Styrylsulfonates and -Sulfonamides through Pd-Catalysed Matsuda–Heck Reactions of Vinylsulfonic Acid Derivatives and Arenediazonium Salts

Article abstract of DOI:10.1002/ejoc.201600469

Arene diazonium salts undergo Matsuda–Heck reactions with vinylsulfonates and -sulfonamides to give styrylsulfonic acid derivatives in high to excellent yields and with high to excellent selectivities. By quantifying the evolution of nitrogen over time in a gas-meter apparatus, the reactivities of ethylvinylsulfonate and the benchmark olefin methyl acrylate were compared for an electron-rich and an -deficient arene diazonium salt. Tertiary sulfonamides react in Matsuda–Heck couplings with high conversions, but require long reaction times, which prevents the determination of kinetic data through the measurement of nitrogen evolution. Secondary sulfonamides were found to be unreactive. From these results, the following order of reactivity could be deduced: H₂C=CHCO₂Me > H₂C=CHSO₂OEt > H₂C=CHSO₂N(Me)Bn >> H₂C=CHSO₂NHBn. Through the Matsuda–Heck coupling of 5-indolyldiazonium salt and a tertiary vinylsulfonamide, the synthesis of the C-5-substituted indole part of the antimigraine drug naratriptan was accomplished in high yield.

Full text of DOI:10.1002/ejoc.201600469

DOI: 10.1002/ejoc.201600469
Full Paper
Cross-Coupling Reactions
Styrylsulfonates and -Sulfonamides through Pd-Catalysed
Matsuda–Heck Reactions of Vinylsulfonic Acid Derivatives and
Arenediazonium Salts
Bernd Schmidt,*[a] Felix Wolf,[a] and Heiko Brunner[b]
Abstract: Arene diazonium salts undergo Matsuda–Heck reac- times, which prevents the determination of kinetic data
tions with vinylsulfonates and -sulfonamides to give styryl- through the measurement of nitrogen evolution. Secondary
sulfonic acid derivatives in high to excellent yields and with sulfonamides were found to be unreactive. From these results,
high to excellent selectivities. By quantifying the evolution of the following order of reactivity could be deduced: H2C=
nitrogen over time in a gas-meter apparatus, the reactivities of CHCO2Me > H2C=CHSO2OEt > H2C=CHSO2N(Me)Bn >> H2C=
ethylvinylsulfonate and the benchmark olefin methyl acrylate CHSO2NHBn. Through the Matsuda–Heck coupling of 5-indol-
were compared for an electron-rich and an -deficient arene yldiazonium salt and a tertiary vinylsulfonamide, the synthesis
diazonium salt. Tertiary sulfonamides react in Matsuda–Heck of the C-5-substituted indole part of the antimigraine drug nar-
couplings with high conversions, but require long reaction atriptan was accomplished in high yield.
Introduction
In the aftermath of Domagk's serendipitous discovery that sulf-
onamides are effective antibiotics,[1] the sulfonyl group was in-
creasingly recognized as a carbonyl bioisostere.[2,3] Due to this
bioisosterism, the sulfonyl group has played, and still plays, a
prominent role in medicinal chemistry, which has resulted in
the development of numerous sulfonyl-containing drugs and
drug candidates (Figure 1).
For example, the antibacterial agent sulfadiazin (1), the diu-
retic furosemide (2), the anticonvulsant zonisamide (3), and the
antimigraine agent naratriptan (4) are well-established and
commonly used drugs.[4] Bosentan (5) has been approved for
the treatment of the rare disease pulmonary arterial hyperten-
sion. It acts as an endothelin receptor A (ET-A) antagonist, and
thereby prevents the binding of the strongly vasoconstrictive
peptide hormone endothelin-1.[5] A substantially improved
binding affinity and selectivity for the ET-A receptor was re-
ported for bosentan analogue 6, in which the arylsulfonyl moi-
ety was replaced by a styrylsulfonyl group.[6] With a view to-
wards the development of antiinflammatory therapeutics, some
other styrylsulfonamides and styrylsulfonates have more re-
cently been evaluated as inhibitors of the inducible nitric oxide
synthase.[7] A styrylsulfonamide was also found to be a promis-
[a] Institut für Chemie, Universität Potsdam,
Karl-Liebknecht-Strasse 24–25, 14476 Potsdam-Golm, Germany
E-mail: bernd.schmidt@uni-potsdam.de
http://www.chem.uni-potsdam.de/groups/schmidt/
[b] Atotech Deutschland GmbH,
Erasmusstrasse 20, 10553 Berlin, Germany
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600469.
Figure 1. Sulfonyl drugs and drug candidates, and two non-sulfonyl bioisosteres.
