DOI: 10.1002/slct.

201801951 Communications

1
2 z Organic & Supramolecular Chemistry
3
4
5
Straightforward Synthesis of Novel Difluorinated
6 2-Hydroxyl-Substituted Dihydroquinolones Through
7
8 Selectfluor-triggered Annulation of
9
10
2-Aminoarylenaminones
11 Qing-Lan Zhao,[a] Hao-Yue Xiang,*[a] Chun-Hao Yang,[b] Jun-An Xiao,[c] Peng-Ju Xia,[a] Xiao-
12
Qing Chen,[a] and Hua Yang*[a]
13
14
A series of novel difluorinated 2-hydroxyl-substituted dihydro- tetrahydroquinolines. Consequently, developing practical strat-
15
quinolones have been firstly synthesized via selectfluor- egies to assemble this significant scaffold is still persistently
16
triggered tandem cyclizations of 2-aminoarylenaminones. This desired.
17
new approach could occur under mild reaction conditions, and Generally, two major known strategies have been devel-
18
features easy operation and scalability. oped for accessing azaflavanone skeletons (Scheme 1). The first
19
20
21
The quinoline skeletons are privileged structural motifs that are
22
widely found in various pharmaceuticals and natural products
23
with numerous biological activities (Figure 1).[1] Specifically, 2,3-
24
25
26
27
28
29
30
31
Scheme 1. Synthetic profiles of 2-substituted 2,3-dihydro-4-quinolones..
32
33
34
pathway relies on transition-metal (TM)-catalysed intermolecu-
35
lar conjugated addition to 4-quinolones,[3] in which multiple
36
synthetic steps and expensive transition-metals are usually
37
Figure 1. Selected natural products and synthetic compounds containing requisite. Alternatively, organocatalytic or Lewis acid-catalysed
38
quinoline core. intramolecular aza-Michael addition of amino-chalcone ana-
39
logues emerged as another tool to afford azaflavanone
40
skeletons in a more step-economic manner.[4] Despite these
41
dihydro-4-quinolone derivatives, also known as azaflavanones, advances, synthetic routes conducive to the facile modification
42
represent a new class of antimitiotic antitumor agents.[2] of substitution patterns on this type of important biological
43
Moreover, they could act as key building blocks in the scaffold are always appealing. Meanwhile, it is well known that
44
preparation of a range of quinolone derivatives, especially fluorinated derivatives of pharmaceuticals often possess unique
45
chemical, physical and biological properties, such as improved
46
[a] Dr. Q.-L. Zhao, Dr. H.-Y. Xiang, Dr. P.-J. Xia, Prof. X.-Q. Chen, Prof. H. Yang lipophilicity, electronegativity, bioavailability, and metabolic
47
College of Chemistry and Chemical Engineering, Central South University, stability.[5] Among various fluorinated moieties, CF2 group is
48 Changsha 410083, P. R. China usually known to be a bioisostere for carbonyl unit, and many
49 E-mail: hyangchem@csu.edu.cn
difluorinated analogues are of great medicinal importance.[6]
50 xianghaoyue@csu.edu.cn
[b] Prof. C.-H. Yang Unfortunately, none of success has been achieved so far for
51
State Key Laboratory of Drug Research, Shanghai Institute of Materia accessing 3,3-difluoro-engineered quinolines.
52 Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China We envisioned that the strategy by merging difluorination
53 [c] Dr. J.-A. Xiao
and cyclization might offer an innovative solution for the
54 College of Chemistry and Materials Science, Guangxi Teachers Education
University, Nanning, P. R. China existing dilemma of the quinolone library (Scheme 1, bottom).
