Molybdenum-mediated synthesis of quinazolin-4(3H)-ones via cyclocarbonylation using microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2011.05.052

A new, efficient and practical synthesis of quinazolin-4(3H)-ones is reported via molybdenum-mediated cyclocarbonylation using microwave irradiation. These methods allow access to a wide range of quinazolin-4(3H)-ones in reasonable yields without the need for gaseous carbon monoxide and palladium catalysts. A range of reactions illustrating the wide scope of this chemistry was carried out and all proceeded in reasonable yields.

Full text of DOI:10.1016/j.tetlet.2011.05.052

Tetrahedron Letters 52 (2011) 3793–3796
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Molybdenum-mediated synthesis of quinazolin-4(3H)-ones via
cyclocarbonylation using microwave irradiation
⇑
Bryan Roberts , David Liptrot, Tim Luker, Michael J. Stocks, Catherine Barber, Nicola Webb,
Robert Dods, Barrie Martin
Department of Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics LE11 5RH, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 February 2011
Revised 4 May 2011
Accepted 13 May 2011
Available online 19 May 2011
A new, efficient and practical synthesis of quinazolin-4(3H)-ones is reported via molybdenum-mediated
cyclocarbonylation using microwave irradiation. These methods allow access to a wide range of quinaz-
olin-4(3H)-ones in reasonable yields without the need for gaseous carbon monoxide and palladium cat-
alysts. A range of reactions illustrating the wide scope of this chemistry was carried out and all proceeded
in reasonable yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Quinazolin-4(3H)-ones
Cyclocarbonylation
Molybdenum-mediated
Microwave chemistry
Carbodiimides
Quinazolin-4(3H)-ones are very important scaffolds in the field
of medicinal chemistry possessing a diverse range of biological and
pharmacological activity.1 For example, compounds containing the
quinazolin-4(3H)-one scaffold have shown promise as antibacte-
rial,2 antiinflammatory,3 anticancer,4 antihypertensive,5 anticon-
vulsant,6 and antimalarial7 agents. There are numerous methods
for the synthesis of quinazolin-4(3H)-ones in the literature,8 how-
ever, the routes often require many steps or harsh reaction condi-
tions resulting in low efficiency. Of direct relevance to the work
presented here are: (1) synthesis of quinazolin-4(3H)-ones by the
reaction of amines with carbodiimides derived from 2-amin-
obenzoates;9 (2) synthesis from 2-iodoanilines with heterocumu-
lenes or from N-(2-iodophenyl)-N’-phenyl-carbodiimides with
nucleophiles via palladium-catalysed cyclocarbonylation.8 Whilst
these methods are efficient, they require long reaction times, and
for cyclocarbonylation, high pressures of carbon monoxide gas,
requiring specialised equipment.
We recently reported molybdenum-mediated carbonylation of
aryl halides with nucleophiles to give carbonyl products under
microwave irradiation.10 Subsequently, Yamane reported a similar
molybdenum-mediated carbamoylation of aryl halides under ther-
mal conditions with sub-stoichiometric amounts of molybdenum
carbonyl complexes.11 Continuing our work in this area, in search
of expedient and efficient methods to synthesise biologically active
molecules, we now report the synthesis of quinazolin-4(3H)-ones
via molybdenum-mediated cyclocarbonylation.
The required carbodiimides, prepared by literature proce-
dures8,9,12 were subjected to the reaction conditions shown in
Table 1. Starting with an equimolar mixture of carbodiimide 1a,
butylamine, Mo(CO)6 and Et4NÁCl in 1,4-dioxane, an optimisation
study of the reaction was performed with respect to time and tem-
perature.13 A reaction time of 2 h at 130 °C gave a single regioisomer
2 in 82% yield (Table 1, entry 1). To check for palladium contamina-
tion, ICP analysis of the reaction mixture was performed and palla-
dium was not detected (limit of detection <9.5 Â 10À9 mol %).
