One-pot synthesis of tricyclo-1,4-benzoxazines via visible-light photoredox catalysis in continuous flow

Article abstract of DOI:10.1016/j.tetlet.2017.02.068

A facile one-pot synthesis of tricyclo-1,4-benzoxazines has been developed via metal-free intramolecular cyclization of indole derivates. These reactions were efficiently achieved at ambient temperature by using visible-light photoredox catalysis in conti

Full text of DOI:10.1016/j.tetlet.2017.02.068

Accepted Manuscript
One-Pot Synthesis of Tricyclo-1,4-Benzoxazines Via Visible-Light Photoredox
Catalysis In Continuous Flow
Guolin Wu, Tingting Lv, Wenhui Mo, Xiping Yang, Yu Gao, Haijun Chen
PII:
S0040-4039(17)30247-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.068
TETL 48679
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 January 2017
20 February 2017
21 February 2017
Please cite this article as: Wu, G., Lv, T., Mo, W., Yang, X., Gao, Y., Chen, H., One-Pot Synthesis of Tricyclo-1,4-
Benzoxazines Via Visible-Light Photoredox Catalysis In Continuous Flow, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.02.068
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One-Pot Synthesis of Tricyclo-1,4-Benzoxazines Via Visible-Light Photoredox
Catalysis In Continuous Flow
†
Guolin Wu , Tingting Lv , Wenhui Mo, Xiping Yang, Yu Gao, Haijun Chen*
†
College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
†
These authors contribute equally to this work.
ABSTRACT: A facile one-pot synthesis of tricyclo-1,4-benzoxazines has been
developed via metal-free intramolecular cyclization of indole derivates. These
reactions were efficiently achieved at ambient temperature by using visible-light
photoredox catalysis in continuous flow. This directed intramolecular cyclization
could be easily handled and scaled up in an open flask, enabling construction of a
focused compound library for further pharmacological evaluation.
Graphical Abstract
Home-Made Continuous-Flow
Photoreactor with Two
Reaction Towers
~
$460
Out
Balloon
Air or O or Ar)
(
2
In
Keywords: One-pot; Flow chemistry; Intramolecular cyclization; Metal-free; Room
temperature

Introduction
1,4-Benzoxazines as one of the common structural scaffolds ubiquitously exist in a
1
large number of pharmacological compounds which exhibit various fundamental
2
biological functions including neuroprotective, antitumor, anti-inflammatory,
3
4
5
-7
8
as well as antihypertensive effects. In particular, some
antithrombotic,
9
,10
11
benzoxazines have been developed as antibacterial agents,
antipsychotic agents,
1
2
and cardiovascular drugs . For example, levofloxacin (Figure 1) with 1,4-
benzoxazine moiety exhibits excellent antibiotic activities against a range of
1
bacteria. Similar fragment is also found in the antiemetic agent azasetron which has
3
1
4
3
been recognized as a typical member of 5-HT receptor antagonists. DIMBOA (2,4-
dihydroxy-7-methoxy-1,4-benzoxazin-3-one) is a naturally-occurring hydroxamic
acid found in maize, which has the property of modifying the binding affinity of
1
5,16
auxins to receptor sites.
More recently, our previous work by utilizing scaffold
1
repurposing approach has identified tricyclo-1,4-benzoxazine derivatives as potent
7
anticancer agents with promising antiproliferative activities against various cancer
1
8
cell lines.
Figure 1. Representative 1,4-benzoxazine-containing pharmacological compounds.

The extensive utility of 1,4-benzoxazines derives organic chemists to develop a
range of preparative strategies with easy scalability, improvement in efficiency, as
well as reduction in cost/waste. Traditional methods to synthesize 1,4-benzoxazines
8
,14,19
20,21
involve multistep processes including cyclocondensation
, epoxide opening
2
2-24
and metal catalyzed reaction.
In our continuing effort to develop novel diversified
analogues, we directed our library construction based on the scaffold of tricyclo-1,4-
benzoxazines. Although extensive studies have been carried out for the synthesis of
benzoxazines, there are few reports on this scaffold. One similar report by Saito
involved the reaction of 3-substituted indoles with singlet oxygen followed by
2
5,26
catalytic HCI induced rearrangement of the resulting peroxidic intermediates.
We
employed the starting material 1a, the photocatalyst rose bengal, and MeOH. The
mixture was vigorously stirred and irradiated with a tungsten-bromine lamp in the
o
at -70 C for 4 h. Treatment of the resulting hydroperoxide with
present of O
2
catalytic amounts of HCI at room temperature provided 2a in 43% yield. After many
trials under this condition, we found that this procedure suffered from several
disadvantages. Firstly, the reaction is limited in scope by the relatively low
o
temperatures (-70 C) and two steps required. Secondly, it is difficult to perform on
gram scale and the reaction always needs longer reaction time, resulting in low yields.
Thirdly, the application scope is limited, only few substrates could be performed
under this condition. Thus, there is a demand for development of a more general and
environment friendly procedure. Herein, we report our one-pot synthesis of tricyclo-
1,4-benzoxazines via visible-light photoredox catalysis in continuous flow.
Results and discussion

According to our previous work on practical N-demethylation by using our
2
7
25
upgraded home-made continuous-flow photoreactor and Saito’s procedure , we
envisioned that mild conditions (one-pot synthesis), satisfactory yields and simple
operation could be achieved. As rearrangement of the peroxidic intermediates might
be induced by acid, we first selected 1a as template substrate in the present of
catalytic methylene blue (MB) and different acids under 34 W white LEDs light
irradiation in continuous flow for the condition optimization (Table 1). Initial results
revealed that among the most tested acid (Table 1, entries 2–8), good to excellent
yields of 2a were obtained, while the replacement of TsOH with AcOH or CH
afforded 2a in low yields (entries 2 and 8). No desired product was detected if the
acid was omitted (entry 1). Notably, in the absence of O , it resulted in a loss of
3 3
SO H
2
reactivity (entries 9-10). This indicated that oxygen was crucial for the reaction to
occur. Encouraged by these promising results, we next surveyed the amount of the
acid under air atmosphere (entries 9, 11-12). Lowering the amount of TsOH to 0.5 or
0
.1 equiv slightly decreased the yield to 91% or 73%, respectively (entries 11-12).
Extensive efforts on the investigation of the molar ratios of alcohol used in the
reaction were conducted. Disappointingly, when using CH CN as the solvent and
3
lowering the amount of alcohol, the reaction requires a long time, resulting in
unsatisfied yield (entries 13). This reaction also worked smoothly in the presence of
TsOH·H
influence on the cyclization of indole derivates. Further evaluation of the
commercially available photoredox catalysts revealed that Ru(bpy) Cl •6H O can also
2
O and air (entry 14), indicating that the presence of water has a minor
3
2
2
provide the good yield (entry 15). The photoredox reaction was conducted in batch
under the similar condition. As anticipated, complete conversion of the reaction

requires more than 24 h, in contrast to flow chemistry requiring only 1 h (entries 7,
6).
Table 1. Optimization of the reaction conditions.
1
a
b
Entry
Acid (equiv.)
0
AcOH (1.0)
HCl (1.0)
Atm. Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
5
1
trace
27
1
1
1
1
91
94
87
95
H
2
SO
HNO
CF CO
4
(1.0)
(1.0)
H (1.0)
3
3
2
TsOH (1.0)
CH SO H (1.0)
1
4
99
60
3
3
TsOH (1.0)
TsOH (1.0)
TsOH (0.5)
TsOH (0.1)
TsOH (1.0)
Air
N
Air
Air
2
24
2
2
3
93
trace
91
73
60
98
89
1
1
1
0
1
2
2
c
1
3
O
O
O
O
2
2
2
2
1
4
TsOH·H O (1.0)
TsOH (1.0)
TsOH (1.0)
2
1
d
1
5
6
1
24
e
1
73
a
Reaction condition: 1a (0.2 mmol), MB (4 mol%) in MeOH (25 mL), ambient
b
temperature, irradiated with 34 W LEDs under a specific atmosphere. Isolated yield
c
3
unless otherwise noted. Reaction was conducted in CH CN (25 mL) and MeOH
d
100.0 equiv). Ru(bpy)
e
(
batch.
3 2 2
Cl •6H O as the photocatalyst. Reaction was conducted in
Having identified the optimal reaction conditions, we next set out to examine the
scopes of photoredox catalysis synthesis of 1,4-benzoxazines. As shown in Table 2, a
variety of alcohols as solvents were examined. The commonly used alcohols, such as
methanol, ethanol and propanol, underwent the cyclization smoothly which provided
the desired tricyclebenzoxazines in good yields (2a-2d). When the reaction was
3
conducted in CH CN solvent and 2-methoxyethan-1-ol was used as the nucleophiles,
gratifyingly, a moderate yield was observed (2e). In addition, the substrate scope of

