TMPZnOPiv?LiCl: A new base for the preparation of air-stable solid zinc pivalates of sensitive aromatics and heteroaromatics

Article abstract of DOI:10.1021/ol400242r

A wide range of aryl and heteroaryl zinc pivalates bearing sensitive functionalities were prepared by selective metalation using TMPZnOPiv?LiCl, a new hindered zinc amide base. The new zinc reagents are easy-to-handle solids, which maintain their activity almost entirely (>95%) after 4 h of air exposure and smoothly undergo Negishi cross-couplings and reactions with various electrophiles such as Cu(I)-catalyzed acylations and allylations.

Full text of DOI:10.1021/ol400242r

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1302–1305
TMPZnOPiv•LiCl: A New Base for the
Preparation of Air-Stable Solid Zinc
Pivalates of Sensitive Aromatics and
Heteroaromatics
Christos I. Stathakis, Sophia M. Manolikakes, and Paul Knochel*
€
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13,
€
81377 Mu€nchen, Germany
Paul.Knochel@cup.uni-muenchen.de
Received January 28, 2013
ABSTRACT
A wide range of aryl and heteroaryl zinc pivalates bearing sensitive functionalities were prepared by selective metalation using TMPZnOPiv•LiCl, a
new hindered zinc amide base. The new zinc reagents are easy-to-handle solids, which maintain their activity almost entirely (>95%) after 4 h of air
exposure and smoothly undergo Negishi cross-couplings and reactions with various electrophiles such as Cu(I)-catalyzed acylations and allylations.
Organozinc reagents hold a special position among
other organometallics due to their compatibility with a
wide range of sensitive functional groups.1 In addition,
they have proven to be valuable synthetic tools in CÀC
bond formation reactions, via transition-metal catalyzed
transformations.2 A major drawback is their lability when
exposed to air and the pyrophoric properties of some of
their low molecular weight members. To tackle this prob-
lem, we have recently described the preparation of aryl
and heteroaryl zinc pivalates which are easy-to-handle
solids with exceptional stability when exposed to air.3
These zinc reagents have been prepared via either
(1, TMP = 2,2,6,6-tetramethylpiperidyl) and subsequent
transmetalation to Zn(OPiv)2.3b However, none of the
above methods can be applied efficiently when sensitive
functionalities, such as an aldehyde, a nitro group, or other
electron-withdrawing groups, are present.
To overcome this limitation, we envisioned the use of a
milder zinc amide base. The latter are known to provide
zinc reagents which are compatible with most functional-
ities. In his pioneering work, Kondo introduced lithium di-
tert-butyl-tetramethylpiperidino zincate (t-Bu2Zn(TMP)Li)
as an excellent base for the directed metalation of aro-
matics.4 Since then, other zincates and related ate bases
have been reported.5 We have also described the
Mg insertion in the presence of Zn(OPiv)2 2LiCl3a
3
or directed metalation using TMPMgCl LiCl
3
(4) (a) Kondo, Y.; Shilai, H.; Uchiyama, M.; Sakamoto, T. J. Am.
Chem. Soc. 1999, 121, 3539. (b) Imahori, T.; Uchiyama, M.; Kondo, Y.
Chem. Commun. 2001, 2450. (c) Schwab, P. F. H.; Fleischer, F.; Michl, J.
J. Org. Chem. 2002, 67, 443. (d) Uchiyama, M.; Miyoshi, T.; Kajihara,
Y.; Sakamoto, T.; Otami, Y.; Ohwada, T.; Kondo, Y. J. Am. Chem. Soc.
2002, 124, 8514.
(5) (a) Uchiyama, M.; Matsumoto, Y.; Nobuto, D.; Furuyama, T.;
Yamaguchi, K.; Morokuma, K. J. Am. Chem. Soc. 2006, 128, 8748. (b)
Clegg, W.; Dale, S. H.; Drummond, A. M.; Hevia, E.; Honeyman,
G. W.; Mulvey, R. E. J. Am. Chem. Soc. 2006, 128, 7434. (c) Hevia, E.;
Honeyman, G. W.; Mulvey, R. E. J. Am. Chem. Soc. 2005, 127, 13106.
