (295 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of chlorotrimethylsilane
(120 mg, 1.1 mmol) and workup as described above yielded 5d (185 mg,
64%) as a colorless oil. Rf =0.60 (hexane/ethyl acetate, 15:1); 1H NMR
(CDCl3, 400 MHz): d=7.11–7.06 (m, 2H), 6.84–6.79 (m, 1H), 6.76–6.73
(m, 1H), 4.14 (t, J=5.3 Hz, 1H), 3.34 (q, J=6.0 Hz, 1H), 1.85–1.62 (m,
5H), 1.58–1.46 (m, 1H), 1.30–1.04 (m, 5H), 1.00 (d, J=6.5 Hz, 2H), 0.03
(s, 9H) ppm; 13C NMR (CDCl3, 101 MHz): d=159.1, 133.3, 127.7, 124.0,
119.8, 108.9, 94.6, 42.7, 40.8, 29.4, 27.3, 26.4, 26.2, 25.9, 24.6, À0.5 ppm;
LRMS (70 eV, EI): m/z (%): 288 (21) [M]+, 73 (100); HRMS (EI) calcd
for C18H28OSi: 288.1909; found: 288.1911.
2-(7-tert-Butyl-5-methyl-2,3-dihydrobenzofuran-3-yl)-1,1-diphenylethanol
(7b): Ether 6a (283 mg, 1 mmol) was treated with tBuLi (1.33 mL,
2 mmol) and TMEDA (0.33 mL, 2.2 mmol). Addition of benzophenone
(200 mg, 1.1 mmol) and workup as described above yielded 7b (282 mg,
73%) as a colorless oil. Rf =0.28 (hexane/ethyl acetate, 5:1); 1H NMR
(CDCl3, 400 MHz): d=7.57–7.47 (m, 4H), 7.44–7.29 (m, 6H), 6.95 (s,
1H), 6.87 (s, 1H), 4.44 (t, J=9.0 Hz, 1H), 4.00 (t, J=9.0 Hz, 1H), 3.56–
3.46 (m, 1H), 3.00 (dd, J=14.1, 2.1 Hz, 1H), 2.64 (dd, J=14.1, 10.3 Hz,
1H), 2.37 (s, 3H), 2.30 (s, 1H), 1.41 (s, 9H) ppm; 13C NMR (CDCl3,
101 MHz): d=155.5, 147.0, 146.3, 132.4, 131.5, 129.0, 128.3, 128.2, 127.2,
127.0, 126.0, 125.9, 125.3, 121.8, 78.0, 77.6, 47.1, 37.8, 33.8, 29.2, 21.0 ppm;
LRMS (70 eV, EI): m/z (%): 386 (52) [M]+, 355 (100); HRMS (EI) calcd
for C27H30O2: 386.2246; found: 386.2245.
(R*,S*)-2-Cyclohexyl-3-phenylthiomethyl-2,3-dihydrobenzofuran
(5e):
Ether 1b (295 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of diphenyl disulfide
(237 mg, 1.1 mmol) and workup as described above yielded 5e (260 mg,
80%) as a colorless oil. Rf =0.27 (hexane/ethyl acetate, 30:1); 1H NMR
(CDCl3, 400 MHz): d=7.44–7.39 (m, 2H), 7.37–7.30 (m, 3H), 7.27–7.16
(m, 2H), 6.91–6.86 (m, 1H), 6.86–6.82 (m, 1H), 4.45 (dd, J=6.0, 4.5 Hz,
1H), 3.49–3.43 (m, 1H), 3.29 (dd, J=12.8, 5.5 Hz, 1H), 3.10 (dd, J=12.8,
8.6 Hz, 1H), 1.89–1.52 (m, 6H), 1.30–1.02 (m, 5H) ppm; 13C NMR
(CDCl3, 101 MHz): d=159.5, 135.9, 129.1, 129.0, 128.9, 128.7, 126.1,
124.5, 119.9, 109.2, 91.7, 43.7, 42.5, 39.5, 28.4, 27.5, 26.2, 25.9, 25.7 ppm;
LRMS (70 eV, EI): m/z (%): 324 (35) [M]+, 83 (100); elemental analysis
calcd (%) for C21H24OS: C 77.73, H 7.46; found: C 77.70, H 7.47.
3-Bromomethyl-7-tert-butyl-5-methyl-2,3-dihydrobenzofuran (7c): Ether
6a (283 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and
TMEDA (0.33 mL, 2.2 mmol). Addition of 1,2-dibromoethane (207 mg,
1.1 mmol) and workup as described above yielded 7c (178 mg, 63%) as a
1
white solid. M.p. 65–678C; H NMR (CDCl3, 400 MHz): d=6.96 (s, 1H),
(R*,S*)-3-(2-Cyclohexyl-2,3-dihydrobenzofuran-3-ylmethyl)-3-pentanol
(5 f): Ether 1b (295 mg, 1 mmol) was treated with tBuLi (1.33 mL,
2 mmol) and TMEDA (0.33 mL, 2.2 mmol). Addition of 3-pentanone
(95 mg, 1.1 mmol) and workup as described above yielded 5 f (221 mg,
73%) as a colorless oil. Rf =0.18 (hexane/ethyl acetate, 10:1); 1H NMR
6.91 (s, 1H), 4.64 (t, J=9.2 Hz, 1H), 4.46 (dd, J=9.2, 5.3 Hz, 1H), 3.84–
3.75 (m, 1H), 3.65 (dd, J=10.0, 4.4 Hz, 1H), 3.40 (t, J=10.0 Hz, 1H),
2.32 (s, 3H), 1.36 (s, 9H) ppm; 13C NMR (CDCl3, 101 MHz): d=156.0,
133.2, 129.5, 127.9, 126.7, 122.4, 75.3, 44.7, 35.2, 33.9, 29.2, 21.0 ppm;
LRMS (70 eV, EI): m/z (%): 284 (55) [M+2]+, 282 (59) [M]+, 267 (100);
Chem. Eur. J. 2005, 11, 5397 – 5407
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5403

J. Barluenga et al.
elemental analysis calcd (%) for C14H19BrO: C 59.37, H 6.76; found: C
59.44, H 6.79.
