Intramolecular oxidative coupling: I2/TBHP/NaN3-mediated synthesis of benzofuran derivatives

Article abstract of DOI:10.1039/c5ob00577a

A novel intramolecular oxidative coupling reaction has been established to prepare benzofuran derivatives via direct C(sp²)-H functionalization for the formation of C-O bond. This transformation is mediated by I₂/TBHP/NaN₃ under metal-free conditions and a catalytic amount of NaN₃ plays a crucial role in the reaction. Furthermore, the reaction tolerates a broad substrate scope with average to excellent yields.

Full text of DOI:10.1039/c5ob00577a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: F. Zhang, W. Xu,
Q. Li, C. Cao and H. zheng, Org. Biomol. Chem., 2015, DOI: 10.1039/C5OB00577A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Organic & Biomolecular Chemistry
Page 1 of 4Organic &
Dynamic Article Links►
View Article Online
DOI: 10.1039/C5OB00577A
Biomolecular Chemistry
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
communication
Intramolecular Oxidative Coupling: I2/TBHP/NaN3-mediated Synthesis
of Benzofuran Derivatives
Wengang Xu, Qingcui Li, Chuanpeng Cao, Fanglin Zhang* and Hua Zheng*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000
A
novel intramolecular oxidative coupling reaction is
Alessandra Lattanzi11 and Duan12 separately developed a new
strategy for the synthesis of benzofuran derivatives via C(sp2)ꢀO
established to prepare benzofuran derivatives via direct
C(sp2)–H functionalization for the formation of C–O bond. 50 coupling reaction(Type II, a). However, their methods are only
This transformation is mediated by I2/TBHP/NaN3 under
efficient for electronꢀrich systems. Later, liu13, Yoshikai14 and
Zhu15 reported Pd or Cu catalyzed C(sp2)ꢀH functionalization of
2ꢀarylphenols via oxidative cyclization respectively (Type II, b).
At present, there is no report describing intramolecular oxidative
10 metal-free conditions and catalytic amount of NaN3 plays a
crucial role in the reaction. Further, the reaction shows a
broad substrate scope with middle to excellent yields.
Oxidative coupling reaction is a novel strategy to construct 55 functionalization of electronꢀdeficient systems for preparing
C–C bond1 and Cꢀheteroatom bond2, which avoids preꢀ
15 functionalization of easily available chemicals while improving
the atom economy and step economy and has received significant
interest over the last ten years. Especially, the efficient
construction of useful heterocyclic compounds by using oxidative
coupling reaction is an important research area in organic
20 synthesis.3 Numerous methods have been developed for carbonꢀ
heteroatom bond formation in last decades.4 It is wellꢀknown that
traditional oxidative coupling reactions are most dependent on
transition metal catalyst. As a result, residual transition metal
contaminant seriously limits their applications. Consequently, an
25 economical, environmentally friendly and metalꢀfree strategy is
drawing many chemists’ attention.5
Benzofuran and their derivatives are the core structure of
many clinical drugs and natural products, which have attracted
the exploration of their synthesis methods. Molecules containing
30 these structural units have been shown to exhibit activities against
cancer, plasmodium falciparum and so on.6 Series of methods for
the synthesis of benzofuran derivatives have been reported.7
However, investigation on direct CꢀH functionalization and CꢀO
bond formation of benzofuran derivatives remains rare.
benzofuran derivatives under metalꢀfree conditions. Accordingly,
exploration of this novel oxidative coupling methods is still of
great significance.
Previous work
60
65
70
75
80
Intermolecular C(sp2)-H bond functionalization and C-O bond formation
Type I
O
O
HO
transgenic
plants
O
HO
Type II Intramolecular C(sp2)-H bond functionalization and C-O bond formation
EDG
Metal catalyst
or others
a
EDG
O
OH
OH
b
Metal catalyst
O
This work
Intramolecular C(sp2)-H bond functionalization and C-O bond formation
EWG
35
To date, a lot of novel strategies of CꢀH functionalization
and CꢀO bond formation via oxidative coupling make a big
breakthrough.8 However, there are extreme conditions in
oxidative coupling reaction with phenolic hydroxyl due to
phenols are ready to undergo oxidative dearomatization to yield
Metal-free
EWG
O
OH
Scheme 1 Different kinds of CꢀH Functionalization
40 quinones.9 To our best knowledge, oxidative C(sp2)ꢀH
functionalization and CꢀO bond formation with phenolic
hydroxyl generally falls into one of the following types. Type I,
Recently, I2 (iodine) system16 has received considerable
attention as a mild, nonꢀtoxic and selective reagent in organic
early in 2000, Boudet and his coꢀworkers10 revealed that 4ꢀ 85 synthesis. As
a
continuous study on the direct CꢀH
hydroxycinnamyl aldehydes incorporate into lignins by
45 examining transgenic plants via intermolecular radical coupling
reactions (Scheme 1). And authors think that this process appears
to reflect simple chemical coupling propensities. Type II,
functionalization and CꢀO bond formation, we herein describe an
efficient I2ꢀcatalyzed intramolecular oxidative coupling reaction
of 2ꢀhydroxychalcones under metalꢀfree conditions. In addition,
catalytic amount of NaN3 plays a crucial role in the oxidative
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Organic & Biomolecular Chemistry
Page 2 of 4
View Article Online
DOI: 10.1039/C5OB00577A
coupling reaction and a new plausible mechanism which may be
virtually through C(sp3)ꢀH functionalization has been proposed.
addition, when I2 was replaced by other acids, including CuCl2,
FeCl3, BF3·Et2O, pꢀTSA and TfOH, no product was observed
(Table 1, entry 15). What’s more, when KI or TBAI
30 (tetrabutylammonium iodide) was used, the desired coupling
product 2a was also obtained in the yield lesser than I2 as the
catalyst (Table 1, entries 16 and 17). On the basis of these results,
the optimized reaction conditions were concluded to be 0.1
equivalent of I2, 0.2 equivalent of NaN3 and 2.0 equivalent of
35 TBHP in C2H5OH at 80 °C.
Table 1 Optimization of the Reaction Conditionsa
5
O
O
catalyst
oxidant
O
base, solvent
temp
OH
Table 2 Exploring Generality and Scope of the Novel Reactiona,b
2a
Catalyst Yieldb
1a
Entry
1
2
3
4
5
6
7
8
Oxidant
TBHPc
/
Additive Solvent
NaN3
NaN3
/
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3NO2
DCE
dioxane
CH3CNf
toluene
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
I2
40
I2
I2
/
I2
I2
I2
I2
I2
NO
NO
NO
NO
NO
NO
NO
NO
60
TBHP
TBHP
Othersd
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
NaN3
NaN3
Otherse
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
O
O
O
9
10
11
12
13
14
15
16
17
I2
O
O
O
I2
20
2c(82%)
O
2b(94%)
O
2a(88%)
O
I2
87
g
NaN3
NaN3
NaN3
NaN3
I2
87
h
I2
88
NO
78
Othersi
KI
h
O
O
O
O
O
h
2f(73%)
2e(84%)
O
2d(92%)
O
h
NaN3
TBAI
83
O
Br
aReaction conditions: 1a (0.25 mmol), oxidant (0.5 mmol), additive (1 mmol)
Br
and catalyst (0.025 mmol) in solvent (4.0 mL) at 80℃, unless otherwise stated.
c
O
bIsolated yields. NO means that no product was observed. All TBHP (70% in
O
Br
water). dOther oxidants include PIDA, mCPBA, K2S2O8, DTBP. eOther
additives include K2CO3, Na2CO3, NaHCO3, NaOH, NaH2PO4·2H2O,
KH2PO4, K3PO4·3H2O, KSCN, (NH4)3PO3·3H2O. fCH3CN:H2O=1:1. g2.0
2g(49%)
O
2i(85%)
2h(82%)
O
O
Cl
NO2
h
i
equivalent of NaN3 was used. 0.2 equivalent of NaN3 was used. Other acids
include pꢀTSA, BF3·Et2O, TfOH, FeCl3, CuCl2.
