N-tosylcarboxamide as a transformable directing group for Pd-catalyzed C-H ortho-arylation

Article abstract of DOI:10.1021/ol3004244

The N-tosylcarboxamide group offers the possibility of directing the Pd-catalyzed C-H arylation of arenes providing a new entry to biarylcarboxamides. Moreover, its ability to react according to different reaction conditions including intramolecular reactions makes it a pivotal directing group for a divergent synthesis of biaryl-based compounds.

Full text of DOI:10.1021/ol3004244

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1827–1829
N-Tosylcarboxamide as a Transformable
Directing Group for Pd-Catalyzed CÀH
Ortho-Arylation
ꢀ ꢀ ꢀ
Florent Peron, Christine Fossey, Thomas Cailly, and Frederic Fabis*
ꢀ
Universite de Caen Basse-Normandie, EA 4258 CERMN - FR CNRS 3038 INC3M - SF
4206 ICORE, UFR des Sciences Pharmaceutiques, F-14032 Caen, France
frederic.fabis@unicaen.fr
Received February 21, 2012
ABSTRACT
The N-tosylcarboxamide group offers the possibility of directing the Pd-catalyzed CÀH arylation of arenes providing a new entry to
biarylcarboxamides. Moreover, its ability to react according to different reaction conditions including intramolecular reactions makes it a
pivotal directing group for a divergent synthesis of biaryl-based compounds.
Palladium-catalyzed CÀH arylation of directing-group-
containing arenes has emerged as a powerful tool for
the synthesis of biaryl compounds.1 Numerous directing
groups such as nitrogen-containing heterocycles,2 anilides,3
amides,4 oximes,5 benzylamines,6 and carboxylic acids7
have been used in the arylation of arenes, leading to a wide
variety of important ortho-functionalized biaryl com-
pounds. However, most of these groups were developed
to achieve high regioselectivities and yields in the arylation
step, but only a few of them were used for further trans-
formations.8,9 Very recently, the carboxylic acid group was
described as a removable ortho-directing group for a
formal meta-arylation reaction.10 Some directing groups
have been used in tandem ortho-arylation/intramolecular
cyclization reactions to give straightforward access to
biaryl-based heterocycles such as fluorenones5,11 or phe-
nanthrene derivatives.11,12 Among them, N-substituted
benzamides have been described for ortho-arylation and
subsequent formation of fluorenone or phenanthridinone
derivatives depending on the nitrogen substituent.9,13
These cascade reactions using CÀH arylation as the first
step provide new perspectives for the construction of
complex molecules starting from simple starting materials.
Nevertheless, the issue of the second transformation is
most often directing group-dependent. O-Acetyl oxime14
and pyridylsilyl15 groups have been recently described as
(1) For reviews, see: (a) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147–1169. (b) Ackermann, L.; Vicente, R.; Kapdi, A. R.
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Shabashov, D. Acc. Chem. Res. 2009, 42, 1074–1086. (d) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238.
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B. J.; Yu, D. G.; Wang, Y.; Shi, Z. J. Org. Lett. 2010, 12, 184–187.
(6) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211–5213.
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Breazzano, S. P.; Saunders, L. B.; Yu, J. Q. J. Am. Chem. Soc. 2007, 129,
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50, 9880–9883. (b) Wang, G. W.; Yuan, T. T.; Li, D. D. Angew. Chem.,
Int. Ed. 2011, 50, 1380–1383.
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10.1021/ol3004244
2012 American Chemical Society
Published on Web 03/22/2012

