Efficient preparation of 3-substituted quinazolinediones directly from anthranilic acids and isocyanates

Article abstract of DOI:10.1002/jhet.551

An efficient and practical synthesis of 3-substituted quinazolinediones is described. The protocol uses readily available isocyanates and anthranilic acids as precursors in a one-pot operation and has been demonstrated on >50 g scale. Isolation of the pro

Full text of DOI:10.1002/jhet.551

March 2011
Efficient Preparation of 3-Substituted Quinazolinediones Directly
from Anthranilic Acids and Isocyanates
473
Natalie Koay and Louis-Charles Campeau*
Department of Process Research, Merck Frosst Centre for Therapeutic Research,
´
Pointe-Claire-Dorval, Quebec H9R 4P8, Canada
*E-mail: louis-charles_campeau@merck.com
Received March 10, 2010
DOI 10.1002/jhet.551
Published online 10 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
Dedicated in memory of Keith Fagnou, 1971–2009.
An efficient and practical synthesis of 3-substituted quinazolinediones is described. The protocol uses
readily available isocyanates and anthranilic acids as precursors in a one-pot operation and has been
demonstrated on >50 g scale. Isolation of the products via filtration directly from the reaction media is
facile, affording high-purity material. This procedure was then applied to the synthesis of Zenarestat.
J. Heterocyclic Chem., 48, 473 (2011).
INTRODUCTION
as activated precursors (see Scheme 1) [2]. However,
reports of regioselective reactions at the 3-position are
very scarce and typically require separation of a mixture
of compounds [4]. Instead, chemists have turned to the use
of prefunctionalized building blocks for the selective intro-
duction of substituents. Anthranilate esters [6], o-amino
benzonitriles [7], and 2-nitro benzoates [8] have all been
used in the preparation of the 3-substituted quinazoline-
diones. Transition metal-catalyzed processes have also
been developed using o-halo benzoates [9] and o-iodoa-
nilides [10].
Quinazolinedione heterocycles are important struc-
tural motifs in a variety of natural products as well as
active pharmaceutical ingredients [1]. They can also
serve as building blocks for other classes of com-
pounds such as substituted quinazolinones and quinazo-
lines. As a result, the preparation of this privileged
motif has been extensively studied [1]. Of the many
reports that discuss the preparation of the 1H,3H-quina-
zolinediones, the most direct approach results from the
reaction of anthranilic acids with urea or with sodium
or potassium cyanate as exemplified by the preparation
of 1, in the synthesis of Zenarestat, a novel aldose re-
ductase inhibitor for the treatment of diabetic compli-
cations (Scheme 1) [2].
In the context of developing a scale-up route of an
active pharmaceutical ingredient, we were faced with
the preparation of
a 3-alkyl quinazolinedione. It
occurred to us that the most direct route to such a motif
would be from the commercially available anthranilic
acid and isocyanate coupling partner. If anthranilic acids
would be capable of directly forming the urea without
protection of the acid moiety, a simple cyclization reac-
tion could then occur to furnish the 3-alkyl quinazoline-
dione in a single pot. This approach was seldomly
described in the literature [11] but has been observed as
a side reaction [7a,b]. Nonetheless, we were pleased to
see that high yields and purities could be obtained and
that simple isolation of the desired compounds via filtra-
tion was possible. Herein, we disclose convenient and
scaleable procedures (mutligram scale) for the one-pot
synthesis of 3-substituted quinazolinediones, which is
general for a wide variety of anthranilic acids as well as
aliphatic, benzylic, and aromatic isocyanates.
Zenarestat, as with many other medicinally interesting
examples of quinazolinediones, have unsymmetrical sub-
stitution patterns across the two nitrogen atoms [3]. The
completion of its synthesis from 1 relies on the selective
reaction of an alkylating agent with the parent hetero-
cycle. However, the dependence on selective alkylation
in the use of 1H,3H-quinazolinediones as building
blocks for their substituted derivatives often proves diffi-
cult leading to mixtures of regioisomers [2,4].
Therefore, methods which allow for selective substitu-
tion on one of the nitrogen atoms are of great value in
the preparation of these important molecules [5]. Selec-
tive alkylation reactions have been shown to be possible
at the 1-position using bis(trimethylsilyloxy)quinazolines
C
V
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N. Koay and L.-C. Campeau
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Scheme 1. Preparation of 7-chloroquinazoline-(1H,3H)dione in the
synthesis of Zenarestat.
under standard ester hydrolysis conditions, followed by
reisolation of the product effectively destroyed and
rejected this impurity (Scheme 2).
