Dedicated to Prof. Alain Krief on the occasion of his 80th birthday
Key words
hypervalent iodine - oxidation - stereoselective synthesis - sulfoximines - sulfur
derivatives
Chiral hypervalent iodine reagents are widely used as active reagents in stereoselective
synthesis.[1]
[2]
[3]
[4] They are extensively studied in a wide range of stereoselective transformations
under stoichiometric and catalytic conditions. Stereoselective synthesis of chiral
sulfur compounds,[5,6] oxidative phenol dearomatisation,[7–11] α-functionalisation of carbonyl compounds,[12]
[13]
[14]
[15] difunctionalisation of alkenes,[16]
[17]
[18]
[19]
[20] and oxidative rearrangement reactions[21]
[22]
[23]
[24] are efficiently achieved with high degree of stereochemical control using diverse
chiral hypervalent iodine reagents.
The incorporation of chirality into hypervalent iodine reagents is typically achieved
through substituents of the iodoarene moiety containing a stereogenic centre (Figure
[1]). Using chiral ligands to the iodine is another strategy, even though limited.[25]
[26]
[27] The vast majority of chiral hypervalent iodine reagent are synthesised by the oxidation
of chiral iodoarenes containing chiral tetrahedral carbon centres I, II or C–C axis of chirality III. C–N axially chiral hypervalent iodine reagents of type IV are also gaining interest lately.[28]
[29] On the other hand, the synthesis of hypervalent iodine reagents with chiral sulfur
moieties is scarcely developed, even though there are a few examples known.[30]
[31] To the best of our knowledge only one report on the synthesis and reactions of diaryliodonium
salts containing chiral sulfoxide moiety has been published.[32] Herein, we report our efforts towards the synthesis of this challenging class of
chiral hypervalent iodine reagents from precursors of types V and VI (Figure [1]).
Figure 1 Strategies of introducing chirality into iodoarene scaffolds
The main challenge of synthesis of hypervalent iodine reagents with chiral sulfoxide
moiety is the loss of chirality due to the possible oxidation of sulfoxides to sulfones
under the oxidation conditions to prepare iodine(III) reagents.[32] We envisaged that the introduction of a chiral sulfinamide (type V) or sulfoximine (type VI) and adjusting the substitution pattern around the central sulfur could alleviate
this problem.
A first set of sulfinamide-based precursors was easily obtained from 2-iodobenzaldehyde
(1) and (R)-tert-butanesulfinamide (2) (Scheme [1]). Condensation of 1 and 2 in the presence of excess Lewis acids such as titanium(IV) alkoxides[33]
[34] or under iodine-catalysed solvent-free mechanochemical conditions[35] provided imine 3 in high yields (95% and 73%). Reduction of imine 3 with NaBH4 led to sulfinamide 4 in 93% yield,[36] which was then converted into the N-methyl derivative 5 upon treatment with NaH and iodomethane. Addition of phenylmagnesium bromide to the
chiral imine 3 proceeded smoothly with a high degree of stereochemical control delivering 6 as a single diastereomer (dr >20:1) in 85% yield.[37] The absolute configuration of compound 6 was determined by X-ray crystallography.[38] Treatment of 6 with NaH/MeI led to the N-methyl derivative 7 in 82% yield.
Scheme 1 Synthesis of sulfinamide-based chiral iodoarenes
To probe the potential of selective oxidation of the iodine centre without affecting
the sensitive sulfoxide moiety, precursors 3–7 were subjected to oxidation using various oxidants and conditions. It is not surprising
that the labile sulfoxide group was not tolerated under most of the oxidation protocols.
Many oxidants typical for preparing iodine(III) compounds such as Selectfluor, Oxone,
perborates, and Koser’s reagent [PhI(OH)OTs] were investigated; in addition, anodic
oxidation was also attempted.[39]
[40] The iodine precursors 3–7 were not reactive under many reaction conditions, only sodium perborate oxidation
was productive (Scheme [2]). Generally, the selective oxidation of the iodine centre was not possible under
the reaction conditions investigated and is either oxidised along with the sulfoxide
moiety or the latter is solely oxidised and hence the chirality is lost. Oxidation
of the chiral imine 3 with sodium perborate in acetic acid led to the achiral cyclic hypervalent iodine
reagent 8 in 85% yield. The chemical constitution of compound 8 was additionally confirmed by X-ray crystallography.[38] Oxidation of precursors 4 and 5 with sodium perborate led to the corresponding achiral sulfones 9
[38] and 10 with the iodine centre untouched, which could not be further oxidised using perborate
or Koser’s reagent, while with Oxone in the presence of trifluoroacetic acid the tert-butanesulfoxide moiety was cleaved to form 11. Similarly, the oxidation of precursor 6 with perborate led to sulfone 12 in 95% yield in 2.5 hours. Extended reaction times (12 h) or further oxidation of
12 formed the cyclic iodine(III) compound 13, which is chiral, but does no longer have a stereogenic sulfur centre. On the other
hand, attempted oxidation of 7 via iodine metathesis[41]
[42] using Koser’s reagent led to the cleavage of the tert-butanesulfoxide moiety and formed salt 14.
