Iodine-Catalyzed Construction of Dihydrooxepines via 3-Methyl-5-Pyrazolones C?H Oxidation/Functionalization of Quinolines Cascade

Article abstract of DOI:10.1002/ejoc.202100541

An efficient iodine-catalyzed [3+3+1] annulation for the construction of dihydrooxepine scaffolds with quinoline units was developed. This strategy involves a seven-membered dihydrooxepine with a broad substrate scope through a formal three-component tandem reaction. Further derivation of the target product produced a trioxabicycle scaffold, which formed the basic core of natural products and pharmaceutical molecules.

Full text of DOI:10.1002/ejoc.202100541

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doi.org/10.1002/ejoc.202100541
Iodine-Catalyzed Construction of Dihydrooxepines via 3-
Methyl-5-Pyrazolones CÀ H Oxidation/Functionalization of
Quinolines Cascade
Rong Zhang,[a] Jun Wang,[a] Weiwei Jin,[a] Yonghong Zhang,[a] Bin Wang,[a] Yu Xia,*[a] and
Chenjiang Liu*[a]
1001. Therefore, assembling them from readily available
precursors can be of great value. In recent years, several
important approaches have been realized, including [4+3] and
[5+2] metal-catalyzed cyclization, to construct oxepine and
hydrooxepine derivatives.[8] In 2013, Lautens and co-workers
used a Rh/Pd catalytic system to develop a domino cyclization
leading to a series of aza-dihydrodibenzoxepines with excellent
chemoselectivity (Scheme 1a).[9] Soon after, Mascareñas and
An efficient iodine-catalyzed [3+3+1] annulation for the
construction of dihydrooxepine scaffolds with quinoline units
was developed. This strategy involves a seven-membered
dihydrooxepine with a broad substrate scope through a formal
three-component tandem reaction. Further derivation of the
target product produced a trioxabicycle scaffold, which formed
the basic core of natural products and pharmaceutical mole-
cules.
Gulías’ group used
a Rh-catalyzed cycloaddition strategy
involving a CÀ H activation process to realize an efficient
construction of benzoxepines (Scheme 1b).[10] In 2017, Wu’s
group developed I2-catalyzed with an organic strong acid to
construct Dihydrooxepines (Scheme 1c).[11] The use of precious
metals and additive is necessary in the previous works, but
reported herein is the use of iodine catalysis without additive to
describe a successful design process involving the functionaliza-
tion of quinolines and three-component cyclization of 3-meth-
yl-5-pyrazolones.
Introduction
Quinoline and its derivatives are important building blocks of
heterocyclic species. They are widely present in bioactive
reagents and seen in the material sciences.[1] Because they have
so many applications, chemists continue to pay a great deal of
attention to the highly functionalized quinolines to develop
novel means of synthesizing them.[2] As a Lewis base, quinoline
inactivates Lewis acids and consequently suppresses Friedel-
Crafts reactions.[3] This creates a challenge for the functionaliza-
tion of quinoline. Significant advance in CÀ H functionalization Results and Discussion
has revealed one method of producing directly functionalized
quinolones.[4] Even though there are several elegant means of
synthesizing functionalized quinolines, the use of harsh reaction
conditions and some limits based on the nature of the involved
reagents make the development of more efficient methods of
synthesis a significant problem in organic chemistry.[5] Thus, the
exploitation of metal-free catalysis and avoidance of oxidants
strategies are a desirable part of the method for the functional-
ization of quinoline.
The initial discovery and optimization began via use of the
commercially available 2-methylquinoline (1a) and easily pre-
pared 3-methyl-1-phenyl-5-pyrazolones (2a) as the standard
partners. Encouragingly, our anticipated product 3a was
Medium-sized heterocycles are one of the most significant
classes of cyclic compounds due to their importance in organic
chemistry.[6] With respect to the seven-membered heterocycles,
the oxepine and hydrooxepine frameworks form the basic core
of natural products and pharmaceutical molecules,[7] such as
artemisinin, dihydroartemisinin, acetylapoaranotin, and (+)-MPC
[a] R. Zhang, J. Wang, Dr. Prof. W. Jin, Dr. Prof. Y. Zhang, Dr. B. Wang,
Dr. Prof. Y. Xia, Dr. Prof. C. Liu
Urumqi Key Laboratory of Green Catalysis and Synthesis Technology,
The Key Laboratory of Oil and Gas Fine Chemicals,
Ministry of Education & Xinjiang Uygur Autonomous Region,
School of Chemistry, Xinjiang University,
Urumqi 830046, P. R. China
E-mail: xiayu920@xju.edu.cn
pxylcj@126.com
Scheme 1. Strategies for the construction of oxepine and hydrooxepine
Derivatives.
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°
produced using I2 and DMSO at 120 C for 25 h (Table 1,
11). No product formed in the absence of I2 (entry 12). The
optimized reaction conditions were characterized as follows:
entry 1). Subsequently, various iodine sources were screened in
the reaction, but an inferior performance was observed in
comparison with I2 (entries 2–3). Much to our delight, when the
amount of I2 decrease to 20 mol%, thus producing 44% yield of
the product (entry 4–5). No better results were obtained after
investigating the effect of the solvents (entries 6–7). The
subsequent adjustment of the loading of 2a had excellent yield
(entries 8–9). Further screening of the reaction temperature and
time produced lower yields for the formation of 3a (entries 10–
°
0.2 mmol 1a, 0.8 mmol 2a, and 0.2 equiv. I2 in DMSO at 120 C
for 25 h.
With the optimized reaction conditions in hand, a series of
2-methylquinolines were converted into the corresponding
products in generally satisfactory yields (Scheme 2). The pres-
ence of the electron-donating groups at the 2-methylquinoline,
such as 6-methyl and 6-methoxy, performed with moderate
yields (3b and 3c). The electron-withdrawing groups were
tolerated better than the electron-donating groups, forming
(3d–3f ) in 45%-54% yields. Furthermore, the substituent
groups of 8-methoxy, 8-chloro, 8-bromo, and 8-nitro were also
compatible with the reaction (3g–3j). We tested 4-meth-
ylquinoline instead of 2-methylquinoline, producing the corre-
sponding product 3k in 53% yield. 2-Methylquinoxaline was
also found to participate in the reaction (3l). Unfortunately, 2-
methyl-1,8-naphthyridine failed to react under the optimized
conditions (3m). We used 1-methylisoquinoline for the desired
cyclization to produce the product 3n at a 30% yield.
Table 1. Optimization of reaction conditions.[a]
Entry[a]
2a [mmol]
[I] [equiv]
Solvent
Yield[b] [%]
To further ascertain the scope of the chosen reaction
conditions, study of the electronic effect of substituted 3-
methyl-5-pyrazolones. was necessary (Scheme 3). The aryl group
on the 3-methyl-5-pyrazolones. was explored first, thus afford-
ing the corresponding products in moderate to good yields
(3o–3x). The electron-donating groups, including 4-methyl, 4-
ethyl, and 4-tert-butyl, were tolerated and produced satisfactory
yields (3o–3q). Moreover, electron-withdrawing groups at the
para-position were also found to undergo the [3+3+1]
cyclization with good results (3r–3u). Regardless of substituents
at the ortho- or meta-position, they all reacted smoothly to
produce compounds 3v–3x with 65%–80% yields. Unfortu-
nately, substrate 2y failed to produce the corresponding
product 3y.
1
2
3
4
5
6
7
8
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.6
0.8
0.8
0.8
0.8
I2 (1.0)
NIS (1.0)
TBAI (1.0)
I2 (0.2)
I2 (0.1)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
-
DMSO
DMSO
DMSO
DMSO
DMSO
Sulfolane
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
36
28
trace
44
36
trace
0
58
75
0
9
10[c]
11[d]
12
56
-
[a] Reaction conditions: 1a (0.2 mmol), 2a, [I], solvent (1.0 mL), 25 h under
air at 120 C. [b] Isolated yields. [c] At 100 C. [d] Reaction time=20 h.
°
°
Scheme 2. Substrate scope with respect to the 2-methylquinolines.[a]
Scheme 3. Substrate scope with respect to the 3-methyl-5-pyrazolones.[a]
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Substrates other than quinolines are desired for the reaction
scope. After screening a variety of N-heteroarylmethanes, we
found that benzoxazole and benzothiazole could also be used
in the current catalytic system. The results are summarized in
Scheme 4. Although the 2-methylbenzoxazole was reacted and
produced 5a only 15% yield, 2-methylbenzothiazole was
tolerated smoothly and showed good yield (5b). The chloro
group on the benzothiazole was also evaluated, and this
produced product 5c. The process also worked for substituted
3-methyl-5-pyrazolones, thus affording corresponding products
(5d–5g) in moderate yields.
