α-Lithiated Aryl Benzyl Ethers: Inhibition of [1,2]-Wittig Rearrangement and Application to the Synthesis of Benzo[b]furan Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b01964

The use of t-BuLi at low temperature selectively leads to α-lithiation of benzyl phenyl ether generating a stable organolithium, which can be efficiently trapped with a variety of selected electrophiles prior to suffering the expected [1,2]-Wittig rearrangement. In the case of (o-alkynyl)phenyl benzyl ethers, the intermediate α-aryloxyorganolithium undergoes an unexpected anti intramolecular carbolithiation reaction leading to functionalized benzo[b]furan derivatives.

Full text of DOI:10.1021/acs.orglett.5b01964

Letter
pubs.acs.org/OrgLett
α‑Lithiated Aryl Benzyl Ethers: Inhibition of [1,2]-Wittig
Rearrangement and Application to the Synthesis of Benzo[b]furan
Derivatives
Rocío Velasco, Claudia Feberero, and Roberto Sanz*
́
Area de Química Organ
́
ica, Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Banuelos s/n, 09001
̃
Burgos, Spain
S
* Supporting Information
ABSTRACT: The use of t-BuLi at low temperature selectively
leads to α-lithiation of benzyl phenyl ether generating a stable
organolithium, which can be efficiently trapped with a variety of
selected electrophiles prior to suffering the expected [1,2]-Wittig
rearrangement. In the case of (o-alkynyl)phenyl benzyl ethers, the
intermediate α-aryloxyorganolithium undergoes an unexpected
anti intramolecular carbolithiation reaction leading to function-
alized benzo[b]furan derivatives.
Scheme 1. Previous Work and Proposed α-Lithiation of Aryl
Benzyl Ethers
α-Alkoxyorganolithiums, usually generated by deprotonation of
ethers1 or by Sn−Li exchange,2 are generally unstable under-
going either elimination or Wittig rearrangements.3 For the [1,2]
variant of the Wittig rearrangement,4 the use of allyl or benzyl
ethers allows the migrating group to be benzylic, secondary, or
primary alkyl, but not methyl. This reluctance of the methyl
group to undergo migration has allowed the trapping of α-
lithiobenzyl methyl ether with electrophiles.5 In this context, it
would be highly interesting to find a way to avoid the Wittig
rearrangement and allow functionalization of other α-lithioben-
zyl ethers. The most accepted mechanism for the [1,2]-Wittig
rearrangement is a two-stage process that involves the homolysis
of the α-anion intermediate and subsequent recombination of
the radical and radical anion fragment. This proposal mainly
satisfies the observed migratory aptitude for the R1 groups
(Scheme 1, eq 1). However, the migration of aryl groups from
aryl benzyl ethers has received much less attention (Scheme 1, eq
2).6
Our interest in this field7 led us to report that α-lithiobenzyl o-
lithiophenyl ethers, generated from benzyl 2-halophenyl ethers,
do not undergo Wittig rearrangement probably due to the
reluctance of the o-lithiophenoxy ring to migrate (Scheme 1, eq
3).8 At this point, we thought about the possibility of inhibiting
the Wittig rearrangement from aryl α-lithiobenzyl ethers without
the requirement of the additional lithium atom at the aryl ring.
With all these results in mind, and considering the unexplored
potential synthetic usefulness of aryl α-lithiobenzyl ethers,9 we
proposed to study the α-lithiation of aryl benzyl ethers with the
aim of finding suitable conditions in which these anionic
intermediates were stable enough to avoid the Wittig rearrange-
ment (Scheme 1). In this paper, we report the successful
generation of α-lithiated aryl benzyl ethers and their function-
alization with selected electrophiles, including intramolecular
anti carbolithiation reactions onto unactivated C−C triple bonds
to generate benzo[b]furan derivatives.