and workup as described above yielded 7i (166 mg, 75%) as a colorless
oil. Rf =0.52 (hexane/ethyl acetate, 20:1); 1H NMR (CDCl3, 400 MHz):
d=7.12–7.07 (m, 2H), 4.73 (t, J=8.7 Hz, 1H), 4.10 (dd, J=8.7, 7.8 Hz,
1H), 3.61–3.51 (m, 1H), 2.41 (s, 3H), 1.42–1.38 (m, 2H), 0.40 (s,
9H) ppm; 13C NMR (CDCl3, 50 MHz): d=162.8, 133.2, 130.8, 128.9,
125.5, 119.2, 77.9, 36.0, 20.8, 18.7 (t, J=19.5 Hz), À1.2 ppm; LRMS
(70 eV, EI): m/z (%): 221 (97) [M]+, 75 (100); HRMS calcd for
C13H19DOSi: 221.1346; found: 221.1342.
2-(7-tert-Butyl-5-methyl-2,3-dihydrobenzofuran-3-yl)-N-phenylacetamide
(7d): Ether 6a (283 mg, 1 mmol) was treated with tBuLi (1.33 mL,
2 mmol) and TMEDA (0.33 mL, 2.2 mmol). Addition of phenyl isocya-
nate (131 mg, 1.1 mmol) and workup as described above yielded 7d
(197 mg, 61%) as a white solid. M.p. 132–1348C; 1H NMR (CDCl3,
400 MHz): d=7.69 (s, 1H), 7.51–7.45 (m, 2H), 7.33–7.27 (m, 2H), 7.15–
7.09 (m, 1H) 6.93 (s, 1H), 6.85 (s, 1H), 4.68 (t, J=9.1 Hz, 1H), 4.27 (dd,
J=9.1, 5.7 Hz, 1H), 3.94–3.84 (m, 1H), 2.74 (dd, J=15.0, 5.7 Hz, 1H),
2.59 (dd, J=15.0, 8.8 Hz, 1H), 2.27 (s, 3H), 1.36 (s, 9H) ppm; 13C NMR
(CDCl3, 101 MHz): d=169.5, 155.5, 137.4, 132.8, 129.7, 129.4, 128.9,
125.9, 124.4, 122.2, 120.1, 75.8, 42.5, 38.5, 33.9, 29.2, 20.9 ppm; LRMS
(70 eV, EI): m/z (%): 323 (18) [M]+, 135 (100); elemental analysis calcd
(%) for C21H25NO2: C 77.98, H 7.79, N 4.33; found: C 78.03, H 7.74, N
4.35.
2-(5-Methyl-7-trimethylsilyl-2,3-dihydrobenzofuran-3-yl)-N-phenylacet-
amide (7j): Ether 6c (299 mg, 1 mmol) was treated with tBuLi (1.33 mL,
2 mmol) and TMEDA (0.33 mL, 2.2 mmol). Addition of phenyl isocya-
nate (131 mg, 1.1 mmol) and workup as described above yielded 7j
(255 mg, 75%) as a white solid. M.p. 130–1328C; 1H NMR (CDCl3,
400 MHz): d=7.74 (s, 1H), 7.54–7.45 (m, 2H), 7.35–7.26 (m, 2H), 7.16–
7.09 (m, 1H), 7.04 (s, 1H), 6.99 (s, 1H), 4.66 (t, J=9.2 Hz, 1H), 4.24 (dd,
J=9.2, 5.8, 1H), 3.96–3.85 (m, 1H), 2.73 (dd, J=15.2, 6.2, 1H), 2.60 (dd,
J=15.2, 8.5, 1H), 2.27 (s, 3H), 0.30 (s, 9H) ppm; 13C NMR (CDCl3,
50 MHz): d=169.5, 162.7, 137.4, 133.9, 129.1, 128.9, 127.9, 125.9, 124.4,
120.1, 119.7, 75.9, 42.5, 38.3, 20.7, À1.3 ppm; LRMS (70 eV, EI): m/z (%):
339 (28) [M]+, 135 (100); elemental analysis calcd (%) for C20H25NO2Si:
C 70.75, H 7.42, N 4.13; found: C 70.67, H 7.38, N 4.09.
3-Deuteriomethyl-5,7-dimethyl-2,3-dihydrobenzofuran (7e): Ether 6b
(241 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and
TMEDA (0.33 mL, 2.2 mmol). Addition of deuterium oxide (excess) and
workup as described above yielded 7e (101 mg, 62%) as a colorless oil.
Rf =0.22 (hexane/ethyl acetate, 20:1); 1H NMR (CDCl3, 400 MHz): d=
6.80 (s, 1H), 6.76 (s, 1H), 4.66 (t, J=8.7 Hz, 1H), 4.04 (dd, J=8.7,
7.6 Hz, 1H), 3.54–3.45 (m, 1H), 2.27 (s, 3H), 2.18 (s, 3H), 1.30–1.26 (m,
2H) ppm; 13C NMR (CDCl3, 101 MHz): d=155.8, 131.5, 129.7, 129.6,
121.6, 119.0, 78.2, 36.7, 20.7, 18.9 (t, J=19.5 Hz), 15.0 ppm; LRMS
(70 eV, EI): m/z (%): 163 (74) [M]+, 147 (100); HRMS (EI) calcd for
C11H13DO: 163.1106; found: 163.1110.
