Low-Temperature Intramolecular [4+2] Cycloaddition of Allenes with Arenes for the Synthesis of Diene Ligands

Article abstract of DOI:10.1002/anie.202012299

The intramolecular [4+2] cycloaddition between arenes and allenes first reported by Himbert gives rapid access to rigid polycyclic scaffolds. Herein, we report a one-pot oxyalkynylation/cycloaddition reaction proceeding under mild conditions (23–90 °C) an

Full text of DOI:10.1002/anie.202012299

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Accepted Article
Title: Low-Temperature Intramolecular [4+2] Cycloaddition of Allenes
with Arenes for the Synthesis of Diene Ligands
Authors: Durga Prasad Hari, Guillaume Pisella, Matthew D. Wodrich,
Artem V. Tsymbal, Farzaneh Fadaei Tirani, Rosario Scopelliti,
and Jerome Waser
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10.1002/anie.202012299
Angewandte Chemie International Edition
RESEARCH ARTICLE
Low-Temperature Intramolecular [4+2] Cycloaddition of Allenes
with Arenes for the Synthesis of Diene Ligands
Durga Prasad Hari,†[a] Guillaume Pisella,†[a] Matthew D. Wodrich,[a] Artem V. Tsymbal,[a] Farzaneh
Fadaei Tirani,[b] Rosario Scopelliti[b] and Jerome Waser*[a]
Abstract: The intramolecular [4+2] cycloaddition between arenes and
allenes first reported by Himbert gives rapid access to rigid polycyclic
scaffolds. Herein, we report a one-pot oxyalkynylation/cycloaddition
reaction proceeding under mild conditions (23-90 °C) and providing
complex polycyclic architectures with high efficiency, atom and step
economy. The bicyclo[2.2.2]octadiene products were obtained with a
wide variety of useful functional groups and were successfully applied
as chiral ligands for metal catalysis. Computational studies gave a first
rationalization of the low activation energy for the cycloaddition based
on counter-intuitive favorable dispersive interactions in the transition
state.
convergent [4+2] cycloaddition (Scheme 1B): reaction of
cyclohexadienes with alkynes (a), or reaction of arenes with
alkenes (b). The first approach is now well established.[11] In
contrast, the second strategy is less investigated due to the large
aromatic stabilization energy of arenes.[12] From the synthetic
point of view however, such an approach is highly attractive, as
arenes are easier to access than cyclohexadienes.
Introduction
The development of multiple bond-forming transformations to
increase molecular complexity and diversity from simple
precursors is a constant quest in synthetic chemistry with
important applications in the pharmaceutical and agrochemical
industries.[1] Among multiple bond-forming transformations,
cycloadditions occupy a privileged position.[2,3] They have found
applications in the synthesis of natural products,[4] organic
materials,[5] and pharmaceutical agents.[6] In particular, the Diels-
Alder reaction has been investigated extensively.[7] When using
cyclic dienes, it gives access after reduction to
bicyclo[2.2.2]octane derivatives, an important class of organic
compounds due to their rigidity allowing a precise disposition of
functional groups in space. Numerous bioactive natural products,
such as the alkaloid kopsinine (1),[8] or synthetic compounds, such
as the broadly prescribed opioid analgesic buprenorphine (2),[9]
contain this scaffold (Scheme 1A). Less saturated
bicyclo[2.2.2]octadienes constitute another interesting subclass,
as they have found broad applications as (chiral) ligands for late
transition metal catalysts (Scheme 1A, dienes 3 and 4).[10] As
unsaturated compounds, they are also ideal starting materials for
the synthesis of more functionalized saturated derivatives. Two
different strategies can be envisioned to access them by a
Scheme 1. A. Importance of the bicyclo[2.2.2]octane core. B. [4+2]
cycloadditions for accessing bicyclo[2.2.2]octadienes. C. Himbert reaction. D.
Unexpected Himbert reaction at room temperature. E. One-pot
oxyalkynylation/Himbert reaction.
