Access to 1a, 6b-dihydro-1H-benzofuro[2, 3-b]azirines and benzofuran-2-amines via visible light triggered decomposition of α-azidochalcones

Article abstract of DOI:10.1021/acs.orglett.7b02643

A novel, efficient, organic process that involves a photocatalyst- free visible light triggered decomposition of α-azidochalcones, followed by intramolecular cyclization, 1, 2-acyl migration, and isomerization to construct benzofuran based molecular archi

Full text of DOI:10.1021/acs.orglett.7b02643

Letter
pubs.acs.org/OrgLett
Access to 1a,6b‑Dihydro‑1H‑benzofuro[2,3‑b]azirines and
Benzofuran-2-amines via Visible Light Triggered Decomposition of
α‑Azidochalcones
Satheesh Borra,†,‡ D. Chandrasekhar,†,‡ Susmita Khound,†,‡ and Ram Awatar Maurya*,†,‡
†Applied Organic Chemistry Group, Chemical Sciences & Technology Division, CSIR-North East Institute of Science & Technology
(NEIST), Jorhat, Assam-785006, India
‡Academy of Scientific and Innovative Research (AcSIR), CSIR-NEIST Jorhat, Assam-785006, India
S
* Supporting Information
ABSTRACT: A novel, efficient, organic process that involves a photo-
catalyst-free visible light triggered decomposition of α-azidochalcones,
followed by intramolecular cyclization, 1,2-acyl migration, and isomer-
ization to construct benzofuran based molecular architectures, is described.
The scope and limitation of the synthetic strategy were studied by
synthesizing over 30 structurally diverse benzofurans in high yields.
Scheme 1. Proposed Photodecomposition of α-
Azidochalcones into 2H-Azirines and Its Intramolecular
Trapping
eveloping innovative solutions that access heterocyclic
scaffolds through tuning the novel reactivity of reaction
D
intermediates is a continuous enterprise in academia and
industry.1 Light is considered a traceless and nonpolluting
reagent in organic chemistry that can be readily obtained from
renewable sources.2 Early development of photochemical
reactions largely utilized high energy ultraviolet (UV) radiation.
However, in recent years, visible light driven organic trans-
formations have become more popular due to the selectivity, ease
of handling, safety, and economics perspectives.2−7 Most of the
visible light driven synthetic methodologies reported to date
require an organic,4 metal5 or semiconductor6 based photo-
catalyst for their success. Examples of visible light driven organic
transformations without using photocatalysts are very few.7 It is
largely because most of the organic compounds are transparent
in the visible range of the electromagnetic radiation. This
manuscript describes an efficient photochemical process that
harvests visible light energy without using any external
photocatalyst to construct exigent benzofuran scaffolds.
opening and rearrangement, in principle, might access 3-amino
substituted benzofurans, benzothiophenes, and indoles. Pre-
sented in this manuscript are the results of a visible light triggered
decomposition of 2-azido-3-(2-hydroxyphenyl)-1-phenylprop-2-
en-1-ones to access substituted benzofurans.
To test our hypothesis, 2-azido-3-(2-hydroxyphenyl)-1-
phenylprop-2-en-1-one 1a (0.1 M in CH3CN) was illuminated
with a 17 W white compact fluorescent lamp (CFL) in the
presence of 0.1 mol % of Ru(bpy)3(PF6)2 (Scheme 2). The
reaction gave a clean new spot on TLC, and after workup and
purification using column chromatography, a yellow solid (60%)
was isolated which was characterized as (2-aminobenzofuran-3-
yl)(phenyl)methanone 2a rather than ((3-aminobenzofuran-2-
yl)(phenyl)methanone 2a′. Structural assignment of the product
α-Azidochalcones are among the highly reactive azido species
that have been widely utilized as a pivotal three-atom synthon for
the formation of numerous fine chemicals and pharmaceut-
icals.8,9 Our recent investigations on visible light driven coupling
of α-keto vinyl azides with several substrates have established the
generation of highly electrophilic 2H-azirines in a photo-
sensitized manner.9 During the course of our study, we were
curious if the 2H-azirines could be trapped intramolecularily to
construct remarkable aziridine scaffolds. In particular, we
wondered if the lone pair of the heteroatom (X) could trigger
the release of the strain embedded in the aziridine system III to
generate another intermediate such as IV, which could be further
rearranged (Scheme 1). If successful, this unprecented ring
1
2a was done by comparing its H/13C NMR/IR spectra and
Received: August 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02643
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the photocatalyst with the same light source and noticed the
complete decomposition of 1a in a period of 24 h. After
purification of the crude reaction product, we obtained 2-
aminobenzofuran 2a in 40% yield along with some uncharac-
terized products. As the yield of 2a was better (60% vs 40%) and
the reaction time was shorter (6 h vs 24 h) in the presence of the
photocatalyst, a few other α-azidochalcones 1b−n were
photodecomposed in the presence of the same photocatalyst
(Figure 1).
Scheme 2. Formation of the 2-Aminobenzofuran 2a from α-
Azidochalcone 1a, and Its Conversion to 3a
melting point with those reported in literature.10 Though its
spectral data were in good agreement with the reported values,
the melting point of our product (132−133 °C) was lower by 7
°C compared to the literature report (138.9−140.3 °C). We,
therefore, synthesized a known derivative of our product 3a by
reacting it with formamide in the presence of Sc(OTf)3. All the
spectral data including the melting point of the compound 3a
matched well with the literature reports.10b
Formation of 2a can be rationalized by considering the ring
opening of the initially formed aziridine III via generation of a
benzylic carbocation VI followed by 1,2-acyl migration (Scheme
3). Preferential formation of VI over IV can be accounted for by
Scheme 3. Mechanistic Rationalization for the Formation of
the 2-Aminobenzofuran 2a from α-Azidochalcone 1a
Figure 1. Visible light photodecomposition of α-azidochalcones 1 to
synthesize benzofurans.
The 2-aminobenzofurans 2b (60%), 2c (60%), 2d (63%), 2e
(61%), 2f (63%), and 2g (65%) were easily synthesized using the
same method in moderate yields. It is worth noting here that, in
all these examples 2a−g, the substituent R of the hydroxyphenyl
ring of the substrate 1 is either H or an electron-donating (OEt
and OMe) group. When the substituent R is an electron-
withdrawing group such as NO2 or halogen (Cl, Br), the reaction
exclusively yielded the aziridine product 4h−n in high yields
(80−85%). The chemical structures of these aziridines were
tentatively assigned as depicted in Figure 1 based on expected
intramolecular trapping of the initially generated 2H-azirine II
considering the higher stability of the benzylic carbocation over
the other alternative. Synthesis of 2-aminobenzofurans is
challenging as they are considered unstable compounds, unless
there is some substitution at the nitrogen atom or 3-position of
the ring.10a This unprecendented reaction utilizes a unique
reaction cascade (photodecomposition of α-azidochalcone into
2H-azirine, its intramolecular trapping by neighboring OH
group, 1,2-acyl migration, and isomerization) to yield 2-
aminobenzofurans. A careful survey of the literature revealed
that 1,2-acyl migration is well explored though its application in
the synthesis of heterocylic scaffolds is rather limited.11 This
prompted us to investigate in detail the scope and limitation of
the method for synthesizing this important class of heterocycle
which is challenging to construct with the existing method-
ologies.
An attempt to synthesize 2a through refluxing a solution of 1a
(0.1 M in CH3CN) for 6 h in the absence of light and catalyst
failed, as it produced multiple spots on TLC which could not be
purified. While working with compound 1a, we found it to be
light sensitive. Indeed, the UV−visible spectrum of compound
1d (wide infra) showed a strong absorption of light in the 430−
300 nm range with the absorption maxima at 378 nm. It showed
that these compounds absorb light in the long UV to visible
(violet-blue) range of the electromagnetic radiation. Therefore,
we illuminated a solution of 1a (0.1 M CH3CN) in the absence of
1
and were supported by their H/13C NMR, IR, and HRMS
spectra. The corresponding aziridine products for the substrates
1a−g were never isolated in any case.
Aziridines are highly strained molecules which readily undergo
ring opening.12 However, in the examples 4h−n, it appears that
the electron-withdrawing substituents (NO2, Cl, Br) deactivate
the ring toward the generation of o-quinone methides VI and
thereby prevent further rearrangements (1,2-acyl migration and
isomerization). It led us to reoptimize the reaction conditions for
the formation of 2-aminobenzofurans. We wondered if a
Bronsted or Lewis acid would ease the ring opening of the
aziridines 4h−n via its interaction with the lone pair of electrons
of the nitrogen atom. The aziridine substrate 4h when treated
with AcOH (20 mol %), InCl3 (20 mol %), Yb(OTf)3 (20 mol
%), and p-toluenesulfonic acid (p-TSA) (20 mol %) in
acetonitrile gave 2-aminobenzofuran 2h in 0% (no conversion),
77%, 70%, and 90% yields, respectively (Scheme 4).
As the addition of p-TSA led to a very clean formation of 2-
aminobenzofuran 2h from the corresponding aziridine 4h
(Scheme 4), we thought of investigating the photodecomposi-
tion of another α-azidochalcone 1j in its presence (Table 1).
Illuminating α-azidochalcone 1j with 17 W CFL for 24 h led to its
B
DOI: 10.1021/acs.orglett.7b02643
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Organic Letters
Letter
As the addition of p-TSA significantly increased the yields of 2-
aminobenzofurans, we next performed the photodecomposition
of a number of α-azidochalcones using the same method (Figure
2). A series of α-azidochalcones (1a−z, 1aa−bb) were
Scheme 4. Ring Opening of the Aziridine 4h To Yield 2-
Aminobenzofuran 2h
Table 1. Decomposition of α-Azidochalcone 1j To Yield 2-
a
Aminobenzofuran 2j and Aziridine 4j
time yield of yield of
entry light/heating
catalyst/additives
none
(h)
2j (%) 4j (%)
1
2
17 W CFL
24
12
0
80
0
heating at
60 °C in
dark
20 mol % p-TSA
60
3
4
17 W CFL
17 W CFL
20 mol % p-TSA
24
6
75
75
0
0
20 mol % p-TSA and
0.1 mol %
Ru(bpy)3(PF6)2
5
6
7
8
9
sunlight
20 mol % p-TSA
10 mol % p-TSA
5 mol % p-TSA
20 mol % p-TSA
24
24
24
48
12
73
0
17 W CFL
17 W CFL
17 W LED
17 W LED
55
0
40
0
Figure 2. Visible light photodecomposition of α-azidochalcones 1 to
synthesize 2-aminobenzofurans 2 in the presence of p-TSA.
