Convenient synthesis and transformation of 2,6-dichloro-4-iodopyridine

Article abstract of DOI:10.1021/ol0169269

(Matrix Presented) We describe a convenient scalable synthesis of 2,6-dichloro-4-iodopyridine and demonstrate its utility by stepwise elaboration to a number of 2,4,6-trisubstituted pyridines.

Full text of DOI:10.1021/ol0169269

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4263-4265
Convenient Synthesis and
Transformation of
2,6-Dichloro-4-iodopyridine
Jesse V. Mello and Nathaniel S. Finney*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500
Gilman DriVe, La Jolla, California 92093-0358
nfinney@chem.ucsd.edu
Received October 17, 2001
ABSTRACT
We describe a convenient scalable synthesis of 2,6-dichloro-4-iodopyridine and demonstrate its utility by stepwise elaboration to a number of
2,4,6-trisubstituted pyridines.
In the course of extending our work on arylpyridine
fluorescent chemosensors,1 we required ready access to 2,4,6-
trisubstituted pyridines. While such compounds can be
prepared by any of a number of condensation methods,2,3
we were drawn to the comparative simplicity and conver-
gence of directly installing the substituents via transition
metal catalyzed coupling to a pyridine precursor. The dearth
of procedures for the preparation of appropriate trihalo-
pyridines has led us to develop a four-step, scalable synthesis
of 2,6-dichloro-4-iodopyridine (4, Scheme 1). As described
here, 4 is a versatile intermediate in the synthesis of
trisubstituted pyridines. Such polysubstituted pyridines and
their associated metal complexes possess interesting and
useful structural, electronic, and optical properties,4 and we
anticipate this methodology will be of use to a broad range
of practicing chemists.
Our synthesis of 4 begins with the inexpensive pyridine
derivative citrazinic acid.5,6 Treatment with POCl3 at elevated
temperature afforded the corresponding 2,6-dichloroisoni-
cotinoyl chloride.7 To facilitate purification, the reaction was
quenched with methanol; methyl ester 1 was isolated in 76%
Scheme 1. Synthesis of 2,6-Dichloro-4-iodopyridinea
(1) Mello, J. V.; Finney, N. S. Angew. Chem., Int. Ed. 2001, 40, 1536.
(2) For authoriative treatment of pyridine synthesis, see: (a) Katritzky,
A. R. Handbook of Heterocyclic Chemistry, 2nd ed.; Pergammon: New
York, 2000. (b) ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds; Pergammon: New York, 1984; Vol. 2.
(3) For recent examples of the condensation of chalcones with acetophe-
none derivatives to form 2,4,6-triarylpyridines, see: (a) Chiu, C.; Tang,
Z.; Ellingboe, J. J. Comb. Chem. 1999, 1, 73-77. (b) Katritzky, A. R.;
Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999,
2114-2118.
(4) For representative overviews, see: (a) Biradha, K.; Fujita, M. AdV.
Supramol. Chem. 2000, 6, 1. (b) Long, N. J. In Optoelectronic Properties
of Inorganic Compounds; Roundhill, D. M., Fackler, J. P., Jr., Eds.;
Plenum: New York, 1999; pp 107-167. Publisher: Plenum Publishing
Corp., New York. (c) Krasovitskii, B. M.; Bolotin, B. M. Organic
Luminescent Materials; VCH: New York, 1988.
a Reagents and conditions: (a) POCl3, Me4NCl, ∆; CH3OH, 76%;
(b) LiOH, THF/H2O, 100%; (c) (COCl)2, CH2Cl2; NaN3; TFA, ∆;
K2CO3, CH3OH, 78%; (d) NaNO2, HCl; aqueous KI, 57%.
10.1021/ol0169269 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/30/2001

