2-Chloro-4-tetrafluorophenoxypyrimidine: A versatile reagent for C-2 prior to C-4 functionalizations

Article abstract of DOI:10.1016/j.tetlet.2016.03.057

A novel synthetic route to 2,4-functionalized pyrimidines is reported. The approach uses 2-chloro-4-tetrafluorophenoxypyrimidine, that enables sequential palladium catalyzed functionalization at the pyrimidine C-2 position, followed by S_NAr displacement with diverse amines at C-4. The broad utility of this 'C-2 then C-4' functionalization sequence has been demonstrated with a range of cross-coupling partners and amines.

Full text of DOI:10.1016/j.tetlet.2016.03.057

Accepted Manuscript
2-Chloro-4-tetrafluorophenoxypyrimidine: a versatile reagent for C-2 prior to
C-4 functionalizations
Michael O’Donnell, Jean-Damien Charrier
PII:
S0040-4039(16)30279-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.057
TETL 47445
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 February 2016
15 March 2016
17 March 2016
Please cite this article as: O’Donnell, M., Charrier, J-D., 2-Chloro-4-tetrafluorophenoxypyrimidine: a versatile
reagent for C-2 prior to C-4 functionalizations, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.03.057
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Corresponding author:
Jean-Damien Charrier
Chemistry Department, Vertex Pharmaceuticals (Europe) Ltd
86-88 Jubilee Avenue, Milton Park, Abingdon, OX14 4RW, UK
E-mail: jean-damien_charrier@vrtx.com
2-Chloro-4-tetrafluorophenoxypyrimidine: a versatile reagent for C-2
prior to C-4 functionalizations
Abstract:
A novel synthetic route to 2,4-functionalized pyrimidines is reported. The
approach uses 2-chloro-4-tetrafluorophenoxypyrimidine, that enables
sequential palladium catalyzed functionalization at the pyrimidine C-2 position,
followed by SNAr displacement with diverse amines at C-4. The broad utility of
this ‘C-2 then C-4’ functionalization sequence has been demonstrated with a
range of cross-coupling partners and amines.
1. Introduction
The pyrimidine nucleus is found in many natural products and has been used
as a core scaffold in numerous drug discovery programmes,1-7 some leading
to marketed drugs such as Imatinib (Glivec),8 Nilotinib (Tasigna),9 Radotinib
(Supect),10 or lately Osimertinib (Tagrisso).11
In an attempt to provide an array of receptor antagonists, we sought a
versatile approach that would install an aryl or an alkyl group at the pyrimidine
C-2 position and then allow simple exploration of the C-4 position with a
diverse range of amines. 2,4-Dihalopyrimidines have provided useful building
blocks for parallel synthesis routes. However, due to the higher electrophilicity
of the C-4 position, these dihalopyrimidines are not the most suitable starting
points in cases where the objective is the simple variation at position 4. For
such an approach, 4-chloropyrimidines with an aryl/alkyl group already
installed at the C-2 position are preferred; one of the standard methods for the
preparation of 2-aryl/alkyl -4-chloropyrimidines involves the condensation of
an appropriate aryl/alkyl amidine with a ketoester and further treatment with
POCl3.12-14 While this sequence can be high yielding, the scope is limited by
the variety of commercial amidines, the difficulty in their syntheses and the
fact that the resultant hydroxypyrimidine may not react favorably with
phosphorus oxychloride. An alternative method is the derivatisation of 2-
chloro-4-methoxypyrimidine
via
metal
assisted
cross-coupling
methodology.15,16 Once again, the harsh conditions required for further
elaboration limits the scope.
Previously, we have shown that 2-chloro-4-tetrafluorophenoxypyrimidine 1
(Fig. 1) displays reverse regiochemistry to that of 2,4-dichloropyrimidine,
when subjected to sequential SNAr substitutions with amines.17 In the current
paper, we assessed (a) the potential of readily available pyrimidine 1 to react
regiospecifically at the C-2 position with various coupling partners, under

