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

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%).

Recently, molecules that are chiral owing to rotational restriction around a C–N bond have attracted considerable attention in the fields of synthetic and structural organic chemistry.[1] Almost all C–N axially chiral compounds contain an ortho-substituted aniline skeleton, and the relationship between the rotational barrier and the ortho-substituent has been explored in detail (Figure [1]; compounds I and II).[2] It has been demonstrated that the rotational barrier around a C–N chiral axis is significantly influenced by the steric bulk of the ortho-substituent.[2]

Although stereoselective reactions of C–N axially chiral compounds have been reported by many groups,[3] the relationship between the stereoselectivity and the ortho-substituent has not yet been systematically investigated. In substrates possessing a small ortho-substituent (low rotational barrier), the evaluation of stereoselectivity should be difficult because interconversion between diastereomeric products through C–N bond rotation occurs readily at ambient temperature. For examples, amides IIIa and imides IVa bearing an ortho-tert-butylphenyl group have stable C–N axially chiral structures (ΔG^‡ = 28–30 kcal mol^–1), and highly diastereoselective reactions with IIIa and IVa have been achieved,[3a] [b] [c] [d] [e] whereas the rotational barriers of the ortho-methyl derivatives IIIb and IVb were too low (ΔG^‡ ≈ 20 kcal mol^–1) to permit the isolation of diastereomeric products.[3a] [b]

We recently reported diastereoselective α-alkylations of C–N axially chiral 2-ethylquinazolin-4-one bearing an ortho-bromophenyl group on the nitrogen atom (Scheme [1]).[4] The reaction proceeded in a stereocontrolled manner, as a result of the axial chirality of the substrate, to afford the (P, S)-isomer as the major product. The diastereoselectivity strongly depended on the steric bulk of alkyl halide (dr = 3.8:1 to 25.6:1) and it increased with increasing the bulkiness of ­alkyl halide. This reaction provides a new method for the construction of pharmaceutically interesting quinazolinone skeletons possessing elements of axial and central chirality.[5]

In 3-arylquinazolin-4-one derivatives, because compounds bearing ortho-methyl, ortho-chloro, or ortho-bromo groups are known to be rotationally stable (ΔG^‡ > 30 kcal mol^–1),[1a] [5] we hoped that α-alkylation of 3-arylquinazolinone substrates bearing ortho-substituents of various sizes might be systematically investigated. In this communication, we report the relationship between the bulk of the ­ortho-substituent and the diastereoselectivity of α-alkylations with anionic species prepared from various C–N axially chiral quinazolinone derivatives (Scheme [2]).

Racemic 3-aryl-2-ethylquinazolin-4-ones 1a–h bearing various ortho-substituents X (X = F, Cl, Br, I, Me, Et, i-Pr, CF₃) were easily prepared through the cyclocondensation of N-propionylanthranilic acid with the corresponding ortho-substituted aniline in the presence of PCl₃ (see Supplementary Information),[6] and their α-allylations were conducted under the conditions shown in Table [1].

Table 1 α-Allylation of Quinazolinones Bearing Various ortho-Substituents

Entry	Substrate	X	Products	Yielda (%)	dr 2/2′
1	1a	F	2a, 2′a	96	1:1b
2	1b	Cl	2b, 2′b	96	4.8:1c
3	1c	Br	2c, 2′c	85	7.5:1c
4	1d	I	2d, 2′d	92	17.9:1c
5	1e	Me	2e, 2′e	89	6.1:1c
6	1f	Et	2f, 2′f	95	10:1c
7	1g	i-Pr	2g, 2′g	91	> 50:1c
8	1h	CF3	2h, 2′h	98	> 50:1c

^a Isolated yield.

^b Ratio based on isolated yields.

^c Ratio based on ¹H NMR analysis of the mixture of 2 and 2′.

