Trisubstituted pyrimidine derivatives from tetrafluoropyrimidine

Article abstract of DOI:10.1016/j.tet.2010.05.094

The use of tetrafluoropyrimidine as a scaffold for the synthesis of 2,4,6-trisubstituted pyrimidine derivatives by three sequential nucleophilic aromatic substitution processes is assessed. Reactions of tetrafluoropyrimidine with various amine nucleophiles followed by a series of nitrogen and oxygen centred nucleophilic species gave a range of 4,6-disubstituted-2,5- difluoropyrimidine systems regioselectively and in good yield. Displacement of a further fluorine atom from representative difluoropyrimidine derivatives proceeded to give trisubstituted pyrimidine derivatives although mixtures of products could be obtained depending upon the substrate.

Full text of DOI:10.1016/j.tet.2010.05.094

Tetrahedron 66 (2010) 6195e6204
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Trisubstituted pyrimidine derivatives from tetrafluoropyrimidine
,
b
b
c
Emma L. Parks a, Graham Sandford a , Dmitry S. Yufit , Judith A.K. Howard , John A. Christopher ,
*
David D. Miller c
a Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK
b Chemical Crystallography Group, Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK
c GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts., SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of tetrafluoropyrimidine as a scaffold for the synthesis of 2,4,6-trisubstituted pyrimidine de-
rivatives by three sequential nucleophilic aromatic substitution processes is assessed. Reactions of tet-
rafluoropyrimidine with various amine nucleophiles followed by a series of nitrogen and oxygen centred
nucleophilic species gave a range of 4,6-disubstituted-2,5-difluoropyrimidine systems regioselectively
and in good yield. Displacement of a further fluorine atom from representative difluoropyrimidine de-
rivatives proceeded to give trisubstituted pyrimidine derivatives although mixtures of products could be
obtained depending upon the substrate.
Received 12 March 2010
Received in revised form 10 May 2010
Accepted 24 May 2010
Available online 31 May 2010
Keywords:
Heterocycle
Pyrimidine
Ó 2010 Elsevier Ltd. All rights reserved.
Scaffold
Polyfunctional pyrimidine
Nucleophilic aromatic substitution
Tetrafluoropyrimidine
1. Introduction
There are a variety of well established synthetic processes that
have been adopted by many organic and medicinal chemistry
Many pyrimidine derivatives bearing a wide range of function-
ality have found applications in a significant number of commer-
cially important life-science products1 and some examples,
including two 5-fluoropyrimidine systems relevant to the chemis-
try described in this paper,2 are shown in Figure 1.
groups for the preparation of polyfunctional pyrimidine systems,
such as cyclocondensation reactions of amidine, guanidine or
thiourea derivatives with appropriate 1,3-diketone or 1,3-diester
systems3,4 and the use of polyhalogenated pyrimidine systems as
versatile multi-functional scaffolds.5 Chlorinated pyrimidine sub-
N
Cl
F
N
N
N
N
N
N
F
O
BMY 14802
O
N
N
N
H
N
N
H
HO
antipsychotic agent
F
OH
N
N
Thonzylamine
HO
Aronixil
N
O
N
N
HO
F
N
N
H
N
F
N
O
N
N
Enazadrem
Buspirone
N
N
Voriconazole
antifungal agent
Figure 1. Pyrimidine systems with useful biological activity.
strates can, for example, be utilised in various palladium catalysed
cross-coupling reactions6 and nucleophilic aromatic substitution
* Corresponding author. Tel.: þ44 1913342039; fax: þ44 1913844737; e-mail
address: Graham.Sandford@durham.ac.uk (G. Sandford).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.094

6196
E.L. Parks et al. / Tetrahedron 66 (2010) 6195e6204
processes.7,8 However, for many reactions involving nucleophilic
aromatic substitution of chlorine from polychlorinated pyrimidine
derivatives, harsh reaction conditions are frequently required.
Furthermore, of particular concern, low regioselectivity is often
obtained because these processes can be affected by a combination
of both electronic and steric factors,5 limiting the use of highly
chlorinated scaffolds in automated parallel synthesis. For example,
reaction of an amine nucleophile with 2,6-dichloropyrimidine 1 in
the first step of the synthesis of the diaminated pyrimidine system
systems,20,11 the use of this polyfunctional scaffold for the synthesis
of multi-substituted fluoropyrimidine systems by sequential sub-
stitution and an assessment of the regioselectivity of such pro-
cesses has not been explored to any great extent.
2. Results and discussion
Reactions of tetrafluoropyrimidine 4 with a representative range
of nitrogen centred nucleophiles 5 in THF, with DIPEA present as an
O
O
H
H
N
H
N
N
R
N
N
Cl
O
H2N
N
Cl
N
Cl
N
Et3N, THF
rt, 2 h
+
2
N
O
H
N
1
Cl
N
O
H
R =
N
N
O
H
N
N
Cl
N
Cl
N
Cl
H2N
N
Cl
NH2, EtOH
+
N
N
H2O3PO
N
N
3
NH2
NH2
1
Scheme 1. Synthesis of poly-substituted pyrimidine derivatives from polychlorinated pyrimidine scaffolds.9,10
2 (Scheme 1), a potent non peptide gonadotropin releasing hor-
mone (GnRH) receptor antagonist, leads to two products that must
be separated before further processing to the desired biologically
active system 2.9 Similarly, the synthesis of disubstituted derivative
3, a non-peptide antagonist of the SH2 domain of GRB2, is com-
plicated by the formation of isomeric pyrimidine systems in the
first synthetic SNAr step, leading to a low overall yield.10
HF scavenger, proceeded very efficiently to give products 6 arising
from regiospecific substitution of fluorine attached to the 4-posi-
tion in high yield (Table 1), consistent with earlier observations.20
All products were purified very readily by crystallisation of the
crude product mixtures.
Table 1
Reactions of tetrafluoropyrimidine 4 with amines
In principle, highly fluorinated pyrimidine derivatives provide
a range of highly effective scaffolds for sequential derivatisation by
nucleophilic aromatic substitution processes because, for these
systems, the regioselectivity of SNAr processes are generally not
affected by steric factors due to the relatively small size of the
fluorine atom.11 Indeed, in an ongoing research programme, we are
exploiting the use of perfluorinated heteroaromatic substrates,
such as pentafluoropyridine and tetrafluoropyridazine, as scaffolds
for the synthesis of a wide range of poly-functional pyridine,12
pyridazinone,13 [5,6]- and [6,6]-ring fused bicyclic14e16 and tri-
cyclic17,18 derivatives, exemplifying the use of various highly fluo-
rinated heteroaromatic systems as useful scaffolds.
R1 R2
N
F
F
THF, 0 o
DIPEA (3 eq)
C
F
F
N
N
amine
+
F
N
4
F
N
6
F
5
Amine
Product,%
H
Et
N
EtNH2
5a
F
F
6a, 75
N
N
O
F
In attempts to develop a convenient scaffold for the synthesis of
multi-functional pyrimidine derivatives, we assessed the use of 5-
chloro-2,4,6-trifluoropyrimidine as the starting material but found
that this system is not an ideal scaffold for analogue synthesis or for
multiple substitution processes because of the observed low
regioselectivity of reactions with nucleophiles.19 There remains,
therefore, a requirement for efficient, synthetic methodology that
allows the synthesis of polysubstituted pyrimidine derivatives that
undergo regioselective, sequential nucleophilic aromatic sub-
stitution, to meet the demands of rapid analogue synthesis tech-
niques for applications in medicinal chemistry programmes.
