Manganese-Catalyzed N-Alkylation of Sulfonamides Using Alcohols

Article abstract of DOI:10.1021/acs.joc.9b00203

An efficient manganese-catalyzed N-alkylation of sulfonamides has been developed. This borrowing hydrogen approach employs a well-defined and bench-stable Mn(I) PNP pincer precatalyst, allowing benzylic and simple primary aliphatic alcohols to be employed as alkylating agents. A diverse range of aryl and alkyl sulfonamides undergoes mono-N-alkylation in excellent isolated yields (32 examples, 85% average yield).

Full text of DOI:10.1021/acs.joc.9b00203

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Manganese-Catalyzed N‑Alkylation of Sulfonamides Using Alcohols
Benjamin G. Reed-Berendt and Louis C. Morrill*
Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, U.K.
S
* Supporting Information
ABSTRACT: An efficient manganese-catalyzed N-alkylation
of sulfonamides has been developed. This borrowing hydrogen
approach employs a well-defined and bench-stable Mn(I) PNP
pincer precatalyst, allowing benzylic and simple primary
aliphatic alcohols to be employed as alkylating agents. A
diverse range of aryl and alkyl sulfonamides undergoes mono-
N-alkylation in excellent isolated yields (32 examples, 85%
average yield).
Scheme 1. Sulfonamide Importance and Project Overview
he sulfonamide functional group is present in a diverse
T
array of bioactive compounds.1 More specifically, N-
alkylsulfonamides are commonly employed in drug discovery
programs, with examples including the development of
thromboxane receptor antagonists,2a antitrypanosomal
agents,2b and secreted frizzled-related protein-1 inhibitors
(Scheme 1A).2c Classical methods for N-alkylsulfonamide
synthesis include the reaction of amines with activated sulfonyl
derivatives (commonly sulfonyl chlorides),3 N-alkylation of
primary sulfonamides with alkyl halides,4 and reductive
amidation using aldehydes.5 Drawbacks of these methods
include limited availability and stability of specific sulfonyl
chlorides, the use of toxic alkylating agents, and the
stoichiometric generation of undesired byproducts. In contrast,
the borrowing hydrogen (BH) approach allows commodity
alcohols to be employed as alkylating agents, with water
generated as the only byproduct.6 Traditionally, BH processes
have employed precious metal catalysts. However, as part of
ongoing efforts to reduce our dependence on precious metal
catalysts,7 recent advances have demonstrated the use of earth-
abundant first-row transition-metal catalysts across a variety of
borrowing hydrogen processes.8
The BH alkylation of sulfonamides using alcohols has been
reported employing various homogeneous precious metal
catalyst systems based on ruthenium, rhodium, palladium,
rhenium, and iridium (Scheme 1B).9−11 The work of Xu and
co-workers10d provides a particularly relevant comparison to
the present work with MnO2-catalyzed chemistry that proceeds
at 135 °C for a number of sulfonamide substrates. With respect
to earth-abundant first-row transition metals, Shi and Beller
reported the Cu(OAc)2-catalyzed N-alkylation of sulfona-
mides.12 Interestingly, the reaction performs best in an air
atmosphere, with the in situ formation of bis-sulfonylated
amidines observed, which may serve as ligands to stabilize the
catalyst. Subsequently, Shi and Deng described the FeCl2-
catalyzed N-alkylation of sulfonamides.13 Despite these notable
advances, both approaches largely employ benzylic alcohols
and require an excess of the alkylating agent (4−5 equiv).
Furthermore, the development of an efficient catalytic BH N-
alkylation of sulfonamides using well-defined complexes based
Received: January 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00203
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The Journal of Organic Chemistry
Note
on earth-abundant first-row transition metals remains an
unsolved problem. To this end, herein we report the use of
PNP pincer complexes based on manganese for the N-
alkylation of sulfonamides using both benzylic and simple
primary aliphatic alcohols (Scheme 1C).14
For optimization, the N-alkylation of p-toluenesulfonamide
2 with benzyl alcohol 1 was selected as a model system (Table
1). After extensive optimization,15 it was found that a BH
agents, giving the corresponding mono-N-alkylated sulfona-
mides in excellent isolated yields (products 4 and 6−15, 84%
average yield). Within the aryl unit, 4-Me, 3-Me, and 2-Me
substitution is tolerated in addition to electron-donating (4-
OMe) and electron-withdrawing (4-CF3) substituents. How-
ever, the sterically congested 2,4,6-trimethylbenzyl alcohol was
unreactive. 4-Iodobenzyl alcohol can be employed as the
alkylating agent, incorporating an additional functional handle
into sulfonamide 11 for subsequent elaboration via established
cross-coupling methods. Interestingly, thiophene-3-ylmethanol
can be converted to sulfonamide 12 in 87% isolated yield, but
thiophene-2-ylmethanol gives no conversion to the corre-
sponding sulfonamide, suggesting that it may inhibit catalysis
via coordination to Mn. The catalytic system exhibits
chemoselectivity, tolerating the reducible benzyl ether, olefin,
and ester moieties present within products 13−15. We were
pleased to discover that less activated simple primary aliphatic
alcohols can also be employed as alkylating agents in this
process (products 16−19, 84% average yield). In each case, the
alcohol was used as solvent in order to obtain high isolated
yields of the N-alkylated sulfonamides. Methanol is challenging
to employ as the alkylating agent in borrowing hydrogen
processes, which can partly be attributed to the increased
energy of dehydrogenation compared to higher alcohols (e.g.,
ΔH (MeOH) = +84 kJ mol−1, cf. ΔH (EtOH) = +68 kJ
mol−1).19 In this system employing 1 equiv of K2CO3, N-
methylation of p-toluenesulfonamide proceeds efficiently,
affording 19 in 89% isolated yield.20 Unfortunately, despite
examining a range of alternative reaction conditions, we found
that allylic and propargylic alcohols produce multiple
unidentified products whereas secondary alcohols are un-
reactive in this N-alkylation procedure.
a
Table 1. Optimization of Mn-Catalyzed N-Benzylation
b
entry
variation from “standard” conditions
none
no [Mn] precatalyst
yield (%)
1
2
3
98 (86)
<2
5
no K2CO3
4
5
6
7
[Mn] precatalyst 5 (5 mol %) instead of 3
Cs2CO3 (10 mol %) instead of K2CO3
KOH (10 mol %) instead of K2CO3
KOt-Bu (10 mol %) instead of K2CO3
[1] = 0.5 M
<2
94
5
41
92
8
9
[1] = 2 M
92
10
11
12
13
110 °C
reaction time = 6 h
[Mn] precatalyst 3 (4 mol %)
[Mn] precatalyst 3 (3 mol %)
18
82
94
42
Next, we explored the scope of the reaction with respect to
variation within the sulfonamide component (Scheme 2C/D).
