New synthesis of aryl and heteroaryl N-acylureas via microwave-assisted palladium-catalysed carbonylation

Article abstract of DOI:10.1002/adsc.201000395

A new, practical synthesis of aryl and heteroaryl N-acylureas has been developed via palladium-catalysed carbonylation of aryl or heteroaryl halides in the presence of urea nucleophiles. A range of reactions illustrating the wide scope of this reaction was carried out under microwave irradiation, using either carbon monoxide gas in a vessel equipped with a gas inlet adapter, or molybdenum hexacarbonyl as the carbon monoxide source in standard microwave vials. The reactions proceeded in good to excellent yields. To illustrate the usefulness of this method a one-step synthesis of the important insecticide diflubenzuron is reported.

Full text of DOI:10.1002/adsc.201000395

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DOI: 10.1002/adsc.201000395
New Synthesis of Aryl and Heteroaryl N-Acylureas via
Microwave-Assisted Palladium-Catalysed Carbonylation
David Liptrot,a Lilian Alcaraz,a and Bryan Robertsa,*
a
Department of Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics, LE11 5RH, United
Kingdom
Fax : (+44)-1509-645-571; phone: (+44)-1509-644-542; e-mail: bryan.roberts@astrazeneca.com
Received: May 19, 2010; Published online: August 20, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000395.
Abstract: A new, practical synthesis of aryl and het-
eroaryl N-acylureas has been developed via palladi-
um-catalysed carbonylation of aryl or heteroaryl
halides in the presence of urea nucleophiles. A
range of reactions illustrating the wide scope of this
reaction was carried out under microwave irradia-
tion, using either carbon monoxide gas in a vessel
equipped with a gas inlet adapter, or molybdenum
hexacarbonyl as the carbon monoxide source in
standard microwave vials. The reactions proceeded
in good to excellent yields. To illustrate the useful-
ness of this method a one-step synthesis of the im-
portant insecticide diflubenzuron is reported.
often make these methods environmentally undesira-
ble. Moreover, the scope of these transformations is
often limited by the availability and stability of the re-
quired carboxylic acids which can, in some cases, be
difficult to handle or are prone to facile decarboxyla-
tion.
Continuing our work in the area of palladium-cata-
lysed carbonylation,[11] we report the first synthesis of
aryl and heteroaryl N-acylureas from aryl and hetero-
aryl halides via microwave-assisted, palladium-cata-
lysed carbonylation with urea nucleophiles using
either carbon monoxide gas in pre-pressurised micro-
wave vials or Mo(CO)6 in standard microwave vials
(Scheme 1).
Keywords: N-acylureas; carbonylation; homoge-
nous catalysis; microwave heating; palladium; ureas
Heck and co-workers[12] first reported the palladi-
um-catalysed reaction of carbon monoxide, aryl hal-
ides, and alcohols or amines to give the respective
benzoate and benzamide products. Since then the
scope of the reaction has been developed such that a
wide range of nucleophiles can be used, enabling the
The N-acylurea moiety is an important functional efficient synthesis of numerous carbonyl com-
group in the fields of medicinal chemistry[1] and phy- pounds.[13] We began by examining the reaction
tochemistry.[2] Some N-acylureas are known to possess shown in Table 1. Using bromobenzene as a model
analgesic, anti-inflammatory, anti-fungal, and anthel- aryl halide for reactions with substituted urea 1a, tri-
mintic properties.[3] Moreover, a number of benzoylur-
eas show promising anti-tumour properties[4] and
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
some have found commercial use in agriculture as in- monoxide pressure was fixed at 65 psi and an optimi-
secticides.[5]
sation of the reaction was carried out in the micro-
To date N-acylureas are classically prepared by acy- wave system with respect to time and temperature. A
lating ureas with suitably activated carboxylic acids temperature of 1008C and reaction time of 4 h
such as acid chlorides, anhydrides and carbodi-
ACHTUNGTRENNUNG
imides.[6] The condensation of amines with acyl iso-
cyanates[7] or S-allyl N-acylmonothiocarbamates[8] is
also known to give N-acylureas. Other routes starting
from ureas involve acylation with alkenyl esters[9] and
boronic acid-catalysed condensation with acids.[10]
When using these routes to synthesise N-acylureas the
yields are often variable and the use of stoichiometric
Scheme 1. Synthesis of aryl and heteroaryl N-acylureas via
amounts of coupling agents or hazardous isocyanates microwave-assisted palladium-catalysed carbonylation.
