Unexpected Substituent Effects in Spiro-Compound Formation: Steering N-Aryl Propynamides and DMSO toward Site-Specific Sulfination in Quinolin-2-ones or Spiro[4,5]trienones

doi:10.1021/acs.joc.1c00775

. 2021 Jul 16;86(14):9490-9502.

doi: 10.1021/acs.joc.1c00775. Epub 2021 Jun 29.

Unexpected Substituent Effects in Spiro-Compound Formation: Steering N-Aryl Propynamides and DMSO toward Site-Specific Sulfination in Quinolin-2-ones or Spiro[4,5]trienones

Xiaoxian Li¹, Yuanxun Wang², Yaxin Ouyang¹, Zhenyang Yu¹, Beibei Zhang¹, Jingran Zhang¹, Haofeng Shi¹, Han Zuilhof^{1

3

4}, Yunfei Du¹

Affiliations

¹ School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
² National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
³ Laboratory of Organic Chemistry, Wageningen University, Stippeneng 4, 6703 WE Wageningen, The Netherlands.
⁴ Department of Chemical and Materials Engineering, Faculty of Engineering, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

PMID: 34184892
PMCID: PMC8291627
DOI: 10.1021/acs.joc.1c00775

Unexpected Substituent Effects in Spiro-Compound Formation: Steering N-Aryl Propynamides and DMSO toward Site-Specific Sulfination in Quinolin-2-ones or Spiro[4,5]trienones

Xiaoxian Li et al. J Org Chem. 2021.

. 2021 Jul 16;86(14):9490-9502.

doi: 10.1021/acs.joc.1c00775. Epub 2021 Jun 29.

Authors

Xiaoxian Li¹, Yuanxun Wang², Yaxin Ouyang¹, Zhenyang Yu¹, Beibei Zhang¹, Jingran Zhang¹, Haofeng Shi¹, Han Zuilhof^{1

3

4}, Yunfei Du¹

Affiliations

¹ School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
² National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
³ Laboratory of Organic Chemistry, Wageningen University, Stippeneng 4, 6703 WE Wageningen, The Netherlands.
⁴ Department of Chemical and Materials Engineering, Faculty of Engineering, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

PMID: 34184892
PMCID: PMC8291627
DOI: 10.1021/acs.joc.1c00775

Abstract

A highly substituent-dependent rearrangement allows for the novel and SOCl₂-induced divergent synthesis of 3-methylthioquinolin-2-ones and 3-methylthiospiro[4.5]trienones through intramolecular electrophilic cyclization of N-aryl propyamides. DMSO acts as both solvent and sulfur source, and use of DMSO-h₆/d₆ enables the incorporation of SCH₃ or SCD₃ moieties to the 3-position of the heterocyclic framework. Different para-substituents trigger divergent reaction pathways leading to the formation of quinolin-2-ones for mild substituents and spiro[4,5]trienones for both electron-withdrawing and -donating substituents, respectively. On the basis of both computational and experimental results, a new mechanism has been put forward that accounts for the exclusive spirolization/defluorination process and the surprising substituent effects.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

**Scheme 1. Strategies for the Synthesis of 3-Sulfenylated Quinolin-2-ones and Azaspiro[4,5]trienones**

**Scheme 2. Reported Mechanistic Pathways of Defluorination**

**Scheme 3. Proposed Mechanistic Pathways: (Top) Initial, Incorrect Hypothesis; (Bottom) Detailed Routes Leading to Either 2a or 3a in Highly Substituent-Dependent Manners**

**Figure 1**
Free energy profile (kcal/mol) of the formation of intermediate D or 3-(methylthio) spiro[4,5]trienone 3a.

**Scheme 4. Control Experiment Confirming That DMSO Is the Oxygen Source**

See this image and copyright information in PMC

Cited by

Recent Advances in the Use of Dimethyl Sulfoxide as a Synthon in Organic Chemistry.
Lu H, Tong Z, Peng L, Wang Z, Yin SF, Kambe N, Qiu R. Lu H, et al. Top Curr Chem (Cham). 2022 Oct 28;380(6):55. doi: 10.1007/s41061-022-00411-8. Top Curr Chem (Cham). 2022. PMID: 36306032 Review.

