European Journal of Organic Chemistry
10.1002/ejoc.201601364
COMMUNICATION
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
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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
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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]
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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
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[7]
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