Synthesis of novel thiophene-based chiral ligands and their application in asymmetric Henry reaction

Article abstract of DOI:10.1002/aoc.2969

Novel chiral thiolated amino alcohols were synthesized from norephedrine and thiophene carbaldehydes (methyl- or ethyl-substituted) and applied to the catalytic asymmetric Henry reaction of various aldehydes with nitromethane to provide β-hydroxy nitroalkanols in high conversion (92%). The reaction was optimized in terms of the metal, solvent, temperature and amount of chiral ligand. The corresponding catalyst with Cu(OTf)₂ and 2-propanol as the solvent provided the best enantioselectivities (up to 96% ee) of the corresponding nitroalcohols for aliphatic aldehydes. Copyright 2013 John Wiley & Sons, Ltd. Chiral thiophene contanining amino alcohol ligands were synthesized from norephedrine and substituted 5-thiophene-2-carbaldehyde. This novel chiral ligands were used to catalyze enantioselective Henry reaction of various aldehydes and nitroalkanes in high yields with good to high enantio- and diastereoselectivities. Copyright

Full text of DOI:10.1002/aoc.2969

Full Paper
Received: 17 October 2012
Revised: 17 December 2012
Accepted: 23 December 2012
Published online in Wiley Online Library: 25 March 2013
(wileyonlinelibrary.com) DOI 10.1002/aoc.2969
Synthesis of novel thiophene-based chiral
ligands and their application in asymmetric
Henry reaction
A. Ebru Aydin*
Novel chiral thiolated amino alcohols were synthesized from norephedrine and thiophene carbaldehydes (methyl- or
ethyl-substituted) and applied to the catalytic asymmetric Henry reaction of various aldehydes with nitromethane to
provide b-hydroxy nitroalkanols in high conversion (92%). The reaction was optimized in terms of the metal, solvent,
temperature and amount of chiral ligand. The corresponding catalyst with Cu(OTf)2 and 2-propanol as the solvent provided
the best enantioselectivities (up to 96% ee) of the corresponding nitroalcohols for aliphatic aldehydes. Copyright © 2013
John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: enantioselective synthesis; Henry reaction; chiral amino alcohols; thiolated amino alcohols; copper complex
In our previous studies, norephedrine-based chiral ligands
Introduction
with N-substituted chiral pyrrole have been synthesized and
applied in the addition of diethylzinc to aldehydes.[26] We
The Henry or nitro aldol reaction is one of the most important
methods for the formation of CꢀC bond in organic chemistry.[1]
showed that the absolute configuration of the norephedrine
The resulting products of this reaction, a coupling between
nitroalkanes and carbonyl groups, can be converted into
synthetically useful derivatives such as carboxylic acids and
amino alcohols and other useful compounds.[2,3] b-Nitroalkanols
are useful intermediates in the asymmetric synthesis of the
b-receptor agonists (ꢀ)-denopamine and arbutamine,[4] the
b-blockers (S)-metoprolol,[5a] (S)-propranolol[5b] and (S)-pindolol,[5c]
and pharmacologically important b-amino alcohol derivatives such
as chloroamphenicol,[6a] ephedrine[6b] and sphingosine.[6c]
The first asymmetric Henry reaction was reported by Sasai
et al.,[7] who used Lanthanide/1-10-binaphthol (BINOL) com-
plexes. Since then, various type of catalyst systems, containing
metal such as Zn,[8] Co,[9] Mg,[10] Cu[11] and rare earth metal
complexes11a,12 and non-metal-based chiral catalysts have
been reported for the asymmetric Henry reaction with chiral
ligands such as BINOL,[13] amino alcohols,[8b,14] bisoxazolines,[15]
bisoxazolidines,[8c,11c,16] (ꢀ)-sparteine,[17] sulfonamides,[18] chiral
diimine,[19] N,N0-dioxides[20] and aminopyridines[21] such as 1a–e
(Scheme 1).
moiety plays an important role in the configuration of addition
products. Herein we report the synthesis of norephedrine-based
amino alcohol ligands bearing a substituted thiophene ring and
their application in the asymmetric Henry reaction. These ligands
were readily prepared in two steps from quite inexpensive
commercially available starting materials. These chiral ligands
were prepared from the reaction of substituted thiophene-2-
carbaldehydes (6a,b) with both enantiomers of norephedrine (7).
