Mild and efficient boronic acid catalysis of Diels-Alder cycloadditions to 2-alkynoic acids

Article abstract of DOI:10.1016/j.tetlet.2010.04.132

The concept of boronic acid catalysis (BAC) for the activation of unsaturated carboxylic acids is applied to the Diels-Alder cycloaddition between 2-alkynoic acids as dienophiles and various dienes. These [4+2] cycloadditions produce cyclohexadienyl carboxylic acids, which can be oxidized in situ to produce polysubstituted aromatic carboxylic acids. The boronic acid catalyst is suspected to provide activation by a LUMO-lowering effect of the unsaturated carboxylic acid likely via a covalent, monoacylated hemiboronic ester intermediate.

Full text of DOI:10.1016/j.tetlet.2010.04.132

Tetrahedron Letters 51 (2010) 3561–3564
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Mild and efficient boronic acid catalysis of Diels–Alder cycloadditions to
2-alkynoic acids
*
Hongchao Zheng, Dennis G. Hall
Department of Chemistry, Gunning-Lemieux Chemistry Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
a r t i c l e i n f o
a b s t r a c t
Article history:
The concept of boronic acid catalysis (BAC) for the activation of unsaturated carboxylic acids is applied to
the Diels–Alder cycloaddition between 2-alkynoic acids as dienophiles and various dienes. These [4+2]
cycloadditions produce cyclohexadienyl carboxylic acids, which can be oxidized in situ to produce poly-
substituted aromatic carboxylic acids. The boronic acid catalyst is suspected to provide activation by a
LUMO-lowering effect of the unsaturated carboxylic acid likely via a covalent, monoacylated hemiboronic
ester intermediate.
Received 13 April 2010
Revised 30 April 2010
Accepted 30 April 2010
Available online 7 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The quest for new ways of catalyzing important organic reactions
is of utmost importance in order to expand the substrate scope or the
selectivity of existing transformations, or to allow new bond-form-
ing processes to occur.1 Catalytic activation of carboxylic acids is dif-
ficult to achieve because of the inherent chemical properties of this
functional group. The acidic character of carboxylic acids can create
chemical compatibility issues. As a result, the carboxylic acid func-
tionality is usually handled in a masked form such as a suitable car-
boxylic ester, which requires additional synthetic steps. A direct
method for electrophilic (or LUMO-lowering) activation of unsatu-
rated carboxylic acids toward cycloadditions would be very advan-
tageous in terms of atom- and step-economy. We recently
demonstrated this concept in [4+2] cycloadditions of acrylic acid
catalyzed by arylboronic acids (Fig. 1).2 The same concept was also
applied to several classical dipolar [3+2] cycloadditions.3 Herein,
we extend this concept to the use of 2-alkynoic acids in [4+2] cyc-
loadditions to access polysubstituted cyclohexadienes and arenes
functionalized with a carboxylic acid (Fig. 1). Faster reactions, milder
conditions, and increased regioselectivity are the main benefits pro-
vided by boronic acid catalysis (BAC).4
ortho-Halo-substituted arylboronic acids were previously found
to be potent catalysts in [4+2] cycloadditions of acrylic acid, there-
fore our initial screening of potential catalysts focused on the same
class of boronic acids along with a few more electron-poor arylbo-
ronic acids (Table 1, entries 1–6). It was found that ortho-bromo-
phenylboronic acid was the most efficient amongst the boronic
acids tested (Table 1, entry 6). Solvent dependency was next exam-
ined and chlorinate solvent CH2Cl2 was found to be superior for
this reaction (Table 1, entries 6–10), whereas the same cycloaddi-
tion gave only 3% yield in the absence of the boronic acid catalyst
(Table 1, entry 13). It is noteworthy that a low yield was obtained
in the presence of molecular sieves (Table 1, entry 11), which is in
line with our previous reports on [4+2] cycloadditions2 of acrylic
acid and [3+2] dipolar cycloadditions.3 Indeed, as depicted in
Figure 1, a small amount of water formed by the condensation be-
tween the boronic acid and the carboxylic acid is necessary to al-
low the catalyst turnover. However, excess water reduced the
product yield substantially (Table 1, entry 12).
Using the optimal conditions, the scope of diene was explored
using propiolic acid as the dienophile (Table 2).5 In the event, a
wide selection of substituted butadienes was tolerated. In all cases,
the boronic acid-catalyzed variant gave greatly improved yields.
O
O
OH
OH
R
R
ArB(OH)2
H2O
H
H
O
O
B
O
O
B
O
Ar
O
Ar
R
Figure 1. Catalytic cycle for the boronic acid-catalyzed Diels–Alder cycloadditions
of unsaturated carboxylic acids.
* Corresponding author. Tel.: +1 780 492 3141; fax: +1 780 492 8231.
E-mail address: dennis.hall@ualberta.ca (D.G. Hall).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.132