In this paper, we report the use of tetrafluoropyrimidine 4 as
a scaffold for the synthesis of a range of polysubstituted 5-fluo-
ropyrimidine systems by sequential SNAr processes. Whilst
reactions of tetrafluoropyrimidine 4 with a variety of nucleophiles
have been reported previously to give various 4-substituted
H
N
O
N
6b, 84
F
F
N
N
5b
N
N
F
F
NH2
H
F
F
6c, 68
5c
N
The 4-aminopyrimidine derivatives 6 are relatively electrophilic
heterocyclic systems and reactions of these substrates with a nu-
cleophilic species could, in principle, lead to three products arising
from displacement of fluorine from the 2- or 6-positions or the
amino substituent itself (Scheme 2).
Nuc1
N
Nuc1
N
Nuc2
N
Nuc1
N
F
F
F
F
F
F
F
+
Nuc2
or
or
F
N
F
N
Nuc2
Nuc2
N
F
N
Scheme 2. Possible reactions of 4-substituted pyrimidine derivatives.

E.L. Parks et al. / Tetrahedron 66 (2010) 6195e6204
6197
Reaction of model 4-aminopyrimidine systems 6aec with var-
Table 2 (continued)
Substrate, 6
ious oxygen and nitrogen centred nucleophiles was carried out and
these results are collated in Table 2. In all cases, the amino de-
rivatives 6aec gave products 7 arising from regiospecific dis-
placement of fluorine located at the 6-position and the structures of
7c and 7h were confirmed by X-ray crystallography (Fig. 2).
Nucleophile conditions
Product 7, %
H
N
H
N
ONa
F
F
N
N
EtOH, rt
Table 2
O
N
F
Reactions of 4-amino-2,5,6-trifluoropyrimidine derivatives 6aec
F
N
6c
F
F
7h, 64
R
R'
R
R'
N
N
F
F
F
Nucleophile
Conditions
N
N
N
F
Nuc
N
F
H
N
H
ONa
6
7
N
F
F
F
N
N
Substrate, 6
Nucleophile conditions
Product 7, %
THF, rt
O
N
7i, 79
F
N
6c
O
O
N
N
NH2
F
F
N
DIPEA
THF, rt
N
The regioselectivity of the nucleophilic substitution processes
N
H
N
F
F
N
F
shown in Table 2 can be explained by a consideration of the acti-
vating effects of the ring substituents on each of the most reactive
2- and 6-positions of the pyrimidine ring (Fig. 3). It is well estab-
lished that nitrogen para to the site of nucleophilic attack activates
more strongly than ortho nitrogen by a factor of approximately 3:1
and that fluorine para to the site of nucleophilic attack is slightly
deactivating with respect to hydrogen.20,11 Consequently, we would
expect fluorine located at the 2-position to be deactivated relative
to the 6-position and nucleophilic attack to occur preferentially at
the 6-position and this is indeed observed in these cases (Table 2).
Several model disubstituted difluoropyrimidine systems were
then used as substrates for reactions with nucleophiles in order to
assess the viability of using tetrafluoropyrimidine 4 as a scaffold for
the synthesis of trisubstituted derivatives. In our initial study, 7e
was reacted with an excess of piperidine under microwave irradi-
ation at 140 ꢀC and gave the expected major product 8a, confirmed
by X-ray analysis (Fig. 4), arising from substitution of the fluorine
atom at the 2-position and a minor product 8b, derived from dis-
placement of both the fluorine at the 2-position and the phenoxide
group at the 6-position, in a 6:1 ratio. 19F NMR and mass spec-
trometry analysis of the reaction mixture showed that fluorine was
displaced by piperidine exclusively before substitution of the
phenoxy group occurred and, consequently, when the reaction was
carried out under less forcing conditions and only 2 equiv of
piperidine, 8a was the only product obtained. Similarly, reaction of
7e with 2 equiv of ethylamine under similar conditions resulted in
the formation of 8c, which was characterised by X-ray crystallo-
graphy (Fig. 4) (Scheme 3).
Furthermore, controlled reactions of the related system 7f with
butylamine and piperidine gave single products 8d and 8e,
respectively, and their structures were also resolved by X-ray
crystallography (Fig. 5) (Scheme 4).
Reaction of 7e with a representative oxygen nucleophile,
sodium ethoxide, resulted in the formation of two products 8f and
8g in a 1.5:1 ratio. The major product 8f arose from displacement of
both the phenoxide group and the fluorine atom located at the
2-position whilst the minor product 8g resulted from replacement
of the fluorine at the 2-position only (Scheme 5).
All attempts to reduce the formation of the bis-ethoxy product
8f by screening multiple reaction conditions such as varying the
reaction time, solvent and concentration of the reagents gave
mixtures of products on all occasions. However, purification and
isolation of both 8f and 8g was achieved by reverse phase HPLC and
their structures were confirmed by X-ray crystallography (Fig. 6).
6b
7a, 61
O
O
N
N
N
N
H
F
F
F
N
DIPEA
THF, rt
N
N
F
N
6b
F
7b, 51
H
H
H
N
N
N
N
NH2
F
F
F
DIPEA
N
N
THF, rt
N
H
F
N
6c
F
F
7c, 72
H
N
N
F
F
F
ONa
N
EtOH, rt
O
N
F
N
6a
7d, 77
H
H
N
N
ONa
F
F
F
N
N
N
N
O
N
F
THF, rt
N
6a
F
F
F
7e, 63
O
N
O
N
ONa
F
F
F
N
EtOH, rt
O
N
F
N
6b
7f, 71
O
N
O
N
ONa
F
F
F
N
THF, rt
O
N
7g, 70
F
N
6b

6198
E.L. Parks et al. / Tetrahedron 66 (2010) 6195e6204
Figure 2. Molecular structures of (a) 7c and (b) 7h.
NR2
N
Similarly, reaction of 7f with sodium ethoxide resulted in the for-
F
F
mation of two products 8h and 8i in a 7:1 ratio and, again, all at-
tempts to establish reaction conditions that gave only a single
product were unsuccessful.
The results of the nucleophilic substitution reactions involving
7e and 7f described above reflect the fact that phenoxide is a suf-
ficiently good leaving group that, when attached to the activated
para N strongly activating
N
6
F
2 ortho N activating
meta F activating
para F deactivating
ortho N activating
ortho F activating
meta F activating
Figure 3. Activating effects for 4-amino-pyrimidine derivatives.
Figure 4. Molecular structures of (a) 8a and (b) 8c.
NHEt
N
NHEt
N
NHEt
N
F
F
F
THF, MW
+
4
+
F
140 oC, 1h
N
H
PhO
N
N
N
PhO
N
7e
N
N
8a 8b
:
, 6 : 1
8a, 73%
8b
NHEt
N
NHEt
N
THF, MW
140 oC, 1h
F
F
2 H2NEt
+
PhO
N
F
PhO
N
NHEt
7e
8c, 63%
Scheme 3. Reactions of 7e with nucleophiles.

E.L. Parks et al. / Tetrahedron 66 (2010) 6195e6204
6199
Figure 5. Molecular structures of (a) 8d (only one of the two independent molecules is shown) and (b) 8e.
systems (Scheme 6) and, in this case, only single products 8j and 8k,
the structures of which were confirmed by X-ray analysis (Fig. 6),
were obtained from reactions with piperidine and sodium phen-
oxide, respectively. Since amino groups are much poorer leaving
groups than phenoxide, competing displacement reactions are not
observed in the case of this substrate.
O
N
O
N
F
F
THF, MW
140 oC, 1h
N
N
+
H N
4
2
PhO
N
7f
F
PhO
N
N
H
8d, 50%
3. Conclusions
O
N
O
Tetrafluoropyrimidine 4 is an effective scaffold for the synthesis
of various polyfunctional pyrimidine systems by utilising sequen-
tial nucleophilic aromatic substitution processes. Reactions of tet-
rafluoropyrimidine 4 with nucleophiles are regioselective20 and, in
this paper, we have shown that 4-aminotrifluoropyrimidine de-
rivatives 6 react regioselectively with various nitrogen and oxygen
centred nucleophiles to give a range of disubstituted 2,5-difluori-
nated pyrimidine systems 7. Reactions of model disubstituted sys-
tems 7c,e,f allowed the synthesis, purification and isolation of
a range of 2,4,6-trisubstituted pyrimidine systems but the reaction
conditions required to enable the third nucleophilic substitution
processes to occur can lead to the displacement of substituents
already attached to activated positions of the pyrimidine ring.
