α-Alkylation of N–C Axially Chiral Quinazolinone Derivatives Bearing Various ortho-Substituted Phenyl Groups: Relation between Diastereoselectivity and the ortho-Substituent

Mizuki Matsuoka; Asumi Iida; Osamu Kitagawa

doi:10.1055/s-0037-1610110

Synlett, Table of Contents

Synlett 2018; 29(16): 2126-2130
DOI: 10.1055/s-0037-1610110

cluster

α-Alkylation of N–C Axially Chiral Quinazolinone Derivatives Bearing Various ortho-Substituted Phenyl Groups: Relation between Diastereoselectivity and the ortho-Substituent

Mizuki Matsuoka

Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo, 135-8548, Japan Email: kitagawa@shibaura-it.ac.jp

,

Asumi Iida

Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo, 135-8548, Japan Email: kitagawa@shibaura-it.ac.jp

,

Osamu Kitagawa *

Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo, 135-8548, Japan Email: kitagawa@shibaura-it.ac.jp

› Author Affiliations

Abstract

All articles of this category

Published as part of the Cluster Atropisomerism

Dedicated to the late Professor Kurt Mislow with the deepest respect.

Abstract

2-Ethylquinazolin-4-one derivatives bearing various ortho-substituted phenyl groups were revealed to possess a stable C–N axially chiral structure at ambient temperature. The reactions of alkyl halides with the anionic species prepared from these quinazolinones were systematically explored. The α-alkylation reactions proceeded with diastereoselectivities ranging from 1:1 to >50:1, depending upon the steric bulk of the ortho-substituent, to afford products having the elements of axial and central chirality in high yields (85–98%).

Key words

axial chirality - quinazolinones - alkylation - diastereoselectivity

Full Text

References

References and Notes

For reviews, see:

1a Alkorta I. Elguero J. Roussel C. Vanthuyne N. Piras P. Adv. Heterocycl. Chem. 2012; 105: 1
1b Takahashi I. Suzuki Y. Kitagawa O. Org. Prep. Proced. Int. 2014; 46: 1
1c Kumarasamy E. Raghunathan R. Sibi MP. Sivaguru J. Chem. Rev. 2015; 115: 11239

For representative papers, see:

2a Mintas M. Mihaljević V. Koller H. Schuster D. Mannshreck A. J. Chem. Soc., Perkin Trans 2 1990; 619
2b Oğuz SF. Doğan İ. Tetrahedron: Asymmetry 2003; 14: 1857
2c Yilmaz EM. Doğan İ. Tetrahedron: Asymmetry 2008; 19: 2184
2d Hasegawa F. Kawamura K. Tsuchikawa H. Murata M. Bioorg. Med. Chem. 2017; 25: 4506
2e Belot V. Farran D. Jean M. Albalat M. Vanthuyne N. Roussel C. J. Org. Chem. 2017; 82: 10188

For representative papers on the application of rotationally stable C–N axially chiral compounds in stereoselective reactions, see:

3a Kishikawa K. Tsuru I. Kohomoto S. Yamamoto M. Yamada K. Chem. Lett. 1994; 1605
3b Curran DP. Qi H. Geib SJ. DeMello NC. J. Am. Chem. Soc. 1994; 116: 3131
3c Kitagawa O. Izawa H. Sato K. Dobashi A. Taguchi T. Shiro M. J. Org. Chem. 1998; 63: 2634
3d Hughes AD. Price DA. Simpkins NS. J. Chem. Soc., Perkin Trans. 1 1999; 1295
3e Bach T. Schröder J. Harms K. Tetrahedron Lett. 1999; 40: 9003
3f Dantale S. Reboul V. Metzner P. Philouze C. Chem. Eur. J. 2002; 8: 632
3g Sakamoto M. Shigekura M. Saito A. Ohtake T. Mino T. Fujita T. Chem. Commun. 2003; 2218
3h Kitagawa O. Yoshikawa M. Tanabe H. Morita T. Takahashi M. Dobashi Y. Taguchi T. J. Am. Chem. Soc. 2006; 128: 12923
3i Clayden J. Turner H. Helliwell M. Moir E. J. Org. Chem. 2008; 73: 4415
3j Nakazaki A. Miyagawa K. Miyata N. Nishikawa T. Eur. J. Org. Chem. 2015; 4603

4 Matsuoka M. Goto M. Wzorek A. Soloshonok V. Kitagawa O. Org. Lett. 2017; 19: 2650

5a Mannschreck A. Koller H. Stühler G. Davis MA. Traber J. Eur. J. Med. Chem. 1984; 19: 381
5b Junghänel J. Buss V. Beyrich T. Jira T. Chirality 1998; 10: 253
5c Welch WM. Ewing FE. Huang J. Menniti FS. Pagnozzi MJ. Kelly K. Seymour PA. Guanowsky V. Guhan S. Guinn MR. Critchett D. Lazzaro J. Ganong AH. DeVries KM. Staigers TL. Chenard BL. Bioorg. Med. Chem. Lett. 2001; 11: 177
5d Chenard BL. Welch WM. Blake JF. Butler TW. Reinhold A. Ewing FE. Menniti FS. Pagnozzi MJ. J. Med. Chem. 2001; 44: 1710
5e Dolma S. Lessnick SL. Hahn WC. Stockwell BR. Cancer Cell 2003; 3: 285
5f Tokitoh T. Kobayashi T. Nakada E. Inoue T. Yokoshima S. Takahashi H. Natsugari H. Heterocycles 2006; 70: 93
5g Lodola A. Bertolini S. Biagetti M. Capacchiu S. Facchinetti F. Gall PM. Pappani A. Mor M. Pala D. Rivara S. Visentini F. Corsi M. Capelli AM. J. Med. Chem. 2017; 60: 4304
5h Toenjes ST. Gustafson JL. Future Med. Chem. 2018; 10: 409

