TMPZnCI.LiCI: A new active selective base for the directed zincation of sensitive aromatics and heteroaromatics

Article abstract of DOI:10.1021/ol900342a

A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF via direct zincation using TMPZnCILiCI, a new exceptionally mild and efficient base. Activated arenes and heteroarenes are metalated at room temperature. Remarkably, sensitive functions such as an aldehyde as well as a nitro group are tolerated, expanding significantly the scope of directed metalations.

Full text of DOI:10.1021/ol900342a

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1837-1840
TMPZnCl·LiCl: A New Active Selective
Base for the Directed Zincation of
Sensitive Aromatics and
Heteroaromatics
Marc Mosrin and Paul Knochel*
Department Chemie & Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received February 16, 2009
ABSTRACT
A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF via direct zincation using TMPZnCl·LiCl, a
new exceptionally mild and efficient base. Activated arenes and heteroarenes are metalated at room temperature. Remarkably, sensitive functions
such as an aldehyde as well as a nitro group are tolerated, expanding significantly the scope of directed metalations.
Directed metalation of aromatic and heterocyclic compounds
is an important method for the functionalization of these
scaffolds. Lithium bases have been extensively used for
performing the ortho-metalation of various unsaturated
systems.1 The use of magnesium bases, pioneered by Eaton,2
has found a renewed interest.3 Recently, lithium magnesi-
ates4,5 have found useful synthetic applications. Mixed Mg/
Li bases of type R2NMgCl·LiCl such as 2,2,6,6-tetrameth-
ylpiperidide magnesium chloride lithium chloride (TMP-
MgCl·LiCl; Turbo-Hauser base) proved to be an especially
effective metalating agent, compatible with functional groups
such as an ester, a nitrile, or an aryl ketone.6 However, more
sensitive functionalities such as an aldehyde or a nitro group
are not tolerated. Also sensitive heterocycles may undergo
fragmentation.7 Therefore a range of zinc amides have been
(3) (a) Hevia, E.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E.;
Sherrington, D. C. Angew. Chem., Int. Ed. 2005, 44, 68. (b) Andrikopolous,
P. C.; Armstrong, D. R.; Graham, D. V.; Hevia, E.; Kennedy, A. R.; Mulvey,
R. E.; O’Hara, C. T.; Talmard, C. Angew. Chem., Int. Ed. 2005, 44, 3459.
(c) Kondo, Y.; Akihiro, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
1996, 2331. (d) Shilai, M.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 2001, 442. (e) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.;
Bischoff, L.; Tre´court, F.; Que´guiner, G.; Marsais, F.; Blanco, F.; Abarca,
B.; Ballesteros, R. J. Org. Chem. 2005, 70, 5190. (f) Eaton, P. E.; Zhang,
M.-X.; Komiya, N.; Yang, C.-G.; Steele, I.; Gilardi, R. Synlett 2003, 9,
1275.
(1) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Clayden, J.; Stimson,
C. C.; Keenan, M. Chem. Commun. 2006, 1393. (c) Schlosser, M. Angew.
Chem., Int. Ed. 2005, 44, 376. (d) Henderson, K. W.; Kerr, W. J.
Chem.-Eur. J. 2001, 3431. (e) Turck, A.; Ple´, N.; Mongin, F.; Que´guiner,
G. Tetrahedron 2001, 57, 4489. (f) Mongin, F.; Que´guiner, G. Tetrahedron
2001, 57, 4059. (g) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. ReV. 2005,
105, 827. (h) Kauch, M.; Hoppe, D. Synthesis 2006, 1578. (i) Clegg, W.;
Dale, S. H.; Hevia, E.; Honeyman, G. W.; Mulvey, R. E. Angew. Chem.,
Int. Ed. 2006, 45, 2371. (j) Hodgson, D. M.; Miles, S. M. Angew. Chem.,
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Organometallics; Knochel, P. Ed.; Wiley-VCH: Weinheim, Germany, 2005;
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Chem., Int. Ed. 2000, 39, 2481. (b) Farkas, J.; Stoudt, S. J.; Hannawalt,
E. M.; Pajeski, A. D.; Richey, H. G. Organometallics 2004, 23, 423. (c)
Awad, H.; Mongin, F.; Tre´court, F.; Que´guiner, G.; Marsais, F.; Blanco,
F.; Abarca, B.; Ballesteros, R. Tetrahedron Lett. 2004, 45, 6697.
(5) (a) Garcia-Alvarez, P.; Graham, D. V.; Hevia, E.; Kennedy, A. R.;
Klett, J.; Mulvey, R. E.; O’Hara, C. T.; Weatherstone, S. Angew. Chem.,
Int. Ed. 2008, 47, 8079. (b) Mulvey, R. E. Organometallics 2006, 25, 1060.
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Eaton, P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111, 8016. (c)
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10.1021/ol900342a CCC: $40.75
Published on Web 03/24/2009
2009 American Chemical Society

