Synthesis of 6-substituted salicylates via biomimetic aromatization utilizing the cross metathesis of a vinyl dioxinone with homoallylic alcohols

Article abstract of DOI:10.1139/v2012-071

We herein report biomimetic syntheses of 6-substituted salicylates from the cross metathesis of 2,2-dimethyl-6-vinyl-1,3-dioxin-4-one with homoallylic alcohols, oxidation, and aromatization of the intermediate enone-dioxinones. Of particular note is the u

Full text of DOI:10.1139/v2012-071

975
Synthesis of 6-substituted salicylates via
biomimetic aromatization utilizing the cross
metathesis of a vinyl dioxinone with
homoallylic alcohols
Peter S. Blencowe and Anthony G.M. Barrett
Abstract: We herein report biomimetic syntheses of 6-substituted salicylates from the cross metathesis of 2,2-dimethyl-
6-vinyl-1,3-dioxin-4-one with homoallylic alcohols, oxidation, and aromatization of the intermediate enone–dioxinones.
Of particular note is the use of the catalyst 1,4-diazabicyclo[2.2.2]octane in the microwave thermolytic ketene generation
and trapping, cyclization, and dehydration reaction sequence.
Key words: salicylates, biomimetic synthesis, dioxinone, polyketide synthesis.
Résumé : Dans ce travail, on rapporte les synthèses biomimétiques de salicylates substitués en position-6, par le biais
d’une réaction de métathèse croisée de la 2,2-diméthyl-6-vinyl-1,3-dioxin-4-one avec des alcools homoallyliques, suivie
d’une oxydation et d’une aromatisation de l’intermédiaire énone–dixoinones. Il est important de noter l’utilisation du
1,4-diazabicyclo[2.2.2]octane comme catalyseur dans la génération thermolytique du cétène, de son piégeage, de sa
cyclisation et de sa déshydrogénation dans la séquence réactionnelle.
Mots-clés : salicylates, synthèse biomimétique, dioxinone, synthèse d’un polycétide.
[Traduit par la Rédaction]
[3 ϩ 3] additions,13 and domino “Michael–retro-Michael–
Introduction
Wittig” reactions.14
Salicylates have long been applied in medicine, fragrances,
flavorings, and cosmetics. Simple examples include acetyl
salicylic acid and methyl salicylate (oil of wintergreen).1
6-Substituted salicylates also occur widely in natural prod-
ucts, which show a wide variety of activities. These include
macrocyclic salicylates such as salicylihalamide A and B;2
apicularen A;3 and marinomycins A–D,4 which show anti-
cancer activity (the latter class also displaying antibacterial
activity); the fungal metabolite CJ-12 950,5 which has the
potential to treat hypercholesterolemia and hyperlipidemia;
long-chain salicylic acids such as anacardic acid and deriv-
atives that are antibiotics and antioxidants;6 and the diace-
tylenic natural product frutescin.7
The most common syntheses of salicylates are via modification
of salicylic acid (itself available from the Kolbe–Schmitt reac-
tion)8 by esterification or through modification via classical
aromatic chemistry. De novo syntheses of these systems are
less common but include methods such as oxidative cycl-
ization,9,10 cycloaromatization of conjugated polyenynes,11
Diels–Alder reactions,12 titanium(IV) chloride mediated
Previously reported biomimetic syntheses of salicylates
have involved the synthesis of polycarbonyl precursors via
partially reduced pyrones 215 or by addition reactions to
␤-ketoaldehydes 4 (Scheme 1).16 In the first case, substrates
were limited to those that could be selectively reduced (i.e.,
not 6-phenacyl-4-hydroxy-2-pyrone), and in the second case a
tert-butyl ester was necessary to prevent self-condensation of
sodioformylacetone.
Inspired by the polyketide biosynthesis for aromatic natural
products and the related biomimetic synthesis studies by Harris
and Harris,17 we sought to extend our work on the synthesis of
resorcylates from diketodioxinones,18 to the synthesis of
6-substituted salicylates. We reasoned that salicylates 7 would
be available by intramolecular aldol condensation of diketo
esters 8, synthesized by ketene generation and trapping from
dioxinone 9, itself available through cross metathesis of dioxi-
none 10 and enone 11 (Scheme 2).
Herein, we report the concise synthesis of 6-substituted
salicylates using dioxinones as stable precursors without the
requirement for protecting groups or harsh reaction conditions.
