Deprotonative zincation of heteroaromatics using ZnI2 and tert-Bu-P4 base

Article abstract of DOI:10.3987/COM-08-S(N)107

The direct deprotonative zincation of diazines was accomplished using the combination of ZnI₂ and t-Bu-P4 base and unique regioselectivities of zincation were observed.

Full text of DOI:10.3987/COM-08-S(N)107

HETEROCYCLES, Vol. 76, No. 2, 2008
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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1057 - 1060. © The Japan Institute of Heterocyclic Chemistry
Received, 26th April, 2008, Accepted, 9th June, 2008, Published online, 12th June, 2008. COM-08-S(N)107
DEPROTONATIVE ZINCATION OF HETEROAROMATICS USING ZnI2
AND tert-Bu-P4 BASE
Tatsushi Imahori, Koichi Suzawa, and Yoshinori Kondo*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama,
Aoba-ku, Sendai 980-8578, Japan
Dedicated to Professor Ryoji Noyori on the occasion of his 70th Birthday
Abstract – The direct deprotonative zincation of diazines was accomplished
using the combination of ZnI2 and t-Bu-P4 base and unique regioselectivities of
zincation were observed.
Selective functionalization of nitrogen heteroaromatic compounds has been regarded as one of the most
important subjects in heterocyclic chemistry oriented toward drug discovery research. Organometallic
chemistry have played an important role and various heteroarylmetal compounds have been prepared for
the selective bond formation to introduce substituents.1 Deprotonation using a metallic base is a
common method for the preparation of heteroarylmetal and is known to show high regioselectivity.
Especially, deprotonative lithiation has been intensively investigated and the reaction generally proceeds
at adjacent position of heteroaroms in heteroaromatic compounds.2 The lithiated heteroaromatic
compounds can be easily converted to heteroarylzinc compounds by the treatment with zinc halides.
Synthetic utility of organozinc compounds are well recognized as a useful coupling partner in palladium
catalyzed cross coupling reaction of aryl and alkenyl halides and also in copper mediated coupling
reactions with various electrophiles.3 Organozinc compounds usually have high compatibility with
various electrophilic functional groups and considered to be suitable reactive molecules for medicinal
chemistry. In connection with our recent interests on aromatic and heteroaromatic carbanion chemistry
using deprotonative zincation,4 we investigated zincation of diazines using the combination of organic
super base and zinc halide.
Phosphazene bases developed by Schwesinger are known as strong non-metallic organic bases.5 Among
them, t-Bu-P4 base shows extremely high basicity and has been used for various selective deprotonative
transformation and other catalytic reactions.6,7

