Synthesis of Novel Hydroxymethyl-Substituted Fused Heterocycles

Article abstract of DOI:10.1055/s-0035-1561355

Examples of hydroxymethylated analogues of heteroaryl cores such as quinazolin-4-ones, isoquinolin-1(2H)-ones, pyrido[3,4-d]pyrimidin-4(3H)-ones, chromen-4-ones and pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones are sparse or non-existent in the scientific literature. We have demonstrated that such compounds are accessible by using standard procedures from readily available raw materials.

Full text of DOI:10.1055/s-0035-1561355

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, A–I
paper
A
J. L. Holmes et al.
Paper
Synthesis
Synthesis of Novel Hydroxymethyl-Substituted Fused Heterocycles
Jane L. Holmes*a
Lynsie Almeidab
O
O
O
Bernard Barlaama
Rosemary A. Crofta
Allan P. Dishingtona
Laksmaiah Gingipallib
Lorraine A. Hassalla
Janet L. Hawkinsa
Stephanos Ioannidisb
Jeffrey W. Johannesb
Thomas M. McGuire*a,◊
Jane E. Moorea
OH
O
Y
Z
X = Z = C; Y = O
X = Y = C; Z = N
X
Ar
HO
O
O
OH
NH2
OH
NH2
X = Y = Z = N
X = C; Y = Z = N
N
Anil Patela
Kurt G. Pikea
Timothy Pontzb
Xiaoyun Wub
Tao Wangb
Hai-Jun Zhangb
Xiaolan Zhengb
a AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Thomas.McGuire@astrazeneca.com
b AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA
◊ Current address: AstraZeneca R&D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
Received: 17.12.2015
Accepted after revision: 08.01.2016
Published online: 18.02.2016
hydroxyl and a glutamate residue. We therefore needed to
retain the hydroxymethyl functionality to maintain poten-
cy whilst investigating other parts of the molecule.
DOI: 10.1055/s-0035-1561355; Art ID: ss-2015-t0725-op
O
O
Abstract Examples of hydroxymethylated analogues of heteroaryl
cores such as quinazolin-4-ones, isoquinolin-1(2H)-ones, pyrido[3,4-
d]pyrimidin-4(3H)-ones, chromen-4-ones and pyrrolo[2,1-f][1,2,4]tri-
azin-4(3H)-ones are sparse or non-existent in the scientific literature.
We have demonstrated that such compounds are accessible by using
standard procedures from readily available raw materials.
NH
NH
N
N
HO
N
Key words cross-coupling,
fused-ring
systems,
heterocycles,
N
quinazolinones, isoquinolinones, chromenones, triazinones
AZ0926
Figure 1 The 2-phenylquinazolin-4-one lead identified by high-
throughput screening and optimised quinazolin-4-one AZ0926
Fused heterocycles such as quinazolin-4-ones, isoquino-
lines and azaquinazolinone feature in a large number of
pharmaceutical products and, as such, there is an extensive
body of work in the literature describing their syntheses.1
As part of a drug discovery programme, we identified,
via a high-throughput screen, a 2-phenylquinazolin-4-one
(Figure 1) as a potential lead.2 Further elaboration of this
core revealed that increased potency could be achieved by
substitution at the 8-position with a hydroxymethyl moi-
ety. Closer examination of the crystal structure of AZ0926
(a potent inhibitor, Figure 1), bound in the target enzyme
suggested that this was due to an interaction between the
Whilst the preparation of these fused heterocycles is
well represented in the literature,1 we were unable to find
examples of 8-hydroxymethyl-substituted quinazolinones.
We thus commenced a programme of work to develop syn-
thetic routes to these motifs. This paper details the various
strategies employed in the preparation of a range of novel
hydroxymethyl-substituted quinazolinones and other fused
heterocycles.
Our initial work centred on the development of a set of
8-(hydroxymethyl)quinazolin-4(3H)-ones. Quinazolinones
are a class of fused heterocycles of considerable interest to
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

B
J. L. Holmes et al.
Paper
Synthesis
the pharmaceutical industry. Found in a range of drug sub-
stances (Figure 2), including anticonvulsants3 such as cen-
tazolone, antiinflammatories,4 antibacterials,5 antimalarials
(febrifugine)6 and diabetic treatments (balaglitazone),7 tra-
ditional syntheses involve condensation with anthranilic
acids or amides,8 whilst more recent methods have used
copper-catalysed processes9 to provide the 2-substituted
and 2,3-substituted quinazolinones.
We initially began our syntheses of 8-(hydroxymeth-
yl)quinazolin-4(3H)-ones 3 by using the traditional method
of condensation between an aldehyde 2 and a substituted
anthranilic amide derivative 1 (Scheme 1). Copper(II) chlo-
ride in DMSO was found to provide the best results with a
range of aldehydes 2a–e from our collection. Further deri-
vatisation of compound 3e using Suzuki–Miyaura cross
coupling proved difficult, providing the target compounds
in poor yield. In addition to this, the scope of the condensa-
tion step was limited to the availability of aldehydes. We
decided therefore to explore routes that would provide us
with a more versatile intermediate that could be function-
alised in the 2-position at a late stage giving us access to a
wide range of 8-hydroxymethyl quinazolinone analogues.
It was envisaged that we could obtain this desired versa-
tility if we could first prepare a 2-chloroquinazoline such as
compound 9 (Scheme 2). Our route to 2-chloroquinazoli-
O
N
H
N
N
O
HO
febrifugine
O
N
N
O
O
NH
O
S
balaglitazone
O
NH2
N
N
centazolone
Figure 2
nones started with the commercially available anthranilic
acid 5, which was converted into amide 6 by using standard
coupling conditions. Cyclisation to provide imide 7 followed
by chlorination provided us with the desired chloro-
quinazolinone 8. Hydrolysis and regioselective displace-
ment of the chloro with piperazine derivatives followed by
O
O
O
NH
NH2
a)
H
+
R
N
NH2
R
HO
HO
1
2a–e
3a–e
O
O
N
b)
NH
N
NH
HO
Ar
HO
Br
3e
4
O
O
O
H
H
H
N
N
O
N
O
2a
2b
2c
O
O
H
H
Br
2d
2e
N
Cl
Scheme 1 Reagents and conditions: (a) FeCl3, H2O, benzaldehyde, 44%; (b) ArB(OR)2, Cs2CO3, Pd(PPh3)4, dioxane, H2O, 145 °C (microwave), 14%
(Ar = 2-methyl-3-pyridine).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

C
J. L. Holmes et al.
Paper
Synthesis
O
O
O
O
Cl
N
O
OH
NH2
NH
OH
NH2
NH2
b)
NH
a)
a)
N
b)
O
N
H
NH2
O
N
H
O
N
Cl
O
O
c)
O
O
O
12
13
14
Cl
O
O
7
5
6
c)
e), f)
d)
Cl
NH
NH
O
N
Cl
N
Cl
N
Ar
N
NH
d)
Cl
N
Br
AcO
HO
Cl
N
17a–c
16
15
O
O
HO
O
O
g), f)
8
9
NH
NR2
O
O
N
N
e)
f)
NH
NH
HO
O
18a–h
N
N
N
Ar =
NR
NR
HO
O
HO
N
10
11a–f
O
N
N
OH
F
R =
N
N
N
N
NR2 =
Scheme 2 Reagents and conditions: (a) HATU, NH4OH, DIPEA, DMF, r.t.,
quant; (b) CDI, K2CO3, DMF, 90 °C, 76%; (c) POCl3, 100 °C, quant; (d)
KOH, H2O, 105 °C; (e) DIPEA, MeCN, 4-R-substituted piperazine, 80 °C;
(f) LAH, THF, r.t., 13–29% over 3 steps. HATU = O-(7-azabenzotriazol-1-
yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; CDI = 1,1′-car-
bonyldiimidazole.
N
N
N
O
N
N
N
lithium aluminium hydride reduction afforded the desired
(hydroxymethyl)quinazolinones 11a–f (Scheme 2).
N
N
O
N
O
N
Although material was initially produced in this manner
(Scheme 2), the yields were low, especially the reduction
step. The solubility of the acid intermediates 9 and 10 was
also poor, making isolation difficult. To avoid the final LAH
reduction whilst improving the solubility of our intermedi-
ates in organic solvents, we devised an expedient and reli-
able route to a protected 8-(hydroxymethyl)quinazolinone
16 from a cheap and readily available anthranilic acid 12
(Scheme 3). Multi-gram quantities of 12 were stocked in-
house which would allow for scale-up as the project pro-
gressed.
Anthranilic acid 12 was converted into the benzylic bro-
mide 15 using standard procedures (Scheme 3).2 Nucleo-
philic substitution and simultaneous hydrolysis of the 4-
chloro motif with CsOAc afforded the acetylated precursor
16. This latter transformation was initially conducted with
KOAc, but yields were variable. Investigation into this step
revealed that by switching to CsOAc in NMP/H2O, yields
were much improved and the reaction was less capricious.
The results of this study are shown in Table 1. Acetate 16
N
N
O
S
O
O
O
O
Cl
Scheme 3 Reagents and conditions: (a) urea, NMP, 150 °C, 74%; (b) POCl3,
100 °C, 79%; (c) NBS, AIBN, EtOAc, 65 °C, 78%; (d) CsOAc, NMP/H2O,
r.t., 70%; (e) Pd(PPh3)4, Cs2CO3, ArX, dioxane, H2O, 100 °C; (f) K2CO3,
MeOH, 50 °C, 30–98% over 2 steps; (g) DIPEA, DMF, 100 °C, HNR2.
was then manipulated to provide either 2-amino- or 2-aryl-
substituted quinazolinones 17 or 18 via chloride displace-
ment by using a range of amines or Suzuki–Miyaura cou-
pling, respectively, as shown in Scheme 3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

D
J. L. Holmes et al.
Paper
Synthesis
Table 1 Conditions for Conversion of 15 into 16
known examples,10–12 we were unable to find any examples
of 8-hydroxymethyl-substituted azaquinazolinones in the
literature.
Base
KOAc
Solvent
Temp (°C)
Time (h)
Conv. (%)a
Our approach to the synthesis of the desired
MeCN
acetone
DMF
70
70
50
25
50
25
50
50
50
50
2
2
30
azaquinazolinones followed
a
similar route to our
KOAc
5
quinazolinone synthesis. We converted the readily available
pyridine 21, which was in plentiful supply in our stores,
into our desired azaquinolinones 27 in nine steps as shown
in Scheme 5.
KOAc
2
40
KOAc
DMF
24
2
20
KOAc
NMP
50
KOAc
NMP/H2O
NMP
16
2
50
O
O
O
NaOAc
CsOAc
CsOAc
CsOAc
no product
b)
a)
O
OH
NH2
NH2
NH2
NH2
DMF
2
50
50
70
N
N
N
NMP
2
NH2
23
Cl
NMP/H2O
4
21
22
a As measured by peak area (UPLC).
O
N
NH
NH2
c)
d)
N
N
A wide range of non-aromatic nitrogen nucleophiles
from azetidines through to diazepanes were introduced in
this manner. We were however, unable to introduce less nu-
cleophilic five-membered heterocycles such as imidazoles
by using these conditions. We explored protecting the free
quinazolinone NH group by using a tosyl protecting group
and found, to our delight, that it was now possible to pre-
pare the desired imidazoles 20 (Scheme 4). Acetate depro-
tection by using standard basic conditions furnished the
novel 8-(hydroxymethyl)quinazolinone products.
NH2
24
25
Br
O
O
e), f)
g)–i)
Br
NH
NH
N
N
N
N
AcO
Ar
HO
26
27a,b
Ar =
O
N
O
S
O
N
a), b)
N
O
N
O
N
N
N
N
Cl
N
N
N
AcO
HO
Ar
19
20a,b
Scheme 5 Reagents and conditions: (a) NH4Cl, HATU, DMF, 87%; (b)
concd HCl, H2O2, r.t., 27%; (c) Pd(OAc)2, RuPhos, K2CO3, B(OMe)3,
Ar =
toluene, 100 °C, 86%; (d) Ga(OTf)3 (10 mol%), 4-bromobenzaldehyde,
DMSO, 85 °C, then DDQ, r.t., 66%; (e) mCPBA, CH2Cl2, 65%; (f) Ac2O,
120 °C, 30%; (g) [Pd(dppf)2Cl2]·CH2Cl2, KOAc, bis(pinacolato)diboron,
DME, 85 °C, 85%; (h) ArBr, [Pd(dtbpf)Cl2], K3PO4, DMF/H2O; (i) K2CO3,
MeOH, 65–74% over 2 steps.
Scheme 4 Reagents and conditions: (a) 4-aryl-1H-imidazole, DIPEA,
DMA, sodium methanesulfinate, 80 °C; (b) K2CO3, MeOH, 50 °C, 7–13%
over 2 steps.
Amidation and chlorination13 provided the 2-chloropy-
ridine 23, which was converted into the corresponding 2-
methylpyridine 24 by Suzuki–Miyaura cross coupling
(Scheme 5). Condensation of this intermediate with bromo-
benzaldehyde in the presence of catalytic gallium triflate14
provided the azaquinazolinone core 25. We initially at-
tempted this reaction by using copper(II) chloride in DMSO,
as this had been successful in the synthesis of the
quinazolinone series. Unfortunately, although we did ob-
serve the desired product, we also observed undesired side
products which rendered purification difficult. The combi-
With the 8-hydroxymethylquinazolin-4-ones in hand,
our attention turned to analogues of alternative fused het-
erocyclic cores. We next explored the synthesis of pyri-
do[3,4-d]pyrimidin-4(3H)-ones or ‘azaquinazolinones’. Lit-
erature syntheses of pyrido[3,4-d]pyrimidin-4(3H)-ones or
azaquinazolinones typically use similar approaches to
those used for quinazolinones, e.g. condensation with aza-
anthranilates10 or copper-catalysed coupling of a urea with
a bromoisonicotinic acid.11 Despite a significant number of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

E
J. L. Holmes et al.
Paper
Synthesis
nation of gallium triflate with DDQ in DMSO furnished the
desired azaquinazolinone core in higher yield. Bromination
using NBS and AIBN, as used in the synthesis of the
quinazolinones, failed to give appreciable quantities of the
desired benzylic bromide. The reaction proceeded very
slowly, and when heated further, yielded mainly the dibro-
minated product. Installation of the 8-hydroxymethyl moi-
ety to give 26 was achieved instead via the Boekelheide re-
action.15 Functionalisation of the pendant aromatic ring
was realised through borylation and Suzuki–Miyaura cross
coupling with several aryl halides. Final deprotection, as
before, furnished our examples of 8-(hydroxymeth-
yl)azaquinazolinones 27.
O
O
O
b), c)
a)
OH
N
OH
e)
28
29
30
N
Cl
Cl
d)
N
N
Cl
Cl
32
Br
31
O
O
We next turned to the synthesis of 8-(hydroxymeth-
yl)isoquinolin-1(2H)-one derivatives. Many known synthe-
ses of isoquinolinones involve lithiation of an ortho-methyl-
phenylamide.16 Alternate syntheses include a recent rhodi-
f), g)
h)–i)
N
NH
Cl
Ar
um-catalysed C–H activation with vinyl esters.17
A
33
HO
HO
34a,b
rhodium-catalysed approach has been used to make MIDA
boronates of isoquinolinones,18 which has led to a variety of
substituted isoquinolinones. However, to our knowledge, no
5-hydroxymethyl-substituted analogues have appeared in
the literature.
