α-Lithiobenzyloxy as a Directed Metalation Group in ortho-Lithiation Reactions

Article abstract of DOI:10.1021/acs.orglett.0c02199

The α-lithiobenzyloxy group, easily generated from aryl benzyl ethers by selective α-lithiation with t-BuLi at low temperature, behaves as a directed metalation group (DMG) providing a direct access to o-lithiophenyl α-lithiobenzyl ethers. This ortho-directing effect is reinforced in substrates bearing an additional methoxy group at the meta position. The generated dianions can be reacted with a selection of electrophiles including carboxylic esters and dihalosilanes or germanes, which afford interesting benzofuran, sila(germa)dihydrobenzofuran, and silachroman derivatives from simple aryl benzyl ethers.

Full text of DOI:10.1021/acs.orglett.0c02199

pubs.acs.org/OrgLett
Letter
α‑Lithiobenzyloxy as a Directed Metalation Group in ortho-
Lithiation Reactions
́
Carlos Sedano, Rocío Velasco, Claudia Feberero, Samuel Suarez-Pantiga, and Roberto Sanz*
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ABSTRACT: The α-lithiobenzyloxy group, easily generated from
aryl benzyl ethers by selective α-lithiation with t-BuLi at low
temperature, behaves as a directed metalation group (DMG)
providing a direct access to o-lithiophenyl α-lithiobenzyl ethers.
This ortho-directing effect is reinforced in substrates bearing an
additional methoxy group at the meta position. The generated
dianions can be reacted with a selection of electrophiles including
carboxylic esters and dihalosilanes or germanes, which afford
interesting benzofuran, sila(germa)dihydrobenzofuran, and silach-
roman derivatives from simple aryl benzyl ethers.
Scheme 1. Previous Work and Proposed o-Lithiation of Aryl
α-Lithiobenzyl Ethers
xygenated organolithium compounds are useful inter-
mediates for the preparation of functionalized molecules
O
containing oxygen.1 In this field, α-oxygen-functionalized
organolithiums present an ambiphilic behavior as nucleophiles
or electrophiles, which causes them to be considered
carbenoids, in the same way as α-lithiated halogens,2 and
also complicate the reactivity of these species.3 Although
lithiation α to oxygen is unfavorable due to antibonding
interactions of the oxygen’s lone pairs with the C−Li bond, the
presence of an aryl (or vinyl) group on the side chain helps to
stabilize the α-oxygenated organolithium through Li−π
interactions. Thus, deprotonations of benzyl ethers are easily
3
achieved by their treatment with more basic Csp -based
organolithiums.4 Alternatively, α-lithiated ethers can also be
prepared by Sn−Li exchange.5 Nevertheless, nonstabilized
acyclic α-alkoxy organolithiums are generally unstable under-
going either elimination or Wittig rearrangements, which leads
to lithium alkoxides through the isomerization of these
carbanions.6 In this field, we reported that aryl α-lithiobenzyl
ethers could be generated by anion translocation from benzyl
o-lithioaryl ethers and subsequently undergo [1,2]-Wittig
rearrangement.7 More recently, we have described that these
aryl α-lithiobenzyl ethers 2, generated by selective α-lithiation
of aryl benzyl ethers 1, resulted in being sufficiently stable at
low temperatures allowing their functionalization by prevent-
ing the Wittig rearrangement that would lead to benzhydrols 3
(Scheme 1, eq 1).8 In addition, we have also found that benzyl
2-halophenyl ethers afford α-lithiobenzyl o-lithiophenyl ethers
4, avoiding competitive Wittig rearrangement likely due to the
reluctance of the o-lithiophenoxy ring to migrate (Scheme 1,
eq 2).9
prepare by classical routes such as electrophilic aromatic
substitutions and hydrogen nucleophilic aromatic substitutions
that typically present significant drawbacks concerning
regioselectivity.10 Alternatively, DoM ensures very high
Received: July 3, 2020
On the other hand, directed ortho-metalation (DoM) is a
powerful method for the synthesis of ortho-functionalized
arenes, which otherwise are significantly more challenging to
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© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
regioselectivity for the ortho-functionalization of arenes bearing
a suitable directed metalation group (DMG).11 Although a
wide variety of DMGs have been described, many of them
possess some limitations mainly related to the additional steps
required to install and further remove them. Among oxygen-
based DMGs12 the O-carbamate developed by Snieckus is
probably the most useful one, affording a large number of
applications.13 An interesting variation in this chemistry is the
one in which the DMG could be a versatile functional group
for subsequent manipulations, or the DMG itself could be
considered a useful functional group.14 Thus, one of the main
research efforts in the field has been devoted to the discovery
of new DMGs.15
As established above, benzylic ethers easily undergo benzylic
lithiation, and so, they cannot be employed as DMGs.16
Nonetheless, herein, we report that the α-lithiobenzyloxy
group behaves as an effective oxygen-based DMG for aryl
systems providing a straightforward methodology for the
regioselective o,α-difunctionalization of simple aryl benzyl
ethers (Scheme 1, eq 3).
