Highly regioselective synthesis of 4-tosylthiomorpholine: Via intramolecular cyclization of N -tethered thioalkenols

Article abstract of DOI:10.1039/c6ob01869f

A one-pot, metal-free procedure has been developed for the synthesis of 4-tosylthiomorpholine from N-tethered thioalkenols via bromination, cyclization and subsequent elimination reaction in good yields. The reaction is found to be highly regioselective.

Full text of DOI:10.1039/c6ob01869f

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ARTICLE TYPE
1
2
Highly Regioselective Synthesis of 4-Tosylthiomorpholine via
Intramolecular Cyclization of N-Tethered Thioalkenols
3
Anil K. Saikia,*a Manash J. Dekaa and Upasana Borthakura
4
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
6
7
8
Oneꢀpot, metalꢀfree procedure has been developed for the synthesis of 4ꢀtosylthiomorpholine from Nꢀtethered thioalkenols via
bromination, cyclization and subsequent elimination reaction in good yields. The reaction is found to be highly regioselective.
regioselectivity. As control in selectivity is the primary
challenging aspect in elimination reaction, development of new
Introduction
methodologies with high degree of selectivity is highly desirable.
Saturated heterocyclic compounds containing nitrogen and
Herein we would like to describe a methodology for the oneꢀpot,
sulphur atoms, such as thiomorpholines, thiazines, thiazolidines
and thiazepines and their oxidized derivatives are considered as
metal free and regioselective synthesis of 4ꢀtosylthiomorpholines
from Nꢀtethered thioalkenols in good yields. Although
important structural motif in organic synthesis. On the other
investigators have prepared the benzothiomorpholines11 less
hand, presence of double bond in cyclic system is not only
attention have been given to the synthesis of thiomorpholines.12
responsible for their biological properties but also serves as a
functional group for further manipulations in organic synthesis.1
Results and discussion
They can also be used as building blocks in organic synthesis.2
Many sulphur and nitrogen containing heterocycles such as
benzothiomorpholines possess antibacterial, antiarrhythmic,
antidiabatic, antihypertensive, and antitumor activities.3
As a part of our ongoing interest in sulfur heterocyclic
compounds,13 we recently used thioalkenols for the synthesis of
thiazolidine
and
thiomorpholine
via
intramolecular
Similarly,
thiomorpholines
display
local
anesthetic,4
hydrothioalkoxilation of Nꢀtethered thioalkenols.14 To further
validate the synthetic applicability of Nꢀtethered thioalkenols we
envisioned that bromination of double bond followed by
nucleophilic attack by thiol would generate bromide intermediate,
which after dehydrodebromination by suitable base would give
thiomorpholines (Scheme 1). To start with thioalkenol 1a (1.0
equiv) was treated with molecular bromine in chloroform at 0 oC.
anticonvulsant,5 antimycobacterial,6 antiꢀinflammatory,7 and
antidiabetic activities.8 Moreover, thiomorpholine or its
disulfoxide ring containing molecules such as sutezolid A9 and
artemisone B10 are undergoing human clinical trials for the
treatment of malaria and tuberculosis, respectively (Figure 1).
Due to their enormous biological activities, the synthesis of these
molecules is an important topic for the academia and industrial
Scheme 1. Proposed reaction pathway
After 15 minutes, DBU (2.0 equiv) was added to the reaction
mixture. The reaction mixture was stirred at room temperature for
4 h and 2ꢀmethyleneꢀ4ꢀtosylthiomorpholine 2a was obtained in
80% yield. Other bases such as K2CO3, Et3N and KOH were
found to be inefficient (Table 1). On the other hand, reaction with
tetrabutylammonium tribromide (TBATB), which is known for
its brominating ability of different functionalities,15 and DBU in
CHCl3 afforded 70% yield (Table 1, entry 5). Similarly,
cetyltrimethylammonium tribromide (CTMATB), another
brominating agent, under basic (DBU) conditions yielded only
Fig. 1 Examples of biologically active thiomorpholines
chemistry. These procedures should have economical advantages.
In such an approach the reduction of number of steps, metal free
and increase in selectivity is a valuable standard for a green
synthesis. A general way to improve synthetic efficiency is the
design of chemical transformations in oneꢀpot with high
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Table 1. Optimization of the reaction
Table 2. Synthesis of thiomorpholine
68% yield.16 The reaction with Nꢀbromosuccinimide (NBS) failed
to give the product. The reaction was also carried out in different
solvents such as DMSO, CH2Cl2, DMF and THF. But CHCl3 was
found to be the best amongst the solvents studied. It was evident
that 1.1 equivalents of molecular bromine and 2 equivalents of
DBU in CHCl3 are the optimal conditions for the reaction. With
this optimized conditions in hand, a variety of Nꢀtethered
thioalkenols were evaluated as substrates and the results are
summarized in Table 2. It was observed from Table 2 that the
reaction provides only exoꢀolefinic 4ꢀtosylthiomorpholine 2aꢀl in
good to high yields, regioselectively. The reaction proceeds with
differently substituted thioalkenols such as alkyl (entry4),
benzylic (entry 5) and aryl (entries 6ꢀ8) to give substituted
thiomorpholines in good yields. Terminal and 1,1ꢀdisubstituted
alkenes gave single products, whereas 1,2ꢀdisubstituted alkene 1b
produced inseparable cis-trans isomeric mixture with a ratio of
1:3 which was determined by 1H NMR. Substrate 1i having a 2,2ꢀ
disubstituted alkene gave intermediate bromo compound 2ꢀ
(bromomethyl)ꢀ2ꢀmethylꢀ4ꢀtosylthiomorpholine 2i (Scheme 3).
