Fe-promoted cross coupling of homobenzylic methyl ethers with Grignard reagents via sp3 C-O bond cleavage

Article abstract of DOI:10.1039/c3cc43616k

The first iron-catalyzed formal cross coupling of homobenzylic methyl ethers with alkyl Grignard reagents is realized. The reaction is proposed to proceed through a sequence of dehydroalkoxylation to form the vinyl-intermediate, followed by Fe-catalyzed selective carbometalation to form a benzylic Grignard reagent.

Full text of DOI:10.1039/c3cc43616k

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Fe-promoted cross coupling of homobenzylic methyl
ethers with Grignard reagents via sp3 C–O bond
cleavage†
Cite this: Chem. Commun., 2013,
49, 7794
Received 14th May 2013,
Accepted 2nd July 2013
a
a
Shuang Luo,z Da-Gang Yu,z Ru-Yi Zhu,a Xin Wang,b Lei Wangb and
Zhang-Jie Shi*ac
DOI: 10.1039/c3cc43616k
www.rsc.org/chemcomm
The first iron-catalyzed formal cross coupling of homobenzylic is indispensable for the transformation. However, cross coupling
methyl ethers with alkyl Grignard reagents is realized. The reaction of unsymmetrical normal homobenzylic ethers has never been
is proposed to proceed through a sequence of dehydroalkoxylation achieved. Herein we reported the first Fe-catalyzed cross coupling
to form the vinyl-intermediate, followed by Fe-catalyzed selective of homobenzylic methyl ethers with Grignard reagents through sp3
carbometalation to form a benzylic Grignard reagent.
C–O bond cleavage.
Our evaluation was initiated from the reaction of 1-(2-
Iron catalysis is now playing a more and more important role in methoxyethyl)naphthalene 1a with nhexylMgCl (Table S1, see ESI†).
organic synthesis.1 Due to their low price, low toxicity and easy Various catalysts that have potential abilities to cleave C–O bonds
availability, iron catalysts show great advantages over other were tested. To our delight, the desired cross-coupling product 3aa
frequently used noble metals. Moreover, iron catalysts exhibit was obtained in 30% of GC yield in the presence of NiCl2(PCy3)2 as
significantly different reactivities in various transformations, which the catalyst and PCy3 as an additional ligand in o-xylene. Using NiF2
could not be easily performed with other transition metals.
as the catalyst improved the yield to 51%. Due to the good activity in
Dialkyl ethers broadly exist in nature and industry and are often C–O bond activation, iron catalysts also attracted our attention.6
used as solvents in organic reactions. Actually, C–O bonds of dialkyl Although various iron salts, such as FeBr2, Fe(OAc)2, FeBr3, FeF3,
ethers are among the most unreactive chemical bonds due to the and Fe(acac)3, gave very low conversions, FeF2 gave the best result
poor leaving ability of alkoxides. In most cases, alkyl ethers are very with 55% yield. Other kinds of fluoride salts, such as CoF2 and
stable towards bases and reductants, while the cleavage of C–O CuF2, were also tested and showed no reactivity. The yields
bonds of ethers occurs when the strong Brønsted/Lewis acids are increased along with the increasing amount of Grignard reagent
present.2 In the past few decades, remarkable progress has been and reaction time. The desired product 3aa could be obtained in
reported in the development of transition metal-catalyzed selective 64% of isolated yield along with the main byproduct 1-(oct-1-
cleavage of inert C–O bonds, which showed great importance due enyl)naphthalene (30aa, in 10% GC yield) when 4.0 equivalents of
to its potential utility in organic synthesis.3 In contrast to sp2 C–O 2a was used in the presence of FeF2 as the catalyst and the yields
bonds, the cleavage of sp3 C–O bonds, especially in the ether could be higher if more 2a was used. Little of the desired product
substrates, is less reported.4 Only a few examples have been was detected in the absence of additional catalyst, which may arise
demonstrated to apply unactivated alkyl ethers as coupling from the contaminant of iron salts in the Grignard reagent.
partners.5 For example, Kakiuchi and Kochi reported a beautiful
With the optimized reaction conditions in hand, we
example of Ru-catalyzed coupling of alkyl ethers bearing 2- or examined the scope of Grignard reagents (Table 1). Primary
4-pyridyl groups with arylboroxines.5d In their study, the N-atom alkyl Grignard reagents with different chain lengths reacted
well to give the desired products in moderate to good yields.
Notably, the counter anion of Grignard reagents is crucial for
a Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
this reaction. For example, nhexylMgCl reacted well, while
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College
nhexylMgBr completely failed. It is important to note that both
of Chemistry and Green Chemistry Center, Peking University, Beijing 100871,
methyl and phenyl Grignard reagents were completely unreac-
tive, which indicated that the presence of b-H was intrinsically
important to this transformation. To our delight, secondary
Grignard reagents were even better than primary ones to
proceed this chemistry. However, tertiary Grignard reagents
completely failed under these conditions, which is similar to
previous observation.6b
China. E-mail: zshi@pku.edu.cn; Fax: +86 10-6276-0890; Tel: +86 10-6276-0890
b Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000,
China
c State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
† Electronic supplementary information (ESI) available: Experimental procedures
and compound characterization data. See DOI: 10.1039/c3cc43616k
‡ These authors contributed equally to this work.
c
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Table 1 Substrate scope of Grignard reagentsa
63% yield. Unfortunately, the secondary alkyl ether 1l did not
undergo this transformation, which may be induced by the
steric hindrance.
Substrates with leaving groups other than methoxyl were
also examined (eqn (1)). The reaction of ethyl ether 1m with 2a
proceeded to give 3aa in 40% GC yield, while tert-butyl ether 1n
and phenyl ether 1o were much less reactive and most of the
starting materials were recovered. Substrates with other leaving
groups, such as pivalate 1p, carbamate 1q and alcohol 1r, did
not afford the desired coupling product and the alcohol 1r was
obtained in all these three cases.
Entry
RMgX
Product
Yieldb (%)
1
2
3
4
5
6
7
8
nHexylMgCl
nOctylMgCl
nBuMgCl
EtMgCl
3aa
3ab
3ac
3ad
3aa
3ae
3af
3ag
3ah
3ai
75 (10)
75 (9)
63 (12)
33 (13)
o5c
nHexylMgBr
MeMgCl
o5c
PhMgCl
o5c
tBuMgCl
o5c
9
cHexylMgCl
cPentylMgCl
iPrMgCl
85 (7)
84 (7)
82 (8)
71 (10)
10
11
12
(1)
3aj
3ak
iBuMgCl
a
Reaction conditions: 0.2 mmol of 1a, 1.2 mmol of Grignard reagent,
b
0.02 mmol of FeF2, 0.08 mmol of PCy3, 2 mL of o-xylene. Isolated
c
yields. Numbers in parentheses are GC yields of 30. Determined by GC
During the optimization of the reaction, the styrene derivatives
were observed as the major by-product along with different amounts
of the Grignard reagent. We hypothesized that the desired cross
coupling reaction might go through the sequence of dehydro-
alkoxylation and carbometalation, in which the styrene derivative
was generated as a key intermediate. To prove our supposition,
1-vinylnaphthalene 4a was submitted to the typical conditions.
Actually, the addition between 4a and 2a was performed, however,
in a relatively low yield (eqn (2), see ESI†). Notably, this kind of
addition reaction could not proceed smoothly in the absence of
FeF2, which indicated the importance of the iron catalyst.7
If the carbometalation took place, a new benzyl Grignard reagent
should be generated and could be quenched by other electrophiles.
When the reaction was quenched with CD3OD, the corresponding
alkylated product 3aa was obtained in 63% isolated yield with 66%
deuterium at the benzylic position within 12 h (eqn (3), see ESI†),
which verified our hypothesis to some extent. However, the relatively
low ratio of deuterium incorporation indicated that other possibi-
lities, such as direct cross coupling of C–OMe with the Grignard
reagent, were also possible in this reaction.
using decane as an internal standard.