Adv. Synth. Catal. 2010, 352, 2183 – 2188
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David Liptrot et al.
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catalysts.[14] However, an activated aryl chloride did
provide a resonable yield of product, albeit with a
longer reaction time (Table 1, entry 22). 2,6-Disubsti-
tuted aryl bromides (Table 1, entries 19 and 20) were
not converted using our protocol. We believe the
modest yields obtained with ortho-substituted and no
reaction with 2,6-disubstituted aryl bromides are due
to steric hindrance around the intermediate acyl-pal-
ladium species. It is worth noting that increasing reac-
tion temperature or reaction times gave no improve-
ment in yields for these substrates. Guided by our
Table 1. Pd-catalysed carbonylation of urea 1a with aryl hal-
ides using method A.[a]
À
Entry
Ar X
Yield [%][b]
1
2
3
4
5
6
7
8
C6H5Br
3-Cl-C6H4Br
74
76
55
69
60
53
72
50
60
74
85
57
30
46
45
50
52
65
0
previous experience and reports in the literature,[15]
a
3-MeO-C6H4Br
3-CF3-C6H4Br
3-NC-C6H4Br
3-Me-C6H4Br
4-Cl-C6H4Br
4-MeO-C6H4Br
4-CF3-C6H4Br
4-NC-C6H4Br
4-Me2NC(O)-C6H4Br
4-t-Bu-C6H4Br
2-Cl-C6H4Br
second optimisation on these difficult substrates was
carried out, in one case using the same reagents but
with the addition of DMAP, with these conditions a
reaction time of 7 h was optimal (method B). In a
second case we used PdACTHNUTRGNE(NUG OAc)2/Xantphos reported by
9
Buchwald as a useful carbonylation catalyst,[16] with
these conditions a reaction time of 4 h was optimal
(method C). Gratifyingly both of these new reaction
conditions provided the ortho-substituted products
with much improved yields (Table 2 entries 1-4). For
method B we postulate that DMAP reacts with the
intermediate acyl-palladium species thus reducing
steric effects and allowing the urea nucleophile to
react more readily. Application of method B to other
aryl bromides (Table 2, entry 5) also gave an in-
creased yield, in comparison to Table 1, entry 8. Inter-
estingly we saw differences when these methods were
applied to 2,6-disubstituted aryl bromides. Using
method B, no products were isolated whereas with
10
11
12
13
14
15
16
17
18
19
20
21
22
2-F-C6H4Br
2-MeO-C6H4Br
2-c-Hex-C6H4Br
2-Me-C6H5Br
2-naphthyl-Br
2,6-F2-C6H3Br
2,6-Me2-C6H3Br
4-MeO-C6H4Cl
4-NC-C6H4Cl
0
0
68[c]
[a]
Method A: aryl halide (1 equiv.), urea (1a, 2 equiv.), 1,4-
dioxane (0.3M), PdCl2A(dppf)·CH2Cl2 (0.1 equiv.), triethyl-
CTHUNGTRENNUNG
amine (3 equiv.), CO 65 psi, 1008C, 4 h.
Isolated and purified products.
20 h.
[b]
[c]
Table 2. Pd-catalysed carbonylation of urea 1a with aryl bro-
mides using methods B and C.
(method A) gave complete conversion of bromoben-
zene and afforded the desired acyl urea in 74% yield
(Table 1, entry 1).
