Iron-Mediated Selective Sulfonylmethylation of Aniline Derivatives with p-Toluenesulfonylmethyl Isocyanide (TosMIC)

Article abstract of DOI:10.1021/acs.joc.1c00500

An iron-mediated highly selective C-H sulfonylmethylation of aniline derivatives with p-toluenesulfonylmethyl isocyanide in a mixture solvent of H2O and PEG400 under an Ar atmosphere has been realized. This transformation proceeds with operational convenience, use of earth-abundant metal catalyst and nontoxic media, broad substrate scope, and good functional group tolerance. The current methodology could be applied to the regioselective C-H sulfonylmethylation of indolines, tetrahydroquinolines, and tertiary anilines.

Full text of DOI:10.1021/acs.joc.1c00500

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Article
Iron-Mediated Selective Sulfonylmethylation of Aniline Derivatives
with p‑Toluenesulfonylmethyl Isocyanide (TosMIC)
Yigao Li, Xu-Yan Wang, Xiaohuang Ren, Baoheng Dou, Xinju Zhu, Xin-Qi Hao,* and Mao-Ping Song*
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ABSTRACT: An iron-mediated highly selective C−H sulfonylme-
thylation of aniline derivatives with p-toluenesulfonylmethyl
isocyanide in a mixture solvent of H2O and PEG400 under an Ar
atmosphere has been realized. This transformation proceeds with
operational convenience, use of earth-abundant metal catalyst and
nontoxic media, broad substrate scope, and good functional group
tolerance. The current methodology could be applied to the
regioselective C−H sulfonylmethylation of indolines, tetrahydro-
quinolines, and tertiary anilines.
Scheme 1. Site-Selectively Functionalized Anilines and
Indolines
INTRODUCTION
■
The aniline fragment is recognized as a valuable subunit in
bioactive molecules and donor−acceptor compounds with
wide application in pharmaceuticals, agrochemicals, and
materials chemistry.1 Meanwhile, indolines are also unique
N-heterocycles widely existent in many natural products and
medicinally important compounds.2 Consequently, it is highly
desirable to develop novel strategies to access functionalized
anilines and indolines site-selectively for diversity-oriented
synthesis in medicinal chemistry.3 With development of
chelation-assisted C−H functionalization, ortho-substituted4
anilines and C7-functionalized5 indolines have been well
explored (Scheme 1a). Through introduction of directing
templates or extended ligand architectures, the past decade has
witnessed great advances in remote C−H functionalization,6
which gave access to meta-substituted7 anilines and C6-
functionalized8 indolines (Scheme 1b). Nevertheless, the
general methodology for direct functionalization of anilines
at the para position remains to be developed.9 In the case of
indolines, only limited C5-functionalization has been reported,
including difluoromethylation, nitration, chalcogenation, alky-
lation, olefination, and amination (Scheme 1c).10
Isocyanides are useful organic synthons due to their
reactivity toward electrophiles, nucleophiles, and radicals
with wide application in multicomponent reactions,11 insertion
reactions,12 and cycloaddition reactions.13 Especially, p-
toluenesulfonylmethyl isocyanide (TosMIC), originally intro-
duced by Van Leusen,14 has attracted much attention due to its
impressive structural features and unique reactivity.15 Over the
past decades, [3 + 2] cycloaddition of TosMIC with polarized
functionalities, such as aldehydes, imines, alkenes, and alkynes,
have been extensively explored to access five-membered
heterocycles.16 Meanwhile, TosMIC also served as the
promising C1,17 N1,18 and C1N119 building block. Recently,
utilization of TosMIC as sulfinyl20 and sulfonyl21 sources has
also been reported. For example, Bi and co-workers have
reported the synthesis of benzoheteroles via heteroaromatiza-
tion of propargylic alcohols with TosMIC.21a Xia et al. have
prepared α-sulfonated ketones via coupling between a-bromo
ketones with TosMIC.21b The groups of Bi, Tiwari,
Yallapragada, and Shen have independently developed the
Received: March 2, 2021
Published: May 7, 2021
https://doi.org/10.1021/acs.joc.1c00500
© 2021 American Chemical Society
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synthesis of vinyl sulfones via functionalization of olefins or
alkynes with TosMIC.21c−f Despite the above progress, the
exploration of TosMIC in other transformations remains to be
developed.
employed to afford product 3a in 83% yield (Table 1, entry 7).
Moreover, the amount of Fe salt was optimized and C5-
tosylmethylated indoline 3a could be isolated in 81% yield in
the presence of 30 mol % FeCl2·4H2O (Table 1, entries 9).
Unfortunately, the efficiency was significantly decreased when
the dosage of FeCl2·4H2O was adjusted from 30 to 20 mol %
(Table 1, entry 10). Finally, the molar ratio of 2a/1a, reaction
time, and temperature were also evaluated, which all gave
inferior results (Table S4). The structure of compound 3a was
further confirmed by NMR, HRMS, and X-ray diffraction (see
Supporting Information for details).
Our group has been interested in functionalization of
biologically important heterocyclic frameworks. We have
developed C7-functionalized indolines via chelation-assisted
strategy.22 Meanwhile, Cu-mediated direct C−H sulfonylation
of benzoic acids with TosMIC has also been reported using a
PyO-directing group.23 Recently, we have also realized C−H
sulfonylmethylation of imidazopyridines and indoles using
TosMIC as the sulfonylmethylating reagent.24 In continuation
of our previous work,23−25 we herein report iron-induced26
para-selective sulfonylmethylation of aniline derivatives with
TosMIC in a solvent mixture of H2O and PEG400 (Scheme
1d). In this protocol, TosMIC serves as a source of the
sulfonylmethyl group instead of a typical 1,3 dipole. Mean-
while, the utilization of base-metal and nontoxic reaction
medium makes this methodology more practical and
convenience to access functionalized anilines. Moreover, C5-
sulfonylmethylated indolines were first realized, which could be
further oxidized to the corresponding C5-functionalized
indoles.