Consequently, the use of fluorinated pyrimidine systems for parallel
N
N
N
THF, MW
140 oC, 1h
+
F
F
F
N
N
H
PhO
N
7f
PhO
N
8e
, 90%
Scheme 4. Reactions of 7f with amines.
6-position of a pyrimidine ring, it can be displaced in competing
processes with the substitution of fluorine atoms located at the less
activated 2-position.
Diaminated pyrimidine system 7c was then assessed as a sub-
strate for the synthesis of trisubstituted 5-fluoropyrimidine
NHEt
NHEt
NHEt
THF, MW,
F
F
140 oC
F
+
N
N
N
EtONa
+
15 min
EtO
OEt
N
PhO
OEt
PhO
N
F
N
8f : 8g, 1.5 : 1
8g, 13%
7e
8f, 16%
O
N
O
N
O
N
THF, 1h, 90 oC
F
F
F
+
+
1.5 NaOEt
N
N
N
8h : 8i, 7 : 1
PhO
N
OEt
EtO
N
OEt
PhO
N
7e
F
8h
, 25%
8i
Scheme 5. Reactions of 7e and 7f with sodium ethoxide.

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E.L. Parks et al. / Tetrahedron 66 (2010) 6195e6204
Figure 6. Molecular structures of (a) 8f, (b) 8g and (c) 8k (only one independent molecule is shown).
coupling constants are given in hertz. Mass spectra were recorded on
eitheraVG7070EspectrometeroraFisonsVGTrio1000spectrometer
coupled with a Hewlett Packard 5890 series II gas chromatograph.
Elemental analyses were obtained on either a PerkineElmer 240 or
a Carlo Erba Elemental Analyser. Melting points were recorded at
atmospheric pressure and are uncorrected. Column chromatography
was carried out on silica gel (Merck No.1-09385, 230e400 mesh) and
TLC analysis was performed on silica gel TLC plates.
HN
N
HN
THF, MW
DIPEA
F
F
N
N
+
N
H
EtHN
N
EtHN
N
F
7c
8j, 56%
4.2. Reactions of tetrafluoropyrimidine 4
HN
N
HN
THF, MW
F
F
4.2.1. Reactions with aminesdgeneral procedure. A mixture of tet-
rafluoropyrimidine 4, amine, DIPEA and THF was stirred at 0 ꢀC for
2 h. The solvent was evaporated and DCM (40 mL) and brine
(40 mL) were added. The mixture was stirred and passed through
a hydrophobic frit and the DCM layer collected. The DCM was
evaporated and column chromatography on silica gel or recrystal-
lisation gave the product.
N
PhONa
+
EtHN
N
OPh
EtHN
N
7c
F
8k
, 59 %
Scheme 6. Reactions of 7c with nucleophiles.
synthesis techniques is not general and the illustrative reactions
described in this paper show that regioselective synthesis of tri-
substituted derivatives may be limited to those pyrimidine systems
bearing multiple substituents that are not readily displaced by
nucleophiles.
4.2.1.1. N-Ethyl-2,5,6-trifluoropyrimidin-4-amine 6a. Tetrafluoro-
pyrimidine 4 (2.02 g, 13.3 mmol), ethylamine (6.65 mL, 13.3 mmol,
2 M in THF), DIPEA (5.16 g, 40.0 mmol) and THF (200 mL) and col-
umn chromatography using ethyl acetateehexane (1:4) as eluent
gave N-ethyl-2,5,6-trifluoropyrimidin-4-amine 6a (1.76 g, 75%) as
a yellow solid; mp 57e58 ꢀC (Found: C, 40.7; H, 3.4; N, 23.7.
C6H6F3N3 requires: C, 40.7; H, 3.4; N, 23.7%); IR (neat, v cmꢁ1) 3313,
3001, 1644, 1596, 1448, 1389, 1276, 1136, 1039, 788, 760; dH 1.29 (3H,
t, JHH 6.8, CH3), 3.56 (2H, q, JHH 6.8, CH2); dC 14.2 (s, CH3), 36.2 (s,
CH2), 127.4 (ddd, 1JCF 250, 2JCF 23, 4JCF 9, C-5), 154.7 (ddd, 1JCF 217, 3JCF
21, 4JCF 3, C-2),155.4 (ddd,1JCF 247, 2JCF 19, 3JCF 13, C-6), 156.1 (ddd, 2JCF
18, 3JCF 11, 3JCF 6, C-4); dF ꢁ48.80 (1F, d, 4JFF 25, F-2), ꢁ87.72 (1F, d, 3JFF
16, F-6), ꢁ174.15 (1F, s, F-5); m/z (ESþ) 176 ([MH]þ, 85%).
4. Experimental
4.1. General
3
3
All starting materials were obtained commercially (Sigmae
Aldrich) apart from tetrafluoropyrimidine, which was prepared by
literature procedures.20 and all solvents were dried using standard
laboratory procedures.21 NMR spectra were recorded in deuterio-
chloroform, unless otherwise stated, on a Varian VXR 400S NMR
spectrometer with tetramethylsilane and trichlorofluoromethane as
internal standards. Spectral assignments were made with the aid of
data collected by 1He1H COSYand 1He13C HETCOR experiments and
4.2.1.2. 4-(2,5,6-Trifluoropyrimidin-4-yl)morpholine 6b. Tetra-
fluoropyrimidine
4
(1.01 g, 6.64 mmol), morpholine (0.58 g,
6.67 mmol), resin bound DIPEA (2.00 g, 8 mmol, 4 mmol/g) and THF

E.L. Parks et al. / Tetrahedron 66 (2010) 6195e6204
6201
(150 mL) and recrystallisation from n-hexane gave 4-(2,5,6-tri-
fluoropyrimidin-4-yl)morpholine 6b (1.22 g, 84%) as a white solid; mp
65e66 ꢀC (Found: C, 43.7; H, 3.7; N,19.2. C8H8F3N3O requires: C, 43.8;
H, 3.7; N,19.2%); dH 3.70e3.90 (8H, m, CH2); dC 46.9 (s, NCH2), 66.8 (s,
OCH2),129.5 (ddd, 1JCF 251, 2JCF 25, 4JCF 9, C-5),154.4 (ddd, 1JCF 217, 3JCF
23, 4JCF 4,C-2),154.5(ddd, 2JCF 16, 3JCF 6,3JCF 6,C-4),159.7(ddd,1JCF 281,
2JCF 35, 3JCF 16, C-6); dF ꢁ47.90 (1F, d, 4JFF 26, F-2), ꢁ84.66 (1F, d, 3JFF 17,
F-6), ꢁ172.30 to ꢁ172.42 (1F, m, F-5); m/z (EIþ) 219 ([M]þ, 32%), 176
(60), 134 (100).
hexane gave N4-ethyl-2,5-difluoro-N6-phenylpyrimidine-4,6-diamine
7c (0.99 g, 88%) as an orange solid; mp 131e132 ꢀC (Found C, 57.3; H,
4.8; N, 22.2. C12H12F2N4 requires C, 57.6; H, 4.8; N, 22.4%); dH 1.28 (3H,
t, 3JHH 7.6, CH3), 3.51 (2H, q, 3JHH 7.6, CH2), 4.81 (1H, s, NH), 6.58 (1H, s,
NH), 7.10e7.50 (5H, m, AreH);dC 15.4(s, CH3), 36.2(s, CH2),120.5(s, C-
20),123.8(s, C-40),128.2(dd,1JCF 234,4JCF 7, C-5),129.5(s, C-30),138.4(s,
C-10),148.6 (dd, 2JCF 29, 3JCF 9, C-4),152.6 (dd, 2JCF 31, 3JCF 11, C-6), 157.4
(dd, 1JCF 207, 4JCF 3, C-2); dF ꢁ49.1 (1F, d, 5JFF 27, F-2), ꢁ149.2 (1F, d, 5JFF
27, F-5); m/z (ESþ) 251 ([MH]þ, 100%).
4.2.1.3. 2,5,6-Trifluoro-N-phenylpyrimidin-4-amine 6c. Tetrafluoro-
pyrimidine 4 (1.01 g, 6.64 mmol), aniline (0.63 g, 6.77 mmol), resin
bound DIPEA (2.02 g, 8 mmol, 4 mmol/g) and THF (150 mL) and
recrystallisation from n-hexane gave 2,5,6-trifluoro-N-phenyl-
pyrimidin-4-amine 6c (0.64 g, 43%) as a cream solid; mp 91e93 ꢀC
(Found: C, 53.0; H, 2.7; N, 18.4. C10H6F3N3 requires: C; 53.3, H; 2.7, N;
18.7%); IR (neat, v cmꢁ1): 3413, 2364, 1628, 1583, 1536, 1478, 1446,
1390, 1290, 1228, 751; dH 7.20e7.65 (5H, m, AreH); dC 121.4 (s, C-20),
125.7 (s, C-40), 127.3 (ddd, 1JCF 278, 2JCF 32, 4JCF 9, C-5), 129.7 (s, C-30),
140.9 (s, C-10), 154.0e154.2 (m, C-4), 154.2 (ddd, 1JCF 218, 3JCF 21, 4JCF 3,
C-2), 155.5 (ddd, 1JCF 283, 2JCF 32, 3JCF 9, C-6); dF ꢁ46.1 (1F, d, 4JFF 27, F-
2), ꢁ84.1 (1F, d, 3JFF 18, F-6), ꢁ177.8 (1F, m, F-5); m/z (EIþ) 224 ([M]þ,
100%), 205 (10), 186 (6).
4.3.2. Reactions of 6 with oxygen nucleophilesdgeneral procedure.
A mixture of 2,5,6-trifluoropyrimidin-4-amine derivative 6, alkox-
ide and solvent was stirred at rt for 17 h. The solvent was evapo-
rated and DCM (20 mL) and brine (20 mL) were added. The mixture
was stirred and passed through a hydrophobic frit and the DCM
layer was collected. The DCM was evaporated and recrystallisation
or column chromatography on silica gel gave pure product.
4.3.2.1. 6-Ethoxy-N-ethyl-2,5-difluoropyrimidin-4-amine 7d. N-
Ethyl-2,5,6-trifluoropyrimidin-4-amine 6a (1.00 g, 5.71 mmol), so-
dium ethoxide (0.38 g, 5.71 mmol) and ethanol (150 mL) and
recrystallisation from n-hexane gave 6-ethoxy-N-ethyl-2,5-difluor-
opyrimidin-4-amine 7d (0.88 g, 77%) as a white solid; mp 81e83 ꢀC
(Found: C, 47.3; H, 5.5; N, 20.7. C8H11F2N3O requires: C, 47.3; H, 5.5; N,
3
3
4.3. Disubstituted products 7dreactions of
trifluoropyrimidine derivatives 6
20.7%); dH 1.24 (3H, t, JHH 7.6, CH3), 1.41 (3H, t, JHH 7.6, CH3), 3.49
(2H, q, 3JHH 7.6, NCH2), 4.41 (2H, q, 3JHH 7.6, OCH2), 4.87 (1H, s, NH); dC
14.8 (s, CH3), 15.3 (s, CH3), 36.3 (s, CH2), 63.8 (s, CH2), 130.5 (dd, 1JCF
231, 4JCF 9, C-5), 154.5 (dd, 2JCF 30, 3JCF 11, C-4), 154.8 (dd, 1JCF 214, 4JCF
4, C-2), 156.3 (dd, 2JCF 27, 3JCF 10, C-6); dF ꢁ49.33 (1F, d, 5JFF 27, F-2),
ꢁ186.07 (1F, d, 5JFF 27, F-5); m/z (EIþ) 203 ([M]þ, 32%), 188(40).
4.3.1. Reactions of 6 with aminesdgeneral procedure. A mixture of
trifluoropyrimidin-4-amine derivative 6, amine nucleophile, DIPEA
and THF was stirred at rt for 12 h. The solvent was evaporated and
DCM (40 mL) and brine (40 mL) were added. The mixture was
stirred and passed through a hydrophobic frit and the DCM layer
collected. The DCM was evaporated and column chromatography
on silica gel or recrystallisation gave the product.
4.3.2.2. N-Ethyl-2,5-difluoro-6-phenoxypyrimidin-4-amine 7e. N-
Ethyl-2,5,6-trifluoropyrimidin-4-amine 6a (1.01 g, 5.77 mmol),
sodium phenoxide (0.67 g, 5.77 mmol) and THF (50 mL) after
recrystallisation from n-hexane gave N-ethyl-2,5-difluoro-6-phenox-
ypyrimidin-4-amine 7e (0.91 g, 63%) as a white solid; mp 97e99 ꢀC
(Found: C, 57.3; H, 4.3; N, 16.6. C12H11F2N3O requires: C, 57.4; H, 4.4;
4.3.1.1. N-Ethyl-2,5-difluoro-6-morpholin-4-ylpyrimidin-4-amine
7a. 4-(2,5,6-Trifluoropyrimidin-4-yl)morpholine 6b (1.03 g, 4.70
mmol), ethylamine (0.27 g, 6.00 mmol), DIPEA (0.22 g, 17.1 mmol)
and THF (100 mL) and recrystallisation from n-hexane gave 4-(2,5,6-
trifluoropyrimidin-4-yl)morpholine 7a (0.68 g, 61%) as a white solid;
mp 61e62 ꢀC (Found: C, 49.2; H, 5.8; N, 22.8. C10H14F2N4O requires:
C, 49.2; H, 5.8; N, 22.9%); dH 1.23 (3H, t, 3JHH 7.2, CH3), 3.45e3.52 (2H,
m, CH2), 3.60e3.81 (8H, m, CH2), 4.81 (1H, br s, NH); dC 15.3 (s, CH3),
36.2 (s, CH2CH3), 46.7 (s, NCH2), 67.0 (s, OCH2),128.0 (dd,1JCF 228, 4JCF
7, C-5),150.1 (dd, 2JCF 14, 3JCF 4, C-4),154.8e154.9 (m, C-6),157.1 (dd,
1JCF 206, 4JCF 3, C-2); dF ꢁ50.11 (1F, d, 5JFF 28, F-2), ꢁ175.77 (1F, d, 5JFF
28, F-5); m/z (ESþ) 245 ([MH]þ, 100%).
3
N, 16.7%); dH 1.32 (3H, t, JHH 7.2, CH3), 3.55e3.60 (2H, m, CH2),
7.20e7.53 (5H, m, AreH); dF ꢁ47.8 (1F, d, 5JFF 25, F-2), ꢁ180.2 (1F, d,
5JFF 25, F-5); m/z (ESþ) 252 ([MH]þ, 100%).
