Alkaline earth catalysis for the 100% atom-efficient three component assembly of imidazolidin-2-ones

Article abstract of DOI:10.1039/c4cc05223d

A variety of functionalised imidazolidin-2-ones may be synthesised under very mild reaction conditions using non-toxic and cost-effective alkaline earth bis(amide) pre-catalysts in a 100% atom-efficient, intermolecular one-pot assembly from inexpensive al

Full text of DOI:10.1039/c4cc05223d

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Alkaline earth catalysis for the 100% atom-efficient
three component assembly of imidazolidin-2-ones†
Cite this: Chem. Commun., 2014,
50, 12676
Merle Arrowsmith, William M. S. Shepherd, Michael S. Hill* and
Received 7th July 2014,
Accepted 4th September 2014
Gabriele Kociok-Kohn
¨
DOI: 10.1039/c4cc05223d
www.rsc.org/chemcomm
A variety of functionalised imidazolidin-2-ones may be synthesised
under very mild reaction conditions using non-toxic and cost-
effective alkaline earth bis(amide) pre-catalysts in a 100% atom-
efficient, intermolecular one-pot assembly from inexpensive alkyne
and cumulene reagents.
Heterocyclic molecules play a crucial role in biological processes1
and are a constituent in two-thirds of the top-selling small molecule
pharmaceuticals in the USA.2 Azole derivatives are a particularly
widespread motif in natural products and are among the 30 most
frequently-used heterocycles in anticancer, anti-HIV and antibacterial
drug molecules.3,4 Whilst many complex and challenging hetero-
cyclic syntheses may be achieved with catalytic methods,5 a vast
majority of these processes require either the preparation of specia-
lised substrates and pre-catalysts derived from low abundance
transition metals or are atom-inefficient from production of halide
by-products.6 Since our initial report of the calcium-catalysed intra-
molecular hydroamination of aminoalkenes (Scheme 1A),7 we and
others have applied pre-catalysts derived from the biologically
compatible, inexpensive and environmentally benign alkaline earth
(Ae) elements to an ever-growing array of multiple bond heterofunc-
tionalisation and dehydrocoupling reactions.8 Of direct relevance to
the current work are the group 2 catalysed hydroacetylenation of
carbodiimides (Scheme 1B)9 and the recently reported magnesium-
mediated but stoichiometric synthesis of complex bis(hydantoins)
(I, inset Scheme 1) from phenylacetylene and isocyanates.10 This
Scheme 1
latter process was rationalised as a cascade of hydroacetylenation, generalised one pot catalytic regime. This is achieved through an
isocyanate insertion, intramolecular hydroamination and protono- initial and precedented catalytic reaction of a carbodiimide and
lysis steps akin to those depicted in Scheme 1. In this contribution terminal acetylene to provide a propargylamidine (II, Scheme 1B).9
we demonstrate that the readily available homoleptic amides, We speculated that, upon completion of this catalysis, addition
[Ae{N(SiMe3)2}2(THF)2] (1a, Ae = Mg; 1b, Ae = Ca; 1c, Ae = Sr), of an isocyanate would instigate the formation of imidazolidin-
may be employed for the ready elaboration of this chemistry to a 2-ones (IV) through further insertion and protolytic reactivity
(Scheme 1C).
An initial reaction of tert-butylisocyanate with (N,N0-di-isopropyl)-
phenylpropargylamidine, synthesised in situ using 5 mol%
[Sr{N(SiMe3)2}2(THF)2], 1c, resulted in quantitative formation of
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
E-mail: msh27@bath.ac.uk
† Electronic supplementary information (ESI) available: Details of the synthesis,
characterization data and the crystallographic protocols employed in this study
the imidazolidin-2-one (2) within the first point of analysis at r.t.
(Scheme 2, Table 1, entry 3). Analysis by H NMR spectroscopy
are given. CCDC 1008314–1008316. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4cc05223d.
1
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Scheme 2
Scheme 3
Table 1 Isocyanate scope for catalytic cyclisation with (N,N0-di-isopropyl)-
phenylpropargylamidine
Table
2
Propargylamidine scope for the synthesis of 1-isopropyl-
Ent. R, compd no.
Cat (mol%) Time (h) NMR yield (%) Z/E (%)
(5-benzylidene-4-imino)imidazolidin-2-ones
1
2
3
4
5
6
7
8
tBu, 2
tBu, 2
tBu, 2
tBu, 2
Et, 3
1a 5.0
1b 5.0
1c 5.0
1c 0.5
1c 0.5
1c 0.5
1c 0.5
1c 0.5
1c 0.5
1c 0.5
4 d
2
0.1
18
0.3
0.5
3
53
87
499
87
91
97
98
499
92
499
98
78
33 : 67
30 : 70
22 : 78
23 : 77
83 : 17
90 : 10
41 : 59
40 : 60
32 : 68
85 : 15
98 : 2
R0, compd
no.
