Chiral ureas and thioureas supported on polystyrene for enantioselective aza-Henry reactions under solvent-free conditions

Article abstract of DOI:10.1039/c4gc02474e

Novel bifunctional ureas and thioureas immobilized on sulfonylpolystyrene have been prepared as recoverable and reusable organocatalysts and have been used in the stereoselective aza-Henry reaction under solvent-free conditions. The activity and stereoselection of the catalysts are dependent on the length of the tether bridging the active site and the polymer, the catalyst derived from 1,6-hexane diamine being the best one. It has also been demonstrated that the supported catalysts are more effective than the homologous soluble catalysts.

Full text of DOI:10.1039/c4gc02474e

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Page 1 of 28
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Chiral Ureas and Thioureas Supported on Polystyrene for Enantioselective Aza-
Henry Reaction in Solvent-free conditions.
Rafael Pedrosa,* José M. Andrés,* Deisy P. Ávila, Miriam Ceballos and Rodrigo
Pindado
Instituto CINQUIMA and Departamento de Química Orgánica. Facultad de Ciencias,
Universidad de Valladolid. Paseo de Belén 7, 47011ꢀValladolid. Spain
Eꢀmail: pedrosa@qo.uva.es .
Web: http://sintesisasimetrica.blogs.uva.es
Abstract.
Novel bifunctional ureas and thioureas inmovilized on sulfonylpystyrene have been
prepared as recoverable and reusable organocatalysts and used in the stereoselective
azaꢀHenry reaction under solventꢀfree conditions. The activity and stereoselection of
the catalysts are dependent on the length of the tether bringing the active site and the
polymer, being the catalyst derived from 1,6ꢀhexane diamine the best one. It has been
also demonstrated that the supported catalysts are more effective than the homologous
soluble catalysts.

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Introduction
The azaꢀHenry reaction constitutes an important CꢀC forming process, which can
result in the formation of two contiguous stereocenters containing nitrogen
substituents. The resulting nitroamines are valuable chiral building blocks that are
easily converted in 1,2ꢀdiamines1 or αꢀamino substituted carbonyl derivatives,2 and
the development of asymmetric version of the reaction has attracted continuous
interest.
The first asymmetric azaꢀHenry reaction was attempted by using chiral
heterobimetallic complexes derived from binaphtol3 or bisoxazolineꢀCu(II)
complexes,4 leading to the corresponding 2ꢀnitroamines with good yields and
enantiomeric excesses (ee). More recently, chiral bifunctional thioureas derived from
transꢀ1,2ꢀcyclohexane diamine have been successfully used as organocatalysts in the
enantioselective addition of nitromethane to Nꢀphosphinoylimines5 and NꢀBoc
imines6 yielding the azaꢀHenry products with moderate to good enantioselectivities.
Ureas and thioureas attached to different chiral structures, such as alkaloids,7
diamines,8 carbohydrates,9 steroids,10 sulfinyl group,11 triaryliminophosphoryl,12
oxazolino thioureas,13 guanidino thioureas,14 and bisꢀthioureas15 have been used to
promote enantioselective azaꢀHenry reactions.
The use of chiral squaramides16 and bisamidine triflate salts17 has been also
documented for the diastereo and enantioselective addition of nitroethane to NꢀBoc
imines, and chiral BINOL phosphates also act as bifunctional catalysts in the addition
of nitroalkanes to aldimines.18 In a different approach, enantioselective azaꢀHenry
reactions have been carried out from carbamateꢀprotected imines generated in situ
from αꢀamido sulfones under phaseꢀtransfer catalysis by using guanidinium,19

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phosphonium,20 or quaternary ammonium salts derived from cinchone,21 and amino
acids.22
In general, all the ureas and thioureas described until now are highly active catalysts,
but methods leading to improvement of the recovering and reuse of the catalysts are
desirable, and one possible solution consists on their immobilization onto a polymeric
material.23 In that way, chiral thioureas have been anchored into different
functionalized polymers,24 mesoporous silica gel,25 and magnetic nanoparticles,26 but
to the best of our knowledge, there are not antecedents on the use of these catalysts in
the enantioselective azaꢀHenry reaction.
Because the use of organocatalysts supported on chemically inert material made the
process more sustainable and greener,27 and based on our previous experience in the
used of sulfonyl polystyrene as support,28 we envisaged that it was possible to anchor
bifunctional ureas and thioureas to be able to promote enantioselective azaꢀHenry
reactions. The catalytic activity of these materials is dependent on a lot of parameters,
including the accessibility of the reactants to the active site, whereas the recyclability
and durability of the catalyst is dependent on the robustness of the bond linking the
catalyst to the polymer.23 We have prepared catalysts from sulfonylpolystyrene and
bifunctional ureas and thioureas with an additional amino group because the
sulfonamide group is very stable. The supported catalysts differ in the size of the
tether connecting the catalyst with the sulfonyl group and the substitution pattern on
the nitrogen atom in the sulfonamide.
The general approach to the catalysts is depicted in Figure 1. Essentially, the catalysts
were prepared by condensation of supported chiral triamines with 3,5ꢀbis(trifluoro
methyl) phenyl isocyanate or isotiocyanate. Chiral triamines were prepared instead by
reaction of 1,2ꢀ or 1,6ꢀdiamines with natural αꢀamino acids followed by reduction. In

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our case, we chose Lꢀvaline as a source of the chiral environment because we have
previously demonstrated that bifunctional ureas and thioureas derived from this amino
acid are excellent organocatalysts in several enantioselective transformations.29
Figure 1. Proposed synthesis of supported catalysts.
Results and discussion
Starting ethylene diamine and 1,6ꢀhexane diamine derivatives with different
substituents at the nitrogen atoms were prepared, in two steps and good yields, from
Bocꢀglycine and NꢀBoc amino hexanoic acid,30 respectively, as summarized in
Scheme 1.
Scheme 1. : (i) 1. ClCO2Et, NMM, THF, 0 ºC, then Bn2NH for 1 and 3, or BnNHMe
for 2. (ii) LAH, THF, reflux.

