Key words
sulfoximidation - thiol -
N-sulfenylsulfoximine - hypervalent iodine reagents - ligand exchange
Sulfoximines are monoaza analogues of sulfones with relevance for asymmetric synthesis[1] and applications in crop protection and medicinal chemistry.[2] They exhibit manifold reaction behavior, as reflected by Trost and Matsuoka, who
described N-nitrosulfoximines as ‘chemical chameleons’.[3] In general, substituents at the sulfoximidoyl group affect the properties of the
respective molecules,[4]
[5] allowing, for example, fine-tuning of important parameters such as pK
a
[6] and solubility.[7] The N-substituent plays a key role in this context. Besides introducing it directly by
sulfide or sulfoxide imidation,[4]
[8] it can be varied by functionalizing NH-sulfoximines 1, which are readily accessible by various routes.[1]
[9] Most protocols involve deprotonated intermediates A, which react with electrophiles to give acylated, alkylated, or arylated products
among others.[10] Alternative N-modification pathways via radicals B or cationic species C are rare.
In 2016 we introduced hypervalent iodine(III) compounds 2 with the vision to apply them synthetically as sulfoximidoyl transfer agents (Scheme
[1]).[11]
[12] To our delight, photocatalysis allowed activation of the central I–N bond of 2 leading to functionalizations of benzylic C–H bonds by the resulting sulfoximidoyl
moieties.[10g,13] In terms of the mechanism, the process was suggested to proceed via radicals such
as B. While searching for new applications of iodine reagents 2, we began focusing on pathways via (formally) cationic species C. Until now, only one transformation reflecting such reactivity is known. In the respective
reaction scheme, reagents 2 react with terminal alkynes in the presence of a base affording N-alkynylated sulfoximines 3.[11] After screening a series of other nucleophiles, we have now also discovered that
deprotonated thiols were capable of reacting with 2 leading to N-sulfenylsulfoximines with the general structure 5. Products of type 5 were known, but the common synthetic procedures started from NH-sulfoximines 1, which were either N-derivatized by deprotonation followed by treatment with electrophilic
sulfur reagents (such as ArSCl)[14] or coupled with preformed[15] or thiol-derived disulfides[16]
[17] under metal catalysis. Thus, our new approach contrasted all previous ones.
Scheme 1 General reaction behavior of NH-sulfoximines 1 and access to target compounds 5 via iodine reagents 2
The initial studies were performed with S-methyl-S-phenyl derivative 2a and thiophenol (4a) as representative substrates. In dichloroethane (DCE), both compounds did not reacted
at ambient temperature or at 70 °C, and only the starting materials were recovered
(Table [1], entries 1 and 2). Also the addition of DBU, K2CO3, or KOt-Bu did not lead to a breakthrough, and at best, traces of the expected product 5aa were observed (Table [1], entries 3–5). The situation changed, when NaH was applied as base, and after a
short optimization of the reaction conditions (Table [1], entries 6–11), N-sulfenylsulfoximine 5aa was obtained in 91% yield (Table [1], entry 11).
Table 1 Optimization of the Reaction Parametersa
|
|
Entry
|
Base (equiv)
|
Solvent
|
Temp (°C)
|
Yield (%)
|
|
1
|
–
|
DCE
|
25
|
n.r.
|
|
2
|
–
|
DCE
|
70
|
n.r.
|
|
3
|
DBU (2.1)
|
DCE
|
25
|
trace
|
|
4
|
K2CO3 (2.1)
|
DCE
|
25
|
n.d.
|
|
5
|
KOt-Bu (2.1)
|
DCE
|
25
|
trace
|
|
6
|
NaH (2.1)
|
DCE
|
25
|
27
|
|
7
|
NaH (2.1)
|
DCE
|
50
|
71
|
|
8
|
NaH (2.1)
|
MeCN
|
50
|
21
|
|
9
|
NaH (2.1)
|
THF
|
50
|
17
|
|
10
|
NaH (2.1)
|
CH2Cl2
|
50
|
75
|
|
11b
|
NaH (4.2)
|
CH2Cl2
|
50
|
91
|
a Reaction conditions (0.2-mmol scale): iodine reagent 2a, thiophenol (4a; 2 equiv), base, solvent (2 mL), sealed tube, 16 h. n.r. = no reaction, n.d. = not
detected.
b Use of 4 equiv of 4a.
