Heavier group 2 element-catalysed hydroamination of isocyanates

Article abstract of DOI:10.1039/b809649j

The heteroleptic calcium amides [{ArNC(Me)CHC(Me)NAr}Ca(NR ₂)(THF)] (Ar = 2,6-di-iso-propylphenyl, R = SiMe₃, Ph) and the homoleptic heavier alkaline earth amides, [M{N(SiMe₃) ₂}₂] (M = Ca, Sr and Ba)

Full text of DOI:10.1039/b809649j

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Heavier group 2 element-catalysed hydroamination of isocyanatesw
Anthony G. M. Barrett,*b Tanya C. Boorman,a Mark R. Crimmin,b
¨
Michael S. Hill,* Gabriele Kociok-Kohn and Panayiotis A. Procopiou
a
a
c
Received (in Cambridge, UK) 9th June 2008, Accepted 28th July 2008
First published as an Advance Article on the web 12th September 2008
DOI: 10.1039/b809649j
The heteroleptic calcium amides [{ArNC(Me)CHC(Me)NAr}-
Ca(NR2)(THF)] (Ar = 2,6-di-iso-propylphenyl, R = SiMe3,
Ph) and the homoleptic heavier alkaline earth amides,
[M{N(SiMe3)2}2] (M = Ca, Sr and Ba) are reported as
pre-catalysts for the hydroamination of isocyanates.
Scheme 1 Reaction of 1 and 3 with 1-adamantyl isocyanate.
The importance of the urea functional group to biological
systems was well known before Wohler’s 1828 landmark
¨
Our current interest lies in developing, understanding and
exploiting the reaction chemistry of heavier alkaline earth
complexes (M = Ca, Sr and Ba). In this regard we have
previously reported Chisholm et al.’s b-diketiminate calcium
synthesis.1 Whilst this latter discovery overturned the theory
of vitalism and arguably led to the birth of organic chemistry,
in the countless studies that have followed urea derivatives
have found myriad applications in synthetic, pharmaceutical
and industrial chemistry. Despite their obvious significance,
catalytic, atom-efficient, methods for the synthesis of ureas
remain limited to a small number of protocols. Important
examples include, (i) the transition-metal catalysed oxidative
carbonylation of amines with CO in the presence of an oxidant
such as O2 or I2,2,3 (ii) the reductive coupling of nitro
compounds with amines and CO mediated by transition-metals
or elemental sulfur or selenium,4,5 (iii) the carbonylation of
amines with CO2 in the presence of catalytic Ph3SbO–P4S10,6
and (iv) the ruthenium-mediated dehydrogenative coupling of
formamides and amines.7
amide
[{ArNC(Me)CHC(Me)NAr}Ca{N(SiMe3)2}(THF)]
(Ar = 2,6-di-iso-propylphenyl, 1)12 as a suitable pre-catalyst
for the hydroamination and hydrophosphination of alkenes,
alkynes and carbodiimides.13 We now report the preliminary
findings from our studies upon the application of 1 and the
simple heavier alkaline earth amides [M{N(SiMe3)2}2]2 (2a, M
= Ca; 2b, M = Sr; 2c, M = Ba) to the catalytic hydroamina-
tion of isocyanates to form unsymmetrical ureas.
To investigate the feasibility of the controlled single insertion
of an isocyanate into a calcium–nitrogen bond,14 the reaction
of both 1 and [{ArNC(Me)CHC(Me)NAr}Ca{NPh2}(THF)]
(3) with 1-adamantyl isocyanate in C6D6 was monitored by 1H
and 13C NMR. Although in both instances consumption of the
starting materials was observed at the first point of analysis,
only the diphenylamide compound 3 gave the desired insertion
product in effectively stoichiometric yield (Scheme 1, 4).
Notable by its absence in these studies is the potential
synthesis of ureas by the catalytic hydroamination of isocya-
nates. Whilst readily achievable under uncatalysed conditions,8
this reaction is often limited to nucleophilic amines, where
preparations frequently require elevated reaction temperatures
or prolonged reaction times to afford the urea products in high
yield. As such, homogeneous catalysis may offer the potential
for improved substrate scope and reaction kinetics. In this
regard, although previous studies upon well-defined organo-
lanthanide(III) amides have demonstrated that these species
undergo insertion reactions with isocyanates to form the corre-
sponding metal ureido complexes,9 this reactivity has not been
extended to a catalytic synthesis of ureas. Rather, a number of
f-block (and similarly s-block) mediated isocyanate oligo-
merisation or polymerisation reactions have been reported.10,11
a Department of Chemistry, University of Bath, Claverton Down,
Bath, UK BA2 7AY
b Department of Chemistry, Imperial College London, Exhibition
Road, South Kensington, London, UK SW7 2AZ
Fig. 1 ORTEP representation of 4. Thermal ellipsoids at 20%
probability. H-atoms and disordered atoms omitted for clarity.
