Halogen-Bond-Promoted Direct Cross-Coupling of 2-Bromo- propionitrile Derivatives with Coumarins/Quinolinones: Synthesis and Transformation

doi:10.6023/cjoc202504009

Abstract

A halogen bond-promoted cross-coupling reaction between 2-bromopropionitrile derivatives and coumarin/quino- linone compounds was reported. The developed methodology features a simple reaction system, mild conditions, and provides target products in moderate to good yields. The cyano functional group in the obtained compounds could be efficiently converted into 2H-tetrazole derivatives under mild conditions. Comparative studies using ester analogs demonstrated significantly reduced reactivity compared to their cyano counterparts, highlighting the crucial role of the cyano group in this transformation. Preliminary cellular experiments revealed that compound 4b selectively inhibited MDA-MB-231 cells with an IC₅₀ value of (22.8±1.3) μmol/L, while most other compounds exhibited non-toxic or low toxicity toward both tumor cells and HL-7702 normal cells. These findings establish a foundation for further investigations into other biological activities such as antioxidant and antibacterial properties.

Key words: halogen bond, coumarins/quinolinones, 2-bromopropionitrile derivatives, cross-coupling reaction

Cite this article

Jilin Wen, Peng Guo, Guoliang Pu, Xueyu Man, Chun-Yang He. Halogen-Bond-Promoted Direct Cross-Coupling of 2-Bromo- propionitrile Derivatives with Coumarins/Quinolinones: Synthesis and Transformation[J]. Chinese Journal of Organic Chemistry, 2025, 45(12): 4405-4416.

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Fig. & Tab. 8

Figure 1. (a) Drugs containing a cyano group; (b) coumarin-based drug molecules

Scheme 1. Reaction design

Entry	Electron donor	LED light/nm	Solvent	Yield^b/%
1	DMAP	410~415	DMSO	52
2	DMAP	410~415	DCM	N. D.
3	DMAP	410~415	THF	N. D.
4	DMAP	410~415	CH₃OH	N. D.
5	DMAP	410~415	DMF	31
6	DMAP	410~415	CH₃CN	N. D.
7	PPh₃	410~415	DMSO	N. D.
8	HE	410~415	DMSO	N. D.
9	PhOH	410~415	DMSO	N. D.
10	Et₃N	410~415	DMSO	44
11	DBU	410~415	DMSO	Trace
12	DIPEA	410~415	DMSO	16
13	DMAP	390~395	DMSO	38
14^c	DMAP	440~445	DMSO	49
15^d	DMAP	410~415	DMSO	41
16^e	DMAP	410~415	DMSO	58
17^f	DMAP	410~415	DMSO	68
18^g	DMAP	410~415	DMSO	69
19	—	410~415	DMSO	N.D.
20^h	DMAP	—	DMSO	N.D.

Table 1. Representative results for the optimization of cross-coupling between 1a and coumarin (2a)a

Scheme 2. Investigation of substrate scope in the cross-coupling reaction of compound 1 with coumarin (2a) a Reaction conditions (unless otherwise specified): 1 (0.2 mmol, 1.0 equiv.), 2a (2.0 mmol, 10.0 equiv.), DMAP (2.0 equiv.), DMSO (1.0 mL), purple LED (410~415 nm 10 W), 30 ℃ 12 h. b Recovery ratio of coumarin. c 5.0 mmol scale.

Scheme 3. Investigation of substrate scope in the cross-coupling reaction of compound 1' with heterocycles (2) a Reaction conditions (unless otherwise specified): 1 (0.2 mmol, 1.0 equiv.), 2 (2.0 mmol, 10.0 equiv.), DMAP (2.0 equiv.), DMSO (1.0 mL), purple LED (410~415 nm 10 W), 30 ℃, 12 h; N.D.=Not detected. b Recovery ratio of heterocycles. c 48 h. d 1.5 mL of DMSO.

Scheme 4. Derivatization study of the cyano group a Reaction conditions (unless otherwise specified): 3/4 (0.2 mmol, 1.0 equiv.), ZnCl2 (0.25 mmol, 1.25 equiv.), TMSN3 (0.4 mmol, 2.0 equiv.), iPrOH (1.0 mL), 95 ℃, 4 h.

Scheme 5. Mechanism research

Scheme 6. Proposed mechanism

References 13

[1]	(a) Chen L.; Pu M.-P.; Li S.-Y.; Sang V X.-P; Liu X.-H.; Wu Y.-D.; Feng X.-M. J. Am. Chem. Soc. 2021, 143, 19091. doi: 10.1021/jacs.1c08382
	(b) Benedicto A. M.; Lucantoni F.; Fuster-Martínez I.; Diaz-Pozo P.; Dorcaratto D.; Muñoz-Forner E.; Victor V. M.; Esplugues J. V.; Blas-García A.; Apostolova N. Biomed. Pharmacother. 2024, 178, 117206. doi: 10.1016/j.biopha.2024.117206
	(c) Flick A. C.; Ding H. X.; Leverett C. A.; Kyne R. E.; Liu K. K.-C.; Fink S. J.; O’Donnell C. J. Bioorg. Med. Chem. 2016, 24, 1937. doi: 10.1016/j.bmc.2016.03.004
	(d) Dhureja M.; Deshmukh R. Eur. J. Pharm. 2024, 975, 176635. doi: 10.1016/j.ejphar.2024.176635
	(e) Dong J.-Z.; Gong Y.-C.; Liu J.; Chen X.-F.; Wen X.-A.; Sun H.-B. Bioorg. Med. Chem. 2014, 22, 1383. doi: 10.1016/j.bmc.2013.12.061
[2]	(a) Tulichala R. N. P.; Swamy K. C. K. Chem. Commun. 2015, 51, 12008. doi: 10.1039/C5CC03160E pmid: 36876451
	(b) Liu Y.-X.; He S.-P.; Quan Z.-Y.; Cai H.-Z.; Zhao Y.; Wang B. Green Chem. 2019, 21, 830. doi: 10.1039/C8GC03285H pmid: 36876451
	(c) Li J.-J.; Liu Y.-X.; Tang W.-J.; Xue D.; Li C.-Q.; Xiao J.-L.; Wang C. Chem.-Eur. J. 2017, 23, 14445. doi: 10.1002/chem.v23.58 pmid: 36876451
	(d) Chouhan K. K.; Chowdhury D.; Mukherjee A. Org. Biomol. Chem. 2023, 21, 2429. doi: 10.1039/d3ob00062a pmid: 36876451
	(e) Xie S.-M.; Cai F.-F.; Liu L.-X.; Su L.-B.; Dong J.-Y.; Zhou Y.-B. Chin. J. Chem. 2024, 42, 2299. pmid: 36876451
[3]	(a) Chen Y. F.; Hsieh J. C. Org. Lett. 2014, 16, 4642. doi: 10.1021/ol502237a pmid: 32050047
	(b) Meda K. M.; Lesch R. W.; Edioma F. B.; Wrenn S. P.; Ndahayo V.; Mulcahy S. P. Org. Lett. 2020, 22, 3135. doi: 10.1021/acs.orglett.0c00891 pmid: 32050047
	(c) Kuang J.; Chen B.; Ma S. Org. Chem. Front. 2014, 1, 186. doi: 10.1039/C4QO00007B pmid: 32050047
	(d) Bian Q.-L.; Wu C.-L.; Yuan J.-P.; Shi Z.-D.; Ding T.; Huang Y.-W.; Xu H.; Xu Y.-Q. J. Org. Chem. 2020, 85, 4058. doi: 10.1021/acs.joc.9b03070 pmid: 32050047
	(e) Pieczykolan M.; Sadowski B.; Gryko D. T. Angew. Chem. Int. Ed. 2020, 59, 7528. doi: 10.1002/anie.201915953 pmid: 32050047
[4]	(a) Frédérick R.; Robert S.; Charlier C.; Ruyck J.; Wouters J.; Pirotte B.; Masereel B.; Pochet L. J. Med. Chem. 2005, 48, 7592. pmid: 16302799
	(b) Abdelhafez O.; Amin K.; Batran R.; Mahe T.; Nada S. Bioorg. Med. Chem. 2010, 18, 3371. doi: 10.1016/j.bmc.2010.04.009 pmid: 16302799
[5]	(a) Yang X.; Zeng C.; Avula S.; Peng X.; Geng R.; Zhou C. Eur. J. Med. Chem. 2023, 245, 114891. doi: 10.1016/j.ejmech.2022.114891
	(b) Liu J.; Zhao S.; Hu J.-Y.; Chen Q.-X.; Jiao S.-M.; Xiao H.-C.; Zhang Q.; Xu J.; Zhao J.-F.; Zhou H.-B.; Zheng J.-X.; Sun P.-H. J. Med. Chem. 2023, 66, 14735. doi: 10.1021/acs.jmedchem.3c01268
[6]	Yan N. L.; Santos-Martins D.; Nair R.; Chu A.; Wilson I. A.; Johnson K. A.; Forli S.; Morgan G. J.; Petrassi H. M.; Kelly J. W. J. Med. Chem. 2021, 64, 6273. doi: 10.1021/acs.jmedchem.1c00339
[7]	(a) Zhang L.-F.; Xu Z. Eur. J. Med. Chem. 2019, 181, 111587. doi: 10.1016/j.ejmech.2019.111587
	(b) Chilin A.; Battistutta R.; Bortolato A.; Cozza G.; Zanatta S.; Poletto G.; Mazzorana M.; Zagotto G.; Uriarte E.; Guiotto A.; Pinna L. A.; Meggio F.; Moro S. J. Med. Chem. 2008, 51, 752. doi: 10.1021/jm070909t
[8]	(a) Zhu M.; Ma L.; Wen J.-J.; Dong B.; Wang Y.-J.; Wang Z.; Zhou J.-M.; Zhang G.-N.; Wang J.-X.; Guo Y.; Liang C.; Cen S.; Wang Y.-C. Eur. J. Med. Chem. 2020, 186, 111900. doi: 10.1016/j.ejmech.2019.111900 pmid: 9003523
	(b) Zhao H.; Neamati N.; Hong H.; Mazumder A.; Wang S.; Sunder S.; Milne G. W. A.; Pommier Y.; Burke T. R. J. Med. Chem. 1997, 40, 242. pmid: 9003523
[9]	(a) Reddy M. S.; Thirupathi N.; Babu M. H. Eur. J. Org. Chem. 2012, 29, 5803.
	(b) Abdelhafez O.; Amin K.; Batran R.; Mahe T.; Nada S.; Sethumadhavan S. Bioorg. Med. Chem. 2010, 18, 3371. doi: 10.1016/j.bmc.2010.04.009
[10]	For recent methods of alkylating coumarin, see: (a) Song H.-Y.; Liu M.-Y.; Huang J.; Wang D.; Jiang J.; Chen J.-Y.; Yang T.-B.; He W.-M.. J. Org. Chem. 2023, 88, 2288. doi: 10.1021/acs.joc.2c02679
	(b) Jafarpour F.; Darvishmolla M.; Azaddoost N.; Mohaghegh F. New J. Chem. 2019, 43, 9328. doi: 10.1039/c8nj06410e
	(c) Gan X.; Wu S.; Geng F.; Dong J.; Zhou Y. Tetrahedron Lett. 2022, 96, 153720. doi: 10.1016/j.tetlet.2022.153720
	(d) Jin C.; Yan Z.-Y.; Sun B.; Yang J. Org. Lett. 2019, 21, 2064. doi: 10.1021/acs.orglett.9b00327
	(e) Tao M.-L.; Wang A.-J.; Guo P.; Li W.-P.; Zhao L.; Tong J.; Wang H.-Y.; Yu Y.-B.; He C.-Y. Adv. Synth. Catal. 2022, 364, 24. doi: 10.1002/adsc.v364.1
	(f) Sun J.; Yang H.; Zhang B. Green Chem. 2022, 24, 858-863. doi: 10.1039/D1GC03992J
	(g) Guo P.; Pu G.-L.; Wang G.-R.; Zeng L.-Y.; Li W.-P.; Li X.-F.; Zhou P.-P.; He C.-Y. Org. Lett. 2024, 26, 3097. doi: 10.1021/acs.orglett.4c00717
	(h) Pu G.-L.; Song S.-Y.; Yang J.; Guo P.; Jia J.; Liu P.-J.; Li X.-F.; Liu P.; He C.-Y. Org. Chem. Front. 2024, 11, 3320. doi: 10.1039/D4QO00484A
	(i) Liu L.; Pan N.; Sheng W.; Su L.; Liu L.; Dong J.; Zhou Y.; Yin S.-F. Adv. Synth. Catal. 2019, 361, 4126. doi: 10.1002/adsc.v361.17
	(j) Mao T.; Ma M.-J.; Zhao L.; Xue D.-P.; Yu Y.-B.; Gu J.-W.; He C.-Y. Chem. Commun. 2020, 56, 1815. doi: 10.1039/C9CC09517A
	(k) Wang G.-R.; Guo P.; Pu G.L.; Wang P.; Wang A.-J.; Liu P.; Jia J.; Li X.; He C.-Y. Org. Chem. Front. 2024, 11, 4722. doi: 10.1039/D4QO00966E
[11]	(a) Wei L.; Wang J.-X.; Zhang X.-L.; Wang P.; Zhao Y.-P.; Li J.-Q.; Hou Tao.; Qu L.-L.; Shi L.-Y.; Liang X.-M.; Fang Y. J. Med. Chem. 2017, 60, 362. doi: 10.1021/acs.jmedchem.6b01431
	(b) Dinparast L.; Hemmati S.; Zengin G.; Alizadeh A. A.; Bahadori M. B.; Kafil H. S.; Dastmalchi S. Chem. Select. 2019, 4, 9211.
	(c) He M.-M.; Wang R.; Zhang R.-F.; Miao P.-C.; Wang P.-Y.; Wei Z.-Y.; Leng X.-F.; Li Y.; Fan J.-L.; Peng X.-J.; Sun W. Adv. Funct. Mater. 2023, 33, 2300780. doi: 10.1002/adfm.v33.26
	(d) Cheng X.-H.; Tang R.-L.; Jia H.-Z.; Feng J.; Qin J.-G.; Li Z. ACS Appl. Mater. Inter. 2012, 4, 4387. doi: 10.1021/am3010412
[12]	(a) Lee S.; Sivakumar K.; Shin W.-S.; Xie F.; Wang Q. Bioorg. Med. Chem. Lett. 2006, 16, 4596. doi: 10.1016/j.bmcl.2006.06.007 pmid: 30059123
	(b) Zhang R.-X.; Jin S.-Z.; Liu Q.; Lin S.; Yan Z.-H. J. Org. Chem. 2018, 83, 13030. doi: 10.1021/acs.joc.8b01508 pmid: 30059123
	(c) Xiang P.-J.; Sun K.; Wang S.; Chen X.-L.; Qu L.-B.; Yu B. Chin. Chem. Lett. 2022, 33, 5074. doi: 10.1016/j.cclet.2022.03.096 pmid: 30059123
	(d) Nicolai J.; Fantoni T.; Butcher T. W.; Arlow S. I.; Ryabukhin S. V.; Volochnyuk D. M.; Hartwig J. F. J. Am. Chem. Soc. 2024, 146, 15464. doi: 10.1021/jacs.4c03618 pmid: 30059123
	(e) Zhang W.; Yang C.; Pan Y.-L.; Li X.; Cheng J.-P. Org. Biomol. Chem. 2018, 16, 5788. doi: 10.1039/c8ob01513a pmid: 30059123
[13]	Cavallo G.; Metrangolo P.; Milani R.; Pilati T.; Priimagi A.; Resnati G.; Terraneo G. Chem. Rev. 2016, 116, 2478. doi: 10.1021/acs.chemrev.5b00484

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