When the optimized reaction conditions (Table 1, entry 1) are
employed, a variety of aryl sulfonamides undergo efficient
mono-N-alkylation with benzyl alcohol (products 20−32, 85%
average yield). Sulfonamides containing sterically encumbered
aryl units such as o-tolyl, mesityl, trisyl, and 1-naphthyl were all
well tolerated. Within the aryl unit, electron-donating (4-
OMe) substituents are readily accommodated, whereas solvent
quantities of benzyl alcohol and 1 equiv of K2CO3 were
required when less nucleophilic 4-(trifluoromethyl)-
benzenesulfonamide was used, accessing 28 in 61% isolated
yield. In line with this observation, employing 4-nitro-
benzenesulfonamide and 4-cyanobenzenesulfonamide gave no
observable N-alkylation products, with starting materials
returned in both cases. 4-Bromobenzenesulfonamide was
readily tolerated, incorporating an additional functional handle
into product 29. Thiophene-2-sulfonamide underwent efficient
N-benzylation, giving 30 in 73% isolated yield. However, a
sulfonamide containing a pyridine ring did not give any
observable conversion to the corresponding N-alkylated
product, which may be attributed to coordination to the
catalyst. Reducible functionalities within the sulfonamide
nucleophile are conserved, providing products 31 and 32 in
95% and 70% isolated yields, respectively. A selection of alkyl
sulfonamides was also tolerated, giving products 33−36 in
excellent isolated yields. Employing benzamide and methyl-
carbamate as nucleophiles resulted in recovered starting
materials in both cases, despite examining a range of reaction
conditions.
a
Reactions performed using 1 (1 mmol), 2 (1 mmol), and bench-
b
grade xylenes. [2] = 1 M. Yield after 24 h as determined by 1H NMR
analysis of the crude reaction mixture with 1,3,5-trimethylbenzene as
the internal standard. Isolated yield given in parentheses.
system composed of bench-stable Mn(I) PNP pincer
precatalyst 3 (5 mol %)16 and K2CO3 (10 mol %) as base in
xylenes ([2] = 1 M) at 150 °C for 24 h enabled the N-
benzylation of 2, giving 4 in 98% NMR yield and 86% isolated
yield (entry 1). Importantly, only 1 equiv of the alkylating
agent and catalytic quantities of base were required for
complete conversion, giving a high atom economy process.17
No alkylation occurs in the absence of the manganese
precatalyst 3,(entry 2), with only 5% conversion observed in
the absence of K2CO3 (entry 3). It was found that manganese
precatalyst 5, introduced by Sortais and co-workers,14d was
ineffective for the desired transformation, resulting in no
observable formation of sulfonamide 4 (entry 4). When
Cs2CO3, KOH, or KO-t-Bu was used as base, lower
conversions to 4 (entries 5−7) was observed. Furthermore,
altering the reaction concentration (entries 8 and 9), lowering
reaction temperature (entry 10), reducing the reaction time
(entry 11), or reducing the catalyst loading (entries 12 and 13)
all lowered the efficiency of the N-benzylation of 2.
The full scope of the Mn-catalyzed BH N-alkylation of
sulfonamides was explored, starting with the N-alkylation of p-
toluenesulfonamide 2 (Scheme 2A/B).18 When the optimized
reaction conditions (Table 1, entry 1) are used, various
substituted benzylic alcohols can be employed as alkylating
B
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Note
Scheme 2. Scope of the Mn-Catalyzed BH N-Alkylation of Sulfonamides*
*
Reactions performed using 1 mmol of alcohol and sulfonamide starting materials and bench-grade xylenes. All yields are isolated yields after
a
chromatographic purification. Alcohol used as solvent and K2CO3 (1 equiv).
a
To obtain insight into the reaction mechanism, equimolar
quantities of benzyl alcohol 1 and p-tolualdehyde 37 were
subjected to the “standard” reaction conditions, which gave a
mixture of alcohols (1 and 38) and aldehydes (37 and 39),
providing evidence that alcohol dehydrogenation is reversible
(Scheme 3A).21 Furthermore, replacing p-tolualdehyde 39
with N-sulfonyl imine 40 produced 4 in 85% NMR yield,
indicating that 40 is a plausible reaction intermediate (Scheme
3B). In line with these observations, and previous related
investigations,14 a plausible reaction mechanism initiates with
activation of precatalyst 3 with K2CO3 in a dehydrobromina-
tion reaction to form the active manganese complex (Scheme
4). Alcohol coordination forms an alkoxo-type complex, with
subsequent dehydrogenation forming an aldehyde and a
manganese hydride species. Condensation with p-toluenesul-
fonamide 2 forms an N-sulfonylimine, which is reduced by the
manganese hydride species to give the N-alkylated product 4
with regeneration of the catalytically active species.
Scheme 3. Mechanistic Control Experiments
a
1
Yield after 24 h as determined by H NMR analysis of the crude
reaction mixture with 1,3,5-trimethylbenzene as the internal standard.
In conclusion, we have developed an efficient Mn-catalyzed
N-alkylation of sulfonamides using benzylic and simple primary
aliphatic alcohols as alkylating agents. A diverse array of aryl
and alkyl sulfonamides undergoes mono-N-alkylation in
excellent isolated yields (32 examples, 85% average yield).
EXPERIMENTAL SECTION
■
General Information. Unless stated otherwise, all reactions were
performed using oven-dried 10 mL microwave vials sealed with
aluminum crimp caps and were stirred with Teflon-coated magnetic
stirrer bars. Dry tetrahydrofuran (THF), toluene, hexanes, and diethyl
C
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Note
mL). The combined organic layers were dried over MgSO4 and
filtered, and the solvent was removed in vacuo. The crude solid was
recrystallized from boiling petroleum ether 40−60 to remove major
impurities, yielding 4-vinylbenzoic acid that was used directly in the
next step. Following a literature procedure,23 a flame-dried round-
bottomed flask was charged with a magnetic stirrer bar, lithium
aluminum hydride (758 mg, 20.0 mmol), and THF (80 mL) under
inert atmosphere. The resulting slurry was cooled to 0 °C under rapid
stirring, and a solution of 4-vinylbenzoic acid (500 mg, 3.37 mmol) in
Et2O (25 mL) was added dropwise. The resulting reaction mixture
was then warmed to room temperature, stirred for 1 h at this
temperature, and then quenched with dropwise H2O (256 μL), 10%
w/w NaOH/H2O (512 μL), and then H2O (768 μL). The mixture
was stirred vigorously until a white solid was formed and then was
filtered. The filtrate was dried with MgSO4, filtered, and concentrated
in vacuo. The resulting crude material was then purified by flash
column chromatography (30 × 110 mm silica, 10−20% ethyl acetate/
petroleum ether 40−60) to give the title compound (423 mg, 94%) as
Scheme 4. Plausible Catalytic Cycle
1
a colorless oil: Rf 0.20 (20% EtOAc/petroleum ether 40−60); H
NMR (500 MHz, CDCl3) δH 1.70 (1H, s, br), 4.68 (2H, s), 5.25 (1H,
dd, J 10.9, 0.8), 5.75 (1H, dd, J 17.6, 0.8), 6.72 (1H, dd, J 17.6, 10.9),
7.33 (2H, d, J 8.2), 7.40−7.42 (2H, m); 13C{1H} NMR (126 MHz,
CDCl3) δC 65.3, 114.1, 126.5, 127.3, 136.6, 137.2, 140.5.
Spectroscopic data are in accordance with the literature.24
ether were obtained after these previously degassed solvents were
passed through activated alumina columns (Mbraun, SPS-800). All
other solvents and commercial reagents were used as supplied without
further purification unless stated otherwise. Manganese precatalysts
314b and 514d were prepared according to literature procedures.
Benzaldehyde was vacuum distilled at 75 °C prior to use. Room
temperature (rt) refers to 20−25 °C. Ice/water baths were used to
obtain temperatures of 0 °C. All reactions involving heating were
carried out using DrySyn blocks and a contact thermometer. In vacuo
refers to reduced pressure through the use of a rotary evaporator.