However, substrate having terminal phenyl group on the alkene
side chain yielded brominated thiomorpholine 2j as an
inseparable diastereomeric mixture with a ratio of 4:1 in 65%
yield (entry 10). This might be due to the steric hindrance
imparted by phenyl group to incoming bulky DBU. On the other
hand, aromatic thioalkenols 1k and 1l gave thiazepines 2k and 2l
in 78 and 75% yields, respectively. Chiral starting materials 1dꢀ1f
produced corresponding chiral thiomorpholines 2d-2f, in 65, 67
and 65% yields, respectively.
There was no endo olefinic thiomorpholine formation although
endo cyclic enamide 3a is more stable than exocyclic amide 2a
(Scheme 2). This indicates that the reaction is kinetically
controlled.
The mechanism of the reaction can be explained as follows. The
reaction proceeds in two steps. In the first step molecular bromine
adds to the double bond to form bromonium ion A, which after
nucleophilic attack by thiol gives bromide B. The bromide B after
dehydrobromination under basic condition gives desired product
2 (Scheme 3). To prove the formation of intermediate B, amino
thiol 1a was treated with bromine in absence of DBU (Scheme 4).
It was observed that intermediate monobrominated compound 2m
was obtained in 85% yield.
Scheme 2. Selective formation of exoꢀcyclic thiomorpholine
2
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added into the reaction mixture at 0 oC. It was allowed to warm to
25 oC and stirred for additional 5 h. It was stirred with 1: 1
mixture of hexane:diethylether; triphenylphosphine oxide was
filtered off. The filtrate was concentrated. The crude mixture (1
o
equiv) was added portion wise at 0 C to a stirred solution of
LiAlH4 (1 equiv) in anhydrous THF (10 mL). The reaction
mixture was stirred for 30 min at room temperature. The reaction
was quenched by addition of ethyl acetate (30 mL) followed by
water (30 mL) at 0 oC. The aqueous layer was extracted with
ethyl acetate (3 X 50 mL) and the organic layer was dried over
anhydrous Na2SO4. After concentration under vacuum, the crude
product was chromatographed on silica gel (eluent = hexane/ethyl
acetate, 9:1) to furnish the compound thiols.
Scheme 3. Plausible mechanism of the reaction
(E,
Z)-N-(But-2-en-1-yl)-N-(2-mercaptoethyl)-4-methyl-
benzenesulfonamide (1b; E:Z::3:1):
o
White solid; mp 86ꢀ88 C; Rf (hexane/ EtOAc 9:1) 0.55; yield
399 mg, 55%; 1H NMR (600 MHz, CDCl3) δ 1.65 (d, J = 6.6 Hz,
3 H), 2.43 (s, 3 H), 2.78ꢀ2.84 (m, 2 H), 3.30ꢀ3.37 (m, 2 H), 3.73
(d, J = 6.6 Hz, 2 H, major), 3.85 (d, J = 7.2 Hz, 2 H, minor), 5.27ꢀ
5.32 (m, 1 H), 5.59ꢀ5.64 (m, 1 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.71
(d, J = 8.4 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 17.8, 21.6,
49.5, 51.6, 61.2, 125.7, 127.4, 129.8, 129.9, 131.1, 143.6; IR
(KBr, neat) 2921, 2826, 1598, 1447, 1338, 1160, 1090, 932, 715
cmꢀ1; HRMS (ESI) calcd. for C13H20NO2S2 (M + H)+ 286.0930,
found 286.0912.
Scheme 4. Formation of brominated thiomorpholine
Conclusions
In conclusion, we have developed a oneꢀpot, metal free, mild and
efficient method for the synthesis of 4ꢀtosylthiomorpholine from
Nꢀtethered thioalkenols via bromination, cyclization and
subsequent elimination reaction in good yields. An important
aspect of this reaction is that it produces exoꢀcyclic
tosylthiomorpholine regioselectively. The method can also be
extended for the synthesis of benzo[1,4]thiazepine.