With the optimized conditions in hand (Table 1, entry 9),
the substrate scope of N-alkylindolines and N-methyl
tetrahydroquinolines was investigated to examine the general-
ity of this reaction (Table 2). Initially, C2- and C3-substituted
Table 2. Substrate Scope of Indolines and
a
Tetrahydroquinolines
RESULTS AND DISCUSSION
■
Our investigation commenced with reaction between N-
methylindoline 1a and TosMIC 2a in the presence of
FeSO4·7H2O in a solvent mixture of H2O and PEG400
(Table 1). To our delight, the desired C5-tosylmethylated
a
Table 1. Optimization of Reaction Conditions
Entry
Iron salt (mol %)
Solvent (ratio)
Yield (%)
1
2
3
4
5
6
7
8
FeSO4·7H2O (100)
FeCl2·4H2O (100)
Fe(NO3)3·9H2O (100)
Fe(acac)3 (100)
H2O/PEG400 (7:3)
H2O/PEG400 (7:3)
H2O/PEG400 (7:3)
H2O/PEG400 (7:3)
H2O/PEG400 (7:3)
H2O/PEG400 (1:1)
H2O/PEG400 (3:7)
H2O/PEG400 (1:9)
H2O/PEG400 (3:7)
H2O/PEG400 (3:7)
61
65
16
20
trace
80
83
42
81
64
FeCl3 (100)
FeCl2·4H2O (100)
FeCl2·4H2O (100)
FeCl2·4H2O (100)
FeCl2·4H2O (30)
FeCl2·4H2O (20)
9
10
a
Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), iron salt, H2O/
PEG400 (2 mL), 100 °C, 10 h. Isolated yield.
a
Reaction conditions: 1 (0.1 mmol), 2a (0.3 mmol), FeCl2·4H2O
indoline 3a was obtained in 61% yield at 100 °C for 10 h under
Ar (Table 1, entry 1). Subsequently, various earth-abundant
metal complexes, including Fe, Ni, Cu, and Al salts, were
screened, which indicates Fe salts show better catalytic
performance than other metal salts (Table S1). Besides, in
the evaluation of iron salts, such as FeCl2·4H2O, Fe(NO3)3·
9H2O, Fe(acac)3, and FeCl3 (Table 1, entries 2−5), FeCl2·
4H2O was the best choice to afford product 3a in 65% yield
(Table 1, entry 2). Next, the effect of solvent on the reactivity
was examined. Replacement of solvent mixture H2O/PEG400
with other solvents, such as CH3OH, EtOH, and DMF, was
found to be detrimental (Table S2). The volumetric ratio of
H2O/PEG400 was also screened, and H2O/PEG400 (3/7) was
(0.03 mmol), H2O/PEG400 (3/7, 2 mL), 100 °C, 10 h, under Ar.
Isolated yield. 50% of starting material was retrieved.
b
N-methylindolines were examined to provide the correspond-
ing products 3b−e in 58−78% yields. Subsequently, indolines
bearing substitutions on the aryl moiety were also employed.
Pleasingly, both electron-donating (Me, OMe, and OBn,) and
electron-withdrawing (F, Cl, and Br) groups at the C4, C6, or
C7 position were well tolerated to afford C5-tosylmethylated
products 3f−q in 42−83% yields. Nevertheless, C7-fluoro
substituted indoline was less reactive to give the corresponding
product 3r in 20% yield. Next, N-methyl tetrahydroquinolines
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were also employed under the optimized conditions. It was
found that both methyl and chloro substituted tetrahydroqui-
nolines proceeded smoothly to provide C6-tosylmethylated
products 3s−v in 50−74% yields. Moreover, N-methyl
benzomorpholine, the scaffold of which is present in some
pharmaceuticals,27 could undergo tosylmethylation to give
product 3w in 20% yield, which is further confirmed by X-ray
analysis (see the Supporting Information). Finally, N-ethyl
indoline was also tested to furnish product 3x in 65% yields.
However, N-acetyl indoline failed to deliver the corresponding
product 3y. When strongly electron-withdrawing group CF3
was introduced at the C6 position, no corresponding product
could be detected. Meanwhile, when the C5 position was
blocked by a methoxy group, no desired C7-substituted
product 3z could be detected. Likewise, NH-free indolines and
tetrahydroquinolines were also proven to be unsuccessful for
tosylmethylation transformations.
Scheme 2. Substrate Scope of TosMIC, Gram-Scale
Synthesis and Derivatization
Next, the variation of tertiary aniline derivatives with
different substitution patterns was also examined to expand
the applicability of the current methodology (Table 3). As
To explore the reaction mechanism, a set of control
experiments were conducted (Scheme 3). In a radical trap
a
Table 3. Substrate Scope of Anilines
Scheme 3. Control Experiments
experiment, stoichiometric TEMPO, BQ, and BHT were
utilized as radical scavengers. The reaction efficiency was
suppressed to some extent, which gave product 3a in 10%,
29%, and 70% yields. This suggested a radical mechanism
might not be involved. In the absence of FeCl2·4H2O, no
desired product 3a could be detected, which indicated the
necessity of iron salt. Consequently, we speculated that Fe2+
could coordinate with isocyanide to facilitate C−N cleavage.
Moreover, compared with electron-rich indolines, the ones
bearing electron-withdrawing (F, Cl, and Br or N-acetyl)
groups led to a decreased yield or deactivation of the reaction,
indicating tosylmethylation undergoes a Friedel−Crafts-type
reaction mechanism.
On the basis of above discussion and previous literature
reports,10,24 a plausible reaction mechanism was proposed
(Scheme 4). Initially, Fe2+ coordinated with isocyanide to form
intermediate A. Next, cleavage of the C−N bond gave carbon
cation species B. Finally, aromatic electrophilic substitution
between B and 1a generated intermediate C, which underwent
a deprotonation process to deliver the desired product 3a.
a
Reaction conditions: 4 (0.1 mmol), 2a (0.3 mmol), FeCl2·4H2O
(0.03 mmol), H2O/PEG400 (3/7, 2 mL), 100 °C, 10 h, under Ar.
Isolated yield.
expected, tertiary anilines were tosylmethylated at the para-
position to afford product 5a−e in 56−71% yields. The
structure of 5d was also determined by X-ray analysis (see the
Supporting Information). However, N-methylcarbazole exhib-
its no reactivity. When cyclic amine N-phenylpiperidine was
employed, the corresponding product 5g was obtained in 21%
yield. Meanwhile, the secondary or primary anilines were also
tested, which unfortunately failed to give the corresponding
products.
Moreover, substituted TosMIC derivatives 2 were employed
to generate products 6a−c in 58−76% yields (Scheme 2a). To
demonstrate the synthetic utility of the current methodology, a
gram-scale reaction was conducted, and the tosylmethylated
product 3a was isolated in 61% yield. Meanwhile, the obtained
3a could undergo further derivatizations (Scheme 2b), which
delivered methoxymethyl-substituted compound 7 and hy-
droxy-substituted compound 8 in 91% and 44% yield,
respectively. Notably, oxidation of 3a with diethyl azodicarbox-
ylate (DEAD) as a milder oxidant in dichloromethane at room
temperature for 2 h gave indole 9 in 90% yield, which could
further be converted into double-tosylmethylated product 10
in 50% yield.
Scheme 4. Proposed Reaction Mechanism
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18.7. HRMS (ESI) m/z: (M + H)+ calcd for C18H21NO2S, 316.1366;
found, 316.1369.
CONCLUSION
■
In conclusion, we have developed an iron-mediated highly
selective C−H sulfonylmethylation of aniline derivatives with
TosMIC in a mixture solvent of H2O and PEG400. A wide
range of substrate, including indolines, tetrahydroquinolines,
and tertiary anilines, were well tolerated to afford the
corresponding products in moderate to high yields. A gram-
scale production and multiple derivatizations were investigated
to highlight the practical application of this protocol. Notably,
the obtained C5-sulfonylmethylated indolines could undergo
oxidation and another C3-sulfonylmethylation to give the
corresponding disubstituted indole derivatives. Finally, a
plausible Friedel−Crafts-type aromatic electrophilic reaction
mechanism was proposed.
