Visible-light driven synthesis of polycyclic benzo[: D] [1,3]oxazocine from 2-aminochalcone

Article abstract of DOI:10.1039/d0cc02416c

Herein, we report a tandem cycloisomerization/nucleophilic addition/cyclization of 2-amino chalcone with bifunctional nucleophiles driven by visible light. This cascade process is realized by the irradiation of a blue LED at room temperature, which provides a concise route to structurally diverse benzo[d][1,3]oxazocine scaffolds. Mechanistic studies show that the reaction is initiated with the E to Z isomerization of a C-C double bond upon the irradiation of visible light, followed by cyclization/rearomatization to generate a transient quinolinium intermediate, which is trapped by the nucleophile and cyclized to produce the polycyclic benzo[d][1,3]oxazocine.

Full text of DOI:10.1039/d0cc02416c

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DOI: 10.1039/D0CC02416C
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Visible-Light Driven Synthesis of Polycyclic Benzo[d][1,3]oxazocine
From 2-Aminochalcone
Received 00th January 20xx,
Accepted 00th January 20xx
Yu-Qi Gao,a Yi, Hou,a Liming Zhu,c Junhan Chen,a Ruoxin Li,a Sheng-Yong Zhang,b* Yu-Peng He,c*
and Weiqing Xiead*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein, we report
a
tandem cycloisomerization/nucleophilic
Harnessing visible light in the presence of photoredox
addition/cyclization of 2-amino chalcone with bifunctional catalyst for chemical synthesis has experienced incredible
nucleophiles driven by visible light. This cascade process is progresses due to the increasing demand for developing green
realized by the irradiation of blue LED at room temperature, which and sustainable chemistry.4 In most cases, photoredox catalyst
provides
a
concise
access
to
structurally diverse plays an important role in transferring light energy to reaction
benzo[d][1,3]oxazocine scaffold. Mechanistic studies show that partners via redox neutral pathway. Depending on the unique
the reaction is initiated with the E to Z isomerization of C-C double activating mode of photoredox catalyst, molecules could be
bond upon the irradiation of visible light, followed by activated via energy transfer or single electron transfer (SET)
cyclization/rearomatization to generate a transient quinolinium pathways and involved in the subsequent transformations. In
intermediate, which is trapped by the nucleophile and cyclized to this context, the directly utilizing visible light for
produce the polycyclic benzo[d][1,3]oxazocine.
dearomatization reaction in the absence of any photoredox
catalyst or sensitizer has remained scarcely developed.5
Dearomatization is a promising strategy for creating
complex architecture from easily available aromatic
molecules.1 Particularly, it enables building up sp3-rich
carbocyclic molecules with unique three-dimensional structure
from planar molecules via cycloaddition or cascade process,
1. previous works
R4
R1
R4
R2
alkylation
R2
OH
R1
R1
N
R3
2
N
O
N
base
heating
R3
R2
X
which offer
a competent tool for increasing structural
1
3
complexity. However, this strategy largely relies on the innate
reactivity of aromatic compounds and those with higher
resonance energy often show inert reactivity, which needs
force reaction conditions (e.g. Birch reduction, using
organolithium reagent) to break up the aromaticity.2 Therefore,
generation of reactive species by combining hetereoaromatic
molecules with activating reagents constitutes an alternative
strategy for the dearomatization reaction.3 However, this
protocol needs the pre-activation of the hetereoaromatic
compounds, which complicates the operation.
need of base as acid scavenger;
narrow substrate scope;
stepwise synthesis;
preactivation of quilonine;
2. this work
C
blue
LED
O
C
O
R1
R1
O
R2
R2
R1
N
R3
R2
(in situ)
N
R3
6
HX (cat.)
NHR3
X
4
5
free of base;
wide substrate scope;
visible light driven synthesis;
mild reaction coditions;
Figure 1. Previous protocols for the synthesis polycyclic benzo[d][1,3]oxazocine and a
light-driven synthesis of such scaffold.
