Exploring the Reactivity of α-Lithiated Aryl Benzyl Ethers: Inhibition of the [1,2]-Wittig Rearrangement and the Mechanistic Proposal Revisited

Article abstract of DOI:10.1002/chem.201602254

By carefully controlling the reaction temperature, treatment of aryl benzyl ethers with tBuLi selectively leads to α-lithiation, generating stable organolithiums that can be directly trapped with a variety of selected electrophiles, before they can undergo the expected [1,2]-Wittig rearrangement. This rearrangement has been deeply studied, both experimentally and computationally, with aryl α-lithiated benzyl ethers bearing different substituents at the aryl ring. The obtained results support the competence of a concerted anionic intramolecular addition/elimination sequence and a radical dissociation/recombination sequence for explaining the tendency of migration for aryl groups. The more favored rearrangements are found for substrates with electron-poor aryl groups that favor the anionic pathway.

Full text of DOI:10.1002/chem.201602254

DOI: 10.1002/chem.201602254
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&
Synthetic Methods
Exploring the Reactivity of a-Lithiated Aryl Benzyl Ethers:
Inhibition of the [1,2]-Wittig Rearrangement and the Mechanistic
Proposal Revisited
Rocꢀo Velasco,[a] Carlos Silva Lꢁpez,[b] Olalla Nieto Faza,*[b] and Roberto Sanz*[a]
Abstract: By carefully controlling the reaction temperature,
treatment of aryl benzyl ethers with tBuLi selectively leads
to a-lithiation, generating stable organolithiums that can be
directly trapped with a variety of selected electrophiles,
before they can undergo the expected [1,2]-Wittig rear-
rangement. This rearrangement has been deeply studied,
both experimentally and computationally, with aryl a-lithiat-
ed benzyl ethers bearing different substituents at the aryl
ring. The obtained results support the competence of a con-
certed anionic intramolecular addition/elimination sequence
and a radical dissociation/recombination sequence for ex-
plaining the tendency of migration for aryl groups. The
more favored rearrangements are found for substrates with
electron-poor aryl groups that favor the anionic pathway.
Introduction
alternative intramolecular nucleophilic substitution mechanism
involving a bridged aryl intermediate [Scheme 1, reaction (2)].
However, Schlosser and Strunk have more recently studied the
Wittig rearrangement of lithiated allyl aryl ethers [Scheme 1,
Eq. (3)]. They suggested an intramolecular addition/elimination
process that accounts for the observed lesser tendency of the
4-tert-butylphenyl group to undergo migration in comparison
with the parent phenyl group (~10 times slower).[9] In addition,
it should also be considered that due to the higher strength of
aromatic CÀH bonds, it is known that a phenyl radical is signifi-
cantly less stable than alkyl radicals, including a methyl radical
(radical stabilization energy for phenyl radical=+32.9 kJmolÀ1
versus 0 kJmolÀ1 for methyl or À26.8 kJmolÀ1 for isopropyl).[10]
Additionally, it is known that if G is vinyl or aryl, that is, lithi-
ated allyl or benzyl ethers [Scheme 1, reaction (1)], then the
migrating group may be benzylic, secondary or, primary alkyl
(but not methyl). Due to the reluctance of the methyl group to
migrate, a-methoxyaryl methyl carbanions can be trapped
with electrophiles.[11] The suppression of the Wittig rearrange-
ment in other substrates apart from benzyl methyl ethers,[12]
would allow the selective a-functionalization of benzyl ethers
expanding the synthetic potential of their a-carbanions. How-
ever, little is known about the nucleophilic additions or substi-
tution reactions of a-oxybenzyllithiums.
The [1,2]-Wittig rearrangement,[1] first reported by Wittig and
Lçhmann in the reactions of benzylic ethers with PhLi,[2] in-
volves the [1,2]-alkyl migration from an oxygen atom to an a-
carbanion center leading to a lithium alkoxide. The intermedi-
ate a-oxygen carbanion is usually generated by deprotonation
of the corresponding ether or by tin-lithium exchange.[3] These
a-oxygenated organolithiums[4] are generally unstable, under-
going either a-elimination or Wittig rearrangements. Although
different mechanisms have been proposed for the [1,2]-Wittig
rearrangement,[5] the most well-recognized case that better ac-
commodates the experimental results (migratory ability of R
groups increases with the stability order of the corresponding
C
R ) involves two steps: homolytic dissociation and subsequent
radical recombination to give a radical anion that collapses
into a lithium alkoxide [Scheme 1, reaction (1)].[1b] Whereas
most of the reported examples have alkyl and benzyl migrat-
ing groups,[6] the related shifts of vinyl[7] and aryl[8] groups are
less common. For the migration of aryl groups in aryl benzyl
ethers, Eisch and colleagues established that the radical anion-
ic mechanism previously proposed for a-alkoxyorganolithiums
is also operating.[8a] Moreover, these authors clearly rejected an
Following our research in this field,[13] we have previously re-
ported that a-lithiobenzyl o-lithiophenyl ethers, generated
from benzyl 2-halophenyl ethers by halogen-lithium exchange
and further a-lithiation, do not suffer a Wittig rearrangement,
allowing their trapping with carboxylic esters and leading to
benzo[b]furan derivatives (Scheme 2).[14] With all these results
in mind, we have recently described that the Wittig rearrange-
ment of an a-lithiobenzyl phenyl ether can be suppressed by
a careful control of the reaction temperature, allowing the in-
termediate organolithium to be functionalized prior to under-
going the expected [1,2]-Wittig rearrangement (Scheme 2).[15]
[a] R. Velasco, Prof. Dr. R. Sanz
ꢀrea de Quꢁmica Orgꢂnica, Departamento de Quꢁmica
Facultad de Ciencias
Universidad de Burgos
Pza. Misael BaÇuelos s/n, 09001 Burgos (Spain)
E-mail: rsd@ubu.es
[b] Dr. C. Silva Lꢃpez, Dr. O. Nieto Faza
Departamento de Quꢁmica Orgꢂnica
Universidade de Vigo
Campus As Lagoas, 32004- Ourense, Galicia (Spain)
E-mail: faza@uvigo.es
Supporting information and the ORCID number(s) for the author(s) of this
article can be found under http://dx.doi.org/10.1002/chem.201602254.
Chem. Eur. J. 2016, 22, 1 – 12
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Results and Discussion
a-Lithiation of aryl benzyl ethers 1 and [1,2]-Wittig rear-
rangement of aryl a-lithiobenzyl ethers 2
Our previous report allowed us to establish the reaction condi-
tions for the selective a-lithiation of benzyl phenyl ether 1a, as
well as those for the subsequent Wittig rearrangement of the
intermediate organolithium 2a.[15] To gain further insight into
the mechanistic aspects of this reaction, we prepared a wide
selection of aryl benzyl ethers 1a–n,[16] and carried out a de-
tailed study concerning their lithiation conditions and the sta-
bility of the corresponding intermediate aryl a-lithiobenzyl
ether 2 with respect to the temperature (Table 1). Regarding
the model substrate 1a, when treated with a slight excess of
tBuLi in THF at À788C, only the deuterated ether 3a was ob-
tained after quenching with MeOD. At room temperature,
complete conversion of 1a to diphenyl methanol 4a, a product
derived from the expected [1,2]-Wittig rearrangement, took
place. We also studied the stability of intermediate organolithi-
um 2a towards reaction temperature, finding that the [1,2]-
Wittig rearrangement initiates at about À308C (Table 1,
entry 1). Benzyl ethers 1b and 1c, bearing alkyl substituents at
the para-position of the aryl moiety, also underwent selective
benzylic deprotonation at À788C, and the corresponding deu-
terated ethers 3b and 3c were obtained after treatment with
MeOD (entries 2 and 3). In the same way, starting ethers 1d–
h,l,n bearing an o-, m- or p-MeO group, p-Me2N, p-Cl, m-Ph, or
2-naphthyl groups were also tested, giving rise to the corre-
sponding a-deuterated ethers 3d–h,l,n also at À788C (en-
tries 4–8, 12, and 14). Only for ethers 1j and 1k, possessing an
o-Cl or p-Ph group, respectively, was a slight increase in the re-
action temperature required to reach complete a-lithiation (en-
tries 10 and 11). In the specific case of benzyl 3-chlorophenyl
ether 1i, it was impossible to achieve selective a-lithiation
likely due to competitive o-lithiation leading to aryne genera-
tion and further decomposition (entry 9). Surprisingly, a signifi-
cant increase in the reaction temperature was necessary to ef-
fectively lithiate benzyl 1-naphtyl ether 1m at the a-position.
Whereas no reaction took place at À788C, the a-lithiation reac-
tion started from about À508C, immediately followed by the
[1,2]-Wittig rearrangement of the corresponding organolithium
2m, which prevented the isolation of the deuterated ether 3m
(entry 13). Methoxy-functionalized ethers 1d,f,g were efficient
and selectively lithiated at the a-position without significant
competition for lithiation at the aryl ring. This fact is especially
significant for benzyl 3-methoxyphenyl ether 1 f, which pos-
sesses an aromatic proton flanked by two alkoxy groups
(entry 6). It is also important to remark that all the deuterated
ethers 3, except 3m, were isolated in very high yields and with
almost complete deuteration at the a-position.
Scheme 1. Previous work: Mechanistic proposals for the [1,2]-Wittig rear-
rangement of aryl ethers.
Here, we wish to report a detailed study about the a-lithiation
of a wide variety of aryl benzyl ethers in order to collect new
data, both experimental and computationally, to determine
which of the proposed mechanisms for aryl migration is oper-
ating. Considering the underexplored reactivity of a-lithioben-
zyl ethers, we have also deeply studied their reactions with dif-
ferent electrophiles.
To evaluate the influence of different substituents on the
stability of a-lithiated species 2 towards the [1,2]-Wittig rear-
rangement, we carried out lithiation reactions at the tempera-
ture that model substrate 1a starts to rearrange (À308C) and
at room temperature, when 1a has completely undergone the
Wittig rearrangement. Thus, organolithiums 2b and 2c bearing
Scheme 2. This work: Inhibition and mechanistic studies for the [1,2]-Wittig
rearrangement of aryl benzyl ethers.
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Table 1. a-Lithiation and further transformation of aryl benzyl ethers 1.
Entry
Starting
ether
R
T
[8C]
3
Yield
[%][a]
Products for
T to À308C (ratio)[b]
Products for
À308C to RT (ratio)[b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
H
À78
À78
À78
À78
À78
À78
À78
À78
3a
3b
3c
3d
3e
3 f
3g
3h
–
96
91
89
87
98
95
94
97
–
3a+4a (15/1)
3b
3c
3d
3e
3 f[c]
3g+4g (12/1)
3h[e]+4h (1/1.6)
–
4a
4-Me
4-tBu
4-MeO
4-Me2N
3-MeO
2-MeO
4-Cl
3b+4b+5 (10/5/1)
3c+4c (1/1.6)
3d
3e
3 f[d]+4 f (3/1)
4g
4h[f]
–
[g]
3-Cl
–
10
11
12
13
14
1j
1k
1l
1m[h]
1n[j]
2-Cl
4-Ph
3-Ph
2,3-(CH)4
3,4-(CH)4
À70
À65
À78
3j
3k
3l
–
3n
90
86
89
–
3j+4j (11/1)
3k+4k (1/15)
3l+4l (5/1)
4m
4j
4k
4l
4m
4n
[i]
–
À78
91
4n
[a] Isolated yield. [b] Isolated yield of mixtures with typically >85%. [c] Partially deuterated at ortho and para positions of the methoxyphenyl ring. [d] 3 f
is benzyl 2-deuterio-3-methoxyphenyl ether (~80% D). [e] Ca. 80% deuterium incorporation. [f] Ca. 15% of starting ether 1h was also isolated. [g] 3i and/
or 4i were not obtained likely due to competitive elimination processes. [h] Benzyl 1-naphthyl ether. [i] At À788C, no metalation took place; at À508C,
a mixture of non-lithiated 1m and rearranged alcohol 4m was obtained; at À308C, 4m was generated along with trace amounts of 1m. [j] Benzyl 2-naph-
thyl ether.
