Aromatic C-F activation at Ni in the presence of a carbon-chlorine bond: The nickel mediated synthesis of new pyrimidines

Article abstract of DOI:10.1039/b110128e

Treatment of [Ni(COD)₂]/PCy₃ with 5-chloro-2,4,6-trifluoropyrimidine affords the C-F activation product trans-[NiF(4-C₄N₂ClF₂)(PCy₃) ₂] 2, which reacts with iodine to form 5-chloro-2,6-difluoro-4-iodo-pyrimidine 5.

Full text of DOI:10.1039/b110128e

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Aromatic C–F activation at Ni in the presence of a carbon–
chlorine bond: the nickel mediated synthesis of new pyrimidines†
Marianna I. Sladek, Thomas Braun,* Beate Neumann and Hans-Georg Stammler
Fakultät für Chemie, Universität Bielefeld, Postfach 100131, D-33501 Bielefeld, Germany.
E-mail: thomas.braun@uni-bielefeld.de
Received 7th November 2001, Accepted 14th December 2001
First published as an Advance Article on the web 7th January 2002
Treatment of [Ni(COD)2]/PCy3 with 5-chloro-2,4,6-
trifluoropyrimidine affords the C–F activation product
trans-[NiF(4-C4N2ClF2)(PCy3)2] 2, which reacts with iodine
to form 5-chloro-2,6-difluoro-4-iodo-pyrimidine 5.
Several methods have been described for the activation of
carbon–fluorine bonds of fluoroaromatic compounds by reac-
tion at transition metal centres.1 Catalytic C–F activation has
also become a reality.2–4 However, the formation of new organo-
fluorine compounds via C–F activation, followed by func-
tionalisation within the coordination sphere of the metal is still
little developed.3–6 Nevertheless, the activation of a C–F bond
in pentafluoropyridine, 2,3,5,6-tetrafluoropyridine or 2,4,6-
trifluoropyrimidine at a nickel centre can be used as a remark-
able approach to obtain fluorinated derivatives which are
otherwise inaccessible.4,6–8 While C–F activation at nickel is
selective over C–H activation,2,4,9,10 the activation of a C–F
bond in the presence of a C–Cl bond in the same ring has never
been observed. Crespo et al. reported the C–F activation of the
imine (C F )CH᎐NCH (2-ClC H ) at a Pt() centre, but with
᎐
the C–F 6an5d C–Cl bon2d on different rings.11 In this communi-
cation we describe (1) the activation of a C–F bond in the
presence of a much weaker C–Cl bond in the same aromatic
ring, (2) that the chemospecificity of the activation of a C–X
bond (X = F, Cl) in 5-chloro-2,4,6-trifluoropyrimidine by
[Ni(COD)2]/PR3 (R = Et, Cy; COD = cycloocta-1,5-diene) is
controlled by the size of the phosphine, (3) the nickel-mediated
synthesis of new fluorinated pyrimidines by C–F activation.
The stepwise treatment of [Ni(COD)2] with PEt3 and 5-
chloro-2,4,6-trifluoropyrimidine in hexane solution at room
temperature results in the formation of trans-[NiCl(5-C4N2F3)-
(PEt3)2] 1, which was crystallised at Ϫ20 ЊC (Scheme 1).‡ The
isolated yield of 20% was limited principally by the extreme
solubility of the product. However, there was a minor amount
(5%) of a yellow solid, insoluble in all common solvents, which
could not, as yet, be identified. The 19F NMR spectrum of 1
shows two resonances at δ Ϫ37.77 and Ϫ55.72 with a ratio of
2 : 1 revealing the presence of the trifluoropyrimidyl group.
The observed preference for C–Cl activation is fully consistent
with comparable reactions of chloropentafluorobenzene and
3,5-dichlorotetrafluoropyridine, which are described in the
literature.9
On using PCy3 instead of PEt3 exclusive activation of the
C–F bond takes place. Treatment of [Ni(COD)2] with PCy3 in
the presence of 5-chloro-2,4,6-trifluoropyrimidine results in the
formation of trans-[NiF(4-C4N2ClF2)(PCy3)2] 2.‡ The 31P and
19F NMR spectrum of the reaction solution reveals the pres-
ence of a minor product (18%), which was assigned as trans-
[NiCl(4-C4N2ClF2)(PCy3)2] 3.‡ However, after recrystallisation
we obtained a pure sample of 2 in moderate yield (34%). The
19F NMR spectrum of 2 exhibits a triplet at δ Ϫ377.56 (JPF
40 Hz) characteristic of the metal fluoride and two further
resonances at δ Ϫ49.86 and Ϫ73.67 with a 1 : 1 ratio revealing
6
4
Scheme 1 Reactivity of [Ni(COD)2] towards 5-chloro-2,4,6-trifluoro-
pyrimidine.
the presence of a difluoropyrimidyl group.4,8–10 The 31P NMR
spectrum displays a doublet resonance at δ 19.65 (JPF 39 Hz)
for the two equivalent phosphorus nuclei coupled to the
metal-bound fluorine.
