Transition-Metal-Free Photoinduced Intramolecular Annulation of 2,3-Di(hetero)arylchromen-4-one

Article abstract of DOI:10.1021/acs.orglett.7b01531

An efficient transition-metal-free photoinduced intracyclization of 4H-chromen-4-ones in EtOH-H₂O (7:1, v/v) at ambient temperature for the construction of complicated fused-ring heteroaromatics is established. The reaction proceeds smoothly without requiring any catalysts/additives.

Full text of DOI:10.1021/acs.orglett.7b01531

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Photoinduced Intramolecular Annulation of
2,3-Di(hetero)arylchromen-4-one
Jie Han, Tao Wang, Yong Liang,† Ying Li, Chenchen Li, Rui Wang, Siqi Feng,
and Zunting Zhang*
Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering
Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, and School of Chemistry and Chemical
Engineering, Shaanxi Normal University, Xi’an 710119, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient transition-metal-free photoinduced
intracyclization of 4H-chromen-4-ones in EtOH−H2O (7:1, v/
v) at ambient temperature for the construction of complicated
fused-ring heteroaromatics is established. The reaction proceeds
smoothly without requiring any catalysts/additives.
olycyclic heteroaromatics (PHAs) have been extensively
Pstudied in various research areas during the past decade,
and various synthetic methods have been developed.1 Tradi-
tionally, one of the most versatile and frequently used
approaches in PHA chemistry is transition-metal-catalyzed
annulation, which not only closes the ring but also installs
expected functional groups. Recently, however, alternative
approaches have begun to compete with the classical protocol.
Such approaches include C−H activation and dehydrogenative
functionalization, which is based on only one activated
component (e.g., halides or Ts, among others) or on two C−
H bonds from both components. Although methods in PHA
chemistry have dramatically improved, the need for transition
metals, which are crucial for annulation, remains the major
drawback that limits the applications of these approaches. Thus,
it is important to continue developing better synthetic methods.
Recently, photocatalyzed organic reactions have drawn
greatly increased attention due to their sustainability and cost
efficiency compared with reactions that use transition metal
catalysts.2 The photocatalyzed formation of C−C or C−
heteroatom bonds in the presence of transition metals has been
well developed and reviewed.2,3 Although a few examples of
light-promoted intramolecular annulation that proceeds
smoothly requiring oxidant O2 or I2 have been reported,4 the
application of photoinduced oxidative annulation in chromone
(benzopyran-4-one) substrates remains unaddressed.
have not previously been explored. Current methods for the
synthesis of benzo[c]furo[2,3-a]xanthen derivatives require the
presence of transition metals and a high reaction temperature;
these requirements limit the application of these approaches
(Scheme 1a).7
Scheme 1. Intermolecular and Intramolecular Annulation
Given our interest in the development of direct C−H
functionalization8 and photoinduced annulation9 as well as the
existence of limited literature reports on dehydrogenative
annulation, which was thought to require transition metals10
and/or oxidative additives,11,12 in this letter, we report an
efficient transition-metal-free photoinduced intramolecular
dehydrogenative annulation of 4H-chromen-4-ones for the
synthesis of benzo[c]furo[2,3-a]xanthenone derivatives that
does not require catalysts or additives (Scheme 1b).
Benzopyran-4-one based natural products, such as chro-
mones, chromanones, flavones, isoflavones, and 2-styrylchro-
mones, exhibit a wide range of biological activities.5 Many
chemical modification approaches for the synthesis of novel
derivatives have been developed to satisfy growing biological
and medicinal requirements.5b,6 Benzo[c]furo[2,3-a]xanthen
analogs, which are polycyclic derivatives of benzopyran-4-one,
Received: May 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01531
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The substrate 3-(furan-2-yl)-2-phenyl-4H-chromen-4-one
(1a) was synthesized using an approach described in a
literature report.13 The photoinduced intramolecular dehydro-
genative annulation of compound 1a was carried out by exciting
the cinnamoyl group (π−π* band) at hv = 365 nm [absorption
spectrum of 1a is shown in Figure 4 in the Supporting
Information (SI)] at ambient temperature under a dry argon
atmosphere. Various parameters, such as solvent, concentration,
and irradiation time, were screened. Experimental data are
presented in Table 1. The irradiation of 1a in CH2Cl2 (100
furo[2,3-a]xanthen-13-one is approximately 0.121 in EtOH−
H2O (7:1, v/v) (SI).
