Synthesis and asymmetric catalytic activity of (1S,1′S)-4,4′- biquinazoline-based primary amines

Article abstract of DOI:10.1016/j.tetasy.2011.01.009

A series of (1S,1′S)-4,4′-biquinazoline-based primary amines were prepared from natural amino acids via a six-step reaction sequence of protection and condensation followed by key synthetic steps including chlorination, nickel(0)-mediated homocoupling, and deprotection. These novel amines were screened for the asymmetric ethylation of aryl aldehydes to yield alcohols with an (S)-configuration with enantiomeric excesses (ee) varying from 2% to 95%.

Full text of DOI:10.1016/j.tetasy.2011.01.009

Tetrahedron: Asymmetry 22 (2011) 300–308
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and asymmetric catalytic activity of
(1S,10S)-4,40-biquinazoline-based primary amines
Murat Cakici a, Mustafa Catir a,b, Semistan Karabuga c, Sabri Ulukanli d, Hamdullah Kilic a,
⇑
a Faculty of Sciences, Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey
b Faculty of Arts and Sciences, Department of Chemistry, Erzincan University, Erzincan, Turkey
c Faculty of Science and Letters, Department of Chemistry, Kilis 7 Aralık University, Kilis, Turkey
d Faculty of Science and Letters, Department of Chemistry, Osmaniye Korkut Ata University, Osmaniye, Turkey
a r t i c l e i n f o
a b s t r a c t
A series of (1S,10S)-4,40-biquinazoline-based primary amines were prepared from natural amino acids via
a six-step reaction sequence of protection and condensation followed by key synthetic steps including
chlorination, nickel(0)-mediated homocoupling, and deprotection. These novel amines were screened
for the asymmetric ethylation of aryl aldehydes to yield alcohols with an (S)-configuration with enantio-
meric excesses (ee) varying from 2% to 95%.
Article history:
Received 15 December 2010
Accepted 12 January 2011
Available online 4 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
R
R
R
R
1. Introduction
N
N
N
N
OH
OH
NH2
NH2
A variety of chiral secondary or tertiary amines1 have been
developed and received considerable attention in enantioselective
organocatalytic reactions; however, the use of primary amines as
organocatalysts has been neglected in the early 2000s. Presumably,
this negligence rests on the literature claim that primary amines
form unfavorable imine-enamines at equilibrium, which is signifi-
cantly shifted in favor of the latter in acyclic compounds. Following
the discovery that chiral primary amines2 are efficient asymmetric
catalysts for a variety of important reactions, remarkable progress
in this area has been made, and many chiral primary amine cata-
lysts have been developed for asymmetric transformations includ-
ing aldol reactions,3 Mannich reactions,4 Michael additions,5
amination reactions,6 and so on.
N
N
N
N
1a–d
2a–d
1a, 2a R = Me
1b, 2b R = iPr
1c, 2c R = t-Bu
1d, 2d R = Bn
Figure 1. Quinazoline-based organocatalysts.
Recently, we reported the efficient synthesis of (1S,10S)-biqui-
nazoline alcohols 1a–d from the corresponding amino acids, in
which we used an effective sequence of amidation, condensation,
chlorination, and nickel(0)-mediated homocoupling.7 The most
challenging aspect of the synthesis was developing a fast and sim-
ple protocol for the large-scale preparation of enantiomerically
pure biquinazoline alcohols 1a–d inexpensive starting materials.
Following this success, we anticipated that this protocol could be
extended to the synthesis of (1S,10S)-4,40-biquinazoline-based pri-
mary amines 2a–d Fig. 1 from (S)-amino acids. Herein, we report
the successful implementation of this strategy, resulting in the
synthesis of enantiomerically pure (1S,10S)-4,40-biquinazoline-
based primary amines 2a–d (Schemes 1 and 2) and the preliminary
results of their application as organocatalysts in a model reaction,
namely, the asymmetric addition reaction of diethylzinc to aryl
aldehydes
8
2. Results and Discussion
The ethyl chloroformate-mediated reaction9 of (S)-N-Boc-amino
acids 3a–e, readily available from the corresponding (S)-amino
acids, with 2-aminobenzamide 4 afforded condensation products
5a–e. The enantiomeric purities of amides 5a–d were determined
using an HLPC system equipped with a chiralyser, which showed
that amides 5a–d had enantiomeric purities of 99% and retained
their original (S)-configuration with no partial racemisation. On
the contrary, amide 5e, derived from (S)-N-Boc-phenylglycine 3e,
underwent complete racemisation [(0% enantiomeric excess (ee)]
under the reaction conditions. Thus, the synthesis of phenyl
⇑
Corresponding author. Tel.: +90 442 231 4426; fax: +90 442 236 0948.
E-mail address: hkilic@atauni.edu.tr (H. Kilic).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.009

M. Cakici et al. / Tetrahedron: Asymmetry 22 (2011) 300–308
301
O
NH2
O
O
Cl
N
NH2
NH2
4
+
NH
N
a
b
c
NH
NHBoc
NHBoc
O
N
R
O
R
R
R
OH
NHBoc
5a–e
6a–d
7a–d
NHBoc
3a–e
3a R = Me; 3b R = iPr;
3c R = t-Bu; 3d R = Bn;
3e R = Ph
Scheme 1. Synthesis of chloroquinazolines 7. Reagents and conditions: (a) EtOCOCl (1 equiv), NEt3 (1 equiv), 4 (1.5 equiv), room temperature (rt), THF; (b) 10 M NaOH, rt,
EtOH; (c) POCl3 (3 equiv), N,N-diethylaniline (2 equiv), 80 °C, benzene.
substituted derivative 2e was abandoned, and we continued with
amides 5a–d. To obtain quinazolinones 6a–d from the precursor
amides 5a–d, we used NaOH-mediated cyclisation.10 This one-
pot cyclization afforded quinazolinones 6a–d with excellent yields
(>95%). The quinazolinones 6a–d were characterized by elemental
analysis, IR, and NMR. Chiral HPLC analysis of 6a–d showed that
the enantiomeric purities were ꢀ99%. The chloroquinazolines 7a–
d were prepared by the chlorination10,11 of quinazolinones 6a–d
with phosphoryl chloride in the presence of N,N-diethyl aniline.
After short-column chromatography using silica gel, air-sensitive
chloroquinazolines 7a–d were obtained in high yields (95%). The
key step of the synthesis of 2a–d was the homocoupling12 of the
chloroquinazolines 7a–d mediated by Ni(0) generated from NiCl2
in the presence of PPh3, zinc dust, and Bu4NI in anhydrous THF.
Under the optimized conditions, in addition to the homocoupling
products 8a–d, the quinazolinones 6a–d and the reduction prod-
ucts 9a–d were also isolated in different ratios depending on the
substituent attached to the stereogenic center. After the products
were purified by silica gel column chromatography followed by
characterization using spectroscopic methods, deprotection of
8a–d with TFA gave the desired biquinazoline amines 2a–d.
After successfully synthesizing the above organocatalysts, we
tested the efficacy of 2a–d in an asymmetric reaction. The
addition of Et2Zn to aldehydes was considered as a model reaction
because it provides a good testing ground for ligand development
and optimization.8 Benzaldehyde was used as a model substrate
to test the reactivity (percent conversion of the aldehyde) and
enantioselectivity of catalysts 2a–d. The results obtained for the
catalysts are shown in Table 1. The substituted aldehydes used
are listed in Table 2. All examples of asymmetric ethylation of
benzaldehyde with 2a–d afforded alcohols with an (S)-configura-
tion. The results in Table 1 indicate that the reactivity of the
catalytic system, measured in terms of benzaldehyde conversion
at 0 °C, gave the following order for the solvents tested:
Et2O <DCM/hexane–toluene/hexane–THF/hexane–hexane (entries
1–8). From Table 1, it can be seen that ligands 2a,b and 2d gave
poor enantiomeric excesses (13%, 65%, and 34% ee, respectively,
Table 1, entries 1, 2, and 4), while ligand 2c achieved moderate
enantioselectivity under the same conditions (73% ee, entry 3).
Therefore, ligand 2c was chosen as the catalyst model for further
optimization of the conditions. The solvent played an important
role in the enantioselective process. A solvent mixture of THF/
hexane (2:1, v/v) gave the best result of 95% ee (Table 1, entry
5). The presence of hexane, DCM/hexane, or Et2O/hexane lowered
the ee value of the resulting alcohol (Table 1, entries 6, 7, and 8).
Therefore, THF/hexane (2:1, v/v) was selected as the reaction sol-
vent to establish other parameters of the reaction conditions such
as the effects of catalyst loading and temperature for ligand 2c.