N-(1-Mercaptopropan-2-yl)-4-methyl-N-(3-methylbut-2-en-1-
yl)benzenesulfonamide (1d):
Gum; Rf (hexane/ EtOAc 9:1) 0.55; yield 428 mg, 60%; 1H NMR
(600 MHz, CDCl3) δ 1.11 (d, J = 7.2 Hz, 3 H), 1.41 (t, J = 8.4 Hz,
1 H), 2.40 (s, 3 H), 2.45ꢀ2.50 (m, 1 H), 2.67ꢀ2.71 (m, 1 H), 3.67
(dd, J = 16.2 and 7.2 Hz, 1 H), 3.88 (dd, J = 16.2 and 5.4 Hz, 1
H), 3.94 (t, J = 6.6 Hz, 1 H), 5.10 (d, J = 10.2 Hz, 1 H), 5.18 (d, J
= 16.8 Hz, 1 H), 5.80ꢀ5.87 (m, 1 H), 7.27 (d, J = 7.8 Hz, 2 H),
7.69 (d, J = 8.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 17.4,
21.6, 30.0, 46.8, 57.3, 117.7, 127.3, 129.8, 136.1, 138.0, 143.4;
IR (KBr, neat) 2925, 2855, 1598, 1452, 1336, 1158, 1090, 815,
661 cmꢀ1; HRMS (ESI) calcd. for C13H20NO2S2 (M + H)+
286.0930, found 286.0905.
Experimental section
General Information: All the reagents were of reagent grade (AR
grade) and were used as purchased without further purification.
Silica gel (60ꢀ120 mesh size) was used for column
chromatography. Reactions were monitored by TLC on silica gel
GF254 (0.25 mm). Melting points were recorded in an open
capillary tube and are uncorrected. Fourier transformꢀinfra red
(FTꢀIR) spectra were recorded as neat liquid or KBr pellets.
NMR spectra were recorded in CDCl3 with tetramethylsilane as
1
the internal standard for H (600 MHz, 400 MHz) or 13C (150
N-Allyl-N-(2-mercapto-1-phenylethyl)-4-methylbenzene-
sulfonamide (1f):
MHz, 100 MHz) NMR. Chemical shifts (δ) are reported in ppm
and spinꢀspin coupling constants (J) are given in Hz. HRMS
spectra were recorded using QꢀTOF mass spectrometer.
Elemental analysis was performed on Perkin Elmer 2400 series II
CHNS analyzer. Starting compounds 1a, 1c, 1e and 1i are known
and their analytical data are in agreement with the reported
compounds.14,17
Gum; Rf (hexane/ EtOAc 9:1) 0.55; yield 520 mg, 58%; 1H NMR
(600 MHz, CDCl3) 1.38 (t, J = 8.4 Hz, 1 H), 2.43 (s, 3 H), 2.97ꢀ
3.03 (m, 1 H), 3.22ꢀ3.28 (m, 1 H), 3.43 (dd, J = 15.6 and 3.0 Hz,
1 H), 3.88 (dd, J = 16.2 and 5.4 Hz, 1 H), 5.02ꢀ5.08 (m, 3 H),
5.59ꢀ5.65 (m, 1 H), 7.09 (s, 2 H), 7.27ꢀ5.28 (m, 5 H), 7.69 (d, J =
7.2 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 21.7, 26.7, 47.5,
64.2, 117.8, 127.5, 128.8, 128.9, 129.8, 135.8, 138.1, 143.6; IR
(KBr, neat) 2924, 2855, 1598, 1449, 1336, 1156, 1091, 814, 736
cmꢀ1; HRMS (ESI) calcd. for C18H22NO2S2 (M + H)+ 348.1086,
found 348.1085.
General procedure for the synthesis of thiols:
To a stirred solution of triphenylphosphine (1.5 equiv) in
anhydrous THF (10 mL) DIAD (1.5 equiv.) was added at 0 C
o
and stirred for 30 min. Then a solution of amino alcohol (2.5
mmol) (1 equiv) and thioacetic acid (1 equiv) in THF (5 mL) was
N-(2-(4-Fluorophenyl)-2-mercaptoethyl)-4-methyl-N-(3-
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methylbut-2-en-1-yl)benzene-sulfonamide (1g):
N-(2-(Mercaptomethyl)phenyl)-4-methyl-N-(3-methylbut-2-
en-1-yl)benzenesulfonamide (1l):
Gum; Rf (hexane/ EtOAc 9:1) 0.55; yield 510 mg, 50%; 1H NMR
(400 MHz, CDCl3) 1.53 (s, 3 H), 1.60 (s, 3 H), 2.12 (d, J = 5.2
Hz, 1 H), 2.42 (s, 3 H), 3.33 (dd, J = 14.4 and 8.0 Hz, 1 H), 3.46
(dd, J = 14.4 and 7.2 Hz, 1 H), 3.52 (dd, J = 15.6 and 6.8 Hz, 1
H), 3.72 (dd, J = 15.6 and 7.2 Hz, 1 H), 4.35ꢀ4.41 (m, 1 H), 4.70
(dt, J = 6.8 and 1.6 Hz, 1 H), 7.00 (t, J = 8.4 Hz, 2 H), 7.26ꢀ7.31
(m, 4 H), 7.64 (d, J = 8.0 Hz, 2 H); 13C NMR (150 MHz, CDCl3)
δ 17.9, 25.9 (2C), 42.9, 47.1, 55.7, 115.7 (d, J = 21.5 Hz), 118.7
(d, J J = 7.7 Hz), 127.5, 129.5, 129.6, 129.8, 136.6, 136.7, 136.8,
137.4, 143.6, 162.3 (d, 245.3 Hz); IR (KBr, neat) 2924, 2840,
1600, 1447, 1342, 1159, 1091, 837, 655 cmꢀ1; HRMS (ESI) calcd.
for C20H25FNO2S2 (M + H)+ 394.1305, found 394.1307.
