Palladium-Catalyzed Formal (5 + 2) Annulation between ortho-Alkenylanilides and Allenes

Article abstract of DOI:10.1021/acs.orglett.7b00467

2-Alkenyltriflylanilides react with allenes upon treatment with catalytic amounts of Pd(OAc)₂ and Cu(II) to give highly valuable 2,3-dihydro-1H-benzo[b]azepines, in good yields, and with very high regio- and diastereoselectivities. Density functional theory (DFT) calculations suggest that the C-H activation of the alkenylanilide involves a classical concerted metalation-deprotonation (CMD) mechanism.

Full text of DOI:10.1021/acs.orglett.7b00467

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Formal (5 + 2) Annulation between ortho-
Alkenylanilides and Allenes
Borja Cendon,† Noelia Casanova,† Cezar Comanescu,†,§ Rebeca García-Fandino,†,‡ Andres Seoane,†
́
́
̃
Moises Gulías,*,† and Jose L. Mascarenas*,†
́
́
̃
†Centro Singular de Investigacion
Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
́ ́ ́
en Química Bioloxica e Materiais Moleculares (CIQUS) and Departamento de Química Organica,
‡CIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, P-4169-007,
Porto, Portugal
§Department of Inorganic Chemistry, University Politehnica of Bucharest, 1, Polizu street, RO-011061 Bucharest, Roman
̂
ia
S
* Supporting Information
ABSTRACT: 2-Alkenyltriflylanilides react with allenes upon
treatment with catalytic amounts of Pd(OAc)2 and Cu(II) to
give highly valuable 2,3-dihydro-1H-benzo[b]azepines, in good
yields, and with very high regio- and diastereoselectivities.
Density functional theory (DFT) calculations suggest that the
C−H activation of the alkenylanilide involves a classical concerted metalation−deprotonation (CMD) mechanism.
The reaction was hypothesized to involve the initial formation
of an oxapalladacycle such as II by formal activation of the
terminal C−H bond of the alkene, followed by migratory
insertion of the allene and reductive elimination. Experimental
studies suggested that the C−H activation does not proceed
through a classical concerted metalation−deprotonation
(CMD), but rather it might involve an intramolecular attack of
the conjugated alkene to the palladium center to give an
intermediate such as I, followed by a base-induced rear-
omatization to form the six-membered palladacycle II (Scheme
1A).
As a natural extension of these studies, we questioned whether
ortho-alkenylanilides might also engage in similar annulations,
which would provide a straightforward and atom economical
access to highly relevant benzazepine skeletons (Figure 1).5,6 At
the outset, the success was not guaranteed since ortho-
alkenylanilines could provide indole products when treated
with a Pd(II) catalyst,7 and also because there were no
precedents on the reactivity of allenes with related anilides.8,9
he assembly of heterocycles from simple precursors is a
Ttopic of major interest. In this context, the use of metal-
catalyzed annulations is especially attractive owing to their
intrinsic complexity-increasing potential. However, many of
these reactions require the preparation of precursors containing
specific functional groups. In recent years, there has been a
growing number of reports on metal-promoted annulations that
involve the formal activation of C−H bonds and therefore do not
require elaborated substrates.1,2
Similarly, our group has developed metal-promoted cyclo-
additions of 2-alkenylphenols with alkynes3 or allenes4 to give a
variety of oxacyclic products. Remarkably, while allenes react
with 2-alkenylphenols in the presence of Rh(III) catalysts to give
chromene-type products, under Pd(II) catalysis the reaction
provides interesting benzoxepine skeletons (Scheme 1A).
Scheme 1. Palladium-Promoted Annulations with Allenes
Figure 1. Drugs with benzazepine skeletons.
Received: February 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00467
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Organic Letters
Letter
a b
,
Herein, we report a palladium(II)-catalyzed (5 + 2) formal
oxidative cycloaddition between 2-alkenyltriflylanilides and
allenes (Scheme 1B). The reaction provides a straightforward
and regioselective access to a variety of interesting benzazepine
skeletons in good yields. Importantly, DFT calculations suggest
that while the C−H activation step in the annulations of
alkenylphenols is better explained in terms of a nonconcerted
electrophilic addition to Pd(II) followed by rearomatization, in
the case of the anilides the C−H activation is more consistent
with a concerted metalation deprotonation mechanism (CMD).
