Oxidation of sp3C—H bonds in N-alkylhydrazides: Access to 2,5-disubstituted 1,3,4-oxadiazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2016.11.018

The oxidation of sp³C[sbnd]H bonds in N-alkylhydrazides was achieved en route to the efficient synthesis of a broad series of 1,3,4-oxadiazoles. Mechanistic studies have revealed that N-acylhydrazone is a key intermediate in this catalytic transformation.

Full text of DOI:10.1016/j.tetlet.2016.11.018

Accepted Manuscript
Oxidation of sp3 C–H Bonds in N-Alkylhydrazides: Access to 2,5-Disubstituted
1,3,4-Oxadiazole Derivatives
Liang Zhang, Xiaolong Zhao, Xiaobi Jing, Xuewen Zhang, Shiwei Lü,
Liangliang Luo, Xiaodong Jia
PII:
S0040-4039(16)31474-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.018
TETL 48304
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 September 2016
3 November 2016
4 November 2016
Please cite this article as: Zhang, L., Zhao, X., Jing, X., Zhang, X., Lü, S., Luo, L., Jia, X., Oxidation of sp3 C–H
Bonds in N-Alkylhydrazides: Access to 2,5-Disubstituted 1,3,4-Oxadiazole Derivatives, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.018
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Oxidation of sp3 C–H Bonds in N-
Alkylhydrazides: Access to 2,5-Disubstituted
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Liang Zhang,a Xiaolong Zhao, *, a Xiaobi Jing,b Xuewen Zhang,b Shiwei Lü,a Liangliang Luo,a Xiaodong Jia *, a, b

1
Tetrahedron Letters
Oxidation of sp3 C–H Bonds in N-Alkylhydrazides: Access to 2,5-Disubstituted
1,3,4-Oxadiazole Derivatives
Liang Zhang,a Xiaolong Zhao, *, a Xiaobi Jing,b Xuewen Zhang,b Shiwei Lü,a Liangliang Luo,a Xiaodong Jia
, a, b
*
a College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China
b College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu 225002, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The oxidation of sp3 C–H bonds in N-alkylhydrazides was achieved en route to the efficient
synthesis of a broad series of 1,3,4-oxadiazoles. Mechanistic studies have revealed that N-
acylhydrazone is a key intermediate in this catalytic transformation.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
C-H oxidation
N-Alkylhydrazides
1,3,4-Oxadiazoles
Cross-Dehydrogenative Coupling
N-Acylhydrazone
[2]
Since the pioneering work of Murahashi[1] and Li, cross-
dehydrogenative couplings (CDC) have become widely utilized
for the direct construction of C–C bonds directly by two C–H
functionalizations. This strategy avoids the need to use
prefunctionalized substrates, and due to the ubiquity of C–H
Furthermore, compounds containing 1,3,4-oxadiazole core could
also be used in material science and supermolecular chemistry.[18]
Several methods have been reported in literatures for the
synthesis of substituted 1,3,4-oxadiazoles.[19] The most
representative route to them is by cyclization of diacylhydrazides
[3]
bonds, increases their applicability. This new concept inspired
catalyzed by a variety of reagents, generally under harsh reaction
blow-out of CDC reactions, and a variety of research groups
devoted their concentration on developing more useful and
applicable variants of CDC reactions.[4-11] Numerous catalytic
systems have been developed to realize many examples of these
CDC reactions, namely, metal-catalyzed examples involving Cu,
[19g-l]
conditions.
However, some limitations also exist in these
efficient approaches, such as toxic reagents, laborious reaction
procedures and more importantly, narrow scope. Therefore, the
synthesis of structurally diverse 1,3,4-oxadiazoles through more
simple, atom-economical and applicable methods is still highly
desirable.
[4] Ni, [5] Fe, [6] Rh [7] and Pd [8], those mediated by light,[9] as well
[10]
as those proceeding in the absence of any metal catalyst
and
others [11]. However, the discovery of the substrates lags out.
Generally, two kinds of model substrates were widely
investigated tetrahydroisoquinoline (THIQ) and N-arylglycines
(Figure 1, eq 1). Therefore, in order to expand the scope of the
CDC process, the development of transformations which utilize
novel classes of substrates is important.
Figure 1. CDC Reactions
In this regard, we questioned whether the CDC process could
also be applied to the C-H oxidation of N-alkylhydrazides to
synthesize the 1,3,4-oxadizaole derivatives. It is well-known that
the 1,3,4-oxadiazole core is an important structural motif to
pharmaceutical industry, due to its wide biological activities,[12]
[14]
such as anti-inflammatory,[13] anti-hypotensive,
tyrosinase
[15]
[16]
inhibitor,
anti-HCV agents
.
Beside the numerous
Recently, free radical mediated C–H functionalizations have
applications in medicinal chemistry, 1,3,4-oxadiazole derivatives
are also important building blocks in synthesis of natural
products. For example, a series of Aspidosperma alkaloids were
attracted considerable attention, and many elegant methodologies
[20]
have been established.
As part of our ongoing program of
[21]
radical mediated transformations,
we focused on constructing
[17]
important heterocyclic skeletons by using new CDCs.[22] It is
synthesized by Boger, based on oxadiazole intermediates.

2
Tetrahedron
well-known that the -C–H bonds adjacent to nitrogen atoms
are relatively reactive, and can be oxidized to assist in the
generation of radical and iminium species. So THIQ and N-
arylglycines were designed as model substrates and widely
applied in CDC reactions. Inspired by these structures, we
wondered whether the C–H bonds in N-alkylhydrazides could
also be oxidized. More importantly, after C-H oxidation, an N-
acylhydrazone intermediate would result, which is a versatile
electrophile for the synthesis of nitrogen-containing compounds
(Figure 1, eq 2). [23] If this plan could be realized, a series of new
reactions based on N-acylhydrazones will be found. Herein, the
preliminary results of C–H oxidation in N-alkylhydrazides will
be reported.
Table 1. Optimization of Reaction Conditions a
Cu
Additive
(mol %)
none
none
none
none
none
none
none
none
none
CF3CO2H
TfOH
PTSA
H2SO4
Yield
(%) b
38
trace
0
13
15
0
trace
0
Entry
[O]
Solvent
(mol %)
CuBr
CuBr
CuBr
CuCl
CuI
none
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
With the optimal conditions in hand, the scope of the
substrates was explored. series of reactions of N-
1
2
3
4
5
6
7
8
TBHP
DTBP
BPO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CHCl3
A
alkylhydrazides with various ester groups readily proceeded with
good yields (Scheme 1). The reaction of methyl
benzamidoglycinate gave the 1,3,4-oxadiazole products in 70%
yield (2b). Other N-alkylhydrazides with straight esters produced
the corresponding oxygenated compounds 2a-2f in 61-70%
yields. Bulky esters such as the iso-propyl and tert-butyl analogs
did not greatly affect the efficiency of the reaction, and the 1,3,4-
oxadiazole products were isolated in 66% (2g) and 60% (2h)
yields, respectively. Esters containing cycloalkyl group could be
converted into the desired products in 79% (2i) and 72% (2j)
yields. In order to extend the reaction scope, we installed some
carbon-carbon unsaturated bonds on the substrates such as allyl,
cinnamyl, pent-2-en-1-yl and but-3-yn-1-yl to afford the desired
products (2k−2n) in good yields. The existence of another active
benzyl sp3 C−H bond, which might disturb the oxidation process,
did not exert negative effect on this reaction (2o). Susceptible
cyclopropylmethyl group remained unchanged under the
oxidative conditions (2p), showing good functional group
tolerance.
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DCE
9
1,4-dioxane
CH3CN
CH3CN
CH3CN
CH3CN
0
45
52
46
10
11
12
13
66
a Unless otherwise specified, the reaction was carried out with
1a (0.5mmol) in the presence of oxidant (3 eq), catalyst (30 mol
%), additive (10 mol %) and anhydrous solvent (3.0 mL) at 60oC
for 12h. b Isolated yields.
We chose ethyl benzamidoglycinate (1a) as the model
substrate to test the possibility of oxidation of N-alkylhydrazide.
Initially, different peroxides were tested in the presence of a
copper catalyst (Table 1, entries 1-3). To our delight, the
corresponding N-acylhydrazone was readily detected in the
presence of 3 equivalents of TBHP, and after prolonged stirring,
the desired1,3,4-oxadiazolecould be isolated in 38% yield (entry
1). [24] Other peroxides did not provide a significant improvement
of the yield of the desired product. Further optimization
demonstrated that using CuBr as the catalyst gave improved
results (entries 4-5), and in the absence of copper, no desired
product was detected (entry 6). Screening of reaction solvents
indicated that MeCN was the most effective media for this
reaction (entries 7-9). After evaluation of reaction temperature,
the best result was obtained at 60oC (for details, see supporting
information). Since the yield still remained unsatisfied, some
additives were then tested (entries 10-13). By switching between
different acid additives, H2SO4 resulted in a marked improvement
in the yield of 2a (entry 13).
Scheme 2. Reaction of Substituted N-Alkylhydrazides
The utility of the protocol was further extended to the
synthesis of 1,3,4-oxadiazoles with different functional groups at
the 2- and 5-positions (Scheme 2). The reaction of N-
benzylhydrazide also exhibited high reactivity, giving the 2,5-
diphenyloxadiazole in 45% yield (2q). Higher yield (58%) was
obtained when N-(4-methyl)benzylhydrazide was used in the
reaction (2r). When the reaction’s tolerance to variously
substituted benzoyl groups was tested, the desired 1,3,4-
oxadiazoles could be obtained. As shown in Scheme 2, electron-
Scheme 1. Reaction of Alkyl Benzamidoglycinates

3
donating substituents (i.e Me, OMe) and electron-withdrawing
groups (Cl) do not have any deleterious effects on the reaction,
and the desired products are afforded in high yields (2s to 2u).
Other heterocyclic derivatives are also suitable for this
transformation.
For
example,
ethyl
(furan-2-
carboxamido)glycinate could be smoothly oxidized and
underwent the domino cyclization to 1,3,4-oxadiazole in 68%
yield (2v) and the analogue with electron-deficient pyridine ring
produced the target compound in 60% yield (2w).
Scheme 3. Control Experiments
In conclusion, we have developed
a
copper-catalyzed
intramolecular -functionalization of N-alkylhydrazide which
proceeds via a C–H bond oxidation sequence. This method
allows efficient access to diversely substituted 1,3,4-oxadiazoles
compounds from the corresponding N-alkylhydrazides.
Compared with other methods to 1,3,4-oxadiazoles, this method
is very simple and efficient. Most importantly, since the
generated intermediate, N-acylhydrazone, is
a
versatile
electrophile for the synthesis of nitrogen-containing compounds,
this new variant of CDC reaction could be potentially extended to
more general structures. Further mechanistic studies and
applications of the reaction are underway in our laboratory and
will be disclosed in due course.
Acknowledgments
The authors thank David A. Petrone for valuable advice and
language improvements. We also thank National Natural Science
Foundation of China (NNSFC, No. 21362030 and 21562038) for
supporting our research.
Subsequently, in order to understand the reaction mechanism
in this reaction, some control experiments were performed
(Scheme 3). First, a radical-inhibiting experiment was carried out
by employing TEMPO as the radical scavenger. Only a trace
amount of 2a was obtained when 3 equiv of TEMPO were added
(eq 1), suggesting that this oxidation reaction might proceed
through a radical pathway. The efficiency of the reaction was not
affected when run under and argon atmosphere, this suggested
that TBHP is the terminal oxidant and dioxygen was not involved
in the C-H oxidation step (eq 2). In the presence of 10% CuBr,
the oxidation of 1q was conducted, and only the corresponding
N-acylhydrazone was isolated in 30% yield (eq 3). The reason of
the lower yield of N-acylhydrazone was attributed to
decomposition of hydrazone. Hence, the hydrazone was
subjected to the standard conditions, and the desired product 2q
was isolated in 78% yield (eq 4), which implied that hydrazone is
a feasible intermediate in this reaction. To confirm the catalyst in
the intramolecular cyclization step, the cyclization of hydrazone
was individually performed in the presence of TBHP, CuBr or
H2SO4, respectively (eq 5-7). However, no desired product was
detected, implying that the cyclization of hydrazone was
promoted by TBHP and CuBr (see Table 1, entry 1).
References and notes
1.
(a) Murahashi, S.-I.; Naota, T.; Yonemura, K. J. Am. Chem. Soc.
1988, 110, 8256. (b) Murahashi, S.; Naota, T.; Miyaguchi, N.;
Nakato, T. Tetrahedron Lett. 1992, 33, 6991. (c) Murahashi, S.-I.;
Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003, 125,
15312.
2.
3.
(a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (b) Li, Z.;
Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
8928. (c) Li, C. J. Acc. Chem. Res. 2009, 42, 335.
For recent review, see: (a) Girard, S. A.; Knauber, T.; Li, C.-J.
Angew. Chem. Int. Ed. 2014, 53, 74; (b) Kozhushkov, S. I.;
Ackermann, L. Chem. Sci. 2013, 4, 886; (c) Shang, X.; Liu, Z.-Q.
Chem. Soc. Rev. 2013, 42, 3253; (d) Liu, C.; Zhang, H.; Shi, W.;
Lei, A. Chem. Rev. 2011, 111, 1780; (e) Yeung, C. S.; Dong, V.
M. Chem. Rev. 2011, 111, 1215; (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J.
Chem. Rev. 2011, 111, 1293. (g) Ashenhurst, J. A. Chem. Soc.
Rev. 2010, 39, 540.
4.
(a) Mao, Z.; Wang, Z.; Xu, Z.; Huang, F.; Yu, Z.; Wang, R. Org.
Lett., 2012, 14, 3854. (b) Rout, S. K.; Guin, S.; Ali, W.; Gogoi,
A.; Patel, B. K. Org. Lett., 2014, 16, 3086. (c) Wu, J.-J.; Li, Y.;
Zhou, H.-Y.; Wen, A.-H.; Lun, C.-C.; Yao, S.-Y.; Ke, Z.; Ye, B.-
H. ACS Catal., 2016, 6, 1263. (d) Sun, S.; Li, C.; Floreancig, P.
E.; Lou, H.; Liu L. Org. Lett., 2015, 17, 1684. (e) Zhang, J.;
Tiwari, B.; Xing, C.; Chen, X.; Chi, Y. R. Angew. Chem. Int. Ed.
2012, 51, 3649. (f) Xiong, T.; Li, Y.; Bi, X.; Lv, Y.; Zhang, Q.
Angew. Chem. Int. Ed. 2011, 50, 7140.
Based on the results of control experiments and reported
CDCs, we have proposed a mechanism involving radical
intermediates (Scheme 4). In the presence of TBHP and Cu(I),
the N-alkylhydrazide was oxidized to the corresponding N-
acylhydrazone A, which can then coordinate to the Cu(I) salt. In
the presence of H2SO4, complex A can be converted to O-bound
Cu(I) complex B, which after oxidation by TBHP, generates a
5.
6.
(a) Jin, L.-K.; Wan, L.; Feng, J.; Cai, C. Org.
Lett., 2015, 17, 4726. (b) Whittaker, A. M.; Dong, V. M. Angew.
Chem. Int. Ed. 2015, 54, 1312.
(a) Wertz, S.; Leifert, D.; Studer, A. Org. Lett., 2013, 15, 928. (b)
Cheng, Y.; Dong, W.; Wang, L.; Parthasarathy, K.; Bolm, C. Org.
Lett., 2014, 16 , 2000. (c) Zhao, J.; Fang, H.; Zhou, W.; Han, J.;
Pan, Y. J. Org. Chem., 2014, 79, 3847.
[25]
imidoyl radical bound to a Cu(II) center (intermediate C).
Finally, an intramolecular C–O oxidative coupling of
intermediate C provides the desired 1,3,4-oxadiazole, and
regenerates the active Cu(I) salt.
7.
(a) Wang, P.; Rao, H.; Hua, R.; Li, C.-J. Org. Lett., 2012, 14, 902.
(b) Kuhl, N.; Hopkinson, M. N.; Glorius, F. Angew. Chem. Int. Ed.
2012, 51, 8230. (c) Tan, Y.; Yuan, W.; Gong, L.; Meggers, E.
Angew. Chem. Int. Ed. 2015, 54, 13045.
Scheme 4. Mechanism of Formation of 1,3,4-Oxadiazoles

4
Tetrahedron
8. (a) Guin, S.; Rout, S. K.; Banerjee, A.; Nandi, S.; Patel, B. K. Org.
B. J.; Sun, J.; Sarjeant, A.; Lee, H.-J.; Katz, H. E. J. Am. Chem.
Soc. 2009, 131, 1692. (c) Yang, Y.-K.; Yook, K.-J.; Tae, J. J. Am.
Chem. Soc. 2005, 127, 16760. (d) Lin, L.-Y.; Lin, X.-Y.; Lin, F.;
Wong, K.-T. Org. Lett. 2011, 13, 2216.
Lett., 2012, 14, 5294. (b) Shen, D.; Han, J.; Chen, J.; Deng, H.;
Shao, M.; Zhang, H.; Cao, W. Org. Lett., 2015, 17, 3283. (c) Li,
G.; Qian, S.; Wang, C.; You, J. Angew. Chem. Int. Ed. 2013, 52,
7837. (d) Bugaut, X.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50,
7479. (e) Shi, Z.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51,
9220.
(a) Wu, C.-J.; Zhong, J.-J.; Meng, Q.-Y.; Lei, T.; Gao, X.-W.;
Tung, C.-H.; Wu, L.-Z. Org. Lett., 2015, 17, 884; (b) Xiao, T.;
Li, L.; Lin, G.; Mao, Z.; Zhou L. Org. Lett., 2014, 16, 4232. (c)
Pandey, G.; Laha, R. Angew. Chem. Int. Ed. 2015, 54, 14875.
19. (a) Dolman, S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. E. J. Org.
Chem. 2006, 71, 9548. (b) Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.;
Liu, J.; Yi, H.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 4666. (c)
Chu, W. J.; Yang, Y.; Chen, C. F. Org. Lett. 2010, 12, 3156. (d)
Levins, C. G.; Wan, Z. K. Org. Lett. 2008, 10, 1755. (e) Yang, S.-
J.; Lee, S.-H.; Kwak, H.-J.; Gong, Y.-D. J. Org. Chem. 2013, 78,
438. (f) Ji, F.; Li, X.; Guo, W.; Wu, W.; Jiang, H. J. Org. Chem.
2015, 80, 5713. (g) Guin, S.; Ghosh, T.; Rout, S. K.; Banerjee, A.;
Patel, B. K. Org. Lett., 2011, 13, 5976. (h) Li, Z.; Wang, L. Adv.
Synth. Catal. 2015, 357, 3469. (i) Wang, L.; Cao, J.; Chen, G.; He,
M. J. Org. Chem. 2015, 80, 4743. (j) Li, A.-F.; He, H.; Ruan,
Y.-B, Wen, Z.-C.; Zhao, J.-S.; Jiang, Q.-J.; Jiang, Y.-B. Org.
Biomol. Chem., 2009, 7, 193.
20. (a) Zhang, L.; Hang, Z.; Liu, Z.-Q. Angew. Chem. Int. Ed. 2016,
55, 236. (b) Zhang, L.; Liu, D.; Liu, Z.-Q. Org.
Lett., 2015, 17, 2534. (c) Duan, X.-Y.; Yang, X.-L.; Jia, P.-P.;
Zhang, M.; Han, B. Org. Lett., 2015, 17, 6022. (d) Qin, G.;
Chen, X.; Yang, L.; Huang, H. ACS Catal., 2015, 5, 2882. (e) Xie,
Y.; Guo, S.; Wu, L.; Xia, C.; Huang, H. Angew. Chem. Int. Ed.
2015, 54, 5900.
9.
10. (a) Chen, X.; Cui, X.; Yang, F.; Wu, Y. Org. Lett., 2015, 17, 1445;
(b) He, T.; Yu, L.; Zhang, L.; Wang, L.; Wang, M. Org.
Lett., 2011, 13, 5016; (c) Tanoue, A.; Yoo, W.-J.; Kobayashi, S.
Org. Lett., 2014, 16, 2346; (d) Matcha, K.; Antonchick, A. P.
Angew. Chem. Int. Ed. 2013, 52, 2082.
11. (a) Rajamanickam, S.; Majji, G.; Santra, S. K.; Patel, B. K. Org.
Lett. 2015, 17, 5586. (b) Nobuta, T.; Tada, N.; Fujiya, A.;
Kariya, A.; Miura, T.; Itoh, A. Org. Lett., 2013, 15 , 574. (c)
Neel, A. J.; Hehn, J. P.; Tripet, P. F.; Toste, F. D. J. Am. Chem.
Soc., 2013, 135, 14044. (d) Tang, S.; Zeng, L.; Liu, Y.; Lei, A.
Angew. Chem. Int. Ed. 2015, 54, 15850.
12. (a) O´ Neal, J. B.; Rosen, H.; Russel, P. B.; Adams, A. C.;
Blumenthal, A. J. Med. Pharm. Chem. 1962, 5, 617. (b) Ankersen,
M.; Peschke, B.; Hansen, B. S.; Hansen, T. K. Bioorg. Med.
Chem. Lett. 1997, 7, 1293. (c) Watjen, F.; Baker, R.; Engelstoff,
M.; Herbert, R.; MacLeod, A.; Knight, A.; Merchant, K.;
Moseley, J.; Saunders, J.; Swain, C. J.; Wong, E.; Springer, J. P. J.
Med. Chem. 1989, 32, 2282.
13. (a) Mullican, M. D.; Wilson, M. W.; Connor, D. T.; Kostlan, C.
R.; Schrier, D. J.; Dyer, R. D. J. Med. Chem. 1993, 36, 1090. (b)
Song, Y.; Connor, D. T.; Sercel, A. D.; Sorenson, R. J.;
Doubleday, R.; Unangst, P. C.; Roth, B. D.; Beylin, V. G.;
Gilbertsen, R. B.; Chan, K.; Schrier, D. J.; Guglietta, A.;
Bornemeier, D. A.; Dyer, R. D. J. Med. Chem. 1999, 42, 1161.
14. (a) Turner, S.; Myers, M.; Gadie, B.; Nelson, A. J.; Pape, R.;
Saville, J. F.; Doxey, J. C.; Berridge, T. L. J. Med. Chem. 1988,
31, 902. (b) Turner, S.; Myers, M.; Gadie, B.; Hale, S. A.;
Horsley, A.; Nelson, A. J.; Pape, R.; Saville, J. F.; Doxey, J. C.;
Berridge, T. L. J. Med. Chem. 1988, 31, 907.
21. Jia, X.-D. Synthesis 2016, 48, 18.
22. (a) Jia, X.-D.; Peng, F.-F.; Qing, C.; Huo, C.-D.; Wang, X.-C.
Org. Lett. 2012, 14, 4030. (b) Jia, X.-D.; Wang, Y.-X.; Peng, F.-
F.; Huo, C -D.; Yu, L.-L.; Wang, X.-C. J. Org. Chem. 2013, 78,
9450. (c) Wang, Y.-X.; Peng, F.-F.; Liu, J.; Huo, C.-D.; Wang, X.-
C.; Jia, X.-D. J. Org. Chem. 2015, 80, 609. (d) Liu, J.; Liu, F.;
Zhu, Y.-Z.; Ma, X.-G.; Jia, X.-D. Org. Lett. 2015, 17, 1409. (e)
Liu, F.; Yu, L.; Lv, S.; Yao, J.; Liu, J.; Jia, X. Adv. Synth. Catal.
2016, 358, 459.
23. For reviews, see: Sugiura, M.; Kobayashi, S. Angew. Chem. Int.
Ed. 2005, 44, 5176.
24. Besides the desired product 2a, the corresponding intermediate N-
acylhydrazone was detected, implying that the intramolecular
cyclization was not efficient.
25. For similar mechanistic process, see: (a) Lu, Q.; Liu, Z.; Luo, Y.;
Zhang, G.; Huang, Z.; Wang, H.; Liu, C.; Miller, J. T.; Lei, A. Org.
Lett. 2015, 17, 3402.(b) Rostovskii, N. V.; Sakharov, P. A.;
Novikov, M. S.; Khlebnikov, A. F.; Starova, G. L. Org. Lett. 2015,
17, 4148. (c) Rokade, B. V.; Prabhu, K. R. J. Org. Chem. 2014, 79,
8110. (d) Xie, Z.; Cai, Y.; Hu, H.; Lin, C.; Jiang, J.; Chen, Z.;
Wang, L.; Pan, Y. Org. Lett. 2013, 15, 4600. (e) Ilangovan, A.;
Satish, G. Org. Lett. 2013, 15, 5726.
15. Hassan Khan, M. T.; Choudhary, M. I.; Mohammed Khan, K.;
Rani, M.; Rahman, A. Bioorg. Med. Chem. 2005, 13, 3385.
16. Sherif, A. R.; Manal, A. S.; Maha, A. E. Eur. J. Med. Chem. 2003,
38, 959.
17. (a) Yuan, Z. Q.; Ishikawa, H.; Boger, D. L. Org. Lett. 2005, 7,
741. (b) Sears, J. E.; Barker, T. J.; Boger, D. L. Org. Lett. 2015,
17, 5460. (c) Kato, D.; Sasaki, Y.; Boger, D. L. J. Am. Chem. Soc.
2010, 132, 3685. (d) Lee, K.; Boger, D. L. J. Am. Chem. Soc.
2014, 136, 3312. (e) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi,
Y.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10596.
Supplementary Material
Copies of all 1H NMR and 13C NMR spectra of all
compounds.
18. (a) Li, Q.; Cui, L.-S.; Zhong, C.; Jiang, Z.-Q.; Liao, L.-S. Org.
Lett. 2014, 16, 1622. (b) Lee, T.; Landis, C. A.; Dhar, B. M.; Jung,

5
1. The oxidation of sp3 C–H bonds in N-
alkylhydrazides was achieved.
2. A series of functionalized 1,3,4-oxadiazoles were
formed in good yields.
3. The mechanistic study shows that the N-
acylhydrazones are a key intermediate.