Copper-catalyzed oxidative cyclization of glycine derivatives toward 2-substituted benzoxazoles

Article abstract of DOI:10.1039/d0ob02490b

A novel and straightforward intramolecular cyclization of glycine derivatives to 2-substituted benzoxazoles through copper-catalyzed oxidative C-H/O-H cross-coupling was described. A variety of glycine derivatives involving short peptides underwent cross-dehydrogenative-coupling readily to afford diverse 2-substituted benzoxazoles. The synthetic method has the advantages of simple operation, broad substrate scope and mild reaction conditions, thus providing an alternative effective approach for benzoxazole construction.

Full text of DOI:10.1039/d0ob02490b

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Copper-catalyzed oxidative cyclization of glycine
derivatives toward 2-substituted benzoxazoles†
Shan Liu,a Zhi-Qiang Zhu, *a Zhi-Yu Hu,a Juan Tangb and En Yuanc
Cite this: Org. Biomol. Chem., 2021,
19, 1616
A novel and straightforward intramolecular cyclization of glycine derivatives to 2-substituted benzoxa-
zoles through copper-catalyzed oxidative C–H/O–H cross-coupling was described. A variety of glycine
derivatives involving short peptides underwent cross-dehydrogenative-coupling readily to afford diverse
2-substituted benzoxazoles. The synthetic method has the advantages of simple operation, broad sub-
strate scope and mild reaction conditions, thus providing an alternative effective approach for benzoxa-
zole construction.
Received 13th December 2020,
Accepted 26th January 2021
DOI: 10.1039/d0ob02490b
rsc.li/obc
Direct cross-dehydrogenative-coupling (CDC) reactions have
been considered as attractive and reliable strategies to produce
Introduction
Benzoxazoles are an important class of heterocyclic scaffolds new chemical bonds since these reactions avoid functional
and are frequently found as key structural motifs in a number group interconversion and are step- and atom-economical.11
of biologically active natural products, pharmaceuticals, and Great interest has been focussed on direct C–H functionali-
functional materials.1 In particular, 2-substituted benzoxazoles zation of glycine derivatives.12–14 However, C–heteroatom bond
possess a wide range of remarkable biological activities,2 such forming via dehydrogenative α-C(sp3)–H functionalization of
as anti-cancer,3 antitumor,4 antimicrobial,5 antibacterial,6 and glycine derivatives remains rare.14 For example, in 2016, Li and
antiviral properties.7 Different substituent groups at the C-2 coworkers disclosed a simple and efficient copper-catalyzed
position of benzoxazole have a significant impact on its bioac- phosphorylation of glycine derivatives to α-aminophosphonates
tivity. Consequently, continuous research interest has been via C–H/P–H oxidative cross-coupling.14a In 2018,
attracted to construct benzoxazoles with various substituents Chandrasekharam et al. described copper-catalyzed amida-
at the C-2 position in the past decades. Classical methods to tion/imidation of glycine derivatives with amides via dehydro-
synthesize 2-substituted benzoxazoles are mainly through the genative C–N coupling.14b Recently, Huang and coworkers
condensation of 2-aminophenols with aldehydes, carboxylic revealed CBr4-mediated cross-coupling between α-amino car-
acids or acetyl halides, followed by oxidative cyclization under bonyl compounds and alcohols to construct C–O bonds.15
either acidic or heating conditions.8 In addition, direct C–H However, N-arylglycine esters could not lead to the desired pro-
activation and crossing-coupling of benzoxazoles with halides ducts at all. Owing to the biological importance of 2-substi-
or organoboronic acids by transition-metal catalysis9 and tuted benzoxazoles, and in continuation of our research
many other alternative approaches were also developed for the toward CDC reactions,16 herein, we describe a simple and
construction of benzoxazole and its derivatives.10 Despite efficient intramolecular oxidative cyclization of glycine deriva-
these notable advances, exploring new and straightforward tives to 2-substituted benzoxazoles through copper-catalyzed
procedures to synthesize structurally diverse 2-substituted ben- C–H/O–H cross-coupling at room temperature.
zoxazoles is still highly desired.
Results and discussion
aJiangxi Province Key Laboratory of Synthetic chemistry, School of Chemistry, Biology
Our initial study began with ethyl (2-hydroxyphenyl)glycinate
and Material Science, East China University of Technology, Nanchang 330013,
1a under the catalysis of 5 mol% CuI and 2 eq. of TBHP in
MeCN at room temperature (entry 1, Table 1). Gratifyingly, the
desired cyclization product 2a was isolated in 27% yield at
room temperature. A variety of metal salts were examined, and
the results showed that CuCl is superior to the other catalysts,
including CuI, CuBr, CuCl2, Cu(OAc)2, AgOAc and FeCl3, and
2a was obtained in 53% yield (Table 1, entries 1–7). Other oxi-
China. E-mail: zhuzq@ecut.edu.cn
bMinistry of Education Key Laboratory of Functional Small Organic Molecule,
Department of Chemistry and chemical engineering, Jiangxi Normal University,
Nanchang 330022, China
cCollege of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang,
330004, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob02490b
1616 | Org. Biomol. Chem., 2021, 19, 1616–1619
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope for the cyclization reactiona,b
Entry
Catalyst
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
TBPB
DCP
BPO
O2
BPO
BPO
BPO
BPO
BPO
—
BPO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
EtOAc
DCE
27
20
53
10
26
Trace
30
15
46
Trace
66
Trace
35
51
40
72
36
Trace
73
84
CuBr
CuCl
CuCl2
Cu(OAc)2
CoCl2
FeCl3
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
—
9
10
11
12
13
14
15
16
17c
18d
19e
20f
DCM
DCM
DCM
DCM
CuCl
CuCl
CuCl
BPO
DCM
a Reaction conditions: 1a (0.2 mmol), catalyst (5 mol%), oxidant (2
equiv.), solvent (2 mL) at room temperature for 2–4 h. b Isolated yield.
c In the absence of a catalyst. d No oxidant. e Na2CO3 (1 eq.) was used.
f K2CO3 (1 eq.) was used.
a Reaction conditions: 1 (0.2 mmol), CuCl (5 mol%), BPO (2 equiv.),
DCM (2 mL) at room temperature for 2–4 h. b Isolated yield. c AgOAc
(5 mol%) was used instead of CuCl.
dants were evaluated in the reaction (Table 1, entries 8–12),
and BPO (benzoyl peroxide) gave the best yield of 2a. Upon
further screening of various solvents, it was found that DCM
was the best choice, resulting in the formation of the desired
cyclization product 2a in 72% yield (Table 1, entries 13–16). In 59% to 73% when AgOAc was used as a catalyst (Table 2).
the absence of a catalyst, a significantly diminished yield of Glycine derivatives 1i and 1j bearing either electron-rich or
product 2a was observed (Table 1, entry 17). Only a trace electron-deficient substituents at the para-position of the
amount of product 2a was detected without the use of BPO amido unit on the benzene rings underwent the oxidative cycli-
(Table 1, entry 18). Further screening results revealed that the zation reaction readily to generate the desired products 2i and
yield of 2a was improved to 73% and 84% when Na2CO3 and 2j in moderate yields. When the substituents were located at
K2CO3 were added into the reaction, respectively (Table 1, the para-position of the hydroxyl group on the benzene rings,
entries 19 and 20). After exploring different parameters, the the reaction proceeded well to give the desired products 2k
optimal conditions are 1a (0.2 mmol), CuCl (5 mol%) and BPO and 2l. However, with a very strong electron-withdrawing group
(2 equiv.) in DCM (2 mL) at room temperature for 2 h.
like nitro on the benzene ring, only a trace amount of the cycli-
With the optimal reaction conditions in hand, various zation product was detected by LC-MS analysis. The experi-
glycine derivatives 1 were investigated in this oxidative cycliza- mental results indicated that electron-rich groups on the aryl
tion, and the results are shown in Table 2. Initially, steric vari- rings of glycine esters worked more efficiently as compared to
ations in R1 of glycine derivatives 1 were examined under the their counterparts with electron-deficient groups. Interestingly,
standard conditions. A number of substituents in the ester α-amino ketone 1m was found to be a suitable substrate,
moiety, such as methyl, n-propyl, isopropyl, n-butyl, tert-butyl, affording the desired product 2m in a good yield. In addition
benzyl and phenyl, were found to be suitable for this trans- to glycine esters, a series of glycine amides were also tested
formation, delivering the corresponding cyclization products under the current conditions and the experimental results
2a–h in moderate to good yields. Due to the relatively low revealed that a range of glycine amides including methyl,
yields of products 2c–e obtained under the standard con- ethyl, benzyl, and N,N-dimethyl amides were also able to
ditions, we further screened several transition-metal catalysts. furnish the corresponding cyclization products 2n–q in moder-
To our surprise, the yields of 2c–e were improved efficiently by ate yields. Moreover, a variety of short peptides 1r–1u were also
silver catalysis; for example, the yield of 2e increased from found to be efficient for the oxidative cyclization, providing the
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1616–1619 | 1617

View Article Online
Paper
Organic & Biomolecular Chemistry
the dehydrogenative coupling cyclization readily, producing
the desired 2-substituted benzoxazoles via C–O bond for-
mation. The synthetic protocol has potential to be used for the
construction of natural products and bioactive molecules.
Conflicts of interest
There are no conflicts to declare.
Scheme 1 Control experiments.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (11765002), the Science Foundation for Excellent
Young Scholars of Jiangxi Province (20202ZDB01003),
the Postdoctoral Science Foundation of Jiangxi Province
(2019KY41) and the Scientific Research Foundation of East
China University of Technology (DHBK2016112) for financial
support.
Scheme 2 Proposed mechanism.
References
corresponding products 2r–2u with satisfactory yields. To
demonstrate the practicability of this methodology, (2-hydroxy-
phenyl)glycine ester 1a (6 mmol, 1.17 g) was reacted on a gram
scale and the desired 2-substituted benzoxazole 2a was iso-
lated in 61% yield.
1 (a) S. Nol, S. Cadet, E. Gras and C. Hureau, Chem. Soc. Rev.,
2013, 42, 7747–7762; (b) Z. Jin, Nat. Prod. Rep., 2011,
28, 1143–1191; (c) G. V. Boyd, in Science of Synthesis:
Houben-Weyl Methods of Molecular Transformation, ed.
E. Schaumann, Thieme, Stuttgart, 2002, vol. 11, pp. 481–
492.
2 (a) A.-M. M. E. Omar, O. M. Aboulwafa, M. S. El-Shoukrofy
and M. E. Amr, Bioorg. Chem., 2020, 96, 103593;
(b) C. S. Demmer and L. Bunch, Eur. J. Med. Chem., 2015,
97, 778–785.
3 (a) S. Singh, G. Veeraswamy, D. Bhattarai, J. I. Goo, K. Lee
and Y. Choi, Asian J. Org. Chem., 2015, 4, 1338–1631;
(b) M. B. Labib, J. N. Philoppes, P. F. Lamie and
E. R. Ahmed, Bioorg. Chem., 2018, 76, 67–80;
(c) M. N. Noolvia, H. M. Patel and M. Kaur, Eur. J. Med.
Chem., 2012, 54, 447–462.
4 S. M. Rida, F. A. Ashour, S. A. M. El-Hawash, M. M. El-
Semary, M. H. Badr and M. A. Shalaby, Eur. J. Med. Chem.,
2005, 40, 949–959.
5 (a) T. E. Bolelli, I. Yildiz and S. O. Ozgacar, Med. Chem.
Res., 2016, 25, 553; (b) L. Xiao, H. Gao, J. Kong, G. Liu and
S. Wang, Chin. J. Org. Chem., 2014, 6, 1048–1060.
6 (a) L. J. Scott, Drugs, 2014, 74, 1371–1378; (b) C. Hohmann,
K. Schneider, C. Bruntner, E. Irran, G. Nicholson,
A. T. Bull, A. L. Jones, R. Brown, J. E. Stach, M. Goodfellow,
W. Beil, M. Krämer, J. F. Imhoff, R. D. Süssmuth and
H. P. Fiedler, J. Antibiot., 2009, 62, 99–104.
7 (a) K. Van derpoorten, H. Ucar, G. Andrei, R. Snoeck,
J. Balzarini, E. De Clercq and J. H. Poupaert, Antiviral.
Chem. Chemother., 1999, 10, 87–97; (b) H. Razavi,
S. K. Palaninathan and E. T. Powers, Angew. Chem., Int. Ed.,
2003, 42, 2758–2761.
