Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

Article abstract of DOI:10.3762/bjoc.12.61

The catalytic activity of different supported bifunctional thioureas on sulfonylpolystyrene resins has been studied in the nitro-Michael addition of different nucleophiles to trans-β-nitrostyrene derivatives. The activity of the catalysts depends on the l

Full text of DOI:10.3762/bjoc.12.61

Supported bifunctional thioureas as recoverable and reusable
catalysts for enantioselective nitro-Michael reactions
José M. Andrés*, Miriam Ceballos, Alicia Maestro, Isabel Sanz and Rafael Pedrosa*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 628–635.
Instituto CINQUIMA and Departamento de Química Orgánica,
Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7,
47011-Valladolid, Spain
doi:10.3762/bjoc.12.61
Received: 27 November 2015
Accepted: 12 March 2016
Published: 01 April 2016
Email:
José M. Andrés* - jmandres@qo.uva.es; Rafael Pedrosa* -
pedrosa@qo.uva.es
This article is part of the Thematic Series "Bifunctional catalysis".
Guest Editor: D. J. Dixon
* Corresponding author
Keywords:
© 2016 Andrés et al; licensee Beilstein-Institut.
License and terms: see end of document.
bifunctional organocatalysts; organocatalysis; stereoselective
nitro-Michael addition; supported catalysts; thioureas
Abstract
The catalytic activity of different supported bifunctional thioureas on sulfonylpolystyrene resins has been studied in the nitro-
Michael addition of different nucleophiles to trans-β-nitrostyrene derivatives. The activity of the catalysts depends on the length of
the tether linking the chiral thiourea to the polymer. The best results were obtained with the thiourea derived from (L)-valine and
1,6-hexanediamine. The catalysts can be used in only 2 mol % loading, and reused for at least four cycles in neat conditions. The
ball milling promoted additions also worked very well.
Introduction
The use of chiral bifunctional thioureas that allow the simulta- [16], polystyrene [18-22], and magnetic nanoparticles [12].
neous activation of a electrophile, by hydrogen bonding, and a Cinchona-derived thioureas have been also prepared by
nucleophile, by deprotonation, plays a major role in the stereo- co-polymerization of polyfunctionalized thiols with olefins
selective formation of C–C bonds in different transformations [23].
[1-5]. In these processes one of the major problems is related to
the recovering of the catalysts. The support of the small mole- Our interest in the search for novel bifunctional thioureas as
cules on different materials has been proposed as a solution, in- organocatalysts [24-27] lead us to consider the preparation of
cluding their use in continuous flow processes [6-9]. The most different polymeric materials decorated with chiral bifunctional
popular supports include nanoparticles [10-12], inorganic solids thioureas looking for a greener process [28], easier recovering
[13,14], and different polystyrene derivatives [15-20].
and recyclability of the catalyst, and solvent-free reaction
conditions. Along these lines, we have recently reported the
Bifunctional thioureas were first supported on PEG [21], and bottom-up synthesis of polymeric thioureas [29], and the
later on different materials such as poly(methylhydrosiloxane) anchorage of (L)-valine-derived thiourea I [30] onto
628

Beilstein J. Org. Chem. 2016, 12, 628–635.
sulfonylpolystyrene resin leading to catalysts II–V (Figure 1), tions were faster, and much more stereoselective for ketoester
which differ in the length of the diamine linker or in the substi- 3a than for diethyl malonate 2a, and that the difference was
tution pattern of the nitrogen in the sulfonamide. These materi- specially remarkable when supported ethylenediamine-derived
als, and the related unsupported thiourea VI, have been previ- thioureas II and III were used as catalysts (compare entries 2
ously tested as excellent organocatalysts in the stereoselective and 3 versus 9 and 10 in Table 1). It is noteworthy that the
aza-Henry reaction [31]. Now we describe the results obtained results obtained in the reaction catalyzed by supported thiourea
in different stereoselective nitro-Michael additions promoted by IV were better than those observed in the addition catalyzed by
these materials.
the parent thiourea I (compare Table 1, entries 1 and 4).
