A cascade synthesis of aminohydantoins using in situ-generated N-substituted isocyanates

Article abstract of DOI:10.1002/chem.201405648

Nitrogen-substituted isocyanates are rarely utilized but powerful building blocks for the development of cascade reactions in heterocyclic synthesis. These reactive amphoteric intermediates can be accessed in situ via an equilibrium that allows controlled reactivity in the presence of bifunctional partners such as a-amino esters. A cascade reaction has been carried out that forms 3-aminohydantoin derivatives using simple phenoxycarbonyl derivatives of hydrazides and hydrazones as precursors of Nsubstituted-isocyanates. This method allows rapid assembly of complex aminohydantoin derivatives, including analogues of medicinally-relevant compounds, using simple reactants.

Full text of DOI:10.1002/chem.201405648

DOI: 10.1002/chem.201405648
Communication
&
Cascade Reactions |Hot Paper|
A Cascade Synthesis of Aminohydantoins Using In Situ-Generated
N-Substituted Isocyanates
Jean-FranÅois Vincent-Rocan, Christian Clavette, Kyle Leckett, and Andrꢀ M. Beauchemin*[a]
Abstract: Nitrogen-substituted isocyanates are rarely uti-
lized but powerful building blocks for the development of
cascade reactions in heterocyclic synthesis. These reactive
amphoteric intermediates can be accessed in situ via an
equilibrium that allows controlled reactivity in the pres-
ence of bifunctional partners such as a-amino esters. A
cascade reaction has been carried out that forms 3-amino-
hydantoin derivatives using simple phenoxycarbonyl de-
rivatives of hydrazides and hydrazones as precursors of N-
Figure 1. Available therapeutics containing aminohydantoin motifs.
substituted-isocyanates. This method allows rapid assem-
bly of complex aminohydantoin derivatives, including ana-
and then react with nucleophiles such as amines, alcohols, and
logues of medicinally-relevant compounds, using simple
thiols.[6d–e] Using this reactivity, we developed a cascade substi-
reactants.
tution/hydroamination sequence allowing rapid assembly of
saturated nitrogen heterocycles from hydrazide starting materi-
als.[6e] This reactivity showed that amino-isocyanates can
Hydantoins are important heterocycles that display a wide
range of biological activities. For example, dantrolene (anti-
spasmodic), azimilide (antiarrhythmic), and nitrofurantoin (anti-
bacterial) are valuable pharmaceuticals (Figure 1).[1] A variety of
hydantoin syntheses have been described, including cascade
reactions from simple starting materials.[1,2] In contrast fewer
approaches to aminohydantoin derivatives have been report-
ed,[3] despite their importance as pharmaceuticals and agro-
chemicals and growing interest in the inclusion of NÀN func-
tionalities into molecular scaffolds. Unfortunately, current
methods require multistep synthesis and can suffer from che-
moselectivity issues that are typically associated with the use
of complex hydrazine derivatives.[4] Cascade reactions could
provide a streamlined access to this important subunit.
engage in controlled cascade reactions forming products bear-
ing the NÀNÀC=O motif, and hinted that other cascades could
be designed. We were drawn to aminohydantoins given their
biological activities and the need for more convergent and ver-
satile synthetic approaches. Herein, we report that complex
aminohydantoin derivatives are rapidly assembled using a cas-
cade reaction in which both hydrazides and hydrazones are
suitable N-substituted isocyanate precursors (Scheme 1).
In contrast to normal (C-substituted) isocyanates, the reactiv-
ity of N-substituted isocyanates has received little attention
from the synthetic community.[5] Recently, we reported that
amphoteric amino- and imino-isocyanates can be formed in
situ under mild conditions and engage in high-yielding alkene
cycloadditions[6a–c] and nucleophilic additions,[6d,e] despite their
known tendency to dimerize or oligomerize.[7,8] Hydrazones[6b–d]
and hydrazides[6a,e] are bench-stable, convenient “blocked” N-
substituted isocyanate precursors[9] that form the desired iso-
cyanates via an equilibrium induced under mild conditions,
Scheme 1. Cascade reactions exploiting blocked N-substituted isocyanates.