Analytical thin-layer chromatography was carried out using aluminum
plates coated with silica (Kieselgel 60 F254 silica), and visualization
was achieved using ultraviolet light (254 nm) followed by staining
with a 1% aqueous KMnO4 solution. Flash chromatography used
Kieselgel 60 silica in the solvent system stated. Melting points were
recorded on a Gallenkamp melting point apparatus and corrected by
linear interpolation of melting point standards benzophenone (47−49
°C) and benzoic acid (121−123 °C). Infrared spectra were recorded
on a Shimadzu IRAffinity-1 Fourier Transform ATIR spectrometer as
thin films using a Pike MIRacle ATR accessory. Characteristic peaks
are quoted (νmax/cm−1). 1H, 13C, and 19F NMR spectra were obtained
Benzyl 4-(Hydroxymethyl)benzoate. A 100 mL round-bottomed
flask equipped with a magnetic stirrer bar was charged with 4-
(hydroxymethyl)benzyl alcohol (3.04 g, 20 mmol), K2CO3 (3.04 g, 22
mmol), N,N-dimethylformamide (23 mL), and benzyl bromide (2.40
mL, 3.42 g, 20 mmol) and the reaction heated at 30 °C for 24 h using
a heating block. The resulting mixture was then cooled and H2O
added (30 mL). The mixture was then transferred to a separatory
funnel filled with EtOAc (50 mL). The organic layer was collected,
and the aqueous layer was washed with EtOAc (2 × 50 mL). The
organics were then combined, washed with brine (7 × 100 mL), dried
over MgSO4, filtered, and concentrated in vacuo. Purification by
recrystallization gave the title compound as a white solid (3.7 g, 76%):
mp 56−58 °C (Et2O/hexanes); Rf = 0.16 (20% EtOAc/petroleum
ether 40−60); νmax/cm−1 (film) 1719, 1611, 1454, 1416, 1366, 1263,
1171, 1115, 1098, 1080, 1040, 1015, 934, 914, 845, 822, 785, 746,
1
700, 598, 523, 465, 438, 415, 403; H NMR (500 MHz, CDCl3) δH:
1.83 (1H, t, J 6.0), 4.77 (2H, d, J 6.0), 5.37 (2H, s), 7.30−7.50 (7H,
m), 8.07 (2H, d, J 8.0); 13C{1H} NMR (126 MHz, CDCl3) δC: 64.9,
66.9, 126.6, 128.3, 128.4, 128.7, 129.4, 130.1, 136.2, 146.2, 166.4;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H15O3 243.1021,
found 243.1002.
1
on either a Bruker Avance 400 (400 MHz H, 101 MHz 13C, 376
MHz 19F) or a Bruker Avance 500 (500 MHz 1H, 126 MHz 13C, 471
MHz 19F) spectrometer at rt in the solvent stated. Chemical shifts are
reported in parts per million (ppm) relative to the residual solvent
signal. All coupling constants, J, are quoted in hertz. Multiplicities are
reported with the following symbols: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet and multiples thereof. The
abbreviation Ph is used to denote phenyl, br to denote broad. High-
resolution mass spectrometry (HRMS, m/z) data was acquired either
at Cardiff University on a Micromass LCT spectrometer or at the
EPSRC UK National Mass Spectrometry Facility at Swansea
University.
(4-Vinylphenyl)methanol. Following modified literature proce-
dures,22 a flame-dried round-bottomed flask was charged with a
magnetic stirrer bar, magnesium turnings (262 mg, 11.5 mmol), a
crystal of iodine, and dry THF (20 mL) under inert atmosphere. The
resulting suspension was cooled to 0 °C under vigorous stirring. To
the reaction mixture was added 4-bromostyrene dropwise (1.00 mL,
7.64 mmol) over 30 min, and the reaction was warmed to room
temperature. After being stirred at this temperature for 4 h, a
multinecked flame-dried round-bottomed flask was fitted with a
drying column of anhydrous calcium sulfate, fitted with a suba seal.
Through the side arm of the flask were added small quantities of
CO2(s), and the side arm was sealed with a suba seal. The resultant
CO2(g) was passed through the drying column and bubbled into the
reaction solution at rt by use of a cannula. This process was continued
with a low flow rate for 3 h, after which time the reaction mixture was
quenched with 2 M H2SO4(10 mL) and extracted in Et2O (3 × 20
3-Methylbenzenesulfonamide. Following a modified literature
procedure,25 a round-bottomed flask was charged with a magnetic
stirrer bar, 3-methylbenzene sulfonyl chloride (290 μL, 2.00 mmol),
and acetone (3 mL). The resulting solution was stirred and cooled to
0 °C. Concentrated ammonium hydroxide solution (28−30% w/w, 8
mL, 118 mmol) was then added, and the resulting solution was
allowed to warm to room temperature before being stirred at this
temperature for 4 h. The reaction was then concentrated in vacuo
until a precipitate was observed. The resulting slurry was then filtered
and washed with water to yield the title compound (112 mg, 33%) as
a white solid: mp 107−108 °C (lit.26 mp 109−111 °C); Rf 0.20 (30%
1
EtOAc/petroleum ether 40−60); H NMR (400 MHz, CDCl3) δH
2.43 (3H, s), 4.81 (2H, s, br), 7.38−7.43 (2H, m), 7.72−7.75 (2H,
m); 13C{1H} NMR (101 MHz, CDCl3) δC 21.5, 123.7, 127.0, 129.2,
133.7, 139.6, 141.9. Spectroscopic data are in accordance with the
literature.26
4-Vinylbenzenesulfonamide. Following a literature procedure,27
a
round-bottomed flask was charged with a magnetic stirrer bar and
dimethylformamide (8.3 mL). Thionyl chloride (4.14 mL, 41.0
mmol) was then added dropwise over the course of 30 min. The
reaction mixture was then stirred at 0 °C for 6 h before stirring was
stopped, and the reaction vessel was sealed and left in the refrigerator
overnight. The solution was then poured slowly over ice−water (15
mL), extracted in diethyl ether (3 × 7 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. To the resulting
D
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The Journal of Organic Chemistry
Note
crude mixture was then added a magnetic stirrer bar, and
concentrated ammonium hydroxide solution (28−30% w/w, 18
mL) was added slowly. This reaction mixture was then stirred for 2 h
before dilution in water (5 mL) and subsequent extraction in diethyl
ether (3 × 5 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo to yield the title
compound (400 mg, 43%) as a white solid: mp 138−140 °C (lit.28
mp 141 °C); Rf 0.21 (30% EtOAc/petroleum ether 40−60); 1H
NMR (500 MHz, CDCl3) δH 4.81 (2H, s, br), 5.44 (1H, d, J 10.9),
5.88 (1H, d, J 17.6), 6.75 (1H, dd, J 10.9, 17.6), 7.53 (2H, d, J 8.1),
7.88 (2H, d, J 8.1); 13C{1H} NMR (126 MHz, CDCl3) δC 117.8,
127.0, 127.1, 135.5, 140.9, 142.3. Spectroscopic data are in
accordance with the literature.28
7.33 (5H, m), 7.75−7.78 (2H, m); 13C{1H} NMR (126 MHz,
CDCl3) δC 21.7, 47.5, 127.4, 128.0, 128.1, 128.9, 129.9, 136.4, 137.0,
143.7. Spectroscopic data are in accordance with the literature.31
4-Methyl-N-(2-methylbenzyl)benzenesulfonamide (6). The title
compound was prepared according to general procedure A, using p-
toluenesulfonamide (171 mg, 1.00 mmol) and 4- methylbenzyl
alcohol (122 mg, 1.00 mmol), and was purified by flash column
chromatography (30 × 100 mm silica, 20% ethyl acetate/petroleum
ether 40−60) to yield the title compound (263 mg, 96%) as a pale
yellow solid: mp 93−94 °C (lit.32 mp 95 °C {cyclohexane/ethyl
1
acetate}); Rf 0.25 (20% ethyl acetate/petroleum ether 40−60); H
NMR (500 MHz, CDCl3) δH 2.31 (3H, s), 2.44 (3H, s), 4.07 (2H, d,
J 6.1), 4.56 (1H, t, J 5.9), 7.06−7.10 (4H, m), 7.30−7.32 (2H, d, J
8.0), 7.76 (2H, d, J 8.2); 13C{1H} NMR (126 MHz, CDCl3) δC 21.2,
21.7, 47.2, 127.4, 128.0, 129.5, 129.9, 133.3, 137.0, 137.9, 143.6.