To establish the scope of this transformation, the
reaction conditions were applied to a range of aryl
halides (Table 1). A variety of functional groups were
tolerated and both electron-donating and electron-
withdrawing groups on the aryl bromide gave moder-
ate to good isolated yields. meta- (Table 1, entries 2–
6) and para-substituted (Table 1, entries 7–12) systems
performed well in the reaction. In the preceding ex-
amples the complete chemoselectivity observed for
bromine over chlorine is worth noting (Table 1, en-
tries 2 and 7). However, ortho-substituted aryl bro-
mides, were not as well tolerated in the reaction
(Table 1, entries 13–17) giving only modest yields of
product. Attempts to use unactivated aryl chlorides
met with no success, just recovery of the starting
halide (Table 1, entry 21). This is not too suprising
since carbonylation of aryl chlorides usually requires
more forcing conditions, and/or alternative palladium
À
Entry
Ar Br
Yield [%][a]
Method B[b]
Method C[c]
1
2
3
4
5
6
7
2-Cl-C6H4Br
70
90
90
89
82
0
not done
not done
70
70
not done
50
4
2-MeO-C6H4Br
2-Me-C6H4Br
2-F-C6H4Br
4-MeO-C6H4Br
2,6-F2-C6H3Br
2,6-Me2-C6H3Br
0
[a]
Isolated and purified product.
Method B: aryl halide (1 equiv.), urea (1a, 2 equiv.), 1,4-
dioxane (0.3M), Pd(dppf) (0.1 equiv.), triethylamine
(3 equiv.), DMAP (1 equiv.), CO 65 psi, 1008C, 7 h.
Method C: aryl halide (1 equiv.), urea (1a, 2 equiv.), 1,4-
[b]
AHCTUNGTRENNUNG
[c]
dioxane (0.3M), PdACTHNUTRGNE(UGN OAc)2 (0.1 equiv.), Xantphos
(0.15 equiv.), triethylamine (1 equiv.), CO 65 psi, 1008C,
4 h.
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New Synthesis of Aryl and Heteroaryl N-Acylureas
method C, a moderate yield of product was isolated without further optimisation. As shown in Table 3 the
from 2,6-difluorobromobenzene (Table 2 entries 6 and methodology is applicable to a wide range of hetero-
7).
cyles such as 5-membered (Table 3, entries 1–3), 6-
Having established a wide scope with aryl bro- membered (Table 3, entries 4 and 5) and fused sys-
mides, application of the methods to heteroaryl hal- tems (Table 3, entries 6–9). However, the one hetero-
ides was performed (Table 3). Gratifyingly the condi- aryl chloride studied only achieved modest conversion
tions optimised for aryl bromides (method A) provid- after an extended time. (Table 3, entry 10).
ed moderate to good yields of heteroaryl N-acylureas
Next we turned our attention to the urea partner in
these carbonylation reactions. A selection of ureas
wase subjected to our initial reaction conditions
(method A), using bromobenzene as a representative
aryl halide (Table 4).Variations to the dialkylated por-
tion of the urea did not significantly affect the out-
come of the reaction (Table 4, entry 1). A range of
Table 3. Pd-catalysed carbonylation of urea 1a with hetero-
aryl halides using method A.
Table 4. Pd-catalysed carbonylation of substitued ureas with
bromobenzene using method A.
[a]
Isolated and purified product.
20 h.
[b]
[a]
Isolated and purified product.
Adv. Synth. Catal. 2010, 352, 2183 – 2188
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David Liptrot et al.
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monosubstituted alkyl (Table 4, entries 2–4) and
phenyl substrates (Table 4, entry 5) also performed
well. It is worth noting that in all these cases complete
regioselectivity was observed with the reaction taking
place on the least substituted nitrogen. This regiose-
lectivity is possibly due to steric effects around the in-
termediate acyl-palladium species. Exploring the
steric requirements of this reaction further, cyclic
ureas gave moderate yields of product (Table 4, en-
tries 6 and 7). However increasing the urea substitu-
tion further by using an N,N’-disubstituted urea
(Table 4, entry 8) gave a low yield of product repre-
senting a limitation of these conditions.
Scheme 2. Synthesis of the insecticide diflubenzuron.
Guided by our previous experience for overcoming
steric effects on the aryl bromide we synthesised a
The usefulness of this methodology was illustrated
series of N,N’-disubstituted ureas[17] and subjected by a single-step synthesis of the important insecticide
them to the 3 newly developed reaction conditions, diflubenzuron in 45% yield from commercially avail-
using bromobenzene as a representative aryl halide able starting materials (Scheme 2).
(Table 5). When the disubstituted N’-ethyl-N-methyl-
Finally, whilst the methods outlined are simple and
urea was subjected to the 3 reaction conditions we efficient with a wide substrate scope they do require
saw that with method A, regioselectivity was retained, the use of specialised carbonylation equipment which
reaction taking place on the least hindered nitrogen is not available in all laboratories. Furthermore, the
but the yield was poor (Table 5, entry 1). It should be methods are not easily adaptable to parallel synthesis
noted that increasing the reaction time was detrimen- and automation often required in modern medicinal
tal to the yield. Using methods B and C the yield of chemistry laboratories. In order to address these
product was much improved but the regioselectivity issues we investigated the use of a solid source of CO
was lost giving a 4:3 mixture of products in favour of in the palladium-catalysed carbonylation.
the least hindered nitrogen (Table 5, entries 2 and 3).
In recent years a number of CO gas-free carbonyla-
A similar pattern was seen with the N’-propyl-N- tive conditions have been reported using formamides
methyl-disubstituted urea (Table 5 entries 4–6). These or solid metal carbonyls as CO sources.[18] The palla-
results suggest that method B and method C lead to a dium-catalysed Mo(CO)6-mediated carbonylative cou-
less sterically demanding intermediate acyl-palladium pling of aryl and heteroaryl halides with a variety of
species when compared with method A. Interestingly nucleophiles under microwave-assisted conditions is
when a monosubstituted urea was subjected to the 3 now well established in the literature and ideally
reaction conditions, the yields of isolated product suited to small-scale laboratory reactions, parallel syn-
were consistent and there was no change in regiose- thesis and semi-automation.[19]
lectivity with the reaction taking place exclusively at
the unsubstituted position (Table 5, entries 7–9).
We started our optimisation of the reaction using
conditions reported recently for the synthesis of aryl
and heteroaryl acylsulfonamides.[20] Using bromoben-
zene as a model aryl halide, for reactions with urea
1a, DBU as base, 1,4-dioxane as solvent, Mo(CO)6, as
Table 5. Pd-catalysed carbonylation of substitued ureas with
bromobenzene using methods A, B and C.
CO source, {Pd
N
ACHTUGNRTNE(NUNG o-tolyl)3]2} as the palladium
source and P(t-Bu) CHTUNGTRENNUNG
A
of the reaction was performed in the microwave with
respect to time and temperature. A reaction time of
2.5 h and a temperature of 1008C gave complete con-
version of bromobenzene but only 51% yield of the
desired acylurea. Further optimisation of the reaction
using identical conditions but with the addition of
DMAP (method D) gave an improved yield (Table 6,
entry 1). In order to establish the scope of this trans-
formation, these reaction conditions were applied to a
small set of aryl and heteroaryl bromides (Table 6).
The reaction tolerated a range of functional groups
and both electron-donating and electron-withdrawing
groups gave moderate to excellent isolated yields
(Table 6, entries 2–6).
Entry
Urea
Method Product Ratio N:N’ Yield [%][a]
R1 R2
1
2
3
4
5
6
7
8
9
Et Me
Et Me
Et Me
Pr Me
Pr Me
Pr Me
A
B
C
A
B
C
A
B
C
1:0
4:3
4:3
1:0
1:1
1:1
1:0
1:0
1:0
23
70
50
17
50
70
91
93
70
Me
Me
Me
H
H
H
[a]
Isolated and purified product.
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New Synthesis of Aryl and Heteroaryl N-Acylureas
Table 6. Pd-catalysed Mo(CO)6-mediated carbonylative cou-
pling of urea 1a with aryl and heteroaryl bromides using
method D.
(0.1 mmol). The vial was then charged with anhydrous diox-
ane (3 mL) and triethylamine (3 mmol). The vial was pres-
surised with CO to 65 psi, then purged and refilled, 3 times.
The reaction mixture was then microwave heated to 1008C
for 4 h. with stirring. The reaction mixture was allowed to
cool and excess carbon monoxide vented. The crude mixture
was concentrated under vacuum and neutralised with glacial
acetic acid. This residue was dissolved in methanol, filtered
and purified directly by RPHPLC on a Symmetry column
eluted with a 5:95% gradient of acetonitrile/0.2% aqueous
TFA to yield the corresponding aryl N-acylurea.
Entry
Ar Br
Yield [%][a,b]
À
1
2
3
4
5
6
C6H5Br
83 (51)c
71
55
60
78
3-Cl-C6H4Br
4-MeO-C6H4Br
4-CF3-C6H4Br
2-Me-C6H4Br
3-thienyl-Br
Typical Procedure for Method B
A 10-mL microwave vial was charged with aryl halide
(1 mmol),
urea
(1a,
2 mmol),
PdCl2ACHTUNGTERNNU(G dppf)·CH2Cl2
60
(0.1 mmol) and DMAP (1 mmol). The vial was then charged
with anhydrous dioxane (3 mL) and triethylamine (3 mmol).
The vial was pressurised with CO to 65 psi then purged and
refilled, 3 times. The reaction mixture was then microwave
heated to 1008C for 7 h; with stirring. The reaction mixture
was allowed to cool and excess carbon monoxide vented.
The crude mixture was concentrated under vacuum and
neutralised with glacial acetic acid. This residue was dis-
solved in methanol, filtered and purified directly by
RPHPLC on a Symmetry column eluted with a 5:95% gra-
dient of acetonitrile/0.2% aqueous TFA to yield the corre-
sponding aryl N-acylurea.
[a]
Isolated and purified product.
[b]
Method D: aryl bromide (1 equiv.), urea (1a, 2 equiv.),
1,4-dioxane (0.3M), {Pd(OAc)[P(o-tolyl)3)]2} (0.1 mmol),
(t-Bu)3A[HBF4] (0.2 mmol), DBU (3 equiv.), Mo(CO)6
A
ACHTUNGTRENNUNG
PN
CHTUNGTRENNUNG
(1 equiv.) in 1,4-dioxane (0.3M), 1008C, 2.5 h.
DMAP not added.
[c]
In summary, we have developed a new, efficient
route to aryl and heteroaryl N-acylureas via a palladi-
um-catalysed carbonylation of readily available aryl
or heteroaryl bromides in the presence of urea
nucleoACHTUNGTRENNUNGphiles. The reaction tolerates a wide range of
Typical procedure for Method C
substituted ureas and substituted aryl or heteroaryl
halides. The reactions can be carried out using either
CO gas or Mo(CO)6. We anticipate that this new
method will find broad application for the synthesis
of a wider variety of aryl and heteroaryl N-acylureas
than currently accessible through the known method-
ologies.
A 10-mL microwave vial was charged with aryl halide
(1 mmol), urea (1a, 2 mmol), PdOAc2 (0.1 mmol) and Xant-
phos (0.15 mmol). The vial was then charged with anhydrous
dioxane (3 mL) and triethylamine (3 mmol). The vial was
pressurised with CO to 65 psi then purged and refilled, 3
times. The reaction mixture was then heated to 1008C for
4 h. with stirring. The reaction mixture was allowed to cool
and excess carbon monoxide vented. The crude mixture was
concentrated under vacuum and neutralised with glacial
acetic acid. This residue was dissolved in methanol, filtered
and purified directly by RPHPLC on a Symmetry column
eluted with a 5:95% gradient of acetonitrile/0.2% aqueous
TFA to yield the corresponding aryl N-acylurea.
Experimental Section
General Remarks
For methods A, B and C reactions were performed with a
CEM Discover single mode microwave reactor equipped
with a 300 W source. A 10-mL fibre optic accessory was
equipped with a gas inlet to allow introduction of carbon
monoxide gas to the reaction vessel and each of the reac-
tions was performed in a CEM 10-mL microwave reaction
vial. All temperature measurements were performed with a
fibre optic probe. For method D reactions were performed
with a CEM Discover single mode microwave reactor
equipped with a 300 W source set to 50 W. Each of the reac-
tions was performed in a CEM 10-mL microwave reaction
vial. All temperature measurements were performed with
an infra-red probe.
Typical Procedure for Method D
A 10-mL microwave tube was charged with aryl halide
(1 mmol), urea 1a (2 mmol), Mo(CO)6 (1 mmol), DBU
(3 mmol),
DMAP
(1 mmol),
{PdACHTGNUERTNNU(G OAc)[PACHTUNGTERN(NUNG o-tolyl)3]2}
(0.1 mmol), and P
N
3A[HBF4] (0.2 mmol). 3 mL of 1,4-di-
oxane were then added. The vessel was sealed and micro-
wave heated to 1008C for 2.5 h (“hold time”). The reaction
mixture was allowed to cool, and then taken up in ethyl ace-
tate (40 mL). The resulting solution was washed with satu-
rated NaHCO3 solution (2ꢁ50 mL).The aqueous phase was
acidified with 2N HCl, and extracted with ethyl acetate (2ꢁ
100 mL). The organic phase had the solvent removed under
vacuum and was dissolved in methanol, filtered and purified
by preparative RPHPLC on a Symmetry column eluted with
a 5:95% gradient of acetonitrile/0.2% aqueous TFA to yield
the corresponding aryl N-acylurea.
Typical Procedure for Method A
A 10-mL microwave vial was charged with aryl halide
(1 mmol), urea (1a, 2 mmol) and PdCl2ACTHUNTRGNE(UGN dppf)·CH2Cl2
Adv. Synth. Catal. 2010, 352, 2183 – 2188
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2187

David Liptrot et al.
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[9] B. Seiller, D. Hins, C. Bruneau, P. H. Dixneuf, Tetrahe-
dron 1995, 51, 10901.
[10] T. Maki, K. Ishihara, H. Yamamoto, Synlett 2004, 8,
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[11] B. Roberts, D. Liptrot, L. Alcaraz, Org. Lett. 2010, 12,
1264.
Supporting Information
Experimental procedures and full characterisation (1H and
13C NMR data and spectra, HR-MS and purity analysis) for
all new compounds are provided in the Supporting Informa-
tion.
[12] a) A. Schoenberg, I. Bartoletti, R. F. Heck, J. Org.
Chem. 1974, 39, 3318; b) A. Schoenberg, R. F. Heck, J.
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carbonylation reactions, see: R. Grigg, S. P. Mutton,
Tetrahedron 2010, doi: 10.1016/j.tet.2010.03.090; c) C. F.
Barnard, J. Organometallics 2008, 27, 5402.
Acknowledgements
We are grateful to Sara Griffiths and Richard Evans both of
AstraZeneca Charnwood Chemistry Department for their
expert assistance with MS studies and microwave equipment,
respectively. We also thank Dr. Tim Luker and Dr. Michael J.
Stocks of AstraZeneca Charnwood Chemistry Department
for their comments on the manuscript.
[14] D. A. Watson, X. Fan, S. L. Buchwald, J. Org. Chem.
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[15] L. R. Odell, J. Sꢂvmarker, M. Larhed, Tetrahedron Lett.
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