Palladium-Catalyzed [4+2] and [5+2] Annulation for the Synthesis of Tetrahydroquinolines and 1,4-Benzoxazepines

Article abstract of DOI:10.1002/ejoc.202000262

Palladium-catalyzed [4+2] and [5+2] annulations of propargyl carbonates with malonate-tethered anilines and 2-aminobenzylic alcohols were developed, giving the corresponding tetrahydroquinolines and 1,4-benzoxazepines, respectively, in good to excellent yields.

Full text of DOI:10.1002/ejoc.202000262

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Palladium-Catalyzed [4+2] and [5+2] Annulation for the Synthesis
of Tetrahydroquinolines and 1,4-Benzoxazepines
Authors: Zhao-Fei Zhang, Yan Zhang, Chun-Lin Zhang, and Song Ye
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000262
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01/2020

10.1002/ejoc.202000262
European Journal of Organic Chemistry
COMMUNICATION
Palladium-Catalyzed [4+2] and [5+2] Annulation for the Synthesis
of Tetrahydroquinolines and 1,4-Benzoxazepines
Zhao-Fei Zhang,[a],[b] Yan Zhang,[a] Chun-Lin Zhang,*,[a] and Song Ye*,[a],[b]
[a]
Dr. Z.-F. Zhang, Y. Zhang, Dr. C-L. Zhang, S. Ye
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy
of Sciences, 100190 Beijing, China
E-mail: zhangchunlin@iccas.ac.cn; songye@iccas.ac.cn
Dr. Z.-F. Zhang, S. Ye
[b]
University of Chinese Academy of Sciences, Beijing 100049, China.
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Palladium-catalyzed [4+2] and [5+2] annulations of
propargyl carbonates with malonate-tethered anilines and 2-
aminobenzylic alcohols were developed, giving the corresponding
tetrahydroquinolines and 1,4-benzoxazepines, respectively, in good
to excellent yields.
Tetrahydroquinoline and benzoxazepine derivatives are
ubiquitous structural motifs in numerous bioactive products and
pharmaceuticals (Figure 1).[1] Consequently, significant attention
has been devoted to the synthesis of these molecules. Many
synthetic methods for tetrahydroquinolines have been developed,
including hydrogenation of quinolines,[2] aza-Diels-Alder
reactions,[3] and Reissert-type reactions.[4] Benzoxazepines can
be accessed by Beckmann or Schmidt rearrangements,[5]
transition-metal catalyzed cross-coupling.[6]
Scheme 1. Palladium catalyzed annulations for the synthesis of
tetrahydroquiolines and 1,4-benzoxazepines.
The model reaction of malonate-tethered aniline 1a and
propargyl carbonate 2a was investigated under palladium
catalysis (Table 1). We were happy to find the desired [4+2]
annulation product 3a was formed in 62% NMR yield when the
reaction was carried out using 10 mol% Pd2dba3•CHCl3 and 20
mol% DPPF as the catalyst and ligand at 80 oC in toluene (entry
1). A series of bisphophine ligands were then screened (entries
2-7) and DPPP performed best to give 3a in 92% yield (entry 3).
o
Lowering the reaction temperature to 40 C decreased the yield
(entry 8). Screening of the solvent revealed that 1,4-dioxane was
the best of choice, giving 3a in near-quantitative yield (entries 8-
10). The excellent yield (99%) was kept when the loading of
palladium catalyst was reduced to 3 mol% (entry 11). Further
reducing of the loading of Pd catalyst to 1 mol% resulted in
decreased yield (70%, entry12). Other typical metal complex,
such as Pd(OAc)2, [Pd(η3-C3H5)Cl]2 and Ni(cod)2 could not give
better results (entries 13-15). Control experiments revealed that
the reaction did not occur in the absence of palladium or ligand
(entries 16-17).
Figure 1. Selected biologically active tetrahydroquinolines and 1,4-
benzazepines.
The
palladium-catalyzed
cyclization
of
propargylic
compound,[7] particularly of propargylic carbonates,[8] via the key
intermediate of π-propargyl palladium has been well developed
for the synthesis of various cyclic compounds. In this paper, we
reported a palladium-catalyzed [4+2] annulation of propargylic
carbonates with malonate-tethered anilines[9] to give
tetrahydroquinoline (Scheme 1, reaction a). The corresponding
[5+2] annulation of propargylic carbonates with 2-aminobenzylic
alcohols to give 1,4-benzoxazepines was also realized (Scheme
1, reaction b).
1
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10.1002/ejoc.202000262
European Journal of Organic Chemistry
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Table 1. Optimization of the Reaction Conditions. [a]
Entry
1
[M]
Ligand
DPPF
DPPE