[a]
Dr. Durga Prasad Hari, Guillaume Pisella, Dr. Matthew D. Wodrich,
Artem V. Tsymbal and Prof Dr. Jerome Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fédérale de Lausanne
EPFL SB ISIC LCSO, BCH 1402, 1015 Lausanne (CH)
Fax: (+)41 21 693 97 00
E-mail: jerome.waser@epfl.ch
In 1982, Himbert and Henn reported an unusual thermal
intramolecular [4+2] cycloaddition of allenecarboxanilides to
access complex bridged polycyclic architectures.[13] The Himbert
and Orahovats groups then studied the scope of allenecarboxylic
acid derivatives including esters,[14] amides,[15] thioesters,[16]
†These authors contributed equally.
Dr. R Durga Prasad Hari
Present address: School of Chemistry
University of Bristol
Cantock's Close, Bristol BS8 1TS, UK
Dr. Farzaneh Fadaei Tirani, Dr. Rosario Scopelliti
Institute of Chemistry and Chemical Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL SB ISIC-GE, BCH 2111, 1015 Lausanne (CH)
Supporting information for this article is given via a link at the end of
[b]
1
the document.
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10.1002/anie.202012299
Angewandte Chemie International Edition
RESEARCH ARTICLE
imides,[17] phosphinamides,[18] and phosphinic esters (Scheme
1C).[19] In 2013, Vanderwal and co-workers extended the Himbert
cycloaddition to benzyl allenyl ketones.[20] In 2015, Li and co-
workers reported a Ugi/Himbert reaction sequence to synthesize
strained polycyclic skeletons.[21] Despite its great potential to
assembly complex molecules in a single step, the [4+2]
cycloaddition of allenes and arenes has found only a few
applications in synthetic chemistry.[22] The Himbert reaction often
requires high reaction temperatures. Examples at ambient
temperature required conformationally constrained amides[17,23] or
were performed under light irradiation.[24]
led to a lower yield (Table 1, entries 5 and 6). Addition of Et3N•3HF
at the start of the reaction did not lead to the formation of the
desired product 6a (Table 1, entry 7). Among the solvents tested,
DCE was the best (Table 1, entries, 5 and 8-10). We were able to
reduce the amount of diazo 8a to 1.2 equivalents without a
change in yield (Table 1, entry 11). Finally, the yield could be
improved to 94% by lowering the concentration of the reaction
(Table 1, entry 12). Furthermore, the reaction proved to be easily
scalable, as the yield did not change on gram scale.
Table 1. Optimization of the Reaction Conditions[a]
Our group has been interested in electrophilic alkynylation
reactions using hypervalent iodine reagents for more efficient and
flexible alkyne synthesis.[25] Recently, we developed a copper-
catalyzed oxyalkynylation of diazo compounds using
ethynylbenziodoxol-(on)e (EBX) reagents.[26] When attempting
the deprotection of silyl alkyne 5a with Et3N•3HF at room
temperature, we did not obtain the expected terminal alkyne 7a.
Instead, polycyclic product 6a was isolated in excellent yield,
probably resulting from a [4+2] cycloaddition of the arene on the
in situ formed allene (Scheme 1D). The exceptionally mild
conditions combined with synthetic accessibility motivated us to
investigate this transformation.
Entry
Fluoride source (x equiv)
Solvent
Yield[b] (%)
1
2
Et3N•3HF (2.0)
TASF (2.0)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
PhCl
DCE
DCE
88
26
<5
<5
88
65
<5
46
<5
45
87
94
3
TBAF (2.0)
Herein, we report our studies on this fascinating reaction. The
cycloaddition proceeded under mild conditions (RT to 90 °C) and
exhibited a broad scope of substituents on both arene and allene.
By developing a one-pot oxy-alkynylation/cycloaddition process,
complex tricyclic compounds are now accessible in a single
manipulation from broadly available EBX reagents and diazo
esters (Scheme 1E). Preliminary computational studies shed first
light on the exceptionally low activation energy of the
cycloaddition step, resulting from a combination of attractive
interactions from the benzene substituents with the allene and an
electronic effect of the oxygen substituent on the allene. This
interesting class of heteroatom-substituted allenes has been only
rarely investigated so far[27] and the high reactivity observed is
promising for other transformations. Furthermore, the
iodobenzoyl ester could be easily removed for further modification.