To establish the diversity of this reaction, a trioxabicycle
scaffold containing quinoline was prepared with good yield
(Scheme 5a), 6a). Notably, the core structure of artemisinin also
involves a trioxabicycle scaffold. By tuning the group of 3-
methyl-5-pyrazolones, the uncyclized product was used to
produce 49% yield (Scheme 5b), 7a). When the TsOH was used
as additive, cyclized product was obtained with 40% yield
(Scheme 5c), 8a), Another eminent advantage of this protocol is
that the reaction could be scaled up to gram quantities
(Scheme 5d).
For the sake of further investigating the reaction mecha-
nism, a suite of controlled experiments was carried out. 2-
methylquinoline 1a (0.2 mmol) was heated with I2 (0.04 mmol)
°
in DMSO at 120 C to gain quinoline-2-carbaldehyde B and the
corresponding hydrated species C (Scheme 6a). As previously
reported,[12] 2-methylquinoline could be iodinated employing
iodine to generate A, the α-iodoquinoline A with 3-methyl-1-
phenyl-5-pyrazolones 2a was found successful, and the product
3a was obtained in moderate yields both with and without I2
(Scheme 6b). Quinoline-2-carbaldehyde B was also subjected to
the optimized reaction conditions and produced 3a with 80%
yield, whereas no product was obtained in the absence of
iodine, demonstrating that iodine played an important role in
the oxidation process (Scheme 6c). These results suggested that
α-iodoquinoline A and quinoline-2-carbaldehyde B were key
intermediates in this transformation.
Scheme 4. Substrate Scope with Respect to the other N-heteroarylmethane-
s.[a]
Scheme 5. Diversification of this protocol.
Scheme 6. Control experiments.
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organic layers were washed with brine, dried over anhydrous
On the basis of the results of control experiments, and
results of previously published works,[11]À [13] a plausible mecha-
nism was proposed (Scheme 7). First, N-heteroaromatic meth-
anes underwent an enamine tautomerization under specific
conditions,[14] and 2-methylquinoline was iodinated with iodine
by DMSO to generate α-iodoquinoline A. The α-iodoquinoline
A was oxidized by DMSO to form quinoline-2-carbaldehyde B
via Kornblum oxidation with the removal of HI and DMS. Then
intermediate B trapped by the enol form of 3-methyl-1-phenyl-
5-pyrazolones 2a to gain intermediate D, which came through
further dehydration to yield intermediate E. Next, intermediate
E reacted with another equivalent of 2a to provide intermedi-
Na2SO4 and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(eluent: petroleum ether/EtOAc=10/1) to afford the product 3a.
Crystallographic data: Deposition Numbers 2015638 (for 3a) and
2015653 (for 5b) contain the supplementary crystallographic data
for this paper. These data are provided free of charge by the joint
Cambridge Crystallographic Data Centre and Fachinformationszen-
trum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
ate F via Michael addition. Intermediate F would be iodinated Acknowledgements
to produce intermediate G. Afterward, intermediate G under-
went an in-situ iodine-based oxidative coupling to generate the
desired product 3a. Finally, HI was oxidized to I2 to fulfill the
catalytic cycle.
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21961037, 21702175 and 21572195). the
Natural Science Foundation of Xinjiang Uygur Autonomous
Region (2020D01C077) and the Doctoral Research Foundation of
Xinjiang University (620312378) for the support of this research.
Conclusion
In conclusion, we reported an efficient functionalization of Conflict of Interest
quinolines under an iodine-catalyzed system, thus affording
seven-membered dihydrooxepine scaffolds. Notably, the diverse
N-heteroarylmethanes could also be executed to improve the
efficiency of the reactions. More importantly, in the derivatiza-
tion of this protocol, the synthesis of trioxabicycle scaffold
reveals a potential biological activity.
The authors declare no conflict of interest.
Keywords: Dihydrooxepines
· Iodine · Quinoline · Three-
component tandem reaction · Trioxabicycle
[1] a) V. F. Batista, D. C. G. A. Pinto, A. M. S. Silva, ACS Sustainable Chem. Eng.
2016, 4, 4064–4078; b) T. Ma, J. Mater. Chem. B 2014, 2, 31–35; c) H. Shi,
Y. Lu, J. Weng, K. L. Bay, X. Chen, K. Tanaka, P. Verma, K. N. Houk, J.-Q.
Yu, Nat. Chem. 2020, 12, 399–404; d) D. M. Pimpalshende, S. J. Dhoble,
Luminescence 2014, 29, 451–455; e) K. Suresh, B. Sandhya, G. Himanshu,
Mini-Rev. Med. Chem. 2009, 9, 1648–1654; f) Z. Yuan, R. Cheng, P. Chen,
G. Liu, S. H. Liang, Angew. Chem. Int. Ed. 2016, 55, 11882–11886; Angew.
Chem. 2016, 128, 12061–12065.
[2] a) V. E. Murie, R. H. V. Nishimura, L. A. Rolim, R. Vessecchi, N. P. Lopes,
G. C. Clososki, J. Org. Chem. 2018, 83, 871–880; b) K. Chinthapally, N. P.
Massaro, H. L. Padgett, I. Sharma, Chem. Commun. 2017, 53, 12205–
12208; c) R. K. Saunthwal, M. Patel, A. K. Verma, Org. Lett. 2016, 18,
2200–2203; d) Y. Li, L. L. Wong, Angew. Chem. Int. Ed. 2019, 58, 9551–
9555; Angew. Chem. 2019, 131, 9651–9655; e) W.-Z. Bi, K. Sun, C. Qu, X.-
L. Chen, L.-B. Qu, S.-H. Zhu, X. Li, H.-T. Wu, L.-K. Duan, Y.-F. Zhao, Org.
Chem. Front. 2017, 4, 1595–1600; f) P. B. Arockiam, L. Guillemard, J.
Wencel-Delord, Adv. Synth. Catal. 2017, 359, 2571–2579.
Experimental Section
General procedure for the synthesis of 3a: A dried 25 ml glass
tube containing a stir bar was charged with 3-methyl-1-phenyl-5-
pyrazolones (2a, 0.8 mmol, 139.4 mg) and iodine (0.04 mmol,
10.2 mg). After addition of 2-methylquinoline (1a, 0.2 mmol, 27 μL)
and 1 mL DMSO under air atmosphere, the mixture was stirred at
°
120 C for 25 h. till almost completed conversion of the substrates
by TLC analysis, the mixture was quenched with saturation Na2S2O3
solution (60 mL), extracted with CH2Cl2 (3×15 mL). The combined
[3] K. Murakami, S. Yamada, T. Kaneda, K. Itami, Chem. Rev. 2017, 117,
9302–9332.
[4] a) A. Modi, P. Sau, N. Chakraborty, B. K. Patel, Adv. Synth. Catal. 2019,
361, 1368–1375; b) S. Yotphan, R. G. Bergman, J. A. Ellman, Org. Lett.
2010, 12, 2978–2981; c) M. Meazza, F. Tur, N. Hammer, K. A. Jørgensen,
Angew. Chem. Int. Ed. 2017, 56, 1634–1638; Angew. Chem. 2017, 129,
1656–1660; d) B. Bieszczad, L. A. Perego, P. Melchiorre, Angew. Chem.
Int. Ed. 2019, 58, 16878–16883; Angew. Chem. 2019, 131, 17034–17039;
e) X. Li, X. Li, N. Jiao, J. Am. Chem. Soc. 2015, 137, 9246–9249.
[5] S. Yu, H. L. Sang, S. Ge, Angew. Chem. Int. Ed. 2017, 56, 15896–15900;
Angew. Chem. 2017, 129, 16112–16116.
[6] a) L. Yet, Chem. Rev. 2000, 100, 2963–3008; b) A. H. Hoveyda, A. R.
Zhugralin, Nature 2007, 450, 243–251; c) I. Shiina, Chem. Rev. 2007, 107,
239–273; d) A. Deiters, S. F. Martin, Chem. Rev. 2004, 104, 2199–2238;
e) V. Martí-Centelles, M. D. Pandey, M. I. Burguete, S. V. Luis, Chem. Rev.
2015, 115, 8736–8834; f) K. Parthasarathy, H. Han, C. Prakash, C.-H.
Cheng, Chem. Commun. 2012, 48, 6580–6582.
[7] a) R. T. Yu, R. K. Friedman, T. Rovis, J. Am. Chem. Soc. 2009, 131, 13250–
13251; b) N. Brown, B. Xie, N. Markina, D. VanderVelde, J.-P. H.
Scheme 7. Proposed mechanism
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Perchellet, E. M. Perchellet, K. R. Crow, K. R. Buszek, Bioorg. Med. Chem.
[12] a) M. Liu, T. Chen, Y. Zhou, S.-F. Yin, Catal. Sci. Technol. 2016, 6, 5792–
5796; b) S. Mohammed, R. A. Vishwakarma, S. B. Bharate, J. Org. Chem.
2015, 80, 6915–6921; c) Y.-P. Zhu, Z. Fei, M.-C. Liu, F.-C. Jia, A.-X. Wu,
Org. Lett. 2013, 15, 378–381; d) Z. Yan, C. Wan, Y. Yang, Z. Zha, Z. Wang,
RSC Adv. 2018, 8, 23058–23065; e) M. Liu, X. Chen, T. Chen, Q. Xu, S.-F.
Yin, Org. Biomol. Chem. 2017, 15, 9845–9854.
[13] a) Y.-F. Liang, X. Li, X. Wang, M. Zou, C. Tang, Y. Liang, S. Song, N. Jiao, J.
Am. Chem. Soc. 2016, 138, 12271–12277; b) R. Ye, Y. Cao, X. Xi, L. Liu, T.
Chen, Org. Biomol. Chem. 2019, 17, 4220–4224.
[14] a) R. Vanjari, K. N. Singh, Chem. Soc. Rev. 2015, 44, 8062–8096; b) B.
Qian, S. Guo, C. Xia, H. Huang, Adv. Synth. Catal. 2010, 352, 3195–3200;
c) M. Rueping, N. Tolstoluzhsky, Org. Lett. 2011, 13, 1095–1097; d) H.
Komai, T. Yoshino, S. Matsunaga, M. Kanai, Org. Lett. 2011, 13, 1706–
1709; e) M. Liu, X. Chen, T. Chen, S.-F. Yin, Org. Biomol. Chem. 2017, 15,
2507–2511.
Lett. 2008, 18, 4876–4879; c) S. Yamaguchi, N. Tsuchida, M. Miyazawa, Y.
Hirai, J. Org. Chem. 2005, 70, 7505–7511; d) Y. Ren, L. B. S. Kardono, S.
Riswan, H. Chai, N. R. Farnsworth, D. D. Soejarto, E. J. Carcache de Blan-
co, A. D. Kinghorn, J. Nat. Prod. 2010, 73, 949–955; e) S. Dong, K.
Indukuri, D. L. J. Clive, J. M. Gao, Chem. Commun. 2016, 52, 8271–8274;
f) J. A. Codelli, A. L. A. Puchlopek, S. E. Reisman, J. Am. Chem. Soc. 2012,
134, 1930–1933; g) J. Krieger, T. Smeilus, M. Kaiser, E.-J. Seo, T. Efferth, A.
Giannis, Angew. Chem. Int. Ed. 2018, 57, 8293–8296; Angew. Chem. 2018,
130, 8425–8428; h) L. Zheng, Y.-M. Liang, J. Org. Chem. 2017, 82, 7000–
7007; i) X.-S Zhang, Y.-F. Zhang, Z.-W. Li, F.-X. Luo, Z.-J. Shi, Angew.
Chem. Int. Ed. 2015, 54, 5478–5482; Angew. Chem. 2015, 127, 5568–
5572.
[8] a) B. M. Trost, Z. Zuo, Angew. Chem. Int. Ed. 2020, 59, 1243–1247; Angew.
Chem. 2020, 132, 1259–1263; b) K. Gao, Y.-G. Zhang, Z. Wang, H. Ding,
Chem. Commun. 2019, 55, 1859–1878.
[9] A. A. Friedman, J. Panteleev, J. Tsoung, V. Huynh, M. Lautens, Angew.
Chem. Int. Ed. 2013, 52, 9755–9758; Angew. Chem. 2013, 125, 9937–
9940.
[10] A. Seoane, N. Casanova, N. Quiñones, J. L. Mascareñas, M. Gulías, J. Am.
Chem. Soc. 2014, 136, 834–837.
[11] X. Wu, X. Geng, P. Zhao, Y.-D. Wu, A.-X. Wu, Org. Lett. 2017, 19, 4584–
4587.
Manuscript received: April 30, 2021
Revised manuscript received: June 15, 2021
Accepted manuscript online: June 23, 2021
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