We selected benzyl p-tolyl ether 1a as a model substrate due
to its higher reluctance to undergo Wittig rearrangement once
the corresponding α-lithiobenzyl ether 2a was generated,
compared with benzyl phenyl ether.8b After a thorough study
for the regioselective dilithiation process, optimal conditions
for model substrate 1a were established as 4 equiv of t-BuLi in
THF at 0 °C for 20 min (for further details, see Supporting
Information).17 Under these conditions, only minor amounts
of competitive Wittig rearranged product 3a and mono-
functionalized 5aa were obtained (Scheme 2).
Table 1. Competitive ortho-Directing Groups. Substituents
Effects on the Regioselectivity of the ortho-Lithiation
a
b
entry
1
R
Product
C2/C3
yield (%)
c d
,
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
1g
1h
1i
Cl
F
NMe2
OMe
Oi-Pr
6ba
6ca
6da
6ea
6fa
−
6ha
6ia
7ja
1/0
1/0
1/0
10/1
1/0
−
12/1
1/0
<1/15
74
76
77
70
80
−
71
57
50
c
c
c
e
OPh
f
CH2NMe2
CH2OH
CONEt2
g
f
1j
a
1
Regioisomeric ratio determined by H NMR analysis of the crude
b
reaction mixture. Yield of isolated product referred to starting ether
1. t-BuLi (3.5 equiv) was used. Carried out at −10 °C.
trimethylated derivative appears at the same time as the dimethylated
one by using more than 2.5 equiv of base. An ∼5/1 ratio of the
corresponding products 6 and benzhydrols 3 was obtained. t-BuLi (6
c
d
e
A
f
g
equiv) was used.
equivalents of t-BuLi employed (entry 6);18 in its place, a
complete and regioselective trilithiation reaction was observed
by using an excess of base (see Scheme 3). In addition, other
Scheme 3. Trilithiation of Benzyl 4-Phenoxyphenyl Ether
1g: Synthesis of Trifunctionalized Ethers 9
Scheme 2. Optimized Conditions for the Dilithiation of
Benzyl p-Tolyl Ether 1a
benzylic DMGs such as dimethylaminomethyl and hydrox-
ymethyl were also surpassed by the α-lithiobenzyloxy group in
ethers 1h and 1i (entries 7 and 8). On the other hand, not
unexpectedly, lithiation of N,N-diethyl-4-benzyloxybenzamide
1j took place selectively at C3 instead of at C2 (entry 9). With
these intramolecular lithiation competition experiments, α-
lithiobenzyloxy was found to outperform halogens, dimethy-
lamino, and alkoxy groups as well as hydroxymethyl and
dimethylaminomethyl groups.
With the optimized dilithiation conditions, a variety of α,o-
difunctionalized aryl benzyl ethers 6ab−6ae were prepared
from 1a by using selected electrophilic reagents (Table 2,
entries 1−4). Starting benzyl phenyl ethers bearing halogen
(1b,c), or dimethylamino (1d) substituents, were also
successfully difunctionalized with high yields (entries 5−9).
As above-mentioned, the dilithiation of benzyl 4-methox-
yphenyl ether 1e was not completely regioselective leading to
the corresponding difunctionalized derivatives 6ec and 6ee
with trace amounts of their regioisomers 7 (entries 10 and 11).
