Diels-alder reactions of β-acylacrylic acids

Article abstract of DOI:10.1080/00397911.2012.686002

The Diels-Alder reaction of β-acylacrylic acids with dienes gave good yields and good regio-or stereoselectivity of the corresponding cycloaddition products with the use of Lewis acids.

Full text of DOI:10.1080/00397911.2012.686002

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Diels-Alder Reactions of β-Acylacrylic Acids
William H. Miles a , Evan M. Cohen a & Barbara J. Naimoli a
a Department of Chemistry, Lafayette College, Easton, Pennsylvania, USA
Accepted author version posted online: 22 Jan 2013.
To cite this article: William H. Miles , Evan M. Cohen & Barbara J. Naimoli (2013): Diels-Alder Reactions of β-Acylacrylic
Acids, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI:10.1080/00397911.2012.686002
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Diels-Alder Reactions of β-Acylacrylic Acids
William H. Miles1, Evan M. Cohen1, Barbara J. Naimoli1
1Department of Chemistry, Lafayette College, Easton, Pennsylvania, USA
William H. Miles, Department of Chemistry, Lafayette College, Easton, PA 18042, USA
E-mail: milesw@lafayette.edu
Abstract
The Diels-Alder reaction of β-acylacrylic acids with dienes gave good yields and good
regio- or stereoselectivity of the corresponding cycloaddition products with the use of
Lewis acids.
KEYWORDS: Diels-Alder; Lewis acid; β-Acylacrylic acid, Acylboronate
INTRODUCTION
The Diels-Alder reaction is the most powerful synthetic method for the stereoselective
construction of cyclic compounds.1 Even for cases of diminished regio- and
stereoselectivity under thermal conditions, the addition of Lewis acid-catalysts often
enhances the selectivity to synthetically useful levels. (E)-1,2-disubstituted dienophiles
with two different electron-withdrawing groups are desirable partners in the Diels-Alder
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reaction because of their enhanced reactivity with dienes, but their synthetic utility is
diminished due to the necessity of differentiating between the two substituents (Scheme
1). Under thermal conditions, compounds such as (E)-methyl 4-oxopent-2-enoate,2 (E)-4-
oxopent-2-enoic acid,3 (E)-4-oxo-4-phenylbut-2-enoic acid,4 the monoethyl ester of
fumaric acid,5 (E)-3-(phenylsulfinyl)acrylic acid,6 and (E)-γ-oxo-α,β-unsaturated
thioesters7 react unselectively with cyclopentadiene to give a mixture of cycloaddition
products. There are examples of thermal Diels-Alder reactions of (E)-1,2-disubstituted
dienophiles exhibiting modest stereoselectivity and/or regioselectivy,8-10 with
Danishefsky’s study of trans-methyl β-nitroacrylate being the standard for regiochemical
(but not stereochemical) control.10
The employment of Lewis acid catalysts often dramatically improves the stereo- and/or
regioselectivy of the Diels-Alder reactions for many (E)-1,2-disubstituted
dienophiles.7,8,11-17 The improved selectivity appears to be the result of selective
complexation of one of the electron withdrawing groups. For example, the Ti(IV)-
catalyzed reaction of (E)-ethyl 4-oxopent-2-enoate with 2-substituted-1,3-butadienes
proceeds with excellent regiochemical control.14,15 The selective complexation of
unsymmetrical (E)-1,2-disubstituted dienophiles also appears to be operative for several
of the enantioselective catalysts used for the Diels-Alder reaction.16 The incorporation of
an alkoxy chelating group has directed the course of the Diels-Alder reactions for a series
of (E)-2-ene-1,4-diketones.17 Using a different strategy based on steric considerations,
Yamamoto employed a bulky Lewis acid to discriminate between different esters of
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unsymmetrical fumarates, with selective coordination and activation of the smaller (Me)
ester to dictate both regiochemistry and stereoselectivity.18
The use of acrylic acids in the Diels-Alder reaction is problematic because they are
viewed as sluggish dienophiles and can lead to decomposition of sensitive dienes.19-22
The generation of acylboronates, either by the reaction of acrylic acids with boron
hydrides19 or boronic acids,20,21 has partially ameliorated these problems. The reaction of
acrylic acid with BH3·THF to form the acylboronate greatly accelerated the Diels-Alder
reaction (relative to acrylic acid) with cyclopentadiene.19 Further improvements have
been made employing boronic acids as the catalysts for the reaction of acrylic acid20 and
2-alkynoic acids21 with dienes. In the case of β-acylacrylic acids, the thermal Diels-Alder
reactions with cyclopentadiene are not diastereoselective.3,4 We are unaware of any
studies employing Lewis acids or boronic acids to influence the outcome of the Diels-
Alder reaction of β-acylacrylic acids despite their synthetic potential. This paper
describes a systematic examination of the Diels-Alder reaction of β-acylacrylic acids
under various conditions with the goal of selectively activating either the acyl group or
the carboxylic acid to give products with high diastereo- or regioselectivity (Scheme 2).
