1
Supporting Information
Factors Influencing the Selectivity in Asymmetric
Oxidation of Sulfides Attached to Nitrogen
Containing Heterocycles
Muthu Seenivasaperumal,a Hans-Jürgen Federsel,b Anne Ertanbc and Kálmán J. Szabóa*
aStockholm University, Arrhenius Laboratory, Department of Organic Chemistry
SE-106 91 Stockholm, Sweden; bGlobal Process R&D and cEarly Development,
Pharmaceutical and Analytical R&D, AstraZeneca, SE-151 85 Södertälje, Sweden
E-mail: [email protected]. Fax: +46-8-15 49 08
Contents:
- General procedures and characterization of the products
- 1H and 13C NMR spectra of 5a-g and 5i-k
- X-ray structure determination of 5e
2
Description of the Experimental Procedures and Characterization of the Products
The starting materials were purchased from Aldrich and Lancaster. Sulfides 1c-1j were
prepared following published literature procedures.1-7 Racemic sulfoxides of 5a-5k
(applied as standards for the determination of the ee values) were prepared according to
the reported procedures.1 Merck silica gel 60 (230-400 mesh) was used for
chromatography. Unless otherwise stated the 1H and 13C NMR spectra were recorded in
CDCl3 on Varian 300 or 400 MHz spectrometers. The chemical shifts (ppm) were
obtained by using CHCl3 as internal standard (1H NMR: 7.26 ppm; 13C NMR: 77.36
ppm). The optical rotation data ( [c] = g substance /100 mL solvent) was obtained on a
Perkin Elmer 241 polarimeter. The HPLC data was obtained on “Waters AcquityTM
Ultraperformance LC” instrument (for chromatographic conditions see the corresponding
entries).
General Procedure for catalytic oxidation of sulfides: To a solution of sulfide 1 (0.25
mmol) in toluene (0.5 mL), water (0.001 mL, 0.055 mmol) and D-(-)-diethyl tartrate 4
(0.025 mL, 0.152 mmol) was added. This solution was heated to 50 oC and stirred at this
temperature for 15 min. Then, titanium(IV)isopropoxide 3 (0.022 mL, 0.076 mmol) was
added; and the reaction mixture was kept at 50 oC for 45 min. Subsequently, the
temperature was lowered (see Table 1 for specific cases) followed by addition of di-
isopropylethylamine (0.013 mL, 0.076 mmol) and cumene hydroperoxide 2 ( 0.1 mL of
2.5 M solution in toluene, 0.25 mmol). The obtained reaction mixture was stirred at the
alloted times and temperatures (Table 1). The reaction was then quenched by addition of
water, followed by extraction with EtOAc (2 x 10 mL). The combined organic layers
were washed with brine (1 x 5 mL), then dried (MgSO4) and concentrated in vacuum.
The crude product (5) was purified by column chromatography over silica gel using an
appropriate ratio of pentane/EtOAc as eluent.
Esomeprazole (5a). This product was prepared according to the above general procedure
except that it was isolated as a potassium salt (78% yield and 97% ee) by addition of
potassium methoxide to the reaction mixture. The 1H-NMR data obtained for 5a agrees
3
with the literature values.8 1H NMR (DMSO-d6): δ 8.25 (s, 1H), 7.37 (d, 8.6 Hz, 1H),
7.02 (d, 2.6 Hz, 1H), 6.60 (dd, 2.5 Hz, 8.4 Hz, 1H), 4.72 and 4.46 (d (AB system, 12.7
Hz, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 2.21(s, 6H); 13C NMR (DMSO-d6): δ 163.4, 161.8,
153.7, 151.9, 149.1, 147.0, 141.6, 126.5, 124.9, 117.5, 109.0, 99.4, 59.7, 55.2, 48.6, 12.9,
11.3. [α]D20 = +30.1 (c 1.0, H2O); Lit.8: [α]D
20 = +30.5 (c 1.0, H2O) for (S), 99.5% ee.
The ee was determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH/AcOH
50:50:0.1, flow rate 0.6 mL/min; tR (minor) = 9.9 min; tR (major) = 11.7 min, λ = 300.3
nm).
