Transition-Metal-Free Regioselective One-Pot Synthesis of Aryl Sulfones from Sodium Sulfinates via Quinone Imine Ketal

Article abstract of DOI:10.1021/acs.joc.8b02835

A novel, efficient, and regioselective transition-metal-free one-pot synthesis of aryl sulfones via the reactive quinone imine ketal intermediate is demonstrated using easily accessible bench-stable sulfinate salts. A broad range of functionality on p-ani

Full text of DOI:10.1021/acs.joc.8b02835

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Article
Transition-Metal-Free Regioselective One-Pot Synthesis of
Aryl Sulfones from Sodium Sulfinates via Quinone Imine Ketal
Priyanka Halder, Vivek T. Humne, and Santosh B. Mhaske
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 09 Jan 2019
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The Journal of Organic Chemistry
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Transition-Metal-Free Regioselective One-Pot Synthesis of Aryl Sul-
fones from Sodium Sulfinates via Quinone Imine Ketal
Priyanka Halder,†‡ Vivek T. Humne,† and Santosh B. Mhaske†‡*
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†Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune- 411008, India
‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
Supporting Information Placeholder
ABSTRACT: A novel, efficient and regioselective
transition-metal-free one-pot synthesis of aryl sulfones
via the reactive quinone imine ketal intermediate is
demonstrated using easily accessible bench-stable sul-
finate salts. A broad range of functionality on p-
anisidine substrates as well as sulfinate salts was toler-
ated under the mild reaction condition to provide the
corresponding aryl sulfones in good to excellent yields.
INTRODUCTION
ly, Peddinti et al reported catalyst-free sulfonylation of 2-
methoxyphenols via masked o-benzoquinone using sulfonyl
hydrazides at 70 OC.9f Zeng et al developed electrochemical
oxidation of aminophenols in the presence of benzenesul-
finate.9j Previously, Kolesnikov and co-workers reported sul-
fonylation of N-(arylthio)-1,4-benzoquinonimines with ben-
zenesulfininate to obtain various aryl sulfones.9k In 2011,
Maloney and co-workers developed the transition-metal-free
sulfonylation of pyridines using sulfinate salts (Scheme 1, eq.
1).10 In 2014, we reported the method for the synthesis of aryl
sulfones using in situ generated arynes (eq. 2).11 Very recently,
Shao and co-workers reported the difunctionalization of imid-
azo[1,2-a]-pyridine to access sulfones using sulfinate salts (eq.
Organosulfones are recognized as privileged functional groups
having an immense application in agrochemicals,1 pharmaceu-
ticals2 and material chemistry.3 Among them, aryl sulfones are
known to be antifungal,4 antibacterial5 and antitumoral6 agents
as well as the inhibitors of HIV-1 reverse transcriptase.7 Fig-
ure 1 shows selected biologically active molecules featuring
Scheme 1. Selected Transition-Metal-Free approaches to
Aryl Sulfones using Sodium Sulfinates
Figure 1. Bioactive compounds containing sulfone1,2,7
aJ. Agric. Food Chem. 2006, 54, 7724. Copyright [2006] Ameri-
can Chemical Society.
aryl sulfone pharmacophore.1,2,7 In addition to their medicinal
importance, aryl sulfones are also versatile reactive intermedi-
ates in organic synthesis and used in well-known organic
transformations such as the Ramberg−Backlund reaction and
the Julia olefination.8 In the past decades, tremendous efforts
have been devoted to the development of novel methodologies
for the incorporation of sulfone-containing substituents into
organic frameworks.9 Due to their compelling synthetic utility8
and substantial biological1,2,4-7 as well as material applica-
tions,3 the development of facile methods for aryl sulfones has
stimulated considerable interest.
The most common method utilizes the reaction of pre-
functionalized aromatic/heteroaromatic halides and sulfinate
salts in the presence of a transition-metal catalyst.9c,g,i Recent-
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3).12 In addition to these advancements few other transition-
product 3a was obtained in excellent yield (entry 10).
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metal-free methods using sodium sulfinate salts had been de-
veloped for the synthesis of organosulfones,13 but to the best
of our knowledge quinone imine ketal (QIK) has not been
utilized for the synthesis of aryl sulfones.
With the optimized reaction condition (Table 1, entry 10)
in hand, we investigated the substrate scope of this newly de-
veloped protocol by reacting different sulfinate salts 2a-k with
1a (Scheme 2). The optimized condition worked well for a
variety of aryl, alkyl and heteroaryl sulfinate salts. Unsubsti-
tuted as well as alkyl substituted aryl sulfone moiety-
containing compounds 3a, 3b and 3c were formed in excellent
yields. The aryl sulfinate containing an electron withdrawing
substituent furnished the corresponding sulfone 3d in excellent
QIK has emerged as the powerful synthetic intermediate
for the development of novel methodologies14 and total syn-
thesis of natural products.15 Their remarkable electrophilicity
addresses a variety of organic transformation such as cycload-
dition reaction,14h nucleophilic addition reaction,14a,b,d-g multi-
component reaction,14c among others. We hypothesized that
the QIK formed in situ in the reaction mixture could be uti-
lized as a latent sulfone functionalized aromatic ring employ-
ing acid-mediated activation. This design will ultimately en-
rich the chemistry of quinone-related compounds. Herein, we
report the mild and efficient protocol for the synthesis of aryl
sulfones utilizing QIK as a potent intermediate.
