Benzosultam Synthesis by Gold(I)-Catalyzed Ammonium Formation/Nucleophilic Substitution

Article abstract of DOI:10.1021/acs.orglett.9b01962

The synthesis of benzosultams has been achieved through a gold(I)-catalyzed ammonium formation strategy. Starting from easily available N-(2-alkynyl)phenylsulfonyl azetidine derivatives, a cyclization reaction generated a spiroammonium gold intermediate t

Full text of DOI:10.1021/acs.orglett.9b01962

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Benzosultam Synthesis by Gold(I)-Catalyzed Ammonium Formation/
Nucleophilic Substitution
́
Romain Pertschi, Jean-Marc Weibel, Patrick Pale, and Aurelien Blanc*
̀
́
́
́
Laboratoire de Synthese, Reactivite Organiques et Catalyse, Institut de Chimie, UMR 7177 - CNRS, Universite de Strasbourg, 4 rue
Blaise Pascal, 67070 Strasbourg, France
S
* Supporting Information
ABSTRACT: The synthesis of benzosultams has been
achieved through a gold(I)-catalyzed ammonium formation
strategy. Starting from easily available N-(2-alkynyl)-
phenylsulfonyl azetidine derivatives, a cyclization reaction
generated a spiroammonium gold intermediate that was ring-
opened by nucleophilic alcohol or indole. This new method-
ology is compatible with the large variation in the substrates
and nucleophiles and allowed the formation of benzosultams in high yield (18−98%, 20 examples). This strategy also allowed
the preparation of benzosultam analogs via iododeauration and subsequent cross-coupling reactions.
ulfonamides were among the first antibiotics developed
from non-natural sources (sulfamides; sulfanilamide and
efficient methods allowing us to reach benzosultams with the
largest diversity are still highly sought after.
S
prontosil, prodrug of the former, the first ever known, in Figure
To reach such goals, various metal-catalyzed cyclization
processes have been more recently explored, mostly involving
C−H activation, electrophilic cyclization, and ring-closing
metathesis. Surprisingly, benzozultam syntheses involving
alkyne or azetidine functions seem to have been less
investigated. Classical amination of alkynes was applied to
the synthesis of benzosultams with silver or copper salts as the
catalyst (eq 1 in Scheme 1).8,9 Cooperative ruthenium/gold
photoredox catalysis has been applied to the preparation of
3,4-diarylbenzosultams from 2-(trimethylsilylethynyl)-
benzenesulfonamides in the presence of aryldiazonium salts
(eq 2 in Scheme 1).10 Benzosultams were accessible by the
rhodium-catalyzed oxidative C−H activation of acylated
sulfonamides and the subsequent addition of internal alkynes
(eq 3 in Scheme 1).11 Rhodium also catalyzed the rearrange-
ment reaction of chiral N-arenesulfonyl azetidin-3-ols into
benzosultams via a C−C bond cleavage by β-carbon
elimination (eq 4 in Scheme 1).12 However, no synthetic
methods of sultams only based on gold catalysis13 have been
reported to date.
In this context, we reasoned that our recently disclosed gold-
catalyzed ammonium formation-based cascade reactions14
would offer a new and interesting route toward benzosultams
2. Applied to N-(2-alkynyl)aryl sulfonyl azetidines 1, such a
reaction would produce a spiroammonium intermediate A,
which should then be opened by external protic nucleophiles
while allowing protodemetalation (Scheme 1, bottom).
To set up reaction conditions, one of the simplest and easily
available N-(2-alkynyl)-phenylsulfonyl azetidines,15 compound
1a, was prepared from tosylsulfonamide in three steps (see the
1),1 and some are still in use nowadays (e.g., sulfamethazole
Figure 1. Representative sulfamides and sultams of therapeutic
interest.
and sulfadiazine in Figure 1). Their cyclic analogs named
sultams have also been screened for their biological properties,
and they exhibit a large variety of activities, such as antiviral,
antimicrobial, antiparasitic, anticancer, antidiabetic, and anti-
inflammatory activities. Among them, benzosultams represent
an important subclass with broad biological activities.2 Some
are currently used as drugs to treat hypertension (brinzola-
mide),3 as endothelin receptor antagonists (CI-1034),4 or as
nonsteroidal anti-inflammatory drugs (the oxicam family, such
as piroxicam).5 Besides these important therapeutic applica-
tions, sultams also contributed to the development of stereo-
and enantioselective synthesis.6
With such high interest, numerous methods have been
developed to access sultams.7 Because most applications are in
the medicinal area, these methods are often driven toward
diversity-oriented approaches. Nevertheless, mild, simple, and
Received: June 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01962
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Adjusting the phosphine ligand properties revealed that the
Buchwald-type ligand greatly improved the chemical yield
(80%, entry 4 vs 3). Further tuning of the gold complex
counterion increased the efficiency while reducing reaction
times. Among them, the most effective catalyst was obtained
with the less coordinating hexafluoroantimonate anion (entry
5). The use of other poorly coordinating anions such as triflate
or tetrafluoroborate led to minor degradation products (entries
6 and 7 vs 5). Knowing that hydrogen bonding plays an
important role in the preactivation of protic nucleophile,16 the
overactivity of theses anions can be attributed to their higher
hydrogen bond basicity.17 Without any catalyst or any
nucleophile, or with 5 mol % of HSbF6, no transformation
was observed (entries 8−10).