Scheme 2 Oxidation of sulfinamide-based iodoarenes 3–7
In view of these results, we envisaged that a replacement of the chiral sulfinamide
moiety with a chiral sulfoximine would lead to chiral sulfur-based iodoarene derivatives
that could be oxidised to the corresponding hypervalent iodine reagents without loss
of chirality. Initially, oxidation of compounds 3, 4, and 5 to the corresponding sulfoximines was attempted. However, oxidations using typical
procedures such as [Rh2(OAc)4] and (diacetoxyiodo)benzene[43] or t-BuOCl[44] in the presence of an amine were unsuccessful and led to complex reaction mixtures.
The 1H NMR spectra of the crude reaction mixtures showed the absence of the t-Bu moiety suggesting that it cleaved under these conditions. Also, the oxidation
of (R)-N,2-dimethylpropane-2-sulfinamide with tBuOCl in the presence of aniline resulted in the formation of N-methyl-N′-phenyl-sulfamide proved that the t-Bu group is not tolerated under the reaction conditions used to convert sulfinamides
into sulfoximines.
To avoid the difficulties encountered during the oxidation of the above compounds,
the synthesis of different sulfoximine containing chiral iodoarenes was attempted
(Scheme [3]). Relying on the oxidation of thioanisole (15) and 2-iodothioanisole (16) to sulfoximines 17 and 18 followed by chiral resolution with (+)-camphorsulfonic acid (CSA), the chiral sulfoximine
derivatives (S)-17 and (S)-18 were obtained and converted into the N-substituted derivatives 20–22 in high yields.
Scheme 3 Synthesis of iodoarene scaffolds with chiral sulfoximine moieties
The oxidation of (S)-20 to the corresponding chiral hypervalent iodine reagent using Selectfluor in the presence
of acetic acid was unsuccessful, leaving the starting material unreacted. Sodium perborate
as oxidant or aerobic oxidation in the presence of a CoCl2 catalyst[45] led to complex reaction mixtures with 2-iodobenzoic acid identified as one of the
products. Similar outcomes were obtained upon oxidation of compounds (S)-18, (S)-21, and (S)-22 using Selectfluor or the CoCl2-catalysed aerobic oxidation protocol.
With sodium perborate the formation of a cyclic chiral hypervalent iodine reagent
(S)-24 was observed as a major product in the case of precursors (S)-18 and (S)-22 and as a minor product in the case of precursor (S)-21 (Scheme [4]). The 1H NMR analysis of the crude reaction mixture showed the formation of the hypervalent
iodine reagent (S)-23 along with the cyclic product (S)-24 that is formed most likely through cyclization of (S)-23.
Scheme 4 Oxidation of chiral sulfoximine-based iodoarenes 18, 21, and 22
The ratio of 23:24 varies with the reaction time and the equivalents of sodium perborate, but 24 was the major product in all cases. The non-cyclic product 23 was only detected in the crude reaction mixture, but could not be isolated, while
the cyclic product 24 was isolated and crystallised. The structure of (S)-24 was proven by single crystal X-ray crystallography (Figure [2]). Analysis of the X-ray data of compound 24 showed a strong interaction (2.100 Å) between the sulfoximine nitrogen [(N(1)] and
the iodine centre [I(1)], which is shorter than the iodine–oxygen bond [I(1)–O(2),
2.249 Å]. The observed angle [N(1)–I(1)–O(2)] of compound 24 (167.15°) is in the range of the distorted T-shaped geometry characteristic to λ3-iodanes.[30]
[46]
Figure 2 3D structure and absolute configuration the cyclic chiral sulfoximine-based hypervalent
iodine reagent (S)-24
In conclusion, various sulfur-based chiral iodoarenes were synthesised starting with
readily available chemicals. Chiral iodoarenes containing sulfinamide units and compounds
containing sulfoximine unit have been prepared. Oxidation of both categories to the
corresponding chiral hypervalent iodine reagents was cumbersome. All sulfinamide derivatives
underwent overoxidation and, hence, the chirality is lost. Chiral sulfoximine units
are more robust and cannot undergo further oxidation. However, the oxidation of the
sulfoximines to the corresponding chiral hypervalent iodine reagents was not easy
due to the degradation of some precursors. Only the oxidation of chiral 1-iodo-2-(S-methylsulfonimidoyl)benzene derivatives was successful and led to a cyclic chiral-at-sulfur
iodine(III) reagent. Applications of sulfur-based chiral hypervalent iodine reagents
in stereoselective oxidative transformations are ongoing in our laboratory.
All starting materials were purchased from commercial suppliers and used without further
purification and all solvents used were dried and purified by standard techniques.
Reactions requiring the exclusion of moisture were carried out under an atmosphere
of argon or N2 in oven-dried glassware. Flash chromatography was carried out using Merck silica
gel (35–70 μm) or on a Biotage Isolera Four platform using SNAP Ultra (25 μm) cartridges.
Melting points were recorded on a Gallenkamp MPD350 apparatus. IR measurements were
taken using a PerkinElmer 1600 FTIR spectrometer. NMR spectra were recorded on Bruker
DPX 300, Bruker DPX 400, or Bruker DPX 500. 1H NMR spectra were measured at 300, 400, and 500 MHz. 13C {1H} NMR spectra were recorded at 75, 100, and 125 MHz using CDCl3 as the solvent and internal reference. Coupling constants J are given in hertz (Hz). Standard abbreviations were used for denoting multiplicity.
