Synthesis of 2-heterosubstituted quinazolinone atropisomeric phosphine ligands by direct lithiation of a 2-unsubstituted quinazolinone system

Article abstract of DOI:10.1016/S0957-4166(98)00496-0

The syntheses of 2-heterosubstituted atropisomeric quinazolinone phosphine ligands 7e-g have been achieved in good yield by the straightforward direct lithiation of the 2-unsubstituted quinazolinone ligand 7d followed by electrophilic substitutions.

Full text of DOI:10.1016/S0957-4166(98)00496-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 25–29
Synthesis of 2-heterosubstituted quinazolinone atropisomeric
phosphine ligands by direct lithiation of a 2-unsubstituted
quinazolinone system
Xuedong Dai ∗,† and Scott Virgil ‡
Department of Chemistry, Massachusetts Institute of Technology, 77 Mass Ave, Cambridge, MA 02139, USA
Received 29 November 1998; accepted 3 December 1998
Abstract
The syntheses of 2-heterosubstituted atropisomeric quinazolinone phosphine ligands 7e–g have been achieved
in good yield by the straightforward direct lithiation of the 2-unsubstituted quinazolinone ligand 7d followed by
electrophilic substitutions. © 1999 Elsevier Science Ltd. All rights reserved.
Recent syntheses of some atropisomeric phosphine ligands (1a–c, 2, and 3) demonstrated that direct
metalation1 of five-membered heteroaromatic rings (in particular, indoles and imidazoles) was an
efficient methodology for obtaining chiral ligands.2
However, direct lithiation of six-membered aromatic heterocycles, particularly for diaza compounds,
is a less studied topic, possibly because of their high reactivity toward nucleophilic addition. Lithiation of
pyrimidine using lithium alkylamides such as LDA (lithium diisopropylamide) or LTMP (lithium 2,2,6,6-
tetramethylpiperidylamide) which are less prone to nucleophilic addition than alkyl- or aryllithium have
been reported. However, to our knowledge, there is no report on direct lithiation of a 2-unsubstituted
3-aryl-4(3H)-quinazolinone ring system.3
∗
†
‡
Corresponding author. E-mail: xddai@mit.edu
Current address: Center for Cancer Research, Rm. E17-132, MIT, 77 Massachusetts Ave., Cambridge, MA 02139, USA.
Current address: Agouron Pharmaceuticals, Inc., 3565 General Atomic Court, San Diego, CA 92121, USA.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00496-0

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X. Dai, S. Virgil / Tetrahedron: Asymmetry 10 (1999) 25–29
Recently, Smith et al. reported the synthesis of 2-substituted 4(3H)-quinazolinone by ortho-directed
lithiation of 2-unsubstituted quinazolinones (4a and 4b, Scheme 1) with LDA followed by reaction of the
resulting intermediate 5 with a variety of electrophiles.4 They claimed that the ortho-directing groups (the
3-pivaloylamino group and the 3-acetylamino group) were necessary for the lithiation of quinazolinones
4a and 4b to take place.
Scheme 1.
In the case of compound 4b, it is interesting that lithiation of the 2-position occurred in the presence of
the acidic α-protons of the 3-acetylamino group. Deprotonation of the α-protons of simple acetanilides
occurs readily and accounts for the preferred use of the pivaloylamino group in directed lithiation
reactions.5 The regioselective lithiation of compound 4b suggests that the proton at the 2-position is
more acidic than the methyl protons of the 3-acetylamino group.
The successful syntheses and resolutions of ligands 7a–c6 encouraged us to develop 2-
heterosubstituted quinazolinone phosphine ligands, such as 7e–g. The heteroatoms at the 2-position of
the quinazolinone ring together with the PPh2 group on the 3-aryl ring are designed to chelate metals
in a similar way as BINAP. Many variations of bidentate ligands have been shown to associate strongly
with the metal centers and thereby bring metals closer to the chiral environment provided by the ligands.
This feature underlies their enhanced stereoselectivity in asymmetric catalysis.7
We anticipated that the proton at the 2-position of quinazolinone ligand 7d would be acidic enough to
be directly lithiated without an apparent directing group. If the regioselective lithiation could be realized,
subsequent quenching of the carbanion with electrophiles (such as PPh2Cl, S8, and MeSSMe) would
afford chelating ligands 7e–g in a straightforward fashion.
The synthesis of 2-unsubstituted ligand 7d was initiated with the formation of 4H-3,1-benzoxazin-4-
one (8) by the condensation of 2.2 equiv. anthranilic acid with 5.0 equiv. trimethyl orthoester following
the method reported by Khajavi et al.8 After removal of the excess orthoester, the crude 8 was mixed
with a solution of 1.0 equiv. aminophosphine 96 in toluene. The mixture was heated to reflux for 6 h to
afford quinazolinone 7d (88%, 25 g scale) (Scheme 2).
Scheme 2.