Spectroscopic data are in accordance with the literature.32
N-Benzylidene-4-methylbenzenesulfonamide (40). Following a
literature procedure,29 an oven-dried pressure tube was charged with a
magnetic stirrer bar, p-toluenesulfonamide (1.03 g, 6.0 mmol), and
DCM (18.8 mL). The solution was stirred vigorously, and
benzaldehyde (704 μL, 7.2 mmol), molecular sieves (6.0 g, 1 g/
mmol), and pyrrolidine (49.3 μL, 0.6 mmol) were added. The
reaction vessel was then sealed and heated to 60 °C in an oil bath for
24 h. The reaction vessel was cooled to room temperature and filtered
through a pad of Celite. The solvent was removed in vacuo to yield a
crude oil. The residual benzaldehyde was removed under high vacuum
with gentle heating (40 °C), to yield the title compound (1.38 g,
89%) as a yellow solid: mp 104−106 (lit.30 105 °C); Rf 0.30 (20%
3-Methyl-N-(2-methylbenzyl)benzenesulfonamide (7). The title
compound was prepared according to general procedure A, using p-
toluenesulfonamide (171 mg, 1.00 mmol) and 3-methylbenzyl alcohol
(122 mg, 1.00 mmol), and was purified by flash column
chromatography (30 × 110 mm silica, 20% EtOAc/petroleum ether
40−60) to yield the title compound (264 mg, 96%), as an off-white
solid: mp 65−66 °C (lit.33 mp 64−66 °C); Rf 0.29 (20% EtOAc/
petroleum ether 40−60); 1H NMR (500 MHz, CDCl3) δH 2.28 (3H,
s), 2.44 (3H, s), 4.09 (2H, d, J 6.2), 4.68 (1H, t, J 5.9), 6.97−6.98
(2H, m), 7.05−7.08 (1H, m), 7.14−7.17 (1H, m), 7.31 (2H, d, J 7.9),
7.74−7.77 (2H, m); 13C{1H} NMR (126 MHz, CDCl3) δC 21.4, 21.7,
47.4, 125.0, 127.4, 128.7, 128.8, 128.8, 129.9, 136.3, 137.1, 138.6,
143.7. Spectroscopic data are in accordance with the literature.33
2-Methyl-N-(2-methylbenzyl)benzenesulfonamide (8). The title
compound was prepared according to general procedure A, using p-
toluenesulfonamide (171 mg, 1.00 mmol) and 2-methylbenzyl alcohol
(122 mg, 1.00 mmol), and was purified by flash column
chromatography (30 × 100 mm silica, 20% EtOAc/petroleum ether
40−60) to yield the title compound (219 mg, 80%) as a pale yellow
solid: mp 115−117 °C (lit.33 mp 113−117 °C); Rf 0.24 (20% EtOAc/
petroleum ether 40−60); 1H NMR (500 MHz, CDCl3) δH 2.25 (3H,
s), 2.45 (3H, s), 4.09 (2H, d, J 6.0), 4.44 (1H, t, br, J 5.7), 7.10−7.13
(3H, m), 7.16−7.20 (1H, m), 7.32 (2H, d, J 8.0), 7.76−7.78 (2H, m);
13C{1H} NMR (126 MHz, CDCl3) δC 18.9, 21.7, 45.6, 126.4, 127.4,
128.4, 129.0, 129.9, 130.8, 134.0, 136.8, 136.9, 143.7. Spectroscopic
data are in accordance with the literature.33
1
EtOAc/petroleum ether 40−60); H NMR (500 MHz, CDCl3) δH
2.44 (3H, s), 7.35 (2H, d, J 8.1), 7.49 (2H, t, J 7.7), 7.62 (1H, t, J 7.4)
7.89 (2H, d, J 8.2), 7.93 (2H, d, J 7.3), 9.04 (1H, s); 13C{1H} NMR
(126 MHz, CDCl3) δC 21.8, 128.3, 129.3, 130.0, 131.5, 132.6, 135.1,
135.3, 144.8, 170.3. Spectroscopic data are in accordance with the
literature.30
General Procedure A. A 10 mL microwave vial was charged with
a magnetic stirrer bar, an amide (1.00 mmol), potassium carbonate
(13.8 mg, 10 mol %), [Mn] precatalyst 3 (24.8 mg, 0.05 mol %), an
alcohol (1.00 mmol), and xylenes (1 mL). The vial was then crimped
shut and stirred vigorously at 150 °C for 24 h using a heating block.
The reaction vessel was then cooled and decrimped, and to the
reaction mixture were added mesitylene (69.6 μL, 0.5 mmol), water
(1 mL), and ethyl acetate (1 mL). The reaction mixture was then
stirred for an additional 5 min, sampled directly, and analyzed by
proton NMR. The crude reaction mixture was then separated,
washing the aqueous layer with ethyl acetate (3 × 5 mL). The organic
layers were then combined, dried over MgSO4, and filtered. The
resulting solution was then concentrated under reduced pressure,
loaded directly onto silica, and purified by flash column chromatog-
raphy. Extra purification steps are listed as applicable.
General Procedure B. A 10 mL microwave vial was charged with
a magnetic stirrer bar, an amide (1.00 mmol), potassium carbonate
(138 mg, 1.00 mmol), [Mn] precatalyst 3 (24.8 mg, 5 mol %), and an
alcohol (1 mL). The vial was then crimped shut and stirred vigorously
at 150 °C for 24 h using a heating block. The reaction vessel was then
cooled and decrimped, and to the reaction mixture were added
mesitylene (69.6 μL, 0.5 mmol), water (1 mL), and ethyl acetate (1
mL). The reaction mixture was then stirred for an additional 5 min,
then sampled directly, and analyzed by proton NMR. The crude
reaction mixture was then separated, washing the aqueous layer with
ethyl acetate (3 × 5 mL). The organic layers were then combined,
dried over MgSO4, and filtered. The resulting solution was then
concentrated under reduced pressure, loaded directly onto silica, and
purified by flash column chromatography. Extra purification steps are
listed as applicable.
N-(4-Methoxybenzyl)-4-methylbenzenesulfonamide (9). The
title compound was prepared according to general procedure A,
using p-toluenesulfonamide (171 mg, 1.00 mmol) and 4-methox-
ybenzyl alcohol (138 mg, 1.00 mmol), and was purified by flash
column chromatography (30 × 100 mm silica, 20% EtOAc/petroleum
ether 40−60) to yield the title compound (269 mg, 91%) as an off-
white solid: mp 120−123 °C (lit.33 mp 119−121 °C); Rf 0.13 (20%
1
EtOAc/petroleum ether 40−60); H NMR (500 MHz, CDCl3) δH
2.44 (3H, s), 3.78 (3H, s), 4.06 (2H, d, J 6.1), 4.51 (1H, t, J 5.7), 6.80
(2H, d, J 8.7), 7.11 (2H, d, J 8.6), 7.31 (2H, d, 8.0), 7.76 (2H, d, J
2.8); 13C{1H} NMR (126 MHz, CDCl3) δC 21.7, 47.0, 55.4, 114.2,
127.4, 128.4, 129.4, 129.9, 137.0, 143.4, 159.5. Spectroscopic data are
in accordance with the literature.33
4-Methyl-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide
(10). The title compound was prepared according to general
procedure A, using p-toluenesulfonamide (171 mg, 1.00 mmol) and
(4-(trifluoromethyl)phenyl)methanol (126 μL, 1.00 mmol) and was
purified by flash column chromatography (30 × 110 mm silica, 20%
EtOAc/petroleum ether 40−60) and trituration in petroleum ether
40−60 to give the title compound (235 mg, 70%) as an off-white
solid: mp 134−137 °C; Rf 0.29 (20% EtOAc/petroleum ether 40−
60); νmax/cm−1 (film) 3263, 2980, 1618, 1446, 1317, 1308, 1288,
1155, 1111, 1092, 1067, 1018, 878, 822, 812, 731, 706, 662, 631, 594,
N-Benzyl-4-methylbenzenesulfonamide (4). Compound 4 was
prepared according to general procedure A, using p-toluenesulfona-
mide (171 mg, 1.00 mmol) and benzyl alcohol (101 μg, 1.00 mmol)
and purified by flash column chromatography (30 × 150 mm silica,
20% ethyl acetate/petroleum ether 40−60) to give the title
compound (225 mg, 86%) as a white crystalline powder: mp 163−
165 °C (lit.31 mp 166−168 °C); Rf 0.20 (20% ethyl acetate/
petroleum ether 40−60); 1H NMR (500 MHz, CDCl3) δH 2.44 (3H,
s), 4.13 (2H, d, J 6.2), 4.61 (1H, t, J 5.8), 7.19−7.21 (2H, m), 7.24−
1
561, 544, 490, 419; H NMR (500 MHz, CDCl3) δH 2.43 (3H, s),
4.20 (2H, d, J 6.4), 4.91 (1H, t, br, J 6.3), 7.28 (2H, d, J 8.0), 7.30
(2H, d, J 8.0), 7.51 (2H, d, J 8.1), 7.72 (2H, d, J 8.3); 19F{1H} NMR
(471 MHz, CDCl3) δF:-62.65; 13C{1H} NMR (126 MHz, CDCl3) δC
21.7, 46.8, 124.1 (q, J 272.5), 125.8 (q, J 3.8), 127.2, 128.2, 130.0,
E
DOI: 10.1021/acs.joc.9b00203
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
130.1 (q, J 32.5), 136.8, 140.5, 143.9; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C15H15NO2SF3 330.0776, found 330.0774.
1032, 1018, 982, 907, 883, 853, 814, 787, 762, 733, 719,708, 694, 656,
648, 583, 561, 546, 530, 519, 492,459, 419; H NMR (500 MHz,
1
N-(4-Iodobenzyl)-4-methylbenzenesulfonamide (11). The title
compound was prepared according to general procedure A, using p-
toluenesulfonamide (171 mg, 1.00 mmol) and (4-iodophenyl)-
methanol (234 mg, 1.00 mmol), and was purified by flash column
chromatography (30 × 100 mm silica, 20% EtOAc/petroleum ether
40−60) to give the product (326 mg, 84%) as an off-white solid: mp
135−137 °C (lit.34 mp 135−137 °C); Rf 0.22 (20% EtOAc/
petroleum ether 40−60); 1H NMR (500 MHz, CDCl3) δH 2.45 (3H,
s), 4.08 (2H, d, J 6.3), 4.62 (1H, t, br, J 6.0), 6.95 (2H, d, J 8.4), 7.30
(2H, d, J 8.0), 7.60 (2H, d, J 8.3), 7.73 (2H, d, J 8.3); 13C{1H} NMR
(126 MHz, CDCl3) δC 21.7, 46.9, 93.6, 127.3, 129.9, 129.9, 136.1,
137.0, 137.9, 143.9. Spectroscopic data are in accordance with the
literature.34
4-Methyl-N-(thiophene-3-ylmethyl)benzenesulfonamide (12).
The title compound was prepared according to general procedure
A, using p-toluenesulfonamide (171 mg, 1.00 mmol) and thiophene-3-
ylmethanol (94.3 μL, 1.00 mmol), and was purified by flash column
chromatography (30 × 150 mm silica, 20% EtOAc/petroleum ether)
to give the title compound (234 mg, 87%) as a dark yellow solid: mp
CDCl3) δH 2.42 (3H, s), 4.18 (2H, d, J 6.3), 4.79 (1H, t, br, J 6.0),
5.35 (2H, s), 7.28−7.44 (9H, m), 7.74 (2H, d, J 7.9), 7.97 (2H, d, J
8.0); 13C{1H} NMR (126 MHz, CDCl3) δC 21.7, 47.0, 66.9, 127.3,
127.8, 128.3, 128.5, 129.8, 130.0, 130.2, 136.1, 136.9, 141.7, 143.9,
166.1; HRMS (AP-TOF) m/z [M + H]+ calcd for C22H22NO4S
396.1270, found 396.1274.
4-Methyl-N-phenethylbenzenesulfonamide (16). The title com-
pound was prepared according to general procedure B, using p-
toluenesulfonamide (171 mg, 1.00 mmol) and 2-phenylethanol (1
mL), and was purified by flash column chromatography (45 × 115
mm silica, 5−20% EtOAc/petroleum ether 40−60), followed by
trituration in petroleum ether 40−60 to give the title compound (198
mg, 72%) as a white solid: mp 59−60 °C (lit.36 mp 62−64 °C); Rf
1
0.27 (20% EtOAc/petroleum ether 40−60); H NMR (500 MHz,
CDCl3) δH 2.43 (3H, s), 2.76 (2H, t, J 6.9), 3.22 (2H, q, J 6.8), 4.36
(1H, t, br, J 5.9), 7.08 (2H, d, J 6.9), 7.20−7.23 (1H, m), 7.26−7.30
(4H, m), 7.39 (2H, d, J 8.3); 13C{1H} NMR (126 MHz, CDCl3) δC
21.7, 35.9, 44.3, 127.0, 127.2, 128.9, 128.9, 129.9, 137.1, 137.8, 143.6.
Spectroscopic data are in accordance with the literature.37
108−110 °C; Rf 0.18 (20% EtOAc/petroleum ether 40−60); νmax
/
4-Methyl-N-pentylbenzenesulfonamide (17). The title compound
was prepared according to general procedure B, using p-
toluenesulfonamide (171 mg, 1.00 mmol) and n- pentanol (1 mL),
and was purified by flash column chromatography (30 × 80 mm silica,
20% EtOAc/petroleum ether 40−60) to yield the title compound
(208 mg, 86%) as a yellow oil: Rf 0.31 (20% EtOAc/petroleum ether
40−60); 1H NMR (500 MHz, CDCl3) δH 0.83−0.85 (3H, m), 1.20−
1.27 (4H, m), 1.42−1.48 (2H, m), 2.43 (3H, s), 2.93 (2H, q, J 7.1),
4.35 (1H, t, br, J 6.0), 7.31 (2H, d, J 8.0), 7.73−7.76 (2H, m);
13C{1H} NMR (126 MHz, CDCl3) δC 14.0, 21.7, 22.3, 28.8, 29.4,
43.4, 127.2, 129.8, 137.1, 143.5. Spectroscopic data are in accordance
with the literature.38
cm−1 (film) 3264, 1599, 1456, 1422, 1335, 1319, 1308, 1163, 1094,
1
1065, 874, 856, 812, 772, 706, 696, 656, 590, 552, 540, 509, 476; H
NMR (500 MHz, CDCl3) δH 2.44 (3H, s), 4.16 (2H, d, J 6.1), 4.56
(1H, t, br, J 5.7), 6.89 (1H, dd, J 5.0, 1.1), 7.03−7.07 (1H, m), 7.24
(1H, dd, J 5.0, 3.0), 7.31 (2H, d, J 8.1), 7.75 (2H, d, J 8.3); 13C{1H}
NMR (126 MHz, CDCl3) δC 21.7, 42.6, 123.1, 126.8, 127.2, 127.3,
129.9, 137.0, 137.2, 143.7; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C12H14NO2S2 268.0466, found 268.0470.
N-(4-(Benzyloxy)benzyl)-4-methylbenzenesulfonamide (13). The
title compound was prepared according to general procedure A, using
p-toluenesulfonamide (171 mg, 1.00 mmol) and (4-(benzyloxy)-
phenyl)methanol (214 mg, 1.00 mmol), and was purified by flash
column chromatography (30 × 125 mm silica, 20% EtOAc/petroleum
ether) to yield the title compound (342 mg, 92%) as a white solid: mp
N-Ethyl-4-methylbenzenesulfonamide (18). The title compound
was prepared according to general procedure B, using p-
toluenesulfonamide (171 mg, 1.00 mmol) and ethanol (1 mL), and
was purified by flash column chromatography (30 × 150 mm silica,
20% EtOAc/petroleum ether 40−60) to yield the title compound
(68.3 mg, 34%) as a yellow oil: Rf 0.30 (20% EtOAc/petroleum ether
123−126 °C; Rf 0.19 (20% EtOAc/petroleum ether 40−60); νmax
/
cm−1 (film) 3291, 3269, 1616, 1597, 1585, 1495, 1452, 141412, 1383,
1323, 1256, 1153, 1090, 1028, 862, 841, 812, 743, 723, 689, 565, 546,
1
1
532, 513, 492, 461; H NMR (500 MHz, CDCl3) δH 2.44 (3H, s),
40−60); H NMR (500 MHz, CDCl3) δH 1.10 (3H, t, J 7.2), 2.43
4.06 (2H, d, J 6.1), 4.46 (1H, t, br, J 6.0), 5.04 (2H, s), 6.87−6.89
(2H, m), 7.09−7.12 (2H, m), 7.31−7.34 (3H, m), 7.36−7.42 (4H,
m), 7.75−7.77 (2H, m); 13C{1H} NMR (126 MHz, CDCl3) δC 21.7,
47.0, 70.2, 115.2, 127.4, 127.6, 128.2, 128.7, 128.8, 129.4, 129.9,
136.9, 137.1, 143.7, 158.7; HRMS (EI-TOF) m/z [M + H]+ calcd for
C21H21NO3S 367.1242, found 367.1237.