2-Methyl(sulfinyl)benzimidazole (5b). This product was prepared according to the
above general procedure affording 5b as a white solid in 65% yield and 98% ee. The 1H-
NMR data obtained for 5b agrees with the literature values given for its racemic form.1
1H NMR: δ 7.78, (br s, 1H), 7.58 (br s, 1H), 7.31 (m, 2H), 3.18 (s, 3H); 13C NMR: δ
153.9, 143.9, 134.9, 124.7, 123.5, 120.4, 112.5, 41.6. [α]D20 = +39.3 (c 5.53, acetone)¸
Lit.9a: [α]D20 = -20.8 (c 1.0, acetone) for (R), 61% ee. The ee was determined by HPLC
(Chiralcel OJ-H column, isohexane/i-PrOH 95:5, flow rate 0.8 mL/min; tR (major) = 20.9
min; tR (minor) = 26.5 min, λ = 280.2 nm). HRMS (ESI): calc for [C8H8N2OS+H]+: m/z,
181.0430, found: 181.0432.
2-Methyl(sulfinyl)-5-methoxybenzimidazole (5c): Sulfoxide 5c was prepared according
to the above general procedure, except that additional 1 mL of toluene was added to the
reaction mixture after the addition of cumene hydroperoxide. The chiral sulfoxide 5c was
obtained as a gummy gel in 63% yield and 94% ee. The 1H-NMR data obtained for 5c
agrees with the literature values given for its racemic form.1 1H NMR (CD3OD): δ 7.50
(d, 8.59 Hz, 1H), 7.07 (s, 1H), 6.91 (dd, 2.49 Hz, 8.71 Hz, 1H), 3.78 (s, 3H), 3.08 (s, 3H); 13C NMR (CD3OD): δ 159.9, 155.3, 140.2, 136.5, 119.4, 116.3, 99.1, 57.1, 41.9. [α]D
20
= +45.7 (c 1.04, acetone). The ee was determined by HPLC (Chiralcel OJ-H column,
hexane/i-PrOH 90:10, flow rate 1.0 mL/min; tR (major) = 15.4 min; tR (minor) = 19.9
min, λ = 302.8 nm). HRMS (ESI): calc for [C9H10N2O2S+H]+: m/z, 211.0536, found:
211.0539.
4
2-Methyl(sulfinyl)-N-methyl-benzimidazole (5d): This product was prepared
according to the above general procedure affording 5d as a white solid in 48% yield and
<2% ee). The 1H-NMR data obtained for 5c agrees with the literature values given for its
racemic form.1 1H NMR: δ 7.82 (m, 1H), 7.42 (m, 2H), 7.36 (m, 1H), 4.14 (s, 3H), 3.26
(s, 3H); 13C NMR: δ 152.2, 141.9, 137.1, 124.8, 123.7, 121.2, 110.1, 39.3, 31.1. HRMS
(ESI): calc for [C9H10N2OS+H]+: m/z, 195.0587, found: 195.0588.
2-Methyl(sulfinyl)imidazole (5e): Sulfoxide 5e was prepared according to the above
general procedure, except that additional 1 mL of toluene was added to the reaction
mixture after the addition of cumene hydroperoxide. The chiral sulfoxide 5e was obtained
as a white solid in 62% yield and 97% ee. 1H NMR: δ 7.18 (s, 2H), 3.04 (s, 3H); 13C
NMR: δ 146.5, 125.7, 40.8. [α]D20 = +73.3 (c 1.57, acetone). The ee was determined by
HPLC (Chiralpak AS column, isohexane/i-PrOH 90:10, flow rate 0.8 mL/min; tR (minor)
= 29.8 min; tR (major) = 31.5 min, λ = 238.7 nm). HRMS (ESI): calc for
[C4H6N2OS+Li]+: m/z, 137.0355, found: 137.0358.
