Expedient synthesis of biologically important sulfonylmethyl pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2014.04.111

Two novel synthetic strategies that allow rapid diversification of the sulfone moiety in sulfonylmethyl pyrimidines, a class of compounds with a wide range of biological activity, which are of interest in a wide variety of drug discovery programmes, are described.

Full text of DOI:10.1016/j.tetlet.2014.04.111

Accepted Manuscript
Expedient synthesis of biologically important sulfonylmethyl pyrimidines
Kevin Blades, Julie Demeritt, Shaun Fillery, Kevin M. Foote, Ryan Greenwood,
Clare Gregson, Lorraine A. Hassall, Thomas M. McGuire, Kurt G. Pike, Emma
Williams
PII:
S0040-4039(14)00748-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.111
TETL 44573
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 December 2013
10 April 2014
30 April 2014
Please cite this article as: Blades, K., Demeritt, J., Fillery, S., Foote, K.M., Greenwood, R., Gregson, C., Hassall,
L.A., McGuire, T.M., Pike, K.G., Williams, E., Expedient synthesis of biologically important sulfonylmethyl
pyrimidines, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.111
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Expedient synthesis of biologically
important sulfonylmethyl pyrimidines
Kevin Blades, Julie Demeritt, Shaun Fillery, Kevin M. Foote, Ryan Greenwood, Clare Gregson,
Lorraine Hassall, Thomas M. McGuire*, Kurt G. Pike, Emma Williams

1
Tetrahedron Letters
journal homepage: www.els evier.c om
Expedient synthesis of biologically important sulfonylmethyl pyrimidines
Kevin Blades, Julie Demeritt, Shaun Fillery, Kevin M. Foote, Ryan Greenwood, Clare Gregson, Lorraine
A. Hassall, Thomas M. McGuire,* Kurt G. Pike, Emma Williams
Oncology Chemistry, Astrazeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG
ARTICLE INFO
ABSTRACT
Article history:
Received
Two novel synthetic strategies that allow rapid diversification of the sulfone
moiety in sulfonylmethyl pyrimidines, a class of compounds with a wide range of
biological activity, which are of interest in a wide variety of drug disovery
programs, are described.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Sulfone, pyrimidines, ATR, mTOR
The sulfonylmethyl pyrimidine moiety can be found in a large
number of biologically active molecules. Compounds
containing this functionality have been shown to modulate
activity in a number of biological targets (Figure 1) including
Shn3, Runx2, WWP1,1 inhibition of which could be useful in
the treatment of osteoporosis, γ-secretase modulators,2 which
are implicated in Alzheimer’s disease, NGFI-B,3 and several
oncology targets including VEGF-24 and a number of proteins
belonging to the PI3-kinase like kinase (PIKK)5,6 family of
proteins. The PIKK targets have been of particular interest to
drug discovery programs within Astrazeneca and include
ATR (ataxia telangiectasia and rad3 related kinase),5 which is
involved in the repair and maintenance of the genome and its
stability,7 and mTOR (mammalian target of rapamycin
kinase),6 which regulates cell growth, proliferation and
motility.8
As such, we were interested in developing expedient routes
toward molecules with this type of moiety. We envisaged
synthesis of the desired sulfones from
a substituted
pyrimidine intermediate either by disconnection at the C-S
bond or by disconnection at the C-C bond of the pendant
sulfone group (Figure 2).
Figure 2. Retrosynthetic analysis of sulfonylmethyl pyrimidines.
We have been particularly interested in the synthesis of
pyrimidines when R1 = morpholine and R3 = H. Molecules of
this type have proven potent inhibitors of ATR5 and mTOR.6
We believed disconnection of the C-S bond would allow rapid
diversification of the sulfone moiety and thus began our
investigation there. We recently reported the synthesis of
N
F
R
HN
N
O
N
O
O
S
N
N
O
O
S
N
N
sulfonyl-morpholino-pyrimidines
3
from an advanced
VEGF2 inhibitor
pyrimidine intermediate via a three step procedure involving
formation of a masked thiolate 2 from corresponding mesylate
1 followed by alkylation and oxidation (Scheme 1).9
Y-secretase inhibitor
OMe
OH
N
O
HO
N
N
O
O
N
N
S
O
O
OH
S
N
OH
NGFI-B inhibitor
O
Shn3, Runx2, WWP1 inhibitor
O
N
N
N
N
O
O
O
O
N
S
F
S
N
O
N
N
N
H
H
ATR inhibitor
mTOR kinase inhibitor
Figure 1. Biologically active molecules containing
pyrimidine moiety.
a sulfonylmethyl

2
Tetrahedron
O
N
O
N
We treated the benzyl iodides with sodium sulfinates as
shown in Table 1. Initial reactions were attempted on the
methylmorpholine-containing compound 10 due to the needs
of our drug discovery program. The reactions were carried out
at 80 οC in acetonitrile, which led to formation of the desired
products 11a-e in high yields. Subsequently, we carried out a
number of substitution reactions on pyrimidine 9. In an
attempt to reduce reaction temperature we tried the reaction in
a number of different solvents, it was discovered the use of
DMF allowed us to carry the reactions out at room
temperature. In the majority of cases this led to complete
conversion in 1-2 hours affording the desired compounds 11f-
p in reasonable to good yields. Interestingly the ortho-nitrile
containing sulfinic acid (entry 17) underwent an in situ
cyclisation reaction to afford a bicyclic heterocycle 12. The
only limitation we found with this methodology was when
attempting to react a trifluorosulfinate salt. No evidence of
product was observed, even at elevated temperatures in DMF.
i) SC(NH2)2
N
N
ii) R-Br, base
S
MsO
R
N
N
N
2
1
N
H
H
O
N
[O]
N
O
O
S
R
N
3
N
H
Scheme 1. Three step sulfone formation.
Although this process allowed us to access a number of useful
compounds we wished to develop a more expedient route to
these molecules, which would allow more-rapid late stage
diversification. We believed reaction of benzylic iodide
intermediates with sodium sulfinates would lead to rapid
formation of the requisite products. This transformation was
not known in the literature for benzylic pyrimidines although
a single example of reaction of a benzylic bromide exists.10
We embarked upon a synthesis of the two intermediates 9 and
10 (Scheme 2) containing the desired iodine functionality.
Initial base-catalysed substitution of commercially available
dichloropyrimidine 411 gave the morpholine-containing
compounds 5 and 6 with no evidence of substitution at the 2
position. Subsequent reduction with LiBH4 to afford alcohols
7 and 8 followed by mesylation and treatment with LiI
afforded the desired benzyl iodides 9 and 10 in excellent
overall yields.
Table 1. Nucleophilic attack on benzylic iodides 9 and 10 to form sulfones
11a-p.13
Entr
y
Sulfinate
Iodi
de
Product
Conditio Yield
ns
1
2
10
10
11a
A
A
95%
76%
O
Cl
N
N
R
N
LiBH4, THF,
r.t.
morpholine,
N
11b
O
Et3N, CH2Cl2, r.t.,
N
Cl
O
Cl
O
O
4
5 R =H 80%
R =(S)-Me 76%
6
O
N
O
3
4
10
10
11c
11d
A
A
74%
85%
R
N
R
1) MeSO2Cl, Et3N, CH2Cl2, r.t.
N
N
2) LiI, 1,4-dioxane, 100 oC
I
HO
N
Cl
N
Cl
9
R= H 87%
10 R= (S)-Me 88%
7 R= H 96%
R= (S)-Me 96%
8
Scheme 2. Formation of benzylic iodides intermediates.
Only a small number of the requisite sodium sulfinates were
commercially available (Table 1, entries 1, 6-8, 11, 12 and
18); the remainder were synthesised from commercially
available sulfonyl chlorides (Scheme 3).12
5
6
10
11e
A
84%
9
9
11f
B
B
94%
49%
11g
Scheme 3. Sulfinic acid formation.
7

3
pyrimidine cores thus allowing us to arrive at biologically
active sulfonyl methylpyrimidines even more rapidly. 2-
Methylsulfonylacetates have been used in both palladium-
catalysed cross-coupling14 and SNAr15 reactions, however,
substitution of diazines had never been attempted. We
proposed that under basic conditions methyl 2-
(methylsulfonyl)acetate should undergo an SNAr reaction with
chloro-pyrimidine-containing compounds. Furthermore the
use of the methyl ester should allow for rapid decarboxylation
under basic conditions to afford benzylic sulfones. We
initially attempted this reaction with morpholine-pyrimidine
13 (Scheme 4). Methyl 2-(methylsulfonyl)acetate was treated
with sodium hydride in DMF followed by pyrimidine 13 and
the reaction was heated for 24 hours. Unfortunately no
reaction was observed.
8
9
11h
B
63%
9
9
9
9
9
9
11i
11j
B
B
B
A
B
76%
65%
93%
73%
64%
10
11
12
13
11k
11l
11m
Scheme 4. Failed SNAr reaction
We reasoned the morpholine-substituted pyrimidine ring must
be too electron rich to undergo the nucleophilic attack. As
such, we decided to attempt a nucleophilic substitution on a
more electron-poor system, dichloropyrimidine 15.
Pleasingly, the reaction proceeded well affording the desired
product in a reasonable 58% yield. Subsequent morpholine
addition proceeded quantitatively to afford compound 16.
This sequence has been carried out on multi-gram scale.
Treatment of the ester with sodium hydroxide in methanol at
60 οC led to complete decarboxylation after one hour with the
desired sulfone 17 being isolated in 96% yield (Scheme 5).
14
9
11n
B
59%
15
16
9
9
11o
11p
B
B
36%
46%
17
18
9
12
B
B
57%
Scheme 5. SNAr reaction
Following this promising result we further explored the scope
of the reaction (see Table 2). A range of pyrimidines, 18a-f,
were subjected to the SNAr reaction. We found the reaction
worked for electron-poor substrates, 18a-d, however the
reaction failed for relatively electron-rich compounds, 18e, f.
Selectivity was good for substrates 18b and 18c with no 2-
substituted product observed. Decarboxylation of 19a-d
proceeded in modest to good yields. Substrates 19a-c
underwent a second substitution during the decarboxylation
reaction to afford methoxypyrimidines 20a-c.
9
No
reaction
0%
The above strategy allowed rapid diversification at the sulfone
moiety and showed a wide range of compounds could be
accessed using this methodology. We were, however, also
keen to develop methodology that would allow benzylic
sulfones to be introduced directly into commercially available

4
Tetrahedron
1. Glimcher, L. H. PCT Int. Appl. WO 2008103314; Chem. Abstr.
2008, 149, 299867.
Table 2. Two-step SNAr decarboxylation sequence on chloropyrimidines
18a-g.16
2. Rivkin, A.; Ahearn, S.P.; Chichetti, S. M.; Kim, Y. R.; Li, C.;
Rosenau, A.; Kattar, S. D.; Jung, J.; Shah, S.; Hughes, B. L.;
Crispino, J. L.; Middleton, R. E.; Szewczak, A. A.; Munoz, B.;
Shearman, M. S.; Bioorg. Med. Chem. Lett. 2010, 20, 1269-1271.
3. Martin, R.; Mohan, R.; Ordentlich, P.; PCT Int. Appl.
WO 2005047268; Chem. Abstr. 2005, 142, 476293.
4. Artman, G. D. III; Elliott, J. M.; Ji, N.; Liu, D.; Ma, F.; Mainolfi,
N.; Meredith, E.; Miranda, K.; Powers, J. J.; Rao, C. PCT Int.
Appl. WO 2010066684; Chem. Abstr. 2010, 153, 87648.
5. (a) Foote, K. M.; Blades, K.; Cronin, A.; Fillery S.; Guichard, S.;
Hassall, L.; Hickson, I.; Jacq, X.; Jewsbury, P. J.; McGuire, T.;
Nissink, W.; Odera, R.; Page, K.; Perkins, P.; Suleman, A.; Tam,
K. Y.; Thommes, P.; Broadhurst, R.; Wood, C.; J. Med. Chem.
2013, 56, 2125 – 2138. (b) Foote, K. M.; Nissink, J. W. M. PCT
Int. Appl. WO 2010073034; Chem. Abstr. 2010, 153, 145523.
6. (a) Morris, J. J; Pike, K. G. PCT Int. Appl. WO 2009007748;
Chem. Abstr. 2019, 150, 144501. (b) Finlay, M. R.; Buttar, D.;
Critchlow, S. E.; Dishington, A.P.; Fillery, S. M.; Fisher, E.;
Glossop, S.C.; Graham, M. A.; Johnson, T.; Lamont, G. M.;
Mutton, S.; Perkins, P.; Pike, K. G.; Slater, A. M. Bioorg. Med.
Chem. Lett. 2012, 12, 4163-4168.
E
nt
ry
Starting
material
Ester
Product
Yield
17%
Final
Product
Yiel
d
20a
R5=OMe
R2= H
R3= H
1
19a
19b
44%
29%
7. Cimprich, K. A.; Cortez, D. Nat. Rev. Mol. Cell Biol. 2008, 9,
616-627.
8.
Beevers , C.; Li, F.; Liu, L.;
Huang, S. Int. J. Cancer 2006, 119, 757-764.
20b
R5= H
R2= OMe
R3=CF3
2
3
36%
9. Dishington, A.; Fillery, S.; Finlay M. R. V. Tetrahedron Lett.
2010, 51, 4211-4213.
10. Farag, A. M.; Kheder, N. A.; Dawood, K. M. Heterocycles 2009,
78, 937-946.
11. Miltschitzky, S.; Michlova, S.; Stadlbauer, S.; Koenig, B.
Heterocycles 2006, 67, 135-160.
20c
R5= H
R2=OMe
R3=F
12. Krishna, S., J. Chem. Soc., Trans. 1923, 123, 156-160.
13. Typical procedure for the preparation of the sulfones by reaction
of sulfinic acids with benzyl iodides: 4-[2-chloro-6-
(methylsulfonylmethyl)pyrimidin-4-yl]morpholine (11f).
Sodium methanesulfinate (6.49 g, 63.61 mmol) was added in one
portion to 4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)morpholine
(18 g, 53.01 mmol) in DMF (200 ml). The resulting mixture was
stirred at 25 °C for 2 h. The mixture was diluted with CH2Cl2 and
washed with H2O (2 x 300 ml), aq. sodium thiosulfate (400 ml),
brine (400 ml), dried over MgSO4 and concentrated in vacuo. The
crude solid was triturated with MeOH to give a solid which was
collected by filtration and dried under vacuum to give 4-[2-chloro-
6-(methylsulfonylmethyl)pyrimidin-4-yl]morpholine (14.50 g,
94%) as a cream solid; 1H NMR (400 MHz, DMSO-d6) δ 6.95 (s,
1H), 4.45 (s, 2H), 3.57 - 3.73 (m, 8H) and 3.11 (s, 3H); 13C NMR
(DMSO-d6, 176 MHz): δ (ppm) 163.0, 159.3, 158.9, 103.5, 41.3,
65.4, 60.6 and 44.1; m/z (ES+), 292.05173 [MH]+ C10H15O3N3ClS
requires 292.05172.
19c
19d
28%
36%
57%
75%
CF3
20d
R5=CF3
R2=H
R3=H
N
4
5
Cl
18d
N
N
No
reaction
SMe
Cl
N
-
-
-
-
-
18e
14. (a) Mitin, A. V.; Kashin, A. N.; Beletskaya, I. P. Russ. J. Org.
Chem. 2004, 40, 802–812. (b) Mitin, A. V.; Kashin, A. N.;
Beletskaya, I. P.; Wife, R. Tetrahedron Lett. 2002, 43, 2539-2542.
(c) Fukuda, S.; Fukuda, Y.; Goka, K.; Kumata, T.; Tsutsumiuchi,
K. PCT Int. Appl. WO 2009075080; Chem. Abstr. 2009, 151,
56879.
6
No
reaction
-
15. (a) Goumont, R.; Faucher, N.; Moutiers, G.; Tordeux, M.;
Wakselman, C. Synthesis 1997, 691-695. (b) Kumamoto, K.;
Miyazaki, H.; PCT Int. Appl. WO 2009025397; Chem. Abstr.
2009, 150, 306502.
In conclusion, we have developed two useful novel synthetic
strategies for the rapid synthesis of sulfonylmethyl
pyrimidines, molecules which have been extremely important
in recent drug discovery programs. The benzylic iodide
substitution strategy allows for rapid diversification of the
sulfone moiety and has been used to synthesise over 100
compounds. The direct SNAr-decarboxylation strategy is
useful for the synthesis of electron-poor pyrimidines and
allows even more rapid entry into this type of system.
Supplementary data
16. Typical procedure for the preparation of sulfones via the SNAr-
decarboxylation
sequence:
2-[methylsulfonyl)-2-(6-
(trifluoromethyl)pyrimidin-4-yl]acetate (19d). Methyl 2-
(methylsulfonyl)acetate (275 mg, 1.81 mmol) was dissolved in
DMF (4 ml), to this was added NaH (131 mg, 3.29 mmol) and the
reaction was stirred for 5 min. before the addition of 4-chloro-6-
(trifluoromethyl)pyrimidine (300 mg, 1.64 mmol). The reaction
was stirred overnight at room temperature, quenched with 2 M aq
HCl (100 ml) and extracted with EtOAc (3 x 50 ml). The organic
layer was dried over MgSO4, filtered and evaporated to afford a
yellow gum. The crude product was purified by flash silica gel
chromatography, elution gradient 0% to 50% EtOAc in heptane.
Fractions were evaporated to dryness to afford methyl 2-
[methylsulfonyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl]acetate
(176 mg, 36%) as an off-white solid. 1H NMR (DMSO-d6, 400
MHz): δ 9.56 (s, 1H), 8.24 (d, J 1.3Hz, 1H), 6.32 (s, 1H), 3.79 (s,
3H) and 3.29 (s, 3H); m/z 299.03073 [MH]+ C9H10F3N2O4S
requires 299.03079.
Supplementary data associated with this article can be found
in the online version at……
References and notes

5
4-[(methylsulfonyl)methyl)-6-(trifluoromethyl]pyrimidine
(20d) Methyl 2-[methylsulfonyl)-2-(6-(trifluoromethyl]pyrimidin-
4-yl)acetate (160 mg, 0.54 mmol) was dissolved in MeOH (4.00
mL)/H2O (1 mL), to this was added NaOH (0.380 mL, 0.76
mmol) and the reaction was stirred at 60 οC for 5 h followed by
overnight at 50 °C. The reaction was cooled, quenched with 2 M
aq HCl (50 mL), evaporated and extracted EtOAc with 2 x 100
mL). The organic layer was dried over MgSO4, filtered and
evaporated to afford a pale yellow gum. The crude material was
purified by flash silica gel chromatography using elution gradient
30 to 100% EtOAc in heptane. Pure fractions were evaporated to
dryness
to
afford
4-[(methylsulfonyl)methyl)-6-
(trifluoromethyl]pyrimidine (96 mg, 75%) as an off-white solid.
1H NMR (DMSO-d6, 400 MHz): δ 9.50 – 9.52 (m, 1H), 8.17 (d,
J= 1.2 Hz, 1H), 4.92 (s, 2H) and 3.15 (s, 3H); 13C NMR (DMSO-
d6, 176 MHz): δ 162.3, 159.2, 154.2, 119.6, 119.0, 60.1 and 42.0;
m/z (ES+), 241.02534 [MH]+ C7H8F3N2O2S requires 241.02531.