Sulfonamides as Amine Component in the Petasis-Borono Mannich Reaction: A Concise Synthesis of α-Aryl- and α-Alkenylglycine Derivatives

Article abstract of DOI:10.1055/s-0037-1610440

A catalyst-free three-component synthesis of α-aryl- and α-alkenylglycine derivatives starting from glyoxylic acid, sulfonamides, and aryl- or alkenylboronic acids is described. This operationally simple method tolerates a broad range of functional groups and enables the generation of a wide array of α-amino acids. Sulfonamides were utilized as amine component in the classic Petasis reaction for the first time.

Full text of DOI:10.1055/s-0037-1610440

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
A. M. Diehl et al.
Paper
Synthesis
Sulfonamides as Amine Component in the Petasis-Borono Mannich
Reaction: A Concise Synthesis of α-Aryl- and α-Alkenylglycine
Derivatives
Andreas M. Diehl
Omar Ouadoudi
Eleni Andreadou
Georg Manolikakes*
COOH
O
O
O
CH3NO2
O
O
Ar-B(OH)2
or
S
+
+
S
R1
N
R1
Ar/Alkenyl
NH2
H
COOH
60 °C
Alkenyl-B(OH)2
H
0
0
0
0
0-
0
0
2
4-
0
1
3
5-
7
5
7
38 examples
up to 98% yield
first application of sulfonamides
in classic Petasis reaction
Department of Chemistry, TU Kaiserslautern,
Erwin-Schrödinger-Strasse 54, 67663 Kaiserslautern,
Germany
manolikakes@chemie.uni-kl.de
Received: 13.04.2018
Accepted after revision: 30.05.2018
Published online: 18.07.2018
a) Previous work:
COOH
Ar-B(OH)2
or
O
R1
H
+
+
N
N
R2
Ar/Alkenyl
R1
R2
DOI: 10.1055/s-0037-1610440; Art ID: ss-2018-z0255-op
H
COOH
Alkenyl-B(OH)2
R1 = aryl, alkyl or tBuSO
2 = H, aryl or alkyl
Abstract A catalyst-free three-component synthesis of α-aryl- and
R
α-alkenylglycine derivatives starting from glyoxylic acid, sulfonamides,
and aryl- or alkenylboronic acids is described. This operationally simple
method tolerates a broad range of functional groups and enables the
generation of a wide array of α-amino acids. Sulfonamides were utilized
as amine component in the classic Petasis reaction for the first time.
b) This work:
COOH
O
O
O
CH3NO2
O
O
Ar-B(OH)2
or
60 °C
Alkenyl-B(OH)2
+
+
S
S
R1
N
R1
NH2
Ar/Alkenyl
H
COOH
H
Key words multicomponent reaction, Petasis-borono Mannich reac-
tion, sulfonamides, amino acids, catalyst free
38 examples
up to 98% yield
first application of sulfonamides
in classic Petasis reaction
The Petasis-borono Mannich reaction, a three-compo-
nent coupling of an aldehyde and an amine with an organo-
boron species, represents an operationally simple approach
towards the synthesis of α-substituted amines.1–5 This
method provides straightforward access to important syn-
thetic intermediates and biologically active products.
Therefore, the Petasis reaction has become a powerful tool
for the construction of small nitrogen-containing mole-
cules. Of particular importance are transformations with
glyoxylic acid as the aldehyde component, providing direct
access to vinyl- or arylglycine analogues [Scheme 1 (a)].
Various amine components, such as primary or secondary
alkylamines, hydrazines, or hydroxylamines have been uti-
lized for the synthesis of the corresponding glycine deriva-
tives.
In the course of our work on the palladium-catalyzed,
stereoselective three-component synthesis of α-substituted
amides,6–9 we became aware of a gap in the substrate scope.
Whereas reactions with sulfinamides have been de-
scribed,10,11 there is, to the best of our knowledge, no report
using sulfonamides as substrates in the classical, transition-
metal-free Petasis reaction. Considering the importance of
Scheme 1 Synthesis of glycine derivatives by the Petasis reaction
the sulfonamide group in medicinal chemistry,12 the intro-
duction of this functional group in a multicomponent ap-
proach would be highly useful.
Herein we wish to report the first Petasis reaction based
on sulfonamides as the amine component [Scheme 1 (b)].
This method provides a versatile and operationally simple
access to sulfonylated aryl- and vinylglycines.
Our investigations commenced with the reaction of gly-
oxylic acid (2), employed as the solid and easy-to-handle
monohydrate, and phenylboronic acid (3a) with sulfon-
amide 1a, which should lead to the corresponding 2,2,4,6,7-
pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonyl (Pbf)13
protected phenylglycine 4a (Table 1).
Surprisingly, this transformation proceeds quite effi-
ciently in various common aprotic organic solvents, such as
DCE, THF, EtOAc, or toluene (entries 1–6); the desired gly-
cine derivative 4a was obtained in 65–94% yield after 12 h
at 60 °C. The best results were achieved with nitromethane
(entry 6). Protic solvents (MeOH, EtOH, or H2O) proved to
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
A. M. Diehl et al.
Paper
Synthesis
Table 1 Influence of the Reaction Parametersa
First reactions with different sulfonamides were investi-
gated (Scheme 2). In general, good to excellent yields of the
desired sulfonylated phenylglycines 4 were obtained. Aro-
matic, heteroaromatic, or aliphatic sulfonamides are suit-
able amine components for this multicomponent reaction.
Only in the case of very electron-poor sulfonamides (4f and
4r) or substrates containing a basic nitrogen (4j) was no
product isolated.
COOH
Ph
O
·H2O
Ph B(OH)2
Pbf NH2
Pbf
+
+
N
H
COOH
H
1a
2
3a
4a
(1.0 equiv)
(1.3 equiv)
(2.0 equiv)
O
S
O
= Pbf
O
COOH
O
O
B(OH)2
O
CH3NO2
O
O
·H2O
S
+
+
R
N
S
Entry
Solvent/variation
Temp (°C)
Yieldb (%)
H
COOH
60 °C, 12 h
H
R
NH2
1
2
3a
4
1
2
DCE
60
60
60
60
60
60
60
60
60
25
40
60
91
87
90
89
65
94
–
(1.0 equiv)
(1.3 equiv)
(2.0 equiv)
THF
3
toluene
EtOAc
acetone
CH3NO2
MeOH
EtOH
COOH
Ph
O
COOH
Ph
O
COOH
O
O
O
S
O
S
4
S
N
N
N
Ph
H
H
H
5
S
O
6
4a, 90%
4b, 95%
4c, 95%
7
8
–
COOH
Ph
O
COOH
Ph
O
O
O
COOH
Ph
O
O
S
S
9
H2O
–
S
F3C
N
N
Me3Si
N
H
H
10
11
12
CH3NO2
CH3NO2
81
90
82
H
4f, -%
4e, 78%
4d, 96%
CH3NO2,
Ph-BF3K
COOH
Ph
O
O
S
COOH
Ph
13
14
CH3NO2,
Ph-Bpin
60
60
69
–
O
4g Alkyl = Me
4h Alkyl = Pr
4i Alkyl = tBu
O
N
94%
95%
87%
H
S
Alkyl
N
N
H
CH3NO2,
Ph-MIDA
4j, -%
a Reaction conditions: Pbf-NH2 (1a; 0.25 mmol), glyoxylic acid monohy-
drate (2; 1.3 equiv), PhB(OH)2 (3a; 2 equiv), solvent (1.5 mL), temp, 12 h;
reactions were carried out without exclusion of air and moisture.
b Yield of isolated product.
4k R = H
90%
84%
81%
96%
4o R = F
4p R = Br
4q R = CF3
4r R = NO2
60%
COOH
Ph
O
O
4l R = Me
4m R = tBu
4n R = OMe
62%
56%
-
S
N
H
R
be not suitable for this transformation (entries 7–9). Per-
forming the reaction at lower temperatures still furnished
phenylglycine 4a in high yields (entries 10 and 11). For all
further studies, a reaction temperature of 60 °C was select-
ed, since it enables a fast and reproducible product forma-
tion for almost any kind of substrate combination. Other or-
ganoboron species can be used to replace the boronic acid.
The reaction of the corresponding phenyltrifluoroborate
salt afforded 4a in 82% yield (entry 12). With the pinacol es-
ter a yield of 69% was achieved (entry 13). Only in the case
of the MIDA boronate no product formation was observed
(entry 14).
It has to be emphasized, that the reaction is very simple
to perform. Exclusion of air or moisture is not necessary
and no exogenous base, desiccant, or additive has to be add-
ed. All starting materials are commercially available and
were used without further purification. With the optimized
conditions in hand (Table 1, entry 6), we explored the sub-
strate scope of this transformation.
Scheme 2 Variation of the sulfonamide component (all yields are given
for isolated products)
This might be due to slow imine formation in the case of
electron-poor, less nucleophilic sulfonamides or an inter-
ference of basic nitrogen atoms in the case of the quinolone
4j. Full conversion of the sulfonamide was observed for all
successful examples. Next reactions with different boronic
acids were investigated (Scheme 3). A wide variety of differ-
ent aryl- and heteroarylboronic acids are suitable starting
materials and furnished the corresponding arylglycines 5a–
s in 48–98% yield. Electron-poor boronic acids, which are
often problematic in the classical Petasis reaction,1 perform
satisfactorily and the ester- as well as the trifluoromethyl-
substituted glycine derivatives 5d and 5i were obtained in
49% and 61% yield, respectively; longer reaction times
proved to be beneficial in case of 5i. Again, reactions with
heteroarylboronic acids bearing basic nitrogen atoms were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
A. M. Diehl et al.
Paper
Synthesis
not successful (5m). On the other hand, alkenylboronic ac-
ids are compatible with this transformation, furnishing the
corresponding vinylglycines 5n–p in 69–95% yield.
COOH
O
O
O
O
O
CH3NO2,
∗ H2O
S
S
R
Ph-B(OH)2
+
(Het)Ar
N
R
Ph
+
H
(Het)Ar
N
H
COOH
60 °C, 12 h
6
2
3a
7
(1.0 equiv)
(1.3 equiv)
(2.0 equiv)
COOH
R
CH3NO2
O
·H2O
R-B(OH)2
COOH
Ph
PbfNH2
O
O
+
+
Pbf
COOH
Ph
O
COOH
Ph
O
O
N
O
60 °C, 12 h
H
COOH
S
H
S
S
N
N
1a
2
3
N
R
5
Me
(1.0 equiv)
(1.3 equiv)
(2.0 equiv)
Me
O
F3C
89%
90%
7a R = Me
7b R = Bn
7c, 90%
7d, 92%
COOH
N
COOH
5a R = Br
5b R = F
5c R = OMe
62%
81%
98%
5e, 48%
Pbf
Pbf
N
N
H
H
Scheme 4 Reactions with secondary sulfonamides (all yields are given
for isolated products)
5d R = COOEt 49%
R
PhO2S
COOH
COOH
COOH
Pbf
Pbf
N
CF3
N
Pbf
cules. For this purpose, we investigated the reaction of sul-
Cl
H
H
N
fonamide 1s, a structural analogue of sildenafil,14 with gly-
Me
H
oxylic acid
2 and 4-methoxyphenylboronic acid (3c)
5f Cl = -ortho
85%
5g Cl = -para 89%
5j Me = -ortho
5k Me = -para 90%
87%
5i, 61%
(Scheme 5). To our delight, the desired arylglycine deriva-
tive 8 was isolated in 30% yield in THF as solvent. Although
the obtained yield is rather low, this reaction showcases the
potential application of this 3-component reaction as a tool
for a late-stage library synthesis from complex scaffolds.
In summary, we have reported the first version of the
Petasis reaction with sulfonamides as the amine compo-
nent. This operational very simple multicomponent reac-
tion offers a versatile approach towards sulfonylated α-
aryl- and α-alkenylglycines from readily available building
blocks. Various glycine derivatives, useful building blocks
for the construction of biologically active molecules, were
synthesized in good to excellent yields. The introduction of
the sulfonamide group provides a useful handle, either as
protecting group or as tool to manipulate the biological
properties of the final product. The reaction displays a high
functional group tolerance and can be used for the late-
stage diversification of complex scaffolds. Studies towards
the application of this multicomponent reaction for the
construction of target-focused libraries are currently un-
derway in our laboratory.
80%
5h Cl = -meta
COOH
COOH
Pbf
Pbf
COOH
N
H
N
H
Pbf
N
H
R
N
S
5n R = Pr
5o R = CH2Cl 90%
5p R = Ph
69%
5m, -%
5l, 90%
95%
COOH
COOH
COOH
Pbf
Pbf
Pbf
S
N
H
N
H
N
H
O
O
5q, 75%
5s, 82%
5r, 60%
Scheme 3 Variation of the boronic acid component (all yields are given
for isolated products); a stirred for 64 h at 60 °C
The reaction is not limited to primary sulfonamides.
Secondary sulfonamides perform equally well (Scheme 4).
The desired products 7a–d were obtained in a uniformly
high 87–92% yield, even in the case of the sterically hin-
dered substrate 6b.
As the sulfonamide moiety can be found in many bio-
logically active molecules and is a frequent motif in medici-
nal chemistry, we explored the potential application of our
method in the late-stage diversification of drug-like mole-
All reactions and manipulations were carried out in screwable glass
tubes with PP-caps without avoiding ambient air or moisture. TLC
was performed on precoated aluminum plates (TLC silica gel 60
F254). The resulting spots were visualized by UV light. Flash column
chromatography was performed using Silica 60 (0.04–0.063 mm,
230–400 mesh). All yields refer to isolated yields. Unless stated, all
O
O
N
NH
O
O
N
2 (1.3 equiv)
3c (2.0 equiv)
N
NH
COOH
O
S
O
N
N
NH2
S
N
N
THF
60 °C, 64 h
H
EtO
EtO
OMe
1s
(1.0 equiv)
8
30%
Scheme 5 Synthesis of an arylglycine analogue of sildenafil (the yield is given for the isolated product)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
A. M. Diehl et al.
Paper
Synthesis
starting materials were purchased from different commercial sources
and used without further purification. Solvents for reactions were ob-
tained from commercial suppliers in p.a. quality and used as received.
Solvents for flash column chromatography were technical standard.
Methanesulfonamide, benzenesulfonamide, propane-1-sulfonamide,
2,4,6-triisopropylbenzenesulfonamide, 4-nitrobenzenesulfonamide,
4-fluorobenzenesulfonamide, 4-methoxybenzenesulfonamide, 4-bro-
mobenzenesulfonamide, 4-tert-butylbenzenesulfonamide, naphtha-
lene-2-sulfonamide, thiophene-2-sulfonamide, 2,2,4,6,7-pentameth-
yl-2,3-dihydrobenzofuran-5-sulfonamide, 4-ethoxy-3-(1-methyl-7-
oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-
sulfonamide, o-tolylboronic acid, p-tolylboronic acid, 4-methoxy-
phenylboronic acid, 4-fluorophenylboronic acid, 4-bromophenylbo-
ronic acid, 4-chlorophenylboronic acid, 3-chlorophenylboronic acid,
2-chlorophenylboronic acid, and 3-trifluorophenylboronic acid were
prepared according to previously reported procedures.15,16 Melting
points are uncorrected. 1H, 13C, and 19F NMR were recorded at a fre-
quency of 500 MHz (1H), 126 MHz (13C), and 471 MHz (19F). Chemical
shifts are reported relative to the respective solvent peak: (CDCl3: δ =
7.26 (1H), δ = 77.16 (13C), or DMSO-d6: δ = 2.50 (1H), δ = 39.52 (13C).
Mass spectra were measured using ESI techniques. HRMS were mea-
sured using MALDI techniques. Infrared spectra were recorded on a
FT-IR spectrometer including a diamond universal ATR sampling
The reaction was performed on a 2.5-mmol scale as follows: A 50-mL
flask was charged with a magnetic stirring bar, 2,2,4,6,7-pentameth-
yl-2,3-dihydrobenzofuran-5-sulfonamide (1a; 680.0 mg, 2.5 mmol,
1.0 equiv), glyoxylic acid monohydrate (2; 300.0 mg, 3.3 mmol, 1.3
equiv), phenylboronic acid (3a; 610.0 mg, 5.0 mmol, 2.0 equiv), and
nitromethane (0.17 M wrt sulfonamide, 15.0 mL) and closed with a
rubber septum. The resulting mixture was stirred at 60 °C for 64 h.
After cooling to r.t. the viridescent mixture was diluted with acetone
and filtered through a Celite/silica gel mixture and the filtrate was
concentrated under reduced pressure. Purification of the crude resi-
due by flash column chromatography afforded the product (1.6 g,
81%); mp 81–82 °C; Rf = 0.76 (n-hexane/acetone/AcOH 1:1:0.2).
IR (ATR): 2972, 2929, 1718, 1456, 1289, 1157, 1138, 1089, 850, 782,
696, 660, 637, 614, 561, 544, 521, 505 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.25–7.12 (m, 5 H), 5.63 (d, J = 6.8 Hz, 1
H), 4.99 (d, J = 6.7 Hz, 1 H), 2.93–2.83 (m, 2 H), 2.46 (s, 3 H), 2.38 (s, 3
H), 2.02 (s, 3 H), 1.45 (s, 6 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 174.3, 160.0, 139.6, 135.0, 134.2,
128.8, 128.7, 127.9, 127.3, 125.2, 118.1, 87.0, 77.2, 59.1, 43.2, 28.7,
28.7 (partial overlap), 19.4, 17.8, 12.5.
MS (ESI): m/z calcd for C21H25NO5S: 403.15; found: 404.15 [M + H]+.
HRMS (MALDI): m/z [M + Na]+ calcd for C21H25NO5SNa: 426.13456;
technique from 4000–400 cm–1
.
found: 426.13409.
2-Alkylsulfonamido- or 2-(Hetero)arylsulfonamido-2-phenyl-
acetic Acids 4a–r and 7a–d by Variation of the Sulfonamide;
General Procedure (GP1)
2-Phenyl-2-(2-thienylsulfonamido)acetic Acid (4b)
Prepared from thiophene-2-sulfonamide (41.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 4:1:0.2 → 1:1:0.2) afforded
the product (71 mg, 95%) as a colorless solid; mp 150–151 °C; Rf =
0.38 (n-hexane/acetone/AcOH 1:1:0.2).
A 10–mL screw cap glass tube with a PP-cap was charged with a mag-
netic stirring bar, sulfonamide 1 or 6 (0.25 mmol, 1.0 equiv), glyoxylic
acid monohydrate (2; 30.0 mg, 0.33 mmol, 1.3 equiv), phenylboronic
acid (3a; 61.0 mg, 0.5 mmol, 2.0 equiv), and nitromethane (1.5 mL,
0.17 M wrt sulfonamide) and firmly closed. The resulting mixture
was stirred at 60 °C for 12 h. After cooling to r.t., the mixture was di-
luted with acetone and filtered through a short plug of Celite/silica
gel. The plug was rinsed with additional acetone and the filtrate was
concentrated under reduced pressure. Purification of the crude resi-
due by flash column chromatography afforded the product.
IR (ATR): 3250, 1729, 1325, 1133, 1067, 732, 678, 580, 523 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.97 (d, J = 9.2 Hz, 1 H), 7.83 (dd, J =
5.0, 1.3 Hz, 1 H), 7.49 (dd, J = 3.7, 1.3 Hz, 1 H), 7.33–7.25 (m, 5 H), 7.06
(dd, J = 4.9, 3.8 Hz, 1 H), 4.95 (d, J = 9.2 Hz, 1 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 170.9, 141.9, 136.4, 132.5,
131.8, 128.5, 128.1, 127.4, 127.4, 59.7.
MS (ESI): m/z calcd for C12H11NO4S2: 297.01; found: 295.97 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C12H11NO4S2Na: 320.00217;
2-Alkenyl- or 2-(Hetero)aryl-2-(2,2,4,6,7-pentamethyl-2,3-dihy-
drobenzofuran-5-ylsulfonamido)acetic Acids 5a–s by Variation of
the Boronic Acid Derivative; General Procedure 2 (GP2)
found: 320.00211.
A 10-mL screw-cap glass tube with PP-cap was charged with a mag-
netic stirring bar, 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-
sulfonamide (1a; 68.0 mg, 0.25 mmol, 1.0 equiv), glyoxylic acid
monohydrate (2; 30.0 mg, 0.33 mmol, 1.3 equiv), boronic acid 3 (0.5
mmol, 2.0 equiv), and nitromethane (1.5 mL, 0.17 M wrt sulfon-
amide) and firmly closed. The resulting mixture was stirred at 60 °C
for 12 h. After cooling to r.t., the mixture was diluted with acetone
and filtered through a Celite/silica gel mixture and the filtrate was
concentrated under reduced pressure. Purification of the crude resi-
due by flash column chromatography afforded the product.
2-Phenyl-2-(2,4,6-triisopropylphenylsulfonamido)acetic Acid (4c)
Prepared from 2,4,6-triisopropylbenzenesulfonamide (71.0 mg,
0.25 mmol, 1.0 equiv) according to GP1. Purification by flash column
chromatography (n-hexane/acetone/AcOH 9:1:0.2
→ 4:1:0.2 →
1:1:0.2) afforded the product (99 mg, 95%) as a colorless solid; mp
118–120 °C; Rf = 0.72 (n-hexane/acetone/AcOH 1:1:0.2).
IR (ATR): 3182, 2959, 1702, 1456, 1257, 1164, 1070, 881, 697, 662,
561 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.26–7.17 (m, 5 H), 7.07 (s, 2 H), 5.59
(d, J = 6.9 Hz, 1 H), 5.11 (d, J = 6.9 Hz, 1 H), 4.08–3.97 (m, 2 H), 2.90–
2.81 (m, 1 H), 1.27–1.12 (m, 18 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 174.3, 153.3, 150.4, 135.1, 132.6,
129.0, 127.4, 123.8, 58.9, 34.3, 30.0, 24.9, 24.9, 23.7, 23.7.
MS (ESI): m/z calcd for C23H31NO4S: 417.20; found: 416.12 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C23H31NO4SNa: 440.18660;
2-(2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonami-
do)-2-phenylacetic Acid (4a)
Prepared from phenylboronic acid (140.2 mg, 1.15 mmol, 2.3 equiv)
according to GP1. Purification by flash column chromatography (n-
hexane/acetone/AcOH 9:1:0.2 → 4:1:0.2) afforded the product (180
mg, 90%) as a colorless solid.
found: 440.18608.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

E
A. M. Diehl et al.
Paper
Synthesis
2-(2-Naphthylsulfonamido)-2-phenylacetic Acid (4d)
1H NMR (500 MHz, DMSO-d6): δ = 8.14 (d, J = 9.2 Hz, 1 H), 7.51–7.27
(m, 5 H), 4.99 (d, J = 9.0 Hz, 1 H), 2.92–2.76 (m, 2 H), 1.73–1.49 (m, 2
H), 0.83 (t, J = 7.4 Hz, 3 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 171.8, 137.5, 128.6, 128.1,
127.6, 59.3, 54.4, 16.7, 12.6.
MS (ESI): m/z calcd for C11H15NO4S: 257.07; found: 256.09 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C11H15NO4SNa: 280.06140;
Prepared from naphthalene-2-sulfonamide (52.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2) afforded
the product (82 mg, 96%) as a colorless solid; mp 160–161 °C; Rf =
0.50 (n-hexane/acetone/AcOH 1:1:0.2).
IR (ATR): 3282, 1742, 1330, 1153, 738, 695, 630, 562, 491 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.90–8.81 (m, 1 H), 8.35 (s, 1 H),
8.07 (d, J = 7.9 Hz, 1 H), 8.00 (t, J = 9.0 Hz, 2 H), 7.80–7.75 (m, 1 H),
7.69–7.61 (m, 2 H), 7.34–7.25 (m, 2 H), 7.24–7.13 (m, 3 H), 5.01–4.95
(m, 1 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 171.0, 138.0, 136.6, 134.1,
131.6, 129.2, 129.0, 128.6, 128.3, 127.9, 127.7, 127.4, 127.3, 127.3,
122.5, 59.6.
found: 280.06154.
2-(tert-Butylsulfonamido)-2-phenylacetic Acid (4i)
Prepared from 2-methylpropane-2-sulfonamide (34.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2) afforded
the product (59 mg, 87%) as a colorless solid; mp 155–156 °C; Rf =
0.65 (n-hexane/acetone/AcOH 1:1:0.2).
MS (ESI): m/z calcd for C18H15NO4S: 341.07; found: 340.03 [M – H]–.
Analytical data are consistent with the literature.17
IR (ATR): 3201, 2987, 1728, 1465, 1286, 1210, 1173, 1108, 940, 868,
702, 656, 505 cm–1
.
2-Phenyl-2-[2-(trimethylsilyl)ethylsulfonamido]acetic Acid (4e)
1H NMR (500 MHz, DMSO-d6): δ = 8.04 (d, J = 9.7 Hz, 1 H), 7.45 (d, J =
7.7 Hz, 2 H), 7.39–7.29 (m, 3 H), 4.95 (d, J = 9.6 Hz, 1 H), 1.21 (s, 9 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 172.2, 138.1, 128.5, 127.9,
Prepared from 2-(trimethylsilyl)ethanesulfonamide (45.0 mg,
0.25 mmol, 1.0 equiv) according to GP1. Purification by flash column
chromatography (n-hexane/acetone/AcOH 9:1:0.2
→ 4:1:0.2 →
127.4, 60.4, 58.7, 23.7.
1:1:0.2) afforded the product (62 mg, 78%) as a colorless solid; mp
120–122 °C; Rf = 0.68 (n-hexane/acetone/AcOH 1:1:0.2).
MS (ESI): m/z calcd for C12H17NO4S: 271.09; found: 270.13 [M – H]–.
Analytical data are consistent with the literature.19
IR (ATR): 3251, 2958, 1714, 1326, 1173, 1150, 932, 840, 740, 720, 694,
507 cm–1
.
2-Phenyl-2-(phenylsulfonamido)acetic Acid (4k)
1H NMR (500 MHz, DMSO-d6): δ = 8.08 (d, J = 9.3 Hz, 1 H), 7.49–7.28
(m, 5 H), 4.98 (d, J = 9.2 Hz, 1 H), 2.78–2.67 (m, 2 H), 0.92–0.64 (m, 2
H), –0.09 (s, 9 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 171.7, 137.7, 128.5, 128.1,
127.6, 59.4, 48.8, 9.8, –2.0.
MS (ESI): m/z calcd for C13H21NO4SSi: 315.10; found: 314.08 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C13H21NO4SSiNa: 338.08528;
Prepared from benzenesulfonamide (39.0 mg, 0.25 mmol, 1.0 equiv)
according to GP1. Purification by flash column chromatography (n-
hexane/acetone/AcOH 9:1:0.2 → 4:1:0.2 → 1:1:0.2) afforded the prod-
uct (66 mg, 90%) as a colorless solid; mp 161–162 °C; Rf = 0.57 (n-hex-
ane/acetone/AcOH 1:1:0.2).
IR (ATR): 3275, 2892, 1711, 1338, 1162, 1085, 789, 723, 688, 607, 576,
526 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.74 (d, J = 9.3 Hz, 1 H), 7.73–7.70
(m, 2 H), 7.56–7.52 (m, 1 H), 7.48–7.43 (m, 2 H), 7.28–7.21 (m, 5 H),
4.90 (d, J = 9.2 Hz, 1 H).
found: 338.08565.
2-(Methylsulfonamido)-2-phenylacetic Acid (4g)
13C{1H} NMR (126 MHz, DMSO-d6): δ = 170.9, 141.0, 136.5, 132.2,
128.8, 128.4, 127.9, 127.3, 126.5, 59.6.
MS (ESI): m/z calcd for C14H13NO4S: 291.06; found: 290.10 [M – H]–.
Analytical data is consistent with the literature.17
Prepared from methanesulfonamide (24.0 mg, 0.25 mmol, 1.0 equiv)
according to GP1. Purification by flash column chromatography (n-
hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2) afforded the prod-
uct (54 mg, 94%) as a colorless oil; Rf = 0.40 (n-hexane/acetone/AcOH
1:1:0.2).
IR (ATR): 3247, 2930, 1724, 1313, 1147, 1096, 976, 696, 510 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.48–7.34 (m, 5 H), 5.50 (d, J = 6.2 Hz, 1
H), 5.28 (d, J = 6.4 Hz, 1 H), 2.76 (s, 3 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 173.0, 135.2, 129.3, 129.5, 127.6,
59.3, 42.4.
.
2-(4-Methylphenylsulfonamido)-2-phenylacetic Acid (4l)
Prepared from 4-methylbenzenesulfonamide (43.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 4:1:0.2) afforded the prod-
uct (63 mg, 84%) as a colorless solid; mp 178–180 °C; Rf = 0.69 (n-hex-
ane/acetone/AcOH 1:1:0.2).
MS (ESI): m/z calcd for C9H11NO4S: 229.04; found: 228.18 [M – H]–.
Analytical data are consistent with the literature.18
IR (ATR): 3279, 2901, 1709, 1333, 1161, 1090, 918, 811, 693, 590, 528
cm–1
.
2-Phenyl-2-(propylsulfonamido)acetic Acid (4h)
1H NMR (500 MHz, DMSO-d6): δ = 8.63 (d, J = 9.2 Hz, 1 H), 7.61 (d, J =
8.3 Hz, 2 H), 7.29–7.23 (m, 7 H), 4.86 (d, J = 9.2 Hz, 1 H), 2.33 (s, 3 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 171.0, 142.5, 138.2, 136.6,
129.3, 128.4, 127.9, 127.3, 126.6, 59.5, 20.9.
MS (ESI): m/z calcd for C15H15NO4S: 305.07; found: 304.02 [M – H]–.
Prepared from propane-1-sulfonamide (31.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 4:1:0.2 → 1:1:0.2) afforded
the product (61 mg, 95%) as a brown solid; mp 89–90 °C; Rf = 0.41 (n-
hexane/acetone/AcOH 1:1:0.2).
Analytical data are consistent with the literature.20
IR (ATR): 3222, 2927, 1731, 1462, 1316, 1137, 1101, 933, 715, 562,
501 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
A. M. Diehl et al.
Paper
Synthesis
2-(4-tert-Butylphenylsulfonamido)-2-phenylacetic Acid (4m)
1H NMR (500 MHz, DMSO-d6): δ = 8.86 (d, J = 9.4 Hz, 1 H), 7.69–7.60
(m, 4 H), 7.2–7.21 (m, 5 H), 4.91 (d, J = 9.4 Hz, 1 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 170.8, 140.3, 136.3, 131.9,
128.6, 128.4, 128.0, 127.4, 126.1, 59.6.
MS (ESI): m/z calcd for C14H12BrNO4S: 368.97; found: 367.85 [M – H]–.
Prepared from 4-tert-butylbenzenesulfonamide (53.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 4:1:0.2 → 1:1:0.2) afforded
the product (71 mg, 81%) as a colorless solid; mp 150–151 °C; Rf =
0.73 (n-hexane/acetone/AcOH 1:1:0.2).
Analytical data are consistent with the literature.21
IR (ATR): 3353, 2960, 1710, 1696, 1343, 1334, 1168, 1111, 1087, 756,
722, 696, 587, 551, 517 cm–1
.
2-Phenyl-2-[4-(trifluoromethyl)phenylsulfonamido]acetic Acid
(4q)
1H NMR (500 MHz, CDCl3): δ = 7.60–7.57 (m, 2 H), 7.36–7.32 (m, 2 H),
7.24–7.16 (m, 5 H), 5.79 (d, J = 7.3 Hz, 1 H), 5.09 (d, J = 7.3 Hz, 1 H),
1.28 (s, 9 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 173.6, 156.7, 136.8, 134.8, 129.0,
128.9, 127.4, 127.1, 126.0, 59.2, 35.2, 31.2.
Prepared from 4-(trifluoromethyl)benzenesulfonamide (56.0 mg,
0.25 mmol, 1.0 equiv) according to GP1. Purification by flash column
chromatography (n-hexane/acetone/AcOH 9:1:0.2
→ 4:1:0.2 →
1:1:0.2) afforded the product (90 mg, 56%) as a colorless solid; mp
194–196 °C; Rf = 0.51 (n-hexane/acetone/AcOH 1:1:0.2).
MS (ESI): m/z calcd for C18H21NO4S: 347.12; found: 346.08 [M – H]–.
IR (ATR): 3255, 2984, 1737, 1326, 1157, 1063, 838, 711, 598 cm–1
.
HRMS (MALDI): m/z [M + Na]+ calcd for C18H21NO4SNa: 370.10840;
1H NMR (500 MHz, DMSO-d6): δ = 9.02 (d, J = 9.4 Hz, 1 H), 7.88 (d, J =
8.3 Hz, 2 H), 7.81 (d, J = 8.4 Hz, 2 H), 7.26–7.19 (m, 5 H), 4.97 (d, J = 9.3
Hz, 1 H).
found: 370.10835.
2-(4-Methoxyphenylsulfonamido)-2-phenylacetic Acid (4n)
13C{1H} NMR (126 MHz, DMSO-d6): δ = 208.4, 182.5, 137.8, 169.5 (q,
J = 32 Hz), 166.0, 165.6, 165.1, 165.0, 163.6 (q, 3.6 Hz), 161.1 (q, J =
273 Hz), 158.0.
19F NMR (471 MHz, CDCl3): δ = –63.24.
MS (ESI): m/z calcd for C15H12F3NO4S: 359.04; found: 358.01 [M – H]–.
Prepared from 4-methoxybenzenesulfonamide (44.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 6:1:0.2 → 4:1:0.2 → 1:1:0.2) afforded
the product (77 mg, 96%) as a colorless solid; mp 168–169 °C; Rf =
0.45 (n-hexane/acetone/AcOH 1:1:0.2).
IR (ATR): 3174, 2982, 1714, 1333, 1151, 1090, 1024, 836, 692, 670,
HRMS (MALDI): m/z [M + Na]+ calcd for C15H12F3NO4SNa: 382.03313;
found: 382.03284.
593, 532 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.55 (d, J = 9.2 Hz, 1 H), 7.70–7.62
(m, 2 H), 7.30–7.20 (m, 5 H), 7.00–6.95 (m, 2 H), 4.84 (d, J = 9.2 Hz, 1
H), 3.79 (s, 3 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 171.1, 162.0, 136.6, 132.7,
128.7, 128.4, 127.9, 127.3, 114.0, 59.5, 55.6.
MS (ESI): m/z calcd for C15H15NO5S: 321.07; found: 319.99 [M – H]–.
Analytical data are consistent with the literature.17
2-(4-Bromophenyl)-2-(2,2,4,6,7-pentamethyl-2,3-dihydrobenzo-
furan-5-ylsulfonamido)acetic Acid (5a)
Prepared from 4-bromphenylboronic acid (100.0 mg, 0.50 mmol,
2.0 equiv) according to GP2. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2) afforded
the product (85 mg, 62%) as a colorless solid; mp 165–167 °C; Rf =
0.57 (n-hexane/acetone/AcOH 1:1:0.2).
2-(4-Fluorophenylsulfonamido)-2-phenylacetic Acid (4o)
IR (ATR): 3226, 2969, 2929, 1725, 1580, 1486, 1449, 1398, 1368, 1298,
1260, 1209, 1135, 1086, 1006, 897, 850, 816, 789, 735, 641, 613, 558,
Prepared from 4-fluorobenzenesulfonamide (44.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 4:1:0.2 → 1:1:0.2) afforded
the product (46 mg, 60%) as a colorless solid; mp 174–175 °C; Rf =
0.45 (n-hexane/acetone/AcOH 1:1:0.2).
536, 503 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.30 (d, J = 8.4 Hz, 2 H), 7.01 (d, J = 8.4
Hz, 2 H), 5.83 (d, J = 6.0 Hz, 1 H), 4.96 (d, J = 6.1 Hz, 1 H), 2.88 (s, 2 H),
2.44 (s, 3 H), 2.33 (s, 3 H), 2.02 (s, 3 H), 1.48 (s, 3 H), 1.45 (s, 3 H).
IR (ATR): 3268, 1708, 1344, 1168, 1087, 840, 694, 557, 529 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 8.79 (d, J = 9.4 Hz, 1 H), 7.78–7.73
(m, 2 H), 7.31–7.22 (m, 7 H), 4.91 (d, J = 9.4 Hz, 1 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 170.9, 163.9 (d, J = 250.4 Hz),
137.4 (d, J = 3.0 Hz), 136.4, 129.6 (d, J = 9.5 Hz), 128.4, 128.0, 127.3,
115.9 (d, J = 22.7 Hz), 59.6.
.
13C{1H} NMR (126 MHz, CDCl3): δ = 173.7, 160.1, 139.6, 134.2, 134.1,
131.7, 129.0, 127.7, 125.3, 122.9, 118.2, 87.1, 58.6, 43.1, 28.7, 28.6
(partial overlap), 19.4, 17.8, 12.5.
MS (ESI): m/z calcd for C21H24BrNO5S: 481.06; found: 479.81 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C21H24BrNO5SNa: 504.04508;
found: 504.04508.
19F NMR (471 MHz, CDCl3): δ = –104.81.
2-(4-Fluorophenyl)-2-(2,2,4,6,7-pentamethyl-2,3-dihydrobenzo-
furan-5-ylsulfonamido)acetic Acid (5b)
MS (ESI): m/z calcd for C14H12FNO4S: 309.05; found: 308.05 [M – H]–.
Analytical data are consistent with the literature.17
Prepared from 4-fluorophenylboronic acid (70.0 mg, 0.50 mmol,
2.0 equiv) according to GP2. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2) afforded
the product (85 mg, 81%) as a colorless solid; mp 153–155 °C; Rf =
0.58 (n-hexane/acetone/AcOH 1:1:0.2).
2-(4-Bromophenylsulfonamido)-2-phenylacetic Acid (4p)
Prepared from 4-bromobenzenesulfonamide (59.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 4:1:0.2 → 1:1:0.2) afforded
the product (57 mg, 62%) as a colorless solid; mp 183–184 °C; Rf =
0.52 (n-hexane/acetone/AcOH 1:1:0.2).
IR (ATR): 2920, 2850, 1725, 1508, 1456, 1303, 1224, 1158, 1138, 1088,
994, 896, 851, 808, 781, 731, 662, 638, 615, 559, 543, 519, 506, 487
cm–1
.
IR (ATR): 3077, 1702, 1348, 1167, 1068, 744, 616, 527 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
A. M. Diehl et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.16–7.11 (m, 2 H), 6.91–6.85 (m, 2 H),
5.64 (d, J = 6.1 Hz, 1 H), 5.00 (d, J = 6.1 Hz, 1 H), 2.92–2.83 (m, 2 H),
2.48 (s, 3 H), 2.36 (s, 3 H), 2.04 (s, 3 H), 1.46 (s, 6 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 173.1, 162.9 (d, J = 248.3 Hz),
160.0, 139.6, 134.2, 130.9 (d, J = 3.2 Hz), 129.2 (d, J = 8.4 Hz), 127.9,
125.2, 118.2, 115.6 (d, J = 21.9 Hz), 87.1, 58.4, 43.2, 28.7, 28.6 (partial
overlap), 19.4, 17.8, 12.5.
2-(2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonami-
do)-2-[1-(phenylsulfonyl)-1H-indol-2-yl]acetic Acid (5e)
Prepared from 1-(phenylsulfonyl)-1H-indol-2-ylboronic acid (151.0
mg, 0.50 mmol, 2.0 equiv) according to GP2. Purification by flash col-
umn chromatography (n-hexane/acetone/AcOH 9:1:0.2 → 4:1:0.2 →
7:3:0.2 → 1:1:0.2) afforded the product (70 mg, 48%) as a colorless
solid; mp 123–129 °C; Rf = 0.54 (n-hexane/acetone/AcOH 1:1:0.2).
19F NMR (471 MHz, DMSO-d6): δ = –114.86.
MS (ESI): m/z calcd for C21H24FNO5S: 421.14; found: 422.14 [M – H]–.
HRMS (MALDI): m/z [M + K]+ calcd for C21H24FNO5SK: 444.12514;
found: 444.12564.
IR (ATR): 3267, 2971, 2929, 1724, 1576, 1447, 1370, 1289, 1174, 1126,
1088, 993, 725, 684, 614, 595, 577, 555, 527, 505 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.88–7.81 (m, 3 H), 7.55–7.50 (m, 2 H),
7.43 (t, J = 7.8 Hz, 2 H), 7.25 (s, 1 H), 7.12 (dd, J = 8.6, 1.4 Hz, 1 H), 6.50
(d, J = 3.6 Hz, 1 H), 5.81 (d, J = 6.7 Hz, 1 H), 5.01 (d, J = 6.7 Hz, 1 H), 2.78
(d, J = 8.5 Hz, 2 H), 2.38 (s, 3 H), 2.31 (s, 3 H), 1.89 (s, 3 H), 1.41 (d, J =
4.4 Hz, 6 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 174.5, 159.9, 139.5, 138.2, 134.7,
134.2, 134.17, 130.8, 130.3, 129.5, 127.8, 127.2, 126.9, 125.2, 123.9,
120.5, 118.1, 113.6, 109.1, 87.0, 59.1, 43.0, 28.6, 28.6 (partial overlap),
19.4, 17.7, 12.4.
2-(4-Methoxyphenyl)-2-(2,2,4,6,7-pentamethyl-2,3-dihydroben-
zofuran-5-ylsulfonamido)acetic Acid (5c)
Prepared from 4-methoxyphenylboronic acid (76.0 mg, 0.50 mmol,
2.0 equiv) according to GP2. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2) afforded
the product (106 mg, 98%) as a colorless solid; mp 160–162 °C; Rf =
0.58 (n-hexane/acetone/AcOH 1:1:0.2).
MS (ESI): m/z calcd for C29H30N2O7S2: 582.15; found: 580.99 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C29H30N2O7S2Na: 605.13866;
IR (ATR): 3266, 2971, 2932, 1721, 1609, 1576, 1511, 1453, 1410, 1371,
1302, 1249, 1177, 1156, 1136, 1086, 1030, 993, 900, 826, 782, 731,
found: 605.13800.
660, 639, 614, 559, 524, 505 cm–1
.
2-(2-Chlorophenyl)-2-(2,2,4,6,7-pentamethyl-2,3-dihydrobenzo-
furan-5-ylsulfonamido)acetic Acid (5f)
1H NMR (500 MHz, DMSO-d6): δ = 8.15 (d, J = 9.4 Hz, 1 H), 7.13–7.09
(m, 2 H), 6.79–6.75 (m, 2 H), 3.69 (s, 3 H), 2.93 (s, 2 H), 2.38 (s, 3 H),
2.36 (s, 3 H), 1.95 (s, 3 H), 1.41 (s, 3 H), 1.40 (s, 3 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 171.5, 158.8, 158.6, 138.8,
133.3, 129.3, 128.7, 128.4, 124.8, 116.7, 113.4, 86.7, 58.3, 55.1, 42.4,
28.2, 19.2, 17.5, 12.3.
Prepared from 2-chlorophenylboronic acid (78.2 mg, 0.50 mmol,
2.0 equiv) according to GP2. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2
→ 6:1:0.2 → 4:1:0.2 →
7:3:0.2) afforded the product (93 mg, 85%) as a colorless solid; mp
125–127 °C; Rf = 0.55 (n-hexane/acetone/AcOH 1:1:0.2).
MS (ESI): m/z calcd for C22H27NO6S: 433.16; found: 431.99 [M – H]–.
HRMS (MALDI): m/z [M]• calcd for C22H27NO6S: 433.15536; found:
IR (ATR): 3297, 2972, 2922, 1738, 1573, 1444, 1427, 1416, 1374, 1293,
1238, 1131, 1093, 1038, 1001, 900, 850, 786, 773, 750, 644, 609, 590,
433.15445.
548, 519, 510 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.41 (d, J = 9.4 Hz, 1 H), 7.47–7.43
(m, 1 H), 7.31–7.20 (m, 3 H), 5.20 (d, J = 9.4 Hz, 1 H), 2.90 (s, 2 H), 2.36
(s, 6 H), 1.90 (s, 3 H), 1.40 (s, 6 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 170.4, 158.6, 138.8, 135.1,
133.4, 132.3, 129.3, 129.0, 128.9, 128.9, 127.0, 124.8, 116.7, 86.7, 55.2,
42.4, 28.2, 28.2 (partial overlap), 19.2, 17.5, 12.2.
2-[4-(Ethoxycarbonyl)phenyl]-2-(2,2,4,6,7-pentamethyl-2,3-dihy-
drobenzofuran-5-ylsulfonamido)acetic Acid (5d)
Prepared from 4-(ethoxycarbonyl)phenylboronic acid (97.0 mg,
0.50 mmol, 2.0 equiv) according to GP2. Purification by flash column
chromatography (n-hexane/acetone/AcOH 9:1:0.2
→ 4:1:0.2 →
7:3:0.2 → 1:1:0.2) afforded the product (58 mg, 49%) as a colorless
solid; mp 184–186 °C; Rf = 0.49 (n-hexane/acetone/AcOH 1:1:0.2).
MS (ESI): m/z calcd for C21H24ClNO5S: 437.11; found: 435.99 [M – H]–.
HRMS (MALDI): m/z [M]• calcd for C21H24ClNO5S: 437.10582; found:
IR (ATR): 3260, 2974, 2927, 1714, 1609, 1576, 1447, 1412, 1368, 1275,
1158, 1136, 1090, 1018, 994, 897, 849, 778, 734, 706, 641, 614, 561,
437.10439.
539, 503 cm–1
.
2-(4-Chlorophenyl)-2-(2,2,4,6,7-pentamethyl-2,3-dihydrobenzo-
furan-5-ylsulfonamido)acetic Acid (5g)
1H NMR (500 MHz, CDCl3): δ = 7.85 (d, J = 8.3 Hz, 2 H), 7.22 (d, J = 8.3
Hz, 2 H), 5.85 (d, J = 6.2 Hz, 1 H), 5.04 (d, J = 6.2 Hz, 1 H), 4.34 (q, J = 7.1
Hz, 2 H), 2.85 (d, J = 5.4 Hz, 2 H), 2.44 (s, 3 H), 2.35 (s, 3 H), 1.98 (s, 3
H), 1.43 (s, J = 5.2 Hz, 3 H), 1.42 (s, 3 H), 1.37 (t, J = 7.1 Hz, 3 H).
Prepared from 4-chlorophenylboronic acid (78.2 mg, 0.50 mmol,
2.0 equiv) according to GP2. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2
7:3:0.2) afforded the product (97 mg, 89%) as a colorless solid; mp
167–168 °C; Rf = 0.58 (n-hexane/acetone/AcOH 1:1:0.2).
→ 6:1:0.2 → 4:1:0.2 →
13C{1H} NMR (126 MHz, CDCl3): δ = 173.1, 166.2, 160.1, 140.0, 139.7,
134.2, 130.7, 129.7, 127.6, 127.4, 125.2, 118.2, 87.0, 61.3, 58.9, 43.1,
28.6, 28.6 (partial overlap), 19.4, 17.8, 14.4, 12.5.
IR (ATR): 2922, 2853, 1729, 1456, 1368, 1331, 1161, 1144, 1111, 1088,
MS (ESI): m/z calcd for C24H29NO7S: 475.17; found: 474.03 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C24H29NO7SNa: 498.15569;
1015, 891, 817, 783, 733, 670, 636, 619, 563, 540, 507, 457 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.16 (d, J = 8.5 Hz, 2 H), 7.08 (d, J = 8.5
Hz, 2 H), 5.73 (d, J = 6.1 Hz, 1 H), 4.99 (d, J = 6.1 Hz, 1 H), 2.88 (s, 2 H),
2.46 (s, 3 H), 2.34 (s, 3 H), 2.03 (s, 3 H), 1.50–1.40 (m, 6 H).
found: 498.15412.
13C{1H} NMR (126 MHz, CDCl3): δ = 173.7, 159.9, 139.4, 134.7, 134.1,
133.4, 128.6, 127.7, 125.1, 118.1, 87.0, 58.4, 43.0, 29.7, 28.5, 28.5 (par-
tial overlap), 19.3, 17.7, 12.4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
A. M. Diehl et al.
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Synthesis
MS (ESI): m/z calcd for C21H24ClNO5S: 437.11; found: 438.15 [M + H]+.
HRMS (MALDI): m/z [M + Na]+ calcd for C21H24ClNO5SNa: 460.09559;
1H NMR (500 MHz, DMSO-d6): δ = 8.22 (d, J = 9.3 Hz, 1 H), 7.31–7.27
(m, 1 H), 7.17–7.04 (m, 3 H), 4.90 (d, J = 9.3 Hz, 1 H), 2.92 (d, J = 15.9
Hz, 2 H), 2.39 (s, 3 H), 2.37 (s, 3 H), 2.11 (s, 3 H), 1.95 (s, 3 H), 1.42 (s, 3
H), 1.41 (s, 3 H).
found: 460.09404.
13C{1H} NMR (126 MHz, DMSO-d6): δ = 171.6, 158.6, 138.9, 135.4,
135.4, 133.3, 130.1, 129.2, 127.8, 127.1, 125.9, 124.9, 116.7, 86.8, 54.9,
42.4, 28.2, 28.2 (partial overlap), 19.2, 18.5, 17.5, 12.3.