While the current protocol was optimized for allyl
isocyanate, we briefly investigated the use of other iso-
cyanates in this transformation. We were particularly
interested in verifying the applicability of the protocol
over a diverse class of isocyanates. We therefore turned
our attention to aryl, benzyl, and branched aliphatic sub-
strates. Anthranilic acid was reacted under the same
conditions as before with a variety of isocyanates as out-
lined in Table 2. In general, we were pleased to observe
that the reaction was very effective in affording good
yields of the quinazolinedione products. In the case of
branched aliphatics, we found that cyclic isocyanates
(Entry 6) were tolerated but that others reacted slug-
gishly as illustrated by sec-butylisocyanate (Entry 7).
However, as the procedure was not optimized for each
different isocyanate, initial purities were generally
slightly lower. When compounds obtained were not pure
enough for analytical characterization, an isopropanol
trituration improved the purity to an acceptable level
(Entry 3). For benzyl isocyanates, we found that higher
purities were obtained when the isocyanate was used as
the limiting reagent (entries 4 and 5) [16].
RESULTS AND DISCUSSION
As a probe for the scope of anthranilic acids that par-
ticipate in this reaction, we chose allyl isocyanate as the
coupling partner. All anthranilic acids that we tested in
this protocol reacted well with excess (1.1–1.5 equiv.)
allyl isocyanate at reflux in tetrahydrofuran (THF).
Reaction times were moderate (3–6 h), but no detrimen-
tal effects on conversion or purity was observed if the
reaction was left overnight for convenience. We also did
not observe any advantages to the use of additives such
as base (Et3N) or nucleophilic catalysts (DMAP and
NMI). Once the addition reactions had reached high
conversion [12], the solvent was switched from THF to
EtOH [13] and ꢀ10 equiv. (2.5 mL/g) of concentrated
HCl was added to the mixture, which was then heated
to 70ꢁC. The cyclization step was generally fast 1–3 h
but was variable depending on the substitution pattern
[14]. We were pleased to find that the high crystallinity
of the substituted quinazolinediones allowed for direct
crystallization from the reaction. Once the reaction was
cooled in an ice bath (internal temperature ꢀ5ꢁC), water
(20 mL/g) was added to the mixture. This slurry was
stirred for 30 min, filtered, washed with water, and then
heptanes before drying under a stream of nitrogen. Table
1 outlines the scope of anthranilic acids used in this pro-
cedure. All reactions were performed on multigram scale
(ꢀ2 g) and were scaled to 55 g for 5-methoxy anthranilic
acid (Entry 4). We found that substitution at all positions
of the ring was tolerated. Moreover, we did not observe
any significant electronic effects with the exception of
strong electron withdrawing substituents at the 6-position,
such as nitro, which did not allow for the initial addition
reaction to occur efficiently. In most cases, we observed
very high purities [15] and compounds were suitable for
full characterization without further purification.
While column chromatography can be used to upgrade
purity, the high insolubility of these crystalline compounds
complicates chromatography and is not recommended on
gram scale. We found that the purities obtained using this
protocol were more than sufficient to perform subsequent
steps on these very useful building blocks. This is exem-
plified by the formal synthesis of Zenarestat (Scheme 3).
Known isocyanate 4 [17] was reacted with commer-
cially available 4-chloro anthranilic acid under our
standard protocol on. The quinazolinedione 5 [18] was
obtained (1 g) as a white solid in 68% yield. This mate-
rial was then directly used in the subsequent alkylation
with ethyl bromoacetate to afford ethyl ester 6 in 90%
yield. Hydrolysis of this ester was already described on
kilo scale to afford Zenarestat [2,18].
In conclusion, we have developed a very efficient and
facile one-pot procedure for the preparation of 3-substi-
tuted quinazolinediones, which allows for the direct use
Scheme 2. Purity upgrade with 3-allyl-6-bromo quinazoline-dione.