ND
72
ND
0
20 mol % p-TSA and
0.1 mol %
Ru(bpy)3(PF6)2
photodecomposed in the presence of p-TSA to give 2-
aminobenzofurans (2a−z, 2aa-bb) in decent yields (up to
80%). Two α-azidochalcones (1aa and 1bb) were photo-
decomposed under natural sunlight, yielding the corresponding
2-aminobenzofurans in 70−75% yields. The α-azidochalcones
bearing electron-donating, electron-withdrawing, and halogen
groups in the hydroxyphenyl ring yielded 2-aminobenzofurans in
good yields. The corresponding aziridine products were never
obtained in any case. The electron-withdrawing as well as
electron-donating functional groups in the aroyl group were well
tolerated by this method. The substrate 1 where the substituent
R1 of the COR1 fragment is H or aliphatic chain was not
accessible; therefore, the 1,2-acyl migration with such substrates
could not be attempted.
In order to test whether the 1,2-acyl migration is
intermolecular or intramolecular, a crossover experiment was
performed with the α-azidochalcones 1a and 1d (Scheme 5).
After workup, the reaction mixture yielded 2-aminobenzofurans
2a and 2d in 75% and 73% yields, respectively. As no crossover
product was detected, the 1,2-acyl migration was suggested to be
intramolecular.
a
Reaction condition: 1j (0.1 M in CH3CN), catalyst/additive, stir,
ambient temperature, N2 atmosphere. Yields refer to isolated yields
after column chromatography. ND = Not determined.
complete decomposition yielding 4j (80%), exclusively (Table 1,
entry 1). In the presence of p-TSA, illuminating and heating the
solution of 1j independently gave 2j in 75% and 60% yields,
respectively (Table 1, entries 2−3). It is noteworthy that p-TSA
guided the formation 2j in both the thermal and photochemical
conditions. It was also observed that the addition of the
photocatalyst along with p-TSA did not affect the yield of 2j,
though the reaction time was significantly decreased from 24 to 6
h (Table 1, entry 4). A high yield of 2j (73%) was achieved when
the solution of 1j containing p-TSA (20 mol %) was exposed to
sunlight (Table 1, entry 5). Decreasing the amount of p-TSA
from 20 to 5 mol % decreased the yield of 2j (Table 1, entries 6−
7). The aziridine 4j was never detected in the reaction mixture
when p-TSA was used (Table 1). The decomposition of 1j was
incomplete even after 48 h when the light source was changed
from CFL to white LED (17 W) (Table 1, entry 8). However, 2j
was isolated in 72% yield in the presence of catalytic
Ru(bpy)3(PF6)2 and the LED light (Table 1, entry 9). As the
UV−visible absorption maxima of the α-azidochalcones lies at
378 nm, their photocatalyst-free decomposition by CFL or
sunlight might be attributed to the long UV radiation associated
with these light sources. In the presence of LED and
photocatalyst, the reaction follows photosensitized decomposi-
tion of the α-azidochalcones9 (Figure 1).
In conclusion, we have developed a visible light driven, high
yielding, proficient, synthetic strategy to access 2-amino-
benzofurans. The striking features of the method include
harvesting visible light energy without any external photocatalyst,
and the use of natural sunlight to access complex benzofurans in
high yields. It involves visible light triggered decomposition of α-
azidochalcones into 2H-azirines that undergo intramolecular
trapping with the neighboring hydroxyl group. In the presence of
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02643.
1
Experimental procedures, characterization data, H/13C
NMR spectra of all the products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(10) (a) Murai, M.; Miki, K.; Ohe, K. Chem. Commun. 2009, 3466.
(b) Murai, M.; Okamoto, K.; Miki, K.; Ohe, K. Tetrahedron 2015, 71,
4432.
*E-mail: ram.cdri@gmail.com; rammaurya@neist.res.in.
ORCID
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Ed. 2014, 53, 12201. (d) He, C.; Hu, J.; Wu, Y.; Ding, H. J. Am. Chem.
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Ram Awatar Maurya: 0000-0003-2431-8614
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are thankful to the Director of CSIR-NEIST, Jorhat,
Assam for providing encouragement and the necessary infra-
structure and to the Science and Engineering Research Board,
Department of Science & Technology, Ministry of Science and
Technology India for financial support (GAP-0744, GPP-0313).
S.B. is thankful to the University Grants Commission, New Delhi
for his fellowship.
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