Tropylium-promoted carbonyl-olefin metathesis reactions

Article abstract of DOI:10.1039/c8sc00907d

The carbonyl-olefin metathesis (COM) reaction is a highly valuable chemical transformation in a broad range of applications. However, its scope is much less explored compared to analogous olefin-olefin metathesis reactions. Herein we demonstrate the use of tropylium ion as a new effective organic Lewis acid catalyst for both intramolecular and intermolecular COM and new ring-opening metathesis reactions. This represents a significant improvement in substrate scope from recently reported developments in this field.

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Tropylium-Promoted Carbonyl-Olefin Metathesis Reactions
Uyen P. N. Tran,a Giulia Oss,a Domenic P. Pace,a Junming Ho*a and Thanh V. Nguyen*a
Received 00th January 20xx,
Accepted 00th January 20xx
The carbonyl-olefin metathesis (COM) reaction is a highly valuable chemical transformation in a broad range of
applications. However, its scope is much less explored compared to analogous olefin-olefin metathesis reaction. Herein we
demonstrate the use of tropylium ion as a new effective organic Lewis acid catalyst for both intramolecular and
intermolecular COM and new ring-opening metathesis reactions. This represents a significant improvement in substrate
scope from recently reported developments in this field.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
The olefin-olefin metathesis reaction has been extensively
studied in the past decades due to its applicability in direct
carbon-carbon bond formation.1 The analogous carbonyl-olefin
metathesis (COM) reaction,2 however, is much less
investigated, despite the fact that chemistry of carbonyl
compounds has been exploited ubiquitously in organic
synthesis.3 There might be several reasons for this, with one
linked to the same versatile reactivity of the carbonyl
functionality such that other chemical transformations often
compete and overshadow the possible metathesis reaction.2-3
Until recently, there were only
a small number of
stoichiometric Lewis acid-facilitated protocols4 for the COM
reaction (Scheme 1a) and relevant stoichiometric olefination
reactions of carbonyl moieties.5
In the last two years, the Schindler’s group6 and Li’s group7
reported elegant studies in which they utilized salts of iron(III),
an abundant transition metal,8 to promote intramolecular
cyclization COM reactions (Scheme 1a). However, the full
potential of this chemical transformation3,9 has not been
adequately studied for ring-opening10 (Scheme 1b) or
intermolecular2,11 (Scheme 1c) COM reactions, which are
typical variations of the well-studied olefin-olefin metathesis.
Therefore, the substrate scope of the COM reaction needs to
be expanded beyond intramolecular cyclization to deliver the
prospective synthetic applications it invokes.3,9 Although
iron(III) catalysts have enjoyed some success, the infancy
status of this field beckons further exploratory work in
developing a more diverse catalyst pool for the COM reaction.
Based on our previous work on the aromatic tropylium ion,12
we envisage that tropylium could be a suitable organocatalyst
Scheme 1. Carbonyl-Olefin Metathesis (COM) Reactions
for the carbonyl-olefin metathesis reaction. The concept of
using an organic compound as promoter for this type of
reaction became attractive after recent developments from
the Lambert’s group using hydrazine2 and Franzen’s group
using tritylium salts.11 The former system catalyzed the
reaction via the formation of covalently bonded hydrazonium
intermediate13 while the latter catalyst activated the carbonyl
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compound via Lewis acid-base coordination. The aryl groups or carbonyl/carboxyl moieties gave the normal
electrophilicity of the unsubstituted tropylium ion, as reported ring-closing metathesis products (3d 3n, Scheme 2). Two
by Mayr and co-workers, is comparable to that of tritylium biphenyl substrates gave the phenanthrene-type products (3o
ions stabilized by electron-donating substituents such as and 3p with significant formation of the carbonyl-ene
-
)
methoxy group.14 Tropylium ion15 might therefore be a products (3o’ and 3p’, Scheme 2).17 These reaction outcomes
suitable Lewis acid catalyst with adequate electrophilicity and and observations are comparable to that of iron(III)-catalyzed
oxophilicity for the COM reaction.12e Gratifyingly, our study systems reported by Schindler and co-workers,6 hinting that
demonstrated that tropylium ion could indeed be used as an these intramolecular COM reactions probably proceeded
organic Lewis acid catalyst to efficiently promote the carbonyl- through some analogous pathways, despite being facilitated by
olefin metathesis reaction with good to excellent outcomes on two totally different catalysts.