(d) Armstrong, D. R.; Clegg, W.; Dale, S. H.; Hevia, E.; Hogg, L. M.;
Honeyman, G. W.; Mulvey, R. E. Angew. Chem., Int. Ed. 2006, 45, 3775.
(1) (a) Knochel, P.; Almena, J.; Jones, P. Tetrahedron 1998, 54, 8275.
(b) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int.
Ed. 2000, 39, 4115. (c) Knochel, P.; Leuser, H.; Cong, L.-Z.; Perrone, S.;
Kneisel, F. F. Handbook of Functionalized Organometallics; Knochel, P.,
Ed.; Wiley-VCH: Weinheim, Germany, 2005; p 251.
(2) (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2390. (b) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93,
2117. (c) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (d) Erdik, E. Tetrahedron 1992, 48, 9577.
(3) (a) Bernhardt, S.; Manolikakes, G.; Kunz, T.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 9205. (b) Stathakis, C. I.; Bernhardt, S.; Quint,
V.; Knochel, P. Angew. Chem., Int. Ed. 2012, 51, 9428.
r
10.1021/ol400242r
Published on Web 03/05/2013
2013 American Chemical Society

preparation of TMP2Zn 2MgCl2 2LiCl (2)6 and TMP-
THF, 25 °C, 30 min), and the corresponding zinc pivalate
(6a) was formed in 78% yield (Scheme 2). After evapora-
tion of the solvent under high vacuum, a fine powder was
obtained which was left in a vial open to air. The content of
the active zinc species was determined after different
periods of air exposure, and it was found that after 2 h
the entire content was still active (>99%) while after 4 h
this percentage was 96%. A number of other substrates
were examined and found to follow the same trend.9
3
3
ZnCl LiCl (3)7 as two highly chemoselective bases for the
3
metalation of sensitive aromatics and heterocycles.
Herein we wish to report the preparation of a new base
tentatively written as TMPZnOPiv Mg(OPiv)Cl LiCl (4)8
3
3
which is compatible with functionalities such as a nitro
group, an aldehyde, or sensitive heteroaromatic rings. In
addition, we show that the new base 4 provides a fast and
efficient access, after removal of the solvent, to solid zinc
pivalates, which exhibit significant tolerance toward
hydrolysis or oxidation after air exposure.
TMPZnOPiv LiCl (4, Mg(OPiv)Cl is omitted for
3
Scheme 2. Preparation of 5-(4,6-Dichloropyrimidinyl)zinc
Pivalate (6a) by Metalation of 4,6-Dichloropyrimidine (5a)
with TMPZnOPiv LiCl (4) and Reactivity towards Various
clarity) is prepared by the addition of solid Zn(OPiv)2
(1.05 equiv, 0 °C) to a solution of TMPMgCl LiCl (1, 1.23M
in THF) and subsequent dilution with dry THF until a
clear solution arises (final concentration: 0.85 M; Scheme 1).
3
3
Electrophiles
Scheme 1. Preparation of the New Zinc Amide Base
TMPZnOPiv LiCl (4) from TMPMgCl LiCl (1)
3
3
The new zinc amide base (4) was tested for the metala-
tion of a broad range of aromatic and heterocyclic sub-
strates bearing sensitive functionalities and of hetero-
aromatics prone to fragmentation. In most cases, the
metalation proceeded with excellent regio- and chemos-
electivity, in short reaction times (<2 h), using 1.1 to 2.0
equiv of the base at 25 °C or by mild heating at 50 °C. After
removal of the solvent under high vacuum (0.1 mmHg,
3 h), a fine powder was obtained which was exposed to air
in order to determine the stability of the zinc reagents.9 The
vast majority of the organozinc pivalates tested exhibited
exceptional air stability (>95% activity after 4 h of air
exposure), which compared favorably with the stability of
Next, the reactivity of the zinc pivalate of 4,6-dichloro-
pyrimidine (6a) toward various electrophiles was ex-
plored. Therefore, the organozinc pivalate 6a was sub-
jected to a Negishi cross-coupling2c,10 with 4-iodothioanisole
7a using Pd(dba)2/TFP (dba = dibenzylideneacetone,
TFP = tri-o-furylphosphine)11 as the catalytic system
(Scheme 2). The coupling product 8a was obtained in
91% isolated yield. When the zinc compound 6a was
thezincpivalatespreparedbymetalationwithTMPMgCl
3
LiCl (1, > 85% activity after 4 h in air).3b
Thus, 4,6-dichloropyrimidine (5a) was metalated selec-
tively at position 5 using TMPZnOPiv LiCl (4, 1.1 equiv,
3
transmetalated with CuCN 2LiCl (1.1 equiv, À20 °C)
3
(6) (a) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007,
46, 7685. (b) Wunderlich, S. H.; Knochel, P. Org. Lett. 2008, 10, 4705. (c)
Mosrin, M.; Knochel, P. Chem.;Eur. J. 2009, 15, 1468.
(7) (a) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837. (b) Mosrin,
M.; Monzon, G.; Bresser, T.; Knochel, P. Chem. Commun. 2009, 5615.
(c) Bresser, T.; Mosrin, M.; Monzon, G.; Knochel, P. J. Org. Chem.
2010, 75, 4686. (d) Bresser, T.; Knochel, P. Angew. Chem., Int. Ed. 2011,
50, 1914. (e) Duez, S.; Steib, A.; Manolikakes, S. M.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 7686.
and then reacted with 2-furoyl chloride (7b), the acylated
pyrimidine 8b was isolated in 96% yield. Finally, the
allylation of 6a with allyl bromide (7c) was readily
performed, in the presence of catalytic amounts of
CuCN 2LiCl (5 mol %), to furnish the substituted pyr-
3
imidine 8c in 88% yield (Scheme 2). Comparison with
(8) The somewhat lower reactivity of the new base 4 compared to
TMPZnCl LiCl (3) led us to prefer the formula TMPZnOPiv
Mg(OPiv)Cl LiCl rather than TMPZnCl Mg(OPiv)2 LiCl.
(9) Typical titration via iodolysis was not possible for most of the
solid zinc pivalates due to their deep redish or brownish color. In these
cases the content of active zinc species was determined by GC analysis
and calculation of the iodinated compound derived by iodolysis of a
certain amount of zinc pivalate, based on a calibration curve using an
external standard. See Supporting Information.
(10) (a) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977,
42, 1821. (b) Wang, G.; Yin, N.; Negishi, E. Chem.;Eur. J. 2011, 17,
4118. (d) Negishi, E.; Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.; Huang, Z.
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 815.
(11) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(b) Klement, I.; Rottlander, M.; Tucker, C. E.; Majid, T. N.; Knochel,
P.; Venegas, P.; Cahiez, G. Tetrahedron 1996, 52, 7201.
3
3
3
3
3
Org. Lett., Vol. 15, No. 6, 2013
1303

Table 1. Transition-Metal Catalyzed Reactions of Zinc Pivalates 6bÀh with Various Electrophiles
a Temperature and reaction time for the metalation of 5bÀg with TMPZnOPiv LiCl (4). Unless otherwise stated the reaction was performed in THF
3
(0.5 M) using 1.1 equiv of the base. b Isolated yield. c 2.0 equiv of the base were used.
previous preparations of compounds 8b and 8c using the
corresponding heteroarylzinc chloride (prepared by meta-
Thus, 2,4-difluoro-1-nitrobenzene (5c) was readily zinc-
ated with TMPZnOPiv LiCl (4, 1.1 equiv, THF, 25 °C,
3
lation with TMPZnCl LiCl, 3) revealed comparable or
3
45 min) leading to the organozinc pivalate 6c in 83%
yield.7a The latter was subjected to cross-coupling with
the aryl iodide 7e or was trapped with either I2 or benzoyl
even improved yields (in the case of 8b).7a
A broad selection of other zinc pivalates was prepared
by metalation with TMPZnOPiv LiCl (4), and their re-
chloride (after transmetalation with CuCN 2LiCl) to
3
3
activity in transition-metal catalyzed transformations with
a range of electrophiles is presented (Table 1).
5-Bromo-2,4-dimethoxypyrimidine (5b) was success-
provide the expected products 8fÀh in 59À98% yield
(entries 3À5). In the same manner, 3-(2-ethoxycarbonyl-
5-nitrofuranyl)zinc pivalate (6d) was prepared with excel-
lent regioselectivity (>98:2) using 2.0 equiv of the base 4
(À10 °C, 1 h). The zinc compound 6d underwent smoothly
Negishi cross-coupling with aryl iodide 7h and allylation
with 3-bromocyclohexene (in the presence of 10 mol %
fully zincated using TMPZnOPiv LiCl (4, 1.1 equiv,
3
THF, 25 °C, 3 h) at the position R to the halogen leaving
group providing a stable pyrimidylzinc pivalate (6b), which
afforded the Negishi cross-coupling product 8d in 81%
yield (entry 1). The allylation of 6b with 3-bromocyclo-
CuCN 2LiCl) in66% and 70% yields, respectively (entries
3
hexene, after addition of CuCN 2LiCl (10 mol %), was
accomplished in 89% yield (entry 2).
6 and 7). Metalation with the new base 4 of the sensitive
6-nitrobenzothiazole (5e) proceeded in 79% yield under
mild conditions (25 °C, 10 min). The resulting zinc reagent
6e reacted with E-alkenyl iodide 7i12 to furnish the
3
Moreover, the new base 4 was applied effectively in the
metalation of substrates bearing the sensitive nitro-group.
1304
Org. Lett., Vol. 15, No. 6, 2013

indolylzinc pivalate 6f.7c The reaction of the latter in Negishi
cross-coupling with the aryl iodide 7k and in CuCN 2LiCl
3
Scheme 3. Reactivity of Heterobenzylzinc Pivalates 6i and 6j
towards Negishi Cross-Coupling and Allylation Reactions with
Various Aryl and Allyl Bromides
catalyzed allylation with 3-bromocyclohexene (7d) gave the
indoles 8mÀn in 91 to 98% yield (entries 10 and 11).
Other sensitive heterocycles which occur in a plethora of
natural products with significant biological properties
were also functionalized via their zinc pivalate precursors.
Hence, chromone (5g) was metalated with TMPZnOPiv
LiCl (4), exclusively at the β-position to the carbonyl
3
group (À30 °C, 1 h), after preactivation with BF3 OEt2.13
3
The zinc reagent 6g participated effectively in a Negishi
cross-coupling with the aryl iodide 7l and in an acylation
reaction with acyl chloride 7m after transmetalation to
CuCN 2LiCl (entries 12 and 13). Moreover, the coumarin
3
derived zincpivalate 6h wasformedusing the new zinc base
4 and microwave irradiation (80 °C, 1 h).7b Quenching
with I2 or allyl bromide (after addition of 10 mol %
CuCN 2LiCl) and Pd-catalyzed coupling with the aryl
iodide 7n afforded the anticipated products 8qÀs in
3
92À98% yield (entries 14À16).
Finally, TMPZnOPiv LiCl (4) proved to be successful
3
for the metalation at the benzylic position of five- and six-
membered heterocycles. More specifically, 2-picoline (5i)
was zincated smoothly after 1 h at 25 °C to provide the
corresponding zinc pivalate 6i,7e while metalation of
MOM-protected 2-methylbenzimidazole 5j (25 °C, 1 h)
led to zinc compound 6j (Scheme 3).14 Both zinc pivalates
underwent Negishi cross-coupling with aryl bromides 7o
and 7p, respectively (using Pd(OAc)2 and S-Phos15 as the
catalytic system), as well as copper catalyzed allylation
with the bromides 7c and 7q. The expected heteroaryls
8tÀw were obtained in good yields (73À79%, Scheme 3).16
In summary, we have reported the preparation of a new
coupling product 8k in 95% yield and with complete
retention of the double-bond configuration (entry 8).
Addition of 2-bromomethylpropene (7j) to 6e, in the
presence of 10 mol % CuCN 2LiCl, led to the allylated
derivative 8l in 88% yield (entry 9).
3
selective zinc amide base, TMPZnOPiv LiCl (4).17 This
Furthermore, sensitive heterocyclic aldehydes could ef-
ficiently be metalated using the new zinc base TMPZnO-
Piv LiCl (4). Thus, N-methyl-3-formylindole (5f) was
3
base provides a fast and efficient access to zinc pivalates of
a wide range of aromatic and heteroaromatic substrates
with sensitive functionalities such as a nitro group or an
aldehyde. The latter are easy-to-handle powders and ex-
hibit excellent air stability. In addition, they smoothly
3
successfully zincated at position 2 (25 °C, 30 min) providing
(12) Alkenyl iodide 7i was prepared in 87% yield according to the
procedure described in: Krishnamurthy, V. R.; Dougherty, A.; Haller,
C. A.; Chaikof, E. L. J. Org. Chem. 2011, 76, 5543.
(13) Klier, L.; Bresser, T.; Nigst, T. A.; Karaghiosoff, K.; Knochel, P.
J. Am. Chem. Soc. 2012, 134, 13584.
(14) Duez, S.; Steib, A.; Knochel, P. Org. Lett. 2012, 14, 1951.
(15) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2004, 127, 4685.
undergo Negishi cross-couplings, as well as CuCN 2LiCl
3
mediated allylations and acylations with various electro-
philes. Further investigations on the reactivity of organo-
zinc pivalates are currently in progress in our laboratory.
(16) Due to the unstable nature of the corresponding iodides
(resulting from iodolysis of 6i and 6j) the yield of the metalation was
not possible to be determined; therefore the overall yield is provided.
(17) Typical procedure: 4,6-Dichloropyrimidine (5a; 298 mg, 2.0
Acknowledgment. The research leading to these results
has received funding from the European Research Council
under the European Community’s seventh Framework Pro-
gramme (FP7/2007-2013) ERC Grant Agreement No. 227763.
We thank the Fonds der Chemischen Industrie for financial
support and are grateful to BASF AG and Rockwood
Lithium GmbH for the generous gift of chemicals.
mmol) was dissolved in dry THF (4 mL), and TMPZnOPiv LiCl
3
(4, 2.6 mL, 0.85 M, 2.2 mmol) was added dropwise at 25 °C. Upon
completion of the metalation (30 min), the solventwas carefully removed
in high vacuum (0.1 mmHg, 3 h) providing solid 5-(4,6-dichloro-
pyrimidyl) zinc pivalate (6a) as a fine yellow powder. This crude material
was titrated,9 and the active zinc species concentration was found to be
0.81 mmol/g, which corresponds to a 78% yield. Next, the solid zinc
pivalate 6a (1.2 g, 1.00 mmol) was dissolved in dry THF (2 mL), and the
solution was cooled to À20 °C. CuCN 2LiCl (1.1 mL, 1.00 M, 1.1 mmol)
3
Supporting Information Available. Experimental pro-
cedures and characterization data of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
was added followed, after 20 min, by 2-furoyl chloride (392 mg, 3.0
mmol). The reaction mixture was warmed slowly to 25 °C and stirred for
3 h. Then, sat. aq. NH4Cl (10 mL) was added, and the aqueous layer was
extracted with EtOAc (3 Â 20 mL). The combined organic phases were
dried over anhydrous Na2SO4 and evaporated in vacuo. Purification by
flash chromatography (silica gel, ihexane/EtOAc = 10:1) afforded the
pyridine 6b (233 mg, 96%) as a brown solid.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
1305