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Scheme 2: Synthesis of Sulfones from Various Sodium Sul-
finatesa,b
RESULTS AND DISCUSSION
The optimization of the protocol was achieved by changing
various reaction parameters. Initially, N-tosyl QIK 1a’ gener-
ated in situ from N-tosyl p-anisidine (1a) in methanol was
treated with sulfinate salt (1.1 equiv) and AcOH (10 equiv) at
rt. The expected product 3a was obtained in 32% yield in 12 h
(Table 1, entry 1). To our delight, the yield improved substan-
tially and the reaction time also reduced to 6 h when THF was
used as the solvent for the second step (entry 2). The addition
of less or more equivalents of AcOH resulted into low yields
(entries 3-7). For further improvement in the yield, more
equivalents of sulfinate salt was used, however, the yield did
not improve (entry 8). Hence, the addition sequence of the
second step was modified. The solution of QIK 1a’ and sul-
finate salt 2a in THF was stirred for 1 h followed by the addi-
tion of acetic acid, which resulted in the enhancement of the
yield (entry 9). When 2 equiv of 2a was used, the desired
b
aReaction was performed on 50 mg scale of 1a, Isolated yield,
cReaction carried out at 60 oC.
Table 1: Optimization of Reaction Conditiona
yield under the optimized condition. On the other hand, prob-
ably due to the electron releasing effect of the methoxy group,
aryl sulfinate 2e needed little extra time and temperature than
anticipated to obtain the product 3e in better yield. The halo
substituted sulfinate salt showed similar effect on the reaction
and the desired product 3f was formed in moderate yield. The
polyaromatic sulfinate salt reacted well and conceded the
product 3g in moderate yield. The sulfinate salt having the
heteroaromatic ring also underwent the reaction smoothly to
provide the product 3h in good yield. Overall, the reaction of
sulfinate salts having electron rich aromatic ring (2e-h) was
slower and provided lower yields as compared to the aryl sul-
finate salts having electron neutral/deficient aromatic ring (2a-
d). Pleasingly, aliphatic sulfinate salts also reacted well under
the developed protocol and the corresponding sulfones 3i and
3j were synthesized in excellent yields. Trifluoromethyl sub-
stituted sulfone 3k was synthesized in very good yield under
these conditions.
AcOH
(equiv)
2a
(equiv)
time
(h)
yield
(%)c
entry
solventb
1
2
MeOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
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10
01
02
08
15
20
10
10
10
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.0
1.5
2.0
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03
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03
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97
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9d
10d
After exploring the reactivity pattern of various sulfinate
salts, we further planned to explore the scope of the reaction
using variously substituted p-anisidines (Scheme 3 and 4).
Various N-substituents, as well as O-substituents on p-
anisidines (1b-i) were tested under the developed protocol.
b
aAll the reactions were performed on 20 mg scale of 1a, Sol-
c
d
vent for the second step, Isolated yield, Acetic acid was added
after 1 h to the reaction mixture containing sulfinate salt.
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The in situ formation of QIKs (1b’-f’) from the corresponding
ucts 3x and 3y were formed under the optimized conditions,
but at high temperature exclusively disulfone 3y was formed
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amide and carbamate containing substrates (1b-f) required
addition of triethylamine and more time as compared to the
sulfonamide containing substrates (1g-i). The benzoate pro-
tected p-anisidine 1b provided the product 3l in an excellent
Scheme 4: Synthesis of Sulfones using Various Aryl Ring-
Substituted p-Anisidinesa,b
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Scheme 3: Synthesis of Sulfones from Various N, O-
Substituted p-Anisidinesa,b
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aReaction was performed on 50 mg scale of 1j-m, bIsolated
yield, Reaction at 60 C, Reaction was performed on 100 mg
scale of 1n.
c
o
d
in good yield. The product 3y may be formed by the displace-
ment of iodine group. In general, substituted p-anisidines re-
sulted in inferior yields (Scheme 4) than that of the unsubstit-
ued p-anisidnes (Scheme 2 and 3) because the reaction leads to
more substituted aromatic ring. Furthermore, the presence of
electron rich substituents on p-anisidines (1j, 1k) provided
lower yields (3t, 3u) due to less electrophilic QIK intermedi-
ates, whereas p-anisidines having electron withdrawing sub-
stituents (1l, 1m and 1n) provided better yields (3v, 3w and
3x,y) because of the more electrophilic QIK intermeidates.
b
aReaction was performed on 50 mg scale of 1b,d-i, Isolated
yield, cTriethylamine (3 eqiv) was used for the preparation of QIK
1b’-f’, dReaction was performed on 100 mg scale of 1c, eReaction
carried out at 60 oC.
yield. Whereas, pivaloyl protected p-anisidine 1c furnished
sulfone 3m in low yield. It can be reasoned that the steric hin-
drance of the bulkier pivaloyl moiety present in the close prox-
imity of the amide nitrogen resists the reaction with PIDA. the
The carbamate group-containing substrates 1d, 1e, and 1f pro-
vided the desired products 3n, 3o, and 3p respectively in very
good yields. Various sulfonamide containing sulfones 3q and
3r were synthesized in excellent yields. The scope of the pro-
tocol was also tested using ethoxy substituted sulfonamide
substrate 1i and the expected product 3s was formed in a mod-
erate yield under the optimized protocol. The steric hindrance
of the ethyl group might be inhibiting the nucleophilic attack
of the sulfinate salt at rt. However, the yield of 3s was signifi-
cantly increased to 93% by elevating the reaction temperature.