a methyl or t-butyl group (respectively) at the para-position
were stable enough at À308C to give rise exclusively to the
corresponding deuterated ethers 3b and 3c after quenching
with MeOD. At room temperature, however, only moderate
yields of the corresponding rearranged alcohols 4b and 4c
were obtained showing that the rearrangement is clearly
slower than in the case of 1a.[17] In addition, trace amounts of
cyclopropane derivative 5, from an a-elimination process of in-
termediate organolithium 2, were obtained for 1b (entries 2
and 3). Notably, a-lithiobenzyl ethers 2d and 2e bearing p-
methoxyphenyl and p-dimethylaminophenyl groups, respec-
tively, were reluctant to undergo the rearrangement even at
room temperature because they were stable enough to allow
their deuteration to proceed and subsequent isolation of
ethers 3d and 3e (entries 4 and 5). The same tendency is ob-
served with starting ether 1 f, bearing a m-MeO group, be-
cause deuterated ether 3 f was the only product at À308C, al-
though partial deuteration at the ortho-position was observed
probably due to an anion translocation process. In this sense,
only a small amount of the corresponding alcohol 4 f could be
obtained at room temperature, with ether 3 f being the major
compound mostly deuterated at the ortho-position (entry 6).
Considering the result of p-methoxy-functionalized ether 1d,
o-methoxy-functionalized ether 1g unexpectedly showed
a similar behavior as that observed with parent ether 1a, lead-
ing selectively to the rearranged alcohol 4g at room tempera-
ture (entry 7). Moreover, aryl a-lithiumbenzyl ethers 2, bearing
electron-withdrawing groups such as chloro or phenyl, under-
went the [1,2]-Wittig rearrangement at a lower temperature
than the model substrate 1a, with the alcohol as the only or
the major product at room temperature (entries 8, 10–12).
Also, the fact that a-deuteriobenzyl 1-naphthyl ether 3m was
never obtained means that the corresponding organolithium
2m is really prone to proceed through the [1,2]-Wittig rear-
rangement even at low temperature (entry 13). A similar be-
havior towards the rearrangement can be observed in the case
of benzyl 2-naphthyl ether 1n; the rearranged alcohol 4n was
the only product at À308C, as well as at RT (entry 14).
Finally, we also checked that, as previously reported,[8a] 6H-
benzo[c]chromene 1o also undergoes Wittig rearrangement
leading to 9-fluorenol 4o, although an excess of base was re-
quired for complete conversion. The behavior of 1o is similar
to benzyl 1-naphthyl ether 1m because the corresponding
deuterated ethers 3 were never obtained and the rearrange-
ment is complete even at À308C (Scheme 3).
Scheme 3. Wittig rearrangement of 6H-benzo[c]chromene 1o.
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Theoretical studies
larization functions, on the previously optimized geometries.
The Orca program[21] was used for this. All the calculations
have been carried out in THF solution, using either PCM[22]
(low level geometry optimizations) or COSMO[23] (energy refine-
ments).
Some of the obtained results seem to be contradictory if we
consider the existence of only one of the proposed mecha-
nisms (Scheme 2). For instance, the unexpected reluctance of
p-methoxy or p-dimethylaminophenyl ethers 1d and 1e, re-
spectively, to undergo Wittig rearrangement could lead us to
think that the anionic pathway is operating. However, the dif-
ferent behavior of the regioisomeric o-methoxyphenyl ether
1g is in disagreement with this assumption. Similarly, the fact
that 1o also undergoes Wittig rearrangement, seems to be
against the anionic proposal that would involve the formation
of a highly strained bridged intermediate. Moreover, the
higher tendency of 4-biphenyl ether 1k, as well as naphthyl
ethers 1m and 1n to undergo Wittig rearrangement, could
not be easily explained through the radical pathway. To shed
more light on the mechanism of the Wittig rearrangement in
aryl benzyl ethers and understand the results obtained for the
different substrates in Table 1, we decided to use DFT to
model two different paths, one of radical nature and the other
of anionic character (Figure 1).
Computational results
The radical pathway would involve the homolitic cleavage of
the ether ArÀO bond in I, leading to the aryl radical II and ben-
zyloxy radical III (Figure 1). Recombination of these two radi-
cals through a barrierless transition state ts(III–IV) provides the
reorganized product IV. An alternative anionic path would in-
volve an attack of the benzylic anion on the aryl group that
would be concerted with the cleavage of the ArÀO bond, di-
rectly leading to the reorganized product IV. For anionic char-
acter, we also proposed a third option where the attack of the
anion on the aryl group would lead to an oxirane intermediate
V that would then undergo ring-opening to produce IV; how-
ever, we were not able to locate such an intermediate, at least
for when Ar is Ph.
