Intramolecular cyclization and subsequent rearrangements of alkyne-tethered N-heterocyclic carbenes

Article abstract of DOI:10.1016/j.tetlet.2012.08.038

Alkyne-tethered imidazole and 1,2,4-triazole-based N-heterocyclic carbene precursors have been prepared and studies of the intramolecular reactions of carbenes are performed. Products consistent with intramolecular cyclizations and subsequent rearrangemen

Full text of DOI:10.1016/j.tetlet.2012.08.038

Tetrahedron Letters 53 (2012) 5663–5666
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular cyclization and subsequent rearrangements
of alkyne-tethered N-heterocyclic carbenes q
Marc C. B. Legault a,b, Craig S. McKay a,b, Joseph Moran a, Matthew A. Lafreniere a,b, John Paul Pezacki a,b,c,
⇑
a National Research Council Canada, 100 Sussex Dr., Ottawa, ON, Canada K1A 0R6
b Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, ON, Canada K1N 6N5
c Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkyne-tethered imidazole and 1,2,4-triazole-based N-heterocyclic carbene precursors have been pre-
pared and studies of the intramolecular reactions of carbenes are performed. Products consistent with
intramolecular cyclizations and subsequent rearrangements were observed. Mechanistic studies using
crossover experiments showed that the products did arise from intramolecular carbene additions. The
reactions are proposed to go through vinylogous diaminocarbene intermediates similar to vinylogous
dialkoxycarbenes formed during Boger cycloaddition reactions. Imidazole substituted dienes were
observed to be the major products of tandem cyclization and elimination reactions that were observed
for imidazole-based N-heterocyclic carbenes.
Received 17 July 2012
Revised 8 August 2012
Accepted 9 August 2012
Available online 17 August 2012
Keywords:
N-heterocyclic carbenes
Intramolecular cyclization
Diels–Alder cycloaddition
Ó 2012 Elsevier Ltd. All rights reserved.
The unique characteristics of N-heterocyclic carbenes (NHCs)
have been exploited in many synthetic applications ranging from
ligands in transition metal catalyzed reactions to organocataly-
sis.1–4 In organocatalysis, NHCs have most commonly been used
to perform aldehyde umpolung reactions.5 Generally imidazolium,
thiazolium, and triazolium based-salts have been successfully em-
ployed. NHC catalyzed benzoin condensations between aldehydes
have been utilized in numerous syntheses, employing the concept
tuted nucleophilic carbenes such as, for example, those generated
from thermal elimination of carbene intermediates from norborne-
none ketals,28,29 from oxadiazolines using the method of Warkentin
et al.,30–33 or vinylogous dioxycarbenes generated from cycloprope-
none ketals by the Boger reaction.34,35 As shown in Eq. 1, the ther-
mally promoted formation of the three carbon 1,3-dipole or
p-
delocalized vinyl carbene from cyclopropenone ketal starting mate-
rial, followed the initial studies of the physical and chemical prop-
erties of these strained molecules by Baucom and Butler.36 Herein,
we have generated and studied analogous intermediates that con-
stitute vinylogous NHCs through intramolecular addition reactions
of NHCs onto intramolecular alkyne traps, as shown in Eq. 2.
of reverse polarity to generate a-keto alcohols, either intermolecu-
larly6–11 or intramolecularly.12–14 In the aza-benzoin variant, the
coupling of aldehydes with acyl imines has been used to prepare
a-amino and
a
-amido ketones.15–18 An extension of the Benzoin
reaction to ,b-unsaturated carbonyl compounds, namely the Stet-
a
ter reaction, has been used extensively to generate 1,4-dicarbonyl
compounds,19 and has also been used with other Michael acceptors
O
H
O
O
H
O
O
H
O
O
O
such as
a
,b-unsaturated nitriles and sulfones.20 These reactions
(1)
have been performed in both organic and aqueous media.21,22
The reactivity largely mimics the types of transformations preva-
lent in biological systems performed by the co-factor thiamine,
which can be considered a naturally occurring NHC.6
The applications of NHCs in organic synthesis have not been lim-
ited to catalysis, since NHCs are also nucleophilic carbenes and they
can act as reactive partners with different substrates including
maleimides,23 alkenes,24 isocyanates,25 and alkynes such as di-
methyl acetylenedicarboxylate (DMAD).26,27 The products of these
reactions resemble those obtained from other diheteroatom-substi-
Ph
Ph
N
I
N
N
N
Base
X
N
N
(2)
X
X
Solvent
Ph
X = CH, N
Ph
q
N
This Letter is dedicated to Professsor John Warkentin (McMaster) on the
N
occasion of his 80th birthday.
X
⇑
Corresponding author.
E-mail address: John.Pezacki@nrc.ca (J.P. Pezacki).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.038

5664
M. C. B. Legault et al. / Tetrahedron Letters 53 (2012) 5663–5666
Vinylogous diheteroatom substituted carbenes show interesting
reactivity that is consistent with both carbene and ylide resonance
structures. For example, the cyclopropenone ketal used by Boger
and co-workers can be thermally (70–80 °C) reacted with electron
deficient olefins to yield the corresponding functionalized cyclopen-
tene rings via formal [3+2] cycloaddition.34,37 Reactions with less
electron deficient olefins bearing a single electron withdrawing
substituent provide the corresponding cyclopropanes as the prod-
ucts of [1+2] carbene cycloaddition arising from reaction of the sin-
glet carbene.38 The application of cyclopropenone ketal has been
further extended to the reactions with aldehydes and ketones to
give butenolide ortho esters via [3+2] cycloaddition.39–42 Addition-
ally, the thermal [3+4] cycloadditions of cyclopropenone ketal with
Ph
Ph
N
N
-
I
2a
+
KOt-Bu
KOt-Bu
Ph
N
N
N
N
Ph
THF
THF
N
X
1a: X = CH
3
1b
: X = N
N
N
2b
Scheme 1. Base-catalyzed rearrangement of azolium salts in THF.
a
-pyrone afford annulated cycloadducts.34 Recent studies have
stable, or because t-BuOH acts as a catalyst toward the formation
of products 2a–b and 3 rather than undergoing O–H insertion
reactions.
demonstrated that this type of reactivity can be attained in an intra-
molecular fashion as well.37,43 While the reactivity at different tem-
peratures and with different substrates from the intramolecular
variant led to the formation of unexpected tricyclic or tetracyclic
products, both arise from the common carbene intermediate. Fur-
thermore, the intramolecular reaction shows tolerance to varying
tether lengths and substitution patterns.37,43
Dipoles with vinylogous di-heteroatom-substituted carbene
character have also been generated by intramolecular nucleophilic
additions of diheteroatom-substituted carbenes onto alkyne
groups giving rise to a number of interesting, if not unexpected
products.31,44 Given the unique chemical reactivity and diversity
of reactions that dipoles with vinylogous diheteroatom substituted
carbene character display, we sought to develop other dipoles
using intramolecular nucleophilic additions of NHCs onto tethered
alkynes, as shown in Eqn 2. These may in turn be utilized in peri-
cyclic reactions giving rise to privileged scaffolds for molecules
with unique medicinal properties. Herein we show that indeed
such dipoles are accessible via the base-promoted intramolecular
cyclization of alkyne-tethered azolium salts via an N-heterocyclic
carbene intermediate. Interestingly, we find that these intermedi-
ates undergo further intramolecular rearrangement giving rise to
novel heterocycle-substituted dienes.
Imidazolium (1a,1c, and 1d) and triazolium (1b) salts compris-
ing carbon tethers to alkyne moieties attached to a nitrogen were
synthesized from 4-pentyn-1-ol and either imidazole or triazole
starting materials according to the procedures described in the
Supplementary data (Scheme S1). Briefly, 4-pentyn-1-ol was first
alkylated at the terminal alkyne by Sonogashira coupling with an
aryliodide.45 Following mesylation of the corresponding alcohol
and substitution with imidazole or 1,2,4-triazole,46 the alkyne-
tethered azoles were methylated providing the azolium iodide
salts 1a–d.
The reaction of imidazolium salt, 1a with KOt-Bu (2 equiv) gave
rise to the unusual rearrangement products 2a and 2b in 63% yield
overall (Scheme 1). These products likely occurred via the addition
of the in situ generated NHC onto the alkyne group either intramo-
lecularly or by an intermolecular cascade of reactions. Interest-
ingly, when 1b was reacted under the same set of reaction
conditions, the cyclized product 3 was obtained in 32% yield, sug-
gesting that the vinylogous diaminocarbene and/or dipole from Eq.
2 may have been formed during the reaction. Reducing the number
of equivalents of base to 1.0 and 0.5 only reduced the respective
yields of the reaction products but no new products were isolable
under these conditions.
Ph
O
H
N
t-BXuOH
I
N
KOt-Bu
(3)
N
Ph
N
X
THF
N
X
N
1a
: X = CH
1b: X = N
X
Ph
Boger and co-workers observed that methanol trapping of an anal-
ogous carbene led to protonation at the carbene center but addition
of methoxide at a different carbon atom.37 In the reaction involving
triazolium salt 1b with t-BuOH quenching, t-BuOÀ may have alter-
natively reacted at the methyl carbon bound at N-4 of triazolium
salt, leading to the formation of 3 (Scheme 2).
Further attempts to trap carbene intermediates from 1a used
diethyl(ethoxymethylene)malonate, a dienophile that has in the
past been utilized in [3+2] cycloadditions with the Boger interme-
diate derived from cyclopropenone ketal. In our case this resulted
in the formation of compound 4 (Eq. 4). It was also apparent that
introducing heat was not favoring desired reactivity, rather pro-
moted decomposition pathways and the formation of additional
undesired products. Thus, it was believed that while deprotonation
might be kinetically favored, the cyclization was not occurring in a
timely fashion compared with intermolecular trapping. Further at-
tempts to generate the vinylogous diaminocarbene and/or dipole
intermediate prior to reaction with the dienophile trap did not
yield any cyclized products, only 4. This suggests that cyclization
may be reversible.
-
COOEt
OEt
Ph
I
N
N
EtOOC
+
COOEt
OEt
EtOOC
KOt-Bu
(4)
N
THF
N
-
I
1a
4
Ph
Ot-Bu
H
-
N
Ph
+
N
N
Ph
N
N
+
-
N
I
N
N
KOt-Bu
H
t-BuOH
N
3
THF
Attempts to trap the carbene intermediate formed during reac-
tions of 1a and 1b with t-BuOH were unsuccessful (Eq. 3). It is ex-
pected that carbene O–H insertion would follow a mechanism
involving first proton transfer followed by nucleophilic attachment
of the alkoxide anion.47,48 The lack of trapped products can be ac-
counted for if carbene was diverted through other intermolecular
reactions too quickly, or if the O–H insertion products were not
H
+
N
N
N
Ph
Ph
1b
Ph
N
N
N
X
tBuO-
Scheme 2. Proposed mechanism for the formation of 3.

M. C. B. Legault et al. / Tetrahedron Letters 53 (2012) 5663–5666
5665
The (Z,E) and (E,E) diastereomeric diene rearrangement products, 2a
Ar
Ar
N
N
N
N
and 2b, were initially observed as the major products by treatment
of 1a with an excess of KOt-Bu (2–10 equiv). In order to confirm
that these products were formed through intramolecular nucleo-
philic addition rather than intermolecular reactions, we synthesized
the imidazolium salt 1c and performed a cross-over experiment as
shown in Scheme 3. The incorporation of an aryl group onto the al-
kyne with a methyl in the meta position allows for the tracking of
these components during cross-over reactions containing equimo-
lar concentrations of 1a and 1c. No cross-over products were ob-
served, indicating that the products were forming exclusively
through an intramolecular rearrangement.
A better understanding of the elimination pathway was gained
through crossover experiments, suggesting that a mechanism as
shown in Scheme 4 was operative. The inability to trap the reactive
intermediates prompted further investigation into the pathway.
We decided to substitute the hydrogen atoms in alkyne tether that
were proposed to be involved in the elimination step of the mech-
anism leading to the novel diene, with gem di-methyl groups, thus
avoiding the elimination pathway.
N
N
HOt-Bu
H
KOt-Bu
-
+
KI
Ot-Bu
+
THF
+
-
I
Ar
Ar
H
-
N
N
N
N
N
N
H+
Ar
Ar
Ar
+
+
H
Ot-Bu
H
H
Ar
N
N
-
N
N
Ot-Bu
2
,
5
Scheme 4. Proposed mechanism for the formation of dienes 2a,b, 5 and 7.
The imidazolium salt 1d containing a gem-dimethyl substituent
as shown in Scheme 5 was synthesized through a short sequence
described in the Supplementary data (Scheme S2) and was tested
under our base-promoted cyclization conditions for the formation
of diene products. According to the proposed mechanism, 1d
should essentially shut down the pathway leading to diene prod-
ucts. Treating the gem-dimethyl imidazolium salt 1d with an ex-
cess of KOt-Bu in THF failed to yield any diene product, as
expected. This further supports the proposed mechanism for diene
formation as presented in Scheme 4. A significant amount of the
urea byproduct 6 was isolated, suggesting that the reactive inter-
mediate, without a reactive partner and inability to eliminate, fa-
vored formation of the oxidized product 6 (Scheme 5). It has
been previously proposed that this kind of reactivity occurs from
a Wanzlick intermediate in the case of bridged imidazolylidenes
reacting with triplet oxygen.49 However, formation of the vinylo-
gous diaminocarbene and/or dipole intermediate may be reversible
and that formation of 6 may have been facilitated by water. None-
theless, the presence of the gem-dimethyl group prevented diene
formation.
N
N
N
N
N
N
O
KOt-Bu
+
-
6
THF
I
1d
H
-
N
N
N
N
Ph
Ph
H+
+
+
X
-
Ot-Bu
Scheme 5. Attempted cyclization of gem-dimethyl alkyne tethered imidazolium
salt 1d.
from cyclization of imidazolium salt 1e, was reacted with N-phenyl
maleimide in toluene, heated to 80 °C for 24 h, and underwent
[4+2] Diels–Alder reaction. The thermodynamically favored exo
cycloadduct 8 was isolated in 76% yield. Interestingly, when the
solution was acidified with dilute perchloric acid or p-toluenesul-
fonic acid, no Diels–Alder reaction products were obtained. This
is consistent with a dramatic change in the electron demand of
diene upon protonation. These data suggest that these dienes can
be further modified and reacted with dienophiles to generate un-
ique imidazole linked products and that these reactions are tun-
able through protonation or through metal coordination of the
imidazole nitrogen atom.
Dienes 2a,b, 5, and 7 have not been reported previously, and
themselves are structurally interesting, particularly due to the
imidazole moiety that has the potential to tune the reactivity of
diene depending on its protonation/ligation state. To demonstrate
the unique properties of the obtained dienes, [4+2] cycloadditions
were conducted to determine if the reactivity could be tuned for
Diels–Alder reactions. According to Scheme 6, E,E diene 7, obtained
Ph
Ph
In summary, we have synthesized and tested the reactivity of
alkyne tethered NHC precursor azolium salts in base promoted
intramolecular cyclizations. The triazolium salt 1b led to the isola-
tion of a de-methylated cyclic product 3, whereas imidazolium
salts 1a,1c and 1e led to unique diene products 2a,b, 5, and 7,
respectively. The possible mechanisms leading to these various
products have been proposed and tested by various experiments
including cross-over experiments and the blocking of an elimina-
tion pathway through site-specific introduction of methyl groups
in place of acidic hydrogen atoms. The unique rearrangement
products observed here both expand our understanding of the
chemistry of NHCs and provide further opportunity for their use
in synthesis since they represent an interesting class of heterocy-
cle-substituted dienes. Applications of the imidazole-linked diene
1a
N
I-
N
+
N
2a, 2b
N
N
N
KOt-Bu
not observed
THF
I-
Ph
N
N
1c
N
N
N
N
not observed
5
Scheme 3. Cross-over experiment to establish intramolecularity of rearrangements
of imidazolium salts.

5666
M. C. B. Legault et al. / Tetrahedron Letters 53 (2012) 5663–5666
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Acknowledgments
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Sciences and Engineering Council of Canada (NSERC). We thank
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