Palladium-catalyzed site-selective hydrogen isotope exchange (HIE) reaction of arylsulfonamides using amino acid auxiliary

Article abstract of DOI:10.1016/j.tet.2018.06.024

Hydrogen isotope exchange (HIE) is a versatile method for the introduction of deuterium to organic compounds. Herein, regioselective deuteration of sulfonamides is achieved by palladium-Catalyzed HIE reaction. By using amino acid as weakly coordination-di

Full text of DOI:10.1016/j.tet.2018.06.024

Tetrahedron xxx (2018) 1e8
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed site-selective hydrogen isotope exchange (HIE)
reaction of arylsulfonamides using amino acid auxiliary
Wei Liu, Xingyu Xu, Hongyan Zhao, Xiaoyu Yan*
Department of Chemistry, Renmin University of China, Beijing 100872, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydrogen isotope exchange (HIE) is a versatile method for the introduction of deuterium to organic
compounds. Herein, regioselective deuteration of sulfonamides is achieved by palladium-Catalyzed HIE
reaction. By using amino acid as weakly coordination-directing auxiliary, a variety of sulfonamides are
efficiently deuterated at the ortho-position. Placing competing directing groups on the aromatic ring
does not affect the site-selectivity.
Received 8 May 2018
Received in revised form
7 June 2018
Accepted 11 June 2018
Available online xxx
© 2018 Elsevier Ltd. All rights reserved.
Keywords:
Deuteration
Palladium catalysis
Sulfonamide
C-H activation
1. Introduction
systems were also applicable for tritium labeling, but depending on
hydrogen isotope resources. Ir,6 Fe,9 and part of Ru catalytic sys-
Deuterium-labeled compounds find widespread application in a
range of different scientific fields, such as reaction mechanisms,
analytical methods as internal standards, optoelectronics, clinical
pharmacology, and drug discovery.1,2 In particular, Deuterium-
labeled compounds have attracted growing interests in pharma-
ceutical industry because the incorporation of deuterium can
change ADME properties of the existing drugs, while retaining their
original efficiency and selectivity.3,4 The first deuterated drug
(deutetrabenazine, SD-809), has been approved by FDA in 2017.5
Usually, isotopically labeled organic compounds can be achieved
by multistep syntheses involving functional-group transformation
with deuterium reagents. However, the most versatile way to
introduce deuterium atoms into organic molecules is through
hydrogen-isotope exchange (HIE) reaction, which allows direct
incorporation of deuterium and circumvents the need for additional
synthetic steps.1 Recent years, transition metal-catalyzed aromatic
HIE reactions have been well established. For example, Homoge-
neous iridium catalysts have been widely used for selective
deuteration ortho to directing groups on aromatic rings.6 More
recently, other transition metals, such as Ru,7 Pd8 and Fe9 catalysts,
were also employed in aromatic HIE reactions. These catalytic
tems,7a,b which involve D2 as hydrogen isotope resource, were
perfectly adapted to tritium labeling by using T2 gas. On the other
hand, Pd catalytic systems, which usually using deuterated solvents
as hydrogen isotope resources, were still not applicable for catalytic
tritation. However, Hoover and coworkers8e have successfully ach-
ieved Pd mediated C-H tritation in stepwise stoichiometric reaction.
Sulfonamide functional groups have long been acclaimed as an
important structural fragment widely existing in drug molecules
for the characters of a series of sulfonamide-containing drugs, such
as sulfamethoxazole, sumatriptan, and gliclazide.10 Despite the
importance of sulfonamide in pharmaceutical industry, ortho-
directed deuterium labeling of sulfonamides was rarely explored.
Several iridium complexes were reported to catalyzed the HIE re-
action of sulfonamides.11e13 Among them, Kerr's NHC catalyst,12
Burgess catalyst13 and Tamm catalyst14 were reported to catalyze
reaction with high deuterium incorporation. However, these pro-
tocols still have some limitations. For example, when substrate
containing competitive directing groups, such as amino and
carbonyl groups, low site-selectivity and decreased deuterium
incorporation were observed. Another limitation for further utili-
zation was that Ir catalysts were too expensive. Herein, we report
Pd(OAc)2 catalyzed selective ortho-deuteration of sulfonamides by
using amino acid as weakly coordination-directing auxiliary
(Scheme 1). The reaction results in efficient deuterium incorpora-
tion as well as excellent site-selectivity.
* Corresponding author.
E-mail address: yanxy@ruc.edu.cn (X. Yan).
https://doi.org/10.1016/j.tet.2018.06.024
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Liu W, et al., Palladium-catalyzed site-selective hydrogen isotope exchange (HIE) reaction of arylsulfonamides
using amino acid auxiliary, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.024

2
W. Liu et al. / Tetrahedron xxx (2018) 1e8
Table 1
Optimization of palladium-catalyzed ortho-deuteration of sulfonamides.a
Scheme 1. Pd(OAc)2 catalyzed ortho-deuteration of sulfonamides.
2. Results and discussion
We initiated our studies towards a palladium-catalyzed HIE
reaction of sulfonamide by treatment of 4-
methylbenzenesulfonamide 1a in CH3COOD in the presence of
Pd(OAc)2 as catalyst and NaOAc as base. However, no deuterium
incorporation was observed when heating of the reaction mixture
at 120 ꢀC for 18 h (Table 1, entry 1). By using amino acid as weakly
coordination-directing auxiliary,8a,15 ortho-deuteration reaction of
sulfonamide derivative 2a occurred and 45% of D-incorporation
was achieved (Table 1, entry 2). Different deuterium-containing
solvents (D2O, CF3COOD, and CD3OD) were also tested, but lower
D-incorporation were observed in these reactions (Table 1, entries
3e5). Then different bases were investigated, and K2CO3 gave the
best result (Table 1, entries 2, 6e8). The fact that carbonate bases
are prior to acetate bases indicated that small amount of water
(generated by reaction of carbonate with acetic acid) may promote
the HIE reaction through formation of hydrogen bonds with reac-
tion intermediate. When 3 Å molecular sieve was added, the D-
incorporation dropped significantly (Table 1, entry 9). When 0.1 mL
of D2O was added as co-solvent, D-incorporation was increased to
84% (Table 1, entry 10). The D-incorporation was raised to 87% when
CD3COOD was used instead of CH3COOD (Table 1, entry 11). Finally,
when enhancing the steric hindrance of amino acid auxiliary,
excellent D-incorporation (97%) was achieved (Table 1, entry 12).16
With optimized reaction conditions in hand, variety of sulfon-
amide derivatives 2 were examined, including both electron-
deficient and electron-rich substrates (Scheme 2). Benzenesulfo-