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Reaction of NꢀBoc protected amino acids with dibenzylamine or benzyl methylamine
lead to amides 1ꢀ3, which were transformed into Nꢀmethyl amines 4ꢀ6 by reduction
with lithium aluminum hydride in THF at reflux.
Supported catalysts 19ꢀ24 were prepared as summarized in Scheme 2. The reaction of
a mixture of NꢀBocꢀLꢀvaline and DCC with diamines 4ꢀ6 or the commercially
available 1,6ꢀN,N´ꢀdimethyl hexane diamine in DCM lead to NꢀBocꢀLꢀvalinamides 7ꢀ
9 and 10, respectively. These were transformed into triamines 11ꢀ14 by sequential
o
quimioselective reduction of the amide function with LAH in THF at 0 C, followed
by hydrogenolysis of the benzyl groups in the presence of palladium on carbon or
Perlman´s catalyst.
The covalent immobilization onto the polystyrene resin was done by reacting
triamines 11ꢀ14 with chlorosulfonyl polystyrene and triethylamine in DCM at rt for 4
days leading to supported materials that were transformed into 15ꢀ18 by deprotection
with trifluoroacetic acid in DCM for 6 h at rt, in good yields. Finally, 15 and 16,
which differ in the substitution pattern on the nitrogen of the sulfonamide, were
transformed into thioureas 19 and 21 by condensation with 3,5ꢀbis(trifluromethyl)
isothiocyanate, whereas ureas 20 and 21 were also obtained from the same supported
amines by reaction with 3,5ꢀbis(trifluromethyl) isocyanate. In the same way, thioureas
23 and 24 result in the reaction of 17 and 18, respectively, with the corresponding
isothiocyanate. For comparative purposes, we also prepared the tosyl thiourea 26,
unsupported homologous of 24, from triamine 14 by tosylation to 25 followed by
deprotection and condensation with 3,5ꢀbis(trifluromethyl) isothiocyanate.

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Scheme 2. Reagents and conditions: (i) DCC, CH2Cl2, diamines 4ꢀ6 for 7ꢀ9 or
MeNH(CH2)6NHMe for 10, 0 ºC to rt. (ii) 1. LAH, THF, 0 ºC, 1h. 2. H2, Pd(OH)2ꢀC,
MeOH for 11 and 13; H2, Pd/C, MeOH for 12 and 14. (iii) 1. Sulfonyl chloride,
polymer bound, CH2Cl2, Et3N, rt, 4 days. 2. TFA, CH2Cl2, rt, 18 h. (iv) 3,5ꢀ
o
o
(CF3)2C6H3NCX, CH2Cl2, 0 C to rt 24h. (v) TsCl, Et3N, CH2Cl2, 0 C to rt. (vi) 1.
TFA, CH2Cl2, rt, 6h. 2. 3,5ꢀ(CF3)2C6H3NCS, CH2Cl2, 0 oC to rt 24h.
The supported materials were characterized by IR spectroscopy, and the analytical
data allowed the calculation of effective functionalization f (urea or thiourea contents
per gram of resin) of the functionalized polymer, that varied from f = 0.95 for 19 to f
= 1.11 for 22.31
For comparison of the activity of the different catalysts, and optimization of the
reaction conditions, we studied the reaction of NꢀBocꢀbenzaldimine 29a with
nitromethane, and the results are collected in Table 1. Initially, we test the influence

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of the solvent in the reaction catalyzed by 5 mol% of thiourea 24 at rt (entries 1ꢀ4 in
Table 1), observing that the reaction rate decreased when increasing the polarity of
the solvent, but both the yield and the enantioselectivity increased. Fortunately,
searching for greener conditions, 24 (10 mol%) was able to catalyze the reaction
under solventꢀfree conditions, leading to the addition product 30a with excellent yield
(95%) and enantioselectivity (98/2 er) after only 3 h of reaction (entry 5).
These results are comparable with those obtained in homogeneous reaction conditions
by employing urea 27 and thiourea 2832 as soluble catalysts, although in these cases
the time decreased to 1h and 8h for the reactions without solvent or in DCM,
respectively (entries 6ꢀ8 in Table 1). The catalytic activity of the supported ureas and
thioureas derived from 1,2ꢀethylene diamine (19ꢀ22) is moderate. In neat conditions,
both the yields and the enantioselection are lesser than the obtained with 24 (compare
entry 5 versus 9ꢀ12 in Table 1). Moreover, thioureas 19 and 21 gave better results
than ureas 20 and 22 (compare entries 9 versus 10 and 11 versus 12), and Nꢀmethylꢀ
substituted derivatives 21 and 22 are better catalysts that unsubstituted sulfonamides
19 and 20. This behavior parallels that of thioureas derived from 1,6ꢀhexane diamine,
being better catalyst Nꢀmethyl substituted derivative 24 than supported unsubstituted
sulfonamide 23 (compare entry 5 versus 13).

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Table 1. Screening of thiourea catalysts and optimization of enantioselective azaꢀ
Henry reaction conditions of NꢀBocꢀimine 29a with nitromethane.
Entrya
Yield (%)b Erc
Catalyst,
(mol %)
24 (5%)
24 (5%)
24 (5%)
24 (5%)
24 (10%)
27 (10%)
28 (10%)
28 (10%)
19 (10%)
20 (10%)
21 (10%)
22 (10%)
23 (10%)
23 (5%)
23 (2%)
24 (5%)
24 (2%)
24 (5%)
24 (5%)
26 (5%)
Solvent t (h) T (ºC)
1
2
toluene
CH2Cl2
THF
MeCN
neat
10
24
20
24
3
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
72
76
86
88
95
99
84
85
45
34
72
68
85
80
78
93
85
88
89
84
94:6
94:6
94:6
96:4
98:2
96:4
96:4
98:2
91:9
83:17
93:7
85:15
95:5
95:5
95:5
98:2
97:3
97:3
97:3
96:4
3
4
5
6
neat
1
7
CH2Cl2
neat
8
8
1
9
neat
32
48
28
24
3
10
11
12
13
14
15
16
17
18
19
20
neat
neat
neat
neat
neat
5
neat
24
5
neat
neat
16
6
neat
neat
15
3
ꢀ18
rt
neat
a
b
c
Reactions were conducted at 0.3 mmol scale in 0.1 mL of nitromethane (6 equiv). Isolated yield.
Enantiomeric ratio determined by HPLC analysis using a chiral column, and absolute configuration
was determined by comparison of the HPLC retention time with that of literature data.
Otherwise a comparison of the results obtained with the supported catalysts derived
from ethylene diamine (19ꢀ22) and 1,6ꢀhexane diamine (23, 24) showed that both the
yields and enantioselectivities increased with the size of the length of the tether
connecting the catalytic structure and the polymer. The effect of the amount of

