A microwave-assisted multicomponent synthesis of substituted 3,4-dihydroquinazolinones

Article abstract of DOI:10.1039/c4ob02417f

A microwave-assisted, multicomponent protocol for the synthesis of substituted 3,4-dihydroquinazolinones via a novel cascade imine/cyclization/aza-Henry reaction sequence is reported. Starting from o-formyl carbamates, a series of structurally diverse 3,4-dihydroquinazolinones was synthesized via a cyclic iminium ion intermediate in moderate to excellent yields. Notably, the reaction is fast, flexible, simple to perform and tolerates a variety of functional groups. This journal is

Full text of DOI:10.1039/c4ob02417f

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Organic & Biomolecular Chemistry
Journal Name
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DOI: 10.1039/C4OB02417F
ARTICLE
A Microwave-Assisted Multicomponent
Synthesis of Substituted 3,4-
Dihydroquinazolinones
Cite this: DOI: 10.1039/x0xx00000x
Marc Y. Stevens, #,‡ Krzysztof Wieckowski,#,‡,† Peng Wu, #,§ Rajiv T. Sawant# and
Luke R. Odell #,*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
microwave-assisted, multicomponent protocol for the synthesis of substituted 3,4-
dihydroquinazolinones via novel cascade imine/cyclization/aza-Henry reaction sequence is
reported. Starting from o-carbamoyl aldehydes, series of structurally diverse 3,4-
a
a
dihydroquinazolinones was synthesized via a cycliciminium ion intermediate in moderate to
excellent yields. Notably, the reaction is fast, flexible, simple to perform and tolerates a variety of
functional groups.
Introduction
The 3,4-dihydroquinazolinone scaffold is present in a wide
range of biologically active molecules utilized in the treatment
of convulsive disorders,1 infectious diseases,2 autoimmune
diseases,3 cardiovascular conditions4 and inflammatory
diseases5 (see Scheme 1). Given their biological relevance,
significant effort has been directed towards the synthesis of 3,4-
dihydroquinazolinones. The most commonly employed
methods include a cyclization/reduction sequence starting from
2-trichloroacetamidobenzophenones,4a,6 the ring closure of 2-
acyl or 2-cyanocarbamates,7 reaction of
anilines with a suitable carbonyl compound,1,4b,8 or by using
Grignard reagents to effect cyclization of 2-
carboxamidobenzonitriles.9 More recently, Glorius and co-
workers reported a Rh-catalyzed synthetic route using
methoxy,
’- arylureas,10 and Sotelo and co-workers disclosed
o-acyl or o-amino
a
Scheme 1. Elaboration of cyclic iminium ion I via aza-Henry/ Mannich reactions
leading to the dihydroquinazolinone scaffold with 5 points of diversity. Also
displayed are three representative 3,4-dihydroquinazolinones
N-
N
the synthesis of a quinazoline using a Vilsmeier–Haack-based
carboannulation strategy.11 Despite these advances, the
currently available procedures12 still suffer from a number of
drawbacks, including multistep reaction sequences, lack of
flexibility, the use of moisture-sensitive organometallic
reagents and costly transition metal catalysts. Consequently, the
development of new, flexible, expedient and metal-free
protocols for the preparation of this valuable heterocycle is of
significant importance.
As part of our continued interest in the efficient synthesis of N-
heterocycles,13 we decided to explore a multi-component14
synthesis of 3,4-dihydroquinazolinones (Scheme 1). It was
envisioned that treatment of an
o-formyl carbamate with a
primary amine would lead to the formation of a cyclic iminium
ion intermediate via an imine formation/cyclization sequence.7a
Iminium ion
Henry15 or Mannich16 reactions with an appropriate carbon
nucleophile, generating the target structures. Although the aza
I would then be poised to undergo subsequent aza-
-
Henry reaction between amines, aldehydes and nitroalkanes has
been extensively studied, to the best of our knowledge, this is
the first example of the use of an
o
-formyl carbamate as the
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carbonyl component. Such an approach would allow (entries 2b and 2c). Benzylamine was found to be a productive
unprecedented access to diversely substituted 3,4- substrate (2d) and the presence of an alpha substituent was well
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dihydroquinazolinones in a rapid, convergent and efficient tolerated, with cyclopropylamine returning an excellent 93%
DOI: 10.1039/C4OB02417F
fashion generating only methanol and water as byproducts. yield of 2e. The introduction of an electron-withrawing ester
Herein, we report a simple and efficient, one-pot, three- substituent proved to be detrimental to the reaction, presumably
component procedure for the microwave-assisted synthesis of due to the lower nucleophilicity of these substrates (2f and 2g).
3,4-dihydroquinazolinones using readily available starting Similarly, the use of substituted anilines afforded moderate
materials.
yields of the
2i
N3-aryl substituted quinazolinone products 2h and
.
Results and Discussion
Scheme 2 - Effect of variation of amine nucleophilesa
As a starting point for our investigation, we chose to examine
the reaction between methylcarbamate 1a, nitromethane and
NH4OAc. Carbamate 1a and NH4OAc were chosen to minimize
any potentially unfavorable steric effects and nitromethane due
to its known propensity to participate in aza-Henry reactions.
Gratifyingly, microwave irradation of 1a with an excess of
H
N
O
nitromethane and NH4OAc in MeOH for 10 minutes at 130 °C
N
gave dihydroquinazolinone 2a in 71% isolated yield (Table 1).
Next, we examined the effect of different solvents on the
reaction outcome. Polar solvents proved to be the most
productive and AcOH delivered 2a in 81% yield and was
identified as the solvent of choice (entry 4). Reduction to 2
equivalents of nitromethane furnished 2a in a slightly reduced
yield of 71% yield but simplified purification considerably
(entry 5). Increasing the reaction scale to 3 mmol and heating
for 20 min gave 2a in 88% yield (Scheme 2). Notably, full
conversion of 1a to the cyclized product was not achieved with
conventional heating, even after prolonged reaction time
(Scheme 2).
Me
NO2
2a, 88%b, 60%c
2d, 74%, 81%d
2g, 24%b
2b, 95%
2e, 93%
2h, 40%e
2c, 92%
2f, 57%e
2i, 36%e
aIsolated yields. bHeated for 20 min. cConventional heating for 2 h.
dOne-pot, two step procedure. eHeated for 30 min
Table 1 - Investigation of reaction conditions for the cyclization of 1a
using MeNO2 and NH4OAca
We then proceeded to investigate the effect of different aryl
substituents on the o-formyl carbamate component (Scheme 3).
Electron-withdrawing substituents gave good, albeit slightly
lowered yields (3a-3e), most probably due to their tendency to
reduce the rate of amine-induced cyclization (see below for a
mechanistic discussion). In the case of 3b, prolonged heating
and addition of 6 equiv. of nitromethane was required for full
consumption of the starting material. Notably, the pyridine
aldehyde 1f was transformed into 3e in 61% yield. Conversely,
substrates containing electron-donating susbtituents performed
well, affording very good to excellent yields of the desired
entry
1
2
3
4
5
6
7
8
solvent
methanol
2-propanol
ethanol
acetic acid
acetic acid
DMF
water
ethyl acetate
DME
yield(%)
71
45
79
81
71b
58
48
36
products 3f and 3g
.
The compatibility of the protocol with different carbon
nucleophiles was then examined (Scheme 4). The reaction
performed well with a range of substituted nitroalkanes,
9
10
24
c
THF
-
aIsolated yields. Typical procedure: Compound 1a (0.2 mmol),
NH4OAc (0.4 mmol), MeNO2 (2 mmol) and glacial acetic acid (1.0
affording moderate to good yields of the target products 4a–4d
.
b
mL), heated by MW for 10 min at 130 °C in a sealed vessel. 2 equiv
In general, the isolated yield was found to decrease as a factor
of increasing steric bulk at the alpha carbon and
unsymmetrically substituted nitroalkanes gave mixtures of
diastereomers in 4a and 4b. Next, we examined the effect of
using different carbon nucleophiles. Initial test reactions with
diethyl malonate showed extensive formation of a styrene
nitromethane. cNo product isolated
With these conditions in hand, we then sought to explore the
scope and limitations of our methodology by exploring various
amine nucleophiles. As seen in Scheme 2, the reaction
performed well with a range of primary amines, with
methylamine and hexylamine giving isolated yields over 90%
derivative via a competing Knoevenagel condensation with 1a
.
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Scheme 3. - Aryl substrate scopea
benzyl and para-methoxybenzyl substrates (5e and 5f) returned
comparable results to the parent o-formyl carbamate, indicating
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a tolerance for steric hindrance at N-1. The introduction of an
DOI: 10.1039/C4OB02417F
ethyl ester led to a reduction in the isolated yield (5d), due to
competing intramolecular cyclization of the starting carbamate
1l. Finally, the bis-quinazolinone 5g was prepared from the
corresponding benzyl-linked bis o-formyl carbamate 1o in 53%
yield.
3a, 75%
3e, 61%
3b, 62%b,c
3c, 73%c
3g, 91%
3d, 71%
Scheme 5. Substrate scope of
N-1 substituted
o-formyl carbamates
3f, 82%
aIsolated yields. b60 min of heating. c4 equiv MeNO2.
Further attempts to transform this intermediate into the desired
product, through extended heating and the addition of excess
ammonium acetate, were unsuccessful. In order to overcome
this, a one-pot, two-step protocol was developed whereby
aldehyde 1a and NH4OAc were first heated at 130 °C for 10
5a, 85%
5e, 73%
5b, 80%
5f, 65%
5c, 72%
5d, 52%
minutes to afford the putative cyclic imine intermediate
I
(monitored by ESI-MS). Diethyl malonate was then added and
the mixture heated for an additional 10 minutes at 130 °C.
Gratifyingly, this modified protocol resulted in full conversion
5g, 55%
of the starting material and 4e was isolated in 75% yield. Isolated yields.