Under these optimised conditions other primary amines, iso-propyl,
benzyl and tert-butyl all performed well and gave 2 as a single
regioisomer (Table 1, entries 2–4). Interestingly, anhydrous ammo-
nia gave exclusively regioisomer 3 in 83% yield (Table 1, entry 5). The
secondary amine, pyrrolidine gave the highest yield of product
under these conditions (Table 1, entry 6). However, morpholine
and piperidine required both higher temperature and extended
reaction time to achieve modest yields (Table 1, entries 7–10). A
low yield was obtained with aniline (Table 1, entry 11), which we
suspect was due to slow formation of the intermediate guanidine
and competing reaction of aniline with the molybdenum carbonyl
complex. Gratifyingly, the yield was improved by the initial in situ
formation of the guanidine prior to addition of Mo(CO)6 and NEt4ÁCl
(Table 1, entry 12). Using Mo(CO)6 alone gave the product in reduced
yield (Table 1, entry 13), although this yield was improved with
further heating (Table 1, entry 14). Carbodiimide 1b also performed
well in the reaction (Table 1, entry 15). However, with benzylamine
⇑
Corresponding author.
E-mail address: bryan.roberts@astrazeneca.com (B. Roberts).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.052

3794
B. Roberts et al. / Tetrahedron Letters 52 (2011) 3793–3796
Table 1
kyl (Table 1, entry 16) an inseparable mixture of products was ob-
tained. We speculate that the regiochemical outcome of the
reaction is determined by a combination of the intermediate guani-
dine geometry and steric effects.
Molybdenum-mediated cyclocarbonylation of carbodiimides 1a–b with various
aminesa
H
N
O
N
O
N
To extend further this methodology to the synthesis of quinaz-
oline-2,4-diones we examined the reactions shown in Table 2. Ini-
tially the required precursor ureas were synthesised and isolated
via literature methods from 2-iodoaniline (route B).15 Subsequent
reactions were performed in one-pot from the precursor isocya-
nates without isolation of the intermediate ureas (route A). Initial
optimisation of the reaction was performed in the microwave
apparatus with respect to time and temperature using a 1:1 mix-
ture of isolated urea 7a, and Mo(CO)5ClÁNEt4 in DMF.16 A time of
5 h and temperature of 150 °C gave the required product in 65%
yield (Table 2, entry 1). Using a 1:1 mixture of Mo(CO)6 and Et4NÁCl
gave a similar result (Table 2, entry 2), whereas using Mo(CO)6
alone gave the product in reduced yield (Table 2, entry 3). These
reactions were repeated with a second urea, substrate 7c, and an
identical trend was seen where Mo(CO)6 alone gave the lowest
yield (Table 2, entries 4–6). Using route B, the amine and precursor
isocyanate were stirred for 15 min in DMF at ambient temperature,
before adding Mo(CO)5ClÁNEt4 or a 1:1 mixture of Mo(CO)6 and
Et4NÁCl. Benzyl-, butyl-, phenyl- and cyclopentyl-amines all gave
reasonable yields of product in this one-pot procedure (Table 2, en-
tries 7–11). It is worth noting that all these reactions can be per-
I
R1
R2
R2
R3
N
N
+
R3
R1
N
C N
[Mo]
N
N
H
R1
R2
1
1a
2
3
, R = Ph
, R1 = Me
1b
Entry
R1
R2
R3
Yieldb (%)
2
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
n-Butyl
iso-Propyl
Benzyl
tert-Butyl
H
Pyrrolidine
Morpholine
Morpholine
Piperidine
Piperidine
Phenyl
Phenyl
n-Butyl
n-Butyl
Pyrrolidine
Benzyl
H
H
H
H
H
82
88
56
52
0
92
10
55c
<5
54c
10
56d
32e
47f
62
41
0
0
0
0
83
H
H
H
H
0
0
0
0
Table 2
Molybdenum-mediated cyclocarbonylation of aryl ureas 7a–g via routes Aa or Bb
H
14g
a
Mo(CO)6 (0.5 mmol) and NEt4ÁCl (0.5 mmol), amine (0.5 mmol), carbodiimide 1
(0.5 mmol) and 1,4-dioxane (4 mL) were microwave heated in a sealed vial to
130 °C for 2 h.
X
X
or
b
X = I, Br
Isolated and purified.
150 °C for 4 h.
Aniline (0.5 mmol) and carbodiimide (0.5 mmol) were sealed and microwave
c
NH2
NCO
d
R1NH2
R1NCO
A
B
heated at 60 °C for 10 min, cooled and Mo(CO)6 (0.5 mmol) and NEt4ÁCl (0.5 mmol)
added, sealed and microwave heated to 130 °C for 2 h.
