Libraries of C-5 Substituted Imidazoles and Oxazoles by Sequential Van Leusen (VL)–Suzuki, VL–Heck and VL–Sonogashira in Imidazolium-ILs with Piperidine-Appended-IL as Base

Article abstract of DOI:10.1002/ejoc.201800804

Facile access to diverse C5-substituted imidazoles and oxazoles via sequential Van Leusen–Suzuki, Van Leusen–Heck, and Van Leusen–Sonogashira protocols, employing imidazolium-ILs as solvents along with piperidine-appended imidazolium [PAIM][NTf₂

Full text of DOI:10.1002/ejoc.201800804

DOI: 10.1002/ejoc.201800804
Communication
Sequential Reactions | Very Important Paper |
Libraries of C-5 Substituted Imidazoles and Oxazoles by
Sequential Van Leusen (VL)–Suzuki, VL–Heck and VL–
Sonogashira in Imidazolium-ILs with Piperidine-Appended-IL as
Base
Hemantkumar M. Savanur,[a] Rajesh G. Kalkhambkar,*[a] and Kenneth K. Laali*[b]
Abstract: Facile access to diverse C5-substituted imidazoles strated, in a high-yielding one-pot method, starting with readily
and oxazoles via sequential Van Leusen–Suzuki, Van Leusen– available aldimines (for imidazole) or aldehydes (for oxazole)
Heck, and Van Leusen–Sonogashira protocols, employing imid- and tosylmethylisocyanide (Tos-MIC), under mild conditions
azolium-ILs as solvents along with piperidine-appended imidaz- with potential for recycling and reuse of the IL solvent. The
olium [PAIM][NTf2] as task-specific basic IL has been demon- scope of the method is supported 49 examples.
Introduction
In continuation of our work on developing synthetic meth-
ods in ILs as catalysts and solvents,[12] and in relation our recent
study on sequential reactions in ILs employing task-specific ILs
as base,[13] we wish to report here a facile entry into diversely
C-5 substituted imidazoles and oxazoles via sequential van
Leusen–Suzuki, van Leusen–Heck, and van Leusen–Sonogashira
Imidazoles and oxazoles are highly important classes of hetero-
cyclic compounds that are present in numerous bioactive natu-
ral products and are widely utilized as building blocks in medic-
inal chemistry and drug discovery.[1,2] Imidazolium salts in par-
ticular are widely employed as ionic liquids and have found
wide application as solvents and catalysts.[3] It is therefore
highly desirable to develop synthetic methods that provide fac-
ile access to diversely functionalized imidazoles and oxazoles
that can serve as small molecule building blocks for further
elaboration.
The Van Leusen tricomponent imidazole and oxazole synthe-
ses are practical one-pot protocols that utilize the unique reac-
tivity of tosylmethylisocyanide (Tos-MIC) to prepare imidazoles
from aldimines and oxazoles from aldehydes.[4] Continuing de-
velopments in multi-component (MC) sequential reactions have
created a new life for the van Leusen reaction, by combining
this key reaction with other transformations such as cycloaddi-
tion,[5] C–H bond activation,[6] ring closing metathesis,[7] and
other C–C bond forming reactions sequential reactions.[8–10]
We are aware of only one previous report in which
[BMIM][Br] was used as solvent to prepare oxazoles by Van
Leusen reaction using mono-substituted Tos-MICs along with
base.[11] To the best of our knowledge IL-mediated MC-sequen-
tial methods involving the van Leusen reaction have not been
reported.
protocols, employing imidazolium-ILs as solvent along with the
[13]
piperidine-appended imidazolium-NTf2
as task-specific basic
IL, in one-pot high yielding reactions starting from readily avail-
able aldimines (for imidazole) or aldehydes (for oxazole) and
tosylmethylisocyanide (Tos-MIC), under mild conditions. The
potential for recycling and reuse of the IL solvent is also demon-
strated, and scope of the method is highlighted by providing
49 examples.
Results and Discussion
At the onset, the potential to efficiently perform the van Leusen
imidazole and oxazole reactions in [BMIM][X] with X = PF6 and
BF4 as solvent with piperidine-appended imidazolium IL
[PAIM][NTf2] as base was examined, by using p-bromo-benz-
aldimines and benzaldehyde respectively, in one-pot reactions
using Tos-MIC, and the reactions were monitored by TLC. The
reactions went to completion at 60–70 °C typically after 5–6
hours (see exp. in SI file). The method also proved applicable
when using p-bromo-furan-aldimine and p-bromo-furan-
carboxaldehyde.
In the next phase, the feasibility to perform multi-compo-
nent (MC) van Leusen imidazole–Suzuki and oxazole–Suzuki se-
quential reactions were examined by introducing Pd(OAc)2 and
[PAIM][NTf2] along with various aryl/heteroaryl boronic acids
into the same reaction tube with mild heating and TLC monitor-
ing. The results are summarized in Table 1–Table 2 with 23 ex-
amples provided, and with isolated yields in the 70–80 % range
[a] Department of Chemistry, Karnatak University's Karnatak Science College,
Dharwad Karnatak 580001, India
E-mail: rgkalkhambkar31@gmail.com
[b] Department of Chemistry, University of North Florida,
1 UNF Drive, Jacksonville, FL, 32224, USA
E-mail: Kenneth.Laali@UNF.edu
http://www.unf.edu/coas/chemistry/faculty/Kenneth_Laali.aspx
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800804.
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using fresh IL solvent, decreasing gradually when using recycled
IL.
Table 2. The Van Leusen oxazole–Suzuki sequence.
Table 1. The Van Leusen imidazole–Suzuki sequence.
[a] Recycled IL was used (1st time). [b] bRecycled IL was used (2nd time). [c]
