Stereoselective -olefination of substituted cyclobutenediones by organocatalysis

Article abstract of DOI:10.1055/s-0031-1289879

Methods are described for the stereoselective synthesis of alkenyl-substituted cyclobutenediones from alkyl-substituted cyclobutenediones and aldehydes in 70-91% yields using pyrrolidine as catalyst under mild reaction conditions. Georg Thieme Verlag Stut

Full text of DOI:10.1055/s-0031-1289879

2834
LETTER
Stereoselective g-Olefination of Substituted Cyclobutenediones by
Organocatalysis
Stereoselective
g
-Olefi
a
nation llesh Beesu, Mariappan Periasamy*
School of Chemistry, University of Hyderabad, Hyderabad 500046, A.P., India
Fax +91(40)23012460; E-mail: mpsc@uohyd.ernet.in
Received 13 August 2011
(1a) and benzaldehyde (2a) in MeOH solvent was inves-
tigated (Scheme 1). It was found that a catalytic amount of
pyrrolidine (20 mol%) is enough to catalyze the reaction,
giving the desired condensation product in 88% yield at
25 °C (Table 1, entry 1).
Abstract: Methods are described for the stereoselective synthesis
of alkenyl-substituted cyclobutenediones from alkyl-substituted cy-
clobutenediones and aldehydes in 70–91% yields using pyrrolidine
as catalyst under mild reaction conditions.
Key words: cyclobutenediones, g-olefination, organocatalysis
Ph
H
H
H3C
Ph
O
O
The broad utility of cyclobutenedione derivatives in or-
ganic synthesis has led to considerable interest in the de-
velopment of new synthetic methods for their synthesis.1–
O
O
pyrrolidine
MeOH
Ph-CHO
+
Ph
4
The derivatives of alkenyl-substituted cyclobutenedi-
1a
2a
3a
ones are of interest to medicinal chemistry,5,11 and as syn-
thons for the synthesis of biologically active quinones6
and triquinanes.7 Some cyclobutenedione derivatives also
have the potential for use as sensors8 and organic optical
materials.9 Accordingly, the preparation of this molecular
architecture is of considerable synthetic significance.
Scheme 1 Aldol condensation of 3-methyl-4-phenylcyclobutene-
dione (1a) with benzaldehyde (2a) in the presence of pyrrolidine ca-
talyst
Table 1 Stereoselective Olefination of 3-Methyl-4-phenylcyclo-
butenedione (1a) Using Organic Catalysts in a Range of Solventsa
Previously, cyclobutenedione derivatives were prepared
by using a stoichiometric amount of organic bases,10 pal-
ladium reagents,11 and strong Lewis acids.12 These meth-
ods suffer from harsh reaction conditions, long reaction
times, expensive reagents, and low yields. In recent years,
we have reported several simple and convenient methods
for the synthesis of cyclobutenedione derivatives using
iron carbonyl reagents and alkynes.13
Ph
H
Me
Ph
O
O
O
O
H
catalyst
solvent
PhCHO
+
Ph
1a
2a
3a
Entry Catalyst
Solvent
Cat.loadingTime Yield
(mol%)
(h)
(%)b
88
86
82
85
83
85
80
88
80
75
78
There is immense current interest in the development of
carbon–carbon bond-forming transformations mediated
by organocatalysts based on small molecules.14 One of the
more extensively studied organocatalysed reactions is the
aldol condensation of aldehydes and ketones. Among var-
ious organic catalysts, L-proline and secondary amines
have been widely used.15 However, to the best of our