Dimethyl malonate and ethyl cyanoacetate were also
To futher investigate the scope and limitations, our protocol
was applied to the cyclization of an
-keto carbamate17
(Scheme 6, 1p). When the reaction was performed using our
optimized conditions, only traces of the desired product were
successfully introduced into the quinazolinone products 4f and
4g, with 4g being isolated as a diastereomeric mixture in an
excellent yield of 90%.
o
6
observed by LC/MS analysis. Increasing the reaction
temperature to 150 °C and reaction time to 20 min led to
Scheme 4. Effect of variation of carbon nucleophilea
noticeable conversion and compound
6 could be isolated in
14% yield. Unfortunately, further increasing the reaction
temperature or time did not lead to any improvements in the
isolated yield. Despite the low yield of
6, the formation of a
quaternary carbon center using this methodology is noteworthy
Scheme 6. Synthesis of 4-methyl 3,4-dihydroquinazolinone
6
4a, 80%b
4e, 75%d
4b, 68%bc
4f, 76%d
4c, 55%c
4d, 72%
4g, 90%de
a Isolated yields. bMixture of diastereomers. cHeated for 20 min. dOne-pot,
two-step procedure. e4 equiv ethyl cyanoacetate.
Finally, to demonstrate the utility of our protocol towards the
synthesis of aminomethyl dihydroquinazolinone derivatives,
compound 2a was reduced to the corresponding amine
7 in
quantitative yield, thus unmasking an excellent handle for
further functionalization or the preparation of biologically
Next, we investigated the effect of substitution in the
position of the o-formyl carbamate component (Scheme 5).
N-1
relevant compound libraries. To demonstrate this,
7 was
Carbamates bearing alkyl and allyl substituents in the
position (5a 5c) were cyclized in good to very good yields.
N
-1
-1
acylated using chloroacetyl chloride to provide in 73% yield.
8
–
N
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Subsequent base mediated cyclization afforded
contains previously unreported
9
, which
fused
a
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piperazinonequinazolinone skeleton that is structurally related
to the antihelminthic drug praziquantel. Finally, the -Boc
DOI: 10.1039/C4OB02417F
N
protected amine 10 could be prepared from compound 2a in
76% yield.
Scheme 7 - Synthetic utility of compound 2a
Figure 1. Proposed reaction pathway and two-step formation of 2d
.
Based on the results above we believe that the reaction
proceeds by the pathway presented in Figure 1. The reaction
begins with formation of imine
b from the amine nucleophile
and -formyl carbamate . Intramolecular attack of the imine
o
a
nitrogen on the carbonyl carbon of the pendant carbamate,
followed by the loss of methanol generates the cyclic iminium
ion
c
. Finally, attack on the electrophilic carbon in
c
by an enol
nucleophile generates the final product
d
and the structure of 4e
was confirmed by X-ray crystallographic analysis18 (see Figure
2). However, an alternative pathway could be proposed
Figure 2. ORTEP representation of 4e
whereby imine
the acyclic aza-Henry intermediate
cyclization via attack on the carbonyl, providing final product
. However, despite careful monitoring (ESI-MS), could not
be detected under the acidic reaction conditions even at reduced
temperatures. Similarly, formation of nitrostyrene and its
amine adduct was not observed, suggesting that that the
reaction proceeds via the cyclic aldimine (detected by ESI-
MS). Attempts to independently synthesize19 nitrostyrene
and
amine adduct , which could then be cyclized under acidic
reaction conditions, were unsuccessful, resulting almost
exclusively in the formation of iminium ion . Futhermore, 2d
b
is attacked by an enol nucleophile, generating
f
. This may then undergo
Conclusions
d
f
In summary, a novel and expedient one-pot multicomponent
protocol for the synthesis of substituted 3,4-
dihydroquinazolinones from -formyl methylcarbamates
utilizing a variety of activated carbon and primary amine
nucleophiles is reported. Notably, the reaction allows for the
introduction of five points of diversity in a single operation,
e
o
f
c
e
f
facilitating
the
preparation
of
various
3,4-
dihydroquinazolinones in a highly flexible and controlled
manner. Yields range from moderate to excellent, and in
general, slightly lower yields were obtained using electron-poor
or sterically hindered substrates or nucleophiles. This
methodology has been utilized to prepare 31 novel compounds
bearing different aryl, nitrogen and α-carbon substituents.
Furthermore, the reaction was exemplified by transforming 2a
into a number of useful derivatives, including the hitherto
c
was also synthesized via a two-step protocol where 1a and
benzylamine were first heated in acetic acid to give a single
intermediate with an
m/z consistent with the formation of the
corresponding cyclic iminium ion. This was further supported
by NMR analysis that showed the absence of the characteristic
OMe signal at 3.80 ppm and the appearance of a signal from
the imine proton at 5.26 ppm (see Electronic Supplementary
Information). Subsequent addition of MeNO2 and heating gave
2d in 81% isolated yield. Taken together, these data provide
support for the facile formation of an electrophilic
imine/iminium ion intermediate, which is highly favored under
our acidic reaction conditions.
unknown fused piperazinonequinazolinone
demonstrated, for the first time, that the amine induced
cyclization of -formyl methylcarbamates is a facile process
9
.
We have
o
and provides a novel synthetic platform for the preparation of
3,4-dihydroquinazolinones. Work is currently underway in our
laboratory to further expand the scope of this process and to
develop an asymmetric version of this synthetic protocol.
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ARTICLE
1
(0.62 g, 78%); H NMR (400 MHz, CDCl3) δ 3.71 (s, 3H),
7.21 (dd,
8.36 (dd,
J
J
= 8.5, 3.5 Hz, 1H), 7.25 (dd,
J = 7.8, 3.1 Hz, 2H),
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Experimental
General Methods
= 9.1, 4.6 Hz, 1H), 9.76 (s, 1DHO),I: 1100..130339(/sC,41OHB0)2;41137CF
NMR (100 MHz, CDCl3) δ 52.6, 120.3 (d, 3JCF = 6.8 Hz), 120.8
2
3
2
Analytical thin-layer chromatography was performed on silica (d, JCF = 22.4 Hz), 121.9 (d, JCF = 5.5 Hz), 123.1 (d, JCF
=
gel 60 F-254 plates and visualized by UV light or ninhydrin 22.2 Hz), 137.4 (d, 4JCF = 2.7 Hz), 154.0, 157.2 (d, 1JCF = 243.7
stain. Flash column chromatography was performed using silica Hz). 193.9. MS (ESI) calc´d for C9H9FNO3 [M + H+] m/z
+
gel (60, particle size 40-63 nm). 1H NMR spectra were recorded 198.0561, found m/z 198.0557.
at 400 MHz and 13C NMR spectra at 100 MHz. The chemical General procedure for preparation of compounds 2a–2i,
shifts for H NMR and 13C NMR were referenced to TMS via 3a–3g, 4a–4d, 5a–5g and 6, exemplified by 4-(nitromethyl)-
1
residual solvent signals (1H, CDCl3 at 7.26 ppm; 13C, CDCl3 at 3,4-dihydroquinazolin-2(1
H)-one (2a). A Pyrex process vial
77.36 ppm; H, DMSO-d6 at 2.45 ppm; 13C, DMSO-d6 at 39.43 (0.5–2 mL) was charged with 1a (89.6 mg, 0.50 mmol), AcOH
1
ppm, H, CD3OD at 3.31 ppm; 13C, CD3OD at 49.0 ppm). (1 mL), NH4OAc (77.0 mg, 1.00 mmol) and MeNO2 (55.2 µL,
1
Microwave reactions were performed in an Initiator single 1.00 mmol). The resulting solution was heated by microwave
mode reactor producing controlled irradiation at 2450 MHz and irradiation at 130 °C for 10 min, and then concentrated in
the temperature was monitored using the built in online IR vacuo. The residue was purified by silica gel chromatography
sensor. LC/MS was performed on an instrument equipped with (50–100% EtOAc in
a CP-Sil 8 CB capillary column (50 x 3.0 mm, particle size 2.6 as a white solid (74 mg, 71%); H NMR (400 MHz, CDCl3) δ
µm, pore size 100 Å) operating at an ionization potential of 70 4.63 – 4.65 (m, 2H), 5.04 – 5.08 (m, 1H), 6.82 (d, = 7.2 Hz,
= 9.4 and 1.2 Hz, 1H), 7.17 – 7.20 (m, 2H),
n-pentane) to provide the title compound
1
J
eV using a CH3CN/H2O gradient (0.05% HCOOH). Accurate 1H), 6.89 (dt,
J
mass values were determined on a mass spectrometer equipped 7.29 (s, 1H), 9.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 51.9,
with an electrospray or electron impact ion source and 7-T 80.4, 114.0, 116.3, 121.1, 126.3, 128.8, 137.7, 152.7. MS (ESI)
+
hybrid ion trap (LTQ) or TOF detector, respectively. All calc’d. for C9H10N3O3 [M + H+] m/z 208.0722, found m/z
reactions were performed in sealed Pyrex microwave- 208.0724.
transparent process vials designed for 0.5–2 mL reaction General procedure for preparation of compounds 4e–4g
volumes. Reagents were purchased at the highest commercial and 2d, exemplified by diethyl 2-(2-oxo-1,2,3,4-
quality and were used without further purification. Solvents tetrahydroquinazolin-4-yl)malonate (4e). A 0.5-2 mL process
used for extraction and silica gel chromatography (EtOAc, vial equipped with a stirring bar was charged with compound
hexanes,
n-pentane and dichloromethane) were used without 1a (90 mg, 0.5 mmol), NH4OAc (77 mg, 1 mmol) and acetic
purification or removal of water.
acid (1.0 mL). The vessel was sealed under air and exposed to
microwave heating for 10 min at 130 °C. Diethyl malonate
General procedure for preparation of carbamates 1c–1h, (305 µL, 2 mmol) was added and the mixture was once again
exemplified by methyl (4-fluoro-2-formylphenyl)carbamate subjected to microwave heating for 10 min at 130 °C. The
(1d). Starting from the known or commercially available amino resulting mixture was cooled to room temperature and
alcohol, carbamates 1b
following the procedure outlined below.
