1,1′-Binaphthyldiamine-based lewis bases as readily available and efficient grganocatalysts for the reduction of N-Aryl and N-Alkyl ketimines

Article abstract of DOI:10.1002/ejoc.200900524

The development of simple, low-cost, efficient, and sustainable routes to enantiomerically pure amines is a topic of extraordinary interest, specially in view of future industrial applications. In this context, we wish to report a chemical and stereochemical efficient synthesis of chiral amines through the Lewis base activated trichlorosilane reduction of ketimines. An organocatalyst, easily prepared in a single step through the condensation of picolinic acid and commercially available 1,1′-binaphthyldiamine, is the key element of this metal-free methodology, that allowed the synthesis of chiral secondary and primary amines in high yields and stereose-lectivity. Noteworthy, such catalysts are able to promote the reduction of N-alkyl ketimines, often in quantitative yield and up to 87% enantioselectivity; it: is worth mentioning that for such transformations only one other organocatalytic system has been reported so far.

Full text of DOI:10.1002/ejoc.200900524

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900524
1,1Ј-Binaphthyldiamine-Based Lewis Bases as Readily Available and Efficient
Organocatalysts for the Reduction of N-Aryl and N-Alkyl Ketimines
Stefania Guizzetti,[a] Maurizio Benaglia,*[a] and Giuseppe Celentano[b]
Keywords: Reduction / Lewis bases / Organocatalysis / Binaphthyldiamines / Enantioselectivity
The development of simple, low-cost, efficient, and sustain-
able routes to enantiomerically pure amines is a topic of ex-
traordinary interest, specially in view of future industrial ap-
plications. In this context, we wish to report a chemical and
stereochemical efficient synthesis of chiral amines through
the Lewis base activated trichlorosilane reduction of ket-
imines. An organocatalyst, easily prepared in a single step
through the condensation of picolinic acid and commercially
available 1,1Ј-binaphthyldiamine, is the key element of this
metal-free methodology, that allowed the synthesis of chiral
secondary and primary amines in high yields and stereose-
lectivity. Noteworthy, such catalysts are able to promote the
reduction of N-alkyl ketimines, often in quantitative yield
and up to 87% enantioselectivity; it is worth mentioning that
for such transformations only one other organocatalytic sys-
tem has been reported so far.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
The demand for enantiomerically pure primary and sec- were successfully employed in a process that involves the
ondary amines has called for a considerable effort to be use of a dihydropyridine-based compound as the reducing
placed in the development of efficient stereoselective cata- agent.[6] In the other case, the reducing agent is trichlorosi-
lytic processes;[1] among the different approaches, the re- lane, which is activated by coordination with Lewis bases,
duction of ketimines represents a powerful and widely used such as N,N-dimethylformamide, acetonitrile, and trialkyl-
transformation that allows the generation of a new nitro- amines, to generate a hexacoordinate hydridosilicate, which,
gen-bearing stereocenter. Although hydrosilylation of im- under mild conditions, operates as the actual reducing
ines[2] and enantioselective hydrogenation[3] have been agent.[7] The use of chiral Lewis bases has been widely ex-
widely studied over the last few years, it must be said that plored in the last few years and has led to the development
only a few efficient chiral catalytic organometallic systems of some stereochemical efficient catalysts.[8] However, both
are currently available for C=N bond reduction.[4] More- methodologies have been shown to be efficient with N-aryl
over, they suffer from some drawbacks: they are generally ketimines but unable to control the stereochemical outcome
quite expensive species, typically composed of an enantio- for the reduction of N-alkyl imines. Only very recently, the
merically pure ligand (whose synthesis may be costly, long, organocatalyzed enantioselective reduction of N-alkyl
and difficult) and a metal species, in many cases a precious imines was reported.[9] Here, we wish to report the results
element. Since chiral amines are finding applications in an of our studies on the use of 1,1Ј-binaphthyldiamine-based
always increasing number of fields, such as pharmaceuti- chiral Lewis bases as efficient organocatalysts for the re-
cals, agrochemicals, and fragrances, the possibility of de- duction of both N-aryl and N-alkyl ketimines.
