On the role of additives in alkyl-alkyl Negishi cross-couplings

Article abstract of DOI:10.1039/c002759f

An additives study for the alkyl-alkyl Negishi reaction using an NHC-Pd catalyst revealed that bromide salts promote coupling while the cation is mechanistically benign. A double titration revealed that the cross-coupling begins at a 1 1 ratio of LiBr

Full text of DOI:10.1039/c002759f

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On the role of additives in alkyl–alkyl Negishi cross-couplingsw
George T. Achonduh, Niloufar Hadei, Cory Valente, Stephanie Avola, Christopher J. O’Brien
and Michael G. Organ*
Received (in Cambridge, UK) 9th February 2010, Accepted 2nd March 2010
First published as an Advance Article on the web 19th March 2010
DOI: 10.1039/c002759f
An additives study for the alkyl–alkyl Negishi reaction using an
NHC–Pd catalyst revealed that bromide salts promote coupling
while the cation is mechanistically benign. A double titration
revealed that the cross-coupling begins at a 1 : 1 ratio of
n
LiBr : BuZnBr, suggesting that a higher-order zincate, presumably
LimZn(nBu)Br3(2Àm)À, is the active transmetalating agent.
The precise role of additives in transition metal-mediated
cross-couplings remains a topic of interest and conjecture.1
Fig. 1 A comparison of two methods for the preparation of alkylzinc
However, it is generally accepted that, whereas ligands
halides via the oxidative addition of activated Zn* into an alkyl–X
primarily influence oxidative addition and reductive elimination,
bond.
additives influence the transmetalation step of the catalytic
cycle. Suzuki et al.2 discovered early on that an exogenous
and functional group-tolerant procedures. These include the
in situ-activation of Zn metal for efficient oxidative
addition,5,10 directed zincation of functionalised arenes
with mixed-metal organozincates11 and direct zinc–halogen
exchange processes.12
base was required to achieve adequate reaction kinetics in the
coupling of alkenylboranes with alkenyl, alkynyl and aryl
halides. Mechanistic studies by Matos and Soderquist3 show
that, in the presence of hydroxide, a hydroxyl-bound ‘‘borate’’
complex is formed in situ, and this is the active transmetalating
agent. An alternate path wherein a transient (oxo)palladium(II)
intermediate is formed prior to transmetalation with a
neutral organoborane is also likely.3,4 Both pathways may
be operational concurrently, and it is not immediately obvious
as to why one pathway predominates under a particular set of
reaction conditions. More recently, Knochel’s group has
found that LiCl not only promotes zinc5 and magnesium6
insertion into C–X bonds, but that LiX salts promote
transmetalation of the resulting organometallic reagents,
which was also demonstrated by Oshima and co-workers.7
In fact, a great deal of the recent chemistry employing
organozinc reagents inherently takes place in the presence of
this non-innocent species. However, relatively less experimental
work has gone into elucidating the exact role of additives in
the Negishi cross-coupling reaction. This may be due to the
fact that the full potential of organozinc reagents in cross-
couplings has been thwarted by relatively inefficient preparative
methods, despite their exceptional functional group tolerance
and stability.8 Recently, however, newly developed and/or
optimized methods for the preparation of organozinc reagents,
alongside a myriad of organozinc halides making their way to
the marketplace, have rekindled interest in organozinc
chemistry and the Negishi reaction. Conventional metathesis
of an organolithium or -magnesium reagent with ZnX2 and
the relatively laborious reduction of ZnX2 salts to generate
highly reactive Zn* metal9 are giving way to more practical
Recently, we reported high-yielding alkyl–alkyl Negishi
cross-couplings wherein the alkylzinc reagents were efficiently
prepared using either Rieke’s9a or Huo’s10 protocol (Fig. 1),
with the latter being more user-friendly. These transforma-
tions were catalyzed by an in situ-generated imidazolium salt
IPrÁHCl/Pd2(dba)3 catalyst system13 and, subsequently, by an
air- and moisture-stable NHC–Pd(II) precatalyst,14 namely
Pd-PEPPSI-IPr.15 All things being equal, marked differences
in cross-coupling yields were observed depending on the
source of the alkylzinc reagent (Table 1, entries 1 and 2). We
reasoned that the presence of two equiv. of LiX salt, a
byproduct in the Rieke preparation,9 is an essential additive
in this cross-coupling. Thus, it was not surprising that, upon
doping in 2.0 equiv. of LiBr (based on the organozinc reagent)
to the same cross-coupling using Huo’s alkylzinc halide,
quantitative conversion to the product was observed (entry 3).
