Organic Letters
Letter
phosphonium salts like 27−30 is their use for a convenient two-
step homologation of aldehydes to ketones. This general
strategy was identified decades ago by Mukaiyama13,21 and
Corey14b,22 but has been hindered by a lack of access to the
requisite thioalkyl phosphonium salts. Access to these Wittig
salts now enables this broad strategy of versatile ketone synthesis
via Wittig olefination and vinyl sulfide hydrolysis. The hydrolysis
of vinyl sulfides to ketones has been reported under forceful
reaction conditions including refluxing in concentrated acid13 or
in the presence of HgCl214b,23 or TiCl4.21 Relative to enol ethers,
vinyl sulfides are resistant to hydrolysis, and this orthogonality
has been previously exploited in the context of synthetic
strategy.18,24 We briefly explored several milder alternatives and
found that the treatment of vinyl sulfides with TsOH·H2O in
refluxing dichloroethane resulted in hydrolysis to ketones in
good yields. We demonstrated this chemistry with the
preparation of ketones 68−73 from their corresponding vinyl
sulfides (66, Scheme 6).
synthesize aldehydes via the hydrolysis of vinyl sulfides (such as
35−46, Scheme 4). Unlike ketones, enolizable aldehydes do not
survive the acidic reaction conditions required for vinyl sulfide
hydrolysis. Both the Wittig chemistry with ketones and the
hydrolysis of vinyl sulfides to aldehydes are challenges of interest
to our laboratory that we hope to address in the future.
In summary, we have reported a new preparation of thioalkyl
phosphonium salts from sulfoxides with unprecedented ease and
versatility. We used these Wittig salts to make unique vinyl
sulfides via olefination chemistry. The hydrolysis of the vinyl
sulfides to their corresponding ketones demonstrates an efficient
and perhaps strategically valuable approach to ketone synthesis.
ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
Detailed experimental procedures and compound char-
acterization data and NMR spectra of all new compounds
Scheme 6. Hydrolysis of Vinyl Sulfides to Ketones and Two-
Step Homologation on a Multigram Scale
AUTHOR INFORMATION
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Corresponding Author
Jakob Magolan − Department of Chemistry and Chemical
Biology, Department of Biochemistry and Biomedical Sciences,
and M. G. DeGroote Institute for Infectious Disease Research,
McMaster University, Hamilton, Ontario L8S 4L8, Canada;
Authors
Meghan Fragis − Department of Chemistry and Chemical
Biology, McMaster University, Hamilton, Ontario L8S 4L8,
Canada
Jackson L. Deobald − Department of Chemistry, University of
Idaho, Moscow, Idaho 83843, United States
Srinivas Dharavath − Department of Biochemistry and
Biomedical Sciences, McMaster University, Hamilton, Ontario
L8S 4L8, Canada; Present Address: S.D.: Department of
Chemistry, IIT Kanpur, Kanpur, India.
Jeffrey Scott − Department of Chemistry, University of Idaho,
Moscow, Idaho 83843, United States
a
Amount of TsOH·H2O was increased to 3 equiv.
Complete contact information is available at:
Ketones 68, 69, and 70 were prepared from vinyl sulfides 57,
54, and 62 in good yields. Four vinyl sulfides (49−52) that had
been made by olefination of the same aldehyde (4-methyl-3-
nitrobenzaldehyde, 74) were hydrolyzed to their corresponding
methyl-, ethyl-, and propyl-ketones 71−73. This versatility
suggests that the two-step process of olefination followed by
hydrolysis constitutes a general strategic approach to α-aryl
ketones that might be considered complementary to transition-
metal-catalyzed α-arylation chemistry. (See the Supporting
To further demonstrate the practicality of this approach, we
synthesized a 2.68 g batch of ketone 71 via the olefination of 4.06
g of aldehyde 74 with phosphonium salt 29 followed by
hydrolysis of the crude reaction product without chromatog-
raphy. This corresponded to a 56% two-step yield.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This research was supported by an NSERC Discovery Grant
(RGPIN-2018-06438). M.F. was supported by a Canada
Graduate Scholarship (CGS-M). J.L.D. and J.S. received
undergraduate fellowship support from an IDeA award from
the NIGMS (grant no. P20GM103408). We are grateful for
generous contributions to our program from McMaster
University’s Faculty of Health Sciences Dean’s Fund, the
Michael G. DeGroote Institute for Infectious Disease Research,
and the Boris Family.
To date, we have been unable to extend this olefination
chemistry to ketone substrates. In addition, we are unable to
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Org. Lett. 2021, 23, 4548−4552