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HETEROCYCLES, Vol. 76, No. 2, 2008
P1
P4
t-Bu
NMe2 N
P2
t-Bu
N
t-Bu
N
NMe2
NMe2
N P NMe2
Me2N
P
N
P
N
P
N
P
NMe2
Me2N
P
NMe2
Me2N
P
NMe2
Me2N
NMe2
NMe2
t-Bu-P1 base
NMe2 NMe2
NMe2
t-Bu-P2 base
NMe2
t-Bu-P4 base
We recently reported novel deprotonative functionalization of aromatic and heteroaromatic compounds
using t-Bu-P4 base and unique regioselectivities in the deprotonation of diazines were disclosed.7f It is
well known that the conventional deprotonation using lithium tetramethylpiperidide (LTMP) proceeds at
α position adjacent to ring nitrogen,8 and in contrast to this, the deprotonation using t-Bu-P4 base
proceeded at the most remote position from the ring nitrogen. Based on these backgrounds, we
investigated direct zincation of diazines using t-Bu-P4 base in the presence of zinc iodide.
Table 1. Deprotonative Zincation of Pyridazine
entry
t-Bu-P4 base (eq)
ZnI2 (eq)
Yield (%)
ZnI
I
ZnI2, t-Bu-P4 base, THF
-78 oC to rt 1 h
I2
1
2
3
4
5
1.0
1.0
1.0
1.5
3.0
1.0
1.6
2.0
3.0
6.0
0
trace
14
N
N
N
N
N
N
[t-Bu-P4 base]HI
46
83
First, pyridazine was chosen as a substrate and was reacted with zinc iodide and t-Bu-P4 base in THF at
–78 oC followed by warming up to room temperature under various ratio of reagents as shown in Table 1.
The formation of pyridazinylzinc iodide was monitored by the treatment of the organozinc with I2 to form
iodopyridazine. When 1equiv. t-Bu-P4 base and 1 equiv. ZnI2 was used for the reaction followed by the
quench with I2, no formation of 4-iodopyridazine was observed (Table 1, entry 1). This fact suggests
that no pyridazinylzinc iodide was formed under this reaction condition. The reaction was then
conducted with 1 equiv. t-Bu-P4 base and 2 equiv. ZnI2 followed by treatment with I2, and
4-iodopyridazine was obtained in 14% yield (Table 1, entry 3). In order to optimize the yield of
iodopyridazine, the molar ratios of t-Bu-P4 base and ZnI2 were further increased and the conditions with
3equiv. t-Bu-P4 base and 6 equiv. ZnI2 gave the iodide in 83% yield (Table 1, entry 5). Under this
condition, the conversion of pyridazine to pyridazinylzinc iodide is considered to be reasonable. Here
the regioselectivity of the metallation is important and the zincation proceeded exclusively at the
4-position of pyridazine.
Pyrimidine was then reacted under the similar reaction conditions, namely by treatment with 3equiv.
t-Bu-P4 base and 6 equiv. ZnI2, 5-pyrimidinylzinc iodide was formed, which was treated with I2 to give
5-iodopyrimidine in 66% yield (Scheme 1). Here the unique regioselectivity at 5-position was observed
in contrast to the conventional deprotonative lithiation.

HETEROCYCLES, Vol. 76, No. 2, 2008
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Scheme 1 Deprotonative Zincation of Pyrimidine
ZnI
I
ZnI2, t-Bu-P4 base, THF
-78 oC to rt, 1 h
N
N
N
N
N
N
66%
These diazinylzinc compounds prepared from the direct zincation using t-Bu-P4 base and ZnI2, were
reacted with aryl halides in the presence of palladium catalyst to give heterobiaryl compounds.
Excellent one-pot arylations of diazines was achieved.
Table 2 Palladium Catalyzed Coupling Reaction of Heteroarylzinc Derivatives
ZnI2, t-Bu-P4 base, THF
Ar-X
Pd(PPh3)4
Het-Ar-H
Het-Ar-ZnI
Het-Ar-Ar
-78 oC to rt, 1 h
Hetr-Ar-Ar
Het-Ar-H
Ar-X
Yield (%)
Entry
76
91
89
92
71
73
1
2
3
4
5
6
N
N
I
N
N
N
N
EtOOC
EtOOC
O2N
I
I
O2N
MeO
NC
N
N
MeO
NC
I
Br
I
N
N
N
N
N
N
N
N
o
Pyridazine was reacted with zinc iodide and t-Bu-P4 base in THF at –78 C followed by warming up to
room temperature and the pyridazinylzinc iodide was treated with iodobenzene in the presence of
Pd(PPh3)4 at room temperature for 24 h to give 4-phenylpyridazine in 76% yield (Table 2, entry 1).
Other aryl halides with functional groups, such as ethyl 4-iodobenzoate, 4-iodonitrobenzene,
4-iodoanisole, 4-bromobenzonitrile reacted smoothly with the pyridazinylzinc iodide to give
4-arylpyridazines in good yields (Table 2, entries 2-5). Pyrimidine was also reacted with zinc iodide and
o
t-Bu-P4 base in THF at –78 C followed by warming up to room temperature and the pyrimidinylzinc
iodide was treated with iodobenzene in the presence of Pd(PPh3)4 at room temperature for 24 h to give
5-phenylpyrimidine in 73% yield (Table 2, entry 6).
In summary, direct deprotonative zincation of diazines was accomplished using the combination of ZnI2
and t-Bu-P4 base and unique regioselectivities were observed. To the best of our knowledge, simple
4-pyridazinylzinc halide and 5-pyrimidinylzinc halide without substituents on the rings were first
prepared by the present method. Further investigations for the scope and limitation of the aromatic
zincation and the mechanistic studies of the reaction are underway.

