A magnesium-mediated cascade assembly for the atom-economical synthesis of bis(imidazolidine-2,4-dione)s

Article abstract of DOI:10.1002/anie.201301489

Bicycle race: Structurally complex bis(imidazolidine-2,4-dione) molecules may be synthesized with complete atom-efficiency from simple building blocks by a kinetically controlled magnesium-mediated cascade of intermolecular isocyanate insertion and intramolecular alkyne hydroamination reaction steps. Copyright

Full text of DOI:10.1002/anie.201301489

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Angewandte
Communications
DOI: 10.1002/anie.201301489
N-Heterocycles
A Magnesium-Mediated Cascade Assembly for the Atom-Economical
Synthesis of Bis(imidazolidine-2,4-dione)s**
Michael S. Hill,* David J. Liptrot, and Mary F. Mahon
The ubiquity of N-heterocycles, particularly as components of
drug and natural product structures, has stimulated enormous
interest in the development of new methods for their
preparation.[1] Driven by considerations of atom-efficiency
and energy use, the catalytic intramolecular hydroamination
of aminoalkenes and aminoalkynes, for example, has gar-
nered particularly intense attention.[2] Our own work has
concentrated upon the utility of heavier alkaline earth (Mg,
À
Ca, Sr, Ba) complexes for the catalysis of just these C N bond
forming processes in which the activation barriers toward rate
=
determining C C insertion have been found to be profoundly
influenced by the identity of the Group 2 metal cation
(Scheme 1).[3] Application of the same suite of pre-catalysts to
Scheme 2.
reactivity of these heterocumulenes with Group 2 and other
electrophilic metal centers has been dominated by polymer-
ization or oligomerization to form poly- or oligo-isocyanu-
rates.[8] This latter C N coupling reactivity has been ration-
À
alized to proceed by multiple isocyanate insertion, the
viability of which has been most relevantly demonstrated by
Harder and co-workers through their isolation of a double
insertion product from the reaction of cyclohexyl isocyanate
with a calcium bis(iminophosphorano)diide.[9] Mindful of this
possibility and other recent examples of magnesium-medi-
ated cascade reactivity,[10] we here demonstrate that similar
isocyanate oligomerization may be combined with an intra-
molecular alkyne insertion step reminiscent of that depicted
in Scheme 1. The resultant cascade process allows the syn-
thesis of unprecedented and structurally complex bis(imid-
azolidine-2,4-dione) molecules from these simple building
blocks and with complete atom efficiency.
Scheme 1.
the intermolecular heterofunctionalization of carbodiimides
with protic amine, phosphine, or terminal alkyne reagents has
À
À
À
also provided access to the respective C N, C P and C C
coupled products and a plethora of guanidine,[4] phosphagua-
nidine,[5] and propargylamidine[6] molecules (Scheme 2).
Although the formation of substituted ureas by the hydro-
amination of organic isocyanates has also been shown to
proceed with considerable efficacy,[7] previously reported
An initial NMR scale reaction was performed by addition
of an excess (10 molar equivalents) of n-propyl isocyanate to
a 2:1 mole ratio of phenylacetylene and commercial di-
butylmagnesium in tetrahydrofuran (THF). This process
provided evidence for consumption of the isocyanate reagent
through the appearance of a number of non-equivalent and
broadened resonances in the aliphatic region of the resultant
1H NMR spectrum. Encouraged by this observation, the
reaction was repeated on a preparative scale, whereupon
work-up under moist aerobic conditions and crystallization at
À188C from toluene solution provided single crystals of
compound 1 suitable for single-crystal X-ray diffraction
analysis.[11] The results of this analysis, shown in Figure 1a,
revealed that compound 1 is a structurally complex bis(imid-
azolidine-2,4-dione), which may be considered to be a product
[*] Prof. M. S. Hill, D. J. Liptrot, Dr. M. F. Mahon
Department of Chemistry, University of Bath
Claverton Down, Bath, BA2 7AY (UK)
E-mail: msh27@bath.ac.uk
[**] We thank the EPSRC (UK) for funding.
Supporting information for this article (details of the synthesis,
characterization data, and the crystallographic protocols) is avail-
able on the WWW under http://dx.doi.org/10.1002/anie.