namide and para-substituted benzenesulfonamide derivatives gave
the desired di-deuterated products with 46e99% D-incorporation
(3b-3j). In general, substrates with electron-donating groups gave
the higher D-incorporation than substrates with electron-
withdrawing groups. It is noteworthy that substrates with acet-
amido, acyl, pyrazolyl, methoxycarbonyl and carbamoyl groups,
which usually serve as directing groups in transition metal-
catalyzed C-H activation, only gave the ortho-deuterated sulfon-
amides with high site-selectivity (3f-3j). The selectivity was mainly
due to preferring of chelating coordination of palladium with N^O
auxiliary. The acetyl groups and pyrazolyl were partially deuterated
during the reaction. When meta-substituted benzenesulfonamide
derivatives were employed, the di-deuterated products were
formed in 95e98% D-incorporation, in which C6 position has the
slightly higher D-incorporation than C2 position (3k-3l). ortho-
Substituted substrates gave mono-deuterated products in 84e97%
D-incorporation (3m-3o). The steric effect has little influence on
the deuteration reaction. The HIE reaction was also extended to
other aromatic sulfonamides. When 1-naphthylsulfonamide 2p
was employed, the deuteration occurred at C2 and C8 position with
99% and 79% D-incorporation respectively. The result suggested
that formation of five-membered palladacycle was preferred over
six-membered palladacycle. When 2-naphthylsulfonamide 2q was
employed, the deuteration occurred at C1 and C3 position with 85%
and 96% D-incorporation respectively. Deuteration of 2-
thiophenesulfonamide gave the products 3r in 33% and 27% D-
incorporation. No reaction was occurred for 3-pyridinesulfamide
2s. When benzylsulfonamide was employed, 70% of ortho-D-
b
Entry
substrate
solvent
base
D
(%)
Yieldb (%)
1
2
3
4
5
6
7
8
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
CH COOD
3
Na
Na
Na
Na
Na
O
O
O
O
O
Ac
Ac
Ac
Ac
Ac
0
0
CH COOD
3
45
23
15
13
58
65
61
21
84
87
97
97
99
95
99
92
90
93
95
93
94
96
D O
2
CF3COOD
CD OD
3
CH COOD
3
Na2CO
3
K CO
2 3
CH COOD
3
CH COOD
3
KOAc
9c
10
11
12
CH COOD
3
K
K
K
K
gCO
3
d
d
d
CH COOD
3
/
D
O
O
O
CO
CO
CO
2
2
2
2
3
CD COOD
3
/
/
D
2
2
3
3
CD COOD
3
D
a
Reaction conditions: 1a or 2 (0.2 mmol), base (0.4 mmol), Pd(OAc)2 (0.01 mmol),
deuterated solvent (0.6 mL), 120 ꢀC, 18 h. The reactions were carried out in a 25 mL
sealed tube.
Deuterium incorporation and yields was determined by 1H NMR spectroscopy
b
analysis.
c
3 Å molecular sieve was added.
0.1 mL of D2O was added as co-solvent.
d
incorporation was achieved (3t). The Pd-catalyzed HIE reaction of
alkylsulfonamide was unsuccessful and no deuterated product was
observed with propylsulfonamide 2u. The Pd-catalyzed ortho-
deuteration reaction can be scaled up without significant decrease
of yield and D-incorporation. For example, we checked 1 mmol
reaction for 2b, 2d, 2e, 2f, 2k, and 2n, and the D-incorporation was
consistence with that shown in Scheme 2.
The amino acid auxiliary of sulfonamide derivatives can be
easily removed by CuO in DMSO to give the ortho-deuterated sul-
fonamides
4 in high yields (Scheme 3). In most cases, no
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W. Liu et al. / Tetrahedron xxx (2018) 1e8
3
Scheme 4. Synthesis of deuterated tolbutamide.
reaction of sulfamides was preceded via coordination of N^O
auxiliary with palladium and subsequent dehydropalladation with
the aid of acetate to form C^N^O chelated pallacycle. Depalladation
by CD3COOD afforded the deuterated product (Scheme 5). In a
stoichiometric reaction, when sulfonamide 2b was treated with 1
eq. of Pd(OAc)2 and 2 eq. of K2CO3 in THF, intermediate 6 was
formed in high yield and characterized by 1H NMR and 13C NMR. In
the NMR spectra, we also observed the formation of ca 2 eq. of
KOAc, which was consistence of proposed reaction mechanism
(Scheme 5).
3. Conclusions
In summary, we have developed an efficient method for the site-
selective hydrogen isotope exchange (HIE) of sulfonamides by using
amino acid as weakly coordination-directing auxiliary. The reaction
resulted in efficient deuterium incorporation as well as excellent
ortho-selectivity with a wide range of functional groups. Placing
competing directing groups on the aromatic ring did not affect the
site-selectivity. The amino acid auxiliary could be easily removed to
afford ortho-deuterated sulfonamides, which can be converted to
deuterated sulfa drugs such as tolbutamide-d2 in single step. We
proposed one possible mechanism and isolated the reaction in-
termediate to support the mechanism. Further investigations are
still in progress in this area.
Scheme 2. Pd-catalyzed ortho-deuteration of sulfonamide derivatives 2: 2 (0.2 mmol),
Pd(OAc)2 (0.01 mmol), and K2CO3 (0.4 mmol) in CD3COOD/D2O (0.6mL/0.1 mL) at
120 ꢀC for 18 h. Deuterium incorporation was determined by 1H NMR spectroscopic
analysis and given in square brackets. Yields were given as NMR yields, isolated yields
were given in parenthesis.
dedeuteration reaction was observed during the reaction. One
exception was para-nitro-substituted sulfonamide 3e, in which
partial dedeuteration reaction was observed and D-incorporation
of 4e was decreased to 75%. The resulting sulfonamides can be
further used for the synthesis of deuterium-labeled sulfa drugs. As
an example, treatment of 4b with phenyl butyl carbamate afforded
deuterated tolbutamide 5 in 76% isolated yield (Scheme 4).17
Mechanistically, we proposed that the palladium catalyzed HIE
4. Experimental section
4.1. General
All manipulations were conducted in sealed tube. 1H NMR
spectra were recorded on Bruker 400 MHz spectrometer and the
chemical shifts were reported in parts per million (d) relative to
internal standard TMS (0 ppm) for DMSO‑d6. The peak patterns are
indicated as follows: s, singlet; d, doublet; dd, doublet of doublet; t,
triplet; m, multiplet; q, quartet. The coupling constants, J, are re-
ported in Hertz (Hz). 13C NMR spectra were obtained at Bruker
100 MHz and referenced to the internal solvent signals (central
peak is 39.96 ppm in DMSO‑d6). Flash column chromatography was
performed over silica gel 200e300 mesh. All chemical reagents and
deuterated solvent were purchased from Alfa, Acros, Aldrich, TCI,
Scheme 3. Removal of auxiliary by CuO catalyst: 3 (0.5 mmol), CuO (0.15 mmol),
DMSO (1 mL), 120 ꢀC, 12 h. Deuterium incorporation was determined by 1H NMR
spectroscopic analysis and given in square brackets. Isolated yields were given in
parenthesis.
Scheme 5. Proposed reaction mechanism.
Please cite this article in press as: Liu W, et al., Palladium-catalyzed site-selective hydrogen isotope exchange (HIE) reaction of arylsulfonamides
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W. Liu et al. / Tetrahedron xxx (2018) 1e8
and J&K and used without further purification. All bases used are
anhydrous.
