Iron-Catalyzed Grignard Cross-Couplings with Allylic Methyl Ethers or Allylic Trimethylsilyl Ethers

Article abstract of DOI:10.1055/s-0036-1591774

We have found that cross-coupling between aryl Grignard reagents and allylic methyl ethers proceeded well in the presence of a catalytic amounts of Fe(acac) ₃ to afford the corresponding allylic substitution products in good yields. Under the same conditions, allylic trimethylsilyl ethers also reacted with Grignard reagents to give the corresponding cross-coupling products.

Full text of DOI:10.1055/s-0036-1591774

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, 1211–1214
letter
1211
en
C. Seto et al.
Letter
Synlett
Iron-Catalyzed Grignard Cross-Couplings with Allylic Methyl
Ethers or Allylic Trimethylsilyl Ethers
Chika Seto
R'-MgX
Takeshi Otsuka
R
OMe
Fe(acac)3 (1–5 mol%)
Yoshiki Takeuchi
Daichi Tabuchi
R
R'
THF, rt
R
OSiMe3
R' = octyl, Me, Ar
10–98% yield
15 examples
Takashi Nagano*
R = Ar, alkyl
Department of Chemistry, Faculty of Science, Kochi University,
2-5-1 Akebono-cho, Kochi 780-8520, Japan
tnagano@kochi-u.ac.jp
Received: 29.01.2018
Accepted after revision: 13.02.2018
Published online: 19.03.2018
(a) Allylphosphates as substrates
R3MgX
R1
O2P(OPh)2
R1
R3
Fe(acac)3 cat.
ref. 4
ref. 5
Ar
DOI: 10.1055/s-0036-1591774; Art ID: st-2018-u0061-l
R2
THF
R2
Abstract We have found that cross-coupling between aryl Grignard
reagents and allylic methyl ethers proceeded well in the presence of a
catalytic amounts of Fe(acac)3 to afford the corresponding allylic substi-
tution products in good yields. Under the same conditions, allylic
trimethylsilyl ethers also reacted with Grignard reagents to give the cor-
responding cross-coupling products.
(b) Allyl phenyl ethers as substrates
R4
OPh
R4MgX
Fe(acac)3 cat.
R1
R3
R1
R3
DCE–NMP
R2
R2
(c) This work
R
ArMgX
Fe(acac)3 cat.
OMe (or OTMS)
Key words iron catalysis, Grignard reagents, cross-coupling, allylic
substitution, allylic ethers
R
OMe (or OTMS)
THF
(TMS = –SiMe3)
R
The iron-catalyzed cross-coupling reaction, originally
developed by Tamura and Kochi in 1971,1 has recently ma-
tured into one of the most important synthetic tools for
creating new C–C bonds.2 Although iron-catalyzed Grignard
cross-couplings with organic halides have been well stud-
ied in the last decade, little attention has been paid to the
development of iron-catalyzed allylic substitution reactions
using hard carbon nucleophiles.3 In 1991, Yamamoto and
co-workers reported that an iron-catalyzed allylic substitu-
tion with allylic phosphates as substrates proceeded in an
SN2 fashion to afford the corresponding coupling products
in good yields and with high regioselectivities (Scheme
1a).4 Recently, Li and co-workers reported an iron-catalyzed
allylic substitution of allyl phenyl ethers with Grignard re-
agents in a DCE–NMP mixed solvent; in this case, the phe-
noxy group was the leaving group of choice (Scheme 1b).5
During the course of our studies on iron-catalyzed organic
transformations,6 we found that allyl methyl ethers, which
can be easily prepared from the corresponding allylic alco-
hol and methyl iodide by Williamson’s ether synthesis,
were examined as potential candidate for an iron-catalyzed
Grignard allylic substitution reaction (Scheme 1c).7
Scheme 1 Iron-catalyzed allylic substitutions with Grignard reagents
Cross-coupling of the allyl methyl ether 1a and the
phenyl Grignard reagent 2a proceeded in the presence of 5
mol% of Fe(acac)3 in THF at ambient temperature to afford
the corresponding allylic substitution product 3aa in 79%
isolated yield (Table 1, entry 1), although the allylic methyl
ether 1a has been reported to be a less-reactive substrate
under Li’s condition.8 The use of the corresponding allyl
ethyl ether resulted in similar yield (entry 2). The allyl phe-
nyl ether could also be used as substrate, but the yield of
3aa was slightly lower than that observed in the reaction of
1a (entry 3). Although other iron salts such as FeCl3 and
FeCl2 also promoted the allylic substitution with 1a to af-
ford 3aa, neither palladium(II) chloride nor nickel(II) chlo-
ride showed catalytic activity under ligand-free conditions
(entries 4–7). Reactions conducted at lower temperatures
(–20, –40, or –78 °C) gave the product 3aa in reduced yields
(entries 8–10).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 1211–1214

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C. Seto et al.