Results and Discussion
The catalyst loading was decreased to 5 mol % for supported
The ability of the supported catalysts (II–V) to promote the hexanediamine-derived catalyst IV, observing that the level of
stereoselective nitro-Michael reaction was first tested in the stereoselectivity was maintained for both reactions, although at
reaction of trans-nitrostyrene (1a) with diethyl malonate (2a), expenses of slight increasing the reaction time (compare
leading to the enantioenriched addition product 4aa with a Table 1, entries 4 versus 5, and 11 versus 12). In these condi-
single stereocenter. In order to the creation of two tertiary- tions, supported catalyst V, which differs from IV in the substi-
quaternary contiguous stereocenters (5aa) we also used ethyl tution pattern of the sulfonamide, was the best catalyst for the
2-oxocyclopentanecarboxylate (3a) as nucleophile in neat addition of both 2a and 3a to nitrostyrene, yielding products
conditions and in different solvents. For comparative purposes, 4aa and 5aa, respectively, in much better yield maintaining the
the same reactions were studied in the presence of unsupported stereoselectivity in shorter reaction time (compare entries 5
catalysts I and VI, and the results are summarized in Scheme 1 versus 6 and 12 versus 13 in Table 1). An increase in both the
and Table 1.
yield and the enantioselectivity for the reaction of 1a with 2a
(Table 1, entries 6 and 7), but no differences in the reaction of
Initially, the reactions were carried out in neat conditions at rt 1a with 3a (Table 1, entries 13 and 14) were observed when the
with twofold excess of nucleophile and 10 mol % of catalysts unsupported thiourea VI, homologous to V, was used as
(entries 1–4 and 9–11 in Table 1). As a general trend, the reac- organocatalyst.
Figure 1: Parent and supported bifunctional thioureas used in this work.
Scheme 1: Reaction of nitrostyrene with diethyl malonate and 2-ethoxycarbonyl cyclopentanone.
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Beilstein J. Org. Chem. 2016, 12, 628–635.
Table 1: Screening of catalysts and optimization of the reaction conditions for the additions of diethyl malonate and ethyl 2-oxocyclopentanecarboxy-
late to β-nitrostyrene.
Entrya
Catal. (mol %)
Solvent
T (°C)
t (h)
Product yieldb (%)
drc
erd
1
2
I (10)
II (10)
III (10)
IV (10)
IV (5)
V (5)
VI (5)
I (5)
neat
neat
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
rt
rt
rt
rt
rt
rt
0
rt
24
120
120
16
24
16
16
1
4aa (80)
4aa (77)e
4aa (63)f
4aa (92)
4aa (80)
4aa (92)
4aa (100)
5aa (95)
5aa (100)
5aa (90)
5aa (100)
5aa (100)
5aa (98)
5aa (100)
5aa (93)
5aa (97)
5aa (86)
5aa (83)
5aa (74)
5aa (66)
5aa (55)
5aa (79)
5aa (82)
5aa (86)
–
92:8
78:22
85:15
91:9
90:10
89:11
94:6
95:5
90:10
92:8
95:5
95:5
95:5
95:5
95:5
94:6
94:6
94:6
93:7
94:6
94:6
95:5
95:5
92:8
–
3
neat
–
4
neat
–
5
neat
–
6
neat
–
7
neat
–
8
neat
95:5
89:11
87:13
88:12
88:12
89:11
89:11
89:11
90:10
88:12
88:12
90:10
89:11
89:11
89:11
88:12
89:11
9
II (10)
III /10)
IV (10)
IV (5)
V (5)
VI (5)
V (2)
V (2)
V (2)
V (2)
V (2)
V (2)
V (2)
V (2)
V (2)
V (2)
neat
4
10
11
12
13
14
15
16
17g
18h
19
20
21
22
23
24g
neat
8
neat
4
neat
7
neat
0.5
2
neat
neat
1
neat
24
8
neat
neat
2.5
1
CH2Cl2
PhMe
THF
5
1.5
1.5
8
MeCN
MeCN
MeCN
8
aReaction performed with 2 equiv of nucleophile at room temperature. bYields refer to isolated compounds. cDetermined by 1H NMR in the reaction
mixture. dDetermined by chiral HPLC. e13% of unreacted nitrostyrene was recovered. f15% of unreacted nitrostyrene was recovered. gReaction per-
formed with 1.1 equiv of ketoester. hReaction performed with 1.5 equiv of ketoester.