reported that provide after metalation organozinc reagents
compatible with most functionalities. In pioneer work,
lithium di-tert-butyl-(2,2,6,6-tetra-methylpiperidino)zincate
(t-Bu2Zn(TMP)Li) was reported by Kondo to be an excellent
base for the zincation of various aromatics.8 The use of
highly reactive zincates or related ate-bases9 is sometimes
not compatible with sensitive functions such as an aldehyde
or a nitro group. Recently, we have reported the preparation
of a highly chemoselective base TMP2Zn·2MgCl2·2LiCl for
the directed zincation of sensitive aromatics and heteroaro-
matics.10 However, with this reagent some electron-poor
functionalized arenes and heteroarenes still give unsatisfac-
tory results in terms of yields and reaction selectivity.
Moreover, several activated aromatics or heteroaromatics
such as nitro derivatives or pyridazines require metalations
below -50 °C, which is not convenient for reaction
upscaling.10a,11 Thus, we have explored the preparation of a
more selective zinc base that would allow chemoselective
metalations at 25 °C for the directed zincation of sensitive
aryl and heteroaryl substrates. The treatment of 2,2,6,6-
tetramethylpiperidine (1; TMP-H) with n-BuLi (1.0 equiv,
-40 to -10 °C, 1 h) followed by the addition of ZnCl2 (1.1
equiv, -10 °C, 30 min) provides a ca. 1.3 M solution of
TMPZnCl·LiCl (2), stable at room temperature (Scheme 1).12
Table 1. Products Obtained by Regio- and Chemoselective
Zincation of Diazines of Type 3, 6, and 9 with TMPZnCl·LiCl
(2; 1.1 equiv; 25 °C) and Quenching with Electrophiles
Scheme 1. Preparation of 2,2,6,6-Tetramethylpiperidide Zinc
Chloride Lithium Chloride (TMPZnCl·LiCl) (2)
In constrast to TMP2Zn·2MgCl2·2LiCl, this complex base
showed a very good chemoselectivity for the zincation at
25 °C of various sensitive aromatics and heterocycles.
Several sensitive heteroarenes10 such as pyridazines,11
pyrimidines,13 and pyrazines14 are cleanly zincated at 25 °C
using the new base TMPZnCl·LiCl (2; Scheme 2 and Table
a Isolated, analytically pure product. b Transmetalation performed with
1.1 equiv of CuCN·2LiCl. c Obtained by palladium-catalyzed cross-coupling
using Pd(dba)2 (3 mol %) and (o-furyl)3P (6 mol %). d Transmetalation
performed with 5 mol % of CuCN·2LiCl.
Scheme 2. Zincation of 3,6-Dichloropyridazine (3),
4,6-Dichloropyrimidine (6), and 2,6-Dichloropyrazine (9) using
TMPZnCl·LiCl (2; 1.1 equiv; 25 °C) and Trapping with
Electrophiles
ing to the expected products 5a-c in 83-96% yield
(entries 1-3 of Table 1). Zincations of other sensitive
heteroaromatics can be readily achieved by the addition of
TMPZnCl·LiCl (2). Thus, 4,6-dichloropyrimidine (6) is
(6) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.; Knochel, P. Org. Lett.
2006, 8, 5673. (c) Mosrin, M.; Knochel, P. Org. Lett. 2008, 10, 2497. (d)
Mosrin, M.; Boudet, N.; Knochel, P. Org. Biomol. Chem. 2008, 6, 3237.
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2007, 46, 7681. (f) Rohbogner, C. J.; Clososki, G. C.; Knochel, P. Angew.
Chem., Int. Ed. 2008, 47, 1503.
1). Thus, the treatment of 3,6-dichloropyridazine (3) with
TMPZnCl·LiCl (2; 1.1 equiv, 25 °C, 30 min) leads to the
zincated species (4), which can be trapped with I2 or
4-fluorobenzoyl chloride (after transmetalation with
CuCN·2LiCl)15 or undergo a Negishi16 cross-coupling lead-
1838
Org. Lett., Vol. 11, No. 8, 2009

converted within 45 min at 25 °C to the 5-zincated species.
Trapping with I2 is furnishing the iodopyrimidine 8a in 83%
yield (entry 4). Reaction with furoyl chloride (after trans-
metalation with CuCN·2LiCl)15 provides the 5-ketopyrimi-
dine 8b in 71% (entry 5). An allylation (after addition of
CuCN·2LiCl) leads to the allyled derivative 8c in 89% (entry
6). Similarly, 2,6-dichloropyrazine (9) is zincated quantita-
tively with TMPZnCl·LiCl (2; 1.1 equiv, 25 °C, 30 min) and
reacted with iodine or undergoes a Negishi16 cross-coupling
or an allylation with ethyl 2-(bro-momethyl)acrylate17 (after
addition of CuCN·2LiCl) affording the expected products
11a-c in 72-90% yields (entries 7-9).
led to the purine derivatives 14a and 14b, respectively, in
74% and 69% yields.
A unique advantage of the zinc base 2 is that very sensitive
functional groups such as a nitro group can be tolerated at
25 °C.20 Thus, 2,4-difluoronitrobenzene (15) was converted
to the corresponding zinc reagent 16 by treatment with
TMPZnCl·LiCl (2; 1.1 equiv, 25 °C, 45 min). A Negishi16
cross-coupling can be readily performed to furnish the aryl
derivative 17a in 92% yield (Scheme 4). Trapping with
benzoyl chloride (after transmetalation with CuCN·2LiCl)15
provides the ketone 17b in 84% yield. After trapping with
I2, the iodobenzene derivative 17c was obtained in 90% yield.
Other sensitive heterocycles such as purines18 can be
metalated as well under mild conditions (Scheme 3). Thus,
Scheme 4. Zincation of 2,4-Difluoronitrobenzene (15) using
TMPZnCl·LiCl (2; 1.1 equiv; 25 °C) and Trapping with
Electrophiles
Scheme 3. Zincation of Caffeine (12) using TMPZnCl·LiCl (2;
1.1 equiv; 25 °C) and Trapping with Electrophiles
caffeine (12)19 undergoes a smooth zincation using TMP-
ZnCl·LiCl (2; 1.1 equiv, 25 °C, 5 min) furnishing the zinc
species 13. Negishi16 cross-coupling or trapping with ethyl
2-(bromomethyl)acrylate17 (after addition of CuCN·2LiCl)
Other sensitive electron-poor arenes and heteroarenes are
metalated as well using the new base 2. Accordingly,
2-chloro-3-nitropyridine (18) undergoes a smooth metalation
with TMPZnCl·LiCl (2; 1.1 equiv, 25 °C, 45 min) furnishing
the zinc species 19. Trapping with 3-bromocyclohexene (after
addition of CuCN·2LiCl) provides the pyridine 20 in 73%
yield. Similarly, 4-fluoro-1-methoxy-2-nitrobenzene (21) was
converted within 6 h at 25 °C to the corresponding zinc
reagent 22. Quenching with ethyl 2-(bromomethyl)acrylate17
(after addition of CuCN·2LiCl) leads to the allyled derivative
23 in 67% yield. Zincation of methyl 5-nitrofuran-2-
carboxylate (24) can also be readily carried out using 2 (1.1
equiv) and furnishes the zinc species 25 in 30 min at 25 °C.
Allylation with 3-bromocyclohexene (after addition of
CuCN·2LiCl) gives the furan 26 in 72% yield (Scheme 5).
An aldehyde is also tolerated.21 Thus, benzo[b]thiophene-
3-carbaldehyde (27) was converted to the zinc species 28 at
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Org. Lett., Vol. 11, No. 8, 2009
1839

Scheme 5
.
Zincation of 2-Chloro-3-nitropyridine (18),
Scheme 6. Zincation of Benzo[b]thiophene-3-carbaldehyde (27)
4-Fluoro-1-methoxy-2-nitrobenzene (21) and Methyl
5-nitrofuran-2-carboxylate (24) using TMPZnCl·LiCl (2; 1.1
equiv, 25 °C) and Trapping with Electrophiles
using TMPZnCl·LiCl (2; 1.1 equiv; 25 °C) and Trapping with
Electrophiles
In summary, we have described a new mild and selective
complex base TMPZnCl·LiCl23 (2), which allows chemose-
lective zincations at room temperature that tolerate sensitive
functions such as an aldehyde or a nitro group. Especially,
the compatibility with nitro groups opens new avenues in
metalations of aromatic and heterocyclic substrates. Further
studies on the scope of this base are currently underway in
our laboratories.
25 °C using TMPZnCl·LiCl (2; 1.1 equiv) within 30 min
reaction time. The formation of a subsequent carbon-carbon
bond is also easily carried out by a Negishi16 cross-coupling
or a Sonogashira22 reaction giving the arylated heterocycles
29a-c in 63-92% yield.
(21) (a) Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem., Int.
Ed. 2004, 43, 1017. (b) Gong, L.-Z.; Knochel, P. Synlett 2005, 267.
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Organic Synthesis; Pergamon Press: New York, 1991; Vol. 3.
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft (DFG), and
the European Research Council (ERC) for financial support.
We also thank Evonik GmbH, BASF AG, and Chemetall
GmbH for the generous gift of chemicals.
(23) Typical Procedure. 2,4-Difluoro-1-nitrobenzene 15 (159 mg, 1.0
mmol) in THF (2 mL) was added to a solution of TMPZnCl·LiCl (2) (1.3
M in THF, 0.85 mL, 1.1 mmol) at 25 °C, and the reaction mixture was
then stirred at this temperature for 45 min. CuCN·2LiCl (1.0 M solution in
THF, 1.1 mL, 1.1 mmol) was slowly added at -40 °C, and the reaction
mixture was stirred at the same temperature for 30 min. Then, benzoyl
chloride (281 mg, 2.0 mmol) was added dropwise at -40 °C, and the
resulting mixture was allowed to warm up slowly to 25 °C overnight. The
reaction mixture was then quenchend with a saturated aq NH4Cl solution
(20 mL), extracted with diethyl ether (3 × 50 mL), and dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification
by flash chromatography (CH2Cl2/pentane, 1:2) furnished compound 17b
(221 mg, 84% yield) as a colorless solid.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL900342A
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Org. Lett., Vol. 11, No. 8, 2009