A Rh-Catalyzed Cycloisomerization/Diels-Alder Cascade Reaction of 1,5-Bisallenes for the Synthesis of Polycyclic Heterocycles

Article abstract of DOI:10.1021/acs.orglett.9b02032

A novel methodology to transform bisallenes into a variety of polycyclic derivatives employing rhodium(I) catalysis has been developed. This transformation encompasses an intramolecular Rh-catalyzed cycloisomerization of bisallenes 1 to deliver a reactive

Full text of DOI:10.1021/acs.orglett.9b02032

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Rh-Catalyzed Cycloisomerization/Diels−Alder Cascade Reaction of
1,5-Bisallenes for the Synthesis of Polycyclic Heterocycles
́
̀
Albert Artigas, Jordi Vila, Agustí Lledo, Miquel Sola,* Anna Pla-Quintana, and Anna Roglans*
̀
Institut de Química Computacional i Catalisi (IQCC) and Departament de Química, Universitat de Girona (UdG), Facultat de
̀
̀
Ciencies, C/Maria Aurelia Capmany, 69, 17003-Girona, Catalunya, Spain
S
* Supporting Information
ABSTRACT: A novel methodology to transform bisallenes
into a variety of polycyclic derivatives employing rhodium(I)
catalysis has been developed. This transformation encom-
passes an intramolecular Rh-catalyzed cycloisomerization of
bisallenes 1 to deliver a reactive cycloheptadiene, which
concomitantly undergoes a regioselective [4 + 2] cyclo-
addition with alkenes. A complete mechanistic study of this
transformation has been undertaken including DFT calcu-
lations. Overall, the methodology presented here constitutes a
new and straightforward entry to polycyclic dihydroazepine
and dihydrooxepine derivatives employing catalytic methods.
ransition-metal catalyzed cyclization reactions of unsatu-
rated compounds have enormous synthetic potential for
and an external double bond of the two allene moieties,
T
affording 5-membered rhodacycles fused to either 5- or 6-
membered rings, respectively (Scheme 1a). The same group9
the preparation of a wide range of carbocyclic and heterocyclic
scaffolds in a single step with perfect atom economy.1 Among
the different unsaturated substrates available, increasing
attention has been focused toward the use of allenes, which
have now become an established member of the synthetic
arsenal for cyclization reactions and related processes.2 Given
that allenes are cumulated systems with two contiguous
carbon−carbon double bonds, the control of the chemo-
selectivityi.e., which of the two double bonds reactsmakes
the construction of various products from one single substrate
possible. The available chemical space is obviously increased
when two allene moieties are involved.
Scheme 1. Previous Studies in Rh(I)-Catalyzed Cyclization
Reactions of 1,5-Bisallenes
When 1,5-bisallenes are treated under catalysis by transition
metals, products with 5-, 6-, or 7-membered rings can be
obtained. Palladium, platinum, and gold favor carbocyclization
processes. Under palladium catalysis, 5-membered rings have
been obtained by the groups of Ma, Yu, and Kang.3 More
̈
recently, Backvall and co-workers described the formation of 7-
membered rings.4 A similar trend was observed using platinum,
which allowed the synthesis of products featuring 5-5 and 7-
membered6 rings. An unexpected example of a rare [2 + 2]
cycloaddition of bisallenes has been described using N-
heterocyclic carbene gold(I) catalysis to deliver 6-membered
rings.7
On the other hand, rhodium-promoted cyclizations of 1,5-
bisallenes are postulated to proceed via oxidative cyclization.
Ma and co-workers8 described a 2-fold cyclization of terminal
bisallene under rhodium catalysis. The mechanism was
postulated to be a [2 + 2 + 2] cycloaddition followed by a
Diels−Alder reaction. The initial oxidative coupling can
involve either the two internal double bonds or an internal
Received: June 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02032
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Organic Letters
Letter
described the synthesis of seven-membered trienes via Rh-
catalyzed cycloisomerization of 1,5-bisallenes with substituents
at the terminal positions (Scheme 1b). When these dienes
were treated with N-ethyl maleimide under rhodium catalysis,
the expected [4 + 2] adduct was not obtained, but rather a
product derived from an initial isomerization of the double
bonds followed by Diels−Alder cycloaddition. Mukai and co-
workers10 also managed to isolate an exocyclic diene when the
initial bisallene was terminal although these bisallenes had the
particularity of having two SO2Ph groups at the internal carbon
atom of the allene (Scheme 1c). Carbonylative [2 + 2 + 1]
cycloadditions have been described by the groups of
Mukai10,11 (Scheme 1c) and Chung,12 although this latter
group used cobalt/rhodium heterobimetallic nanoparticles. In
both cases, the authors postulated that the external double
bonds of both allenes were involved in the oxidative cyclization
step, affording a seven-membered scaffold. In Mukai’s studies,
a [2 + 2] cycloadduct without CO incorporation was usually
obtained as by-product.
1(7),2-diene skeleton, and the seven-membered cross-con-
jugated triene 4a. When the bulky phosphine DTBM-Segphos
was used, the yield of 3aa was improved to 65%, and the yield
of triene 4a was reduced to 5%. However, 5a, originating from
the cycloisomerization of the bisallene, was obtained in 15%
yield.15 Lowering the temperature to 40 °C avoided the
formation of 4a, resulting in our optimized set of conditions
(see the Supporting Information (SI) for the complete
optimization study).
Having established the optimum reaction conditions, the
scope of the reaction was then evaluated, as shown in Figure 1.
Azepine- and oxepine-containing fused ring systems are
found in some pharmacologically active compounds and in
natural products,13 and their efficient synthesis is still highly
challenging. Therefore, developing cycloaddition reactions of
bisallenes with a third unsaturation being able to control the
formation of a seven-membered ring is highly desirable. To the
best of our knowledge, the Pauson−Khand-type reaction
developed by Mukai11 is the only example of such a process
reported to date. Given these precedents, and based on our
previous experience with Rh-catalyzed cycloaddition reactions
involving allenes,14 we envisaged developing a cycloaddition
reaction between 1,5-bisallenes and alkenes with the aim of
controlling the reaction toward the synthesis of fused seven-six-
membered bicyclic systems.
We started by studying the cycloaddition of N-tosyl-tethered
bisallene 1a and ethyl acrylate 2a (see Table 1) using 10% mol
of cationic rhodium complex [Rh(cod)2]BF4 with (R)-BINAP
in THF/CH2Cl2 (4:1). Two different compounds were
obtained: compound 3aa, with a 4-aza-bicyclo[5.4.0]undeca-
Figure 1. Scope of the cycloaddition of bisallenes 1 with alkenes 2.
Table 1. Optimization of the Rhodium(I)-Catalyzed
Cycloaddition of Bisallene 1a with Alkene 2a
Overall, the reaction proceeds in good to moderate yields with
a wide range of alkenes. Reactions involving alkyl and aryl
acrylates (2a−2f) deliver products in yields ranging between
50% and 68%. Vinyl alkyl ketones 2g and 2h also produced the
corresponding cycloadducts in 72% and 75% yields,
respectively. In some cases, byproduct 5a was also formed
and separated from the desired product by column
chromatography.16 Disubstituted cyclic alkenes, such as
maleimide (2i), N-ethyl maleimide (2j), and maleic anhydride
(2k), underwent the cycloaddition reaction efficiently to
produce derivatives 3ai, 3aj, and 3ak in excellent yields and
avoiding the formation of byproduct 5a. The use of phenyl
vinyl sulfone (2l) and phenyl vinyl sulfonate (2m) afforded
derivatives 3al and 3am in 31% and 60% yields, respectively,
and, again, no traces of 5a. In addition, two 1 mmol scale
reactions using ethyl acrylate 2a and vinyl methyl ketone 2g
were performed, affording a 69% yield of 3aa (15% yield of 5a)
and a 77% yield of 3ag (14% yield of 5a), respectively. Single
crystal X-ray diffraction analysis of compound 3am (CCDC
1915067) allowed us to unambiguously establish the structure
of the cycloadduct obtained.17
a
temp
(°C)
reaction time
(h)
yield (%) 3aa/
4a/5a
entry
ligand
1
2
(R)-BINAP
(R)-DTBM-
SegPhos
65
65
4
4
49/45/−
65/05/15
3
(R)-DTBM-
SegPhos
40
16
60/−/15
a
Reaction conditions: 0.18 mmol of 1a ([1a] = 9 mM), 50 equiv of
2a, 10% mol of Rh catalyst in 20 mL of THF/CH2Cl2 (4:1) at the
indicated temperature and time. The 10% mol mixture of [Rh-
(cod)2]BF4 and phosphine was treated with hydrogen in dichloro-
methane (CH2Cl2) solution for catalyst activation prior to substrate
addition.