Gum; Rf (hexane/ EtOAc 9:1) 0.55; yield 542 mg, 58%; 1H NMR
(400 MHz, CDCl3) 1.41 (s, 3 H), 1.59 (s, 3 H), 1.96 (t, J = 8.0
Hz, 1 H), 2.44 (s, 3 H), 3.80ꢀ3.88 (m, 2 H), 3.98 (dd, J = 14.0 and
5.2 Hz, 1 H), 4.39 (dd, J = 14.0 and 6.4 Hz, 1 H), 5.12 (t, J = 7.2
Hz, 1 H), 6.52 (d, J = 8.0 Hz, 1 H), 7.06 (t, J = 7.6 Hz, 1 H), 7.25ꢀ
7.30 (m, 3 H), 7.55ꢀ7.57 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ
17.8, 21.7, 24.4, 25.8, 49.7, 118.3, 127.3, 127.9, 128.1, 128.9,
129.6, 130.7, 135.7, 137.1, 138.3, 143.3, 143.7; IR (KBr, neat)
2963, 2827, 1598, 1451, 1345, 1159, 1091, 809, 711, 654 cmꢀ1;
HRMS (ESI) calcd. for C19H24NO2S2 (M + H)+ 362.1243, found
362.1253.
N-(2-(4-Chlorophenyl)-2-mercaptoethyl)-4-methyl-N-(3-
General Procedure for the synthesis 4-tosylthiomorpholine:
methylbut-2-en-1-yl)benzene-sulfonamide (1h):
To a stirred solution of thioalkenols (0.5 mmol) (1aꢀ1k) in CHCl3
(2 mL) at 0˚C was added molecular bromine (0.5 mmol)
dropwise. After 15 minutes, DBU (1.0 mmol) was added to the
reaction mixture. The reaction mixture was stirred at room
temperature for 4h. The progress of the reaction was monitored
by TLC using ethyl acetate and hexane as eluents. After
completion of the reaction, the reaction mixture was treated with
saturated sodium bicarbonate solution (5.0 mL). The product was
extracted with ethyl acetate (2 x 10.0 mL) and washed with brine.
Organic layer was separated and dried over anhydrous Na2SO4
and evaporated using rotary evaporator to give the crude product.
The crude product was purified by silica gel column
chromatography using ethyl acetate and hexane as eluents to
afford the cyclic compounds in 60ꢀ80% yield.
Gum; Rf (hexane/ EtOAc 9:1) 0.55; yield 532 mg, 52%; 1H NMR
(400 MHz, CDCl3) 1.53 (s, 3 H), 1.60 (s, 3 H), 2.10 (d, J = 5.2
Hz, 1 H), 2.43 (s, 3 H), 3.32 (dd, J = 14.4 and 8.4 Hz, 1 H), 3.45
(dd, J = 14.4 and 6.8 Hz, 1 H), 3.53 (dd, J = 15.6 and 6.8 Hz, 1
H), 3.70 (dd, J = 15.6 and 7.2 Hz, 1 H), 4.33ꢀ4.38 (m, 1 H), 4.69
(t, J = 6.4 Hz, 1 H), 7.26ꢀ7.31 (m, 6 H), 7.63 (d, J = 8.0 Hz, 2 H);
13C NMR (100 MHz, CDCl3) δ 18.0, 21.7, 26.0, 42.9, 47.2, 55.5,
118.6, 127.5, 129.0, 129.3, 129.8, 133.7, 136.5, 137.5, 139.6,
143.7; IR (KBr, neat) 2964, 2825, 1597, 1492, 1342, 1163, 1092,
914, 736 cmꢀ1; HRMS (ESI) calcd. for C20H25ClNO2S2 (M + H)+
410.1010, found 410.0940.
N-Cinnamyl-N-(2-mercaptoethyl)-4-methylbenzenesulfonamide
(1j):
Typical procedure for the synthesis of 2-methylene-4-
tosylthiomorpholine 2a:
Gum; Rf (hexane/ EtOAc 9:1) 0.55; yield 477 mg, 55%; 1H NMR
(600 MHz, CDCl3) 1.39 (t, J = 8.4 Hz, 1 H), 2.43 (s, 3 H), 2.72
(q, J = 8.4 Hz, 2 H), 3.30 (t, J = 7.8 Hz, 2 H), 3.97 (d, J = 6.6 Hz,
1 H), 5.95ꢀ6.01 (m, 1 H), 6.45 (d, J = 16.2 Hz, 1 H), 7.26ꢀ7.27
(m, 3 H), 7.29ꢀ7.32 (m, 4 H), 7.73 (d, J = 7.8 Hz, 2 H); 13C NMR
(150 MHz, CDCl3) δ 21.7, 24.0, 51.1, 51.4, 124.2, 126.7, 127.4,
128.3, 128.8, 130.0, 134.3, 136.1, 136.9, 143.8; IR (KBr, neat)
3495, 2923, 2868, 1597, 1450, 1339, 1162, 1092, 913, 815, 740,
668 cmꢀ1; HRMS (ESI) calcd. for C18H22NO2S2 (M + H)+
348.1086, found 348.1086.