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ing carbonic anhydrase inhibitor;[8] such molecules are currently acceptor reactivity of styrylsulfonates, which undergo conju-
clinically used as antiglaucoma agents (e.g., dorzolamide[9]), but gate addition of deprotonated nitromethane, followed by re-
are believed to have potential as anticancer drugs as well.[10] duction of the nitro group to give a primary amine.[25] Consider-
Styryl sulfone 7, derived from chalcone skeleton 8 by bioiso- able efforts have been made over the past decade to render
steric replacement of the carbonyl group with a sulfonyl moiety, similar conjugate additions of nucleophiles to α,ꢀ-unsaturated
was very recently reported to be a potent activator of cellular sulfones and sulfonic acid derivatives enantioselective.[26–31] In
defense systems against oxidative stress. This could lead to the Scheme 1, representative examples of synthetic transformations
development of neuroprotective agents with a potential appli- of vinylsulfonyl derivatives in general, and styrylsulfonyl deriva-
cation in the treatment of Parkinson's disease.[11] Vinylsulfones tives in particular, are shown. Isoindole 12 results from the in-
in general are attracting increasing attention for applications tramolecular conjugate addition of an amine to an α,ꢀ-unsatu-
in medicinal chemistry,[12] mainly due to their ability to inhibit rated sulfonamide.[32] α,ꢀ-Unsaturated sulfones can be deproto-
cysteine proteases through Michael addition of cysteine thiol nated selectively at the α position, and then trapped with elec-
groups located at the active site of the enzymes.[13,14] Malfunc- trophiles, as shown for the formation of 13, which results from
tions of cysteine proteases have been linked to various diseases lithiation of the parent sulfone with MeLi, and alkylation with
such as arthritis, osteoporosis, or Alzheimer's disease,[15] but the MeI.[33] Ethylenesulfonamide substituents (–CH2CH2SO2NRR′)
inhibition of cysteine proteases is also expected to become an linked directly to arenes are very common structural elements
effective therapeutic approach for the treatment of infectious in medicinal chemistry. They are often synthesized by Pd-cata-
diseases. For example, vinylsulfonyl-based inhibitors of cruzain, lysed hydrogenation of a styrylsulfonyl derivative.[34–37] One ex-
a cysteine protease of the parasite Trypanosomas cruzi, which ample is sulfonamide 14, which was tested as a potential inhibi-
causes Chagas disease, have been developed recently.[16–18] Be- tor of the prostaglandin-E2 receptor EP-3.[35] Epoxide 15 was
yond their immediate applications in medicinal chemistry, vinyl- obtained from the underlying styrylsulfonamide by epoxidation
sulfones and vinylsulfonic acid derivatives are versatile starting with KOCl; it was tested successfully for the treatment of filarial
materials for the synthesis of other sulfonyl derivatives, which infections in an animal model.[38] Sharpless dihydroxylation of
can also be useful for medicinal chemistry purposes.[12] Exam- vinyl sulfones proceeds with subsequent elimination of sulf-
ples of this include the homotaurine derivatives saclofen (9) inate, and gives enantiomerically pure α-hydroxy aldehydes,[39]
and 2-hydroxysaclofen (10). Saclofen (9) is derived from baclo- which can be further transformed, e.g., into enantiomerically
fen (11), an approved GABAB-receptor agonist (GABA = γ-ami- and diastereomerically pure piperidines such as 16.[40] Styryl-
nobutyric acid), which is used clinically as a muscle relaxant,[4] sulfonamides have also been used for the synthesis of pyrrole-
through bioisosteric replacement of the carboxylate moiety by and pyrazolesulfonamides (e.g., 17)[41] by reaction with tosyl-
a sulfonate group. Although saclofen (9) is not an approved methyl isocyanide (Tosmic) or diazomethane, respectively
drug, several physiological studies have reported its application, (Scheme 1).
and that of other 2-aryl-homotaurine derivatives, as GABAB-re-
The sulfonyl derivatives resulting from these transformations
ceptor antagonists, e.g., for studying the competitive binding of might be interesting in themselves because of their biological
ligands to this receptor.[19–22] One of the previously reported properties, but they can also serve as useful reagents for the
syntheses[23,24] of 2-arylhomotaurines exploits the Michael- synthesis of desulfonylated organic products.[42]
Scheme 1. Synthetic transformations of styrylsulfonyl derivatives.
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Synthetic routes to vinylsulfones, including some styryl- an industrial scale in electroplating baths and for the prepara-
sulfones, have been reviewed.[12] Most syntheses rely on phos- tion of tensides, so it is commercially available at low cost. Eth-
phonate-based olefination reactions, an approach that can also ylvinyl sulfonate (19a)[101] and N-benzylvinylsulfonamide
be used for sulfonic acid esters and amides.[30,31,43,44] A stereo- (19b)[102] were synthesized from 21 by reaction with ethanol or
selective synthesis of Z-vinylsulfones by Peterson olefination benzylamine, respectively, as described previously in the litera-
has recently been reported.[45] Another group of syntheses pro- ture. Tertiary vinylsulfonamide 19c was synthesized by methyl-
ceeds through transition-metal-catalysed allylic substitution– ation of 19b under basic conditions (Scheme 2).
isomerization sequences[46,47] or cross-coupling reactions[48,49]
using sodium aryl sulfinates or sulfinate surrogates as nucleo-
philes. In a third class of syntheses, the C–C double bond of the
vinylsulfonyl derivatives is formed by elimination of water or
hydrogen halide after introduction of the sulfone.[50–54] An ap-
proach to vinylsulfones from terminal alkynes proceeds through
hydrozirconation and trapping of the vinylzirconium intermedi-
ate with a sulfonyl chloride.[55] Finally, styrylsulfonyl derivatives
can also be accessed through Heck arylation of vinylsulfonyl
derivatives. Compared to the plethora of examples of Heck
arylations of acrylates, the analogous couplings of vinylsulfones
and vinylsulfonic acid derivatives have hardly been ex-
plored.[32,56–65] Generally, successful Heck reactions of these
substrates require aryl bromides, activating phosphine ligands
such as PPh3 or occasionally P(o-tolyl)3, reaction temperatures
higher than 100 °C, and reaction times of several hours. We are
aware of only one study that compares the reactivity of vinyl
sulfur compounds with different oxidation states at sulfur in
Heck coupling reactions with different aryl bromides. Vinyl-
sulfides and vinyl sulfoxides couple in moderate to fair yields,
and high yields of coupling products were obtained for vinyl-
sulfones and vinylsulfonates.[61]
Considering the importance of styrylsulfonyl derivatives in
medicinal chemistry and as intermediates in organic synthesis,
we were surprised by the rather limited number of approaches
to their synthesis based on Heck couplings. The reasons might
be, as mentioned above, the comparatively high reaction tem-
peratures and the occasionally reported high loadings of Pd
precatalysts and expensive ligands. Based on our own[66–72] and
others'[73–92] positive experiences with arene diazonium salts as
electrophilic coupling partners in Pd-catalysed coupling reac-
tions, we investigated these reagents in the Heck reactions of
vinylsulfonates and vinylsulfonamides. Heck reactions using ar-
ene diazonium salts were pioneered by Matsuda and coworkers
in the late 1970's, and are therefore referred to as Matsuda–
Heck reactions.[93] Over the past decade, the progress in this
field has been documented in several reviews.[94–97]
Scheme 2. Synthesis of vinylsulfonyl derivatives 19.
The Heck arylations of vinylsulfonyl derivatives cited in the
introduction generally require temperatures above 100 °C and
activating phosphine ligands, but these reaction conditions are
known to be detrimental for Matsuda–Heck reactions, because
hydrodediazonation of the diazonium salt and other uncon-
trolled side reactions dominate.[94,103] For these reasons, we
aimed to develop ligand-free and ambient temperature reac-
tion conditions. Methanol and acetonitrile were tested as sol-
vents, based on the previous experience of ourselves and oth-
ers. Information about the role of the base in Matsuda–Heck
reactions is somewhat ambiguous. We found previously that
basic conditions lead to a significantly lower yield for the cou-
pling of most arene diazonium salts with electron-deficient ole-
fins in methanol, which can be attributed to competing hydro-
dediazonation.[67] On the other hand, work from Correia and
coworkers suggests that electron-rich olefins react preferentially
with diazonium salts in acetonitrile in the presence of a
base.[104] These authors were able to prove by thorough ESI-MS
studies that cationic Pd–acetonitrile complexes are mechanisti-
cally relevant.[80] When acetonitrile is present as a coordinating
ligand, it should stabilize the cationic PdII–hydride intermediate
formed by ꢀ-hydride elimination better than methanol; this
might explain why Matsuda–Heck reactions in acetonitrile nor-
mally require the presence of a base to induce deprotonation
of the Pd–H intermediate and close the catalytic cycle. Bearing
these aspects in mind, we started the optimization study using
18a and vinylsulfonate 19a in different ratios in methanol un-
der base-free conditions with Pd(OAc)2 as the precatalyst. The
isolated yields of styrylsulfonate 22aa were high, and were vir-
tually unaffected by the degree of excess of the olefin (Table 1,
entries 1–3).
Results and Discussion
Optimization of Reaction Conditions
Reaction conditions were optimized for the moderately elec-
tron-rich diazonium salt 4-methoxybenzene diazonium tetra-
fluoroborate (18a).[98] As olefinic coupling partners, ethyl vinyl-
sulfonate (19a), secondary sulfonamide 19b, and tertiary sulf-
Carrying out the coupling in acetonitrile in the presence of
onamide 19c were chosen. Vinylsulfonic acid derivatives can be NaOAc did not result in improved yields (Table 1, entries 4–
synthesized from ꢀ-chloroethane sulfonyl chloride (21),[99] 6). This prompted us to return to methanol under base-free
which is in turn obtained from sodium isethionate (20) by treat- conditions and test different precatalysts (Table 1, entries 7–9).
ment with thionyl chloride.[100] Sodium isethionate is used on Of the precatalysts tested, only Pd2(dba)3·CHCl3 (dba = diben-
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Table 1. Optimization of reaction conditions.
Entry
Alkene
R
Ratio 18/19 Cat. (mol-%)
Base
Solvent
Product
Yield [%]
1
2
3
4
5
6
7
8
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19b
19b
19c
19c
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
NHBn
NHBn
NCH3Bn
NCH3Bn
1:2
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd2(dba)3·CHCl3 (2.5)
[PdCl(η3-C3H5)]2 (2.5)
Pd/C[b] (5.0)
Pd(OAc)2 (2.5)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
–
–
–
methanol
methanol
methanol
CH3CN
CH3CN
CH3CN
methanol
methanol
methanol
methanol
methanol
methanol
methanol
methanol
22aa
22aa
22aa
22aa
22aa
22aa
22aa
22aa
–
22aa
–
–
22ac
22ac
84
79
83
82
74
1:1.5
1:1.1
1:2
1:1.5
1:1.1
1:2
1:2
1:2
1:2
1:2
NaOAc
NaOAc
NaOAc
75
–
–
–
–
–
–
–
–
71
n.d.[a]
[c]
9
–
10
11
12[d]
13
14
70
[c]
–
–
[c]
1:2
1:2
1:0.83
n.d.[e]
80
[a] n.d.: not determined; product 22aa was observed in trace amounts. [b] Pd/C with 10 wt.-% of Pd. [c] No conversion. [d] Reaction temperature of 50 °C.