5-Methyl-3-tributylstannylmethyl-7-trimethylsilyl-2,3-dihydrobenzofuran
(7k): Ether 6c (299 mg, 1 mmol) was treated with tBuLi (1.33 mL,
2 mmol) and TMEDA (0.33 mL, 2.2 mmol). Addition of tributyltin chlo-
ride (358 mg, 1.1 mmol) and workup as described above yielded 7k
(351 mg, 69%) as a colorless oil. Rf =0.43 (hexane); 1H NMR (CDCl3,
400 MHz): d=7.08–7.03 (m, 2H), 4.71 (t, J=8.3 Hz, 1H), 4.01 (t, J=
8.3 Hz, 1H), 3.85–3.70 (m, 1H), 2.39 (s, 3H), 1.64–1.34 (m, 13H), 1.20
(dd, J=13.2, 9.2 Hz, 1H), 1.03–0.81 (m, 15H), 0.38 (s, 9H) ppm; 13C
NMR (CDCl3, 101 MHz): d=162.6, 133.1, 132.4, 128.9, 125.5, 119.2, 78.9,
39.9, 29.2, 27.4, 20.8, 14.5, 13.7, 9.3, À1.2 ppm; LRMS (70 eV, EI): m/z
(%): 453 (53) [MÀC4H9]+, 179 (100); elemental analysis calcd (%) for
C25H46OSiSn: C 58.94, H 9.10; found: C 58.85, H 9.04.
2-(5,7-Dimethyl-2,3-dihydrobenzofuran-3-yl)-1,1-diphenylethanol
(7 f):
Ether 6b (241 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of benzophenone (200 mg,
1.1 mmol) and workup as described above yielded 7 f (227 mg, 66%) as a
colorless oil. Rf =0.21 (hexane/ethyl acetate, 5:1); 1H NMR (CDCl3,
400 MHz): d=7.56–7.29 (m, 10H), 6.84–6.81 (m, 2H), 4.42 (t, J=9.0 Hz,
1H), 4.02 (t, J=9.0 Hz, 1H), 3.58–3.48 (m, 1H), 2.97 (dd, J=14.1,
2.1 Hz, 1H), 2.62 (dd, J=14.1, 10.3 Hz, 1H), 2.39 (s, 1H), 2.34 (s, 3H),
2.24 (s, 3H) ppm; 13C NMR (CDCl3, 101 MHz): d=155.7, 147.0, 146.2,
130.3, 129.8, 129.3, 128.2, 128.1, 127.2, 126.9, 126.0, 125.9, 121.5, 118.9,
77.9, 77.8, 47.2, 38.2, 20.6, 15.0 ppm; LRMS (70 eV, EI): m/z (%): 344
(17) [M]+, 146 (100); HRMS (EI) calcd for C24H24O2: 344.1776; found:
344.1776.
3-Bromomethyl-5-methyl-7-trimethylsilyl-2,3-dihydrobenzofuran
(7l):
Ether 6c (299 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of 1,2-dibromoethane
(207 mg, 1.1 mmol) and workup as described above yielded 7l (224 mg,
75%) as a white solid. M.p. 26–288C; 1H NMR (CDCl3, 400 MHz): d=
7.11–7.06 (m, 2H), 4.64 (t, J=9.3 Hz, 1H), 4.44 (dd, J=9.3, 5.4 Hz, 1H),
3.87–3.78 (m, 1H), 3.66 (dd, J=10.0, 4.6 Hz, 1H), 3.42 (t, J=10.0 Hz,
1H), 2.33 (s, 3H), 0.32 (s, 9H) ppm; 13C NMR (CDCl3, 101 MHz): d=
163.1, 134.7, 129.2, 126.1, 126.0, 120.2, 75.4, 44.6, 35.1, 20.7, À1.3 ppm;
LRMS (70 eV, EI): m/z (%): 300 (100) [M+2]+, 298 (92) [M]+; HRMS
(EI) calcd for C13H19BrOSi: 298.0389; found: 298.0390.
5,7-Dimethyl-3-phenylthiomethyl-2,3-dihydrobenzofuran (7g): Ether 6b
(241 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and
TMEDA (0.33 mL, 2.2 mmol). Addition of diphenyl disulfide (237 mg,
1.1 mmol) and workup as described above yielded 7g (176 mg, 65%) as a
colorless oil. Rf =0.21 (hexane/ethyl acetate, 20:1); 1H NMR (CDCl3,
400 MHz): d=7.48–7.43 (m, 2H), 7.40–7.34 (m, 2H), 7.30–7.24 (m, 1H),
6.95 (s, 1H), 6.86 (s, 1H), 4.66 (t, J=9.0 Hz, 1H), 4.49 (dd, J=9.0,
5.7 Hz, 1H), 3.70–3.61 (m, 1H), 3.38 (dd, J=12.9, 4.8 Hz, 1H), 3.03 (dd,
J=12.9, 9.9 Hz, 1H), 2.34 (s, 3H), 2.26 (s, 3H) ppm; 13C NMR (CDCl3,
101 MHz): d=156.1, 135.5, 130.5, 129.5, 128.9, 128.2, 126.2, 122.1, 119.3,
75.7, 41.8, 38.5, 20.6, 15.0 ppm; LRMS (70 eV, EI): m/z (%): 270 (28)
[M]+, 147 (100); HRMS (EI) calcd for C17H18OS: 270.1078; found:
270.1076.
3-Methyl-7-trimethylsilyl-2,3-dihydrobenzofuran (7m): Ether 6d (285 mg,
1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and TMEDA
(0.33 mL, 2.2 mmol). Addition of water (excess) and workup as described
above yielded 7m (144 mg, 70%) as a colorless oil. Rf =0.56 (hexane/
ethyl acetate, 10:1); 1H NMR (CDCl3, 400 MHz): d=7.26–7.19 (m, 2H),
6.91 (t, J=7.3 Hz, 1H), 4.69 (t, J=8.5 Hz, 1H), 4.07 (t, J=8.5 Hz, 1H),
3.60–3.49 (m, 1H), 1.37 (d, J=6.9 Hz, 3H), 0.34 (s, 9H) ppm; 13C NMR
(CDCl3, 101 MHz): d=164.8, 132.9, 130.7, 124.8, 119.9, 119.7, 77.8, 36.1,
19.1, À1.2 ppm; LRMS (70 eV, EI): m/z (%): 206 (38) [M]+, 75 (100);
HRMS calcd for C12H18OSi: 206.1127; found: 206.1129.