To a stirred solution of thioalkenols (269 mg, 1 mmol) in CHCl3
(5 mL) at 0˚C was added molecular bromine (0.1 mL, 1 mmol)
dropwise. After 15 minutes, DBU (0.4 mL, 2.0 mmol) was added
to the reaction mixture. The reaction mixture was stirred at room
temperature for 4h. The progress of the reaction was monitored
by TLC using ethyl acetate and hexane as eluents. After
completion of the reaction, the reaction mixture was treated with
saturated sodium bicarbonate solution (5.0 mL). The product was
extracted with ethyl acetate (2 x 10.0 mL) and washed with brine.
The organic layer was separated and dried over anhydrous
Na2SO4 and evaporated using rotary evaporator to leave the crude
product which was purified by column chromatography over
silica gel using ethyl acetate and hexane as eluents to give
methyleneꢀ4ꢀtosylthiomorpholine 2a.
N-Allyl-N-(2-(mercaptomethyl)phenyl)-4-methylbenzene-
sulfonamide (1k):
Light yellow solid; mp 128ꢀ130 oC; Rf (hexane/ EtOAc 9:1) 0.55;
1
yield 466 mg, 55%; H NMR (400 MHz, CDCl3) 1.98 (t, J = 8.0
Hz, 1 H), 2.44 (s, 3 H), 3.80 (dd, J = 13.6 and 7.6 Hz, 1 H), 3.87ꢀ
4.00 (m, 2 H), 4.44 (dd, J = 13.6 and 8.4 Hz, 1 H), 4.98 (d, J =
17.2 Hz, 1 H), 5.03 (d, J = 10.4 Hz, 1 H), 5.75ꢀ5.82 (m, 1 H),
6.49 (d, J = 7.6 Hz, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 7.27ꢀ7.31 (m,
3 H), 7.53ꢀ7.57 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ 21.7,
24.4, 55.0, 119.9, 127.4, 128.0, 128.2, 129.0, 129.7, 130.7, 132.5,
135.2, 136.8, 143.0, 143.9; IR (KBr, neat) 2923, 2868, 1597,
1454, 1344, 1160, 1092, 922, 814, 657 cmꢀ1; HRMS (ESI) calcd.
for C17H20NO2S2 (M + H)+ 334.0930, found 334.0933.
2-Methylene-4-tosylthiomorpholine (2a):
White solid; mp 105ꢀ107 oC; Rf (hexane/ EtOAc 9:1) 0.5.8; yield
1
215 mg, 80%; H NMR (600 MHz, CDCl3) δ 2.43 (s, 3 H), 2.73
(t, J = 5.4 Hz, 2 H), 2.43ꢀ2.45 (m, 2 H), 3.82 (s, 2 H), 5.27 (s, 1
H), 5.29 (s, 1 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 7.8 Hz, 2
H); 13C NMR (150 MHz, CDCl3) δ 21.7, 28.1, 46.8, 53.1, 116.9,
127.8, 130.0, 134.1, 134.6, 144.1; IR (KBr, neat) 2923, 2850,
1615, 1597, 1449, 1348, 1163, 1092, 902, 753 cmꢀ1; HRMS (ESI)
4
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calcd. for C12H16NO2S2 (M + H)+ 270.0617, found 270.0620.
and 5.4 Hz, 1 H), 3.00 (dd, J = 14.4 and 8.4 Hz, 1 H), 4.02 (dd, J
= 16.2 and 3.0 Hz, 1 H), 4.59 (d, J = 16.2 Hz, 1 H), 4.92 (s, 1 H),
5.11 (s, 1 H), 5.12 (t, J = 6.0 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 2 H),
7.28 (t, J = 7.2 Hz, 1 H), 7.35 (t, J = 7.2 Hz, 2 H), 7.39 (d, J = 7.2
Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H); 13C NMR (150 MHz, CDCl3)
δ 21.8, 31.0, 47.5, 58.0, 110.7, 126.5, 127.9, 128.0, 128.9, 129.6,
136.8, 137.5, 140.2, 143.7; IR (KBr, neat) 2924, 2853, 1611,
1494, 1345, 1156, 1044, 945, 732 cmꢀ1; HRMS (ESI) calcd. for
C18H20NO2S2 (M + H)+ 346.0930, found 346.0899.
