Diamine-catalyzed conjugate addition to acrylate derivatives

Article abstract of DOI:10.1021/ol201013x

Diamines were found to promote catalytic conjugate addition of α-cyano active methine nucleophiles to various acrylate derivatives.

Full text of DOI:10.1021/ol201013x

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2948–2951
Diamine-Catalyzed Conjugate Addition to
Acrylate Derivatives
Benny Meng Kiat Tong and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received April 16, 2011
ABSTRACT
Diamines were found to promote catalytic conjugate addition of R-cyano active methine nucleophiles to various acrylate derivatives.
Conjugate addition of carbon nucleophiles to electron-
deficient CdC bonds is one of the most essential carbonꢀ
carbon bond forming reactions in organic synthesis.1
Recently, catalytic use of artifically functionalized organic
amines such as cinchona alkaloid and R-amino acid deri-
vatives has been extensively studied for asymmetric con-
jugate addition reactions.2 Although R,β-unsaturated
aldehydes and ketones3 as well as vinyl sulfones4 and
nitroalkenes2e,5 are commonly employed as an electrophile
in the organic amine-catalyzed conjugate addition, utiliza-
tion of R,β-unsaturated acid derivatives, especially, simple
acrylates, is much more unprecedented.6ꢀ8 This is attrib-
uted mainly to the less electrophilic nature of acrylates and
the fact that they could not form an iminium ion bearing a
lower LUMO energy by the reaction with amino catalysts.
Therefore, analternative approach thatpossesses a distinct
activating function towardboth acrylates and nucleophiles
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Sun, B.; Wang, B.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131,
418. (b) Zu, L.; Wang, J.; Li, H.; Xie, H.; Jiang, W.; Wang, W. J. Am.
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J. Am. Chem. Soc. 2006, 128, 9413. (d) Hoashi, Y.; Okino, T.; Takemoto,
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(a) Li, X.; Luo, S.; Cheng, J.-P. Chem.;Eur. J. 2010, 16, 14290. (b)
Wang., B.; Wu, F.; Wang, Y.; Liu, X.; Deng., L. J. Am. Chem. Soc. 2007,
129, 768. (c) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128,
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(9) For selected reports on phase transfer catalyzed conjugate addi-
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Maruoka, K. Org. Lett. 2009, 11, 2023. (b) Arai, S.; Takahashi, F.; Tsuji,
R.; Nishida, A. Heterocycles 2006, 67, 495. (c) Akiyama, T.; Hara, M.;
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Shibasaki, M. Tetrahedron Lett. 2002, 43, 9539. (e) Corey, E. J.; Noe,
M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347.
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H.; Deng, L. Tetrahedron 2009, 65, 3139. (c) Zhu, Q.; Cheng, L.; Lu, Y.
Chem. Commun. 2008, 6315.
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Mar Sanchez Duque, M.; Bonne, D.; Constantieux, T.; Rodriguez, J.
Org. Lett. 2010, 12, 5246. (b) Xiao, J.; Xu, F.-X.; Lu, Y.-P.; Loh, T.-P.
Org. Lett. 2010, 12, 1220. (c) Rodriguez-Llansola, F.; Miravet, J. F.;
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Escuder, B. Chem.;Eur. J. 2010, 16, 8480. (d) Aleman, J.; Milelli, A.;
Cabrera, S.; Reyes, E.; Jørgensen, K. A. Chem.;Eur. J. 2008, 14, 10958.
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r
10.1021/ol201013x
Published on Web 05/05/2011
2011 American Chemical Society

would be needed for the conjugate addition to acrylate
derivatives.9 Herein, we report the catalytic reactivity of
diamines to promote the conjugate addition of R-cyano
active methine nucleophiles to various acrylate derivatives.
To achieve the conjugate addition of carbon nucleophiles
to acrylates, we planned to use diamines as a catalyst
where the amines could be oriented in such a way as
to cooperatively bind a single proton from the prenucleo-
phile. It was speculated that the acidꢀbase complex gener-
ated from the prenucleophile (NuꢀH) and the diamine base
could activate acrylates electrophilically via multihydrogen
bonding10 that would result in efficient assembly of the
prenucleophile and the acrylate followed by smooth con-
jugate addition and consecutive protonation (Scheme 1).
Table 1. Diamine-Catalyzed Conjugate Addition of 2-Methyl-
malononitrile (1a) and Ethyl 2-Azidoacrylate (2a)a
Scheme 1. A Working Hypothesis
Based on this hypothesis, we embarked on the investiga-
tion of conjugate addition reactions of 2-methylmalononi-
trile (1a) and ethyl 2-azidoacrylate (2a)11,12 with various
organic diamines to target R-azido ester derivatives, which
could be utilized as a potential precursor for R-amino
acids13 (Table 1). As expected, 1,2-diaminocyclohexanes
AꢀC exhibited remarkable catalytic reactivity to the con-
jugate addition at 0 °C, affording ethyl 2-azido-4,4-dicya-
nopentanoate (3aa) in good yields (Table 1, entries 1ꢀ3).
Other types of diamines were next examined (entries 4ꢀ10).
Among ethylenediamine derivatives (entries 4ꢀ8), the
reaction with N,N0-dimethylethylenediamine (DMEDA)
E was the most efficient (87% yield, entry 5), whereas that
with N,N,N0,N0-tetramethylethylenediamine (TMEDA) H
bearing two tertiary amine motifs was sluggish (entry 8).
It was noteworthy that utilization of propane-1,3-diamine
I led to a remarkable promotion in the reaction effeciency,
resulting in the formation of 3aa in 98% yield within 4 h
(entry 9), while butane-1,4-diamine J led to a reduction in
the yield (entry 10). In the presence of triethylenetetramine
K, the reaction was finished within 0.5 h, whereas the yield
of 3aa was moderate (entry 11). trans-1,2-Diaminocy-
a Reactions were carried out on the scale of 0.5 mmol of 1a and 1.5
equiv of 2a in toluene (1 mL) at 0 °C under a N2 atmosphere. b Isolated
yields. c Recovery yields of 1a. d A racemic form was utilized.
clohexane-derived primary amine thiourea L (called as
bifunctional thiourea) did not promote the reaction, pro-
viding 3aa only in 28% yield even after 10 days (entry 12).
The reactions with a series of alkyl monoamines as well as
aryl amines such as aniline, 1,2-diaminobenzene, and 1,8-
diaminonaphthalene resulted in no reaction.
By utilizing organic diamines as a base, we surveyed a
variety of prenucleophiles for the conjugate addition to
ethyl 2-azidoacrylate (2a), and Table 2 lists the best diamine
catalyst for each nucleophile.14 As a substituent at C2 of
malononitirile, benzyl, phenyl, and allyl moieties could be
introduced (entries 1ꢀ3). In the case of 2-propargylmalo-
nonitrile (1e), the desired conjugate addition was followed
by intramolecular azideꢀalkyne cycloaddition to form
bicyclic 1,2,3-triazole 4ea in moderate yield in a one-pot
fashion (entry 4). The reaction of malononitrile bearing an
ethyoxycarbonyl functionality 1f proceeded smoothly to
(10) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(11) For our reports on synthesis of azaheterocycles from vinyl
azides, see: (a) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131,
12570. (b) Wang, Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K. Org. Lett.
2008, 10, 5019. (c) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K.
Org. Lett. 2008, 10, 313.
(12) For a report on conjugate addition of alcoholates and thiolates to
ethyl 2-azidoacrylate (2a) under strong basic conditions, see: Kakimoto,
M.; Kai, M.; Kondo, K.; Hiyama, T. Chem. Lett. 1982, 527.
(13) (a) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584. (b)
Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013.
(14) Optimization of the reaction conditions by varying diamine
catalysts has been done for each nucleophile in combination with 2a;
see Supporting Information.
Org. Lett., Vol. 13, No. 11, 2011
2949

Table 2. Diamine-Catalyzed Conjugate Addition to Ethyl
2-Azido Acrylate (2a)a
Table 3. 1,2-Diamine-Catalyzed Conjugate Addition of
2-Methylmalononitrile (1a) to Various Acrylates 2a
a Reactions were carried out on the scale of 0.5 mmol of 1 and 1.5
equiv of vinyl azide 2a in toluene (1 mL) at 0 °C under a N2 atmosphere.
b Isolated yields. c The reaction mixture was stirred at 0 °C until 1e
was consumed, before being heated at 40 °C for 10 h. d Diastereomer
ratio determined by 1H NMR. The relative stereochemistry was not
confirmed.
a Reactions were carried out on the scale of 0.5 mmol of 1a and 1.5
equiv of 2a in toluene (1 mL) at 0 °C under a N2 atmosphere. b Isolated
yields.
yield was shown for each acrylate in Table 3.16,17 As
2-aminoacrylates, methyl 2-phthalimidoacrylate (2b)18
and ethyl 2-acetoamidoacrylate (2c)19 were examined in-
stead of 2-azidoacrylate 2a for the synthesis of R-amino
acid derivatives. The reaction of 2-phthalimidoacrylate 2b
catalyzed by primary amine catalysts, ethylenediamine D,
provided conjugate addition product 3ab in good yield
(entry 1), whereas, in the case of 2-acetoamidoacrylate
(2c), the yields of conjugate addition product 3ac were
moderate (entry 2). Ethyl 2-bromoacrylate (2d) reacted
with 1a to give R-bromo ester 3ad in 96% yield with
propane-1,3-diamine I (entry 3). Ethyl 2-phenylacrylate
give corresponding R-azido ester 3fa in exellent yields
(entry 5). Methyl 2-cyano-2-phenylacetate (1g) could also
be utilized for this catalytic conjugate addition, providing
3ga in good yields albeit with an almost 1:1 diastereoselec-
tivity and a longer reacton time (25 h) (entry 6).15
Next, diamine-catalyzed conjugate additions of 2-methyl-
malononitrile (1a) to a series of acrylate derivatives were
investigated, and the diamine catalyst realizing the best
(15) The reactions of malononitrile were complicated by the forma-
tion of di- and monoalkylated products as well as polymelization of
acyrylate derivatives so that 2-substituted malononitriles and their
derivatives were utilized for this study. Nucleophiles derived from 1,3-
diketones and malonate esters resulted in no reaction under the present
reaction conditions.
(16) Optimization of the reaction conditions by varying diamine
catalysts has been done for each acrylate in combination with 1a; see
Supporting Information.
(17) An experimental procedure: Diamine (20 mol%) was added to a
mixture of acrylates (0.75 mmol, 1.5 equiv) and a prenucleophile
(0.5 mmol) in toluene (1 mL, 0.5 M) at 0 °C. The mixture was stirred
under a N2 atmosphere at 0 °C. Upon completion indicated by TLC,
toluene was removed under reduced pressure and the crude mixture was
subjected to column chromatography to yield conjugate addition
products.
(18) For a report on enantioselective protonation of 2-phthalimidoa-
crylate (2b) by the reaction with thiols catalyzed by a chiral bicyclic
guanidine, see: Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H.
Angew. Chem., Int. Ed. 2008, 47, 5641.
(19) For a report on an NHC-catalyzed enantioselective Stetter
reaction of ethyl 2-acetoamidoacrylate (2c), see: Jousseaume, T.; Wurz,
N. E.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1410.
(20) For a report of conjugate addition of malonates to methyl
acrylate under the Et3NꢀLiClO4 catalyst system, see: Saidi, M. R.;
Azizi, N.; Akbari, E.; Ebrahimi, F. J. Mol. Catal. A: Chem. 2008, 292, 44.
(21) For reviews on enantioselective protonation, see: (a) Mohr, J. T.;
Hong, A. Y.; Stoltz, B. M. Nat. Chem. 2009, 1, 359. (b) Duhamel, L.;
Duhamel, P.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2004, 15, 3653.
2950
Org. Lett., Vol. 13, No. 11, 2011

We finally explored a possibility for the construction of
an R-chiral center in the conjugate addition of 2-methyl-
malononitrile (1a) toethyl 2-phenylacrylate (2e) by using a
series of chiral diamine catalysts (MꢀR) as shown in
Scheme 2.21 It was found that several chiral diamines such
as (1R,2R)-1,2-diphenyl-1,2-ethanediamine (N) and (S)-
2-(N-aminomethyl)pyrrolidines (O and P) provided low
but reproducible enantioselectivities (5ꢀ8% ee). Interest-
ingly, C2-symmetric bisprolinamide Q22 showed reverse
chiral induction (ꢀ8% ee). The reaction with diamine R
derived from quinidine23 was very sluggish. Although the
obtained enantioselectivity was not practically valuable
yet, these results might uphold the working hypothesis
depicted in Scheme 1 including a certain interaction of
the prenucleophile (NuꢀH) and the acrylate through
the acidꢀbase complex of the prenucleophile and the
diamine base.
Scheme 2. Enantioselective Induction Using Chiral Diaminesa
In summary, we have developed a diamine-catalyzed
intermolecular conjugate addition of R-cyano active methine
nucleophiles to various acrylate derivatives. Further investi-
gation on the detailed reaction mechanism and reaction scope
as well as rational design of the catalysts based on the diamine
functionality for enhancing enantio- and diastereoselectivity
is currently underway and will be reported in due course.
a Reactions were carried out on the scale of 0.5 mmol of 1a and 1.5
equiv of 2a in toluene (1 mL) at 0 °C under a N2 atmosphere. Isolated
yields.
(2e) resulted in a smooth reaction with 1a, giving R-phenyl
ester 3ae in excellent yield (entry 4). It was found that
β-substituents retarded the conjugate addition. For exam-
ple, the reaction of ethyl crotonate (2f) was sluggish,
providing ethyl 4,4-dicyano-3-methylpentanoate (3af) in
26% yield even after 7 days (entry 5). Finally, conjugate
addition of 1a to ethyl acrylate (2g) was tested,20 where
propane-1,3-diamine I could complete the reaction within
3 h, leading to the formation of 3ag in almost quantitative
yields (entry 6).
Acknowledgment. This work was supported by funding
from Nanyang Technological University and Singapore
Ministry of Education (Academic Research Fund Tier 2:
MOE2010-T2-1-009). We thank Prof. Guofu Zhong
(Nanyang Technological University) and Prof. Choon
Hong Tan (National University of Singapore) for their
helpful suggestions to the present work.
Supporting Information Available. Experimental pro-
cedures, characterization of new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(22) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G. Org. Lett. 2005, 7,
5321.
(23) Brunner, H.; Bugler, J.; Nuber, B. Tetrahedron: Asymmetry
1995, 6, 1699.
Org. Lett., Vol. 13, No. 11, 2011
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