(2.55 g, 1 mmol) was added dropwise over 30 min. Then the reac-
tant was stirred at rt for 14 h, the precipitate obtained through
filtered, washed with cold water. The rude product recrystallized
with DCM and PE. The white solid (2.6 g, 74%, m.p. 95.6e97.5 ꢀC)
4.2. General procedure for synthesis sulfonamide derivatives
was obtained. 1H NMR (400 MHz, DMSO)
d 8.29 (s, 1H), 7.80 (d,
A 50 mL round-bottom flask equipped with a stir bar was
charged with amino acid or its derivative (10 mmol) and NaOH
aqueous solution (20 mmol, 2 M) and stirred vigorously at 0 ꢀC.
When solid was dissolved in water, arylsulfonyl chlorides
(20 mmol) were added dropwise over 20 min, then the mixture was
allowed to warm to room temperature for 12 h. The reaction
mixture was acidified with concentrated HCl at 0 ꢀC to pH 2. After
stirring for further 30 min the precipitates were collected by
filtration, washed with cold water and dried in vacuo to give the
desired product 2a-2g and 2k-2u in good to excellent yields.
J ¼ 8.7 Hz, 2H), 7.71 (d, J ¼ 8.7 Hz, 2H), 3.94 (q, J ¼ 7.1 Hz, 2H),1.30 (s,
6H), 1.11 (t, J ¼ 7.1 Hz, 3H). 13C NMR (100 MHz, DMSO)
d 173.6, 143.1,
132.5, 128.7, 126.2, 61.1, 58.5, 26.3, 14.2. HRMS (ESI-TOF) m/z Calcd
for C12H16BrNO4S [MþNa]þ 371.9881, found 371.9874.
Ethyl
2-(4-(1H-pyrazol-1-yl)benzenesulfonylamino)-2-methyl-
propionic acid. A mixture of ethyl 2-((4-bromophenyl)sulfona-
mido)-2-methyl-propionic acid (339 mg, 0.97 mmol), pyrazol
(43.5 mg, 0.64 mmol), Cu2O (9.2 mg, 0.064 mmol), Cs2CO3 (417 mg,
1.28 mmol) were mixed in a dry sealed tube. Under an argon at-
mosphere anhydroud DMF (1.5 mL) was added. The tube was sealed
under argon, and the mixture was heated at 110 ꢀC for 18 h. The
reaction was cooled to room temperature. The crude reaction
mixture was then concentrated in vacuo to remove DMF. Optional
further purification was via silica gel column chromatography (4:1
petroleum ether/ethyl acetate). The white solid (179 mg, 83%, m.p.
4.2.1. 2-(4-methyl-benzenesulfonylamino)-propionic acid (2a)
1H NMR (400 MHz, DMSO)
J ¼ 8.3 Hz, 2H), 7.37 (d, J ¼ 8.0 Hz, 2H), 3.74 (quintet, J ¼ 7.2 Hz, 1H),
2.38 (s, 3H), 1.13 (d, J ¼ 7.2 Hz, 3H).
d
8.07 (d, J ¼ 8.3 Hz, 1H), 7.68 (d,
124.5e125.9 ꢀC) was obtained. 1H NMR (400 MHz, CDCl3)
d 8.02 (d,
4.2.2. 2-(toluene-4-sulfonylamino)-2-methyl-propionic acid (2b)
d 12.54 (s, 1H), 7.91 (s, 1H), 7.69 (d,
J ¼ 8.3 Hz, 2H), 7.35 (d, J ¼ 8.1 Hz, 2H), 2.37 (s, 3H), 1.25 (s, 6H).
J ¼ 2.5 Hz, 1H), 7.98 (d, J ¼ 8.8 Hz, 2H), 7.85 (d, J ¼ 8.8 Hz, 2H), 7.77
(d, J ¼ 1.5 Hz, 1H), 6.53 (t, J ¼ 2.0 Hz, 1H), 5.63 (s, 1H), 4.15 (q,
J ¼ 7.1 Hz, 2H), 1.47 (s, 6H), 1.26 (t, J ¼ 7.1 Hz, 3H). 13C NMR
1H NMR (400 MHz, DMSO)
(100 MHz, CDCl3)
d 174.0, 142.8, 142.2, 139.8, 128.7, 126.9, 118.7,
4.2.3. 2-Benzenesulfonylamino-2-methyl-propionic acid (2c)
108.8, 62.0, 59.1, 25.7, 14.0. HRMS (ESI-TOF) m/z Calcd for
C
1H NMR (400 MHz, DMSO)
d
12.56 (s, 1H), 8.01 (s, 1H), 7.81 (dd,
15H19N3O4S [MþH]þ 338.1169, found 338.1171.
J ¼ 8.0, 1.3 Hz, 2H), 7.65e7.48 (m, 3H), 1.26 (s, 6H).
A 50 mL round-bottom flask equipped with a stir bar was
charged with ethyl 2-(4-(1H-pyrazol-1-yl)benzenesulfonylamino)-2-
methyl-propionic acid (200 mg, 0.6 mmol) and 10% NaOH (5 mL) at
room temperature for 12 h. When reaction was complete moni-
tored by TLC, The reaction mixture was acidified with concentrated
HCl at 0 ꢀC to pH ¼ 2; solid precipitated out and stirred for further
30min. The crystals were collected by filtration, washed with cold
water and dried in vacuo to give the title compound 2h (127 mg,
4.2.4. 2-(4-Chloro-benzenesulfonylamino)-2-methyl-propionic acid
(2d)
White solide, m.p. 157.4e160.2 ꢀC. 1H NMR (400 MHz, DMSO)
d
8.11 (s, 1H), 7.80 (d, J ¼ 8.5 Hz, 2H), 7.63 (d, J ¼ 8.5 Hz, 2H), 1.28 (s,
6H). 13C NMR (100 MHz, DMSO)
d 175.5, 142.9, 137.2, 129.5, 128.6,
58.4, 26.3. HRMS (ESI-TOF) m/z Calcd for C10H12ClNO4S [MþNa]þ
300.0074, found 300.0066.
64%) as a white solid. 1H NMR (400 MHz, DMSO)
d 8.63 (d,
J ¼ 2.5 Hz, 1H), 8.05 (s, 1H), 8.04 (d, J ¼ 8.9 Hz, 2H), 7.90 (d,
4.2.5. 2-(4-Nitro-benzenesulfonylamino)-2-methyl-propionic acid
J ¼ 8.8 Hz, 2H), 7.83 (d, J ¼ 1.4 Hz, 1H), 6.62 (t, J ¼ 2.2 Hz, 1H), 1.30 (s,
(2e)
6H). 13C NMR (100 MHz, DMSO)
d 175.5, 142.5, 142.3, 141.0, 128.8,
1H NMR (400 MHz, DMSO)
d
8.43 (s, 1H), 8.39 (d, J ¼ 8.8 Hz, 2H),
128.4, 118.6, 109.2, 58.3, 26.3. HRMS (ESI-TOF) m/z Calcd for
8.04 (d, J ¼ 8.8 Hz, 2H), 1.31 (s, 6H).
C
13H15N3O4S [MþNa]þ 332.0681, found 332.0669.
4.2.6. 2-(4-Acetamide-benzenesulfonylamino)-2-methyl-propionic
acid (2f)
4.2.9. 2-(4-methoxalyl-benzenesulfonylamino)-2-methyl-propionic
acid (2i)
White solid, m.p. 105.2e106.5 ꢀC. 1H NMR (400 MHz, DMSO)
The reactions were carried out in a one-neck round bottom
flask. The corresponding 2-amino-2-methylpropanoic acid (0.88 g,
8.5 mmol) and triethylamine (3.4 g, 34 mmol) were added to a
vigorously stirred mixture of water (5 mL) at 0 ꢀC. When solid
completely dissolved in water, 4-chlorosulfonyl benzoic acid
methyl ester (1 g, 4.3 mmol) was added dropwise over 30 min. Then
the reaction was stirred at rt for 12 h, the product was extracted
with EtOAc (3 ꢁ 50 mL). Combined organic layers were dried over
Na2SO4, concentrated in vacuo. The residue was purified by silica
gel column chromatography (DCM/MeOH ¼ 30/1) to afford the
desired product. Yellow solid, m.p. 170.2e173.6 ꢀC. 1H NMR
d
12.51 (s, 1H), 10.29 (s, 1H), 7.84 (s, 1H), 7.72 (s, 4H), 2.09 (s, 3H),
1.25 (s, 6H). 13C NMR (100 MHz, DMSO)
d
175.8, 169.4, 142.8, 137.8,
127.8, 118.8, 58.1, 26.2, 24.6. HRMS (ESI-TOF) m/z Calcd for
C
12H16N2O5S [MþH]þ 301.0853, found 301.0842.
4.2.7. 2-(4-Acetyl-benzenesulfonylamino)-2-methyl-propionic acid
(2g)
White solide, m.p. 161.4e163.5 ꢀC. 1H NMR (400 MHz, DMSO)
d
8.22 (s, 1H), 8.11 (d, J ¼ 8.2 Hz, 2H), 7.93 (d, J ¼ 8.2 Hz, 2H), 2.64 (s,
3H), 1.28 (s, 6H). 13C NMR (100 MHz, DMSO)
d
197.8, 175.5, 147.8,
139.5, 129.2, 126.9, 58.4, 27.5, 26.3. HRMS (ESI-TOF) m/z Calcd for
C
(400 MHz, DMSO)
d
8.24 (s, 1H), 8.10 (d, J ¼ 8.4 Hz, 2H), 7.93 (d,
12H15NO5S [MþNa]þ 308.0569, found 308.0563.
J ¼ 8.4 Hz, 2H), 3.88 (s, 3H), 1.28 (s, 6H). 13C NMR (100 MHz, DMSO)
d
175.5, 165.7, 148.0, 132.9, 130.2, 127.0, 58.4, 53.0, 26.2. HRMS (ESI-
4.2.8. Synthesis of 2-(4-(1H-pyrazol-1 yl)benzenesulfonylamino)-
2-methyl-propionic acid (2h)
TOF) m/z Calcd for C12H15NO6S [MþNa]þ 324.0518, found 324.0504.
Ethyl 2-((4-bromophenyl)sulfonamido)-2-methyl-propionic acid.
A 50 mL round-bottom flask equipped with a stir bar was charged
with ethyl 2-amino-2-methylpropanoate18 (1.96 g, 10 mmol) and
K2CO3 aqueous [2.7 g, 10 mL (H2O), 2 M] at 0 ꢀC. When solid
completely dissolved in water, 4-bromobenzenesulfonyl chloride
4.2.10. Synthesis of 2-(4-N-butylaminocarbonyl-
benzenesulfonylamino)-2-methyl-propionic acid (2j)
4-(Butylcarbamoyl)benzenesulfonyl chloride. To a stirred solution
of (chlorosulfonyl)benzoyl chloride19 (2 g, 8.4 mmol) and triethyl-
amine (1.7 g, 16.8 mmol) in CH2Cl2 (12 mL) cooled to ꢂ78 ꢀC was
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W. Liu et al. / Tetrahedron xxx (2018) 1e8
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added dropwise n-butylamine (0.6 g, 8.4 mmol). The reaction was
4.2.17. 2-(2-naphthalenesulfonylamino)-2-methyl-propionic acid
allowed to warm to room temperature over 1 h and then poured
into 15 mL of ice water. The organic layer was separated and the
aqueous phase extracted with CH2Cl2 (3 ꢁ 25 mL). The combined
organic phases were dried (MgSO4) and evaporated in vacuo to a
white solid. The solid was chromatographed (CH2Cl2) to obtain the
title compound (1.8 g, 78%). White solid, m.p. 91.3e93.4 ꢀC. 1H NMR
(2q)
White solide, m.p. 167.6e171.1 ꢀC. 1H NMR (400 MHz, DMSO)
8.40 (d, J ¼ 9.0 Hz, 1H), 8.13 (d, J ¼ 7.8 Hz, 1H), 8.08 (t, J ¼ 4.3 Hz,
d
2H), 8.01 (d, J ¼ 7.7 Hz, 1H), 7.83 (d, J ¼ 8.6 Hz, 1H), 7.71e7.61 (m,
2H), 1.26 (s, 6H). 13C NMR (100 MHz, DMSO)
d 175.7, 141.1, 134.4,
132.1, 129.7, 129.4, 129.0, 128.2, 127.9, 127.0, 122.9, 58.3, 26.2. HRMS
(ESI-TOF) m/z Calcd for C14H15NO4S [MþNa]þ 316.0620, found
316.0610.
(400 MHz, CDCl3)
d
8.10 (d, J ¼ 8.5 Hz, 2H), 8.00 (d, J ¼ 8.6 Hz, 2H),
6.42 (br, 1H), 3.49 (q, J ¼ 7.1 Hz, 2H), 1.64 (quintet, J ¼ 7.1 Hz, 2H),
1.43 (sextet, J ¼ 7.4 Hz, 2H), 0.98 (t, J ¼ 7.3 Hz, 3H). 13C NMR
(101 MHz, CDCl3)
d 165.3, 146.1, 141.1, 128.3, 127.3, 40.2, 31.5, 20.2,
4.2.18. 2-Thiophenesulfonylamino-2-methyl-propionic acid (2r)
11H14ClNO3S [MþNa]þ
1H NMR (400 MHz, DMSO)
d
8.20 (s, 1H), 7.87 (dd, J ¼ 5.0, 1.0 Hz,
13.8. HRMS (ESI-TOF) m/z Calcd for
298.0281, found 298.0269.
C
1H), 7.56 (d, J ¼ 3.5 Hz, 1H), 7.12 (dd, J ¼ 4.7, 3.9 Hz, 1H), 1.33 (s, 6H).