Scheme 1. Known Routes to Benzosultams through Alkyne
Cyclization or Azetidine Ring Opening and the Newly
Proposed Gold-Catalyzed Synthesis
With a catalyst and conditions in hand (Table 1, entry 5),
we explored the possibilities offered by the present gold-
catalyzed transformation.
Various nucleophiles were first applied to this cascade
(Scheme 2). Alkyl alcohols provided the expected products
Scheme 2. Screening of Nucleophiles in the Rearrangement
a
of 1a into Benzosultams 2
Supporting Information) and submitted to different gold
complexes as a catalyst. Methanol was used as an external
nucleophile in the presence of dichloromethane as a non-
coordinating solvent. Rewardingly, room temperature proved
to be sufficient to promote the expected cascade with the right
catalysts, providing the expected benzosultam 2a in high yield
(Table 1).
The electron-poor phosphite complex was totally ineffective
(entry 1). In contrast, an electron-rich NHC complex allowed
some conversion within 8 h, and the expected product was
obtained in modest yield (entry 2). Interestingly, the Gagosz
catalyst proved to be slightly more effective, providing a similar
yield of the expected product within 8 h (entry 3 vs 2).
a
b
Reaction run with 10 equiv of nucleophiles, c = 0.1 mol/L. Reaction
c
performed with 1.6 equiv of benzylic alcohol. Reaction performed at
d
70 °C in DCE. Reaction performed with CyJohnPhosAuCl and
Table 1. Screening of Gold Catalysts for the Rearrangement
a
hydrated sample of AgSbF6 as the source of water and activator.
of 1a in the Presence of Methanol
e
Reaction performed at 70 °C with 3 equiv of indole.
(2a−f) in high yield (∼90%), whatever their size and
hindrance. The reaction with tert-butanol was nevertheless
slower and required 6 h instead of 1 h (see 2d). Benzylic and
allylic alcohols reacted as well, although allyl alcohol also
required a longer reaction time (2f vs 2e). For comparison, the
less nucleophilic trifluoroethanol and phenol were evaluated.
The latter was unable to induce the expected cascade, whereas
the former could but after heating and a long reaction time
(see 2g). These results clearly reflect the nucleophilicity of the
alcohol. Although water would be a good nucleophile for this
reaction, the expected product could not be obtained by the
addition of water to the reaction mixture. Rewardingly, water
could be introduced by simply using hydrated silver
hexafluoroantimonate and 5 mol % CyJohnPhosAuCl as a
precatalyst. Although the reaction time was equivalent to that
of the best nucleophiles, the yield of hydroxysultam 2i was
lower. This result can be assigned to the fact that the formed
hydroxysultam plays the role of a competitive nucleophile and
b
entry
catalyst (5 mol %)
time (h)
yield (%) 2a
c
d
1
2
3
4
5
6
7
8
9
10
(RO)3PAu(MeCN)SbF6
IPrAuNTf2
Ph3PAuNTf2
24
8
8
8
1
1
1
24
24
24
30
37
80
94
78
CyJohnPhosAuNTf2
CyJohnPhosAu(MeCN)SbF6
CyJohnPhosAuCl/AgBF4
CyJohnPhosAuCl/AgOTf
90
d
de
,
CyJohnPhosAu(MeCN)SbF6
HSbF6
d
a
b
1
c = 0.1 mol/L. Calculated yield from H NMR integration relative
to an internal standard (dimethyl terephthalate). P(OR)3 = tris(2,4-
di-tert-butylphenyl)phosphite. No conversion. Reaction run without
methanol. Tf = Triflate.
c
d
e
B
DOI: 10.1021/acs.orglett.9b01962
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Organic Letters
Letter
leads to a dimerization.14b Other nucleophiles, such as amines
or thiols, did not promote any reaction, probably by poisoning
the gold catalyst. Nevertheless, indole could act as a
nucleophile, although it was necessary to increase the reaction
temperature to 70 °C to get full conversion in a reasonable
reaction time and yield of 2j. Indolyl benzosultams were thus
available through this straightforward method.
