Synthesis of Cyclopentenones with Reverse Pauson-Khand Regiocontrol via Ni-Catalyzed C-C Activation of Cyclopropanone

Article abstract of DOI:10.1021/acs.orglett.0c03246

A formal [3 + 2] cycloaddition between cyclopropanone and alkynes via Ni-catalyzed C-C bond activation has been developed, where 1-sulfonylcyclopropanols are employed as key precursors of cyclopropanone in the presence of trimethylaluminum. The transformation provides access to 2,3-disubstituted cyclopentenones with complete regiocontrol, favoring reverse Pauson-Khand products, where the large substituent is located at the 3-position of the ring. In the process, the trimethylaluminum additive is thought to play multiple roles, including as a Br?nsted base triggering the equilibration to cyclopropanone and liberation of methane, as well as a source of Lewis acid to activate the carbonyl group toward Ni-catalyzed C-C activation.

Full text of DOI:10.1021/acs.orglett.0c03246

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Letter
Synthesis of Cyclopentenones with Reverse Pauson−Khand
Regiocontrol via Ni-Catalyzed C−C Activation of Cyclopropanone
Yujin Jang and Vincent N. G. Lindsay*
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ABSTRACT: A formal [3 + 2] cycloaddition between cyclopropanone and alkynes via Ni-catalyzed C−C bond activation has been
developed, where 1-sulfonylcyclopropanols are employed as key precursors of cyclopropanone in the presence of
trimethylaluminum. The transformation provides access to 2,3-disubstituted cyclopentenones with complete regiocontrol, favoring
reverse Pauson−Khand products, where the large substituent is located at the 3-position of the ring. In the process, the
trimethylaluminum additive is thought to play multiple roles, including as a Brønsted base triggering the equilibration to
cyclopropanone and liberation of methane, as well as a source of Lewis acid to activate the carbonyl group toward Ni-catalyzed C−C
activation.
disubstituted cyclohexenone derivatives (Scheme 1a).9a
A
ransition metal-catalyzed C−C bond activation of strained
Torganic compounds constitutes an elegant and syntheti- distinct approach was disclosed by Dong and co-workers,
where a rhodium(I) catalyst was employed to activate the
C(1)−C(2) bond of cyclobutanone via direct oxidative addition
(Scheme 1b).10a Despite these considerable advances, the
analogous use of cyclopropanone derivatives for such a process
remains unknown, likely due to the inherent kinetic instability of
these highly strained substrates.2,11 Indeed, while cyclo-
propanone itself can be synthesized by reaction of diazomethane
with ketene at −78 °C followed by distillation at the same
temperature,12 its widespread adoption in organic synthesis has
been precluded by the difficulties associated with its preparation
and storage, as it cannot be isolated in pure form and rapidly
polymerizes at room temperature.
cally valuable approach to the elaboration of complex
molecules.1 In the case of small ring systems, the inherent strain
energy2 of the substrate plays a key role as a driving force to
facilitate the C−C activation process. Such a bond-cleaving
event is typically achieved via two distinct mechanistic pathways
depending on the reaction conditions and specific substrates
used, the first of which involves the direct oxidative addition of
one of the C−C bonds of the ring to an electron-rich transition
metal complex.1a Alternatively, a β-carbon elimination of an O-
bound cycloalkanol-metal complex, as commonly encountered
in metal-homoenolate chemistry when starting from cyclo-
propanols,3 is also possible and leads to ring-opened carbonyl-
containing nucleophilic species capable of further reactivity.1g,4
The catalytic formation of organometallic intermediates
resulting from such C−C bond activation has found widespread
use in the development of ring-expansion methodologies,
typically by reaction with π-systems such as alkenes, alkynes,
and arenes.1 In the past decades, numerous strained ring systems
such as vinylcyclopropanes,5 alkylidenecyclopropanes,6 cyclo-
propenes,7 and cyclobutanes1g,8 have been extensively studied in
this regard. Mainly owing to the work of the Murakami9 and
Dong10 groups, strained ketones such as cyclobutanones have
recently emerged as particularly versatile substrates for such
formal cycloadditions to afford ring-enlarged cyclic ketones with
defined substitution patterns. Specifically, Murakami and co-
workers reported a nickel(0)-catalyzed formal cycloaddition of
cyclobutanones and alkynes via an oxidative cyclization/β-
carbon elimination pathway, eventually leading to 2,3-
As a result, the vast majority of disconnections involving
cyclopropanone building blocks utilize synthetic equivalents
such as their ketal or hemiketal forms to generate the
corresponding ketone in situ via α-elimination (e.g., 1), though
these unstable precursors typically require harsh conditions to
react, often leading to low yields of desired product.11d,13
Moreover, these same cyclopropanone equivalents are more
commonly known to competitively equilibrate to β-nucleophilic
esters in basic conditions,3,14 thus often reacting more like
Received: September 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03246
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Scheme 1. Formal Cycloadditions of Strained Rings with
Alkynes
Table 1. Optimization of the Formal Cycloaddition Using
Substrate 2a
a
entry
deviation from initial conditions
yield (%)
1
2
3
4
none
21
23
<5
<5
<5
35
40
42
Ni(cod)(DQ) instead of Ni(cod)2
AlMe2Cl instead of AlMe3
without AlMe3
without Ni(cod)2
NiBr2/Zn0 (10 mol % each) instead of Ni(cod)2
NiBr2/Zn0 (20 mol % each) instead of Ni(cod)2
NiBr2/Zn0 (20 mol % each) instead of Ni(cod)2
NiBr2/Zn0 (30 mol % each) instead of Ni(cod)2
NiBr2/Zn0 (30 mol % each) instead of Ni(cod)2
NiBr2/Zn0 (30 mol % each), CuBr2 (3 mol %)
NiBr2/Zn0 (30 mol % each), CuBr2 (3 mol %)
Ni(cod)2 (30 mol %), CuBr2 (3 mol %)
no Ni cat, CuBr2 (5 mol %), Zn0 (30 mol %)
5
b
6
b
7
8
bc
,
bc
,
d
9
46
c e
,
10
11
12
13
14
29
e f
,
dg
,
48
15
6
e fh
, ,
f
c
<5
a
Yield determined by 1H NMR using 1,3,5-trimethoxybenzene as
b
c
standard unless otherwise noted. NiBr2 (98% pure) was used. The
reaction was run for 5 h. Displayed yields are the average of three
d
cyclopropanols rather than cyclopropanones. For example,
Crimmins and co-workers reported a formal [3 + 2] cyclo-
addition of silyl ethyl ketal 1 with acetylenic esters in the
presence of ZnCl2, leading to 2-carbalkoxycyclopentenones via
zinc-homoenolate formation and conjugate addition chemistry
(Scheme 1c).15 Due to the absence of robust precursors capable
of smoothly equilibrating to cyclopropanone in mild conditions,
a number of potential disconnections including the transition-
metal-catalyzed C−C activation of cyclopropanones are still
inaccessible. Recently, our group reported the synthesis of a
variety of crystalline 1-sulfonylcyclopropanols 2 and their
application as stable yet highly reactive and modular precursors
of cyclopropanones in basic conditions.16,17 With these
substrates in hand, we hypothesized that such well-behaved
precursors might be key to unlock the C−C activation chemistry
of cyclopropanones. Herein, we report a nickel-catalyzed formal
[3 + 2] cycloaddition of cyclopropanone and internal alkynes
using 1-sulfonylcyclopropanols as precursors in the presence of
trimethylaluminum, leading to a variety of 2,3-disubstituted
cyclopentenones (Scheme 1d). Notably, the products formed
are analogous to the ones obtained in the classical Pauson−
Khand reaction18 but with reverse regiocontrol, with the largest
substituent located at C(3), consistent with an oxidative
cyclization/β-carbon elimination mechanism. Considering the
relevance of substituted cyclopentenones as building blocks in
numerous organic transformations,19 this reaction should find
utility in the elaboration of biologically relevant molecules.
To evaluate the viability of the proposed formal cycloaddition,
1-phenylsulfonylcyclopropanol 2a was elected as a model
substrate and initially subjected to Murakami’s conditions in
the presence of excess 1-phenylpropyne 3a, Ni(cod)2, and PCy3
in toluene at 100 °C.9a,20 Unfortunately, the desired 2,3-
disubstituted cyclopentenone was not observed, and most of the
starting materials were recovered under these conditions.
Evaluation of various reagents that could potentially promote
cyclopropanone formation without negatively interfering in the
catalysis identified trimethylaluminum as a key additive,21
leading to cyclopentenone 4a in 21% yield as a single
regioisomer when the reaction was run at room temperature
without added ligand (Table 1, entries 1 and 2).22 As the role of
e
f
runs. NiBr2 (99.9% pure) was used. The reaction was run for 7 h.
g
h
Isolated yield = 43%. Alkyne 3a was used as limiting reagent with 2
equiv of 2a.
the trimethylaluminum remained unclear at that point, several
Lewis acids such as TiCl4, SnCl4, BF3·OEt2, and organometallic
reagents analogous to AlMe3 such as Et2Zn were also evaluated,
but none afforded the cyclopentenone product.20 Performing
the reaction in the absence of this additive or with AlMe2Cl21
instead led to no detectable yield of product, presumably due to
the absence of base capable of triggering equilibration of 2a
toward cyclopropanone (entries 3 and 4). Notably, either
increasing or decreasing the temperature was detrimental to the
reaction efficiency, as we observed trimerization of the alkyne
substrate and decomposition of both the 1-sulfonylcyclopropa-
nol 2a and cyclopentenone 4a when performing the reaction at
50 °C.20 Although the presence of a Ni(0) catalyst proved
essential to the desired reactivity (entry 5), the transformation
was found to be more efficient when such a species was
generated in situ from NiBr2 and Zn(0), with an optimal loading
of 30 mol % each (entries 6−9). Interestingly, we serendip-
itously found that the efficiency of the reaction was significantly
reduced when it was carried out with 99.9% pure NiBr2 rather
than 98% pure (entry 10). A survey of various metal bromide
salts suspected to act as beneficial impurities in the 98% pure
NiBr2 was thus performed, identifying CuBr2 as a competent
catalytic additive (entry 11). Although its exact mechanistic role
in the transformation remains unknown, omission of NiBr2 from
the reaction conditions or replacing it with Ni(cod)2 led to little
to no product formation (entries 13 and 14), confirming that
CuBr2 alone does not act as a competent catalyst in the formal
cycloaddition.
Submission of various other internal alkynes 3a−m to these
optimized conditions in the presence of cyclopropanone
precursor 2a afforded a number of sterically and electronically
distinct 2,3-disubstituted cyclopentenones, with complete
regiocontrol in all cases (Scheme 2). Substitution at the ortho,
meta, or para positions of 1-arylpropynes was found to be
tolerated, with considerable variability with regard to the
B
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a
Scheme 2. Scope of Accessible 2,3-Disubstituted
Cyclopentenones
Scheme 3. Effect of the Cyclopropanone Precursor Used
a
a
Yield determined by 1H NMR using 1,3,5-trimethoxybenzene as
b
standard unless otherwise noted. Isolated yield in parentheses.
c
Displayed yields are the average of three runs.
A plausible mechanism for the developed formal [3 + 2]
cycloaddition is shown in Scheme 4. Considering precedents in
a
All yields correspond to yields of isolated product on 0.25 mmol
b
scale of 2a unless otherwise noted. Displayed yields are the average
c
of three runs. Isolated yield on 1 mmol scale of 2a in parentheses.
d
Scheme 4. Postulated Mechanism for the Ni-Catalyzed
Formal [3 + 2] Cycloaddition of Cyclopropanone and
Alkynes
Displayed yields are the average of two runs.
electronics of the arene moiety (4a−g). Importantly, both
symmetrical dialkyl- and diarylacetylenes were shown to be
compatible in the reaction (4h,i), as well as a 3-indolyl-
substituted alkyne (4j). Moreover, unsymmetrical alkynes 3k
and 3l allowed further investigation of the origin of the
regioselectivity observed, affording in both cases a single isomer
with the most sterically hindered group (Cy and t-Bu,
respectively) at C(3). Interestingly, such a selectivity could be
fully reversed when using an electronically biased alkyne such as
TMS-substituted 3m, which has previously been observed in
analogous systems (4m).9f It should be noted that even after
extensive investigation, the use of 2-substituted chiral cyclo-
propanone precursors was found to be incompatible in the
reaction (not shown),16a thus precluding the use of this method
for the direct production of chiral cyclopentenones. Although
the yields observed for 4a−m remain modest due to significant
cyclopropanone oligomerization, the elaboration of such 2,3-
disubstituted cyclopentenones in a regiocontrolled manner
typically requires multiple synthetic steps,19 which can be
streamlined here in a single step using a novel synthetic
disconnection, starting from a readily accessible stable and
crystalline precursor (2a).
Compared with the analogous formal [4 + 2] cycloaddition of
cyclobutanones,9,10 an additional challenge in the developed
reaction consists of controlling the initial equilibrium leading to
cyclopropanone as the effective substrate. Indeed, its concen-
tration must remain low at all times in order to avoid undesired
oligomerization, a common decomposition pathway in cyclo-
propanone chemistry.11 To further investigate the modular
character of 1-sulfonylcyclopropanols as cyclopropanone
equivalents16a and to compare their reactivity with more
established precursors,11d we also deemed it valuable to evaluate
other substrates with different leaving groups at C(1) (Scheme
3). Interestingly, whereas all sulfonylcyclopropanols 2a−e
evaluated led to cyclopentenone 4a with varying efficiency, the
classical precursor 1′ did not afford any product in our reaction
conditions, again highlighting the poor reactivity and generality
of such an unstable and volatile hemiketal as cyclopropanone
equivalent.
the literature for the Ni-catalyzed C−C activation of strained
ketones1,9 as well as the complete regiocontrol observed in our
reaction, a direct oxidative addition of the ring to a Ni(0)
catalyst, as commonly seen with Rh(I) catalysts, was quickly
ruled out as the effective mechanism. Thus, it is proposed that
following reduction of NiBr2 and AlMe3-mediated formation of
cyclopropanone, oxidative cyclization can occur, leading to the
corresponding oxanickelacyclopentene, which undergoes β-
carbon elimination and reductive elimination. In the process, the
aluminum salt (RSO2AlMe2) liberated in the first step likely
activates cyclopropanone toward the subsequent oxidative
cyclization by enhancing the π-coordination effect of the
carbonyl group toward the Ni(0) metal center, in analogy to
Ogoshi’s Ni-catalyzed formal cycloaddition of cyclopropylke-
tones and alkynes.21
Although this mechanism is consistent with analogous
literature precedents,9a,21 it is also known that Ni(II)-
homoenolates can be generated from cyclopropanols in the
presence of Zn(II) salts.23 Thus, a mechanism akin to the one
observed by Crimmins (see Scheme 1c), involving a
carbometalation of the alkyne followed by Claisen-type
condensation, must also be considered. Indeed, substrate 2a is
C
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also technically a cyclopropanol derivative, and its direct
equilibration to a metal-homoenolate species is a reasonable
consideration. However, different observations led us to discard
this hypothesis, including the fact that the reaction was shown to
be productive with Ni(cod)2 in the absence of zinc salts (see
Table 1, entry 1), which are conditions unlikely to generate
metal-homoenolates.3 Moreover, the observed regioselectivity
of the transformation is inconsistent with such a mechanism, as
it was previously shown that metal-homoenolates typically react
with alkynes such as 3a with opposite selectivity,24 generating a
more stable 1-arylalkenyl-metal intermediate following carbo-
metalation.25
In summary, we describe the first formal [3 + 2] cycloaddition
of cyclopropanone and alkynes, providing access to 2,3-
disubstituted cyclopentenones with complete regiocontrol,
favoring products with reverse Pauson−Khand selectivity.26
To the best of our knowledge, this work constitutes the only
example of a Ni-catalyzed C−C activation of cyclopropanone,
where the use of 1-sulfonylcyclopropanols as well-behaved
cyclopropanone precursors was found to be essential to achieve
the desired reactivity. A key trimethylaluminum additive is
thought to play multiple roles in the process, including as a
Brønsted base triggering the equilibration to cyclopropanone as
well as a source of Lewis acid to activate the cyclopropanone
toward Ni-catalyzed C−C activation via oxidative cyclization
and β-carbon elimination. Considering the relevance of
transition-metal-catalyzed C−C activation in the elaboration
of complex scaffolds1 and the ubiquity of substituted cyclo-
pentenones in organic synthesis,19 this work should find broad
utility in the construction of biologically relevant molecules.
to NC State University for a Burroughs Wellcome Fellowship in
Organic Chemistry.
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ASSOCIATED CONTENT
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Experimental details and spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Vincent N. G. Lindsay − Department of Chemistry, North
Carolina State University, Raleigh, North Carolina 27695,
United States; orcid.org/0000-0002-7126-325X;
Email: vlindsa@ncsu.edu
Author
Yujin Jang − Department of Chemistry, North Carolina State
University, Raleigh, North Carolina 27695, United States
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by North Carolina State University
startup funds. All Nuclear Magnetic Resonance (NMR) and
High Resolution Mass Spectrometry (HRMS) measurements
were performed by the Molecular Education, Technology, and
Research Innovation Center (METRIC) at NC State University,
which is supported by the State of North Carolina. Y.J. is grateful
D
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E
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