2-Benzyl(sulfinyl)imidazole (5f): Sulfoxide 5f was prepared according to the above
general procedure, except that additional 1 mL of toluene was added to the reaction
mixture after the addition of cumene hydroperoxide. The chiral sulfoxide 5f was obtained
as a white solid in 61% yield and 95% ee. 1H NMR: δ 11.59 (br s, 1H), 7.23 (m, 5H), 7.0
(m, 2H), 4.21 and 4.41 (d (AB-system), 13.5 Hz, 2H); 13C NMR: δ 144.7, 130.7, 130.6,
129.1, 128.9, 128.8, 61.2. [α]D20 = -85.3 (c 1.04, acetone). The ee was determined by
HPLC (Chiralcel OJ-H column, hexane/i-PrOH 80:20, flow rate 0.8 mL/min; tR (major)
= 7.0 min; tR (minor) = 8.7 min, λ = 246.9 nm). HRMS (ESI): calc for
[C10H10N2OS+H]+: m/z, 207.0587, found: 207.0584.
4,5-Diphenyl-2-methyl(sulfinyl)imidazole (5g): Sulfoxide 5g was prepared according to
the above general procedure, except that additional 1 mL of toluene was added to the
reaction mixture after the addition of cumene hydroperoxide. The chiral sulfoxide 5g
was obtained as a white solid in 50% yield and 80% ee. 1H NMR (DMSO-d6): δ 7.48 (d,
6.9 Hz, 4H), 7.35 (m, 6H), 3.09 (s, 3H); 13C NMR (DMSO-d6): δ 148.4, 133.2, 129.2,
5
128.5, 39.5 (The quartnary carbons are not visible due to line broadening). [α]D20 =
+37.6 (c 0.75, CHCl3) ). The ee was determined by HPLC (Chiralpak AD-H column,
hexane/i-PrOH 95:5, flow rate 1.1 mL/min; tR (minor) = 8.5 min; tR (minor) = 9.4 min, λ
= 270.2 nm). HRMS (ESI): calc for [C16H14N2OS+H]+: m/z, 283.0900, found: 283.0897.
2-Methyl(sulfinyl)-N-methylimidazole (5h): Sulfoxide 5h was prepared according to
the above general procedure, except that the reaction was carried out in toluene-d8. The
yield (33%) was determined by 1H-NMR spectroscopy using naphthalene as internal
standard. The 1H-NMR shifts were determined from the crude reaction mixture. 1H NMR
(toluene-d8): δ 6.33(d, 1.2 Hz, 1H), 6.26 (br, s, 1H), 3.27 (s, 3H), 2.71( s, 3H). Addition
of shift reagent ((S)-(+)-N-(3,5-dinitrobenzoyl)-α-methylbenzylamine) showed that the
product is racemic (< 2 %ee).
2-Methyl(sulfinyl)indole (5i): Sulfoxide 5i was prepared according to the above general
procedure, except that additional 1 mL of toluene was added to the reaction mixture after
the addition of cumene hydroperoxide. The chiral sulfoxide 5i was obtained as a white
solid in 55% yield and 69% ee. 1H NMR: δ 11.46 (br s, 1H), 7.64 (d, 7.8 Hz, 1H), 7.50
(d, 8.4 Hz, 1H), 7.29 (t, 7.6 Hz, 1H), 7.14 (t, 7.3 Hz, 1H), 6.89 (m, 1H), 3.09 (s, 3H); 13C
NMR: δ 138.6, 135.9, 127.0, 124.9, 122.0, 121.0, 112.8, 105.8, 41.5. [α]D20 = -39.1 (c
0.42, acetone). The ee was determined by HPLC (Chiralpak AD-H column, hexane/i-
PrOH 80:20, flow rate 0.8 mL/min; tR (minor) = 7.8 min; tR (major) = 4.4 min, λ = 275.1
nm). HRMS (ESI): calc for [C9H9N2OS+H]+: m/z, 180.0478, found: 180.0481.
2-Methyl(sulfinyl)pyrimidine (5j): This product was prepared according to the above
general procedure affording 5j as a gummy liquid in 35% yield and 40% ee. 1H NMR: δ
8.89 (d, 4.8 Hz, 2H), 7.42 (t, 4.6 Hz, 1H), 2.95 (s, 3H); 13C NMR: δ 174.4, 158.8, 122.0,
40.5. The ee was determined by 1H-NMR spectroscopy using shift reagent ((S)-(+)-N-
(3,5-Dinitrobenzoyl)-α-methylbenzylamine). [α]D20 = -5.4 (c 1.0, acetone). HRMS (ESI):
calc for [C5H6N2OS+H]+: m/z, 143.0274, found: 143.0273.
