A novel Ireland-Claisen rearrangement/Diels-Alder tandem reaction of propargylic acrylates with acyclic dienophiles

Article abstract of DOI:10.1016/j.cclet.2013.01.004

A novel DABCO-catalyzed Ireland-Claisen rearrangement/Diels-Alder tandem reaction of propargylic acrylates 3 with dienophiles 4 was developed in the presence of an excess TMSCl and DBU with 1% hydroquinone as polymerization inhibitor in acetonitrile at refluxing temperature under air. This protocol gave cyclic α,β-unsaturated carboxylic acids 5 with complete regioselectivity.

Full text of DOI:10.1016/j.cclet.2013.01.004

Chinese Chemical Letters 24 (2013) 137–139
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
A novel Ireland–Claisen rearrangement/Diels–Alder tandem reaction of
propargylic acrylates with acyclic dienophiles
*
Yun-Xia Li , Yi-Lin Sheng, Bi-Song Zhang
College of Pharmaceutics and Material Engineering, Jinhua College of Profession and Technology, Jinhua 321007, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A novel DABCO-catalyzed Ireland–Claisen rearrangement/Diels–Alder tandem reaction of propargylic
acrylates 3 with dienophiles 4 was developed in the presence of an excess TMSCl and DBU with 1%
hydroquinone as polymerization inhibitor in acetonitrile at refluxing temperature under air. This
Received 18 October 2012
Received in revised form 14 December 2012
Accepted 21 December 2012
Available online 29 January 2013
protocol gave cyclic
a,b-unsaturated carboxylic acids 5 with complete regioselectivity.
ß 2013 Yun-Xia Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords:
Ireland–Claisen rearrangement
Diels–Alder reaction
Tandem reaction
Propargylic acrylates
1. Introduction
absorptions are given in wavenumbers (cmÀ1). NMR spectra were
recordedinCDCl3 solutionswithJeolECA400 orBruker AvanceDMX
In recent years, combining two or more reactions into one
operation has attracted significant attention because it reduces the
duration of the synthesis of a target compound compared to a
conventional reaction [1]. Currently, the Ireland–Claisen [3,3]-
sigmatropic rearrangement of allylic acrylate units is widely used
in both the construction of natural products and further
methodology development [2]. Moreover, the new applications
of the Ireland–Claisen rearrangement in many tandem sequences
and other reactions have been reported [3]. In this paper, we report
a novel Ireland–Claisen rearrangement/Diels–Alder tandem reac-
tion of propargylic acrylates with acyclic dienophiles. This
500 spectrometer using TMS as an internal reference. Coupling
constant (J) values are given in Hertz. Mass spectra were determined
with Agilent Technologies 5975 inert Mass Selective Detector.
Silica gel Merck 60 (200–300 mesh) was used for flash column
chromatography with hexane/acetone mixtures for elution.
General procedure for the tandem reaction: To a solution of
propargylic acrylates 3 (7.25 mmol) and dienophiles 4 (28.9 mmol)
in acetonitrile (20 mL per gram of 3) was added DABCO (0.16 g,
1.45 mmol), TMSCl (2.75 mL, 21.7 mmol), DBU (2.20 g, 14.5 mmol)
and hydroquinone (0.072 mmol). The mixture was heated under
reflux and stirred for 10–24 h, and then concentrated under
reduced pressure. The residue was dissolved in ether (30 mL) and
washed with 3 mol/L hydrochloric acid (15 mL), then brined and
dried with anhydrous MgSO4. Concentration under reduced
pressure and silica gel column chromatography (hexane: ace-
tone = 5: 1) afforded 5a–i as colorless solids (Table 1).
represents an efficient access to cyclic
a,b-unsaturated carboxylic
acids. The cyclic -unsaturated carboxylic acids are potentially
a,b
useful key intermediates or pharmacophores in pharmaceutical
research, which can be further functionalized to generate
candidate compounds. However, the synthesis of cyclic
a,b-
unsaturated carboxylic acids remains elusive and no reports are
available in the literature.