Cat
(mol%) (h)
Time NMR
Z/E
Ent.
R
yield (%) (%)
1
2
3
4
5
6
iPr
Cy
tBu
Et
iPr, 5
Cy, 11
tBu, 12
tBu, 13
5.0
5.0
5.0
5.0
5.0
0.1
0.1
40
98
97
75
99
97
89
41 : 59
25 : 75
25 : 75
34 : 66
75 : 25
Pr, 4
iPr, 5
0.1
p-tol p-tol, 14
4a
Cy, 6
Adamantyl, 7
Ph, 8
3
b
9
18
0.5
6
Et
(CH2)3NMe2, 15 5.0
4a
—
10
11
12
a
b
2 eq. RNQCQNR0, 80 1C. Mixture of all 4 regioisomers.
2,4,6-Me3Ph, 9 1c 0.5
2,6-iPr2C6Ph, 10 1c 0.5
18
90 : 10
highly dependent on the steric demands of the amidine
revealed a 22 : 78 mixture of the Z and E isomers displaying N-substituents (Scheme 3). While the di(isopropyl) and dicyclohexyl
characteristic benzylidene singlet resonances at 6.50 and 5.95 ppm, derivatives provided essentially instantaneous and quantitative con-
respectively. Lowering the catalyst loading to 0.5 mol% afforded the version at r.t. using 5 mol% catalyst (Table 2, entries 1–2), the larger
same isomer mixture in 87% yield after 18 h at r.t. (Table 1, entry 4). di(tert-butyl) derivative required much longer reaction times (40 h)
Performance of an identical reaction with 5 mol% of the analogous to achieve high conversion (Table 2, entry 3). The unsymmetrical
magnesium and calcium pre-catalysts, 1a and 1b, revealed the 1-ethyl-3-(tert-butyl)amidine substrate provided evidence for kinetic
intermediacy of a highly moisture-sensitive urea derivative discrimination in these reactions through exclusive isocyanate
(Scheme 2), identified by comparison with isolated compounds insertion at the N-ethyl nitrogen atom, with a product isomer ratio
synthesised by direct reaction between the isocyanate and the intermediate between that of the di(isopropyl) and di(tert-butyl)
amidine (see ESI†).
derivatives (entry 4). Substrates with smaller functionalities,
Subsequent reactions were performed at r.t. with 0.5 mol% 1c, such as di( p-tolyl)carbodiimide and [1-(N,N0-dimethylamino-
using (N,N0-di-isopropyl)phenylpropargylamidine and the range of propyl)-3-(tert-butyl)carbodiimide] did not provide access to the
isocyanates shown in Table 1. In all cases isocyanate insertion was desired propargylamidines but underwent double carbodiimide
virtually instantaneous at r.t. whereas the rate of cyclisation to the insertion/cyclization to yield N,N0-[(5-benzylidene-imidazolidin-
corresponding imidazolidin-2-one was found to be dependent on 2,4-ylidene)diamine] products (Scheme 3, Table 2, entries 5, 6).
the steric pressure exerted by the isocyanate substituent: ethyliso- In the case of the tetra( p-tolyl)-substituted N-heterocycle (14), a
cyanate afforded a 91% NMR yield within 20 min at r.t. (Table 1, 75% selectivity for the Z-isomer was observed (entry 5), in line
entry 5), while the larger, tert-butyl-, adamantyl and 2,6-di-iso- with observations for products derived from arylisocyanates
propylphenyl-isocyanates, required 18 hours to achieve good (Table 1, entries 10–12). Analysis of the product distribution
conversions (Table 1, entries 4, 9 and 12).
from the reaction of the 1-(N,N0-dimethylaminopropyl)-3-tert-
With 5 mol% 1c, all reactions proceeded to completion within butyl derivative was marred by the presence in solution of all
less than 5 min at r.t. The Z/E product isomer ratio was found to be 4 possible insertion regioisomers as well as E/Z-isomerism
governed both by steric and electronic factors. Arylisocyanates pre- (Table 2, entry 6).
dominantly yielded the Z isomer, independent of substituent steric
In contrast, the strontium-catalysed reaction of isocyanates
demands (Table 1, entries 10–12). For alkylisocyanates, however, with (N,N0-di-isopropyl)-n-butylpropargylamidine did not afford
selectivity was observed to shift from predominantly Z for substitu- the desired imidazolidin-2-ones but only the urea insertion
ents of lower steric demands (Table 1, entries 5, 6) to predominantly products (16, 17) (Scheme 4). The latter species did not undergo
E for those exerting greater steric pressure (Table 1, entries 1–4, 7–9). cyclisation even after prolonged heating at 100 1C. Similarly,
To evaluate the scope of amidine N-substitution a variety of phenyl- group 2-mediated intramolecular hydroamination of amino-
propargylamidines were synthesised in situ from phenylacetylene alkenes has been observed to be hindered by the presence of
and commercially available carbodiimides using 1c as a pre-catalyst. terminal alkyl substituents on the alkene moiety, whereas term-
Upon full conversion to the amidine 1 eq. isopropylisocyanate inal aryl substitution promotes cyclisation due to an activating
was added. Formation of the heterocyclic products proved electronic effect.11
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Scheme 4
Fig. 2 ORTEP representation of compound 18. Ellipsoids at 30% prob-
ability. Hydrogen atoms omitted for clarity.