The regioselectivity of the interesting protocol was con-
firmed by the 2D NMR analysis of the substrates 3a, 3v, 3x
and 3y. The scalability of the reaction was also investigated.
We performed the reaction of 1a on 1 mmol scale, and the
expected product 3a was obtained in 88% yield.
The scope of the reaction using various substituents on the
aryl ring of p-anisidines was also studied (Scheme 4). It has
been observed that higher temperature was necessary for the
reaction with methyl substituted p-anisidine to obtain the sul-
fone 3t in moderate yield. Unfortunately, electron donating
substituents on p-anisidine did not afford the sulfone 3u under
the developed protocol. Hence, we isolated the corresponding
QIK 1k’ and performed the next reaction, but the product 3u
was formed in only trace amount. We were unable to isolate
sufficient quantity of the product 3u by usual flash column
chromatography, but HRMS analysis showed the product for-
mation. Electron withdrawing group on p-anisidine moiety
was well tolerated and the product 3v was obtained in very
good yield at little higher temperature. The phenyl substituted
compound 3w was formed in a good yield. Interestingly, from
the substrate 1n containing iodine group, two different prod-
Figure 2. Plausible Reaction Mechanism
A plausible mechanism of the reaction based on the above
observations and literature report16 is depicted in Figure 2.
First, the QIK was formed in the presence of PIDA by the
usual mechanism.17 Phenyl sulfinate attacks QIK to form the
intermediate [A] by Michael addition. The rearomatization
occurs by the removal of methanol in the presence of acetic
acid to get the desired sulfone product.
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stirred at 0 °C for 1 h and gradually warmed to rt. After com-
Page 4 of 8
CONCLUSION
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plete consumption of 1b-f, MeOH was evaporated on a rotato-
ry evaporator and the residue was dissolved in THF (0.1 M).
To the resulting solution was added sulfinate salt 2a (2 equiv)
and the reaction mixture was stirred for 1 h at room tempera-
ture followed by the addition of AcOH (10 equiv). After being
stirred for 4-6 h at room temperature, THF was evaporated on
a rotatory evaporator and the residue was purified by flash
silica gel column chromatography using a gradient of ethyl
acetate-petroleum ether to afford the corresponding sulfones
3l-p in good to excellent yields.
In conclusion, a convenient one-pot transition-metal-free pro-
tocol has been developed for the preparation of aryl sulfones
regioselectively via the formation of QIKs in good to excellent
yields. This developed protocol is operationally simple, high
yielding and does not require excess reagent and additives.
Various types of sulfones such as diaryl sulfones, aryl-alkyl
sulfones, and aryl-heteroaryl sulfones can be prepared easily
by following this method. We are in the process of applying
this method for the synthesis of bioactive molecules, natural
products, drugs, and drug intermediates.
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C] Synthesis of Sulfones 3q-y:
EXPERIMENTAL SECTION
To a solution of N-substituted p-anisidine 1g-n (50 mg, 1
equiv) in methanol (0.12 M) was added PIDA (1.1 equiv) at 0
General Considerations. All reagents and solvents were used
as received from commercial sources unless and otherwise
noted. All experiments were carried out in a round bottom
flask equipped with a stirring bar. Aluminium plates precoated
with silica gel 60 PF254, 0.25 mm or 0.5 mm, were utilized
for thin-layer chromatography (TLC) to monitor the progress
of a reaction. Visualization of the developed TLC plate was
performed by irradiation with UV light. Column chromato-
graphic purifications were carried out on flash silica gel
(240−400 mesh) using ethyl acetate and petroleum ether as
oC. The resulting mixture was stirred at 0 C and the reaction
o
progress was monitored by TLC (approx. 5 min). After com-
plete consumption of 1g-n, MeOH was evaporated on a rotato-
ry evaporator and the residue was dissolved in THF (0.1 M).
To this solution was added sulfinate salt 2a (2 equiv) and the
reaction mixture was stirred for 1 h at room temperature fol-
lowed by the addition of AcOH (10 equiv). After stirring for
4-18 h at room temperature, THF was evaporated in vacuo and
the residue was purified by flash silica gel column chromatog-
raphy using a gradient of ethyl acetate-petroleum ether to af-
ford the corresponding sulfones 3q-y in good to excellent
yields.
1
eluents. The H and 13C{1H} NMR spectra were recorded on
200/400/500 MHz and 100/125 MHz NMR spectrometers
respectively, in CDCl3 or DMSO-d6. Chemical shifts were
reported as δ values from standard peaks. The melting points
were recorded on a Buchi instrument, and are uncorrected.