To roughly establish the relative strength of the α-
lithiobenzyloxy group as DMG, we also decided to investigate
the metalation and functionalization of different aryl benzyl
ethers 1b−j further substituted at the para-position of the aryl
fragment (Table 1). Benzyl p-halophenyl ethers 1b,c, as well as
benzyl p-(dimethylamino)phenyl ether 1d, undergo regiose-
lective o-lithiation at C2, the nearest position to the α-
lithiobenzyl group, providing dimethylated derivatives 6ba−da
after treatment with methyl iodide (entries 1−3). We then
turned our attention to study the relative activation ability of
different oxygen-based DMGs. The obtained results with
benzyl ethers 1e,f suggest that the α-lithiobenzyloxy group is
stronger than methoxy or isopropoxy groups, although the
methoxy-functionalized benzyl ether 1e gave rise to small
amounts of regioisomeric dimethylated ether 7ea (entries 4
and 5). Surprisingly, with benzyl 4-phenoxyphenyl ether 1g
selective dilithiation could not be achieved irrespective of the
B
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Table 2. Synthesis of Difunctionalized Aryl Benzyl Ethers 6
Scheme 4. Synthesis of Oxametallacycles 10 and 2-Phenyl-3-
Substituted Benzo[b]furans 11 from Aryl Benzyl Ethers 1
a
entry
1
R
Product
E
yield (%)
b
1
1a
1a
1a
1a
1b
1b
1b
1c
1d
1e
1e
1f
1f
1f
1f
1k
1k
1k
1k
1l
4-Me
4-Me
4-Me
4-Me
4-Cl
4-Cl
4-Cl
4-F
4-NMe2
4-MeO
4-MeO
4-i-PrO
4-i-PrO
4-i-PrO
4-i-PrO
2-MeO
2-MeO
2-MeO
2-MeO
H
6ab
6ac
6ad
6ae
6bb
6bc
6be
6cc
6dc
6ec
6ee
6fb
6fc
D
83
72
60
59
77
71
60
69
83
66
60
95
80
61
68
b
2
SiMe3
SnBu3
C(OH)Me2
D
SiMe3
C(OH)Me2
SiMe3
SiMe3
SiMe3
C(OH)Me2
D
b
3
b
4
c
5
c
6
c
7
8
9
b
d
10
11
12
13
14
15
16
17
18
19
d
SiMe3
SnBu3
C(OH)Me2
Me
6fd
6fe
e
6ka
6kb
6kc
6ke
6la
74
78
70
55
64
68
D
e
SiMe3
C(OH)Me2
Me
f
g
20
21
f
g
1l
H
6lb
D
a
b
Yield of isolated product referred to starting ether 1. t-BuLi (4
dichlorides as electrophiles. Interestingly, sila- and germa-
dihydrobenzofurans 10 were obtained in moderate to high
yield, with the benzenoid fragment of these silylated and
germylated heterocycles being functionalized with halogens as
well as alkoxy or dimethylamino groups, which are initially
present in the starting aryl benzyl ethers 1. On the other hand,
the reaction of dianions 4 with carboxylic esters afforded, after
an acidic hydrolysis, benzo[b]furan derivatives 11.9 Both
heteroaromatic and alkylic carboxylic esters could be employed
leading to the corresponding benzofurans 11 in moderate to
high yields (Scheme 4).
The steric effect of a large alkyl group at one of the meta
positions was evaluated with 3-tert-butylphenyl benzyl ether
1m resulting in complete regiocontrol of the o-lithiation in
favor of the least congested ortho position as demonstrated
with the preparation of 6ma. As it was observed with 1l, the
Wittig rearrangement was partially competitive (Scheme 5, eq
1). On the other hand, a synergetic action of the alkoxy and α-
lithiobenzyloxy groups in the stabilization of the corresponding
dianions 4n,o could explain the lower amount of base required
for the complete dilithiation of ethers 1n,o. In this way, a
selection of difunctionalized benzyl 3-methoxyaryl ethers 6 as
well as oxasilacycles 10 and benzofurans 11 were efficiently
synthesized in high yields (Scheme 5, eq 2).23
Finally, to determine if there was a difference in the
nucleophilicity of both lithiated positions (ortho- and α-
positions), chloro(chloromethyl)dimethylsilane was employed
as an electrophile, since it has two differentiated electrophilic
centers. As shown in Scheme 6, the reaction of selected
dianions 4 with this electrophilic reagent led to the
regioselective formation of silachromans 12, in which the
silicon atom is attached to the aromatic ring. This selectivity
could be the result of a combination of the expected higher
nucleophilicity and basicity of the o-lithiated aromatic ring
(since it is the second position to be lithiated), and the greater
c
d
equiv) was used. Carried out at −10 °C. Isolated along with minor
amounts of the regioisomeric ethers 7ec and 7ee. Isolated with trace
e
f
amounts of other regioisomer. Carried out at −15 °C for 5 h.
g
Diphenylmethanol (3l) was also formed (∼15%).
This issue was nicely solved by using benzyl 4-isopropox-
yphenyl ether 1f that allowed the preparation of difunction-
alized derivatives 6fb−fe in good to high yields (entries 12−
15). Interestingly, the dilithiation/functionalization sequence
for benzyl 2-methoxyphenyl ether 1k proved to be highly
regioselective leading almost exclusively to difunctionalized
ethers 6ka−ke (entries 16−19). Finally, with the parent benzyl
phenyl ether 1l the [1,2]-Wittig rearrangement resulted in
being competitive with the o-lithiation process leading to a
mixture of the desired dimethylated or dideuterated ethers 6la
or 6lb and diphenylmethanol (3l) (entries 20 and 21), even by
performing the reaction at lower temperature.19
As shown in Table 1 (entry 6), the dilithiation of benzyl 4-
phenoxyphenyl ether 1g was not selective since a competitive
lithiation of the phenoxy group was observed.20 Gratifyingly,
by using an excess of t-BuLi, the regioselective and complete
trilithiation of ether 1g was achieved. The trilithiated ether 8
was further functionalized by its treatment with selected
electrophiles leading to trifunctionalized ethers 9 in moderate
to high yields (Scheme 3).