X. Dai, S. Virgil / Tetrahedron: Asymmetry 10 (1999) 25–29
27
As we expected, the lithiation of ligand 7d using LDA proceeded readily at −78°C in THF under
argon to give a yellow solution of anion 10 without the pivaloylamino or acetylamino ortho-directing
groups (Scheme 3). Anion 10 was found to be unstable at temperatures higher than −20°C. Hence,
the subsequent addition of electrophiles (neat chlorodiphenylphosphine (PPh2Cl), solid sulfur (S8), and
dimethyl disulfide (MeSSMe)) was carried out at −78°C. The reaction mixture was stirred at −78°C for
1 h before warming slowly to room temperature. Normal workup procedures afforded ligands 7e–g in
good isolated yield (84–88%). All of the reactions were carried out on a 3 g scale and ligands 7e–g were
fully characterized.9
Scheme 3.
1
Based on H NMR and 13C NMR analyses, ligand 7f is only in the thioamide form (Scheme 4).10
To our knowledge, only one class of P–S atropisomeric ligand (11a–d, Scheme 4) has been thus far
developed from binaphthol by multiple-step transformations.11,12
Scheme 4.
Racemic ligand 7d can be resolved by (−)-di-µ-chlorobis[(S)-dimethyl-(1-naphthylethyl)-aminato-
C2,N]dipalladium(II)13 using a similar resolution procedure as for ligands 7a–c.6,14 Therefore, enan-
tiomers of ligands 7e–g could be derived from enantiomers of ligand 7d.
We further found that diphosphine ligand 7e could be directly resolved using (−)-di-µ-chlorobis[(S)-
dimethyl-(1-phenylethyl)aminato-C2,N]dipalladium(II) (12) according to the literature procedure
(Scheme 5).15 The white precipitate, formed from the methanol solution of racemic ligand 7e and
complex 12 upon addition of aqueous NaBF4 solution was recrystallized from benzene. X-Ray
crystallography analysis of the colorless prisms revealed that only the (S)-7e enantiomer and the
resolving agent formed the less soluble complex 13.16 The PPh2 group on the 3-aryl ring of ligand (S)-7e
was trans to the dimethylamino group; the PPh2 group at the 2-position was cis to the dimethylamino
group, suggesting that the two phosphine groups are electronically different. This feature may have
special utility for the catalyst design. Treatment of complexes 13 and 14 with ethylenediamine in CH2Cl2
released free ligand (S)-(−)-7e and (R)-(+)-7e, respectively.17
The concise one-pot syntheses of ligands 7e–g from ligand 7d offers an efficient access to a new class
of P–S and P–P chelate atropisomeric ligands. This discovery has also added a new tool for the structural
modification of the quinazolinone ring system.