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H. Zheng, D. G. Hall / Tetrahedron Letters 51 (2010) 3561–3564
Table 1
Table 2
Optimization of reaction conditions for the BAC of a model Diels–Alder cycloaddition
Substrate scope for the BAC of Diels–Alder cycloadditions with propiolic acida
with propiolic acida
o-Br-C6H4B(OH)2
COOH
(20 mol%)
R
diene
+
cycloadduct
CH2Cl2 1.0 M
25 °C, 48 h
B(OH)2
1
(2 equiv)
(1 equiv)
COOH
COOH
(20 mol%)
+
Entry
1
Diene
t (h)
Product
Yieldb (%)
86 (3)
solvent1.0 M
25 oC, 48h
(2 equiv)
(1 equiv)
1a
COOH
48
48
8
Entry
R=
Solventb
Yieldc (%)
1a
1
2
3
4
5
6
7
8
9
10
11d
12e
13f
I
F
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
MeOH
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
80
52
71
39
82
86
80
6
59
24
20
71
3
Cl
CN
NO2
Br
Br
Br
Br
Br
Br
Br
—
COOH
2
3
83c (6d)
91 (6)
1b
COOH
1c
H
H3C
H3C
CH3
COOH
a
92e (3f)
Reaction procedure: propiolic acid (1.0 mmol) and boronic acid (0.2 mmol)
were mixed in the indicated solvent (1 mL), stirred at 25 °C for 10 min, followed by
the addition 2,3-dimethyl-1,3-butadiene (2.0 mmol), and stirred at 25 °C for 48 h.
4
6
H3C
H3C
b
Dry, distilled solvents were employed.
Isolated yields of product after purification by flash column chromatography.
With 4 Å molecular sieves (1.0 g) added.
1d
COOH
c
d
O
O
e
With 1.0 equiv of water added.
O
O
f
5
6
6
2
98 (Trace)
96 (4)g
Control reaction: no boronic acid was added.
1e
O
Acyclic dienes proceeded smoothly under optimized conditions
(Table 2, entries 1 and 2). Interestingly, for the asymmetric diene,
complete regioselectivity was realized under BAC (Table 2, entry
2). Compared to the linear dienes, cyclopentadiene reacted even
more efficiently (Table 2, entry 3). In the case of a substituted
cyclopentadiene, a mixture of diastereoisomers (3:1) was obtained
(Table 2, entry 4). To our satisfaction, furans are also suitable sub-
strates for this cycloaddition, the double Diels–Alder cycloadduct
1e and the dienecarboxylic acid 1f (not stable at room temperature
after isolation) were obtained in excellent yields (Table 2, entries 5
and 6). The ring size of cyclic dienes played an important role in the
reaction, the larger the ring size, the lower the reaction yield (Ta-
ble 2, entries 3–9). For instance, only trace amount of product in
the crude reaction mixture was detected with cycloocta-1,3-diene
after 30 days (Table 2, entry 9).
COOH
COOH
COOH
1f
7
8
48
72
82 (Trace)
62 (Trace)
1g
1h
COOH
9
720
Trace (0)
1i
To further expand this methodology, substituted 2-butynoic
acids were employed as the dienophiles (Table 3). With 2,3-di-
methyl-1,3-butadiene, the desired dienecarboxylic acids 2a–c
were obtained in acceptable yields using a slightly elevated tem-
perature and longer reaction times (Table 3, entries 1–3). Com-
pared to 2,3-dimethyl-1,3-butadiene, cyclopentadiene showed
much better reactivity and could react with substituted 2-butynoic
acids to provide the desired cycloadducts 2d–f in excellent yields
under relatively mild conditions (Table 3, entries 4–6).
a
Reaction procedure: see Table 1.
Isolated yields of product after purification by flash column chromatography.
b
Yields in bracket represent the control reactions performed without boronic acid as
the catalyst.
c
Only one regioisomer was obtained.
Regioisomeric ratio: 1:1.
Diastereomeric ratio: 3:1.
Diastereomeric ratio: 3:1.
d
e
f
g
Product is unstable and decomposes quite rapidly at room temperature.
The 1,4-cyclohexadienyl carboxylic acids 1 and 2 synthesized
by this method could be conveniently converted to synthetically
and biologically useful polysubstituted arylcarboxylic acids
(Scheme 1).6 Thus, DDQ-mediated aromatization of dienecarboxy-
lic acid 1a afforded the polysubstituted arene 3a in nearly quan-
Although the underlying mechanism remains to be elucidated,
previous mechanistic NMR studies3 using the Childs method9
showed that this concept of BAC of Diels–Alder cycloadditions of
2-alkynoic acids most likely operates through a powerful LUMO-
lowering activation of the dipolarophile by the formation of a cova-
lent adduct between the boronic acid and the unsaturated carbox-
ylic acid (Fig. 1).
In summary, we have reported the application of boronic acid
catalysis (BAC) for the activation of propiolic acid and 2-butynoic
acids in the classical [4+2] cycloaddition involving acyclic and cyclic
titative yield.7 Based on this promising result,
a one-pot
sequential boronic acid-catalyzed Diels–Alder cycloaddition/aro-
matization was envisioned for maximizing step-economy and
synthetic efficiency (Scheme 2). Following the one-pot proce-
dure,8 the polysubstituted arenes 3a–c were obtained in good
to excellent yields.