Table 2 Substrate scope of arylethyl methyl ethersa
a
Reaction conditions: 0.2 mmol of 1, 1.2 mmol of 2h, 0.02 mmol of
FeF2, 0.08 mmol of PCy3, 2 mL of o-xylene. Numbers in parentheses are
b
GC yields of 30. Reduction products were detected in 5% GC yield.
c
2-Methoxy-6-vinylnaphthalene was detected in 7% GC yield.
d 1H NMR yield (0.2 mmol of benzyl methyl ether was used as an
internal standard). 4-Vinylbiphenyl was detected in 14% GC yield.
Furthermore, to demonstrate the utility of this new metho-
dology, carbon-based electrophiles and silyl chlorides were
used to trap the generated secondary benzylic Grignard reagent
(Table 3). For example, the carbomagnesiation of 1a for 12 h,
followed by trapping with MeI, Me3SiCl or Et3SiCl, gave the
corresponding products respectively.
e
Various methyl ethers bearing different aryl groups at the
b-position were further examined (Table 2). Fused ring sub-
strates 1a–1d reacted well and afforded the corresponding
products in moderate to good yields. The desired product 3ad
was also obtained in 47% yield with retention of aryl C–OMe
under identical reaction conditions. The lower yield arose from
the partial reduction of aryl C–OMe by the cleavage of the sp2
C–O bond. To our interest, the coupling product of aryl C–OMe
was not observed. Besides the fused ring substrates, the phenyl
substrates 1e–1k could also accomplish this transformation
with good activities. Notably, the steric effect on the aryl ring
did not have a significant influence on the reactivity (1e and 1f).
Alkyl- and aryl-substituted phenyl substrates (1g and 1h)
reacted smoothly to afford the desired products. N-containing
groups, such as N-pyrrolyl (1j) and N-pyrrolidinyl (1k), were also
tolerated well. Similar to 1d, the aryl C–OMe bond in 1i was also
partly reduced, yet the desired product could be obtained in
Previous research indicated that activated olefins, such as cyclo-
propenes,8 vinyl cyclopropanes,9 activated allenes10 and conjugated
Table 3 Trapping with different electrophilesa
a
Reaction conditions: 0.5 mmol of 1a, 3.0 mmol of 2h, 0.075 mmol of
b
c
FeF2, 0.2 mmol of PCy3, 3 mL of o-xylene. MeI (3.0 mmol). Me3SiCl
(3.0 mmol). Et3SiCl (3.0 mmol).
d
c
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Scheme 1 Proposed mechanism.
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(Scheme 1): dialkyl ether 1 underwent dehydroalkoxylation
under the reaction conditions to give the corresponding
olefin 4. FeF2 was converted to alkyl-Fe species 5 in the
presence of alkyl Grignard reagent 2 and PCy3. Subsequently,
the carbometallation between alkyl-Fe species 5 and the olefin 4
afforded benzylic iron species 6, followed by transmetallation
with alkyl Grignard reagent 2 to produce alkyl-Fe species 5 and
benzylic Grignard reagent 7, which was terminated with EtOH
to give the product 3. The byproduct 30 would be generated
from the b-H elimination of the benzylic metal species 6 or 7.
However, the pathway of the direct cross coupling could not be
ruled out due to the relatively moderate efficiency of direct
addition from styrene derivatives and deuterium incorporation.
In conclusion, the first Fe-catalyzed formal cross coupling of
homobenzylic methyl ethers with alkyl Grignard reagents was
realized through cleavage of homobenzylic sp3 C–O bonds.
The reaction presumably proceeded through the sequence of
dehydroalkoxylation to form the vinyl-intermediate, followed by
carbometalation to form benzylic Grignard reagents and
quenching with proton. The first example of iron-catalyzed
carbomagnesiation of styrenes was also demonstrated other
than hydromagnesiation. Further studies to reduce the amount
of Grignard reagents, increase the catalytic efficiency, clearly
understand the detailed mechanism as well as use other
electrophilic reagents to efficiently react with the generated
benzylic Grignard reagents are in progress.
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more unconfirmed byproducts under identical conditions, which
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Support of this work by the ‘‘973’’ Project from the MOST of
China (2009CB825300) and NSFC (No. 20925207, and 21002001)
is gratefully acknowledged.
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c
7796 Chem. Commun., 2013, 49, 7794--7796
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