Rerouting nucleophilic substitution from the 4-position to the 2- or 6-position of 2,4-dihalopyridines and 2,4,6-trihalopyridines: The solution to a long-standing problem

Article abstract of DOI:10.1021/ol047826g

(Chemical Equation Presented) 2,4-Difluoro-, 2,4,6-trifluoro-, and 2,3,4,6-tetrafluoropyridine undergo nucleophilic substitution preferentially if not exclusively at the 4-position. However, after the introduction of a trialkylsilyl group at C-3 or C-5, t

Full text of DOI:10.1021/ol047826g

ORGANIC
LETTERS
2005
Vol. 7, No. 1
127-129
Rerouting Nucleophilic Substitution from
the 4-Position to the 2- or 6-Position of
2,4-Dihalopyridines and
2,4,6-Trihalopyridines: The Solution to a
Long-Standing Problem
Manfred Schlosser,* Thierry Rausis, and Carla Bobbio
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fe´de´rale, BCh,
CH-1015 Lausanne, Switzerland
manfred.schlosser@epfl.ch
Received October 22, 2004
ABSTRACT
2,4-Difluoro-, 2,4,6-trifluoro-, and 2,3,4,6-tetrafluoropyridine undergo nucleophilic substitution preferentially if not exclusively at the 4-position.
However, after the introduction of a trialkylsilyl group at C-3 or C-5, the halogen at the 6-(2-)position is displaced selectively. This synthetically
valuable regiocontrol can also be realized with other halopyridines such as 2,4-dichloro- and 2,4,6-trichloropyridine.
Fluoropyridines and chloropyridines have two major reaction
modes enabling the introduction of functional groups. They
can be selectively lithiated to be subsequently combined with
a huge variety of electrophiles.1 Alternatively, the halogens,
if located at activated centers, may be displaced by a
manifold of nucleophiles such as alkoxy, amino, or cyano
groups.2,3 Whenever two or three halogens simultaneously
occupy 2-(6-) and 4-positions, the reaction is found to occur
preferentially or exclusively at the latter.4 Previous attempts
to reverse this order of priority met only limited success.
The 4- to 2-substitution ratios were found to decrease from
>10:1 to 1:1 or 1:2 when the substrates pentafluoropyridine,
3-chlorotetrafluoropyridine, and 3,5-dichlorotrifluoropyridine
were treated with lithium or sodium oximates rather than
with standard nucleophiles.5
We are now able to suggest a more rigorous and, at the
same time, convenient approach to this regioselectivity issue.
The approach is based on the accidental finding that bulky
trialkylsilyl groups totally suppress the nucleofugal mobility
of neighboring halogen atoms. Having scrutinized a series
(1) (a) Schlosser, M. In Organometallics in Synthesis: A Manual;
Schlosser, M., Ed.; Wiley: Chichester, 2002; pp 1-352, spec. 247 [Table
144]. (b) Marzi, E.; Bigi, A.; Schlosser, M. Eur. J. Org. Chem. 2001, 1371-
1376. (c) Bobbio, C.; Schlosser, M. Eur. J. Org. Chem. 2001, 4533-4536.
(d) Schlosser, M.; Bobbio, C. Eur. J. Org. Chem. 2002, 4174-4180. (e)
Cottet, F.; Marull, M.; Lefebvre, O.; Schlosser, M. Eur. J. Org. Chem. 2003,
1559-1568.
(2) Spitzner, D. In Houben-Weyl: Methoden der Organischen Chemie
(Kreher, R. P., Ed.); Thieme: Stuttgart, 1992; Vol. E7b, pp 286-686, spec.
604-625.
(3) Crampton, M. R. In Organic Reaction Mechanisms; Knipe, A. C.,
Watts, W. E., Eds.; Wiley: Chichester, 2003; pp 275-286 and previous
volumes of this series.
(4) (a) Banks, R. E.; Burgess, J. E.; Cheng, W. M.; Haszeldine, R. N. J.
Chem. Soc. 1965, 575-581. (b) Chambers, R. D.; Drakesmith, F. G.;
Musgrave, W. K. R. J. Chem. Soc. 1965, 5045-5048. (c) Aksenov, V. V.;
Vlasov, V. M.; Yakobson, G. G. J. Fluorine Chem. 1982, 20, 439-458.
(d) Mittelbach, M. Synthesis 1988, 479-480. (e) Laev, S. S.; Shteingarts,
V. D. J. Fluorine Chem. 1999, 96, 175-185. (f) Miller, A. D.; Krasnov,
V. I.; Peters, D.; Platonov, V. E.; Miethchen, R. Tetrahedron Lett. 2000,
41, 3817-3819.
(5) (a) Banks, R. E.; Jondi, W. J.; Tipping, A. E. J. Fluorine Chem.
1996, 77, 87-92. (b) Banks, R. E.; Jondi, W. J.; Tipping, A. E. J. Fluorine
Chem. 1996, 80, 109-116.
10.1021/ol047826g CCC: $30.25
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of different nucleophiles, we soon settled upon hydrazine
as our favorite reagent. The resulting hydrazinopyridines6
are unusually versatile intermediates. Other than being
