Reaction Route and Mechanism of the Direct N-Alkylation of Sulfonamides on Acidic Mesoporous Zeolite β-Catalyst

Article abstract of DOI:10.1021/acscatal.8b02030

Development of highly active heterogeneous catalysts with strong acidity and mesoporous structure is a highly attractive strategy for organic synthesis. In this study, a mesoporous zeolite beta (HBeta-M) with bulky particle size and strong acidity was synthesized and used in the direct N-alkylation of sulfonamides with alcohols. The strongly acidic HBeta-M had a higher intrinsic activity with initial turnover frequency of 11 × 10^-2 s^-1 than those of H-form mordenite nanosheets (3.3 × 10^-2 s^-1) and montmorillonite (4.0 × 10^-2 s^-1) catalysts. The experiment and characterization results demonstrate that there are two parallel reaction routes on the acidic catalysts. One route is the reaction of benzhydrol with p-toluenesulfonamide (route I). Another route is the reaction of dibenzhydryl ether, arising from route I, with p-toluenesulfonamide (route II), which is found in this work. The reaction rate of route I (13 × 10^-3 mol kg^-1 s^-1) was higher than that of route II (9.8 × 10^-3 mol kg^-1 s^-1) on HBeta-M, but route II predominantly contributed to the formation of the target product with high selectivity. Hereby, a complete reaction mechanism is proposed in this work.

Full text of DOI:10.1021/acscatal.8b02030

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Article
Reaction route and mechanism of the direct N-alkylation of
sulfonamides on acidic mesoporous zeolite Beta catalyst
Wenqian Fu, Runsheng Shen, Enhui Bai, Lei Zhang, Qun Chen, Zhongxue
Fang, Guangchao Li, Xianfeng Yi, Anmin Zheng, and Tiandi Tang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02030 • Publication Date (Web): 17 Aug 2018
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Reaction route and mechanism of the direct Nꢀ
alkylation of sulfonamides on acidic mesoporous
zeolite Beta catalyst
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Wenqian Fu,† Runsheng Shen,† Enhui Bai,† Lei Zhang,† Qun Chen,*† Zhongxue Fang,†
Guangchao Li,‡ Xianfeng Yi, ‡ Anmin Zheng,*‡ Tiandi Tang*†
†Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School of
Petrochemical Engineering, Changzhou University, Changzhou, Jiangsu 213164, P. R. China.
‡State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National
Center for Magnetic Resonance in Wuhan, Key Laboratory of Magnetic Resonance in Biological
Systems, Wuhan Institute of Physics and Mathematics, the Chinese Academy of Sciences,
Wuhan 430071, P. R. China.
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ABSTRACT: Development of highly active heterogeneous catalysts with strong acidity and
mesoporous structure is a highly attractive strategy for organic synthesis. In this study, a
mesoporous zeolite Beta (HBetaꢀM) with bulky particle size and strong acidity was synthesized
and used in the direct Nꢀalkylation of sulfonamides with alcohols. The strongly acidic HBetaꢀM
had a higher intrinsic activity, with initial turnover frequency of 11×10ꢀ2 sꢀ1, than Hꢀform
mordenite nanosheets (3.3×10ꢀ2 sꢀ1) and montmorillonite (4.0×10ꢀ2 sꢀ1) catalysts. The experiment
and characterization results demonstrate that there are two parallel reaction routes on the acidic
catalysts. One route is the reaction of benzhydrol with pꢀtoluenesulfonamide (RouteꢀI). Another
route is the reaction of dibenzhydryl ether, arising from RouteꢀI, with pꢀtoluenesulfonamide
(RouteꢀII), which is found in this work. The reaction rate of RouteꢀI (13×10ꢀ3 mol·kgꢀ1·sꢀ1) was
higher than that of RouteꢀII (9.8×10ꢀ3 mol·kgꢀ1·sꢀ1) on HBetaꢀM, but RouteꢀII predominantly
contributed to the formation of the target product with high selectivity. Hereby, a complete
reaction mechanism was proposed in this work.
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KEYWORDS: Mesoporous zeolite Beta, Strong acidity, Nꢀalkylation, Reaction route, Reaction
mechanism
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INTRODUCTION
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The direct Nꢀalkylation of amines with alcohols as the alkylation reagents is an important route
for the construction of nitrogenꢀcontaining compounds, which are significant building blocks for
pharmaceuticals and novel bioꢀactive compounds.1ꢀ3 Generally, this reaction requires suitable
promoters due to the poor leaving ability of the hydroxyl group in alcohols,4,5 leading to the
formation of stoichiometric amounts of salt waste. Although other alkylating agents such as alkyl
halides, sulfonates, aldehydes, diazomethane and carboxylic acid were replaced with alcohols for
the Nꢀalkylation of amines, byꢀproducts are inevitably formed during these reactions.6ꢀ8 Alcohols,
which are readily available, are still good alkylation reagents for Nꢀalkylation reaction. To
directly use alcohols as alkylation reagents while avoiding the waste formation, it is critical to
develop highly efficient catalysts. With respect to this aspect, noble metal9,10 and Lewis acid
metal catalysts11ꢀ13 have been developed for the direct substitution of alcohols with various
nitrogen nucleophiles, such as amides, sulfonamides, carboxamides, carbamates, and amines.
Among these protocols, a noble metalꢀcatalyzed the Nꢀalkylating sulfonamides with alcohols is
an effective synthetic method using borrowing hydrogen methodology.14 However, the high
price of noble metal catalysts and the insufficient activity of Lewis acid metals limit their
practical applications. Furthermore, the separation of products and metal salts from the reaction
system is difficult and complicated, resulting in a tedious purification process and the formation
of inevitable solid waste. These protocols not only did not meet the requirement of the green
synthesis chemistry, but also was harmful to environmentally sustainable development. Solid
catalysts, such as heteropoly acids,15 protonꢀexchanged montmorillonite16,17 and the acidic resin
Amberlystꢀ15 in ionic liquid,18 have also been employed for the amidation of alcohols. However,
problems remain, including the dissolution of heteropoly acid, and the thermoꢀ and chemicalꢀ
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stability of the resins. The low surface area and the weak acidity of the montmorillonite also
result in unsatisfactory activity in this transformation. On the other hand, it is notable that the
proposed reaction mechanisms in the literatures are vague,16,17,19 and have not been verified by
experiment. Thus, developing highly efficient and green catalyst for the direct Nꢀalkylation of
amines with alcohols is critical. In addition, clarifying this reaction route and mechanism by
experiment method is of significant importance.