Selected analytical and spectroscopic data: Compound 5a: IR (KBr,
n
/cmÀ1): 3000, 2983, 1734, 1662, 1619, 1425, 1277, 1176, 1047,
954; 1H NMR (400 MHz, CDCl3):
d 7.78 (s, 1H), 4.13 (q, 2H,
J = 7.4 Hz), 3.68 (m, 1H), 2.55–2.50 (m, 1H), 2.31–2.26 (m, 2H), 1.99
(s, 3H), 1.87 (s, 3H), 1.70–1.63 (m, 1H), 1.23 (t, 3H, J = 6.8 Hz); 13C-
2. Experimental
NMR (100 MHz, CDCl3):
d 173.16 (s), 172.89 (s), 141.67 (s), 135.77
General information: IR spectral data were obtained for liquid film
or KBr discs with a Bruker Tensor 27 spectrophotometer and
(d), 125.81 (s), 125.72 (s), 60.62 (t), 40.98 (d), 24.91 (t), 21.84 (q),
20.72 (t), 20.71 (q), 14.22 (q); EI-MS: m/z (%) 238 (M)+, 220 (M-
H2O)+. Compound 5d: IR (KBr, /cm-1): ca. 3000, 2950, 2237, 1672,
n
1621, 1429, 1294, 1178, 921; 1H NMR (400 MHz, CDCl3):
(s, 1H), 3.85 (m, 1H), 2.68-2.47(m, 2H), 2.28–2.25 (m, 1H), 2.00 (s,
d 7.70
* Corresponding author.
E-mail address: lyxjinhua@163.com (Y.-X. Li).
1001-8417/$ – see front matter ß 2013 Yun-Xia Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.01.004

138
Y.-X. Li et al. / Chinese Chemical Letters 24 (2013) 137–139
Table 1
Tandem reaction of Ireland–Claisen rearrangement and Diels–Alder reaction.a
Entry
1
Substrate
Dienophiles
Time (h)
Product
Yieldb (%)
Ratioc (E/Z)
COOH
O
O
12
42
O
OC H
C H O C
2
5
2
5 2
4a
3a
5a
COOH
O
2
3
4
3a
3a
3a
10
24
13
45
35
44
OCH
4b
H COC
3
3
5b
COOH
CHO
OHC
NC
4c
5c
COOH
CN
4d
5d
O
O
COOH
5
6
7
8
3a
3b
3c
10
10
11
12
12
37
43
45
35
36
HOOC
5e
4e
O
COOH
O
4a
4b
4a
4b
>99:1
>97:3
>95:5
>93:7
O
C H O C
2
5 2
3b
5f
COOH
H CO C
3
2
5g
COOH
O
C H O C
2
5 2
O
3c
5h
COOH
H CO C
3
2
9
5i
a
The reaction were carried out in CH3CN (20 mL per gram of 3) under reflux, using 3 (1.0 equiv), DABCO (0.2 equiv), TMSCl (3.0 equiv), DBU (2.0 equiv), hydroquinone
(0.01 equiv), and dienophiles 4 (4.0 equiv).
b
Isolated yields by silica gel column chromatography (hexane:acetone = 5:1).
c
E/Z by GC/MS and NOESY.
3H), 1.99 (s, 3H), 1.75–1.64 (m, 1H); 13C NMR (100 MHz, CDCl3):
172.21 (s), 143.20 (s), 134.04 (d), 126.27 (s), 122.78 (s), 119.53 (s),
d
m/z (%) 210 (M)+, 192 (M-H2O)+. Compound 5g: IR (KBr,
3000, 2964, 1737, 1673, 1596, 1429, 1276, 1167, 1095, 928; 1H-
NMR (400 MHz, CDCl3): 7.88 (s, 1H), 3.71 (m, 1H), 3.67 (s, 3H),
3.31 (sept, J = 6.8 Hz, 1H), 2.52–2.47 (m, 1H), 2.31–2.23 (m, 2H),
1.78 (s, 3H), 1.75–1.72 (m, 1H), 1.05 (d, 3H, J = 5.9 Hz), 1.04 (d, 3H,
J = 6.8 Hz); 13C NMR (100 MHz, CDCl3):
d 173.85 (s), 173.28 (s),
150.97 (s), 134.91 (d), 126.01 (s), 124.65 (s), 52.04 (q), 41.34 (d),
29.88 (d), 25.07 (t), 21.04 (q), 20.99 (q), 20.82 (t), 13.87 (q); EI-MS:
m/z (%) 252 (M)+, 234 (M-H2O)+.
n
/cm-1): ca.
27.06 (d), 25.17 (t), 21.71 (q), 20.81 (q), 20.48 (t); EI-MS: m/z (%)
d
191 (M)+, 164 (M-CN-H)+. Compound 5e: IR (KBr,
n
/cmÀ1): ca.
