A mild, chemoselective, one-pot synthesis of δ-keto α-cyano esters by organocatalysis

Article abstract of DOI:10.1016/j.tetlet.2013.10.145

A sequential condensation of α-cyano esters, aldehydes, and ketones with catalytic amount of pyrrolidine/HOAc at room temperature has been developed. This method offers a chemoselective, one-pot cascade access to δ-keto α-cyano esters with moderate to good yields under mild conditions.

Full text of DOI:10.1016/j.tetlet.2013.10.145

Tetrahedron Letters 55 (2014) 189–192
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A mild, chemoselective, one-pot synthesis of d-keto a-cyano esters
by organocatalysis
⇑
Gang Liu, Yingcai Wang
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A sequential condensation of
dine/HOAc at room temperature has been developed. This method offers a chemoselective, one-pot cas-
a-cyano esters, aldehydes, and ketones with catalytic amount of pyrroli-
Received 7 October 2013
Revised 28 October 2013
Accepted 29 October 2013
Available online 6 November 2013
cade access to d-keto -cyano esters with moderate to good yields under mild conditions.
a
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Keto-esters
One-pot synthesis
Organocatalysis
Condensation
Michael addition
d-Keto esters, as a class of 1,5-dicarbonyl compounds, are very
common, yet important synthetic intermediates, especially in ter-
penoid synthesis and d-lactone/lactam preparation.1 The classic
synthetic pathway (Scheme 1, pathway A) entails the disconnec-
tion leading to a malonate type synthon that functions as a highly
O
R1
O
O
R1
O
R1
O
R2
RO
RO
R3 = EWG
pathway A: two steps, strong bases, undesired self aldol condensations
R1
R2
H
O
R2
R3
R3
O
O
reactive nucleophile under basic conditions, and an
a,b unsatu-
O
R1
X
O
rated ketone as the corresponding electrophile.2 Retrosynthetical-
ly, the latter usually goes further back to an aldehyde and a
ketone by Claisen–Schmidt condensation.3,4
R2
RO
R2
RO
R2
R3
:
R3
O
X
R
3 = EWG
:
OM, OSi, NR2,
B
pathway
Another logically reasonable disconnection (Scheme 1, pathway
B) is the Michael addition of a ketone enolate, or the equivalent
thereof, to an alkylidene malonate type conjugate electrophile.
The principal challenge of pathway B lies in the generation of a
reactive yet selective nucleophile from ketones under mild condi-
tions. Formation of a ketone enolate (X = OM) normally requires
a strong base. This type of nucleophiles is highly reactive but not
selective. The 1,4 addition to conjugate electrophiles is compli-
cated with the addition to carbonyl groups of the conjugated sys-
tem (1,2 addition) and further addition to the keto groups of the
initial 1,4 addition products. Vinyl silyl ether or enamine formation
in a stoichiometric fashion is an alternative, mild way to activate
the ketones (X = OSi, NR2),5 however, it requires an extra step to
prepare these compounds from the corresponding ketones in addi-
tion to the preparation of the conjugate electrophile.
X=OM: strong bases, non-selective
A
R1
X
R1
O
=OSi, NR2: three steps
moisture sensitive
further activation needed
RO
O
RO
R3
R3
O
R1
O
O
O
O
R2
RO
RO
R1
H
R2
CN
CN
this work: catalytic, three components, two C-C bonds formed, mild conditions
Scheme 1. Pathways to d-keto ester synthesis.
the bond disconnection strategies in organic synthesis design.6
Enamine catalysis, as one of the major models of activation in
organocatalysis, provides a reversible and mild way to activate
In the past decade, organocatalysis has been brought to the
attention of synthetic chemists and has profoundly diversified
the
a-position of carbonyl compounds. Amine catalyzed Michael
addition, particularly, has attracted considerable attention
recently.7 The Michael acceptors are often confined to highly
reactive conjugated systems such as nitroalkenes and alkylidene
malonates. The Michael donors are mainly aldehydes and specific
⇑
Corresponding author. Tel.: +1 650 244 2231; fax: +1 650 837 9369.