Moc protection. To
–
1g were prepared in two steps concentrated under reduced pressure. The residue was
thereafter purified by flash column chromatography on silica
stirred solution of (2-amino-5- gel (gradient from 20–100% EtOAc in pentane) to provide the
a
fluorophenyl)methanol20 (0.75 g, 5.32 mmol) and pyridine (557 title compound as yellow crystals, mp 117–122 °C (96 mg,
1
µL, 6.92 mmol) in dichloromethane (20 mL) at 0 °C was slowly 75%); H NMR (400 MHz, DMSO-d6) δ 1.06 (dt,
J
= 16.8, 7.1
= 6.4 Hz, 1H), 3.82 – 4.12 (m, 4H), 5.00
= 6.4, 3.7 Hz, 1H), 6.66 – 6.88 (m, 3H), 6.98 – 7.31 (m,
stirred for 16 h. The reaction was quenched by the addition of 2H), 9.24 (d,
= 2.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6
added methyl chloroformate (453 µL, 5.86 mmol). After 5 min Hz, 6H), 3.65 (d,
of stirring, the reaction was brought to room temperature and (dd,
J
J
J
)
0.1 M HCl and extracted twice with DCM (30 mL). The δ 13.7, 52.8, 58.6, 61.2, 61.3, 113.9, 118.0, 121.0, 126.3, 128.5,
+
combined organic layers were washed with brine, dried over 137.9, 153.3, 166.4, 166.6. MS (ESI) calcd. for C15H19N2O5
MgSO4 and concentrated in vacuo. Silica gel chromatography [M + H+] m/z 307.1288, found m/z 307.1293.
(1:2 EtOAc/hexanes) provided the desired compound as a white Preparation of methyl (2-formylphenyl)carbamate (1a)
.
solid (0.91 g, 86%); H NMR (400 MHz, CDCl3) δ 3.75 (s, Prepared according to the literature procedure.21 Spectral data
3H), 4.62 (d, = 5.7 Hz, 2H), 6.90 (dd, = 8.6, 3.0 Hz, 1H), were in agreement with reported values.
6.95 – 7.02 (m, 1H), 7.67 (s, 1H), 7.76 (s, 1H); 13C NMR (100 Preparation
of methyl
MHz, CDCl3) δ 52.8, 63.9, 115.7 (d, 2
CF = 22.0 Hz), 115.8 (d, formylphenyl)carbamate) (1b). Following a modified version
2JCF = 22.9 Hz), 123.6, 133.6, 155.2, 159.2 (d, 1 CF = 243.5 Hz). of the literature procedure,21 the title compound was obtained
1
J
J
(4-chloro-2-
J
J
Oxidation of alcohol. To a stirred solution of methyl (2- after silica gel chromatography (15% EtOAc in petroleum
(hydroxymethyl)-4-methylphenyl)carbamate (0.80 g, 4.02 ether) as a pink solid, used in the next step without further
+
mmol) in DCM (20 mL) was added MnO2 (3.49 g, 40.2 mmol). purification (3.65 g, 98%). MS (ESI) C8H9ClNO2 [M + H+]
After 16 h, the reaction mixture was passed through a short m/z 185.89. To a stirred solution of the above solid (1.86 g,
silica gel column to provide the title compound as a white solid 10.0 mmol) in anhydrous THF (20 mL) under N2 atmosphere at
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-78 °C was added sec-BuLi (18 mL, 1.4M in cyclohexane). mL). The combined organics were washed with sat. NaHCO3
After 4h at -20 °C, DMF (1.20 mL, 15.6 mmol) was added and (50 mL) and H2O (50 mL), dried over Na2SO4 and concentrated
the reaction mixture stirred for 60 min, before being partitioned in vacuo
.
The residue was purifDieOdI: 10b.1y03V9ie/wsCi4AlirOtcicBale02O4ng1li7neFel
between H2O and EtOAc (50 mL of each). The aqueous layer chromatography (10% EtOAc in hexanes) to yield the title
1
was extracted with EtOAc (50 mL) and the combined organics compound as a white solid (0.46 g, 79%); H NMR (400 MHz,
were concentrated in vacuo, dried over MgSO4 and purified by CDCl3) δ 2.64 (s, 3H), 3.77 (s, 3H), 6.89 – 7.17 (m, 1H), 7.53
silica gel chromatography (20% EtOAc in petroleum ether) to (t,
J
= 7.7 Hz, 1H), 7.86 (d,
provide the title compound as a yellow solid (0.92 g, 43%); H 1H), 11.19 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 29.0, 52.7,
NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 7.78 (dd, = 9.0, 2.5 119.6, 121.8, 121.9, 132.1, 135.5, 141.8, 154.8, 202.7. MS
J = 7.3 Hz, 1H), 8.46 (d, J = 8.5 Hz,
1
J
Hz, 1H), 7.98 (d, J = 2.5 Hz, 1H), 8.14 (d, J
= 9.0 Hz, 1H), 9.97 (ESI) calc’d. for C10H12NO3 [M + H+] m/z 194.0817, found
+
(s, 1H), 10.40 (s, 1H); 13C NMR (100 MHz, CDCl3) 52.9, m/z 194.0824.
121.4, 124.5, 127.0, 133.7, 135.5, 139.4, 154.1, 194.5. MS (EI) Methyl
(2-formyl-5-(trifluoromethyl)phenyl)carbamate
+
calc´d for C9H8ClNO3 [M+] m/z 213.0193, found m/z (1c). Following the general procedure starting from (2-amino-4-
213.0188.
(trifluoromethyl)phenyl)methanol,23 the title compound was
1
Preparation of methyl (3-formylpyridin-2-yl)carbamate obtained as a white solid (0.65 g, 65%); H NMR (400 MHz,
(1f). Following a modified version of the literature procedure,22 CDCl3) δ 3.84 (s, 3H), 7.31 – 7.57 (m, 1H), 7.61 – 8.04 (m,
the title compound was obtained a yellow solid (0.15 g, 25%); 1H), 8.80 (s, 1H), 9.99 (s, 1H), 10.64 (br s, 1H); 13C NMR (100
1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 7.16 (dd,
J
J
= 7.6, MHz, CDCl3) δ 52.7, 115.6 (q, 3JCF = 4.1 Hz), 118.3 (q, JCF
= 4.9, 4.0 Hz), 122.8 (q, JCF = 1.4 Hz), 122.9 (q, JCF = 236.7 Hz)
=
3
4
1
4.9 Hz, 1H), 8.01 (dd,
J
= 7.6, 2.0 Hz, 1H), 8.66 (dd,
2.0 Hz, 1H), 9.92 (s, 1H), 10.36 (s, 1H); 13C NMR (100 MHz, 136.2 (s), 136.8 (d, JCF = 32.6 Hz), 141.5, 153.9, 194.4. MS
2
CDCl3) δ 52.7, 116.7, 118.0, 143.8, 152.0, 154.4, 193.0. MS (ESI) calc´d for C10H8F3NO3 [M+] m/z 247.0456, found m/z
+
(ESI) calc’d. for C8H9N2O3+ [M + H+] m/z 181.0622, found m/z 247.0452.
181.0613.
Methyl (3-chloro-2-formylphenyl)carbamate (1e). Following
general procedure starting from (2-amino-6-
General procedure for preparation of carbamates 1i–1o, the
exemplified
methoxybenzyl)carbamate (1n). To a stirred solution of 1a white solid (79 mg, 14%); H NMR (400 MHz, CDCl3) δ 3.80
(100 mg, 0.55 mmol) in 5 mL anhydrous MeCN was added 4- (s, 3H), 7.10 (d, = 7.9 Hz, 1H), 7.48 (t, = 8.3 Hz, 1H), 8.42
methoxybenzyl chloride (131 mg, 0.84 mmol) and anhydrous (d,
= 8.7 Hz, 1H), 10.56 (s, 1H), 11.09 (s, 1H); 13C NMR (100
by
methyl
(2-formylphenyl)(4- chlorophenyl)methanol, the title compound was obtained as a
1
J
J
J
K2CO3 (154 mg, 1.11 mmol). After 20 h of heating at reflux MHz, CDCl3) δ 49.5, 117.5, 124.9, 136.8, 139.6, 143.4, 154.7,
+
under N2 atmosphere, the reaction mixture was taken up in H2O 159.2, 192.9. MS (EI) calc´d for C9H8ClNO3 [M+] m/z
and extracted with EtOAc. Concentration and purification by 213.0186, found m/z 213.0193.
silica gel chromatography (15% EtOAc in
the title compound as a colourless oil (91 mg, 55%); H NMR Following the general procedure starting from (2-amino-3-
(400 MHz, CDCl3) δ 3.52 – 3.70 (m, 3H), 3.76 (s, 3H), 4.65 – methylphenyl)methanol,24 the title compound was obtained as a
n
-pentane) provided Methyl
(2-formyl-6-methylphenyl)carbamate
(1g).
1
1
5.10 (m, 2H), 6.59 – 6.90 (m, 2H), 7.05 – 7.09 (m, 2H), 7.09 – white solid (80 mg, 22%); H NMR (400 MHz, CDCl3) δ 2.01
7.18 (m, 1H), 7.42 (dt,
J = 7.6, 0.9 Hz, 1H), 7.52 – 7.71 (m, (s, 3H), 3.46 (s, 3H), 6.92 – 7.03 (m, 1H), 7.17 (dd, J = 7.8, 1.6
1H), 7.84 (dd,
J
= 7.8, 1.7 Hz, 1H), 9.71 (s, 1H); 13C NMR (100 Hz, 1H), 7.24 – 7.31 (m, 1H), 8.05 (br s, 1H), 9.68 (s, 1H); 13
C
MHz, CDCl3) δ 53.3, 54.5, 55.2, 113.9, 127.9, 128.4, 128.9, NMR (100 MHz, CDCl3) δ 18.9, 53.2, 125.9, 132.0, 135.4,
129.0, 130.3, 132.9, 134.8, 143.3, 156.1, 159.3, 189.6. MS 137.4, 137.6, 137.7, 155.1, 193.7. MS (ESI) calc’d. for
(ESI) calc’d. for C17H17NO4Na+ [M + Na+] m/z 322.1055, C10H12NO3+ [M + H+] m/z 194.0817, found m/z 194.0821.
found m/z 322.1071.