O
e
[Mo]
DMF
Mo(CO)6 (0.5 mmol), amine (0.5 mmol), carbodiimide 1 (0.5 mmol) and 1,4-
X
R1
O
O
N
dioxane (4 mL) were microwave heated in a sealed vial to 130 °C for 2 h.
R1
f
Mo(CO)6 (0.5 mmol), amine (0.5 mmol), carbodiimide 1 (0.5 mmol) and 1,4-
150 °C
N
H
N
H
N
H
5 h
dioxane (4 mL) were microwave heated in a sealed vial to 150 °C for 4 h.
g
Ratio 2:3(3:1).
7a R1 = Et, X = I,
7b R1 = Bu, X = I,
R
R
1 = Bn, X = I,
= cPent, X = I,
R = Ph, X = I,
R = Bu, X = Br,
1
7c
7e
7d
7f
1
1
7g R1 = Bn, X = Br
the product was isolated as an inseparable mixture of regioisomers
(Table 1, entry 16). HPLC/MS analyses of the reaction mixtures prior
to microwave heating confirmed that the cyclocarbonylation reac-
tion proceeds via the in situ formation of tautomeric guanidines,
4–6 (Scheme 1). It is interesting to note that when R1 is phenyl
and R2 is alkyl the reactions are regioselective. Preferential cyclisa-
tion of the guanidine intermediate occurs from an NH-aryl rather
than an NH-alkyl group. Similar selectivity has been observed by
others in the synthesis of 2-alkylamino-quinazolin-4(3H)-ones9
and in the synthesis of benzimidazoles from mixed aryl/alkyl guan-
idines.14 However, when R1 is phenyl and R2 is H (Table 1, entry 5)
the regiochemistry was reversed and when R1 is methyl and R2 is al-
Entry
Route
Urea
[Mo]-complex
Yield (%)c
1
2
3
4
5
6
7
8
A
A
A
A
A
A
B
B
B
B
B
A
B
B
B
7a
7a
7a
7c
7c
7c
7c
7b
7b
7d
7e
7c
7b
7f
Mo(CO)5ClÁNEt4
65
64
40
58
54
40
55
75
74
53
63
40d
41d
47e
30e
Mo(CO)6 + Et4NÁCl
Mo(CO)6
Mo(CO)5ClÁNEt4
Mo(CO)6 + Et4NÁCl
Mo(CO)6
Mo(CO)5ClÁNEt4
Mo(CO)6 + Et4NÁCl
Mo(CO)5ClÁNEt4
Mo(CO)5ClÁNEt4
Mo(CO)5ClÁNEt4
Mo(CO)5ClÁNEt4
Mo(CO)5ClÁNEt4
Mo(CO)5ClÁNEt4
Mo(CO)5ClÁNEt4
9
10
11
12
13
14
15
R1
N
C
N
R1
N
7g
R1
NH
R1
NH
R2HN
a
R2HN
R2N
[Mo]-complex (1 mmol) or Mo(CO)6 (1 mmol) and NEt4ÁCl (1 mmol), urea 7
(1 mmol) and DMF (3 mL) were microwave heated in a sealed vial to 150 °C for 5 h.
R2NH2
NH
b
N
I
NH
A mixture of arylisocyanate (1 mmol) and amine (1.2 mmol) in DMF (3 mL) was
stirred for 15 min, Mo(CO)5ClÁNEt4 (1 mmol) or Mo(CO)6 (1 mmol) and NEt4ÁCl
I
I
(1 mmol) were added and microwave heated in a sealed vial to 150 °C for 5 h.
I
c
Isolated and purified
Mo(CO)5ClÁNEt4 (0.25 mmol) was used and reactions heated in the microwave
4
5
6
d
for 10 h.
Scheme 1. In situ formation of tautomeric guanidines from carbodiimides 1a and
1b.
e
Heated in the microwave for 10 h.

