Synthesis and biological evaluation of (S)-4-aminoquinazoline alcohols

Article abstract of DOI:10.1016/j.tetasy.2010.05.040

A simple synthetic method for the preparation of enantiomerically pure (S)-4-aminoquinazoline alcohols from (S)-quinazolinone alcohols by key steps including chlorination, nucleophilic ipso substitution, and deacetylation is presented. Mutagenic and antim

Full text of DOI:10.1016/j.tetasy.2010.05.040

Tetrahedron: Asymmetry 21 (2010) 2027–2031
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and biological evaluation of (S)-4-aminoquinazoline alcohols
d
e
Murat Cakici a, Mustafa Catir b, Semistan Karabuga c, Hamdullah Kilic a, , Sabri Ulukanli , Medine Gulluce ,
*
Furkan Orhan e
a Faculty of Sciences, Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey
b Faculty of Arts and Sciences, Department of Chemistry, Erzincan University, 24100 Erzincan, Turkey
c Faculty of Science and Letters, Department of Chemistry, Kilis 7 Aralik University, 79100 Kilis, Turkey
d Faculty of Science and Letters, Department of Chemistry, Korkut Ata University, 80100 Osmaniye, Turkey
e Faculty of Sciences, Department of Biology, Ataturk University, 25240 Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple synthetic method for the preparation of enantiomerically pure (S)-4-aminoquinazoline alcohols
from (S)-quinazolinone alcohols by key steps including chlorination, nucleophilic ipso substitution, and
deacetylation is presented. Mutagenic and antimutagenic properties of the (S)-4-aminoquinazoline alco-
hols were investigated by using Salmonella typhimurium TA1535, and Escherichia coli WP2uvrA tester
Received 13 May 2010
Accepted 25 May 2010
Available online 21 June 2010
strains at 0.01, 0.1, and 1
genotoxically safe at the tested concentrations. Among the tested (S)-4-aminoquinazoline alcohols, the
best antimutagenic activity was obtained with a methyl derivative at 0.1 g/plate dose.
lg/plate concentrations. (S)-4-aminoquinazoline alcohols were found to be
l
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
e.23 The most challenging aspect of the synthesis was a fast and
simple protocol for large-scale preparation of enantiomerically
pure quinazolinone alcohols from cheap starting materials. Follow-
ing this success, we envisaged that this protocol could be success-
fully extended to the synthesis of (S)-4-aminoquinazoline alcohols
from (S)-quinazolinone alcohols 5a–e by a reaction sequence that
employs acetylation of hydroxy functionality, chlorination with
POCl3, and nucleophilic ipso substitution of chloride by ammonia;
subsequent unmasking should then cleanly provide the desired
(S)-4-aminoquinazoline alcohols 3a–e. Herein, we report a conve-
nient procedure for obtaining the hitherto unknown homochiral
4-aminoquinazolines 3a–e possessing a secondary alcohol group
from the readily accessible enantiomerically pure (S)-quinazoli-
none alcohols 5a–e, and an assessment of their mutagenic and
antimutagenic activities. It was found that (S)-4-aminoquinazoline
alcohols 3a–e have no mutagenic effects on the tested strains, and
3a–c exhibit moderate antimutagenicity against N-methyl-N0-ni-
tro-N-nitrosoguanidine (MNNG).
Quinazolin-4(3H)-ones 1 and related quinazolines1–5 2 are a
class of nitrogen-containing heterocycles of considerable interest,
owing to their diverse pharmacological activities including anti-
bacterial,6 antitubercular,7 antifungal,8 antihyperglycemic,9 anti-
inflammatory,10 bronchodilatory,11 cholinesterase inhibitory,12
antifolate,13 antitumor,14 protein kinase inhibitory,15 and many
others.16
O
R1
NH2
N
R1
R2
N
N
OH
N
1
N
2
R2
N
3
R
Additionally, 4-aminoquinazoline and its derivatives are useful
as fungicides and anti-inflammatory, antimicrobial, and antihyper-
tensive agents.17–20 In particular, they are potent and highly selec-
tive inhibitors of tyrosine kinase.21 Therefore, in recent years, the
synthesis of 4-aminoquinazolines has attracted much attention.22
Among the structural variations of quinazoline that have been re-
ported, to the best of our knowledge, no previous studies have
dealt with the preparation of optically active 4-aminoquinaozoline
alcohols 3. Recently, we reported the efficient synthesis of 5a–e
from the readily accessible enantiomerically pure (S)-amides 4a–
2. Results and discussion
The starting quinazolinone alcohols 5a–e23 were prepared from
cyclization of the corresponding enantiomerically pure (S)-amides
4 by NaOH in EtOH at room temperature (Scheme 1). The quinaz-
oline alcohols 3a–e, all of which have terminal amino groups at the
4-position of the quinazoline scaffold, were synthesized by a three-
step reaction sequence starting from the enantiomerically pure
quinazolinone alcohols 5a–e as shown in Scheme 2. Hydroxy
groups in (S)-quinazolinone alcohols 5a–e were protected by treat-
* 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 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.040

2028
M. Cakici et al. / Tetrahedron: Asymmetry 21 (2010) 2027–2031
lecular ipso substitution step. 4-Aminoquinazolines 3a–e were syn-
O
N
O
NH2
H
N
thesized by two consecutive nucleophilic substitution and
hydrolysis reactions. At first, we tried a one-pot method to prepare
3a–e, but we only observed substitution at C-4 and partial hydroly-
sis of the acetate functionality using aqueous ammonia. Therefore,
we split the synthesis of 3a–e into two individual steps. Firstly, the
4-chloroquinazoline acetates 7a–e were coupled with aqueous
ammonia at room temperature to introduce an amino group at
the C-4 position. Secondly, the mixture was mixed with K2CO3 to
give the desired 4-aminoquinazoline alcohols 3a–e together with
quinazoline alcohols 5a–e (3–5%). The (S)-4-aminoquinazolinone
alcohols 3a–e were purified by means of column chromatography
on silica gel eluting with hexane and ethyl acetate (2:1) The struc-
ture assignments of 3a–e are based on their analytical and spectral
data. The elemental analyses of 3a–e revealed the empirical for-
mula while the 13C NMR spectrum displayed the expected carbon
resonances. The 13C NMR spectrum possesses the two expected car-
bon resonances at around 165–168 and 160–162 ppm, which con-
firm the presence of 4-aminoquinazoline functionality. The intense
band at around 3332 cmꢀl in the IR spectrum indicated the pres-
ence of an amino group in 3a–e. Chiral HPLC analysis of 3a–e shows
that enantiomeric purities are around 99%.
R
NH
NaOH
OAc EtOH
75-98%
OH
O
R
4a
5a-e
R= Me
4b R= iPr
4c
4d
R= t-Bu
R= Ph
4e R= Bn
Scheme 1. Synthesis of the (S)-quinazolinone alcohols 5a–e.
ment with acetic anhydride in the presence of pyridine (3:2) to
give the corresponding acetate 6 in a yield of 79–94%.
The structural assignments of the acetates 6a–e were secured on
the basis of physical behavior. Thus, elemental analysis confirmed
the molecular formula, while the acetate functionalities were
established by their NMR and IR spectra. The enantiomeric purities
of the acetates 6a–e were determined by a HPLC system equipped
with a Chiralyser, which revealed that the acetates 6a–e have enan-
tiomeric purities of 99%, and retain their original (S)-configuration
with no partial racemization. However, the 1H NMR (400 MHz,
CDCl3, and DMSO-d6) and specific rotation of the known compound
6d24 were in disagreement with those reported previously. The re-
ported synthesis of 6d involved the initial reaction of 2-aminobenz-
amide with 2-acetoxy-2-phenylacetic anhydride to give 4d that
subsequently underwent cyclization to form 6d in the absence of
a base. To the best of our knowledge, the use of a strong base is re-
quired for the cyclization reaction; otherwise the reaction would
stop at the stage of acylation of 2-aminobenzamide with 2-acet-
oxy-2-phenylacetic anhydride. We therefore concluded that the
structural assignment of 6d was incorrect and should be revised
to 4d, as established by comparison with the reported 1H NMR
and specific rotation data.23 The treatment of the acetates 6a–e
with phosphoryl chloride in benzene for 3–4 h resulted in excellent
yields of 4-chloroquinozoline acetates 7a–e, which were purified by
short column chromatography on silica gel using a mixture of hex-
ane and ethyl acetate (3:1). The 4-chloroquinazoline acetates 7a–e
so obtained were characterized on the basis of analytical data and
spectral evidence. We next turned our attention to the key intramo-
(S)-4-Aminoquinazoline alcohols 3a–e at three different concen-
trations (0.01, 0.1, and 1 lg/plate) showed no mutagenic effect in
the mutagenicity assays performed with Salmonella typhimurium
TA1535 and Escherichia coli WP2uvrA.25 Antimutagenic activities
of 3a–e at three different concentrations (0.01, 0.1, and 1 lg/plate)
were evaluated in vitro against NaN3, and N-methyl-N0-nitro-N-
nitrosoguanidine (MNNG) in S. typhimurium TA1535 and E. coli
WP2uvrA, respectively. In the antimutagenicity assays performed
with E. coli WP2uvrA strains, 3a–c had moderate antimutagenic
activity at 0.01 and 0.1
nicity at any concentration. The inhibition rates of 3a–c were 31.1%
(3a 0.1 g/plate), 24.7% (3b 0.01 g/plate), and 24.3% (3c 0.1 g/
lg/plate, while 3d,e showed no antimutage-
l
l
l
plate), respectively. A plausible explanation for this observation
might be that 3a–c inhibit the formation of O6-methylguanine.
3. Conclusion
In summary, a highlyefficient and generalapproach toenantiome-
rically pure 4-aminoquinazoline alcohols with an (S)-configuration
O
O
Cl
POCl3 (3.0 equiv)
PhNEt2 (2.0 equiv)
Ac2O (3.0 equiv)
pyridine (2.0 equiv)
NH
NH
N
OH
OAc
OAc
DCM, 20 ο
C
Benzene
N
N
N
0 ο
C
reflux
→
R
R
R
5a
R= Me
5b R= iPr
5c
6a (94%)
6b (79%)
6c (85%)
6d (93%)
6e (93%)
7a (97%)
7b (89%)
7c (96%)
7d (99%)
7e (97%)
R= t-Bu
5d R= Ph
5e
R= Bn
1) NH3 (25%)
2) K2CO3
DMF, 20 οC
NH2
O
N
N
NH
+
OH
OH
N
R
R
5a e
-
3a
(88%)
3b (88%)
3c (85%)
3d (83%)
3e (87%)
Scheme 2. Synthesis of the (S)-4-aminoquinazoline alcohols 3a–e.

M. Cakici et al. / Tetrahedron: Asymmetry 21 (2010) 2027–2031
2029
starting from readily accessible compounds has been established. The
total yield of this synthetic route from 5 to 3 was over 60%, and the
compounds were purified by either recrystallization or short column
chromatography on silica gel in each step. Based on the biological
activity assays, (S)-4-aminoquinazoline alcohols 3a–e are genotox-
ically safe at the tested concentrations. In addition, 3a–c exhibit mod-
erate antimutagenicity. It is evident from this study that
antimutagenicity decreases as steric hindrance increases in the prox-
imity of the hydroxy functionality.
1.05 (d, J = 5.3 Hz, 3H), 1.03 (d, J = 5.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d 170.5, 163.2, 153.7, 148.9, 134.9, 127.9,
127.1, 126.4, 121.4, 78.1, 32.4, 21.1, 18.9, 17.7; IR (KBr, cmꢀ1
)
3188, 3137, 3076, 2969, 2924, 2868, 1751, 1670, 1611, 1469,
1371, 1227, 1031. Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20;
N, 10.76. Found: C, 66.35; H, 6.03; N, 10.79; ½a D20
¼ ꢀ64:2 (c 1,
ꢂ
EtOH); ee: 99%; retention time: 7.5 min, Chiralcel OD, 90:10 n-hex-
ane–iPrOH, flow rate of 1 ml/min, 225 nm.
4.2.3. (S)-2,2-Dimethyl-1-(4-oxo-3,4-dihydroquinazolin-2-
yl)propyl acetate 6c
4. Experimental
4.1. General
Crystallization from EtOH gave a white powder. Yield: 85%; mp
157–159 °C; 1H NMR (400 MHz, CDCl3, ppm) d 10.94 (br s, 1H),
8.28 (d, J = 8.0 Hz, 1H), 7.82–7.70 (m, 2H), 7.49 (ddd, J = 8.0, 6.4,
1.8 Hz, 1H), 5.40 (s, 1H), 2.25 (s, 3H), 1.10 (s, 9H);13C NMR
(100 MHz, CDCl3, ppm) d 170.3, 163.0, 152.6, 148.7, 134.9, 128.1,
127.2, 126.4, 121.6, 80.7, 35.7, 26.4, 21.1; IR (KBr, cmꢀ1) 3181,
3135, 3078, 2970, 1750, 1670, 1612, 1470, 1371, 1335, 1235,
1137, 1058, 1028. Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61;
Reagents and solvents were purchased from standard chemical
suppliers and were purified to match the reported physical and
spectral 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
Varian (400 MHz, 100 MHz) spectrometer in CDCl3. Elemental
analyses were obtained with a Leco CHNS 932 analyzer. Enantio-
meric excesses were determined by HPLC analysis using a chiral
column with n-hexane–iPrOH eluent, and detection was performed
at 210–254 nm. Optical rotations were measured with a Belling-
ham + Stanley, ADP220, 589 nm spectropolarimeter in a 1 dm
tube; concentrations are given in g/100 mL. A polarimetric Chiraly-
ser detector was used to assess the specific rotation sign of the
enantiomer formed. Column chromatography was performed on
silica gel. Mutagenicity and antimutagenicity tests were carried
out as described in the literature.25
N, 10.21. Found: C, 65.47; H, 6.56; N, 10.23; ½a D20
¼ ꢀ19:2 (c 0.52,
ꢂ
EtOH); ee: 99%; retention time: 7.0 min, Chiralcel OD, 90:10 n-hex-
ane–iPrOH, flow rate of 1 ml/min, 225 nm.
4.2.4. (S)-(4-Oxo-3,4-dihydroquinazolin-2-yl)(phenyl)methyl
acetate 6d
Crystallization from EtOH gave a white powder. Yield: 93%; mp
154–156 °C; 1H NMR (400 MHz, CDCl3, ppm) d 11.72 (br s, 1H),
8.29 (d, J = 7.8 Hz, 1H), 7.83–7.71 (m, 2H), 7.66 (d, J = 6.7 Hz, 2H),
7.50 (ddd, J = 8.1, 6.2, 2.2 Hz, 1H), 7.42–7.30 (m, 3H), 6.69 (s, 1H),
2.31 (s, 3H); 1H NMR (400 MHz, DMSO-d6, ppm) d 12.65 (br s,
1H), 8.09 (dd, J = 8.0, 1.1 Hz, 1H), 7.82–7.78 (m, 1H), 7.66 (d,
J = 7.7 Hz, 1H), 7.59–7.57 (m, 2H), 7.52–7.45 (m, 1H), 7.43–7.31
(m, 3H), 6.38 (s, 1H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm) d 169.7, 163.5, 153.3, 149.0, 135.9, 135.0, 129.3, 129.1,
128.1, 127.4, 127.3, 126.4, 121.5, 75.5, 21.2; IR (KBr, cmꢀ1) 3070,
2967, 2924, 2874, 1741, 1616, 1570, 1482, 1372, 1344, 1312,
1236, 1034. Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.79; N,
4.2. General procedure for the acetates 6a–e
To a solution of (S)-5 (26.3 mmol) in 50 mL of CH2Cl2 were
added pyridine (52.6 mmol) and acetic anhydride (78.9 mmol).
The resulting mixture was stirred at room temperature for 3–5 h
and then quenched by the addition of saturated NaHCO3. The aque-
ous layer was extracted with CH2Cl2 (3 ꢁ 50 mL). The combined or-
ganic layers were washed with brine, dried over Na2SO4, and
filtered. The solvent was removed under reduced pressure and
the resulting solid was recrystallized from ethanol to afford (S)-
acetate 6 in a yield of 79–94%.
9.52. Found: C, 69.29; H, 4.93; N, 9.62; ½a D20
¼ þ49:0 (c1, EtOH);
ꢂ
ee: 99%; retention time: 13.8 min, Chiralcel OD, 90:10 n-hexane–
iPrOH, flow rate of 1 ml/min, 225 nm.
4.2.5. (S)-1-(4-Oxo-3,4-dihydroquinazolin-2-yl)-2-phenylethyl
acetate 6e
Crystallization from EtOH gave a white powder. Yield: 93%; mp
121–123 °C; 1H NMR (400 MHz, CDCl3, ppm) d 11.19 (br s, 1H),
8.28 (dd, J = 8.1, 1.0 Hz, 1H), 7.93–7.63 (m, 2H), 7.52 (ddd, J = 8.1,
6.7, 1.7 Hz, 1H), 7.30–7.15 (m, 5H), 5.90 (dd, J = 8.1, 4.8 Hz, 1H),
3.44 (dd, J = 14.1, 4.8 Hz, A part of AB system, 1H), 3.31 (dd,
J = 14.1, 8.1 Hz, B part of AB system, 1H), 2.17 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d 170.1, 163.1, 153.4, 148.8, 135.8, 135.0,
129.8, 128.6, 127.9, 127.3, 127.3, 126.5, 121.5, 74.1, 39.5, 21.0; IR
(KBr, cmꢀ1) 3182, 3137, 3031, 2918, 1750, 1671, 1610, 1470,
1370, 1336, 1226, 1135, 1049. Anal. Calcd for C18H16N2O3: C,
70.12; H, 5.23; N, 9.09. Found: C, 70.16; H, 5.33; N, 9.15;
4.2.1. (S)-1-(4-Oxo-3,4-dihydroquinazolin-2-yl)ethyl acetate 6a
Crystallization from EtOH gave a white powder. Yield: 94%; mp
186–188 °C; 1H NMR (400 MHz, CDCl3, ppm) d 11.51 (br s, 1H),
8.27 (dd, J = 8.1, 1.4 Hz, 1H), 7.78 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H),
7.73 (dd, J = 8.3, 1.2 Hz, 1H), 7.50 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H),
5.80 (q, J = 6.7 Hz, 1H), 2.24 (s, 3H), 1.72 (d, J = 6.7 Hz, 3H); 13C
NMR (100 MHz, CDCl3, ppm) d 170.3, 163.5, 154.5, 148.9, 135.0,
127.9, 127.3, 126.5, 121.4, 70.3, 21.3, 19.0; IR (KBr, cmꢀ1) 3176,
3126, 3046, 2980, 2918, 1749, 1681, 1608, 1468, 1369, 1230,
1094, 1050. Anal. Calcd for C12H12N2O3: C, 62.06; H, 5.21; N,
½
a 2D0
ꢂ
¼ ꢀ16:5 (c 1, EtOH); ee: 99%; retention time: 15.8 min, Chiral-
12.06. Found: C, 62.34; H, 5.17; N, 11.91; ½a D20
¼ ꢀ70:9 (c 1, EtOH);
ꢂ
cel OD, 90:10 n-hexane–iPrOH, flow rate of 1 ml/min, 225 nm.
ee: 99%; retention time: 13.9 min, Chiralcel OD, 90:10 n-hexane–
iPrOH, flow rate of 1 ml/min, 225 nm.
4.3. General procedure for the preparation of 7a–e
4.2.2. (S)-2-Methyl-1-(4-oxo-3,4-dihydroquinazolin-2-yl)propyl
acetate 6b
To a solution of (S)-6 (12.93 mmol) in dry benzene (30 mL) were
added PhNEt2 (25.86 mmol) and then POCl3 (38.8 mmol) at room
temperature. The reaction mixture was then refluxed for 3–4 h,
cooled to room temperature, and diluted with EtOAc (50 mL).
The mixture was washed successively with icy water (40 mL),
2 M HCl (40 mL), and brine (50 mL). The organic layer was dried
over Na2SO4, and evaporated under reduced pressure (20 °C,
Crystallization from EtOH gave a white powder. Yield: 79%; mp
173–175 °C; 1H NMR (400 MHz, CDCl3, ppm) d 11.39 (br s, 1H),
8.27 (ddd, J = 8.1, 1.5, 0.6 Hz, 1H), 7.77 (ddd, J = 8.2, 6.8, 1.5 Hz,
1H), 7.73 (ddd, J = 8.2, 1.5, 0.6 Hz, 1H), 7.49 (ddd, J = 8.1, 6.8,
1.5 Hz, 1H), 5.51 (d, J = 5.87 Hz, 1H), 2.44 (m, 1H), 2.26 (s, 3H),

2030
M. Cakici et al. / Tetrahedron: Asymmetry 21 (2010) 2027–2031
15 mbar). Purification by column chromatography (silica gel, hex-
ane–EtOAc, 3:1) gave 4-chloroquinazoline acetate 7 in a yield of
89–99%.
4.4. General procedure for the preparation of 3a–e
To a solution of (S)-4-chloroquinazolin acetate 7 (9.58 mmol) in
25 mL of DMF was added 50 mL of NH3 (25% in water) and the
resulting mixture was stirred at room temperature for 12 h. Upon
completion of the ipso substitution of chloride by ammonia (TLC
monitoring), K2CO3 (19.16 mmol) was added to this solution and
the mixture was stirred for an additional 36 h to remove the acetyl
group. The mixture was extracted with ethyl acetate (3 ꢁ 50 mL)
and the combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under vacuum. Purification by
column chromatography (silica gel, hexane–EtOAc, 2:1) gave 4-
aminoquinazoline alcohol 3 in a yield of 83–88%.
4.3.1. (S)-1-(4-Chloroquinazolin-2-yl)ethyl acetate 7a
Crystallization from hexane–EtOAc gave a white powder. Yield:
97%; mp 75–77 °C; 1H NMR (400 MHz, CDCl3, ppm) d 8.24 (d,
J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.93 (ddd, J = 8.4, 7.0,
1.3 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 5.95 (q, J = 6.8 Hz, 1H), 2.20 (s,
1H), 1.72 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) d
170.7, 164.4, 163.1, 151.4, 135.1, 128.9, 128.9, 125.9, 122.9, 73.1,
21.3, 19.8. IR (KBr, cmꢀ1) 3075, 2987, 2936, 1744, 1616, 1572,
1557, 1480, 1371, 1309, 1237, 1086. Anal. Calcd. for C12H11ClN2O2:
C, 57.49; H, 4.42; N, 11.17. Found: C, 57,67; H, 4.29; N, 11.23;
½
a 2D0
ꢂ
¼ ꢀ98:7 (c 1, CH2Cl2).
4.4.1. (S)-1-(4-Aminoquinazolin-2-yl)ethanol 3a
Crystallization from EtOH gave a white powder. Yield: 88%; mp
4.3.2. (S)-1-(4-Chloroquinazolin-2-yl)-2-methylpropyl acetate 7b
Colorless liquid. Yield: 89%; 1H NMR (400 MHz, CDCl3, ppm) d
8.23 (dd, J = 8.4, 1.0 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.93 (ddd,
J = 8.4, 7.0, 1.4 Hz, 1H), 7.68 (ddd, J = 8.4, 7.0, 1.0 Hz, 1H), 5.64 (d,
J = 6.0 Hz, 1H), 2.59–2.44 (m, 1H), 2.21 (s, 3H), 1.00 (d, J = 6.9 Hz,
6H); 13C NMR (100 MHz, CDCl3, ppm) d 171.1, 163.3, 162.8,
151.3, 135.0, 129.0, 128.8, 125.9, 122.8, 81.0, 32.2, 21.1, 19.3,
17.6. IR (KBr, cmꢀ1) 3070, 2967, 2924, 2874, 1741, 1616, 1570,
1481, 1372, 1312, 1236, 1034; MS (FAB) m/z 279 (MH+); HRMS
(FAB); calcd for C14H16ClN2O2 [MH+] 279.0900; found: 279.0896;
174–176 °C; 1H NMR (400 MHz, DMSO-d6, ppm)
d 8.20 (d,
J = 8.2 Hz, 1H), 7.85 (br s, 2H), 7.76–7.70 (m, 1H), 7.67 (d,
J = 8.4 Hz, 1H), 7.46–7.40 (m, 1H), 4.93 (d, J = 4.9 Hz, 1H), 4.58 (qd,
J = 6.5, 4.9 Hz, 1H), 1.39 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6, ppm) d 168.8, 162.8, 150.1, 133.5, 127.7, 125.7, 124.2,
113.9, 69.9, 23.6; IR (KBr, cmꢀ1) 3335, 3103, 1664, 1574, 1558,
1507, 1367, 1348, 1311, 1055. Anal. Calcd for C10H11N3O: C,
63.48; H, 5.86; N, 22.21. Found: C, 63.25; H, 5.85; N, 21.85;
½
a 2D0
ꢂ
¼ ꢀ66:5 (c 1, EtOH); ee: 99%; retention time: 23.0 min, Chiral-
cel OD, 90:10 n-hexane–iPrOH, flow rate of 1 ml/min, 254 nm.
½
a 2D0
ꢂ
¼ ꢀ86:7 (c 1, CH2Cl2).
4.4.2. (S)-1-(4-Aminoquinazolin-2-yl)-2-methylpropan-1-ol 3b
Crystallization from EtOH gave a white powder. Yield: 88%; mp
139–140 °C; d 7.91–7.79 (m, 1H), 7.75 (m, 2H), 7.54–7.37 (m, 1H),
5.96 (br s, 2H), 4.54–4.62 (m, 2H), 2.45–2.21 (m, 1H), 1.13 (d,
J = 6.9 Hz, 1H), 0.74 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3,
ppm) d 166.6, 161.6, 149.6, 133.6, 128.3, 126.0, 122.0, 113.3,
77.4, 33.8, 20.2, 15.5; IR (KBr, cmꢀ1) 3336, 3202, 2963, 2868,
1640, 1618, 1575, 1504, 1463, 1366, 1324, 1143, 1015, 911; Anal.
Calcd for C12H15N3O: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.17;
4.3.3. (S)-1-(4-Chloroquinazolin-2-yl)-2,2-dimethylpropyl
acetate 7c
Colorless liquid. Yield: 96%; 1H NMR (400 MHz, CDCl3, ppm) d
8.23 (ddd, J = 8.3, 1.4, 0.6 Hz, 1H), 8.05 (ddd, J = 8.5, 1.1, 0.6 Hz,
1H), 7.92 (ddd, J = 8.5, 7.0, 1.4 Hz, 1H), 7.68 (ddd, J = 8.3, 7.0,
1.1 Hz, 1H), 5.53 (s, 1H), 2.18 (s, 3H), 1.07 (s, 9H); 13C NMR
(100 MHz, CDCl3, ppm) d 171.2, 162.7, 162.1, 151.2, 134.9, 129.0,
128.8, 125.9, 122.9, 83.7, 35.4, 26.6, 21.2. IR (KBr, cmꢀ1) 2966,
2908, 2863, 1741, 1616, 1570, 1481, 1372, 1310, 1242, 1059,
1028; MS (FAB) m/z 293 (MH+); HRMS (FAB); calcd for
H, 6.89; N, 19.17; ½a D20
¼ ꢀ56:6 (c 1, EtOH); ee: 99%; retention
ꢂ
time: 16.3 min, Chiralcel OD, 90:10 n-hexane–iPrOH, flow rate of
C
15H18ClN2O2 [MH+] 293.1057; found: 293.1052; ½a 2D0
ꢂ
¼ ꢀ17:0 (c
1 ml/min, 210 nm.
1, CH2Cl2).
4.4.3. (S)-1-(4-Aminoquinazolin-2-yl)-2,2-dimethylpropan-1-ol
3c
4.3.4. (S)-(4-Chloroquinazolin-2-yl)(phenyl)methyl acetate 7d
Colorless liquid. Yield: 99%; 1H NMR (400 MHz, CDCl3, ppm) d
8.19 (ddd, J = 8.4, 1.4, 0.6 Hz, 1H), 8.06 (ddd, J = 8.5, 1.0, 0.6 Hz,
1H), 7.91 (ddd, J = 8.5, 7.0, 1.4 Hz, 1H), 7.68–7.61 (m, 3H), 7.40–
7.28 (m, 3H), 6.86 (s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm) d 170.6, 163.2, 162.9, 151.4, 137.2, 135.1, 129.0, 128.9, 128.8,
128.8, 128.1, 125.9, 122.9, 78.4, 21.3; IR (KBr, cmꢀ1) 3066, 3031,
2930, 1745, 1615, 1568, 1482, 1371, 1311, 1233, 1045; MS (FAB)
m/z 313 (MH+); HRMS (FAB); calcd for C17H14ClN2O2 [MH+]
Crystallization from EtOH gave a white powder. Yield: 85%; mp
163–165 °C; 1H NMR (400 MHz, CDCl3, ppm) d 7.83 (d, J = 8.4 Hz,
1H), 7.78–7.72 (m, 2H), 7.44 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 6.04
(br s, 2H), 4.59 (d, J = 6.0 Hz, 1H), 4.35 (d, J = 6.0 Hz, 1H), 1.00 (s,
9H); 13C NMR (100 MHz, CDCl3, ppm) d 165.7, 160.5, 149.4,
133.2, 128.2, 125.8, 121.6, 113.0, 80.5, 36.6, 26.3; IR (KBr, cmꢀ1
)
3333, 3159, 2957, 1660, 1636, 1616, 1576, 1508, 1361, 1321,
1016; Anal. Calcd for C13H17N3O: C, 67.51; H, 7.41; N, 18.17. Found:
313.0744; found: 313.0741; ½a D20
ꢂ
¼ þ52:0 (c 1, CH2Cl2).
C, 67.63; H, 7.48; N, 17.79; ½a D20
¼ ꢀ57:0 (c 1, EtOH); ee: 99%;
ꢂ
retention time: 19.1 min, Chiralcel OD, 90:10 n-hexane–iPrOH,
4.3.5. (S)-1-(4-Chloroquinazolin-2-yl)-2-phenylethyl acetate 7e
Crystallization from hexane–EtOAc gave a white powder. Yield:
97%; mp 78–80 °C; 1H NMR (400 MHz, CDCl3, ppm) d 8.26 (ddd,
J = 8.4, 1.4, 0.6 Hz, 1H), 8.05 (ddd, J = 8.5, 1.1, 0.6 Hz, 1H), 7.95
(ddd, J = 8.5, 7.0, 1.4 Hz, 1H), 7.71 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H),
7.35–7.25 (m, 5H), 7.25–7.19 (m, 1H), 6.07 (dd, J = 9.6, 4.3 Hz,
1H), 3.44 (dd, J = 14.1, 4.3 Hz, A part of AB system, 1H), 3.30 (dd,
J = 14.1, 9.6 Hz, B part of AB system, 1H), 2.13 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d 170.6, 163.2, 163.1, 151.4, 137.1, 135.1,
129.6, 129.0, 129.0, 128.5, 126.9, 126.0, 123.0, 77.3, 40.2, 21.1; IR
(KBr, cmꢀ1) 3070, 3019, 2930, 1744, 1611, 1570, 1482, 1371,
1315, 1233, 1067. Anal. Calcd for C18H15ClN2O2: C, 66.16; H,
flow rate of 1 ml/min, 210 nm.
4.4.4. (S)-(4-Aminoquinazolin-2-yl)(phenyl)methanol 3d
Crystallization from EtOH gave colorless needles. Yield: 83%;
mp 168–171 °C; 1H NMR (400 MHz, CDCl3, ppm) d 7.87 (d,
J = 8.4 Hz, 1H), 7.78 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.57–7.42 (m,
4H), 7.40–7.31 (m, 3H), 5.88 (br s, 2H), 5.65 (s, 1H), 5.59 (s, 1H);
13C NMR (100 MHz, CDCl3, ppm) d 165.4, 161.7, 149.0, 142.8,
133.4, 128.3, 128.1, 127.9, 127.6, 126.1, 121.6, 113.2, 75.1; IR
(KBr, cmꢀ1) 3332, 3182, 1638, 1574, 1503, 1454, 1372, 1323,
1041; Anal. Calcd for C15H13N3O: C, 71.70; H, 5.21; N, 16.72. Found:
C, 71.63; H, 5.46; N, 16.68; ½a D20
¼ þ30:4 (c 1, EtOH); ee: 99%;
ꢂ
4.63; N, 8.57. Found: C, 66.25; H, 4.58; N, 8.61; ½a D20
ꢂ
¼ ꢀ35:5 (c
retention time: 31.4 min, Chiralcel OD, 90:10 n-hexane–iPrOH,
1, CH2Cl2).
Flow rate of 1 ml/min, 220 nm.

M. Cakici et al. / Tetrahedron: Asymmetry 21 (2010) 2027–2031
8. Dandia, A.; Singh, R.; Sarawgi, P. J. Fluorine Chem. 2005, 126, 307–312.
2031
4.4.5. (S)-1-(4-Aminoquinazolin-2-yl)-2-phenylethanol 3e
Crystallization from EtOH gave a white powder. Yield: 87%; mp
131–133 °C; 1H NMR (400 MHz, CDCl3, ppm) d 7.81 (d, J = 8.3 Hz,
1H), 7.75 (t, J = 7.9 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.45 (t,
J = 7.5 Hz, 1H), 7.30–7.20 (m, 4H), 7.20–7.14 (m, 1H), 5.96 (br s,
2H), 4.96 (dd, J = 8.2, 3.7 Hz, 1H), 4.65 (br s, 1H), 3.40 (dd,
J = 13.8, 3.7 Hz, 1H), 3.01 (dd, J = 13.8, 8.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3, ppm) d 166.1, 161.4, 149.5, 138.5, 133.4, 129.6,
128.0, 126.1, 125.9, 121.7, 113.0, 73.9, 43.3; IR (KBr, cmꢀ1) 3336,
3198, 1636, 1617, 1574, 1503, 1454, 1374, 1321, 1058; Anal. Calcd
for C16H15N3O: C, 72.43; H, 5.70; N, 15.84, found: C, 72.23; H, 5.79;
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Acknowledgments
The financial support from the Scientific and Technological Re-
search Council of Turkey (TUBITAK) (TBAG-108T116) is gratefully
acknowledged. In addition, the authors would like to thank Dr.
Graham Eaton from the Leicester University for the HRMS
measurements.
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