In Table 2, we show the relative Gibbs free energies of the
different structures found along these two paths for some rep-
resentative ethers from Table 1. We found that there is not
a generally preferred mechanism, and that in some instances,
the radical and anionic concerted paths can be considered to
be competitive and can coexist. If we compare the activation
energies for ts(I–II) (the later collapse of the two radicals is
found to be a barrierless process) and ts(I–IV), we find that the
concerted path is favored when Ar is Ph (1a), 4-ClC6H4 (1h), 1-
naphthyl (1m), 2-naphthyl (1n), and 6H-benzo[c]chromene
(1o) (entries 1 and 6–9, respectively, underlined in Table 2),
and slightly preferred when Ar is 4-MeC6H4 (1b) (entry 2). In
contrast, ts(I–II) is preferred with more electron-rich aryl
groups, such as when Ar is 4-MeOC6H4 (1d), 4-Me2NC6H4 (1e)
and 2-MeOC6H4 (1g) (entries 3–5, respectively). In these cases
(italicized in Table 2), however, (as with Ar=4-MeC6H4 (1b),
entry 2) both paths are competitive, with differences between
Figure 1. Mechanisms for the Wittig rearrangement considered in the DFT
study.
the two rate-determining steps of less than 1.0 kcalmolÀ1
.
The preference for a radical or anionic concerted mechanism
seems to be electronic in nature, because we found that one
of the largest differences between the activation energy of the
two alternative paths is found in 6H-benzo[c]chromene (1o).
For this ether, the preferred anionic concerted mechanism
could be expected to be prevented by the rigidity of the struc-
ture. The observed trends in reactivity are well replicated in
our calculations: 1o, naphthyl ethers 1m and 1n, and 4-
chlorophenyl ether 1h rearrange faster than the parent phenyl
ether 1a, whereas 4-methoxyphenyl (1d) or 4-aminomethyl
(1e) ethers do not rearrange at all. The fact that we do not
find a rearrangement product for 4-methoxyphenyl ether 1d,
although 2-methoxyphenyl ether 1g rearranges readily, is puz-
zling from a purely electronic point of view, because the differ-
ence in activation of the phenyl ring should not be very large
between the two systems. What is found here is that the ge-
ometry of the substrate is key in determining the reactivity.
The barriers for ts(I–II) and ts(I–IV) are comparable for when
Computational methods
We used DFT to locate the stationary points depicted in the
first two reaction paths in Figure 1. We carried out geometry
optimizations with the B3LYP hybrid exchange-correlation
functional with the double-z 6-31G* basis set, as implemented
in the Gausian 09 code.[18] We confirmed that the wavefunc-
tions are stable and used harmonic analysis to characterize
these structures as either minima or transition states in the po-
tential energy surface. These harmonic frequencies have been
used to calculate the thermal corrections needed to obtain
free energies. In some cases, we ran IRC (intrinsic reaction co-
ordinate) calculations to unambiguously connect transition
states and the corresponding minima. For obtaining more ac-
curate electronic energies, we used the double hybrid B2PLYP
functional with Grimme’s dispersion correction (B2PLYP-D3),[19]
with the triple-z basis def2-tzvpp,[20] which includes extra po-
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Table 2. B2PLYP/def2-tzvpp(COSMO,THF)//B3LYP/6-31G*(PCM,THF) Gibbs free energies [kcalmolÀ1] relative to I for the structures depicted in Figure 1.[a]
Structures strongly favoring the concerted anionic mechanism are underlined, those favoring the radical mechanism appear in bold, and those in which
the two mechanisms are expected to be competitive, italicized.
Entry
Ether
Ar
I
ts(I–II)
II+III
ts(III–IV)
ts(I–IV)
IV
1
2
3
1a
1b
1d
1e
1g
1h
1m
1n
1o
Ph
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
28.3
26.8
26.9
25.8
18.9/28.2
26.5
27.8
27.0
31.2
28.1
20.9
19.6
20.1
18.7
20.0
21.3
20.5
20.8
1.4
À0.2
À0.6
À0.8
À1.1
À8.3
À2.2
À3.0
À1.0
4.0
24.6
26.0
27.8
26.5
19.4/26.9
23.6
21.1
22.5
20.1
À39.0
À40.1
À40.0
À40.6
À40.5
À40.1
À38.2
À40.5
À39.2
À39.4
À38.2
4-MeC6H4
4-MeOC6H4
4-Me2NC6H4
2-MeOC6H4
4-ClC6H4
2,3-(CH)4
3,4-(CH)4
4
5[b]
6
7
8
9
10
11
[c]
–
[d]
–
4-NO2C6H4
2,4,6-(Me2N)3C6H2
23.8
30.8
À2.2
–
14.1
27.3
[d]
–
22.5
[a] They also correspond to activation free energies in the case of ts(I-II) and ts(I-IV). [b] The two values for ts(I-II) and ts(I-IV) correspond to the structures
with (the lowest values) and without the directing effect of the methoxy group (see Figure 2). [c] 6H-benzo[c]chromene (1o). [d] Benzyl 4-nitrophenyl
ether and 2,4,6-tris(dimethylamino)phenyl ether were not verified experimentally.
Ar is 4-methoxyphenyl (26.9 and 27.8 kcalmolÀ1, respectively,
entry 3, Table 2) or 2-methoxyphenyl (28.2 and 26.9 kcalmolÀ1,
entry 5), provided that the lithium cation is not allowed to in-
teract with the methoxy substituent. If the methoxy group is
located so that it can coordinate with lithium, the two barriers
are lowered significantly (18.9 kcalmolÀ1 for ts(I–II) and
19.4 kcalmolÀ1 for ts(I–IV)), making this reaction much more
favorable than the rearrangement of the 4-methoxyphenyl
system (Figure 2).
respondingly raise the barrier. The effect of the charge of the
aryl group, however, is opposite and more pronounced in the
anionic concerted mechanism, with electron-poor aryl groups
clearly favoring this path. The structure of ts(I–IV), in which
the attacking carbanion can overlap with the p-system of the
aromatic ring, fully supports this observation.
