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A. Dishington et al. / Tetrahedron Letters 51 (2010) 4211–4213
O
O
N
O
N
2-bromoacetamide /
1.1 m-CPBA /
1.3 NaMnO4
1,4-dioxane:H2O (3:1)
NaOH /
DMF-H2O
/
O
N
N
O
O
H2N
NH
H2N
N
H2N
N
N
S
S
S
N
N
O
N
N
N
H
H
H
7
6
8
Scheme 2. Preparation and oxidation of the sulfide.
The dichloropyrimidine3 2 was treated with morpholine and trieth-
ylamine in dichloromethane to give the mono-chloropyrimidine 3
in 89% yield. This chloride was coupled with 5-indolylboronic acid
under Suzuki conditions using dichlorobis(triphenylphosphine)pal-
ladium(II) and sodium carbonate in 18% N,N-dimethylformamide, in
7:3:2 dimethoxyethane/water/ethanol at 120 °C for 30 min in a
microwave reactor to afford the ester 4 in 86% yield. Reduction of
ester 4 was achieved with lithium aluminium hydride to give alco-
hol 5 in 61% yield. Conversion of alcohol 5 into the mesylate (meth-
anesulfonyl chloride/triethylamine/dichloromethane) and then
reaction with thiourea gave thioimidate 6 in 48% yield after SCX
purification (Isolute SCX-2, the desired product was eluted with
0.35 M ammonia/methanol) (Scheme 1).
Table 1
One-pot oxidation of sulfides 7a–h to sulfones 8a–h
O
O
N
1.1 m-CPBA /
1.3 NaMnO4
/
N
N
1,4-dioxane:H2O (3:1) /
1 h
R
S
N
R
S
N
O
N
O
N
N
H
H
7a-h
8a-h
Sulfide 7
R=
Yield (%)
F
The masked thiolate was revealed and then alkylated in a one-
pot procedure with sodium hydroxide and the appropriate alkyl
bromide in N,N-dimethylformamide and water to give the sulfide.4
Thus, reaction of the masked thiolate 6 with 2-bromoacetamide
gave thiolate 7. Initial attempts were made to oxidise sulfide 7 to
sulfone 8 with m-chloroperoxybenzoic acid and Oxone. However,
despite apparent facile oxidation to the sulfoxide as was evident
from LC–MS analysis, further oxidation to sulfone 8 was plagued
with over-oxidation problems, presumably linked to N-oxidation
of the pyrimidine ring.
O
7a
7b
7c
46
76
43
N
H
O
NC
O
It is known that sodium permanganate is a mild and selective
oxidant for sulfoxides to sulfones.5 We reasoned that the one-pot
combination of the oxidants m-chloroperoxybenzoic acid and so-
dium permanganate would provide, selectively, the required sulf-
ones from the sulfides. Gratifyingly when sulfide 7 was treated
with m-chloroperoxybenzoic acid and sodium permanganate in
1,4-dioxane/water (3:1) for 5 h sulfone 8 was obtained in 56% yield
after purification by SCX chromatography (Scheme 2). We next
sought to determine whether this one-pot procedure was widely
applicable. A range of sulfides 7a–h was prepared and oxidised un-
der the standard conditions (Table 1).6
In total, over 100 sulfones were prepared in a library fashion
using this procedure although the yields were not optimised. The
crude reaction mixtures were subjected to SCX purification and
then reverse-phase HPLC to provide pure isolated material in good
to moderate yields. A range of functional groups are tolerated
including nitriles, amines and nitrogen-containing heterocycles.
In conclusion, we have found a one-pot reagent combination
allowing the selective conversion of sulfides into sulfones in the
presence of other oxidisable functions within the same molecule.
H
N
7d
7e
34
66
H
N
O
O
H2N
7f
52
N
NC
NC
N
7g
7h
56
68
O
N
H
sulfones and since the diversification would be introduced in the
penultimate sulfide-forming step, a reliable method for the oxida-
tion of a sulfide group to the sulfone, subsequent to the diversifica-
tion step, was required.2
O
References and notes
N
1. Pike, K.; Finlay, M. R. V.; Fillery, S.; Dishington, A. PCT Int. Appl. (2007), WO
2007080382; Chem. Abstr. 2007, 147, 166337.
R
S
N
2. (a) Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.; Cai, D.-W.; Palucki, M.;
Wu, J.; Larson, R. D.; Rossen, K.; Pye, P. J.; DiMichele, L.; Dormer, P.; Reider, P. J. J.
Org. Chem. 2000, 65, 8415; (b) Kluge, R.; Schulz, M.; Liebsch, S. Tetrahedron 1996,
52, 5773.
O
N
O
3. Miltschitzky, S.; Michlova, S.; Stadlbauer, S.; Koenig, B. Heterocycles 2006, 67,
135.
4. Repetto, E.; Marino, C.; Laura, U. M.; Varela, O. Bioorg. Med. Chem. 2009, 17, 2703.
N
H
1
Dishington, Allan