High-resolution mass spectrometry (HRMS) was carried out using a Waters LCT Premier
XE mass spectrometer using electrospray ionisation (ESI). Optical rotations were measured
with a UniPol L polarimeter at 20 °C. High-performance liquid chromatography (HPLC)
analysis was conducted using Shimadzu LC-10 AD coupled diode array-detector SPD-MA-10A-VP.
2-Iodobenzaldehyde (1)
Pyridinium chlorochromate (3.11 g, 14.45 mmol, 1.16 equiv) and Celite (13.12 g, 21.84
mmol, 1.74 equiv) were dried under vacuum in a 3-necked round-bottomed flask and then
flushed with N2, and suspended in anhyd CH2Cl2 (145 mL). A solution of 2-iodobenzyl alcohol (2.92 g, 12.5 mmol) in anhyd CH2Cl2 (40 mL) was added dropwise at rt. The reaction mixture turned from red to brown to
black and is stirred at rt overnight. After filtration through Celite, the solvent
was removed under reduced pressure. The crude product was purified by flash chromatography
(9:1 hexane:EtOAc); yield: 2.15 g (9.26 mmol, 74%); white solid; mp 37.3–37.4 °C (Lit.[21] mp 37 °C).
1H NMR (400 MHz, CDCl3): δ = 10.07 (s, 1 H), 7.96 (d, J = 7.9 Hz, 1 H), 7.89 (d, J = 7.7 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 196.0, 140.8, 135.6, 135.3, 130.4, 128.9, 100.9.
The spectral data are in agreement with literature.[44]
(R,E)-N-(2-Iodobenzylidene)-2-methylpropane-2-sulfinamide (3)
(R,E)-N-(2-Iodobenzylidene)-2-methylpropane-2-sulfinamide (3)
A solution of 2-iodobenzaldehyde (1; 1.12 g, 4.82 mmol) and Ti(OEt)4 (5.05 mL) in anhyd CH2Cl2 (48 mL) was stirred for 5 min under N2. Then, (R)-(+)-2-methyl-2-propanesulfinamide (2; 0.58 g, 4.82 mmol) was added portionwise. The reaction mixture was stirred at rt
for 20 h. Sat. aq NaHCO3 (30 mL) was added until white titanium salt stopped precipitating. The suspension
was filtered off a short pad of Celite washing with small portions of EtOAc. The aqueous
filtrate was extracted with EtOAc and the combined organic layers were washed with
brine, dried (anhyd MgSO4), and concentrated in vacuo. The crude product (yellow oil) was purified by flash
chromatography (silica gel, 9:1 hexane:EtOAc) to give the pure sulfinamide 3 as a yellow solid; yield: 1.53 g (4.58 mmol, 95%); mp 77.5–77.7 °C; [α]D –179.18 (c 1.23, CHCl3).
IR (neat): 2956, 2360, 1577, 1554, 1460, 1074, 1012, 771, 740, 441 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.94 (d, J = 7.9 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.18 (t, J = 7.6 Hz, 1 H), 1.28 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 166.7, 140.5, 135.6, 133.5, 129.9, 128.6, 101.4, 58.2, 22.9.
The spectral data are in agreement with literature.[34]
(R)-N-(2-Iodobenzyl)-2-methylpropane-2-sulfinamide (4)
(R)-N-(2-Iodobenzyl)-2-methylpropane-2-sulfinamide (4)
Sulfinamide 3 (1.71 g, 5.1 mmol) was dissolved in 98:2 THF:H2O (15 mL) and cooled down to 0 °C. NaBH4 (0.579 g, 15.32 mmol, 3 equiv) was added and the resulting solution was warmed to
rt and monitored by TLC (7:3 hexane:EtOAc). After 1 h, the TLC showed the consumption
of the starting material. Then, H2O (20 mL) was added, and the mixture was stirred at rt for 5 min. THF was evaporated
off before extracting with CH2Cl2 (3 × 10 mL). The combined CH2Cl2 layers were dried (anhyd MgSO4) and evaporated off to give the crude product, which was purified by flash chromatography
(silica gel, 9:1 hexane:EtOAc) to give the pure reduced imine 4 as a white solid; yield: 1.61 g (4.77 mmol, 93%); mp 134.6 °C; [α]D –15.45 (c 1.03, CHCl3).
IR (neat): 3194, 3059, 2976, 2360, 1583, 1564, 1436, 1363, 1074, 1040, 744, 428 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.85 (dd, J =7.9, 1.2 Hz, 1 H), 7.39 (dd, J = 7.6, 1.8 Hz, 1 H), 7.34 (td, J = 7.4, 1.2 Hz, 1 H), 7.00 (td, J = 7.6, 1.8 Hz, 1 H), 4.42 (dd, J = 14.2, 5.4 Hz, 1 H), 4.29 (dd, J = 14.2, 7.7 Hz, 1 H), 3.58 (t, J = 5.6 Hz, 1 H), 1.24 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 141.0, 139.9, 129.9, 129.6, 128.7, 99.5, 56.3, 54.1, 22.8.
