Improved air-stable solid aromatic and heterocyclic zinc reagents by highly selective metalations for negishi cross-couplings

Article abstract of DOI:10.1002/anie.201204526

Directed metalation using TMPMgCl·LiCl (TMP=2,2,6,6- tetramethylpiperidide) and subsequent transmetalation with Zn(OPiv)₂ leads to aryl and heteroaryl zinc pivalates. After solvent evaporation, easy-to-handle fine powders are obtained that reta

Full text of DOI:10.1002/anie.201204526

Angewandte
Chemie
DOI: 10.1002/anie.201204526
Organozinc Reagents
Improved Air-Stable Solid Aromatic and Heterocyclic Zinc Reagents
by Highly Selective Metalations for Negishi Cross-Couplings**
Christos I. Stathakis, Sebastian Bernhardt, Valentin Quint, and Paul Knochel*
Organozinc reagents constitute a very important class of
Table 1: Air stability of 4aa–4ae.
organometallic compounds,[1] which is mainly due to their
efficiency in cross-coupling reactions.[2] However, their broad
implementation in industrial laboratories is hampered by
their limited stability towards air and moisture. Responding
to the demand for more stable and easy-to-handle zinc
organometallics, we have recently described the preparation
1a
1b
1c
1d
1e
of the first solid salt-stabilized aryl, heteroaryl, and benzylic
zinc reagents of the general formula RZnOPiv·Mg-
(OPiv)X·2LiCl (X = Cl, Br, I; OPiv = pivalate).[3] These new
organozinc species, prepared by magnesium insertion on
halogenated precursors and in situ trapping of the Grignard
intermediates with Zn(OPiv)2·2LiCl (1a), exhibit excellent
reactivity in Negishi cross-coupling reactions and undergo
MgII-promoted additions to carbonyl compounds.[4]
X:
t[h]
in air
0
1
2
Remaining active arylzinc species 4aa–4ae [%][a]
100
83
59
41
>10
100
100
95
100
92
83
100
99
93
82
20
100
100
99
4
24
90
70
98
Although the aryl and heteroaryl halides used in the
preparation of the solid organozinc pivalates are readily
available, we envisioned preparing these organometallics by
directed metalation, which allows the use of various arenes
and heteroarenes as even more convenient starting materi-
als.[5,6] Furthermore, we were interested in enhancing the
stability of the solid zinc species, as currently these can only
be handled over a period of few minutes when exposed to air
without losing a substantial portion of their reactivity.[3]
Towards this aim, we envisioned that the nature of the
counterion could play an important role on the stabilization of
the arylzinc compound. Therefore, we have examined the
metalation of ethyl 3-fluorobenzoate (2a), using
TMPMgCl·LiCl (3; TMP = 2,2,6,6-tetramethylpiperidide,
1.1 equiv, THF, 08C, 2 h)[5] followed by transmetalation with
various ZnII salts as the model reaction (Table 1). First, we
tested Zn(OPiv)2·2LiCl (1a), and the resulting zinc com-
pound (4aa) was found to exhibit increased stability com-
pared to the organozinc pivalates prepared by magnesium
insertion (83% of its initial concentration was maintained
after 1 h of air exposure, while this percentage drops to 41%
after 4 h).[7] Several other ligands 1(b–e) were also tested
(Table 1).
24
>10
43
[a] The content of active zinc species was determined by iodometric
titration.[7]
Using Zn(OPiv)2 (1b) instead of Zn(OPiv)2·2LiCl (1a)[8]
for the transmetalation further improved the stability towards
hydrolysis and air oxidation. LiCl is known to be highly
hydrophilic and has a deleterious effect.[9] Thus, organozinc
compound 4ab was found now to maintain 90% of its initial
concentration after 4 h in air. Next, N-benzylalaninate (1c)
was examined. Despite the additional N-coordination, it
proved to be an inferior ligand (70% of the initial concen-
tration of 4ac remains after 4 h). Comparable with the
pivalate 4ab was also the stability profile of zinc reagent 4ad
obtained by using n-propyl pivalamide (1d). By increasing the
coordination sites on the ligand with an additional methoxy
group, as in N-(2-methoxyethyl) pivalamide (1e), a much
more robust compound 4ae was obtained, which preserved
almost all of its activity after 4 h in air, while even after 24 h,
a respectful amount of it (43%) was still active. When tested
for their reactivity in Negishi cross-couplings with ethyl 4-
iodobenzoate (5a), compounds 4aa–4ae delivered the
desired product 6a[10] in high yields (87–93%). For the sake
of simplicity, in addition to its low cost, we decided to focus
our studies on the LiCl-free Zn(OPiv)2 (1b), as the ligand of
choice.
[*] Dr. C. I. Stathakis, M. Sc. S. Bernhardt, B. Sc. V. Quint,
Prof. Dr. P. Knochel
Ludwig-Maximilians-Universitꢀt Mꢁnchen, Department Chemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Herein, we report the synthesis of various functionalized
solid aryl and heteroarylzinc pivalates (4a–m) by highly regio-
and chemoselective metalations of arenes and heteroarenes
(2) using TMPMgCl·LiCl (3),[5] followed by transmetalation
with Zn(OPiv)2 (1b; Scheme 1 and Table 2). All of them show
an excellent stability in air over time. As a general trend, the
[**] We thank the Fonds der Chemischen Industrie and the European
Research Council (ERC) for financial support. We also thank BASF
SE (Ludwigshafen) and Chemetall GmbH (Frankfurt) for the
generous gift of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204526.
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concentration of the new zinc reagents is preserved almost
entirely (> 94%) after 2 h of air exposure, while this
percentage remains greater than 85% even after 4 h in
air.[11] The aryl and heteroaryl zinc pivalates of type 4 proved
to be excellent nucleophiles in Negishi cross-couplings.
Thus, the zinc pivalate 4ab was prepared by metalation of
ethyl 3-fluorobenzoate (2a) with TMPMgCl·LiCl (3,
1.1 equiv, THF, 08C, 2 h) and subsequent transmetalation
with Zn(OPiv)2 (1b, 1.2 equiv, 0 to 258C, 15 min; Scheme 2).
After evaporation of the solvent in high vacuum (0.1 mm Hg,
Scheme 1. Preparation of solid air-stable zinc pivalates of type 4 by
selective metalation of arenes and heteroarenes 2. The solid zinc
reagents 4 contain also PivOMgCl and LiCl. FG=functional group.
Table 2: Negishi cross-coupling of various aryl and heteroaryl zinc pivalates 4b–k with a range of electrophiles.[12]
Entry Zinc Reagent
Electrophile[b]
Product
Yield
[%][c]
Entry Zinc Reagent
Electrophile[b]
Product
Yield
[%][c]
(T [8C], t)[a]
(T [8C], t)[a]
1
4b (0, 6 h)
5c
6c
76[f]
8
4h (25, 1 h)
5i
6j
78[f]
2
3
4b
5d
5e
6d
6e
71[f]
9
4i (À30, 30 min) 5j
6k
6l
97[d]
4c (0, 3 h)
79[e]
10
4i
5k
75[e]
4
5
4d (0, 3 h)
5 f
6 f
78[f]
11
12
4j (À25, 45 min) 5l
6m
6n
78[d]
4e (25, 15 min)
5g
6g
76[e]
4j
5m
99[d]
6
7
4 f (À40, 45 min)
4g (À45, 2 h)
5a
5h
6h
6i
90[d]
13
4k (25, 111h)
5e
6o
75[e]
89[d]
[a] Temperature [8C] and time used for the zinc pivalates preparation by metalation with 3. [b] 0.84 equiv of electrophile were used. [c] Yields refer to
analytically pure products. [d] 3% [Pd(dba)2], 6% TFP, THF, 258C. [e] 2% PEPPSI-iPr, THF, 508C. [f] 2% Pd(OAc)2, 4% X-Phos, THF, 508C.
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(entries 8–10). This Negishi cross-coupling is compatible with
the use of aryl bromide 5i, which bears an amidic acidic
proton, affording the amide 6j in 78% yield (entry 8).[16a] In
the same vein, the zinc pivalate of ethyl 5-bromofuranoate 4j
was coupled under mild conditions (258C, 2 h) with iodide 5l,
which bears a free amine (entry 11).[16b] The isoquinolylzinc
pivalate 4k,[5a] prepared by magnesiation at 258C for 1 h and
addition of Zn(OPiv)2 (1b), efficiently participated in
PEPPSI-iPr[14] catalyzed cross-coupling with bromide 5e,
affording compound 6o in 75% yield (entry 13).