(E/Z)-2-Ethylidene-4-tosylthiomorpholine (3:1)(2b):
White solid; mp 110ꢀ112 oC; Rf (hexane/ EtOAc 9:1) 0.5.8; yield
204 mg, 72%; 1H NMR (600 MHz, CDCl3) δ 1.72 (d, J = 6.6 Hz,
3 H, minor), 1.75 (d, J = 7.2 Hz, 3 H, major), 2.43 (s, 3 H), 2.67ꢀ
2.71 (m, 2 H), 3.45 (t, J = 4.8 Hz, 2 H, minor), 3.48 (t, J = 4.8 Hz,
2 H, major), 3.77 (s, 2 H, minor), 3.91 (s, 2 H, major), 5.80 (q, J
= 6.6 Hz, 1 H, minor), 5.84 (q, J = 6.6 Hz, 1 H, major), 7.32 (d, J
= 7.8 Hz, 2 H), 7.65 (d, J = 7.8 Hz, 2 H); 13C NMR (150 MHz,
CDCl3) δ 14.0, 14.6, 21.7, 27.4, 28.9, 47.3, 47.7, 54.0, 125.0,
127.5, 127.7, 127.8, 128.0, 129.9, 130.0, 134.5, 143.9; IR (KBr,
neat) 2924, 2852, 1639, 1597, 1450, 1355, 1166, 1092, 1060,
920, 742 cmꢀ1; HRMS (ESI) calcd. for C13H18NO2S2 (M + H)+
284.0773, found 284.0775.
2-(4-Fluorophenyl)-6-(propan-2-ylidene)-4-tosylthio-
morpholine (2g):
Colourless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 246 mg, 63%;
1H NMR (400 MHz, CDCl3) δ 1.89 (s, 3 H), 1.91 (s, 3 H), 2.45
(s, 3 H), 2.93 (dd, J = 19.8 and 16.8 Hz, 1 H), 3.24 (d, J = 19.8
Hz, 1 H), 4.05ꢀ4.10 (m, 2 H), 4.83 (d, J = 19.8 Hz, 1 H), 7.00 (t, J
= 7.2 Hz, 2 H), 7.27ꢀ7.31 (m, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.65
(d, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 20.8, 21.7,
22.6, 45.6, 48.5, 53.6, 115.7, 115.8 (d, J = 32.1 Hz), 119.2, 127.6,
129.7, 129.9, 130.0, 144.0, 162.6 (d, J = 245.8 Hz); IR (KBr,
neat) 2924, 2865, 1599, 1340, 1228, 1161, 1093, 837, 760, 657
cmꢀ1; HRMS (ESI) calcd. for C20H23FNO2S2 (M + H)+ 392.1149,
found 392.1148.
2-(Propan-2-ylidene)-4-tosylthiomorpholine (2c):
Colourless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 232 mg, 78%;
1H NMR (600 MHz, CDCl3) δ 1.85 (s, 6 H), 2.43 (s, 3 H), 2.68 (t,
J = 5.4 Hz, 2 H), 3.46 (t, J = 5.4 Hz, 2 H), 3.97 (s, 2 H), 7.31 (d, J
= 7.8 Hz, 2 H), 7.64 (d, J = 7.8 Hz, 2 H); 13C NMR (150 MHz,
CDCl3) δ 20.6, 21.7, 22.5, 28.4, 47.4, 48.9, 118.4, 127.7, 129.9,
130.0, 134.8, 143.8; IR (KBr, neat) 2963, 2925, 1637, 1458,
1422, 1356, 1297, 1164, 1091, 927, 739 cmꢀ1; HRMS (ESI) calcd.
for C14H20NO2S2 (M + H)+ 298.0930, found 298.0934.
2-(4-Chlorophenyl)-6-(propan-2-ylidene)-4-tosylthio-
morpholine (2h):
5-Methyl-2-methylene-4-tosylthiomorpholine (2d):
Colourless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 267 mg, 65%;
1H NMR (400 MHz, CDCl3) δ 1.88 (s, 3 H), 1.91 (s, 3 H), 2.44
(s, 3 H), 2.94 (dd, J = 12.4 and 11.2 Hz, 1 H), 3.26 (d, J = 12.4
Hz, 1 H), 4.03ꢀ4.07 (m, 2 H), 4.80 (d, J = 12.4 Hz, 1 H), 7.24ꢀ
7.30 (m, 4 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H);
13C NMR (100 MHz, CDCl3) δ 20.8, 21.7, 22.6, 45.6, 48.5, 53.4,
119.0, 127.6, 129.1, 129.3, 130.0, 134.1, 134.6, 135.8, 136.9,
144.0; IR (KBr, neat) 2922, 2853, 1597, 1491, 1351, 1163, 1092,
1014, 928, 708 cmꢀ1; HRMS (ESI) calcd. for C20H23ClNO2S2 (M
+ H)+ 408.0853, found 408.0834.
Colourless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 184 mg, 65%;
1H NMR (400 MHz, CDCl3) δ 1.37 (d, J = 6.4 Hz, 3 H), 2.42 (s,
3 H), 2.46 (d, J = 6.4 Hz, 1 H), 2.80 (dd, J = 13.6 and 4.4 Hz, 1
H), 3.89 (d, J = 15.6 Hz, 1 H), 4.18ꢀ4.24 (m, 1 H), 4.39 (d, J =
15.6 Hz, 1 H), 5.01 (s, 1 H), 5.15 (s, 1 H), 7.26 (d, J = 8.0 Hz, 2
H), 7.70 (d, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ
18.3, 21.7, 32.6, 46.0, 49.4, 112.5, 127.6, 129.6, 136.7, 137.0,
143.5; IR (KBr, neat) 2924, 2848, 1653, 1457, 1351, 1272, 1152,
1089, 860, 669 cmꢀ1; HRMS (ESI) calcd. for C13H18NO2S2 (M +
H)+ 284.0773, found 284.0775.
2-(Bromomethyl)-2-methyl-4-tosylthiomorpholine (2i):
5-Benzyl-2-methylene-4-tosylthiomorpholine (2e):
Colourless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 280 mg, 77%;
1H NMR (600 MHz, CDCl3) δ 1.28 (s, 3 H), 2.43 (s, 3 H), 2.49
(d, J = 12.6 Hz, 1 H), 2.51 (d, J = 13.8 Hz, 1 H), 2.64 (t, J = 12.0
Hz, 1 H), 2.99 (dt, J = 13.8 and 2.4 Hz, 1 H), 3.61 (d, J = 10.8
Hz, 1 H), 3.88 (d, J = 12.0 Hz, 1 H), 3.95 (d, J = 12.0 Hz, 1 H),
3.99 (d, J = 11.4 Hz, 1 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.63 (d, J =
8.4 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 21.7, 23.2, 25.4,
42.8, 47.4, 49.5, 54.2, 127.7, 130.1, 133.8, 144.1; IR (KBr, neat)
2926, 2851, 1597, 1452, 1339, 1164, 1096, 916, 741 cmꢀ1; HRMS
(ESI) calcd. for C13H19BrNO2S2 (M + H)+ 364.0035, found
364.0040.
Colourless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 241mg, 67%;
1H NMR (600 MHz, CDCl3) δ 2.40 (s, 3 H), 2.46 (dd, J = 13.8
and 6.6 Hz, 1 H), 2.63 (d, J = 13.8 Hz, 1 H), 3.03 (dd, J = 13.2
Hz, 1 H), 3.27 (t, J = 11.4 Hz, 1 H), 3.85 (d, J = 15.6 Hz, 1 H),
4.20ꢀ4.25 (m, 1 H), 3.38 (d, J = 15.6 Hz, 1 H), 5.01 (s, 1 H), 5.15
(s, 1 H), 7.23ꢀ7.31 (m, 7 H) 7.68 (d, J = 7.8 Hz, 2 H); 13C NMR
(150 MHz, CDCl3) δ 21.7, 31.8, 38.7, 47.0, 55.1, 112.5, 127.0,
127.7, 128.9, 129.6, 129.7, 136.6, 136.8, 137.4, 143.7; IR (KBr,
neat) 2924, 2856, 1611, 1495, 1345, 1157, 1091, 1032, 750 cmꢀ1;
HRMS (ESI) calcd. for C19H22NO2S2 (M + H)+ 360.1086, found
360.1184.
2-(Bromo(phenyl)methyl)-4-tosylthiomorpholine
(diastereomeric mixture, 6:1, 2j):
2-Methylene-5-phenyl-4-tosylthiomorpholine (2f):
Colourless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 224 mg, 65%;
Colourless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 276 mg, 65%;
1H NMR (600 MHz, CDCl3) δ 2.42 (s, 3 H, minor), 2.44 (s, 3 H,
1H NMR (600 MHz, CDCl3) δ 2.42 (s, 3 H), 2.91 (dd, J = 14.4
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major), 2.60ꢀ2.63 (m, 1 H, major), 2.68ꢀ2.71 (m, 1 H, major),
2.80ꢀ2.83 (m, 1 H, minor), 3.01 (dt, J = 10.8 and 2.4 Hz, 1 H),
3.10 (t, J = 9.0 Hz, 1 H), 3.25 (t, J = 10.8 Hz, 1 H), 3.48ꢀ3.51 (m,
1 H, major), 3.56ꢀ3.58 (m, 1 H, minor), 3.81 (d, J = 10.8 Hz, 1
H), 4.16 (brs, 1 H, minor), 4.26 (d, J = 8.4 Hz, 1 H), 7.28 (d, J =
8.4 Hz, 2 H), 7.32ꢀ7.37 (m, 5 H), 7.64 (d, J = 8.4 Hz, 2 H); 13C
NMR (150 MHz, CDCl3) δ 21.7, 22.9, 26.6, 28.8, 45.5, 47.3,
47.7, 48.3, 50.1, 127.5, 127.6, 127.7, 127.8, 128.5, 128.8, 128.9,
130.0, 131.8, 134.3, 139.7, 143.8; IR (KBr, neat) 2924, 2853,
1597, 1452, 1354, 1164, 1093, 916, 718 cmꢀ1; Anal. calcd. for
C18H20BrNO2S2: C, 50.70; H, 4.73; N, 3.28. Found: C, 50.66; H,
4.64; N, 3.34.
Authors are also thankful to Central Instrument Facility (CIF) of
IIT Guwahati for NMR and XRD facilities.
