A complementary route to diaminopyrimidines through regioselective SNAr amination reactions

Article abstract of DOI:10.1016/j.tet.2015.01.043

A novel approach towards the production of diverse sets of diaminopyrimidines through sequential S_NAr reactions is reported. The readily prepared 2-chloro-4-tetrafluorophenoxypyrymidine reacts regioselectively with amines at the C-2 position. The tetrafluorophenoxy at C-4 can then be replaced with amines in a second S_NAr to afford easy access to a different and complementary set of diaminopyrimidines. The broad utility of this 'C-2 then C-4' two-step sequence has been demonstrated with a range of aromatic and aliphatic amines.

Full text of DOI:10.1016/j.tet.2015.01.043

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Tetrahedron 71 (2015) 1515e1522
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A complementary route to diaminopyrimidines through
regioselective SNAr amination reactions
*
Michael O’Donnell, Jean-Damien Charrier
Vertex Pharmaceuticals (Europe) Limited, 86-88 Jubilee Avenue, Milton Park, Abingdon OX14 4RW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach towards the production of diverse sets of diaminopyrimidines through sequential SNAr
reactions is reported. The readily prepared 2-chloro-4-tetrafluorophenoxypyrymidine reacts re-
gioselectively with amines at the C-2 position. The tetrafluorophenoxy at C-4 can then be replaced with
amines in a second SNAr to afford easy access to a different and complementary set of diaminopyr-
imidines. The broad utility of this ‘C-2 then C-4’ two-step sequence has been demonstrated with a range
of aromatic and aliphatic amines.
Received 8 September 2014
Received in revised form 6 January 2015
Accepted 19 January 2015
Available online 23 January 2015
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Diaminopyrimidines
Nucleophilic aromatic substitution
Regioselectivity
Tetrafluorophenoxy
1. Introduction
The pyrimidine nucleus is found in many natural products and
has been used as a core scaffold in numerous drug discovery pro-
grammes.1e7 Its widespread presence in pharmaceutical substances
can, in part, be attributed to the versatility of readily available re-
active pyrimidine building blocks such as 2,4-dichloropyrimidine 1.
Nucleophilic
aromatic
substitutions
(SNAr)
of
2,4-
dichloropyrimidine occur preferentially at the most electron-
deficient C-4 position.1e3 However, product mixtures arising from
substitution at C-2 in addition to C-4 are generally obtained, with
ratios depending on the nature of the nucleophile. While the pu-
rification of products from these mixtures can often prove
difficult,8e14 2,4-dihalopyrimidines have provided privileged
blocks for parallel synthesis in drug discovery,15 mostly through
diversification at C-4 followed by a substitution at C-2 (Scheme 1).
The complementary set of molecules derived from substitution at
C-2 followed by diversification at C-4 can be obtained from a 4-
methoxypyrimidine or 4-pyrimidinone with a leaving group at
Scheme 1. Two complementary approaches for the SNAr diamination of pyrimidines
where LG1 and LG2 are leaving groups.
In this work we describe a new methodology of broad utility,
that allows C-2 substitution followed by C-4 on a pyrimidine,
without recourse to an intermediate step and its consequential
limitations (Scheme 1). For this, we required a 2,4-disubsituted
pyrimidine with a leaving group LG1 that would render the C-2
position more reactive than the C-4 position, when exposed to
nucleophiles. An important criterion in our quest was that the
pyrimidine starting point should be readily available.
position-2
(e.g.,
Cl,
SMe),16e19
or
4-thioalkyl-2-
chloropyrimidines.20 In these cases though, an intermediate step
is required between the two SNAr reactions: chlorination of the 4-
position (e.g., using phosphoryl chloride) in the first two examples,
and oxidation of the thioalkyl group in the third. The need for these
intermediate reactions can limit the scope of the final products.
2. Results and discussion
Pentafluorophenoxide is widely used as a leaving group in
peptide chemistry21 and its reactivity is generally considered to be
similar to that of chloride. The leaving group capability of the
polyfluorophenoxy type can be adjusted according to the number
of fluorine substituents.22 We envisaged using three different pol-
yfluorophenoxy leaving groups at C-4, the pentafluorophenoxy, the
* Corresponding author. Tel.: þ44 (0)1235 438800; fax: þ44 (0)1235 820440;
e-mail address: jean-damien_charrier@vertex.com (J.-D. Charrier).
http://dx.doi.org/10.1016/j.tet.2015.01.043
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

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M. O’Donnell, J.-D. Charrier / Tetrahedron 71 (2015) 1515e1522
2,3,5,6-tetrafluorophenoxy and the 2,4,6-trifluorophenoxy (as in
3a, 3b and 3c, respectively).
stoichiometric amount of aliphatic amines in dichloromethane, in
the presence of triethylamine (2 equiv) at ambient temperature for
w20 h (method B). SNAr with aromatic amines were exquisitely
selective for the C-2 substitution, the undesired C-4 isomers occa-
sionally being detected only in trace amounts (ꢁ2%), whereas sig-
nificant amounts of C-4 adducts (5e10%) were observed in reactions
with aliphatic amines. We were also able to show that the C2/C4
selectivity, in the case of aliphatic amines could also be undermined
by use of inappropriate solvents, such as DMF or DMSO, which have
been reported to direct SNAr towards the C-4 substitution.10
In each case, calculation of the electrophilicity at C-4 was lower
than if it had been substituted by a chlorine atom and was also
lower than that of the chlorine-substituted C-2 (Fukui indices23 at
C-4: 0.26, 0.08, 0.09 and 0.008 for 1, 3a, 3b and 3c, respectively;
Fukui indices at C-2: 0.01, 0.12, 0.11 and 0.12 for 1, 3a, 3b and 3c,
respectively). Based on these calculations, we predicted SNAr would
take place at the C-2 position preferentially. Interestingly, Fukui
indices suggested that the electron density at the
polyfluorophenoxy-substituted C-4 was barely affected by the
number of fluorine atoms on the benzene ring. Therefore, we car-
ried out a number of experiments to reveal the relative merits of
the different polyfluorophenoxy leaving groups.
2-Chloro-4-pentafluorophenoxypyrimidine 3a was obtained
from 2,4-dichloropyrimidine and 1 equiv of pentafluorophenol in
the presence of DIPEA, in high yield (82%). The high C-4 regiose-
lectivity obtained for this substitution is in agreement with the
literature for SNAr with species such as phenoxides.24 2-Chloro-4-
pentafluorophenoxypyrimidine 3a reacted readily with aniline to
provide a mixture of three compounds, where substitution at the C-
2 position provided the major product in a 4:1 ratio (Table 1).
Scheme 2. Synthesis of disubstituted pyrimidines 5 via C-2 then C-4 regioselective
SNAr reactions.
2,3,5,6-Tetrafluorophenoxypyrimidine
trifluorophenoxypyrimidine 3c were prepared in high yields (84%
and 90%, respectively) in similar fashion to their penta-
3b
and
the
2,4,6-
Table 2
a
First SNAr displacement of 3b at C-2 with aromatic and aliphatic amines
fluorophenoxy analogue 3a. These compounds also reacted readily
with aniline, but this time, the products resulting from substitution
at C-2, 2-anilino-4-tetrafluorophenoxypyrimidine and 2-anilino-4-
trifluorophenoxypyrimidine, were formed almost exclusively. The
trifluorophenoxy leaving group, however, was found to be in-
sufficiently reactive to be useful as a starting point for the parallel
derivatization to form diamino-substituted pyrimidines. Despite
the fact that the pentafluoropyrimidine appeared to have the best
Entry
HNR1R01
Methoda
Product
Yieldb (%)
1
2
3
4
5
A
A
A
A
A
4a
4b
4c
4d
4e
83
74
90
89
73
reactivity,
we
chose
to
use
the
2,3,5,6-
tetrafluorophenoxypyrimidine variant 3b because of the regiose-
lectivity advantage in its use in SNAr reactions.
