Oxygen-Substituted Isocyanates: Blocked (Masked) Isocyanates Enable Controlled Reactivity

Article abstract of DOI:10.1002/adsc.201701046

Oxygen-substituted isocyanates (O-isocyanates) are rare isocyanates with a reported propensity to trimerize, a side-reaction that severely limited their use in synthesis. Herein, the development of blocked (masked) O-isocyanate precursors that form this reactive intermediate in situ provide controlled reactivity, allowing the first examples of cascade reactions involving O-isocyanates. Complex hydroxylamine-derived hydantoins and dihydrouracil compounds can be rapidly assembled from α- and β-amino esters, illustrating the convenience of masked O-isocyanates as hydroxylamine derived building blocks. Evidence for the intermediacy of an O-isocyanate intermediate is provided. (Figure presented.).

Full text of DOI:10.1002/adsc.201701046

Title: Oxygen-Substituted Isocyanates: Blocked (Masked) Isocyanates
Enable Controlled Reactivity
Authors: Ryan Ivanovich, Dilan Polat, and André Beauchemin
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10.1002/adsc.201701046
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Oxygen-Substituted Isocyanates: Blocked (Masked) Isocyanates
Enable Controlled Reactivity
Ryan A. Ivanovich, Dilan E. Polat, André M. Beauchemin*[a]
a
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of
Ottawa, 10 Marie Curie, Ottawa, Ontario, K1N 6N5, Canada
e-mail: andre.beauchemin@uottawa.ca
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Oxygen-substituted isocyanates (O-isocyanates)
are rare isocyanates with a reported propensity to trimerize,
a side-reaction that severely limited their use in synthesis.
Herein, the development of blocked (masked) O-isocyanate
precursors that form this reactive intermediate in situ provide
controlled reactivity, allowing the first examples of cascade
reactions
involving
O-isocyanates.
Complex
hydroxylamine-derived hydantoins and dihydrouracil
compounds can be rapidly assembled from α- and β-amino
esters, illustrating the convenience of masked O-isocyanates
as hydroxylamine derived building blocks. Evidence for the
intermediacy of an O-isocyanate intermediate is provided.
Keywords: cascade reactions; hydantoins; isocyanates;
synthetic methods; hydroxylamine derivatives
Isocyanates are important reagents with a rich history
that dates back to the inception of synthetic organic
chemistry. Today, isocyanates have a wide range of Figure 1. A: Selected examples of acyclic oxyaminoureas in
applications (>100,000 publications & patents) and pharmaceuticals and agrochemicals. B: Selected examples of
yearly global sales over 10 billion €. While carbon- hydroxylamine containing heterocycles in bioactive lead
substituted isocyanates are ubiquitous, O-isocyanates compounds.
are rare, despite interest in their reactivity for over a
century.[1] Initial studies were aimed at the study of the
hypothetical acid HO-N=C=O, which has yet to be
However from a synthetic perspective, O-isocyanates
isolated. The synthesis and isolation of O-isocyanates could be versatile reagents for the synthesis of
has been a longstanding challenge, with documented hydroxamic acids, hydroxamates, and hydroxylamines.
unsuccessful attempts.[2] In contrast, solid evidence of Hydroxamic acids and their derivatives are valuable
these rare reactive intermediates has been obtained from synthetic intermediates: for example as chiral ligands,[9]
spectroscopic data, for example via the thermolysis of or directing groups,[10] and are present in potent
N-methoxycarbonyl-O-methylhydroxylamine and the bioactive molecules displaying high affinity for various
photolysis of methyl azidoformate.[3-5] However, the enzymatic receptors (Figure 1).[11] Unfortunately such
rare reactions[6] of O-isocyanates were most frequently derivatives can be difficult to synthesize due to their
encountered
during
unanticipated
Lossen- weak N-O bond, and in general routes using
rearrangements of O-activated-hydroxylamines.[7] hydroxylamines are often preferred if this precursor is
Unfortunately, once formed O-isocyanates often readily available. Based on recent work on nitrogen-
promptly engage in homotrimerization to the substituted isocyanates in which the use of blocked
corresponding aromatic isocyanurate.[8] This competing isocyanate precursors enabled new reactivity by
reaction has severely hampered potential applications of preventing competing side reactions,[12] we speculated
these reactive intermediates.
that controlled reactivity of O-isocyanates is also
possible. Indeed, blocked isocyanate precursors could
provide control over the temperature and concentration
1
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10.1002/adsc.201701046
Advanced Synthesis & Catalysis
during in situ formation of these reactive intermediates. irradiation, allowing to reach completion within 2 hours
Herein, we report that the use of suitable masked at 120 °C (entry 7-8).
