The Role of LiBr and ZnBr2 on the Cross-Coupling of Aryl Bromides with Bu2Zn or BuZnBr

Article abstract of DOI:10.1002/chem.201903931

The impact of LiBr and ZnBr₂ salts on the Negishi coupling of alkylZnBr and dialkylzinc nucleophiles with both electron-rich and -poor aryl electrophiles has been examined. Focusing only on the more difficult coupling of deactivated (electron-rich) oxidative addition partners, LiBr promotes coupling with BuZnBr, but does not have such an effect with Bu₂Zn. The presence of exogenous ZnBr₂ shuts down the coupling of both BuZnBr and Bu₂Zn, which has been shown before with alkyl electrophiles. Strikingly, the addition of LiBr to Bu₂Zn reactions containing exogenous ZnBr₂ now fully restores coupling to levels seen without any salt present. This suggests that there is a very important interaction between LiBr and ZnBr₂. It is proposed that Lewis acid adducts are forming between ZnBr₂ and the electron-rich Pd⁰ centre and the bromide from LiBr forms inorganic zincates that prevent the catalyst from binding to ZnBr₂. This idea has been supported by catalyst design as chlorinating the backbone of the NHC ring of Pd-PEPPSI-IPent to produce Pd-PEPPSI-IPent^Cl catalyst now gives quantitative conversion, up from a ceiling of only 50 % with the former catalyst.

Full text of DOI:10.1002/chem.201903931

A Journal of
Accepted Article
Title: The Role of LiBr and ZnBr2 on the Coupling of sp2-Hybridized
Oxidative Addition Partners with sp3-Hybridized Organozincs
Authors: Michael G Organ and Philip Eckert
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To be cited as: Chem. Eur. J. 10.1002/chem.201903931
Link to VoR: http://dx.doi.org/10.1002/chem.201903931
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COMMUNICATION
The role of LiBr and ZnBr
2
on the cross-coupling of aryl bromides
with Bu Zn or BuZnBr.
2
[a]
[a]
Philip Eckert, and Michael G. Organ*
Abstract: The impact of LiBr and ZnBr
2
salts on the Negishi coupling
impacts the coupling at the TM stage with our Pd-NHC (N-
heterocyclic carbene) coupling system. We have shown that Pd-
PEPPSI catalysts are able to couple organolithium reagents at -
78 ºC, which shows the very high reactivity of these complexes.[10]
The corresponding Negishi couplings with otherwise identical
substrates and reaction conditions could be done as low as -20
ºC, but no lower.[8,11] This illustrates that oxidative addition (OA)
and reductive elimination (RE) are indeed very rapid process for
bulky Pd-PEPPSI catalysts and suggests that the rate-limiting
step of the process involves the organometallic, at least when
NHC ligands are employed. Again, this points to a likely and
significant involvement of the salts at the TM stage of the catalytic
cycle.
of alkylZnBr and dialkylzinc nucleophiles with both electron-rich and
electron-poor aryl electrophiles has been examined. Focusing only on
the more difficult coupling of deactivated (electron-rich) oxidative
addition partners, LiBr promotes coupling with BuZnBr, but does not
have such an effect with Bu
shuts down the coupling of both BuZnBr and Bu
shown before with alkyl electrophiles. Strikingly, the addition of LiBr to
Bu Zn reactions containing exogenous ZnBr now fully restores
coupling to levels seen without any salt present. This suggests that
there is a very important interaction between LiBr and ZnBr . It is
proposed that Lewis acid adducts are forming between ZnBr and the
electron-rich Pd(0) centre and the bromide from LiBr forms inorganic
zincates that prevent the catalyst from binding to ZnBr . This idea has
2
Zn. The presence of exogenous ZnBr
2
2
Zn, which has been
2
2
2
2
2
The TM of an alkyl group is known to be intrinsically more
difficult that the corresponding sp2 hybridized carbon fragment.[
In the case of our sp3-sp3 coupling, TM is doubly difficult as the
OA partner is also alkyl and therefore electron-donating making
the OA intermediate less electrophilic and less able to undergo
TM.[4c,6] This is why we believe that LiX salt is so critical to
enhancing the nucleophilicity of the alkylzinc halide, thereby
helping to facilitate TM. We envisioned that if instead we focused
on the OA partner and enhanced its electrophilicity, then the need
for the LiX salt might diminish, if not disappear. One way to do
that is to use aryl bromides, which are intrinsically electron-poor,
where the electronics can be tuned further (i.e., Hammett-type
analysis) without a significant alteration in the physical footprint.
been supported by catalyst design as chlorinating the backbone of the
12]
Cl
NHC ring of Pd-PEPPSI-IPent to produce Pd-PEPPSI-IPent catalyst
now gives quantitative conversion, up from a ceiling of only 50% with
the former catalyst.