Finally, the diene products were effective ligands for rhodium,
resulting in quantitative complexation. Preliminary investigations
showed that good enantioselectivity can be achieved in rhodium-
catalyzed conjugate addition of boronic acids to cyclohexenone
using these chiral diene ligands.
4
Py•HF (2.0)
5
Et3N•3HF (1.0)
Et3N•3HF (0.5)
Et3N•3HF (1.0)
Et3N•3HF (1.0)
Et3N•3HF (1.0)
Et3N•3HF (1.0)
Et3N•3HF (1.0)
Et3N•3HF (1.0)
6
7[c]
8
9
10
11[d]
12[e]
[a]Reaction conditions: 0.30 mmol diazo ester (8a), 0.15 mmol TIPS-EBX (9a),
copper catalyst (2.0 mol%), 10 (2.5 mol%), solvent (0.05 M). [b]Yield after
purification by column chromatography. [c]Et3N•3HF was added at the start of
the sequence. [d]1.2 equiv of diazo ester instead of 2.0 equiv. [e]0.025 M instead
of 0.05 M. DCM = dichloromethane, THF = tetrahydrofuran.
With the optimized conditions in hand, the scope of the reaction
was first examined using TIPS-EBX (9a) and various diazo esters
bearing tert-butyl substituents in ortho positions of the benzene
ring (Scheme 2A). Para-substituted products 6a-f with alkyl, ether,
bromine or hydrogen substituents were obtained in 83-96% yield,
showing that there was no strong steric or electronic effects at this
position.[28] In contrast, the ortho substituent size had a strong
effect on the reaction outcome. When 2,6-di-iso-propyl-phenyl 2-
diazoacetate (8g) was subjected to the standard reaction
conditions, we could not observe the desired product 6g. Heating
to higher temperature led to decomposition. This was due to the
presence of the copper catalyst. Removal of the catalyst and
heating the reaction at 90 °C, gave the product 6g in excellent
yield. This temperature is significantly lower than reported for
similar substrates lacking the oxygen substituent on the allene
(140 °C).[14a] Diphenyl- and dimethyl-benzene substituted diazo
esters could also be used in the reaction (products 6h and 6i).
The formation of the product 6i is particularly interesting as a
similar o-dimethylbenzene substituted allene without α-oxygen
substitution failed to give the corresponding Himbert product even
at 140 °C.[14a] Mono-substituted benzene diazo esters also
Results and Discussion
Optimization and Scope
We started our investigations on developing a one-pot oxy-
alkynylation/Himbert reaction by screening various fluoride
sources, using 2,6-di-tert-butyl-4-methylphenyl 2-diazoacetate
(8a) with 1-[(triiso-propylsilyl)-ethynyl]-1,2-benziodoxol-3(1H)-one
(TIPS-EBX (9a)), diimine ligand 10 and Cu(CH3CN)4BF4 as the
copper source in 1,2-dichloroethane (DCE, Table 1).[26a]
Compound 6a was obtained in 88% yield when Et3N•3HF was
used, whereas trissulfonium difluorotrimethylsilicate (TASF) gave
the desired product in 26% yield only (Table 1, entries 1 and 2).
The use of tetrabutylammonium fluoride (TBAF) and pyridine
hydrofluoride (Py•HF) resulted in decomposition of the
oxyalkynylated product (Table 1, entries 3 and 4). One equivalent
of Et3N•3HF was sufficient, whereas a sub-stoichiometric amount
2
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10.1002/anie.202012299
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RESEARCH ARTICLE
underwent the desired transformation successfully to give
products 6j and 6k as single diastereoisomers in 91% and 55%
yield, respectively.[29] Substitutions at different positions than
ortho were envisaged: p-Substituted and unsubstituted benzene
diazo esters gave the corresponding products 6l-n in moderate to
good yield. Dimethyl-substituted benzene diazo esters also gave
the desired products 6o and 6l in moderate yields. Amide tethered
Himbert product 6p was obtained in 40% yield.
limited to linear alkyl-EBX reagents: Cyclo-propyl, -pentyl, and –
hexyl substituted products 6aj-l were obtained in 60-93% yield.