[e] Quantitative conversion of 18a; isolated yield not determined (see text).
zylideneacetone) turned out to be moderately effective, giving try 10). To ensure high conversions irrespective of the diazo-
an isolated yield of 22aa of 71 % (Table 1, entry 7). Decreasing nium salt, we decided to adopt the parameters listed in Table 1,
the catalyst loading of Pd(OAc)2 to 2.5 mol-% under otherwise entry 1 as standard conditions for the Matsuda–Heck reactions
identical conditions led to a comparable yield (Table 1, en- of vinylsulfonates. In the next step, these standard conditions
Table 2. Scope and limitations of Matsuda–Heck couplings of vinylsulfonate 19a.
Entry
Diazonium salt[a]
R1
R2
R3
R4
Product
Yield [%]
1
2
3
4
5
6
7
8
18a[98]
18b[67]
18c[98]
18d[67]
18e[98]
18f[98]
18g[67]
18h[98]
18i[98]
H
H
H
H
H
H
H
H
H
NO2
NO2
H
H
H
H
H
H
H
H
Br
Br
Br
NO2
NO2
NO2
H
H
CF3
H
H
H
OMe
OH
OBn
OH
OMe
OBn
OH
OMe
OBn
OMe
OBn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
22aa
22ba
22ca
22da
22ea
22fa
22ga
22ha
22ia
84
quant.
94
90
99
83
95
94
88
71
80
93
71
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
18j[98]
22ja
22ka
22la
18k[98]
18l[b]
18m[106]
18n[106]
18o[106]
18p[106]
18q[107]
18r[67]
18s[67]
18t[67]
18u[70]
18v[70]
18w[108]
18x[b]
CN
22ma
22na
22oa
22pa
22qa
22ra
22sa
22ta
22ua
22va
22wa
22xa
C(O)Me
NO2
Br
OMe
OH
OMe
OH
OMe
H
92
quant.
quant.
76
94
53
72
68
88
27
H
H
H
H
H
OMe
CO2Me
CO2Me
CO2H
H
H
H
H
C(O)Ph
C(O)p-(FC6H4)
CH=CHCO2Me
H
H
SH
32
[a] Reference for synthesis and characterization of diazonium salt 18. [b] This work.
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were applied to secondary vinylsulfonamide 19b. After a reac- entry 14) can be reliably applied to a broad range of substituted
tion time of 12 h at ambient temperature, the expected styryl- arene diazonium salts (Table 3).
sulfonamide (i.e., 22ab) was not detected in the reaction mix-
Table 3. Scope and limitations of Matsuda–Heck couplings of vinylsulfon-
amide 19c.
ture (Table 1, entry 11). Instead, the starting material (i.e., 19b)
was recovered unchanged. At elevated temperature (50 °C), the
same outcome was observed under otherwise identical condi-
tions (Table 1, entry 12). Although tertiary sulfonamide 19c un-
derwent quantitative conversion to the expected styrylsulfon-
amide (i.e., 22ac), the standard conditions turned out to be
unsuitable for this olefin, because the very similar polarities of
19c and 22ac hindered chromatographic purification (Table 1,
entry 13). For these reasons, a slight excess of the diazonium
salt was used for all coupling reactions with tertiary vinylsulfon-
amide 19c. Styrylsulfonamide 22ac was isolated under
these modified standard conditions in 80 % yield (Table 1, en-
try 14).
Entry Diazonium
salt[a]
R1
R2
R3
R4
Product
Yield
[%]
1
2
3
4
5
6
7
8
9
18a[98]
18b[67]
18d[67]
18e[98]
18g[67]
18h[98]
18j[98]
H
H
H
H
H
H
NO2
H
H
H
H
OMe
OH
OH
OMe
OH
OMe
OMe
C(O)Me
Br
H
H
H
H
H
H
H
H
H
H
22ac
22bc
22dc
22ec
22gc
22hc
22jc
22nc
22pc
22sc
80
81
67
60
78
88
92
77
88
81
Br
Br
NO2
NO2
H
18n[106]
18p[106]
18s[67]
H
H
Scope and Limitations of Matsuda–Heck Reactions of
Vinylsulfonic Acid Derivatives
10
H
CO2Me OMe
[a] Reference for synthesis and characterization of diazonium salt 18.
The optimized conditions (Table 1, entry 1) for Matsuda–Heck
reactions of vinylsulfonate 19a were applied to other arene
diazonium salts 18b–18x. As can be seen from the results listed
in Table 2, a variety of electron-donating and -withdrawing
groups attached to different positions of the arene are toler-
ated. In particular, high yields were obtained for several unpro-
tected phenol diazonium salts (Table 2, entries 2, 4, 7, 18, and
20), including one example with an unprotected carboxylate
substituent (Table 2, entry 20). The only examples with yields
lower than 50 % were the transformations of 18w (Table 2, en-
try 23) and thiophenol diazonium salt 18x (Table 2, entry 24).
In the former case, the low yield probably originates from se-
lectivity problems, because the cinnamate moiety might also
undergo a Matsuda–Heck arylation. In the latter case, the thiol
group can lead to decreased catalyst activity. Diazonium salts
18l and 18x have not previously been described in the litera-
ture. They were synthesized from 23 and 24, using our de-
acetylation–diazotization protocol[98] or a routine diazotization
protocol,[105] respectively (Scheme 3).