RESULTS AND DISCUSSION
β-Acylacrylic acids are readily available by a variety of synthetic approaches such as the
Mannich reaction of ketones with glyoxylic acid,23 Friedel-Crafts reaction of maleic
anhydride,24 the oxidation of furans,25,26 and the isomerization of electron-deficient
propargylic alcohols.27 We centered our initial studies on the Diels-Alder reactions of
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commercially available (E)-(4-CH3C6H4)COCH=CHCO2H, 1a. We observed a narrow
range of diastereoselectivity in the thermal reaction of 1a with cyclopentadiene in various
solvents (entries 1-5, Table 1), from 42/58 (endo-2a/exo-2a; the endo and exo
designations used here are arbitrary but simplifies the abbreviated labels for the
compounds) in benzene to 61/39 in methanol. Although water often leads to enhanced
diastereoselectivity in the Diels-Alder reaction, we observed nearly equal amounts of
endo-2a and exo-2a (entry 5) in the reaction of 1a with cyclopentadiene. Deprotonation
of the carboxylic acid to generate the carboxylate lead to greater selectivity (~3:1; entries
6-11) but slower reactions in organic solvents (entries 10 and 11). Inexplicably, the
counter ion and solvent appeared to have very little effect on the diastereoselectivity. The
addition of some common Lewis acids (SnCl4, TiCl4, BF3) that promote Diels-Alder
reactions led to only moderate yields and/or products difficult to purify in the reaction of
1a with cyclopentadiene under conditions where the thermal reaction was slow. The
reaction proceeded more cleanly and in higher yields if the carboxylate was first prepared
before the addition of the Lewis acid (entry 12 and 13). The optimal amount of SnCl4 was
high (2 mol equiv per 1a); we assume one equivalent of SnCl4 is consumed in the
reaction of the carboxylate to make the tin carboxylate. Sc(OTf)3 stands out as the only
Lewis acid we uncovered that did not require an equivalent of amine (entry 14). With
lower catalyst loading, Sc(OTf)3 gave more erratic yields but comparable
diastereoselectivity. The stoichiometric generation of the acylboronate by the addition of
1/3 equiv of BH3·THF lead to a reversal in the diastereoselectivity, favoring the exo
product by a 4:1 ratio (entry 15).
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With the optimized procedures secured from our studies of the reaction of 1a with
cyclopentadiene, we examined the reaction of 1a with 1,3-cyclohexadiene, 2,3-dimethyl-
1,3-butadiene and isoprene (Scheme 1). The thermal reaction of 1a with 1,3-
cyclohexadiene was relatively unselective (entry 1, Table 2), but the DIPEA/TiCl4
protocol (entry 2) gave excellent diastereoselectivity and yields of 3a. Although there are
no selectivity issues in the reaction of 2,3-dimethyl-1,3-butadiene with 1a, the
DIPEA/SnCl4 protocol efficiently catalyzed the reaction (entries 3, 4) to give 4. The
thermal Diels-Alder reaction of 1a with isoprene gave regioisomers para-5a and meta-5a
(the para and meta designations used here again are arbitrary) with little selectivity, but
the DIPEA/SnCl4 and DIPEA/TiCl4 protocols gave 5a in good yields and moderate
regioselectivity (entries 5-7). Lowering the temperature for this reaction gave improved
regioselectivity (10-15:1, para-5a:meta-5b) but came at the cost of incomplete
conversion. Activation of 1a by the formation of the acylboronate (entry 8) reversed the
regioselectivity of the reaction of 1a with isoprene. The use of Sc(OTf)3 as a catalyst in
the reaction of 1a with the less reactive dienes 1,3-cyclohexadiene and isoprene gave
only low to moderate yields of the Diels-Alder products. A similar problem was
encountered in attempting to activate the carboxylic acid group of 1a by the addition of
BH3·THF. The reaction of the acylboronate with 1,3-cyclohexadiene and isoprene was
very slow and gave only moderate yields of Diels-Alder products.