To achieve this result, the following parameters were important: First, the ratio
of starting materials 2a and 4a had to be 1:4. Second, the solvent needed to be dichloromethane, and third, the reaction
temperature had to be 50 °C.
With the optimized conditions in hand, the substrate scope was examined. The results
for reactions performed on a 0.2-mmol scale with respect to 2a (in sealed tubes) are summarized in Scheme [2]. First, various aromatic thiols were reacted with hypervalent iodine reagent 2a. All products 5aa–aj were obtained in good to high yields (52–91%). Electronic or steric effects induced
by substituents on the thiophenol did not have an apparent impact on the reaction
efficiency. Also ortho-substituted thiols reacted remarkably well as reflected by the results for products
5af–ah, which were isolated in yields of 81%, 80%, and 72%, respectively. Reactions of 2a with aliphatic thiols proved more difficult. Thus, 5ak and 5al stemming from couplings of 2a with 2-methylpropane-2-thiol (4k) and cyclohexanethiol (4l) were obtained in only 21% and 30%, respectively. Varying the structure of the hypervalent
iodine reagent was possible too, and applying S,S-diphenyl and S-(4-fluorophenyl)-S-methyl derivatives 2b and 2c in reactions with thiophenol (4a) led to the corresponding products 5ba and 5ca in 77% and 46% yield, respectively. With tetrahydrothiophene derivative 2d as the coupling agent for 4a, only traces of the corresponding product 5da were observed. The attempt to use 1-sulfoximidoyl-1,2-benziodoxole 6 in the reaction with 4a remained unsuccessful.[18]
Scheme 2 Syntheses of N-sulfenylsulfoximines
Based on previous reports,[11]
[19]
[20] we suggest the pathway depicted in Scheme [3] for the formation of N-sulfenylsulfoximines 5. First, thiol 4 is deprotonated by sodium hydride, and the resulting thiolate reacts with hypervalent
iodine reagent 2 by tosylate substitution. This ligand exchange leads to the formation of a transient
intermediate 7, which upon elimination of iodobenzene provides product 5.
Scheme 3 Possible reaction pathway
In summary, we developed a new approach towards N-sulfenylsulfoximines by electrophilic sulfoximidations of thiols with sulfoximidoyl-containing
hypervalent iodine(III) reagents. Both N-(arylsulfenyl)- as well as N-(alkylsulfenyl)sulfoximines can easily be obtained under metal-free conditions.
Unless otherwise noted, all chemicals were purchased from commercial suppliers (Abcr,
Acros, Sigma Aldrich, Merck) and used without further purification. When required,
solvents were dried according to general purification methods. The product mixtures
were analyzed by TLC using silica gel plates (Merck-Schuchardt) with fluorescent indicator
(λ = 254 nm). The purification of the products was performed by flash column chromatography
using silica gel 60 (63–200 μm) from Merck. NMR spectra were recorded on Agilent VNMRS
600, Agilent VNMRS 400 or Varian Mercury 300 in deuterated solvents. The IR spectra
were recorded with a PerkinElmer Spectrum 100 spectrometer with an attached UATR device
Diamond KRS-5; all IR data were collected by attenuated total reflectance (ATR). Mass
spectra were recorded on a Finnigan SSQ Finnigan 7000 spectrometer (EI, 70 eV). HRMS
were recorded on a Thermo Scientific LTQ Orbitrap XL spectrometer. Melting points
(mp) were measured on a Büchi B-540 melting point apparatus.