3000, 2938, 1728, 1672, 1296, 979; 1H NMR (400 MHz, CDCl3):
d
7.77 (s, 1H), 3.64 (m, 1H), 2.53–2.49 (m, 1H), 2.34–2.28 (m, 2H),
1.99 (s, 3H), 1.87 (s, 3H), 1.73–1.64 (m, 1H); 13C NMR (100 MHz,
CDCl3):
d 173.03 (s), 171.49 (s), 141.90 (s), 135.89 (d), 125.78 (s),
125.68 (s), 41.57 (d), 24.99 (t), 21.97 (q), 20.82 (t), 20.81 (q); EI-MS:

Y.-X. Li et al. / Chinese Chemical Letters 24 (2013) 137–139
139
H(2), H(3) and H(4) are adjacent, which allowed establishment of
the E configuration of the C-3 double bond for 5g (Fig. 1) [7].
Analogously, differential NOE experiments for 5f–i indicated
predominant E-configured isomers.
CO2H
N
OTMS
O
N
H
OTMS
O
R1
R2
R1
aq.HCl
75-90%
DABCO
TMSCl/DBU
O
R1
R1
O
R2
R2
R2
I
II
III
IV
It is worth noting that in the reaction of propargylic acrylate 3a
with the dienophile 4e, the general Diels–Alder adduct 6e (Fig. 1)
was transferred further into 5e after releasing one molecule of CO2
(Table 1, entry 5). Furthermore, this tandem reaction applied only to
the dienophiles carrying electron-withdrawing group(s). Dieno-
philes with electron-releasing groups were proved to be unreactive.
Scheme 1. DABCO-catalyzed Ireland–Claisen rearrangement of allyl acrylates I.
O
COOH
COOH
COOH
H3CO2C
O
H
3
4
1
R1
H
H C
2
CH
3
O
R2
6e
M
NOESY correlations of compound 5g
4. Conclusion
Fig. 1. The planar structures of compound M, 5g and 6e.
In conclusion, we have developed a novel Ireland–Claisen
rearrangement/Diels–Alder tandem reaction of propargylic acry-
lates (3) to furnish cyclic a,b-unsaturated carboxylic acids (5) with
acyclic dienophiles (4). This protocol tolerated a wide range of
propargylic acrylates and dienophiles with electron-withdrawing
group(s) in moderate yields with complete regioselectivity.
Further application of the products for cycloaddition reactions
under sunlights was undergone in our lab currently.
1
O
O
R
HO
ii.
i.
2
1
R
R
2
1
HC CH
R
R
O
2
CH =CHCOCl
2
R
3
1
2
COOH
COOH
iii.
iii.
1
Z
R
CH =CH-Z
2
Acknowledgment
1
2
2
R
4
R
R
M
5
The authors gratefully acknowledge the financial support from
the Education Department of Zhejiang Province (No. Y201120940).
Scheme 2. Condition and reagent: (i) acetylene/t-BuOK/THF/0 8C; (ii) acryloyl
chloride/Et3N/CH2Cl2/0 8C – r.t.; (iii) DABCO/TMSCl/DBU/hydroquinone/reflux.
References
3. Results and discussion
[1] (a) P.A. Wender, Introduction: frontiers in organic synthesis, Chem. Rev. 96 (1996)
1–2;
Inanearlierpaper,wehavereporteda DABCO-catalyzedIreland–
Claisen [3,3]-rearrangement of allylic acrylates I in the presence of
excess TMSCl and DBU in acetonitrile (Scheme 1) [4]. Using this
procedure, the silylketene acetals II were prepared by a conjugate
addition of DABCO to the acrylates I and subsequent silylation of the
zwitterionic intermediates. Rearrangement of these intermediates
(b) L.F. Tietze, U. Beifuss, sequential transformations in organic chemistry: a
synthetic strategy with a future, Angew. Chem., Int. Ed. Engl. 32 (1993) 131–163;
(c) L.F. Tietze, Domino reactions in organic synthesis, Chem. Rev. 96 (1996) 115–
136;
(d) T.L. Ho, Tandem Organic Reactions, John Wiley, New Work, 1992;
(e) T. Hudlicky, Design constraints in practical syntheses of complex molecules:
current status, case studies with carbohydrates and alkaloids, and future perspec-
tives, Chem. Rev. 96 (1996) 3–30;
followed by the elimination of DABCO produced a-methylene-g,d-
unsaturated carboxylic acids IV in good yields.
(f) R.A. Bunce, Recent advances in the use of tandem reactions for organic synthe-
sis, Tetrahedron 51 (1995) 13103–13159;
(g) S.E. Denmark, A. Thorarensen, Tandem [4+2]/[3+2] cycloadditions of nitroalk-
enes, Chem. Rev. 96 (1996) 137–166.