be a distorted square pyramidal bis(N-(2-phenylpropargylimidoyl)-
carbamimidate) magnesium complex, with a THF molecule in the
axial position. Coordination in the basal plane is provided by the
oxygen atoms of the inserted isocyanates and the imino-nitrogen
of the amidinate moieties, forming two 6-membered [MgNCNCO]
metallacycles (Fig. 2). The rather short C–O bond lengths
[1.275(4), 1.274(4) Å], elongated C1–N1 [1.451(4) Å] and C29–N4
bonds [1.452(4) Å] and the planarity of the N1 and N4 nitrogen
atoms suggest some degree of delocalisation over the chelate
rings. The short C1–N3 [1.289(4) Å] and C29–N6 [1.291(4) Å] bond
lengths are clearly indicative of pendant imine functionalities.
Complex 18 provided similar catalytic activity to 1a for the
formation of 2, suggesting that molecules of this type are formed
as intermediates during the catalysis. Variable temperature 1H NMR
experiments performed on compound 18 also indicated the
potential for isocyanate de-insertion at higher temperatures. A van’t
Hoff analysis of this equilibrium provided DH1 = +88 kJ molꢀ1 and
DS1 = 208 J Kꢀ1 molꢀ1 allowing DG1(298 K) to be estimated as
+26 kJ molꢀ1 for the dissociative process. Interpretation of this
latter value remains difficult as it requires deconvolution of
both the de-insertion and the potential for dimerization of the
resultant propargylamidinate species.9a The positive but low
Fig. 1 ORTEP representations of compounds (Z)-10 (left) and (E)-2 (right).
Ellipsoids at 30% probability. Hydrogen atoms omitted for clarity except H4.
Single crystal X-ray diffraction experiments performed on
the products resulting from the reactions of (N,N0-di-isopropyl)-
phenylpropargylamidine with 2,6-di-isopropyl-phenyl- and
tert-butylisocyanate, respectively, revealed the structures of
compounds (Z)-10 and (E)-2, which corresponded to the major
isomers formed in the reactions as observed by solution NMR
analysis (Fig. 1). In both cases bond lengths and angles are
within the range expected for these (5-benzylidene-4-imino)-
imidazolidin-2-ones.
To investigate the nature of the alkaline earth species at
work in this catalysis, a stoichiometric reaction between 1a,
2 eq. (N,N0-di-isopropyl)phenylpropargylamidine and 2 eq. 2,6-di-
isopropyl-phenylisocyanate was performed. This did not yield the
expected magnesium insertion complex but was observed by NMR
analysis to provide complete conversion of substrates to the
corresponding N-heterocyclic product 10 with reformation of 1a.
This result suggests that cyclisation is assisted by the presence of
protic [HN(SiMe3)2] liberated upon amidine protonolysis of 1a. A
similar concerted mechanism has previously been proposed for
the intramolecular cyclisation of aminoalkenes (Scheme 1A).11,12
Use of [Mg(CH2Ph)2(THF)2] in place of 1a yielded the desired
homoleptic insertion complex, compound 18, in quantitative
yield (Scheme 5). An X-ray diffraction experiment revealed 18 to
Scheme 5
Scheme 6
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free energy change at 298 K, however, indicates that this
potential reversibility is likely to be significant during the course
of the catalysis at ambient or slightly elevated temperatures. This
observation and the notable regioselectivity of the catalysis
toward imidazolidine formation, thus, lead us to suggest the
refined mechanistic hypothesis depicted in Scheme 6.
In conclusion we have demonstrated the applicability of readily
available and inexpensive alkaline earth bis(amide) precatalysts to the
facile one-pot, 100% atom-efficient, stepwise synthesis of a wide
variety of highly functionalized imidazolidin-2-ones from simple
commercially available building blocks. We are currently seeking to
develop extensions to this catalytic heterocycle synthesis through the
incorporation of alternative heterocumulenes into catalytic manifolds
analogous to those shown in Schemes 1B/C and 6 and to exploit the
additional functionality inherent in molecules such as (Z)-10 and (E)-2
in subsequent, sequential atom-efficient transformations.
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We thank the EPSRC for funding.
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