Highly Stereoselective Synthesis of Imine-Containing Dibenzo[b,d]azepines by a Palladium(II)-Catalyzed [5+2] Oxidative Annulation of o-Arylanilines with Alkynes

Article abstract of DOI:10.1002/anie.201508850

A novel palladium(II)-catalyzed [5+2] oxidative annulation of readily available o-arylanilines with alkynes has been developed for building a seven-membered N-heterocyclic architecture containing a biaryl linkage. This method is applicable to a wide range of unprotected o-arylanilines and internal alkynes, and results in the chemoselective preparation of imine-containing dibenzo[b,d]azepines in high yields with excellent diastereoselectivity with respect to the two types of stereogenic elements.

Full text of DOI:10.1002/anie.201508850

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201508850
German Edition: DOI: 10.1002/ange.201508850
CÀH Activation
Highly Stereoselective Synthesis of Imine-Containing Dibenzo-
b,d]azepines by a Palladium(II)-Catalyzed [5+2] Oxidative
Annulation of o-Arylanilines with Alkynes
[
Zhijun Zuo, Jingjing Liu, Jiang Nan, Liangxin Fan, Wei Sun, Yaoyu Wang, and Xinjun Luan*
Abstract: A novel palladium(II)-catalyzed [5+2] oxidative
annulation of readily available o-arylanilines with alkynes has
been developed for building a seven-membered N-heterocyclic
architecture containing a biaryl linkage. This method is
applicable to a wide range of unprotected o-arylanilines and
internal alkynes, and results in the chemoselective preparation
of imine-containing dibenzo[b,d]azepines in high yields with
excellent diastereoselectivity with respect to the two types of
stereogenic elements.
Recently, transition-metal-catalyzed CÀH functionaliza-
tion has emerged as an efficient and versatile method for
[5]
accessing various heterocycles and carbocycles. In partic-
ular, nitrogen-group-assisted heteroannulations of nitrogen-
containing coupling partners with alkynes by a CÀH cleavage/
alkyne insertion/cyclization cascade have been widely used to
generate structurally diverse N-heterocyclic compounds, such
[
6]
[7]
[8]
[9]
as indoles, pyrroles, isoquinolines, isoquinolinones, and
so on.
[10]
Remarkably, most of these transformations were
realized by formal [3+2] or [4+2] cycloadditions to give five-
D
ibenzo[b,d]azepines represent an important class of
or six-membered rings, but the construction of larger rings by
[10c,e]
medium-sized N-heterocycles because they are the key
structural motifs in many natural products and bioactive
compounds (Figure 1). For example, dimeric erythrivarine B,
which contains the seven-membered skeleton, was isolated
means of related annulations is quite rare.
In this context,
we set out to develop a new type of [5+2] annulation between
simple biaryl precursors and alkynes involving a CÀH
activation step for the synthesis of functionalized dibenzo-
[
1]
[11]
from cultivated E. variegata. LY-411575 was identified
as an effective g-secretase inhibitor for the treatment of
melanoma and Alzheimerꢀs disease.
[b,d]azepines.
This work originated from our recent studies on
ruthenium(II)-catalyzed oxidative annulation of o-arylphenol
derivatives with alkynes through a CÀH activation strategy
[
2]
Functionalized
dibenzo[b,d]azepines were also investigated as serotonin (5-
[
3]
[4]
[12]
HT) receptor and potassium channel inhibitor. Therefore,
the search for new reliable synthetic approaches for the
preparation of dibenzo[b,d]azepines from readily available
starting materials is of great interest.
(Scheme 1a). It is noteworthy that the reaction proceeded
exclusively by a dearomatizing [3+2] annulation pathway to
generate spirocyclic enones as the sole product, but not
dibenzoxepines through a possible [5+2] cycloaddition route.