DPPP
DPPB
Xantphos
DPEphos
XPhos
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
/
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
Yield (%)[b]
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd(OAc)2
62
89
92
80
24
31
24
70
98
>99
2
Scheme 2. Synthesis of tetrahydroquinolines 3.
3
4
With the optimized condition in hand, a series of malonate-
tethered anilines was then tested for the palladium catalyzed
[4+2] annulation reaction (Scheme 2). It was found that the N-
benzenesulfonyl group worked as well as the N-tosyl group,
giving the corresponding tetrahydroquinoline (3b) in high yield.
Besides diethyl, dimethyl malonate-tethered anilines worked as
well (3c), while diisopropyl malonate resulted in some decreased
yield (3d). Both electron-donating groups and electron-
withdrawing groups were well tolerated on the anilines, giving
the corresponding products (3e-3i) in good to high yields.
Interestingly, the malonate-tethered 2-aminopyridine (1j) worked
as well to give the corresponding tetrahydronaphthyridine 3j in
good yield, which is a core structure for various bioactive
compounds.[10]
5
6
7
8c
9
10
11[d]
12[f]
13[d]
14[d]
15[d]
16
17
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
>99 (98[e]
)
70[e]
37
70
10
0
[Pd(η3-C3H5)Cl]2
Ni(cod)2
/
Pd2dba3·CHCl3
0
Scheme 3. Synthesis of benzazepine 5.
[a] Reaction condition: 1a (0.2 mmol, 83.0 mg), 2a (0.26 mmol, 40 L),
Cs2CO3 (0.2 mmol), Pd2dba3•CHCl3 (0.02 mmol), ligand (0.04 mmol), N2
atmosphere. [b] NMR yield using 1,3,5-trimethoxybenzene as an internal
standard. [c] The reaction was conducted at 40 oC. [d] 3 mol % [M] and 6
mol % ligand were used. [e] Isolated yield. [f] 1 mol% [M] and 2 mol% ligand
were used.
The [5+2] annulation of malonate-tethered aniline 4 with one
more carbon linkage was also carried out in the standard
conditions, which afforded the desired benzazepine 5 in 81%
yield (Scheme 3).
Scheme 4. Synthesis of 1,4-benzoxazepines 7.
2
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10.1002/ejoc.202000262
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The investigation was continued by using 2-amino benzyl
alcohol 6 as the 1,5-bisnucleophile for the reaction, which led to
synthesis of the corresponding 1,4-benzoxazepines (7a-7e) in
good yields (Scheme 4).[11]
Scheme 5 Synthesis of piperazines
In addition, the reaction of benzene-1,2-diamine and ethane-
1,2-diamine worked well for the reaction, giving the
corresponding piperazines 8a and 8b, respectively, in good
yields (Scheme 5).[8h]
Scheme 6. Further chemical transformations.
The resulted highly functionalized tetrahydroquinolines
affords many possible further chemical transformations. For
example, the N-tosyl group in compound 3c could be removed
by Mg/MeOH (Scheme 6, reaction a). Compound 3f could
readily undergo the cross-coupling reactions with phenylboronic
acid and aniline to give the corresponding products 10 and 11,
respectively, in good to high yields.[13]
The structure of compound 3c was determined by X-ray
analysis of its single crystal (Figure 2).[12]
In summary, the palladium-catalyzed [4+2] and [5+2]
annulations of propargyl carbonate with malonate-tethered
anilines and 2-aminobenzylic alcohol were developed, giving the
corresponding tetrahydroquinolines and 1,4-benzoxazepines,
respectively, in good to high yields. The reaction features ready
available starting materials, efficient construction of six- and
seven-membered heterocycles with potential bioactivities.
Acknowledgements ((optional))
This work was supported by Beijing National Laboratory for
Molecular Sciences (BNLMS-CXXM-202003), the National
Natural Science Foundation of China (Nos 21521002,
21831008).
Figure 2. X-ray structure of 3c
Keywords: Tetrahydroquinolines • 1,4-Benzoxazepines •
Annulation • Palladium Catalysis • Propargyl carbonates
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Entry for the Table of Contents
Key Topic: N-heterocycles Synthesis
A general strategy for the synthesis of tetrahydroquinolines and 1,4-benzoxazepines has been developed via palladium-catalyzed
[4+2] and [5+2] annulations of propargyl carbonates with malonate-tethered anilines and 2-aminobenzylic alcohols. A series of six-
and seven-membered heterocycles with potential bioactivities was obtained in good to excellent yields.
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