Our efforts toward cascade reactions using a-amino esters
build on our recent discovery that substitution reactivity on
hydrazides proceeds at 60–1008C [Eq. (1)]. We speculated that
this could be optimized, and that, upon heating, cyclization
would occur. This cyclization was first observed with a l-pro-
line ester and led to the selective formation of a 5-membered
hydantoin over the 6-membered aza-diketopiperazine
[Eq. (2)].[10]
[a] J.-F. Vincent-Rocan, C. Clavette, K. Leckett, Prof. Dr. A. M. Beauchemin
Centre for Catalysis Research and Innovation
Department of Chemistry, University of Ottawa
10 Marie-Curie, Ottawa, ON K1N 6N5 (Canada)
E-mail: andre.beauchemin@uottawa.ca
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405648.
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ences[11] of the semicarbazide intermediate. In addition, even
a b-amino ester cyclized to yield an amino dihydrouracil deriv-
ative (Table 1, entry 6). Finally, N,N-dibenzylcarbazate 1c
(Table 1, entry 7) also cyclized in good yield. In contrast to the
previous examples (LG=OPh; Table 1, entries 1–6), a tempera-
ture of 1508C was required to ensure the formation of the
amino-isocyanate intermediate using OtBu as
a leaving
group.[6a] This leaving group was chosen to facilitate the syn-
thesis of the starting material (1c), due to the lability observed
during the formation of OPh derivative. It is important to note
that cyclizations with enantiopure a-amino esters yield racemic
hydantoins, due to their ease of enolization (see the Support-
ing Information).[4k,m]
Encouraged by this unoptimized reactivity and high chemo-
selectivity, we explored the scope of the reaction using simple
N-benzyl carbazates and a-amino esters (Table 1). We were
pleased that N-substituted glycine esters formed aminohydan-
toins in good yields at 1008C (Table 1, entries 1 and 2), where-
as alanine (entry 3), leucine (entry 4) and proline (entry 5)
esters also cyclized in moderate to good yields but required
higher temperatures, likely due to the conformational prefer-
Having established the reactivity of hydrazides, we wanted
to expand the scope to other N-substituted isocyanate precur-
sors. To our knowledge, there have been no examples of cas-
cade reactions involving either imino-isocyanates (C=NÀNCO)
or amido-isocyanates [C(=O)NÀNCO] reported to date, and we
felt that this extension would significantly broaden the applica-
bility of this approach to aminohydantoins. Thus we first inves-
tigated the ability of imino-isocyanates to engage in cascade
reactions, building on our recent report on their substitution
reactivity.[6d] We were pleased that several hydrazones used as
imino-isocyanate precursors afforded the desired aminohydan-
toins in the presence of N-methyl glycine ethyl ester (Table 2).
Encouragingly, both aliphatic and aromatic hydrazones af-
forded the desired aminohydantoins (4a,b,g and 4c–f,h–i).
The cascade sequence also proceed efficiently using both alde-
Table 1. Initial scope using N-benzyl carbazates and amino esters.[a,b]
Entry Amino ester
T
[8C]
Product
Yield
[%]
Table 2. Hydrazone scope using N-methyl glycine ethyl ester.[a]
1
R1 =Me,R2 =H,R5 =Et 100 R1 =Me,R2 =H,R3 =Bn (2a) 82
2[c]
R1 =Bn,R2 =H,R5 =Et 100
R1 =Bn,R2 =H,R3 =OMB
(2b)
72
3
4
R1 =H,R2 =Me,R5 =
150 R1 =H,R2 =Me,R3 =Bn (2c) 70
Me
R1 =H,R2 =iBu,R5 =
Me
150 R1 =H,R2 =iBu,R3 =Bn (2d) 62
5
100
150
150
49
62
81
(2e)
(2 f)
6
7[d]
(2g)
[a] Conditions: Carbazate (1 equiv), amino ester (1.1 equiv), iPr2NEt
(1.2 equiv) in PhCF3 (0.3m), heated for 6 h (sealed vial, microwave reac-
tor); [b] using N-benzyl reagent 1a (LG=OPh); [c] using N-OMB reagent
1b (LG=OPh); [d] using N,N-dibenzyl carbazate 1c (LG=OtBu). LG=leav-
ing group; OMB=o-methoxybenzyl.