The spectral data are in agreement with literature.[45]
(R)-N-(2-Iodobenzyl)-N,2-dimethylpropane-2-sulfinamide (5)
(R)-N-(2-Iodobenzyl)-N,2-dimethylpropane-2-sulfinamide (5)
To a solution of the sulfinamide 4 (317 mg, 0.94 mmol) in anhyd THF (5.5 mL) were added 60% NaH in mineral oil (68 mg,
1.69 mmol, 1.8 equiv) and MeI (760 mg, 0.33 mL, 5.36 mmol, 5.7 equiv). The reaction
mixture was stirred at rt under N2 for 1 h, and the solvent was removed under reduced pressure. The residue was dissolved
in Et2O (5 mL) and washed with H2O (5 mL). The aqueous phase was extracted with Et2O (3 × 5 mL). The combined Et2O extracts were washed with 10% aq Na2S2O3 (5 mL) and H2O (5 mL), dried (MgSO4), filtered. The filtrate was evaporated under vacuum to give methylated product 5 as a pale-yellow oil; yield: 277 mg (0.79 mmol, 84%); [α]D +20.54 (c 0.73, CHCl3).
IR (neat): 2953, 2864, 2360, 2331, 1562, 1508, 1458, 1435, 1359, 1068, 1012, 748,
432 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.81 (dd, J = 7.9, 1.1 Hz, 1 H), 7.39 (dd, J = 7.7, 1.7 Hz, 1 H), 7.33 (td, J = 7.5, 1.2 Hz, 1 H), 6.95 (td, J = 7.8, 1.8 Hz, 1 H), 4.27 (d, J = 15.8 Hz, 1 H), 4.18 (d, J = 15.9 Hz, 1 H), 2.66 (s, 3 H), 1.18 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 139.8, 139.4, 129.2, 129.2, 128.5, 99.5, 77.4, 61.7, 58.8, 23.6.
HRMS (ESI+): m/z [M + H+] calcd for C12H19INOS: 352.0227; found: 352.0230.
(R)-N-[(S)-(2-Iodophenyl)(phenyl)methyl]-2-methylpropane-2-sulfinamide (6)
(R)-N-[(S)-(2-Iodophenyl)(phenyl)methyl]-2-methylpropane-2-sulfinamide (6)
To a solution of the imine 3 (322 mg, 0.96 mmol) in CH2Cl2 (5.8 mL) was added phenylmagnesium bromide (348 mg, 0.69 mL, 1.92 mmol, 2 equiv)
at –48 °C. The reaction mixture was stirred at –48 °C for 6 h and then allowed to
warm to rt and stirred overnight. The mixture was quenched with sat. aq NH4Cl (2 mL) and the aqueous layer was extracted with EtOAc (3 × 3 mL). The combined
organic layers were dried (Na2SO4) and concentrated to provide the crude product, which was purified by crystallization
from hexane:CH2Cl2 (10:1) to give the pure product 6 as colourless crystals; yield: 337 mg (0.82 mmol, 85%); mp 145–146 °C; [α]D –68.14 (c 0.66, CHCl3).
IR (neat): 3213, 2981, 2962, 1560, 1494, 1465, 1448, 1357, 1033, 391 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.85 (dd, J = 7.9, 1.2 Hz, 1 H), 7.56 (dd, J = 7.8, 1.7 Hz, 1 H), 7.41–7.36 (m, 3 H), 7.33 (ddd, J = 7.4, 4.6, 1.4 Hz, 2 H), 7.30–7.26 (m, 1 H), 6.99 (td, J = 7.6, 1.7 Hz, 1 H), 5.97 (d, J = 2.8 Hz, 1 H), 3.73 (d, J = 2.4 Hz, 1 H), 1.25 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 143.4, 141.2, 140.2, 129.5 (2 C), 129.0, 128.4, 128.2, 128.1, 100.1, 65.8,
56.2, 22.8.
HRMS (ESI+): m/z [M + H+] calcd for C17H21INOS: 414.0383; found: 414.0382.
(R)-N-[(S)-(2-Iodophenyl)(phenyl)methyl]-N,2-dimethylpropane-2-sulfinamide (7)
(R)-N-[(S)-(2-Iodophenyl)(phenyl)methyl]-N,2-dimethylpropane-2-sulfinamide (7)
To a solution of the sulfinamide 6 (413 mg, 1 mmol) in anhyd THF (6 mL) were added 60% NaH in mineral oil (72 mg, 1.8
mmol, 1.8 equiv) and MeI (795 mg, 0.34 mL, 5.6 mmol, 5.6 equiv). The reaction mixture
was stirred at rt under N2 for 1 h, and the solvent was removed under reduced pressure. The residue was dissolved
in Et2O (5 mL) and washed with H2O (5 mL). The aqueous phase was extracted with Et2O (3 × 5 mL). The combined ether extracts were washed with 10% aq Na2S2O3 (5 mL) and H2O (5 mL), dried (MgSO4), filtered, and the filtrate was evaporated under vacuum to give methylated product
7 as a white solid; yield: 350 mg (0.82 mmol, 82%); mp 98–99 °C; [α]D +88.11 (c 1.29, CHCl3).
