α-Alkylation of N-C Axially Chiral Quinazolinone Derivatives Bearing Various ortho -Substituted Phenyl Groups: Relation between Diastereoselectivity and the ortho -Substituent

Article abstract of DOI:10.1055/s-0037-1610110

2-Ethylquinazolin-4-one derivatives bearing various ortho -substituted phenyl groups were revealed to possess a stable C-N axially chiral structure at ambient temperature. The reactions of alkyl halides with the anionic species prepared from these quinazolinones were systematically explored. The α-alkylation reactions proceeded with diastereoselectivities ranging from 1:1 to >50:1, depending upon the steric bulk of the ortho -substituent, to afford products having the elements of axial and central chirality in high yields (85-98%).

Full text of DOI:10.1055/s-0037-1610110

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
cluster
A
en
M. Matsuoka et al.
Cluster
Synlett
α-Alkylation of N–C Axially Chiral Quinazolinone Derivatives Bear-
ing Various ortho-Substituted Phenyl Groups: Relation between
Diastereoselectivity and the ortho-Substituent
Mizuki Matsuoka
axial chirality
X
X
O
O
Asumi Iida
axial chirality
1) LiHMDS
2) R-Y
Osamu Kitagawa*
0
0
0
0
0-
0
0
1
7-
9
6
4
1-
8
7
9
N
N
R
THF, –20 °C
N
N
C2H5
Department of Applied Chemistry, Shibaura Institute of
Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo, 135-8548,
Japan
central chirality
Me
12 examples (85–98%)
X = F, Cl, Me, Br, Et, I, i-Pr, CF3
diastereoselectivity
kitagawa@shibaura-it.ac.jp
Published as part of the Cluster Atropisomerism
high
low
Dedicated to the late Professor Kurt Mislow with the
deepest respect.
Received: 19.03.2018
Accepted after revision: 11.04.2018
Published online: 29.05.2018
Although stereoselective reactions of C–N axially chiral
compounds have been reported by many groups,3 the rela-
tionship between the stereoselectivity and the ortho-sub-
stituent has not yet been systematically investigated. In
substrates possessing a small ortho-substituent (low rota-
tional barrier), the evaluation of stereoselectivity should be
difficult because interconversion between diastereomeric
products through C–N bond rotation occurs readily at am-
bient temperature. For examples, amides IIIa and imides
IVa bearing an ortho-tert-butylphenyl group have stable C–N
axially chiral structures (ΔG‡ = 28–30 kcal mol–1), and high-
ly diastereoselective reactions with IIIa and IVa have been
achieved,3a–e whereas the rotational barriers of the ortho-
methyl derivatives IIIb and IVb were too low (ΔG‡ ≈ 20 kcal
mol–1) to permit the isolation of diastereomeric prod-
ucts.3a,b
We recently reported diastereoselective α-alkylations of
C–N axially chiral 2-ethylquinazolin-4-one bearing an ortho-
bromophenyl group on the nitrogen atom (Scheme 1).4 The
reaction proceeded in a stereocontrolled manner, as a result
of the axial chirality of the substrate, to afford the (P, S)-iso-
mer as the major product. The diastereoselectivity strongly
depended on the steric bulk of alkyl halide (dr = 3.8:1 to
25.6:1) and it increased with increasing the bulkiness of
DOI: 10.1055/s-0037-1610110; Art ID: st-2018-d0173-c
Abstract 2-Ethylquinazolin-4-one derivatives bearing various ortho-
substituted phenyl groups were revealed to possess a stable C–N axially
chiral structure at ambient temperature. The reactions of alkyl halides
with the anionic species prepared from these quinazolinones were sys-
tematically explored. The α-alkylation reactions proceeded with diaste-
reoselectivities ranging from 1:1 to >50:1, depending upon the steric
bulk of the ortho-substituent, to afford products having the elements
of axial and central chirality in high yields (85–98%).