cRecycled IL was used (3rd time); *Isolated yield of pure compounds.
The efficacy to perform MC van Leusen imidazole–Heck and
oxazole–Heck sequential reactions was examined next. For
these reactions, following the completion of the van Leusen
step, styrene or p-methyl-styrene was introduced along with
Pd(OAc)2 and [PAMI][NTf2] with no other additives with mild
heating. Isolated yields using fresh IL solvent were in the 78–
68 % range and decreasing gradually when recycled IL was em-
ployed. The results are summarized in Table 3–Table 4 with 17
examples provided.
In a subsequent study, the van Leusen imidazole–Sonoga-
shira and oxazole–Sonogashira sequential reactions were per-
formed by introducing substituted alkynes along with 6 mol-
% Pd(OAc)2 and with CuI as additive. The reactions went to
completion after overnight stirring and mild heating. Average
isolated yields were in 70–60 % range and again lower yields
were obtained by using recycled IL. The results are gathered in
Table 5–Table 6 with 12 examples provided.
[a] Recycled IL was used (1st time). [b] Recycled IL was used (2nd time). [c]
Recycled IL was used (3rd time); *Isolated yield of pure compounds.
Control experiments showed that it is possible to perform
the reactions by using [PAIM][NTf2] alone, however this required
To get a sense for the limits of recovery and reuse of the IL
a larger quantity of the basic-IL as it also acts as solvent for the solvent, one reaction was selected from each category and was
reaction, and was not deemed economical, since the basic-IL is repeated in [BMIM][BF4] and [BMIM][PF6] up to five times to
not recycled. Optimal results were achieved by a combined use compare isolated yields. The results are presented in graphical
of [BMIM][X] acting as solvent and [PAIM][NTf2] acting as a com- form in the SI file. The data show a relatively consistent trend
patible base.
of decreasing yields by about 10 % after each cycle. For some
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Table 3. The Van Leusen imidazole–Heck sequence.
Table 5. The Van Leusen imidazole–Sonogashira sequence.
[a] Recycled IL was used (1st time). [b] Recycled IL was used (2nd time); *Iso-
lated yield of pure compounds.
[a] Recycled IL was used (1st time). [b] Recycled IL was used (2nd time). [c]
Recycled IL was used (3rd time); *Isolated yield of pure compounds.
Table 6. The Van Leusen oxazole–Sonogashira sequence.
Table 4. The Van Leusen oxazole–Heck sequence.
[a] Recycled IL was used (1st time). [b] Recycled IL was used (2nd time); *Iso-
lated yield of pure compounds.
[a] Recycled IL was used (1st time). [b] Recycled IL was used (2nd time). *Iso-
lated yield of pure compounds.
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[1] Selected reviews on imidazoles: a) L. Zhang, X.-M. Peng, G. L. V. Damu, R.-
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of the transformations [BMIM][PF6] appears more resilient and
would be the preferred IL solvent.
In summary, we have demonstrated the potential for se-
quential Van Leusen imidazole and oxazole with Suzuki, Heck,
and Sonogashira coupling protocols, employing imidazolium-
ILs as solvent along with [PAIM][NTf2] as task-specific basic IL,
starting with readily available aldimines (for imidazole) or alde-
hydes (for oxazole) and tosylmethylisocyanide (Tos-MIC) under
mild conditions and highlighted the scope of these sequential
reactions with 49 examples. We also demonstrated the possibil-
ity to recycle and reuse the IL solvent for a limited number of
cycles.
Supporting Information (see footnote on the first page of this
article): Synthetic procedures, IL recycling feasibility studies, analyti-
cal data for isolated compounds, and NMR spectroscopic data
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Acknowledgments
Authors at Karnatak University thank the University Scientific
and Instrument Center, KUD for IR, GC, GC-MS, 1H and 13C NMR,
and the NMR Research Centre at Indian Institute of Science Ban-
1
galore for H and 13C NMR Spectra. They also acknowledge fi-
nancial assistance by Department of Science and Technology,
Science and Engineering Research Board New Delhi (DST-SERB)
Project No. SB/FT/CS-175/2013. K. K. L. thanks University of
North Florida for the outstanding faculty scholarship and presi-
dential professorship awards, as well as faculty scholarship and
UNF Foundation Board grants.
[10] J. Maiti, S. Biswas, R. Das, Asian J. Chem. 2016, 28, 1519–1522.
[11] B. Wu, J. Wen, Z. Zhang, J. Li, Y.-Z. Xiang, X.-Q. Yu, Synlett 2009, 500–504.
[12] K. K. Laali, ARKIVOC 2016, i, 150–171.
[13] H. M. Savanur, R. G. Kalkhambkar, K. K. Laali, Appl. Catal. A 2017, 543,
150–161.
Keywords: Synthetic methods · C-C coupling · Domino
reactions · Ionic liquids
Received: May 24, 2018
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Communication
Sequential Reactions
H. M. Savanur, R. G. Kalkhambkar,*
K. K. Laali* ............................................ 1–5
Libraries of C-5 Substituted Imidaz-
oles and Oxazoles by Sequential
Van Leusen (VL)–Suzuki, VL–Heck
and VL–Sonogashira in Imidazol-
ium-ILs with Piperidine-Appended-
IL as Base
By sequencing the Van Leusen imidaz- imidazoles and oxazoles were synthe-
ole and oxazole syntheses with Suzuki, sized in one-pot reactions employing
Heck and Sonogashira reactions, di- [BMIM][X] as a solvent and [PAIM]-
verse libraries of C5-functionalized [NTf2] as a base.
DOI: 10.1002/ejoc.201800804
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