[a] Conditions: Carbazate (1 equiv), amino ester (1.1 equiv), iPr2NEt
(1.2 equiv) in PhCF3 (0.3m), heated at 1008C for 6 h (sealed vial, micro-
wave reactor).
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hyde- and ketone-derived hydrazones (3a–f vs. 3g–i). We were
pleased that electron-rich (3c,f) and electron-poor (3d,e) aro-
matic hydrazones proved applicable reagents. In general,
higher yields were obtained using hydrazones (Table 2), rather
than hydrazides (Table 1), as isocyanate precursors, which is in
line with the easier purification of the products by chromatog-
raphy.
action [Eq. (4) vs. 4i (Table 2)].[12] Moreover, we were also able
to cyclize acyl carbazate 7b to yield amidohydantoin 8c
[Eq. (5)]. Overall, these extensions further highlight that this
substitution/cyclization sequence is broadly applicable for the
synthesis of complex aminohydantoins and related heterocy-
cles.
Pleased by the generality of the cascade with hydrazones,
we proceeded to survey its applicability by treating several
amino esters with anisole-derived hydrazone 3c (Table 3). Grat-
Table 3. Cascade reaction of several a-amino esters with hydrazone
3c.[a,b]
Finally, we looked at the potential of our method for medici-
nal chemistry purposes. As previously mentioned, aminohydan-
toin subunits are present in many pharmaceuticals; however,
the hydantoin core often lacks substitution. We thus became
interested in a late-stage formation of substituted hydantoins
from a common precursor. Our approach led to the rapid for-
mation of several products related to azumolene (Table 4),
a veterinary drug that displays unique activity.[13]
[a] Conditions: Carbazate (1 equiv), amino ester (1.1 equiv), iPr2NEt
(1.2 equiv) in PhCF3 or MeCN (0.3m), heated for 6 h (sealed vial, micro-
wave reactor); [c] T: 6a: 1008C, 6b: 1208C, 6c–f: 1508C. PMP=p-me-
thoxyphenyl.
As illustrated, a variety of N-substituted azumolene ana-
logues were formed in good to excellent yields from
a common hydrazone (3j; Table 4). Strategically, this late-stage
hydantoin assembly nicely complements other approaches in-
volving diversification from a common NÀH aminohydantoin
precursor. For example, N-alkylation can be challenging (e.g.
secondary substituents, 3g), and N-arylation can be problemat-
ic in the presence of aromatic halides (e.g. the bromide pres-
ent in 3j). Gratifyingly the assembly of both N-alkyl (9b,d–f)
and N-aryl (9c) iminohydantoins was achieved in one step and
was amenable to the incorporation of functional groups
(9d,e). We were also pleased to see that no silica gel column
was necessary for the purification of the intermediate or any of
the final compounds, making this method practical for late-
stage incorporation of an iminohydantoin subunit.