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X. Dai, S. Virgil / Tetrahedron: Asymmetry 10 (1999) 25–29
Scheme 5.
Acknowledgements
The authors thank Dr. William Davis for solving the crystal structure of complex 13.
References
1. (a) Davies, D. T. Aromatic Heterocyclic Chemistry; Oxford University Press: New York, 1992 and references cited therein.
(b) Grimmett, M. R. Imidazole and Benzimidazole Synthesis; Academic Press: San Diego, 1997.
2. (a) Benincori, T.; Brenna, E.; Sannicolò, F.; Trimarco, L.; Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org.
Chem. 1996, 61, 6244. (b) Benincori, T.; Brenna, E.; Sannicolò, F.; Trimarco, L.; Antognazza, P.; Cesarotti, E.; Demartin,
F.; Pilati, T.; Zotti, G. J. Organomet. Chem. 1997, 529, 445. (c) Berens, U.; Brown, J. M.; Long, J.; Selke, R. Tetrahedron:
Asymmetry 1996, 7, 285.
3. Review: Turck, A.; Plé, N.; Quéguiner, G. Heterocycles 1994, 37, 2149.
4. Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M. A. J. Org. Chem. 1996, 61, 647.
5. (a) Snieckus, V. Chem. Rev. 1990, 90, 879. (b) Wakefield, B. J. Organolithium Methods; Academic Press, 1988.
6. Dai, X.; Wong, A.; Virgil, S. C. J. Org. Chem. 1998, 63, 2597–2600.
7. (a) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH: New York, 1993. (b) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; John Wiley & Sons: New York, 1994.
8. (a) Khajavi, M. S.; Montazari, N.; Hosseini, S. S. S. J. Chem. Res. (S) 1997, 286. (b) Kornet, M. J.; Varia, T.; Beaven, W.
J. Heterocycl. Chem. 1983, 20, 1553.
9. Data for ligand 7d: mp 140–142°C; Rf=0.38 (silica, 1:2 ethyl acetate:hexane); FTIR (thin film, cm−1) 3049, 1686, 1607,
1471, 1434, 1289, 1272, 909, 775, 744, 697; 1H NMR (300 MHz, CDCl3) δ 8.26 (dd, 1H, J=1.4, 7.9 Hz), 7.76 (ddd, 1H,
J=1.5, 6.8, 8.3 Hz), 7.70 (dd, 1H, J=1.8, 8.2 Hz), 7.62 (d, 1H, J=1.6 Hz), 7.47 (ddd, 1H, J=1.7, 6.7, 7.9 Hz), 7.17–7.40
(m, 11H), 6.80 (dd, 1H, J=2.2, 3.2 Hz), 2.27 (s, 3H), 2.10 (s, 3H); 31P{1H} NMR (202 MHz, CDCl3): δ −15.1 (s);
HRMS 434.15476 (calcd for C28H23N2OP 434.15480). Data for ligand 7e: mp 238–241°C; Rf=0.58 (silica, 1:2 ethyl
acetate:hexane); FTIR (thin film, cm−1) 3051, 1687, 1542, 1468, 1434, 1246, 1193, 742, 695; 1H NMR (300 MHz, CDCl3)
δ 7.89 (dd, 1H, J=1.5, 7.8 Hz), 7.77 (ddd, 1H, J=1.5, 7.1, 8.1 Hz), 7.62 (dd, 1H, J=1.2, 8.1 Hz), 7.46–7.55 (m, 4H),
7.30–7.45 (m, 12H), 7.10–7.38 (m, 5H), 6.97 (d, 1H, J=1.5 Hz), 6.82 (dd, 1H, J=2.0, 3.4 Hz), 2.30 (s, 3H), 1.29 (s, 3H);
31P{1H} NMR (202.3 MHz, CDCl3): δ −2.16 (d, J=71.38 Hz), −12.70 (d, J=71.38 Hz); HRMS 618.19810 (calcd for
C40H32N2OP 618.19899). Data for ligand 7f: mp: >300°C; Rf=0.43 (silica, 1:2 ethyl acetate:hexane); FTIR (thin film,
cm−1) 3248, 3037, 1701, 1666, 1618, 1528, 1484, 1396, 1199, 743, 694; 1H NMR (300 MHz, CDCl3) δ 10.96 (br s, 1H),
7.99 (dd, 1H, J=1.0, 7.8 Hz), 7.60 (tdd, 1H, J=1.5, 7.3, 8.3 Hz), 7.35–7.42 (m, 2H), 7.16–7.52 (m, 10H), 7.14 (d, 1H,
J=8.3 Hz), 6.96 (dd, 1H, J=2.0, 3.9 Hz), 2.28 (s, 3H), 2.18 (s, 3H); 31P{1H} NMR (202.3 MHz, CDCl3): δ −17.0 (s);
HRMS 466.12644 (calcd for C28H23N2OPS 466.12687). Data for ligand 7g: mp 130–132°C; Rf=0.55 (silica, 1:2 ethyl
acetate:hexane); FTIR (thin film, cm−1) 3052, 1684, 1546, 1467, 769, 743, 695; 1H NMR (300 MHz, CDCl3) δ 8.10 (dd,
1H, J=1.46, 7.81 Hz), 7.72 (ddd, 1H, J=1.46, 6.84, 8.30), 7.66 (dd, 1H, J=1.46, 8.30), 7.15–7.42 (m, 12H), 6.99 (dd,
1H, J=1.46, 3.42), 2.51 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H); 31P{1H} NMR (202.3 MHz, CDCl3): δ −16.72 ppm; HRMS
480.14240 (FAB, 3-nitrobenzyl alcohol) (calcd for C29H25N2OP 480.142524).
10. Thioamide form of quinazolinone: Brown, D. J. Quinazolines. Supplement 1; Wiley: New York, 1996.
11. Gladiali, S.; Dore, A.; Fabbri, D. Tetrahedron: Asymmetry 1994, 5, 1143.
12. Kang, J.; Yu, S. H.; Kim, J. I.; Cho, H. G. Bull. Korean Chem. Soc. 1995, 16, 439.
13. (a) Roberts, N. K.; Wild, S. B. J. Chem. Soc., Dalton Trans. 1979, 2015. (b) Allen, D. G.; McLaughlin, G. M.; Robertson,
G. B.; Steffem, W. L.; Salem, G.; Wild, S. B. Inorg. Chem. 1982, 21, 1007.

