Synthesis of 2-(2-Oxo-2-phenylethyl)cyclopentanone by Rhodium-Catalyzed Tandem Alkynyl Cyclobutanols Hydroacylation and Semipinacol Rearrangement

Article abstract of DOI:10.1021/acs.orglett.8b03973

A rhodium-catalyzed tandem reaction of alkynyl cyclobutanols with salicylaldehydes has been developed. The reaction offers a new and atom-economical approach for the selective preparation of multisubstituted 2-(2-oxo-2-phenylethyl)cyclopentanone in high y

Full text of DOI:10.1021/acs.orglett.8b03973

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 2‑(2-Oxo-2-phenylethyl)cyclopentanone by Rhodium-
Catalyzed Tandem Alkynyl Cyclobutanols Hydroacylation and
Semipinacol Rearrangement
Rui Guo, Xueling Mo, and Guozhu Zhang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular
Synthesis, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R.
China
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed tandem reaction of alkynyl cyclobutanols with salicylaldehydes has been developed. The
reaction offers a new and atom-economical approach for the selective preparation of multisubstituted 2-(2-oxo-2-
phenylethyl)cyclopentanone in high yields under mild reaction conditions with tolerance of a broad range of substituted
alkynyl cyclobutanols and salicylaldehyes. The isolation of intermediate suggests that the reaction proceeds through a sequential
process of intermolecular hydroacylation and semipinacol rearrangement.
he hydroacylation of alkynes with aldehydes is an efficient
Tand atom-economic approach for the synthesis of α,β-
unsaturated ketones.1 Of those, rhodium-catalyzed intermo-
lecular hydroacylation of alkynes with chelating aldehydes is
one of the well-established strategies due to the compatibility
of readily available aldehyde and alkyne as well as its
availability to rapidly generate complicated molecular skeletons
through tandem reactions.2 These cascade processes also have
been exploited in the efficient synthesis of a variety of
heterocyclic ketones and medicinally relevant natural prod-
ucts.3
In 2011, the Willis group achieved the synthesis of highly
substituted furans through a cascade process of intermolecular
hydroacylation and acid-catalyzed dehydrative cyclization.4
Subsequently, they reported a stepwise method to synthesize
dihydroquinolones through tandem rhodium-catalyzed hydro-
acylation of alkynes with 2-aminobenzaldehydes and Lewis
acid catalyzed aza-Michael addition.5 Inspired by the pioneer-
ing work of Miura,6 the Stanley group and Yoshikai group
respectively developed a one-pot tandem process including
alkyne hydroacylation with salicylaldehydes and oxo-Michael
addition to generate chroman-4-ones by using a rhodium or
cobalt catalyst7 (Scheme 1A). Given the capability of rhodium-
catalyzed hydroacylation, development of a novel cascade
process leading to complex molecular skeletons with synthetic
and medicinal potential is still highly desired.
As a kind of privileged building blocks, cyclobutanols are
frequently studied in the field of transition-metal-catalyzed
carbon−carbon bond selective cleavage and reconstruction.8
However, to our knowledge, there are few examples of
combining the unique reactivity of hydroacylation and C−C
bond cleavage of strained rings through ring opening.9 We
recently reported the intermolecular hydroacylation of alkenyl
cyclobutanols with nonchelating aldehydes to afford different
1,5-diketones10 (Scheme 1B). Along with our continuing
interests in this area, we envisioned the possibility of
hydroacylation and transformation of alkynyl cyclobutanols.
Herein, we report a new method for the synthesis of
multisubstituted 2-(2-oxo-2-phenylethyl)cyclopentanone
through hydroacylation of alkynyl cyclobutanols with salicy-
laldehydes followed by semipinacol rearrangement which
represents a useful transformation and has been widely used
in the total synthesis of natural products.11 The resulting 1,4-
diketone motifs have been found widely in natural products
and pharmaceuticals.12 In addition, as a kind of highly useful
synthetic building blocks, 1,4-diketones are frequently being
used to synthesize various heterocyclic and carbocyclic
compounds.13
Received: December 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
increased to 91% by using 1,2-dichloroethane (DCE) as the
solvent and K2CO3 as the base (entries 6−9). Further catalyst
optimization revealed that an excellent yield (94%) of 3a could
be obtained when removing the base and using [Rh(COD)-
OH]2 instead of [Rh(COD)Cl]2 as the catalyst (entries 11).
Several other Rh catalysts were surveyed with no positive
effects for this chemistry (entries 10, 12).
Scheme 1. Rhodium-Catalyzed Intermolecular
Hydroacylation Reactions
With the optimal reaction conditions in hand, we evaluated
the substrate scope of salicylaldehyde 2 with various electronic
and steric properties of substituents. The results are
summarized in Scheme 2. For 3-, 4-, or 5-position substituted
Scheme 2. Substrate Scope with Respect to
a b
,
Salicylaldehydes
At the outset of our investigation, we drew on the experience
of our previous optimal conditions.10 As shown in Table 1,
salicylaldehyde was reacted with 1-ethynyl cyclobutanol in
xylene at 140 °C in the presence of a 2.5 mol % of
[Rh(COD)Cl]2, 5 mol % of K2CO3, and 10 mol % of PPh3
ligand. A low yield (20%) of 1,4-diketons product 3a, which
contains a cyclopentane substructure, is isolated (entry 1).
After preliminary temperature screening, the yield of product
3a could increase to 79% at 70 °C in toluene by extending the
reaction time (entries 2, 3). We also isolated the hydro-
acylation product 4 when the reaction was carried out at room
temperature for 48 hours (entries 4, 5). As was expected,
compound 4 could be converted to 1,4-diketone product 3a
through rearrangement under heating conditions confirming
the cascade hydroacylation and semipinacol rearrangement
occurred. After different combinations of solvent and base
were screened, it was determined the yield could be further
a
Reaction conditions: salicylaldehyde 2 (0.2 mmol), 1a (0.3 mmol),
[Rh(COD)OH]2 (2.5 mol %), PPh3 (10 mol %), DCE (0.2 M) at 70
°C for 12 h, unless noted otherwise. Isolated yield. 3.0 equiv of 1a
were used.
b
c
salicylaldehydes, a variety of electron-poor (3b−3d, 3g−3i,
3k), electron-rich (3e, 3j, 3n), and sterically demanding (3f,
3m) substituents were tolerated to afford the corresponding
Table 1. Evaluation of Reaction Parameters
a
b
b
entry
catalyst
base
solvent
temp (°C)
time (h)
yield 3a (%)
yield 4 (%)
1
2
3
4
5
6
7
8
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
Rh(PPh3)2Cl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
K2CO3
−
xylene
toluene
toluene
toluene
DCE
DCE
THF
DCE
DCE
140
110
70
rt
6
20
47
79
22
35
91
65
86
80
61
94
88
n.d.
n.d.
n.d.
47
12
12
48
48
12
12
12
12
12
12
12
rt
39
70
70
70
70
70
70
70
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
9
10
11
12
DCE
DCE
toluene
[Rh(COD)OH]2
[Rh(COD)OH]2
−
a
Reaction conditions: salicylaldehyde 2a (0.2 mmol), 1-ethynyl cyclobutanol 1a (0.3 mmol), [Rh] catalyst (2.5 mol %), ligand (10 mol %), base (5
b
mol %), solvent (0.2 M), unless noted otherwise. Isolated yield.
B
DOI: 10.1021/acs.orglett.8b03973
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Organic Letters
Letter
1,4-diketones in good to excellent yields. The salicylaldehyde
with a strongly electron-withdrawing and polar nitro group
could react smoothly to provide the product in moderate yield
(3h). It was noteworthy that the allyl group could also be
compatible with this reaction conditions to give the 1,4-
diketone product 3l with the double bond intact. In addition to
phenyl, 1-hydroxyl or 2-hydroxyl substituted naphthaldehyde
also demonstrated good compatibility with current reaction
conditions (30, 3p). Moreover, 4-tert-butyl-2,6-diformylphenol
underwent double hydroacylation and ring expansion success-
fully in the presence of 3.0 equiv of 1a, which fully showed the
practicability of this method (3q).
Scheme 4. Stepwise Method of Hydroacylation and
Rearrangement
acids, as shown in Scheme 4, we found that p-toluenesulfonic
acid (PTSA) could promote the rearrangement reaction
efficiently to give product 3z in 74% yield with moderate
diastereoselectivity (two steps).14
Subsequently, our attention turned to the variation of
ethynyl cyclobutanol with different substituents on the four-
membered ring (Scheme 3). Ethynyl cyclobutanol with various
As shown in Scheme 5, under the optimized stepwise
reaction conditions, salicylaldehyde with different electronic
Scheme 5. Substrate Scope with Respect to Cyclobutanols
and Salicylaldehydes
a c
,
Scheme 3. Substrate Scope with Respect to
Cyclobutanols
a b
,
a
Reaction conditions: salicylaldehyde 2a (0.2 mmol), 1 (0.3 mmol),
[Rh(COD)OH]2 (2.5 mol %), PPh3 (10 mol %) and DCE (0.2 M) at
b
70 °C for 12 h, unless noted otherwise. Isolated yield.
a
The reaction was carried out under standard conditions, unless
b
noted otherwise. Reaction conditions: methyl 3-formyl-4-hydrox-
substitutions, such as phenyl, benzyl ether, sulfur ether, and
ester groups, on the 3-position underwent expected hydro-
acylation and rearrangement to provide the desired 1,4-
diketones in moderate to good yields (3r−3v). 3-Ethynyl-
oxetan-3-ol 1g was a suitable substrate for this transformation
to afford 3w in 74% yield. In addition, ethynyl cyclobutanol 1h
fused with a cyclopentene ring also reacted with salicylalde-
hyde smoothly to provide 3x in moderate yield. It is
remarkable that 1i [(E)-1-ethynyl-2-(4-methoxybenzylidene)-
cyclobutan-1-ol] underwent simultaneous double bond migra-
tion to give more stable unsaturated cyclopentenone product
3y.
We then proceeded to investigate the influence of the
terminal substituent in the ethynyl group on this reaction. As
shown in Scheme 4, 1-(1-propyn-1-yl)cyclobutanol could react
with salicylaldehyde under the standard conditions to produce
a hydroacylation intermediate smoothly. However, simple
heating conditions could not initiate the rearrangement
process. After screening a series of Lewis acids and Bronsted
ybenzoate (0.2 mmol), 1j (0.3 mmol), [Rh(COD)OH]2 (2.5 mol %),
PPh3 (10 mol %) and DCE (0.2 M) at rt for 48 h. Then PTSA (0.5
c
equiv) and DCE (0.2 M) at 40 °C for 6 h. Isolated yield.
substituents could react successfully to afford 1,4-diketone
products in moderate yields (3aa−3ag). The benzyl ether or
fused ring structure of cyclobutanol resulted in a slight
reduction in yield (3ah, 3ai). Notably, The high diaster-
eoisomer ratio of 3ah probably attributed to the steric effect of
benzyl ether. Furthermore, propyl, phenyl ethyl, and
chlorinated alkyl substituted alkynyl cyclobutanols were also
appropriate substrates which reacted successfully under the
same conditions to provide various 2,3- disubstituted 1,4-
diketone products (3aj−3al).
Finally, we carried out several derivatization reactions of 1,4-
diketones (Scheme 6). Compound 3a could be produced at
the gram scale in 82% yield and used to prepare different
heterocyclic molecules. For example, treatment of 3a with
C
DOI: 10.1021/acs.orglett.8b03973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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salicylaldehydes with a broad substrate scope and mild
conditions. This reaction provides a new approach for the
selective preparation of 2-(2-oxo-2-phenylethyl)cyclo-
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ASSOCIATED CONTENT
* Supporting Information
■
S
́
Chem. Soc. 2010, 132, 5340. (g) Alvarez-Bercedo, P.; Flores-Gaspar,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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A.; Correa, A.; Martin, R. J. Am. Chem. Soc. 2010, 132, 466.
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Experimental details and spectral data for new
compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guozhuzhang@sioc.ac.cn.
ORCID
Layton, M. E.; Shair, M. D. J. Am. Chem. Soc. 2000, 122, 12610.
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Guozhu Zhang: 0000-0002-2222-6305
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to NSFC-21421091, 21821002,
XDB20000000, the “Thousand Plan” Youth Program, the
State Key Laboratory of Organometallic Chemistry, the
Shanghai Institute of Organic Chemistry, and the Chinese
Academy of Sciences.
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