Cinchona-Derived Picolinamides: Effective Organocatalysts for Stereoselective Imine Hydrosilylation

Article abstract of DOI:10.1002/ejoc.201403180

Picolinamide-cinchona organocatalysts for the successful enantioselective reduction of ketomines were developed. For the first time, a new type of chiral Lewis base, a cationic species, is reported to efficiently organocatalyze the addition of trichlorosi

Full text of DOI:10.1002/ejoc.201403180

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403180
Cinchona-Derived Picolinamides: Effective Organocatalysts for Stereoselective
Imine Hydrosilylation
Pedro C. Barrulas,[a] Andrea Genoni,[b] Maurizio Benaglia,*[b,c] and Anthony J. Burke*[a]
Keywords: Alkaloids / Imines / Reduction / Organocatalysis / Lewis bases
Picolinamide–cinchona organocatalysts for the successful
enantioselective reduction of ketomines were developed. For
the first time, a new type of chiral Lewis base, a cationic
species, is reported to efficiently organocatalyze the addition
of trichlorosilane to imines. Excellent yields with good to
high enantioselectivities (up to 91%) were obtained in the
reduction of differently substituted substrates. Noteworthy,
remarkably high turnover frequencies for the hydrosilylation
of imines were observed; the catalyst of choice proved to be
active even at a loading of only 1 mol-%. The loading was
further reduced to 0.5 mol-%, and for very short reaction
times (15 min) very impressive asymmetric catalyst efficiency
speed values were reached.
over, as far as we are aware, we have achieved the highest
turnover frequency for the hydrosilylation of imines to
date.[10]
Introduction
Organocatalysis[1] has already made significant contri-
butions to the production and discovery of new pharmaceu-
ticals, agrochemicals, and other high added-value com-
pounds.[2] Metal-free catalysts based on the cinchona skel-
eton are well known and have been employed for a diversity
of reactions.[3] On the other hand, Lewis base based
organocatalysts have been exploited with success in the
stereoselective trichlorosilane-mediated reduction of N-sub-
stituted ketoimines[4] and in the asymmetric Biginelli reac-
tion.[5] The hydrosilylation reaction is a widely employed
method for accessing enantiomerically enriched amines,[6]
and it is extremely useful from an industrial perspective,
as it affords chiral products by using typically very cheap
reducing agents.[7] Several groups have used the organocata-
lytic strategy for the hydrosilylation of ketoimines.[8] Among
the most successful Lewis bases used to activate HSiCl3 are
the picolinamides, simply synthesized by connecting
picolinic acid to a chiral carbon skeleton.[9]
Results and Discussion
Two types of picolinamide–cinchona catalysts were
studied: neutral derivatives and pyridine-N-methylated
compounds (methylated pyridinium salts 4 and 5, Figure 1).
Our rationale was that in the former case the picolinamide
unit would coordinate to the silicon atom with the
carboxyamide group and the pyridine nitrogen atom in an
octahedral hexacoordinate complex, as usual for this class
of catalysts; in the latter case, different HSiCl3 activation
modes may be envisaged: hexacoordination of the Si atom
with the CO amide group and the quinuclidine N atom or
complexation of trichlorosilane with the only amide oxygen
atom to generate a pentacoordinate silane are both possible.
Organocatalysts 1–7 were prepared by using amide cou-
pling and methylation (in the case of 4 and 5) procedures
(Figure 1, for further details see the Supporting Infor-
mation).[10] All the catalysts were screened in a preliminarily
test reaction: the hydrosilylation of the N-phenyl imine of
acetophenone by using trichlorosilane (3 equiv.) and the
catalyst (10 mol-%) in dry CH2Cl2 (Scheme 1; R1 = H, R2
= Ph, R3 = Me).[11]
We now wish to report our preliminary results on the
application of novel picolinamide–cinchona organocatalysts
for the successful highly enantioselective trichlorosilane-
mediated reduction of ketomines to chiral amines; more-
[a] Department of Chemistry and Chemistry Center of Évora,
University of Évora,
Rua Romão Ramalho 59, 7000 Évora, Portugal
E-mail: ajb@dquim.uevora.pt
In all cases, excellent yields and high enantioselectivities
ranging from 77 to 90% ee were obtained (Table 1).
Whereas epi-quinine derivatives 2 and 3 catalyzed the reac-
tion generally with 80% ee, epi-quinidine derivatives 6 and
7 were more efficient in terms of both chemical and stereo-
chemical efficiency; they afforded the chiral amine (with the
opposite absolute configuration) in up to 90% ee. Lowering
the reaction temperature resulted in only a marginal
[b] Dipartimento di Chimica, Università degli Studi di Milano,
Via Golgi 19, 20133 Milano, Italy
E-mail: maurizio.benaglia@unimi.it
http://www.dipchi.unimi.it
http://www.unimi.it
[c] Istituto di Scienze e Tecnologie Molecolari, ISTM-CNR,
Via Golgi 19, 20133 Milano, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403180.
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P. C. Barrulas, A. Genoni, M. Benaglia, A. J. Burke
SHORT COMMUNICATION
Table 2. Reduction of ketoimines promoted by neutral chiral
picolinamides.
Entry
R1/R2/R3[a]
Catalyst
T
[°C]
Yield
[%]
ee
[%]
1
2
3
4
5
6
7
8
9
H/Ph/Et
H/Ph/Me
H/Ph/Me
H/Ph/Me
H/PMP/Me
1
1
6
7
7
7
7
7
7
6
7
25
0
0
0
0
0
0
0
0
0
0
77
97
93
99
97
99
98
77
93
87
99
81 (S)
80 (S)
81 (R)
90 (R)
90 (R)
91 (R)
88 (R)
89 (R)
80 (S)
83 (R)
90 (R)
4-Cl/PMP/Me
4-Br/PMP/Me
3-Br/PMP/Me
H/PMP/CO2Me
H/PMP/CH2CO2Me
H/PMP/CH2CO2Me
10
11
[a] PMP = p-methoxyphenyl.
We also looked at imino esters: whereas α-imino deriva-
tives were reduced with decent enantioselectivity (Table 2,
Entry 9; 93% yield with 80% ee), β-imino esters were con-
verted into β-amino esters in up to 99% yield with 90% ee
(Table 2, Entries 10 and 11).
Figure 1. Cinchona–pyridinecarboxyamide catalysts studied in this
work.
The activity of methylated, cationic catalysts was also
investigated (Table 3). By using cationic species 4 and 5,
derived from epi-cinchonidine, in the reduction of the N-
phenyl imine of propiophenone, the corresponding (S)
chiral amine was obtained as the major enantiomer; this
indicated that the mechanism for the hydrosilylation of
imines was equivalent to that operating with neutral
picolinamides 1–3. The product was isolated in up to 84%
ee at room temperature (Table 3, Entry 3).
Scheme 1. Enantioselective organocatalytic reduction of keto-
imines.
increase in the enantioselectivity. Noteworthy, epi-quinine-
derived methylated pyridinium salts 4 and 5 promoted the
formation of the (S) enantiomer, as did corresponding neu-
tral compound 1, with higher enantioselectivity, up to 90%
ee in the case of tetrafluoroborate salt 5 (Table 1, Entry 5).
Table 3. Hydrosilylation of ketoimines promoted by cationic
picolinamide 5.
Entry
R1/R2/R3[a]
T
[°C]
Yield
[%]
ee
[%]
1
2
H/Ph/Et
H/Ph/Et
H/Ph/Et
0
–20
25
25
25
25
25
25
25
25
0
80
79
86
47
68
58
10
75
20
73
71
85
93
72
Ͼ99
80 (S)
80 (S)
84 (S)
65(S)
83 (S)
84 (S)
69 (S)
76[c]
Table 1. Screening results with catalysts 1–7 in the hydrosilylation
of the N-phenyl imine of acetophenone.
3
4[b]
5
H/Ph/Et
Yield[a] [%]
ee[b] [%]
4-NO2/Ph/Me
4-MeO/Ph/Me
4-MeO/4-BrC6H4/Me
4-NO2/3-BrC6H4/Me
4-MeO/3-BrC6H4/Me
H/Ts/Et
H/PMP/Me
Cl/PMP/Me
H/PMP/CO2Me
H/Ph/CH2CO2Et
Br/PMP/CH2CO2Me
Entry
Catalyst
T [°C]
6
7
8
9
10
11
12
13
14
15
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
6
6
0
0
0
0
0
0
0
–20
–40
97
91
83
77
75
98
99
51
23
80 (S)
77 (S)
81 (S)
79 (S)
90 (S)
81 (R)
90 (R)
83 (R)
84 (R)
69[c]
73(S)
89(S)
83(S)
81 (R)
70[c]
0
0
25
0
85 (S)
[a] Yield of isolated product. [b] Determined by HPLC on a chiral
stationary phase.
[a] Ts = p-tolylsulfonyl. [b] Reaction was run in chloroform.
[c] Major enantiomer configuration unknown.
The catalytic behavior of neutral picolinamides 1, 6, and
The catalyst promoted the reaction with good chemical
7 in the reduction of different substrates was then briefly and stereochemical efficiency for a wide range of aryl keto-
investigated (Scheme 1, Table 2). epi-Quinidine-based cata- imines. Interestingly, a good level of enantioselectivity was
lyst 7 featuring a hydroxy group on the quinoline ring maintained in the reduction of N-tosyl imines (Table 3, En-
proved to be constantly the best performer; it often afforded try 10), whereas higher ee values were obtained with N-p-
the corresponding chiral amines in quantitative yields with methoxyphenyl-substituted ketoimines (Table 3, Entries 11–
90% ee.
13 and 15).
2
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Effective Organocatalysts for Stereoselective Imine Hydrosilylation
Having thus determined the scope of catalyst 5 in the newly developed multifunctional chiral Lewis bases repre-
hydrosilylation reaction, we studied various loadings of this sent an easy entry in an unexplored class of catalysts for
novel organocatalyst and looked at the turnover frequency stereoselective reductions that are characterized by multiple
(TOF), with a view to its industrial application. The results possible modes of action. We are currently investigating the
were very encouraging (Table 4): the loading of the catalyst mechanism of these catalysts, looking at their application
was reduced to 1 mol-%, but the product was still obtained in the synthesis of biologically active targets, and optimiz-
in 86% yield with 80% ee after a reaction time of 18 h ing their immobilization to solid supports.
(Table 4, Entry 4). Upon reducing the quantity of tri-
chlorosilane to 1.5 equiv., the highest TOF of 31.0 h–1 (at a
loading of 10 mol-% catalyst) was reached with a remark-
able 87% ee. Noteworthy, these results favorably compare
Experimental Section
General Remarks: Cinchonidine and all other reagents and solvents
used in this work were purchased from Sigma–Aldrich, Fluka, or
Acros Organics and were used as received. The imine substrates
were prepared by using known methods.[14,15] All details on the
synthesis of the catalysts, analyses of the products, and characteri-
zation data are reported in the Supporting Information.
with the best results so far obtained with organocatalysts.
Table 4. Catalyst loading optimization studies of 5 in the hydro-
silylation of the N-phenyl imine of propiophenone.
Entry
5
Yield[a]
[%]
ee[b]
[%]
TOF
[h–1]
ACES[12]
[h–1]
[mol-%]
1[c]
2[c]
3[c]
4[c]
5[c]
6[d]
7[d]
8[d]
9[d]
20
10
5
85
86
88
86
80
85
84
82
80
72
90
88
88
87
0.24
0.48
0.98
4.78
8.67
8.1
13.4
15.4
31.0
0.08
0.17
0.34
1.61
2.64
3.08
4.98
5.72
8.03
General Procedure for the Catalytic Asymmetric Hydrosilylation
with Catalysts 1–7: The ketoimine (0.33 mmol) and the organocata-
lyst (0.1–20 mol-%) were dissolved in dry CH2Cl2 (1 mL). The mix-
ture was then cooled in an ice bath; after 15 min, HSiCl3 (1.5–
3 equiv.) was added dropwise. Once the addition was complete, the
mixture was stirred at room temperature for 15 min to 18 h. The
reaction was quenched by the addition of a saturated solution of
NaHCO3 (2 mL). The organic phase was extracted with CH2Cl2
(3ϫ 10 mL), dried with anhydrous MgSO4, filtered, and concen-
trated in vacuo. The resulting residue was purified by column
chromatography with silica gel by using literature conditions. The
enantiomeric excess was determined by using HPLC with chiral
columns (for further details see the Supporting Information).
1
0.5
10
5
10
10
81[e]
67[e]
77[f]
55[g]
[a] Yield of isolated product. [b] Determined by HPLC on a chiral
stationary phase. [c] Reaction time: 18 h. [d] HSiCl3 (1.5 equiv.) was
added. [e] Reaction time: 1 h. [f] Reaction time: 30 min. [g] Reac-
tion time: 15 min.
We also evaluated the asymmetric catalyst efficiency
speed (ACES) on the basis of the asymmetric catalyst effi-
ciency equation that was originally developed by El-
Fayyoumy et al. in 2009.[12] This formula allows one to un-
ambiguously compare the overall efficiency and briskness
of any asymmetric catalytic process; the central dogma is
that an asymmetric catalyst may be considered more
efficient if fewer atoms are utilized to give a product with a
specific ee value. The best result was obtained at a catalyst
loading of 10 mol-% with 1.5 equiv. of silane over 15 min
(8.03 h–1; Table 4, Entry 9).
Overall, by using the ACES formula, this represents an
excellent performance in terms of catalytic efficiency for the
imine hydrosilylation reaction. For instance, in the case of
this reaction the best ACES values were between 0.1 and
0.3 h–1. To date, only the imidazole-based catalyst reported
by Jones’s group in 2009 favorably compares with catalyst
5.[4b,13] For the sake of comparison, in the case of the pion-
eering Hajos–Parrish–Eder–Sauer–Wiechert reaction[1] with
l-proline, the best ACES of 2.31 h–1 was obtained.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and characterization of the catalysts, synthesis of
the imine, enantioselective reduction procedures, NMR and mass
spectra, and HPLC traces of the organocatalytic reductions.
Acknowledgments
P. C. B. is grateful to the Fundação para a Ciência e a Tecnologia
(FCT)for the award of a Ph.D. grant (SFRH/BD/61913/2009). This
work was conducted by using finances from the FCT through
strategic project PEst-OE/QUI/UI0619/2011. We acknowledge
LabRMN at FCT-UNL for the acquisition of the NMR spectra;
the NMR spectrometers are part of the National NMR Facility
supported by the Fundação para a Ciência e a Tecnologia (RECI/
BBB-BQB/0230/2012). The staff at the MS laboratory at CACTI,
University of Vigo, is acknowledged for the MS analyses. We thank
Dr. Olivia Furtado Burke, Laboratório Nacional de Energia e Geo-
logia (LNEG), Lisbon, for performing some of the optical rotation
measurements. Chiratecnics Lda (www.chiratecnecnics.com) is ac-
knowledged for its interest in this project and its valuable support.
M. B. thanks European Cooperation in Science and Technology
(COST) action CM9505 “ORCA” Organocatalysis. A. G. acknowl-
edges the Università degli Studi di Milano for a Ph.D. fellowship.
Conclusions
We reported a group of picolinamide–cinchona deriva-
tives, including for the first time a chiral cationic picolin-
amide, that give excellent results in the hydrosilylation of
ketoimines. Our studies revealed that we could reduce the
loading of the catalyst down to 0.5 mol-% and still obtain
satisfactory results and very impressive ACES values. The
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P. C. Barrulas, A. Genoni, M. Benaglia, A. J. Burke
SHORT COMMUNICATION
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Received: September 8, 2014
Published Online: ᭿
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Effective Organocatalysts for Stereoselective Imine Hydrosilylation
Organocatalysis
Cinchona derivatives for the successful en-
antioselective addition of trichlorosilane to
ketimines are developed. Excellent yields
with good to high enantioselectivities (up
to 91%) are obtained in the reduction of
differently substituted substrates. Remark-
ably high turnover frequencies for imine
hydrosilylation are observed at a catalyst
loading of only 1 mol-%.
P. C. Barrulas, A. Genoni, M. Benaglia,*
A. J. Burke* ...................................... 1–5
Cinchona-Derived Picolinamides: Effective
Organocatalysts for Stereoselective Imine
Hydrosilylation
Keywords: Alkaloids / Imines / Reduction /
Organocatalysis / Lewis bases
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