New preparation of TMPZnCl·LiCl by Zn insertion into TMPCl. Application to the functionalization of dibromodiazines

Article abstract of DOI:10.1021/ol400248e

A practical zinc insertion starting from cheap commercial zinc powder and TMPCl (1-chloro-2,2,6,6-tetramethylpiperidine) allows a fast and efficient synthesis of the zinc base TMPZnCl·LiCl under mild conditions in high yields. This base is kinetically highly active and was used for the regio- and chemoselective functionalization of dibromodiazines (pyridazines and pyrazines).

Full text of DOI:10.1021/ol400248e

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
New Preparation of TMPZnCl LiCl by Zn
3
Insertion into TMPCl. Application to the
Functionalization of Dibromodiazines
Andreas Unsinn,† Mark J. Ford,*,‡ and Paul Knochel*,†
€
€
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13,
€
81377 Mu€nchen, Germany, and Bayer CropScience AG, Industriepark Hochst, G836,
65926 Frankfurt am Main, Germany
Paul.Knochel@cup.uni-muenchen.de; Mark.Ford@bayer.com
Received January 28, 2013
ABSTRACT
A practical zinc insertion starting from cheap commercial zinc powder and TMPCl (1-chloro-2,2,6,6-tetramethylpiperidine) allows a fast and
efficient synthesis of the zinc base TMPZnCl LiCl under mild conditions in high yields. This base is kinetically highly active and was used for the
regio- and chemoselective functionalization of dibromodiazines (pyridazines and pyrazines).
3
The preparation of functionalized aromatic molecules
and heterocycles is of great importance due to their
potential biological activity. These structures are present
in many pharmaceuticals or agrochemicals.1 Direct meta-
lation has proven to be an excellent tool for the regiose-
lective functionalization of these compounds.2 Therefore
the availability of chemoselective as well as kinetically
highly active bases is an important synthetic goal.3
highly selective zincations to be performed in a convenient
temperature range (typically 0 to 80 °C).4 The preparation
of 1 has been done in two steps starting from 2,2,6,6-
tetramethylpiperidine (2: TMPH) in >95% yield. Thus,
the amine 2 is first deprotonated with n-BuLi in hexanes
(1 equiv, À10 °C, 1 h) leading to TMPLi (3) in quantitative
yield. Transmetalation with ZnCl2 (1.05 equiv, À10 to
25 °C, 0.5 h) furnishes after evaporation of the hexanes/
THF solvent mixture and redissolution in dry THF
Recently, we have shown that TMPZnCl LiCl (1) is an
exceptionally active and chemoselective base, allowing
3
1.2À1.4 M solutions of TMPZnCl LiCl (1). Although
3
the overall yield of this synthesis is high (ca. 90%; Pathway
A; Scheme 1), it has several drawbacks. The reaction
conditions require the use of dry ZnCl2. Also n-BuLi is
only available in nonpolar solvents (alkanes or toluene).
Since this solvent mixture reduces significantly the solubi-
†
€
Ludwig-Maximilians-Universitat M€unchen.
‡ Bayer CropScience AG.
(1) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles;
Thieme: Stuttgart, 1995. (b) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.
Comprehensive Heterocyclic Chemistry II; Pergamon: Oxford, 1996.
(2) (a) Chatani, N. Topics in Organometallic Chemistry: Directed
Metallation; Springer: Berlin, 2007. (b) Dyker, G. Handbook of CÀH
lity of TMPZnCl LiCl (1) and therefore alsoits metalation
3
ꢀ
Transformations: Wiley-VCH: Weinheim, 2005. (c) Turck, A.; Ple, N.;
power, a tedious solvent evaporation and redissolution are
required. These impractical conditions as well as the rela-
tively high price of n-BuLi solution and safety considera-
ꢀ
Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4489. (d) Whisler, M. C.;
MacNeil, S.; Beak, P.; Snieckus, V. Angew. Chem. 2004, 116, 2256.
Angew. Chem., Int. Ed. 2004, 43, 2206.
(3) (a) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew.
Chem. 2007, 119, 3876. Angew. Chem., Int. Ed. 2007, 46, 3802. (b) Haag,
B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P. Angew. Chem. 2011,
123, 9968. Angew. Chem., Int. Ed. 2011, 50, 9794.
(4) (a) Klier, L.; Bresser, T.; Nigst, T. A.; Karaghiosoff, K.; Knochel,
P. J. Am. Chem. Soc. 2012, 134, 13584. (b) Bresser, T.; Knochel, P.
Angew. Chem. 2011, 123, 1954. Angew. Chem., Int. Ed. 2011, 50, 1914. (c)
Duez, S.; Steib, A. K.; Manolikakes, S. M.; Knochel, P. Angew. Chem.
2011, 33, 7828. Angew. Chem., Int. Ed. 2011, 50, 7686. (d) Mosrin, M.;
Knochel, P. Org. Lett. 2009, 11, 1837.
tions led us to design a new synthesis of TMPZnCl LiCl
3
(1) which would be conducted in a more favorable tem-
perature range and involve cheap and safe reagents.5
TMPH (2) is readily converted either by chlorination with
NCS or by treatment with an aqueous bleach solution
(5) A patent application has been filed.
r
10.1021/ol400248e
XXXX American Chemical Society

(13% aq NaOCl) at 25 °C tothe corresponding chloramine
1-chloro-2,2,6,6-tetramethylpiperidine (4: TMPCl) in 84%
yield.6 We have envisioned the direct insertion of a metal
(Met) intothe nitrogenÀchlorinebondofTMPCl(4) inthe
presence of LiCl, which would afford the metallic amides
The high electrophilicity of these heterocycles requires
low temperatures for their metalation. TMPZnCl LiCl (1)
3
proved to be especially well suited for zincation of hetero-
cycles of type 5 and related scaffolds since more active bases,
such as TMP2Zn 2MgCl2 2LiCl8 or TMPMgCl LiCl,9
3
3
3
TMPMetCl LiCl. Preliminary results showed that for,
lead to the decomposition of these sensitive heterocyclic
bromides.10 In contrast, treatment of the dibromopyridazine
3
Met = magnesium (turnings or powder), only reduction
of the chloroamine (4) is observed. However, switching to
zinc dust and performing a slow addition of the chloroamine
via syringe pump at 0 °C allows the preparation of
5a11 with TMPZnCl LiCl (1; 1.1 equiv, 25 °C, 0.5 h) led to
the quantitative formation of the zincated pyridazine 6a
which after transmetalation with CuCN 2LiCl12 (1.1 equiv)
and benzoylation (PhCOCl, 1.2 equiv, À40 to 25 °C, 3 h)
provides the ketone 7a in 86% isolated yield (Scheme 2).
3
3
TMPZnCl LiCl (1) in 90% yield as indicated by titration
3
with benzoic acid7,10c (Pathway B; 50 mmol scale; Scheme 1).
Scheme 1. Preparation of TMPZnCl LiCl (1)
3
Scheme 2. Directed Zincation of 3,5-Dibromopyridazine (5a)
Similary, the zincated pyridazine 6a reacted smoothly
with iodine and allylic bromides, leading to the N-hetero-
cycles 7bÀd in 71À76% yield (Table 1, entries 1À3).
Equally well 2,5-dibromopyrazine 5b13 was zincated with
the base 1 (1.1 equiv, 25 °C, 1 h). Copper-mediated acyla-
tion with various acid chlorides furnishes the expected acyl-
pyrazines 7eÀh in 53À79% yield (Table 1, entries 4À6). The
symmetrical 2,6-dibromopyrazine 5c14 was readily zincated
(1, 1.1 equiv, 25 °C, 1 h). It reacts with iodine, allyl bromide,
and 1-bromophenylacetylene15 under standard conditions
TMPZnCl LiCl (1) was directly obtained in concentra-
3
tions that made evaporation of solvents obsolete. The
excess of zinc powder can simply be removed by filtration.
Thus, a fast preparation of this organozinc base is possible
starting from cheap commercial zinc and the N-chloroamine
TMPCl (4).
(6) (a) Bodor, N.; Kaminski, J. J.; Worley, S. D.; Colton, R. J.; Lee,
T. H.; Rabalais, J. W. J. Pharm. Sci. 1974, 63, 1387. (b) Deno, N. C.;
Fishbein, R.; Wyckoff, J. C. J. Am. Chem. Soc. 1971, 93, 2065.
(7) We have applied the method also to other N-chloroamines, such
as 1-chloro-diisopropylamine, 1-chloro-tert-butylisopropylamine, or
1-chloro-piperidine. However, the yields of the corresponding zinc
amide drop significantly. A possible reason for this yield decrease could
be enamine formation in the course of the insertion. See Supporting
Information. Note: N-Chloroamines which can readily eliminate HCl
are energy-rich compounds that are inherently much less stable than
TMPCl, as such considereable care must be taken during their prepara-
tion and use.
We have verified that the deprotonation power (tem-
perature, reaction time) of TMPZnCl LiCl (1) prepared
3
by pathways A and B are identical and report herein some
new directed zincations of bromo-substituted pyridazine
5a and pyrazines 5bÀe. Pyrazines and pyridazines are
biologically highly active, and therefore their functionali-
zation is of great interest since many examples of natural
products or pharmaceutically important compounds con-
tain these scaffolds (Figure 1).
(8) (a) Zhang, C. Y.; Tour, J. M. J. Am. Chem. Soc. 1999, 121, 8783.
(b) Liu, W.; Wise, D. S.; Townsend, L. B. J. Org. Chem. 2001, 66, 4783.
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(c) Buron, F.; Ple, N.; Turck, A.; Queguiner, G. J. Org. Chem. 2004, 70,
2616. (d) Chevallier, F.; Mongin, F. Chem. Soc. Rev. 2008, 37, 595.
(9) (a) Unsinn, A.; Knochel, P. Chem. Commun. 2012, 48, 2680. (b)
Jaric, M.; Haag, B. A.; Unsinn, A.; Karaghiosoff, K.; Knochel, P.
Angew. Chem. 2010, 122, 5582. Angew. Chem., Int. Ed. 2010, 49, 5451. (c)
Wunderlich, S. H.; Knochel, P. Angew. Chem. 2007, 119, 7829. Angew.
Chem., Int. Ed. 2007, 46, 7685.
(10) (a) Wunderlich, S. H.; Rohbogner, C. J.; Unsinn, A.; Knochel, P.
Org. Process Res. Dev. 2010, 14, 339. (b) Kunz, T.; Knochel, P. Angew.
Chem. 2012, 124, 1994. Angew. Chem., Int. Ed. 2012, 51, 1958. (c)
Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem. 2006, 118,
3024. Angew. Chem., Int. Ed. 2006, 45, 2958.
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(11) Decrane, L.; Ple, N.; Turck, A. J. Heterocycl. Chem. 2005, 42,
509.
(12) Dankulich, W. P.; McGarry, D. G.; Burns C.; Gallagher T. F.;
Volz F. A. Substituted (aminoiminomethyl or aminomethyl) benzohe-
teroaryl compounds. U.S. Patent 6,541,505, April, 01, 2003.
(13) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(14) Ellingson, R. C.; Henry, R. L. J. Am. Chem. Soc. 1949, 71, 2798.
(15) Erickson, A. E.; Spoerri, P. E. J. Am. Chem. Soc. 1946, 68, 400.
Figure 1. Biologically active compounds containing a pyrazine
or pyridazine scaffold.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Monofunctionalization of Bromodiazines of Type 5
a Yield of analytically pure isolated product. b Catalyzed by 5 mol % of CuCN 2LiCl. c Obtained after transmetalation with CuCN 2LiCl (1.1 equiv).
3
3
providing the trisubstituted pyrazines 7iÀk in 74À90%
yields (Table 1, entries 8À10). The isomeric 2,3-dibromo-
pyrazine 5d16 is only zincated at elevated temperatures
reagent which was allylated with 3-bromocyclohexene
in the presence of 5% CuCN 2LiCl to furnish the fully
substituted pyridazine 8a in 72% yield (Scheme 3).
3
with TMPZnCl LiCl, since no adjacent bromine substi-
3
tuent is available for further acidification of the protons,
(1; 1.1 equiv, 50 °C, 12 h) leading to the expected zinc
reagent which was iodinated to give the iodopyrazine 7l
(71%, Table 1, entry 11). Copper-mediated acylation
provides the heterocyclic ketones 7mÀn in 56À76% yields
(Table 1, entries 12, 13). Finally, the tribromopyrazine
Scheme 3. Further Functionalizations of (3,6-Dibromopyrida-
zin-4-yl)(phenyl)methanone (7a)
5e17 is zincated with TMPZnCl LiCl (1, 1.1 equiv, 25 °C,
3
1 h) leading to a sensitive zinc reagent. Copper-catalyzed
allylation and acylation provide the tetrasubstituted
pyrazines in 55À66% yields (Table 1, entries 14, 15).
These diazines can be further functionalized via a second
zincation. Thus, the treatment of 7a with TMPZnCl LiCl
(1, 1.1 equiv, 0 °C, 1 h) provides an intermediate zinc
3
(16) Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1989, 30, 4799.
(17) Karmas, G.; Spoerri, P. E. J. Am. Chem. Soc. 1957, 79, 680.
Org. Lett., Vol. XX, No. XX, XXXX
C

or copper catalyzed allylation to the diiododibromopyrida-
zine 8e and the fully functionalized pyrazine 8f in yields of
74 and 70%, respectively (Table 2, entries 4 and 5). Further-
more the dibromopyridazine 7a undergoes a regioselective
Pd-catalyzed Sonogashira reaction18 with 1-octyne in the pre-
sence of 4% PdCl2(PPh3)2, 10% CuI, and Et3N (50 °C, 3 h)
to afford the pyridazine 9a in 80% yield. Also, the mixed
iodobromopyrazines such as 7b, 7i, and 7l leads as expected
to the preferential cross-coupling of the iodide in various
Negishi cross-couplings19 with arylzinc iodides20 giving the
pyrazines 9bÀd in 49À79% yields (Table 2, entries 6À8).
Finally, these dibromopyrazines are also regioselectively
converted to annulated heterocycles, which are potentially
biologically active.21 Thus, the treatment of 7a with hy-
drazine hydrate (MeOH, 50 °C, 1 h) gives the pyrazolo-
pyrazine 10a in 75% yield (Scheme 3). The same reaction
converts the pyrazine 7e to the condensed heterocycle 10b
in 84% yield (Table 2, entry 9).
Table 2. Further Functionalization of Compounds of Type 7
In summary, we have described a new practical prepara-
tion of the sterically hindered zinc amide TMPZnCl LiCl
3
(1) and demonstrated its utility for the zincation and further
functionalization of dibromodiazines. Further extensions to
the metalation of related heterocycles are underway.
Acknowledgment. The research leading to these results
has received funding from the European Research Council
under the European Community’s Seventh Framework
Programme (FP7/2007-2013) ERC Grant Agreement
No. 227763. We thank the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft (DFG) for fi-
nancial support. We also thank BASF SE (Ludwigshafen),
Heraeus Holding GmbH (Hanau), and Rockwood Lithium
GmbH (Frankfurt) for the generous gift of chemicals.
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.
(18) Brachwitz, H. J. Prakt. Chem. 1969, 311, 40.
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Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
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Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado, N. J.
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Furuyama, T.; Yasuike, S.; Muranaka, A.; Morokuma, K.; Uchiyama,
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a Yield of analytically pure isolated product. b Obtained after trans-
metalation with CuCN 2LiCl (1.1 equiv). c Catalyzed by 5 mol % of
3
CuCN 2LiCl. d Obtained by palladium-catalyzed cross-coupling using
2 mol % Pd(dba)2 and 4 mol % P(2-furyl)3.
3
€
(22) (a) Brenk, R.; Naerum, L.; Gradler, U.; Gerber, H.-D; Garcia,
G. A.; Reuter, K.; Stubbs, M. T.; Klebe, G. J. Med. Chem. 2003, 46,
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Ife, R. J.; Liddle, J.; Saunders, M.; Smith, D. G.; Ward, R. W. Bioorg.
Med. Chem. Lett. 2003, 13, 1577.
This zincated pyridazine is also iodinated and acylated
providing the expected pyridazines 8bÀd in 57À67% yield
(Table 2, entries 1À3). Similarly, the iododibromopyrida-
zine 7b and the iododibromopyrazine 7i are zincated with
TMPZnCl LiCl (1, 1.1 equiv, 0 °C, 1 h) leading after iodolysis
The authors declare no competing financial interest.
3
D
Org. Lett., Vol. XX, No. XX, XXXX