Diversity-oriented synthesis of hydrazine-derived compounds from amino isocyanates generated in situ

Article abstract of DOI:10.1002/anie.201306379

Behind the mask: Nitrogen-substituted isocyanates are rare and their synthetic potential is virtually untapped. Simple masked precursors can form amphoteric amino isocyanate intermediates in situ, and allows the synthesis of complex hydrazine derivatives upon addition with amines. This reactivity was used in a cascade substitution/hydroamination sequence, and in the assembly of azadipeptide analogues. Copyright

Full text of DOI:10.1002/anie.201306379

Angewandte
Chemie
DOI: 10.1002/anie.201306379
Hydroamination
Diversity-Oriented Synthesis of Hydrazine-Derived Compounds from
Amino Isocyanates Generated In Situ**
Christian Clavette, Jean-FranÅois Vincent Rocan, and Andrꢀ M. Beauchemin*
The ability to rapidly assemble complex molecules from
simple starting materials is essential to improve current
chemical processes and discovery efforts. Development of
novel pharmaceuticals relies on practical synthetic strategies
offering step-economy and chemoselectivity. This conse-
quently restricts the use of certain reagents bearing unique
and interesting functionalities. For example hydrazine deriv-
atives have inherent chemoselectivity issues because of the
possibility that both nitrogen atoms could react and form
different products.[1] Nevertheless, the importance of these
motifs led to many recent reports, but inclusion of hydrazines
in molecular scaffolds can be problematic. Difficult control
over reaction outcomes has made their use in cascade
sequences challenging and therefore scarce, especially for
the assembly of peptidomimetics.[2] For this reason, develop-
ment of nitrogen-substituted isocyanate equivalents as syn-
thetic reagents is particularly attractive. Indeed, amino
Scheme 1. Novel reactivity using amino isocyanates.
isocyanates combine the highly electrophilic nature of
isocyanates while retaining differentiation and nucleophilicity
of only one nitrogen atom. Such amphoteric intermediates are
rare and have not been used in cascade reactions.[3] Herein we
describe the use of amino isocyanate equivalents for the
synthesis of complex semicarbazide derivatives including
azadipeptide motifs, and formation of diverse heterocyclic
faced the issue that intramolecular alkene hydroaminations
are generally not amenable to rapid generation of molecular
complexity.[7,8]
Indeed, synthesis of the precursors typically requires
several steps, and cyclization can only form one product. To
address this fundamental limitation and to explore the use of
nitrogen-substituted isocyanates in reaction sequences, we
targeted using amino isocyanate intermediates to form
diverse hydroamination precursors in situ, precursors which
then cyclize to afford various heterocyclic derivatives through
a substitution/hydroamination sequence.
structures by
a
substitution/hydroamination reaction
sequence (Scheme 1).
Recently, our group has reported the use of nitrogen-
substituted isocyanates to access b-amincarbonyl motifs from
alkenes.[4] We were surprised to find only a few reports of
nitrogen-substituted isocyanates in the literature, especially
considering the synthetic and industrial relevance of isocya-
nates.[5,6a,b] In further studies, we noted that amino isocyanates
can be conveniently generated in situ from simple precursors
and reacted to generate hydrazine derivatives.[6] As part of
our ongoing work on Cope-type hydroaminations, we often
We first validated this approach using a stepwise process
(Scheme 2). After optimization, we observed that the OPh
leaving group present in the carbazate 1a was rapidly
[*] C. Clavette,[+] J.-F. Vincent Rocan,[+] 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
[+] These authors contributed equally to this work.
Scheme 2. Stepwise substitution/hydroamination sequence.
[**] We thank the University of Ottawa, NSERC (DAS, CREATE, and CRD
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. C.C. and J.-F.V.R. thank
NSERC (CREATE on medicinal chemistry and biopharmaceutical
development) and OGS (C.C.) for scholarships.
exchanged for a pyrrolidinyl substituent in the presence of
a slight excess of the amine nucleophile at 808C. The resulting
semicarbazide 1b was isolated and then submitted to our
Cope-type hydroamination conditions (1208C) to provide the
cyclization product 2a in good yield. In contrast to our
previous report on the amination reactivity of simpler semi-
Supporting information for this article (experimental procedures,
and characterization of all new products) is available on the WWW
under http://dx.doi.org/10.1002/anie.201306379.
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Table 2: Substitution/hydroamination cascade: Amine scope.[a]
carbazides,[4a] we were delighted to note the absence of
a competing aminocarbonylation pathway.
We then attempted to combine both steps in a substitu-
tion/hydroamination sequence. Using the same reagents, the
reaction mixture was directly heated at 1208C since we
expected rapid substitution under the hydroamination con-
ditions. Gratifyingly, the desired sequence was achieved in
excellent yield (Table 1, entry 1). We thus embarked on
Table 1: Substitution/hydroamination sequence using carbazates.[a]
Entry Alkenyl
hydrazide
T
t
Product
Yield
[%][b]
[8C] [h]
[a] Reaction conditions: carbazate (1 equiv), amine (1.1 equiv) in PhCF3
(0.3m) heated in a sealed vial (microwave reactor, 1208C, 6 h). Yields
shown are those of the isolated product. [b] Yield determined by NMR
spectroscopy using 1,3,5-trimethoxybenzene as the internal standard.
1
2
3
R1 =R2 =R3 =H; 1a
120
80
175
6
6
6
2a
2b
2c
88
99
86
R1 =R2 =CH3,R3 =H; 1c