ifyingly, various functional groups were tolerated on the a-
amino ester partner. For example, a nitrile did not interfere
with the cyclization and yielded the hydantoin 6a in excellent
yield. Addition/cyclization using diethyl iminodiacetate also
provided the ester-substituted hydantoin 6b. More sterically
hindered substituents on the nitrogen of the a-amino ester
were also tolerated, as observed for the formation of N-isopro-
pyl (6c) and N-aryl (6d–f) hydantoins. We were very pleased
that N-aryl glycine esters proved competent reaction partners
(6d–f), since anilines are rather poor nucleophiles. However,
this result is in line with the proposed involvement of imino-
isocyanate intermediates, given their high electrophilicity.[5]
At this stage we became interested in variations of this cas-
cade to form other interesting classes of molecules. For exam-
ple, we were pleased that a cascade involving substitution/cyc-
lization via 1,4-addition occurred on a suitable amine precursor
to yield imidazolidinone 8a [Eq. (3)]. Next, we used a novel ac-
tivated reagent to generate an amino-isothiocyanate in situ
and isolated aminothiohydantoin 8b from a related cascade re-
In summary, we have developed a cascade reaction forming
aminohydantoins relying on the use of simple hydrazides and
hydrazones as precursors of N-substituted isocyanates. The cas-
cade relies on the addition of a-amino esters to isocyanate in-
termediates generated in situ, followed by cyclization to afford
the desired hydantoins. The broad applicability of the reaction
sequence is remarkable considering that N-substituted-isocya-
nates are amphoteric molecules, and that this amphotericity is
known to lead to unwanted side reactions (e.g. dimerization).
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Table 4. Cascade synthesis of azumolene analogues.[a]
Keywords: cascade reactions · hydantoins · isocyanates ·
isothiocyanates · synthetic methods
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[a] Conditions: Carbazate (1 equiv), amino ester (1.1 equiv), iPr2NEt
(1.2 equiv) in PhCF3 or MeCN (0.3m), heated at 1508C for 6 h (sealed vial,
microwave). C.A. = Commercially Available.
Overall, these results highlight the synthetic potential of these
rarely utilized N-substituted-isocyanates in heterocycle synthe-
sis and medicinal chemistry. The discovery of new reaction se-
quences building on this work is ongoing and will be reported
in due course.
[4] For reviews on hydrazines and hydrazides, see: a) E. F. Rothgery, Kirk–
Othmer Encyclopedia of Chemical Technology, Vol. 13, 5th ed., Wiley, New
York, 2004, pp. 562–607; b) U. Ragnarsson, Chem. Soc. Rev. 2001, 30,
205.
Experimental Section
[5] For selected reports on the reactivity of nitrogen-substituted isocya-
nates, see: Amino isocyanates: a) W. S. Wadsworth, W. D. Emmons, J.
Org. Chem. 1967, 32, 1279; b) W. J. S. Lockley, W. Lwowski, Tetrahedron
Lett. 1974, 15, 4263; c) M. Kurz, W. Reichen, Tetrahedron Lett. 1978, 19,
1433; Imino isocyanates: d) D. W. Jones, J. Chem. Soc. Chem. Commun.
1982, 766; e) W. Theis, W. Bethꢄuser, M. Regitz, Chem. Ber. 1985, 118,
28, (CONR-NCO) f) H. Han, K. D. Janda, J. Am. Chem. Soc. 1996, 118,
2539; For reviews, see: g) W. Reichen, Chem. Rev. 1978, 78, 569; h) C.
Wentrup, J. J. Finnerty, R. Koch, Curr. Org. Chem. 2011, 15, 1745.
[6] a) J.-G. Roveda, C. Clavette, A. D. Hunt, C. J. Whipp, S. I. Gorelsky, A. M.
Beauchemin, J. Am. Chem. Soc. 2009, 131, 8740; b) C. Clavette, W. Gan,
A. Bongers, T. Markiewicz, A. B. Toderian, S. I. Gorelsky, A. M. Beauche-
min, J. Am. Chem. Soc. 2012, 134, 16111; c) W. Gan, P. J. Moon, C. Clav-
ette, N. Das Neves, T. Markiewicz, A. B. Toderian, A. M. Beauchemin, Org.
Lett. 2013, 15, 1890; d) K. Garland, W. Gan, C. Depatie-Sicard, A. M.
Beauchemin, Org. Lett. 2013, 15, 4074; e) C. Clavette, J.-F. Vincent-
Rocan, A. M. Beauchemin, Angew. Chem. Int. Ed. 2013, 52, 12705–
12708; Angew. Chem. 2013, 125, 12937–12940.