We also investigated the Diels-Alder reaction of aliphatic acyl compounds 1b and 1c
(Table 3). The thermal Diels-Alder reactions of 1b with cyclopentadiene, and 1b and 1c
with 1,3-cyclohexadiene proceeded with little diastereoselectivity (entries 1, 4, and 11).
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The DIPEA/SnCl4 protocol greatly improved the diastereoselectivity to give the
cycloadducts with high endo-acyl selectivity in good yields (entries 2, 5, and 12). Once
again, Sc(OTf)3 was an excellent catalyst in the reaction of 1b with cyclopentadiene
(entry 3), but did not give synthetically useful yields in the reactions of 1b or 1c with 1,3-
cyclohexadiene or isoprene. The reaction rate of 1b with 2,3-dimethylbutadiene was
enhanced by the SnCl4/DIPEA protocol (entries 6 and 7) although gave lower yields of
cycloaddition product 4b. The thermal reaction of 1b and 1c with isoprene proceeded
with little regioselectivity (entries 8 and 13) but was greatly improved by the
SnCl4/DIPEA protocol (entries 9 and 14), although the yields were only moderate. There
was a modest activation of the carboxylic acid group of 1b by BH3·THF to give meta-5b
in its reaction with isoprene but the yields and stereoselectivity were only fair (entry 10).
Our success in using the SnCl4/DIPEA and TiCl4/DIPEA protocols appears to be the
result of selective complexation of the acyl group over the carboxylate (Scheme 3). The
first equivalent of SnCl4 reacts with the carboxylate that was formed upon the addition of
DIPEA to 1 to give the tin carboxylate, and the second equivalent of SnCl4 complexes
with the acyl group. To test this mechanistic interpretation, we did several control
experiments. The reaction of 1a with 1,3-cyclohexadiene (one equiv of SnCl4, 1.05 equiv
of DIPEA; -42 °C ; 2 h) gave recovered starting material and less than a 5% yield of
Diels-Alder products 3a. The reaction of acrylic acid with 1,3-cyclohexadiene (two equiv
of SnCl4, 1.05 equiv of DIPEA; -42°C; 2 h) gave only recovered starting materials and no
Diels-Alder products, whereas the reaction of methyl vinyl ketone with 1,3-
cyclohexadiene (one equiv of SnCl4; -42°C; 2 h) gave an excellent yield of the endo-
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Diels-Alder product. In the case of Sc(OTf)3, the selectivity appears to be a selective
complexation of the acyl group over the carboxylic acid. Using the original Yamamota
procedure,19 the addition of BH3·THF to 1 gave acylboronates that appear to induce a
greater electron deficiency at the carboxylic terminus than at the acyl terminus, leading to
modest selectivity. We attempted to employ Hall’s recent chemistry20,21 employing
boronic acids as activators, but there was very little enhancement of the rate of reaction of
1 with less reactive dienes, even when we employed a full equivalent of the boronic acid.
Since a first step involves the carboxylic acid reacting with the boronic acid to give the
acylboronate and water, the nucleophilicity of the carboxylic acid, greatly reduced due to
the electron-withdrawing acyl group, may be not be sufficient for this key step in the
catalytic cycle. There are a number of other experimental variables, however, so we are
continuing to investigate improvements in the activation of the carboxylic group.
CONCLUSION
We have successfully employed acylacrylic acids as stereo- and regioselective
dienophiles in the Diels-Alder reaction. The selective activation of the acyl group was
affected by the use of SnCl4/DIPEA, TiCl4/DIPEA or Sc(OTf)3 in many examples. The
complimentary activation of the carboxylic acid was affected by the generation of the
acylboronate, although regio- and stereoselectivity were modest and yields were usually
poorer. These studies will be useful for guiding efforts in the Diels-Alder reactions of
related acrylic acids and for the development of intramolecular versions employing
acrylic acids.
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ACKNOWLEDGMENTS
We thank the Petroleum Research Foundation, administered by the American Chemical
Society, and Lafayette College’s Academic Research Committee, for financial support.
We gratefully acknowledge a grant from the Kresge Foundation for the purchase of a 400
MHz NMR spectrometer.
