Phase-transfer-catalyzed asymmetric conjugate cyanation of alkylidenemalonates with KCN in the presence of a Br?nsted acid additive

Article abstract of DOI:10.1021/ol400143m

Highly enantioselective conjugate cyanation of alkylidenemalonates with KCN was achieved under mild phase-transfer conditions with a bifunctional phase-transfer catalyst. The effect of Br?nsted acid additives was examined based on the hypothetical catalytic cycle, and the Br?nsted acid additive was found to be essential to promote the conjugate cyanation efficiently.

Full text of DOI:10.1021/ol400143m

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1230–1233
Phase-Transfer-Catalyzed Asymmetric
Conjugate Cyanation of
Alkylidenemalonates with KCN in the
Presence of a Brønsted Acid Additive
Yan Liu, Seiji Shirakawa, and Keiji Maruoka*
Laboratory of Synthetic Organic Chemistry and Special Laboratory of Organocatalytic
Chemistry, Department of Chemistry, Graduate School of Science, Kyoto University,
Sakyo, Kyoto 606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received January 17, 2013
ABSTRACT
Highly enantioselective conjugate cyanation of alkylidenemalonates with KCN was achieved under mild phase-transfer conditions with a
bifunctional phase-transfer catalyst. The effect of Brønsted acid additives was examined based on the hypothetical catalytic cycle, and the
Brønsted acid additive was found to be essential to promote the conjugate cyanation efficiently.
Asymmetric conjugate cyanation of R,β-unsaturated
carboxylic acid derivatives offers an efficient synthetic
method for chiral β-substituted γ-aminobutyric acids
(GABA),1 which are an important class of pharmaceutical
compounds. Hence, the development of efficient asym-
metric conjugate cyanation of R,β-unsaturated carbonyl
compounds is an important task for organic chemistry.2
Although several catalytic asymmetric cyanations of R,β-
unsaturated carbonyl compounds have recently been
developed using HCN,3 TMSCN,4 ethyl cyanoformate,5
and acetone cyanohydrin6 as cyanide sources, further
advances in practical methods for the asymmetric trans-
formation are still highly desirable. In this context, we
are interested in the development of the phase-transfer-
catalyzed7 asymmetric conjugate cyanation of alkylidene-
malonates 1 with KCN8 as one of the most economical and
(6) (a) Provencher, B. A.; Bartelson, K. J.; Liu, Y.; Foxman, B. M.;
Deng, L. Angew. Chem., Int. Ed. 2011, 50, 10565. (b) Kawai, H.; Okusu,
S.; Tokunaga, E.; Sato, H.; Shiro, M.; Shibata, N. Angew. Chem., Int.
Ed. 2012, 51, 4959.
(7) For recent reviews on asymmetric phase-transfer catalysis, see:
(a) O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3. (b) Maruoka, K.;
Ooi, T. Chem. Rev. 2003, 103, 3013. (c) O’Donnell, M. J. Acc. Chem. Res.
2004, 37, 506. (d) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
(e) Vachon, J.; Lacour, J. Chimia 2006, 60, 266. (f) Ooi, T.; Maruoka, K.
Angew. Chem., Int. Ed. 2007, 46, 4222. (g) Ooi, T.; Maruoka, K.
Aldrichimica Acta 2007, 40, 77. (h) Hashimoto, T.; Maruoka, K. Chem.
Rev. 2007, 107, 5656. (i) Maruoka, K. Org. Process Res. Dev. 2008, 12,
679. (j) Jew, S.-s.; Park, H.-g. Chem. Commun. 2009, 7090. (k) Maruoka,
K. Chem. Rec. 2010, 10, 254.
(8) (a) Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern,
T. A.; Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin,
L. C.; Granger, E. J.; Karrick, G. L. Org. Process Res. Dev. 1997, 1, 26.
(b) Silverman, R. B. Angew. Chem., Int. Ed. 2008, 47, 3500. (c) Martinez,
C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L. Org. Process
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(1) (a) Roberts, E. Biochem. Pharmacol. 1974, 23, 2637. (b) Sytinsky,
I. A.; Soldatenkov, A. T.; Lajtha, A. Prog. Neurobiol. 1978, 10, 89. (c)
Sivilotti, L.; Nistri, A. Prog. Neurobiol. 1991, 36, 35.