Synthesis of the C-5-Substituted Indole Core of
Naratriptan
Naratriptan (see Figure 1) is a serotonin receptor agonist that is
in clinical use for the treatment of severe migraines.[109] The
drug has an indole core with a 4-piperidinyl substituent at C-3,
and an N-methylsulfonamidoethyl side-chain at C-5. Previous
syntheses using a Heck reaction start from 5-bromoindole,
which is either first transformed at C-3 through electrophilic
substitution and then coupled at C-5 with a vinylsulfonamide,
or vice versa.[4,36] Töke and coworkers have developed a
naratriptan synthesis that proceeds via C-5-substituted indole
29b, which was synthesized by olefination of para-nitrobenz-
aldehyde with a methanesulfonamide, conversion to an α-anili-
noacetaldehyde diacetal, and cyclization to the indole.[110] We
have applied the Matsuda–Heck protocol developed in this
work to the synthesis of Töke's naratriptan intermediate 29b
(Scheme 4).
We started from commercially available 5-nitroindole 25,
which was first tosylated to give 26. This was then reduced to
give 5-amino indole 27, and subsequent diazotization gave ind-
ole diazonium salt 18y. Matsuda–Heck coupling of 18y with
vinylsulfonamide 19c was successful, both in methanol under
base-free conditions and in acetonitrile under basic conditions,
and gave 22yc. Attempts to carry out the Pd-catalysed coupling
and the hydrogenation of the C–C double bond in a one-pot
fashion, by adding charcoal and stirring the Matsuda–Heck re-
action mixture under an atmosphere of hydrogen, resulted in a
complex mixture of products. We decided to cleave the tosyl
group first by basic methanolysis. Hydrogenation of 28 was fac-
Scheme 3. Synthesis of diazonium salts 18l and 18x.
For some diazonium salts 18, Matsuda–Heck couplings with ile, and was accomplished quantitatively with Pd/C under at-
tertiary sulfonamide 19c were investigated. The results show mospheric pressure of hydrogen. Töke's intermediate 29b was
that the conditions optimized for this substrate (see Table 1, synthesized by this sequence in six steps and 41 % overall yield.
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period of 12 h. For these reasons, sulfonamide 19b was not
included in the gas-meter measurement.
To rationalize the failure observed for this particular olefin,
we refer to the mechanism proposed for Matsuda–Heck reac-
tions by Correia and coworkers,[80,111] with the caveat that a full
adaptation of their proposal to the case described here is not
possible, because the reaction conditions are different in some
aspects (Scheme 5). According to this mechanism, the arenedi-
azonium cation coordinates to Pd0 catalyst A to give a Pd–
diazenido complex B. From B, nitrogen is extruded to give cat-
ionic Pd–σ-aryl complex C, which coordinates the olefin. The
resulting η2 complex D undergoes migratory insertion to give
σ complex E. The product (i.e., 22) is liberated from E by ꢀ-
hydride elimination, and cationic Pd–hydride complex F is
formed. The formation of catalytically active species A occurs
by deprotonation of F with methanol, if — as in our case — no
other base is present.
Scheme 4. Synthesis of the C-5-substituted indole core of naratriptan.
Comparative Investigation of Methyl Acrylate,
Vinylsulfonate, and Vinylsulfonamides in Matsuda–Heck
Reactions
Scheme 5. Catalytic cycle for Matsuda–Heck reactions.
As previously demonstrated by one of us,[72] the quantification
of nitrogen evolution over time is a useful tool for measuring
the progress of Matsuda–Heck reactions and acquiring kinetic
data. To gain deeper insight into the reactivity of the vinyl-
sulfonic acid derivatives, Matsuda–Heck reactions of model dia-
zonium salts 18a (R3 = OMe, electron-donating), 18b (R3 = OH,
strongly electron-donating) and 18n (R3 = acetyl, electron-with-
drawing) were carried out in a closed vessel connected to a
commercial laboratory-scale drum-type gas meter. Such devices
allow the direct measurement of the volumes of flowing gases
over time, in our case the volume of nitrogen evolving from the
reaction mixture. For comparison, we included methyl acrylate
For the failure of Matsuda–Heck reactions with 19b, we pro-
pose inhibition of the catalyst by chelate formation with the
starting material or the product as a possible explanation. Al-
though precoordination of the Pd catalyst by a pendant donor
substituent has been identified as a powerful tool for steering
selectivity and reactivity in Heck reactions,[112] this approach
relies on an inherent lability of the intermediate chelate. If the
pendant functional group forms a stable complex with Pd, the
catalytic cycle will be interrupted. We propose three different
modes of catalyst inhibition (Scheme 6).
First, the intermediate resulting from migratory insertion
(19d), the benchmark olefin for the evaluation of Heck reac- might form a four-membered chelate, which could then react
tions. As was mentioned in the optimization section, out of the to give a Pd–amido complex G upon deprotonation. Although
three vinylsulfonic acid derivatives investigated, only secondary the formation of four-membered chelates appears to be rather
sulfonamide 19b turned out to be completely unreactive at unlikely, a similar Pd chelate has previously been used to ex-
ambient and elevated temperatures (see Table 1, entries 11 and plain catalyst inhibition in a Suzuki–Miyaura coupling.[113] The
12). In contrast, vinylsulfonate 19a and tertiary sulfonamide 19c two remaining modes of catalyst inhibition might occur from
both react to give the expected Matsuda–Heck coupling prod- Pd–hydride species F. This Pd hydride could react either with
ucts (i.e., 22aa and 22ac, respectively) in high yields over a the product (i.e., 22) or with the starting material (i.e., 19b) in
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monitored by the gas meter. Although the conversion into 22ac
was quantitative after 12 h, a flat line was recorded in the gas-
meter measurement over the full monitoring period. This can
be explained by the low detection threshold of the technical
setup, which requires a minimum gas flow of 1 L h–1. Similar
observations were made for diazonium salts 18b (Figure 3) and
18n (Figure 4), which both reacted with sulfonamide 19c too
slowly to allow monitoring of the reaction progress by quantify-
ing the gas evolution. Nevertheless, high conversions to the
respective products (i.e., 22bc and 22nc) were obtained after
Scheme 6. Proposed modes of catalyst inhibition with sulfonamide 19b.
a hydropalladation reaction, which would pave the way for the
formation of five-membered amidochelates H and I, respec-
tively, after deprotonation. Similar five-membered chelate com-
plexes formed through a dynamic equilibrium of ꢀ-hydride
elimination and reinsertion have been observed spectroscopi-
cally during mechanistic investigations into the Heck reactions
of acrylates.[114–116] In these examples, however, the Pd hydride
was stabilized by phosphine ligands. While effective catalyst in-
hibition through the formation of a five-membered chelate ap-
pears to be far more plausible than inhibition through the for-
mation of the alternative four-membered chelate (i.e., G), the
crucial cationic Pd-hydride species F should be short-lived in
our case, because no stabilizing ligands are present. This im-
plausibility might be resolved if one assumes a coordinative
stabilization of the cationic Pd by the sulfonamido group at
stage E, preceding the ꢀ-hydride-elimination step. The ꢀ-
hydride elimination must involve a syn-hydrogen as in con-
former E′, and would then lead to a presumably more stable
η1-η2-chelated Pd-hydride complex J, which could finally react
to give the proposed five-membered chelate H by intramolecu-
lar migratory insertion of hydride.
Figure 2. Conversion vs. time for Matsuda–Heck reactions of 18a.
In a first set of gas-meter experiments, we monitored the
Matsuda–Heck reactions of 18a with olefins 19a, 19c, and 19d
on a 5 mmol scale. Conversion vs. time curves were obtained
only for vinylsulfonate 19a and methyl acrylate 19d (Figure 2),
because the reaction of sulfonamide 19c was too slow to be
Figure 3. Conversion vs. time for Matsuda–Heck reactions of 18b.
2978 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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12 h. For these reasons, the determination of kinetic parameters the olefin. Similar conclusions have previously been drawn from
from conversion vs. time curves is limited to the Matsuda–Heck mechanistic investigations into Heck reactions of aryl iodides
reactions of olefins 19a and 19d (Table 4).
on the basis of competition experiments and kinetic stud-
ies.[115–117] These experiments show that acrylates react faster
and with far higher regioselectivity than styrenes in the inser-
tion step, a result of the positively polarized ꢀ position. On the
other hand, observations by Myers and coworkers point to a
slower ꢀ-hydride elimination if electron-withdrawing substitu-
ents are attached to the α position (this observation can be
rationalized by assuming that a certain degree of back-donation
from the metal into the σ* orbital of the ꢀ C–H bond is required
to trigger the cleavage of this bond).[115] It is difficult to decide
whether a carboxylate or a sulfonate substituent exerts a
stronger electron-withdrawing effect, and whether the lower
reactivity of 19a compared to 19d is caused by a slower inser-
tion or ꢀ-hydride-elimination step. However, it can be assumed
that the sulfonamido group in 19c is less electron-withdrawing
than the sulfonate group in 19a; this would tentatively point
towards the insertion as the rate-determining step. It should be
clearly noted that on the basis of our results and in the absence
of spectroscopically observable intermediates, any assignment
of rate-limiting steps remains uncertain. Unfortunately, observa-
tion of catalytically relevant species in Matsuda–Heck reactions
under ligand-free and base-free conditions is very challenging,
and to date we have not been successful in this regard.
b) For all the Matsuda–Heck reactions investigated in this
study, initiation periods were recorded. Initiation periods are
observed when the formation of the actual catalyst from the
precatalyst is comparatively slow. For example, Correia and co-
workers observed in their seminal ESI-MS study of the Matsuda–
Heck reaction mechanism with Pd–dba complexes in aceto-
nitrile under basic conditions, that the formation of the catalyti-
cally most competent Pd0 species proceeds through oxidative
addition of the diazonium ion and a series of ligand-exchange
reactions within a time span of 1.5 h.[111] As can be seen from
Figures 2, 3, and 4 and from Table 4, entries 2, 4, and 6, the
initiation times vary for methyl acrylate (19d) from 9 s for elec-
tron-deficient diazonium salt 18n to 121 s for electron-rich
phenol diazonium salt 18b. This is in line with the well-known
accelerating effect of electron-withdrawing groups on the oxi-
dative addition of haloarenes to Pd0 complexes.[118] However, a
comparison of the initiation periods observed for the reactions
of methyl acrylate and vinylsulfonate with the same diazonium
salt shows that the olefin also has an influence on the initiation.
For all three diazonium salts, the initiation occurs faster with
methyl acrylate, and for two of the three diazonium salts, i.e.,
electron-deficient 18n and the most electron-rich 18b, the dif-
ference in initiation time between methyl acrylate and ethyl
vinylsulfonate is substantial. For example, in the case of phenol
diazonium salt 18b, the initiation period is more than 30 times
longer for vinylsulfonate 19a (I > 1 h) than for methyl acrylate
(19d; I = 121 s). This observation suggests that under our reac-
tion conditions, the alkene is involved in the reduction of
Pd(OAc)2 to Pd0 through a pathway similar to that originally
proposed by Heck[119] and later proved by Correia and cowork-
ers for Matsuda–Heck reactions with 2,3-dihydrofuran on the
basis of ESI-MS studies.[80] Thus, coordination of electrophilic
Figure 4. Conversion vs. time for Matsuda–Heck reactions of 18n.
Table 4. Kinetic parameters for Matsuda–Heck reactions of 19a and 19d.[a]
Entry 18a
19a
v [mmol (mL h)–1
]
TOF [h–1
]
Initiation time I [s]
1
2
3
4
18a
18a
18b
18b
18n
18n
18a
19a
19d
19a
19d
19a
19d
19a
3.7
4.7
2.4
9.3
1.7
41.8
0.9
720
940
470
1840
320
8350
180
210
84
3967
121
367
9
5
6
7[b]
257
[a] All experiments with Pd(OAc)2 (5 mol-%) as precatalyst. [b] 2.5 mol-% of
Pd(OAc)2 as precatalyst.
Although we can not yet present a comprehensive mecha-
nistic scenario, the conversion vs. time curves and the kinetic
parameters deduced from them, in combination with previous
observations by others, allow us to draw some conclusions:
a) Irrespective of the diazonium salt, the reaction rates and
turnover frequencies are substantially higher for methyl acrylate
(19d) than for ethyl vinylsulfonate (19a). The corresponding val-
ues for sulfonamide 19c can be assumed to be even lower, for
the reasons outlined above. In summary, the olefins investi-
gated in this study show the following order of reactivity in
Matsuda–Heck-reactions: H2C=CHCO2Me > H2C=CHSO2OEt >
H2C=CHSO2N(CH3)Bn >> H2C=CHSO2NHBn. This suggests that
the oxidative addition, which does not involve the olefin, is
faster than migratory insertion and ꢀ-hydride-elimination,
which are both affected by the electronic and steric nature of
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Whenever the solubility of the sample or the spectral resolution
were insufficient in CDCl3 one of the following solvents was used:
Pd(OAc)2 to the alkene enables the addition of methanol, and
results in the formation σ-alkyl complex K, from which — pre-
sumably via an agostic bond — a vinyl ether is liberated by ꢀ-
hydride elimination to give Pd hydride L. This then undergoes
reductive elimination to give catalytically active species A. As
speculated in the previous paragraph, the electron-withdrawing
properties of the sulfonate group might lead to a retarded ꢀ-
hydride elimination (K → L), which would result in an overall
longer initiation time (Scheme 7).
1
[D6]DMSO ([D5]DMSO as internal standard for H NMR spectra, δ =
2.50 ppm; [D6]DMSO as internal standard for 13C NMR spectra, δ =
39.5 ppm); [D6]acetone ([D5]acetone as internal standard for 1H
NMR spectra, δ = 2.05 ppm; [D6]acetone as internal standard for
13C NMR spectra, δ = 29.9 ppm). IR spectra were recorded as ATR-
FTIR spectra. Wavenumbers (ν) are given in cm–1. The peak intensi-
˜
ties are defined as strong (s), medium (m) or weak (w). Low- and
high-resolution mass spectra were obtained using EI-TOF or ESI-TOF
methods. Kinetic measurements were obtained with a drum-type
gas meter TG05 from Dr.-Ing. Ritter Apparatebau GmbH & Co KG,
Bochum, Germany.
Representative Example of a Matsuda–Heck Reaction
(E)-N-Benzyl-2-(1-tosyl-1H-indole-5-yl)-N-methylethene-1-sulf-
onamide (22yc): Pd(OAc)2 (7.8 mg, 5 mol-%) was added to a sus-
pension of 18y (328 mg, 0.85 mmol) and 19c (148 mg, 0.70 mmol)
in methanol (10 mL), and the reaction mixture was stirred for 12 h
at ambient temperature. After this time, the solvent was evapo-
rated, the residue was dissolved in MTBE (methyl tert-butyl ether),
and the resulting solution was washed with water. The aqueous
layer was extracted with MTBE (3 ×). The combined organic extracts
were dried with MgSO4, and filtered, and the solvents were evapo-
rated. The residue was purified by column chromatography on silica
(hexane/MTBE mixtures of increasing polarity) to give 22yc
(271 mg, 0.56 mmol, 81 %) as a colourless solid, m.p. 168 °C. 1H
NMR (300 MHz, CDCl3): δ = 8.03 (d, J = 8.7 Hz, 1 H), 7.79 (d, J =
8.4 Hz, 2 H), 7.66 (d, J = 1.6 Hz, 1 H), 7.63 (d, J = 3.7 Hz, 1 H), 7.56
(d, J = 15.4 Hz, 1 H), 7.45 (dd, J = 8.7, 1.5 Hz, 1 H), 7.42–7.33 (m, 5
H), 7.27 (d, J = 8.4 Hz, 2 H), 6.70 (dd, J = 3.7, 0.6 Hz, 1 H), 6.67 (d,
J = 15.4 Hz, 1 H), 4.31 (s, 2 H), 2.74 (s, 3 H), 2.37 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 145.4, 142.8, 135.9, 135.7, 135.0, 131.2,
130.0, 128.7, 128.4, 128.0, 127.9, 127.7, 126.8, 124.1, 122.2, 121.3,
Scheme 7. Olefin-initiated PdII → Pd0 reduction.