6a Wolfe JF. Rathman TL. Sleevi MC. Campbell JA. Greenwood TD. J. Med. Chem. 1990; 33: 161
6b Xu Y.-L. Lin H.-Y. Cao R.-J. Ming Z.-Z. Yang W.-C. Yang G.-F. Bioorg. Med. Chem. 2014; 22: 5194
6c Kumar D. Jadhaver PS. Nautiya M. Sharma H. Meena PK. Adane L. Pancholia S. Chakraborti AK. RSC Adv. 2015; 5: 30819

7 Although the quinazoline-4-one bearing an ortho-tert-butylphenyl group was also prepared, its alkylation was not investigated due to its extremely low solubility in THF and other organic solvents.
8 It has been reported that the separation of enantiomers of 2-(alkylthio)quinazolin-4-ones bearing an ortho -fluorophenyl group is difficult because of the low rotational barrier around the C–N bond; see: Jira T. Schopplich C. Bunke A. Leuthold L. Junghänel J. Theiss R. Kottke K. Besch A. Beyrich T. Pharmazie 1996; 51: 379
9 α-Alkylation of 3-(2-Bromophenyl)-2-ethylquinazolin-4-one (1c); Typical Procedure A 1.3 M solution of LiHDMS in THF (0.346 mL, 0.45 mmol) was added to a solution of rac-1c (99 mg, 0.3 mmol) in THF (2.0 mL) under N₂ at –20 °C, and the mixture was stirred for 30 min at –20 °C. Allyl bromide (54 mg, 0.45 mml) was added at –20 °C, and the mixture was stirred for 30 min at –20 °C. The mixture was then poured into saturated aq NH₄Cl solution (10 mL) and extracted with EtOAc (3 × 20 mL). The extracts were washed with brine, dried (MgSO₄), filtered, and evaporated to dryness. The residue was purified by column chromatography [silica gel, hexane–EtOAc (1:4)] to give a mixture of 2c and 2c′; yield: 94 mg (85%). The diastereomeric ratio of 2c and 2c′ (7.5:1) was determined by ¹H NMR analysis. 2c and 2c′ were completely separated by MPLC (hexane–EtOAc, 1:8) to give diastereomerically pure 2c and 2c′
(P*,S*)-3-(2-Bromophenyl)-2-(1-methylbut-3-en-1-yl)quinazolin-4(3H)-one (2c) White solid; yield: 82 mg; mp 114–116 °C. IR (neat): 1684 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.29 (dd, J = 0.8, 7.6 Hz, 1 H), 7.73–7.80 (m, 3 H), 7.51 (dt, J = 1.6, 7.6 Hz, 1 H), 7.47 (ddd, J = 2.0, 6.8, 7.6 Hz, 1 H), 7.39 (dt, J = 1.6, 8.0 Hz, 1 H), 7.33 (dd, J = 1.6, 7.6 Hz, 1 H), 5.57 (tdd, J = 6.8, 10.8, 16.0 Hz, 1 H), 4.94 (d, J = 10.8 Hz, 1 H), 4.94 (d, J = 16.0 Hz, 1 H), 2.41–2.56 (m, 2 H), 2.20 (td, J = 6.8, 13.6 Hz, 1 H), 1.33 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.8, 159.8, 147.7, 136.7, 135.5, 134.6, 133.8, 130.7, 128.6, 127.3, 127.0, 126.5, 123.3, 120.6, 117.2, 40.4, 37.9, 18.9. MS: m/z = 391 [M + Na]⁺ (⁷⁹Br); HRMS: m/z [M + Na]⁺Calcd for C₁₉H₁₇ ⁷⁹BrN₂NaO: 391.04220; found: 391.04207. (P*,R*)-3-(2-Bromophenyl)-2-(1-methylbut-3-en-1-yl)quinazolin-4(3H)-one (2c′) White solid; yield: 12 mg; mp 78–80 °C. IR (neat): 1680 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.28 (dd, J = 1.6, 8.0 Hz, 1 H), 7.73–7.81 (m, 3 H), 7.51 (dt, J = 1.2, 7.2 Hz, 1 H), 7.47 (ddd, J = 1.2, 7.2, 8.4 Hz, 1 H), 7.40 (dt, J = 2.0, 8.0 Hz, 1 H), 7.35 (dd, J = 2.0, 8.0 Hz, 1 H), 5.71 (m, 1 H), 5.04 (d, J = 17.2 Hz, 1 H), 4.97 (d, J = 10.0 Hz, 1 H), 2.75 (m, 1 H), 2.31–2.40 (m, 2 H), 1.17 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.8, 160.0, 147.6, 136.6, 136.2, 134.6, 133.9, 130.8, 130.2, 128.7, 127.3, 127.1, 126.6, 123.3, 120.6, 117.0, 39.1, 38.0, 19.4. MS: m/z = 391 [M + Na]⁺ (⁷⁹Br); HRMS: m/z [M + Na]⁺Calcd for C₁₉H₁₇ ⁷⁹BrN₂NaO: 391.04220; found: 391.04071.

Supplementary Material

Supporting Information