Zolimidine analogues: The synthesis of imidazo[1,2-α]pyridine-based sulfilimines and sulfoximines

Article abstract of DOI:10.1055/s-0034-1380109

Zolimidine is a methylsulfonyl-substituted drug with an imidazo[1,2-α]pyridine core used for the treatment of peptic ulcer. Herein, we report the synthesis of unprecedented N-acetylsulfilimine and -sulfoximine- analogues under mild conditions. Deprotection of the N-acetylsulfoximine allows the preparation of the corresponding NH-sulfoximine.

Full text of DOI:10.1055/s-0034-1380109

SYNTHESIS
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-
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1
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-
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0
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1190–1194
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C. M. M. Hendriks et al.
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Synthesis
Zolimidine Analogues: The Synthesis of Imidazo[1,2-α]pyridine-
Based Sulfilimines and Sulfoximines
Christine M. M. Hendriks
O
N
O
Pinchas Nürnberg
Carsten Bolm*
S
N
Me
sulfide and sulfoxide
imination
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
mild conditions
O
O
S
O
N
N
O
NH
S
Me
S
Me
Me
Me
Me
O
S
Received: 12.12.2014
Accepted after revision: 20.12.2014
Published online: 28.01.2015
N
O
N
Me
DOI: 10.1055/s-0034-1380109; Art ID: ss-2014-z0762-op
zolimidine (1)
Abstract Zolimidine is a methylsulfonyl-substituted drug with an imid-
azo[1,2-α]pyridine core used for the treatment of peptic ulcer. Herein,
we report the synthesis of unprecedented N-acetylsulfilimine and
-sulfoximine analogues under mild conditions. Deprotection of the
N-acetylsulfoximine allows the preparation of the corresponding NH-
sulfoximine.
this work:
N
O
NR
N
N
NR
Me
S
S
N
Me
sulfilimine 2
sulfoximine 3
Key words imidazo[1,2-α]pyridine, sulfoximine, sulfilimine, zolimi-
dine, imination
Figure 1 Zolimidine (1) and derivatives 2 and 3, presented in this work
Imidazo[1,2-α]pyridines are widely applied in chemis-
try, biology, and materials science.1–3 Incorporated in nu-
merous natural products and pharmaceuticals,4 they show
an extraordinary variety of biological activities such as an-
tifungal,5 antiviral,6 antibacterial,7 anticancer,8 and antiul-
cer.9 As a consequence, several imidazo[1,2-α]pyridine-
containing drugs exist, namely alpidem, zolpidem, necop-
idem, and saripidem (anxiolytic agents),10 olprinone (treat-
ment of heart failure),11 GSK812397 (candidate for treat-
ment of HIV),12 rifaximin (antibiotic),13 and zolimidine (1,
used for treatment of peptic ulcer).9a,b,14 Among them, the
latter compound 1 caught our attention because it contains
a methylsulfonyl moiety (Figure 1).
The mono-aza analogues of sulfones, namely sulfoxi-
mines,15 have attracted much attention in crop protection16
and drug development.17 Recent studies revealed the
change of a sulfone into a sulfoximine to induce interesting
bioactivities.18 Furthermore, in contrast to sulfones, sulfoxi-
mines can be modified at the nitrogen atom, which allows
improving the solubility of the corresponding mole-
cules.18c,19 Sulfilimines, possessing a nitrogen substituent
and a free electron pair at the sulfur atom, are intermedi-
ates in the sulfoximine synthesis and have shown interest-
ing insecticidal activities.16c,20
Surprisingly, to our knowledge, no imidazo[1,2-α]pyri-
dines with sulfoximidoyl and sulfilimidoyl substituents
have been reported to date.21 In order to fill this synthetic
gap, we envisaged a sulfone-to-sulfoximine exchange on
zolimidine and thereby the syntheses of analogues 2 and 3
(Figure 1). The preparation of these compounds would also
allow an evaluation of the existing preparative approaches
towards sulfoximines and sulfilimines and an analysis of
their value in accessing heteroatom-containing derivatives.
For the synthesis of sulfilimines 2 and sulfoximines 3
three different synthetic pathways were considered
(Scheme 1). First, the sulfide 4 seemed a good starting point
for an imination/oxidation sequence (route A) involving the
synthesis of the desired sulfilimine 2 as an intermediate.
Similarly, starting from 4 an oxidation/imination sequence
(route B) would lead to sulfoximine 3 via sulfoxide 5. Alter-
natively, it was considered to synthesize the imidazo[1,2-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1190–1194

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C. M. M. Hendriks et al.
Paper
Synthesis
α]pyridine entity by a reaction of methyl ketone 6, contain-
ing a sulfoximidoyl functionality, with 2-aminopyridine (7)
(route C).22
tions using potassium tert-butoxide and N-bromosuccinim-
ide (NBS),23 halogenation of the heterocycle solely occurred
(Table 1, entry 1).24
Also the replacement of NBS and the strong base by io-
dobenzene diacetate,25 did not allow sulfide imination with
cyanamide (entry 2). Instead, traces of the corresponding
sulfoxide 5 were observed. Further attempts to form N-cya-
route A
route B
1. imination
1. oxidation
S
R1
Me
4
PG
Me
nosulfilimines
or
N-cyanosulfoximines
(route
C,
N
S
O
S
Scheme 1),22a by reaction of 1-[4-(N-cyanomethylsulfilimi-
doyl)phenyl]ethanone or 1-[4-(N-cyanomethylsulfoximi-
doyl)phenyl]ethanone with 2-aminopyridine, were ineffec-
tive.
R1
R1
Me
2
5
O
N
PG
2. imination
2. oxidation
S
Next, we focused on metal-catalyzed imination meth-
ods involving different protecting groups on the nitrogen
atom. Unexpectedly, the frequently applied rhodium-cata-
lyzed imination protocol26 led to decomposition (entry 3).
Likewise, the milder iron-catalyzed procedure useful in the
imination of heterocyclic sulfoximines27 did not afford the
product (entry 4). Finally, a ruthenium-catalyzed photo-
chemical approach, recently developed in our group, using
3-methyl-1,4,2-dioxazol-5-one as nitrene source, led to
success (entry 5).28 The mild reaction conditions allowed to
obtain the desired N-acetylsulfilimine 2a in 83% yield,
thereby demonstrating the value of this method regarding
heterocyclic substrates.
R1
Me
3
route C
O
N
PG
NH2
S
Me
+
N
Me
6
7
O
N
R1
=
N
PG = protecting group
The first target compound in hand, following route A,
the oxidation of 2a to sulfoximine 3a was investigated
(Scheme 2). Initial attempts of using a one-pot procedure
involving the aforementioned photochemical imination of
4, and subsequent oxidation with sodium periodate re-
mained unsuccessful not leading to sulfoximine 3a.28 Simi-
larly, an oxidation with potassium permanganate, often
used with heterocyclic starting materials,27b did not afford
3a.
Scheme 1 Synthetic pathways towards sulfilimine 2 and sulfoximine 3
Initially, the imination of sulfide 4 was investigated
(route A, Scheme 1). As N-cyanosulfilimines and N-cyano-
sulfoximines have previously shown interesting bioactivi-
ties,18d,20b the imination with cyanamide was attempted
first. However, when applying transition metal-free condi-
Table 1 Imination of Sulfide 4 Following Route A
NR
Me
N
conditions
4
S
N
2
2a (R = acetyl)
Entry
Conditions
R
Yield (%) of 2a
b
1
2
3
4
5
NH2CN, t-BuOK, NBS, MeOH, r.t., 30 min
CN
–
c
NH2CN, PhI(OAc)2, MeOH, r.t., 4 h
CN
–
d
Rh2(OAc)4 (2.5 mol%), trifluoroacetamide, MgO, PhI(OAc)2, CH2Cl2, r.t., 24 h
Fe(OTf)2 (15 mol%), PhI=NNS, 4 Å molecular sieves, MeCN, 50 °C, 20 h
Ru(TPP)CO (0.5 mol%), 3-methyl-1,4,2-dioxazol-5-one, toluene, hv, r.t., 1 h
COCF3
nosyl
COMe
–
e
–
83
a After purification by column chromatography.
b Formation of 3-bromo-2-[4-(methylthio)phenyl]imidazo[1,2-α]pyridine.
c Formation of traces of sulfoxide 5.
d Decomposition.
e No conversion.
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ported in Hz. Standard abbreviations were used to denote coupling
patterns. IR spectra were recorded on a PerkinElmer FT-IR Spectrum
100 (KBr disk). Wave numbers are given in reciprocal centimeters
(cm–1). Mass spectra were recorded on a Finnigan SSQ 7000 spec-
trometer and HRMS on a Thermo Scientific LTQ Orbitrap XL spec-
trometer. Elementary analyses were performed on an Elementar
Vario El instrument. Melting points were determined in open-end
capillary tubes on a Büchi B-540 melting point apparatus. Irradiation
was conducted with a Philips HPK 125 W high-pressure mercury va-
por lamp cooled with water. Reactions were carried out under air if
not described differently. Solvents were distilled prior to use. Chemi-
cals were purchased from commercial suppliers and used without
further purification. 2-[4-(Methylthio)phenyl]imidazo[1,2-α]pyri-
dine (4)22a and 3-methyl-1,4,2-dioxazol-5-one were prepared accord-
ing to reported procedures.28a Flash column chromatography was car-
ried out with Merck silica gel 60 (35–70 mesh). Analytical TLC was
performed with aluminum sheets silica gel 60 F254 (Merck), and the
products were visualized by UV detection and/or staining solutions.