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catalyst in the reaction was examined by using supported thioureas 23 and 24, and the
results shown that the catalysts loading could be reduced to 2 mol% without affecting
the enantioselectivity for 23 and slightly decreasing for 24, but in both cases, at
expenses of decreasing the yields, and increasing the reaction time (compare entries
13ꢀ15 and 5, 16ꢀ17 in Table 1). It is interesting to note that supported thiourea 24
provided better yield and enantioselectivity than the soluble tosyl thiourea 26 with the
same functionality (compare entries 16 and 20).
In order to increase the enantioselection, the effect of the temperature was also
studied, but not improvement in the er was observed when the reactions were carried
out at 0 oC or ꢀ18 oC (entries 18, and 19).
After the optimization studies, we decide that the best reaction conditions consisted in
using 5 mol% of supported catalysts 23 or 24, without solvent and performing the
reactions at rt. Under these conditions, we tested the generality of the reaction of
nitromethane with different NꢀBoc aldimines 29aꢀk, which differ in the electronic
nature of the aryl group (Scheme 3 and Table 2).
From the data collected in Table 2 it was observed that, as a general trend, catalyst 24
was better than 23, yielding the addition products in higher yields and
enantioselectivities except for imines 29b and 29f with substituents with strong
withdrawing effect, or imine 29j derived from 1ꢀnaphtaldehyde.
Scheme 3. Enantioselective azaꢀHenry reaction with different aldimines.

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Table 2. Enantioselective azaꢀHenry reaction of nitromethane with aldimines 29a-k
in the presence of catalyst 23 and 24.
Entrya
Erc
Ar
Catalyst t (h)
Product
Yield (%)b
30a (88)
30a (93)
30b (81)
30b (78)
30c (70)
30c (88)
30d (90)
30e (82)
30f (95)
30f (89)
30g (73)
30g (91)
30h (73)
30h (96)
30j (98)
30j (91)
30i (70)
30i (93)
30k (67)
30k (73)
30a (83)
30a (85)
30a (82)
1
2
C6H5
C6H5
5
5
95:5
98:2
23
24
23
24
23
24
24
24
23
24
23
24
23
24
23
24
23
24
23
24
23
24
24g
3
pꢀNO2C6H4
pꢀNO2C6H4
pꢀClC6H4
pꢀClC6H4
oꢀClC6H4
mꢀClC6H4
pꢀCF3C6H4
pꢀCF3C6H4
pꢀMeOC6H4
pꢀMeOC6H4
pꢀMeC6H4
pꢀMeC6H4
1ꢀnaphtyl
1ꢀnaphtyl
2ꢀnaphtyl
2ꢀnaphtyl
2ꢀfuryl
2
95:5
4
2
95:5
5
3
95:5
6
2
97:3
7
2
94:6
8
2
96:4
9
2
98:2
10
11
12
13
14
15
16
17
18
19
20
21d
22d
23e
3
97:3
10
5
92:8
97:3
6
94:6
5
95:5
4
94:6
4
94:6
5
95:5
2
96:4
2
88:12
2ꢀfuryl
2
91:9
C6H5
6
95:5 (100:0)f
96:4 (100:0)f
97:3 (100:0)f
C6H5
6
C6H5
16
a
The reactions were carried out with imines 29a-k (0.3 mmol) and nitromethane (6 equiv) at room
b
c
temperature in the presence of catalyst 23 or 24 (0.05 equiv). Isolated yield after chromatography.
Enantiomeric ratio determined by HPLC analysis using a chiral column and absolute configuration was
d
determined by comparison of the HPLC retention time with that of literature data. Reaction
e
f
performed with 3 mmol of imine. Reaction performed with 6 mmol of imine. Numbers in
parenthesis indicated the er after recrystallization in hexaneꢀEtOAc, and 100:0 means that only one
enantiomer was detected in the HPLC trace. g Only 2 mol% of catalyst was used.

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Otherwise, the reactions occurred in high yields (67ꢀ96%) and enantioselection (88:12
to 98:2 er) independently of the donating or withdrawing character of the substituent
at the aromatic ring, including aldimine 29k with a heteroaromatic substituent.
On the light of these results, we decide to scaleꢀup the reaction (entries 21ꢀ23 in Table
2). Both catalysts 23 and 24 were able to promote the reaction of 0.567 g (3 mmol) of
benzaldimine 29a with nitrometane yielding the addition product in excellent yield
and 95:5 or 96:4 er, respectively. A single recrystallization leaded nitroamine 30a
enantiomerically pure (entries 21, 22 in Table 2). Similar results were obtained
increasing the amount of aldimine 29a to 6 mmol, and using only 2 mol% of catalyst
24, although at expenses to increase the reaction time to 16 h. (entry 23 in Table 2).
The generality of the reaction was extended to different nitroalkanes searching for
stereoselective azaꢀHenry reaction. To this end, NꢀBoc imines derived from
benzaldehyde (29a) and 4ꢀchlorobenzaldehyde (29c) were reacted with different
nitroalkanes (31aꢀe) in the presence of 5 mol% of catalysts 23 and 24 (Scheme 4), and
the results are summarized in Table 3.
Scheme 4. Diastereoꢀ and enantioselective azaꢀHenry reaction.
The reaction of imines with nitroalkanes 31aꢀd yielded the known antiꢀaddition
products as major diastereoisomers with stereoselectivities that are dependent on the
nature of the nitroalkane. Thus, nitroethane (31a) or nitropropane (31b) provided the
addition products with good diastereoselectivity and very good enantioselectivity
(entries 1ꢀ3 in Table 4), but phenyl nitromethane (31d) leaded to 32ad in good