The formation of product 6aj exclusively indicated that radical
intermediates were probably not involved in the reaction.
Scheme 3. Scope of diazo esters with different EBX reagents.
Mechanism Investigations
To
confirm
our
hypothesis
for
a
successive
oxyalkynylation/allene formation/ [4+2] cycloaddition sequence,
we isolated each intermediate before engaging it in the next step
using less reactive alkyne 5g (Scheme 4A).
Scheme 2. Scope of diazo esters with TIPS-EBX (9a).
To further increase the molecular complexity of the products,
we investigated the reaction of the more reactive ortho di-tert-
butylbenzene substituted diazo esters with functionalized EBX
reagents (Scheme 3).[30] Optimization of the reaction conditions
showed that it was best to perform the oxyalkynylation at 50 °C
and the cycloaddition at room temperature using caesium
carbonate as base.[31] The carbonate base is not compatible with
the oxyalkynylation and needs to be added afterwards. Under
these conditions, the desired product 6q could be isolated in 91%
yield as a single diastereoisomer using 1.1 equiv of Cs2CO3 as a
base at room temperature.[32] When the reaction was performed
on gram-scale, compound 6r was obtained in 91% yield. Various
benzene diazo esters bearing an alkyl chain, an ether, a halogen
or a hydrogen substituent in para position gave excellent yields
(Scheme 3, products 6s-w). We then turned our attention to the
scope of aryl-EBX reagents using 8a. The desired products 6x-
6ae bearing alkyl, fluorine, bromine, trifluoromethyl or aldehyde in
para, meta or ortho position were obtained in 60-99% yield,
demonstrating the tolerance of the reaction towards functional
groups and substitution patterns. Next, the scope of alkyl-EBX
reagents was examined.[33] Methyl- and long alkyl chain- derived
EBX reagents worked well in the reaction, giving products 6af and
6ag in 53% and 79% yield, respectively. The reaction was also
successful in the case of chlorine and alkynyl group bearing alkyl
EBX reagents (products 6ah and 6ai). The reaction was not
Scheme 4. Control experiments.
In presence of Et3N•3HF after removal of the copper catalyst,
5g was cleanly converted to allene 11g, which was stable at room
temperature. Upon heating to 90 °C, [4+2] cycloaddition then
occurred in 91% yield. As allene 11g is non-chiral, no transfer of
chirality is possible when starting from enantioenriched alkynes.
However, when using aryl- or alkyl- substituted alkynes, a chiral
allene would be formed. We wondered if in this case transfer of
3
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10.1002/anie.202012299
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RESEARCH ARTICLE
chirality would be possible. However, racemic 6r was isolated
starting from enantioenriched alkyne 5r (Scheme 4B).[34]
strain energy. However, this substitution also results in a less
favorable interaction energy for the methyl variant while the ester
variant provides a more favorable interaction. Overall, this results
in the ester having a lower energy transition state barrier relative
to either a hydrogen or methyl group.
Having established that the reaction most probably proceeds
via a [4+2] cycloaddition of the allene with the arene ring, we
turned to density functional theory computations (at the PBE0-
dDsC/TZ2P//M06-2X/def2-SVP level, see SI for full computational
details) to better understand the observed amazing reactivity.
When comparing the transition state energies of nine different
cycloadditions in dependence of the substituents on the benzene
ring and allene, computations clearly show the favorable nature
that bulky tert-butyl groups have on the transition state barrier
heights (Scheme 5). The free energies with tert-butyl groups
(14.7-18.3 kcal/mol) were significantly lower than with methyl
(20.3-25.3 kcal/mol) or hydrogen (22.1-25.3 kcal/mol),
independently from the substituent on the allene. In addition, the
reactivity was further enhanced by the carboxy substituent on the
allene, although the effect was weaker. These results are in good
accordance with the reaction rates observed experimentally.
Figure 1. Activation strain model results (computed at the M06-2X/def2-SVP
level) in dependence on the R1 group on the benzene for R2 = H on the allene.
Note that the plots depict electronic energies, as opposed to free energies.
Scheme 5. Free energies of transition states in dependence of substituents on
benzene and allene. Free energies computed at the PBE0-dDsC/TZ2P//M06-
Figure 2. Activation strain model results (computed at the M06-2X/def2-SVP
level) in dependence on the R2 group on the allene for R1 = tBu on the benzene.
