Diastereoselective Synthesis of Dibenzo[b,d]azepines by Pd(II)-Catalyzed [5 + 2] Annulation of o-Arylanilines with Dienes

Article abstract of DOI:10.1021/acs.orglett.7b00503

An efficient method for the construction of dibenzo[b,d]azepines containing two distinct stereogenic elements in a highly diastereoselective fashion is described. The key of the [5 + 2] reaction is to form a π-allylpalladium species through sequential C-H

Full text of DOI:10.1021/acs.orglett.7b00503

Letter
pubs.acs.org/OrgLett
Diastereoselective Synthesis of Dibenzo[b,d]azepines by Pd(II)-
Catalyzed [5 + 2] Annulation of o‑Arylanilines with Dienes
Lu Bai,‡ Yan Wang,‡ Yicong Ge, Jingjing Liu, and Xinjun Luan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry &
Materials Science, Northwest University, Xi’an 710127, China
S
* Supporting Information
ABSTRACT: An efficient method for the construction of
dibenzo[b,d]azepines containing two distinct stereogenic
elements in a highly diastereoselective fashion is described.
The key of the [5 + 2] reaction is to form a π-allylpalladium
species through sequential C−H activation and regiospecific
migratory insertion of the diene. This observation contrasts
with the behavior of 1,2-alkenes that generally underwent direct alkenylation via β-hydride elimination.
he ubiquity of various azaheterocycles continues to make
the development of new applicable methods for their
Huang showed a Rh(III)-catalyzed alkenylation/amidation
domino reaction to access a variety of dibenzo[b,d]azepinones.7
In this letter, we describe a novel Pd(II)-catalyzed [5 + 2]
reaction by employing 1,3-dienes as two-carbon synthons to
couple with aminobiaryls, leading to a new class of intriguing
dibenzo[b,d]azepines with both axial and central stereogenic
elements in a highly diastereoselective manner (Scheme 1a).
T
preparation an important research topic.1 Dibenzo[b,d]azepines,
which usually possess one asymmetric center and one
atropisomeric biphenyl axis, represent a unique structural motif
for many biologically active natural products and pharmaceut-
icals (Figure 1).2 Traditional synthetic methods for accessing
Scheme 1. Pd(II)-Catalyzed Annulations of Aminobiaryls
with Olefins
Figure 1. Selected examples containing the dibenzo[b,d]azepine core.
these scaffolds were mainly established through intramolecular
cyclizations of highly functionalized substrates that often require
multistep synthesis.3 Therefore, the pursuit of alternative
methods starting from less expensive and more readily available
reagents is of foremost interest. In this context, transition-metal-
catalyzed C−H functionalization4 has proven to be a powerful
tool for rendering shorter synthetic routes to these frameworks
through intermolecular annulation of free aminobiaryls with two-
carbon synthons.5−7 For instance, Zhang reported an elegant
example of Pd(II)-catalyzed free-amine-directed alkenylation/
hydroamination cascade with α-branched styrenes to build up
the seven-membered rings bearing a quaternary center.5 Later
on, our group disclosed a Pd(II)-catalyzed [5 + 2] oxidative
annulation of aminobiaryls with alkynes for the stereoselective
synthesis of imine-type dibenzo[b,d]azepines.6 Very recently,
During the course of our exploration for the transition-metal-
catalyzed C−H functionalization/dearomatizing spiroannula-
tions of biaryls with unsaturated partners,8 the reaction between
N-Ts-2-arylanilines and 1,3-dienes was found to proceed through
an alternative [5 + 2] annulation pathway under Pd(II)-catalysis.
Remarkably, this reaction represents a very rare example of [5 +
2] annulations with olefins involving a C−H activation step for
the one-step assembly of seven-membered heterocycles.9 In
sharp contrast to the prior reports5,10,11 on the formal [5 + 1]
annulations of aminobiaryls with monosubstituted olefins
Received: February 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
(Scheme 1b), which were realized by cyclizing the C−H
alkenylated product A′ to give dihydrophenanthridines10 or
phenanthridine,5,11 this new [5 + 2] annulation process occurred
with a completely different mechanistic mode through the direct
reductive elimination of π-allylpalladium intermediate A to
generate dibenzo[b,d]azepines.
Scheme 2. Survey the Scope of 2-Arylanilines
At the outset, we started the studies by reacting N-tosyl-2-
aminobiphenyl (1a) with an electron-deficient diene 2a that
engaged well in the known C−H functionalization reactions,12
and the representative data are summarized in Table 1. When the
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
[M]
oxidant
solvent
3a
4a
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Cu(OAc)2
Cu(TFA)2
CuCO3·Cu(OH)2
AgOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1,4-dioxane
DMSO
DMF
46
22
13
20
0
10
0
2
3
2
4
15
0
5
BQ
6
K2S2O8
0
59
11
6
7
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
68
82
0
8
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
9
5
10
11
12
0
38
22
29
74
66
DMA
a
0.2 mmol of 1a, 0.4 mmol of 2a, 5.0 mol % of [Pd], and 0.4 mmol of
b
oxidant were used. Isolated yield.
reaction was performed in the presence of Pd(OAc)2 (5 mol %)
and Cu(OAc)2 (2.1 equiv) in MeCN at 120 °C for 36 h, the
envisioned [5 + 2] annulation product dibenzo[b,d]azepine 3a
was obtained in 46% yield, albeit with the concomitant
generation of 10% byproduct 4a (entry 1). The examination
on other oxidants (entries 2−6) indicated that Cu(OAc)2 was
clearly the better choice for the [5 + 2] annulation. For instance,
the reaction with K2S2O8 only provided N-Ts-substituted
carbazole 4a,13 while the expected alkene migratory insertion
for the generation of product 3a did not occur at all (entry 6). To
our delight, the reaction performance was greatly improved by
using more electrophilic Pd(TFA)2 (entry 8). Further attempts
with other solvents that were often used for Pd(II)-catalyzed C−
H functionalization reactions led to either poor reactivities or low
chemoselectivities (entries 9−12). Remarkably, the potential
alkenylated byproduct through β-hydride elimination was
completely prevented by using conjugated diene 2. Finally, it is
important to mention that no similar [5 + 2] annulation reaction
was observed with the aminobiaryls being N-substituted with a
carbonyl, alkyl, aryl, or heteroaryl group.
a
b
Isolated yield. The reaction was run at 1.0 mmol scale.
cyano (1d), chloro (1e), ester (1f), and nitro (1i) groups were
well tolerated, offering valuable synthetic handles for further
derivatization of dibenzo[b,d]azepines. Moreover, the reaction
was compatible with several challenging substrates (1h,m,p) that
would cause more sever steric clash for assembling the seven-
membered N-heterocycles, giving products 3h, 3m, and 3p in
72%, 66%, and 29% yield, respectively. Remarkably, substrate 1o,
containing two possible C−H functionalization sites, proceeded
preferentially at the least sterically encumbered position to
generate 3o as the sole product.
We next investigated the scope of 1,3-dienes for the [5 + 2]
oxidative annulation (Scheme 3). In all cases, the reaction
occurred regiospecifically toward the terminal double bond, and
other possible regioisomers were not detected. Notably, the
more electron-deficient 1,3-diene (2b) containing two ester
groups could undergo the title [5 + 2] annulation with 1a,
affording a diastereomeric mixture (5:1 dr) of 3a′ in 62% yield.
As expected, the amide substrate 2c was applicable for the
generation of 3b′. More interestingly, (E)-2,4-pentadienoic acid
(2d) was found to participate well in this Pd(II)-catalyzed [5 + 2]
annulation, providing compound 3c′ in moderate yield (42%).
To our knowledge, it is the first time that the carboxylate diene
With the optimized reaction conditions in hand, we first
examined the substrate scope with respect to 2-arylanilines. As
shown in Scheme 2, a number of 2-arylanilines 1a−r bearing
various substituents on both aromatic rings reacted properly with
2a, providing the desired [5 + 2] products 3a−r in 29−83%
yields with excellent diastereoselectivities (>19:1). Gratifyingly, a
broad range of synthetically variable functional groups such as
B
DOI: 10.1021/acs.orglett.7b00503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
(Scheme 4). The KIE result suggested that the palladium-
Scheme 3. Survey the Scope of 1,3-Dienes
mediated C−H cleavage might not be involved in the rate-
Scheme 4. Kinetic Isotope Experiment
determining step for this domino reaction. On the basis of the
results of the experiment and precedent literature,5,9−12
a
plausible reaction mechanism for the Pd(II)-catalyzed [5 + 2]
annulation reaction is presented in Scheme 5. The catalytic cycle
Scheme 5. Proposed Mechanism
a
Isolated yield.
was successfully used as a two-carbon coupling partner for the
transition-metal-catalyzed annulation reactions, although the
related Heck-process has been known.14 Moreover, the ester
group of 2a could be replaced with a variety of aromatic groups
being substituted with both electron-donating group (2f) and
electron-withdrawing groups (2g,h), giving products 3d′−g′ in
excellent yields (82−91%). It is notable that the reactions with
1,3-dienes (2i,j) bearing a 2-thienyl or a 2-furyl group were able
to proceed smoothly to deliver 3h′−i′. In addition, alkyl-
substituted diene 2k was found to be tolerable as well, providing
3j′ in 89% yield. However, the limitation of this [5 + 2] oxidative
annulation protocol became apparent when 1,3-dienes 2l−m
were tested.