Variations on the three key building blocks of the starting N-
(2-alkynyl)phenylsulfonyl azetidine were then introduced to
evaluate their effect and compatibility with the present gold-
catalyzed rearrangement (Scheme 3).
affected the cascade, as revealed by the very slow reaction of
the methoxyphenyl derivative 2o compared with the normal
behavior of the trifluoromethylphenyl analog 2p.
The azetidine moiety could also be functionalized, as shown
by the good reactivity of the hydroxymethylazetidine
derivatives 1h−i, which provided sultams 2q−r in high yield
within 5 h. It is worth noting that in both cases, in the absence
of an external nucleophile, no intramolecular opening by the
hydroxy group present on the azetidine moiety took place. For
the substrate 1i, the ring opening of the unsymmetrical
azetidinium intermediate (see A, Scheme 1) by methanol
exclusively led to sultam 2r. The highly regioselective
substitution at the more hindered position could be attributed
to hydrogen bonding between the free alcohol of the substrate
and the nucleophile (methanol).
Scheme 3. Synthesis of Various Benzosultams 2 from N-(2-
Alkynyl)-phenylsulfonyl Azetidines 1 Using Methanol as the
a
Nucleophile
Interestingly, terminal alkynes could also be engaged in the
present cascade but with an unexpected reactivity. Under our
standard conditions at 70 °C, the product 2s was formed
together with a new compound 3 starting from 1s. Structural
investigations revealed the five-membered sultam and aminal
structure of 3. Decreasing temperature, while increasing the
catalyst loading and the amount of nucleophile, selectively led
after 4 days to aminal 3 in good yield.18 Monitoring the
1
reaction by H NMR allowed us to detect the corresponding
five-membered methylene sultam, which was clearly the
intermediate of the aminal 3 (see the Supporting Information).
The favored 5-exo-dig pathway at lower temperature is
consistent with the known cyclization of terminal alkynes19
and with the involvement of a σ,π-digold acetylide complex in
the mechanism.20
To assess the proposed mechanism, a series of blank and
trapping experiments were performed (Scheme 4). As
Scheme 4. Blank and Isotopic Labeling Experiments and
Mechanistic Hypothesis
a
b
Reaction run with 10 equiv of nucleophiles, c = 0.1 mol/L. Reaction
c
performed at 70 °C in a DCE/MeOH (1/1) mixture. No conversion.
d
e
Reaction performed at 70 °C in a DCE. Reaction performed at
room temperature with 10 mol % of catalyst in CH2Cl2/MeOH (1/
1).
The alkynyl chain could be modified, even with a functional
group, as far as the latter was protected (see 2k vs 2l, Scheme
2). Nevertheless, the presence of a larger group adjacent to the
acetylenic moiety imposed the use of some extra equivalent of
nucleophile, heating, and a long reaction time, probably due to
some hindrance with the catalyst upon coordination (see 2m
and 2n).
mentioned above, no reaction occurred without a catalyst
(see Table 1, entry 8), and no reaction was also observed
without the acetylenic moiety on the substrate 4, excluding the
azetidine ring opening through Lewis acid activation21 (eq 1,
Scheme 4). Both results highlighted the importance of the
acetylenic part and its coordination. In attempts to prove the
presence of a vinyl gold intermediate A after cyclization
(Scheme 4, bottom), the reaction in the presence of deuterated
Electronic effects were briefly examined upon varying the
substitution on the phenyl moiety. These effects strongly
C
DOI: 10.1021/acs.orglett.9b01962
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Letter
methanol as the nucleophile was also performed on 1g (eq 2,
Scheme 4). The formed product 2t was, as expected,
deuterated at the position where gold should be according to
the proposed mechanism.
These results strongly supported the formation of a
spiroammonium intermediate A upon gold activation of the
acetylenic moiety and cyclization, its opening with a protic
nucleophile, which induced the product formation, and the
catalyst regeneration by protodeauration (Scheme 4, bottom).
Trapping the organogold intermediate B with N-iodosucci-
nimide (NIS) produced useful vinyl iodide derivatives 2u−v in
good to excellent yield (Scheme 5), which can be subsequently
ACKNOWLEDGMENTS
■
We acknowledge the French Ministry of Research and the
CNRS for financial support. R.P. thanks the French Ministry of
Research for the Ph.D. fellowship.
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Suzuki−Miyaura Cross-Coupling Reaction
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01962.
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Experimental details and copies of spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ablanc@unistra.fr
ORCID
́
Aurelien Blanc: 0000-0003-4240-3281
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b01962
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Letter
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