Table 1
Comparison of regioselectivity profiles following SNAr with aniline
Entry
Substrate
LG1
Ratio 4/6/7
6
7
A
A
4f
53
76
1
2
3
4
1
Cl
35:47:18
80:8:12
93:1:6
3a
3b
3c
Pentafluorophenoxy
2,3,5,6-Tetrafluorophenoxy
2,4,6-Trifluorophenoxy
4g
97:1:2
8
A
4h
77
2.1. Scope of regioselective substitution at C-2
9
B
B
B
B
4i
4j
4k
4l
76
90
77
87
We next examined the scope of the regioselectivity with various
nucleophilic amines reacting with 3b under standard conditions:
acid catalysis for aromatic amines (pivalic acid) and basic conditions
for aliphatic amines (triethylamine) (Scheme 2). With aromatic
amines, reaction of 3b provided the C-2 substituted products 4aeh
(Table 2) in moderate to excellent yields (53e90%). Typically, we
used 1.5 equiv of amine, in the presence of pivalic acid (10 equiv) at
60 ꢀC for 2 h (method A). The reaction rates were in line with the
expectations, dependent on the hindrance and the nucleophilicity
of the reacting amine. Similarlygood yields (76e87%) were obtained
when 3b was treated with aliphatic amines25 under basic condi-
tions. Tetrafluorophenoxypyrimidine 3b was found to react with
10
11
12
13
B
4m
85
a
Method A: amine (1.5 equiv), pivalic acid (10 equiv), 60 ꢀC, 2 h. Method B: amine
(1 equiv), TEA (2 equiv), DCM, rt, 12 h.
b
Isolated yield.

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M. O’Donnell, J.-D. Charrier / Tetrahedron 71 (2015) 1515e1522
1517
Table 3
2.2. Scope of regioselective substitution at C-4
Second SNAr displacement of 4a and 4j at C-4 with aromatic and aliphatic amines
We then needed to establish if the 2,3,5,6-tetrafluorophenoxy
moiety was a sufficiently good leaving group to ensure versatile
and high yielding substitution at C-4 in the presence of an amine at
C-2. For this experiment, we chose to use 2-anilinopyrimidine 4a
and 2-morpholino 4j as representative examples of an aromatic
and an aliphatic amine at the C-2 position (Table 3). Both substrates
4a and 4j reacted with a variety of aromatic amines under acid-
catalyzed conditions. Pivalic acid catalysis, as used in the previous
reaction set (method A), led to unacceptable reaction times,
whereas catalytic HCl provided universal high yields of the desired
products at the C-4 position (5aep, 43e95%). Typically, tetra-
fluorophenoxypyrimidines 4a and 4j were treated with 1.5 equiv of
aromatic amine, in the presence of a catalytic amount of hydro-
chloric acid in aqueous ethanol, at 95 ꢀC overnight (method C). The
yields of the SNAr reaction at C-4 were similarly high for both
substrates 4a and 4j and largely independent of the nature of the
aniline substituents. The most hindered 2-chloroaniline and the
deactivated 3-aminopyridine gave moderate yields of the C-4 ad-
duct when the anilino substrate 4a was used (5k and 5o, 43% and
50%, respectively). However, these aromatic amines gave signifi-
cantly better yields of the C-4 adducts with the more reactive
morpholino substrate 4j (5l and 5p, 84% and 64%, respectively). In
addition, this methodology could be extended to secondary aniline
(5m and 5n).
Entry
Substrate
HNR2R02
Methoda
C
Product
Yieldb (%)
1
4a
4j
5a
5b
5c
5d
5e
5f
84
77
86
81
83
83
84
85
86
95
43
84
70
62
50
64
89
87
92
81
90
86
89
92
2
3
4a
4j
C
C
C
C
C
C
C
D
D
D
D
4
5
4a
4j
6
7
4a
4j
5g
5h
5i
Both 4a and 4j reacted with aliphatic amines to afford the C-4
substituted products 5qex in excellent yields (86e92%). Substrates
4a and 4j were treated with a slight excess of aliphatic amines in
NMP, in the presence of diisopropylethylamine (2 equiv) at 110 ꢀC
overnight (method D).