Interest in the Negishi Reaction[1] has soared as more organozinc
reagents have come available, in particular air-stabile versions,[2]
as more catalysts have been invented that are especially adept at
cross-coupling organozinc partners,[3] and as key mechanistic
details have been elucidated that have helped broaden
[
4]
application through increased understanding. Important to the
last point is the key role that salts play in this Nobel Prize-winning
transformation.[
4e,5,6]
Unnoticed, or perhaps just ignored for years,
Table 1. Negishi Coupling of BuZnBr with arylbromides with, and without, LiBr.
LiBr (or LiCl) is the natural byproduct of the Rieke protocol to
make alkylzincs,[7] which remains the most common method used
to prepare these reagents. Similarly, the same salts are also the
byproduct of the preparation of sp2 hybridized organozincs that
come from transmetallation (TM) of the corresponding
[
8]
organolithium or Grignard reagent. The necessity of LiX or MgX
2
salts was not made clear until methods were developed to
stringently remove them. When the Hou protocol[9] was used to
eliminate LiX formation, alkyl-alkyl (sp3-sp3) couplings were
shown to go from rapid, quantitative transformations to no
reaction at all.[4c,6] In the case of aryl-aryl couplings, diarylzinc
reagents were found not to have a reliance on the presence of
alkali salts whereas with arylzinc halides (ArZnX) they were again
shown to be essential for any coupling whatsoever.[6c]
With RZnX structured reagents we have argued that LiX has
a significant impact on the structure of the organozinc in solution,
be it through the formation of zincates[4c,6a,b] and/or alterations in
the aggregation state of the organozinc,[6c] and this markedly
Entry 1
compound)
FG
Percent Conv.
No LiBr[
Percent Conv.
3.2 equiv. LiBr
a]
[a]
(
1
(3a)
2 (3b)
(3c)
4 (3d)
NO
2
93
88
82
96
60
28
98
90
86
92
72
65
25
CHO
3
COCH
3
CO CH3
2
5
6
7
(3e)
(3f)
H
[
a]
Mr. P. Eckert and Professor M. G. Organ (Director, Centre for
Catalysis Research and Innovation (CCRI)), Department of
Chemistry and Biomolecular Sciences, University of Ottawa,
Ottawa, Ontario, K1N6N5 (Canada)
OCH
N(CH
3
(3g)
3
)
2
trace
Email: organ@uottawa.ca
1
[
a] Percent conversion was determined by H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard. Experiments were carried out in
duplicate and the average result is reported.
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In our initial experiments, salt-free BuZnBr was prepared
using the Hou protocol[9] and reacted with a series of aryl
bromides (Table 1). Whereas alkylzinc reagents experienced zero
coupling with alkyl electrophiles until at least 1.0 equivalents of
LiBr was present,[4c,6] bromobenzene could be coupled to 60%
conversion without any LiBr added (entry 5).[13] When electron-
poor electro-philes were examined, all gave excellent conversion
without LiBr, which did improve slightly when it was added (entries
mechanism is more involved when poorly reactive OA partners,
such as 1g, are employed.
2
The impact of salts on the coupling of Bu Zn was next
evaluated. Interestingly, whereas adding LiBr had a major effect
on BuZnBr, it failed to move coupling beyond the 50% conversion
that was attained in its absence. In fact, increasing equivalence of
the salt from 0.3 to 1.2 did not statistically alter conversion at all
(Table 2, Series 1, Entry a vs. Entries b-e). Conversely, when
1-5). In the case of electron-donating groups, conversion without
2
ZnBr was added to the transformation in increasing amounts,
salt was low (entry 6) or non-existent (entry 7), yet when LiBr was
added a dramatic increase in conversion was observed in all
cases.
coupling was proportionally reduced (Table 2, Series 2, Entry a
vs. Entries b-e). There are two possible explanations for this result.
The increasing amounts of ZnBr
2
could allow the Schlenk
equilibrium to become active and more BuZnBr forms but it is not
capable of coupling with such a deactivated electrophile and
If an argument can be made that the LiBr is enhancing the
nucleophilicity of the organozinc reagent as we have suggested
previously,[4c,6] and this is why we see such a stark increase in
conversion in entries 5-7 in Table 1, we should expect to see a
similarly dramatic increase in conversion simply by constructing a
more electron-rich organozinc reagent. Indeed, when we
conversion plummets.[4-6] Alternatively, ZnBr
is certainly more
2
Lewis acidic than LiBr and can bind to the reduced Pd(0) strongly
enough following RE to poison it in an off-cycle resting state.[14]
2 2
In the case of Bu Zn, neither LiBr nor ZnBr (both natural
prepared dibutylzinc (Bu
2
Zn (5)), freshly distilled) and reacted it
byproducts of making the organometallic and the coupling,
respectively) seem to help the transformation. Structurally and
functionally, these two salts are quite different. LiBr has significant,
often overlooked Lewis basic behaviour through the halide as a
consequence of a looser ion pair with the low electronegativity
lithium (= 1.0). Conversely, the more electronegative zinc (=
1.6) creates a tighter metal-halide bond and the Lewis acidic
properties of zinc dominate for the salt as a whole.
with 1g, a poorly reactive OA partner, under similar conditions to
those used in Table 1, 50% conversion was attained without any
LiBr (Table 2, Series 1, Entry a). Interestingly, now adding any
amount of this salt (0.3 – 1.2 equiv., series 1, entries b-e) did not
further increase conversion. Even 3.2 equivalents of LiBr made
no difference (series 1, entries f).