Cl
N
N
NHBoc
R
7a–d
a
R
N
O
NHBoc
NHBoc
N
N
NH
N
+
+
NHBoc
NHBoc
N
N
R
R
N
R
6a 5%
8a 75%
8b 45%
8c 56%
8d 45%
9a 10%
9b 25%
9c 4%
6b 10%
6c 14%
6d 10%
9d 40%
b
2a–d
Scheme 2. Synthesis of biquinazoline amines 2. Reagents and conditions: (a) NiCl2 (0.6 equiv), PPh3 (2.4 equiv), Zn (1.5 equiv), Bu4NI (1 equiv), 70 °C, THF; (b) TFA (10 equiv),
room temperature (rt), DCM.

302
M. Cakici et al. / Tetrahedron: Asymmetry 22 (2011) 300–308
Table 1
Comparison of the electron-withdrawing-substituted aldehydes
and the electron-donating-substituted aldehydes showed that
electronic properties affected the conversion and enantioselectivi-
ty of the addition. Electron-donating-substituted aldehydes exhib-
ited lower reactivity compared with the electron-withdrawing-
substituted aldehydes. The addition of diethylzinc to benzaldehyde
gave the (S)-alcohols with poor to high enantioselectivity. The
ortho-electron-withdrawing substituents in the phenyl ring gave
lower ee values, varying from 2% to 27%, as shown in entries 2, 3,
and 5 in Table 2. However, 2-methylbenzaldehyde with a methyl
group at the ortho-position improved the ee value up to 68% in this
addition reaction (entry 4). The meta- and para-substituents on the
phenyl ring gave higher ee values, regardless of whether the sub-
stituent was electron-withdrawing or electron-donating (entries
Asymmetric addition of diethylzinc to benzaldehyde using 2a–d as catalystsa
OH
(1S,1'S)–2a–d
Ph CHO
Et2Zn
Ph
+
solvent
Entry
(S)-2 (%)
Solvent (2:1, v/v)
Convnb (%)
MBb,c (%)
eed (%)
1
2
3
4
5
6
7
8
2a (10)
2b (10)
2c (10)
2d (10)
2c (10)
2c (10)
2c (10)
2c (10)
2c (5)
Toluene/hexane
Toluene/hexane
Toluene/hexane
Toluene/hexane
THF/hexane
hexane
DCM/hexane
Et2O/hexane
THF/hexane
THF/hexane
THF/hexane
92
94
95
89
96
93
49
56
65
56
94
82
93
91
92
85
74
80
86
94
89
88
13
65
73
34
95
44
42
10
44
40
93
9
6–13). Ethylation of
a-naphthaldehyde and b-naphthaldehyde
10
2c (2.5)
2c (10)
11e
showed high enantioselectivities (91% and 93% ee, respectively)
(entries 14 and 15).
a
Reaction conditions: benzaldehyde (1 mmol), Et2Zn (3 mmol), 0 °C, 30 h, argon
atmosphere.
b
3. Conclusion
The conversions and mass balances (MBs) were assessed by GC on a b-DEX 120
column with diphenylmethane as an internal standard.
c
Mass balance refers to the sum of the yields of the characterized product (S)-1-
We have described a new type of catalyst that can be easily pre-
pared from the corresponding amino acid. To the best of our
knowledge, this is the first report of this type of catalyst applied
for the asymmetric ethylation of aromatic aldehydes. In the pres-
ence of 10 mol % of chiral catalyst 2c, the corresponding alcohols
with (S) configuration were obtained with poor to high levels of
enantioselectivity (up to 95% ee). Further investigation of the ef-
fects of catalysts 2a–d on the enantioselective process is currently
in progress.
phenylpropan-1-ol, benzyl alcohol and the recovered benzaldehyde.
d
Determined by GC on a b-DEX 120 column.
The recovered ligand 2c was reused in a subsequent cycle.
e
Table 2
Asymmetric addition of Et2Zn to aryl aldehydes catalyzed by ligand 2ca
OH
(1S,1'S)–2c
Et2Zn
ArCHO
+
Ar
(S)
4. Experimental
4.1. General
Entry
Aldehyde
C6H5CHO
o-ClC6H4CHO
o-BrC6H4CHO
o-MeC6H4CHO
o-MeOC6H4CHO
m-ClC6H4CHO
m-BrC6H4CHO
m-MeC6H4CHO
m-MeOC6H4CHO
p-ClC6H4CHO
p-BrC6H4CHO
p-MeC6H4CHO
p-MeOC6H4CHO
Convnb (%)
MBb (%)
eec (%)
1
2
3
4
5
6
7
8
96
99
99
63
69
95
99
90
98
98
98
80
50
90
99
85
91
93
77
75
86
86
89
86
93
96
79
93
92
87
95
27
02
68
05
94
95
94
92
94
85
88
87
91
93
Reagents and solvents were purchased from standard chemical
suppliers and purified to match the reported physical and spectro-
scopic data. Tetrahydrofuran (THF) was distilled prior to use from
sodium benzophenone ketyl under argon. Solvents were concen-
trated at reduced pressure (ca. 20 °C, 20 Torr). Melting points were
determined with a Gallenkamp apparatus. IR spectra were ob-
tained on KBr pellets with a Perkin–Elmer apparatus. 1H and 13C
NMR spectra were recorded on a Varian (400) spectrometer. Enan-
tiomeric excesses (ee) were determined by chiral GC analysis using
Supelco beta-DEX 120 column, 30 m length, 0.25 mm inner diam-
eter. 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. All column chromatography was
performed on silica gel. Radial chromatography was performed
on a Harrison Research Chromatotron by using plates coated with
Merck Kieselgel 60 PF254. Air- and moisture-sensitive reactions
were conducted in flame-dried or oven dried glassware equipped
with tightly fitted rubber septa and under a positive atmosphere
of dry argon. Reagents and solvents were handled using standard
syringe techniques.
9
10
11
12
13
14
15
a
-Naphthaldehyde
b-Naphthaldehyde
a
Reaction conditions: aldehyde (1 mmol), catalyst 1c (0.1 mmol), Et2Zn
(3 mmol); THF/hexane (2:1, v/v); 0 °C; 30 h.
The conversions and mass balances (MBs) were assessed by 1H NMR analysis
b
with diphenylmethane as an internal standard.
c
Determined by GC on a b-DEX 120 column.
No reaction was observed when the temperature of the reaction
was decreased from 0 °C to ꢁ20 °C (data not shown). Loadings
of less than 10 mol % for catalyst 2c decreased both the conversion
and ee (entries 9 and 10). The recovered ligand 2c was reused in a
subsequent cycle as the catalyst in the ethylation of benzalde-
hyde, giving the same results as a freshly prepared catalyst with
no obvious decrease in yield or ee value (entry 11).
To study the scope and limitations of ligand 2c as a catalyst, a
set of aryl aldehydes with electron-donating and electron-
withdrawing substituents were examined under the optimized
conditions specified in Table 1, entry 5. The results are presented
in Table 2. Excellent mass balances were obtained from the cata-
lytic reaction, and the products were substituted (S)-1-phenylpro-
pan-1-ol, substituted benzyl alcohol, and unreacted aldehyde.
4.2. General procedure for the N-Boc-amino acid 3
At first, Na2CO3 (166.8 mmol) and Boc2O (91.7 mmol) were
added to a solution of the appropriate amino acid (83.4 mmol) in
H2O/THF (110 mL) (10:1) at 0 °C. The resulting mixture was stirred
at room temperature for 12 h, and acidified by HCl (10%) until pH 2
was reached. The mixture was then extracted with EtOAc
(3 ꢂ 100 mL), washed with brine, and dried over Na2SO4. After re-
moval of the solvents under reduced pressure, the crude N-Boc-
amino acid 3 was obtained in a yield of 95–99%.

M. Cakici et al. / Tetrahedron: Asymmetry 22 (2011) 300–308
303
4.2.1. (S)-2-(tert-Butoxycarbonylamino)propanoic acid 3a
White solid. Yield: 95%; mp 79–81 °C; 1H NMR (400 MHz,
DMSO-d6, ppm) d 12.35 (br s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 3.90 (p,
J = 7.5 Hz, 1H), 1.35 (s, 9H), 1.19 (d, J = 7.5 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6, ppm) d 175.3, 155.9, 78.5, 49.4, 28.8, 17.7;
IR (KBr, cmꢁ1) 3384, 2989, 1732, 1692, 1520, 1456, 1373, 1294,
13.67. Found: C, 58.66; H, 6.85; N, 13.66; ½a D20
ꢃ
¼ ꢁ66:3 (c 1, EtOH);
ee: 99%; retention time: 18.6 min, Chiralcel OD-H, n-hexane/i-
PrOH, 90:10, flow rate of 1 mL/min, 254 nm.
4.3.2. (S)-tert-Butyl 1-(2-carbamoylphenylamino)-3-methyl-1-
oxobutan-2-ylcarbamate 5b
1234, 1165; ½a 2D0
ꢃ
¼ ꢁ26 (c 2, AcOH); ee: 99%.
Crystallization from a mixture of hexane/DCM gave a white so-
lid. Yield: 77%; mp 115–117 °C; Rf 0.28 (hexane/EtOAc (1:1)); 1H
NMR (400 MHz, DMSO-d6, ppm) d 11.92 (br s, 1H), 8.50 (d,
J = 8.0 Hz, 1H), 8.20 (br s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.59 (br s,
1H), 7.50–7.39 (m, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.18–7.01 (m,
1H), 3.74 (t, J = 6.5 Hz, 1H), 2.28–2.02 (m, 1H), 1.38 (s, 9H), 0.89
(d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6, ppm) d 171.4, 171.0, 156.6, 139.9, 132.7, 129.2, 123.0,
4.2.2. (S)-2-(tert-Butoxycarbonylamino)-3-methylbutanoic acid
3b
White solid. Yield: 97%; mp 77–80 °C; 1H NMR (400 MHz,
DMSO-d6, ppm) d 12.45 (br s, 1H), 6.92 (d, J = 8.6 Hz, 1H), 3.76
(dd, J = 8.6, 6.1 Hz, 1H), 2.06–1.90 (m, 1H), 1.36 (s, 9H), 0.85 (d,
J = 6.5 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6, ppm) d 174.1, 156.4, 78.6, 59.7, 30.2, 28.8, 19.8, 18.8;
IR (KBr, cmꢁ1) 3330, 2971, 2935, 1715, 1660, 1512, 1396, 1369,
120.7, 120.6, 78.9, 62.6, 30.2, 28.9, 19.8, 18.7; IR (KBr cmꢁ1
)
3410, 3341, 3214, 2965, 2933, 1673, 1624, 1521, 1452, 1392,
1282, 1240, 1172, 1044; Anal. Calcd for C17H25N3O4: C, 60.88; H,
1163; ½a 2D0
¼ ꢁ6 (c 1, AcOH); ee: 99%.
ꢃ
7.51; N, 12.53. Found: C, 60.88; H, 7.54; N, 12.46; ½a D20
¼ ꢁ62:0
ꢃ
4.2.3. (S)-2-(tert-Butoxycarbonylamino)-3,3-dimethylbutanoic
acid 3c
(c 1, EtOH); ee: 99%; retention time: 11.2 min, Chiralcel OD-H, n-
hexane/i-PrOH, 90:10, flow rate of 1 mL/min, 254 nm.
White solid. Yield: 99%; mp 118–121 °C; 1H NMR (400 MHz,
DMSO-d6, ppm) d 12.44 (br s, 1H), 6.81 (d, J = 8.9 Hz, 1H), 3.73 (d,
J = 8.9 Hz, 1H), 1.36 (s, 9H), 0.91 (s, 9H); 13C NMR (100 MHz,
DMSO-d6, ppm) d 173.5, 156.3, 78.7, 62.9, 33.8, 28.8, 27.3; IR
(KBr, cmꢁ1) 3374, 2980, 2940, 1748, 1724, 1662, 1536, 1397,
4.3.3. (S)-tert-Butyl 1-(2-carbamoylphenylamino)-3,3-dimethyl-
1-oxobutan-2-ylcarbamate 5c
Crystallization from a mixture of hexane/DCM gave a white so-
lid. Yield: 49%; mp 133–134 °C; Rf 0.33 (hexane/EtOAc (1:1)); 1H
NMR (400 MHz, DMSO-d6, ppm) d 11.91 (br s, 1H), 8.48 (d,
J = 8.3 Hz, 1H), 8.22 (br s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.64 (br s,
1H), 7.46 (t, J = 7.8 Hz, 1H), 7.11–7.07 (m, 2H), 3.67 (d, J = 7.3 Hz,
1H), 1.37 (s, 9H), 0.97 (s, 9H); 13C NMR (100 MHz, DMSO-d6,
ppm) d 171.2, 170.5, 156.4, 139.9, 132.8, 129.2, 123.0, 120.6,
120.4, 79.0, 65.8, 34.2, 28.8, 27.5; IR (KBr cmꢁ1) 3357, 3185,
2979, 2933, 1690, 1617, 1513, 1449, 1367, 1247, 1168, 1054; Anal.
Calcd for C18H27N3O4: C, 61.87; H, 7.79; N, 12.03. Found: C, 61.83;
1368, 1159; ½a 2D0
¼ ꢁ4 (c 1, AcOH); ee: 99%.
ꢃ
4.2.4. (S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanoic
acid 3d
White solid. Yield: 99%; mp 87–89 °C; 1H NMR (400 MHz,
DMSO-d6, ppm) d 12.59 (br s, 1H), 7.37–7.14 (m, 5H), 7.09 (d,
J = 8.5 Hz, 1H), 4.07 (ddd, J = 10.4, 8.5, 4.5 Hz, 1H), 3.00 (dd,
J = 13.8, 4.5 Hz, A part of AB system, 1H), 2.80 (dd, J = 13.8,
10.4 Hz,
B
part of AB system, 1H), 1.30 (s, 9H); 13C NMR
H, 7.93; N, 11.95; ½aꢃD ¼ ꢁ43:0 (c 1, EtOH); ee: 99%; retention time:
(100 MHz, DMSO-d6, ppm) d 174.2, 156.1, 138.7, 129.7, 128.7,
8.7 min, Chiralcel OD-H, n-hexane/i-PrOH, 90:10, flow rate of 1 mL/
126.9, 78.6, 55.8, 37.1, 28.8; IR (KBr, cmꢁ1) 3419, 3332, 2979,
min, 254 nm.
2930, 1717, 1648, 1499, 1404, 1369, 1165, 1056; ½a D20
¼ þ26 (c 1,
ꢃ
EtOH); ee: 99%.
4.3.4. (S)-tert-Butyl 1-(2-carbamoylphenylamino)-1-oxo-3-
phenylpropan-2-ylcarbamate 5d
4.3. General procedure for the amide 5
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 76%; mp 174–175 °C; Rf 0.25 (hexane/EtOAc (1:1)); 1H
NMR (400 MHz, DMSO-d6, ppm) d 12.07 (br s, 1H), 8.52 (d,
J = 8.3 Hz, 1H), 8.18 (br s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.59 (br s,
1H), 7.48 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.28–7.24 (m,
4H), 7.22–7.14 (m, 1H), 7.11 (t, J = 7.7 Hz, 1H), 4.89–3.54 (m, 1H),
3.16 (dd, J = 13.7, 4.0 Hz, A part of AB system, 1H), 2.86 (dd,
J = 13.7, 10.8 Hz, B part of AB system, 1H), 1.31 (s, 9H); 13C NMR
(100 MHz, DMSO-d6, ppm) d 171.5, 171.0, 156.1, 139.9, 139.0,
132.7, 129.7, 129.2, 128.8, 126.9, 123.1, 120.7, 120.6, 79.0, 58.4,
37.3, 28.8; IR (KBr cmꢁ1) 3420, 3347, 2980, 2930, 1699, 1628,
1589, 1503, 1449, 1389, 1297, 1251, 1159, 1048; Anal. Calcd for
To a solution of N-Boc-amino acid 3 (63.5 mmol) in THF
(100 mL) at 0 °C were added triethylamine (63.5 mmol) and ethyl
chloroformate (63.5 mmol) over a period of ca. 10 min, and the
reaction mixture was stired for 30 min. After the addition of the
2-aminobenzamide 4 (95.25 mmol), the mixture was stirred for
an additional 1 h at 0 °C. Then, the reaction mixture was warmed
to room temperature, and kept stirring overnight. After the solvent
was evaporated under reduced pressure, the residue was dissolved
in EtOAc (150 mL) and washed with 3 M HCl (2 ꢂ 100 mL), and
brine (100 mL). The organic layer was dried over Na2SO4 and the
solvent was evaporated under reduced pressure (20 mbar, 20 °C).
Crystallization of crude mixture gave the corresponding amide 5.
C
21H25N3O4: C, 65.78; H, 6.57; N, 10.96. Found: C, 65.68; H, 6.65;
N, 11.05; ½a 2D0
¼ ꢁ48:0 (c 1, EtOH); ee: 99%; retention time:
ꢃ
30.8 min, Chiralcel OD-H, n-hexane/i-PrOH, 90:10, flow rate of
4.3.1. (S)-tert-Butyl 1-(2-carbamoylphenylamino)-1-oxopropan-
2-ylcarbamate 5a
1 mL/min, 254 nm.
Crystallization from a mixture of hexane/DCM gave a white so-
lid. Yield: 87%; mp 107–109 °C; Rf 0.13 (hexane/EtOAc (1:1)); 1H
NMR (400 MHz, DMSO-d6, ppm) d 12.00 (br s, 1H), 8.52 (d,
J = 8.4 Hz, 1H), 8.19 (br s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.58 (br s,
1H), 7.53–7.39 (m, 2H), 7.18–7.02 (m, 1H), 3.95–3.91 (m, 1H),
1.39 (s, 9H), 1.27 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, DMSO-
d6, ppm) d 172.7, 171.0, 156.0, 140.1, 132.7, 129.2, 122.9, 120.6,
120.5, 79.0, 52.3, 28.9, 18.0; IR (KBr cmꢁ1) 3417, 3331, 3225,
2978, 2934, 1692, 1627, 1586, 1504, 1450, 1391, 1293, 1249,
1163, 1062; Anal. Calcd for C15H21N3O4: C, 58.62; H, 6.89; N,
4.3.5. (S)-tert-Butyl 2-(2-carbamoylphenylamino)-2-oxo-1-
phenylethylcarbamate 5e
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 55%; mp 131–133 °C; Rf 0.23 (hexane/EtOAc (1:1)); 1H
NMR (400 MHz, DMSO-d6, ppm) d 12.23 (br s, 1H), 8.45 (d,
J = 8.4 Hz, 1H), 8.24 (br s, 1H), 7.87–7.75 (m, 2H), 7.69 (br s, 1H),
7.53–7.37 (m, 3H), 7.38–7.24 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 5.11
(d, J = 6.8 Hz, 1H), 1.38 (s, 9H); 13C NMR (100 MHz, DMSO-d6,
ppm) d 171.1, 170.0, 156.0, 140.1, 138.1, 132.9, 129.2, 129.0,
128.6, 128.5, 123.1, 120.4, 120.2, 79.3, 61.1, 28.8; IR (KBr cmꢁ1
)

304
M. Cakici et al. / Tetrahedron: Asymmetry 22 (2011) 300–308
3427, 3315, 3070, 2979, 1660, 1619, 1585, 1523, 1453, 1391, 1368,
1228, 1246, 1166; Anal. Calcd for C20H23N3O4: C, 65.03; H, 6.28; N,
11.37. Found: C, 65.25; H, 6.35; N, 11.26; ee: 0%; retention time:
21.3 and 24.6 min, Chiralcel OD-H, n-hexane/i-PrOH, 90:10, flow
rate of 1 mL/min, 254 nm.
4.4.4. (S)-tert-Butyl 1-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-
phenylethylcarbamate 6d
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 98%; mp 223–225 °C; Rf 0.39 (hexane/EtOAc/2:1); 1H
NMR (400 MHz, CDCl3, ppm) d 11.22 (br s, 1H), 8.30 (d, J = 7.7 Hz,
1H), 7.79 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.50 (t,
J = 7.1 Hz, 1H), 7.33–7.09 (m, 5H), 5.52 (br s, 1H), 5.05–4.82 (m,
1H), 3.35 (dd, J = 13.9, 5.6 Hz, A part of AB system, 1H), 3.27–3.13
(m, 1H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) d 163.1,
155.5, 149.0, 136.3, 134.9, 129.5, 128.8, 127.7, 127.2, 127.0,
126.7, 121.3, 80.7, 55.4, 40.0, 28.4; IR (KBr, cmꢁ1) 3360, 3175,
3029, 2980, 2918, 1702, 1685, 1611, 1519, 1468, 1366, 1337,
1243, 1170, 1048; Anal. Calcd for C21H23N3O3: C, 69.02; H, 6.34;
4.4. General procedure for the preparation of 6
To a solution of amide 5 (60 mmol) in 100 mL of ethanol at
0 °C was added freshly prepared 10 M NaOH (240 mmol) drop-
wise over 5 min. The mixture was then stirred for 30 min at room
temperature and re-cooled to 0 °C and neutralized with concen-
trated 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. Crystallization from hexane/EtOAc afforded quinaz-
olinone 6.
N, 11.50. Found: C, 68.87; H, 6.30; N, 11.42; ½a D20
¼ ꢁ41:0 (c 1,
ꢃ
DCM); ee: 99%; retention time: 22.3 min, Chiralcel OD-H, n-hex-
ane/i-PrOH, 90:10, flow rate of 1 mL/min, 254 nm.
4.5. General procedure for the preparation of 4-chloro-
quinazolines 7
4.4.1. (S)-tert-Butyl 1-(4-oxo-3,4-dihydroquinazolin-2-yl)-
ethylcarbamate 6a
To a solution of quinazolinone 6 (5.2 mmol) in dry benzene
(25 mL) were added PhNEt2 (10.4 mmol) followed by POCl3
(15.6 mmol) at 0 °C. The reaction mixture was then refluxed for
30 min, 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 pres-
sure (20 °C, 15 mbar). Purification by column chromatography (sil-
ica gel, hexane/EtOAc, 80:20) gave 4-chloroquinazoline 7 in a yield
of ca. 95%.
Crystallization from a mixture of hexane/EtOAc gave a white
solid. Yield: 95%; mp 196–197 °C; Rf 0.20 (hexane/EtOAc (2:1));
1H NMR (400 MHz, CDCl3, ppm) d 11.76 (br s, 1H), 8.30 (d,
J = 7.9 Hz, 1H), 7.81–7.73 (m, 1H), 7.73–7.68 (m, 1H), 7.52–7.40
(m, 1H), 5.69 (br s, 1H), 5.00–4.69 (m, 1H), 1.61 (d, J = 7.0 Hz,
3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) d 163.7, 156.9,
155.7, 149.0, 134.9, 127.7, 126.9, 126.6, 121.2, 80.6, 50.0, 28.5,
20.1; IR (KBr, cmꢁ1) 3358, 3182, 3134, 2981, 2932, 1691, 1612,
1513, 1449, 1367, 1327, 1247, 1168, 1055; Anal. Calcd for
C
15H19N3O3: C, 62.27; H, 6.62; N, 14.52. found: C, 61.91; H, 6.68;
N, 14.32; ½a 2D0
¼ ꢁ58:0 (c 1, EtOH); ee: 99% retention time:
ꢃ
19.1 min, Chiralcel OD-H, n-hexane/i-PrOH, 90:10, flow rate of
4.5.1. (S)-tert-Butyl 1-(4-chloroquinazolin-2-yl)ethylcarbamate
7a
1 mL/min, 254 nm.
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 95%; mp 80–82 °C; Rf 0.50 (hexane/EtOAc (4:1)); 1H NMR
(400 MHz, CDCl3, ppm) d 8.23 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 8.4 Hz,
1H), 7.93 (t, J = 7.7 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 5.84 (br s, 1H),
5.15–4.99 (m, 1H), 1.58 (d, J = 6.9 Hz, 3H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3, ppm) d 166.1, 163.1, 155.4, 151.3, 135.1, 128.7,
128.6, 126.0, 122.7, 79.6, 52.5, 28.6, 22.0; IR (KBr, cmꢁ1) 3425,
3347, 2977, 2931, 1715, 1616, 1572, 1483, 1459, 1366, 1251,
1167, 1052; Anal. Calcd for C15H18ClN3O2: C, 58.54; H, 5.89; N,
4.4.2. (S)-tert-Bttyl 2-methyl-1-(4-oxo-3,4-dihydroquinazolin-2-
yl)propylcarbamate 6b
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 95%; mp 145–147 °C; Rf 0.40 (hexane/EtOAc (2:1)); 1H
NMR (400 MHz, CDCl3, ppm) d 11.90 (br s, 1H), 8.31 (dd, J = 8.0,
1.0 Hz, 1H), 7.80–7.74 (m, 1H), 7.74–7.71 (m, 1H), 7.48 (t,
J = 7.4 Hz, 1H), 5.75 (br s, 1H), 4.65–4.56 (m, 1H), 2.38–2.28 (m,
1H), 1.41 (s, 9H), 1.04 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.2 Hz, 3H);
13C NMR (100 MHz, CDCl3, ppm) d 163.8, 156.0, 155.9, 149.1,
134.9, 127.7, 126.8, 126.6, 121.0, 80.2, 59.7, 32.6, 28.5, 19.8, 18.0;
IR (KBr, cmꢁ1) 3379, 3177, 3132, 2975, 2929, 1689, 1613, 1512,
1469, 1366, 1334, 1236, 1167, 1087; Anal. Calcd for C17H23N3O3:
C, 64.33; H, 7.30; N, 13.24. Found: C, 64.60; H, 7.44; N, 13.18;
13.65. Found: C, 58.64; H, 5.90; N, 13.70; ½a D20
¼ ꢁ54:1 (c 1.6,
ꢃ
DCM).
4.5.2. (S)-tert-Butyl 1-(4-chloroquinazolin-2-yl)-2-
methylpropylcarbamate 7b
½
a 2D0
ꢃ
¼ ꢁ69:0 (c 1, EtOH); ee: 99%; retention time: 6.5 min,
Colorless oil. Yield: 95%; Rf 0.60 (hexane/EtOAc (4:1)); 1H NMR
(400 MHz, CDCl3, ppm) d 8.23 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.5 Hz,
1H), 7.93 (t, J = 7.5 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 5.68 (d,
J = 8.9 Hz, 1H), 4.93 (dd, J = 8.9, 5.2 Hz, 1H), 2.48–2.21 (m, 1H),
1.45 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3, ppm) d 165.1, 162.6, 156.0, 151.1, 135.0,
128.8, 128.6, 125.9, 122.6, 79.4, 61.3, 33.8, 28.6, 19.9, 17.5; IR
(KBr, cmꢁ1) 3439, 3365, 2967, 2931, 1714, 1616, 1571, 1499,
Chiralcel OD-H, n-hexane/i-PrOH, 90:10, flow rate of 1 mL/min,
254 nm.
4.4.3. (S)-tert-butyl 2,2-dimethyl-1-(4-oxo-3,4-dihydro-
quinazolin-2-yl)propylcarbamate 6c
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 99%; mp 93–95 °C; Rf 0.50 (hexane/EtOAc (2:1)); 1H NMR
(400 MHz, CDCl3, ppm) d 11.96 (br s, 1H), 8.33 (d, J = 7.8 Hz, 1H),
7.88–7.66 (m, 2H), 7.48 (t, J = 6.9 Hz, 1H), 5.97 (d, J = 8.9 Hz, 1H),
4.60 (d, J = 8.9 Hz, 1H), 1.38 (s, 9H), 1.08 (s, 9H); 13C NMR
(100 MHz, CDCl3, ppm) d 163.7, 155.8, 155.0, 149.0, 134.8, 127.8,
1482, 1390, 1366, 1303, 1250, 1171; ½a D20
¼ ꢁ52:9 (c 1.1, DCM).
ꢃ
4.5.3. (S)-tert-Butyl 1-(4-chloroquinazolin-2-yl)-2,2-dimethyl-
propylcarbamate 7c
Colorless oil. Yield: 95%; Rf 0.65 (hexane/EtOAc (4:1)); 1H NMR
(400 MHz, DMSO-d6, ppm) d 8.10 (d, J = 7.8 Hz, 1H), 7.89–7.73 (m,
2H), 7.54 (t, J = 7.5 Hz, 1H), 7.08 (br s, 1H), 4.53 (d, J = 7.8 Hz, 1H),
1.34 (s, 9H), 0.96 (s, 9H); 13C NMR (100 MHz, DMSO-d6, ppm) d
161.4, 158.1, 155.9, 145.8, 135.6, 127.8, 126.7, 125.6, 121.3, 79.4,
61.7, 35.9, 28.7, 27.1; IR (KBr, cmꢁ1) 3442, 3402, 2969, 2866,
126.8, 126.6, 121.0, 80.0, 62.2, 36.0, 28.5, 26.9; IR (KBr, cmꢁ1
)
3397, 3181, 3135, 2973, 2932, 1671, 1611, 1499, 1469, 1367,
1336, 1240, 1169, 1057; Anal. Calcd for C18H25N3O3: C, 65.23; H,
7.60; N, 12.68. Found: C, 65.58; H, 7.78; N, 12.61; ½a D20
¼ ꢁ91:0
ꢃ
(c 1, DCM); ee: 99%; retention time: 7.8 min, Chiralcel OD-H, n-
hexane/i-PrOH, 90:10, flow rate of 0.6 mL/min, 254 nm.

M. Cakici et al. / Tetrahedron: Asymmetry 22 (2011) 300–308
305
1715, 1616, 1568, 1557, 1498, 1481, 1366, 1307, 1251, 1171, 1057;
¼ ꢁ53:4 (c 1.1, DCM).
4.6.3. tert-Butyl (1S,10S)-1,10-(4,40-biquinazoline-2,20-
diyl)bis(2,2-dimethylpropane-1,1-diyl)dicarbamate 8c
½ ꢃ
a 2D0
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 56%; mp 109–111 °C; Rf 0.64 (hexane/EtOAc (2:1)); 1H
NMR (400 MHz, DMSO-d6, ppm) d 8.16 (d, J = 8.5 Hz, 2H), 8.06 (t,
J = 7.6 Hz, 2H), 7.74–7.54 (m, 4H), 6.94 (d, J = 9.0 Hz, 2H), 4.76 (d,
J = 9.0 Hz, 2H), 1.30 (s, 18H), 0.97 (s, 18H); 13C NMR (100 MHz,
DMSO-d6, ppm) d 165.0, 163.7, 156.2, 150.9, 135.7, 129.0, 128.8,
126.8, 121.9, 78.6, 65.5, 36.0, 28.8, 27.5; IR (KBr, cmꢁ1) 3443,
2970, 1720, 1616, 1561, 1497, 1455, 1367, 1329, 1230, 1170,
1058; Anal. Calcd for C36H48N6O4: C, 68.76; H, 7.69; N, 13.37.
4.5.4. (S)-tert-Butyl 1-(4-chloroquinazolin-2-yl)-2-phenyl-
ethylcarbamate 7d
Colorless oil. Yield: 95%; Rf 0.56 (hexane/EtOAc (4:1)); 1H NMR
(400 MHz, CDCl3, ppm) d 8.24 (d, J = 8.3 Hz, 1H), 8.02–7.86 (m, 2H),
7.69 (t, J = 7.2 Hz, 1H), 7.24–7.08 (m, 3H), 7.03–6.97 (m, 2H), 5.71
(d, J = 7.3 Hz, 1H), 5.37–5.30 (m, 1H), 3.44 (dd, J = 13.6, 5.2 Hz, A
part of AB system, 1H), 3.25 (dd, J = 13.6, 6.7 Hz, B part of AB sys-
tem, 1H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) d 164.5,
162.9, 155.4, 151.1, 137.0, 135.1, 129.7, 128.7, 128.7, 128.3,
126.6, 126.0, 122.6, 79.6, 57.3, 41.1, 28.6; IR (KBr, cmꢁ1) 3425,
3348, 3028, 2976, 2930, 1712, 1615, 1571, 1496, 1483, 1457,
Found: C, 68.26; H, 7.74; N, 13.22; ½a D20
¼ ꢁ36:5 (c 1, EtOH); ee:
ꢃ
99%; retention time: 6.9 min, Chiralcel OD-H, n-hexane/i-PrOH,
90:10, flow rate of 0.6 mL/min, 254 nm.
1390, 1366, 1309, 1252, 1168, 1052; ½a D20
¼ ꢁ46:5 (c 1.3, DCM).
ꢃ
4.6.4. tert-Butyl (1S,10S)-1,10-(4,40-biquinazoline-2,20-diyl)bis(2-
phenylethane-1,1-diyl)dicarbamate 8d
4.6. General procedure for the Ni(0)-mediated coupling of
chloroquinazoline 7
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 45%; mp 235–236 °C; Rf 0.47 (hexane/EtOAc (2:1)); 1H
NMR (400 MHz, CDCl3, ppm) d 8.11 (d, J = 8.3 Hz, 2H), 7.93 (m,
2H), 7.49 (m, 4H), 7.18 (m, 6H), 7.01 (m, 4H), 5.85 (br s, 2H),
5.56–5.44 (m, 2H), 3.56–3.41 (m, 2H), 3.42–3.24 (m, 2H), 1.43 (s,
18H); 13C NMR (100 MHz, CDCl3, ppm) d 164.1, 163.6, 155.4,
151.6, 137.3, 134.6, 129.9, 128.9, 128.4, 128.2, 126.7, 126.5,
122.1, 79.5, 57.6, 57.6, 41.6, 28.6; IR (KBr, cmꢁ1) 3377, 3061,
3027, 2980, 2933, 1692, 1613, 1557, 1524, 1494, 1452, 1390,
1340, 1249, 1170, 1046; Anal. Calcd for C42H44N6O4: C, 72.39; H,
Zinc powder (4.88 mmol) was added to a stirred solution of
NiCl2ꢄ6H2O (1.95 mmol), triphenyl phosphine (7.8 mmol), and
Bu4NI (3.25 mmol) in 10 mL of dry THF under an argon atmosphere
and heated to 70 °C. After stirring for 1 h, a solution of 4-chloroqui-
nazoline 7 (3.25 mmol) in 5 mL of dry THF was injected into the
mixture using a syringe. After stirring for 12 h, the mixture was
cooled to room temperature, treated with ammonia (50 mL, 28%
in water), and the crude mixture was extracted with EtOAc
(3 ꢂ 100 mL). The organic layer was washed with brine, dried over
Na2SO4, and the solvent was removed under reduced pressure
(20 °C, 15 mbar). The residue was chromatographed with silica
gel column by eluting with hexane to give triphenyl phosphine
as the first fractions. Later fractions were eluted with EtOAc/hex-
ane (1:4) to afford 8, 9, and 6, respectively.
6.36; N, 12.06. Found: C, 72.04; H, 6.29; N, 12.01; ½a D20
¼ ꢁ109:0
ꢃ
(c 1, DCM); ee: 99%; retention time: 7.9 min, Chiralcel OD-H, n-
hexane/i-PrOH, 90:10, flow rate of 1 mL/min, 254 nm.
4.6.5. (S)-tert-Butyl 1-(quinazolin-2-yl)ethylcarbamate 9a
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 10%; mp 46–48 °C; Rf 0.25 (hexane/EtOAc (2:1)); 1H NMR
(400 MHz, CDCl3, ppm) d 9.36 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.95–
7.84 (m, 2H), 7.62 (t, J = 7.5 Hz, 1H), 6.05 (br s, 1H), 5.21–5.01 (m,
1H), 1.59 (d, J = 6.8 Hz, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3,
ppm) d 166.8, 160.9, 155.5, 150.1, 134.4, 128.3, 127.6, 127.3, 123.8,
79.4, 52.8, 28.6, 22.4; IR (KBr, cmꢁ1) 3421, 2977, 2931, 1710, 1620,
1585, 1572, 1493, 1457, 1406, 1366, 1248, 1168, 1051.
4.6.1. tert-Butyl (1S,10S)-1,10-(4,40-biquinazoline-2,20-
diyl)bis(ethane-1,1-diyl)dicarbamate 8a
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 75%; mp 218–220 °C; Rf 0.33 (hexane/EtOAc (2:1)); 1H
NMR (400 MHz, CDCl3, ppm) d 8.15 (d, J = 8.5 Hz, 2H), 7.95 (t,
J = 7.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.55 (t, J = 7.6 Hz, 2H), 5.99
(br s, 2H), 5.29–5.17 (m, 2H), 1.64 (d, J = 6.9 Hz, 6H), 1.47 (s,
18H); 13C NMR (100 MHz, CDCl3, ppm) d 165.8, 164.1, 155.5,
151.7, 134.7, 128.9, 128.2, 126.6, 122.2, 79.5, 52.9, 28.6, 22.4; IR
(KBr, cmꢁ1) 3357, 2980, 2931, 1679, 1614, 1562, 1524, 1458,
1444, 1370, 1329, 1306, 1247, 1166, 1059; Anal. Calcd for
4.6.6. (S)-tert-Butyl 2-methyl-1-(quinazolin-2-yl)pro-
pylcarbamate 9b
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 25%; mp 117–119 °C; Rf 0.45 (hexane/EtOAc (2:1)); 1H
NMR (400 MHz, CDCl3, ppm) d 9.35 (s, 1H), 8.01 (d, J = 8.4 Hz,
1H), 7.94–7.84 (m, 2H), 7.62 (t, J = 7.5 Hz, 1H), 5.85 (d, J = 8.4 Hz,
1H), 4.99 (dd, J = 8.4, 5.2 Hz, 1H), 2.42–2.27 (m, 1H), 1.46 (s, 9H),
0.98 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d 165.8, 160.3, 156.1, 150.0, 134.2, 128.4,
127.5, 127.2, 123.7, 79.2, 61.5, 34.2, 28.6, 19.9, 17.6; IR (KBr,
cmꢁ1) 3346, 2965, 2934, 1698, 1620, 1584, 1572, 1514, 1488,
1366, 1298, 1235, 1166, 1014.
C
30H36N6O4: C, 66.16; H, 6.66; N, 15.43. Found: C, 65.58; H, 6.52;
N, 15.33; ½a 2D0
¼ ꢁ49:0 (c 1, DCM); ee: 99%; retention time:
ꢃ
7.0 min, Chiralcel OD-H, n-hexane/i-PrOH, 90:10, flow rate of
1 mL/min, 220 nm.
4.6.2. tert-Butyl (1S,10S)-1,10-(4,40-biquinazoline-2,20-diyl)bis(2-
methylpropane-1,1-diyl)dicarbamate 8b
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 45%; mp 89–91 °C; Rf 0.54 (hexane/EtOAc (2:1)); 1H NMR
(400 MHz, CDCl3, ppm) d 8.16 (d, J = 8.5 Hz, 2H), 7.94 (t, J = 7.6 Hz,
2H), 7.84 (d, J = 8.1 Hz, 2H), 7.55 (t, J = 7.6 Hz, 2H), 5.84 (d,
J = 8.9 Hz, 2H), 5.10 (dd, J = 8.9, 5.0 Hz, 2H), 2.50–2.32 (m, 2H),
1.46 (s, 18H), 1.04 (d, J = 6.8 Hz, 6H), 0.91 (d, J = 6.8 Hz, 6H); 13C
NMR (100 MHz, CDCl3, ppm) d 164.7, 163.6, 156.1, 151.5, 134.5,
129.1, 128.1, 126.6, 122.2, 79.3, 61.6, 34.1, 28.6, 20.1, 17.5; IR
(KBr, cmꢁ1) 3443, 3358, 2967, 2931, 2872, 1713, 1614, 1562,
1528, 1499, 1455, 1390, 1362, 1330, 1292, 1253, 1170, 1089; Anal.
Calcd for C34H44N6O4: C, 67.98; H, 7.38; N, 13.99. Found: C, 68.01;
4.6.7. (S)-tert-Butyl 2,2-dimethyl-1-(quinazolin-2-yl)pro-
pylcarbamate 9c
Crystallization from a mixture of hexane/EtOAc gave a white
solid. Yield: 4%; mp 82–84 °C; Rf 0.55 (hexane/EtOAc (2:1)); 1H
NMR (400 MHz, CDCl3, ppm) d 9.34 (s, 1H), 8.01 (d, J = 9.1 Hz,
1H), 7.93–7.85 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 5.95 (d, J = 9.2 Hz,
1H), 4.94 (d, J = 9.2 Hz, 1H), 1.43 (s, 9H), 0.99 (s, 9H); 13C NMR
(100 MHz, CDCl3, ppm) d 165.2, 159.5, 155.9, 149.9, 134.1, 128.6,
127.5, 127.1, 123.7, 79.1, 64.3, 36.7, 28.6, 27.0; IR (KBr, cmꢁ1
3439, 2969, 2871, 1714, 1620, 1585, 1571, 1557, 1496, 1391,
1366, 1281, 1232, 1172, 1050.
)
H, 7.47; N, 13.97; ½a D20
¼ ꢁ55:0 (c 1, EtOH); ee: 99%; retention
ꢃ
time: 8.1 min, Chiralcel OD-H, n-hexane/i-PrOH, 95:5, flow rate
of 0.6 mL/min, 254 nm.

306
M. Cakici et al. / Tetrahedron: Asymmetry 22 (2011) 300–308
4.6.8. (S)-tert-Butyl 2-phenyl-1-(quinazolin-2-
4.7.4. (1S,10S)-1,10-(4,40-Biquinazoline-2,20-diyl)bis(2-
yl)ethylcarbamate 9d
phenylethanamine) 2d
Crystallization from a mixture of hexane/EtOAc gave a white so-
lid. Yield: 40%; mp 92–94 °C; Rf 0.42 (hexane/EtOAc (2:1)); 1H NMR
(400 MHz, CDCl3, ppm) d 9.36 (s, 1H), 7.98–7.82 (m, 3H), 7.63 (t,
J = 7.31 Hz, 1H), 7.25–7.07 (m, 3H), 6.94 (m, 2H), 5.91 (d,
J = 7.3 Hz, 1H), 5.42–5.37 (m, 1H), 3.47 (dd, J = 13.5, 5.4 Hz, A part
of AB system, 1H), 3.30 (dd, J = 13.5, 6.1 Hz, B part of AB system,
1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) d 165.2, 160.6,
155.4, 150.0, 137.3, 134.4, 129.8, 128.3, 128.2, 127.7, 127.3,
126.5, 123.7, 79.4, 57.5, 41.3, 28.6; IR (KBr, cmꢁ1) 3347, 3061,
3024, 2981, 2925, 1691, 1618, 1572, 1529, 1489, 1367, 1250,
1171, 1049.
White solid. Yield: 93%; mp 185–188 °C; 1H NMR (400 MHz,
CDCl3, ppm) d 8.16 (d, J = 8.5 Hz, 2H), 7.94 (t, J = 7.7 Hz, 2H), 7.62
(d, J = 8.3 Hz, 2H), 7.50 (t, J = 7.7 Hz, 2H), 7.31–7.18 (m, 10H),
4.66 (dd, J = 8.4, 5.3 Hz, 2H), 3.47 (dd, J = 13.3, 5.3 Hz, A part of
AB system, 2H), 3.09 (dd, J = 13.3, 8.4 Hz, B part of AB system,
2H), 1.98 (br s, 4H); 13C NMR (100 MHz, CDCl3, ppm) d 167.7,
164.0, 151.8, 138.8, 134.5, 129.7, 128.9, 128.6, 128.0, 126.6,
126.6, 122.2, 59.7, 44.6; IR (KBr, cmꢁ1) 3363, 3055, 3017, 2943,
2892, 1613, 1560, 1487, 1452, 1312, 1255, 1124; Anal. Calcd for
C
32H28N6: C, 77.39; H, 5.68; N, 16.92. Found: C, 76.96; H, 5.61; N,
17.10; HRMS (TOF MS ES+) m/z calcd for C32H29N6 [M+H]+
497.2454, found 497.2448; ½a D20
¼ þ71:0 (c 1, DCM).
ꢃ
4.7. General procedure for the deprotection of 8: synthesis of
biquinazoline amine 2
4.8. Typical procedure for the addition of diethylzinc to
aldehyde
To a solution (S,S)-8 (1 mmol) in 10 mL of dichloromethane was
slowly added triflouroacetic acid (10 mmol) at 0 °C after which the
reaction mixture was stirred at room temperature for 24 h. The
reaction proceeding was monitored by TLC. After the total conver-
sion of the starting material, the crude mixture was diluted with
saturated NaHCO3 (15 mL) and extracted with dichloromethane
(3 ꢂ 25 mL). The solvent was removed under reduced pressure
(15 mbar, 20 °C) to give (S,S)-biquinazoline amine 2.
A solution of diethylzinc (1.5 mL of 1 M hexane solution,
1.5 mmol) was added dropwise to
a solution of ligand 2
(0.05 mmol, 10 mol %) in dry THF (2 mL) under an argon atmo-
sphere and the mixture was stirred at room temperature for 1 h.
The mixture was cooled to 0 °C and a solution of benzaldehyde
(0.5 mmol) in dry THF (1 mL) was added with a syringe. After stir-
ring for 30 h, the reaction was quenched by the addition of satu-
rated aqueous NH4Cl (4 mL) and diphenylmethane (42 mg,
0.25 mmol) was added as an internal standard. The mixture was
extracted with EtOAc (3 ꢂ 8 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and evap-
orated under reduced pressure. The conversion and yield were
determined by 1H NMR analysis directly on the crude mixture.
The crude product was purified by preparative radial thinlayer
chromatography (Chromatotron) over silica gel eluting with hex-
ane/EtOAc (90:10) and the enantiomeric excess of the product
was determined by GC on a Chiral b-DEX 120 capillary column.
4.7.1. (1S,10S)-1,10-(4,40-Biquinazoline-2,20-diyl)diethanamine 2a
White solid. Yield: 94%; mp 142–145 °C; 1H NMR (400 MHz,
CDCl3, ppm) d 8.15 (d, J = 8.5 Hz, 2H), 7.94 (t, J = 8.3 Hz, 2H), 7.82
(d, J = 8.4 Hz, 2H), 7.54 (t, J = 8.1 Hz, 2H), 4.50 (q, J = 6.8 Hz, 2H),
2.02 (br s, 4H), 1.62 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3,
ppm) d 169.4, 164.2, 151.8, 134.5, 129.0, 127.9, 126.5, 122.2,
54.0, 24.0; IR (KBr, cmꢁ1) 3224, 2967, 2870, 1613, 1562, 1488,
1370, 1355, 1305, 1250, 1189, 1149, 1064; Calcd for C20H20N6: C,
69.75; H, 5.85; N, 24.40. Found: C, 69.98; H, 5.99; N, 24.10; HRMS
(TOF MS ES+) m/z calcd for C20H21N6 [M+H]+ 345.1828, found
345.1838; ½a 2D0
ꢃ
¼ þ16:5 (c 1, DCM).
4.8.1. 1-Phenylpropan-1-ol
83% yield, 95% ee determined by GC analysis (supelco b-DEX
120, He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 167 °C (2 min), split: 100:1). Retention times:
(R)-enantiomer 19.28 min; (S)-enantiomer. 19.57 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.41–7.22 (m, 5H), 4.60 (t, J = 6.3 Hz,
1H), 1.90 (br s, 1H), 1.87–1.68 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3, ppm) d 144.8, 128.6, 127.6, 126.1, 76.2,
32.0, 10.3.
4.7.2. (1S,10S)-1,10-(4,40-Biquinazoline-2,20-diyl)bis(2-methyl-
propan-1-amine) 2b
White solid. Yield: 93%; mp 137–139 °C; 1H NMR (400 MHz,
CDCl3, ppm) d 8.15 (d, J = 8.4 Hz, 2H), 7.93 (ddd, J = 8.4, 6.8,
1.4 Hz, 2H), 7.79 (ddd, J = 8.4, 1.4, 0.6 Hz, 2H), 7.53 (ddd, J = 8.4,
6.8, 1.1 Hz, 2H), 4.16 (d, J = 5.8 Hz, 2H), 2.35 (sext.d, J = 6.8,
5.8 Hz, 2H), 2.16 (br s, 4H), 1.02 (d, J = 6.8 Hz, 6H), 0.98 (d,
J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3, ppm) d 167.8, 163.7,
151.4, 134.3, 128.8, 127.7, 126.2, 121.9, 63.5, 34.1, 20.3, 17.2; IR
(KBr, cmꢁ1) 3375, 2958, 2920, 2870, 1614, 1560, 1486, 1379,
1315, 1176, 1148; Anal. Calcd for C24H28N6: C, 71.97; H, 7.05; N,
20.98. Found: C, 71.55; H, 7.02; N, 20.76; HRMS (TOF MS ES+) m/
4.8.2. 1-(Naphthalen-1-yl)propan-1-ol
89% yield, 91% ee determined by GC analysis (supelco b-DEX
120, He: 2.4 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 160 °C,
split: 100:1). Retention times: (S)-enantiomer 38.39 min; (R)-
enantiomer. 39.96 min. 1H NMR (400 MHz, CDCl3, ppm) d 8.12 (d,
J = 7.7 Hz, 1H), 7.88 (dd, J = 6.8, 1.7 Hz, 1H), 7.78 (d, J = 8.1 Hz,
1H), 7.64 (d, J = 6.8 Hz, 1H), 7.60–7.41 (m, 3H), 5.41 (t, J = 5.9 Hz,
1H), 2.11–1.83 (m, 3H), 1.04 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d 140.4, 134.0, 130.7, 129.1, 128.1, 126.1,
125.7, 125.6, 123.4, 123.1, 72.8, 31.3, 10.7.
z
calcd for
C
24H29N6 [M+H]+ 401.2454, found 401.2452;
½ ꢃ ¼ þ50:0 (c 1, DCM).
a 2D0
4.7.3. (1S,10S)-1,10-(4,40-Biquinazoline-2,20-diyl)bis(2,2-
dimethylpropan-1-amine) 2c
White solid. Yield: 95%; mp 104–107 °C; 1H NMR (400 MHz,
CDCl3, ppm) d 8.14 (d, J = 8.4 Hz, 2H), 7.92 (ddd, J = 8.4, 6.9,
1.4 Hz, 2H), 7.76 (ddd, J = 8.4, 1.4, 0.6 Hz, 2H), 7.51 (ddd, J = 8.4,
6.9, 1.1 Hz, 2H), 4.10 (s, 2H), 2.04 (br s, 4H), 1.05 (s, 18H); 13C
NMR (100 MHz, CDCl3, ppm) d 167.5, 163.4, 151.3, 134.3, 129.1,
127.7, 126.4, 122.1, 66.8, 36.2, 27.0; IR (KBr, cmꢁ1) 3384, 2962,
2866, 1681, 1615, 1561, 1487, 1376, 1343, 1311, 1201, 1180,
1134; Anal. Calcd for C26H32N6: C, 72.86; H, 7.53; N, 19.61. Found:
C, 72.41; H, 7.57; N, 19.78; HRMS (TOF MS ES+) m/z calcd for
4.8.3. 1-(Naphthalen-2-yl)propan-1-ol
85% yield, 93% ee determined by GC analysis (supelco b-DEX
120, He: 2.4 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 160 °C,
split: 100:1). Retention times: (R)-enantiomer 38.83 min; (S)-
enantiomer. 39.82 min. 1H NMR (400 MHz, CDCl3, ppm) d 7.89–
7.80 (m, 3H), 7.78 (m, 1H), 7.54–7.42 (m, 3H), 4.77 (t, J = 6.6 Hz,
1H), 1.99 (br s, 1H), 1.96–1.79 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3, ppm) d 142.1, 133.5, 133.2, 128.4,
128.1, 127.8, 126.3, 125.9, 124.9, 124.3, 76.3, 32.0, 10.3.
C
26H33N6 [M+H]+ 429.2767, found 429.2765; ½a 2D0
¼ þ161:0 (c 1,
ꢃ
DCM).

M. Cakici et al. / Tetrahedron: Asymmetry 22 (2011) 300–308
307
4.8.4. 1-(2-Chlorophenyl)propan-1-ol
(S)-enantiomer 28.66 min; (R)-enantiomer. 29.53 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.29 (dd, J = 7.4, 1.6 Hz, 1H), 7.27–7.21
(m, 1H), 6.95 (td, J = 7.4, 0.9 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 4.78
(t, J = 6.6 Hz, 1H), 3.85 (s, 3H), 2.56 (br s, 1H), 1.88–1.76 (m, 2H),
0.95 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 156.8,
132.6, 128.4, 127.2, 120.9, 110.7, 72.6, 55.4, 30.3, 10.6.
88% yield, 27% ee determined by GC analysis (supelco b-DEX
120, He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 190 °C (10 min), split: 100:1). Retention times:
(R)-enantiomer 28.43 min; (S)-enantiomer. 29.08 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.54 (dd, J = 7.7, 1.5 Hz, 1H), 7.35–7.25
(m, 2H), 7.19 (td, J = 7.7, 1.7 Hz, 1H), 5.50–4.62 (m, 1H), 1.99 (br
s, 1H), 1.90–1.66 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d 142.1, 132.2, 129.5, 128.5, 127.3, 127.2,
72.2, 30.6, 10.2.
4.8.11. 1-(3-Methoxyphenyl)propan-1-ol
84% yield, 92% ee determined by GC analysis (supelco b-DEX
120, He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 190 °C (10 min), split: 100:1). Retention times:
(R)-enantiomer 31.63 min; (S)-enantiomer. 31.86 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.26 (t, J = 8.1 Hz, 1H), 6.94–6.88 (m,
2H), 6.81 (ddd, J = 8.4, 2.4, 1.0 Hz, 1H), 4.60–4.54 (m, 1H), 3.81 (s,
3H), 1.93 (br s, 1H), 1.88–1.67 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3, ppm) d 159.9, 146.5, 129.5, 118.5,
113.1, 111.6, 76.1, 55.4, 32.0, 10.3.
4.8.5. 1-(3-Chlorophenyl)propan-1-ol
84% yield, 94% ee determined by GC analysis (supelco b-DEX
120, He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 167 °C (2 min), split: 100:1). Retention times:
(R)-enantiomer 30.14 min; (S)-enantiomer. 30.42 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.35–7.33 (m, 1H), 7.30–7.16 (m, 3H),
4.60–4.55 (m, 1H), 1.98 (br s, 1H), 1.84–1.67 (m, 2H), 0.91 (t,
J = 7.4, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 146.8, 134.5,
129.8, 127.7, 126.3, 124.3, 75.5, 32.1, 10.1.
4.8.12. 1-(4-Methoxyphenyl)propan-1-ol
84% yield, 87% ee determined by GC analysis (supelco b-DEX
120, He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 190 °C (10 min), split: 100:1). Retention times:
(R)-enantiomer 32.12 min; (S)-enantiomer. 32.40 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.27–7.25 (m, AA0 part of AA0BB0 system,
2H), 6.89–6.87 (m, BB0 part of AA0BB0 system, 2H), 4.54 (td, J = 6.7,
2.7 Hz, 1H), 3.80 (s, 3H), 1.96–1.63 (m, 3H), 0.90 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3, ppm) d 159.2, 136.9, 127.3, 114.0, 75.8,
55.4, 31.9, 10.3.
4.8.6. 1-(4-Chlorophenyl)propan-1-ol
92% yield, 94% ee determined by GC analysis (supelco b-DEX
120, He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 190 °C (10 min), split: 100:1). Retention times:
(R)-enantiomer 30.48 min; (S)-enantiomer. 30.94 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.32–7.25 (m, 4H), 4.58 (t, J = 6.3 Hz,
1H), 1.93 (br s, 1H), 1.84–1.66 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3, ppm) d 143.2, 133.3, 128.7, 127.5, 75.4,
32.1, 10.1.
4.8.13. 1-o-Tolylpropan-1-ol
57% yield, 68% ee determined by GC analysis (supelco b-DEX
120, He: 2.4 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 160 °C,
split: 100:1). Retention times: (R)-enantiomer 4.82 min; (S)-enan-
tiomer. 4.94 min. 1H NMR (400 MHz, CDCl3, ppm) d 7.46 (d,
J = 7.5 Hz, 1H), 7.28–7.08 (m, 3H), 4.87 (t, J = 6.3 Hz, 1H), 2.34 (s,
3H), 1.81–1.69 (m, 3H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d 142.9, 134.8, 130.5, 127.3, 126.4, 125.4,
72.3, 31.1, 19.2, 10.5.
4.8.7. 1-(2-Bromophenyl)propan-1-ol
89% yield, 2% ee determined by GC analysis (supelco b-DEX 120,
He: 2.4 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 160 °C, split:
100:1). Retention times: (R)-enantiomer 10.45 min; (S)-enantio-
mer. 11.03 min. 1H NMR (400 MHz, CDCl3, ppm) d 7.57–7.43 (m,
2H), 7.36–7.30 (m, 1H), 7.12 (td, J = 7.9, 1.7 Hz, 1H), 5.04–4.99
(m, 1H), 2.01 (br s, 1H), 1.89–1.79 (m, 1H), 1.77–1.68 (m, 1H),
1.01 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 143.7,
132.8, 128.9, 127.8, 127.5, 122.3, 74.3, 30.7, 10.2.
4.8.14. 1-m-Tolylpropan-1-ol
77% yield, 94% ee determined by GC analysis (supelco b-DEX
120, He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 167 °C (2 min), split: 100:1). Retention times:
(R)-enantiomer 22.76 min; (S)-enantiomer. 22.93 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.62–6.67 (m, 1H), 7.19–6.53 (m, 3H),
4.94–3.99 (m, 1H), 2.36 (s, 3H), 1.92–1.63 (m, 3H), 0.92 (t,
J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) d 141.8, 137.3,
129.2, 126.1, 76.1, 32.0, 21.2, 10.3.
4.8.8. 1-(3-Bromophenyl)propan-1-ol
84% yield, 95% ee determined by GC analysis (supelco b-DEX
120, He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 167 °C (2 min), split: 100:1). Retention times:
(R)-enantiomer 35.22 min; (S)-enantiomer. 35.43 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.51 (s, 1H), 7.40 (dt, J = 7.6, 1.6 Hz,
1H), 7.32–7.15 (m, 2H), 4.58 (dt, J = 6.6, 3.3 Hz, 1H), 1.87 (d,
J = 3.3 Hz, 1H), 1.85–1.68 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3, ppm) d 147.1, 130.7, 130.1, 129.2, 124.7,
122.7, 75.4, 32.1, 10.1.
4.8.15. 1-p-tolylpropan-1-ol
73% yield, 88% ee determined by GC analysis (supelco b-DEX
120, He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 167 °C (2 min), split: 100:1). Retention times:
(R)-enantiomer 22.68 min; (S)-enantiomer. 23.14 min. 1H NMR
(400 MHz, CDCl3, ppm) d 7.24–7.22 (m, AA0 part of AA0BB0 system,
2H), 7.17–7.15 (m, BB0 part of AA0BB0 system, 2H), 4.56 (td, J = 6.9,
2.2 Hz, 1H), 2.35 (s, 3H), 1.92–1.64 (m, 3H), 0.91 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3, ppm) d 144.7, 128.5, 126.8, 123.2, 76.2,
32.0, 21.6, 10.3.
4.8.9. 1-(4-Bromophenyl)propan-1-ol
94% yield, 85% ee determined by GC analysis (supelco b-DEX
120, He: 2.4 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 160 °C,
split: 100:1). Retention times: (R)-enantiomer 13.04 min; (S)-
enantiomer. 13.46 min. 1H NMR (400 MHz, CDCl3, ppm) d 7.47–
7.43 (m, AA0 part of AA0BB0 system, 2H), 7.22–7.18 (m, BB0 part of
AA0BB0 system, 2H), 4.55 (t, J = 6.5, Hz, 1H), 2.02 (br s, 1H), 1.89–
1.53 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3,
ppm) d 143.7, 131.6, 127.9, 121.4, 75.5, 32.1, 10.1.
Acknowledgments
4.8.10. 1-(2-Methoxyphenyl)propan-1-ol
The financial support from the Scientific and Technological
Research Council of Turkey (TUBITAK) (TBAG-108T116) is grate-
fully acknowledged. In addition, the authors would like to thank
59% yield, 5% ee determined by GC analysis (supelco b-DEX 120,
He: 1.0 mL/min, det.: 250 °C (FID), inj.: 240 °C, oven: 110 °C
(1 min), 2 °C/min to 190 °C (10 min), split: 100:1). Retention times:

308
M. Cakici et al. / Tetrahedron: Asymmetry 22 (2011) 300–308
Ramasastry, S. S. V.; Tanaka, F.; Barbas, C. F. Adv. Synth. Catal. 2008, 350, 791–
796; (g) Yalalov, D. A.; Tsogoeva, S. B.; Shubina, T. E.; Martynova, I. M.; Clark, T.
Angew. Chem., Int. Ed. 2008, 47, 6624–6628.
Dr. Graham Eaton from Leicester University for the HRMS
measurements.
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