In some cases, we did observe formation of an ethyl
ester of the urea adduct as an impurity. In general, this
was rejected under the current isolation protocol; how-
ever, in some cases, as with 5-bromo anthranilic acid, it
was impossible to completely reject this impurity. We
were pleased to see that simple treatment of the solid
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DOI 10.1002/jhet

March 2011
Efficient Preparation of 3-Substituted Quinazolinediones Directly from Anthranilic
Acids and Isocyanates
475
Table 1
General procedure A (2 g scale). In round-bottomed
flask with a magnetic stir bar, the anthranilic acid deriv-
ative is dissolved in THF (10 mL/g) and 1.1 equiv. of
isocyanate is added to the mixture, which is stirred in
an oil bath at 70ꢁC. Once complete (or a minimum of
80%) conversion to addition adduct is achieved, the
reaction is cooled and the solvent is rotary evaporated
and replaced with EtOH (10 mL/g). Then, 2 mL/g of
concentrated HCl (12.1M) is added and the mixture is
reheated to 70ꢁC until complete conversion to the 3-sub-
stituted quinazolinedione is determined by high pressure
liquid chromatography (HPLC). The reaction mixture is
cooled in an ice bath (internal temperature ꢀ5ꢁC) and
water (20 mL/g) is added, which causes a precipitate to
form. This slurry is stirred for 30 min, filtered, washed
with water (10 mL/g), and then heptanes (3 ꢂ 10 mL/g)
before drying the solids under a stream of nitrogen. Prod-
ucts are generally obtained as white or off-white solids.
Scope of anthranilic acid with allyl isocyanate.
Anthranilic
acid
3-Allyl
quinazolinedione
Entry
Yield (%)b
1
71
2
66
General procedure B (used for a reaction on 55 g
scale; Table 1, Entry 4). In a three-neck round-bot-
tomed flask equipped with a mechanical stirrer, internal
temperature probe, and a condenser, anthranilic acid is
charged to THF (10 mL/g). To this stirring mixture is
added 1.1 equiv. of isocyanate and the mixture is stirred
at reflux. Once complete (or a minimum of 80%) con-
version to addition adduct is achieved, the solvent was
switched to EtOH (10 mL/g). Then, 2 mL/g of concen-
trated HCl (12.1M) is added and the mixture is reheated
to an internal temperature of 70ꢁC until complete conver-
sion to the 3-substituted quinazolinedione is determined
by HPLC. The reaction mixture is cooled in an ice bath
(internal temperature ꢀ5ꢁC) and water (20 mL/g) is
added over 15 min, which causes a precipitate to form.
This slurry is stirred for 30 min, filtered, washed with
water (10 mL/g), and then heptanes (3 ꢂ 10 mL/g)
before drying the solids under a stream of nitrogen. Prod-
ucts are generally obtained as white or off-white solids.
3-Allylquinazoline-2,4(1H,3H)-dione (Table 1, Entry 1).
Prepared according to general procedure A. Melting
point (ꢁC): 181.4–184.5 (EtOH/H2O). IR (vmax/cmꢃ1):
752, 958, 1652, 1709, 3071; 1H-NMR (400 MHz,
CHCl3-d): d 4.73 (d, J ¼ 5.71 Hz, 2 H); 5.23 (d, J ¼
10.25 Hz, 1 H); 5.33 (d, J ¼ 17.18 Hz, 1 H); 5.91–6.04
(m, 1 H); 7.15 (d, J ¼ 8.14 Hz, 1 H); 7.25 (m, 1 H);
7.63 (t, J ¼ 7.71 Hz, 1 H); 8.14 (d, J ¼ 7.95 Hz, 1 H);
10.62 (s, 1 H). 13C-NMR (101 MHz, CHCl3-d): d 42.9,
114.6, 115.2, 117.9, 123.4, 128.4, 131.7, 135.1, 138.6,
152.1, 162.1. HRMS calculated for C11H10N2O2 [M þ
H]þ 203.0815; Found: 203.0815.
3
4
5
6
84
79
64
69
7
8
63
72c
aLCAP, liquid chromatography area percent at 215 nm.
b Isolated yield.
cProduct treated with H2SO4 in EtOH to complete esterification.
of anthranilic acids and isocyanates. As many of these
reagents are commercially available or readily prepared,
we anticipate this procedure should find significant use
in the preparation of this important pharmacophore.
EXPERIMENTAL SECTION
All reagents and solvents were used as received from
their commercial supplier [15]. See Supporting Informa-
tion available for 1H and 13C NMR spectra for all new
compounds.
3-Allyl-5-methylquinazoline-2,4(1H,3H)-dione (Table 1,
Entry 2). Prepared according to general procedure A.