4.3.2.3. 4-(6-Ethoxy-2,5-difluoropyrimidin-4-yl)morpholine
7f. 2,4,5-Trifluoro-6-morpholinopyrimidine 6b (1.25 g, 5.71 mmol),
sodium ethoxide (0.39 g, 5.71 mmol) and ethanol (150 mL) and
recrystallisation from n-hexane gave 4-(6-ethoxy-2,5-difluoropyr-
imidin-4-yl)morpholine 7f (0.99 g, 71%) as a white solid; mp
97e98 ꢀC (Found: C, 48.8; H, 5.3; N, 17.1. C10H13F2N3O2 requires: C,
49.0; H, 5.3; N,17.1%); dH 1.42 (3H, t, 3JHH 7.2, CH3), 3.70e3.90 (8H, m,
CH2), 4.43 (2H, q, 3JHH 7.2, CH2); dC 14.7 (s, CH3), 47.0 (d, 4JCF 7, NCH2),
4.3.1.2. 4-(2,5-Difluoro-6-(piperidin-1-yl)pyrimidin-4-yl) morpho-
line 7b. 4-(2,5,6-Trifluoropyrimidin-4-yl)morpholine 6b (1.03 g,
4.70 mmol), piperidine (0.50 g, 5.88 mmol), DIPEA (0.22 g,
17.5 mmol) and THF (100 mL) and column chromatography using
ethyl acetateehexane (1:3) as eluent gave 4-(2,5-difluoro-6-
(piperidin-1-yl)pyrimidin-4-yl)morpholine 7b (0.68 g, 51%) as
a white solid; mp 59e60 ꢀC (Found: C, 54.7; H, 6.4; N, 19.5.
C13H18F2N4O requires: C, 54.9; H, 6.4; N, 19.7%); dH 1.50e1.75 (6H,
m, CH2), 3.21e3.85 (12H, m, CH2); dC 24.9 (s, CH2) 26.3 (s, CH2),
4
64.2 (s, OCH2), 66.9 (s, OCH2), 128.4 (dd, 1JCF 244, JCF 9, C-5), 152.6
2
3
4
(dd, JCF 22, JCF 4, C-4), 154.0 (dd, 1JCF 210, JCF 3, C-2), 160.6e160.7
(m, C-6); dF ꢁ49.59 (1F, d, 5JFF 27, F-2), ꢁ172.81 (1F, d, 5JFF 27, F-5); m/z
(ESþ) 246 ([MH]þ, 100%).
4.3.2.4. 4-(2,5-Difluoro-6-phenoxypyrimid-4-yl)morpholine 7g.
2,4,5-Trifluoro-6-morpholinopyrimidine 6b (1.07 g, 4.88 mmol),
sodium phenoxide (0.56 g, 4.90 mmol) and THF (100 mL) and
recrystallisation from n-hexane gave 4-(2,5-difluoro-6-phenox-
ypyrimid-4-yl)morpholine 7g (1.12 g, 78%) as a white solid; mp
128e130 ꢀC (Found: C, 57.3; H, 4.5; N, 14.3. C14H13F2N3O2 requires:
C, 57.3; H, 4.5; N, 14.3%); dH 3.50e3.80 (8H, m, CH2), 7.10e7.50 (5H,
m, ArH); dC 46.8 (s, NCH2), 66.9 (s, OCH24), 121.4 (s, C-20), 126.0 (s, C-
1
47.5 (s, NCH2), 48.3 (s, NCH2), 67.1 (s, OCH2), 128.0 (dd, JCF 240,
4JCF 8, C-5), 154.0e154.2 (m, C-4), 154.2e154.3 (m, C-6), 153.8 (dd,
4
5
1JCF 203, JCF 2, C-2); dF ꢁ50.66 (1F, d, JFF 27, F-2), ꢁ163.61 (1F, d,
5JFF 27, F-5); m/z (ESþ) 285 ([MH]þ, 100%).
4.3.1.3. N4-Ethyl-2,5-difluoro-N6-phenylpyrimidine-4,6-diamine
7c. 2,5,6-Trifluoro-N-phenylpyrimidin-4-amine 6c (1.01 g, 4.51
mmol), ethylamine (0.26 g, 5.78 mmol), DIPEA (0.23 g, 17.5 mmol)
and THF (100 mL) at 40 ꢀC for 12 h and recrystallisation from n-
40), 129.9 (s, C-30), 132.0 (dd, JCF 244, JC4F 9, C-5), 152.5 (s, C-10),
1
153.5e153.6 (m, C-4), 154.0 (dd, 1JCF 213, JCF 3, C-2), 159.8e159.9
(m, C-6); dF ꢁ48.3 (1F, d, 5JFF 28, F-2), ꢁ170.7 (1F, d, 5JFF 28, F-5); m/z
(ESþ) 294 ([MH]þ, 100%).

6202
E.L. Parks et al. / Tetrahedron 66 (2010) 6195e6204
4.3.2.5. 6-Ethoxy-2,5-difluoro-N-phenylpyrimidin-4-amine 7h.
4-morpholino-6-phenoxypyrimidin-2-amine 8d (0.71 g, 50%) as
a white solid; mp 126e127 ꢀC (Found: C, 62.4; H, 6.7; N, 16.1.
C18H23FN4O2 requires: C, 62.4; H, 6.7; N, 16.2%); dH 0.89 (3H, t, 3JHH
7.6, CH3), 1.25e1.50 (4H, m, CH2), 3.10e3.20 (2H, m, CH2), 3.65e3.85
(8H, m, CH2), 4.76 (1H, NH), 7.10e7.40 (5H, m, ArH); dC 14.1 (s, CH3),
20.3 (s, CH2), 32.0 (s, CH2), 41.7 (s, NHCH2), 46.9 (s, NCH2), 67.1 (s,
OCH2), 121.4 (s, C-20), 124.8 (s, C-40), 127.5 (d, 1JCF 240, C-5), 129.4 (s,
C-30), 153.1e153.2 (m, C-4), 153.6 (s, C-10), 156.3e156.4 (m, C-2),
158.1e158.2 (m, C-6); dF ꢁ179.4 (s); m/z (ESþ) 347.2 ([MH]þ, 100%);
crystals suitable for X-ray analysis were grown from MeOH.
2,5,6-Trifluoro-N-phenylpyrimidin-4-amine 6c (1.28 g, 5.71 mmol),
sodium ethoxide (0.66 g, 9.71 mmol) and ethanol (150 mL) and
recrystallisation from n-hexane yielded 6-ethoxy-2,5-difluoro-N-
phenylpyrimidin-4-amine 7h (0.72 g, 50%) as an off-white solid; mp
105e106 ꢀC (Found: C, 57.2; H, 4.4; N, 16.9. C12H11F2N3O requires: C,
57.4; H, 4.4; N, 16.7%); dH 1.47 (3H, t, 3JHH 7.2, CH3), 4.49 (3H, q, 3JHH
7.2, CH2), 7.10e7.65 (5H, m, AreH); dC 14.7 (s, CH3), 64.3 (s, CH2),
120.8 (s, C-20), 124.5 (s, C-40), 128.9 (dd, 1JCF 253, 4JCF 9, C-5), 129.4 (s,
C-30), 137.8 (s, C-10), 151.5 (dd, 2JCF 29, 3JCF 9, C-6), 154.4 (dd, 1JCF 216,
4JCF 4, C-2), 158.0 (dd, 2JCF 27, 3JCF 10, C-4); dF ꢁ49.97 (1F, d, 5JFF 28, F-
2), ꢁ179.31 (1F, 5JFF 28, F-5); m/z (ESþ) 252 ([MH]þ, 100%).
4.3.3.4. 4-(5-Fluoro-6-phenoxy-2-(piperidin-1-yl)pyrimidin-4-yl)
morpholine 8e. 2,5-Difluoro-4-morpholino-6-phenoxypyrimidine
7f (0.83 g, 3.38 mmol), piperidine (0.29 g, 3.41 mmol) and THF
(15 mL) and recrystallisation from hexane gave 4-(5-fluoro-6-phe-
noxy-2-(piperidin-1-yl)pyrimidin-4-yl)morpholine 8e (1.10 g, 90%) as
a white solid; mp 128e130 ꢀC; (Found: C, 64.0; H, 6.6; N, 15.4.