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diastereoselectivity and poor enantioselection (entry 5).33 Both diastereoꢀ and
o
enantioselection slightly improved when the reaction was carried out at 0 C. In these
conditions NꢀBocꢀ4ꢀchloro benzaldimine (29c) yielded 32cd17b with excellent
diastereoselection but poor enantioselection when reacted with phenyl nitromethane
(entry 7 in Table 4). In an attempt to prepare 2ꢀnitroꢀ3ꢀaminopropanol derivatives, we
reacted 2ꢀnitroethanol (31e) with imine 29a, but the ethanol derivative behaved as
nucleophile by the hydroxyl group leading to the N,Oꢀacetal 33 in excellent yield as a
racemic mixture (entry 8 in Table 3). The use of the protected nitroalcohol 31c as a
nucleophile allowed the isolation of the azaꢀHenry product 32ac in good yield,
although with poor diastereoselectivity and moderate enantioselectivity (entry 4 in
Table 3).
Table 3. Stereoselective azaꢀHenry reactions with representative nitroalkanes.
Entrya
Drc
Erd
Reactants Catalyst
t
Product
(%)b
(mol %) (h)
1
2
23 (5%)
24 (5%)
24 (5%)
24 (5%)
24 (5%)
24 (5%)
24 (5%)
24 (5%)
3
2
32aa (81)
32aa (94)
32ab (78)
32ac (77)
32ad (93)
32ad (71)
32cd (60)
33 (88)
83/17 91:9
82/18 93:7
88/12 97:3
56/44 88:12
87/13 69:31
91/9 71:29
96/4 66:34
29a/31a
29a/31a
29a/31b
29a/31c
29a/31d
29a/31d
29c/31d
29a/31e
3
3
4
8
5
3
6e
7e
8
3
20
2
ꢀ
50/50
a The reactions were carried out with imines (0.3 mmol) and nitroalkanes (6 equiv) at room temperature
b
c
in the presence of catalyst (0.05 equiv). Isolated yield after chromatography. Diastereomeric and
d
e
enantiomeric ratio determined by chiral HPLC. Values refer to the major anti diastereosiomers.
Reaction performed at 0 oC.
Finally, the recyclability of the supported catalysts was tested for 23 and 24 in the
reaction of NꢀBoc benzaldimine with nitromethane at rt under solventꢀfree conditions,

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and 5 mol% of catalysts. The reaction time (6 h) was maintained constant in each
cycle, the catalyst used was recovered by filtration, washed, and used in the next
cycle. Supported catalyst 23 was used three times affording azaꢀHenry product 30a
without loss of activity and enantiocontrol (entries 1ꢀ3 in Table 4). Catalyst 24 was
recycled five times, maintaining the enantioselection, but it means that the activity
slightly decreased for the fifth cycle, although the IR spectrum and analytical data of
the recovered material did not show any difference with the starting catalyst.
Table 4. Recyclability of catalyst 23 and 24 under the optimized conditions.a
Yield (%)b
Erc
95:5
95:5
95:5
98:2
96:4
97:3
98:2
96:4
Entry
Catalyst
t (h)
6
6
6
6
6
6
6
6
1
2
3
4
5
6
7
8
23 (cycle 1)
23 (cycle 2)
23 (cycle 3)
24 (cycle 1)
24 (cycle 2)
24 (cycle 3)
24 (cycle 4)
24 (cycle 5)
88
89
86
82
84
88
86
74
a Reactions were performed with 3 mmol imine 29a and 6 equiv of nitromethane at rt in the presence of
5 mol% of catalyst. b Isolated yield after column chromatography.c Determined by chiral HPLC.
Conclusions
In summary, we have prepared novel supported bifunctional ureas and thioureas on a
matrix of sulfonylpolystyrene in few steps from cheap and commercially accessible
materials. These materials have been employed as stereoselective organocatalysts in
the azaꢀHenry reaction, under solvent free conditions, leading to the addition products
with moderate diastereoselectivity and excellent enantioselectitity. The activity and
enantioselection of the catalysts is dependent on the length of the tether connecting
the urea or thiourea functionality with the polymer, and the best results were obtained
for catalyst 24, derived from 1,6ꢀhexane diamine. Catalysts 23 and 24 can be recycled

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for three or five times, respectively, without loss of enantioselection and slight
decrease in the activity.
Experimental part
General
1H NMR (500 MHz) and 13C NMR (126 MHz) spectra were recorded in CDCl3 as
solvent. Chemical shifts for protons are reported in ppm from TMS with the residual
CHCl3 resonance as internal reference. Chemical shifts for carbons are reported in
ppm from TMS and are referenced to the carbon resonance of the solvent. 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.
Specific rotations were measured on a Perkin–Elmer 341 digital polarimeter using a
5ꢀmL cell with a 1ꢀdm path length, and a sodium lamp, and concentration is given in
g per 100 mL. Infrared spectra were recorded on a Perkin–Elmer Spectrum One FT–
IR spectrometer and are reported in frequency of absorption (only the structurally
most important peaks are given). Melting points were obtained with open capillary
tubes and are uncorrected. Flash chromatography was carried out using silica gel
(230–240 mesh). TLC analysis was performed on glassꢀbacked plates coated with
silica gel 60 and an F254 indicator, and visualized by either UV irradiation or by
staining with phosphomolybdic acid solution. Chiral HPLC analysis was performed
on a JASCO HPLC system (JASCO PUꢀ2089 pump and UVꢀ2075 UV/Vis detector)
and on Hewlett–Packard 1090 Series II instrument equipped with a quaternary pump,
using a Daicel Chiralcel OD, Chiralcel OJ, Chiralpak ADꢀH, Chiralpak ASꢀH or
Chiralpak IA analytical columns (250 x 4.6 mm). UV detection was monitored at 220
or at 254 nm. Elemental analyses were carried out at the Elemental Analysis Center of
the Complutense University of Madrid, using a Perkin Elmer 2400 CHN analyzer.

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ESI mass spectra were obtained on a 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 Å molecular
sieves.
General procedure to enantioselective Aza-Henry reaction using immobilized
catalysts. To a mixture of Bocꢀimine 29 (0.3 mmol) and catalyst (0.015 mmol, 0.05
eq), nitromethane (0.1 mL, 1.8 mmol, 6 equiv) was added and the reaction mixture
was stirred at rt in a wheaton vial until consumption of the starting material. The
catalyst was filtered off and washed with CH2Cl2 (3 x 1 mL). After solvent removal
under reduced pressure, the crude mixture was purified by flash column
chromatography to afford the corresponding product. The enantiomeric excess was
determined by chiralꢀphase HPLC analysis using mixtures of hexane/isopropanol as
eluent.
General procedure to enantioselective Aza-Henry reaction using homogeneous
catalysts. To a mixture of Bocꢀimine 29a (62 mg, 0.3 mmol) and catalyst 26 (10 mg,
0.015 mmol, 0.05 eq), nitromethane (0.1 mL, 1.8 mmol, 6 equiv) was added and the
reaction mixture was stirred at rt in a wheaton vial until consumption of the starting
material. After solvent removal under reduced pressure, the crude mixture was
purified by flash column chromatography to afford the corresponding product. The
enantiomeric excess was determined by chiralꢀphase HPLC analysis using mixtures of
hexane/isopropanol as eluent.
Recyclability of the supported thiourea catalysts in aza-Henry reaction. At the
end of the azaꢀHenry reaction between Bocꢀimine 29a and nitromethane, the catalysts
were filtered and washed with CH2Cl2. After being dried under vacuum, the supported
catalysts were reused directly without further purification.

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tert-Butyl (S)-(1-phenyl) 2-nitroethylcarbamate (30a).34 Obtained according to the
general procedure, using NꢀBocꢀimine 29a (62 mg, 0.3 mmol), nitromethane (0.1 mL,
1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude reaction mixture was
purified by flash column chromatography (hexane/ethyl acetate: 8:1) to yield
1
compound 30a (78 mg, 0.28 mmol, 93%). Colorless solid. HꢀNMR (500 MHz,
CDCl3) δ 1.44 (s, 9H, CH3), 4.71 (m, 1H, CHHN), 4.85 (m, 1H, CHHN), 5.29 (m, 1H,
CHN), 5.35 (br. s, 1H, NH); 7.31ꢀ7.39 (m, 5H, Har). HPLC (Chiralpak ADꢀH,
hexano/isopropanol 90:10, 1mL/min, λ= 210 nm) tR = 18.5 min (mayor, S), 20.3 min
(minor, R). (er 98:2).
tert-Butyl
(S)-1-(4-nitrophenyl)-2-nitroethylcarbamate
(30b).34 Obtained
according to the general procedure, using NꢀBocꢀimine 29b (75 mg, 0.3 mmol),
nitromethane (0.1 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude
reaction mixture was purified by flash column chromatography (hexane/ethyl acetate:
8:1) to yield compound 30b (73 mg, 0.24 mmol, 78%). Colorless solid.1HꢀNMR (500
MHz, CDCl3): δ 1.43 (s, 9H), 4.79 (m, 1H, CHHN), 4.89 (m, 1H, CHHN), 5.50 (m,
1H, CHN), 5.70 (br. s, 1H, NH), 7.53 (d, J = 8.7 Hz, 2H, Har), 8.22 (d, J = 8.7 Hz,
2H, Har). HPLC (Chiralpak ADꢀH, hexane/isoꢀpropanol = 90:10, 254 nm, 1.0
mL/min): tR = 32.4 min (major, S), 74.8 min (minor, R). (er 95:5).
tert-Butyl
(S)-1-(4chlorophenyl)-2-nitroethylcarbamate
(30c).34 Obtained
according to the general procedure, using NꢀBocꢀimine 29c (72 mg, 0.3 mmol),
nitromethane (0.1 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude
reaction mixture was purified by flash column chromatography (hexane/ethyl acetate:
1
8:1) to yield compound 30c (79 mg, 0.26 mmol, 88%). Colorless solid. HꢀNMR
(500 MHz, CDCl3) δ 1.44 (s, 9H, CH3), 4.66 (dd, J = 5.0Hz, 12.6 Hz, 1H, CHHN),
4.79 (m, 1H, CHHN), 5.30 (m, 1H, CHN), 5.38 (br s, 1H, NH), 7.25 (d, J= 8.5Hz, 2H,

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Har), 7.36 (d, J= 8.5Hz, 2H, Har). HPLC (Chiralpak ADꢀH column, hexane/isoꢀ
propanol = 95:5, 220nm, 1.0 mL/min): tR = 31.7 min (major, S), 43.6 min (minor, R).
(er 96:4).
(S)-tert-Butyl-1-(2-chlorophenyl)-2-nitroethylcarbamate
(30d).34
Obtained
according to the general procedure, using NꢀBocꢀimine 29d (72 mg, 0.3 mmol),
nitromethane (0.1 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude
reaction mixture was purified by flash column chromatography (hexane/ethyl acetate:
1
8:1) to yield compound 30d (81 mg, 0.27 mmol, 90%). Colorless solid. HꢀNMR
(500 MHz, CDCl3): δ 1.44 (s, 9H, CH3), 4.79 (m, 1H, CHHN), 4.86 (m, 1H, CHHN),
5.73 (m, 1H, CHN), 5.75 (br. s, 1H, NH), 7.30ꢀ7.40 (m, 4H, Har). HPLC (Chiralpak
ADꢀH, hexane/isoꢀpropanol = 90:10, 210 nm, 1.0 mL/min): tR = 14.0 min (major, S),
21.0 min (minor, R). (er 94:6).
tert-Butyl
(S)-1-(3-chlorophenyl)-2-nitroethylcarbamate
(30e).34 Obtained
according to the general procedure, using NꢀBocꢀimine 29e (72 mg, 0.3 mmol),
nitromethane (0.1 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude
reaction mixture was purified by flash column chromatography (hexane/ethyl acetate:
8:1) to yield compound 30e (83 mg, 0.28 mmol, 92%). Colorless solid.1HꢀNMR (500
MHz, CDCl3): δ 1.43 (s, 9H, CH3), 4.69 (m, 1H, CHHN), 4.81 (m, 1H, CHHN), 5.35
(m, 1H, CHN), 5.47 (br s, 1H), 7.20ꢀ7.30 (m, 4H, Har). HPLC (Chiralpak ADꢀH
column hexane/isoꢀpropanol = 90:10, 210nm, 1.0 mL/min): tR = 12.5 min (major, S),
16.7 min (minor, R). (er 96:4).
tert-Butyl
(S)-1-(4-trifluoromethylphenyl)-2-nitroethylcarbamate
(30f).22
Obtained according to the general procedure, using NꢀBocꢀimine 29f (82 mg, 0.3
mmol), nitromethane (0.1 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The
crude reaction mixture was purified by flash column chromatography (hexane/ethyl