The zinc pivalates were also able to couple with excep-
tional efficiency with sterically hindered aromatic halides. For
instance, 2,4-dimethoxypyrimidine derived zinc pivalate 4e
reacted with 2-bromo-meta-xylene (5n) in the presence of 2%
PEPPSI-iPr as the catalyst to deliver the cross-coupling
product 6p in 84% yield, after heating at 508C for 2 h
(Scheme 3). Furthermore, an alkenyl iodide, such as the E-
iodoalcohol derivative 5o,[17] undergoes a fast coupling with
Scheme 2. Preparation of zinc pivalate 4ab and Negishi cross-coupling
with aryl chloride 5b, using Pd(OAc)2/X-Phos as the catalyst.
3 h), the solid arylzinc pivalate, which contains also Piv-
OMgCl and LiCl, was obtained as a yellow fine powder in
92% yield, as determined by iodometric titration.[7] If this
powder is exposed to air for 4 h, 90% of its concentration in
active zinc species is preserved. Furthermore, this zinc
reagent is stable for, at least, several weeks under argon or
nitrogen in a closed vial. Redissolution of the solid zinc
compound 4ab in dry THF (0.5m), followed by addition of
2% Pd(OAc)2 and 4% X-Phos[13] and subsequently 4-
chlorobenzophenone (5b, 0.84 equiv), led to biphenyl 6b in
84% yield (calculated based on the electrophile amount)
after heating at 508C for 12 h (Scheme 2).
This air stability and cross-coupling behavior was general
for a range of aromatic and heteroaromatic substrates (see
Table 2). Whereas Pd(OAc)2/X-Phos[13] or either PEPPSI-
iPr[14] proved to be excellent catalytic systems for the cross-
coupling of unsaturated chlorides and bromides, [Pd(dba)2]/
TFP (dba = dibenzylideneacetone, TFP = tri-o-furylphos-
phine)[15] was found to be the best catalyst when iodides
were utilized as the electrophilic component.
Scheme 3. Negishi cross-coupling of zinc pivalates 4e and 4l with the
sterically hindered bromide 5n and alkenyl iodide 5o. TIPS=triisopro-
pylsilyl, Tos=tosyl.
The scope and limitations of the solid zinc pivalates (4b–
k) reactivity in Negishi cross-couplings with various aryl and
heteroaryl halides is described in Table 2. Aromatic com-
pounds bearing an ester, a Boc protected phenol,[5b] or
a phosphoramidate directing group[5f] were readily magnesi-
ated with TMPMgCl·LiCl (3, 1.1 equiv, 08C, 2–6 h). After
transmetalation with Zn(OPiv)2 (1b, 1.2 equiv), Pd-catalyzed
cross-coupling with functionalized aryl and heteroaryl bro-
mides (5c–f) proceeded in 71–79% yields (entries 1–4).
Similarly, pyrimidines were efficiently employed in the
directed metalation/cross-coupling sequence. The zinc piva-
late of 2,4-dimethoxypyrimidine 4e,[5e] smoothly reacted with
3-bromonitrobenzene (5g) to deliver the coupling product 6g
in 76% yield after heating for 2 h at 508C (entry 5).
Furthermore, the ester-substituted pyrimidylzinc pivalate 4 f
was coupled with iodide 5a (258C, 2 h) in the presence of
catalytic amounts of [Pd(dba)2]/TFP[15] to afford the coupling
product 6h in 90% yield (entry 6). The zincated dichloropyr-
azine 4g[5g] was arylated under the same conditions with 2-
iodotoluene (5h) to provide the diazine 6i in 89% yield
(entry 7). Correspondingly, the zinc pivalates of five-mem-
bered nitrogen heterocycles such as pyrazoles 4h and 4i,[5c]
were subjected to coupling with aryl iodides and bromides
the indolylzinc pivalate (4l), prepared by metalation of the
corresponding protected indole with TMPMgCl·LiCl (3,
258C, 45 min) and transmetalation with Zn(OPiv)2 (1b), to
furnish the E-alkenylated indole 6q in 95% yield and
complete retention of the double-bond configuration.
