A further decrease in the catalyst loading for the palladium-catalyzed direct intramolecular arylation of amides and sulfonamides

Article abstract of DOI:10.1002/adsc.201401129

The direct arylation of N-substituted o-bromobenzanilides and benzenesulfonamides via C-H bond functionalization has been developed using very low catalyst loadings. This novel cost-effective and more sustainable method relies on a PCN-type palladium pincer complex as a highly active palladium source, providing a general and efficient access to phenanthridinones, biaryl sultams and related heterocyclic systems. The beneficial effect of water as cosolvent has been observed in this process, which is not seriously influenced by electronic effects at the arene moieties or sterically demanding substituents at the amide or sulfonamide nitrogen. In addition, a number of experiments (kinetic plot, poisoning assays, TEM, ESI) have been performed in order to understand the role of the employed palladium complex in this reaction.

Full text of DOI:10.1002/adsc.201401129

UPDATES
DOI: 10.1002/adsc.201401129
A Further Decrease in the Catalyst Loading for the Palladium-
Catalyzed Direct Intramolecular Arylation of Amides and
Sulfonamides
Nerea Conde,a Fꢀtima Churruca,a Raul SanMartin,a,* Marꢁa Teresa Herrero,a
and Esther Domꢁngueza,*
a
Department of Organic Chemistry II, Faculty of Science and Technology, University of the Basque Country (UPV-EHU),
48940 Leioa, Spain
Fax : (+34)-946012748; phone: (+34)-946015435; e-mail: raul.sanmartin@ehu.es or qopdopee@lg.ehu.es
Received: December 3, 2014; Revised: February 19, 2015; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201401129.
Abstract: The direct arylation of N-substituted o-
bromobenzanilides and benzenesulfonamides via
C H bond functionalization has been developed
Phenanthridinones are important structural scaf-
folds found in many natural products that exhibit re-
markable biological and pharmaceutical properties.[4]
In the last years, novel alternative synthetic ap-
proaches have been developed to the synthesis of the
phenanthridinone core and related lactams, most of
them based on palladium-catalyzed direct functionali-
zation of arenes.[5] Although recent efforts have been
focused on the discovery of complementary routes in
order to avoid the substantial costs associated to the
relative big amounts of catalysts required (2–
10 mol%),[6] still, the palladium-catalyzed intramolec-
À
using very low catalyst loadings. This novel cost-ef-
fective and more sustainable method relies on
a PCN-type palladium pincer complex as a highly
active palladium source, providing a general and ef-
ficient access to phenanthridinones, biaryl sultams
and related heterocyclic systems. The beneficial
effect of water as cosolvent has been observed in
this process, which is not seriously influenced by
electronic effects at the arene moieties or sterically
demanding substituents at the amide or sulfona-
mide nitrogen. In addition, a number of experi-
ments (kinetic plot, poisoning assays, TEM, ESI)
have been performed in order to understand the
role of the employed palladium complex in this re-
action.
À
ular direct C H arylation reaction has proved to be
one of the most versatile, reliable and efficient
method for the access of phenanthridinones. Further-
more, related heterobiaryls and biaryl heterocyclic
compounds as well as biaryl sultams have been suc-
cessfully prepared under equivalent direct arylation
procedures.[6a,7a–c] Therefore, it would be desirable to
develop a novel palladium-catalyzed approach for the
direct functionalization of arenes using very low cata-
lyst loadings,[7d–e] which would provide a cost-effective
and environmentally very attractive procedure for the
preparation of such compounds. Moreover, consider-
ing the problems associated to the minute quantities
À
Keywords: biaryl sultams; C H arylation; palladi-
um; phenanthridinones; pincer complexes
À
Palladium-catalyzed direct functionalization of C H of metal particles usually detected in the products of
bonds has emerged over the last years as a modern transition metal catalyzed reactions,[8] such method
and sustainable tool in organic synthesis.[1] The in- would prevent metal contamination of the product
creasing demand for green chemistry in industry as and therefore be of added interest regarding its po-
well as in academia has lead to the development of tential application in medicinal chemistry.
innovative, environmentally friendly and highly effi-
Our group has ample experience in the synthesis
cient synthetic strategies.[2] Thus, regarding both atom and application of pincer-type palladium complexes
and step economy, the formation of carbon–carbon as very active catalysts or pre-catalysts (cat. loading ꢀ
bonds through C H functionalization has appeared as 0.1 mol%) in a variety of chemical transformations.[9]
À
a convenient methodology with broad application in The power of pincer complexes lies in their unique
total synthesis and medicinal chemistry.[3]
balance of stability vs reactivity, which confers them
extraordinary catalytic performance.[10] Thus, we en-
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Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst [Pd]
Base
Additive
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.1 mol%
0.05 mol%
0.05 mol%
0.05mol%
0.03 mol%
0.01 mol%
PdCl2 (0.1 mol%)
Pd(OAc)2 (0.1 mol%)
PdCl2 (0.05 mol%)
Pd(OAc)2 (0.05 mol%)
PdCl2 (0.05 mol%)
Pd(OAc)2 (0.05 mol%)
NEt3
DBU
DMPU
DMA
DMF
DMA
DMA
DMA
DMF
DMPU
DMI
DMA
DMA
DMA
[c]
–
–
–
[c]
KOtBu
K2CO3
K2CO3
KOAc
KOAc
KOAc
KOAc
K2CO3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
[c]
-
20 mol% PivOH
-
-
-
<5
24
[c]
–
8
–
[c]
9
-
10
11
12
13
14
15
16
17
18
19
20[f]
21 [g]
22
23
24
25
26
27
28
29
30
31
32
33
20 mol% benzoic acid
17
20 mol% BA[d]
<5
7–18
19
25 mol% surfactant[e]
25 mol% TBAB
DMA
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
DMA/o-xylene (1:1)
DMA/DMSO (1:1)
DMA/THF (1:1)
DMA/H2O (9.5:0.5)
DMA/H2O (9:1)
DMA/H2O (7.5:2.5)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA/H2O (9:1)
DMA
23
[c]
–
51
57
68
<5
68
75
83
<5
70
89 (88)
78
57
29
33
10
11
<5
<5
[f], [g]
[g]
[f,g]
[f,g,h]
[f,g,i]
[f,g]
[f,g]
[f,g]
[f,g]
[f,g]
[f,g]
DMA
[a]
Reaction conditions: 2a (0.3 mmol), 1 (0.1 mol%), base (1.5 equiv), solvent (0.06m), 1308C, sealed tube, 20 h under Ar
unless otherwise noted. DMPU: N,N’-Dimethylpropyleneurea; DMI: 1,3-Dimethyl-2-imidazolidinone.
Determined by H NMR spectroscopy. Diethylene glycol dimethyl ether was used as internal standard. Isolated yield is
[b]
1
displayed in parentheses.
Recovery of starting material.
BA: Brønsted acids (pivaloic acid, benzoic acid and p-toluensulfonic acid).
CTAB: Hexadecyltrimethylammonium bromide; DDA: Dimethyldioctadecylammonium bromide.
3.0 equiv of KOAc were used
Solvent (0.3m)
Reaction time: 48 h.
Reaction time: 96 h.
[c]
[d]
[e]
[f]
[g]
[h]
[i]
visaged that such palladium complexes would be amides for the general access of phenanthridinones
a suitable tool to achieve a more efficient direct aryla- and related biaryl sultams using palladium pincer
tion of arenes.[11] Herein we report an unprecedented complex 1 under very low catalyst loadings.
palladium-catalyzed intramolecular direct arylation of
A series of screening experiments were conducted
N-substituted o-bromobenzanilides and benzosulfon- by employing a set of palladium pincer complexes
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Table 2. Intramolecular direct arylation of arenes.[a]
prepared by our group[9] in only 0.1 mol% with N-
methyl-N-phenyl-2-bromobenzamide[12] 2a as sub-
strate (Table 1, entries 1–7). In contrast with other
bases/solvents assayed, the use of PCN catalyst 1 pro-
duced the desired phenanthridinone 3a in a 24%
yield using KOAc as base in DMA (entry 6). Encour-
aged by this initial result, we proceeded to optimize
the reaction conditions.
Tentative attempts to employ alternative solvents
with the same base resulted ineffective (entries 7-9),
as also occured by the addition of Brønsted acids
such as pivalic acid (PivOH), benzoic or p-toluenesul-
fonic acid (entries 10–11). Similarly, the use of tetra-
butylammonium bromide or cationic surfactants
CTAB and DDA as additives did not benefit the reac-
tion (entries 12–13). In contrast, the mixture of sol-
vents as THF or water with DMA did improve the
conversion rate (entries 16–18), obtaining the best re-
sults when 10% of water in DMA was employed
(68%, entry 18). Other variables such as the amount
of base, solvent concentration and especially the cata-
lyst loadings were also examined (entries 20–27). In
addition, control experiments carried out with com-
mercially available palladium sources (PdCl2 and
Pd(OAc)2) confirmed the convenience of palladacycle
1 and water as co-solvent (entries 28–33). Thus, after
careful experimentation, we succeeded to obtain phe-
nanthridinone 3a in
a very good yield (88%,
entry 25) with only 0.05 mol% of palladium pincer
complex 1 using 3 equiv of KOAc in a relatively con-
centrated solution of DMA/H2O (9:1, 0.3m). More-
over, a further decrease of the catalyst loading down
to 0.01 mol% was also possible, affording desired
phenanthridinone 3a although at the cost of lower
yields (78% and 57%, entries 26–27) even at longer
reaction times. To the best of our knowledge, these
values represent the lowest catalyst loadings achieved
so far not only for the direct arylation of N-substitut-
ed o-halobenzanilides, but for any biaryl coupling of
an aryl halide with a nonfunctionalized arene.[13] To
relate this to the previous state of art, the elegant pro-
cedure reported by Fagnou and co-workers[5a] afford-
ed a turnover number (TON) of 41.5 for 3a, signifi-
cantly lower than our TONs of 1760 (entry 17) and
5700 (entry 19). It should be also pointed out that the
latter reactions were carried out in an air atmosphere
with no effect on the reaction yield, thus providing an
additional advantage from a practical point of view.
With the establishment of an optimal catalyst load-
ing of 0.05 mol% as the most effective, the generality
and scope of the reaction were initially studied with
a variety of o-bromo-N-alkyl-N-aryl(hetero)arylcar-
boxamides 2b–g.[12]
[a]
Reaction conditions:
2 (0.3 mmol), 1 (0.05 mol%),
KOAc (3 equiv), DMA-H2O (9:1, 0.3m), 1308C, sealed
tube, 20 h under air. Isolated yields.
1.5 equiv of KOAc were used.
[b]
[c]
0.09 mol% of 1 was used.
As summarized in Table 2, the functional tolerance
of this procedure was observed by synthesizing vari-
ous phenanthridinones and related heterocyclic qui- nature of the substituents seemed to have a little
nolinones with good to excellent yields. The electronic effect on the product yields, according to the slightly
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lower yield obtained for the phenanthridinone 3c
containing the electron-withdrawing CF3 group on the
N-aryl ring (73%). Besides, the reaction with differ-
ent aromatics as naphthalene and heterocycles such
as furan, thiophene or tetrahydroquinoline proceeded
selectively in this C(sp2)-H arylation (78–98%). Even
sterically hindered substrates as N-cyclohexyl amide
2d afforded the desired product 3d in an 86% yield.
Considering the excellent activity of the pincer-type
complex 1 to access biaryl lactams and as an attempt
to further extend the potential of our approach, we
investigated the applicability of this protocol to struc-
turally related o-halo-N-arylsulfonamides. Sulfona-
mide group is one of the most important pharmaco-
phores, and sulfonamide containing compounds, in-
cluding sultams, display a vast array of biological ac-
tivity.[14] While the recent application of palladium-
catalyzed direct coupling reactions has significantly
improved the access of biaryl sultams in terms of ver-
satility and efficiency, considerably high loadings of
palladium catalyst are still required (1-10 mol%).[5a,7c]
Accordingly, a series of o-bromo-N-(hetero)aryl-
benzenesulfonamides 2i–s were readily prepared[12]
and reacted with only 0.05 mol% pincer catalyst
1 (Table 2). To our delight, the direct functionaliza-
Scheme 1. Access to the benzoisothiazoloindole 5,5-dioxide
and benzothiazinoindole 7,7-dioxide skeletons.
tion of N-(hetero)arylsulfonamides with such low cat- thiazolo[2,3-a]indole 5,5-dioxides (see for instance
alyst loadings afforded regioselectively the corre- transformation of 2q into 3q in Scheme 1), we envis-
sponding biaryl sultams. It is worth mentioning the aged a complementary protocol to access the ben-
good results obtained for the construction of benzo- zo[5,6]thiazino[4,3,2-hi]indole 7,7-dioxide framework.
pyrroloisothiazole-, benzoisothiazolindole- and ben- Indeed, whereas the intramolecular direct arylation of
zo[4,5]isothiazolopyrrolopyridine S,S-dioxides 3p– 2-substituted indoles affords the desired benzothiazi-
s bearing a more constrained 5-membered sultam noindoles, a 7-bromoindole derivative has been de-
ring. To date, the preparation of such tetracyclic sys- scribed as essential for the selective preparation of
tems have been only possible in moderate to good unsubstituted benzothiazinoindoles in C2 position.[17]
yields (<70%),[15] illustrating the difficulty to perform Alternatively, we carried out the oxidation of benzo-
this particular intramolecular cyclization.
thiazinoindoline 3o, readily available from N-(o-bro-
Therefore, although the yields obtained in our case mobenzenesulfonyl)indoline 2o, to afford the target
are in accordance with literature precedents and, on indole derivative 3t in a good yield over two steps
average, not as high as the ones obtained for the cor- (Scheme 1).
responding 6-membered ring sultams 3h–o, the signif-
As mentioned above, one of the major drawbacks
icantly smaller amounts (0.05–0.09 mol%) of catalyst of transition metal catalyzed reactions in drug discov-
required make our protocol into the most effective ery is the presence of trace metals contaminants in
approach to benzoisothiazoloindoles and related het- the products, as only residual palladium levels below
erocycles.
<10 ppm are allowed in drug products.[8] We predict-
In the last years, indole derivatives with constrained ed that the use of a highly active palladium source
sulfonamide ring have gained interest as novel 5-HT6 like 1 in such a low amount (0.05 mol%) would avoid
receptor ligands, which play an important role in CNS such contamination issues while still accomplishing
disorders such as schizophrenia, dementia, Alzheim- the desired transformations. Accordingly, the mea-
erꢃs disease and Parkinsonꢃs disease.[15,16] In particular, surement of the palladium content in benzothiazino-
benzoisothiazoloindoles and benzothiazinoindoles of dihydroquinoline 3n was conducted using IPC-MS[12]
general structure I[16a] and II[16b] respectively and determined as low as 0.29 ppm. Therefore, our
(Scheme 1) have been reported as potent 5-HT6 re- method not only provides a cost-effective and more
ceptor ligands with good affinity towards 5-HT6R and sustainable access to biaryl amide and sultam contain-
selectivity over known GPCRs. Having established ing heterocycles, but also offers an additional benefit
the direct arylation of N-(o-bromobenzenesulfonyl)in- regarding the avoidance of scavenger resins or further
doles mediated by palladium pincer complex 1 as an purification steps[8] in order to suppress metal contam-
efficient and straightforward access to benzo[4,5]iso- ination in the products.
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Table 3. Summary of poisoning experiments.
Entry
Poisoning additive
Conv. [%][a]
1
Hg (one drop)[b]
0
2
3
4
5
CS2 (0.5 equiv per metal atom)
CS2 (2.0 equiv per metal atom)
PPh3 (0.03 equiv per metal atom)
PPh3 (0. 3 equiv per metal atom)
PPh3 (4.0 equiv per metal atom)
Py (150 equiv per metal atom)
PVPy (300 equiv per metal atom)
2
0
76
71
70
8
Figure 1. Conversion rate (%) of 1-((2-bromophenyl)sulfon-
yl)-1,2,3,4-tetrahydroquinoline 2n vs time.
6
7[c]
8[d]
A number of experiments were then performed to
shed light on the high catalytic profile observed for
pincer complex 1. Recycling or reuse of the reaction
media containing the catalytic species was initially ex-
amined. After submitting sulfonamide 2n to the opti-
mized reaction conditions, water was added, the mix-
ture was extracted with ethyl acetate and the aqueous
layer was concentrated to dryness. To this crude oil
2n, KOAc and DMA were added and the reaction re-
88
[a]
1
Measured by H NMR. Diethyleneglycol dimethyl ether
was used as internal standard.
See ref. 19 for further details on the use of Hg drop
test.[19]
[b]
[c]
[d]
Py: Pyridine
PVPy: Polyvinylpyridine.
peated. However, a significant drop in the conversion es Pd(0) species that re-enter the catalytic cycle. The
rate was observed (24%), and further runs provided above intermediates A–F were detected by electro-
negligible results.
spray ionization mass spectrometry (ESI-MS).[12] In
The possible presence of palladium nanoparticles addition, the use of diphenylphosphine oxide as
was also evaluated by examination of transmission ligand along with Pd(OAc)2 (0.05 mol%) under opti-
electron microscopy (TEM) images from the reaction mized conditions (KOAc, DMA/H2O, 1308C) provid-
crude. The interference caused by the presence of sto- ed a 54% yield of 3n from o-bromosulfonamide 2n.
ichiometric amounts of potassium bromide was avoid-
In summary, we have developed a method for the
À
ed by using a cationic exchange resin in order to intramolecualr direct arylation of arenes via C H
remove selectively potassium ions. No such Pd nano- bond functionalization at very low catalyst loadings.
particles were detected in the organic or aqueous With only 0.05 mol%, palladium pincer complex
layers after initial work-up, even when TEM was 1 promotes efficiently the direct functionalization of
combined with Energy-dispersive X-ray spectroscopy a series of N-arylbenzanilides and N-arylsulfonamides
(EDS).[12] In addition, conversion vs time curve providing a novel versatile and sustainable access to
(Figure 1) showed neither sigmoidal shape nor induc- phenanthridinones, biaryl sultams and related hetero-
tion time, thus suggesting the intermediacy of homo- cyclic derivatives. A number of experiments indicate
geneous catalysts.[18] Nevertheless, the results from a relatively complex mechanism that might involve
a series of poisoning assays (Table 3) account for the different catalytically active species and cooperative
possible participation of heterogeneous species.
catalysis between them. Further studies on the scope
The somewhat puzzling outcome from the latter re- of the substrates, applications, and the precise mecha-
cycling, TEM, kinetic and poisoning measurements nism are ongoing in our laboratory.
might be related to a mechanistic pathway based on
a cocktail of in situ generated and preformed cata-
lysts[20] after steady decomposition of 1. A tentative
Experimental Section
proposal for the formation of benzothiazinodihydro-
quinoline 3n is shown in Scheme 2. Hydrolysis[21] of
General procedure for the direct arylation of arenes
phosphinoamine A generates 3-(1H-pyrazol-1-yl)ani-
DMA (0.8 mL) and water (0.1 mL) were added to a heavy-
line B and diphenylphosphine oxide or its tautomer
wall pressure tube charged with substrate 2 (0.35 mmol) and
diphenylphosphinous acid C, which upon complexa-
KOAc (1.05 mmol) at room temperature. Then, a solution
of pincer complex 1 in DMA (1.75 mm, 0.1 mL, 0.175 mmol
of 1) was added, the tube was closed and it was heated to
tion with Pd(0) species provides phosphine oxide
complex(es) D.[22,23] After oxidative addition of aryl
halide 2n and formation of palladacyclic intermediate
1308C for 20 h. After cooling, the crude reaction mixture
F, reductive elimination renders target 3n and releas- was diluted with H2O (2 mL) and washed with EtOAc (2ꢄ
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Nerea Conde et al.
Scheme 2. Proposed mechanism for the direct intramolecular coupling of o-bromosulfonamide 2n in the presence of palladi-
um complex 1.
3 mL). The combined organic phase was dried over anhy-
drous sodium sulfate, and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography (EtOAc in hexane) to give the desired
product 3.
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Acknowledgements
This research was supported by the Basque Government (IT-
774–13), the Spanish Ministry of Economy and Competitive-
ness (CTQ2013–46970-P) and the University of the Basque
Country (UFI QOSYC 11/12). N.C. thanks the Basque Gov-
ernment for a predoctoral scholarship. The authors also
thank Petronor, S. A. for generous donation of hexane. Final-
ly, technical and human support provided by SGIker (UPV/
EHU, MICINN, GV/EJ, ESF) is gratefully acknowledged.
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ÞÞ
These are not the final page numbers!

UPDATES
8 A Further Decrease in the Catalyst Loading for the
Palladium-Catalyzed Direct Intramolecular Arylation of
Amides and Sulfonamides
Adv. Synth. Catal. 2015, 357, 1 – 8
Nerea Conde, Fꢀtima Churruca, Raul SanMartin,*
Marꢁa Teresa Herrero, Esther Domꢁnguez*
8
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!