C19H23FN4O2 requires: C, 63.7; H, 6.5; N, 15.6%); dH 1.40e1.63 (6H,
m, CH2), 3.42e3.84 (12H, m, CH2), 7.10e7.35 (5H, m, ArH); dF ꢁ180.0
(s); m/z (ESþ) 359 ([MH]þ, 100%). Crystals suitable for X-ray analysis
were grown from MeOH.
4.3.2.6. 2,5-Difluoro-6-phenoxy-N-phenylpyrimidin-4-amine 7i.
2,5,6-Trifluoro-N-phenylpyrimidin-4-amine 6c (1.00 g, 4.46 mmol),
sodium phenoxide (0.46 g, 3.99 mmol) and THF (100 mL) and
recrystallisation from n-hexane gave 2,5-difluoro-6-phenoxy-N-
phenylpyrimidin-4-amine 7i (0.93 g, 70%) as a white solid; mp
128e130 ꢀC (Found: C, 64.1; H, 3.7; N,14.0. C16H11F2N3O requires: C,
64.2; H, 3.7; N, 14.0%); dH 6.90 (1H, br s, NH), 7.25e7.68 (10H, m,
ArH); dC 121.0 (s, ArH), 121.4 (s, ArH), 124.9 (s, ArH), 126.1 (s, ArH),
129.1 (dd, 1JCF 248, 4JCF 9, C-5), 129.2 (s, ArH), 129.9 (s, ArH), 137.4 (s,
NHeC), 152.4 (s, CeO), 152.5 (dd, 2JCF 10, 3JCF 9, C-6), 154.3 (dd, 1JCF
217, 4JCF 4, C-2), 156.6 (dd, 2JCF 10, 3JCF 7, C-4); dF ꢁ46.5 (1F, br s, F-2),
ꢁ176.9 (1F, br s, F-5); m/z (EIþ) 299 ([M]þ, 17%), 259 (5).
4.3.3.5. 2,6-Diethoxy-N-ethyl-5-fluoropyrimidin-4-amine 8f and
2-ethoxy-N-ethyl-5-fluoro-6-phenoxypyrimidin-4-amine
8g. N-
Ethyl-2,5-difluoro-6-(phenyloxy)-4-pyrimidinamine 7e (1.01 g,
4.02 mmol), sodium ethoxide (0.27 g, 4.02 mmol) and THF (50 mL)
gave a crude yellow solid (1.56 g) containing 8f and 8g in a 1.5:1
ratio by 19F NMR analysis. Preparative scale HPLC on a reverse phase
column with a solvent gradient running from 5%:95% MeCNeH2O
(0.1% formic acid) to 85%:15% gave 2,6-diethoxy-N-ethyl-5-fluo-
ropyrimidin-4-amine 8f (0.15 g, 16%) as a white solid; mp 58e60 ꢀC
(Found: C, 52.3; H, 7.0; N,18.3. C12H16FN3O2 requires: C, 52.4; H, 7.0;
N,18.3%); dH 1.27 (3H, t, 3JHH 7.2, CH3), 1.38 (6H, t, 3JHH 7.2, CH3), 3.49
4.3.3. Trisubstituted products 8dgeneral procedure. A mixture of
difluoropyrimidine derivative 7, nucleophile and solvent was sub-
jected to microwave irradiation at 140 ꢀC for 15 min. The solvent
was evaporated and DCM (40 mL) and brine (40 mL) were added.
The mixture was stirred and passed through a hydrophobic frit and
the DCM layer collected. The DCM layer was dried (MgSO4) and
evaporated to give a crude yellow solid, which was recrystallised or
purified by column chromatography.
3
3
(2H, q, JHH 7.2, CH2), 3.49 (4H, q, JHH 7.2, OCH2); dC 14.8 (s, CH3),
14.9 (s, CH3), 15.5 (s, CH3), 36.1 (s, CH2), 62.8 (s, CH2), 63.4 (s, CH2),
2
2
4.3.3.1. N-Ethyl-5-fluoro-6-phenoxy-2-(piperidin-1-yl)pyrimidin-
4-amine 8a. N-Ethyl-2,5-difluoro-6-(phenyloxy)-4-pyrimidinamine
7e (1.01 g, 4.02 mmol), piperidine (0.66 g, 7.76 mmol) and THF
(50 mL) and column chromatography on silica gel using ethyl aceta-
teehexane (1:15) as eluent gave N-ethyl-5-fluoro-6-phenoxy-2-
(piperidin-1-yl)pyrimidin-4-amine 8a (0.92 g, 73%) as a yellow solid;
mp 78e80 ꢀC (Found: C, 64.5; H, 6.6; N,17.4. C17H21FN4O requires: C,
64.5; H, 6.7; N,17.7%); dH 1.30 (3H, t, 3JHH 7.2, CH3), 3.32e3.54 (4H, m,
CH2), 4.56 (1H, s, NH), 7.05e7.35 (5H, m, ArH); dC 15.4 (s, CH3) 25.0 (s,
CH2), 25.8(s, CH2), 36.0(s, NHCH2), 45.3(s, NCH2),120.9(s, C-20),124.3
(s, C-40),125.4 (d, 1JCF 238, C-5),129.2 (s, C-30),153.9 (s, C-10),153.9 (d,
2JCF 10, C-4), 154.1 (d, 2JCF 8, C-6),156.1 (d, 4JCF 4, C-2);dF ꢁ190.7 (s); m/z
(ESþ) 317 ([MH]þ, 100%).
127.3 (d, 1JCF 237, C-5), 153.7 (d, JCF 10, C-4), 156.2 (d, JCF 9, C-6),
158.6 (d, JCF 4, C-2); dF ꢁ191.2 (s); m/z (EIþ) 229 ([M]þ, 40%), 214
4
(44), 201 (42); crystals suitable for X-ray analysis were grown from
MeOH; and, 2-ethoxy-N-ethyl-5-fluoro-6-phenoxypyrimidin-4-
amine 8g (0.14 g, 13%) as a white solid; mp 109e110 ꢀC (Found: C,
60.4; H, 5.8; N, 15.1. C14H16FN3O2 requires: C, 60.6; H, 5.8; N, 15.2%);
dH 1.22e1.27 (3H, m, CH3), 1.28e1.32 (3H, m, CH3), 3.55 (2H, q, 3JHH
7.6, CH2), 4.10e4.25 (2H, m, CH2), 7.10e7.60 (5H, m, ArH); dC 14.6 (s,
CH3), 15.3 (s, CH3), 36.2 (s, CH2), 63.6 (s, CH2),121.2 (s, C-20),125.0 (s,
C-40), 127.7 (d, 1JCF 241, C-5), 129.5 (s, C-30), 153.20 (s, C-10), 154.7 (d,
2JCF 9, C-4), 154.8 (d, 2JCF 10, C-6), 158.7 (d, 4JCF 4, C-2); dF ꢁ185.2 (s);
m/z (EIþ) 277 ([M]þ, 20%), 262 (8), 234 (10); crystals suitable for X-
ray analysis were grown from MeOH.
4.3.3.2. N2,N4-Diethyl-5-fluoro-6-phenoxypyrimidine-2,4-di-
amine 8c. N-Ethyl-2,5-difluoro-6-(phenyloxy)-4-pyrimidinamine
7e (1.01 g, 5.71 mmol), ethylamine (0.66 g, 5.71 mmol) and THF
(50 mL) and recrystallisation from ethyl acetate gave N2,N4-diethyl-
5-fluoro-6-phenoxypyrimidine-2,4-diamine 8c (0.69 g, 63%) as a yel-
low solid; mp 88e89 ꢀC (Found: C, 60.6; H, 6.4; N, 20.4. C14H17FN4O
requires: C, 60.9; H, 6.2; N, 20.3%); dH 1.30 (3H, t, 3JHH 7.2, CH3), 1.40
4.3.3.6. 4-(2-Ethoxy-5-fluoro-6-phenoxypyrimidin-4-yl)morpho-
line
8h. 2,5-Difluoro-4-morpholino-6-phenoxypyrimidine
7f
(0.50 g, 2.04 mmol), sodium ethoxide (0.17 g, 2.55 mmol) and THF
(50 mL) and column chromatography using hexaneeethyl acetate
(12:1) as eluent gave 4-(2-ethoxy-5-fluoro-6-phenoxypyrimidin-4-
yl)morpholine 8h (0.14 g, 26%) as a white solid; mp 87e88 ꢀC
(Found: C, 60.0; H, 5.7; N, 13.4. C16H18FN3O3 requires: C, 60.2; H,
5.7; N, 13.2%); dH 1.23 (3H, t, 3JHH 7.2, CH3), 3.70e3.95 (8H, m, CH2),
4.15 (2H, q, 3JHH 7.2, CH2), 7.10e7.45 (5H, m, AreH); dF ꢁ175.0 (s); m/
z (EIþ) 319 ([M]þ, 90%), 234 (100).
3
(3H, t, JHH 7.2, CH3), 3.35e3.50 (4H, m, CH2), 4.56 (2H, s, NH),
7.01e7.35 (5H, m, ArH); dC 15.2 (s, CH3), 15.4 (s, CH3), 36.0 (s, CH2),
36.8 (s, CH2), 121.0 (s, C-20), 124.6 (s, C-40), 125.4 (d, 1JCF 237, C-5),
129.3 (s, C-30),153.8 (s, C-10),154.2 (d, 2JCF 10, C-4),154.5 (d, 2JCF 8, C-
6), 156.8 (d, 4JCF 6, C-2); dF ꢁ189.8 (s); m/z (ESþ) 277 ([MH]þ, 100%).
4.3.3.7. N4-Ethyl-5-fluoro-N6-phenyl-2-piperidin-1-ylpyrimidine-
4,6-diamine 8j. N4-Ethyl-2,5-difluoro-N6-phenylpyrimidine-4,6-di-
amine 7c (1.03 g, 4.12 mmol), piperidine (0.49 g, 5.82 mmol) and
THF (15 mL) and recrystallisation from n-hexaneeDCM gave N4-
ethyl-5-fluoro-N6-phenyl-2-piperidin-1-ylpyrimidine-4,6-diamine 8j
(0.70 g, 56%) as a pale orange solid; mp 131e132 ꢀC (Found: C, 64.6;
4.3.3.3. N-Butyl-5-fluoro-4-morpholino-6-phenoxypyrimidin-2-
amine 8d. 2,5-Difluoro-4-morpholino-6-phenoxypyrimidine 7f
(1.00 g, 4.08 mmol), butylamine (0.99 g, 13.6 mmol) and THF
(15 mL) and recrystallisation from n-hexane gave N-butyl-5-fluoro-

E.L. Parks et al. / Tetrahedron 66 (2010) 6195e6204
6203
H, 7.0; N, 22.1. C17H22FN5 requires: C, 64.7; H, 7.0; N, 22.2%); dH 1.25
(3H, t, JHH 7.6, CH3), 1.50e1.65 (6H, m, CH2), 3.40e3.80 (6H, m,
Crystal data for 8d: C18H23FN4O2, M¼346.40, triclinic, space
3
group P ꢁ1, a¼9.549(2), b¼9.985(2), c¼20.876(2) Å,
a¼92.04(3),
CH2), 4.23 (1H, s, NH), 6.16 (1H, s, NH), 7.25e7.45 (5H, m, ArH); dC
15.7 (s, CH3), 25.2 (s, CH2), 26.0 (s, CH2), 35.8 (s, NHCH2), 45.7 (s,
NCH2), 119.4 (s, C-20), 122.0 (s, C-40), 127.5 (d, 1JCF 223, C-5), 129.0 (s,
C-30), 140.2 (s, C-10), 147.0 (d, 2JCF 7, C-4), 151.1 (d, 2JCF 8, C-6), 156.8
(d, 4JCF 4, C-2); dF ꢁ191.96 (s); m/z (ESþ) 316 ([MH]þ, 100%).
b
¼95.04(3),
g
¼118.18(3)ꢀ, U¼1741.0(6) Å3, F(000)¼736, Z¼4,
Dc¼1.322 mg mꢁ3
,
m
¼0.096 mmꢁ1. 24,835 reflections yielded 8376
unique data (Rmerg¼0.0515). Final wR2(F2)¼0.1750 for all data
(636 refined parameters), conventional R1(F)¼0.0615 for 7481
reflections with Iꢂ2 , GOF¼1.066.
s
Crystal data for 8e: C19H23FN4O2, M¼358.41, monoclinic, space
4.3.3.8. N4-Ethyl-5-fluoro-2-phenoxy-N6-phenylpyrimidine-4,6-
group P 21/c, a¼17.4666(6), b¼5.4244(2), c¼19.3478(6) Å, ¼109.29
b
diamine
8k. N4-Ethyl-2,5-difluoro-N6-phenylpyrimidine-4,6-di-
(1)ꢀ, U¼1730.2(1) Å3, F(000)¼760, Z¼4, Dc¼1.376 mg mꢁ3
,
amine 7c (1.03 g, 4.12 mmol), sodium phenoxide (0.82 g,
7.07 mmol) and THF (15 mL) and recrystallisation from n-hex-
aneeDCM gave N4-ethyl-5-fluoro-2-phenoxy-N6-phenylpyrimidine-
4,6-diamine 8k (1.02 g, 79%) as a white solid; mp 124e112 ꢀC
(Found: C, 64.5; H, 6.6; N, 17.4. C18H17FN4O requires: C, 66.7; H, 5.3;
m
¼0.099 mmꢁ1
. 16,777 reflections yielded 3411 unique data
(Rmerg¼0.0247). Final wR2(F2)¼0.2304 for all data (229 refined pa-
rameters), conventional R1(F)¼0.0839 for 2772 reflections with
Iꢂ2 , GOF¼1.085.
s
Crystal data for 8f: C10H16FN3O2, M¼229.26, monoclinic, space
3
3
N, 17.3%); dH 1.22 (3H, t, JHH 7.2, CH3), 3.58 (2H, q, JHH 7.2, CH2),
4.76 (1H, br s, NH), 6.42 (1H, br s, NH), 6.95e7.45 (10H, m, ArH); dC
15.5 (s, CH3) 36.1 (s, CH2), 119.2 (s, Ar), 122.6 (s, Ar), 122.7 (s, Ar),
125.0 (s, Ar), 127.4 (d, 1JCF 235, C-5), 129.4 (s, Ar), 129.5 (s, Ar), 139.2
(s, CeN), 147.3 (d, 2JCF 8, C-4), 152.3 (d, 2JCF 10, C-6), 153.9 (s, CeO),
156.8 (d, 4JCF 4, C-2); dF ꢁ186.3 (s); m/z (ESþ) 325 ([MH]þ, 100%).
group P 21/c, a¼11.3774(6), b¼12.0944(9), c¼8.5144(6) Å, ¼97.39
b
(3)ꢀ, U¼1161.9(4) Å3, F(000)¼488, Z¼4, Dc¼1.311 mg mꢁ3
,
m
¼0.103 mmꢁ1
. 7167 reflections yielded 2388 unique data
(Rmerg¼0.0539). Final wR2(F2)¼0.1457 for all data (209 refined pa-
rameters), conventional R1(F)¼0.0549 for 2074 reflections with
Iꢂ2 , GOF¼1.090.
s
Crystal data for 8g: C14H16FN3O2, M¼277.30, orthorhombic, space
group P bca, a¼10.7762(2), b¼8.9759(2), c¼28.1543(6) Å, U¼2723.3
4.4. X-ray crystallography
(9) Å3, F(000)¼1168, Z¼8, Dc¼1.353 mg mꢁ3
,
m
¼0.102 mmꢁ1. 24,438
reflections yielded 3610 unique data (Rmerg¼0.0465). Final wR2(F2)¼
0.1022 for all data (245 refined parameters), conventional R1(F)¼
Single crystal X-ray data were collected on SMART 6000 (7c, 7h,
8c, 8e, 8k) and Rigaku R-AXIS Spider IP (8a, 8d, 8f, 8g) diffrac-
tometers equipped with Cryostream (Oxford Cryosystems) nitro-
0.0427 for 3362 reflections with Iꢂ2 , GOF¼1.138.
s
Crystal data for 8k: C18H17FN4O, M¼324.36, monoclinic, space
gen coolers at 120 K using graphite monochromated Mo K
radiation (
a
group P c, a¼12.6975(3), b¼12.8198(3), c¼20.7884(5) Å, ¼106.44
b
l
¼0.71073 Å). All structures were solved by direct
(1)ꢀ, U¼3245.6(1) Å3, F(000)¼1360, Z¼8, Dc¼1.328 mg mꢁ3
,
method and refined by full-matrix least squares on F2 for all data
using SHELXTL software. All non-hydrogen atoms were refined
with anisotropic displacement parameters, H-atoms were located
on the difference map and refined isotropically in all structures
except 8e (disordered morpholine moiety) and 8k, where they
were placed in the calculated positions and refined in riding mode.
Crystallographic data for the structures have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publications CCDC 768245d768253.
m
¼0.094 mmꢁ1
. 43,044 reflections yielded 9470 unique data
(Rmerg¼0.0372). Final wR2(F2)¼0.0968 for all data (897 refined pa-
rameters), conventional R1(F)¼0.0368 for 8372 reflections with
Iꢂ2 , GOF¼1.026.
s
Acknowledgements
We thank GlaxoSmithKline R&D and EPSRC for funding.
Crystal data for 7c: C12H12F2N4, M¼250.26, orthorhombic, space
group P bca, a¼11.2752(4), b¼8.5143(3), c¼24.4971(10) Å, U¼2351.7
Supplementary data
(2) Å3, F(000)¼1040, Z¼8, Dc¼1.414 mg mꢁ3
,
m
¼0.111 mmꢁ1. 28,797
reflections yielded 3274 unique data (Rmerg¼0.0314). Final wR2(F2)¼
0.1266 for all data (211 refined parameters), conventional R1(F)¼
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.05.094.
0.0428 for 2676 reflections with Iꢂ2 , GOF¼1.030.
s
Crystal data for 7h: C12H11F2N3O, M¼251.24, monoclinic, space
References and notes
group P 21/n, a¼7.8769(3), b¼5.4557(2), c¼25.5645(10) Å, ¼90.90
b
(1)ꢀ, U¼1098.47(7) Å3, F(000)¼520, Z¼4, Dc¼1.519 mg mꢁ3
,
1. Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell: Oxford, 2000.
2. Fluorinated Heterocyclic Compounds; Petrov, V. A., Ed.; John Wiley and Sons:
New York, NY, 2009.
3. Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry; Pergamon:
Oxford, 1984; Vols. 1e8.
4. Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Thieme: Stuttgart, 1995.
5. Polychloroaromatic Compounds; Suschitzky, H., Ed.; Plenum: London, 1974.
6. Peng, Z. H.; Journet, M.; Humphrey, G. Org. Lett. 2006, 8, 385e398.
7. Collins, I. J. Chem. Soc., Perkin Trans. 1 2000, 2845e2861.
8. Collins, I. J. Chem. Soc., Perkin Trans. 1 2002, 1921e1940.
9. Luthin, D. R.; Hong, Y. F.; Tompkins, E.; Anderes, K. L.; Paderes, G.; Kraynov, E.
A.; Castro, M. A.; Nared-Hood, K. D.; Castillo, R.; Gregory, M.; Vazir, H.; May, J.
M.; Anderson, M. B. Bioorg. Med. Chem. Lett. 2002, 12, 3635e3639.
10. Caravatti, G.; Rahuel, J.; Gay, B.; Furet, P. Bioorg. Med. Chem. Lett. 1999, 9,
1973e1978.
m
¼0.124 mmꢁ1
. 12,034 reflections yielded 3064 unique data
(Rmerg¼0.0305). Final wR2(F2)¼0.1310 for all data (207 refined pa-
rameters), conventional R1(F)¼0.0455 for 2452 reflections with
Iꢂ2 , GOF¼1.074.
s
Crystal data for 8a: C17H21FN4O, M¼316.38, monoclinic, space
group P 21/n, a¼15.164(3), b¼6.5763(13), c¼16.377(3) Å, ¼93.29
b
(3)ꢀ, U¼1630.5(6) Å3, F(000)¼672, Z¼4, Dc¼1.289 mg mꢁ3
,
m
¼0.091 mmꢁ1
. 31,813 reflections yielded 4308 unique data
(Rmerg¼0.0398). Final wR2(F2)¼0.1144 for all data (292 refined pa-
rameters), conventional R1(F)¼0.0443 for 4205 reflections with
Iꢂ2 , GOF¼1.117.
s
11. Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Oxford, 2004.
12. Chambers, R. D.; Hoskin, P. R.; Sandford, G.; Yufit, D. S.; Howard, J. A. K. J. Chem.
Soc., Perkin Trans. 1 2001, 2788e2795.
Crystal data for 8c: C14H17FN4O, M¼276.32, monoclinic, space
group P 21/c, a¼8.8074(2), b¼8.1779(2), c¼19.7704(4) Å, ¼101.40
b
(1)ꢀ, U¼1395.89(5) Å3, F(000)¼584, Z¼4, Dc¼1.315 mg mꢁ3
,
13. Pattison, G.; Sandford, G.; Yufit, D. S.; Howard, J. A. K.; Christopher, J. A.; Miller,
¼0.096 mmꢁ1. 19,449 reflections yielded 4447 unique data
D. D. J. Org. Chem. 2009, 74, 5533e5540.
14. Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. J. Org. Chem. 2005,
70, 7208e7216.
15. Baron, A.; Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. J. Org.
Chem. 2005, 70, 9377e9381.
m
(Rmerg¼0.0246). Final wR2(F2)¼0.1434 for all data (249 refined pa-
rameters), conventional R1(F)¼0.0465 for 3606 reflections with
Iꢂ2 , GOF¼1.037.
s

6204
E.L. Parks et al. / Tetrahedron 66 (2010) 6195e6204
16. Cartwright, M.W.; Parks, E.L.; Pattison, G.; Slater, R.; Sandford, G.; Wilson, I.;
Yufit, D.S.; Howard, J.A.K.; Christopher, J.A.; Miller, D.D. Tetrahedron 2010, 66,
3221e3227.
17. Cartwright, M. W.; Sandford, G.; Bousbaa, J.; Yufit, D. S.; Howard, J. A. K.;
Christopher, J. A.; Miller, D. D. Tetrahedron 2007, 63, 7027e7035.
18. Cartwright, M. W.; Convery, L.; Kraynck, T.; Sandford, G.; Yufit, D. S.; Howard, J.
A. K.; Christopher, J. A.; Miller, D. D. Tetrahedron 2010, 66, 519e529.
19. Parks, E. L.; Sandford, G.; Christopher, J. A.; Miller, D. D. BJOC 2008, 4, 22e26.
20. Brooke, G. M. J. Fluorine Chem. 1997, 86, 1e76.
21. Vogel, A. I. Practical Organic Chemistry; Longmans: London, 1962.