Benzoxazocine is a family of molecules embedding both
oxygen and nitrogen in the eight-membered ring system,
which exhibits important pharmaceutical properties including
analgesic, antithrombotic, anticancer and antioxidant
activities.6 In this regard, benzo[d][1,3]oxazocine is far less
studied despite of its tetrahydruquinoline7 and N,O-acetal8
moieties which are commonly existed in natural products and
pharmaceutical molecules. In previous reports,9 quinolinium
salts 2 have been employed for the synthesis of such skeleton
a. Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of
Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling
712100, Shaanxi, China. Email: xiewq@nwafu.edu.cn
b. Department of Chemistry, Fourth Military Medical University, Xi’an 710032,
China. Email: syzhang@fmmu.edu.cn
c. College of Chemistry, Chemical Engineering and Environmental Engineering,
Liaoning Shihua University, Dandong Lu West 1, Fushun 113001, China. Email:
yupeng.he@lnpu.edu.cn
d. Key Laboratory of Botanical Pesticide R&D in Shaanxi Province, Yangling, Shaanxi
712100, China.
Electronic Supplementary Information (ESI) available: General experimental
procedures, and spectroscopic date for the all new compounds. See
DOI: 10.1039/x0xx00000x
via
nucleophilic
dearomatization
with
bifunctional
nucleophiles (Figure 1). However, base is needed to
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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functionalize as the acid scavenger and a preformation of yield (Table 1, entries 2 to 5). Survey of solvent was then
View Article Online
quinolinium from quinoline is necessitated. Furthermore, performed (Table 1, entries 6 to 11). EDthOeI:r1e0a.1l0s3o9/lvDe0nCtCs02(E41t62OC
those precedents showed narrow substrate scope and only and THF) as well as toluene were all suitable for this reaction,
phenol or naphthol have been surveyed as the bifunctional while longer time was needed to secure the full consumption
nucleophile.
of 4a (Table 1, entries 6 to 8). Non-polar solvents such as CCl4,
Recently, we disclosed a bio-inspired synthesis of hybrid gave much lower yields, while other halogenated solvents (eg.
flavonoids from 2-hydroxychalconet.10 This reaction relies on CHCl3 and CH2ClCH2Cl) gave comparable yields (Table 1, entries
the generation of a reactive transient flavylium from 2- 9 to 12). To our surprise, almost quantitative yield was
hydroxychalcone under the irradiation of 24W CFL followed by obtained in control reaction with the absence of any promoter
dehydrated cyclization, which in situ engaged in the (Table 1, entry 12). This result indicated a different reaction
subsequent cascade transformations to deliver hybrid pathway may be involved compared with our previous report.
flavonoids. In continuation of our work on this bio-inspired In contrast, no product could be detected when the reaction
strategy, we surmised that under the irradiation of visible light, was performed in dark, which was consisted with our previous
2-amiochalcone
4
would
undergo
tandem
E-Z observation (Table 1, entry 13).
isomerization/cyclization/dehydration process to yield
a
O
C
transient quinolinium 5. Subsequently, this intermediate
would involve in cascade nucleophilic addition/cyclization
process, delivering polycyclic benzo[d][1,3]oxazocine 6. Herein,
we would like to report our preliminary results on this visible-
light driven synthesis, which eliminates the pre-activation of
quinoline and the use of strong base.