O-isocyanates enables controlled reactivity and
prevents trimerization, as illustrated in efficient cascade Table 2. A cascade for the synthesis of hydantoins and their
reactions
affording
hydroxylamine-containing derivatives.[a]
heterocyclic systems.
Strategically,
hydroxylamine-containing
heterocyclic systems were targeted due to the possibility
to rapidly assemble complex architectures through
cascade reactions of O-isocyanates. As shown in Figure
1B, several interesting biological activities have been
reported for such heterocycles,[13] which possess the
ability to form unique hydrogen-bonding motifs[14] and
strong chelates with metalloproteins.[15] Cascade
reactions are also an ideal testing ground to develop O-
isocyanate reactivity, since high control is inherently
required in multistep reaction sequences occurring
under the same reaction conditions. In addition,
hydantoins continue to be an important scaffold, with a
recent review unveiling the scarcity of N-hydroxy
derivatives.[16] To explore this opportunity and allow
comparison with reactions of blocked N-isocyanates,[17]
optimization began with the reaction of sarcosine ethyl
ester hydrochloride and two masked O-isocyanates
possessing phenol as a blocking group (Table 1).
Table 1. Optimization of O-isocyanate cascade reaction.[a]
[a]
Reaction conditions: Carbamate (1 equiv), -amino
Entry[a]
R1
Temp
(C)
Time (h)
Yield
(%)
ester (1 equiv), i-Pr2NEt (0.1 equiv or 1.1 equiv if the -
amino ester is an HCl salt), MeCN (0.3 M, 120 C, 2 h,
microwave reactor) unless noted otherwise. Isolated yields
are shown.
[b] See [a] but in THF, at 70 C (oil bath), 16 h.
[c] Gram scale reaction.
1
2
3
4
5
6
7
8
H[b]
H[b]
H[b]
Me[c]
Me[c]
Me[c]
Me[c]
Me[c]
120 (w)
120 (w)
70 (oil bath)
90 (oil bath)
90 (oil bath)
120 (w)
6
2
16
16
30
6
60
60
91
54
99
99
99
90
[d] See [b] but at 90°C.
[e] See [a] but using 5 mol% DBU.
120 (w)
120 (w)
2
0.5
[a]
Reaction conditions: Carbamate (1 equiv), sarcosine
With optimized conditions in hand for both O-
isocyanate reagents, the scope of the reaction could be
evaluated (Table 2). Small (2a-c) and hindered (2d-e)
N-substituted α-aminoesters reacted in high yields to
form the corresponding hydantoins. Functional group
tolerance also proved excellent, with substrates
possessing cyclopropyl (2f), allyl (2g), propargyl (2h-i),
ester (2j-k) and cyano (2l) groups, or aromatic (2m-o)
and saturated lewis basic (2p) heterocycles cyclizing
efficiently. Cyclic -amino-esters also cyclized to
afford bicyclic derivatives (2q-r). Anilines readily
participate in this cascade with 1b, providing the N-aryl
hydantoins (2s-u) in good yield. In contrast, aniline
derivatives proved unreactive with reagent 1a. Primary
amino aminoesters also failed to cyclize even at higher
temperatures, likely due to the strong conformational
bias for the s-cis urea intermediate, which cannot
cyclize. Encouragingly however, methyl glycolate and
thioglycolate engaged in this cascade, providing oxygen
ethyl ester•HCl (1 equiv), i-Pr2NEt (1.1 equiv), solvent
(0.3 M), Temp, Time. Isolated yields are shown. w:
microwave heating.
[b] In THF.
[c] In MeCN.
Encouragingly, formation of the desired heterocycles
were observed with both O-isocyanate precursors
(Table 1), even if it rapidly became apparent that N-OH
reagent 1a was more sensitive than 1b under microwave
heating conditions (entry 1-2 vs 6-7). Changing to
milder conventional heating resulted in a significant
improvement for the cascade reaction with 1a (entry 3).
In contrast, conventional heating of 1b required a longer
reaction time to form product 2b efficiently (entry 4-5).