Selected bond lengths (A) and angles (1), Ca–O(1) 2.2805(14),
Ca–(3) 2.3383(16), Ca–N(4) 2.3546(16), Ca–O(2) 2.3670(15),
Ca–N(2) 2.4356(16), N(1)–C(1) 1.450(2), N(1)–C(2) 1.302(3),
O(1)–C(1) 1.280(2), N(3)–Ca–N(4) 81.36(5), O(1)–Ca–N(2) 56.59(5).
c GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertfordshire, UK SG1 2NY
w Electronic supplementary information (ESI) available: Experimental
details along with cif files for 4 and 5. CCDC reference numbers
690638 and 690639. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b809649j
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increase their solubility in hydrocarbon solvents.13c The reactions
of diphenylamine with both 1-adamantyl isocyanate and
2,6-di-iso-propylphenyl isocyanate with 5–6 mol% 2a in C6D6
1
were monitored by H NMR spectroscopy. In these instances
kinetic analyses, using the liberated hexamethydisilazane (formed
quantitatively) or tetrakis(trimethylsilyl)silane as an internal stan-
dard, demonstrated that the hydroamination reaction proceeded
cleanly with simultaneous consumption of the substrates and
production of the urea (Fig. 2a). Whilst the hindered aryl
isocyanate required slightly more forcing conditions (60 1C) than
the alkyl-substituted analogue (25 1C), in both instances moni-
toring the isocyanate and amine concentrations over the reaction
period revealed no significant polymerisation or oligomerisation
side-reactions of the heterocumulene, with both substrates being
consumed at equal rates (Fig. 2a and b, and ESI Fig. S2w).
In both reactions, product concentrations plateaued at high
conversions and yields of the urea did not reach greater than
86% and 62% for 5 and 6 respectively as deduced by NMR
(isolated yields 48–70%). Consideration of the plot of the
logarithm of substrate concentration versus time for the reac-
tion with 1-adamantyl isocyanate provides an explanation for
this effect. The reaction is not first-order in either amine or
isocyanate. Importantly, at longer reaction times (or higher
conversion) the rate of the reaction begins to slow leading to the
observed pseudo first-order data. We propose that this effect is
due to product inhibition of catalysis and, whilst the change in
the chemical shift of the diphenylamine –NH resonance over
the course of the reaction (Fig. 3, t = 5 min, 1Hd = 5.2 ppm;
t = 40 min, 1Hd = 5.6 ppm) provides evidence for the
formation of intermolecularly hydrogen-bonded adducts
between the product and substrates, it is likely this effect is
due to the urea acting as a ligand for the catalytically active
calcium species and hindering substrate coordination and
activation at the metal.
Scheme 2 Group 2-catalysed hydroamination of isocyanates.
The proposed structure of 4 (Fig. 1) was confirmed unambi-
guously, following its synthesis and isolation on a preparative
scale,z by a single crystal X-ray diffraction analysis.y In the solid
state 4 consists of a penta-coordinate calcium centre in which
coordination is provided by the bidentate b-diketiminate and
ureido ligands and a single molecule of THF. The metal demon-
strates approximate trigonal bipyramidal geometry (t = 0.84).15
Although bond lengths and angles about the b-diketiminate
chelate are comparable to previously characterised five-coordinate
heteroleptic b-diketiminate/guanidinate complexes of calcium,16
the ureido ligand binds via a k2-O,N-chelate and is the first
example in calcium coordination chemistry.
Catalyst turnover may be envisaged by
protonolysis reaction of 4 with diphenylamine to regenerate
the amide and liberate the hydroamination product
a further
3
1,10-diphenyl-3-(1-adamantyl)urea (5). Accordingly, the
addition of 5 mol% 4 to diphenylamine and 1-adamantyl
isocyanate at room temperature in C6D6 gave, after 2 h, 5 in
92% yield as monitored by 1H NMR spectroscopy. Similarly,
both 1 and 3 proved catalytically active and yielded the
product in 89% and 93%, respectively under identical reaction
conditions (Scheme 2). The structure of the urea 5 was
confirmed by multinuclear NMR and infrared spectroscopy,
mass spectrometry and single crystal X-ray diffraction (see ESI
Fig. S1w) following a preparative scale synthesis. A back-
ground experiment, conducted in C6D6, demonstrated no
reaction between diphenylamine and 1-adamantyl isocyanate
over a period of 4 weeks at room temperature or 16 h at 80 1C
further underscoring the efficacy of catalysis.
Extension of this catalytic reactivity to the heavier congeners
of the alkaline earths, strontium and barium, employing 2b and
2c, provided notable results. Following the reaction of
2,6-di-iso-propylphenyl isocyanate with diphenylamine, using
6 mol% 2a–c in C6D6 at 60 1C with near constant catalyst
[40–45 mM] and substrate starting concentrations [0.65–0.70 M],
Previous studies upon the catalytic hydroamination of carbo-
diimides, have demonstrated that homoleptic group 2 metal
amide complexes are suitable pre-catalysts for this transformation
and it is proposed that the reaction products may act as ligands to
not only kinetically stabilise intermediate group 2 species but also
1
by H NMR spectroscopy revealed an apparent effect of ionic
radius on the course of the reaction (Fig. 2c). Although, in
Fig. 2 Plot of (a) [substrate] and [product] versus time and (b) log [substrate] versus time for the reaction of 1-adamantyl isocyanate,
diphenylamine and 5 mol% [Ca{N(SiMe3)2}2]2 at rt. (c) Plot of yield versus time for the reaction of 2,6-di-iso-propylphenyl isocyanate,
diphenylamine and 6 mol% [M{N(SiMe3)2}2]2 (M = Ca, Sr and Ba) or no catalyst at 60 1C.