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1
acetate: 8:1) to yield compound 30f (73 mg, 0.27 mmol, 89%). Colorless solid. Hꢀ
NMR (500 MHz, CDCl3) δ 1.44 (s, 9H, CH3), 4.74 (d, J= 11.8Hz, 1H, CHHN), 4.86
(m, 1H, CHHN), 5.43 (m, 1H, CHN), 5.43 (br s, 1H, NH), 7.46 (d, J = 8.0 Hz, 2H,
Har), 7.66 (d, J = 8.0 Hz, 2H, Har). HPLC (Chiralpak ADꢀH, hexane/isoꢀpropanol =
90:10, 210 nm, 1.0 mL/min): tR =10.5 min (major, S), 16.7 min (minor, R) (er 97:3).
tert-Butyl (S)-1-(4-methoxyphenyl)-2-nitroethylcarbamate (30g).34 Obtained
according to the general procedure, using NꢀBocꢀimine 29g (70 mg, 0.3 mmol),
nitromethane (0.1 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude
reaction mixture was purified by flash column chromatography (hexane/ethyl acetate:
1
8:1) to yield compound 30g (81 mg, 0.27 mmol, 91%). Colorless solid. HꢀNMR
(500 MHz, CHCl3) δ 1.45 (s, 9H, CH3), 3.81 (s, 3H, CH3), 4.68 (dd, J = 12.5 Hz, 5.5
Hz, 1H, CHHN), 4.85 (m, 1H, CHHN), 5.19 (m, 1H, CHN), 5.32 (br s, 1H, NH), 6.90
(m, 2H, Har), 7.23 (m, 2H, Har). HPLC (Chiralcel OD, hexane/isoꢀpropanol = 90:10,
220 nm, 1 mL/min): tR = 35.0 min (minor, R), 39.6 min (major, S). (er 97:3).
tert-Butyl (S)-1-(p-tolyl)-2-nitroethylcarbamate (30h).14 Obtained according to the
general procedure, using NꢀBocꢀimine 29h (62 mg, 0.3 mmol), nitromethane (0.1 mL,
1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude reaction mixture was
purified by flash column chromatography (hexane/ethyl acetate: 8:1) to yield
1
compound 30h (81 mg, 0.29 mmol, 96%). Colorless solid. HꢀNMR (500 MHz,
CDCl3): δ 1.45 (s, 9H, CH3), 2.35 (s, 3H, CH3), 4.70 (m, 1H, CHHN), 4.84 (m, 1H,
CHHN), 5.23 (m, 1H, CHN), 5.34 (br s, 1H, NH), 7.19 (s, 4H, Har). HPLC (Chiralcel
OJ, hexane/isoꢀpropanol = 90:10, 220 nm, 1.0 mL/min): tR = 17.8 min (major, S), 23.3
min (minor, R). (er 95:5).
tert-Butyl (S)-1-(naphthalen-2-yl)-2-nitroethylcarbamate (30i).22 Obtained
according to the general procedure, using NꢀBocꢀimine 29i (77 mg, 0.3 mmol),

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nitromethane (0.1 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude
reaction mixture was purified by flash column chromatography (hexane/ethyl acetate:
8:1) to yield compound 30i (87 mg, 0.28 mmol, 91%). Colorless solid.1HꢀNMR (500
MHz, CDCl3) δ 1.46 (s, 9H, CH3), 4.81 (dd, J = 12.5 Hz, 5.5 Hz, 1H, CHHN), 4.95
(m, 1 H, CHHN), 5.42 (m, 1H, CHN), 5.56 (br s, 1H, NH), 7.41 (dd, J = 8.5 Hz, 2.0
Hz, 1H, Har), 7.50ꢀ7.53 (m, 2H, Har), 7.78 (s, 1H, Har), 7.83ꢀ7.85 (m, 2H, Har), 7.88
(d, J = 8.5 Hz, 1H, Har). HPLC (Chiralpak ADꢀH, hexane/isoꢀpropanol = 95:5, 254
nm, 1.0 mL/min): tR = 21.2 min (major, S), 34.5min (minor, R). (er 94:6).
tert-Butyl (S)-1-(naphthalene-1-yl)-2-nitroethylcarbamate (30j).34 Obtained
according to the general procedure, using NꢀBocꢀimine 29j (77 mg, 0.3 mmol),
nitromethane (0.1 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude
reaction mixture was purified by flash column chromatography (hexane/ethyl acetate:
8:1) to yield compound 30j (88 mg, 0.28 mmol, 93%). Colorless solid. 1HꢀNMR (500
MHz, CDCl3): δ 1.45 (s, 9H, CH3), 4.91 (m, 2H, CHHN), 5.31 (m, 1H, CHN), 6.28
(br. s, 1H, NH), 7.47 (m, 2H, HAr), 7.56 (t, J = 7.5 Hz, 1H, Har), 7.62 (t, J = 7.3 Hz,
1H, Har), 7.86 (dd, J = 5.7, 3.5 Hz, 1H, Har), 7.91 (d, J = 8.2 Hz, 1H, Har), 8.13 (d, J
= 8.2 Hz, 1H, Har). HPLC (Chiralpak ADꢀH, hexane/isoꢀpropanol = 90:10, 210 nm,
1.0 mL/min): tR = 45.7 min (major, S), 58.5 min (minor, R). (er 96:4).
(S)-tert-Butyl 1-(furan-2-yl)-2-nitroethylcarbamate (30k).34 Obtained according to
the general procedure, using NꢀBocꢀimine 29k (59 mg, 0.3 mmol), nitromethane (0.1
mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol).The crude reaction mixture was
purified by flash column chromatography (hexane/ethyl acetate: 8:1) to yield
compound 30k (56 mg, 0.22 mmol, 73%). Colorless solid.1HꢀNMR (500 MHz,
CDCl3): δ 1.45 (s, 9H, CH3), 4.71ꢀ4.74 (dd, J = 12.9, 5.7 Hz, 1H, CHHN), 4.85 (m,
1H, CHHN), 5.29 (m, 1H, CHN), 5.45 (br s, 1H, NH), 6.30ꢀ6.34 (m, 2H, Har), 7.37

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(s, 1H, Har). HPLC (Daicel Chiralpak ADꢀH, hexane/isoꢀpropanol = 90:10, 220nm,
1.0 mL/min): tR = 13.7min (major, S) 15.8 min (minor, R). (er 91:9).
tert-Butyldimethyl(2-nitroethoxy)silane (31c). To a solution of the 2ꢀnitroethanol
(0.79 mL, 11 mmol) and imidazole (1.87 g, 27.5 mmol, 2.5 equiv) in DMF (15 mL)
was added tertꢀbutyldimethylsilyl chloride (1.98 g, 13.2 mmol, 1.2 equiv) and the
mixture was stirred at room temperature overnight. The reaction was quenched with
aqueous saturated NH4Cl solution (25 mL) and decanted. The aqueous phase was
extracted with ether (4 x 15 mL), the combined organic phases where washed with
brine (4 x 15 mL), dried (MgSO4) and the solvent was evaporated to yield an oil
1
which was used without further purification. Yield (2.15 g, 10.5 mmol, 95%). Hꢀ
NMR (500 MHz, CDCl3): δ 0.05 (s, 6H, CH3), 0.85 (s, 9H, CH3), 4.13 (m, 2H, CH2),
4.44 (m, 2H, CH2). 13C ꢀNMR (126 MHz, CDCl3) δ 3.6 (CH3), 25.6 (CH3), 25.7
(C(CH3)3), 59.5 (CH2O), 77.6 (CH2N). IR (ATR): 2953, 2934, 2858, 1554, 1468,
1373, 1259, 1116, 944, 830, 778 cmꢀ1. HRMS calcd. for C8H19NO3Si + H: 206.1207;
found: 206.1202.
tert-Butyl [(1R, 2S)-2-nitro-1-phenylpropyl]carbamate (32aa).14 Obtained
according to the general procedure, using NꢀBocꢀimine 29a (62 mg, 0.3 mmol),
nitroethane (0.13 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude
reaction mixture was purified by flash column chromatography (hexane/ethyl acetate:
15:1) to yield compound 32aa as a mixture of anti/syn diastereomers (69 mg, 0.25
1
mmol, 84%). Colorless solid. HꢀNMR (500 MHz, CDCl3) δ 1.44 (s, 9H, CH3), 1.54
(d, J = 7.0 Hz, 3H, CH3), 4.92 (br s, 1H, NH), 5.11 (m, 0.2H, CHHN), 5.19 (t, J = 7.5
Hz, 0.8H, CHHN), 5.34 (br s, 0.8H, CHHN), 5.58 (m, 0.2H, CHHN), 7.22ꢀ7.27 (m,
2H, Har), 7.32ꢀ7.37 (m, 3H, Har). HPLC (Chiralpak IA, hexane/isoꢀpropanol = 98:2,
220 nm, 1 mL/min): dr (anti:syn): 82:18; major (anti): tr (major) = 23.1 min, tr

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(minor) = 24.4 min, (er 92:8), tr minor (syn): tr (major) = 36.0 min, tr (minor) = 26.4
min. (er 83:17).
tert-Butyl [(1R, 2S)-2-nitro-1-phenylbutyl]carbamate (32ab).14 Obtained according
to the general procedure, using NꢀBocꢀimine 29a (62 mg, 0.3 mmol), 1ꢀnitropropane
(0.16 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude reaction
mixture was purified by flash column chromatography (hexane/ethyl acetate: 15:1) to
yield compound 32ab as a mixture of anti/syn diastereomers (68 mg, 0.23 mmol,
1
77%). Colorless solid. HꢀNMR (500 MHz, CDCl3) δ 0.98 (t, J = 7.0 Hz, 3H, CH3),
1.42 (s, 9H, CH3), 1.85ꢀ1.90 (m, 1H, CHH), 2.04 (m, 1H, CHH), 4.73 (br s, 1H, NH),
5.13 (m, 2H, CHHN), 7.22 (m, 2H, HAr), 7.34 (m, 3H, HAr). HPLC (Chiralpak ADꢀ
H, hexane/isoꢀpropanol = 95:5, 220 nm, 1 mL/min): dr (anti:syn): 78/22; major
(anti): tr (major) = 13.9 min, tr (minor) 15.5 min. (er 96:4), minor (syn): tr (major) =
11.9 min, tr (minor) = 17.3 min (er 72:28).
(1S,2R)-3-(tert-Butyldimethylsilyloxy)-2-nitro-1-phenylpropyl carbamic acid t-
butyl ester (32ac).14 Obtained according to the general procedure, using NꢀBocꢀimine
29a (62 mg, 0.3 mmol), tertꢀButyldimethyl(2ꢀnitroethoxy)silane (31c) (0.37g, 1.8
mmol) and thiourea 24 (15 mg, 0.015 mmol).The crude reaction mixture was purified
by flash column chromatography (nꢀpentane/ CH2Cl2: 2:1) to yield compound 32ac as
a mixture of anti/syn diastereomers (91 mg, 0.22 mmol, 74%). Colorless oil.1HꢀNMR
(500 MHz, CDCl3): δ 0.05 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.89 (s, 9H, CH3), 1.40
(s, 9H, CH3), 3.99 (dd, J = 5.9 Hz, 11.9 Hz, 1H, CHHOTBDMS), 4.12ꢀ4.15 (dd, J =
3.2 Hz, 11.9 Hz, 1H, CHHOTBDMS), 4.73 (m, 1H, CHN), 5.43 (m, 1H, CHNO2),
5.81 (br s, 1H, NH), 7.28ꢀ7.35 (m, 5H, Har). HPLC [Chiralpak ADꢀH, hexane/isoꢀ
propanol = 98:2, λ 220 nm, 1 mL/min]: dr (anti:syn): 56/44 ; major (anti): tr (major)

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18.3 min, tr (minor) 41.5 min; minor (er 88:12); (syn): tr (major) 31.7 min, tr (minor)
21.1 min (er 87:13).
tert-Butyl
(1S,2R)-2-nitro-1,2-diphenylethyl)carbamate
(32ad).
Obtained
according to the general procedure, using NꢀBocꢀimine 29a (62 mg, 0.3 mmol),
phenylnitromethane (0.213 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The
crude reaction mixture was purified by flash column chromatography (hexane/ethyl
acetate: 15:1) to yield compound 32ad as a mixture of anti/syn diastereomers (81 mg,
0.24 mmol, 79%). Colorless solid. 1HꢀNMR (500 MHz, CDCl3): δ 1.26 (s, 9H, CH3),
4.77 (s, 1H, NH), 5.69 (br s, 1H, CHN), 5.78 (br s, 1H, CHN), 7.35ꢀ7.59 (m, 9H,
Har). 13Cꢀ NMR (126 MHz, CDCl3) δ 27.4 (CH3), 56.1 (CHNO2), 78.6 (C(CH3)3),
94.1 (CHN), 127.7, 128.3, 128.7, 128.8, 130.1 (CHar), 132.7 (Car), 138.9 (Car), 154.5
(CO). IR (ATR): 3390, 2978, 2924, 2849, 1684, 1545, 1521, 1456, 1367, 1288, 1253,
1010, 891, 856, 792, 757, 742, 697, 588, 539 cmꢀ1. HRMS calcd. for C19H22N2O4 +
Na: 365.1472; found: 365.1475. HPLC (Chiralpak ADꢀH, hexane/isoꢀpropanol =
95:5, 210 nm, 1 mL/min): dr (anti:syn): 91:9; major (anti): tr (major) = 52.7 min, tr
(minor) 59.3 min (er 71:29), minor (syn): tr (major) = 37.1 min, tr (minor) = 81.4 min
(er 66:35). Recrystallization from toluene provided 32ad as a colorless solid of dr
97:3 and er 65:35. [α]D23 = +11.5 (c = 1.0, CHCl3).
tert-Butyl (1S,2R)-1-(4-chlorophenyl)-2-nitro-2-phenylethylcarbamate (32cd).17b
Obtained according to the general procedure, using NꢀBocꢀimine 29c (62 mg, 0.3
mmol), phenylnitromethane (0.213 g, 1.8 mmol) and thiourea 24 (15 mg, 0.015
mmol). The crude reaction mixture was purified by flash column chromatography
(hexane/ethyl acetate: 15:1) to yield compound 32cd as a mixture of anti/syn
23
diastereomers (91 mg, 0.25 mmol, 84%). Colorless solid. [α]D = +4.0 (c = 1,
1
CHCl3). HꢀNMR (500 MHz, CDCl3): δ 1.26 (s, 9H, CH3), 4.86 (br s, 1H, NH), 5.62

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(br s, 1H, CHN), 5.76 (br s, 1H, CHNO2), 7.28ꢀ7.55 (m, 9H, Har). HPLC (Chiralpak
IA, hexane/isoꢀpropanol = 97:3, 230 nm, 1 mL/min): dr (anti:syn): 96:4; major
(anti): tr (major) = 44.5 min, tr (minor) 33.0 min (er 66:34), minor (syn): tr (major) =
86.5 min, tr (minor) = 37.8 min (er 72:28).
tert-Butyl ((2-nitroethoxy)(phenyl)methyl)carbamate (33). Obtained according to
the general procedure, using NꢀBocꢀimine 29a (62 mg, 0.3 mmol), 2ꢀnitroethanol
(0.13 mL, 1.8 mmol) and thiourea 24 (15 mg, 0.015 mmol). The crude reaction
mixture was purified by flash column chromatography (hexane/ethyl acetate: 4:1) to
yield compound 33 as a racemate (78 mg, 0.26 mmol, 88%). Colorless oil. 1HꢀNMR
(500 MHz, CDCl3): δ 1.49 (s, 9H, CH3), 4.22 (dd, J = 55.9, 5.9 Hz, 2H, CHHO), 4.61
(d, J = 2.7 Hz, 2H, CHHN), 5.20 (d, J = 10Hz, 1H, NH), 6.00 (d, J = 9.9 Hz, 1H,
CHN), 7.36 (m, 5H, HAr). 13Cꢀ NMR (126 MHz, CDCl3) δ 28.3 (CH3), 63.5 (CH2N),
75.0 (CH2O), 80.6 (C(CH3)3), 82.3 (CHO), 125.8 (Car, 2C), 128.6 (Car, 2C), 138.48
(Car), 155.34 (C=O). IR (ATR): 3343, 3060, 2982, 2937, 1693, 1553, 1513, 1362,
1247, 1167, 1101, 1021, 876, 695 cmꢀ1. HRMS calcd. for C14H20N2O5 + Na:
319.1264; found: 319.1266. HPLC (Chiralpak ADꢀH, hexano/isopropanol 95:5,
1mL/min, λ= 210 nm) tR = 15.8 min (mayor, S), 19.8 min (minor, R) (er 50:50).
Acknowledgements. Authors thank the Spanish DGICYT (Project CTQ 2011ꢀ28487)
and JC y L (Project VA064U13) for the financial support.
Electronic Supplementary Information Available: Experimental procedure for the
synthesis of supported catalysts, copies of 1HꢀNMR and 13CꢀNMR spectra for all new
compounds and copies of the HPLC chromatograms are available as supplementary
information.
Notes and references

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1. (a) D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem. Int. Ed. 1998, 37, 2580. (b)
K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V. Gothelf, K. A. Jørgensen, J. Am.
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Lett. 2008, 10, 5305. (d) L. Bernardi, B. F. Bonini, G. Dessole, M. Fochi, M. Comesꢀ
Franchini, S. Gavioli, A. Ricci, J. Org. Chem. 2003, 68, 1418. (e) T. A. Davis, J. N.
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Chiral recoverable supported bifunctional ureas or thioureas promote highly
enantioselective Aza-Henry reactions under solvent-free conditions.