Our work started by identifying appropriate substituents at the
N atom of the alkenylanilide that could favor the formation of the
desired products. The reaction was tested with catalytic amounts
of Pd(OAc)2 and 0.5 equiv of Cu(OAc)2·H2O in acetonitrile,
under air, using 2-vinylidenecyclohexane (2a) as a partner. The
parent aniline (2-(prop-1-en-2-yl)aniline) gave a very low yield
of the desired product; however, the isopropylanilide partici-
pated in the process leading to the expected benzazepine in
moderate yield (Table 1, entry 2). Curiously, while the acetyl
Scheme 2. Scope with Different Allenes
a
Table 1. Screening of Amine R Groups
a
Conditions: 1a (1 equiv), 2a (1 equiv), 7.5 mol % Pd(OAc)2, Et3N
(2 equiv), 0.5 equiv Cu(OAc)2·H2O, CH3CN (0.095 M), 82 °C, under
b
c
air, 3−8 h. E/Z are >20:1, unless otherwise noted. 5 mol % of
Pd(OAc)2.
process. The heavily substituted product 6ag could be obtained
in a 70% yield, while with the allene 2h we observed the
formation of a 1.1:1 mixture of isomeric products 3ah and 6ah
(56% overall yield).11
entry
R group
base
3 (%)
<10
4/5 (%)
1
2
3
4
5
6
7
8
H
−
−
−
−
−
−
−
−
−
iPr
58
Ac
−
43
As shown in Scheme 3, the reaction is not restricted to the 2-
alkenylanilide 1a, but also works with related substrates bearing
other substituents at the internal position of the alkene, such as
isopropyl (1b) or aryl (1c, 1d). In all the cases the expected
benzazepine adducts were obtained in good to excellent yields
(3ba−3da, 62−90% yields). Curiously the reaction does not
work with the substrate that bears a simple vinyl group (3ea),
apparently because it is not stable enough under the reaction
conditions. Importantly, the reaction is also operative with 2-
phenylanilides, to give the expected dibenzazepines such as 3fa in
good yields, albeit achieving good conversions required longer
times.12 In order to analyze functional group compatibilities, we
also tested the reactivity of precursors with different substituents
in the aryl group of the anilide precursors. Sensible functionalities
such as fluoride (3ga, 72%) or bromide (3ha, 91%) are well
tolerated in ortho or meta positions to the alkenyl group.
Substituents para to the alkenyl group are also tolerated,
irrespective of whether they are electron donors (3ia, 68% yield,
3ka, 52% yield) or acceptors (3ja, 92% yield).
While the above data confirm the synthetic potential of the
annulations, the transformation entails interesting mechanistic
issues, particularly in relation with the C−H activation process.
Control experiments with substrate 1a in the absence of the
allene, using the standard reaction conditions, revealed the
formation of a mixture of products from which we could isolate
the indoline 4a and indole 5a in an overall 18% yield (Scheme 4).
These products, particularly 4a, might arise from an aza-Wacker-
type mechanism involving the addition of the amine to the alkene
followed by β-hydride elimination of the resulting Pd-complex.13
The formation of the indole could also be explained in terms of a
reductive elimination from II′ (Scheme 5).7,14
b
Ts
8
b
Ns
51
∼10
Tf (1a)
Tf (1a)
Tf (1a)
55 (3aa)
27 (3aa)
82 (3aa)
8 (4a)
c
Cs2CO3
8
d
Et3N
10 (4a)
a
Conditions: 0.19 mmol of 1a, 0.19 mmol of 2a, 10 mol % Pd(OAc)2,
0.5 equiv of Cu(OAc)2·H2O, CH3CN (2 mL), 82 °C, under air, 12 h.
Mixture of indolidene 4 and indole 5. 1 equiv of Cs2CO3. 5 mol %
b
c
d
of Pd(OAc)2, Et3N (2 equiv), 3 h.
derivative failed to react (the starting material was mostly
recovered), the presence of tosyl, nosyl, or trifluoromethylsul-
fonyl substituents at the N atom allowed the formation of the
corresponding adducts in moderate yields (43−55% yields),
together with variable amounts of the indoline (4) and indole (5)
products.7,10 Importantly, the addition of triethylamine allowed
an increase in the yield of the reaction, so that the desired product
3aa was obtained in 82% yield using just 5 mol % of Pd(OAc)2
(Table 1, entry 8).
