Synthesis of Cyclic Azomethine Imines by Cycloaddition Reactions of N-Isocyanates and N-Isothiocyanates

Article abstract of DOI:10.1021/acs.orglett.6b01788

Various nitrogen-substituted iso(thio)cyanates engage in [3 + 2]-cycloaddition reactions to form azomethine imines containing triazolone, triazole-thione, and pyrazole-thione cores. First, iminoisothiocyanates are shown to undergo aminothiocarbonylation reactions with strained alkenes, and a comparison with recently reported reactions of iminoisocyanates highlights their reduced reactivity. In contrast, amino(thio)carbonylation reactions of imines with iminoisocyanates and iminoisothiocyanates proved more efficient, providing access to triazolone and triazole-thione cores. The dipole products can be converted to valuable heterocyclic cores through simple derivatization reactions.

Full text of DOI:10.1021/acs.orglett.6b01788

Letter
pubs.acs.org/OrgLett
Synthesis of Cyclic Azomethine Imines by Cycloaddition Reactions of
N‑Isocyanates and N‑Isothiocyanates
Amanda Bongers, Indee Ranasinghe, Philippe Lemire, Alyssa Perozzo, Jean-Franco
̧ is Vincent-Rocan, and
Andre M. Beauchemin*
́
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa,
10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada
S
* Supporting Information
ABSTRACT: Various nitrogen-substituted iso(thio)cyanates engage in [3 + 2]-cycloaddition reactions to form azomethine
imines containing triazolone, triazole−thione, and pyrazole−thione cores. First, iminoisothiocyanates are shown to undergo
aminothiocarbonylation reactions with strained alkenes, and a comparison with recently reported reactions of iminoisocyanates
highlights their reduced reactivity. In contrast, amino(thio)carbonylation reactions of imines with iminoisocyanates and iminoiso-
thiocyanates proved more efficient, providing access to triazolone and triazole−thione cores. The dipole products can be
converted to valuable heterocyclic cores through simple derivatization reactions.
socyanates and isothiocyanates are important building blocks
in heterocyclic synthesis.1 Their use in intermolecular
the synthesis of heterocycles possessing the N−N−CO motif
(Scheme 1B),5−7 though their use is rare.6d As part of our program
on the use of N-isocyanates, we were drawn to their potential to
provide new routes to useful heterocycles.
More precisely, we recently reported the intermolecular amino-
carbonylation reaction of iminoisocyanates with alkenes, which
involves a stereospecific [3 + 2] cycloaddition (Scheme 2A).8,9
I
cycloadditions is also established, the most well-known being
the [2 + 2] reaction of chlorosulfonyl isocyanate with alkenes
to synthesize β-lactams.1b,c Isocyanates are also key starting
materials in modular syntheses of heterocycles, including systems
containing the N−N−CO subunit, which exists in many pharma-
ceuticals and agrochemicals (Scheme 1C).2−4 However, there
Scheme 2. Intermolecular [3 + 2] Cycloaddition of Alkenes
and Imines with Iso(thio)cyanate Precursors
Scheme 1. Structures and Synthesis of Useful Heterocycles
with N−N−CO and N−N−CS Motifs
In this work, hydrazones and semicarbazones provide the reactive
N-isocyanate intermediate through loss of the blocking group, in
analogy to blocked (masked) isocyanates used in industry.10 This
approach provides access to N−N−CO-containing heterocycles
can be practical difficulties with current modular syntheses
involving hydrazine derivatives (Scheme 1A), including sensi-
tivity or chemoselectivity issues. Toxicity and poor functional
group diversity associated with the isocyanate component can
also be problematic. From this perspective, nitrogen-substituted
isocyanates (N-isocyanates) offer alternative disconnections for
Received: June 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01788
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Letter
by derivatization of the azomethine imine product,11 including
pyrazolones and enantioenriched pyrazolidinones.9d,12
In alkene aminothiocarbonylation reactions with 1, strained
norbornene derivatives were the best substrates, providing
dipoles 2a−f in 26−68% isolated yields (Scheme 3). It was
observed that the NMR yields were considerably higher than the
isolated yields (2a NMR yield = 93%). These reduced yields
upon isolation are attributed to the high polarity of the products
and degradation during chromatographic isolation. Overall, imino-
isothiocyanates as reactive intermediates proved less versatile
compared to iminoisocyanates,9b,d showing only modest reactiv-
ity with unactivated alkenes (see the Supporting Information).
Nevertheless this work presents a proof of concept for the
aminothiocarbonylation of alkenes. These results also support
that the stabilizing frontier molecular orbital interaction during
these [3 + 2] cycloadditions involves the HOMO of the alkene
with the LUMO of the iminoiso(thio)cyanate.
