Tuning the reactivity of isocyano group: Synthesis of imidazoles and imidazoliums from propargylamines and isonitriles in the presence of multiple catalysts

Article abstract of DOI:10.1002/anie.201410113

The reaction of propargyl amines with tert-butylisonitrile in the presence of a catalytic amount of both Yb(OTf)₃ and AgOTf afforded imidazoles, whereas the same reaction with primary and secondary alkylisonitriles, as well as arylisonitriles, in the presence of three metal salts [Yb(OTf)₃/AgOTf/KOTf] resulted in the 1,3,4,5-tetrasubstituted imidazoliums in excellent yields. Both chiral amines and chiral isonitriles can be used to provide corresponding chiral heterocycles without racemization. In this multiple catalytic system, Yb(OTf)₃ catalyzed the insertion of isonitriles to the N-H bond of amines, AgOTf catalyzed the 5-exo-dig cyclization of the resulting amidine nitrogen to the tethered triple bond, and KOTf promoted the salt metathesis, thus providing at the same time the counterion to the imidazolium. Against common knowledge, the isocyano group acted in these reactions as a polarized triple bond instead of conventional carbene-like function.

Full text of DOI:10.1002/anie.201410113

Angewandte
Chemie
DOI: 10.1002/anie.201410113
Synthetic Methods
Tuning the Reactivity of Isocyano Group: Synthesis of Imidazoles and
Imidazoliums from Propargylamines and Isonitriles in the Presence of
Multiple Catalysts**
Shuo Tong, Qian Wang, Mei-Xiang Wang, and Jieping Zhu*
Abstract: The reaction of propargyl amines with tert-butyl-
isonitrile in the presence of a catalytic amount of both
Yb(OTf)3 and AgOTf afforded imidazoles, whereas the same
reaction with primary and secondary alkylisonitriles, as well as
arylisonitriles, in the presence of three metal salts [Yb(OTf)3/
AgOTf/KOTf] resulted in the 1,3,4,5-tetrasubstituted imidazo-
liums in excellent yields. Both chiral amines and chiral
isonitriles can be used to provide corresponding chiral hetero-
cycles without racemization. In this multiple catalytic system,
at developing new reactivity patterns of given functional
groups remain scarce.
We have been interested in isonitrile chemistry for years[6]
and have recently initiated a research program aimed at
exploiting the new reactivity profiles of isocyano groups.[7] It
is well-established that the divalent carbon atom of the
isonitriles (1), known to have a pronounced nucleophilicity,
reacts readily with electrophiles to afford the nitrilium
intermediate A, which upon addition of a nucleophile pro-
vides the a-adduct B (Scheme 1a). Indeed, most of the
À
Yb(OTf)3 catalyzed the insertion of isonitriles to the N H bond
of amines, AgOTf catalyzed the 5-exo-dig cyclization of the
resulting amidine nitrogen to the tethered triple bond, and
KOTf promoted the salt metathesis, thus providing at the same
time the counterion to the imidazolium. Against common
knowledge, the isocyano group acted in these reactions as
a polarized triple bond instead of conventional carbene-like
function.
T
he development of catalytic domino processes has attracted
much attention among synthetic chemists.[1] One of the recent
and promising advances in this field is the emergence of dual
catalysis for the construction of complex molecular architec-
tures from simple starting materials. Different combinations
including metal/organo,[2] metal/enzyme,[3] organo/organo,[4]
and metal/metal catalysts[5] have been exploited for this
purpose. In developing such processes, one generally pays
particular attention on the sequence design and the compat-
ibility of the multicatalytic systems to facilitate the planned
multiple catalytic cycles. In spite of the recent intensive
research efforts, the types of reactions incorporated in
multicatalytic processes are still limited and examples aimed
Scheme 1. Reactivity patterns of isonitriles. Tf=trifluoromethane-
sulfonyl.
isonitrile-based organic transformations, including the power-
ful Passerini three-component reaction[8] and the Ugi four-
component reaction,[9] were developed by relying on the
carbene-like reactivity of the isocyano group.[10] We report
herein multicatalytic reactions in which the isocyano group
acts formally as a polarized triple bond rather than a carbene
(Scheme 1b).[11] Thus, reaction of propargylamines with tert-
butylisonitrile in the presence of a catalytic amount of
Yb(OTf)3 and AgOTf afforded the 1,4,5-trisubstituted imid-
azoles 3, whereas the same reaction with the primary and
secondary alkylisonitriles, as well as arylisonitriles in the
presence of Yb(OTf)3/AgOTf/KOTf afforded the 1,3,4,5-
tetrasubstituted imidazoliums 4 in excellent yields. In this
multiple catalytic system, Yb(OTf)3 catalyzed the insertion of
[*] Dr. S. Tong, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Prof. Dr. M.-X. Wang
Laboratory of Bioorganic Phosphorous Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (China)
[**] We thank the EPFL (Switzerland), Swiss National Science Founda-
tion (SNSF), Swiss State Secretariat for Education and Research
(SER), and National Natural Science Foundation of China for
financial support.
