Paper
Organic & Biomolecular Chemistry
isolated yield and ee via a quite simple operation. Note that
the pathway and origin of enantioselectivity in such a reaction
was also well elucidated through DFT calculations.
Experimental section
General information
Reagents and solvents were purchased from common commer-
cial suppliers and were used without further purification.
Column chromatography was generally performed on silica gel
Fig. 2 Transition states calculated for the intramolecular nucleophilic
attack from amide to the iminium.
(
200–300 mesh). Melting points were determined with a Büchi
1
B-545 melting-point apparatus. 600 MHz H NMR and
1
1
3
50 MHz C NMR spectra were recorded on Varian VMS-600
ion (1a-I) with an energy barrier of 7.8 kcal mol− . A proton
transfer process occurs facilely from the aminium cation to
the phosphate anion and gives a more stable compound 1a-II.
The following step is a dehydration process to give iminium.
The intramolecular nucleophilic attack from amide to
iminium is the rate- and enantio-determining step to form the
chiral quinazolinone.
1
spectrometers, respectively. The chemical shifts are reported
in ppm (δ scale) relative to internal tetramethylsilane, and
coupling constants are reported in hertz (Hz). High-resolution
mass spectra (HRMS) were obtained on an Agilent 6502 Q-TOF
HPLC and using mass spectrometry.
General procedure for the synthesis of
There are several factors that can determine the energy of
the transition states (TS) for the enantio-determining intra-
molecular nucleophilic attack from amide to iminium, (i) the
hydrogen bonding strength between the substrate and the
catalyst; (ii) the stability of iminium and (iii) the chiral pocket
of the catalyst. From the literature, we can know that (i) the
chiral phosphoric acid should have a stronger hydrogen
bonding strength with a more protic hydrogen and (ii) the
E-isomer of iminium is generally more stable than the
Z-isomer. On the basis of the above knowledge, we can
propose a model as shown in Fig. 2, in which the phosphate
interacts with the two N–H moieties of the E-isomer of
iminium. A similar model was also proposed by a very recent
2
,3-dihydroquinazolinones 3
A mixture of 2-aminobenzamide (0.2 mmol), catalyst cat. 14
1 mol%), aldehyde (0.24 mol), and m-xylene (4 mL) was
(
stirred at room temperature for 12 h and then concentrated
under reduced pressure. The resulting orange gum was puri-
fied by column chromatography on a silica gel column [eluting
with PE : i-PrOH (10 : 1)] to obtain 3 as white or yellow solid.
Gram-scale synthesis of 3ad, 3ae, 3ag, 3ak, 3ai, and 3pd
A mixture of 2-aminobenzamide (5 mmol), catalyst cat. 14
(
0.1 mol%), aldehyde (6 mol), and m-xylene (100 mL) was
stirred at room temperature for 12 h. Then reaction tempera-
ture was lowered from room temperature to −20 °C and kept
for 0.5 h along with slow precipitation of the desired products.
After simple filtration, a series of products were collected.
1
1
calculation study. The computer gave us expected results that
the TS3cat.14(Re) is the most stable TS leading to the main
product R-3aa. The TS3cat.14(Si) leading to S-3aa is less stable
than TS3cat.14(Re) by 2.4 kcal mol− , indicating a calculated ee
value of 96%. The chiral pocket of cat. 14 induces more steric
1
Conflicts of interest
3 6 2
C H ] of the cat.
repulsion between the Ar group [2,4,6-(i-Pr)
4 and the Ar group (-C ) of the substrate.
1
6 4
H
There are no conflicts to declare.
Conclusions
Notes and references
In summary, an efficient, practical and scalable protocol to
prepare chiral 2,3-dihydroquinazolinones was developed under
catalysis of the spirocyclic SPINOL-phosphoric acid. Using this
methodology, a wide range of chiral 2,3-dihydroquinazoli-
nones bearing different functional groups were synthesized in
excellent yields and ee. What’s more, 2-(N-methylamino)-benz-
amide, always as a non-reactive substrate in previous reports,
was smoothly transformed to the desired 2,3-dihydroquinazoli-
none product under this condition. Most importantly, the scal-
ability and practicability of this protocol got well elucidated via
gram-scale reactions and a series of substituted chiral 2,3-dihy-
droquinazolinones were prepared on a gram scale with >90%
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