CH2Cl2
R2
R1
O
R1
+
Nu
blue LED
4A MS
RT
Bn
N
R2
N
H
Bn
4
6
Nu = cyclohexan-1,3-dione (7)
O
O
5
6
, R2 = 2-OMePh
, R2 = 4-OMePh 87%
R1
7
6ae
6af
95%
Table 1. Survey of the reaction conditions.a
8
, R2 = 4-MePh
, R2 = 4-ClPh
, R2 = 4-BrPh
6ag
79%
82%
O
N
N
O
6ah
6ai
R2
Bn
Bn
Ph
, R2 = Ph
O
85%
96%
93%
92%
92%
O
99%
99%
6aa
2 = 4-FPh
6aj,
6ak
6al,
R
conditions
O
1 mmol scale
6ab
O
Ph
, R2 = Me
, R1 = 6-Me 96%
+
R
2 = i-Bu
blue LED
RT
O
N
6ac,
6ad
R
1 = 6-Cl
, R1 = 7-Br
91%
90%
NHBn
, R2 = t-Bu
6am
Bn
Ph
6aa
6aa
ORTEP of
4a
7
Nu = 4-hydroxycoumarin (8)
O
entry
catalyst
solvent
time
yieldb
(%)
97
95
96
95
98
97
90
96
70
97
98
99
ND
, R3 = 2-OMePh
, R3 = 4-OMePh
, R3 = 4-MePh
, R3 = 4-ClPh
O
5
75%
97%
94%
6be
R16
7
O
O
6bf
(min)
20
10
10
20
15
25
65
25
90
15
10
10
13
6bg
6bh
6bi
1
2
3
4
5
6
7
8
HCl
TsOH
CSA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Et2O
PhCH3
CCl4
CH2ClCH2Cl
CHCl3
CH2Cl2
CH2Cl2
8
99%
N
O
N
O
, R3 = 4-BrPh
R2
Bn
95%
98%
R2
, R3 = Ph
Bn
3 = 4-FPh
6bj,
6bk
6bl,
R
99%
89%
6ba
, R3 = Me
88%
80%
97%
(PhO)2O=POH
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
--
1 mmol scale
6bb
R
3 = i-Bu
, R3 = 6-Me 84%
, R3 = t-Bu
6bm
, R3 = 6-Cl
, R3 = 7-Br
95%
6bc
6bd
99%
6ba
ORTEP of
Scheme 1. Substrate scope with respect to cyclohexan-1,3-dione and 4-
hydroxycoumarin as nucleophile.
9
10
11
12
13c
With the optimal reaction conditions being on hand, we
turned our attention to examine the substrate scope of this
reaction (Scheme 1). Electron-donating and electron-
withdrawing groups (R1) presented on the aniline ring were all
tolerated, delivering benzo[d][1,3]oxazocine 6aa11 to 6ad in 90%-
96% yields. On the other hand, 2-aminochalcone with both
electron-rich and electron-deficient phenyl (R2) could also be
smoothly transferred to benzo[d][1,3]oxazocine 6 in good
excellent yields (Scheme 1, 6ae to 6aj). It was noteworthy that
the alkyl substituted enone (R2 = Me, i-Bu and t-Bu) could also
be employed, affording benzo[d][1,3]oxazocine 6ak to 6am in
excellent yields. Furthermore, tetrahydroquinoline hybrid
coumarin could be facilely established by using 4-
hydroxycoumarin as the reaction partner under the irradiation
of blue LEDs. Slight decrease in isolated yield was observed
when electron-donating group was attached on the aniline ring
(R1 = 6-Me), while electron-withdrawing groups (R1 = 6-Cl or 7-
Br) were compatible (Scheme 1, 6ba to 6bd). Excellent yields
--
a
Reaction conditions: To a mixture of 2-aminochalcone 4a (0.1 mmol) and
cyclohexan-1,3-dione 7 (0.12 mmol) was added solvent (3 mL) and 4Å MS (100
mg). The reaction mixture was stirred with the irradiation of blue LED. isolated
yields. c The reaction was carried out in dark.
b
On the outset, reaction of 2-aminochalcone 4a with
cyclohexan-1,3-dione
7 was evaluated to validate our
hypothesis. To our delight, the desired benzoxazocine 6aa
could be isolated in 97% yield under the irradiation of
household blue LED in the presence of catalytic amount of
hydrochloride (Table 1, entry 1). It should be pointed out that
the reaction proceeded very fast, reaching full conversion of
4a only in 10 min. Subsequently, screening of different
Brønsted acids revealed that benzoic acid was the most
optimal promoter, which provided the desired product in 98%
2 | J. Name., 2012, 00, 1-3
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were detected for hybrid coumarin 6bf to 6bj excepting 6be, cyclohexan-1,3-dione was observed (Scheme 3, eqn (1)).