following route A:
1. Ru(TPP)CO (0.5 mol%)
O
S
N
N
N
O
hν, toluene, r.t., 1 h
4
, CH2Cl2/H2O
Me
2. NaIO4
Me
r.t., 18 h
3a
O
KMnO4
N
N
Me
S
acetone, 60 °C
16 h
N
Me
2a
following route B:
aq H2O2 (30%)
O
N
AcOH
S
4
N
r.t., 4 h, 71%
Me
5
Imination Reaction;28 General Procedure
Ru(TPP)CO (1 mol%)
hν, toluene, r.t., 1.5 h
58%
To a solution of 4 or 5 (1 equiv) and 3-methyl-1,4,2-dioxazol-5-one (1
equiv) in anhydrous toluene under argon was added Ru(TPP)CO (0.5
or 1 mol%). After stirring at r.t. under irradiation with a 125 W high-
pressure mercury lamp, the solvent was removed under reduced
pressure. Purification by flash column chromatography afforded
product 2 or 3, respectively.
O
N
N
O
S
N
Me
K2CO3, MeOH
70 °C, 1.5 h
Me
89%
3a
O
S
2-[4-(N-Acetyl-S-methylsulfilimidoyl)phenyl]imidazo[1,2-α]pyri-
dine (2a)
N
N
NH
Me
Following the general procedure using 4 (120 mg, 0.5 mmol), 3-meth-
yl-1,4,2-dioxazol-5-one (51 mg, 0.5 mmol), Ru(TPP)CO (1.9 mg, 0.5
mol%), and anhydrous toluene (5 mL) for 1 h, the product was ob-
tained after flash column chromatography (EtOAc); yield: 123 mg
(83%); light brown solid; mp 176–179 °C.
3b
Scheme 2 Different routes towards sulfoximines 3a and 3b
IR (KBr): 3004, 1739, 1568, 1359, 1293 cm–1
.
Changing the strategy, we switched to synthetic route B
(Scheme 1). To our delight, oxidation of sulfide 4 with an
aqueous dihydrogen peroxide solution in acetic acid29 pro-
ceeded well, giving sulfoxide 5 in 71% yield (Scheme 2). The
previously proven mild ruthenium-catalyzed light-promot-
ed conditions allowed obtaining sulfoximine 3a in a yield of
58%.28 Finally, the acetyl protecting group was removed us-
ing potassium carbonate in methanol at 70 °C,30 leading to
NH-sulfoximine 3b in 89% yield (Scheme 2).
1H NMR (600 MHz, CDCl3): δ = 8.11 (d, J = 6.7 Hz, 1 H), 8.07 (d, J = 8.3
Hz, 2 H), 7.91 (s, 1 H), 7.78 (d, J = 8.3 Hz, 2 H), 7.60 (d, J = 9.1 Hz, 1 H),
7.20–7.17 (m, 1 H), 6.79 (t, J = 6.7 Hz, 1 H), 2.82 (s, 3 H), 2.13 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 182.0, 145.8, 143.7, 137.9, 134.1,
127.2, 127.1, 125.7, 125.3, 117.7, 112.9, 109.2, 34.5, 24.3.
MS (EI): m/z (%) = 297 ([M]+, 2), 207 (28), 190 (74), 179 (27), 166 (33),
155 (35), 146 (26), 120 (25), 103 (43), 78 (100).
HRMS (ESI): m/z calcd for C16H16N3OS [M + H]+: 298.1009; found:
298.1010.
In conclusion, we have synthesized unprecedented N-
acetylsulfilimidoyl- and N-acetylsulfoximidoyl-substituted
derivatives of zolimidine. The evaluation of various synthet-
ic pathways revealed that only the recently introduced
light-promoted ruthenium catalysis using 3-methyl-1,4,2-
dioxazol-5-one as N-acylnitrene source allowed an efficient
imination of the sulfur atom at the imidazo[1,2-α]pyridine
core. Finally, the NH-sulfoximine was obtained in good
yield by deprotection of the acetyl group.
2-[4-(N-Acetyl-S-methylsulfoximidoyl)phenyl]imidazo[1,2-α]pyri-
dine (3a)
Following the general procedure using 5 (64 mg, 0.25 mmol), 3-meth-
yl-1,4,2-dioxazol-5-one (25 mg, 0.25 mmol), Ru(TPP)CO (1.9 mg, 1
mol%), and anhydrous toluene (3 mL) for 1.5 h, the product was ob-
tained after flash column chromatography (acetone–EtOAc, 1:5);
yield: 45 mg (58%); light brown solid; mp 198–200 °C (dec.).