Ester = 2-iodobenzoate. Note that the plots depict electronic energies, as
opposed to free energies.
2X/def2-SVP level). Ester
= 2-iodobenzoate. Note that column colors
correspond to those of the activation strain model computations shown in
Figures 1 and 2.
Synthetic Applications
To gain additional insight, we analyzed the energetic profiles
of these nine reactions using the activation strain model.[35]
Initially, we speculated that the bulky tert-butyl groups in R1 could
diminish the planarity of the benzene ring, lowering the distortion
energy and making it easier to break aromaticity. However, the
calculation results showed that the presence of the bulky
substituents in R1 causes energetically favorable dispersive
interactions at longer C-C distances, whereas no major difference
in strain energy was observed (Figure 1). This results in an earlier,
lower energy transition state for the tert-butyl containing variant
relative to methyl or hydrogen. Substitution on the allene is
characterized by a more complicated picture in which both the
unfavorable strain energy and stabilizing interaction energy are
influenced by the substituent (Figure 2). Replacing the hydrogen
atom with either a methyl or a carboxy group slightly reduces the
The cycloaddition of allene and benzene rings gave access to
[6,6,5] ring systems. It is also important to access other polycyclic
systems. In this respect, an interesting preliminary result was
obtained with furan-derived diazoester 12: The oxyalkynylation-
Himbert sequence gave a new [5,5,6] ring system 13 in 83% yield
(Scheme 6A). Furthermore, the iodobenzoyl ester on the product
can be cleaved directly after cycloaddition, giving access to
ketoesters 14a and 14b (in their enol form) on gram-scale in one-
pot (Scheme 6B). Bromination of 14a yielded highly strained
cyclopropane 15 in 86% yield.[36] Alcohol 14a was quantitatively
transformed into the corresponding triflate 16 by reaction with
triflic anhydride. Palladium catalyzed reduction of 16 gave
unsaturated ester 17 in 88% yield. Reaction of triflate 16 with 3-
phenylprop-2-yn-1-ol or diethyl phosphonate gave access to
products 18 and 19 respectively.
4
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10.1002/anie.202012299
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RESEARCH ARTICLE
ligand 4. Enantiopure (+)-6p was isolated by preparative chiral
high performance liquid chromatography (HPLC). We were able
to obtain a X-ray crystal structure of the corresponding dimeric
complex 20b (Scheme 8A)[38] and we could compare it with the
diene complex 20c reported by Hayashi and co-workers (Scheme
8B).[39] The immediate coordination sphere around the rhodium
was not distorted by the lower symmetry of ligand 20b: all bonds
between the metal and the olefins were of same length, and within
error margin also identical to those in complex 20c.[40] In contrast,
1
the 13C and even more the H NMR signals on the olefins were
clearly separated for complex 20b, indicating that this ligand will
induce a non-symmetrical electronic environment. From this point
of view, it is clearly different from the classical Hayashi dienes.
As a proof of concept for its use in asymmetric catalysis, we
then used (+)-6p as chiral ligand for the rhodium-catalyzed
conjugate addition of phenyl boronic acid (21) to cyclohexenone
(22) under standard reported conditions (Scheme 8C).[10d] The
resulting β-functionalized ketone 23 was obtained in 75% yield
with 87% ee. This is promising when considering that the methyl
substituent is smaller than the phenyl or benzyl groups used in
previous works[10d] and no attempt was made to optimize the
reaction conditions.
Scheme 6. [4+2] Cycloaddition with furan and product derivatization. Tf = Triflyl.
When considering that bicyclo[2.2.2]octadienes are an
important class of ligands for late transition metals,[10] we then
attempted the formation of a rhodium complex. The complexation
was not successful when using tert-butyl substituted dienes,
probably due to excessive steric hindrance. In contrast, dimer 20a
was cleanly formed, by just mixing diene 6m with [RhCl(C2H4)2]2
in chloroform (Scheme 7A). X-ray quality crystals of 20a could be
obtained, allowing us to confirm its structure.[37]
Scheme 8. A. X-ray structure of Rhodium complex 20b with bond lengths and 1H and
13C NMR data. B. X-ray structure of Hayashi's Rhodium complex 20c with bond lengths
and 1H and 13C NMR data. C. Enantioselective conjugate addition with ligand (+)-6p.