E-mail address: yingcaiw@amgen.com (Y. Wang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.145

190
G. Liu, Y. Wang / Tetrahedron Letters 55 (2014) 189–192
ketones, that is cyclic aliphatic ketones and acetone.8 High levels of
enantioselectivity (up to 99% ee) have been reported on conjugate
addition of aldehydes or ketones to b-dimethyl(phenyl)silylmeth-
ylene malonate and trifluoroethylidene malonates.9
Along with our studies in multicomponent reactions to prepare
pyridones,10 we became interested to explore the preparation of d-
keto esters through a one-pot, three-component condensation of
ketones, aldehydes, and malonates (Scheme 1). Barbas’s group re-
ported that (S)-1-(2-pyrrolidinylmethyl)pyrrolidine catalyzed
three-component reaction of diethyl malonate, acetone, and benz-
aldehydes in moderate enantioselectivities.8c List and Castello re-
Table 1
Optimization of the reaction conditions
O
O
Ph
O
Ph
O
amine/acid
+
+
EtO
EtO
Ph
H
O
Ph
1 mmol
DMSO (0.2 mL)
CN
CN
1 mmol
1 mmol
5a
O
S
N
H
N
N
N
H
6c
N
H
6d
H
6a
6b
6e
ported that L-proline is efficient in catalyzing a three-component
Entrya
Amine (equiv)
Acid (equiv)
T (h)
Yieldb (%)
reaction between Meldrum’s acid, acetone (or cyclic ketones),
and a range of aldehydes.11 Herein we describe a pyrrolidine cata-
1
2
3
4
5
6
7
8
9
10
11
12
13
6a (0.3)
6b (0.3)
6c (0.3)
6d (0.3)
6e (0.3)
6a (0.3)
6a (0.3)
6a (0.3)
6a (0.3)
6a (0.3)
6a (0.3)
6a (0.2)
6a (0.2)
HOAc (0.3)
HOAc (0.3)
HOAc (0.3)
HOAc (0.3)
HOAc (0.3)
No acids
24
24
24
24
24
24
24
24
24
24
72
48
48
76
55
32
5
lyzed three component condensation of
a-cyano ethyl acetate with
a wide range of aldehydes and ketones.12
To realize the preparation of d-keto esters by amine catalyzed
addition of ketones to conjugated system, the choice of suitable
c
—
—
c
a,b unsaturated ester as the Michael acceptor is critical. The accep-
TFA (0.3)
45
69d
80e
tor must be electrophilic enough to ensure the reactivity, yet the
electrophilicity must also be maintained at a certain level so that
the amine catalyst would not be quenched by an azo-Michael addi-
tion to the Michael acceptor. At the outset of our study, failure was
encountered when alkylidenemalonate 1 was used as the substrate
with pyrrolidine/acetate salt as the catalysts in DMSO (Scheme 2).
Unsaturated ketone 4 was obtained as the major product, arising
from the retro Knoevenagel reaction and subsequent aldol-conden-
sation of benzyl ketone and benzaldehyde. Another candidate,
alkylidenemalononitrile 2, gave a very complex mixture, though
previously reported as a suitable Michael acceptor in a primary
amine catalyzed Michael addition reaction.8g Pleasingly, desired
product 5a was obtained when 3 was used as the Michael acceptor.
Furthermore, cyanoacrylate 3 could be prepared in situ, making
HOAc (0.3)
HOAc (0.3)
HOAc (0.3)
HOAc (0.3)
HOAc (0.2)
HOAc (0.2)
53f
85e
88e
92e,g
a
Condition: 1 mmol scale in 0.2 mL DMSO; amine was added slowly followed by
HOAc.
b
Values refer to isolated yields after column chromatography.
No desired product observed.
0.4 mL DMSO.
0.1 mL DMSO.
Neat condition.
c
d
e
f
g
2 equiv ketone was used.
this process an attractive method by which an aldehyde, an a-cy-
(6b–6d) are inferior to pyrrolidine (entries 2–4). Tertiary amine
6e was not capable of catalyzing this reaction at all (entry 5), pro-
ducing only ethyl 2-cyano-3-phenylacrylate as the Knoevenagel
condensation product along with unreacted acetophenone. The ab-
sence of an acid counterpart did not produce desired product (en-
try 6), and a stronger acid (TFA) did not help to improve the yield
(entry 7). Performing the reaction under more dilute conditions led
to decreased yield (entry 8), while running the reaction neat gave
only modest yield (entry 10). The optimal concentration was
ano ester, and a ketone are condensed sequentially to give the de-
sired d-ketoester with the formation of two C–C bonds under mild
conditions in a catalytic fashion.
Thus, when an equimolar mixture of
a-cyano ethyl acetate,
benzaldehyde, and acetophenone was added with 0.3 equiv of pyr-
rolidine and followed by 0.3 equiv of acetic acid, desired d-keto
product 5a was obtained with good yield (Table 1, entry 1). Further
screening of the amines showed that other secondary amines
O
CO2Et
(1 equiv.)
O
Ph
EtO2C
pyrrolidine (1 equiv.)
Ph
Ph
Ph
HOAc (1 equiv.)
DMSO
1
4
CN
same condition
same condition
NC
unidentified mixture
Ph
2
Ph
O
CO2Et
EtO2C
NC
Ph
Ph
CN
3
5a
Scheme 2. Identification of suitable Michael acceptors.

G. Liu, Y. Wang / Tetrahedron Letters 55 (2014) 189–192
191
Table 2
Synthesis of
With the optimized condition we then investigated the general-
ity of this method by expanding the substrate scope to both ali-
phatic and aromatic aldehydes and ketones (Table 2).
a
-cyano d-keto estersa,b
O
R1
O
O
O
R1
pyrrolidine (0.2 equiv.)
Aliphatic aldehydes are applicable to this method with modest
yields (5b–5d), while aromatic aldehyde gave excellent yields,
independent of the electronic nature of the substituents (5e–5h).
Aliphatic ketones with various substitutions also worked well
(5i–5l). When aromatic ketones were examined, it was found that
strong electron withdrawing substituent (5p) lowered the yield
considerably comparing to the electron donating substituents
(5m, 5o).
To demonstrate the scalability of this method, a gram scale syn-
thesis of ketoester 5q was executed (Scheme 3). A mixture of a-cy-
ano ester, 4-chloro benzaldehyde, and slightly excessive 4-chloro
acetophenone in DMSO was sequentially treated with a catalytic
amount of pyrrolidine and acetic acid. After stirring at ambient
temperature for 48 h, a clean product was obtained with excellent
yield following purification by Flash chromatography.13
+
+
EtO
R2
EtO
H
O
HOAc (0.2 equiv.)
DMSO, rt, 48h
R2
CN
CN
6
7
8
5
Cl
Ph
Ph
O
O
O
O
EtO2C
EtO2C
EtO2C
Ph
Ph
CN
CN
CN
5g,
5l,
69 %
O
5b,
92%
44%
CO2Me
O
Ph
EtO2C
EtO2C
Ph
Ph
EtO2C
EtO2C
CN
5m, 90%
CN
Ph
CN
5h, 93%
In summary, a catalytic, three-component condensation of an
5c,
50%
a
-cyano ester, an aldehyde, and a ketone has been realized by a
sequential Knoevenagel–Michael reaction under very mild condi-
tions. This method provides versatile access to d-keto -cyano es-
Ph
O
Ph
O
O
a
EtO2C
EtO2C
ters in a single step from simple, commercially available materials.
CN
CN
CN
5n, 95%
Cl
5i,
5d, 46%
76%
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.145. These data include MOL files and InChiKeys of the most
important compounds described in this article.
Ph
O
Ph
O
EtO2C
EtO2C
O
CN
EtO2C
CN
Ph
Ph
OMe
CN
5o
5j,
, 83%
80%
5e, 87%
References and notes
OMe
1. (a) Gawley, R. E. Synthesis 1976, 777; (b) Jung, M. E. Tetrahedron 1976, 32, 3; (c)
Brown, H. C.; Racheria, U. S.; Singh, S. M. Synthesis 1984, 922; (d) Duhamel, P.;
Hennequin, L.; Poirier, J. M.; Tavel, G.; Vottero, C. Tetrahedron 1986, 42, 4777.
2. (a) Warren, S. Designing Organic Syntheses: A Programmed Introduction to the
Synthon Approach; Wiley: New York, 1978; (b) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033.
3. For review, see: Heathcock, C. H. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Heathcock, C. H., Eds.; Pergamon Elsevier: Oxford, 1991; p 133.
Vol. 2.
Ph
O
Ph
O
EtO2C
EtO2C
O
EtO2C
CN
CN
5k, 65%
CO2Me
CN
5f,
5p, 61%
82%
4. For recent
a,b unsaturated ketone synthesis: (a) Wang, W.; Mei, Y.; Li, H.;
a
Condition: 1 mmol scale, pyrrolidine (0.2 equiv) was added followed by HOAc
Wang, J. Org. Lett. 2005, 7, 601; (b) Chimni, S. S.; Mahajan, D. Tetrahedron 2005,
61, 5019; (c) Yang, S. D.; Wu, L. Y.; Yan, Z. Y.; Pan, Z. L.; Liang, Y. M. J. Mol. Catal.
A 2007, 268, 107; (d) Zeidan, R. K.; Davis, M. E. J. Catal. 2007, 247, 379; (e) Cota,
I.; Gonzalez-Olmos, R.; Iglesias, M.; Medina, F. J. Phys. Chem. B 2007, 111,
12468; (f) Chi, Y.; Scroggins, S. T.; Boz, E.; Fréchet, J. M. J. J. Am. Chem. Soc. 2008,
130, 17287; (g) Zumbansen, K.; Doring, A.; List, B. Adv. Synth. Catal. 2010, 352,
1135.
(0.2 equiv), DMSO (0.1 mL), room temperature, 48 h.
Cl
5. (a) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am.
Chem. Soc. 1963, 85, 207; (b) Yamada, S.; Hiroi, K.; Achiwa, K. Tetrahedron Lett.
1969, 10, 4233; (c) Yamada, S.; Otani, G. Tetrahedron Lett. 1969, 10, 4237; (d)
Blarer, S. J.; Schweizer, W. B.; Seebach, D. Helv. Chim. Acta 1982, 65, 1637; (e)
Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. J. Am. Chem. Soc. 1990, 112,
7625.
Cl
pyrrolidine
(0.2 equiv.)
O
O
H
O
HOAc
(0.2 equiv.)
EtO2C
10 mmol
6. MacMillan, D. W. C. Nature 2008, 455, 304.
EtO2C
DMSO (1mL)
r.t. 48 h
7. For reviews on organocatalytic conjugate addition, see: (a) Almasi, D.; Alonso,
D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299; (b) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701.
CN
5q
3.63 g, 93%
Cl
CN
10 mmol
Cl
12 mmol
8. For examples of ketones and aldehydes addition to alkylidene malonate or
analogues thereof, see: (a) Betancort, J. M.; Sakthivel, K.; Thayummanavan, R.;
Barbas, C. F., III Tetrahedron Lett. 2001, 42, 4441; (b) Melchiorre, P.; Jørgensen, K.
A. J. Org. Chem. 2003, 68, 4151; (c) Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III Synthesis 2004, 1509; (d)
Wang, J.; Li, H.; Zu, L.; Wang, W. Adv. Synth. Catal. 2006, 348, 425; (e) Kojimaa,
S.; Suzukia, M.; Watanabea, A.; Ohkata, K. Tetrahedron Lett. 2006, 47, 9061; (f)
Zhao, G.-L.; Vesely, J.; Sun, J.; Christensen, K. E.; Bonneau, C.; Cordova, A. Adv.
Synth. Catal. 2008, 350, 657; (g) Yue, L.; Du, W.; Liu, Y.-K.; Chen, Y.-C.
Tetrahedron Lett. 2008, 49, 3881; (h) Liu, J.; Yang, Z.; Liu, X.; Wang, Z.; Liu, Y.;
Bai, S.; Lin, L.; Feng, X. Org. Biomol. Chem. 2009, 7, 4120; (i) Magar, D. R.; Chang,
C.; Ting, Y.-F.; Chen, K. Eur. J. Org. Chem. 2010, 2062.
Scheme 3. Gram scale synthesis of 5q.
highly concentrated to maintain the reaction a homogeneous mix-
ture (entry 9). After a brief survey of the reaction time and catalyst
loading, the optimal condition was identified (entry 12). It is note-
worthy that under this condition, an equimolar mixture of the
three components gave excellent yield, and two equivalents of ke-
tone gave only slightly higher yield under the optimized condition
(entry 13), which implies no large excess of ketone is needed to
drive the reaction to completion.
9. Examples for highly enantioselective enamine catalysis of ketone or aldehyde
addition to alkylidene malonates: (a) Chowdhury, R.; Ghosh, S. K. Org. Lett.
2009, 11, 3270; (b) Wen, L.; Shen, Q.; Lu, L. Org. Lett. 2010, 12, 4655.

192
G. Liu, Y. Wang / Tetrahedron Letters 55 (2014) 189–192
10. Wang, Y.; Liu, G.; Reyes, J. C. P.; Duverna, R. One-Pot Synthesis of 3-Cyano-2-
Pyridones, manuscript submitted to Tetrahedron, TET-D-13-01845.
11. List, B.; Castello, C. Synlett 2001, 1687.
12. Cyanoacrylates as Michael acceptor in amine catalyzed reactions have been
documented recently: (a) Wu, L.-Y.; Bencivenni, G.; Mancinelli, M.; Mazzanti,
A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7196; (b) Zhao, G.-
L.; Dziedzic, P.; Ullah, F.; Eriksson, L.; Cordova, A. Tetrahedron Lett. 2009, 50,
3458; (c) Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli, M.; Sambri, L.; Bartoli,
G.; Melchiorre, P. Chem. Eur. J. 2008, 14, 4788.
10 mmol), and 1-(4-chlorophenyl)ethanone (1.85 g, 12 mmol) in 1 mL of
DMSO were added pyrrolidine (142 mg, 2 mmol) and acetic acid (120 mg,
2 mmol). After stirring at ambient temperature for 48 h, the crude mixture,
without any work-up, was purified directly by medium pressure flash
chromatography using 0–30% EtOAc in hexanes to give ethyl 3,5-bis
(4-chlorophenyl)-2-cyano-5-oxopentanoate 5q as a colorless oil (3.63 g, 93%
yield). 1H NMR (500 MHz; DMSO-d6): d = 12.61 (br s, 2H), 8.22 (d, J = 0.9 Hz,
1H), 7.96 (d, J = 0.9 Hz, 1H), 7.82 (dd, J = 7.7, 1.9 Hz, 2H), 7.55–7.53 (m, 3H),
7.26 (s, 1H); 13C NMR (125 MHz; DMSO-d6): d = 162.6, 151.1, 150.2, 137.3,
134.6, 132.6, 130.9, 129.0, 127.4, 120.9, 117.7, 102.7, 93.1 ppm.
13. Representative procedure for the synthesis of
a-Cyano d-keto esters: To a mixture
of ethyl cyanoacetate (1.13 g, 10 mmol), 4-chlorobenzaldehyde (1.40 g,