Although we are confident that our results point towards a
decisive involvement of the alkene in the catalyst-activation
step, we must concede that the initiation mechanism is more
complex, and apparently involves both reaction partners.
c) For the Matsuda–Heck reaction of 18a and 19a (see Fig-
ure 2 and Table 4, entry 7) a lower catalyst loading of 2.5 mol-
% (instead of 5 mol-% under standard conditions) was tested.
While the initiation time was only moderately longer, the reac-
tion rate and turnover frequency dropped to a quarter of the
values observed with the higher catalyst loading.
114.1, 109.0, 53.9, 34.3, 21.6 ppm. IR (ATR): ν = 1610 (w), 1455 (m),
˜
1372 (s), 1335 (s), 1120 (s), 1147 (s) cm–1. HRMS (EI): calcd. for
C
25H24N2O4S2 [M]+ 480.1178; found 480.1166.
Conclusions
(E)-N-Benzyl-2-(1H-indole-5-yl)-N-methylethene-1-sulfonamide
(28): A solution of 22yc (120 mg, 0.25 mmol) and KOH (42 mg,
0.75 mmol) in methanol (6 mL) and THF (2 mL) was heated at reflux
until the starting material was fully consumed. The mixture was
then cooled to ambient temperature, brine (10 mL) was added, and
the phases were separated. The aqueous layer was extracted with
ethyl acetate (3 ×). The combined organic extracts were dried with
MgSO4, and filtered, and the solvents were evaporated. The residue
was purified by column chromatography on silica (hexane/MTBE
mixtures of increasing polarity) to give 28 (60 mg, 0.18 mmol, 74 %)
In summary, we could demonstrate that a wide range of arene
diazonium salts react with vinylsulfonates and tertiary vinyl-
sulfonamides in Matsuda–Heck reactions, using Pd(OAc)2 as the
precatalyst, and running the reaction in methanol under base-
free and ligand-free conditions. With very few exceptions, the
isolated yields were high, and selectivities were excellent. The
coupling of a vinylsulfonamide and an indole diazonium salt
was applied to the synthesis of a precursor of the antimigraine
drug naratriptan. By quantifying the nitrogen evolution over
time, the reactivity of vinylsulfonyl derivatives in Matsuda–Heck
reactions could be compared with the benchmark olefin methyl
acrylate for three selected diazonium salts. This led to an order
of reactivity for the olefins, and allowed us to determine some
kinetic parameters for the coupling reactions.
1
as a colourless solid, m.p. 135 °C. H NMR (300 MHz, [D6]acetone):
δ = 10.54 (s, 1 H), 7.92 (s, 1 H), 7.60 (d, J = 15.4 Hz, 1 H), 7.52 (d,
J = 8.5 Hz, 1 H), 7.50 (dd, J = 8.5, 1.5 Hz), 7.43–7.40 (m, 3 H), 7.37
(t, J = 7.7 Hz, 2 H), 7.31 (t, J = 7.3 Hz, 1 H), 7.00 (d, J = 15.4 Hz, 1
H), 6.57 (m, 1 H), 4.33 (s, 2 H), 2.76 (s, 3 H) ppm. 13C NMR (75 MHz,
[D6]acetone): δ = 145.0, 138.5, 137.6, 129.4, 129.3, 129.2, 128.4,
127.2, 125.3, 123.3, 122.0, 119.6, 112.8, 103.3, 54.4, 34.7 ppm. IR
(ATR): ν = 3404 (sm), 1599 (m), 1333 (s) 1148 (s) cm–1. HRMS (EI):
˜
calcd. for C18H18N2O2S [M]+ 326.1089; found 326.1077.
Experimental Section
N-Benzyl-2-(1H-indole-5-yl)-N-methylethane-1-sulfonamide
(29b): A suspension of 28 (81 mg, 0.25 mmol) and Pd/C (9 mg,
10 wt.-%) in methanol (5 mL) was stirred for 12 h at ambient tem-
perature under an atmosphere of hydrogen (1 bar). After this time,
the solvent was evaporated, and the residue was purified by column
chromatography on silica (eluent hexane/MTBE mixtures of increas-
ing polarity) to give 29b (78 mg, 0.23 mmol, 95 %) as a colourless
General Methods: All experiments were carried out in dry reaction
vessels under an atmosphere of dry nitrogen. Solvents were purified
by standard procedures. 1H NMR spectra were obtained at 300 MHz
in CDCl3, with CHCl3 (δ = 7.26 ppm) as an internal standard. Cou-
pling constants are given in Hz. 13C NMR spectra were recorded at
75 MHz in CDCl3, with CDCl3 (δ = 77.0 ppm) as an internal standard.
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˜
1318 (s), 1148 (s), 725 (s) cm–1. HRMS (EI): calcd. for C18H20N2O2S
[M]+ 328.1245; found 328.1254.
Acknowledgments
The authors thank Evonik Oxeno for generous donations of sol-
vents, and Umicore (Hanau, Germany) for generous donations
of catalysts.
Keywords: Homogeneous catalysis · Cross-coupling ·
Palladium · Sulfonamides · Alkenes · Drug design
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