New highly asymmetric henry reaction catalyzed by CuII and a C1-symmetric aminopyridine ligand, and its application to the synthesis of miconazole

Article abstract of DOI:10.1002/chem.200800069

A new catalytic asymmetric Henry reaction has been developed that uses a C₁ -symmetric chiral aminopyridine ligand derived from camphor and picolylamine. A variety of aromatic, heteroaromatic, aliphatic, and unsaturated aldehydes react with nit

Full text of DOI:10.1002/chem.200800069

FULL PAPER
DOI: 10.1002/chem.200800069
New Highly Asymmetric Henry Reaction Catalyzed by CuII and a C1-
Symmetric Aminopyridine Ligand, and Its Application to the Synthesis of
Miconazole
Gonzalo Blay,* Luis R. Domingo, Victor Hernµndez-Olmos, and JosØ R. Pedro*[a]
Abstract: A new catalytic asymmetric
Henry reaction has been developed
that uses a C1-symmetric chiral amino-
pyridine ligand derived from camphor
and picolylamine. A variety of aromat-
ic, heteroaromatic, aliphatic, and unsa-
turated aldehydes react with nitrome-
thane and other nitroalkanes in the
presence of DIPEA (1.0 equiv), Cu-
AHCTRE(UNG OAc)2·H2O (5 mol%), and an amino-
pyridine ligand (5 mol%) to give the
expected products in high yields (up to
99%), moderate-to-good diastereose-
lectivites (up to 82:18), and excellent
enantioselectivities (up to 98%). The
reaction is air-tolerant and has been
used in the synthesis of the antifungal
agent miconazole.
Keywords: aldol reaction · antifun-
gal agents · asymmetric catalysis ·
copper · nucleophilic addition
Introduction
ievements have been obtained, however, with copper com-
plexes. Evans et al. reported the copper acetate/bisoxazo-
line-catalyzed addition of nitromethane to aldehydes and
obtained enantiomeric excess (ee) values up to 94%.[10] Jør-
gensen et al. used a related CuII–BOX (BOX= bisoxazo-
line) system for the addition of silyl nitronates to aldehydes
with moderate enantioselectivity.[11] Maheswaran et al. have
used the dichloro[(À)-sparteine-N,N’]copper(II) complex for
the Henry reaction with nitromethane and obtained ee
values from 73 to 97%.[12] You and Ma[13] have reported the
synthesis of new chiral bisimidazoline ligands and their ap-
plication to the copper(II)-catalyzed Henry reaction with
which very high ee values (up to 98%) were obtained.
Highly enantioselective Henry reactions catalyzed by cop-
per(II) complexes with diamino ligands have been described
very recently by the groups of Bandini[14] and Arai.[15] Final-
ly, Feng and co-workers have described the use of copper(I)
complexes with tetrahydrosalen and N,N’-dioxide ligands.[16]
In addition to these metal-based procedures, a number of
organocatalytic methods have been recently described.[17]
However, despite the recent advances in this reaction and
the high enantioselectivities obtained, some limitations are
still encountered: high catalyst loading (40–100%),[7] activa-
tion of nitroalkanes as silyl nitronates,[11,17e] the substrate
scope is limited to aliphatic or aromatic aldehydes,[5,9,16b,17c,f,h]
difficulties in obtaining the catalyst in both enantiomeric
forms,[12] and so forth. Moreover, with the exception of a
few procedures,[5,11,15,16a,17f,h] these methods do not work or
have not been tested with nitroalkanes other than nitrome-
thane. Finally, some of the ligands employed are prepared in
The Henry or nitroaldol reaction constitutes one of the most
useful methodologies for carbon–carbon bond formation.[1]
Owing to the chemical versatility of the nitro group,[2] the
resulting b-hydroxynitroalkanes, especially in an optically
active form, are valuable intermediates for the synthesis of
polyfunctionalized molecules and biologically active com-
pounds.[3] Consequently, considerable effort has been direct-
ed towards the development of catalytic asymmetric ver-
sions of this reaction.[4] However, with the exception of ear-
lier work by Shibasaki et al. with lanthanide–BINOL com-
plexes (BINOL=1,1’-bi-2-naphthol),[5] highly enantioselec-
tive Henry reactions have not been implemented until very
recently. These reactions use metal complexes with chiral li-
gands. Examples include dinuclear zinc (Trost),[6] zinc tri-
flate–amino alcohol (Palomo),[7] and cobalt–ketoimino
(Yamada)[8] complexes, the last two were used in combina-
tion with Brønsted bases. Choudary et al. have also de-
scribed the use of nanocrystalline MgO for asymmetric
Henry and Michael reactions.[9] The most outstanding ach-
[a] Dr. G. Blay, Dr. L. R. Domingo, V. Hernµndez-Olmos,
Prof. Dr. J. R. Pedro
Departament de Química Orgànica
Facultat de Química, Universitat de Val›ncia
Dr. Moliner 59, 46100 Burjassot (Val›ncia) (Spain)
Fax : (+34)963-544-328
E-mail: gonzalo.blay@uv.es
jose.r.pedro@uv.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org or from the author.
