Nickel-Catalyzed system for the cross-coupling of alkenyl methyl ethers with grignard reagents under mild conditions

Article abstract of DOI:10.1021/acs.orglett.8b00313

A nickel-catalyzed cross-coupling of alkenyl methyl ethers with Grignard reagents, under mild conditions, is described. These conditions allowed access to various stilbenes and heterocyclic stilbenic derivatives as well as to a potential anticancer agent DMU-212.

Full text of DOI:10.1021/acs.orglett.8b00313

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed System for the Cross-Coupling of Alkenyl Methyl
Ethers with Grignard Reagents under Mild Conditions
Thomas Hostier, Zeina Neouchy, Vincent Ferey,† Domingo Gomez Pardo, and Janine Cossy*
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), UMR 8231, ESPCI Paris/CNRS/PSL
Research University, 10 rue Vauquelin, Paris 75231 Cedex 05, France
S
* Supporting Information
ABSTRACT: A nickel-catalyzed cross-coupling of alkenyl
methyl ethers with Grignard reagents, under mild conditions,
is described. These conditions allowed access to various
stilbenes and heterocyclic stilbenic derivatives as well as to a
potential anticancer agent DMU-212.
ransition-metal-catalyzed cross-couplings are important
reactions to synthesize molecules in modern chemistry.
Scheme 1. Nickel-Catalyzed Cross-Coupling of Alkenyl
Methyl Ethers with Grignard Reagents
T
Since 1970, these coupling reactions have been widely used to
construct C−C and C−heteroatom bonds.1 In this context,
Grignard reagents are often used and coupled with halides and
pseudohalides involving metal catalysts, such as palladium,
copper, manganese, silver, iron, and nickel.2 Since the pioneering
work of Kumada et al.2f,3 and Corriu and Masse,4 nickel-catalyzed
cross-coupling of Grignard reagents with halides has demon-
strated its synthetic value to form C−C bonds, and many
exampleshavebeenreported.5 ThechoiceofGrignardreagents as
organometallic partners is very popular due to their easy
accessibility and advantages of not being toxic and for not
generating toxic wastes.6 Recently, replacement of halides by
methylethersascross-couplingpartnershasgainedimportanceto
form C−C bonds using Grignard reagents.7 In particular, cross-
coupling of aryl methyl ethers with alkyl,8 alkynyl,9 and aryl
Grignard reagents10 has been widely studied. Although a few
examples have been reported for the coupling of alkenyl methyl
ethers with Grignard reagents,11−13 either harsh conditions or
complex, expensive, and/or nonstable catalysts are used (Scheme
1, eqs 1−3). Herein, we report a nickel-catalyzed cross-coupling
of alkenyl methyl ethers with Grignard reagents, mostly aryl
Grignard, under mild conditions using a stable nickel catalyst
(Scheme 1, eq 4). Different nickel catalysts are available, but the
less expensive one is Ni(OAc)2, and we chose to test this latter
catalyst.14
When the coupling reaction of 1a with p-tolylmagnesium
bromide 2 was achieved with Ni(OAc)2 at 40 °C,15 3a was
obtainedin39%yieldforaconversionof1aof58%(Table1,entry
2).NotethatwhenthereactionwasperformedwithoutNi(OAc)2
at 40 °C, only traces of 3a were detected (Table 1, entry 1). To
increase the conversion of 1a and the yield of 3a, a screening of
ligands was realized. Among the ligands tested, amines (Table 1,
entries 3 and 4), phosphines (Table 1, entries 5−8), and
phosphine oxides (Table 1, entries 9 and 10), triphenylphosphine
oxide was the best one,16 as 1a was totally converted to 3a, and the
latter was obtained in 70% yield with an E/Z ratio of 60:40 (Table
1, entry 10). In all cases, homocoupling product 4 was present as
tracesandupto26%, andbyusing(O)PPh3, 4wasisolatedin20%
yield. When the reaction was performed only with (O)PPh3, no
reaction occurred (Table 1, entry 11).