Melting point (ꢁC): 211.6–214.8 (EtOH/H2O). IR (vmax
/
1
cmꢃ1): 729, 940, 1448, 1648, 1702, 2901; H-NMR d
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N. Koay and L.-C. Campeau
Vol 48
cmꢃ1): 815, 1335, 1642, 1702, 2889; 1H-NMR (400
MHz, CHCl3-d): d 3.87 (s, 3 H); 4.72 (d, J ¼ 5.66 Hz,
2 H); 5.23 (d, J ¼ 10.24 Hz, 1 H); 5.32 (d, J ¼ 17.17
Hz, 1 H); 5.92–6.04 (m, 1 H); 7.06 (d, J ¼ 8.82 Hz, 1
H); 7.24 (dd, J ¼ 2.85, 8.77 Hz, 1 H); 7.56 (d, J ¼ 2.88
Hz, 1 H); 10.11 (s, 1 H). 13C-NMR (101 MHz, CHCl3-
d): d 43.0, 55.8, 108.8, 115.1, 116.6, 117.8, 124.7,
131.8, 132.7, 151.5, 155.8, 162.0. HRMS calculated for
Table 2
Scope of isocyanate with anthranilic acid.
Yield
(%)b
Entry
Isocyanate
Quinazolinedione
C12H12N2O3 [M þ H]þ 233.0921; Found: 233.0911.
3-Allyl-7-methoxyquinazoline-2,4(1H,3H)-dione (Table 1,
Entry 4). Prepared according to general procedure B.
1
2
3
4
5
67
82
Melting point (ꢁC): 220 (EtOH/H2O). IR (vmax/cmꢃ1):
761, 1432, 1618, 1711, 3198; 1H-NMR (400 MHz,
CHCl3-d): d 3.89 (s, 3 H); 4.67 (d, J ¼ 5.66 Hz, 2 H);
5.21 (d, J ¼ 10.20 Hz, 1 H); 5.29 (d, J ¼ 17.11 Hz, 1
H); 5.91–5.97 (m, 1 H); 6.44 (s, 1 H); 6.79 (d, J ¼ 8.91
Hz, 1 H); 8.05 (d, J ¼ 8.82 Hz, 1 H); 8.88 (s, 1 H).
13C-NMR (101 MHz, CHCl3-d): d 42.8, 55.8, 98.1,
111.5, 117.6, 130.4, 132.0, 140.3, 151.7, 165.1. HRMS
calculated for C16H14N2O3 [M þ Na]þ 255.0740;
72c
89d
84d
Found: 255.0733.
3-Allyl-8-methoxyquinazoline-2,4(1H,3H)-dione (Table 1,
Entry 5). Prepared according to general procedure A.
Melting point (ꢁC): 210.2 (EtOH/H2O). IR (vmax/cmꢃ1):
744, 1076, 1264, 1642, 3069; 1H-NMR (400 MHz,
CHCl3-d): d 3.96 (s, 3 H); 4.67 (d, J ¼ 5.65 Hz, 2 H);
5.21 (d, J ¼ 10.26 Hz, 1 H); 5.29 (d, J ¼ 17.20 Hz, 1
H); 5.88–6.01 (m, 1 H); 7.09 (d, J ¼ 7.96 Hz, 1 H);
7.16 (t, J ¼ 7.96 Hz, 1 H); 7.70 (d, J ¼ 7.91 Hz, 1 H);
8.18 (s, 1 H). 13C-NMR (101 MHz, CHCl3-d): d 42.9,
56.2, 114.3, 114.9, 117.7, 119.4, 122.8, 129.0, 131.7,
145.4, 149.9, 162.0. HRMS calculated for C12H12N2O3
[M þ Na]þ 255.0740; Found: 255.0736.
6
7
80
3-Allyl-6-fluoroquinazoline-2,4(1H,3H)-dione (Table 1,
Entry 6). Prepared according to general procedure A.
Melting point (ꢁC): 202.0–204.8 (EtOH/H2O). IR (vmax
/
<10
cmꢃ1): 768, 1280, 1440, 1616, 1659; 1H-NMR (400
MHz, CHCl3-d): 4.71 (d, J ¼ 5.63 Hz, 2 H); 5.25 (d, J
¼ 10.22 Hz, 1 H); 5.33 (d, J ¼ 17.19 Hz, 1 H); 5.90–
6.03 (m, 1 H); 6.84 (d, J ¼ 8.82 Hz, 1 H); 6.96 (t, J ¼
aLCAP, liquid chromatography area percent at 215 nm.
b Isolated yields.
c Product triturated in iPrOH.
d Isocyanate used as the limiting reagent.
