A C-H Insertion Approach to Functionalized Cyclopentenones

Article abstract of DOI:10.1021/jacs.6b04297

Cyclopentenones are synthetically versatile structures, and their straightforward construction from alkynone substrates by employing synthetically streamlining C-H insertion is conceptually appealing and of high synthetic potential. But, its implementation is very limited. Herein we report a Au-catalyzed version, which affords 2-bromocyclopent-2-en-1-ones with a broad scope and synthetically desirable diastereoselectivities. The proposed key intermediate capable of the observed insertion into unactivated C-H bonds is a fully functionalized gold vinylidene, which is generated via a novel intermolecular strategy. This flexible access of likely gold vinylidenes opens various opportunities to explore their versatile reactivities.

Full text of DOI:10.1021/jacs.6b04297

Communication
pubs.acs.org/JACS
A C−H Insertion Approach to Functionalized Cyclopentenones
Youliang Wang,† Maxence Zarca,† Liu-Zhu Gong,‡ and Liming Zhang*,†
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
‡Hefei National Laboratory for Physical Sciences at Microscale and Department of Chemistry, University of Science and Technology
of China, Hefei 230026, China
S
* Supporting Information
Scheme 1. C−H Insertion Approaches to Functionalized
a
ABSTRACT: Cyclopentenones are synthetically versatile
structures, and their straightforward construction from
alkynone substrates by employing synthetically stream-
lining C−H insertion is conceptually appealing and of high
synthetic potential. But, its implementation is very limited.
Herein we report a Au-catalyzed version, which affords 2-
bromocyclopent-2-en-1-ones with a broad scope and
synthetically desirable diastereoselectivities. The proposed
key intermediate capable of the observed insertion into
unactivated C−H bonds is a fully functionalized gold
vinylidene, which is generated via a novel intermolecular
strategy. This flexible access of likely gold vinylidenes
opens various opportunities to explore their versatile
reactivities.
Cyclopentenones
yclopentenones are versatile and indispensable structural
Cmotifs in the synthesis of functional molecules. Its
straightforward construction via alkynone cyclization employs
a synthetically streamlining C−H insertion by a reactive
alkenylidene intermediate1 (i.e., A, Scheme 1a). Despite the
approach being conceptually appealing and of high synthetic
potential, its reported implementations are limited to flash
vacuum pyrolysis (FVP, >600 °C)2 and in one study the use of
hazardous α-ketoethynyl(phenyl)iodonium salts.3 Both ap-
proaches, however, have no additional control of the reactivities
of alkenylidene intermediates. Consequently, these reactions
have limited scope and often display poor regioselectivity and
low diastereoselectivity (as exemplified in Scheme 1b).2a
a
An enduring and highly rewarding practice of modulating the
reactivities of reactive species and achieving their chemo-/regio-/
stereoselective transformations is the employment of transition-
metal complexes. As such, metal vinylidene/alkenylidene
complexes with various transition metals, many stable and
isolable, have been employed as versatile and often catalytic
intermediates en route to the development of various valuable
synthetic methods.4 Despite extensively researched, they seldom
undergo insertions into C−H bonds.5 Consequently, the metal-
catalyzed formation of cyclopentenones via C−H insertion by
metal vinylidene species has not been realized.
Recent developments in homogeneous Au catalysis have
revealed that in situ-generated gold vinylidenes are uniquely
reactive and do undergo insertions into C−H bonds.6 For the
cases with DFT support,6a,c,e their generations are, however,
confined to conformationally rigid (2-ethynylphenyl)alkynes,
which are of necessity due to a limiting intramolecular generation
(a) Formation of cyclopentenones via C−H insertions of vinylidene
intermediates in the absence of corresponding metal-mediated or
-catalyzed process. (b) Poor selectivity in one example of α-alkynone
cyclization. (c) Design for intermolecular access to fully functionalized
gold vinylidenes from ynones and their C−H insertion reactions.
mechanism. As such, there is a need of developing flexible
intermolecular generation of versatile gold vinylidenes.
To develop a novel intermolecular strategy of generating gold
vinylidenes and especially so in the context of forming the
synthetically highly valuable cyclopentenones via richly function-
alized metal vinylidene B, it is envisioned that, as shown in
Scheme 1c, the α-alkynone 1 could first be converted to the
alkynylgold complex C when treated with a cationic Au complex.
Received: April 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b04297
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Journal of the American Chemical Society
Communication
was used as the metal ligand (entry 1). The counteranion is
important, and among the ones examined (entries 1−3), SbF6− is
the most effective, and the cyclopentenone products were
formed in 61% yield at room temperature (entry 3). We then
varied the amount of AgSbF6 (entries 4 and 5), and it appeared
that 2 equiv of it to IPrAuCl is ideal. Different brominating
reagents were then screened. In comparison to NBS, the more
reactive NBP (N-bromophthalimide) led to a diminished yield
(entry 6), while 86% yield was achieved by using N-
bromoacetamide (NBA), a less reactive brominating reagent
(entry 7). With 1a-TMS (Y = TMS) as substrate, the reaction
was even more efficient, affording 2a in an outstanding 95% yield
without noticeable impact on the reaction rate (entry 8). On the
other hand, sterically more demanding TES greatly retarded the
reaction, resulting in a low conversion in 48 h (entries 9).
Notably, the bromoalkynone 1a-Br did not participate in the
reaction (entry 10), which rules out its potential role as a reaction
intermediate, and the silver salt alone is not the catalyst (entry
11). We also observed residual H2O from undried vial is
beneficiary to the reaction. In its absence (entry 12), the reaction
was much less efficient, and the addition of H2O (4 equiv) led to
an accelerated reaction, despite a slightly lower yield (entry 13).
Finally, DCM is an equally accommodating solvent, and the α-
bromocyclopentenone product was isolated in 95% yield. In all
the cases the reaction is highly regioselective, as the methylene
C−H bonds are preferred over the methyl ones by a ratio of >20/
1, consistent with IPrAu modulating the reactivity of reactive
vinylidene.
Table 1. Initial Reaction Discovery and Condition
Optimization
Notably, cyclopentenones are in general of exceptional
synthetic utility, and the products accessible via this streamlining
C−H insertion strategy possess additional α-bromination and
hence are of even higher synthetic value. Synthetic applications
of these compounds include, to name a few, enantioselective
synthesis of aplyviolene,8 a concise route to bioactive
hypnophilin,9 and the synthesis of marine prostanoid ana-
logues.10
This rapid access to highly versatile α-bromocyclopentenone
prompted us to explore extensively the reaction scope, which is
shown in Table 2. Similar to 1a-TMS, TMS-terminated ynones
1b−1d bearing α′-quaternary C centers all undergo the C−H
insertive cyclization smoothly, regardless of the increased steric
congestion in entries 1 and 3 and a deactivated benzylic C−H
bond in entry 2. In the latter case, side products derived from
methyl C−H insertion and phenyl participationare observed.11
The reaction is not limited to α-alkynones bearing α-quaternary
C’s. The unbranched TMS-terminated ynone 1e (entry 4)
worked smoothly, affording 2e in a good 74% yield. Functional
groups such as OTs, OTBDPS, and Br can be tolerated (entries
5−7). However, we observed that the closer an inductively
electron-withdrawing group is to the inserted C−H bond, the
more sluggish the reaction is. For example, the reaction of 1f with
a γ′-OTBDPS group led to 51% yield with a higher catalyst
loading and in longer time (entry 5). If the siloxyl group is
replaced with a more inductive OTs, no desired C−H insertion
product was detected. This phenomenon suggests an asynchro-
nous C−H insertion step where partial positive charge is
developed at the carbon center in the transition state.
a
1
Reactions run in vial. Yields estimated by H NMR using diethyl
b
c
d
phthalate as internal reference. No Au used. 4 Å MS added. H2O (4
equiv relative to 1a) added.
The byproduct of this process, i.e., Y+, might then activate the
electron-withdrawing acyl group of C, thereby further polarizing
its C−C triple bond. As such, the C(sp) β to Au might possess
significant nucleophilicity, as reflected in the allenylidene
mesoisomer D′7 and could react with an electrophile to render
a fully functionalized gold vinylidene E. Intramolecular C−H
insertions by this likely reactive species would afford the
functionalized cyclopentenone 2. Alternatively, C might react
with electrophiles to arrive via F, at E or the Au-coordinated
electrophile-substituted alkynone 3.
We set out to probe the validity of our design by using the
alkynone 1a-H (Y = H) as the substrate and NBS as the
electrophilic source (Table 1). 1a-H bears an α′-quaternary
carbon center, which should facilitate the desired intramolecular
C−H insertion due to the Thorpe−Ingold effect. While only
trace amount of the desired products 2a/2a′ were detected in the
presence of Au catalysts with phosphine ligands such as Ph3P,
BrettPhos, and Mor-DalPhos at 80 °C, much to our delight, it
was formed in an encouraging 5% yield along with trace amount
of the bromoalkyne 1a-Br when the N-heterocyclic carbene IPr
The diastereoselectivity and regioselectivity of this reaction
were then interrogated. While the reaction of the α′-methyl
ynone 1i displays synthetically useful preference (dr = 4/1)
toward the trans-isomer (entry 8), replacing its n-butyl group
with an isopropyl group in 1j, as expected, substantially improved
the diastereoselectivity (entry 9). On the other hand, a
B
DOI: 10.1021/jacs.6b04297
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Journal of the American Chemical Society
Communication
a
Table 2. Scope of Au-Catalyzed Cyclopentenone Synthesis
a
b
Typical reaction conditions: 1 (0.05 M in DCM), IPrAuCl (5 mol%), AgSbF6 (10 mol%), NBA (1.5 equiv), rt, 7 h. Structures of side products are
c
d
shown in ref 11. Conditions: 1 (0.05 M in DCM), IPrAuCl (10 mol%), AgSbF6 (20 mol%), NBA (3 equiv), rt, 24 h. Conditions: 1 (0.05 M in
DCM), IPrAuCl (7.5 mol%), AgSbF6 (15 mol%), NBA (2 equiv), rt, 7 h.
TBDPSOCH2 group in 1k led to significant amount of insertion
into methyl C−H bonds (entry 10), which is consistent with the
retarding effect of electron-withdrawing groups, while the
diastereoselectivity of the major product 2k remained serviceable
and the combined yield is good. When the methyl group of 1k is
replaced by a propyl group (1l), the regioselectivity now favors
insertion into the nonfunctionalized alkyl chain by a ratio of 4/1,
highlighting the useful control of regiochemistry by subtle
electronic difference (entry 11). In the same vein, the C−H
bonds at the allylic position of an α,β-unsaturated ester 1m is
largely deactivated for the intended insertion, and only the
insertion into the n-propyl en route to 2m was observed (entry
12). Finally, the ynone 1n with two electronically similar but
sterically different alkyl chains was subjected to the reaction
conditions. The reaction is highly efficient, but with a
regioselectivity of 1.5/1 favoring insertion into the sterically
more hindered methylene group (entry 13). This surprising
outcome reflects the insensitive nature of the gold vinylidene
toward steric hindrance due to its linear structure, and the slight
preference for 2n is consistent with that electronically an α-
isopropyl group is better accommodating the development of
partial positive charge than an α-methyl group.
The synthetic utility of this Au catalysis is further
demonstrated by insertions into carbocycles of varying sizes/
C
DOI: 10.1021/jacs.6b04297
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Journal of the American Chemical Society
Communication
temperature and most important, owing to the modulation by
Au, enables C−H insertion with good regio- and diastereo-
selectivities. In addition, this work demonstrates an unprece-
dented intermolecular strategy to access functionalized gold
vinylidenes, which enables valuable flexibility in exploring their
versatile synthetic utility.
Table 3. Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b04297.
■
S
Experimental details and data (PDF)
a
1
Reactions run in vial. Yields estimated by H NMR using diethyl
AUTHOR INFORMATION
Corresponding Author
*zhang@chem.ucsb.edu
■
phthalate as internal reference.
types (entries 14−22) including a strained cyclobutane (entry
14). These reactions are highly efficient, with yield up to an
outstanding 93% and, moreover, display excellent diastereo-
selectivities of cis-ring fusion in the bicyclic products including
the cyclohexane-fused ones 2r−2t and the cycloheptane-fused
one 2u. In the reactions of cyclopentane and cyclohexane
substrates, the Thorpe−Ingold effect does lead to improved
yields, with the latter more significant (comparing entries 17 and
18). This reaction also worked with 1-adamantyl ketone 1v, and
the adamantane-fused 2-bromocyclopentenone 2v is isolated in a
good 79% yield. Using dithiane Umpolung strategy, TBDPSO-
substituted cyclohexyl ynone diastereomers 1w and 1x were
facilely synthesized in four steps from cyclohexenone and ((1,3-
dithian-2-yl)ethynyl)trimethylsilane and separated pure. Due to
the steric and electronic deactivating effect of TBDPSO group,
high regioselectivities were achieved in both cases, and
synthetically versatile 2w and 2x were isolated in good yields.
To offer mechanistic support to our initial design, we
synthesized the alkynylgold complex 1e-Au and treated it with
NBA (Table 3). The consumption of 1e-Au took 36 h. To our
surprise, the desired product 2e was not detected. Instead, the
bromoalkynone 1e-Br was isolated in 70% yield. As
bromoalkynones are not the reaction intermediate en route to
the 2-bromocyclopentenones (see Table 1, entry 10), this
outcome suggests a critical role of the in situ-generated TMS+/
H+ and/or excess AgSbF6. Indeed, the desired vinylidene
insertion could be resurrected when AgSbF6 (entries 2 and 4)
or TMSOTf (entry 5) was added, albeit with lower yields. These
results confirmed the intermediacy of 1e-Au. In all the cases, 1e-
Br was formed immediately but subsequently decomposed
during the reaction. It is plausible that these acidic additives
might play the role of activating NBA to make its bromine more
electrophilic. To test this hypothesis, we replaced NBA with
more reactive NBS. 1e-Au was consumed in only 50 min by NBS
(entry 6), but to our surprise, only 1e-Br was formed. This result
does not support the role of the acidic species in activating NBA
but is consistent with the mechanism outlined in Scheme 1c,
where the gold ynone intermediate C is instead activated by
acidic Y+ and undergoes the formation of gold vinylidene E via
the allenylidene species D′.7 It is noteworthy that bromoalkynes
are formed in the absence of the carbonyl group.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank NSF (CHE-1301343) for financial support.
■
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(11) Side products are
In summary, we have developed the first metal-catalyzed
alkynone cyclization, which enables facile access to synthetically
highly versatile functionalized cyclopentenones. While non-
catalytic reactions involving reactive vinylidene intermediates,
typically lead to poor selectivities, the Au catalysis developed here
permits the use of readily available substrates at ambient
D
DOI: 10.1021/jacs.6b04297
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX