Continuous synthesis of organozinc halides coupled to Negishi reactions

Article abstract of DOI:10.1002/adsc.201400243

The Negishi cross-coupling is a powerful C-C bond forming reaction. The method is less commonly used relative to other cross-coupling methods in part due to lack of availability of organozinc species. While organozinc species can be prepared, problems wit

Full text of DOI:10.1002/adsc.201400243

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DOI: 10.1002/adsc.201400243
Continuous Synthesis of Organozinc Halides Coupled to Negishi
Reactions
Nerea Alonso,b,c L. Zane Miller,a Juan de M. MuÇoz,b Jesus Alcꢀzar,b,*
and D. Tyler McQuadea,*
a
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA
E-mail: mcquade@chem.fsu.edu
Janssen Research and Development, Janssen-Cilag, S.A, C/Jarama 75, 45007 Toledo, Spain
b
Fax : (+34)-9-2524-5771; phone: (+34)-9-2524-5750; e-mail: jalcazar@its.jnj.com
Facultad de Quꢁmica, Universidad de Castilla-La Mancha, Avda. Camilo Josꢂ Cela, 10, 13071 Ciudad Real, Spain
c
Received: March 9, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400243.
Abstract: The Negishi cross-coupling is a powerful
C C bond forming reaction. The method is less
nolithium and organomagnesium species is low and
that solutions of organozinc species decompose readi-
ly. This feature contributes to the lack of commercial-
ly available organozinc species and may also contrib-
ute to less wide-spread use of the Negishi reaction.
We hypothesized that an ideal situation would be
to avoid handling organozinc reagents altogether and
instead create a continuous system whereby an orga-
nozinc reagent is prepared from a shelf-stable organo-
halide and immediately used in a subsequent reac-
tion.[4] It is well documented that continuous flow is
an ideal tool for handling unstable and highly reactive
intermediates, integrating several steps into one single
streamlined process.[5] The key challenge is to define
zinc metal activation conditions that would enable an
organozinc halide to be produced within a column of
zinc metal (Figure 1) and then to pass the organozinc
halide directly into a column of supported transition
metal catalyst to facilitate a Negishi reaction. Recent-
ly, we have demonstrated that NHC-copper(I) transi-
tion metal complexes could be readily formed by
passing a solution of imidazolium chloride through
À
commonly used relative to other cross-coupling
methods in part due to lack of availability of orga-
nozinc species. While organozinc species can be
prepared, problems with reproducibility and han-
dling of these sensitive species can complicate these
reactions. Herein, we describe the continuous for-
mation, using an activated packed-bed of metallic
zinc, and subsequent use of organozinc halides. We
demonstrate that a single column of zinc can pro-
vide excellent yields of organozinc halides and that
they can be used downstream in subsequent Negishi
cross-couplings. The preparation of the zinc column
and the scope of the reaction are discussed.
Keywords: cross-coupling; flow chemistry; Negishi
reaction; organozinc halides; supported catalysts
Transition metal-based cross-coupling reactions are a packed-bed of copper(I) oxide.[6] The desired com-
[1]
À
powerful synthetic tools for forming C C bonds.
plexes were formed in high yield and could then be
While organoboranes (Suzuki) are often the first coupled to downstream catalytic reactions. We specu-
choice in cross-coupling partner, organozincs (Ne- lated that this concept could be applied to the forma-
gishi) often show superior reaction rates and are used
when organoboranes are too unreactive. Moreover,
the Negishi reaction facilitates the coupling of sp3 car-
bons, increasing their prevalence in drug discovery
compounds and thus allowing medicinal chemists to
access new chemical space.[2] Despite outstanding in-
novations with regard to organozinc synthesis, the
paucity of commercially available organozinc species
compared to the abundance of organoboranes limits
use of the Negishi reaction.[3] In our experience, the
Figure 1. Experimental set-up of the flow system (tR =resi-
stability of organozinc species even compared to orga- dence time).
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Nerea Alonso et al.
tion of a wide range of organometallic species such as
the formation of organozinc halides.
Herein, we demonstrate that organozinc halides
can be rapidly formed with reproducible titers by
simply passing organohalides through a column of ap-
propriately active zinc metal. The organozinc halides
can then be used in downstream Negishi couplings.
Not only is the two-step process rapid and high yield-
ing, the method also enables a wide range of Negishi
couplings without the need to handle the sensitive or-
ganozinc reagents.
When creating a reactive packed-bed for use in
a continuous reaction the following factors must be
considered.
Particle size of the packed-bed material: in general
we have found that solids with mesh sizes similar to
silica gel form beds that enable reasonable flow rates
without high back pressures. For this reaction, we
found that zinc dust works poorly while zinc particles
or powder with a size of ~30 mesh works well.