Methyl
(2-formyl-6-methoxyphenyl)carbamate
(1h).
Preparation of methyl (2-acetylphenyl)carbamate (1p). A Following the general procedure starting from (2-amino-3-
solution of o-nitroacetophenone (0.5 g, 3.03 mmol) and 10% methoxyphenyl)methanol,23 the title compound was obtained as
Pd/C (50 mg) in MeOH (10 ml) was hydrogenated at atm. a white solid (0.27 g, 57% ); 1H NMR (400 MHz, CDCl3) δ
pressure for 12 h. After consumption of starting material (as 3.78 (s, 3H), 3.89 (s, 3H), 7.07 – 7.19 (m, 2H), 7.21 – 7.31 (m,
confirmed by TLC, 10% EtOAc in hexanes, ninhydrin stain), 1H), 7.46 (dd,
J
= 7.8, 1.3 Hz, 1H); 10.03 (s, 1H); 13C NMR
the reaction mixture was filtered through a pad of Celite, (100 MHz, CDCl3) δ 53.1, 56.1, 115.6, 120.9, 125.9, 128.2,
+
washed with methanol and concentrated under reduced pressure 130.0, 152.0, 155.8, 189.9. MS (ESI) calc’d. for C10H12NO4
to afford a yellow oil (0.41 g). The crude compound was used [M + H+] m/z 210.0771, found m/z 210.0766.
for next step without any further purification. MS (ESI) for Methyl (2-formylphenyl)(methyl)carbamate (1i) Following
C8H11NO+ [M + H+] m/z 136.08.
the general procedure but with 10 equiv. alkyl halide, the title
1
To a stirred solution of the above oil (0.41 g, 3.02 mmol) and compound was obtained as a white solid (91 mg, 85 %); H
pyridine (0.36 g, 4.54 mmol) in DCM (8 mL) at ambient NMR (400 MHz, CDCl3) δ 3.33 (s, 3H), 3.53 – 3.69 (m, 3H),
temperature was added methyl chloroformate (0.37 g, 3.93 7.27 (d,
mmol). After 5 h of stirring, 0.1 M HCl (10 mL) was added (m, 1H), 7.90 (ddd,
and the resulting aqueous layer extracted with DCM (2 x 30 NMR (100 MHz, CDCl3) δ 38.6, 53.2, 127.7, 129.5, 132.2,
J
= 7.8 Hz, 1H), 7.43 (d,
J = 1.6 Hz, 1H), 7.58 – 7.65
J
= 7.8, 1.6, 0.5 Hz, 1H), 10.08 (s, 1H); 13C
This journal is © The Royal Society of Chemistry 2012
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Page 7 of 11
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
133.5, 134.9, 144.9, 156.1, 189.6. MS (ESI) calc’d. for Preparation of 2a by conventional heating. A 2–5 mL Pyrex
C10H12NO3+ [M + H+] m/z 194.0817, found m/z 194.0820.
process vial equipped with a magnetic stirring bar was charged
Methyl butyl(2-formylphenyl)carbamate (1j). Following the with 1a (45.1 mg, 0.25 mmol), NH4OAc (45 mg,Vie0w.5A9rticmle Omnolinle)
DOI: 10.1039/C4OB02417F
general procedure, the title compound was obtained as a white and AcOH (1 mL).
The vial was sealed and the
1
solid (70 mg, 53%); H NMR (400 MHz, CDCl3) δ 0.89 (t,
J =
reaction mixture brought to 130 °C on a heating plate. After 2
7.3 Hz, 3H), 1.25 (s, 2H), 1.47 – 1.65 (m, 2H), 3.52 – 3.66 (m, h, the vial was cooled to ambient temperature and purified
3H), 3.66 – 3.74 (m, 2H), 7.35 – 7.06 (m, 1H), 7.44 (tt, J = 7.5, following the general procedure.
0.9 Hz, 1H), 7.63 (ddd, J = 8.0, 7.4, 1.7 Hz, 1H), 7.93 (ddd, J = 3-Methyl-4-(nitromethyl)-3,4-dihydroquinazolin-2(1H)-one
7.7, 1.7, 0.5 Hz, 1H), 10.10 (s, 1H); 13C NMR (100 MHz, (2b). Following the general procedure, the title compound was
1
CDCl3) δ 13.7, 20.0, 29.7, 51.2, 53.1, 127.7, 128.6, 132.8, obtained as a white solid (105 mg, 95%); H NMR (400 MHz,
+
134.8, 189.8. MS (ESI) calc’d. for C13H18NO3 [M + H+] m/z DMSO-d6) δ 3.00 (s, 3H), 4.86 (t,
J
= 5.3 Hz, 1H), 5.25 (t,
= 8.0 Hz, 1H), 6.95 (t, = 7.5 Hz, 1H),
= 7.6 Hz, 1H), 7.23 (td, = 7.6, 1.6 Hz, 1H), 9.44 (s,
J =
236.1287, found m/z 236.1279.
5.3 Hz, 1H), 6.85 (d,
J
J
Methyl allyl(2-formylphenyl)carbamate (1k). Following the 7.19 (d,
general procedure, the title compound was obtained as a white 1H); 13C NMR (100 MHz, DMSO-d6) δ 33.3, 59.2, 77.7, 114.1,
solid (48 mg, 78%); H NMR (400 MHz, CDCl3) δ 3.63 (s, 117.2, 121.7, 126.5, 129.4, 138.0, 153.2. MS (ESI) calc’d. for
J
J
1
3H), 4.12 – 4.45 (m, 2H), 5.07 – 5.25 (m, 2H), 5.90 (ddt,
16.8, 10.2, 6.5 Hz, 1H), 7.22 – 7.28 (m, 1H), 7.44 (t, = 7.6 Hz, 3-Hexyl-4-(nitromethyl)-3,4-dihydroquinazolin-2(1
1H), 7.62 (ddd, = 7.9, 7.5, 1.7 Hz, 1H), 7.90 (dd, = 7.7, 1.7 (2c). Following the general procedure (0.3 mmol scale), the title
Hz, 1H), 10.07 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 53.3, compound was obtained as a white solid (78 mg, 92%); H
54.0, 119.1, 127.9, 128.7, 129.5, 132.5, 132.7, 134.8, 143.5, NMR (400 MHz, DMSO- 6) δ 0.51 – 0.93 (m, 3H), 1.01 – 1.25
155.8, 189.9. MS (ESI) calcd. for C12H14NO3 [M + H+] m/z (m, 6H), 1.29 – 1.57 (m, 2H), 2.90 (ddd,
= 13.9, 8.5, 5.5 Hz,
220.0974, found m/z 220.0972. 1H), 3.76 (ddd, = 13.7, 8.7, 6.6 Hz, 1H), 4.70 (dd, = 5.5, 1.8
Ethyl N-(2-formylphenyl)-N-(methoxycarbonyl)glycinate Hz, 2H), 5.15 (t, = 5.5 Hz, 1H), 6.78 (dd, = 8.0, 1.1 Hz, 1H),
= 7.5, 1.1 Hz, 1H), 7.11 (dd, = 7.7, 1.4 Hz, 1H),
= 7.7, 1.5 Hz, 1H), 9.33 (s, 1H); 13C NMR (100
J
=
C10H12N3O3+ [M + H+] m/z 222.0879, found m/z 222.0881.
J
H)-one
J
J
1
d
+
J
J
J
J
J
(1l). Following the general procedure but with 4 h of heating , 6.86 (td,
J
J
the title compound was obtained as a white solid (40 mg, 27%); 7.15 (td,
J
1H NMR (400 MHz, CDCl3) δ 1.27 (t,
J
= 6.9 Hz, 3H), 3.67 (s, MHz, DMSO-d6) 14.8, 22.9, 26.7, 28.3, 31.8, 45.6, 57.5, 78.6,
3H), 4.21 (q,
(m, 1H), 7.63 (td,
J = 7.0 Hz, 2H), 4.27 – 4.45 (m, 2H), 7.41 – 7.53 114.6, 118.2, 122.2, 126.9, 129.9, 138.6, 153.6. MS (ESI)
J
= 7.7, 1.7 Hz, 1H), 7.92 (dd, J
= 7.8, 1.7 calcd. for C17H25N4O3+ [M + H+ + MeCN] m/z 333.1940, found
Hz, 1H), 10.27 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1. m/z 333.1937.
52.4, 53.6, 61.5, 128.1, 128.2, 129.4, 132.5, 134.8, 143.3, 3-Benzyl-4-(nitromethyl)-3,4-dihydroquinazolin-2(1H)-one
155.9, 169.1, 190.2. MS (ESI) calc’d. for C13H16NO5+ [M + H+] (2d). Following the general procedure, the title compound was
1
m/z 266.1028, found m/z 266.1029.
Methyl benzyl(2-formylphenyl)carbamate (1m). Following DMSO-d6) δ 4.24 (d,
the general procedure, the title compound was obtained as a 5.06 (t, = 5.2 Hz, 1H), 5.18 (d,
white solid (147 mg, 98%); 1H NMR (400 MHz, CDCl3) δ 3.63 (m, 2H), 7.10 (d,
= 7.5 Hz, 1H), 7.20 (t,
(s, 3H), 4.65 – 5.01 (m, 2H), 7.09 – 7.15 (m, 1H), 7.15 – 7.20 – 7.29 (m, 3H), 7.29 – 7.37 (m, = 8.0 Hz, 2H), 9.43 – 9.70 (m,
(m, 2H), 7.21 – 7.28 (m, 3H), 7.37 – 7.44 (m, 1H), 7.56 (dtd,
1H); 13C NMR
obtained as a white solid (110 mg, 74%); H NMR (400 MHz,
J
= 15.7 Hz, 1H), 4.69 – 4.94 (m, 2H),
= 15.7 Hz, 1H), 6.78 – 6.93
= 7.6 Hz, 1H), 7.24
J
J
J
J
J
J
= 7.3, 7.5, 1.7 Hz, 1H), 7.84 (dd,
J = 7.7, 1.7 Hz, 1H), 9.73 (s, (100 MHz, DMSO-d6) δ 48.1, 57.1, 78.3, 117.8, 122.3, 126.9,
1H); 13C NMR (100 MHz, CDCl3) δ 53.4, 55.1, 127.9, 128.0, 128.2, 128.3, 129.5, 130.0, 138.4, 138.5, 153.7. MS (ESI)
128.6, 128.8, 129.2, 132.8, 134.8, 136.4, 143.2, 156.1, 189.5. calc’d. for C16H16N3O3 [M + H+] m/z 298.1192, found m/z
MS (ESI) calc’d. for C16H16NO3 [M + H+] m/z 270.1130, 298.1202.
+
+
found m/z 270.1132.
Preparation of 2d using one-pot, two-step protocol.
Methyl(2-
Following the general procedure, the title compound was
formylphenyl)(2(((methoxycarbonyl)(phenyl)amino)methyl) obtained as a white solid (54 mg, 81%).
benzyl)carbamate (1o). Following the general procedure, the 3-Cyclopropyl-4-(nitromethyl)-3,4-dihydroquinazolin-
1
title compound was obtained as a white solid (92 mg, 71%); H 2(1
H
)-one (2e). Following the general procedure, the title
1
NMR (400 MHz, CDCl3) δ 3.63 (s, 6H), 4.30 – 4.98 (m, 4H), compound was obtained as a white solid (115 mg, 93%); H
7.01 – 7.16 (m, 6H), 7.39 (tt, = 7.6, 0.9 Hz, 2H), 7.46 – 7.63 NMR (400 MHz, DMSO-d6) δ 0.54 (dd, = 8.3, 4.4 Hz, 1H),
(m, 2H), 7.78 (dd, = 8.2 Hz, 2H), 0.90 (td, = 7.4, 6.6, 2.6 Hz, 1H),
= 7.7, 1.8 Hz, 2H), 9.60 (s, 2H); 13C NMR 0.66 (d,
(100 MHz, CDCl3) δ 51.4, 53.8, 128.5, 128.8, 129.3, 130.0, 2.62 (td, = 5.5, 2.6 Hz, 1H), 4.83 (dd, = 5.3, 2.2 Hz, 2H),
130.3, 131.0, 133.2, 135.2, 142.9, 156.3, 189.5. MS (ESI) 5.16 (t, = 5.4 Hz, 1H), 6.71 – 6.86 (m, 1H), 6.90 (t, = 7.5
calc’d. for C26H25N2O6 [M + H+] m/z 461.1713, found m/z Hz, 1H), 7.18 (t, = 7.2 Hz, 2H), 9.49 (s, 1H); 13C NMR (100
J
J
J
J
J
J
J
J
J
+
J
461.1712.
MHz, DMSO-d6) δ 5.7, 11.0, 28.1, 58.2, 78.1, 114.1, 117.9,
121.6, 126.6, 129.4, 137.5, 153.9. MS (ESI) calc’d. for
C12H14N3O3+ [M + H+] m/z 248.1035, found m/z 248.1038.
Dialkylation was observed
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

Organic & Biomolecular Chemistry
Page 8 of 11
ARTICLE
Journal Name
Ethyl
3(2
4-(4-(nitromethyl)-2-oxo-1,4-dihydroquinazolin- 5.13 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 7.26 (dd, J = 8.8 and 2.0
H
)-yl)butanoate (2f). Following the general procedure (0.3 Hz, 1H), 7.35 – 7.37 (m, 2H), 9.40 (s, 1H); 13C NMR (100
View Article Online
mmol scale) but with 30 min of heating and 1.3 equiv. amine, MHz, DMSO-d6) δ 51.4, 80.2, 115.6, D1O1I:81.03.,101392/6C.42O, B1022481.77F,
the title compound was obtained as a white solid (51 mg, 57%); 136.8, 152.4. MS (ESI) calc’d. for C9H8ClN3O3 [M + H+] m/z
+
1H NMR (400 MHz, CDCl3) δ 1.22 (t,
2.07 (m, 2H), 2.32 (t,
6.1 Hz, 1H), 3.93 – 4.18 (m, 3H), 4.38 – 4.65 (m, 2H), 5.18 (t,
= 6.7 Hz, 1H), 6.89 (dd, = 8.0, 1.1 Hz, 1H), 6.99 (td, = 7.8, scale) but with 30 min of heating and 4 equiv. MeNO2, the title
1.1 Hz, 1H), 7.08 (ddd, = 7.8, 1.5, 0.6 Hz, 1H), 7.27 (ddd,
8.0, 7.4, 1.5 Hz, 1H), 8.97 (s, 1H); 13C NMR (100 MHz, NMR (400 MHz, DMSO-d6) δ 4.70 (ddd,
CDCl3) δ 14.2, 23.6, 29.7, 31.2, 45.7, 57.8, 60.5, 114.6, 117.1, Hz, 2H), 5.12 – 5.20 (m, 1H), 7.06 (s, 1H), 7.20 (d,
122.7, 125.7, 129.8, 136.8, 154.5, 172.9. MS (ESI) calc’d. for 1H), 7.40 (s, 1H), 7.43 (dd, = 6.8, 3.1 Hz, 1H), 9.51 (s, 1H);
C15H20N3O5+ [M + H+] m/z 322.1403, found m/z 322.1404. 13C NMR (100 MHz, DMSO-d6) δ 51.6, 80.2, 110.3 (q, JCF
Methyl 4-(4-(nitromethyl)-2-oxo-1,4-dihydroquinazolin- 4.4 Hz), 117.7 (q, JCF = 4.3 Hz), 124.2 (q, JCF = 272.0 Hz),
3(2 )-yl)propanoate (2g). Following the general procedure 129.3 (d, JCF = 31.5 Hz), 138.8,152.3. MS (ESI) calc’d. for
(0.45 mmol scale) but with 30 min of heating and 1.8 equiv. C10H9F3N3O3+ [M + H+] m/z 276.0596, found m/z 276.0604.
amine, the title compound was obtained as a white solid (32 6-Fluoro-4-(nitromethyl)-3,4-dihydroquinazolin-2(1 )-one
= 17.0, (3c). Following the general procedure (0.5 mmol scale) but
= 17.0, 8.9, 5.8 Hz, 1H), 3.39 (ddd, with 4 equiv. of MeNO2, the title compound was obtained as a
J
= 7.1 Hz, 3H), 1.85 – 242.0332, found m/z 242.0335.
= 7.2 Hz, 2H), 3.04 (ddd, = 13.9, 7.7, 4-(Nitromethyl)-6-(trifluoromethyl)-3,4-dihydroquinazolin-
2(1 )-one (3b). Following the general procedure (0.3 mmol
J
J
J
H
J
J
1
J
J
=
compound was obtained as a white solid (40 mg, 62%); H
= 17.2, 12.7, 5.5
= 8.1 Hz,
J
J
J
3
=
3
1
2
H
H
1
mg, 24 %); H NMR (400 MHz, CDCl3) δ 2.62 (dt,
5.1 Hz, 1H), 2.80 (ddd,
= 14.2, 8.9, 5.3 Hz, 1H), 3.61 (s, 3H), 4.14 (dt,
1H), 4.46 (dd, = 11.9, 6.6 Hz, 1H), 4.62 (dd,
1H), 5.41 (t,
7.6, 1.1 Hz, 1H), 7.10 (dd,
1H), 8.85 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 33.5, 43.3, MHz, DMSO-d6) δ 52.2, 80.6, 113.5 (d, 2
J
J
J
1
J
J
= 14.1, 5.4 Hz, white solid (91 mg, 73 %); H NMR (400 MHz, DMSO-d6) δ
J
= 11.9, 6.6 Hz, 4.28 – 4.83 (m, 2H), 5.09 (dd,
= 8.8, 4.8 Hz, 1H), 7.04 (td,
J
= 9.3, 5.2 Hz, 1H), 6.81 (dd,
= 8.9, 3.4 Hz, 1H), 7.16 (dd,
= 7.7, 1.4 Hz, 1H), 7.22 – 7.30 (m, 9.3, 3.4 Hz, 1H), 7.33 (br s, 1H), 9.34 (s, 1H); 13C NMR (100
J
=
J
= 6.6 Hz, 1H), 6.83 – 6.90 (m, 1H), 6.99 (td,
J
=
J
J
J
J
CF = 22.9 Hz), 115.7
CF = 22.9 Hz), 118.3 (d, JCF
3
2
3
51.8, 59.2, 77.4, 114.6, 117.3, 122.8, 125.7, 129.8, 136.6, (d,
154.3, 172.3. MS (ESI) calc’d. for C13H16N3O5 [M + H+] m/z 7.9 Hz), 134.9 (d, 4
294.1090, found m/z 294.1095.