À
the isonitrile to the N H bond of amine, AgOTf catalyzed the
5-exo-dig cyclization of the resulting amidine to the tethered
triple bond, and KOTf promoted the salt metathesis thereby
providing at the same time the counterion to the imidazolium.
Imidazoles and imidazolium salts, are important heterocycles
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410113.
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in pharmaceuticals and in organic synthesis, and have
attracted chemists for many years.[12] However, efficient and
general catalytic methods are still under intensive develop-
ment.[13–15]
The reaction between tert-butylisonitrile (1a) and N-
benzyl-1,3-diphenylprop-2-yl-1-amine (2a)[16] was initially
investigated by varying the metal salts, the solvents, and the
temperature (Scheme 2). Key observations are summarized
Scheme 2. Multicatalysis: Synthesis of 1,4,5-trisubstituted imidazoles.
as follows: a) Y(OTf)3, La(OTf)3, and Yb(OTf)3 were effec-
tive Lewis acids to catalyze the insertion of isocyanide to the
À
N H bond of the secondary amine, with Yb(OTf)3 being the
best, to afford the amidine 5a in a quantitative yield.
Interestingly, other metal salts such as CuCl, AgOAc,
AgOTf, NaAuCl3, which are known to catalyze/promote the
amine insertion to isonitriles,[17] failed to produce 5a,
probably because of the preferential coordination of these
p-acidic metal salts to the triple bond, thus inhibiting the
insertion reaction; b) Yb(OTf)3 is an ineffective catalyst for
the conversion of amidine 5a into 3a. Silver salts, especially
AgOTf, catalyzed the 5-exo-dig cyclization of 5a leading to 3a
in a quantitative yield;[18] c) Yb(OTf)3 and AgOTf are
compatible and the two catalytic cycles did not interfere
with each other. Therefore in practice, there was neither need
to isolate the amidine intermediate nor to introduce the two
catalysts sequentially;[19] d) Xylenes gave the best result
among solvents screened (THF, 1,4-dioxane, DMF, DCE,
toluene and xylene). Overall, the all-in-one protocol consisted
of heating a xylenes solution (1308C) of 1a and 2a in the
presence of Yb(OTf)3 (0.2 equiv) and AgOTf (0.1 equiv).
Under these reaction conditions, the imidazole 3a, whose
structure was confirmed by X-ray structural analysis, was
isolated in 99% yield.[20]
The scope of this imidazole synthesis turned out to be very
general (Scheme 3). Aryl groups with different electronic
properties including heterocycles (3e–h) and alkyl groups can
be introduced into the 1-, 4-, and 5-positions of imidazoles.
The reaction was not sensitive to steric hindrance as
compound 3q (R3 = 2,4,6-trimethylbenzyl) can be obtained
in 90% yield. Chiral propargylamines can be converted into
enantioenriched imidazoles without racemization as is evi-
denced by the synthesis of the two enantiomers 3v and 3w.
The 1-benzyl-5,6-dihydroimidazo[5,1-a]isoquinoline 3x, an
important bicyclic compound in medicinal chemistry,[21] is
readily synthesized from the corresponding cyclic secondary
amine. It is interesting to note that when N-aryl propargyl-
amines (R3 = Ar, 3r–u) were used as substrates, the compet-
itive direct cyclization of 3r–u leading to quinolines was not
observed.[22]
Scheme 3. Scope of reaction. [a] Reaction was performed at 1408C.
Scheme 4. Further structural elaboration of functionalized imidazole.
The so-obtained imidazole could be further elaborated to
more complex polycyclic structure (Scheme 4). For example,
heating a toluene solution of 3u in the presence of a catalytic
amount of Pd(OAc)2, PPh3, and Cs2CO3 afforded 1-
benzylimidazo[1,5-f]phenanthridine (6) in 88% yield.[20,23]
It is known that isonitrile can form a complex with both
YbIII[24] and AgI[25] salts. In addition, we found that the pre-
synthesized complex Ag(OTf)(tBuNC)n has the same cata-
lytic activity as AgOTf.[26] It is therefore reasonable to assume
that both Yb(OTf)3 and AgOTf, upon mixing with isocyanide,
will form the complexes 7 and 8, respectively (Scheme 5).
Ytterbium triflate, which is azophilic, would further coordi-
nate to the amine,[27] while silver triflate, which is more p-
acidic,[28] would prefer to coordinate to the triple bond to
produce 9. Migrative insertion from 9 would produce 10 and
TfOH. Salt metathesis between 10 and TfOH would produce
the amidine 11 with the concurrent regeneration of Yb(OTf)3.
