Synthesis of substituted benzofurans by the tandem one-pot intramolecular carbolithiation-cyclization-substitution sequence

Article abstract of DOI:10.1080/00397911.2013.830132

A convenient methodology for the synthesis of 3-sustituted-2,3- dihydrobenzofurans was developed based on the tandem intramolecular carbolithiation-cyclization of 2-bromophenyl-3-phenylprop-2-enyl ether, followed by trapping of the new lithiated intermediate by suitable electrophiles. Several electrophiles were tested, affording good to excellent yields. Alkyl bromides show better results than chlorides and when doubly halogenated alkyl chains are used as electrophiles only one position reacts, affording substituted benzofurans conveniently functionalized to undergo further reactions. The performance of both butyl and phenyllithium as lithiating agents was examined. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.830132

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Synthesis of Substituted Benzofurans
by the Tandem One-Pot Intramolecular
Carbolithiation–Cyclization–Substitution
Sequence
Cristian Rodríguez a & Norma Sbarbati Nudelman a
a Departamento de Química Orgánica, Facultad de Ciencias Exactas
y Naturales , Universidad de Buenos Aires , Buenos Aires , Argentina
Accepted author version posted online: 28 Oct 2013.Published
online: 20 Feb 2014.
To cite this article: Cristian Rodríguez & Norma Sbarbati Nudelman (2014) Synthesis of Substituted
Benzofurans by the Tandem One-Pot Intramolecular Carbolithiation–Cyclization–Substitution Sequence,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:6, 772-778, DOI: 10.1080/00397911.2013.830132
To link to this article: http://dx.doi.org/10.1080/00397911.2013.830132
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Synthetic Communications1, 44: 772–778, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.830132
SYNTHESIS OF SUBSTITUTED BENZOFURANS BY THE
TANDEM ONE-POT INTRAMOLECULAR
CARBOLITHIATION–CYCLIZATION–SUBSTITUTION
SEQUENCE
´
Cristian Rodrıguez and Norma Sbarbati Nudelman
Departamento de Quımica Organica, Facultad de Ciencias Exactas y
´
´
Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
GRAPHICAL ABSTRACT
Abstract A convenient methodology for the synthesis of 3-sustituted-2,3-dihydrobenzofur-
ans was developed based on the tandem intramolecular carbolithiation–cyclization of
2-bromophenyl-3-phenylprop-2-enyl ether, followed by trapping of the new lithiated inter-
mediate by suitable electrophiles. Several electrophiles were tested, affording good to excel-
lent yields. Alkyl bromides show better results than chlorides and when doubly halogenated
alkyl chains are used as electrophiles only one position reacts, affording substituted benzo-
furans conveniently functionalized to undergo further reactions. The performance of both
butyl and phenyllithium as lithiating agents was examined.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Alkylation; benzofurans; intramolecular carbocyclization; intramolecular
carbolithiation; organolithium
Received July 17, 2013.
Address correspondence to Norma Sbarbati Nudelman, Departamento de Quımica Organica,
´
´
´
Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon 2, Ciudad
Universitaria, C1428EGA Buenos Aires, Argentina. E-mail: nudelman@qo.fcen.uba.ar
772

TANDEM SYNTHESIS OF BENZOFURANS
773
INTRODUCTION
Tandem sequences involving organolithium compounds continue to provide
fascinating approaches to challenging synthetic issues.[1] The subtle control of
chemo-, regio-, and stereoselectivity achievable within carbolithiation points the
way to exciting applications in carbocyclic, heterocyclic, alkene, and alkane syn-
thesis.[2,3] Carbolithiation reactions of vinyl, alkyl, and aryllithium to unactivated
alkenes and alkynes are especially fruitful; the value of these transformations lies
in their ability to regio- and stereoselectively construct carbon–carbon bonds in
tandem with generating a new organolithium species.[1,2,4] Particularly the intramol-
ecular carbolithiation–electrophilic substitution tandem sequence is a well-suited,
one-pot process for the building of cyclic structures.[5,6] On the other hand, 2,3-
dihydrobenzofuran (cumaran) is a basic skeleton found in a number of biologically
interesting compounds, such as the neolignans.[7] Attempts to build this skeleton
using 2-bromophenyl-(E)-2-propenyl ether failed due to c-elimination.[8]
A
likely strategy to overcome the c-elimination could be substitution by a phenyl
moiety that could provide increased resonance stabilization to the cyclic lithium
intermediate.[9] We synthesized 2-bromophenyl-3-phenylprop-2-enyl ether, 1, and
conditions were searched for the cyclization to occur in good yields.[10] Based on
the operational simplicity of this approach, we studied the scope of this tandem
procedure in synthesis; herewith we report a convenient and efficient route to new
3-substituted 2,3-dihydrobenzofurans.
RESULTS AND DISCUSSION
The reaction of 1 with n-BuLi in tetrahydrofuran (THF), leads to the
formation of three products, noted as 2, 3, and 4 in Scheme 1. The production of
cyclic structures, like 3, were synthetically interesting, and reaction conditions were
searched to increase its yield.
A detailed mechanistic study proved that the reaction occurs via a polar rather
than a radical mechanism.[11] The reaction mechanism giving rise to products 3 and 4
is outlined in Scheme 2. Organolithium 5 is assumed to be formed through an ate-
complex intermediate, favored by the presence of Br and O in the substrate.[12]
The acyclic lithium intermediate 5 can then undergo cyclization to the new lithiated
cyclic intermediate 6, which yields the substituted 2,3-dihydrobenzofuran 3, by
Scheme 1. Reaction products of 2-bromo-phenyl-3-phenylprop-2-enyl ether with n-BuLi.

´
C. RODRIGUEZ AND N. S. NUDELMAN
774
Scheme 2. Mechanisms for the formation of products 3 and 4.
further reaction with the n-butyl bromide previously generated in the halogen–metal
exchange reaction. The new lithiated intermediate 6 is very reactive. In fact, when
a methyl group replaces the phenyl moiety, an undesirably drawback is the c-
elimination, leading to cyclopropylphenol derivatives. In the present case, the phenyl
group attached to the double bond provides stabilization to the cyclized carbanion,
preventing the c-elimination.
The experimental finding that deuterium is not incorporated at the aryl pos-
ition when quenching with MeOD the by-product 4 suggests that the by product 4
should be formed via an intramolecular rearrangement of the carbanion 5 with
the allylic protons, followed by isomerization to the more stable benzylic carbanion,
which immediately reacts with the n-butyl bromide present in the reaction mixture.
The (Z)-structure of the by-product 4 can be visualized through the intermediate 7,
stabilized by Li=oxygen coordination. The formation of (Z)-N-(1-propenyl)benza-
mides observed in the reaction of N-allylbenzamides and n-BuLi has been explained
by a similar coordination of the lithium atom to the nitrogen atom at the
c-carbon.[13]
Scheme 3 shows how substrate 1 can be transformed into conveniently sub-
stituted 2,3-dihydrobenzofuran derivatives, 8, by a fast tandem cyclization–c-
alkylation sequence, trapping the cyclic lithium intermediate 6 by an appropriate
electrophile (E) in a 5 min reaction under very mild reaction conditions.
Table 1 summarizes the results obtained using several electrophiles. It is worth-
while to note that in all cases there is a competition between the added electrophile
and the butyl bromide generated in situ in the first step of the reaction. Nevertheless,
under the conditions described complete reaction of 1 occurs and good to excellent
yields of functionalized 2,3-dihydrobenzofuran derivatives are obtained with a large
variety of primary alkyl bromides. It can be observed that when two primary bro-
mine atoms are present (entry g and h), only one position reacts; similarly, when

TANDEM SYNTHESIS OF BENZOFURANS
775
Scheme 3.
chlorine and bromine are present (entry f) the chlorine atom does not react under
the present reaction conditions. In these cases, substituted 2,3-dihydrobenzofuran
derivatives conveniently functionalized for further reactions are obtained, with good
yields and conversions (ꢀ90%). Bromobenzene and methyl iodide did not afford a
good yield of 4. Bromobenzene gave 80% of 3 and methyl iodide rendered 85% of
2-methylphenyl-(E)-2-propenyl ether.
To avoid the competitive reaction with butyl bromide the lithiation reagent was
changed to PhLi. Several reaction conditions were tested. Finally by using a high
[PhLi]–[1] ratio the reaction afforded different 2,3-dihydrofuran derivatives in good
yield; complete conversion of 1 is observed for [PhLi]:[1] ꢁ 3. As shown in Table 2 all
the relative yields are improved compared to the same reaction using BuLi, although
the diastereomer selectivity is slightly diminished.
An intriguing feature of this approach is the fact that a diastereomeric process
is taking place. Although four diastereomers (two racemic pairs) can be formed,
because the product contains two stereogenic centers, under the reaction conditions
one of the pair is formed in a greater amount than the other. To search for a
Table 1. Reaction of 1 with n-BuLi quenched by different electrophiles, Ea
Yields (%)b
Entry
Electrophilec
EtBr
2
3
4
9
8 (dr %)d
a
b
c
0
9
3
3
9
79 (80:20)
73 (97:3)
93 (60:40)
74 (83:17)
61 (95:5)
70 (98:2)
77 (98:2)
80 (82:18)
CH3(CH2)2Br
CH3(CH2)3Br
CH3(CH2)5Br
0
0
9
—
11
3
15
7
—
4
d
e
0
11
0
=
CH2 CHCH2Br
32
23
14
3
4
f
Br(CH2)3Cl
Br(CH2)3Br
Br(CH2)4Br
4
2
1
g
h
7
2
0
12
3
2
a1.5 equivalent BuLi was added to a solution of 1 at ꢂ85ꢃC in THF. After 5 min the E was added. The
reaction mixture was warmed up to rt, and then it was quenched with MeOH after 5 min.
bRelative yields determined by NMR and GC.
cIn all cases 8 eq. of E were used.
ddr, determined by NMR.

´
C. RODRIGUEZ AND N. S. NUDELMAN
776
Table 2. Reaction of 1 with PhLi quenched by different electrophiles, Ea
Yields (%)b
8 (dr %)d
Entry
Electrophilec
EtBr
CH3(CH2)2Br
[PhLi]:[1]
1 recovered (%)
9
a
3
2
3
5
3
2
3
2
3
2
3
0
26
10
0
100 (80:20)
74 (85:15)
94 (85:15)
70 (85:15)
100 (70:30)
100 (80:20)
100 (70:30)
80 (80:20)
70 (80:20)
84 (77:23)
79 (74:26)
—
24
6
b
25
—
—
—
20
20
4
c
d
e
f
CH3(CH2)3Br
CH3(CH2)5Br
=
CH2 CHCH2Br
Br(CH2)3Cl
15
15
0
20
0
g
Br(CH2)3Br
Br(CH2)4Br
6
h
0
20
aReactions were carried out under the same conditions describe for BuLi, adding different
equivalents of PhLi according to the [PhLi]:[1] ratio given in the table.
bRelative yields determined by NMR and GC.
cIn all cases 8 equivalents of E were used.
ddr, determined by NMR.
plausible mechanistic interpretation for the observed stereoselectivity, theoretical
modeling of each one of all likely lithiated intermediates using B3LYP is in progress.
In conclusion, a variety of 3-sustituted-2,3-dihydrobenzofurans can be con-
veniently synthesized by the tandem intramolecular carbolithiation–cyclization of
2-bromophenyl-3-phenylprop-2-enyl ether, followed by in situ trapping of the new
lithiated intermediate by suitable electrophiles. This one-pot synthesis occurs under
mild reaction conditions and shows certain diastereoselectivity control.
EXPERIMENTAL
All reactions involving organolithium reagents were carried out by standard
techniques for the manipulation of air- and water-sensitive compounds.[14] NMR
1
spectra were determined using a Bruker AC200 MHz instrument The H chemical
shifts are referenced relative to tetramethylsilane (TMS), and the 13C-chemical shifts
are referenced relative to CDCl3 at d ¼ 77 ppm. The gas chromatographic (GC)
analyses were carried out on a 5890 Hewlett-Packard gas chromatograph, using a
HP-5 column and a FID detector. GC-MS were determined by a QP 5050A
Shimadtzu a gas chromatograph mass spectrometer, using electron impact ionization
(EI, 70 eV).
Full Experimental Details for the General Procedure
n-Butyllithium and phenyllithium were prepared and titrated as previously
described.[15] 2-Bromophenyl 3-phenyl-2-propenyl ether, 1, was prepared by reaction
of 2-bromophenol with cinnamyl bromide in acetone as previously described (yield
82%).[16] Compound 1 (0.05 mol) in 10 mL of THF was placed in a two-necked,

TANDEM SYNTHESIS OF BENZOFURANS
777
septum-capped, round-bottomed flask equipped with a thermometer under a dry
nitrogen atmosphere at ꢂ85 ꢃC. Then 0.75 mL of 1.00 M n-BuLi in hexane was
added dropwise via syringe in 1–2 min After 5 min at ꢂ85 ꢃC, the electrophile (pure
or as a solution in THF) was added rapidly via syringe. The reaction was immedi-
ately allowed to reach room temperature and stand for 5 min before quenching with
MeOH. The reaction mixture was extracted with CH2Cl2, washed with aqueous 3 M
NH4Cl solution and brine, and dried with anhydrous MgSO4 online. The reaction
1
mixture was analyzed by H and 13C NMR, GC-FID, and GC-MS. The products
were isolated by column chromatography or preparative thin-layer chromatography
(TLC) using a mixture of 2% ethyl acetate, 70% cyclohexane, and 28% hexane as
eluant. In some cases only the main diastereomer could be isolated. The pure
1
compounds were characterized by H and 13C NMR and MS. Full data for key
compounds are shown.
(2-d)-Phenyl (E)-3-phenyl-2-propenyl Ether (2)
1
Solid, mp 67.5–68.5 ꢃC. H NMR (200 MHz, CDCl3) d 4.70 (dd, 2H, J ¼ 5.7
and 1.3 Hz), 6.42 (dt, 1H, J ¼ 15.8 and 5.7 Hz), 6.74 (d, 1H, J ¼ 15.8 Hz), 6.94–
6.98 (m, 2H), 7.23–7.43 (m, 7H). MS m=z (rel. ab.): 211(5) [Mþ], 117 (100), 115
(83), 91 (60).
3-(1-Phenylpentyl)-2,3-dihydrobenzofuran (3)
Oil. Main diastereoisomer. 1H NMR (200 MHz, CDCl3) d 0.80 (t, 3H,
J ¼ 7.1 Hz), 1.08 (m, 2H), 1.25 (m, 2H), 1.67 (m, 2H), 2.73 (m, 1H), 3.68 (td, 1H,
J ¼ 6.2 and 8.8 Hz), 4.44 (dd, 1H, J ¼ 6.2 and 9.1 Hz), 4.61 (dd, 1H, J ¼ 8.8 and
9.1 Hz), 6.26 (d, 1H, J ¼ 7.7 Hz), 6.59 (dt, 1H, J ¼ 1.0 and 7.5 Hz), 6.71 (d, 1H,
J ¼ 8.0 Hz), 7.09 (m, 3H), 7.26 (m, 3H). 13C NMR (50 MHz, CDCl3) d 13.85,
22.56, 29.48, 33.04, 48.05, 50.37, 75.06, 109.29, 119.80, 125.41, 126.57, 128.10,
1
128.34, 128.53, 129.07, 142.98, 160.34. Minor diastereomer. H NMR (200 MHz,
CDCl3) d 0.79 (t, 3H, J ¼ 7.1 Hz), 1.08 (m, 2H), 1.25 (m, 2H), 1.67 (m, 2H), 2.73
(m, 1H), 3.55 (td, 1H, J ¼ 4.0, and 8.8 Hz), 4.17 (dd, 1H, J ¼ 4.4 and 9.1 Hz), 4.28
(dd, 1H, J ¼ 8.8 and 9.1 Hz), 6.76 (d, 1H, J ¼ 8.8 Hz), 6.85 (dt, 1H, J ¼ 1.0 and
7.5 Hz), 7.10 (m, 4H), 7.26 (m, 3H). 13C NMR (50 MHz, CDCl3) d 13.85, 22.66,
29.40, 32.48, 47.92, 49.94, 75.52, 109.72, 119.91, 125.97, 126.40, 128.34, 128.49,
128.53, 129.50, 143.06, 160.60. MS m=z (rel. ab.): 266 (16) [Mþ], 209 (22), 120
(32), 119 (100), 115 (36), 92 (27), 91 (50), 77 (19), 65 (30). Anal. calcd. for
C19H22O: C, 85.67; H, 8.32. Found: C, 85.60; H, 8.34.
Phenyl-(Z)-3-phenyl-1-heptenyl Ether (4)
Oil. 1H NMR (200 MHz, CDCl3) d 0.86 (t, 3H, J ¼ 6.6 Hz), 1.32 (m, 4H), 1.72
(m, 2H), 3.94 (m, 1H), 4.96 (dd, 1H, J ¼ 6.2 and 9.9 Hz), 6.39 (d, 1H, J ¼ 6.2 Hz),
7.00 (m, 3H), 7.27 (m, 7H). 13C NMR (50 MHz, CDCl3) d 14.02, 22.58, 29.70,
36.21, 40.34, 116.38, 117.05, 122.49, 125.90, 127.30, 128.38, 129.52, 139.74, 145.53,
157.49. MS m=z (rel. ab.): 266 (4) [Mþ], 209 (50), 131 (13), 115 (100), 91 (12), 77
(18). Anal. calcd. for C19H22O: C, 85.67; H, 8.32. Found: C, 85.02; H, 8.16.

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C. RODRIGUEZ AND N. S. NUDELMAN
778
SUPPORTING INFORMATION
1
Full experimental detail and H and 13C NMR spectra can be found via the
Supplementary Content section of this article’s webpage.
ACKNOWLEDGMENTS
The authors are grateful to Graciela Garcia. The financial support from the
Agency for the Promotion of Science and Technology (ANPCyT) and the National
Research Council of Argentine (CONICET) is gratefully acknowledged.
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