Oxidative Radical-Mediated Addition of Ethers to Quinone Imine Ketals: An Access to Hemiaminals

Article abstract of DOI:10.1021/acs.joc.0c02254

The highly regioselective synthesis of substituted hemiaminal via addition of ethers to quinone imine ketals (QIKs) has been developed under metal-free conditions. In the presence of tetrabutylammonium chloride and potassium persulfate (K2S2O8), QIKs coup

Full text of DOI:10.1021/acs.joc.0c02254

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Article
Oxidative Radical-Mediated Addition of Ethers to Quinone Imine
Ketals: An Access to Hemiaminals
Satish G. More,§ Rohit B. Kamble,§ and Gurunath Suryavanshi*
Cite This: J. Org. Chem. 2021, 86, 2107−2116
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ABSTRACT: The highly regioselective synthesis of substituted hemiaminal via addition of ethers to quinone imine ketals (QIKs)
has been developed under metal-free conditions. In the presence of tetrabutylammonium chloride and potassium persulfate
(K2S2O8), QIKs couple efficiently with cyclic and acyclic ethers to give hemiaminals. This strategy offers an easy access to
substituted hemiaminal ethers with high functional group tolerance in good to excellent yields.
INTRODUCTION
■
The construction of C−N bonds has been a major research
topic in organic synthesis. Nitrogen-containing frameworks are
the backbone of around 25% biologically active compounds
and synthetic intermediates. Among the various compounds
containing C−N bonds having the hemiaminal moiety
represents the core structure in many biologically active
natural products and pharmaceutical agents.1 The typical
example that includes Aspidophylline A, an alkaloid from the
Apocynaceae family, displays an antiviral activity.2a,b However,
(−)-physovenine shows anti-cholinergic and miotic activities,2c
while the indole nitrogen-bearing tetrahydrofuran (THF) ring
acts as an HCV inhibitor, as shown in Figure 1.2d In particular,
hemiaminal ether with sulfonamide as the core structure shows
an interesting antitumor activity against the MGC-803 cell line
with an IC50 value 1.06.2e Also, the substituted N-sulfonamides
Figure 1. Biologically active cyclic ethers.
were present in a large number of bioactive molecules.2f
Furthermore, hemiaminal ethers act as key synthons for
these are greener and more eco-friendly approaches over
various organic transformations and also in the synthesis of
metal-catalyzed reactions. Despite the various methods
natural products.3,4 Due to the increasing importance of
available for the synthesis of hemiaminals, use of costly
hemiaminals in medicinal and synthetic chemistry, various
transition metals and hazardous byproducts formed in these
efforts have been made for the development of new methods
reactions makes our approach more feasible.
thereof. Initially, most of the synthetic endeavors to assemble
this bioactive core using Pd-mediated reactions.5 In recent
years, there was immense progress made using various metal
Received: September 18, 2020
Published: January 25, 2021
catalysts such as Cu, Co, Mn, Ru, Ni, and Fe utilized for the
synthesis of hemiaminals from diversified N-heterocycles.6,7
The limited methods were known for the synthesis of
hemiaminals under metal-free conditions. Therefore, these
metal-free reactions attract much attention of chemists8a−i as
https://dx.doi.org/10.1021/acs.joc.0c02254
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Scheme 1. Utilization of QIK
Recently, quinone imine ketals (QIKs) have emerged
extensively as an electrophilic center for a variety of
nucleophilic addition reactions, hence making a fascinating
target for such addition reactions.9 In 2001, Banfield and Kerr
developed [4 + 2] Diels−Alder reaction of QIKs and diene,10a
which leads to the formation of the ergot skeleton. In
continuation, Zhang and co-workers in 2014 achieved Lewis
acid-catalyzed [3 + 2] cycloaddition reaction of 3-methyl-1-
indole with QIK.10b Further, in 2014, Shi et al. demonstrated
an oxidative rearrangement of QIK with styrenes to accomplish
the oxyarylation products.10c Recently, Mhaske and co-workers
achieved C−S bond formation via nucleophilic addition of
phenyl sodium sulfinate salts on QIK as depicted in Scheme
1.10d
QIK as well as related cyclohexadienone motifs served as a
useful synthetic intermediate to establish the functionalized
aromatic rings as being a highly reactive key synthon and an
important intermediate in various reactions.11 In addition to
these advancements, our continuous efforts toward generation
and utilization of the α-oxyalkyl radical12 under metal-free
conditions have encouraged us to synthesize hemiaminals from
QIK. To the best of our knowledge, herein, for the first time,
we demonstrate an efficient radical-mediated C−N bond
formation via addition of ethers on QIK to accomplish the
synthesis of hemiaminals.
RESULTS AND DISCUSSION
■
We began our investigation using N-tosyl QIK 1a′ prepared in
situ from p-anisidine (1a)10d employed as a model substrate
and THF as a solvent as well as a coupling partner. On the
basis of our previous work, we start with K2S2O8 as an oxidant,
tetrabutylammonium chloride (TBACl) as an additive, and
NaOAc as a base in 1 equiv to carry out the reaction at
ambient temperature (Table 1). Unfortunately, the desired
product 3a was not observed (entry 1). However, when the
reaction temperature was raised up to 90 °C, the desired
product 3a was obtained in 23% within 4 h of reaction time
(entry 2). Further, with the increase in equivalents of the
reagent, the yield of 3a was dramatically enhanced from 23 to
91% (entry 4). When the reaction was carried out in the
absence of the additive and base, the reaction failed to proceed
further, and the starting material remained unreacted (entries
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a
Table 1. Optimization Conditions for Addition of Ethers to QIKs
b
entry
oxidant (equiv)
additive (equiv)
base (equiv)
temperature (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (2)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
Na2S2O8 (3)
Oxone (3)
TBHP (3)
DTBP (3)
BPO (3)
A (1)
A (1)
A (2)
A (3)
A (3)
NaOAc (1)
NaOAc (1)
NaOAc (2)
NaOAc (3)
RT
90
90
90
90
90
90
90
90
110
90
90
90
90
90
90
90
90
90
90
24
4
4
NR
23
64
c
4
91
24
24
24
4−24
4−24
4
24
24
24
24
24
24
24
24
24
24
24
NR
NR
NR
trace
trace
NaOAc (3)
B (3)
C (3)
A (3)
A (3)
A (3)
A (3)
A (3)
A (3)
A (3)
A (3)
A (3)
A (3)
A (3)
A (3)
NaOAc (3)
NaOAc (3)
NaOAc (3)
KOAc (3)
d
NR
17
K2CO3 (3)
NaOEt (3)
Cs2CO3 (3)
NaOtBu (3)
Bu4NOH (3)
NaOAc (3)
NaOAc (3)
NaOAc (3)
NaOAc (3)
NaOAc (3)
NR
37
NR
NR
NR
35
NR
NR
trace
NR
90
a
b
c
d
Reaction conditions: 1a (0.36 mmol), 2a (10 mmol), oxidant, additive, and base. Isolated yields. TBACl in 50% aq solution. Decomposition of
1a′ was observed, NRno reaction.
5−7). Thus, it is confirmed that the base and additive are
essential to initiate the reaction. During optimization,
tetrabutylammonium bromide and tetrabutylammonium io-
dide were used as additives, and 3a was observed only in a
trace amount (entries 8−9). Enhancement in the temperature
of the reaction mixture resulted in the decomposition of the
staring material (entry 10). Further, screening of various bases
using the same oxidant observed no increment in the yields of
hemiaminal 3a (entries 11−16). Moreover, alteration of
various oxidants produced discouraging results to deliver the
desired product 3a (entries 17−21). In conclusion, the best
optimized reaction condition was preferred as entry 4 in Table
1.
With the optimized reaction conditions in hand, the study of
the substrate scope was investigated to justify our approach.
Initially, N-sulfonates containing QIK (N-Ts, N-Ms, and N−
SO2Ph) subjected to hemiaminal synthesis using our optimized
reaction conditions showed the excellent feasibility with
various cyclic as well as acyclic ethers, that is, THF,
tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane, to
deliver the desired products 3a to 3l in good to excellent
yields (72−91%), and 3a was performed on a gram scale to
obtain 84% yield (0.840 gm) in 6 h, as shown in Scheme 2.
Unfortunately, N-Ns, N-acetyl, N-Boc, and N-Allyl (entries
3m−3p) groups did not lead to give the corresponding
hemiaminal products. Further, 2-Me THF reacts smoothly
with 1a′ under optimized reaction conditions to deliver the
corresponding hemiaminal 3q in 61% yield with a 2:1
diastereomeric ratio. In addition, when tetrahydrothiophene
was used as a solvent instead of THF along with QIK, it
afforded the corresponding thioether amine 3r in 86% yield.
Unfortunately, when reaction of QIK 1a′ was carried out with
Boc-protected alkyl amines such as piperidine and pyrrolidine,
it failed to give the expected products 3s−3t.
After the successful approach to synthesize hemiaminals
from different N-sulfonates, further, we extended the scope of
the reaction to study the electronic effect of various
substituents containing electron-withdrawing as well as
electron-donating groups present on the QIK as shown in
Scheme 3. Interestingly, good yields of hemiaminals (entries
5a−5d), that is, 62−76%, were observed, when electron-
donating groups such as −OMe were present at the ortho
position of the acetal group. Also, the presence of −Me to the
meta position of the acetal group did not affect the reactivity of
QIK to give desired hemiaminal 5i in 78% yield. However,
electron-withdrawing groups such as −Br and −Ts groups
ortho to acetal of QIK were utilized for C−N bond formation
with ethers to give the corresponding hemiaminal 5e and 5f in
moderate yields compared to electron-donating groups (58%
and 76%, respectively). However, −NO2 and −CO2Et-
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Scheme 2. Substrate Scope for the Synthesis of
Hemiaminals
Scheme 3. Substrate Scope for the Synthesis of
Hemiaminals from Substituted QIKs
a
a
,b
,b
a
Reaction conditions: 4a−4g (0.36 mmol), 2a−d (3.6 mmol),
K2S2O8 (1.08 mmol), TBACl (1.08 mmol, 50% in aq soln.), NaOAc
(1.08 mmol), 90 °C, 4 h, under air; [b] isolated yields after column
chromatographic purification are shown.
Scheme 4. Synthetic Transformation of the Formed Product
Scheme 5. Control Experiments
a
Reaction conditions: 1a−p (0.36 mmol), 2a−d (3.6 mmol), K2S2O8
(1.08 mmol), TBACl (1.08 mmol, 50% in aq soln.), NaOAc (1.08
mmol), 90 °C, 4 h, under air; [b] isolated yields after column
chromatographic purification are shown.
substituted QIK 4g′and 4h′ failed to afford the corresponding
hemiaminal 5g and 5h. This might be due to high radical
stability of withdrawing groups on QIK which leads to C−N
bond cleavage. It is noteworthy that the reaction of electron-
donating groups containing QIK is faster than that of the
electron-withdrawing groups.
To check the synthetic utility of our formed key product, N-
(4-methoxyphenyl)-4-methyl-N-(tetrahydrofuran-2-yl) benze-
nesulfonamide 3a was subjected to reduction reaction using 5
equiv of NaBH4 in EtOH, which undergoes cleavage of the C−
O bond to afford amino alcohol 6 in 73% yield, as shown in
Scheme 4.13
To check the reaction pathway, we carried out few control
experiments as shown in Scheme 5. Initially, the reaction of 1a
was carried out under our optimized reaction conditions which
failed to give the desired product 3a, and the starting material
was recovered.
Scheme 5b,c. Initially, the reaction was carried out in the
presence of 1 equiv of (2,2,6,6-tetramethylpiperidin-1-yl) oxyl
(TEMPO) as a radical scavenger under optimized reaction
conditions, and 3a was formed in trace amounts, whereas the
major amount of TEMPO−THF-trapped product 7 was
observed. The formed adduct 7 was confirmed by liquid
chromatography−mass spectrometry (LCMS). Additionally, 1
equiv of butylated hydroxytoluene (BHT) was added in the
reaction mixture which afforded BHT−THF product 8. The
Moreover, to get more insight into the reaction mechanism,
some radical scavenging experiments were done, as shown in
1
formation of compound 8 was confirmed by H, 13C, Fourier
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transform infrared (IR) (FT-IR) spectroscopy, and high-
resolution mass spectrometry (HRMS).
intermediate C undergoes O-chelation with NaOAc,12a,b
followed by elimination of MeOH, and leads to the formation
of desired product 3a.
The electron paramagnetic resonance (EPR) experiments
have been carried out on a frozen aliquot of the incomplete
reaction mixture of 1a′, K2S2O8, TBACl, and NaOAc in THF,
suggesting the presence of a carbon-centric organic radical, as
shown in Figure 2. The g-factor of the crossover point of the
peak was found to be 2.003.
CONCLUSIONS
■
The study established an efficient metal-free approach for the
synthesis of hemiaminals from QIK and various ethers.
Further, this strategy highlights the optimized reaction
conditions to obtain the desired products in good to excellent
yields and shows the broad substrate scope and high functional
group tolerance with hemiaminals. Also, the formation of the
α-oxyalkyl radical in the reaction was confirmed by radical
scavenger experiments, and the C-centered radical was
confirmed by the EPR spectroscopy experiment.
EXPERIMENTAL SECTION
■
General Information. Most of the starting materials and reagents
used were purchased from commercial sources and used as such. All
N-substituted p-anisidine compounds were prepared using known
literature procedures.10d,16 QIKs were prepared as per the reported
procedure.10d,11 All solvents were highly purified before use.
Petroleum ether (boiling point: 60−80 °C) was used for column
Figure 2. EPR spectrum of an incomplete reaction mixture.
