Diastereoselective synthesis of Dibenzoazepines through Chelation on Palladium(IV) intermediates

Article abstract of DOI:10.1021/ol403525c

Joint palladium/norbornene organometallic catalysis allows for straightforward access to dibenzo[c,e]azepines. These synthetically challenging polycyclic frameworks form in one pot via a three-component coupling of an aryl iodide, a bromobenzylamine, and an olefin. A key, atroposelective aryl-aryl coupling from chelated Pd(IV) intermediates dictates the outcome of the cascade. DFT modeling sheds light on the complex mechanism that allows the complete diasteroselectivity to be observed.

Full text of DOI:10.1021/ol403525c

Letter
pubs.acs.org/OrgLett
Diastereoselective Synthesis of Dibenzoazepines through Chelation
on Palladium(IV) Intermediates
Vanessa Narbonne,† Pascal Retailleau,† Giovanni Maestri,*,† and Max Malacria*,†,‡
†Institut de Chimie des Substances Naturelles, ICNS-CNRS, UPR 2301, Gif sur Yvette Cedex 91198, France
‡Institut Parisien de Chimie Molec
́ ́
ulaire, UPMC Universite Paris 06, IPCM-UMR 7201, Paris Cedex 75005, France
S
* Supporting Information
ABSTRACT: Joint palladium/norbornene organometallic catalysis allows for
straightforward access to dibenzo[c,e]azepines. These synthetically challenging
polycyclic frameworks form in one pot via a three-component coupling of an
aryl iodide, a bromobenzylamine, and an olefin. A key, atroposelective aryl−aryl
coupling from chelated Pd(IV) intermediates dictates the outcome of the
cascade. DFT modeling sheds light on the complex mechanism that allows the
complete diasteroselectivity to be observed.
alladium catalysis is a powerful synthetic tool for the
synthesis of complex nitrogen-containing polycyclic frame-
properties of chelation5b,c on in situ generated Pd(IV)
intermediates. Previous studies have revealed that a suitable
chelating group can control the chemoselectivity of Pd(IV)
reductive elimination (Scheme 2, way a).2c Herein we used
P
works from readily available precursors.1 A broad domain of
applications has indeed stimulated the development of a variety
of methods to create 5- and 6-membered (poly)heterocycles.
Sequences affording the 7-membered azepine ring are far less
developed.2 Beside their renowned biological properties,3
dibenzo[c,e]azepines in particular are at the heart of versatile
organocatalysts and ligands (Scheme 1).4 Their preparation
Scheme 2. Pd(IV) Strategies to Dibenzoazepines
Scheme 1. Applications of Dibenzo[c,e]azepines
chelation as a relay to induce an atroposelective aryl−aryl
coupling and then prevent rotation around the biaryl axis until a
Heck reaction occurred, paving the way for a stereospecific aza-
Michael cyclization that eventually delivered target azepines
(Scheme 2, way b).
In an initial experiment (Table 1, entry 1), iodotoluene (1.1
equiv) reacted with bromobenzylamine and acrylonitrile (4
equiv) in the presence of 5 mol % of Pd(OAc)2, 10 mol % of
trifurylphosphine, and 60 mol % of norbornene in DMF at 130
°C under argon for 24 h. Azepine 1 was isolated (in a low 5%
yield) together with its imino derivative 2 formed via retro-
Mannich elimination of acetonitrile (6%, vide infra) and 8% of
3, the analogue of 1 N-alkylated by a second olefin molecule.
requires multistep syntheses, and access to functionalized
frameworks is often costly. This affects the readily accessible
pool of structures and thus ultimately limits the development of
novel ligands, organocatalysts, and bioactive molecules
incorporating this core.
