Access to sultams by rhodium(III)-catalyzed directed C-H activation

Full text of DOI:10.1002/anie.201206191

Angewandte
Chemie
DOI: 10.1002/anie.201206191
Homogenous Catalysis
À
Access to Sultams by Rhodium(III)-Catalyzed Directed C H
Activation**
Manh V. Pham, Baihua Ye, and Nicolai Cramer*
The aryl sulfonamide moiety is a very important and
ubiquitous functional group which is closely linked to
pharmaceutical activity, and plays a significant role as
a structural design element in medicinal chemistry.[1] Both
primary sulfonamides and sulfonyl ureas are common motifs
is drugs as exemplified by celecoxib, brinzolamide, sultiame,
and glibenclamide (Figure 1).[2] Acylated sulfonamides, which
Reported methods for the synthesis of benzosultams are
based on intramolecular cyclizations of elaborated precursors,
thus requiring several reaction steps.[6] Intermolecular reac-
tions are much rarer and need prefunctionalized starting
materials such as ortho-halosulfonamides[7] or benzothiatri-
azine derivatives.[8] A direct intermolecular and efficient
method starting from simple and widely available sulfon-
amides would not only enable a new set of accessible
scaffolds, but also allow additional and late-stage modifica-
tions of existing compounds having biological properties.
The activation and subsequent functionalization of aro-
À
matic C H bonds ortho to directing groups has evolved
rapidly over the past years.[9] In this context, rhodium(III)-
catalyzed reactions[10] using a wide range of carbonyl-derived
directing groups such as benzamides,[11] acetanilides,[12]
imines,[13] ketones,[14] and carboxylic acids[15] were reported,
thus illustrating the utility of this reactivity concept. Despite
their critical importance, aryl sulfonamides have, to the best
of our knowledge, not been explored with rhodium catalysts.
Very recently, a single report from Yu and co-workers
described the use of perfluoroaryl-substituted sulfonamides
as competent directing groups in palladium(II)-catalyzed
reactions.[16] Herein, we report a rhodium(III)-catalyzed
À
oxidative C H activation of simple acylated sulfonamides
(1) and subsequent addition of internal alkynes (3) to give
access to the benzosultams 4 (Scheme 1).[17]
Figure 1. Drugs with a sultam and sulfonamide substructure motif.
are subject to facile deacylation, can be used as prodrugs.[3]
Besides aryl sulfonamides, their cyclic analogues, benzosul-
tams, play an important role given their broad biological
activities.[4] Piroxicam and brinzolamide demonstrate the
utility of annulated sultams.[5]
À
Scheme 1. Benzosultams by sulfonamide-directed C H activations.
At first, we evaluated the influence of different substitu-
ents on the sulfonamide nitrogen atom (Table 1). While
primary or N-alkylated sulfonamides were completely
unreactive (entries 1 and 2), an N-acetyl group was best
suited and gave the product 4aa under optimized reaction
conditions in 90% yield (entry 3). The trifluoroacetyl deriv-
ative is too labile and undergoes unproductive deacylation
(entry 5). A bulky pivaloyl group shuts the reactivity com-
pletely down. The defined and highly soluble [Cp*Rh(OAc)2]
(A; Cp* = C5Me5) catalyst[18,19] is advantageous compared to
the commonly utilized [{Cp*RhCl2}2] precatalyst and its in
situ alteration methods to give cationic or acetate containing
species (entries 6 and 7). 1,2-Dichloroethane and tert-amyl
alcohol are inferior to toluene as a solvent (entries 8 and 9).
The classical CuI/CuII redox couple provides better yields than
[*] M. V. Pham, B. Ye, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA
BCH 4305, CH-1015 Lausanne (Switzerland)
E-mail: Nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
[**] This work is supported by the EPFL and the European Research
Council under the European Community’s Seventh Framework
Program (FP7 2007–2013)/ERC Grant agreement no 257891. We
thank Dr. R. Scopelliti for X-ray crystallographic analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206191.
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Table 1: Optimization of the substrate and reaction conditions.[a]
Entry
R
Changes from
standard reaction
conditions
Conv.
[%][b]
Yield
[%][b]
1
2
3
4
5
H
none
none
none
none
none
<5
<5
100
<5
100
–
–
Bu
Ac
Piv
Tfa
90[c]
–
0[d]
6
Ac
2.5 mol% [{Cp*RhCl2}2]
10 mol% AgSbF6
8
8
40 mol% Cu(OAc)2·H2O
7
Ac
2.5 mol% [{Cp*RhCl2}2]
2.5 equiv Cu(OAc)2·H2O
54
54
8
9
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
tAmOH instead of toluene
DCE instead of toluene
20 mol% Cu(OAc)2·H2O
2.5 equiv Cu(OAc)2·H2O, no O2
tBuOOH instead of O2
K2S2O8 instead of O2
1 bar air instead of O2
2 equiv AcOH
34
43
75
78
13
26
70
25
100
93
34
43
52
75
7
21
70
10
0
10
11
12
13
14
15
16
17
2 equiv CsOAc
2 equiv NaHCO3
10
[a] Standard reaction conditions: 1a (0.10 mmol), 3a (0.125 mmol),
[Cp*Rh(OAc)2] (A; 5.0 mmol), CuIOAc (20mmol), toluene (for final
concentration of 0.2m), O2 (50 mbar), 908C, 18 h. [b] Determined by
1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal
standard. [c] Yield of isolated product. [d] Deacylation. Tfa=trifluoro-
acetyl
other oxidants such as K2S2O8 or tBuO2H (entries 10–13).
However, with stoichiometric as well as catalytic amounts of
copper(II) acetate, the reaction stalls and does not go to
completion. Closer examination showed that the reaction is
sensitive to both free carboxylic acid and additional base
(entries 15–17). Acetic acid leads to almost complete inhib-
ition of the reaction. We presume that it stabilizes the
complex A and that the initial displacement step of acetate
from A by the substrate is not very favorable. Cesium acetate
and sodium bicarbonate decompose 1a by acetyl cleavage.
Catalytic amounts of copper(I) acetate and molecular oxygen
as a terminal oxidant minimize the amount of free acetic acid
during this redox cycle and improves conversions and yields
substantially.
The scope of the reaction is outlined in Scheme 2. The
reaction is tolerant of different substitutions on the aromatic
substrate. In this respect, electron-rich or electron-poor
substituents as well as ortho and meta substitution are
accepted. Heterocycles and condensed aromatic substrates
were tested and are compatible. Concerning the scope of the
alkynes 3, we found that the often reluctant dialkyl alkynes
work very well when tert-amyl alcohol is used as the solvent
instead of toluene. Unsymmetrical alkynes display moderate
Scheme 2. Scope of the sultam formation. Conditions A:
1 (0.10 mmol), tAmOH (for final concentration of 0.2m), 3 (1.5 equiv),
A (5 mol%), Cu(OAc) (20 mol%), 1108C, 18 h; O2 (50 mbar). Con-
ditions B: 1 (0.10 mmol), toluene (for final concentration of 0.2m), 3
(1.5 equiv), A (5 mol%), Cu(OAc) (20mol%), 1108C, 18 h; O2
(50 mbar). All yields refer to pure isolated 4. [a] Reaction performed
with 2ꢀ5 mol% A, 40 mol% CuOAc, 0.1m.
to good regioselectivities, which are somewhat dependent
upon the alkyne concentration. Higher concentrations lower
the regioselectivity.
2
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In analogy to amide directing groups, the catalytic cycle of
the reaction is initiated by exchanging of one acetate ligands
of [Cp*Rh(OAc)2] with the an acetylsulfonamide substrate,
thus leading to the intermediate 5 with the rhodium(III)
bound to the directing group (Scheme 3). Subsequent cyclo-
Scheme 4. Activation competition between sulfonamide and amide.
Ts =4-toluenesulfonyl.
Scheme 3. Presumed catalytic cycle for the cyclization.
À
Scheme 5. Consecutive C H functionalizations of the COX-2 inhibitor
Celecoxib.
metalation by an acetate-assisted concerted metalation–
deprotonation (CMD) pathway[20] and loss of a second
molecule of acetic acid forms 6. Association of the alkyne
and migratory insertion would provide the rhodacycle 7.
Formation of the carbon–nitrogen bond by reductive elimi-
nation expels the product 4. The concomitantly formed
rhodium(I) species is oxidized by copper(II) acetate which
in turn is reoxidized itself in a coupled cycle by molecular
oxygen, thus not increasing the overall acidity of the reaction
media.
and the nitrogen atmosphere replaced by oxygen, thus
delivering the differentially functionalized Celecoxib deriva-
tive 10 in 99% yield.
An advantage of the N-acyl sulfonamide directing group is
its relative lability. As already observed as side reaction
À
during the C H functionalization, it can be removed very fast
under mildly basic conditions or, alternatively, by using acid
to give 11 (Scheme 6). The double bond of the ensulfonamide
To rank the acyl sulfonamide in the context of the
established carbonyl-based directing groups, an internal
directing group competition of tosyl benzamide (1p) was
undertaken. Under the established reaction conditions, an
exclusive functionalization of the benzamide portion results,
thus leading to a mixture of the quinolone 8a and its
detosylated congener 8b (Scheme 4).[11k] This result confirms
that sulfonamides have an attenuated directing group char-
acter which might be attributed to a different hybridization
(sp3-hybridized sulfur atom versus sp2-hybridized carbon
atom) and a less favorable alignment for the cyclometalation.
To further highlight the reported reactivity and the
different directing group power, we chose to modify the
Scheme 6. Deprotection and reduction of sultam 4bb.
can be reduced by palladium-catalyzed hydrogenation to
selectively give the saturated derivative 12 as the cis diaster-
eomer.
In conclusion, we have established acylated sulfonamides
as suitable directing groups for rhodium(III)-catalyzed C H
bond activations. The cyclometalated intermediates readily
react with a broad range of internal alkynes and open a rapid
and general access to aryl sultams. The significance of aryl
sulfonamides as well as aryl sultams as design elements in
pharmacologically active substances should render this
method attractive for synthetic and medicinal chemistry.
acylated COX-2 inhibitor Celecoxib[21] (9) through sequential
À
[22]
À
C H activation modes (Scheme 5). The pyrazole group
exhibits a stronger directing group effect and reacts first. In
contrast to previous reports, no stoichiometric amounts of
Cu(OAc)2 were required for high conversion in the alkyne
hydroarylation reaction. It turned out that the reaction works
best in the presence of catalytic amounts of CuOAc under
anaerobic conditions.[24] When the first functionalization step
is completed, 3-hexyne (3c) is added to the reaction mixture,
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Received: August 2, 2012
Published online: && &&, &&&&
À
Keywords: C H activation · heterocycles ·
homogenous catalysis · rhodium · sulfonamides
.
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À
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Communications
Homogenous Catalysis
M. V. Pham, B. Ye,
N. Cramer*
&&&& — &&&&
Access to Sultams by Rhodium(III)-
Director’s cut: The pharmaceutically rel-
evant sulfonamide group is shown to be
a competent directing group for [Cp*Rh-
vide access to a wide range of sultam
derivatives. The reaction is high yielding
and works best under aerobic conditions
with catalytic amounts of CuOAc as an
oxidation mediator. Cp*=C5Me5.
À
Catalyzed Directed C H Activation
À
(OAc)2]-catalyzed C H functionaliza-
tions. Reactions of the cyclometalated
intermediate with internal alkynes pro-
6
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