Solvent/base effects in the selective domino synthesis of phenanthridinones that involves high-valent palladium species: Experimental and theoretical studies

Article abstract of DOI:10.1002/chem.201101354

The domino reaction of o-bromobenzamides 1-a-m in the presence of K ₂CO₃ and the [PdCl₂(PPh₃) ₂] catalyst granted a selective access to phenanthridinones 2 or to the new 1-carboxamide phenanthridinones 3 depending on the solvent, DMF or 1,4-dioxane, respectively. Investigations of the reaction parameters provided the first example of a direct correlation between the base dissociation and the solvent polarity on the selectivity observed. Moreover, mechanistic studies (NMR spectroscopy and ESI-MS monitoring) allowed us to characterize Pd^II palladacycle 4 and biaryl species as common intermediates for these two domino processes. On that basis, C(sp²)iC(sp²) bond formation is envisaged by generation of a Pd^IV complex after oxidative addition of 1 into Pd^II palladacycle 4, a rationale that is supported by DFT calculations. A general catalytic cycle is proposed to account for these observations. Domino theory: The domino reaction of o-bromobenzamides 1 in the presence of K₂CO₃ and [PdCl₂(PPh ₃)₂] granted a selective access to phenanthridinones 2 or to the new 1-carboxamide phenanthridinones 3 depending on the solvent (see scheme). Investigations showed a direct correlation between the base dissociation and the solvent polarity on the selectivity.

Full text of DOI:10.1002/chem.201101354

FULL PAPER
DOI: 10.1002/chem.201101354
Solvent/Base Effects in the Selective Domino Synthesis of Phenanthridinones
That Involves High-Valent Palladium Species: Experimental and Theoretical
Studies
Ludovic Donati,[a] Pascale Leproux,[a] Elise Prost,[a] Sylvie Michel,[a]
FranÅois Tillequin†,[a] Vincent Gandon,*[b] and FranÅois-Hugues Porꢀe*[a]
In memory of Professor FranÅois Tillequin
Abstract: The domino reaction of o-
bromobenzamides 1a–m in the pres-
vent polarity on the selectivity ob-
served. Moreover, mechanistic studies
(NMR spectroscopy and ESI-MS moni-
toring) allowed us to characterize PdII
palladacycle 4 and biaryl species as
common intermediates for these two
domino processes. On that basis, C-
2
ence of K2CO3 and the [PdCl
N
(sp ) C
(sp2) bond formation is envis-
À
catalyst granted a selective access to
phenanthridinones 2 or to the new 1-
carboxamide phenanthridinones 3 de-
pending on the solvent, DMF or 1,4-di-
oxane, respectively. Investigations of
the reaction parameters provided the
first example of a direct correlation be-
tween the base dissociation and the sol-
aged by generation of a PdIV complex
after oxidative addition of 1 into PdII
palladacycle 4, a rationale that is sup-
ported by DFT calculations. A general
catalytic cycle is proposed to account
for these observations.
Keywords: basicity · density func-
tional
calculations
·
domino
reactions
·
phenanthridinones
·
reductive coupling
Introduction
Several examples of preparation of heterocycles-containing
biaryls have been reported, either in an inter- or intramolec-
ular fashion.[5] In this context, we recently described[6] the
Pd-catalyzed selective formation of phenanthridinones 2[7]
or unprecedented 1-carboxamide phenanthridinones 3, from
readily available o-bromobenzamides 1, depending on the
solvent, DMF or 1,4-dioxane, respectively (Scheme 1).
Beyond the potential applications of these compounds in
medicinal chemistry,[8] the mechanistic aspects of these cata-
lytic reactions are of fundamental value. Some crucial issues
remain to be addressed and their understanding should give
some profitable data for other related Pd-catalyzed re-
The biaryl subunit constitutes a very important template for
many fields of chemistry, as it is found in natural products,
pharmaceuticals, agrochemicals, catalysts, as well as materi-
als (polymers).[1] The widespread need for such motifs led to
the development of several efficient preparative methods
2
that are typically based on C
G
(sp2) bond formation
À
between two aryl moieties. Classical approaches involve
transition-metal-catalyzed cross-coupling reactions and, in
À
recent years, Pd-mediated C H activation and direct aryla-
tions.[2,3] Besides, the formation of the biaryl axis may repre-
sent the key event of metal-catalyzed domino processes.[4]
AHCTUNGTRENNUNG
II
II
À
domino processes. A possible Pd Pd transmetalation
pathway has been proposed on the basis of DFT calcula-
tions.[9] However, the generation of high-valent Pd inter-
mediates could also be invoked. Moreover, the formation of
tricycles 2 and 3 is totally selective, and one may wonder
whether this selectivity is only governed by the solvent po-
larity, or by others factors such as the base, also involved in
[a] Dr. L. Donati, P. Leproux, E. Prost, Prof. S. Michel, Prof. F. Tillequin,
Dr. F.-H. Porꢀe
Laboratoire de Pharmacognosie UMR CNRS 8638
Universitꢀ Paris Descartes, 4 Avenue de lꢁObservatoire
75006 Paris (France)
Fax : (+33)140-46-96-58
E-mail: francois-hugues.poree@parisdescartes.fr
[b] Prof. V. Gandon
Universitꢀ Paris Sud
Institut de Chimie Molꢀculaire et des Matꢀriaux dꢁOrsay
UMR CNRS 8182, Laboratoire de Catalyse Molꢀculaire
91405 Orsay (France)
Fax : (+33)1-69-15-46-80
E-mail: vincent.gandon@u-psud.fr
[†] Deceased, February 7, 2011.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101354.
Scheme 1. Pd-catalyzed coupling of o-bromobenzamides.
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the discrimination between ipso substitution and direct aryl-
ation routes.
Because these Pd-mediated domino reactions raised many
questions with regards to the mechanism involved, a de-
tailed experimental and theoretical study was carried out
and the results are presented herein.