Scheme 3. Formal synthesis of Zenarestat.
(ppm) (CHCl3-d): 2.79 (s, 3 H,), 4.69 (d, J ¼ 5.54 Hz,
2 H), 5.22 (d, J ¼ 10.23 Hz, 1 H), 5.32 (d, J ¼ 17.20
Hz, 1 H), 5.91–6.04 (m, 1 H), 6.99 (d, J ¼ 7.58 Hz, 2
H), 7.44 (t, J ¼ 7.75 Hz, 1 H), 10.67 (s, 1 H). 13C-
NMR (101 MHz, CHCl3-d): d 22.7, 42.8, 113.0, 113.3,
117.5, 126.5, 132.1, 133.9, 139.8, 142.7, 151.8, 162.5.
HRMS calculated for C12H12N2O2 [M þ H]þ 217.0972;
Found: 217.0992.
3-Allyl-6-methoxyquinazoline-2,4(1H,3H)-dione (Table 1,
Entry 3). Prepared according to general procedure A.
Melting point (ꢁC): 198.7–202.9 (EtOH/H2O). IR (vmax
/
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March 2011
Efficient Preparation of 3-Substituted Quinazolinediones Directly from Anthranilic
Acids and Isocyanates
477
8.54 Hz, 1 H); 8.16 (t, J ¼ 7.16 Hz, 1 H); 10.76 (s, 1
H). 13C-NMR (101 MHz, CHCl3-d): d 43.0; 101.8 (d, J
¼ 26.1 Hz); 111.2 (d, J ¼ 1.65 Hz); 111.9 (d, J ¼ 22.7
Hz); 118.1, 131.4, 131.5 (d, J ¼ 3.6 Hz); 140.5 (d, J ¼
12 Hz); 152.2, 161.2, 166.8 (d, J ¼ 255.8 Hz). HRMS
calculated for C11H10FN2O2 [M þ H]þ 221.0721;
5.36 (m, 2 H); 5.89–6.00 (m, 1 H); 7.01 (d, J ¼ 8.59
Hz, 1 H); 7.71 (d, J ¼ 8.62 Hz, 1 H); 8.27 (s, 1 H);
10.01 (s, 1 H). 13C-NMR (101 MHz, CHCl3-d): 43.1,
116.1, 116.2, 118.2, 131.0, 131.4, 137.3, 138.0, 151.4,
160.8. HRMS calculated for C11H9BrN2O2 [M þ H]þ
280.9920; Found: 280.9921.
3-(4-Methylphenyl)quinazoline-2,4(1H,3H)-dione (Table 2
Entry 1). Prepared according to general procedure A.
Found: 221.0721.
3-Allyl-7-chloroquinazoline-2,4(1H,3H)-dione (Table 1,
Entry 7). Prepared according to general procedure A.
Melting point (ꢁC): 265.3–267.1 (EtOH/H2O). IR (vmax
/
Melting point (ꢁC): 205.6–209.5 (EtOH/H2O). IR (vmax
/
cmꢃ1): 753, 1397, 1648, 1723, 3194; 1H-NMR (400
MHz, CHCl3-d): d 2.44 (s, 3 H); 6.89 (d, J ¼ 8.15 Hz,
1 H); 7.16–7.25 (m, 3 H); 7.34 (d, J ¼ 7.82 Hz, 2 H);
7.48–7.56 (m, 1 H); 8.14 (d, J ¼ 7.92 Hz, 1 H); 9.84 (s,
1 H). 13C-NMR (101 MHz, CHCl3-d): d 21.3, 114.8,
115.3, 123.4, 128.2, 128.6, 130.1, 132.1, 135.2, 138.8,
138.8, 151.8, 162.7. HRMS calculated for C15H13N2O2
cmꢃ1): 767, 1077, 1434, 1609, 2862; 1H-NMR (400
MHz, CHCl3-d): d 4.71 (d, J ¼ 5.67 Hz, 2 H); 5.19–
5.38 (m, 2 H); 5.90–6.03 (m, 1 H); 7.13 (s, 1 H); 7.15–
7.30 (m, 2 H); 8.08 (d, J ¼ 8.50 Hz, 1 H); 10.30 (s, 1
H). 13C-NMR (101 MHz, DMSO-d6): d 42.5, 113.2,
115.0, 116.9, 123.2, 130.0, 133.0, 139.8, 141.0, 150.2,
161.4. HRMS calculated for C11H10ClN2O2 [M þ H]þ
[M þ H]þ 253.0972; Found: 253.0966.