We selected benzyl phenyl ether 1a as model substrate and
performed the metalation reaction under the conditions reported
by Eisch et al. As expected, a complete conversion to
diphenylmethanol 3a takes place by using BuLi at 0 °C, in
agreement with their results (Scheme 2).6a In order to generate
the lithiated intermediate 2a at a lower temperature, we decided
to use a stronger base (t-BuLi). Gratifyingly, deuteriated ether 4a
was selectively and almost quantitatively obtained by reacting 1a
with a slight excess of t-BuLi at −78 °C (Scheme 2). This result
Received: July 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01964
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Organic Letters
Letter
Scheme 2. α-Lithiation of Benzyl Phenyl Ether 1a
Scheme 3. Reaction of α-Lithiobenzyl Phenyl Ether 2a with
Caboxylic Esters: Synthesis of Ketones 6, 8, and 9
Table 1. Reaction of Aryl α-Lithiobenzyl Ethers 2 with
Electrophiles: Synthesis of Funtionalized Ethers 5
a
yield
entry
1
R1
R2
4, 5
E
(%)
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
H
H
4a
D
96
95
88
95
62
79
71
81
78
79
65
95
Scheme 4. Intramolecular Cyclization of o-Alkynylphenyl
Ethers and Proposed Intramolecular Carbolithiation
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5aa
5ab
5ac
5ad
Me
3
CH2CHCH2
4
SiMe3
5
SnBu3
b
6
5ae
CH(OH)(4-ClC6H4)
CH(OH)i-Pr
C(OH)Ph2
c
7
5af
8
5ag
5ah
d
9
C(OH)PrPh
C(OH)(2-Th)c-C3H5
CH(Ph)NHPh
e
10
11
12
5ai
5aj
5ak
b
f
CH−
(CH2)4CH(OH)−
13
14
15
16
1b
1b
1c
1c
Cl
H
H
H
H
4b
D
97
83
90
88
b
Cl
5ba
4c
CH(OH)i-Pr
OMe
OMe
D
f
5ca
CH−
(CH2)4CH(OH)−
17
18
19
20
1d
1d
H
H
H
H
Cl
4d
D
Et
D
94
92
93
70
Scheme 5. Intramolecular anti-Carbolithiation of o-
(Alkynyl)aryl Benzyl Ethers 10
Cl
5da
g
h
1e
1e
OMe
OMe
4e
g
5ea
C(OH)Ph2
a
b
Yield of isolated product referred to starting ether 1. Obtained as a
c
1:1 mixture of diastereoisomers. Obtained as a 1.25:1 mixture of
diastereoisomers. The major one could be isolated in pure form.
d
e
Obtained as 4:1 mixture of diastereoisomers. Obtained as 3.3:1
f
mixture of diastereoisomers. Cyclohexene oxide as electrophile. 5ak
and 5ca were obtained as a ca. 1.5:1 mixture of diastereoisomers.
g
h
Lithiation was carried out from −78 to −35 °C. ∼92%-D
incorporation.
shows that simply by decrease of the temperature, the [1,2]-
Wittig rearrangement can be suppressed. We also studied the
stability of intermediate α-alkoxyorganolithium 2a by gradually
increasing the reaction temperature, finding that the [1,2]-Wittig
rearrangement initiates at ca. −30 °C (Scheme 2). In addition,
when the lithiation reaction of 1a was carried out in Et2O, it was
not until −30 °C that complete lithiation took place, implying
that in this solvent organolithium 2a is stable at higher
temperatures than when using THF.10 With this study, we
have shown how 1a can be efficiently and selectively lithiated at
low temperature in THF to generate organolithium intermediate
2a, which remains stable up to ca. −30 °C.
These optimized lithiation conditions were used to prepare a
variety of α-functionalized aryl benzyl ethers 5aa−5ak after
electrophilic quenching (Table 1, entries 2−12). Addition of
alkyl halides gave high yields of the corresponding α-alkylated
ethers (entries 2 and 3). In the same way, the use of TMSCl or
Bu3SnCl resulted in the production of functionalized ethers 5ac
and 5ad (entries 4 and 5). Typical carbonyl electrophiles such as
aldehydes (entries 6 and 7) and ketones (entries 8−10) gave the
B
DOI: 10.1021/acs.orglett.5b01964
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Letter
Table 2. Synthesis of Benzo[b]furan Derivatives 12 and 14
a
entry
10
R
E+
prod.
E
yield (%)
b
1
10a
10a
10a
10b
10c
10a
10a
10a
10a
10a
10a
Ph
Ph
Ph
I2
12ab
I
86
84
80
71
70
72
85
82
70
60
78
b
2
Me3SiCl
12ac
12ad
SiMe3
SnMe3
b
3
Me3SnCl
c
4
n-Bu
c-C6H9
Ph
4-ClC6H4CHO
Me2CO
12bb
C(H)OH(4-ClC6H4)
C(OH)Me2
SiMe3
d
5
12cb
14ab
14ac
14ad
6
Me3SiCl
7
Ph
CH2CHCH2Br
CH2CHCH2
C(OH)Me2
CH(OH)Ph
CO2Et
8
Ph
Me2CO
c
9
Ph
PhCHO
14ae
14af
14ag
10
11
Ph
ClCO2Et
Ph
(p-TolS)2
S(p-Tol)
a
b
Yield of isolated product after column chromatography referred to starting ether 10. Obtained as a ca. 1.2−2:1 mixture of geometrical isomers.