Title compound 2j as a white solid, m.p. 162.8e165.9 ꢀC. 1H NMR
(400 MHz, DMSO)
d
8.64 (t, J ¼ 5.5 Hz, 1H), 8.13 (s, 1H), 7.97 (d,
4.2.19. 3-Pyridinesulfonylamino-2-methyl-propionic acid (2s)
Yellow solide, m.p. 162.4e165.7 ꢀC. 1H NMR (400 MHz, DMSO)
J ¼ 8.4 Hz, 2H), 7.86 (d, J ¼ 8.4 Hz, 2H), 3.27 (q, J ¼ 6.8 Hz, 2H), 1.51
(quintet, J ¼ 7.0 Hz, 2H),1.33 (sextet, J ¼ 7.4 Hz, 2H),1.27 (s, 6H), 0.90
d
8.94 (d, J ¼ 2.0 Hz, 1H), 8.78 (d, J ¼ 4.6 Hz, 1H), 8.29 (s, 1H), 8.17 (d,
J ¼ 8.1 Hz, 1H), 7.61 (dd, J ¼ 8.0, 4.8 Hz, 1H), 1.31 (s, 6H). 13C NMR
(100 MHz, DMSO) 175.3, 153.0, 147.2, 140.2, 134.7, 124.4, 58.7, 26.4.
(t, J ¼ 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO)
d 175.6, 165.5, 146.1,
138.1, 128.2, 126.6, 58.3, 39.5, 31.6, 26.2, 20.1, 14.2. HRMS (ESI-TOF)
d
m/z Calcd for C15H22N2O5S [MþNa]þ 365.1147, found 365.1139.
HRMS (ESI-TOF) m/z Calcd for C9H12N2O4S [MþNa]þ 267.0415,
found 267.0409.
4.2.11. 2-(3-methyl- benzenesulfonylamino)-2-methyl-propionic
acid (2k)
4.2.20. 2-(Benzylsulfonylamino)-2-methyl-propionic acid (2t)
White solide, m.p. 188.6e189.9 ꢀC. 1H NMR (400 MHz, DMSO)
1H NMR (400 MHz, DMSO)
d
7.94 (s, 1H), 7.60 (d, J ¼ 7.5 Hz, 2H),
7.48e7.37 (m, 2H), 2.38 (s, 3H), 1.26 (s, 6H).
d
12.70 (s, 1H), 7.41e7.34 (m, 5H), 7.29 (s, 1H), 4.34 (s, 2H), 1.39 (s,
6H). 13C NMR (100 MHz, DMSO)
d 176.2, 131.5, 131.0, 128.7, 128.4,
61.1, 58.9, 26.9. HRMS (ESI-TOF) m/z Calcd for C11H15NO4S [MþNa]þ
4.2.12. 2-(3-Chloro-benzenesulfonylamino)-2-methyl-propionic
acid (2l)
280.0620, found 280.0610.
White solid, m.p. 161.3e164.2 ꢀC. 1H NMR (400 MHz, DMSO)
d
12.64 (s, 1H), 8.19 (s, 1H), 7.80 (s, 1H), 7.76 (d, J ¼ 7.8 Hz, 1H), 7.69
4.2.21. 2-Methyl-2-(propylsulfonamido)propanoic acid (2u)
White solide, m.p. 139.3e140.3 ꢀC. 1H NMR (400 MHz, DMSO)
(d, J ¼ 8.1 Hz, 1H), 7.60 (t, J ¼ 7.9 Hz, 1H), 1.29 (s, 6H). 13C NMR
(100 MHz, DMSO)
d 175.4, 145.9, 133.9, 132.4, 131.5, 126.3, 125.3,
d
12.58 (s, 1H), 7.27 (s, 1H), 2.98 (t, J ¼ 7.6 Hz, 2H), 1.69 (sextet,
58.5, 26.3. HRMS (ESI-TOF) m/z Calcd for C10H12ClNO4S [MþNa]þ
J ¼ 7.4 Hz, 2H), 1.39 (s, 7H), 0.97 (t, J ¼ 7.4 Hz, 3H). 13C NMR
300.0074, found 300.0067.
(101 MHz, DMSO) d 176.2, 58.3, 57.1, 26.9, 17.5, 13.2. HRMS (ESI-TOF)
m/z Calcd for C7H15NO4S [MþNa]þ 232.0620, found 232.0611.
4.2.13. 2-(toluene-2-sulfonylamino)-2-methyl-propionic acid (2m)
1H NMR (400 MHz, DMSO)
d
8.03 (s, 1H), 7.84 (d, J ¼ 7.8 Hz, 1H),
4.3. General procedure for Pd-Catalyzed ortho-deuteration
7.48 (t, J ¼ 7.4 Hz, 1H), 7.35 (t, J ¼ 8.2 Hz, 2H), 2.59 (s, 3H), 1.23 (s,
6H).
A 25 mL sealed tube equipped with a stir bar was charged with
2-arylsulfonyl-2-methyl-propionic
acid
(0.2 mmol),
K2CO3
4.2.14. 2-(2-Trifluoromethyl-benzenesulfonylamino)-2-methyl-
propionic acid (2n)
(0.4 mmol) and palladium acetate (0.01 mmol). The sealed tube and
reactants were dried in vacuum. Then 0.6 mL d4-AcOH and 0.1 mL
D2O were added and the mixture was heated to 120 ꢀC for 18 h. The
resulting residue was purified by silica gel column chromatography
with the following eluent system: AcOEt / AcOEt (added 5%
concentrated hydrochloric acid).
White solide, m.p. 143.2e145.6 ꢀC. 1H NMR (400 MHz, DMSO)
d
8.27 (s, 1H), 8.21 (d, J ¼ 7.8 Hz, 1H), 7.94 (d, J ¼ 7.4 Hz, 1H), 7.87 (t,
J ¼ 7.5 Hz, 1H), 7.80 (t, J ¼ 7.6 Hz, 1H), 1.31 (s, 6H). 13C NMR
3
(100 MHz, DMSO)
d
175.8, 142.7, 133.4, 132.9, 130.5, 128.5 (q, JC-
¼ 5.8 Hz), 126.0 (q, 2JC-F ¼ 32.8 Hz), 123.5 (q, 1JC-F ¼ 274.1 Hz), 58.9,
F
26.0. HRMS (ESI-TOF) m/z Calcd for
C
11H12F3NO4S [MþNa]þ
4.3.1. 2-(Toluene-4-sulfonylamino)-2-methyl-propionic acid-d2
(3b)
334.0337, found 334.0332.
Yellow solid, 44.2 mg, 86% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
7.90 (s,
4.2.15. 2-(2-chloro-benzenesulfonylamino)-2-methyl-propionic
1H), 7.34 (s, 2H), 2.36 (s, 3H), 1.25 (s, 6H). 13C NMR (100 MHz,
acid (2o)
1H NMR (400 MHz, DMSO)
7.66e7.56 (m, 2H), 7.55e7.47 (m, 1H), 1.27 (s, 6H).
d
8.17 (s, 1H), 7.97 (d, J ¼ 8.1 Hz, 1H),
DMSO)
d
175.8, 142.5, 141.2, 129.7, 126.4 (t, J ¼ 24.8 Hz), 58.1, 26.2,
21.4. HRMS (ESI-TOF) m/z Calcd for
C
11H13D2NO4S [MþNa]þ
282.0745, found 282.0738.