[2] (a) G. Koch, P. Janser, G. Kottirsch, E. Romero-Giron, Highly diastereoselective
Lewis acid promoted Claisen-Ireland rearrangement, Tetrahedron Lett. 43 (2002)
4837–4840;
As a continuation of the study, we investigated the DABCO-
catalyzed Ireland–Claisen rearrangement on propargylic acrylates.
Although the expected rearrangement indeed proceeded, the
rearranged allenes products M (Fig. 1) were found to be unstable
and polymerize rapidly. Therefore, we tried to trap the unstable
(b) C.M. McFarland, M.C. McIntosh, The Ireland–Claisen rearrangement (1997–
2004), in: M. Hiersemann, U. Nubbemeyer (Eds.), The Claisen Rearrangement:
Methods and Applications, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2007,
pp. 117–120;
(c) A.M. Martı´n Castro, Claisen rearrangement over the past nine decades, Chem.
Rev. 104 (2004) 2939–3002.
allenes
Conveniently, when propargylic acrylates were treated with
dienophiles (compounds 4) cyclic -unsaturated carboxylic
M by adding dienophiles in the reaction mixture.
a,b
acids 5 were formed. Therefore, we describe here a novel
Ireland–Claisen rearrangement/Diels–Alder tandem reaction of
propargylic acrylates with acyclic dienophiles to obtain various
[3] (a) S.A. Frank, A.B. Works, W.R. Roush, Studies on the synthesis of the decahydro-
as-indacene ring system of (-)-spinosyn A via transannular Diels–Alder reactions of
substituted (E,E,E)-cyclododeca-1,6,8-trienes, Can. J. Chem. 78 (2000) 757–771;
(b) S. Gil, M.A. La´zaro, M. Parra, E. Breitmaiter, R. Mestres, g-Alkylation of unsatu-
rated carboxylic acids. Stereoselective synthesis of 2Z- and 2E,6E-3-methyldeca-
2,6-dienoic acids from 3-methylbut-2-enoic acid through consecutive Ireland
Claisen and Cope rearrangements, Synlett 1 (1998) 70–72;
cyclic a,b-unsaturated carboxylic acids. The synthetic sequence is
shown in Scheme 2. The required propargylic alcohols 2 were
prepared by the reaction of acyclic ketones 1 with monopotassium
acetylide [5]. Compounds 2 were further esterified 3 by treatment
with acryloyl chloride [6]. The tandem reaction of esters 3
(1.0 equiv) and acyclic dienophiles 4 (4.0 equiv) were carried out in
the presence of trimethylsilyl chloride (TMSCl, 3.0 equiv), DBU
(2.0 equiv) and hydroquinone (0.01 equiv) catalyzed by DABCO
(0.2 equiv) refluxing in acetonitrile. To prevent the possible
polymerization of dienophiles 4, a trace hydroquinone was added
into the reaction mixture. After acidic work-up, the expected
Diels–Alder adducts 5 were obtained in moderate yield (Table 1).
The configuration and stereochemistry of the compounds 5 were
fully characterized by IR, NMR, MS and 2D NMR spectra. The 1H–1H
COSY of the compound 5g reveals locational spaces of H(1) and
(c) P. Kraft, W. Eichenberger, G. Fra´ter, Synthesis of a constitutional isomer of nerol
by consecutive Ireland–Claisen and Cope rearrangements, Eur. J. Org. Chem. 11
(1999) 2781–2785;
(d) W. Ulrich, T. Frank, F. Roland, H. Gu¨ nter, Novel synthesis of 4-fluoropyridines
based on 2-fluoroallylic alcohols by succeeding Ireland–Claisen and aza-Cope
rearrangements as key steps, Synthesis 13 (2006) 2085–2096.
´
[4] Y.X. Li, Q.R. Wang, A. Goeke, G. Frater, An efficient DABCO-catalyzed Ireland–
Claisen rearrangement of allylic acrylates, Synlett 2 (2007) 288–292.
[5] Q. Zhang, Y. Chen, Y. Xia, Z.Y. Yang, P. Xia, Novel heterocycles: 4-methyl-2H-
pyrano[6,5-f]cycloalka[2,1-b]2H-chromen-2-ones, Heterocycles 63 (2004) 1637–
1643.
[6] A.B. Dounay, C.J. Forsyth, Synthetic studies toward the C5–C20 domain of the
azaspiracids, Org. Lett. 3 (2001) 975–978.
[7] G.C. Yang, Z.L. Li, W. Li, H.M. Hua, The structure of a furanosesquiterpenoid
extracted from myrrh elucidated by NMR spectroscopy, Chinese J. Magn. Reson.
25 (2008) 541–548.