Results and Discussion
Synthesis of Chiral Ligands
As shown in Scheme 3, novel chiral ligands were synthesized
from 5-substituted thiophene-2-carbaldehyde and both enantio-
mers of norephedrine.
The formylation of 2-substituted thiophene was performed
according to the Vilsmeier–Haack method.[27] Formylated pro-
ducts were reacted with both of enantiomers of norephedrine
to form imines in dry benzene under a Dean-Stark trap.
Chiral ligands (8a,b and 9a,b) were obtained by reduction of these
imines (Scheme 3). After purification of crude products by column
chromatography, thiophene ring-containing norephedrine-
based amino alcohols (8a,b and 9a,b) were obtained with
68%, 73%, 70%, 75% chemical yields, respectively (Scheme 3
and Table 1).
Although many chiral ligands derived from amino alcohols
have found applications as catalysts in asymmetric reactions, only
a few thiophene-based ligands have been employed in the Henry
reaction[22,23] or other asymmetric reactions.[24] Bandini et al.[23a]
reported a new type of C2-symmetric diamino ligand (4), bearing
oligothienyl groups, and their catalytic activity in the asymmetric
Henry reaction (Scheme 2).
Thiophene-based ligands (5) were used as catalysts for
asymmetric Henry reaction by Mansawat et al.,[25] who reported
that homochiral amino alcohols carrying N-2-thienyl methyl
substituent provided much better enantioselectivities compared
to those with N-(2-alkylthio)benzyl substituent for the Henry
reaction (Scheme 2).
*
Correspondence to: A. Ebru Aydin, Department of Chemistry, Mustafa Kemal
University, 31040 Hatay, Turkey. E-mail: aydin@mku.edu.tr
Department of Chemistry, Mustafa Kemal University, 31040 Hatay, Turkey
Appl. Organometal. Chem. 2013, 27, 283–289
Copyright © 2013 John Wiley & Sons, Ltd.

A. E. Aydin
Scheme 1. Different chiral ligands used in asymmetric Henry reaction.
Scheme 2. Chiral thiophene ligands for asymmetric Henry reaction.
The Asymmetric Henry Reaction
chiral ligand series (Table 1, entry 2) and was selected for optimiz-
ing further the reaction conditions.
The reactivity and enantioselectivity of chiral ligands 8 and 9a,b for
the Henry reaction were investigated. The reaction between p-nitro-
benzaldehyde and nitromethane in the presence of chiral ligand
(10% mol) and copper acetate monohydrate (Cu(OAc)2.H2O, 5 mol
%) in 2-propanol (iPrOH) at room temperature was chosen as a
model reaction. Initially, all chiral ligands were screened in this
model reaction (Scheme 4) and the results are listed in Table 1.
The use of enantiomeric chiral ligands (1R,2S)-8a and (1S,2R)-8b led
to opposite enantiomers of b-nitroalkanol with 68% and 74%
ee, respectively. It was found out that absolute configuration
of b-nitroalkanol is mainly by the stereogenic centers of
norephedrine on chiral ligands.[25] Chiral ligands (1R,2S)-8a
with (R)-configuration at OH-bearing carbon gave the product with
an (R)-configuration. Chiral ligand (1S,2R)-8b with an (S)-configura-
tion at the same stereogenic center gave the (S)-product. Thus the
configuration of b-nitroalkanol depended on the configuration of
the alcohol part of the chiral ligand. Mansawat et al.[25] reported a
homochiral thiolated amino alcohol which has asymmetric
carbon bearing the amino groups. The use of (1R,2S)-9a and
(1S,2R)-9b as chiral ligand afforded nitro aldol product 3a in
90% yield with 65% ee and 87% yield with 67% ee for the major
(S)-enantiomer, respectively (Table 1, entries 1 and 2).
The reactivity and enantioselectivity of the Henry reaction
strongly depend upon the nature of the solvent used.[28]
Therefore, the Henry reaction was performed in different solvents
such as ethanol (EtOH), tetrahydrofuran (THF), CH2Cl2 (DCM),
MeCN, toluene and n-propanol (nPrOH) (Table 2). As can be
seen in Table 2, iPrOH was the most appropriate solvent.
MeCN, toluene, THF and DCM gave moderate yields and ee
values. It is clear that protic alcoholic solvents are superior to
aprotic solvents. It was found out that enantioselectivity
increased in the order MeOH < EtOH < nPrOH < iPrOH (Table 2,
entries 1–7).
Next, a series of metal salts were screened for the enantiose-
i
lective Henry reaction using ligand (1S,2R)-8b in PrOH. The
effect of metal salts was investigated for the model reaction
at room temperature. Copper triflate (Cu(OTf)2) was found to
be best metal salt for the reaction (Table 3, entry 2). Other salts
such as NiCl2.6H2O, AgOTf, CuI, CuCl2.2H2O and CoCl2.2H2O
afforded nitroaldol adduct in moderate yield but with poor
enantioselectivity.
Schätz et al.[29] reported that ligand/metal ratio influences
enantioselectivity, and the effect of the ligand/metal ratio was
tested at room temperature (Table 4). The influence of the ratio
of ligand (1S,2R)-8b to metal source such as Cu(OAc)2.H2O
and Cu(OTf)2 on reactivity and enantioselectivity was studied
Since (1S,2R)-8b gave the highest enantioselectivity in the
Henry reaction, it was identified as more effective among the
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Appl. Organometal. Chem. 2013, 27, 283–289

Henry reaction catalyzed by Cu complexes of b-amino alcohol
Scheme 3. Synthesis of chiral ligand derivatives – reagents and conditions: (i) norephedrine, benzene, reflux; (ii) LiAlH4, ether, reflux.
Table 1. Optimization of chiral ligands for the enantioselective Henry reactiona
Entry
Sub. thiophene carbaldehyde (R)
Amino alcohol
Ligand (yield, %)
Yield (%)b 3a
ee (%)c 3a
Config.d
1
2
3
4
ꢀCH3 6a
(1R,2S)-7a
(1S,2R)-7b
(1R,2S)-7a
(1S,2R)-7b
(1R,2S)-8a (68)
(1S,2R)-8b (73)
(1R,2S)-8a (70)
(1S,2R)-8b (75)
91
88
90
87
68
74
65
67
R
S
R
S
ꢀCH3 6a
ꢀCH2CH3 6b
ꢀCH2CH3 6b
aAll reaction were carried out with 0.2 mmol p-nitrobenzaldehyde and 0.6 ml nitromethane in 2 ml PrOH
in the presence of 10 mol% ligand and 10 mol% Cu(OAc)2.H2O, at room temperature.
bValues are isolated yields after chromatographic purification.
cDetermined by HPLC analysis (Chiralcel OD-H).
dThe absolute configuration of products was determined by comparison with literature values.8b,12c,14b,15b
i
Scheme 4. Asymmetric Henry reaction catalyzed by 8 and 9-Cu(OAc)2.H2O complex.
(Table 4). When the amount of Cu(OAc)2.H2O was kept con-
stant at 10 mol%, a gradual increase in the amount of ligand
(1S,2R)-8b from 5 to 15 to 20 mol% gave comparable enan-
tioselectivity. Decreasing the amount of ligand (1S,2R)-8b to
5 mol% resulted in lower ee value (68%) (entry 1). Changing the
amount of ligand (1S,2R)-8b from 10 to 15 mol% had only a
small effect on the enantioselectivity (74% and 75%, respectively)
(entries 4 and 5). In the presence of 20mol% ligand (1S,2R)-8b,
the product was obtained in 65% yield with 80% ee (entry 4). The
reaction was performed using different amounts of Cu(OAc)2.H2O
in the presence of 10 mol% ligand (1S,2R)-8b (Table 4). After
changing the ratio of Cu(OAc)2.H2O from 10 to 15mol%, the enan-
yield with 70% ee (entries 8 and 9). Increasing the amount of
ligand (1S,2R)-8b to 20 mol%, the product was obtained in
86% ee, but the yield dropped to 58% (entry 11). When the
amount of (1S,2R)-8b was kept at 10 mol%, a gradual increase
in the amount of ligand Cu(OTf)2 from 5 to 10 to 15 to 20 mol%
led to a decrease in the enantioselectivity from 88% to 79% to
73% to 70%, respectively. The optimal ratio of ligand (1S,2R)-8b to
Cu(OTf)2 is 1:2 and the use of 5 mol% Cu(OTf)2 gave the highest
enantioselectivity.
The reaction temperature also plays an important role in the
chemical yield and ee value of nitroalkanols.[30] When the
reaction temperature was reduced from room temperature to
ꢀ20 ꢁC, the corresponding product was obtained in 72% yield
with 53% ee (Table 4, entry 16). The highest ee (89%) was
achieved at 0 ꢁC with 75% yield (entry 15). The homochiral N-
thienylmethyl-substituted amino alcohol ligand 2, which has a
asymmetric carbon bearing the amino group,[25] gave a high yield
(92%) and the ee value was moderate (63%). Chiral ligands 8 and
9a,b with two chiral centers gave a higher enantioselectivity than
amino alcohol carrying N-thienylmethyl substituted 5.
tioselectivity and yield decreased to 69
% and 71%,
respectively. In the presence of 10 mol% (1S,2R)-8b and
5mol% Cu(OAc)2.H2O, the highest enantioselectivity obtained
was 83%, but the yield of product decreased to 68% (entry 5).
Next, the effect of the amount of chiral ligand was examined
in the presence of Cu(OTf)2 as metal source (Table 4). By keeping
the Cu(OTf)2 ratio at 10 mol% and reducing the ligand (1S,2R)-8b .
ratio from 10 mol% to 5 mol%, the product was obtained in 75%
Appl. Organometal. Chem. 2013, 27, 283–289
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A. E. Aydin
Overall, the optimized reaction conditions were found to be
Cu(OTf)2–(1S,2R)-8b (1:2) complex catalyst, PrOH used as solvent,
at 0 ꢁC.
the alcohol part of the chiral ligand. Further investigation is being
carried out on the application of these ligands for the diastereo-
selective Henry reaction and the other asymmetric reactions.
i
With the optimized conditions in hand, the catalytic efficiency
of ligand (1S,2R)-8b was also tested in the Henry reaction
between nitromethane and various aldehydes. As can be seen
from Table 5, aromatic aldehydes with either electron-donating
or electron-withdrawing groups gave the products with moderate
to good ee values and yields. High ee values are observed for
aromatic aldehydes bearing substituents in the ortho position.
The heteroaromatic aldehyde furan-2-carbaldehyde also furnished
the nitro aldol product with 83% ee. Next, the scope of the asym-
metric Henry reaction was studied with aliphatic aldehydes using
(1S,2R)-8b. The aliphatic aldehydes provided the corresponding
adduct with higher enantioselectivity than did aromatic aldehydes.
For aliphatic aldehydes, the enantioselectivity increased with an
increase of the chain length of aldehydes. Branched aliphatic
aldehydes such as cyclohexanecarboxaldehyde gave the
corresponding products with excellent enantioselectivities of up
to 96% (entries 18, 20 and 22).
Experimental
General Methods
All solvents were dried before use according to standard proce-
dures. Melting points were obtained using an electrothermal
digital melting point apparatus (Gallenkamp). 1H and 13C NMR
spectra were measured with a Bruker 400 MHz NMR spectrometer
using CDCl3 as solvent at room temperature. Chemical shifts
(ppm) were reported relative to Me4Si. Coupling constants
were expressed as J values in hertz units. Optical rotations were
measured with an Autopol IV polarimeter. All reactions were
carried out under Ar atmosphere and monitored by thin-layer
chromatography (TLC) on Merck silica gel plates (60 F-254) using
UV light or phosphomolybdic acid in methanol. E. Merck silica gel
(60, particle size 0.040–0.063 mm) was used for flash chromatog-
raphy. Enantiomeric excesses were determined by HPLC analysis
using a Thermo Finnigan Surveyor equipped with an appropriate
chiral phase column.
Conclusion
We synthesized thiophene ring-containing chiral amino alcohols
from 5-substituted thiophene-2-carbaldeydes and both enantio-
mers of norephedrine. Their catalytic activity was determined
in enantioselective Henry reaction between nitromethane and ar-
omatic aldehydes. High enantioselectivities were obtained with
(1S,2R)-8b and (1S,2R)-9b in the Henry reaction. The chiral ligand
pairs induced opposite enantioselectivity and the absolute
configuration of b-nitroalkanol is similar to the configuration of
Synthesis of Ligands
Formylation of 2-substituted thiophenes
DMF (2.56 ml, 33 mmol) in CH2Cl2 (5ml) was cooled to 0 ꢁC
and POCl3 (2.94 ml, 32 mmol) was added dropwise very slowly.
Table 3. Influence of metal salts on the asymmetric Henry reaction
of 4-nitrobenzaldehyde and nitromethane under the chiral ligand
(1S,2R)-8ba
Table 2. Effects of solvents on the asymmetric Henry reaction of
4-nitrobenzaldehyde and nitromethane under the chiral ligand
(1S,2R)-8ba
Entry
Metal salt
Yield (%)b 3a
ee (%)c 3a
1
Cu(OAc)2.H2O
Cu(OTf)2
NiCl2.6H2O
AgOTf
92
68
68
30
82
55
73
48
15
62
17
57
74
79
21
12
70
68
45
64
22
50
21
40
Entry
Solvent
Yield (%)b 3a
ee (%)c 3a
2
3
1
2
3
4
5
6
7
8
MeOH
EtOH
iPrOH
MeCN
Toluene
THF
82
88
92
70
60
65
75
89
62
70
74
30
50
54
60
72
4
5
Cu(OAc)2.H2O
CuCl
6
7
CuI
8
CuBr
9
CuCl2.2H2O
CuBr2
CH2Cl2
nPrOH
10
11
12
Zn(OTf)2
CoCl2.2H2O
aAll reaction were carried out with 0.2 mmol p-nitrobenzaldehyde
and 0.6 ml nitromethane in 2 ml solvent
aAll reactions were carried out with 0.2 mmol p-nitrobenzaldehyde
and 0.6 ml nitromethane in 2 ml iPrOH in the presence of 10 mol%
ligand (1S,2R)-8b and 10 mol% metal salt, at room temperature.
in the presence of 10 mol% ligand and 10 mol% Cu(OAc)2.H2O,
at room temperature.
bValues are isolated yields after chromatographic purification.
cEnantiomeric excesses were determined by HPLC using
Chiralcel OD-H column. The absolute configuration (S) was
determined by comparison with literature values.8b,12c,14b,15b
bValues are isolated yields after chromatographic purification.
cEnantiomeric excesses were determined by HPLC using
Chiralcel OD-H column. The absolute configuration (S) was
determined by comparison with literature values.8b,12c,14b,15b
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Henry reaction catalyzed by Cu complexes of b-amino alcohol
Table 4. Effects of ligand loading, solvents and reaction temperature on the asymmetric Henry reaction of 4-nitrobenzaldehyde and nitromethane
under the chiral ligand (1S,2R)-8ba
Entry
Metal salt
Metal salt (mol %)
(1S,2R)-8b (mol %)
Temp. (ꢁC)
Yield (%)b
ee (%)c
1
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OTf)2
10
10
10
10
5
5
10
15
20
10
10
10
5
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
80
92
68
65
68
71
80
75
68
70
58
65
80
80
75
72
68
74
75
80
83
69
66
70
79
81
86
88
73
70
89
53
2
3
4
5
6
15
20
10
10
10
10
5
7
8
9
Cu(OTf)2
10
15
20
10
10
10
10
10
10
11
12
13
14
15
16
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
15
20
5
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
5
ꢀ20
aAll reaction were carried out with 0.2 mmol of p-nitrobenzaldehyde and 0.6 ml nitromethane in 2 ml solvent in the presence of ligand (1S,2R)-6a,
using Cu(OAc)2.H2O or Cu(OTf)2, at room temperature.
bValues are isolated yields after chromatographic purification.
cEnantiomeric excesses were determined by HPLC using Chiralcel OD-H column. The absolute configuration (S) was determined by comparison
with literature values.8b,12c,14b,15b
After the addition the mixture was stirred for 30min at 0ꢁC. 2-
Substituted thiophene (methyl- or ethyl-) (25 mmol) was dissolved
General procedure for the synthesis of thiophene-based chiral amino
alcohols
in 10 ml CH2Cl2 and added to the mixture dropwise over 45min
5-Substituted thiophene-2-carbaldehydes (5mmol, 6a or 6b) were
dissolved in 10 ml benzene to which was added norephedrine
at 0 ꢁC. After warming to room temperature, the mixture was
heated further and at about 70ꢁC a vigorous reaction occurred.
(0.756 g, 5 mmol) under nitrogen atmosphere. The mixture was
Immediately an ice bath was put under the vessel until no further
refluxed for 4 h and water was removed in a Dean–Stark trap.
Reaction was controlled by TLC. Imine was concentrated to dryness
without purification. The synthesized imine was dissolved in 15 ml
Et2O and added to a suspension of 1.35 mmol LiAlH4 in 10 ml
HCl gas evolved. The mixture was then heated for 1 h at 110ꢁC.
After cooling to room temperature the mixture was poured into
ice water (200 ml) and neutralized with sodium bicarbonate. The
mixture was extracted with diethyl ether (3ꢂ 100ml) and dried
Et2O. The mixture was refluxed for 8 h and controlled by TLC.
(Na2SO4).After evaporation of the solvent the crude product was
When the reaction was completed, the mixture was cooled to
purified by flash column chromatography (EtOAc–hexane, 1:5).
room temperature and quenched with 15ml water. It was
5-Methyl thiophene-2-carbaldehyde (6a) was characterized by
extracted with ether (3ꢂ 10 ml) and dried over MgSO4. The
mixture was filtered and the solvent was evaporated. Crude
products 8a,b and 9a,b were purified by flash column chroma-
tography (EtOAc–hexane, 1:5) (See supporting information for
1H and 13C NMR of chiral ligands 8,9a-b).
comparing their 1H and 13C NMR spectra with those published in
the literature.[27b]
5-Ethyl thiophene-2-carbaldehyde (6b): brown oil; 85% yield;
Rf 0.41 (EtOAc–hexane, 1:3); 1H NMR (400 MHz CDCl3) d 9.74
(s, 1H, COH), 7.54 (d, 1H, J = 3.7 Hz, C(3)H), 6.85 (d, 1H, J = 3.7 Hz,
C(4)H ), 2.84 (q, 2H, J = 7.5, CH2CH3), 1.27 (t, 2H, J = 7.5 Hz,
CH2CH3). 13C NMR (CDCl3, 100 MHz,) d 182.72 (CHO), 159.21
(thiophene ring, C(2)), 141.6 7 (thiophene ring, C(5)), 137.16
(thiophene ring, C(3)), 125.55 (thiophene ring, C(4)), 24.22
(1R,2S)- 2-((5-Methylthiophen-2-yl)methylamino-1-phenylpro-
panol ((1R,2S)-(8a)): brown oil; 68% yield; Rf 0.32 (EtOAc–hexane,
25
1:1); ½aꢃD = ꢀ0.78 (c = 0.54, CHCl3).1H NMR (400 MHz, CDCl3) d
7.27–7.18 (m, 5H, ArH), 6.64 (d, 1H, J = 3.2 Hz, thiophene ring, C
(3)H), 6.51 (d, 1H, J = 3.2 Hz, thiophene ring, C(4)H,), 4.67 (d, 1H,
J = 3.6 Hz, CHOH), 3.99 (d, 1H, J = 14.4 Hz, NHCH2), 3.88 (d, 1H,
J = 14.4 Hz, NHCH2), 2.99–2.89 (m, 1H, CHCH3), 2.40 (s, 3H, CH3),
0.77 (d, 3H, J = 6.4, CHCH3). 13C NMR (100 MHz, CDCl3) d 151.70
(ArꢀC), 151.41 (thiophene ring, C(2)), 141.25 (thiophene ring, C
(CH3CH2), 15.60 (CH3CH2). IR (KBr)
n ) 3077, 2973,
(cmꢀ1
2925,1661, 1454, 1228, 1082, 1030, 812, 757, 665 Anal. Calcd for
C7H8OS: C, 59.97; H,5.75; O, 11.41; S, 22.87. Found: C,59.86; H,
1
4.84; O, 11.46; S, 22.91 (See supporting information for H and
13C NMR of 6b).
Appl. Organometal. Chem. 2013, 27, 283–289
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A. E. Aydin
Table 5. Asymmetric Henry reaction of nitromethane with various
(1R,2S)- 2-((5-Ethylthiophen-2-yl)methylamino-1-phenylpropanol
((1R,2S)-(9a)): brown oil; 70% yield; Rf 0.30 (EtOAc–hexane,
aromatic aldehydesa
25
1:1); ½aꢃD = ꢀ1.38 (c = 0.42, CHCl3).1H NMR (400 MHz, CDCl3)
d 7.26–7.19 (m, 5H, ArH), 6.68 (d, 1H, J = 3.6 Hz, thiophene
ring, C(3)H), 6.54 (d, 1H, J = 3.6 Hz, thiophene ring, C(4)H),
4.68 (d, 1H, J = 3.6 Hz, CHOH), 3.95 (d, 1H, J = 14.4 Hz, NHCH2),
3.86 (d, 1H, J = 14.4 Hz, NHCH2), 2.99–2.94 (m, 1H, NHCHCH3),
2.74 (q, 2H, J = 7.2 Hz, CH2CH3), 1.97 (s, 3H, CH3), 0.79 (d, 3H,
J = 6.4, NHCHCH3). 13C NMR (100 MHz, CDCl3) d 146.97 (ArꢀC),
141.19 (thiophene ring, C(2)), 140.80 (thiophene ring, C(5)),
128.12–126.15 (ArꢀC), 124.79 (thiophene ring, C(3)), 122.82
(thiophene ring, C(4)), 73.22 (CHOH), 57.25 (NHCHCH3), 45.96
(NHCH2), 23.59 (CH3CH2), 15.94 (CH3CH2), 1462 (NHCHCH3). IR
(KBr) n (cmꢀ1) 3412, 2977, 2922, 1492, 1450, 1383, 1217,
1018, 784, 736, 697. Anal. Calcd for C16H21NOS: C, 68.93; H,
7.33; N, 5.36; O, 6.12; S, 12.27. Found: C, 69.77; H, 7.64; N,
5.12; O, 5.84; S, 11.63.
Entry
Aldehyde
Product 3
Yield (%)b
3
ee (%)c 3
1
4-NO2C6H4
2-NO2C6H4
3-NO2C6H4
PhCHO
3a
3b
3c
92
89
80
74
70
69
78
66
70
68
82
80
82
80
82
78
75
78
77
68
70
74
89
90
83
65
69
72
67
62
67
63
71
75
79
78
77
87
83
87
90
93
96
96
2
3
4
3d
3 e
3 f
5
4-MeOC6H4
2-MeOC6H4
3-MeOC6H4
4-MeC6H4
2- MeC6H4
3- MeC6H4
4-ClC6H4
2-ClC6H4
2-FC6H4
6
7
3 g
3 h
3 i
(1S,2R)- 2-((5-Ethylthiophen-2-yl)methylamino-1-phenylpropanol
((1S,2R)-(9b)): brown oil; 75% yield; Rf 0.30 (EtOAc–hexane,
8
9
25
1:1); ½aꢃD = +1.27 (c = 0.46, CHCl3).1H NMR (400 MHz, CDCl3)
10
11
12
13
14
15
16
17
18
19
20
21
22
3 j
d 7.25–7.17 (m, 5H, ArH), 6.66 (d, 1H, J = 3.60 Hz, thiophene
ring C(3)H), 6.55 (d, 1H, J = 3.6Hz, thiophene ring, C(4)H,), 4.69
(d, 1H, J = 4.0 Hz, CHOH), 3.96 (d, 1H, J = 14.4Hz, NHCH2), 3.89 (d,
1H, J = 14.0 Hz, NHCH2), 2.97–2.95 (m, 1H, NHCHCH3), 2.75 (q, 2H,
J = 7.20 Hz, CH2CH3), 1.22 (t, 3H, J = 7.20 Hz, CH3), 0.78 (d, 3H,
J = 6.80, NHCHCH3). 13C NMR (100MHz, CDCl3) d 146.92 (ArꢀC).
141.17 (thiophene ring, C(2)), 140.82 (thiophene ring, C(5)),
126.04–128.34 (ArꢀC), 124.78 (thiophene ring, C(3)), 122.78
(thiophene ring, C(4)) 73.19 (CHOH), 57.22 (NHCHCH3), 45.92
(NHCH2), 23.57 (CH3CH2), 15.93 (CH3CH2), 14.59 (NHCHCH3). IR
(KBr) n (cmꢀ1) 3415, 2974, 2919, 1495, 1448, 1385, 1216, 1020,
790, 738, 693. Anal. Calcd for C16H21NOS: C, 68.93; H, 7.33; N, 5.36;
O, 6.12; S, 12.27. Found: C, 69.77; H, 7.64; N, 5.12; O, 5.84; S, 11.63.
Found: C, 69.75; H, 7.62; N, 5.13; O, 5.86; S, 11.64.
3 k
3 l
3 m
3 n
3 o
3 p
3 q
3 r
3 s
3 t
1-Naphthyl
2-Naphthyl
PhCH2CH2
2-Furfuryl
Cyclohexyl
nPr
iPr
nBu
3 u
3 v
iBu
aAll reactions were carried out with 0.2 mmol aromatic aldehyde
and 0.6 ml nitromethane in 2 ml iPrOH in the presence of
10 mol% ligand and 5 mol% Cu(OTf)2, 0 ꢁC.
bValues are isolated yields after chromatographic purification.
cEnantiomeric excesses were determined by HPLC using
Chiralcel OD-H column. The absolute configuration (S) was
determined by comparison with literature values.8b,12c,14b,15b
General procedure for the catalytic enantioselective Henry reaction
The representative procedure for enantioselective Henry reaction
is available online as supporting information. The enantiomeric
purity of the product was determined by HPLC analysis. The
absolute configuration of the products was assigned by compar-
ison to the literature data and the details can be found in the
Supporting Information.
(5)), 128.25–126.13 (ArꢀC), 108.08 (thiophene ring, C(3)), 105.94
(thiophene ring, C(4)), 72.97 (CHOH), 57.23 (CHCH3), 43.54
(CH2NH), 14.1125 (CH3), 13.58 (CHCH3), IR (KBr) n (cmꢀ1) 3419,
2975, 2919, 1490, 1448,1339, 1254, 1117, 796, 697. Anal. Calcd
for C15H19NOS: C, 69.78; H, 7.69; N, 5.09; O, 5.81; S, 11.64. Found:
C, 69.77; H, 7.64; N, 5.12; O, 5.84; S, 11.63.
Acknowledgment
This research (08F0201) is financially supported by the Scientific
Research Commission of Mustafa Kemal University.
(1S,2R)-2-((5-Methylthiophen-2-yl)methylamino-1-phenylpropa-
nol ((1S,2R)-(8b)): brown oil; 73% yield; Rf 0.32 (EtOAc–hexane, 1:1);
References
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wileyonlinelibrary.com/journal/aoc
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Copyright © 2013 John Wiley & Sons, Ltd.
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