O
O
O
Cl
2k(86%)
O
2j(51%)
O
2l(63%)
O
Initially, transꢀ2ꢀhydroxychalcone (1a, 0.25 mmol) was
used as the model substrate for the synthesis of desired product
(2a). As shown in table 1, 2a was obtained in 40% yield in the
O
O
2n(85%)
O
Br
O
O
Cl
Br
2o(61%)
2m(98%)
10 presence of catalytic amount of I2 (iodine), 0.5 mmol TBHP (tertꢀ
butylhydroperoxide, 70% in water) and 1 mmol NaN3 (Table 1,
entry 1). In the absence of I2, TBHP or NaN3, no product was
obtained (Table 1, entries 2ꢀ4). To further optimize the conditions,
different oxidants, additives and catalysts were tested. Employing
15 other oxidants: PIDA (iodobenzene diacetate), mCPBA (mꢀ
chloroperoxybenzoic acid), K2S2O8 or DTBP (tertꢀbutyl
peroxide), unfortunately, yielded no product (Table 1, entry 5).
Using other additives instead of NaN3, we also did not observe
desired product (Table 1, entry 6). Solvent screening showed that
20 EtOH, MeCN/H2O, and toluene were also effective for the
reaction, while DCE and 1,4ꢀdioxane were ineffective for the
reaction (Table 1, entries 7ꢀ12). Decreasing NaN3 to 0.5 mmol
made no difference to the yield (Table 1, entry 13). Catalytic
amount of NaN3 (0.05 mmol) was employed out of concern that
25 NaN3 could be recycled in reaction process and, as expected,
target product was obtained in good yield (Table 1, entry 14). In
O
O
N
O
O
N
O
Br
2q(87%)
2p(48%)
2r(86%)
O
O
O
2s(75%)
aAll the reactions were carried out using 1 (0.25 mmol), I2 (0.025 mmol),
TBHP (0.5 mmol) and NaN3 (0.05 mmol) in C2H5OH (4.0 mL) at 80℃.
bIsolated yields.
40
With the optimal reaction conditions in hand, we then
examined the transformation of transꢀ2ꢀhydroxychalcones
equipped with a variety of substituents to explore generality and
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 4
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB00577A
scope. It was observed that substituents on the R1 ring almost
leaded to good yields (Table 2, 2bꢀ2f, 2h, 2i, 2k and 2l). Oꢀ 60 were employed instead of NaN3, no desired product was obtained
According to our experimental data, when other additives
methyl and pꢀmethyl conducted almost complete transformation
(Table 2, 2b and 2d). Mꢀmethyl, pꢀmethoxyl, mꢀbromo, oꢀbromo
(Table 1, entry 6). Besides, target product was got while catalytic
amount of NaN3 was used (Table 1, entry 14). On the basis of
these results, a plausible mechanism was shown in Scheme 4.
First, NaN3 as a nucleophile reacts with 1a via Michaelꢀtype
5
and oꢀchloro gave target products in
＞80% yields (Table 2, 2c, 2e,
2h and 2k), while pꢀBr, pꢀCl led to the corresponding products in
moderate yields (Table 2, 2g and 2j). When changing the 65 addition reaction to deliver unstable intermediate A. This
substituents on R2 Ring, different results appeared (Table 2, 2mꢀ
2p). Substrates equipped with 5ꢀCl or 5ꢀBr gone through great
10 transformation. Similarly, substrate equipped with methoxyl got
middle yield. When R2 was a strong electronꢀwithdrawing group
transformation efficiency could be improved in the presence of
catalytic amount of iodine. Subsequently, A could easily be
oxidized by iodine to give intermediate B, which is converted to
the product C after loss of NaI. Then, C losses HN3 catalyzed by
(5ꢀNO2), trace desired product was observed under the optimized 70 I2, which is similar to loss H2O. At last, NaI and HN3 exchanged
reaction conditions. Remarkably, this strategy was further
successfully applied to heterocyclic substrates to synthesize
15 corresponding products in good yields (Table 2, 2qꢀ2s).
and oxidized by TBHP to I2 and NaN3. Obviously, formation of
2a was more favorable and fast process.
In summary, this paper described a novel and efficient
method for the synthesis of benzofuran derivatives under metalꢀ
75 free conditions. In this transformation, a broad substrate scope
has been demonstrated and catalytic amount of NaN3 plays a
crucial role in the oxidative coupling reaction. The possible
domino Michael addition and intramolecular oxidative coupling
reaction mechanism is also proposed. Studies on novel oxidative
80 functionalization are being actively pursued in this laboratory.
