Self-supported chiral titanium cluster (SCTC) as a robust catalyst for the asymmetric cyanation of imines under batch and continuous flow at room temperature

Article abstract of DOI:10.1002/chem.201200528

A robust heterogeneous self-supported chiral titanium cluster (SCTC) catalyst and its application in the enantioselective imine-cyanation/Strecker reaction is described under batch and continuous processes. One of the major hurdles in the asymmetric Strecker reaction is the lack of availability of efficient and reusable heterogeneous catalysts that work at room temperature. We exploited the readily hydrolyzable nature of titanium alkoxide to synthesize a self-supported chiral titanium cluster (SCTC) catalyst by the controlled hydrolysis of a preformed chiral titanium-alkoxide complex. The isolated SCTC catalysts were remarkably stable and showed up to 98% enantioselectivity (ee) with complete conversion of the imine within 2 h for a wide variety of imines at room temperature. The heterogeneous catalysts were recyclable more than 10 times without any loss in activity or selectivity. The robustness, high performance, and recyclability of the catalyst enabled it to be used in a packed-bed reactor to carry out the cyanation under continuous flow. Up to 97% ee and quantitative conversion with a throughput of 45 mgh^-1 were achieved under optimized flow conditions at room temperature in the case of benzhydryl imine. Furthermore, a three-component Strecker reaction was performed under continuous flow by using the corresponding aldehydes and amines instead of the preformed imines. A good product distribution was obtained for the formation of amino nitriles with ee values of up to 98%. Synthetically useful ee values were also obtained for challenging α-branched aliphatic aldehyde by using the three-component continuous Strecker reaction.

Full text of DOI:10.1002/chem.201200528

FULL PAPER
DOI: 10.1002/chem.201200528
Self-Supported Chiral Titanium Cluster (SCTC) as a Robust Catalyst for the
Asymmetric Cyanation of Imines under Batch and Continuous Flow at Room
Temperature
Abdul M. Seayad,*[a] Balamurugan Ramalingam,*[a] Christina L. L. Chai,[a, b]
Chuanzhao Li,[c] Marc V. Garland,[c] and Kazuhiko Yoshinaga[d]
Abstract: A robust heterogeneous self-
supported chiral titanium cluster
(SCTC) catalyst and its application in
the enantioselective imine-cyanation/
Strecker reaction is described under
batch and continuous processes. One of
the major hurdles in the asymmetric
Strecker reaction is the lack of availa-
bility of efficient and reusable hetero-
geneous catalysts that work at room
temperature. We exploited the readily
hydrolyzable nature of titanium alkox-
ide to synthesize a self-supported chiral
titanium cluster (SCTC) catalyst by the
controlled hydrolysis of a preformed
chiral titanium-alkoxide complex. The
isolated SCTC catalysts were remarka-
bly stable and showed up to 98% enan-
tioselectivity (ee) with complete con-
version of the imine within 2 h for
a wide variety of imines at room tem-
perature. The heterogeneous catalysts
were recyclable more than 10 times
without any loss in activity or selectivi-
ty. The robustness, high performance,
and recyclability of the catalyst enabled
it to be used in a packed-bed reactor to
carry out the cyanation under continu-
ous flow. Up to 97% ee and quantita-
tive conversion with a throughput of
45 mghÀ1 were achieved under opti-
mized flow conditions at room temper-
ature in the case of benzhydryl imine.
Furthermore,
a
three-component
Strecker reaction was performed under
continuous flow by using the corre-
sponding aldehydes and amines instead
of the preformed imines. A good prod-
uct distribution was obtained for the
formation of amino nitriles with ee
values of up to 98%. Synthetically
useful ee values were also obtained for
challenging a-branched aliphatic alde-
hyde by using the three-component
continuous Strecker reaction.