3-(4-Cyanophenyl)quinazoline-2,4(1H,3H)-dione (Table 2
Entry 3). Prepared according to general procedure A.
237.0425; Found: 237.0424.
Ethyl 3-allyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-car-
boxylate (Table 1, Entry 8). Prepared according to general
The solid obtained from this procedure was suspended
in isopropyl alcohol and stirred for 3 h. The slurry was
then filtered and washed with water (10 mL/g) and then
heptanes (3 ꢂ 10 mL/g) before drying the solids under
a stream of nitrogen.
Melting point (ꢁC): 262.4 (IPA). IR (vmax/cmꢃ1): 749,
1
1490, 1667, 2216, 2932; H-NMR (400 MHz, DMSO-
procedure A. The solid obtained from this procedure was
then resuspended in EtOH (10 mL/g) and 2 mol equiv. of
H2SO4 was added. The reaction was then heated in an oil
bath at 70ꢁC. On complete conversion of the mixture to
the ethyl ester product, the reaction was cooled to ꢀ5ꢁC
and water (20 mL/g) was added, which causes a precipi-
tation to form. This slurry was then filtered and washed
with water (10 mL/g) and then heptanes (3 ꢂ 10 mL/g)
before drying the solids under a stream of nitrogen.
d6): d 7.22–7.27 (m, 2 H); 7.61 (d, J ¼ 8.08 Hz, 2 H);
7.72 (t, J ¼ 7.77 Hz, 1 H); 7.94 (d, J ¼ 8.06 Hz, 1 H);
7.98 (d, J ¼ 8.11 Hz, 2 H); 11.65 (s, 1 H). 13C-NMR
(101 MHz, DMSO-d6): d 40.4, 40.6, 111.6, 114.8,
115.8, 119.0, 123.1, 128.1, 131.1, 133.4, 135.9, 140.3,
140.7, 150.3, 162.5. HRMS calculated for C15H9N3O2
Melting point (ꢁC): 202.6–209.0 (EtOH/H2O). IR
(vmax/cmꢃ1): 742, 1222,1277, 1637, 1719, 3184; 1H-
NMR d (ppm) (DMSO-d6): 1.32 (3 H, t, J ¼ 7.02 Hz),
4.33 (2 H, q, J ¼ 7.06 Hz), 4.47 (2 H, s), 5.06–5.16 (2
H, m), 5.81–5.91 (1 H, m), 7.65 (1 H, d, J ¼ 8.17 Hz),
7.72 (1 H, s), 7.99 (1 H, d, J ¼ 8.15 Hz), 11.58 (1 H,
s). 13C-NMR (101 MHz, DMSO-d6): d 14.5, 42.7, 62.0,
116.6 (s), 117.0 (s), 117.3 (s), 122.7 (s), 128.5 (s), 133.0
(s), 135.7 (s), 139.9 (s), 150.2 (s), 161.6 (s), 165.1 (s).
HRMS calculated for C14H15N2O4 [M þ H]þ 275.1026;
[M þ H]þ 264.0768; Found: 264.0775.
3-(4-Methoxybenzyl)quinazoline-2,4(1H,3H)-dione (Table 2
Entry 4). Prepared according to general procedure A.
The material obtained from this procedure was 94
LCAP. A small sample was purified via silica gel chro-
matography to obtain an analytically pure sample using
EtOAc/DCM gradient 0–50% DCM.
Melting point (ꢁC): 213.8 (EtOAc/DCM). IR (vmax
/
Found: 275.1025.
cmꢃ1): 751, 1242, 1653, 1710, 2901; 1H-NMR (400
MHz, CHCl3-d): d 3.77 (s, 3 H); 5.20 (s, 2 H); 6.83 (d,
J ¼ 8.27 Hz, 2 H); 7.01 (d, J ¼ 8.17 Hz, 1 H); 7.17–
7.28 (m, 5 H); 7.50 (d, J ¼ 8.27 Hz, 2 H); 7.60 (t, J ¼
7.75 Hz, 1 H); 8.14 (d, J ¼ 7.95 Hz, 1 H); 8.99 (s, 1
H). 13C-NMR (101 MHz, CHCl3-d): d 43.6, 55.2, 113.7,
114.7, 115.0, 123.4, 128.5, 129.1, 130.6, 135.0, 138.5,
152.2, 159.1, 162.3. HRMS calculated for C16H14N2O3
[M þ Na]þ 305.0897; Found: 305.0890.
