Asymmetric cyanation of activated olefins with ethyl cyanoformate catalyzed by a modular titanium catalyst

Article abstract of DOI:10.1021/ol100169r

"Chemical Equation Presented" Asymmetric cyanation of a class of easily available olefins with a favorable cyanide source ethyl cyanoformate (CNCOOEt) was realized by an interesting modular catalyst. High yields and ee values were obtained for a range of substrates under solvent-free and mild reaction conditions. The products obtained could be easily transformed to the enantioenriched useful intermediates 5,6, and pharmaceutically Important γ-aminobutyric acid 7.

Full text of DOI:10.1021/ol100169r

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1280-1283
Asymmetric Cyanation of Activated
Olefins with Ethyl Cyanoformate Catalyzed
by a Modular Titanium Catalyst
Jun Wang, Wei Li, Yanling Liu, Yangyang Chu, Lili Lin, Xiaohua Liu, and
Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, P. R. China
xmfeng@scu.edu.cn
Received January 22, 2010
ABSTRACT
Asymmetric cyanation of a class of easily available olefins with a favorable cyanide source ethyl cyanoformate (CNCOOEt) was realized by
an interesting modular catalyst. High yields and ee values were obtained for a range of substrates under solvent-free and mild reaction
conditions. The products obtained could be easily transformed to the enantioenriched useful intermediates 5, 6, and pharmaceutically important
γ-aminobutyric acid 7.
Compared with the intensively studied asymmetric catalytic
cyanation of CdO and CdN double bonds,1,2 asymmetric
catalytic cyanation of the CdC double bond is less explored.3
Until now, only two efficient catalyst systems were revealed,
namely, the salen-Al(III) catalyst reported by the Jacobsen
group for the cyanation of R,ꢀ-unsaturated imides3a-d and
polymetallic Gd(III) catalysts reported by the Shibasaki group
for the cyanation of R,ꢀ-unsaturated N-acylpyrroles3e,f and
R,ꢀ-unsaturated ketones.3g Besides, Fochi, Ricci, and co-
workers reported a quaternary ammonium salt catalyzed
(1) For recent reviews on the asymmetric cyanation of aldehydes and
ketones, see: (a) Khan, N. H.; Kureshy, R. I.; Abdi, S. H. R.; Agrawal, S.;
Jasra, R. V. Coord. Chem. ReV. 2008, 252, 593. (b) North, M.; Usanov,
(3) (a) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
4442. (b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 9928. (c) Mazet, C.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2008, 47, 1762. (d) Madhavana, N.; Weck, M. AdV. Synth. Catal. 2008,
350, 419. (e) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 514. (f) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato,
A.; Furusho, S.; Kanaia, M.; Shibasaki, M. Tetrahedron 2007, 63, 5820.
(g) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130,
6072. (h) Bernardi, L.; Fini, F.; Fochi, M.; Ricci, A. Synlett 2008, 1857.
D. L.; Young, C. Chem. ReV. 2008, 108, 5146
.
(2) For reviews on the asymmetric Strecker reaction, see: (a) Yet, L.
Angew. Chem., Int. Ed. 2001, 40, 875. (b) Gro¨ger, H. Chem. ReV. 2003,
103, 2795. (c) Spino, C. Angew. Chem., Int. Ed. 2004, 43, 1764. (d) Connon,
S. J. Angew. Chem., Int. Ed. 2008, 47, 1176. (e) Merino, P.; Marque´s-
lo´pez, E.; Tejero, T.; Herrera, R. P. Tetrahedron 2009, 65, 1219
.
10.1021/ol100169r  2010 American Chemical Society
Published on Web 02/23/2010

cyanation of ꢀ,ꢀ′-disubstituted nitroolefins, obtaining moder-
ate yields and ee values.3h It is undoubted that more efforts
are still required to contribute to this field. Significantly, the
synthetic importance of this cyanide addition could be
exemplified by the synthesis of various optically active
γ-aminobutyric acids (GABA), which are pharmaceutically
important for their anticonvulsant, antidepressant, and an-
tineuropathic pain properties.3a-f
Table 1. Optimization of Reaction Conditionsa
Recently, we disclosed an interesting modular catalyst
generated from cinchona alkaloid, tetraisopropyl titanate
(Ti(O-i-Pr)4), and achiral 3,3′-disubstituted biphenol,4 in
which the achiral biphenol would selectively adopt a chirally
matched configuration during the catalyst formation (eq 1).5
As the catalytic property could be facilely tuned by altering
either cinchona alkaloid or substituent on biphenol, this
catalyst system proved generally efficient for the asymmetric
cyanation of many kinds of substrates including aldehyde,
ketone, aldimine, and ketimine. Encouraged by these features,
we desired to extend this catalyst system to the challenging
conjugate addition of cyanide to the CdC bond. After
systematical screening and optimization, asymmetric catalytic
cyanation of diethyl alkylidenemalonate with ethyl cyano-
formate (CNCOOEt) as cyanide source was successfully
achieved, affording the product in up to 99% yield and 94%
ee under mild and neat reaction conditions. It should be noted
the cyanide source used in the previous efficient cyanide
conjugate addition was focused on trialkylsilyl cyanide
(TMSCN3a-f and TBSCN3g), whereas the relatively cheap
and less toxic alternative cyanide source, CNCOOEt, has
never been explored before.6,7
temp time yieldc
eed
(%)
entry olefin R3-CN ligands
(°C)
(h)
(%)
1
1
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
7a, 8a
7a, 8a
7a, 8a
7a, 8a
7a, 8a
7b, 8a
7c, 8a
7d, 8a
7d, 8a
7d, 8b
7d, 8b
-20
-20
-20
-20
0
72
72
18
58
19
19
19
19
36
42
42
trace
trace
46
27
50
67
25
53
50
2
2
3
3
11
42
20
-64
16
-76
-89
-92
-93
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4a
0
0
0
0
0
0
10
48
86
11b
a Unless otherwise noted, reactions were carried out with 7/Ti(O-i-Pr)4/8
(1/1/1, 20 mol % for entries 1-4 and 10 mol % for others), olefin (0.1
mmol), cyanide reagent (0.2 mmol), and i-PrOH (0.2 mmol) in toluene (0.2
mL). b CNCOOEt (0.5 mmol), i-PrOH (0.5 mmol), and no solvent were
used. c Isolated yield. d Determined by chiral HPLC. The minus sign signified
opposite absolute configuration to others.
TMSCN as the cyanide source, the enantioselectivity was
greatly enhanced to 89% ee (Table 1, entry 9).8
Our preliminary studies showed that with TMSCN as the
cyanide source and 20 mol % of quinidine 7a/Ti(O-i-Pr)4/
biphenol 8a (1:1:1) as the catalyst, the diethyl benzyliden-
emalonate 4a exhibited the most promising enantioselectivity,
although the reactivity was rather low (Table 1, entries 1-4).
When the catalyst loading was decreased from 20 to 10 mol
% and the temperature elevated from -20 to 0 °C, slightly
improved reactivity but poor enantioselectivity was observed
(Table 1, entry 4 vs 5). Screening commercially available
cinchona alkaloids indicated cinchonidine 7d was the optimal
choice, giving 76% ee and moderate yield (Table 1, entries
6-8). Unexpectedly, when CNCOOEt was used instead of
Then, some biphenols with other 3,3′-substituents were
examined, and 8b turned out to be the best, giving 92% ee
(Table 1, entry 10). However, the reactivity of the reaction
was still a big problem (42 h, 48% yield). Intensive studies
showed that satisfying results could be obtained by increasing
the stoichiometry of CNCOOEt as well as 2-propanol to 5.0
equiv under solvent-free conditions, delivering the product
6a in 86% yield and 93% ee (Table 1, entry 11). Other
parameters such as catalyst loading, temperature, and solvent
were also investigated, but no better result was achieved. In
addition, some other benzylidenemalonic esters were exam-
ined, and comparable ee values while inferior yields were
afforded (for details, see the Supporting Information).
Under optimized conditions, a series of diethyl alkyliden-
emalonates were examined with results compiled in Table
2. Generally high yields and ee values were obtained
regardless of the substituted position and electronic properties
of the substituent on the benzene ring of the model substrate
4a (Table 2, entries 1-12). The olefins derived from
(4) (a) Wang, J.; Hu, X. L.; Jiang, J.; Gou, S. H.; Huang, X.; Liu, X. H.;
Feng, X. M. Angew. Chem., Int. Ed. 2007, 46, 8468. (b) Wang, J.; Wang,
W. T.; Li, W.; Hu, X. L.; Shen, K.; Tan, C.; Liu, X. H.; Feng, X. M.
Chem.sEur. J. 2009, 15, 11642.
(5) For reviews on the asymmetric activation of racemic ligands, see:
(a) Walsh, P. J.; Lurain, A. E.; Balsells, J. Chem. ReV. 2003, 103, 3297. (b)
Faller, J. W.; Lavoie, A. R.; Parr, J. Chem. ReV. 2003, 103, 3345. (c)
Mikami, K.; Yamanaka, M. Chem. ReV. 2003, 103, 3369. (d) Ding, K.;
Du, H.; Yuan, Y.; Long, J. Chem.sEur. J. 2004, 10, 2872.
Org. Lett., Vol. 12, No. 6, 2010
1281

Table 2. The Substrate Scopea
Scheme 1. Elaboration of Product 6a
racemic 6a could be elaborated to the optically active
pyrrolidine 10 in seven steps,9b which could be further
transformed to GABA and other useful compounds.9a,b In
sharp contrast, with enantioenriched 6a in hand herein,
enantioenriched 10 could be readily prepared in three steps
(Scheme 1). In addition, the optically active intermediate
pyrrolidinone 9 could be facilely obtained by hydrogenation
of 6a (93% ee) with Raney nickel9b or Pd/C as catalyst. It
should be noted when Raney nickel was used, addition of
acetic acid was necessary to avoid partial racemization, which
might be caused by the weak alkalinity of the catalyst
prepared from Ni-Al alloy and NaOH (aq). The relative
configuration of product was determined by H,H-NOESY
spectroscopy, which indicated trans-9 was formed selectively
(for details, see the Supporting Information). Saponification
of the ester 9 with alcoholic potassium hydroxide followed
by acidification gave the corresponding acid, which was
decarboxylated upon heating in m-xylene, providing 4-phen-
yl-2-pyrrolidinone 10 without loss of enantiopurity. The
absolute configuration of 10 was determined to be R by
comparison of optical rotation with reported value (see the
Supporting Information). With 10 as material, the optically
active GABA 11 and the pyrrolidine 12 could be easily
prepared.9 Similarly, 3-(aminomethyl)-5-methylhexanoic acid
(pregabalin) and 3-(4-Cl-phenyl)-GABA (baclofen) could
also be easily synthesized starting from enantioenriched 6c
and 6q.
a Unless otherwise noted, reactions were carried out with 7d/Ti(O-i-
Pr)4/8b (1:1:1, 10 mol %), olefin (0.1 mmol), CNCOOEt (0.5 mmol), and
i-PrOH (0.5 mmol) at 0 °C for 72 h. b 8c was used instead of 8b for entries
15-18. c 0.1 mLof toluene was used as solvent. d Isolated yield. e Determined
by chiral HPLC. The absolute configuration was assigned by converting
4a to pyrrolidinone 10 and comparing its optical rotation with literature
value.
2-naphthaldehyde and 3-thienyl aldehyde also showed good
results (Table 2, entries 13 and 14). It is noteworthy that
when it came to the aliphatic substrates, the biphenol 8c
proved superior to 8b, giving the products with good ee
values (Table 2, entries 15-18).
Interestingly, according to our previous studies,4 when
cinchonine 7c or quinidine 7a was subjected to catalyst
preparation, the S configuration was selectively adopted by
the biphenol 8a to generate the complex 7a (or 7c)/Ti/(S)-
8a, whereas the R configuration was preferred when cin-
chonidine 7d was used, which was believed should also
happen in the current catalyst system. As expected, when
The synthetic utility of this methodology was then
investigated. It was reported by a resolution strategy that
(6) For the asymmetric cyanation of aldehydes and ketones with
CNCOOEt as cyanide source, see: (a) Tian, S. K.; Deng, L. J. Am. Chem.
Soc. 2001, 123, 6195. (b) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki,
M. Angew. Chem., Int. Ed. 2002, 41, 3636. (c) Tian, J.; Yamagiwa, N.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2003, 5, 3021. (d) Belokon, Y. N.;
Blacker, A. J.; Clutterbuck, L. A.; North, M. Org. Lett. 2003, 5, 4505. (e)
Belokon, Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L. A.; North, M.
Tetrahedron 2004, 60, 10433. (f) Yamagiwa, N.; Tian, J.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 3413. (g) Lundgren, S.;
Wingstrand, E.; Penhoat, M.; Moberg, C. J. Am. Chem. Soc. 2005, 127,
11592. (h) Belokon, Y. N.; Ishibashi, E.; Nomura, H.; North, M. Chem.
Commun. 2006, 1775. (i) Li, Q. H.; Chang, L.; Liu, X. H.; Feng, X. M.
Synlett 2006, 1675. (j) Gou, S. H.; Chen, X. H.; Xiong, Y.; Feng, X. M. J.
Org. Chem. 2006, 71, 5732. (k) Gou, S. H.; Wang, J.; Liu, X. H.; Wang,
W. T.; Chen, F. X.; Feng, X. M. AdV. Synth. Catal. 2007, 349, 343. (l)
Gou, S. H.; Liu, X. H.; Zhou, X.; Feng, X. M. Tetrahedron 2007, 63, 7935.
(m) Chen, S. K.; Peng, D.; Zhou, H.; Wang, L. W.; Chen, F. X.; Feng,
X. M. Eur. J. Org. Chem. 2007, 639. (n) Wang, W. T.; Gou, S. H.; Liu,
X. H.; Feng, X. M. Synlett 2007, 2875. (o) Belokon, Y. N.; Clegg, W.;
Harrington, R. W.; Ishibashi, E.; Nomura, H.; North, M. Tetrahedron 2007,
63, 9724. (p) Peng, D.; Zhou, H.; Liu, X. H.; Wang, L. W.; Chen, S. K.;
Feng, X. M. Synlett 2007, 2448. (q) Reference 4b.
(7) For the asymmetric cyanation of aldimines and ketimines with
CNCOOEt as cyanide source, see: Abell, J. P.; Yamamoto, H. J. Am. Chem.
Soc. 2009, 131, 15118, and reference 4b.
(8) When TMSCN was used as cyanide source, mono- and di-TMS
biphenol were detected by TLC in the reaction mixture. So as the reaction
proceeded, the catalyst might be partially decomposed. In contrast,
CNCOOEt was much less reactive than TMSCN to react with biphenol. In
fact, no ethoxyformate protected biphenol was observed. Therefore, it might
be one of the reasons for the fact that CNCOOEt gave better result. Also,
it could not be ruled out the possibility that different reaction pathway might
go for these two structurally total different cyanide sources.
(9) (a) Sobocinska, M.; Zobacheva, M. M.; Perekalin, V. V.; Kuprysze-
wski, G. Pol. J. Chem. 1979, 53, 435. (b) Zelle, R. Z. Synthesis 1991, 1023.
(c) Martinez, C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L.
Org. Process. Res. DeV. 2008, 12, 392.
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Org. Lett., Vol. 12, No. 6, 2010

(R)- or (S)-3,3′-di-2-naphthyl-1,1′-bi-2-naphthol was used
instead of the biphenol 8a in the catalyst (7d/Ti/8a) for the
cyanation of the olefin 4a, the (R)-isomer gave a better
result.10
In summary, asymmetric cyanation of a class of easily
available R,ꢀ-unsaturated carboxylic derivatives with a
favorable cyanide source (CNCOOEt) was realized by an
interesting modular titanium catalyst. High yields and ee
values were generally obtained for a range of substrates under
solvent-free and mild reaction conditions. Moreover, the
products could be easily transformed to many enantioen-
riched compounds of great synthetic utility and pharmaceuti-
cal importance. Compared with the previously reported
methodologies, the present protocol held its own merits with
regard to supplying key precursors for the GABA synthesis:
(1) R,ꢀ-unsaturated diester was potentially advantageous in
view of its low cost and facile availability/preparation;11 (2)
the cyanide source (CNCOOEt) employed herein was
relatively cheap and less toxic, which would benefit the
practical handling. Detailed mechanism studies and further
application of this catalyst system to other reactions are
underway.
Acknowledgment. We thank the National Natural Science
Foundation of China (Nos. 20732003 and 20872097), PC-
SIRT(No. IRT0846), and the Major State Basic Research
and Development Program (No. 2010CB833300) for finan-
cial support. We also thank Sichuan University Analytical
& Testing Center for NMR analysis.
(10) Reactions were carried out with cinchonidine 7d/Ti(O-i-Pr)4/(R)-
or (S)-3,3′-di-2-naphthyl-1,1′-bi-2-naphthol (1/1/1, 10 mol %) as catalyst,
olefin 4a (0.1 mmol), CNCOOEt (0.2 mmol), and i-PrOH (0.2 mmol) in
toluene (0.2 mL) for 45 h at 0 °C. Product 6a was obtained in 33% yield
with 91% ee for (R)-3,3′-di-2-naphthyl-1,1′-bi-2-naphthol and 23% yield
with 85% ee for (S)-enantiomer.
(11) R,ꢀ-Unsaturated diesters could be prepared in a single step by
Knoevenagel condensation of the corresponding aldehydes and diethyl
malonate, both of which were very cheap and easily available. In fact,
R,ꢀ-unsaturated diester has been employed as key intermediate for the large-
scale synthesis of (S)-(+)-3-isobutyl-GABA (pregabalin). However, due to
lack of efficient asymmetric method for the cyanation step, resolution
procedures were generally involved in these processes (see: reference 9c
and Silverman, R. B. Angew. Chem., Int. Ed. 2008, 47, 3500, and references
therein).
Supporting Information Available: Experimental details
and analytic data (NMR, HPLC, and ESI-HRMS). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100169R
Org. Lett., Vol. 12, No. 6, 2010
1283