Received 26 June 2012. Accepted 31 July 2012. Published at www.nrcresearchpress.com/cjc on 29 November 2012.
P.S. Blencowe and A.G.M. Barrett. Department of Chemistry, Imperial College, London, SW7 2AZ, UK.
Corresponding author: Anthony G.M. Barrett (e-mail: agm.barrett@imperial.ac.uk).
This article is part of a Special Issue dedicated to Professor Derrick Clive. Dedicated to Derrick Clive in recognition of his scholarship and
original elegant contributions to synthetic organic chemistry.
Can. J. Chem. 90: 975–984 (2012)
doi:10.1139/v2012-071
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Scheme 1. Previous biomimetic routes to 6-substituted salicylic acid derivatives.
Scheme 2. Retrosynthesis of salicylates from dioxinone precursor 10.
Subsequently, we examined the oxidation of the cross me-
tathesis product 15a to give enone–dioxinone 16a (Table 1).
Our initial attempts involving pyridinium chlorochromate and
manganese dioxide were unsuccessful with unreacted starting
material being recovered (Table 1, entries 1 and 2). Modified
Oppenauer oxidation24 was of limited use owing to contami-
nation of the product with the hydrogen acceptor 2,4-
dinitrobenzaldehyde. Swern conditions gave an intractable
mixture of products possibly because of chlorination as has
been observed for aryl vinyl ketones.25
Results and discussion
Vinyl dioxinone 10 was prepared by the procedure of Gebauer
and Blechert19 from tert-butyl 5-chloro-3-oxopentanoate20 in a
72% yield over two steps. The homoallylic alcohols 14a–14k
were synthesized in 82%–94% yields by reaction of al-
lylmagnesium bromide with the corresponding aldehydes.21
Oxidation of homoallylic alcohol 14a with pyridinium chlo-
rochromate (PCC)22 gave the enone 11 in a 64% yield, but
attempted cross metathesis of 11 with vinyl dioxinone 10
using the Grubbs–Hoveyda II catalyst 12 was unsuccessful
and only gave rise to the enedione 13 in a poor yield. In
contrast, cross metathesis of homoallylic alcohol 14a with
vinyl dioxinone 10 gave dioxinone 15a in an 81% yield
(Scheme 3).23
In contrast to these failures, oxidations with hypervalent
iodine reagents were more useful. While oxidation with
iodoxybenzoic acid (IBX) in dimethyl sulfoxide (DMSO)26
resulted in overoxidation, reaction in ethyl acetate27 gave
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Blencowe and Barrett
977
Scheme 3. Cross metathesis reactions of vinyl dioxinone 10.
Table 1. Conditions for the oxidation of 15a.
Entry
Oxidation conditions
Yield of 16a (%)
1
2
3
4
5
PCC, CH2Cl2, 20 °C
MnO2, CH2Cl2, 20 °C
IBX, EtOAc, 80 °C
DMP, CH2Cl2, 20 °C
DMP, CH2Cl2, 0 °C
0
0
67
40
77
Note: PCC, pyridinium chlorochromate; IBX, iodoxybenzoic acid; DMP, Dess–Martin periodinane.
enone–dioxinone 16a in a 67% yield (Table 1, entry 3).
Dess–Martin periodinane (DMP)28 was found to be most ef-
ficient and oxidation at 0 °C gave enone 16a in a 77% yield
(Table 1, entries 4 and 5).
Reflux of a toluene solution of dioxinone 16a and in situ
trapping of the resultant ketene with 2-propanol gave the
salicylate 17a in a 53% yield (Table 2, entry 1). When heating
of 16a was carried out under microwave conditions, ketene
generation and trapping was complete within 45 min (as
observed by 1H NMR spectroscopy), and heating of the inter-
mediate for a further 8 h to effect aromatization gave salicylate
17a in a 14% yield (Table 2, entry 2).29 It was found that the
microwave reaction of 16a in the presence of 1,4-diazabicyclo
[2.2.2]octane (DABCO) was more rapid and gave salicylate
17a in a 55% yield after 1.5 h (Table 2, entry 3). Excess
DABCO was not required for the acceleration (Table 2, entry
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Can. J. Chem. Vol. 90, 2012
Table 2. Optimization of ketene generation, trapping by isopropanol, and aromatization.