Keywords: amino alcohols · asym-
metric synthesis
· cluster com-
pounds · continuous-flow reactions ·
Strecker reaction
Introduction
The synthesis of amino acids has traditionally been dominat-
ed by biocatalytic or enzymatic methods.[5] Although the
chemical synthesis of chiral a-amino acids from the asym-
metric cyanation of imines (modified Strecker reaction) has
been known since 1996 on a laboratory scale,[6] the technolo-
gy has not been scaled-up for large-scale preparations. Re-
cently, Jacobsen and co-workers[7] reported the synthesis of
N-Boc-protected unnatural a-amino acids on a 3–14 g scale
by using the cyanation of preformed imines with thiourea-
based catalysts at low temperatures (À30 to 08C). The
major hurdles that still need to be overcome in the enantio-
selective three-component Strecker reaction or the cyana-
tion of imines[8,9] are the requirement of low temperature to
achieve high enantioselectivity (ee) and the lack of availabil-
ity of simple, inexpensive, and readily available chiral cata-
lysts.
Natural and unnatural a-amino acids[1] are essential for life
and are frequently used as food additives and as chiral auxil-
iaries for the synthesis of drugs,[2] catalysts,[3] and polymers.[4]
[a] Dr. A. M. Seayad, Dr. B. Ramalingam, Dr. C. L. L. Chai
Organic Chemistry
Institute of Chemical and Engineering Sciences
8, Biomedical Grove, Neuros, 07-01, 138665 (Singapore)
Fax : (+65)6464-2102
E-mail: abdul_seayad@ices.a-star.edu.sg
balamurugan_ramalingam@ices.a-star.edu.sg
[b] Dr. C. L. L. Chai
Department of Pharmacy
National University of Singapore
18 Science Drive 4, 117543 (Singapore)
In an effort to address these issues, we recently report-
ed[10] a simple catalyst system that was derived from partially
hydrolyzed titanium alkoxide (PHTA) and chiral N-salicyl-
b-amino-alcohol ligands as a highly enantioselective catalyst
for the cyanation of imines by using TMSCN or HCN under
homogeneous reaction conditions at room temperature. We
rationalized that the development of heterogeneous chiral
catalysts[11] for the Strecker reaction would be highly desira-
ble for industrial applications in view of the ease of separa-
[c] Dr. C. Li, Dr. M. V. Garland
Process Science and Modelling
Institute of Chemical and Engineering Sciences
1, Pesek Road, Jurong Island, 627833 (Singapore)
[d] Dr. K. Yoshinaga
Mitsui Chemicals Inc.
580-32, Nagauram, Sodegaura-City
Chiba 299-0265 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200528.
Chem. Eur. J. 2012, 18, 5693 – 5700
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5693

tion of the product and the reusability of the catalyst. For
this purpose, we took advantage of the readily hydrolyzable
nature of titanium alkoxides and their tendency to form
supramolecular assemblies.[12] Herein, we report a class of
robust chiral heterogeneous self-supported catalysts[13] for
the asymmetric cyanation of imines that gave high enantio-
selectivities at room temperature. The catalyst was easy to
separate and was recycled efficiently. This system was also
placed in a packed-bed reactor to demonstrate the asymmet-
ric Strecker reaction under continuous flow, which has not
yet been reported.
Scheme 1. Preparation of self-supported chiral titanium cluster (SCTC)
catalysts.
Results and Discussion
Catalyst synthesis: The formation of a m3-oxo-bridged tetra-
nuclear titanium cluster by the partial hydrolysis of mono-
complex [Ti
(binolato)
E
larger microsized particles. Regular microsized particles of
3–5 mm were formed when R1 =3-Me-indyl (SCTC 7). TGA
analysis showed that the SCTC compounds were robust and
the weight loss was not significant until 3008C (see the Sup-
porting Information).
nium alkoxide and chiral binol as a bidentate ligand, has
been reported previously.[14] This soluble complex was re-
ported to catalyze the enantioselective aldol and carbonyl-
ene reactions. By adopting a similar procedure to that of
Mikami et al.,[14] we attempted the synthesis of a self-sup-
ported chiral titanium cluster (SCTC) by using the triden-
tate amino-alcohol ligand, H2L. Various chiral catalysts
(SCTC 1–7) were synthesized from 1:1 complexes of titani-
Cyanation of imines: SCTC materials 1–7 were evaluated
for the asymmetric cyanation of benzhydryl- (9a) and
benzyl imines (9b) under the optimized conditions reported
previously by ourselves for titanium-based homogeneous
catalysts.[10] Very high enantioselectivities (up to 99%) and
quantitative yields were observed for the cyanation of com-
pound 9a in 1 h with 1.5 equivalents of TMSCN and 10 mg
of the SCTC catalyst in the presence of n-butanol as
a proton source in toluene at room temperature (Table 1).