veloping an organocatalytic approach has attracted much
attention because it might present a solution to the prob-
lems related to the presence of toxic metals, whose leaching
could contaminate the product.[5]
Basically, two metal-free catalytic methodologies have re-
cently been employed in the stereoselective reduction of ket-
imines; in one case, binaphthol-derived phosphoric acids
Our approach is based on the idea that the metal-free
catalyst should easily be obtained by modification of an
inexpensive, commercially available, enantiopure material
whose manipulation must be kept to minimum. In this con-
text, a very short route to chiral Lewis bases was envisaged
in the reaction between 2-pyridinecarboxylic acid and enan-
tiomerically pure, commercially available diamines.[10] This
straightforward approach was extended to binaphthyl-di-
amine derivatives, commercialized in both the enantiomeric
forms. Picolinic acid was condensed with (R)-N,NЈ-dimeth-
ylamino binaphthyl diamine[11] to afford product 1 in 73%
yield after chromatographic purification. (Figure 1) Analo-
gously, starting from the same chiral diamine, other C1-
symmetric picolinamide derivatives 2–5 were prepared by a
simple two-step sequence in order to better investigate the
[a] Dipartimento di Chimica Organica e Industriale,
Università degli Studi di Milano,
Via Golgi 19, 20133 Milano, Italy
Fax: +39-0250314159
E-mail: maurizio.benaglia@unimi.it
[b] Istituto di Chimica Organica della Facolta’ di Farmacia,
Università degli Studi di Milano,
Via Golgi 19, 20133 Milano, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900524.
Eur. J. Org. Chem. 2009, 3683–3687
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3683

S. Guizzetti, M. Benaglia, G. Celentano
SHORT COMMUNICATION
Figure 1. Structures of compounds 1–5.
structure–activity relationship of the catalyst in the ket- Table 1. Enantioselective catalytic reduction in DCM at 0 °C of N-
imine reduction (see Supporting Information).[12]
aryl imines 6–10.
First, the addition of trichlorosilane to N-aryl imines de-
rived from aryl/alkyl ketones was investigated (Scheme 1).
The results are collected in Table 1. It was observed that
Entry
Catalyst
Imine
Yield[a] [%]
ee[b] [%]
1
1
1
1
2
3
4
5
1
1
1
1
6
6
6
6
6
6
6
7
8
9
10
99
99
93
99
99
95
25
99
98
99
99
75
67
70
75
Ͻ5
55
45
81
80
83
81
2[c]
bis(picolinoylamide) 1 was able to promote the reduction 3[d]
4
5
6
7
8
9
10
11
of the N-phenyl imine of acetophenone in quantitative yield
after 12 h at 0 °C in dichloromethane and 75% ee.[12] Inter-
estingly, the catalyst maintained a similar level of stereose-
lectivity also when employed in small amounts, 1 mol-%
(Entry 3, Table 1). Catalyst 2, in which one picolinoyl group
is substituted with a benzoyl residue, still showed an excel-
lent chemical activity as an organocatalyst for ketimine re-
duction (Entry 4, Table 1); the same level of enantio-
selectivity was observed.[13] However, the presence of a hy-
drogen atom, which is able to interfere with the coordina-
tion mode of trichlorosilane to the picolinamide group, was
deleterious for the efficiency of the catalyst (catalyst 3, En-
try 5, Table 1). Based on this observation, we decided to
investigate the role of the aryl group as a steric and/or elec-
tronic shield of the catalytic site made up by the pyridine
nitrogen atom and the amide CO group. Binaphthyldi-
amine-derived picolinamide 4, featuring a 2,4,6 trimeth-
ylphenyl ring, proved to be an excellent catalyst, but the
product was afforded in lower enantioselectivity, while
Lewis base 5, bearing an electron deficient aromatic ring,
showed only a modest catalytic ability (Entries 6 and 7).
[a] Yields determined after chromatographic purification, reaction
time 12 h. [b] Enantiomeric excess determined by HPLC on chiral
stationary phase. [c] Reaction run in chloroform. [d] Reaction run
with 1 mol-% catalyst.
thesis of chiral N-phenylamines derived from 2-aceto-
naphtone and methyl-4-trifluoromethylphenyl ketone with
an enantioselectivity that is higher than 80% (Entries 8 and
9).
More importantly, catalyst 1 also reduced N-2-meth-
oxyphenyl and N-4-methoxyphenyl imines 9 and 10 in
quantitative yields and up to 83% enantioselectivity, which
led to products that are immediate precursors of the corre-
sponding primary amine (Entries 10 and 11).
On the basis of these positive results, catalyst 1 was tested
in the more challenging reduction of N-benzyl and N-alkyl
ketimines (Scheme 2). The results obtained in the tri-
chlorosilane addition to N-benzyl imines of methyl aryl
ketones are collected in Table 2. The reduction of the N-
benzyl imine of acetophenone 16 was selected as the reac-
tion model in order to find the best experimental condi-
tions. By performing the trichlorosilane addition in chloro-
form at 0 °C in the presence of 10 mol-% of catalyst 1, the
product was isolated in 70% yield and 83% enantio-
selectivity (Entry 1, Table 2). The enantiomeric excess was
Scheme 1.
The catalyst of choice, C2-symmetric bis(picolinamide) further increased to 87% by working in dichloromethane
1,[14] was employed in the reduction of other differently sub- (Entry 2, Table 2). The result is extremely interesting in view
stituted imines. It was able to efficiently promote the syn- of the possibility of removing the benzyl group by selective
3684
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3683–3687

Organocatalysts for the Reduction of Ketimines
hydrogenation, which opens the route for the preparation temperatures did not help the reaction. Further, with this
of enantiomerically enriched primary amines.[15] By lower- substrate, C1-symmetric catalyst 2 promoted the reaction,
ing the reaction temperature, the stereoselectivity did not but in lower yield and stereoselectivity (Table 3, Entry 5).
improve. It must also be noted that catalyst 2, which fea-
Table 3. Enantioselective reduction of N-alkyl imines 20–22 pro-
tures one pyridinecarboxyamide group only, was able to
promote the reaction in 90% yield and 83% ee (Table 2,
Entry 5).
moted by catalyst 1.
Entry Solvent
T [°C]
Imine
Yield[a] [%]
ee[b] [%]
1
2
3
CHCl3
DCM
CHCl3
DCM
DCM
DCM
DCM
0
0
–20
–20
0
0
0
20
20
20
20
20
21
22
98
99
98
98
45
97
99
73
85
66
71
75
71
83
4
5[c]
6
7
[a] Yields determined after chromatographic purification, reaction
time 12 h. [b] Enantiomeric excess determined by HPLC on chiral
stationary phase. [c] Reaction run with catalyst 2.
The reduction of N-allyl imines was also successfully ac-
complished at 0 °C in dichloromethane; the results were
found to be dependent on the electronic features of the ket-
imine: while the N-allyl imine of acetophenone 21 reacted
to afford the corresponding amine in 71% ee, imine 22 de-
rived from 4-methoxyacetophenone was reduced to the chi-
ral amine 29 in quantitative yield and 83% ee.
Scheme 2.
Table 2. Enantioselective reduction of N-benzyl imines 16–19 pro-
moted by catalyst 1.
Entry Solvent
T [°C]
Imine
Yield[a] [%]
ee[b] [%]
In conclusion, we have developed a very convenient and
efficient methodology for the synthesis of chiral primary
and secondary amines by trichlorosilane addition to ket-
imines; the low cost of the metal-free catalyst, which is eas-
ily prepared in one step only from commercially available
compounds, the mild reaction conditions, and the general
applicability of the catalyst to a wide variety of substrates
are all positive features of this new family of organocata-
lysts. It is worth noting that the binaphthyldiamine-derived
bis(picolinamide)s showed a remarkable and almost un-
precedented activity in performing the reduction of N-aryl
and N-benzyl and N-alkyl ketimines with up to 87%ee.
Even if the level of stereoselection is slightly inferior to that
obtained with the only other catalytic system reported for
N-alkyl imine reduction so far,[9] the easier and straightfor-
ward preparation of bis(picolinoylamide) 1, its availability
in both enantiomeric forms, the low catalyst loading, the
fact that the best performance was obtained at 0 °C without
the need for lower temperatures are all characteristics that
favorably compare with those of already known catalysts.
Further studies aimed to explore the variation in the cata-
lyst structure and to increase the enantioselectivity are cur-
rently underway and will be reported in due course.
1
2
3
4
CHCl3
DCM
CHCl3
DCM
DCM
DCM
DCM
DCM
DCM
0
0
–20
–20
0
0
0
0
0
16
16
16
16
16
16
17
18
19
70
99
43
98
90
90
99
99
99
82
87
77
78
83
80
77
81
87
5[c]
6[d]
7
8
9
[a] Yields determined after chromatographic purification, reaction
time 12 h. [b] Enantiomeric excess determined by HPLC on chiral
stationary phase. [c] Reaction run with catalyst 2. [d] Reaction run
with 1 mol-% catalyst.
It is worth noting that it was possible to further decrease
the catalyst loading. By performing the reduction in the
presence of only 1 mol-% of catalyst 1, it was possible to
isolate the product in 90% yield and 80% ee.
The reduction of N-benzyl imine derived from methyl
aryl ketones bearing either electron-withdrawing or elec-
tron-donating groups was accomplished; for example, the
reaction of trichlorosilane reaction with imine 17 obtained
from 2-acetonaphthone afforded the product in quantitative
yield and 77% ee. With catalyst 1, chiral amine 25 derived
from the imine of 4-trifluoromethyl acetophenone 18 was
formed in 99% yield and 81% enantioselectivity, while it
performed even better in the reduction of the imine of 4-
methoxyacetophenone 19 to give amine 26 in 99% yield and
87% ee (Entries 7–9, Table 2).
Finally, the methodology was further extended to N-
alkyl and N-allyl derivatives (see Table 3). The reaction of
the N-butyl imine of acetophenone 20 at 0 °C was investi-
gated; as in the previous case of N-benzyl imine 16, catalyst
1 performed better in dichloromethane than in chloroform,
which led to the chiral amine 27 in quantitative yield and
Experimental Section
All reactions were carried out in oven-dried glassware with mag-
netic stirring under a nitrogen atmosphere, unless otherwise stated.
Dry solvents were purchased by Fluka and stored under nitrogen
over molecular sieves (bottles with crown cap). Reactions were
monitored by analytical thin-layer chromatography (TLC) by using
silica gel 60 F254 pre-coated glass plates (0.25-mm thickness) and
visualized by using UV light or phosphomolybdic acid. Proton
NMR spectra were recorded on spectrometers operating at 200,
85% enantioselectivity (Entries 1 and 2, Table 3). Lower 300 or 500 MHz, respectively. Proton chemical shifts are reported
Eur. J. Org. Chem. 2009, 3683–3687
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3685

S. Guizzetti, M. Benaglia, G. Celentano
SHORT COMMUNICATION
in ppm (δ) with the solvent reference relative to tetramethylsilane
(TMS) employed as the internal standard (CDCl3 δ = 7.26 ppm).
13C NMR spectra were recorded on 300 or 500 MHz spectrometers
operating at 75 and 125 MHz, respectively, with complete proton
decoupling. Carbon chemical shifts are reported in ppm (δ) relative
to TMS with the respective solvent resonance as the internal stan-
dard (CDCl3, δ = 77.0 ppm). Optical rotations were obtained on a
polarimeter at 589 nm by using a 5-mL cell with a length of 1 dm.
HPLC for ee determination was performed on Agilent 1100 instru-
ments under the conditions reported below. Mass spectra (MS)
were obtained with a hybrid quadrupole time-of-flight mass spec-
trometer equipped with an ESI ion source. Microwave-accelerated
reactions were performed in a CEM Discover class S instrument.
C34H26N4O2 (522.21): calcd. C 78.14, H 5.01, N 10.72; found C
78.19, H 5.07, N 10.68.
Synthesis of Imines: In a typical experiment, the amine (1 equiv.)
reacted in toluene with ketone (1 equiv.) in the presence of mont-
morillonite (250 mg for 5 mmol of reagent) in a microwave reactor
(PW = 200 W; T = 130 °C; t = 4 h 30 min). The product was puri-
fied by fractional distillation.
Imine Reduction – General Procedure: The imine (1 mmol/equiv.)
was added to a stirred solution of catalyst (0.1–0.01mol-%/
equiv.mmol) in the chosen solvent (2 mL). The mixture was then
cooled to the chosen temperature, and trichlorosilane (3.5 mmol/
equiv.) was added dropwise by means of a syringe. After stirring
at the appropriate temperature, the reaction was quenched by the
addition of a saturated aqueous solution of NaHCO3 (1 mL). The
mixture was warmed to room temperature, and water (2 mL) and
dichloromethane (5 mL) were added. The organic phase was sepa-
rated, and the combined organic phases were dried with Na2SO4,
filtered, and concentrated under vacuum at room temperature to
afford the crude product. If necessary, the amine was purified by
flash chromatography. Selected examples are given.
Synthesis of the Catalysts – General Procedure: A stirred solution of
the picolinic acid or its derivatives (1 molequiv.) in thionyl chloride
(1 mL/mmol substrate) was heated at reflux for 2 h. The solvent
was then evaporated under vacuum, and the residue, dissolved in
THF (2 mL) with a few drops of DMF, was added to a solution of
chiral amino alcohol (1 molequiv.) and TEA (3 molequiv.) in THF.
The reaction mixture was stirred for 12 h at reflux. The organic
phase was quenched with an aqueous saturated solution of
NaHCO3 and brine. The organic phase was then dried with
Na2SO4, filtered, and concentrated under vacuum to give the crude
product. Purification by flash chromatography afforded the prod-
ucts.
N-Benzyl-1-phenylethanamine (23): The product was purified with
1
a hexane/ethyl acetate mixture (8:2) as eluent. The H NMR spec-
troscopic data are in agreement with those reported in the litera-
ture. 1H NMR (300 MHz, CDCl3): δ = 7.38–7.24 (m, 10 H, Ar),
3.82 (q, J = 11.5 Hz, 1 H CH–N), 3.67, 3.60 (AB, J = 12.0 Hz, 2
H, N–CH2), 1.57 (br. s, 1 H, NH), 1.37 (d, J = 11.5 Hz, 3 H,
CH3) ppm. The enantiomeric excess was determined by HPLC on
a Chiralcel OD-H column (99:1 hexane/2-propanol; flow rate:
0.8 mL/min; λ = 210 nm): tR = 7.8 min, tS = 8.4 min.
Synthesis of Catalyst 1
N-(1-Phenylethyl)butan-1-amine (27): The product was purified
1
with a hexane/ethyl acetate mixture (8:2) as eluent. The H NMR
spectroscopic data are in agreement with those reported in the lit-
erature. 1H NMR (300 MHz, CDCl3): δ = 7.3–7.1 (m, 5 H, Ph),
3.73 (q, J = 11.0 Hz, 1 H CH–N), 2.40 (m, 2 H, N–CH2), 1.36 (m,
2 H, N–CH2CH2), 1.32 (d, J = 11.0 Hz, 3 H, CH3), 1.19 (m, 2 H,
CH2CH2), 0.79 (t, J = 9.0 Hz, 3 H, CH3) ppm. The enantiomeric
excess was determined by analysis of the acetamide obtained by
reaction of the isolated amine with acetic anhydride at 25 °C for
N,NЈ-Dimethyl-(R)-1,1Ј-binaphthyldiamine-bis-2-pyridinecarboxy-
amide (1): This catalyst was obtained (73% yield, 0.35 g) by the
condensation of binaphthyldiamine (1 mmol, 0.28 g) with picoli-
noyl chloride (2 mmol, 0.28 g).
1
12 h. H NMR (300 MHz, CDCl3): δ = 7.4 (m, 5 H, Ph), 6.0 (q, J
= 12.0 Hz, 1 H CH–N), 5.0* (q, J = 10.0 Hz, 1 H CH–N), 3.3–2.8
(m, 2 H, N–CH2), 2.2 (s, 3 H, N-Ac), 2.1* (s, 3 H, N-Ac), 1.6 (d,
J = 12.0 Hz, 3 H), 1.5* (d, J = 10.0 Hz 3 H), 1.4 (m, 2 H, N–
CH2CH2), 1.2 (m, 2 H, CH2CH2), 0.8 (t, J = 12.0 Hz, 3 H) ppm.
The enantiomeric excess was determined by HPLC on a Chiralcel
IB column (9:1 hexane/2-propanol; flow rate: 0.8 mL/min; λ
210 nm): tR = 8.5 min, tS = 9.4 min.
Rotamer 1:1H NMR (500 MHz, CDCl3): δ = 8.57 (d, J = 2.7 Hz,
2 H, 7, 7Ј), 8.05 (d, J = 8.8 Hz, 2 H, 2, 2Ј), 7.95 (d, J = 8 Hz, 2 H,
3, 3Ј), 7.87 (d, J = 9, 2 Hz, 1, 1Ј), 7.72 (d, J = 7.8 Hz, 2 H, 10, 10Ј),
7.7 (t, 2 H, 9, 9Ј), 7.48 (t, J = 8.1 Hz, 2 H, 4, 4Ј), 7.29 (t, J =
6.8 Hz, 2 H, 5, 5Ј), 7.25 (t, 2 H, 8, 8Ј), 7.2 (d, 2 H, 6, 6Ј), 2.98 (s,
6 H, 11Ј, 11) ppm. 13C NMR (125 MHz, CDCl3): δ = 169 (2 C),
155.2 (2 C), 148.2 (2 C), 141.2 (2 C), 137.2 (2 C), 133.8 (2 C), 132.4
(2 C), 130.1 (2 C), 128.4 (2 C), 127.9 (2 C), 126.7 (2 C), 126.4 (2
C), 125.7 (2 C), 124.2 (2 C), 124 (2 C), 123.9 (2 C), 39.1 (2 C) ppm.
N-{1-[4-(Methoxy)phenyl]ethyl}prop-2-en-1-amine (29): The prod-
uct was purified with a hexane/ethyl acetate mixture (9:1) as eluent.
1H NMR (300 MHz, CDCl3): δ = 7.2 (d, J = 14.0 Hz, 2 H, H meta
to OMe), 6.8 (d, J = 14.0 Hz, 2 H, H ortho to OMe), 5.9 (m, 1 H,
CHCH2), 5.1 (m, CHCH2), 3.9 (m, 4 H, OMe and CHN), 3.1 (m,
2 H, NCH2), 1.4 (d, J = 11.0 Hz, 3 H) ppm. The enantiomers of
N–CF3CO-29 were analyzed by HPLC by using a chiral OD-H
column (99:1 hexane/2-propanol; flow rate: 0.8 mL/min; λ =
254 nm); tR = 10.6 min, tS = 11.1 min.
Rotamer 2:1H NMR (300 MHz, CDCl3): δ = 8.28 (d, J = 4.4 Hz,
2 H, 7, 7Ј), 7.83 (d, J = 8.8 Hz, 2 H, 3, 3Ј), 7.72 (d, J = 7.8 Hz, 2
H, 10, 10Ј), 7.60 (d, J = 8.7 Hz, 2 H, 2, 2Ј), 7.59 (t, 2 H, 9, 9Ј),
7.45 (t, J = 7.5 Hz, 2 H, 4, 4Ј), 7.29 (t, J = 6.8 Hz, 2 H, 5, 5Ј), 7.1
(t, 4 H, 8, 8Ј, 6, 6Ј), 6.93 (d, J = 8.8 Hz, 2 H, 1, 1Ј), 2.64 (s, 6 H,
11, 11Ј) ppm. 13C NMR (125 MHz, CDCl3): δ = 171 (2 C), 153.4
(2 C), 148.2 (2 C), 143.4 (2 C), 136 (2 C), 134.6 (2 C), 131.4 (2 C), Supporting Information (see footnote on the first page of this arti-
129.6 (2 C), 128.6 (2 C), 128.2 (2 C), 126.9 (2 C), 126.7 (2 C), 126.1 cle): Synthesis and characterization of catalysts 2–5, characteriza-
1
(2 C), 124.4 (2 C), 124 (2 C), 123.9 (2 C), 37.3 (2 C) ppm. IR
tion of all the amines obtained by ketimine reduction, selected H
NMR and HPLC chromatograms of the chiral amines are pre-
(DCM): νC=O = 1650, 1458, 1380 cm–1. [α]2D5 = +353.6 (solvent:
DCM; c = 0.1 g/100 mL; λ = 589 nm). MS (ESI+): m/z = 523.6. sented.
3686
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3683–3687

Organocatalysts for the Reduction of Ketimines
Wei, P. Wu, A. Zhang, J. Sun, Org. Lett. 2006, 8, 999; f) D. Pei,
Z. Wang, S. Wei, Y. Zhang, J. Sun, Org. Lett. 2006, 8, 5913; g)
D. Pei, Y. Zhang, S. Wei, M. Wang, J. Sun, Adv. Synth. Catal.
2008, 350, 619; h) P. Wu, Z. Wang, M. Cheng, L. Zhou, J. Sun,
Tetrahedron 2008, 64, 11304; i) H. Zheng, J. Deng, W. Lin, X.
Zhang, Tetrahedron Lett. 2007, 48, 7934; j) F.-M. Gautier, S.
Jones, S. J. Martin, Org. Biomol. Chem. 2009, 7, 229; k) A. V.
Malkov, M. Figlus, S. Stoncius, P. Kocovský, J. Org. Chem.
2007, 72, 1315–1325; l) C. Baudequin, D. Chaturvedi, S. B.
Tsogoeva, Eur. J. Org. Chem. 2007, 2623–2629; m) L. Zhou, Z.
Wang, S. Wei, J. Sun, Chem. Commun. 2007, 2977–2979. For
the first report where picolinamides were used as catalysts see:
n) F. Iwasaki, O. Onomura, K. Mishima, T. Kanematsu, T.
Maki, Y. Matsumura, Tetrahedron Lett. 2001, 42, 2525.
[9] C. Wang, X. Wu, L. Zhou, J. Sun, Chem. Eur. J. 2008, 14, 8789.
[10] For a preliminary report on chiral diamine-derived Lewis bases
in ketimine reductions see: S. Guizzetti, M. Benaglia, F. Cozzi,
S. Rossi, G. Celentano, Chirality 2009, 21, 233.
Acknowledgments
Financial support by the Ministero dell’ Istruzione, Università e
ricerca (MIUR) – (Nuovi metodi catalitici stereoselettivi e sintesi
stereoselettiva di molecole funzionali) is gratefully acknowledged.
[1] T. Okhuma, R. Noyori in Comprehensive Asymmetric Catalysis,
Suppl. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, New York, 2004.
[2] X. Verdaguer, U. E. W. Lange, S. L. Buchwald, Angew. Chem.
Int. Ed. 1998, 37, 1103.
[3] For a special issue on hydrogenation and transfer hydrogena-
tion see: M. J. Krische, Y. Sun (Editors), Acc. Chem. Res. 2007,
40, Issue 12.
[4] H.-U. Blaser, B. Pugin, F. Spindler, M. Thommen, Acc. Chem.
Res. 2007, 40, 1240 and references cited therein. See also R.
Kadyrov, T. H. Riermeier, Angew. Chem. Int. Ed. 2003, 42,
5472.
[11] The compound was easily prepared in a two steps, one purifica-
tion only procedure in 90% yield, see: M. C. Mimmi, M. Gul-
lotti, L. Santagostini, R. Pagliarin, L. De Gioia, E. Monzani,
L. Casella, Eur. J. Inorg. Chem. 2003, 3934.
[12] S.Guizzetti, M. Benaglia, European Patent Application No.
EP07023240.0, September 22, 2008.
[5] Reviews: a) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed.
2004, 43, 5138; b) A. Dondoni, A. Massi, Angew. Chem. Int.
Ed. 2008, 47, 4638. For reviews on supported organic catalysts
see: c) A. Puglisi, F. Cozzi, M. Benaglia, Chem. Rev. 2003, 103,
3401–3430; d) F. Cozzi, Adv. Synth. Catal. 2006, 348, 1367– [13] The use of the bisbenzamide of the 1,1Ј-binaphthyl diamine as
1390; e) M. Benaglia, New J. Chem. 2006, 30, 1525–1533.
[6] Reviews: a) S. J. Connon, Org. Biomol. Chem. 2007, 5, 3407; b)
T. Akiyama, Chem. Rev. 2007, 107, 5744; c) M. Terada, Chem.
Commun. 2008, 4098.
organocatalyst led to the formation of the chiral amine in only
20% yield and with no stereoselectivity, as clear demonstration
of the fundamental role of the picolinamide moiety to guaran-
tee high chemical and stereochemical efficiency of the catalyst.
[14] The introduction of a substituent in the 3 or 6 position of the
pyridine ring decreased the stereochemical efficiency of the cat-
alyst, while substitution in the 4 position seems not to have any
remarkable effect.
[7] Reviews: a) M. Benaglia, S. Guizzetti, L. Pignataro, Coord.
Chem. Rev. 2008, 252, 492; b) S. E. Denmark, G. L. Beutner,
Angew. Chem. Int. Ed. 2008, 47, 1560.
[8] Selected references: a) A. V. Malkov, A. Mariani, K. N. Mac-
Dougal, P. Kocˇovský, Org. Lett. 2004, 6, 2253; b) A. V. Malkov, [15] For selective debenzylation reactions see: M. Kanai, M. Yasu-
S. Stoncˇius, P. Kocˇovský, Angew. Chem. Int. Ed. 2007, 46, 3722;
c) A. V. Malkov, M. Figlus, P. Kocˇovský, J. Org. Chem. 2008,
73, 3985; d) Y. Matsumura, K. Ogura, Y. Kouchi, F. Iwasaki,
O. Onomura, Org. Lett. 2006, 8, 3789; e) Z. Wang, X. Ye, S.
moto, Y. Kuriyama, K. Inomiya, Y. Katsuhara, K. Higashi-
yama, A. Ishii, Org. Lett. 2003, 5, 1007.
Received: May 11, 2009
Published Online: June 24, 2009
Eur. J. Org. Chem. 2009, 3683–3687
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3687