incorporated into pyrazoles7 by condensation with 1,3-
dicarbonyl compounds and reduced to aminopyridines by
NN-cleaving hydrogenolysis,8 they may lose both nitrogen
atoms by dediazotation of a transient diazenylpyridine. The
latter species can be generated by oxidation of the hydrazi-
nopyridine with copper(II) sulfate9 or by base-promoted 1,6-
dehydrogenation of a tautomeric form of the halohydrazi-
nopyridine.10 In either case the hydrazino group is replaced
by a hydrogen atom, whereas a bromine atom enters instead
if the dehydrogenation of the hydrazinopyridine is ac-
complished with elemental bromine.11
Scheme 2. Regiodivergent Substitution of
2,4,6-Trifluoropyridine and
2,4,6-Trifluoro-3-(triethylsilyl)pyridine
Prepared from the hydrazine compound 12 (see Scheme
2), 2,4-difluoropyridine reacted with hydrazine to afford
Scheme 1. Regiodivergent Substitution of
2,4-Difluoropyridine and 2,4-Difluoro-5-(trimethylsilyl)pyridine
(4) with Hydrazine
of regioselectivity, but this time in favor of the 2-position
(Scheme 1). The resulting 4-fluoro-2-hydrazino-5-(trimeth-
ylsilyl)pyridine (5, 63%) was converted into the targeted
4-fluoro-2-hydrazinopyridine (6, 53%) by protodesilylation
using tetrabutylammonium fluoride hydrate (“TBAF”).
2,4,6-Trifluoropyridine4b underwent nucleophilic substitu-
tion solely at the 4-position, thus producing, for example,
4-(dimethylamino)-2,6-difluoropyridine (7; 86%) and 2,6-
difluoro-4-hydrazinopyridine (8; 85%). On the other side,
2,4,6-trifluoro-3-(triethylsilyl)pyridine (9; from 2,4,6-tri-
fluoropyridine by consecutive reaction with butyllithium and
chlorotriethysilane in 84% yield) condensed with hydrazine
at the 6-position to afford the key intermediate 10 (98%),
which gave the 2,4-difluoro-3-(triethylsilyl)pyridine 11 (89%)
by copper(II)-mediated dehydrogenating dediazotation and
2,4-difluoro-3-iodopyridine (2, 93%) by iododesilylation. The
2,4-difluoro-6-hydrazinopyridine (12), obtained by protode-
silylation of intermediate 10 in 85% yield, provided 2-bromo-
4,6-difluoropyridine (13, 71%) and 2,4-difluoropyridine (14,
51%12) through oxidation with elemental bromine and copper
sulfate, respectively (Scheme 2).
The silencing of nucleophilic exchange centers in the
vicinity of trialkylsilyl groups is a phenomenon that holds
the promise of universal applicability. We have applied the
method to 2,3,4,6-tetrafluoro-5-(trimethylsilyl)pyridine (15),
2,4-dichloro-5-(triethylsilyl)pyridine (16), and 2,4,6-trichloro-
3-(trimethylsilyl)pyridine (17). Reaction with hydrazine and,
except in the case of 16, subsequent protodesilylation
(producing the transient intermediates 18-20) and oxidative
dediazotation afforded the final products 2,4,5-trifluoropy-
ridine (21), 4-chloro-3-(triethylsilyl)pyridine (22), and 2,4-
2-fluoro-4-hydrazinopyridine (1; 73%) exclusively. 2,4-
Difluoro-5-(trimethylsilyl)pyridine (4), made in three steps
starting from 2,4-difluoropyridine through 2,4-difluoro-3-
iodopyridine (2; see Scheme 1) and 2,4-difluoro-5-iodopy-
ridine (3), exhibited toward hydrazine the same high degree
(6) Brooke, G. M.; Burdon, J.; Stacey, M.; Tatlow, J. C. J. Chem. Soc.
1960, 1768-1771.
(7) Stanovnik, B.; Svete, J. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; Neier, R., Ed.; Thieme: Stuttgart,
2002; pp 15-205, spec. 22-84.
(8) (a) Newbold, B. T. In The Chemistry of the Hydrazo, Azo and Azoxy
Groups; Patai, S., Ed.; Wiley: London, 1975; Part 2, pp 600-641, spec.
630 - 631. (b) Holland, D.; Moore, G. J.; Tamborski, C. J. Org. Chem.
1964, 29, 1562-1565. (c) Chambers, R. D.; Hutchinson, J.; Musgrave, W.
K. R. J. Chem. Soc. 1964, 3736-3739.
(9) (a) Kornblum, N. Org. React. 1944, 2, 262-340, spec. 287-288.
(b) Birchall, J. M.; Haszeldine, R. N.; Parkinson, A. R. J. Chem. Soc. 1962,
4966-4976.
(10) Collins, I.; Roberts, S. M.; Suschitzky, H. J. Chem. Soc. C 1971,
167-174.
(11) (a) Seide, O. A.; Scherlin, S. M.; Bras, G. J. J. Prakt. Chem. 1933,
138, 55-68, spec. 65. (b) Joshi, S. S.; Deorha, D. S. J. Chem. Soc. 1957,
2414-2414.
(12) In reality, the yield is high but almost half of the product is lost
upon steam distillation because of its extreme volatility.
128
Org. Lett., Vol. 7, No. 1, 2005