yield after passage through a plug of silica gel to remove
colored impurities. Saponification then provided acid 2 in
quantitative yield without purification.
Table 1. Symmetrical Trisubstituted Pyridines
Transformation to 3 was effected by conversion to the acyl
azide, thermal Curtius rearrangement, and hydrolysis of the
resulting trifluoroacetamide to provide 2,6-dichloro-4-ami-
nopyridine (3).8 While this method for converting 2 to 3 is
nominally three steps, it requires only a single extractive
workup and the steps can thus be carried out in rapid
succession. 3 was converted directly to 4 by diazotization
and reaction with potassium iodide,9 providing 4 in reason-
able yield and excellent purity after trituration with acetone.
This short sequence of reactions allows for preparation of 4
in ∼35% overall yield, requires no chromatography beyond
a single filtration through a plug of silica gel, and has allowed
the routine preparation of 5-10 g quantities of this inter-
mediate. Unlike many 4-halopyridines, we have found 4 to
be stable for several months at room temperature if protected
from light.
slightly more forceful conditions leads to trisubstituted
pyridines in fair to excellent yield.1213 While steric hindrance
appears to have little influence, the electron-deficient boronic
acids couple less efficiently. In the case of 7, further
elaboration leads to interesting functionalized fluorophores
such as 12 and 13 (Scheme 3), which are suitable for
The value of 4 for our purposes is its ready transformation
to fluorophores such as 7-10 (Scheme 2, Table 1). Selective
Scheme 2. Selective Reaction of the 4-Iodo Substituenta
Scheme 3. Elaboration of 7 to Novel Fluorophoresa
a Reagents and conditions: (a) catalytic PdCl2(PPh3)2, catalytic
CuI, Et2NH, TIPSCtCH, THF, 100%; (b) PhZnCl, catalytic
Pd(PPh3)4, THF, 98%; (c) ArB(OH)2, catalytic Pd2(dba)3/P(tBu)3,
Cs2CO3, THF, ∆. See Table 1 for structures and yields of 7-10.
Pd-catalyzed coupling of the iodide to either triisopropyl-
silylacetylene or phenylzinc chloride provides the corre-
sponding monocoupled products (5, 6) in excellent yield.10,11
Subsequent condensation with arylboronic acids under
a Reagents and conditions: (a) TBAF, THF, 69%; (b) ArI,
catalytic PdCl2(PPh3)2, catalytic CuI, Et2NH, THF (12, 40%; 13,
92%).
(5) The preparation of 4 from 2,6-dichloro-4-aminopyridine has been
previously described. We have found the reported procedures for the
synthesis and transformation of this key intermediate difficult to reduce to
practice and have thus devised the approach presented here. See: Talik,
T.; Plazek, E. Rocz. Chem. 1959, 33, 387, and references therein.
(6) Complete experimental and spectroscopic details are provided in the
Supporting Information.
immobilization on solid support or incorporation into oli-
gonucleotides.
We had hoped to extend the utility of 4 by transforming
5 and 6 to 4,6-disubstituted-2-chloropyridines (14-17,
Scheme 4, Table 2). However, under the numerous conditions
tried, differentiation of the chlorine atoms was modest at
best.14 While subsequent conversions of 14 and 16 to 18 and
(7) Henegar, K. E.; Ashford, S. A.; Baughman, T. A.; Sih, J. C.; Gu,
R.-L. J. Org. Chem. 1997, 62, 6588.
(8) Pfister, J. R.; Wymann, W. E. Synthesis 1983, 38.
(9) It is necessary to stir 3 in cold hydrochloric acid for several hours
prior to diazotization in order to obtain an acceptable yield. See Supporting
Information for details.
(10) For a recent review, see: (a) Sonogashira, K. In Metal-Catalyzed
Cross Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
New York, 1998; Chapter 5. (b) Negishi, E.-i. In Metal-Catalyzed Cross
Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New
York, 1998; Chapter 1.
(11) For recent examples of the chemoselective cross-coupling of
chloroiodo- and bromoiodopyridines, see: (a) Baxter, P. N. W. J. Org.
Chem. 2000, 65, 1257-1272. (b) Loren, J. C.; Siegel, J. S. Angew. Chem.,
Int. Ed. 2001, 40, 754-757. For representative earlier examples of the cross-
coupling of halopyridines, see: (c) Zhang, H.; Chan, K. S. Tetrahedron
Lett. 1996, 37, 1043-1044. (d) Lohse, O.; Thevenin, P.; Waldvogel, E.
Synlett 1999, 45-48.
(12) The combination of Pd2(dba)3 and PtBu3 consistently provided the
best yields of dicoupled products. See: (a) Old, D. W.; Wolfe, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722-9723. (b) Littke, A.
F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1997, 37, 33387-3388. (c) Wolfe,
J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413-2416. (d)
Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-4028.
(13) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457-2483. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(14) The reactions proceed cleanly, with residual starting material and
decoupled products as the other major components of the reaction mixture.
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Org. Lett., Vol. 3, No. 26, 2001

in DMF cleanly provides the corresponding monoether 20
in excellent yield,15 and subsequent arylation proceeds
smoothly to provide 21. Hydrogenolysis of the benzyl group
and conversion to the corresponding triflate (22) sets the stage
for a second arylation. With slightly modified coupling
conditions,16 19 can now be obtained in much improved yield
(64% over four steps vs 28% via 16). A further advantage
of intermediate 20 is that it may be simultaneously dechlo-
rinated and debenzylated, providing convenient access to 2,4-
biarylpyridines such as 24 (Scheme 6).17
Scheme 4. Selective Coupling of the Chloro Substituentsa
a Reagents and conditions: (a) limiting ArB(OH)2, catalytic
PdCl2(PPh3)2, Cs2CO3, THF, ∆; (b) ArB(OH)2, catalytic Pd2(dba)3/
P(tBu)3, Cs2CO3, THF, ∆ (18, 79%; 19, 57%). See Table 2 for
structures and yields of 14-17.
Scheme 6. Synthesis of 2,4-Biarylpyridinesa
19, respectively, proceed in acceptable yield, an alternative
approach to pyridine derivatives with unique substituents at
positions 2, 4, and 6 was clearly desirable.
Table 2. Monocoupling of Dichloropyridines
a Reagents and conditions: (a) H2, Pd/C, EtOH; (b) Tf2O, Py, 0
°C, ∼60% over two steps; (c) ArB(OH)2, catalytic Pd(OAc)2/
BINAP, THF, ∆, 88%.
In conclusion, we have described a convenient procedure
for the multigram preparation of 2,6-dichloro-4-iodopyridine
(4). We have further shown that 4 is a versatile precursor to
both di- and trisubstituted pyridines and that fully differenti-
ated 2,4,6-trisubstituted pyridines can be readily prepared.
In light of the facility with which halopyridines undergo
nucleophilic substitution and the number of commercially
available boronic acid coupling partners, we anticipate that
ready access to 4 will allow convenient preparation of a wide
range of new pyridine derivatives.
Such an alternative is provided by nucleophilic aromatic
substitution (Scheme 5). Heating 6 with sodium benzyloxide
Acknowledgment. The authors thank the National Sci-
ence Foundation for support of this research (CHE-9876333)
and the departmental NMR facilities (CHE-9709183) and
Jennifer Davis for assistance in manuscript preparation.
Scheme 5. Stepwise Transformation of 6a
Supporting Information Available: Complete experi-
mental details. All relevant spectroscopic data, including 1H
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0169269
(15) For representative examples of SNAr monosubstitution of dihalopy-
ridines, see ref 7 and the following: (a) Testaferri, L.; Tiecco, M.; Tingoli,
M.; Bartoli, D.; Massoli, A. Tetrahedron 1985, 41, 1373-1384. (b) Murata,
N.; Sugihara, T.; Kondo, Y.; Sakamoto. Synlett 1997, 298-300.
(16) Pd-catalyzed amination of certain pyridyl triflates has been shown
to require a chelating bisphosphine ligand: Arterburn, J. B.; Rao, K. V.;
Ramdas, R.; Dible, B. R. Org. Lett. 2001, 3, 1351-1354.
(17) The pyridone formed upon dechlorination and debenzylation of 20
is prone to over-reduction, although this problem is not observed in the
hydrogenolysis of 21.
a Reagents and conditions: (a) BnOH, DMF, NaH, ∆, 95%; (b)
ArB(OH)2, catalytic Pd2(dba)3/P(tBu)3, Cs2CO3, THF, ∆, 93%; (c)
H2, Pd/C, THF; (d) Tf2O, Py, 0 °C, 85% over two steps; (e)
ArB(OH)2, catalytic Pd(OAc)2/BINAP, Cs2CO3, THF, ∆, 85%.
Org. Lett., Vol. 3, No. 26, 2001
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