55
Supporting information for this article is available on the WWW under In our previous work, a cyclization of o-hydroxyarylenaminones
56
https://doi.org/10.1002/slct.201801951 was promoted by Selectfluor to facilely furnish difluorinated
57

ChemistrySelect 2018, 3, 9218 – 9221 9218 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Communications
chromone derivatives.[7] It is highly desirable to employ this further improved by varying the equivalence of Selectfluor
1
strategy to realize the synthesis of difluorinated quinolones as (Table 1, entries 12 13). In addition, the structure of 3 a was
2
the assembly of quinoline skeletons from o-aminoarylenami- unequivocally established by X-ray crystallographic analysis.[10]
3
nones was rarely explored.[8] As part of our continuing interest To explore the versatility of this approach, various (E)-tert-
4
in bioactive fluorinated heterocycles and nitrogen-containing butyl (2-(3-(dimethylamino)acryloyl)phenyl)carbamates were
5
heterocycles,[9] we herein disclose our synthetic studies on the prepared and reacted under the optimized reaction conditions
6
difluorinated 2-hydroxyl-substituted 2,3-dihydro-4-quinolones (Scheme 2). Several substitution patterns on the phenyl moiety
7
with Selectfluor under mild reaction conditions.
8
The reaction of (E)-tert-butyl (2-(3-(dimethylamino)acryloyl)
9
phenyl)carbamate (1 a) with Selectfluor (2) was initially tested
10
(Table 1). Pleasingly, the reaction performed at room temper-
11
12
13 Table 1. Screening of Reaction Conditions.[a]
14
15
16
17
18
19
20 entry Solvent (v/v) Yield[b] (%)
21 1 acetone 52
22 2 acetone/H2O (1:1) 93
23 3 acetone/H2O (1:5) 66
24 4 H2O 60
5 CH2Cl2/H2O (1:1) trace
25 6 CHCl3/H2O (1:1) trace
26 7 MeCN/H2O (1:1) 86
27 8 ethanol/H2O (1:1) 71
28 9 acetone/H2O (1:1) 88 [c]
10 acetone/H2O (1:1) 88 [d] Scheme 2. Substrate scope. Reaction conditions: 1 (0.2 mmol, 1 equiv),
29 11 acetone/H2O (1:1) 85 [e] Selectfluor (2) (0.4 mmol, 2 equiv), NaOAc (0.4 mmol, 2 equiv) in acetone/
30 12 acetone/H2O (1:1) 94 [f] H2O = 1:1 (v/v) (2.0 mL) at rt for 1 h.
31 13 acetone/H2O (1:1) 93 [g]
32 [a]
Unless otherwise noted, all reactions were performed on 1 a (0.2 mmol),
33 Selectfluor (2) (0.6 mmol, 3 equiv), and base (0.4 mmol, 2 equiv) in solvent
(2.0 mL) at rt for 1 h. [b]Isolated yield. [c]1 equiv. of NaOAc used. [d]3 equiv. of
of compound 1 were tolerated well in the reaction. Pleasingly,
34
NaOAc used. [e]Without base. [f]2 equiv. of Selectfluor used. [g]4 equiv. of product 3 b bearing Br was furnished in a moderate yield,
35
Selectfluor used. which would facilitate the expansion to a wider variety of
36
functionalized dihydro-4-quinolones through the subsequent
37
cross-coupling reactions. Meanwhile, various aryl substituents,
38
including naphthyl group, were also suitable substrates, giving
39
ature in acetone for 1 h gave the desired difluorinated product the desired products in good to excellent yields (Scheme 2, 3 c-
40
3 a in 52% yield (Table 1, entry 1), along with a small amount of h). Notably, such aryl substituted quinolone analogues exhib-
41
2-N-substituted quinolone. Unexpectedly, the N,N-dimethyl- ited attractive anti-cancer activities in the previous studies.[11]
42
amine group was hydrolyzed to deliver the corresponding Furthermore, substrate possessing heteroaromatic substituent -
43
alcohol, which would facilitate further structural modifications thienyl group also delivered the target quinolone derivative 3 i
44
for drug discovery. Consequently, H2O was intentionally added in good yield.
45
to this reaction system and the corresponding proudct 3 a was Subsquently, we turned our attention to the effect of N-
46
obtained in 93% yield in the mixture of acetone and H2O (1:1, substituent (as illustrated in Scheme 3). Obviously, the elec-
47
v/v) (Table 1, entry 2). Following, different mixed solvents were tronic character of N-substituent had sizable impact on the
48
investigated (Table 1, entries 2–8), and the mixture of acetone selectfluor-triggered tandem cyclization process. In general, the
49
and water still gave the best result. Noticeably, the reaction introduction of electron-withdrawing substituents onto the
50
also occurred in water, albeit with moderate yield (Table 1, nitrogen atom in substrate 1 gave the corresponding products
51
entry 4), rendering this synthetic procedure more eco-friendly. in superior yield than electron-donating substituents
52
Then, it was found that the amount of NaOAc had slight impact (Scheme 3, 3 a/4 a-c vs 4 d-g).
