Palladium-Catalyzed Intramolecular Trost–Oppolzer-Type Alder–Ene Reaction of Dienyl Acetates to Cyclopentadienes

Article abstract of DOI:10.1002/anie.201711797

A new approach to the synthesis of highly substituted cyclopentadienes, indenes, and cyclopentene-fused heteroarenes by means of the Pd-catalyzed Trost–Oppolzer-type intramolecular Alder–ene reaction of 2,4-pentadienyl acetates is described. This unpreced

Full text of DOI:10.1002/anie.201711797

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Accepted Article
Title: Palladium-Catalyzed Intramolecular Trost-Oppolzer-Type Alder-
Ene Reaction of Dienyl Acetates to Cyclopentadienes
Authors: Siddheshwar K. Bankar, Bara Singh, Pinku Tung, and S. S. V.
Ramasastry
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10.1002/anie.201711797
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Palladium-Catalyzed Intramolecular Trost-Oppolzer-Type Alder-
Ene Reaction of Dienyl Acetates to Cyclopentadienes
Siddheshwar K. Bankar, Bara Singh, Pinku Tung and S. S. V. Ramasastry*
Dedicated to Professor Kavirayani R. Prasad
Abstract: A new approach for the synthesis of highly substituted
cyclopentadienes, indenes and cyclopentene-fused heteroarenes via
the Pd-catalyzed Trost-Oppolzer-type intramolecular Alder-ene
reaction of 2,4-pentadienyl acetates is described. This
unprecedented transformation combines the electrophilic features of
the Tsuji-Trost reaction with the nucleophilic features of the Alder-
ene reaction. The overall outcome can be perceived as a hitherto
unknown ‘acid-free’ iso-Nazarov-type cyclization. The versatility of
this strategy was further demonstrated via the formal synthesis of
paucifloral F, a resveratrol-based natural product.
(Scheme 2).[4] Subsequent inspiring contributions by various
research groups were responsible for the further advancement
of this area.[5] These methods provide efficient access to
architecturally complex carbo- and heterocycles.
The Tsuji-Trost (TT) reaction is a powerful synthetic tool for the
formation of C-C and C-X (X = N, O, S, etc.) bonds.[1] A typical
TT reaction involves the Pd-catalyzed allylation of a wide range
of nucleophiles such as active methylenes, enolates, amines,
alcohols, to mention a few (Scheme 1a). In an analogous
manner, fewer studies pertaining to the Pd-catalyzed allylic
alkylation of 2,4-pentadienyl substrates were reported by Trost,
Backvall, Shimizu, and others from experimental and theoretical
standpoint (Scheme 1b).[2] Due to the versatility and potential,
TT-type allylation reactions have been extensively employed in
the synthesis of several bioactive natural products and
pharmaceutically relevant compounds.[1,3]
Scheme 2. Palladium-ene reactions: General representation of the seminal
contributions of Trost and Oppolzer.
Having been inspired by these pioneering works, we
postulated that the dienyl acetate A in the presence of a
palladium catalyst could generate the vinyl (-allyl)palladium
species B, Scheme 3. Further, an intramolecular Alder-ene-type
reaction of B can generate the cyclopentenyl cation C, which
upon proton loss forms either D or E. This hypothesis combines
the nucleophilic features of the ene reaction with the electrophilic
features of the TT reaction. In addition, the overall
transformation represents
a Pd-catalyzed (acid-free) iso-
Nazarov-type reaction,[6] which, to the best of our knowledge, is
without precedence.[7]
A few important aspects about the substrate design were
considered prior to investigating the hypothesis presented in
Scheme 3. It was anticipated that a favourable A1,3-strain
exerted by R2 and R3 (when R2, R3  H) could prompt the
substrate (B) to organize itself for an intramolecular Alder-ene
reaction. Additionally, R1 should be able to offer stabilization to
the Pd-species (such as B) and prevent its elimination, while not
taking part in the reaction.
Scheme 1. Tsuji-Trost reaction of allyl and pentadienyl substrates.
Lg=Leaving group, Nu=Nucleophile.
Among the inter- and intramolecular allylic alkylation
reactions, the seminal contributions of Trost and Oppolzer on
the Pd-catalyzed Alder-ene reaction are particularly noteworthy
[*]
S. K. Bankar, B. Singh, P. Tung, Prof. Dr. S. S. V. Ramasastry
Organic Synthesis and Catalysis Lab, Department of Chemical
Sciences, Indian Institute of Science Education and Research
(IISER) Mohali, Knowledge City, Sector 81, S. A. S. Nagar, Manauli
PO, Punjab 140306, India.
E-mail: ramsastry@iisermohali.ac.in; ramsastrys@gmail.com
Homepage: http://14.139.227.202/faculty/sastry/
Supporting information for this article is given via a link at the end of
the document.
Scheme 3. Our hypothesis for the synthesis of cyclopentadienes.
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By incorporating the aforementioned considerations, a
model substrate 1a was prepared (Table 1).[8,9] Various
combinations of metal catalysts and solvents were evaluated,
and the key results are summarized in Table 1. Initial screening
with Pd(0) catalysts provided no product (entries 1 and 2).
However, the Pd(II) catalysts such as Pd(OAc)2 and PdCl2
delivered, to our surprise, the tetrasubstituted cyclopentadiene
2a in 58% and 69% yields, respectively (entries 3 and 4). The
structure of 2a was readily distinguished from among the other
expected products 3a and 4a based on a two-proton singlet in
the 1H-NMR, and was eventually confirmed by the single-crystal
X-ray diffraction analysis of 2f (vide infra).[10] It is important to
note that 2,4-dienyl acetates have been employed in the TT-type
reactions,[2] but no report of cyclopentadiene formation exists.
feature of this reaction is that it involves the formation of a new
sp2-sp2 C-C bond, unlike the TT reaction or the ene reaction.
With the optimized conditions in hand, the substrate scope
was then evaluated. It is evident from Table 2 that a wide range
of tetrasubstituted cyclopentadienes possessing sterically and
electronically diverse substituents can be assembled in good to
excellent yields (2b-2k).[11,12] Interestingly, the dienyl acetate 1k
generated the cyclopenta[a]naphthalene derivative 2k,
presumably via the Alder-ene reaction/aromatization sequence.
It is worth noting that the formation of no other cyclopentadiene
isomers was observed during the course of the present study,
thereby highlighting the selectivity and efficiency aspects of this
method. Further, the flexibility provided by this methodology to
introduce a variety of alkyl, aryl and heteroaryl groups across the
cyclopentadiene core can be particularly advantageous in the
preparation of a diverse set of metallocene complexes.[13]
Among the multiply substituted cyclopentadienes, 1,2,3,4-
tetrasubstituted cyclopentadienes accessible herein are unique
because this substitution pattern will not only enhance the
rigidity but can also increase the solubility of the respective
metallocenes and thus influence their reactivity significantly.[14]
Table 1. Optimization of the reaction parameters.[a]
OAc
Ar
Ar
Ph
Ar
Ph
[Pd] [solvent]
80 o
Ph
Ar
C
Ph
2a (formed)
1a
[Ar = 2,6-(OMe)2C6H3]
3a
4a
(not observed)
Entry
1[c]
2[c]
3
Catalyst (mmol%)
Pd(PPh3)4 (5)
Pd2(dba)3 (5)
Pd(OAc)2 (5)
PdCl2 (5)
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,2-DCE
CH3CN
DMF
Time (h)
50
Yield of 2a [%][b]
Table 2. Substrate scope: 1,2,3,4-Tetrasubstituted cyclopentadienes.[a,b]
OAc
R2
-
R3
PdCl2 (10 mol%)
R4
R1
48
-
Toluene, 80 o
C
R1
R4
R3 R2
24
58
69
-
1
2
4[d]
5[c]
6
35
OMe
OMe
Ni(cod)2 (5)
[Ir(cod)Cl]2 (5)
PdCl2 (10)
48
48
40
79
75
48
32
75
78
OMe
Ph
7[e,f]
8
Ph
2b, 10 h, 61%
Ph
20
R
R
2c, R = Me, 20 h, 78%
2d, R = C6H13, 20 h, 81%
2e, R = Me, 18 h, 78%
2f, R = C6H13, 20 h, 80%
PdCl2 (10)
25
9
PdCl2 (10)
50
S
OMe
MeO
10
11[g]
12[h]
PdCl2 (10)
48
OMe
S
PdCl2 (10)
Toluene
Toluene
35
PdCl2 (10)
39
Ar
[a] Reaction conditions: See the Supporting Information for details. [b] Isolated
yield after column chromatography. [c] 1a remained as such. [d] Other Pd(II)
catalysts such as Pd(dppf)Cl2 and PdCl2(PPh3)2 gave no product. [e] 1a
remains as such at room temperature, and it decomposes at 100 oC. [f] Under
these conditions, 2a was isolated in 68% yield with the OBoc-1a. [g] In the
presence of 1 equiv of N,N-dimethylaminopyridine (DMAP). [h] In the presence
of 1 equiv of 2,6-di-tert-butyl-4-methylpyridine (DTBMP).
Ph
2i, 24 h, 76%
MeO
OMe
2j, 18 h, 79%
2g, Ar = (p-Br)C6H4, 18 h, 82%
2h, Ar = (p-Ph)C6H4, 15 h, 85%
OAc
As part of our efforts to improve the efficiency of the
reaction, Ni- and Ir-based catalysts were employed, but only
poor results were obtained (entries 5 and 6). However, a marked
improvement in the yield was realized when the catalyst loading
was increased to 10 mol% (entry 7). Subsequent evaluation of
solvents could not provide any better result (entries 8-10). The
reactions which were performed in the presence of N,N-
1k
2k, 20 h, 75%
[a] Reaction conditions: See the Supporting Information for details. [b] Isolated
yield after column chromatography.
Having established an unprecedented approach for the
synthesis of highly substituted cyclopentadienes, we intended to
further expand the scope and generality of the concept by
considering new substrate designs (Scheme 4). It was
anticipated that an appropriate fusion of the diene system with
aromatic or heteroaromatic groups would present new substrate
classes F and G, which, by undergoing Trost-Oppolzer-type
Alder-ene reaction could deliver the cyclopentene-fused arenes
and heteroarenes H and I, respectively.
dimethylaminopyridine
(DMAP)
and
2,6-di-tert-butyl-4-
methylpyridine (DTBMP), to rule out the possibility of any traces
of HCl catalyzing the reaction, furnished 2a in good yields
(entries 11 and 12).
Thus, an unusual approach for the synthesis of 2a starting
from the dienyl acetate 1a was established. Unlike many Pd-
catalyzed reactions, intriguingly, this reaction does not require
any additives, re-oxidants, bases, etc. Further, a distinctive
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R2
OAc
R1
[Pd]
Ar/
Het-Ar
Ar/
Het-Ar
Ar/
Het-Ar
R2
R2
OAc
[Pd]
Ar/
Het-Ar
R2
R1
R1
R1
G
I
F
H
Scheme 4. Hypothesis-driven substrate designs.
Scheme 5. Reaction of (–)-5a under the optimized conditions.
Based on the aforementioned design considerations, the
acetate 5a was prepared and was subjected to the optimized
conditions described for 2 (Table 3). To our delight, the desired
product 1,2-diphenylindene 6a was obtained in 82% yield. But,
when 5 mol% PdCl2 was employed, the reaction required a
longer time to complete and generated 6a in lower yield. As
expected, no reaction was observed in the absence of PdCl2 and
the reaction of 5a even in the presence of proton sponge
provided 6a in 80% yield.
Nevertheless, we proceeded to pursue a new substrate
design detailed in Scheme 4. Accordingly, the synthesis of the
acetate 7a was taken up (Table 4). Gratifyingly, the reaction of
7a under the prototypical conditions described in Table 2 and 3
conveniently provided 8a in good yield. This method eventually
turned out to be a powerful approach to synthesize electronically
diverse 1,2-disubstituted indenes (8b-8g), cyclopentannulated
benzothiophenes (8h and 8i) and cyclopenta[b]indoles (8j).[15]
Table 4. Substrate scope: Cyclopentene-fused arenes and heteroarenes.[a]
Table 3. Substrate scope: Cyclopentene-fused arenes and heteroarenes.[a]
OAc
R2
Ar/
Het-Ar
PdCl2 (10 mol%)
R2
Ar/
Het-Ar
Ar/
Het-Ar
R1
PdCl2 (10 mol%)
Toluene, 100 oC
R2
Ar/
Toluene, 100 o
C
Het-Ar
OAc
R2
R1
7
8
R1
R1
5
6
R
6a, 24 h, 82%
8a, R = Me, 20 h, 77%
8b, R = C6H13, 21 h, 82%
8c, R = CH2Ph, 15 h, 78%
C6H13
6a, 36 h, 73%[b]
6a, 120 h, 0%[c]
6a, 48 h, 80%[d]
OMe
Ph
Ph
OMe
Ph
MeO
Ar
Ph
Ph
6b, 25 h, 81%
8d, Ar = 2,6-(Me)2C6H3, 25 h, 85%
8e, Ar = 2,4,6-(Me)3C6H2, 28 h, 87%
MeO
MeO
6c, R = Ph, 25 h, 87%
6d, R = OAc, 24 h, 87%
6e, R = OMe, 25 h, 85%
Ar
R
OMe
Ph
MeO
S
6f, 20 h, 85%
N
R
Ts
8h, Ar = 2,6-(OMe)2C6H3, 20 h, 80%
8i, Ar = 2,4,6-(Me)3C6H2, 24 h, 84%
8f, R = Ph, 24 h, 80%
8g, R = OMe, 20 h, 85%
[a] Isolated yield after column chromatography.
Ph
Ph
R1
8j, 24 h, 85%
Ph
Ph
Indanes (and indenes) are the primary molecular
architectures present in many bioactive natural products and
drug candidates,[17] and on the other hand, cyclopentannulated
heteroarenes find potential applications in medicinal chemistry
as well as in materials science.[18] With this understanding, we
decided to apply the current strategy in the total synthesis of the
resveratrol-based natural product, paucifloral F 9 (Scheme 6).[19]
For this purpose, the desired acetate 13 was synthesized by the
addition of the lithiated form of 12[19a] to 3,5-
dimethoxybenzaldehyde followed by acylation of the
intermediate alcohol. The reaction of 13 promoted by PdCl2
S
S
R2
6i, R1 = H, R2 = Ph; 15 h, 75%
6j, R1 = Ph, R2 = H; 24 h, 80%
6g, 23 h, 86%
6h, 20 h, 90%
[a] Isolated yield after column chromatography. [b] With 5 mol% PdCl2. [c] In
the absence of PdCl2. [d] In the presence of 1 equiv of proton sponge.
An evaluation of the substrate scope with an array of 2-
styrylbenzyl acetates (5) revealed the generality of this method
in providing access to a series of 1,2-disubstituted indenes (6a-
6h). Both arenes (bearing electron-donating as well as electron-
withdrawing groups) and heteroarenes were well-tolerated at R1
and R2. Otherwise difficult-to-access cyclopentene-fused
benzothiophenes (6j and 6h) could also be readily
synthesized.[15]
On the other hand, several of our efforts to develop a
catalytic enantioselective variant met with no success.[16]
Intrigued by the lack of asymmetric induction, the chiral acetate
(–)-5a was prepared to gain insights about the mechanism of the
transformation (Scheme 5). Interestingly, under the optimized
conditions, the reaction of (–)-5a generated 6a as a racemic
mixture. This result gave us sufficient indication that the
development of a chiral version may not be feasible under the
current set-up.
provided the indene 14 in 81% yield.
A
subsequent
hydrogenation and SeO2-mediated benzylic oxidation furnished
the enone 15, an advanced intermediate in the Sarpong’s
synthesis of paucifloral F 9,[19b] in an unexpected manner. The
synthetic methodology delineated herein is general and can
pave the way for the rapid synthesis of other related resveratrol
natural products such as ampelopsin D 10 and caraphenol B 11.
In summary, an unprecedented Pd(II)-promoted cyclization
of 2,4-pentadienyl acetates to cyclopentadienes, indenes and
cyclopentene-fused heteroarenes is presented. Some of the
noteworthy features of the present study are: i) easy synthesis of
starting compounds, ii) mild, straightforward and practical
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[3]
[4]
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reaction conditions, iii) unusual access to cyclopentanoids with
defined substitution patterns. The synthetic methods described
herein hold great potential and will stimulate further research in
the synthesis of new carbocycles and heterocycles.
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[6]
For some selected articles on iso-Nazarov-type reactions, see: a) M. E.
Jung, D. Yoo, J. Org. Chem. 2007, 72, 8565; b) O. N. Faza, C. S.
Lꢀpez, R. Alvarez, A. R. de Lera, Chem. Eur. J. 2009, 15, 1944; c) W. T.
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M. J. Riveira, M. P. Mischne, J. Org. Chem. 2014, 79, 8244; e) A. M.
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Marsili, M. P. Mischne, Org. Biomol. Chem. 2017, DOI:
10.1039/c7ob02220d.
Scheme 6. A novel approach for the synthesis of Sarpong’s indenone 15.
Acknowledgements
IISER Mohali is thanked for funding, and for the NMR, mass and
departmental X-ray facilities. S.K.B., B.S. and P.T. thank IISER
Mohali, UGC and DST, respectively, for research fellowships.
[7]
Some selected articles on Pd-catalyzed Nazarov cyclizations, see: a) C.
Bee, E. Leclerc, M. A. Tius, Org. Lett. 2003, 5, 4927; b) A. K. Basak, N.
Shimada, W. F. Bow, D. A. Vicic, M. A. Tius, J. Am. Chem. Soc. 2010,
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Keywords: Palladium • Cyclopentadienes • Indanes • Tsuji-
Trost reaction • Alder-ene reaction • Heterocycles
[1]
Some selected articles: a) J. Tsuji, H. Takahashi, M. Morikawa,
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[8]
[9]
See the Supporting Information for the synthesis of 1a and other
analogues employed in this study.
The choice of 2,6-dimethoxybenzene group at R1 was to restrict any
undesired side reactions such as elimination and provide stabilization
through its electron-donating ability. The ortho positions were blocked
to restrict the formation of Nazarov-type products.
[10] CCDC 1583859 (for 2g) and 1583860 (for 6g) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
[11] Cyclopentadienes are excellent intermediates in synthetic chemistry,
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Mamedov, E. I. Klabunovskii, Russ. J. Org. Chem. 2008, 44, 1097.
[12] See the Supporting Information for the synthesis of Diels-Alder adducts
of 2e and 2f with maleic anhydride and N-ethylmaleimide.
[2]
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965; b) M. Kotora, Top. Organomet. Chem. 2004, 8, 57; c) M. Enders,
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[16] See the Supporting Information for details.
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Entry for the Table of Contents
COMMUNICATION
Siddheshwar K. Bankar, Bara Singh,
Pinku Tung, S. S. V. Ramasastry*
OAc
Ar/
Het-Ar
[Pd]
Ar/
Ar/
Het-Ar
Het-Ar
Ar/
Het-Ar
Page No. – Page No.
* Palladium-ene reaction of 2,4-pentadienyl acetates to cyclopentadienes
* No requirement of additives, re-oxidants or bases
* 32 unique examples; good to excellent yields
Palladium-Catalyzed Intramolecular
Trost-Oppolzer-Type Alder-Ene
Reaction of Dienyl Acetates to
Cyclopentadienes
Out of the box: Palladium-catalyzed intramolecular allylic alkylation of 2,4-dienyl
acetates provides unusual access to tetrasubstituted cyclopentadienes, 1,2-
disubstituted indenes and cyclopentene-fused heteroarenes. The methods
described herein can provide short and efficient access to a large number of
bioactive natural products and therapeutically important compounds.
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