This reaction was thus performed using microwave
2
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10.1002/adsc.201701046
Advanced Synthesis & Catalysis
(2v) and sulfur (2w) heterocyclic analogues in modest Table 4. A cascade for the synthesis of dihydrouracils and
yields. Alternative conditions were required for these their derivatives.[a]
substrates, and the use of DBU at higher temperatures
emerged as suitable cyclization conditions.
Interestingly, attempts under the conditions optimized
for α-aminoesters or at lower temperatures with DBU
were plagued by competing formation of the
O-isocyanate trimer.
Table 3. Formation of O-isocyanate precedes Lossen
rearrangement with O-benzoyl carbamates.[a]
[a] Reaction conditions: Carbamate (1 equiv), -amino ester
(1 equiv), i-Pr2NEt (0.1 equiv or 1.1 equiv if the -amino
ester is an HCl salt), MeCN (0.3 M, 120 C, 4 h,
microwave reactor) unless noted otherwise. Isolated yields
are shown.
[b] Performed on a 5 mmol scale, in THF.
[a]
Reaction conditions: Carbamate (1 equiv), -amino
[c]
See conditions [a] (except time: 6 h, using 5 equiv.
anthranilate), NMR yield using 1,3,5-trimethoxybenzene
as internal standard.
ester (1 equiv), i-Pr2NEt (0.1 equiv or 1.1 equiv if the -
amino ester is an HCl salt), MeCN [0.3 M, 90 (2x, 2y) or
120 °C (2z), 2 h, microwave reactor]. Isolated yields are
shown.
To probe the possibility that O-isocyanates are
intermediates in these cascade reactions, methoxy
carbamate 1e possessing an N-methyl substituent was
synthesized, and the cascade was attempted with
sarcosine ethyl ester (Eq 1). If this reaction was
Controlled cascade reactions also occurred with
benzoyl-O-isocyanate precursor 1d (Table 3).
Gratifyingly, this process proceeded without
competition from a Lossen rearrangement that could
arise from N-O bond cleavage and extrusion of benzoate
anion, a common reaction reported for similar reagents
under basic conditions.[18] This unprecedented level of
control was achieved in the presence of excess base to
yield 2x in good yield. Pleasingly, under conditions
where base catalysis could be used, an excellent yield of
the cascade was obtained (2y), and even an electron-
deficient aniline could participate in this reaction (2z).
Studies then shifted to examine the use of -
aminoesters as substrates (Table 4). Encouragingly,
using ethyl 3-(benzylamino)propionate under standard
conditions produced the 6-membered products 3a and
3b in high yields. From reagent 1a, the hydroxy-
dihydrouracil 3a could be formed on gram-scale in
identical yield to the 0.8 mmol reaction. Functional
group tolerance was again briefly evaluated, and an
acetal (3c), a Boc-carbamate (3d), and an alcohol (3e)
proved compatible. Methyl N-methyl-anthranilate
could also participate in the reaction cascade, affording
the aromatic cycle 3f in near-quantitative yield but
required a large excess of the anthranilate, and a longer
reaction time, likely due to a reversible addition on the
O-isocyanate.
proceeding through formation of
a
tetrahedral
intermediate via nucleophilic attack on the carbamate,
then this N-methyl group should only have a minimal
impact on the efficiency of the reaction. In contrast, the
N-H group is required to form the O-isocyanate through
extrusion of phenol. However, using N-methyl
derivative 1e there was no observed product, even upon
heating at higher temperatures (up to 175 °C): phenol
was not formed and both starting materials were
recovered (Eq. 1).[19]
Me
ClH2N
O
O
OMe
OEt
O
PhO
N
C
OMe
no reaction
(1)
N
Me
Me
110% i-Pr2NEt,
120 - 175 °C, mw
1e
To probe the influence of the blocking group used on
the reactivity, p-nitrophenyl hydroxycarbamate 1f was
synthesized and the cascade was attempted [Eq. (2)].