The influence of the temperature was next studied. The
same selectivity was observed when heating the reaction in
an oil bath or by microwave irradiation. Moreover when the
reaction was carried out in 1,4-dioxane and heated at a tem-
perature close to the boiling point of DMF under micro-
ACHTUNGTRENNUNG
wave irradiation, phenanthridinones
3 were exclusively
formed. Thus the selectivity of these reactions is not gov-
erned by thermal or microwave effects.
Results and Discussion
We next focused on the influence of the carbonate base
on the selectivity of the reaction (Table 2). Three bases were
selected: Na2CO3, K2CO3, and Cs2CO3, which exhibit in-
creasing salt solubility.[12] In addition, THF, which is a
common solvent in Pd chemistry, was chosen for its inter-
mediate polarity between DMF and 1,4-dioxane. In the ab-
sence of base, no reaction occurred, thereby outlining the
crucial role played by the alkaline agent in these processes
(Table 2, entry 1). In 1,4-dioxane, 3a was exclusively ob-
tained when using Na2CO3 or K2CO3 (entries 2 and 3). By
contrast, a mixture of 2a and 3a was isolated with the more
easily dissociated Cs2CO3 (entry 4). In THF, compound 3a
was obtained with weakly dissociated Na2CO3, whereas the
use of more soluble Cs2CO3 led to phenanthridinone 2a
(entry 2 versus 4). By contrast, K2CO3 led to a mixture of
the two tricycles (entry 3). Interestingly, the use of THF as
solvent resulted in a significant increase in the yields of 2a
or 3a. In DMF, a selectivity opposite to that observed in
1,4-dioxane ensued: a mixture of compounds 3a and 2a was
formed with Na2CO3, and 2a was isolated as a sole product
using either K2CO3 or Cs2CO3. Thus, for the first time, a
direct correlation between the base dissociation and the sol-
vent polarity could be established. A diagonal line can be
drawn in Table 2 that highlights a complementarily between
the base and the solvent for maximizing the selectivity. The
combination of a poorly soluble carbonate and a weakly
polar solvent constitutes a weakly dissociating medium in
which 1-carboxamide phenanthridinones 3 are preferentially
formed. Conversely, the association of a more soluble base
with a polar solvent establishes a dissociating medium that
favors the formation of phenanthridinones 2.
Reaction scope: To investigate the scope of the title re-
ACHTUNGTRENNUNGactions, a wide array of o-bromobenzamides 1a–m that
differ in their N-protecting groups (R: benzyl, p-methoxy-
benzyl (PMB), allyl, methyl) and in the substituents at the
aromatic ring (R1 and R2: OCH3, OCH2O, Cl, NO2, H) were
engaged. As shown in Table 1, the reaction is totally selec-
tive depending on the solvent. The nature of the N-protect-
ing group does not influence the outcome of the reaction
(Table 1, entries 1, 4, 9, and 10), except in the case of the
allyl group with which a double bond isomerization was ob-
served in 1,4-dioxane (entries 10–12).[10] The best yields
were obtained when the aromatic core was substituted by
electron-donating groups such as methoxy and methylene-
dioxy (entries 2, 3, 5, 6, 11, and 12). The presence of a de-
ACHTUNGTRENNUNGactivating group such as chlorine or an electron-withdrawing
group such as nitro induced low to moderate yields (en-
tries 7, 8, and 13). Moreover, in the latter case, the corre-
sponding
debrominated
benzamide
was
isolated
(entry 13).[11]
The reactions were carried out using different Pd com-
plexes (Pd0 and PdII). The results were found very similar,
regardless of the Pd source.[6]
Table 1. Reaction scope.
Product, yield [%][a]
Substrate
Substituents
in DMF
in dioxane
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1 f
1g
1h
1i
R=Bn; R1 =R2 =H
2a, 55
2b, 88
2c, 91
2d, 71
2e, 80
2 f, 99
2g, 54
2h, 46
2i, 90
2j, 55
2k, 80
2l, 95
3a, 49
3b, 63
3c, 80
3d, 48
3e, 82
3 f, 80
3g, 43
3h, 61
3i, 80
Table 2. Role of the base.[a]
R=Bn; R1 =R2 =OCH3
R=Bn; R1, R2 =OCH2O
R=PMB; R1 =R2 =H
R=PMB; R1 =R2 =OCH3
R=PMB; R1, R2 =OCH2O
R=Bn; R1 =H; R2 =Cl
R=PMB; R1 =H; R2 =Cl
R=CH3; R1 =R2 =H
Product (global yields [%]/selectivity)
[b]
1j
1k
1l
R=allyl; R1 =R2 =H
–
–
–
Base
in dioxane
in THF
in DMF
R=allyl; R1 =R2 =OCH3
R=allyl; R1, R2 =OCH2O
R=PMB; R1 =H; R2 =NO2
[b]
[b]
1
2
3
4
no base
Na2CO3
K2CO3
no reaction
3a (traces)
3a (49)
no reaction
3a (86)
3a/2a (56/1:1.4)
2a (90)
no reaction
3a/2a (64/1:3.3)
2a (55)
[c]
[d]
1m
–
–
[a] Reaction conditions: [PdCl2ACHTUNRGTNEUNG(PPh3)2] (5 mol%), K2CO3 (3 equiv), o-
Cs2CO3
3a/2a (69/1.5:1)
2a (80)
bromobenzamide (1 equiv), DMF or 1,4-dioxane (20 mL) at 155 or
1058C, respectively.[b] E/Z isomerization of the double bond of 1j–l was
observed. [c] The debrominated amide was isolated from the reaction
mixture. [d] p-Methoxybenzaldehyde was isolated as the major product.
[a] Reaction conditions: [PdCl2ACHTUNRGTNEUNG(PPh3)2] (5 mol%), K2CO3 (3 equiv), o-
bromobenzamide 1a (1 equiv), dioxane, THF or DMF (20 mL) at 100,
60, or 1508C, respectively.