Table 2. Impact of LiBr and ZnBr
2 2
on Negishi Coupling using Bu Zn nucleophile
and 4-bromo-N,N-dimethylaniline (1g).[a]
We wondered if LiBr and ZnBr , might interact in some way to
2
exert either a positive or negative influence over the coupling
(
Table 3). With no LiBr added we are reminded of the increasingly
negative impact of the presence of exogenous ZnBr as
2
conversion drops from 39 to 13 percent as the amount of this salt
is increased from 0.3 to 0.9 equivalents (Series 1-3, Entry a).
Strikingly, when equi-molar or slightly higher amounts of LiBr were
2
added to the reaction mixtures containing ZnBr cross-coupling
Entry (Equivalents of Salt Employed)
was restored to the level seen with no salt at all (Series 1-3,
Entries d and e compared with Table 2, entry a).
Series
Salt
a
b
c
d
e
f
(0)
(0.3)
(0.6)
(0.9)
(1.2)
(3.2)
Table 3. Impact of adding LiBr and ZnBr
2
together on Negishi Coupling using
Bu
2
Zn nucleophile with 4-bromo-N,N-dimethylaniline.[a]
1
2
LiBr
50[b]
50[b]
50
39
49
20
52
13
50
10
43
-
ZnBr
2
[
1
a] Percent conversion to 3g was determined by 1H NMR spectroscopy using
,3,5-trimethoxybenzene as an internal standard. Experiments were carried out
in duplicate and the average result is reported. [b] Under otherwise identical
reaction conditions, 1.0 equivalents of Bu Zn led to 55% conversion.
2
Since both butyl groups could be transferred there
could/should have been full conversion to 3g with only 0.6 equiv.
Entry (LiBr Equivalents Used)
2
of Bu Zn. This raised the question as to whether the Schlenk
a (0)
b (0.3)
c (0.6)
d (0.9)
e (1.2)
equilibrium was active under our coupling conditions. That is,
without LiBr, BuZnBr may not be active enough to couple with a
Series
ZnBr
Equiv.
Used)
1 (0.3)
2 (0.6)
3 (0.9)
39
20
13
49
37
23
48
38
30
52
46
36
61
49
44
(
deactivated OA partner (e.g., Table 1, Entry 7), and Bu
forming in these runs so no coupling takes place. Conversely, if
only Bu Zn is able to react (in the absence of LiBr) when it is all
2
Zn is not
2
consumed there is nothing left that is competent to couple, so the
reactions halts near 50% conversion. When we increased the
a] Percent conversion was determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard. Experiments were carried out in
duplicate and the average result is reported.
[
2
amount of Bu Zn to 1.0 equiv., there was only ~5% increase in
conversion (Table 2, Footnote [b]). This implies that the
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That LiBr failed to improve conversion of the dialkylzinc
80
77
69
60
nucleophile in the absence of ZnBr
conversion when ZnBr was present, suggests that the most
important interaction of LiBr is not with Bu Zn, which may be
different in the case of BuZnBr, but rather with ZnBr . We propose
that the Lewis basic bromide ion coordinates to ZnBr to form
LiZnBr and/or possibly Li ZnBr . This eliminates the Lewis acidic
nature of zinc by strong coordinative saturation of the metal centre.
A related hypothesis has been proposed by Koszinowski using a
Pd S-PHOS complex.[4e] If this situation is operative, we
envisioned that we could incorporate catalyst design elements to
aid in circumventing poisoning.
2
, but so profoundly increased
[
a] Percent conversion was determined by 1H NMR spectroscopy using 1,3,5-
2
trimethoxybenzene as an internal standard. Experiments were carried out in
duplicate and the average result is reported.
2
2
2
above, when ZnBr was added in increasing amounts (Table 4,
2
Entries b-d) conversion to 3g slightly decreased whereas when
the same amounts of this salt were added to the reaction with 4,
conversion dropped by a factor of four (Table 2, Series 2).