Key words axial chirality, quinazolinones, alkylation, diastereoselec-
tivity
Recently, molecules that are chiral owing to rotational
restriction around a C–N bond have attracted considerable
attention in the fields of synthetic and structural organic
chemistry.1 Almost all C–N axially chiral compounds con-
tain an ortho-substituted aniline skeleton, and the relation-
ship between the rotational barrier and the ortho-substitu-
ent has been explored in detail (Figure 1; compounds I and
II).2 It has been demonstrated that the rotational barrier
around a C–N chiral axis is significantly influenced by the
steric bulk of the ortho-substituent.2
O
R
O
n-Pr
S
N
R2
X
R1
O
N
O
N
S
N
H2N
N
O
Br
N
Br
N
O
N
X
O
N
X
X
1) LiHMDS
2) R-Y
I
III
IV
II
R
(1)
THF, –20 °C
C2H5
(25.1–33.5
kcal/mol)
(19.7–37.5
kcal/mol)
IIIa, IVa: X = t-Bu (28–30 kcal/mol)
IIIb, IVb: X = Me (ca. 20 kcal/mo)
Me
R–Y = Et–I, allyl–Br, Bn–Br, i-Pr–I
axially chiral
(racemic or
enantiopure)
axially and
central chiral
dr = 3.8:1 to 26.5:1
X = F, OMe, Cl, Me, Br, Et, I, CF3
Figure 1 Various C–N axially chiral compounds and their rotational
barriers
Scheme 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
M. Matsuoka et al.
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Synlett
alkyl halide. This reaction provides a new method for the
construction of pharmaceutically interesting quinazolinone
skeletons possessing elements of axial and central chirality.5
In 3-arylquinazolin-4-one derivatives, because com-
pounds bearing ortho-methyl, ortho-chloro, or ortho-bromo
groups are known to be rotationally stable (ΔG‡ > 30 kcal
mol–1),1a,5 we hoped that α-alkylation of 3-arylquinazoli-
none substrates bearing ortho-substituents of various sizes
might be systematically investigated. In this communica-
tion, we report the relationship between the bulk of the
ortho-substituent and the diastereoselectivity of α-alkyla-
tions with anionic species prepared from various C–N axial-
ly chiral quinazolinone derivatives (Scheme 2).
Table 1 α-Allylation of Quinazolinones Bearing Various ortho-Substitu-
ents
X
X
O
N
LiO
N
LiHMDS
(1.5 equiv)
N
N
C2H5
THF
–20 °C, 30 min
Me
X
1 (racemic)
X
O
O
allyl-Br
(1.5 equiv)
N
N
N
+
THF
–20 °C, 30
min
N
Me
Me
2'
2
X
X
O
O
1) LiHMDS
2) R-Y
N
N
(2)
Entry
Substrate
X
Products
Yielda (%) dr 2/2′
R
N
THF, –20 °C
N
C2H5
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
F
2a, 2′a
2b, 2′b
2c, 2′c
2d, 2′d
2e, 2′e
2f, 2′f
96
96
85
92
89
95
91
98
1:1b
4.8:1c
7.5:1c
17.9:1c
6.1:1c
10:1c
Me
R–Y = allyl–Br, Et–I
2 or 3
1
Cl
X = F, Cl, Br, I, Me, Et, i-Pr, CF3
dr = 1:1–> 50:1
Br
I
Scheme 2
Me
Et
Racemic 3-aryl-2-ethylquinazolin-4-ones 1a–h bearing
various ortho-substituents X (X = F, Cl, Br, I, Me, Et, i-Pr, CF3)
were easily prepared through the cyclocondensation of N-
propionylanthranilic acid with the corresponding ortho-
substituted aniline in the presence of PCl3 (see Supplemen-
tary Information),6 and their α-allylations were conducted
under the conditions shown in Table 1.