a broad range of substrates. This organocatalytic system is of The double bond isomerization (3a-3c) is presumably catalyzed
particular interest for future developments in this field as it by trace amounts of Brønsted acid that might form if moisture
proves to be a universally versatile promoter for both inter- was present in the reaction mixture. However, when we
and intra-molecular reactions as well as the new ring-opening carried out the reactions in very anhydrous conditions (using a
carbonyl-olefin metathesis.
glovebox), the same results were observed, implying that it
might not be the case. Unfortunately, further control
experiments with hindered proton scavengers (such as 2,6-
dimethyl or 2,6-di(t-butyl) pyridines) in addition to our
tropylium catalyst only led to low conversion of the starting
material to the product. This was exactly the outcome for
other control experiments where we used those pyridine
additives with Schindler’s iron (III) catalyst, which hinted that
the pyridines interfered with the general COM reaction. We
also found that the tropylium ion reacted directly with these
pyridines to form the corresponding N-cycloheptatrienyl
pyridinium salts,12g which ruled out the validity of these
Brønsted pathway control experiments at this stage.
Results and Discussions
Intramolecular COM Reactions with Tropylium Catalyst
Our proof-of-concept study met with instant success for the
cyclization COM reaction of substrate 1a (Scheme 2, also see
Table S1 in page S3 in the Supporting Information – SI for
optimization of reaction conditions), a substrate known to
work smoothly from Schindler’s work employing iron(III)
catalyst.6a The non-paramagnetic nature of the tropylium
organocatalyst enabled us to follow the progress of this
reaction by NMR spectroscopy as illustrated in Figure 1 (also
see Figure S1 in the SI for more details). The conversion of a
similar substrate (1b, also see Scheme 2) to 3b and acetone
We observed a clear pattern in the reactivity of different
substrates studied in Scheme 2 that the reactions generally
worked more efficiently when they produced acetone as a by-
product (R1, R2 = Me). When the by-products were an aldehyde
(R1, R2 = H) or aromatic ketone (R1, R2 = Ph), there were
(
4a, (CH3)2C=O at 2.2 ppm) over time was very clean and
completed after ca. 48 h at 45 °C. Similar to Schindler’s iron(III)
catalytic reaction, 3b was formed as the thermodynamically
favored olefin product.6a We subsequently applied the
intramolecular COM reaction to a broad range of substrates
(Scheme 2).16 Most of tested precursors went through the
tropylium-catalyzed COM reactions smoothly to afford the
cyclized products in moderate to excellent yields.
dramatic decreases in product yields (3g, 3p, Scheme 2). We
believe that the volatility of acetone might play a role in
driving the reaction equilibrium to the productive pathway
(also see entry 14, Table 1). Another possibility is that that the
formation of acetone is particularly thermodynamically-
favored for the tropylium-catalyzed ring-closing carbonyl-
olefin metathesis reactions, as such phenomenon was also
observed for Schindler’s and Li’s systems.6-7
Notably, substrates with methyl substituents at the
to the original carbonyl group normally produced the
rearranged thermodynamically stable olefin products (3a 3c
Scheme 2). On the other hand, the replacement of Me with
α-position
-
,
AND
BF4
(2)
1
15 mol%
MeO
O
3
CO2Et
CO2Et
R2
R1
CO2Et
CO2Et
EtO
EtO
neat, 90 °C, 6-48 h
(see optimization of reaction conditions at page S3 in the SI)
O
R2
3h’
R1
3h
3h + 3h’ (1 : 1), 58%
R1 = R2 = Me
3i, 74% (+ traces of 3i’)17 3j, 66% (+ traces of 3j’)17
4
R1 = R2 = Me R1 = R2 = Me
MeO
CO2Et
Allyl
CO2Et
Me
CO2iPr
Allyl
