Selective unusual pd-mediated biaryl coupling reactions: Solvent effects with carbonate bases

Article abstract of DOI:10.1021/ol902570s

"Chemical Equation Presented" A one-step Pd-catalyzed reaction performed on an o-bromobenzamide permitted the selective formation of either phenanthridinones 2 via an ipso substitution or new phenanthridinone-1- carboxamides 3 through a direct N-arylation. A direct correlation between the solvent polarity and the carbonate base on the selectivity has been observed. The proposed catalytic cycle involves the initial formation of a common intermediate and depends on the base assistance.

Full text of DOI:10.1021/ol902570s

ORGANIC
LETTERS
2010
Vol. 12, No. 1
156-158
Selective Unusual Pd-Mediated Biaryl
Coupling Reactions: Solvent Effects
with Carbonate Bases
Ludovic Donati, Sylvie Michel, Franc¸ois Tillequin, and Franc¸ois-Hugues Pore´e*
Laboratoire de Pharmacognosie UMR CNRS 8638, UniVersite´ Paris Descartes,
4 AVenue de l’ObserVatoire, F-75006 Paris, France
francois-hugues.poree@parisdescartes.fr
Received November 5, 2009
ABSTRACT
A one-step Pd-catalyzed reaction performed on an o-bromobenzamide permitted the selective formation of either phenanthridinones 2 via an
ipso substitution or new phenanthridinone-1-carboxamides 3 through a direct N-arylation. A direct correlation between the solvent polarity
and the carbonate base on the selectivity has been observed. The proposed catalytic cycle involves the initial formation of a common intermediate
and depends on the base assistance.
o-Bromobenzamide units such as 1 are of particular interest
in the Pd-mediated synthesis of natural products, as well as
CNS and anticancer candidates.1 It was recently shown that
Pd-catalyzed coupling of two molecules of 1a furnished
phenanthridinone 2a, when treated by Pd(OAc)2, a triaryl
phosphine ligand, and a carbonate base.2 In our hands,
compound 2a was also selectively obtained with the system
PdCl2(PPh3)2 and K2CO3 in DMF (Table 1). Surprisingly,
when 1,4-dioxane was used instead of DMF, the coupling
reaction followed a completely different pathway, leading
to the selective formation of the unexpected 1-carboxamide
phenanthridinone 3a.
We investigated these reactions to understand the origin
of the difference of selectivity observed. The results are
presented in this communication.
A large variety of o-bromobenzamides 1a-k differing by
the N-protecting groups (R: benzyl, PMB, allyl) and the
substituents on the aromatic ring (R1 and R2: OCH3, OCH2O,
Cl) were selected. The scope of these coupling processes
was first studied, and the results are listed in Table 1.
In all conditions, a single product was obtained in moderate
to excellent yield, but its structure depended upon the solvent
used. Indeed, only phenanthridinones 2 were formed in DMF,
whereas 1-carboxamide phenanthridinones 3 were exclu-
sively obtained in dioxane. Moreover, the coupling is faster
in DMF than in dioxane (3 h versus 24 h). The variations
observed are similar in both series. Thus, the nature of the
N-protecting group does not influence the outcome of the
reactions. In addition, a Pd(II)-mediated E/Z isomerization
of the allyl double bond was observed in dioxane for 1g,
(1) Dewick, P. W. Medicinal Natural Products: A Biosynthetic Ap-
proach, 3rd ed.; Wiley-Blackwell: Oxford, 2009; p 311. Bastida, J.; Lavilla,
R.; Viladomat, F. The Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 2006; Vol. 63, p 87. Wermuth, C. G. The Practice of Medicinal
Chemistry, 2nd ed.; Wermuth, C. G., Ed.; Academic Press: London, 2003.
(2) (a) Ferraccioli, R.; Carenzi, D.; Motti, E.; Catellani, M. J. Am. Chem.
Soc. 2006, 128, 722. (b) Furata, T.; Kitamura, Y.; Hashimoto, A.; Fujii, S.;
Tanaka, K.; Kan, T. Org. Lett. 2007, 9, 183. First example of this reaction,
see: Caddick, S.; Kofie, W. Tetrahedron Lett. 2002, 43, 9347. See also:
Thansandote, P.; Hulcoop, D. G.; Langer, M.; Lautens, M. J. Org. Chem.
2009, 74, 1673. For a review on transition-metal catalyzed direct arylation,
see: Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174.
Thansandote, P.; Lautens, M. Chem.sEur. J. 2009, 15, 5874.
10.1021/ol902570s  2010 American Chemical Society
Published on Web 12/01/2009

Table 1. Scope of the Coupling Reactionsa
Table 2. Solvent Effect and Pd Sourcea
product (selectivity) - Pd complex
entry
solvent
PdCl2(PPh3)2
PdCl2(dppf)
Pd(PPh3)4
1
2
3
dioxane
THF
DMF
3a
3a
3a
3a/2a (1:1.4)
2a
3a/2a (2:1)
2a
3a/2a (3:1)
2a
a Reaction conditions: Pd complex (5 mol %), K2CO3 (3 equiv),
o-bromobenzamide 1a (1 equiv), dioxane, THF, or DMF (20 mL) at 100,
60, or 150 °C, respectively.
product (yield) - solvent
entry
substrate
DMF
dioxane
3a, 49%
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a, 55%
2b, 88%
2c, 91%
2d, 71%
2e, 80%
2f, 99%
2g, 55%
2h, 80%
2i, 95%
2j, 54%
2k, 46%
3b, 63%
3c, 80%
K2CO3, and Cs2CO3 was studied in dioxane, THF, and DMF.
As shown in Table 3, the selectivity of the reactions directly
3d, 48%
3e, 82%
3f, 80%
E/Z isomerization
E/Z isomerization
E/Z isomerization
3j, 43%
Table 3. Nature of the Base and Solvent Effecta
9
10
11
1j
1k
3k, 61%
a Reaction conditions: PdCl2(PPh3)2 (5 mol %), K2CO3 (3 equiv),
o-bromobenzamide (1 equiv), dioxane or DMF (20 mL) at 100 or 150 °C,
respectively.
product (global yields, selectivity) - solvent
entry
1
base
dioxane
THF
DMF
1h, and 1i, in which case no coupling process occurred
(entries 7-9).3 The presence of electron-donating substitu-
ents, such as OCH3 and OCH2O, dramatically increased the
yields of the reactions (entries 2, 3, 5, 6, 8, and 9). In contrast,
substitution by a deactivating chlorine led to moderate yields,
close to those observed with an unsubstituted aromatic ring
(entries 10 and 11 vs entries 1, 4, and 7).
no base no reaction
no reaction
no reaction
3a/2a
(64%, 1:3.3)
2
3
4
Na2CO3 3a (traces)
3a (86%)
3a/2a
(56%, 1:1.4) 2a (55%)
K2CO3
3a (49%)
3a/2a
Cs2CO3
(69%, 1.5:1) 2a (90%) 2a (80%)
a Reaction conditions: PdCl2(PPh3)2 (5 mol %), base (3 equiv), o-bromo
arylcarboxamide 1a (1 equiv), dioxane, THF, or DMF (20 mL) at 100, 60,
or 150 °C, respectively.
To understand the selectivity observed, the role of the
solvent was studied more precisely with different Pd(II) and
Pd(0) complexes (Table 2). THF, a usual solvent in Pd
chemistry, was chosen for its intermediate polarity between
dioxane and DMF. Remarkably, results are very homoge-
neous. In less polar dioxane, only compound 3a was
obtained, whereas tricycle 2a was selectively formed in
DMF, independently of the Pd source (entries 1 and 3,
respectively).4 In THF, a mixture of 2a and 3a was observed,
suggesting that the solvent polarity could be directly involved
in the selectivity (entry 2).
depends upon the solvent polarity and the base dissociation.
Without base, no reaction was observed, outlining the
importance of the alkaline agent in these reactions (entry
1). For example, in moderately polar THF, compound 3a
was obtained with weakly dissociated sodium carbonate,
whereas the use of easily dissociated cesium carbonate led
to phenanthridinone 2a (entries 2 and 4). Interestingly, the
use of THF as solvent also resulted in a significant increase
in the yields of 2a or 3a (see Table 1, entry 1 for
comparison). Potassium carbonate led to a mixture of 2a and
3a (entry 3). Consequently, these results show a direct
correlation between the base dissociation and the formation
of 2a, suggesting that the base is directly involved in the
reaction mechanism.5
The fact that Furata and co-workers only reported the
formation of 2a in dioxane when using Cs2CO3 as a base
prompted us to investigate the influence of the solvent/base
association on the reaction.2b Thus, the effect of Na2CO3,
(3) Pd(II)-mediated isomerization of heteroatom-allyl is known, see:
Negishi, E.-i. Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., de Meijeire A., Eds.; Wiley: New York, 2002; p
2783.
To account for these results, a plausible catalytic cycle is
proposed in Scheme 1. Both reactions involve an aryl-aryl
(4) In a similar polar solvent, CH3CN, compound 2a was also obtained
selectively.
Org. Lett., Vol. 12, No. 1, 2010
157

elimination of an RNCO unit (or RNH2 + CO2) gives
complex 8, which releases tricycle 2 after reductive elimina-
tion.8
Scheme 1. Plausible Mechanistic Pathways
In weakly dissociating medium, no carbonate-bromide
exchange occurs. A Pd(II)-mediated N-arylation can occur
to release compound 3 after reductive elimination. To the
best of our knowledge, this is one of the first examples of
an N-Pd(II) species insertion into a C-H bond.9
In summary, we describe here simple and efficient reaction
conditions to access selectively two differently substituted
phenanthridinone skeletons from a common precursor in a
one-step sequence. The reaction pathway proposed involves
the formation of a common aryl-aryl Pd(II) intermediate
which can undergo either an ipso substitution or an N-
arylation depending on the medium. This selectivity is
governed by the base dissociation which, in dissociating
medium, can directly participate in the reaction pathway. The
scope of the N-Pd(II) species insertion into a C-H bond in
other (hetero)polycyclic series is currently under investiga-
tion.
Acknowledgment. E. Prost and P. Leproux (Universite´
Paris Descartes UMR CNRS 8638) are gratefully acknowl-
edged for their technical assistance (NMR and Mass spectra).
Dr. L. Micouin (Universite´ Paris Descartes UMR CNRS
8638) is acknowledged for fruitful discussions. We are
grateful to Dr. A. Jutand (Ecole Normale Supe´rieure,
De´partement de Chimie UMR CNRS-ENS-UPMC 8640) for
helpful discussions during the preparation of the manuscript.
connection followed by an N-aryl coupling step.6 Starting
from in situ generated Pd(0), insertion into the C-Br bond
gives rise to five-membered Pd(II) palladacycle 4. Then
insertion into a second arylcarboxamide unit occurs, produc-
ing Pd(IV) intermediate 5, which can undergo an aryl-aryl
bond reaction to give Pd(II) intermediate 6.
At this point, two different intramolecular pathways can
proceed. In dissociating medium, carbonate may exchange
with bromide on Pd(II) complex 6 (Scheme 2). Then a
´
Supporting Information Available: Experimental pro-
cedures and compound characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 2. Proposed Role of the Carbonate Base
OL902570S
(5) A possible base counterion effect is conceivable. A study of base
effects in intramolecular direct N-arylation was conducted by Fagnou and
co-workers, but the conclusion remained elusive. See: Campeau, L.-C.;
Parisien, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. See also: Garcia-
Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren,
A. M. J. Am. Chem. Soc. 2007, 129, 6880.
(6) Catellani, M.; Motti, E.; Della Ca’, N. Acc. Chem. Res. 2008, 41,
1512, and references cited.
(7) For an example of amide deprotonation induced by a carbonate base
in a Pd process, see: Erb., W.; Neuville, L.; Zhu, J. J. Org. Chem. 2009,
74, 3109.
concerted mechanism proceeds including a carbonate-induced
amide deprotonation with concomitant rotation of the aryl
unit A around the aryl-aryl bond, followed by a nucleophilic
attack of the nitrogen with departure of HCO3 . An ipso
substitution on the resulting Pd(II) intermediate 7 with
(8) Example of Pd-catalyzed arylation with concomitant decarbamoy-
lation, see: Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2002, 124, 5286.
7
-
(9) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald,
S. L. J. Org. Chem. 2008, 73, 7603.
158
Org. Lett., Vol. 12, No. 1, 2010