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(21b) behaved in a similar way to its homologue derived from
cyclopentanone 21a, leading to 22ab in good yield and dia-
stereoselectivity and excellent enantioselectivity (compare en-
tries 1 and 5 in Table 3). On the contrary, the reaction of a-sub-
stituted cycloheptanone 21c was much less diastereoselective,
although the enantioselectivity was maintained (Table 3,
entry 6). 2-Acetylcyclopentanone (21d) quickly reacted with
the nitroolefin, yielding the addition product 22ad with mod-
erate stereoselection, and the reaction of a-acetyl-g-lactone
(21e) occurred with excellent yield and enantioselectivity, but
moderate diastereoselectivity (Table 3, entry 8). Interestingly,
the reaction of the more acidic a-nitrocyclohexanone with 18a
was slow (12 h), leading to 22af as a single diastereoisomer,
but in moderate yield and enantioselectivity.
under different conditions, allowed the synthesis of four differ-
ent polymeric materials, which were used as chiral organocata-
lysts in enantioselective aza-Henry and nitro-Michael additions.
The best results were obtained with catalyst 13, derived from
1,6-hexanediamine, which was able to promote both reactions
with high stereoselectivity and excellent enantioselectivity in
solvent-free conditions. The catalyst could be recycled without
modification of the catalytic activity.
Experimental Section
General
The sense of the stereoselection observed in both the aza-
Henry and nitro-Michael reactions can be explained by accept-
ing the formation of the ternary complexes depicted in
Scheme 4a and b, respectively. It is well known that thioureas
13C (126 MHz) and 1H NMR (500 MHz) spectra were recorded in
CDCl3 as the solvent. Chemical shifts for carbon atoms are reported
in ppm from tetramethylsilane (TMS) and are referenced to the
carbon resonance of the solvent. Chemical shifts for protons are re-
ported in ppm from TMS with the residual CHCl3 resonance as an
internal reference. Data are reported as follows: chemical shift,
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=
multiplet, br=broad), coupling constants in Hertz, and integration.
IR spectra were recorded on a FTIR spectrometer and are reported
in frequency of absorption (only the structurally most important
bands are given). Melting points were obtained with open capillary
tubes and are uncorrected. Flash chromatography was performed
by using silica gel (230–240 mesh). TLC analysis was performed on
glass-backed plates coated with silica gel 60 and an F254 indicator,
and visualized by either UV irradiation or by staining with a solution
of phosphomolybdic acid. Specific rotations were measured on
a digital polarimeter by using a 5 mL cell with a 1 dm path length,
and a sodium lamp, and concentration was given in gram per
100 mL. Chiral HPLC analysis was performed by using Daicel Chiral-
cel OD, Chiralcel OJ, Chiralpak AD-H, Chiralpak AS-H, or Chiralpak
IA analytical columns (2504.6 mm). UV detection was monitored
at l=220 or 254 nm. Elemental analyses were performed at the El-
emental Analysis Center of the Complutense University of Madrid.
Scheme 4. Plausible ternary complexes that explain the stereoselection for
the aza-Henry (a) and nitro-Michael (b) reactions.
behave as bifunctional catalysts able to activate both the elec-
trophile and nucleophile. The high degree of enantioselectivity
observed in the aza-Henry reaction could be explained by ac-
cepting the formation of highly coordinated ternary complex I
(Scheme 4a) through thiourea activation of the nitro group,
followed by deprotonation by the tertiary amine to the corre-
sponding nitronate, and subsequent coordination of the imine
carbamate.[25] The major diastereomers 17 should be formed
through the addition of the si face of the nitronate to the re
face of the imine.
ESI mass spectra were obtained on an Agilent 5973 inert GC/MS
system. Commercially available organic and inorganic compounds
were used without further purification. Solvents were dried and
stored over microwave-activated 4 molecular sieves. Boc-imines
15a–i were prepared according to reported procedures.[27]
The mechanism and stereochemical outcome of the nitro-
Michael addition is also well known.[23,26] In that case, the terti-
ary amine will be responsible for deprotonation of the acidic
hydrogen and the thiourea will activate the nitroalkene
through hydrogen bonding, leading to the ternary complex
shown in Scheme 4b. Addition of the re face of the enolate to
the si face of the nitroolefin yielded compounds 20 and 22 as
major diastereomers.
General procedure for the enantioselective aza-Henry reac-
tion with immobilized catalysts (11–14)
Nitromethane (0.1 mL, 1.8 mmol, 6 equiv) was added to a mixture
of Boc-imine (0.3 mmol) and catalyst (0.015 mmol, 0.05 equiv), and
the reaction mixture was stirred at RT in a Wheaton vial until con-
1
sumption of the starting material (monitored by H NMR spectros-
copy). The catalyst was filtered off and washed with MeOH (3
1 mL). After removal of the solvent under reduced pressure, the
crude mixture was purified by flash column chromatography to
afford the corresponding product. The enantiomeric excess was
determined by chiral-phase HPLC analysis by using mixtures of
hexanes/isopropanol as the eluent.
Conclusion
We have prepared two different styryl thioureas derived from
l-valine and commercially available diamines. The copolymeri-
zation of these thioureas with styrene and divinylbenzene,
ChemPlusChem 2016, 81, 86 – 92
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