1
chromatography. H and 13C spectra were recorded on a 200, 400,
On the basis of literature reports,14 control experiments, and
the EPR study, we believe that the reaction mechanism
proceeds via the radical pathway. The reaction starts with
homolytic cleavage of persulfate under thermal conditions in
the presence of tetrabutylammonium chloride15 to form the
sulfate radical anion as shown in Scheme 6. The formed sulfate
radical anion abstracts the proton from the α-position to
oxygen of ether and generates α-oxyalkyl radical A as a reactive
intermediate. The reactive radical intermediate A undergoes
C−N addition through the nitrogen atom of QIK 1a′ to form
the C−N bond and forms intermediate B. Further, the
presence of the hydrogen sulfate anion leads to the formation
of intermediate C through single electron transfer.15a Then,
and 500 MHz NMR spectrometer. HRMS data were recorded on an
Orbitrap mass analyzer associated with an Accela 1250 pump. IR
spectra were recorded using a Bruker FT-IR and are reported in terms
of frequency of absorption (cm−1). EPR spectra were recorded on a
JESFA200 ESR Spectrometer with the X- and Q-bands [Standard
Frequency (X-band)8.75−9.65 GHz] at 100 K. All compounds
were purified by column chromatography (silica of 100−200 mesh).
All reactions were carried out in a highly predried round-bottom flask.
The reactions were monitored by thin-layer chromatography (TLC).
Coupling constants are given in hertz (Hz), and the classical
abbreviations are used to describe the signal multiplicities.
General Experimental Procedure for the Synthesis of N-
Substituted Hemiaminals (3a−3t). In a 25 mL round-bottom
flask, N-substituted p-anisidine (100 mg, 0.36 mmol, 1 equiv) was
Scheme 6. Proposed Reaction Mechanism
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taken in MeOH (3 mL). To this, diacetoxyiodobenzene
[phenyliodine(III) diacetate (PIDA)] (0.39 mmol, 1.1 equiv) was
added in portions at 0 °C, and the reaction was slowly brought to
room temperature (rt). The progress of the reaction was monitored
by TLC. After completion of the reaction, MeOH was evaporated on
a rotary evaporator under reduced pressure. The obtained residue was
dissolved in the corresponding ether (3.6 mmol, 3 mL), and K2S2O8
(1.08 mmol, 3 equiv), sodium acetate (1.08 mmol, 3 equiv), and
TBACl·H2O (1.08 mmol, 3 equiv) were added sequentially to the
reaction mixture. Then, the reaction mixture was refluxed in a
preheated oil bath at 90 °C for 4 h with continuous monitoring of the
reaction with TLC. After completion of the reaction, the resulting
reaction mixture was cooled to rt and concentrated in vacuo. The
formed residue was extracted with ethyl acetate (3 × 3 mL) and
washed with brine (10 mL). Then, the combined organic phase was
dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The
crude product was purified by flash chromatography (silica gel 100−
200 mesh) using petroleum ether/ethyl acetate (vol/vol, 8/2) to
afford the corresponding aryl hemiaminals with good to excellent
yields of the desired product.
N-(4-Methoxyphenyl)-N-(tetrahydrofuran-2-yl) Methanesulfona-
mide (3e). Purification on silica gel (petroleum ether/EtOAc = 8:2)
yield: 87%, 102 mg; yellow oil; IR (neat, cm−1) νmax: 2941.05,
2872.83, 1608.82, 1493.80, 1392.23, 1317.99, 1249.31, 1145.09,
1029.90, 970.85, 905.61, 761.75, 630.54, 504.64; 1H NMR (200
MHz, CDCl3): δ 7.2−7.3 (m, 2H),6.7−6.9 (m, 2H), 5.1 (t, J = 6.95
Hz, 1H), 4.1 (q, J = 6.84 Hz, 1H), 3.9 (d, J = 7.83 Hz, 1H), 3.8 (s,
3H), 2.3−2.5 (m, 1H), 2.9 (s, 3H), 1.5−1.7 (m, 1H), 1.8−2.0 (m,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 159.9, 132.4, 128.3,
114.4, 89.3, 68.2, 55.4, 39.5, 29.5, 24.7; HRMS (ESI) m/z: [M + Na]+
calcd for C12H17O4NNaS, 294.0770; found, 294.0769.
N-(4-Methoxyphenyl)-N-(tetrahydro-2H-pyran-2-yl)methane-
sulfonamide (3f). Purification on silica gel (petroleum ether/EtOAc
= 8:2) yield: 79%, 97 mg; colorless gum; IR (neat, cm−1) νmax
:
2923.99, 2862.05, 1733.75, 1602.38, 1504.09, 1380.07, 1333.33,
1230.03, 1155.54, 1067.57, 1025.77, 970.84, 733.94, 701.37, 646.82,
592.54; 1H NMR (400 MHz, CDCl3): δ 7.4 (m, J = 8.55 Hz, 2H), 6.9
(m, J = 9.16 Hz, 2H), 5.2−5.3 (m, 1H), 4.0−4.1 (m, 1H), 3.8 (s, 3H),
3.6 (td, J = 11.75, 2.75 Hz, 1H), 3.0 (s, 3H), 1.7−1.8 (m, 2H), 1.5−
1.6 (m, 4H), 1.3−1.4 (m, 1H), 1.0−1.2 (m, 1H); 13C{1H} NMR(101
MHz, CDCl3): δ 23.2, 24.9, 29.8, 39.7, 55.3, 67.9, 86.8, 114.0, 128.8,
132.0, 159.6; HRMS (ESI) m/z: [M + H]+ calcd for C13H20O4NS,
286.1108; found, 286.1107.
N-(1,4-Dioxan-2-yl)-N-(4-methoxyphenyl)methanesulfonamide
(3g). Purification on silica gel (petroleum ether/EtOAc = 8:2) yield:
72%, 89 mg; brown gel; IR (neat, cm−1) νmax: 2923.04, 2853.55,
1730.61, 1606.07, 1498.92, 1461.71, 1384.69, 1324.63, 1249.97,
1152.20, 1112.87, 1033.17, 971.80, 877.20, 815.13, 731.59, 523.14;
1H NMR (200 MHz, CDCl3): δ 7.29 (br s, 1H), 7.24 (s, 1H), 6.84
(d, J = 8.60 Hz, 2H), 4.93−5.00 (m, 1H), 3.91−4.01 (m, 4H), 3.83
(s, 4H), 3.72−3.79 (m, 2H), 3.24 (dd, J = 11.19, 9.87 Hz, 1H), 2.96
(s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 154.3, 129.3, 128.1,
123.5, 121.9, 110.9, 72.5, 71.2, 67.3, 66.4, 55.6, 38.9; HRMS (ESI) m/
z: [M + Na]+ calcd for C12H17O5NNaS, 310.0720; found, 310.0707.
N-(1,2-Dimethoxyethyl)-N-(4-methoxyphenyl) Methanesulfona-
mide (3h). Purification on silica gel (petroleum ether/EtOAc = 8:2)
yield: 76%, 95 mg; brown gel; IR (neat, cm−1) νmax: 2911.75, 2851.32,
1725.48, 1598.80, 1496.93, 1449.15, 1396.39, 1330.25, 1156.96,
1110.11, 1026.59, 877.0, 811.87, 663.75, 546.49; 1H NMR (200
MHz, CDCl3): δ 7.2−7.3 (m, 2H), 6.9−7.0 (m, 2H), 5.4 (dd, J =
8.60, 4.52 Hz, 1H), 3.8−3.9 (m, 3H), 3.5−3.6 (m, 3H), 3.4−3.4 (m,
3H), 3.3−3.3 (m, 1H), 3.1−3.2 (m, 1H), 3.0−3.1 (m, 3H); 13C{1H}
NMR (101 MHz, CDCl3): δ 40.3, 55.4, 55.5, 56.0, 58.7, 70.9, 87.6,
114.4, 114.7, 124.8, 126.3, 132.5, 159.9; HRMS (ESI) m/z: [M +
Na]+ calcd for C12H19O5NNaS, 312.0876; found, 312.0865.