Chem. Eur. J. 2008, 14, 4725 – 4730
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4725

long synthetic sequences, some of which involve racemic res-
olution, use expensive starting materials and have a very
high molecular weight.
places C1-Me of the camphor skeleton very close to the
copper coordination site trans to the pyridine, which may
hinder the reaction partners from accessing the metal
center. To increase electronic differentiation between the
two equatorial coordination sites and to provide the ligand
with bigger flexibility, we decided to reduce the C=N bond
of the iminopyridine ligands. The new ligands should coordi-
nate to the copper ion with a strongly basic amine N (sp3)
atom and a weekly basic pyridine N (sp2) atom, to form a
square-planar complex, in which both equatorial coordinat-
ing positions of the hypothetical square-planar complex
would have greater electronic differentiation. Furthermore,
The discovery and development of novel chiral ligands
are of significant importance in asymmetric catalysis. The
ideal ligand should be easily prepared, cheap, stable under
the reaction conditions, storable, and highly selective for a
large number of processes. Ligands with two N (sp2) coordi-
nating atoms have found wide application in enantioselec-
tive metal-catalyzed reactions.[18] BOX ligands have proved
to be a privileged class of chiral ligands that are capable of
forming a broad variety of metal complexes that can cata-
lyze a great number of reactions with outstanding enantiose-
lectivity. High enantioselectivities have also been achieved
with other C2-symmetric N,N-ligands, such as bisimines,[19]
and bispyridines.[20] Application of the desymmetrization
concept to these ligands has also led to C1-symmetric ligands
with two differentiated N (sp2) atoms, such as oxazolinyl
pyridines[21] and iminopyridines.[22] According to this last
strategy, we developed a new family of modular C1-symmet-
ric iminopyridine ligands, which are easily prepared (one
step) from readily available monoterpene ketones and pyri-
dylalkylamines. These ligands were used in a copper(II)-cat-
alyzed Henry reaction to give the corresponding products in
high yields, albeit with moderate enantioselectivity
(Scheme 1).[23] In this article, we report a highly enantiose-
À
the possibility of rotation around the C N bond would
allow better accommodation of the camphor skeleton in the
metal complex (Figure 1).
Figure 1. Design of aminopyridine ligands from iminopyridine ligands.
The imine C=N double bond in 1 was reduced upon treat-
ment with NaBH4/NiCl2 to give 2 as only one diastereomer
in a yield of 64% (Scheme 2).[26] The stereochemistry of the
Scheme 1. Henry reaction catalyzed by CuII and iminopyridine ligand 1.
Scheme 2. Synthesis of aminopyridine ligand
2 from 1 (4.1 mmol).
i) NaBH4 (1.0 equiv), NiCl2 (2.0 equiv), MeOH (60 mL), À308C, 3 h.
lective Henry reaction with aldehydes that uses a new ami-
nopyridine ligand based on our previous design for imino-
pyridine ligands.
resulting amine was determined by NOE and NOESY ex-
periments, which showed the spatial proximity of the CH2-N
methylene to the 1-Me (d=1.09) and 7s-Me (d=0.95)
groups of the camphor framework, as well as the proximity
between the 2-H (d=2.64) and 5n-H (d=1.05) protons.[27]
For purposes of comparison, we added nitromethane to
Results and Discussion
Studies carried out with unsymmetrical bidentate ligands
have shown that the electronic and steric differentiation of
the two opposite equatorial coordination sites of the metal
by the ligand has a profound effect on both the catalyst ac-
tivity and the enantioselectivity.[24,25] Iminopyridine ligands,
such as 1, provide highly sterically differentiated surround-
ings for both equatorial coordination sites of the copper ion.
However, because both nitrogen atoms have the same hy-
bridation (although with different functional groups), the
two equatorial coordination sites of copper should have sim-
ilar electronic features, that is, similar acidity and coordinat-
ing ability. On the other hand, the Z geometry of the imine
benzaldehyde in the presence of CuACHTRE(UGN OAc)2·H2O (5 mol%)
and 2 (5 mol%) in EtOH at 08C. We were very pleased to
observe that the new catalyst showed enhanced catalytic ac-
tivity and enantioselectivity with respect to 1, and provided
the expected product in a yield of 95% with an ee value of
91% after 51 h (Scheme 3), and proved the expected superi-
ority of the amino ligands with respect to the related imino-
pyridines.
Based on our previous experience with iminopyridine li-
gands, further improvement was achieved by performing the
reaction at a lower temperature and in the presence of diiso-
propylethylamine (DIPEA) to activate the nitromethane. In
4726
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4725 – 4730

Enantioselective Henry Reaction
FULL PAPER
to be suitable substrates, with the Henry reaction providing
the expected products in high-to-quantitative yields with ex-
cellent enantioselectivities, above ee values of 95% in most
cases, regardless of the location of the substituent and its
electronic nature (Table 1, entries 1 and 5–17). Only the
presence of a strongly electron-withdrawing nitro group
(Table 1, entries 8 and 15) or two electron-withdrawing
chlorine atoms (Table 1, entry 16) brought about a small de-
crease in the enantioselectivity. Most remarkably, the reac-
tion could also be performed with unbranched and even
branched or sterically hindered aliphatic aldehydes (Table 1,
entries 18–21). In these cases,
Scheme 3. Comparative reaction of 2-anisole and nitromethane in the
presence of ligands 1 (10 mol%) and 2 (5 mol%). i) L/CuACHTRE(UNG OAc)2, EtOH,
08C. L=1: 88 h, 98% yield, 67% ee; L=2: 51 h, 95% yield, 91% ee.
this way, the expected product was obtained in an almost
quantitative yield and with an excellent enantioselectivity
(98% ee; Table 1, entry 1). We prepared three other amino-
pyridines 3–5 that differ in the spacer length, substitution on
Table 1. Asymmetric addition of nitromethane to aldehydes catalyzed by copper(II) acetate and ligands 2–5.
the reaction was carried out at
a higher temperature (À208C),
and the resulting products were
obtained in high yields and en-
antiomeric excesses above 90%
in all cases. Finally, the reaction
with the 6s exclusively afforded
the 1,2-addition product in
almost quantitative yield with
an ee value of 96% (Table 1,
entry 22).
Entry[a]
L
Aldehyde
T [8C]
t [h]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
2
3
4
5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
benzaldehyde (6a)
benzaldehyde (6a)
benzaldehyde (6a)
benzaldehyde (6a)
À50
À50
À50
À50
À50
À50
À50
À40
À50
À50
À50
À50
À50
À50
À50
À50
À50
À20
À20
À20
À20
À50
22
24
24
24
3
99
90
90
90
99
99
98
82
99
99
94
99
95
99
86
70
99
98
79
95
97
97
98
71
44
47
98
98
96
86
98
98
97
98
98
97
85
2-methoxybenzaldehyde (6b)
2-methylbenzaldehyde (6c)
2-chlorobenzaldehyde (6d)
2-nitrobenzaldehyde (6e)
3-methoxybenzaldehyde (6 f)
3-methylbenzaldehyde (6g)
3-chlorobenzaldehyde (6h)
4-methoxybenzaldehyde (6i)
4-methylbenzaldehyde (6j)
4-chlorobenzaldehyde (6k)
4-nitrobenzaldehyde (6l)
2,4-dichlorobenzaldehyde (6m)
thiophen-3-carbaldehyde (6n)
decanal (6o)
2
23
35
23
10
10
17
6
22
24
24
21
22
23
22
10
24
Because of the good results
obtained with the addition of
nitromethane to aldehydes by
9
10
11
12
13
14
15
16
17
18
19
20
21
22
using the CuACHTRE(UNG OAc)2/2/DIPEA
system, we decided to extend
the reaction to other nitroal-
kanes. As stated in the intro-
89 (98)[d]
98
92
94
90
91
duction, only
a
very small
number of catalytic systems
work or have been tested in the
Henry reaction with nitroal-
kanes other than nitromethane.
The results are shown in
Table 2. Ligand 2 was again
found to give better results
than ligands 3–5 (Table 2, en-
tries 1–4). The CuII/2 system
dihydrocinnamaldehyde (6p)
cyclohexanecarbaldehyde (6q)
isovaleraldehyde (6r)
cinnamaldehyde (6 s)
96
[a] Reactions were carried out on a 0.5 mmol scale of aldehydes in a mixture of EtOH (2 mL) and nitrome-
thane (0.27 mL). [b] Isolated yield. [c] Determined by HPLC analysis. The absolute configurations were estab-
lished by comparison with literature data or with one another (see the Supporting Information). [d] ee value
after a single crystallization.
the pyridine ring, and the chiral scaffold (see the Supporting
Information) and tested them with benzaldehyde under sim-
ilar conditions. The resulting nitroalkanol had a lower enan-
tioselectivity than with ligand 2 (Table 1, entries 1–4).
The substrate scope was studied by using ligand 2. A vari-
ety of aromatic and heteroaromatic aldehydes were found
worked efficiently with nitroethane (9, R’=Me; Table 2, en-
tries 1 and 5–10), nitropropane (9, R’=Et; Table 2, en-
tries 11–17) and with the almost unstudied 2-phenylnitro-
ethane (9, R’=PhCH2; Table 2, entry 18). With aromatic al-
dehydes, the reaction took place with good diastereoselec-
tivity (from 61:39 to 82:18) favoring the anti product, which
was obtained with ee values above 89% for the addition of
nitroethane and nitropropane (Table 2, entries 1, 5–9, and
11–16), and an ee value of 83% for the addition of the bulk-
ier 2-phenylnitroethane (Table 2, entry 18). On the other
hand, reaction of nitroethane and nitropropane with 6p
(Table 2, entries 10 and 17, respectively) afforded chiefly the
syn product, although with a lower diastereoselectivity and
ee value than the reaction with aromatic aldehydes.
As a synthetic application of the procedure, we have ach-
ieved the enantioselective synthesis of (S)-miconazole
(Scheme 4),
a
potent antifungal agent.[28] (S)-1-(2,4-
Chem. Eur. J. 2008, 14, 4725 – 4730
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4727

G. Blay, J. R. Pedro et al.
Table 2. Asymmetric addition of nitroalkanes to aldehydes catalyzed by
copper(II) acetate and ligands 2–5.
Entry[a]
L
Aldehyde 9 R’
t
Yield[b]
[h] [%]
anti/syn[c]
[%]
ee[c]
[%]
1
2
3
4
5
6
7
8
2
3
4
5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
6a
6a
6a
6a
6b
6c
6i
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
47
48
48
24
19
46
49
44
49
53
64
64
45
40
46
48
72
99
97
95
90
95
95
91
99
97
75
97
96
96
90
96
95
73
90
80:20
53:47
53:47
63:37
82:18
79:21
66:34
81:19
80:20
47:53
71:29
70:30
75:25
61:39
65:35
74:26
39:61
68:32
95/91
15/3
5/3
Figure 2. Optimized geometry for the [Cu(2)ACHTRE(UNG OAc)2] complex (left) and a
possible transition state (right) that shows the addition of the nitronate
to the Re face of the aldehyde.
9/35
95/94
91/91
91/85
95/84
92/63
77/80
94/92
93/95
89/90
89/93
91/87
91/75
80/80
83/54
dehyde, and ammonium acetate,[29] to give 14 in a yield of
70%.[30] Finally alkylation of the hydroxyl group with 2,4-di-
chloro-1-(chloromethyl)benzene[31] afforded (S)-miconazole
(15) in a yield of 76% with an ee value of 98%, without loss
of optical purity in any of the steps of the synthetic se-
quence.
6k
6l
9
10[d]
11
12
13
14
15
16
17[d]
18
6p
6a
6b
6c
6i
6k
6l
6p
6a
Suitable crystals of the [Cu(2)
ACHTRE(UNG OAc)2] complex could not
be obtained for X-ray analysis. To account for the observed
stereoselectivity, the geometry of [Cu(2)CATHRE(UGN OAc)2] was opti-
mized at the UB3LYP/6-31G* level of theory[32] with the
Gaussian 03 suite of programs[33] (Figure 2, left). The com-
plex shows a large deviation from planar geometry with one
of the acetate groups out of the N-Cu-N plane and forming
PhCH2 52
[a] Reactions were carried out on a 0.5 mmol scale of aldehydes in mix-
ture of EtOH (2 mL) and the nitroalkane (10.0 equiv) at À408C. [b] Iso-
lated yield. [c] Determined by HPLC analysis. The absolute configura-
tions were established by comparison with literature data or with one an-
other (see the Supporting Information). [d] Reaction carried out at
À208C.
À
a hydrogen bond with the N H group. The acetate groups
are oriented upwards and downwards, respectively, and the
upper apical coordination site of the copper ion is shielded
by the camphor framework. Based on this modeled com-
plex, and the previously reported electronic considera-
tions,[10] we propose a possible transition-state model that
accounts for the absolute configuration of the obtained
products (Figure 2, right). In the active species, the aldehyde
will coordinate the copper(II) ion trans to the less electron-
donating pyridine ligand for maximum electrophilic activa-
tion,[34] whereas the nitronate will occupy the less coordinat-
ing apical position for maximum nucleophilic activation.
Transfer of the nitronate from the less hindered apical posi-
tion to the exposed Re face of the aldehyde carbonyl group
would yield products with an (S) configuration.
DichloroACHTREUNGphenyl)-2-nitroethanol (8m), obtained from the
Henry reaction of nitromethane and 6m was reduced in a
yield of 82% to the corresponding hydroxyamine 13 by
treatment with zinc/HCl. This transformation was not suc-
cessful with other procedures, such as catalytic hydrogena-
tion, because they caused hydrogenolysis of the C Cl bond.
The imidazole ring was synthesized from 13, glyoxal, formal-
À
Conclusion
In conclusion, we have presented a new class of copper-ami-
nopyridine catalysts for the highly enantioselective Henry
reaction. A modular design of the catalyst is possible by
varying the starting chiral ketone and the pyridylalkylamine.
The most effective ligand for this reaction is readily pre-
pared (two steps) from very cheap starting materials, and it
can be obtained in both enantiomeric forms starting from
the suitable camphor enantiomer, both of which are com-
mercially available.
Scheme 4. Enantioselective synthesis of (S)-miconazole (15). i) Zn, HCl,
EtOH/H2O, reflux, 82%; ii) glyoxal, 38% aqueous formaldehyde,
NH4OAc, MeOH, reflux, 70%; iii) 1. NaH, THF/DMF, RT, 2. 2,4-di-
chloro-1-(chloromethyl)benzene, tetrabutylammonium iodide, RT, 76%.
This Henry reaction is general in scope and provides the
expected products with high-to-quantitative yields and ex-
4728
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4725 – 4730

Enantioselective Henry Reaction
FULL PAPER
(10 mL) and water (10 mL) were added, and the mixture was extracted
with EtOAc (3”25 mL). The organic phase was dried (MgSO4), concen-
trated under reduced pressure, and the residue chromatographed on
silica gel (EtOAc/EtOH 99:1 to 7:3) to give 13 (72 mg, 82%). [a]2D5 =+
73.5 (c=0.51 in CHCl3, 98%ee); 1H NMR (300 MHz, CDCl3): d=7.51
cellent enantioselectivities with a broad range of aromatic,
heteroaromatic, aliphatic, and unsaturated aldehydes, by
using nitromethane and other nitroalkanes in the presence
of a moderate catalyst loading (5 mol%). The operational
procedure is very simple and does not require special care
with respect to the exclusion of air or moisture. As a conse-
quence of all these features, the present catalytic system is
one of the most convenient procedures for the synthesis of
nitroalkanols. The applicability of the procedure has been
demonstrated with the synthesis of miconazole, a known an-
tifungal agent.
(d, J
(H,H)=8.4, 2.1 Hz, 1H), 4.98 (dd, J
4H), 2.66 ppm (dd, J
(H,H)=12.6, 7.8 Hz, 1H); 13C NMR (75.5 MHz,
A
ACHTRE(UGN H,H)=2.1 Hz, 1H), 7.25 (dd, J-
A
ACHTREUNG
AHCTREUNG
CDCl3): d=138.5 (C), 133.5 (C), 132.2 (C), 129.0 (CH), 128.3 (CH),
127.3 (CH), 69.9 (CH), 46.8 ppm (CH2); MS (FAB, 30 kV): m/z (%): 206
(4) [M+1]+; HRMS calcd for C8H10NOCl2 [M+1]+: 206.0139, found:
206.0147.
(S)-1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (14): 40% Aque-
ous glyoxal (73.2 mL, 0.64 mmol), ammonium acetate (50.9 mg,
0.64 mmol), and 38% aqueous formaldehyde (48.4 mL, 0.64 mmol) were
added to a solution of 13 (66 mg, 0.32 mmol) in methanol (0.75 mL). The
mixture was heated at reflux for 4 h. After this time, the volatile com-
pounds were removed under reduced pressure and the residue was treat-
ed with 2m aqueous KOH (15 mL). The mixture was extracted with
CH2Cl2 (5”20 mL), and the organic layer was dried (MgSO4) and con-
centrated under reduced pressure. Column chromatography (CH2Cl2/
MeOH, 100:0 to 95:5) gave 14 (57.5 mg, 70%). [a]2D5 =+87.3 (c=0.89 in
CHCl3, 98% ee; lit.:[29] [a]D25 =+83.8); 1H NMR (300 MHz, CDCl3): d=
Experimental Section
General methods: Commercial reagents were used as purchased. Re-
agent quality absolute EtOH without additional drying was used for all
enantioselective reactions, which were carried out in test tubes stoppered
with a septum. No special precautions were observed for the exclusion of
air or moisture. Reactions were monitored by TLC analysis with Merck
silica gel 60F-254 thin-layer plates. Flash column chromatography was
performed on Merck silica gel 60 (0.040–0.063 mm). Specific optical rota-
7.58 (d, J
1H), 6.89 (brs, 1H), 6.81 (brs, 1H), 5.21 (d, J
(brs, 1H), 4.20 (d, J(H,H)=14.1 Hz, 1H), 3.87 ppm (dd, JACHTREUNG
A
ACHTRE(UNG H,H)=8.4 Hz,
AHCTREUNG
C
tions were recorded by using
a Perkin–Elmer 241 polarimeter with
8.1 Hz); 13C NMR (75.5 MHz, CDCl3): d=137.5 (C), 137.3 (CH), 134.1
(C), 131.9 (C), 129.0 (CH), 128.7 (CH), 128.0 (CH), 127.7 (CH), 119.6
(CH), 69.5 (CH), 53.5 ppm (CH2); MS (EI, 70 eV): m/z (%): 256 (2.8)
[M]+, 221 (30), 174 (38), 111 (25), 82 (100), 81 (39); HRMS: calcd for
C11H10N2OCl2 [M]+: 256.0170, found: 256.0174; the ee value (98%) was
determined by HPLC on a Chiralpack AD-H column, hexane/iPrOH
sodium light (D line 589 nm). NMR spectra were recorded by using
Bruker Avance spectrometers in the deuterated solvents as stated. Resid-
ual non-deuterated solvent was used as the internal standard and CFCl3
as the internal standard for 19F NMR. J values are given in Hz. The
carbon type was determined by DEPT experiments. Mass spectra were
recorded by using a Fisons Instruments VG Autospec GC 8000 series
spectrometer. EI mass spectra were run at 70 eV and FAB mass spectra
were run at 30 kV in a meta-nitrobenzyl alcohol (MNBA) matrix. Chiral
HPLC analyses were performed by using a Hitachi Elite Lachrom instru-
ment equipped with a Hitachi UV diode array L-4500 detector with
chiral stationary columns from Daicel. Retention times are given in min.
(90:10), flow rate=1.0 mLminÀ1
minor enantiomer (R) tr =15.5 min.
, major enantiomer (S) tr =10.1 min,
(S)-1-(2-(2,4-Dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl)-1H-imida-
zole (miconazole, 15): NaH (60% dispersion in mineral oil, 6.7 mg,
0.17 mmol) was added to a solution of 14 (17.3 mg, 0.067 mmol) in THF/
DMF (1 mL, 10:1) at 08C, under nitrogen. After 15 min, 2,4-dichloro-1-
(chloromethyl)benzene (14 mL, 0.10 mmol) was added followed by tetra-
butylammonium iodide (2.5 mg, 0.0067 mmol). After stirring for 5 h at
RT, water (10 mL) was added. The mixture was extracted with CH2Cl2
(3”15 mL), dried (MgSO4), and concentrated under reduced pressure.
Column chromatography (hexane/EtOAc, 5:5 to 1:9) gave 15 (21.1 mg,
76%). [a]2D5 =+57.9 (c=1.3 in CHCl3, 98% ee); 1H NMR (300 MHz,
Compound 2: Sodium borohydride (1.59 g, 4.13 mmol) was added por-
tionwise to
a solution of 1 (1.00 g, 4.13 mmol) and NiCl2 (1.09 g,
8.26 mmol) in MeOH (60 mL) at À308C under a nitrogen atmosphere
over a period of 1 h. After 2 h, the solvent was evaporated under reduced
pressure. Column chromatography (eluent=EtOAc) gave 2 as an oil
(624 mg, 62%). [a]2D5 =À80.6 (c=1.01 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=8.53 (ddd, J
(H,H)=7.8, 1.8 Hz, 1H; pyr), 7.32 (d, J
(ddd, J(H,H)=7.5, 5.0, 0.6 Hz, 1H; pyr), 3.92 (d, J
CH2N), 3.88 (d, J(H,H)=14.4 Hz, 1H; CH2N), 2.64 (dd, J
4.3 Hz, 1H; 2n-H), 2.26 (brs, 1H; NH), 1.69 (s, 1H; 4-H), 1.70–1.56 (m,
3H; 3n-H, 3x-H, 5x-H), 1.09 (s, 3H; 1-Me), 1.05 (d, J(H,H)=8.4 Hz, 2H;
ACHTRE(UNG H,H)=5.0, 1.8, 0.6 Hz, 1H; pyr), 7.63 (td, J-
CDCl3): d=7.54 (brs, 1H), 7.45 (d, J
(H,H)=1.8 Hz, 1H), 7.31–7.29 (m, 2H), 7.24 (dd, J
1H), 7.18 (d, J(H,H)=8.4 Hz, 1H), 7.05 (brs, 1H), 6.91 (brs, 1H), 5.02
(dd, J(H,H)=7.2, 2.7 Hz, 1H), 4.49 (d, J(H,H)=12.6 Hz, 1H), 4.34 (d, J-
(H,H)=12.6 Hz, 1H), 4.25 (dd, J(H,H)=14.7, 2.7 Hz), 4.08 ppm (dd, J-
(H,H)=14.7, 7.2 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=137.8 (CH),
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
5n-H, 6n-H), 0.95 (s, 3H; 7s-Me), 0.80 ppm (s, 3H; 7a-Me); 13C NMR
(75.5 MHz, CDCl3): d=160.4 (C), 149.0 (CH), 136.3 (CH), 122.2 (CH),
121.7 (CH), 66.4 (CH), 53.9 (CH2), 48.4 (C), 46.7 (C), 45.2 (CH), 38.5
(CH2), 36.8 (CH2), 27.3 (CH2), 20.5 (CH3), 20.5 (CH3), 12.2 ppm (CH3);
MS (EI, 70 eV): m/z(%): 244 (0.8)[M]+, 152 (100), 135 (29), 95 (41), 93
(92); HRMS: calcd for C16H24N2 [M]+: 244.1939, found: 244.1936.
135.0 (C), 134.3 (C), 133.68 (C), 133.64 (C), 133.24 (C), 133.21 (C), 130.0
(CH), 129.7 (CH), 129.3 (CH), 129.2 (CH), 128.3 (CH), 128.0 (CH),
127.3 (CH), 119.8 (CH), 77.6 (CH), 68.2 (CH2), 51.3 ppm (CH2); MS
(EI): m/z (%): 414 (6.2) [M]+, 334 (18), 161 (65), 159 (100); HRMS:
calcd for C18H14N2OCl4 [M]+: 413.9860, found: 413.9865; the ee (98%)
was determined by HPLC on a Chiralcel OD-H column, hexane/iPrOH
(90:10), flow rate=1.0 mLminÀ1
minor enantiomer (R) tr =19.6 min.
, major enantiomer (S) tr =20.8 min,
General procedure for the catalytic enantioselective Henry reaction: A
solution of 2 (6.7 mg, 0.025 mmol) in absolute EtOH (2 mL) was added
to CuACHTREUNG(OAc)2·H2O (5.0 mg, 0.025 mmol) in a test tube. The test tube was
stoppered with a septum, and the solution was stirred for 1 h to give a
blue solution. The aldehyde (0.5 mmol) was added, and the tube was
placed in a bath at the reaction temperature. After 5 min, the nitroalkane
(5 mmol) was added followed by DIPEA (87.1 mL, 0.5 mmol). After the
indicated time, the solvent was removed under reduced pressure and the
product was isolated by column chromatography.
Acknowledgements
(S)-2-Amino-1-(2,4-dichlorophenyl)ethanol (13): Zn powder (314 mg,
4.78 mmol) was added to a solution of 8m (100 mg, 0.212 mmol, 98% ee)
in ethanol/H2O (3.4:0.8 mL) followed by concentrated HCl (0.66 mL).
The mixture was heated at reflux for 1 h. Aqueous saturated NaHCO3
Financial support from the Ministerio de Educación y Ciencia (CTQ
2006-14199) and the Generalitat Valenciana (GV 05/10) is gratefully ac-
knowledged. V.H.-O. thanks the Universitat de Val›ncia for a pre-doctor-
al grant (V. Segles program).
Chem. Eur. J. 2008, 14, 4725 – 4730
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4729

G. Blay, J. R. Pedro et al.
[19] D. A. Evans, T. Lectka, S. J. Miller, Tetrahedron Lett. 1993, 34,
7027–7030.
[1] a) G. Rosini, in Comprehensive Organic Synthesis, Vol. 2 (Eds.:
B. M. Trost, I. Fleming), Pergamon, New York, 1991, pp. 321–340;
b) F. A. Luzzio, Tetrahedron 2001, 57, 915–945.
[2] N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New
York, 2001.
[20] G. Chelucci, R. P. Thummel, Chem. Rev. 2002, 102, 3129–3170.
[21] a) H. Brunner, U. Obermann, Chem. Ber. 1989, 122, 499–507; b) G.
Chelucci, M. G. Sanna, S. Gladiali, Tetrahedron, 2000, 56, 2889–
2893; c) H. Brunner, H. Kagan, G. Kreutzer, Tetrahedron: Asymme-
try 2003, 14, 2177–2187.
[22] a) Y. Himeda, N. Onozawa-Komatsuzaki, H. Sugihara, H. Arakawa,
K. Kasuga, J. Mol. Catal. A: Chem 2003, 195, 95–100; b) C. A. Lu-
chaco-Cullis, H. Mizutani, K. E. Murphy, A. H. Hoveyda, Angew.
Chem. 2001, 113, 1504–1508; Angew. Chem. Int. Ed. 2001, 40, 1456–
1460; .
[23] a) G. Blay, E. Climent, I. Fernµndez, V. Hernµndez-Olmos, J. R.
Pedro, Tetrahedron: Asymmetry 2006, 17, 2046–2049; b) G. Blay, E.
Climent, I. Fernµndez, V. Hernµndez-Olmos, J. R. Pedro, Tetrahe-
dron: Asymmetry 2007, 18, 1603–1612.
[24] a) K. Inoguchi, S. Sakuraba, K. Achiwa, Synlett 1992, 169–178;
b) A. Togni, C. Breutel, A. Schnyder, F. Spindler, H. Landert, A.
Tijani, J. Am. Chem. Soc. 1994, 116, 4062–4066.
[25] The effect of the ligand on the steric and electronic differentiation
of the two trans disposed coordination sites (trans effect) has impor-
tant implications in many Pd-catalyzed reactions, such as allylic sub-
stitution; for a discussion, see: A. C. Humphries, A. Pfaltz in Stimu-
lating Concepts in Chemistry (Eds.: F. Vçgtle, J. F. Stoddart, M. Shi-
bashaki), Wiley-VCH, Weinheim, 2000, pp. 89–103.
[26] A. Gayet, C. Bolea, P. G. Andersson, Org. Biomol. Chem. 2004, 2,
1887–1893.
[27] The endo-isomer of 2 has been used as a co-ligand in the enantiose-
[3] For examples, see: a) H. Li, B. Wang, L. Deng, J. Am. Chem. Soc.
2006, 128, 732–733; b) L. Allmendiger, G. Bauschke, F. F. Paintner,
Synlett 2005, 2615–2618; c) N. Gogoi, J. Boruwa, N. C. Barua, Tetra-
hedron Lett. 2005, 46, 7581–7582; d) F. F. Paintner, L. Allmendiger,
G. Bauschke, P. Klemmann, Org. Lett. 2005, 7, 1423–1426.
[4] a) M. Shibasaki, H. Gçger in Comprehensive Asymmetric Catalysis
Vol. III (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, 1075–1090; b) M. Shibashaki, H. Gçger, M. Kanai in
Comprehensive Asymmetric Catalysis Supplement 1 (Eds.: E. N. Ja-
cobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 2004, 131–
133; c) C. Palomo, M. Oiarbide, A. Mielgo, Angew. Chem. 2004,
116, 5558–5560; Angew. Chem. Int. Ed. 2004, 43, 5442–5444; d) J.
Boruwa, N. Gogoi, P. P. Saikia, N. C. Barua, Tetrahedron: Asymme-
try 2006, 17, 3315–3326; e) C. Palomo, M. Oiarbide, A. Laso Eur. J.
Org. Chem. 2007, 2561–2574.
[5] a) H. Sasai, T. Suzuki, S. Arai, T. Arai, M, Shibasaki, J. Am. Chem.
Soc. 1992, 114, 4418–4420; b) T. Arai, Y. M. A. Yamada, N. Yama-
moto, H. Sasai, M. Shibasaki, Chem. Eur. J. 1996, 2, 1368–1372;
c) H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shiba-
saki, J. Org. Chem. 1995, 60, 7388–7389; d) J. M. Saµ, F. Tur, J. Gon-
zµlez, M. Vega, Tetrahedron: Asymmetry 2006, 17, 99–106.
[6] a) B. M. Trost, V. S. C. Yeh, Angew. Chem. 2002, 114, 889–891;
Angew. Chem. Int. Ed. 2002, 41, 861–863; ; b) B. M. Trost, V. S. C.
Yeh, H. Ito, N. Bremeyer, Org. Lett. 2002, 4, 2621–2623.
[7] C. Palomo, M. Oiarbide, A Laso, Angew. Chem. 2005, 117, 3949–
3952; Angew. Chem. Int. Ed. 2005, 44, 3881–3884; .
lective Diels–Alder reaction catalyzed by iridiumACHTREU(NG III) complexes
with low enantioselectivity, see: D. Carmona, M. P. Lamata, F.
Viguri, R. Rodríguez, F. J. Lahoz, I. T. Dobrinovitch, L. Oro, Dalton
Trans. 2007, 1911–1921.
[8] a) Y. Kogami, T. Nakajima, T. Ashizawa, S. Kezuka, T. Ikeno, T.
Yamada, Chem. Lett. 2004, 614–615; b) Y. Kogami, T. Nakajima, T.
Ikeno, T. Yamada, Synthesis 2004, 1947–1950.
[9] B. M. Choudary, K. V. S. Ranganath, U. Pal, M. L. Kantam, B.
Sreedhar, J. Am. Chem. Soc. 2005, 127, 13167–13171.
[10] D. A. Evans, D. Seidel, M. Rueping, H. W. Lam, J. T. Shaw, C. W.
Downey, J. Am. Chem. Soc. 2003, 125, 12692–12693.
[11] T. Risgaard, K. V. Gothelf, K. A. Jørgensen, Org. Biomol. Chem.
2003, 1, 153–156.
[28] a) A. W. Fothergill, Expert Rev. Anti-Infect. Ther. 2006, 4, 171–175;
b) M. H. Stranz, Drug Intell. Clin. Pharm. 1980, 14, 86–95; c) Anti-
fungal agents: Advances and Problems (Ed.: E. Jucker), Burkhꢁuser,
Basel, 2003.
[29] Y. Matsuoka, Y. Ishida, D. Sasaki, K. Saigo, Tetrahedron 2006, 62,
8199–8206.
[30] a) I. C. Lennon, J. A. Ramsden, Org. Process Res. Dev. 2005, 9, 110–
112; b) S. N. Bisaha, M. F. Malley, A. Pudzianowski, H. Monshizade-
gan, P. Wang, C. S. Madsen, J. Z. Gougoutas, P. D. Stein, Bioorg.
Med. Chem. Lett. 2005, 15, 2749–2751.
[31] C. Chan, R. Heid, S. Zheng, J. Guo, B. Zhou, T. Furuuchi, S. J. Dani-
shefsky, J.Am.Chem.Soc. 2005, 127, 4596–4598.
[12] H. Maheswaran, K. L. Prasant, G. G. Krishna, K. Ravikumar, B.
Sridhar, M. L. Kantam, Chem. Commun. 2006, 4066–4068.
[13] K. Ma, J. You, Chem. Eur. J. 2007, 13, 1863–1871.
[14] M. Bandini, F. Piccinelli, S. Tommasi, A. Umani-Ronchi, C. Ventrici,
Chem. Commun. 2007, 616–618.
[32] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
[15] T. Arai, M. Watanabe, A. Yanagisawa, Org. Lett. 2007, 9, 3595–
3597.
[16] a) Y. Xiong, F. Wang, X. Huang, Y. Wen, X. Feng, Chem. Eur. J.
2007, 13, 829–833; b) B. Qin, X. Xiao, X. Liu, J. Huang, Y. Wen, X.
Feng, J. Org. Chem. 2007, 72, 9323–9328.
[33] Gaussian 03, Revision C.02, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomer-
y, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyen-
gar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wall-
ingford CT, 2004.
[17] For guanidine catalysis, see: a) Y. Sohtome, Y. Hashimoto, K. Naga-
sawa, Adv. Synth. Catal. 2005, 347, 1643–1648; b) Y. Sohtome, Y.
Hashimoto, K. Nagasawa, Eur. J. Org. Chem. 2006, 2894–2897; for
cinchona alkaloids, see: c) M. Marcelli, R. N. S. van der Haas, J. van
Maarseveen, H. Hiemstra, Angew. Chem. 2006, 118, 943–945;
Angew. Chem. Int. Ed. 2006, 45, 929–931; d) H. Li, B. Wang, L.
Deng, J. Am. Chem. Soc. 2006, 128, 732–733; for phase-transfer
conditions, see: e) E. J. Corey, F.-Y. Zhang, Angew. Chem. 1999, 111,
2057–2059; Angew. Chem. Int. Ed. 1999, 38, 1931–1934; f) T. Ooi,
K. Doda, K. Maruoka, J. Am. Chem. Soc. 2003, 125, 2054–2055;
g) D. Uraguchi, S. Sakaki, T. Ooi, J. Am. Chem. Soc. 2007, 129,
12392–12393; for biocatalysis, see: h) T. Purkarthofer, K. Gruber,
M. Gruber-Khadjawi, K. Waich, W. Skrank, D. Mink, H. Griengl,
Angew. Chem. 2006, 118, 3532–3535; Angew. Chem. Int. Ed. 2006,
45, 3454–3456; .
[34] F. R. Hartley, Chem. Soc. Rev. 1973, 2, 163–179.
[18] G. Desimoni, G. Faita, K. A. Jørgensen, Chem. Rev. 2006, 106,
3561–3651.
Received: January 14, 2008
Published online: April 2, 2008
4730
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4725 – 4730