Cascade reactions of nitrogen-substituted isocyanates: A new tool in heterocyclic chemistry

Article abstract of DOI:10.1039/c5sc03197d

In contrast to normal C-substituted isocyanates, nitrogen-substituted isocyanates (N-isocyanates) are rare. Their high reactivity and amphoteric/ambident nature has prevented the scientific community from exploiting their synthetic potential. Recently, we have developed an in situ formation approach using a reversible equilibrium, which allows controlled generation and reactivity of N-isocyanates and prevents the dimerization that is typically observed with these intermediates. This blocked (masked) N-isocyanate approach enables the use of various N-isocyanate precursors to assemble heterocycles possessing the N-N-CO motif, which is often found in agrochemicals and pharmaceuticals. Cascade reactions for the rapid assembly of several valuable 5- and 6-membered heterocycles are reported, including amino-hydantoins, acyl-pyrazoles, acyl-phthalazinones and azauracils. Over 100 different compounds were synthesized using amino-, imino- and amido-substituted N-isocyanates, demonstrating their potential as powerful intermediates in heterocyclic synthesis. Their reactivity also enables access to unprecedented bicyclic derivatives and to substitution patterns of azauracils that are difficult to access using known methods, illustrating that controlled reactivity of N-isocyanates provides new disconnections, and a new tool to assemble complex N-N-CO containing motifs.

Full text of DOI:10.1039/c5sc03197d

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R. A. Ivanovich, C. Clavette, K. Leckett, J. Bejjani and A. M. Beauchemin, Chem. Sci., 2015, DOI:
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Journal Name
ARTICLE
Cascade Reactions of Nitrogen-Substituted Isocyanates: A New
Tool in Heterocyclic Chemistry
Received 00th January 20xx,
Accepted 00th January 20xx
Jean-François Vincent-Rocan, Ryan A. Ivanovich, Christian Clavette, Kyle Leckett, Julien Bejjani,
André M. Beauchemin*
DOI: 10.1039/x0xx00000x
In contrast to normal C-substituted isocyanates, nitrogen-substituted isocyanates (N-isocyanates) are rare. Their high
reactivity and amphotheric ∕ ambident nature has prevented the scientific community from exploiting their synthetic
potential. Recently, we have developed an in situ formation approach using a reversible equilibrium, which allows
controlled generation and reactivity of N-isocyanates and prevents the dimerization that is typically observed with these
intermediates. This blocked (masked) N-isocyanate approach enables the use of various N-isocyanate precursors to
assemble heterocycles possessing the N-N-C=O motif, which is often found in agrochemicals and pharmaceuticals. Cascade
reactions for the rapid assembly of several valuable 5- and 6-membered heterocycles are reported, including amino-
hydantoins, acyl-pyrazoles, acyl-phthalazinones and azauracils. Over 100 different compounds were synthesized using
amino-, imino- and amido-substituted N-isocyanates, demonstrating their potential as powerful intermediates in
heterocyclic synthesis. Their reactivity also enables access to unprecedented bicyclic derivatives and to substitution
patterns of azauracils that are difficult to access using known methods, illustrating that controlled reactivity of N-
www.rsc.org/
isocyanates provides new disconnections, and
a new tool to assemble complex N-N-C=O containing motifs.
from an isocyanate and a blocking group (e.g. phenol, t-BuOH,
caprolactam, 3,5-dimethylpyrazole and methyl ethyl
ketoxime)2 — allow the release of isocyanates upon heating or
using catalysis, which can be fine-tuned for use in a selected
application. Blocked-isocyanates allow process engineering,
and have thus been extensively studied2 for two main reasons:
1) The slow release of isocyanates at different temperatures is
a useful way of controlling isocyanate concentration and
reactivity, which can ultimately minimize side reactions and
lead to products with different properties; 2) Isocyanates are
known to have acute toxicity, which can lead to worker
sensitization upon exposure. Therefore, blocking groups have
been carefully investigated and various oxygen, nitrogen and
even carbon-based blocking groups have emerged with
reactivity suited to their intended uses or their mode of
activation (e.g. thermolysis, base, acid, and metal catalyzed
formation).2
Introduction
Since their discovery in 1848 by Wurtz, isocyanates have
received significant attention from the synthetic community.1
Isocyanates are important bulk and fine chemicals and are
used industrially in coatings, paints, foams, adhesives,
elastomers, and as building blocks for pharmaceuticals and
agrochemicals. Over 4,000 isocyanates are also commercially
available. Perhaps most notably, isocyanates are used to form
polyurethanes. In 2011, 14 million tons of polyurethanes were
produced, corresponding to ca. 5% of the global polymer
market.1d Consequently, it is difficult to downplay the
industrial importance of isocyanates.1d
The high reactivity of isocyanates is essential to many
industrial processes but their promiscuous nature can be
problematic. Therefore, for a variety of applications the use of
isocyanate precursors is enabling. Classical rearrangement
reactions such as the Curtius, Schmidt, Lossen and Hoffman
rearrangements are commonly used to form isocyanates in
situ. In contrast, blocked (masked) isocyanates are simple
Isocyanates attached to heteroatoms are also known, but
are less developed and used than normal C-substituted
isocyanates.4 Nitrogen-substituted isocyanates (N-isocyanates)
are
a class of heterocumulene possessing comparable
precursors releasing isocyanates through
equilibrium. Such blocked isocyanates — typically generated
a
chemical
synthetic potential to C-substituted isocyanates. However,
despite the early discovery of N-isocyanates,4a,b the synthetic
potential of these reactive intermediates remains virtually
Centre for Catalysis Research and Innovation, Department of Chemistry and
Biomolecular Sciences, University of Ottawa. 10 Marie-Curie, Ottawa, ON, K1N
6N5, Canada.
untapped. Their scarcity in the literature is likely
a
a
consequence of their amphoteric nature,3 as both
nucleophilic nitrogen atom and an electrophilic isocyanate are
present on the same molecule. They share the same
connectivity as α-amino aldehydes, and these amphoteric
Electronic Supplementary Information (ESI) available: Complete experimental
procedures,
characterization
data,
and
NMR
spectra.