An extreme case of this electronic effect on the preference
for one path or the other and on the reaction barrier is found
when a very good electron-accepting aryl group (Ar=4-
NO2C6H4) is used (entry 10, Table 2). This substrate has not
been tested experimentally, but computational data predict for
As a general trend, we found that electron-rich aryl groups
(Ar) lower the barrier of the usually more energetic radical
path (ts(I–II)), as expected from the electron-deficient nature
of the radical intermediate II, whereas electron-poor aryls cor-
it to have the lowest barrier in the studied set (14.1 kcalmolÀ1
and a very strong preference for the anionic path. Conversely,
very strong electron-donating aryl group (Ar=2,4,6-
)
a
(Me2N)3C6H2, entry 11) is able to induce a mechanism switch so
that the radical path is clearly preferred now (with a difference
in activation barrier of 4.9 kcalmolÀ1), thus validating our
model.
Functionalization of a-lithiobenzyl ethers 2
With a general protocol in place to obtain the corresponding
a-lithiated ethers 2 from easily available aryl benzyl ethers 1,
we next surveyed the reactivity of ethers 1 with representative
electrophiles to demonstrate the applicability of this approach
for accessing functionalized aryl benzyl ethers 6 (Table 3). Sev-
eral electrophilic reagents were reacted with 1a under the op-
timized conditions. Addition of alkyl halides gave high yields
of the corresponding a-alkylated ethers 6aa and 6ab (entries 1
and 2, respectively). Likewise, the use of TMSCl or Bu3SnCl re-
sulted in the direct formation of functionalized ethers 6ac and
Figure 2. Structures of the two alternate structures for ts(I–IV) and ts(I–II)
when Ar=2-MeOC6H4. The first structure is considerably lower in energy
than the second due to the extra coordination of the oxygen in the meth-
oxy substituent with the lithium cation (see entry 5 in Table 2).
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6ad (entries 3 and 4, respectively). Different carbonyl com-
pounds are also useful electrophilic partners for the intermedi-
ate organolithiums 2. Their reactions with aliphatic and aro-
matic ketones and aldehydes also proceeded efficiently, lead-
ing to the expected alcohols 6ae–am in good yields (en-
tries 5–13, respectively). The reaction was also amenable to an
imine or an epoxide as electrophiles, giving rise to products
6an and 6ao, respectively (entries 14 and 15). Unfortunately,
when we tested an electophilic aromatic nitrile, the reaction
yielded the expected ketone 6ap in low yield after acidic
workup (entry 16). We have also investigated the metalation
and subsequent functionalization of other aryl benzyl ethers
(entries 17–23), which all showed exactly the same behavior as
the parent ether 1a. In all cases, when two stereogenic centers
were generated, the final compound was obtained as a variable
mixture of diastereomers.
Table 3. Functionalization of aryl a-lithiobenzyl ethers 2 (generated from
ethers 1) with electrophiles for the synthesis of ethers 6.
Entry Starting
ether
R
Product
d.r.[a]
Yield
[%][b]
1
2
3
4
1a
1a
1a
1a
H
H
H
H
6aa
6ab
6ac
6ad
–
–
–
–
95
88
95
62
5
6
7
8
1a
1a
1a
1a
H
H
H
H
6ae[c] 1/1
6af[c]
79
68
2/1
Transition metal-free homocoupling of a-lithiobenzyl
ethers 2
6ag[c] 3.7/1 85
6ah[c] 2/1
The oxidative coupling of two nucleophilic carbon atoms is
a powerful methodology for constructing CÀC bonds, which is
typically catalyzed by transition metal complexes.[24] Few exam-
ples of transition metal-free protocols employing organic oxi-
dants for the oxidative coupling of Grignard reagents or other
organometallic compounds have been reported.[25] In this field,
the oxidative coupling of benzyl anions, derived from toluene
variants, with 1,2-dibromoethane has been described by
O’Shea and co-workers.[26] We decided to tackle the homo-oxi-
dative coupling of a-lithiobenzyl phenyl ether 2a using differ-
ent halogen-based reagents. As shown in Scheme 4, a variety
of organic halides were tested and in all cases the diether 7a
was formed. This study revealed that the best yield was ob-
tained when one equivalent of hexachloroethane was used.
This inexpensive reagent was tested as the oxidant with a se-
lection of ethers 1 giving rise to the corresponding dimers
7d,h,k in good to excellent yields, which were each obtained
as an approximate 1:1 mixture of diastereomers. Interestingly,
compounds 7 are diaryl protected 1,2-diphenylethanediols,
which are generated in a straightforward manner from aryl
benzyl ethers. Only 7a had been previously prepared in very
low yield by radical dimerization of benzyl phenyl ether in the
presence of tert-butyl peroxide,[27] or by photolysis of benzoin
phenyl ether.[28] Regarding the mechanism, two alternative
pathways could be proposed for the formation of the coupled
products 7. One of them would involve an initial halogenation
of the corresponding organolithium 2 and the subsequent
trapping of the new halogenated intermediate by the remain-
ing unreacted 2 (path a). Alternatively, a one-electron oxidation
of 2 with further dimerization of the corresponding radical
would also account for the obtained results (path b). The gen-
eration of 7 as an almost equimolecular mixture of meso and
d/l dimers in all cases supports the radical pathway, because it
is known that steric and polar factors are not important in the
87
9
10
11
12
1a
1a
1a
1a
H
H
H
H
6ai[c]
6aj[d]
6ak
6al
1.3/1 71
2.5/1 70
–
81
78
4/1
13
14
15
16
17
1a
1a
1a
1a
1d
H
6am
6an
3.3/1 79
H
1/1
65
H
6ao[e] 1.5/1 95
H
6ap
–
30
4-MeO
6da[e] 1.5/1 88
18
1 f
3-MeO
6 fa
4/1
70
19
1g
1h
1j
2-MeO
4-Cl
6ga[d] 1.7/1 71
20
6ha
6ja[c]
6la
1/1
1/1
83
60
21[e]
22
2-Cl
1l
3-Ph
2.6/1 79
C
dimerization of PhC HOPh radical, which leads to equal
amounts of both dimers.[29] It is also remarkable that as the
generation of the two nucleophiles is achieved through CÀH
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addition of methyl iodide, prior to aqueous workup, ketone 10
bearing an a-quaternary center was obtained (Scheme 5). It is
also remarkable that by employing carboxylic esters as electro-
philes, ketones 8 are obtained in significantly higher yields
than when using aromatic nitriles (see Table 3, entry 16).