EXPERIMENTAL
All reactions were carried out under Ar. All glassware was dried in the oven (110 °C)
before use. IR spectra were obtained on a Mattson Satellite FT-IR. The 1H and 13C NMR
spectra were recorded at 400 MHz and 100 MHz, respectively, on a JEOL Eclipse+400
spectrometer. All chemical shifts in the 1H NMR are reported in ppm relative to TMS
(δ=0.00 ppm) or CHCl3 (δ=7.26 ppm) and in the 13C NMR are reported in ppm relative to
CDCl3 (δ=77.16 ppm). Flash chromatography was performed on 60 Å silica gel (40-75
µm). Methylene chloride was dried over molecular sieves. Melting points were measured
on a Mel-Temp II and are uncorrected.
Typical Procedure For The Diels-Alder Reaction Of 1
To a solution of 4-(4-methylphenyl)-4-oxobut-2-enoic acid 1a (0.384 g, 2.00 mmol) in
CH2Cl2 (5 mL) was added DIPEA (0.44 mL, 0.33 g, 2.5 mmol) and 1,3-cyclohexadiene
(0.57 mL, 0.48 g, 6.0 mmol). The reaction mixture was cooled to -42 °C and TiCl4 (0.33
mL, 0.57 g, 3.0 mmol) was added dropwise. After stirring for 2 h at -42 °C, the reaction
mixture was poured into water (10 mL) and stirred for 10 min. The reaction mixture was
transferred to a separatory funnel and extracted with CH2Cl2 (2 x 25 mL). The combined
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organic phases were gently washed with brine (50 mL), dried over Na2SO4, filtered, and
concentrated on the rotary evaporator (the crude 1H NMR indicated a 96:4 ratio of endo-
3a:exo-3a). The crude product was purified by flash chromatography (25 g silica gel;
hexanes → 25% EtOAc in hexanes) to give endo-3a (endo-3a:exo-3a 96:4) as a white
solid (0.503 g, 93% yield).
Compound Characterization
3-Endo-(4-Methylbenzoyl)Bicyclo[2.2.1]Hept-5-Ene-2-Exo-Carboxylic Acid (Endo-
2a).5
White solid (endo-2a:exo-2a, 93:7), mp = 117-122 °C; IR (CH2Cl2) 1740, 1702, 1678
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H),
6.31 (dd, J = 3.3, 5.5 Hz, 1H), 5.82 (dd, J = 2.6, 5.5 Hz, 1H), 4.26 (app t, J = 4.0 Hz, 1H),
3.31 (br s, 1H), 3.28 (d, J = 1.5 Hz, 1H), 3.10 (dd, J = 1.5, 4.7 Hz, 1H), 2.42 (s, 3H), 1.81
(d, J = 8.4 Hz, 1H), 1.52 (dd, J = 1.5, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 198.2,
181.1, 144.0, 137.4, 134,2, 133.9, 129.4, 128.6, 51.2, 48.2 (2C), 48.1, 45.7, 21.8. exo-2a.
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 6.43
(dd, J = 3.1, 5.5 Hz, 1H), 6.24 (dd, J = 2.9, 5.5 Hz, 1H), 3.75 (app t, J = 4.0 Hz, 1H), 3.60
(dd, J = 1.5, 4.4 Hz, 1H), 3.35 (br s, 1H), 3.05 (br s, 1H), 2.42 (s, 3H), 1.68 (d, J = 8.8
Hz, 1H), 1.42 (dd, J = 1.5, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 199.3, 180.0,
144.2, 137.7, 136.1, 134.0, 129.5, 128.9, 50.1, 48.9, 46.8, 46.7, 45.9, 21.8.
3-Endo-(4-Methylbenzoyl)Bicyclo [2.2.2]Oct-5-Ene-2-Exo-Carboxylic Acid (Endo-
3a).
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White solid (endo-3a:exo-3a, 96:4), mp = 143-146 °C; IR (CH2Cl2) 1739, 1702, 1679
cm-1; 1H NMR (400 MHz, CDCl3) δ7.86 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H),
6.41 (t, J = 7.5 Hz, 1H), 6.00 (t, J = 7.1 Hz, 1H), 4.02 (dd, J = 1.6, 5.7 Hz, 1H), 3.33-3.29
(m, 1H), 3.13-3.09 (m, 1H), 2.92-2.88 (m, 1H), 2.41 (s, 3H), 1.89-1.79 (m, 1H), 1.74-
1.65 (m, 1H), 1.35 (tt, J = 3.7, 11.7 Hz, 1H), 1.29-1.19 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ199.5, 180.4, 143.9, 134.6, 133.6, 131.4, 129.5, 128.7, 47.5, 44.4, 34.2, 32.5,
25.6, 21.7, 20.6. Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.46; H, 6.80.
exo-3a. 1H NMR (400 MHz, CDCl3) δ7.89 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H),
6.45 (t, J = 7.0 Hz, 1H), 6.31 (t, J = 7.1 Hz, 1H), 3.84-3.80 (m, 1H), 3.56-3.52 (m, 1H),
3.15-3.11 (m, 1H), 2.85-2.81 (m, 1H), 2.42 (s, 3H), 1.74-1.64 (m, 1H), 1.41-1.20 (m,
2H), 1.03-0.93 (m, 1H); 13C NMR (100 MHz, CDCl3) δ199.3, 180.9, 144.0, 134.7, 133.8,
133.2, 129.5, 128.8, 48.8, 43.7, 33.8, 32.4, 24.2, 21.7, 19.7.
3,4-Dimethyl-6-(4-Methylbenzoyl)Cyclohex-3-Enecarboxylic Acid (4a).27
White solid, mp = 161-163.5 °C (lit 167.5 °C). IR (CH2Cl2) 1748, 1709, 1675 cm-1; 1H
NMR (400 MHz, CDCl3) δ7.86 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 7.7 Hz, 2H), 3.73 (dt, J =
5.4, 11.4 Hz, 1H), 3.05 (dt, J = 5.8, 11.4 Hz, 1H), 2.40 (s, 3H), 2.41-2.34 (m, 1H), 2.29-
2.18 (m, 2H), 1.98 (br t, J = 13.7 Hz, 1H), 1.65 (s, 3H), 1.59 (s, 3H); 13C NMR (100
MHz, CDCl3) δ202.5, 181.3, 144.0, 133.7, 129.5, 128.8, 124.4 (2 C), 43.8, 41.9, 35.5,
34.6, 21.8, 18.81, 18.76.
3-Methyl-6-(4-Methylbenzoyl)Cyclohex-3-Enecarboxylic Acid (Para-5a).
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White solid (para-5a:meta-5a, 82:18), mp = 137-148 °C. IR (CH2Cl2) 1744, 1712, 1680
cm-1; 1H NMR (400 MHz, CDCl3) δ7.85 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H),
5.39 (br s, 1H), 3.69 (dt, J = 5.2, 11.1 Hz, 1H), 3.11 (dt, J = 5.7, 11.3 Hz, 1H), 2.40 (s,
3H), 2.40-2.17 (m, 3H), 2.04-1.93 (m, 1H), 1.70 (br s, 3H); 13C NMR (100 MHz, CDCl3)
δ202.6, 181.6, 144.0, 133.6, 132.6, 129.4, 128.7, 119.4, 43.4, 42.9, 33.0, 29.6, 23.1, 21.7.
Anal. Calcd for C16H18O3: C, 74.39; H, 7.02. Found: C, 74.21; H, 7.20. Meta-5a ; 1H
NMR (400 MHz, CDCl3) δ7.86 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 7.7 Hz, 2H), 5.44 (br s,
1H), 3.78 (dt, J = 5.1, 11.0 Hz, 1H), 3.10 (dt, J = 5.5, 11.2 Hz, 1H), 2.53-2.43 (m, 1H),
2.40 (s, 3H), 2.40-2.20 (m, 2H), 2.04-1.91 (m, 1H), 1.64 (br s, 3H); 13C NMR (100 MHz,
CDCl3) δ202.5, 181.5, 144.0, 133.6, 132.6, 129.4, 128.7, 119.4, 43.4, 41.2, 33.9, 28.5,
23.1, 21.7.
3-Endo-Acetylbicyclo[2.2.1]Hept-5-Ene-2-Exo-Carboxylic Acid (Endo-2b).2,3
White solid (endo-2b:exo-2b, 89:11), mp = 116-120 °C. IR (CH2Cl2) 1740, 1708, 1678
(shoulder) cm-1; 1H NMR (400 MHz, CDCl3) δ6.25 (dd, J = 3.1, 5.7 Hz, 1H), 5.98 (dd, J
= 2.7, 5.4 Hz, 1H), 3.40 (t, J = 4.2 Hz, 1H), 3.31 (br s, 1H), 3.20 (br s, 1H), 2.81 (dd, J =
1.5, 4.7 Hz, 1H), 2.17 (s, 3H), 1.65 (br d, J = 8.8 Hz, 1H), 1.52-1.47 (m, 1H), ; 13C NMR
(100 MHz, CDCl3) δ206.8, 180.7, 137.8, 134.0, 56.7, 48.1, 47.7, 46.0, 45.2, 28.9. Exo-
2b. 1H NMR (400 MHz, CDCl3) δ6.30 (dd, J = 3.2, 5.6 Hz, 1H), 6.17 (dd, J = 2.7, 5.7
Hz, 1H), 3.45 (t, J = 4.0 Hz, 1H), 3.26 (br s, 1H), 3.05 (br s, 1H), 2.79 (dd, J = 1.8, 4.4
Hz, 1H), 2.27 (s, 3H), 1.46 (br d, J = 8.8 Hz, 1H), 1.39 (dd, J = 1.5, 8.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 208.4, 179.8, 137.7, 135.9, 55.5, 46.80, 46.76, 46.5, 45.4,
29.7.
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3-Endo-Acetylbicyclo[2.2.2]Oct-5-Ene-2-Exo-Carboxylic Acid (Endo-3b).
White solid (endo-3b:exo-3b, 92:8), mp = 77-84 °C. IR (CH2Cl2) 1740, 1710, 1680
(shoulder) cm-1; 1H NMR (400 MHz, CDCl3) δ6.32 (br t, J = 7.3 Hz, 1H), 6.07 (br t, J =
7.5 Hz, 1H), 3.10 (dd, J = 1.8, 5.5 Hz, 1H), 3.05-2.90 (m, 3H), 2.16 (s, 3H), 1.69-1.55
(m, 2H), 1.40-1.28 (m, 1H), 1.20-1.11 (m, 1H); 13C NMR (100 MHz, CDCl3) δ208.1,
180.0, 134.9, 131.5, 53.4, 44.0, 32.40, 32.36, 28.2, 25.1, 20.6. Anal. Calcd for C11H14O3:
C, 68.02; H, 7.27. Found: C, 68.09; H, 7.37. Exo-3b. 1H NMR (400 MHz, CDCl3) δ6.38
(br t, J = 7.3 Hz, 1H), 6.24 (br t, J = 7.3 Hz, 1H), 3.29 (dd, J = 2.2, 5.1 Hz, 1H), 3.05-2.90
(m, 3H), 2.21 (s, 3H), 1.60-1.20 (m, 3H), 1.14-1.04 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ208.0, 180.5, 134.5, 133.2, 55.4, 43.3, 32.3, 32.2, 28.7, 24.1, 20.0.
6-Acetyl-3,4-Dimethylcyclohex-3-Enecarboxylic Acid (4b).28
White solid, mp = 158-160 °C (lit 166-167 °C with sintering, after recrystallization). IR
(CH2Cl2) 1744, 1709, 1680 (shoulder) cm-1; 1H NMR (400 MHz, CDCl3) δ2.92 (dt, J =
5.4, 8.5 Hz, 1H), 2.82 (dt, J = 5.4, 8.5 Hz, 1H), 2.35-2.20 (m, 2H), 2.21 (s, 3H), 1.99-1.87
(m, 1H), 1.62 (br s, 6H); 13C NMR (100 MHz, CDCl3) δ211.2, 181.6, 124.4, 123.9, 49.0,
41.6, 34.3, 33.8, 29.0, 18.8, 18.7.
6-Acetyl-3-Methylcyclohex-3-Enecarboxylic Acid (Para-5b).
White solid (para-5b:meta-5b, 92:8), mp = 127.5-130 °C. IR (CH2Cl2) 1745, 1708,
1680 (shoulder) cm-1; 1H NMR (400 MHz, CDCl3) δ5.40 (br s, 1H), 2.90-2.83 (m, 2H),
2.40-2.28 (m, 2H), 2.22 (s, 3H), 2.16-2.04 (m, 1H), 1.99-1.86 (m, 1H), 1.66 (br s, 3H);
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13C NMR (100 MHz, CDCl3) δ211.3, 181.6,132.7, 118.9, 48.0, 41.3, 32.7, 29.0, 27.8,
23.1. Anal. Calcd for C10H14O3: C, 65.91; H, 7.74. Found: C, 66.38; H, 7.89. Meta-5b. 1H
NMR (400 MHz, CDCl3) δ5.40 (br s, 1H), 2.98 (dt, J = 5.5, 11.4 Hz, 1H), 2.80 (dt, J =
5.7, 11.0 Hz, 1H), 2.40-2.28 (m, 2H), 2.23 (s, 3H), 2.10-1.92 (m, 2H), 1.66 (br s, 3H). 13C
NMR (100 MHz, CDCl3) δ211.1, 181.7, 132.2, 118.9, 48.6, 40.8, 32.2, 28.3, overlap,
23.0.
