Palladium-catalyzed C(sp 3)-C(sp 2) cross-coupling of (trimethylsilyl)methyllithium with (hetero)aryl halides

Article abstract of DOI:10.1021/acs.orglett.5b00905

The palladium-catalyzed direct cross-coupling of a range of organic chlorides and bromides with the bifunctional C(sp³)-(trimethylsilyl)methyllithium reagent is reported. The use of Pd-PEPPSI-IPent as the catalyst allows for the preparation of structurally diverse and synthetically versatile benzyl- and allylsilanes in high yields under mild conditions (room temperature) with short reaction times.

Full text of DOI:10.1021/acs.orglett.5b00905

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed C(sp3)−C(sp2) Cross-Coupling of
(Trimethylsilyl)methyllithium with (Hetero)Aryl Halides
Dorus Heijnen,† Valentín Hornillos,† Brian P. Corbet, Massimo Giannerini, and Ben L. Feringa*
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands
S
* Supporting Information
ABSTRACT: The palladium-catalyzed direct cross-coupling of a range
of organic chlorides and bromides with the bifunctional C(sp3)-
(trimethylsilyl)methyllithium reagent is reported. The use of Pd-
PEPPSI-IPent as the catalyst allows for the preparation of structurally
diverse and synthetically versatile benzyl- and allylsilanes in high yields
under mild conditions (room temperature) with short reaction times.
Scheme 1. Pd-Catalyzed Cross-Coupling of Aryl Halides
Employing TMSCH2Li and Possible Further
Transformations at the TMSCH2 Group
he development of new catalytic methods for carbon−
T
carbon bond formation continues to present major
challenges in organic synthesis.1 In particular, palladium-
catalyzed cross-coupling of organometallic reagents with
organic halides represents one of the most powerful methods
for C−C bond formation.2 Several well established methods for
this transformation are available using different organometallic
partners including organozinc,3 organotin,4 organoboron,5
organosilicon,6 and organomagnesium7 reagents. Murahashi
and co-workers pioneered the use of highly reactive aryl and
alkyllithium reagents in catalytic cross-coupling reactions.8 Our
group recently described methods for the palladium-catalyzed
direct cross-coupling of organolithium reagents with (hetero)-
aryl- and alkenyl (pseudo)halides under mild conditions,
avoiding side reactions such as lithium−halogen exchange or
homocoupling.9,10 Additionally, we also reported the reaction
of sp3 carbon nucleophiles with aryl bromides that allows a fast,
selective, and high yielding coupling of primary and secondary
alkyl groups with the notorious β-hydride elimination being
suppressed in nearly all cases.9a,e,11 Preliminary experiments
showed the successful use of the functionalized C(sp3)
nucleophile TMSCH2Li in metal-catalyzed cross-coupling
reactions.9a,e This bifunctional CH2 moiety enables the
preparation of stable ArCH2SiMe3 products that can further
undergo a wide array of possible transformations including
Peterson olefination,12 photocatalyzed13 and gold catalyzed14
reactions, and oxidation to the corresponding acylsilanes15
(Scheme 1). Furthermore, the CH2 group can act as a
nucleophile in fluoride-mediated processes giving rise to the
formation of saturated products.16a Following our initial
report,9a the use of this functionalized organolithium reagent
recently attracted increasing attention in metal-catalyzed cross-
couplings reactions, specifically using Ni catalysis.16 Consider-
ing the relevance of the (trimethylsilyl)methyllithium nucleo-
phile, we wondered if readily available but less reactive organic
chlorides17 could also be a precursors for the synthesis of highly
versatile TMSCH2-functionalized compounds. Costs, waste
production, and availability benefit from the use of aryl
chlorides as starting materials. However, due to their low
reactivity, the use of high temperatures and long reaction times
is usually required while the use of aryl chlorides in metal-
catalyzed C(sp3)−C(sp2) cross-coupling reactions with organo-
lithium reagents remains a challenge.18
Here, we report the development of a Pd-catalyzed cross-
coupling reaction employing aryl chlorides and TMSCH2Li that
allows selective preparation of a variety of ArCH2TMS
compounds in high yields under mild conditions (rt) and
short reaction times (1 h) (Scheme 1).