An oven-dried microwave tube with a stir bar was capped with
a septum, purged with argon, and fitted with an outlet for 5 min.
The carbazate (1.0 equiv), amino ester hydrochloride salt
(1.1 equiv), N,N-diisopropylethylamine (1.2 equiv) and a,a,a-tri-
fluorotoluene (0.3m) were added to the seal tube, while keeping it
under an argon atmosphere. The septum was removed and the
tube was then quickly sealed with a microwave cap and heated for
six hours at 80–1508C. The tube was allowed to cool to ambient
temperature, concentrated under reduced pressure, and purified
by silica gel chromatography to give the corresponding products.
See the Supporting Information for details.
Acknowledgements
We thank the University of Ottawa, NSERC (DAS, CREATE, and
CRD grants to A.M.B.), CFI, and the Ontario MRI for generous fi-
nancial support. Support of related work by AstraZeneca
Canada and OmegaChem is gratefully acknowledged. C.C. and
J.F.V.R. thank NSERC (CREATE on medicinal chemistry and bio-
pharmaceutical development, PGS-D for J.F.V.R) and OGS for
scholarships. K.L. thanks NSERC for a USRA scholarship.
[7] For an example with amino-isocyanates, see reference [5b].
[8] For examples of nitrogen-containing amphoteric reagents, see: a) R.
Hili, A. K. Yudin, J. Am. Chem. Soc. 2006, 128, 14772; b) Z. He, A. Zajdlik,
J. D. St. Denis, N. Assem, A. K. Yudin, J. Am. Chem. Soc. 2012, 134, 9926;
c) N. Assem, R. Hili, Z. He, T. Kasahara, B. L. Inman, S. Decker, A. K. Yudin,
J. Org. Chem. 2012, 77, 5613; d) R. Hili, S. Baktharaman, A. K. Yudin, Eur.
J. Org. Chem. 2008, 5201.
[9] For an entry in the blocked isocyanate literature, see: a) D. A. Wicks,
Z. W. Wicks, Jr., Prog. Org. Coat. 1999, 36, 148; b) D. A. Wicks, Z. W.
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Wicks, Jr., Prog. Org. Coat. 2001, 41, 1; c) E. Delebecq, J.-P. Pascault, B.
Boutevin, F. Ganachaud, Chem. Rev. 2013, 113, 80.
[10] CCDC 1026461 (2e) contains the supplementary crystallographic 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.
[13] For synthesis of azumolene, see: a) R. L. White, Jr., F. L. Wessels, T. J.
Schwan, K. O. Ellis, J. Med. Chem. 1987, 30, 263; for biological activity
see: b) P. L. do Carmo, G. Zapata-Sudo, M. M. Trachez, F. Antunes, S. E. F.
Guimar¼es, R. Debom, M. D. R. Rizzi, R. T. Sudo, J. Vet. Intern. Med. 2010,
24, 1224 and references therein.
[11] For an excellent discussion, see: E. Licandro, D. Perdicchia, Eur. J. Org.
Chem. 2004, 665.
Received: October 14, 2014
[12] Nitromethane was used as solvent to ensure solubility of the starting
material and thus increase reaction efficiency.
Published online on && &&, 0000
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COMMUNICATION
&
Cascade Reactions
J.-F. Vincent-Rocan, C. Clavette, K. Leckett,
A. M. Beauchemin*
&& – &&
A Cascade Synthesis of
Go seek hydantoins: In contrast to
normal (C-substituted) isocyanates, N-
substituted isocyanates are rarely used
in synthesis. However, simple hydrazides
and hydrazones can act as bench-stable
precursors, yet release the amphoteric
isocyanates upon heating. A cascade re-
action exploiting these intermediates
rapidly assembles the medicinally im-
portant aminohydantoin motif.
Aminohydantoins Using In Situ-
Generated N-Substituted Isocyanates
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