8
9
4a
4j
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
5j
3. Conclusions
4a
4j
5k
5l
We have developed a method that enables the sequential bis-
amination of the pyrimidine nucleus, starting with a regiose-
lective SNAr reaction at the C-2 position, followed by a second SNAr
reaction at the C-4 position. This simple approach is based on the
use of 2-chloro-4-tetrafluorophenoxypyrimidine 3b as a starting
building block. The presence of the tetrafluorophenoxy leaving
group affects the reactivity of the electrophilic centres at C-2 and C-
4, leading to the unconventional C-2 then C-4 regioselective bis-
amination. The method is applicable to a wide range of primary/
secondary aromatic and aliphatic amines. This novel approach
complements the more conventional C-4 then C-2 displacement
sequence and is likely to become a valuable tool for researchers
aiming at a rapid and facile exploration at position C-4 of the py-
rimidine nucleus.
4a
4j
5m
5n
5o
5p
5q
5r
4a
4j
4a
4j
4. Experimental section
4.1. General
4a
4j
5s
1H NMR, 13C NMR and 19F NMR spectra were recorded at
500 MHz, 125 MHz and 470 MHz, respectively. MS samples were
analyzed on a mass spectrometer operated in single MS mode with
electrospray ionization. Samples were introduced into the mass
spectrometer using chromatography. HRMS spectra were recorded
on a QTOF spectrometer operating in positive electrospray mode.
Flash chromatography were carried out on an automated system,
with silica as a solid support and eluting with a 0e100% EtOAc/
5t
4a
4j
5u
5v
5w
5x
4a
4j
a
Method C: amine (1.5 equiv), HCl, EtOH/H2O, 95 ꢀC, 12 h. Method D: amine
(1.5 equiv), DIPEA (2 equiv), NMP, 110 ꢀC, o/n.
b
Isolated yield.

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M. O’Donnell, J.-D. Charrier / Tetrahedron 71 (2015) 1515e1522
petroleum ether gradient. All final products had a purity ꢂ95%,
unless specified otherwise in the experimental details. The purity of
the final compounds was determined using HPLC method: analyt-
ical reverse phase HPLC equipped with a 5 mm C-18 reverse phase
column; the mobile phases were acetonitrile/methanol (1:1) and
water (10 mm ammonium acetate). Commercially available re-
agents and solvents were used without further purification.
4.3.1. N-Phenyl-4-(2,3,5,6-tetrafluorophenoxy)pyrimidin-2-amine
4a. Following the general procedure, the reaction was carried out
with aniline to provide title compound (200 mg, 83%) as a white
solid, mp 151 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.39 (d, J¼7.0 Hz, 1H),
7.36e7.32 (m, 2H), 7.28e7.25 (m, 1H), 7.25e7.20 (m, 2H), 7.10e7.05
(m, 1H), 7.05e7.00 (m, 1H), 6.56 (d, J¼7.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3)
d 167.8, 160.3, 159.6, 147.1, 145.2, 142.2, 140.3,
138.6, 131.5, 128.6, 123.0, 119.4, 102.7, 98.2; MS m/z: 336.0 (MþH)þ;
HRMS (ESI): calcd for C16H9F4N3O (MHþ) 336.0760; found 336.0761.
4.2. General method for the preparation of compounds 3aec
4.3.2. N-(3-Chlorophenyl)-4-(2,3,5,6-tetrafluorophenoxy)pyrimidin-
2-amine 4b. Following the general procedure, the reaction was
carried out with 3-chloroaniline to provide title compound
(196 mg, 74%) as a white solid, mp 171 ꢀC; 1H NMR (500 MHz,
To a solution of 2,4-dichloropyrimidine 1 (1 g, 6.71 mmol) in
DMF (2 mL) was added the required polyfluorophenol 2 (1 equiv,
6.71 mmol), followed by DIPEA (1.04 g, 1.4 mL, 8.05 mmol) and the
mixture heated to 80 ꢀC for 1 h. The reaction mixture was cooled to
ambient temperature and partitioned between a mixture of water
(50 mL) and diethyl ether (70 mL). The organic layer was washed
with water (30 mLꢃ2), aqueous 0.1 M NaOH (30 mL) and brine. The
organic layer was then dried (MgSO4), filtered and concentrated in
vacuo to yield 3aec as colourless oils, which slowly solidified to
waxy solids upon standing.
CDCl3)
d
8.40 (d, J¼7.0 Hz, 1H), 7.54e7.52 (m, 1H), 7.42 (br s, 1H),
7.18e7.05 (m, 3H), 7.01e6.97 (m, 1H), 6.62 (d, J¼7.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3)
d 168.0, 159.8, 159.0, 147.2, 145.2, 142.1,
139.7, 134.5, 129.6, 122.9, 118.9, 117.1, 103.3, 98.9; MS m/z: 370.0
(MþH)þ; HRMS (ESI): calcd for C16H8ClF4N3O (MHþ) 370.0370;
found 370.0378.
4.3.3. N-(3-Methoxyphenyl)-4-(2,3,5,6-tetrafluorophenoxy)pyr-
imidin-2-amine 4c. Following the general procedure, the reaction
was carried out with 3-methoxyaniline to provide title compound
(236 mg, 90%) as a white solid, mp 99 ꢀC; 1H NMR (500 MHz, CDCl3)
4.2.1. 2-Chloro-4-(2,3,4,5,6-pentafluorophenoxy)pyrimidine
3a. Following the general procedure, the reaction was carried out
with pentafluorophenol to provide title compound (1.63 g, 82%) as
a white solid, mp 78 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 8.61 (d,
d
8.39 (d, J¼5.6 Hz, 1H), 7.22 (br s, 1H), 7.15e7.11 (m, 1H), 7.09e7.03
(m, 2H), 6.90e6.87 (m, 1H), 6.60e6.56 (m, 2H), 3.78 (s, 3H); 13C
NMR (125 MHz, CDCl3) 167.8, 160.1, 159.5, 147.2, 145.2, 142.2,
J¼5.7 Hz, 1H), 7.11 (d, J¼5.7 Hz, 1H);13C NMR (125 MHz, CDCl3)
d
167.9, 161.0, 160.5, 142.5, 140.5, 138.9, 137.2, 106.6; MS m/z: 296.7
d
(MþH)þ; HRMS (ESI): calcd for C10H2ClF5N2O (MHþ) 296.9854;
139.8, 129.3, 111.8, 107.7, 106.0, 102.8, 98.4, 55.2; MS m/z: 366.0
(MþH)þ; HRMS (ESI): calcd for C17H11F4N3O2 (MHþ) 366.0866;
found 366.0875.
found 296.9858.
4.2.2. 2-Chloro-4-(2,3,5,6-tetrafluorophenoxy)pyrimidine
3b. Following the general procedure, the reaction was carried out
with 2,3,5,6-tetrafluorophenol to provide title compound (1.57 g,
84%) as a white solid, mp 90 ꢀC; 1H NMR (500 MHz, DMSO-d6)
4.3.4. Methyl
3-((4-(2,3,5,6-tetrafluorophenoxy)pyrimidin-2-yl)
amino)benzoate 4d. Following the general procedure, the reaction
was carried out with methyl 3-aminobenzoate to provide title
compound (251 mg, 89%) as a white solid, mp 162 ꢀC; 1H NMR
d
8.84 (d, J¼5.7 Hz, 1H), 8.07e8.0 (m, 1H), 7.61 (d, J¼5.7 Hz, 1H); 13
C
NMR (125 MHz, CDCl3)
d
168.0, 160.9, 160.5, 146.1 (1JCeF 253 Hz),
(500 MHz, CDCl3)
(m, 2H), 7.33e7.27 (m, 2H), 7.10e7.02 (m, 1H), 6.61 (d, J¼5.6 Hz, 1H),
3.93 (s, 3H); 13C NMR (125 MHz, CDCl3)
167.8, 166.7, 160.2, 159.4,
d
8.42 (d, J¼5.6 Hz, 1H), 7.95 (br s, 1H), 7.72e7.68
140.9 (1JCeF 252 Hz), 130.4, 106.6, 103.7 (2JCeF 23 Hz); MS m/z: 279.0
(MþH)þ; HRMS (ESI): calcd for C10H3ClF4N2O (MHþ) 278.9948;
found 278.9960.
d
147.1, 145.2, 142.1, 140.0, 138.8, 130.8, 128.7, 124.1, 123.9, 120.7, 102.9,
98.9, 52.2; MS m/z: 394.2 (MþH)þ; HRMS (ESI): calcd for
4.2.3. 2-Chloro-4-(2,4,6-trifluorophenoxy)pyrimidine 3c. Following
the general procedure, the reaction was carried out with 2,4,6-
trifluorophenol to provide title compound (1.57 g, 90%) as a white
C
18H11F4N3O3 (MHþ) 394.0815; found 394.0820.
