Preparation of solid salt-stabilized functionalized organozinc compounds and their application to cross-coupling and carbonyl addition reactions

Article abstract of DOI:10.1002/anie.201104291

Powdered organozinc reagents: Various aryl and heteroaryl bromides as well as benzylic chlorides react with Mg and Zn(OPiv)₂·2 LiCl (OPiv=pivalate) to provide solid organozinc reagents after solvent evaporation. These powders can be stored at room temperature under argon for months and can be manipulated in air for a short time. They undergo smooth Negishi cross-coupling and carbonyl addition reactions (see scheme). Copyright

Full text of DOI:10.1002/anie.201104291

DOI: 10.1002/anie.201104291
Organozinc Reagents
Preparation of Solid Salt-Stabilized Functionalized Organozinc
Compounds and their Application to Cross-Coupling and Carbonyl
Addition Reactions**
Sebastian Bernhardt, Georg Manolikakes, Thomas Kunz, and Paul Knochel*
Organozinc reagents have found numerous synthetic appli-
cations, especially in the Negishi cross-coupling reaction.[1,2]
Various methods for the preparation of organozinc com-
pounds have been reported.[3] However, polyfunctional zinc
reagents of type RZnX (X = halide)[4] or R2Zn are highly
sensitive to moisture and air. These properties represent a
serious drawback for their practical use in the laboratory and
on an industrial scale. Thus, the availability of more easy to
handle organozinc compounds is highly desirable. Since their
reactivity is strongly influenced by the presence of salts,[5] we
anticipated that the presence of appropriate metallic salts
may lead to an improved stability towards air and water.
Charette et al. have already demonstrated that alkoxides
greatly stabilize zinc carbenoids for enantioselective cyclo-
propanations.[6] Furthermore, Herrmann et al. reported that
methylzinc acetate can be efficiently used for the synthesis of
methyltrioxorhenium (MTO), even on large scales.[7]
acceleration is essential for tolerating sensitive functional
groups. This route is widely applicable and after evaporation
of the THF, the resulting solid arylzinc reagents are obtained
in 57–84% yield as easy to handle powders (Scheme 1). This
is in contrast to regular zinc reagents which produce only
highly viscous oils when the solvents are evaporated.
Herein, we report the preparation of solid salt-stabilized
functionalized aryl, heteroaryl, and benzylic zinc reagents of
the general formula RZnOPiv·Mg(OPiv)(X)·2LiCl (X = Cl,
Br, or I; OPiv = pivalate; abbreviated RZnOPiv for clarity).
These new zinc reagents are readily prepared by a one-pot
synthesis in which the organic halide (RX; X = Cl, Br) is
treated with magnesium turnings (2.5 equiv)[8] and the THF-
soluble salt Zn(OPiv)2·2LiCl[9] (2; 1.5 equiv). Under these
conditions, the formation of the zinc reagent is observed at
258C within 2 h.[10] The presence of Zn(OPiv)2·2LiCl (2) not
only stabilizes the resulting zinc reagent, but also accelerates
its formation dramatically. Whereas 4-bromo-1,2-dimethyl-
benzene (1a) requires 2 h in the presence of Mg/
ZnCl2·2LiCl,[8] the insertion reaction is complete within
20 min when using the combination Mg/Zn(OPiv)2·2LiCl
(2). After evaporation of the solvent, the corresponding solid
organozinc pivalate 3a is obtained in 77% yield.[11] This rate
Scheme 1. Preparation of solid functionalized arylzinc pivalates of type
3 from the corresponding aromatic bromides of type 1 by using Mg
and Zn(OPiv)2·2LiCl (2). [a] Complexed Mg(OPiv)X (X=Br, I) and LiCl
are omitted for clarity. [b] Prepared by I/Mg or Br/Mg exchange with
iPrMgCl·LiCl and transmetalation with Zn(OPiv)2·2LiCl (2). TIPS=tri-
isopropylsilyl, TMS=trimethylsilyl.
By using this method we have prepared a range of arylzinc
reagents bearing electron-donating substituents (3a–f; FG =
Me, OMe, SMe, OTIPS, TMS, OCONEt2; 57–81%) or
electron-deficient substituents (3g–j; FG = F, CF3, CO2Et,
CN; 59–84%; Scheme 1). Although the ester- and nitrile-
substituted zinc reagents 3i and 3j can be prepared in
satisfactory yields (59–64%) by direct insertion, an improve-
ment has been achieved by using an I/Mg or Br/Mg exchange
with iPrMgCl·LiCl followed by transmetalation with
Zn(OPiv)2·2LiCl (2; 72–89%).[12]
Moreover, the solid zinc reagents of type 3 are stable
under argon at room temperature for several months without
significant loss of activity. Importantly, these zinc compounds
can now be weighed in air (95% of the active zinc species 3h
is titrated after 5 min in air). Some decomposition is observed
after longer exposure to air (66% of the active zinc species 3h
still remains after 15 min).
[*] MSc. S. Bernhardt, MSc. T. Kunz, 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
Dr. G. Manolikakes
Johann Wolfgang Goethe-Universitꢀt Frankfurt
Institut fꢁr Organische Chemie und Chemische Biologie
Max-von-Laue-Strasse 7, 60438 Frankfurt am Main (Germany)
[**] We thank the Fonds der Chemischen Industrie and the European
Research Council (ERC) for financial support. We also thank
BASF AG (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.201104291.
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9205