Interestingly, the catalyst loading could be lowered to 1 mg
without a significant loss in the conversion and ee value
(Table 1, entry 3). With benzhydryl imine (9a) as the sub-
strate, no significant difference in the catalytic performance
um alkoxide (TiACHTUNGTRENNUNG(OnBu)4/TiHCATUNGTERN(NUGN OiPr)4) and chiral N-salicyl-b-
amino alcohol ligands (H2L) by hydrolysis using 0.5–
1.0 equivalent of water at 908C for 2 h (Scheme 1).[15] Inter-
estingly, the solubility of the SCTC compounds in common
organic solvents mainly depended on the R1 substituent at
the stereogenic center of the chiral ligand. For example, the
obtained SCTC compound was completely soluble in tolu-
ene when R1 =iPr (2) and partially soluble when R1 =tBu
(3, 4). Completely insoluble materials were obtained when
R1 =Bn (5, 6) and 3-Me-indyl (7). All of these isolated
SCTC compounds were air- and moisture stable
and had long shelf-lives.
The soluble and partially soluble clusters (1–4)
showed broad 1H NMR signals that corresponded
to oligomeric cluster-type structures. IR absorptions
in the region 400–650 cmÀ1 suggested the presence
À À
of Ti O Ti structural units.
TOF MS showed complex patterns for soluble clus-
ters 1–4 (see the Supporting Information), with m/z
values of up to 1500, which suggested that the clus-
ters may have consisted of more than one titanium
atom with repeated OTi(L) basic units (Scheme 1).
SEM surface-characterization (Figure 1) showed
distinct morphologies for the SCTC compounds
with different R1 groups at the stereogenic center:
Soluble SCTC material 2 (R1 =iPr) had a sheet-like
morphology, which was formed by the aggregation
of nanosized particles. Partially soluble SCTC 4
(R1 =tBu) aggregated as irregular microsized units
of various shapes. In the case of insoluble SCTC 6
Entry
Catalyst
[mg][a]
PG
t
Conv.
[%][b]
ee
[h]
[%][c]
1
2
3
4
5
6
7
8
SCTC 1 (10)
SCTC 1 (5)
SCTC 1 (1)
SCTC 2 (1)
SCTC 4 (1)
SCTC 6 (1)
SCTC 7 (1)
SCTC 1 (1)
SCTC 4 (1)
SCTC 6 (1)
CHPh2 (9a)
CHPh2 (9a)
CHPh2 (9a)
CHPh2 (9a)
CHPh2 (9a)
CHPh2 (9a)
CHPh2 (9a)
CH2Ph (9b)
CH2Ph (9b)
CH2Ph (9b)
1
2
2
2
2
2
2
1
1
1
98
99
99
99
99
99
98
99
99
99
99
98
97
96
96[d]
97[d]
94
72
86
64
9
10
[a] The catalysts were prepared as described in Scheme 1. [b] Determined by
1H NMR spectroscopy. [c] Determined by HPLC. [d] Similar results were obtained
(R1 =Bn), the nanoparticles aggregated to form with SCTC 3 and SCTC 5.
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Self-supported Chiral Titanium Clusters
FULL PAPER
Figure 1. SEM images of the SCTC catalysts.
was observed between the SCTC catalysts, whereas SCTC 4
was the best catalyst for benzyl-protected imine 9b (Table 1,
entry 9). A number of solvents were tested as the reaction
medium with 1.0 mg catalyst loading. Conversions and ee
values for the cyanation of compound 9a in Et2O (99%,
88% ee), methyl tert-butyl ether (98%, 86% ee), THF
(80%, 60% ee), and 1,4-dioxane (79%, 66% ee) were all in-
ferior to those in toluene.