Taking advantage of the 1,4-relationship of dianions 4, we
turned our attention to test the possibility of generating O-
heterocyclic derivatives. For this purpose, different bis-
electrophilic reagents were made to react with the previously
prepared dianions 4 (Scheme 4). Considering the relevance of
silylated heterocycles, due to the potential effect of a C−Si
switch on the biological properties of drugs,21 and the lack of
general procedures for their synthesis with tetraorganosilicon
moieties,22 we decided to use silicon and germanium
C
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Scheme 5. Steric and Cooperative Effects in the α- and o-
Lithiation of Benzyl 3-Substituted Aryl Ethers 1m−o
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02199.
Full experimental procedures, characterization data, and
copies of NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a−o, 3m, 5aa, 5ga, 5la, 6aa, 6ab, 6ac, 6ad,
6ae, 6ba, 6bb, 6bc, 6be, 6ca, 6cc, 6da, 6dc, 6ea, 6ec,
6ee, 6fa, 6fb, 6 fc, 6fd, 6fe, 6ha, 6ia, 6ka, 6kb, 6kc, 6ke,
6la, 6lb, 6ma, 6na, 6nb, 6nc, 6nf, 6oa, 6oc, 7ja, 9a, 9b,
9c, 10aa, 10ab, 10ac, 10ba, 10ca, 10cb, 10da, 10fa,
10ka, 10na, 10oc, 11aa, 11da, 11eb, 11fb, 11kb, 11nb,
11oa, 12′o, 12a, 12n, 12o (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
́
́
́
Roberto Sanz − Area de Quimica Organica, Departamento de
́
Quimica, Facultad de Ciencias, Universidad de Burgos, 09001
Burgos, Spain; orcid.org/0000-0003-2830-0892;
Email: rsd@ubu.es
Authors
́
́
́
Carlos Sedano − Area de Quimica Organica, Departamento de
́
Quimica, Facultad de Ciencias, Universidad de Burgos, 09001
Burgos, Spain
Scheme 6. Reactions of Selected Dianions 4 with
ClCH2SiMe2Cl: Synthesis of Silachromans 12
́
́
́
Rocío Velasco − Area de Quimica Organica, Departamento de
́
Quimica, Facultad de Ciencias, Universidad de Burgos, 09001
Burgos, Spain
́
́
́
Claudia Feberero − Area de Quimica Organica, Departamento
́
de Quimica, Facultad de Ciencias, Universidad de Burgos,
09001 Burgos, Spain
́
́
́
́
Samuel Suarez-Pantiga − Area de Quimica Organica,
́
Departamento de Quimica, Facultad de Ciencias, Universidad
de Burgos, 09001 Burgos, Spain; orcid.org/0000-0002-
4249-7807
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02199
Notes
electrophilicity of the chlorosilane entity compared to the
chloromethyl one. However, this selectivity was not complete,
as minor amounts of the regioisomeric benzoxasilines 12′ were
also formed (Scheme 6).24
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge Ministerio de Ciencia e Innovacion
and FEDER (CTQ2016-75023-C2-1-P), and Junta de Castilla
■
́
In summary, the DMG ability of the α-lithiobenzyloxy group
in DoM chemistry has been described. Through a comparative
study we have established the directing power of this group for
regioselective o-lithiation, which was found to be comparable
or stronger than that of other alkoxy groups and halogens as
well as dimethylaminomethyl. The DoM capability of the α-
lithiobenzyloxy group provides a straightforward convenient
access to a variety of cores such as difunctionalized ethers,
benzo[b]furans, oxasilacycles, and oxagermacycles from
unfunctionalized starting materials, surpassing in terms of
atom economy the previous reports based on the use of benzyl
2-haloaryl ethers. Finally, this C−H bond double functional-
ization strategy was successfully applied to the synthesis of
silachromans with a high degree of regioselectivity, which
demonstrates that both lithiated positions own a differential
reactivity.
́
y Leon and FEDER (BU291P18), for financial support. S.S.-P.
́
thanks Junta de Castilla y Leon and FEDER for a postdoctoral
́
contract. C.S. thanks Ministerio de Educacion for a FPU
predoctoral contract.
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