View Article Online
indicating the reaction was insensitive to the electronic Irradiation of 4a in (CD3)2CO with bDluOeI: 1L0E.1D03s9/lDe0dCCt0o24t1h6Ce
1
property of R2. The low yield for 6be may be originated from identification of the putative N,O-acetal 11 by H NMR, which
steric hindrance of 2-OMe. Eventually, when R2 was alkyl such was too unstable to be isolated (Scheme 3, eqn (2)).
as Me, i-Bu and t-Bu, corresponding hybrid coumarins 6bk to Fortunately, the quinolinium salt 12 could be obtained from 4a
6bm could be isolated in high yields.
in quantitative yield in the presence of stoichiometric TFA
under the irradiation of blue LEDs, while no product were
detected when the reaction was run in the dark (Scheme 3,
eqn (3)). Furthermore, nucleophilic attack of cyclohexan-1,3-
dione to quinolinium salt 12 proceeded very slowly (Scheme 3,
eqn (4)), which needed four days to reach full conversion.
However, this reaction was significantly accelerated when
stoichiometric Et3N was employed as acid scavenger.
R4
O
O
R1
OH
OH
CH2Cl2
R2
R1
+
HO
R3
blue LED
4A MS
RT
N
N
R4
R3
R2
6
H
4
9
HO
5
6
, R2 = 2-OMePh
R1
7
6ce
6cf
65%
HO
OH
, R2 = 4-OMePh 80%
, R2 = 4-MePh
6cg
OH
82%
62%
69%
33%
62%
O
8
O
CH2Cl2
in the dark
O
2
N
6ch
6ci,
6cj,
6ck
, R = 4-BrPh
2 = 4-FPh
O
O
Bn
Ph
O
N
(1)
R
R
+
R2
Bn
2d, NR
2
2
83%
6ca
6cb
6cc
6cd
, R = Ph
= Me
NHBn
O
N
, R1 = 6-Me
, R1 = 6-Cl
, R1 = 7-Br
, R = t-Bu
2
51%
45%
42%
4a
Bn
Ph
6aa
O
5
6
, R1 = H
R1
7
95%
93%
98%
96%
(CD3)2CO
6co
(2)
(3)
OH
OH
HO
1 mmol scale
Ph
OH
blue LED
RT
N
NHBn
8
6cp
R
1 = 6-Me
73% by 1H NMR
O
O
Bn
N
OH
, R1 = 7-Br
4a
6cq
Bn
11
Ph
O
N
R3
O
TFA (1 equiv)
CH2Cl2
Ph
, R3 = Boc
, R3 = Ts
3 = Me
, R2 = 4-MePh
, R2 = 4-ClPh
6cr
86%
93%
90%
6cl
N
Ph
ND
6cs
6ct
1. blue LED, RT, 85%
2. in dark, RT, ND
TFA
NHBn
6cm
6cn,
Bn
, R2 = t-Bu
ND
59%
N
R
12
R2
Me
Bn
4a
O
O
O
HO
in dark
(4)
OH
Me
N
1. none, 4d, 84%
2. Et3N (1 equiv.), 10 min, 99%
O
N
TFA
Bn
Bn
N
O
N
O
Ph
6aa
Bn
Bn
Ph
12
Ph
6cu
6co
ORTEP of
6cv
, 57%
, 42%
Scheme 3. Mechanistic studies.
Scheme 2. Substrate scope using other bifunctional nucleophiles.
Based on the mechanistic studies together with previous
reports,13 we proposed the reaction pathway for this reaction.