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ACKNOWLEDGMENT
This work was partly supported by the Grant-in Aid for Scientific Research (No. 19020005, No.
20036007, No. 19390002) from the Ministry of Education, Science, Sports and Culture, Japan and grants
from the Sumitomo Foundation and Yamada Science Foundation.
REFERENCES AND NOTES
1. a) J. A. Joule and K. Mills, Heterocyclic Chemistry, Blackwell Science, Oxford, 2000. b) R.
Chinchilla, C. Nájera, and M. Yus, Chem. Rev., 2004, 104, 2667.
2. a) F. Mongin and G. Quéguiner, Tetrahedron, 2001, 57, 4059. b) A. Turck, N. Plé, F. Mongin, and
G. Quéguiner, Tetrahedron, 2001, 57, 4489. c) G. Quéguiner, F. Marsais, V. Snieckus, and J.
Epsztajin, Adv. Heterocycl. Chem., 1991, 52, 187. d) V. Snieckus, Chem. Rev., 1990, 90, 879. e) H.
W. Gschwend and H. R. Rodriguez, Org. React., 1979, 26, 1.
3. a) P. Knochel and P. Jones, Eds. Organozinc Reagents, A Practical Approach, Oxford University
Press: New York, 1999. b) J. J. Li and G. W. Gribble, Palladium in Heterocyclic Chemistry,
Elsevier, Oxford, 2000. c) E. Negishi, Acc. Chem. Res., 1982, 15, 340.
4. a) Y. Kondo, J. V. Morey, J. C. Morgan, H. Naka, D. Nobuto, P. R. Raithby, M. Uchiyama, and A.
E. H. Wheatley, J. Am. Chem. Soc., 2007, 129, 12734. b) M. Uchiyama, T. Miyoshi, Y. Kajihara, T.
Sakamoto, Y. Otani, T. Ohwada, and Y. Kondo, J. Am. Chem. Soc., 2002, 124, 8514. c) Y. Kondo,
M. Shilai, M. Uchiyama, and T. Sakamoto, J. Am. Chem. Soc., 1999, 121, 3539.
5. a) R. Schwesinger and H. Schlemper, Angew. Chem., Int. Ed. Engl., 1987, 26, 1167. b) R.
Schwesinger, H. Schlemper, C. Hasenfratz, J. Willaredt, T. Dambacher, T. Breuer, C. Ottaway, M.
Fletschinger, J. Boele, H. Fritz, D. Putzas, H. W. Rotter, F. G. Bordwell, A. V. Satish, G.-Z. Ji, E.-M.
Peters, K. Peters, H. G. von Schnering, and L. Walz, Liebigs Ann., 1996, 1055.
6. a) G. A. Kraus, N. Zhang, J. G. Verkade, M. Nagarajan, and P. B. Kisanga, Org. Lett., 2000, 2, 2409.
b) T. Pietzonka and D. Seebach, Chem. Ber., 1991, 124, 1837. c) T. Pietzonka and D. Seebach,
Angew. Chem., Int. Ed. Engl., 1993, 32, 716. d) I. Leito, T. Rodima, I. A. Koppel, R. Schwesinger,
and V. M. Vlasov, J. Org. Chem., 1997, 62, 8479.
7. a) T. Imahori, C. Hori, and Y. Kondo, Adv. Synth. Catal., 2004, 346, 1090. b) M. Ueno, C. Hori, K.
Suzawa, M. Ebisawa, and Y. Kondo, Eur. J. Org. Chem., 2005, 1965. c) K. Kobayashi, M. Ueno,
and Y. Kondo, Chem. Commun., 2006, 3128. d) M. Ueno, A. E. H. Wheatley, and Y. Kondo, Chem.
Commun., 2006, 3549. e) K. Suzawa, M. Ueno, A. E. H. Wheatley, and Y. Kondo, Chem. Commun.,
2006, 4850. f) T. Imahori and Y. Kondo, J. Am. Chem. Soc., 2003, 125, 8082.
8. a) N. Plé, A. Turck, K. Couture, and G. Quéguiner, J. Org. Chem., 1995, 60, 3781. b) M. L. Davis,
B. J. Wakefield, and J. A. Wardell, Tetrahedron, 1992, 48, 939.