Organic Letters
Letter
Pd(II) complexes are well-known to form palladacycle
derivatives by Csp2−H activation reactions in phenethylamine
derivatives.15 In 2015, Luan16 and Sun17 reported the first Pd-
catalyzed [5 + 2] oxidative cycloadditions of arylanilines and
indolo-anilines with alkynes to benzazepines (Scheme 1, eq
a).18 In both cases, the directing group is an aniline, a L-type
ligand, that possess the correct rigidity (biaryl-type) to
facilitate the C−H bond activation, the insertion of the alkyne
into the corresponding metallacycle, and also the final
reductive elimination step via removal of HX.19 In the case
of X-type anilide ligands as directing groups, Luan20 and
with only 0.5 equiv of Cu(OAc)2·H2O and 0.1 equiv of Et3N in
CH3CN saturated with O2 (to facilitate a better reoxidation
system) gave an excellent yield of 3aa (entry 5).25
Having established optimal conditions, we next investigated
the scope of the two reaction partners. Using phenethyltri-
flamide 1a as a standard substrate, the scope of 1-aryl-1,3-
dienes 2 was explored and found to be very broad,
encompassing a wide range of electron-rich, electron-poor,
and heteroaroamatic 1,3-dienes in any position. In the case of
electron-poor aryl dienes, o-bromo (2b), o-nitro (2d), and p-
trifluoromethyl (2f) substituents worked very well. In the case
of electron-rich aryl dienes, o-methyl (2c), m-methoxy (2e),
and heteroaromatic p-thiophene-yl (2i) substituents worked
relatively well, but a p-dimethylamino-substituted aryl diene
(2g) failed to react due to extensive polymerization. Electron-
rich meta- and para-disubstituted aryl diene 2h gave also fairly
good yields. Either simple nonsubstituted 1,3-butadiene 2j or
alkyl-substituted penta-1,3-diene 2k (as a 1:1 mixture of
isomers) worked in relatively good yields. The 3-benzazepine
3ak was obtained as a 9:1 mixture of E/Z isomers, which
confirms the regio- and chemoselectivity of the reaction giving
the more stable alkenyl-substituted product as the major one.
Interestingly, functionalized dienamide 2l gave the correspond-
ing 3-benzazepine 3al in a fairly good yield that foresees
interesting derivatization of the installed Weinreb amide.
Unfortunately, 2-susbtituted 1,3-dienes (e.g., isoprene) and
1,2- or 1,4-disubstituted dienes failed to react as other
cycloadditions.26,22
Mascaren
̃
as21 reported the Pd-catalyzed [5 + 2] oxidative
cycloaddition with 1,3-dienes and allenes, respectively
(Scheme 1, eq b). In both cases, the nature of the directing
group and, therefore, the rigidity of the corresponding
metallacycle did not allow the insertion of alkynes; however,
1,3-dienes22 or allenes14 could be inserted to form more stable
allylic intermediates. We herein report that phenethyltrifla-
mides (X-type ligands), with a nonrigid Csp3 tether between
the two reacting centers efficiently undergo chemo-, regio- and
diastereoselective Pd-catalyzed [5 + 2] heteroannulations with
1,3-dienes to afford bioactive 2-alkenyl-3-benzazepines
(Scheme 1, eq c) in good to excellent yields.15b The best
conditions found for the catalytic cycle involve the
combination of Cu(OAc)2 and O2 as oxidant system.
Initially, we began our investigation by examining the
intermolecular Pd-catalyzed [5 + 2] cycloaddition between
phenethyl N-triflamide 1a and (E)-buta-1,3-dien-1-ylbenzene
(2a) as model partners (Table 1). Under classical palladium/
Electronic effects of the ring substituents in phenethyltri-
flamide 1 were then analyzed in the reaction with diene 2a and
were found to be similarly broad in terms of electron-
withdrawing and electron-donating capability in any position
(3ba−3fa) (Scheme 2). When p-OMe phenethyltriflamide 1e
was used, a 1:1 mixture of 3-benzazepines 3ea and 3ea′ was
obtained. The strongly polarized p-NO2 substituent is poorly
tolerated in the reaction giving rise to the corresponding 3-
benzazepine 3fa in a low 30% yield. Substitution on the tether
alkyl chain was then pursued, which allowed us to analyze the
diastereoselectivity of the reaction. Thus, the β-substituted
phenethyltriflamide 1g gave rise to 3ga in a good 80% yield as
a 3:1 mixture of diastereomers. To our delight, the α-
substituted L-phenylalaninate 1h, with a substituent closer to
the coordinating nitrogen atom, reacted smoothly with the
diene 2a to afford 3ha (50% yield) as a single diastereoisomer
without racemization as confirmed by NMR experiments and
X-ray crystallography. Interestingly, both substitutions in the
alkyl chain and the aromatic ring are well-tolerated, giving 3ia
(80%) and 3ja (70%) as single diastereoisomers.
a
Table 1. Optimization of Reaction Conditions
b
yield
a
entry
conditions
BQ (2 equiv), Et3N (2 equiv)
Cu(OAc)2·H2O (2 equiv), Et3N (2 equiv)
Cu(OAc)2·H2O (2 equiv), Et3N (2 equiv), DMF
(10 equiv)
(%)
1
2
3
35
50
c
4
Cu(OAc)2·H2O (0.5 equiv), Et3N (0.1 equiv), DMF (10
40
95
equiv), air
d
5
Cu(OAc)2·H2O (0.5 equiv), Et3N (0.1 equiv), DMF (10
equiv), O2
a
Typical conditions: 1a (0.2 mmol, 1 equiv), 2a (0.4 mmol, 2 equiv),
b
c
0.5 mL of MeCN. Internal standard 3,5-dinitromethylbenzoate. The
d
solution was bubbled with an air balloon for 10 min. The solution
was bubbled with an O2 balloon for 10 min.
In an effort to gain an insight into the reaction mechanism,
several stoichiometric experiments to form the cyclometalated
palladium cis-PdX2L2 complexes were conducted.27 The six-
membered cyclometalated Pd(II) complex 4a was formed by
heating 1a with 1 equiv of Pd(OAc)2 in MeCN for 12 h that
could be characterized by 1H NMR (Scheme 3, eq 1).
Gratifyingly, X-ray structural characterization was possible
when complex 4a was stirred in the presence of 2,2′-bipy
ligand to give 4a′ as off-white crystals. Furthermore, 4a reacts
with 1 equiv of 2a to give 3-benzazepine 3aa in quantitative
yield after heating at 30 °C for 2 h (Scheme 3, eq 2).28 To gain
further information about the diastereoselectivity, the pallada-
cycle 4h′ was also isolated and crystallized as off-white crystals
(Scheme 3, eq 3).
benzoquinone oxidative combinations or using other oxidants
such as PIFA or PIDA the cycloaddition failed (entry 1 and
Cu(OAc)2·H2O as oxidant allowed the isolation of 3-
benzazepine 3aa albeit in low yield (entry 2).21 It could be
increased up to 50% using the same oxidant in the presence of
10 equiv of strong coordinating solvents such as DMF or
DMSO (entry 3). These solvents might help to reoxidize
Pd(0) to Pd(II) and, therefore, restart the catalytic cycle
avoiding the polymerization of Pd(0) to ineffective dark
palladium.24 Interestingly, the amount of base and oxidant
could be reduced when the solution was saturated in air
keeping a moderate 40% yield (entry 4) and, to our delight,
B
Org. Lett. XXXX, XXX, XXX−XXX
Saá, Carlos