Intramolecular nucleophilic addition of the amidine nitrogen
atom to the silver-coordinated triple bond through a 5-exo-dig
mode afforded the intermediate 12, which upon dealkylation
(R = tBu), would produce 13 and TfOH.[29] Protonation of 13
followed by double-bond isomerization would produce 3 with
2
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Scheme 5. Reaction pathways leading to imidazoles and imidazolium
salts.
the concurrent regeneration of AgOTf. We stress that
alternative cyclization of 10 to 14[30] and its isomerization
product 15, resulting from the normal carbene-like reactivity
Scheme 6. Scope of imidazolium synthesis.
of isonitrile, was not isolated, probably because of the rapid
In summary, we developed novel and efficient syntheses
of imidazoles and imidazoliums in which the isocyano group
acted formally as a polarized triple bond rather than a carbene
function. Reaction of propargylamines with tert-butyliso-
nitrile in the presence of a catalytic amount of Yb(OTf)3 and
AgOTf afforded 1,4,5-trisubstituted imidazoles, while reac-
tion of propargylamines with primary and secondary alkyl-
isonitriles, as well as arylisonitriles, in the presence of
Yb(OTf)3/AgOTf/KOTf provided 1,3,4,5-tetrasubstituted
imidazoliums in excellent yields. In the latter reaction, three
task-specific metal salts, belonging to f-, d-, and s-blocks,
acted synergistically to drive the reaction towards the
formation of chiral tetrasubstituted imidazolium salts, which
are difficult to access by existing synthetic methodologies.
[30]
À
metathesis of the C Yb bond.
Based on the above mechanistic hypothesis, we assumed
that it would be possible to divert the reaction towards the
formation of imidazolium if the dealkylation step (pathway a;
Scheme 5) was slowed down and if additional metal salt
(MOTf) was added to promote the salt metathesis with 12
(pathway b; Scheme 5). This path would produce 16 with
concurrent regeneration of AgOTf. The former, upon proto-
nation and double-bond isomerization would then afford the
imidazolium 4.
Experimentally, it was found that simply heating a xylenes
solution (1408C) of 1 and 2 in the presence of three metal
salts, Yb(OTf)3 (0.2 equiv), AgOTf (0.1 equiv), and KOTf
(0.5 equiv), afforded the salts 4 in excellent yields. As
summarized in Scheme 6, the reaction is applicable to
a wide range of substrates including primary and secondary
alkylisonitriles, as well as arylisonitriles. Chirality can be
introduced to the products through both 1 and 2 without
erosion of enantiopurity and a variety of chiral imidazoliums
including the C2-symmetric ones (4h, 4i) were readily
accessible.[31] Bulky isonitriles such as 2,4,6-trimethylphenyl-
isonitrile was tolerated to afford the chiral 4l and 4m in
excellent yields. It is interesting to note that chiral imidazo-
lium salts of type 4 have been seldom used as chiral ionic
liquids or as chiral N-heterocyclic carbene precursors in
asymmetric synthesis, probably because of their low synthetic
accessibility.[32] We expect that the present general and robust
synthesis could facilitate the exploitation of this subclass of
imidazolium salts.
Received: October 15, 2014
Published online: && &&, &&&&
Keywords: heterocycles · homogeneous catalysis ·
.
multicomponent reactions · silver · synthetic methods
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ꢀ
[26] Characteristic spectroscopic data of Ag(OTf)(tBuNC)n. IR: N
C vibrational frequency 2181 cmÀ1 [Dn˜(N
= 47 cmÀ1].
ꢀ
ꢀ
C)coord-(N C)free
13C NMR: dNꢀC = 143 ppm (s); dNꢀ (free) = 152 (t). We were
unable to isolate pure Yb(OTf)3–tBuNC complex. In addition,
YbIII species, which is paramagnetic, cannot be characterized by
13C NMR spectroscopy.
C
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4
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A. G. Neo, A. Bornadiego, J. Dꢄaz, S. Marcaccini, C. F. Marcos,
Org. Biomol. Chem. 2013, 11, 6546 – 6555. We thank one of the
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À
À
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
S. Tong, Q. Wang, M.-X. Wang,
J. Zhu*
&&&& — &&&&
Tuning the Reactivity of Isocyano Group:
Synthesis of Imidazoles and
Imidazoliums from Propargylamines and
Isonitriles in the Presence of Multiple
Catalysts
Salty stuff: The reaction of propargyl-
amines with tert-butylisonitrile in the
presence of a catalytic amount of Yb-
(OTf)3 and AgOTf afforded 1,4,5-trisub-
stituted imidazoles, whereas the same
reaction with primary and secondary
alkylisonitriles, as well as arylisonitriles,
in the presence of Yb(OTf)3/AgOTf/KOTf
afforded 1,3,4,5-tetrasubstituted imid-
azolium salts in excellent yields. Tf=tri-
fluoromethanesulfonyl.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!