N-(4-Methoxyphenyl)-N-(tetrahydrofuran-2-yl)benzenesulfon-
amide (3i). Purification on silica gel (petroleum ether/EtOAc = 8:2)
yield: 90%, 102 mg; colorless solid; IR (neat, cm−1) νmax: 2943.06,
2842.62, 1602.44, 1504.45, 1340.73, 1297.34, 1160.67, 1083.96,
1028.18, 932.47, 888.19, 719.68, 682.03, 637.91; 1H NMR (200
MHz, CDCl3): δ 7.8−8.0 (m, 1H),7.7−7.8 (m, 1H), 7.4−7.6 (m,
3H), 6.9−7.0 (m, 2H), 6.7−6.8 (m, 2H), 6.3 (dd, J = 7.22, 4.91 Hz,
1H), 3.7−3.8 (m, 3H), 3.5−3.7 (m, 2H), 2.0−2.3 (m, 1H), 1.5−1.8
(m, 2H), 1.2−1.3 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ
159.7, 139.7, 133.1, 132.4, 128.9, 128.4, 128.1, 127.4, 113.9, 89.3,
68.4, 55.3, 30.3, 24.6; HRMS (ESI) m/z: [M + H]+ calcd for
C17H20O4NS, 334.1108; found, 334.1110.
N-(4-Methoxyphenyl)-4-methyl-N-(tetrahydrofuran-2-yl) Benze-
nesulfonamide (3a). Purification on silica gel (petroleum ether/
EtOAc = 8:2) yield: 91%, 102 mg; colorless oil; IR (neat, cm−1) νmax
:
3260.86, 2921.03, 1599.74, 1503.36, 1454.01, 1398.64, 1335.57,
1293.49, 1245.15, 1156.20, 1086.95, 1026.05, 806.10, 663.20, 548.48;
1H NMR (200 MHz, CDCl3): δ 7.6 (d, J = 8.27 Hz, 2H), 7.2 (d, J =
8.05 Hz, 2H), 7.0−7.1 (m, 2H), 6.8 (m, J = 9.04 Hz, 2H), 6.2 (dd, J =
7.28, 4.96 Hz, 1H), 3.8 (s, 3H), 3.6−3.7 (m, 2H), 2.4 (s, 3H), 2.0−
2.2 (m, 1H), 1.6−1.8 (m, 2H), 1.2−1.4 (m, 1H); 13C{1H} NMR (101
MHz, CDCl3): δ 159.6, 143.1,133.2, 129.1, 128.1, 127.7, 113.9, 89.3,
68.3, 55.3, 30.3, 24.6, 21.5; HRMS (ESI) m/z: [M + H]+ calcd for
C18H22O4NS, 348.1264; found, 348.1264.
N-(4-Methoxyphenyl)-4-methyl-N-(tetrahydro-2H-pyran-2-yl)
Benzenesulfonamide (3b). Purification on silica gel (petroleum
ether/EtOAc = 8:2) yield: 86%, 101 mg; yellow oil; IR (neat, cm−1)
νmax: 2918.84, 2839.67, 1602.13, 1447.99, 1328.24, 1244.76, 1158.20,
1
1115.06, 1009.8, 929.16, 802.62, 650.55, 582.93, 544.44; H NMR
(200 MHz, CDCl3): δ 7.6 (m, J = 8.38 Hz, 2H); 7.2 (m, J = 8.16 Hz,
2H), 7.0−7.1 (m, 2H), 6.7−6.8 (m, 2H), 5.5 (dd, J = 10.80, 1.87 Hz,
1H), 3.9 (dt, J = 11.47, 2.09 Hz, 1H), 3.8 (s, 3H), 3.6 (td, J = 11.60,
2.81 Hz, 1H), 2.4 (s, 3H), 1.7−1.8 (m, 1H), 1.5−1.6 (m, 2H), 1.2−
1.4 (m, 2H), 0.9−1.1 (m, 1H); 13C{1H} NMR (50 MHz, CDCl3): δ
159.4, 143, 136.9, 132.8, 128.8, 128.4, 113.6, 86.6, 67.7, 55.3, 30.4,
24.8, 23.4, 21.5; HRMS (ESI) m/z:[M + H]+ calcd for C19H24O4NS,
362.1421; found, 362.1421.
N-(1,4-Dioxan-2-yl)-N-(4-methoxyphenyl)-4-methylbenzenesul-
fonamide (3c). Purification on silica gel (petroleum ether/EtOAc =
8:2) yield: 81%, 95 mg; colorless oil; IR (neat, cm−1) νmax: 2916.71,
2851.54, 1724.14, 1599.20, 1455.71, 1390.79, 1329.91, 1156.79,
1110.03, 1026.52, 876.48, 811.73, 664.00, 545.88; 1H NMR (200
MHz, CDCl3): δ 7.5−7.8 (m, 2H),7.2−7.4 (m, 3H), 6.9−7.2 (m,
2H), 6.7 (d, J = 8.49 Hz, 1H), 4.9 (dd, J = 9.70, 2.32 Hz, 1H), 3.9 (d,
J = 7.50 Hz, 4H), 3.7−3.8 (m, 3H), 3.5−3.7 (m, 1H), 3.1 (d, J =
10.58 Hz, 1H), 2.4 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ
153.8, 143.3, 135.9, 129.3, 129.2, 127.3, 127.2, 123.6, 122.4, 110.4,
72.0, 70.9, 67.0, 66.2, 55.3, 21.3; HRMS (ESI) m/z: [M + Na]+ calcd
for C16H22O5NNaS, 363.1111; found, 363.1113.
N-(4-Methoxyphenyl)-N-(tetrahydro-2H-pyran-2-yl) Benzenesul-
fonamide (3j). Purification on silica gel (petroleum ether/EtOAc =
8:2) yield: 85%, 100 mg; brown solid; IR (neat, cm−1) νmax: 2939.17,
2842.81, 1731.43, 1601.18, 1504.68, 1445.21, 1298.68, 1212.62,
1161.25, 1083.18, 1030.22, 936.38, 887.55, 800.82, 719.11, 682.35,
N-(1,2-Dimethoxyethyl)-N-(4-methoxyphenyl)-4-methylbenze-
nesulfonamide (3d). Purification on silica gel (petroleum ether/
EtOAc = 8:2) yield: 83%, 98 mg; colorless oil; IR (neat, cm−1) νmax
:
2934.06, 1729.54, 1596.96, 1509.87, 1457.27, 1328.24, 1233.26,
1157.80, 1023.74, 811.01, 766.81, 659.03; 1H NMR (400 MHz,
CDCl3): δ 7.60 (m, J = 8.25 Hz, 2H),7.22 (m, J = 8.25 Hz, 2H),
6.88−6.94 (m, 2H), 6.79 (m, J = 8.88 Hz, 2H), 5.57 (dd, J = 7.63,
5.25 Hz, 1H), 3.79 (s, 3H), 3.58 (s, 3H), 3.27 (s, 3H), 3.22−3.26 (m,
1H), 3.03 (dd, J = 10.26, 7.63 Hz, 1H), 2.42 (s, 3H); 13C{1H} NMR
(200 MHz, CDCl3): δ 159.7, 143.2, 137.3, 133.1, 129.0, 128.0, 126.2,
113.9, 87.6, 71.4, 58.6, 56.3, 55.3, 21.5; HRMS (ESI) m/z: [M + Na]+
calcd for C18H23O5NNaS, 388.1189; found, 388.1185.
1
637.54, 543.78; H NMR (200 MHz, CDCl3): δ 7.7−7.7 (m, 2H),
7.3−7.6 (m, 3H),7.0−7.1 (m, 2H), 6.7−6.8 (m, 2H), 5.5 (dd, J =
10.75, 1.93 Hz, 1H), 3.9−4.0 (m, 1H),3.7−3.9 (m, 3H), 3.6 (td, J =
11.60, 2.92 Hz, 1H), 1.5−1.7 (m, 3H), 1.3−1.4 (m, 1H), 0.9−1.2 (m,
1H), 0.8−0.9 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 159.4,
139.7, 137.4, 132.7, 132.3, 130.2, 128.3, 128.1, 113.6, 86.5, 67.6, 55.2,
30.3, 24.8, 23.4; HRMS (ESI) m/z: [M + H]+ calcd for C18H22O4NS,
348.1264; found, 348.1263.
2112
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J. Org. Chem. 2021, 86, 2107−2116

The Journal of Organic Chemistry
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Article
N-(1,4-Dioxan-2-yl)-N-(4-methoxyphenyl) Benzenesulfonamide
(3k). Purification on silica gel (petroleum ether/EtOAc = 8:2)
yield: 82%, 97 mg; yellow gel; IR (neat, cm−1) νmax: 2960.91, 2851.72,
1610.36, 1498.21, 1393.38, 1326.26, 1157.11, 1100.23, 1026.85,
877.13, 814.69, 686.24, 630.10, 575.79; 1H NMR (200 MHz,
CDCl3): δ 7.6−7.8 (m, 2H), 7.4−7.6 (m, 3H), 7.0−7.1 (m, 2H),
6.9 (s, 1H), 6.7−6.8 (m, 1H), 4.9 (dd, J = 9.70, 2.54 Hz, 1H), 3.8−3.9
(m, 4H), 3.7−3.8 (m, 4H), 3.6−3.7 (m, 1H), 3.0−3.1 (m, 1H);
13C{1H} NMR (101 MHz, CDCl3): δ 154.2, 138.9, 132.7, 129.1,
vol, 8/2) to afford the corresponding substituted aryl hemiaminals
with good to excellent yields of the desired product.
N-(3,4-Dimethoxyphenyl)-4-methyl-N-(tetrahydrofuran-2-yl)
Benzenesulfonamide (5a). Purification on silica gel (petroleum
ether/EtOAc = 8:2) yield: 76%, 85 mg; IR (neat, cm−1) νmax: 2923.73,
2851.71, 1710.65, 1597.57, 1510.78, 1457.04, 1394.28, 1332.61,
1233.39, 1157.39, 1089.15, 1022.84, 968.78, 895.01, 810.78, 758.46,
663.25, 545.81; 1H NMR (200 MHz, CDCl3): δ 7.6 (m, J = 8.27 Hz,
2H), 7.2 (m, J = 8.05 Hz, 2H), 6.6−6.8 (m, 2H), 6.5−6.6 (m, 1H),
6.2 (dd, J = 7.11, 5.02 Hz, 1H), 3.8−3.9 (m, 3H), 3.5−3.7 (m, 5H),
2.4 (s, 3H),2.0−2.2 (m, 1H), 1.6−1.8 (m, 2H), 1.1−1.3 (m, 2H);
13C{1H} NMR (101 MHz, CDCl3): δ 149.2, 136.7, 129.3, 128.9,
128.9, 128.8, 127.6, 127.3, 126.3, 124.3, 122.9, 110.6, 72.1, 71.1, 67.1,
66.3, 55.5; HRMS (ESI) m/z: [M + H]+ calcd for C17H20O5NS,
350.1057; found, 350.1054.
128.2, 127.2, 124.7, 115.1, 111.1, 110.3, 107.6, 89.3, 68.3, 55.7, 30.1,
24.5, 21.4; HRMS (ESI) m/z: [M + H]+ calcd for C19H24O5NS,
378.1370; found, 378.1368.
N-(1,2-Dimethoxyethyl)-N-(4-methoxyphenyl) Benzenesulfona-
mide (3l). Purification on silica gel (petroleum ether/EtOAc = 8:2)
yield: 88%, 105 mg; yellow gel; IR (neat, cm−1) νmax: 2934.34,
2836.40, 1605.20, 1505.83, 1448.01, 1335.99, 1247.04, 1161.87,
N-(3,4-Dimethoxyphenyl)-4-methyl-N-(tetrahydro-2H-pyran-2yl)
Benzenesulfonamide (5b). Purification on silica gel (petroleum
ether/EtOAc = 8:2) yield: 68%, 78 mg; white solid; IR (neat, cm−1)
νmax: 2934.48, 2849.25, 1595.91, 1509.69, 1454.39, 1413.19, 1343.58,
1264.40, 1231.49, 1098.97, 1021.05, 959.50, 926.46, 880.71, 820.25,
766.78, 547.19; 1H NMR (400 MHz, CDCl3): δ 7.6 (m, J = 8.24 Hz,
2H), 7.2 (m, J = 7.79 Hz, 2H), 6.8 (d, J = 2.29 Hz, 1H), 6.5 (d, J =
2.75 Hz, 1H), 4.6 (dd, J = 10.99, 1.83 Hz, 1H), 4.1 (dt, J = 11.22, 1.95
Hz, 1H), 3.8 (s, 6H), 3.5−3.7 (m, 1H), 2.4 (s, 3H), 1.8−1.9 (m, 2H),
1.6−1.7 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3): δ 152.6, 143.6,
143.0, 137.4, 136.1, 132.6, 129.5, 127.3, 112.1, 105.8, 74.2, 68.9, 60.9,
55.8, 33.4, 25.8, 23.9, 21.5; HRMS (ESI) m/z: [M + H]+ calcd for
C20H26O5NS, 392.1527; found, 392.1535.