We became interested in using related [3 + 2] cycloadditions
to access more diverse azomethine imines and their derivatiza-
tion products. This led us to explore the reactivity of other inter-
mediates, iminoisothiocyanates,7 and different electron-rich
double bonds, such as imines (Scheme 2B). Herein, we report
the synthesis of sulfur- and nitrogen-containing azomethine imines
and related heterocyclic cores using rare iminoisothiocyanates and
the unprecedented cycloaddition of iminoisocyanates with imines.
Alkenes are abundant and readily available but rarely used as
substrates in the synthesis of heterocycles with the pyrazolone
core.13a,b Furthermore, the addition of nitrogen and CS across
the double bond of an alkene (aminothiocarbonylation) is a rare
transformation, with only two reports.13b,c With iminoisothiocya-
nates, this intermolecular reaction would provide thioxoazomethine
imines (2, 3-thioxopyrazolidin-1-ium-2-ides). Such compounds
have been synthesized only by the treatment of the parent
carbonyl-containing azomethine imines with Lawesson’s reagent.14
Thus, the development of new aminothiocarbonylation reactivity
holds potential as a streamlined approach to pyrazolidine-3-thiones,
pyrazole-3-thiones, and other β-amino-thiocarbonyl compounds.
To access these products, we required a precursor to the imino-
isothiocyanate with a suitable blocking group (Scheme 2). In our
previous studies with the parent carbonyl precursors, we found
that PhO− served as an excellent blocking group, providing the
iminoisocyanate in situ for the cycloaddition reaction.9b However,
the synthesis of the analogous isothiocyanate precursor was
difficult, and yields were not reproducible. Fortunately, we found
that thiosemicarbazone precursors 1 (BG = p-(NO2)C6H4NH−)15
effectively produced the reactive iminoisothiocyanates for the
intermolecular alkene aminothiocarbonylation reaction. These
precursors are easy to synthesize from simple hydrazones and
4-nitrophenyl thioisocyanate. Optimization with reagent 1 revealed
that the reaction required anhydrous solvent and excess alkene, and
these conditions were used to survey the alkene scope (Scheme 3,
see the Supporting Information for optimization data).
We then explored the use of imines (CN bonds) as alter-
native substrates to alkenes in such [3 + 2] cycloadditions, with the
objective to form azomethine imines containing a triazolethione core
(Scheme 4). Optimization of the reaction with iminoisothiocyanate
Scheme 4. Intermolecular CN Aminocarbonylation of
a
Aldimines Using Iminoisothiocyanate Precursors
Scheme 3. Intermolecular Alkene Aminothiocarbonylation
a
Using Iminoisothiocyanate Precursors
a
Conditions: 1 (1.5 equiv), imine 3 (1.0 equiv), MeCN (0.05 M), heated
(microwave) to 120 °C in a sealed vial under argon. Isolated yields are
b
provided (except 4d). NMR yield with 1,3,5-trimethoxybenzene
internal standard.
precursor 1a and imine 3a revealed that using the imine as the
limiting reagent gave the highest yields (Supporting Information).
This shows that imines are significantly more reactive than alkenes
in cycloadditions with iminoisothiocyanates. Under these con-
ditions, 1a also provided products with electron-poor (4b)
and electron-rich (4c) aromatic N-methylimines. A variety of
aldehyde-derived thiosemicarbazones (1c−h) were also synthe-
sized and tested. In the reaction with imine 3a, furyl- and thienyl-
containing precursors gave lower yields of azomethine imines
(4d, 27% NMR yield; 4e, 53% isolated yield) compared to 1a.
These lower yields are in line with the observation that
the products are prone to degradation by hydrolysis. An unex-
pected transformation occurred with electron-withdrawing R1
a
Conditions: 1a or 1b (1.0 equiv), alkene (10 equiv), MeCN (0.05 M),
heated (microwave) to 120 °C in a sealed vial under argon. Isolated
yields are provided. NMR yield (shown in square brackets) with
1,3,5-trimethoxybenzene as internal standard. Mixture of methylene
regioisomers for 2c (1.3:1) and 2f (1.1:1); major isomer is shown.
b
c
B
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Letter
substituents: isomerization to yield aromatic derivatives, the
thiotriazoliniumides 5a−d.16 In these cases, only the isomerized
product could be detected.
Given the high reactivity observed, we were optimistic that
imines would also engage in cycloaddition reactions with imino-
isocyanates. After exploring various carbazones with 3a, we
found that iminoisocyanate precursors derived from aldehydes
provided the best reactivity (Scheme 5), with furyl (6a) and
Figure 1. Single-crystal X-ray structure of 7b. Proximity of the thienyl
sulfur and N− is shown (S···N distance = 2.84 Å). Dihedral angles φ1 =
0.59°, φ2 = −1.20°.
