Enantioselective addition of nitromethane to 2-acylpyridine N -Oxides. Expanding the generation of quaternary stereocenters with the henry reaction

Article abstract of DOI:10.1021/ol500082d

The direct asymmetric Henry reaction with prochiral ketones, leading to tertiary nitroaldols, is an elusive reaction so far limited to a reduced number of reactive substrates such as trifluoromethyl ketones or α-keto carbonyl compounds. Expanding the scop

Full text of DOI:10.1021/ol500082d

Letter
pubs.acs.org/OrgLett
Enantioselective Addition of Nitromethane to 2‑Acylpyridine
N‑Oxides. Expanding the Generation of Quaternary Stereocenters
with the Henry Reaction
Melireth Holmquist,† Gonzalo Blay,*,† M. Carmen Munoz,‡ and Jose R. Pedro*,†
́
̃
†Departament de Química Organ
Spain
‡Departament de Física Aplicada, Universitat Politec
̀
ica, Facultat de Química-Universitat de Valen
̀
cia, C/Dr. Moliner 50, E-46100Burjassot (Valen
̀
cia),
̀
nica de Valen
̀
cia, E-46071 Valencia, Spain
̀
S
* Supporting Information
ABSTRACT: The direct asymmetric Henry reaction with prochiral
ketones, leading to tertiary nitroaldols, is an elusive reaction so far limited
to a reduced number of reactive substrates such as trifluoromethyl
ketones or α-keto carbonyl compounds. Expanding the scope of this
important reaction, the direct asymmetric addition of nitromethane to 2-
acylpyridine N-oxides catalyzed by a BOX-Cu(II) complex to give the
corresponding pyridine-derived tertiary nitroaldols having a quaternary
stereogenic center with variable yields and good enantioselectivity, is
described.
Here, we describe the catalytic enantioselective addition of
nitromethane to 2-acyl pyridine N-oxides to give the
corresponding tertiary nitroaldols bearing a quaternary stereo-
center bonded to a 2-pyridyl moiety.
symmetric nucleophilic additions to prochiral carbonyl
Acompounds provide an attractive approach toward chiral
building blocks containing a stereocenter bearing a hydroxyl
group. In particular, the enantioselective addition of nitro-
alkanes to carbonyl compounds (Henry or nitroaldol reaction)
allows the preparation of enantiomerically enriched nitro-
alkanols,1 which have a high scientific and commercial value as
building blocks for the synthesis of pharmaceuticals and
agrochemicals.2 In recent years, a considerable advance in the
development of asymmetric procedures for the addition of
nitroalkanes to aldehydes3 and aldimines4 leading to products
with tertiary stereocenters has been achieved. In contrast, the
asymmetric addition of nitroalkanes to ketones that would give
rise to the challenging formation of a quaternary stereogenic
center has experienced little progress.5 In fact, even for the
nonenantioselective version only a few methods are available
with a limited substrate scope.6 Regarding asymmetric
methodologies for the synthesis of tertiary nitroaldols,
Shibasaki7 has reported a kinetic resolution of racemic mixtures,
while the direct nucleophilic addition of nitromethane has been
carried out only with very reactive substrates such as
trifluoromethyl ketones,8 α-keto esters, and α-keto amides.9
Very recently, our group has described the asymmetric addition
of nitromethane to the ketone group of substituted glyoxal
hydrates bearing a latent aldehyde carbonyl in the α-position.10
On the other hand, pyridine derivatives are of great
importance for the pharmaceutical industry, as demonstrated
by the existence of more than 7000 drugs featuring this
heterocyclic ring, as well as for the agrochemical industry due to
their applications as herbicides, fungicides, or bactericides.11
Furthermore, the pyridine moiety is present in a good number
of chiral ligands for asymmetric catalysis.12
We13 and others14 have shown the excellent chelating
properties of the 2-acyl pyridine N-oxide moiety in several
asymmetric metal-catalyzed reactions. Following this strategy,
our investigation was started by studying the addition of
nitromethane to ketone 1a in the presence of different metal
complexes with nitrogenated ligands as catalysts (Scheme 1).
According to the conditions of our previously reported
Henry reaction with keto esters,9h the reaction was initially
carried out in nitromethane as the solvent and in the presence
of triethylamine. Several complexes of divalent metal triflates
(Cu, Zn, Mg) with ligand BOX1, as well as complexes of
trivalent metal triflates (La, Yb, Sc, In) with ligand pyBOX1,
were tested as catalysts. This screening showed the
combination of Cu(OTf)2 with BOX1 to be the most active
catalyst in this reaction (see Table S-1 in the Supporting
Information (SI)). Other bases were tested in the presence of
this complex, showing little effect (see Table S-2 in the SI).
When the yield and enantioselectivity of the reaction were
considered, diisopropylamine was determined to be the best
option which afforded compound 3a in 50% yield with 44% ee
when the reaction was performed at −15 °C (Table 1, entry
1).15 Several BOX ligands were then tested (Table 1, entries 1−
7). BOX4 gave the best enantiomeric excess (72%) for 3a,
although with a low yield (Table 1, entry 4).
Received: January 9, 2014
Published: February 11, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
these conditions was only moderate, no other byproducts were
formed during the reaction and the unreacted starting material
1a could be recovered after column chromatography. More-
over, it should be taken into account that this yield is close to
the maximum yield affordable via kinetic resolution of a racemic
mixture according to Shibasaki’s procedure,7 especially if we
consider the overall yield of the racemic synthesis−kinetic
resolution process. Taking into account this consideration and
encouraged by the high ee obtained in the synthesis of
compound 3a, we studied the applicability of the reaction to
other related substrates (Table 2).
Scheme 1. Enantioselective Henry Reaction with Ketone 1a
and Ligands Used in This Research
Table 2. Enantioselective Addition of Nitromethane to 2-
a
Acylpyridine N-Oxides 1; Scope of the Reaction
b
entry
1
1
R1
R2
t (h)
yield (%)
ee (%)
a
H
Ph
96
96
96
96
24
24
48
48
96
48
48
48
66
72
96
48
48
72
39
17
19
85
80
87
84
65
−
72
96
84
85
87
90
73
79
80
96
87
90
61
86
81
84
70
−
84
76
81
89
55
48
91
92
91
c
2
b
c
d
e
f
H
4-MeOC6H4
3
H
4-ClC6H4
3-ClC6H4
Me
4
H
Table 1. Enantioselective Addition of Nitromethane to
Ketone 1a Catalyzed by Cu(II)-BOX Complexes; Screening
5
H
6
H
Et
a
of Ligands and Solvents
7
g
h
i
H
Bu
8
H
i-Pr
Me
temp
(°C)
yield
(%)
ee
(%)
b
9
3-Me
4-Me
4-Ph
5-Me
5-Br
6-Me
6-Br
4-Ph
5-Me
5-Br
entry
L
solvent
t (h)
10
j
Me
1
2
3
4
5
6
7
8
BOX1 CH3NO2
BOX2 CH3NO2
BOX3 CH3NO2
BOX4 CH3NO2
BOX5 CH3NO2
BOX6 CH3NO2
BOX7 CH3NO2
−15
−15
−15
−15
−15
−15
−15
−15
44
42
45
42
44
44
44
44
50
21
19
24
32
9
−44
−52
−40
72
c
11
k
l
Me
12
Me
c
13
m
n
o
p
q
r
Me
14
15
Me
62
Me
64
c
16
Et
35
34
−51
75
17
Et
BOX4 EtOH/CH3NO2
c
18
Et
(2:1)
a
9
BOX4 CH2Cl2/CH3NO2
−15
44
24
77
1 (0.33 M), Cu(OTf)2 (20 mol %), BOX4 (20 mol %), i-Pr2NH (25
b
(2:1)
mol %), EtOH/CH3NO2 (5:1), −30 °C. Ee determined by HPLC.
c
10
11
BOX4 Et2O/CH3NO2 (2:1)
−15
−30
46
90
38
40
62
95
Reaction carried out at −20 °C
BOX4 EtOH/CH3NO2
(5:1)
Compounds 1b and 1c bearing a p-substituted phenyl group
with an electron-donating (MeO) or an electron-withdrawing
(Cl) group, respectively, gave similar results providing the
expected products with low yields but good ee (Table 2, entries
2, 3), while the 3-chlorophenyl derivative 1d reacted with
CH3NO2 to give compound 3d (Table 2, entry 4) with high
yield (85%) and fair ee (61%). More consistent results were
obtained with aliphatic ketones. High yields and enantiomeric
excesses above 80% were obtained with methyl, ethyl, or butyl
ketones 1e−g (Table 2, entries 5−7). The branched isopropyl
ketone 1h was less reactive and gave compound 3h with a 65%
yield but still 70% ee (Table 2, entry 7). Then we studied the
effect of substituents on the pyridine ring. The reaction was
sensitive to steric factors. The presence of a substituent (Me or
Br) at position 6 of the pyridine ring led to the corresponding
products with moderate enantioselectivities although high
yields (Table 2, entries 14, 15), while the presence of a methyl
group at position 3 of the pyridine ring completely prevented
the reaction from taking place. However, compounds
substituted at the 4 and 5 positions of the pyridine ring
12
BOX4 EtOH/CH3NO2
−30
90
39
96
c
(5:1)
a
1a (0.17 M), Cu(OTf)2 (20 mol %), L (20 mol %), i-Pr2NH (25 mol
%). Ee determined by HPLC. The sign indicates the optical rotation
sign of the major enantiomer. 1a (0.33 M).
b
c
In order to minimize a possible nonenantioselective
background reaction that could be detrimental to the
enantioselectivity, we carried out the reaction in the presence
of a solvent to reduce the concentration of nitromethane. A
slight increase of enantioselectivity was observed in ethanol and
dichloromethane (Table 1, entries 8 and 9). But more
important, the use of other solvents also allowed a decrease
in the reaction temperature. In this way, compound 3a could be
obtained with very high ee (95%), although in moderate yield
(40%) by using a 5:1 ethanol/CH3NO2 mixture at −30 °C
(Table 1, entry 11). The amount of solvent and nitromethane
could be reduced without any effect on the result (Table1,
entry 12). Although the yield of the nitroaldol obtained under
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Organic Letters
Letter
provided the nitroaldol products in good yields and remarkable
enantioselectivities, with enantiomeric excesses above 90% for
ethyl ketones 1p−r (Table 2, entries 16−18). The nitroalkanols
obtained in this reaction can be transformed into pyridyl
aminoalcohols bearing a quaternary stereocenter. For instance,
compound 3e was quantitatively transformed into 4 upon
hydrogenation over 5% Pd/C in methanol (Scheme 2). To
square planar complex13,14a,b with both the oxygen atom of the
N-oxide and that of the carbonyl group occupying the most
acidic equatorial positions for the maximum electrophilic
activation.17 The nitronate is positioned in one of the apical
positions for nucleophilic activation.17 Attack of the nitronate
from the si-face of the carbonyl group is hampered by one of
the Indane moieties of the ligand, and therefore it takes place
preferentially from the re-face to give the nitroaldol with the R
configuration.
Scheme 2. Hydrogenation of 3e and Synthesis of Amide 5
In summary, a novel direct asymmetric Henry reaction with
ketones was reported. A Cu(II)-BOX complex catalyzed the
addition of nitromethane18 to 2-acylpyridine N-oxides to give
the corresponding tertiary nitroaldols bearing a quaternary
stereocenter bonded to a pyridine ring with good yields and
moderate to high enantiomeric excesses. The reaction expands
the scope of the elusive enantioselective Henry reaction with
ketones.
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional optimization data. Experimental procedures, char-
determine the absolute stereochemistry of the nitroaldol
products, compound 4 was transformed into amide 5 by
treatment with (+)-(S)-mandelic acid using dicyclohexylcarbo-
diimide (DCC) and N-hydroxysuccinimide as a coupling
reagent in THF.
1
acterization data, H and 13C NMR spectra for compounds 1,
3−5, and chiral analysis for compounds 3. CIF file for
compound 5. This material is available free of charge via the
Internet at http://pubs.acs.org.
X-ray analysis of amide 5 crystals, obtained by successive
crystallizations from chloroform and toluene, allowed determin-
ing that the quaternary stereogenic center in compound 5, and
hence in compounds 4 and 3e, was of an R configuration
(Figure 1). For the remainder of nitroaldol products 3, the
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gonzalo.blay@uv.es.
*E-mail: jose.r.pedro@uv.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Ministerio de Economia y
Competitividad (Gobierno de Espana) and FEDER (EU)
(CTQ2009-13083) and from Generalitat Valenciana
(ACOMP2012-212 and ISIC 2012/001) is acknowledged.
■
́
̃
́
M.H. thanks the GV for a predoctoral grant (Santiago Grisolia
Program).
Figure 1. Ortep plot for the X-ray structure of compound 5. The
thermal ellipsoids are drawn at the 50% probability level.
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