4.2.16. 2-(1-Naphthalenesulfonylamino)-2-methyl-propionic acid
(2p)
4.3.2. 2-Benzenesulfonylamino-2-methyl-propionic acid-d2 (3c)
White solide, m.p. 171.2e174.3 ꢀC. 1H NMR (400 MHz, DMSO)
Yellow solid, 43.3 mg, 89% yield. Characterization data for the
d
8.69 (d, J ¼ 8.4 Hz, 1H), 8.34 (s, 1H), 8.17 (dd, J ¼ 12.5, 7.8 Hz, 2H),
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
8.00 (s,
8.07 (d, J ¼ 7.8 Hz, 1H), 7.74e7.58 (m, 3H), 1.22 (s, 6H). 13C NMR
1H), 7.63e7.52 (m, 3H), 1.26 (s, 6H). 13C NMR (100 MHz, DMSO)
(100 MHz, DMSO)
d
176.1, 139.3, 134.2, 133.8, 129.3, 128.0, 128.0,
d
175.8, 144.0, 132.4, 129.2, 126.3 (t, J ¼ 25.1 Hz), 58.2, 26.2. HRMS
127.9, 127.1, 125.5, 124.9, 58.4, 25.9. HRMS (ESI-TOF) m/z Calcd for
(ESI-TOF) m/z Calcd for C10H11D2NO4S [MþNa]þ 268.0589, found
C
14H15NO4S [MþNa]þ 316.0620, found 316.0613.
268.0583.
Please cite this article in press as: Liu W, et al., Palladium-catalyzed site-selective hydrogen isotope exchange (HIE) reaction of arylsulfonamides
using amino acid auxiliary, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.024

6
W. Liu et al. / Tetrahedron xxx (2018) 1e8
4.3.3. 2-(4-Chloro-benzenesulfonylamino)-2-methyl-propionic
acid-d2 (3d)
4.3.10. 2-(3-Methyl-benzenesulfonylamino)-2-methyl-propionic
acid-d2 (3k)
Yellow solid, 48.3 mg, 87% yield. Characterization data for the
Faint yellow solid, 43.7 mg, 85% yield. Characterization data for
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
8.11 (s,
175.5,
the deuterated compound only: 1H NMR (400 MHz, DMSO)
d 7.92
1H), 7.62 (s, 2H), 1.28 (s, 6H). 13C NMR (100 MHz, DMSO)
d
(s, 1H), 7.41 (dd, J ¼ 8.6, 7.6 Hz, 2H), 2.37 (s, 3H), 1.27 (s, 6H). 13C
142.7, 137.2, 129.4, 128.4 (t, J ¼ 26.0 Hz), 58.4, 26.3. HRMS (ESI-TOF)
NMR (100 MHz, DMSO) d 175.8, 144.0, 138.8, 133.0, 129.1, 126.5 (t,
m/z Calcd for C10H10D2ClNO4S [MþNa]þ 302.0199, found 302.0190.
J ¼ 26.5 Hz), 123.5 (t, J ¼ 24.1 Hz), 58.2, 26.2, 21.3. HRMS (ESI-TOF)
m/z Calcd for C11H13D2NO4S [MþNa]þ 282.0745, found 282.0733.
4.3.4. 2-(4-Nitro-benzenesulfonylamino)-2-methyl-propionic acid-
d2 (3e)
4.3.11. 2-(3-Chloro-benzenesulfonylamino)-2-methyl-propionic
acid-d2 (3l)
Yellow solid, 49.0 mg, 85% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
8.38 (s,
Yellow solid, 48.8 mg, 88% yield. Characterization data for the
3H), 1.30 (s, 6H). 13C NMR (100 MHz, DMSO)
d
175.3, 149.6, 149.2,
deuterated compound only: 1H NMR (400 MHz, DMSO)
d 8.17 (s,
127.9 (t, J ¼ 25.7 Hz), 124.6, 58.7, 26.4. HRMS (ESI-TOF) m/z Calcd for
1H), 7.68 (d, J ¼ 8.1 Hz, 1H), 7.60 (d, J ¼ 8.1 Hz, 1H), 1.29 (s, 6H). 13
C
C
10H10D2N2O6S [MþNa]þ 313.0440, found 313.0434.
NMR (100 MHz, DMSO) d 175.4, 145.8, 133.8, 132.4, 131.3, 126.0 (t,
J ¼ 25.6 Hz), 125.0 (t, J ¼ 24.6 Hz), 58.5, 26.4. HRMS (ESI-TOF) m/z
4.3.5. 2-(4-Acetamide-benzenesulfonylamino)-2-methyl-propionic
acid-d2 (3f)
Calcd for C10H10D2ClNO4S [MþNa]þ 302.0199, found 302.0195.
Yellow solid, 50.5 mg, 84% yield. Characterization data for the
4.3.12. 2-(Toluene-2-sulfonylamino)-2-methyl-propionic acid-d1
(3m)
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
10.43 (s,
1H), 7.73 (s, 2H), 7.20 (s, 1H), 2.08 (s, 72% of undeuterated CH3), 1.21
(s, 6H). 13C NMR (100 MHz, DMSO)
177.2, 169.4, 142.8, 138.2, 127.5
Yellow solid, 45.2 mg, 88% yield. Characterization data for the
d
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
7.99 (s,
1H), 7.47 (t, J ¼ 7.4 Hz, 1H), 7.38e7.30 (m, 2H), 2.60 (s, 94% of
undeuterated CH3), 1.24 (s, 6H). 13C NMR (100 MHz, DMSO)
176.1,
(t, J ¼ 20.9 Hz), 118.8, 59.3, 26.4, 24.6. HRMS (ESI-TOF) m/z Calcd for
C
12H14D2N2O5S [MþNa]þ 325.0803, found 325.0800.
d
142.1,136.8,132.6,132.5,127.9 (t, J ¼ 24.4 Hz),126.3, 58.2, 26.0, 20.2.
HRMS (ESI-TOF) m/z Calcd for C11H14DNO4S [MþNa]þ 281.0683,
found 281.0673.
4.3.6. 2-(4-Acetyl-benzenesulfonylamino)-2-methyl-propionic
acid-d2 (3g)
Yellow solid, 48.4 mg, 85% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
8.21 (s,
1H), 8.10 (s, 2H), 2.59 (s, 6% of undeuterated CH3), 1.28 (s, 6H). 13
NMR (100 MHz, DMSO) 197.9, 175.5, 147.6, 139.5, 129.1, 126.7 (t,
4.3.13. 2-(2-Trifluoromethyl-benzenesulfonylamin o)-2-methyl-
propionic acid-d1 (3n)
C
d
Yellow solid, 51.6 mg, 83% yield. Characterization data for the
J ¼ 24.6 Hz), 58.4, 26.7 (t, J ¼ 19.3 Hz), 26.3. HRMS (ESI-TOF) m/z
deuterated compound only: 1H NMR (400 MHz, DMSO)
d 8.25 (s,
Calcd for C12H13D2NO5S [MþNa]þ 310.0694, found 310.0687.