Table 3. (Continued)
Entry Starting
ether
R
Product
d.r.[a]
1/1
Yield
[%][b]
23
1n
3,4-(CH)4
6na
73
[a] Diastereomeric ratio (d.r.) determined by 1H NMR analysis of the crude
reaction mixture. [b] Isolated yield is based on the starting ether 1.
[c] Both diastereoisomers were independently isolated. [d] The major dia-
stereoisomer was isolated in pure form. [e] Lithiation carried out from
À78 to À708C.
deprotonation, this strategy allows the direct access to func-
tionalized 1,2-diarylethanes from simple coupling partners
without any preactivation or the use of a transition-metal cata-
lyst.
Scheme 5. Reaction of aryl a-lithiobenzyl ethers 2 with carboxylic esters:
Synthesis of ketones 8 and 10.
Table 4. Carboxylic esters as electrophiles for the synthesis of ketones 8.
Entry
Starting
ether
R
Product
Ar
Yield
[%][a]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1h
1l
H
H
H
H
8aa
8ab
8ac
8ad[b]
8ae
8be
8ha
8lb
Ph
73
60
72
76
83
74
70
65
66
2-thienyl
2-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
Ph
H
4-Me
4-Cl
3-Ph
3,4-(CH)4
2-thienyl
Ph
1n
8na
[a] Isolated yield based on the starting ether 1. [b] This ketone is the
same as that obtained when using 4-chlorobenzonitrile as electrophile
(see product 6ap, Table 3, entry 16).
Furthermore, taking advantage of the initial formation of
these ketones 8, we attempted the diastereoselective synthesis
of alcohols 6af–ah, previously synthesized with different dia-
stereoisomeric ratios by reaction of a-lithiobenzyl phenyl ether
2a with (hetero)aromatic carboxaldehydes. Interestingly, it was
possible to selectively obtain either one diastereoisomer or the
other of the corresponding alcohol 6 by treating selected a-
phenoxy ketones 8aa,ab,ae with Red-Al (sodium bis(2-meth-
oxyethoxy)aluminumhydride) or Al(OiPr)3/iPrOH (Table 5). Thus,
Red-Al gave rise to the corresponding monoprotected 1,2-anti-
diols anti-6 in good to excellent yields and high diastereoselec-
tivity through a 1,2-chelation-controlled reduction.[30] In con-
trast, high syn selectivity was obtained by Felkin–Anh control
using a Meerwein–Ponndorf–Verley reduction allowing the
preparation of protected 1,2-syn-diols syn-6.[31] Remarkably in
addition to diastereoselectively accessing diol derivatives 6,
Scheme 4. Mechanistic proposals for dimerization of organolithiums 2 (top)
and synthesis of diaryl protected glycols 7 (middle and bottom).
Reactions of a-lithiobenzyl ethers 2 with carboxylic esters
Surprisingly, when ethyl benzoate was used as the electrophilic
quencher of 2a, the aromatic ketone 8aa was exclusively ob-
tained rather than the expected tertiary alcohol, irrespective of
the amount of ester added (Scheme 5 and Table 4). In this way,
a wide variety of ketones 8 were synthesized in good yields
using a selection of carboxylic esters derived from (hetero)aro-
matic acids (Table 4). To account for this unexpected result, we
propose that the initially formed ketone 8 undergoes deproto-
nation by lithium ethoxide, generated in the first step, leading
to the corresponding enolate 9, which remains intact prior to
hydrolysis. Our proposal is supported by the fact that, upon
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poration at the trialkoxyphenyl ring, was obtained at room
temperature (Scheme 6).
Table 5. Diastereoselective access to alcohols 6af–ah.
The above study showed that 2,3-dimethoxyphenyl and 3,5-
dimethoxyphenyl ethers, 1p and 1q, respectively, could be se-
lectively a-lithiated at low temperature, without significant
competition of alternative ortho-lithiation processes. We envis-
aged that the presence of these highly electron-rich aromatic
rings could lead to intramolecular Friedel–Crafts reactions with
properly functionalized ethers affording interesting oxygen
heterocyclic scaffolds. To this end, we evaluated the behavior
of the a-lithiated ethers 2p and 2q towards different (hetero)-
aromatic carbonyl compounds as electrophilic partners
(Table 6). In this way, a variety of a-aryloxy alcohol derivatives
11 were prepared in good yields with low to moderate diaste-
reoselectivity, when aldehydes or non-symmetric ketones were
used (entries 2 and 4–10). Again the major diastereomer ob-
tained when (hetero)aromatic aldehydes were employed re-
sulted to be the syn case (entries 4–5 and 9–10), the same ten-
dency observed for benzyl phenyl ether 1a (see Table 3, en-
tries 6–8).
Entry Ketone Ar
Reagent
Red-Al
anti/syn Product Yield
[%]
1
2
3
4
5
6
8ab
8ab
8ae
8ae
8aa
8aa
2-thienyl
2-thienyl
4-MeOC6H4 Red-Al
4/1
anti-6af 93
syn-6af 89
>20/1 anti-6ag 96
4-MeOC6H4 Al(OiPr)3/iPrOH <1/20 syn-6ag 91
Al(OiPr)3/iPrOH 1/17
Ph
Ph
Red-Al
>20/1 anti-6ah 92
Al(OiPr)3/iPrOH <1/20 syn-6ah 90
this study allowed us to establish that reactions of organolithi-
um 2a with (hetero)aromatic aldehydes always take place with
moderate syn selectivity (see Table 3, entries 6–8).
Lithiation of dimethoxyphenyl benzyl ethers 1p–r and reac-
tions with carbonyl compounds
With these benzyl dimethoxyphenyl ether derivatives 11 in
hand, possessing an electron-rich aromatic ring and an activat-
ed secondary or tertiary hydroxyl group, we proceeded to
carry out an intramolecular Friedel–Crafts reaction that would
lead to 2,3-dihydrobenzo[b]furan derivatives 12 (Table 7). The
direct nucleophilic substitution of p-activated alcohols to build
CÀX or CÀC bonds is nowadays a well-established methodolo-
gy that avoids the transformation of hydroxyl groups into the
corresponding halides or sulfonates for reacting with nucleo-
philes.[32] Different Lewis and Brønsted acid-catalyzed proce-
dures have been developed in the last years for this reaction,
which, in the case of using aromatic groups as the nucleophilic
partner, could be considered catalytic Friedel–Crafts reac-
tions.[33] Taking advantage of our previous experience in this
field,[34] we used a simple Brønsted-acid-like 2,4-dinitroben-
zenesulfonic acid (DNBSA) as the catalyst to attempt the cycli-
zation of a selection of alcohols 11. Satisfactory results were
obtained for starting compounds 11 a,c,g,h bearing tertiary
highly activated hydroxyl groups, which led to the correspond-
ing dihydrobenzofuran derivatives 12a,c,g,h in high yield.[35]
However, this catalyst proved unsuccessful for substrates pos-
sessing secondary hydroxyl groups such as 11 d and 11 j,
which could be cyclized in low yield to the corresponding di-
hydrobenzofuran 12 as a variable mixture of diastereomers
employing Hg(OTf)2 as catalyst.[36] Interestingly, benzofuran de-
rivative 12g was obtained as a single diastereomer, for which
the configuration was initially assigned as the trans isomer
based on the comparison between the experimental and
mPW1PW91/6-311+G(2d,p)(PCM,CH2Cl2) 1H NMR spectra for
the two diastereomers.[37] In addition, the complete stereose-
lectivity was further supported by the computational charac-
terization of the four diastereomeric cyclization transition
states between 11 g and 12g. This showed that the transition
state responsible for the formation of the trans isomer is about
1.86 kcalmolÀ1 lower in energy than the lowest energy transi-
tion state leading to the cis product.[37] Later on, this initial as-
sumption was confirmed by X ray analysis.[38]
Considering the complete selectivity for the a-lithiation of
benzyl 3-methoxyphenyl ether 1 f, we decided to study the
lithiation reaction of dimethoxyphenyl ethers 1p–r (Scheme 6).
At low temperature (À788C for 1q and 1r, or À558C for 1p),
we found that 1p and 1q were selectively a-lithiated with
Scheme 6. Lithiation reactions of benzyl dimethoxyphenyl ethers 1p–r.
tBuLi leading to the corresponding a-deuterated ethers 3p
and 3q on quenching with MeOD. By contrast, 3,4-dimethoxy-
phenyl ether 1r was mainly lithiated at the aryl ring generating
2’r, with a higher degree of metalation as the reaction temper-
ature increases (almost complete lithiation at À308C). It should
be pointed out that related 3-methoxyphenyl ether 1 f and
3,5-dimethoxyphenyl ether 1q were exclusively a-lithiated at
À788C. By raising the temperature to room temperature, 2,3-
dimethoxyphenyl ether 1p efficiently underwent Wittig rear-
rangement affording exclusively benzhydrol derivative 4p
(Scheme 6). Nonetheless, under the same conditions, 3,5-di-
methoxyphenyl ether 1q evolved through partial anion trans-
location to the activated aryl ring and thus, a mixture of rear-
ranged alcohol 4q and benzyl ether 3q, with deuterium incor-
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Table 6. a-Lithiation of dimethoxyphenyl ethers 1p,q and reactions with
carbonyl compounds. Synthesis of a-aryloxy alcohols 11.
Table 7. Synthesis of dihidrobenzo[b]furan derivatives 12.[a]
Entry Ether R1
R2
Product
d.r.[a] Yield
[%][b]
1
2
1p
1p
MeO
MeO
H
H
11 a
–
82
70
11 b 1:1
3
4
1p
1p
MeO
MeO
H
H
11 c
–
74
[a] Method A: DNBSA (10 mol%), MeCN, reflux; method B: FeCl3
(15 mol%), AgSbF6 (45 mol%), DCE, 508C; method C: Hg(OTf)2 (1 mol%),
toluene, reflux.
11 d 2.2:1 88
11 e 1.6:1 73
5
1p
MeO
H
chelate effect explains the unexpectedly different reactivity of
4-methoxyphenyl and 2-methoxyphenyl ethers. The easy prep-
aration of these a-lithiated aryl benzyl ethers has allowed the
study of their reactivity towards different electrophiles. In this
way, a wide variety of a-functionalized aryl benzyl ethers has
been accessed, including their efficient oxidative coupling with
hexachloroethane. Interestingly, their reactions with carboxylic
esters lead to ketones instead of the expected tertiary alcohols,
likely due to the fast generation of the corresponding enolate.
Moreover, further reactions of some of the obtained com-
pounds has led to the diastereselective synthesis of mono-pro-
tected 1,2-diarylethyl-1,2-diols and dihydrobenzo[b]furan deriv-
atives.