Communications
Table 1: PEPPSI-iPr-catalyzed cross-coupling of aromatic organozinc
pivalates of type 3 in THF (or AcOEt) within 2 h at 258C.
The organozinc compounds of type 3 undergo Negishi
cross-coupling reactions under similarly mild conditions as
the standard zinc reagents RZnX (X = halide) by using 2%
PEPPSI-iPr[13] as the catalyst. Thus, the reaction of a solution
of the arylzinc pivalate 3i in THF with the pyridyl chloride 4a
at 258C leads to the desired cross-coupling product 5a in 84%
yield within 2 h.
Interestingly, these cross-coupling reactions can be per-
formed in various solvents. Hence, the coupling of organozinc
pivalate 3i with the chloropyridine 4a in technical grade ethyl
acetate[14] as the solvent provides the biphenyl 5a in 96%
yield. Although aryl bromides bearing relatively acidic
protons, such as, for example, on an amide function, are
suitable for Negishi cross-coupling reactions, a slow addition
of the zinc reagent over 90 min was usually required.[15]
However, the use of arylzinc pivalates such as 3i combined
with PEPPSI-iPr[13] as the catalyst allows the bromobenza-
mide 4b to be added at once without special precautions, and
leads within 2 h at 258C to the biphenyl 5b in 87% yield
(Scheme 2).
Entry
Arylzinc
reagent
Electrophile[a]
Product
yield [%][b]
1
2
3b
3b
4c
4d
5c: 86
5d: 67
3
3c
4e
5e: 88
4
5
3d
3e
4 f[c]
4g
5 f: 89
5g: 83
6
7
3 f
4h
4i
5h: 80
5i: 80
3g
Scheme 2. PEPPSI-iPr-catalyzed one-pot cross-coupling of organozinc
reagents of type 3 in THF or AcOEt.
8
3g
4j
5j: 79
The scope of Negishi cross-coupling reactions with
arylzinc pivalates 3b–j and functionalized aryl bromides or
chlorides as well as heteroaryl bromides is very broad
(Table 1). The generally fast reactions (2 h) were performed
at 258C[16] and the expected products were obtained in high
yields (67–99%). The presence of an unprotected amine
function in the aryl bromides is well tolerated (Table 1,
entries 8 and 12). Chloro- and bromoacetophenones 4d and
4g also react in satisfactory yields (67–83%; Table 1, entries 2
and 5). No appreciable enolization of the acetyl function
could be detected and thus no excess of the organozinc
reagents is required.
9
3g
3h
4k
4l
5k: 99
5l: 78
10
11
3i
4m
5m: 91
(99%)[d]
Similarly, we have prepared a range of heteroaromatic
À
zinc pivalates starting from heterocyclic bromides (HetAr
12
13
3i
3j
4n
4o
5n: 69
Br) of type 6. The solid organozinc pivalates 7a–d were
obtained in 64–71% yield under mild conditions (258C, 2 h,
Scheme 3). The pyrazoylzinc pivalate 7e was prepared from
the corresponding heteroaryl chloride in a moderate yield
(50%).
5o: 94[d]
Furthermore, the method was also applicable to the
synthesis of various benzylic zinc pivalates of type 9 by using
benzylic chlorides of type 8. The insertion with Mg/Zn-
(OPiv)2·2LiCl (2) proceeded well at 258C within 2 h, and the
solid organozinc compounds 9a–e were obtained in 67–80%
yield after evaporation of the solvent (Scheme 4).[17]
14
3j
4k
5p: 88
[a] 0.84 equiv of electrophile was used. [b] Yield of isolated analytically
pure product. [c] The cross-coupling was perfomed at 508C. [d] The
cross-coupling was performed in AcOEt.
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Table 2: PEPPSI-iPr-catalyzed cross-coupling of heteroaromatic and
benzylic organozinc pivalates of type 7 and 9 in THF in 2 h at 258C.
Entry
Zinc
reagent
Electrophile[a]
Product
Yield [%][b]
1
2
3
7a
7b
7b
4a
4p
4q
10a: 91
10b: 80
10c: 71
Scheme 3. Preparation of solid functionalized heteroaromatic zinc
pivalates of type 7 from the corresponding heteroaromatic bromides 6.
[a] Complexed Mg(OPiv)X (X=Br, Cl) and LiCl are omitted for clarity.
[b] Prepared from 5-chloro-3-methyl-1-phenyl-1H-pyrazole.
4
5
7c
7d
4b
10d: 84
10e: 99
4 f[c]
6
7
8
7e
9a
9b
4 f[c]
4r
10 f: 98
11a: 81
11b: 70
Scheme 4. Preparation of solid functionalized benzylic zinc pivalates of
type 9 from the corresponding benzylic chlorides 8. [a] Complexed
Mg(OPiv)Cl and LiCl are omitted for clarity.
4c
The heteroaromatic zinc pivalates (7a–c) and the benzylic
zinc pivalates (9a–d) also react with various heteroaryl
halides and aryl bromides in high yields (66–91%, Table 2)