6
Benzylphenylsulfoxide (5k): This product was prepared according to the above general
procedure affording 5k as a as a white solid in 64% yield and 10% ee. The 1H-NMR data
obtained for 5k agrees with the literature values.9b 1H NMR: δ 7.39 (m, 5H), 7.23 (m,
3H), 6.95 (m, 2H), 3.97 and 4.06 (d, (AB-system, 12.6 Hz, 2H); 13C NMR: δ 143.0,
131.4, 130.0, 129.4, 129.1, 128.7, 128.5, 124.6, 63.8. [α]D20 = -21.2 (c 1.0, acetone);
Lit.9b: [α]D20 = -169.8 (c 1.0, acetone) for (S), 79% ee. The ee was determined by HPLC
(Chiralcel OJ-H column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min; tR (major) = 9.6
min; tR (minor) = 14.2 min, λ = 250.6 nm). HRMS (ESI): calc for [C13H12OS+H]+: m/z,
217.0682, found: 217.0684.
Competetive Sulfoxidation of Benzimidazole Derivative 1b with Imidazole 1e or
Indole Derivative 1i. To a solution of 1b (0.25 mmol) and 1e or 1i (0.25 mmol) in
toluene-d8 (0.7 ml), water (2 μl) and D-(-)-diethyl tartrate 4 (0.3 mmol) was added. This
solution was heated to 50 oC and stirred at this temperature for 15 min. Then,
titanium(IV)isopropoxide 3 (0.15 mmol) was added and the reaction mixture was kept at
50 oC for 45 min. Subsequently, the temperature was reduced to -20 oC followed by
addition of diisopropylethylamine (0.13 mmol) and cumene hydroperoxide 2 (0.25
mmol). The obtained reaction mixture was stirred at -20 oC for 1.5 h (for competive
oxidation of 1b and 1e) or 0.5 h (for competive oxidation of 1b and 1i). According to the 1H-NMR spectrum of the crude mixture imidazole derivative 1e was completely
converted to 5e, while the benzimidazole derivative 1b remained unchanged. Likewise, in
the competitive oxidation of 1b and 1i indole derivative 1i was completely converted to
5i, while 1b did not react at all.
7
Details for the X-ray Structure Determination of 5e
The crystal structure and absolute configuration of 5e (C H N OS) is reported (Figure 1).
Experimental details of the investigation are enclosed both in Table 1 and in the archived
cif file. The substance crystallises in a noncentrosymmetric orthorhombic space group
P2 2 2 with four molecules in the unit cell. The absolute configuration around the chiral
S6 atom was determined to (S).
4 6 2
1 1 1
The Flack’s chirality parameter x was refined to
0.07(11) giving strong evidence that the correct enantiomer has been chosen.
10b
The final R-
value is 3.7 %. The unit cell contains no additional residual solvent accessible void. The
unit cell dimensions at room temperature are a = 6.7300(4), b = 9.0670(6), c = 9.8150(4)
Å, α= β= γ= 90°, volume = 598.91(6) Å3.
Experimental.10 The reported data set was collected at room temperature with graphite
monochromated MoK(α) radiation on a KappaCCD Single-Crystal X-Ray diffractometer
equipped with an κ-axis goniometer and a CCD area detector (Nonius, 1998). The
diffraction raw data were processed within the Denzo-SMN program package
converting the information from the digital image frame to a file containing h, k, l
indices, background and Lp corrected intensities of the diffraction spots, along with
estimate of errors. A total of 181 image frames were collected, each by rotating the ϕ-
axis 2.0°. All diagrams and calculations were performed using maXus (Bruker Nonius,
Delft & MacScience, Japan), SHELXL-97 (Sheldrick G., 1997) and Platon (Spek,
University of Utrecht, Netherlands).