palladium catalysis (Suzuki, Negishi and Sonogashira), and (b) the ability of
the tetrafluorophenoxy group to be subsequently displaced with a range of
amines without recourse to an intermediate step.
Figure 1: Structure of 1
2. Results and discussion
2-Chloro-4-tetrafluorophenoxypyrimidine 1 was readily obtained in high yield
(84%) and complete C-4 regioselectivity,17 from the reaction of 2,4-
dichloropyrimidine and one equivalent of tetrafluorophenol in the presence of
DIPEA. Compound 1 reacted smoothly with a variety of aryl boronic acids,
under Suzuki coupling conditions to afford the C-2 aryl adducts in excellent
yields and complete regioselectivity (Table 1, Entries 1-4). Electronic effects
(Entries 2-3) and steric hindrance (Entry 4) of the arylboronic acid had no
bearing on the outcome of the coupling reactions. The best results were
obtained using Pd(OAc)2/SPhos as catalyst in dioxane/water, with lithium
hydroxide as a base,18 although good yields were also observed using
Pd(PPh3)4 and Na2CO3 in dioxane/water. Cross-coupling reactions with
zincate partners, under Negishi conditions using Pd(OAc)2/CPhos as a
catalyst in THF, equally afforded the desired C-2 adducts in high yields and
regioselectivity (Table 1, Entries 5-7), allowing access to an alkyl group at the
C-2 position (Entries 6,7). Alkyl zincates underwent coupling at room
temperature whilst the reaction of 2-pyridylzincate required warming to 50°C
for full conversion. Sonogashira coupling with phenylacetylene, using
PdCl2(MeCN)2/ X-Phos as catalyst in THF provided alkyne 9 in good yield.
Note that, the Sonogashira cross-coupling reaction proceeded poorly under
standard conditions using CuI/Pd(PPh3)4 and was much improved under
copper free conditions.
Table 1. C-2 Regioselective Suzuki, Negishi and Sonogashira cross-coupling
reactions of 1

(a) Method A: ArB(OH)2 (1.2 eq), LiOH (4 eq), Pd(OAc)2 (5 mol%), S-Phos
(10 mol%), dioxane/water, 80 °C, 2 h; Method B: RZnBr (1.2 eq), Pd(OAc)2 (5
mol%), C-Phos (10 mol%), THF, rt or 50 °C, 12 h; Method C: alkyne (1.5 eq),
PdCl2(MeCN)2 (5 mol%), X-Phos (7.5 mol%), THF, 60 °C, 2 h
(b) Isolated yields
We then needed to assess the potential of 2,3,5,6-tetrafluorophenoxide as a
leaving group at the C-4 position, in the presence of various substituents at
position 2. In this study, we selected representative substrates from Table 1
and subjected them to treatment with morpholine/Et3N/NMP (Table 2). In all
cases, the products were obtained in high yields, demonstrating the versatility
of this displacement in the presence of functional groups such as aryl, alkyl or
alkynyl. Solvents other than NMP were successfully used, including DMF (at
120 °C) and acetonitrile (at reflux), although longer reaction times were
required in the latter case. DIPEA or DBU could also be utilized as bases in
these displacements, with similar results.

Table 2. SNAr reaction of 4-tetrafluorophenoxypyrimidines with morpholine
(a) Method D: 4-tetrafluoropyrimidine (0.50 mmol), morpholine (0.55 mmol),
Et3N (0.55 mmol), NMP (1 mL), 120 °C, 12 h
(b) Isolated yields
The variety of the amines that can be used to substitute the 2,3,5,6-
tetrafluorophenoxy group at C-4 was then investigated by reacting compound
2 with a range of aliphatic and aromatic amines (Table 3). Treatment of 2 with
a slight excess of aliphatic amine in NMP, in the presence of triethylamine,
afforded the desired products in high yields (Table 3, Entries 1-4). The SNAr
reaction with a set of aromatic amines under a range of base-catalysed
conditions (DMF/DIPEA or DMSO/lutidine or MeCN/K2CO3) were
unsuccessful and only trace amounts of the desired products, even at
temperatures up to 100 °C, were obtained, whilst microwave irradiation at 110
°C improved the outcome and moderate yields (typically 20-30%) of the
desired products could be obtained from the resultant complex reaction
mixtures. The reaction of 2 with the same set of aromatic amines under acid-
catalysed conditions proved to be more successful; the use of catalytic HCl in
EtOH/water resulted in clean reaction profiles and provided good yields of the
desired 4-substituted products (Table 3, Entries 5-7).

Table 3. SNAr reaction of 4-tetrafluorophenoxypyrimidine 2 with diverse
amines
(a) Method D: 4-tetrafluoropyrimidine (0.50 mmol), amine (0.55 mmol), Et3N
(0.55 mmol), NMP (5 mL), 120 °C, 12 h; Method E: HCl, EtOH/water, 90 °C
(b) Isolated yields
In summary, we have described a versatile synthetic route for the sequential
‘C-2 then C-4’ functionalization of pyrimidines using readily available 2-chloro-
4-tetrafluorophenoxy pyrimidine 1. The route enables functionalization at the
C-2 position of pyrimidines, using palladium catalyzed cross-coupling
conditions, followed by SNAr amination at C-4. This general method therefore
allows facile derivatisation at the C-4 position of the pyrimidine nucleus with
no restrictions due to functional group incompatibility. We have shown that
compound 1 affords the opposite regiochemistry compared to that obtained
with commonly used dihalopyrimidines, therefore offering a complementary
tool for the synthesis of pyrimidine-containing compounds.

References
1. Hurst, D. T. In An Introduction to the Chemistry and Biochemistry of
Pyrimidines, Purines and Pteridines; Wiley: Chichester, 1980.
2. Brown, D. J. In Comprehensive Heterocyclic Chemistry,Vol. 3; Katritzky,
A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1984, Chap. 2.13.
3. Brown, D. J. In The Pyrimidines; Wiley Interscience: New York, 1994.
4. Chen, X.; Zhan, P.; Li, D.; De Clercq, E.; Liu, X. Curr. Med. Chem.
2011, 18, 359-376.
5. Sorbera, L. A.; Serradell, N.; Rosa, E.; Bolós, J. Drugs Future 2007, 32,
1046-1052.
6. Wang, S.; Meades, C.; Wood, G.; Osnowski, A.; Anderson, S.; Yuill, R.;
Thomas, M.; Mezna, M.; Jackson, W.; Midgley, C.; Griffiths, G.;
Fleming, I.; Green, S.; McNae, I.; Wu, S.-Y.; McInnes, C.; Zheleva, D.;
Walkinshaw, M. D.; Fischer, P. M. J. Med. Chem. 2004, 47, 1662-1675.
7. Bukowski, R. M.; Yasothan, U.; Kirkpatrick, P. Nat. Rev. Drug Discov.
2010, 9, 17-18.
8. Cohen, M.; Williams, G.; Johnson, J.; Duan, J.; Gobburu, J.; Rahman,
A.; Benson, K.; Leighton, J.; Kim, S.; Wood, R.; Rothmann, M; Chen,
G; Staten, A; Pazdur, R. Clin. Canc. Res., 2002, 8, 935-42.
9. Hazarika, M.; Jiang, X.; Liu, Q.; Lee, S.-L.; Ramchandani, R.; Garnett,
C.; Orr, M. S.; Sridhara, R.; Booth, B.; Leighton, J. K.; Timmer, W.;
Harapanhalli, R.; Dagher, R.; Justice, R.; Pazdur, R. Clin. Canc. Res.,
2008, 14, 5325-5331.
10.Zabriskie, M. S.; Vellore, N. A.; Gantz, K. C.; Deininger, M. W.; O'Hare,
T. Leukemia, 2015, 29, 1939-1942.
11.S Ayeni, D.; Politi, K.; Goldberg, S. B. Clin. Cancer Res., 2015, 21,
3818–20.
12.Katritzky, A. R.; Yousaf, T. I. Can. J. Chem. 1986, 64, 2087–2093.
13.Opitz, A.; Sulger, W.; Daltrozzo, E.; Koch, R. Australian Journal of Chemistry,
2015, 68, 814-824.
14.Negoro, K.; Yonetoku, Y.; Maruyama, T.; Yoshida, S.; Takeuchi, M.;
Ohta, M. Bioorg Med Chem. 2012, 20, 2369-2375.
15.Yoon, T.; De Lombaert, S.; Brodbeck, R.; Gulianello, M.; Krause, J. E.;
Hutchison, A.; Horvath, R. F.; Ge, P.; Kehne, J.; Hoffman, D.;
Chandrasekhar, J.; Doller, D.; Hodgetts, K. J. Bioorg. Med. Chem. Lett.
2008, 18, 4486– 4490.
16.Chou, C.C.; Chen, P.H.; Hu, F.C.; Chi, Y.; Ho, S.T.; Kai, J.J.; Liu, S.H.;
Chou, P.T. J. Mater. Chem. A, 2014, 2, 5418-5426.
17.O’Donnell, M; Charrier, J-D. Tetrahedron, 2015, 1515-1522.
18.Asano, S.; Kamioka, S.; Isobe, Y. Tetrahedron, 2012, 68, 272-279.

Graphical abstract

Highlights
 Description of uses of 2-chloro-4-tetrafluorophenoxypyrimidine
 Description of its reactivity for the preparation of 2,4-disubstituted
pyrimidines
 First functionalization occurs at C-2, under metal-catalysed cross-
coupling reactions
 Second functionalization occurs at C-4, with aliphatic or aromatic
amines
 Approach offers complementary tool for the synthesis of
pyrimidine-containing compounds