Additive
(equiv)
Temperature
(°C)a
Time
(h)
Yield of
17a (%)
Entry
Solventb
1
2
3
4
5
—
—
Refluxc
120
120
120
120
PhMe
26
8
1.5
2
53
14
55
47
51
EtOAc
EtOAc
EtOAc
EtOAc
DABCO (10)
DABCO (1)
DABCO (1)
8
aMicrowave heating.
bi-PrOH (40 equiv.) was added as the trapping agent.
cConventional heating.
Fig. 1. Possible benzodioxinone product.
Conclusion
A range of isopropyl 6-aryl and 6-alkyl salicylate esters
were prepared from the vinyl dioxinone 10 by cross metathesis
with the homoallylic alcohols 14a–14i, Dess–Martin periodi-
nane (DMP) oxidation, and aromatization via generation and
trapping of enedione–ketenes. The methodology is a mild and
convenient process for the preparation of salicylates with these
substitution patterns. Further aspects of this methodology will
be reported in due course. 1H and 13C NMR spectra for all new
compounds can be found in the Supplementary data.
4) and prolonged heating failed to give any further conversion
(Table 2, entry 5). The mechanism of rate enhancing action by
DABCO is yet to be determined, though alkene (trans to cis)
isomerization is a possibility.30
As has been shown previously, reaction of diketodioxinones
with triethylamine smoothly gave the corresponding benzo-
dioxinones.31 In contrast, we have now found that the reaction
of enone–dioxinone 16a with triethylamine, Hünig’s base,
5 mol/L hydrochloric acid, or ammonium acetate resulted only
in decomposition and the arene 18 was not formed. No reac-
tion was observed with acetic acid (Fig. 1).
The optimized reaction conditions for the cross metathesis,
oxidation, and aromatization were applied to synthesize a
range of salicylates 17a–17i in good yields (Scheme 4). Effi-
cient cross metathesis in some cases required the use of an
increased amount (10 mol %) of catalyst 12 to achieve an
acceptable yield. In these cases, some self-metathesis of vinyl
dioxinone 10 was observed (Ͻ10%). The homoallylic alcohol
15k failed to undergo cross metathesis, presumably because of
coordination of the pyridine nitrogen to ruthenium, resulting in
catalyst deactivation.
In all cases, aromatization proceeded in good yield except in
one instance (16j ¡ 17j). In this example, steric hindrance
presumably suppressed the initial intramolecular aldol reac-
tion. Notably, the nature of the para substituent on the aryl unit
(R) had little effect with both electron-donating groups (16e)
and electron-withdrawing groups (16b) undergoing aromati-
zation with comparable efficiency.
Experimental
General methods
All reactions were carried out in oven-dried glassware under
N2, using commercially supplied solvents and reagents unless
otherwise stated. CH2Cl2 was redistilled from CaH2. Flash
chromatography was carried out on silica gel (eluents are
given in parentheses). Analytical TLC was performed on
precoated silica gel F254 aluminum plates with visualization
under UV light and by staining with acidic vanillin or acidic
potassium permanganate solutions. Melting points were
determined using a hot-stage microscope and are uncor-
rected. 1H and 13C NMR spectra were, respectively, re-
corded at 400 and 101 MHz with the solvent used in each
case specified and spectra referenced to residual solvent
peaks. Elemental analysis was carried out by the London
Metropolitan elemental analysis service.
With the exception of commercially available pent-4-en-2ol
(14g) the homoallylic alcohols 14a,32 14b,33 14c,34 14d,34
14e,32 14f,32 14h,35 14i,35 14j,32 and 14k,36 were prepared as
described in the literature from the corresponding aldehydes
by reaction with allylmagnesium bromide.21
General procedure A for cross metathesis of homoallylic
alcohols 14a–14k
Catalyst 12 (5–10 mol %) was added with stirring to vinyl
dioxinone 10 (1.5–2 equiv) and homoallylic alcohol (14a–14k,
0.1 mol/L) in CH2Cl2 at reflux and heating was continued for
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Blencowe and Barrett
979
Scheme 4. Synthesis of 6-aryl and 6-alkyl salicylates.
14–18 h. The mixture was rotary evaporated and chromato-
graphed to give the corresponding dioxinone (15a–15j).
in EtOAc (10 mL) and washed with 1 mol/L aqueous HCl. The
aqueous layer was extracted further with EtOAc (2 ϫ 10 mL),
and the combined organic layers were dried (MgSO4), rotary
evaporated, and chromatographed to give the salicylates
17a–17i.
General procedure B for oxidation of dioxinones 15a–15j
DMP (1.4 equiv) was added with stirring to dioxinone
(15a–15j, 0.1 mol/L) in CH2Cl2 at 0 °C and stirring continued
at this temperature for 0.75–3.5 h. The mixture was chromato-
graphed eluting with Et2O, and the fractions containing prod-
uct were rotary evaporated. Chromatography of the residue
gave the enone–dioxinone (16a–16j).
(E)-6-(4-Hydroxy-4-phenylbut-1-enyl)-2,2-dimethyl-4H-1,3-
dioxin-4-one (15a)
According to general procedure A, reaction of alcohol 14a
(210 mg, 1.42 mmol) and dioxinone 10 (328 mg, 2.13 mmol)
with catalyst 12 (45 mg, 0.071 mmol) for 14 h and chroma-
tography (hexanes–Et2O, 7:3 to 1:1) gave dioxinone 15a
(315 mg, 81%) as a brown oil. IR (thin film, cm–1): 3422,
1703, 1649, 1589, 1389, 1373, 1273, 1252, 1200, 1018, 967,
903, 757, 700. 1H NMR (400 MHz, CDCl3, ppm) ␦: 7.40–7.32
(m, 5H), 6.64–6.55 (m, 1H), 6.02–5.95 (m, 1H), 5.25 (s, 1H),
4.84 (dd, J ϭ 7.8, 4.9 Hz, 1H), 2.70–2.60 (m, 2H), 2.27 (br s,
1H), 1.70 (s, 6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 162.9,
General procedure C for aromatization of
enone–dioxinones 16a–16j
Molecular sieves (100 mg per 0.1 mmol 16a–16j), DABCO
(10 equiv), i-PrOH (40 equiv), and enone-dioxinone (16a–16j)
in EtOAc (0.02 mol/L) were placed in a 10 mL microwave vial
and microwave heated at 120 °C for 2 h. The resulting mixture
was filtered and rotary evaporated. The residue was taken up
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Can. J. Chem. Vol. 90, 2012
162.0, 143.5, 137.9, 128.6, 128.0, 125.6, 125.0, 106.4, 93.9,
73.3, 42.3, 25.0. MS (EI) m/z: 275 [M ϩ H]ϩ. HR-MS (EI)
m/z calcd for C16H19O4: 275.1283 [M ϩ H]ϩ; found:
275.1288. Anal. calcd for C16H18O4: C 70.06, H 6.61; found:
C 70.15, H 6.71.
(E)-6-(4-Hydroxy-4-(4-methoxyphenyl)but-1-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (15e)
According to general procedure A, reaction of alcohol 14e
(120 mg, 0.67 mmol) and dioxinone 10 (156 mg, 1.01 mmol)
with catalyst 12 (21 mg, 0.034 mmol) for 18 h and chroma-
tography (hexanes–Et2O, 3:2 to 2:3) gave dioxinone 15e
(158 mg, 78%) as a brown oil. IR (thin film, cm–1): 3424,
(E)-6-(4-(4-Bromophenyl)-4-hydroxybut-1-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (15b)
1
1702, 1650, 1512, 1389, 1374, 1245, 1018, 831. H NMR
According to general procedure A, reaction of alcohol 14b
(491 mg, 2.16 mmol) and dioxinone 10 (500 mg, 3.25 mmol)
with catalyst 12 (68 mg, 0.11 mmol) for 16 h and chromatog-
raphy (hexanes–Et2O, 7:3 to 1:3) gave dioxinone 15b (577 mg,
76%) as a brown solid; mp 85–90 °C (Et2O–pentane). IR (thin
film, cm–1): 3451, 1689, 1651, 1590, 1391, 1375, 1275, 1201,
1010, 971, 820, 600. 1H NMR (400 MHz, CDCl3, ppm) ␦: 7.49
(d, J ϭ 8.3 Hz, 2H), 7.23 (d, J ϭ 8.3 Hz, 2H), 6.56 (dt, J ϭ 15.6,
7.8 Hz, 1H), 5.97 (d, J ϭ 15.6 Hz, 1H), 5.24 (s, 1H), 4.81 (t, J ϭ
6.1 Hz, 1H), 2.64–2.56 (m, 2H), 2.31 (br s, 1H), 1.70 (s, 6H).
13C NMR (101 MHz, CDCl3, ppm) ␦: 162.8, 162.0, 142.5,
137.3, 131.7, 127.4, 125.3, 121.7, 106.4, 94.0, 72.6, 42.3, 25.0.
MS (ESI) m/z: 355 [M(81Br) ϩ H]ϩ, 353 [M(79Br) ϩ H]ϩ.
HR-MS (ESI) m/z calcd for C16H18BrO4: 353.0388 [M ϩ H]ϩ;
found: 353.0389. Anal. calcd for C16H17BrO4: C 54.41, H
4.85; found: C 54.25, H 4.73.
(400 MHz, CDCl3, ppm) ␦: 7.30–7.27 (m, 2H), 6.92–6.89 (m,
2H), 6.59 (dt, J ϭ 15.7, 7.8 Hz, 1H), 5.99 (d, J ϭ 15.6 Hz,
1H), 5.26 (s, 1H), 4.79 (dd, J ϭ 7.8, 4.9 Hz, 1H), 3.82 (s, 3H),
2.73–2.54 (m, 2H), 1.90 (br s, 1H), 1.71 (s, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 162.9, 162.0, 159.3, 138.0, 135.6,
126.9, 125.0, 114.0, 106.4, 93.9, 73.0, 55.3, 42.3, 25.0. MS
(ESI) m/z: 305 [M ϩ H]ϩ. HR-MS (ESI) m/z calcd for
C17H21O5: 305.1389 [M ϩ H]ϩ; found: 305.1382. Anal. calcd
for C17H20O5: C 67.09, H 6.62; found: C 66.96, H 6.55.
(E)-6-(4-(Furan-2-yl)-4-hydroxybut-1-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (15f)
According to general procedure A, reaction of alcohol 14f
(138 mg, 1 mmol) and dioxinone 10 (308 mg, 2 mmol) with
catalyst 12 (63 mg, 0.1 mmol) for 18 h and chromatography
(hexanes–Et2O, 3:2 to 1:1) gave dioxinone 15f (228 mg, 86%)
as a brown gum. IR (thin film, cm–1): 3400, 1689, 1654, 1590,
1379, 1280, 1197, 1017, 1003, 973, 728, 596. 1H NMR
(400 MHz, CDCl3, ppm) ␦: 7.41–7.38 (m, 1H), 6.58 (dt, J ϭ
16.1, 7.8 Hz, 1H), 6.36 (dd, J ϭ 2.9, 2.0 Hz, 1H), 6.27 (d,
J ϭ 3.4 Hz, 1H), 6.02 (d, J ϭ 15.6 Hz, 1H), 5.27 (s, 1H),
4.89–4.80 (m, 1H), 2.80–2.72 (m, 2H), 2.19 (d, J ϭ 4.4 Hz,
1H), 1.70 (s, 6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 162.8,
162.0, 155.5, 142.2, 137.0, 125.2, 110.3, 106.4, 106.3, 94.0,
66.6, 38.8, 25.0. MS (ESI) m/z: 265 [M ϩ H]ϩ. HR-MS (ESI)
m/z calcd for C14H17O5: 265.1076 [M ϩ H]ϩ; found:
265.1075. Anal. calcd for C14H16O5: C 63.63, H 6.10; found:
C 63.53, H 6.05.
(E)-6-(4-(4-Chlorophenyl)-4-hydroxybut-1-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (15c)
According to general procedure A, reaction of alcohol 14c
(183 mg, 1 mmol) and dioxinone 10 (308 mg, 2 mmol) with
catalyst 12 (63 mg, 0.1 mmol) for 18 h and chromatography
(hexanes–Et2O, 3:2 to 2:3) gave dioxinone 15c (271 mg, 88%)
as a brown solid; mp 76–80 °C (Et2O–pentane). IR (thin
film, cm–1): 3457, 1690, 1652, 1591, 1394, 1376, 1279, 1203,
1
1087, 1021, 971, 830. H NMR (400 MHz, CDCl3, ppm) ␦:
7.36–7.26 (m, 4H), 6.55 (dt, J ϭ 15.7, 7.8 Hz, 1H), 5.97 (d,
J ϭ 15.6 Hz, 1H), 5.24 (s, 1H), 4.85–4.77 (m, 1H), 2.66–2.56
(m, 2H), 2.14 (d, J ϭ 3.4 Hz, 1H), 1.70 (s, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 162.7, 161.9, 141.9, 137.2, 133.6,
128.8, 127.0, 125.4, 106.4, 94.1, 72.6, 42.4, 25.0. MS (ESI)
m/z: 311 [M(37Cl) ϩ H]ϩ, 309 [M(35Cl) ϩ H]ϩ. HR-MS (ESI)
m/z calcd for C16H18ClO4: 309.0894 [M ϩ H]ϩ; found:
309.0887. Anal. calcd for C16H17ClO4: C 62.24, H 5.55;
found: C 62.18, H 5.43.