N-(3,4-Dimethoxyphenyl)-N-(1,4-dioxan-2-yl)-4-methylbenzene-
sulfonamide (5c). Purification on silica gel (petroleum ether/EtOAc
= 8:2) yield: 62%, 72 mg; yellow oil; IR (neat, cm−1) νmax: 2930.57,
2849.03, 1689.02, 1595.76, 1509.28, 1453.68, 1343.04, 1230.43,
1161.85, 1097.85, 1020.84, 958.91, 925.35, 879.75, 765.86, 705.17,
545.41; 1H NMR (200 MHz, CDCl3): δ 7.6 (d, J = 8.16 Hz, 2H),7.2
(d, J = 8.05 Hz, 2H), 6.6 (s, 1H), 6.7−6.8 (m, 2H), 5.7 (dd, J = 9.65,
2.48 Hz, 1H), 3.8−4.0 (m, 6H), 3.7−3.8 (m, 1H),3.7 (s, 4H), 3.5−
3.6 (m, 1H), 3.2−3.4 (m, 1H), 3.0 (t, J = 10.36 Hz, 1H), 2.4 (s, 4H);
13C{1H} NMR (101 MHz, CDCl3): δ 149.4, 148.4, 143.5, 136.4,
1
1111.72, 930.61, 832.27, 801.67, 723.52, 687.51, 588.51; H NMR
(200 MHz, CDCl3): δ 7.6−7.8 (m, 2H),7.4−7.6 (m, 3H), 6.9−6.9
(m, 2H), 6.7−6.8 (m, 2H), 5.6 (dd, J = 7.72, 5.07 Hz, 1H), 3.8 (s,
3H), 3.6 (s, 3H), 3.4−3.5 (m, 1H), 3.2 (s, 3H), 3.0−3.1 (m, 1H),
13C{1H} NMR (101 MHz, CDCl3): δ 159.7, 140.1, 133.0, 132.5,
128.9, 128.3, 128.0, 125.9, 113.9, 87.7, 71.2, 58.6, 56.2, 55.3; HRMS
(ESI) m/z: [M + Na]+ calcd for C17H21O5NNaS, 374.1033; found,
374.1027.
N-(4-Methoxyphenyl)-4-methyl-N-(5-Methyltetrahydrofuran-2-
yl) Benzenesulfonamide (3q). Purification on silica gel (petroleum
ether/EtOAc = 8:2) yield: 61%, 71 mg, yellow oil; IR (neat, cm−1)
νmax: 3252.86, 2965.17, 1599.28, 1498.82, 1458.62, 1390.50, 1326.19,
1246.20, 1154.71, 1088.08, 1027.28, 908.86, 812.33, 664.01; 1H NMR
(200 MHz, CDCl3): δ 7.55−7.63 (m, 3H), 7.21 (d, J = 7.94 Hz, 3H),
6.88−7.04 (m, 2H), 6.67−6.79 (m, 2H), 5.17 (t, J = 6.84 Hz, 1H),
3.97−4.18 (m, 1H), 3.76−3.79 (m, 3H), 3.23−3.50 (m, 1H), 2.38 (s,
4H), 1.86−2.03 (m, 2H), 1.48−1.59 (m, 2H), 1.24−1.28 (m, 3H);
13C{1H} NMR (126 MHz, CDCl3): δ 154.5, 154.3, 143.6, 143.5,
136.3, 136.1, 133.7, 133.5, 129.7, 129.4, 127.5, 127.3, 126.5, 125.5,
123.6, 123.5, 122.0, 121.6, 116.2, 114.4, 110.7, 110.6, 85.0, 84.9, 75.6,
75.3, 55.5, 33.7, 33.7, 33.3, 33.2, 21.5, 21.4, 20.9, 20.7; HRMS (ESI)
m/z: [M + H]+ calcd for C19H24O4NS, 362.1421; found, 362.1423.
N-(4-Methoxyphenyl)-4-methyl-N-(tetrahydrothiophen-2-yl)
Benzenesulfonamide (3r). Purification on silica gel (petroleum
ether/EtOAc = 8:2) yield: 86%, 101 mg, yellow oil; IR (neat, cm−1)
νmax: 3264.19, 2938.07, 1731.05, 1597.31, 1486.58, 1381.98, 1331.83,
1279.66, 1159.27, 1090.24, 1035.21, 907.97, 868.80, 813.00, 728.04,
663.64, 605.93; 1H NMR (200 MHz, CDCl3): δ 7.50−7.68 (m, 3H),
7.14−7.35 (m, 3H), 6.72−6.90 (m, 2H), 3.75 (s, 3H), 3.44−3.50 (m,
1H), 2.50 (t, J = 7.22 Hz, 2 H), 2.36 (s, 3H), 1.71−1.83 (m, 2H),
1.51−1.67 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 156.7,
143.8, 136.1, 130.7, 129.5, 127.7, 127.2, 123.1, 118.8, 114.4, 55.4,
44.1, 34.9, 31.2, 26.3, 21.4; HRMS (ESI) m/z: [M + H]+ calcd for
C18H22O3NS2, 364.1036; found, 364.1038.
General Experimental Procedure for the Synthesis of Aryl-
Substituted Hemiaminals (5a−5i). In a 25 mL round-bottom flask,
aryl-substituted p-anisidine (100 mg, 0.36 mmol, 1 equiv) was taken
in MeOH (3 mL). To this, diacetoxyiodobenzene (PIDA) (0.39
mmol, 1.1 equiv) was added in portions at 0 °C, and the reaction
mixture was brought to room temperature. The reaction progress was
monitored by TLC. After completion of the reaction, MeOH was
evaporated on a rotary evaporator under reduced pressure. Then, the
residue was dissolved in the corresponding ether (3.6 mmol, 3 mL),
followed by sequential addition of K2S2O8 (1.08 mmol, 3 equiv),
sodium acetate (1.08 mmol, 3 equiv), and TBACl·H2O. The reaction
mixture was refluxed in a preheated oil bath at 90 °C for 4 h. After
completion of the reaction (with TLC monitoring), the resulting
reaction mixture was cooled to room temperature and concentrated in
vacuo. The formed residue was extracted with ethyl acetate (3 × 3
mL) and washed with brine (10 mL). Then, the combined organic
phase was dried over anhydrous Na2SO4, filtered, and evaporated in
vacuo. The crude product was purified by flash chromatography
(silica gel 100−200 mesh) and petroleum ether/ethyl acetate (vol/
129.0, 128.5, 127.8, 124.0, 114.7, 110.3, 82.6, 68.8, 66.7, 65.5, 55.8,
21.5; HRMS (ESI) m/z: [M + H]+ calcd for C19H24O6NS, 394.1319;
found, 394.1317.
N-(1,2-Dimethoxyethyl)-N-(3,4-dimethoxyphenyl)-4-methylben-
zenesulfonamide (5d). Purification on silica gel (petroleum ether/
EtOAc = 8:2) yield: 66%, 77 mg; colorless gel; IR (neat, cm−1) νmax
:
2933.16, 1731.93, 1594.54, 1507.39, 1456.93, 1326.94, 1232.44,
1024.17, 929.37, 848.64, 811.75, 764.93, 657.7; 1H NMR (200 MHz,
CDCl3): δ 7.6 (d, J = 7.83 Hz, 2H), 7.2 (br s, 2H), 6.7 (d, J = 8.49
Hz, 1H), 6.5−6.6 (m, 1H), 6.4 (s, 1H), 5.5−5.6 (m, 1H), 3.8 (s, 3H),
3.6 (s, 3H), 3.4 (d, J = 8.16 Hz, 1H), 3.2−3.3 (m, 4H), 2.9−3.1 (m,
1H), 2.4 (s, 3H), 13C{1H} NMR (101 MHz, CDCl3) δ:149.3, 148.4,
143.2, 137.2, 128.9, 128.2, 126.2, 124.6, 114.9, 110.4, 87.7, 71.2, 58.5,
56.2, 55.8, 55.6, 21.5; HRMS (ESI) m/z: [M + Na]+ calcd for
C19H25O6NNaS, 418.1295; found, 418.1282.