The substrate scope for the imine in the cyanation reac-
tion was examined with SCTC 4 as the representative cata-
lyst (Scheme 2). Benzhydryl-protected imines 9c–9 f gave
very high ee values (94–98%) of the corresponding amino
nitriles 10c–10 f. Moderate ee values (86–89%) were ach-
ieved in the case of benzyl-protected amino nitriles 10g–10i.
The stereochemistry of the amino nitriles were assigned in
comparison with the reported optical rotation values.[7,8] The
amino nitriles were readily converted into their correspond-
ing a-amino acids by hydrolysis, as reported previously.[9]
Scheme 2. Substrate scope for the cyanation of imines.
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A. M. Seayad, B. Ramalingam et al.
The interest in developing technologies for organic reactions
under continuous flow[18] has increased in recent years
owing to its many advantages, such as low mass-transfer lim-
itations, the safe and easy handling of large amounts of haz-
ardous reagents, uniform reaction conditions throughout the
reaction, easy scale-up, etc. We expected that packing the
catalyst together with some inert materials would be more
practical than packing the catalyst alone in a column reac-
tor. To select a suitable inert material, 5.0 mg of SCTC 6
was independently mixed with equal amounts (by weight) of
silica gel, alumina, powdered molecular sieves, and celite,
and the catalytic performance was evaluated for the cyana-
tion of imine 9b under the batch conditions described in
Scheme 2 (see the Supporting Information).
When the catalyst was mixed with silica and alumina,
complete conversion into compound 10b was obtained with
only 10% ee. On the other hand, mixing the catalyst with
either molecular sieves or celite did not affect the ee value,
whilst higher conversion was obtained with celite. Hence,
a mixture of SCTC 6 (250 mg) and celite (250 mg) was
packed into a fixed-bed tubular reactor (4 mmꢁ80 mm) and
used as a catalyst for the continuous-flow asymmetric cyana-
tion reaction. Toluene solutions of compound 9b (0.25m), n-
butanol (0.25m), and TMSCN (0.37m, 1.50 equiv)[19] were in-
fused through the catalyst cartridge at the flow of
10 mLminÀ1 of each reagent by using high-pressure syringe
pumps. However, only 81% conversion was obtained with
very a low ee value of 17% (Table 2, entries 1 and 2), which
may have been due to the formation of HCN during the hy-
drolysis of TMSCN in the presence of excess n-butanol.[20]
Scheme 3. A) Catalyst-recycling study and B) catalyst-leaching study.
Recycling and leaching studies: In contrast to SCTCs 1–4,
catalysts 5–7 were completely insoluble in the reaction
medium and could easily be recovered and recycled. The re-
cyclability of the catalysts was examined by using 5.0 mg of
SCTCs 5 and 6 in the cyanation of compound 9a under the
optimized conditions (Scheme 2). Interestingly, both cata-
lysts were efficiently recycled more than 10 times without
any significant loss in catalytic performance
(Scheme 3A). After each run, the reaction mixture
Table 2. Flow-rate optimization for the cyanation of imines.
was centrifuged to recover the catalyst, which was
washed with toluene before charging with a fresh
reaction mixture.
To understand the heterogeneous nature of the
SCTC catalysts, leaching experiments were per-
formed (Scheme 3B). SCTC 6 was stirred with
imine 9a and n-butanol in toluene for 2 h in the ab-
sence of TMSCN. The catalyst was separated by
centrifugation and TMSCN was added to the clear
solution and stirred for 2 h. Only 20% conversion
was observed, with the formation of racemic amino
nitrile. On the other hand, the recovered SCTC 6
catalyzed the cyanation of imine 9a with 99% con-
version and 96% ee when a fresh reaction mixture
(9a, TMSCN, and n-butanol) was added. These ob-
servations indicated that no appreciable amount of
chiral catalyst had leached into the solution and
that the enantioselectivity originated from the solid
catalyst.
Entry
PG
Flow rate [mLminÀ1
]
t
Conv.
[%][b]
ee
Imine
TMSCN
n-Butanol
[h][a]
[%][c]
1
2
3
4
5
6
7
8
CH2Ph (9b)
CH2Ph (9b)
CH2Ph (9b)
CH2Ph (9b)
CH2Ph (9b)
CH2Ph (9b)
CH2Ph (9b)
CH2Ph (9b)
CH2Ph (9b)
CHPh2 (9a)
CHPh2 (9a)
CHPh2 (9a)
CHPh2 (9a)
CHPh2 (9a)
CHPh2 (9a)
10
10
10
10
10
10
10
10
10
10
10
5
10
10
10
10
10
10
10
8
10
10
5
5
5
2.5
2.5
5
1
2
1
2
3
1
2
2
3
1
2
2
4
1
2
81
83
>99
>99
>99
86
17
16
54
63
65
37
40
63
64
98
97
97
97
97
97
91
>99
>99
92
92
80
91
99
99
9
8
5
10
11
12
13
14
15
8
5
8
5
4
4
10
10
2.5
2.5
5
Cyanation of imines under continuous flow: The ro-
bustness and efficient recyclability of the SCTC cat-
alyst encouraged us to use it as a solid-phase cata-
lyst for the continuous-flow asymmetric cyanation
5
10
10
5
[a] Time at which the sample was taken and analyzed. [b] Determined by 1H NMR
reaction, which has not been reported previously.[17] spectroscopy. [c] Determined by HPLC.
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Self-supported Chiral Titanium Clusters
FULL PAPER
We anticipated that this hydrolysis could be minimized by
reducing the amount of n-butanol. Interestingly, reducing
the flow rate of n-butanol to 5 mLminÀ1 (0.5 equiv with re-
spect to the imine) improved both the conversion (>99%)
and ee value (65%) (Table 2, entry 5) to values that were
comparable to those from the batch reaction (Table 1, entry
10). Further decrease in the flow rate of n-butanol had a neg-
ative effect on both the conversion and ee value (Table 2,
entries 6 and 7). It would also be desirable to reduce the
amount of excess TMSCN whilst maintaining the conversion
and ee value. Accordingly, the flow rate of TMSCN was re-
duced to 8 mLminÀ1 (1.2 equiv with respect to the imine)
without a significant change in the catalytic performance
(Table 2, entries 9 and 10).
Next, the cyanation of compound 9a, which was less-reac-
tive towards cyanide addition than compound 9b, was car-
ried out under the above-optimized flow rates. Lower con-
versions were obtained (Table 2, entries 10 and 11), although
the ee values were comparable to those in the batch reac-
tion. Increasing the flow rate of TMSCN to 10 mLminÀ1 was
necessary to drive the conversion to 99% (Table 2, en-
tries 14 and 15). Under the optimized conditions, the cyana-
tion of compound 9a was carried out for 85 h without a sig-
nificant loss in activity or enantioselectivity (Figure 2). This
asymmetric Strecker reaction was carried out by using the
corresponding aldehydes and amines instead of the pre-
formed imines. Quantitative imine formation is necessary to
carry out the three-component Strecker reaction under con-
tinuous flow. Often, this reaction leads to the formation of
a cyanohydrin side-product from the addition of cyanide to
the aldehyde. In principle, the imine can be obtained by in-
fusing the aldehyde and amine through a column that is
filled with any dehydrating agent or an acid catalyst. There-
fore, for our initial experiments, the column (4 mmꢁ50 mm)
was packed with MgSO4, and 0.5m solutions of benzalde-
hyde and benzhydryl amine in toluene were infused at
a flow rate of 5.0 mLminÀ1. Only 46% of the aldehyde was
converted into the corresponding imine. Similar results were
obtained when the column was packed with powdered mo-
lecular sieves and sulfamic acid. Interestingly, when TiO2
(MC 150) was added to the column as a catalyst, complete
conversion was obtained with a residence time of 25 min.
However, the imine began to precipitate inside the tube at
low flow rates.
To avoid this problem, we carried out the imine formation
at elevated temperature by using a stainless steel coil reac-
tor without any packing material (Figure 3). Imine forma-
tion was successfully achieved by passing 0.5m solutions of
the aldehydes and benzhydryl amine in toluene through
a stainless steel coil that was preheated to 708C (residence
time, 50 min). The in-situ-formed imine[21] and TMSCN[22]
were passed through a cartridge that was filled with catalyst
SCTC 6 and celite. No n-butanol was added because the
water that had formed during the imine formation was suffi-
cient to act as a proton donor.[23] A similar throughput
(45.0 mghÀ1) was achieved with the exclusive formation of
amino nitrile; no cyanohydrin side-product was observed. In
the three-component Strecker reaction, the flow of TMSCN
was optimized to 1.3 equivalents with respect to the imine
without compromising the yield. The three-component reac-
tion proceeded well with good product distribution for the
formation of amino nitriles from their corresponding alde-
hydes. Synthetically useful ee values were obtained (Table 3,
entries 3–8) when benzhydryl amine was used as the amine
partner. Interestingly, in the case of more-challenging a-
branched aldehydes, such as 3-phenylacetaldehyde, an im-
proved ee value of 87% was achieved for the formation of
compound 10o under the optimized flow conditions com-
pared to that of the batch reaction (70% ee). This method-
ology paves the way for the Strecker reactions of relatively
less stable imines.
Figure 2. Conversion and ee value for the continuous-flow cyanation of
compound 9a for 85 h.
system afforded a throughput of 45.0 mghÀ1 with a residence
time of 40 min. Excess cyanide was quenched by bubbling
through a saturated solution of FeACTHNUTRGNEUNG(SO4)2. The amino nitrile
product (10a) did not contain any cyanide impurities and no
significant leaching of the titanium catalyst was noticed. In
an independent experiment, the collected amino nitrile
(10a) was mixed with imine 9a and the ratio was deter-
mined to be 33:67 (9a/10a, 98% ee) by NMR spectroscopy.
TMSCN and n-butanol were added to the above mixture,
which was stirred for 12 h at room temperature and then an-
alyzed. The ratio only changed to 24:76 (9a/10a, 92% ee).
Thus, the lower ee value and increased amount of compound
10a suggested the presence of an uncatalyzed background
reaction.
Conclusion
A highly active and robust heterogeneous self-supported
chiral titanium cluster catalyst was developed for the enan-
tioselective Strecker reaction at room temperature. The cat-
alyst was successfully recycled more than 10 times without
any significant loss in the catalytic performance. The robust-
ness and ease of recovery of the heterogeneous catalyst
Three-component Strecker reaction under continuous flow:
To make this process more practical, a three-component
Chem. Eur. J. 2012, 18, 5693 – 5700
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5697

A. M. Seayad, B. Ramalingam et al.
Figure 3. Customized flow reactor for the three-component Strecker reaction.
hazardous cyanide reagents. To the best of our
knowledge, this is the first heterogeneous catalyst
that shows high activity and enantioselectivity at
room temperature for the cyanation of imines and
the three-component asymmetric Strecker reaction
under continuous flow.
Table 3. Continuous-flow three-component Strecker reaction using benzaldehyde and
benzhydryl amine.
Experimental Section
Entry
Aldehyde
Amine
Product distribution [%]
Aldehyde Imine Aminonitrile (ee)
General procedure for the synthesis of the SCTC catalyst: Ti-
ACHUTNRGEN(NUG OnBu)4 (0.68 g, 2.00 mmol) or TiACHTUNGTREN(NUNG OiPr)4 (0.59 g, 2.00 mmol)
1
2
3
PhCHO
PhCHO
PhCHO
benzyl amine[a]
PMP amine[a]
benzhydryl amine
<1
absent
<1
2
<2
1
>97 (61), 10b
>98 (47), 10j
>98 (97), 10a
was added to a flame-dried two-necked flask and dry toluene
(60 mL) was added. The ligand (2.00 mmol) was added in por-
tions under a flow of argon. After stirring the contents for 1 h
at room temperature, H2O (18.0 mL, 1.00 mmol in 1.00 mL
THF) was added dropwise using a syringe. The reaction mix-
ture was heated to 908C and stirred for 2 h. The volatile com-
pounds were removed by distillation to obtain the SCTC cata-
lyst. The catalyst was washed with cold toluene (2ꢁ10 mL),
dry n-hexane (2ꢁ10 mL), and the solid was dried under re-
duced pressure. SCTC catalysts 6 and 7 precipitated during the
heating at 908C and were filtered as solids from a hot toluene
solution.
4
5
6
7
benzhydryl amine
benzhydryl amine
<1
<1
<1
<1
3
>99 (93), 10k
>99 (97), 10d
96 (86), 10l
benzhydryl amine
benzhydryl amine
benzhydryl amine
1
<1
<1
1
>99 (98), 10m
8
9
9
1
>90 (97), 10n
General procedure for the cyanation of imines: To the SCTC
catalyst (1.0 mg), toluene (0.7 mL), imine (0.20 mmol), trime-
thylsilyl cyanide (TMSCN, 41 mL, 0.30 mmol),[23] and n-butanol
(18 mL, 0.20 mmol) were added sequentially and the mixture
was stirred at RT for 2 h. The reaction mixture was filtered
through a plug of celite/silica gel, washed with CH2Cl2, and the
volatile compounds were removed to obtain the amino nitriles.
For the recycling experiments, the SCTC catalyst was recov-
benzhydryl amine[a] absent
>99 (87),[b] 10o
[a] Temperature for imine formation was 608C. [b] 70% ee was obtained under batch
reaction conditions with SCTC 6.
from the reaction mixture is attractive for the large-scale
ered by centrifugation and added to a fresh reaction mixture.
synthesis of a-aryl and a-alkyl amino nitriles. The continu-
ous-flow asymmetric Strecker reaction reported herein
offers operational advantages over batch processes, such as
increased atom-efficiency and safer handling of toxic and
Cyanation of imines under continuous flow: A 0.25m solution of imine
9a (0.29 g in 6.0 mL) or 9b in toluene (0.41 g in 6.0 mL), n-butanol
(92 mL in 6.0 mL, 0.25m), and TMSCN (240 mL in 6.0 mL, 0.33m,
1.50 equiv) were taken-up in separate syringe pumps. The three reagents
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Self-supported Chiral Titanium Clusters
FULL PAPER
were infused through the catalyst cartridge at a specified flow rate. The
outlet was bubbled through saturated FeSO4 solution to quench the
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Acknowledgements
This work was supported by the Agency for Science, Technology, and Re-
search (A*STAR), Singapore, and Mitsui Chemicals Ltd., Japan.
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[19] The concentrations of the reagents and the flow rate were initially
chosen to mimic the batch conditions.
[20] When a 0.40m solution of HCN in toluene (flow rate: 10 mLminÀ1
)
was used as the cyanide source instead of TMSCN for the cyanation
of compound 9a, only 17% conversion was obtained and a racemic
amino nitrile product was obtained.
[21] The quantitative formation of the imine was confirmed by on-line
IR spectroscopy (see the Supporting Information).
[22] Under the reaction conditions, TMSCN could be hydrolyzed to
form extremely poisonous HCN gas. The reaction vial should be
Chem. Eur. J. 2012, 18, 5693 – 5700
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5699

A. M. Seayad, B. Ramalingam et al.
properly sealed. Proper safety precautions must be adhered to and
appropriate safety equipment must be used, such as a cyanide detec-
tor and personal protection equipment. The reactions must be car-
ried out in a well-ventilated fume-hood.
to obtain high ee values under batch conditions in the case of homo-
geneous titanium catalysts.
[23] We have previously observed that controlled quantities of water (up
to 0.5 equiv) is also effective as a proton source instead of alcohols
Received: February 17, 2012
Published online: March 21, 2012
5700
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5693 – 5700