(E)-6-(4-Hydroxypent-1-enyl)-2,2-dimethyl-4H-1,3-
dioxin-4-one (15g)
According to general procedure A, reaction of alcohol 14g
(103 ␮L, 1.00 mmol) and dioxinone 10 (308 mg, 2.00 mmol)
with catalyst 12 (63 mg, 0.10 mmol) for 18 h and chromatog-
raphy (pentane–Et2O, 55:45 to 1:3) gave dioxinone 15g
(173 mg, 82%) as a brown oil. IR (thin film, cm–1): 3435¸ 1702,
1650, 1590, 1389, 1374, 1273, 1253, 1201, 1123, 1017, 971,
903, 816, 796, 603. 1H NMR (400 MHz, CDCl3, ppm) ␦: 6.60
(dt, J ϭ 15.4, 7.5 Hz, 1H), 6.01 (dt, J ϭ 15.6, 1.0 Hz, 1H),
5.28 (s, 1H), 3.99 (m, 1H), 2.35–2.42 (m, 2H), 1.72–1.75 (m,
7H), 1.26 (d, J ϭ 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3,
ppm) ␦: 163.0, 162.1, 138.2, 124.9, 106.4, 93.8, 67.0, 42.3,
25.1, 25.0, 23.4. MS (ESI) m/z: 213 [M ϩ H]ϩ. HR-MS (ESI)
m/z calcd for C11H17O4: 213.1127 [M ϩ H]ϩ; found:
213.1123. Anal. calcd for C11H16O4: C 62.25, H 7.60; found:
C 62.12, H 7.48.
(E)-6-(4-(4-Fluorophenyl)-4-hydroxybut-1-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (15d)
According to general procedure A, reaction of alcohol 14d
(166 mg, 1 mmol) and dioxinone 10 (308 mg, 2 mmol) with
catalyst 12 (63 mg, 0.1 mmol) for 18 h and chromatography
(hexanes–Et2O, 3:2 to 2:3) gave dioxinone 15d (244 mg, 84%)
as a brown gum. IR (thin film, cm–1): 3429, 1701, 1650, 1603,
1
1508, 1390, 1375, 1274, 1202, 1156, 1018, 835. H NMR
(400 MHz, CDCl3, ppm) ␦: 7.35–7.30 (m, 2H), 7.08–7.03 (m,
2H), 6.56 (dt, J ϭ 15.2, 7.8 Hz, 1H), 5.98 (d, J ϭ 15.6 Hz,
1H), 5.25 (s, 1H), 4.83 (dd, J ϭ 7.8, 4.9 Hz, 1H), 2.70–2.55
(m, 2H), 2.21 (br s, 1H), 1.70 (s, 6H). 13C NMR (101 MHz,
CDCl3, ppm) ␦: 162.8, 162.0, 162.3 (d, J ϭ 245.7 Hz), 139.3,
137.5, 127.3 (d, J ϭ 8 Hz), 125.2, 115.4 (d, J ϭ 22.5 Hz),
106.4, 94.0, 72.6, 42.4, 25.0. MS (ESI) m/z: 293 [M ϩ H]ϩ.
HR-MS (ESI) m/z calcd for C16H18FO4: 293.1189 [M ϩ H]ϩ;
found: 293.1177. Anal. calcd for C16H17FO4: C 65.74, H 5.86;
found: C 65.90, H 5.90.