B. Roberts et al. / Tetrahedron Letters 52 (2011) 3793–3796
3795
Mo(CO)6
Cl.NEt4
Cl-Mo(CO)5.NEt4
I
D
C
I
O
[Mo]
O
[Mo]
R
R
X
N
R
N
N
G
N
H
X
reductive
elimination
CO insertion
N
H
N
H
X
[Mo] = Mo(CO)5
I
or intermediate F
X
[Mo] = Mo(CO)4
R
reductive
elimination
N
H
N
H
oxidative
addition
X = O , NR1
[Mo] = Mo(CO)4
[Mo]
I
[Mo]
R
N
O
[Mo]
I
O
I
R
[Mo]
oxidative
addition
HN
I
Cl
R
N
R
N
N
H
X
N
H
X
CO insertion
N
H
X
N
X
[Mo] = Mo(CO)5
[Mo] = Mo(CO)5
H
E
F
B
A
Scheme 2. Speculative mechanism for the synthesis of quinazolin-4(3H)-ones via molybdenum-mediated cyclocarbonylation.
formed with sub-stoichiometric amounts of Mo(CO)5ClÁNEt4
although the yields of product are reduced and longer reaction
times are required for complete consumption of the starting mate-
rials (Table 2, entries 12 and 13). Further work to identify the opti-
mal ratio of [Mo]-complex and reaction concentration is on-going.
This methodology was applicable to aryl bromides, although the
yields were reduced and longer reaction times were required
(Table 2, entries 14 and 15). In all these reactions we saw no evi-
dence of intramolecular cyclisation via the urea oxygen to give
4H-benzo[d][1,3]oxazin-4-one products which we have observed
when performing this urea cyclisation under standard palladium-
catalysed carbonylation conditions using carbon monoxide gas.17
In both of the outlined reactions, we speculate that urea and
guanidine decomposition is a competing reaction at high tempera-
tures and the lower yields obtained using Mo(CO)6 compared to
the Mo(CO)5ClÁNEt4 complex are due to the fact that the chloride
ligand in Mo(CO)5ClÁNEt4 is more readily displaced by the urea or
guanidine nitrogen than a CO ligand in Mo(CO)6 (see proposed
mechanism discussed below).
The mechanism of these reactions is unclear at present, but one
can speculate on possible pathways (Scheme 2).18 In our previous
work we demonstrated that Et4NÁCl readily displaces a CO ligand
from Mo(CO)6 to give Mo(CO)5ClÁNEt4 and this complex reacts
readily with nitrogen nucleophiles.10 Thus we postulate that inter-
mediate B could be generated in the reaction. This could then
undergo oxidative-addition followed by CO insertion to give D.
Reductive elimination furnishes product G. Alternatively interme-
diate B could undergo CO insertion, to give E, followed by oxida-
tive-addition to give intermediate F. Once again reductive
elimination would give the product.
The methods are ideally suited for parallel synthesis and automa-
tion often required in modern drug discovery. Further develop-
ment of the sub-stoichiometric versions of these reactions is in
progress.
Acknowledgements
We are grateful to Hema Pancholi of AstraZeneca Charnwood
Chemistry Department for assistance with MS studies. We also
thank Tony Shephard of AstraZeneca Charnwood PARD Depart-
ment for palladium analyses.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.052.
References and notes
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4280.
It should be noted that we cannot rule out direct oxidative-
addition to the aryl halide of a molybdenum species followed by
CO insertion to generate an acyl molybdenum species in an analo-
gous manner to palladium-catalysed cyclocarbonylation.8 How-
ever, when we heated
a 1:1 mixture of iodobenzene and
11. Ren, W.; Yamane, M. J. Org. Chem. 2010, 75, 8410.
12. Volonterio, A.; Zanda, M. J. Org. Chem. 2008, 73, 7486.
Mo(CO)6 in 1,4-dioxane in a microwave at 150 °C for 1 h we were
unable to detect any reaction and iodobenzene remained intact.
In summary, we have developed an efficient and practical strat-
egy for the synthesis of quinazolin-4(3H)-ones via molybdenum-
mediated cyclocarbonylation. These methods allow access to a
wide range of quinazolin-4(3H)-ones in reasonable yield without
the need for gaseous carbon monoxide and palladium catalysts.
13. All reactions were performed in a CEM Discover single mode microwave
reactor equipped with a 300 W power source set either to 100 or 150 W. The
reactions were performed in a CEM 10 mL microwave reaction vial and new
rare earth Teflon coated magnetic stir bars were used to stir the reaction
mixtures. All temperature measurements were performed with an IR probe.
Caution: Mo(CO)6 and its derivatives are toxic and these sealed reactions
should only be carried out using specialised microwave equipment.

3796
B. Roberts et al. / Tetrahedron Letters 52 (2011) 3793–3796
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