1-Methyl-2-phenyl-5-(tosylmethyl)indoline (3c). Purified by ana-
lytical TLC on silica gel with dichloromethane as an eluent with Rf =
1
0.6, white solid (21.9 mg, 58%), mp = 153−154 °C. H NMR (600
MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.35−7.40 (m, 4H), 7.31 (t,
J = 7.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 6.84 (s, 1H), 6.78 (d, J =
8.0 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 4.39 (dd, J = 10.4, 9.2 Hz, 1H),
4.19 (s, 2H), 3.28 (dd, J = 15.7, 8.9 Hz, 1H), 2.86 (dd, J = 15.7, 10.7
Hz, 1H), 2.59 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 153.7, 144.4, 142.1, 135.6, 130.7, 129.4, 129.0, 128.7, 128.6,
127.7, 127.2, 126.5, 116.7, 106.4, 71.9, 62.9, 39.1, 33.8, 21.6. HRMS
(ESI) m/z: (M + H)+ calcd for C23H23NO2S, 378.1522; found,
378.1524.
1,3-Dimethyl-5-(tosylmethyl)indoline (3d). Purified by analytical
TLC on silica gel with dichloromethane as an eluent with Rf = 0.3,
white solid (23.3 mg, 74%), mp = 105−107 °C. 1H NMR (600 MHz,
CDCl3) δ 7.52 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.77 (d, J
= 8.0 Hz, 1H), 6.67 (s, 1H), 6.32 (d, J = 8.0 Hz, 1H), 4.18 (q, J = 14.0
Hz, 2H), 3.52 (t, J = 8.5 Hz, 1H), 3.22−3.16 (m, 1H), 2.81 (t, J = 8.4
Hz, 1H), 2.72 (s, 3H), 2.41 (s, 3H), 1.18 (d, J = 6.8 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 153.3, 144.3, 135.6, 135.4,
130.5, 129.4, 128.8, 125.5, 116.6, 106.7, 63.9, 63.0, 35.7, 35.0, 21.6,
18.5. HRMS (ESI) m/z: (M + H)+ calcd for C18H21NO2S, 316.1366;
found, 316.1369.
EXPERIMENTAL SECTION
■
General Experimental Details. Unless otherwise indicated, all
the starting materials (including 4a−d and 4g) and reagents were
commercially available and used without further purification. Aniline
derivatives 1a−1v,10g 1w,28a 1x,28e 1y,28c 1z,28d 4e,28g 4f,28f and
TosMIC derivatives 228b are known compounds and synthesized
according to previously reported methods. Melting points were
determined on a melting point apparatus. Flash column chromatog-
raphy was performed using 200−300 mesh silica gel. Analytical and
preparative thin-layer chromatography (TLC) plates coated with
commercial silica gel GF254 were used to monitor the reactions and
purify products. 1H, 13C{1H}, and 19F NMR spectra were recorded on
Bruker DPX 400 or Bruker DPX 600 instruments using TMS as an
internal standard. Data are reported as follows: chemical shift (δ
ppm), multiplicity (s = single, d = doublet, t = triplet, m = multiplet),
integration, and coupling constants (J) in hertz (Hz). HRMS were
determined on a Q-Tof micro MS/MS system ESI spectrometer. The
structures of products 3a (CCDC file Number 2050319), 3w (CCDC
file Number 2050332), and 5d (CCDC file Number 2050333) were
further confirmed by X-ray diffraction collected on a diffractometer
with graphite-monochromated Mo Kα radiation.
General Procedure for the Preparation of Compound of 3,
5 and 6. To a 15 mL sealed tube were added indolines or
tetrahydroquinolines 1 or anilines 4 (0.1 mmol), TosMIC derivatives
2 (0.3 mmol), and FeCl2·4H2O (0.03 mmol, 6.0 mg) in a mixed
solvent of PEG400 and H2O (2 mL) under an Ar atmosphere. The
reaction mixture was heated at 100 °C for 10 h. After cooling down to
room temperature, the reaction mixture was diluted by H2O (10 mL)
and extracted by dichloromethane (3 × 10 mL). The combined
organic layers were dried by Na2SO4, filtered through Celite, and
concentrated under reduced pressure. The residue was purified by
preparative TLC on silica gel plates using dichloromethane as the
eluent to give the corresponding products.
1-Methyl-5-(tosylmethyl)indoline (3a). Purified by analytical TLC
on silica gel with dichloromethane as an eluent with Rf = 0.3, white
solid (24.4 mg, 81%), mp = 147−148 °C. 1H NMR (600 MHz,
CDCl3) δ 7.54 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.86 (s,
1H), 6.69 (d, J = 7.9 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 4.17 (s, 2H),
3.31 (t, J = 8.2 Hz, 2H), 2.89 (t, J = 8.2 Hz, 2H), 2.74 (s, 3H), 2.42 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 153.8, 144.3, 135.5, 130.7,
130.4, 129.4, 128.7, 126.7, 116.4, 106.5, 62.9, 56.0, 35.8, 28.4, 21.6.
HRMS (ESI) m/z: (M + H)+ calcd for C17H19NO2S, 302.1209;
found, 302.1208.
1,2-Dimethyl-5-(tosylmethyl)indoline (3b). Purified by analytical
TLC on silica gel with dichloromethane as an eluent with Rf = 0.3,
white solid (24.6 mg, 78%), mp = 119−120 °C. 1H NMR (600 MHz,
CDCl3) δ 7.54 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.82 (s,
1H), 6.68 (d, J = 8.0 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 4.16 (s, 2H),
3.47−3.40 (m, 1H), 3.02 (dd, J = 15.4, 8.3 Hz, 1H), 2.69 (s, 3H),
2.53 (dd, J = 15.4, 10.0 Hz, 1H), 2.42 (s, 3H), 1.30 (d, J = 6.1 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 153.8, 144.3, 135.5, 130.4,
129.6, 129.4, 128.7, 126.5, 116.4, 106.4, 63.0, 62.7, 37.0, 33.3, 21.6,
1,2,3-Trimethyl-5-(tosylmethyl)indoline (3e). Purified by analyt-
ical TLC on silica gel with dichloromethane as an eluent with Rf = 0.3,
1
white solid (24.4 mg, 74%), mp = 78−79 °C. H NMR (600 MHz,
CDCl3) δ 7.52 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 6.75 (d, J
= 8.0 Hz, 1H), 6.66 (s, 1H), 6.31 (d, J = 8.0 Hz, 1H), 4.18 (q, J = 12.8
Hz, 2H), 2.86−2.81 (m, 1H), 2.71−2.68 (m, 4H), 2.41 (s, 3H), 1.30
(d, J = 6.1 Hz, 3H), 1.18 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 153.3, 144.3, 135.4, 134.5, 130.5, 129.4, 128.8, 125.0,
116.8, 106.7, 71.0, 63.0, 43.1, 33.7, 21.6, 17.5, 16.7. HRMS (ESI) m/
z: (M + H)+ calcd for C19H23NO2S, 330.1522; found, 330.1523.
4-Fluoro-1-methyl-5-(tosylmethyl)indoline (3f). Purified by ana-
lytical TLC on silica gel with dichloromethane as an eluent with Rf =
1
0.4, white solid (19.5 mg, 61%), mp = 140−141 °C. H NMR (400
MHz, CDCl3) δ 7.58 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H),
6.88 (t, J = 7.7 Hz, 1H), 6.16 (d, J = 8.0 Hz, 1H), 4.25 (s, 2H), 3.38
(t, J = 8.4 Hz, 2H), 2.87 (t, J = 8.4 Hz, 2H), 2.75 (s, 3H), 2.43 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.0 (d, J = 232.3 Hz),
156.6 (d, J = 6.1 Hz), 144.4, 135.6, 132.3 (d, J = 3.6 Hz), 129.4,
128.7, 114.9(d, J = 22.0 Hz), 104.1(d, J = 15.4 Hz), 102.7 (d, J = 2.4
Hz), 56.0 (d, J = 2.0 Hz), 55.9, 35.4, 24.7, 21.6. 19F NMR (565 MHz,
CDCl3) δ −124.33. HRMS (ESI) m/z: (M + H)+ calcd for
C17H18FNO2S, 320.1115; found, 320.1117.
4-Chloro-1-methyl-5-(tosylmethyl)indoline (3g). Purified by
analytical TLC on silica gel with dichloromethane as an eluent with
1
Rf = 0.5, white solid (17.1 mg, 51%), mp = 143−144 °C. H NMR
(400 MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.0 Hz,
2H), 7.02 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H),
3.39 (t, J = 8.4 Hz, 2H), 2.90 (t, J = 8.4 Hz, 2H), 2.76 (s, 3H), 2.43 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.7, 144.5, 135.8, 132.5,
131.5, 129.4, 128.8, 128.6, 114.0, 104.8, 59.1, 55.1, 35.4, 28.3, 21.7.
HRMS (ESI) m/z: (M + H)+ calcd for C17H18ClNO2S, 336.0820;
found, 336.0821.
1,4-Dimethyl-5-(tosylmethyl)indoline (3h). Purified by analytical
TLC on silica gel with dichloromethane as an eluent with Rf = 0.4,
white solid (19.2 mg, 61%), mp = 149−151 °C. 1H NMR (600 MHz,
CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 6.69 (d, J
= 8.0 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H), 4.27 (s, 2H), 3.33 (t, J = 8.3
Hz, 2H), 2.84 (t, J = 8.3 Hz, 2H), 2.73 (s, 3H), 2.43 (s, 3H), 2.01 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 147.6, 144.4, 135.9, 133.7,
132.3, 129.4, 128.8, 121.6, 112.0, 110.4, 59.2, 50.7, 38.8, 27.2, 21.9,
21.7. HRMS (ESI) m/z: (M + H)+ calcd for C18H21NO2S, 316.1366;
found, 316.1367.
4-Methoxy-1-methyl-5-(tosylmethyl)indoline (3i). Purified by
analytical TLC on silica gel with dichloromethane as an eluent with
Rf = 0.3, white solid (18.6 mg, 56%), mp = 95−96 °C. 1H NMR (600
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MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H),
6.85 (d, J = 8.0 Hz, 1H), 6.13 (d, J = 8.0 Hz, 1H), 4.32 (s, 2H), 3.59
(s, 3H), 3.32 (t, J = 8.2 Hz, 2H), 3.00 (t, J = 8.2 Hz, 2H), 2.73 (s,
3H), 2.42 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 156.5, 155.3,
144.1, 136.4, 131.9, 129.3, 128.8, 118.2, 108.9, 102.2, 59.3, 56.7, 56.1,
35.8, 27.1, 21.6. HRMS (ESI) m/z: (M + H)+ calcd for C18H21NO3S,
332.1315; found, 332.1317.
Hz, 2H), 2.96 (s, 3H), 2.86 (t, J = 8.5 Hz, 2H), 2.42 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 146.1, 144.4, 141.9, 135.4, 132.5, 129.4,
128.8, 120.3, 118.6, 114.1, 63.0, 57.4, 55.7, 39.3, 29.1, 21.6. HRMS
(ESI) m/z: (M + H)+ calcd for C18H21NO3S, 332.1315; found,
332.1316.
7-(Benzyloxy)-1-methyl-5-(tosylmethyl)indoline (3q). Purified by
analytical TLC on silica gel with dichloromethane as an eluent with Rf
= 0.4, white solid (25.7 mg, 63%), mp = 141−142 °C. 1H NMR (600
MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.38−7.37 (m, 4H), 7.34−
7.30 (m, 1H), 7.25 (d, J = 7.9 Hz, 2H), 6.51 (s, 1H), 6.40 (s, 1H),
4.82 (s, 2H), 4.16 (s, 2H), 3.27 (t, J = 8.5 Hz, 2H), 2.97 (s, 3H), 2.87
(t, J = 8.5 Hz, 2H), 2.40 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3)
δ 145.2, 144.4, 142.2, 137.0, 135.5, 132.8, 129.4, 128.8, 128.5, 127.9,
127.5, 120.7, 118.5, 115.5, 71.0, 63.0, 57.4, 39.3, 29.1, 21.6. HRMS
(ESI) m/z: (M + H)+ calcd for C24H25NO3S, 408.1628; found,
408.1631.
6-Fluoro-1-methyl-5-(tosylmethyl)indoline (3j). Purified by ana-
lytical TLC on silica gel with dichloromethane as an eluent with Rf =
1
0.4, white solid (24.9 mg, 78%), mp = 154−156 °C. H NMR (600
MHz, CDCl3) δ 7.57 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H),
6.95 (d, J = 7.2 Hz, 1H), 5.94 (d, J = 11.0 Hz, 1H), 4.23 (s, 2H), 3.38
(t, J = 8.3 Hz, 2H), 2.90 (t, J = 8.2 Hz, 2H), 2.72 (s, 3H), 2.42 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 161.9 (d, J = 245.5 Hz),
155.4 (d, J = 12.2 Hz), 144.4, 135.6, 129.4, 128.6, 127.0 (d, J = 4.5
Hz), 125.9 (d, J = 2.2 Hz), 102.2 (d, J = 16.5 Hz), 93.9 (d, J = 27.6
Hz), 56.0, 55.9 (d, J = 3.2 Hz), 35.2, 27.7, 21.7. 19F NMR (565 MHz,
CDCl3) δ −119.18. HRMS (ESI) m/z: (M + H)+ calcd for
C17H18FNO2S, 320.1115; found, 320.1119.
7-Fluoro-1-methyl-5-(tosylmethyl)indoline (3r). Purified by ana-
lytical TLC on silica gel with dichloromethane as an eluent with Rf =
1
0.4, white solid (6.4 mg, 20%), mp = 124−125 °C. H NMR (600
6-Chloro-1-methyl-5-(tosylmethyl)indoline (3k). Purified by
analytical TLC on silica gel with dichloromethane as an eluent with
MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H),
6.67 (s, 1H), 6.47 (d, J = 12.5 Hz, 1H), 4.13 (s, 2H), 3.32 (t, J = 8.4
Hz, 2H), 2.94−2.91 (m, 5H), 2.43 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 148.7 (d, J = 241.2 Hz), 144.6, 140.1 (d, J = 8.6 Hz),
135.3, 134.4 (d, J = 5.7 Hz), 129.5, 128.6, 122.8 (d, J = 2.0 Hz), 118.0
(d, J = 6.3 Hz), 117.8 (d, J = 20.8 Hz), 62.3, 57.0, 38.1 (d, J = 7.0
Hz), 29.3, 21.6. 19F NMR (565 MHz, CDCl3) δ −137.88. HRMS
(ESI) m/z: (M + H)+ calcd for C17H18FNO2S, 320.1115; found,
320.1115.
1
Rf = 0.5, white solid (18.1 mg, 54%), mp = 149−150 °C. H NMR
(600 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz,
2H), 7.09 (s, 1H), 6.24 (s, 1H), 4.39 (s, 2H), 3.39 (t, J = 8.3 Hz, 2H),
2.93 (t, J = 8.3 Hz, 2H), 2.73 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 154.6, 144.5, 135.7, 134.6, 129.6, 129.4, 128.8,
127.8, 113.6, 106.8, 59.4, 55.8, 35.2, 27.9, 21.7. HRMS (ESI) m/z: (M
+ H)+ calcd for C17H18ClNO2S, 336.0820; found, 336.0821.
6-Bromo-1-methyl-5-(tosylmethyl)indoline (3l). Purified by ana-
lytical TLC on silica gel with dichloromethane as an eluent with Rf =
0.5, white solid (16.0 mg, 42%), mp = 142−143 °C. H NMR (600
1-Methyl-6-(tosylmethyl)-1,2,3,4-tetrahydroquinoline (3s). Puri-
fied by analytical TLC on silica gel with dichloromethane as an eluent
with Rf = 0.4, white solid (22.1 mg, 70%), mp = 101−102 °C. H
1
1
MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H),
7.13 (s, 1H), 6.42 (s, 1H), 4.42 (s, 2H), 3.39 (t, J = 8.3 Hz, 2H), 2.92
(t, J = 8.3 Hz, 2H), 2.73 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 154.7, 144.5, 135.7, 130.3, 129.5, 128.9, 127.9, 125.0,
115.4, 109.9, 61.8, 55.8, 35.1, 28.0, 21.7. HRMS (ESI) m/z: (M + H)+
calcd for C17H18BrNO2S, 380.0315; found, 380.0314.
NMR (600 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.5
Hz, 2H), 6.72 (d, J = 8.3 Hz, 1H), 6.67 (s, 1H), 6.42 (d, J = 8.3 Hz,
1H), 4.14 (s, 2H), 3.22 (t, J = 5.8 Hz, 2H), 2.86 (s, 3H), 2.65 (t, J =
6.4 Hz, 2H), 2.42 (s, 3H), 1.95−1.91 (m, 2H). 13C{1H} NMR (151
MHz, CDCl3) δ 146.9, 144.2, 135.6, 131.2, 129.6, 129.4, 128.7, 122.7,
114.5, 110.5, 62.6, 51.1, 38.9, 27.6, 22.2, 21.6. HRMS (ESI) m/z: (M
+ H)+ calcd for C18H21NO2S, 316.1366; found, 316.1369.
1,4-Dimethyl-6-(tosylmethyl)-1,2,3,4-tetrahydroquinoline (3t).
Purified by analytical TLC on silica gel with dichloromethane as an
eluent with Rf = 0.6, white solid (23.1 mg, 70%), mp = 126−127 °C.
1H NMR (600 MHz, CDCl3) δ 7.52 (d, J = 8.2 Hz, 2H), 7.23 (d, J =
8.0 Hz, 2H), 6.83 (dd, J = 8.3, 1.9 Hz, 1H), 6.59 (d, J = 1.4 Hz, 1H),
6.45 (d, J = 8.4 Hz, 1H), 4.16 (q, J = 14.0 Hz, 2H), 3.26−3.16 (m,
2H), 2.87 (s, 3H), 2.76−2.71 (m, 1H), 2.41 (s, 3H), 1.99−1.94 (m,
1H), 1.65−1.60 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 146.2, 144.2, 135.5, 130.2, 129.6, 129.3, 128.8,
127.7, 114.6, 110.6, 62.8, 48.0, 39.0, 30.6, 29.6, 22.3, 21.6. HRMS
(ESI) m/z: (M + H)+ calcd for C19H23NO2S, 330.1522; found,
330.1526.
1,5-Dimethyl-6-(tosylmethyl)-1,2,3,4-tetrahydroquinoline (3u).
Purified by analytical TLC on silica gel with dichloromethane as an
eluent with Rf = 0.7, white solid (24.4 mg, 74%), mp = 156−157 °C.
1H NMR (600 MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H), 7.25 (d, J =
7.2 Hz, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 8.5 Hz, 1H), 4.30
(s, 2H), 3.17 (t, J = 6.6 Hz, 2H), 2.86 (s, 3H), 2.60 (t, J = 6.6 Hz,
2H), 2.43 (s, 3H), 2.00−1.96 (m, 5H). 13C{1H} NMR (151 MHz,
CDCl3) δ 147.4, 144.3, 136.5, 136.1, 130.6, 129.4, 128.7, 121.7, 114.0,
109.0, 60.8, 50.7, 39.7, 25.37, 22.5, 21.6, 15.6. HRMS (ESI) m/z: (M
+ H)+ calcd for C19H23NO2S, 330.1522; found, 330.1525.
1,6-Dimethyl-5-(tosylmethyl)indoline (3m). Purified by analytical
TLC on silica gel with dichloromethane as an eluent with Rf = 0.3,
white solid (26.2 mg, 83%), mp = 141−142 °C. 1H NMR (600 MHz,
CDCl3) δ 7.55 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 6.80 (s,
1H), 6.18 (s, 1H), 4.23 (s, 2H), 3.30 (t, J = 8.1 Hz, 2H), 2.85 (t, J =
8.1 Hz, 2H), 2.73 (s, 3H), 2.42 (s, 3H), 1.97 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 153.9, 144.4, 137.6, 136.0, 129.4, 128.7, 128.2,
127.7, 114.8, 108.8, 60.3, 56.1, 35.8, 28.1, 21.6, 19.7. HRMS (ESI) m/
z: (M + H)+ calcd for C18H21NO2S, 316.1366; found, 316.1366.
6-Methoxy-1-methyl-5-(tosylmethyl)indoline (3n). Purified by
analytical TLC on silica gel with dichloromethane as an eluent with
1
Rf = 0.2, white solid (27.2 mg, 82%), mp = 127−128 °C. H NMR
(600 MHz, CDCl3) δ 7.52 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.0 Hz,
2H), 6.97 (s, 1H), 5.80 (s, 1H), 4.30 (s, 2H), 3.33 (t, J = 8.2 Hz, 2H),
3.31 (s, 3H), 2.88 (t, J = 8.2 Hz, 2H), 2.73 (s, 3H), 2.40 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 158.1, 155.2, 143.7, 136.3,
128.9, 128.8, 127.6, 121.9, 104.4, 90.7, 56.9, 56.4, 55.0, 35.7, 27.7,
21.5. HRMS (ESI) m/z: (M + H)+ calcd for C18H21NO3S, 332.1315;
found, 332.1316.
1,7-Dimethyl-5-(tosylmethyl)indoline (3o). Purified by analytical
TLC on silica gel with dichloromethane as an eluent with Rf = 0.3,
white solid (22.7 mg, 72%), mp = 115−116 °C. 1H NMR (600 MHz,
CDCl3) δ 7.56 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 5.9 Hz, 2H), 6.70 (s,
1H), 6.50 (s, 1H), 4.13 (s, 2H), 3.29 (t, J = 8.5 Hz, 2H), 2.92 (s, 3H),
2.85 (t, J = 8.5 Hz, 2H), 2.42 (s, 3H), 2.26 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 151.8, 144.3, 135.6, 133.6, 131.5, 129.4, 128.7,
124.8, 119.6, 117.9, 62.7, 57.4, 39.8, 28.6, 21.6, 19.3. HRMS (ESI) m/
z: (M + H)+ calcd for C18H21NO2S, 316.1366; found, 316.1365.
7-Methoxy-1-methyl-5-(tosylmethyl)indoline (3p). Purified by
analytical TLC on silica gel with dichloromethane as an eluent with
Rf = 0.2, white solid (20.5 mg, 62%), mp = 93−94 °C. 1H NMR (600
MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H),
6.50 (s, 1H), 6.29 (s, 1H), 4.17 (s, 2H), 3.62 (s, 3H), 3.26 (t, J = 8.5
7-Chloro-1-methyl-6-(tosylmethyl)-1,2,3,4-tetrahydroquino-line
(3v). Purified by analytical TLC on silica gel with dichloromethane as
an eluent with Rf = 0.6, white solid (17.4 mg, 50%), mp = 106−107
°C. 1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.24 (d,
J = 8.0 Hz, 2H), 6.93 (s, 1H), 6.37 (s, 1H), 4.36 (s, 2H), 3.25 (t, J =
6.3 Hz, 2H), 2.85 (s, 3H), 2.68 (t, J = 6.3 Hz, 2H), 2.42 (s, 3H),
1.96−1.92 (m, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 147.6,
144.4, 135.8, 133.7, 132.3, 129.4, 128.8, 121.6, 112.0, 110.4, 59.2,
50.7, 38.7, 27.2, 21.9, 21.7. HRMS (ESI) m/z: (M + H)+ calcd for
C18H20ClNO2S, 350.0976; found, 350.0979.
7183
https://doi.org/10.1021/acs.joc.1c00500
J. Org. Chem. 2021, 86, 7179−7188

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4-Methyl-7-(tosylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxaz-ine
(3w). Purified by analytical TLC on silica gel with dichloromethane as
an eluent with Rf = 0.6, white solid (6.3 mg, 20%), mp = 106−107 °C.
1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.25 (d, J =
Hz, 4H), 2.42 (s, 3H), 1.70−1.66 (m, 4H), 1.60−1.57 (m, 2H).
13C{1H} NMR (151 MHz, CDCl3) δ 152.2, 144.4, 135.4, 131.6,
129.4, 128.7, 117.7, 115.84, 62.4, 50.0, 25.6, 24.3, 21.6. HRMS (ESI)
m/z: (M + H)+ calcd for C19H23NO2S, 330.1522; found, 330.1520.
1-Methyl-5-((phenylsulfonyl)methyl)indoline (6a). Purified by
analytical TLC on silica gel with dichloromethane as an eluent with
8.3 Hz, 2H), 6.56−6.51 (m, 3H), 4.24 (t, J = 4.3 Hz, 2H), 4.14 (s,
2H), 3.25 (t, J = 4.3 Hz, 2H), 2.86 (s, 3H), 2.42 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 144.4, 144.0, 136.9, 135.6, 129.4, 128.6,
124.1, 118.2, 117.0, 112.0, 64. 7, 62.5, 48.9, 38.6, 21.6. HRMS (ESI)
m/z: (M + H)+ calcd for C17H19NO3S, 318.1159; found, 318.1157.
1-Ethyl-5-(tosylmethyl)indoline (3x). Purified by analytical TLC
on silica gel with dichloromethane as an eluent with Rf = 0.3, white
solid (20.5 mg, 65%), mp = 114−115 °C. 1H NMR (600 MHz,
CDCl3) δ 7.54 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.85 (s,
1H), 6.67 (d, J = 8.0 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.16 (s, 2H),
3.35 (t, J = 8.3 Hz, 2H), 3.12 (q, J = 7.2 Hz, 2H), 2.89 (t, J = 8.3 Hz,
2H), 2.42 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 152.7, 144.3, 135.5, 130.7, 130.3, 129.4, 128.7, 126.8,
116.1, 106.5, 62.9, 52.1, 42.7, 28.2, 21.6, 11.8. HRMS (ESI) m/z: (M
+ H)+ calcd for C18H21NO2S, 316.1366; found, 316.1366.
N,N-Dimethyl-4-(tosylmethyl)aniline (5a). Purified by analytical
TLC on silica gel with dichloromethane as an eluent with Rf = 0.4,
white solid (20.5 mg, 71%), mp = 107−108 °C. 1H NMR (600 MHz,
CDCl3) δ 7.52 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.93 (d, J
= 8.7 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 4.19 (s, 2H), 2.93 (s, 6H),
2.41 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 150.6, 144.3,
135.5, 131.6, 129.4, 128.7, 115.1, 112.2, 62.5, 40.3, 21.6. HRMS (ESI)
m/z: (M + H)+ calcd for C16H19NO2S, 290.1209; found, 290.1211.
N,N,3-Trimethyl-4-(tosylmethyl)aniline (5b). Purified by analytical
TLC on silica gel with dichloromethane as an eluent with Rf = 0.5,
white solid (20.0 mg, 66%), mp = 144−145 °C. 1H NMR (600 MHz,
CDCl3) δ 7.54 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.88 (d, J
= 8.3 Hz, 1H), 6.47−6.45 (m, 2H), 4.26 (s, 2H), 2.93 (s, 6H), 2.43
(s, 3H), 2.05 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 150.8
144.4, 138.9, 135.9, 132.8, 129.5, 128.7, 114.1, 113.9, 110.1, 59.9,
40.3, 21.6, 19.9. HRMS (ESI) m/z: (M + H)+ calcd for C17H21NO2S,
304.1366; found, 304.1365.
1
Rf = 0.5, white solid (18.1 mg, 63%), mp = 121−122 °C. H NMR
(600 MHz, CDCl3) δ 7.67−7.66 (m, 2H), 7.59 (t, J = 7.5 Hz, 1H),
7.46 (t, J = 7.8 Hz, 2H), 6.84 (s, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.29
(d, J = 8.0 Hz, 1H), 4.19 (s, 2H), 3.31 (t, J = 8.2 Hz, 2H), 2.88 (t, J =
8.2 Hz, 2H), 2.73 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
153.8, 138.4, 133.4, 130.7, 130.4, 128.8, 128.7, 126.7, 116.2, 106.5,
62.9, 55.9, 35.8, 28.4. HRMS (ESI) m/z: (M + H)+ calcd for
C16H17NO2S, 288.1053; found, 288.1050.
5-(((4-Methoxyphenyl)sulfonyl)methyl)-1-methylindoline (6b).
Purified by analytical TLC on silica gel with dichloromethane as an
eluent with Rf = 0.3, white solid (24.1 mg, 76%), mp = 118−119 °C.
1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 8.8 Hz, 2H), 6.90 (d, J =
8.8 Hz, 2H), 6.86 (s, 1H), 6.68 (d, J = 7.9 Hz, 1H), 6.30 (d, J = 8.0
Hz, 1H), 4.16 (s, 2H), 3.86 (s, 3H), 3.31 (t, J = 8.2 Hz, 2H), 2.89 (t, J
= 8.2 Hz, 2H), 2.73 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
163.5, 153.7, 130.9, 130.7, 130.3, 130.0, 126.7, 116.7, 113.9, 106.5,
63.1, 56.0, 55.6, 35.8, 28.4. HRMS (ESI) m/z: (M + H)+ calcd for
C17H19NO3S, 318.1159; found, 318.1165.
5-(((4-Chlorophenyl)sulfonyl)methyl)-1-methylindoline (6c). Pu-
rified by analytical TLC on silica gel with dichloromethane as an
eluent with Rf = 0.5, white solid (18.7 mg, 58%), mp = 139−140 °C.
1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 8.5 Hz, 2H), 7.42 (d, J =
8.5 Hz, 2H), 7.26 (s, 1H), 6.67 (d, J = 7.9 Hz, 1H), 6.29 (d, J = 8.0
Hz, 1H), 4.19 (s, 2H), 3.33 (t, J = 8.3 Hz, 2H), 2.89 (t, J = 8.2 Hz,
2H), 2.74 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 153.9, 140.2,
136.8, 130.8, 130.4, 130.2, 129.0, 126.6, 115.8, 106.4, 63.0, 55.9, 35.7,
28.3. HRMS (ESI) m/z: (M + H)+ calcd for C16H16ClNO2S,
322.0663; found, 322.0664.
Gram-Scale Synthesis. To a 500 mL Schlenk bottle were added
1a (10 mmol, 1.33 g), 2a (30 mmol, 5.86 g), and FeCl2·4H2O (3
mmol, 0.60 g) in a mixed solvent of PEG400 and H2O (200 mL) under
an Ar atmosphere. The reaction mixture was heated at 100 °C for 10
h. After cooling down to room temperature, the reaction mixture was
diluted by H2O (100 mL) and extracted by dichloromethane (3 ×
150 mL). The combined organic layers were dried by Na2SO4, filtered
through Celite, and concentrated under reduced pressure. The residue
was purified through a silica gel column using petroleum ether/
dichloromethane = 1/1 as the eluent to give pure products 3a in 61%
isolated yield (1.84 g was isolated).
N,N-Diethyl-4-(tosylmethyl)aniline (5c). Purified by analytical
TLC on silica gel with dichloromethane as an eluent with Rf = 0.4,
white solid (20.3 mg, 64%), mp = 104−105 °C. 1H NMR (600 MHz,
CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.90 (d, J
= 8.6 Hz, 2H), 6.54 (d, J = 8.6 Hz, 2H), 4.17 (s, 2H), 3.33 (q, J = 7.1
Hz, 4H), 2.42 (s, 3H), 1.14 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (151
MHz, CDCl3) δ 148.0, 144.2, 135.6, 131.9, 129.4, 128.7, 113.9, 111.5,
62.6, 44.3, 21.6, 12.5. HRMS (ESI) m/z: (M + H)+ calcd for
C18H23NO2S, 318.1522; found, 318.1520.
N,N-Diethyl-3-methyl-4-(tosylmethyl)aniline (5d). Purified by
analytical TLC on silica gel with dichloromethane as an eluent with
Rf = 0.5, white solid (22.5 mg, 68%), mp = 82−83 °C. 1H NMR (600
MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H),
6.85 (d, J = 8.1 Hz, 1H), 6.42−6.40 (m, 2H), 4.25 (s, 2H), 3.32 (q, J
= 7.1 Hz, 4H), 2.43 (s, 3H), 2.06 (s, 3H), 1.14 (t, J = 7.1 Hz, 6H).
13C{1H} NMR (151 MHz, CDCl3) δ 148.1, 144.3, 139.1, 136.1,
133.0, 129.4, 128.7, 113.3, 112.7, 109.5, 59.9, 44.2, 21.6, 20.1, 12.5.
HRMS (ESI) m/z: (M + H)+ calcd for C19H25NO2S, 332.1679;
found, 332.1678.
5-(Methoxymethyl)-1-methylindoline 7. To a 15 mL sealed
tube were added 3a (0.2 mmol, 60.3 mg), NaOH (1.0 mmol, 40 mg),
and then CH3OH (2 mL). The vessel was sealed with a Teflon-lined
cap, and the reaction mixture was allowed to stir at 90 °C (oil bath)
for 12 h. Then the solvent was directly evaporated, and the residue
was purified by preparative TLC on silica gel plates using petroleum/
ethyl acetate = 5/1 as the eluent to give the desired product 7 in 91%
1
yield. Rf = 0.6, colorless liquid (32.3 mg, 91%). H NMR (600 MHz,
CDCl3) δ 7.06 (s, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.44 (d, J = 7.9 Hz,
1H), 4.32 (s, 2H), 3.33 (s, 3H), 3.28 (t, J = 8.1 Hz, 2H), 2.92 (t, J =
8.1 Hz, 2H), 2.74 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
153.3, 130.7, 127.8, 127.4, 124.6, 106.7, 75.1, 57.6, 56.3, 36.3, 28.6.
HRMS (ESI) m/z: (M + H)+ calcd for C11H15NO, 178.1227; found,
178.1227.