To extend the methodology to other 1,5-bisallenes, oxygen-
tethered bisallene 1b was prepared and reacted with three
different alkenes: ethyl acrylate 2a, methyl vinyl ketone 2g, and
B
DOI: 10.1021/acs.orglett.9b02032
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Organic Letters
Letter
Figure 2. Gibbs energy profile for the tandem cycloisomerization/Diels−Alder cycloaddition (Path A, blue) leading to product 3aa and
cycloisomerization reaction (Path B, red) leading to product 4a. RC = Reactant complex.
N-ethylmaleimide 2j affording the corresponding derivatives
3ba, 3bg, and 3bj in moderate yields ranging from 17% to
32%.
Since a stereogenic center was generated in derivatives 3, the
enantiomeric excess was measured in all cases, but no
enantioinduction was observed regardless of the substrate or
the ligand used. This result is commensurate with the
mechanism proposed for this transformation (vide infra).
To gain further understanding of the reaction mechanism,
we completed our study by evaluating computationally the
process that transforms 1a into 3aa. The Gibbs energy profile
computed at 313.15 K and 1 atm with the M06L-D3/cc-
pVTZ-PP/SMD(76% THF, 24% CH2Cl2)18//B3LYP-D3/cc-
pVDZ-PP method is depicted in Figure 2, and the catalytic
cycle is shown in Figure 3 and the molecular structures of the
TSs in Figure S4. To reduce the computational effort required,
BINAP was chosen as the model phosphine ligand instead of
the optimal ligand (R)-DTBM-Segphos (see SI for a complete
description of the computational methods).
The reaction starts with η4-coordination of [Rh(BINAP)]+
to the two internal double bonds of 1,5-bisallene 1a to form
the square-planar 16-electron intermediate A1. This process is
exergonic by 13.2 kcal/mol. Upon coordination, intermediate
A1 readily experiences oxidative coupling at the central carbon
atoms of both allene moieties to deliver intermediate A2, a
rhodabicyclo[3.2.1]octane complex featuring two contiguous
exocyclic methylene groups. This first step has a Gibbs energy
barrier of 24.7 kcal/mol through TS A1A2 and is exergonic by
20.2 kcal/mol. Intermediate A2 is an 18-electron species and
shows a distorted octahedral geometry in which one of the O
atoms of the tosyl group occupies one of the six positions
(dRh−O= 2.231 Å) and one of the two exocyclic double bonds is
η2-coordinated to the Rh center (dRh−C = 2.196 and 2.132 Å).
The fact that internal bonds in allenes are more reactive than
their external counterparts has already been reported in
previous studies by our group.14a,d An alternative mechanism
Figure 3. Catalytic cycle for the two Rh(I)-catalyzed tandem
cycloisomerization reactions of 1,5-bisallene 1a leading to inter-
mediate A5 (Path A, blue) and product 4a (Path B, red).
for this transformation by which a bisallylic rhodacyclopentane
intermediate resulted from the initial oxidative coupling was
proposed by Ma9 and by Mukai,10 although no mechanistic
studies were reported. Our computational calculations seem to
contradict this proposal, although care should be taken when
comparing these two transformations owing to the different
substitution patterns of the bisallene precursors involved.