To gain insight into the mechanism of this transformation,
several control experiments were conducted (Scheme 1). When
the radical inhibitor 2,6-di-tert-butyl-4-methylphenol (BHT) or
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added into
the reaction, the yield of 2a was partially suppressed
(Scheme 1). Note that high-resolution mass spectrometry
revealed that a trace of the adduct of BHT was generated. This
result implies that the reaction may proceed through a radical
pathway. On the basis of the above experimental results and
previous reports,14,15 a possible mechanism of this conversion
is proposed as follows (Scheme 2). Initially, the reaction com-
mences with the Cu(I)-assisted cleavage of BPO to produce the
benzoxy radical and Cu(II). Then, the corresponding α-amino
acid ester 1a undergoes hydrogen atom abstraction by the
benzoxy radical to generate alkyl radical intermediate A, which
can be likely converted into iminium ion B through a single
electron transfer (SET) assisted by Cu(II). Immediately,
iminium ion B can convert into imine intermediate C under
basic conditions. Finally, intramolecular oxidative cyclization
occurs to give the desired product 2a.
Conclusions
In conclusion, we have described a simple and direct intra-
molecular oxidative cyclization reaction of glycine esters
through copper-catalyzed C–H bond functionalization. A broad
range of glycine derivatives involving short peptides underwent
1618 | Org. Biomol. Chem., 2021, 19, 1616–1619
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
8 (a) A. J. Blacker, M. M. Farah, M. I. Hall, S. P. Marsden,
O. Saidi and J. M. J. Williams, Org. Lett., 2009, 11, 2039–
74–100; (b) H. Wang, X. Gao, Z. Lv, T. Abdelilah and A. Lei,
Chem. Rev., 2019, 119, 6769–6787.
2042; (b) H. Sharma, N. Singh and D. O. Jang, Green Chem., 12 (a) Y. Yuan, S. Zhang, Z. Sun, Y. Su, Q. Ma, Y. Yuan and
2014, 16, 4922–4930; (c) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai,
X. Qi, Y. Lan and A. Lei, Angew. Chem., Int. Ed., 2014, 53,
502–506; (d) J. A. GarduÇo and J. J. Garcia, ACS Catal.,
2015, 5, 3470–3477; (e) J. Jiang, H. Zou, Q. Dong, R. Wang,
L. Lu, Y. Zhu and W. He, J. Org. Chem., 2016, 81, 51–56;
(f) W. Chen, W. An, Y. Wang and A. Yu, J. Org. Chem., 2016,
X. Jia, Org. Lett., 2020, 22, 6294–6298; (b) H. Tian, W. Xu,
Y. Liu and Q. Wang, Org. Lett., 2020, 22(13), 5005–5008;
(c) Z. Q. Zhu, L. J. Xiao, Z. B. Xie and Z. G. Le, Chin. J. Org.
Chem., 2019, 39, 2345–2364; (d) M. San Segundo and
A. Correa, Synthesis, 2018, 50, 2853–2866 and references
therein.
81, 10857–10862; (g) J. Liu and J. M. Hoover, Org. Lett., 13 (a) X.-W. Gao, Q.-Y. Meng, J.-X. Li, J.-J. Zhong, T. Lei,
2019, 12, 4510–4514.
X.-B. Li, C.-H. Tung and L.-Z. Wu, ACS Catal., 2015, 5,
2391–2396; (b) X. Yang, Y. Zhu, Z. Xie, Y. Li and Y. Zhang,
Org. Lett., 2020, 22, 1638–1643; (c) C. Wang, H. Qi,
H. Xue, Y. Shen, M. Chang, Y. Chen, R. Wang and
Z. Xu, Angew. Chem., 2020, 132, 7531–7536 and references
therein.
9 (a) S. Zhang, Y.-H. Niu and X.-S. Ye, Org. Lett., 2017, 19,
3608–3611; (b) Y. Li, M. Wang, W. Fan, F. Qian, G. Li and
H. Lu, J. Org. Chem., 2016, 81, 11743–11750; (c) S. Yamada,
K. Murakami and K. Itami, Org. Lett., 2016, 18, 2415–2418;
(d) C. M. Filloux and T. Rovis, J. Am. Chem. Soc., 2015, 137,
508–517; (e) M. Corro, M. Besora, C. Maya, E. Alvarez, 14 (a) H. Zhi, S. P.-M. Ung, Y. Liu, L. Zhao and C.-J. Li, Adv.
J. Urbano, M. R. Fructos, F. Maseras and P. J. Perez, ACS
Catal., 2014, 4, 4215–4222; (f) R. S. Sanchez and
F. A. Zhuravlev, J. Am. Chem. Soc., 2007, 129, 5824–5825;
(g) S. L. Niu, J. Hu, K. He, Y. C. Chen and Q. Xiao, Org.
Lett., 2019, 11, 4250–4254; (h) S. Wang, S. Xu, C. Yang,
H. L. Sun and J. B. Wang, Org. Lett., 2019, 6, 1809–1812.
10 For selected papers, see: (a) Q. Song, Q. Feng and M. Zhou,
Org. Lett., 2013, 15, 5990–5993; (b) A. R. Tiwari and
Synth. Catal., 2016, 358, 2553–2557; (b) V. D. Ramana and
M. Chandrasekharam, Org. Chem. Front., 2018, 5, 788–792;
(c) J. Ren, C. Pi, Y. Wu and X. Cui, Org. Lett., 2019, 21,
4067–4071; (d) R. Rohlmann, T. Stopka, H. Richter and
O. G. Mancheno, J. Org. Chem., 2013, 78, 6050–6064;
(e) B. Sun, Y. Wang, D. Li and W. Su, Org. Biomol. Chem.,
2018, 16, 2902–2909; (f) B. Sun, J. Deng, D. Li, C. Jin and
W. Su, Tetrahedron Lett., 2018, 59, 4364–4369.
B. M. Bhanage, Org. Biomol. Chem., 2016, 14, 7920–7926; 15 X. Liu, J. Pu, X. Luo, X. Cui, Z. Wu and G. Huang, Org.
(c) S. Ueda and H. Nagasawa, Angew. Chem., Int. Ed., 2008, Chem. Front., 2018, 5, 361–365.
47, 6411–6413; (d) T. Okitsu, K. Nagase, N. Nishio and 16 (a) Z.-Q. Zhu, P. Bai and Z.-Z. Huang, Org. Lett., 2014, 16,
A. Wada, Org. Lett., 2012, 14, 708–711; (e) J. Sedelmeier,
F. Lima, A. Litzler, B. Martin and F. Venturoni, Org. Lett.,
2013, 15, 5546–5549; (f) S. S. K. Boominathan, W. P. Hu,
G. C. Senadi, J. K. Vandavasi and J. J. Wang, Chem.
Commun., 2014, 50, 6726–6728; (g) X. Chen, F. Ji, Y. Zhao,
Y. Liu, Y. Zhou, T. Chen and S.-F. Yin, Adv. Synth. Catal.,
2015, 357, 2924–2930.
4881–4883; (b) Z.-Q. Zhu, Z.-B. Xie and Z.-G. Le, J. Org.
Chem., 2016, 81, 9449–9454; (c) Z.-Q. Zhu, Z.-B. Xie and
Z.-G. Le, Synlett, 2017, 28, 485–488; (d) Z.-Q. Zhu, L.-J. Xiao,
Y. Chen, Z.-B. Xie, H.-B. Zhu and Z.-G. Le, Synthesis, 2018,
50, 2775–2783; (e) Z.-Q. Zhu, L.-J. Xiao, D. Guo, X. Chen,
J.-J. Ji, X. Zhu, Z.-B. Xie and Z.-G. Le, J. Org. Chem., 2019,
84, 435–442; (f) Z.-Q. Zhu, D. Guo, J.-J. Ji, X. Zhu, J. Tang,
Z.-B. Xie and Z.-G. Le, J. Org. Chem., 2020, 85, 15062–
15071.
11 For selected reviews on CDC reactions, see: (a) S. A. Girard,
T. Knauber and C. J. Li, Angew. Chem., Int. Ed., 2014, 53,
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1616–1619 | 1619