Synthesis and Catalytic Asymmetric Applications of Quinazolinol Ligands

Article abstract of DOI:10.1055/s-0035-1561584

A range of chiral quinazolinol ligands were efficiently synthesized and subsequently investigated for catalytic chiral induction in both the asymmetric phenylation of aryl aldehydes and the asymmetric epoxidation of chalcones. Encouragingly, high enantioselectivities (up to 95%) and yields (up to 98%) were achieved under the optimized reaction conditions.

Full text of DOI:10.1055/s-0035-1561584

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
I. Karakaya et al.
Paper
Synthesis
Synthesis and Catalytic Asymmetric Applications of Quinazolinol
Ligands
Idris Karakayaa
Semistan Karabugab
Mehmet Marta
Ramazan Altundasc
Sabri Ulukanli*a
O
OH
L* (10 mol%), Et2Zn
toluene, 0 °C, 24 h
+ PhB(OH)2
R'
R
O
R
Ph
67–98% yield
up to 94% ee
N
R
O
O
N
L* (10 mol%), Et2Zn, CMHP
OH
R1
R2
R1
R2
L*
hexane:THF (10:1), –20 °C, 24 h
a Chemistry Department, Faculty of Science and Letters,
Osmaniye Korkut Ata University, 80000 Osmaniye,
Turkey
52–94% yield
up to 95% ee
sabriulukanli@osmaniye.edu.tr
b Chemistry Department, Faculty of Science and Letters,
Kahramanmaras Sütcü Imam University,
46100 Kahramanmaras, Turkey
c Chemistry Department, Faculty of Science, Ataturk
University, 25240 Erzurum, Turkey
Received: 22.12.2015
Accepted after revision: 24.02.2016
Published online: 17.03.2016
enantiomers using the same chiral ligand by simply inter-
changing the reactive groups on both reaction partners: the
arylboronic acid and aldehyde.8
DOI: 10.1055/s-0035-1561584; Art ID: ss-2015-n0729-op
Another exciting field of asymmetric catalysis is asym-
metric epoxidation of α,β-unsaturated ketones. Containing
both ketone and epoxide moieties, these remarkable chiral
synthons can be easily converted into large quantities of
enantiomerically enriched molecules in a few simple steps.
A wide variety of methods, which are inspired from the
Weitz–Scheffer epoxidation, have been developed for the
enantioselective epoxidation of electron-deficient olefins.9
In general, chiral metal peroxides,10 asymmetric phase-
transfer catalysts,11 enantiomerically pure hydroperox-
ides,12 polyamino acid catalysts,13 chiral dioxiranes,14 L-pro-
line-based derivatives, cinchona alkaloids,15 or other or-
ganocatalysts have been used. Although these methods
have been successful in a number of contexts, the potential
of these catalyst systems has not been fully realized due to
the requirements for large quantities of expensive chiral li-
gands. Several other procedures have been developed that
employ chiral metal complexes bearing zinc, magnesium,16
lithium17 and some lanthanides.18 In particular, Enders has
reported the asymmetric epoxidation of α,β-unsaturated
ketones under oxygen using stoichiometric quantities of di-
ethylzinc and a chiral amino-alcohol,19 while Pu and co-
workers improved this stoichiometric process obtaining
similar results with catalytic amounts of diethylzinc and
chiral polybinaphthyl ligands with stoichiometric tert-butyl
hydroperoxide as the oxidant.20
Abstract A range of chiral quinazolinol ligands were efficiently synthe-
sized and subsequently investigated for catalytic chiral induction in
both the asymmetric phenylation of aryl aldehydes and the asymmetric
epoxidation of chalcones. Encouragingly, high enantioselectivities (up
to 95%) and yields (up to 98%) were achieved under the optimized reac-
tion conditions.
Key words quinazolines, quinazolinones, enantioselective arylations,
Weitz–Scheffer epoxidation, α,β-unsaturated ketones
Enantioselective C–C bond formation is one of the most
frequently studied operations to construct chiral organic
compounds. Therefore, significant efforts have been devot-
ed to designing efficient catalytic systems in recent years.
Among the variety of enantioselective reactions, the aryla-
tion of aldehydes is one of the most attractive research ar-
eas, because optically active aryl carbinols are important
and common precursors for the preparation of pharmaco-
logically and biologically active compounds such as (R)-
neobenodine, (S)-carbinoxamine and (R)-orphenadrine.1 To
date, several useful catalytic approaches have been devel-
oped that employ aryltitanium, phenyllithium,2 diphenyl-
zinc,1b,3 arylboronic acids,4 aryl Grignard reagents,5 aryl
bromides6 and aryltrifluoroborates7 as aryl sources in alde-
hyde addition chemistry. Although some of these reagents
are commercially available, many are very expensive and,
therefore, their cost limits their widespread application. Of
those reagents commonly employed, arylboronic acids are
most attractive due to their low-cost, widespread availabili-
ty, and their chemical robustness (air- and moisture-insen-
sitivity). Furthermore, the widespread availability of boron-
ic acid and benzaldehyde partners enables access to both
In our previous work, we examined quinazolinones and
their derivatives as chiral ligands in the catalytic enantiose-
lective addition of diethylzinc to aldehydes resulting in sec-
ondary alcohols in good to excellent yields and ee values.21
We also showed that the addition of phenylacetylide to al-
dehydes using alcohol derivatives of bisquinazolines gave
the desired propargylic alcohols in modest ee values
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
I. Karakaya et al.
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Synthesis
(75%).22 Furthermore, using 4-phenylquinazolinols 1a–e in
alkynylzinc additions to aldehydes has enabled improved
enantioenrichment of the resulting propargylic alcohols
from 75% to 97% (Scheme 1).23
temperature for four hours in benzene. For the dehalogena-
tion reactions, chloroquinazolines 3a–d were treated with
NaBH4 and TMEDA with a catalytic amount of Pd(PPh3)4 (5
mol%) at reflux under an N2 atmosphere for two hours. Fi-
nally, the synthesis of the chiral ligands was completed by
removal of the TBDMS protecting groups using TBAF in THF
for three hours. The chiral 4H-quinazoline alcohols 5a–d
were obtained in enantiopure form (99% ee). To synthesize
5a–d we also attempted to dehalogenate the acetylated pro-
tected chloroquinazolines 6a–d; unfortunately, this result-
ed in very low yields ranging between 30–40%. Switching
OAc to the TBDMS protecting group improved the yields
dramatically, affording 4H-quinazolines 4a–d in excellent
yields (71–85%).
L* (1a) (10 mol%)
Ti(Oi-Pr)4 (40 mol% )
OH
O
Ph
+
R
R
H
Et2Zn, THF, –10 °C
Ph
up to 97% ee
OH
N
R
N
The chiral 4-phenylquinazolinol ligands 1a–d were easi-
ly prepared starting from (S)-3H-quinazolinones following
O-protection with Ac2O, chlorination with POCl3 and Suzuki
coupling with PhB(OH)2 in three steps, as recently report-
ed.23 While we were able to synthesize the ligands 1a–d in
enantiopure form, ligand 1e could only be obtained in 72%
ee (Scheme 3).
The reaction conditions were revised in an attempt to
achieve an enantiopure form of ligand 1e. It was reasoned
that high temperature and basic conditions could be the
cause of the racemization. Lowering the reaction tempera-
ture to room temperature allowed the isolation of ligand 1e
with much higher enantiopurity (91%), but even when con-
tinued for two weeks the reaction yield remained less than
5%. Also, we attempted to accelerate the reaction and avoid
racemization by performing the reaction in a Schlenk tube
at high temperature (about 150 °C). Although the reaction
was completed in 30 minutes, the enantiopurity remained
around 10%. Additionally, employing a Grignard protocol
with chloroquinazolines following established literature24
failed to give better enantiopurity, affording ligand 1e with
identical enantioinduction to that obtained in the first
method (Scheme 4).
1a R = Me; 1b R = i-Pr; 1c R = t-Bu;
1d R = Bn; 1e R = Ph
Scheme 1 Catalytic enantioselective alkynylzinc additions to alde-
hydes
In the present work we sought to synthesize quinazo-
line alcohols 5a–d containing hydrogen instead of a phenyl
group at the 4-position in order to explore the catalytic ac-
tivity of these ligands (not only 5a–d, but also 1a–e) in both
the catalytic asymmetric addition of phenylzinc species to
aryl aldehydes and in the catalytic enantioselective epoxi-
dation of chalcones.
Synthesis of Chiral Ligands
The syntheses of 4H-quinazolinols 5a–d were carried
out according to the general synthetic route shown in
Scheme 2. The quinazolinone alcohols 2a–d were prepared
according to the literature,22 and these alcohols were subse-
quently protected with tert-butyldimethylsilyl chloride
(TBDMSCl) in the presence of imidazole by heating at reflux
temperature for two hours in DMF. To obtain the chloro-
quinazolines 3a–d, the TBDMS-protected quinazolinones
were reacted with POCl3 and N,N-diethylaniline at reflux
Cl
N
O
N
N
TBAF
NaBH4, TMEDA, Pd(PPh3)4
THF, 60 °C, 2 h
N
NH
R
R
N
R
R
N
THF, r.t., 3 h
N
OH
OTBDMS
OTBDMS
OH
4a–d
5a–d
2a–d
3a–d
Scheme 2 Synthesis of 4H-quinazolinols 5a–d
OH
O
N
Cl
PhB(OH)2, Pd(PPh3)4,
R
Na2CO3
NH
N
N
R
EtOH, DME, 110 °C, 12 h
R
N
N
OH
OAc
2a–e
6a–e
1a–e
Scheme 3 Synthesis of 4-phenylquinazolinol ligands 1a–e
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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I. Karakaya et al.
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Synthesis
Table 1 Asymmetric Addition of Phenylzinc to m-Methoxybenzalde-
hyde Catalyzed by Ligands 1a–e and 5a–d
PhB(OH)2, Pd(PPh3)4,
Na2CO3
ligand 1e
91% ee
Cl
EtOH, DME, r.t., 2 weeks
<5% yield
O
OH
N
L* (10% mol)
Et2Zn (6 equiv)
Ph
OAc
Ph
N
+ PhB(OH)2
PhB(OH)2, Pd(PPh3)4,
Na2CO3
6e
toluene, 0 °C, 24 h
ligand 1e
10% ee
95% yield
OMe
OMe
EtOH, DME,150 °C, 30 min
PhMgBr, MnCl2
THF, 0 °C
Entry Ligand (mol%) Co-cat.
ee (%)a
Yield (%)b Configc
ligand 1e
72% ee
80% yield
1
2
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
5a (10)
5b (10)
5c (10)
5d (10)
1c (20)
1c (5)
–
24
39
75
29
35
15
23
40
26
75
63
66
54
69
70
70
75
62
61
74
84
80
65
70
72
67
77
85
90
75
89
76
73
89
89
50
94
76
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
–
Scheme 4 Revised reaction conditions for the synthesis of ligand 1e
3
–
4
–
5
–
Application of Enantioselective Phenylboronic Acid
Addition to Aldehydes
6
–
In order to examine the catalytic asymmetric induction
abilities of the ligands, we initiated our research by choos-
ing m-methoxybenzaldehyde as a model substrate for phe-
nylation. As model reaction conditions, 10 mol% of the li-
gand in toluene at 0 °C was initially selected. The phenyl-
zinc reagent was prepared in situ by transmetalation using
diethylzinc and phenylboronic acid in toluene at 60 °C for
12 hours. All the ligands (1a–e and 5a–d) were then
screened in the model reaction and furnished the desired
alcohol in moderate to high yields with varying levels of en-
antiocontrol (15–75% ee) (Table 1).
In general, the 4-phenylquinazoline ligands 1a–e gave
better enantioselectivities than the 4H-quinazoline ligands
5a–d. In light of these results, it can be argued that the
strong electron-donating phenyl substitution at the 4-posi-
tion of the ligand provides a favorable effect on the enantio-
selection compared to the weak electron-donating hydro-
gen. For both ligand families, as the size of the alkyl group
attached to the chiral center increased, the enantiomeric
excess of the diarylmethanols gradually improved, with the
bulkiest ligand 1c giving the best enantioselectivity (75%).
Benzyl and phenyl substituents at the chiral center of the 4-
phenylquinazoline ligands 1d,e resulted in the desired alco-
hol having enantioselectivities of 29% and 35%, respectively.
While the product yield improved with a 20% catalyst load-
ing, the enantiomeric excess remained the same. However,
in the presence of less ligand (5 mol%), the enantioselectivi-
ty and yield of the alcohol were slightly diminished. There-
fore, 10 mol% of 1c was selected to explore the effects of
other reaction parameters such as solvent, co-catalyst,
equivalents of Et2Zn and temperature.
7
–
8
–
9
–
10
11
12
13
14
15
16
17
18
19
–
–
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)d
1c (10)e
1c (10)f
1c (10)g
molecular sieves
HMPA
N-ethylimidazole
Ti(Oi-Pr)4
–
–
–
–
a Determined by chiral HPLC (Chiralcel OD-H).
b Yield of isolated product.
c The absolute configuration of the adduct was assigned in accordance with
the literature.25
d Et2Zn (4 equiv) was used.
e Et2Zn (7 equiv) was used.
f The reaction was conducted at r.t.
g The reaction was conducted at –10 °C.
screening conditions employed an excess of Et2Zn/PhB(OH)2
because reducing or increasing the amount had no effect on
the enantioselectivities nor the product yields. With opti-
mized conditions in hand, we next studied the phenylbo-
ronic acid addition to several aromatic aldehydes (Table 2).
The electron-deficient o-, m- and p-chlorobenzalde-
hydes, m-bromobenzaldehyde and 1-naphthylaldehyde
(Table 2, entries 2–5 and 9) gave moderate enantioselectivi-
ties, ranging between 50% and 66% ee, and good to excellent
yields. Remarkably, the best enantioselectivity (94%) was
obtained from the reaction with p-bromo-substituted
benzaldehyde (Table 2, entry 6). Electron-rich m-methoxy-
benzaldehyde and m- and p-substituted methylbenzalde-
hydes (Table 2, entries 1, 7 and 8) produced very good en-
antioselection (75–92% ee) and yields (77–98%) of the cor-
responding diaryl carbinols. p-Nitrobenzaldehyde gave only
Hexanes, THF and diethyl ether gave similar enantiose-
lectivity (70% ee for hexanes, 64% ee for THF, 60% ee for di-
ethyl ether), but worse than when using toluene. We also
investigated the effects of co-catalysts such as molecular
sieves, HMPA, N-ethylimidazole and Ti(Oi-Pr)4 in this addi-
tion reaction. However, none of these provided improve-
ments in the ee values. It was apparent that the standard
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
I. Karakaya et al.
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Synthesis
41% ee but returned a good yield (86%) (Table 2, entry 10).
To ensure the scalability of this process, a gram-scale reac-
tion was established with p-methylbenzaldehyde and the
desired carbinol was produced with the same enantioselec-
tivity and in a higher yield (Table 2, entry 8).25
Table 3 Asymmetric Epoxidation of (E)-Chalcone Catalyzed by Ligands
1a–e and 5a–d
O
L*
O
Et2Zn
O
CMHP (1.2 equiv)
hexane–THF (10:1)
Table 2 Asymmetric Addition of Phenylboronic Acid to Aromatic Alde-
hydes Using Ligand 1c as the Catalyst
Entry
Ligand (mol%) Et2Zn (mol%) Temp (°C) ee (%)a
Yield (%)b
1
2
1a (20)
1b (20)
1c (20)
1d (20)
1e (20)
5a (20)
5b (20)
5c (20)
5d (20)
–
20
20
20
20
20
20
20
20
20
20
30
20
10
5
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
33
45
42
68
72
40
40
33
54
0
95
86
79
92
90
98
88
78
67
78
86
75
83
65
77
80
82
94
65
79
86
90
1c (10% mol)
Et2Zn (6 equiv)
O
OH
+
PhB(OH)2
3
toluene, 0 °C
R
R
P
4
Entry
R
ee (%)a
Yield (%)b
Configc
5
1
2
m-MeOC6H4
o-ClC6H4
75
65
66
50
61
94
92
85
51
41
98
S26
R27
S28
–
6
67
7
3
m-ClC6H4
p-ClC6H4
96
8
4
95
9
5
m-BrC6H4
p-BrC6H4
78
S28
R29
–
10
11
12
13
14
15
16
17
18
19
20c
21d
22e
0
6
82
1e (30)
1e (20)
1e (10)
1e (5)
0
0
87
81
88
84
65
47
92
95
96
94
94
70
7
m-MeC6H4
p-MeC6H4
1-naphthyl
p-O2NC6H4
98
8
77 (85)d
75
S27
S26
S4d
0
9
0
10
86
1e (10)
1e (10)
1e (10)
1e (10)
1e (10)
1e (10)
1e (10)
1e (10)
5
0
a Determined by chiral HPLC (Chiralcel OD-H).
b Yield of isolated product.
15
10
10
10
10
10
10
0
c The absolute configuration of the adduct was assigned in accordance with
–10
–20
–30
–20
–20
–20
the literature.
d Reaction run on gram scale.
Application to the Enantioselective Epoxidation of
Chalcones
To determine optimum reaction conditions for the ep-
oxidation of chalcones, a model reaction was performed us-
ing (E)-chalcone in the presence of a chiral ligand (20 mol%)
and cumene hydroperoxide (CMHP) (1.2 equiv) at ambient
temperature in hexanes for 24 hours under an inert atmo-
sphere. The results are summarized in Table 3. All the chiral
quinazolinols (1a–e, 5a–d) were examined under these
conditions and interestingly, the best enantioselection was
obtained in the presence of ligand 1e which can be synthe-
sized in up to 72% ee from L-mandelic acid. The other li-
gands (1a–d and 5a–c) gave much lower enantioselectivi-
ties (between 33–54%), except for ligand 1d (68% ee) de-
rived from L-phenylalanine. Further examination was
carried out to obtain better enantioselectivity via screening
the ligand and Et2Zn loadings. It was observed that the best
ligand and Et2Zn loading ratio was 10 mol%. To optimize the
process further, different temperatures were screened and
the best result was achieved at –20 °C. A series of solvents
were also screened, but with no apparent improvements
being identified.
a Determined by chiral HPLC (Chiralcel OD-H).
b Yield of isolated product.
c Reaction in heptanes.
d Reaction in decane.
e Reaction in toluene.
With suitable conditions in hand [chalcone (1.0 equiv),
CMHP (1.2 equiv), ligand 1e (10 mol%), Et2Zn (10 mol%),
hexanes–THF (10:1), –20 °C, 24 h], an exploration of the
scope of the chalcones was initiated. As shown in Table 4,
different chalcones were converted into the corresponding
epoxides with modest to high enantiomeric excess. Elec-
tron-rich methoxy groups at the para positions of the phe-
nyl rings at both sides of the chalcones showed similar ef-
fects on the asymmetric epoxidation (induction) (Table 4,
entries 2 and 3). Interestingly, an o-methoxy substituent at
the α-position of the chalcone gave enhanced enantioselec-
tivity and a high reaction yield (Table 4, entry 4). Similarly,
the substrate bearing an o-chlorophenyl at the β-position of
the chalcone gave high selectivity and yield (Table 4, entry
6), while the p-chlorophenyl substituent on the phenacyl
group at the α-position of the chalcone resulted in moder-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
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Synthesis
ate selectivity (Table 4, entry 7). Although the high reaction
yield was maintained, the enantiopurity of the product re-
mained very low in the presence of an electron-deficient p-
bromophenyl substituent at the β-position (Table 4, entry
5).
The full experimental details for 1a–e are provided in our previous
publication.23 Reagents and solvents were purchased from chemical
suppliers and purified to match the reported physical and spectro-
scopic data. Column chromatography was performed on Aldrich silica
gel (230–400 mesh). Solvents were concentrated under reduced pres-
sure. Melting points were determined with a Gallenkamp apparatus.
IR spectra (KBr pellets) were obtained on a Perkin–Elmer spectrome-
Table 4 Asymmetric Epoxidation of Chalcones Using Ligand 1ea as the
1
ter. H and 13C NMR spectra were recorded on Varian (200, 400) and
Catalyst
Bruker 400 spectrometers in CDCl3. Enantiomeric excesses were de-
termined by HPLC analysis using a chiral column (eluent, n-hexane–
i-PrOH) and detection was performed at 254 nm. Optical rotations
were measured with a Bellingham +Stanley, ADP220, 589 nm spec-
tropolarimeter in a 1 dm tube; concentrations are given in g/100 mL.
L* (1e) (10 mol%)
Et2Zn (10 mol%)
CMHP (1.2 equiv)
O
O
O
R1
R2
R1
R2
hexane–THF (10:1)
–20 °C, 24 h
(S)-2-{1-[(tert-Butyldimethylsilyl)oxy]ethyl}quinazoline (4a); Typ-
ical Procedure 1
Entry
R1
Ph
R2
Ph
ee (%)
Yield (%) Configb
To a solution of (S)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-chlo-
roquinazoline (3a) (2 g, 6.19 mmol) in dry THF (15 mL) was added
TMEDA (1.22 g, 10.53 mmol), Pd(PPh3)4 (190 mg, 0.165 mmol) and
NaBH4 (398 mg, 10.53 mmol), and the mixture was heated at reflux
temperature for 2 h under an N2 atm. The mixture was cooled to r.t.,
diluted with CH2Cl2 (100 mL) and washed with H2O (3 × 50 mL). The
separated organic phase was dried over Na2SO4 and concentrated un-
der reduced pressure. The crude residue was purified by column
chromatography (hexanes–EtOAc, 20:1) to give (S)-2-{1-[(tert-bu-
tyldimethylsilyl)oxy]ethyl}quinazoline (4a) as a colorless oil in 80%
yield (1.42 g).
[α]D20 –16 (c 2.5, CH2Cl2).
IR (KBr): 2928, 2855, 1620, 1585, 1488, 1251, 1098 cm–1
1H NMR (400 MHz, CDCl3): δ = 9.35 (s, 1 H), 8.98 (d, J = 6.53 Hz, 1 H),
7.86–7.55 (m, 3 H), 5.17 (q, J = 6.51 Hz, 1 H), 1.58 (d, J = 6.51 Hz, 3 H),
0.83 (s, 9 H), 0.00 (s, 6 H).
1
2
3
4
5
6
7
8
95
82
81
92
26
90
67
75
94
65
52
86
93
88
85
88
2R,3S30
2S,3R30
2S,3R13b
–
p-MeOC6H4
Ph
Ph
p-MeOC6H4
o-MeOC6H4
Ph
Ph
p-BrC6H4
o-ClC6H4
Ph
–
Ph
2R,3S30
2R,3S13b
2R,3S30
p-ClC6H4
p-MeC6H4
Ph
a Ligand 1e (72% enantioenriched) was used.
b The absolute configuration of the adduct was assigned in accordance with
the literature.
.
In summary, we have successfully developed methods
for the catalytic asymmetric phenylation of arylaldehydes
and the epoxidation of chalcones in the presence of chiral
quinazolinols (1a–e and 5a–d). Contrary to the more ex-
pensive diphenylzinc, phenylboronic acids proved to be
highly effective reagents for phenyl group transfer in the
asymmetric phenylation of aromatic aldehydes. Our results
demonstrate that the chiral environment at the 2-position
of the quinazolinol has a crucial effect on enantioinduction,
where greater steric bulk (increasing from methyl to tert-
butyl) provides significant enhancement. Generally, elec-
tron-donating aldehydes brought about higher enantiose-
lection, while the addition of phenylboronic acid to alde-
hydes with electron-withdrawing substituents afforded the
corresponding carbinols with moderate enantioselectivi-
ties. Additionally, in Weitz–Scheffer epoxidations, chal-
cones with electron-deficient substituents were converted
into the corresponding optically active epoxyketones, with
high yields and enantioselectivities, via reactions involving
nucleophilic CMHP. We anticipate that due to the simplicity
of the ligand synthesis and the ease of ligand modification,
these chiral quinazolinols may establish a new set of func-
tional catalysts for other enantioselective reactions.
13C NMR (100 MHz, CDCl3): δ = 168.6, 160.8, 150.2, 134.0, 128.4,
127.4, 127.1, 123.8, 73.1, 25.9, 25.7, 23.9, 18.5, –3.6, –4.6, –4.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H25N2OSi: 289.1738; found:
289.1733.
(S)-2-{1-[(tert-Butyldimethylsilyl)oxy]-2-methylpropyl}quinazo-
line (4b)
Typical procedure 1 was followed using (S)-2-{1-[(tert-butyldimeth-
ylsilyl)oxy]-2-methylpropyl}-4-chloroquinazoline (3b) (550 mg, 1.56
mmol), TMEDA (309 mg, 2.66 mmol), Pd(PPh3)4 (89 mg, 0.078 mmol)
and NaBH4 (100.6 mg, 2.66 mmol) in a solution of THF (10 mL). The
crude residue was purified by column chromatography (hexanes–
EtOAc, 20:1) to give (S)-2-{1-[(tert-butyldimethylsilyl)oxy]-2-methyl-
propyl}quinazoline (4b) as a colorless oil in 85% yield (420 mg).
[α]D20 –48.8 (c 2.5, CH2Cl2).
IR (KBr): 3063, 2957, 2856, 1620, 1585, 1487, 1252, 1071 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.38 (s, 1 H), 8.02 (dd, J = 8.5 Hz, 0.74
Hz, 1 H), 7.89–7.58 (m, 3 H), 4.62 (d, J = 7.7 Hz, 1 H), 2.28 (m, 1 H),
1.05 (d, J = 6.6 Hz, 3 H), 0.80 (s, 9 H), 0.76 (d, J = 6.6 Hz, 3 H), 0.00 (s, 3
H), –0.17 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.8, 160.5, 150.0, 134.0, 128.4,
127.4, 127.1, 123.7, 82.5, 34.8, 25.9, 19.1, 18.7, 18.4, –4.6, –4.9.
HRMS (ESI): m/z [M + H]+ calcd for C18H29N2OSi: 317.2051; found:
317.2054.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
I. Karakaya et al.
Paper
Synthesis
(S)-2-{1-[(tert-Butyldimethylsilyl)oxy]-2,2-dimethylpro-
13C NMR (100 MHz, CDCl3): δ = 168.1, 160.9, 149.5, 134.6, 127.9,
pyl}quinazoline (4c)
127.6, 127.3, 123.7, 69.9, 23.3.
HRMS (ESI): m/z [M + H]+ calcd for C10H11N2O: 175.0873; found:
175.0872.
Typical procedure 1 was followed using (S)-2-{1-[(tert-butyldimeth-
ylsilyl)oxy]-2,2-dimethylpropyl}-4-chloroquinazoline (3c) (1.4 g, 3.84
mmol), TMEDA (0.76 g, 6.54 mmol), Pd(PPh3)4 (0.22 g, 0.192 mmol)
and NaBH4 (0.25 g, 6.54 mmol) in a solution of THF (10 mL). The crude
residue was purified by column chromatography (hexanes–EtOAc,
20:1) to give (S)-2-{1-[(tert-butyldimethylsilyl)oxy]-2,2-dimethyl-
propyl}quinazoline (4c) as a colorless oil in 71% yield (0.9 g).
(S)-2-Methyl-1-(quinazolin-2-yl)propan-1-ol (5b)
Typical procedure 2 was followed using (S)-2-{1-[(tert-butyldimeth-
ylsilyl)oxy]-2-methylpropyl}quinazoline (4b) (275 mg, 0.87 mmol)
and TBAF (315 mg, 2.61 mmol) in a solution of THF (5 mL). The crude
residue was purified by column chromatography (hexanes–EtOAc,
6:1) to give (S)-2-methyl-1-(quinazolin-2-yl)propan-1-ol (5b) as a
colorless solid in 88% yield (155 mg).
[α]D20 –51.1 (c 1.8, CH2Cl2).
IR (KBr): 3063, 2955, 2857, 1675, 1620, 1566, 1472, 1101 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.38 (s, 1 H), 8.02 (d, J = 8.5 Hz, 1 H),
7.90–7.58 (m, 3 H), 4.75 (s, 1 H), 0.99 (s, 9 H), 0.85 (s, 9 H), –0.01 (s, 3
H), –0.27 (s, 3 H).
Mp 25–27 °C; [α]D20 +2.5 (c 0.4, CH2Cl2); ee 99%; tR = 8.4 min (Chiralcel
OD-H; n-hexane–i-PrOH, 90:10; flow rate = 1 mL/min; 254 nm).
IR (KBr): 3452, 3063, 2961, 1620, 1585, 1488, 1376, 1019 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 167.1, 159.6, 149.8, 133.8, 128.5,
127.3, 127.0, 123.6, 84.1, 40.6, 36.7, 26.4, 25.9, 25.7, 18.3, 18.1, –2.9,
–4.7, –5.1.
HRMS (ESI): m/z [M + H]+ calcd for C19H31N2OSi: 331.2200; found:
331.2206.
1H NMR (400 MHz, CDCl3): δ = 9.40 (s, 1 H), 8.04 (d, J = 8.12 Hz, 1 H),
7.97–7.64 (m, 3 H), 4.87 (dd, J = 6.01 Hz, 3.35 Hz, 1 H), 4.32 (d, J = 6.01
Hz, 1 H), 2.44 (m, 1 H), 1.17 (d, J = 6.93 Hz, 3 H), 0.74 (d, J = 6.72 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 166.9, 160.5, 149.3, 134.5, 128.0,
(S)-2-{1-[(tert-Butyldimethylsilyl)oxy]-2-phenylethyl}quinazo-
127.6, 127.3, 123.7, 34.0, 19.9, 15.4.
line (4d)
HRMS (ESI): m/z [M + H]+ calcd for C12H15N2O: 203.1186; found:
Typical procedure 1 was followed using (S)-2-{1-[(tert-butyldimeth-
ylsilyl)oxy]-2-phenylethyl}-4-chloroquinazoline (3d) (260 mg, 0.65
mmol), TMEDA (128.5 mg, 1.1 mmol), Pd(PPh3)4 (37 mg, 0.032 mmol)
and NaBH4 (41.9 mg, 1.1 mmol) in a solution of THF (5 mL). The crude
residue was purified by column chromatography (hexanes–EtOAc,
20:1) to give (S)-2-{1-[(tert-butyldimethylsilyl)oxy]-2-phenyleth-
yl}quinazoline (4d) as a colorless oil in 80% yield (189 mg).
203.1187.
(S)-2,2-Dimethyl-1-(quinazolin-2-yl)propan-1-ol (5c)
Typical procedure 2 was followed using (S)-2-{1-[(tert-butyldimeth-
ylsilyl)oxy]-2,2-dimethylpropyl}quinazoline (4c) (720 mg, 2.17
mmol) and TBAF (2.06 g, 6.53 mmol) in a solution of THF (5 mL). The
crude residue was purified by column chromatography (hexanes–
EtOAc, 9:1) to give (S)-2,2-dimethyl-1-(quinazolin-2-yl)propan-1-ol
(5c) as a colorless solid in 75% yield (352 mg).
[α]D20 –20.0 (c 3.5, CH2Cl2).
IR (KBr): 3063, 2954, 2855, 1619, 1570, 1471, 1255, 1098 cm–1
.
Mp 62–65 °C; [α]D20 –21.54 (c 1.3, CH2Cl2); ee 99%; tR = 6.0 min (Chi-
ralcel OD-H; n-hexane–i-PrOH, 90:10; flow rate = 1 mL/min; 254
nm).
1H NMR (400 MHz, CDCl3): δ = 9.43 (s, 1 H), 8.06 (d, J = 8.56 Hz, 1 H),
7.93–7.16 (m, 8 H), 5.18 (dd, J = 9.25 Hz, 4.09 Hz, 1 H), 3.19 (m, 2 H),
0.69 (s, 9 H), –0.21 (s, 3 H), –0.27 (s, 3 H).
IR (KBr): 3462, 2955, 1620, 1574, 1489, 1377, 1067 cm–1
1H NMR (400 MHz, CDCl3): δ = 9.37 (s, 1 H), 8.04–7.27 (m, 4 H), 4.66
(d, J = 7.69 Hz, 1 H), 4.32 (d, J = 7.69 Hz, 1 H), 1.02 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 166.3, 159.4, 149.3, 134.3, 128.1,
127.6, 127.2, 123.7, 81.0, 36.9, 26.2.
.
13C NMR (100 MHz, CDCl3): δ = 167.6, 160.8, 150.2, 138.7, 134.1,
130.1, 128.4, 128.1, 127.5, 127.2, 126.3, 123.8, 78.7, 44.3, 25.7, 25.7,
18.3, –2.9, –5.2, –5.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H29N2OSi for: 365.2044; found:
365.2029.
HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O: 217.1342; found:
217.1345.
(S)-1-(Quinazolin-2-yl)ethan-1-ol (5a); Typical Procedure 2
TBAF (2.65 g, 8.42 mmol) was added in portions to a solution of (S)-2-
{1-[(tert-butyldimethylsilyl)oxy]ethyl}quinazoline (4a) (810 mg, 2.8
mmol) in THF (5 mL), and the resulting mixture was stirred for 3 h at
ambient temperature. The reaction was quenched with sat. NH4Cl (50
mL) and extracted with CH2Cl2 (2 × 50 mL). The organic phase was
dried over Na2SO4 and concentrated under reduced pressure. The
crude residue was purified by column chromatography (hexanes–
EtOAc, 6:1) to give (S)-1-(quinazolin-2-yl)ethan-1-ol (5a) as a color-
less oil in 91% yield (443 mg).
(S)-2-Phenyl-1-(quinazolin-2-yl)ethan-1-ol (5d)
Typical procedure 2 was followed using (S)-2-{1-[(tert-butyldimeth-
ylsilyl)oxy]-2-phenylethyl}quinazoline (4d) (1 g, 2.74 mmol) and
TBAF (2.59 g, 8.22 mmol) in a solution of THF (10 mL). The crude resi-
due was purified by column chromatography (hexanes–EtOAc, 9:1) to
give (S)-2-phenyl-1-(quinazolin-2-yl)ethan-1-ol (5d) as a colorless
solid in 86% yield (590 mg).
Mp 85–87 °C; [α]D20 –78.67 (c 1.5, CH2Cl2); ee 99%; tR = 12.8 min (Chi-
ralcel OD-H; n-hexane–i-PrOH, 90:10; flow rate = 1 mL/min; 254
nm).
20
[α]D –6.67 (c 1.5, CH2Cl2); ee 99%; tR = 6.4 min (Chiralcel OD-H; n-
hexane–i-PrOH, 90:10; flow rate = 1 mL/min; 254 nm).
IR (KBr): 3430, 2975, 1620, 1586, 1489, 1377, 1103 cm–1
.
IR (KBr): 3251, 1619, 1565, 1087 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.40 (s, 1 H), 8.03 (d, J = 8.47 Hz, 1 H),
7.96–7.64 (m, 3 H), 5.12 (m, 1 H), 4.50 (d, J = 4.67 Hz, 1 H), 1.67 (d, J =
6.64 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 9.41 (s, 1 H), 7.99–7.93 (m, 3 H), 7.67
(ddd, J = 8.09 Hz, 6.91 Hz, 1.17 Hz, 1 H), 7.25–7.22 (m, 4 H), 7.20–7.15
(m, 1 H), 5.57 (dd, J = 7.65 Hz, 3.80 Hz, 1 H), 4.34 (br s, 1 H), 3.49 (dd,
J = 13.76 Hz, 3.83 Hz, 1 H), 3.12 (dd, J = 13.77 Hz, 7.68 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
I. Karakaya et al.
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Synthesis
13C NMR (100 MHz, CDCl3): δ = 166.7, 160.9, 149.6, 138.1, 134.8,
129.9, 128.4, 128.4, 128.2, 127.9, 127.5, 126.5, 123.9, 74.5, 43.7.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O: 251.1186; found:
251.1189.
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M.; Alberto, E. E.; Paixao, M. W.; Soares, L. A.; Schneider, P. H.;
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Norrby, P. O. J. Am. Chem. Soc. 2005, 127, 1548.
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(b) Tatina, M. B.; Kusunuru, A. K.; Mukherjee, D. Org. Lett. 2015,
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C.; Chang, J. B. J. Org. Chem. 2014, 79, 6087. (d) Moro, A. V.;
Tiekink, E. R. T.; Zukerman-Schpector, J.; Ludtke, D. S.; Correia,
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Catalytic Asymmetric Addition of Phenylzinc Species to Alde-
hydes; General Procedure
Et2Zn (2.41 mL, 1 M in hexanes) was added in one portion to a solu-
tion of phenylboronic acid (100 mg, 0.81 mmol) in toluene (2 mL) in a
10 mL oven-dried sealed tube (N2 atm), and the mixture was heated
for 12 h at 60 °C. The mixture was cooled to r.t. and a solution of chi-
ral ligand 1c (12 mg, 0.04 mmol) in toluene (0.5 mL) was syringed
into the sealed tube and the contents stirred for a further 30 min. The
reaction mixture was then cooled to 0 °C. After 10 min, a solution of
freshly distilled aldehyde (0.41 mmol) in toluene (0.5 mL) was added
and the mixture was stirred for 24 h at 0 °C. The reaction mixture was
quenched with HCl (5 wt%, 6 mL) and extracted with EtOAc (3 × 5
mL). The organic phase was dried over anhydrous Na2SO4, filtered and
concentrated. The crude residue was purified by flash column chro-
matography (EtOAc and hexane) to give the product. The enantiomer-
ic excess was determined by HPLC using a Chiralcel OD-H column.
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Catalytic Asymmetric Epoxidation of Chalcones; General Proce-
dure
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Chiral ligand 1e (0.024 mmol) was added to a sealed tube and the
tube was purged with N2 (× 3). Dry hexanes (ca. 1 mL) was added and
the mixture stirred for 10 min. Et2Zn (0.024 mmol, 1 M in hexanes)
was then added to the reaction mixture. After stirring for 1 h at ambi-
ent temperature, a solution of the chalcone (0.24 mmol) in hexanes–
THF (1.2 mL, 5:1) was added to the suspension and stirring was con-
tinued for 30 min. The temperature was decreased to –20 °C and
CMHP (0.36 mmol, 1.6 M in toluene) was added to the reaction mix-
ture. The resulting mixture was stirred for 24 h, and then quenched
with sat. NaHSO3 (5 mL) and extracted with EtOAc (3 × 5 mL). The
combined organic layers were dried (Na2SO4), filtered, concentrated
under reduced pressure, and the residue purified by column chroma-
tography (EtOAc and hexane) to afford the corresponding epoxide.
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Org. Lett. 2010, 12, 3564. (b) Demizu, Y.; Yamagata, N.; Nagoya,
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Acknowledgment
We thank David N. Primer (University of Pennsylvania) for proofread-
ing.
(16) Calvalho, J. F. S.; Silva, M. M. C.; Melo, M. L. S. E. Tetrahedron
2009, 65, 2773.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561584.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H