Organocatalytic tandem three-component reaction of aldehyde, alkyl vinyl ketone, and amide: One-pot syntheses of highly functional alkenes

Article abstract of DOI:10.1039/c0ob00644k

An EtPPh₂- or PPh₃-catalyzed tandem three-component reaction of aldehyde, alkyl vinyl ketone, and amide is developed. Its further application in one-pot syntheses of highly functional alkenes starting from aldehydes, alkyl vinyl keto

Full text of DOI:10.1039/c0ob00644k

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 363
www.rsc.org/obc
COMMUNICATION
Organocatalytic tandem three-component reaction of aldehyde, alkyl vinyl
ketone, and amide: one-pot syntheses of highly functional alkenes†
De-Wei Wang, Siang-en Syu, Yi-Ting Hung, Pei-yi Chen, Chia-Jui Lee, Ko-Wei Chen, Yu-Jhang Chen and
Wenwei Lin*
Received 30th August 2010, Accepted 18th October 2010
DOI: 10.1039/c0ob00644k
An EtPPh2- or PPh3-catalyzed tandem three-component reac-
tion of aldehyde, alkyl vinyl ketone, and amide is developed.
Its further application in one-pot syntheses of highly func-
tional alkenes starting from aldehydes, alkyl vinyl ketones,
and amides is realized. A wide variety of highly functional
a,b-unsaturated ketones can be furnished in 68–99% yields
with high stereoselectivity (E/Z up to 98 : 2) within overall
3–29.5 h.
Carbon–carbon or carbon–heteroatom bond formation is of
importance in organic synthesis with numerous interesting stud-
ies concerning reactivity, chemoselectivity and stereoselectivity.1
Among all well-developed methodologies, the multicomponent
reaction plays an important role due to its allowance of generation
Scheme 1 One-pot syntheses of alkenes 8–11 via three-component
reactions of aldehydes 1, alkyl vinyl ketones 2 and amides 3 catalyzed
by EtPPh2 or PPh3.
of an adduct in a single operation from three or more reactants
with high atom economy and bond-forming efficiency.2 Successful
application of a multicomponent reaction highly relies on the good
chemoselectivities in the presence of all the reactants.3
Practically, a more reactive catalyst than PPh3, such as EtPPh2,
The Baylis–Hillman adduct, starting from alkyl vinyl ketone
was seldom used in Morita–Baylis–Hillman reaction of an alde-
and aldehyde, is a good Michael acceptor according to the ketone
hyde and an a,b-unsaturated ketone due to a significant amount
of side reaction resulting from the EtPPh2-catalyzed Michael
addition of the a,b-unsaturated ketone toward the corresponding
Baylis–Hillman adduct. Besides, dimerization of a,b-unsaturated
ketone occurred even when PPh3 was used. Therefore, it is common
to use excess amount of a,b-unsaturated ketone (at least 3.0 equiv)
in Morita–Baylis–Hillman reactions.7 Surprisingly, in the presence
of EtPPh2 (5 mol%), 4-nitrobenzaldehyde (1a) (2.0 mmol) reacted
with merely 1.2 equivalent of methyl vinyl ketone (2a) and
phthalimide (3a) (1.1 equiv) in dry THF (2.0 mL) smoothly at
room temperature within 1 h, providing the highly functional
three-component adduct 4a in 95% yield (Table 1, entry 1). Even
less reactive PPh3 (20 mol%) can effectively catalyze this type of
three-component reaction of 1a, 2a (1.5 equiv) and 3a (1.4 equiv),
furnishing 4a in 97% yield within 4.5 h. The reactions of other
aryl-substituted aldehydes 1b–i as well as heteroaryl-substituted
aldehydes 1k–n underwent smoothly with 2a and 3a in the presence
of EtPPh2 (5 mol%), leading to the corresponding adducts 4b–i
and 4k–n within 1–7 h (T1) in 54–98% yields (entries 2–9 and
11–14). The reactivity of an aldehyde had strong influence on the
reaction time, and therefore 2a (1.3 equiv) and 3a (1.2 equiv) are
necessary for the formation of 4f–h and 4k–n.7,8 PPh3 (20 mol%)
also catalyzed the reactions of 1b–n, 2a (1.5 or 2.0 equiv) and
function activated by the neighboring hydroxy group.4,5 Numerous
successful applications for syntheses of highly functional com-
pounds were achieved by the Michael addition of nucleophiles
toward the Baylis–Hillman adducts as routine protocols.5 How-
ever, the Baylis–Hillman reaction is notorious for its slow reaction
with moderate to high yield,6 and therefore the whole process often
takes long time to obtain the final Michael product. Therefore, it
remains a strong demand to develop an efficient approach.