Me
Me
Ph
Me
3e, 82%
CO2Bn
3l, 54%
R1 = R2 = Me
Me
3m, 72%
MeO
3n, 51%
3a, 92%
3b, 85%
3c, 83%
3d, 36%
R1 = R2 = Me
3k, 65%
R1 = R2 = Me
R1 = R2 = Me
R1 = R2 = Me
R1 = R2 = Me
R1 = R2 = Me
R1 = R2 = Me
R1 = R2 = Me
H2C
Me
Me
H2C
Me
Me
Me
AND
AND
COPh
CO2Et
CO2Et
3g, 39%
R1 = H, R2 = Ph
CO2Et
3g, 18%
R1 = Me, R2 = Ph
3f, 61%
3g, 90%
R1 = R2 = Me
3o
65%
3o’
32%
3p
29%
3p
+ 3p’
3o
+ 3o’
3p’
20%
R1 = R2 = Me
R1 = R2 = Me
R1 = H, R2 = Me
Scheme 2. Intramolecular COM reactions
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Figure 1. Progress of the tropylium-catalyzed intramolecular carbonyl-olefin metathesis reaction from 1b to 3b by 1H NMR studies (CD2Cl2, 25 °C)
Intermolecular COM Reactions with Tropylium Catalyst
feasibility and synthetic potential of the intermolecular
carbonyl-olefin metathesis reactions with tropylium catalyst. In
contrast to the intramolecular reaction discussed above (see
Scheme 2), this intermolecular reaction however did not seem
to work with ketone substrates or strongly eletron-poor
aromatic aldehydes. Indeed, the replacement of 2-
naphthaldehyde (5a) with substrates such as acetophenone
The intermolecular carbonyl-olefin metathesis is arguably a
more synthetically valuable or more versatile version of this
reaction (also see Scheme 1). Thus far, there has been no
report on a practical catalyst system to promote this type of
process,3,9b,9c including Schindler’s6 and Li’s7 iron(III) catalysts,
except the moderately successful tritylium-catalyzed reaction
reported by Franzen and co-workers.11 We therefore believe
that it would be a challenging but suitable reaction scope to
probe the catalytic activity of our tropylium catalyst. We
started our investigation by looking at the intermolecular
(
5k) or 2-acetonaphthone (5l) did not produced to any
observable formation of the expected metathesis products.
Electron-deficient aryl aldehydes (5j 5j, Scheme 3) did not lead
-
to any productive reaction outcomes either. Heteroaromatic
aldehyde 5h formed adduct with tropylium ion at the nitrogen-
centre and hence deactivated the reaction system. Aliphatic
aldehydes also led to complicated reaction mixtures with some
aldol and carbonyl-ene18 byproducts.
carbonyl-olefin
metathesis
reaction
between
2-
naphthaldehyde (5a) and amylenes (6a). Pleasingly, a test
reaction with 20 mol% tropylium tetrafluoroborate in
acetonitrile at 90 °C afforded the formation of the desired
product in promising yield (see page S16 in the Supporting
Information for more details). Interestingly, the olefin product
was formed predominantly as the trans-isomer,17 similar to the
selectivity observed from from Franzen’s tritylium-catalyzed
reactions.11 Encouraged by this initial success, further studies
were carried out on the effect of solvent, reaction
temperature, catalyst loading and ratio of reagents (also see
page S16 in the SI for more details). The optimal reaction
conditions for the intermolecular reaction involved an excess
amount of the aldehyde 5a and 10 mol% tropylium catalyst in
The vast difference between the inter-and intramolecular
reactions is presumably due to the different coordinating
affinity of the weakly Lewis acidic tropylium ion to these
substrate systems, but a conclusive explanation cannot be
R
BF4
(2)
O
10 mol%
O
R
Ar
H
Ar
DCM, MW 80 ºC, 0.5 h
6
7
4a
5
Me
Me
7d, 48%
Me
Me
7c, 62%
dichloromethane at 80 °C for 0.5 hour under pressurized
microwave irradiation conditions to give the COM product 7a
7b, 56% Me
Br
7a, 52%
O
nBu
Ph
CO2Me
in 52% yield.
H
N
7g, 59%
Thus, we subsequently applied the optimal conditions
7e, 45%
7f, 70%
5h, no reaction
MeO
developed to
a
family of aromatic aldehydes and
O
H
O
O
O
isopropylidene- bearing olefin substrates (Scheme 3).
