Enantioselective hydrocyanation of N-protected aldimines

Article abstract of DOI:10.1021/ol203408w

Enantioselective hydrocyanation of N-benzyloxycarbonyl aldimines catalyzed by a Ru[(S)-phgly]₂[(S)-binap]/C₆H₅OLi system or a bimetallic complex [Li{Ru[(S)-phgly]₂[(S)-binap]}]Cl affords the amino nitriles in 92 - 99% ee. The reaction is carried out in tert-C ₄H₉OCH₃ with a substrate-to-catalyst molar ratio in the range of 500 - 5000 at -20 to 0°C. Primary, secondary, and tertiary alkyl imines as well as the aryl and heteroaryl substrates are smoothly cyanated to produce the desired products in high yield.

Full text of DOI:10.1021/ol203408w

ORGANIC
LETTERS
2012
Vol. 14, No. 3
882–885
Enantioselective Hydrocyanation of
N-Protected Aldimines
Masato Uemura, Nobuhito Kurono, and Takeshi Ohkuma*
Division of Chemical Process Engineering, Faculty of Engineering, Hokkaido
University, Sapporo, Hokkaido 060-8628, Japan
ohkuma@eng.hokudai.ac.jp
Received December 21, 2011
ABSTRACT
Enantioselective hydrocyanation of N-benzyloxycarbonyl aldimines catalyzed by a Ru[(S)-phgly]2[(S)-binap]/C6H5OLi system or a bimetallic
complex [Li{Ru[(S)-phgly]2[(S)-binap]}]Cl affords the amino nitriles in 92ꢀ99% ee. The reaction is carried out in tert-C4H9OCH3 with a substrate-to-
catalyst molar ratio in the range of 500ꢀ5000 at ꢀ20 to 0 °C. Primary, secondary, and tertiary alkyl imines as well as the aryl and heteroaryl
substrates are smoothly cyanated to produce the desired products in high yield.
Catalytic enantioselective hydrocyanation of aldimines
(Strecker-type reaction) is a facile and straightforward
method to produce optically active R-amino nitriles, which
are readily transformed to the proteinogenic and the non-
proteinogenic R-amino acids.1 Both natural-type and un-
natural-type amino acids can be selectively prepared by
using this asymmetric reaction when two enantiomers of
catalysts are available. Chiral organocatalysts2 and metal-
based catalysts3 have eminently contributed to the progress
in this important field of chemistry. However, the develop-
ment of a catalytic system that shows high activity and
enantioselectivity as well as a wide scope of substrates would
be desirable from a scientific and practical point of view.
We recently reported asymmetric conjugate addition of
HCN to R,β-unsaturated ketones (R1CHdCHCOR2) by
using a Ru(phgly)2(binap)/C6H5OLi catalyst system.4,5
A series of aromatic and aliphatic β-cyano ketones was
obtained in high ee. The bimetallic species [Li{Ru(phgly)2-
(binap)}]þ prepared in situ is expected to act as a chiral
Lewis acidic catalyst.5c We therefore considered that the
π-isoelectronic N-alkoxycarbonyl aldimines (R1CHd
NCO2R2) could react with HCN in the presence of the
Ru(phgly)2(binap)/Li salt catalyst system to afford the
protected amino nitriles in high ee.
(2) For selected leading studies, see: (a) Iyer, M. S.; Gigstad, K. M.;
Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910–4911. (b)
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901–4902.
(c) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157–160. (d) Sigman,
M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279–
1281. (e) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012–
10014. (f) Jiao, Z.; Feng, X.; Liu, B.; Chen, F.; Zhang, G.; Jiang, Y. Eur.
J. Org. Chem. 2003, 3818–3826. (g) Huang, J.; Corey, E. J. Org. Lett.
2004, 6, 5027–5029. (h) Ooi, T.; Uematsu, Y.; Maruoka, K. J. Am. Chem.
Soc. 2006, 128, 2548–2549. (i) Rueping, M.; Sugiono, E.; Azap, C.
Angew. Chem., Int. Ed. 2006, 45, 2617–2619. (j) Herrera, R. P.; Sgarzani,
V.; Bernardi, L.; Fini, F.; Pettersen, D.; Ricci, A. J. Org. Chem. 2006, 71,
9869–9872. (k) Pan, S. C.; Zhou, J.; List, B. Angew. Chem., Int. Ed. 2007,
46, 612–614. (l) Ooi, T.; Uematsu, Y.; Fujimoto, J.; Fukumoto, K.;
Maruoka, K. Tetrahedron Lett. 2007, 48, 1337–1340. (m) Wen, Y.;
Xiong, Y.; Chang, L.; Huang, J.; Liu, X.; Feng, X. J. Org. Chem.
2007, 72, 7715–7719. (n) Negru, M.; Schollmeyer, D.; Kunz, H. Angew.
Chem., Int. Ed. 2007, 46, 9339–9341. (o) Wen, Y.; Gao, B.; Fu, Y.; Dong,
S.; Liu, X.; Feng, X. Chem.;Eur. J. 2008, 14, 6789–6795. (p) Zuend,
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r
10.1021/ol203408w
Published on Web 01/19/2012
2012 American Chemical Society

We selected an N-benzyloxycarbonyl (Cbz) imine 1a
derived from benzaldehyde according to the reported
method6 as a typical substrate tooptimizethe reaction con-
ditions (Scheme 1 and Table 1). The reaction of 1a (1.0 mmol,
0.15 M) and HCN prepared in situ by mixing (CH3)3SiCN
(3.0 mmol) and CH3OH (3.0 mmol) in tert-C4H9OCH3
at 0 °C smoothly proceeded in the presence of Ru[(S)-
phgly]2[(S)-binap] ((S,S,S)-3: 2.0 μmol; substrate-to-
catalyst molar ratio (S/C) = 500) and C6H5OLi (0.10 M in
THF, 2.0 μmol) to afford (R)-2a in 97% ee quantitatively
in 30 min (Table 1, entry 1). An even higher ee value of
98% was achieved at ꢀ20 °C (entry 2). A high level of
enantioselectivity was obtained in the reaction even at 25 °C
(entry 3).7 The enantioselectivity was decreased under the
substrate concentration higher than 0.15 M, although
the lower concentration little affected the stereoselective
outcome (entries 4 and 5). A comparable result was ob-
tained by using isolated HCN8 instead of the in situ formed
one, suggesting that the reaction is the net hydrocyana-
tion without substantial influence by the existing silicone
compounds (entry 6). A bimetallic salt [Li{Ru[(S)-phgly]2-
[(S)-binap]}]Cl ((S,S,S)-4)5c prepared from (S,S,S)-3 and
LiCl also acted as a highly enantioselective catalyst for this
reaction without additives, but the catalytic activity was
lower than that of the (S,S,S)-3/C6H5OLi system (entry 7 vs
entry 1). The high catalytic efficiency of (S,S,S)-3/C6H5OLi
system achieved complete conversion of the cyanation with
an S/C of 2500 (1 h) and 5000 (2 h) affording 2a in 95 and
96% ee, respectively (entries 8 and 9).
Table 1. Enantioselective Hydrocyanation of N-Cbz Aldimine 1aa
entry [1a]0, M S/Cb temp, °C time, h % yieldc % eed
1
0.15
0.15
0.15
0.45
0.05
0.15
0.15
0.15
0.15
500
500
0
ꢀ20
25
0
0.5
0.5
0.5
0.5
0.5
0.5
99
98
97
98
89
94
97
96
98
95
96
Scheme 1. Enantioselective Hydrocyanation of N-Cbz Aldimine
1a with the 3/C6H5OLi Catalyst System or 4
2
3
500
98
4
500
100
100
98
5
500
0
6e
7f
8g
9h
500
0
500
0
20
53
2500
5000
0
1
2
99
0
95
a Unless otherwise stated, reactions were conducted using 1a (1.0 mmol)
and HCN (3.0 mmol) in tert-C4H9OCH3 with a solid (S,S,S)-3 and
C6H5OLi (100 mM in THF). 3:C6H5OLi = 1:1. HCN was in situ
prepared from (CH3)3SiCN and CH3OH in a 1:1 ratio. b Substrate-to-
catalyst (3) molar ratio. c Isolated yield of 2a. d Determined by chiral
HPLC analysis. e Isolated HCN was used. f 4 was used instead of the 3/
C6H5OLi system as a catalyst. g Reaction using 5.1 mmol of 1a. h Reac-
tion using 10.0 mmol of 1a.