3-Bromomethyl-5,7-dimethyl-2,3-dihydrobenzofuran (7h): Ether 6b
(241 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and
TMEDA (0.33 mL, 2.2 mmol). Addition of 1,2-dibromoethane (207 mg,
1.1 mmol) and workup as described above yielded 7h (159 mg, 66%) as a
colorless oil. Rf =0.33 (hexane/ethyl acetate, 20:1); 1H NMR (CDCl3,
400 MHz): d=6.87 (s, 1H), 6.84 (s, 1H), 4.64 (t, J=9.2 Hz, 1H), 4.45 (dd,
J=9.2, 5.3 Hz, 1H), 3.87–3.79 (m, 1H), 3.63 (dd, J=10.0, 4.6 Hz, 1H),
3.39 (t, J=10.0 Hz, 1H), 2.28 (s, 3H), 2.20 (s, 3H) ppm; 13C NMR
(CDCl3, 101 MHz): d=156.4, 131.1, 129.7, 126.6, 122.2, 119.7, 75.6, 45.1,
35.1, 20.6, 15.0 ppm; LRMS (70 eV, EI): m/z (%): 242 (4) [M+2]+, 240
(4) [M]+, 147 (100); elemental analysis calcd (%) for C11H13BrO: C
54.79, H 5.43; found: C 54.84, H 5.40.
2-(7-Trimethylsilyl-2,3-dihydrobenzofuran-3-yl)-N-phenylacetamide (7n):
Ether 6d (285 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of phenyl isocyanate
(131 mg, 1.1 mmol) and workup as described above yielded 7n (228 mg,
1
70%) as a white solid. M.p. 129–1318C; H NMR (CDCl3, 400 MHz): d=
7.81 (s, 1H), 7.51–7.43 (m, 2H), 7.33–7.23 (m, 3H), 7.19–7.08 (m, 2H),
6.86 (t, J=7.3 Hz, 1H), 4.68 (t, J=9.1 Hz, 1H), 4.24 (dd, J=9.1, 5.8 Hz,
1H), 3.98–3.88 (m, 1H), 2.72 (dd, J=15.1, 6.2 Hz, 1H), 2.59 (dd, J=15.1,
8.5 Hz, 1H), 0.32 (s, 9H) ppm; 13C NMR (CDCl3, 50 MHz): d=169.5,
164.7, 137.4, 133.7, 128.9, 127.7, 125.2, 124.5, 120.2, 120.1, 75.8, 42.5, 38.2,
À1.3 ppm; LRMS (70 eV, EI): m/z (%): 325 (13) [M]+, 135 (100); ele-
mental analysis calcd (%) for C19H23NO2Si: C 70.11, H 7.12, N 4.30;
found: C 70.17, H 7.18, N 4.25.
3-Deuteriomethyl-5-methyl-7-trimethylsilyl-2,3-dihydrobenzofuran (7i):
Ether 6c (299 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of deuterium oxide (excess)
5404
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 5397 – 5407

Enantioselective Synthesis of Functionalized Dihydrobenzofurans
FULL PAPER
3-Tributylstannylmethyl-7-trimethylsilyl-2,3-dihydrobenzofuran
(7o):
7.1 ppm; LRMS (70 eV, EI): m/z (%): 184 (34) [M+2]+, 182 (100) [M]+;
Ether 6d (285 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of tributyltin chloride
(358 mg, 1.1 mmol) and workup as described above yielded 7o (361 mg,
73%) as a colorless oil. Rf =0.69 (hexane/ethyl acetate, 10:1); 1H NMR
(CDCl3, 400 MHz): d=7.21–7.14 (m, 2H), 6.87 (t, J=7.3 Hz, 1H), 4.65
(t, J=8.5 Hz, 1H), 3.94 (t, J=8.5 Hz, 1H), 3.79–3.68 (m, 1H), 1.56–1.25
(m, 13H), 1.12 (dd, J=13.2, 9.3 Hz, 1H), 0.95–0.72 (m, 15H), 0.30 (s,
9H) ppm; 13C NMR (CDCl3, 101 MHz): d=164.5, 132.8, 132.3, 124.8,
120.0, 119.7, 78.7, 39.9, 29.1, 27.4, 14.5, 13.7, 9.3, À1.2 ppm; LRMS
(70 eV, EI): m/z (%): 439 (59) [MÀC4H9]+, 179 (100).
3-Phenylthiomethyl-7-trimethylsilyl-2,3-dihydrobenzofuran (7p): Ether
6d (285 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and
TMEDA (0.33 mL, 2.2 mmol). Addition of diphenyl disulfide (237 mg,
1.1 mmol) and workup as described above yielded 7p (248 mg, 79%) as a
colorless oil. Rf =0.39 (hexane/ethyl acetate, 10:1); 1H NMR (CDCl3,
400 MHz): d=7.51–7.46 (m, 2H), 7.42–7.26 (m, 5H), 6.96 (t, J=7.3 Hz,
1H), 4.67 (t, J=9.2 Hz, 1H), 4.49 (dd, J=9.2, 5.9 Hz, 1H), 3.73–3.64 (m,
1H), 3.41 (dd, J=12.9, 5.1 Hz, 1H), 3.08 (dd, J=12.9, 9.7 Hz, 1H), 0.40
(s, 9H) ppm; 13C NMR (CDCl3, 101 MHz): d=164.9, 135.5, 133.8, 129.6,
128.9, 127.5, 126.3, 125.4, 120.1, 120.0, 75.3, 41.1, 38.6, À1.3 ppm; LRMS
(70 eV, EI): m/z (%): 314 (46) [M]+, 191 (100); HRMS (EI) calcd for
C18H22OSSi: 314.1161; found: 314.1157.
HRMS (EI) calcd for C10H11ClO: 182.0498; found: 182.0496.
General procedure for the protodesilylation of 2,3-dihydrobenzofuran de-
rivatives 7i,k,m,o: Preparation of 2,3-dihydrobenzofuran derivatives 5i,j
and 7t,u :
A solution of the 7-trimethylsilyl-2,3-dihydrobenzofuran
7i,k,m,o (0.5 mmol) in CH2Cl2 (5 mL) at 08C was treated with HBF4
(0.083 mL of a 54 wt.% solution in diethyl ether, 0.6 mmol) and the reac-
tion mixture was stirred for 2 h at this temperature prior to the addition
of water. The organic layer was washed with
a saturated aqueous
NaHCO3 solution and the mixture was extracted with ethyl acetate (3”
10 mL). The combined organic layers were dried with anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography.
3-Deuteriomethyl-5-methyl-2,3-dihydrobenzofuran (7t): Reaction of 2,3-
dihydrobenzofuran 7i (111 mg, 0.5 mmol) and HBF4 (0.083 mL,
0.6 mmol) in CH2Cl2 (5 mL) followed by workup as described above
yielded 7t (56 mg, 75%) as a colorless oil. Rf =0.20 (hexane/ethyl ace-
tate, 20:1); 1H NMR (CDCl3, 400 MHz): d=6.99 (s, 1H), 6.94 (d, J=
8.1 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 4.68 (t, J=8.6 Hz, 1H), 4.07 (dd,
J=8.6, 7.6 Hz, 1H), 3.57–3.47 (m, 1H), 2.33 (s, 3H), 1.34–1.30 (m,
2H) ppm; 13C NMR (CDCl3, 101 MHz): d=157.5, 132.1, 129.6, 128.2,
124.3, 108.8, 78.4, 36.4, 20.7, 18.8 (t, J=19.6 Hz) ppm; LRMS (70 eV, EI):
m/z (%): 149 (72) [M]+, 133 (100); HRMS (EI) calcd for C10H11DO:
149.0950; found: 149.0955.
3-Ethyl-7-trimethylsilyl-2,3-dihydrobenzofuran (7q): Ether 6d (285 mg,
1 mmol) was treated with tBuLi (1.33 mL, 2 mmol) and TMEDA
(0.33 mL, 2.2 mmol). Addition of dimethyl sulfate (139 mg, 1.1 mmol)
and workup as described above yielded 7q (148 mg, 67%) as a colorless
oil. Rf =0.43 (hexane/ethyl acetate, 20:1); 1H NMR (CDCl3, 300 MHz):
d=7.26–7.20 (m, 2H), 6.90 (t, J=7.3 Hz, 1H), 4.64 (t, J=8.9 Hz, 1H),
4.22 (dd, J=8.9, 6.5 Hz, 1H), 3.43–3.31 (m, 1H), 1.93–1.78 (m, 1H) 1.71–
1.55 (m, 1H), 1.03 (t, J=7.5 Hz, 3H), 0.33 (s, 9H) ppm; 13C NMR
(CDCl3, 75 MHz): d=165.0, 133.0, 129.4, 125.3, 119.7, 119.6, 75.9, 43.0,
27.6, 11.5, À1.3 ppm; LRMS (70 eV, EI): m/z (%): 220 (86) [M]+, 163
(100); HRMS (EI) calcd for C13H20OSi: 220.1283; found: 220.1285.
5-Methyl-3-tributylstannylmethyl-2,3-dihydrobenzofuran (7u): Reaction
of 2,3-dihydrobenzofuran 7k (255 mg, 0.5 mmol) and HBF4 (0.083 mL,
0.6 mmol) in CH2Cl2 (5 mL) followed by workup as described above
yielded 7u (181 mg, 83%) as a colorless oil. Rf =0.47 (hexane/ethyl ace-
tate, 10:1); 1H NMR (CDCl3, 400 MHz): d=6.95 (s, 1H), 6.89 (d, J=
8.2 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 4.63 (t, J=8.5 Hz, 1H), 3.94 (dd,
J=8.5, 7.4 Hz, 1H), 3.73–3.62 (m, 1H), 2.29 (s, 3H), 1.50–1.23 (m, 13H),
1.08 (dd, J=13.2, 9.5 Hz, 1H), 0.92–0.73 (m, 15H) ppm; 13C NMR
(CDCl3, 101 MHz): d=157.3, 133.8, 129.6, 128.1, 124.3, 108.9, 79.5, 40.3,
29.1, 27.4, 20.8, 14.6, 13.6, 9.3 ppm; LRMS (70 eV, EI): m/z (%): 381
(100) [MÀC4H9]+; elemental analysis calcd (%) for C22H38OSn: C 60.43,
H 8.76; found: C 60.35, H 8.71.
2-(7-Isopropyl-2,3-dihydrobenzofuran-3-yl)-1,1-diphenylethanol
(7r):
Ether 6e (255 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of benzophenone (200 mg,
1.1 mmol) and workup as described above yielded 7r (279 mg, 78%) as a
colorless oil. Rf =0.42 (hexane/ethyl acetate, 3:1); 1H NMR (CDCl3,
400 MHz): d=7.51–7.26 (m, 10H), 7.03 (d, J=7.5 Hz, 1H), 6.97 (d, J=
7.5 Hz, 1H), 6.85 (t, J=7.5 Hz, 1H), 4.41 (t, J=9.0 Hz, 1H), 4.00 (t, J=
9.0 Hz, 1H), 3.57–3.47 (m, 1H), 3.08 (sept., J=7.0 Hz, 1H), 2.95 (dd, J=
14.0, 2.0 Hz, 1H), 2.62 (dd, J=14.0, 10.3 Hz, 1H), 2.22 (s, 1H), 1.27–1.21
(m, 6H) ppm; 13C NMR (CDCl3, 101 MHz): d=157.0, 147.0, 146.2, 130.6,
130.4, 128.3, 128.2, 127.2, 127.0, 126.0, 125.9, 124.8, 121.0, 120.2, 78.0,
77.9, 47.3, 38.2, 28.0, 22.3, 22.2 ppm; LRMS (70 eV, EI): m/z (%): 358
(30) [M]+, 327 (100); HRMS (EI) calcd for C25H26O2: 358.1933; found:
358.1930.
3-Methyl-2,3-dihydrobenzofuran (5i):[12f] Reaction of 2,3-dihydrobenzo-
furan 7m (103 mg, 0.5 mmol) and HBF4 (0.083 mL, 0.6 mmol) in CH2Cl2
(5 mL) followed by workup as described above yielded 5i (57 mg, 84%)
1
as a colorless oil. Rf =0.29 (hexane/ethyl acetate, 15:1); H NMR (CDCl3,
400 MHz): d=7.21–7.17 (m, 1H), 7.16–7.13 (m, 1H), 6.94–6.88 (m, 1H),
6.85–6.82 (m, 1H), 4.71 (t, J=8.6 Hz, 1H), 4.10 (dd, J=8.6, 7.5 Hz, 1H),
3.62–3.51 (m, 1H), 1.36 (d, J=6.9 Hz, 3H) ppm; 13C NMR (CDCl3,
101 MHz): d=159.5, 132.1, 127.8, 123.7, 120.3, 109.3, 78.3, 36.3, 19.2 ppm;
LRMS (70 eV, EI): m/z (%): 134 (66) [M]+, 119 (100); HRMS (EI)
calcd. for C9H10O: 134.0732; found: 134.0730.
3-Tributylstannylmethyl-2,3-dihydrobenzofuran (5j): Reaction of 2,3-di-
hydrobenzofuran 7o (248 mg, 0.5 mmol) and HBF4 (0.083 mL, 0.6 mmol)
in CH2Cl2 (5 mL)followed by workup as described above yielded 5j
(190 mg, 90%) as a colorless oil. Rf =0.45 (hexane/ethyl acetate, 10:1);
1H NMR (CDCl3, 400 MHz): d=7.18–7.14 (m, 1H), 7.13–7.08 (m, 1H),
6.90–6.84 (m, 1H), 6.80–6.76 (m, 1H), 4.66 (t, J=8.5 Hz, 1H), 3.99 (t, J=
8.5 Hz, 1H), 3.82–3.66 (m, 1H), 1.57–1.25 (m, 13H), 1.13 (dd, J=13.2,
9.5 Hz, 1H), 0.97–0.77 (m, 15H) ppm; 13C NMR (CDCl3, 101 MHz): d=
159.4, 133.8, 127.7, 123.6, 120.4, 109.4, 79.3, 40.2, 29.1, 27.3, 14.6, 13.6, 9.2;
elemental analysis calcd (%) for C21H36OSn: C 59.60, H 8.57; found: C
59.66, H 8.51.
5-Chloro-7-methyl-3-(phenylthiomethyl)-2,3-dihydrobenzofuran
(7 s):
Ether 6 f (262 mg, 1 mmol) was treated with tBuLi (1.33 mL, 2 mmol)
and TMEDA (0.33 mL, 2.2 mmol). Addition of diphenyl disulfide
(237 mg, 1.1 mmol) and workup as described above yielded 7 s (172 mg,
1
59%) as a pale yellow solid. M.p. 39–418C; H NMR (CDCl3, 400 MHz):
d=7.42–7.37 (m, 2H), 7.35–7.29 (m, 2H), 7.27–7.21 (m, 1H), 7.04 (s,
1H), 6.95 (s, 1H), 4.62 (t, J=9.2 Hz, 1H), 4.46 (dd, J=9.2, 5.7 Hz, 1H),
3.64–3.55 (m, 1H), 3.28 (dd, J=13.1, 5.1 Hz, 1H), 2.98 (dd, J=13.1,
9.5 Hz, 1H), 2.17 (s, 3H) ppm; 13C NMR (CDCl3, 101 MHz): d=156.9,
135.0, 129.9, 129.8, 129.6, 129.0, 126.6, 124.6, 121.8, 121.2, 76.1, 41.7, 38.5,
15.0 ppm; LRMS (70 eV, EI): m/z (%): 292 (14) [M+2]+, 290 (35) [M]+,
167 (100); elemental analysis calcd (%) for C16H15ClOS: C 66.08, H 5.20;
found: C 65.99, H 5.13.
