Synthesis of 4,4′-biquinazoline alcohols as chiral catalysts in enantioselective alkynylation of aldehydes with phenyl acetylene

Article abstract of DOI:10.1016/j.tetasy.2009.12.002

Optically active propargylic alcohols are important chiral-building blocks in asymmetric synthesis, while the asymmetric addition of a terminal alkyne to an aldehyde is one of the most important procedures to prepare these chiral-building blocks. In this work, a family of chiral 4,4′-biquinazoline alcohols has been conveniently prepared from the easily accessible (S)-2-acetoxycarboxylic acid chlorides by reaction sequences beginning with condensation and followed by key synthetic steps including chlorination, nickel(0)-mediated homocoupling, and deprotection in addition to being examined as potential ligands in the enantioselective addition of phenylacetylene to aldehydes. These chiral ligands can be combined with Ti(OiPr)₄ and then used to catalyze the asymmetric addition of zinc acetylide, produced in situ by the reaction of phenylacetylene with diethylzinc, to aldehydes. The best enantiomeric excess obtained in this study was 75%.

Full text of DOI:10.1016/j.tetasy.2009.12.002

Tetrahedron: Asymmetry 20 (2009) 2845–2853
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Tetrahedron: Asymmetry
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Synthesis of 4,40-biquinazoline alcohols as chiral catalysts in enantioselective
alkynylation of aldehydes with phenyl acetylene
a
a,
Mustafa Catir a, Murat Cakici a, Semistan Karabuga b, Sabri Ulukanli c, , Ertan Sßahin , Hamdullah Kilic
*
*
a Faculty of Sciences, Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey
b Faculty of Science and Letters, Department of Chemistry, Kilis 7 Aralık University, Kilis, Turkey
c Faculty of Science and Letters, Department of Chemistry, Korkut Ata University, Osmaniye, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically active propargylic alcohols are important chiral-building blocks in asymmetric synthesis, while
the asymmetric addition of a terminal alkyne to an aldehyde is one of the most important procedures to
prepare these chiral-building blocks. In this work, a family of chiral 4,40-biquinazoline alcohols has been
conveniently prepared from the easily accessible (S)-2-acetoxycarboxylic acid chlorides by reaction
sequences beginning with condensation and followed by key synthetic steps including chlorination,
nickel(0)-mediated homocoupling, and deprotection in addition to being examined as potential ligands
in the enantioselective addition of phenylacetylene to aldehydes. These chiral ligands can be combined
with Ti(OiPr)4 and then used to catalyze the asymmetric addition of zinc acetylide, produced in situ by
the reaction of phenylacetylene with diethylzinc, to aldehydes. The best enantiomeric excess obtained
in this study was 75%.
Received 19 October 2009
Accepted 1 December 2009
Available online 8 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
alcohols,3n,8 oxazoline,9 ferrocenyl-substituted aziridinylmetha-
nols3h,10 and amino acids11 have also been reported to catalyze this
Chiral propargylic alcohols are useful and versatile building
blocks in asymmetric synthesis as they are used in the preparation
of a diverse range of molecules, including natural products, phar-
maceuticals, and macromolecules.1 For this reason, propargyl alco-
hols have been used as starting materials in many efficient
syntheses. The two most common methods to prepare optically
active propargylic alcohols include the asymmetric reduction of
an ynone2 and the asymmetric metal-catalyzed alkynylation of
an aldehyde.3 In recent years, great progress has been made in
the asymmetric addition reactions of alkynylzinc to aldehydes to
yield chiral propargylic alcohols with a high ee of up to 99%. Carre-
ira et al. developed a method for the preparation of optically active
propargylic alcohols based on the treatment of aldehydes with zinc
acetylides in the presence of (+)-N-methylephedrine.3f,4 Chan et al.
have found that a combination of chiral BINOL and sulfonamide
with Ti(OiPr)4 produces a highly enantioselective catalyst which
catalyzes the addition of in situ-generated alkynylzinc to aromatic
aldehydes.5 Pu et al. developed a convenient process, utilizing the
BINOL/Ti(OiPr)4/Et2Zn system, to produce secondary propargylic
alcohols with high enantioselectivities.3i,l,6 Wang et al. found that
complexes of sulfonamide alcohols and Ti(OiPr)4 also catalyze the
highly enantioselective addition of phenylacetylene to both alkyl
and aromatic aldehydes.7 Other chiral ligands, including amino
asymmetric addition reaction. New structural motifs play impor-
tant roles in determining enantioselectivities and reactivities for
a given transformation. For example, bipyridine alcohol 1 has been
explored as an effective scaffold for the asymmetric addition of
diethylzinc to aldehydes.12
R
N
OH
OH
OH
OH
2a R = Me
2b R = iPr
2c R = t-Bu
2d R = Ph
2e R = Bn
N
N
N
N
N
R
1
2a-e
Prompted by these studies, we chose to make unknown chiral
ligands that possess biquinazoline alcohol moiety. Herein, we
report the synthesis of these novel chiral 4,4-biquinazoline
0alcohols 2a–e from readily accessible enantiomerically pure (S)-
2-acetoxycarboxylic acids 3a–e13–17 and their catalytic activities
in the asymmetric addition of phenyl acetylene to aldehydes in
the presence of Et2Zn and Ti(OiPr)4. Furthermore metabolite
chrysogine 5a18,19 derivatives 5b,c,d, and e have been made avail-
able in enantiomerically pure forms.
* Corresponding authors. Tel.: +90 442 231 4426; fax: +90 442 236 0948 (H.K.).
E-mail addresses: sabriulukanli@osmaniye.edu.tr (S. Ulukanli), hkilic@atauni.
edu.tr (H. Kilic).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.002

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M. Catir et al. / Tetrahedron: Asymmetry 20 (2009) 2845–2853
of chirality. The compound crystallizes in the orthorhombic space
2. Results and discussion
group C2221 (No: 20), with four molecules in the unit cell
(Fig. 1b). In the structure, quinazoline fragments are almost planar
(maximum deviation from mean plane for C7 is 0.029 Å) and rather
rotated along the C8–C8a symmetry axis. O1–Hꢀ ꢀ ꢀN1 and O1a–
Hꢀ ꢀ ꢀN1a are the strong intramolecular hydrogen bonds detected
in the structure and stabilize the quinazoline planes with the
substituted units (O1–Hꢀ ꢀ ꢀN1 = 2.585(4) Å, O1–Hꢀ ꢀ ꢀN1 = 120°).
The newly prepared biquiazoline ligands 2a,b,c, and e were
screened for the asymmetric alkynylation of benzaldehyde with
phenylacetylene at 0 °C. Unfortunately, the ee of the benzyl deriv-
ative 2d could not be accurately determined; thus 2d was not
tested in the asymmetric alkynylation reaction. Among them 2b
and 2e provided promising results in terms of enantioselectivity
as shown in Table 1 (entries 1–4). The conditions of the asymmet-
ric alkynylation of benzaldehyde in the presence of chiral ligands
2b and e were optimized (data not shown). We found that the
reaction was influenced by the solvents. THF was found to be the
best, while other solvents made the reaction sluggish and low
enantioselectivities were obtained. Decreasing the reaction tem-
perature from 0 °C to ꢁ10 °C led to slow conversions and low
enantioselectivities. Increasing the amount of ligand from 10 to
20 mol % resulted in a low ee of 54%. Under the optimized reaction
conditions, 2b and e were employed as chiral catalysts for the
asymmetric alkynylation of substituted arylaldehydes 10,10,33 and
the results are summarized in Table 1. Depending on the structure
of the ligand and aldehyde, the conversions vary from 0% to 67%.
Most of the substituted arylaldehydes underwent the addition
reaction with lower levels of enantioselectivity compared with
the parent benzaldehyde. Comparison of the chloro-substituted
aldehydes and the methoxy-substituted aldehydes show that elec-
tronic properties have an effect on the conversion and enantiose-
lectivity of the addition.