2
N-monosubstituted tryptamines was explored. Typical N-protecting groups (R = Ts,
SO R, COR) on the side chain of tryptamine were all well tolerated, providing the
2
desired tricyclo-1,4-benzoxazines in good yields (2f-2g). Furthermore, reactions of
tryptophol or other tryptamines with varied alcohols were proceeded smoothly (2l-2p).
Notably, gram-scale reaction of 1a was also performed to evaluate the practicality of
this photoredox reaction. As showed in Figure 2, the corresponding product 2a was
obtained in 78%. The chemical structure of 2a was further confirmed by X-ray
2
8
analysis.
a
Table 2. Substrate scope of tricyclo-2,3-dihydro-1,4-benzoxazines.
a
Unless otherwise noted, the reaction condition was as followed: indole 1 (0.2 mmol),

3
2
MB (1.0 mmol%), TsOH (0.2 mmol), R OH (25 mL), 34 W LED light source, O , 1-3
h. Yield of isolated product. 2a-2e were synthesized from the starting material 1a, 2f
from 1b, 2g from 1c, 2h from 1d, 2i from 1e, 2j from 1f, 2k from 1g, 2l-2o from
b
tryptophol, 2p from 1h. See the Supporting Information for more details. CH
the solvent and 2-methoxyethanol (10 mmol).
3
CN as
Figure 2. The gram-scale reaction.
The proposed mechanism was depicted in Figure 3. First, methylene blue (MB)
+
is excited under visible light irradiation to produce its excited state species [MB ]*,
2
9
which interacts with A to generate cation radical B via the electron transfer. In this
+
process, the excited state [MB ]* turns to the semireduced form MB•. The radical
intermediate B readily undergoes intramolecular cyclization to give tricyclo-indole
−
2
radical C. The radical MB• transfers an electron to oxygen to produce superoxide O •
3
0
−
2
and MB• returns to its ground state. Subsequently, the generated O • reacts with the
tricyclo-indole radical C to yield hydroperoxide D. In the presence of acid, the
terminal hydroperoxy oxygen atom is protonated followed by phenyl group migration
from the benzyl carbon to the adjacent oxygen, producing a resonance stabilized
tertiary carbocation E. The tricycle-benzoxazine cation can be trapped by the O-
nucleophile, furnishing exclusively the desired product.
Conclusion
In conclusion, a practical method for the cyclization of indole derivatives via
visible-light photoredox catalysis in continuous flow has been developed. To the best
of our knowledge, there is little information available in literature about the

cyclization of tryptamine via visible-light photoredox catalysis in flow. This reaction
can be run in one-pot fashion, and does not require expensive metal-free catalysts,
providing a focused compound library in good yields within remarkably short time.
Figure 3. Proposed Mechanism.
Experimental section
General Information. All reactions were performed under a designated atmosphere
in flame‐dried round bottom flasks, magnetically stirred. Preparative column
chromatography was performed using silica gel 60, particle size 0.063–0.200 mm
(
70–230 mesh, flash). Analytical TLC was carried out employing silica gel 60 F254
plates (Merck, Darmstadt). Visualization of the developed chromatograms was
performed with detection by UV (254 nm and 365 nm). Proton Nuclear Magnetic
1 13
Resonance ( H NMR) spectra and carbon nuclear magnetic resonance ( C NMR)
1
13
spectra were recorded on a Bruker‐400 ( H, 400 MHz; C, 101 MHz) spectrometer.
Chemical shifts for protons are reported in parts per million and are references to the