c
d
Obtained as a mixture of diastereoisomers. Obtained as ca. 1:1 mixture of geometrical isomers.
corresponding hydroxyl-functionalized ethers in high yields. The
process was also amenable to an imine or an epoxide as
electrophiles, giving rise to products 5aj and 5ak, respectively
(entries 11 and 12). In all cases, when two stereogenic centers are
generated, the final compound is obtained as a variable mixture of
diastereoisomers.
We have also investigated the metalation and functionalization
of other aryl benzyl ethers 1b−e related to the parent benzyl
phenyl ether 1a. Benzyl ethers 1b,c bearing a chloro or a methoxy
substituent at the para position of the aryl moiety undergo
selective benzylic deprotonation on treatment with t-BuLi, and
the corresponding α-lithiated species 2b,c can be trapped with
selected electrophiles (entries 13−16). In the same way, starting
ethers 1d,e substituted at para position of the benzylic moiety
were also tried and the corresponding α-deuteriated or α-
functionalized benzyl ethers 4 and 5 were obtained (entries 17−
20). Only with ether 1e, possessing a 4-methoxybenzyl group, a
significant increase in the reaction temperature was required to
reach an almost complete lithiation.11 This fact is likely due to the
lower acidity of the benzylic hydrogen imposed by the p-methoxy
group.
Surprisingly, when ethyl benzoate was tested as electrophile,
the aromatic ketone 6a was selectively obtained instead of the
expected tertiary alcohol, independently of the amount of the
ester added to 2a. This result was general for a selection of esters
derived from aromatic acids, allowing the synthesis of ketones 6
in good yields (Scheme 3, eq 1).12 To account for this
unexpected result, we propose that the initially formed ketone
6 undergoes deprotonation by the lithium ethoxide generated in
the first step, leading to the corresponding enolate 7, which
remains intact prior to hydrolysis. Our proposal was supported
by the fact that, upon addition of methyl iodide, prior to aqueous
workup, ketone 8 bearing an α-quaternary center was isolated
(Scheme 3, eq 2). Moreover, the addition of ethyl chloroformate
as the electrophilic partner afforded α,α′-difunctionalized ketone
9 as a 2:1 mixture of diastereoisomers in high yield (Scheme 3, eq
3). Interestingly, this ketone was always selectively obtained
irrespective of the stoichiometry of the reactants.
formation of a C−O bond. Several transition metal-catalyzed or
base-mediated processes have been described in the last years
(Scheme 4, eq 1).14 However, just a few reports for accessing the
benzo[b]furan skeleton have appeared involving the C2−C3
bond formation as an alternative methodology.15 Most of them
are related to base-mediated or catalyzed cyclizations of o-
(alkynyl)phenyl benzyl ethers. Although this transition metal-
free approach is highly interesting, developed procedures do not
allow further functionalization of the generated benzofuran
derivative, thus representing a drawback of these methodologies
(Scheme 4, eq 2).16 Taking advantage of the easy and efficient
lithiation that we had developed, we envisaged that an α-lithiated
o-(alkynyl)phenyl benzyl ether could undergo an intramolecular
carbolithiation17 giving rise to a new organolithium intermediate,
which could be further functionalized with electrophiles
(Scheme 4, eq 3).