Metal activation is another crucial consideration:
commerical zinc granules often arrive with a passivat-
ing layer that must be etched away. We found that
common activation strategies work well; however, ac-
Figure 2. Activation of zinc column: HCl wash (black dia-
monds) and TMSCl/dibromoethane wash (grey squares).
tivation with TMSCl (2M, 10 mL), 1,2-dibromoethane for more detail), yields quantitative formation of or-
(1M, 10 mL) followed by washing with THF (20 mL) ganozinc halides at room temperature when benzyl
provided the most active column.
and allylic halides are used and between 30–608C
Column packing is best achieved by using a column when alkyl iodides are used. Aryl halides under the
with removable ends similar to an HPLC column (we conditions we examined do not yield organozinc hal-
prefer Omni-fit columns). We place an inert material ides even above 1108C. We are now examining alter-
such as silica gel or cotton at the end of the column native conditions that might enable formation of aryl-
to prevent zinc fines from exiting the column and zinc halides.
fouling the downstream reaction.
While organozinc halides are suitable nucleophiles
Column heating must be considered: we have used for use in a wide range of reactions, we concentrated
HPLC column heaters, nichrome heating tape and our efforts towards coupling the formation of organo-
commercial heaters associated with flow chemistry zinc halides. In particular, a Negishi reaction that al-
systems. The ideal heater will uniformly heat the lowed introduction of functional alkyl groups for easy
column without forming hot spots.
access to more complex compounds. With this in
Integrating these considerations, we filled a 10 mm mind, we examined the formation of organozinc hal-
internal diameter Omni-fit column with 12 g of zinc ides using THF as the solvent as this will support both
and placed it in a Vapourtec R2+R4 system.[7] The the zinc reagent formation and the subsequent Ne-
performance of the column was assessed by pumping gishi reaction.
0.63M benzyl bromide (1a) in THF through the zinc
We have recently published a series of manuscripts
and measuring the consumption via GC. Figure 2 il- describing efficient and rapid continuous cross-cou-
lustrates that the column has an induction period pling reactions using supported palladium com-
where total consumption of 1a is not complete until plexes.[9] In particular, SiliaCat DPP-Pd[10] was found
~3 min into the run. In this case, the column was acti- to support a wide range of Negishi reactions.[9b] We
vated using dilute HCl followed by washing with dry proceeded to leverage this knowledge by creating
THF. The induction period can be eliminated by a two column reactor system whereby the zinc
switching the column activation wash from dilute packed-bed was placed upstream of a 6.6 mm internal
HCl, black diamonds, to TMSCl/dibromoethane, grey diameter Omni-fit column containing 1 g of SiliaCat
squares (see the Supporting Information). Selected DPP-Pd (Table 1). We started examining the per-
data points were titrated using the Knochel method.[8] formance of this two column system by surveying the
The titrations indicated a 1:1 correlation between con- range of coupling partners that could undergo suc-
sumption of 1a and organozinc halide (2a) formation. cessful cross-coupling. As shown in Table 1, Negishi
We have determined that a zinc column, activated cross-couplings between aryl halides and organozinc
as described above (see the Supporting Information halides formed from alkyl (1b–1d) and benzylic hal-
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Continuous Synthesis of Organozinc Halides
Table 1. Initial survey of coupling partners supported by
a two column system (scale 0.8 mmol).
Scheme 1. Survey of functional group tolerance: scale
0.8 mmol.
examine a range of aryl halide-based coupling reac-
tions to examine the functional group tolerance of the
system (Scheme 1). In this way, electron-rich and elec-
tron-poor aryl substrates react in good to excellent
yields. In addition, the process is tolerant of five- and
six-membered ring heterocyclic coupling partners
under mild reaction conditions. In contrast to the zinc
insertion step, nitro groups are well tolerated as cou-
pling partners (4q). In the case of bromo-iodo deriva-
tives, coupling proceeded selectively at the iodine
atom (4m). The data presented thus far indicate that
a two column system whereby a shelf-stable organo-
[a]
Zn column, r.t.; Silicat DPP-Pd column 608C.
Zn column, 608C; Silicat DPP-Pd 608C.
Zn column, 608C and LiCl (1 equiv.) as additive; Silicat
DPP-Pd column, 808C.
Zn column, 1108C and LiCl (1 equiv.) as additive; Silicat
DPP-Pd column, 608C.
Zn column, r.t.; Silicat DPP-Pd column, 808C.