Previous work has illustrated that enantiopure (S)-2-acetoxy-
carboxylic acid chloride and 2-aminobenzamide are useful build-
ing blocks that allow the preparation of enantiopure mold
metabolite chrysogine 5a in one step.19 We envisaged that chlori-
nation of the mold metabolite chrysogine derivatives 5a–e with
POCl3 and subsequent nickel(0)-mediated homocoupling would
produce the target compounds. The potential utility of this tech-
nique has been aptly illustrated in the literature by numerous
examples in different fields of organic chemistry.20–23 In this
context, in order to reach the targeted compounds, we selected
appropriate (S)-2-acetoxycarboxylic acid chlorides14,15,24–26 and
2-aminobenzamide as key templates. Enantiomerically pure
(S)-2-acetoxycarboxylic acids 3a–e were converted into (S)-2-acet-
oxycarboxylic acid chlorides by treatment of SOCl2, and reacted
with 2-aminobenzamide to yield the corresponding amides 4a–e
(Scheme 1). The enantiomeric purities of amides 4a–e were deter-
mined by a HLPC system equipped with a chiralyser, which gives
the amides 4a–e with enantiomeric purities in 99%, and prevent
their original (S)-configuration with no partial rasemization; how-
ever we noticed that (S)-2-acetoxycarboxylic acids 3a–e undergo
gradual rasemization on standing at room temperature. The mea-
sured specific rotation of the known compound 4a is in good agree-
ment with the observed values.19 Cyclization27 of amides 4a–e by
NaOH to form 5a–e was carried out in EtOH at room temperature.
A solution of (S)-amide 4 in ethanol at 0 °C was treated with 10 M
NaOH and stirred for 1 h at room temperature and neutralized with
concentrated HCl at 0 °C. The reaction mixture was concentrated in
vacuo (45 °C, 20 mbar) to a thick paste and diluted with water. The
precipitate was filtered, washed with water, and air-dried.
Crystallization from EtOH/H2O afforded the corresponding (S)-qui-
nazoline-4(3H)-one alcohols 5a–e in yield of 75–95%. All spectro-
scopic data of the known compounds 5a and d20,28,29 are
identical with those reported in the literature. The unknown com-
pounds 5b,c and 5e were characterized by elemental analyses, IR
and NMR spectra. Chiral HPLC analysis of 5a–e shows that enantio-
meric purities are around 99%. The observed enantiomeric purity of
5d is higher than that (ee 80%) reported by Bergman.19 The result-
ing quinazolinone alcohols 5a–e were converted to the corre-
sponding silyl ether 6a–e with TBDMSCl.30
3. Conclusion
In conclusion, we have prepared (S)-biquinazoline alcohols 2
from readily accessible starting materials, and employed then as
chiral catalysts in the asymmetric addition of phenylacetylene to
various aldehydes. The ligands 2b and e showed good enantioselec-
tivities (up to 75% ee) in the asymmetric alkynylation of aldehydes.
The chlorination27 of the quinazolinone derivatives 6a–e with
phosphoryl chloride in the presence of N,N-diethyl aniline pro-
vided 7a–e in excellent yields (Scheme 2). The chloroquinazolines
7a–e were subjected to Ni(0)-mediated homocoupling31 in DMF, to
afford the desired products 8a–e together with 6 and 9. After puri-
fication of 8 on a silica gel column, deprotection32 of 8a–e with
TBAF gave the desired biquinazoline alcohols 9a–e. The structural
assignments of the biquinazoline alcohols relied upon their
1H NMR, 13C NMR, and mass spectra. An X-ray diffraction analysis
of 2c confirmed the proposed structure (Fig. 1a). The absolute
configuration of 2c was determined to be (S) the basis of its source
4. Experimental
4.1. General
Reagents and solvents were purchased from standard chemical
suppliers and purified to match the reported physical and spectro-
scopic data. Melting points were determined with a Gallenkamp
apparatus. Solvents were concentrated at reduced pressure (ca.
20 °C, 20 Torr). IR spectra were obtained on KBr pellets with a Per-
kin–Elmer apparatus. 1H and 13C NMR spectra were recorded on a
CONH2
O
N
O
N
O
NH
NH
a, b
c
R
NH
d
OH
OH
OTBDMS
R
OAc
O
R
R
OAc
3
4
5
6
3a, R = Me; 3b, R = iPr
3c, R = t-Bu; 3d, R = Ph
3e, R = Bn
5a 94%; 5b 98%; 5c 75%
5d 95%; 5e 90%
6a 96%; 6b 94%; 6c 97%
6d 95%; 6e 96%
4a 92%; 4b 87%; 4c 91%
4d 95%; 4e 89%
Scheme 1. Synthesis of quinazolinones 6. Reagents and conditions: (a) SOCl2 (3.0 equiv); (b) anthranilamide (2.2 equiv), 5 °C, DCM; (c) 10 M NaOH (4 equiv), EtOH, rt, 1 h;
(d) TBDMSCl (2.0 equiv), imidazole (2.5 equiv).

M. Catir et al. / Tetrahedron: Asymmetry 20 (2009) 2845–2853
2847
OTBDMS
N
Cl
N
R
O
N
N
N
N
a
b
N
NH
6
+
+
R
N
R
OTBDMS
OTBDMS
R
OTBDMS
N
7
8
6
9
OTBDMS
7a 98%; 7b 97%; 7c 97%
7d 98%; 7e 96%
8a 50%; 8b 48%; 8c 52%
8c 30%; 8e 42%
c
R
N
OH
N
N
2a 95%; 2b 95%; 2c 95%
2d 48%; 2e 93%
OH
N
R
2
Scheme 2. Synthesis of the biquinazoline alcohols 2. Reagents and conditions: (a) POCl3 (1.2 equiv), PhNEt2 (2.0 equiv); (b) PPh3 (4.0 equiv), NiCl2ꢀ6H2O (1.0 equiv), Zn
(1.5 equiv), DMF, 50 °C; Ratio of 8:6:9; 8a:6a:9a = 64:19:17; 8b:6b:9b = 54:46:0; 8c:6c:9c = 53:47:0; 8d:6d:9d = 37:12:51; 8e:6e:9e = 48:52:0; (c) Bu4NF (2.5 equiv), THF,
20 °C.
Figure 1b. Packing diagram of 2c along the a-axis. Dashed lines indicate intramo-
lecular hydrogen bonds.
Figure 1a. X-ray crystal structure of biquinazoline 2c. The asymmetric unit
contains half of the molecule. Displacement ellipsoids are shown at the 40%
probability level.
at room temperature. Excess SOCl2 was evaporated in vacuo to give
corresponding acyl chloride. Without any further purification the
acyl chloride was used in the next step. Then, to a pre cooled sus-
pension of anthranilamide (29.9 g, 0.22 mol) in diethyl ether
(150 mL) was added a solution of acyl chloride prepared as de-
scribed above in diethylether (15 ml) over 1h. During vigorous stir-
ring, a solution of acyl chloride prepared as described above in
CH2Cl2 (15 mL) was added dropwise over 1 h. After the addition
was complete, the mixture was stirred at room temperature over-
night. The reaction mixture was washed with 2 M HCl (2 ꢂ 100
mL) and water (100 mL), the organic layer dried over Na2SO4, and
the solvent removed under reduced pressure (20 mbar, 20 °C). Crys-
tallization of crude mixture gave the corresponding amide 4.
Varian (200, 400) spectrometer in CDCl3. Enantiomeric excesses
were determined by HPLC analysis using a chiral column with elu-
ent n-hexane–i-PrOH, and detection was performed at 254 nm.
Optical rotations were measured with a Bellingham + Stanley,
ADP220, 589 nm spectropolarimeter in a 1 dm tube; Concentra-
tions were given in g/100 mL. A polarimetric Chiralyser detector
was used to assess the sign of configuration of the enantiomer
formed. All column chromatography was performed on silica gel.
4.2. General procedure for the amide 4
4.2.1. (S)-1-(2-Carbamoylphenylamino)-1-oxopropan-2-yl
acetate 4a
At first, SOCl2 (47.2 g, 0.4 mol) was added to (S)-2-acetoxycarb-
oxylic acid 3 (0.1 mol) dropwise over 1 h at 0 °C. After the addition
was complete, the reaction mixture was stirred for an additional 4 h
Crystallization from a mixture of EtOAc–hexane gave colorless
needles. Yield: 92%; mp 131–133 °C; 1H NMR (400 MHz, CDCl3,

2848
M. Catir et al. / Tetrahedron: Asymmetry 20 (2009) 2845–2853
34.5, 33.5, 26.5, 21.1; IR (KBr cmꢁ1) 3355, 3218, 2966, 2873,
1746, 1667, 1614, 1583, 1450, 1374, 1307, 1240, 1057; Anal. Calcd
for C15H20N2O4: C, 61.63; H, 6.90; N, 9.58. Found: C, 61.23; H, 7.02;
Table 1
Asymmetric alkynylation of aryldehydes with phenylacetylene in the presence of
ligands 2a,b,c, and 2e
a 2D0
ꢃ
¼ ꢁ136 (c 1, EtOH); ee: 99%; retention time:
Ph
C
CH (2 equiv)
(2 equiv)
N, 9.57;
½
O
O∗H
ZnEt2
21.9 min, Chiralcel OD-H, n-hexane–iPrOH, 90:10, flow rate of
L* (10 mol%), Ti(OiPr)4 (25 mol%)
H
1 mL/min, 220 nm.