The enantioselective hydrocyanation catalyzed by the
(S,S,S)-3/C6H5OLi system or (S,S,S)-4 was applied to a
series of N-protected aldimines (Scheme 2). These results
are summarized in Table 2. Cbz was the most preferable
protective group in terms of stereoselectivity (Table 2,
entry 1). The cyanation of tert-butoxycarbonyl- and benzoyl-
protected aldimines, 1b and 1c, with the 3/C6H5OLi system
resulted in a somewhat lower ee of products (entries 2 and 3).
Both the reaction rate and enantioselectivity were significantly
decreased in the reaction of N-benzyl imine 1d (entry 4).
N-Cbz imines of 2-, 3-, and 4-methylbenzaldehydes, 1e,
1f, and 1h, were smoothly cyanated under the typical
conditions with the 3/C6H5OLi catalyst system to produce
the amino nitriles, 2e, 2f, and 2h, in the same ee of 97%
(3) For selected leading studies, see: (a) Ishitani, H.; Komiyama, S.;
Kobayashi, S. Angew. Chem., Int. Ed. 1998, 37, 3186–3188. (b) Sigman,
M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315–5316.
(c) Crueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.;
Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 4284–4285. (d) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobaya-
shi, S. J. Am. Chem. Soc. 2000, 122, 762–766. (e) Takamura, M.;
Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2000, 39, 1650–1652. (f) Porter, J. R.; Wirschun, W. G.; Kuntz,
K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122,
2657–2658. (g) Keith, J. M.; Jacobsen, E. N. Org. Lett. 2004, 6, 153–155.
(h) Banphavichit, V.; Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T.
Tetrahedron 2004, 60, 10559–10568. (i) Blacker, J.; Clutterbuck, L. A.;
Crampton, M. R.; Grosjean, C.; North, M. Tetrahedron: Asymmetry
2006, 17, 1449–1456. (j) Wang, J.; Hu, X.; Jiang, J.; Dou, S.; Huang, X.;
Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2007, 46, 8468–8470. (k)
Nakamura, S.; Nakashima, H.; Sugimoto, H.; Sano, H.; Hattori, M.;
Shibata, N.; Toru, T. Chem.;Eur. J. 2008, 14, 2145–2152. (l) Hatano,
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X.; Shen, K.; Tan, C.; Liu, X.; Feng, X. Chem.;Eur. J. 2009, 15, 11642–
11659. (o) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2009, 131,
15118–15119. (p) Seayad, A. M.; Ramalingam, B.; Yoshinaga, K.;
Nagata, T.; Chai, C. L. L. Org. Lett. 2010, 12, 264–267. (q) Kaur, P.;
Pindi, S.; Wever, W.; Rajale, T.; Li, G. J. Org. Chem. 2010, 75, 5144–
5150. (r) Karimi, B.; Maleki, A.; Elhamifar, D.; Clark, J. H.; Hunt, A. J.
Chem. Commun. 2010, 46, 6947–6949.
(5) For asymmetric cyanation of aldehydes and R-keto esters with
combined catalysts of Ru(phgly)2(binap) and Li compounds, see:
(a) Kurono, N.; Arai, K.; Uemura, M.; Ohkuma, T. Angew. Chem.,
Int. Ed. 2008, 47, 6643–6646. (b) Kurono, N.; Uemura, M.; Ohkuma, T.