o-(Alkynyl)phenyl benzyl ether 10a was the chosen model to
initiate the study of the proposed intramolecular carbolithiation
reaction. In this case, it was necessary to raise the temperature to
−20 °C in order to complete lithiation at the α-position and
subsequent cyclization, obtaining product 12aa as a mixture of
geometrical isomers (Scheme 5). When performing this
optimization study,18 we noticed that deuteriated 10a at the α-
position was never obtained, which demonstrates that the
lithiation is slower than the carbolithiation reaction. Based on
previous reports about the cyclization of acetylenic organo-
lithiums,19 the addition of the C−Li unit to the triple bond to
produce a 5-membered ring was expected to proceed in a syn
fashion, and depending on the stability of the formed
vinyllithium, it could undergo a cis−trans isomerization
afterward. Unsurprisingly, compound 12aa was obtained as a
mixture of Z and E isomers. However, alkyl-substituted
vinyllithiums are known to be configurationally stable, so the
isolation of deuteriated dihydrobenzofuran 12ba as a single
geometrical Z isomer was really unexpected, meaning that an anti
addition of the C−Li bond to the alkyne had taken place in the
former case as well.20 Furthermore, benzyl ether 10c, bearing a
cyclohex-1-enyl substituent, also undergoes an anti addition,
although without complete selectivity, probably due to the
configurational instability of the resulting vinyllithium, as in the
case of the phenyl substituent (Scheme 5). Although an anti
carbolithiation of propargyl o-lithioaryl ethers has been
Due to the interest in benzo[b]furan derivatives, a wide variety
of approaches for their synthesis have been reported.13 One of
the most useful methodologies involves the intramolecular
cyclization of o-(alkynyl)phenyl ethers or o-alkynylphenols by
C
DOI: 10.1021/acs.orglett.5b01964
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Organic Letters
Letter
reported,21 in that specific case an interaction of a heteroatom
located at the terminal position of the alkyne with the lithium
atom seems to be the cause for the observed anti addition.22
On the other hand, we also checked that when the reaction
temperature is raised to rt, the intermediate organolithium 11a
(R = Ph) smoothly undergoes isomerization giving rise to the
deuteriated benzofuran derivative 14aa after deuteriolysis in high
yield (Scheme 5).23
To further demonstrate the utility of this new carbolithiation
reaction in the synthesis of benzofuran derivatives, a variety of
representative electrophiles were used for trapping the
intermediate organolithiums 11 or 13a (Table 2). Functionalized
dihydrobenzofurans 12 were obtained in average to good yields
as mixtures of geometrical isomers except in the case of 12bb
bearing R = n-Bu (entries 1−5). The scope of the reaction was
further explored by synthesizing a selection of 3-benzyl-2-
arylbenzo[b]furan derivatives 14ab−ag using different electro-
philes (entries 6−11).
(4) (a) Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann./Recueil
1997, 1997, 1275−1281. For selected synthetic applications, see:
(b) Tomooka, K.; Yamamoto, K.; Nakai, T. Angew. Chem., Int. Ed. 1999,
38, 3741−3743. (c) Nakano, T.; Soeta, T.; Endo, K.; Inomata, K.; Ukaji,
Y. J. Org. Chem. 2013, 78, 12654−12661.
(5) Azzena, U.; Demartis, S.; Fiori, M. G.; Melloni, G.; Pisano, L.
Tetrahedron Lett. 1995, 36 (31), 5641−5644.
(6) (a) Eisch, J. J.; Kovacs, C. A.; Rhee, S.-G. J. Organomet. Chem. 1974,
65, 289−301. See also: (b) Yang, J.; Dudley, G. B. J. Org. Chem. 2009,
74, 7998−8000. (c) Gao, G.; Gu, F.-L.; Jiang, J.-X.; Jiang, K.; Sheng, C.-
Q.; Lai, G.-Q.; Xu, L.-W. Chem. - Eur. J. 2011, 17, 2698−2703.
(7) Barluenga, J.; Fananas
́
, F. J.; Sanz, R.; Marcos, C.; Trabada, M. Org.
̃
Lett. 2002, 4, 1587−1590.
́
(8) Sanz, R.; Miguel, D.; Martínez, A.; Perez, A. J. Org. Chem. 2006, 71,
4024−4027.
(9) By study of the o-lithiation of benzyl fluorophenyl ethers, a partial
metalation of the benzylic position of 1a was observed: Chodakowski, J.;
́
Klis, T.; Serwatowski, J. Tetrahedron Lett. 2005, 46, 1963−1965.
(10) See Supporting Information for a detailed study of the α-lithiation
of ether 1a.
In summary, easily available aryl benzyl ethers have been
shown to be selectively α-lithiated at low temperature, being
stable enough to avoid the expected [1,2]-Wittig rearrangement.
The α-aryloxy benzyllithiums generated can be trapped with a
wide range of electrophiles. Starting from o-(alkynyl)phenyl
benzyl ethers, an intramolecular carbolithiation is triggered after
α-lithiation providing a direct entry to functionalized 2-
arylbenzo[b]furan derivatives. Moreover, the addition takes
place in an unexpected anti fashion representing the first example
of an anti carbolithiation of an unactivated triple bond without
coordination of the lithium cation and the terminal substituent of
the alkyne.
(11) Increasing the reaction temperature over −35 °C to force
complete lithiation leads to the competitive formation of diarylmethanol
3e derived from [1,2]-Wittig rearrangement.
(12) Nevertheless, when an aliphatic ester such as ethyl isobutyrate was
used, the reaction resulted in a mixture of the corresponding ketone and
tertiary alcohol.
(13) (a) De Luca, L.; Nieddu, G.; Porcheddu, A.; Giacomelli, G. Curr.
Med. Chem. 2009, 16, 1−20. (b) Yeung, K.-S.; Yang, Z.; Peng, X.-S.;
Hou, X.-L. Prog. Heterocycl. Chem. 2011, 22, 181−216.
(14) See, for instance: (a) Nakamura, I.; Mizushima, Y.; Yamamoto, Y.
J. Am. Chem. Soc. 2005, 127, 15022−15023. (b) Furstner, A.; Davies, P.
̈
W. J. Am. Chem. Soc. 2005, 127, 15024−15025. (c) Sakiyama, N.;
Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed. 2012, 51, 5976−5980.
(15) See, for instance: (a) Shen, Z.; Dong, V. M. Angew. Chem., Int. Ed.
2009, 48, 784−786. (b) Ma, X.; Wu, F.; Yi, X.; Wang, H.; Chen, W.
Chem. Commun. 2015, 51, 6862−6865. (c) Hu, M.; Song, R.-J.; Li, J.-H.
Angew. Chem., Int. Ed. 2015, 54, 608−612.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01964.
(16) (a) Kanazawa, C.; Goto, K.; Terada, M. Chem. Commun. 2009,
5248−5250. (b) Hu, J.; Wu, L.-Y.; Wang, X.-C.; Hu, Y.-Y.; Niu, Y.-N.;
Liu, X.-Y.; Yang, S.; Liang, Y.-M. Adv. Synth. Catal. 2010, 352, 351−356.
(c) Chen, P.-Y.; Wang, T.-P.; Huang, K.-S.; Kao, C.-L.; Tsai, J.-C.; Wang,
E.-C. Tetrahedron 2011, 67, 9291−9297. (d) Grimaldi, T. B.; Back, D.
F.; Zeni, G. J. Org. Chem. 2013, 78, 11017−11031.
Full experimental procedures, characterization data, and
copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
́
(17) Fananas, F. J.; Sanz, R. Intramolecular Carbolithiation Reactions.
̃
■
In The Chemistry of Organolithium Compounds; Rappoport, Z., Marek, I.,
Eds.; The Chemistry of Functional Groups; Rappoport, Z., Series Ed.;
Wiley & Sons: Chichester, 2006; Vol. 2, Chapter 4, pp 295−379. For
* E-mail: rsd@ubu.es
Notes
our previous work in this field, see: (a) Barluenga, J.; Fananas
́
, F. J.; Sanz,
̃
R.; Marcos, C. Org. Lett. 2002, 4, 2225−2228. (b) Barluenga, J.; Fananas
́
,
̃
The authors declare no competing financial interest.
F. J.; Sanz, R.; Marcos, C. Chem. - Eur. J. 2005, 11, 5397−5407. (c) Sanz,
R.; Ignacio, J. M.; Rodríguez, M. A.; Fananas, F. J.; Barluenga, J. Chem. -
́
̃
ACKNOWLEDGMENTS
We are grateful to the Junta de Castilla y Leon
BU237U13) and Ministerio de Economia y Competitividad
(MINECO) and FEDER (Grant CTQ2013-48937-C2-1-P) for
■
Eur. J. 2007, 13, 4998−5008.
́
(Grant
(18) See Supporting Information for further details.
(19) Bailey, W. F.; Ovaska, T. V. J. Am. Chem. Soc. 1993, 115, 3080−
3090.
́
(20) Double bond configurations were determined by NOESY
experiments with the corresponding nondeuteriated (E = H) derivatives
12 (see Supporting Information).
financial support. R.V. thanks Junta de Castilla y Leo
́
n
́
(Consejeria de Educacion
PIRTU contract.
́
) and Fondo Social Europeo for a
(21) (a) Fressigne,
Angew. Chem., Int. Ed. 2008, 47, 891−893. (b) Lhermet, R.; Ahmad, M.;
Fressigne,
C.; Durandetti, M.; Maddaluno, J. Chem.Eur. J. 2014, 20,
10249−10254.
(22) (a) Fressigne,
Maddaluno, J. J. Org. Chem. 2013, 78, 9659−9669. (b) Lhermet, R.;
Ahmad, M.; Hauduc, C.; Fressigne, M.; Durandetti, M.; Maddaluno, J.
́
C.; Girard, A.-L.; Durandetti, M.; Maddaluno, J.
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D
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