201301489.
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tute a very well established
class of cyclic ureides,[12]
used as anticonvulsant
drugs (e.g. phenytoin and
its derivatives)[13] and are
components of a plethora
of other commercial phar-
maceutical products such as
small-molecule inhibitors
of cell division and non-
steroidal androgen recep-
tor antagonists or ago-
nists,[14] structures of the
type exemplified by com-
pounds 1–4 have not been
hitherto reported in the
literature possibly owing
to the complexity of their
formation by conventional
methods. We propose that
both the course and the
diastereoselectivity
of
these reactions may be
readily accounted for by
consideration of well pre-
cedented Group 2-based
reactivity summarized in
Schemes 1 and 2. A mech-
anism for the formation of
compounds 1–4, which
accounts for the diastereo-
selectivity, is, thus, illus-
trated in Scheme 4.
Figure 1. ORTEP representations of compounds 1 (a), 2 (b), 3 (c), and 4 (d). Thermal ellipsoids are depicted
at 50% probability. Hydrogen atoms except those attached to C(16) (1), C(14) (2), and C(23) (3) and the
phenyl rings of the benzyl groups of compound 3 attached through C(10), C(17), C(26) and C(34) are omitted
for clarity.
A series of insertion
from the combination of a single equivalent of phenylacety-
lene and four equivalents of n-propyl isocyanate (Scheme 3).
The potential generality of this reaction was demonstrated
by extension of the reaction protocol to the synthesis of the
analogous bis(imidazolidine-2,4-dione) compounds 2–4,
through use of the alternative ethyl (2), benzyl (3), and
phenyl (4) isocyanate substrates, respectively. In each case
identical reaction and work-up procedures yielded the
crystalline bis(imidazolidine-2,4-dione) products in high
yield (Figure 1b–d).
The crystallographic analyses and yields greater than 50%
confirmed that the formation of products 1–4 had, in each
case, occurred diastereoselectively to provide either the R,S/
S,R (1–3) or the R,R/S,S (4) pair of diastereomers.[11]
Although the imidazolidine-2,4-diones (hydantoins) consti-
steps underpin this reaction as follows; steps (a), (b), (d),
and (e) are isocyanate insertions into metal–acetylide and
metal–amidate bonds similar to those observed by both the
groups of Hill and Harder for the heavier Group 2 con-
geners.[7,9] Steps (c) and (f) are hydroaminations of an alkyne
and alkene, respectively. These reactions are known to be
catalyzed by magnesium albeit with lower reactivity than its
heavier congeners and step (g) to yield the bis(imidazolidine-
2,4-dione) products requires protonolysis of the as-formed
metal alkyl. The geometry of the intermediate alkene formed
may be predicted by consideration of the syn-addition which
typically defines Group 2-catalyzed hydroamination.[3] The
observed diastereoselectivity is thus predicated upon a keto–
enol tautomerization whereby the formation of a metal
chelate directs protonation to the least hindered face of the
sp2 b-carbon (step (g), Scheme 4). The absence of larger rings
can be attributed to the rapidity of alkyne hydroamination
yielding five-membered rings in preference to larger rings and
the likely irreversibility of this step. Finally, the lack of
intermolecular hydroamination can be attributed to the
relatively large entropic penalty this reaction would incur,
making it disfavored with regards to the proposed intra-
molecular hydroamination.
A study of these reactions by electrospray ionization mass
spectrometry (ESI-MS) performed on aliquots removed from
Scheme 3.
Angew. Chem. Int. Ed. 2013, 52, 5364 –5367
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Angewandte
Communications
In summary, we have reported the diaste-
reoselective synthesis of a series of structurally
complicated and unprecedented bis(imidazoli-
dine-2,4-dione). Initial mechanistic evidence
suggests a cascade of well precedented steps
mediated by a Group 2 center that is viable for
a range of alkyl and aryl isocyanates. Work is
continuing to examine the broader scope of this
reactivity through the inclusion of other hetero-
cumulenes, alongside the viability of extending
this process to a catalytic regime.
Received: February 20, 2013
Revised: March 20, 2013
Published online: April 15, 2013
Keywords: alkyne · heterocycle ·
.
homogeneous catalysis · isocyanate · magnesium
[1] See, for example; The Chemistry of Heterocycles,
(Eds.: T. Eicher, S. Hauptmann), Wiley-VCH,
Weinheim, 2003.