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Table 1 Optimization of Conditionsa
Table 2 Scope of the Grignard Reagenta
PhMgBr (2a) (2 equiv)
catalyst (5 mol%)
RMgX (2) (2 equiv)
Fe(acac)3 (5 mol%)
Ph
OR
Ph
Ph
Ph
OMe
Ph
R
THF, temp., 4 h
THF, rt, 4 h
1
3aa
1a
3
Entry
R
Catalyst
Temp (°C)
Yieldb (%)
Entry
R
X
Product
Yield (%)b
1
2
Me (1a)
Et
Fe(acac)3
Fe(acac)3
Fe(acac)3
FeCl3
rt
79 (84)
(78)
1
2
3
4
5
6
7
8d
9
Ph
Br
Br
Br
Br
Br
Br
Br
I
3aa
3ab
3ac
3ad
3ae
3af
–
79
81c
98
73
91
71
0
rt
4-Tol
2-Tol
3
Ph
rt
(72)
74
78
0
4
Me
Me
Me
Me
Me
Me
Me
rt
4-MeOC6H4
2-MeOC6H4
4-FC6H4
Mes
5
FeCl2
rt
6
PdCl2
rt
7
NiCl2
rt
(6)
50
33
18
8
Fe(acac)3
Fe(acac)3
Fe(acac)3
–20
–40
–78
Mee
3ah
3ai
42
10
9
Me(CH2)7
Br
10
a Reaction conditions: 1a (0.5 mmol), ~1 M 2 in THF (2 equiv), THF (5.0 mL).
b Isolated yield.
a Reaction conditions: 1 (0.5 mmol), ~1 M PhMgBr in THF (2 equiv), THF
c A mixture of 3ab and a small amount of an inseparable double-bond re-
gioisomer was obtained (see Ref. 9 and the Supporting Information).
d The reaction was carried out on a 10 mmol scale because 3ah is volatile.
e A solution of MeMgI in Et2O was used.
(5 mL).
b Isolated yield. NMR yields with MeNO2 as internal standard are shown in
parentheses.
With the optimized conditions in hand, we then ex-
plored the substrate scope (Table 2). A variety of aryl
Grignard reagents bearing such substituents as methyl, me-
thoxy, or fluoro reacted with the allyl methyl ether 1a to
give the corresponding allylic substitution products 3aa–af
in good to excellent yields (Table 2, entries 1–6).9 Unfortu-
nately, the sterically demanding mesityl Grignard reagent
2g was found to be inert (entry 7). The reaction of alkyl
Grignard reagents 2h and 2i with allyl methyl ether 1a gave
the corresponding coupling products 3ah and 3ai in 42%
and 10% yield, respectively (entries 8 and 9).10
We then carried out several reactions with branched
substrates (Scheme 2). As mentioned above, the reaction of
the linear allylic methyl ether 1a with PhMgBr gave product
3aa with perfect E-selectivity (Scheme 2, Equation 1),
whereas the reaction of the corresponding branched sub-
strate 1a′ gave 3aa as a mixture of E- and Z-isomers
(Scheme 2, Equation 2);11 no branched product was ob-
served in this reaction. In the case of the alkyl-substituted
linear substrate 1b, the allylic substitution product 3ba was
obtained as a mixture of the E- and Z-isomers and a
branched isomer.12 As in the case of 1a′, the reaction of the
corresponding branched substrate 1b′ gave a Z-enriched
coupling product (Scheme 2, Equation 3).13
uct through transmetalation and reductive elimination at
the sterically less-hindered position. As mentioned above,
the reaction using the branched substrate 1a′ afforded the
Z-isomer as a minor product, although the major product
was the E-isomer. This small but important difference
might be attributed to a rapid transmetalation–reductive
elimination sequence. The oxidative addition of a branched
substrate to the catalytically active iron species produces
both syn- and anti-π-allylic intermediates A and B. These
species undergo rapid transmetalation, followed by reduc-
tive elimination, before reaching a π–σ–π equilibrium.15
PhMgBr (2a) (2 equiv)
Fe(acac)3 (5 mol%)
(1)
(2)
Ph
OMe
Ph
Ph
THF, rt, 4 h
1a
(E)-3aa
79%
OMe
same as above
Ph
+
Ph
Ph
Ph
Ph
(Z)-3aa
1a'
(E)-3aa
73% (E/Z = 86:14)
nHex
nHex
OMe
nHex
Ph
+
1b
(E)-3ba
(Z)-3ba
On the basis of these observations, we assumed that the
present iron-catalyzed allylic substitution reaction pro-
ceeds via a π-allylic iron intermediate (Scheme 3). Oxidative
addition of the linear E-substrate to a low-valent iron spe-
cies [Fe]14 gives the thermodynamically stable syn-π-allylic
intermediate A. Intermediate A then gives a linear E-prod-
same as above
Ph
(3)
or
+
Ph
OMe
nHex
nHex
Substrate Yield (%)
E/Z/b
b-3ba
1b
1b'
74
71
71:3:26
53:22:25
1b'
Scheme 2 Cross-coupling reactions with branched substrates
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 1211–1214