The association of palladium and norbonene forms a unique
dual organometallic catalytic system able to deliver complex
polycyclic structures from simple precursors. Its versatility has
led to numerous synthetic applications in the last 20 years,
mainly reported by the group of Catellani and Lautens.5,6
We present herein the first catalytic method for the
diastereoselective one-pot synthesis of dibenzo[c,e]azepines
from commercially available precursors by exploiting the
Received: December 11, 2013
Published: December 31, 2013
© 2013 American Chemical Society
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Letter
a
alkylated product 3h in 50% yield. In all of these reactions,
minor amounts of 2 and 3 were invariably observed (less than
10% each).
Table 1. Optimization of Reaction Conditions
By using an enolizable olefin such as methyl vinyl ketone, a
retro-Mannich reaction on 1 smoothly occurs under the
reaction conditions, selectively delivering 2 and thus off-setting
the nitrogen alkylation responsible for the formation of 3
(Figure 2). Electron-donating groups such as alkyl chains,
entry
ligand
yield of 1a (%) entry
ligand
yield of 1a (%)
b,c
1
2
3
P(2-furyl)3
P(O-i-Pr)3
PMe3
5
55
51
4
5
6
PEt3
62
75
65
P(i-Pr)3
P(i-Pr)3
d
a
Reaction conditions: Pd(OAc)2 5 mol %, 0.02 M, ligand 10 mol %,
norbornene 60 mol %, Ar−I 0.29 mmol, 1.1 equiv, olefin 2 equiv,
K2CO3 2.2 equiv in DMF under Ar at 130 °C for 24 h. 1H NMR yield
b
using benzoylnitromethane as internal standard. With 4 equiv of
c
d
olefin. With Cs2CO3. 2.5 mol % of Pd for 36 h.
Phosphorus ligands possessing alkyl substituents provided
better results (entries 3−5). In particular, the use of 10 mol
% of trisisopropylphosphine delivered 1a in 75% yield (entry
5). Palladium could be reduced to 2.5 mol %, although a longer
reaction time slightly favors formation of imine product 2a,
lowering the yield to 65% (entry 6). Conversion of the iodide
partner was always complete, direct Heck-type coupling with
the olefin being the most concerning side reaction. By way of
contrast, unreacted aryl bromide could be recovered at the end
of these experiments.
We tested the method toward differently substituted aryl
halides and olefins (Figure 1). Gratifyingly, product 1a could be
Figure 2. Conditions: as Figure 1, with 4 equiv of olefin for 24 h;
isolated yields on the average of at least two runs.
ethers, and amines or a fused aromatic fragment are generally
well tolerated on both halides (2a−h). Fluorinated bromides
react smoothly (2i,j), providing higher yields than a fluorine-
substituted iodide (2k, 43%). Reaction of racemic amines
affords the corresponding products 2 as a single diastereomer in
synthetically useful yields (2k−p).
Previous studies5,6 and our present DFT-based analysis
suggest that the mechanism of Scheme 3 is at work in these
sequences. Complex I forms, upon Ar−I oxidative addition and
subsequent insertion of norbornene, intermediate II. C−H
activation readily occurs in the basic environment,8 and
electron-rich metallacycle III can thus undergo a second
oxidative addition to chelated Pd(IV) complex IV.2c,5 Chemo-
selective, nonreversible sp2−sp2 coupling provides V. Nitrogen
chelation is retained and prevents rotation of the biaryl axis.
This key feature is kept in VI that forms by steric congestion-
driven extrusion of norbornene. A careful tuning of the reaction
conditions then allowed us to offset the intramolecular
Buchwald−Hartwig coupling previously exploited to synthesize
dihydrophenanthrines using these coupling partners.9 An
intermolecular Heck reaction can instead occur and generate
4.10 The relative conformation of the biaryl is responsible for
the stereoselectivity of the aza-Michael cyclization and
eventually delivers 1 as a single diastereomer. Release of the
syn-pentane steric strain in 1 could induce a retro-Mannich
reaction in the basic media leading to 2. While chelation has
been already used as a relay to induce atroposelective formation
Figure 1. Reaction conditions: as entry 5 of Table 1 for 8−16 h.
Isolated yields on average of at least two runs: (a) 1.1 equiv of olefin;
(b) 4 equiv of olefin added after full conversion.
isolated in 75% yield, after 8 h, as a single diastereoisomer.
Different donor groups, including aliphatic chains or ethers,
were tolerated by the sequence and delivered 1 in synthetically
useful yields compared to existing multistep procedures.
Electron-withdrawing groups were less tolerated on the aryl
iodide (1c, 41%) than on the bromide partner (1d, 52%). We
were delighted that the reaction of racemic bromides delivers
1e and 1f as a single diastereomer out of the four possible (the
unreacted bromide recovered at the end of these reactions did
not present any enantiomeric excess).7 Less volatile acrylates
could be used in stoichiometric amounts (1g, 32%). Further
addition of the olefin, upon full conversion, delivered N-
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Letter
equatorial ligands are displaced by the substrate, providing
square-planar complexes (S)-III and (R)-III (trimethylpho-
spine used in calculation). Oxidative addition slightly favors the
reactivity of the (S)-bromide (orange pathway, ΔΔG of −0.6
kcal/mol between the two transition states), delivering Y-
distorted, trigonal bipyramidal Pd(IV) complex (S)-IV.
Pentacoordinated high-valent palladium complexes are often
more reactive than their octahedral counterparts.5a,13
Scheme 3. Proposed Mechanistic Rationale
The subsequent reductive elimination is also easier (by 1.5
kcal/mol in ΔG). Furthermore, intermediate (S)-V is less
stable than its (R)-V diastereomer by 8.1 kcal/mol. All these
features contribute to a lower energy span for the orange
pathway over the grey one (by 8.3 kcal/mol in ΔG), and thus,
the turnover frequency of the former outpaces its peer.14 Steric
reasons are responsible for these energetic differences, as shown
by short contacts highlighted for two competing oxidative
addition transition states on III (0.29 Å longer in the favored
TS, left).
This situation is reversed for the enantiomer of complex III,
on which the (R)-bromide reacts faster instead (III′, Scheme
4). The mechanism thus resembles a parallel kinetic
Scheme 4. Parallel Kinetic Resolution of Racemic Bromides
of biaryls,11 to the very best of our knowledge this would be the
first application of this strategy in Pd(IV) sequences. Indeed,
Pd/norbornene-cocatalyzed cascades are reported to afford
products as mixture of diastereoisomers in the absence of a
chelating group on substrates.12
Among modeled pathways, most relevant mechanistic
features are highlighted hereafter with full details provided in
the Supporing Information. Formation of 1 as a single out of
four possible diastereomers employing racemic bromides relies
on discrimination in energetic barriers before the nonreversible
C−C bond formation of the Pd(IV) reductive elimination.
Figure 3 shows calculated pathways for the (R)- and (S)-
bromide on the enantiomer of the Pd(II)metallacycle III.
Lower energy intermediates from III are those in which both its
resolution15 in which each enantiomer of a racemic substrate
reacts faster with a particular enantiomer of the in situ
generated Pd(II) metallacycle. A similar outcome in Pd(IV)
sequences has not been reported yet.
Metal chelation is then retained up to the release of 4.
Indeed, both norbornene extrusion from V and the subsequent
Heck coupling on VI are more favorable pathways than the
corresponding biaryl rotations that require the release of
nitrogen coordination. This is consistent with the experimen-
tally observed diastereoselectivity, as rotation of the benzyl-
amine fragment would ultimately deliver a mixture of
diastereoisomers, observed in similar cascades employing
nonchelating halides.12 The most favorable rotation barrier is
expectedly found examining 4, which is the least sterically
hindered intermediate. Its calculated transition state is
nevertheless energy demanding (+27.6 kcal/mol in ΔG) and
easily outmatched by a base-mediated aza-Michael cyclization
(ΔG +3.9 kcal/mol), which locks the configuration of products
to prevent the formation of diastereomers.
Figure 3. Calculated pathways for the reaction of (R)- and (S)-methyl-
2-bromobenzylamine with palladacycle III.
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Letter
(b) Martins, A.; Mariampillai, B.; Lautens, M. Top. Curr. Chem. 2010,
292, 1−33.
(7) A 1:1 mixture of diastereomers was instead obtained employing
L-menthyl acrylate with an aryl iodide and either bromobenzylamine or
a substituted, racemic one. For an in-depth DFT-based rationalization,
vide infra, see the Supporting Information.
(8) (a) García-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880−
6886. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147−
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N.; Maestri, G. Coord. Chem. Rev. 2010, 254, 456−469.
(9) Maestri, G.; Larraufie, M.-H.; Derat, E.; Ollivier, C.; Fensterbank,
In summary, we have developed a one-pot catalytic method
for the synthesis of dibenzo[c,e]azepines and their imine
analogues via palladium/norbornene joint organometallic
catalysis. The complete distereoselectivity observed originates
from a chelated Pd(IV) complex via atroposelective aryl−aryl
coupling. This behavior is coupled with a parallel kinetic
resolution-like mechanism that employs racemic bromides and
exerts the same remarkable selectivity. We hope that these
findings will benefit the future design of (dia)stereoselective
Pd/norbornene arylation cascades and contribute to spreading
further the applications of dibenzo[c,e]azepines.
̂
L.; Lacote, E.; Malacria, M. Org. Lett. 2010, 12, 5692−5695.
(10) This strategy has been already adopted to synthesize
phenanthridines using protected bromoanilines: (a) Della Ca’, N.;
Motti, E.; Mega, A.; Catellani, M. Adv. Synth. Catal. 2010, 352, 1451−
1454. (b) Della Ca’, N.; Motti, E.; Catellani, M. Adv. Synth. Catal.
2008, 350, 2513−2516. However, unlike bromobenzylamines,
protected bromoanilines did not chelate Pd(IV); see ref 2c for details.
(11) Recent examples: (a) Campolo, D.; Gastaldi, S.; Roussel, C.;
Bertrand, M. P.; Nechab, M. Chem. Soc. Rev. 2013, 42, 8434−8466.
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray of 2i (CIF), detailed computational studies, experimental
procedures, and spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
́
(b) Joncour, A.; Decor, A.; Thoret, S.; Chiaroni, A.; Baudoin, O.
■
Angew. Chem., Int. Ed. 2006, 45, 4149−4152. (c) Ingalls, E. L.; Sibbald,
P. A.; Kaminsky, W.; Michael, F. E. J. Am. Chem. Soc. 2013, 135,
8854−8856. (d) Trost, B. M.; Osipov, M. Angew. Chem., Int. Ed. 2013,
52, 9176−9181.
Corresponding Authors
*E-mail: giovanni.maestri@icsn.cnrs-gif.fr.
*E-mail: max.malacria@cnrs.fr.
(12) (a) Maestri, G.; Della Ca’, N.; Catellani, M. Chem. Commun.
2009, 4892−4894. (b) Della Ca’, N.; Maestri, G.; Catellani, M.
Chem.Eur. J. 2009, 15, 7850−7854.
Notes
The authors declare no competing financial interest.
(13) Maestri, G.; Malacria, M.; Derat, E. Chem. Commun. 2013,
10424−10426.
ACKNOWLEDGMENTS
■
(14) (a) Kozuch, S.; Shaik, S. Acc. Chem. Res. 2011, 44, 101−110.
(b) Kozuch, S.; Jutand, A.; Amatore, C.; Shaik, S. Organometallics
2005, 24, 2319−2330.
(15) For reviews on parallel kinetic resolution, see: (a) Miller, R. C.;
Sarpong, R. Chem. Soc. Rev. 2011, 40, 4550−4562. (b) Dehli, J. R.;
Gotor, V. Chem. Soc. Rev. 2001, 31, 365−372.
We thank Prof. Marta Catellani (Universita
meaningful discussions and Ms. Marion Garreau (ICSN) for
help. We thank CNRS and IUF (M.M.) for funding.
̀
di Parma) for
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