Gratifyingly, most of the electron-rich, neutral or weakly
electron-poor aldehyde substrates gave the target products in
H
F3C
O2N
5i, traces of 7i
5j, traces of 7j
5k, no reaction
5l, no reaction
moderate to good yields (7a-7g, Scheme 3), confirming the
Scheme 3. Intermolecular COM reactions.
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easily derived. There are also several other factors limiting the
efficiency of this reaction, such as the low boiling point of
amylenes and their tendency to polymerize in the presence of
the tropylium catalyst. Although these intermolecular COM
reactions only give moderate success, they still provide an
important benchmark for this research field, as this is the only
second time11 the intermolecular COM reaction was
investigated in catalytic sense. Both of the first study from the
Franzen group with tritylium catalysts11 and our study with
tropylium catalyst has proven that it might be problematic to
adapt the COM reaction to bimolecular systems. In terms of
entropy change, the intermolecular COM reaction (two
molecules react to form another two molecules) is presumably
less favourable than the intramolecular version (one molecule
cyclizes to form two products).
O
BF4
5-15 mol%
O
(2)
(H2C)n
(2:1)
(CH2)n
R
H
Ar
Ar
neat, 40-70 oC, 4-24 h
O
R
5
8
9
9c, 31%
O
O
O
9g3, 48%
9g6, 45%
9g2, 59%
9g1, 56%
Br
O
O
O
9g4, 26%
9g5, 37%
Br
Cl
O
Reactivity test reaction with 5c
:
H
n = 1
Intermolecular Ring-opening COM Reactions
While both catalytic intramolecular and intermolecular COM
reactions have been recently realized by seminal contributions
from the Schinder and Li groups6-7 and the Franzen group11
respectively, the ‘intermolecular’ ring-opening carbonyl-olefin
metathesis reaction10a has been rather neglected. An elegant
study from Lambert and co-workers exploited a hydrazine
organocatalytic system to promote this type of reaction
between aromatic aldehydes and ring-strained cyclopropene
substrates.2 These reactions, however, followed a totally
different metathesis paradigm involving hydrazonium
intermediates and subsequent [2+3] cycloaddition followed by
rearrangement to form the products. Therefore, it was of great
interest to examine the potential of our tropylium catalyst as
an organo-Lewis acid promoter for the ring-opening COM
reaction in a similar manner to intra- and intermolecular
reactions discussed earlier in this work.
F3C
Me
8a
8b
(very volatile substrate) traces
no reaction
n = 2
n = 3
8c
Me
reactive (but also volatile) substrate
HO2C
H
Me
H
8d
8e
8f
8g
no reaction
no reaction
no reaction
reactive substrate
n = 4
n = 5
8h
Me no reaction
8i
8j
H
no reaction Me
H no reaction
8k
We focus the preliminary study to the tropylium-catalyzed
intermolecular ring-opening reactions (Scheme 4) of some
no reaction
Me
Scheme 4. Intermolecular ring-opening COM reactions
readily accessible cycloalkenes with aromatic aldehyde 5c
,
which proved to be a good substrate for the intermolecular
COM reaction (Scheme 3). Interestingly, six-membered and
oligomerization reactions, which need to be addressed by
further work in reaction design. Highly-substituted
cyclopropene 8b, a substrate that we had access to from
another project in our group, did not show any reactivity.
We subsequently used substrate 8c and substrate 8g to
seven-membered cycloalkenes (8h-8k, n = 4 or 5, Scheme 4)
did not metathesize to the target products while 1-methyl
cyclopentene 8g reacted smoothly to give the product 9g2 in
good yield (Scheme 4). It seems that six- and seven-membered
cycloalkenes probably do not possess the ring-strain necessary
prepare a range of ω-enone products with moderate to good
yields via this newly developed ring-opening intermolecular
for the ring-opening reaction. Furthermore,
a methyl
COM reactions (Scheme 4) with aromatic aldehydes. Notably,
substituent on the C-C double bond also helps to promote the
metathesis reaction in the similar way to how acetone
formation is favored for the normal intra- and inter-molecular
reactions. This phenomenon is clearly demonstrated in
Scheme 4 with n = 3, where other substituted or non-
all of the products were formed with excellent trans
-
stereoselectivity. A full investigation on the ring-opening
metathesis reactions with other types of cycloalkene
substrates is currently underway.
substituted cyclopentenes 8d
knowledge to prepare and test the ring-opening COM reaction
with 1-methyl cyclobutene 8c (n 2) and 1-methyl
-8f did not react. We used this
Comparison of Catalytic Activity Between Tropylium, Tritylium and
Iron(III) Lewis Acid Catalysts – Role of Brønsted Acids?
=
cyclopropene 8a (n = 1). These two substrates gave promising
results, however the efficiency of the reactions was severely
affected by their high volatility. Pressurized reaction conditions
to prevent substrate evaporation led to other issues with side
As discussed above for Scheme 3, the intermolecular COM
reaction seems to be the bottleneck of the development in this
field. We were curious to see if iron(III) catalysts from the
Schindler6 and Li7 groups, so far only known to catalyze the
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intramolecular version, could address this issue. At the same which HBF4 was used as a potential catalyst at different
time, there is also a question of whether or not Franzen’s loadings. These reactions were performed at various
tritylium catalysts11 can catalyze the ring-closing conditions for both inter- and intramolecular COM reactions
intramolecular COM reaction. To examine these questions and (Scheme 5) but all led to non-productive outcomes. A simple
also to probe the efficiency of our tropylium catalytic system Brønsted acid catalytic pathway is unlikely to be productive for
(
2
) to the known Schindler’s iron(III)6 and Franzen’s tritylium11 the COM reaction as the Tiefenbacher has recently discovered
catalysts, we carried out
comparative study on the in their interesting supramolecule-assisted COM study.19
intramolecular COM reaction of substrate 1g (Scheme 5a) and Therefore, it can be concluded that the Lewis acidity of
a
the intermolecular COM reaction of substrate 5a (Scheme 5b). tropylium catalyst
Using the optimal reaction conditions developed by Schindler the COM reactions.
and Franzen for their catalytic systems6,11 against our catalyst,
2 indeed plays a crucial role in promoting
it was interesting to find out that tropylium ion can act
Mechanistic Studies
efficiently for both intra/inter-molecular reactions while
iron(III) chloride and tritylium ion seem to be good catalysts
for only one type of reaction or another (Scheme 5).
Mechanistically, these metathesis reactions involve a non-
photochemical [2+2] cycloaddition and [2+2] cycloreversion,
each of which could proceed via a concerted or stepwise
pathway. The former is forbidden by orbital symmetry rules,
and would normally entail a barrier that is too high to
overcome through thermal activation. In recent studies by
Schlinder and co-workers,6a-c the authors demonstrated that
Lewis acidic FeCl3 could stabilize the zwitterionic intermediate
(through coordination to the carbonyl oxygen) and provided
compelling experimental and computational evidence to
support an asynchronous concerted pathway.
It is not surprising to see the bulky tritylium ion failed to
facilitate the sterically demanding intramolecular reaction; but
to why the iron(III) catalyst performed poorer than expectation
for the intermolecular reaction9b would require further
investigation. This comparison is obviously imperfect, as it
does not take into account the reaction temperature and
reaction time as well as catalyst loading. It is, however,
indicative of the versatility of the tropylium catalyst where its
electronic and steric properties in combination with
oxophilicity/Lewis acidity are suitable for both inter- and
To better understand the catalytic role of tropylium, we have
carried out high-level ab initio calculations in conjunction with
the SMD implicit model20 to compare the energetics of three
COM pathways: (1) in the absence of tropylium ion, (2)
aldehyde hydrogen bonded to tropylium ion, and (3)
coordination of aldehyde to tropylium ion (see page S26 in the
ESI for 1H NMR spectroscopic evidence and computational
studies of tropylium-carbonyl interactions). For pathways (1)
and (2), the reactants and products are connected by two
concerted cycloaddition transition states and a cycloaddition
intermediate (Figure 2), whilst pathway (3) involves four
stepwise transition states and additionally two zwitterionic
intermediates (Figure 3). Consistent with orbital symmetry
rules, both pathways (1) and (2) are accompanied by very high
barriers (TS1 and TS2) exceeding 200 kJ mol-1, and are unlikely
to occur under thermal activation. As shown in Figure 2, it is
also interesting to note that H-bonding to tropylium ion does
not provide any stabilization of the transition states.
Presumably, the concerted nature of these transition states
(no charged intermediates) also means that any electrostatic
stabilization from tropylium is likely to be minimal.
intramolecular COM reactions
.
As tropylium salts and many other Lewis acids (including FeCl3)
might react with moisture present in the reaction system to
produce strong Brønsted acids, it is necessary to confirm that
Brønsted acids, if any, are not interfering with the COM
reactions. Thus, we also carried out some control studies in
Figure 3 shows the free energy profile for the stepwise
pathway and it is evident that coordination of the anionic
oxygen to tropylium ion lowers the barriers significantly.
Specifically, the rate-limiting step for this pathway is about 90
kJ mol-1 lower compared to the reaction in the absence of
tropylium ion (153 c.f. 245 kJ mol-1). This result is somewhat
surprising because coordination to oxygen to form the
heptatriene adduct inevitably disrupts the aromaticity of the
tropylium ring. Presumably, this enthalpic cost is more than
compensated when the anionic oxygen is neutralized through
coordination to tropylium.
Scheme 5. Catalytic activity comparison
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The structures of the stepwise transition states hint at a estimated by quantum chemical implicit solvation models.20b
termolecular mechanism, although intrinsic reaction Regardless, it is clear from the calculations that the reaction is
coordinate (IRC) simulations of these transition states show significantly enhanced only when tropylium acts as a Lewis
that they relax to reactants and products where the tropylium acid to stabilize the zwitterionic intermediate formed in the
ion remains coordinated. On the other hand, potential energy stepwise pathway.
scans indicate that addition of CO oxygen to tropylium (while
the remaining atoms are constrained to positions at the
Conclusions
transition state geometry) is approximately barrier-less (see
ESI). A plausible mechanistic picture is that tropylium exists as
We have developed a novel catalytic system employing the
a
π-stacked complex with aldehyde 5b (c.f. Table S3
tropylium ion as an organo-Lewis acid to promote the
carbonyl-olefin metathesis reaction. The carbonyl-olefin
metathesis reaction has always been considered a highly
valuable chemical transformation but much less explored than
its analogous olefin-olefin metathesis. We have demonstrated
that the tropylium ion can efficiently catalyze this type of
reaction on a broad range of substrates, which are applicable
to both intramolecular and intermolecular reactions as well as
the ring-opening metathesis.
configuration C, page S28 in the ESI), which spontaneously
coordinates to the C-O oxygen as the anionic charge develops
upon nucleophilic addition. Indeed, our kinetic experiments
show that the rate of metathesis is first-order with respect to
the concentration of tropylium ion.17 It is also worth pointing
out that the computed barriers in Figure 3 are likely to
represent upper bound estimates of the actual values. This is
because these reactions involve the consumption of an
aromatic cation (tropylium) and the generation of a localized
carbocation, so the solvation contribution is likely to be under-
TS2-HB
TS1-HB
O
Ph
O
Ph
TS2
TS1
244.8 kJ mol-1
TS2-HB
(253.9 kJ mol-1
218.5 kJ mol-1
TS1-HB
(235.3 kJ mol-1
)
)
O
Ph
Ph
O
+
11
O
Ph
+
25.2 kJ mol-1
6a
5b
4a
7b
0 kJ mol-1
-38.1 kJ mol-1
Figure 2. G3(MP2)-RAD+SMD(DCM) free energies for reactions in the absence of tropylium, and with H-bonding to tropylium. The barriers for the latter are shown in parenthesis.
Figure 3. G3(MP2)-RAD+SMD(DCM) free energies (at 298 K) for reactions catalyzed by coordination of CO oxygen to tropylium.
6 | Chem. Sci., 2018, 8, 1-7
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Green Metathesis Chemistry, eds. V. Dragutan, A. Demonceau, I.
Dragutan and E. S. Finkelshtein, Springer Netherlands, Dordrecht,
2010, pp. 305-314.
Conflicts of interest
There are no conflicts to declare.
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This work is financially supported by Australian Research
Council (grant DE150100517 awarded to TVN and grant
DE160100807 awarded to JH). JH acknowledges the Australian
NCI and Intersect NSW for generous allocation of
supercomputer resources.
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TOC entry
The non-benzenoid aromatic tropylium ion acts as an efficient promoter for carbonyl-olefin
metathesis reaction.