IR (neat): 2954, 2920, 1452, 1072, 565 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.87 (dd, J = 7.9, 1.2 Hz, 1 H), 7.56 (dd, J = 7.8, 1.6 Hz, 1 H), 7.40 (td, J = 7.6, 1.2 Hz, 1 H), 7.31–7.25 (m, 3 H), 7.22–7.18 (m, 2 H), 6.99 (td, J = 7.6, 1.6 Hz, 1 H), 5.95 (s, 1 H), 2.60 (s, 3 H), 1.12 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 142.4, 140.3, 138.7, 129.7, 129.6, 129.4, 128.5, 128.5, 127.8, 101.2, 77.1,
59.1, 29.8, 24.2.
HRMS (ESI+): m/z [M + H+] calcd for C18H23INOS: 428.0540; found: 428.0535.
2-(tert-Butylsulfonyl)-3-oxo-2,3-dihydro-1H-1λ3-benzo[d][1,2]iodazol-1-yl Acetate (8)
2-(tert-Butylsulfonyl)-3-oxo-2,3-dihydro-1H-1λ3-benzo[d][1,2]iodazol-1-yl Acetate (8)
To a solution of sulfinamide 3 (67 mg, 0.2 mmol) in glacial AcOH (4 mL) was added NaBO3·4H2O (312 mg, 2.0 mmol, 10 equiv). The reaction mixture was stirred at 40–45 °C for 4
h. The solvent was removed under reduced pressure and the white solid left was partitioned
between H2O (5 mL) and CH2Cl2 (5 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL) and dried (anhyd
MgSO4), filtered, and concentrated under pressure to give the crude product 8 as a white solid, which was purified by recrystallisation from hexane:AcOH (8:2)
to obtain 8 as a white solid; yield: 73 mg (0.17 mmol, 85%).
1H NMR (400 MHz, acetone-d
6): δ = 8.17 (dd, J = 7.6, 1.1 Hz, 1 H), 8.13 (d, J = 8.4 Hz, 1 H), 8.03 (t, J = 7.2 Hz, 1 H), 7.84 (t, J = 7.5 Hz, 1 H), 2.19 (s, 3 H), 1.54 (s, 9 H).
13C NMR (101 MHz, acetone-d
6): δ = 176.4, 163.2, 137.2, 134.5, 132.9, 132.0, 130.6, 117.8, 64.0, 25.1, 20.5.
N-(2-Iodobenzyl)-2-methylpropane-2-sulfonamide (9)
N-(2-Iodobenzyl)-2-methylpropane-2-sulfonamide (9)
To a solution of sulfinamide 4 (135 mg, 0.4 mmol) in glacial AcOH (6 mL) was added NaBO3·4H2O (615 mg, 4 mmol, 10 equiv) and the reaction mixture was stirred at 40–45 °C. After
1 h, the TLC (hexane:EtOAc 7:3) showed the consumption of the starting material. The
solvent was removed under reduced pressure and the white solid left was treated with
H2O (5 mL) and CH2Cl2 (5 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried (anhyd
MgSO4), filtered, and concentrated under pressure to give the sulfonamide 9 as a pale-yellow solid; yield: 128 mg (0.36 mmol, 90%); mp 77–78 °C.
IR (neat): 3277, 2976, 2879, 2360, 1683, 1456, 1436, 1398, 1300, 1112, 1010, 742,
511 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.83 (dd, J = 7.9, 1.2 Hz, 1 H), 7.47 (dd, J = 7.7, 1.7 Hz, 1 H), 7.36 (td, J = 7.5, 1.2 Hz, 1 H), 7.01 (td, J = 7.6, 1.7 Hz, 1 H), 4.40 (d, J = 6.2 Hz, 2 H), 4.36–4.30 (m, 1 H), 1.41 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 140.3, 139.7, 130.1, 130.0, 129.0, 99.0, 60.3, 53.0, 24.5.
HRMS (ESI+): m/z [M + H+] calcd for C11H17INO2S: 354.0019; found: 354.0018.
N-(2-Iodobenzyl)-N,2-dimethylpropane-2-sulfonamide (10)
N-(2-Iodobenzyl)-N,2-dimethylpropane-2-sulfonamide (10)
To a solution of sulfinamide 5 (140 mg, 0.4 mmol, 1 equiv) in glacial AcOH (6 mL) was added NaBO3·4H2O (615 mg, 4 mmol, 10 equiv). The reaction mixture was stirred at 40–45 °C. After
1 h, the TLC (hexane:EtOAc 7:3) showed the consumption of the starting material. The
solvent was removed under reduced pressure and the white solid left was partitioned
between H2O (5 mL) and CH2Cl2 (5 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL) and dried (anhyd
MgSO4), filtered, and concentrated under pressure to give the sulfonamide 10 as a pale-yellow solid; yield: 126 mg (0.34 mmol, 86%); mp 82–83 °C.
IR (neat): 2360, 1695, 1581, 1436, 1317, 1261, 1120, 1016, 790, 511, 418 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.82 (dd, J = 7.9, 1.2 Hz, 1 H), 7.55 (dd, J = 7.8, 1.6 Hz, 1 H), 7.40 (td, J = 7.7, 1.2 Hz, 1 H), 6.99 (td, J = 7.8, 1.7 Hz, 1 H), 4.52 (s, 2 H), 2.90 (s, 3 H), 1.47 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 139.5, 138.3, 129.5, 129.1, 128.9, 98.8, 62.4, 59.8, 36.4, 25.2.
HRMS (ESI+): m/z [M + H+] calcd for C12H19INO2S: 368.0176; found: 368.0179.
1-(2-Iodophenyl)-N-methylmethanamine (11)
1-(2-Iodophenyl)-N-methylmethanamine (11)
To a solution of 10 (43 mg, 0.12 mmol) in a mixture of trifluoroacetic acid (1.2 mL) and CHCl3 (0.4 mL) was added Oxone (111 mg, 0.18 mmol, 1.5 equiv). The reaction mixture was
stirred at rt and monitored by TLC. After completion of reaction, the solvent was
evaporated under vacuum and the residue was treated with CHCl3 (2 mL). The insoluble residue of inorganic salts was collected by filtration, washed
with CHCl3 (2 mL), and discarded. Evaporation of combined CHCl3 layers under reduced pressure afforded amino compound 11 as a pale-yellow oil; yield: 21 mg (0.0841 mmol, 70%).
IR (neat): 3014, 2818, 2742, 2358, 2331, 1778, 1670, 1176, 1138, 1014, 798, 756, 403
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.82 (dd, J = 8.0, 1.2 Hz, 1 H), 7.48 (dd, J = 7.7, 1.6 Hz, 1 H), 7.33 (td, J = 7.6, 1.2 Hz, 1 H), 7.02 (td, J = 7.8, 1.6 Hz, 1 H), 3.79 (s, 2 H), 2.47 (s, 3 H).
The spectral data are in agreement with literature.[47]
(S)-N-[(2-Iodophenyl)(phenyl)methyl]-2-methylpropane-2-sulfonamide (12)
(S)-N-[(2-Iodophenyl)(phenyl)methyl]-2-methylpropane-2-sulfonamide (12)
To a solution of sulfinamide 6 (52 mg, 0.125 mmol) in glacial AcOH (2.5 mL) was added NaBO3·4H2O (289 mg, 1.88 mmol, 15 equiv). The reaction mixture was stirred at 40–45 °C. After
2.5 h, the TLC (hexane:EtOAc 3:1) showed the consumption of the starting material.
The solvent was removed under reduced pressure and the white solid left was treated
with H2O (5 mL) and CH2Cl2 (5 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL) and dried (anhyd
MgSO4), filtered, and concentrated under pressure to give the sulfonamide 12 as a white solid; yield: 51 mg (0.12 mmol, 95%).
1H NMR (300 MHz, CDCl3): δ = 7.87 (dd, J = 7.9, 0.7 Hz, 1 H), 7.53–7.40 (m, 2 H), 7.36–7.19 (m, 5 H), 7.04 (ddd, J = 7.9, 6.7, 2.4 Hz, 1 H), 6.03 (d, J = 9.0 Hz, 1 H), 4.81 (d, J = 8.9 Hz, 1 H), 1.32 (s, 9 H).
(S)-2-(tert-Butylsulfonyl)-3-phenyl-2,3-dihydro-1H-1λ3-benzo[d][1,2]iodazol-1-yl Acetate (13)
(S)-2-(tert-Butylsulfonyl)-3-phenyl-2,3-dihydro-1H-1λ3-benzo[d][1,2]iodazol-1-yl Acetate (13)
Compound 13 was prepared following the above procedure (for compound 12) starting with 6 or 12 but using 12 h as reaction time leading to 13 as a white solid; yield: 40 mg (0.082 mmol, 82%); mp 144–146 °C; [α]D +29.67 (c 0.4, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 9.4 Hz, 1 H), 7.50–7.46 (m, 1 H), 7.46–7.43 (m, 1 H), 7.42–7.38 (m, 1 H), 7.37–7.29
(m, 5 H), 6.23 (s, 1 H), 2.13 (s, 3 H), 1.26 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 143.7, 140.7, 140.4, 129.6, 129.0, 128.9, 128.8, 128.00, 127.97, 99.1, 65.3,
60.3, 24.3.
(S)-1-(2-Iodophenyl)-N-methyl-1-phenylmethanamine 4-Methylbenzenesulfonate (14)
(S)-1-(2-Iodophenyl)-N-methyl-1-phenylmethanamine 4-Methylbenzenesulfonate (14)
Koser’s reagent (42 mg, 0.11 mmol) was added to a stirred solution of 12 (50 mg, 0.12 mmol, 1.1 equiv) in anhyd CH2Cl2 (1 mL) at rt. The reaction was stirred and monitored by TLC. After the completion
of the reaction, the solvent was removed under reduced pressure and the solid residue
was filtered and washed with Et2O several times, then dried in vacuum to give 14 as a white solid; yield: 48 mg (0.114 mmol, 83%).