4.3.5. N-(4-(2,3,5,6-Tetrafluorophenoxy)pyrimidin-2-yl)-1H-indol-5-
amine 4e. Following the general procedure, the reactionwas carried
out with 1H-indol-5-amine to provide title compound (196 mg,
solid, mp 95 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d
8.56 (d, J¼5.7 Hz,
1H), 7.07 (d, J¼5.7 Hz, 1H), 6.82e6.88 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 168.6, 160.6, 160.5, 158.7, 156.4, 154.2, 106.5, 101.4; MS m/z:
73%) as a white solid, mp 168 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.41 (d,
260.0 (MþH)þ; HRMS (ESI): calcd for C10H4ClF3N2O (MHþ)
J¼5.6 Hz, 1H), 8.24 (br s, 1H), 7.48e7.42 (m, 1H), 7.38 (s, 1H),
261.0043; found 261.0045.
7.20e7.17 (m, 1H), 7.13e7.11 (m, 1H), 7.09e6.98 (m, 2H), 6.58 (d,
J¼5.6 Hz,1H), 6.56e6.53 (m,1H); 13C NMR (125 MHz, CDCl3)
d 167.9,
4.3. General procedure for the nucleophilic aromatic sub-
stitution of 2-chloro-4-(2,3,5,6-tetrafluorophenoxy)pyrimi-
dine with aromatic amines to afford products 4aeh
(method A)
160.2,160.0,147.2,145.2,142.3,140.3,136.4,130.9,123.4,122.2,120.1,
110.0, 106.6, 102.6, 98.8, 97.9; MS m/z: 375.1 (MþH)þ.
4.3.6. N-(2-Chlorophenyl)-4-(2,3,5,6-tetrafluorophenoxy)pyrimidin-
2-amine 4f. Following the general procedure, the reaction was
carried out with 2-chloroaniline to provide title compound
(141 mg, 53%) as a white solid, mp 119 ꢀC; 1H NMR (500 MHz,
To a mixture of 2-chloro-4-(2,3,5,6-tetrafluorophenoxy)pyrim-
idine 3b (200 mg, 0.72 mmol) and 2,2-dimethylpropanoic acid
(733 mg, 0.412 mL, 7.2 mmol, 10 equiv) was added the aromatic
CDCl3)
d
8.42 (d, J¼5.7 Hz, 1H), 7.98 (d, J¼8.2 Hz, 1H), 7.52 (s, 1H),
amine (1.08 mmol, 1.5 equiv) and the mixture was heated to 60 ꢀ
C
7.37e7.34 (m, 1H), 7.12e7.04 (m, 2H), 6.97e6.93 (m, 1H), 6.63 (d,
for 2 h. The reaction mixture was partitioned between a mixture of
water (20 mL) and diethyl ether (30 mL). The organic layer was
washed with water (20 mLꢃ2), aqueous 0.1 M NaOH (20 mL) and
brine (20 mL). The organic layer was then dried (MgSO4), filtered
and concentrated in vacuo to yield light yellow solids, which were
triturated in a small amount of 50:50 diethyl ether/petroleum
ether, filtered and dried to yield compounds 4aeh as white solids.
J¼5.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 167.8, 160.3, 159.2, 147.1,
145.2, 142.1, 140.2, 135.4, 129.2, 126.8, 123.3, 122.8, 120.4, 102.8,
99.1; MS m/z: 370.1 (MþH)þ.
4.3.7. N-Methyl-N-phenyl-4-(2,3,5,6-tetrafluorophenoxy)pyrimidin-
2-amine 4g. Following the general procedure, the reaction was
carried out with N-methylaniline to provide title compound