Scheme 5. Intermolecular CN Aminocarbonylation of
a
and φ2 = −1.20°. This conformation is attributed to maximized
charge delocalization into the aromatic ring.
Imines Using Iminoisocyanate Precursors
The azomethine imines in Schemes 3−5 are precursors to a
variety of useful heterocycles with the pyrazolone or triazolone
core, as illustrated by simple derivatization reactions (eqs 1−3).18
In addition, products unstable toward hydrolysis (e.g., 7c,
Scheme 5) can be isolated in the stable, reduced form (red-7c) by
simple reduction of the crude mixture with NaBH4 (eq 4).
In summary, we expanded the applicability of underexplored
[3 + 2] cycloaddition reactions of iminoisocyanates and iminoiso-
thiocyanates. First, it was shown that iminoisothiocyanates also
a
Conditions: 6 (1.0 equiv), imine 3 (1.5−2.0 equiv), PhCF3 (0.05−
b
0.10 M), heated (microwave or conventional) to Heated (micro-
wave or conventional) to 120 °C for 1−3 h in a sealed vial under
c
argon. Isolated yields are provided. Heated (microwave or conven-
tional) to 130 °C for 1−3 h in a sealed vial under argon. Isolated yields
d
are provided. NMR yield (shown in square brackets) with 1,3,5-
e
trimethoxybenzene as internal standard. NMR yield of 7c = 50%.
Isolation by reduction of 7c with NaBH4; isolated yield = 39% over
two steps.
thienyl (6b) carbazones leading to the highest yields and facil-
itating product isolation. Again in contrast to the modest reactivity
observed with alkenes,9c using only a slight excess of the imines
(1.5−2.0 equiv) was sufficient. Imines prepared from aromatic
aldehydes bearing electron-withdrawing (7f, 41% yield) and
electron-donating (7g, 69% yield) substituents showed good
reactivity. Higher yields were obtained in the presence of N-alkyl
substituents (7a−d,f−h), while an N-Ph imine provided 7e in only
39% yield. Unfortunately, no products were observed with keti-
mines (e.g., benzophenone imine, N-methylacetonimine). Due to
their sensitivity, the products were isolated by trituration of the crude
mixture in Et2O, and thus, yields were often higher at larger scale.
An X-ray crystal structure was obtained for 7b (Figure 1),
providing unambiguous proof of structure. This also gave insight
into the cyclization efficiency and improved product stability
observed with the thienyl group (see the Supporting Information
for competition experiments), resulting from potential S···N
chalcogen bonding.17 The S···N distance is 2.84 Å, which is less
than the sum of the van der Waals radii (S + N = 3.35 Å) and
within the range of known thienyl S···N noncovalent interactions
(2.7−3.0 Å).17 The thienyl group and triazolone core are near
coplanar, with dihedral angles (S−C−C−N−N) of φ1 = 0.59°
engage in reactions with alkenes but showed reduced reactivity
compared to iminoisocyanates. Conditions to engage both types
of reagents in aminocarbonylation reactions of imines were also
developed and showed increased reactivity. Overall, this modular
approach provides a new strategy for the synthesis of hetero-
cycles with high-heteroatom content and includes proof-of-concept
results for aminothiocarbonylation reactions of electron-rich double
bonds. Other new reactivity of amphoteric reagents is currently
being pursued and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01788.
Complete experimental procedures, characterization and
optimization data, and X-ray crystallographic information
(PDF)
X-ray crystallographic data for 7b (CIF)
C
DOI: 10.1021/acs.orglett.6b01788
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Letter
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: andre.beauchemin@uottawa.ca.
Notes
The authors declare no competing financial interest.
(10) (a) Wicks, D. A.; Wicks, Z. W., Jr. Prog. Org. Coat. 1999, 36, 148−
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ACKNOWLEDGMENTS
■
We thank the University of Ottawa (URC to A.M.B.; Dr. Yu
Scholarship to I.R.; UROP to P.L.) and NSERC (Discover Grant to
A.M.B; CGS-D3 to A.B.; USRA to P.L.; PGS-D to J.-F.V-R.) for
generous financial support. We thank Dr. Bulat Gabidullin
(University of Ottawa) for assistance in determining the structure
of 7b and Kaitlyn Lavergne for exploratory aminothiocarbonylation
experiments involving enol ethers.
Muck-Lichtenfeld, C.; Studer, A. Chem. Sci. 2015, 6, 1252−1257.
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