Received: January 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00313
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Ligand in the Nickel-Catalyzed
Cross-Coupling of Alkenyl Methyl Ether 1a with p-TolMgBr
Table 2. Scope of the Nickel-Catalyzed Cross-Coupling of
Various Alkenyl Methyl Ethers with p-TolMgBr
a
a
a
Ni(OAc)2
(x mol %)
ligand L
(y mol %)
τc
yield (%) of
E/Z
3a
entry
(%)
3a (4)
1
2
traces
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
58
95
88
36
19
47
73
39 (18)
61 (18)
58 (26)
14 (traces)
7 (traces)
25 (7)
68:32
63:37
64:36
72:28
73:27
60:40
62:38
59:41
60:40
3
NMM (10)
TMEDA (5)
dppe (5)
4
5
6
dppf (5)
7
XantPhos (5)
PPh3 (10)
8
61 (5)
9
(O)PCy3 (10) 100
64 (22)
70 (20)
10
(O)PPh3 (10)
100
11
(O)PPh3 (10)
a
Conversion, yield, and E/Z were obtained by analysis of the 1H NMR
spectra of the crude sample with CH2Br2. NMM = N-methylmorpho-
line, TMEDA = tetramethylethylene diamine.
To study the scope and limitation of the reaction, different
alkenyl methyl ethers were coupled with the p-tolyl Grignard
reagent 2 (Table 2). When the aromatic ring in 1 is substituted by
an electron-donating group at the para-, meta-, or ortho-position,
the yields in the coupling products were good and, in most cases,
the E/Z ratios were close to those of the starting materials. The
reaction is chemoselective as, with the substrates incorporating an
aryl methyl ether, only the methoxy vinylic group reacts (Table 2,
entries 2−5). Furthermore, basic groups are tolerated as the
catalytic system is not deactivated by the presence of an amino
group (Table 2, entries 6 and 7). On the contrary, when an
electron-withdrawing group was present on thearomatic ring, as a
nitro group at the para-position, no coupling product was
observed. Alkenyl methyl ethers, substituted with heteroaro-
matics, can also be involved in the coupling reaction. The results
are reported in Table 3.
a
b
Yield of isolated product. E/Z ratio determined by 1H NMR.
c
Homocoupling product of 1 was observed.
Scheme 2. Nickel-Catalyzed Cross-Coupling Reaction of an
Coupling products 3 were obtained in decent yields (50−64%)
when amino heterocycles were present in 1 (pyridine, indole,
pyrrole) (Table 3, entries 1−3). The reaction also took place
whenafuranorathiophenewaspresent(Table3,entries4and5).
In these cases, the product was obtained as a mixture of
stereoisomers enriched in the E-isomer compared to the starting
material(e.g., E/Z=36:64for1jandE/Z=71:29for3j)(Table3,
entry 2).
Alkenyl methyl ether 1n could be involved in a coupling
reaction with Grignard 2 to produce 3n in 59% yield, with a good
retention of the configuration of the alkene (Scheme 2).
Different Grignard reagents, such as aryl, vinyl, alkyl, and
heteroaromatic Grignard reagents, can be involved in the process.
Aryl Grignard reagents gave the desired products in high yields
(Table 4, entries 1−3). However, in the case of anilines, the yield
was higher when the amino group was at the ortho-position rather
than at the meta-position (Table 4, entries 4 and 5). When
activated alkyl Grignard reagents were used, the coupling
products were obtained in 62−69% yields (Table 4, entries 7
and 8). In most examples, the E/Z ratio was modified, compared
to the starting material (e.g., E/Z = 55:45 for 1a and E/Z = 82:18
for 6g) (Table 4, entries 1 and 3−9).
Aliphatic Alkenyl Methyl Ether with p-TolMgBr
When1owastreatedwithisopropylmagnesiumchloride 5j, the
yield in the coupling product was only 18% with an E/Z ratio
greater than 95:5 (Scheme 3).17
Accordingtopreviousresults,thecouplingreactionseemstobe
stereoselective. Indeed, foreach example, apartial inversionofthe
configuration of the double bond of the starting material was
observed in favor of the E-isomer. To emphasize this
phenomenon, which was already observed by Chatani et al.,18
the couplingreactions wereperformed frompure (E)-1aand(Z)-
1a (Scheme 4). Complete conversion of (Z)-1a was observed
after 20 min when the latter was involved in a coupling reaction
with Grignard 2 to afford 3a in 80% yield in an E/Z ratio of 23:77.
We canassume thatthe formation of (E)-3afrom (Z)-1acould be
explained by two distinct processes: (1) partial isomerization of
B
DOI: 10.1021/acs.orglett.8b00313
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Organic Letters
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Table 3. Scope of the Nickel-Catalyzed Cross-Coupling of
Heteroaromatic-Containing Alkenyl Methyl Ethers with p-
TolMgBr
Table 4. Scope of the Nickel-Catalyzed Cross-Coupling of
Alkenyl Methyl Ether 1a with Various Grignard Reagents
a
b
c
Yield of isolated product. E/Z ratio determined by 1H NMR. Yield
1
was obtained by analyzing the H NMR spectra of the crude sample
with 1,3,5-trimethoxybenzene.
Scheme 3. Nickel-Catalyzed Cross-Coupling of Alkenyl
Methyl Ether 1o with Alkyl Grignard Reagents
a
b
c
Yield of isolated product. E/Z ratio determined by 1H NMR. Yield
1
was obtained by analyzing the H NMR spectra of the crude sample
with 1,3,5-trimethoxybenzene. Yield was obtained using 5 mol % of
intermediate (Z)-C into intermediate (E)-C; (2) partial isomer-
ization of (Z)-3a to (E)-3a under catalytic conditions. In the case
of (E)-1a, the reaction was slower than for (Z)-1a as a complete
conversion was observed for (E)-1a after 12 h and 3a was
obtained in 65% yield as a single stereoisomer (E/Z = 100:0).
With these results in hand, we hypothesize that for (Z)-1a and
(E)-1a, the oxidative addition/ligand exchange produces
intermediates (Z)-C and (E)-C, respectively. In the case of
(Z)‑C, the reductive elimination step is much faster than for (E)-
C, probably due to steric hindrance. We have verified that, for a
complete conversion of (Z)-1a, the percentage of (Z)-3a
decreased in favor of (E)-3a over time under our catalytic
conditions (see Supporting Information).
After the versatility of the coupling on E/Z mixtures was
studied, the reactivity of (E)-alkenyl methyl ethers was examined
(Table 5). Whenalkenyl methylethers (E)-1c, (E)-1f, and(E)-1g
were coupled with aryl Grignard 2, the desired products were
isolated in 60−64% yields (Table 5, entries 1−3). Good yields of
(E)-6a and (E)-6b were obtained for the coupling of (E)-1a with
aryl Grignard 5a and 5b (Table 5, entries 4 and 5). However, (E)-
d
Ni(OAc)2, 20 mol % of (O)PPh3, and 2.0−2.6 equiv of RMgBr.
6k was isolated in lower yield when aryl Grignard 5k was involved
in the process (Table 5, entry 6). Encouraged by these results, we
decided to apply the coupling conditions to the synthesis of
DMU-212, which shows anticancer properties.19 Cross-coupling
between (E)-1p and 5b gave DMU-212 in 67% yield (Scheme 5).
In summary, we demonstrated that alkenyl methyl ethers and
Grignard reagents can be cross-coupled stereoselectively under
mild conditions using a simple and robust catalytic system,
Ni(OAc)2/(O)PPh3. Cross-coupling can be performed on
diversely substituted alkenyl methyl ethers with a variety of
Grignard reagents. This nickel-catalyzed cross-coupling method
can give access to stilbene derivatives with potential anticancer
properties, such as DMU-212. Mechanistic studies are in progress
to determine the intermediates involved in the coupling reaction
and will be reported in due course.
C
DOI: 10.1021/acs.orglett.8b00313
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Notes
Scheme 4. Stereoselectivity of the Nickel-Catalyzed Cross-
Coupling
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
T.H. thanks Sanofi for a grant.
■
REFERENCES
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b
1
2
3
4
5
6
(E)-1c
(E)-1f
(E)-1g
(E)-1a
(E)-1a
(E)-1a
2
(E)-3c
(E)-3f
(E)-3g
(E)-6a
(E)-6b
(E)-6k
63
64
60
80
57
49
2
2
5a
5b
b
b
p-NMe2C6H4MgBr, 5k
a
b
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Scheme 5. Synthesis of DMU-212
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(15) When the coupling reaction was performed at 100 °C with
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.8b00313.
■
S
Experimental procedures, characterization, and 1H and 13C
NMR spectra of isolated compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: janine.cossy@espci.fr.
ORCID
Domingo Gomez Pardo: 0000-0003-0540-0321
Present Address
†Chemistry and Biotechnology Development, SANOFI, 371 rue
du Professeur Blayac, 34184 Montpellier Cedex 04, France.
(19) Piotrowska, H.; Myszkowski, K.; Abraszek, J.; Kwiatkowska-
Borowczyk, E.; Amarowicz, R.; Murias, M.; Wierzchowski, M.; Jodynis-
Liebert, J. Biomed. Pharmacother. 2014, 68, 397.
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DOI: 10.1021/acs.orglett.8b00313
Org. Lett. XXXX, XXX, XXX−XXX