3-Endo-Isobutyrylbicyclo[2.2.2]Oct-5-Ene-2-Exo-Carboxylic Acid (Endo-3c).
White solid (endo-3c:exo-3c, 93:7), mp = 75-78 °C. IR (CH2Cl2) 1739, 1704, 1680
(shoulder) cm-1; 1H NMR (400 MHz, CDCl3) δ6.36 (app t, J = 7.3 Hz, 1H), 6.04 (app t, J
= 7.5 Hz, 1H), 3.29-3.25 (m, 1H), 3.07-3.01 (m, 2H), 2.94-2.88 (m, 1H), 2.84 (heptet, J =
6.8 Hz, 1H), 1.73-1.58 (m, 2H), 1.40-1.31 (m, 1H), 1.24-1.15 (m, 1H), 1.08 (d, J = 7.0
Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 214.0, 180.2, 134.7,
131.6, 51.0, 44.0, 38.6, 32.6, 326.3, 25.7, 20.5, 19.3, 18.4. Anal. Calcd for C13H18O3: C,
70.24; H, 8.16. Found: C, 71.07; H, 8.37. Exo-3c. Partial 1H NMR (400 MHz, CDCl3) δ
6.40 (app t, J = 7.5 Hz, 1H), 6.27 (app t, J = 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ213.9, 180.7, 134.7, 133.2, 52.2, 43.6, 39.0, 32.3, 32.1, 24.3, 20.0, 19.5, 17.9.
6-Isobutyryl-3-Methylcyclohex-3-Enecarboxylic Acid (Para-5c).
White solid (para-5c:meta-5c, 98:2), mp = 85-88 °C. IR (CH2Cl2) 1745, 1707, 1680
(shoulder) cm-1; 1H NMR (400 MHz, CDCl3) δ5.39 (br s, 1H), 3.02 (dt, J = 5.2, 11.9 Hz,,
1H), 2.93 (dt, J = 5.6, 11.0 Hz,, 1H), 2.81 (heptet, J = 6.9 Hz, 1H), 2.39-2.29 (m, 2H),
2.19-2.07 (m, 1H), 1.98-1.85 (m, 1H), 1.68 (br s, 3H), 1.11 (d, J = 7.0 Hz, 3H), 1.07 (d, J
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= 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 217.2, 181.3, 132.6, 119.2, 46.1, 41.6, 39.9, 32.9, 28.6, 23.1, 18.8, 18.1. Anal. Calcd for
C12H18O3: C, 68.54; H, 8.63. Found: C, 68.89; H, 8.76. meta-5c Partial 1H NMR (400
MHz, CDCl3) δ5.40 (br s, 1H), 3.10 (dt, J = 5.5, 11.4 Hz,, 1H), 1.12 (d, J = 7.0 Hz, 3H),
1.06 (d, J = 7.0 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 217.1, 181.8, 132.4, 119.2, 46.6,
41.1, 39.9, 33.0, 28.5, 23.5, 18.8, 18.1,
ACKNOWLEDGMENTS
We thank the Petroleum Research Foundation, administered by the American Chemical
Society, and Lafayette College’s Academic Research Committee, for financial support.
We gratefully acknowledge a grant from the Kresge Foundation for the purchase of a 400
MHz NMR spectrometer.
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Table 1. Diels-Alder Reaction of 1a with cyclopentadiene
Entry Solvent
Reagent/Cataly T
Time
(h)
18
1
Yield (%)b Endo-2a/exo-
sta
(°C)
2ac
1
C6H6
None
22
22
22
22
22
22
22
22
22
22
22
-78
-78
-78
0
100
98
99
93
98
81
87
96
95
98
93
56
86
96
66
42/58
56/44
47/53
61/39
56/44
74/26
77/23
77/23
76/24
77/23
73/27
91/9
2
CH3CN None
3
CH2Cl2
MeOH
H2O
None
None
None
NaOHd
1
4
18
3
5
6
H2O
1.5
1
d
7
H2O
K2CO3
Cs2CO3
DIPEA
d
8
H2O
1
9
H2O
1
10
11
12
13
14
15
CH3CN DIPEA
22
22
1
CH2Cl2
CH2Cl2
CH2Cl2
DIPEA
DIPEA/SnCl4
e
f
DIPEA/TiCl4
1
81/19
93/7
g
CH3CN Sc(OTf)3
1
CH2Cl2
BH3·THFh
1
19/81
aFor reactions employing DIPEA, 1.25 equiv of DIPEA per equiv of 1a.
bYield of isolated product as a mixture of endo-2a and exo-2a.
cDetermined by 1H NMR of the crude reaction mixture.
d1.0 equiv of base per equiv of 1a.
e2.0 equiv of SnCl4 per equiv of 1a.
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f1.5 equiv of TiCl4 per equiv of 1a.
g0.10 equiv of Sc(OTf)3 per equiv of 1a.
h0.33 equiv of BH3·THF per equiv of 1a.
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Table 2. Diels-Alder Reaction of 1a with dienes
Entry Dienea
Reagent/Cata T (°C) Time Yield Products (Ratio)d
lystb
(h)
24
2
(%)c
1
2
C6H8
C6H8
None
110
83
endo-3a/exo-3a (54/46)
endo-3a/exo-3a (96/4)
DIPEA/TiCl4 -42
93
e
3
4
(CH2=CMe) None
110
2
3
96
89
4a
4a
2
(CH2=CMe) DIPEA/SnCl4 -42
f
2
5
6
Isoprene
Isoprene
None
110
24
3
98
90
para-5a/meta-5a (53/47)
para-5a/meta-5a (80/20)
DIPEA/SnCl4 -42 to
f
0
7
Isoprene
DIPEA/TiCl4 -42 to
3
81
para-5a/meta-5a (81/19)
e
0
8
Isoprene
BH3·THFg
22
68
69
para-5a/meta-5a (21/79)
a Three equiv of diene per equiv of 1a.
bFor reactions employing DIPEA, 1.25 equiv per equiv of 1a.
cYield of isolated product as a mixture of stereoisomers for 3a and 5a.
dDetermined by 1H NMR of the crude reaction mixture.
e1.5 equiv of TiCl4 per equiv of 1a.
f2.0 equiv of SnCl4 per equiv of 1a.
g0.33 equiv of BH3·THF per equiv of 1a.
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Table 3. Diels-Alder Reactions of 1b and 1c with dienes
Entr
y
R
Dienea
Reagent/Cat T (°C)
alystb
Tim Yiel Products (Ratio)d
e (h) dc
(%)
1
2
CH3 Cp
CH3 Cp
None
22
22
1
90
83
endo-2b/exo-2b (48/52)
endo-2b/exo-2b (89/11)
DIPEA/SnC -78 to -
e
l4
20
f
3
CH3 Cp
Sc(OTf)3
-78 to -
20
1.5
74
endo-2b/exo-2b (97/3)
4
5
CH3 C6H8
CH3 C6H8
None
110
22
2
92
83
endo-3b/exo-3b (53/47)
endo-3b/exo-3b (94/6)
DIPEA/SnC -42
e
l4
6
7
CH3 (CH2=CMe None
110
22
2
86
58
4b
4b
)
2
CH3 (CH2=CMe DIPEA/SnC -42
e
)
l4
2
8
9
CH3 isoprene
CH3 isoprene
None
110
24
3
91
58
para-5b/meta-5b (52/48)
para-5b/meta-5b (91/9)
DIPEA/SnC -42 to 0
e
l4
10
11
12
CH3 isoprene
i-Pr C6H8
i-Pr C6H8
BH3·THFg
22
64
20
44
85
82
para-5b/meta-5b (36/64)
endo-3c/exo-3c (54/46)
endo-3c/exo-3c (92/8)
None
110
DIPEA/SnC -42 to 0 2.5
e
l4
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13
i-Pr isoprene
None
110
20
83
57
para-5c/meta-5c (51/49)
para-5c/meta-5c (97/3)
14
i-Pr isoprene
DIPEA/SnC -42 to 0 2.5
e
l4
a Three equiv. of diene per equiv of 1.
bFor reactions employing DIPEA, 1.05 equiv per equiv of 1.
cYield of isolated product as a mixture of stereoisomers for 2b, 3b, 5b, 3c, and 5c.
dDetermined by 1H NMR of the crude reaction mixture.
e2.0 equiv of SnCl4 per equiv of 1.
f0.10 equiv of Sc(OTf)3 per equiv of 1.
g0.33 equiv of BH3·THF per equiv of 1.
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Scheme 1. Diels-Alder reaction of (E)-1,2-disubstituted dienophiles.
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Scheme 2. Diels-Alder reactions of 1 with dienes.
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25

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Scheme 3. Proposed intermediates in the reaction of 1 with dienes.
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26