X. Dai, S. Virgil / Tetrahedron: Asymmetry 10 (1999) 25–29
29
14. Data for ligand (R)-(−)-7d: mp 168–170°C (white needles); [α]D=−189 (c=1.09, CHCl3) (99% ee based on chiral HPLC
analysis, Chiralcel-OD column, 98:2 hexane:2-propanol, flow rate 0.50 mL/min, λ=295 nm, tR=32.4 min). Data for ligand
(S)-(+)-7d: mp 169.5–170.5°C (white needles); [α]D=+204 (c=1.01, CHCl3), (>99.5% ee based on chiral HPLC analysis,
same conditions as for ligand (R)-(−)-7d, tR=17.8 min).
15. Roberts N. K.; Wild, S. B. J. Am. Chem. Soc. 1979, 101, 6254.
16. X-Ray data for complex 13 (C50H46BF4N3OP2Pd; MW=960.10): orthorhombic system, space group P212121, a=15.6576(3)
Å, b=16.1037(4) Å, c=19.6933(3) Å and Z=4. A total of 14 973 reflections were collected at −90°C using a Siemens
SMART/CCD diffractometer. Least squares refinement of the data using 4640 reflections converged upon the structure
with R=0.0932 and a goodness of fit=1.061. The atomic co-ordinates for this work are available on request from the
Director of the Cambridge Crystallographic Data Centre, University Chemical Laboratory, Lensfield Road, Cambridge
CB2 1EW. Any request should be accompanied by the full literature citation for this communication.
17. Data for ligand (S)-(−)-7e: mp 238–240°C (white bricks); [α]D=−21.2 (c=1.20, CHCl3), (98% ee based on chiral HPLC
analysis, Daicel Chiralcel-OD, 98:2 hexane:2-propanol, flow rate 0.50 mL/min, λ=295 nm, tR=17.8 min). Data for ligand
(R)-(+)-7e: mp 238–240°C (white bricks); [α]D=+16.8 (c=1.46, CHCl3) (90% ee based on chiral HPLC analysis, same
conditions as for ligand (S)-(−)-7e, tR=19.4 min).