[2] See, for example; S. Hong, T. J. Marks, Acc.
Chem. Res. 2004, 37, 673.
[3] a) M. R. Crimmin, I. J. Casely, M. S. Hill, J. Am.
Chem. Soc. 2005, 127, 2042; b) M. R. Crimmin,
M. Arrowsmith, A. G. M. Barrett, I. J. Casely,
M. S. Hill, P. A. Procopiou, J. Am. Chem. Soc.
2009, 131, 9670; c) M. Arrowsmith, M. R. Crim-
min, A. G. M. Barrett, M. S. Hill, G. Kociok-
Kçhn, P. A. Procopiou, Organometallics 2011, 30, 1493; d) B.
Liu, T. Roisnel, J.-F. Carpentier, Y. Sarazin, Angew. Chem. 2012,
124, 5027; Angew. Chem. Int. Ed. 2012, 51, 4943.
Scheme 4. Proposed stepwise mechanism yielding bis(imidazolidine-2,4-dione)s
through metallocarboration and metalloamination steps.
THF solutions of reaction mixtures containing each of the
isocyanates, phenylacetylene, and di-butylmagnesium in an
8:2:1 ratio and diluted in methanol provided strong evidence
[4] a) J. Lachs, A. G. M. Barrett, M. R. Crimmin, G. Kociok-Kçhn,
M. S. Hill, M. F. Mahon, P. A. Procopiou, Eur. J. Inorg. Chem.
2008, 4173; b) A. G. M. Barrett, M. R. Crimmin, M. S. Hill, P. B.
Hitchcock, P. A. Procopiou, Dalton Trans. 2008, 4474.
[5] a) M. R. Crimmin, A. G. M. Barrett, M. S. Hill, P. B. Hitchcock,
P. A. Procopiou, Organometallics 2008, 27, 497; b) T. M. A. Al-
Shboul, G. Volland, H. Gçrls, M. Westerhausen, Z. Anorg. Allg.
Chem. 2009, 635, 1568.
[6] A. G. M. Barrett, M. R. Crimmin, M. S. Hill, P. B. Hitchcock,
S. L. Lomas, M. F. Mahon, P. A. Procopiou, K. Suntharalingam,
Organometallics 2008, 27, 6300.
[7] A. G. M. Barrett, T. C. Boorman, M. R. Crimmin, M. S. Hill, G.
Kociok-Kçhn, P. A. Procopiou, Chem. Commun. 2008, 5206.
[8] See, for example; a) A. J. Burt, L. J. Fetters, Chem. Rev. 1976, 76,
727; b) V. E. Shashoua, W. Sweeny, R. F. Tietz, J. Am. Chem.
Soc. 1959, 81, 866; c) J. Shi, Z.
for the course of reaction illustrated in Scheme 4. The results
of this study, shown in Table 1, revealed the presence of both
the product of initial isocyanate insertion into the magnesium
À
acetylide Mg C bond, the propargyl amide, A, and the result
À
of intramolecular alkyne Mg N insertion, the alkene, B.
Although alkene, B, could not be observed directly during the
formation of compound 3, we propose that this is likely to be
a consequence of the propensity of the isocyanate to insert
into the intermediate vinylmagnesium species. Identical ESI-
MS studies of analogous reactions quenched with MeOD also
provided ions assignable to the analogous deuterated versions
of 1–4.
Guo, X. Wei, D. Liu, M. F. Lap-
Table 1: Details of the mass spectrometric analysis of the magnesium-mediated bicycle formation giving
insight into the mechanism of the reaction.
pert, Synlett 2011, 1937.
[9] a) L. Orzechowski, S. Harder,
Organometallics 2007, 26, 2144;
see also, b) L. Orzechowski, S.
Harder, Organometallics 2007, 26,
5501.
[10] V. L. Blair, W. Clegg, A. R. Ken-
nedy, Z. Livingstone, L. Russo, E.
Hevia, Angew. Chem. 2011, 123,
10031; Angew. Chem. Int. Ed.
2011, 50, 9857.