20
Acknowledgements
25
This work was supported by the National Natural Science
Foundation of China (51273156).
Scheme 2 Further Application of the Novel Reaction
Notes and references
85 aSchool of Chemistry, Chemical Engineering and Life Sciences, Wuhan
University of Technology, Wuhan, 430070, Hubei, China. Fax: (+86)027
30
We further applied this practical procedure to the transꢀ2ꢀ
hydroxychalcone substituted by alkyl groups (Scheme 3). An
interesting result occurred. When alkyl groups linked to the the
carbonyl group with primary carbon or secondary carbon, no
desired products was isolated. However, transꢀ2ꢀhydroxychalcone
8774
9300;
Tel:
(+86)027
8774
9300;
E-mail:
fanglinzhang0210@gmail.com or zhenghua.whut@126.com
†Electronic Supplementary Information (ESI) available: See
90 DOI: 10.1039/b000000x/
1
(a) J. A. Ashenhurst, Chem. Soc. Rev., 2010, 39, 540ꢀ548. (b) W. Shi,
C. Liu and A. Lei, Chem. Soc. Rev., 2011, 40, 2761ꢀ2776.
(a) A. Corma, A. LeyvaꢀPerez and M. J. Sabater, Chem. Rev., 2011,
111, 1657ꢀ1712. (b) I. P. Beletskaya and V. P. Ananikov, Chem. Rev.,
2011, 111, 1596ꢀ1636.
(a) W. Gong, L. Xu, T. Ji, P. Xie, X. Qi, C. U. Pittman and A. Zhou,
RSC Adv., 2014, 4, 6854ꢀ6857. (b) P. Li, J. Zhao, C. Xia and F. Li,
Org. Lett., 2014, 16, 5992ꢀ5995.
(a) J. Yuan, C. Liu and A. Lei, Chem. Commun., 2015, 51, 1394ꢀ1409.
(b) Q. Wang, H. Zheng, W. Chai, D. Chen, X. Zeng, R. Fu and R.
Yuan, Org. Biomol. Chem., 2014, 12, 6549ꢀ6553. (c) X. Li, B. Li, J.
You and J. Lan, Org. Biomol. Chem., 2013, 11, 1925ꢀ1928.
(a) J. Zhao, P. Li, C. Xia and F. Li, Chem. Commun., 2014, 50, 4751ꢀ
4754. (b) R. Samanta, K. Matcha and A. P. Antonchick, Eur. J. Org.
Chem., 2013, 2013, 5769ꢀ5804.
(a) Z. Yu, J. A. Brannigan, D. K. Moss, A. M. Brzozowski, A. J.
Wilkinson, A. A. Holder, E. W. Tate and R. J. Leatherbarrow, J. Med.
Chem., 2012, 55, 8879ꢀ8890. (b) R. E. Ziegert, J. Torang, K. Knepper
and S. Brase, J. Comb. Chem., 2005, 7, 147ꢀ169. (c) B. L. Flynn, E.
Hamel and M. K. Jung, J. Med. Chem., 2002, 45, 2670ꢀ2673. (d) B.
Carlsson, B. N. Singh, M. Temciuc, S. Nilsson, Y. L. Li, C. Mellin
and J. Malm, J. Med. Chem., 2002, 45, 623ꢀ630.
35 bearing tertiary carbon was successfully transformed to 1ꢀ
(benzofuranꢀ2ꢀyl)ꢀ2ꢀmethylpropanꢀ1ꢀone in 48% yield (Scheme 3,
2t ).
2
95
100
105
110
115
120
N3
O
N3 OH
3
4
40
45
50
55
I
I2
ONa
ONa
B
A
5
6
TBHP
NaN3
NaI
1a
N3
HN3
O
O
O
O
2a
C
7
(a) J. Chen, J. Li and W. Su, Org. Biomol. Chem., 2014, 12, 4078ꢀ
4083. (b) Y. Ji, P. Li, X. Zhang and L. Wang, Org. Biomol. Chem.,
2013, 11, 4095ꢀ4101. (c) C. Martinez, R. Alvarez and J. M.