General procedure for the enantioselective carbolithiation of ethers 6:
Preparation of enantioenriched 2,3-dihydrobenzofuran derivatives 7b,d–
g,j,n,q,r: A solution of the corresponding starting ether 6 (1 mmol) in dii-
sopropyl ether (10 mL) cooled in a dry ice/acetone bath at À788C was
treated with tBuLi (1.33 mL, 2 mmol) and the reaction mixture was stir-
red for 15 min at this temperature. (À)-Sparteine (0.50 mL, 2.2 mmol)
was added to the resulting solution at À788C and the reaction mixture
was stirred for an additional 30 min at this temperature. The mixture was
allowed to warm to À658C for ether 6a, À408C for ether 6b, À508C for
ethers 6c,d, and À608C for ether 6e and then stirred at this temperature
overnight. The corresponding electrophile (1.1 mmol) at À788C was
2-Chloro-6-cyclopropyl-4-methylphenol (9): Ether 6g (262 mg, 1 mmol)
was treated with tBuLi (1.33 mL, 2 mmol) and TMEDA (0.33 mL,
2.2 mmol). Workup as described above yielded 9 (124 mg, 68%) as a col-
orless oil. Rf =0.38 (hexane/ethyl acetate, 5:1); 1H NMR (CDCl3,
400 MHz): d=6.95 (s, 1H), 6.60 (s, 1H), 5.58 (s, 1H), 2.21 (s, 3H), 2.10–
2.03 (m, 1H), 0.98–0.93 (m, 2H), 0.69–0.64 (m, 2H) ppm; 13C NMR
(CDCl3, 101 MHz): d=147.9, 130.3, 130.0, 126.4, 125.4, 119.1, 20.4, 9.8,
Chem. Eur. J. 2005, 11, 5397 – 5407
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5405

J. Barluenga et al.
added to the solution and stirring was continued for 30 min at this tem-
perature and for 5 h at room temperature prior to the addition of water.
The mixture was extracted with ethyl acetate (3”10 mL) and the com-
bined organic layers were washed with 1m HCl (2”10 mL), dried with
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography. The physi-
cal and spectroscopic data of the resulting dihydrobenzofuran derivatives
have been reported above and the ee values were determined by HPLC
(except for 7q).
[1] For general references, see: a) W. F. Bailey, T. V. Ovaska in Advan-
ces in Detailed Reaction Mechanisms, Vol. 3 (Ed.: J. M. Coxon), JAI
Press, Greenwich, CT, 1994, pp. 251–273; b) M. J. Mealy, W. F.
Bailey, J. Organomet. Chem. 2002, 646, 59–67; c) J. Clayden in Or-
ganolithiums: Selectivity for Synthesis, Pergamon Press, Oxford,
2002, pp. 273–335.
[2] a) G. A. Ross, M. D. Koppang, D. E. Bartak, N. F. Woolsey, J. Am.
Chem. Soc. 1985, 107, 6742–6743; b) W. F. Bailey, T. Daskapan, S.
Rampalli, J. Org. Chem. 2003, 68, 1334–1338.
[3] H. Nishiyama, N. Sakata, H. Sugimoto, Y. Motoyama, H. Wakita, H.
Nagase, Synlett 1998, 930–932.
[4] J. Barluenga, R. Sanz, A. Granados, F. J. FaÇanµs, J. Am. Chem. Soc.
1998, 120, 4865–4866.
7b: HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=96:4, flow rate=
0.8 mLminÀ1, l=210 nm): tR =9.59 (minor), 20.64 (major) min.
7d: HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=90:10, flow rate=
0.8 mLminÀ1, l=210 nm): tR =15.19 (major), 25.47 (minor) min.
7e: HPLC (Daicel Chiralcel OD-H, hexane, flow rate=0.8 mLminÀ1, l=
[5] a) D. Zhang, L. S. Liebeskind, J. Org. Chem. 1996, 61, 2594–2595;
b) W. F. Bailey, X.-L. Jiang, J. Org. Chem. 1996, 61, 2596–2597.
[6] R. Pedrosa, C. AndrØs, J. M. Iglesias, A. PØrez-Encabo, J. Am.
Chem. Soc. 2001, 123, 1817–1821.
290 nm): tR =12.33 (major), 14.02 (minor) min.
7 f: HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=96:4, flow rate=
0.8 mLminÀ1, l=210 nm): tR =15.54 (minor), 24.21 (major) min.
[7] For a review, see: J. F. Normant, Topics Organomet. Chem. 2003, 5,
287–310.
7g: HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=99.5:0.5, flow
rate=0.8 mLminÀ1, l=210 nm): tR =40.62 (minor), 52.48 (major) min.
[8] a) I. Coldham, R. Hufton, D. J. Snowden, J. Am. Chem. Soc. 1996,
118, 5322–5323; b) M. J. Woltering, R. Frçhlich, D. Hoppe, Angew.
Chem. 1997, 109, 1804–1805; Angew. Chem. Int. Ed. Engl. 1997, 36,
1764–1766; c) H. Laqua, R. Frçhlich, B. Wibbeling, D. Hoppe, J.
Organomet. Chem. 2001, 624, 96–104.
[9] a) W. F. Bailey, M. J. Mealy, J. Am. Chem. Soc. 2000, 122, 6787–
6788; b) G. Sanz Gil, U. M. Groth, J. Am. Chem. Soc. 2000, 122,
6789–6790; c) J. Barluenga, F. J. FaÇanµs, R. Sanz, C. Marcos, Org.
Lett. 2002, 4, 2225–2228; d) M. J. Mealy, M. R. Luderer, W. F.
Bailey, M. B. Sommer, J. Org. Chem. 2004, 69, 6042–6049.
[10] For a recent review on neolignan synthesis, see: M. Sefkow, Synthe-
sis 2003, 2595–2625.
[11] The vast majority of the reported syntheses of dihydrobenzofuran
neolignans are based on the biomimetic oxidation of phenylpro-
penes, following Erdtmanꢁs procedure: a) H. Erdtman, Liebigs Ann.
Chem. 1933, 503, 283–294; for different recent approaches to these
compounds, see: b) B. B. Snider, L. Han, X. Chaoyu, J. Org. Chem.
1997, 62, 6978–6984; c) J. S. Yadav, B. V. S. Reddy, G. Kondaji, Syn-
thesis 2003, 1100–1104; d) W. Kurosawa, T. Kan, T. Fukuyama, Syn-
lett 2003, 1028–1030.
[12] Free radical species: a) A. L. J. Beckwith, G. F. Meijs, J. Chem. Soc.