Ar =
N
O
N
N
Our approach to the synthesis was a modification of a
literature strategy which involved the condensation of an
acid with a benzylic nitrile.19 The starting material for our
synthesis was 4-methylindenone (28) which was converted
to isoquinolinone 34 in ten steps (Scheme 6). The indenone
28 was converted into the corresponding keto oxime 29,
which was hydrolysed by using sodium hydroxide. Subse-
quent dehydration of the oxime with tosyl chloride fur-
nished benzylic nitrile 30. Cyclisation and chlorination us-
ing a combination of PCl5 and POCl3 provided the methyl-
isoquinoline 31. With this material in hand, we were able to
brominate the benzylic position as before, and displace the
bromide in 32 with acetate by using the CsOAc conditions
developed for the quinazolinone synthesis (Scheme 3). Un-
fortunately, concomitant hydrolysis of the 2-chloro func-
tionality did not occur in this series. So the product of
acetylation was subsequently treated with NaOMe in MeOH
to give compound 33. Diversity was then introduced at the
3-position by using Suzuki–Miyaura cross coupling. Final
deprotection by using HCl at 80 °C successfully delivered
the desired 5-(hydroxymethyl)isoquinolines 34 (Scheme 6).
Our initial approach to the synthesis of 8-(hy-
droxymethyl)chromen-4-ones (Scheme 7) followed a strat-
egy similar to that used for the quinazolinones and isoquin-
olines. Benzylic bromination of a key intermediate 35 with
NBS and AIBN was expected to provide us with a substrate
that could be further manipulated to yield a diverse range
of (hydroxymethyl)chromenones. Unfortunately, bromina-
tion was capricious and frequently led to a mixture of prod-
ucts which became even more problematic on gram scales.
NH
Scheme 6 Reagents and conditions: (a) n-butyl nitrite, concd HCl, r.t.,
70%; (b) 2 M NaOH, 50 °C; (c) TsCl, 80 °C, 99% over 2 steps; (d) PCl5,
POCl3, 0 °C to r.t., 70%; (e) NBS, AIBN, EtOAc, reflux, 75%; (f) CsOAc (7
equiv), H2O, NMP, 60 °C; (g) NaOMe in MeOH, 60 °C, 75% over 2 steps;
(h) [Pd(dtbpf)Cl2], K3PO4, dioxane, H2O, ArB(OH)2, 80 °C; (i) 6 M HCl,
80 °C, 22–45%.
Although it was possible to isolate the desired chromenone
36, the poor yield meant that a more reliable route was
sought.
An alternative approach was found and we were able to
produce a number of chromenones in an eight-step se-
quence from the commercially available phenol 39 (Scheme
8).20 Bromination of 40 was carried out with NBS and AIBN
as before. The bromine was displaced with methoxide to
give the substrate for the condensation reaction to provide
diketone 42. Cyclisation to yield the chromenone core was
effected in AcOH with HBr and proceeded in two stages.
Monitoring of the reaction by using LCMS revealed that dis-
placement of the pendant methoxide with bromine oc-
curred at 80 °C; an increase in temperature to 100 °C in-
duced cyclisation. The bromine was subsequently displaced
with acetate to afford chromenone 43. As in previous exam-
ples, the final steps involved Suzuki–Miyaura cross cou-
pling or Buchwald coupling and deprotection, yielding 44 in
yields ranging from 22–42% over the two steps.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

F
J. L. Holmes et al.
Paper
Synthesis
O
O
O
O
Br
+
O
O
Br
Br
Br
Br
Br
37
36
35
O
O
Br
+
O
O
Br
Br
38
35
Scheme 7 Reagents and conditions: NBS, AIBN, EtOAc, reflux.
Despite numerous examples of pyrrolo[2,1-f][1,2,4]tri-
azine-4(3H)-one cores in the literature,21,22 we found no ex-
amples of 7-hydroxymethyl-substituted ‘triazinones’. Typi-
cal literature22 approaches to the triazinone core involve
base cyclisation of an amidopyrroloamide. We employed
similar chemistry using aminopyrrole 45 as the starting
material to form the triazinone 47 in two steps (Scheme 9).2
Key precursor 50 was easily accessed in three further
steps.2
Accela/CTC/PDA with Acquity 50 × 2.1 C18 CSH 1.7 μm columns at 40
°C. NMR spectra were obtained on Bruker AV400, Drx500 and AV700
MHz systems using DMSO-d6, CDCl3 or CD3OD and are reported rela-
tive to a protiated solvent signal or tetramethylsilane.
O
O
O
O
b)
a)
O
O
O
OH
O
The final methoxy-deprotection step was initially con-
ducted by using dilute acid and gentle heating, but this led
to elimination of the hydroxy group and a variety of prod-
ucts via suspected intermediate 51. To avoid formation of
this unwanted byproduct, an alternate deprotection proto-
col, using sodium thiomethoxide in DMF at a temperature
between 50 and 70 °C (depending on the compound), pro-
vided the desired product 52 in good yield (Scheme 9).
A range of novel hydroxymethyl-substituted fused het-
erocycles has been prepared as part of a medicinal chemis-
try programme. Despite many of these cores being preva-
lent in the literature, there are few examples, if any, of hy-
droxymethyl-substituted analogues. We have successfully
developed routes to access such compounds and, using this
chemistry, we have been able to prepare an extensive num-
ber of novel analogues.
Br
39
40
41
O
O
O
c), d)
e), f)
Br
O
O
O
Br
AcO
42
43
O
g), h)
O
R
HO
44a–c
R =
N
N
N
All materials were sourced from commercial suppliers and used as
provided. Reaction progress was monitored by Waters Aquity UPLC
with Waters 3100 Mass detection or TLC using glass plates pre-coated
with 0.25 mm 300–400 mesh silica gel impregnated with a fluores-
cent indicator (254 nm). Visualisation was by exposure to UV light.
Flash column chromatography was performed using pre-loaded Sili-
cycle columns containing silica gel (60 Å pore size, standard grade)
and an Isco Combi-Flash Companion. Reverse phase chromatography
was performed using pre-loaded RediSep Rf cartridges containing
C18 silica and a Teledyne Isco Combi-Flash Rf. Details of preparative
HPLC purification are contained within the experimental information
where relevant. The HRMS was performed using a Thermo LTQ-FT/
N
N
NH
NH
N
Scheme 8 Reagents and conditions: (a) MeI, K2CO3, acetone, reflux,
57%; (b) AIBN, NBS, MeCN, 80 °C, 80%; (c) NaOMe, MeOH, MeCN, 65
°C, quant; (d) 4-bromoacetophenone, NaH, dioxane, 80 °C, 41%; (e)
HBr, AcOH, 80 °C, 1 h, then 100 °C, 2 h, quant; (f) NaOAc, DMF, 100 °C,
87%; (g) ArB(OH)2, Pd(PPh3)4, Cs2CO3, dioxane, 85 °C or Pd2(dba)3,
BINAP, Nat-OBu, 110 °C, toluene; (h) MeOH, K2CO3, 50 °C, 13–42% over
2 steps.
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G
J. L. Holmes et al.
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Synthesis
ture stirred for 1 hour. The mixture was filtered and the solid collect-
ed and dried to provide the desired product as a light brown/beige
powder as the HCl salt. This material was used with no further purifi-
cation.
O
O
b)
N
N
N
a)
O
NH2
NH
O
NH
N
NH2
Lithium aluminum hydride (5.69 mL, 5.69 mmol) (1 M solution in
THF) was added dropwise to the acid (1.90 mmol) in THF (10 mL) at
ambient temperature under nitrogen. The resulting suspension was
stirred at 50 °C for 3 hours, cooled to ambient temperature and
quenched by the addition of sat. aqueous ammonium chloride (100
mL). The mixture was extracted into EtOAc (3 × 150 mL) and the com-
bined organic extracts were dried over MgSO4, filtered and concen-
trated to provide the crude product as a yellow gum. The crude prod-
uct was purified by preparative HPLC (Waters XBridge Prep C18 OBD
column, 5μ silica, 50 mm diameter, 100 mm length), using decreas-
ingly polar mixtures of water (containing 1% NH3) and MeCN as elu-
ents. Pure fractions were evaporated to dryness to afford the desired
compounds.
NH2
45
46
47
Br
Br
Cl
HO
HO
O
N
N
N
c), d)
e)
N
N
N
48
49
Br
Br
8-(Hydroxymethyl)-2-[4-(2-hydroxyphenyl)piperazin-1-
yl]quinazolin-4(3H)-one (11a)
O
N+
HO
The above method was used to provide the target 11a as a colourless
solid; yield: 89 mg (62%).
O
f), g)
h)
N
N
various
products
N
1H NMR (400 MHz, DMSO-d6): δ = 2.98–3.05 (m, 4 H), 3.75–3.82 (m, 4
H), 4.80 (d, J = 5.3 Hz, 2 H), 5.07 (t, J = 5.3 Hz, 1 H), 6.73–6.78 (m, 1 H),
6.92 (dd, J = 1.3, 7.8 Hz, 1 H), 7.14–7.22 (m, 1 H), 7.70 (d, J = 7.1 Hz, 1
H), 7.78–7.87 (m, 1 H), 9.02 (s, 1 H), 11.43 (br s, 1 H).
13C NMR (176 MHz, DMSO-d6): δ = 44.99, 49.73, 59.15, 115.60,
116.35, 118.89, 119.39, 121.59, 123.20, 123.85, 130.85, 136.45,
139.38, 139.48, 147.15, 150.15, 163.14.
N
N
51
Ar
n
50
Ar
i)
HO
O
HRMS: m/z [M
+
H]+ calcd for C19H21N4O3: 353.16082; found
N
N
353.16077.
N
Quinazolin-4(3H)-ones 17a–c; General Procedure
Pd(PPh3)4 (139 mg, 0.12 mmol) was added to a degassed mixture of
(2-chloro-4-oxo-3,4-dihydroquinazolin-8-yl)methyl acetate (16; 149
mg, 0.59 mmol), boronic acid/ester ArX (0.65 mmol, 1.1 equiv) and
Cs2CO3 (388 mg, 1.19 mmol) in dioxane (4 mL) and H2O (3 mL). The
resulting suspension was degassed and stirred at 100 °C for 3 hours
under a nitrogen atmosphere. The reaction mixture was cooled to
50 °C and K2CO3 (164 mg, 1.19 mmol) and MeOH (3 mL) were added.
The mixture was stirred at 50 °C for 2 hours and then allowed to cool
to ambient temperature. The reaction mixture was filtered and the
filtrate was concentrated to provide the crude product. Purification
by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica,
50 mm diameter, 100 mm length) using decreasingly polar mixtures
of H2O (containing 1% NH3) and MeCN as eluents provided the desired
compounds.
52a,b
Ar
Ar =
N
N
N
N
NH
N
Scheme 9 Reagents and conditions: (a) Et3N, 4-BrC6H4COCl, MeCN, r.t.,
89%; (b) NH4OH, 100 °C, 53%; (c) POCl3, DMF, 95 °C; (d) NaBH4, THF, 0
°C, 85%; (e) NaOMe, MeOH, 60 °C, 98%; (f) [Pd(dppf)2Cl2], KOAc,
bis(pinacolato)diboron, dioxane; (g) ArBr, [Pd(dtbpf)Cl2], K3PO4, DMF,
105 °C; (h) 2–6 M HCl or TMSCl; (i) NaSMe, DMF, 50–70 °C, 29–64%.
8-(Hydroxymethyl)-2-[4-(1-methylpiperidin-4-yloxy)phe-
nyl]quinazolin-4(3H)-one (17a)
The above method was used to provide the target 17a as a colourless
solid; yield: 116 mg (54%).
Quinazolin-4(3H)-ones 11a–f; General Procedure
1H NMR (400 MHz, CDCl3): δ = 1.91 (dtd, J = 3.6, 8.0, 12.0 Hz, 2 H),
2.00–2.11 (m, 2 H), 2.29–2.39 (m, 5 H), 2.67–2.76 (m, 2 H), 4.37 (br s,
1 H), 4.42–4.51 (m, 1 H), 5.09 (s, 2 H), 7.07 (d, J = 8.9 Hz, 2 H), 7.42 (t,
J = 8.0 Hz, 1 H), 7.68 (d, J = 6.3 Hz, 1 H), 8.03 (t, J = 8.9 Hz, 2 H), 8.23
(dd, J = 1.4, 8.0 Hz, 1 H), 10.21 (br s, 1 H).
13C NMR (176 MHz, DMSO-d6): δ = 30.42, 45.73, 52.26, 58.89, 72.05,
115.48, 120.11, 123.84, 124.77, 125.60, 129.50, 131.28, 139.17,
145.68, 150.93, 159.85, 162.39.
2-Chloro-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (634 mg,
2.82 mmol) was added to amine (2.82 mmol) and DIPEA (0.64 mL,
3.67 mmol) in MeCN. The resulting suspension was heated at 80 °C
for 7 hours during which time further additions of DIPEA and solvent
were made to help drive the reaction to completion. The reaction
mixture was concentrated and the resulting residue acidified with
2 M HCl in dioxane (25 mL). MeOH (10 mL) was added and the mix-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

H
J. L. Holmes et al.
Paper
Synthesis
HRMS: m/z [M
366.18127.
+
H]+ calcd for C21H24N3O3: 366.18122; found
Further experimental details and compound data are available in the
Supporting Information.
Quinazolin-4(3H)-ones 18a–k; General Procedure
Acknowledgments
DIPEA (0.30 mL, 1.70 mmol) was added in one portion to (2-chloro-4-
oxo-3,4-dihydroquinazolin-8-yl)methyl acetate (16; 101 mg, 0.40
mmol) and amine HNR2 (0.40 mmol) in DMF (3 mL). The resulting
solution was stirred at 100 °C for 30–60 minutes. K2CO3 (273 mg, 1.98
mmol) and MeOH (5 mL) were added and the mixture was stirred
overnight at 50 °C. The crude product was purified by preparative
HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diame-
ter, 100 mm length) using decreasingly polar mixtures of H2O (con-
taining 1% NH3) and MeCN as eluents. Fractions containing the de-
sired compound were evaporated to dryness to afford the desired
products.
We would like to thank Rebecca Burton, Gemma Mayers, Caroline Mc-
Millan, Nia Lock, Howard Beeley and Paul Davey for purification, NMR
and mass spectrometry assistance.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561355.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
8-(Hydroxymethyl)-2-[3-(4-methoxyphenyl)azetidin-1-
yl]quinazolin-4(3H)-one (18a)
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1H NMR (500 MHz, DMSO-d6): δ = 3.75 (s, 3 H), 3.81–3.95 (m, 1 H),
4.03 (dd, J = 6.4, 8.6 Hz, 2 H), 4.48 (t, J = 8.6, 2 H), 4.78 (s, 2 H), 6.87–
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+
H]+ calcd for C19H20N3O3: 338.14992; found
338.14972.
Quinazolin-4(3H)-ones 20a,b; General Procedure
DIPEA (0.15 mL, 0.88 mmol) was added to the imidazole (0.29 mmol,
1 equiv) in DMA (6 mL) and the mixture was stirred for 10 minutes.
(2-Chloro-4-oxo-3-tosyl-3,4-dihydroquinazolin-8-yl)methyl acetate
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OBD column, 5μ silica, 19 mm diameter, 100 mm length) using de-
creasingly polar mixtures of H2O (containing 1% NH3) and MeCN as
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+
H]+ calcd for C18H15N4O2: 319.11895; found
319.11893.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

I
J. L. Holmes et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I