With optimized conditions determined for the intramolecular
annulation, we proceeded to explore the generality and
functional group tolerance of this annulation with various
substrates (Scheme 2). In general, substrates with electron-
a
Scheme 2. Examination of Substrate Scope
a
Table 1. Optimization of the Intramolecular Cyclization
concn
(mM)
time
(h)
conv
b
yield
b
entry
solvent (v/v)
CH2Cl2
(%)
(%)
1
5
5
3
3
3
3
3
3
3
3
3
1
2
4
6
3
41
31
52
73
76
88
81
100
57
37
66
92
98
83
28
7
2
Me2CO
3
5
MeCN
16
36
43
60
40
38
43
30
52
48
50
4
5
EtOH
5
5
EtOH−H2O (9:1)
EtOH−H2O (7:1)
EtOH−H2O (4:1)
EtOH−H2O (7:1)
EtOH−H2O (7:1)
EtOH−H2O (7:1)
EtOH−H2O (7:1)
EtOH−H2O (7:1)
EtOH−H2O (7:1)
EtOH−H2O (7:1)
6
5
5
7
8
1
9
10
5
10
11
12
13
14
5
5
5
c
5
36
a
a
On the 0.5 mmol scale, 1a in various solvents (100 mL, 5 mM) was
irradiated with a 500 W high-pressure mercury lamp at ambient
All reactions were performed on a 0.5 mmol scale of 1 at ambient
temperature in EtOH/H2O (100 mL, 7:1, v/v) with the isolated yields
listed.
b
c
temperature. Isolated yield. On the 0.5 mmol scale, 1a in EtOH−
H2O (7:1, v/v, 100 mL, 5 mM) was irradiated with a 500 W high-
pressure mercury lamp in the open air at ambient temperature.
donating groups (e.g., Me, OMe, and OH) at the R1, R2, R3, or
R4 position produced better yields than the substrate bearing an
electron-withdrawing group (Br). Notably, the presence of a
free hydroxyl group and amine could also be tolerated, although
slightly reduced yields were obtained (50%−61%). With
respect to regioselectivity, substrate 1r yielded 2r and 2r′ as a
mixture of regioisomers with partial selectivity that could
readily be explained by steric hindrance. Thus, 2r was obtained
as a major regioisomer (55%). Interestingly, only one
regioisomer was isolated in 61% yield for the 2-naphthalene
substrate 1s. Both 2-(fur-2-yl)- and 2-(thiophen-2-yl)-sub-
stituted chromone derivatives afforded the corresponding
annulation products in moderate yields (46%−65%). However,
much longer irradiation times were required (10−20 h), likely
due to the lower activity of the C3−H of the heteroaromatics
relative to the original substrate.
mL) with a high-pressure mercury lamp (500 W) at ambient
temperature under an argon atmosphere for 3 h afforded 2a
with a yield of 28% (Table 1, entry 1). Yields of 2a decreased
dramatically in acetone and acetonitrile (7−16%, entries 2−3),
whereas a similar yield of 2a was obtained in ethanol (36%,
entry 4). Interestingly, the yield of 2a was significantly affected
by the presence of H2O (entries 5−7). The optimal yield was
obtained when EtOH−H2O (7:1, v/v) was utilized as the
reaction solvent (60%, entry 6). Notably, lower or higher
reaction concentrations decreased cyclization yields (entries 6,
8−9).
Finally, the irradiation time was also optimized; in particular,
3 h of irradiation clearly resulted in the best photoinduced
cyclization (entries 6, 10−13). It is important to note that
lower yields were observed due to the decomposition of 2a
upon prolonged irradiation (entries 12 and 13). Furthermore,
when the cyclization was performed in the presence oxygen
(open air), 2a was obtained in 36% yield (entry 14). Thus, the
irradiation of 5 mM 1a in EtOH−H2O (7:1, v/v) at ambient
temperature for 3 h was determined to be the optimal
approach. The quantum yield of photochemical conversion of
3-(furan-2-yl)-2-phenyl-4H-chromen-4-one into 13H-benzo[c]-
1
The structure of 2 was established via (a) H NMR, 13C
NMR, HRMS, UV, and IR and (b) the X-ray structure of 2a.
The absorption and fluorescence spectra of 2a are shown
Figures 2 and 3 in the SI. Due to the formation of a conjugated
system, the π−π* band absorption for 2a is red-shifted, which
decreased the probability of photoexcitation upon irradiation at
365 nm.
The molecular structure of 2a is presented in Figure 1.14 The
13H-benzo[c]furo[2,3-a]xanthen-13-ones moiety includes
B
DOI: 10.1021/acs.orglett.7b01531
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
restoration of aromaticity for the benzene ring and the entire
conjugated system, which share a similar concept with a
literature report for the restoration of aromaticity by
elimination of the methane molecule.15 Since the cyclization
product 2a was successfully obtained with the presence of
oxygen (open air), we believe the photochemical cyclization
proceeded through the S1 state.
Experiments were conducted to further establish the
rationality of the proposed mechanism. In particular, the
reduction of 1a by LiAlH4·AlCl3 in THF at 0 °C for 30 min
afforded 4a with a yield of 54% (Scheme 4).18 As expected, the
Figure 1. X-ray crystal structure of 2a.