Presumably, a clear steric clash between the two twisted
aromatic groups of the intermediate A played a key role in
driving the essential ring contraction from A to B, thus
hampering the reductive elimination of A to form a dibenzox-
epine and rendering the [3+2] spiroannulation more favor-
able than a seven-membered ring formation. Moreover,
a recent seminal report from the group of MascareÇas and
Gulías demonstrated that simple o-vinylphenols (R = H),
which cannot engage in a similar steric interaction, were well
suited for a rhodium(III)-catalyzed [5+2] annulation to give
[13]
benzoxepines (Scheme 1b). These prior studies imply that
adapting the sterically more hindered biaryl coupling partner
for a potential [5+2] annulation with alkynes represents
a formidable challenge, and to date, no example of such
transformations has been realized. To address this limitation,
we switched gears to attempt analogous o-arylaniline deriv-
atives by exchanging the hydroxy group for an amino group.
Herein, we report the successful development of a palladium-
Figure 1. Selected examples bearing the dibenzo[b,d]azepine core
structure.
[
*] Z. Zuo, Prof. Dr. J. Liu, J. Nan, L. Fan, W. Sun, Prof. Dr. Y. Wang,
Prof. Dr. X. Luan
(II)-catalyzed [5+2] annulation of easily accessible o-arylani-
lines with alkynes for the direct synthesis of imine-containing
dibenzo[b,d]azepines (Scheme 1c).
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of the Ministry of Education, College of Chemistry &
Materials Science, Northwest University
Xi’an, 710069 (China)
At the outset, we first examined a series of commonly
[14]
used o-arylanilines, which were N-substituted with a car-
bonyl, sulfonyl, alkyl, aryl, or heteroaryl groups, for the
anticipated [5+2] annulation by using either rhodium(III)-,
ruthenium(II)-, or palladium(II)-catalyzed CÀH activation
E-mail: xluan@nwu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508850.
Angew. Chem. Int. Ed. 2015, 54, 15385 –15389
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
15385

.
Angewandte
Communications
[a]
Table 1: Optimization of the reaction conditions.
[b]
Entry [M]
mol% Solvent
T [8C] Yield [%]
1
2
3
4
5
6
7
8
9
1
Pd(OAc)2
5.0
5.0
5.0
5.0
5.0
5.0
5.0
2.5
DMF
1,4-dioxane
THF
100
100
100
100
100
100
120
120
120
120
57
29
18
23
16
72
91
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CH CN
3
tAmOH
DMSO
DMSO
DMSO
DMSO
DMSO
Pd(OAc)
2
Pd(OAc)2
[{Cp*RhCl } ]
2
2
[RuCl (p-cymene) ] 2.5
0
0
2
2
0
–
0
[
a] Reactions were conducted with 0.30 mmol of 1a. [b] Yield of isolated
product. DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide,
THF=tetrahydrofuran.
arylanilines (1a–t) to react with 2a, and it was found that
substrates containing substituents of varying electronic and
steric character, at any position of either aromatic ring, were
tolerated, thus providing the desired [5+2] annulation
products 3a–t in moderate to good yields (47–94%;
Table 2). Notably, the reaction with the substrate 1n, which
contains two possible CÀH functionalization sites, proceeded
Scheme 1. Development of [5+2] oxidative annulations of biaryls with
alkynes. a) Ruthenium(II)-catalyzed annulation of o-arylphenol deriva-
tives with alkynes (Ref. [12]). b) Rhodium(III)-catalyzed [5+2] annula-
tion of o-vinylphenols with alkynes (Ref. [13a]). c) This work:
Palladium(II)-catalyzed [5+2] annulation of o-arylanilines with alkynes.
preferentially at the least sterically encumbered position to
give 3n as the major regioisomer (12.5:1 r.r.). The substrate
1o, featuring the increased steric hindrance for CÀH func-
under various reaction conditions. Unfortunately, no desired
[
5+2] dibenzo[b,d]azepine product was observed. A key
tionalization, also participated in the process, although the
yield was slightly lower (54% yield). More importantly, the
reaction was compatible with several challenging substrates
(1m, 1s,t), which would cause more severe steric clash in the
intermediate A’’ (see Scheme 1), and the anticipated products
3m, 3s, and 3t were isolated in 91, 51, and 47% yield,
respectively.