Notes and references
aDepartment of Chemistry, Indian Institute of Technology
Guwaqhati, Guwahati 781039, Assam, India. Fax: +91 361 269
0762; Tel: +91 361 258 2316; E-mail: asaikia@iitg.ernet.in
1
† Electronic Supplementary Information (ESI) available: H and
13C NMR spectra and mass spectra of all new compounds. See
DOI: 10.1039/b000000x/
1(a) P. Johannesson, G. Lindeberg, A. Johansson , A.; Gregory
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1767ꢀ1777; (b) H. S. Sader, D. M. Johnson, R. N. Jones,
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3-Methylene-1-tosyl-1,2,3,5-tetrahydrobenzo[e][1,4]thiazepine
(2k):
Colousless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 258 mg, 78%;
1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3 H), 3.29 (s, 2 H), 4.45
(s, 2 H), 5.43 (s, 1 H), 5.49 (s, 1 H), 7.16 (t, J = 8.4 Hz, 1 H),
7.25ꢀ7.28 (m, 4 H), 7.32ꢀ7.36 (m, 1 H), 7.58 (d, J = 8.0 Hz, 2 H);
13C NMR (100 MHz, CDCl3) δ 21.8, 34.2, 57.6, 122.2, 127.5
(2C), 128.5, 129.1 (2C), 129.8, 137.7, 138.5, 138.8, 140.3, 143.8;
IR (KBr, neat) 2923, 2847, 1698, 1489, 1349, 1162, 1091, 814,
735, 659 cmꢀ1; HRMS (ESI) calcd. for C17H18NO2S2 (M + H)+
332.0773, found 332.0774.
3-(Propan-2-ylidene)-1-tosyl-1,2,3,5
benzo[e][1,4]thiazepine (2l):
tetrahydro-
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Colousless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 269 mg, 75%;
1H NMR (400 MHz, CDCl3) δ 1.81 (s, 3 H), 1.95 (s, 3 H), 2.41
(s, 3 H), 3.08 (s, 2 H), 4.54 (s, 2 H), 7.05ꢀ7.08 (m, 1 H), 7.21ꢀ7.25
(m, 4 H), 7.41ꢀ7.44 (m, 1 H), 7.47 (d, J = 8.4 Hz, 2 H); 13C NMR
(150 MHz, CDCl3) δ 21.2, 21.8, 23.2, 34.3, 53.7, 121.2, 127.4,
128.1, 128.7, 128.8, 129.7, 131.1, 137.2, 138.5, 139.3, 141.5,
143.7; IR (KBr, neat) 2924, 2854, 1598, 1490, 1348, 1163, 1093,
1034, 807, 683 cmꢀ1; HRMS (ESI) calcd. for C19H22NO2S2 (M +
H)+ 360.1086, found 360.1085.
6 S. Indumathi, S. Perumal, D. Banerjee, P. Yogeeswari, Eur. J.
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7 P. TheodosisꢀNobelos, M. Kourti, A. Gavalas, E. A. Rekka,
Bioorg. Med. Chem. Lett., 2016, 26, 910ꢀ913.
2-(Bromomethyl)-4-tosylthiomorpholine (2m):
8 B. Han, J. L. Liu, Y. Huan, P. Li, Q. Wu, Z. Y. Lin, Z. F. Shen,
D. L. Yin, H. H. Huang, Chin. Chem. Lett., 2012, 23, 297ꢀ300.
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Cynamon, J. O. Kilburn, S. P. Klemens, S. E. Glickman, K. C.
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Heilmann, H.ꢀW. Chan, S. L. Croft, L. Vivas, L. Rattray, L.
Stewart, W. Peters, B. L. Robinson, M. D. Edstein, B. Kotecka,
D. E. Kyle, B. Beckermann, M. Gerisch, M. Radtke, G.
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Angew. Chem. Int. Ed., 2006, 45, 2082ꢀ2088.
Colousless oil; Rf (hexane/ EtOAc 9:1) 5.8; yield 280 mg, 85%;
1H NMR (600 MHz, CDCl3) δ 2.01ꢀ2.06 (m, 2 H), 2.43 (s, 3 H),
2.75ꢀ2.77 (m, 2 H), 2.84 (t, J = 12.0 Hz, 2 H), 3.46ꢀ3.51 (m, 3 H),
7.30 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 8.4 Hz, 2 H); 13C NMR
(150 MHz, CDCl3) δ 21.7, 31.3, 31.9, 36.2, 49.0, 54.0, 127.0,
130.0, 137.1, 143.5; IR (KBr, neat) 2922, 2853, 1598, 1452,
1330, 1157, 1092, 923, 715, 548 cmꢀ1; Anal. calcd. for
C12H16BrNO2S2: C, 41.14; H, 4.60; N, 4.00. Found: C, 41.20; H,
4.52; N, 4.05.
Acknowledgements
MJD gratefully acknowledges Council of Scientific and Industrial
Research (CSIR), New Delhi for his fellowship. Authors are
grateful to Council of Scientific and Industrial Research (CSIR),
New Delhi, for financial support (Grant No. 02/0159/13/EMRꢀII).
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DOI: 10.1039/C6OB01869F
Graphical Content
Highly regioselective synthesis of 4-tosylthiomorpholine via intra-
molecular cyclization of N-tethered thioalkenols
Anil K. Saikia,*a Manash J. Dekaa and Upasana Borthakura
One-pot, metal-free procedure has been developed for the synthesis of 4-
tosylthiomorpholine from N-tethered thioalkenols via bromination, cyclization and
subsequent elimination reaction in good yields. The reaction is highly regioselective.