Insights into the mechanism of the Negishi reaction: ZnRX versus ZnR 2 reagents

Article abstract of DOI:10.1021/ja070235b

The observation that their transmetalations with trans-[PdRfCl(PPh₃)₂] (Rf = fluoroaryl) give stereoselectively a different isomer of [PdRfMe(PPh₃)₂] suggests that Negishi reactions with ZnRX or ZnR₂ could show very different evolutions. Copyright

Full text of DOI:10.1021/ja070235b

Published on Web 03/01/2007
Insights into the Mechanism of the Negishi Reaction: ZnRX versus ZnR2
Reagents
Juan A. Casares,* Pablo Espinet,* Beatriz Fuentes, and Gorka Salas
Qu´ımica Inorga´nica, Facultad de Ciencias, UniVersidad de Valladolid, E-47071 Valladolid, Spain
Received January 11, 2007; E-mail: espinet@qi.uva.es; casares@qi.uva.es
Many palladium catalyzed cross-coupling reactions follow a quite
general pathway: oxidative addition of R1X to Pd(0) to give a
[PdR1XL2] intermediate, transmetalation from [M]R2 to give
[PdR1R2L2], and reductive elimination to afford the product R1R2
and regenerate the Pd(0) catalyst. The former and later steps are
common to all the cycles and have been studied in some depth.1,2
The various cross-coupling reactions differ in the nucleophile used
for transmetalation and, consequently, in the transmetalation step.
Powerful distinct synthetic protocols are available for different
couplings partners using the Negishi process,3 recently including
alkyls.4 The Negishi reaction is peculiar in that two types of
organometallic reagent, ZnRX and ZnR2, are available. Both are
actually used depending on the protocol.3 The choice of one or the
other seems to be totally empirical or based on the ease of access
to them.
Compared to other reactions (Stille, Suzuki-Miyaura), mecha-
nistic proposals on the transmetalation step in Negishi couplings
Figure 1. Concentration/time data for the reaction 1 + ZnMe2 obtained
by 19F NMR, in THF at 298 K. Starting conditions: [1] ) 1.65 × 10-2 M;
[ZnMe2] ) 0.33 M.
are purely speculative, and the essential stereochemical and kinetic
aspects remain obscure. We report here what are the first experi-
mental observations on the transmetalation in a Negishi coupling.
An unexpected observation is made: in the transmetalation with
ZnMe2 or ZnMeCl, using [PdRfCl(PPh3)2] (1, Rf ) 3,5-dichloro-
2,4,6-trifluorophenyl) as a model,5 each methylating reagent affords
stereoselectively a different isomer (cis or trans) of the [PdRfMe-
(PPh3)2] coupling intermediate. Moreover, the isomerization of these
isomers is a slow process. This is a key point to understand that
the choice of the organozinc reagent could strongly affect the
outcome of the Negishi cycle.
Observation and Isolation of Intermediates. In refluxing THF,
the coupling reactions of ZnMe2 or ZnClMe with RfI catalyzed by
trans-[PdRfCl(PPh3)2] afford in both cases RfMe. Hence the system
is a real model of the Negishi coupling. At room temperature the
reductive elimination of RfMe proceeds very slowly (this should
be undesired for synthetic purposes, but it is convenient for the
observation of intermediates and potential side reactions).5
A
mixture of trans-[PdRfMe(PPh3)2] (2) and cis-[PdRfMe(PPh3)2] (3)
was produced in both cases, along with other products (see below).
Both isomers were independently prepared and fully characterized.6
Studies on the Transmetalation Step. The transmetalation
reactions of trans-[PdRfCl(PPh3)2] (1) with ZnMe2 and with
ZnClMe were monitored by 19F NMR, with concentrations of
reagents as would be found in a catalysis with 5% Pd catalyst.
Transmetalation with ZnMe2. Figure 1 shows the reaction
course of 1 with ZnMe2 (Zn/Pd ) 20:1). The starting complex is
consumed very fast giving rise to trans-[PdRfMe(PPh3)2] (2) (eq