1g
1h
i-Pr
CF3
2g, 2′g
2h, 2′h
> 50:1c
> 50:1c
a Isolated yield.
b Ratio based on isolated yields.
c Ratio based on 1H NMR analysis of the mixture of 2 and 2′.
When 1.5 equivalents of LiHMDS was added to
quinazolinone substrates 1a–h in THF at –20 °C, the color-
less solution changed to a wine-red solution, indicating
successful formation of the desired anionic species. Subse-
quent addition of 1.5 equivalents of allyl bromide at –20 °C
led to the formation of the corresponding α-allylation prod-
ucts 2 and 2′. All reactions of 1a-h were complete within 30
min at –20 °C and they gave the corresponding products
2a–h and 2′a–f in high yields (85–98%; Table 1, entries 1–
8). In the allylation of 1a–d bearing a halogen in the ortho-
position, a clear relationship between the diastereoselectiv-
ity and the steric bulk of the halogen atom was observed
(entries 1–4). With the ortho-fluoro derivative 1a, no dias-
tereoselectivity was observed (entry 1), whereas the reac-
tions of the ortho-chloro and ortho-bromo derivatives 1b
and 1c gave the corresponding products 2b and 2′b and 2c
and 2′c in diastereomeric ratios of 4.8:1 and 7.5:1, respec-
tively (entries 2 and 3). In the case of the ortho-iodo deriva-
tive 1d, a high diastereoselectivity was observed with 2d
and 2′d being obtained in a ratio of 17.9:1 (entry 4). Thus,
the diastereoselectivity increased with the increasing steric
bulk of the halogen substituent.
Allylation of quinazolinone derivatives 1e–h bearing
ortho-alkyl groups was further examined (Table 1, entries
5–8). The reaction with ortho-methyl and ortho-ethyl de-
rivatives 1e and 1f, respectively, gave the corresponding
products 2e and 2′e and 2f and 2′f in diastereomeric ratios
of 6.1:1 and 10:1, respectively (entries 5 and 6). With ortho-
isopropyl and ortho-trifluoromethyl derivatives 1g and 1h,
perfect stereocontrol was observed and, in these cases, no
minor diastereomers were detected (entries 7 and 8).
Again, in the ortho-alkyl derivative series, the diastereo-
selectivity and the steric factors correlated well. Further-
more, the van der Waals radius (Å) of the ortho-substituent
(halogen atoms or Me group) showed a near linear correla-
tion with the logarithm of the diastereomeric ratios 2a–
e/2′a–e (Figure 2), confirming that stereocontrol by the or-
tho-substituents is quantitatively correlated to their steric
factors.
Because it was not possible to demonstrate a difference
in the steric bulk of isopropyl and trifluoromethyl groups in
the reaction with allyl bromide, we examined the corre-
sponding reaction with ethyl iodide, a less bulky alkylation
reagent. The results of this study are shown in Table 2. Un-
der the same conditions as those in Table 1, ethylation of
1e–h proceeded smoothly to afford the corresponding dias-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