1213
C. Seto et al.
Letter
Synlett
good yields with perfect E-selectivity. Likewise, the use of
branched substrates resulted in the formation of mixtures
of E- and Z-isomers. The reaction of o-substituted phenyl
Grignard reagents gave 3ac and 3ae in high yields, although
the reason for this is unclear at present (See also Table 2,
entries 3 and 5).
From linear (E)-substrate
From branched substrate
OMe
R
OMe
[Fe]
R
OMe
oxidative
addition
same as
left-hand side
[Fe]
OMe
OMe
R
R
[Fe]
[Fe]
R
ArMgBr (4 equiv)
Fe(acac)3 (1 mol%)
OMe
OMe
Fe
R
Fe
Ph
OTMS
Ph
Ph
Ar
Ar
THF, rt, 25 h
4a
3
R
A
B
ArMgBr (2 equiv)
Fe(acac)3 (1 mol%)
OTMS
syn-π-allyl
anti-π-allyl
transmetalation
and reductive
elimination
Ph
THF, rt, 24 h
fast
3
fast
linear (Z)- and branched
4a'
linear (E)- and branched
(From branched substrate 4a')
Ar = Ph (3aa): 84% (E/Z = 97:3)
(From linear substrate 4a)
Ar = Ph (3aa): 78%
Scheme 3 Plausible explanation for the stereochemical outcome
Ar = 4-Tol (3ab): 67%
Ar = 4-Tol (3ab): 56% (E/Z = 93:7)
Ar = 4-MeOC6H4 (3ad): 74%
Ar = 4-FC6H4 (3af): 76%
Ar = 2-Tol (3ac): 88% (E/Z = 98:2)
Ar = 4-MeOC6H4 (3ad): 77% (E/Z = 88:12)
Ar = 2-MeOC6H4 (3ae): 95% (E/Z = 95:5)
Ar = 4-FC6H4 (3af): 81% (E/Z = >99:1)
The above mechanism was also supported by experi-
mental results obtained from the reaction of (Z)-1a as a
substrate (Scheme 4). As the reaction temperature was low-
ered, the Z-selectivity increased. Low temperatures might
suppress the π–σ–π equilibrium shift from the initially
formed anti-π-allylic intermediate B to the syn-π-allylic
species A, resulting in the formation of a Z-enriched cou-
pling product.
Scheme 6 Preliminary exploration of the substrate scope
Finally, we attempted to perform a chemoselective
cross-coupling by using substrate 5, which contained both
aryl triflate and allyl silyl ether moieties (Scheme 7). This
bifunctional substrate 5 can be easily prepared by silylation
of the starting alcohol, whereas the synthesis of the corre-
sponding allyl methyl ether by Williamson method failed
due to incompatibility of the aryl triflate moiety with metal
hydride. Iron-catalyzed Grignard cross-coupling with 5 af-
forded 65% yield of the allylic substitution product 6, leav-
ing the triflate group intact.17
PhMgBr (2 equiv)
Fe(acac)3 (5 mol%)
Ph
Ph
Ph
OMe
THF, 4 h
(Z)–1a
(E)- and (Z)–3aa
Temp. (°C) Yield (%)
E/Z
50
rt
0
53
52
63
94:6
85:15
59:41
decreasing E-selectivity
OH
OMe
1) NaH
2) MeI
Scheme 4 Allylic substitution with a Z-substrate
TfO
TfO
0%
We next turned our attention to allylic silyl ethers as
potential substrates for the allylic substitution reaction, be-
cause these can be easily prepared from the corresponding
allylic alcohols under mild conditions without the use of a
metal hydride. The reaction of allyl silyl ether 4a with four
equivalents of PhMgBr in the presence of 1 mol% of
Fe(acac)3 successfully gave the allylic substitution product
3aa in 78% isolated yield (Scheme 5).16
TMSCl (2 equiv)
Et3N, rt, 15 h
89%
OTMS
Ph
PhMgBr (2 equiv)
Fe(acac)3 (1 mol%)
THF, rt, 24 h
TfO
TfO
5
6
65%
Chemoselective coupling
Scheme 7 Chemoselective cross-coupling
PhMgBr (4 equiv)
Fe(acac)3 (1 mol%)
Ph
OTMS
Ph
Ph
In summary, we have reported iron-catalyzed Grignard
allylic substitution reactions of allyl methyl ethers and allyl
silyl ethers.18 Reactions using linear E-substrates gave E-
products in good yields. Interestingly, the corresponding
branched substrates gave Z-products as minor products.
Studies on further applications of the Fe(acac)3/ArMgX cat-
alyst system are in progress in our laboratory.
THF, rt, 25 h
4a
3aa
78%
Scheme 5 Allylic substitution using an allylic silyl ether
The results of a preliminary exploration of the substrate
scope with allyl silyl ethers are shown in Scheme 6. As in
the case of allyl methyl ethers, the linear substrate 4a gave
the linear coupling products 3aa, 3ab, 3ad, and 3af in
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 1211–1214

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C. Seto et al.
Letter
Synlett
Funding Information
assume that an isomerization pathway from the normal cou-
pling product to its double-bond regioisomer exists in the reac-
tion system of the allylic methyl ether. A plausible mechanism is
as follows. Oxidative addition of R–OMe to the low-valent iron
species gives R–[Fe]–OMe. β-Hydrogen elimination from the
methyl group results in the formation of an iron hydride species
R–[Fe]–H. Insertion of olefin 3ab into the iron–hydride bond,
followed by β-hydrogen elimination, affords the corresponding
double-bond regioisomer.
This work was supported by JSPS KAKENHI Grant-in-Aid for Young
Scientists (B) (Grant Number 25810064).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591774.
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(10) We also attempted to react 1a with Me(CH2)7MgBr (2i) under
Li’s conditions (DCE–NMP, –15 °C, 1 h; Ref. 5), but the yield of
3ai was only 5% (76% of 1a was recovered.). With our catalyst
system (Table 2, entry 9), 1a was fully consumed, and large
amounts of (1E)-prop-1-en-1-ylbenzene were formed.
References and Notes
(1) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487.
(2) For reviews on iron-catalyzed cross-coupling reactions, see:
(a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104,
6217. (b) Fürstner, A.; Martin, R. Chem. Lett. 2005, 34, 624.
(c) Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41, 1500.
(d) Czaplik, W. M.; Mayer, M.; Cvengroš, J.; von Wangelin, A. J.
ChemSusChem 2009, 2, 396. (e) Nakamura, E.; Hatakeyama, T.;
Ito, S.; Ishizuka, K.; Ilies, L.; Nakamura, M. Org. React. (N. Y.)
2014, 83, 1. (f) Bauer, I.; Knölker, H.-J. Chem. Rev. 2015, 115,
3170.
(3) For pioneering works on iron-catalyzed allylic substitutions
using soft carbon nucleophiles, see: (a) Roustan, J. L.; Mérour, J.
Y.; Houlihan, F. Tetrahedron Lett. 1979, 20, 3721. (b) Dieter, J.;
Nicholas, K. M. J. Organomet. Chem. 1981, 212, 107. (c) Ladoulis,
S. J.; Nicholas, K. M. J. Organomet. Chem. 1985, 285, C13.
(d) Silverman, G. S.; Strickland, S.; Nicholas, K. M. Organometal-
lics 1986, 5, 2117. (e) Xu, Y.; Zhou, B. J. Org. Chem. 1987, 52, 974.
(f) Zhou, B.; Xu, Y. J. Org. Chem. 1988, 53, 4419.
(4) (a) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Synlett 1991, 513.
(b) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Tetrahedron
1994, 50, 6017.
(5) Qui, L.; Ma, E.; Jia, F.; Li, Z. Tetrahedron Lett. 2016, 57, 2211.
(6) (a) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297. (b) Nagano,
T.; Hayashi, T. Org. Lett. 2005, 7, 491. (c) Nagano, T.; Kobayashi,
S. Chem. Lett. 2008, 37, 1042.
(7) For allylic substitution reaction of allylic ethers with aryl metal
reagents catalyzed by other transition metals, see: (a) Hayashi,
T.; Konishi, M.; Yokota, K.-i.; Kumada, M. J. Chem., Soc., Chem.