Herein, we wish to report a phosphine-catalyzed three-
component reaction starting from the Baylis–Hillman reaction of
aldehyde 1 and alkyl vinyl ketone 2, which is followed by Michael
addition of amide 3 toward the resulting adduct. Efficient one-pot
syntheses of highly functional alkenes 8–11 via EtPPh2- or PPh3-
catalyzed tandem three-component reactions of 1, 2 and 3 are also
demonstrated (Scheme 1).
Department of Chemistry, National Taiwan Normal University, 88, Section
4, Tingchow Road, Taipei 11677, Taiwan, ROC. E-mail: wenweilin@
ntnu.edu.tw; Fax: (+886)-2-29324249; Tel: (+886)-2-77346131
† Electronic supplementary information (ESI) available: Experimental
section, X-ray crystallographic data and NMR spectra. CCDC refer-
ence numbers 769605, 770519, 775300, 778973 and 778974. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00644k
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 363–366 | 363
©

View Article Online
Table 1 A three-component reaction of 1, 2a, and 3a catalyzed by EtPPh2
or PPh3
Table 2 One-pot syntheses of 8 and 9a
Entry 1/2/3
T1a;T2b/h Product 8 or 9
E/Zc; Yield (%)d
Entry
Ar
T1a; T2b/h
Yield of 4 (%)c,d
1
2
3
4
5
6
7
8
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-BrC6H4
4-ClC6H4
2-ClC6H4
C6H5
4-CH3C6H4
4-Pyridyl
3-Pyridyl
2-Pyridyl
2-Furyl
1; 4.5
1; 4
4ae, 95; 97
4b, 95; 98
4c, 88; 96
4d, 90; 98
4e, 93; 97
4f, 87; 98
4g, 83; 96
4he, 91; 98
4i, 54; 86
4j, –h; 62
4k, 97; 95
4l, 98; 92
4m, 94; 87
4n, 77; 98
1.5; 24
1.5; 5.5
1.5; 24
2f; 17g
3f; 18g
5f; 26g
7; 62g
–; 62g
1f; 7g
1
2
3
4
5
1a/2a/3a 1e; 3
8a: R = 4-NO2
8b: R = 3-NO2
8c: R = 4-CF3
8d: R = 4-Cl
8e: R = 2-Cl
92/8; 81f
91/9; 83
93/7; 81h
94/6; 77
97/3; 76
1b/2a/3a 1e; 3
1e/2a/3a 1.5g; 4.5
1g/2a/3a 3; 5
1h/2a/3a 5; 4i
9
10
11
12
13
14
1f; 11g
5f; 48g
5f; 25g
6
7
8
1k/2a/3a 1; 2
1l/2a/3a 1; 3
1m/2a/3a 5; 6i
8f: R = 4-pyridyl
8g: R = 3-pyridyl
8h: R = 2-pyridyl
92/8; 96
91/9; 99
98/2; 90f
a Reactions were carried out with 1 (2.0 mmol), 2a (1.2 equiv) and 3a
(1.1 equiv) catalyzed by EtPPh2 (5 mol%) in THF (2.0 mL) at rt. b 1
(1.0 mmol), 2a (1.5 equiv) and 3a (1.4 equiv) were used in the presence of
PPh3 (20 mol%) in THF (1.0 mL) at rt. c Yield of isolated product. d For
the diastereomeric ratios of 4, see the ESI.† e The structures of threo-4a
(CCDC no. 778973) and erythro-4h (CCDC no. 778974) were confirmed by
X-ray analysis. f 2a (2.0 equiv) and 3a (1.3 equiv) were used. g 2a (2.0 equiv)
and 3a (1.5 equiv) were used. h The trace amount of 4j was observed.