References

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1. Tedesco R.; Shaw A. N.; Bambal R.; Chai D. P.; Concha N. O.; Darcy M. G.; Dhanak D.; Fitch D. M.; Gates A.; Gerhardt W. G.; Halegoua D. L.; Han C.; Hofmann G. A.; Johnston V. K.; Kaura A. C.; Liu N. N.; Keenan R. M.; Lin-Goerke J.; Sarisky R. T.; Wiggall K. J.; Zimmerman M. N.; Duffy K. J. 3-(1,1-Dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase. J. Med. Chem. 2006, 49, 971–983. 10.1021/jm050855s. - DOI - PubMed
1. Crawley G. C.; Briggs M. T.; Dowell R. I.; Edwards P. N.; Hamilton P. M.; Kingston J. F.; Oldham K.; Waterson D.; Whalley D. P. 4-Methoxy-2-methyltetrahydropyrans-chiral leukotriene biosynthesis inhibitors, related to ICI D2138, which display enantioselectivity. J. Med. Chem. 1993, 36, 295–296. 10.1021/jm00054a016. - DOI - PubMed
2. Shiro T.; Takahashi H.; Kakiguchi K.; Inoue Y.; Masuda K.; Nagata H.; Tobe M. Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E2 synthase-1 inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 285–288. 10.1016/j.bmcl.2011.11.015. - DOI - PubMed
3. Shiro T.; Kakiguchi K.; Takahashi H.; Nagata H.; Tobe M. Synthesis and biological evaluation of substituted imidazoquinoline derivatives as mPGES-1 inhibitors. Bioorg. Med. Chem. 2013, 21, 2068–2078. 10.1016/j.bmc.2013.01.018. - DOI - PubMed
1. Ikuma Y.; Hochigai H.; Kimura H.; Nunami N.; Kobayashi T.; Uchiyama K.; Furuta Y.; Sakai M.; Horiguchi M.; Masui Y.; Okazaki K.; Sato Y.; Nakahira H. Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Bioorg. Med. Chem. 2012, 20, 5864–5883. 10.1016/j.bmc.2012.07.046. - DOI - PubMed
2. Ikuma Y.; Nakahira H. Preparation of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction. Tetrahedron 2011, 67, 9509–9517. 10.1016/j.tet.2011.10.015. - DOI

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[1] Khan S. R.; Mhaka A.; Pili R.; Isaacs J. T. Modified synthesis and antiangiogenic activity of linomide. Bioorg. Med. Chem. Lett. 2001, 11, 451–452. 10.1016/S0960-894X(00)00699-5. - DOI - PubMed

Jonsson S.; Andersson G.; Fex T.; Fristedt T.; Hedlund G.; Jansson K.; Abramo L.; Fritzson I.; Pekarski O.; Runstrom A.; Sandin H.; Thuvesson I.; Bjork A. Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship. J. Med. Chem. 2004, 47, 2075–2088. 10.1021/jm031044w. - DOI - PubMed

Natsugari H.; Ikeura Y.; Kiyota Y.; Ishichi Y.; Ishimaru T.; Saga O.; Shirafuji H.; Tanaka T.; Kamo I.; Doi T.; Otsuka M. Novel, potent, and orally-active substance-P antagonists-synthesis and antagonist activity of N-benzylcarboxamide derivatives of pyrido [3,4-b] pyridine. J. Med. Chem. 1995, 38, 3106–3120. 10.1021/jm00016a014. - DOI - PubMed

Řehulka J.; Vychodilová K.; Krejčí P.; Gurská S.; Hradil P.; Hajdúch M.; Džubák P.; Hlaváč J. Fluorinated derivatives of 2-phenyl-3-hydroxy-4(1H)-quinolinone as tubulin polymerization inhibitors. Eur. J. Med. Chem. 2020, 192, 112176.10.1016/j.ejmech.2020.112176. - DOI - PubMed

[2] Khan S. R.; Mhaka A.; Pili R.; Isaacs J. T. Modified synthesis and antiangiogenic activity of linomide. Bioorg. Med. Chem. Lett. 2001, 11, 451–452. 10.1016/S0960-894X(00)00699-5. - DOI - PubMed

[3] Jonsson S.; Andersson G.; Fex T.; Fristedt T.; Hedlund G.; Jansson K.; Abramo L.; Fritzson I.; Pekarski O.; Runstrom A.; Sandin H.; Thuvesson I.; Bjork A. Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship. J. Med. Chem. 2004, 47, 2075–2088. 10.1021/jm031044w. - DOI - PubMed