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13C NMR (C6D6, 100 MHz, 298 K) 24.5, 24.8, 25.0, 25.3, 28.3, 30.4, 36.8,
44.1, 51.7, 70.4, 93.5, 122.0, 122.5, 124.2, 124.4, 129.4, 141.5, 146.6, 146.8,
165.3, 165.5. Elemental analysis calc. for C56H74CaN4O2: C, 76.77; H,
8.45; N, 6.40%. Found C, 76.77; H, 8.43; N, 6.31%.
y X-Ray diffraction data for 4. C56H74CaN4O2, M = 875.27, monoclinic,
P21/n, a = 12.3837(2) A, b = 19.3136(3) A, c = 21.3459(4) A,
b = 93.5240(10)1, V = 5095.73(15) A3, Z = 4, r = 1.141 g cmꢁ3
,
Temperature 150(2) K, R1 [I 4 2s(I)] = 0.0532, wR2 [I 4 2s(I)] =
0.1118, R1 [all data] = 0.0935, wR2 [all data] = 0.1313, measured
reflections = 51 119, unique reflections = 11 481, Rint = 0.0843.
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Fig. 3 Stack plot of 1H NMR data from the reaction of 1-adamantyl
isocyanate and diphenylamine with 5 mol% 2a at rt. Spectra recorded
at (a) 5 (b) 7 (c) 11 (d) 14 (e) 22 and (f) 40 min. Substrate (s) and
product (p) peaks annotated.
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accordance with previous studies upon the hydroamination of
carbodiimides,13d the strontium analogue 2b provided a higher
yield and a faster rate of reaction than the calcium amide 2a,
catalytic reactions employing the barium compound 2c were
accompanied by the precipitation of a colourless solid. Although
this material was not characterised further, it is most likely that the
increased dicationic radius of barium (1.35 A)17 allows
the formation of insoluble polymeric amide or ureido species,
the precipitation of which depletes the potentially catalytically
active species from solution.
In summary, we have demonstrated that inexpensive and easily
prepared alkaline earth amides of calcium and strontium may be
applied to catalytic urea synthesis via an amide–isocyanate
coordination–insertion mechanism. Although our studies are
presently limited to the catalytic assembly of diphenylamine and
relatively sterically demanding organic isocyanates, we are
continuing to broaden the scope of our studies and these results
will be communicated in subsequent publications.
We thank GlaxoSmithKline for a generous endowment (to
A.G.M.B.), the Royal Society for a University Research
Fellowship (M.S.H.) and Royal Society Wolfson Research
Merit Award (A.G.M.B.) and the Engineering and Physical
Sciences Research Council and GlaxoSmithKline for generous
support of our studies.
Notes and references
z To a solution of 3 (0.85 g, 1.22 mmol) in hexane (15 mL) was added a
solution of 1-adamantyl isocyanate (0.22 g, 1.24 mmol) in the same
solvent (10 mL). The reaction mixture was stirred for 4 h at room
temperature and the solvent volume reduced to ca. 15 mL. The product
was isolated by hot recrystallisation from this concentrated solution.
Filtration gave colourless crystals of 4 (0.38 g, 0.43 mmol, 36%
unoptimised). 1H NMR (C6D6, 400 MHz, 298 K) 1.16–1.20 (m, 6H),
1.19 (d, 12H, J = 6.8 Hz), 1.23 (m, 4H, THF), 1.34 (d, 12H, J = 6.4 Hz),
1.40–1.49 (m, 6H), 1.69–1.72 (m, 3H), 1.72 (s, 6H), 3.25 (broad heptet,
4H, J = 6.4 Hz), 3.72 (m, 4H, THF), 4.79 (s, 1H), 6.84 (t, 2H, J =
7.2 Hz), 6.93 (d, 4H, J = 8.0 Hz), 7.06–7.09 (m, 4H), 7.13–7.16 (m, 6H);
Kohn, M. S. Hill, M. F. Mahon and P. A. Procopiou, Eur. J.
¨
Inorg. Chem., 2008, 4173.
14 For an example of isocyanate trimerisation at calcium see: L.
Orzechowski and S. Harder, Organometallics, 2007, 26, 2144.
15 A. W. Addison, T. N. Rao, J. Reedijk, J. van Rijn and G. C.
Verschoor, J. Chem. Soc., Dalton Trans., 1984, 1349.
16 A. G. M. Barrett, M. R. Crimmin, M. S. Hill, P. B. Hitchcock and
P. A. Procopiou, Dalton Trans., 2008, 4474.
17 Values quoted for 6 coordinate M2+, R. D. Shannon, Acta
Crystallogr., Sect. A, 1976, A32, 751–767.
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5208 | Chem. Commun., 2008, 5206–5208