With the optimized conditions at hand, we investigated the
scope of the reaction with regard to the allene component
(Scheme 2). Other 1,1-disubstituted symmetrical allenes such as
dimethyl and diphenyl allenes led to the corresponding products
3ab and 3ac (40 and 61% yield). The lower yield obtained in the
case of 3ab is probably associated with the high volatility of the
allene. Nonsymmetrical allenes, such as 2d and 2e, led to the
corresponding products (3ad and 3ae) in good yields and good
to excellent E/Z ratios. Cyclonona-1,2-diene is also a good
annulation partner, leading to the formation of a tricyclic product
3af in 62% yield. Trisubstituted allenes also engage in the
B
DOI: 10.1021/acs.orglett.7b00467
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conditions. These results suggest that the presence of the allene
partner opens accessible pathways that avoid the decomposition
of the alkenylanilides or promote the reactivity of the arylanilides.
In order to gain more information about the C−H activation
step and compare the reactivity of 2-alkenylphenols and 2-
alkenylanilides, we carried out DFT calculations with 2-(prop-1-
en-2-yl)phenol and the triflylanilide 1a.15 In consonance with our
previous hypothesis based on experimental data,4a in the case of
the phenol derivative the initially formed palladium alkoxide
evolves rapidly to a species that is better accommodated with a
structure such as I (Figure 2), exhibiting partial dearomatization
Scheme 3. Scope with Respect to the Alkenylanilide
Component
a
Conditions: 1a (1 equiv), 2a (1 equiv), 5 mol % Pd(OAc)2, Et3N (2
equiv), 0.5 equiv Cu(OAc)2·H2O, CH3CN (2 mL), 82 °C, under air,
3−8 h. 10 mol % of Pd(OAc)2, 1 equiv of Cu(OAc)2.
b
Figure 2. Energetic profiles of pathways for the C−H activation step in
the phenolic and triflylanilide substrates. The Pd center in the
intermediates contains an additional ligand (acetic acid, not shown)
that contributes favorably to their stabilization. Values are given in kcal/
mol and correspond to ΔG in acetonitrile.
Scheme 4. Control Experiments in the Absence of Allene
of the phenyl ring. Analysis of the C−C distances confirms that
the C1−C2 bond order is less than 2, while the C2−C3 distance
has gained considerable double bond character. Moreover, the
C1−Pd distance is 2.06 Å, which is characteristic for C−Pd σ-
bonding. This compound evolves by rearomatization to form a
six-membered palladacycle II, by intramolecular abstraction of
one of the hydrogens by the acetate (TS1, 15.6 kcal/mol).
Interestingly, the palladium complex obtained with the nitro-
genated substrate 1a presents a structure with a standard η2
coordination of the alkene to the Pd center, while the C2−C3
distance (1.50 Å) is typical for a single C−C bond (structure I′).
Therefore, in this case the coordination to the metal center does
not drive the dearomatization of the molecule. Importantly, the
TS for the C−H activation process (TS1′) is fully consistent with
a CMD-type mechanism (see the Supporting Information for
details).16
Scheme 5. Mechanistic Hypothesis
Therefore, the most probable catalytic cycle for the annulation
process might involve an initial ligand exchange between the
alkenylanilide derivative 1a and the palladium acetate complex to
give a species of type I′, which undergoes a C−H activation to
form the six-membered palladacycle II′ through a CMD
mechanism. Coordination of the allene followed by regiose-
lective migratory insertion gives a π-allylic palladacycle IV′,17
which undergoes reductive elimination to the benzo[b]azepine
(Scheme 5).18 The resulting Pd(0) species is reoxidized to Pd(II)
by copper diacetate and air. The regioselectivity of the ring
closing depends on the allene structure and electronic character-
istics of the substituents.