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Chem. Eur. J. 2011, 17, 12809 – 12819

Synthesis of Phenanthridinones
FULL PAPER
From these results and previous observations,[7a,b,13] over-
lapping catalytic cycles were initially proposed (Scheme 2).[6]
After oxidative addition of the in situ generated Pd0 species
attempts to detect the reaction intermediates by means of
NMR and ESI-MS spectroscopy. Toward this end, the re-
AHCTUNGTREGaNNUN ctions were directly performed in an NMR spectroscopy
2
À
into the C
G
tube and heated at 1208C for [D7]DMF, or 908C for [D8]1,4-
dioxane within the NMR spectrometer (Scheme 3).[21] Free
induction decay (FID) acquisitions were achieved every
30 min. When a significant modification was observed by
1H NMR spectroscopy, an aliquot of the reaction mixture
was analyzed by ESI-MS. Benzamide 1 f was selected for
these experiments because it reacts in high yields (see
Table 1) and displays structural probes such as the methyl-
sponding PdII palladacycle 4.[14] Then, oxidative addition of
a second o-bromobenzamide unit occurred to generate a
transient high valent PdIV complex 5.[15] The latter could fur-
nish, after reductive elimination, the corresponding biaryl–
PdII intermediate 6. Consequently, depending on the re-
ACHTUNGTRENNUNGaction medium, two different pathways can be envisaged for
the intramolecular N CACTHNUTRGNEUNG
(sp2) bond formation: 1) in a dissoci-
À
ating medium, ligand exchange between bromine and car-
bonate occurs, followed by an ipso substitution and elimina-
tion of an isocyanate unit; 2) in a weakly dissociating
medium, a direct arylation leads to the formation of tricycle
3.
enedioxy moiety and the PMB CH2 group.[22]
ACHTUNGTRENNUNG
Scheme 3. NMR spectroscopy and ESI-MS monitoring of the transforma-
tion of 1 f.
Reaction in [D7]DMF: The reaction was first carried out
with an excess amount of Pd catalyst (1.2 equiv of [PdCl2-
AHCTUNTGRENGUN(N PPh3)2]). In the absence of base, no reaction occurred, as
shown previously (Table 2, entry 1). The signals that corre-
1
sponded to 1 f were clearly observed in the H NMR spec-
trum, and the baseline was straight (see the Supporting In-
formation). Immediately after addition of K2CO3 (3 equiv),
the baseline was markedly modified, thus demonstrating the
crucial role of the base in the generation of Pd0 species.
After one hour, signals attributable to PdII intermediates
2
À
that resulted from oxidative addition into the C
bond were observed in ESI-MS(À) (Figure 1).
G
These complexes are readily identifiable by their charac-
teristic isotope pattern. In particular, cluster peaks that cor-
Scheme 2. Mechanistic rationale (ligands are omitted for clarity).
responded to [ArPdBrÀH]À and [ArPd
ACHTUNGTRENNUNG
detected (m/z 470 and 735, respectively). These complexes
were accompanied by [ArPdClÀH]À and [ArPd-
However, some events proposed in these catalytic cycles
have to be clarified. First, the formation of the biaryl axis
from a PdII palladacycle such as 4 and an arylhalide is not
well established.[16] Most commonly, the Pd0/PdII redox pair
is preferred to the PdII/PdIV one.[9,17,18] Besides, PdIII com-
plexes were recently recognized as putative intermediates in
catalysis, particularly in some Pd-catalyzed reactions previ-
ously suggested to proceed by means of PdII/PdIV redox
cycles.[19] In these cases, the addition of an oxidant such as
(PPh3)ClÀH]À species that resulted from a halogen ex-
change (m/z 426 and 688, respectively), which is a conse-
quence of the over-stoichiometric addition of [PdCl2-
AHCTUNTGRENNG(UN PPh3)2]. Observation of these insertion products is fully in
line with the expected mechanism. In ESI-MS(+), a cluster
peak attributable to palladacycle 4 (m/z 652 [M+H]+) was
detected (Figure 2). The observed isotope pattern for this
cluster matches well with its calculated one. Thus, ESI-MS
analysis supports the formation of both [ArPdIIX] and palla-
dacycle species in the reaction mixture, which are probably
in equilibrium.[23]
Evolution of the reaction shows complete consumption of
amide 1 f with exclusive formation of the dehalogenated
amide 9 (Scheme 4). Neither biaryl nor tricycle were ob-
served in mass spectroscopy or isolated after chromatogra-
phy.
PhI
existence of two reaction pathways according to the medium
ACHTUNGTRENNUNG
(OAc)2 proved necessary.[20] Secondly, the possible co-
ACHTUNGTRENNUNG
should be explored. Lastly, the exact implication of the base
in these processes has to be rationalized.
Mechanistic investigations—NMR spectroscopy and mass
spectrometry (ESI-MS) monitoring: To gain further insights
into the mechanism of these reactions, we have made some
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F.-H. Porꢀe, V. Gandon et al.
(Scheme 5). However, this pro-
cess was not observed here,
which indicates that the trans-
metalation step between two
PdII species is unlikely to be in-
volved in the formation of the
2
C
(sp ) C
(sp2) bond in these
À
domino reactions. Moreover,
under the conditions of cataly-
sis, such a step may not be fast
enough to compete efficiently
with the oxidative addition of
an aryl halide unit into the PdII
palladacycle, which is con-
trolled by the concentration of
1, the latter being much higher
than that of the catalyst. If
Figure 1. ESI-MS(À) spectrum after one hour ([D7]DMF).
II
II
À
there is no Pd Pd transmeta-
lation process, the formation of
a transient PdIV intermediate
should be considered.[24] Never-
theless, it is not possible at this
stage to specify whether inser-
tion of a second benzamide unit
occurs in a PdII palladacycle or
an Ar-PdII-X species.
We next carried out the re-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
was actually higher than the
quantities used in the reaction
(20 versus 5 mol%), yet this
feature proved necessary to ob-
serve the formation of inter-
mediates by spectroscopy. The
1H NMR spectroscopic kinetic
profile of the reaction is depict-
Figure 2. ESI-MS (+) spectrum after one hour ([D7]DMF).
ed in Figure 3.
Consumption of amide 1 f is
correlated to the formation of tricycle 2 f. One hour after
the beginning of the reaction, the ESI-MS(+) spectrum
showed a cluster peak attributable to 1 f (m/z 402/404
[M+K]+) and two characteristic cluster peaks assigned to
phosphinopalladacycle 4 (m/z 690 [M+K]+ and m/z 652
[M+H]+) (Figure 4). Moreover, a new interesting peak was
detected at m/z 607, attributable to an uncyclized biaryl de-
rivative (m/z calcd 607 [M+K]+). This observation also
agrees with the proposed mechanism (Scheme 2). Indeed,
Scheme 4. Pd-mediated dehalogenation of 1 f.
This result is essential when considering the mechanism
proposed in the literature for the formation of C
2
2
À
À
(sp ) C-
after oxidative addition into the C
major step of the process is the formation of the C
G
2
A
involves two PdII species has been postulated.[9] However,
this mechanism involves the interaction of two different or-
ganometallic species present at very low concentrations
under the conditions of a catalytic reaction. In the present
case, a large amount of Ar-PdII-X and PdII palladacycle was
formed in the reaction medium, thereby allowing a high
(sp2) bond. Unfortunately, the corresponding biaryl–PdII in-
ACHTUNGTRENNUNG
termediate 6 was not observed by ESI-MS.[25] This is proba-
II
bly due to the sensitivity of the N Pd bond of this inter-
mediate, which precludes its detection. Thus only the organ-
ic fragment at m/z 607 appears. After 6 h, the 1H NMR spec-
trum clearly indicated that tricycle 2 f was accumulating in
the suspension, in correlation with the consumption of the
II
II
À
probability for
a
Pd Pd transmetalation to occur
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Synthesis of Phenanthridinones
FULL PAPER
Figure 5. 1H NMR spectrum after 6 h ([D7]DMF): PMB-CH2 ( ) and
&
*
methylenedioxy ( ) signals of phenanthridinone 2 f.
starting amide 1 f (Figure 5).[26] In ESI-MS(À) a cluster peak
attributable to an ArPdIIBr intermediate was observed (m/z
470). In ESI-MS(+) the cluster peak that corresponded to
2c (m/z 442 [M+K+]) was clearly detected accompanied by
the signal of the biaryl intermediate (m/z 607 [M+K+]) and
traces of the palladacycle 4 (m/z 690 [M+K+]) (Figure 6).
From these experimental results, it can be deduced that
2
À
after initial oxidative insertion into the C
G
formation of the biaryl intermediate constitutes the second
major step of this catalytic process. Tricycle 2 f is the end
product of the reaction.
Scheme 5. Transmetalation versus oxidative addition pathways.
Reaction in [D8]1,4-dioxane: The reaction was carried out
with 0.2 equiv of [PdCl2ACHTNUTRGNE(NUG PPh3)2]. The same type of kinetic
profile was observed (see the Supporting Information). As
previously noted, the reaction started immediately after in-
1
troduction of the alkaline agent. After one hour, H NMR
spectroscopic signals that correspond to phenanthridinone
3 f were observed, thus indicating that the reaction had
started (Figure 7). In ESI-MS(+) four species were detected
after 6 h: amide 1 f (m/z 386, 388 and 402, 404, [M+Na]+
and [M+K]+, respectively); palladacycle 4; the previously
observed uncyclized biaryl ligand of 6 (m/z 591 and m/z 607,
[M+Na]+ and [M+K]+, respectively); and tricycle 3 f (m/z
389 and m/z 605, [M+Na]+
Figure 3. Reaction in [D7]DMF (1H monitoring).
and [M+K]+, respectively)
(Figure 8).
Moreover
ESI-
MS(À) spectrum provided evi-
dence for the formation of ArP-
dIIX species (see the Supporting
Information).
Because the same intermedi-
ates are formed in both
[D7]DMF and [D8]1,4-dioxane,
the initial hypothesis of two
overlapped
catalytic
cycles
seems plausible. From the re-
sults presented in Table 2, the
discrimination between one
pathway over the other relies
on the participation of the car-
bonate base in the reaction
Figure 4. ESI-MS (+) spectrum after one hour ([D7]DMF).
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F.-H. Porꢀe, V. Gandon et al.
mechanism. Our initial hypoth-
esis was based on a Br–carbon-
ate exchange on the biaryl in-
termediate 6; such an exchange
could only be hypothesized in a
dissociating medium in which
sufficient amount of carbonate
base is dissolved. The presumed
role of the base is then to stabi-
lize the biaryl intermediate in
such a conformation that the
two carboxamide functionalities
are close enough to react. The
ipso substitution could then
occur to furnish the correspond-
ing phenanthridinone 2. To vali-
date this hypothesis, two com-
plementary experiments were
carried out.
Figure 6. ESI-MS(+) spectrum after 6 h ([D7]DMF).
Additional experiments on the role of the carbonate base:
In some direct arylation reactions, the dramatic influence of
the carbonate base was rationalized by the concerted metal-
ation–deprotonation pathway (CMD pathway).[27] However,
studies aimed at determining the solubility in the medium
indicated that very little carbonate base was actually dis-
solved.[11] To increase the amount of dissolved base, the in-
fluence of the addition of several carboxylic acids was stud-
ied. After optimization, the best yields were reached upon
addition of 30 mol% of pivalic acid.[28] Therefore, it was de-
cided to submit amide 1c to the Pd-catalyzed reaction con-
ditions in 1,4-dioxane in the presence of this additive. The
replacement of the carbonate by a more soluble carboxylate
should allow, in a weakly dissociating medium, the coexis-
tence of the two reaction pathways as previously observed
in moderately polar THF (Table 2, entry 3). As expected,
whereas a total selectivity was observed in 1,4-dioxane
(Table 2, entry 3), the addition of pivalic acid led to a mix-
ture of the two tricycles 2 f and
Figure 7. 1H NMR spectra in [D8]1,4-dioxane: Evolution of the PMB-
&
*
*
) signals: amide 1 f (full symbols),
CH2 ( , &) and methylenedioxy (
,
~
.