The reaction between 4-methoxychlorobenzene 1a, a
reluctant aryl chloride in coupling reactions, and TMSCH2Li
was chosen as a model system since conditions for the
successful coupling of this substrate will enable access to a wide
variety of other coupling partners. Under the optimized
conditions for the cross-coupling of alkyllithium reagents with
aryl bromides,9a using Pd(PtBu3)219 as a catalyst (Table 1, entry
1), less than 5% conversion to the coupling product 2a was
observed. The in situ prepared palladium complexes, using
Pd2(dba)3 in combination with P(tBu)3 or dialkylbiaryl
phosphines,20 previously reported to be effective for the Pd-
catalyzed cross-coupling with other aryl and alkyllithium
reagents, led to similar results (Table 1, entries 2−4).
Employing NHC ligands, we were delighted to find that the
air stable Pd-PEPPSI-IPent catalyst, introduced by the group of
Organ,21 afforded full conversion and nearly perfect selectivity
Received: March 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00905
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Screening of Different Ligands
Scheme 2. Pd-Catalyzed Cross-Coupling of TMSCH2Li with
(hetero)aryl chlorides.
a
a
b
entry
[Pd]
ligand
conv (%)
2a:3:4
1
2
3
4
5
6
Pd(PtBu3)2
<5
c
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
L1, P(tBu)3
L2, SPhos
L3, XPhos
<5
<5
<5
Pd-PEPPSI-IPent
Pd-PEPPSI-IPr
full
∼85
98:<1:< 1
98:<1:< 1
a
Conditions: TMSCH2Li (0.72 mL, 1.0 M in pentane) was added to a
solution of 4-bromoanisole (0.6 mmol) in toluene (2 mL). 1 h
b
c
addition time. 2a:3:4 ratios determined by GC analysis. 7.5 mol %
was used. dba = dibenzylideneacetone.
a
Conditions: Aryl halide (0.6 mmol), TMSCH2Li (0.72 mmol, 1.0 M
in pentane), toluene (2 mL). 1 h addition time. Selectivity >98%. Yield
b
values refer to isolated yields after purification. iPrMgCl (1.0 equiv, 2
toward the coupled product 2a at rt in 1 h, avoiding
dehalogenation or homocoupling side products 3 and 4
(entry 5, Table 1). It should be mentioned that, for the
corresponding Pd-catalyzed cross-couplings of 1a with
aryllithium reagents, higher temperatures (40 °C) and longer
addition times (3 h) of the organolithium reagent were
necessary to reach full conversion and high selectivity.9c The
corresponding Pd-PEPPSI-IPr also performed well in the
reaction, although full conversion was not reached (entry 6).
With Pd-PEPPSI-IPent as a highly efficient catalyst system,
we set out to investigate the cross-coupling between
TMSCH2Li and different aryl chlorides (Scheme 2). The
reactions employing other electron-rich aryl chlorides such as
1b, 1c, or more sterically hindered 1d also proceed with full
conversion and high selectivity without the need to increase the
temperature or reaction time. Remarkably, highly deactivated
amine-substituted aryl chlorides 1e and 1f, which did not
perform well in the cross-coupling with aryllithium reagents,9c
were also converted under the optimized reaction conditions to
the desired product in good yields and with excellent
selectivities (Scheme 2). It should be emphasized that benzyl
alcohol 1g, as the Mg alkoxide, and 6-chloro-1H-indole 1h, as
the Mg amide, were also tolerated, affording products 2g and
2h with high selectivity. The catalytic system proved to be also
efficient in the reaction with 1- and 2-chloronaphthalene 1i and
1j, providing the corresponding trimethyl(naphthalenyl-
methyl)silanes 2i and 2j with no trace of regioisomers,
indicating that benzyne intermediates via 1,2-elimination are
not formed. Importantly, 2j was obtained quantitatively when
the reaction was scaled up to 4.0 mmol. The electron-deficient
1-chloro-4-(trifluoromethyl)benzene 1k and 4-chloro-1-fluoro-
2-methylbenzene 1l underwent clean coupling, giving high
isolated yields of the fluorinated structures 2k and 2l. Pyridyl
rings, which are susceptible to nucleophilic addition of
alkyllithium reagents, also participated in the cross-coupling
with high selectivity, albeit with lower yield after purification, as
illustrated for substrate 1m. Facile multiple coupling is
M in Et2O) was added over 5 min prior to the organolithium.
c
TMSCH2Li (1.44 mmol).
illustrated in the reaction of 1n with 2.1 equiv of TMSCH2Li
providing bis-silylated product 2n in good yield.
After having established Pd-PEPPSI-IPent as a highly
efficient catalyst for the cross-coupling of TMSCH2Li with
aryl chlorides, we studied the scope of this catalyst in the
reaction with challenging organic bromides. Sterically hindered
bromides, known for being more reluctant substrates for the
coupling of alkyl units,22 were tested for the first time in
combination with TMSCH2Li. As shown in Scheme 3, a variety
of bulky organic bromides (5a−d) could be coupled with
excellent selectivity at room temperature within 1 h, indicating
that the transmetalation step takes place rapidly, facilitating a
fast coupling process. Notably, di-ortho-substituted tert-butyl
aryl bromide 5d was tolerated, affording the TMS-function-
alized product 6d at rt in high yield. Remarkably, bromo-
fluorene was successfully employed, despite the acidity of the
benzylic protons (pKa = 22). Alkenyl bromide 5f also
undergoes this cross-coupling, leading to allyltrimethylsilane
6f with high selectivity with no presence of Fritsh−
Butlenberg−Wiechell type rearrangement side products.23
Fluorinated bromides 5g and 5h also underwent clean coupling
without any traces of side products. Similar to the
corresponding aryl chloride 1g, (4-bromophenyl)methanol 5i,
bearing an unprotected hydroxyl group, could also be coupled
with this organolithium reagent, provided the corresponding
Mg alkoxide was first generated. In the presence of an excess of
TMSCH2Li, both the −OTf and −Cl groups present in aryl
bromides 5j and 5k were also coupled leading to products
which contain two or three TMSCH2 functional groups.
As shown above, the Pd-PEPPSI-IPent complex has been
shown to be an extremely efficient and versatile catalyst for the
cross-coupling of (trimethylsilyl)methyllithium with (hetero)-
aryl chlorides, bromides, and triflates. However, the use of aryl
chlorides presents additional advantages compared to the
B
DOI: 10.1021/acs.orglett.5b00905
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
corresponding aryl chloride 7b led to the desired silylated
product 8 with nearly perfect selectivity and high yield, in
accordance with the reduced tendency to undergo halogen−
lithium exchange, and this enhanced selectivity will be
beneficial in synthetic applications.
Scheme 3. Pd-Catalyzed Cross-Coupling of TMSCH2Li with
Alkenyl and Aryl Bromides
a
In summary, we have shown the direct Pd-catalyzed cross-
coupling of TMSCH2Li with organic (pseudo)halides, includ-
ing reluctant but cheap and readily available organic chlorides,
in high yields and excellent selectivity. The method is based on
the use of the commercially available Pd-PEPPSI-IPent catalyst.
The reactions take place under mild conditions with a broad
substrate scope. The products formed are attractive, stable, α-
C-activated,25 and precursors for various further transforma-
tions.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: b.l.feringa@rug.nl.
Author Contributions
†D.H. and V.H. contributed equally to this work.
a
Conditions: Aryl halide (0.6 mmol), TMSCH2Li (0.72 mmol, 1.0 M
Notes
in pentane), toluene (2 mL). Selectivity >98%. Yield values refer to
b
isolated yields after purification. Yield determined by 1H NMR using
The authors declare no competing financial interest.
c
tetrachloroethane as internal standard. Moderate yield obtained after
purification by column chromatography. iPrMgCl (1.0 equiv, 2 M in
Et2O) was added over 5 min prior to the organolithium. TMSCH2Li
(1.44 mmol). TMSCH2Li (2.16 mmol).
d
e
ACKNOWLEDGMENTS
■
f
The Netherlands Organization for Scientific Research (NWO-
CW), the National Research School Catalysis (NRSC-C), the
European Research Council (ERC Advanced Grant 227897 to
B.L.F.), the Royal Netherland Academy of Arts and Sciences
(KNAW), and the Ministry of Education Culture and Science
(Gravitation Program 024.601035) are acknowledged for
financial support.
aforementioned, as they are less prone to undergo halogen−
lithium exchange with the organolithium compound,
preventing the formation of homocoupling or dehalogenated
side products.24 We have recently shown that this different
behavior is evidenced in the Pd-catalyzed cross-coupling of 2-
alkoxy-substituted bromo- and chloroarenes where the
coordination of the ortho-methoxy group with the organo-
lithium compound facilitates the Li−Br exchange and further
stabilizes the resulting aryllithium compound.9f Here, the
C(sp3) character of TMSCH2Li, when compared with C(sp2)
in aryl lithium reagents, could further enhance this effect. As
shown in Scheme 4, this difference in reactivity was confirmed
in the cross-coupling with 1-bromo-2-methoxybenzene 7a,
where the TMSCH2 functionalized product was obtained along
with a homocoupling side product. However, the use of the
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