breakthrough was ultimately achieved by identifying 2-
phenylaniline (1a) as an effective substrate for the envisioned
transformation. It has long been known that N-unprotected o-
arylanilines could undergo cyclometalation by transition-
[15]
metal-mediated CÀH bond cleavage, whereas the related
catalytic processes, which might be suppressed by the tight
coordination of the free amino group to the metal center,
The structure of the dibenzo[b,d]azepines 3 was then
further elucidated by X-ray crystallographic studies on 3d,
[16]
were not reported until very recently. In our investigation,
the initial observation showed that a [5+2] annulation
product, the imine-containing dibenzo[b,d]azepine 3a, was
formed in 57% yield upon treatment of 1a and 2a in the
[
17]
3m, and 3n. It is clear that they exist in the imine form.
Moreover, the stereochemistry is of particular interest in that,
in addition to the one tertiary carbon center, the moiety has
a chiral biaryl axis. Notably, a single diastereomer was always
observed as the sole product for all the reactions between 1a–
t and 2a, and the relative configuration is depicted in Figure 2.
Next, we sought to investigate the scope with respect to
the alkynes (Table 3). Regarding symmetrical alkynes (2b–e)
containing either electron-rich or electron-deficient aromatic
groups, the anticipated [5+2] annulation proceeded smoothly
to generate the imines 3a’–d’ as single diastereomeric
products in good yields (62–90%). When the unsymmetrical
diaryl alkyne 2 f was tested, the reaction led to a mixture of
two separable regioisomers 3e’ (2.4:1 r.r.) possessing the same
presence of a catalytic amounts of Pd(OAc) (5.0 mol%) and
2
2
.1 equivalents of Cu(OAc) in DMF at 1008C for 5 hours
2
(
Table 1, entry 1). The optimal reaction conditions were then
quickly established by switching the solvent to DMSO
entry 6) and elevating the temperature to 1208C (entry 7),
(
thus providing 3a in 91% yield upon isolation. Control
experiments indicated that replacing Pd(OAc) with either
2
[
{Cp*RhCl } ] or [RuCl (p-cymene) ], or removing the cata-
2 2 2 2
lyst completely shut down the titled reaction (entries 8–10).
Notably, 3a was obtained as the sole product under the
optimized reaction conditions, without giving either an
enamine-containing dibenzo[b,d]azepine or other side prod-
ucts.
[17]
relative configuration. Moreover, the dialkylacetylene 2g
was tolerated under the reaction conditions, thus the provid-
ing compound 3 f’ in 67% yield with 6.2:1 d.r. Notably, the
incorporation of an alkyl group into the tertiary carbon center
Under the optimal reaction conditions, the reaction scope
was then surveyed by employing a great number of o-
1
5386 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 15385 –15389

Angewandte
Chemie
Table 2: The reaction substrate scope of o-arylanilines.
Table 3: The reaction substrate scope of alkynes.
(2j versus 2i). Finally, it should be noted that ethyl 3-
phenylpropiolate was also an excellent coupling partner for
the [5+2] annulation, thus giving the imine-formed dibenzo-
[
b,d]azepine 3j’ in 94% yield with 10.1:1 d.r., and the
[17]
structure of its major diastereomer was confirmed by X-ray.
We conducted a series of experiments to probe the
reaction mechanism (Scheme 2). An intermolecular competi-
tion between 1a and [D ]-1a demonstrated a kinetic isotope
5
effect (k /k = 3.2; Scheme 2a), which suggests that the CÀH
H
D
activation is probably involved in the rate-determining step.
Treatment of the o-arylanilines 2r (4-MeO) and 2p (4-CF3)
Figure 2. X-ray structures of 3d, 3m, and 3n (from left to right).