6
7
1q
1q
1q
1q
1q
H
H
H
H
H
MeO
MeO
MeO
MeO
MeO
11 f 1.5:1 83
11 g 3.5:1 80
11 h 2.5:1 74
8
9
11 i 2:1
76
10
11 j 3.5:1 72
1
[a] Ratio of diastereoisomers determined by H NMR analysis of the crude
reaction mixture. [b] Isolated yield based on the starting ether 1p,q.
Experimental Section
Typical procedure for the synthesis of a-funtionalized aryl
benzyl ethers 6–8 and 11: Synthesis of 1-(2-chlorophenyl)-2-phen-
oxy-2-phenylethanone (8ac): To an oven-dried Schlenck flask under
N2, anhydrous THF (2.5 mL) and ether 1a (92 mg, 0.5 mmol) were
added. This solution was cooled to À788C and then tBuLi (0.38 mL
of a 1.7m solution in pentane, 0.65 mmol) was added. The mixture
was stirred for 20 min at this temperature. Then, ethyl 2-choroben-
zoate (120 mg, 0.65 mmol) was added, and after 5 min, the cooling
bath was removed, allowing the reaction mixture to warm up to
RT. Finally, the reaction mixture was quenched with H2O (15 mL)
and extracted with Et2O (3ꢃ10 mL). The organic layers were com-
bined, dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel
using hexane:EtOAc (15:1) as eluent to afford ketone 8ac (116 mg,
72%) as a colorless oil; Rf =0.24 (hexane/EtOAc=15/1); 1H NMR
(300 MHz, CDCl3, 258C): d=7.50–7.43 (m, 2H), 7.40–7.30 (m, 5H),
7.29–7.20 (m, 4H), 7.00–6.92 (m, 3H), 6.32 ppm (s, 1H); 13C NMR
(75.4 MHz, CDCl3, 258C): d=198.9 (C), 157.4 (C), 137.2 (C), 134.9 (C),
131.9 (CH), 131.2 (C), 130.3 (CH), 129.6 (2ꢃCH), 129.5 (CH), 129.0
(2ꢃCH), 128.98 (CH), 127.5 (2ꢃCH), 126.6 (CH), 121.9 (CH), 116.1
Conclusions
In summary, we have demonstrated that aryl benzyl ethers can
be selectively a-lithiated, and by controlling the reaction tem-
perature, the resulting aryl a-lithiobenzyl ethers were stable
enough to prevent the expected, and previously described,
[1,2]-Wittig rearrangement. Additionally, we studied the stabili-
ty of a series of ethers, functionalized at the aryl ring, towards
the Wittig rearrangement. DFT calculations revealed that two
mechanisms for this rearrangement can coexist: i) homolytic
cleavage of the ArÀO and barrierless recombination of the re-
sultant radicals, and ii) attack of the benzylic anion at the aryl
group concerted with ArÀO cleavage. Electron-rich aryls favor
the radical path and electron-poor aryls prefer the concerted
anionic route. As the electronic effect is much larger in the
latter case, the easiest rearrangements are found for electron-
poor aryl groups, in agreement with the experimental data. A
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(2ꢃCH), 84.5 ppm (CH); LRMS(EI): m/z (%): 183 [(MÀC7H4ClO)+,
100], 155 (31), 77 (25); HRMS (EI) calcd for C20H15ClO: 322.0761;
found: 322.0757.
[12] Inhibition of Wittig rearrangement of alkyl benzyl ethers has been ach-
ieved through coordination to chromium tricarbonyl: S. G. Davies, N. J.
Holman, C. A. Laughton, B. E. Mobbs, J. Chem. Soc. Chem. Commun.
1983, 1316–1317. For a particular example of intramolecular addition
of a metalated benzyl ether to a carbonyl group, see: M. Matsumoto, N.
Watanabe, A. Ishikawa, H. Murakami, Chem. Commun. 1997, 2395–
2396.
Acknowledgements
[13] J. Barluenga, F. J. FaÇanꢅs, R. Sanz, C. Marcos, M. Trabada, Org. Lett.
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We gratefully acknowledge the Junta de Castilla y Leꢁn and
FEDER (BU237U13 and BU076U16) and Ministerio de Economꢀa
y Competitividad (MINECO) and FEDER (CTQ2013-48937-C2-1P
and 2-P) for financial support. R.V. thanks Junta de Castilla y
Leꢁn (Consejerꢀa de Educaciꢁn) and Fondo Social Europeo for
a PIRTU contract. We also thank the Centro de Supercomputa-
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[17] Prolonged reaction times (5 h) with 1c led to competitive proton ab-
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Keywords: density functional calculations · lithiation · oxygen
heterocycles · reaction mechanisms · Wittig rearrangement
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[38] CCDC 1478974 (12g) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
Received: May 12, 2016
Revised: July 11, 2016
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Published online on && &&, 0000
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FULL PAPER
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Synthetic Methods
R. Velasco, C. Silva Lꢃpez, O. Nieto Faza,*
R. Sanz*
&& – &&
Exploring the Reactivity of a-Lithiated
Aryl Benzyl Ethers: Inhibition of the
[1,2]-Wittig Rearrangement and the
Mechanistic Proposal Revisited
Wittig cannot win: A full account for
the selective a-lithiation of aryl benzyl
ethers is reported. By carefully control-
ling the reaction temperature, aryl a-
lithiobenzyl ethers are stable enough to
be trapped by a wide variety of electro-
philes leading to functionalized ethers.
The mechanism of the expected [1,2]-
Wittig rearrangement in these a-
oxygen-substituted organolithiums is
discussed based on DFT calculations.
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Chem. Eur. J. 2016, 22, 1 – 12
www.chemeurj.org
12
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!