1H NMR (300 MHz, CD3OD): δ = 8.02 (d, J = 7.80 Hz, 1 H), 7.70 (d, J = 8.02 Hz, 2 H), 7.66–7.57 (m, 1 H), 7.53–7.39 (m, 5 H), 7.23 (d, J = 7.78 Hz, 2 H), 7.20–7.13 (m, 1 H), 5.71 (s, 1 H), 2.72 (s, 3 H), 2.37 (s, 3 H),
1.15 (s, 1 H).
rac-S-Methyl-S-phenylsulfoximine (17)
rac-S-Methyl-S-phenylsulfoximine (17)
To a solution of thioanisole 15 (1.24 g, 10.0 mmol) in MeOH (100 mL) was added (NH4)2CO3 (1.50 g, 15.6 mmol, 1.5 equiv). After the dissolution of (NH4)2CO3, (diacetoxyiodo)benzene (7.43 g, 23.1 mmol, 2.3 equiv) was added. The reaction mixture
was stirred at rt overnight, then evaporated to dryness and purified by column chromatography
(hexane:EtOAc 1:1) affording pure 17 as a yellow oil that solidified after few days; yield: 1.43 g (9.20 mmol, 92%); mp
33–34 °C (Lit.[48] mp 34–35 °C).
1H NMR (400 MHz, CDCl3): δ = 8.05–8.00 (m, 2 H), 7.66–7.60 (m, 1 H), 7.59–7.53 (m, 2 H), 3.13 (s, 3 H).
The spectral data are in agreement with literature.[49]
rac-S-Methyl-S-2-iodophenylsulfoximine (18)
rac-S-Methyl-S-2-iodophenylsulfoximine (18)
Prepared following the above procedure (for 17), starting with 2-iodothioanisole (16; 1.0 g, 4.0 mmol). Compound 18 was obtained as a yellow oil that solidified after a few days; yield: 0.765 g (2.72
mmol, 68%); mp 64–66 °C.
IR (neat): 3287, 1564, 1422, 1314, 1204, 1080, 986, 932, 754, 700, 509 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 7.9 Hz, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 3.28 (s, 3 H), 2.75 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 145.6, 143.1, 133.9, 130.6, 129.0, 93.3, 42.6.
HRMS: m/z [M + H]+ calcd for [C7H9INOS]: 281.9444; found: 281.9452.
(+)-(S)-S-Methyl-S-phenylsulfoximine [(S)-17]
(+)-(S)-S-Methyl-S-phenylsulfoximine [(S)-17]
To a solution of racemic S-methyl-S-phenylsulfoximine (rac-17; 1.43 g, 9.2 mmol) in acetone (6 mL) was added a solution of (+)-camphorsulfonic
acid (1.2 g, 5.1 mmol 0.55 equiv) in acetone (14 mL). The reaction mixture was stirred
at rt overnight. The formed precipitate was collected by filtration and washed thoroughly
with acetone. The obtained solid was then suspended in CH2Cl2 (30 mL). Sat. aq K2CO3 (30 mL) was added with stirring. Stirring was continued at rt for 1 h. The organic
phase was separated, and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4) and evaporated to dryness affording pure (S)-17 as a colourless oil that solidified after a few days; yield: 0.46 g (2.95 mmol, 32%).
1H NMR (400 MHz, CDCl3): δ = 8.04–7.99 (m, 1 H), 7.65–7.60 (m, 1 H), 7.58–7.53 (m, 1 H), 3.11 (s, 3 H).
(+)-(S)-S-Methyl-S-2-iodophenylsulfoximine [(S)-18]
(+)-(S)-S-Methyl-S-2-iodophenylsulfoximine [(S)-18]
Obtained following the above procedure [for (S)-17], starting with racemic S-methyl-S-2-iodophenylsulfoximine (rac-18; 0.764 g, 2.72 mmol) and (+)-camphorsulfonic acid (0.32 g, 1.36 mmol 0.5 equiv).
Compound (S)-18 was obtained as a colourless oil that solidified after a few days; yield: 0.36 mg
(1.28 mmol, 47%); mp 63–65 °C; [α]D +30 (c 2.6, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 7.9 Hz, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 3.28 (s, 3 H), 2.75 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 145.6, 143.1, 133.9, 130.6, 129.0, 93.3, 42.6.
(S)-N-2-Iodobenzyl-S-methyl-S-phenylsulfoximine [(S)-20]
(S)-N-2-Iodobenzyl-S-methyl-S-phenylsulfoximine [(S)-20]
To a solution of (S)-S-methyl-S-phenylsulfoximine [(S)-17; 0.459 g, 2.95 mmol) in DMSO (1.5 mL) was added KOH (0.33 g, 5.9 mmol, 2.0 equiv).
The reaction was stirred at rt under argon for 5 min. 2-Iodobenzyl bromide (19; 1.31 g, 4.42 mmol, 1.5 equiv) was added and stirring was continued at rt overnight.
The reaction was quenched by the addition of H2O (5 mL) and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic layers were combined, dried (anhyd MgSO4) and evaporated under reduced pressure. The crude product was purified by column
chromatography (hexane:EtOAc 9:1) affording pure (S)-20 as a dark yellow oil; yield: 0.73 g (1.95 mmol, 66%); [α]D +1.23 (c 0.6, CHCl3)
IR (neat): 1445, 1221, 1140, 1011, 741, 689, 513 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 7.6 Hz, 2 H), 7.75 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.56 (t, J = 7.5 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 4.15 (d, J = 15.5 Hz, 1 H), 4.05 (d, J = 15.5 Hz, 1 H), 3.20 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 143.0, 139.3, 139.1, 133.3, 129.7, 129.3, 128.8, 128.5, 128.4, 98.8, 52.4,
45.4.