NMR solvent peak (CDCl
3
: δ 7.26). Chemical shifts for carbons are reported in parts
per million and are referenced to the carbon resonances of the NMR solvent (CDCl
3
:
δ 77.16). Signals are listed in ppm, and multiplicity identified as s = singlet, d =
doublet, t = triplet, dd = doublet of doublets, m = multiplet. Chemical shifts were
expressed in ppm, and J values were given in Hz. High resolution mass spectra
(
HRMS) were obtained from Thermo Fisher Scientific Exactive Plus mass
spectrometer. Melting point was determined using the X‐4A melting point apparatus
Shanghai Yidian Co., Ltd.) and uncorrected. Purified compounds were further dried
(
under high vacuum (0.01–0.10 Torr). Yields refer to purified and spectroscopically
pure compounds, unless otherwise noted. All commercially available starting
materials and solvents were reagent grade, and used without further purification.
General procedure for the reaction in continuous flow. A 100 mL round
bottom flask equipped with a magnetic stir bar was charged with 1 (0.2 mmol), TsOH
(
0.2 mmol) and catalytic amount of MB. The corresponding alcohol (25 mL) was
added. The resulting blue solution was sucked into the Home‐Made Continuous‐Flow
Photoreactor at one end and returned at the other (rpm = 50, flow rate is ~10 mL/min).
2
The flow reaction was conducted under O in the home-made capillary photoreactor
with a LongerPump (Pump model: YZ1515x). Two 20 mL Reaction Towers were in
series connection, each with a LED corn light bulb (34 W) in the center. Relatively
mild heating (< 30 °C) of the reaction mixture was observed after a long period of
time. The flow reaction was completed in 1-3 h. After completion of the reaction by
TLC analysis, the mixture was collected and concentrated under reduced pressure.
The residue was purified by silica gel chromatography to give 2 (52-99% yields).
(
3aR,9aS)-3a-methoxy-1-tosyl-1,2,3,3a,9,9a-hexahydrobenzo[b]pyrrolo[2,3-
e][1,4]Oxazine (2a). To a solution of 1a (63 mg, 0.2 mmol) in MeOH (20 mL) was

added TsOH (34 mg, 0.2 mmol) and MB (3 mg, 4 mol%). The resulting solution was
then irradiated by a LED strip and stirred for 1 h in continuous flow. The reaction
mixture was removed from the light source and concentrated to give crude product
under reduced pressure. The residue was purified by silica gel chromatography
(
PE/EtOAc = 2:1) to give the target product as a white solid (71 mg, 99%). Physical
o
State: white solid; Melting Point: 181.2-182.7 C; TLC: R
f
= 0.36 (PE/EtOAc = 4:1);
1
H NMR (400 MHz, CDCl ) δ 7.67 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.91
3
–
6.79 (m, 2H), 6.76 – 6.69 (m, 1H), 6.65 (d, J = 7.7 Hz, 1H), 5.02 (s, 1H), 4.97 (d, J
=
3.2 Hz, 1H), 3.50 – 3.40 (m, 2H), 3.36 (s, 3H), 2.40 (s, 3H), 2.36 – 2.30 (m, 1H),
1
3
1
1
2
3
.82 – 1.71 (m, 1H); C NMR (101 MHz, CDCl ) δ 143.87, 140.48, 135.12, 129.87,
29.17, 127.41, 122.77, 119.48, 116.89, 115.06, 101.12, 70.41, 51.39, 44.21, 32.02,
+
S [M + H] m/z 361.1217, found 361.1221.
1.58; HRMS (ESI): calcd for C18
H
20
N
2
O
4
AUTHOR INFORMATION
Corresponding Author
*
E-mail: chenhaij@gmail.com. Phone: +86 591 22866234. Fax: +86 591 22866227.
Notes
The authors declare no competing financial interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Nos.
8
1402781 and 81571802), the Scientific Research Foundation for the Returned
Overseas Chinese Scholars, Natural Science Foundation of Fujian Province
2016J06020).
(

Supplementary data
1
13
Supplementary data (Characterization data, copies of H and C NMR spectra of all
synthesized compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/xxx.
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Highlights
•
•
•
•
A facile continuous-flow method to access tricyclo-1,4-benzoxazines.
The reaction was efficiently achieved at ambient temperature.
The procedure could be easily handled and scaled up.
Enabling construction of a focused compound library.