Preparation of 6-aminoquinazolin-4(3H)-ones via direct SNAr on the quinazoline ring

Article abstract of DOI:10.1016/j.tet.2011.11.008

The preparation of 6-aminoquinazolin-4(3H)-ones requires the use of platinum-metal group catalysis on the corresponding C-6-iodo or 6-bromo precursors. Herein, we report to our knowledge the first successful S _NAr reaction directly at the unact

Full text of DOI:10.1016/j.tet.2011.11.008

Tetrahedron 68 (2012) 534e543
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of 6-aminoquinazolin-4(3H)-ones via direct SNAr on the quinazoline
ring
*
Bernard Barlaam, Craig S. Harris , Jonathan Lecoq, Ha Thi Hoang Nguyen
AstraZeneca, Oncology iMed, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 August 2011
Received in revised form 3 November 2011
Accepted 4 November 2011
Available online 19 November 2011
The preparation of 6-aminoquinazolin-4(3H)-ones requires the use of platinumemetal group catalysis on
the corresponding C-6-iodo or 6-bromo precursors. Herein, we report to our knowledge the first suc-
cessful SNAr reaction directly at the unactivated C-6 position of the quinazolin-4(3H)-one nucleus.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Direct SNAr
Unactivated fluorides
Quinazolin-4-(3H)-one
1. Introduction
chemical space. Moreover, the particular substitution pattern that
we designed having a methyl substituent at C-2, C-6-amino sub-
Substituted quinazolines have been the focus of much research
in recent years from pharmaceutical and academic groups, notably,
as small molecule ATP-competitive kinase inhibitors.1 At present,
there are eight C-4-substituted quinazolines in late-stage clinical
development (Fig. 1) amongst which gefinitib,2 and erlonitib3 are
already commercialised for the treatment of non-small cell lung
cancer and lapatinib,4 for hormone-positive and HER2-positive
advanced breast cancer (Fig. 1).4
During a recent discovery program, we became interested in
exploring C-4-substituted quinazolines having substitution at C-6
and C-8 on the phenyl ring5 but before starting synthetic work, we
carried out a quick search of the existing literature to determine our
freedom to operate. Inspection of the literature revealed that the C-
4-substituted quinazoline family comprises more than 144,000 CAS
members exemplified in 3843 patents to date (entry 1). Within this
family, perhaps not surprisingly we discover that C-4,6,7-
trisubstituted quinazolines are the most dominant representing
40,641 CAS members exemplified in 1999 patents (entry 6). If we
limit the searches specifically to amine substitution at C-4 and
ether substitution at C-6 and C-7, we find this particular family is
responsible for more than 96% of all patents in this sub-family
(entry 7). Finally, the C-4,6,8-trisubstituted family, with just 4352
CAS members exemplified in just 61 patents, is one of the least
studied cores thus offering potentially more freedom to explore this
stitution and any substitution at C-8 has no existing references
(entry 9) (Table 1).6
With this knowledge in hand, we set about designing a valid
route to the scaffold, which would allow us to vary preferentially all
three key positions in an orthogonal manner. With so few references
in the literature, we decided to employ Kepner-Tregoe8 decision
analysis in order to help us with route selection, recently employed
by our process research and development colleagues at Avlon,
Bristol.9 We envisaged three routes to access the key synthon (10)
having the potential to vary all key positions of the quinazoline
nucleus, all based on a Niementowski cyclisation strategy.10 Route A,
possibly the longest of all routes, focused on manipulating 2-amino-
isophthalic acid (1) as the starting material. Halogenation at C-4
followed bycyclisation following recognised cyclisationprotocol11,12
should afford intermediate 2 leaving a BuchwaldeHartwig amina-
tion followed by functional group transformation of the carboxyl
functionality to a halogen atom via a standard functional group
manipulation relying on the Curtius rearrangement. The key step for
route B is dependant on a smooth ortho-halogenation of anthranilic
acid derivative 5. Electrophilic halogenation of p-disubstituted
aminobenzenes in general is quite rare with seemingly only one
reference13 but if successful, we were confident the rest of the se-
quence would be straightforward. Based on existing literature an in-
house chemistry experience, route C was possibly the least likely to
succeed as its key step relied on direct amination at the unactivated
C-6eF position of a quinazolin-4(3H)-one, for which there were no
supporting references. However, if successful, this route would be
arguably the most convergent allowing us to target the synthesis of
* Corresponding author. Tel.: þ33 (0) 3 26 61 5912; fax: þ33 (0) 3 26 61 6842;
e-mail address: craig.harris2@astrazeneca.com (C.S. Harris).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.008

B. Barlaam et al. / Tetrahedron 68 (2012) 534e543
535
F
Br
O
HN
Cl
HN
N
HN
N
O
O
F
O
O
O
N
N
O
O
N
N
O
N
Gefitinib
N
Vandetanib
Erlotinib
Cl
H
N
H
N
H
N
F
O
O
N
O
O
HN
N
Cl
O
F
O
O
HN
O
O
O
N
N
N
N
N
N
O
N
O
Ceranitib
Cediranib
KRN951
F
O
Cl
N
HN
N
H
S
O
H
N
HN
N
O
HN
O
N
O
F
N
HO
N
O
N
Barasertib
Lapatinib
Fig. 1. A selection of C-4-substituted quinazolines on the market or in late-stage clinical trials.
Table 1
Current literature distribution of C-4-substituted quinazolines with two sub-
Table 1 (continued)
stituents on the phenyl ring A¼any atom apart from H
Entry
Substructure
CAS
Nos
Total
references/ total references/
patents patent
% Share of
Total
% Share of
CAS
Nos
Entry
Substructure
references/ total references/
patents
patent
A
N
4
4
1
2
3
4
N
144,293 12,845/3843 d
6
O
61.0/45.7
96.0/87.9a
7
15,688 7840/1758
N
N
N
O
N
A
N
7
4
N
N
129,026 9754/2654 75.9/69.1
4
6
A
8
4352
367
127/61
95/48
1.0/1.6
0.7/1.2
A
A
A
5
4
N
A
6
A
A
8
12,252 291/111
2.3/2.9
1.0/2.3
N
N
A
N
A
4
N
5
4
9
1111
426
131/87
7
N
A
8
A
7
N
A
A
5
4
A
R1
N
4
N
6
5
6
210/142
1.6/3.7
N
R2
10 (Target)
0
0
d
N
8
N
A
8
A
N
A
4
6
A
a
40,641 8167/1999 63.6/52.0
N
Refers specifically to percentage share of the C-4,6,7-trisubstituted family
(entry 6).6,7
7
A

536
B. Barlaam et al. / Tetrahedron 68 (2012) 534e543
the most flexible intermediate in relation to the vectors that we
wished to explore (Fig. 2).
From Table 2, we decided on the ‘must haves’ being the avail-
ability of a reasonable starting material and the tractability from
that starting material to the final key synthon 10 as judged by
both key vectors selectively, if successful with the SNAr reaction at
the unactivated C-6 position. Likewise route B also scored highly
furnishing a similar bifunctional intermediate, albeit after consid-
erably more steps. Route A was the least appealing as the amine
group at C-6 was fixed early on in the sequence, therefore, per-
R2
N
O
N
O
N
O
I
NH
OH
NH
R1
R1
OH
NH2
OH
route A
O
O
O
O
O
3
2
1
R2
N
O
R2
N
O
R2
N
O
O
F
OH
R1
NH
R1
OH
NO2
NH2
route B
route C
NH2
N
X = Br / I
6
X = Br / I
Key synthon (10)
5
4
O
O
O
F
F
F
NH
OH
NH2
OH
NH2
N
X =Br / I
X =Br / I
9
7
8
Fig. 2. Retrosynthetic analysis of key synthon.
Table 2
Our Kepner-Tregoe scoring of the three routes
mitting for linear variations from the C-8 position at the end of the
sequence. In terms of SHE (safety, health and environment), the
scoring of route C>B>A is a simple reflection on the number of
steps required to effect the sequence reducing. Finally, in terms of
‘added-value’ or novelty, while efficient SNAr reactions on the
quinazoline nucleus are known, usually at the activated positions
2,4,5,716 and also recently at the unactivated C-8 position,17 there
are no references at the unactivated C-6 position of a quinazolin-
4(3H)-one ring. Therefore, if successful, this would be worthy ad-
dition to the quinazoline literature as opposed to the other two
routes, which even if successful, could be classed as standard
functional group manipulation.
Factor
Route A
Route B
Route C
Tractability
Readily-available SMs
Few steps
OK
OK
3
OK
OK
7
5
3
7
3
25
OK
OK
8
2
8
8
7
33
Supporting literature
Orthogonality
Safety aspects
Added-value
Total
9
3
3
5
23
existing literature and in-house experience in the quinazoline
field.10 From that point, we scored the routes based on what we
regarded as the key factors to a successful route. In terms of the
number of steps, route A was the least appealing as starting from 2-
amino-isophthalic acid, we envisaged a total of eight steps to get to
synthon 1 compared to five steps for route B and four steps for
route C. However, in terms of supporting literature, it was clear that
route A seems like the most evident having more or less close
analogies for each step reported. While route B seemed logical, the
key step was going to control a selective electrophilic halogenation
ortho to the aniline in the presence of another donor amine already
in place at para, for which there are no supporting references. The
key step for route C relied on an efficient SNAr at the unactivated C-
6eF of the quinazolin-4(3H)one ring, for which there are no sup-
porting references. However, direct SNAr on unactivated aryl fluo-
rides14 can be viewed as an acceptable strategy affording moderate
to excellent yields of substituted product with notable successes in
recent literature.15 Route C scored highly for orthogonality as the
intermediate 6-Fe8-Br/I precursor (9) would allow us to explore
2. Results and discussion
Influenced by the results obtained from the Kepner-Tregoe
analysis, we set about work on route C. The synthesis started
from 4-fluoroanthranilic acid. Bromination using N-bromosuccini-
mide in refluxing AcOH and iodination using iodonium chloride
under acidic conditions18 afforded 11 and 14, respectively. Cyclisa-
tion afforded 12/15, which were transformed to the corresponding
quinazolin-4(3H)-ones 13/16 using concd aqueous ammonia in
a sealed tube.19 Both processes were carried out without resorting
to purification by silica gel chromatography (Scheme 1).
With the key synthons in hand, we set about validating the
route by testing the SNAr reaction using morpholine directly as the
solvent. Before starting experimental work on 13 or 16, we ob-
served that direct SNAr on 6-fluoroquinazolin-4(3H)-one was not
possible resulting in only traces of desired compound despite
prolonged periods of heating at 220 ꢀC under microwave

B. Barlaam et al. / Tetrahedron 68 (2012) 534e543
537
O
O
O
N
O
N
F
F
F
F
a
OH
NH2
OH
NH2
b
NH
c
O
or b
X
X
X
X = Br (12)
X = I (15)
X = Br (11)
X = I (14)
7
X = Br (13)
X = I (16)
Scheme 1. Synthesis of key synthon 1. Reagents and conditions: (a) ICl, HCl (aq), H2O, rt, 74%; (b) NBS, AcOH, rt, 66%; (c) Ac2O, 140 ꢀC, 93% (X¼Br) 95% (X¼I); (d) NH4OH, 100 ꢀC, 74%
(X¼Br), 84% (X¼I).
Table 3
irradiation (entry 1). On the contrary and to our surprise the SNAr
reaction proceeded with, perhaps unexpectedly, competition at C-8
at 180 ꢀC under microwave irradiation using 13 as the starting
material (entry 2). In order to improve selectivity, we decided to
study the effects of lowering the reaction temperature and heating
for longer periods. The effects of lowering the temperature from
180 ꢀC to 160 ꢀC notably increased selectivity significantly from 1/1
to 2/1 in favour of the desired product (entry 3). We continued this
study finally deducing we could achieve acceptable conversions
with reasonable selectivity by operating the reaction at 120 ꢀC for 6
days (entries 3e5 vs 6). Not surprisingly attempts to add a mineral
base to irreversibly neutralise the mole of HF formed resulted in no
conversion. We postulate that the substitution was discouraged due
to the quantitative deprotonation of the quinazolin-4(3H)-one
skeleton resulting in the thermodynamically-stable ion potassium
salt. Reaction in neat morpholine or in presence of a tertiary base
does not stop the reaction as deprotonation of the quinazolin-
4(3H)-one is rather transient with the equilibrium lying towards
the active non-protonated form (entry 7 vs entry 8). To further
improve selectivity, we found that 16 was a superior substrate to 13
(entries 9e11) even if the rate of substitution was significantly
decreased due to a weaker inductive effect (entries 2 and 3 vs en-
tries 9 and 10). One of the key conclusions we deduced is that
a relatively inert halogen atom inducing a weak inductive effect
meta to the CeF bond is actually sufficient to allow the SNAr re-
action to take place with weak nucelophiles.20
Optimisation study using morpholine as the solvent. N/A¼not applicable
O
O
O
O
N
F
N
F
NH
NH
NH
H
N
N
N
X
X
N
O
O
A
B
Entry
X
Temperature/time
% Conv.b
% Ab
% Bb
1
H
Br
Br
Br
Br
Br
Br
Br
I
180e220 ꢀC/16 h
180 ꢀC/2 h
160 ꢀC/16 h
140 ꢀC/2 days
130 ꢀC/3 days
120 ꢀC/6 days
Et3N/120 ꢀC/3 days
K2CO3/120 ꢀC/3 days
180 ꢀC/2 h
160 ꢀC/3 days
140 ꢀC/6 days
0
89
64
84
90
91
76
0
d
N/A
42
36
31
30
28
32
d
2a
3
58
64
69
70
72
68
d
4
5
6
7
8
9a
10
29
60
93
63
77
84c
37
23
16
I
I
11 (Cpd 17)
a
b
c
Reaction performed under microwave irradiation.
Figures determined by analytical LCMS.
Isolated yield.
In order to quickly confirm this hypothesis and that the fused
pyrimidinone ring was playing no role in activating the C-6-F to-
wards SNAr, we applied similar reaction conditions to simple hal-
ogen substituted fluorobenzenes using morpholine as the solvent.
From Table 3, it appears evident that the presence of a halogen
atom at the meta position to the fluorine leaving group enhances
greatly the rate of substitution compared to ortho position (entries
5e8 vs entries 2e4) with para-substitution exerting little affect
(entries 9 and 10). We postulate that while evidently the inductive
effect of having a halogen atom ortho to the leaving group is more
important than at the meta position, the approach of the nucleo-
phile on the ipso position is more sterically and electronically
hindered explaining the higher conversions (entries 5e7 vs entries
2e4). It appears also clear, by the conversion rates, that the pres-
ence of the pyrimidinone ring is slowing down rather than accel-
erating the rate of substitution (Table 4, entry 7 vs Table 3, entry 3).
We were also curious to see if introduction of an activating
mesomericgroupatC-8wouldsignificantlyincreasethereactionrate.
Therefore, we transformed the C-8eBr to the C-8eCN in excellent
yieldusingaMAOS(microwave-assistedorganicsynthesis)palladium
catalysed cyanation process recently communicated by Pitts et al.21
However, to our surprise the presence of a C-8eCN group did not
increase the reaction rate and we also observed a significant problem
of addition of morpholine onto the C-8eCN group (Scheme 2).
Although the approach was adequate for the introduction of
secondary amine nucleophiles, this approach could not be used for
alkoxides due to deprotonation and inactivation of the quinazoline
Table 4
The
fluorobenzenes
%
SNAr conversion as judged by LCMS on simple halogen substituted
O
O
F
NH
N
X
X
160 °C, 16 h
Entry
X
% Conversion
1
2
3
4
5
6
7
8
9
10
H
0
33
0
2-F
2-Br
2-I
0
3-F
3-Cl
3-Br
3-I
4-F
4-Br
82
74
79
44
0
0
ring towards substitution. Therefore, we decided to protect the N-3
position with a PMB (p-methoxybenzyl) group with the knowledge
that we should be able to deprotect the group with relative ease.22
Selective N-protection of 16 was achieved using a slight excess of
PMB-Cl in refluxing acetone overnight in the presence of potassium
carbonate to afford 21 in good yield (Scheme 3, Table 5).

538
B. Barlaam et al. / Tetrahedron 68 (2012) 534e543
O
N
O
O
N
O
O
N
F
F
N
a
F
NH
b
NH
NH
NH
H
N
N
Br
CN
CN
19
NH
20
N
13
O
18
O
Scheme 2. Reagents and conditions: (a) Zn(CN)2, Pd2(dba)3, xantphos, DMA, 160 ꢀC, microwave, 10 min, 76%; (b) morpholine, 140 ꢀC, 2 days, 78% conversion (19 (65%); 20 (35%)).
O
O
N
O
N
O
N
F
PMB
F
PMB
R'R''N
a
PMB
F
NH
b
N
N
N
N
I
I
I
NR'R''
16
21
A
B
Scheme 3. Reagents and conditions: (a) PMB-Cl, K2CO3, acetone, reflux, 16 h, 85%; (b) R0R00NH, 140 ꢀC, 3 days.
Table 5
Table 5 (continued)
Effect of varying the amine on yield and conversion after 3 days at 140 ꢀC
Entry
(compound)
% Aa
14c
% B
Entry
(compound)
Compound
Amine
% Aa
% B
12
Compound
Amine
NH
9
30
31
N/D
1
2
3
22
68
NH2
O
O
O
16c
N/D
N
NH2
NH
10
11
23
24
78
68
9c
HO
NH
32
33
39
N/D
N/D
NH
N
7c
N
O
12
N/D
NH2
NH2
NH
N/D¼not detected.
O
a
Isolated yield.
4
5
6
7
8
25b
26
27
28
29
21
43
45
41
17
N/D
N/D
N/D
N/D
N/D
b
Reaction mixture heated at 180 ꢀC for 3 days.
Reaction mixtures not isolated.
c
O
The results in Table 3 demonstrate clearly the advantage of
N
NH2
protecting the N-3 position. Displacement with morpholine pro-
ceeds in half of the time while retaining the same selectivity (85/
15). As expected, unhindered secondary amine nucleophiles gave
O
the best results (entries 1e3) apart from L-prolinamide (entry 4),
NH2
which gave a particularly poor yield even at higher temperatures
presumably due to reduced basicity and increased steric hindrance
due to the presence of the C-2-carboxamide functionality. Un-
hindered primary amines also reacted in acceptable yields (entries
5e7). Not surprisingly, very hindered primary amines (entries
8e10) reacted very slowly but heteroaromatic bases, such as im-
idazole gave acceptable conversions (entry 11) and aromatic
amines (e.g., aniline, entry 12) gave only traces of substituted
product.
O
NH2
HO
NH2
HO
After having demonstrated the amine substrate scope for 21, we
turned our attention to the introduction of other nucleophiles.

B. Barlaam et al. / Tetrahedron 68 (2012) 534e543
539
Initially, we focused on introducing alkoxides but after the first
experiments, only traces of the desired product (36) were detected.
In fact after much experimentation, only the ring-opened by-
product (35) was detected despite operating the reaction under
anhydrous conditions. Surprised by this result, we proposed that
the side product was possibly the kinetic product, which would
have a strong thermodynamic driving force to re-cyclise to the
quinazolinone to re-afford the starting material. We postulate that
downfield from internal TMS in appropriate organic solutions. The
purity and the structures of the products were confirmed by LCMS
on a Waters 2690 photodiode array detector system using the fol-
lowing conditions: Column, Symmetry C-18; Solvent A, water 0.1%
formic acid; Solvent B, CH3CN; flow rate, 2.5 ml/min; run time,
4.5 min; gradient, from 0 to 100% solvent B; mass detector,
micromass ZMD. Preparative LCMS was carried out using Waters
600 Pumps linked to a Waters 2700 Sample Manager and a Waters
RO-
O
O
R
O
F
ROH, KOtBu
THF, 120 °C
N
N
O
N
O
N
I
I
21
36
low
high
temperature
temperature
F
OH2
O
O
N
O
R
F
F
O
H
OH
N
N
N
N
I
I
N
I
H
RO-
34
35
O
O
O
the enhanced lability of the carbonyl of the quinazolinone could be
explained by the stabilisation of the negative charge by the
resulting amidine moiety after ring opening. The intermediate ester
(34), the most probable by-product, was never detected by LCMS,
therefore, we assumed the ester 34 was quickly hydrolysing to the
acid possibly via a reactive ketene intermediate during analysis
affording the acid 35.
Table 6
Results obtained with other nucleophiles
Entry
Compound
Nucleophile
% Yield
In order to confirm the theory, we simply increased the oper-
ating temperature from 80 ꢀC to 120 ꢀC. To our satisfaction, at
120 ꢀC, all the starting material was transformed to the desired
product (36) and only traces of 35 were detected. We quickly
evaluated the substrate scope with ethereal side chains often
employed to improve physicochemical properties of quinazolines
(entries 1e3 after deprotection). Perhaps surprisingly, we also
successfully introduced phenyl ether substitution (entry 4) with
a satisfactory yield. However, attempts to introduce carbon or
amide nucleophiles (entries 5 and 6) failed and sulfur nucleophiles
afforded no selectivity (Table 6).
1
2
37
38
OH
OH
51
70
O
OH
3
39
42
O
N
O
OH
3. Conclusion
4
5
40
41
51
In conclusion, we have demonstrated an efficient and orthogo-
nal route to access a poorly studied quinazoline template that
highlights a novel direct SNAr at the unactivated C-6 position of the
quinazoline ring. In addition, we managed to show that a halogen
atom meta to the fluorine leaving group exerts a sufficient inductive
effect to permit the substitution under standard laboratory
conditions.
Na
O
O
d
O
K
N
6
42
43
d
4. Experimental
O
SH
4.1. General methods
7
Mixture
1H and 13C NMR spectra were recorded on a Bruker Biospin
AVANCE 500 spectrometer. Chemical shifts are reported as
d
values
Isolated yields.

540
B. Barlaam et al. / Tetrahedron 68 (2012) 534e543
micromass ZMD mass detector. Samples are routinely filtered and
injected at concentrations of around 50 mg of expected product per
ml of DMF. All strength measurements are carried out as follows: in
a 2 ml vial, precisely ca. 10 mg of the compound is added. We add
precisely ca. 2 mg of the reference compound (maleic acid). This
mixture is dissolved in a mixture of DMSO-d6 (0.55 ml) and
CD3COOD (5 drops). This mixture is warmed if necessary to obtain
a complete dissolution. A proton spectrum is recorded with a long
pulse delay (8 s) in order to obtain a quantitative measurement.
Strength is calculated using the formula below:
HRMS m/z (ESIþ) calculated for C9H7N2BrF: 256.97203; found:
256.97205.
4.1.4. 2-Amino-5-fluoro-3-iodobenzoic acid (14). A solution of io-
dine monochloride (14.2 ml, 283.6 mmol) in water (170 ml) and
concd HCl (40.0 ml) at 0 ꢀC (iodine monochloride was added to the
aqueous hydrochloric acid solution at 0 ꢀC, then used immediately),
was added to a stirred solution of 2-amino-5-fluorobenzoic acid (7,
40.0 g, 257.9 mmol) dissolved in water (300 ml) and in concd HCl
(25.0 ml). The reaction mixture was shielded from light and stirred
over a period of 2 days at room temperature. The resulting pre-
cipitate was collected by filtration, washed with water (30 ml) and
Ic ꢁ wr ꢁ Mc ꢁ nHr
Force ¼
ꢁ PR
Ir ꢁ wc ꢁ Mr ꢁ nHc
dried to
a constant weight to afford 2-amino-5-fluoro-3-
iodobenzoic acid (14, 57.0 g, 79%) as a pale brown solid: LCMS
(tR¼0.87 min, purity¼100%), ESIꢂ m/z, 280 (MꢂH)ꢂ; 1H NMR
(DMSO-d6) 7.56 (d, J¼3.0 and 8.6 Hz, 1H), 7.82 (dd, J¼3.0 and 7.6 Hz,
where: I¼Integration; w¼weight; M¼Molecular weight;
n¼Number of proton in the studied signal; c¼Compound;
r¼Reference; PR¼Reference purity.
1H); 13C NMR (DMSO-d6),
JCeF¼7.1 Hz); 117.2 (d, JCeF¼22.1 Hz); 131.5 (d, JCeF¼24.8 Hz); 147.8;
152.3 (d, JCeF¼J¼236.2 Hz); 168.5 (d, JCeF¼2.7 Hz); HRMS m/z (ESIþ)
calculated for C7H5O2NFI: 280.93435; found: 280.93212.
d
(ppm): 86.2 (d, JCeF¼8.0 Hz); 110.3 (d,
All small scale SNAr reactions were carried out in 2 ml capacity
microwave pressure tubes with a magnetic stirrer bar.
4.1.1. 2-Amino-3-bromo-5-fluorobenzoic acid (11). N-Bromosucci-
nimide (631 mg, 3.55 mmol) was added portionwise to a stirred
solution of 2-amino-5-fluorobenzoic acid (7, 500 mg, 3.22 mmol)
dissolved in acetic acid (5 ml) and the reaction mixture was stirred
overnight at room temperature. The resulting precipitate was col-
lected by filtration, washed with petroleum ether (20 ml) and dried
to a constant weight to afford 2-amino-3-bromo-5-fluorobenzoic
acid (11, 501 mg, 66.4%) as a clear beige solid, which was used
without further purification: LCMS (tR¼1.35 min, purity¼100%), ESI
4.1.5. 6-Fluoro-8-iodo-2-methyl-4H-3,1-benzoxazin-4-one (15). 2-
Amino-5-fluoro-3-iodobenzoic acid (14, 57.0 g, 202.8 mmol) in
Ac2O (181 ml, 1622.6) was stirred at reflux (140 ꢀC) for 2 h. The
reaction mixture was allowed to cool to room temperature. The
reaction mixture was concentrated to dryness. The reaction mix-
ture was diluted with ethyl acetate (500 ml) and the reaction
mixture was concentrated to dryness to give the desired 6-fluoro-
8-iodo-2-methyl-4H-benzo[d][1,3]oxazin-4-one (15, 61.4 g, 99%) as
a pale brown solid, which was used without further purification:
LCMS (tR¼3.42 min, purity¼100%), ESIþ m/z, no ion detected; 1H
m/z, no ion detected; 1H NMR (DMSO-d6)
d
(ppm) 6.76 (br s, 2H),
7.55 (dd, J¼3.0 Hz, JHeF¼9.4 Hz, 1H), 7.71 (dd, J¼3.0 Hz, JHeF¼7.8 Hz,
1H), 12.72 (br s, 1H); 13C NMR (DMSO-d6)
(ppm) 109.4 (d,
d
NMR (DMSO-d6),
JHeF¼8.0 Hz, 1H); 8.35 (dd, J¼2.7 Hz, JHeF¼8.0 Hz, 1H).
d
(ppm): 2.44 (s, 3H); 7.88 (dd, J¼3.0 Hz,
JCeF¼7.1 Hz); 111.1 (d, JCeF¼7.1 Hz), 116.2 (d, JCeF¼22.1 Hz), 124.9 (d,
JCeF¼24.8 Hz), 145.1, 151.4 (d, JCeF¼235.3 Hz), 168.1 (d, JCeF¼2.7 Hz).
4.1.6. 8-Iodo-6-fluoro-2-methylquinazolin-4(3H)-one (16). A sus-
pension of 6-fluoro-8-iodo-2-methyl-4H-benzo-[d][1,3]oxazin-4-
one (15, 61.4 g, 201.28 mmol) in concd aqeous NH3 (28% v/v,
330 ml) was stirred at reflux (100 ꢀC) for 2 h. The reaction mixture
was filtered, the resulting precipitate was washed with water
(400 ml) and dried to a constant weight to afford 6-fluoro-8-iodo-2-
methylquinazolin-4(3H)-one (16, 56.5 g, 92%) as an off white solid:
(tR¼2.10 min, purity¼90%), ESIꢂ m/z, 303 (MꢂH)ꢂ. 1H NMR (DMSO-
4.1.2. 6-Fluoro-8-bromo-2-methyl-4H-3,1-benzoxazin-4-one
(12). 2-Amino-3-bromo-5-fluorobenzoic acid (472 mg, 2.02 mmol)
in Ac2O (4 ml) was stirred at reflux (140 ꢀC) for 2 h. The reaction
mixture was allowed to cool to room temperature. The reaction
mixture was concentrated to dryness and diluted with ethyl acetate
(10 ml). The reaction mixture was concentrated to dryness to give
the desired 8-bromo-6-fluoro-2-methyl-4H-benzo[d][1,3]oxazin-
4-one (12, 490 mg, 94%) as a pale brown solid, which was used
without further purification: LCMS (tR¼3.42 min, purity¼100%),
d6),
d
(ppm) 2.39 (s, 3H); 7.80 (dd, J¼3.0 Hz, JHeF¼8.2 Hz, 1H); 8.27
(dd, J¼3.0 Hz, JHeF¼8.0 Hz,1H); 12.49 (br s,1H); 13C NMR (DMSO-d6)
ESIþ m/z, no ion detected; 1H NMR (DMSO-d6),
d (ppm): 2.44 (s,
d
(ppm) 21.6, 101.0 (d, JCeF¼8.0 Hz), 110.8 (d, JCeF¼22.1 Hz), 121.2 (d,
3H), 7.89 (dd, 1H, J¼2.7 Hz, JHeF¼7.8 Hz), 8.25 (dd, 1H, J¼2.7 Hz,
JHeF¼8.2 Hz); 13C NMR (DMSO-d6),
d (ppm) 21.1, 112.9 (d,
JCeF¼8.8 Hz),132.0 (d, JCeF¼25.7 Hz),145.1 (d, JCeF¼1.8 Hz),154.5 (d,
JCeF¼1.8 Hz), 158.8 (d, JCeF¼248.6 Hz), 160.8 (d, JCeF¼3.5 Hz); HRMS
m/z (ESIþ) calculated for C9H7ON2FI: 304.95816; found: 304.95807.
JCeF¼23.9 Hz), 119.1 (d, JCeF¼9.7 Hz), 121.6 (d, JCeF¼9.7 Hz), 127.7 (d,
JCeF¼26.5 Hz), 141.0 (d, JCeF¼2.7 Hz), 159.4 (d, JCeF¼1.8 Hz), 159.6
(d, JCeF¼250.3 Hz), 168.6.
4.1.7. 8-Iodo-2-methyl-6-(morpholin-4-yl)quinazolin-4(3H)-one
(17). 6-Fluoro-8-iodo-2-methylquinazolin-4(3H)-one (16, 56.5 g,
185.8 mmol) and morpholine (553 ml, 6317.8 mmol) were heated
at 129 ꢀC over a period of 5 days. The reaction mixture was con-
centrated to dryness, diluted with water (500 ml). The resulting
precipitate was collected by filtration, washed with water
(5ꢁ50 ml) and dried to a constant weight to afford 8-iodo-2-
methyl-6-morpholinoquinazolin-4(3H)-one (17, 58.8 g, 84%) as
a pale white solid; LCMS (tR¼1.98 min, purity¼100%), ESIþ m/z, 372
4.1.3. 8-Bromo-6-fluoro-2-methylquinazolin-4(3H)-one (13). A sus-
pension of 8-bromo-6-fluoro-2-methyl-4H-benzo[d][1,3]oxazin-
4-one (12, 466 mg, 1.81 mmol) in concd aqueous NH3 (28% v/v,
8 ml) was stirred at reflux (100 ꢀC) for 1.5 h. The reaction mixture
was concentrated. The resulting precipitate was collected by fil-
tration, washed with water (20 ml) and dried to a constant
weight to afford 8-bromo-6-fluoro-2-methylquinazolin-4(3H)-
one (14, 342 mg, 73.7%) as a pale white solid, which was used
without further purification: (tR¼2.40 min, purity¼100%), ESIþ
(MþH)þ; 1H NMR (DMSO-d6),
(ppm) 2.35 (s, 3H), 3.19 (t, J¼4.8 Hz,
d
m/z, no ion detected; 1H NMR (DMSO-d6),
d (ppm) 2.39 (s, 3H),
4H), 3.74 (t, J¼4.8 Hz, 4H); 7.42 (d, J¼2.9 Hz, 1H), 7.99 (d, J¼2.9 Hz,
1H); 13C NMR (DMSO-d6)
d (ppm) 21.4, 47.89, 65.8, 100.8, 108.6,
7.80 (dd, J¼3.0 Hz, JHeF¼8.2 Hz, 1H), 8.13 (dd, J¼2.7 Hz,
121.0, 132.3, 141.5, 149.5, 151.7, 161.3; HRMS m/z (ESIþ) calculated
JHeF¼8.2 Hz, 1H), 12.54 (br s, 1H); 13C NMR (DMSO-d6)
d (ppm)
for C13H14O2N3I: 372.02035; found: 372.02029.
21.6, 110.7 (d, JCeF¼23.0 Hz), 122.9 (d, JCeF¼9.7 Hz), 123.0 (d,
JCeF¼8.8 Hz), 126.5 (d, JCeF¼26.6 Hz), 143.9 (d, JCeF¼2.7 Hz), 155.3
(d, JCeF¼1.8 Hz), 159.0 (d, JCeF¼247.7 Hz), 161.1 (d, JCeF¼3.5 Hz);
4.1.8. 6-Fluoro-2-methyl-4-oxo-1,4-dihydroquinazoline-8-
carbonitrile (18). To
a solution of 8-bromo-6-fluoro-2-methyl-

B. Barlaam et al. / Tetrahedron 68 (2012) 534e543
541
quinazolin-4(3H)-one (13, 100 mg, 0.39 mmol) in DMF (1 ml), was
successively added N1,N1,N2,N2-tetramethylethane-1,2-diamine
(0.012 ml, 0.08 mmol), dicyanozinc (0.015 ml, 0.23 mmol), tris(di-
benzylideneacetone)dipalladium (17.81 mg, 0.02 mmol) and (9,9-
dimethyl-9H-xanthene-4,5-diyl)bis-(diphenylphosphine) (2.251 mg,
2H), 7.48 (d, J¼2.7 Hz, 1H), 8.06 (d, J¼2.7 Hz, 1H); 13C NMR (DMSO-
d6) d (ppm) 23.36, 46.45, 48.29, 55.44, 66.29, 101.43, 109.50, 114.53,
120.71, 128.22, 128.63, 132.93, 140.12, 150.35, 152.90, 158.85, 161.50;
HRMS m/z (ESIþ) calculated for C21H22O3N3I: 492.07004; found:
492.07023;
and
6-fluoro-3-(4-methoxybenzyl)-2-methyl-8-
3.89
m
mol). The reaction tube was sealed, sparged with argon and
morpholino-quinazolin-4(3H)-one (22b, 6.0 mg, 12%) LCMS
heated to 160 ꢀC over a period of 200 s in the microwave reactor. The
resulting suspension was filtered and the filtrate was concentrated to
dryness. The resulting liquid was diluted with water (we obtain
a suspension) and triturated with diethyl ether to give a solid, which
was collected by filtration and dried under vacuum to give 6-fluoro-2-
methyl-4-oxo-3,4-dihydroquinazoline-8-carbo-nitrile (18, 60 mg,
76%) as a clear beige solid, which was used without further purifica-
tion; LCMS (tR¼1.53 min, purity¼98%), ESIꢂ m/z, 202.0 (MꢂH)ꢂ; 1H
(tR¼1.78 min, purity¼100%), ESIþ m/z, 384.4 (MþH)þ; 1H NMR
(DMSO-d6)
d
(ppm) 8.32 (dd, J1¼2.85 Hz, J2¼8.0 Hz, 1H), 7.89 (m,
1H), 7.18 (d, J¼8.59 Hz, 2H), 6.91 (d, J¼8.65 Hz, 2H), 5.30 (s,1H), 3.73
(s, 1H), 2.54 (s, 1H); 13C NMR (DMSO-d6)
d
(ppm) 24.15, 46.85, 51.95,
55.95, 66.93, 103.16 (J¼23.6 Hz), 110.33 (J¼26.5 Hz), 115.05, 122.83
(J¼10.2 Hz), 122.87, 128.79, 129.01, 150.79 (J¼9.4), 152.51, 159.39,
162.15e160.09 (JCeF¼243.26 Hz), 162.19; HRMS m/z (ESIþ) calcu-
lated for C21H22O3N3F: 384.16397; found: 384.16384.
NMR (DMSO-d6),
d
(ppm) 2.41 (s, 3H), 8.08 (dd, J¼3.0 Hz, JHeF¼8.2 Hz,
1H), 8.37 (dd, J¼3.0 Hz, JHeF¼8.2 Hz, 1H); 12.70 (br s, 1H); 13C NMR
(DMSO-d6) 22.5, 102.0, 114.8, 115.2, 115.3, 138.9, 159.0, 162.9, 166.3;
HRMS m/z (ESIþ) calculated for C10H6ON3F: 204.05677; found:
204.05670.
4.1.12. 6-(4-Hydroxypiperidin-1-yl)-8-iodo-3-(4-methoxy-benzyl)-
2-methylquinazolin-4(3H)-one (23). A solution of 6-fluoro-8-iodo-
3-(4-methoxybenzyl)-2-methylquinazolin-4(3H)-one (21, 52 mg,
0.12 mmol) in piperidin-4-ol (62.0 mg, 0.61 mmol) was stirred at
140 ꢀC over weekend. The reaction mixture was purified by pre-
parative LCMS to afford 6-(4-hydroxypiperidin-1-yl)-8-iodo-3-(4-
methoxybenzyl)-2-methylquinazolin-4(3H)-one (23, 46 mg, 78%)
as a yellow solid: LCMS (tR¼2.70 min, purity¼100%), ESIþ m/z, 506.3
4.1.9. 2-Methyl-6-(morpholin-4-yl)-4-oxo-1,4-dihydro-quinazoline-
8-carbonitrile (19). 6-Fluoro-2-methyl-4-oxo-3,4-dihydroquinazo-
line-8-carbo-nitrile (18, 49 mg, 0.24 mmol) and morpholine
(0.63 ml, 7.2 mmol) were sealed into a microwave tube. The reaction
was degassed and heated at 160 ꢀC for 16 h. The reaction mixture was
cooled to room temperature and purified by preparative LCMS to af-
ford 2-methyl-6-(morpholin-4-yl)-4-oxo-1,4-dihydro-quinazoline-8-
carbonitrile (19, 42 mg, 65%): LCMS (tR¼1.43 min, purity¼98%), ESIþ
(MþH)þ; 1H NMR (DMSO-d6)
d (ppm) 1.47 (m, 2H), 1.83 (m, 2H),
2.98 (td, J¼9.9 Hz, 2H), 3.55 (m, 3H), 3.74 (s, 3H), 4.72 (d, J¼4.2 Hz,
1H), 5.27 (s, 2H), 6.90 (d, J¼8.7 Hz, 2H), 7.13 (d, J¼8.6 Hz, 2H), 7.45
(d, J¼2.7 Hz, 1H), 8.01 (d, J¼2.7 Hz, 1H); 13C NMR (DMSO-d6)
d
(ppm) 22.86, 33.38, 45.86, 45.96, 54.97, 65.55, 100.95, 109.16,
m/z, 271.3 (MþH)þ; 1H NMR (DMSO-d6)
d
1.36 (s, 3H), 3.22e3.29 (m,
114.05, 120.34, 127.75, 128.22, 132.87, 138.93, 149.65, 151.97, 158.37,
161.02; HRMS m/z (ESIþ) calculated for C22H25O3N3I: 506.09351;
found: 506.09314.
4H), 3.72e3.78 (m, 4H), 7.63 (d, 1H), 8.01 (d, 1H), 12.39 (br s, 1H); 13C
NMR (DMSO-d6)d25.1, 47.6,102.6,114.7,115.5,120.6,123.5,141.1,146.0,
158.7, 168.8; HRMS m/z (ESIþ) calculated for C14H15O2N4: 271.11895;
found: 271.11888.
4.1.13. 6-(4-Acetylpiperazin-1-yl)-8-iodo-3-(4-methoxy-benzyl)-2-
methylquinazolin-4(3H)-one (24). A solution of 6-fluoro-8-iodo-3-
(4-methoxybenzyl)-2-methylquinazolin-4(3H)-one (17, 50 mg,
0.12 mmol) in 1-(piperazin-1-yl)ethanone (76 mg, 0.59 mmol) was
stirred at 140 ꢀC for 3 days. The reaction mixture was purified by
preparative LCMS to afford 6-(4-acetylpiperazin-1-yl)-8-iodo-3-(4-
methoxybenzyl)-2-methylquinazolin-4(3H)-one (24, 33.0 mg, 53%)
as a yellow foam; LCMS (tR¼2.67 min, purity¼100%), ESIþ m/z,
4.1.10. 6-Fluoro-8-iodo-3-(4-methoxybenzyl)-2-methyl-quinazolin-
4(3H)-one (21). p-Methoxybenzyl chloride (0.535 ml, 3.95 mmol)
was added to a suspension of 6-fluoro-8-iodo-2-methylquinazolin-
4(3H)-one (16, 1 g, 3.29 mmol) and potassium carbonate (0.909 g,
6.58 mmol) in acetone (20 ml) and the resulting suspension was
stirred at 60 ꢀC for 24 h. The mixture was evaporated and absorbed
on silica gel. The crude product was purified by flash chromatog-
raphy on silica gel eluting with 5e15% ethyl acetate in petroleum
ether. The solvent was evaporated to dryness to afford 6-fluoro-8-
533.3 (MþH)þ; 1H NMR (DMSO-d6)
(ppm) 2.06 (d, J¼11.6 Hz, 3H),
d
2.49 (s, 3H), 3.23 (m, 2H), 3.30 (m, 2H), 3.59 (m, 4H), 3.72 (s, 3H),
5.28 (s, 2H), 6.90 (d, J¼8.7 Hz, 2H), 7.14 (d, J¼8.6 Hz, 2H), 7.48 (d,
iodo-3-(4-methoxybenzyl)-2-methyl-quinazolin-4(3H)-one
(19,
J¼2.7 Hz, 1H), 8.07 (d, J¼2.7 Hz, 1H); 13C NMR (DMSO-d6)
d (ppm)
1.130 g, 81%) as
a
clear white solid; LCMS (tR¼3.87 min,
21.11, 22.90, 40.41, 45.10, 45.98, 47.64, 47.86, 54.98, 98.99, 100.98,
109.49, 114.06, 120.25, 127.76, 128.15, 133.86, 139.49, 149.41, 152.40,
158.38, 160.94; HRMS m/z (ESIþ) calculated for C22H25O3N3I:
533.09659; found: 533.09641.
purity¼100%), ESIþ m/z, 425.2 (MþH)þ; 1H NMR (DMSO-d6)
d
(ppm) 2.54 (s, 1H), 3.73 (s,1H), 5.30 (s, 1H), 6.91 (d, J¼8.65 Hz, 2H),
7.18 (d, J¼8.59 Hz, 2H), 7.89 (dd, Jortho¼2.84 Hz, JHeF¼8.31 Hz, 1H),
8.32 (dd, Jortho¼2.85 Hz, JHeF¼8.0 Hz, 1H); 13C NMR (DMSO-d6)
d
(ppm) 23.59, 46.68, 55.45, 101.69, 111.95 (JCeF¼23 Hz), 114.54,
4.1.14. 1-[8-Iodo-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-
dihydroquinazolin-6-yl]-L-prolinamide (25). A solution of 6-fluoro-
120.82, 128.22, 128.34, 144.26 (JCeF¼24.77 Hz), 155.78, 158.58
(JCeF¼248.56 Hz), 158.93, 160.51, 161.25; HRMS m/z (ESIþ) calcu-
lated for C17H14O2N2FI: 425.00785; found: 425.00745.
8-iodo-3-(4-methoxybenzyl)-2-methylquinazolin-4(3H)-one (21,
50 mg, 0.12 mmol) and (S)-pyrrolidine-2-carboxamide (67.3 mg,
0.59 mmol) in NMP (0.1 ml) was stirred at 140 ꢀC for 2 days. Further
(S)-pyrrolidine-2-carboxamide (67.3 mg, 0.59 mmol) was added to
the mixture and the reaction mixture was heated at 180 ꢀC over-
night. The reaction mixture was purified by preparative LCMS to
4.1.11. 8-Iodo-3-(4-methoxybenzyl)-2-methyl-6-morpholino-quina-
zolin-4(3H)-one (22a) and 6-fluoro-3-(4-methoxybenzyl)-2-methyl-
8-(morpholin-4-yl)quinazolin-4(3H)-one (22b). A solution of 6-
fluoro-8-iodo-3-(4-methoxybenzyl)-2-methylquinazolin-4(3H)-
afford
(S)-1-(8-iodo-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-
one (21, 52.6 mg, 0.12 mmol) in morpholine (400
m
l, 4.57 mmol)
dihydro-quinazolin-6-yl)pyrrolidine-2-carboxamide (25, 13.0 mg,
was stirred under argon at 140 ꢀC over weekend. After 3 days, the
reaction mixture was cooled to room temperature and purified
preparative LCMS to afford 8-iodo-3-(4-methoxybenzyl)-2-methyl-
6-morpholinoquinazolin-4-(3H)-one (22a, 42 mg, 68%) as a yellow
solid: LCMS (tR¼1.98 min, purity¼100%), ESIþ m/z, 492.3 (MþH)þ;
21%) as a yellow solid: LCMS (tR¼2.52 min, purity¼98%), ESIþ m/z,
519.23 (MþH)þ; 1H NMR (DMSO-d6)
d (ppm) 1.99 (m, 3H), 2.24 (m,
1H), 2.46 (s, 2H), 3.59 (m, 1H), 3.72 (s, 3H), 4.05 (d, J¼8.0 Hz, 1H),
5.28 (d, J¼16.6 Hz, 2H), 6.90 (d, J¼8.6 Hz, 2H), 7.08 (d, J¼2.6 Hz, 1H),
7.12 (d, J¼8.4 Hz, 2H), 7.51 (d, J¼2.5 Hz, 1H); 13C NMR (DMSO-d6)
1H NMR (DMSO-d6)
d
(ppm) 2.49 (s, 1H), 3.26 (m, 4H), 3.73 (s, 1H),
d (ppm) 23.26, 23.92, 31.56, 46.36, 48.85, 55.44, 62.73e61.84,
3.79 (m, 4H), 5.28 (s, 2H), 6.91 (d, J¼8.7 Hz, 2H), 7.14 (d, J¼8.6 Hz,
101.20, 106.43, 114.53, 120.95, 128.19, 128.69, 129.52, 137.75, 146.28,

542
B. Barlaam et al. / Tetrahedron 68 (2012) 534e543
150.99, 158.81, 161.19, 174.95; HRMS m/z (ESIþ) calculated for
C22H25O3N3I: 519.08876; found: 519.08887.
494.33 (MþH)þ; 1H NMR (DMSO-d6)
d (ppm) 1.27 (s, 6H), 2.44 (s,
3H), 3.43 (d, J¼5.1 Hz, 2H), 3.72 (s, 3H), 4.88 (m, 1H), 5.26 (s, 2H),
5.75 (s, 1H), 6.90 (d, J¼8.6 Hz, 2H), 7.13 (d, J¼8.6 Hz, 2H), 7.32 (d,
4.1.15. 8-Iodo-3-(4-methoxybenzyl)-2-methyl-6-{[2-(morpholin-4-
yl)ethyl]amino}quinazolin-4(3H)-one (26). A solution of 6-fluoro-8-
iodo-3-(4-methoxybenzyl)-2-methylquinazolin-4(3H)-one (21,
J¼2.5 Hz, 1H), 7.82 (d, J¼2.5 Hz, 1H); 13C NMR (DMSO-d6)
d (ppm)
23.27, 24.35, 46.34, 54.86, 55.51, 67.88, 100.49, 107.04, 114.59,
121.00, 128.26, 128.92, 134.03, 137.86, 147.39, 151.00, 158.83, 161.47;
HRMS m/z (ESIþ) calculated for C21H24O3N3I: 494.09351; found:
493.09363.
50 mg, 0.12 mmol) in 2-morpholinoethanamine (400 ml, 3.05 mmol)
was stirred under argon at 160 ꢀC over weekend. The reaction mix-
ture was purified by preparative LCMS to afford 8-iodo-3-(4-
methoxybenzyl)-2-methyl-6-(2-morpholinoethylamino)-quinazolin-
4(3H)-one (26, 26.0 mg, 41%) as a clear yellow solid: LCMS
(tR¼2.80 min, purity¼99%), ESIþ m/z, 535.36 (MþH)þ; 1H NMR
4.1.19. 6-(1H-Imidazol-1-yl)-8-iodo-3-(4-methoxybenzyl)-2-
methylquinazolin-4(3H)-one (32). A solution of 6-fluoro-8-iodo-3-
(4-methoxybenzyl)-2-methylquinazolin-4(3H)-one (21, 52.4 mg,
0.12 mmol) and 1H-imidazole (57 mg, 0.84 mmol) in NMP (0.1 ml)
was stirred at 160 ꢀC for 72 h. The reaction mixture was purified by
preparative LCMS to afford 6-(1H-imidazol-1-yl)-8-iodo-3-(4-
methoxybenzyl)-2-methylquinazolin-4(3H)-one (32, 24 mg, 39%)
as a clear beige solid: LCMS (tR¼2.65 min, purity¼100%), ESIþ m/z,
(DMSO-d6)
d
(ppm) 2.44 (m, 7H), 2.52 (m, 2H), 3.20 (dd, J¼6.2,
12.0 Hz, 2H), 3.59 (m, 4H), 3.72 (s, 4H), 5.27 (s, 2H), 6.17 (t, J¼5.2 Hz,
1H), 6.88 (d, J¼8.7 Hz, 2H), 7.13 (2d, J¼2.8, 8.69 Hz, 3H), 7.76 (d,
J¼2.5 Hz,1H); 13C NMR (DMSO-d6)
d (ppm) 23.18, 40.37, 46.33, 53.75,
55.44, 57.18, 66.54, 100.99, 104.65, 114.51, 121.37, 128.18, 128.83,
131.25, 137.89, 148.65, 150.75, 158.82, 161.42; HRMS m/z (ESIþ) cal-
culated for C23H28O3N4I: 535.12006; found: 535.11969.
473.24 (MþH)þ; 1H NMR (DMSO-d6)
d (ppm) 2.56 (s, 3H), 3.73 (s,
3H), 5.32 (s, 2H), 6.91 (d, J¼8.7 Hz, 2H), 7.14 (s,1H), 7.19 (d, J¼8.6 Hz,
2H), 7.96 (s, 1H), 8.31 (d, J¼2.5 Hz, 1H), 8.46 (s, 1H), 8.68 (d,
4.1.16. 6-[(2,4-Dimethoxybenzyl)amino]-8-iodo-3-(4-meth-oxy-
benzyl)-2-methylquinazolin-4(3H)-one (27). A solution of 6-fluoro-
8-iodo-3-(4-methoxybenzyl)-2-methylquinazolin-4(3H)-one (21,
52.9 mg, 0.12 mmol) and (2,4-dimethoxyphenyl)methanamine
(0.094 ml, 0.62 mmol) in NMP (0.1 ml) was stirred at 140 ꢀC for 3
days. The reaction mixture was purified by preparative LCMS to af-
ford 6-(2,4-dimethoxybenzylamino)-8-iodo-3-(4-methoxybenzyl)-
2-methylquinazolin-4(3H)-one (27, 32 mg, 44%) as a clear yellow
solid: LCMS (tR¼3.38 min, purity¼100%), ESIþ m/z, 572.32 (MþH)þ;
J¼2.5 Hz, 1H); 13C NMR (DMSO-d6)
d (ppm) 23.24, 46.26, 54.99,
101.61, 114.08, 117.02, 118.12, 120.39, 127.84, 130.14, 135.23, 135.82,
145.17, 156.02, 158.47, 160.78; HRMS m/z (ESIþ) calculated for
C20H18O2N4I: 473.04690; found: 473.04745.
4.1.20. 8-Iodo-6-methoxy-3-(4-methoxybenzyl)-2-methyl-quinazo-
lin-4(3H)-one (37). Potassium tert-butoxide (88 mg, 0.87 mmol)
was added in one portion to a stirred solution of methanol
(0.035 ml, 0.86 mmol) dissolved in anhydrous THF (1 ml) under
argon at room temperature for 30 min and the mixture was added
to the solution of 6-fluoro-8-iodo-3-(4-methoxybenzyl)-2-
methylquinazolin-4(3H)-one (21, 110.5 mg, 0.26 mmol) in THF
(0.25 ml) under argon. The mixture was heated at 120 ꢀC overnight.
The reaction mixture was purified by preparative LCMS to afford 8-
iodo-6-methoxy-3-(4-methoxybenzyl)-2-methylquinazolin-
4(3H)-one (58 mg, 51%) as a clear yellow solid; LCMS (tR¼3.79 min,
1H NMR (DMSO-d6)
d (ppm) 2.43 (s, 3H), 3.72 (s, 6H), 3.84 (s, 3H), 4.19
(d, J¼5.6 Hz, 2H), 5.23 (s, 2H), 6.48 (m, 1H), 6.58 (d, J¼2.2 Hz, 1H),
6.67 (t, J¼5.9 Hz, 1H), 6.89 (d, J¼8.5 Hz, 2H), 7.09 (m, 3H), 7.74 (d,
J¼2.4 Hz, 1H); 13C NMR (DMSO-d6)
d (ppm) 23.04, 55.43, 55.52,
55.86, 98.70, 100.88, 104.84, 114.50, 118.69, 121.26, 128.15, 128.36,
128.77, 129.07, 137.90, 148.53, 150.74, 158.33, 158.79, 160.13, 161.40;
HRMS m/z (ESIþ) calculated for C26H27O4N3I 572.10408; found:
572.10449.
purity¼100%), ESIþ m/z, 437.3 (MþH)þ; 1H NMR (DMSO-d6)
d (ppm)
2.50 (s, 3H), 3.72 (s, 3H), 3.88 (s, 3H), 5.29 (s, 2H), 6.90 (d, J¼8.7 Hz,
2H), 7.15 (d, J¼8.7 Hz, 2H), 7.57 (d, J¼2.8 Hz, 1H), 7.96 (d, J¼2.8 Hz,
4.1.17. 6-[(2-Hydroxyethyl)amino]-8-iodo-3-(4-methoxy-benzyl)-2-
methylquinazolin-4-(3H)-one (28). A solution of 6-fluoro-8-iodo-3-
(4-methoxybenzyl)-2-methylquinazolin-4(3H)-one (21, 52.9 mg,
0.12 mmol) and 2-aminoethanol (0.038 ml, 0.62 mmol) in NMP
(0.1 ml) at 140 ꢀC for 31 h. The reaction mixture was purified by
preparative LCMS to afford 6-(2-hydroxyethylamino)-8-iodo-3-(4-
methoxy-benzyl)-2-methylquinazolin-4(3H)-one (28, 24.0 mg,
41%) as a clear yellow solid: LCMS (tR¼2.48 min, purity¼100%), ESIþ
1H); 13C NMR
d (ppm) 23.44, 46.54, 55.47, 56.61, 97.46, 108.41,
113.32, 123.54, 125.39, 129.95, 131.16, 144.04, 157.42, 158.88, 159.69,
160.21; HRMS m/z (ESIþ) calculated for C18H17O3N2I: 437.02784;
found: 437.02321.
4.1.21. 8-Iodo-3-(4-methoxybenzyl)-6-(2-methoxyethoxy)-2-
methylquinazolin-4(3H)-one (38). A solution of 6-fluoro-8-iodo-3-
(4-methoxybenzyl)-2-methylquinazolin-4(3H)-one (50 mg, 0.12 mmol)
and sodium 2-methoxyethanolate (116 mg, 0.24 mmol) in NMP
(0.1 ml) was stirred at 120 ꢀC for 1 h. The reaction mixture was pu-
rified bypreparativeLCMSto afford8-iodo-3-(4-methoxybenzyl)-6-
(2-methoxyethoxy)-2-methylquinazolin-4(3H)-one (40 mg, 70%) as
a clear brown solid: LCMS (tR¼3.02 min, purity¼100%), ESIþ m/z,
m/z, 466.29 (MþH)þ; 1H NMR (DMSO-d6)
d (ppm) 2.44 (s, 3H), 3.16
(q, J¼5.8 Hz, 2H), 3.57 (q, J¼5.3 Hz, 2H), 3.72 (s, 3H), 4.78 (t,
J¼5.1 Hz, 1H), 5.26 (s, 2H), 6.29 (t, J¼5.6 Hz, 1H), 6.90 (d, J¼8.7 Hz,
2H), 7.13 (m, 3H), 7.74 (d, J¼2.6 Hz, 1H); 13C NMR (DMSO-d6)
d
(ppm) 23.17, 45.76, 46.32, 55.44, 59.64, 100.98, 104.43, 114.51,
121.38, 128.19, 128.84, 131.25, 137.76, 148.81, 150.67, 158.81, 161.48;
HRMS m/z (ESIþ) calculated for C19H21O3N3I: 466.06221; found:
466.06210.
481.27 (MþH)þ; 1H NMR (DMSO-d6)
d (ppm) 2.51 (s, 3H), 3.31 (s, 3H),
3.69 (m, 2H), 3.72 (s, 3H), 4.23 (m, 2H), 5.29 (s, 2H), 6.90 (d, J¼8.7 Hz,
2H), 7.15 (d, J¼8.6 Hz, 2H), 7.58 (d, J¼2.8 Hz, 1H), 7.97 (d, J¼2.8 Hz,
4.1.18. 6-[(1-Hydroxy-2-methylpropan-2-yl)amino]-8-iodo-3-(4-
methoxybenzyl)-2-methylquinazolin-4(3H)-one (29). A solution of
6-fluoro-8-iodo-3-(4-methoxybenzyl)-2-methylquinazolin-4(3H)-
one (21, 50 mg, 0.12 mmol) and 2-amino-2-methylpropan-1-ol
(0.056 ml, 0.59 mmol) in NMP (0.1 ml) was stirred at 140 ꢀC for 3
days. Further 2-amino-2-methylpropan-1-ol (0.056 ml, 0.59 mmol)
was added and the reaction mixture was heated at 200 ꢀC for 2
days. The reaction mixture was purified by preparative LCMS to
1H); 13C NMR (DMSO-d6)
d (ppm) 23.44, 46.56, 55.45, 58.54, 68.20,
70.52, 99.38, 101.42, 108.56, 114.53, 120.67, 128.28, 128.49, 133.76,
141.71,153.92,157.20,158.88,161.33; HRMS m/z (ESIþ) calculated for
C20H21O4N2I: 480.05405; found: 480.05127.
4.1.22. tert-Butyl 4-(8-iodo-3-(4-methoxybenzyl)-2-methyl-4-oxo-
3,4-dihydroquinazolin-6-yloxy)piperidine-1-carboxylate
(39). Potassium tert-butoxide (79 mg, 0.71 mmol) was added por-
tionwise to a stirred solution of tert-butyl 4-hydroxypiperidine-1-
carboxylate (149 mg, 0.74 mmol) dissolved in anhydrous DME (1 ml)
under argon at room temperature for 30 min and the mixture (0.3 ml)
afford
6-(1-hydroxy-2-methylpropan-2-ylamino)-8-iodo-3-(4-
methoxybenzyl)-2-methylquinazolin-4(3H)-one (29, 10 mg, 17%)
as a clear yellow solid. LCMS (tR¼2.79 min, purity¼100%), ESIþ m/z,

B. Barlaam et al. / Tetrahedron 68 (2012) 534e543
543
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wasadded tothe solution of 6-fluoro-8-iodo-3-(4-methoxybenzyl)-2-
methylquinazolin-4(3H)-one (21, 50 mg, 0.12 mmol) and the reaction
mixturewasstirredat120 ꢀC3 h. Thereactionmixturewaspurified by
preparative LCMS to afford tert-butyl 4-(8-iodo-3-(4-methoxy-
benzyl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-yloxy)piperidine-
1-carboxylate (39, 32 mg, 45%) as a clear yellow solid: LCMS
(tR¼3.98 min, purity¼100%), ESIþ m/z, 606.42 (MþH)þ; 1H NMR
(DMSO-d6) d (ppm) 1.41 (s, 9H), 1.56 (m, 2H), 1.91 (m, 2H), 2.50 (s, 3H),
3.23 (s, 2H), 3.65 (m, 2H), 3.72 (s, 3H), 4.76 (m,1H), 5.28 (s, 2H), 6.90 (d,
J¼8.6 Hz, 2H), 7.15 (d, J¼8.6 Hz, 2H), 7.62 (d, J¼2.7 Hz, 1H), 7.99 (d,
J¼2.7 Hz,1H); 13C NMR (DMSO-d6)
d (ppm) 23.44, 28.43, 46.56, 55.45,
73.24, 79.14, 101.47, 110.36, 114.53, 120.84, 128.29, 128.47, 134.74,
141.76, 153.99, 154.29, 155.63, 158.88, 161.30; HRMS m/z (ESIþ) calcu-
lated for C27H33O5N3I: 606.14594; found: 606.14600.
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4.1.23. 8-Iodo-3-(4-methoxybenzyl)-2-methyl-6-phenoxy-quinazo-
lin-4(3H)-one (40). A solution of 6-fluoro-8-iodo-3-(4-methoxy-
benzyl)-2-methylquinazolin-4(3H)-one (51 mg, 0.12 mmol) and so-
dium phenolate (27.9 mg, 0.24 mmol) in NMP (0.2 ml) at 120 ꢀC for
5 h. The reaction mixturewaspurified by preparative LCMSto afford 8-
iodo-3-(4-methoxybenzyl)-2-methyl-6-phenoxy-quinazolin-4(3H)-
one (40, 32 mg, 51%) as a clear brown solid: LCMS (tR¼3.73 min,
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12. Takase, Y.; Saeki, T.; Watanabe, N.; Adachi, H.; Souda, S.; Saito, I. J. Med. Chem.
1994, 37, 2106e2111.
13. Meegalla, S. K.; Wall, M. J.; Chen, J.; Wilson, K. J.; Ballentine, S. K.; DesJarlais, R. L.;
Schubert, C.; Crysler, C. S.; Chen, Y.; Molloy, C. J.; Chaikin, M. A.; Manthey, C. L.;
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purity¼100%), ESIþ m/z, 499.30 (MþH)þ; 1H NMR (DMSO-d6)
d
(ppm)
2.53 (s, 3H), 3.72 (s, 3H), 5.27 (s, 2H), 6.90 (d, J¼8.7 Hz, 2H), 7.16 (2d,
J1¼8.68 Hz, J2¼7.97 Hz, 4H), 7.27 (t, J¼7.4 Hz,1H), 7.49 (m, 3H), 8.09 (d,
J¼2.7 Hz, 1H); 13C NMR (DMSO-d6)
d (ppm) 23.71, 46.79, 55.61,101.97,
113.20, 114.70, 120.35, 120.99, 125.35, 128.48, 130.98, 135.57, 143.34,
155.21, 161.34, 159.07, 156.15, 155.98; HRMS m/z (ESIþ) calculated for
C23H20O3N2I: 499.05131; found: 499.05164.
Acknowledgements
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The authors would like to thank senior analysts Christian
Delvare, Paul Davey, Becky Burton, Julie Demeritt and Madeleine
Vickers for their support.
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