High-resolution mass spectrometry (HRMS) was performed
on a TOF/Q-TOF mass spectrometer. All the N-substituted p-
anisidines were prepared using known literature procedures.14f,
II] Typical Experimental Procedure for the Preparation of
3a on 0.18 mmol scale:
To a solution of 1a (50 mg, 1 equiv) in methanol (1.5 mL,
0.12 M) was added PIDA (64 mg, 1.1 equiv) at 0 C. The re-
sulting mixture was stirred at 0 C and the reaction progress
o
o
18
The quinone imine ketals were prepared in situ as per the
was monitored by TLC (approx. 5 min). After complete con-
sumption of 1a, MeOH was evaporated on a rotatory evapora-
tor and the residue was dissolved in THF (1.8 mL, 0.1 M). To
this solution was added 2a (59 mg, 2 equiv) and the reaction
mixture was stirred for 1 h at room temperature followed by
the addition of AcOH (108 μL, 10 equiv). After stirring for 3 h
at room temperature, THF was evaporated in vacuo and the
residue was purified by flash silica gel column chromatog-
raphy using a gradient of ethyl acetate-petroleum ether (2:3) to
afford the sulfone 3a in 97% yield (73 mg).
literature procedures.14f,
Sodium sulfinates 2a, 2i and 2k
17a
were purchased from commercial sources and rest of the sodi-
um sulfinates were prepared using known literature proce-
dures.13e, 19
Experimental Procedures:
I] General Experimental Procedure for the Synthesis of
Sulfones:
A] Synthesis of Sulfones 3a-k:
To a solution of tosylated p-anisidine 1a (50 mg, 1 equiv) in
III] Experimental Procedure for the Preparation of 3a on 1
mmol scale:
methanol (0.12 M) was added (diacetoxyiodo)benzene (PIDA,
o
64 mg, 1.1 equiv) at 0 C. The resulting mixture was stirred at
0 oC and the reaction progress was monitored by TLC (approx.
5 min). After complete consumption of 1a, MeOH was evapo-
rated on a rotatory evaporator and the residue was dissolved in
THF (0.1 M). To this solution was added the corresponding
sulfinate salt 2a-k (2 equiv) and the reaction mixture was
stirred for 1 h at room temperature followed by the addition of
AcOH (10 equiv). After stirring for 3-15 h at room tempera-
ture, THF was evaporated in vacuo and the residue was puri-
fied by flash silica gel column chromatography using a gradi-
ent of ethyl acetate-petroleum ether to afford the correspond-
ing sulfones 3a-k in good to excellent yields.
To a solution of 1a (277 mg, 1 mmol) in methanol (8.3 mL,
0.12 M) was added PIDA (354 mg, 1.1 mmol) at 0 C. The
resulting mixture was stirred at 0 C and the reaction progress
o
o
was monitored by TLC (approx. 5 min). After complete con-
sumption of 1a, MeOH was evaporated on a rotatory evapora-
tor and the residue was dissolved in THF (10 mL, 0.1 M). To
this solution was added 2a (328 mg, 2 mmol) and the reaction
mixture was stirred for 1 h at room temperature followed by
the addition of AcOH (600 μL, 10 mmol). After stirring for 3 h
at room temperature, THF was evaporated in vacuo and the
residue was purified by flash silica gel column chromatog-
raphy using a gradient of ethyl acetate-petroleum ether (2:3) to
afford the sulfone 3a in 88% yield (367 mg).
B] Synthesis of Sulfones 3l-p:
To a solution of N-substituted p-anisidine 1b-f (50 mg, 1
equiv) and NEt3 (3 equiv) in MeOH (0.34 M), a solution of
PIDA (2 equiv) in MeOH (0.34 M) was added dropwise at 0
°C under an argon atmosphere. The reaction mixture was
N-(4-Methoxy-3-(phenylsulfonyl)phenyl)-4-
methylbenzenesulfonamide (3a). Obtained as an off white sol-
id, (73 mg, 97% yield); Mp = 190-192 oC; Reaction time: 3 h;
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1
Rf: 0.5 (2:3 EtOAc:Pet. Ether); H NMR (400 MHz, DMSO-
d6) δ 10.21 (s, 1H), 7.76-7.66 (m, 4H), 7.59 (d, J = 7.9 Hz,
4H), 7.41-7.30 (m, 3H), 7.06 (d, J = 9.2 Hz, 1H), 3.64 (s, 3H),
2.37 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 153.6,
143.4, 140.5, 136.0, 133.5, 130.4, 129.7, 129.2, 129.0, 128.2,
127.7, 126.8, 121.9, 114.4, 56.2, 20.9; HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C20H19NO5S2Na 440.0597, found
440.0594.
6.90 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 3.77 (s, 3H), 2.45 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ 154.9, 144.2, 139.9,
139.2, 135.6, 131.1, 129.9, 129.8, 129.4, 128.9, 128.8, 127.3,
124.5, 113.4, 56.2, 21.6; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C20H19ClNO5S2 452.0388, found 452.0383.
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N-(4-Methoxy-3-(naphthalen-2-ylsulfonyl)phenyl)-4-
methylbenzenesulfonamide (3g). Obtained as a white solid, (46
o
mg, 55% yield); Mp = 168-170 C; Reaction time: 5 h; Rf:
1
N-(4-Methoxy-3-tosylphenyl)-4-methylbenzenesulfonamide
(3b). Obtained as a white solid, (76 mg, 98% yield); Mp =
191-193 oC; Reaction time: 5 h; Rf: 0.7 (2:3 EtOAc:Pet.
0.5 (2:3 EtOAc:Pet. Ether); H NMR (400 MHz, CDCl3) δ
8.55 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 6.1 Hz, 2H),
7.81-7.74 ( m, 2H), 7.71-7.60 (m, 4H), 7.52 (dd, J = 9.2 and
3.1 Hz, 1H), 7.27 ( t, J = 8.2 Hz, 2H), 7.14 (s, 1H), 6.82 (d, J =
8.5 Hz, 1H), 3.71 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 154.9, 144.1, 137.6, 135.5, 135.0, 131.9,
130.8, 130.2, 129.7, 129.4, 129.3, 129.1, 129.0, 128.6, 127.8,
127.4, 127.3, 124.5, 123.2, 113.4, 56.2, 21.6; HRMS (ESI-
TOF) m/z: [M+Na]+ calcd for C24H21NO5S2Na: 490.0753,
found: 490.0751.
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Ether); H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.9 Hz,
2H), 7.63-7.55 (m, 3H), 7.51 (dd, J = 8.6 and 2.4 Hz, 1H),
7.31-7.23 (m, 4H), 6.84 (d, J = 9.2 Hz, 1H), 6.71 (s, 1H), 3.74
(s, 3H), 2.43 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
155.0, 144.2 (2C), 137.8, 135.5, 131.0, 129.8, 129.5, 129.2
(2C), 128.5, 127.3, 124.6, 113.4, 56.2, 21.6; HRMS (ESI-
TOF) m/z: [M+Na]+ calcd for C21H21NO5S2Na 454.0753,
found 454.0751.
N-(3-((5-Bromothiophen-2-yl)sulfonyl)-4-methoxyphenyl)-4-
methylbenzenesulfonamide (3h). Obtained as an off white sol-
id, (59 mg, 65% yield); Mp = 177-179 oC; Reaction time: 5 h;
N-(3-((4-(tert-Butyl)phenyl)sulfonyl)-4-methoxyphenyl)-4-
methylbenzenesulfonamide (3c). Obtained as a white solid,
o
1
(77 mg, 90% yield); Mp = 176-178 C; Reaction time: 4 h;
Rf: 0.5 (1:1 EtOAc:Pet. Ether); H NMR (400 MHz, CDCl3)
1
Rf: 0.6 (2:3 EtOAc:Pet. Ether); H NMR (400 MHz, CDCl3)
δ 7.61-7.51 (m, 4H), 7.46 (s, 1H), 7.26 (d, J = 7.9 Hz, 2H),
7.05 (s, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 3.92 (s,
3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.1,
144.3, 142.5, 135.4, 134.5, 131.4, 130.2, 129.9, 129.4, 129.1,
127.3, 124.3, 122.0, 113.5, 56.3, 21.6; HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C18H1681BrNO5S3Na 525.9246, found
525.9241.
δ 7.77 (d, J = 8.6 Hz, 2H), 7.64-7.57 (m, 3H), 7.53-7.45 (m,
3H), 7.25 (d, J = 8.5 Hz, 2H), 6.87 (s, 1H), 6.84 (d, J = 9.2 Hz,
1H), 3.76 (s, 3H), 2.42 (s, 3H), 1.33 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3) δ 157.1, 155.0, 144.1, 137.7, 135.5, 130.8,
129.8, 129.4, 129.2, 128.3, 127.3, 125.5, 124.6, 113.4, 56.2,
35.2, 31.0, 21.6; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C24H27NO5S2Na 496.1223, found 496.1222.
N-(4-Methoxy-3-(methylsulfonyl)phenyl)-4-
N-(4-Methoxy-3-((4-nitrophenyl)sulfonyl)phenyl)-4-
methylbenzenesulfonamide (3i). Obtained as a white solid, (58
mg, 91% yield); Mp = 206-208 C; Reaction time: 4 h; Rf:
o
methylbenzenesulfonamide (3d). Obtained as a pale yellow
solid, (74 mg, 89% yield); Mp = 171-173 C; Reaction time:
0.5 (1:1 EtOAc:Pet. Ether); 1H NMR (400 MHz, DMSO-d6) δ
10.24 (s, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 2.4 Hz,
1H), 7.37-7.32 (m, 3H), 7.19 (d, J = 8.5 Hz, 1H), 3.86 (s, 3H),
3.18 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 153.6, 143.4, 136.2, 130.4, 129.8, 128.5, 128.0, 126.7,
121.3, 114.1, 56.5, 42.5, 21.0; HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C15H17NO5S2Na 378.0440, found
378.0439.
o
1
6 h; Rf: 0.5 (2:3 EtOAc:Pet. Ether); H NMR (400 MHz,
CDCl3) δ 8.32 (d, J = 6.7 Hz, 2H), 8.05 (d, J = 7.3 Hz, 2H),
7.72 (s, 1H), 7.65 (d, J = 7.3 Hz, 2H), 7.52 (d, J = 8.6 Hz, 1H),
7.28 (d, J = 6.1 Hz, 2H), 7.19 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H),
3.76 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 154.8, 150.4, 146.4, 144.4, 135.4, 131.4, 129.8, 129.7 (2C),
127.6, 127.3, 124.4, 123.8, 113.5, 56.3, 21.6; HRMS (ESI-
TOF) m/z: [M+Na]+ calcd for C20H18N2O7S2Na 485.0448,
found 485.0445.
N-(3-(Butylsulfonyl)-4-methoxyphenyl)-4-
methylbenzenesulfonamide (3j). Obtained as a white solid, (69
o
N-(4-Methoxy-3-((4-methoxyphenyl)sulfonyl)phenyl)-4-
mg, 97% yield); Mp = 134-136 C; Reaction time: 5 h; Rf:
1
methylbenzenesulfonamide (3e). Obtained as a white solid, (58
0.5 (2:3 EtOAc:Pet. Ether); H NMR (400 MHz, CDCl3) δ
o
o
mg, 72% yield (at 60 C); Mp = 178-180 C; Reaction time:
7.65-7.57 (m, 3H), 7.43 (d, J = 3.1 Hz, 1H), 7.22 (d, J = 7.9
Hz, 2H), 7.03 (s, 1H), 6.98 (d, J = 8.5 Hz, 1H), 3.94 (s, 3H),
3.29 (t, J = 7.9 Hz, 2H), 2.38 (s, 3H), 1.54 (m, 2H), 1.37 (m,
2H), 0.88 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 155.0, 144.1, 135.6, 130.3, 129.8, 129.7, 127.3,
127.0, 124.8, 113.3, 56.6, 53.9, 24.4, 21.5, 21.4, 13.5; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C18H24NO5S2 398.1090,
found 398.1085.
1
15 h; Rf: 0.4 (1:1 EtOAc:Pet. Ether); H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 8.5 Hz, 2H), 7.64-7.56 (m, 3H), 7.50
(dd, J = 8.5 and 2.4 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H), 6.94 (d,
J = 8.5 Hz, 2H), 6.83 (d, J = 8.6 Hz, 1H), 6.75 (s, 1H), 3.87 (s,
3H), 3.76 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 163.4, 154.9, 144.1, 135.6, 132.3, 130.7 (2C), 129.9,
129.8, 129.2, 127.3, 124.4, 113.7, 113.4, 56.2, 55.6, 21.6;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H21NO6S2Na
470.0702, found 470.0699.
N-(4-Methoxy-3-((trifluoromethyl)sulfonyl)phenyl)-4-
methylbenzenesulfonamide (3k). Obtained as a white solid, (55
o
N-(3-((4-Chlorophenyl)sulfonyl)-4-methoxyphenyl)-4-
mg, 75% yield); Mp = 112-114 C; Reaction time: 5 h; Rf:
1
methylbenzenesulfonamide (3f). Obtained as a white solid, (49
0.5 (2:3 EtOAc:Pet. Ether); H NMR (400 MHz, CDCl3) δ
o
mg, 60% yield); Mp = 186-188 C; Reaction time: 7 h; Rf:
8.61 (s, 1H), 7.87 (d, J = 9.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H),
7.28 (m, 4H), 3.81 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 155.7, 144.8, 135.6, 133.1, 129.9, 127.4,
125.6, 122.3, 119.6 (q, J = 326.0 Hz, CF3), 117.4, 115.7, 56.0,
1
0.4 (2:3 EtOAc:Pet. Ether); H NMR (500 MHz, CDCl3) δ
7.81 (d, J = 8.8 Hz, 2H), 7.66-7.61 (m, 3H), 7.54 (dd, J = 8.8
and 2.3 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.32-7.25 (m, 2H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
21.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
Page 6 of 8
7.62 (m, 7H), 7.61-7.52 (m, 4H), 7.35 (dd, J = 8.5 and 1.8 Hz,
1H), 7.06 (d, J = 9.2 Hz, 1H), 3.64 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 153.8, 140.5, 138.8, 133.6, 133.1,
130.2, 129.6, 129.3, 129.0, 128.3, 127.8, 126.8, 122.3, 114.4,
56.2; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H18NO5S2
404.0621, found 404.0616.
1
2
3
4
5
6
7
8
C15H15F3NO5S2 410.0338, found 410.0334.
N-(4-Methoxy-3-(phenylsulfonyl)phenyl)benzamide (3l). Ob-
tained as a white solid, (78 mg, 96% yield); Mp = 176-178 oC;
1
Reaction time: 5 h; Rf: 0.5 (2:3 EtOAc:Pet. Ether); H NMR
(400 MHz, CDCl3) δ 8.85 (s, 1H), 8.37 (dd, J = 8.5 and 1.8
Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 7.9 Hz, 2H),
7.87 (d, J = 7.3 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.50-7.40
(m, 3H), 7.31 (t, J = 7.6 Hz, 2H), 6.91 (d, J = 9.2 Hz, 1H),
3.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (one aro-
matic carbon overlaps): 166.1, 153.4, 140.9, 134.2, 133.1,
131.8, 131.7, 128.5, 128.5, 128.4, 128.3, 127.2, 121.7, 113.2,
56.2; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H18NO4S
368.0951, found 368.0946.
N-(4-Methoxy-3-(phenylsulfonyl)phenyl)-4-
nitrobenzenesulfonamide (3r). Obtained as a pale yellow solid,
(69 mg, 95% yield); Mp = 183-185 C; Reaction time: 5 h;
Rf: 0.5 (1:1 EtOAc:Pet. Ether); H NMR (400 MHz, DMSO-
d6) δ 10.64 (s, 1H), 8.41 (d, J = 9.2 Hz, 2H), 7.95 (d, J = 8.4
Hz, 2H), 7.75 (d, J = 6.9 Hz, 2H), 7.72-7.63 (m, 2H), 7.56 (t,
J = 7.6 Hz, 2H), 7.37 (dd, J = 9.2 and 3.1 Hz, 1H), 7.10 (d, J =
9.2 Hz, 1H), 3.66 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 154.2, 150.0, 144.2, 140.4, 133.7, 130.0, 129.4, 129.0,
128.5, 128.4, 127.9, 124.7, 122.7, 114.6, 56.3; HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C19H17N2O7S2 449.0472, found
449.0466.
o
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(4-Methoxy-3-(phenylsulfonyl)phenyl)pivalamide
(3m).
Obtained as a white solid, (28 mg, 17% yield); Mp = 129-131
1
oC; Reaction time: 5 h; Rf: 0.6 (2:3 EtOAc:Pet. Ether); H
NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 8.3 and 2.3 Hz, 1H),
8.00 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 7.5 Hz, 2H), 7.65 (s, 1H),
7.57 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 6.87 (d, J =
9.0 Hz, 1H), 3.72 (s, 3H), 1.30 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 177.0, 153.5, 141.1, 133.1, 131.4, 128.6,
128.5, 128.3, 128.2, 121.7, 113.2, 56.2, 39.5, 27.5; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C18H22NO4S 348.1264,
found 348.1260.
N-(4-Ethoxy-3-(phenylsulfonyl)phenyl)-4-
methylbenzenesulfonamide (3s). Obtained as a white solid, [33
o
mg, 45% yield (at rt); 69 mg, 93% yield (at 60 C)]; Mp =
168-170 oC; Reaction time: 5 h; Rf: 0.5 (2:3 EtOAc:Pet.
1
Ether); H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.3 Hz,
2H), 7.66-7.56 (m, 4H), 7.53-7.43 (m, 3H), 7.25 (d, J = 7.9
Hz, 2H), 6.94 (s, 1H), 6.80 (d, J = 9.2 Hz, 1H), 3.94 (q, J = 7.3
Hz, 2H), 2.42 (s, 3H), 1.28 (t, J = 7.3 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 154.4, 144.1, 140.8, 135.5, 133.1, 131.1,
129.7, 129.0, 128.8, 128.6, 128.4, 127.3, 124.6, 113.9, 65.0,
21.6, 14.2; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C21H22NO5S2 432.0934, found 432.0928.
Ethyl (4-methoxy-3-(phenylsulfonyl)phenyl)carbamate (3n).
Obtained as a white solid, (84 mg, 98% yield); Mp = 141-143
1
oC; Reaction time: 6 h; Rf: 0.4 (2:3 EtOAc:Pet. Ether); H
NMR (400 MHz, CDCl3) δ 7.98-7.95 (m, 3H), 7.84 (bs, 1H),
7.60-7.55 (m, 1H), 7.51-7.45 (m, 2H), 6.93 (s, 1H), 6.87 (d, J
= 9.2 Hz, 1H), 4.22 (q, J = 7.6 Hz, 2H), 3.72 (s, 3H), 1.29 (t, J
= 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.9,
153.0, 141.1, 133.0, 131.3, 128.9, 128.5, 128.4, 126.4, 120.5,
113.4, 61.4, 56.2, 14.5; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C16H18NO5S 336.0900, found 336.0897.
N-(4-Methoxy-3-methyl-5-(phenylsulfonyl)phenyl)-4-
methylbenzenesulfonamide (3t). Obtained as a white solid, [31
o
o
mg, 42% yield (at 60 C)]; Mp = 169-171 C; Reaction time:
1
18 h; Rf: 0.6 (2:3 EtOAc:Pet. Ether); H NMR (400 MHz,
CDCl3) δ 7.83 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H),
7.58 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 3.1 Hz, 1H), 7.47 (t, J =
8.1 Hz, 2H), 7.35 (d, J = 2.3 Hz, 1H), 7.26 (d, J = 8.4 Hz, 3H),
3.78 (s, 3H), 2.42 (s, 3H), 2.20 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 153.8, 144.2, 141.2, 135.7, 135.1, 134.9,
133.2, 132.5, 130.7, 129.8, 128.7, 127.9, 127.3, 120.2, 61.8,
21.6, 16.2; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C21H21NO5S2Na 454.0753, found 454.0754.
tert-Butyl
(4-methoxy-3-(phenylsulfonyl)phenyl)carbamate
(3o). Obtained as a white solid, (69 mg, 85% yield); Mp =
182-184 oC; Reaction time: 5 h; Rf: 0.6 (2:3 EtOAc:Pet.
1
Ether); H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.3 Hz,
3H), 7.81 (bs, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.6 Hz,
2H), 6.85 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 3.71 (s, 3H), 1.51
(s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.9, 152.8,
141.3, 133.0, 131.8, 129.1, 128.5, 128.4, 126.2, 120.5, 113.4,
80.9, 56.2, 28.3; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C18H21NO5SNa 386.1033, found 386.1031.
N-(3,4-Dimethoxy-5-(phenylsulfonyl)phenyl)-4-
methylbenzenesulfonamide (3u). HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C21H21NO6S2Na 470.0702, found 470.0697.
Benzyl (4-methoxy-3-(phenylsulfonyl)phenyl)carbamate (3p).
Methyl
2-methoxy-5-(4-methylphenylsulfonamido)-3-
Obtained as a white solid, (73 mg, 95% yield); Mp = 170-172
(phenylsulfonyl)benzoate (3v). Obtained as a white solid, [58
1
o
o
oC; Reaction time: 5 h; Rf: 0.6 (2:3 EtOAc:Pet. Ether); H
mg, 82% yield (at 60 C)]; Mp = 172-174 C; Reaction time:
5 h; Rf: 0.4 (1:49 Acetone:DCM); 1H NMR (400 MHz,
CDCl3) δ 7.96 (s, 2H), 7.84 (d, J = 7.6 Hz, 2H), 7.70 (d, J =
8.4 Hz, 2H), 7.62-7.55 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.26
(d, J = 7.6 Hz, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.41 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 155.5, 144.5,
140.6, 136.9, 135.4, 133.6, 132.6, 130.1, 129.9, 128.9, 128.1,
127.4, 126.6, 125.9, 64.1, 52.8, 21.6; HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C22H21NO7S2Na 498.0652, found 498.0655.