3
2
4
In this manuscript we have shown that LiBr has a profound
effect on the coupling of alkylZnBr nucleophiles with deactivated
(
electron-rich) aryl OA partners, but its role is less important with
activated (electron-deficient) ones. We propose that in this case,
Chlorinating the backbone of Pd-PEPPSI-IPent to produce
Pd-PEPPSI-IPentCl (6) has been shown to profoundly accelerate
the rate of cross-coupling in general,[15] while at the same time
like with alkyl OA partners that we have investigated in the
past,[
4c,6a,6b]
that alkyl zincates are again forming with LiBr that are
necessary to help drive TM. If the OA arene is electron-poor, this
makes Pd more electron-deficient and this helps to drive TM and
LiBr is much less important.
improving selectivity in the coupling of secondary alkyl
nucleophiles.[16] The dramatic improvements in these reaction
attributes were ascribed to electronic and steric influences of the
chlorines.[15,16] N-heterocyclic carbene (NHC) ligands are among
the strongest  donators making the metal centre quite electron
Dialkylzincs, which are now much more nucleophilic than
alkylZnBr, might be anticipated to undergo TM more readily with
the deactivated (electron-rich) OA partners. Indeed, this is what
we observed; whereas 1g did not react at all with BuZnBr (2), it
[17]
rich. While this is beneficial for OA, it makes TM and RE more
difficult. It also renders the metal more susceptible to Lewis acids,
such as ZnBr
2
,[14] so chlorinating the NHC reduces the Lewis
reacted to 50% conversion with Bu
addition of LiBr had zero impact on conversion. When ZnBr
added to the reaction with 1g with Bu Zn (5), coupling plummeted.
However, the addition now of LiBr, which initially had no impact,
2
Zn. Interestingly, now the
basic nature of Pd(0),[16,17] thereby making it less susceptible to
poisoning.
2
was
2
From a steric perspective, chlorinating the NHC backbone
forces the N-aryl substituents in toward the metal, which was
shown to be the primary reason for selectivity in the
aforementioned selective secondary alkyl cross-coupling
reactions.[16] In that case, pushing the aryl groups forward
hindered the formation of the 4-centred transition state necessary
for-hydride elimination that is necessary for migratory insertion
leading to isomerization, while at the same time driving RE, a 3-
centred transition state. Perhaps, sterically, this might disfavour
restored full coupling in the presence of ZnBr
no salt was present at all.
2
to levels seen when
The fact that Bu
of LiBr, but shows dramatic improvement when ZnBr
mixture points to a different, or at least an additional, important
role. We propose this role is to coordinatively saturate ZnBr , a
2
Zn couplings see no benefit upon the addition
2
is in the
2
Lewis acid that can bind to the electron-rich NHC-Pd(0) centre,
thereby helping to keep the catalyst on cycle. In support of this,
when we modified the catalyst with two chlorines on the back of
the NHC ring, coupling dramatically increased (still in the absence
of any LiBr). One can argue that the chlorines withdraw electron
density away from Pd(0) making it less basic. In addition, there in
now an increased steric presence in the coordination sphere of
the metal as repulsion between the chlorines and N-aryl
substituents on the NHC force these two rings toward Pd.
the ability of ZnBr
2
from binding to Pd(0). Taken together,
chlorinating the NHC core should aid in resisting poisoning, both
sterically and electronically.
When Pd-PEPPSI-IPentCl (6) was substituted for Pd-PEPPSI-
IPent (4) consumption of 1g was now quantitative with 80%
conversion to 3g (Table 4, Entry a), up from 50% with 4 (Table 2,
Series 1, Entry a). Consistent with the developing hypothesis
Together these two features disfavour binding to ZnBr
avoiding the formation of off-cycle resting states.
2
, thus
Table 4. Influence of NHC backbone chlorination of Pd-PEPPSI-IPent (to create
Cl
Pd-PEPPSI-IPent (6)) on the negative impacts of ZnBr
2
in the Negishi
Coupling of Bu
2
Zn nucleophile (5) with 4-bromo-N,N-dimethylaniline (1g).[a]
Acknowledgements
This work was supported by NSERC Canada in the form of a CRD
grant and by the Eli Lilly Research Award Program (LRAP).
Keywords: PEPPSI • Negishi coupling • salt effect • catalyst
poisoning
Entry (ZnBr
2
Equivalents Employed)
c (0.6)
[
[
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a (0) b (0.3)
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COMMUNICATION
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The role of LiBr and ZnBr
cross-coupling of aryl bromides with
Bu Zn or BuZnBr
2
on the
2
Butylzinc bromide requires LiBr to cross-couple with alkylbromides, presumably to
form zincates to enhance transmetallation given the electron richness (deactivation)
of the electrophile. Here we show that butylzinc bromide will couple with electron
poor (activated) arylbromides without salt, but will not couple electron-rich ones until
salt is added. Dibutylzinc, a more powerful nucleophile, now couples deactivated
aryl bromides without LiBr and adding the salt fails to further enhance conversion.
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