N-Benzyl-N-ethyl-4-(tosylmethyl)aniline (5e). Purified by analyt-
ical TLC on silica gel with dichloromethane as an eluent with Rf = 0.5,
1
white solid (21.3 mg, 56%), mp = 71−72 °C. H NMR (600 MHz,
CDCl3) δ 7.51 (d, J = 7.9 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.24−
7.18 (m, 5H), 6.87 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 4.49
(s, 2H), 4.15 (s, 2H), 3.45 (q, J = 7.0 Hz, 2H), 2.39 (s, 3H), 1.19 (t, J
= 7.0 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 148.6, 144.3,
138.8, 135.5, 131.8, 129.4, 128.7, 128.6, 126.9, 126.5, 114.7, 112.0,
62.5, 53.8, 45.3, 21.6, 12.1. HRMS (ESI) m/z: (M + H)+ calcd for
C23H25NO2S, 380.1679; found, 380.1678.
(1-Methylindolin-5-yl)methanol 8. To a 15 mL sealed tube
were added 3a (0.2 mmol, 60.3 mg), NaOH (1.0 mmol, 40 mg), and
then H2O (2 mL). The vessel was sealed with a Teflon-lined cap, and
the reaction mixture was allowed to stir at 100 °C (oil bath) for 12 h.
Then the solvent was extracted by dichloromethane (3 × 5 mL). The
combined organic layers were dried by Na2SO4, filtered through
Celite, and concentrated under reduced pressure. The residue was
purified by preparative TLC on silica gel plates using dichloro-
methane/ethyl acetate = 1/1 as the eluent to give the desired product
1-(4-(Tosylmethyl)phenyl)piperidine (5g). Purified by analytical
TLC on silica gel with dichloromethane as an eluent with Rf = 0.4,
1
white solid (6.9 mg, 21%), mp = 155−156 °C. H NMR (600 MHz,
1
CDCl3) δ 7.52 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 6.94 (d, J
= 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.19 (s, 2H), 3.15 (t, J = 5.3
8 in 44% yield. Rf = 0.4, colorless liquid (14.4 mg, 44%). H NMR
(600 MHz, d6-DMSO) δ 7.00 (s, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.44
7184
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J. Org. Chem. 2021, 86, 7179−7188

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(d, J = 7.9 Hz, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.33 (d, J = 5.5 Hz, 2H),
3.21 (t, J = 8.1 Hz, 2H), 2.84 (t, J = 8.1 Hz, 2H), 2.67 (s, 3H).
13C{1H} NMR (151 MHz, d6-DMSO) δ 152.9, 132.1, 130.3, 126.4,
123.8, 106.9, 63.7, 56.3, 36.6, 28.6. ESI-MS (m/z): (M + H)+ calcd
for C10H13NO, 164.1070; found, 164.1035.
AUTHOR INFORMATION
■
Corresponding Authors
Xin-Qi Hao − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China; orcid.org/0000-
0003-1942-8309; Email: xqhao@zzu.edu.cn
1-Methyl-5-(tosylmethyl)-1H-indole 9. To a solution of 3a (0.1
mmol, 30.1 mg) in CH2Cl2 (10 mL) DEAD (0.11 mmol, 19.2 mg)
was added. The mixture was stirred at the room temperature for 2 h
and then concentrated and purified by preparative TLC on silica gel
plates using dichloromethane as the eluent to give the desired product
9 in 90% yield. Rf = 0.4, white solid (27.0 mg, 90%), mp = 176−177
°C. 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.5 Hz, 2H), 7.32 (s,
1H), 7.20 (d, J = 8.0 Hz, 3H), 7.04 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H),
6.39 (s, 1H), 4.39 (s, 2H), 3.77 (s, 3H), 2.40 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 144.3, 136.7, 135.4, 129.5, 129.4, 128.7, 128.5,
124.1, 123.6, 118.7, 109.2, 101.2, 63.4, 32.9, 21.6. HRMS (ESI) m/z:
(M + H)+ calcd for C17H17NO2S, 300.1053; found, 300.1055.
1-Methyl-3,5-bis(tosylmethyl)-1H-indole 10. To a 15 mL
sealed tube were added 9 (0.1 mmol, 29.9 mg), TosMIC 2a (0.3
mmol, 58.6 mg), and FeCl2·4H2O (0.03 mmol, 6.0 mg) in a mixed
solvent of PEG400 and H2O (2 mL) under an Ar atmosphere. The
reaction mixture was heated at 100 °C for 10 h. After cooling down to
room temperature, the reaction mixture was diluted by H2O (10 mL)
and extracted by dichloromethane (3 × 10 mL). The combined
organic layers were dried by Na2SO4, filtered through Celite, and
concentrated under reduced pressure. The residue was purified by
preparative TLC on silica gel plates using dichloromethane/ethyl
acetate = 20/1 as the eluent to give the desired product 10 in 50%
Mao-Ping Song − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China; orcid.org/0000-
0003-3883-2622; Email: mpsong@zzu.edu.cn
Authors
Yigao Li − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China
Xu-Yan Wang − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China
Xiaohuang Ren − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China
Baoheng Dou − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China
Xinju Zhu − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China; orcid.org/
0000-0003-1966-3480
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00500
Notes
1
yield. Rf = 0.4, white solid (23.5 mg, 50%). mp = 175−176 °C. H
The authors declare no competing financial interest.
NMR (600 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0
Hz, 2H), 7.22 (d, J = 7.9 Hz, 4H), 7.16 (d, J = 8.4 Hz, 1H), 7.01 (d, J
= 8.5 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 4.39 (s, 2H), 4.29 (s, 2H),
3.72 (s, 3H), 2.39 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 144.5, 144.4, 136.7, 135.7, 135.4, 131.1, 129.5, 129.4, 128.6,
128.5, 127.7, 124.7, 121.6, 119.4, 109.5, 101.3, 63.2, 54.1, 33.0, 21.6,
21.5. HRMS (ESI) m/z: (M + Na)+ calcd for C25H25NO4S2,
490.1117; found, 490.1117.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (Grant Nos. 21803059, U1904212, and
U2004191) and the Natural Science Foundation of Henan
Province (202300410477) is gratefully appreciated.
Reaction in the Presence of Radical Scavengers. To a 15 mL
sealed tube were added 1a (0.1 mmol, 13.3 mg), TosMIC derivatives
2 (0.3 mmol, 58.6 mg), and FeCl2·4H2O (0.03 mmol, 6.0 mg) and
radical scavengers (TEMPO, BQ, BHT, 1.0 equiv) in a mixed solvent
of PEG400 and H2O (2 mL) under an Ar atmosphere. The reaction
mixture was heated at 100 °C for 10 h. After cooling down to room
temperature, the reaction mixture was diluted by H2O (10 mL) and
extracted by dichloromethane (3 × 10 mL). The combined organic
layers were dried by Na2SO4, filtered through Celite, and
concentrated under reduced pressure. The residue was purified by
preparative TLC on silica gel plates using dichloromethane as the
eluent to give the corresponding products 3a in 10%, 29%, and 70%
yields, respectively.
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