[11] X-ray diffraction data for 1:
C24H34N4O4, M = 442.55, mono-
clinic, C2/c, a = 20.8696(3), b =
Product
R
[A+H]+
[B+Na]+
[C+Na]+
Expected
Observed
Expected
Observed
Expected
Observed
1
2
3
4
Pr
Et
Ph
Bz
188.1075
174.0919
222.0919
236.1075
188.1071
174.0915
222.0925
295.1422
267.1109
363.1109
391.1422
295.1438
267.1107
465.2478
409.1852
601.1852
657.2478
465.2480
409.1879
601.1860
657.2469
391.1417
5366
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Angew. Chem. Int. Ed. 2013, 52, 5364 –5367

Angewandte
Chemie
13.0729(3),
c = 18.5290(4) ꢀ,
b = 106.566(1)8,
V=
2s(I)] = 0.1579, R1 [all data] = 0.1677, wR2 [all data] = 0.1780,
measured reflections = 12194, unique reflections = 6811, Rint
0.0668. CCDC 925518–925521 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
4845.36(17) ꢀ3, Z = 8, 1 = 1.213 gcmÀ3, T= 150(2) K, R1 [I >
2s(I)] = 0.0596, wR2 [I > 2s(I)] = 0.1108, R1 [all data] =
0.1104, wR2 [all data] = 0.1265, measured reflections = 44500,
unique reflections = 5469, Rint = 0.1110. 2: C27H40N4O5.75, M =
512.63, monoclinic, P21/a, a = 9.6689(2), b = 23.2345(8), c =
12.8044(4) ꢀ, b = 97.154(2)8, V= 2854.14(15) ꢀ3, Z = 4, 1 =
1.193 gcmÀ3, T = 150(2) K, R1 [I > 2s(I)] = 0.0795, wR2 [I >
2s(I)] = 0.1964, R1 [all data] = 0.1471, wR2 [all data] = 0.2316,
=
[12] E. Ware, Chem. Rev. 1950, 46, 403.
[13] a) D. D. Claeys, C. V. Stevens, N. Dieltiens, Eur. J. Org. Chem.
2008, 171; b) G. G. Muccioli, D. Martin, G. K. E. Scriba, W.
Poppitz, J. H. Poupaert, J. Wouters, D. M. Lambert, J. Med.
Chem. 2005, 48, 2509; c) C. Zha, G. B. Brown, W. J. Brouillette, J.
Med. Chem. 2004, 47, 6519; d) M. Jansen, H. Potschka, C.
Brandt, W. Lçscher, G. Dannhardt, J. Med. Chem. 2003, 46, 64.
[14] a) V. Kumar, M. P. Kaushik, A. Mazumdar, Eur. J. Org. Chem.
2008, 1910; b) D. Zhang, X. Xing, G. D. Cuny, J. Org. Chem.
2006, 71, 1750; c) S. Hotha, J. C. Yarrow, J. G. Yang, S. Garrett,
K. V. Renduchintala, T. U. Mayer, T. M. Kapoor, Angew. Chem.
2003, 115, 2481; Angew. Chem. Int. Ed. 2003, 42, 2379; d) B.
Maiti, K. Chanda, C.-M. Sun, Org. Lett. 2009, 11, 4826.
measured reflections = 41517, unique reflections = 6480, Rint
=
0.0862. 3: C40H34N4O4, M = 634.71, monoclinic, P21/n, a =
11.9110(3), b = 20.4610(5), c = 13.1590(4) ꢀ, b = 101.447(2)8,
V= 3143.20(15) ꢀ3, Z = 4, 1 = 1.341 gcmÀ3, T = 150(2) K, R1
[I > 2s(I)] = 0.0563, wR2 [I > 2s(I)] = 0.1278, R1 [all data] =
0.1179, wR2 [all data] = 0.1557, measured reflections = 52000,
unique reflections = 7205, Rint = 0.1176. 4: C43H34N4O4, M =
670.74, monoclinic, P21/n, a = 16.8320(8), b = 9.5660(7), c =
22.1100(4) ꢀ, b = 108.493(4)8, V= 3376.2(4) ꢀ3, Z = 4, 1 =
1.320 gcmÀ3, T = 150(2) K, R1 [I > 2s(I)] = 0.0967, wR2 [I >
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