Two-Component Assembly of Thiochroman-4-ones and Tetrahydrothiopyran-4-ones Using a Rhodium-Catalyzed Alkyne Hydroacylation/Thio-Conjugate-Addition Sequence

Article abstract of DOI:10.1021/acs.orglett.6b02909

β′-Thio-substituted-enones, assembled from the combination of β-tert-butylthio-substituted aldehydes and alkynes, using rhodium catalysis, are shown to smoothly undergo in situ intramolecular S-conjugate addition to deliver a range of S-heterocycles in a one-pot process. Aryl, alkenyl, and alkyl aldehydes can all be employed, to provide thiochroman-4-ones, hexahydro-4H-thiochromen-4-ones, and tetrahydrothiopyran-4-ones, respectively. A variety of in situ oxidations are also performed, allowing access to S,S-dioxide derivatives, as well as unsaturated variants.

Full text of DOI:10.1021/acs.orglett.6b02909

Letter
pubs.acs.org/OrgLett
Two-Component Assembly of Thiochroman-4-ones and
Tetrahydrothiopyran-4-ones Using a Rhodium-Catalyzed Alkyne
Hydroacylation/Thio-Conjugate-Addition Sequence
Anaïs Bouisseau, John Glancy, and Michael C. Willis*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: β′-Thio-substituted-enones, assembled from the combination of β-tert-butylthio-substituted aldehydes and
alkynes, using rhodium catalysis, are shown to smoothly undergo in situ intramolecular S-conjugate addition to deliver a range of
S-heterocycles in a one-pot process. Aryl, alkenyl, and alkyl aldehydes can all be employed, to provide thiochroman-4-ones,
hexahydro-4H-thiochromen-4-ones, and tetrahydrothiopyran-4-ones, respectively. A variety of in situ oxidations are also
performed, allowing access to S,S-dioxide derivatives, as well as unsaturated variants.
ecent years have seen the emergence of alkene and alkyne
Rhydroacylation reactions as useful methods for the
synthesis of ketones and enones, respectively.1 For metal-
catalyzed variants,2−5 strategies based on the use of some form
of chelation control, with the coordinating group pendant to
the aldehyde6−10 or alkene/alkyne,11 have been shown to
deliver efficient, selective reactions,6c,7b,12,11b,13 with a generally
broad substrate scope. The inherent limitation of a chelation-
controlled approach is that the coordinating substituent, which
is crucial to achieve a successful reaction, is inevitably present in
the product. Approaches to mitigate this situation include
exploiting the coordinating group in subsequent catalyst-
controlled transformations,14 and also incorporating the
group, usually via derivatization, into a target structure. In the
context of this latter strategy, our laboratory demonstrated that
dihydroquinolones could be conveniently prepared from an
alkyne hydroacylation/N-conjugate addition sequence com-
mencing with 2-aminobenzaldehyde substrates.7c More re-
cently, the Stanley group reported the development of a
tandem alkyne hydroacylation/oxa-Michael addition process to
synthesize trans-2,3-disubstituted chroman-4-ones from O-
chelating benzaldehydes (Scheme 1a).15 In this Letter we
show that S-chelating aldehydes can be used to access a variety
of S-heterocycles from related hydroacylation/conjugate
addition sequences (Scheme 1b). A crucial difference with
the present study is that the use of S-chelating aldehydes allows
access to heterocycles of much greater variety than either the
N-or O-based chemistries.
is shown in Scheme 1b and involves chelate-controlled alkyne
hydroacylation followed by an acid triggered thio-conjugate
addition.17 Although encouraging precedent is provided from
our own reports of hydroquinolone synthesis,7c and Stanley’s
chroman-4-one chemistry,15 both of these sequences are
limited to aryl aldehyde substrates, thus constraining the
structural variation accessible in the products. Of the chelating
aldehydes that have been reported, S-substituted examples
allow arguably the most structural variation with alkyl,8a
alkenyl,12c aryl,8c and heteroaryl18 derivatives all being
competent substrates. We reasoned that exploiting this feature
of S-chelation control would allow access to not only
thiochromanones but also the related saturated and partially
saturated derivatives.
Our general approach requires aldehyde substrates bearing a
sulfide substituent that would ideally be cleaved under the
cyclization conditions. Given the proposed acid mediated
cyclization (i.e., I → II → III, Scheme 1b) we settled on the use
of t-Bu-sulfides.19 Although β-t-Bu-S-substituted aldehydes have
never been previously reported as substrates for alkene or
alkyne hydroacylation, we were pleased to find that the use of
established reaction conditions, developed mainly for β-Me-S-
substituted variants, led to efficient hydroacylation.20 For
example, coupling between 2-tert-butyl-sulfide-substituted
benzaldehyde 1a and 4-tolylacetylene using 5 mol % of
commercially available Rh(nbd)2BF4 and the dcpm ligand in
1,2-dichloroethane at 55 °C resulted in quantitative formation
of the enone product. A short investigation of possible
cyclization conditions established that in situ treatment of the
Thiochromanones and related heterocycles, notably S,S-
dioxide derivatives and unsaturated variants, are present in a
number of medicinally relevant molecules (Scheme 1c),16 and
as such we envisaged a general synthetic route that would allow
access to a broad range of related S-heterocycles. Our approach
Received: September 27, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b02909
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Letter
Scheme 1. Tandem Hydroacylation/Conjugate Addition
Sequences Towards Heterocycles, Together with
Biologically Relevant S-Heterocycles
Scheme 2. Variation of Alkyne Structure in the Formation of
Thio-4-chromanones
a
hydroacylation adduct with excess trifluoroacetic acid (TFA)
resulted in clean conversion to the S-heterocycle.
Scheme 2 shows our exploration of these reaction conditions
using aldehyde 1a in combination with a range of alkyne
substrates (2). The transformation was successfully applied to
phenyl acetylene derivatives bearing a variety of electron-
donating (3a−c) and electron-withdrawing groups (3d−g).
Substituents on the alkyne moiety were tolerated at all
positions of the benzene rings. Notable among those examples
is 3c, which has been reported as a potent antioxidant
displaying high inhibitory activity against nitric oxide
production.16f The tandem reaction was also achieved employ-
ing reactive cyano groups (3g, 3o) and a simple heterocycle
(3h). Alkynes possessing aliphatic chains also afforded
thiochroman-4-ones in excellent yields (3i−o), even when
employing a bulky tert-butyl substituent (3l). Pleasingly, the
tandem process was also found to be applicable on a gram scale
reaction using 4-tolylacetylene, with only 1 mol % of rhodium
catalyst and ligand delivering the final product in comparable
yield.
We next examined the scope of the aldehyde component
(Scheme 3). A variety of 2-(tert-butylthio)benzaldehyde
derivatives (1) were combined with 4-tolylacetylene, delivering
diversely substituted thiochroman-4-ones possessing electron-
donating (3p, 3q, 3u) and electron-withdrawing (3r−u)
functional groups in moderate to excellent yields. The use of
an alkenyl derived S-chelating aldehyde led to thiochromen-4-
one 3v in good yield. Pleasingly, tetrahydrothiopyran-4-ones
could also be accessed (3w−y) with acceptable yields and
diastereoselectivities. The tandem process was also found to be
applicable to internal alkynes, enabling the formation of
tetrahydrothiopyran-4-one 3z featuring three stereogenic
centers. Employing the same internal alkyne in combination
with aromatic aldehyde 1a was also a successful reaction;
a
Reaction conditions: Rh(nbd)2BF4 (5 mol %), dcpm (5 mol %),
aldehyde 1a (1.0 equiv), alkyne (1.05 equiv), DCE (1.0 M), 55 °C, 2
h, then TFA (10.0 equiv), 1 h, rt. K2CO3, MeOH, 16 h, rt, after acid
step. Isolated yields.
b
however, in this case the disubstituted thiochroman-4-one
(3aa) was obtained as an inseparable 1:1.8 mixture of
diastereomers. This level of diastereoselectivity is consistent
with that seen by Stanley for the corresponding chroman-4-one
series.15
Aware that the S,S-dioxide derivatives of thiochromanones
and tetrahydrothiopyranones are of interest as medicinal agents,
we adapted our process to allow access to this class of
compounds directly (Scheme 4). Simply adding an aqueous
solution of hydrogen peroxide at the completion of the
cyclization step resulted in oxidation to the desired sulfone
derivatives. Aryl- and alkyl-substituted thiochromanones (4a,b),
together with an alkyl-substituted tetrahydrothiopyranone (4c),
provided the oxidized products in moderate to good yields.
We developed a further modification of our hydroacylation-
based route to S-heterocycles, whereby addition of N-
chlorosuccinimide (NCS) subsequent to S-conjugate addition
allowed access to thiochromenone and dihydrothiopyran-4-one
derivatives (Scheme 5). Following a report from Chen,21 we
investigated the addition of NCS directly to the reaction
mixtures. However, the excess TFA used to promote the S-
cyclization was incompatible with this approach. The solution
was to remove the excess TFA in vacuo before addition of the
NCS and pyridine to the crude reaction mixture. Using this
B
DOI: 10.1021/acs.orglett.6b02909
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Organic Letters
Letter
Scheme 3. Variation of Aldehyde Structure in the Formation
of Thiochroman-4-ones, Thiochromen-4-ones, and
Tetrahydrothiopyran-4-ones
Scheme 5. NCS-Mediated Formation of Thiochromenones
and Dihydrothiopyranones
a
a
a
Reaction conditions: (i) Rh(nbd)2BF4 (5 mol %), dcpm (5 mol %),
a
Isolated yields of pure diasteromers. Reaction conditions: Rh-
aldehyde (1.0 equiv), alkyne (1.05 equiv), DCE (1.0 M), 55 °C, 2 h;
(ii) TFA (10.0 equiv), 1 h, rt. NCS (1.1 equiv), pyridine (1.1 equiv),
DCE (0.5 M), rt, 2 h. NCS (3.0 equiv), pyridine (3.0 equiv), DCE
(0.5 M), rt, 2 h. Isolated yields.
(nbd)2BF4 (5 mol %), dcpm (5 mol %), aldehyde (1.0 equiv), alkyne
b
(1.05 equiv), DCE (1.0 M), 55 °C, 2 h, then TFA (10.0 equiv), 1 h, rt.
c
b
d
e
c
Rh(nbd)2BF4 and dcpm (both 7.5 mol %). alkyne (1.2 equiv).
Crude dr values: 3w: 15:1, 3x: 19:1, 3y: 17:1, 3z: 11.5:2.1:1.5:1.0.
f
Product contains traces of the minor diastereomer. Rh(nbd)2BF4 and
dppm (both 10.0 mol %), alkyne (1.5 equiv), DCE (1.0 M), 80 °C, 2
g
h. dppm (5 mol %) used in place of dcpm. Isolated as an inseparable
1:1.8 mixture of diastereomers.
In conclusion, we have developed a tandem alkyne
hydroacylation/thio-conjugate addition sequence to synthesize
thiochroman-4-one, hexahydro-4H-thiochromen-4-one, and
tetrahydrothiopyran-4-one derivatives, and their corresponding
sulfones, from readily accessible starting materials. The addition
of NCS and pyridine as a final step in the sequence allowed for
the preparation of thiochromen-4-ones and dihydrothiopyran-
4-ones, as well as their chlorinated derivatives. The key
hydroacylation step exploits β-(t-Bu-S)-substituted aldehydes as
substrates for the first time.
a
Scheme 4. In Situ Preparation of S,S-Dioxide Derivatives
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02909.
a
Reaction conditions: (i) Rh(nbd)2BF4 (5 mol %), dcpm (5 mol %),
aldehyde 1a (1.0 equiv), alkyne (1.05 equiv), DCE (1.0 M), 55 °C, 2
h; (ii) TFA (10.0 equiv), 1 h, rt; (iii) H2O2 (3.0 equiv), rt. Isolated
yields. H2O2 (4.5 equiv). Crude dr 19:1.
b
c
Experimental procedures and full characterization for all
compounds (PDF)
AUTHOR INFORMATION
■
approach we were able to access both thiochromen-4-ones and
dihydrothiopyran-4-ones in good yields after three steps (5a−
d). As suggested by Chen, addition of excess NCS and pyridine
provided the α-chloro adducts (6a−d). It is interesting to note
the selective formation of dihydrothiopyranones 5d and 6d
where oxidation has taken place adjacent to the aryl substituent.
Corresponding Author
*E-mail: michael.willis@chem.ox.ac.uk.
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.6b02909
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Organic Letters
Letter
2011, 13, 3900. (c) Poingdestre, S. J.; Goodacre, J. D.; Weller, A. S.;
Willis, M. C. Chem. Commun. 2012, 48, 6354.
ACKNOWLEDGMENTS
■
The research leading to these results has received funding from
the EPSRC and the People Programme (Marie Curie Actions)
of the European Union’s Seventh Framework Programme
(FP7/2007-2013) under REA Grant Agreement No. 316955.
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