The formation of compound 3 can be explained by a reaction
2 with free 5-chloro-2,4,6-trifluoropyrimidine. Indeed,
of
treatment of a solution of 2 with the organic substrate affords
complex 3. A comparable substitution of a metal-bound
fluoride by a chloro ligand using chloropentafluorobenzene has
been described at a rhodium centre.12 Complex 3 can also be
synthesised by reaction of 2 with NaCl (Scheme 2).
Complex 2 was crystallised at Ϫ20 ЊC from hexane. The
structure was determined by X-ray diffraction at low temper-
ature (Fig. 1).§ Despite a rotational disorder of the aromatic
ring in 2 (62 : 38) the structure provides useful data.The Ni–F
bond of 1.845(2) Å is comparable to the distance found in
trans-[NiF(2-C5NF3H)(PEt3)2] [1.856(2) Å].9 The distance
found for the Ni–C bond in 2 [1.828(8) Å, 1.863(12) Å] is in
the same range as the values found in 1 [1.8849(13) Å] and
trans-[NiF(2-C5NF3H)(PEt3)2] [1.869(4) Å].†9
We believe that a precoordination of the aromatic system
at the nickel centre, via a nitrogen atom or in an η2 mode,
is a crucial step in the activation of a C–X bond in 5-chloro-
2,4,6-trifluoropyrimidine. Similar intermediates have been
discussed in the C–F activation of hexafluorobenzene, octa-
fluoronaphthalene and pentafluoropyridine at Ni(PEt3)2.4,9,10,13
It has been proposed that these reactions proceed by a con-
certed oxidative addition mechanism. The observed chemo-
specificity in the formation of 1 and 2 might therefore be
attributed to different intermediates or, more likely, different
transition states.13,14 Although there is a small difference in the
electronic properties of PEt3 and PCy3 at nickel, we believe that
the chemospecificity is determined by steric factors.15 However,
† Electronic supplementary information (ESI) available: synthesis
details for compounds 1–3 and crystal data for 1. See http://
www.rsc.org/suppdata/dt/b1/b110128e/
DOI: 10.1039/b110128e
J. Chem. Soc., Dalton Trans., 2002, 297–299
This journal is © The Royal Society of Chemistry 2002
297

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reactions at nickel with a unique regioselectivity and a prefer-
ence for C–F over C–H activation have been studied before.8–10
We have now demonstrated that the scope of these reactions
can be expanded to the activation of a carbon–fluorine bond
in 5-chloro-2,4,6-trifluoropyrimidine using a sterically more
hindered phosphine. The described reaction provides an
unusual entry to new fluoropyrimidines bearing three different
substituents by selective replacement of one fluorine atom at
the already functionalised heterocycle.
Acknowledgements
We would like to acknowledge the Deutsche Forschungs-
gemeinschaft (grants BR-2065/1-1 and BR-2065/1-2) for finan-
cial support. We are also grateful to Ms. J. Grota for recording
the mass spectra. T. B. thanks Professor P. Jutzi for his generous
support.
Notes and references
‡ Selected data for 1, 2 and 3. 1: (Found: C, 40.84; H, 6.53; N, 5.99%.
C16H30ClF3N2NiP2 requires: C, 41.46; H, 6.52; N, 6.04%). 31P NMR
(202.5 MHz, C6D6, 300 K): δ 15.83 (s). 19F NMR (470.4 MHz, C6D6,
300 K): δ Ϫ37.77 (s, br, 2 F), Ϫ55.72 (s, br, 1 F). 2: (Found: C, 60.50; H,
8.35; N, 3.59%. C40H66ClF3N2NiP2 requires: C, 60.97; H, 8.44; N,
Scheme 2 Reactivity of 2.
3.55%). 31P NMR (202.5 MHz, C6D6, 300 K): δ 19.65 (d, JPF 39 Hz). 19
F
NMR (470.4 MHz, C6D6, 300 K): δ Ϫ49.86 (s, 1 F), Ϫ73.67 (s, 1 F),
Ϫ377.56 (t, JPF 40 Hz, 1 F). 3: (Found: C, 59.92; H, 8.70; N, 3.10%.
C40H66Cl2F2N2NiP2 requires: C, 59.72; H, 8.27; N, 3.48%). 31P NMR
(202.4 MHz, C6D6, 300 K): δ 15.67 (s). 19F NMR (470.4 MHz, C6D6,
300 K): δ Ϫ48.91 (s, 1 F), Ϫ73.77 (s, 1 F).
§ Crystal data for 2: C40H66ClF3N2NiP2, M = 788.05, monoclinic, space
group P21/n, a = 13.8320(10), b = 20.2110(15), c = 14.5510(10) Å,
β = 90.459(6)Њ, U = 4067.7(5) Å3, T = 100 K, µ(Mo-Kα) = 0.665 mmϪ1
,
Z = 4, Dc = 1.287 g cmϪ3, 28171 reflections measured, 9114 unique
(Rint = 0.0409). The disorder of the pyrimidyl ligand on two positions
was refined to an occupancy of 62 : 38. Final R1, wR2 values on all
data 0.06457, 0.0942. R1, wR2 values on [Io > 2σ(Io), 7325 reflections]
data 0.0449, 0.0890. CCDC reference number 173741. See http://
www.rsc.org/suppdata/dt/b1/b110128e/ for crystallographic data in CIF
or other electronic format.
1
¶ Selected spectroscopic data for 4 and 5. 4: NMR (C6D6, 300 K): H
(500.1 MHz): δ 7.37 (d, br, JFH 11 Hz, CH), 19F (470.4 MHz): δ Ϫ45.69
(s, br, 1 F), Ϫ59.15 (s, br, 1 F). Mass spectrum (EI) m/z 152 (Mϩ, 33%),
150 (Mϩ, 100). Accurate mass spectrum (EI) m/z calcd. for C4HN2F2Cl,
149.9796; found, 149.9814. 5: NMR (C6D6, 300 K): 19F (470.4 MHz):
δ Ϫ45.64 (s, 1 F), Ϫ55.36 (s, 1 F). Mass spectrum (EI) m/z 278 (Mϩ,
30%), 276 (Mϩ, 100).
Fig. 1 An ORTEP18 diagram of 2. Ellipsoids are drawn at the 50%
probability level. Note that the rotational disorder (62 : 38) about Cl(1),
N(1), N(2), F(2), F(3) and C(37)–C(40) leads to average locations
across the pyrimidyl ring. The two rotamers have identical bond
distances within 3σ. Data for the second rotamer are marked by a #.
Selected bond lengths (Å) and angles (Њ): Ni(1)–F(1) 1.845 (2), Ni(1)–
C(37) 1.828(8), Ni(1)–C(37#) 1.863(12), N(2)–C(37) 1.362(7), N(2)–
C(40) 1.307(6), N(1)–C(40) 1.297(7), N(1)–C(39) 1.30(2), C(37)–C(38)
1.398(7), C(38)–C(39) 1.40(2), Cl(1)–C(38) 1.713(4), F(2)–C(39)
1.31(2), F(3)–C(40) 1.344(5); C(37)–Ni(1)–F(1) 172.98(18), C(37#)–
Ni(1)–F(1) 170.4(3), P(1)–Ni(1)–P(2) 168.74(2).
1 J. Burdeniuc, B. Jedlicka and R. H. Crabtree, Chem. Ber., 1997, 130,
145 and references therein; J. L. Kiplinger, T. G. Richmond and
C. E. Osterberg, Chem. Rev., 1994, 94, 373 and references therein;
E. F. Murphy, R. Murugavel and H. W. Roesky, Chem. Rev., 1997,
97, 3425 and references therein; T. G. Richmond, in Topics in
Organometallic Chemistry, vol. 3, ed. S. Murai, Springer, New York,
1999, pp. 243–269 and references therein.
2 M. Aizenberg and D. Milstein, Science, 1994, 265, 359; M. Aizen-
berg and D. Milstein, J. Am. Chem. Soc., 1995, 117, 8674; V. P. W.
Böhm, C. W. K. Gstöttmayr, T. Weskamp and W. A. Herrmann,
Angew. Chem., Int. Ed., 2001, 40, 3387; Y. Kiso, K. Tamao and
M. Kumada, J. Organomet. Chem., 1973, 50, C12.
3 Y. Ishii, N. Chatani, S. Yorimitsu and S. Murai, Chem. Lett., 1998,
157.