3-(4-Methoxyphenyl)-4-(nitromethyl)-3,4-
J
CF = 8.2 Hz), 116.1 (d,
J
=
+
J
CF = 2.3 Hz), 153.1, 157.2 (d, 1
J
CF = 236.7
Hz). MS (ESI) calc’d. for C9H9FN3O3+ [M + H+] m/z 226.0628,
found m/z 226.0631.
dihydroquinazolin-2(1H)-one (2h). Following the general 5-Chloro-4-(nitromethyl)-3,4-dihydroquinazolin-2(1H)-one
procedure (0.2 mmol scale) but with 30 min of heating, the title (3d). Following the general procedure (0.4 mmol scale), the
1
compound was obtained as a white solid (28mg, 40%); 1H title compound was obtained as a white solid (64 mg, 71%); H
NMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 4.57 (dd,
J
= 11.9, 7.3 NMR (400 MHz, DMSO-d6) δ 4.48 – 4.79 (m, 2H), 5.18 (dt,
J
Hz, 1H), 4.68 (dd,
Hz, 1H), 6.80 (d,
(t,
1H), 7.30 (d,
MHz, CDCl3) δ 55.7, 61.5, 76.9, 114.9, 115.0, 117.1, 122.9, for C9H9ClN3O3+ [M + H+] m/z 242.0327, found m/z 242.0325.
126.0, 129.1, 130.1, 132.8, 136.9, 153.3, 159.0. MS (ESI) 4-(Nitromethyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1 )-
calc’d. for C16H16N3O4 [M + H+] m/z 314.1141, found m/z one (3e). Following the general procedure (0.1 mmol scale), the
J
= 11.9, 5.3 Hz, 1H), 5.44 (dd,
J
= 7.3, 5.3 = 6.8, 4.3 Hz, 1H), 6.85 (dd,
J
= 8.1, 1.0 Hz, 1H), 7.05 (dd,
J
=
J
= 8.0 Hz, 1H), 6.95 (d,
J
= 8.7 Hz, 2H), 7.00 8.1, 1.0 Hz, 1H), 7.26 (d,
J
= 8.0 Hz, 1H), 7.70 (d, J = 4.0, 1.2
J
= 7.6 Hz, 1H), 7.10 (d,
= 8.7 Hz, 2H), 8.25 (s, 1H); 13C NMR (100 79.2, 113.8, 114.6, 122.5, 131.1, 140.6, 153.1. MS (ESI) calc’d.
J
= 7.5 Hz, 1H), 7.23 – 7.27 (m, Hz, 1H), 9.69 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 51.0,
J
H
+
314.1139.
title compound was obtained as a yellow solid (11 mg, 61%);
1H NMR (400 MHz, DMSO-d6) δ 4.69 – 4.80 (m, 2H), 5.13 –
3-(4-iso-propylphenyl)-4-(nitromethyl)-3,4-
dihydroquinazolin-2(1
procedure but with 30 min of heating, the title compound was 7.2,1.6 Hz, 1H), 8.14 (dd,
H
)-one (2i). Following the general 5.17 (m, 1H), 6.94 – 6.97 (m, 1H), 7.43 (s, 1H), 7.66 (dd,
J
=
C
J
= 5.2, 1.6 Hz, 1H), 9.75 (s, 1H); 13
1
obtained as a white solid (26 mg, 36%); H NMR (400 MHz, NMR (100 MHz, DMSO-d6) δ 50.7, 80.2, 111.8, 117.3, 134.9,
+
CDCl3) δ 1.28 (dd,
J
= 6.9, 0.6 Hz, 6H), 2.79 – 3.10 (m, 1H), 148.0, 150.3, 152.8. MS (ESI) calc’d. for C8H9N3O4 [M + H+]
4.61 (dd,
6.83 (dd,
J
J
= 11.9, 7.8 Hz, 1H), 4.70 (dd,
= 8.1, 1.1 Hz, 1H), 7.02 (td,
J
J
= 11.9, 5.1 Hz, 1H), m/z 209.0675, found m/z 209.0668.
= 7.5, 1.1 Hz, 1H), 8-Methyl-4-(nitromethyl)-3,4-dihydroquinazolin-2(1H)-one
7.08 – 7.14 (m, 1H), 7.25 – 7.30 (m, 2H), 7.32 (s, 4H), 8.32 (s, (3f). Following the general procedure (0.4 mmol scale), the title
1
1H); 13C NMR (100 MHz, CDCl3) δ 23.9, 33.8, 47.0, 61.0, compound was obtained as a white solid (74 mg, 82%); H
76.6, 114.7, 117.1, 122.8, 125.9, 127.3, 127.7, 130.0, 136.6, NMR (400 MHz, DMSO-d6) δ 2.19 (s, 3H), 4.65 (d, J = 5.9 Hz,
+
137.5, 148.5. MS (ESI) calc’d. for C18H20N3O3 [M + H+] m/z 2H), 5.03 – 5.09 (m, 1H), 6.83 (t,
326.1505, found m/z 326.1510.
J = 7.6 Hz, 1H), 7.01 – 7.09
(m, 2H), 7.35 – 7.41 (m, 1H), 8.60 (s, 1H); 13C NMR (100
6-Chloro-4-(nitromethyl)-3,4-dihydroquinazolin-2(1
H
)-one
MHz, DMSO-d6) δ 17.1, 52.0, 80.5, 116.7, 121.2, 122.4, 124.1,
+
(3a). Following the general procedure (0.2 mmol scale), the 130.3, 135.8, 153.1. MS (ESI) calc’d. for C10H12N3O3 [M +
title compound was obtained as a yellow solid (35 mg, 75%); H+] m/z 222.0879, found m/z 222.0873.
1H NMR (400 MHz, DMSO-d6) δ 4.71 4.73 (m, 2H), 5.10 –
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 8

Page 9 of 11
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
8-Methoxy-4-(nitromethyl)-3,4-dihydroquinazolin-2(1
H)-
Dimethyl
2-(2-oxo-1,2,3,4-tetrahydroquinazolin-4-
one (3g). Following the general procedure, the title compound yl)malonate (4f). Following the general procedure, the title
View Article Online
DOI: 10.1039/C4OB02417F
1
1
was obtained as a white solid (53 mg, 91%); H NMR (400 compound was obtained as a yellow solid (104 mg, 76%); H
MHz, DMSO-d6) δ 3.79 (s, 3H), 4.66 – 4.68 (m, 2H), 5.07 – NMR (400 MHz, DMSO-d6) δ 3.55 (s, 3H), 3.62 (s, 3H), 3.72
5.10 (m, 1H), 6.80 – 6.82 (m, 1H), 6.90 – 6.91 (m, 2H), 7.35 (s, (d,
J
= 6.6 Hz, 1H), 5.02 (dd,
J
= 6.6, 3.6 Hz, 1H), 6.81 (d,
J
J
=
=
1H), 8.18 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 51.9, 7.6 Hz, 1H), 6.85 (d,
J = 6.4 Hz, 1H), 6.98 (s, 1H), 7.09 (d,
55.6, 80.2, 110.6, 116.9, 117.9, 121.5, 126.6, 145.1, 152.3. MS 7.5 Hz, 1H), 7.16 (t,
J
= 7.6 Hz, 1H), 9.27 (s, 1H); 13C NMR
+
(ESI) calc’d. for C10H11N3O4 [M + H+] m/z 238.0828, found (100 MHz, DMSO-d6) δ 52.4, 52.5, 52.9, 58.3, 114.0, 117.9,
m/z 238.0835.
4-(1-Nitroethyl)-3,4-dihydroquinazolin-2(1
121.0, 126.2, 128.6, 137.9, 153.4, 166.8, 166.9. MS (ESI)
+
H)-one
(4a)
.
calc’d. for C13H15N2O5 [M + H+] m/z 279.0981, found m/z
Following the general procedure, the title compound was 279.0984.
obtained as a white solid (90 mg, 80% as a 0.7:1 mixture of Ethyl
diastereomers); H NMR (400 MHz, DMSO-d6, major isomer) yl)acetate (4g). Following the general procedure (0.3 mmol
2-cyano-2-(2-oxo-1,2,3,4-tetrahydroquinazolin-4-
1
δ 1.33 (d,
1H), 6.83 (dd,
7.12 (dd, = 14.6, 7.5 Hz, 1H), 7.20 (t,
7.37 (m, 1H), 9.31 (s, 1H), ,; 13C NMR (100 MHz, DMSO-d6) δ (m, 2H), 4.43 (d,
12.4, 56.5, 87.4, 114.1, 116.3, 121.3, 126.7, 129.0, 138.0, (ddd, = 9.3, 8.1, 1.1 Hz, 1H), 6.84 – 6.88 (m, 1H), 6.89 – 6.95
J = 9.8 Hz, 3H), 4.69 – 4.81 (m, 1H), 4.96 – 5.03 (m, scale), the title compound was obtained as a yellow oil (81 mg,
1
J
= 8.0, 2.9 Hz, 1H), 6.90 (t,
= 7.7 Hz, 1H), 7.31 – DMSO-d6, major isomer) δ 1.16 – 1.28 (m, 3H), 4.13 – 4.17
= 3.3 Hz, 1H), 5.13 (t, = 3.3 Hz, 1H), 6.78
J = 7.4 Hz, 1H), 90% as a 0.8:1 mixture of diastereomers); H NMR (400 MHz,
J
J
J
J
J
+
153.3. MS (ESI) calc’d. for C10H12N3O3 [M + H+] m/z (m, 1H), 7.10 – 7.21 (m, 1H), 7.38 (dd,
222.0879, found m/z 222.0876.