1H), 7.93 (d, J ¼ 7.6 Hz, 1H), 7.87 (d, J ¼ 7.0 Hz, 1H), 7.80 (t, J ¼ 7.6 Hz,
1H), 1.31 (s, 6H). 13C NMR (100 MHz, DMSO)
d 175.8, 142.7, 133.3,
3
2
4.3.7. 2-(4-(1H-pyrazol-1-yl)benzenesulfonylamin o)-2-methyl-
propionic acid-d2 (3h)
132.9, 130.2 (t, J ¼ 27.6 Hz), 128.5 (q, JC-F ¼ 5.8 Hz), 126.0 (q, JC-
¼ 32.6 Hz), 123.5 (q, 1JC-F ¼ 274.0 Hz), 58.9, 25.0. HRMS (ESI-TOF)
F
Faint yellow solid, 46.3 mg, 82% yield. Characterization data for
m/z Calcd for C11H11DF3NO4S [MþNa]þ 335.0400, found 335.0394.
the deuterated compound only: 1H NMR (400 MHz, DMSO)
d 8.62
(s, 66% of undeuterated at pyrazol C5-H), 8.06 (s, 1H), 8.04 (d,
J ¼ 9.1 Hz, 54% of undeuterated at phenyl C2-H), 7.91 (t, J ¼ 3.7 Hz,
3H), 7.83 (s, 1H), 6.61 (t, J ¼ 2.3 Hz, 64% of undeuterated at pyrazol
4.3.14. 2-(2-Chloro-benzenesulfonylamino)-2-methyl-propionic
acid-d1 (3o)
Yellow solid, 46.6 mg, 84% yield. Characterization data for the
C4-H), 1.30 (s, 6H). 13C NMR (100 MHz, DMSO)
d
175.6, 142.3 (t,
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
8.13 (s,
1H), 7.63e7.59 (m, 2H), 7.51e7.49 (m, 1H), 1.27 (s, 6H). 13C NMR
(100 MHz, DMSO) 175.8, 141.2, 134.0, 132.0, 130.9, 129.8 (t,
J ¼ 11.8 Hz), 141.0, 128.7 (t, J ¼ 9.5 Hz), 128.4, 128.3, 118.6, 109.0 (t,
J ¼ 14.8 Hz), 58.2, 26.3. HRMS (ESI-TOF) m/z Calcd for
d
C
13H13D2N3O4S [MþNa]þ 334.0807, found 334.0789.
J ¼ 24.7 Hz), 127.8, 58.6, 26.0. HRMS (ESI-TOF) m/z Calcd for
C
10H11DClNO4S [MþNa]þ 301.0136, found 301.0130.
4.3.8. 2-(4-methoxalyl-benzenesulfonylamino)-2-methyl-propionic
acid-d2 (3i)
4.3.15. 2-(1-Naphthalenesulfonylamino)-2-methyl-propionic acid-
d2 (3p)
Yellow solid, 51.2 mg, 85% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
8.25 (s,
Faint yellow solid, 51.6 mg, 88% yield. Characterization data for
1H), 8.11 (s, 2H), 3.88 (s, 4H),1.28 (s, 7H). 13C NMR (100 MHz, DMSO)
the deuterated compound only: 1H NMR (400 MHz, DMSO)
d 8.33
d
175.5, 165.7, 147.8, 132.9, 130.1, 126.8 (t, J ¼ 25.7 Hz), 58.4, 53.0,
(s, 1H), 8.17 (d, J ¼ 8.3 Hz, 1H), 8.05 (d, J ¼ 8.1 Hz, 1H), 7.69 (d,
26.3. HRMS (ESI-TOF) m/z Calcd for C12H13D2NO6S [MþNa]þ
J ¼ 6.5 Hz, 1H), 7.67e7.58 (m, 2H), 1.23 (s, 6H). 13C NMR (100 MHz,
326.0644, found 326.0631.
DMSO)
d
176.1, 139.2, 134.2, 133.8, 129.3, 127.9 (t, J ¼ 12.3 Hz), 127.9,
127.8, 127.1, 125.3 (t, J ¼ 29.0 Hz), 124.8, 58.4, 25.9. HRMS (ESI-TOF)
4.3.9. 2-(4-N-butylaminocarbonyl-benzenesulfonyla mino)-2-
methyl-propionic acid-d2 (3j)
m/z Calcd for C14H13D2NO4S [MþNa]þ 318.0745, found 318.0731.
Yellow solid, 57.4 mg, 84% yield. Characterization data for the
4.3.16. 2-(2-Naphthalenesulfonylamino)-2-methyl-propionic acid-
d2 (3q)
deuterated compound only: 1H NMR (400 MHz, DMSO)
d 8.63 (br,
1H), 8.13 (s, 1H), 7.97 (s, 2H), 3.28 (q, J ¼ 6.2 Hz, 2H), 1.52 (quintet,
Yellow solid, 52.2 mg, 89% yield. Characterization data for the
J ¼ 6.7 Hz, 2H), 1.34 (sextet, J ¼ 7.1 Hz, 2H), 1.27 (s, 6H), 0.90 (t,
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
8.15 (d,
J ¼ 7.8 Hz, 1H), 8.10 (d, J ¼ 5.1 Hz, 2H), 8.03 (d, J ¼ 8.0 Hz, 1H),
7.72e7.62 (m, 2H), 1.29 (s, 6H). 13C NMR (100 MHz, DMSO)
175.6,
J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, DMSO)
d 175.6, 165.6, 146.0,
138.1, 128.1, 126.3 (t, J ¼ 25.8 Hz), 58.3, 39.5, 31.6, 26.2, 20.1, 14.1.
HRMS (ESI-TOF) m/z Calcd for C15H20D2N2O5S [MþNa]þ 367.1273,
found 367.1264.
d
140.9, 134.3, 132.0, 129.5, 129.2, 128.9, 128.2, 127.8, 126.7 (t,
J ¼ 28.0 Hz), 122.6 (t, J ¼ 24.3 Hz), 58.2, 26.2. HRMS (ESI-TOF) m/z
Please cite this article in press as: Liu W, et al., Palladium-catalyzed site-selective hydrogen isotope exchange (HIE) reaction of arylsulfonamides
using amino acid auxiliary, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.024

W. Liu et al. / Tetrahedron xxx (2018) 1e8
7
Calcd for C14H13D2NO4S [MþNa]þ 318.0745, found 318.0736.
NMR (100 MHz, DMSO)
d
144.4, 138.9, 132.8, 129.2, 126.1 (t,
J ¼ 28.3 Hz), 123.0 (t, J ¼ 25.4 Hz), 21.3. HRMS (ESI-TOF) m/z Calcd
4.3.17. 2-Thiophenesulfonylamino-2-methyl-propionic acid-d2 (3r)
for C7H7D2NO2S [MþNa]þ 196.0378, found 196.0369.
Faint yellow solid, 41.1 mg, 83% yield. Characterization data for
the deuterated compound only: 1H NMR (400 MHz, DMSO)
d 8.18
4.4.6. 2-Trifluoromethyl-benzenesulfonamide-d1 (4n)
(s, 1H), 7.85 (d, J ¼ 4.9 Hz, 73% of undeuterated at C5-H), 7.56 (d,
White solid, 90.5 mg, 80% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
7.95 (d,
J ¼ 3.0 Hz, 67% of undeuterated at C3-H), 7.11 (m, 1H), 1.33 (s, 6H).