N-Thiosulfoximines 5aa–da; General Procedure
N-Thiosulfoximines 5aa–da; General Procedure
Thiol 4 (0.80 mmol), NaH (0.80 mmol, 32 mg, wt = 60%), and CH2Cl2 (2.0 mL) were added to a flame-dried reaction tube (15 mL) equipped with a magnetic
stirring bar, and the mixture was stirred at 50 °C for 4 h. Then, the hypervalent
iodine(III) salt 2 (0.20 mmol) was added to the mixture in one portion. The resulting solution was stirred
for 12 h at 50 °C and then cooled to r.t. Concentration under reduced pressure and
subsequent purification of the product by column chromatography (silica gel, EtOAc/pentane
1:2) afforded N-thiosulfoximines 5.
N-(Phenylthio)-S-methyl-S-phenylsulfoximine (5aa)[15]
N-(Phenylthio)-S-methyl-S-phenylsulfoximine (5aa)[15]
Pale yellow viscous oil; yield: 48 mg (91%).
1H NMR (600 MHz, CDCl3): δ = 7.98–7.94 (m, 2 H), 7.68–7.65 (m, 1 H), 7.60–7.56 (m, 2 H), 7.41–7.38 (m, 2
H), 7.27–7.25 (m, 2 H), 7.09 (t, J = 7.3 Hz, 1 H), 3.28 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3): δ = 142.1, 138.7, 133.7, 129.5, 128.5, 128.4, 125.1, 123.8, 43.8.
N-(4-Methylphenylthio)-S-methyl-S-phenylsulfoximine (5ab)
N-(4-Methylphenylthio)-S-methyl-S-phenylsulfoximine (5ab)
Pale yellow viscous oil; yield: 45 mg (81%).
IR (ATR): 3476, 3309, 3018, 2922, 2325, 2015, 1907, 1735, 1487, 1217, 1091, 987, 804,
738, 686 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.95–7.93 (m, 2 H), 7.67–7.64 (m, 1 H), 7.59–7.56 (m, 2 H), 7.32–7.31 (d, J = 6.0 Hz, 2 H), 7.10–7.08 (m, 2 H), 3.26 (s, 3 H), 2.30 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3): δ = 138.8, 138.2, 135.3, 133.6, 129.4, 129.3, 128.4, 125.0, 43.7, 21.0.
MS (EI): m/z = 277 (13, M+), 261 (4), 140 (23), 125 (21), 123 (100), 91 (22), 77 (72).
HRMS: m/z calcd for [C14H15NOS2 + H]+: 278.0668; found: 278.0668.
N-(4-Chlorophenylthio)-S-methyl-S-phenylsulfoximine (5ac)
N-(4-Chlorophenylthio)-S-methyl-S-phenylsulfoximine (5ac)
Pale yellow oil; yield: 51 mg (87%).
IR (ATR): 3459, 3064, 2923, 2662, 2331, 2100, 1739, 1469, 1391, 1211, 1089, 981, 816,
735, 683 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.94–7.92 (m, 2 H), 7.69–7.66 (m, 1 H), 7.60–7.58 (m, 2 H), 7.33–7.31 (d, J = 6.0 Hz, 2 H), 7.23–7.21 (m, 2 H), 3.28 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3): δ = 140.9, 138.5, 133.9, 130.6, 129.6, 128.6, 128.4, 125.1, 43.9.
MS (EI): m/z = 298 (95, M+), 143 (88), 140 (48), 125 (84), 124 (100), 111 (21), 77 (81).
HRMS: m/z calcd for [C13H12ClNOS2 + H]+: 298.0122; found: 298.0122.
N-(4-Fluorophenylthio)-S-methyl-S-phenylsulfoximine (5ad)
N-(4-Fluorophenylthio)-S-methyl-S-phenylsulfoximine (5ad)
Yellow oil; yield: 29 mg (52%).