Eur. J. Org. Chem. 2010, 1455–1459. (c) Kurono, N.; Yoshikawa, T.;
Yamasaki, M.; Ohkuma, T. Org. Lett. 2011, 13, 1254–1257.
(6) (a) Petrini, M. Chem. Rev. 2005, 105, 3949–3977. (b) Tillman,
A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191–1193.
(7) Careful operations are required for hydrocyanation at room
temperature because of the high volatility of HCN.
(8) Glemser, O. In Handbook of Preparative Inorganic Chemistry,
2nd ed.; Brauer, G., Riley, R. F., Eds.; Academic Press: New York, 1963; pp
658ꢀ660.
(4) Kurono, N.; Nii, N.; Sakaguchi, Y.; Uemura, M.; Ohkuma, T.
Angew. Chem., Int. Ed. 2011, 50, 5541–5544.
Org. Lett., Vol. 14, No. 3, 2012
883

Table 2. Enantioselective Hydrocyanation of Aldimines 1a
Scheme 2. Enantioselective Hydrocyanation of Aldimines 1
with the 3/C6H5OLi Catalyst System or 4
entry
1
cat.b S/Cc temp, °C time, h % yieldd % eee
1
1a
1b
1c
A
A
A
A
A
A
A
A
A
A
A
B
A
A
A
A
B
A
A
B
A
A
A
500
500
500
500
500
500
500
500
500
500
500
500
500
500
5000
500
500
500
500
500
500
500
5000
0
0
0.5
0.5
0.5
99
99
91
95
97
97
98
95
96
96
98
93
96
98
93
59i
72i
86
89
93
99
98
100
97
91
86
ꢀ14f
97
97
98
99
97
97
19
97
92
97
96
80
96
92
95
94
92
96
93
2
3
0
4
1d
1e
1f
0
18
5
0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
6
0
7
1g
1g
1h
1i
0
8
ꢀ20
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0
1j
0
1j
0
1k
1l
0
0.5
0.5
3
0
1lg
1mh
1mh
1n
1n
1n
1o
1o
1og
0
0
0.5
2
(Table 2, entries 5, 6, and 9). The reactions of a 3-bromo-
phenyl imine 1g with an S/C of 500 at 0 and ꢀ20 °C
afforded 2g in 98% ee and 99% ee, respectively (entries 7
and 8). A substrate with anelectron-donating CH3O group
at the C4-position 1i was converted to 2i with high stereo-
selectivity (entry 10). However, an imine bearing an
electron-withdrawing CF3 moiety 1j was reacted under
the same conditions to give 2j in only 19% ee (entry 11). A
noncatalytic NCꢀ addition to the imine was considered to
be a main reason for the low ee value of the product. This
0
0
0.5
0.5
2
ꢀ20
0
0
0.5
0.5
2
ꢀ20
0
a Unless otherwise stated, reactions were conducted using 1 (1.0 mmol,
0.15 M) and 3 equiv of HCN in tert-C4H9OCH3 with a catalyst. HCN
wasinsitupreparedfrom(CH3)3SiCN and CH3OH in a 1:1 ratio. b Catalyst:
A:(S,S,S)-3and C6H5OLi (100 mM in THF). 3:C6H5OLi = 1:1. B:(S,S,S)-
4. c Substrate-to-catalyst molar ratio. d Isolated yield of 2. e Determined by
chiral GC or HPLC analysis. f The opposite enantiomer was the major
product. g Reaction using 10 mmol of 1. h Crude 1m was used as a substrate.
i Yield in two steps from the precursor of 1m.
problem was solved just by using the less basic Ru Li
3
bimetallic complex 4 instead of the 3/C6H5OLi system. The
ee value of 2j was dramatically increased to 97% (entry 12).
The cyanation of 20-furyl and 20-thienyl imines, 1k and 1l,
catalyzed by the 3/C6H5OLi system quantitatively af-
forded the amino nitriles, 2k and 2l, in 92 and 97% ee,
respectively, without injury at the heteroaromatic rings
(entries 13 and 14). Complete conversion in the reaction of
1l with an S/C of 5000 was achieved in 3 h with main-
tenance of high enantioselectivity (entry 15).
Scheme 3. Hydrolysis of (R)-2a and Preparation of (R,R,R)-3
Asymmetric hydrocyanation of imines derived from
aliphatic aldehydes is difficult, so that only limited catalyst
systems have achieved high enantioselectivity.1ꢀ3 An N-
Cbz imine of butanal, a primary alkyl aldehyde, 1m
smoothly reacted with HCN in the presence of the 3/
C6H5OLi catalyst system (S/C = 500, 0 °C, 30 min) to
afford2min 80% ee(Table2, entry 16).9 The eevalue of 2m
jumpedup to 96% whenbimetallic complex 4 wasusedasa
catalyst (entry 17).10 The cyclohexyl imine 1n, a second-
ary alkyl imine, was converted to 2n in 92% ee (0 °C) and
95% ee (ꢀ20 °C) with the 3/C6H5OLi catalyst system
(entries 18 and 19). A slightly higher selectivity at 0 °C
was obtained in the reaction with the catalyst 4 (entry 20).
A tertiary alkyl imine 1o was also cyanated with high
enantioselectivity without detectable loss of the reaction
rate (entries 21 and 22). The reaction with an S/C of 5000
was completed in 2 h (entry 23).
The cyanated product (R)-2a in 97% ee was readily
converted to (R)-phenylglycine ((R)-5a) in 96% ee with an
acidic treatment (Scheme 3). Then (R,R,R)-3 was pre-
pared from RuCl2[(R)-binap](dmf)n11 and a sodium salt of
(R)-5a according to our reported method (see the Sup-
porting Information for details).5 The diastereomeric
(9) 1m was used as a crude compound due to its instability under
purification conditions. The isolated yield of 2m in two steps from the
precursor of 1m is indicated in Table 2.
(10) An N-arylsulfonyl primary alkyl imine was cyanated at 0 °C with
96% enantioselectivity catalyzed by a chiral quaternary ammonium salt
(S/C = 100). See ref 2l for details.
884
Org. Lett., Vol. 14, No. 3, 2012

byproducts, (R,R,S)-3 and (R,S,S)-3, were easily removed
with a silica-gel preparative TLC.
reactivity, enantioselectivity, and scope of the sub-
strate to our knowledge.
In conclusion, we have reported the highly reactive and
enantioselective hydrocyanation of N-Cbz imines with our
original Ru(phgly)2(binap)/C6H5OLi system or the bime-
talliccomplex [Li{Ru(phgly)2(binap)}]Cl as a catalyst. The
reactions with an S/C of 500ꢀ5000 were conducted under
mild conditions (ꢀ20 to 0 °C) to afford the chiral amino
nitriles in up to 99% ee. A series of aromatic, heteroaro-
matic, and alkyl-substituted imines was cyanated with
equally high enantioselectivity. Achievement of the
highest level of enantioselectivity for the reaction of a
primary alkyl imine is noteworthy. An aromatic nitrile
product was hydrolyzed to the amino acid with main-
tenance of the enantiomeric purity. Thus, the chiral
Acknowledgment. This work was supported by a
Grants-in-Aid from JSPS (No. 21350048). M.U. is the
grateful recipient of a JSPS Research Fellowship for
Young Scientists. N.K. is the grateful recipient of a fellow-
ship from the Global COE Program, “Catalysis as the
Basis for Innovation in Materials Science” from MEXT
(Japan).
Supporting Information Available. Procedures for
asymmetric hydrocyanation of N-protected aldimines 1,
NMR, GC, and HPLC behavior, [R]D values of products,
and preparative method of the chiral Ru complex (R,R,
R)-3. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ru Li complex is among the best catalysts in terms of
3
(11) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org.
Synth. 1993, 71, 1–13.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
885