53
on the reaction (Table 1, entries 9–10). Interestingly, this Considering the mildness of reaction conditions, we were
54
transformation proceeded smoothly even in the absence of the devoted to exploiting the practicality and scalability of this
55
base (Table 1, entries 11). Furthermore, the amount of the protocol. Thus, the title reaction for enaminone 1 a was
56
fluorine source was investigated. The yield of 3 a could not be performed at gram-scale under standard reaction conditions,
57

ChemistrySelect 2018, 3, 9218 – 9221 9219 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Communications

1
2
3
4
5
6
7
8
9
10
11
Scheme 5. Control experiments.
12
13
14
15
16
17
18
19
20 Scheme 3. Substrate scope. Reaction conditions: 1 (0.2 mmol, 1 equiv),
Selectfluor (2) (0.4 mmol, 2 equiv), NaOAc (0.4 mmol, 2 equiv) in acetone/
21
H2O = 1:1 (v/v) (2.0 mL) at room temperature for 1 h.
22
23
24
which proceeded smoothly to give the corresponding product
25
3 a in almost quantitative yield without any loss of efficiency Scheme 6. Plausible mechanism.
26
(Scheme 4). Significantly, the Boc group in 3 a could be
27
28
29
difluorinated iminium intermediate C could be generated in a
30
similar manner. Subsequently, the reactive iminium ion under-
31
goes the nucleophilic attack by water followed by proton shift
32
to give the corresponding ammonium E, which proceeds
33
intramolecular substitution to afford the expected difluorinated
34
quinolone analogue 3 or 4.
35 Scheme 4. Synthetic utility of this reaction. In conclusion, a practical protocol to access a range of
36
difluorinated 2-hydroxyl-substituted quinolones through a
37
Selectfluor-triggered tandem reaction sequence was devel-
38
removed in the presence of silica gel under reflux for 3 hours oped. These difluorinated quinolones were firstly synthesized
39
(Scheme 4). Interestingly, when MeOH was used as the solvent, under mild conditions. Significantly, these novel difluorinated
40
methylation of OH group occurred to give the corresponding quinolones could surely enrich the library of fluorinated nitro-
41
product 6 in moderate yield. gen-containing heterocycles. The potential utilization and
42
Finally, several control experiments were carried out to extension of this interesting synthetic methodology are
43
better illustrate mechanistically this procedure (Scheme 5). The currently underway in our lab.
44
C-substituted substrate – aza-chalcone 7 was subjected to the
45
standard conditions, but unable to deliver the desired product.
46 Supporting Information Summary
This indicates the importance of the enamine group in this
47
tandem process (Scheme 5, eq a). Additionally, when 2-N- Detailed experimental procedures, compound characterization
48
substituted quinoline 8 was exposed to the standard con- and copies of 1H- and 13C-NMR spectra of synthesized
49
ditions, only trace 2-hydroxyl substituted product was detected compounds are available in the supporting information.
50
(Scheme 5, eq b). The result suggests that the corresponding
51
hydrolysis might occur prior to the cyclization process.
52 Acknowledgements
On the basis of the observed results, a plausible mechanism
53
involving iminium intermediate is proposed in Scheme 6. It can We gratefully acknowledge the financial support from the
54
be assumed that the first round of fluorination of enaminone 1 National Natural Science Foundation of China (21576296 and
55
by Selectfluor forms the intermediate iminium ion A, which 21676302), Natural Science Foundation of Hunan Province
56
facilely tautomerizes to form enamine B. Afterthat, the
57

ChemistrySelect 2018, 3, 9218 – 9221 9220 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Communications
(2017JJ3401) and the State Key Laboratory of Drug Research 982–986; d) P. C. Knipe, M. D. Smith, Org. Biomo.l Chem. 2014, 12, 5094–
1 5097; e) N. Okamoto, T. Sueda, R. Yanada, J. Org. Chem. 2014, 79, 9854–
(SIMM1705KF-15).