Chem. Commun. 1981, 136–137; b) I. Terstiege, R. E. Maleczka, Jr.,
J. Org. Chem. 1999, 64, 342–343; c) A. Studer, S. Amrein, Angew.
Chem. 2000, 112, 3196–3198; Angew. Chem. Int. Ed. 2000, 39, 3080–
3082; d) P. A. Evans, D. K. Leahy, J. Am. Chem. Soc. 2000, 122,
5012–5013; e) K. Inoue, A. Sawada, I. Shibata, A. Baba, J. Am.
Chem. Soc. 2002, 124, 906–907; transition metal species: Sm: f) D. P.
Curran, M. J. Totleben, J. Am. Chem. Soc. 1992, 114, 6050–6058.
Mn: g) J. Nakao, R. Inoue, H. Shinokubo, K. Oshima, J. Org. Chem.
1997, 62, 1910–1911; h) R. Inoue, J. Nakao, H. Shinokubo, K.
Oshima, Bull. Chem. Soc. Jpn. 1997, 70, 2039–2050.
7j: HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=90:10, flow rate=
0.8 mLminÀ1, l=210 nm): tR =14.06 (major), 21.98 (minor) min.
7n: HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=90:10, flow rate=
0.8 mLminÀ1, l=254 nm): tR =14.89 (major), 21.61 (minor) min.
7q: Ether 6d (4.28 g, 15 mmol) in diisopropyl ether (40 mL) was treated
with tBuLi (20 mL, 30 mmol) and (À)-sparteine (7.6 mL, 33 mmol). Ad-
dition of dimethyl sulfate (2.14 g, 17 mmol) and workup as described
above yielded 7q (2.51 g, 76%) as a colorless oil. The ee (81%) was de-
termined by comparing the specific rotation of the transformed (À)-2-
sec-butylphenol ([a]D23 =À15.1) with the literature value ([a]2D3 =À18.6).[19]
7r: HPLC (Daicel Chiralcel OD-H, hexane/2-PrOH=90:10, flow rate=
0.8 mLminÀ1, l=290 nm): tR =13.61 (minor), 14.87 (major) min.
Procedure for the transformation of 7q into (À)-2-sec-butylphenol (10):
Preparation of 3-ethyl-2,3-dihydrobenzofuran: 3-Ethyl-2,3-dihydrobenzo-
furan was prepared from 7-trimethylsilyl-2,3-dihydrobenzofuran 7q fol-
lowing the general procedure for protodesilylation as described above for
2,3-dihydrobenzofuran derivatives 7i,k,m,o. Reaction of 7q (2.20 g,
10 mmol) and HBF4 (1.65 mL, 12 mmol) in CH2Cl2 (20 mL) and workup
as described above yielded 3-ethyl-2,3-dihydrobenzofuran[12f] (1.32 g,
89%) as a colorless oil. Rf =0.43 (hexane/ethyl acetate, 10:1); 1H NMR
(CDCl3, 300 MHz): d=7.23–7.11 (m, 2H), 6.92–6.88 (m, 2H), 4.66 (t, J=
8.9 Hz, 1H), 4.25 (dd, J=8.9, 6.3 Hz, 1H), 3.46–3.39 (m, 1H), 1.91–1.75
(m, 1H), 1.70–1.55 (m, 1H), 1.00 (t, J=7.5 Hz, 3H) ppm; 13C NMR
(CDCl3, 75 MHz): d=159.9, 130.8, 128.0, 124.3, 120.2, 109.3, 76.5, 43.2,
27.6, 11.3 ppm; LRMS (70 eV, EI): m/z (%): 148 (48) [M]+, 119 (100).
Preparation of 2-sec-butylphenol (10): A mixture of lithium (29 mg,
4.2 mmol) and 4,4’-di-tert-butylbiphenyl (DTBB) (1.12 g, 4.2 mmol) in
THF (5 mL) was stirred for 4 h at 08C. 3-Ethyl-2,3-dihydrobenzofuran
(296 mg, 2 mmol) was added and the resulting mixture was stirred for an
additional 6 h at 08C. The reaction was carefully quenched with 1m HCl
at the same temperature and the mixture was extracted with ethyl acetate
(3”10 mL). The combined organic layers were dried with anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/ethyl acetate,
10:1) to afford the title compound (216 mg, 72%) as a colorless oil. Spec-
tral data of the obtained product were in total agreement with those cor-
responding to a commercial sample. The ee (81%) was determined by
comparing its specific rotation ([a]2D3 =À15.1) with the literature value
([a]D23 =À18.6).[19]
[13] W. F. Bailey, E. R. Punzalan, Tetrahedron Lett. 1996, 37, 5435–5436.
[14] a) J. Barluenga, R. Sanz, F. J. FaÇanµs, Tetrahedron Lett. 1997, 38,
2763–2766; b) F. J. FaÇanµs, A. Granados, R. Sanz, J. M. Ignacio, J.
Barluenga, Chem. Eur. J. 2001, 7, 2896–2907; c) J. Barluenga, F. J.
FaÇanµs, R. Sanz, C. Marcos, M. Trabada, Org. Lett. 2002, 4, 1587–
1590; d) J. Barluenga, F. J. FaÇanµs, R. Sanz, J. M. Ignacio, Eur. J.
Org. Chem. 2003, 771–783; e) J. Barluenga, F. J. FaÇanµs, R. Sanz,
Y. Fernµndez, C. R. Acad. Sci. Ser. IIc C. R. Chimie 2004, 7, 855–
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Acknowledgements
We gratefully acknowledge financial support from the DGICYT
(BQU2001–1079 and BQU-2001–3853) and the Junta de Castilla y León
(BU-24/02 and a grant to C. M.).
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www.chemeurj.org
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Enantioselective Synthesis of Functionalized Dihydrobenzofurans
FULL PAPER
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Received: April 4, 2005
Published online: July 8, 2005
Chem. Eur. J. 2005, 11, 5397 – 5407
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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