A2 is converted into intermediate A3 through a β-hydride
elimination mechanism. This process is slightly endergonic by
5.9 kcal/mol and has a Gibbs energy barrier of 10.8 kcal/mol
C
DOI: 10.1021/acs.orglett.9b02032
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Letter
(TS A2A3). The Rh center in intermediate A3 is η2-
coordinated to the newly formed CC bond and presents a
distorted tetrahedral geometry. Reductive elimination from
intermediate A3 to form A4 has to surmount a barrier of 4.0
kcal/mol (TS A3A4) and releases 25.9 kcal/mol. Subsequent
release of the initial Rh(I) complex leads to triene intermediate
A5, completing the catalytic cycle (Path A in Figures 2 and 3).
Alternatively, intermediate A3 can experience a rearrangement
with a rotation through the C−Rh bond that approaches the
hydride coordinated to Rh to one of the CC exocyclic
double bonds giving A3′ (Path B in Figures 2 and 3).
Reductive elimination through TS A3′B1 has a cost of 8.1
kcal/mol and is exergonic by 31.5 kcal/mol. This alternative
mechanism provides a rational explanation for the formation of
compound 4a.
On the other hand (Path A in Figure 2), the formation of
intermediate A5 is followed by [4 + 2] cycloaddition with ethyl
acrylate 2a to deliver compound 3aa. The formation of the
desired reaction product 3aa has an overall reaction energy
(ΔGr) of −75.1 kcal/mol. Importantly, the regiochemistry of
the reaction can also be explained by our computed reaction
mechanism. While “endo a” approximation of the dienophile
(i.e., TS A5−3aa′) has a Gibbs energy barrier of 26.6 kcal/
mol, the “endo b” approximation (i.e., TS A5−3aa) has a lower
cost of 24.0 kcal/mol. Such a difference in energy (ΔΔG‡ = 2.6
kcal/mol) accounts for the selective formation of the actual
reaction product 3aa.
It has not escaped our attention that, in the same way that
intermediate A5 does, intermediates A2, A3, and A4 are ripe to
experience [4 + 2] cycloaddition with ethyl acrylate 2a before
β-hydride elimination, reductive elimination or catalyst release
takes place, respectively. Considering this, we computed all
potential reaction paths leading to reaction product 3aa (see
Figures S5, S6, and S7 in the SI). We found that all alternative
reaction mechanisms analyzed have higher barriers or do not
explain the observed regioselectivity.
In summary, the reaction mechanisms leading to compounds
A5 and 4a (paths A and B in Figure 2) have an energetic span
between the turnover frequency (TOF) determining inter-
mediate (TDI, A1) and TOF determining transition state
(TDTS, TS A1A2) of 24.7 kcal/mol.19 Once formed,
intermediate A5 reacts with ethyl acrylate 2a through a
regioselective catalyst-free Diels−Alder cycloaddition to
provide compound 3aa.
Scheme 2. Additional Mechanistic Experiments Performed
preparation of complex spirocyclic compounds in a straightfor-
ward and selective manner starting from 1,5-bisallenes. The
isolation by Ma and co-workers8 of another homodimer of 1a
(Scheme 1a), when a different catalytic system was employed,
is worth noting and highlights the importance of the
coordination environment in favoring disparate mechanistic
outcomes.
A related work by Breit and co-workers20 was described
during the preparation of this manuscript, reporting on a
rhodium-catalyzed cycloisomerization of 1,6-allenenes to afford
six-membered ring exocyclic 1,3-dienes and further tandem
Diels−Alder reaction. Our allene/allene/alkene triad of
unsaturated partners offers a much complex mechanistic
scenario as exemplified by our mechanistic study, and therefore
a commensurate potential for developing new reactivity
manifolds.