Surprisingly, in the presence of this better leaving group
the yield of the cascade decreased to 40%, with a fast
generation of p-nitrophenol and unreacted -aminoester
being observed by NMR [Eq. (2a)]. Gratifyingly,
addition of phenol (2 equiv) restored the efficiency of
the cascade, likely by acting as a blocking group on the
O-isocyanate (i.e. forming precursor 1a in situ) and
ensuring that the concentration remains low enough to
ensure an efficient cascade and prevent side-reactions
[Eq. (2b)]. Reasoning that this reduced efficiency could
3
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10.1002/adsc.201701046
Advanced Synthesis & Catalysis
be due to reversible protonation of the -aminoester by from - and -amino-esters, yielding useful products
p-nitrophenol, the efficiency of the cascade could be that can be further derivatized. Given that few stable
restored in the presence of excess base [Eq. (2c)]. hydroxylamine derivatives are available for the
Overall, these experiments demonstrate that an O- synthesis of more complex derivatives, and the rich
isocyanate precursor that has both a favourable reactivity of N-O bonds in synthetic transformations,
deblocking/blocking profile (equilibrium & rate) and we anticipate that this new building block will prove
one which releases a “spectator” leaving group is synthetically useful.
critical for the development of efficient cascade
reactions.
Experimental section
O2N
O
Me
ClH2N
O
O
Me
N
OH
O
N
OH
OEt
O
N
Cascade reactions with O-alkyl isocyanates (RO-NCO)
C
OH
H
(2)
N
Conditions below
1f
O
To a 5 mL microwave vial charged with a stir bar was
added the corresponding - or -aminoester (1.00
equiv) then acetonitrile (0.3 M), to which was added
i-Pr2NEt (0.05 equiv, 1.10 equiv for aminoester
hydrochlorides), and finally the N-alkoxycarbamate
(1.00 equiv). The vial was sealed with a microwave cap
and heated for 2 h at the temperature specified (80-
150 °C) via microwave irradiation. The crude products
were then purified by silica gel chromatography to give
the corresponding pure alkoxy-hydantoins and
dihydrouracils. Experimental details, characterisation
data and NMR spectra are provided in the Supporting
Information.
Eq. 2a: Optimized conditions for precursor 1a (1.1 equiv i-Pr2NEt,70 °C): 40%
Eq. 2b: Same as [Eq. 2a] but 2.0 equiv PhOH added: 95%
Eq. 2c: Same as [Eq. 2a] but 2.1 equiv i-Pr2NEt used: 80%
While the products formed via O-isocyanates are
interesting in themselves (e.g. Figure 1), simple
diversification reactions can also broaden their
usefulness and lead to complex hydroxylamine
derivatives (Scheme 1). Transesterification can be
performed with succinate ester 5, enabling the synthesis
of the more complex activated ester (4a).[20] Chan-
Evans-Lam coupling of the hydroxamic acid 3a with a
boronic acid furnishes the O-aryl substituted
dihydrouracil 4b in good yield, providing to our
knowledge the first example that couples a hydroxyurea
with boronic acid. Reductions also provide a convenient
route toward hydroxy imidazolidinones (4c), which are
useful synthetic intermediates, perhaps most notably as
precursors to N-acyliminium ions.[21]
Cascade reactions with OH-isocyanate (HO-NCO)
To a 5 mL microwave vial charged with a stir bar was
added the corresponding - or -aminoester (1.10
equiv) then THF (0.3 M), to which was added i-Pr2NEt
(1.20 equiv), and finally the N-hydroxy-carbamate (1.00
equiv). The vial was sealed with a microwave cap and
heated for 16 h at the temperature specified (70-100 °C)
via conventional (oil bath) heating. The crude products
were then purified by silica gel chromatography to give
the corresponding pure hydroxy-hydantoins and
dihydrouracils. Experimental details, characterisation
data and NMR spectra are provided in the Supporting
Information.
Scheme 1. Derivatization of hydantoin/ dihydrouracil
products.
O
NHBoc
O
N
O
N
O
O
O
O
5
Bn
Bn
OH
O
Bn
O
O
NHBoc
4a
77%
N
N
N
N
N
DBU, MeCN
rt 16 h
3a
(HO)2B
O
O
OH
O
Bn
O
N
N
4b
79%
Acknowledgements
O
Cu(OAc)2, Pyridine
CH2Cl2, rt, 16 h
3a
Cl
Cl
We thank the University of Ottawa and NSERC for generous
financial support. R.A.I. thanks NSERC for a graduate scholarship.
O
O
NaBH4, EtOH
reflux
4c
N
N
N
OMe
N
OMe 99%
1 M HCl workup
2r
O
OH
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201701046
Advanced Synthesis & Catalysis
Oxygen-Substituted Isocyanates: Blocked
(Masked) Isocyanates Enable Controlled
Reactivity
Adv. Synth. Catal. Year, Volume, Page – Page
Ryan A. Ivanovich, Dilan E. Polat, André M.
Beauchemin*
6
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