IR (ATR): 3459, 3302, 3059, 2660, 2323, 2090, 1911, 1739, 1584, 1481, 1399, 1216,
1091, 986, 832, 741, 692 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.94–7.91 (m, 2 H), 7.69–7.65 (m, 1 H), 7.60–7.56 (m, 2 H), 7.41–7.37 (m, 2
H), 6.99–6.95 (m, 2 H), 3.27 (s, 3 H).
13C{1H} NMR (101 MHz, CDCl3): δ = 161.2 (d, J
C-F = 245.4 Hz), 138.6, 136.8, 133.7, 129.5, 128.4, 127.0 (d, J
C-F = 8.1 Hz), 115.6 (d, J
C-F = 22.2 Hz), 43.9.
MS (EI): m/z = 281 (99, M+), 141 (6), 140 (100), 127 (8), 125 (4), 124 (8), 95 (15), 77 (38).
HRMS: m/z calcd for [C13H12FNOS2 + H]+: 282.0417; found: 282.0420.
N-(4-Methoxyphenylthio)-S-methyl-S-phenylsulfoximine (5ae)
N-(4-Methoxyphenylthio)-S-methyl-S-phenylsulfoximine (5ae)
Yellow oil; yield: 44 mg (75%).
IR (ATR): 3460, 3298, 3062, 2929, 2667, 2328, 2096, 1906, 1730, 1586, 1487, 1226,
1091, 986, 825, 740, 686 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.93–7.91 (m, 2 H), 7.65–7.63 (m, 1 H), 7.58–7.56 (m, 2 H), 7.43–7.41 (m, 2
H), 6.84–6.82 (m, 2 H), 3.78 (s, 3 H), 3.23 (s, 3 H).
13C{1H} NMR (101 MHz, CDCl3): δ = 158.7, 138.9, 133.5, 132.7, 129.5, 129.4, 128.5, 114.3, 55.4, 43.9.
MS (EI): m/z = 293 (3, M+), 154 (4), 140 (16), 139 (100), 125 (16), 124 (20), 107 (2), 77 (28).
HRMS: m/z calcd for [C14H15NO2S2 + H]+: 294.0617; found: 294.0618.
N-(2-Methylphenylthio)-S-methyl-S-phenylsulfoximine (5af)
N-(2-Methylphenylthio)-S-methyl-S-phenylsulfoximine (5af)
Pale yellow oil; yield: 45 mg (81%).
IR (ATR): 3458, 3302, 3055, 2924, 2665, 2326, 2103, 1905, 1738, 1584, 1452, 1212,
1092, 986, 738, 685 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.97–7.94 (m, 2 H), 7.66–7.62 (m, 1 H), 7.58–7.54 (m, 2 H), 7.31–7.27 (m, 1
H), 7.02–6.95 (m, 2 H), 3.27 (s, 3 H), 2.14 (s, 3 H).
13C{1H} NMR (101 MHz, CDCl3): δ = 140.7, 138.8, 133.6, 132.1, 129.4, 129.4, 128.4, 126.2, 124.5, 123.3, 43.8,
18.8.
MS (EI): m/z = 277 (91, M+), 137 (20), 125 (29), 124 (44), 123 (14), 91 (14), 77 (31).
HRMS: m/z calcd for [C14H15NOS2 + H]+: 278.0668; found: 278.0670.
N-(2-Bromophenylthio)-S-methyl-S-phenylsulfoximine (5ag)
N-(2-Bromophenylthio)-S-methyl-S-phenylsulfoximine (5ag)
Yellow oil; yield: 55 mg (80%).
IR (ATR): 3458, 3058, 2926, 2669, 2325, 2097, 1915, 1738, 1570, 1438, 1316, 1211,
1092, 982, 912, 735 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.98–7.95 (m, 2 H), 7.67–7.65 (m, 2 H), 7.61–7.57 (m, 2 H), 7.36–7.32 (m, 2
H), 6.95–6.91 (m, 1 H), 3.31 (s, 3 H).
13C{1H} NMR (101 MHz, CDCl3): δ = 143.1, 138.6, 133.9, 131.8, 129.6, 128.3, 127.5, 125.5, 124.3, 115.9, 44.0.