The initial step was the light-driven E to Z isomerization of 2-
aminochalcone, which was followed by cyclization to afford
N,O-acetal 11. In following step, the rearomatization of N,O-
acetal 11 might act as the drive force for the generation of a
quinolinium 14 and hydroxide, which deprotonated the
cyclcohexa-1,3-dione to form an enolate 15. Nucleophilic
attack of enolate 15 to the C4 of quinolinium 14 gave coupled
product 16. The intramolecular proton transfer from the enol
to the enamine moiety of 16 would produce iminium 17, which
eventually underwent intramolecular cyclization to deliver the
benzo[d][1,3]oxazocine 6aa.
Next, we also evaluated pholoroglucinol as bifunctional
nucleophile (Scheme 2). The reaction was sensitive to the
substituents on the aniline ring and much lower yields (42% to
52%) were obtained for both electron-withdrawing and
electron-donating groups (Scheme 2, 6ca to 6cd). With respect
to R2, phenyl with electron-donating group (Scheme 2, 6cf and
6cg) gave higher yields than those with electron-withdrawing
group (Scheme 2, 6ch and 6ci). To our delight, even alkyl group
could be tolerated, albeit resulting in lower isolated yield
(Scheme 2, 6cj and 6ck). Alkyl protected-amino was
indispensable for the success of this reaction as Boc protected
substrate only delivered 2-phenylquinoline in 86% yield
(Scheme 2, 6cl) and Ts protected 2-aminochalcone only led to
recovery of starting material. Less bulky methyl on amino was
detrimental for the outcome (Scheme 2, 6cn). In sharp
contrast, resorcinol was a more suitable nucleophile for this
reaction, delivering 6co11 to 6ct in excellent isolated yields
irrespective to the electronic property of R1 and R2. When
orcinol was employed as nucleophile, two regioisomers 6cu
and 6cv12 were isolated in 57% and 42% yield respectively.
To shed light on the reaction mechanism of this reaction, a
series of control reactions were carried out. When the reaction
was run in the dark, no conversion of 2-aminochalcone 4a or
O
Ph
blue LED
Ph
Ph
OH
O
cyclization
double bond
isomerization
N
NH
NHBn
4a
Bn
Bn
13
O
11
H
OH
O
O
O
H
O
O
O
6aa
N
Ph
Ph
N
N
Ph
O
Bn
Bn
14
Bn
17
15
16
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Scheme 4. Proposed reaction pathway.
113, 5322-5363; (e) T. P. Nicholls, D. Leonori and A. C.
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1433-1435.
In summary, a visible-light driven synthesis of polycyclic
benzo[d][1,3]oxazocine
from
2-aminochalcone
with
5
6
bifunctional nucleophile was described. This protocol enabled
facile construction of diverse benzo[d][1,3]oxazocine from an
array of substituted 2-aminochalcone with different
bifunctional nucleophiles. Mechanistic studies supported the
generation of quinolinium from 2-amonchalcene via tandem E
to Z isomerization/cyclization/rearomatization driven by visible
light, which was in situ captured by bifunctional nucleophiles.
Subsequent cyclization of the coupled product enabled
establishing the bridged ring system.
Conflicts of interest
There are no conflicts to declare
7
8
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Acknowledgement
We are grateful for financial support from the National Natural
Science Foundation of China (grants. 21722206, 21672171 to
WX and 21978124 to YH) and Shaanxi government. Financial
support from Chinese Universities Scientific Fund and the
Scientific Fund of Northwest A&F University are also
acknowledged. Innovative Talent Project of Educational
Department of Liaoning Provincial, (No. LR2018019 to YH).
9
Notes and references
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11 CCDC 1993548 and 1993549 contain the supplementary
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Crystallographic
Data
Centre
via
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12 The structure of 6cu and 6cv was established by 2D NMR
studies (see supporting information for details).
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DOI: 10.1039/D0CC02416C
O
C
Nu
, CH2Cl2
R2
O
R2
R1
blue LEDs
up to 99%
N
R3
NHR3
R2
free of base;
wide substrate scope;
visible light driven synthesis;
mild reaction coditions;