[b]
[c]
[d]
[e]
ides (1a, 1e–1i) proceeded in good to high yields. It is halide is passed through a suitably activated zinc
worth highlighting that many functionalized alkyl and column can be used to perform Negishi couplings.
benzyl species performed well, such as Boc-protected What we have yet to demonstrate is that the system
azetidine (entry 4), as well as secondary benzyl hal- can be used to form meaningful volumes of material.
ides (entry 8). We have only identified that nitro To address the issue of scale, we have examined two
groups are incompatible with the organozinc halide aspects of this system.
forming step which is consistent with previously de-
The first aspect of scale we examined was organo-
zinc halide production. Using the Omnifit column
scribed organozinc chemistry.[3]
Table 1 demonstrates that our hypothesis, organo- filled with 12 g of zinc, we were able to prepare
zinc halides can be prepared continuously and imme- 150 mL of a 0.5M solution of benzylzinc bromide 2a
diately used downstream, is valid. We proceeded to in THF. During this procedure about 5 g of zinc were
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Nerea Alonso et al.
Experimental Section
General Flow Procedure for Zinc Insertion and
Negishi Cross-Coupling
A solution of alkyl halide 0.3M in dry THF (when required
1 equiv. of LiCl was added as additive) was passed through
a 10 mm internal diameter Omni-fit column containing Zn
(12 g) using the R2+R4 system[7] at the desired temperature
and a flow rate of 0.2 mLminÀ1 (tR =10 min). The outlet so-
lution was mixed in a T piece with a solution of haloarene
0.2M in dry THF at 0.2 mLminÀ1 and passed through
a 6.6 mm internal diameter Omni-fit column containing Sil-
iacat DPP-Pd (1 g) at the required temperature (tR =
2.5 min). The crude of the reaction was quenched with a sa-
turated solution of ammonium chloride and extracted with
AcOEt. The organic layer was separated, dried (Na2SO4),
filtered and the solvents evaporated under vacuum. The
crude products were purified by column chromatography
using silica to yield the desired products.
Figure 3. Long-term stability assessment.
consumed. This volume is very practical on the labo-
ratory scale as most organometallic reagents are sold
in 100 mL volumes. These data suggest that use of the
zinc column to produce organozinc halides will be
broadly applicable to reactions beyond the Negishi re-
action.
Acknowledgements
The authors thank NSF (CHE-1152020), Chemring, Inc.,
Prof. Frank Gupton for helping the contact. Prof. Antonio de
la Hoz, Prof. Angel Diaz Ortiz, Prof. Wim de Borggraeve
and Dr. Brecht Egle for their help in the Negishi protocol. D.
Miguel A. PeÇa PiÇon and Dr. Alberto NuÇez OcaÇa for
their help in the large scale preparation of organozinc com-
pounds. Duncan Guthrie, Chris Butters, David Griffin,
Adrian Clarkson, and Lillian Auchincloss from Vapourtec
Ltd. are thanked for their assistance throughout this project.
The second aspect of scale examined was overall
protocol stability with respect to the two column
system. In this case, we measured the formation of
Negishi product as a function of time (Figure 3). The
reaction was performed such that 3.3 mmolhÀ1 was
achieved. The calculated turnover number of the cata-
lyst for the overall process was 175. The isolated yield
of the reaction was 94% and the reaction was stable
over the 13 h that we monitored. These data demon-
strate that this approach is valid on development
scales. We perceive that with larger zinc and catalyst
columns the reaction could be scaled to manufactur-
ing volumes.
In conclusion, we have demonstrated that organo-
zinc halides can be produced from shelf-stable halides
and used in situ in a continuous packed-bed approach.
The data shown in Figure 2 demonstrate that high
and reproducible titers can be realized when the zinc
is appropriately activated. The scope data indicate
that a variety of substrate types are readily converted
into organozinc halides and that coupling the forma-
tion of the zinc species with a Negishi reaction is
a productive approach. The two column system is tol-
erant of many functional groups including those of in-
terest from a medicinal chemistry perspective (hetero-
cycles such as azetidine 1d). The formation of organo-
zinc halides is broadly useful as the approach can sup-
port the formation of 150 mL of 0.5M reagent. Final-
ly, the two stage zinc insertion/Negishi reaction
functions at the high end of laboratory scale with ease
suggesting that the approach is stable and robust
enough to support much larger scale chemistry. Fur-
ther expansion of both zinc insertion and coupling
steps will be the topic of future endeavors.
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6 Continuous Synthesis of Organozinc Halides Coupled to
Negishi Reactions
Adv. Synth. Catal. 2014, 356, 1 – 6
Nerea Alonso, L. Zane Miller, Juan de M. MuÇoz,
Jesus Alcꢀzar,* D. Tyler McQuade*
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