Highly enantioselective titanium-catalyzed cyanation of imines at room temperature

Article abstract of DOI:10.1021/ol902540h

(Figure presented) A highly active and enantioselective titanium-catalyzed cyanatlon of imines at room temperature Is described. The catalyst used Is a partially hydrolyzed titanium alkoxide (PHTA) precatalyst together with a readily available N-salicyl-β-aminoalcohol ligand. Up to 98% ee was obtained with quantitative yields In 15 min of reaction time using 5 mol % of the catalyst. Various N-protecting groups such as benzyl, benzhydryl, Boc, and PMP are tolerated.

Full text of DOI:10.1021/ol902540h

ORGANIC
LETTERS
2010
Vol. 12, No. 2
264-267
Highly Enantioselective
Titanium-Catalyzed Cyanation of Imines
at Room Temperature
Abdul Majeed Seayad,*,† Balamurugan Ramalingam,† Kazuhiko Yoshinaga,‡
Takushi Nagata,‡ and Christina L. L. Chai*,†
Institute of Chemical and Engineering Sciences, 1 Pesek Road, Singapore 627833, and
Mitsui Chemicals Asia Pacific Ltd., 1 Pesek Road, Singapore 627833
abdul_seayad@ices.a-star.edu.sg; christina_chai@ices.a-star.edu.sg
Received November 6, 2009
ABSTRACT
A highly active and enantioselective titanium-catalyzed cyanation of imines at room temperature is described. The catalyst used is a partially
hydrolyzed titanium alkoxide (PHTA) precatalyst together with a readily available N-salicyl-ꢀ-aminoalcohol ligand. Up to 98% ee was obtained
with quantitative yields in 15 min of reaction time using 5 mol % of the catalyst. Various N-protecting groups such as benzyl, benzhydryl, Boc,
and PMP are tolerated.
The asymmetric Strecker reaction or the hydrocyanation of
imines1 followed by hydrolysis is the most common and
effective method for the enantioselective synthesis of R-ami-
no acids,2 an important class of building blocks in synthesis.
In the last two decades, several enantioselective methodolo-
gies for the synthesis of aminonitriles have been reported
that use both metal3,4 and organo5,6 catalysts. However, the
existing methodologies suffer from limitations such as
the use of expensive catalysts and ligands as well as the
requirement for very low temperatures (-75 to -40 °C) to
achieve high enantioselectivities. Hoveyda et al.3c and
Vilaivan et al.7 have reported that higher enantioselectivities
can be achieved at temperatures of 0-4 °C using Ti-peptide
and Ti-salicyl-ꢀ-aminoalcohol based catalyst systems, re-
spectively. However, longer reaction times such as 20-70
h are required to complete the reaction. In this study, we
report a highly active and enantioselective catalyst system
for the cyanation of imines at ambient temperature.8
(3) For metal-catalyzed cyanation of aldimines see: (a) Sigman, M. S.;
Jacobsen, N. E. J. Am. Chem. Soc. 1998, 120, 5315. (b) Ishitani, H.;
Komiyama, S.; Kobayashi, S. Angew. Chem., Int. Ed. 1998, 37, 3186. (c)
Krueger, C. A.; Kuntz, K. W.; Dzierba, C. W.; Wirschun, W. G.; Gleason,
J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284.
(d) Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 2000, 39, 1650. (e) Takamura, M.; Hamashima,
Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Chem. Pharm. Bull. 2000, 48,
1586. (f) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2000, 122, 762. (g) Chavarot, M.; Byrne, J. J.; Chavant, P. Y.;
Vallee´, Y. Tetrahedron: Asymmetry 2001, 12, 1147. (h) Josephson, N. S.;
Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 11594. (i) Hatano, M.; Hattori, Y.; Furuya, Y.; Ishihara, K. Org. Lett.
2009, 11, 2321. (j) Jarusiewicz, J.; Choe, Y.; Yoo, K. S.; Park, C. P.; Jung,
K. W. J. Org. Chem. 2009, 74, 2873.
† Institute of Chemical and Engineering Sciences.
‡ Mitsui Chemicals Asia Pacific Ltd.
(1) For reviews, see: (a) Larry, Y. Angew. Chem., Int. Ed. 2001, 40,
875. (b) Herald, G. Chem. ReV. 2003, 103, 2797. (c) Spino, C. Angew.
Chem., Int. Ed. 2004, 43, 1764.
(2) Na´jera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584.
10.1021/ol902540h  2010 American Chemical Society
Published on Web 12/21/2009

In our initial studies on the cyanation of benzhydryl imine
1a using the easily accessible salicyl-ꢀ-aminoalcohol (L1)
ligand and Ti(OBu-n)4 as a catalyst precursor, we observed
a dramatic enhancement in catalytic activity when small
amounts of water were present during the initial formation
of the active chiral catalyst9 (Table 1, entries 1-4). At very
higher catalytic activities and enantioselectivities.13 The
beneficial effect of oligomeric titanium alkoxide catalysts
was recently reported for the cyanosilylation of aldehydes.14
To further explore the potential of this concept, partially
hydrolyzed titanium alkoxide (PHTA) was prepared by
controlled hydrolysis and used as the catalyst precursor
instead of the monomeric titanium alkoxide for the cyanation
of imines. The purpose of the former is to improve on the
preparation of the purported ‘true’ precatalyst system that
was implied from the studies with the monomers.
Table 1. PHTA-Catalyzed Cyanation of Iminea
The PHTA precatalyst was prepared by hydrolyzing
Ti(OBu-n)4 (0.5 mmol) using residual water (190 ppm)15 in
toluene (10 mL) by stirring for 18 h.16 This 0.05 M solution
was used as the PHTA precatalyst, and the chiral catalyst
was prepared in situ by complexing with 1 equiv of the
salicyl-ꢀ-aminoalcohol for 15-30 min of stirring at room
(5) For organo-catalyzed cyanation of aldimines see: (a) Iyer, M. S.;
Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118,
4910. (b) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157. (c) Sigman,
M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279.
(d) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. (e)
Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027. (f) Ooi, T.; Uematsu, Y.;
Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2548. (g) Rueping, M.; Sugiono,
E.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 2617. (h) Pan, S. C.; Zhou,
J.; List, B. Synlett 2006, 3275. (i) Pan, S. C.; Zhou, J.; List, B. Angew.
Chem., Int. Ed. 2007, 46, 612. (j) Reingruber, R.; Baumann, T.; Dahmen,
S.; Broese, S. AdV. Synth. Catal. 2009, 351, 1019. (k) Merino, P.; Lo´pez,
E. M.; Tejero, T.; Herrera, R. P. Tetrahedron 2009, 65, 1219.
(6) ) For organo-catalyzed cyanation of ketoimines, see: (a) Vachal, P.;
Jacobsen, E. N. Org. Lett. 2000, 2, 867. (b) Rueping, M.; Sugiono, E.;
Moreth, S. A. AdV. Synth. Catal. 2007, 349, 759. (c) Huan, J.; Liu, X.;
Wen, Y.; Qin, B.; Feng, X. J. Org. Chem. 2007, 72, 204. (d) Wang, J.; Hu,
X.; Jiang, J.; Gou, S.; Huang, X.; Liu, X.; Feng, X. Angew. Chem., Int. Ed.
2007, 46, 8468. (e) Hou, Z.; Wang, J.; Liu, X.; Feng, X. Chem.sEur. J.
2008, 14, 4484. (f) Shen, K.; Liu, X.; Cai, Y.; Lin, L.; Feng, X. Chem.sEur.
J. 2009, 15, 6008.
solvent water time yieldb eec
substrate content, ppm (min) (%) (%)
entry
1
catalyst
Ti(OBu-n)4
monomer
1a
10
60
240
1320
30
9
35
95
3
68
83
89
80
90
92
92
91
93
94
94
95
95
96
36
77
78
86
2
3
4
Ti(OBu-n)4
monomer
1a
50
60
23
52
70
38
60
87
99
88
99
99
25
71
93
99
240
360
15
Ti(OBu-n)4
monomer
1a
1a
100
190
60
180
360
15
60
15
15
30
60
15
Ti(OBu-n)4
monomer
PHTA
Ti(OBu-n)4
monomer
(7) (a) Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T. Tetrahedron
Lett. 2003, 44, 3805. (b) Banphavichit, V.; Mansawat, W.; Bhanthumnavin,
W.; Vilaivan, T. Tetrahedron. 2004, 60, 10559. (c) Banphavichit, V.;
Bhanthumnavin, W.; Vilaivan, T. Tetrahedron 2007, 63, 8727. (d) Ban-
phavichit, V.; Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T. Tetrahedron
2009, 65, 5849.
5
6
1a
1b
190
10
7
8
Ti(OBu-n)4
monomer
PHTA
1b
1b
190
190
(8) (a) Part of the results were presented as a poster at the 227 ACS
national meeting held at Salt Lake City, March 22-26, 2009. (b) Seayad,
A. M.; Chai, C. L. L.; Ramalingam, B.; Nagata, T.; Yoshinaga, K. PCT
Int. Appl. WO2008121074, 2008.
(9) The active chiral catalyst was prepared by complexing the titanium
precursor with the ligand for 5-30 min with stirring in toluene.
(10) Further increase in water content gave inconsistent results. In
general, catalytic performance decreases with an increase in water content
beyond 300 ppm.
15
99
87
a Imine, 0.2 mmol. b Yields were determined by 1H NMR spectroscopy.
c Analyzed by HPLC.
low water content of 10 ppm, the reaction was very slow
and required >22 h for complete conversion (entry 1) at room
temperature. At low conversions, the observed ee was only
68%, and the ee improved to 89% when 95% conversion to
the product was achieved. To our surprise, the cyanation
reaction was accelerated with an increased water content in
the solvent, and nearly quantitative conversion was observed
within 1 h of reaction time when toluene with a water content
of 190 ppm was used.10 Similarly, increased water content
in the solvent also resulted in improved ee’s. These observa-
tions may be due to the formation of multicentered chiral
catalysts,11 which are oligomeric in nature,12 and are capable
of activating both the imine and TMSCN thus resulting in
(11) For asymmetric catalysis involving more than one titanium center
in the metal complex, see: (a) Belokon, Y. N.; Caveda-Cepas, S.; Green,
B.; Ikonnikov, N. S.; Khrustalev, V. N.; Larichev, V. S.; Moscalenko, M. A.;
North, M.; Orizu, C.; Tararov, V. I.; Tasinazzo, M.; Timofeeva, G. I.;
Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 3968. (b) Hanawa, H.;
Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708. (c)
Schetter, B.; Ziemer, B.; Schnakenburg, G.; Mahrwald, R. J. Org. Chem.
2008, 73, 813.
(12) For oligomeric metal oxo-alkoxide complexes, see: Bradley, D. C.;
Mehrotra, I. P.; Rothwell, I. P.; Singh, A. Alkoxo and Aryloxo DeriVatiVes
of Metals: Academic Press: London, 2001; pp 405-411 and references
therein.
(13) For similar dual activation of electrophiles and nucleophiles by
adjacent metal centers, see the reviews: (a) Ma, J. A.; Cahard, D. Angew.
Chem. Int. Ed 2004, 43, 4566. (b) Shibasaki, M.; Kanai, M.; Matsunaga,
S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117.
(14) Yoshinaga, K.; Nagata, T. AdV. Synth. Catal. 2009, 351, 1495.
(15) The molar ratio of Ti:H2O is 0.5:0.11.
(16) The calculated amount of water is 0.17 equiv to Ti(OBu-n)4. The
hydrolysis was confirmed by the formation of n-BuOH with concomitant
decrease in the concentration of water as measured by in situ IR. The
hydrolysis is generally faster, and a major part of hydrolysis takes place
within 15 minutes. Hydrated inorganic salts can also be used for partial
hydrolysis.
(4) For metal-catalyzed cyanation of ketoimines, see: (a) Byrne, J. J.;
Chavarot, M.; Chavant, P.-Y.; Vallee’, Y. Tetrahedron Lett. 2000, 41, 873.
(b) Byrne, J. J.; Chavarot, M.; Chavant, P. Y.; Vallee, Y. Tetrahedron:
Lett. 2000, 41, 873. (c) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634.
Org. Lett., Vol. 12, No. 2, 2010
265

temperature. To this chiral catalyst solution, imine substrate
1a or 1b, TMSCN, and additive were added, and the
cyanation reaction was carried out for 15 min. Gratifyingly,
up to 96% ee with quantitative conversion was achieved in
15 min at room temperature using 5 mol % of the catalyst
in the case of 1a (Table 1, entry 5).
Table 2. Optimization Studies Using the PHTA Catalysta
The effect of water and the enhanced catalytic perfor-
mance of PHTA catalyst was also observed when N-benzyl
imine 1b was used as the substrate (Table 1, entries 6-8).
The PHTA precatalyst obtained can be easily handled
without following strict inert conditions, and the cyanation
reactions need not be carried out under argon atmosphere
as was necessary for the reactions carried out with the
Ti-alkoxide monomer. The PHTA precatalyst is easy to
prepare and is stable as no loss of catalytic activity was
observed even after one month of storage. Further
optimization studies were carried out using PHTA as the
precatalyst. The effect of various catalyst and reaction
parameters on the catalytic performance was evaluated
using benzyl imine 1b as a substrate for a short reaction
time of 15 min at room temperature, and the results are
presented in Table 2.
A proton source as an additive was found to be necessary
for high catalytic activity, and to a certain extent, this also
affects the enantioselectivities of the reactions.17 Alcohols
such as n-BuOH (Table 2, entry 1) and EtOH (Table 2, entry
3) as additives gave up to 87% ee and quantitative conver-
sions in 15 min, while i-PrOH gave only 51% yield with
83% ee (Table 2, entry 2). Water can also be used as an
additive, and only 0.5 equiv was required for optimal
performance. Higher equivalents of water reduce the enan-
tioselectivity of the reaction considerably (Table 2, entries
5 and 6).
The tridentate salicyl-ꢀ-aminoalcohol ligand L1 with R1
) t-Bu derived from salicylaldehyde and L-tert-Leucinol
gave the highest enantioselectivity compared to those
ligands with R1 ) i-Pr (L2), Bn (L3), or s-Bu (L4) as
presented in Table 2. The effect of substituents R2 and
R3 on the enantioselectivities of the reaction with imine
1b was also examined. In general, no appreciable differ-
ence in enantioselectivity was observed when R2 ) OMe
(L5) and Me (L7) or even when the sterically hindered
t-Bu (L6) group was used. However, the ee was drastically
decreased when R3 * H as observed with L8-L10. The
effect was very much more pronounced with bulky alkyl
substituents such as t-Bu as compared to the substituents
with coordinating groups such as OEt. Nearly racemic
product was obtained with L9 (R3 ) t-Bu) as compared
to L10 (R3 ) Me), while up to 74% ee was observed when
R3 ) OEt (L8). These results suggest that a larger steric
bulk at the ꢀ-position of the aminoalcohol part of the
ligand and smaller steric bulk at the salicylaldehyde part
are required for optimum enantioselectivity. Hence, the
simple ligand L1 was chosen for further studies.
a Imine, 0.2 mmol. b NMR yield. c Analyzed by HPLC. d 0.5 equiv of
water was used.
investigated, and the results are presented in Table 3.
Benzhydryl and t-butoxycarbonyl (Boc) protecting groups
gave the highest enantioselectivities (96% and 98% ee,
respectively). The results obtained for N-Boc imine (1c) are
particularly remarkable since other catalyst systems that have
been reported thus far gave lower enantioselectivity (up to
75%).5a Benzyl (1b) and allyl (1f) imines gave high
enantioselectivities (87% and 85% ee, respectively), while
p-methoxyphenyl (PMP, 1e) and 9-fluorenyl (1d) protected
imines gave moderate ee’s (45% and 58%, respectively).
The substrate scope for this catalyst system was further
examined with various substituted imines as presented in
Scheme 1. Up to 98% and 97% ee were obtained for o-Cl
(4a) and o-Br (4b) substituted aminonitriles when the
With the above optimized reaction conditions, the effect
of different N-protecting groups on enantioselectivity was
(17) The beneficial effect of alcohols as additives is well known in the
literature, and generally i-PrOH is used.
(18) See Supporting Information for details.
266
Org. Lett., Vol. 12, No. 2, 2010

Table 3. PHTA-Catalyzed Cyanation of Different N-Protected
Scheme 1
.
Substrate Scope for the PHTA-Catalyzed Cyanation
of Iminesa
Iminesa
entry
PG
yield, %b
ee, %
1
2
3
4
5
6
benzhydryl (a)
benzyl (b)
Boc (c)
>99
>99
>99
93
98
99
96d
87d
98d
58d
45e
85e
9-fluorenyl (d)
PMP (e)
allyl (f)c
a Imine, 0.2 mmol; TMSCN, 1.5 equiv. b Yields were determined by
1H NMR spectroscopy. c The aminonitrile obtained was acylated using
trifluoroacetic anhydride to obtain the amide for measuring yield and ee.
d The configuration was assigned based on the specific rotation values
reported for the aminonitrile or the corresponding amino acid.18 e The
stereochemistry of the aminonitrile is tentative.
corresponding benzhydryl imines were used. Sterically
hindered imines 3c with the o-CH3 substituent gave the
product 4c in very high ee (97%). The meta-substituted
aminonitrile 4e was also obtained in 93% ee. A noteworthy
observation is that the cyanation of R,ꢀ unsaturated imine
gave regioselective 1,2-addition product 4f in 97% ee. In
the case of benzyl imines, up to 90% ee was obtained for
o-Cl (4i) and o-Br (4j) aminonitriles. Though unsubstituted
PMP-protected imines gave only 45% ee (Table 3, entry 5),
up to 61% ee was achieved when p-CF3-substituted PMP-
imine (3n) was used as the substrate.
a The stereochemistries of the aminonitriles 4e, 4h, 4i, and 4n-4r are
tentative.
Heterocyclic imines containing oxygen (3o), nitrogen (3p),
and sulfur (3q, 3r) were also found to give the corresponding
cyanation products in very high enantioselectivities using the
present catalyst system.
nature of this catalyst system, its structure, and the mecha-
nism as well as application to other reactions are currently
under investigation.
The aminonitriles 2a, 2c, 4g, and 4j-4 m were hydrolyzed
as per the reported procedures3c,5a,7d to the corresponding
amino acids and found to have the (S) configuration.
Aminonitriles 2b, 2d, 4a-4d, and 4f were assigned the (S)
configuration in comparison to the literature reports.18
In conclusion, partially hydrolyzed titanium alkoxide
(PHTA) catalyst together with salicyl-ꢀ-aminoalcohol as the
ligand provide very high catalytic activity and enantioselec-
tivity for the cyanation of various imines at room tempera-
ture. To the best of our knowledge this is the first report of
a simple catalyst system that giVes up to 98% ee for the
cyanation of imines at room temperature in a short reaction
time. High enantioselectivities were obtained in the case of
various benzhydryl, benzyl, and N-Boc imines. The unique
Acknowledgment. This research work was supported by
A*STAR Singapore and Mitsui Chemicals Asia Pacific Ltd.
We thank Prof. Marc V. Garland and Dr. Li Chuanzhao,
Institute of Chemical and Engineering Sciences, Singapore,
for in situ IR measurements of PHTA catalyst.
Supporting Information Available: Experimental details
and characterization of compounds are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL902540H
Org. Lett., Vol. 12, No. 2, 2010
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