N-(4-Methoxy-3-tosylphenyl)-N-(tetrahydrofuran-2-yl) Methane-
sulfonamide (5e). Purification on silica gel (petroleum ether/EtOAc
= 8:2) yield: 58%, 52 mg; yellow gum; IR (neat, cm−1) νmax: 2962.43,
2876.69, 1721.12, 1464.93, 1379.94, 1241.95, 1152.19, 1039.08,
881.21, 814.74, 563.64, 527.65; 1H NMR (200 MHz, CDCl3): δ
7.49−7.74 (m, 3 H), 7.03−7.46 (m, 3 H), 6.79 (d, J = 8.82 Hz, 1 H),
5.33 (td, J = 6.39, 3.09 Hz, 1 H), 3.79−3.91 (m, 2 H), 3.60−3.76 (m,
3 H), 3.07 (s, 3 H), 2.39 (s, 3 H), 2.13−2.28 (m, 1H), 1.81−1.98 (m,
3 H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.7, 144.1, 137.7,
135.5, 129.6, 129.1, 128.3, 127.3, 124.1, 113.3, 84.9, 67.1,56.0, 42.7,
32.0, 24.1, 21.5; HRMS (ESI) m/z: [M + H]+ calcd for C19H24O6NS2,
426.1040; found, 426.1034.
N-(3-Bromo-4-methoxyphenyl)-4-methyl-N-(tetrahydrofuran-2-
yl) Benzenesulfonamide (5f). Purification on silica gel (petroleum
ether/EtOAc = 8:2) yield: 76%, 83 mg; colorless solid; IR (neat,
cm−1) νmax: 2928.69, 1584.86, 1482.75, 1353.65, 1293.36, 1248.69,
1162.08, 1020.29, 972.66, 908.92, 847.31, 810.85, 738.74, 701.23,
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Article
659.18, 542.37; 1H NMR (400 MHz, CDCl3): δ 7.8−7.9 (m, 1H), 7.6
(d, J = 7.79 Hz, 2H), 7.3 (d, J = 8.24 Hz, 1H), 7.2 (s, 1H), 7.3 (s,
1H), 7.1−7.2 (m, 1H), 7.0 (s, 1H), 6.1−6.2 (m, 1H), 3.9−3.9 (m,
3H), 3.6−3.7 (m, 1H), 3.5 (q, J = 7.17 Hz, 1H), 2.4 (s, 3H), 2.1−2.2
(m, 1H), 1.6−1.7 (m, 2H), 1.3−1.3 (m, 1H); 13C{1H} NMR (101
MHz, CDCl3): δ 143.8,136.6,136.2, 129.5, 129.3, 129.2, 128.5, 128.1,
116.2, 109.7, 90.0, 68.4, 56.7, 29.8, 24.7, 21.6; HRMS (ESI) m/z: [M
+ H]+ calcd for C18H21O4NBrS, 426.0369; found, 426.0366.
N-(4-Methoxy-2-methylphenyl)-4-methyl-N-(tetrahydrofuran-2-
yl) Benzenesulfonamide (5i). Purification on silica gel (petroleum
ether/EtOAc = 8:2) yield: 78%, 87 mg; red gum; IR (neat, cm−1)
νmax: 2930.43, 2872.37, 1651.07, 1602.43, 1497.44, 1457.99, 1388.35,
1303.24, 1221.83, 1159.84, 1035.78, 898.46, 862.56, 812.01, 665.27;
1H NMR (400 MHz, CDCl3): δ 7.57−7.73 (m, 2H), 7.24 (dd, J =
8.57, 0.56 Hz, 2H), 6.81 (d, J = 3.00 Hz, 1H), 6.60 (d, J = 8.75 Hz,
1H), 6.48 (dd, J = 8.76, 2.75 Hz, 1H), 6.24 (t, J = 6.44 Hz, 1H), 3.78
(s, 3H), 3.64 (td, J = 7.69, 5.25 Hz, 1H), 3.48−3.57 (m, 1H), 2.43 (s,
3H), 2.38 (s, 3H), 1.60−1.71 (m, 2H), 1.43−1.54 (m, 1H), 1.27−
1.36 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 159.5, 143.1,
142.5, 137.0, 132.3, 129.0, 128.5, 126.7, 115.7, 111.4, 89.7, 68.1, 55.2,
29.4, 24.9, 21.6, 19.2; HRMS (ESI) m/z: [M + H]+ calcd for
C19H24O4NS, 362.1421; found, 362.1423.
General Experimental Procedure for Synthetic Transformation
of the Formed Product (6). To a solution of 3a (50 mg, 0.14 mmol)
in ethanol (5 mL) was added sodium borohydride (27 mg, 0.72
mmol). The resulting suspension was stirred at rt for 36 h. After
completion, the reaction mixture was concentrated under reduced
pressure. The residue was chromatographed on silica gel (petroleum
ether/ethyl acetate = 6:4) to afford 6 (36 mg, 73%).
N-(4-Hydroxybutyl)-N-(4-methoxyphenyl)-4methylbenzenesulfo-
namide (6). Purification on silica gel (petroleum ether/EtOAc = 6:4)
yield: 73%, 73 mg; colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.47
(m, J = 8.25 Hz, 2H), 7.24 (m, J = 8.13 Hz, 2H), 6.90−6.95 (m, 2H),
6.78−6.83 (m, 2H), 3.80 (s, 3H), 3.61 (t, J = 6.32 Hz, 2H), 3.52 (t, J
= 6.88 Hz, 2H), 2.42 (s, 3H), 1.57−1.66 (m, 2H), 1.44−1.53 (m,
2H); 13C{1H} NMR (101 MHz, CDCl3): δ 159.0, 143.2, 135.2,
131.4, 129.9, 129.3, 127.7, 114.1, 62.3, 55.4, 50.3, 29.2, 24.5, 21.5;
HRMS (ESI) m/z: [M + H]+ calcd for C18H24O4NS, 350.1421;
found, 350.1432.
General Procedure for Gram-Scale Synthesis of N-(4-
Methoxyphenyl)-4-methyl-N-(tetrahydrofuran-2-yl) Benzene-
sulfonamide (3a). In a 100 mL round-bottom flask, N-substituted p-
anisidine (0.800 g, 2.89 mmol, 1 equiv) was taken in MeOH (30 mL).
To this, diacetoxyiodobenzene (PIDA) (3.17 mmol, 1.1 equiv) was
added in portions at 0 °C, and the reaction was slowly brought to rt.
The progress of the reaction was monitored by TLC. After
completion of the reaction, MeOH was evaporated on a rotary
evaporator under reduced pressure. The obtained residue was
dissolved in THF (28.9 mmol, 25 mL), and K2S2O8 (8.66 mmol, 3
equiv), sodium acetate (8.66 mmol, 3 equiv), and TBACl·H2O (8.66
mmol, 3 equiv) were added sequentially to the reaction mixture.
Then, the reaction mixture was refluxed in a preheated oil bath at 90
°C for 6 h with continuous monitoring of the reaction with TLC.