Taking the supported thiourea V as the catalyst of choice, the acetonitrile, a more polar solvent, was used (Table 1, entries
effects of the catalyst loading, the temperature, the ratio of 22–24).
nucleophile, and the use of different solvents were studied for
the reaction of 1a and 3a. Fortunately, the reduction of the We next consider the reaction of some 4-substituted nitro-
amount of catalyst to 2 mol % did not influence the stereoselec- styrenes (1b–d) with diethyl malonate (2a), and the addition of
tivity, and only slightly decreased the yield to 93% (compare a range of β-functionalized nucleophiles 2b–g to 1a promoted
Table 1, entries 13 and 15). The reaction also proceeded at 0 °C, by supported catalysts IV (5 mol %) and V (2 mol %), respec-
leading to the addition product 5aa in 97% and very good tively (Scheme 2 and Table 2). The results obtained in the reac-
stereoselectivity, but in those conditions the reaction time in- tions of 4-chloro- (1b) and 4-fluoronitrostyrene (1c) were very
creased to 24 h (Table 1, entry 16).
similar than those obtained in the reaction with β-nitrostyrene
(1a), maintaining the yield and the enantioselectivity, although
The reduction of the amount of the nucleophile to 1.1 equiva- 1c reacted slowly within 48 h (compare entries 1 and 2 in
lents (Table 1, entry 17) or 1.5 equivalents (Table 1, entry 18) Table 2 versus entry 5 in Table 1), but the less reactive 4-me-
had only a moderate effect on the yield of the reaction time, in- thoxy derivative 1d only yielded the addition product in moder-
creasing it to 8 h and 2,5 h, respectively. The yield dropped to ate 52% yield after 72 h of reaction (entry 3 in Table 2).
55–74%, without change in the stereoselectivity, when the reac-
tion was carried out in less polar solvents such as DCM, tolu- The reaction of different nucleophiles (2a–g) with 1a catalyzed
ene, or THF (Table 1, entries 19–21), although both the yield by IV (5 mol %) also worked well in terms of enantioselectivi-
and diastereo- and enantioselectivity were maintained when ty, maintaining the er near constant around or higher than 90:10,
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Beilstein J. Org. Chem. 2016, 12, 628–635.
Scheme 2: Reaction of nitrostyrenes with malonates and β-diketones.
Table 2: Addition of malonates and β-diketones to nitrostyrenes catalyzed by IV and V.
Entrya
Reagents
Catal. (mol %)
t (h)
Product yieldb (%)
drc
erd
Config.
1
2
1b/2a
1c/2a
1d/2a
1a/2b
1a/2d
1a/2e
1a/2f
1a/2g
1a/2b
1a/2c
1a/2d
1a/2e
1a/2f
1a/2g
IV (5)
IV (5)
IV (5)
IV (5)
IV (5)
IV (5)
IV (5)
IV (5)
V (2)
V (2)
V (2)
V (5)
V (2)
V (2)
6
48
72
36
48
5
4ba (76)
4ca (72)
4da (52)
4ab (64)
4ad (74)
4ae (88)
4af (70)
4ag (99)
4ab (46)
4ac (47)
4ad (43)
4ae (87)
4af (65)
4ag (81)
–
83:17
86:14
89:11
92:8
92:8
89:11
93:7
92:8
91:9
91:9
91:9
92:8
93:7
94:6
(S)
(S)
–
3
–
(S)
4
–
(R)
5
–
(S)
6
–
(S)
7
6
–
(R)
8
7
75:25
(2R,3R)
(R)
9
2
–
10
11
12
13
14
8
–
(R)
2
–
–
(S)
2
(S)
3
–
(R)
6
74:26
(2R,3R)
aReaction performed with 2 equiv of nucleophile. bYields determined after chromatographic purifications. cDiastereomeric excess determined by
1H NMR of the crude reaction mixture. dEnantiomeric ratio determined by chiral HPLC analysis.
although the stereoselectivity for the reaction leading to 4ag, (Scheme 3 and Table 3). The electronic nature of the nitro-
with two contiguous tertiary–quaternary stereocenters was only olefins only affects the yield and the reaction time, being longer
moderate (dr 75:25, entry 8 in Table 2). The main difference as the donating effect of the substituent increases, but main-
in those additions was related with the reaction time, because taining good diastereoselectivity and excellent enantioselectivi-
the less reactive malonates (2b and 2d) reacted slower than ty for all reactions (entries 2–4, Table 3).
the acetylacetone (2e and 2f) or ethyl acetoacetate (2g) deriva-
tives.
With respect to the nucleophile, it is noteworthy that there
seems to be a correlation: With growing size of the cycloalka-
Similar results were obtained when the reaction was run in the none an increase of the reaction time and a decrease of the yield
presence of only 2 mol % of catalyst V (entries 9–14 in can be observed. Cycloheptanone 3c, and specially cyclo-
Table 2). The level of stereoselectivity was maintained, includ- hexanone 3b reacted much more slowly than cyclopentanone
ing the diastereoselectivity for the reaction of 1a with 2g (dr derivative 3a (Table 3, entries 5, 6, and 8), although the reac-
74:26), but the yields for the reactions with 2-substituted tion time could be reduced from 96 h to 10 h in the reaction of
malonates (2b–d) were only moderate (entries 9–11 in Table 2). 1a with 3b by increasing the catalyst loading from 2 mol % to
5 mol % (Table 3, entry 7). It is also noteworthy that 2-acetyl-γ-
Next, we extend the study to the reaction of different β-functio- lactone (3e) reacted very well with 1a, leading to 5ae in excel-
nalized cycloalkanones (3a–c), 2-acetylcyclopentanone (3d), lent yield and enantioselectivity, but only moderate diastereose-
and 2-acetyl-γ-lactone (3e) with nitrostyrene derivatives 1a–d lectivity (dr 70:30, Table 3, entry 10).
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Beilstein J. Org. Chem. 2016, 12, 628–635.
Scheme 3: Reaction of nitrostyrenes with β-keto esters and β-dicarbonyl compounds.
Table 3: Reaction of nitrostyrenes with β-substituted cycloalkanones catalyzed by V.
Entrya
Reagents
Catal. (mol %)
t (h)
Product Yieldb (%)
drc
erd
Config.
1
2
1a/3a
1b/3a
1c/3a
1d/3a
1a/3a
1a/3b
1a/3b
1a/3c
1a/3d
1a/3e
1a/3a
1a/3a
1a/3a
V (5)
V (2)
V (2)
V (2)
V (2)
V (2)
V (5)
V (2)
V (2)
V (2)
V (5)
V (5)
V (5)
0.5
1
5aa (98)
5ba (84)
5ca (76)
5da (74)
5aa (93)
5ab (63)
5ab (62)
5ac (73)
5ad (92)
5ae (89)
5aa (81)
5aa (76)
5aa (82)
89:11
90:10
89:11
89:11
89:11
88:12
88:12
82:18
83:17
70:30
88:12
88:12
88:12
95:5
94:6
93:7
95:5
95:5
96:4
96:4
96:4
93:7
92:8
94:6
95:5
94:6
(S,R)
(S,R)
(S,R)
(S,R)
(S,R)
(S,R)
(S,R)
(S,R)
(R,R)
(R,R)
(S,R)
(S,R)
(S,R)
3
5
4
9
5
1
6
96
10
24
2
7
8
9
10
11e
12f
13g
1
1
1
2
aReaction performed with 2 equiv of nucleophile. bYields determined after chromatographic purifications. cDiastereomeric excess determined by
1H NMR of the crude reaction mixture. dEnantiomeric ratio determined by chiral HPLC analysis. eSecond cycle for entry 1 by using only 1.5 equiva-
lents of nucleophile. fThird cycle for entry 1 by using only 1.5 equivalents of nucleophile. gFourth cycle for entry 1 by using only 1.5 equivalents of
nucleophile.
To test the recyclability of catalyst V we choose the reaction of addition of nitroketone was totally diastereoselective and highly
1a with 3a in neat conditions and 5 mol % of catalyst as model. enantioselective (entries 1–12 in Table 4), whereas both the
Once the reaction had finished (TLC), the catalyst was recov- diastero- and enantioselectivities were moderate for the addi-
ered by filtration, and after washing with methanol and drying tion of nitroester (Table 4, entries 13–15). Additionally, sup-
to constant weight, the catalyst was used in the next cycle ported catalyst V was able to promote more enantioselective
(entries 1 and 11–13 in Table 3). Fortunately, catalyst V can be transformations than unsupported catalyst I (compare Table 4,
reused for at least four cycles yielding 5aa in high yields entry 13 versus 15). The decrease of the temperature slows
(76–82%), and maintaining both the diastereo- and enantiose- down the reaction, increasing the reaction time from 1 h to 6 h
lectivity.
for the reaction of 1a with 6b, catalyzed by I (Table 4, entries
13 and 14), and from 24 h to 48 h for the addition of 6a to 1a
Finally, α-nitrocyclohexanone (6a) and ethyl α-nitropropionate catalyzed for VI (Table 4, entries 7 and 8), but maintaining the
(6b) were included in the screening process in order to compare diastereoselectivity and slightly increasing the enantioselectivi-
the results obtained with more acidic nucleophiles with those ty. The donor character of the substituent in the nitrostyrene de-
obtained with β-dicarbonyl derivatives. The reactions were rivative plays an important role in the process, increasing the
carried out under different conditions by varying the solvent, reaction time, and decreasing the yield (compare Table 4,
the temperature and using unsupported thioureas I and VI, and entries 5, 9, and 11).
V as an example of a supported one (Scheme 4). The most sig-
nificant difference between the reactions of nitroketone and The recent interest in alternative activation modes [32] for
nitroester refers to the stereoselectivity in both processes. The promoting C–C bond formations, led us to consider the catalyt-
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Beilstein J. Org. Chem. 2016, 12, 628–635.
Scheme 4: Reaction of nitrostyrenes with α-nitrocyclohexanone and ethyl α-nitropropionate.
Table 4: Reactions of nitrostyrenes with α-nitrocyclohexanone and ethyl α-nitropropionate.
Entrya
Reagents
Catal. (mol %)
t (h)
Solvent
Product yieldb (%)
drc
erd
1
2
1a/6a
1a/6a
1a/6a
1a/6a
1a/6a
1a/6a
1a/6a
1a/6a
1b/6a
1b/6a
1d/6a
1d/6a
1a/6b
1a/6b
1a/6b
I (5)
I (5)
3
1.5
1
DCM
neat
7aa (62)
7aa (65)
7aa (70)
7aa (60)
7aa (77)
7aa (85)
7aa (64)
7aa (52)
7ba (91)
7ba (48)g
7da(73)
7da(50)h
7ab (75)
7ab (77)
7ab (90)
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
74:26
84:16
90/10
90:10
90:10
91:9
3e
4
I (5)
neat
V (5)
V (5)
V (5)
VI (5)
VI (5)
V (5)
V (5)
V (5)
V (5)
I (5)
48
12
12
24
48
8
DCM
MeCN
neat
5
6e
7
94:6
DCM
DCM
MeCN
neat
85:15
92:8
8f
9
91:9
10e
11
12e
13
14f
15
48
24
360
1
90:10
89:11
87:13
69:31
72:28
74:26
MeCN
neat
neat
I (5)
6
neat
75:25
V (5)
5
neat
76:24
aReaction performed with 1.5 equiv of nucleophile. bYields determined after chromatographic purifications. cDiastereomeric excess determined by
1H NMR of the crude reaction mixture (>98:<2 means that a single diastereomer was detected). dEnantiomeric ratio determined by chiral HPLC analy-
sis. eBall mill conditions. fThe reaction was carried out at −20 °C. g37% of 2-nitrocyclohexanone was recovered unreacted. h30% of 2-nitrocyclohexa-
none was recovered unreacted.
ic addition of α-nitrocyclohexanone (6a) to nitrostyrene deriva- lysts varies with the length of the tether between the polymer
tives 1a, 1b, and 1d under ball milling conditions [33]. We and the thiourea framework, and the best results were obtained
chose these reactions for comparative purposes because they by using catalysts IV and V, derived from 1,6-hexanediamine.
have been previously reported [34]. Although the experimental The reactions work well by using only 2 mol % of catalyst
conditions have not been optimized, we observed that both the loading in neat conditions, and the catalysts can easily be recov-
unsupported (I) and supported (V) catalysts worked very well in ered and reused for four cycles. The results obtained with the
the reaction of 1a with 6a yielding the addition product 7aa in described catalysts are similar to those previously reported by
excellent yields and stereoselectivity (entries 3 and 6 in using bottom-up synthesized materials prepared by co-polymer-
Table 4). On the contrary, the reactions of 6a with 1b and 1d ization of monomeric thioureas as organocatalysts [29]. Cata-
are very slow and 37% and 30% of the nucleophile were recov- lyst V has been also used in the addition of α-nitrocyclohexa-
ered unchanged after 48 h and 360 h of reaction, respectively, none (6a) to β-nitrostyrene (1a) under solvent-free conditions in
although maintaining the stereoselectivity (Table 4, entries 10 a ball mill providing the addition product 7aa in excellent yield,
and 12). The improvement of that process is under study.
total diastereoselectivity, and very good enantioselectitvity.
Experimental
Conclusion
In summary, supported bifunctional thioureas on sulfonylpoly- General remarks
styrene are able to promote highly stereoselective nitro-Michael 13C NMR (126 MHz) and 1H NMR (500 MHz) spectra were re-
reactions with different nucleophiles. The activity of the cata- corded in CDCl3 as the solvent. Chemical shifts for carbons are
633

Beilstein J. Org. Chem. 2016, 12, 628–635.
reported in ppm from TMS and are referenced to the carbon ed by column chromatography. The diastereomeric ratio was
resonance of the solvent. Chemical shifts for protons are re- determined by 1H NMR spectroscopy of the purified product.
ported in ppm from TMS with the residual CHCl3 resonance as
internal reference. Data are reported as follows: chemical shift, Recyclability of the supported thiourea catalysts in nitro-
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = Michael reaction. The supported catalysts were recovered from
multiplet, br = broad), coupling constants in Hertz, and integra- the reaction mixtures by filtration, thoroughly washed with
tion.
methanol, dried and reused in the next cycle.
General procedure for the Michael addition of
2-nitrocyclohexanone to β-nitrostyrene using
immobilized catalyst VI
Flash chromatography was carried out using silica gel
(230–240 mesh). TLC analysis was performed on glass-backed
plates coated with silica gel 60 and an F254 indicator, and visu-
alized by either UV irradiation or by staining with phospho-
molybdic acid solution. Specific rotations were measured on a
digital polarimeter using a 5 mL cell with a 1 dm path length,
and a sodium lamp, and the concentration is given in g per
100 mL. Chiral HPLC analysis was performed by using Daicel
Chiralcel OD or Chiralpak AD-H, analytical columns
(250 × 4.6 mm) by using mixture of n-hexane/isopropanol as
eluent. UV detection was monitored at 220 or at 254 nm. ESI
mass spectra were obtained on an Agilent 5973 inert GC/MS
system. Commercially available organic and inorganic com-
pounds were used without further purification. Solvents were
dried and stored over microwave–activated 4 Å molecular
sieves. Supported thioureas II–V and unsupported thioureas I
and VI were prepared according to reported procedures [30,31].
Racemic reference samples were prepared by using DABCO
Method A, in organic solvent: The reactions were carried out
as previously described [29]. To a stirred solution of 2-nitro-
cyclohexanone (43 mg, 0.3 mmol) and nitroalkene (0.45 mmol,
1.5 equiv) in an adequate solvent (0.4 mL), catalyst VI (15 mg,
0.015 mmol, 0.05 equiv) was added and the reaction mixture
was stirred at room temperature in a Wheaton vial until the
reaction was finished (TLC). The catalyst was filtered off
and washed with DCM (3 × 1 mL). The solvent was removed
under reduced pressure, the crude mixture subjected to flash
chromatography to afford the Michael adduct. The diastereo-
meric ratio was determined by 1H NMR spectroscopy of the
purified product. The enantiomeric excess was determined by
chiral-phase HPLC analysis using mixtures of hexane/
isopropanol as eluent.
(5 mol %) following the same procedure as described below. Method B, under ball-milling conditions: Catalyst VI (15 mg,
0.015 mmol, 0.05 equiv), 2-nitrocyclohexanone (43 mg,
General procedure for the nitro-Michael reaction using ho- 0.3 mmol) and nitroalkene (0.45 mmol, 1.5 equiv) were trans-
mogeneous catalysts (I and VI). The reactions were carried ferred to a clean, dry ball milling vessel (cylinder of 5 mL)
out as previously described [29]. To a mixture of nitrostyrene loaded with two grinding balls with a 7 mm diameter. The
(0.3 mmol) and catalyst (0.015 mmol, 0.05 equiv), the 1,3- vessel was placed in a Mixer Mill MM 200 and the mixture was
dicarbonyl compound (0.6 mmol, 2 equiv) was added and the milled at 5 Hz of vibrational frequency at room temperature
reaction mixture was stirred at rt in a Wheaton vial until until consumption of the starting material (monitored by TLC).
consumption of the starting material (monitoring by TLC). The The vessel and the balls were washed with CH2Cl2, the catalyst
reaction mixture was purified by column chromatography to was filtered off and washed with CH2Cl2 and methanol. The re-
afford the Michael product. The anti- and syn-isomers of the sulting solution was concentrated in vacuo, and the product was
Michael products were not separated by column chromatogra- purified by flash chromatography. The diastereomeric ratio was
phy. The diastereomeric ratio was determined by 1H NMR determined by 1H NMR spectroscopy of the purified product.
spectroscopy of the purified product.
The enantiomeric excess was determined by chiral-phase HPLC
analysis using mixtures of hexane/isopropanol as eluent.
General procedure for the nitro-Michael reaction using
inmobilized catalysts (II, III, IV and V) [29]. To a mixture of
β-nitrostyrene (0.3 mmol) and catalyst (0.015 mmol,
0.05 equiv), 1,3-dicarbonyl compound (0.6 mmol, 2 equiv) was
added and the reaction mixture was stirred at rt in a Wheaton
vial until consumption of the starting material (monitored by
TLC). The catalyst was filtered off and washed with MeOH
(3 × 1 mL). The solvent was removed under reduced pressure,
and the residue was purified by column chromatography. The
anti- and syn-isomers of the Michael products were not separat-
Supporting Information
Supporting Information File 1
Physical and spectral data for all the compounds. Copies of
1H, 13C NMR spectra, and HPLC traces for all compounds
synthesized.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-61-S1.pdf]
634

Beilstein J. Org. Chem. 2016, 12, 628–635.
26.Manzano, R.; Andrés, J. M.; Álvarez, R.; Muruzábal, M. D.;
Acknowledgements
We acknowledge the financial support provided by the Spanish
MINECO (Project CTQ2014-59870-P) and Junta de Castilla y
León (Project VA064U13).
Rodríguez de Lera, A.; Pedrosa, R. Chem. – Eur. J. 2011, 17,
5931–5938. doi:10.1002/chem.201100241
27.Manzano, R.; Andrés, J. M.; Muruzábal, M.-D.; Pedrosa, R.
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