Thermal ellipsoids shown at 60% probability.
eroded the diastereoselectivity in comparison to the examples
having diaryl alkynes (> 19:1 d.r. for all the cases). To further
evaluate the regioselectivity of the reaction with respect to
unsymmetrical alkynes, one sterically differentiated alkyne
(
2h) and two alkyl-aryl mixed alkynes (2i,j) were studied.
Gratifyingly, they participated in the [5+2] annulation to give
g’–i’ in 80–97% yields with excellent regioselectivity (> 19:1
3
r.r.), albeit with low diastereoselectivity. Remarkably, the
diastereoselectivity for the process with alkyl-aryl alkynes
could be enhanced by using alkynes with a larger alkyl group
Scheme 2. Mechanistic studies.
Angew. Chem. Int. Ed. 2015, 54, 15385 –15389
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 15387

.
Angewandte
Communications
with alkyne 2a (1.0 equiv) afforded the corresponding
products 3r and 3p, respectively, in a 1.8:1 ratio (Scheme 2b).
The preferential formation of 3r, having an electron-rich
substituent, implies that the slow hydrogen abstraction might
occur after the electrophilic attack of palladium(II) on the
Keywords: annulations · arenes · CÀH activation · heterocycles ·
palladium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15385–15389
Angew. Chem. 2015, 127, 15605–15609
[18]
aromatic ring in the CÀH activation process. Moreover,
[
[
1] B. Zhang, M. Bao, C. Zeng, X. Zhong, L. Ni, Y. Zeng, X. Cai,
Org. Lett. 2014, 16, 6400.
2] a) J. S. Nair, T. Sheikh, A. L. Ho, G. K. Schwartz, Anticancer Res.
reacting the palladacycle complex 4, which was generated
[15a]
from 1a by palladium(II)-mediated CÀH bond cleavage,
with an equal molar amount of 2a successfully led to 3a in
3% yield (Scheme 2c), thus providing solid evidence to
2
013, 33, 1307; b) G. T. Wong, D. Manfra, F. M. Poulet, Q. Zhang,
9
H. Josien, T. Bara, L. Engstrom, M. Pinzon-Ortiz, J. S. Fine, H. J.
Lee, L. Zhang, G. A. Higgins, E. M. Parker, J. Biol. Chem. 2004,
279, 12876.
support a free-amine-directed CÀH activation mechanism for
the title transformation. Finally, two control reactions were
performed, and the experimental data revealed that 3a was
not formed from 5 by a possible amination/oxidation
[3] R. Rajagopalan, A. Bandyopadhyaya, D. R. Rajagopalan, P.
Rajagopalan, Bioorg. Med. Chem. Lett. 2014, 24, 576.
[4] S. Pegoraro, M. Lang, T. Dreker, J. Kraus, S. Hamm, C. Meere, J.
Feurle, S. Tasler, S. Prütting, Z. Kura, V. Visan, S. Grissmer,
Bioorg. Med. Chem. Lett. 2009, 19, 2299.
[16a]
sequence (Scheme 2d),
but generated through the tauto-
merization of its enamine-counterpart 6 (Scheme 2e).
A plausible reaction mechanism based on the above
results is proposed in Scheme 3. The catalytic cycle is initiated
with an amino-assisted CÀH bond cleavage of 1a by Pd-
[
5] For selected recent reviews, see: a) D. A. Colby, R. G. Bergman,
J. A. Ellman, Chem. Rev. 2010, 110, 624; b) K. Fagnou, Top. Curr.
Chem. 2009, 292, 35; c) T. Satoh, M. Miura, Chem. Eur. J. 2010,
16, 11212; d) J. Wencel-Delord, T. Drçge, F. Liu, F. Glorius,
Chem. Soc. Rev. 2011, 40, 4740; e) C. S. Yeung, V. M. Dong,
Chem. Rev. 2011, 111, 1215; f) K. M. Engle, T. Mei, M. Wasa, J.
Yu, Acc. Chem. Res. 2012, 45, 788; g) L. A. Ackermann, Acc.
Chem. Res. 2014, 47, 281; h) G. Song, X. Li, Acc. Chem. Res.