Ph
º
THF, 0 C, 20 h
X
X
4.2.4. (S)-2-(2-Carbamoylphenylamino)-2-oxo-1-phenylethyl
acetate 4d
10
11
Entry
Aldehyde
Ligand
Convna (%)
Yielda (%)
Eeb (%)
Crystallization from a mixture of EtOAc–hexane gave colorless
needles. Yield: 95%; mp 180–182 °C; 1H NMR (400 MHz, CDCl3,
ppm) d 12.08 (br s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 7.56–7.44
(m, 4H), 7.40–7.32 (m, 3H), 7.08–7.04 (m, 1H), 6.16 (s, 1H), 2.32
(s, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 171.2, 169.9, 167.7,
139.8, 135,6, 133.6, 129.1, 128.9, 127.6, 127.5, 123.4, 121.7,
119.0, 76.2, 21.1; IR (KBr cmꢁ1) 3355, 3176, 3131, 3025, 2919,
1686, 1605, 1450, 1261, 1059; Anal. Calcd for C17H16N2O4: C,
65.38; H, 5.16; N, 8.97. Found: C, 65.09; H, 5.07; N, 8.84;
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C6H5CHO
C6H5CHO
C6H5CHO
C6H5CHO
o-ClC6H4CHO
2a
2b
2c
2e
2b
2e
2b
2e
2b
2e
2b
2e
2b
2e
2b
2e
nd
67
nd
64
63
58
18
0
62
60
15
12
46
60
60
nd
nd
64
nd
62
69
65
70
—
71
86
65
73
65
75
90
nd
rac
(S) 75
rac
(S) 70
(S) 73
(S) 74
(S) 06
—
(S) 32
(S) 38
(S) 60
(S) 68
(S) 08
(S) 13
(S) 58
(S) 28
o-MeOC6H4CHO
m-ClC6H4CHO
m-MeOC6H4CHO
p-ClC6H4CHO
½
a 2D0
ꢃ
¼ þ60 (c 1, EtOH); ee: 99%; retention time: 31.8 min, Chiralcel
OD-H, n-hexane–iPrOH, 90:10, flow rate of 1 mL/min, 220 nm.
4.2.5. (S)-1-(2-Carbamoylphenylamino)-1-oxo-3-phenylpropan-
2-yl acetate 4e
p-MeC6H4CHO
Colorless oil. Yield: 89%; 1H NMR (400 MHz, CDCl3, ppm)
d 11.75 (br s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 7.53–7.42 (m, 2H),
7.29–7.18 (m, 5H), 7.06 (ddd, J = 8.1, 7.5, 0.9 Hz, 1H), 5.47 (dd,
J = 8.7, 3.9 Hz, 1H), 3.35 (dd, A part of AB system, J = 14.3, 3.9 Hz,
1H), 3.14 (dd, B part of AB system, J = 14.3, 8.7 Hz, 1H), 2.18 (s,
3H); 13C NMR (100 MHz, CDCl3, ppm) d 171.2, 170.3, 168.7,
139.3, 136.4, 133.4, 129.6, 128.6, 127.6, 127.1, 123.5, 121.6,
119.3, 74.9, 38.3, 21.0; IR (KBr cmꢁ1) 3434, 351, 3226, 1741,
1664, 1616, 1583, 1523, 1451, 1382, 1306, 1223, 1063; MS (FAB)
m/z 327 (MH+); HRMS (FAB); calcd for C18H19N2O4 [MH+]
a
The conversions and yields were assessed by 1H NMR analysis with 1,4-dime-
thoxybenzene as an internal standard.
b
Determined by chiral HPLC analysis (Chiralcel OD-H); absolute configurations
were determined by comparison of the order of the peaks observed from HPLC with
the literature values. See Refs. 10 and 33.
ppm) d 11.82 (br s, 1H), 8.64 (dd, J = 8.4, 0.8 Hz, 1H), 7.51 (dd,
J = 7.9, 1.3 Hz, 1H), 7.48–7.45 (m, 1H), 7.11–7.07 (m, 1H) 6.34 (br
s, 1H), 5.74 (br s, 1H), 5.31 (q, J = 6.9, Hz, 1H), 2.27 (s, 3H), 1.56
(d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 171.3,
170.3, 169.9, 139.6, 133.5, 127.5, 123.3, 121.6, 119.2, 70.8, 21.2,
18.0; IR (KBr cmꢁ1) 3353, 3221, 1742, 1665, 1615, 1583, 1450,
1375, 1310, 1227, 1088, 1042. Anal. Calcd for C12H14N2O4: C,
57.59; H, 5.64; N, 11.19. Found: C, 57.35; H, 5.65; N, 11.22;
327.1345; found: 327.1342 ½a D20
¼ ꢁ105 (c 2.35, EtOH); ee: 99%;
ꢃ
retention time: 36.8 min, Chiralcel OD-H, n-hexane–iPrOH, 90:10,
flow rate of 1 mL/min, 220 nm.
4.3. General procedure for the preparation of quinazolinone 5
½
a 2D0
ꢃ
¼ ꢁ102:3 (c 1, EtOH)19; ½a D20
¼ ꢁ103 (c 1, EtOH); ee: 99%;
ꢃ
To a solution of (S)-amide 4 (50 mmol) in 60 mL of ethanol at 0 °C
was added freshly prepared 10 M NaOH (10 g, 250 mmol) dropwise
over 25 min. The mixture was then stirred for 1 h at room tempera-
ture and re-cooled to 0 °C and neutralized with concentrated HCl.
The mixture was concentrated in vacuo (45 °C, 20 mbar) to a thick
paste and diluted with water (150 mL). The precipitate was filtered,
washed with a copious amount of water, and air-dried. Crystalliza-
tion from EtOH/H2O afforded quinazolinone 5.
retention time: 25.4 min, Chiralcel OD-H, n-hexane–iPrOH, 90:10,
flow rate of 1 mL/min, 220 nm.
4.2.2. (S)-1-(2-Carbamoylphenylamino)-3-methyl-1-oxobutan-
2-yl acetate 4b
Crystallization from a mixture of EtOAc–hexane gave colorless
needles. Yield: 87%; mp 137–139 °C; 1H NMR (400 MHz, CDCl3,
ppm) d 11.73 (br s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 7.54–7.53
(m, 1H), 7.52–7.41 (m, 1H), 7.07–7.03 (m, 1H), 5.13 (d, J = 4.3 Hz,
1H), 2.40–2.32 (m, 1H), 2.27 (s, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.98
(d, J = 6,9 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 171.3,
170.8, 169.1, 139.4, 133.4, 127.7, 123.4, 121.6, 119.2, 76.9, 30.9,
21.1, 19.1, 17.1; IR (KBr cmꢁ1) 3355, 2963, 2924, 2873, 1731,
1615, 1454, 1306, 1029; Anal. Calcd for C14H18N2O4: C, 60.42; H,
4.3.1. (S)-2-(1-Hydroxyethyl)quinazolin-4(3H)-one 5a
Crystallization from a mixture of EtOAc–H2O gave colorless nee-
dles. Yield: 94%; mp 187–189 °C; 1H NMR (400 MHz, (CD3)2SO,
ppm) d 11.81 (br s, 1H), 8.08 (dd, J = 8.0, 1.1 Hz, 1H), 7.79–7.75
(m, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.48–7.44 (m, 1H), 5.65 (br s,
1H), 4.56 (q, J = 6.6 Hz, 1H), 1.41 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, (CD3)2SO, ppm) d 164.7, 159.8, 150.7, 136.7, 129.2,
128.7, 128.4, 123.1, 69.5, 24.4; IR (KBr cmꢁ1) 3467, 3362, 3187,
3070, 2929, 1673, 1612, 1295, 1236, 1160. Anal. Calcd for
C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.34; H, 5.39;
6.52; N, 10.07. Found: C, 60.16; H, 6.54; N, 10.08; ½a D20
¼ ꢁ120
ꢃ
(c 1, EtOH); ee: 99%; retention time: 20.1 min, Chiralcel OD-H,
n-hexane–iPrOH, 90:10, flow rate of 1 mL/min, 220 nm.
