Diversity-oriented asymmetric catalysis (DOAC): Stereochemically divergent synthesis of thiochromanes using an imidazoline-aminophenol-nickel-catalyzed michael/henry reaction

Article abstract of DOI:10.1021/ol500361w

The (S,S)-diphenylethylenediamine-derived imidazoline-aminophenol-Ni complex catalyzed tandem asymmetric Michael/Henry reaction of 2-mercaptobenzaldehydes with β-nitrostyrenes to give the corresponding (2S,3R,4R)-2-aryl-3-nitrothiochroman-4-ols in up to 9

Full text of DOI:10.1021/ol500361w

Letter
pubs.acs.org/OrgLett
Diversity-Oriented Asymmetric Catalysis (DOAC): Stereochemically
Divergent Synthesis of Thiochromanes Using an Imidazoline−
Aminophenol−Nickel-Catalyzed Michael/Henry Reaction
Takayoshi Arai* and Yushi Yamamoto
Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: The (S,S)-diphenylethylenediamine-derived imidazoline−amino-
phenol−Ni complex catalyzed tandem asymmetric Michael/Henry reaction of 2-
mercaptobenzaldehydes with β-nitrostyrenes to give the corresponding (2S,3R,4R)-
2-aryl-3-nitrothiochroman-4-ols in up to 99% diastereoselectivity with 95% ee was
demonstrated in diversity-oriented asymmetric catalysis. Reduction of the nitro
group of the chiral thiochromanes gave a new series of (2S,3R,4R)-3-amino-2-
arylthiochroman-4-ols with retention of the strereoselectivity.
disease.4 Because the biological activities of such compounds
hromane moieties are often found in various biologically
Csignificant compounds isolated from nature. The bio- are greatly affected by the spatial conformations of the
thiochromane group, significant effort has been devoted to
synthesizing specific thiochromane enantiomers. Both reso-
lution chemistry5 and enantioselective reduction6 have been
applied during the catalytic asymmetric synthesis of thiochro-
manes with the aim of generating products having a
monostereogenic center.7 Considering the significance of the
molecular structure of pharmaceutical compounds, it is vital to
control the isomerism of multiple stereogenic centers when
synthesizing thiochromanes. For this reason, the use of a
tandem, one-pot reaction process that generates multiple σ-
bond represents a promising means of achieving the desired
structural tuning.8
logical activity of these compounds following the replacement
of the oxygen atom in the chromane group with sulfur to form
thiochromanes has been studied with regard to research and
development of pharmaceuticals.1 As an example, the
thiochromane derivative 1 is the sulfur analogue of benzopyr-
anoxazine (PD 128907) and was developed as a dopamine D3
receptor-selective agonist (Figure 1).2 In addition, the anti-
AIDS agent 7-thia-DCK (2) represents an advanced analogue
of the compound suksdorfin, which is isolated from Lomantium
suksdorfii.3 Finally, the conformationally restricted rivastigmine
analogue 3 was designed and synthesized as an acetylcholines-
terase (AChE) inhibitor for the treatment of Alzheimer’s
After reporting the first-ever Michael/aldol/dehydration
cascade reaction of 2-mercaptobenzaldehydes with α,β-
unsaturated aldehydes using a pyrrolidine silyl ether catalyst,9
Wang et al. succeeded in the Michael/aldol reaction of 2-
mercaptobenzaldehydes with α,β-unsaturated oxazolidinones to
give the corresponding 2,3,4-trisubstituted thiochromanes with
all-trans configurations.10 In 2008, Zhao et al. reported the
tandem asymmetric Michael/Henry reaction of 2-mercapto-
benzaldehydes with β-nitrostyrenes. This reaction sequence was
catalyzed by cupreine and generated all-trans 2,3,4-trisubsti-
tuted thiochromanes (Scheme 1a).11−13
With the aim of constructing molecules with contiguous
multiple stereogenic centers in diversity-oriented asymmetric
catalysis (DOAC),14 we initially developed an imidazoline−
aminophenol (IAP)−metal catalyst capable of promoting
tandem reactions.15 The IAP−Cu and IAP−Ni catalyst enabled
the first-ever tandem Friedel−Crafts/Henry reaction15b and
Michael/Mannich reaction15d,e using nitroalkenes, respectively.
Figure 1. Examples of thiochromane groups in pharmaceutical
compounds.
Received: February 5, 2014
Published: March 6, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 1. Stereochemically Divergent Synthesis of
Substituted Thiochromanes
Figure 2. Molecular structure of 6a as determined by X-ray
crystallographic analysis.
Based on this IAP−metal catalyst system, we now report the
Michael/Henry reaction of 2-mercaptobenzaldehydes with β-
nitrostyrenes to give products containing three stereogenic
centers (Scheme 1b).
Our study of the catalytic asymmetric synthesis of
thiochromanes began with the development of an appropriate
catalyst system for the reaction of 2-mercaptobenzaldehyde
(4a) with trans-nitrostyrene (5a).
When an almost 1:1 mixture of 4a with 5a was treated with
the IAP1 (L1)−Ni catalyst in Et2O, the new thiochromane
diastereomer 6a was obtained in 51% ee as the major
diastereomer (dr = 71/29) along with the known all-trans
isomer 6a′ in 4% ee (Table 1, entry 1). The absolute
configuration of (2S,3R,4R)-6a was determined by a single-
crystal X-ray analysis as shown in Figure 2.
At −20 °C, the ee of 6a was improved to 72% with 92/8
diastereoselectivity, although it was necessary to extend the
reaction time to 15 h to obtain the same 70% yield. Attempts to
improve the chemical yield by increasing the relative amount of
4a led to reductions in both the diastereo- and enantiose-
lectivity values (entries 2−4). These results indicated that 4a,
when added in excess, tends to coordinate strongly to the nickel
center and thus poisons the catalyst. This was avoided through
the slow addition of 4a using a syringe pump, which gave the
thiochromane in quantitative yield while maintaining high levels
of the diastereoselectiviy (91/9) and enantioselectivity (78%
ee) for 6a (entry 5). Among the solvents we tested, toluene
gave the highest diastereoselectivity (97/3) for 6a, along with
90% ee (entries 5−10). Finally, when the reaction was
performed under highly dilute conditions (0.025 M) at −40
°C, the thiochromane 6a was obtained in quantitative yield as a
pure diastereomer with up to 95% ee (entry 12). Increasing the
mole ratio of L1 to Ni(OAc)2 to 2:1 did not lead to any further
improvements (entry 13),15f and similarly, the use of the IAP2
(L2)15c catalyst in place of L1 did not result in any appreciable
changes in the product output (compare entries 12 and 14).
The results obtained using other metal salts in the catalytic
system are provided in the Supporting Information.
When the optimized reaction conditions were applied, the
scope and limitations of the L1−Ni-catalyzed thiochromane
synthesis were examined, with the results presented in Scheme
2. Various electron-withdrawing and -donating substituents
were appended to the benzene ring of the β-nitrostyrene, and it
was found that the L1−Ni-catalyzed Michael/Henry reaction
continued to proceed efficiently to give the associated
thiochromanes (6) with high diastereoselectivities and
enantioselectivities ranging from 84 to 95% ee (6a−l). In
addition, when (E)-2-(2-nitrovinyl)thiophene was utilized, 6m
was obtained in a highly diastereoselective manner with 94% ee.
Two substituted 2-mercaptobenzaldehydes were also examined,
and these produced the products 6n and 6o with 80 and 87%
ee, respectively. Unfortunately, the use of an aliphatic
Table 1. Development of the Catalytic Synthesis of Tri-Substituted Thiochromanes Using the IAP−Ni Catalyst
b
entry
x/y
temp (°C)
solvent
z (M)
time (h)
yield (%)
dr 6a/6a′
ee 6a/6a′
1
2
3
4
1/1.1
1/1.1
rt
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−40
−40
−40
Et2O
0.1
1
15
23
23
17
21
18
40
21
18
15
16
17
20
70
70
71/29
92/8
51/4
Et2O
0.1
72/24
62/14
37/0
1.5/1
Et2O
0.1
93
71/29
53/47
91/9
2/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
Et2O
0.1
89
a
5
Et2O
0.1
>99
>99
>99
<66
>99
92
78/50
69/43
86/59
68/47
30/17
90/83
94/ND
95/ND
95/ND
95/ND
a
6
CH2Cl2
CHCl3
THF
0.1
96/4
a
7
0.1
96/4
a
8
0.1
63/37
69/31
97/3
a
9
CH3CN
PhMe
PhMe
PhMe
PhMe
PhMe
0.1
a
10
0.1
a
11
0.025
0.025
0.025
0.025
>99
>99
>99
>99
99/1
a
12
>99/1
>99/1
>99/1
a
,
c
13
14
a
,d
a
b
c
d
1
4a was slowly added over 15 h. Determined by H NMR of the crude product. Using 21 mol % of L1. Using L2 (11 mol %) instead of L1.
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Letter
Scheme 2. L1−Ni-Catalyzed Thiochromane Synthesis
Scheme 3. Reduction of (2S,3R,4R)-Thiochromanes 6
a
Values in parentheses are diastereomeric ratios after silica gel column
b
chromatography. −20 °C, CHCl3 solvent.
nitroalkene resulted in a reduced yield of the desired product
6p as well as asymmetric induction.
During the experimental trials shown in Scheme 2 we
observed the partial epimerization of the newly obtained
(2S,3R,4R)-thiochromanes (6) to the more stable all-trans
(2S,3R,4S)-isomers (6a′) following purification using silica gel
column chromatography. The epimerization of the hydroxy
group at the C4 position is explained by an equilibrium
between the retro-Henry reaction and recyclization. To avoid
the retro-Henry reaction, a portion of the crude (2S,3R,4R)-
thiochromane (6) was isolated and subsequently reduced to the
corresponding amine (7), as described in Scheme 3. To
accomplish this reduction, the L1−Ni-catalyzed Michael/Henry
reaction was first performed on a 6.0 mL scale, following which
5.4 mL of the reaction mixture was reduced with zinc
nanopowder in acidic media to give the corresponding amino
alcohol 7, while the remaining 0.6 mL was analyzed by crude
1H NMR to confirm the original diastereoselectivity of the
thiochromane. In all cases, the amino alcohols (7) were
obtained in good to excellent yields without loss of stereo-
selectivity. In the case of the Michael/Henry product obtained
using p- and m-nitro-β-nitrostyrene, both the nitro group on
the thiochromane ring and on the benzene ring were reduced
to give the diamines 7l and 7m in a one-pot reduction process.
A proposed mechanism explaining the manner in which the
(2S,3R,4R)-thiochromanes (6) are synthesized from the L1−
Li-catalyzed Michael/Henry reaction is provided in Scheme 4.
The process begins with the L1−Ni-catalyzed Michael reaction
of the 2-mercaptobenzaldehyde with the β-nitrostyrene. As a
prelude to this reaction, the high affinity which thiol has for the
nickel center leads to formation of an L1−Ni-tholate
intermediate. The corresponding [L1−Ni-thiolate + H]+
species was observed during ESI-MS analysis based on the
presence of an ion peak at m/z 966.0162 (see the Supporting
a
Since only 90% of the reaction solution (i.e., 5.4 mL) was applied to
the reduction, yields estimated by multiplying by 1.11 are given in
parentheses. The value in parentheses is the dr of 6 as determined by
crude H NMR of 10% of the reaction mixture (i.e., 0.6 mL).
b
1
Scheme 4. Proposed Catalytic Cycle for the L1−Ni-
Catalyzed Michael/Henry Reaction
Information). The 2-mercaptobenzaldehyde, which is present
in excess, displaces the L1 from the nickel center to generate an
achiral nickel thiolate which reduces asymmetric induction in
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Organic Letters
Letter
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tarai@faculty.chiba-u.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology (Japan) and by the Workshop on
Chirality in Chiba University (WCCU).
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