For simplification, only half of the dimeric complexes 20b and 20c is shown.
Conclusion
Scheme 7. A. Synthesis and X-ray structure of Rhodium complex 20a. B. Conjugate
addition of phenylboronic acid (21) on cyclohexenone (22) with 20a as catalyst.
In summary, we have developed a highly efficient strategy for
the rapid assembly of bicyclo[2.2.2]octadienes starting from
simple diazo esters and EBX reagents via a one-pot sequential
oxyalkynylation/[4+2] cycloaddition reaction proceeding between
25 and 90 °C. The reaction tolerated a broad range of functional
groups on both diazo esters and EBX-reagents. Isolation of the
reaction intermediates support a cycloaddition of an in situ formed
Complex 20a was a good catalyst for the conjugate addition
of phenyl boronic acid (21) to cyclohexenone (22) under standard
conditions (Scheme 7B).[10d]
Next, we envisioned an enantioselective transformation. We
decided to take advantage of the pseudo-C2 symmetry of
compound 6p, making it similar to the successful Hayashi-type
5
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10.1002/anie.202012299
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RESEARCH ARTICLE
Danishefsky, G. O. Jones, K. N. Houk, J. Am. Chem. Soc. 2007, 129,
645; c) K. Ishihara, M. Fushimi, J. Am. Chem. Soc. 2008, 130, 7532; d)
J.-P. Krieger, G. Ricci, D. Lesuisse, C. Meyer, J. Cossy, Angew. Chem.,
Int. Ed. 2014, 53, 8705; e) K. B. Hamal, R. Bam, W. A. Chalifoux, Synlett
2016, 27, 2161; f) M. Hatano, T. Sakamoto, T. Mizuno, Y. Goto, K.
Ishihara, J. Am. Chem. Soc. 2018, 140, 16253.
allene with the arene ring. The exceptionally low activation energy
for the cycloaddition could be rationalized by counter-intuitive
favourable dispersive interactions in the transition state,
combined with a weaker effect of the carboxy substituent. The
obtained products were transformed into useful building blocks
and preliminary results indicated that other polycyclic ring
systems could also be accessed using this strategy. Importantly,
this methodology allows straightforward access to versatile diene
ligands for rhodium catalysis with easy variation of the
substituents. Pseudo C2-symmetric ligand 6p could be used in
the enantioselective addition of phenyl boronic acid (21) to
cyclohexenone (22) with 87% enantioselectivity. Our future work
will focus on catalysis of the cycloaddition step with the goal of
[12] F. Fringuelli, A. Taticchi, Dienes in the Diels-Alder Reaction, Wiley, 1990.
[13] G. Himbert, L. Henn, Angew. Chem., Int. Ed. 1982, 21, 620.
[14] a) G. Himbert, D. Fink, Tetrahedron Lett. 1985, 26, 4363; b) G. Himbert,
D. Fink, M. Stürm, Z. Naturforsch. B; Chem. Sci. 1994, 49, 63.
[15] a) L. Henn, G. Himbert, K. Diehl, M. Kaftory, Chem. Ber. 1986, 119, 1953;
b) G. Himbert, K. Diehl, H.-J. Schlindwein, Chem. Ber. 1986, 119, 3227;
c) K. Diehl, G. Himbert, Chem. Ber. 1986, 119, 3812; d) H. ‐ J.
Schlindwein, K. Diehl, G. Himbert, Chem. Ber. 1989, 122, 577; e) G.
Himbert, H.-J. Schlindwein, Z. Naturforsch. B; Chem. Sci. 1992, 47,
1785; d) G. Himbert, D. Fink, J. Org. Chem. 1996, 338, 355.
[16] G. Himbert, D. Fink, J. Prakt. Chem. 1994, 336, 654.
[17] a) L. S. Trifonov, A. S. Orahovats, Helv. Chim. Acta 1986, 69, 1585; b) L.
S. Trifonov, A. S. Orahovats, Helv. Chim. Acta 1987, 70, 1732; c) L. S.
Trifonov, A. S. Orahovats, Helv. Chim. Acta 1987, 70, 262; d) L. S.
Trifonov, A. S. Orahovats, Helv. Chim. Acta 1989, 72, 59.
[18] G. Himbert, M. Ruppmich, H. Knöringer, J. Chinese Chem. Soc. 2003,
50, 143.
developing an enantioselective reaction for
a
more
straightforward access to enantioenriched chiral ligands, and
further study the reactivity of this new type of easily accessible
"push-pull" allenes.
Acknowledgements
[19] L. S. Trifonov, S. D. Simova, A. S. Orahovats, Tetrahedron Lett. 1987,
28, 3391.
We thank the European Research Council (ERC; Starting Grant
iTools4MC, number 334840) the Swiss National Science
Foundation (Grant No. 200020_182798) and the EPFL for
financial support. MDW acknowledges Prof. C. Corminboeuf for
financial support and the Laboratory for Computational Molecular
Design for providing computational resources.
[20] Y. Schmidt, J. K. Lam, H. V. Pham, K. N. Houk, C. D. Vanderwal, J. Am.
Chem. Soc. 2013, 135, 7339.
[21] G. Cheng, X. He, L. Tian, J. Chen, C. Li, X. Jia, J. Li, J. Org. Chem. 2015,
80, 11100.
[22] For the only example of application of the Himbert reaction in total
synthesis, see: J. K. Lam, Y. Schmidt, C. D. Vanderwal, Org. Lett. 2012,
14, 5566.
[23] X. Mo, B. Chen, G. Zhang, Angew. Chem., Int. Ed. 2020, DOI:
10.1002/anie.202000860.
Keywords: [4+2] cycloaddition • alkynes • diene ligands •
hypervalent iodine reagents • diazo compounds
[24] U. Streit, F. Birbaum, A. Quattropani, C. G. Bochet, J. Org. Chem. 2013,
78, 6890.
[25] a) J. Waser, Top. Curr. Chem. 2015, 373, 187; b) Y. Li, D. P. Hari, M. V.
Vita, J. Waser, Angew. Chem., Int. Ed. 2016, 55, 4436.
[1]
[2]
J. Rodriguez, D. Bonne, Stereoselective Multiple Bond-Forming
Transformations in Organic Synthesis, John Wiley & Sons, Inc, Hoboken,
NJ, USA, 2015.
[26] a) D. P. Hari, J. Waser, J. Am. Chem. Soc. 2016, 138, 2190; b) D. P. Hari,
J. Waser, J. Am. Chem. Soc. 2017, 139, 8420.
a) W. Carruthers, Cycloaddition Reactions in Organic Synthesis, Wiley-
VCH Verlag GmbH, Weinheim, FRG, 1990; b) S. Kobayashi, K. A.
Jørgensen, Eds., Cycloaddition Reactions in Organic Synthesis, Wiley-
VCH Verlag GmbH, Weinheim, FRG, 2001; c) N. Nishiwaki, Methods and
Applications of Cycloaddition Reactions in Organic Syntheses, Wiley,
2014.
[27] There are no reports of carboxy-substituted allene esters and only rare
reports of alkoxy substituted allene esters: a) M. J. Sleeman, G. V.
Meehan, Tetrahedron Lett. 1989, 30, 3345; b) Y. Nagao, K. Kim, S. Sano,
H. Kakegawa, W. S. Lee, H. Shimizu, M. Shiro, N. Katunuma,
Tetrahedron Lett. 1996, 37, 861. Simple alkoxy-substituted allenes have
been more often used: c) R. Zimmer, H.-U. Reissig, Angew. Chem., Int.
Ed. 1988, 27, 1518; d) V. M. Schmiedel, H. U. Reissig, Curr. Org. Chem.
2019, 23, 2976.
[3]
a) G. Brieger, J. N. Bennett, Chem. Rev. 1980, 80, 63; b) K. C. Nicolaou,
S. A. Snyder, T. Montagnon, G. Vassilikogiannakis, Angew. Chem., Int.
Ed. 2002, 41, 1668.
[28] The structure of 6r was confirmed by X-ray analysis (available at the
Cambridge Crystallographic Centre, CCDC number 1848760).
[29] The structure of the diastereoisomers was assigned in analogy to the
work in ref 20 and 22.
[4]
[5]
K. Takao, R. Munakata, K. Tadano, Chem. Rev. 2005, 105, 4779.
a) N. Zydziak, B. Yameen, C. Barner-Kowollik, Polym. Chem. 2013, 4,
4072; b) W. Binder, C. Kluger, Curr. Org. Chem. 2006, 10, 1791.
L. C. Bouchez, M. Rusch, M.-H. Larraufie, Curr. Org. Chem. 2016, 20,
2358.
[6]
[7]
[8]
[9]
[30] In the case of less reactive substituted alkynes, the presence of the tert-
butyl groups was necessary for the success of the cycloaddition.
[31] See Supporting Information for details on the optimization of the reaction
conditions.
F. Fringuelli, A. Taticchi, The Diels - Alder Reaction: Selected Practical
Methods, John Wiley & Sons, Ltd, Chichester, UK, 2002.
D. W. Thomas, H. Achenbach, K. Biemann, J. Am. Chem. Soc. 1966, 88,
3423.
[32] The structure of 6r was confirmed by X-ray analysis (available at the
Cambridge Crystallographic Centre, CCDC number 1848773).
[33] The reaction with alkyl-EBXs required 50 °C to form allenes, which
undergo spontaneous cyclization to give the corresponding Himbert
products.
M. Connock, A. Juarez-Garcia, S. Jowett, E. Frew, Z. Liu, R. Taylor, A.
Fry-Smith, E. Day, N. Lintzeris, T. Roberts, A. Burls, R. S. Taylor, Health
Technology Assessment 2007, 11, 1-171.
[10] a) C. Fischer, C. Defieber, T. Suzuki, E. M. Carreira, J. Am. Chem. Soc.
2004, 126, 1628; b) C. Defieber, H. Grutzmacher, E. M. Carreira, Angew.
Chem., Int. Ed. 2008, 47, 4482; c) N. Tokunaga, Y. Otomaru, K. Okamoto,
K. Ueyama, R. Shintani, T. Hayashi, J. Am. Chem. Soc. 2004, 126,
13584; d) Y. Otomaru, K. Okamoto, R. Shintani, T. Hayashi, J. Org.
Chem 2005, 70, 2503; e) K. Okamoto, T. Hayashi, V. H. Rawal, Chem.
Commun. 2009, 4815.
[34] Enantionenriched 5r was obtained following our previously published
methodology, ref. 25b.
[35] F. M. Bickelhaupt, K. N. Houk, Angew. Chem., Int. Ed. 2017, 56, 10070.
And references cited therein.
[36] The structure of 15 was confirmed by X-ray analysis (available at the
Cambridge Crystallographic Centre, CCDC number 1850113).
[37] Available at the Cambridge Crystallographic Centre, CCDC number
1945514.
[11] Selected examples: a) N. Kumar, M. Kiuchi, J. A. Tallarico, S. L.
Schreiber, Org. Lett. 2005, 7, 2535; b) M. Dai, D. Sarlah, M. Yu, S. J.
6
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10.1002/anie.202012299
Angewandte Chemie International Edition
RESEARCH ARTICLE
[38] The X-ray structure of 20b is available at the Cambridge Crystallographic
Centre, CCDC number 2027174 See Supporting Information for details.
[39] T. Nishimura, Y. Ichikawa, T. Hayashi, N. Onishi, M. Shiotsuki, T.
Masuda, Organometallics 2009, 28, 4890.
[40] See Figure S1 in Supporting Information for an overlay of the structures
of 20b and 20c.
.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202012299
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
Breaking aromaticity: A highly efficient strategy for the rapid assembly of bicyclooctadienes starting from simple diazo esters and
EBX reagents via a one-pot sequential oxyalkynylation/ [4+2] allene-arene cycloaddition reaction at low temperature (23-90 °C) is
reported. The obtained products are good chiral ligands for rhodium-catalyzed conjugate addition.
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