In consonance with its lower reactivity and the absence of
competitive aza-Wacker processes, the arylanilide 1f remained
intact after heating for several hours under the standard reaction
C
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ACS Catal. 2016, 6, 498. (f) Gensch, T.; Hopkinson, M. N.; Glorius, F.;
Wencel-Delord, J. Chem. Soc. Rev. 2016, 45, 2900.
The beneficial role of Et3N as an additive is not yet clear, but in
addition to buffer acetic acid it might facilitate the initial
formation of the N−Pd bond and, hence, avoid secondary
pathways involving an outer-sphere Pd(II) activation of the
alkene.
(3) (a) Seoane, A.; Casanova, N.; Quinones, N.; Mascarenas, J. L.;
̃
̃
Gulías, M. J. Am. Chem. Soc. 2014, 136, 7607. (b) Seoane, A.; Casanova,
N.; Quinones, N.; Mascarenas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014,
̃
̃
136, 834.
In summary, we describe a new annulation reaction which
provides a particularly rapid and practical method to obtain 2,3-
dihydro-1H-benzo[b]azepine skeletons. The transformation
consists of a palladium-catalyzed (5 + 2) formal cycloaddition
and involves a formal C−H activation process. In contrast to that
occurring with the alkenylphenol precursors, the C−H activation
in the case of the anilides seems to involve a CMD process.
Probably, the electronic pair of the nitrogen atom is not available
for conjugation with the aromatic ring and as a consequence the
alkene group is less prone to form a species of type I (Scheme 1).
The reaction provides a novel way of obtaining benzazepines
and represents one of the few examples of the synthesis of seven-
membered rings through annulations involving the cleavage of
olefinic C−H bonds.
(4) (a) Casanova, N.; Del Rio, K. P.; García-Fandino, R.; Mascarenas, J.
L.; Gulías, M. ACS Catal. 2016, 6, 3349. (b) Casanova, N.; Seoane, A.;
̃
̃
Mascarenas, J. L.; Gulías, M. Angew. Chem., Int. Ed. 2015, 54, 2374.
̃
(5) For other examples of formal intermolecular (5 + 2) annulations
leading to azepine skeletons, see: (a) Wender, P. A.; Pedersen, T. M.;
Scanio, M. J. C. J. Am. Chem. Soc. 2002, 124, 15154. (b) Zhou, M.-B.;
Song, R.-J.; Wang, C.-Y.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52, 10805.
(c) Feng, J.-J.; Lin, T.-Y.; Zhu, C.-Z.; Wang, H.; Wu, H.-H.; Zhang, J. J.
Am. Chem. Soc. 2016, 138, 2178. (d) Hu, C.; Song, R.-J.; Hu, M.; Yang,
Y.; Li, J.-H.; Luo, S. Angew. Chem., Int. Ed. 2016, 55, 10423.
(6) For examples on the synthesis of benzazepines using C−H
functionalizations, see: (a) Tsvelikhovsky, D.; Buchwald, S. L. J. Am.
Chem. Soc. 2010, 132, 14048. (b) Ye, K.-Y.; He, H.; Liu, W.-B.; Dai, L.-
X.; Helmchen, G.; You, S.-L. J. Am. Chem. Soc. 2011, 133, 19006.
(7) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J.
Org. Chem. 1996, 61, 3584.
(8) For Pd-catalyzed annulations involving C−H activations and
allenes as reaction partners, see: (a) Suresh, R. R.; Swamy, K. C. K. J. Org.
Chem. 2012, 77, 6959. (b) Xia, X.-F.; Wang, Y.-Q.; Zhang, L.-L.; Song,
X.-R.; Liu, X.-Y.; Liang, Y.-M. Chem. - Eur. J. 2014, 20, 5087.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00467.
■
S
(c) Rodríguez, A.; Albert, J.; Ariza, X.; Garcia, J.; Granell, J.; Farras
̀
, J.;
La Mela, A.; Nicolas, E. J. Org. Chem. 2014, 79, 9578.
́
Detailed experimental procedures, characterization data,
computational details, and other information (PDF)
X-ray crystallographic analysis for 6ag, 3fa, 3ha, and 4a
(CIF)
(9) For examples of other metal-catalyzed C−H functionalizations
with allenes, see: (a) Zeng, R.; Wu, S.; Fu, C.; Ma, S. J. Am. Chem. Soc.