9
1d/2b/3a 1.5e; 5
8i
92/8; 76
3a (1.4 or 1.5 equiv), providing the corresponding adducts 4b–n
within 4–62 h (T2) in 62–98% yields (entries 2–14). DABCO (20
mol%), one of the best catalysts for the Baylis–Hillman reaction,
also catalyzed the reaction of 1a, 2a (1.3 equiv) and 3a (1.2 equiv).
However, the reaction rate was very slow (7 days, 86% conversion),
indicating DABCO was not effective for our designed reaction.9
Based on experimental‡ results (Table 1), a plausible reaction
mechanism for this highly chemoselective three-component reac-
tion was proposed (Scheme 2). First, an EtPPh2- or PPh3-catalyzed
Morita–Baylis–Hillman reaction took place, giving rise to the
corresponding adduct 12. The in situ formed basic intermediate
13, which was the nucleophile in the Morita–Baylis–Hillman
reaction, deprotonated an amide 3a, and then 14a underwent the
Michael addition toward 12 followed by protonation, affording the
corresponding adduct 4 with the regeneration of EtPPh2 or PPh3.
10
11
1a/2a/3b 1e; 3
9a: R = 4-NO2
9b: R = 4-CN
88/12; 76f
90/10; 68f
1d/2a/3b 1.5e; 4.5
a Reactions were carried out with 1 (2.0 mmol), 2 (2.0 equiv) and 3
(1.3 equiv) catalyzed by EtPPh2 (5 mol%) in THF (2.0 mL) at rt. b Without
further purification, reactions were carried out using Ac2O (1.2 equiv),
Et3N (2.5 equiv), DMAP (10 mol %), and additional THF (2.0 mL) at
50 ◦C. c Determined by 1H NMR analysis of the crude product. d Yield of
isolated products. e 2a (1.3 equiv) and 3b (1.01 equiv) were used. f Yield
of (E)-form isomer. g 2a (1.5 equiv) and 3b (1.01 equiv) were used. h The
structure of (E)-form of 8c (CCDC no. 769605) was confirmed by X-ray
analysis. i Reactions were carried out in refluxing THF.
Highly functional a,b-unsaturated ketones are bioactive com-
pounds as well as interesting building blocks for organic synthesis,
and the three-component adduct such as 4a can be further
transformed into 8a successfully in our preliminary study.10,11
Encouraged by this result, we envisioned that it should be possible
to develop one-pot procedure for the syntheses of polyfunctional
a,b-unsaturated ketones via our designed three-component re-
actions and acylation of the corresponding adducts followed by
elimination. Thus, the reaction of 1a (2.0 mmol), 2a (1.3 equiv) and
3a (1.01 equiv) catalyzed by EtPPh2 (5 mol%) proceeded in THF
at rt within 1 h, followed by the addition of Ac2O (1.2 equiv), Et3N
(2.5 equiv) and DMAP (10 mol%), and then underwent smoothly
at 50 ◦C within 3 h, providing the highly functional alkene (E)-8a
in 81% yield (Table 2, entry 1). Other aryl-substituted aldehydes,
such as 1b, 1d–e, 1g–h, and 1k–m, worked nicely with 2a (or 2b)
Scheme 2 A proposed mechanism of the three-component reaction of 1,
2a and 3a catalyzed by EtPPh2 or PPh3.
364 | Org. Biomol. Chem., 2011, 9, 363–366
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 3 One-pot syntheses of 10 and 11a
and good stereoselectivities (E/Z = 83/17 to 97/3) according to
our procedure (Table 3, entries 1–12). However, EtPPh2, which
showed better catalytic ability than PPh3 for the three-component
reaction of 1, 2 and 3a–b, gave poor results in case of 3c and 3d,
and was not a suitable catalyst for the preparation of 10 and 11.
Not only aryl-substituted aldehydes 1a–m but also the other
interesting aldehyde, like 1n, reacted successfully with 2a and
3a according to our one-pot protocol, giving the corresponding
highly functional alkene 8j in 69% yield with good stereoselectivity
(E/Z = 93 : 7) (Scheme 3). The amide 3d worked also nicely with
1n and 2a, furnishing the corresponding alkene 11c within 6 h in
92% yield (E/Z = 44 : 56).13
Entry 1/2/3
T1a;T2b/h Product 10 or 11
E/Zc; Yield (%)d
1
2
3
4
5
6
1a/2a/3c 3; 3.5
10a: R = 4-NO2
10b: R = 3-NO2
10c: R = 2-NO2
10d: R = 4-CN
10e: R = 4-CF3
10f: R = 4-Br
84/16; 84
83/17; 88
92/8; 92
89/11; 92
90/10; 90
89/11; 83f
1b/2a/3c 3; 3.5
1c/2a/3c 15; 6
1d/2a/3c 4.5; 3.5
1e/2a/3c 23; 6.5
1f/2a/3c 24; 5e
7
1k/2a/3c 12g; 4
10g
89/11; 92
8
9
10
1a/2b/3c 3.5; 3e
1b/2b/3c 6; 3e
1d/2b/3c 3.5; 4e
10h: R = 4-NO2
10i: R = 3-NO2
10j: R = 4-CN
86/14; 80
87/13; 86
85/15; 83
Scheme 3 One-pot syntheses of 8j or 11c.
In summary, we have developed a general procedure for
one-pot syntheses of highly functional a,b-unsaturated ketones
8–11 via tandem EtPPh2- or PPh3-catalyzed three-component
reaction of aldehydes 1, alkyl vinyl ketones 2 and amides 3, and
acylation of the corresponding adducts followed by elmination.
The reaction condition is very mild, and numerous polyfunctional
alkenes 8–11 can be efficiently afforded in good yields with high
stereoselectivities. The reaction mechanism of our tandem three-
component reaction is proposed to undergo the Morita–Baylis–
Hillman reaction of 1 and 2 followed by the Michael addition
of 3 toward the corresponding adduct. Further studies and the
extensions of this work in imines as well as the use of other
nucleophilic reagents, are currently underway.
11
12
1a/2a/3d 1h; 2
1k/2a/3d 7i; 2
11a
97/3; 83
92/8; 98
11b
a Reactions were carried out with 1 (1.0 mmol), 2 (1.4 equiv) and 3
(1.05 equiv) catalyzed by PPh3 (20 mol%) in THF (1.0 mL) at rt. b Without
further purification, reactions were carried out using Ac2O (1.2 equiv),
Et3N (2.5 equiv), DMAP (10 mol %), and additional THF (1.0 mL) at
The authors thank the National Science Council of the Re-
public of China (NSC Grant No. 97-2113-M-003-003-MY2) and
National Taiwan Normal University (99T3030-6) for financial
support.
50 ◦C. c Determined by H NMR analysis of the crude product. d Yield
1
of isolated products. e Reactions were carried out in refluxing THF. f The
structure of (E)-10f (CCDC no. 770519) was confirmed by X-ray analysis.
g 1j (1.01 equiv) and 2a (1.4 equiv) were used. h 1a (1.05 equiv) and 2a
(1.4 equiv) were used. i 2a (1.4 equiv) and 3d (1.05 equiv) were used.
Notes and references
and 3a according to our protocol, furnishing the corresponding
adducts 8b–i within 3–11 h (T1+T2) in overall 76–99% yields with
high stereoselectivities (E/Z = 91/9 to 98/2) (entries 2–9). The
other amide, like succinimide (3b), was also successfully applied
in our one-pot procedure with 2a and 1a or 1d, affording the
corresponding alkene (E)-9a or (E)-9b within 4 or 6 h in overall
76% or 68% yields, respectively (entries 10 and 11).12
‡ Experimental procedure: Preparation of 8a: A dry and nitrogen-flushed
10-mL Schlenk flask, equipped with a magnetic stirring bar and a septum,
was charged with a solution of 1a (302 mg, 2 mmol) and 3a (297 mg,
1.01 equiv) in dry THF (2 mL). MVK (2a) (211 mL, 1.3 equiv) and EtPPh2
(20.4 mL, 5 mol%) were added, and the reaction mixture was stirred for
1 h (T1) at rt. Without further purification, Ac2O (0.23 mL, 1.2 equiv),
Et3N (0.70 mL, 2.5 equiv), DMAP (24.4 mg, 10 mol%), and additional
THF (2.0 mL) were added, and the resulting mixture was stirred at 50 ◦
C
for 3 h (T2) Thereafter, the solvent was removed by evaporation in vacuo.
Purification by recrystallization (hexanes/CH2Cl2) furnished the alkene
(E)-8a as a yellow solid (568 mg, 81%).
The broad reaction scope of our one-pot protocol was demon-
strated by further studies disclosed in Table 3. It showed that the
syntheses of 10 and 11 starting from the reactions of aldehydes 1,
2a–b, and amides, such as 1-methylhydantoin (3c) and 1-phenyl-
3-pyrazolidinone (3d), in the presence of PPh3 (20 mol%) were
achieved in overall 3–29.5 h (T1+T2) with high yields (80–98%)
1 (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138;
(b) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2001, 40, 3726;
(c) Handbook of functionalized organometallics, ed. P. Knochel, Wiley-
VCH, Weinheim, Germany, 2005.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 363–366 | 365
©

View Article Online
2 For an overview, see: (a) Multicomponent reactions, ed. J. Zhu and
H. Bienayme´, Wiley-VCH, Weinheim, Germany, 2005; for excellent
reviews, see: (b) A. Do¨mling and I. Ugi, Angew. Chem., Int. Ed.,
2000, 39, 3168; (c) H. Bienayme´, C. Hulme, G. Oddon and P.
Schmitt, Chem.–Eur. J., 2000, 6, 3321; (d) R. V. A. Orru and M. de
Greef, Synthesis, 2003, 1471; (e) C. Hulme and V. Gore, Curr. Med.
Chem., 2003, 10, 51; (f) D. J. Ramo´n and M. Yus, Angew. Chem.,
Int. Ed., 2005, 44, 1602; (g) A. Do¨mling, Chem. Rev., 2006, 106,
17.
3 For an overview, see: (a) Domino reactions in Organic Synthesis, ed. L. F.
Tietze, G. Brasche and K. Gericke, Wiley-VCH, Weinheim, Germany,
2006; also see: (b) G. H. Posner, Chem. Rev., 1986, 86, 831; (c) K. C.
Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed.,
2006, 45, 7134.
Myers, O. Illa, M. A. Shaw, S. L. Riches and V. K. Aggarwal, Chem.
Rev., 2007, 107, 5841; (c) D. Basavaiah, K. V. Rao and R. J. Reddy,
Chem. Soc. Rev., 2007, 36, 1581.
7 For double transitional Morita–Baylis–Hillman reactions, please see:
(a) G.-N. Ma, J.-J. Jiang, M. Shi and Y. Wei, Chem. Commun., 2009,
5496, and references cited therein; for the p-NO2C6H4OH and PPh3-
catalyzed Baylis–Hillman reaction of 1a and 2a (3.0 equiv) (98% yield,
rt, 18 h), see: (b) M. Shi and Y.-H. Liu, Org. Biomol. Chem., 2006, 4,
1468.
8 The dimerization of methyl vinyl ketone (2a) occurred during the
reaction progress, and therefore it is necessary to use increasing amount
of 2a when the reaction time of the whole reaction progress was getting
longer. In case of preparation of 4i, there was no further improvement
when increasing amount of 2a was used.
4 Reviews for Morita–Baylis–Hillman reactions, see: (a) D. Basavaiah, A.
J. Rao and T. Satyanarayana, Chem. Rev., 2003, 103, 811, and references
cited therein; (b) P. Langer, Angew. Chem., Int. Ed., 2000, 39, 3049;
(c) D. Basavaiah, K. V. Rao and R. J. Reddy, Chem. Soc. Rev., 2007, 36,
1581; (d) C. Menozzi and P. I. Dalko, Organocatalytic Enantioselective
Morita–Baylis–Hillman Reactions. In Enantioselective Organocataly-
sis, Reactions and Experimental Procedures, ed. P. I. Dalko, Wiley-VCH,
Weinheim, Germany, 2007; recent reviews for application of Baylis–
Hillman adduct, see: (e) G. Masson, C. Housseman and J. Zhu, Angew.
Chem., Int. Ed., 2007, 46, 4614; (f) S. Batra and V. Singh, Tetrahedron,
2008, 64, 4511; (g) D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem.
Rev., 2010, 110, 5447.
5 For selected literature about the addition of carbon nucleophile to
Baylis–Hillman adduct, see: (a) W. Wang and M. Yu, Tetrahedron
Lett., 2004, 45, 7141; for selected literature with nitrogen nucleophile,
see: (b) A. K. Roy, R. Pathak, G. P. Yadav, P. R. Maulik and S. Batra,
Synthesis, 2006, 1021; (c) S. Nag, G. P. Yadav, P. R. Maulik and S.
Batra, Synthesis, 2007, 911.
9 The Baylis–Hillman adduct resulting from 1a and 2a was furnished
efficiently (5 h, 100% conversion). However, the further addition of
3a toward the Baylis–Hillman adduct in the presence of DABCO
proceeded very slowly (7 days, 86% conversion), leading to the expected
adduct 4a in 84% yield.
10 For recent application of functionalized a,b-unsaturated ketones as
inhibitors of specific classes of cysteine proteases, see: Z. Yang, M.
Fonovic´, S. H. L. Verhelst, G. Blum and M. Bogyo, Bioorg. Med. Chem.,
2009, 17, 1071.
11 In our preliminary study, the three-component adduct 4a can be
successfully converted into the corresponding a,b-unsaturated ketone
8a in the presence of Ac2O, Et3N and DMAP at rt.
12 Interestingly, the alkenes, such as 8a–i, were afforded with high
stereoselectivities (E/Z = 91/9 to 98/2) after acylation of the three-
component adducts 4a–b, 4d–e, 4g–h, 4j–k, and 4l followed by
elimination according to our one-pot protocol. However, 4a–b, 4d–
e, 4g–h, 4j–k, and 4l were furnished in poor diastereoselectivities (dr =
1 : 1 to 1 : 4.6).
6 For selected reviews, see: (a) E. A. C. Davie, S. M. Mennen, Y. Xu and
S. J. Miller, Chem. Rev., 2007, 107, 5759; (b) E. M. McGarrigle, E. L.
13 The structure of (E)-form of 11c (CCDC no. 775300) was confirmed
by X-ray analysis.
366 | Org. Biomol. Chem., 2011, 9, 363–366
This journal is
The Royal Society of Chemistry 2011
©