Solid-phase synthesis of disubstituted N -acylureas from resin-bound ureas and acyl chlorides

Article abstract of DOI:10.1021/co100020b

Acylureas (ureides) are valued for their important biological activities. Whereas cyclic acylureas have frequently been the object of solid-phase chemistry, only few reports have focused on the solid-supported preparation of acyclic representatives. We have prepared different types of acylureas on Rink amide resin in three or four steps. The products are either N-acylated (9, 18), N-acylated-N′-alkylated (10, 19), or N-acylated-N-alkylated (22). Characteristic NMR parameters of isomeric acylureas 10, 19, and 22 are discussed.

Full text of DOI:10.1021/co100020b

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Solid-Phase Synthesis of Disubstituted N-Acylureas from Resin-Bound
Ureas and Acyl Chlorides
Hans-Georg H€acker, Manuela Meusel,† Melanie Aschfalk, and Michael G€utschow*
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany
S Supporting Information
b
ABSTRACT: Acylureas (ureides) are valued for their important
biological activities. Whereas cyclic acylureas have frequently
been the object of solid-phase chemistry, only few reports have
focused on the solid-supported preparation of acyclic representa-
tives. We have prepared different types of acylureas on Rink amide
resin in three or four steps. The products are either N-acylated (9, 18), N-acylated-N0-alkylated (10, 19), or N-acylated-N-alkylated
(22). Characteristic NMR parameters of isomeric acylureas 10, 19, and 22 are discussed.
KEYWORDS: acylureas, Rink amide resin, solid-phase synthesis, trimethylsilyl isocyanate
’ INTRODUCTION
are only a few articles on the solid-phase synthesis of acyclic
acylureas.28,33 Ravn et al. reported on the assembly of di- and
trisubstituted acylureas on Wang resin from Fmoc amino acids,
secondary amines and carboxylic acids in six steps. Resin-bound
carbimidoyl chlorides were formed as key intermediates from
thioureas by the use of diphenylphosphine dichloride. Next, reaction
with carboxylic acids gave O-acylisoureas, which subsequently rear-
ranged to the corresponding acylureas.33
Acylated urea functions are common building blocks of bioactive
molecules. Besides cyclic representatives, for example, hydantoins
and barbituric acids, which are known for various biological activities
and therapeutic applications,1-4 acyclic N-acylureas (ureides) have
attracted much attention in medicinal chemistry. Of particular
interest among the bioactive acylureas are those bearing the acyl
portion of valproic acid (2-n-propylvaleric acid) or a related
branched acyl moiety.5-8 For example, tetramethylcyclopropa-
necarbonylurea (TMC-urea) and dimethylbutanoylurea (DBU)
have been considered as promising candidates to become new
potent and safe antiepileptic drugs.9,10
Besides their anticonvulsant properties, many of those substances
showed other central nervous effects, for example, as analgesics or
antiarrhythmics.4,11 Moreover, acylureas were discovered as a novel
class of glycogen phosphorylase inhibitors, a molecular target for the
control of hyperglycemia in type 2 diabetes.12,13 Benzoylurea
derivatives were also found to exhibit antiproliferative properties
in different human tumor cell lines,14,15 as well as antitumor
activity in vivo.16 Lessene et al. recently reported on the ability of the
benzoylurea moiety to mimic R-helices because of the formation of
an intramolecular hydrogen bond.17 The authors anticipated that
benzoylureas might therefore serve as inhibitors of interactions
between proteins that comprise helical binding epitopes.17-19
Various strategies have been reported for the synthesis of ureas
on solid support.2,20-29 Urea formation has been, for example,
achieved by reacting primary or secondary amines with resin-bound
carbamates,20,29 isocyanates,22 or carbamate amides.23 In the ma-
jority of cases, isocyanates were used for the efficient transformation
of immobilized amines into ureas.2,21,24,28 Resin-bound ureas have
been frequently utilized as intermediates for the assembly of cyclic
acyl ureas, such as hydantoins, on solid support.2,4,20,21,23,30,31
Another type of cyclic N-acylurea, N-acyl-benzimidazolinone, was
applied as mild acylating agent in the preparation of thioester
peptides, which could be generated on Rink or Wang linkers and
cleaved from the resin with trifluoroacetic acid.32 Surprisingly, there
In continuation of a previous study,28 we wish to report on
different pathways toward disubstituted acyclic acylureas. In
the present work on the solid-phase chemistry of acylureas, we
started from Rink amide resin, assembled the products in three or
four steps using commercially available chemicals, and generated
a library of the target molecules.
’ RESULTS AND DISCUSSION
Our first approach was based on the reaction of three com-
mercially available acyl isocyanates 2{1-3} with deprotected
Rink amide resin 1 resulting in compounds 9{1-3} (Figure 1,
Scheme 1, Table 1).28 A reductive alkylation step was performed
before acylurea formation to include a second point of diversity.34
For this purpose, benzaldehyde 3{1} or 4-methoxybenzaldehyde
3{2} (Figure 2) were condensed with 1 in a mixture of tetra-
hydrofuran, water, and acetic acid, followed by reduction with
sodium cyanoborohydride to form resins 6. Subsequent reaction
with acyl isocyanates 2{1-3} led to resin-bound chemsets 8 and
the products 10 (Table 1). Mono- and disubstituted acylureas 9
and 10 were obtained in good to excellent yields and high purities
after TFA-mediated cleavage and column chromatography. These
and following products of this study were characterized by 1H and
13C NMR spectroscopy, elemental analysis, and LC-DAD/MS.
With respect to the reactions shown in Scheme 1, the limited
Received: September 28, 2010
Revised:
October 10, 2010
Published: November 10, 2010
r
2010 American Chemical Society
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RESEARCH ARTICLE
Table 1. Acylureas with Corresponding Yields and Purities
Figure 1. Diversity reagents 2{1-3}.
Scheme 1. Preparation of Acylureas 9 and 10 from Resin-
Bound Amines 1, 6, and Acyl Isocyanates 2
entry scheme product
R1
R2
yield (%)a purity (%)b
1
1
2
9{1}
9{2}
9{3}
CH2Cl
CCl3
Ph
89
83
91
80
78
82
83
80
85
84
79
83
69
65
68
66
70
59
45
64
66
69
71
68
53
58
40
54
89
86
89
92
77
75
82
79
72
83
79
66
19
33
97
100
100
100
99
1
1
2
2
2
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
4
4
4
4
4
4
4
4
4
4
3
4
18{3} (CH2)2Ph
18{4} CHdCHPh
18{5} CH2OPh
10{1,1} CH2Cl
10{2,1} CCl3
5
6
95
7
Ph
Ph
Ph
96
8
95
9
10{3,1} Ph
94
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
10{1,2} CH2Cl
10{2,2} CCl3
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
Ph
95
100
97
10{3,2} Ph
19{1,1} CH3
100
95
19{2,1} C2H5
Ph
19{3,1} (CH2)2Ph Ph
19{4,1} CHdCHPh Ph
97
97
19{5,1} CH2OPh
19{6,1} 4-Me-Ph
19{7,1} 4-Cl-Ph
19{8,1} 2-thienyl
19{1,2} CH3
Ph
100
99
Ph
Ph
91
Ph
95
Figure 2. Diversity reagents 3{1-2}.
4-MeO-Ph
4-MeO-Ph
98
availability and instability35 of acyl isocyanates constrained the
diversity of the acyl residue within the target compounds and
prompted us to modify the preparation of acylureas on solid support.
Another approach for the synthesis of N-acyl-N0-alkylureas in
solution comprises the reaction of monosubstituted ureas and
carboxylic acids, anhydrides or chlorides.11,36-39 The prepara-
tion of a corresponding unsubstituted urea resin was already
established by the reaction of Rink amide resin with trichloro-
acetyl isocyanate followed by the cleavage of the trichloroacetyl
group in refluxing dioxane-water.28 To avoid high temperatures
for the deprotection step, trimethylsilyl isocyanate40 was used
instead of trichloroacetyl isocyanate. After reaction with the cor-
responding resins 1 or 6, the trimethylsilyl moiety could be
removed by shaking for one hour in a tetrahydrofuran-water
mixture (Scheme 2). Depending on the reaction sequence, three
urea resins with terminal NH2 groups were generated, the un-
substituted urea resin 13 and two monoalkylated resin-bound
ureas 14{1-2} (R2 =Ph, 4-MeO-Ph). The latter ones were as-
sembled by combining reductive alkylation, reaction with tri-
methylsilyl isocyanate and deprotection. Accordingly, 4-methoxy-
benzylurea 15{2} was obtained in 78% yield after cleavage from
resin 14{2} (R2=4-MeO-Ph) and purification.
19{2,2} C2H5
100
99
19{3,2} (CH2)2Ph 4-MeO-Ph
19{4,2} CHdCHPh 4-MeO-Ph
95
19{5,2} CH2OPh
19{6,2} 4-Me-Ph
19{7,2} 4-Cl-Ph
19{8,2} 2-thienyl
12{3} (CH2)2Ph
12{4} CHdCHPh
12{5} CH2OPh
12{9} Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
100
99
95
93
100
100
100
100
93
22{3,1} (CH2)2Ph n-Pr
22{4,1} CHdCHPh n-Pr
91
22{5,1} CH2OPh
22{8,1} 2-thienyl
n-Pr
n-Pr
88
93
22{3,2} (CH2)2Ph Bn
22{4,2} CHdCHPh Bn
89
99
22{5,2} CH2OPh
22{9,2} Ph
Bn
Bn
81
95
22{4,3} CHdCHPh Ph
22{9,3} Ph Ph
78
85
Next, acylation of the urea resins 13 and 14 was investigated.
Application of established solution-phase conditions (carboxylic
anhydrides, toluene, 80 °C)11 resulted in the formation of side
products, in particular the corresponding carboxylic amides. The
underlying expulsion of HNCO might be due to the elevated
reaction temperature. Therefore, the solution conditions were
modified to be applicable for polymeric support. As can be seen
a Yields based on the weight of purified product relative to the initial
loading of the resin. b Purity determined by HPLC-DAD (see Experi-
mental Section for details).
in Schemes 2 and 3, benzhydrylurea 1128 was selected to mimic
the resin bound urea 13. Acylation reactions of urea moieties at
room temperature have been carried out in pyridine,36,37 or
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RESEARCH ARTICLE
organic solvents in the presence of pyridine.38,39 To retain
adequate swelling of the polystyrene resin, we performed the
solution reactions to produce N-acyl-N0-benzhydrylureas 12
(Scheme 3, Table 1) in mixtures of different solvents and pyridine.
Dichloromethane-pyridine (9:1) seemed to be suitable for
transfer to solid support, as a rapid transformation of 11 with dif-
ferent acyl chlorides was observed. We prepared the resin-bound
acylureas 16 from reagent chemset 4 (Figure 3, Scheme 2) and
released the final acylureas 18{3-5} upon treatment with TFA
(Table 1). A similar process resulted in the synthesis of the N-acyl-
N0-alkylureas 19. These products possess a substituted or unsub-
stituted benzyl moiety at the one, and an aroyl or alkanoyl group
at the other nitrogen. They were obtained in yields between 40
and 71% and purities higher than 90% (Table 1).
parameters for both regioisomers. The characteristic chemical
shifts for representatives 19{5,1} and 22{5,2} are depicted in
Figure 5. On the one hand, the 1H NMR spectra of N-acyl-N0-
alkylureas showed a doublet at ∼4.4 ppm for the benzylic
protons and two distinct signals for the NH protons. The signals
for the benzylic and the urea carbonyl carbons appear at ∼43 ppm
and 153 ppm, respectively. On the other hand, the singlets for the
benzylic protons of N-acyl-N-alkylureas are shifted downfield to
∼5.0 ppm, and the signal for two NH protons arises at ∼7.6 ppm.
A relative shift of benzylic and urea carbonyl carbons to lower
field (∼46 and 155 ppm, respectively) was also observed.
In summary, various routes to acylureas from Rink amide resin
were developed. Key steps of the syntheses were combined to
obtain different disubstituted acylureas. For N-acyl-N0-alkylureas
In a further attempt, the solid-supported synthesis was en-
visaged to obtain products through alkylation and acylation at the
same nitrogen (Scheme 4). Deprotected Rink amide resin 1 was
first reacted with reagent chemset 5 (Figure 4) in dichlorometh-
ane, followed by conversion with reagent chemset 4 (Figure 3),
using the acylation conditions noted above. With the exception
of the N-phenylureas 22{4,3} and 22{9,3}, these acylureas 22
were obtained in good yields (Table 1). Structural characterization
of the products revealed that the terminal and not the inter-
nal nitrogen of urea resins 20 was acylated to indeed produce
N,N-disubstituted derivatives 22. A limit in our approach was ob-
served as follows: When reacting the alkylated resin 6 (Scheme 2)
with isocyanates 5 (similar to Scheme 4), the resulting urea resins
could not be successfully acylated. Instead of the desired acylureas,
disubstituted ureas were obtained after cleavage (data not shown).
Thus, the introduction of a third point of diversity into the target
structure failed.
With the two series of isomeric acylureas, i.e., compounds 10
and 19, as well as 22, in hand, we determined indicative NMR
Figure 3. Diversity reagents 4{1-9}.
Scheme 2. Preparation of Acylureas 18 and 19 from Resin-Bound Ureas 13, 14, and Acyl Chlorides 4
Scheme 3. Deprotected Rink Amide Resin (1, Left) and Synthesis of N-acyl-N0-benzhydrylureas 12 in Solution (Right)
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RESEARCH ARTICLE
Scheme 4. Preparation of N-Acyl-N-alkylureas 22 from Corresponding Resin-Bound Ureas 20 and Acyl Chlorides 4
H2O, MeOH, CH2Cl2, and MeOH (2ꢀ10 mL each) and dried in
vacuo to give resin 2.
General Procedure for the Preparation of Acylurea Resins
7 and 8. Resins 1 or 6 were treated with a mixture of the appro-
priate acyl isocyanate 2(5.0 mmol, 10 equiv) in dry CH2Cl2 (10mL)
Figure 4. Diversity reagents 5{1-3}.
at rt. After they were shaken for 2 h, the reaction solutions were
removed and the resins were washed with CH2Cl2, THF, MeOH,
CH2Cl2, and MeOH (2ꢀ 10 mL each).
General Procedure for the Synthesis of Urea Resins 13
and 14. The appropriate amine resin 1 or 6 was reacted for 2 h at
rt with a solution of trimethylsilyl isocyanate (576 mg, 5.0 mmol,
10 equiv) in dry CH2Cl2 under nitrogen atmosphere. Then, the solvent
was removed, the resin resuspended in THF-H2O (10 þ 2 mL) and
shaken for 1 h, followed by washing with CH2Cl2, THF, MeOH,
CH2Cl2, and MeOH (2ꢀ 10 mL each).
1
Figure 5. Comparison of selected H and 13C NMR chemical shifts
General Procedure for the Preparation of Urea Resins 20.
(ppm) from regioisomers 19{5,1} and 22{5,2}.
Deprotected Rink amide resin 1 was allowed to react with the
appropriate isocyanate 5 (5.0 mmol, 10 equiv) dissolved in dry
CH2Cl2 for 2 h at rt. Washing was performed with CH2Cl2, THF,
MeOH, CH2Cl2, and MeOH (2ꢀ 10 mL each), and the corre-
sponding resin 20 was dried.
these are (i) reductive alkylation, (ii) a novel trimethylsilyl isocyanate-
promoted formation of a urea moiety, and (iii) acylation using
acyl chlorides in dichloromethane/pyridine at room tempera-
ture. N-acyl-N-alkylureas were generated by (i) urea formation
with different isocyanates and (ii) acylation with acyl chlorides.
Thus, a library of potentially bioactive acylureas was generated
and characteristic structural parameters were assigned to regio-
isomeric products.
General Procedure for the Acylation on Solid Support:
Synthesis of Resins 16, 17, or 21. Urea resins 13, 14, or 20
were put in a solution of the appropriate acyl chloride 4 (2.5 mmol,
5 equiv) in dry CH2Cl2-pyridine 9:1 (10 mL) and shaken
overnight at rt. The reaction mixtures were filtered, and the resins
were washed with CH2Cl2, DMF, THF, MeOH, CH2Cl2, and
MeOH (2ꢀ 10 mL each) and dried in vacuo.
’ EXPERIMENTAL PROCEDURES
General Procedure for the Solution-Phase Synthesis of
Benzhydryl Derivatives 12. A solution of the appropriate acyl
chloride 4 (0.60 mmol) in CH2Cl2 (5 mL) was added dropwise
to a mixture of benzhydrylurea 1128 (113 mg, 0.50 mmol), CH2Cl2
(4 mL) and pyridine (1 mL) at rt. Progress of the reactions was
controlled by TLC. After complete consumption of 11 (1-5 h), the
reaction mixture was concentrated in vacuo and purified by column
chromatography (CH2Cl2-MeOH, 50:1).
Fmoc Removal. Fmoc-protected Rink amide resin (695 mg,
0.50 mmol) was deprotected with 20% piperidine in DMF (10 mL)
at rt. After 1 h, the resin was washed with DMF, CH2Cl2, MeOH, and
CH2Cl2 (3ꢀ 10 mL each) and dried to give the deprotected resin 1.
Cleavage. The resin was swollen in CH2Cl2 (10 mL). After
removal of the solvent, cleavage of the material from the resin was
performed using CH2Cl2-TFA 9:1 (10 mL) for 1 h at rt, fol-
lowed by washing with CH2Cl2 (2 ꢀ 5 mL). After the filtrates
were combined, the solution was concentrated in vacuo and puri-
fied by column chromatography as described below. Cleavage of
resins 7 and 16 followed by column chromatography (CH2Cl2-
MeOH, 19:1) gave the corresponding N-acylureas 9 and 18,
respectively. Cleavage of resins 8 and 17 followed by column
chromatography (CH2Cl2-MeOH, 29:1) gave the correspond-
ing N-acyl-N0-alkylureas 10 and 19, respectively. Cleavage of
resins 21 followed by column chromatography (CH2Cl2-
MeOH, 29:1) gave the corresponding N-acyl-N-alkylureas 22.
General Procedure for the Reductive Alkylation: Synthesis
of Resin 6. Reductive alkylation was performed according to
Brown and Nuss.34 AcOH (0.5 mL) and H2O (0.5 mL) were
added to a mixture of resin 1, THF (10 mL) and the appropriate
aromatic aldehyde 3 (0.60 mmol, 1.2 equiv). After shaking for 5 min
at rt, NaCNBH3 (31 mg, 0.50 mmol) was added and the mixture
was shaken for further 3 h. The resin was washed with THF,
’ ASSOCIATED CONTENT
S
Supporting Information. General methods and materials,
b
compound characterization, and 1
H and 13C NMR spectra of all
compounds. This information is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: þ49 228 732317. Fax: þ49 228 732567. E-mail:
guetschow@uni-bonn.de.
Present Addresses
†Boehringer Ingelheim Pharma GmbH & Co. KG, Quality,
Binger Str. 173, D-55216 Ingelheim am Rhein, Germany.
62
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’ ACKNOWLEDGMENT
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Schneider, S. Terhart-Krabbe, and I. Kretschmer for assistance.
This work has been supported by the German Research Founda-
tion (GRK 804).
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