1-carboxamide phenanthridinone 3 f (empty symbols), intermediate
3 f (Scheme 6). The selectivity
observed in this case is in favor
of 2 f. As expected, this result
confirms the crucial role of the
carboxylate moiety in the reac-
tion pathway for the formation
of 2 f.
If the biaryl–Pd intermediate
conformation could be blocked
in such a way that the two car-
boxamide functions are close
enough to react together and
furnish phenanthridinones 2,
then we could confirm our
mechanistic
hypothesis.
N-
PMB-3-methyl-2-bromobenza-
mide 10 was selected for this
purpose. The steric hindrance
Figure 8. ESI-MS(+) spectrum after 6 h ([D8]1,4-dioxane).
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Chem. Eur. J. 2011, 17, 12809 – 12819

Synthesis of Phenanthridinones
FULL PAPER
DFT computations: To support some of the mechanistic
conclusions reached so far, DFT computations were carried
out. All calculations were performed with the Gaussian
series of programs.[29] The geometry optimizations and ther-
modynamic corrections were carried out with hybrid density
functional theory (B3LYP) with the 6-31G(d) (N, O, P, C,
H) and LANL2DZ+ECP basis sets (Pd, Br). Solvation cor-
rections for DMF and 1,4-dioxane were computed by the
polarizable continuum model (PCM) method as implement-
ed in Gaussian 09 with single points at the SDD(Pd)/6-311+
G** (other elements) level. All relative energies presented
in this paper are free energies (DGDMF; DGdioxane) in kiloca-
Scheme 6. Addition of soluble carboxylate in a weakly polar solvent.
of the methyl group should stabilize the biaryl intermediate
by slowing down or preventing the rotation around the C-
2
À
À
(sp ) C
(sp2) biaryl bond. Moreover, since the 3-position is
lories per mole. To save computer time, PH3 and HCO3
2À [27b]
occupied by a methyl group, the formation of the 1-carboxa-
mide phenanthridinone structure should not be possible in
1,4-dioxane and the reaction should stop at the biaryl inter-
mediate stage or follow the pathway observed in a dissociat-
ing medium. The reaction was carried out in DMF and 1,4-
dioxane (Scheme 7). In both cases, the selectivity was total
were used instead of PPh3 and CO3
.
2-Bromo-N-meth-
ylbenzamide was chosen as model benzamide. This com-
pound was actually tested experimentally (compound 1i;
see Table 1). PdCAHTUNGTRENN(UGN PH3)2 was used as active species instead of
Pd(PPh3)2. This simplification proved acceptable in many
AHCTUNGTRENNUNG
cases.[30] Even after this truncation, because of the size of
the starting system (57 atoms with PH3, 117 with PPh3), we
did not attempt to address all mechanistic issues. In particu-
lar, the role of the cation in M2CO3 (M=Na, K, Cs) was not
studied. We rather focused on the implication of the anion
within the catalytic cycle, and on the potential intervention
of PdIV species.
We first computed the oxidative addition steps
(Scheme 8). Among various options, the lowest-lying transi-
tion state that could be found was TSB–C, which connects the
T-shaped ArPdIIBr species C with the Pd0 complex B in
À
which the (PH3)Pd fragment is coordinated to the C Br
bond and the carbonyl functionality of the starting benz-
AHCTUNGTREGaNNNU mide. As expected for reactions that require elevated tem-
peratures, the free energies of activation of this process are
quite high, 23–25 kcalmolÀ1 depending on the solvent, and,
as shown later, represent the highest computed values of the
catalytic cycle.
Rotation of the pendant amide moiety to form the
square-planar PdII palladacycle D is kinetically facile and
appreciably exothermic in both solvents.[31] Elimination of
HBr could be modeled, yet at a high energetic cost of about
Scheme 7. Sterically controlled reversal of selectivity.
and phenanthridinone 11 was isolated as the sole product.
This observation indicates that the selectivity in 1,4-dioxane
is reversed with bulky substituents and confirms the role of
the carbonate base in the stabilization of the biaryl–Pd inter-
mediate in a dissociating medium.
Scheme 8. Oxidative addition steps leading to a PdIV intermediate.
Chem. Eur. J. 2011, 17, 12809 – 12819
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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12815

F.-H. Porꢀe, V. Gandon et al.
40 kcalmolÀ1 from D. Therefore, BrÀ was exchanged by
À
HCO3 prior to deprotonation.[32] Although the substitution
had little impact on the relative free energy of the system, it
had a dramatic influence on the deprotonation barrier to
become around 7 kcalmolÀ1 from E. In the resulting inter-
mediate F, H2CO3 remains hydrogen-bonded to the nitrogen
atom and O-coordinated to palladium.
To reach a PdIV intermediate, a second equivalent of
benzACHTUNGTRENNUNGamide was introduced in the coordination sphere of the
metal. For that matter, PH3 and H2CO3 were removed
before optimization. Various square-planar isomers such as
G in which Br and one heteroatom of the amide fragment
coordinates palladium converged. Complex G, in which the
carbonyl group is trans to N (O-Pd-N arrangement), was
found thermodynamically favored over the others. Besides,
À
oxidative addition into the C Br bond proved also kinetical-
ly more attainable from G.[33] The resulting pentacoordinat-
ed PdIV complex H (Figure 9) is also the most stable of the
possible isomers. Overall, the formation of the PdIV species
H from the starting system is moderately exothermic in
DMF, and moderately endothermic in 1,4-dioxane. It is
made through accessible transition states, provided a ligand
Figure 9. Optimized molecular structures for complexes H (top) and H’
(bottom); selected bond lengths in ꢃ.
exchange between BrÀ and HCO3 takes place. Saturation
9 kcalmolÀ1. The reductive elimination pathway that con-
structs the biaryl unit was investigated next (Scheme 9). It
could not be modeled from H’ but rather from H, which is
À
of the coordination sphere of the metal using PH3 to give
the octahedral species H’ is exothermic by approximately
Scheme 9. Divergent pathways to 5-methylphenanthridin-6ACTHNUTRGNEUNG(5H)-one or N,5-dimethyl-6-oxo-5,6-dihydrophenanthridine-1-carboxamide.
12816
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Chem. Eur. J. 2011, 17, 12809 – 12819

Synthesis of Phenanthridinones
FULL PAPER
consistent with the literature.[34] It requires around 5 kcal
molÀ1 of free energy of activation and leads, with the libera-
tion of around 15 kcalmolÀ1, to the h2-arene PdII complex I,
cornerstone of the two overlapped catalytic cycles postulat-
ed in Scheme 2. Elimination of methylisocyanate converts I
into the ArPdIIBr species J (path i in Scheme 9) by means of
a quite easily accessible transition state and with little influ-
ence on the relative energy of the system. On the other
hand, rotation of the amide fragment to reach the 14-elec-
tron TSJ–K requires more than 20 kcalmolÀ1 and provides
the less stable intermediate K with a trans N-Pd-N arrange-
ment. Again, prior to deprotonation, BrÀ was substituted by
discrepancy between the experimental and computational
studies to the fact that the exact nature of the medium, in-
cluding the presence of alkali metals, was not fully taken
into account. Geometry optimizations in solution could
solve this problem but we were unable to carry them out.
Summary of the mechanistic data and proposed catalytic
cycle: From these results, a new catalytic cycle can be pro-
posed to explain the selective formation of 2 and 3. The first
steps are common and involve two successive oxidative ad-
ditions of an o-bromobenzamide unit into a Pd species. A
PdII intermediate is generated by oxidative addition into the
À
2
À
HCO3 , thereby resulting in the more stable complex L
C
G
from which H2CO3 elimination was found kinetically
straightforward (ꢀ3 kcalmolÀ1 of free energy of activa-
tion).[32] Reductive elimination to give the phenanthridinone
framework could be modeled through the quite high-lying
TSM–N (18–20 kcalmolÀ1 of free energy of activation). Final-
Ar-PdII-Br form and a palladacyclic form. Then oxidative
addition of a second o-bromobenzamide unit occurs to give
a transient PdIV intermediate complex, which leads to a
biaryl-PdII-Br species after reductive elimination. Then de-
pending on the solvent polarity, two intramolecular path-
À
ly, regeneration of the active species Pd
G
ways occur. In a dissociating medium (DMF), Br CO3 ex-
final product in a strongly exothermic fashion, more than
60 kcalmolÀ1 lower than the starting system. Thus, from a
PdIV intermediate, it was possible to compute a pathway
that led to the phenanthridinone core. The highest-lying
transition states of this sequence correspond to the reductive
change allows the rotation and the stabilization of subunit
A. Then elimination of isocyanate RNCO (or RNH2 +CO2)
gives complex 7, which releases tricycle 2 after reductive
elimination. In a weakly dissociating medium, no carbon-
ate–bromide exchange occurs. A PdII direct N-arylation can
proceed to give compound 3 by means of an SEAr-type pro-
cess. The SEAr pathway is favored in this latter step because
the base is not involved in the cyclization, which rules out
the CMD pathway.
À
elimination that forms the C N bond. The ligand exchange
between nitrogen and oxygen by rotation of the amide
moiety is also difficult to achieve, yet those barriers are not
inaccessible under thermal conditions. We then sought a
pathway to 1-carboxamide phenanthridinones from I (path ii
in Scheme 9). An electrophilic aromatic substitution (SEAr)
mechanism could be computed. This implied first a quite
slow and endothermic ligand exchange between the carbon-
yl functionality and one aromatic ring to give the h1-benzene
complex P, to which PH3 was added to complete to coordi-
nation sphere of palladium. In the end, the resulting Whe-
land intermediate Q is more stable than I by 3–5 kcalmolÀ1.
To achieve the subsequent hydrogen elimination, the substi-
Conclusion
In summary, we have described here simple and efficient re-
action conditions to access selectively two differently substi-
tuted phenanthridinone frameworks,
2 and 3, from a
common o-bromobenzamide precursor in a Pd-catalyzed
one-step sequence. The outcome of these domino processes
is strongly influenced by the nature of the substituents on
the aromatic core, and the best yields are reached in the
presence of electron-donating groups. Studies on the re-
tution of BrÀ by HCO3 to give R was found to be more ac-
À
cessible prior to deprotonation and reductive elimination
[35]
À
that creates the C N bond. The transition state that cor-
responds to the latter elementary step is the highest-lying
one of path ii in both solvents (ꢀ20 kcalmolÀ1 of energy of
activation), yet this transformation is strongly exothermic by
approximately 30 kcalmolÀ1. Overall, after regeneration of
the active species of the catalytic cycle, liberation of 52–
59 kcalmolÀ1 relative to the starting system is calculated.
Thus, as in path i, although the transition states that corre-
spond to the ligand exchange and the reductive elimination
are quite high-lying, they should nevertheless be accessible
under the experimental conditions used. The computations
of a viable pathway toward 1-carboxamide phenanthridi-
nones from I, and therefore from the PdIV intermediate H,
supports the mechanistic rationale depicted in Scheme 2
that involves two overlapped catalytic cycles that share 4, 5,
and 6 (i.e., F, H, and I). We realize, however, that the com-
puted energies do not reproduce the clear experimental
switchover between DMF and 1,4-dioxane. We attribute this
ACHTUNGTRENaNUGN ction parameters highlight the dramatic influence of the
carbonate base/solvent alliance in the selective formation of
2 or 3. Thus, in a weakly dissociating medium 1-carboxamide
phenanthridinones 3 are preferentially formed, and con-
versely, formation of phenanthridinones 2 is favored in a dis-
sociating medium. Addition of a soluble carboxylate or the
use of a benzamide that bears bulky substituents leads to a
reversal of the selectivity observed in a weakly dissociating
medium, thus outlining the crucial role of the alkaline agent
in the formation of 3. Mechanistic studies allowed to charac-
terize, by ESI-MS, the PdII palladacycle 4 and biaryl species
as common intermediates for these two domino processes.
Furthermore, the experimental data strongly support the C-
2
À
(sp ) C
(sp2) bond formation by generation of a transient
PdIV intermediate, this rationale being also corroborated by
DFT calculations. A general catalytic cycle is proposed to
account for these observations. Overall, we believe that the
Chem. Eur. J. 2011, 17, 12809 – 12819
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12817

F.-H. Porꢀe, V. Gandon et al.
À
2.49 (s, 3H; CH3), 2.47 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3):
d=162.4 (C, C=O), 158.6 (C, PMB), 137.8 (C, C1), 136.5 (C, C4a), 135.3
(C, C10), 134.4 (CH, C9), 133.8 (C, C10a), 129.0 (C, C6a), 128.4 (C, PMB),
127.9 (2CH, PMB), 127.9 (CH, C3), 127.1 (CH, C8), 125.7 (CH, C7), 124.9
(CH, C4), 119.9 (C, C10b), 114.1 (2CH, PMB), 112.0 (CH, C2), 55.3 (CH3,
OCH3), 46.1 (CH2, PMB), 22.2 (CH3, C1), 21.8 ppm (CH3, C10); MS
(ESI): m/z calcd: 366 [M+Na]+; HRMS (ESI): m/z calcd for
C23H21NNaO2: 366.1470 [M+Na]+; found: 366.1474.
formation of aryl aryl bonds from aryl halides by means of
PdIV intermediates should also be considered in other relat-
ed Pd-catalyzed processes.
Experimental Section
1H NMR spectroscopy and mass spectrometry (ESI-MS) monitoring: In
an NMR spectroscopy tube, 1 f (10 mg, 0,028 mmol, 1 equiv) and [Pd-
AHCTUNGTRENN(GNU PPh3)2Cl2] (1.2 or 0.2 equiv) were successively introduced. The tube was
General procedure for the domino reaction: K2CO3 (3 equiv) and [Pd-
ACHTUNGTRENNUNG(PPh3)2Cl2] (0.05 equiv) were successively added to a solution of the
amide (1 equiv) in anhydrous DMF or 1,4-dioxane (20 mL). The resulting
suspension was purged three times with argon then heated at reflux in a
preheated oil bath at 1558C for 3 h (DMF) or at 1058C for 24 h (1,4-di-
oxane). The reaction mixture was then cooled to RT, and the solvent was
removed in vacuo. H2O was added to the residue and extracted with
CH2Cl2 (3 times). The combined organic extracts were washed with
brine, dried over MgSO4, filtered, and evaporated. The residue was puri-
fied by column chromatography on silica gel to afford the corresponding
phenanthridinone.
sealed by an appropriate septum and purged with argon (3 times). Then
[D7]DMF or [D8]1,4-dioxane (0.7 mL) was added, and the resulting solu-
tion was degassed. The tube was introduced into the spectrometer and
the probe was warmed at 1208C ([D7]DMF) or 908C ([D8]1,4-dioxane).
Then a first FID acquisition was carried out. The solution was cooled to
RT, and K2CO3 (12 mg, 3 equiv) was introduced. The resulting mixture
was homogenized and an aliquot was analyzed by ESI-MS (t=0). The
tube was then placed into the NMR spectrometer and heated at 120 or
908C. FID acquisitions were achieved every 30 min. When a significant
modification was observed by 1H NMR spectroscopy, an aliquot of the
reaction mixture was analyzed by ESI-MS. The 1H NMR spectroscopic
monitoring is reported in Tables 1 and 2 for [D7]DMF and [D8]1,4-diox-
ane, respectively, as the percentage composition of amide 1 f and tricycles
2 f or 3 f based on the methylenedioxy moieties and PMB CH2-group sig-
nals. ESI mass spectra were performed in both positive and negative
modes at 30 and 60 V from the aliquot taken beforehand and diluted in
acetonitrile.
2-Bromo-3-methyl-para-methoxybenzylamide (10): According to the gen-
eral procedure, 10 (451 mg, 1.35 mmol, 58% yield) was obtained from 2-
bromo-3-methylbenzoic acid (500 mg, 2.33 mmol) as
a white solid.
1H NMR (300 MHz, CDCl3): d=7.31 (d, J=8.6 Hz, 2H; PMB), 7.28–
7.18 (m, 3H; H4, H5 and H6), 6.88 (d, J=8.6 Hz, 2H; PMB), 6.17 (brs,
1H; NH), 4.56 (d, J=5.6 Hz, 2H; CH2, PMB), 3.81 (s, 3H; 2OCH3),
3.43 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3): d=168.4 (C, C=O),
159.1 (C, PMB), 139.3 (C, C3), 139.0 (C, C1), 131.8 (CH, C4), 129.8 (C,
PMB), 129.4 (2CH, PMB), 127.3 (CH, C5), 126.3 (CH, C6), 121.7 (C, C2),
114.1 (2CH, PMB), 56.3 (CH3, OCH3, PMB), 43.6 (CH2, PMB), 23.6 ppm
(CH3); MS (ESI): m/z calcd: 356 [M+Na]+; found: 358; HRMS (ESI):
m/z calcd for C16H16BrNNaO2: 356.0262 [M+Na]+; found: 356.0271.