[4] Natsugari H.; Ikeura Y.; Kiyota Y.; Ishichi Y.; Ishimaru T.; Saga O.; Shirafuji H.; Tanaka T.; Kamo I.; Doi T.; Otsuka M. Novel, potent, and orally-active substance-P antagonists-synthesis and antagonist activity of N-benzylcarboxamide derivatives of pyrido [3,4-b] pyridine. J. Med. Chem. 1995, 38, 3106–3120. 10.1021/jm00016a014. - DOI - PubMed

[5] Řehulka J.; Vychodilová K.; Krejčí P.; Gurská S.; Hradil P.; Hajdúch M.; Džubák P.; Hlaváč J. Fluorinated derivatives of 2-phenyl-3-hydroxy-4(1H)-quinolinone as tubulin polymerization inhibitors. Eur. J. Med. Chem. 2020, 192, 112176.10.1016/j.ejmech.2020.112176. - DOI - PubMed

[6] DeVita R. J.; Hollings D. D.; Goulet M. T.; Wyvratt M. J.; Fisher M. H.; Lo J. L.; Yang Y. T.; Cheng K.; Smith R. G. Identification and initial structure-activity relationships of a novel non-peptide quinolone GnRH receptor antagonist. Bioorg. Med. Chem. Lett. 1999, 9, 2615–2620. 10.1016/S0960-894X(99)00446-1. - DOI - PubMed

Aleksic M.; Bertosa B.; Nhili R.; Uzelac L.; Jarak I.; Depauw S.; David-Cordonnier M. H.; Kralj M.; Tomic S.; Karminski-Zamola G. Novel substituted benzothiophene and thienothiophene carboxanilides and quinolones: synthesis, photochemical synthesis, DNA-binding properties, antitumor evaluation and 3D-derived QSAR analysis. J. Med. Chem. 2012, 55, 5044–5060. 10.1021/jm300505h. - DOI - PubMed

Lee J.-F.; Chang T.-Y.; Liu Z.-F.; Lee N.-Z.; Yeh Y.-H.; Chen Y.-S.; Chen T.-C.; Chou H.-S.; Li T.-K.; Lee S.-B.; Lin M.-H. Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases. Eur. J. Med. Chem. 2020, 190, 112074.10.1016/j.ejmech.2020.112074. - DOI - PubMed

[7] DeVita R. J.; Hollings D. D.; Goulet M. T.; Wyvratt M. J.; Fisher M. H.; Lo J. L.; Yang Y. T.; Cheng K.; Smith R. G. Identification and initial structure-activity relationships of a novel non-peptide quinolone GnRH receptor antagonist. Bioorg. Med. Chem. Lett. 1999, 9, 2615–2620. 10.1016/S0960-894X(99)00446-1. - DOI - PubMed

[8] Aleksic M.; Bertosa B.; Nhili R.; Uzelac L.; Jarak I.; Depauw S.; David-Cordonnier M. H.; Kralj M.; Tomic S.; Karminski-Zamola G. Novel substituted benzothiophene and thienothiophene carboxanilides and quinolones: synthesis, photochemical synthesis, DNA-binding properties, antitumor evaluation and 3D-derived QSAR analysis. J. Med. Chem. 2012, 55, 5044–5060. 10.1021/jm300505h. - DOI - PubMed

[9] Lee J.-F.; Chang T.-Y.; Liu Z.-F.; Lee N.-Z.; Yeh Y.-H.; Chen Y.-S.; Chen T.-C.; Chou H.-S.; Li T.-K.; Lee S.-B.; Lin M.-H. Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases. Eur. J. Med. Chem. 2020, 190, 112074.10.1016/j.ejmech.2020.112074. - DOI - PubMed

[10] Tedesco R.; Shaw A. N.; Bambal R.; Chai D. P.; Concha N. O.; Darcy M. G.; Dhanak D.; Fitch D. M.; Gates A.; Gerhardt W. G.; Halegoua D. L.; Han C.; Hofmann G. A.; Johnston V. K.; Kaura A. C.; Liu N. N.; Keenan R. M.; Lin-Goerke J.; Sarisky R. T.; Wiggall K. J.; Zimmerman M. N.; Duffy K. J. 3-(1,1-Dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase. J. Med. Chem. 2006, 49, 971–983. 10.1021/jm050855s. - DOI - PubMed

[11] Tedesco R.; Shaw A. N.; Bambal R.; Chai D. P.; Concha N. O.; Darcy M. G.; Dhanak D.; Fitch D. M.; Gates A.; Gerhardt W. G.; Halegoua D. L.; Han C.; Hofmann G. A.; Johnston V. K.; Kaura A. C.; Liu N. N.; Keenan R. M.; Lin-Goerke J.; Sarisky R. T.; Wiggall K. J.; Zimmerman M. N.; Duffy K. J. 3-(1,1-Dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase. J. Med. Chem. 2006, 49, 971–983. 10.1021/jm050855s. - DOI - PubMed

[12] Crawley G. C.; Briggs M. T.; Dowell R. I.; Edwards P. N.; Hamilton P. M.; Kingston J. F.; Oldham K.; Waterson D.; Whalley D. P. 4-Methoxy-2-methyltetrahydropyrans-chiral leukotriene biosynthesis inhibitors, related to ICI D2138, which display enantioselectivity. J. Med. Chem. 1993, 36, 295–296. 10.1021/jm00054a016. - DOI - PubMed

Shiro T.; Takahashi H.; Kakiguchi K.; Inoue Y.; Masuda K.; Nagata H.; Tobe M. Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E2 synthase-1 inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 285–288. 10.1016/j.bmcl.2011.11.015. - DOI - PubMed

Shiro T.; Kakiguchi K.; Takahashi H.; Nagata H.; Tobe M. Synthesis and biological evaluation of substituted imidazoquinoline derivatives as mPGES-1 inhibitors. Bioorg. Med. Chem. 2013, 21, 2068–2078. 10.1016/j.bmc.2013.01.018. - DOI - PubMed

[13] Crawley G. C.; Briggs M. T.; Dowell R. I.; Edwards P. N.; Hamilton P. M.; Kingston J. F.; Oldham K.; Waterson D.; Whalley D. P. 4-Methoxy-2-methyltetrahydropyrans-chiral leukotriene biosynthesis inhibitors, related to ICI D2138, which display enantioselectivity. J. Med. Chem. 1993, 36, 295–296. 10.1021/jm00054a016. - DOI - PubMed

[14] Shiro T.; Takahashi H.; Kakiguchi K.; Inoue Y.; Masuda K.; Nagata H.; Tobe M. Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E2 synthase-1 inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 285–288. 10.1016/j.bmcl.2011.11.015. - DOI - PubMed

[15] Shiro T.; Kakiguchi K.; Takahashi H.; Nagata H.; Tobe M. Synthesis and biological evaluation of substituted imidazoquinoline derivatives as mPGES-1 inhibitors. Bioorg. Med. Chem. 2013, 21, 2068–2078. 10.1016/j.bmc.2013.01.018. - DOI - PubMed

[16] Ikuma Y.; Hochigai H.; Kimura H.; Nunami N.; Kobayashi T.; Uchiyama K.; Furuta Y.; Sakai M.; Horiguchi M.; Masui Y.; Okazaki K.; Sato Y.; Nakahira H. Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Bioorg. Med. Chem. 2012, 20, 5864–5883. 10.1016/j.bmc.2012.07.046. - DOI - PubMed

Ikuma Y.; Nakahira H. Preparation of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction. Tetrahedron 2011, 67, 9509–9517. 10.1016/j.tet.2011.10.015. - DOI

[17] Ikuma Y.; Hochigai H.; Kimura H.; Nunami N.; Kobayashi T.; Uchiyama K.; Furuta Y.; Sakai M.; Horiguchi M.; Masui Y.; Okazaki K.; Sato Y.; Nakahira H. Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Bioorg. Med. Chem. 2012, 20, 5864–5883. 10.1016/j.bmc.2012.07.046. - DOI - PubMed

[18] Ikuma Y.; Nakahira H. Preparation of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction. Tetrahedron 2011, 67, 9509–9517. 10.1016/j.tet.2011.10.015. - DOI

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Unexpected Substituent Effects in Spiro-Compound Formation: Steering N-Aryl Propynamides and DMSO toward Site-Specific Sulfination in Quinolin-2-ones or Spiro[4,5]trienones

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Unexpected Substituent Effects in Spiro-Compound Formation: Steering N-Aryl Propynamides and DMSO toward Site-Specific Sulfination in Quinolin-2-ones or Spiro[4,5]trienones

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