M. Matsuoka et al.
Cluster
Synlett
This order correlates well with the rotational barriers of
compounds I and II shown in Figure 1.2d,e
As reported previously,4 the stereochemistry of the ma-
jor diastereomer 2c in the allylation product bearing an
ortho-bromo group has been determined to be (P*, S*) by
X-ray crystal-structure analysis.4 Additionally, in other di-
astereomeric alkylation products (Scheme 1) bearing an or-
tho-bromo group, the major isomers were judged to have a
(P*, S*) configuration on the basis of the chemical shift of
the methyl hydrogen atoms in the 1H NMR spectra. That is,
the methyl group in the minor diastereomer appears at a
higher magnetic field than that in the major diastereomer. A
similar shift of the Me group to a higher field in the minor
diastereomer was also observed in the cases of all com-
pounds 2′b–f and 3′e–h shown in Tables 1 and 2 (Δδ = 0.04–
0.22 ppm). Accordingly, the major diastereomers 2b–h and
3e–h in Tables 1 and 2 were judged to have a (P*, S*)-config-
uration. The difference in the chemical shift of the methyl
hydrogens between the diastereomers can be explained as
follows. In both diastereomers 2 and 3 and 2′ and 3′, the
conformers C-2 and C-3 and C-2′ and C-3′ show a direct ex-
posure of the methyl group to the anisotropic effect of the
ortho-substituted phenyl group, and the methyl group ap-
pears at higher magnetic field as a result of the increased
contribution (population) of the conformers C-2 and C-3
and C-2′ and C-3′ (Figure 3). The proportion of C-2′ and C-3′
in the minor diastereomers is higher than that of C-2 and C-
3 in the major diastereomers, leading to a shift of the meth-
yl hydrogen atoms to a higher field (conformer C-2/C-3 is
less favored than conformer C-2′/C-3′ because of steric re-
pulsion between the R group and the ortho-substituent X).
Figure 2 Correlation between the diastereomeric ratios in the reac-
tions of 1a–e and the van der Waals radii of the ortho-substituents
tereomeric products 3e–h and 3′e–h in high yields (85–
94%). As expected, the diastereoselectivities in the ethyla-
tion were somewhat lower in comparison with those in the
allylation reaction. The reaction of methyl and ethyl deriva-
tives 1e and 1f gave the corresponding products 3e and 3′e
and 3f and 3′f in diastereomeric ratios of 2.4:1 and 4.2:1,
respectively (Table 1, entries 1 and 2). In the ethylation re-
action, a difference in diastereoselectivity between the iso-
propyl and trifluoromethyl derivatives 1g and 1h was ob-
served, and the products 3h and 3′h were obtained in a
higher diastereomeric ratio (20.3:1) than 3g and 3′g
(14.7:1) (entries 3 and 4). Therefore, in the ethylation reac-
tion, the trifluoromethyl group acts as a more bulky group
than the isopropyl group.7
other conformers
other conformers
On the basis of the results in Tables 1 and 2, the order of
bulkiness of the ortho-substituents X in the present alkyla-
tion was revealed to be CF3 > i-Pr > I > Et > Br > Me > Cl > F.
X
R
X
H
O
O
N
N
N
N
>
Table 2 α-Ethylation of Quinazolinones Bearing Various ortho-Alkyl
Me
Me
Substituents
higher field
H
R
C-2' or C-3' (minor)
C-2 or C-3 (major)
X
X
O
favored
less favored
O
LiHMDS (1.5 equiv)
Et-I (1.5 equiv)
δ ppm of Me = 1.15–1.19
δ ppm of Me = 1.22–1.37
N
N
+
3'
Et
Figure 3 Stereochemical rationale for the chemical shifts of the methyl
protons of the α-alkylation products
THF
–20 °C, 30 min
N
N
C2H5
Me
3
1 (racemic)
The diastereoselectivity can be explained in terms of
the selective formation of an anionic species (a quinazoli-
none enolate) possessing an E-geometry that attacks the
alkyl halide on the opposite side to the ortho-substituent
(X), preferentially giving the (P*, S*)-products 2 (TS-2 or TS-
3 in Figure 4). The magnitude of the diastereoselectivity de-
creases with decreasing steric bulk of the ortho-substituent
X and, in the reaction with 1a (X = F), no diastereoselectivi-
ty was observed.
Entry
Substrate
X
Products
Yielda (%)
drb 3/3′
1
2
3
4
1e
1f
Me
3e, 3′e
3f, 3′f
94
94
87
85
2.4:1
4.2:1
Et
1g
1h
i-Pr
CF3
3g, 3′g
3h, 3′h
14.7:1
20.3:1
a Isolated yield.
b Ratio based on 1H NMR analysis of the mixture of 3 and 3′.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
M. Matsuoka et al.
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Acknowledgment
‡
Y
R
We are deeply grateful to Professor Christian Roussel for fruitful dis-
cussions on this research work.
X
Li
O
(P*,R*)-
isomer
(P*,S*)-
isomer
N
N
minor
major
Me
Supporting Information
H
E-enolate
Y
R
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610110.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
TS-2 or TS-3
Figure 4 Origin of diastereoselectivity
References and Notes
All the diastereomeric products 2 and 3 and 2′ and 3′
shown in Tables 1 and 2 were separated by medium-pres-
sure liquid chromatography (MPLC) and were isolated
without any isomerization at room temperature. We were
surprised that the C–N bond rotation of the separated dia-
stereomeric ortho-fluoro derivative 2a and 2′a did not oc-
cur at all, even after standing for 24 hours at room tempera-
ture (Scheme 3),8 and it is seems that the diastereomeric ra-
tio (2a/2′a = 1) observed in the reaction of 1a is a result of
kinetic factors rather than of interconversion between 2a
and 2′a.
(1) For reviews, see: (a) Alkorta, I.; Elguero, J.; Roussel, C.;
Vanthuyne, N.; Piras, P. Adv. Heterocycl. Chem. 2012, 105, 1.
(b) Takahashi, I.; Suzuki, Y.; Kitagawa, O. Org. Prep. Proced. Int.
2014, 46, 1. (c) Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.;
Sivaguru, J. Chem. Rev. 2015, 115, 11239.
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Koller, H.; Schuster, D.; Mannshreck, A. J. Chem. Soc., Perkin
Trans 2 1990, 619. (b) Oğuz, S. F.; Doğan, İ. Tetrahedron: Asym-
metry 2003, 14, 1857. (c) Yilmaz, E. M.; Doğan, İ. Tetrahedron:
Asymmetry 2008, 19, 2184. (d) Hasegawa, F.; Kawamura, K.;
Tsuchikawa, H.; Murata, M. Bioorg. Med. Chem. 2017, 25, 4506.
(e) Belot, V.; Farran, D.; Jean, M.; Albalat, M.; Vanthuyne, N.;
Roussel, C. J. Org. Chem. 2017, 82, 10188.
F
O
O
(3) For representative papers on the application of rotationally
stable C–N axially chiral compounds in stereoselective reac-
tions, see: (a) Kishikawa, K.; Tsuru, I.; Kohomoto, S.; Yamamoto,
M.; Yamada, K. Chem. Lett. 1994, 1605. (b) Curran, D. P.; Qi, H.;
Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc. 1994, 116, 3131.
(c) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.;
Shiro, M. J. Org. Chem. 1998, 63, 2634. (d) Hughes, A. D.; Price, D.
A.; Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1999, 1295.
(e) Bach, T.; Schröder, J.; Harms, K. Tetrahedron Lett. 1999, 40,
9003. (f) Dantale, S.; Reboul, V.; Metzner, P.; Philouze, C. Chem.
Eur. J. 2002, 8, 632. (g) Sakamoto, M.; Shigekura, M.; Saito, A.;
Ohtake, T.; Mino, T.; Fujita, T. Chem. Commun. 2003, 2218.
(h) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.;
Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006,
128, 12923. (i) Clayden, J.; Turner, H.; Helliwell, M.; Moir, E. J.
Org. Chem. 2008, 73, 4415. (j) Nakazaki, A.; Miyagawa, K.;
Miyata, N.; Nishikawa, T. Eur. J. Org. Chem. 2015, 4603.
N
N
F
(3)
X
r.t.
N
N
Me
Me
2'a
2a
Scheme 3
In conclusion, we have shown that 3-arylquinazolin-4-
one derivatives9 with C–N axial chirality can be used to
evaluate the relationship between the steric hindrance of
the ortho-substituents and the stereoselectivities observed
in α-alkylations of the corresponding anionic species. The
reaction of alkyl halides with the anionic species prepared
from C–N axially chiral quinazolinones bearing various
ortho-substituents was systematically explored, and it was
verified that the diastereoselectivity increased with in-
creasing steric bulk of the ortho-substituent. Furthermore,
it was found that the C–N axial chirality of the diastereo-
mers bearing an ortho-fluorophenyl group is sufficient sta-
ble to permit their separation.
(4) Matsuoka, M.; Goto, M.; Wzorek, A.; Soloshonok, V.; Kitagawa,
O. Org. Lett. 2017, 19, 2650.
(5) (a) Mannschreck, A.; Koller, H.; Stühler, G.; Davis, M. A.; Traber,
J. Eur. J. Med. Chem. 1984, 19, 381. (b) Junghänel, J.; Buss, V.;
Beyrich, T.; Jira, T. Chirality 1998, 10, 253. (c) Welch, W. M.;
Ewing, F. E.; Huang, J.; Menniti, F. S.; Pagnozzi, M. J.; Kelly, K.;
Seymour, P. A.; Guanowsky, V.; Guhan, S.; Guinn, M. R.;
Critchett, D.; Lazzaro, J.; Ganong, A. H.; DeVries, K. M.; Staigers,
T. L.; Chenard, B. L. Bioorg. Med. Chem. Lett. 2001, 11, 177.
(d) Chenard, B. L.; Welch, W. M.; Blake, J. F.; Butler, T. W.;
Reinhold, A.; Ewing, F. E.; Menniti, F. S.; Pagnozzi, M. J. J. Med.
Chem. 2001, 44, 1710. (e) Dolma, S.; Lessnick, S. L.; Hahn, W. C.;
Stockwell, B. R. Cancer Cell 2003, 3, 285. (f) Tokitoh, T.;
Kobayashi, T.; Nakada, E.; Inoue, T.; Yokoshima, S.; Takahashi,
Funding Information
This work was partly supported by JSPS KAKENHI (C 17K08220).
a
Jp
a
n
S
o
ecity
o
f
r
ht
e
Pro
m
o
itn
of
Secince
C(
1
7
K
0
8
2
2
0)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

E
M. Matsuoka et al.
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Synlett
H.; Natsugari, H. Heterocycles 2006, 70, 93. (g) Lodola, A.;
Bertolini, S.; Biagetti, M.; Capacchiu, S.; Facchinetti, F.; Gall, P.
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M.; Capelli, A. M. J. Med. Chem. 2017, 60, 4304. (h) Toenjes, S. T.;
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hexane–EtOAc (1:4)] to give a mixture of 2c and 2c′; yield: 94
mg (85%). The diastereomeric ratio of 2c and 2c′ (7.5:1) was
determined by 1H NMR analysis. 2c and 2c′ were completely
separated by MPLC (hexane–EtOAc, 1:8) to give diastereomeri-
cally pure 2c and 2c′
(6) (a) Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.;
Greenwood, T. D. J. Med. Chem. 1990, 33, 161. (b) Xu, Y.-L.; Lin,
H.-Y.; Cao, R.-J.; Ming, Z.-Z.; Yang, W.-C.; Yang, G.-F. Bioorg. Med.
Chem. 2014, 22, 5194. (c) Kumar, D.; Jadhaver, P. S.; Nautiya, M.;
Sharma, H.; Meena, P. K.; Adane, L.; Pancholia, S.; Chakraborti,
A. K. RSC Adv. 2015, 5, 30819.
(7) Although the quinazoline-4-one bearing an ortho-tert-butyl-
phenyl group was also prepared, its alkylation was not investi-
gated due to its extremely low solubility in THF and other
organic solvents.
(8) It has been reported that the separation of enantiomers of 2-
(alkylthio)quinazolin-4-ones bearing an ortho-fluorophenyl
group is difficult because of the low rotational barrier around
the C–N bond; see: Jira, T.; Schopplich, C.; Bunke, A.; Leuthold,
L.; Junghänel, J.; Theiss, R.; Kottke, K.; Besch, A.; Beyrich, T.
Pharmazie 1996, 51, 379.
(P*,S*)-3-(2-Bromophenyl)-2-(1-methylbut-3-en-1-
yl)quinazolin-4(3H)-one (2c)
White solid; yield: 82 mg; mp 114–116 °C. IR (neat): 1684 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.29 (dd, J = 0.8, 7.6 Hz, 1 H),
7.73–7.80 (m, 3 H), 7.51 (dt, J = 1.6, 7.6 Hz, 1 H), 7.47 (ddd, J =
2.0, 6.8, 7.6 Hz, 1 H), 7.39 (dt, J = 1.6, 8.0 Hz, 1 H), 7.33 (dd, J =
1.6, 7.6 Hz, 1 H), 5.57 (tdd, J = 6.8, 10.8, 16.0 Hz, 1 H), 4.94 (d, J =
10.8 Hz, 1 H), 4.94 (d, J = 16.0 Hz, 1 H), 2.41–2.56 (m, 2 H), 2.20
(td, J = 6.8, 13.6 Hz, 1 H), 1.33 (d, J = 6.8 Hz, 3 H). 13C NMR (100
MHz, CDCl3): δ = 161.8, 159.8, 147.7, 136.7, 135.5, 134.6, 133.8,
130.7, 128.6, 127.3, 127.0, 126.5, 123.3, 120.6, 117.2, 40.4, 37.9,
18.9. MS: m/z = 391 [M + Na]+ (79Br); HRMS: m/z [M + Na]+Calcd
for C19H1779BrN2NaO: 391.04220; found: 391.04207.
(P*,R*)-3-(2-Bromophenyl)-2-(1-methylbut-3-en-1-
yl)quinazolin-4(3H)-one (2c′)
White solid; yield: 12 mg; mp 78–80 °C. IR (neat): 1680 cm–1
.
(9) α-Alkylation of 3-(2-Bromophenyl)-2-ethylquinazolin-4-one
(1c); Typical Procedure
1H NMR (400 MHz, CDCl3): δ = 8.28 (dd, J = 1.6, 8.0 Hz, 1 H),
7.73–7.81 (m, 3 H), 7.51 (dt, J = 1.2, 7.2 Hz, 1 H), 7.47 (ddd, J =
1.2, 7.2, 8.4 Hz, 1 H), 7.40 (dt, J = 2.0, 8.0 Hz, 1 H), 7.35 (dd, J =
2.0, 8.0 Hz, 1 H), 5.71 (m, 1 H), 5.04 (d, J = 17.2 Hz, 1 H), 4.97 (d,
J = 10.0 Hz, 1 H), 2.75 (m, 1 H), 2.31–2.40 (m, 2 H), 1.17 (d, J = 6.4
Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 161.8, 160.0, 147.6,
136.6, 136.2, 134.6, 133.9, 130.8, 130.2, 128.7, 127.3, 127.1,
126.6, 123.3, 120.6, 117.0, 39.1, 38.0, 19.4. MS: m/z = 391 [M +
A 1.3 M solution of LiHDMS in THF (0.346 mL, 0.45 mmol) was
added to a solution of rac-1c (99 mg, 0.3 mmol) in THF (2.0 mL)
under N2 at –20 °C, and the mixture was stirred for 30 min at –
20 °C. Allyl bromide (54 mg, 0.45 mml) was added at –20 °C,
and the mixture was stirred for 30 min at –20 °C. The mixture
was then poured into saturated aq NH4Cl solution (10 mL) and
extracted with EtOAc (3 × 20 mL). The extracts were washed
with brine, dried (MgSO4), filtered, and evaporated to dryness.
The residue was purified by column chromatography [silica gel,
Na]+
(
79Br); HRMS: m/z [M + Na]+Calcd for C19H1779BrN2NaO:
391.04220; found: 391.04071.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E