When 1.5 equivalents of LiHMDS was added to quinazolinone substrates 1a–h in THF at –20 °C, the colorless solution changed to a wine-red solution, indicating successful formation of the desired anionic species. Subsequent addition of 1.5 equivalents of allyl bromide at –20 °C led to the formation of the corresponding α-allylation products 2 and 2′. All reactions of 1a-h were complete within 30 min at –20 °C and they gave the corresponding products 2a–h and 2′a–f in high yields (85–98%; Table [1], entries 1–8). In the allylation of 1a–d bearing a halogen in the ortho-position, a clear relationship between the diastereoselectivity and the steric bulk of the halogen atom was observed (entries 1–4). With the ortho-fluoro derivative 1a, no diastereoselectivity was observed (entry 1), whereas the reactions of the ortho-chloro and ortho-bromo derivatives 1b and 1c gave the corresponding products 2b and 2′b and 2c and 2′c in diastereomeric ratios of 4.8:1 and 7.5:1, respectively (entries 2 and 3). In the case of the ortho-iodo derivative 1d, a high diastereoselectivity was observed with 2d and 2′d being obtained in a ratio of 17.9:1 (entry 4). Thus, the diastereoselectivity increased with the increasing steric bulk of the halogen substituent.

Allylation of quinazolinone derivatives 1e–h bearing ­ortho-alkyl groups was further examined (Table [1], entries 5–8). The reaction with ortho-methyl and ortho-ethyl derivatives 1e and 1f, respectively, gave the corresponding products 2e and 2′e and 2f and 2′f in diastereomeric ratios of 6.1:1 and 10:1, respectively (entries 5 and 6). With ortho-isopropyl and ortho-trifluoromethyl derivatives 1g and 1h, perfect stereocontrol was observed and, in these cases, no minor diastereomers were detected (entries 7 and 8). Again, in the ortho-alkyl derivative series, the diastereo­selectivity and the steric factors correlated well. Furthermore, the van der Waals radius (Å) of the ortho-substituent (halogen atoms or Me group) showed a near linear correlation with the logarithm of the diastereomeric ratios 2a–e/2′a–e (Figure [2]), confirming that stereocontrol by the ortho-substituents is quantitatively correlated to their steric factors.

Because it was not possible to demonstrate a difference in the steric bulk of isopropyl and trifluoromethyl groups in the reaction with allyl bromide, we examined the corresponding reaction with ethyl iodide, a less bulky alkylation reagent. The results of this study are shown in Table [2]. Under the same conditions as those in Table [1], ethylation of 1e–h proceeded smoothly to afford the corresponding diastereomeric products 3e–h and 3′e–h in high yields (85–94%). As expected, the diastereoselectivities in the ethylation were somewhat lower in comparison with those in the allylation reaction. The reaction of methyl and ethyl derivatives 1e and 1f gave the corresponding products 3e and 3′e and 3f and 3′f in diastereomeric ratios of 2.4:1 and 4.2:1, respectively (Table [1], entries 1 and 2). In the ethylation reaction, a difference in diastereoselectivity between the isopropyl and trifluoromethyl derivatives 1g and 1h was observed, and the products 3h and 3′h were obtained in a higher diastereomeric ratio (20.3:1) than 3g and 3′g (14.7:1) (entries 3 and 4). Therefore, in the ethylation reaction, the trifluoromethyl group acts as a more bulky group than the isopropyl group.[7]

Table 2 α-Ethylation of Quinazolinones Bearing Various ortho-Alkyl Substituents

Entry	Substrate	X	Products	Yielda (%)	drb 3/3′
1	1e	Me	3e, 3′e	94	2.4:1
2	1f	Et	3f, 3′f	94	4.2:1
3	1g	i-Pr	3g, 3′g	87	14.7:1
4	1h	CF3	3h, 3′h	85	20.3:1

^a Isolated yield.

^b Ratio based on ¹H NMR analysis of the mixture of 3 and 3′.

On the basis of the results in Tables 1 and 2, the order of bulkiness of the ortho-substituents X in the present alkylation was revealed to be CF₃ > i-Pr > I > Et > Br > Me > Cl > F. This order correlates well with the rotational barriers of compounds I and II shown in Figure [1].[2d] [e]

As reported previously,[4] the stereochemistry of the major diastereomer 2c in the allylation product bearing an ­ortho-bromo group has been determined to be (P*, S*) by X-ray crystal-structure analysis.[4] Additionally, in other diastereomeric alkylation products (Scheme [1]) bearing an ortho-bromo group, the major isomers were judged to have a (P*, S*) configuration on the basis of the chemical shift of the methyl hydrogen atoms in the ¹H NMR spectra. That is, the methyl group in the minor diastereomer appears at a higher magnetic field than that in the major diastereomer. A similar shift of the Me group to a higher field in the minor diastereomer was also observed in the cases of all compounds 2′b–f and 3′e–h shown in Tables 1 and 2 (Δδ = 0.04–0.22 ppm). Accordingly, the major diastereomers 2b–h and 3e–h in Tables 1 and 2 were judged to have a (P*, S*)-configuration. The difference in the chemical shift of the methyl hydrogens between the diastereomers can be explained as follows. In both diastereomers 2 and 3 and 2′ and 3′, the conformers C-2 and C-3 and C-2′ and C-3′ show a direct exposure of the methyl group to the anisotropic effect of the ortho-substituted phenyl group, and the methyl group appears at higher magnetic field as a result of the increased contribution (population) of the conformers C-2 and C-3 and C-2′ and C-3′ (Figure [3]). The proportion of C-2′ and C-3′ in the minor diastereomers is higher than that of C-2 and C-3 in the major diastereomers, leading to a shift of the methyl hydrogen atoms to a higher field (conformer C-2/C-3 is less favored than conformer C-2′/C-3′ because of steric repulsion between the R group and the ortho-substituent X).

The diastereoselectivity can be explained in terms of the selective formation of an anionic species (a quinazolinone enolate) possessing an E-geometry that attacks the ­alkyl halide on the opposite side to the ortho-substituent (X), preferentially giving the (P*, S*)-products 2 (TS-2 or TS-3 in Figure [4]). The magnitude of the diastereoselectivity decreases with decreasing steric bulk of the ortho-substituent X and, in the reaction with 1a (X = F), no diastereoselectivity was observed.

All the diastereomeric products 2 and 3 and 2′ and 3′ shown in Tables 1 and 2 were separated by medium-pressure liquid chromatography (MPLC) and were isolated without any isomerization at room temperature. We were surprised that the C–N bond rotation of the separated dia­stereomeric ortho-fluoro derivative 2a and 2′a did not occur at all, even after standing for 24 hours at room temperature (Scheme [3]),[8] and it is seems that the diastereomeric ratio (2a/2′a = 1) observed in the reaction of 1a is a result of ­kinetic factors rather than of interconversion between 2a and 2′a.

In conclusion, we have shown that 3-arylquinazolin-4-one derivatives[9] with C–N axial chirality can be used to evaluate the relationship between the steric hindrance of the ortho-substituents and the stereoselectivities observed in α-alkylations of the corresponding anionic species. The reaction of alkyl halides with the anionic species prepared from C–N axially chiral quinazolinones bearing various ­ortho-substituents was systematically explored, and it was verified that the diastereoselectivity increased with increasing steric bulk of the ortho-substituent. Furthermore, it was found that the C–N axial chirality of the diastereomers bearing an ortho-fluorophenyl group is sufficient stable to permit their separation.

Acknowledgment

We are deeply grateful to Professor Christian Roussel for fruitful discussions on this research work.

• References and Notes


For reviews, see:
• 1a Alkorta I. Elguero J. Roussel C. Vanthuyne N. Piras P. Adv. Heterocycl. Chem. 2012; 105: 1
  Search in Google Scholar
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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
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• 2c Yilmaz EM. Doğan İ. Tetrahedron: Asymmetry 2008; 19: 2184
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• 2d Hasegawa F. Kawamura K. Tsuchikawa H. Murata M. Bioorg. Med. Chem. 2017; 25: 4506
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• 2e Belot V. Farran D. Jean M. Albalat M. Vanthuyne N. Roussel C. J. Org. Chem. 2017; 82: 10188
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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
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• 3c Kitagawa O. Izawa H. Sato K. Dobashi A. Taguchi T. Shiro M. J. Org. Chem. 1998; 63: 2634
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• 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
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• 3f Dantale S. Reboul V. Metzner P. Philouze C. Chem. Eur. J. 2002; 8: 632
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• 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
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• 3i Clayden J. Turner H. Helliwell M. Moir E. J. Org. Chem. 2008; 73: 4415
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• 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
  CrossrefPubMedSearch in Google Scholar
• 5a Mannschreck A. Koller H. Stühler G. Davis MA. Traber J. Eur. J. Med. Chem. 1984; 19: 381
  Search in Google Scholar
• 5b Junghänel J. Buss V. Beyrich T. Jira T. Chirality 1998; 10: 253
  CrossrefSearch in Google Scholar
• 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
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• 5d Chenard BL. Welch WM. Blake JF. Butler TW. Reinhold A. Ewing FE. Menniti FS. Pagnozzi MJ. J. Med. Chem. 2001; 44: 1710
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• 5e Dolma S. Lessnick SL. Hahn WC. Stockwell BR. Cancer Cell 2003; 3: 285
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• 5f Tokitoh T. Kobayashi T. Nakada E. Inoue T. Yokoshima S. Takahashi H. Natsugari H. Heterocycles 2006; 70: 93
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• 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
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• 5h Toenjes ST. Gustafson JL. Future Med. Chem. 2018; 10: 409
  CrossrefSearch in Google Scholar
• 6a Wolfe JF. Rathman TL. Sleevi MC. Campbell JA. Greenwood TD. J. Med. Chem. 1990; 33: 161
  CrossrefSearch in Google Scholar
• 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
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• 6c Kumar D. Jadhaver PS. Nautiya M. Sharma H. Meena PK. Adane L. Pancholia S. Chakraborti AK. RSC Adv. 2015; 5: 30819
  CrossrefSearch in Google Scholar
• 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
  Search in Google Scholar
• 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.

• References and Notes


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

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
  CrossrefSearch in Google Scholar
• 2c Yilmaz EM. Doğan İ. Tetrahedron: Asymmetry 2008; 19: 2184
  CrossrefSearch in Google Scholar
• 2d Hasegawa F. Kawamura K. Tsuchikawa H. Murata M. Bioorg. Med. Chem. 2017; 25: 4506
  CrossrefPubMedSearch in Google Scholar
• 2e Belot V. Farran D. Jean M. Albalat M. Vanthuyne N. Roussel C. J. Org. Chem. 2017; 82: 10188
  CrossrefPubMedSearch in Google Scholar

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
  CrossrefSearch in Google Scholar
• 3c Kitagawa O. Izawa H. Sato K. Dobashi A. Taguchi T. Shiro M. J. Org. Chem. 1998; 63: 2634
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 3f Dantale S. Reboul V. Metzner P. Philouze C. Chem. Eur. J. 2002; 8: 632
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 3i Clayden J. Turner H. Helliwell M. Moir E. J. Org. Chem. 2008; 73: 4415
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 5a Mannschreck A. Koller H. Stühler G. Davis MA. Traber J. Eur. J. Med. Chem. 1984; 19: 381
  Search in Google Scholar
• 5b Junghänel J. Buss V. Beyrich T. Jira T. Chirality 1998; 10: 253
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 5d Chenard BL. Welch WM. Blake JF. Butler TW. Reinhold A. Ewing FE. Menniti FS. Pagnozzi MJ. J. Med. Chem. 2001; 44: 1710
  CrossrefPubMedSearch in Google Scholar
• 5e Dolma S. Lessnick SL. Hahn WC. Stockwell BR. Cancer Cell 2003; 3: 285
  CrossrefPubMedSearch in Google Scholar
• 5f Tokitoh T. Kobayashi T. Nakada E. Inoue T. Yokoshima S. Takahashi H. Natsugari H. Heterocycles 2006; 70: 93
  CrossrefSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 5h Toenjes ST. Gustafson JL. Future Med. Chem. 2018; 10: 409
  CrossrefSearch in Google Scholar
• 6a Wolfe JF. Rathman TL. Sleevi MC. Campbell JA. Greenwood TD. J. Med. Chem. 1990; 33: 161
  CrossrefSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 6c Kumar D. Jadhaver PS. Nautiya M. Sharma H. Meena PK. Adane L. Pancholia S. Chakraborti AK. RSC Adv. 2015; 5: 30819
  CrossrefSearch in Google Scholar
• 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
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• 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.

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