J = 3.5, 2.0 Hz, 1H),
9.30 9.22 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.1,
4-(Nitro(phenyl)methyl)-3,4-dihydroquinazolin-2(1H)-one
48.3, 54.5, 63.0, 114.6, 116.0, 116.4, 121.7, 127.0, 129.5,
+
(4b). Following the general procedure (0.3 mmol scale) but 138.3, 152.9, 164.5. MS (ESI) calc’d. for C13H14N3O3 [M +
with 20 min of heating, the title compound was obtained as a H+] m/z 260.1035, found m/z 260.1038.
white solid (54 mg, 68% as a 1:1 mixture of diastereomers); 1H 1-Methyl-4-(nitromethyl)-3,4-dihydroquinazolin-2(1
H)-one
NMR (400 MHz, DMSO-d6) δ 5.34 (dd,
5.46 (dd, = 6.7, 4.0 Hz, 1H), 5.68 (d,
(dd, = 7.8, 1.5 Hz, 1H), 6.53 (td, = 7.5, 1.2 Hz, 1H), 6.70 – NMR (400 MHz, CDCl3) δ 3.33 (s, 3H), 4.42 (dd,
6.75 (m, 1H), 6.82 (d, = 8.0 Hz, 1H), 6.89 (td, = 7.5, 1.2 Hz, Hz, 1H), 4.62 (dd, = 13.4, 9.3 Hz, 1H), 5.21 (dt,
1H), 7.06 (td, = 7.7, 1.5 Hz, 1H), 7.11 – 7.20 (m, 3H), 7.27 – Hz, 1H), 6.27 – 6.47 (m, 1H), 6.96 (dd, = 8.4, 1.1 Hz, 1H),
J = 9.5, 4.4 Hz, 1H), (5a). Following the general procedure (0.2 mmol scale), the
1
J
J
= 9.5 Hz, 1H), 6.38 title compound was obtained as a white solid (46 mg, 85%); H
= 13.4, 4.1
= 9.3, 3.7
J
J
J
J
J
J
J
J
J
7.44 (m, 11H), 7.65 (s, 1H), 9.09 (s, 1H), 9.38 (s, 1H); 13C 7.06 (td,
J = 7.4, 1.1 Hz, 1H), 7.10 – 7.15 (m, 1H), 7.36 (ddd, J
NMR (100 MHz, DMSO-d6) δ 55.8, 56.4, 93.6, 94.1, 127.0, = 8.4, 7.4, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 29.8,
127.7, 127.7, 128.9, 129.0, 129.2, 129.3, 129.4, 129.6, 130.1, 51.9, 79.7, 113.9, 117.9, 122.9, 126.4, 130.0, 139.2, 154.0. MS
+
130.5, 131.2, 131.7, 138.5, 138.8, 153.5, 153.9. MS (ESI) (ESI) calc’d. for C10H12N3O3 [M + H+] m/z 222.0879, found
+
calc’d. for C15H14N3O3 [M + H+] m/z 284.1035, found m/z m/z 222.0870.
284.1037.
1-Butyl-4-(nitromethyl)-3,4-dihydroquinazolin-2(1
H)-one
4-(1-Nitrocyclopentyl)-3,4-dihydroquinazolin-2(1H)-one
(4c). Following the general procedure (0.3 mmol scale), the title title compound was obtained as a white solid (36 mg, 80%); H
(5b). Following the general procedure (0.2 mmol scale), the
1
1
compound was obtained as a white solid (40 mg, 55%); H NMR (400 MHz, CDCl3) δ 0.98 (t,
NMR (400 MHz, DMSO-d6) δ 1.41 – 1.52 (m, 2H), 1.52 – 1.63 (m, 2H), 1.55 – 1.80 (m, 2H), 3.61 – 4.07 (m, 2H), 4.43 (ddd,
(m, 2H), 1.85 – 1.95 (m, 1H), 2.09 – 2.20 (m, 1H), 2.21 – 2.30 = 13.5, 4.0, 0.6 Hz, 1H), 5.20 (dd, = 9.1, 4.0 Hz, 1H), 6.13 (s,
(m, 1H), 2.30 – 2.39 (m, 1H), 4.94 (d, = 4.1 Hz, 1H), 6.80 1H), 6.93 – 6.99 (m, 1H), 7.01 – 7.07 (m, 1H), 7.12 (ddd,
(dd, = 8.0, 1.2 Hz, 1H), 6.86 (td, = 7.5, 1.2 Hz, 1H), 6.96 – 7.1, 1.6, 0.9 Hz, 1H),
7.39 – 7.31 (m, 1H); 13C NMR (100
7.01 (m, 1H), 7.13 – 7.21 (m, 1H), 7.13 – 7.21 (m, 1H), 7.58 MHz, CDCl3) δ 13.8, 20.1, 29.1, 42.1, 51.7, 79.7, 114.1, 117.7,
(dd,
= 4.0, 2.1 Hz, 1H), 9.20 (s, 1H); 13C NMR (100 MHz, 122.6, 126.6, 129.8, 137.8, 153.4. MS (ESI) calc’d. for
DMSO-d6) δ 23.9, 24.1, 32.8, 34.2, 59.6, 105.9, 115.0, 117.0, C13H18N3O3+ [M + H+] m/z 264.1348, found m/z 264.1343.
121.9, 128.0, 129.9, 139.4, 154.3. MS (ESI) calc’d. for 1-Allyl-4-(nitromethyl)-3,4-dihydroquinazolin-2(1 )-one
(5c). Following the general procedure (0.2 mmol scale), the title
J = 7.3 Hz, 3H), 1.37 – 1.50
J
J
J
J =
J
J
J
H
+
C13H16N3O3 [M + H+] m/z 262.1192, found m/z 262.1193.
4-(2-Nitropropan-2-yl)-3,4-dihydroquinazolin-2(1 )-one
(4d). Following the general procedure (0.2 mmol scale), the NMR (400 MHz, CDCl3) δ 4.34 – 4.50 (m, 2H), 4.58 – 4.74 (m,
1
H
compound was obtained as a white solid (25 mg, 72%); H
1
title compound was obtained as a white solid (38 mg, 72%); H 2H), 5.12 – 5.29 (m, 3H), 5.90 (ddt,
NMR (400 MHz, DMSO-d6) δ 1.42 (s, 3H), 1.52 (s, 3H), 4.88 6.95 (d, = 8.4 Hz, 1H), 6.35 (s, 1H), 7.04 (td,
(d, = 4.4 Hz, 1H), 6.79 – 6.97 (m, 2H), 6.97 – 7.07 (m, 1H), 1H), 7.12 (dd, = 7.6, 1.6 Hz, 1H), 7.31 (td,
7.26 (td,
9.34 (s, Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 45.3, 52.2, 80.0,
J = 17.3, 10.5, 4.8 Hz, 1H),
J
J
= 7.5, 1.0 Hz,
J
J
J = 8.1, 7.3, 1.6
J
= 7.6, 1.5 Hz, 1H), 7.52 – 7.76 (m, 1H),
1H); 13C NMR (100 MHz, DMSO-d6) δ 21.9, 22.4, 61.1, 94.1, 115.1, 117.1, 118.0, 123.1, 126.7, 130.0, 132.8, 138.4, 153.8.
115.0, 121.9, 128.4, 130.1, 139.6, 154.5. MS (ESI) calc’d. for MS (ESI) calc’d. for C13H18N3O3 [M + H+] m/z 248.1035,
+
C11H14N3O3+ [M + H+] m/z 236.1035, found m/z 236.1031.
found m/z 248.1040.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 9

Organic & Biomolecular Chemistry
Page 10 of 11
Journal Name
ARTICLE
Ethyl
1(2
mmol scale), the title compound was obtained as a white solid
2-(4-(nitromethyl)-2-oxo-3,4-dihydroquinazolin- 122.1, 126.1, 129.7, 137.9, 152.9. MS (ESI) calc´d for
H
)-yl)acetate (5d). Following the general procedure (0.1 C10H12N3O3+ [M + H+] m/z 222.0879, found m/z 222.0880.
View Article Online
DOI: 10.1039/C4OB02417F
1
(20 mg, 52%); H NMR (400 MHz, CDCl3) δ 1.27 (t,
Hz, 3H), 4.22 (q, = 7.1 Hz, 2H), 4.46 (dd, = 13.8, 4.0 Hz, Synthetic utility of compound 2a
1H), 4.60 (d, = 17.9 Hz, 1H), 4.71 – 4.80 (m, 2H), 5.20 (dt, 4-(Aminomethyl)-3,4-dihydroquinazolin-2(1H)-one
= 9.4, 3.7 Hz, 1H), 6.09 (d, = 3.4 Hz, 1H), 6.75 – 6.81 (m, Compound 2a (180 mg, 0.87 mmol) in methanol (40 mL) was
1H), 7.08 (td, = 7.5, 1.0 Hz, 1H), 7.15 (ddt, = 7.6, 1.7, hydrogenated in the presence of Pd/C (5% on charcoal, 40 mg)
0.5 Hz, 1H), 7.32 (ddd,
= 8.3, 7.4, 1.6 Hz, 1H); 13C NMR for 16 h. Upon full consumption of starting material (as
J = 7.1
J
J
.
J
J
(7).
J
J
J
J
(100 MHz, CDCl3) δ 14.5, 44.1, 52.0, 62.0, 79.5, 113.9, 118.5, confirmed by TLC, 100% EtOAc, ninhydrin stain), the reaction
123.6, 126.9, 130.2, 138.2, 153.8, 169.1,. MS (ESI) calc’d. for mixture was filtered through a pad of celite and concentrated in
C13H16N3O5+ [M + H+] m/z 294.1090, found m/z 294.1089.
1-Benzyl-4-(nitromethyl)-3,4-dihydroquinazolin-2(1 )-one
vacuo to afford a white solid (153 mg, 99%). The residue was
used in the next step without further purification; 1H NMR (400
H
(5e). Following the general procedure (0.2 mmol scale), the title MHz, CD3OD) δ 2.70 – 2.97 (m, 2H), 4.42 (t,
J = 5.6 Hz, 1H),
1
compound was obtained as a white solid (40 mg, 73%); H 6.81 (dd, J = 8.0, 1.1 Hz, 1H), 7.10 – 7.14 (m, 1H), 7.17 (td, J =
NMR (400 MHz, CDCl3) δ 4.47 (dd,
4.65 (dd, = 13.5, 9.2 Hz, 1H), 5.04 (d,
– 5.33 (m, 2H), 6.40 (s, 1H), 6.83 (dd,
7.01 (td, = 7.5, 1.0 Hz, 1H), 7.11 (dd,
7.19 (ddd,
7.36 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 30.4, 46.9, 52.5, yl)methyl)acetamide (8). To a stirred solution of
J
= 13.5, 3.9 Hz, 1H), 7.7, 1.4 Hz, 1H), 7.87 (s, 1H); 13C NMR (100 MHz, CD3OD) δ
J
J
J
= 16.6 Hz, 1H), 5.20 49.6, 57.5, 115.4, 120.6, 123.4, 127.3, 129.5, 138.2, 156.9. MS
= 8.3, 1.0 Hz, 1H), (ESI) calc’d for C9H12N3O+ [M + H+] m/z 178.0980, found m/z
J
J
= 7.6, 1.6 Hz, 1H), 179.0978.
J
= 8.3, 7.4, 1.6 Hz, 1H), 7.22 – 7.28 (m, 2H), 7.28 – 2-chloro-N-((2-oxo-1,2,3,4-tetrahydroquinazolin-4-
(50.0 mg,
7
80.6, 115.6, 118.3, 123.5, 127.0, 127.0, 127.9, 129.5, 120.4, 0.28 mmol) in anhydrous dichloromethane (6 mL) at 0 °C was
+
137.5, 138.7, 154.5. MS (ESI) calc’d. for C16H16N3O3 [M + added pyridine (67.0 mg, 0.85 mmol). After 10 min of stirring,
H+] m/z 298.1192, found m/z 298.1186.
1-(4-Methoxybenzyl)-4-(nitromethyl)-3,4-
chloroacetyl chloride (41.0 mg, 0.37 mmol) was added and the
reaction mixture slowly brought to ambient temperature during
dihydroquinazolin-2(1H)-one (5f). Following the general a period of 30 min. The reaction mixture was stirred for 18 h at
procedure (0.1 mmol scale), the title compound was obtained as ambient temperature, and upon full consumption of starting
a white solid (26 mg, 65%); 1H NMR (400 MHz, CDCl3) δ 3.77 material (as confirmed by TLC, 8% MeOH in DCM), the
(s, 3H), 4.46 (dd,
Hz, 1H), 5.00 (d,
J
J
= 13.7, 3.8 Hz, 1H), 4.62 (dd,
J
= 13.7, 9.3 volatiles were removed in vacuo. The residue was purified by
-((2-oxo-1,2,3,4-
= 16.3 Hz, 1H), 5.17 (d, = 16.3 Hz, 1H), silica gel chromatography to afford 2-chloro-
J
N
5.21 – 5.29 (m, 1H), ), 6.16 (s, 1H), 6.82 – 6.93 (m, 3H), 7.01 tetrahydroquinazolin-4-yl)methyl)acetamide as a white solid
1
(td,
7.24 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 45.7, 51.9, 55.3, 2H), 4.04 (s, 2H), 4.61 (dd,
79.9, 114.3, 115.1, 117.6, 122.8, 126.3, 127.7, 128.8, 129.8, 8.0, 1.1 Hz, 1H), 6.97 (td,
J
= 7.5, 1.0 Hz, 1H), 7.11 (dd,
J
= 7.6, 1.5 Hz, 1H), 7.16 – (52 mg, 73%); H NMR (400 MHz, CD3OD) δ 3.30 – 3.64 (m,
= 7.0, 5.1 Hz, 1H), 6.82 (dd,
= 7.5, 1.2 Hz, 1H), 7.13 – 7.16 (m,
= 7.7, 1.5 Hz, 1H), 8.33 (d, = 7.4 Hz, 1H) ,
7.16 – 7.13 (m, 1H),3.64 3.30 (m, 2H); 13C NMR (100 MHz,
meso-1,1'-(1,3-Phenylenebis(methylene))bis(4-(nitromethyl)- CD3OD) δ 41.7, 45.9, 52.9, 113.9, 118.9, 121.9, 126.1, 128.3,
J
J =
J
+
138.0, 153.7, 158.8. MS (ESI) calc’d. for C16H16N3O3 [M + 1H), 7.19 (td,
H+] m/z 328.1297, found m/z 328.1300.
J
J
+
3,4-dihydroquinazolin-2(1
procedure (0.1 mmol scale), the title compound was obtained as 254.0696, found m/z 254.0689.
H
)-one) (5g). Following the general 136.7, 155.4, 168.3. MS (ESI) C11H13ClN3O2 [M + H+] m/z
1
a white solid (20 mg, 55%); H NMR (400 MHz, DMSO-d6) δ 1,2,7,11b-tetrahydro-6
H-pyrazino[1,2-c]quinazoline-
4.75 – 4.89 (m, 4H), 5.07 – 5.16 (m, 3H), 5.17 – 5.28 (m, 3H), 3,6(4 )-dione (9). A stirred solution of
H
8
(25.0 mg, 0.10
6.71 – 6.77 (m, 2H), 6.94 – 7.04 (m, 2H), 7.04 – 7.11 (m, 2H), mmol), NaI (16.3 mg, 0.11 mmol) and Cs2CO3 (96.3, 0.30
7.15 – 7.25 (m, 2H), 7.27 – 7.37 (m, 2H), 7.85 7.73 (m, 2H); mmol) in anhydrous DMF (2 mL) was heated at 65 °C for 2 h.
13C NMR (100 MHz, DMSO-d6) δ 51.8, 81.1, 114.7, 119.0, After evaporation of the volatiles, the residue was purified by
122.4, 125.6, 126.9, 127.3, 129.5, 134.5, 138.6, 153.3, 176.6. silica gel chromatography to provide the title compound as a
+
MS (ESI) calc’d. for C26H25N6O6 [M + H+] m/z 517.1836, white solid (5 mg, 24%); 1H NMR (400 MHz, CD3OD) δ 3.36 –
found m/z 517.1832.
3.46 (m, 1H), 3. 47 – 3.54 (m, 1H), 3.75 (dd,
J = 18.2, 0.8 Hz,
4-Methyl-4-(nitromethyl)-3,4-dihydroquinazolin-2(1H)-one
1H), 4.83 (d, = 18.2 Hz, 1H), 5.01 (dd, = 10.9, 4.0 Hz, 1H),
J
J
(6). Following the general procedure but on a 0.25 mmol scale 6.79 – 6.83 (m, 1H), 6.96 – 7.01 (m, 1H), 7.16 – 7.23 (m, 2H);
and with heating at 150 °C, the title compound was obtained as 13C NMR (100 MHz, CD3OD) δ 45.4, 46.7, 53.7, 113.9, 122.1,
1
a white solid (8 mg, 14%); H NMR (400 MHz, DMSO-d6) δ 125.7, 128.9, 135.8, 147.1, 168.4. MS (ESI) calc’d for
+
1.56 (s, 3H), 4.58 (d,
1H), 6.75 (dd, = 8.0, 1.2 Hz, 1H), 6.89 (td,
1H), 7.14 (ddd, = 8.1, 7.3, 1.4 Hz, 1H), 7.19 – 7.23 (m, 1H), Tert-butyl
7.31 (dd, = 7.8, 1.4 Hz, 1H), 9.24 (d,
= 2.0 Hz, 1H); 13C yl)methyl)carbamate (10). To a stirred solution of
NMR (100 MHz, DMSO-d6) δ 28.3, 58.0, 85.1, 114.9, 121.6, 0.17 mmol) in anhydrous dichloromethane (6 mL) at 0 °C was
J
= 11.6 Hz, 1H), 4.83 (d,
J
= 11.6 Hz, C13H15N4O2 [M + MeCN + H+] m/z 259.1195, found m/z
J
J
= 7.6, 1.3 Hz, 259.1200.
J
((2-oxo-1,2,3,4-tetrahydroquinazolin-4-
(30.0 mg,
J
J
7
This journal is © The Royal Society of Chemistry 2012
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Page 11 of 11
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
Mishra, A. Bajpai, P. Mishra, R. K. Sharma, V. K. Pandey and V. K. Singh,
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3. E. Lorthiois, P. Bernardelli, F. Vergne, C. Oliveira, A.-VKie.wMAratifcrloeuOdn,linEe.
added Et3N (17.0 mg, 0.17 mmol) and the resulting mixture
stirred for 5 min. Boc-anhydride (37.0 mg, 0.17 mmol) was
then added and the reaction mixture was stirred at ambient
temperature for 24 h. Upon full consumption of starting
material (as confirmed by TLC, 6% MeOH in DCM), the
volatiles were removed in vacuo and the residue purified by
silica gel chromatography, providing the title compound as a
white solid (36 mg, 77%); 1H NMR (400 MHz, CD3OD) δ 1.35
(s, 9H), 3.13 – 3.17 (m, 2H), 4.37 – 4.55 (m, 1H), 6.70 – 6.86
Proust, L. Heuze, F. Moreau, M. Idrissi, A. Tertre, B. Bertin, M. Coupe, R.
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Acknowledgements
The authors wish to thank Gabriella Andersson (Uppsala
University) for experimental assistance. X-ray diffraction
studies and melting point determination for compound 4e were
carried out by Dr. Anatolij Mishnev and Dr. Osvalds Pugovics
at the Latvian Institute of Organic Synthesis. Accurate mass
studies were carried out by Dr. Lisa Haigh at Imperial College
London. Financial support from the Knut and Alice Wallenberg
Foundation is graciously acknowledged.
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Author Statement
The authors declare no competing financial interest.
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Notes and references
Organic Pharmaceutical Chemistry, Department of Medicinal
Chemistry, Uppsala Biomedical Center, Uppsala University, P.
O. Box 574, SE-751 23 Uppsala, Sweden. Phone: +46-18-
4714297,
Fax:
+46-18-4714474.
E-mail:
luke.odell@orgfarm.uu.se
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18. CCDC 1026056 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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†
Present Address: Department of Organic Chemistry,
Jagiellonian University Medical College, Medyczna 9, 30-
688 Kraków, Poland.
§
Present Address: Department of Chemistry, Technical
University of Denmark, DK-2800 Kongens Lyngby, Denmark.
‡ These authors contributed equally to this work
Electronic Supplementary Information (ESI) available: Characterization
data (1H and 13C NMR spectra) for new compounds and X-ray structural
data (CIF) for 4e (CDC 1026056) are available. See
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