(
OAc) to give rise to a stable palladacycle (4). Next, this
2
dimeric palladium complex is broken into its component parts
2
015, 48, 1007.
[
[
6] a) D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K.
Fagnou, J. Am. Chem. Soc. 2008, 130, 16474; b) Z. Shi, C.
Zhang, S. Li, D. Pan, S. Ding, Y. Cui, N. Jiao, Angew. Chem. Int.
Ed. 2009, 48, 4572; Angew. Chem. 2009, 121, 4642; c) D. Zhao, Z.
Shi, F. Glorius, Angew. Chem. Int. Ed. 2013, 52, 12426; Angew.
Chem. 2013, 125, 12652.
7] a) S. Rakshit, F. W. Patureau, F. Glorius, J. Am. Chem. Soc. 2010,
1
1
6
32, 9585; b) L. Wang, L. A. Ackermann, Org. Lett. 2013, 15,
76; c) M. Zhao, Z. Ren, Y. Wang, Z. Guan, Org. Lett. 2014, 16,
08.
[
[
8] a) D. A. Colby, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
2008, 130, 3645; b) N. Guimond, K. Fagnou, J. Am. Chem. Soc.
Scheme 3. Proposed mechanism.
2
009, 131, 12050.
9] a) N. Guimond, C. Gouliaras, K. Fagnou, J. Am. Chem. Soc.
by 2 to form the intermediate I. Notably, it was known from
prior work that migratory insertion of the alkyne 2 with 4
favored a regioselective insertion into the PdÀC bond to
2
2
010, 132, 6908; b) T. K. Hyster, T. Rovis, J. Am. Chem. Soc.
010, 132, 10565; c) X. Xu, Y. Liu, C. Park, Angew. Chem. Int.
Ed. 2012, 51, 9372; Angew. Chem. 2012, 124, 9506; d) D. Yu, F.
Azambuja, T. Gensch, C. G. Daniliuc, F. Glorius, Angew. Chem.
Int. Ed. 2014, 53, 9650; Angew. Chem. 2014, 126, 9804.
[15b]
afford the eight-membered intermediate II.
Furthermore,
CÀN reductive elimination takes place to deliver the enam-
[
10] a) N. Umeda, H. Tsurugl, T. Satoh, M. Miura, Angew. Chem. Int.
Ed. 2008, 47, 4019; Angew. Chem. 2008, 120, 4083; b) M. P.
Huestis, L. Chen, D. R. Stuart, K. Fagnou, Angew. Chem. Int. Ed.
ine-containing dibenzo[b,d]azepine 6 and concomitantly
regenerate Pd(OAc) to complete the cycle. Finally, tautome-
2
rization of 6 leads to the formation of the thermodynamically
more stable 3a as the sole product.
2
011, 50, 1338; Angew. Chem. 2011, 123, 1374; c) L. Wang, J.
Huang, S. Peng, H. Liu, X. Jiang, J. Wang, Angew. Chem. Int. Ed.
2013, 52, 1768; Angew. Chem. 2013, 125, 1812; d) W. Dong, L.
Wang, K. Parthasarathy, F. Pan, C. Bolm, Angew. Chem. Int. Ed.
In summary, we have developed an unprecedented
palladium(II)-catalyzed [5+2] oxidative annulation of biaryl
precursors with alkynes by relying on a CÀH activation
2
013, 52, 11573; Angew. Chem. 2013, 125, 11787; e) X. Wang, H.
Tang, H. Feng, Y. Li, Y. Yang, B. Zhou, J. Org. Chem. 2015, 80,
238; f) Y. Yang, M. Zhou, X. Ouyang, R. Pi, R. Song, J. Li,
Angew. Chem. Int. Ed. 2015, 54, 6595; Angew. Chem. 2015, 127,
695.
approach. This method provides a straightforward and atom-
economical access to a new class of fascinating imine-
containing dibenzo[b,d]azepines in high yields and stereose-
lectivities by using readily available o-arylanilines and
alkynes as starting materials.
6
6
[11] For examples of [5+2] reactions between amines and alkynes,
see: a) M. Zhou, R. Song, C. Wang, J. Li, Angew. Chem. Int. Ed.
2
013, 52, 10805; Angew. Chem. 2013, 125, 11005; b) M. Zhou, R.
Song, J. Li, Angew. Chem. Int. Ed. 2014, 53, 4196; Angew. Chem.
014, 126, 4280.
2
Acknowledgements
[
12] a) J. Nan, Z. Zuo, L. Luo, L. Bai, H. Zheng, Y. Yuan, J. Liu, X.
Luan, Y. Wang, J. Am. Chem. Soc. 2013, 135, 17306; b) Z. Zuo,
X. Yang, J. Liu, J. Nan, L. Bai, Y. Wang, X. Luan, J. Org. Chem.
2015, 80, 3349.
This work was supported by the NSFC (21222201, 21271147,
5
1202192) and the “1000 Youth Talents Plan”.
1
5388 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 15385 –15389

Angewandte
Chemie
[
13] a) A. Seoane, N. Casanova, N. QuiÇones, J. L. MascareÇas, M.
Gulías, J. Am. Chem. Soc. 2014, 136, 834; b) N. Casanova, A.
Seoane, J. L. MascareÇas, M. Gulías, Angew. Chem. Int. Ed.
[16] a) Z. Liang, L. Ju, Y. Xie, L. Huang, Y. Zhang, Chem. Eur. J.
2012, 18, 15816; b) Z. Liang, J. Zhang, Z. Liu, K. Wang, Y.
Zhang, Tetrahedron 2013, 69, 6519; c) C. Suzuki, K. Hirano, T.
Satoh, M. Miura, Org. Lett. 2013, 15, 3990; d) Z. Liang, R. Feng,
H. Yin, Y. Zhang, Org. Lett. 2013, 15, 4544; e) C. Suzuki, K.
Hirano, T. Satoh, M. Miura, Org. Lett. 2015, 17, 1597.
2
015, 54, 2374; Angew. Chem. 2015, 127, 2404; when R ¼
6
H, o-
vinylphenols underwent a dearomatizing [3+2] spiroannulation
with alkynes, see: c) A. Seoane, N. Casanova, N. QuiÇones, J. L.
MascareÇas, M. Gulías, J. Am. Chem. Soc. 2014, 136, 7607; d) S.
Kujawa, D. Best, D. J. Burns, H. W. Lam, Chem. Eur. J. 2014, 20,
[17] CCDC 1422296 (3d), 1422295 (3m), 1422299 (3n), 1422297
(3e’major), 1422298 (3e’minor), and 1430680 (3j’) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
[18] a) X. Zhao, C. S. Yeung, V. M. Dong, J. Am. Chem. Soc. 2010,
132, 5837; b) C. Wang, D. Wang, H. Yan, H. Wang, B. Pan, X.
Xin, X. Li, F. Wu, B. Wan, Angew. Chem. Int. Ed. 2014, 53, 11940;
Angew. Chem. 2014, 126, 12134.
8
599.
14] a) W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc.
005, 127, 14560; b) J. A. Jordan-Hore, C. C. C. Johansson, M.
Gulías, E. M. Beck, M. J. Gaunt, J. Am. Chem. Soc. 2008, 130,
[
[
2
1
1
6184; c) S. H. Cho, J. Yoon, S. Chang, J. Am. Chem. Soc. 2011,
33, 5996.
15] a) J. Albert, J. Granell, J. Zafrilla, M. Font-Bardia, X. Solans, J.
Organomet. Chem. 2005, 690, 422; b) J. Albert, L. DꢀAndrea, J.
Granell, J. Zafrilla, M. Font-Bardia, X. Solans, J. Organomet.
Chem. 2007, 692, 4895.
Received: September 21, 2015
Published online: November 2, 2015
Angew. Chem. Int. Ed. 2015, 54, 15385 –15389
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 15389