10d
10
10g
10j 10k
8
Geometric parameters of 2-(methylsulfinyl)-1H-imidazole (5e)
N
NH
S
O
CH3
Table 1. Crystal data
C H N OS4 6 2 D = 1.444 Mg mx-3
M = 130.18r Mo Kα radiation
Orthorhombic, P2 2 21 1 1 Cell parameters from 4295 reflections
a = 6.7302 (4) Å θ = 1.0–27.5°
b = 9.0666 (6) Å μ = 0.44 mm-1
c = 9.8149 (4) Å T = 293 K
V = 598.91 (6) Å3 Rod, Colourless
Z = 4 0.29 × 0.08 × 0.04 mm
Data collection
KappaCCD diffractometer 889 reflections with I > 2σ(I)
CCD scan R = 0.027int
Absorption correction: none θ = 27.5max °
h = -8 → 8
1376 measured reflections k = -11 → 11
1354 independent reflections l = -12 → 12
9
Refinement
Refinement on F2 Calculated weights w = 1/[σ (F ) +
(0.0508P) ] where P = (F + 2F )/3
2o
2
2o
2c2
R[F > 2σ(F )] = 0.0372 2 (Δ/σ) <0.0001max
wR(F ) = 0.0842 Δρ = 0.15 e Åmax-1
S = 0.89 Δρ = -0.19 e Åmin-1
1354 reflections Extinction correction: none
73 parameters Absolute structure: Flack H D (1983),
Acta Cryst. A39, 876-881
H atoms constrained to parent site Flack parameter: 0.07 (11); 541 Friedel
pairs
Table2. Geometric parameters (Å, °) for 5e
S6—O7 1.4899 (19) N4—H4 0.86
S6—C5 1.772 (2) C2—C3 1.357 (4)
S6—C8 1.777 (3) C2—H2 0.96
N1—C2 1.378 (3) C3—H3 0.96
N1—C5 1.315 (3) C8—H8A 0.96
N4—C3 1.360 (3) C8—H8B 0.96
N4—C5 1.340 (3) C8—H8C 0.96
O7—S6—C5 106.62 (10) N1—C2—C3 110.3 (2)
O7—S6—C8 107.60 (12) N4—C3—C2 105.6 (2)
C5—S6—C8 97.16 (11) N1—C5—N4 112.05 (18)
C2—N1—C5 104.49 (19) S6—C5—N1 123.20 (15)
C3—N4—C5 107.53 (16) S6—C5—N4 124.70 (15)
10
Table 3. Hydrogen-bond parameters (Å, °) for 5e
D—H H...A D...A D—H...A
N4—H4...N1i 0.86 2.06 2.885 (2) 159
C8—H8B...O7ii 0.96 2.45 3.255 (3) 142
Symmetry codes: (i) 1/2-x, -y, 1/2+z; (ii) -x, 1/2+y, 1/2-z.
Figure 1. The molecular conformation is shown with the thermal displacement ellipsoids
drawn at 50% probability and hydrogen atoms as spheres of arbitrary radius. The
crystallographic numbering of the atoms is also shown.
Refinement
The structure was solved by direct methods, SIR97 and refined with full-matrix least
squares within the SHELXL-97 software package within the maXus GUI. Hydrogen
atoms were positioned at their ideal position between 0.86 - 0.96 Å from the parent non-
H atom or found from the difference Fourier maps. The H atoms were refined using a
riding model, with U (H) = 1.2U (C). No absorption correction was done.
10a
10j
iso eq
11
Absolute configuration
The Flack’s x chirality parameter10b is used to determine the absolute configuration based
on the anomalous scattering contribution to the measured diffraction intensities. The x
parameter is defined as follows:
|Fhkl, x|2 = (1-x)|Fhkl|2 + x|F-h-k-l|2.
The x takes the value of 0 when the atomic coordinates and the crystal have the same
chirality, when they are of opposed chirality the value x becomes 1. The Flack’s
parameter was refined to a value of 0.07(11). The absolute configuration around the
chiral S6 sulfur atom was assigned to (S) following the Cahn, Ingold & Prelog sequence
rules.
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12
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