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Generally, acidic solid catalyst is able to cleave the carbonꢀoxygen bond of alcohols to produce
carbocations through H+ interaction with hydroxyl group in alcohols.20 In the past decades, the
mesoporous aluminosilicate zeolites as acidic catalysts show superior catalytic performance in
many reactions.21ꢀ23 In this respect, we synthesized a series of mesoporous zeolites and zeolite
nanocrystal assemblies for applications in organic chemistry. 24ꢀ26 As part of our ongoing focus
on the catalytic application of zeolite catalysts in organic synthesis, in this study, we report a
facile method to synthesize mesoporous zeolite Beta (BetaꢀM) with large particle sizes at a large
scale, which can be readily separated from the reaction mixture by simple filtration. After the
BetaꢀM was ionꢀexchanged with a solution of NH4NO3 and calcined, the obtained Hꢀform
(HBetaꢀM) with strong acidity shows high activity in the direct Nꢀalkylation of sulfonamides
with benzylic alcohols, compared to the Hꢀform of mordenite nanosheets (NSꢀHMOR),
montmorillonite (HMont) and mesoporeꢀfree zeolite Beta (HBeta). Very importantly, this
reaction on acidic HBetaꢀM proceeds through two parallel reaction routes. One route is
adsorption and activation of benzylic alcohols on acidic sites, producing carbocation
intermediates, which are attacked by the sulfonamide nucleophiles to form the Nꢀsubstituted
sulfonamide products (RouteꢀI). The other route is the easy transformation of the benzylic
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alcohols on the strongly acidic sites to ethers, which are more active towards the formation of
carbocation intermediates, facilitating the formation of the target products (RouteꢀII).
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2 Experimental
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2.1 Materials synthesis
A typical synthesis of mesoporous zeolite Beta was performed as follows. 0.34 kg NaOH was
dissolved in 19 L H2O with stirring, followed by addition of 0.73 kg NaAlO2 and 6 L 25 wt.%
tetraethylammonium hydroxide (TPAOH). After stirring at room temperature for 1 h, 8.5 kg
silica gel was added to the above solution and stirred for 1 h. A cationic copolymer (4.5 L)
containing quaternary ammonium groups (RCC) was added dropwise and the mixture was stirred
for 2 h to obtain a gel. The mesoscale template of RCC was synthesized as in our previous
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The
composition
of
this
final
gel
was
Al2O3/32SiO2/2Na2O/0.01RCC/2.6TPAOH/296H2O. This gel was transferred into a 50 L
autoclave for dynamic crystallization at 140 °C for 6 days. The solid product was collected by
filtration, dried, and calcined at 550 °C for 6 h to remove the organic template. The mesoporeꢀ
free zeolite Beta (Beta) was synthesized according to a previously reported method.28
For comparison, mordenite nanosheets (NSꢀMOR) was synthesized according to a previously
reported method.27 Montmorillonite (Mont) was purchased from Sinopharm Chemical Reagent
Co., Ltd. The Hꢀform of these samples was obtained by ion exchange with a 1 M NH4NO3
solution at 80 °C for 4 h, followed by calcination at 550 °C for 4 h. The solid catalysts were
denoted as HBetaꢀM, NSꢀHMOR, HBeta and HMont, respectively.
2.2 Characterization
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The Xꢀray powder diffraction (XRD) pattern was recorded on a D/MAX 2500/PC powder
diffractometer (Rigaku) using a Cu Kα radiation source operated at 40 kV and 200 mA. Nitrogen
physisorption was conducted at ꢀ196 °C on a Micromeritics ASAP 2020M apparatus. The
sample was degassed for 8 h at 300 °C before the measurement. The ratios of Si/Al in the
zeolites were determined by inductively coupled plasma optical emission spectroscopy (ICPꢀ
OES) with a PerkinꢀElmer 3300DV emission spectrometer. Scanning electron microscopy (SEM)
was performed using a SUPRA 55 field emission scanning electron microscope operating at an
acceleration voltage of 5 kV. Before the analysis, the sample was coated with gold to create
contrast. Transmission electron microscopy (TEM) was performed on a JEMꢀ2100F microscope
with a limited line resolution capacity of 1.4 Å at 200 kV. Before characterization by TEM, the
sample was cut into thin slices and dropped onto a Cu grid coated with a carbon membrane.
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The acidity of the catalyst was measured by ammonia temperatureꢀprogrammed desorption
(NH3ꢀTPD) on a Micromeritics ASAP 2920 instrument. Typically, 200 mg of the sample was
placed in a quartz tube and pretreated with a helium stream at 450 °C for 2 h. After the sample
was cooled to 120 °C, an NH3ꢀHe gas mixture (10 vol.% NH3) was flowed over the sample for
30 min. After removing the physically adsorbed NH3 by flowing helium for 2 h at 120 °C, the
sample was heated from 120 to 520 °C at a rate of 10 °C·minꢀ1. The total acidic site density of
the materials can be obtained from the total amount of the desorption ammonia, which was
collected in dilute hydrochloric acid solution and then titrated with a dilute sodium hydroxide
solution. Generally, the strength of the acidic sites is determined by desorption activation energy
of the adsorbed ammonia, which is related to the desorption temperature of the adsorbed
NH3.29,30 Based on the desorption temperature of the adsorbed NH3, the acidic sites can be
classified as weak acidic (120–250 °C), medium strong acidic (250–350°C), and strong acidic
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(>350°C) sites.31 Thus, the obtained NH3ꢀTPD curves were deconvoluted at different maximum
peak temperatures with a Gaussian function for fitting,32 and the peak areas were calculated. The
peak areas were correlated with the amount of adsorbed NH3 in different temperature regions.
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The acidity of the HBetaꢀM was also investigated by solidꢀstate P nuclear magnetic resonance
(31P NMR) on a Bruker Ascendꢀ500 spectrometer. The pyridine and 2,6ꢀdiꢀtertꢀbutylpyridine
temperature programmed desorption (PyꢀTPD and 2,6ꢀDTBPyꢀTPD) were performed on a
Micromeritics ASAP 2920 instrument.
The infrared spectra (IR) of the benzhydrol, dibenzhydryl ether and benzhydrolꢀ and
dibenzhydryl etherꢀchemisorbed catalyst samples were obtained on a Bruker TENSOR 27
infrared spectrophotometer equipped with a reactor cell. Before measurement, the catalyst
sample was evacuated to 10ꢀ2 Pa at 50 °C for 20 h. The spectrum was obtained in absorbance
mode and was shown after subtraction of a background spectrum obtained on the corresponding
pure catalyst sample at 50 °C under vacuum. For comparison, the spectra of benzhydrol and
dibenzhydryl ether were also recorded at room temperature. The ultravioletꢀvisible diffuse
reflection (UVꢀVis DR) spectra of the benzhydrol (1a), dibenzhydryl ether (4a), and 1aꢀ and 4aꢀ
chemisorbed on HBetaꢀM (HBetaꢀMꢀ1a and HBetaꢀMꢀ4a) and HMont (HMontꢀ1a and HMontꢀ
4a) samples were obtained on a Shimadzu UVꢀ3600 spectrometer. Before characterization, the
HBetaꢀMꢀ1a, HBetaꢀMꢀ4a, HMontꢀ1a and HMontꢀ4a solid samples were evacuated to 10ꢀ2 Pa at
50 °C for 20 h and then cooled to room temperature.
2.3 Activity test
2.3.1 Apparent activity of the catalyst
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Before the reaction, the powdered catalyst was calcined at 300 °C for 2 h in air to remove
physically adsorbed water. The typical experimental procedure for the Nꢀalkylation of pꢀ
toluenesulfonamide with benzhydrol was as follows: powdered catalyst (20 mg), benzhydrol 1a
(0.3 mmol), pꢀtoluenesulfonamide 2a (0.6 mmol), and 1,2ꢀdichloroethane (DCE, 1.5 mL), with
diphenylmethane (50 ꢁL) as an internal standard, were placed in a sealed tube (10 mL) under N2
atmosphere. The sealed tube was put in an oil bath when the reaction temperature of the oil
reached 80 °C and maintained at 80 °C for 4 h. The reaction temperature and stirring rate in the
sealed tube was controlled using an IKA stirrer (model of RTC BS025). When the reaction was
finished, the sealed tube was removed from the oil bath. After the reaction mixture in the sealed
tube was cooled to room temperature, the reaction mixture was centrifuged to obtain the liquid
phase. The liquid products were analyzed using an Agilent 7890B GC equipped with a flame
ionization detector. The conversion and product selectivity were calculated as follows.
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Moles of carbon reacted benzhydrol
Benzhydrol conversion=
×100
Moles of carbon in initial benzhydrol
Carbon moles in product i
Product i selectivity=
×100
Sum of carbon moles in product i
The moles of carbon in the products and unreacted benzhydrol were also the same as the moles
of carbon in the initial benzhydrol. The pure product was obtained by flash column
chromatography on silica gel using petroleum ether (60ꢀ90 °C) and ethyl acetate as eluents.
2.3.2 Intrinsic activity of the catalyst
To investigate the intrinsic activity of the catalyst, additional experiments were performed in a
300 mL Parr4848 stainless autoclave (Figure S1) under the reaction conditions that excluded the
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mass and heat transfer limitations. For this purpose, the powdered catalyst sample was pelleted
under a pressure of 7.5 MPa, crushed, and screened to different mesh particles, and then these
particles were calcined at 300 °C for 2 h in air to remove physically adsorbed water before the
reaction test. The experiment was carried out as followed: 0.1 g tableted catalyst, 7.5 mmol
benzhydrol 1a, 15 mmol pꢀtoluenesulfonamide 2a, and 130 mL DCE as the solvent, with 1 mL
diphenylmethane as an internal standard, at a temperature of 80 °C in a N2 atmosphere. In this
case, the initial reaction rate can be calculated as follows.33
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n
dx
robs=
×
W dt
where robs is the initial reaction rate (molꢂkgꢀ1ꢂsꢀ1), n is the initial amount of benzhydrol (mol), x
is the benzhydrol (or dibenzhydryl ether) conversion, W is the catalyst mass (kg), and t is the
reaction time (s), dx is the differential of the benzhydrol (or dibenzhydryl ether) conversion.
In addition, because the micropore sizes in HBetaꢀM and NSꢀHMOR are much smaller than the
dimensions of the bulk reactants and products (Table S1), the Nꢀalkylation reaction mainly
occurs on the acidic sites in the mesopores and on the outer surface of the zeolite catalysts. Thus,
the acidic sites in the mesopores are responsible for the Nꢀalkylation reaction. In this case, the
initial turnover frequency (TOF, sꢀ1) should be calculated based on the acidic site density in the
mesopore, given by the following equation:
robs
TOFini =
MTꢀ
robs
TOFSini =
MT,Sꢀ
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where TOFini is calculated based on the total acidic site density in the mesopores, TOFSini is
calculated based on the strongly acidic site density in the mesopores. MT is the total acidic site
density (mol·kgꢀ1), MT,S is the strong acidic site density (mol·kgꢀ1), and y is the mesoporous
content in the sample, which is calculated from the ratio of the external surface area to the BET
surface area. The y value for the HBetaꢀM, NSꢀHMOR, HMont is 0.25, 0.18 and 1.0,
respectively.
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2.3.3 Catalyst recycle
The recycle experiment for the HBetaꢀM catalyst was performed in a 300 mL Parr4848 stainless
autoclave. When the reaction was finished, the catalyst was separated from the reaction mixture
by filtration and thoroughly washed with dichloromethane. After that, the sample was dried at
100 °C for 12 h and calcined at 550 °C for 4 h in air before use in the next cycle.
2.4. Benzhydrol and dibenzhydryl ether adsorption experiment
The adsorption experiment was carried out following: 0.2 g powdered catalyst, 40 mg of
benzhydrol (or dibenzhydryl ether) and 65 ꢁL diphenylmethane (as an internal standard) was
dissolved in DCE (10 mL) in a 25 mL sealed tube with a magnetic stir bar. Then, the sealed tube
was put in an oil bath at 60 °C for 3 h under stirring. After cooling to room temperature, the
liquid phase was separated by filtration from the suspension and was analyzed using Agilent
7890B GC. The remaining solid sample was washed with DCE (15 mL) 20 times to eliminate the
physically adsorbed benzhydrol (or dibenzhydryl ether) and dried at 60 °C for 48 h. The resulting
solid sample was evacuated (10ꢀ2 Pa) at 50 °C for 20 h and then used for UVꢀVis DR spectrum
and IR characterization as described above.
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3 Results and discussion
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3.1 Catalyst characterization
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Figure 1a shows the powder XRD pattern of the BetaꢀM sample. The sample exhibits typical
diffraction peaks at 7.7°, 21.4°, 22.6°, 25.4° and 27.1°, which are consistent with the Beta
zeolite.34 The nitrogen sorption isotherm of BetaꢀM exhibits a hysteresis loop at a relative
pressure of 0.50ꢀ0.95, indicating the presence of mesoporous structure in the BetaꢀM (Figure 1b).
The pore size distribution shows that the mesoporous diameter is mainly centered at 11 nm (inset,
Figure 1b). The detailed textural parameters of the samples are given in Table 1. HBetaꢀM shows
a high BET surface area (590 m2·gꢀ1), mesoporous surface area (180 m2·gꢀ1) and mesoporous
volume (0.27 cm3·gꢀ1). In contrast, the mesoporeꢀfree HBeta zeolite only has an external surface
area of 58 m2·gꢀ1 (Figure S2 and Figure S3, Table 1).
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b
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a
11 nm
280
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0.0
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Pore width (nm)
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0.0
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0.6
0.8
1.0
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50
2 Theta (deg.)
Relative pressure (P/P0)
Figure 1. (a) XRD pattern and (b) N2 adsorption isotherms of the BetaꢀM sample (inset,
mesoporous size distribution).
Table 1 Textural parameters of the various catalysts.
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Samples
SBETɑ (m2ꢂgꢀ1) Vmic.b (cm3ꢂgꢀ1) Sext.c (m2·gꢀ1)
Vmes.d (cm3·gꢀ1)
0.27
HBetaꢀM
HBeta
590
454
499
474
72
0.16
0.15
0.15
0.15
0.01
0.14
180
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HBetaꢀMe
NSꢀHMORe
HMonte
128
86
0.21
0.19
72
0.14
Reused HBetaꢀM
486
121
0.20
ɑBET surface area. bMicroporous volume. cExternal surface area, including mesoporous surface
area. dMesoporous volume. eThe sample was tableted under the pressure of 7.5 MPa before N2ꢀ
physisorption.
The SEM image reveals the BetaꢀM crystal particles with size of approximately 1 ꢁm (Figure 2a),
which is of significant importance in order to obtain products from the reaction mixture through
separation by simple filtration method. The light areas in the TEM image of the thinꢀsectioned
sample represent mesopore cavities within the crystals (Figure 2b). The size range of the
mesopores, as determined by TEM analysis, is 7ꢀ12 nm, which is in agreement with the pore size
distribution derived from the N2 sorption experiments (inset in Figure 1b). These disordered
mesopores are interconnected with ordered micropores. The morphology and the pore structure
of NSꢀMOR and Mont were also investigated by SEM and TEM techniques and the results are
shown in Figure S4 and Figure S5. It is clearly that the NSꢀMOR assemblies with a flowerꢀ
shaped morphology have abundant interstitial mesoꢀ and macroꢀporous, and these nanosheets are
highly crystalline (Figure S4).The SEM and TEM images of the Mont show that mangy fibers
are present on the surface of the bulky Mont particles (Figure S5).
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Figure 2. (a) SEM image of the BetaꢀM sample and (b) TEM image of the sliced BetaꢀM sample.
Figure 3 shows the NH3ꢀTPD curves of the three catalysts. The total acidic density, which was
obtained by acidꢀbase titration, is given in Table 2. It is clear that NSꢀHMOR has more weak
acid sites than HBetaꢀM and HMont (Figure 3a and Figure 3b), and the total acidic density of
NSꢀHMOR is 607 µmol·gꢀ1, much higher than that of HBetaꢀM (461 µmol·gꢀ1) and HMont (109
µmol·gꢀ1, Table 2). Nevertheless, the relative areas of the deconvoluted peaks in the NH3ꢀTPD
curves (Figure 3a) show that the medium acid sites density, and especially the strong acid site
density of HBetaꢀM is much higher than that of NSꢀHMOR. Among these catalysts, HMont
shows the lowest acidity (Figure 3b). The used HBetaꢀM shows similar NH3 desorption curves
compared to fresh HBetaꢀM (Figure S6). The acid site density of the used HBetaꢀM catalyst is
456 µmol·gꢀ1, lower than that of HBeta (923 µmol·gꢀ1, Table 2, Figure S7). This is due to that
HBeta has a low ratio of Si/Al (Table 2).
The external and internal acid sites of the HBetaꢀM catalyst were examined by 31P NMR spectra
using phosphorus probe molecules with different kinetic diameter (KD) such as
trimethylphosphine oxide (TMPO, KD=0.55 nm) and tributylphosphine oxide (TBPO, KD=0.82
nm). From Figure 4, two intense resonances at 69.1 and 63.8 ppm were observed for the TMPO
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adsorbed on HBetaꢀM. The signal at 69.1 ppm was attributed to the TMPO interaction with
relatively strong acid sites in HBetaꢀM sample.35 The signal at 63.8 ppm was attributed to the
TMPO interaction with relatively weak acid sites in HBetaꢀM sample.35 This result indicates the
presence of abundant acid sites with different acidic strengths in HBetaꢀM sample. For the TBPO
adsorbed on HBetaꢀM (Figure 4a), multiple 31P peaks were observable. The peak at 57.3 ppm
can be ascribed to physically adsorbed TBPO.35 The broad peak at 73.7 ppm, based on the
previous work,35,36 corresponds to the 63.8ꢀ69.1 ppm for TMPO, which indicates that the
external acidic sites have comparable acidic strength with the acidic sites in the micropore
channels. The resonances at 84.4 and 92.3 ppm may be caused by the confinement effect
imposed by the relative pore in the wall of larger channels in HBetaꢀM,35 and such pore is much
larger than the size of TMPO, but match well with the molecule size of TBPO, which lead to the
formation of relatively strong acidic sites in the mesopores. Furthermore, this type of pore could
act as an effective passageway that connects 12ꢀMR and mesopores, which could benefit the
reactant diffusion. In addition, alkyl ammonium temperature programmed desorption (TPD)
experiments were also performed by choosing Py (KD=0.54 nm) and 2,6ꢀDTBPy (KD=1.05 nm)
as probe molecules.37 From the PyꢀTPD and 2,6ꢀDTBPyꢀTPD curves (Figure S8), it was found
that there are present abundant internal and external acidic sites in the HBetaꢀM. Notably, both
of the TPD curves show the desorption signal mainly centered at 211 °C, indicating that the
acidic sites in the mesopores or on the outer surface have comparable acid strength to the internal
acidic sites. It seems that the number of the internal acidic sites is higher than that of the external
acidic sites according to the area of desorption profile. However, because the thermal
conductivity of the Py and 2,6ꢀDTBPy is different, the quantitative comparison of the internal
and external acidic site density based on desorption curves area is unreasonable. Therefore, the
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31P NMR and PyꢀTPD (or 2,6ꢀDTBPyꢀTPD) experimental results clearly illustrate the presence
of abundant accessible acid sites in the mesoporous for the bulky reactants in HBetaꢀM catalyst.
6
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9
0.0025
214
0.10
0.08
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368
0.0020
0.0015
0.0010
0.0005
0.0000
292
NSꢀHMOR
394
176
303
HMont
221
316
395
HBetaꢀM
150 200 250 300 350 400 450 500
Temperature ( C)
150 200 250 300 350 400 450
Temperature (°C)
°
Figure 3. NH3ꢀTPD curves and Gaussian deconvoluted peaks for the (a) HBetaꢀM, NSꢀHMOR
and (b) HMont samples.
Figure 4. 31P NMR spectra of (a) TBPO and (b) TMPO adsorbed on HBetaꢀM zeolite. The
sample spinning rate is 10 kHz. * denotes spinning sidebands.
Table 2. Total acidity and acidic site distribution of the catalysts.
Weak acid sites Medium acid
(µmol·gꢀ1)a
Strong acid sites Total acid sites
(µmol·gꢀ1)b
Catalyst
Si/Alc
sites (µmol·gꢀ1)a (µmol·gꢀ1)a
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HBetaꢀM
212
139
127
26
110
461
607
109
923
16
8
NSꢀHMOR 429
51
HMont
HBeta
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57
ꢀ
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303
122
7
aWeak acid sites, Medium acid sites, Strong acid sites estimated from the relative area of the
deconvoluted peak, respectively. b Total acid site determined by titration technique. c The Si/Al
ratios determined by ICP.
3.2 External and internal mass transfer limitations
To compare the intrinsic activity of the catalysts for the Nꢀalkylation reaction, the mass transfer
limitation was excluded experimentally and theoretically. The external mass transfer limitation in
a batch reactor was investigated through changing the stirring rate33 for the Nꢀalkylation of pꢀ
toluenesulfonamide with the HBetaꢀM, NSꢀHMOR and HMont catalysts. Figure S9 shows the
benzhydrol conversion versus stirring rate. The benzhydrol conversion on the HBetaꢀM catalyst
increased linearly with increasing stirring rate when the stirring rate was less than 150 rpm and
remained almost constant after the stirring rate exceeded 150 rpm. A similar phenomenon was
also observed on the NSꢀHMOR and HMont catalysts. These results indicate that the external
mass transfer limitation could be excluded under stirring speed of 150 rpm. Hence, in the
following studies, 500 rpm was used for the Nꢀalkylation of pꢀtoluenesulfonamide with
benzhydrol.
In addition, a Weisz–Prater analysis was performed.38,39 The Weisz–Prater criterion with the
2
r
ρ R
obs
c
HBetaꢀM catalyst gave CWP
=
p =4.7×10ꢀ4<1. Similarly, the Weisz–Prater criterion with the
D
eff
C
s
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NSꢀHMOR and HMont catalysts was also less than 1, indicating no internal diffusion limitations
(please see the Supporting Information for details).38,39 On the other hand, we also investigated
the effect of the HBetaꢀM particle size on the reaction rate under different reaction temperatures
to further confirm the elimination of internal mass transfer limitation according to previously
reported study.40 The results are shown in Table 3. At 80 °C, the robs for HBetaꢀM remains
almost unchanged when the particle size is less than 120 ꢁm, indicating that the internal mass
transfer limitation could be eliminated for the HBetaꢀM catalyst with a particle size of less than
120 ꢁm. Furthermore, when the temperature was reduced to 70 °C, the robs for HBetaꢀM with a
particle size of 109ꢀ120 ꢁm is similar to that of relatively small particle HBetaꢀM (˂109 ꢁm),
indicating that the activity at 70 and 80 °C is independent of particle size. These results further
demonstrate that the catalytic activity are free from the effect of internal mass transfer at 80 °C
on the HBetaꢀM catalyst with a particle size of 109ꢀ120 ꢁm and a stirring speed of 500 rpm.
Considering that this reaction mixture contains 130 mL 1,2ꢀchloroethane and little benzhydrol 1a
(7.5 mmol) and pꢀtoluenesulfonamide 2a (15 mmol), the effect of the heat transfer limitation on
the reaction activity may be negligible (please see the Supporting Information for details).
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Table 3. Activity for different sized particles of HBetaꢀM catalyst in the Nꢀalkylation of pꢀ
toluenesulfonamide with dibenzhydrol.a
r
obs,1 (×10ꢀ2 mol·kgꢀ1·sꢀ1)
Particle size
80 °C
0.7
70 °C
ꢀ
100ꢀ120 (120ꢀ150 ꢁm)
120ꢀ140 (109ꢀ120 ꢁm)
˃140 (˂109 ꢁm)
1.3
0.33
0.34
1.3
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aReaction conditions: 0.1 g HBetaꢀM catalyst, 7.5 mmol 1a, 15 mmol 2a, 130 mL DCE as
5
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solvent, 1 mL diphenylmethane.
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3.3.1 Apparent activity of the catalyst
Under the catalytic reaction system in 10 mL tubule, the Nꢀalkylation of pꢀtoluenesulfonamide
with benzhydrol produced the desired product 3a, Nꢀsubstituted sulfonamide, and a side product,
dibenzhydryl ether 4a (Table 4). Notably, the conversion of benzhydrol on the HBetaꢀM catalyst
(98%) is higher than that on the NSꢀHMOR (89%), HBeta (12%) and HMont (42%) catalysts.
The Cu(OAc)2 salt gives a very low benzhydrol conversion of 1.3%. In particular, HBetaꢀM
shows the highest target product selectivity (96%), as compared to the NSꢀHMOR (52%), HBeta
(74%) and HMont (21%) catalysts.
Table 4. The Nꢀalkylation of pꢀtoluenesulfonamide with benzhydrol over different catalysts.a
Selectivity b (%)
Entry
Catalyst
Conversion (%)b
Product 3a
Dibenzhydryl ether 4a
1
2
3
4
5
HBetaꢀM
NSꢀHMOR
HMont
98
89
42
1.3
12
96
52
21
55
74
4
48
79
45
26
c
Cu(OAc)2
HBeta
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aReaction conditions: catalyst (20 mg), 1a (0.3 mmol), 2a (0.6 mmol), DCE (1.5 mL) as solvent,
50 ꢁL diphenylmethane, 80 °C for 4 h. b Conversion and selectivity are obtained from GC data.
cCu(OAc)2 (1 mol %).
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In addition, the reaction substrate scope on the HBetaꢀM catalyst was also investigated and the
results are shown in Table 5, Table 6 and Table S2. At first, the Nꢀalkylation of pꢀ
toluenesulfonamide was examined using a series of aromatic alcohols (Table 5). The HBetaꢀM
catalyst tolerated various αꢀmethyl phenylcarbinols with different electronꢀdonating groups (pꢀnꢀ
butyl, oꢀmethoxyl, pꢀmethylmercapto and so on) and electronꢀwithdrawing groups (chlorine and
bromine), affording the corresponding Nꢀsubstituted sulfonamides 3bꢀ3i in high yields (92ꢀ
100%). In addition, the HBetaꢀM catalyst was used in the substitution of benzhydrol with methyl
and bromine groups, also giving the corresponding products (3j and 3k) in good yields (100 and
96%). Furthermore, when the relatively inactive 1ꢀphenylꢀ2ꢀpropyne alcohol was used as a
substrate, the HBetaꢀM catalyst afforded good catalytic performance, giving the product with a
yield of 72% (3l).
Secondly, the generality of the Nꢀalkylation of various amides with benzhydrol on the HBetaꢀM
catalyst was tested (Table 6). The substitution of benzhydrol by a series of benzsulfamides
(containing electronꢀdonating or electronꢀwithdrawing groups) using the HBetaꢀM catalyst
proceeded smoothly, delivering the desired products (3mꢀ3q) in good yields (91ꢀ100%). When
inactive amides, such as pꢀtoluamide and acrylamide were used as substrates, the desired
products (3r and 3s) were obtained in moderate yields using HBeta catalyst (73 and 68%) when
the reaction temperature was raised to 100 °C for 20 h. This could be due to that the pꢀtoluamide
can be transformed to 4ꢀmethylbenzimidic acid, and acrylamide can be transformed to
acrylimidic acid under reaction conditions (Scheme S1)41, resulting in the reduction of the
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nucleophilicity of the amides. In addition, the generality of the HBetaꢀM catalyst in this Nꢀ
alkylation was further investigated through choosing primary benzyl alcohols and alkyl alcohols
as alkylation reagent. The benzyl alcohol, isoamyl alcohol and cyclopentanol were suitable for
this transformation, giving the desired products in good to high yields (Table S2). These results
indicate that HBetaꢀM has good substrate tolerance.
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Table 5. The Nꢀalkylation of pꢀtoluenesulfonamide with a series of alcohols on the HBetaꢀM
catalyst.a
Substrate 1
Substrate 2a
Productb
Conversion (%)c
100
Yield (%)
99
3b
100
100
3c
100
100
100
100
98
3d
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3f
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98
93
92
3g
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3i
100
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100
100
90
100
3j
100
83
96
72
3k
3l
aReaction conditions: catalyst (20 mg), substrate 1 (0.3 mmol), substrate 2a (0.6 mmol), DCE
b
c
(1.5 mL) as solvent, 80 °C for 6 h. Ts = pꢀtoluenesulfonyl. The reaction mixture was analyzed
by GC.
Table 6. The Nꢀalkylation of series of amides with benzhydrol on the HBetaꢀM catalyst.a
Substrate 1a
Substrate 2
Product
Conversion (%)b
Yield (%)
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100
98
100
91
3m
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3n
99
95
~100
92
3o
100
100
3p
3q
88c
81c
73
68
3r
3s
aReaction conditions: catalyst (20 mg), substrate 1a (0.3 mmol), substrate 2 (0.6 mmol), DCE
b
c
(1.5 mL) as solvent, 80 °C for 6 h. The reaction mixture was analyzed by GC. The reaction
temperature is 100 °C and the reaction time is 20 h.
3.3.2 Two reaction routes
Generally, the Nꢀalkylation of sulfonamides with alcohols mainly proceeds on the Brönsted acid
sites. The benzylic alcohol interacted with the acid site (H+) and is protonated by H+ to give an
oxonium ion. This oxonium ion is dehydrated to form a carbocation intermediate, which is
attacked by the electricꢀrich nucleophile of the sulphonamide. The subsequent deprotonation
generates the desired Nꢀsubstituted sulfonamide.15,17 However, in this work, not only was the
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desired product of Nꢀbenzhydrylꢀ4ꢀmethylbenzenesulfonamide 3a formed, but a byꢀproduct,
dibenzhydryl ether 4a, was also observed when the reaction was conducted in a sealed tube (10
mL) or in a 300 mL Parr autoclave where mass transfer was excluded (Table 3 and Table 7). It is
particularly noteworthy that when the byꢀproduct dibenzhydryl ether 4a was used as starting
substrate, the Nꢀalkylation of pꢀtoluenesulfonamide 2a with 4a over the three catalysts also
proceeded smoothly in the 300 mL Parr autoclave (Table 8). It is found that, at a reaction time of
9 h, the product 3a was obtained with high selectivity over the HBetaꢀM (98%) and NSꢀHMOR
(94%) catalysts in the Nꢀalkylation of sulfonamides with dibenzhydryl ether 4a (Table 8), as
compared to the Nꢀalkylation of pꢀtoluenesulfonamide 2a with benzhydrol 1a (90% for HBetaꢀM
and 67% for NSꢀHMOR, Table 7). These results indicate that there could be two reaction routes
yielding the target product 3a in the Nꢀalkylation of sulfonamides on acidic catalysts (Figure 5).
One route is the reaction of benzhydrol 1a with pꢀtoluenesulfonamide 2a, here called RouteꢀI,
which is in agreement with the reported literatures.15,17 The other route is the reaction of the byꢀ
product dibenzhydryl ether 4a, that could be transformed from benzhydrol 1a, with pꢀ
toluenesulfonamide 2a. This reaction route is not reported in previous researches, here named
RouteꢀII in this work.
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Table 7. The product distribution in the Nꢀalkylation of pꢀtoluenesulfonamide with benzhydrol
over different catalysts at reaction time of 9 h.a
Selectivity (%)b
Benzhydrol
Catalyst
Conversion (%)b
Product 3a
Dibenzhydryl ether 4a
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HBetaꢀM
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HMont
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90
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aReaction conditions: 0.1 g catalyst (120ꢀ140 mesh), 7.5 mmol benzhydrol 1a, 15 mmol pꢀ
b
toluenesulfonamide 2a, 130 mL DCE, 1.0 mL diphenylmethane, 80 °C, 500 rpm. Conversion
and selectivity are obtained from GC data.
Table 8. The product distribution in the Nꢀalkylation of pꢀtoluenesulfonamide with dibenzhydryl
ether over different catalysts at reaction time of 9 h.a
Selectivity (%)b
Dibenzhydryl ether
Catalyst
Conversion (%)b
Product 3a
Benzhydrol 1a
HBetaꢀM
NSꢀHMOR
HMont
100
96
98
94
65
2
6
59
35
aReaction conditions: 0.1 g catalyst (120ꢀ140 mesh), 3.75 mmol dibenzhydryl ether 4a, 15 mmol
b
pꢀtoluenesulfonamide 2a, 130 mL DCE, 1.0 mL diphenylmethane, 80 °C, 500 rpm. Conversion
and selectivity are obtained from GC data.
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Figure 5. The reaction route for the Nꢀalkylation of sulfonamides with benzylic alcohols.
To verify whether the benzhydrol 1a could be transformed to dibenzhydryl ether 4a, the
experiments for the conversion of benzhydrol 1a to dibenzhydryl ether 4a (1a→4a) and vice
versa (4a→1a) were carried out under the same reaction conditions in the 300 mL autoclave in
the absence of mass transfer limitations on the HBetaꢀM, NSꢀHMOR and HMont catalysts.
Obviously, 1a was quickly converted to 4a in the 1a→4a reaction (Figure 6a); in contrast, the
transformation from 4a to 1a was relatively difficult in the 4a→1a reaction (Figure 7a). For
clarity, the reaction rate of this reversible reaction was calculated. As expected, the reaction rates
robs,3 of 1a→4a are much higher than the reaction rates robs,4 of 4a→1a on the three catalysts
(Figure 6b and Figure 7b). For example, the robs,3 of 1a→4a (46×10ꢀ3 mol·kgꢀ1·sꢀ1, Figure 6b) is
much higher than the robs,4 of 4a→1a (3.4×10ꢀ3 mol·kgꢀ1·sꢀ1, Figure 7b) on the HBetaꢀM catalyst.
In addition, it is notable that not only robs,3 (1a→4a) but also robs,4 (4a→1a) of HBetaꢀM (46×10ꢀ3
and 3.4×10ꢀ3 mol·kgꢀ1·sꢀ1) are higher than those of NSꢀHMOR (26×10ꢀ3 and and 3.1×10ꢀ3 mol·kgꢀ
1·sꢀ1) and HMont (20×10ꢀ3 and 2.1×10ꢀ3 mol·kgꢀ1·sꢀ1), which suggests that benzhydrol 1a is more
readily converted to dibenzhydryl ether 4a on HBetaꢀM. These results indicated that the 1a was
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4
easily transformed to 4a, which can readily react with 2a, enhancing the reaction selectivity on
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6
the acidic catalysts, especially on the strong acidic HBetaꢀM catalyst.
7
8
0.5
80
b
9
1
a
ꢀ
s
s
1
·
0.4
0.3
0.2
0.1
0.0
ꢀ
·
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g
g
k
k
60
40
20
0
·
l
o
·
l
o
m
1
ꢀ
m
0
1
0
1
1
ꢀ
×
6
2
=
×
6
4
=
3
r
ꢀ
r
3
,
s
b
o
HBetaꢀM
NSꢀHMOR
HMont
HBetaꢀM
NSꢀHMOR
HMont
0
500
1000
1500
Reaction time (s)
2000
2500
0
1
2
3
4
5
Reaction time (h)
Figure 6. (a) Benzhydrol 1a conversion versus reaction time, and (b) kinetics analysis for the
transformation of benzhydrol 1a to dibenzhydryl ether 4a using different catalysts (reaction
conditions: 0.1 g 120ꢀ140 mesh catalyst, 7.5 mmol benzhydrol 1a, 130 mL DCE, 1 mL
diphenylmethane, 80 °C, 500 rpm).
0.20
25
1
ꢀ
a
b
1
ꢀ
20
15
10
5
0.15
0.10
0.05
0.00
3
ꢀ
s
·
l
g
k
·
l
o
3
ꢀ
m
×
s
0
·
1
g
k
·
×
1
.
3
o
=
m
0
1
r
1
.
2
=
r
HBetaꢀM
NSꢀHMOR
HMont
HBetaꢀM
NSꢀHMOR
HMont
0
0
1000 2000 3000 4000 5000 6000 7000 8000
Reaction time (s)
0
1
2
3
4
5
Reaction time (h)
Figure 7. (a) Dibenzhydryl ether 4a conversion versus reaction time, and (b) kinetics analysis for
the transformation of dibenzhydryl ether 4a to benzhydrol 1a using different catalysts (reaction
conditions: 0.1 g 120ꢀ140 mesh catalyst, 3.75 mmol dibenzhydryl ether 4a, 130 mL DCE, 1 mL
diphenylmethane, 80 °C, 500 rpm).
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3.3.3 Comparison of the intrinsic activity on the two reaction routes
5
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8
To compare the reaction activity aroused from the reaction Route I and Route II, the Nꢀalkylation
of pꢀtoluenesulfonamide 2a with benzhydrol 1a and the Nꢀalkylation of 2a with dibenzhydryl
ether 4a were performed in a 300 mL Parr autoclave in the absence of mass transfer limitations.
Clearly, the benzhydrol 1a conversion on the HBetaꢀM catalyst is higher than that on NSꢀHMOR
and HMont catalysts in the same reaction periods (Figure 8a). The product selectivity on the
HBetaꢀM catalyst also rapidly increases with reaction time, but this phenomenon is not observed
on the NSꢀHMOR and HMont catalysts (Figure 8b). It is notable that, comparing the Figure 8a
and Figure 9a, although the 1a conversion is higher than 4a conversion at the same reaction time,
the target product 3a selectivity generated from RouteꢀII is much higher than that from RouteꢀI
(Figure 8b and 9b). For example, the product 3a selectivity on the HBetaꢀM catalyst is 96% from
RouteꢀII at 7 h, higher than that obtained from RouteꢀI (86% at 7 h). For the HMont and NSꢀ
HMOR catalysts, the product 3a selectivity in RouteꢀII is also higher than those in RouteꢀI.
These results indicate that RouteꢀII predominantly contributes to the formation of the product 3a
in the Nꢀalkylation of sulfonamides over the three catalysts.
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100
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0
100
80
60
40
20
HBetaꢀM
NSꢀHMOR
HMont
0.5
0.4
0.3
0.2
0.1
0.0
c
a
b
1
ꢀ
1
ꢀ
90
86
1
s
ꢀ
67
50
1
g
ꢀ
·
k
·
l
o
m
0
1
×
1
,
s
b
o
HBetaꢀM
NSꢀHMOR
HMont
HBetaꢀM
NSꢀHMOR
HMont
0
2000
4000
Reaction time (s)
6000
8000
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
Reaction time (h)
Reaction time (h)
Figure 8. Dependence of (a) benzhydrol conversion, (b) product 3a selectivity and (c) kinetics
analysis on the reaction time in the Nꢀalkylation of pꢀtoluenesulfonamide with benzhydrol.
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100
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100
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98
94
a
b
0.5
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0.0
c
s
·
g
k
1
ꢀ
·
l
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o
m
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1
ꢀ
×
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9
=
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2
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s
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HBetaꢀM
NSꢀHMOR
HMont
HBetaꢀM
HBetaꢀM
NSꢀHMOR
HMont
NSꢀHMOR
HMont
0
1
2
3
4
5
6
7
8
9
0
2000
4000
Reaction time (s)
6000
800
0
1
2
3
4
5
6
7
8
9
10
Reaction time (h)
Reaction time (h)
Figure 9. Dependence of (a) dibenzhydryl ether conversion, (b) product 3a selectivity and (c)
kinetics analysis on the reaction time in the Nꢀalkylation of pꢀtoluenesulfonamide with
dibenzhydryl ether.
To better compare the reaction activity in RouteꢀI and RouteꢀII, the initial reaction rate (robs) was
calculated and the results are shown in Figure 8c and Figure 9c. Clearly, robs,1 (13×10ꢀ3 mol·kgꢀ
1·sꢀ1) for RouteꢀI on the HBetaꢀM catalyst is higher than robs,2 (9.8×10ꢀ3 mol·kgꢀ1·sꢀ1) for RouteꢀII.
A similar phenomenon is observed on HMont catalyst. These results suggest that benzhydrol 1a
may easily be transformed to dibenzhydryl ether 4a on the acidic catalyst and subsequently
reacts with pꢀtoluenesulfonamides 2a. Thus, the reaction RouteꢀII may be responsible for the
formation of 3a in high yield. On the other hand, from Figure 8c and Figure 9c, robs,1 and robs,2 on
the HBetaꢀM (13×10ꢀ3 and 9.8×10ꢀ3 mol·kgꢀ1·sꢀ1) are much higher than those on the NSꢀHMOR
(3.6×10ꢀ3 and 5.2×10ꢀ3 mol·kgꢀ1·sꢀ1) and HMont (2.5×10ꢀ3 and 1.6×10ꢀ3 mol·kgꢀ1·sꢀ1), indicating
that the HBetaꢀM catalyst is more active in the Nꢀalkylation of sulfonamides with benzhydrol 1a
and with dibenzhydryl ether 4a. The initial turnover frequencies (TOF, sꢀ1) were also determined
based on the acid site density in the mesopore, and the results are shown in Table 9. Obviously,
the TOFini,1 for reaction RouteꢀI and the TOFini,2 for reaction RouteꢀII on HBetaꢀM are much
higher than those on the NSꢀHMOR and HMont catalysts in the Nꢀalkylation of pꢀ
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toluenesulfonamide with benzhydrol 1a or dibenzhydryl ether 4a. This is consistent with the
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reaction rate results mentioned above. When the TOFs were determined based on the strong acid
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sites in the mesoporous, the obtained initial turnover frequencies of TOFSini, 1for reaction RouteꢀI
on the HBetaꢀM, HMont and NSꢀHMOR catalysts is 46.1, 38.9 and 7.7×10ꢀ2 sꢀ1, respectively.
This is in line with the order of the initial reaction rates on three catalysts for the RouteꢀI. This
could be due to the fact that HBetaꢀM has a large amount of strong acidic sites (as discussion in
characterization section), which contributes to the highꢀefficiency in the Nꢀalkylation of pꢀ
toluenesulfonamide with benzhydrol. In addition, we also compared the TOFs to relevant
reactions reported in the literatures (Table S3). The HBetaꢀM catalyst has a higher TOF than the
previously reported catalytic systems using homogeneous and heterogeneous noble metal
catalysts.
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Table 9. The reaction rates and turnover frequencies of the different catalysts in Nꢀalkylation of
pꢀtoluenesulfonamide reaction.
a
b
a
b
a
TOFSini,1
robs,1
robs,2
TOFini,1
TOFini,2
Catalyst
(×10ꢀ3 mol·kgꢀ1·sꢀ1) (×10ꢀ3 mol·kgꢀ1·sꢀ1) (×10ꢀ2 sꢀ1)
(×10ꢀ2 sꢀ1)
(×10ꢀ2 sꢀ1)
46.1
HBetaꢀM
13
9.8
5.2
1.6
11.0
3.3
8.3
4.7
2.6
NSꢀHMOR 3.6
HMont 2.5
38.9
4.0
7.7
aReaction condition: 0.1 g catalyst (120ꢀ140 mesh), 7.5 mmol benzhydrol 1a, 15 mmol pꢀ
toluenesulfonamide 2a, 130 mL DCE, 1.0 mL diphenylmethane, 80 °C, 500 rpm.
bReaction condition: 0.1 g catalyst (120ꢀ140 mesh), 3.75 mmol dibenzhydryl ether 4a, 15 mmol
pꢀtoluenesulfonamide 2a, 130 mL DCE, 1.0 mL diphenylmethane, 80 °C, 500 rpm.
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