Scheme 4. Attempted Annulation of 4a under the Optimal
Reaction Conditions
three benzene rings [A (C1−C6), C (C7, C8, C13, C14, C17,
C18), and D (C8−C13)], one pyran ring B (C1, C6, O2, C7,
C18, C19), and one furan ring E (C14−C17, O3). The average
distance of atoms C1 to C19, O2, and O3 from the least-
squares plane (C1−C19, O2, O3) was 0.0302 Å. This finding
indicated that 2a was essentially coplanar. In the crystal
structure of 2a, a dimer was formed via the nonconventional
C−H···O intermolecular hydrogen bonds O1···H16#2−C16#2
[symmetry code #2 (1 − x, 2 − y, −z)] (Figure 1, SI). In
addition, aromatic π···π stacking interactions exist in 2a, linking
xanthenone skeletons into a column along the a axis. Aromatic
π···π stacking between the A and C, B and B, and C and A rings
of two adjacent antiparallel xanthenone skeletons is observed.
CgA−CgC#1 = 3.701 Å, CgB−CgB#1 = 3.665 Å, and CgC−
CgA#1 = 3.701 Å, where CgA, CgB, and CgC are the centers of
rings A, B, and C of the xanthenone skeleton at (x, y, z),
respectively, and CgA#1, CgB#1, and CgC#1 are the centers of
rings A, B, and C of the neighboring xanthenone skeleton at
(−x, 1 − y, −z), respectively (Figure 1, SI).
subjection of 4a to the optimal reaction conditions (hv, rt, 7:1
EtOH/H2O (v/v)) led to the recovery of the starting substrate
due to the lack of keto−enol tautomerization. Thus, no
dehydrogenative annulation product 4b was detected.
In conclusion, we have developed a transition-metal-free
photoinduced intramolecular dehydrogenative annulation of
2,3-di(hetero)arylchromen-4-one in EtOH−H2O (7:1, v/v) at
ambient temperature for the synthesis of 13H-benzo[c]furo-
[2,3-a]xanthen-13-one derivatives. This atom-efficient protocol
eliminates the use of a transition metal catalyst and proceeds
smoothly without additives. In general, substrates bearing
electron-donating groups, either in the chromone or at the C2
position of the aryl group, afforded annulation products in good
yields. The failure of the annulation of 4a further proves the
rationality of the proposed mechanism and the importance of
keto−enol tautomerization in the described mechanism.
Based on our experimental data and a literature report,15
a
plausible mechanism for the formation of 2a was proposed; this
mechanism is presented in Scheme 3. The proposed initial step
Scheme 3. Proposed Mechanism for the Formation of 2a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01531.
Experimental procedures and detailed characterization
data of all new compounds (PDF)
Crystallographic data for the compound 2a (CIF)
AUTHOR INFORMATION
■
in the annulation is the irradiation of 3-(furan-2-yl)-2-phenyl-
4H-chromen-4-one (1a) to produce intermediate A, followed
by a thermal suprafacial [1,5]-H shift16 to form intermediate B.
The rearomatization of the furan ring is the force driving this
[1,5]-sigmatropic shift. Subsequently, keto−enol isomerization
of B leads to the formation of the more stable syn-isomer C.
Similar transformations have previously been described for a
number of structurally related compounds.17 Polar protic
solvent is beneficial to the process of keto−enol isomerization,
which accounts for the higher yield of 2a in EtOH−H2O (7:1)
compared to CH2Cl2, Me2CO, and MeCN. Finally, the
annulation product 2a was generated by the syn-elimination
of a hydrogen molecule (H2) from intermediate C due to the
Corresponding Author
*E-mail: zhangzt@snnu.edu.cn.
ORCID
Jie Han: 0000-0002-5263-2558
Tao Wang: 0000-0002-1494-5297
Yong Liang: 0000-0002-7225-7062
Chenchen Li: 0000-0002-2956-7639
Zunting Zhang: 0000-0003-0806-2452
Present Address
†Department of Molecular Medicine, Beckman Research
Institute of City of Hope Duarte, CA 91010.
C
DOI: 10.1021/acs.orglett.7b01531
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21672132 and 21502110)
and the Fundamental Funds Research for the Central
Universities (No. GK201503034). This research was also
supported by the Fundamental Research Funds for the Central
Universities (No. 2016CSZ004).
REFERENCES
■
(1) (a) Perez, D.; Guitian, E. Chem. Soc. Rev. 2004, 33, 274−283.
̇
(b) Stępien
, M.; Gon
ka, E.; Zyła, M.; Sprutta, N. Chem. Rev. 2017,
117, 3479−3716. (c) Watson, M. D.; Fechtenkotter, A.; Mullen, K.
̈
̈
Chem. Rev. 2001, 101, 1267−1300.