MS (EI): m/z = 241 (25, M+), 186 (2), 154 (2), 140 (12), 138 (2), 125 (45), 124 (100), 77 (18).
HRMS: m/z calcd for [C13H12BrONS2 + Na]+: 363.9436; found: 363.9440.
N-(2-tert-Butylphenylthio)-S-methyl-S-phenylsulfoximine (5ah)
N-(2-tert-Butylphenylthio)-S-methyl-S-phenylsulfoximine (5ah)
Pale yellow oil; yield: 46 mg (72%).
IR (ATR): 3456, 3058, 2960, 2328, 2094, 1911, 1738, 1583, 1446, 1313, 1211, 1092,
983, 741, 684 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.98–7.94 (m, 3 H), 7.64–7.62 (m, 1 H), 7.55–7.52 (m, 2 H), 7.26–7.22 (m, 1
H), 7.22–7.20 (m, 1 H), 7.06–7.03 (m, 1 H), 3.27 (s, 3 H), 1.32 (s, 9 H).
13C{1H} NMR (151 MHz, CDCl3): δ = 144.8, 140.9, 138.9, 133.6, 129.3, 128.4, 126.1, 125.7, 125.6, 124.7, 43.7,
36.0, 29.9.
MS (EI): m/z = 319 (100, M+), 165 (8), 140 (9), 133 (2), 125 (20), 124 (26), 77 (14).
HRMS: m/z calcd for [C17H21NOS2 + K]+: 358.0696; found: 358.0696.
N-(3-Methylphenylthio)-S-methyl-S-phenylsulfoximine (5ai)
N-(3-Methylphenylthio)-S-methyl-S-phenylsulfoximine (5ai)
Colorless oil; yield: 39 mg (70%).
IR (ATR): 3427, 2905, 2655, 2321, 2096, 1920, 1730, 1627, 1583, 1446, 1322, 1244,
1147, 1089, 1000, 870, 746, 683 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.95–7.92 (m, 2 H), 7.66–7.62 (m, 1 H), 7.58–7.54 (m, 2 H), 7.20–7.12 (m, 3
H), 6.91–6.87 (m, 1 H), 3.26 (s, 3 H), 2.29 (s, 3 H).
13C{1H} NMR (101 MHz, CDCl3): δ = 141.8, 138.8, 138.2, 133.6, 129.4, 128.4, 128.4, 126.1, 124.4, 121.1, 43.7,
21.4.
MS (EI): m/z = 277 (100, M+), 140 (32), 125 (43), 124 (94), 123 (81), 91 (47), 77 (66).
HRMS: m/z calcd for [C14H15NOS2 + H]+: 278.0668; found: 278.0668.
N-(Naphthalen-2-ylthio)-S-methyl-S-phenylsulfoximine (5aj)
N-(Naphthalen-2-ylthio)-S-methyl-S-phenylsulfoximine (5aj)
Yellow oil; yield: 48 mg (77%).
IR (ATR): 3461, 3308, 3052, 2924, 2665, 2327, 2092, 1914, 1738, 1584, 1445, 1399,
1211, 1140, 1090, 982, 813, 738, 684 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.98–7.95 (m, 2 H), 7.82–7.80 (m, 1 H), 7.75–7.67 (m, 3 H), 7.66–7.58 (m, 1
H), 7.57–7.54 (m, 2 H), 7.45–7.36 (m, 3 H), 3.31 (s, 3 H).
13C{1H} NMR (101 MHz, CDCl3): δ = 139.7, 138.7, 133.7, 131.6, 129.5, 128.4, 128.0, 127.7, 127.1, 126.3, 125.0,
122.7, 121.4, 43.8.
MS (EI): m/z = 313 (100, M+), 159 (42), 140 (30), 127 (42), 125 (32), 124 (40), 77 (30).
HRMS: m/z calcd for [C17H15NOS2 + H]+: 314.0668; found: 314.0668.
N-(tert-Butylthio)-S-methyl-S-phenylsulfoximine (5ak)
N-(tert-Butylthio)-S-methyl-S-phenylsulfoximine (5ak)
Colorless oil; yield: 10 mg (21%).
IR (ATR): 3272, 2962, 2291, 2094, 1933, 1592, 1408, 1257, 1017, 866, 769, 686 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.96–7.94 (m, 2 H), 7.64–7.60 (m, 1 H), 7.59–7.56 (m, 2 H), 3.14 (s, 3 H),
1.38 (s, 9 H).
13C{1H} NMR (151 MHz, CDCl3): δ = 133.1, 129.5, 128.5, 45.5, 44.2, 31.3.
MS (EI): m/z = 243 (4, M+), 186 (3), 140 (22), 125 (100), 89 (65), 77 (48).
HRMS: m/z calcd for [C11H17NOS2 + H]+: 244.0824; found: 244.0825.
N-(Cyclohexylthio)-S-methyl-S-phenylsulfoximine (5al)
N-(Cyclohexylthio)-S-methyl-S-phenylsulfoximine (5al)
Pale yellow oil; yield: 16 mg (30%).
IR (ATR): 3319, 3223, 2923, 2119, 1837, 1454, 1314, 1142, 1076, 988, 724 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.92–7.90 (m, 2H), 7.65–7.62 (m, 1H), 7.59–7.56 (m, 2H), 3.18 (s, 3H), 3.00–2.97
(m, 1H). 2.12–2.10 (m, 1H), 1.99–1.98 (m, 1H), 1.80–1.73 (m, 2H), 1.62–1.59 (m, 2H),
1.33–1.22 (m, 4H).
13C{1H} NMR (151 MHz, CDCl3): δ = 139.4, 133.3, 129.4, 128.5, 50.3, 43.9, 31.4, 26.0, 25.9.
MS (EI): m/z = 269 (5, M+), 186 (2), 140 (29), 139 (18), 125 (66), 124 (58), 77 (100).
HRMS (EI): m/z calcd for [C16H15NOS2]+: 269.0903; found: 269.0891.
N-(Phenylthio)-S,S-diphenylsulfoximine (5ba)[15]
N-(Phenylthio)-S,S-diphenylsulfoximine (5ba)[15]
Colorless oil; yield: 50 mg (77%).
1H NMR (600 MHz, CDCl3): δ = 8.03–8.01 (m, 4 H), 7.59–7.53 (m, 2 H), 7.52–7.48 (m, 4 H), 7.44–7.42 (m, 2
H), 7.27–7.24 (m, 2 H), 7.09–7.07 (m, 1 H).
13C{1H} NMR (151 MHz, CDCl3): δ = 142.1, 139.9, 133.2, 129.3, 128.5, 128.4, 125.0, 123.9.
N-(Phenylthio)-S-(4-fluorophenyl)-S-methylsulfoximine (5ca)
N-(Phenylthio)-S-(4-fluorophenyl)-S-methylsulfoximine (5ca)
Colorless oil; yield: 26 mg (46%).
IR (ATR): 3459, 3300, 3020, 2926, 2324, 2098, 1899, 1738, 1585, 1482, 1310, 1212,
1089, 980, 823, 736, 683 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.97–7.94 (m, 2 H), 7.39–7.37 (m, 2 H), 7.28–7.23 (m, 4 H), 7.11–7.09 (m, 2
H), 3.28 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3): δ = 165.9 (d, J
C-F = 258.2 Hz), 141.8, 134.5, 131.3 (d, J
C-F = 9.1 Hz), 128.5, 125.3, 124.0, 116.8 (d, J
C-F = 22.7 Hz), 44.0.
MS (EI): m/z = 281 (34, M+), 143 (6), 142 (4), 127 (40), 124 (100), 109 (5), 95 (17), 77 (30).
HRMS: m/z calcd for [C13H13FNOS2 + H]+: 282.0417; found: 282.0417.
