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2
Tetrahedron Letters
Since the identification of methionine sulfoximine (Figure 1,
a) Metal-catalyzed sulfoxide imidation
compound 1) as the agent responsible for the toxicity of the
disease canine hysteria toward the end of 1940s,1 the interest in
sulfoximine chemistry has steadily increased. Not only have
sulfoximines been extensively investigated as chiral auxiliaries, 2
[M], PhI=N-PG
steps
(1)
or [M], H2N-PG
PhI(OAc)2
ligands in asymmetric synthesis3 and building blocks in
4
pseudopeptides,
they also present a promising class of
[M] = Cu, Rh, Ag, Fe, etc.
pharmacophore in drug discovery due to the remarkable
differences between sulfoximines and the corresponding
sulfones.5 Although sulfoximines are isoelectronic with sulfones,
the nitrogen atom of a sulfoximine provides an additional point
of diversity to increase molecular complexity.6 Free sulfoximines
also provide dual functionality as a hydrogen donor (through the
NH group) and a hydrogen acceptor. Moreover, the increased
polarity of sulfoximines can present improved solubility in protic
solvents such as water and alcoholes,7 which may lead to better
oral bioavailability in pharmacokinetics. Therefore, more
research on the physicochemical properties of sulfoximines was
conducted and a number of bioactive compounds containing a
sulfoximine moiety in the pharmacophore have been reported
over the past few years (Figure 1, compounds 1-7).8
PG = SO2Ar, COCF3, CO2R
b) Richards and Ge's work
Rh2(esp)2, DPH
(2)
(3)
c) Metal free methods
(1) R'-CN, Tf2O
(2) H2O
KMnO4
NaOH, H2O
RF = CF3, C4F9
H2NCO2NH4, PhI(OAc)2
or MSH, base
(4)
(5)
L-Methionine (S)-sulfoximine (R = Me, 1)
L-Buthionine (S)-sulfoximine (R = n-Bu, 2)
BAY 1000394 (3)
AZD6738 (4)
NaN3, H2SO4
glutamine synthetase inhibitor
pan-CDK inhibitor
ATR inhibitor
Traditional methods
d) This work
(HOCH2)3CNH3
NaN3, Eaton's reagent
50 oC
(6)
Sudexanox (5)
prophylactic antiasthmatic
Vitamine D analog (6)
VIOXX analog (7)
CYP24 inhibitor
COX-2 inhibitor
R1= alkyl, aryl
R2= alkyl, aryl, heteroaryl
Yield: 52%-92%
Figure 1. Representive sulfoximines used in drug discovery
Sulfoximines can be synthesized by imination of the
corresponding sulfoxides using activated nitrogen species. The
synthetic methods can be divided into two categories: (i) metal-
catalyzed sulfoxide imination via metal-nitrenoid species and (ii)
metal-free NH transfer. Metal-catalyzed formation of NH-
sulfoximines involves the transfer of a protected nitrogen group
to sulfoxides, including the transfer of sulfonamide,
trifluoroacetamide and carbamate groups9 in the presence of
metals such as copper, rhodium, silver or iron (Scheme 1, Eq.
1).10 These reagents typically afford the N-protected sulfoximines,
which require an additional deprotection step to yield the free NH
derivatives. The deprotection step is quite difficult sometimes.
Richards, Ge and co-workers reported the first rhodium-catalyzed
direct synthesis of unprotected NH-sulfoximines using O-(2,4-
Scheme 1. Synthesis of sulfoximine from sulfoxide
providing free sulfoximine directly (Scheme 1, Eq. 5).15, 16 This
reaction is generally carried out with sodium azide and sulfuric
acid in CHCl3 as solvent. However, this reaction is biphasic and
one potential drawback is limited functional group compatibility.
Herein, we describe a highly efficient imination reaction of
sulfoxide using sodium azide in the presence of an inexpensive
and commercially available Eaton’s reagent (phosphorus
pentoxide, 7.7 wt.% solution in methanesulfonic acid) (Scheme 1,
Eq. 6). Various NH-sulfoximines can be obtained from the
corresponding sulfoxide substrates in high yields under mild
conditions. This method is also found to be applicable to the
synthesis of structurally complex sulfoximines (especially
containing heterocyclic and amino group, which are often
pharmacophores of bioactive compounds) with agrochemical and
pharmaceutical utilities.
dinitrophenyl)-hydroxylamine (DPH) as
a nitrogen source
(Scheme 1, Eq. 2).11 However, the use of a precious rhodium
catalyst [Rh2(esp)2] and the possibly demanding work-up to
remove metal residuals (from the perspective of the
pharmaceutical industry) are two potential deficiencies of this
method. Alternatively, the metal-free imination of sulfoxides is
the most straightforward strategy to obtain NH-sulfoximines.
Magnier and co-workers reported the reactions of
perfluoroalkylated sulfoxides with nitriles, trifluoroacetic
anhydride and oxidative work-up to synthesize NH-sulfoximines
(Scheme 1, Eq. 3).12 Luisi, Bull and co-workers recently reported
a method for the synthesis of NH-sulfoximines by using
ammonium salts with diacetoxyiodobenzene (Scheme 1, Eq. 4).13
O-mesitylenesulfonylhydroxylamine (MSH) with base has also
been employed as the nitrogen source in the direct imination of
sulfoxides (Scheme 1, Eq. 4).14 Besides, the reaction of
sulfoxides with HN3 is clearly more atom economic,
In the context of a drug discovery program, we sought after a
robust method for a multi-gram synthesis of 4-chloro-2-
(propylsulfonimidoyl)-7H-pyrrolo[2,3-d]pyrimidine (Table 1, 2a).
Our initial attempt to synthesize 2a was direct imination of
sulfoxide 1a (Table 1) by using NaN3 and H2SO4.15g Substrate 1a
(0.2 mmol) was mixed with NaN3 (2 equiv) in CHCl3 (0.5 mL) at
room temperature. To this mixture was added concentrated
o
H2SO4 (5 equiv.) at 0 C. The reaction mixture was subsequently
o
warmed up to 50 C and further stirred at this temperature for 30
min. As a result of protonation by H2SO4, significant amount of
the substrate precipitated from the CHCl3 phase. The LC-MS
reaction monitoring showed a conversion of only 21% (Table 1,
Entry 1) and no improvement was obtained with a prolonged
Wang, Jianping