See
DOI: 10.1039/x0xx00000x
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molecules are also notoriously difficult to handle.3
Importantly, the amphotericity of N-isocyanates results in
difficult syntheses and a propensity for these intermediates to
homodimerize or oligomerize, even at temperatures as low as
–40 °C.4aaa
View Article Online
DOI: 10.1039/C5SC03197D
Much of the early work studied the formation of N-
isocyanates, and only explored their reactivity.4 The formation
of these intermediates was performed through a Curtius
rearrangement of carbamoyl azides,4c,d,e,x ring opening induced
formation4h,z,bb,cc,gg,ll,mm,pp,rr or by thermolysis of hydrazide
derivatives.4a,b,h,kk,qq,ww,xx Most studies only described their
solvolysis but more complex cycloaddition reactions4cc,dd,gg,ll,nn
and intramolecular cyclizations4c,d,x,rr were also reported.
Recently, Maier4qq and Wentrup4ddd have observed and studied
the reactivity of N-isocyanates under UV photolysis conditions.
Despite this pioneering work, the reaction conditions required
to form these amphoteric intermediates, and their propensity
to dimerize, severely limited their synthetic applications. To
date, only a few reactions are reported using N-isocyanates or
their blocked derivatives. After an extensive literature search,
we only found 57 publications either forming, studying, using
or suggesting the formation of N-isocyanates and N-
isothiocyanates.4 This number is probably underestimated as
some reported reactivity could likely be attributed to N-
isocyanate intermediates. In contrast, there are over 100,000
publications and patents on C-isocyanates, and over 7,000 on
blocked C-isocyanates. The difference between the synthetic
uses of C-isocyanates vs. N-isocyanates is inherently
proportional, and highlights the need for a convenient
procedure to form N-isocyanates and control their reactivity.
Recently we have developed several blocked N-isocyanate
precursors as part of our efforts on intra- and intermolecular
In parallel to this aminocarbonylation work, we noticed the
paucity of simpler reactions of N-isocyanates, for example with
alcohols, amines, and thiols as nucleophiles. This encouraged
us to investigate the generation and reactivity of N-isocyanate
precursors with simple nucleophiles. Gratifyingly, the
substitution
stoichiometric conditions using both hydrazones6 and
hydrazides7 as blocked N-isocyanates
Scheme ). A
reactions
proceeded
efficiently
under
(
1
comparison of the conditions below establishes that imino-
isocyanates react more readily than amino-isocyanates. This
reactivity trend is in line with the observed increased reactivity
of aromatic C-isocyanates relative to aliphatic C-isocyanates in
related reactions.2a Exploring this fundamental reactivity
turned our attention to the prevalence of the N-N-C=O motif in
complex bioactive molecules, including several marketed
agrochemicals and pharmaceuticals (Figure 1). There are
various N-N-C=O containing substructures: fully or partially
incorporated within a heterocycle, or in acyclic molecules.
alkene aminocarbonylation reactions
(Eqs 1-2). These
reactions involve N-isocyanates as key intermediates in a
reaction sequence allowing the transformation of alkenes into
valuable
-aminocarbonyl motifs. This work required the
development of practical reagents: the use of hydrazide and
hydrazone derivatives as N-isocyanate precursors emerged as
a practical and general approach for these reactions. Most
importantly, it allowed the desired concerted [3+2] alkene
cycloaddition to occur in high yield, with little N-isocyanate
dimerization or decomposition (especially in the presence of
excess alkene).5 In addition, the reactivity observed is well
aligned with the blocked C-isocyanate literature: 1) They
appear to follow similar deblocking temperature trends; 2)
Base catalysis is also possible; 3) Observations support a
reversible equilibrium favoring the hydrazide and hydrazone
starting materials.
Scheme 1
Synthetic applications of N-Isocyanate intermediates.
Therefore, the development of strategies for the
incorporation of the N-N-C=O motif in complex molecular
scaffolds is highly desirable. However, it is a considerable
challenge due to the diversity of motifs present and due to
intrinsic chemoselectivity issues associated with hydrazine
derivatives: the presence of two nitrogen atoms that can react
and lead to different products.9 Considering the
underdevelopment of N-isocyanate chemistry and the diversity
of N-N-C=O motifs present, we hypothesized that N-
isocyanates could provide the missing link for a unified
approach to N-N-C=O incorporation in heterocyclic chemistry;
provided that their reactivity could be controlled enough to
allow for new cascade reactions. This article constitutes a
detailed account of our work toward this goal.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5SC03197D
Fig. 1
Prevalence of N-N-C=O Motif in the Agrochemical (Left) and Pharmaceutical Industries (Right).
Herein, we discuss the first cascade reactions developed
using amino-, imino- and amido-substituted N-isocyanates for
the synthesis of heterocyclic molecules. In addition to
previously communicated work toward saturated 5- and 6-
membered azacycles and nitrogen-substituted hydantoins,7,8
we report new cascade reactions furnishing important
heteroaromatic cores incorporating the N-N-C=O motif in
several different orientations. N-Isocyanates were used to
assemble 5- and 6-membered aromatic heterocycles including
acyl-pyrazoles, acyl-phthalazinones and azauracils. Our novel
synthetic approach gives rise to substitution patterns that have
otherwise been difficult or impossible to access, and allows the
formation of new bicyclic heterocycles. With over 100 new
compounds spanning 6 heterocyclic classes assembled using
cascade reactions of amphoteric N-isocyanate intermediates,
this article highlights that highly controlled reactivity is
possible through the use of blocked (masked) N-isocyanate
precursors.
Gratifyingly, N-isocyanate precursors allowed the
formation of several 5- and 6-membered nitrogen heterocycles
incorporating one nitrogen atom (βN) of the amino-isocyanate
in the desired heterocycle (Table 1). This reaction sequence
involves nucleophilic attack of the amine on the in situ
generated N-isocyanate to form the corresponding semi-
carbazide
(A
), which then undergoes
a
Cope-type
hydroamination to form the nitrogen heterocycle. Since
isocyanate generation / addition occurs rapidly (ca. <10
minutes at 80 °C), the hydroamination reaction is rate limiting
and the build-up of the unsaturated semi-carbazide
A is
observed when monitoring these reactions. However, upon
heating at temperatures allowing hydroamination to occur,
this cascade allowed the synthesis of semi-carbazide-based
pyrrolidines (2a,d,f-h), piperidines (2b,e) and piperazine (2c)
using pyrrolidine as the nucleophilic amine. As expected,
substitution was well tolerated on the alkenyl chain, and
incorporation of a Thorpe-Ingold bias was beneficial to achieve
cyclization at a lower temperature (2d) or to reduce the time
required for reaction completion (2e). Unfortunately, the
incorporation of a small chiral centre on the alkenyl chain
didn’t result in any diasteroselecitivty (2f, d.r: 1:1). The
cascade reaction also allowed cyclization via the more
challenging hydroamination of an internal alkene (2h). A
Results and discussion
To acquire proof of concept results to validate that the
controlled reactivity of N-isocyanate precursors could lead to
efficient cascade reactions, we first targeted a reaction
sequence in which reaction of the N-isocyanate would occur
first, followed by cyclization. In addition, we expected that the
substitution of nitrogen nucleophiles (e.g. amines) on N-
isocyanates would be essentially irreversible.7 Building on our
expertise in metal-free hydroamination reactions of hydrazine
derivatives,10 we developed an N-isocyanate addition / Cope-
type hydroamination cascade for the formation of saturated
nitrogen heterocycles (Eq 2), illustrated above using blocked
N-isocyanate 1a.7
protected alcohol on the alkene chain was also tolerated (2g
)
and could allow further functionalization of the desired
product. In addition to providing a cascade for the rapid
assembly of molecular complexity, this data showed that semi-
carbazide formation is essentially irreversible at temperatures
up to 175 °C, a useful finding for the development of other
cascade reactions.
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Table 2. Cascade synthesis of multiple hydroamination products from a single N-
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DOI: 10.1039/C5SC03197D
isocyanate precursora
Before developing other cascade reactions, we decided to
address an important limitation of intramolecular
hydroamination reactions.11 Indeed, these reactions are
generally not well suited for the rapid generation of molecular
complexity. The key limitation is that each substrate is typically
prepared in several steps, and can only provide a single
hydroamination product. In contrast, the use of N-isocyanate
precursors in cascade reactions allows the formation of
multiple hydroamination substrates from
precursor, followed by intramolecular hydroamination events.
This approach led to diversity-oriented synthesis of
pyrrolidines shown in Table 2
a
common
a
.
Table 1 Scope of the N-isocyanate addition / hydroamination cascadea
aConditions: carbazate (1 equiv), amine (1.1 equiv) in PhCF3 (0.3 M) heated in
sealed vial (microwave reactor, 120 °C, 6 h).
Scheme 2
Impact of the hydrazide conformation on hydroamination
reactivity.
The semi-carbazide formed from benzylamine has
increased conformational flexibility, and its
E hydrazide
aConditions: carbazate (1 equiv), amine (1.1 equiv) in PhCF3 (0.3 M) heated in a
sealed vial (microwave reactor).
conformer is thermodynamically favoured.9b In contrast, a
destabilizing A(1,3) allylic strain interaction is present in the
adducts of secondary amines (i.e. destabilizing interaction
Using this N-isocyanate addition
/
Cope-type
between R2 and
N in the E-conformer). Thus, the Z-conformer
hydroamination cascade ten different semi-carbazide-based
pyrrolidines were synthesized from the same carbazate
precursor (1a, Table 2). Cyclic and acyclic amine nucleophiles
were tolerated in this cascade reaction. Azetidine (3a), and
piperidine derivatives (3c-g) yielded the desired product in
good to excellent yield. (S)-Prolinol was also a competent
nucleophile but only showed modest diastereoselectivity.
Product 3g bearing a bromine atom was also formed to
highlight the potential of this metal-free method. The
of these intermediate is thermodynamically favored. Previous
DFT studies suggest that the Z-conformer is the reactive
conformer in Cope-type hydrohydrazidations (Scheme 2).5a
Overall, this study was the first example of a cascade
reaction using amphoteric amino-isocyanates generated in-situ
from carbazates. Strategically, this methodology uses an
external nucleophile to generate a derivative in which the N
subsequently participates in the cyclization event
(hydroamination), with an alkene present on the N-isocyanate
substrate. To further develop cascade reactions of N-
isocyanates, we were drawn to different cascade reactions in
which cyclization would occur on a functional group (FG)
present on the incoming nucleophile. Recently, we reported
such a cascade reaction using α-amino esters to rapidly
medicinally
relevant
2-oxopiperazine
demonstrated
chemoselectivity for the most nucleophilic nitrogen, providing
the desired heterocycle 3h in 85% yield. While both acyclic and
cyclic secondary amines proved competent reaction partners,
the result with primary amine 3j led to a modest, but
preparatively useful yield. We attribute this difference of
reactivity to a more challenging hydroamination step, due to
the relative population of the E-and Z-conformers of the semi-
carbazide.
assemble N-substituted hydantoins
(Scheme 3
).8 Since
encouraging results were obtained for substitution reactions
using amino-esters on blocked N-isocyanates (Scheme 3), we
rationalized that we could develop a new substitution
∕
cyclization reaction cascade. This cascade was first
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investigated with amino-isocyanates since two different general more prone than amino-isocyanates to react with
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products could be formed depending on which nitrogen would nucleophilic amines.6 Aliphatic carbaDzoOnI:e1s0.10a3f9f/oCr5dSeCd0319th7De
cyclize.
desired desired hydantoins in excellent yields (7a, 7b). We
were also pleased that electron-rich and electron-poor
aromatic carbazones both led to efficient product formation
(7c-e). We then surveyed the reactivity of bulky keto-
carbazones: acetophenone, fluorenone and diisopropyl
ketone-derived reagents afforded the cyclized products in
good yields (7f-h). A heteroaromatic carbazone also produced
the desired heterocycle in good yield (7i). We also investigated
the use of several N-glycine esters using the aldcarbazone
derived from 4-methoxybenzaldehyde as a test substrate. We
were pleased to see that the somewhat hindered N-isopropyl
glycine ester afforded the desired hydantoin 7j in moderate
yield.
Table 3 Carbazate scope for the cascade synthesis of amino-hydantoinsa
Scheme 3
Comparison of hydantoin synthesis versus hydroamination cascade.
Indeed, cyclization using the proximal nitrogen (
N) would
yield the 5-membered amino-hydantoin, while cyclization
using the distal nitrogen (N) would yield the 6-membered
aza-diketopiperazine.13 We tested the reaction with a proline
ester, and were pleased to observe complete selectivity for
amino-hydantoin formation (Eq 3).12 After this initial result, we
decided to further explore this reactivity using N-benzyl
carbazate and several amino-esters (Table 3).
aConditions: carbazate (1 equiv), i-Pr2NEt (1.2 equiv), aminoester hydrochloride
(1.1 equiv) in PhCF3 (0.3M) heated in a sealed vial (microwave reactor, 100 °C or
150 °C, 6 h). bReaction at 100 °C. cReaction at 150 °C.
As shown in Table 3, the cascade reaction proved efficient
for several N-substituted glycine esters (5a
, 5b and 5c). Alanine
(
5d), leucine (5e) and proline (5f) esters also cyclized in
Functional groups such as nitriles (7k) and esters (7l) were
tolerated on the nitrogen substituent. To our pleasure, even N-
aryl glycine esters provided the N-aryl substituted amino-
hydantoins. This indicates that electron-rich (7n), electron-
moderate to good yields. However, racemization occurred
under these reaction conditions. In addition, we were pleased
to observe the formation of a dihydrouracil ring (5g) in
moderate yield using a N-benzyl β-aminoester as the reaction
partner. Since the reaction was completely selective for the
cyclization on the proximal nitrogen (αN), we decided to
expand this study to include other N-isocyanate precursors. As
indicated in the introduction, differences are expected and
observed for the formation and reactivity of diverse N-
isocyanates. In the context of this cascade reaction we
wondered if blocked precursors of other amino-isocyanates
neutral
(7m) and even electron-poor (7o) anilines are
competent nucleophiles under the reaction conditions. We
then used this late-stage functionalization strategy to
synthesize 5 azumolene analogues (7s-w), without the use of
chromatography (i.e. purified by filtration). Finally, we
performed exploratory attempts toward three related
cascades. These proved rewarding as we showed that: 1)
Imidazolidinone (7p) formation is possible if ring closure is
achieved via 1,4-addition (rather than 1,2-addition), using an
α,β-unsaturated amino-ester as reagent; 2) An N-
isothiocyanate also engaged in a related cascade14 to form an
(β (β
Nsp3, carbazate precursors), imino-isocyanates Nsp2,
carbazone precursors), and amido-isocyanates would be
suitable reaction partners. The results using various N-
isocyanate precursors are presented in Table 4. Gratifyingly, a
variety of carbazones proved competent reaction partners
with N-alkyl glycine esters (Table 4). It should be highlighted
that carbazones are typically excellent N-isocyanate
precursors: easier to synthesize, stable, often crystalline yet in
amino-thiohydantoin (7q); 3) Amide-substituted hydantoin (7r
)
could be synthesized using an amido-isocyanate precursor.
Collectively, this data suggests that a variety of N-isocyanate
precursors can engage in cascade reactions and display similar
reactivity.
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Table 4 Cascade synthesis of N-substituted-hydantoins using carbazones and other N-isocyanate precursorsa
aConditions: carbazone (1 equiv), i-Pr2NEt (1.2 equiv), aminoester hydrochloride (1.1 equiv) in PhCF3 (0.3 M) heated in a sealed vial (microwave reactor, 100-150 °C, 3-
6 h). bReaction at 100 °C. cReaction at 150 °C. dReaction at 120 °C.
Considering the encouraging results obtained with the two 20 mol% of DBU with O-phenyl carbazate proved to be a
reaction sequences presented above, we felt confident that convenient way of generating NH2-NCO at room temperature.
we could expand this chemistry to different synthetic targets. This was performed in the presence of a nucleophilic amine
The diversity of N-isocyanates that could be used to form N- (1.1 equiv) and afforded the desired semicarbazide products
substituted hydantoins suggested that O-phenyl carbazate
(Table 5).
itself could be a building block for the incorporation of the N-
Using this base catalysis procedure, we studied the
N-C=O motif: indeed it could serve as the precursor to the reaction of different amines with O-phenyl carbazate: the
simplest possible N-isocyanate, NH2-NCO (Eq 4).4qq
results are shown in Table 5 15
. Several semi-carbazides can be
readily formed at room temperature by combining amines and
O-phenyl carbazate using base catalysis. The use of hexylamine
led to an 83% yield of the corresponding semi-carbazide (entry
1, 9a). Both primary (entry 2, 9b) and secondary (entry 3, 9c
)
benzylic amines proved competent reactants yielding the
desired semi-carbazide in good to excellent yield.
Propargylamine underwent the substitution reaction providing
the propargylic semi-carbazide in modest yield (entry 5, 9e). In
general, both acyclic and cyclic secondary amines were
tolerated (entries 4,6-7). An ester functionality was also
tolerated to yield the substituted piperidine based semi-
carbazide (entry 8, 9h). Finally, we were pleased to observe
that double substitution could also be achieved using
piperazine (entry 9, 9i). Overall, the data shown in Table 5
shows that simple reactions of N-isocyanates can also benefit
from base catalysis, with no detectable dimerization or
oligomerization occurring under the reaction conditions. This
Initially we wondered if the lack of steric shielding on the
distal nitrogen atom (i.e. NH2 vs. NHR, previously) would result
in a greater propensity to dimerize. We thus became
interested in achieving even milder reactivity through the use
of base catalysis. Previous studies conducted in the context of
our alkene aminocarbonylation work showed that bases (e.g.
Et3N) lead to imino-isocyanate formation under milder
conditions.5d Related literature on blocked C-isocyanates2 also
suggested that base catalysis could have broad applicability for
other N-isocyanate precursors, which could prove an asset for
the development of other cascade reactions. Gratifyingly using
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new reactivity also provides a new route to semi-carbazides
that can serve as building blocks for more complex
derivatives.16
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Table 5 Base catalyzed synthesis of unprotected semi-carbazidesa
Entry
Nucleophile
Product
Yield (%)
83
1 (9a)
Having established the potential of N-isocyanates to form
77
94
saturated
heterocycles,
amino-hydantoins
and
2 (9b)
3 (9c)
imidazolidinones, we sought to develop reaction cascades
forming aromatic heterocyclic compounds possessing the N-N-
C=O motif. One could expect that the aromaticity of the
product should prove advantageous by either facilitating the
cyclization event or simply by forming stable products that do
not interfere with the cascade reaction. However, this strategy
also inherently implies the use of precursors at a higher
oxidation state, with the unsaturations required for
aromatization being present in their structure.
76
4 (9d)
53
73
83
5 (9e)
6 (9f)
7 (9g)
For the first heteroaromatic synthesis, we wanted to build
on our work on amino-esters, and explore the formation of
carbamoyl-substituted phthalazinones using suitable ester-
containing starting materials (Scheme 4). Only few syntheses
of this biologically-active core17 have been reported. Indeed, a
85
91
8 (9h)
9 (9i)
common
method17d
to
synthesize
functionalized
phthalazinones involves the carbamoylation of the core using
isocyanates. In contrast, our envisioned approach involves the
formation of the phthalazinone core induced by the addition
of amines onto a suitably protected N-isocyanate precursor
(
6
Scheme 4). Our results for this strategy are presented in Table
.
aConditions: O-phenyl carbazate (1 equiv), amine (1.1 equiv), DBU (20 mol%) in
THF (0.3 M) stirred at room temperature for 16 h. bReaction with 0.5 equiv
amine.
A natural extension was to explore if O-phenyl carbazate
could also engage in established cascade reactions. The
advantage of this strategy is the ability to provide a free NH2
group for further derivatization reactions. We were quite
pleased to see that the reaction with N-methyl glycine ethyl
ester provided the NH2-substituted hydantoin in 91% yield on
gram scale (Eq 5). We then used the NH2 group to form
pyrrole-substituted hydantoin 10b in 90% yield (Eq 6). We
were also able to synthesize an imidazolidinone derivative
Scheme 4
substituted phthalazinones.
Comparison of existing method versus N-isocyanate synthesis of
through
a
N-isocyanate cascade exploiting addition
/ cyclization by 1,4-addition (Eq 7).
Pleasingly, optimization provided the desired cascade
reaction, and carbamoyl-substituted phthalazinones were
formed with several secondary amines at 100 °C. The reaction
was tolerant of secondary cyclic amines such as pyrrolidine
(entry 1, 12a), morpholine (entry 2, 12b) and an ether-
containing proline derivative (entry 6, 12f) yielding the desired
heterocycle efficiently after heating for 18 h. Cascade
reactions of secondary acyclic amines required prolonged
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heating (48 h) but yielded the corresponding phthalazinones in to access a facile 5-endo-dig anionic cyclization pathway. It
View Article Online
DOI: 10.1039/C5SC03197D
almost quantitative yields (entries 3-5, 12c-e). Symmetrical was envisioned that we could use milder conditions and
and unsymmetrical amines afforded the desired products, but assemble a library of carbamoyl-substituted pyrazoles using a
mixtures of semi-carbazide rotamers were observed by 1H cascade reaction. Such acyl pyrazoles are somewhat scarce in
NMR for the adducts of unsymmetrical amines. Unfortunately, the literature, but have shown to be both bioactive
all attempts to use primary amine nucleophiles resulted in the compounds20, for example in the core of the agrochemical
free N-H phthalazinone. This observation strongly suggests Dimetilan, and useful building blocks21
(Scheme 5). The
that the desired product was formed, but then acted as a conditions and scope of this cascade reaction are presented in
blocked C-isocyanate precursor by forming the isocyanate Table 7
upon thermal extrusion of N-H phthalazinone. Nevertheless,
despite being limited to secondary amines this cascade
provided us with the first cascade reaction forming a
heteoaromatic core using N-isocyanate intermediates. The
hydantoin and phthalazinone work showcased the cyclization
potential of carbazone-derived N-isocyanates on esters.
.
Table 6 Amine scope for the phthalazinonesa
Scheme 5
Comparison of existing method versus N-isocyanate synthesis of
substituted pyrazoles.
Gratifyingly, the N-isocyanate addition / alkyne annulation
cascade allows the formation of a variety of pyrazoles using
primary and secondary amines (Table 7)22. A wide variety of
amines proved to be competent partners in this reaction
Entry
Nucleophile
Product
Yield (%)
79
1 (12a)
(Table 7, top). Cyclic amines including pyrrolidine (14a),
morpholine 14b and piperazine derivatives 14c-d all
(
)
(
)
cyclized in high yield. A halogen substituted aromatic group is
tolerated in the reaction (14c), which highlights the possibility
of further functionalization. Acyclic amines are also good
reaction partners for the synthesis of acyl pyrazoles (14e-l).
Secondary amines yield the desired heteroaromatic core in
high yield at room temperature. In contrast, primary amines
2 (12b)
3 (12c)
4 (12d)
5 (12e)
6(12f)
87
97
99
90
65
(
14f
desired pyrazoles in good yield. Interestingly, benzylamine
14g and furfurylamine 14j did not require higher
temperature to form the corresponding pyrazoles. Anilines can
also be used as nucleophiles 14k). Given the low
,h,i) required gentle heating at 50 °C but also provided the
(
)
(
)
(
nucleophilicity of anilines, their use in this cascade reaction at
50 °C again supports the formation of a reactive N-isocyanate
intermediate as the participating electrophile. The reaction can
also be highly chemoselective for the most nucleophilic amine
when using diamines, as demonstrated by the selective
formation of adduct 14l. In parallel to efforts using different
amines the cascade reaction was also performed with several
carbazones, using pyrrolidine as a representative nucleophile
aConditions: carbazone ester (1 equiv), amine (1.1 equiv) in PhCF3 (0.3 M) heated
in a sealed vial (oil bath, 100 °C, 18 h for cyclic amine or 48 h for acyclic amine).
To continue our studies, we wanted to expand the
reactivity of N-isocyanates to encompass other types of
cyclization reactions. With a variety of cyclization protocols, an
array of heteroaromatic cores could easily be accessed. The
pyrazole core came as an obvious synthetic target due to its
presence in several pharmaceuticals and agrochemicals.18
Considerable effort has been dedicated to the synthesis of
pyrazoles and several efficient strategies exist. For example,
intramolecular cyclizations furnishing the pyrazole core from
alkynylcarbazones19 are often carried out in the presence of
stoichiometric base. These basic conditions are likely necessary
(
Table 7, bottom). The impact of varying the carbazone (R1
substituent on the outcome of the cascade reaction proved
minimal. Product containing both small (14m
R1 = Me) and
large (14o
R1 = furyl) substituents were formed in high yield.
)
,
,
The result obtained with the methyl-substituted carbazone
(84% yield, 50 °C, 24 h) is especially noteworthy. Indeed, both E
and Z isomers of the carbazone starting material are present,
1
favoring (ca. 9:1 by H NMR) the E isomer which is not the
appropriate configuration to cyclize. Thus the high yield
supports that carbazone or imino-isocyanate isomerization
8 | J. Name., 2012, 00, 1-3
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Journal Name
Article
occurs under the reaction conditions to form the Z-isomer
required for cyclization on the alkyne. Alkyne substitution (R2
=
H) are known to be blocked (masked) C-isocyanate
View Article Online
DOI: 10.1039/C5SC03197D
2
)
precursors. Fortuitously, using the DBU-catalyzed procedure
is also well tolerated and allows the formation of 1,3,5- the products formed would not subsequently decompose. To
trisubsituted pyrazoles under similar conditions 14p ). ensure stability during product,isolation, Et3N-treated silica gel
(
-r
Finally, it should be noted that product formation for these was also needed, suggesting that mildly acidic conditions can
1,3,5-trisubtituted entries was observed at room temperature promote isocyanate formation. Overall, this data illustrates
but that yields were typically higher at 50 °C, and that this the usefulness of milder conditions for the development of
cascade reaction is also scalable (Eq 8).
new reaction cascades.