5-Methylphenanthridin-6(5H)-one-1-methylcarboxamide (3i): According
to the general procedure, 3i (16 mg, 0.06 mmol, 76% yield) was obtained
Acknowledgements
from 1i (59 mg, 0.19 mmol) as
a
white solid. 1H NMR (300 MHz,
CDCl3): d=8.19–8.17 (m, 2H; H7 and H4), 8.07 (d, J=8.1 Hz, 1H; H10),
7.76 (td, J=7.5 and 1.2 Hz, 1H; H9), 7.57 (td, J=7.5, 1.2 Hz, 1H; H8),
We are deeply grateful to Dr. A. Jutand (Ecole Normale Supꢀrieure, Dꢀ-
partement de Chimie UMR CNRS-ENS-UPMC 8640) for her constant
support and her helpful discussions. Calculations were performed at
CRIHAN, plan interrꢀgional du bassin parisien (project 2006-013), and
at the CRI of UPS.
3
5
7.48 (t, J=7.3 Hz, 2H; H2 and H ), 6.62 (s, 1H; NH), 3.72 (s, 3H; N
À
CH3), 3.07 ppm (d, J=4.8 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3):
d=170.7 (C, C1C=O), 162.8 (C, C6 =O), 133.1 (C), 132.6 (CH, C9), 130.3
(CH, C2), 129.5 (C), 128.3 (CH, C7), 128.3 (CH, C8), 127.0 (C), 124.9 (C),
124.6 (CH, C4), 122.3 (CH, C3), 121.7 (CH, C10), 121.0 (C), 36.0 (CH3,
5
À
À
N
CH3), 27.1 ppm (CH3, N CH3); IR (NaCl, film): n˜ =3292, 3072, 1650,
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729, 666 cmÀ1; UV/Vis (MeOH): lmax (loge)=218 (4.7), 228 (4.5), 263 nm
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J=7.5 Hz, 1H; H9), 7.28 (t, J=6.8 Hz, 1H; H3), 7.23 (d, J=8.7 Hz, 2H;
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12818
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Chem. Eur. J. 2011, 17, 12809 – 12819

Synthesis of Phenanthridinones
FULL PAPER
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Inc., Wallingford CT, 2009.
[11] See the Supporting Information.
[12] A comparative solubility study of some carbonate bases has been
performed by Chemetall GmbH and is available at Chemetall.com
(released on February 16, 2011). For a discussion on the solubility of
carbonate bases in organic solvents, see also L. C. Campeau, M. Par-
isien, A. Jean, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581–590.
[13] M. Catellani, E. Motti, N. della Ca, R. Ferraccioli, Eur. J. Org.
Chem. 2007, 4153–4165.
[14] For a discussion on palladacycle and Pd nanoparticles see: V. Farina,
Adv. Synth. Catal. 2004, 346, 1553; J. G. deVries, Dalton Trans. 2006,
421. See also ref. [23].
[15] Oxidative addition of organic halides into PdII species to generate
PdIV complexes is well known. See: a) A. J. Canty, Acc. Chem. Res.
1992, 25, 83–90; b) P. Sehnal, R. J. K. Taylor, I. J. S. Fairlamb, Chem.
Rev. 2010, 110, 824–889, and references cited therein; c) T. W.
Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147–1169, and referen-
ces cited therein.
[30] See inter alia Refs. [9a] and [27b].
[31] The O-bonded isomer is 1.5 kcalmolÀ1 less stable than D.
[32] Manifold efforts failed to locate an assisted intermolecular deproto-
nation pathway, as described in Ref. [27b].
[16] Formation of such PdIV species has been proposed by Catellani and
Dyker but no intermediate was isolated nor characterized. See
Refs. [5b], [6a] and see also: a) M. Catellani, Synlett 2003, 0298–
0313; b) G. Dyker, Angew. Chem. 1992, 104, 1079–1081; Angew.
Chem. Int. Ed. Engl. 1992, 31, 1023–1025.
[17] J. Hassan, V. Penalva, L. Lavenot, C. Gozzi, M. Lemaire, Tetrahe-
dron 1998, 54, 13793–13804.
[18] A. J. Mota, A. Dedieu, C. Bour, J. Suffert, J. Am. Chem. Soc. 2005,
127, 7171–7182.
[19] a) D. C. Powers, M. A. L. Geibel, J. E. M. N. Klein, T. Ritter, J. Am.
Chem. Soc. 2009, 131, 17050–17051; b) D. C. Powers, D. Benitez, E.
Tkatchouk, W. A. Goddard III, T. Ritter, J. Am. Chem. Soc. 2010,
132, 14092–14103.
[33] PH3 can be kept in the oxidative addition transition state, yet it lies
9 kcalmolÀ1 higher than TSG–H
.
[34] It is noteworthy that although hexacoordinated PdIV complexes are
more common that pentacoordinated ones, the latter are more
likely to give reductive elimination products, see: a) T. Furuya, T.
Ritter, J. Am. Chem. Soc. 2008, 130, 10060–10061; b) P. K. Byers,
A. J. Canty, M. Crespo, R. J. Puddephat, J. D. Scott, Organometallics
1988, 7, 1363–1367.
[35] An unassisted SEAr mechanism would involve HBr elimination
without intervention of the base. The computed free energy of acti-
vation of such a process is prohibitively high (ꢀ40 kcalmolÀ1).
[20] To the best of our knowledge, there is no report, to date, that relates
2
À
the formation of a C
(sp ) C
(sp2) biaryl bond through a PdIII inter-
mediate (monomeric or bimetallic species).
[21] See the Supporting Information for details on the experimental pro-
cedure.
Received: May 3, 2011
Published online: September 27, 2011
Chem. Eur. J. 2011, 17, 12809 – 12819
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12819