HRMS: m/z calcd [M + H]+ for [C14H15INOS]: 371.9914; found: 371.9916.
(S)-N-Ethyl-S-methyl-S-2-iodophenylsulfoximine [(S)-21]
(S)-N-Ethyl-S-methyl-S-2-iodophenylsulfoximine [(S)-21]
To a solution of (S)-S-methyl-S-2-iodophenylsulfoximine [(S)-18; 0.168 g, 0.6 mmol] in DMSO (1.5 mL) was added KOH (90 mg, 1.6 mmol, 2.2 equiv).
The reaction was stirred at rt under argon for 5 min. EtBr (0.10 mL, 1.34 mmol, 2.1
equiv) was added and stirring was continued at rt overnight. The reaction was quenched
by the addition of H2O (5 mL) and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic layers were combined, dried (anhyd MgSO4) and evaporated under reduced pressure. The crude product was purified by column
chromatography (hexane:EtOAc 9:1) affording pure (S)-21 as a white solid; yield: 0.151 g (0.49 mmol, 81%); mp 53–55 °C; [α]D +160 (c 5.9, CHCl3).
IR (neat): 2967, 2843, 2359, 1740, 1558, 1217, 1144, 1080, 1013, 750, 517 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.29 (dd, J = 7.9, 1.7 Hz, 1 H), 8.12 (dd, J = 7.8, 1.2 Hz, 1 H), 7.56 (ddd, J = 7.9, 7.4, 1.2 Hz, 1 H), 7.24–7.20 (m, 1 H), 3.26 (s, 3 H), 2.94 (dq, J = 12.2, 7.2 Hz, 1 H), 2.78 (dq, J = 12.2, 7.2 Hz, 1 H), 1.21 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 143.1, 141.5, 133.8, 133.0, 129.2, 93.8, 42.1, 38.9, 18.0.
HRMS: m/z [M + H]+ calcd for [C9H13INOS]: 309.9757; found: 309.9751.
(S)-N-Acetyl-S-methyl-S-2-iodophenylsulfoximine [(S)-22]
(S)-N-Acetyl-S-methyl-S-2-iodophenylsulfoximine [(S)-22]
To a solution of (S)-S-methyl-S-2-iodophenylsulfoximine [(S)-18; 309 mg, 1.09 mmol] in CH2Cl2 (8 mL) at 0 °C was added pyridine (0.12 mL, 0.14 mmol, 1.3 equiv) followed by AcCl
(77 μL, 1.09 mmol). The reaction mixture was stirred at 0 °C for 1 h, then allowed
to warm to rt and stirring was continued overnight. The reaction was quenched with
ice cold water (10 mL). The organic phase was separated, and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4) and evaporated. The crude product was purified by column chromatography (hexane:EtOAc
1:1) affording pure (S)-22 as white crystals; yield: 348 mg (1.08 mmol, 99%); mp 137–139 °C; [α]D +11.5 (c 0.59 in CHCl3).
IR (neat): 2359, 1740, 1636, 1361, 1315, 1213, 1026, 972, 827, 756, 613, 501, 444
cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.32 (dd, J = 8.0, 1.4 Hz, 1 H), 8.12 (dd, J = 7.8, 1.2 Hz, 1 H), 7.63–7.59 (m, 1 H), 7.30–7.26 (m, 1 H), 3.45 (s, 3 H), 2.16
(s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 179.8, 143.3, 140.9, 134.5, 131.5, 129.4, 91.6, 41.2, 26.5.
HRMS: m/z [M + H]+ calcd for [C9H11INO2S]: 323.9550; found: 323.9557.
The spectral data are in agreement with literature.[50]
(S)-3-Methyl-3-oxido-1H-1λ3,3λ4-benzo[d][1,3,2]iodathiazol-1-yl Acetate [(S)-24]
(S)-3-Methyl-3-oxido-1H-1λ3,3λ4-benzo[d][1,3,2]iodathiazol-1-yl Acetate [(S)-24]
To a stirred solution of iodoarene (S)-18, (S)-21, or (S)-22 (1.0 mmol) in AcOH (30 mL) at 45 °C was added NaBO3·4H2O (30 mmol, 30 equiv) portionwise over 15 min. The mixture was stirred at 45 °C overnight.
The AcOH was evaporated under reduced pressure, and to the residue were added H2O (10 mL) and CH2Cl2 (10 mL). The organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). The combined organic layers were dried (anhyd MgSO4), filtered, and concentrated under reduced pressure. The residue was washed with
n-hexane to afford the pure product as a white solid; yield: 275 mg (81%) from (S)-18 and 170 mg (50%) from (S)-22; mp 176–178 °C; [α]D +2.6 (c 1.54, CHCl3).
IR (neat): 3001, 2365, 1717, 1603, 1312, 1208, 991, 754 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J = 7.6 Hz, 1 H), 7.90 (dd, J = 7.0, 1.9 Hz, 1 H), 7.86–7.80 (m, 2 H), 3.40 (s, 3 H), 2.11 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 178.1, 134.4, 133.9, 132.3, 131.3, 128.2, 117.5, 47.7, 22.2.