After showing that N-isocyanates can engage in cascade
reactions forming 5-membered and 6-membered aromatic
heterocycles, we sought to develop a cascade in which the
amine nucleophile would be incorporated within the aromatic
heterocycle formed. Strategically, this represented the most
difficult cascade reaction targeted with N-isocyanates. After
surveying potential scaffolds that could be obtained using this
approach, the 6-azauracil ring system stood out as an excellent
synthetic target due to reported biological activities23 as well
as a lack of efficient syntheses for several substitution
patterns. Interestingly, several 6-azauracil derivatives have
been used for decades as pharmaceuticals and agrochemicals,
and reports document their use as anticoccidials,23i-l-n-o-r
thyroid hormone receptor agonists,23b-e-k CTSK inhibitors,23d
GNRHR antagonists,23c P2X7 receptor antagonists,23f and 5-HT1A
receptor agonists.23a-g-j Despite the importance of this motif,
we could not find cascade reactions allowing the facile
generation of libraries of complex 6-azauracil compounds.
Instead, most syntheses rely on the functionalization of the
commercially available core structure, resulting in limitations
in the substituents that can be included on the ring system
(such as at the 3 position for example). To build on the
reactivity previously described and exploit the ability of N-
isocyanates to readily form semi-carbazones, we envisioned
the use of carbazones derived from α-keto-esters.
Table 7. Scope of a cascade reaction for the formation of acyl-pyrazolesa
As illustrated in Equation 9, using this approach would
provide the ability to incorporate the primary amine reagent at
the 3 position of the azauracil compounds, upon cyclization of
the incoming-nitrogen atom on the ester group of the parent
carbazone.
aConditions: alkynyl carbazone (1 equiv), amine (1.1 equiv), DBU (20 mol%) in THF
at room temperature or 50 °C for 16 h. bReaction at room temperature. cReaction
at 50 °C. dReaction conducted in PhCF3.
Initially, we were confident about the ability to access
semi-carbazone
that both E and Z isomers of
A
under mild conditions. We believed that
would be in equilibrium thus
A
allowing for complete conversion to the stable aromatic
product. However, we expected a strong conformational
preference for this intermediate that would make the
cyclization step difficult, noting that related cyclizations (R2
=
H) typically only proceed at high temperatures.24 Indeed,
It was imperative to use basic conditions for the formation
of these acyl pyrazoles due to the labile nature of products
formed with primary amines. Indeed, attempts to form acyl
pyrazoles upon heating in the absence of base led to formation
during reaction optimization only N-isocyanate addition
products (semi-carbazone
A
) were observed at temperatures
C. However cyclization was typically observed
C, and further optimization showed that the
below 150
around 150
°
°
of free N-H pyrazoles, since the acyl-pyrazoles products 14 (
R4
desired azauracils formed in good yields upon heating at 175
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°
C. With these conditions in hand, we explored the scope of
(
16w), an ester (16v) and a tetrahydrofuryl (16t-u)VigerwoAurtpicleaOt ntlhinee
this cascade reaction: the results are displayed in Table 8
.
R1 position. These substitution patterns have
DOI: 10.1039/Cm5SeCd0i3c1i9n7aDl
Fortunately, the cascade reaction forms a variety of relevance, for example product 16u is a C-linked nucleoside
substituted 6-azauracils effectively (Table 8). First, the scope of analogue. Finally, this cascade tolerates a diverse set of
the amine partner was surveyed using pyruvate-derived functional groups, including a free hydroxyl (16h), allyl (16o
carbazone 15a
R1 = Me). We were pleased that a variety of and propargyl (16b) groups, a nitrile (16i), ethers (16t and
primary amines, a hydrazine and a hydroxylamine could form 16u), an ester (16v), heteroaromatic rings such as thiophene
azauracil products in moderate to high yield (35-85%). The 16x) and N-H indole (16j), a free amide (16k), and aromatic
)
(
(
reaction tolerates the use of hindered amines such as bromides (16p) and fluorides (16e). Collectively, these results
cyclohexylamine (16g, slower cyclization, 35% yield), of less highlight that this cascade reaction has broad applicability to
nucleophilic amines such as anilines (16f), and of primary rapidly assemble 6-azauracil compounds.
amines with a proximal electron-withdrawing group (16i
While conducting the reaction with 4-bromoaniline,
,
16k).
