Mechanistic Insights into the Ru(II)-Catalyzed Intramolecular Formal [3 + 2] Cycloaddition of (E)-1,6-Enynes

Article abstract of DOI:10.1021/acs.orglett.9b02446

Design of a unique reaction pathway in transition-metal-catalyzed 1,6-enynes cyclization to construct valuable synthetic motifs is a significant challenge in organic chemistry. Herein, we report a Ru(II)-catalyzed formal [3 + 2] cycloaddition as an efficient method to prepare unprecedented bicyclo[3.3.0]octenes from readily available (E)-1,6-enynes. Mechanistic studies based on the deuterium labeling experiments and the DFT calculation disclose a reasonable mechanistic pathway, where a ruthenacyclopentene generated by an ene-yne oxidative cyclization undergoes a sequential ?-hydride elimination and intramolecular hydroruthenation to form a ruthenacyclohexene, producing the desirable bicyclo[3.3.0]octenes.

Full text of DOI:10.1021/acs.orglett.9b02446

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Mechanistic Insights into the Ru(II)-Catalyzed Intramolecular Formal
[3 + 2] Cycloaddition of (E)‑1,6-Enynes
Rui Liu,*,† Yajie Chou,† Bing Lian,‡ De-cai Fang,‡ Ming Gao,† Tanyu Cheng,† and Guohua Liu*,†
†Laboratory of Resource Chemistry and Rare Earth Materials, Shanghai Normal University, Shanghai 200241, China
‡College of Chemistry, Beijing Normal University, Beijing 100875, China
S
* Supporting Information
ABSTRACT: Design of a unique reaction pathway in
transition-metal-catalyzed 1,6-enynes cyclization to construct
valuable synthetic motifs is a significant challenge in organic
chemistry. Herein, we report a Ru(II)-catalyzed formal [3 + 2]
cycloaddition as an efficient method to prepare unprecedented
bicyclo[3.3.0]octenes from readily available (E)-1,6-enynes.
Mechanistic studies based on the deuterium labeling experi-
ments and the DFT calculation disclose a reasonable
mechanistic pathway, where a ruthenacyclopentene generated by an ene−yne oxidative cyclization undergoes a sequential ß-
hydride elimination and intramolecular hydroruthenation to form a ruthenacyclohexene, producing the desirable
bicyclo[3.3.0]octenes.
Scheme 1. Transition-Metal-Catalyzed Intramolecular [n +
2] Cycloadditions of Enynes
ransition-metal-catalyzed enyne cyclizations have been
Textensively employed as useful synthetic tools in the
construction of a variety of natural products, pharmaceutically
molecules, and also industrially relevant products.1 Since the
pioneering work reported by Trost on the palladium-catalyzed
cycloisomerization of 1,6-enynes in the middle 1980s,2
numerous reports and well-documented reviews involving
various metal complexes have emerged as conceptual processes
in enynes cyclization reactions,1,3 and the related new
cyclization reactions have continuously appeared in literature
until recently.4 Of all these significant contributions, the
intramolecular [n + 2] (n = 2, 4, 5, 6) cycloadditions of enynes
are especially attractive due to the ubiquitous feature in the
facile syntheses of polycyclic molecules with 4−8 membered
rings (Scheme 1A).5 The first intramolecular [2 + 2]
cycloaddition of enynes was reported by the Trost group,
where the enynes with an electron-withdrawing motif at the
acetylenic carbon could be converted into the cyclobutenes
(Scheme 1A1).5a,6 The initial success of the intramolecular [4
+ 2] cycloaddition of dienynes was reported in 1989 through
the use of a nickel(0) complex (Scheme 1A2).7 Shortly after
Trost also found that the CpRu(MeCN)3PF6 effectively
promoted the [4 + 2] cycloaddition of yne-enones.8 The
pioneering work on the intramolecular [5 + 2] cycloaddition
involving the enynes structures was established by the Wender
group through the use of the in situ formed cationic rhodium
species [Rh(PPh3)3]OTf (Scheme 1A3).9 Subsequently, a
series of 1,6-enynes containing the cyclopropyl group on the
alkene side could be used for the construction of cyclo-
heptadienes via this similar intramolecular [5 + 2] cyclo-
addition. The single example of intramolecular [6 + 2]
cycloaddition of trienynes was reported by the Tenaglia group,
where PtCl2 was used to construct the cyclopentane fused
bicyclo[4.2.1]nona-2,4,7-trienes derivatives (Scheme 1A4).5t
Despite the great achievements with these developed
transformations, to the best of our knowledge, the intra-
molecular [3 + 2] cycloaddition reaction of 1,6-enynes is still
Received: July 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02446
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Letter
challenging (Scheme 1B). One of the main restrictions lies in
the fact that this intramolecular [3 + 2] cycloaddition needs
the participation of a saturated C(sp3)−H bond rather than the
above-observed participation of the carbon−carbon single/
double bonds in the intramolecular [n + 2] (n = 2, 4, 5, 6)
cycloadditions.10 This limitation means a compulsory demand
via a 1,2-hydrogen shift that must undergo the cleavage of a
saturated C(sp3)−H bond. Another restriction ascribes the
corresponding competing cyclization reaction to convert into
the normal Alder-ene monocyclic products (gray part in
Scheme 1B). Therefore, based on valuable information in the
mechanistic study of normal Alder-ene process,11 a systematic
adjustment of the sterically hindered effect in 1,6-enynes with
the suitable substituent at the propargylic position could favor
the conformational match of the [Ru]−H bond and the
pseudoequatorial alkene in ruthenium hydride intermediate
III,12 thus leading to the formation of the ruthenahexene
intermediate IV via hydroruthenation process of III. This is a
reasonable solution to overcome the above restrictions for the
formation of the desirable bicyclic products via the release of
the ruthenacyclohexene IV. In this contribution, we realize this
intramolecular formal [3 + 2] cycloaddition reaction of (E)-
1,6-enynes is mechanistically unusual relative to that of the
AgSbF6-catalyzed intermolecular cyclization of alkenes and
alkyne,13 providing a series of bicyclo[3.3.0]octenes in good
yields under mild reaction conditions. As presented in this
study, the deuterium labeling experiments and the control
experiments, together with the DFT calculations, disclose its
catalytic mechanism of this intramolecular [3 + 2] cyclo-
addition process.
clean bicyclic 2ad in 89% isolated yield, even if in 1 g level of
scale (84%) (entry 4; also see Supporting Information for the
optimization of reaction conditions). This finding indicates
that the methyl groups at the propargylic position are able to
meet a proposed spatial orientation of the [Ru]−H bond and
pendent CC double bond in the intermediate III, which is
indicative of an interesting contribution of the gem-dialkyl
effect reported by Thorpe and Ingold in 1915.16 A further
attempt by using 1ae with a cyclic substituent at the
propargylic position also afforded the desirable bicyclic 2ae
in 85% isolated yield (entry 5), supporting this gem-dialkyl
effect. However, the sole gem-dialkyl effect is not sufficient
since the reaction of the O-linked 1af did not produce the
bicyclic 2af instead of 3af, and those of the C-linked substrates
(1ag−1ah) also only gave the normal Alder-ene monocyclic
products (3ag−3ah) (entries 6−8), indicating a sensitive
hydroruthation process for the tethering atom of enynes.
These comparisons elaborated an integrated contribution of a
spatially configurational sp3 hybridized N-linker and the
assistance of the gem-dialkyl effect for the intramolecular [3
+ 2] cycloaddition, which is distinctly different from the
common homo-hydroalkynylative cyclization adducts and
homo-[2 + 2 + 2] cycloadducts process reported by Tenaglia’s
group.17
In light of this clear configurational unit of substrates, a
series of sulfamide-tethered 1,6-enynes containing an sp3
hybridized N-linker and the dimethyl substituents at the
propargylic position were further investigated as shown in
Table 2. The results showed that the reactions with all the
tested (E)-1,6-enynes could steadily produce the correspond-
In our proof-of-concept experiments, we first examined the
reaction feasibility in the proposed mechanistic pathway of the
intramolecular [3 + 2] cycloaddition by adjusting the
substituents at the propargylic position of the selected (E)-
1,6-enynes. The reactions were carried out through the use of
5% mol of the electron-rich Cp*Ru(cod)Cl as a catalyst since
the reported Cp*Ru(cod)Cl could efficiently catalyze various
enyne cyclization reactions.14 As shown in Table 1, we initially
found that the reaction of the tosylamide 1aa without a
substituent at the propargylic position did not occur, whereas
those of 1ab and 1ac with a monosubstituent at the
propargylic position only afforded the normal Alder-ene
monocyclic 3ab and 3ac (entry 1 versus entries 2−3).11b,15
To our delight, the reaction of 1ad could steadily produce the
Table 2. Ru(II)-Catalyzed Intramolecular Formal [3 + 2]
Cycloaddition Reaction
a
Table 1. Evaluation of Ru(II)-Catalyzed Cyclization of (E)-
a
1,6-Enynes
bc
,
bc
,
entry
enyne: X, R, R′
1aa: NTs, H, H
1ab: NTs, H, Me
1ac: NTs, H, Ph
1ad: NTs, Me, Me
1ae: NTs, −(CH2)5−
1af: O, −(CH2)5−
1ag: C(CO2Et)2, Me, Me
% yield of 2
% yield of 3
1
2
3
4
5
6
7
8
ND (2aa)
<5 (3aa)
55 (3ab)
39 (3ac)
ND (2ab)
ND (2ac)
89 (2ad)
85 (2ae)
ND (2af)
ND (2ag)
ND (2ah)
ND (3ad)
ND (3ae)
82 (3af)
76 (3ag)
73 (3ah)
a
1ah: C(CH2O)2CO, Me, Me
Reaction conditions 1: enyne 1ai−1bd (0.4 mmol), Cp*Ru(cod)Cl
(0.02 mmol), 40 °C, THF, 3 h. Reaction conditions 2: enyne 1be−
a
b
Reaction conditions: enyne 1 (0.4 mmol), Cp*Ru(cod)Cl (0.02
1bf (0.2 mmol), Cp*Ru(cod)Cl (0.02 mmol), 80 °C, THF, 24 h. Dr
b
c
mmol), 40 °C, THF, 3 h. Isolated yield. ND = Not detected.
was determined by crude NMR.
B
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Letter
ing bicyclo[3.3.0]octenes (2ai−2bf) in good to excellent
isolated yields, where a representative structure of 2al was
determined by its X-ray structure (CCDC: 1908820; see
Supporting Information for the single crystal X-ray structure).
In addition, it was found that the substrate scope is well-
tolerant of the alkene side chain of (E)-1,6-enynes, where the
enynes featuring different substituents on the alkene side chain
could undergo this [3 + 2] cycloaddition to provide the
corresponding bicyclic products (2ba−2bf). It was also
notable that the reactions of 1be−1bf required enhanced
loadings of catalyst (10 mol %) at higher temperature (80 °C)
with a prolonged reaction time (24 h).
was found that the tosylamide 1ad-D3 could be steadily
converted into the deuterated 2ad-D3 with complete
deuteration retention. This observation indicated that the
reaction might go through the suggested intermediate III in
this [3 + 2] cycloaddition, demonstrating a metal-assisted
intramolecular hydrogen shift step since a 1,2-hydrogen shift
occurs from the C5(sp3)−D bond to the C4(sp3)−D bond in
2ad-D3 that was proven by the reaction of 1ad in D2O without
deuterium incorporation. In order to explain ruthenium
hydride intermediate II, another deuterium labeling experi-
ment for the reaction of (Z)-4a-D3 was also investigated (eq 4
in Scheme 3). The result presented a similarly intramolecular
hydrogen shift, suggesting the reaction undergoes the
ruthenium hydride intermediate II to produce the deuterated
5a-D3. Further evidence to support the proposed ruthenium
hydride intermediate II and III comes from a parallel reaction
of 1bi, where a representative 1bi with dual methyl groups at
the alkene could be efficiently converted into both bicyclic 2bi
and the Alder-ene monocyclic 3bi (eq 5 in Scheme 3).
In addition to the general practicability, this intramolecular
[3 + 2] cycloaddition also presented an obvious substrate
selectivity as shown in Scheme 2. In the cases of the 1,6-enynes
Scheme 2. Investigations of the Affecting Factors to the
Ru(II)-Catalyzed Intramolecular Formal [3 + 2]
Cycloaddition Reaction
According to the deuterium labeling experiments and the
control experiments, together with the detail DFT calculations
(see Supporting Information), the suggested catalytic cycles for
the intramolecular formal [3 + 2] cycloaddition (pathway 1)
and the Alder-ene cyclization (pathway 1′) were proposed, as
shown in Scheme 4. Initially, both reaction pathways initiate
Scheme 4. Proposed Reaction Mechanism for the
Intramolecular Formal [3 + 2] Cycloaddition and Alder-Ene
Cyclization
bearing a (Z)-configured alkene as the substrate, the reactions
of 4a−4d under the optimal reaction conditions only afforded
the normal Alder-ene monocyclic 5a−5d with high isolated
yields (60%−88%) (eq 1, Scheme 2), which were similar to
Trost’s reported results.11 Notably, no bicyclic products clearly
demonstrated the substrate’s Z/E-configurational selectivity. In
the cases of (E)-1,6-enynes equipped with bulky substituents at
the allylic position (1bg and 1bh), only the normal Alder-ene
monocyclic 3bg and 3bh were observed (eq 2, Scheme 2),
indicating the substrate’s sterically hindered selectivity.
To disclose the nature of an orientational match between the
[Ru]−H bond and pendent CC double bond in the
intermediate III, a deuterium labeling experiment, the [3 + 2]
cycloaddition of 1ad-D3, was performed (eq 3 in Scheme 3). It
through a cod dissociation and substrate coordination,
followed by the ene-yne oxidative cyclization step for the
formation of tetra-coordinated Cp*RuCl-enyne (A and A′), to
produce the common ruthenacyclopentene intermediates I and
I′. In the case of pathway 1 with (E)-1ad as a substrate, the
transformation of A to the intermediate I goes through the
transition state with the highest energy barriers of 13.3 kcal/
mol obtained by a DFT calculation (see Supporting
Information), which is the rate-determining step for the
intramolecular [3 + 2] cycloaddition reaction. Then, the
hydrogen from the pseudoequatorial methyl group in the
intermediate I gets closer to the ruthenium center, favoring the
formation of the vinyl ruthenium hydride intermediate III via a
β-hydride elimination step. Finally, the intramolecular hydro-
ruthenation step of the intermediate III occurs to release the
ruthenacyclohexene intermediate IV, leading to the desired
bicyclic 2ad via a reductive elimination step. However, in the
case of pathway 1′ with (Z)-4a as a substrate, the
transformation of I′ to the intermediates II is the rate-
determining step in the Alder-ene cyclization, where the
Scheme 3. Deuterium Labeling Experiments and
Investigations of the Substitution Effect
C
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Letter
highest energy barrier of transition state is 13.7 kcal/mol
detected by a DFT calculation (see Supporting Information).
Due to the unmatched conformation, the intermediate II tends
to undergo a typical ruthenium reductive elimination step to
provide the Alder-ene monocyclic 5a.11a
For clarity, the detailed elucidations in the formation of
either bicyclic or monocyclic products were addressed, as
shown in Scheme 5. In eq 6, the ruthenium hydride
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ghliu@shnu.edu.cn.
*E-mail: rliu@shnu.edu.cn.
ORCID
Rui Liu: 0000-0002-7916-3675
De-cai Fang: 0000-0003-3922-7221
Tanyu Cheng: 0000-0002-5245-814X
Guohua Liu: 0000-0001-8407-3095
Scheme 5. Proposed Reaction Intermediates
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21672149, 21872095) and China Postdoctoral Science
Foundation (2018M642054) for financial support.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02446.
General and procedural information; X-ray structure of
2al; DFT calculation results; NMR spectra (PDF)
Accession Codes
CCDC 1908820 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.
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