The groups of Knochel6 and Oshima7 have reported that
LiCl acts to enhance the reactivity of organomagnesium and
-zinc reagents, respectively, presumably by breaking apart
polymeric aggregates. Tetra-n-butylammonium iodide
(TBAI) has also been found to enhance the nucleophilicity
of diorganozincs.16 We, therefore, opted to screen various
inorganic and organic salts (entries 4–14) in the hope of
shedding light on the exact contribution these additives play
in the alkyl–alkyl Negishi cross-coupling reaction. The results
of this additives study were complicated by the varied solubilities
of each salt in the THF–DMI co-solvent system. Further
convoluting the matter is the consideration that additive
solubility may change over the course of the reaction.
Department of Chemistry, York University, 4700 Keele Street,
Toronto, Ontario, M3J 1P3, Canada. E-mail: organ@yorku.ca
w Electronic supplementary information (ESI) available: Experimental
procedures and compound data. See DOI: 10.1039/c002759f
Nevertheless, the initial solubility of each salt was qualitatively
assessed under identical reaction conditions to those presented
in Table 1, only without the Pd catalyst. LiBr (entry 3) was
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Table 1 The effect of the nBuZnBr source and additives on the
alkyl–alkyl Negishi cross-coupling catalyzed by Pd-PEPPSI-IPr
fully soluble, while KBr and NaBr (entries 7 and 8) were
only slightly soluble salts. It appeared that both MgBr2
and MgCl2 (entries 6 and 9) reacted with the organozinc
reagent, forming a viscous white suspension. Disproportiona-
tion, as well as the formation of polymeric aggregates,
cannot be ruled out. MgCl2, however, was a much poorer
promoter compared to MgBr2, which may stem from chlorides
superior ability to form bridged species.17 Whereas TBAI and
LiI (entries 5 and 13) were fully soluble, poor conversions
resulted, suggesting that iodide is an ineffective promoter or
acts in a deleterious fashion. Overall, the best performing
additives were those containing bromides (entries 3, 6,
11 and 14), inferring that the counterion does not play a role
mechanistically in this reaction, but affects primarily the
solubility of the ion pair. Maintaining high conversion upon
addition of a stoichiometric quantity of the Li+-complexing
macrocycle 15-crown-5 is consistent with this proposal
(entry 15).
Entry nBuZnBr source Additivea (2.0 equiv.) Conversionb (%)
1
2
3
4
5
6
7
8
Rieke’s method
Huo’s method
None
None
LiBr/Cl
LiOAc
LiI
MgBr2
NaBr
KBr
MgCl2
MgI2
TBAB
TBAC
TBAI
THAB
LiBr + 15-crown-5
Quant.
0
Quant.
0
5
92
0
0
15
0
79
34
2
’’
’’
’’
’’
’’
’’
’’
’’
’’
’’
’’
’’
’’
A titration study was carried out wherein various stoichio-
metries of LiBr were doped into the cross-coupling presented
in Table 1 (Fig. 2). We were intrigued by the finding that
the cross-coupling remained dormant until approximately
9
n
10
11
12
13
14
15
1.0 equiv. of LiBr (based on BuZnBr) was added, at which
point an exponential increase in conversion occurred with each
successive addition of 0.1 equiv. LiBr, until leveling off in the
range of 1.4–2.0 equiv. LiBr. We reason that if the sole
purpose of LiBr is to break up polymeric aggregates and that
the active transmetalating agent is Zn(nBu)Br2À, then simply
adding a sub-stoichiometric quantity of LiBr (i.e., as a
65
84
a
Ac = acetate; PEPPSI = pyridine enhanced pre-catalyst preparation,
stability and initiation; TBAB = tetra-n-butylammonium bromide;
TBAC = tetra-n-butylammonium chloride; TBAI = tetra-n-butyl-
catalyst) should suffice. With the current finding, we postulate
(2Àm)À
b
that a higher-order zincate,18 of the type LimZn(nBu)Br3
,
ammonium iodide; THAB = tetra-n-hexylammonium bromide. Percent
conversion was assessed by GC-MS analysis using undecane as a
calibrated internal standard; reactions were performed in duplicate.
is in fact the active transmetalating agent, reflected in the
enhanced reaction kinetics upon addition of 1.4–2.0 equiv. of LiBr.
Fig. 2 A double titration study wherein various stoichiometries of LiBr (’, x equiv.) and ZnBr2 (grey circle, 2.0–x equiv.) were added to the
alkyl–alkyl Negishi cross-coupling reaction depicted in Table 1: nBuZnBr (1.0 equiv.), 3-bromo-1-phenylpropane (0.63 equiv.), Pd-PEPPSI-IPr
(0.6 mol%), THF–DMI (2 : 1), rt, 2 h. The reaction was found to initiate when the ratio of LiBr to nBuZnBr was 1 : 1 and was optimal between
1.4–2.0 equiv. of LiBr. This suggests that a higher-order organozincate (see proposed equilibria and text) is the active transmetalating agent.
Percent conversion was assessed by GC-MS analysis using undecane as a calibrated internal standard; reactions were performed in duplicate for
each data point.
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higher-order zincate, here presumed to be LimZn(nBu)Br3
(2Àm)À
,
Thus, our original work on the alkyl–alkyl Negishi cross-
coupling using Rieke organozincs13 was serendipitous in that
the solutions of these organometallic reagents intrinsically
contain a two-fold stoichiometry of LiX as a manufacturing
byproduct.
is the active transmetalating agent. Additional studies are
underway to further characterise all intermediates in order to
more fully elucidate the involved species and precise mechanism
of this reaction.
Koszinowski and Bohrer recently examined mixtures of
¨
organozinc(ate) species generated from either (i) LiCl-assisted
oxidative addition of Zn0 into organic halides19 or (ii) metathesis
17
Notes and references
between organolithium compounds and ZnCl2 in THF via
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ed. E.-i. Negishi, John Wiley & Sons, New York, 2002.
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A. Krasovskiy and P. Knochel, J. Am. Chem. Soc., 2007, 129,
12358–12359; (d) A. Metzger, M. Schade and P. Knochel,
Org. Lett., 2008, 10, 1107–1110.
mild anion-mode electrospray ionization (ESI) mass spectro-
metry. Analysis of a 1 : 1 mixÀture of nBuLi and ZnCl2 in THF
revealed mononuclear ZnCl3 and Zn(nBu)Cl2 Àspecies and
À
polynuclear Zn2(nBu)Cl4 and LiZn2(nBu2)Cl4 species iÀn
À
significant quantities, alongside smaller amounts of LiZnCl4
À
and LiZn(nBu)Cl3
. The latter species is analogous to
LimZn(nBu)Br3(2Àm)À, the intermediate we postulate is the
active transmetalating agent in the alkyl–alkyl Negishi cross-
coupling. Importantly, it is evident that complex equilibria are
operational, and that species comparable to those deduced by
Koszinowski and Bohrer are likely present in some relative
¨
6 A. Krasovskiy and P. Knochel, Angew. Chem., Int. Ed., 2004, 43,
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7 H. Ochiai, M. Jang, K. Hirano, H. Yorimitsu and K. Oshima,
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Approach, Oxford University Press, Oxford, 1999.
9 (a) R. D. Rieke, M. V. Hanson and J. D. Brown, J. Org. Chem.,
1996, 61, 2726–2730; (b) L. Zhu, R. M. Wehmeyer and
R. D. Rieke, J. Org. Chem., 1991, 56, 1445–1453.
stoichiometry in our system, notwithstanding the fact that the
solvent, concentration of species and the nature of the halide
affect the equilibria and, thus, the stoichiometry and aggregate
state of these organozinc(ate) complexes. Moreover, the
occurrence of LiZn(nBu)Cl3 in small amounts at a 1 : 1
À
stoichiometry of nBuLi : ZnCl2 is consistent with our finding that
the cross-coupling initiates at a similar ratio of LiBr : nBuZnBr.
Following the LiBr stoichiometry study, we opted to titrate
in various quantities of ZnBr2 to act as a sponge for LiBr
(Fig. 2), given that ZnBr2 is more Lewis-acidic than is
nBuZnBr. The ability of ZnBr2 to sequester bromide is
supported by observations by Anderson and Vicic wherein
ZnBr2 reacts with alkyl bromide complexes of Ni to generate
10 S. Huo, Org. Lett., 2003, 5, 423–425.
11 (a) Y. Kondo, M. Shilai, M. Uchiyama and T. Sakamoto, J. Am.
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10348–10356.
Ni cations and ZnBr3 salts.20 At various stoichiometries of
À
ZnBr2, LiBr is sequestered away to some proportion, leaving
fewer ‘‘effective equivalents’’ of LiBr in solution (Fig. 2, grey
circle data points). A very similar conversion vs. effective
equivalents of LiBr curve is produced relative to the one
wherein LiBr is successively added in the absence of exogenous
ZnBr2 (’ data points). This further supports our proposal
that as LiBr is removed from solution by ZnBr2 sponge, the
concentration of the active transmetalating species, that is
LimZnnBuBr3(2Àm)À, decreases and the reaction is switched off
below the 1.0 equiv. of effective LiBr threshold. To ensure that
ZnBr2 was not shutting down the catalytic cycle through other
means, an additional 2.0 equivalents of LiBr (total of 4.0
equiv. of LiBr, 1.0 equiv. of ZnBr2, 1.0 equiv. of nBuZnBr)
was utilized, and the catalysis was restored to provide 59%
conversion to 1-phenylheptane.
13 (a) N. Hadei, E. A. B. Kantchev, C. J. O’Brien and M. G. Organ,
Org. Lett., 2005, 7, 3805–3807; (b) N. Hadei, E. A. B. Kantchev,
C. J. O’Brien and M. G. Organ, J. Org. Chem., 2005, 70,
8503–8507.
14 M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev,
C. J. O’Brien and C. Valente, Chem.–Eur. J., 2006, 12, 4749–4755.
15 For reviews, see: (a) M. G. Organ, G. A. Chass, D.-C. Fang,
A. C. Hopkinson and C. Valente, Synthesis, 2008, 2776–2797;
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C. J. O’Brien and M. G. Organ, Aldrichimica Acta, 2006, 39,
97–111; (d) C. J. O’Brien, E. A. B. Kantchev, G. A. Chass,
N. Hadei, A. C. Hopkinson, M. G. Organ, D. H. Setiadi,
T.-H. Tang and D.-C. Fang, Tetrahedron, 2005, 61, 9723–9735.
16 A. E. Jensen and P. Knochel, J. Org. Chem., 2002, 67, 79–85.
In summary, we have carried out an additives study for the
alkyl–alkyl Negishi cross-coupling reaction catalyzed by a
NHC–Pd catalyst. Generally, it was found that bromide salts
tended to be superior to chloride and iodide salts, and that the
cation is mechanistically benign in this reaction. A double
titration study revealed that the cross-coupling becomes
operative when approximately 1.0 equivalents of LiBr
(relative to the organozinc reagent) is available, and
optimal when Z 1.4 equiv. is employed. This suggests that a
17 K. Koszinowski and P. Bohrer, Organometallics, 2009, 28,
771–779.
¨
18 (a) R. E. Mulvey, F. Mongin, M. Uchiyama and Y. Kondo,
Angew. Chem., Int. Ed., 2007, 46, 3802–3824; (b) R. E. Mulvey,
Acc. Chem. Res., 2009, 42, 743–755.
¨
19 K. Koszinowski and P. Bohrer, Organometallics, 2009, 28,
100–110.
20 T. J. Anderson and D. A. Vicic, Organometallics, 2004, 23,
623–625.
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Chem. Commun., 2010, 46, 4109–4111 | 4111