(2) Fagnoni, M.; Dondi, D.; Ravelli, D.; Albini, A. Chem. Rev. 2007,
107, 2725−2756.
(3) (a) Shi, L.; Xia, W.-J. Chem. Soc. Rev. 2012, 41, 7687−7697.
(b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013,
113, 5322−5363.
(4) (a) Kellogg, R. M.; Groen, M. B.; Wynberg, H. J. Org. Chem.
1967, 32, 3093−3100. (b) Mori, K.; Murase, T.; Fujita, M. Angew.
Chem., Int. Ed. 2015, 54, 6847−6851. (c) Zheng, Q.-Z.; Feng, P.;
Liang, Y.-F.; Jiao, N. Org. Lett. 2013, 15, 4262−4265.
(5) (a) Francisco, A. Phytochem. Anal. 1995, 6, 55−55. (b) Quideau,
S. Angew. Chem., Int. Ed. 2006, 45, 6786−6787.
(6) (a) Zhang, Z.-T.; Liang, Y.; Ma, Y.-Q.; Xue, D.; Yang, J.-L. J.
Comb. Chem. 2010, 12, 600−603. (b) Zhang, Z.-T.; Ma, Y.-Q.; Liang,
Y.; Xue, D.; He, Q. J. Heterocycl. Chem. 2011, 48, 279−285. (c) Gaspar,
A.; Matos, M. J.; Garrido, J.; Uriarte, E.; Borges, F. Chem. Rev. 2014,
114, 4960−4992.
(7) (a) Liu, Z.-J.; Zhang, X.-X.; Larock, R. C. J. Am. Chem. Soc. 2005,
127, 15716−15717. (b) Yang, J.-F.; Yoshikai, N. Angew. Chem., Int. Ed.
2016, 55, 2870−2874.
(8) (a) Yang, Q.; Wei, T.; He, Y.; Liang, Y.; Zhang, Z.-T. Helv. Chim.
Acta 2015, 98, 953−960. (b) Liang, Y.; Wnuk, S. F. Molecules 2015,
20, 4874−4901. (c) Liang, Y.; Gloudeman, J.; Wnuk, S. F. J. Org.
Chem. 2014, 79, 4094−4103.
(9) Wang, Q.-Y.; Zhang, Z.-T.; Du, Z.-C.; Hua, H.-L.; Chen, S.-S.
Green Chem. 2013, 15, 1048−1054.
(10) Fukuzumi, K.; Unoh, Y.; Nishii, Y.; Satoh, T.; Hirano, K.; Miura,
M. J. Org. Chem. 2016, 81, 2474−2481.
(11) (a) Volvoikar, P. S.; Tilve, S. G. Org. Lett. 2016, 18, 892−895.
(b) Arii, H.; Yano, Y.; Nakabayashi, K.; Yamaguchi, S.; Yamamura, M.;
Mochida, K.; Kawashima, T. J. Org. Chem. 2016, 81, 6314−6319.
(12) Zheng, J.; Li, Z.; Huang, L.-B.; Wu, W.-Q.; Li, J.-X.; Jiang, H.-F.
Org. Lett. 2016, 18, 3514−3517.
(13) Han, J.; Wang, T.; Feng, S.-Q.; Li, C.-C.; Zhang, Z.-T. Green
Chem. 2016, 18, 4092−4097.
(14) Crystallographic data have been submitted to the Cambridge
Crystallographic Data Center [CCDC numbers: 1487909 (2a)] and
can be obtained free of charge from www.ccdc.cam.ac.uk/data_
request/cif.
(15) Lvov, A. G.; Shirinian, V. Z.; Zakharov, A. V.; Krayushkin, M.
M.; Kachala, V. V.; Zavarzin, I. V. J. Org. Chem. 2015, 80, 11491−
11500.
(16) Hoffmann, R.; Woodward, R. B. Acc. Chem. Res. 1968, 1, 17−22.
(17) (a) Schultz, A. G.; Chiu, I. C. J. Chem. Soc., Chem. Commun.
1978, 29−29. (b) Schultz, A. G.; Fu, W. Y.; Lucci, R. D.; Kurr, B. G.;
Lo, K. M.; Boxer, M. J. Am. Chem. Soc. 1978, 100, 2140−2149.
(c) Schultz, A. G.; Lucci, R. D.; Fu, W. Y.; Berger, M. H.; Erhardt, J.;
Hagmann, W. K. J. Am. Chem. Soc. 1978, 100, 2150−2162. (d) Sekiya,
R.; Kuroda, R. Chem. Commun. 2011, 47, 10097−10099.
(18) Pfaltz, A.; Valla, C.; Baeza, A.; Menges, F. Synlett 2008, 2008,
3167−3171.
D
DOI: 10.1021/acs.orglett.7b01531
Org. Lett. XXXX, XXX, XXX−XXX