To elucidate the structure of dibenzo[b,d]azepines 3, we
performed X-ray crystallographic studies on 3b, 3f, and 3b′,15
and it revealed that all the three compounds existed as the
thermodynamically more stable diastereomer with respect to the
tertiary carbon center and atropisomeric biaryl axis (Figure 2).
To obtain some mechanistic information, we carried out an
intermolecular competition experiment between [D1]-1a and
-2a, and the value of the kinetic isotope effect (KIE) was 1.0
is initiated with complexation of Pd(II) species with substrate 1a
and followed by the electrophilic palladation of C−H bond to
generate a six-membered palladium species I. Subsequently,
coordination and migratory insertion of the 1,3-diene 2 with I
forms an eight-membered palladacycle III, which is further
stabilized with the second C−C double bond from 2. Finally, C−
N reductive elimination takes place to deliver the desired product
3 and concomitantly regenerates Pd(II) species with Cu(II)
oxidant to furnish the catalytic cycle. Additionally, it should be
noted that direct reductive elimination of I to form byproduct 4a
could be efficiently inhibited by careful control of reaction
conditions. More importantly, the use of conjugated diene 3
dramatically prevented the potential reaction pathway to give
undesired 5 through the β-hydride elimination of intermediate
III.
In summary, we have developed a novel palladium(II)-
catalyzed [5 + 2] oxidative annulation of o-arylanilines with 1,3-
dienes, providing a highly efficient route to access a new family of
dibenzo[b,d]azepines in good yields with excellent diastereose-
lectivities. Compared to the oxidative Heck processes,5,10,11 this
[5 + 2] annulation reaction suppressed the β-hydride elimination
with the assistance of an additional C−C double bond in the 1,3-
dienes and eventually prevented the formation of undesired
Heck-type alkenylated byproducts. Remarkably, the method may
have potential applications in the synthesis of related natural
products and pharmaceuticals.
Figure 2. X-ray structures of 3b, 3f, and 3b′ (from left to right). Thermal
ellipsoids shown at 30% probability.
C
DOI: 10.1021/acs.orglett.7b00503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Yang, X.; Liu, J.; Nan, J.; Bai, L.; Wang, Y.; Luan, X. J. Org. Chem. 2015,
80, 3349.
(9) To our knowledge, there was only one example within this
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00503.
category, see: Casanova, N.; Del Rio, K. P.; García-Fandino, R.;
̃
Mascarenas, J. L.; Gulías, M. ACS Catal. 2016, 6, 3349.
̃
(10) (a) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J.
Org. Chem. 1998, 63, 5211. (b) Kim, B. S.; Lee, S. Y.; Youn, S. W. Chem. -
Asian J. 2011, 6, 1952.
Experimental procedures and spectral data for all new
compounds (PDF)
Crystallographic data for 3b (CIF), 3f (CIF), and
3b′(CIF)
(11) Liu, Y.-Y.; Song, R.-J.; Wu, C.-Y.; Gong, L.; Hu, M.; Wang, Z.; Xie,
Y.; Li, J. Adv. Synth. Catal. 2012, 354, 347.
(12) (a) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-
́
Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066.
(b) Zhao, D.; Lied, F.; Glorius, F. Chem. Sci. 2014, 5, 2869.
(13) (a) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.;
Buchwald, S. L. J. Org. Chem. 2008, 73, 7603. (b) Youn, S. W.; Bihn, J.
H.; Kim, B. S. Org. Lett. 2011, 13, 3738.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xluan@nwu.edu.cn.
ORCID
(14) Patel, B. A.; Dickerson, J. E.; Heck, R. F. J. Org. Chem. 1978, 43,
5018.
Xinjun Luan: 0000-0002-5692-0936
Author Contributions
‡These authors contributed equally.
(15) The crystal data of 3b, 3f, and 3b′ have been deposited in CCDC
with numbers of 1529191, 1529193, and 1528196.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21672169), the “1000
Youth Talents Plan”, and the Education Department of Shaanxi
Province (12JS113). We thank Ms. Haihua Wang at Northwest
University for X-ray crystallographic assistance.
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