Entry
5). Prepared according to general procedure A. Melting
point (ꢁC): 225.4–227.4 (EtOH/H2O). IR (vmax/cmꢃ1):
691, 752, 1448, 1652, 2901; 1H-NMR (400 MHz,
CHCl3-d): d 5.28 (s, 2 H); 7.06 (d, J ¼ 8.12 Hz, 1 H);
3-Allyl-6-bromoquinazoline-2,4(1H,3H)-dione (Scheme
2). Prepared according to general procedure A. The
solid obtained from this procedure was then dissolved in
THF (10 mL/g) and 2N LiOH (5 mol equiv.) is added to
the stirring mixture at room temperature. On consump-
tion of the ester by-product, the reaction was cooled to
ꢀ5ꢁC and concentrated HCl was added dropwise until
the pH was <2. This caused a precipitate to form, which
was filtered, washed with water (10 mL/g), and then
heptanes (3 ꢂ 10 mL/g) before drying the solids under
a stream of nitrogen.
3-Benzylquinazoline-2,4(1H,3H)-dione (Table
2
Melting point (ꢁC): 232.0–234.3 (EtOH/H2O). IR
1
(vmax/cmꢃ1): 673, 818, 1440, 1644, 2920; H-NMR (400
MHz, CHCl3-d): d 4.69 (d, J ¼ 5.70 Hz, 2 H); 5.19–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

478
N. Koay and L.-C. Campeau
Vol 48
333; (c) Buckley, G. M.; Davies, N.; Dyke, H. J.; Gilbert, P. J.; Han-
nah, D. R.; Haughan, A. F.; Hunt, C. A.; Pitt, W. R.; Profit, R. H.;
Ray, N. C.; Richard, M. D.; Sharpe, A.; Taylor, A. J.; Whitworth, J.
M.; Williams, S. C. Bioorg Med Chem Lett 2005, 15, 751.
[6] (a) Drewe, W. C.; Nanjunda, R.; Gunaratnam, M.; Beltran,
M.; Parkinson, G. N.; Reszka, A. P.; Wilson, W. D.; Neidle, S. J Med
Chem 2008, 51, 7751; (b) Conley, P. B.; Andre, P.; Sinha, U. PCT
Int. Appl. WO 2008137787 A2 20081113, 2008; (c) Li, Z.; Huang, H.;
Sun, H.; Jiang, H.; Liu, H. J Comb Chem 2008, 10, 484.
[7] (a) Papadopoulos, E. P. J Heterocyclic Chem 1980, 17,
1553; (b) Papadopoulos, E. P. J Heterocyclic Chem 1981, 18, 515;
(c) Shiau, C. Y.; Chern, J. W.; Liu, K. C.; Chan, C. H.; Yen, M. H.;
Cheng, M. C.; Wang, Y. J Heterocyclic Chem 1990, 27, 1467;
(d) Jiarong, L.; Xian, C.; Daxin, S.; Shuling, M.; Qing, L.; Qi, Z.;
Jianhong, T. Org Lett 2009, 11, 1193.
7.19–7.35 (m, 4 H); 7.51–7.65 (m, 3 H); 8.14 (d, J ¼
7.94 Hz, 1 H); 10.20 (s, 1 H). 13C-NMR (101 MHz,
CHCl3-d): d 44.2, 114.6, 115.0, 123.5, 127.7, 128.4,
128.5, 128.9, 135.1, 136.8, 138.5, 152.0, 162.3. HRMS
calculated for C15H13N2O2 [M þ H]þ 253.0972; Found:
233.0966.
3-Cyclopentylquinazoline-2,4(1H,3H)-dione (Table
2
Entry 6). Prepared according to general procedure A.
The material obtained from this procedure was 92
LCAP. A small sample was purified via silica gel chro-
matography to obtain an analytically pure sample using
EtOAc/DCM gradient 0–50% DCM.
Melting point (ꢁC): 235.8 (EtOAc/DCM). IR (vmax
/
[8] (a) Shi, D.-Q.; Dou, G.-L.; Li, Z.-Y.; Ni, S.-N.; Li, X.-Y.;
Wang, X.-S.; Wu, H.; Ji, S.-J. Tetrahedron 2007, 63, 9764; (b) Dou,
G.-L.; Wang, M.-M.; Huang, Z.-B.; Shi, D.-Q. J Heterocyclic Chem
2009, 46, 645; (c) Kirincich, S. J.; Xiang, J.; Green, N.; Tam, S.;
Yang, H. Y.; Shim, J.; Shen, M. W. H.; Clark, J. D.; McKew, J. C.