directing groups in the CÀH acyloxylation of arenes and
used for diverse subsequent transformations, but these
examples remain rare, and suitable functional groups for
CÀH activation reactions followed by diverse transforma-
tions are still expected to extend this concept. Recently, the
Falck group has disclosed, for the first time, the N-
tosylcarboxamide group as an efficient directing group in
the Pd- and Rh-catalyzed CÀH olefination of arenes
leading to isoindolinones in a one-pot procedure.16 They
also recently described the N-tosylcarboxamide-directed
Rh-catalyzed CÀH insertion of isocyanides followed by
annulation leading to iminoisoindolinones.17 In these
works, the authors found that the NH acidity of the N-
tosylcarboxamide group was essential for the reaction to
take place. They postulated that the acidity of the NH
facilitated the cyclometalation step. Starting from these
results and the ability of the tosylamide to act as a good
leaving group,18 we reasoned that N-tosylcarboxamide
could serve as an easily transformable directing group
for Pd-catalyzed CÀH arylation of arenes, allowing the
synthesis of various biaryl-based compounds.
Scheme 1. Synthesis of Substituted N-Tosylbiphenyl-2-carbox-
amides 2bÀx by Pd-Catalyzed CÀH Arylationa
We started our investigations with the CÀH arylation of
N-tosylbenzamide 1a with 4-iodotoluene, using Pd(OAc)2
as a catalyst and silver salts as an additive in an acidic
medium (Table 1). We found that ortho-arylation took
place along with diarylation in a nearly 1:1 ratio using
AcOH and Ag2O at 120 °C (entry 1). Replacing AcOH by
TFA led to decomposition of the starting material (entry 2).
Whereas an excess of aryl iodide or Ag2O did not allow
any improvement of these results (entries 3 and 4), we
found that AgOAc gave the best ratio of monoarylated/
diarylated product (entries 5 and 6).
Table 1. Screening Conditions for the Pd-Catalyzed Arylation
of 1a
entry
solvent
additive
1a/2a/3aa
1
AcOH
TFA
Ag2O
0/55/45
0/0/0b
2
Ag2O
3c
4d
5e
6
AcOH
AcOH
AcOH
AcOH
Ag2O
0/28/72
0/65/35
11/79/10
9/82/9
Ag2O
a Reactions were carried out starting from 0.71 to 3.6 mmol of N-
tosylbenzamides 1bÀn. Yields given are isolated yields.
AgOAc
AgOAc
a HPLC/MS observed ratio using pure sample of material as refer-
ences. b Degradation observed. c 4-Iodotoluene, 4 equiv. d Ag2O, 4 equiv.
e AgOAc, 4 equiv.
With these optimized conditions, we evaluated the gen-
erality of the reaction using various substituted N-tosyl-
benzamides and iodoarenes. The results are summarized in
Scheme 1. Ortho- and meta-substituted N-tosylbenzamides
bearing either electron-withdrawing or -donating groups
wereefficiently arylatedwith4-iodotoluene. Only thepara-
substituted benzamides were prone to diarylation lead-
ing to lower isolated yields in monoarylated compounds.
(16) (a) Zhu, C.; Falck, J. R. Org. Lett. 2011, 13, 1214–1217. (b) Zhu,
C.; Falck, J. R. Chem. Commun. 2012, 48, 1674–1676.
(17) Zhu, C.; Xie, W.; Falck, J. R. Chem.;Eur. J. 2011, 17, 12591–
12595.
(18) Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetrahe-
dron Lett. 1985, 26, 657–680.
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Org. Lett., Vol. 14, No. 7, 2012

Scheme 2. Functional Transformations of N-Tosylbenzamides
The reaction was successfully applied to diversely substi-
tuted iodoarenes. Very interestingly, the reaction worked
with ortho-substituted iodoarenes (compounds 2vÀx), even
if extended reaction times were necessary for 2-chloro-
and 2-fluoro- derivatives. These examples remain rare in
Pd-catalyzed CÀH arylation with ortho-substituted
iodoarenes.19 Overall, these results show that the N-tosyl-
carboxamide group can efficiently direct the Pd-catalyzed
ortho-arylation of arenes.
We then turned our attention to the transformation of
the N-acyl-N-tosyl group (Scheme 2). Starting from com-
pound 2b, the tosyl was easily removed using sodium/
naphthalene in THF affording the primary biarylcarbox-
amide 4 in 76% yield. Activation of the carbonyl group of
2bwithTFA at120°C led tothe fluorenone 5inaclean and
high yielding reaction exhibiting the ability of the tosyla-
mide group to serve as a good leaving group.18
group was necessary for nucleophilic additions to take
place. Thus, basic hydrolysis of N-methylated biaryl com-
pound 7 led to the carboxylic acid 9, whereas addition of
sodium methoxide led to the corresponding methyl ester 8.
Finally, the N-tosylcarboxamide group can easily be re-
duced to the corresponding benzyl alcohol 10with LiAlH4.
In summary, we have demonstrated that the N-tosylcar-
boxamide group represents one of the most efficient
groups for both the Pd-catalyzed CÀH arylation of arenes
and further transformations including nucleophilic addi-
tions, electrophilic aromatic substitutions, and intramole-
cular CÀH amination. The flexibility of this directing
group allows, from a unique and simple starting material,
for a wide variety of diversely ortho-functionalized biaryl
compounds or substituted biaryl-based polycyclic struc-
tures to be easily obtained.
Using the conditions developed in the intramolecular
palladium-catalyzed CÀH amination of arenes for the
construction of quinolones,20 we were able, starting from
2g, to directly access the detosylated phenanthridin-6(5H)-
one 6 in a 63% isolated yield. We next investigated
nucleophilic additions to N-tosylbenzenecarboxamides 2.
Due to its high acidity, previous methylation of the NÀH
Acknowledgment. This work was supported by the
CNRS and ERDF fundings. The IS:CE-Chem project
and the Interreg IVA France-(Channel)-England program
are gratefully thanked for their financial support.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data. Copies of 1Han13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
ꢀ
(19) (a) Rene, O.; Fagnou, K. Adv. Synth. Catal. 2010, 352, 2116–
2120. (b) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192–5196.
(20) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. J. Org. Chem. 2010,
75, 3900–3903.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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