2 9859; f) K. Saito, Y. Moriya, T. Akiyama, Org. Lett. 2015, 17, 3202; g) G.-F.
3 Pan, L. Su, Y.-L. Zhang, S.-H. Guo, Y.-Q. Wang, RSC Adv. 2016, 6, 25375–
25378.
4 Conflict of Interest [5] a) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359; b) S. Purser, P. R. Moore,
5 S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320–330; c) J.
The authors declare no conflict of interest.
6 Wang, M. Sanchez-Rosello, J. L. Acena, C. del Pozo, A. E. Sorochinsky, S.
7 Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432–2506;
Keywords: annulation · cyclization · difluorinated · domino d) D. E. Yerien, S. Bonesi, A. Postigo, Org. Biomol. Chem. 2016, 14, 8398–
8
8427.
9 reactions · quinolone [6] a) G. M. Blackburn, D. A. England, F. Kolkmann, J. Chem. Soc., Chem.
10 Commun. 1981, 930–932; b) Q. Zhou, A. Ruffoni, R. Gianatassio, Y.
[1] a) J. Liu, Y. Wang, Y. Sun, D. Marshall, S. Miao, G. Tonn, P. Anders, J. Fujiwara, E. Sella, D. Shabat, P. S. Baran, Angew. Chem., Int. Ed. 2013, 52,
11
Tocker, H. L. Tang, J. Medina, Bioorg. Med. Chem. Lett 2009, 19, 6840– 3949–3952.
12 6844; b) J. Ramnauth, J. Speed, S. P. Maddaford, P. Dove, S. C. Annedi, P. [7] a) H. Xiang, C. Yang, Org. Lett. 2014, 16, 5686–5689; b) M. O. Akram, S.
13 Renton, S. Rakhit, J. Andrews, S. Silverman, G. Mladenova, S. Zinghini, S. Bera, N. T. Patil, Chem. Commun. 2016, 52, 12306–12309; c) X.-Z. Zhang,
14 Nair, C. Catalano, D. K. Lee, M. De Felice, F. Porreca, J. Med. Chem. 2011, D.-L. Ge, S.-Y. Chen, X.-Q. Yu, RSC Adv. 2016, 6, 66320–66323; d) Q. Zhao,
54, 5562–5575; c) V. Sridharan, P. A. Suryavanshi, J. C. Menendez, Chem. H. Xiang, J.-A. Xiao, P.-J. Xia, J.-J. Wang, X. Chen, H. Yang, J. Org. Chem.
15
Rev. 2011, 111, 7157–7259; d) M. L. Quan, P. C. Wong, C. Wang, F. 2017, 82, 9837–9843; e) J. Xu, Z. Kuang, Q. Song, Chinese Chem. Lett.
16 Woerner, J. M. Smallheer, F. A. Barbera, J. M. Bozarth, R. L. Brown, M. R. 2017, 29, 963–966; f) J.-P. Wan, S. Zhong, Y. Guo, L. Wei, Eur. J. Org.
17 Harpel, J. M. Luettgen, P. E. Morin, T. Peterson, V. Ramamurthy, A. R. Chem. 2017, 2017, 4401–4404; g) S. Zhong, Y. Liu, X. Cao, J.-P. Wan,
18 Rendina, K. A. Rossi, C. A. Watson, A. Wei, G. Zhang, D. Seiffert, R. R. ChemCatChem 2017, 9, 465–468.
Wexler, J. Med. Chem. 2014, 57, 955–969; e) A. A. Harland, L. Yeomans, [8] P. Shi, L. Wang, K. Chen, J. Wang, J. Zhu, Org. Lett. 2017, 19, 2418–2421.
19
N. W. Griggs, J. P. Anand, I. D. Pogozheva, E. M. Jutkiewicz, J. R. Traynor, [9] a) J. A. Xiao, P. J. Xia, X. Y. Zhang, X. Q. Chen, G. C. Ou, H. Yang, Chem.
20 H. I. Mosberg, J. Med. Chem. 2015, 58, 8952–8969; f) A. A. Harland, A. M. Commun. 2016, 52, 2177–2180; b) J.-A. Xiao, J. Li, P.-J. Xia, Z.-F. Zhou, Z.-
21 Bender, N. W. Griggs, C. Gao, J. P. Anand, I. D. Pogozheva, J. R. Traynor, X. Deng, H.-Y. Xiang, X.-Q. Chen, H. Yang, J. Org. Chem. 2016, 81, 11185–
22 E. M. Jutkiewicz, H. I. Mosberg, J. Med. Chem. 2016, 59, 4985–4998; g) H. 11194; c) H. Xiang, Q. Zhao, Z. Tang, J. Xiao, P. Xia, C. Wang, C. Yang, X.
Jo, M. Choi, A. S. Kumar, Y. Jung, S. Kim, J. Yun, J. S. Kang, Y. Kim, S. B. Chen, H. Yang, Org. Lett. 2017, 19, 146–149; d) H. Yang, J. Li, J.-A. Xiao,
23
Han, J. K. Jung, J. Cho, K. Lee, J. H. Kwak, H. Lee, ACS Med. Chem. Lett. S.-J. Zhao, H.-Y. Xiang, Synthesis 2017, 49, 4292–4298; e) H. Xiang, Q. L.
24 2016, 7, 385–390; h) B. Wang, D. Chu, Y. Feng, Y. Shen, M. Aoyagi- Zhao, P. J. Xia, J. A. Xiao, Z. P. Ye, X. Xie, H. Sheng, X. Q. Chen, H. Yang,
25 Scharber, L. E. Post, J. Med. Chem. 2016, 59, 335–357; i) Y. A. Sonawane, Org. Lett. 2018, 20, 1363–1366.
26 Y. Zhu, J. C. Garrison, E. L. Ezell, M. Zahid, X. Cheng, A. Natarajan, ACS [10] CCDC-1849833 (for 3 a) contains the supplementary crystallographic
Med. Chem. Lett. 2017, 8, 1183–1187. data. These data can be obtained free of charge via www.ccdc.cam.a-
27
[2] a) Y. Xia, Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Tachibana, S.-C. Kuo, E. Hamel, c.uk.
28 T. Hackl, K.-H. Lee, J. Med. Chem. 1998, 41, 1155–1162; b) C. M. Park, J. I. [11] R. Gosmini, V. L. Nguyen, J. Toum, C. Simon, J. M. Brusq, G. Krysa, O.
29 Choi, J. H. Choi, S. Y. Kim, W. K. Park, C. M. Seong, Bioorg. Med. Chem. Mirguet, A. M. Riou-Eymard, E. V. Boursier, L. Trottet, P. Bamborough, H.
30 Lett. 2011, 21, 698–703. c) A. K. , Chaturvedi, N. Rastogi, Synthesis 2015, Clark, C. W. Chung, L. Cutler, E. H. Demont, R. Kaur, A. J. Lewis, M. B.
47, 249–255. d) E. Kanaani, M. , Nasr-Esfahani, Synthetic Communications Schilling, P. E. Soden, S. Taylor, A. L. Walker, M. D. Walker, R. K. Prinjha, E.
31
2017, 47, 1326–1331. Nicodeme, J. Med. Chem. 2014, 57, 8111–8131.
32 [3] R. Shintani, T. Yamagami, T. Kimura, T. Hayashi, Org. Lett. 2005, 7, 5317–
33 5319.
34 [4] a) X. Liu, Y. Lu, Org. Lett. 2010, 12, 5592–5595; b) M. Castaing, S. L.
Wason, B. Estepa, J. F. Hooper, M. C. Willis, Angew. Chem. Int. Ed. 2013, Submitted: June 26, 2018
35
52, 13280–13283; c) S. Cheng, L. Zhao, S. Yu, Adv. Synth. Catal. 2014, 356, Accepted: August 11, 2018
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57

ChemistrySelect 2018, 3, 9218 – 9221 9221 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim