Organocatalytic Asymmetric Sulfa-Michael Addition of 2-Aminothiophenols to Chalcones: First Enantioselective Access to 2,3,4,5-Tetrahydro-1,5-benzothiazepines

Article abstract of DOI:10.1002/ejoc.201601364

1,5-Benzothiazepine frameworks are highly relevant in medicinal chemistry. Reported catalytic asymmetric approaches to these scaffolds have targeted 2,3-dihydro-1,5-benzothiazepin-4-ones but leave the corresponding amines (i.e., 2,3,4,5-tetrahydro-1,5-ben

Full text of DOI:10.1002/ejoc.201601364

A Journal of
Accepted Article
Title: Organocatalytic Asymmetric Sulfa-Michael Addition of 2-Aminothiophenols
to Chalcones. First Enantioselective Access to 2,3,4,5-Tetrahydro-1,5-
benzothiazepines
Authors: Luca Bernardi; Vasco Corti; Patricia Camarero Gonzalez; Julie Febvay;
Lorenzo Caruana; Andrea Mazzanti; Mariafrancesca Fochi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601364
Link to VoR: https://doi.org/10.1002/ejoc.201601364
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COMMUNICATION
Organocatalytic Asymmetric Sulfa-Michael Addition of 2-
Aminothiophenols to Chalcones. First Enantioselective Access to
2,3,4,5-Tetrahydro-1,5-benzothiazepines
Vasco Corti,[a] Patricia Camarero Gonzalez,[a] Julie Febvay,[a] Lorenzo Caruana,[a] Andrea Mazzanti,[a]
Mariafrancesca Fochi,*[a] and Luca Bernardi*[a]
Abstract: 1,5-Benzothiazepine frameworks are highly relevant in
medicinal chemistry. Reported catalytic asymmetric approaches to
these scaffolds have targeted 2,3-dihydro-1,5-benzothiazepin-4-
ones, leaving the corresponding amines (2,3,4,5-tetrahydro-1,5-
benzo-thiazepines) out of reach. Herein, we present the first entry to
these important compounds in enantioenriched form. Our approach
is based on the catalytic asymmetric sulfa-Michael addition of 2-
aminothiophenols to trans-chalcones, followed by intramolecular
reductive amination. Both reactions have required a careful study to
solve several challenging issues. The resulting optimized two-step
protocol afforded a range of 2,3,4,5-tetrahydro-1,5-benzothiazepines
as single trans-diastereoisomers in moderate to good yields and
enantioselectivities.
subsequent reductive amination on adducts
disubstituted 2,3,4,5-tetrahydro-1,5-benzo-thiazepines
4
gives 2,4-
5,
hitherto unreported in enantioenriched form (Scheme 1, bottom).
As herein presented, the realization of this sequential reaction
required solving different challenging issues:
i) the peculiar features of thiophenols 2, wherein the aniline
functionality can give additional H-bond interactions with the
bifunctional catalysts typically employed in sulfa-Michael
reactions, made in our hands conditions useful for
enantioselective additions of simple thiophenols to trans-
chalcones[5] unsuitable;
ii) the dimerization of
2 to the disulphide, decreasing
substantially the yield of the reaction, appeared to be a facile
process which had to be avoided;
iii) the susceptibility of adducts 4 to racemization during the
reductive amination processes to 5 demanded a careful tuning
of reaction conditions in this cyclization step.
Introduction
The 1,5-benzothiazepine is a heterocyclic scaffold (highlighted in
Scheme 1) commonly found in drugs featuring a variety of
pharmacological properties.[1] For example, thiazesim is an
antidepressant, while diltiazem is used in the treatment of
hypertension and angina. Even if 1,5-benzothiazepines have
attracted much attention in the pharmaceutical field since many
decades,[1] prompting a variety of synthetic approaches, there is
still a high demand for new efficient routes to these compounds
in enantioenriched form.[2] The sulfa-Michael addition of 2-
aminothiophenols to α,β-unsaturated compounds, followed by
cyclization, is one of the most straightforward approaches to this
motif. Accordingly, such type of sequential reaction has been
recently developed in catalytic asymmetric settings.[3]
Carboxylate-based Michael acceptors were used, giving access
to optically active 2,3-dihydro-1,5-benzothiazepin-4-ones
(Scheme 1, top). In contrast, an enantioselective methodology to
access 2,3,4,5-tetrahydro-1,5-benzothiazepines 5, bearing an
amine instead of an amide functionality (Scheme 1, bottom), has
not been developed so far.
To fill this gap, we set out to study the catalytic
enantioselective sulfa-Michael addition of 2-aminothiophenols 2
Scheme 1. Sequential asymmetric sulfa-Michael – cyclization processes to
access 1,5-benzothiazepine derivatives.
to trans-chalcones 1 catalyzed by organic catalysts 3.[4,5]
A
Results and Discussion
[a]
V.Corti, P. Camarero Gonzalez, J. Febvay, L. Caruana, A. Mazzanti,
M. Fochi, L. Bernardi
Department of Industrial Chemistry “Toso Montanari” & INSTM RU
Bologna
Alma Mater Studiorum – University of Bologna
V. Risorgimento 4, 40136 Bologna (Italy)
We began our investigations on the reaction between 2-
aminothiophenol 2a and trans-chalcone 1a (Table 1) using the
reaction conditions reported in literature for the enantioselective
addition of thiophenols to this substrate, entailing the use of
catalyst 3a (Figure 1), in toluene at room temperature.[5a]
Unfortunately, these parameters were not suitable for
E-mail: mariafrancesca.fochi@unibo.it; luca.bernardi2@unibo.it
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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nucleophile 2a (Table 1, entry 1); therefore we started a
thorough optimization of the reaction conditions.[6] A screening
(entries 2-7) of other bifunctional organocatalysts 3b-g featuring
H-bond donors flanked by a basic tertiary amine[7] (Figure 1)
pointed our attention to catalyst 3d, a sulphonamide derived
from 9-amino(9-deoxy)epi cinchonidine,[8] which gave the best
enantioselectivity. Then, we tested different solvents in order to
evaluate their influence on the reaction (entries 8-12). 1,4-
Dioxane was found to be the best candidate. In addition,
reducing the catalyst loading from 10 mol% to 5 mol% slightly
improved the enantioselectivity (entry 13); further lowering to 1
mol% was instead not practical (entry 14). Despite the good
values observed in the first experiment with 5 mol% loading
(entry 13), the enantiomeric excess and the conversion of this
reaction displayed poor reproducibility. After
a thorough
investigation, we found that dimerization of nucleophile 2a to
Table 1. Screening of catalysts 3 and conditions in the test reaction between
2-aminothiophenol 2a and trans-chalcone 1a. Representative results.[a]
Figure 1. Representative bifunctional catalysts 3a-3g screened in the reaction.
Ar = 3,5-(CF3)2C6H3.
Entry
Catalyst 3
Solvent [M]
Conv.[b] [%]
ee[c] [%]
[mol %]
disulphide, occurring to variable extents during the reactions,
could strongly affect the conversion values. Besides, we were
using a protocol involving addition of neat thiophenol 2a to the
reaction mixture containing catalyst 3d and trans-chalcone 1a.
Probably, depending on the addition rate, thiophenol 2a did not
have time to dilute into the mixture before reaction,
compromising in some cases the enantiomeric excess.[9] These
issues were overcome by degassing the reaction solvent to
exclude oxygen, and by adding thiophenol 2a in solution. This
new protocol (entry 15) not only provided satisfactory results, but
proved to be fully reproducible.
1
3a [10]
3b [10]
3c [10]
3d [10]
3e [10]
3f [10]
3g [10]
3d [10]
3d [10]
3d [10]
3d [10]
3d [10]
3d [5]
toluene [0.18]
toluene [0.18]
toluene [0.18]
toluene [0.18]
toluene [0.18]
toluene [0.18]
toluene [0.18]
CH2Cl2 [0.18]
65
32[d]
20[d]
18
2
62
3
84
4
66
70
5
50
rac
50
6
64
7
92
21
8
>99
80
40
We then moved to study the second synthetic step towards
1,5-benzothiazepines 5: the reductive amination. This apparently
simple transformation required instead an in-depth investigation,
since the first attempts of cyclizing and reducing 4a were
accompanied by substantial racemization. Indeed, the
racemization of imine intermediate 6a through a retro-sulfa-
Michael pathway (Scheme 2) may easily occur in the presence
of acids.[10] Acid promoters are normally required to effect
reductive aminations.
9
CH3CN [0.18]
acetone [0.18]
THF [0.18]
62
10
11
12
13
14
15[e]
>99
50
66
74
1,4-dioxane [0.18]
1,4-dioxane [0.18]
1,4-dioxane [0.18]
1,4-dioxane [0.12]
68
80
60
82
3d [1]
46
46
3d [5]
>99
86
[a] Conditions: trans-chalcone 1a (0.10 mmol), catalyst 3 (x mol%), solvent (x
M), 2-aminothiophenol 2a (0.15 mmol), RT, 1-5 h. [b] Determined by 1H NMR
after filtration on a plug of silica gel and solvent evaporation. [c] Determined by
CSP-HPLC. [d] ent-4a was obtained as major enantiomer. [e] Reaction
performed with degassed 1,4-dioxane, adding nucleophile 2a as a 1,4-dioxane
solution.
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European Journal of Organic Chemistry
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the most stable conformation of compound 5a, a twist-boat,[14]
the 1,3-trans stereochemistry arranges the two bulky phenyl
groups in more favourable pseudo-equatorial positions, as
inferred from X-Ray and related literature data.[13c,15] Thus, the
full diastereoselectivity of the reduction can be rationalized
considering
a
transition state resembling the twist-boat
conformation[14] of product 5a, and implicating a selective attack
of the hydride to the Re-face of the iminium ion to place the 4-
phenyl ring in a pseudo-equatorial position (Scheme 4).
Scheme 2. Plausible racemization pathway occurring during reductive
amination.
Scheme 4. Rationalization of the trans-selectivity of the reduction.
After a thorough investigation[11] we found that rather classic
reductive amination conditions (NaBH3CN as reducing agent in
combination with AcOH as acidic promoter, in methanol as
solvent), could be used successfully in the reaction. At room
With optimized conditions for both synthetic steps in hand,
we evaluated the reaction scope (Table 2). All trans-chalcones
Table 2. Scope of the reaction.[a]
temperature, they delivered product 5a as
a
single
diastereoisomer and with only a small deterioration of the
enantiomeric excess. Moreover, lowering the temperature to
0 °C avoided any loss of enantioenrichment (Scheme 3).
Entry
1: Ar1,Ar2
2
5-Yield[b] [%]
ee[c] [%]
1
1a: Ph, Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
5a-80
5b-83
5c-77
5d-85
5e-65
5f-79
5g-82
5h-75
5i-71
5j-90
5k-70
5l-73
86
80
82
79
55
80
80
80
78
71
87
81
Scheme 3. Optimized reaction conditions for the reductive amination step.
2
1b: 4-BrC6H4, Ph
1c: 4-MeC6H4, Ph
1d: 3-MeC6H4, Ph
1e: 2-MeC6H4, Ph
1f: 4-MeOC6H4, Ph
1g: Ph, 4-MeOC6H4
1h: Ph, 4-MeC6H4
1i: 4-MeC6H4, 4-ClC6H4
1j: 1-naphthyl, Ph
1a: Ph, Ph
Product 5a is a crystalline compound, and could be obtained
in nearly enantiopure form after a single crystallization from
methanol (Scheme 3). Single crystal X-Ray analysis allowed to
determine its absolute configuration, as S,S (Figure 2).[12]
3
4
5
6
7
8
9
10
11
12
1b: Ph, Ph
Figure 2. X-Ray structure of compound 5a.
[a] Conditions: i) trans-chalcones 1a-j (0.20 mmol), 1,4-dioxane (870 µL),
catalyst 3d (5 mol%), 2-aminothiophenols 2a-c in 1,4-dioxane (0.30 mmol in
800 µL), RT, 5 h, filtration on silica gel, evaporation; ii) MeOH (1.0 mL),
NaBH3CN (0.80 mmol), AcOH (0.40 mmol), 0 °C. [b] Yield of isolated product
The relative 1,3-trans configuration of 5a, resulting from the
reduction of the imine 6a, is in line with previous literature data
describing the synthesis of compounds 5 in racemic form.[13] In
after chromatography on silica gel.
A single trans-diastereoisomer was
obtained in all cases. [c] Determined by CSP-HPLC on the purified products 5.
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European Journal of Organic Chemistry
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CH2Cl2, and the solvents removed under vacuum. Purification by column
chromatography on silica gel (n-hexane/CH2Cl2 1:1) afforded the
corresponding 2,3,4,5-tetrahydro-1,5-benzothiazepines 5a-l. 1H-NMR
analysis of the products 5a-l showed the presence of a single trans-
diastereoisomer.
1a-j tested, bearing differently substituted aromatic rings,
reacted smoothly and afforded the corresponding 2,3,4,5-
tetrahydro-1,5-benzothiazepines 5a-j in moderate to good yields
(entries 1-9). Enantiomeric excesses for these compounds were
around 80%, with the exception of the 2-methylphenyl and the 1-
naphthyl derivatives 1e and 1j, (entries 5,10) which gave lower
values. These latter results suggest that the steric hindrance in
the chalcone substrate 1 has a negative influence on the
stereoselectivity of the sulfa-Michael reaction.[16] A very good
tolerance to substrate variation was instead found when we
tested 2-aminothiophenols 2b and 2c with a 4-chloro and a 4-
methoxy substituent, which gave the corresponding products 5k
and 5l with good results (entries 11-12). All reactions gave 1,5-
benzothiazepines 5a-l as single diastereoisomers; their relative
and absolute configuration was assigned by analogy with
compound 5a.
Acknowledgements
We acknowledge financial support from the University of
Bologna (RFO program). Elia Romagnoli is gratefully
acknowledged for optimization experiments in the reductive
amination reaction.
Keywords: Amines • Asymmetric Synthesis • Michael Addition •
Organocatalysis • Sulfur Heterocycles
[1]
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To summarize, we have developed a catalytic asymmetric sulfa-
Michael addition of 2-aminothiophenols 2 to trans-chalcones 1,
which after a highly diastereoselective reductive amination
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afforded
the
corresponding
2,3,4,5-tetrahydro-1,5-
benzothiazepines
5
in moderate to good yields and
enantioselectivities. A careful optimization of both reaction steps
was essential to face challenges such as the unsuitability of
previously reported protocols for asymmetric additions of simpler
thiophenols to trans-chalcones 1, the poor stability of 2-
aminothiophenol substrates 2, and the stereochemical lability of
the Michael adducts under the acidic conditions required in the
reductive amination step. Being the catalytic asymmetric
[4]
For comprehensive reviews on organocatalytic sulfa-Michael reactions,
see: a) D. Enders, K. Lüttgen, A. A. Narine, Synthesis 2007, 959; b) P.
Chauhan, S. Mahajan, D. Enders, Chem. Rev. 2014, 114, 8807; for
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Soc. 2016, 138, 1170; f) M. N. Grayson, K. N. Houk, J. Am. Chem. Soc.
2016, 138, 9041.
addition of 2-aminothiophenols
unreported so far, the present protocol represents the first
enantioselective access to 2,3,4,5-tetrahydro-1,5-
2
to trans-chalcones
1
benzothiazepine structures 5.
[5]
Addition of thiophenols to trans-chalcones catalyzed by bifunctional
organocatalysts: a) L. Dai, S.-X. Wang, F.-E. Chen, Adv. Synth. Catal.
2010, 352, 2137; b) J. Skarżewski, M. Zielińska-Błajet, I. Turowska,-
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Singh, J. Org. Chem. 2010, 75, 2089; addition of sodium bisulphite to
trans-chalcones: d) M. Moccia, F. Fini, M. Scagnetti, M. F. A. Adamo,
Angew. Chem. 2011, 123, 7025; Angew. Chem. Int. Ed. 2011, 50, 6893.
It must be noted that many of the reactions performed during the
optimization gave mixtures of the simple addition product 4a (usually
highly predominant) and the corresponding cyclized imine 6a (see
Scheme 2). However, the presence of this latter product did not
compromise the determination of the conversion by 1H NMR (calculated
on both compounds 4a and 6a vs chalcone 1a), nor of the enantiomeric
excess of 4a by CSP-HPLC.
Experimental Section
General procedure for the preparation of enantioenriched products
5a-l In a Schlenk tube equipped with a magnetic stirring bar, under N2
atmosphere, trans-chalcones 1a-j (0.20 mmol) and catalyst 3d (5.6 mg,
0.010 mmol, 5.0 mol%) were dissolved in degassed 1,4-dioxane (870 µL).
A solution of 2-aminothiophenols 2a-c in degassed 1,4-dioxane (0.30
mmol in 800 µL) was then added. The reaction mixture was stirred until
1H-NMR analysis showed complete conversion (less than 5 h). The
mixture was then filtered through a short plug of silica gel, the Schlenk
flask washed two times with CH2Cl2, these washings filtered through the
same plug, the plug flushed with CH2Cl2, and all the solvents evaporated
under vacuum. The thus obtained sulfa-Michael crude products 4 were
re-dissolved in CH2Cl2, transferred to a test tube equipped with a
magnetic stirring bar and the solvent evaporated by flushing the tube with
N2. 1.0 mL of MeOH was then added to the residue, and the resulting
solution cooled to 0 °C with stirring. NaBH3CN (50 mg, 0.80 mmol) and
acetic acid (22.8 µL, 0.40 mmol) were added portion-wise every 2 h until
TLC analysis (eluent n-hexane/EtOAc 5:1) showed complete
consumption of the corresponding sulfa-Michael adducts 4. Afterwards,
the reaction was quenched with 1.0 mL of a saturated Na2CO3 aqueous
solution, and the mixture extracted three times with CH2Cl2. The organic
layers were filtered through a short plug of silica gel, the plug flushed with
[6]
[7]
For some reviews, see: a) M. S. Taylor, E. N. Jacobsen, Angew. Chem.
2006, 118, 1550; Angew. Chem. Int. Ed. 2006, 45, 1520; b) H. Miyabe,
Y. Takemoto, Bull. Chem. Soc. Jpn. 2008, 81, 785; c) S. J. Connon,
Chem. Commun. 2008, 2499; d) S. Ingemann, H. Hiemstra, in
Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions
and Applications, Vol. 2 (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2013,
pp. 119–160; e) Sustainable Catalysis Without Metals or Other
Endangered Metals, Part 2, (Ed.: M. North), RSC, Cambridge, 2016; f)
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Catal. 2015, 357, 253; g) J. Alemán, A. Parra, H. Jiang, K. A.
Jørgensen, Chem. Eur. J. 2011, 17, 6890; for most recent examples
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European Journal of Organic Chemistry
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from our laboratory: h) L. Caruana, M. Mondatori, V. Corti, S. Morales,
A. Mazzanti, M. Fochi, L. Bernardi, Chem. Eur. J. 2015, 21, 6037; i) M.
Fochi, L. Gramigna, A. Mazzanti, S. Duce, S. Fantini, A. Palmieri, M.
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Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[13] a) W. D. Stephens, L. Field, J. Org. Chem. 1959, 24, 1576; b) M.
Muthukumar, K. Thanikasalam, E. M. Mohamed, J. N. Low, C.
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shows the incorrect isomer; the X-Ray structure indicates trans-
stereochemistry.
[8]
[9]
S. H. Oh, H. S. Rho, J. W. Lee, J. E. Lee, S. H. Youk, J. Chin, C. E.
Song, Angew. Chem. 2008, 120, 7990; Angew. Chem. Int. Ed. 2008, 47,
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This reaction is rather rapid, and we found
enantioselectivity with lower dilutions.
a
decrease of the
[14] J. B. Hendrickson, J. Am. Chem. Soc. 1961, 83, 4537.
[15] A. Entrena, J. M. Campos, M. A. Gallo, A. Espinosa, Arkivoc 2005, (vi),
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[10] For 1,5-benzodiazepine racemization through
a
retro-aza-Michael
pathway, see: K. Horiguchi, E. Yamamoto, K. Saito, M. Yamanaka, T.
Akiyama, Chem. Eur. J. 2016, 22, 8078.
[16] Unfortunately, α,β-unsaturated ketone substrates bearing aliphatic
substituents either at the ketone or at the double bond gave worse
results in terms of enantioselectivities (0-40% ee).
[11] Different “organocatalytic” conditions and catalysts/reagents were
investigated, but proved unsuccessful; for details, see the Supporting
Information.
[12] CCDC 1497615 contains the supplementary crystallographic data of
compound 5a. These data can be obtained free of charge from the
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Organocatalysis
Vasco Corti, Patricia Camarero
Gonzalez, Julie Febvay, Lorenzo
Caruana, Andrea Mazzanti,
Mariafrancesca Fochi,* Luca Bernardi*
Page No. – Page No.
Organocatalytic Asymmetric Sulfa-
Michael Addition of 2-
Aminothiophenols to Chalcones. First
Enantioselective Access to 2,3,4,5-
Tetrahydro-1,5-benzothiazepines
A two-step synthetic methodology delivering 2,3,4,5-tetrahydro-1,5-benzothiazepines in
enantioenriched form is presented. The two-step sequence involves an organocatalytic asymmetric
sulfa-Michael reaction, followed by a highly diastereoselective reductive amination.
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