(2) For a review on stereoselective synthesis of γ-amino acids, see:
ꢀ~
Ordonez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3.
(3) Kurono, N.; Nii, N.; Sakaguchi, Y.; Uemura, M.; Ohkuma, T.
Angew. Chem., Int. Ed. 2011, 50, 5541.
(4) (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) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 514. (d) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.;
Sato, A.; Furusho, S.; Kanai, M.; Shibasaki, M. Tetrahedron 2007,63, 5820.
(e) Mazet, C.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2008, 47, 1762. (f)
Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072.
(g) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132,
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r
10.1021/ol400143m
Published on Web 03/05/2013
2013 American Chemical Society

practical cyanide sources (Scheme 1).9 Here we report the
first example of highly enantioselective conjugate cyana-
tion with KCN under phase-transfer conditions.10
slow reaction rate for this conjugate cyanation (Figure 1, left
cycle).12,13
Scheme 1. Phase-Transfer-Catalyzed Conjugate Cyanation of
Alkylidenemalonate for the Synthesis of GABA
Figure 1. Hypothetical catalytic cycle of the phase-transfer-
catalyzed conjugate cyanation in the presence and absence of
a Brønsted acid additive.
In initial attempts of the phase-transfer-catalyzed con-
jugate cyanation in Scheme 1, we have observed a slow rate
of reaction with a catalytic amount of chiral phase-transfer
catalyst (∼2 mol %).11 This slow reaction rate is attributed
to the slow regeneration step of ammonium cyanide
(R4NþCNꢀ). That is to say, the ammonium salt of the
Based on this hypothesis, we examined the effect of
Brønsted acid additives13 in the asymmetric conjugate
cyanation of alkylidenemalonate 1a with KCN under the
influence of chiral bifunctional phase-transfer catalyst
(S)-3a (2 mol %)14,15 in cyclopentaneꢀH2O biphasic con-
ditions16 (Scheme 2). In the absence of a Brønsted acid
additive, the reaction proceeded very sluggishly and only a
trace amount of cyanation product 2a was obtained. On
the other hand, the reaction with anequimolar amountof a
Brønsted acid additive, such as NH4Cl, HCl, or AcOH,
proceeded smoothly, and cyanation product 2a was pro-
duced in good yields (80ꢀ86%) with high enantioselectiv-
ities (88ꢀ90% ee). Reduction of the amount of Brønsted
acid additive (0.2 equiv) caused a decrease in yields
(26ꢀ34% yields). It should be noted that the use of
TMSCN, which generates HCN in the presence of H2O,
as a cyanide source instead of KCN completely shuts off
the reaction. This result indicates that the use of KCN as a
cyanide source is essential to promote the present phase-
transfer-catalyzed conjugate cyanation.
adduct 2 (20 NR4þ) as a result of the conjugate cyanation
3
with ammonium cyanide (R4NþCNꢀ) and alkylidenema-
lonate 1 is relatively stable under the reaction conditions,
and the subsequent step of 20 NR4þ with KCN seems to be
3
relatively slow for the regeneration of the ammonium cya-
nide (R4NþCNꢀ) (Figure 1, right cycle). From this assump-
tion, we expected that addition of a Brønsted acid (HX) as a
proton source might be helpful for the acceleration of the
(9) For catalytic asymmetric cyanation of aldehydes and imines with
ꢀ
KCN, see: (a) Julia, S.; Ginebreda, A. Tetrahedron Lett. 1979, 20, 2171. (b)
Belokon, Y. N.; Carta, P.; Gutnov, A. V.; Maleev, V.; Moskalenko, M. A.;
Yashkina, L. V.; Ikonnikov, N. S.; Voskoboev, N. V.; Khrustalev, V. N.;
North, M. Helv. Chim. Acta 2002, 85, 3301. (c) Belokon, Y. N.; Gutnov,
A. V.; Moskalenko, M. A.; Yashkina, L. V.; Lesovoy, D. E.; Ikonnikov,
N. S.; Larichev, V. S.; North, M. Chem. Commun. 2002, 244. (d) Belokon,
Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L. A.; North, M. Tetrahedron
2004, 60, 10433. (e) Huang, W.; Song, Y.; Wang, J.; Cao, G.; Zheng, Z.
Tetrahedron 2004, 60, 10469. (f) Huang, W.; Song, Y.; Bai, C.; Cao, G.;
Zheng, Z. Tetrahedron Lett. 2004, 45, 4763. (g) Ooi, T.; Uematsu, Y.;
Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2548. (h) Khan, N.-u. H.;
Agrawal, S.; Kureshy, R. I.; Abdi, S. H. R.; Mayani, V. J.; Jasra, R. V. Eur.
J. Org. Chem. 2006, 3175. (i) Belokon, Y. N.; Clegg, W.; Harrington,
R. W.; Young, C.; North, M. Tetrahedron 2007, 63, 5287. (j) Ooi, T.;
Uematsu, Y.;Fujimoto, J.;Fukumoto,K.;Maruoka, K. Tetrahedron Lett.
(13) For asymmetric phase-transfer reactions with Brønsted acid
additives, see: (a) Ooi, T.; Kameda, M.; Taniguchi, M.; Maruoka, K.
J. Am. Chem. Soc. 2004, 126, 9685. (b) Lygo, B.; Beynon, C.; Lumley, C.;
McLeod, M. C.; Wade, C. E. Tetrahedron Lett. 2009, 50, 3363.
€
2007, 48, 1337. (k) Reingruber, R.; Baumann, T.; Dahmen, S.; Brase, S.
Adv. Synth. Catal. 2009, 351, 1019. (l) Khan, N.-u. H.; Sadhukhan, A.;
Maity, N. C.; Kureshy, R. I.; Abdi, S. H. R.; Saravanan, S.; Bajaj, H. C.
Tetrahedron 2011, 67, 7073. (m) Yan, H.; Oh, J. S.; Lee, J.-W.; Song, C. E.
Nat. Commun. 2012, 3, DOI: 10.1038/ncomms2216.
(10) For phase-transfer-catalyzed asymmetric conjugate cyanation
using KCN with modest enantioselectivities, see: Davies, B. S.; Guzman,
M. M.; Martinez, C. A.; McDaid, P. O.; O’Neill, P. M.; Shanmugam, E.
WO 2010070593, 2010.
(11) Various types of binaphthyl-modified chiral phase-transfer cat-
alysts developed in our group (see ref 7), such as commercially available
(S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho-
[2,1-c:10,20-e]azepinium bromide (Simplified Maruoka Catalyst), were
examined in asymmetric conjugate cyanation in Scheme 2 without
Brønsted acid additive. The reactions proceeded very sluggishly, and only
a trace amount of cyanation product was obtained.
(12) For a study on the effect of Brønsted acid additives in organo-
catalyzed asymmetric conjugate addition, see: Patora-Komisarska, K.;
Benohoud, M.; Ishikawa, H.; Seebach, D.; Hayashi, Y. Helv. Chim. Acta
2011, 94, 719.
(14) For examples of chiral bifunctional phase-transfer catalysts, see:
(a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
1984, 106, 446. (b) Loupy, A.; Zaparucha, A. Tetrahedron Lett. 1993, 34,
473. (c) Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J. Am. Chem. Soc.
2004, 126, 6844. (d) Liu, Y.; Provencher, B. A.; Bartelson, K. J.; Deng, L.
Chem. Sci. 2011, 2, 1301. (e) Ohmatsu, K.; Kiyokawa, M.; Ooi, T. J. Am.
Chem. Soc. 2011, 133, 1307. (f) Johnson, K. M.; Rattley, M. S.;
~
Sladojevich, F.; Barber, D. M.; Nunez, M. G.; Goldys, A. M.; Dixon,
D. J. Org. Lett. 2012, 14, 2492.
(15) (a) He, R.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc. 2009,
131, 16620. (b) Wang, X.; Lan, Q.; Shirakawa, S.; Maruoka, K. Chem.
Commun. 2010, 46, 321. (c) Wang, L.; Shirakawa, S.; Maruoka, K.
Angew. Chem., Int. Ed. 2011, 50, 5327. (d) Shirakawa, S.; Terao, S. J.;
He, R.; Maruoka, K. Chem. Commun. 2011, 47, 10557. (e) Shirakawa, S.;
Ota, K.; Terao, S. J.; Maruoka, K. Org. Biomol. Chem. 2012, 10, 5753.
(16) The reaction in cyclopentaneꢀH2O gave the best result in terms
of enantioselectivity.
Org. Lett., Vol. 15, No. 6, 2013
1231

Table 1. Optimization of Reaction Conditionsa
Scheme 2. Effect of Brønsted Acid Additives
Based on these observations, we further optimized the
reaction conditions (Table 1). A change of the alkyl group
(R2) on the nitrogen of the catalyst from (S)-3a (R2 = Me)
to (S)-3b and (S)-3c15 caused a decrease in both reactivities
and enantioselectivities (entries 2 and 3). Importantly,
hydroxy-protected catalyst (S)-3d (R1 = R2 = Me) gave
the product 2a with low enantioselectivity (30% ee,
entry 4). This result indicates that the bifunctional design
of catalyst (S)-3a is essential to achieve high enantioselec-
tivity in this reaction. The importance of the hydroxy
group in catalyst (S)-3a was further supported by X-ray
diffraction analysis of the related ammonium iodide (S)-3e
(Figure 2).17 The hydrogen-bonding interaction between
the hydroxy group and counteranion (Iꢀ) is clearly ob-
served in the crystal structure of (S)-3e, and hence it is
assumed that the position of the cyanide anion in ammo-
nium cyanide derived from (S)-3a is fixed by the hydrogen
bond.
temp
time
(h)
yield
(%)b
ee
entry
catalyst
R0
(°C)
(%)c
1
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3ae
(S)-3a
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
Et
rt
rt
rt
rt
rt
rt
0
8
86
15
59
51
81
82
68
86
64
64
71
90
4
2
72
72
24
0.5
0.5
24
10
72
96
24
3
0
4
30
87
76
93
92
95
91
93
5
6
7
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
8d
9
0
ꢀ10
0
10
11f
0
a Reaction conditions: 1a (0.050 mmol), KCN (0.10 mmol), and
NH4Cl (0.050 mmol) in the presence of (S)-3 (2 mol %) in cyclopentane
(2 mL)/H2O (0.1 mL). b Yield of isolated products. c Determined by
chiral HPLC analysis. d HCl was used instead of NH4Cl. e Reaction
was performed with 0.2 mol % of (S)-3a. f NaCN was used instead
of KCN.
Switching the alkyl group of the ester moiety in the
alkylidenemalonate from tert-butyl to isopropyl and
ethyl gave the products 2aa (R0 = i-Pr) and 2ab (R0 = Et)
in good yields with slightly lower enantioselectivities
(76ꢀ87% ee, entries 5 and 6). Lower reaction temperatures
increased the enantioselectivities slightly (entries 7ꢀ9),
and the highest enantioselectivity was attained at ꢀ10 °C
(95% ee, entry 9). A decrease of the catalyst loading to
0.2 mol % still gave the product 2a in acceptable yield
(64%) with high enantioselectivity (91% ee, entry 10). The
reaction with NaCN gave comparable results with the use
of KCN (compare entries 11 and 7).
Withoptimal reactionconditionsinhand, westudiedthe
substrategenerality of the asymmetricconjugatecyanation
of alkylidenemalonates 1 with KCN and a Brønsted acid
additive (NH4Cl or HCl) in the presence of chiral bifunc-
tional catalyst (S)-3a under the biphasic phase-transfer
conditions(Table2). Varioustypesofalkylidenemalonates
1 were found to be employable for the reactions. The
reactionsofalkylidenemalonates1withsimplealkylchains
gave the corresponding cyanation products 2aꢀd in high
Figure 2. X-ray crystal structure of (S)-3e.
enantioselectivities (88ꢀ93% ee, entries 1ꢀ6). The alkyli-
denemalonates 1 possessing functional groups were also
employable for the reaction to give the corresponding
products 2eꢀg in high enantioselectivities (88ꢀ91% ee,
entries 7ꢀ11). The cyanation with phenyl-substituted al-
kylidenemalonate 1 (R = Ph) gave the product 2h in
moderate enantioselectivity (entry 12).
(17) The crystal structure of (S)-3e has been deposited at the Cambridge
Crystallographic Data Centre (CCDC 911649). The data can be obtained
free of charge via the Internet at www.ccdc.cam.ac.uk/data_request/cif.
The synthetic utility of cyanation product 2f with a chloride
functional group was demonstrated in the intramolecular
1232
Org. Lett., Vol. 15, No. 6, 2013

Table 2. Asymmetric Conjugate Cyanation of
Alkylidenemalonate 1 with KCNa
Scheme 3. Transformation of the Cyanation Product 2f
In summary, we have successfully developed a highly
enantioselective conjugate cyanation of alkylidenemalo-
nates with KCN in the presence of a chiral bifunctional
ammonium bromide under biphasic phase-transfer condi-
tions. The effect of Brønsted acid additives such as NH4Cl
and HCl was examined based on the hypothetical catalytic
cycle, and we found that such an additive is essential to
promote the conjugate cyanation efficiently.
entry
R
additive time (h) yield (%)b ee (%)c
1
(CH3)2CHCH2
NH4Cl
HCl
24
10
36
12
24
24
12
12
8
68 (2a)
86 (2a)
74 (2b)
76 (2b)
76 (2c)
70 (2d)
64 (2e)
75 (2e)
74 (2f)
72 (2f)
84 (2g)
34 (2h)
93
92
92
92
89
88
90
90
90
91
88
50
2
(CH3)2CHCH2
3
Me
NH4Cl
HCl
4
Me
5d
6d
7
Et
HCl
Ph(CH2)2CH2
HCl
CH2dCHCH2CH2 NH4Cl
CH2dCHCH2CH2 HCl
8
9
Cl(CH2)2CH2
Cl(CH2)2CH2
TBSO(CH2)2CH2
Ph
NH4Cl
HCl
Acknowledgment. This work was partially supported
by a Grant-in-Aid for Scientific Research from JSPS and
MEXT (Japan). We are grateful to Dr. Hiroyasu Sato
(Rigaku Corporation) for X-ray crystallographic analysis.
10
11
12
8
HCl
12
48
HCl
a Reaction conditions: 1 (0.050 mmol), KCN (0.10 mmol), and
NH4Cl or HCl (0.050 mmol) in the presence of (S)-3a (2 mol %) in cyclo-
pentane (2 mL)/H2O (0.1 mL) at 0 °C. b Yield of isolated products. c Deter-
mined by chiral HPLC analysis. d Reaction was performed at ꢀ10 °C.
Supporting Information Available. Experimental de-
tails, characterization data for new compounds, and
crystallographic data (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
cyclization to give product 4 as a useful chiral building
block (Scheme 3).
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
1233