13C NMR (100 MHz, DMSO)
d
175.7, 145.4 (t, J ¼ 8.7 Hz), 132.4, 131.6,
J ¼ 7.8 Hz, 1H), 7.90 (d, J ¼ 7.2 Hz, 1H), 7.81 (t, J ¼ 7.7 Hz, 1H), 7.75 (s,
2H). 13C NMR (100 MHz, DMSO)
d 142.8, 133.5, 132.9, 129.6 (t,
127.6 (t, J ¼ 8.8 Hz), 58.6, 26.0. HRMS (ESI-TOF) m/z Calcd for
C8H9D2NO4S2 [MþNa]þ 274.0153, found 274.0146.
J ¼ 30.5 Hz), 128.5 (q, 3JC-F ¼ 5.7 Hz), 126.0 (q, 2JC-F ¼ 32.6 Hz), 123.5
1
(q, JC-F ¼ 274.0 Hz). HRMS (ESI-TOF) m/z Calcd for C7H5DF3NO2S
[MþNa]þ 249.0032, found 249.0025.
4.3.18. 2-(Benzylsulfonylamino)-2-methyl-propionic acid-d2 (3t)
White solid, 45.2 mg, 88% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
7.42e7.31
(m, 3H), 7.28 (s, 1H), 4.34 (s, 94% of undeuterated CH2), 1.39 (s, 6H).
13C NMR (100 MHz, DMSO)
176.2, 131.5, 130.9 (t, J ¼ 8.6 Hz), 128.6
4.5. Synthesis of deuterium tolbutamide
d
A 25 mL sealed tube equipped with a stir bar was charged with
sulfonamide (0.5 mmol, 86.6 mg), carbamate (0.55 mmol,106.3 mg)
in acetonitrile (4 mL), when solid was dissolved, then DBU
(0.75 mmol, 114.1 mg) was added and the reaction mixture was
refluxed. The reaction was monitored by TLC. After completion of
the reaction, the solvent was evaporated in vacuo and then dis-
solved in ethyl acetate and extracted with 0.1 N HCl and saturated
salt solution, dried over Na2SO4 and evaporated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (petroleum ether/EtOAc ¼ 2/1) to afford the desired
product 517 (103.5 mg, 76%) as a white solid. Characterization data
for the deuterated compound only: 1H NMR (400 MHz, CDCl3)
(d, J ¼ 11.4 Hz), 128.5 (d, J ¼ 15.9 Hz), 61.0, 58.9, 26.9. HRMS (ESI-
TOF) m/z Calcd for
282.0733.
C
11H13D2NO4S [MþNa]þ 282.0745, found
4.4. Removal of directing group to synthesis of sulfonamides
A 25 mL sealed tube equipped with a stir bar was charged with
deuterated sulfonamide derivatives (0.5 mmol, 1 equiv), CuO
(0.15 mmol, 30 mol%), DMSO (1 mL). The sealed tube was capped
and heated to 120 ꢀC. After 12 h, the reaction was cooled to ambient
temperature. The reaction solution was then added some water and
extracted with EtOAc. The organic layers were collected and dried
with Na2SO4 concentrated in vacuo. The residue was purified by
silica gel column chromatography (petroleum ether/EtOAc ¼ 3/1)
to afford the desired product 4.
d
9.25 (s, 1H), 7.32 (s, 2H), 6.55 (t, J ¼ 5.2 Hz, 1H), 3.22 (q, J ¼ 6.8 Hz,
2H), 2.45 (s, 3H),1.46 (quintet, J ¼ 7.2 Hz, 2H),1.29 (sextet, J ¼ 7.6 Hz,
2H), 0.90 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 152.2,
144.6, 136.6, 129.7, 126.8 (t, J ¼ 24.9 Hz), 40.0, 31.6, 21.6, 19.9, 13.7.
HRMS (ESI-TOF) m/z Calcd for C12H16D2N2O3S [MþNa]þ 295.1062,
found 295.1056.
4.4.1. 4-Methyl-benzenesulfonamide-d2 (4b)
White solid, 82.3 mg, 95% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
7.37 (s,
d 142.4,
4.6. Synthesis catalyst intermediate 6
2H), 7.29 (s, 2H), 2.38 (s, 3H). 13C NMR (100 MHz, DMSO)
141.7,129.7,125.8 (t, J ¼ 25.3 Hz), 21.4. HRMS (ESI-TOF) m/z Calcd for
A mixture of sulfonamide 2b (51.4 mg, 0.2 mmol), Pd(OAc)2
(44.8 mg, 0.2 mmol), K2CO3 (55.2 mg, 0.4 mmol) and anhydrous
THF (2 mL) were mixed in a dry sealed tube. The mixture was
stirred at 100 ꢀC under N2 for 12 h. The precipitate obtained was
filtered, washed with ethyl acetate, and dried in vacuo to afford
intermediate 6 (containing ca. 2eq. KOAc). 1H NMR (400 MHz,
C7H7D2NO2S [MþNa]þ 196.0378, found 196.0371.
4.4.2. 4-Chloro-benzenesulfonamide-d2 (4d)
White solid, 84.2 mg, 87% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
7.66 (s,
2H), 7.48 (s, 2H). 13C NMR (100 MHz, DMSO)
d 143.3, 137.1, 129.4,
DMSO)
d
7.41 (s, 1H),
d
6.86 (d, J ¼ 9.2 Hz, 1H), 6.84 (d, J ¼ 8.4 Hz,
1H), 2.21 (s, 3H), 1.51 (s, 6H). 13C NMR (100 MHz, DMSO)
152.4, 138.7, 134.5, 133.9, 125.4, 123.0, 64.7, 30.0, 21.9.
d 186.5,
127.8 (t, J ¼ 25.7 Hz). HRMS (ESI-TOF) m/z Calcd for C6H4D2ClNO2S
[MþNa]þ 215.9831, found 215.9826.
4.4.3. 4-Nitro-benzenesulfonamide-d2 (4e)
Acknowledgments
Yellow solid, 87.7 mg, 86% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
8.42 (s,
This work is supported by the Fundamental Research Funds for
the Central Universities, the Research Funds of Renmin University
of China (Program 17XNLF12), and the National Natural Science
Foundation of China (21602249).
2H), 7.76 (s, 2H). 13C NMR (100 MHz, DMSO)
d 149.7, 127.4 (t,
J ¼ 26.0 Hz), 124.9, 124.8. HRMS (ESI-TOF) m/z Calcd for
C6H4D2N2O4S [MþNa]þ 227.0072, found 227.0067.
4.4.4. 4-Acetamide-benzenesulfonamide-d2 (4f)
Appendix A. Supplementary data
Yellow solid, 90.8 mg, 84% yield. Characterization data for the
deuterated compound only: 1H NMR (400 MHz, DMSO)
d
10.27 (s,
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.06.024.
1H), 7.74 (s, 2H), 7.24 (s, 2H), 2.09 (s, 86% of undeuterated CH3). 13
C
NMR (100 MHz, DMSO)
d
169.4, 142.7, 138.4, 126.9 (t, J ¼ 25.9 Hz),
118.8, 24.6. HRMS (ESI-TOF) m/z Calcd for C8H8D2N2O3S [MþNa]þ
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Please cite this article in press as: Liu W, et al., Palladium-catalyzed site-selective hydrogen isotope exchange (HIE) reaction of arylsulfonamides
using amino acid auxiliary, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.024