One-pot synthesis of keto thioethers by palladium/gold-catalyzed click and pinacol reactions

Article abstract of DOI:10.1021/ol502553p

An atom-efficient synthesis of keto thioethers was devised via tandem gold/palladium catalysis. The reaction proceeds through a regioselective thiol attack at the β-position of the alcohol, followed by an alkyl, aryl, or benzyl 1,2-shift. Both acyclic and cyclic systems were studied, in the latter case leading to the ring expansion of cyclic substrates.

Full text of DOI:10.1021/ol502553p

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of Keto Thioethers by Palladium/Gold-Catalyzed
Click and Pinacol Reactions
Alban Cadu,† Rahul A. Watile,† Srijit Biswas,† Andreas Orthaber,‡ Per J. R. Sjoberg,†
̈
and Joseph S. M. Samec*,†
†Department of Chemistry-BMC, Uppsala University, Box 576, SE-75123 Uppsala, Sweden
‡Department of Chemistry-Ångstrom, Uppsala University, Box 523, SE-75123 Uppsala, Sweden
̈
S
* Supporting Information
ABSTRACT: An atom-efficient synthesis of keto thioethers was
devised via tandem gold/palladium catalysis. The reaction proceeds
through a regioselective thiol attack at the β-position of the alcohol,
followed by an alkyl, aryl, or benzyl 1,2-shift. Both acyclic and cyclic
systems were studied, in the latter case leading to the ring expansion of
cyclic substrates.
Scheme 1. Traditional Synthesis of Sulfenylated Carbonyls
he carbon−sulfur bond, which is vital to life, is found in two
Tof the proteinogenic amino acids (Cys and Met). A number
of biologically active compounds and their precursors contain the
α-carbonyl tertiary thioether motif (Figure 1).1 Therefore, the
formation of such bonds are of great value to pharmaceutical and
agrochemical industries.
Efficient synthetic chemistry should rely on catalytic cycles and
strive toward high atom efficiency.5 Recently, novel catalytic
methodologies using gold catalysis have flourished.6 In this
group, AuCl,6k,l CuI,7 and Pd(OAc)2/AuCl systems8 have been
devised to generate secondary thioethers. For terminal alkynes,
palladium was employed in order to promote the addition of the
thiol exclusively to the internal position (Scheme 2).9
A
competing terminal attack was catalyzed by gold in the absence
of the terminal substituent group. Similar systems involving one-
pot gold(I)-catalyzed 1,2-shifts and oxidation of propargylic
alcohols have been developed in Hashmi’s group, leading, when
applicable, to the ring expansion of the substrates.10 The (semi)
Figure 1. Biologically active compounds or precursors containing
tertiary thioether groups.
Scheme 2. This Work: Palladium/Gold-Catalyzed C−S Bond
Formation Followed by a Semipinacol Rearrangement
In this paper, we focus on the synthesis of tertiary sulfenylated
carbonyl compounds. Traditionally, thioethers are synthesized in
several steps from toxic and highly reactive halogenated
compounds with mercury salts, leading to stoichiometric
amounts of toxic waste.2 Alternatively, a sulfenylating agent
can be used, but they require additional synthetic steps and also
generate stoichiometric waste (Scheme 1).3 These wasteful
methods remain prevalent in traditional synthesis, especially for
medicinal applications.4c,e
Received: August 29, 2014
© XXXX American Chemical Society
A
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a
pinacol rearrangement is a well-known reaction, and among its
many uses is the ring expansion of cyclopropyl phenyl sulfites to
form spiro-ketone.11 Recently, the use of the semipinacol
rearrangement in combination with alkyne/ketone metathesis
to synthesize disubstituted furans has been reported.12 The ring
expansions of cyclobutanols and propanols were recently
achieved under photochemical conditions using a dual catalyst
system: Au/Ru or Au/Ir.13
Table 2. Addition and Rearrangement of Acyclic Substrate
On the basis of the system previously developed to operate a
hydride shift in terminal alkynes,8 a brief optimization of the
reaction conditions was performed (Table 1). In all cases, the
a
Table 1. Optimization of the System
b
t1 (°C)
t2 (°C)
solvent
conversion (%)
1
2
3
4
5
6
7
80
80
80
80
80
60
40
80
23
c
MeNO2
MeNO2
MeNO2
1,2-DCE
PhMe
>95
>95
<5
74
23
23
23
23
22
MeNO2
MeNO2
92
57
a
Conditions: alcohol (100 mg, 1 equiv), PhSH (1.5 equiv), Pd(OAc)2
(5 mol %), solvent (1 mL) at t1 °C, overnight, then AuCl (5 mol %),
b
c
at t2 °C overnight. Determined by NMR spectroscopy AuCl and
Pd(OAc)2 added simultaneously.
reactions were run without the need for any additional ligand.
Nitromethane proved to be the optimal solvent. While heating to
80 °C was necessary to perform the thiol addition, room
temperature proved sufficient to promote the alkyl shift (entry
2). The thiol addition was catalyzed faster via AuCl than
Pd(OAc)2, leading to undesirable terminal addition rather than
the desired product (entry 3). Therefore, stepwise addition of the
catalysts was required.
With the reaction conditions optimized, the scope of the
reaction was probed. A number of acyclic substrates were reacted,
giving either good or very good yields (Table 1). Symmetrical
compounds provided the best results (entries 1−4). The
dibenzylic compound yielded 1a in 92% yield, most likely
owing to the benzyl’s electronegativity. Secondary alkyl groups
also migrated smoothly to give products 1b and 1c in very good
yields (entries 2 and 3). A good yield was observed for the di-n-
butyl compound (entry 4), which is gratifying considering the
primary carbon’s lower migrational aptitude compared to a
secondary group. Nonsymmetrical propargylic alcohols were
reacted by this procedure. Overall, the migration of the i-Pr
group proceeded well when competing with linear aliphatic
chains (entries 5−7). An increase in yield of the product from
i‑Pr migration accompanying an increase in chain length of the
nonmigrating linear aliphatic chain was observed. The
combination of a phenyl and an aliphatic group led to good
results (entries 8−10). The aryl group displayed a higher
migrational aptitude than the alkyl groups. However, a diphenylic
substrate yielded a complex product mixture. In order to probe
the electronic effects of the thiophenol, three different
thiophenols were screened (entries 2, 11, and 12), and the
reaction proved to be tolerant of both electron-donating and
-withdrawing groups.
a
Conditions: alcohol (100 mg, 1 equiv), thiol (1.5 equiv), Pd(OAc)2
(5 mol %), MeNO2 (1 mL) at 80 °C, overnight, then AuCl (5 mol %),
at room temperature overnight. Isolated yields. Conversion.
b
c
The methodology was expanded from acyclic to cyclic
substrates. As can be seen in Table 3, the ring expansion was
performed with good to excellent yields in all but one case. The
large difference in yields between 1-ethynylcyclobutanol and 1-
B
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a
Table 3. Ring Expansion of Cyclic Propargylic Alcohols
Scheme 3. Synthesis of D-Ring-Expanded Steroids
a
Conditions: alcohol (100 mg, 1 equiv), PhSH (1.5 equiv), Pd(OAc)2
(5 mol %), MeNO2 (1 mL) at 80 °C, overnight, then AuCl (5 mol %),
b
c
at 80 °C, overnight. Isolated yields. Ratio determined by NMR
spectroscopy.
ethynylcyclopentanol is likely due to the ring stability of the
starting materials (entries 1 and 2). Ring expansion of 1-
ethynylcyclohexanol was attempted, though the stability of the
six-membered ring made an expansion to seven-membered
unfavorable.
Figure 2. X-ray of structure of steroid products 3.a and 3.b. Ellipsoids set
at 50% probability and hydrogen atoms omitted for clarity.
However, another six-membered ring was successfully ring
expanded when the bicyclic norcamphor derivative was
successfully ring expanded from a six-membered to a seven-
membered ring in near quantitative yield (entry 3). The
propensity toward the 1,2 shift was probed through entry 4, as
a 1,3 shift was plausible. However, the four- to six-membered ring
expansion did not occur. Instead, a five-membered ring was
obtained. The alkyne was too distant from the oxygen to have its
usual directing role, which caused an alternate regioselectivity.
The methodology was applied to the biologically active
contraceptive mestranol. The study of D-ring expanded
estrogens are garnering increasing interest, particularly for their
antitumoral and cytostatic activities.14 Therefore, a D-ring
expansion of mestranol was performed using the process
developed above (Scheme 3).
Nitromethane was replaced with 1,2-dichloroethane for
solubility reasons. The reaction proceeded with full conversion
and complete regioselectivity. The stereochemistry of the cycle
was maintained throughout the reaction at the methyl (C20) on
the C13 position (Figure 2). However, the chirality was not
transferred from C17 to C18 in the 1,2-alkyll shift (both
diastereomers were isolated through silica chromatography).
In conclusion, a series of cyclic and acyclic tertiary sulfenylated
ketones were synthesized through a tandem palladium/gold
system in good to excellent yields. The possibilities of this
process were exemplified by the D-ring expansion of an estradiol
to obtain novel homo-D steroids.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectra and crystallographic data.
This material is available free of charge via the Internet at http://
pubs.acs.org. CCDC-1027282 and CCDC-1027283 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
A summary of the data can be found in the Supporting
Information.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: joseph.samec@kemi.uu.se.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Uppsala University, the Wenner-Gren foundation, the
Swedish Institute, Stiftelsen Olle Engkvist Byggmastare, and
■
̈
Vetenskapsradet for financial support as well as Hao Huang
̊
(Uppsala University) for his invaluable help and advice on NMR
analysis.
C
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