In conclusion, we have developed an efficient cascade
process based on an intramolecular Rh-catalyzed cyclo-
isomerization of 1,5-bisallenes (1) leading to a nonisolable
cycloheptadiene intermediate followed by a regioselective
Diels−Alder cycloaddition with alkenes (2). The new process
affords a variety of polycyclic heterocycles 3 containing
dihydroazepine- and dihydrooxepine-fused ring systems. DFT
calculations show that the reaction leading to 3aa from 1a
takes place through an oxidative coupling of the rhodium at the
central carbon atoms of both allenes followed by a β-hydride
elimination to form intermediate A3 and reductive elimination
to give intermediate A5. An uncatalyzed and regioselective
Diels−Alder cycloaddition to A5 generates the final product.
ASSOCIATED CONTENT
* Supporting Information
■
S
With the aim of fully validating the proposed reaction
mechanism, we completed our study by performing additional
experiments. First, the involvement of reaction byproduct 5a as
a reaction intermediate of the catalytic cycle was ruled out by
heating a mixture of this compound and ethyl acrylate 2a in the
absence and presence (Schemes S4 and S5) of the rhodium
catalytic mixture. In both cases, only starting materials were
recovered. Computational calculations are again in good
agreement with the experiments (see Figure S8 in the SI).
Finally, in an attempt to isolate intermediate A5, we
performed the reaction in the absence of a dienophile (Scheme
2). Even though A5 could not be obtained as a stable reaction
product, we found indirect evidence of its formation.
Homodimer 6a was isolated in 58% yield, indicating that it
is a promiscuous intermediate acting as both the diene and the
dienophile in Diels−Alder reactions. Remarkably, only one out
of the four possible isomers of the dimer was obtained. This
last finding not only gives an experimental confirmation of our
computational results, but opens new avenues for the
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02032.
Experimental procedures, optimization of the reaction,
compound characterization data, crystallographic data
and computational data (PDF)
Accession Codes
CCDC 1915067 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: miquel.sola@udg.edu.
D
DOI: 10.1021/acs.orglett.9b02032
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(b) Zhu, C.; Yang, B.; Mai, B. K.; Palazzotto, S.; Qiu, Y.;
*E-mail: anna.roglans@udg.edu.
ORCID
̈
Gudmundsson, A.; Ricke, A.; Himo, F.; Backvall, J.-E. Highly selective
palladium-catalyzed hydroborylative carbocyclization of bisallenes to
seven-membered rings. J. Am. Chem. Soc. 2018, 140, 14324−14333.
(5) Lim, Y. N.; Kim, H.-T.; Yoon, H.-S.; Jang, H.-Y. Regio- and
stereoselective reductive cyclization of 1,5-bisallenes under hydro-
genation conditions. Bull. Korean Chem. Soc. 2011, 32, 3117−3119.
Albert Artigas: 0000-0002-7351-0066
́
Agustí Lledo: 0000-0003-3681-6688
̀
Miquel Sola: 0000-0002-1917-7450
Anna Pla-Quintana: 0000-0003-2545-9048
Anna Roglans: 0000-0002-7943-5706
́
(6) Quiros, M. T.; Hurtado-Rodrigo, C.; Munoz, M. P. Nucleophile
̃
dependent formation of 6-and 7-membered N-heterocycles by
platinum-catalysed cyclisation of 1,5-bisallenes. Org. Biomol. Chem.
2017, 15, 6731−6737.
Notes
The authors declare no competing financial interest.
(7) Kim, S. M.; Park, J. H.; Kang, Y. K.; Chung, Y. K. N-heterocyclic
carbene gold(I) catalyzed transformation of N-tethered 1,5-bisallenes
to 6,7-dimethylene-3-azabicyclo[3.1.1]heptanes. Angew. Chem., Int.
Ed. 2009, 48, 4532−4535.
ACKNOWLEDGMENTS
■
We are grateful for the financial support by the Spanish
Ministry of Economy and Competitivity (MINECO) (Projects
CTQ2017-85341-P and CTQ2017-83587-P, FI predoctoral
grant to A.A., RyC Contract RYC2012-11112 to A.L.), the
Generalitat de Catalunya (Project 2017-SGR-39, Xarxa de
(8) (a) Ma, S.; Lu, P.; Lu, L.; Hou, H.; Wei, J.; He, Q.; Gu, Z.; Jiang,
X.; Jin, X. What can a metal catalyst do with allenes? One-step
formation of steroid scaffolds from readily available starting materials.
Angew. Chem., Int. Ed. 2005, 44, 5275−5278. (b) Ma, S.; Lu, L. RhI-
catalyzed bimolecular cyclization between two different 1,5-bisallenes:
a combinatorial one-step approach to heterosteroids and mechanistic
implications. Chem. - Asian J. 2007, 2, 199−204. (c) Lu, P.; Ma, S. Rh-
catalyzed triple allene approach to bicycle[4.4.0]decene derivatives
and its application for the stepwise synthesis of steroid-like tetracyclic
skeletons. Org. Lett. 2007, 9, 5319−5321.
(9) (a) Lu, P.; Ma, S. Observation of new cycloisomerization pattern
of 1,5-bisallenes. catalyst and substituent effects. Org. Lett. 2007, 9,
2095−2097. (b) Lu, P.; Kuang, J.; Ma, S. Carbon-carbon double-bond
isomerization and Diels-Alder reaction of dimethyl 5-methylene-4-
isopropylidene-2-cycloheptene-1,1-dicarboxylate with dienophiles.
Synlett 2010, 2010, 227−230.
(10) Kawamura, T.; Inagaki, F.; Narita, S.; Takahashi, Y.; Hirata, S.;
Kitagaki, S.; Mukai, C. Rhodium(I)-catalyzed intramolecular carbon-
ylative [2 + 2 + 1] cycloadditions and cycloisomerizations of
bis(sulfonylallene)s. Chem. - Eur. J. 2010, 16, 5173−5183.
(11) Inagaki, F.; Narita, S.; Hasegawa, T.; Kitagaki, S.; Mukai, C.
Rhodium(I)-catalyzed intramolecular carbonylative [2 + 2 + 1]
cycloaddition of bis(allene)s: bicyclo[6.3.0]undecadienones and
bicyclo[5.3.0]decadienones. Angew. Chem., Int. Ed. 2009, 48, 2007−
2011.
(12) Park, J. H.; Kim, E.; Kim, H.-M.; Choi, S. Y.; Chung, Y. K.
Cobalt/rhodium heterobimetallic nanoparticle-catalyzed carbonyla-
tive [2 + 2 + 1] cycloaddition of allenes and bisallenes to Pauson-
Khand-type reaction products. Chem. Commun. 2008, 2388−2390.
(13) For selected reviews, see: (a) Meyer, A. G.; Bissember, A. C.;
Hyland, C. J. T.; Williams, C. C.; Szabo, M.; Abel, S.-A. G.; Bird, M.
J.; Hyland, I. K.; Pham, H. Seven-membered rings, chapter 7. Prog.
Heterocycl. Chem. 2018, 30, 493−550. (b) Nguyen, T. V.; Hartmann,
J. M.; Enders, D. Recent synthetic strategies to access seven-
membered carbocycles in natural product synthesis. Synthesis 2013,
45, 845−873. (c) Riley, D. L.; van Otterlo, W. A. L. Oxepines and
azepines, Chapter 15. Heterocycles in Natural Product Synthesis; Wiley-
VCH: Weinheim, Germany, 2011. (d) Kantorowski, E. J.; Kurth, M. J.
Expansion to seven-membered rings. Tetrahedron 2000, 56, 4317−
4353. (e) Liu, J.-h.; Steigel, A.; Reininger, E.; Bauer, R. Two new
prenylated 3-benzoxepin derivatives as cyclooxygenase inhibitors from
Perilla frutescens var. acuta. J. Nat. Prod. 2000, 63, 403−405. Selected
and recent studies based on the synthesis of benzo[d]azepine
derivatives: (f) Jiang, B.; Liu, J.-X.; Wei, Y.; Shi, M. Nickel-catalyzed
synthesis of benzo[b]naphthol[1,2-d]azepine via intramolecular
radical tandem cyclization of alkyl bromide-tethered alkylidenecyclo-
propanes. Org. Lett. 2018, 20, 6229−6233. (g) Nayak, M.; Kang, Y.
K.; Kim, I. Altering the cyclization modes: temperature-dependent
intramolecular 7-endo-dig vs 6-endo-dig electrophilic ring closures. Org.
Lett. 2017, 19, 1474−1477. (h) Adamovskyi, M. I.; Ryabukhin, S. V.;
Sibgatulin, D. A.; Rusanov, E.; Grygorenko, O. O. Beyond the five and
six: evaluation of seven-membered cyclic anhydrides in the
Castagnoli-Cushman reaction. Org. Lett. 2017, 19, 130−133.
́
̀
̀
Referencia en Quimica Teorica i Computacional, ICREA
Academia 2014 prize for M.S.), and UdG for an IF predoctoral
grant to J.V.
REFERENCES
■
(1) For selected reviews, see: (a) Kotha, S.; Lahiri, K.; Sreevani, G.
Design and synthesis of aromatics through [2 + 2 + 2] cyclo-
trimerization. Synlett 2018, 29, 2342−2361. (b) Yamamoto, Y. Recent
topics of Cp*RuCl-catalyzed annulation reactions. Tetrahedron Lett.
2017, 58, 3787−3794. (c) Neuhaus, J. D.; Willis, M. C.
Homogeneous rhodium(I)-catalysis in de novo heterocycle synthesis.
Org. Biomol. Chem. 2016, 14, 4986−5000. (d) Omae, I. Characteristic
reactions of group 9 transition metal compounds in organic synthesis.
Appl. Organomet. Chem. 2009, 23, 91−107. (e) Michelet, V.; Toullec,
̂
P. Y.; Genet, J.-P. Cycloisomerization of 1,n-enynes: challenging
metal-catalyzed rearrangements and mechanistic insights. Angew.
Chem., Int. Ed. 2008, 47, 4268−4315.
́
(2) For selected and recent reviews, see: (a) Lledo, A.; Pla-Quintana,
A.; Roglans, A. Allenes, versatile unsaturated motifs in transition-
metal-catalysed [2 + 2 + 2] cycloaddition reactions. Chem. Soc. Rev.
2016, 45, 2010−2023. (b) Alcaide, B.; Almendros, P.; Aragoncillo, C.
Cyclization reactions of bis(allenes) for the synthesis of polycarbo-
(hetero)cycles. Chem. Soc. Rev. 2014, 43, 3106−3135. (c) Kitagaki, S.;
Inagaki, F.; Mukai, C. [2 + 2 + 1] Cyclization of allenes. Chem. Soc.
́
Rev. 2014, 43, 2956−2978. (d) Lopez, F.; Mascarenas, J. L. [4 + 2]
̃
and [4 + 3] Catalytic cycloadditions of allenes. Chem. Soc. Rev. 2014,
43, 2904−2915. (e) Ye, J.; Ma, S. Palladium-catalyzed cyclization
reactions of allenes in the presence of unsaturated carbon-carbon
́
bonds. Acc. Chem. Res. 2014, 47, 989−1000. (f) Lopez, F.;
Mascarenas, J. L. Allenes as three-carbon units in catalytic
̃
cycloadditions: new opportunities with transition-metal catalysts.
Chem. - Eur. J. 2011, 17, 418−428. (g) Aubert, C.; Fensterbank, L.;
Garcia, P.; Malacria, M.; Simonneau, A. Transition metal catalyzed
cycloisomerizations of 1,n-allenynes and allenenes. Chem. Rev. 2011,
111, 1954−1993. (h) Chen, G.; Jiang, X.; Fu, C.; Ma, S. The
diversified reactivities of 1,5-bisallenes. Chem. Lett. 2010, 39, 78−81.
(3) (a) Jiang, X.; Cheng, X.; Ma, S. Controllable [2 + 2]
cycloadditions of 1,5-bisallenyl-substituted compounds. Angew.
Chem., Int. Ed. 2006, 45, 8009−8013. (b) Hong, Y.-T.; Yoon, S.-K.;
Kang, S.-K.; Yu, C.-M. A stereoselective carbocyclization of
bis(allenes) with germylstannane catalyzed by palladium complexes.
Eur. J. Org. Chem. 2004, 2004, 4628−4635. (c) Kang, S. K.; Baik, T.
G.; Kulak, A. N.; Ha, Y. H.; Lim, Y.; Park, J. Palladium-catalyzed
carbocyclization/silastannylation and distannylation of bis(allenes). J.
Am. Chem. Soc. 2000, 122, 11529−11530.
̈
(4) (a) Zhu, C.; Yang, B.; Qiu, Y.; Backvall, J.-E. Highly selective
construction of seven-membered carbocycles by olefin-assisted
palladium-catalyzed oxidative carbocyclization-alkoxycarbonylation
of bisallenes. Angew. Chem., Int. Ed. 2016, 55, 14405−14408.
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DOI: 10.1021/acs.orglett.9b02032
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Organic Letters
Letter
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̀
(14) (a) Cassu, D.; Parella, T.; Sola, M.; Pla-Quintana, A.; Roglans,
A. Rhodium-catalyzed [2 + 2 + 2] cycloaddition reactions of linear
allene−ene−ynes to afford fused tricyclic scaffolds: insights into the
mechanism. Chem. - Eur. J. 2017, 23, 14889−14899. (b) Haraburda,
́
E.; Fernandez, M.; Gifreu, A.; Garcia, J.; Parella, T.; Pla-Quintana, A.;
Roglans, A. Chiral induction in intramolecular Rhodium-catalyzed [2
+ 2 + 2] cycloadditions of optically active allene−ene/yne−allene
substrates. Adv. Synth. Catal. 2017, 359, 506−512. (c) Haraburda, E.;
́
Lledo, A.; Roglans, A.; Pla-Quintana, A. Dehydrogenative [2 + 2 + 2]
cycloaddition of cyano-yne-allene substrates: convenient access to 2,6-
naphthyridine scaffolds. Org. Lett. 2015, 17, 2882−2885. (d) Har-
̀
̀
aburda, E.; Torres, O.; Parella, T.; Sola, M.; Pla-Quintana, A.
Stereoselective Rhodium-catalysed [2 + 2 + 2] cycloaddition of linear
allene−ene/yne−allene substrates: reactivity and theoretical mecha-
nistic studies. Chem. - Eur. J. 2014, 20, 5034−5045. For a review, see:
(e) Pla-Quintana, A.; Roglans, A. Chiral induction in [2 + 2 + 2]
cycloaddition reactions. Asian J. Org. Chem. 2018, 7, 1706−1718.
(15) Compound 5a was synthesized by Ma and co-workers [see ref
3a] through a palladium(0)-catalyzed [2 + 2] cycloaddition of
bisallene 1a.
(16) The formation or absence of product 5a is surprising (especially
comparing 3ag and 3ah) and points to a delicate balance of reaction
rates among the multistep processes leading to products 3 and 5.
(17) The thermal ellipsoids in the ORTEP plot of the X-ray
structure of 3am are drawn at 50% probability.
(18) (76% THF, 24% CH2Cl2) is equivalent to a 4:1 v/v ratio of
THF/CH2Cl2.
(19) (a) Kozuch, S.; Shaik, S. Kinetic-quantum chemical model for
catalytic cycles: the Haber-Bosch process and the effect of reagent
concentration. J. Phys. Chem. A 2008, 112, 6032−6041. (b) Kozuch,
S.; Shaik, S. How to conceptualize catalytic cycles? The energetic span
model. Acc. Chem. Res. 2011, 44, 101−110.
(20) Zhou, Y.; Nikbakht, A.; Bauer, F.; Breit, B. Rhodium catalyzed
cycloisomerization and tandem Diels-Alder reaction for facile access
to diverse bicyclic and tricyclic heterocycles. Chem. Sci. 2019, 10,
4805−4810.
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DOI: 10.1021/acs.orglett.9b02032
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