4-Methyl-N-(4-vinylbenzyl)benzenesulfonamide (14). The title
compound was prepared according to general procedure A, using p-
toluenesulfonamide (171 mg, 1.00 mmol) and (4-vinylphenyl)-
methanol (134 mg, 1.00 mmol) and was purified by flash column
chromatography (30 × 95 mm silica, 20% EtOAc/petroleum ether
40−60) to give the title compound (240 mg, 84%) as a pale yellow
solid: mp 108−110 °C (lit.35 mp 111−113 °C); Rf 0.27 (20% EtOAc/
petroleum ether 40−60); 1H NMR (500 MHz, CDCl3) δH 2.44 (3H,
s), 4.11 (2H, d, J 6.2), 4.57 (1H, t, br, J 6.0), 5.24 (1H, dd, J 10.9,
0.5), 5.72 (1H, dd, J 17.6, 0.5), 6.67 (1H, dd, J 17.6, 10.9), 7.15 (2H,
d, J 8.1), 7.30−7.33 (4H, m), 7.52−7.53 (2H, m), 7.76 (2H, d, J 8.3);
13C{1H} NMR (126 MHz, CDCl3) δC 21.7, 47.2, 114.4, 126.6, 127.3,
128.2, 129.9 135.8, 136.3, 137.0, 137.5, 143.8. Spectroscopic data are
in accordance with the literature.35
Benzyl 4-(((4-Methylphenyl)sulfonamido)methyl)benzoate (15).
The title compound was prepared according to general procedure A,
using p-toluenesulfonamide (171 mg, 1.00 mmol) and benzyl 4-
(hydroxymethyl)benzoate (242 mg, 1.00 mmol), and was purified by
flash column chromatography (30 × 120 mm silica, 20% ethyl
acetate/petroleum ether 40−60), followed by trituration in petroleum
ether 40−60, to give the title compound (205 mg, 52%) as a white
solid: mp 120−123 °C; Rf 0.11 (20% ethyl acetate/petroleum ether
40−60); νmax/cm−1 (film) 3250, 1701, 1609, 1499, 1433, 1420, 1383,
1360, 1333, 1315, 1279, 1244, 1179, 1159, 1123, 1113, 1094, 1059,
(3H, s), 3.00 (2H, qd J 7.2, 6.2), 4.39 (1H, t, br, J 5.3), 7.31 (2H, d, J
7.9), 7.74−7.76 (2H, m); 13C{1H} NMR (126 MHz, CDCl3) δC 15.2,
21.7, 38.4, 127.3, 129.8, 137.1, 143.5. Spectroscopic data are in
accordance with the literature.39
N-Methyl-4-methylbenzenesulfonamide (19). The title com-
pound was prepared according to general procedure B, using p-
toluenesulfonamide (171 mg, 1.00 mmol) and methanol (1 mL), and
was purified by flash column chromatography (30 × 150 mm silica,
20% EtOAc/petroleum ether 40−60) to yield the title compound
(30.8 mg, 17%) as a white solid: mp 72−73 °C (lit.40 mp 70−71 °C);
1
Rf 0.28 (20% EtOAc/petroleum ether 40−60); H NMR (500 MHz,
CDCl3) δH 2.43 (3H, s), 2.65 (3H, d, J 5.4), 4.37 (1H, d, br, J 3.8)
7.32 (2H, d, J 2.1), 7.75 (2H, d, J 2.1); 13C{1H} NMR 126 MHz,
CDCl3) δC 22.8, 29.5, 127.4, 129.9, 136.0, 143.7. Spectroscopic data
are in accordance with the literature.40
N-Benzylbenzenesulfonamide (20). The title compound was
prepared according to general procedure A, using benzenesulfona-
mide (157 mg, 1.00 mmol) and benzyl alcohol (109 μL, 1.00 mmol),
and was purified by flash column chromatography (30 × 100 mm
silica, 20% ethyl acetate/petroleum ether 40−60) to give the title
compound (232 mg, 93%) as a yellow solid: mp 77−79 °C (lit.41 mp
1
78−80 °C); Rf 0.27 (20% ethyl acetate/petroleum ether 40−60); H
NMR (500 MHz, CDCl3) δH 4.15 (2H, d, J 6.2), 4.75 (1H, t, br),
7.18−7.20 (2H, m), 7.24−7.30 (3H, m), 7.50−7.54 (2H, m), 7.58−
7.61 (1H, m), 7.87−7.89 (2H, m); 13C{1H} NMR (126 MHz,
CDCl3) δC 47.5, 127.3, 128.0, 128.1, 128.9, 129.3, 132.9, 136.3, 140.0.
Spectroscopic data are in accordance with the literature.41
N-Benzyl-3-methylbenzenesulfonamide (21). The title com-
pound was prepared according to general procedure A, using 3-
methylbenzenesulfonamide (171 mg, 1.00 mmol) and benzyl alcohol
F
DOI: 10.1021/acs.joc.9b00203
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(109 μL, 1.00 mmol), and was purified by flash column
chromatography (30 × 100 mm silica, 20% EtOAc/petroleum ether
40−60) to give the title compound (242 mg, 93%) as a white solid:
sulfonamide (207 mg, 1.00 mmol) and benzyl alcohol (109 μL, 1.00
mmol) and was purified by flash column chromatography (30 × 105
mm silica, 20% EtOAc/petroleum ether 40−60) to give the title
compound (270 mg, 91%) as an off-white solid: mp 121−122 °C
(lit.10a mp 126.5 °C); Rf 0.28 (20% EtOAc/petroleum ether 40−60);
1H NMR (500 MHz, CDCl3) δH 4.18 (2H, d, J 6.2), 4.77 (1H, t, br,
5.9), 7.18−7.25 (5H, m), 7.61−7.68 (2H, m), 7.84 (1H, dd, J 8.7,
1.9), 7.92 (1H, d, J 8.1), 7.96−7.98 (2H, m), 8.45 (2H, d, J 1.2);
13C{1H} NMR (126 MHz, CDCl3) δC 47.6, 122.4, 127.8, 128.0,
128.1, 128.2, 128.8, 128.9, 129.0, 129.4, 129.8, 132.3, 135.0, 136.2,
136.8. Spectroscopic data are in accordance with the literature.10a
N-Benzyl-4-methoxybenzenesulfonamide (27). The title com-
pound was prepared according to general procedure A, using p-
methoxybenzenesulfonamide (187 mg, 1.00 mmol) and benzyl
alcohol (109 μL, 1.00 mmol) and was purified by flash column
chromatography (30 × 100 mm silica, 20−40% ethyl acetate/
petroleum ether 40−60) to give the title compound (255 mg, 92%) as
an off-white solid; mp 109−111 °C (lit.9d mp 112−113 °C); Rf 0.35
mp 46−48 °C; Rf 0.20 (20% EtOAc/petroleum ether 40−60); νmax
/
cm−1 (film) 3265, 1599, 1454, 1427, 1360, 1319, 1256, 1209, 1150,
1099, 1055, 916, 889, 866, 810, 783, 746, 694, 658, 584,559, 527, 511,
1
484, 434, 407; H NMR (500 MHz, CDCl3) δH 2.42 (3H, s), 4.15
(2H, d, J 6.2), 4.61 (1H, t, br, J 5.4), 7.19−7.21 (2H, m), 7.24−7.30
(3H, m), 7.38−7.42 (2H, m), 7.67−7.69 (2H, m); 13C{1H} NMR
(126 MHz, CDCl3) δC 21.5, 47.4, 124.4, 127.6, 128.0, 128.1, 128.8,
129.1, 133.6, 136.3, 139.5, 139.8; HRMS (ESI-TOF) m/z [M + H]+
calcd for C14H16NO2S 262.0902, found 262.0901.
N-Benzyl-2-methylbenzenesulfonamide (22). The title com-
pound was prepared according to general procedure A, using 2-
methylbenzenesulfonamide (171 mg, 1.00 mmol) and benzyl alcohol
(109 μL, 1.00 mmol), and was purified by flash column
chromatography (30 × 100 mm silica, 20% ethyl acetate/petroleum
ether 40−60) to give the title compound (231 mg, 86%) as an off-
white solid: mp 98−100 °C (lit.11bmp 101.2−102.5 °C); Rf 0.27 (20%
ethyl acetate/petroleum ether 40−60); 1H NMR (500 MHz, CDCl3)
δH 2.62 (3H, s), 4.12 (2H, d, J 6.1), 4.67 (1H, t, br, J 4.9), 7.16−717
(2H, m), 7.24−7.34 (m, 5H), 7.47 (1H, td, J 7.5, 1.0), 8.00 (1H, d, J
7.9); 13C{1H} NMR (126 MHz, CDCl3) δC 20.4, 47.3, 126.4, 128.1,
128.2, 128.9, 129.8, 132.7, 133.0, 136.4, 137.2, 137.9. Spectroscopic
data are in accordance with the literature.11b
1
(20% ethyl acetate/petroleum ether 40−60); H NMR (500 MHz,
CDCl3) δ 3.88 (3H, s), 4.12 (2H, d, J 6.2), 4.63 (1H, t, br, J 6.0),
H
6.96−6.99 (2H, m), 7.18−7.21 (2H, m), 7.24−7.30 (3H, m), 7.80−
7.83 (2H, m); 13C{1H} NMR (126 MHz, CDCl3) δC 47.4, 55.8,
114.4, 128.0, 128.1, 128.9, 129.5, 131.6, 136.4, 163.1. Spectroscopic
data are in accordance with the literature.9d
N-Benzyl-4-(trifluoromethyl)benzenesulfonamide (28). The title
compound was prepared according to general procedure B, using 4-
(trifluoromethyl)benzenesulfonamide (225 mg, 1.00 mmol) and
benzyl alcohol (109 μL, 1.00 mmol), and purified by flash column
chromatography (45 × 150 mm silica, 10% EtOAc/petroleum ether
40−60), then triturated in petroleum ether 40−60 to yield the
product (193 mg, 61%) as an off-white solid: mp 119−121 °C; Rf
0.21 (20% EtOAc/petroleum ether 40−60); νmax/cm−1 (film) 3271,
1404, 1323, 1157, 1130, 1111, 1094, 1061, 1028, 1013, 907,876, 841,
N-Benzyl-2,4,6-trimethylbenzenesulfonamide (23). The title
compound was prepared according to general procedure A, using
2,4,6-trimethylbenzenesulfonamide (199 mg, 1.00 mmol) and benzyl
alcohol (109 μL, 1.00 mmol), and was purified by flash column
chromatography (30 × 120 mm silica, 20% EtOAc/petroleum ether
40−60) to yield the title compound (266 mg, 92%) as a white solid:
mp 94−97 °C (lit.42 mp 96−98 °C); Rf 0.41 (20% EtOAc/petroleum
1
ether 40−60); H NMR (500 MHz, CDCl3) δH 2.31 (3H, s), 2.64
1
(6H, s), 4.08 (2H, d, J 6.2), 4.64 (1H, t, br, J 5.8), 6.96 (2H, s), 7.23−
7.25 (1H, m), 7.27−7.29 (2H, m); 13C{1H} NMR (126 MHz,
CDCl3) δC 21.1, 23.1, 46.9, 128.0, 128.0, 128.8, 132.1, 133.5, 136.4,
139.3, 142.5. Spectroscopic data are in accordance with the
literature.42
733, 712, 696, 613, 598, 532, 488, 453, 430; H NMR (500 MHz,
CDCl3) δH 4.21 (2H, d, J 8.1), 4.76 (1H, t, br, J 5.8), 7.16−7.18 (2H,
m), 7.27−7.30 (3H, m), 7.75 (2H, d, J 8.2), 7.96 (2H, d, J 8.2);
19F{1H} NMR (471 MHz, CDCl3) δF −63.16; 13C{1H} NMR (126
MHz, CDCl3) δC 475, 123.4 (q, J 273), 126.4 (q, J 3.7), 127.7, 128.0,
128.2, 128.9, 134.5 (q, J 33.1), 1235.8, 143.8; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C14H13NO2SF3 316.0619, found 316.0623.
N-Benzyl-4-bromobenzenesulfonamide (29). The title compound
was prepared according to general procedure A, using 4-
bromobenzenesulfonamide (236 mg, 1.00 mmol) and benzyl alcohol
(109 μL, 1.00 mmol), and was purified by flash column
chromatography (30 × 150 mm silica, 20% EtOAc/petroleum ether
40−60) to give the title compound (288 mg, 88%) as a white solid:
mp 117−118 °C (lit.11b mp 119−120 °C); Rf 0.32 (20% ethyl
N-Benzyl-2,4,6-triisopropylbenzenesulfonamide (24). The title
compound was prepared according to general procedure A, using
2,4,6-triisopropylbenzenesulfonamide (283 mg, 1.00 mmol) and
benzyl alcohol (109 μL, 1.00 mmol), and was purified by flash
column chromatography (30 × 100 mm silica, 20% EtOAc/petroleum
ether 40−60) to yield the title compound (368 mg, 99%) as a white
powder: mp 83−85 °C; Rf 0.60 (20% EtOAc/petroleum ether 40−
60); νmax/cm−1 (film) 3316, 2959, 2866, 1763, 1599, 1454, 1425,
1383, 1362, 1319, 1298, 1256, 1196, 1152, 1105, 1057, 968, 941, 916,
889, 862, 810, 746, 694, 658, 627, 594, 559, 546, 529, 509, 436, 419;
1H NMR (500 MHz, CDCl3) δH 1.27 (18 H, t, J 6.9), 2.92 (1H, dt, J
13.9, 6.9), 4.15−4.21 (4H, m), 4.51 (1H, t, br, J 6.1), 7.18 (2H, s),
7.19−7.21 (2H, m), 7.27−7.30 (3H, m); 13C{1H} NMR (126 MHz,
CDCl3) δC 23.8, 25.0, 29.9, 34.3, 47.2, 124.0, 128.1, 128.2, 128.9,
132.4, 136.6, 150.5, 153.0; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C22H32NO2S 374.2154, found 374.2153.
N-Benzylnaphthalene-1-sulfonamide (25). The title compound
was prepared according to general procedure A, using naphthalene-1-
sulfonamide (207 mg, 1.00 mmol) and benzyl alcohol (109 μL, 1.00
mmol), and was purified by flash column chromatography (30 × 110
mm silica, 20% EtOAc/petroleum ether 40−60) to give the title
compound (251 mg, 84%) as a white solid: mp 165−166 °C (lit.31
mp 166−168 °C); Rf 0.30 (20% EtOAc/petroleum ether 40−60); 1H
NMR (500 MHz, CDCl3) δH 4.08 (2H, d, J 6.1), 4.82 (1H, t, br, J
5.9), 7.05−7.07 (2H, m), 7.16−7.19 (3H, m), 7.53 (1H, dd, J 8.1,
7.5), 7.60−7.63 (1H, m), 7.65−7.69 (1H,m), 7.96 (1H, d, J 8.1), 8.07
(1H, d, J 8.2), 8.28 (1H, dd, J 7.3, 1.2), 8.65 (1H, d, J 8.6); 13C{1H}
NMR (126 MHz, CDCl3) δC 47.5, 124.3, 124.4, 127.0, 127.9, 128.0,
128.3, 128.6, 128.7, 129.3, 130.1, 134.4, 134.5, 134.5, 136.2.