NMR (400 MHz, CDCl3) δ 8.00-7.91 (m, 3H), 7.85 (bs, 1H),
7.57 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.41-7.29 (m,
5H), 7.00 (s, 1H), 6.86 (d, 9.2 Hz, 1H), 5.20 (s, 2H), 3.72 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.6, 153.1, 141.0,
135.9, 133.0, 131.1, 129.0, 128.6, 128.5, 128.4, 128.3, 128.2,
126.4, 120.6, 113.4, 67.1, 56.2; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C21H20NO5S 398.1057, found 398.1053.
N-(4-Methoxy-3-(phenylsulfonyl)phenyl)benzenesulfonamide
(3q). Obtained as a white solid, (74 mg, 97% yield); Mp =
173-175 oC; Reaction time: 4 h; Rf: 0.5 (2:3 EtOAc:Pet.
Ether); 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.72-
N-(6-Methoxy-5-(phenylsulfonyl)-[1,1'-biphenyl]-3-yl)-4-
methylbenzenesulfonamide (3w). Obtained as a white solid,
o
(50 mg, 72% yield); Mp = 128-130 C; Reaction time: 10 h;
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The Journal of Organic Chemistry
Rf: 0.4 (2:3 EtOAc:Pet. Ether); 1H NMR (400 MHz, CDCl3) δ
Notes
1
2
3
4
5
6
7
8
The authors declare no competing financial interest
7.82 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 3H), 7.52 (t, J =
7.3 Hz, 1H), 7.44-7.39 (m, 3H), 7.28 (s, 6H), 7.19 (d, J = 8.4
Hz, 2H), 3.09 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 152.9, 144.3, 141.2, 137.4, 136.0, 135.7, 135.6,
133.3, 132.6, 130.3, 129.8, 128.8, 128.6, 128.6, 128.3, 128.1,
127.4, 121.2, 61.2, 21.6; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C26H24NO5S2 494.1090, found 494.1085.
ACKNOWLEDGMENTS
P.H. thanks CSIR-New Delhi for the research fellowship. S.B.M.
gratefully acknowledges generous financial support from DST-
SERB, New Delhi.
N-(3-Iodo-4-methoxy-5-(phenylsulfonyl)phenyl)-4-
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9
o
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mg, 23% yield); Mp = 185-187 C; Reaction time: 12 h; Rf:
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1
0.4 (1:4 EtOAc:Pet. Ether); H NMR (500 MHz, CDCl3) δ
7.89 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 7.3 Hz, 2H), 7.73-7.68
(m, 3H), 7.60 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.36
(s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 3.94 (s, 3H), 2.43 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 154.8, 144.6, 140.5,
137.6, 136.0, 135.5, 134.2, 133.7, 130.0, 128.9, 128.1, 127.4,
122.4, 93.7, 63.1, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C20H19INO5S2 543.9744, found 543.9751.
N-(4-Methoxy-3,5-bis(phenylsulfonyl)phenyl)-4-
methylbenzenesulfonamide (3y). Obtained as a white solid (73
o
mg, 53% yield (at rt); 59 mg, 85% yield (at 60 C from 50 mg
o
1n)); Mp = 223-225 C; Reaction time: 12 h; Rf: 0.2 (1:4
1
EtOAc:Pet. Ether); H NMR (500 MHz, DMSO-d6) δ 10.98
(s, 1H), 7.98 (s, 2H), 7.64 (t, J = 7.6 Hz, 4H), 7.57 (d, J = 8.0
Hz, 4H), 7.47 (t, J = 7.6 Hz, 4H), 7.40 (d, J = 8.0 Hz, 2H),
3.89 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-
d6) δ 151.5, 144.2, 139.8, 137.7, 135.4, 135.0, 134.1, 130.0,
129.2, 127.1, 126.8, 125.4, 66.6, 21.0; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C26H24NO7S3 558.0709, found 558.0707.
4-Methyl-N-(3,4,4-trimethoxycyclohexa-2,5-dien-1-
ylidene)benzenesulfonamide (1k’)20. Obtained as a pale yellow
solid (54 mg, 98% yield) as a mixture of trans and cis-isomer
in 1.8:1 ratio; Mp = 115-117 oC; Reaction time: 5 min; Rf: 0.3
1
(2:3 EtOAc:Pet. Ether); H NMR (200 MHz, DMSO-d6) δ
7.81 (d, J = 7.83 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2.4H), 6.91 (d, J
= 10.5 Hz, 0.4H), 6.81 (d, J = 10.1 Hz, 0.6H), 6.63 (s, 0.6H),
6.37 (dd, J = 8.8 and 1.4 Hz, 0.6 H), 5.78 (s, 0.3H), 3.86 (s,
1.9H), 3.81 (s, 1H), 3.21 ( s, 6H), 2.4 (s, 3H); HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C16H20NO5S 338.1057, found
338.1055.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
NMR spectra and HRMS chromatograph of all new compounds
(PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: sb.mhaske@ncl.res.in
ORCID
Santosh B. Mhaske: 0000-0002-5859-0838
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