Bioorg Med Chem 2009, 17, 4383.
cmꢃ1): 757, 1400, 1649, 1171, 2901; 1H-NMR (400
MHz, CHCl3-d): d 1.89–1.97 (m, 2 H); 2.05 (s, 2 H);
2.16–2.26 (m, 2 H); 5.42–5.54 (m, 1 H); 7.08 (d, J ¼
8.12 Hz, 1 H); 7.17–7.29 (m, 1 H); 7.60 (t, J ¼ 7.69
Hz, 1 H); 8.13 (d, J ¼ 7.95 Hz, 1 H); 10.35 (s, 1 H).
13C-NMR (101 MHz, CHCl3-d): d 26.0, 28.6, 53.2,
114.6, 115.1, 123.2, 128.4, 134.8, 138.5, 152.2, 162.7.
HRMS calculated for C13H14N2O2 [M þ H]þ 231.1128;
Found: 231.1121.
[9] Willis, M. C.; Snell, R. H.; Fletcher, A. J.; Woodward, R.
L. Org Lett 2006, 8, 5089.
[10] Larksarp, C.; Alper, H. J Org Chem 2000, 65, 2773.
[11] (a) Andrianjara, C.; Chantel-Barvian, N.; Gaudilliere, B.;
Jacobelli, H.; Ortwine, D. F.; Patt, W. C.; Pham, L.; Kostlan, C. R.;
Wilson, M. W. PCT Int. Appl. WO 2002064572 A1 20020822, 2002;
(b) Green, D. E.; Percival, A. US Patent, 4,731,106 A 19,880,315,
1988; (c) Sulkowski, T. S.; Childress, S. J. J Org Chem 1962, 27,
4424.
Acknowledgments. The authors thank Chad Dalton and
Ravi Sharma for analytical support and Ernest Lee for help-
ful discussions during the preparation of this manuscript.
[12] All reactions had a minimum of 80% conv. before they
were taken forward.
[13] Other solvents were screened but EtOH or iPrOH were optimal.
[14] While 2-amino-3-nicotinic acid reacted with the isocyanate,
its cyclization was very slow (>7 days). The cause of this observation
is currently under investigation.
REFERENCES AND NOTES
[1] Undheim, K.; Benneche, T. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. B., Eds.;
Elsevier: Oxford, UK, 1996; Vol. 6, p 93.
[15] HPLC analysis was performed using the following condi-
tions: Zorbax SB C18, RRHT, 1.8 lm (50 ꢂ 4.6) 0.1% H3PO4 in
water/MeCN start 90:10, ramp to 50:50 over 8 min, ramp to 5:95 over
4 min. Total: 12 min, 2 mL/min, 35ꢁC, 215 nm, 5 lL.
[2] Goto, S.; Tsuboi, H.; Kanoda, M.; Mukai, K.; Kagara, K.
Org Process Res Dev 2003, 7, 700.
[3] (a) Pan, X.-S.; Gould, K. A.; Fisher, L. M.; Antimicrob
Agent Chem 2009, 53, 3822; (b) Kakuta, H.; Tanatani, A.; Nagasawa,
K.; Hashimoto, Y. Chem Pharm Bull 2003, 51, 1273; (c) See Ref. 2.
[4] Ismail, M. A. H.; Barker, S.; El Ella, D. A. A.; Abouzid, K.
A. M.; Toubar, R. A.; Todd, M. H. J Med Chem 2006, 49, 1526.
[5] (a) Beylin, V.; Boyles, D. C.; Curran, T. T.; Macikenas, D.;
Parlett, R. B.; Vrieze, D.; Org Process Res Dev 2007, 11, 441;
(b) Makino, S.; Suzuki, N.; Nakanishi, E.; Tsuji, T. Synlett 2001, 3,
[16] Dibenzylureas formed from excess isocyanate were difficult
to reject under our current protocol.
[17] (a) Cosmo, R. Eur. Pat. Appl. EP 712,849 A2 19,960,522,
1996; (b) Lee, E. E.; Rovis, T. Org Lett 2008, 10, 1231.
[18] Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet