Imidazolones in diastereoselective cyclization reactions and cu ii-catalysed cross-coupling reactions

Article abstract of DOI:10.1002/chem.200900633

Imidazolones in diastereoselective cyclization reactions and Cu ^II-catalyzed cross-coupling reactions was studied. Dry PEGA ₈₀₀ resin derivatized with the HMBA linker and amino acid was swelled in DMF. The building block was dissolve

Full text of DOI:10.1002/chem.200900633

DOI: 10.1002/chem.200900633
Imidazolones in Diastereoselective Cyclization Reactions and CuII-Catalysed
Cross-Coupling Reactions
Frederik Diness and Morten Meldal*[a]
Imidazolones are pharmaceutically interesting compounds
and constitute essential substructures of receptor antagonists
with activities in the low nanomolar regime. The targets in-
clude the neurokinin-1 receptor,[1] the CGRP receptor,[2] the
dopamine receptors[3] and the angiotensin II receptor.[4] Imi-
dazolones are also found in potent PDE4 inhibitors,[5] in
subtype selective b3-adrenergic receptor agonists[6] and in
GABAA receptor ligands.[7] Furthermore, the imidazolone
substructure is present in the natural nikkomycin X antibiot-
ic.[8] However, the chemistry of this heterocycle has received
little attention, although imidazolones are intermediates in
the synthesis of natural compounds, such as biotin,[9] slage-
nins,[10] axinohydantoins[11] and oroidin-derived alkaloids.[12]
Only few systematic studies of the synthesis[2,3,13] and the re-
activity[14] of imidazolones have been reported and there-
fore, the synthetic versatility of these compounds has not
been explored.
In search of constrained small molecules derived from
peptides, the chemistry of 3-Boc-(1,3)-oxazinane (Box)
masked amino aldehydes[15] in electrophilic aromatic substi-
tution-cyclization (EASCy) reactions has been explored.[16]
During this work the Box-masked a-amino aldehyde
building block 1 was coupled with the N-terminus of a resin-
bound Phe-Gly dipeptide to give compound 2a (Scheme 1).
Exposure of 2a to 10% aqueous TFA afforded the 1,4-sub-
stituted imidazolone 3[17] as the only product. This was in
contrast to the result obtained for the same reaction with a
resin-bound Trp-Gly dipeptide (2b), which gave the corre-
sponding 1,2,3,4-tetrahydro-b-carboline derivative 4[17] with
a purity in excess of 95%. The different outcome of the re-
actions of 2a and 2b with acid was found to be independent
of the acidity. Aqueous TFA (10–100%), HCl (1.0m), and
H2SO4 (1.0m) worked equally well and provided the same
results.
Scheme 1. Formation of imidazolone or EASCy product. Yields reported
are those of the pure isolated products.
We therefore speculated how the nature of the C-nucleo-
phile may influence the reactivity. Building block 1 was cou-
pled to a range of dipeptides on solid support affording the
unsymmetrical ureas 5a–f. When exposed to 10% aqueous
TFA all except two of the compounds gave the correspond-
ing imidazolone as the only product (Table 1). The two ex-
ceptions were the more reactive thiophen-3-yl and 3,4-dime-
thoxyphenyl derivatives, which both in addition to the imi-
dazolones (6c and 6d) as the major components gave the
corresponding 4,5,6,7-tetrahydrothienoACTHNUTRGNE[NUG 2,3-c]pyridine and
1,2,3,4-tetrahydroisoqinoline products (7c and 7d) in 34 and
7%, respectively. As a point of interest, it was noted that
subsequent exposure of the resin-bound imidazolones con-
taining 3,4-dimethoxybenzene, thiophene or benzothiophene
(entry a to d, Table 1) to 100% TFA for 12 h, quantitatively
converted these into the cyclized products. The purities of
the final EASCy products (7a–d) were excellent (>95%)
and the diastereoselectivity was better than 19:1 for all com-
pounds. The remaining imidazolones, 6e and 6 f, were com-
pletely stable towards the treatment with 100% TFA. All
[a] Dr. F. Diness, Prof. Dr. M. Meldal
SPOCC Center
Carlsberg Laboratory
Gamle Carlsberg Vej 10
2500 Valby (Denmark)
Fax : (+45)33 27 47 08
E-mail: mpm@crc.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900633.
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Chem. Eur. J. 2009, 15, 7044 – 7047

COMMUNICATION
Table 1. Formation of imidazolones and EASCy products with p-nucleo-
philes.
analysed products were cleaved from the resin with 0.1m
aqueous NaOH before characterisation.
In all these reactions the acid initially deprotects the alde-
hyde, which instantaneously reacts with the urea nitrogen to
afford a mixture of the N,O-hemiacetal (not shown) and the
cyclic N-carbamyliminium ion (see Table 1). The N-carba-
myliminium ion may then be attacked by the electrons of
À
the neighbouring C H bond of the ring, which with loss of a
proton gives the imidazolone (6a–f). The N-carbamylimini-
um ion may alternatively be attacked by the p-electrons in
the aromatic side chain of the subsequent amino acid to
afford the corresponding cyclized product (7a–d). It may be
assumed that the conversion of the cyclic N-carbamylimini-
um ion to the imidazolone is reversible under the strongly
acidic conditions and equilibrium between the two forms is
established. The fraction of N-carbamyliminium ion present
in the equilibrium is then susceptible to irreversible attack
by a reactive C-nucleophile to form the corresponding cy-
clized product. Neither the transformation of imidazolones
to EASCy products nor other examples of nucleophilic
attack on imidazolones have been described previously.
EASCy products containing the saturated 4,4-disubstituted
imidazoldin-2-one core structure have been reported,[18]
however, in this case the 4,4-disubstitution prevented forma-
tion of an imidazolone. In one report a single product con-
taining a mixture of the imidazolone and the cyclized
1,2,3,4-tetrahydroisoqinoline product has been described.[19]
Due to the success with using electron-rich heterocycles
as nucleophiles in the EASCy reaction we have also ex-
plored imidazolones as nucleophile in this reaction. The imi-
dazolone 8 was formed on resin from a 2,3-diamino propion-
ic acid containing dipeptide by the method described above
(Table 1). The EASCy reaction was tested using two other
building blocks (9a–b),[15c] which after coupling and expo-
sure to TFA gave the corresponding cyclized product (11)
or the oxidized cyclized product (12) respectively
(Scheme 2). The purities of 11 and 12 were 82 and 76%, re-
spectively. The charged iminium product 12 is believed to
arise through rapid oxidation upon exposure to air of the in-
itially formed cyclic product. This finding is in accordance
with other results of EASCy reaction using the Abz-derived
building block (9b), which we previously reported.[16]
Entry
Product 6/(7)
10% aq. 100% TFA
TFA
Ratio 6/7[a]
(purity
[%])[b]
Yield [%][c]
Ratio 6/7[a]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
100:0 (95) 0:100 (96)
58 19
a
100:0 (95) 0:100 (98)
68 68
b
c
66:34 (92) 0:100 (97)
nd[d]
45
0:100 (97)
38
d
93:7 (98) 76
100:0 (99) 100:0 (99)
nd 16
e
f
100:0 (99) 100:0 (99)
nd 72
[a] Determined by HPLC and NMR. [b] Determined by HPLC of crude
material cleaved off the resin. [c] Yield of isolation. The products were
isolated on a 1–12 mg scale [d] Not determined.
Scheme 2. Imidazolones as p-nucleophile in EASCy reactions. Yields re-
ported are those of the pure isolated products.
Chem. Eur. J. 2009, 15, 7044 – 7047
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www.chemeurj.org
7045

M. Meldal and F. Diness
(6ꢁ2 min), DMF (6ꢁ2 min), CH2Cl2 (6ꢁ2 min) and lyophilized. The
compound (14a–d) was cleaved off the resin as described above.
We further explored the copper(II)-catalysed oxidative N-
arylation[20] of the imidazolone products with aryl boronic
acids. The imidazolones proved to be excellent substrates
for this type of coupling and the application of imidazolone
13 gave the corresponding products (14a–d) with purities in
excess of 95% (Scheme 3).
Acknowledgements
The financial support to the SPOCC Center from the Danish National
Research Foundation is gratefully acknowledged.
Keywords: autooxidation
· cross-coupling · solid-phase
synthesis · stereoselective synthesis · urea
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Scheme 3. Formation of N-aryl imidazolones. Yields reported are those
of the pure isolated products.
The ability to act selectively as nucleophile or electrophile
under the same reaction conditions and serve as substrate
for copper catalysed cross couplings shows that imidazo-
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to new types of optically pure compounds with potential use
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Experimental Section
General aspects: All purchased chemicals were used without further pu-
rification. All solvents were HPLC-grade. PEGA800 resin was obtained
from VersaMatrix A/S. See ref. [17] and Supporting Information for the
full characterisation of all products.
Synthesis of imidazolone and EASCy products (3, 4, 6a–f, 7a–d, 11, 12
and 13): Dry PEGA800 resin (50–150 mg, 0.30–0.38 mmolgÀ1, 15–57 mmol)
derivatized with the HMBA linker and amino acid was swelled in DMF
(for the preparation of the funtionalised resin see reference [15b]). The
building block (3.0 equiv) (1, 9a or 9b) was dissolved in DMF (10 mLgÀ1
resin) and the solution was added to the resin. After 12 h the resin was
washed with DMF (6ꢁ2 min), CH2Cl2 (6ꢁ2 min) and lyophilized. The
dry PEGA800 resin with HMBA linker, peptide and building block at-
tached (2a–b, 5a–f, 10a or 10b) was swelled in aqueous 10% TFA (1 h).
The resin was washed with 10% aqeous TFA (2ꢁ2 min). Further reac-
tion with TFA was applied when necessary to complete conversion (see
Supporting Information). The resin was washed with H2O until the
eluate had pH 5–7. The resin was washed with DMF (6ꢁ2 min), CH2Cl2
(6ꢁ2 min) and lyophilized. The compound was cleaved from the resin by
swelling the dry PEGA800 resin with the attached HMBA linker and com-
pound in 0.1m aqueous NaOH (10 mLgÀ1 resin). After 2 h aqueous 0.1m
HCl was used for neutralization. Resin was extracted with H2O (2ꢁ
2 min) and acetonitrile/H2O 70:30 (2ꢁ2 min). The solvent from the ex-
tract was removed in vacuo giving the product (3, 4, 6a–f, 7a–d, 11, 12
and 13), as a solid with a white to pale yellow colour.
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Copper(II)-promoted N-arylation of imidazolone product of GlyBB-Phe-
Gly-HMBA-PEGA800
~0.35 mmolgÀ1, 21 mmol) was swelled in DMF. Aryl boronic acid (210
mmol), Cu(AcO)2 (7.5 mg, 42 mmol) and DIPEA (134 mg, 1.05 mmol)
ACHTUNGTRENNUNG(14a–d): The imidazolone product 13 (60 mg,
ACHTUNGTRENNUNG
were added to the resin. Crusted molecular sieves 3 ꢂ (~100 mg) was
added and mixture stirred with dry air bubbling through (12 h). The resin
was washed with DMF (6ꢁ2 min), 1% aqueous TFA (3ꢁ2 min), H2O
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Imidazolones
COMMUNICATION
D.-C. Ha, H.-G. Hahn, J. Cmb. Chem. 2008, 10, 803. For generation
(250 MHz, [D6]DMSO): d=13.28–11.68 (brs, 1H), 9.78 (s, 1H), 8.56
(t, J=5.8 Hz, 1H), 7.31–7.10 (m, 5H), 6.62 (dd, J=2.1, 2.9 Hz, 1H),
6.24 (t, J=2.7 Hz, 1H), 4.95 (dd, J=4.8, 10.7 Hz, 1H), 3.77 (d, J=
5.8 Hz, 1H), 3.19 (dd, J=4.9, 14.4 Hz, 1H), 3.06 ppm (d, J=10.8,
14.1 Hz, 1H); 13C NMR (62.5 MHz, [D6]DMSO): d=170.9, 170.2,
137.3, 128.9, 128.1, 126.4, 116.7, 110.2, 107.1, 55.4, 40.7, 37.1,
30.7 ppm; HRMS (ESI-TOF): m/z: calcd for C14H16N3O4 [M+H]+:
290.1135, found: 290.1123. Yield: 10.2 mg (69%). EASCy product
from GlyBB-Trp-Gly-HMBA-PEGA800 (4): 1H NMR (250 MHz,
[D6]DMSO): d=13.14–11.75 (brs, 1H), 8.44 (t, J=6.0 Hz, 1H), 7.40
(d, J=7.7 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.07 (dt, J=2.4,
15.4 Hz, 1H), 7.02–6.84 (m, 2H), 5.17 (d, J=6.5 Hz, 1H), 4.75 (d,
J=7.0 Hz, 1H), 3.83–3.63 (m, 3H), 3.47 (dd, J=2.8, 8.9 Hz, 1H),
3.31 (d, J=15.7 Hz, 1H), 3.47 ppm (dd, J=1.8, 7.8 15.9 Hz, 1H);
13C NMR (62.5 MHz, [D6]DMSO): d=171.2, 170.6, 161.6, 136.0,
132.5, 126.5, 121.2, 118.5, 117.7, 111.1, 105.7, 51.0, 49.6, 43.3, 40.9,
20.1 ppm; HRMS (ESI-TOF): m/z: calcd for C16H17N4O4 [M+H]+:
329.1244, found: 329.1253. Yield: 12.2 mg (94%).
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[16] F. Diness, J. Beyer, M. Meldal, Chem. Eur. J. 2006, 12, 8056.
[17] Data for imidazolone product 3 and EASCy product 4. Imidazolone
product from GlyBB-Phe-Gly-HMBA-PEGA800 (3): 1H NMR
[19] S. Kano, Y. Yuasa, S. Shibuya, Synth. Commun. 1985, 15, 883.
[20] For reviews see: a) S. V. Ley, A. W. Thomas, Angew. Chem. 2003,
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Received: March 10, 2009
Published online: June 19, 2009
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www.chemeurj.org
7047