dichloropyridine (23) in, respectively, 65, 64, and 48%
overall yields (Scheme 3).
Scheme 4. Two Alternative Images (24a and 24b) of the
Meisenheimer-Type Intermediate Generated upon Addition of a
Nucleophile to a 4-Halo-3-(trialkylsilyl)pyridine
Scheme 3. Regioselective Displacement of Halogen by
Hydrazine in Tetrafluoro-5-(trimethylsilyl)pyridine (15),
2,4-Dichloro-5-(triethylsilyl)pyridine (16) and
2,4,6-Trichloro-3-(trimethylsilyl)pyridine (17)
staggered arrangement (Scheme 4, 24a). However, in reality
the shrinking of the CCC angle from 120° to an estimated
112° must force the tetragonal center out of plane (24b). If,
as we assume, the nucleophile approaches in the ring plane
to occupy a quasiequatorial position (24b) rather than
orthogonally to the ring plane to take an quasiaxial position,
the bulky trialkylsilyl group will interfere with its trajectory
and thus bar its access (Scheme 4).
Acknowledgment. This work was financially supported
by the Schweizerische Nationalfonds zur Fo¨rderung der
wissenschaftlichen Forschung, Bern (Grants 20-55′303-98,
20-63′584-00, and 20-100′336-02), and the Bundesamt fu¨r
Bildung und Wissenschaft, Bern (Grant 97.0083, linked to
the TMR project FMRXCT-970129).
It is by no means obvious how to rationalize how a bulky
substituent shields neighboring halogen atoms against nu-
cleophilic displacement so effectively. If one approximates
the energy of the first transition state to that of the
Meisenheimer-type adduct that emerges from it, one might
rather have predicted a rate acceleration due to relief of inter-
nal strain. At first sight, this should occur when the nucleo-
phile docks at the halogen-bearing carbon atom and thus
transforms a trigonal center into a tetragonal center. The latter
could nicely accommodate a silyl-bound alkyl group in a
Supporting Information Available: Typical experimen-
tal procedures and full characterization of compounds 1-17
1
and 20-23 by their physical constants, H and 13C NMR
spectra, and elementary analyses. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL047826G
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