Spectroscopic data are in accordance with the literature.31
1
acetate/petroleum ether 40−60); H NMR (500 MHz, CDCl3) δH
4.13 (2H, d, J 6.1), 5.11 (1H, t, br, J 5.3), 7.16−7.17 (2H, m), 7.25−
7.26 (3H, m), 7.60 (2H, d, J 8.2), 7.68 (2H, d, J 8.2); 13C{1H} NMR
(126 MHz, CDCl3) δC 47.4, 127.7. 128.0, 128.1, 128.8, 128.8, 132.5,
132.5, 136.0, 139.1. Spectroscopic data are in accordance with the
literature.11b
N-Benzylthiophene-2-sulfonamide (30). The title compound was
prepared according to general procedure A, using 2-thiophenesulfo-
namide (163 mg, 1.00 mmol) and benzyl alcohol (104 μL, 1.00
mmol), and was purified by flash column chromatography (30 × 100
mm silica, 20% ethyl acetate/petroleum ether 40−60) to give the title
compound (186 mg, 73%) as a yellow solid: mp 69−71 °C (lit.9e mp
1
70−72 °C; Rf 0.20 (20% ethyl acetate/petroleum ether 40−60); H
NMR (500 MHz, CDCl3) δH 4.22 (2H, d, J 5.8), 4.94 (1H, s, br),
7.08 (1H, s), 7.22−7.30 (5 H, m) 7.59−7.61 (2H, m); 13C{1H} NMR
(126 MHz, CDCl3) δC 47.7, 127.6, 128.1, 128.3, 129.0, 132.2, 132.6,
136.0, 141.0. All spectroscopic data are in accordance with the
literature.9e
N-Benzyl-4-(benzyloxy)benzenesulfonamide (31). The title com-
pound was prepared according to general procedure A, using 4-
(benzyloxy)benzenesulfonamide (263 mg) and benzyl alcohol (109
μL, 1.00 mmol), and was purified by flash column chromatography
(30 × 95 mm silica, 20% EtOAc/petroleum ether 40−60) to give the
N-Benzylnaphthalene-2-sulfonamide (26). The title compound
was prepared according to general procedure A, using naphthalene-2-
G
DOI: 10.1021/acs.joc.9b00203
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
title compound (315 mg, 99%) as an off-white solid: mp 131−132
°C; Rf 0.22 (20% EtOAc/petroleum ether 40−60); νmax/cm−1 (film)
3265, 1593, 1576, 1497, 1452, 1425, 1321, 1250, 1152, 1094, 1047,
993, 862, 840, 829, 810, 752, 656, 608, 590, 511, 455, 407; 1H NMR
(500 MHz, CDCl3) δH 4.13 (2H, d, J 6.2), 4.60 (1H, t, br, J 6.1), 5.14
(2H, s), 7.05 (2H, d, J 8.7), 7.19−7.20 (2H, m), 7.19 (2H, d, J 6.6),
7.24−7.28 (2H, m), 7.35−7.43 (5H, m) 7.81 (2H, d, J 8.7); 13C{1H}
NMR (126 MHz, CDCl3) δC 47.4, 70.4, 115.2, 127.6, 128.0, 128.0,
128.5, 128.8, 128.9, 129.4, 131.7, 135.9. 136.4, 162.1; HRMS (EI-
TOF) m/z [M + H]+ calcd for C20H20NO3S 354.1164, found
354.1159.
903, 868, 731, 693, 662, 615, 592, 521, 509, 459; H NMR (500
MHz, CDCl3) δH 1.44 (9H, s), 4.08 (1H, t, br, J 5.0), 4.37 (2H, d, J
6.0) 7.29−7.33 (1H, m), 7.34−7.38 (4H, m); 13C{1H} NMR (126
MHz, CDCl3) δC 24.5, 48.8, 63.2, 127.9, 128.1, 129.0, 137.8; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C11H18NO2S 228.1058, found
228.1063.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00203.
N-Benzyl-4-vinylbenzenesulfonamide (32). The title compound
was prepared according to general procedure A, using 4-vinyl-
benzenesulfonamide (183 mg, 1.00 mmol) and benzyl alcohol (109
μL, 1.00 mmol), and purified by flash column chromatography (30 ×
95 mm silica, 20% EtOAc/petroleum ether 40−60) to give the title
compound (191 mg, 72%) as a white solid: mp 85−87 °C; Rf 0.30
(20% EtOAc/petroleum ether 40−60); νmax/cm−1 (film) 3267, 1597,
1495, 1456, 1437, 1395, 1319, 1310, 1153, 1055, 1028, 986, 914, 868,
Optimization data and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: morrilllc@cardiff.ac.uk.
■
ORCID
1
841, 731, 696, 654, 594, 563, 529, 484, 449, 411; H NMR (500
Louis C. Morrill: 0000-0002-6453-7531
MHz, CDCl3) δH 4.14 (2H, d, J 6.2), 4.71 (1H, t, br, J 5.9), 5.44 (1H,
d, J 10.9), 5.89 (1H, d, J 17.6), 6.76 (1H, dd, J 17.6, 10.9), 7.20 (2H,
d, J 7.32), 7.19−7.30 (3H, m), 7.52 (2H, d, J 8.2), 7.82 (2H, d, J 8.3);
13C{1H} NMR (126 MHz, CDCl3) δC 47.5, 177.6, 126.9, 127.6,
128.0, 128.1, 128.9, 135.5, 136.3, 138.8, 142.1; HRMS (ESI-TOF) m/
z [M + H]+ calcd for C15H16NO2S 274.0902, found 274.0903.
N-Benzylmethanesulfonamide (33). The title compound was
prepared according to general procedure A, using methane
sulfonamide (95.1 mg, 1.00 mmol) and benzyl alcohol (109 μL,
1.00 mmol), and was purified by flash column chromatography (30 ×
105 mm silica, 20% ethyl acetate/petroleum ether 40−60) to give the
title compound (158 mg, 85%) as an off-white solid: mp 58−61 °C
(lit.43 mp 57−60 °C); Rf 0.29 (20% ethyl acetate/petroleum ether
40−60); 1H NMR (500 MHz, CDCl3) δH 2.88 (3H, s), 4.34 (2H, d, J
6.1), 4.58 (1H, s, br), 7.31−7.40 (5H, m); 13C{1H} NMR (126 MHz,
CDCl3) δC 41.3, 47.4, 128.1, 128.3, 129.1, 136.8. Spectroscopic data
are in accordance with the literature.43
Notes
The authors declare no competing financial interest.
Information about the data that underpins the results
presented in this article, including how to access them, can
be found in the Cardiff University data catalogue at http://doi.
org/10.17035/d.2019.0069100566 (accessed February 21,
2019).
ACKNOWLEDGMENTS
■
We gratefully acknowledge the School of Chemistry, Cardiff
University, for generous support, the EPSRC Doctoral
Training Grant for a partially funded PhD studentship
(B.G.R-B., EP/M507842/1), and the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
N-Benzylethanesulfonamide (34). The title compound was
prepared according to general procedure A, using ethane sulfonamide
(109 mg, 1.00 mmol) and benzyl alcohol (109 μL, 1.00 mmol), and
was purified by flash column chromatography (30 × 105 mm silica,
20% ethyl acetate/petroleum ether 40−60) to give the title
compound (165 mg, 83%) as a white solid: mp 58−59 °C; Rf 0.31
(20% ethyl acetate/petroleum ether 40−60); νmax/cm−1 (film) 3287,
1456, 1429, 1314, 1283, 1227, 1130, 1055, 993, 854, 779, 758, 718,
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