Stereoselective one-pot synthesis of highly differently substituted thiochromans

Article abstract of DOI:10.1016/j.tetlet.2009.09.009

A highly stereoselective one-pot procedure to anti-configured thiochromans is described. This reaction functions at room temperature in the presence of catalytic amounts of trifluoroacetic acid. The transformation gives a selective but optional access to

Full text of DOI:10.1016/j.tetlet.2009.09.009

Tetrahedron Letters 50 (2009) 6466–6468
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Tetrahedron Letters
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Stereoselective one-pot synthesis of highly differently substituted thiochromans
Andrea Seifert, Rainer Mahrwald *
Institute of Chemistry, Humboldt-University Berlin, Brook-Taylor Str. 2, 12489 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2009
Revised 26 August 2009
Accepted 1 September 2009
Available online 6 September 2009
A highly stereoselective one-pot procedure to anti-configured thiochromans is described. This reaction
functions at room temperature in the presence of catalytic amounts of trifluoroacetic acid. The transfor-
mation gives a selective but optional access to highly substituted thiochromans, which have been not
attainable until now.
Ó 2009 Elsevier Ltd. All rights reserved.
Different substituted thiochromans are of considerable interest
because many of them possess important biological activities.
LiClO
4
in C–C bond formation processes of alcohols19 we also
1
tested thiols in these reactions. By the deployment of thiophenols
we observed a highly stereoselective formation of thiochromans in
the presence of catalytic amounts of carboxylic acids (Scheme 1).
In order to test the scope and limitation of this transformation
we started systematic investigations of the model reaction of
Scheme 1. The reactions were carried out at room temperature
for 12 h. First, we examined the influence of additives in these
reactions. Several other lithium salts (LiCl, LiBr, LiJ) and metal per-
Moreover, there are several thiochromans that are active in the
2
treatment of lipoxygenase-mediated disorders, functional gastro-
3
intestinal disorders (e.g., functional dyspepsia), irritable bowel
4
syndrome (IBS), and in the therapeutic treatment of neurological
5
disorders. They proved to be sufficiently high estrogen pure
6
antagonist through oral administration, acetyl cholinesterase
inhibitors (approved in 2000 for the treatment of Alzheimer dis-
ease), and dopamine D3 receptor-selective agonists.8 Thiochro-
mans inhibit the HIV-1 replication in H9 lymphocytes.9
7
chlorates (NaClO
not be detected for any of these additives. However, a reaction oc-
curs in the presence of LiClO . This result underlines once again the
exceptional position of LiClO
4 4 4 2
, KClO , Mg(ClO ) ) were tested. A reaction could
For the synthesis of thiochromans (4-thioaryl-2,3,4-trihydro-1-
benzothiopyran) several general methods are known. The classical
approach is the thio-Claisen rearrangement of the corresponding
4
2
0
4
as an additive. Also, several Bron-
sted acids were explored with regard to their utility in these reac-
tions. Trifluoroacetic acid (10 mol %) proved to be the optimal
1
0
allyl phenyl sulfides. An access to more substituted thiochromans
can be achieved by an intramolecular electrophilic aromatic substi-
tution of corresponding aryl thioethers.11 This transformation was
extended to a one-pot procedure involving the generation of the
starting aryl thioethers. This implies a 1,4-addition of arylthiols
to a conjugated system, followed by an electrophilic cyclization
of a carbenium intermediate in the presence of Bronsted or Lewis
2
1
catalyst among other acids we tested.
Under optimized reaction conditions, the results are as fol-
lows:Thiochromans 2a–e were isolated in moderate yields when
used with aldehydes. The yields were increased considerably by
deployment of trioxanes—stable and more reactive intermediates
of the corresponding aldehydes. The results of this series are
shown in Table 1. Thiochromans 2a–e were isolated with excep-
tionally high anti-selectivities (with the exception of 2c).
1
2
acids. Also, asymmetric and organocatalytic Michael-aldol pro-
cesses based on the use of 2-mercaptobenzaldehyde were devel-
oped.
a
,b-Unsaturated carbonyl compounds were treated with 2-
Next, we explored cross-coupling reactions. We conducted dif-
ferent trioxanes of enolizable aldehydes under the reaction condi-
tions described above. The corresponding thiochromans 2e–g were
isolated in moderate to good yields (Table 2). As before, extremely
mercaptobenzaldehyde in the presence of several different chiral
organocatalysts. These transformations were carried out with
13
14
15
a,b-unsaturated aldehydes, enones, nitro olefins, unsaturated
1
6
17
18
imides, maleinimides, and benzylidenemalonates. Based on
these reactions, the desired construction of different substituted
quaternary carbon centers at C3 is not possible.
In this Letter we describe a catalytic and stereoselective one-pot
procedure that overcomes this void for the synthesis of C3-substi-
tuted thiochromans. During our ongoing studies on the use of
Ph
S
r.t.
CHO
2a: yield: 35%
de: 100%
+
Ph - SH
S
iPr
*
Corresponding author.
E-mail address: rainer.mahrwald@rz.hu-berlin.de (R. Mahrwald).
Scheme 1. Aldol/cyclization reaction to thiochromans. Reaction conditions:
100 mol % LiClO , 1 mol % CF CO H.
4
3
2
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.009

A. Seifert, R. Mahrwald / Tetrahedron Letters 50 (2009) 6466–6468
6467
Table 1
Although a detailed reaction mechanism remains ambiguous,
the following multistep sequence can be assumed: an aldol addi-
tion of enolizable aldehydes in the presence of thiophenol, fol-
lowed by an electrophilic cyclization of a cationic species. These
considerations are supported by experiments of isolated b-hydrox-
yaldehydes with thiophenol in the presence of catalytic amounts of
trifluoroacetic acid. In these reactions we obtained the correspond-
ing thiochromans in high yields and stereoselectivities. Further
investigations of reaction mechanism and enantioselective execu-
tion of this reaction are underway.
a
Homo-aldol coupling/cyclization of thiochromans 2a–d
Ph
1
S
R
R3
R2
R1
r.t.
O
O
+
R1
Ph - SH
R1
O
S
1
a-d
2a-d
Yield (%)
Entry
Compound
2a: R1–iPr, R2 = R3–Me
2b: R1–Cy, R2 = R3–C
2c: R –(CH)
Anti/synb
1
2
3
4
61
39
48
27
100/0
100/0
75/25
Acknowledgments
5
H
10
1
2
3
c
2
Ph, R –Ph–CH
2
, R –H
1
2
3
2d: R –Me, R = R –H
100/0
The authors thank Deutsche Forschungsgemeinschaft, Bayer-
Schering Pharma AG, Bayer Services GmbH, BASF AG, and Sasol
GmbH for financial support. P. Neubauer and B. Ziemer are grate-
fully acknowledged for single-crystal X-ray structure analyses.
a
Reaction conditions: 100 mol % LiClO
Configurations of thiochromans were determined by a combination of single-
4
, 1 mol % CF
3 2
CO H.
b
crystal X-ray analysis, NMR correlations, NOE experiments and reasonable analogy;
see Supplementary data.
c
For determination of this ratio, see Supplementary data.
Supplementary data
General procedures for the synthesis of thiocromans and char-
acterizations of all reaction products are available. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2009.09.009.
Table 2
a
Cross-coupling/cyclization reactions
Ph
S
R1
iPr
r.t.
References and notes
O
O
O
O
+
+
Ph - SH
1
1
iPr
O
iPr
R
O
R
S
R
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8
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1
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by previously known methods.
3
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Ph
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4
21. For results of this optimization-work see Supplementary data.
4