Aurrecoechea, Org. Lett., 2009, 11, 1083ꢀ1086. (d) Z. Liang, W. Hou,
Y. Du, Y. Zhang, Y. Pan, D. Mao and K. Zhao, Org. Lett., 2009, 11,
4978ꢀ4981. (e) X. Guo, R. Yu, H. Li and Z. Li, J. Am. Chem. Soc.,
2009, 131, 17387ꢀ17393. (f) B. Lu, B. Wang, Y. Zhang and D. Ma, J.
Org. Chem., 2007, 72, 5337ꢀ5341.
tBuOOH
NaN3
I2
NaN3
Scheme 3 Plausible Mechanism
HI
NaI
HN3
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Organic & Biomolecular Chemistry
Page 4 of 4
View Article Online
DOI: 10.1039/C5OB00577A
8
9
(a) X. Q. Hao, L. J. Chen, B. Ren, L. Y. Li, X. Y. Yang, J. F. Gong, J.
L. Niu and M. P. Song, Org. Lett.,2014, 16, 1104ꢀ1107. (b) D. Liang,
M. Wang, Y. Dong, Y. Guo and Q. Liu, RSC Adv., 2014, 4, 6564ꢀ
6567. (c) X. F. Cheng, Y. Li, Y. M. Su, F. Yin, J. Y. Wang, J. Sheng,
H. U. Vora, X. S. Wang and J. Q. Yu, J. Am. Chem. Soc., 2013, 135,
1236ꢀ1239.
(a) M. Ciufolini, N. Braun, S. Canesi, M. Ousmer, J. Chang and D.
Chai, Synthesis, 2007, 2007, 3759ꢀ3772. (b) S. Quideau, L. Pouysegu
and D. Deffieux, Curr. Org. Chem., 2004, 8, 113ꢀ148. (c) P. Wipf and
S. Rodríguez, Synthesis, 2004, 2767ꢀ2783.
5
10
11 H. Kim, J. Ralph, N. Yahiaoui, M. Pean and A. M. Boudet, Org. Lett.,
2000, 2, 2197ꢀ2200.
12 A. Lattanzi, A. Senatore, A. Massa and A. Scettri, J. Org. Chem.,
2003, 68, 3691ꢀ3694.
15 13 X. F. Duan, J. Zeng, Z. B. Zhang and G. F. Zi, J. Org. Chem., 2007,
72, 10283ꢀ10286.
14 B. Xiao, T. J. Gong, Z. J. Liu, J. H. Liu, D. F. Luo, J. Xu and L. Liu, J.
Am. Chem. Soc., 2011, 133, 9250ꢀ9253.
15 Y. Wei and N. Yoshikai, Org. Lett., 2011, 13, 5504ꢀ5507.
20 16 (a) J. Zhao, Y. Wang, Y. He, L. Liu and Q. Zhu, Org. Lett., 2012, 14,
1078ꢀ1081. (b) J. Zhao, Q. Zhang, L. Liu, Y. He, J. Li, J. Li and Q.
Zhu, Org. Lett., 2012, 14, 5362ꢀ5365.
17 (a) M. Chennapuram, N. R. Emmadi, C. Bingi and K. Atmakur, RSC
Adv., 2015, 5, 19418ꢀ19425. (b) K. K. D. R. Viswanadham, M.
25
Prathap Reddy, P. Sathyanarayana, O. Ravi, R. Kant and S. R.
Bathula, Chem. Commun., 2014, 50, 13517ꢀ13520. (c) B. A. Dar, N.
A. Dangroo, A. Gupta, A. Wali, M. A. Khuroo, R. A. Vishwakarma
and B. Singh, Tetrahedron Lett., 2014, 55, 1544ꢀ1548. (d) N. M.
Mishra, D. D. Vachhani, S. G. Modha and E. V. Van der Eycken, Eur.
J. Org. Chem., 2013, 2013, 693ꢀ700. (e) J. Dhineshkumar, M. Lamani,
K. Alagiri and K. R. Prabhu, Org. Lett., 2013, 15, 1092ꢀ1095.
30
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]