4 T. Braun, M. I. Sladek and R. N. Perutz, Chem. Commun., 2001,
2254.
5 B. L. Edelbach, B. M. Kraft and W. D. Jones, J. Am. Chem. Soc.,
1999, 121, 10327.
6 R. Dagani, Chem. Eng. News, 2001, 79, 40.
7 T. Braun, S. Parsons, R. N. Perutz and M. Voith, Organometallics,
1999, 18, 1710.
8 T. Braun, S. P. Foxon, R. N. Perutz and P. H. Walton, Angew. Chem.,
Int. Ed., 1999, 38, 3326.
9 L. Cronin, C. L. Higgitt, R. Karch and R. N. Perutz, Organometal-
lics, 1997, 16, 4920.
10 S. J. Archibald, T. Braun, J. F. Gaunt, J. E. Hobson and R. N. Perutz,
J. Chem. Soc., Dalton Trans., 2000, 2013.
we also cannot exclude that instead of a concerted oxidative
addition mechanism an electron transfer process precedes the
activation of the C–X bond.16 Further mechanistic investiga-
tions are under way.
Treatment of 2 or 3 with an excess HCl in C6D6–diethyl ether
affords, after distillation under vacuum, a solution of 5-chloro-
2,4-difluoropyrimidine 4 (Scheme 2).¶ The reaction of 2 with
iodine in C6D6 yields a solution of 5-chloro-2,6-difluoro-4-
iodopyrimidine 5.¶ The reactions are quantitative according to
the NMR spectra. We have found no previous description of
compound 4 or 5. Fluorinated pyrimidines are of general inter-
est as building blocks in agrochemicals, dyes and because of
their antitumor activity.6,17
In conclusion, we have shown the first activation of an
aromatic carbon–fluorine bond at a metal centre in the presence
of a C–Cl bond in the same ring. Comparable C–F activation
11 M. Crespo, M. Martinez and J. Sales, J. Chem. Soc., Chem.
Commun., 1992, 822; see also: M. Crespo, M. Martinez and
E. de Pablo, J. Chem. Soc., Dalton Trans., 1997, 1231.
298
J. Chem. Soc., Dalton Trans., 2002, 297–299

View Article Online
16 M. K. Whittlesey, R. N. Perutz and M. H. Moore, J. Chem. Soc.,
12 S. T. Belt, M. Helliwell, W. D. Jones, M. G. Partridge and R. N.
Perutz, J. Am. Chem. Soc., 1993, 115, 1429.
Chem. Commun., 1996, 787; T. T. Tsou and J. K. Kochi, J. Am.
Chem. Soc., 1976, 101, 6319.
13 T. Braun, L. Cronin, C. L. Higgitt, J. E. McGrady, R. N. Perutz
and M. Reinhold, New J. Chem., 2001, 25, 19; see also: I. Bach,
K.-R. Pörschke, R. Goddard, C. Kopiske, C. Krüger, A. Rufinska
and K. Seevogel, Organometallics, 1996, 15, 4959; M. W. Holtcamp,
J. A. Labinger and J. E. Bercaw, J. Am. Chem. Soc., 1997, 119,
848.
14 R. Bosque, E. Clot, S. Fantacci, F. Maseras, O. Eisenstein,
R. N. Perutz, K. B. Renkema and K. G. Caulton, J. Am. Chem. Soc.,
1998, 120, 12634.
17 R. E. Banks, B. E. Smart and J. C. Tatlow, Organofluorine Chemistry,
Plenum Press, New York, 1994; A. J. Whittle, in The Chemistry of
Some Fluorinated Aryl, Pyridine and Pyrimidone Insecticides, in
Fluorine in Agriculture, ed. R. E. Banks, Fluorine Technology
Ltd., Cheshire, 1995; T. Benneche, P. Strande, R. Oftebro and
K. Undheim, Eur. J. Med. Chem., 1993, 28, 463; J. S. Driscoll,
V. E. Marquez, J. Plowman, P. S. Liu, J. A. Kelley and J. J. Barchi Jr.,
J. Med. Chem., 1991, 34, 3280.
15 C. A. Tolman, Chem. Rev., 1977, 77, 313; G. M. Bodner, M. P. May
and L. E. McKinney, Inorg. Chem., 1980, 19, 1951.
18 M. N. Burnett and C. K. Johnson, ORTEP3, Report ORNL-6895,
Oak Ridge National Laboratory, Oak Ridge, TN, 1996.
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