IR (KBr): 3022, 1627, 1360, 1268, 1201, 1032 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 8.60 (s, 1 H), 8.57 (d, J = 5.9 Hz, 1
H), 8.24 (d, J = 8.6 Hz, 2 H), 8.00 (d, J = 8.6 Hz, 2 H), 7.63 (d, J = 9.1 Hz,
1 H), 7.31–7.28 (m, 1 H), 6.95–6.93 (m, 1 H), 3.47 (s, 3 H), 2.00 (s, 3 H).
13C NMR (151 MHz, DMSO-d6): δ = 178.8, 145.5, 142.8, 139.3, 137.6,
128.1, 127.6, 126.6, 126.1, 117.4, 113.2, 111.5, 43.6, 26.9.
1H NMR and 13C NMR spectra were recorded on a Varian VNMRS 600
spectrometer in CDCl3, DMSO-d6, or acetone-d6. Chemical shifts (δ)
are given in ppm relative to solvent residual peaks (CDCl3, δ = 7.26;
DMSO-d6, δ = 2.50; acetone-d6, δ = 2.05). Coupling constants J are re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1190–1194

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C. M. M. Hendriks et al.
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Synthesis
MS (EI): m/z (%) = 313 ([M]+, 2), 296 (5), 240 (19), 238 (19), 208 (98),
206 (100), 192 (19), 190 (17), 180 (16), 178 (17).
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HRMS (ESI): m/z calcd for C16H16N3O2S [M + H]+: 314.0958; found:
314.0956.
2-[4-(NH-S-methylsulfoximidoyl)phenyl]imidazo[1,2-α]pyridine
(3b)
A mixture of 3a (69 mg, 0.22 mmol) and K2CO3 (152 mg, 1.10 mmol)
in MeOH (3.65 mL) was stirred at 70 °C30 for 1.5 h. The solvent was
removed under reduced pressure and the product was obtained after
purification by flash column chromatography (EtOAc–MeOH, 9:1);
yield: 53 mg (89%); white solid; mp 200–202 °C.
IR (KBr): 3207, 1596, 1406, 1213, 1096 cm–1
.
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1H NMR (600 MHz, DMSO-d6): δ = 8.56–8.55 (m, 2 H), 8.17 (d, J = 8.4
Hz, 2 H), 7.98 (d, J = 8.4 Hz, 2 H), 7.61 (d, J = 9.1 Hz, 1 H), 7.30–7.27 (m,
1 H), 6.94–6.92 (m, 1 H), 4.24 (s, 1 H), 3.10 (s, 3 H).
13C NMR (151 MHz, DMSO-d6): δ = 145.0, 142.7 (2 C), 137.7, 127.8,
127.1, 125.7, 125.5, 116.8, 112.6, 110.6, 45.8.
MS (EI): m/z (%) = 271 ([M]+, 4), 207 (61), 178 (99), 164 (100), 138
(78), 127 (65), 113 (44), 101 (36).
HRMS (ESI): m/z calcd for C14H14N3OS [M + H]+: 272.0852; found:
272.0851.
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2-[4-(Methylsulfinyl)phenyl]imidazo[1,2-α]pyridine (5)14
To a solution of 4 (70 mg, 0.29 mmol) in AcOH (1.39 mL) at 0 °C was
added 30% aq H2O2 (0.13 mL, 0.29 mmol).29 After stirring for 4 h at r.t.,
the reaction mixture was quenched by the addition of concd aq NaOH
(0.5 mL). H2O (5 mL) was added, and the aqueous phase was extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(MgSO4) and the solvents were removed under reduced pressure. The
product was obtained after purification by flash column chroma-
tography (acetone–EtOAc, 1:1 to acetone–MeOH, 20:1); yield: 53 mg
(71%); light brown solid; mp 160–163 °C.
IR (KBr): 3134, 1633, 1499, 1404, 1088, 1038 cm–1
.
1H NMR (600 MHz, acetone-d6): δ = 8.50 (d, J = 6.8 Hz, 1 H), 8.40 (s, 1
H), 8.22 (d, J = 8.4 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 9.1 Hz,
1 H), 7.28–7.25 (m, 1 H), 6.90 (dt, J = 6.7, 1.0 Hz, 1 H), 2.74 (s, 3 H).
13C NMR (151 MHz, acetone-d6): δ = 146.2, 145.6, 144.1, 136.9, 126.7,
126.4, 125.0, 123.8, 117.1, 112.4, 109.6, 43.4.
MS (EI): m/z (%) = 256 ([M]+, 41), 238 (100), 224 (9), 206 (12), 192
(31), 190 (17), 180 (8).
Anal. Calcd for C14H12N2OS: C, 65.60; H, 4.72; N, 10.93. Found: C,
65.41; H, 4.68; N, 10.64.
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We thank Dr. Vincent Bizet and Laura Buglioni for technical advice
and helpful discussions.
Supporting Information
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S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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