After completion of the reaction, the resulting reaction mixture was
cooled to rt and concentrated in vacuo. The formed residue was
extracted with ethyl acetate (30 × 3 mL) and washed with brine (20
mL). Then, the combined organic phase was dried over anhydrous
Na2SO4, filtered, and evaporated in vacuo. The crude product was
purified by flash chromatography (silica gel 100−200 mesh) using
petroleum ether/ethyl acetate (vol/vol, 8/2) to afford 3a (0.840 g,
84%) as a colorless oil.
(3.6 mmol, 3 mL). To this, K2S2O8 (1.08 mmol, 3 equiv), sodium
acetate (1.08 mmol, 3 equiv), TBACl·H2O (1.08 mmol, 3 equiv), and
TEMPO (0.36 mmol) were added sequentially. Then, the reaction
mixture was refluxed at 90 °C in an oil bath for 4 h. The expected
trapped product was detected by LCMS of the crude reaction mixture.
LCMS (ESI) m/z: 228.1 (please see the Supporting Information).
General Experimental Procedure for the BHT−THF-Trapped
Product (8). To a 25 mL round-bottom flask containing N-tosyl p-
anisidine, 1a (100 mg, 0.36 mmol, 1 equiv) was taken in MeOH (3
mL). To this reaction mixture, diacetoxyiodobenzene (PIDA) (0.39,
1.1 equiv) was added in portions at 0 °C, and the reaction mixture
was allowed to stir at rt; the reaction was monitored by TLC. After
completion of the reaction, MeOH was evaporated under reduced
pressure. Then, the residue was dissolved in THF (3.6 mmol, 3 mL).
To this, K2S2O8 (1.08 mmol, 3 equiv), sodium acetate (1.08 mmol, 3
equiv), TBACl·H2O (1.08 mmol, 3 equiv), and BHT (0.36 mmol)
were added sequentially. Then, the reaction mixture was refluxed at
90 °C in an oil bath for 4 h. The reaction was monitored by TLC;
after completion of the reaction, the resulting mixture was cooled to rt
and concentrated in vacuo. The formed residue was extracted with
ethyl acetate (3 × 3 mL) and washed with brine (20 mL). Then, the
combined organic phase was dried over anhydrous Na2SO4, filtered,
and evaporated in vacuo. The crude product was purified by flash
chromatography (silica gel 100−200 mesh) and petroleum ether/
ethyl acetate (vol/vol, 9/1) to afford the BHT−THF-trapped product
in 52% yield.
2,6-Di-tert-butyl-4-((tetrahydrofuran-2-yl) Methyl) Phenol (8).
Purificationon silica gel (petroleum ether/EtOAc = 9:1) yield: 52%,
73 mg; yellow liquid; IR (neat, cm−1) νmax: 3659.93, 2955.09,
2868.25, 2037.92, 1731.04, 1636.95, 1456.65, 1363.60, 1244.59,
1170.34, 1067.44, 968.77, 913.75, 880.01, 774.24, 733.12, 649.03; 1H
NMR (200 MHz, CDCl3): δ 7.00 (d, J = 5.95 Hz, 1H), 6.55−6.64
(m, 1H), 6.39 (d, J = 2.87 Hz, 1H), 3.86−3.96 (m, 1H), 3.75−3.84
(m, 2H), 2.21−2.32 (m, 1H), 1.67−1.79 (m, 3H), 1.22−1.28 (m, 18
H); 13C{1H} NMR (101 MHz, CDCl3): δ 186.6, 148.2, 147.0, 143.8,
142.8, 84.8, 69.0, 43.9, 34.9, 34.7, 29.5, 29.4, 27.4, 26.4, 23.6; HRMS
(ESI) m/z: [M + H]+ calcd for C19H31O2, 291.2319; found, 291.2328.
Procedure for the EPR Measurement, Representative Procedure.
To a 25 mL round-bottom flask, N-tosyl-substituted p-anisidine (100
mg, 0.36 mmol, 1 equiv) was taken in MeOH (3 mL). To this,
diacetoxyiodobenzene (PIDA) (0.39 mmol, 1.1 equiv) was added in
portions at 0 °C, and the reaction mixture was allowed to stir at rt
with continuous monitoring by TLC. After completion of the
reaction, MeOH was evaporated under reduced pressure. Then, the
residue was dissolved in THF (3.6 mmol, 3 mL). To this, sequential
addition of K2S2O8 (1.08 mmol, 3 equiv), sodium acetate (1.08 mmol,
3 equiv), and TBACl·H2O (1.08 mmol, 3 equiv) was done. The
reaction mixture was refluxed at 90 °C in a preheated oil bath and
stirred for 2 h. At ambient temperature, the reaction tube was
transferred to the glovebox, and an aliquot of the reaction mixture was
transferred to an EPR tube and frozen at 100 K, which was then
subjected to the EPR measurement.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02254.
1H and 13C{1H} NMR spectra of all compounds, LCMS
spectrum of compound 7, HRMS spectrum of
compound 8, and EPR spectrum (PDF)
General Procedure for Control Experiments and the EPR
Study. General Experimental Procedure for the TEMPO−THF-
Trapped Product (7). To a 25 mL round-bottom flask containing N-
tosyl p-anisidine, 1a (100 mg, 0.36 mmol, 1 equiv) was taken in
MeOH (3 mL). To this reaction mixture, diacetoxyiodobenzene
(PIDA) (0.39, 1.1 equiv) was added in portions at 0 °C, and the
reaction mixture was allowed to stir at rt. The reaction was monitored
by TLC. After completion of the reaction, MeOH was evaporated
under reduced pressure and the residue was then dissolved in THF
AUTHOR INFORMATION
Corresponding Author
■
Gurunath Suryavanshi − Chemical Engineering & Process
Development Division, CSIR-National Chemical Laboratory,
Pune 411008, India; Academy of Scientific and Innovative
Research, Ghaziabad, Uttar Pradesh 201 002, India;
2114
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J. Org. Chem. 2021, 86, 2107−2116

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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2676
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Authors
Satish G. More − Chemical Engineering & Process
Development Division, CSIR-National Chemical Laboratory,
Pune 411008, India; Academy of Scientific and Innovative
Research, Ghaziabad, Uttar Pradesh 201 002, India
Rohit B. Kamble − Chemical Engineering & Process
Development Division, CSIR-National Chemical Laboratory,
Pune 411008, India; Academy of Scientific and Innovative
Research, Ghaziabad, Uttar Pradesh 201 002, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02254
Author Contributions
§S.G.M. and R.B.K. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.G.M. and R.B.K. are grateful to CSIR, New Delhi, India, for
the award of senior research fellowships. GMS thanks CSIR,
New Delhi [no. CSIR/21(1110)/20/EMR-II]. Also, the
authors acknowledge DST and SAIF/CRNTS, IIT Bombay,
for providing (ESR-JEOL) the analytical facility for this
research work.
(5) Cheng, X.; Hii, K. Palladium-Catalyzed Addition of R2NH to
Double Bonds. Synthesis of α-Amino Tetrahydrofuran and Pyran
Rings. Tetrahedron 2001, 57, 5445−5450.
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