knowledge, there has been no report on organocatalytic
aldol reactions involving cyclobutenediones. In this pa-
per, we report a novel, one-pot method for the stereoselec-
tive synthesis of alkenyl-substituted cyclobutenediones
(70–91% yields) by using the simple organic catalyst pyr-
rolidine from unmodified cyclobutenediones.
1
2
pyrrolidine
MeOH
EtOH
20
1
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
piperdine
20
1
3
DMSO
THF
20
1
4
20
1.5
1.5
1.5
2
5
CH2Cl2
CHCl3
MeOH
MeOH
MeOH
MeOH
MeOH
20
6
20
7
10
8
30
1
9
20
1
We have observed that the aldol condensation of cy-
clobutenediones with aldehydes in the presence of organic
catalysts give alkenyl cyclobutenediones. Initially, the
condensation of 3-methyl-4-phenylcyclobutene dione
10
11
morpholine
L-proline
20
1
20
8
a All the reactions were carried out using cyclobutenedione 1a (0.5
mmol), aldehyde (1.5 mmol, 3 equiv), and catalyst at 25 °C.
b Yields are for the isolated products and are based on the amount of
1a used.
SYNLETT 2011, No. 19, pp 2834–2840
x
x
.x
x
.2
0
1
1
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289879; Art ID: B15111ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective g-Olefination
2835
We have screened various solvents including methanol, pyrrolidine (20 mol%), the products were obtained in
ethanol, dimethyl sulfoxide (DMSO), dichloromethane, good yields in shorter reaction time in methanol (Table 1).
chloroform, and tetrahydrofuran (THF) for use in this
After establishing the optimal reaction conditions, the
transformation. In all cases, the products were obtained in
generality of this condensation reaction was examined. A
comparable yields (Table 1, entries 1–6). To optimize the
number of alkenyl-substituted cyclobutenediones deriva-
catalyst loading, the conversion was carried out using dif-
tives were synthesized in good yields (Table 2). A variety
ferent catalyst ratios (10, 20, and 30 mol%) of pyrrolidine.
of functional groups such as alkoxy, halide, and amine
The results are summarized in Table 1.
were tolerated in this transformation; the results are sum-
A 20 mol% loading of pyrrolidine was sufficient to push marized in Table 2. We found that electronic effects do
the reaction forward. Higher amounts of catalyst did not not significantly affect the yields of products. Substituted
lead to significant change in the reaction yields. We have benzaldehyde derivatives with either electron-donating
also examined the transformation using other organic cat- (Table 2, entries 4–9) or electron-withdrawing groups af-
alysts such as piperidine, morpholine, and L-proline. In all forded the products in good yields (Table 2, entries 2, 3,
cases, the products were obtained in similar yields and 10).
(Table 1, entries 1, 9, 10, and 11). However, in the case of
Table 2 Stereoselective Synthesis of Alkenyl Cyclobutenediones Using Pyrrolidine in Methanola
Ar
H
R1
Ph
O
O
pyrrolidine
(20 mol%)
O
O
R2
ArCHO
+
MeOH
Ph
1
2
3
R1 = Me, Et, n-Bu
R2 = H, Me, n-Pr
Entry
ArCHO
R1
Productb
3
Yield (%)c
O
O
1
Me
3a
88
CHO
Cl
O
O
2
Me
3b
85
Cl
CHO
Br
O
O
3
Me
3c
82
Br
CHO
Synlett 2011, No. 19, 2834–2840 © Thieme Stuttgart · New York

2836
M. Beesu, M. Periasamy
LETTER
Table 2 Stereoselective Synthesis of Alkenyl Cyclobutenediones Using Pyrrolidine in Methanola (continued)
Ar
H
R1
Ph
O
O
pyrrolidine
(20 mol%)
O
O
R2
ArCHO
+
MeOH
Ph
1
2
3
R1 = Me, Et, n-Bu
R2 = H, Me, n-Pr
Entry
ArCHO
R1
Productb
3
Yield (%)c
Me
O
O
4
5
6
Me
Me
Me
3d
83
Me
CHO
Et
O
3e
85
78
82
Et
CHO
O
i-Pr
MeO
EtO
O
3f
i-Pr
CHO
O
O
O
7
Me
3g
MeO
CHO
O
8
Me
3h
80
EtO
CHO
O
Synlett 2011, No. 19, 2834–2840 © Thieme Stuttgart · New York

LETTER
Stereoselective g-Olefination
2837
Table 2 Stereoselective Synthesis of Alkenyl Cyclobutenediones Using Pyrrolidine in Methanola (continued)
Ar
H
R1
Ph
O
O
pyrrolidine
(20 mol%)
O
O
R2
ArCHO
+
MeOH
Ph
1
2
3
R1 = Me, Et, n-Bu
R2 = H, Me, n-Pr
Entry
ArCHO
R1
Productb
3
Yield (%)c
Me2N
O
O
9
10
11
12
Me
Me
Et
3i
90
Me2N
CHO
F3C
O
3j
3k
3l
91
85
80
F3C
CHO
O
O
O
CHO
O
O
n-Bu
CHO
a All the reactions were carried out using cyclobutenedione 1 (0.5 mmol), aldehyde (1.5 mmol, 3 equiv), and pyrrolidine (0.1 mmol), in MeOH
(2.5 mL) at 25 °C for 1 h.
b The products were identified by spectral data (IR, 1H, 13C NMR and MS).
c Yields are for the isolated products and are based on the amount of 1 used.
The structures of the condensation products 3a and 3k 9 to give the product 3 via intermediate 10, cannot be
were confirmed by single crystal X-ray analyses ruled out (Scheme 2, path B).
(Figure 1).16
This transformation was also successful with dialkyl-
This g-olefination of cyclobutenediones can be explained cyclobutenedione 1b, and highly conjugated dialkenyl-
by considering the tentative mechanism outlined in substituted cyclobutenediones were obtained in excellent
Scheme 2. The pathway involves the reaction of the di- yields in these cases (Table 3).
enolate intermediate 5 with the iminium ion derived from
The structure of 3,4-bis[(E)-1-phenylprop-1-en-2-yl]-
aldehyde to give the product 3 via the intermediate 6
cyclobutene-1,2-dione (4a) was also confirmed by single
(Scheme 2, path A). However, the alternative mechanism
crystal X-ray analysis (Figure 2).16
outlined in Path B, involving the reaction of the dienamine
Synlett 2011, No. 19, 2834–2840 © Thieme Stuttgart · New York

2838
M. Beesu, M. Periasamy
LETTER
Figure 1 ORTEP diagrams of 3a and 3k
The stereoselectivity of the present transformation was (Scheme 2 and Scheme 3). Due to reduced steric hin-
excellent and only one isomer was obtained in all cases. drance between the cyclobutenedione moiety and the hy-
This observation may be rationalized by considering the drogen atom in transition states 6 and 10 compared to the
intermediates and transition states 6 or 6A and 10 or 10A steric hindrance between the cyclobutenedione moiety
Table 3 Stereoselective Olefination of 3,4-Diethylcyclobut-3-ene-1,2-dione Using Pyrrolidine as Catalysta
Ar
Me
Me
Ar
H
O
O
Et
Et
O
O
pyrrolidine
(20 mol%)
ArCHO
+
MeOH, 25 °C, 1.5 h
1b
2
H
4
Entry
1
RCHO
Productb
4
Yield (%)c
Me
Me
O
4a
85
CHO
H
H
O
Me
Me
Me
Me
2
3
4
4b
4c
4d
82
75
70
Me
CHO
H
H
O
O
MeO
OMe
Me
Me
O
MeO
CHO
H
H
O
Me2N
NMe2
Me
Me
O
Me2N
CHO
H
H
O
a All the reactions were carried out using cyclobutenedione 1b (0.5 mmol), aldehyde (2 mmol, 4 equiv), and pyrrolidine (0.1 mmol) in MeOH
(3 mL) at 25 °C for 1.5 h.
b The products were identified by their spectral data (IR, 1H NMR, 13C NMR, and MS).
c Yields are for the isolated products and are based on the amount of 1b used.
Synlett 2011, No. 19, 2834–2840 © Thieme Stuttgart · New York

LETTER
Stereoselective g-Olefination
2839
Ar
Ar
H
N
N+
O
O
O
O
O
R2
R2
H
H
R2
R1
Ar
R1
O–
R1
path A
3 R2 = H
5
6
4 R2 = Me
N+
N
H
H
H
O
O
R2
N
H
R1
1
H
path B
O
R2
O
O
R2
R2
N
H
N
OH
R1
N+
R1
R1
N
OH–
H+
7
8
9
Ar
N+
H
Ar
R2
H
Ar
N
O
O
O
H
R2
R1
R1
N+
3 R2 = H
N
4 R2 = Me
H
10
Scheme 2 Possible reaction mechanisms for the formation of alkenyl cyclobutenediones
and the aryl group found in 6A and 10A, the transition and easy preparation of functionalized cyclobutenediones
states 6 and 10 are favored, leading to the formation of in high yields under very benign reaction conditions. Such
compound 3 as the only product (Scheme 3).
derivatives were previously accessed by multi-step proce-
dures using dialkoxy cyclobutenediones.11 Accordingly,
the method described here has considerable potential for
the synthesis of bioactive molecules and donor–acceptor
cyclobutenedione derivatives for material science appli-
cations.
In conclusion, we have developed a novel, mild, and effi-
cient method for the preparation of highly conjugated
mono- and dialkenyl-substituted cyclobutenediones using
aldehydes and cyclobutenediones under amine catalysis.
The mild nature of the reaction conditions allows the rapid
Ar
R2
H
O
O
O
N+
N
N
O
R2
R2
Ar
R1
R1
R1
3 R2 = H
O
H
H
Ar
H
6
H
10
R1, Ar = aryl
H
Ar
O
O
O
N+
O
O
N
N
R2
R2
R2
H
X
X
R1
R1
R1
3A R2 = H
Ar
Ar
H
H
6A
H
10A
Scheme 3 A rationale for the high diastereoselectivity
Synlett 2011, No. 19, 2834–2840 © Thieme Stuttgart · New York

2840
M. Beesu, M. Periasamy
LETTER
(6) Shi, X.; Amin, S. R.; Liebeskind, L. S. J. Org. Chem. 2000,
65, 1650.
(7) (a) MacDougall, J. M.; Moore, H. W. J. Org. Chem. 1999,
64, 7445. (b) MacDougall, J. M.; Moore, H. W. J. Org.
Chem. 1997, 62, 4554.
(8) Avirah, R. R.; Jyothish, K.; Ramaiah, D. Org. Lett. 2007, 9,
121.
(9) (a) Jyothish, K.; Arun, K. T.; Ramaiah, D. Org. Lett. 2004,
6, 3965. (b) Jyothish, K.; Avirah, R. R.; Ramaiah, D. Org.
Lett. 2006, 8, 111. (c) Volkova, K. D.; Kovalska, V. B.;
Tatarets, A. L.; Patsenker, L. D.; Kryvorotenko, D. V.;
Yarmoluk, S. M. Dyes Pigm. 2007, 72, 285.
Figure 2 ORTEP diagram of 4a
(10) Shinada, T.; Ooyama, Y.; Hayashi, K.-I.; Ohfune, Y.
Tetrahedron Lett. 2002, 43, 6755.
(11) John, A.; Butera, J. A.; Jenkins, D. J.; Lennox, J. R.;
Sheldon, J. H.; Norton, N. W.; Warga, D.; Argentierib, T. M.
Bioorg. Med. Chem. Lett. 2005, 15, 2495.
Supporting Information for this article is available online at
(12) Ried, W.; Vogl, M. Chem. Ber. 1982, 115, 403.
(13) (a) Periasamy, M.; Radhakrishnan, U.; Brunet, J. J.;
Chauvin, R.; Elzaizi, A. J. Chem. Soc., Chem. Commun.
1996, 1499. (b) Rameshkumar, C.; Periasamy, M. Synlett
2000, 1619. (c) Periasamy, M.; Rameshkumar, C.;
Mukkanti, A. J. Organomet. Chem. 2002, 649, 209.
(d) Rameshkumar, C.; Periasamy, M. Organometallics
2000, 19, 2400. (e) Periasamy, M.; Rameshkumar, C.;
Radhakrishnan, U. Tetrahedron Lett. 1997, 38, 7229.
(f) Rameshkumar, C.; Periasamy, M. Tetrahedron Lett.
2000, 41, 2719. (g) Periasamy, M.; Mukkanti, A.;
Shyam Raj, D. Organometallics 2004, 23, 6323.
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the CSIR (New Delhi) for a research fellowship to M.B.
DST support through a J. C. Bose National Fellowship grant to M.P.
is gratefully acknowledged. We also thank the DST for the 400
MHz NMR facility under FIST program, and support for the Natio-
nal single crystal X-ray diffractometer facility and for the DST-
UoH Nanotech Centre project. This research work is also supported
by the UGC under the ‘University of Potential for Excellence’, the
Center for Advanced Study (CAS) and the UGC-MHRD Chemistry
Networking Resource Center programs.
(h) Periasamy, M.; Beesu, M.; Shyam Raj, D. J. Organomet.
Chem. 2008, 693, 2843. (i) Periasamy, M.; Mukkanti, A.;
Shyam Raj, D. Organometallics 2004, 23, 619.
(j) Periasamy, M.; Rameshkumar, C.; Radhakrishnan, U.;
Brunet, J. J. J. Org. Chem. 1998, 63, 4930. (k) Beesu, M.;
Periasamy, M. J. Org. Chem. 2011, 76, 543.
References and Notes
(1) (a) Jewell, C. F. Jr.; Liebeskind, L. S.; Williamson, M. J. Am.
Chem. Soc. 1985, 107, 6715. (b) Liebeskind, L. S.; Iyer, S.;
Jewell, C. F. Jr. J. Org. Chem. 1986, 51, 3065.
(14) For selected organocatalysis reviews, see: (a) Dalko, P. I.;
Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726. (b) List,
B. Tetrahedron 2002, 58, 5573. (c) Notz, W.; Tanaka, F.;
Barbas, C. F. III. Acc. Chem. Res. 2004, 37, 580. (d) Dalko,
P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138.
(e) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem.
Int. Ed. 2007, 46, 1570. (f) Erkkila, A.; Majander, I.; Pihko,
P. M. Chem. Rev. 2007, 107, 5416. (g) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
(15) (a) List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem.
Soc. 2000, 122, 2395. (b) Bertelsen, S.; Marigo, M.;
Brandes, S.; Diner, P.; Jørgensen, K. A. J. Am. Chem. Soc.
2006, 128, 12973. (c) Utsumi, N.; Zhang, H.; Tanaka, F.;
Barbas, C. F. III. Angew. Chem. Int. Ed. 2007, 46, 1878.
(d) Zhao, G. L.; Rios, R.; Vesely, J.; Eriksson, L.; Cordova,
A. Angew. Chem. Int. Ed. 2008, 47, 8468. (e) Ramachary,
D. B.; Ramakumar, K.; Narayana, V. V. Chem. Eur. J. 2008,
14, 9143. (f) Han, B.; Xiao, Y.; He, Z.; Chen, Y. Org. Lett.
2009, 11, 4660. (g) Han, B.; He, Z.; Li, J.; Li, R.; Jiang, K.;
Liu, T.; Chen, Y. Angew. Chem. Int. Ed. 2009, 48, 5474.
(h) Humbeck, J. F. V.; Simonovich, S. P.; Knowles, R. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012.
(16) CCDC 809408 (3a), 809409 (3k), and 809407 (4a) contain
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
(c) Liebeskind, L. S.; Bombrum, A. J. Org. Chem. 1994, 59,
6856. (d) Shi, X.; Amin, R.; Liebeskind, L. S. J. Org. Chem.
2000, 65, 1650. (e) Shi, X.; Liebeskind, L. S. J. Org. Chem.
2000, 65, 1665. (f) Pena-Cabrera, E.; Liebeskind, L. S.
J. Org. Chem. 2002, 67, 1689. (g) Aguilar-Aguilar, A. L.;
Liebeskind, L. S.; Pena-Cabrera, E. J. Org. Chem. 2007, 72,
8539.
(2) (a) Karlsson, J. O.; Nguyen, N. V.; Foland, L. D.; Moore, H.
W. J. Am. Chem. Soc. 1985, 107, 3392. (b) Moore, H. W.;
Decker, O. H. Chem. Rev. 1986, 86, 821. (c) Lee, K. H.;
Moore, H. W. J. Org. Chem. 1995, 60, 735. (d) Taing, M.;
Moore, H. W. J. Org. Chem. 1996, 61, 329.
(3) (a) Negri, J. T.; Morwick, T.; Doyon, J.; Wilson, P. D.;
Hickey, E. R.; Paquette, L. A. J. Am. Chem. Soc. 1993, 115,
12189. (b) Paquette, L. A.; Morwick, T. M. J. Am. Chem.
Soc. 1997, 119, 1230. (c) Paquette, L. A.; Kuo, L. H.; Tae, J.
J. Org. Chem. 1998, 63, 2010. (d) Geng, F.; Liu, J.;
Paquette, L. A. Org. Lett. 2002, 4, 71.
(4) (a) Danheiser, R. L.; Gee, S. K.; Sard, H. J. Am. Chem. Soc.
1982, 104, 7670. (b) Danheiser, R. L.; Gee, S. K. J. Org.
Chem. 1984, 49, 1672. (c) Danheiser, R. L.; Gee, S. K.;
Perez, J. J. J. Am. Chem. Soc. 1986, 108, 806.
(5) (a) Renard, B. C.; Aubert, Y.; Asseline, U. Tetrahedron Lett.
2009, 50, 1897. (b) Planty, B.; Pujol, C.; Lamothe, M.;
Maraval, C.; Horn, C.; Grand, B. L.; Perez, M. Bioorg. Med.
Chem. Lett. 2010, 20, 1735.
www.ccdc.cam.ac.uk/data_request/cif
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