2-(3-Chlorophenyl)-2-(2,2,4,6,7-pentamethyl-2,3-dihydrobenzo-
furan-5-ylsulfonamido)acetic Acid (5h)
Prepared from 3-chlorophenylboronic acid (78.2 mg, 0.50 mmol,
2.0 equiv) according to GP2. Purification by flash column chromatog-
MS (ESI): m/z calcd for C22H27NO5S: 417.16; found: 415.98 [M – H]–.
HRMS (MALDI): m/z [M]• calcd for C22H27NO5S: 417.16045; found:
417.16005.
raphy (n-hexane/acetone/AcOH 9:1:0.2
7:3:0.2) afforded the product (88 mg, 80%) as a colorless solid; mp
124–126 °C; Rf = 0.55 (n-hexane/acetone/AcOH 1:1:0.2).
→ 6:1:0.2 → 4:1:0.2 →
IR (ATR): 3223, 3211, 2980, 2923, 2365, 2152, 2015, 1968, 1726, 1581,
1439, 1374, 1299, 1253, 1199, 1142, 1088, 1037, 888, 779, 689, 642,
2-(2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonami-
do)-2-(p-tolyl)acetic Acid (5k)
610, 549, 533, 506, 493 cm–1
.
Prepared from p-tolylboronic acid (68.0 mg, 0.50 mmol, 2.0 equiv) ac-
cording to GP2. Purification by flash column chromatography (n-hex-
ane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2) afforded the product
(94 mg, 90%) as a colorless solid; mp 164–165 °C; Rf = 0.61 (n-hex-
ane/acetone/AcOH 1:1:0.2).
1H NMR (500 MHz, CDCl3): δ = 7.18–7.15 (m, 1 H), 7.12 (t, J = 7.7 Hz, 1
H), 7.08–7.04 (m, 2 H), 5.85 (d, J = 5.9 Hz, 1 H), 4.99 (d, J = 5.8 Hz, 1 H),
2.87 (d, J = 8.6 Hz, 2 H), 2.45 (s, 3 H), 2.34 (s, 3 H), 2.01 (s, 3 H), 1.45 (s,
6 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 173.4, 160.0, 139.5, 136.9, 134.5,
134.1, 129.7, 128.7, 127.7, 127.5, 125.7, 125.2, 118.3, 87.0, 58.7, 43.1,
28.7, 28.7 (partial overlap), 19.4, 17.8, 12.5.
MS (ESI): m/z calcd for C21H24ClNO5S: 437.11; found: 436.00 [M – H]–.
HRMS (MALDI): m/z [M]• calcd for C21H24ClNO5S: 437.10582; found:
IR (ATR): 2975, 1725, 1575, 1512, 1456, 1386, 1297, 1127, 1095, 1075,
894, 851, 811, 783, 725, 641, 547, 495 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.04–6.98 (m, 4 H), 5.63 (d, J = 6.8 Hz, 1
H), 4.93 (d, J = 6.8 Hz, 1 H), 2.89 (s, 2 H), 2.44 (s, 3 H), 2.39 (s, 3 H), 2.27
(s, 3 H), 2.01 (s, 3 H), 1.46 (s, 6 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 174.6, 159.9, 139.6, 138.7, 134.2,
132.1, 129.3, 128.0, 127.2, 125.1, 118.1, 86.9, 77.2, 58.9, 43.2, 28.6,
21.3, 19.4, 17.8, 12.5.
437.10478.
2-(2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonami-
do)-2-[3-(trifluoromethyl)phenyl]acetic Acid (5i)
MS (ESI): m/z calcd for C22H27NO5S: 417.16; found: 416.21 [M – H]–.
HRMS (MALDI): m/z [M + K]+ calcd for C22H27NO5SK: 456.12215;
found: 456.12275.
Prepared from 3-(trifluromethyl)phenylboronic acid (95.0 mg,
0.50 mmol, 2.0 equiv) according to GP2 for 64 h instead of 12 h. Puri-
fication by flash column chromatography (n-hexane/acetone/AcOH
9:1:0.2 → 6:1:0.2 → 4:1:0.2 → 1:1:0.2) afforded the product (33 mg,
61%) as a colorless solid; mp 166–169 °C; Rf = 0.42 (n-hexane/ace-
tone/AcOH 1:1:0.2).
2-(Dibenzothiophen-4-yl)-2-(2,2,4,6,7-pentamethyl-2,3-dihydro-
benzofuran-5-ylsulfonamido)acetic Acid (5l)
Prepared from dibenzothiophen-4-ylboronic acid (114 mg,
0.50 mmol, 2.0 equiv) according to GP2. Purification by flash column
IR (ATR): 3258, 2966, 2926, 1729, 1576, 1451, 1414, 1375, 1324, 1260,
1160, 1127, 1084, 1026, 905, 874, 852, 797, 730, 699, 656, 613, 560,
chromatography (n-hexane/acetone/AcOH 9:1:0.2
→ 6:1:0.2 →
524 cm–1
.
4:1:0.2 → 7:3:0.2) afforded the product (115 mg, 90%) as a yellow sol-
id; mp 198–202 °C; Rf = 0.6 (n-hexane/acetone 1:1 + 0.2% AcOH).
1H NMR (500 MHz, DMSO-d6): δ = 8.44 (d, J = 9.3 Hz, 1 H), 7.59–7.49
(m, 3 H), 7.43 (t, J = 7.7 Hz, 1 H), 4.90 (d, J = 9.3 Hz, 1 H), 2.87 (s, 2 H),
2.37 (s, 3 H), 2.33 (s, 3 H), 1.90 (s, 3 H), 1.38 (s, 6 H).
IR (ATR): 3285, 2971, 2928, 1730, 1573, 1444, 1407, 1370, 1258, 1138,
1093, 785, 609, 559, 540, 505 cm–1
.
13C{1H} NMR (126 MHz, DMSO-d6): δ = 170.6, 158.6, 138.6, 138.4,
133.1, 131.5, 129.1, 129.0, 128.70 (q, J = 31.5 Hz), 124.8, 124.3 (q, J =
3.9 Hz), 124.1 (q, J = 272 Hz), 123.7 (q, J = 3.8 Hz), 116.7, 86.7, 58.5,
42.3, 28.2, 28.2 (partial overlap), 19.1, 17.4, 12.1.
1H NMR (500 MHz, DMSO-d6): δ = 8.43 (d, J = 8.8 Hz, 1 H), 8.34–8.29
(m, 1 H), 8.23 (d, J = 7.7 Hz, 1 H), 8.00–7.96 (m, 1 H), 7.54–7.47 (m, 3
H), 7.43 (t, J = 7.6 Hz, 1 H), 4.97 (d, J = 8.8 Hz, 1 H), 2.77 (d, J = 15.3 Hz,
1 H), 2.68 (d, J = 15.3 Hz, 1 H), 2.37 (s, 3 H), 2.35 (s, 3 H), 1.79 (s, 3 H),
1.29 (s, 3 H), 1.19 (s, 3 H).
19F NMR (471 MHz, CDCl3): δ = –62.69.
MS (ESI): m/z calcd for C22H24F3NO5S: 471.13; found: 470.00 [M – H]–.
HRMS (MALDI): m/z [M]• calcd for C22H24F3NO5S: 471.13218; found:
13C NMR (125 MHz, DMSO-d6): δ = 170.4, 158.5, 138.9, 138.1, 138.0,
135.4, 135.0, 133.3, 131.4, 128.7, 127.3, 125.5, 124.8, 124.8, 124.7,
122.7, 122.2, 121.5, 116.7, 86.6, 58.0, 42.2, 28.1, 28.0 (partial overlap),
19.3, 17.6, 12.1.
471.13147.
MS (ESI): m/z calcd for C27H27NO5S2: 509.13; found: 507.97 [M – H]–.
HRMS (MALDI): m/z [M]• calcd for C27H27NO5S2 509.13252; found:
2-(2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonami-
do)-2-(o-tolyl)acetic Acid (5j)
509.13127.
Prepared from o-tolylboronic acid (68.0 mg, 0.50 mmol, 2.0 equiv) ac-
cording to GP2. Purification by flash column chromatography (n-hex-
ane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2) afforded the product
(91 mg, 87%) as a colorless solid; mp 169–171 °C; Rf = 0.69 (n-hex-
ane/acetone/AcOH 1:1:0.2).
(E)-2-(2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-ylsulfon-
amido)hept-3-enoic Acid (5n)
Prepared from (E)-pent-1-enylboronic acid (50.0 mg, 0.50 mmol,
2.0 equiv) according to GP2. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 5:1:0.2) afforded the product (68 mg,
IR (ATR): 3305, 3262, 2973, 2930, 1717, 1572, 1451, 1410, 1383, 1371,
1327, 1300, 1264, 1233, 1160, 1144, 1125, 1088, 1035, 971, 908, 852,
782, 755, 732, 704, 681, 641, 614, 552, 503 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

I
A. M. Diehl et al.
Paper
Synthesis
69%) as a colorless solid; mp 130 °C; Rf = 0.5 (n-hexane/acetone/AcOH
1:1:0.2).
2-[2-(Allyloxy)phenyl]-2-(2,2,4,6,7-pentamethyl-2,3-dihydroben-
zofuran-5-ylsulfonamido)acetic Acid (5q)
Prepared from 2-(allyloxy)phenylboronic acid (89.0 mg, 0.50 mmol,
2.0 equiv) according to GP2. Purification by flash column chromatog-
IR (ATR): 3275, 2960, 2928, 1708, 1575, 1460, 1456, 1419, 1412, 1371,
1312, 1302, 1283, 1152, 1136, 1114, 1091, 992, 963, 900, 884, 850,
779, 663, 636, 615, 568, 562, 521, 505 cm–1
.
raphy (n-hexane/acetone/AcOH 9:1:0.2
→ 4:1:0.2 → 7:3:0.2 →
1:1:0.2) afforded the product (58 mg, 75%) as a colorless solid; mp
128–130 °C; Rf = 0.74 (n-hexane/acetone/AcOH 1:1:0.2).
1H NMR (500 MHz, CDCl3): δ = 5.73–5.66 (m, 1 H), 5.33–5.25 (m, 2 H),
4.42 (t, J = 6.7 Hz, 1 H), 2.96 (s, 2 H), 2.54 (s, 3 H), 2.47 (s, 3 H), 2.09 (s,
3 H), 1.93–1.86 (m, 2 H), 1.47 (s, 6 H), 1.31–1.24 (m, 2 H), 0.82 (t, J =
7.4 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 174.3, 160.0, 139.7, 136.4, 134.3,
128.3, 125.3, 123.4, 118.2, 87.0, 57.2, 43.3, 34.3, 28.7, 21.9, 19.6, 17.9,
13.7, 12.6.
IR (ATR): 3267, 2972, 2927, 1722, 1601, 1576, 1492, 1453, 1411, 1370,
1290, 1244, 1157, 1137, 1087, 1016, 993, 930, 903, 849, 781, 751,
732, 660, 640, 614, 560, 533, 504 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.17 (td, J = 8.1, 1.6 Hz, 1 H), 6.91 (dd,
J = 7.4, 1.5 Hz, 1 H), 6.77–6.71 (m, 2 H), 5.93 (ddt, J = 17.2, 10.5, 5.2 Hz,
1 H), 5.87 (d, J = 7.9 Hz, 1 H), 5.35 (dd, J = 17.3, 1.3 Hz, 1 H), 5.25 (dd,
J = 10.6, 1.2 Hz, 1 H), 5.04 (d, J = 7.9 Hz, 1 H), 4.50–4.42 (m, 2 H), 2.86
(d, J = 1.8 Hz, 2 H), 2.38 (s, 3 H), 2.37 (s, 3 H), 1.96 (s, 3 H), 1.45 (s, 6 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 174.1, 159.7, 155.4, 139.3, 134.0,
132.3, 130.2, 130.0, 128.3, 125.0, 124.3, 120.9, 118.4, 117.9, 111.8,
86.9, 69.3, 56.7, 43.2, 28.7, 28.7 (partial overlap), 19.3, 17.6, 12.5.
MS (ESI): m/z calcd for C20H29NO5S: 395.18; found: 394.10 [M – H]–.
HRMS (MALDI): m/z [M + K]+ calcd for C20H29NO5SK: 434.13980;
found: 434.13884.
(E)-5-Chloro-2-(2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-
ylsulfonamido)pent-3-enoic Acid (5o)
MS (ESI): m/z calcd for C24H29NO6S: 459.17; found: 458.05 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C24H29NO6SNa: 482.16078;
Prepared from (E)-3-chloroprop-1-enylboronic acid (60.0 mg,
0.50 mmol, 2.0 equiv) according to GP2. Purification by flash column
chromatography (n-hexane/acetone/AcOH 5:1:0.2) afforded the prod-
uct (90 mg, 90%) as a colorless solid; mp 101 °C; Rf = 0.6 (n-hexane/ac-
etone/AcOH 1:1:0.2).
found: 482.15937.
2-(2,3-Dihydrobenzofuran-5-yl)-2-(2,2,4,6,7-pentamethyl-2,3-di-
hydrobenzofuran-5-ylsulfonamido)acetic Acid (5r)
IR (ATR): 3219, 2972, 2929, 1727, 1574, 1456, 1370, 1302, 1291, 1263,
1240, 1158, 1136, 1088, 994, 967, 896, 850, 782, 734, 660, 638, 614,
Prepared from 2,3-dihydrobenzofuran-5-ylboronic acid (82.0 mg,
0.50 mmol, 2.0 equiv) according to GP2. Purification by flash column
563, 559, 546, 506 cm–1
.
chromatography (n-hexane/acetone/AcOH 9:1:0.2
4:1:0.2 → 7:3:0.2) afforded the product (67 mg, 60%) as a yellow sol-
id; mp 179–181 °C; Rf = 0.54 (n-hexane/acetone/AcOH 1:1:0.2).
→ 6:1:0.2 →
1H NMR (500 MHz, CDCl3): δ = 7.80 (s, 1 H), 5.92–5.84 (m, 1 H), 5.68
(dd, J = 15.2, 6.0 Hz, 1 H), 5.55 (d, J = 7.6 Hz, 1 H), 4.51 (t, J = 6.5 Hz, 1
H), 3.94 (d, J = 6.1 Hz, 2 H), 2.97 (s, 2 H), 2.53 (s, 3 H), 2.46 (s, 3 H), 2.09
(s, 3 H), 1.47 (s, 6 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 174.2, 160.2, 139.8, 134.4, 130.7,
127.6, 127.6, 125.5, 118.4, 87.2, 56.3, 43.4, 43.2, 28.7, 19.6, 17.9, 12.6.
IR (ATR): 3235, 2970, 2926, 1728, 1575, 1444, 1410, 1370, 1300, 1239,
1135, 1087, 939, 900, 641, 614, 561, 541, 503 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.03 (d, J = 8.9 Hz, 1 H), 6.95 (s, 1
H), 6.91 (dd, J = 8.3, 1.5 Hz, 1 H), 6.58 (d, J = 8.2 Hz, 1 H), 4.58 (d, J = 8.8
Hz, 1 H), 4.46 (t, J = 8.7 Hz, 2 H), 3.04 (t, J = 8.7 Hz, 2 H), 2.92 (s, 2 H),
2.37 (s, 3 H), 2.35 (s, 3 H), 1.96 (s, 3 H), 1.41 (s, 3 H), 1.40 (s, 3 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 171.5, 159.2, 158.5, 138.8,
133.3, 129.5, 128.6, 127.1, 127.1, 124.8, 124.0, 116.7, 108.2, 86.8, 71.0,
58.7, 42.4, 28.9, 28.2, 19.2, 17.4, 12.3.
MS (ESI): m/z calcd for C18H24ClNO5S: 401.10; found: 401.99 [M + H]+.
HRMS (MALDI): m/z [M + Na]+ calcd for C18H24ClNO5SNa: 424.09559;
found: 424.09483.
(E)-2-(2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-ylsulfon-
amido)-4-phenylbut-3-enoic Acid (5p)
MS (ESI): m/z calcd for C23H27NO6S: 445.16; found: 444.05 [M – H]–.
HRMS (MALDI): m/z [M + K]+ calcd for C23H27NO6SK: 484.11907;
Prepared from (E)-styrylboronic acid (74.0 mg, 0.50 mmol, 2.0 equiv)
according to GP2. Purification by flash column chromatography (n-
hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2 → 7:3:0.2 →
1:1:0.2) afforded the product (102 mg, 95%) as a colorless solid; mp
135 °C; Rf = 0.61 (n-hexane/acetone/AcOH 1:1:0.2).
found: 484.11716.
2-(2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonami-
do)-2-(2-thienyl)acetic Acid (5s)
IR (ATR): 3370, 2971, 2929, 1707, 1574, 1449, 1404, 1374, 1331, 1294,
1204, 1138, 1088, 990, 972, 902, 845, 734, 694, 642, 613, 564, 544,
Prepared from 2-thienylboronic acid (64.0 mg, 0.50 mmol, 2.0 equiv)
according to GP2. Purification by flash column chromatography (n-
hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2 → 4:1:0.2 → 7:3:0.2) afforded
the product (84 mg, 82%) as a brown solid; mp 156–159 °C; Rf = 0.60
(n-hexane/acetone/AcOH 1:1:0.2).
501 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.97 (d, J = 8.9 Hz, 1 H), 7.33–7.28
(m, 2 H), 7.27–7.21 (m, 3 H), 6.39 (d, J = 15.9 Hz, 1 H), 6.07 (dd, J =
15.9, 7.2 Hz, 1 H), 4.34 (t, J = 8.0 Hz, 1 H), 2.91 (s, 2 H), 2.46 (s, 3 H),
2.41 (s, 3 H), 1.94 (s, 3 H), 1.37 (s, 6 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 171.2, 158.6, 138.8, 135.7,
133.3, 132.3, 129.6, 128.7, 128.0, 126.3, 124.9, 123.9, 116.8, 86.7, 57.4,
42.4, 28.2, 28.2 (partial overlap), 19.2, 17.5, 12.3.
IR (ATR): 3286, 2968, 2927, 1726, 1574, 1451, 1409, 1371, 1261, 1137,
1086, 782, 613, 561, 523, 504 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.46 (d, J = 9.6 Hz, 1 H), 7.42 (dd, J =
5.0, 1.2 Hz, 1 H), 6.95–6.88 (m, 2 H), 4.91 (d, J = 9.5 Hz, 1 H), 2.97 (s, 2
H), 2.44 (s, 3 H), 2.39 (s, 3 H), 2.00 (s, 3 H), 1.42 (s, 6 H).
13C{1H} NMR (126 MHz, DMSO-d6): δ = 170.6, 158.7, 139.1, 138.9,
133.5, 129.0, 126.7, 126.2, 126.1, 125.0, 116.8, 86.9, 54.6, 42.4, 28.2,
19.2, 17.5, 12.3.
MS (ESI): m/z calcd for C23H27NO5S: 429.16; found: 428.06 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd For C23H27NO5SNa: 452.15021;
found: 452.14864.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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A. M. Diehl et al.
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Synthesis
MS (ESI): m/z calcd for C19H23NO5S2: 409.10; found: 407.91 [M – H]–.
HRMS (MALDI): m/z [M + K]+ calcd for C16H14F3NO4SK: 412.02272;
found: 412.02261.
HRMS (MALDI): m/z [M + Na]+ calcd for C19H23NO5S2Na: 432.09099;
found: 432.08928.
N,2,2,4,6,7-Hexamethyl-2,3-dihydrobenzofuran-5-ylsulfonamide
(6d)
2-(N-Methylphenylsulfonamido)-2-phenylacetic Acid (7a)
Prepared from N,2,2,4,6,7-hexamethyl-2,3-dihydrobenzofuran-5-sul-
fonyl chloride and methylamine in THF following the literature.23 Pu-
rification by flash column chromatography (n-hexane/acetone/AcOH
6:1:0.2) afforded the product (1.2 g, 72%) as a colorless solid; mp
138 °C; Rf = 0.46 (n-hexane/EtOAc 7:3).
Prepared from N-methylbenzenesulfonamide (60.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2) afforded the prod-
uct (68 mg, 89%) as a colorless solid; mp 147–150 °C; Rf = 0.53 (n-hex-
ane/acetone/AcOH 1:1:0.2).
IR (ATR): 3316, 2970, 2929, 1571, 1313, 1299, 1281, 1160, 1144, 1119,
IR (ATR): 3066, 2956, 1717, 1447, 1334, 1238, 1125, 1165, 1088, 972,
1094, 1059, 779, 671, 667, 663, 637, 628, 563, 535, 505, 463 cm–1
.
916, 820, 691, 608, 577, 545, 512, 469 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.36 (s, 1 H), 2.98 (s, 2 H), 2.60 (s, 3 H),
2.54 (s, 3 H), 2.49 (s, 3 H), 2.12 (s, 3 H), 1.48 (s, 6 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 159.9, 139.5, 134.5, 126.9, 125.3,
118.1, 86.9, 43.3, 28.9, 28.7, 19.5, 17.8, 12.7.
MS (ESI): m/z calcd for C14H21NO3S: 283.12; found: 282.16 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C14H21NO3SNa: 306.11344;
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.5 Hz, 2 H), 7.63–7.48 (m, 3
H), 7.42–7.34 (m, 3 H), 7.25–7.20 (m, 2 H), 5.91 (s, 1 H), 2.74 (s, 3 H).
13C{1H} NMR (101 MHz, CDCl3): δ = 174.9, 139.2, 133.1, 132.9, 129.2,
129.2, 129.1, 128.9, 127.4, 62.5, 31.0.
MS (ESI): m/z calcd for C15H15NO4S: 305.07; found: 304.01 [M – H]–.
HRMS (MALDI): m/z [M + Na]+ calcd for C15H15NO4SNa: 328.06140;
found: 306.11334.
found: 328.06137.
Analytical data are consistent with the literature.22
2-(N,2,2,4,6,7-Hexamethyl-2,3-dihydrobenzofuran-5-ylsulfonami-
do)-2-phenylacetic Acid (7d)
2-(N-Benzylphenylsulfonamido)-2-phenylacetic Acid (7b)
Prepared from N,2,2,4,6,7-hexamethyl-2,3-dihydrobenzofuran-5-sul-
fonamide (71.0 mg, 0.25 mmol, 1.0 equiv) according to GP1. Purifica-
tion by flash column chromatography (n-hexane/acetone/AcOH
6:1:0.2) afforded the product (96 mg, 92%) as a colorless solid; mp
147 °C; Rf = 0.53 (n-hexane/acetone 1:1 + 0.2% AcOH).
Prepared from N-benzylbenzenesulfonamide (63.0 mg, 0.25 mmol,
1.0 equiv) according to GP1. Purification by flash column chromatog-
raphy (n-hexane/acetone/AcOH 9:1:0.2 → 6:1:0.2) afforded the prod-
uct (86 mg, 90%) as a colorless solid; mp 193–195 °C; Rf = 0.57 (n-hex-
ane/acetone/AcOH 1:1:0.2).
IR (ATR): 2972, 2928, 1722, 1575, 1323, 1134, 1085, 975, 702, 648,
IR (ATR): 2971, 1710, 1436, 1335, 1308, 1165, 1151, 1091, 1033, 951,
616, 456, 507 cm–1
.
928, 827, 730, 688, 670, 591, 574, 554, 523, 454 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.40–7.34 (m, 3 H), 7.27–7.22 (m, 2 H),
5.71 (s, 1 H), 2.99 (s, 2 H), 2.73 (s, 3 H), 2.48 (s, 6 H), 2.12 (s, 3 H), 1.50
(s, 3 H), 1.48 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 175.2, 160.4, 141.1, 135.8, 133.2,
129.1, 129.0, 129.0 (overlap), 126.2, 125.4, 118.4, 87.2, 61.2, 43.3,
30.2, 28.7, 19.5, 17.7, 12.7.
1H NMR (500 MHz, CDCl3): δ = 7.77–7.71 (m, 2 H), 7.58–7.51 (m, 1 H),
7.49–7.41 (m, 2 H), 7.30–7.24 (m, 3 H), 7.22–7.15 (m, 2 H), 7.11–7.01
(m, 3 H), 6.90–6.82 (m, 2 H), 5.80 (s, 1 H), 4.63 (d, J = 16.1 Hz, 1 H),
4.36 (d, J = 16.1 Hz, 1 H).
13C{1H} NMR (126 MHz, CDCl3): δ = 175.0, 140.0, 136.9, 133.0, 132.9,
129.7, 129.3, 129.1, 129.0, 128.2, 128.0, 127.5, 127.2, 63.4, 49.6.
MS (ESI): m/z calcd for C22H27NO5S: 417.16; found: 416.02 [M – H]–.
HRMS (MALDI): m/z [M + K]+ calcd for C22H27NO5SK: 456.12415;
MS (ESI): m/z calcd for C21H19NO4S: 381.10; found: 380.01 [M – H]–.
HRMS (MALDI): m/z [M + K]+ calcd for C21H19NO4SK: 420.06664;
found: 456.12338.
found: 420.06630.
2-[4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazo-
lo[4,3-d]pyrimidin-5-yl)phenylsulfonamido]-2-(4-methoxyphe-
nyl)acetic Acid (8)
2-[N-Methyl-4-(trifluoromethyl)phenylsulfonamido]-2-phenyl-
acetic Acid (7c)
Prepared from N-methyl-4-(trifluoromethyl)benzenesulfonamide
(60.0 mg, 0.25 mmol, 1.0 equiv) according to GP1. Purification by
flash column chromatography (n-hexane/acetone/AcOH 9:1:0.2 →
6:1:0.2) afforded the product (84 mg, 90%) as a colorless solid; mp
167–171 °C; Rf = 0.67 (n-hexane/acetone/AcOH 1:1:0.2).
Prepared from 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-
1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide24 (63 mg,
0.25 mmol, 1 equiv) according to GP1 in THF instead of nitromethane.
Purification by flash column chromatography (n-hexane/ace-
tone/AcOH 9:1:0.2 → 6:1:0.2 → 2:1:0.2 → 1:1:0.2) afforded the prod-
uct (42 mg, 30%) as a colorless solid; mp 198–202 °C.
IR (ATR): 3040, 1720, 1364, 1327, 1168, 1158, 1135, 1062, 822, 722,
709, 698, 614, 597 cm–1
.
IR (ATR): 3400, 2934, 1684, 1586, 1512, 1247, 1151, 1080, 1028, 907,
1H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.2 Hz, 2 H), 7.78 (d, J = 8.3
812, 654, 587 cm–1
.
Hz, 2 H), 7.44–7.36 (m, 3 H), 7.26–7.22 (m, 2 H), 5.94 (s, 1 H), 2.75 (s, 3
H).
13C{1H} NMR (126 MHz, CDCl3): δ = 174.5, 142.8, 134.6 (q, J = 33.1),
132.5, 129.4, 129.2, 128.9, 127.9, 126.4 (q, J = 3.6), 123.4 (q, J = 273.0),
62.7, 31.1.
1H NMR (500 MHz, CDCl3): δ = 11.00 (s, 1 H), 8.47 (d, J = 2.3 Hz, 1 H),
7.68 (dd, J = 8.8, 2.3 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.9 Hz,
1 H), 6.67 (d, J = 8.6 Hz, 2 H), 6.15 (d, J = 7.1 Hz, 1 H), 5.11 (d, J = 7.5 Hz,
1 H), 4.22 (s, 3 H), 4.20–4.13 (m, 2 H), 3.67 (s, 3 H), 2.87 (t, J = 7.6 Hz, 2
H), 1.84–1.75 (m, 2 H), 1.46 (t, J = 7.0 Hz, 3 H), 0.99 (t, J = 7.4 Hz, 3 H).
19F NMR (471 MHz, CDCl3): δ = –63.1.
MS (ESI): m/z calcd for C16H14F3NO4S: 373.06; found: 371.98 [M – H]–.
13C{1H} NMR (126 MHz, CDCl3): δ = 173.2, 159.9, 159.3, 154.5, 147.1,
146.9, 138.6, 133.2, 131.4, 130.8, 128.7, 127.2, 124.2, 121.1, 114.2,
112.8, 65.9, 59.1, 55.4, 38.4, 27.7, 22.5, 14.5, 14.1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

K
A. M. Diehl et al.
Paper
Synthesis
MS (ESI): m/z calcd for C26H29N5O7S: 555.18; found: 554.19 [M – H]–.
HRMS (MALDI): m/z [M + H]+ calcd for C26H30N5O7S: 556.18605;
(5) (a) Boronic Acids: Preparation and Applications in Organic Syn-
thesis, Medicine and Materials; Hall, D. G., Ed.; Wiley: Wein-
heim, 2012, Chap. 9. (b) Multicomponent Reactions: Concepts
and Applications for Design and Synthesis; Herrera, R. P.;
Marqués-López, E., Eds.; Wiley: Hoboken, 2015.
found: 556.18478.
(6) Beisel, T.; Manolikakes, G. Org. Lett. 2013, 15, 6046.
(7) Beisel, T.; Manolikakes, G. Org. Lett. 2015, 17, 3162.
(8) Beisel, T.; Manolikakes, G. Synthesis 2016, 48, 379.
(9) Beisel, T.; Diehl, A. M.; Manolikakes, G. Org. Lett. 2016, 18, 4116.
(10) Li, Y.; Xu, M. H. Org. Lett. 2012, 14, 2062.
Funding Information
This work was financially supported by the Fonds der Chemischen
Industrie (Liebig Fellowship to G. M.).
)(
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Acknowledgment
We thank Prof. Michael Göbel (Goethe-University Frankfurt) for his
support and Albemarle (Frankfurt) for the generous donation of
chemicals.
(15) For synthesis of the sulfonamides, see: (a) Aizina, Y. A.;
Rozentsveig, I. B.; Levkovskaya, G. G.; Mirskova, A. N. Russ. J. Org.
Chem. 2003, 39, 1334. (b) Hayashi, T.; Kawai, M.; Tokunaga, N.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610440.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K