2013, 135, 18284. (b) Kuppusamy, R.; Gandeepan, P.; Cheng, C.-H.
Org. Lett. 2015, 17, 3846. (c) Gandeepan, P.; Rajamalli, P.; Cheng, C.-H.
Chem. - Eur. J. 2015, 21, 9198. (d) Wang, H.; Glorius, F. Angew. Chem.,
Int. Ed. 2012, 51, 7318. (e) Zeng, R.; Fu, C.; Ma, S. J. Am. Chem. Soc.
2012, 134, 9597. (f) Zeng, R.; Ye, J.; Fu, C.; Ma, S. Adv. Synth. Catal.
2013, 355, 1963. (g) Wu, S.; Zeng, R.; Fu, C.; Yu, Y.; Zhang, X.; Ma, S.
Chem. Sci. 2015, 6, 2275. (h) Nakanowatari, S.; Ackermann, L. Chem. -
Eur. J. 2015, 21, 16246. (i) Mazuela, J.; Banerjee, D.; Backvall, J. E. J. Am.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: joseluis.mascarenas@usc.es.
*E-mail: moises.gulias@usc.es.
ORCID
Chem. Soc. 2015, 137, 9559. (j) Collado, A.; Esteruelas, M. A.; Lop
́
ez, F.;
Mascarenas, J. L.; Onate, E.; Trillo, B. Organometallics 2010, 29, 4966.
̃
̃
(10) The Ns and Ts-substituted indoline products slowly isomerize in
CDCl3 to the indole structures.
Jose L. Mascarenas: 0000-0002-7789-700X
́
̃
Notes
(11) Allenamides such as 1-(propa-1,2-dien-1-yl)pyrrolidin-2-one
failed to participate in the annulations, leading to secondary
dimerizations and polymerizations. For other chemistry with
The authors declare no competing financial interest.
allenamides, see: (a) Montserrat, S.; Faustino, H.; Lledo
Mascarenas, J. L.; Lopez, F.; Ujaque, G. Chem. - Eur. J. 2013, 19,
15248. (b) Faustino, H.; Varela, I.; Mascarenas, J. L.; Lopez, F. Chem. Sci.
́
s, A.;
ACKNOWLEDGMENTS
■
́
̃
́
This work has received financial support from Spanish grants
(SAF2013-41943-R, SAF2016-76689-R, CTQ2015-74621-JIN,
̃
2015, 6, 2903.
(12) Zuo, Z.; Liu, J.; Nan, J.; Fan, L.; Sun, W.; Wang, Y.; Luan, X.
Angew. Chem., Int. Ed. 2015, 54, 15385.
́
and CTQ2016-77047-P), the Conselleria de Cultura, Educacion
e Ordenacion Universitaria (GRC2013-041, 2015-CP082 and
Centro Singular de Investigacion de Galicia accreditation 2016-
́
́
(13) For a review on the aza-Wacker mechanism, see: Koco
̌
́
vsky, P.;
́
Backvall, J.-E. Chem. - Eur. J. 2015, 21, 36.
̈
2019, ED431G/09), the European Regional Development Fund
(ERDF), and the European Research Council (Advanced Grant
No. 340055). R.G.-F. thanks an FCT scholarship from Portugal.
The orfeo-cinqa network CTQ2014-51912-REDC is kindly
acknowledged. All calculations were carried out at Centro de
(14) For examples of related substrates involving direct reductive
elimination from palladacycles through a Pd(IV) mechanism, see:
(a) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (b) Youn, S. W.; Bihn, J.
H.; Kim, B. S. Org. Lett. 2011, 13, 3738.
(15) For full details see the Supporting Information.
Supercomputacion
́
de Galicia (CESGA).
(16) A dearomatized structure analogous to I was not found for I′.
(17) An experiment with a chiral allene led to almost racemic
cycloadducts (see Supporting Information).
(18) A mechanism involving an anti attack of nitrogen on the π-allyl
palladium complex cannot be fully discarded.
REFERENCES
■
(1) For a recent review on the field: Gulías, M.; Mascarenas, J. L.
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̃
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tions, see: (a) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y.
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D
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