While studying the scope of azauracil formation, we
speculated what would occur if a diamine was used as a
a
crystalline product (16p) was obtained in 77% yield, and X-ray nucleophile. We hypothesized that the second nitrogen atom
analysis secured the structural assignment (see supporting could participate in the formation of a second heterocycle via
information for details). The use of anilines was also an intramolecular condensation, rather than form a bis-
encouraging since such products inherently face azauracil through cyclization of each nitrogen atom (Scheme
chemoselectivity issues in alternative syntheses relying on the
6). To test this hypothesis, we used 2-aminoaniline and were
arylation of the azauracil core.25 Next, we investigated the quite pleased to observe formation of tricyclic product 17a in
incorporation of heteroatom substituents at the 3 position. 67% yield.26The structure of 17a was secured using X-ray
Gratifyingly the reaction with phenylhydrazine resulted in 60% analysis (see supporting information for details). Following this
of the cyclized product, along with 30% of the uncyclized encouraging lead result, we explored the scope of this reaction
adduct. The reaction with O-benzyl hydroxylamine allowed the with selected substrates and diamines (Table 9).
formation of oxygen-substituted products 16m and 16n
;
surprisingly such derivatives had not been reported in the
azauracil literature. We also tested the ability of the cascade
reaction to proceed with different substituents at the R1
position. This substitution was well tolerated, as shown by the
formation of azauracil products possessing a simple hydrogen
Table 8 Cascade synthesis of 6-azauracil derivativesa
aConditions: carbazone ester (1 equiv), amine (1.1 equiv) in MeCN (0.3M) heated in a sealed vial microwave reactor, 175 °C, 6 h).
10 | J. Name., 2012, 00, 1-3
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Page 11 of 14
Chemical Science
isocyanates will encourage others to develop reactions of N-
isocyanates, also taking advantage of the blocked VNie-wisAortcicyleaOnnalitnee
DOI: 10.1039/C5SC03197D
approach to overcome dimerization. Efforts along these lines
are ongoing in our laboratories and will be reported in due
course.
Table 9 Assembly of bicyclic heterocycles using an N-isocyanate reaction cascadea
Scheme 6
Cascade reactions forming 6-azauracils: possible divergent reactivity of
diamines.
Encouragingly, several diamines engaged in a cascade
reaction forming bicyclic or tricyclic systems. Relatively high
yields (55-76%) were obtained considering that product
formation involves N-isocyanate formation, addition on the N-
isocyanate, cyclization to form the azauracil ring, and a second
cyclization to form the bi- or tri-cyclic ring system. In practice,
the reaction was experimentally simple since most products
(entries 1-2,5) precipitated out of the reaction upon heating in
acetonitrile, and cooling at the end of the reaction. In addition
to encouraging results to form tricyclic systems using 1,2-
aminoaniline (entries 1-2), we were pleased that 1,3-
diaminopropanes yielded the corresponding 6,6-bicyclic
compounds in good yields (entries 3-5). Surprisingly, this ring
system had not been described in the literature, despite
decades of work on the synthesis of purine analogues,25c
further highlighting that cascade reactions of N-isocyanates
can provide access to new heterocycles through simple
reaction sequences.
Entry
Nucleophile
Product
Yield (%)
67
1 (17a)
2 (17b)
3 (17c)
4 (17d)
5 (17e)
76
64
72
55
Conclusions
In summary, we have demonstrated that despite their
amphotheric nature and reported propensity to dimerize, N-
isocyanates are powerful intermediates in heterocyclic
chemistry. Our data shows that the use of N-Isocyanates
aConditions: carbazone ester (1 equiv), diamine (1.1 equiv) in MeCN (0.3M)
heated in a sealed vial (microwave reactor, 175 °C, 6 h).
provides
a versatile strategy to assemble heterocyclic
compounds possessing N-N-C=O motifs, which are common in
agrochemicals and pharmaceuticals. Various heterocycles
could be assembled by taking advantage of the controlled
reactivity provided by the use of blocked (masked) precursors
that reversibly form the desired N-isocyanates upon heating or
in the presence of catalytic bases such as DBU. This reactivity
also demonstrated the ability of different N-isocyanates—
amino-, imino-, and amido-isocyanates—to engage in cascade
reactions and allowed a comparison of their reactivity. We also
demonstrated the use of O-phenyl carbazate as a precursor for
the simplest N-isocyanate, NH2-NCO. Over 100 new
heterocyclic products were formed using new reaction
cascades, including new heterocycles and heterocyclic
products with substitution patterns that are either difficult to
prepare or that have not been reported in the literature.
Beyond providing a new tool in heterocyclic chemistry, this
work addresses an important void in the isocyanate literature:
the lack of reactions exploiting the reactivity of N-isocyanates.
This scarcity is surprising considering that the applications of C-
substituted isocyanates are extremely well developed. We
hope that this first thorough study on the synthetic uses of N-
Acknowledgements
We thank the University of Ottawa, NSERC (Discovery grant,
DAS and CREATE grants to A. M. B.), CFI, and the Ontario MRI
for generous financial support. Support of related work by
AstraZeneca Canada and OmegaChem is gratefully
acknowledged. J.-F. V.-R., C. C. and J. B. thank NSERC (CREATE
on medicinal chemistry and biopharmaceutical development,
PGS-D for J.-F.V.-R) and OGS for scholarships. K. L. also thanks
NSERC for a USRA scholarship.
Notes and references
‡ CCDC 1420522 (16p) and 1420523 (17a) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge
Crystallographic
www.ccdc.cam.ac.uk/data_request/cif.
Data
Centre
via
.
1
For reviews on isocyanates and their use in industry see: (a)
C. Six and F. Richter, Ullmann’s Encyclopedia of Industrial
This journal is © The Royal Society of Chemistry 20xx
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