R1 =R2 =H,R3 =CH3; 1d
hydroamination sequence conditions. As shown in Table 2,
ten different hydroamination products were formed using the
same precursor, 1a. Both cyclic (3a–h) and acyclic (3i)
secondary amines proved to be competent nucleophiles. For
cyclic amines, four- (3a), five- (3b), and six-membered (3c–h)
amines led to the desired hydroamination product. (S)-
Prolinol also proved a competent nucleophile (3b), but only
showed modest diastereoselectivity under the reaction con-
ditions (1.2:1 d.r.). Piperidine derivatives, including the
medicinally relevant 2-oxopiperazine motif, exchanged and
cyclized efficiently (3c,d,h). Other nitrogen heterocycles such
as morpholine and piperazines underwent the reaction
sequence to provide the hydroamination products 3e–g in
good to excellent yields. We then compared the reactivity of
cyclic versus acyclic secondary amines. N,N-Dibenzylamine
provided the hydroamination product 3i in good yield but
proved less reactive than the cyclic derivatives. In contrast,
primary amines such as benzylamine only gave a moderate
yield of the hydroamination product 3j. We explain this
difference in hydroamination reactivity between the adducts
of the primary and secondary amines by the increased
population of the Z conformer present in the hydroamination
substrate. This Z conformer is in the appropriate conforma-
tion to react via the proposed concerted, Cope-type hydro-
amination (hydrohydrazidation) transition-state structure
(Scheme 3).[4a,9,10]
4
5
R1 =H,R2 =CH2OMOM; 1e 175
6
6
2d
2e
74
R1 =CH3,R2 =H; 1 f
120
94[c]
6
7
8
X=CH2; 1g
X=NTs; 1h
X=C(CH3)2; 1i
175 16
175
150 12
2 f
2g
2h
79
86
82
6
[a] Reaction conditions: carbazate (1 equiv), amine (1.1 equiv) in PhCF3
(0.3m) heated in a sealed vial (microwave reactor). [b] Yield of the
isolated product. [c] 1:1 d.r. MOM=methoxymethyl, Ts=4-toluenesul-
fonyl.
a study to determine if this cascade reaction could provide
access to various heterocyclic hydrazides: the results obtained
are shown in Table 1. As expected, the gem-dimethylated
substrate 1c cyclized under milder reaction conditions (808C)
because of
a
favorable Thorpe–Ingold effect (Table 1,
Having demonstrated the versatility of sequential reac-
tions involving amino isocyanates in the context of hydro-
amination, we then focused on the synthesis of other
important and medicinally relevant hydrazine subunits. We
thus sought to demonstrate that this substitution reactivity
could provide access to various azadipeptide subunits.[2]
Indeed, azapeptides and peptoids are part of the rapidly
expanding repertoire of amino acid mimics which are used in
peptidomimetics.[11] The increased metabolic stability of the
resulting unnatural oligomers is well-established. However,
entry 2). Substitution was also tolerated on the distal position
of the alkene but slightly higher temperatures were required
to achieve the parent sequence on both cis and trans alkenes
(entries 3–4). The sequence also proved versatile to form six-
membered-ring systems and led to the formation of piper-
idine and piperazine motifs (entries 6–8).
Since the scope of the sequence had only been explored
using pyrrolidine and morpholine in Table 1, we then
surveyed various amine nucleophiles under our substitution/
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reactions, including a substitution/hydroamination cascade
allowing the synthesis of diverse nitrogen-containing hetero-
cycles from a single, common hydroamination precursor.
Simple substitution of the O-phenyl leaving group with
primary amino esters also provides a convenient synthesis
of azadipeptide-like structures. Overall, these results demon-
strate the usefulness of amino isocyanates to rapidly generate
molecular complexity and assemble complex hydrazide
derivatives. Efforts to develop other reaction sequences and
access different hydrazine-based heterocycles are in progress
and will be reported in due course.
Scheme 3. Cope-type hydroamination transition state. HA=hydroami-
nation.
a notable advantage of azapeptides is that their subunits lack
stereochemical information in contrast to a, b, and g-amino
acids derivatives, which require the use of enantiopure
unnatural amino acids. Consequently, we felt that simple
substitution reactivity would provide a useful tool in pepti-
domimetics, and decided to perform exploratory studies with
the N-benzyl azapeptoid building block 1j (Table 3). Encour-
Received: July 22, 2013
Published online: October 7, 2013
Keywords: azapeptides · hydroamination ·
.
microwave chemistry · nitrogen heterocycles · synthetic methods
Table 3: Synthesis of dipeptide analogues using a substitution reac-
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[a] Reaction conditions: carbazate (1 equiv), amine (1.1 equiv), iPr2NEt
(1.2 equiv) in PhCF3 (0.3m) heated in a sealed vial (1008C, 12 h). Yields
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agingly, the use of the commercially available a-aminoester
ethyl glycinate (HCl salt) provided the azadipeptide subunit
4a in 78% yield. A similar result was obtained with l-alanine
ethyl ester to form 4b, and we ensured that racemization did
not occur under the reaction conditions (see the Supporting
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parent nitrogen analogue (an azatide subunit), tert-butylben-
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butylbenzylcarbazate relative to primary and secondary
amines.
In summary OPh-substituted carbazates allow the con-
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amines, and enable the rapid assembly of various hydrazine-
derived compounds. This reactivity was used in sequential
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