1). Then the methylated complex 2 progresses in two competitive
ways: (i) to give cis-[PdRfMe(PPh3)2] (3) in a very slow process
(eq 2); and (ii) to give ZnRfMe (4) (eq 3).7 Finally, the coupling
product RfMe is produced slowly from 3 (eq 4).
Figure 2. Concentration/time data obtained from 19F NMR in THF, at
298 K for the reaction 1 + ZnMeCl. Starting conditions: [1] ) 1.65 ×
10-2 M; [ZnMeCl] ) 0.33 M.
and [PdMe2(PPh3)2] by aryl for methyl exchange between the metal
centers. After 10 h standing at 298 K, about 60% of the Rf group
was in the form of 4, showing that in the working conditions the
equilibrium was displaced toward ZnRfMe + [PdMe2(PPh3)2]. This
exchange reaction, which is slower than the methyl transfer from
ZnMe2 to 1, explains most of the disappearance of 2 observed in
Figure 1.
Transmetalation with ZnMeCl. Figure 2 shows the reaction
course of 1 with ZnMeCl (Zn/Pd ) 20:1). The Me transfer from
zinc to palladium (measured as the consumption of 1) is slower
with ZnMeCl than with ZnMe2, as expected from the lower
nucleophilicity of ZnMeCl. Initially cis-[PdRfMe(PPh3)2] (3) is
In separate experiments the isolated complexes 2 and 3 were
shown to react with ZnMe2 (Zn/Pd ) 20:1) to give ZnRfMe (4)
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J. AM. CHEM. SOC. 2007, 129, 3508-3509
10.1021/ja070235b CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
induced by the presence of the reagent ZnMe2, while it is a very
minor problem with ZnMeCl. This side reaction can eventually lead
to homocoupling products.
Figure 3. Concentration/time data obtained from 19F NMR in THF at 298 K
for the isomerization and reductive elimination process.
Note that these conclusions should not be extrapolated to less
conventional ligands, solvents, or reagents. Further studies of other
systems are under way.
produced, while trans-[PdRfMe(PPh3)2] (2) is formed only at a
slower rate, possibly by isomerization of 3 (see later). Thus the
behavior of ZnMeCl is different from that observed for the reaction
with ZnMe2, for which the kinetic product is the trans isomer 2.
The concentration of 3 reaches a maximum and then decreases
owing to its isomerization to 2. On the other hand, some ZnRfCl
(5) (amounting toabout 20% of total Rf) is formed fast at the early
stages of the reaction, but then its concentration changes only
modestly during the reaction. In separate experiments the reactions
2 or 3 with ZnMeCl (Pd/Zn ) 20:1) afforded, after 12 h, only small
amounts of ZnRfCl (5) (10% of the total of fluorinated products)
showing that this exchange is shifted toward the fluoroaryl group
on the palladium complex.
Acknowledgment. We thank the Ministerio de Ciencia y
Tecnolog´ıa (Grant CTQ2004-07667), Consolider Ingenio 2010
(Grant CSD2006-0003), and the Junta de Castilla y Leo´n (Grant
VA-060-04) for support.
Supporting Information Available: Details of syntheses, charac-
terization of the complexes, and kinetics experiments. This material is
available free of charge via the Internet at http://pubs.acs.org.
Study of the Cis-Trans Isomerization. The cis-trans isomer-
ization in THF, observed during the transmetalation reactions was
monitored as an isolated step by 19F NMR. An evolution to a cis-
trans equilibrium was observed, whether starting from 2 or from 3
(Figure 3). In a competitive coupling process, RfMe is formed from
3.
The reaction kinetics was fitted to a model that takes into account
these competitive reactions.8 At equilibrium the isomerization is
shifted toward the trans isomer 2, affording Kisom ) 1.9 by 19F NMR
integration when the equilibrium has been reached. The same Kisom
value is obtained from the rate constants obtained in the experi-
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