under mild conditions (258C, 2 h) and PEPPSI-iPr catalysis
(2%). The reaction temperature had to be increased to 508C
for the isoxazolyl- and pyrazolylzinc pivalates 7d and 7e to
obtain full conversion with the bromobenzonitrile 4 f
(Table 2, entries 5 and 6). Electrophiles bearing functional-
ities with acidic protons such as the amide 4b, the phenyl-
acetonitrile 4r, and the benzocaine derivative 4n were also
used in the cross-coupling reactions under our standard
conditions (Table 2, entries 4, 7, and 10).
9
9c
4m
11c: 86
10
11
9c
9d
4n
4s
11d: 66
11e: 85
Recently, we have shown that MgCl2 greatly enhances the
reactivity of organozinc reagents towards carbonyl deriva-
tives.[5i] In fact both MgCl2 and LiCl[18] increase the intrinsic
reactivity of organozinc reagents by boosting their nucleo-
philicity as well as the electrophilicity of the carbonyl
compound (Lewis acid activation).[19]
Such activation is also observed for arylzinc pivalates of
type 3. Thus, the reaction of the arylzinc pivalate 3b with 2-
bromobenzaldehyde (4t) produces rapidly the benzhydryl
alcohol 12a in 72% yield as a consequence of the presence of
additional magnesium salts in reagent 3b. This salt effect can
be overcome by the addition of the powerful Pd catalyst
[a] 0.84 equiv of electrophile was used. [b] Yield of isolated analytically
pure product. [c] The cross-coupling was performed at 508C.
PEPPSI-iPr (2%) which leaves the formyl group of 4t
untouched and provides the Negishi cross-coupling product
5q in 82% yield (Scheme 5).
This behavior has some generality and the reaction of a
benzylic zinc pivalate such as 9e with 4-chlorobenzophenone
(4s) produces, without additional catalyst, the tertiary alcohol
12b in 80% yield in THF. However, the addition of 2%
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Scheme 5. Tuneable reactivity of organozinc compounds of type 3 and
9 by the presence or absence of PEPPSI-iPr.
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[9] Zn(OPiv)2·2LiCl (2) is prepared by treating pivalic acid with
MeLi in THF and subsequent addition of ZnCl2 (0.5 equiv).
Although Zn(OPiv)2 is only moderately soluble in THF, the
presence of LiCl allows the preparation of 0.5–1.0m solutions in
THF; see the Supporting Information.
PEPPSI-iPr leads to the cross-coupled benzophenone deriv-
ative 11 f as the sole product in 73% yield in THF. Repeating
the reaction in AcOEt led to an improved yield of 93%.
In summary, we have prepared solid salt-stabilized aryl,
heteroaryl, and benzylic zinc pivalates from the correspond-
ing aryl- and heteroraryl bromides as well as benzylic
chlorides. These new organozinc pivalates are readily avail-
able in a one-pot procedure under mild conditions by using
Mg and Zn(OPiv)2·2LiCl. After evaporation of the solvent,
they are obtained as easy to handle powders and even a short
manipulation in air is possible. These reagents show an
excellent reactivity in Negishi cross-coupling reactions and
undergo smooth carbonyl additions. Further applications are
currently underway in our laboratory.
[10] A patent application has been filed.
[11] The content of active zinc species was determined by titration
with a 1.0m solution of iodine in THF.
[12] Ethyl 4-iodobenzoate and 4-bromobenzonitrile were used as
starting materials for the halogen – magnesium exchange with
iPrMgCl·LiCl, see A. Krasovskiy, P. Knochel, Angew. Chem.
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[14] Ethyl acetate was purchased from Sigma–Aldrich with a purity
of 99%, and was used without drying or distillation prior to use.
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Received: June 21, 2011
Published online: August 24, 2011
Keywords: carbonyl addition · cross-coupling · Lewis acids ·
.
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[16] Only the cross-coupling of 4-TIPSO-phenylzinc pivalate (3d)
with 4-bromo-3-fluorobenzonitrile (4 f) had to be performed at
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[17] We noticed that the solid benzylic zinc pivalate 9e displays a
slightly lower stability in air compared to the corresponding aryl-
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