N, 14.67; ½a 2D0
ꢃ
¼ ꢁ39:8 (c 2.5, EtOH)19; ½a D20
¼ ꢁ41 (c 2.5, EtOH);
ꢃ
4.2.3. (S)-1-(2-Carbamoylphenylamino)-3,3-dimethyl-1-
oxobutan-2-yl acetate 4c
ee: 99%; retention time: 9.6 min, Chiralcel OD-H, n-hexane–iPrOH,
Crystallization from a mixture of EtOAc–hexane gave colorless
needles. Yield: 91%; mp 66–68 °C; 1H NMR (400 MHz, CDCl3,
ppm) d 11.59 (br s, 1H), 8.63 (d, J = 8.4 Hz, 1H), 7.55–7.53
(m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 4.89 (s,
1H), 2.27 (s, 3H), 1.10 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) d
171.8, 170.8, 168.1, 139.3, 133.4, 127.8, 123.4, 121.7, 119.2, 81.8,
90:10, flow rate of 1 mL/min, 254 nm.
4.3.2. (S)-2-(1-Hydroxy-2,2-dimethylpropyl)quinazolin-4(3H)-
one 5b
Crystallization from a mixture of EtOAc–hexane gave colorless
needles. Yield: 98%; mp 176–178 °C; 1H NMR (400 MHz, CDCl3,

M. Catir et al. / Tetrahedron: Asymmetry 20 (2009) 2845–2853
2849
ppm) d 10.86 (br s, 1H), 8.27 (ddd, J = 8.1, 1.5, 0.5 Hz, 1H), 7.77
(ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.68 (ddd, J = 8.4, 1.2, 0.5 Hz, 1H),
7.48 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 4.62–4.59 (m, 1H), 3.83
(d, J = 5.5 Hz, 1H), 2.35 (d sept., J = 6.9, 3.9 Hz, 1H), 1.14 (d, 3H,
J = 6.9 Hz), 0.91 (d, 3H, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3,
ppm) d 162.7, 156.9, 147.7, 135.1, 127.4, 127.0, 126.7, 121.2,
75.6, 33.8, 19.4, 15.8; IR (KBr cmꢁ1) 3467, 3362, 3187, 3070,
2929, 1673, 1612, 1295, 1236, 1160; Anal. Calcd for C12H14N2O2:
C, 66.04; H, 6.47; N, 12.84. Found: C, 65.71; H, 6.46; N, 12.85;
ture was chromatographed on a silica gel column by eluting with
hexane–ethyl acetate (97:03) to afford 6 in a yield of 95–97%.
4.4.1. (S)-2-(1-(tert-Butyldimethylsilyloxy)ethyl)quinazolin-
4(3H)-one 6a
Crystallization from hexane gave colorless needles. Yield: 96%;
mp 91–93 °C; 1H NMR (400 MHz, CDCl3, ppm) d 9.52 (br s, 1H,
NH), 8.28 (dd, J = 8.2, 1.5 Hz, 1H), 7.75 (ddd, J = 8.2, 7.2, 1.5 Hz,
1H), 7.67–7.61 (m, 1H), 7.49–7.41 (m, 1H), 4.85 (q, J = 6.6 Hz,
1H), 1.54 (d, J = 6.6 Hz, 3H), 0.94 (s, 9H), 0.16 (s, 3H), 0.13 (s,
3H); 13C NMR (100 MHz, CDCl3, ppm) d 161.6, 158.2, 149.1,
134.8, 127.3, 126.8, 126.7, 121.6, 69.4, 26.0, 24.1, 18.3, ꢁ4.4,
ꢁ4.8; IR (KBr cmꢁ1) 3378, 3187, 3137, 3082, 2929, 2857, 1676,
1610, 1469, 1334, 1253, 1121, 1097; Anal. Calcd for C16H24N2O2Si;
C, 63.12; H, 7.95; N, 9.20. Found: C, 63.18; H, 7.80; N, 9.27;
½
a 2D0
ꢃ
¼ ꢁ46 (c 1, EtOH); ee: 99%; retention time: 8.7 min, Chiralcel
OD-H, n-hexane–iPrOH, 90:10, flow rate of 1 mL/min, 254 nm.
4.3.3. (S)-2-(1-Hydroxy-2,2-dimethylpropyl)quinazolin-4(3H)-
one 5c
Crystallization from a mixture of EtOAc–hexane gave colorless
needles. Yield: 75%; mp 153.5–155 °C; 1H NMR (400 MHz, CDCl3,
ppm) d 10.55 (br s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.77–7.73
(m, 1H), 7.68–7.66 (m, 1H), 7.49–7.45 (m, 1H), 4.41 (s, 1H), 4.10
(br s, 1H), 1.08 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) d 162.5,
155.9, 148.5, 134.9, 127.5, 127.0, 126.6, 121.3, 79.0, 36.7, 26.1; IR
(KBr cmꢁ1) 3354, 3207, 3083, 2958, 2872, 1673, 1611, 1567,
1470, 1366, 1328, 1292, 1252, 1136, 1076, 1020. Anal. Calcd for
C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.04; H, 7.13;
½
a 2D0
ꢃ
¼ ꢁ86 (c 1, EtOH); ee: 99%; retention time: 6.1 min, Chiralcel
OD-H, n-hexane–iPrOH, 99:01, flow rate of 1 mL/min, 254 nm.
4.4.2. (S)-2-(1-(tert-Butyldimethylsilyloxy)-2-methylpropyl)qui-
nazolin-4(3H)-one 6b
Colorless oil. Yield: 94%; 1H NMR (400 MHz, CDCl3, ppm) d 9.45
(br s, 1H), 8.30 (dd, J = 8.0, 1.2 Hz, 1H), 7.77 (ddd, J = 8.2, 7.0,
1.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.48 (ddd, J = 8.0, 7.0, 0.8 Hz,
1H), 4.51 (d, J = 4.6 Hz, 1H), 2.15 (d sept., J = 6.9, 4.6 Hz, 1H), 1.00
(d, J = 6.9 Hz, 3H), 0.96 (s, 9H), 0.95 (d, J = 6.9 Hz, 3H), 0.16 (s, 3H),
0.03 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 161.4, 157.0, 148.9,
134.8, 127.4, 126.8), 121.6, 77.6, 35.1, 26.0, 19.1, 18.3, 17.1, ꢁ2.7,
ꢁ4.8; IR (KBr cmꢁ1) 3383, 3182, 3075, 2958, 2924, 2857, 1675,
1612, 1468, 1334, 1253, 1087; MS (FAB) m/z 333 (MH+); HRMS
(FAB) calcd for C18H28N2O2Si [MH+] 333.1998, found 333.1990;
N, 12.07; ½a 2D0
¼ ꢁ33 (c 1, EtOH); retention time: 12.8 min, Chiral-
ꢃ
cel OD-H, n-hexane–iPrOH, 90:10, flow rate of 0.6 mL/min, 254 nm.
4.3.4. (S)-2-[Hydroxy(phenyl)methyl]quinazolin-4(3H)-one 5d
Crystallization from a mixture of EtOAc–hexane gave colorless
needles. Yield: 95%; mp 188–190 °C; 1H NMR (400 MHz, (CD3)2SO,
ppm) d 12.03 (br s, 1H), 8.09–8.06 (m, 1H), 7.76–7.72 (m, 1H),
7.64–7.62 (m, 1H), 7.58–7.56 (m, 2H), 7.46–7.42 (m, 1H), 7.34–
7.31 (m, 2H), 7.23–7.21 (m, 1H), 5.60 (s, 1H), 3.40, (br s, 1H); 13C
NMR (100 MHz, (CD3)2SO, ppm) d 162.4, 159.2, 148.9, 141.6,
135.1, 128.9, 128.4, 127.5, 127.3, 127.1, 126.5, 121.8, 73.9; IR
(KBr cmꢁ1) 3354, 3215, 1739, 1666, 1614, 1521, 1451, 1385,
1306, 1222, 1044. Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79;
½
a 2D0
ꢃ
¼ ꢁ88 (c 1.0, EtOH); ee: 99%; retention time: 4.1 min, Chiralcel
OD-H, n-hexane–iPrOH, 95:05, flow rate of 1 mL/min, 254 nm.
4.4.3. (S)-2-(1-(tert-Butyldimethylsilyloxy)-2,2-dimethylpropyl)-
quinazolin-4(3H)-one 6c
Colorless oil. Yield: 97%; 1H NMR (400 MHz, CDCl3, ppm) d 9.21
(br s, 1H), 8.28 (ddd, J = 8.1, 1.5, 0.5 Hz, 1H), 7.75 (ddd, J = 8.4, 7.1,
1.5 Hz, 1H), 7.68 (ddd, J = 8.4, 1.2, 0.5 Hz, 1H), 7.47 (ddd, J = 8.1, 7.1,
1.2 Hz, 1H), 4.33 (s, 1H), 0.99 (s, 9H), 0.94 (s, 9H), 0.13 (s, 3H),
ꢁ0.07 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 161.3, 155.8,
148.5, 134.9, 127.6, 127.0, 126.8, 121.7, 80.6, 36.9, 26.3, 26.0,
18.3, ꢁ4.9, ꢁ5.0; IR (KBr cmꢁ1) 3385, 3193, 3081, 2927, 2711,
1671, 1608, 1466, 1333, 1254, 1084, 1033; MS (FAB) m/z 347
(MH+); HRMS (FAB) calcd for C19H31N2O2Si [MH+] 347.2125, found
N, 11.10. Found: C, 71.32; H, 4.84; N, 11.00; ½a D20
¼ þ66 (c 1, EtOH);
ꢃ
ee: 99%; retention time: 12.9 min, Chiralcel OD-H, n-hexane–
iPrOH, 90:10, flow rate of 1 mL/min, 254 nm.
4.3.5. (S)-2-(1-Hydroxy-2-phenylethyl)quinazolin-4(3H)-one 5e
Crystallization from a mixture of EtOAc–hexane gave colorless
needles. Yield: 90%; mp 230–231 °C; 1H NMR (400 MHz, (CD3)2SO,
ppm) d 11.97 (br s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.77 (td, J = 8.2,
1.5 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.47 (td, J = 8.2, 1.1 Hz, 1H),
7.24–7.14 (m, 5H), 5.77 (m, 1H), 4.63 (m, 1H), 3.16 (dd, A part of
AB system, J = 13.6, 5.0 Hz, 1H), 2.99 (dd, B part of AB system,
J = 13.6, 8.4 Hz, 1H); 13C NMR (100 MHz, (CD3)2SO, ppm) d 162.2,
159.3, 149.1, 138.7, 135.1, 130.1, 128.7, 128.5, 127.7, 127.1,
126.8, 126.5, 121.9, 73.0, 41.8; IR (KBr cmꢁ1) 3137, 3025, 2918,
1944, 1667, 1605, 1496, 1448, 1128, 1059. Anal. Calcd for
C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C, 72.10; H, 5.33;
347.2131; ½a 2D0
¼ ꢁ111 (c 4.0, EtOH); ee: 99%; retention time:
ꢃ
5.7 min, Chiralcel OD-H, n-hexane, flow rate of 1 mL/min, 254 nm.
4.4.4. (S)-2-((tert-Butyldimethylsilyloxy)(phenyl)methyl)quina-
zolin-4(3H)-one 6d
Crystallization from hexane gave colorless needles. Yield: 95%;
mp 152–154 °C; 1H NMR (400 MHz, CDCl3, ppm) d 9.64 (br s,
1H), 8.26–8.23 (m, 1H), 7.75–7.66 (m, 2H), 7.56–7.54 (m, 2H),
7.46–7.42 (m, 1H), 7.36–7.26 (m, 3H), 5.75 (s, 1H), 0.95 (s, 9H),
0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) d
161.8, 156.5, 149.0, 140.0, 134.8, 128.9, 128.7, 127.6, 127.0,
N, 10.66;
½
a 2D0
ꢃ
¼ ꢁ1 (c 1, AcOH); ee: 99%; retention time:
14.8 min, Chiralcel OD-H, n-hexane–iPrOH, 90:10, flow rate of
126.8, 126.0, 121.8, 75.1, 26.0, 18.5, ꢁ4.6, ꢁ4.9; IR (KBr cmꢁ1
)
1 mL/min, 254 nm.
3354, 3215, 1739, 1666, 1614, 1521, 1451, 1385, 1306, 1222,
1044; Anal. Calcd for C21H26N2O2Si: C, 68.81; H, 7.15; N, 7.64.
4.4. General procedure for the preparation of 6
Found: C, 68.87; H, 7.18; N, 7.70; ½a D20
¼ þ7:0 (c 1.0, EtOH); ee:
ꢃ
To a solution of quinazolinone 5 (30 mmol) in 15 mL of DMF
were added tert-butylchlorodimethylsilane (60 mmol) and imidaz-
ole (75 mmol) at room temperature. After completion of the reac-
tion, the reaction was quenched with water (20 mL). The mixture
was extracted with hexanes (3 ꢂ 100 mL) and the organic layer
washed with plenty of water, dried over Na2SO4, and the solvent
removed under reduced pressure (30 °C, 20 mbar). The crude mix-
99%; retention time: 5.9 min, Chiralcel OD-H, n-hexane–iPrOH,
90:10, flow rate of 1 mL/min, 254 nm.
4.4.5. (S)-2-(1-(tert-Butyldimethylsilyloxy)-2-phenylethyl)quin-
azolin-4(3H)-one 6e
Crystallization from ethanol gave colorless needles. Yield: 96%;
mp 94–95 °C; 1H NMR (400 MHz, CDCl3, ppm) d 9.38 (br s, 1H), 8.2

2850
M. Catir et al. / Tetrahedron: Asymmetry 20 (2009) 2845–2853
(dd, J = 7.96, 1.1 Hz, 1H), 7.82–7.73 (m, 1H), 7.70 (ddd, J = 8.2, 1.1,
0.5 Hz, 1H), 7.48 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 7.30–7.13 (m, 5H),
4.89 (dd, J = 8.2, 3.5 Hz, 1H), 3.20 (dd, A part of AB system,
J = 13.5, 3.5 Hz, 1H), 2.99 (dd, B part of AB system, J = 13.5,
8.1 Hz, 1H), 0.85 (s, 9H), ꢁ0.14 (s, 3H), ꢁ0.17 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d 161.4, 157.0, 148.9, 136.4, 134.8, 130.2,
128.5, 127.4, 127.2, 126.9, 121.7, 74.2, 44.1, 25.9, 18.3, ꢁ5.1,
ꢁ5.3; IR (KBr cmꢁ1) 3461, 2927, 2850, 1736, 1681, 1608, 1492,
1464, 1334, 1258, 1093; Anal. Calcd for C22H28N2O2Si: C, 69.43,
4.5.4. (S)-2-((tert-Butyldimethylsilyloxy)(phenyl)methyl)-4-
chloroquinazoline 7d
Colorless oil. Yield: 98%; 1H NMR (400 MHz, CDCl3, ppm) d 8.20
(d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.90 (ddd, J = 8.4, 7.1,
1.3 Hz, 1H), 7.69–7.62 (m, 3H), 7.34–7.22 (m, 3H), 6.13 (s, 1H),
0.94 (s, 9H), 0.09 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm) d 166.6, 163.0, 151.5, 142.1, 134.8, 129.0, 128.6, 128.3,
127.7, 126.7, 125.9, 122.8, 78.3, 26.1, 18.7, ꢁ4.4, ꢁ4.5; IR (KBr
cmꢁ1) 2928, 2856, 1613, 1567, 1481, 1339, 1307, 1225, 1112,
1065; Anal. Calcd for C21H25ClN2OSi: C, 65.52; H, 6.55; N, 7.28.
H, 7.42, N, 7.36. Found: C, 69.41, H, 7.64; N, 7.41; ½a D20
¼ ꢁ45 (c
ꢃ
1, EtOH); ee: 99%; retention time: 3.8 min, Chiralcel OD-H, n-hex-
ane–iPrOH, 98:02, flow rate of 1 mL/min, 254 nm.
Found: C, 65.14; H, 6.55; N, 7.30; ½a D20
¼ ꢁ55 (c 1, CH2Cl2).
ꢃ
4.5.5. (S)-2-(1-(tert-Butyldimethylsilyloxy)-2-phenylethyl)-4-
chloroquinazoline 7e
4.5. General procedure for the preparation of 7
Crystallization from hexane gave colorless needles. Yield: 96%;
mp 87–88 °C; 1H NMR (400 MHz, CDCl3, ppm) d 8.27 (d, J = 8.4 Hz,
1H), 8.09 (d, J = 8.4 Hz, 1H), 7.98–7.91 (m, 1H), 7.74–7.64 (m, 1H),
7.39–7.16 (m, 5H), 5.13 (dd, J = 9.6, 3.7 Hz, 1H), 3.29 (dd, A part of
AB system, J = 13.3, 3.7 Hz, 1H), 3.11 (dd, B part of AB system,
J = 13.3, 9.6 Hz, 1H), 0.73 (s, 9H), ꢁ0.21 (s, 3H), ꢁ0.22 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm) d 167.0, 162.9, 151.5, 138.7, 135.0,
130.2, 128.9, 128.7, 128.3, 126.5, 126.0, 122.8, 78.3, 44.1, 25.9,
18.5, ꢁ4.9, ꢁ5.0; IR (KBr cmꢁ1) 3025, 2924, 2851, 1567, 1476,
1309, 1253, 1102; Anal. Calcd for C22H27ClN2OSi: C, 66.22; H, 6.82;
N, 7.02. Found: C, 66.17; H, 6.92; N, 7.10; MS (FAB) m/z 399 (MH+);
HRMS (FAB) calcd for C22H27ClN2OSi (MH+) 399.1659, found
To a solution of (S)-6 (20 mmol) in dry benzene (50 mL) were
added PhNEt2 (40 mmol) followed by POCl3 (24 mmol) at 0 °C.
The reaction mixture was then refluxed for 3–4 h, cooled to room
temperature, and diluted with EtOAc (150 mL). The mixture was
washed successively with icy water (3 ꢂ 50 mL), 1 M HCl
(2 ꢂ 50 mL), and brine (50 mL). The organic layer was dried over
MgSO4, and evaporated under reduced pressure (20 °C, 15 mbar).
Purification by column chromatography (silica gel, hexane–EtOAc,
98:02) gave 4-chloroquinazoline 7 in a yield of 96–98%.
399.1654; ½a 2D0
¼ ꢁ1:5 (c 6.5, CH2Cl2).
ꢃ
4.5.1. (S)-2-(1-(tert-Butyldimethylsilyloxy)ethyl)-4-
chloroquinazoline 7a
Colorless oil. Yield: 98%; 1H NMR (400 MHz, CDCl3, ppm) d 8.24
(dd, J = 8.4, 0.7 Hz, 1H), 8.06 (ddd, J = 8.4, 1.1, 0.7 Hz, 1H), 7.93 (ddd,
J = 8.4, 7.0, 1.1 Hz, 1H), 7.68 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H), 5.16 (q,
J = 6.6, Hz, 1H), 1.63 (d, J = 6.6 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 3H),
0.06 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 167.9, 162.8,
151.5, 134.9, 128.9, 128.5, 125.9, 122.8, 72.6, 26.1, 23.7, 18.7,
ꢁ4.3, ꢁ4.7; IR (KBr cmꢁ1) 2974, 2929, 1613, 1558, 1485, 1376,
1306, 1264, 1132, 1104, 1034; MS (FAB) m/z 323 (MH+); HRMS
(FAB) calcd for C16H24ClN2OSi [MH+] 323.1346, found 323.1340;
4.6. General procedure for the Ni(0)-mediated coupling of
chloroquinazoline 7
To a solution of triphenyl phosphine (11 g, 42 mmol) in 30 mL
of DMF was added NiCl2ꢀ6H2O (2.85 g, 12 mmol) and heated to
50 °C under nitrogen atmosphere. After 5 min, zinc dust (15 mmol,
0,975 g) was added and the mixture was stirred for 1 h. Then, a
solution of 4-chloro-quinazoline 7 (10 mmol) in 5 mL of DMF
was injected into the mixture using a syringe. After stirring for
1–12 h, the mixture was cooled to room temperature, treated with
ammonia (50 mL, 28% in water), and the crude mixture was ex-
tracted with hexane (3 ꢂ 100 mL and washed with brine). The or-
ganic layer was dried with Na2SO4, the solvents were removed
under reduced pressure (20 °C, 15 mbar). The residue was chro-
matographed with silica gel column by eluting with hexane to give
triphenyl phosphine as the first fractions. Later fractions eluted
with EtOAc–hexane (5:95) afforded 8, 9 and 6, respectively.
½
a 2D0
ꢃ
¼ ꢁ83 (c 1.0, CH2Cl2).
4.5.2. (S)-2-(1-(tert-Butyldimethylsilyloxy)-2-methylpropyl)-4-
chloroquinazoline 7b
Colorless oil. Yield: 97%; 1H NMR (400 MHz, CDCl3, ppm) d 8.24
(ddd, J = 8.3, 1.4, 0.6 Hz, 1H), 8.05 (ddd, J = 8.5, 1.2, 0.6 Hz, 1H), 7.92
(ddd, J = 8.5, 7.0, 1.4 Hz, 1H), 7.67 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 4.63
(d, J = 7.0 Hz, 1H), 2.36–2.27 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.85 (s,
9H), 0.85 (d, J = 6.6 Hz, 3H), 0.01 (s, 3H), ꢁ0.11 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d 167.3, 162.6, 151.3, 134.8, 128.9, 128.5,
125.9, 122.7, 81.7, 34.6, 26.0, 19.5, 18.6, 18.2, ꢁ4.3, ꢁ4.7; IR (KBr
cmꢁ1) 2952, 2851, 1613, 1567, 1482, 1339, 1306, 1251, 1191,
1127, 1110, 1065; MS (FAB) m/z 351 (MH+); HRMS (FAB) calcd
4.6.1. 2,20-Bis-[1-(tert-Butyldimethylsilanyloxy)-ethyl]-[4,40]-
biquinazoline 8a
Crystallization from hexane gave colorless needles. Yield: 50%;
mp 146–147 °C; 1H NMR (400 MHz, CDCl3, ppm) d 8.17 (d,
J = 8.5 Hz, 2H), 7.96–7.90 (m, 2H), 7.89–7.85 (m, 2H), 7.57–7.48
(m, 2H), 5.32 (q, J = 6.5 Hz, 2H), 1.67 (d, J = 6.5 Hz, 6H), 0.92 (s,
18H), 0.11 (s, 6H), 0.10 (s, 6H); 13C NMR (100 MHz, CDCl3, ppm)
d 167.5, 164.2, 151.8, 134.4, 129.2, 128.0, 126.7, 122.4, 73.2, 26.1,
24.1, 18.7, ꢁ4.2, ꢁ4.5; IR (KBr cmꢁ1) 3467, 2924, 2851, 1611,
1561, 1488, 1367, 1253, 1096; Anal. Calcd for C32H46N4O2Si2: C,
66.85; H, 8.06; N, 9.75. Found: C, 67.23; H, 8.23; N, 9.74;
for C18H28ClN2OSi (MH+) 351.1659, found 351.1652; ½a 2D0
¼ ꢁ56
ꢃ
(c 3, CH2Cl2).
4.5.3. (S)-2-(1-(tert-butyldimethylsilyloxy)-2,2-dimethylpropyl)-
4-chloroquinazoline 7c
Colorless oil. Yield: 97%; 1H NMR (400 MHz, CDCl3, ppm) d 8.25
(dd, J = 8.2, 1.4 Hz, 1H), 8.05 (dd, J = 8.4, 1.2 Hz, 1H), 7.92 (ddd,
J = 8.4, 7.0, 1.4 Hz, 1H), 7.68 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 4.68
(s, 1H), 1.00 (s, 9H), 0.88 (s, 9H), ꢁ0.02 (s, 3H), ꢁ0.27 (s, 3H);
13C NMR (100 MHz, CDCl3, ppm) d 166.6, 161.6, 151.1, 134.6,
128.9, 128.5, 125.8, 122.6, 83.6, 37.0, 26.4, 26.0, 18.5, ꢁ4.5, ꢁ4.9;
IR (KBr cmꢁ1) 2952, 2851, 1619, 1569, 1549, 1476, 1359, 1334,
1306, 1244, 1104; MS (FAB) m/z 365 (MH+); HRMS (FAB) calcd
½
a 2D0
ꢃ
¼ þ70 (c 1.1, chloroform); ee: 99%; retention time: 7.1 min,
Chiralcel OD-H, n-hexane, flow rate of 1 mL/min, 265 nm.
4.6.2. 2,20-Bis-[(S)-1-(tert-Butyldimethylsilyloxy)-2-methylpro-
pyl]-4,40-biquinazoline 8b
Crystallization from hexane gave colorless needles. Yield: 48%;
mp 107–109 °C; 1H NMR (400 MHz, CDCl3, ppm) d 8.18 (d,
J = 8.2 Hz, 2H), 7.92 (ddd, J = 8.4, 6.9, 1.4 Hz, 2H), 7.84 (ddd,
J = 8.4, 1.2, 0.6 Hz, 2H), 7.51 (ddd, J = 8.2, 6.9, 1.2 Hz, 2H), 4.76 (d,
for C19H30ClN2OSi (MH+) 365.1816, found 365.1808; ½a 2D0
¼ ꢁ50
ꢃ
(c 0.6, CH2Cl2).

M. Catir et al. / Tetrahedron: Asymmetry 20 (2009) 2845–2853
2851
J = 7,5 Hz, 2H), 2.40–2.34 (m, 2H), 1.07 (d, J = 6,7 Hz, 6H), 0.88 (s,
18H), 0.87 (d, J = 6.7 Hz, 6H), 0.08 (s, 6H), ꢁ0.06 (s, 6H); 13C NMR
(100 MHz, CDCl3, ppm) d 166.9, 164.1, 151.6, 134.4, 129.2, 128.0,
126.7, 122.4, 82.5, 34.8, 22.6, 19.5, 18.7, 18.6, ꢁ4.1, ꢁ4.6; IR (KBr
cmꢁ1) 3067, 2926, 2851, 2711, 1725, 1615, 1560, 1467, 1383,
1255, 1069, 1006; Anal. Calcd for C36H54N4O2Si2: C, 68.52; H,
4.7.1. (1S,10S)-1,10-(4,40-Biquinazoline-2,20-diyl)diethanol 2a
Crystallization from a mixture of EtOAc–hexane gave colorless
needles. Yield: 95%; mp 171–173 °C; 1H NMR (400 MHz, CDCl3,
ppm) d 8.18 (d, J = 8.5 Hz, 2H), 8.01–7.97 (m, 2H), 7.86 (d, J = 8.5,
0.7 Hz, 2H), 7.59 (td, J = 5.8, 3.8 Hz, 2H), 5.25–5.19 (m, 2H), 4.41
(d, J = 5.2 Hz, 2H), 1.71 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz,
CDCl3, ppm) d 167.3, 164.1, 151.3, 135.1, 128.8, 128.4, 126.6,
122.4, 70.2, 23.5; IR (KBr cmꢁ1) 3467, 2974, 2929, 1613, 1558,
1485, 1376, 1306, 1264, 1104, 1034; Anal. Calcd for C20H18N4O2:
C, 69.35; H, 5.24; N, 16.20. Found: C, 69.21; H, 5.20; N, 16.20; MS
(FAB) m/z 347 (MH+); HRMS (FAB) calcd for C20H18N4O2 (MH+)
8.63; N, 8.88. Found: C, 68.35; H, 8.81; N, 8.93; ½a D20
¼ ꢁ49 (c 1,
ꢃ
EtOH); ee: 99%; retention time: 4.3 min, Chiralcel OD-H, n-hexane,
flow rate of 1 mL/min, 265 nm.
4.6.3. 2,20-Bis-((S)-1-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-
propyl)-4,40-biquinazoline 8c
347.1508, found 347.1504; ½a D20
¼ þ83 (c 1, chloroform); ee:
ꢃ
Crystallization from hexane gave colorless needles. Yield: 52%;
mp 101–103 °C; 1H NMR (400 MHz, CDCl3, ppm) d 8.18 (d,
J = 8.4 Hz, 2H), 7.95–7.84 (m, 2H), 7.51 (ddd, J = 8.2, 6.9, 1.1 Hz,
2H), 4.84 (s, 2H), 1.04 (s, 18H), 0.86 (s, 18H), 0.03 (s, 6H), ꢁ0.25
(s, 6H); 13C NMR (100 MHz, CDCl3, ppm) d 166.3, 163.5, 151.4,
134.1, 129.2, 127.7, 126.7, 122.2, 84.1, 37.1, 26.6, 26.1, 18.5,
ꢁ4.9, ꢁ5.0; IR (KBr cmꢁ1) 3064, 2969, 2927, 2851, 1723, 1615,
1560, 1473, 1362, 1251, 1100, 1032; Anal. Calcd for C38H58N4O2Si2:
C, 69.25; H, 8.87; N, 8.50. Found: C, 69.19; H, 8.87; N, 8.46;
98.5%; retention time: 19.1 min, Chiralcel OD-H, n-hexane–iPrOH,
90:10, flow rate of 1 mL/min, 265 nm.
4.7.2. (1S,10S)-1,10-(4,40-Biquinazoline-2,20-diyl)-bis-(2-methyl-
propan-1-ol) 2b
Crystallization from a mixture of dichloromethane–hexane gave
colorless needles. Yield: 95%; mp 146–148 °C; 1H NMR (400 MHz,
CDCl3, ppm) d 8.19 (d, J = 8.4 Hz, 2H), 7.99 (ddd, J = 8.4, 6.9,
1.4 Hz, 2H), 7.84–7.80 (m, 2H), 7.59 (ddd, J = 8.2, 6.9, 1.1 Hz, 2H),
4.96 (dd, J = 6.1, 3.4 Hz, 2H), 4.28 (d, J = 6.1 Hz, 2H), 2.48 (d sept.,
J = 6.9, 3.4 Hz, 2H), 1.18 (d, J = 6.9 Hz, 6H), 0.82 (d, J = 6.9 Hz, 6H);
13C NMR (100 MHz, CDCl3, ppm) d 166.1, 163.9, 151.0, 135.1,
½
a 2D0
ꢃ
¼ ꢁ87 (c 1, EtOH); retention time: 3.8 min, Chiralcel OD-H,
n-hexane, flow rate of 1 mL/min, 265 nm.
4.6.4. 2,20-Bis-((S)-(tert-Butyldimethylsilyloxy)(phenyl)methyl)-
4,40-biquinazoline (8d)
128.9, 128.4, 126.5, 122.3, 78.0, 34.2, 20.1, 15.7; IR (KBr cmꢁ1
)
3459, 3064, 2961, 2930, 2872, 1714, 1615, 1562, 1488, 1466,
1383, 1317, 1245, 1175, 1139, 1020; Anal. Calcd for C24H26N4O2:
C, 71.62; H, 6.51; N, 13.92. Found: C, 71.39; H, 6.45; N, 13.72;
MS (FAB) m/z 403 (MH+); HRMS (FAB) calcd for C24H26N4O2
Crystallization from ethanol gave colorless needles. Yield: 30%;
mp 138.5–140 °C; 1H NMR (400 MHz, CDCl3, ppm) d 8.17 (d,
J = 8.5 Hz, 2H), 7.91–7.85 (m, 2H), 7.77–7.74 (m, 2H), 7.66–7.63
(m, 4H), 7.41–7.28 (m, 8H), 6.26 (s, 2H), 0.94 (s, 18H), 0.10 (s,
6H), 0.09 (s, H); 13C NMR (100 MHz, CDCl3, ppm) d 165.9, 163.6,
152.0, 142.8, 134.1, 129.1, 128.3, 127.9, 127.5, 127.3, 126.9,
122.3, 78.9, 26.1, 18.7, ꢁ4.3, ꢁ4.5; IR (KBr cmꢁ1) 2928, 2851,
1611, 1560, 1541, 1488, 1356, 1306, 1255, 1219, 1127, 1099,
1065; Anal. Calcd for C42H50N4O2Si2: C, 72.16; H, 7.21; N, 8.01.
(MH+) 403.2134, found 403.2126; ½a 2D0
¼ ꢁ20 (c 1, EtOH); ee:
ꢃ
99%; retention time: 6.8 min, Chiralcel OD-H, n-hexane–iPrOH,
90:10, flow rate of 1 mL/min, 265 nm.
4.7.3. (1S,10S)-1,10-(4,40-Biquinazoline-2,20-diyl)-bis-(2,2-dim-
ethylpropan-1-ol) 2c
Found: C, 72.48; H, 7.46; N, 8.12 ½a D20
ꢃ
¼ ꢁ114 (c 1, EtOH); ee:
Crystallization from a mixture of dichloromethane–hexane gave
colorless needles. Yield: 95%; mp 209–211 °C; 1H NMR (400 MHz,
CDCl3, ppm) d 8.18 (d, J = 8.4 Hz, 2H), 7.97 (ddd, J = 8.4, 7.0,
1.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.56 (ddd, J = 8.4, 7.0, 1.1 Hz,
2H), 4.75 (d, J = 8.1 Hz, 2H), 4.22 (d, J = 8.1 Hz, 2H), 1.05 (s, 18H);
13C NMR (100 MHz, CDCl3, ppm) d 165.4, 163.1, 150.8, 134.9,
128.9, 128.3, 126.5, 122.3, 81.3, 37.3, 26.4; IR (KBr cmꢁ1) 3462,
3064, 2957, 2862, 1614, 1560, 1487, 1311, 1236, 1070, 1019; Anal.
Calcd for C26H30N4O2: C, 72.53; H, 7.02; N, 13.01. Found: C, 72.57;
H, 7.33; N, 12.97; MS (FAB) m/z 431 (MH+); HRMS (FAB) calcd for
99%, retention time: 7.4 min, Chiralcel OD-H, n-hexane, flow rate
of 1 mL/min, 265 nm.
4.6.5. 2,20-Bis-((S)-1-(tert-Butyldimethylsilyloxy)-2-phenylethyl)-
-4,40-biquinazoline 8e
Crystallization from ethanol gave colorless needles. Yield: 42%;
mp 140–141 °C; 1H NMR (400 MHz, CDCl3, ppm) d 8.23 (d,
J = 8.4 Hz, 2H), 8.03–7.87 (m, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.51 (t,
J = 7.6 Hz, 2H), 7.37–7.17 (m, 10H), 5.31 (dd, J = 9.1, 4.3 Hz, 2H),
3.36 (dd, A part of AB system, J = 13.3, 4.3 Hz, 2H), 3.23 (dd, B part
of AB system, J = 13.3, 9.1 Hz, 2H), 0.77 (s, 18H), ꢁ0.17 (s, 12H); 13C
NMR (100 MHz, CDCl3, ppm) d 166.7, 164.2, 151.9, 138.8, 134.5,
130.3, 129.2, 128.3, 128.1, 126.7, 126.5, 122.5, 78.9, 44.4, 26.0,
18.6, ꢁ4.7, ꢁ4.9; IR (KBr cmꢁ1) 3470, 2930, 2857, 2401, 1744,
1563, 1488, 1382, 1258, 1092; Anal. Calcd for C44H54N4O2Si2: C,
72.68; H, 7.49; N, 7.71. Found: C, 72.40; H, 7.64; N, 7.80;
C26H30N4O2 (MH+) 431.2447, found 431.2439; ½a 2D0
¼ ꢁ18 (c 1,
ꢃ
EtOH); ee: 99%; retention time: 9.3 min, Chiralcel OD-H, n-hex-
ane–iPrOH, 90:10, flow rate of 1 mL/min, 265 nm.
4.7.4. (1S,10S)-4,40-Biquinazoline-2,20-diyl-bis-(phenylmethanol)
2d
Crystallization from a mixture of dichloromethane–hexane gave
colorless needles. Yield: 48%; mp 223.5–225 °C; 1H NMR (400 MHz,
CDCl3, ppm) d 8.17 (d, J = 8.5 Hz, 2H), 7.94 (t, J = 7.7 Hz, 2H), 7.58 (d,
J = 6.8 Hz, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.42–7.31 (m, 8H), 6.12 (d,
J = 5.4 Hz, 2H), 5.28 (d, J = 5.4 Hz, 2H); 13C NMR (100 MHz, CDCl3,
ppm) d 164.8, 163.4, 151.2, 142.3, 134.9, 128.6, 128.6, 128.3,
128.0, 127.3, 127.2, 122.3, 75.8; IR (KBr cmꢁ1) 3725, 2918, 2862,
1734, 1611, 1541, 1558, 1507, 1485, 1451, 1306, 1230, 1054.
½
a 2D0
ꢃ
¼ þ56 (c 1, EtOH); retention time: 8.0 min, Chiralcel OD-H,
n-hexane–iPrOH, 98:02, flow rate of 1 mL/min, 265 nm.
4.7. General procedure for the desilylation of 8: synthesis of 2
To a solution (S,S)-8 (1 mmol) in 5 mL of THF was slowly added
tetrabutylammonium fluoride (3 mmol) in portions within 1 h at
room temperature. The reaction proceeding was monitored by
TLC. After the total conversion of the starting material the crude
mixture was diluted with NH4Cl (15 mL) and extracted with
dichloromethane (2 ꢂ 25 mL). The solvent was removed under
reduced pressure (15 mbar, 20 °C) and the residue was chromato-
graphed on a small silica gel column by eluting with EtOAc–hexane
(40:60) to give desilylated (S,S)-biquinazoline alcohol 2.
4.7.5. (1S,10S)-1,10-(4,40-Biquinazoline-2,20-diyl)bis(2-phenyl-
ethanol) 2e
Crystallization from a mixture of ethanol gave colorless needles.
Yield: 93%; mp 205–206 °C; 1H NMR (400 MHz, CDCl3, ppm) d 8.17
(d, J = 8.5 Hz, 2H), 8.02–7.92 (m, 2H), 7.59–7.51 (m, 4H), 7.28–7.19
(m, 10H), 5.42 (m, 2H), 4.34 (br s, 2H), 3.53 (dd, A part of AB

2852
M. Catir et al. / Tetrahedron: Asymmetry 20 (2009) 2845–2853
system, J = 13.8, 4.0 Hz, 2H), 3.27 (dd, B part of AB system, J = 13.8,
7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, ppm) d 165.6, 163.7, 151.2,
137.8, 135.0, 130.0, 128.8, 128.5, 128.3, 126.6, 126.5, 122.2, 74.5,
43.6; IR (KBr cmꢁ1) 3781, 3450, 3064, 3025, 1611, 1568, 1482,
1451, 1376, 1309, 1267, 1118, 1085; MS (FAB) m/z 499 (MH+);
HRMS (FAB) calcd for C32H27N4O2 (MH+) 499.2134, found
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499.2128; ½a 2D0
¼ ꢁ193 (c 1, chloroform); ee: 99%; retention time:
ꢃ
26.3 min, Chiralcel OD-H, n-hexane–iPrOH, 90:10, flow rate of
1 mL/min, 265 nm.
4.8. Typical procedure for the addition of phenylacetylene to
arylaldehyde
Phenylacetylene (2 mmol) and diethylzinc (2 mmol, 1.6 M in
hexane) were dissolved in dry THF (2 mL) and refluxed for 1 h and
cooled to room temperature under a nitrogen atmosphere. Then, a
suspension of chiral ligand 2 (0.1 mmol) and Ti(OiPr)4 (0.25 mmol)
in THF (2 mL) was added to the above solution and stirred at room
temperature for 1 h. The mixture was cooled to 0 °C and arylalde-
hyde (1 mmol in 1 mL THF) was added. After 20 h stirring at 0 °C
under a nitrogen atmosphere, the reaction was quenched with satu-
rated ammonium chloride solution, extracted with diethyl ether
(2 ꢂ 50 mL), washed with brine (2 ꢂ 25 mL), and dried with anhy-
drous Na2SO4. The solvent was removed under reduced pressure,
and the conversion and yield were determined by 1H NMR analysis
with 1,4-dimethoxybenzene as internal standard directly on the
crude mixture.
4.9. X-ray structure analysis
For the crystal structure determination, the single-crystal of
compound 2c was used for data collection on a four-circle Rigaku
R-AXIS RAPID-S diffractometer (equipped with a two-dimensional
area IP detector). The graphite-monochromatized Mo K
a
radiation
(k = 0.71073 Å) and oscillation scans technique with
D
x = 5° for
one image were used for data collection. The lattice parameters
were determined by the least-squares methods on the basis of all
reflections with F2 > 2 (F2). Integration of the intensities, correc-
r
tion for Lorentz and polarization effects and cell refinement was
performed using CrystalClear (Rigaku/MSC Inc., 2005) software.34
The structures were solved by direct methods using the program
SHELXS-9735 and refined by a full-matrix least-squares procedure
using the program SHELXL-97.35 The hydroxy H atom was positioned
with the AFIX 147 command (idealized hydroxy group, torsion
angle from electron density) and refined using a riding model.
The final difference Fourier maps showed no peaks of chemical sig-
nificance. Crystal data for 2c: C26H30N4O2, crystal system, space
group: orthorhombic, C2221; (no:20); unit cell dimensions:
a = 11.085(2), b = 21.440(3), c = 10.146(3) Å,
a = 90°, b = 90°,
10. Koyuncu, H.; Dogan, O. Org. Lett. 2007, 9, 3477–3479.
c
= 90°; volume: 2411.3(2) Å3; Z = 4; calculated density:
11. Han, Z.-J.; Wang, R.; Zhou, Y.-F.; Liu, L. Eur. J. Org. Chem. 2005, 934–938.
12. (a) Bolm, C.; Schlingloff, G.; Harms, K. Chem. Ber. 1992, 125, 1191–1203; (b)
Bolm, C.; Zehnder, M.; Bur, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 205–207; (c)
Kwong, H.-L.; Lee, W.-S. Tetrahedron: Asymmetry 1999, 10, 3791–3801.
13. Athanasellis, G.; Detsi, A.; Prousis, K.; Igglessi-Markopoulou, O.; Markopoulos,
J. Synthesis 2003, 2015–2022.
1.19 mg/m3; absorption coefficient: 0.076 mmꢁ1; F(0 0 0): 920; h
range for data collection 2.1–30.5°; refinement method: full-
matrix least-square on F2; data/parameters: 3712/148; goodness-
of-fit on F2: 1.017; final
R indices [I > 2r(I)]: R1 = 0.078,
14. Atkinson, R. S.; Ayscough, A. P.; Gattrell, W. T.; Raynham, T. M. J. Chem. Soc.,
Perkin Trans. 1 1998, 2783–2793.
wR2 = 0.166; R indices (all data): R1 = 0.178, wR2 = 0.212; largest
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