H. Zheng, D. G. Hall / Tetrahedron Letters 51 (2010) 3561–3564
3563
Table 3
Substrate scope for the BAC of Diels–Alder cycloadditions with substituted 2-butynoic acidsa
o-Br-C6H4B(OH)2
(20 mol%)
solvent 1.0 M
diene
(2 equiv)
+
dienophile
(1 equiv)
cycloadduct
2
Entry
1
Dienophile
Diene
Solvent
CH2Cl2
T (°C)
t (h)
Product
2a
Yieldb (%)
COOH
COOH
COOH
COOH
25
8
89 (18)
COOH
COOH
2
3
ClCH2CH2Cl
50
50
96
48
44 (Trace)
41 (Trace)
2b
CH3
COOH
COOH
Ph
THF
Ph
2c
COOH
COOH
COOH
4
CH2Cl2
25
48
84 (12)
COOH
COOH
2d
2e
COOH
5
6
CH2Cl2
THF
25
25
48
48
81 (7)
CH3
COOH
COOH
85 (12)
Ph
Ph
2f
a
Reaction procedure: see Table 1.
b
Isolated yields of product after purification by flash column chromatography. Yields in bracket represent the control reactions performed without boronic acid as the
catalyst.
butadienes as partners. These cycloadditions produce 1,3-cyclo-
hexadienyl carboxylic acids mildly and effectively. In all cases, boro-
nic acid catalysis provides faster reactions under milder conditions,
with much improved product yields and regioselectivity. Based on
previous work,3 it is assumed that boronic acid catalysis provides
activation by a LUMO-lowering effect of the unsaturated carboxylic
acid via a monoacylated hemiboronic ester intermediate.
COOH
COOH
DDQ (1 equiv)
CH2Cl2, 25 oC
4 h
1a
3a
95%
Scheme 1. DDQ aromatization of 1a into 3a.
Acknowledgments
a)
o-Br-C6H4B(OH)2
(20 mol%)
COOH
COOH
CH2Cl2, 25 oC, 48 h
This research was generously funded by the Natural Sciences
and Engineering Research Council (NSERC) of Canada (E.W.R. Stea-
cie Memorial Fellowship to D.G.H.) and the University of Alberta.
HZ thanks the Alberta Ingenuity Foundation for a Graduate
Scholarship.
+
+
b) DDQ (1 equiv)
25 oC, 4 h
3a
85%
(2 equiv)
(1 equiv)
a)
o-Br-C6H4B(OH)2
(20 mol%)
Supplementary data
COOH
COOH
COOH
DCE, 50 oC, 96 h
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.132.
b) DDQ (1 equiv)
25 oC, 4 h
3b
(2 equiv)
(2 equiv)
(1 equiv)
40%
References and notes
a)
o-Br-C6H4B(OH)2
1. For recent reviews on transition metal catalyzed chemical transformations, see:
(a) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–
4315; (b) Diez-Gonzalez, S.; Marion, N.; Nolan, S. P. Chem. Rev. 2009, 109, 3612–
3676; (c) Homden, D. M.; Redshaw, C. Chem. Rev. 2008, 108, 5086–5130; For
recent reviews on cyclic amine catalyzed chemical transformations, see: (d)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–
5569; (e) MacMillan, D. W. C. Nature 2008, 455, 304–308; (f) Gaunt, M. J.;
Johansson, C. C. C. Chem. Rev. 2007, 107, 5596–5605; (g) Dondoni, A.; Massi, A.
Angew. Chem., Int. Ed. 2008, 47, 4638–4660; For recent reviews on gold catalyzed
chemical transformations, see: (h) Furstner, A.; Davies, P. W. Angew. Chem., Int.
(20 mol%)
COOH
CH2Cl2, 25 oC, 48 h
b) DDQ (1 equiv)
+
25 oC, 4 h
3c
80%
(1 equiv)
Scheme 2. One-pot sequential boronic acid-catalyzed Diels–Alder cycloaddition/
aromatization.

3564
H. Zheng, D. G. Hall / Tetrahedron Letters 51 (2010) 3561–3564
Ed. 2007, 46, 3410–3449; (i) Hashimi, A. S. K. Chem. Rev. 2007, 107, 3180–3211;
title 1,3-cyclohexadienyl carboxylic acid 1a (131 mg, 86%) as a white solid in pure
form. 1H NMR (400 MHz, CDCl3 with one drop DMSO-d6) d 11.70 (br s, 1H), 7.12–
7.08 (m, 1H), 2.90–2.82 (m, 1H), 1.73–1.66 (m, 1H); 13C NMR (100 MHz, CDCl3
with one drop DMSO-d6) d 169.0, 136.5, 128.2, 123.2, 121.1, 34.0, 31.7, 18.4, 17.9;
IR (Microscope, cmÀ1) 3400–2300, 1710, 1649; HRMS (EI) for C9H12O2: calcd
152.08373; found 152.08355.
(j) Arcadi, A. Chem. Rev. 2008, 108, 3266–3325; (k) Jimenez-Nunez, E.;
Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350; (l) Li, Z.; Brouwer, C.; He,
C. Chem. Rev. 2008, 108, 3239–3265; (m) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
Chem. Rev. 2008, 108, 3351–3378; (n) Gorin, D. J.; Toste, F. D. Nature 2007, 446,
395–403.
2. Al-Zoubi, R.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47, 2876–2879.
3. Zheng, H.; McDonald, R.; Hall, D. G. Chem. Eur. J 2010, 16, 5454–5460.
6. Tewari, A. K.; Dubey, R. Bioorg. Med. Chem. 2008, 16, 126–143.
7. For examples of DDQ mediated aromatization, see: (a) Hilt, G.; Danz, M.
Synthesis 2008, 2257–2263; (b) Hilt, G.; Smolko, K. I. Angew. Chem., Int. Ed. 2003,
42, 2795–2797.
8. Typical experimental procedure for the preparations of polysubstituted arenes using
one-pot sequential boronic acid-catalyzed Diels–Alder cycloaddition/DDQ
4. For
a review on boronic acid catalyzed chemical transformations, see: (a)
Georgiou, I.; Ilyashenko, G.; Whiting, A. Acc. Chem. Res. 2009, 42, 756–768; For
examples of boronic acid catalyzed chemical transformations, see: (b) Letsinger,
R. L.; MacLean, D. B. J. Am. Chem. Soc. 1963, 85, 2227–2229; (c) Rao, G.; Philipp,
M. J. Org. Chem. 1991, 56, 1505–1512; (d) Maki, T.; Tshihara, H.; Yamamoto, H.
Synlett 2004, 1355–1358; (e) Debache, A.; Boumold, B.; Amimour, M.; Belfaitah,
A.; Rhouati, S.; Carboni, B. Tetrahedron Lett. 2006, 47, 5697–5699; (f) Debache,
A.; Boulcina, R.; Belfaitah, A.; Rhouati, S.; Carboni, B. Synlett 2008, 509–512; (g)
McCubbin, J. A.; Hosseini, H.; Krokhin, O. V. J. Org. Chem. 2010, 75, 959–962.
5. Typical experimental procedure for boronic acid-catalyzed Diels–Alder cycloadditions
aromatization: To
a solution of propiolic acid (70 mg, 1.0 mmol) in
dichloromethane (1 mL) was added ortho-bromophenylboronic acid (40 mg,
0.2 mmol) and the resulting solution was stirred at room temperature (25 °C) for
10 min. 2,3-Dimethyl-1,3-butadiene (164 mg, 2.0 mmol) was then added and
the resulting mixture was stirred at room temperature (25 °C) for 48 h. DDQ
(227 mg, 1.0 mmol) was added and the resulting mixture was stirred at room
temperature (25 °C) for 4 h. The solvent was removed under vacuum at room
temperature (25 °C). The residue was purified by silica gel column
chromatography (Et2O/n-pentane = 1:3) to give the title polysubstituted arene
3a (128 mg, 85%) as a white solid in pure form. The characterization data for this
compound matched that of a commercially available sample from Aldrich.
9. Childs, R. F.; Mulholland, D. L.; Nixon, A. Can. J. Chem. 1982, 60, 801–808.
of 2-alkynoic acids: To
a solution of propiolic acid (70 mg, 1.0 mmol) in
dichloromethane (1 mL) was added ortho-bromophenylboronic acid (40 mg,
0.2 mmol) and the resulting solution was stirred at room temperature (25 °C) for
10 min. 2,3-Dimethyl-1,3-butadiene (164 mg, 2.0 mmol) was then added and the
resulting mixture was stirred at room temperature (25 °C) for 48 h. The solvent
was removed under vacuum at room temperature (25 °C). The residue was
purified by silica gel column chromatography (Et2O/n-pentane = 1:3) to give the