In accordance to our previous observations,[3] zinc piv-
alates prepared by metalation of arenes and heteroarenes also
demonstrate similar or even improved reactivity in Negishi
cross-couplings compared to standard zinc reagents RZnX
(X = halide). Thus, the Pd-catalyzed cross-coupling of 2,6-
dichloropurinylzinc pivalate (4m) with 4-iodoanisole (5p)
was accomplished at 258C within 12 h in 81% yield, while the
corresponding organozinc chloride 4n required 24 h for
completion and afforded the coupling product 6r in signifi-
cantly lower yield (62%; Scheme 4).[18]
Interestingly, the cross-coupling reactions can be per-
formed with comparable efficiency using technical-grade
THF in air.[19] Whereas the cross-coupling of pyrazolylzinc
pivalate 4h with iodide 5a proceeded under argon and dry
THF (258C, 2 h), affording the product 6s in 91% yield, the
use of technical-grade THF in an open flask led to 6s with
only a minor yield decrement (85%). A similar tendency was
noted even when higher reaction temperatures were required,
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O. Baron, P. Knochel, Org. Lett. 2006, 8, 5673; c) C. Despot-
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Scheme 4. Comparison of the reactivity of 2,6-dichloropurinylzinc piv-
alate 4m and the corresponding zinc chloride 4n in Negishi cross-
coupling with 4-iodoanisole 5p. MOM=methoxymethyl.
as in the coupling of 4h with 5-bromo-2-chloropyridine (5q),
which was conducted at 508C (the yield for 6t drops only from
87 to 81%; Scheme 5).
3326; d) T. Kunz, P. Knochel, Chem. Eur. J. 2011, 17,
866; e) M. Mosrin, N. Boudet, P. Knochel, Org.
Biomol. Chem. 2008, 6, 3237; f) C. J. Rohbogner,
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1526; Angew. Chem. Int. Ed. 2008, 47, 1503; g) M.
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5582; Angew. Chem. Int. Ed. 2010, 49, 5451.
[6] For a recent review on regio- and chemoselective
metalation of arenes and heteroarenes, see: B. Haag,
In summary, we have prepared a pool of new solid
organozinc pivalates by regio- and chemoselective metalation
of various arenes and heterocycles using TMPMgCl·LiCl (3),
M. Mosrin, I. Hiriyakkanavar, V. Malakhov, P. Knochel, Angew.
Chem. 2011, 123, 9968; Angew. Chem. Int. Ed. 2011, 50, 9794.
[7] For a titration method of zinc organometallics, see: A. Krasov-
skiy, P. Knochel, Synthesis 2006, 890. As LiCl is already
embedded in the organozinc materials, neat THF instead of
a 0.5m solution of LiCl in THF can be used as the titration
medium; see the Supporting Information.
[8] LiCl is required for the complete dissolution of Zn(OPiv)2 in
THF, which was essential for the preparation of zinc organo-
metallics by Mg insertion into aryl halides in high yields.
[9] Despite its high hydrophilicity, the presence of 1.1 equiv of LiCl
in the crude solid organozinc material was unavoidable, as LiCl
is essential for the highly kinetic basicity of 3.
followed by transmetalation with Zn(OPiv)2 (1b). The air
stability of these new zinc organometallics was substantially
superior compared to the zinc pivalates prepared by magne-
sium insertion previously described in our laboratory. Fur-
thermore, they exhibit excellent reactivity in Negishi cross-
coupling reactions with a broad selection of electrophiles. The
new, easy-to-handle organozinc pivalates can be regarded as
potential building blocks for basic research and industrial
applications. Further investigations of their properties and
reactivity are currently in progress in our laboratory.
[10] The Negishi cross-coupling of arylzinc species 4aa–ae with ethyl
4-iodobenzoate (5a) was performed at 258C using [Pd(dba)2]/
TFP as the catalyst (dba = dibenzylideneacetone, TFP = tri-o-
furylphosphine):
Received: June 11, 2012
Published online: && &&, &&&&
Keywords: cross-coupling · heterocycles · metalation ·
.
organozinc reagents · palladium
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[19] Technical-grade THF was purchased from AppliChem. with
a purity of > 98%, while the water content was < 0.5%.
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Communications
Organozinc Reagents
C. I. Stathakis, S. Bernhardt, V. Quint,
P. Knochel*
&&&& — &&&&
Improved Air-Stable Solid Aromatic and
Heterocyclic Zinc Reagents by Highly
Selective Metalations for Negishi Cross-
Couplings
Directed metalation using TMPMgCl·LiCl
(TMP=2,2,6,6-tetramethylpiperidide)
and subsequent transmetalation with
Zn(OPiv)2 leads to aryl and heteroaryl
zinc pivalates. After solvent evaporation,
easy-to-handle fine powders are obtained
that retain most of their activity (>85%)
when exposed to air for 4 h. They undergo
smoothly Negishi cross-couplings, and
technical-grade solvents can be used
without significant loss of yield.
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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