Commun. 1981, 313. (b) Hayashi, T.; Konishi, M.; Yokota, K.-i.;
Kumada, M. J. Organomet. Chem. 1985, 285, 359. (c) Sugimura,
H.; Takei, H. Chem. Lett. 1985, 14, 351. (d) Chung, K.-G.; Miyake,
Y.; Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 2725.
(e) Mizutani, K.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2004, 33,
832. (f) Yasui, H.; Mizutani, K.; Yorimitsu, H.; Oshima, K. Tetra-
hedron 2006, 62, 1410. (g) Tsukamoto, H.; Uchiyama, T.; Suzuki,
T.; Kondo, Y. Org. Biomol. Chem. 2008, 6, 3005. (h) Kiuchi, H.;
Takahashi, D.; Funaki, K.; Sato, T.; Oi, S. Org. Lett. 2012, 14, 4502.
(i) Mino, T.; Kogure, T.; Abe, T.; Koizumi, T.; Fujita, T.; Sakamoto,
M. Eur. J. Org. Chem. 2013, 1501.
(11) The isolated mixture of (E)- and (Z)-3aa contained small
amounts
of
the
reductive
homocoupling
product
PhCH=CH(CH2)2CH=CHPh (molar ratio: E/Z/homo = 84:13:3).
This homocoupling product was inseparable from (Z)-3aa. See
Supporting Information.
(12) The formation of the branched isomer b-3ba from the hexyl-
substituted substrates 1b and 1b′ might be due to a decrease in
steric repulsion.
(13) Similar results have been reported in nickel- or palladium-cata-
lyzed allylic substitutions with Grignard reagents, although no
detailed discussion has been reported on the difference
between linear and branched substrates [see Refs. 7 (a) and 7
(b)].
(14) The formation of an Fe(I) species by the reaction of FeX3 with
aryl Grignard reagents has been suggested; see: Hedström, A.;
Lindstedt, E.; Norrby, P.-O. J. Organomet. Chem. 2013, 748, 51.
(15) A similar discussion has been reported in the literature dealing
with the nickel-catalyzed cross-coupling of allylic alcohols with
Grignard reagents; see: (a) Felkin, H.; Swierczewski, G. Tetrahe-
dron Lett. 1972, 13, 1433. (b) Felkin, H.; Swierczewski, G. Tetra-
hedron 1975, 31, 2735.
(16) The use of two equivalents of Grignard reagent resulted in a 69%
yield of 3aa with an 8% yield of the reductive homocoupling
product. In the case of the reaction with four equivalents of 2a
(Scheme 5), the yield of the homocoupling product was 6%.
(17) We have previously reported an iron-catalyzed chemoselective
cross-coupling with a bifunctional substrate possessing both
aryl triflate and alkyl bromide moieties: see Ref. 6(a).
(18) Iron-Catalyzed Allylic Substitutions with Grignard Reagent;
General Procedure
To a solution of Fe(acac)3 (9.0 mg, 0.025 mmol, 5 mol%) in THF
(1 mL) was added the appropriate allylic ether (0.5 mmol) and
additional THF (4 mL). A ~1 M solution of the appropriate Gri-
gnard reagent in THF (1.0 mmol) was added, and the mixture
was stirred for 4 h at rt. The reaction was quenched by the addi-
tion of 1 N aq HCl, and the resulting mixture was extracted with
CH2Cl2. The combined organic layers were dried (MgSO4), fil-
tered, and concentrated. The residue was purified by flash
column chromatography or TLC on silica gel.
(8) When we carried out the reaction of 1a with 2a under Li’s con-
ditions (DCE–NMP, –13 °C, 1 h) (see Ref. 5), we observed the for-
mation of 3aa in 19% yield (75% of 1a was recovered).
(9) The cross-coupling product 3ab (Table 2, entry 2) contained a
small amount of an inseparable double-bond regioisomer,
whereas the sample product 3ab prepared from the corre-
sponding silyl ether (Scheme 6) did not contain this regioiso-
mer (see Supporting Information). From these observations, we
1,1′-(1E)-Prop-1-ene-1,3-diyldibenzene [(E)-3aa]
Colorless oil; yield: 154 mg (79%). 1H NMR (500 MHz, CDCl3):
δ = 7.36–7.28 (m, 10 H), 6.46 (d, J = 15.5 Hz, 1 H), 6.36 (dt,
J = 15.5, 7.0 Hz, 1 H), 3.55 (d, J = 7.0 Hz, 2 H). 13C NMR (125 MHz,
CDCl3): δ = 140.1, 137.4, 131.0, 129.2, 128.6, 128.5 (overlap),
127.1, 126.1, 126.1, 39.3. These NMR data are in agreement
with those previously reported: see Ref. 7 (i).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 1211–1214