(E)-6-(4-Hydroxyhex-1-enyl)-2,2-dimethyl-4H-1,3-
dioxin-4-one (15h)
According to general procedure A, reaction of alcohol 14h
(300 mg, 3.00 mmol) and dioxinone 10 (693 mg, 4.80 mmol)
with catalyst 12 (94 mg, 0.15 mmol) for 18 h and chroma-
tography (hexanes–Et2O, 1:1 to 2:3) gave dioxinone 15h
(372 mg, 55%) as a brown oil. IR (thin film, cm–1): 3427,
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Blencowe and Barrett
981
1707, 1650, 1591, 1340, 1375, 1274, 1254, 1203, 1019, 971,
904, 801, 603. 1H NMR (400 MHz, CDCl3, ppm) ␦: 6.60 (dt,
J ϭ 15.4, 7.5 Hz, 1H), 5.99 (dt, J ϭ 15.7, 1.5 Hz, 1H), 5.26
(s, 1H), 3.63–3.74 (m, 1H), 2.37–2.47 (m, 1H), 2.28–2.37 (m,
1H), 1.70 (s, 7H), 1.45–1.57 (m, 2H), 0.97 (t, J ϭ 7.6 Hz, 3H).
13C NMR (101 MHz, CDCl3, ppm) ␦: 162.9, 162.0, 138.5,
124.7, 106.3, 93.7, 72.1, 40.1, 30.0, 25.0, 9.8. MS (ESI) m/z:
227 [M ϩ H]ϩ. HR-MS (ESI) m/z calcd for C12H19O4:
227.1283 [M ϩ H]ϩ; found: 227.1283. Anal. calcd for
C12H18O4: C 63.70, H 8.02; found: C 63.75, H 8.13.
273.1127 [M ϩ H]ϩ; found: 273.1121. Anal. calcd for
C16H16O4: C 70.58, H 5.92; found: C 70.53, H 5.85.
(E)-6-(4-(4-Bromophenyl)-4-oxobut-1-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (16b)
According to general procedure B, oxidation of dioxinone
15b (23 mg, 0.065 mmol) for 2 h and chromatography
(hexanes–Et2O, 1:1) gave enone–dioxinone 16b (19 mg, 83%) as
a yellow solid; mp 68–72 °C (Et2O–pentane). IR (thin
film, cm–1): 1713, 1693, 1659, 1586, 1391, 1374, 1273, 1199,
1
1011, 991, 970, 800. H NMR (400 MHz, CDCl3, ppm) ␦:
7.85–7.80 (m, 2H), 7.67–7.62 (m, 2H), 6.81 (dt, J ϭ 15.5,
6.9 Hz, 1H), 6.07 (d, J ϭ 15.6 Hz, 1H), 5.30 (s, 1H), 3.89 (dd,
J ϭ 7.1, 1.2 Hz, 2H), 1.72 (s, 6H). 13C NMR (101 MHz,
CDCl3, ppm) ␦: 187.9, 160.9, 141.9, 134.9, 133.5, 132.2,
132.0, 130.2, 129.1, 128.1, 128.0, 107.2, 100.8, 25.1. MS (CI)
m/z: 370 [M(81Br) ϩ H2O]ϩ, 368 [M (79Br) ϩ H2O]ϩ. Anal.
calcd for C16H15BrO4: C 54.72, H 4.31; found: C 54.63,
H 4.21.
(E)-6-(4-Hydroxy-6-methylhept-1-enyl)-2,2-dimethyl-4H-1,3-
dioxin-4-one (15i)
According to general procedure A, reaction of alcohol 14i
(128 mg, 1.00 mmol) and dioxinone 10 (308 mg, 2.00 mmol)
with catalyst 12 (63 mg, 0.10 mmol) for 18 h and chromatog-
raphy (hexanes–Et2O, 55:45 to 45:55) gave dioxinone 15i
(185 mg, 73%) as a brown gum. IR (thin film, cm–1): 3421,
1703,1650, 1590, 1389, 1374, 1273, 1253, 1202, 1017, 969,
903. 1H NMR (400 MHz, CDCl3, ppm) ␦: 6.63 (dt, J ϭ 15.4,
7.5 Hz, 1H), 6.01 (dt, J ϭ 15.6, 1.5 Hz, 1H), 5.28 (s, 1H),
3.81–3.91 (m, 1H), 2.38–2.48 (m, 1H), 2.26–2.37 (m, 1H),
1.77–1.84 (m, 1H), 1.73 (s, 6H), 1.65 (d, J ϭ 4.4 Hz,
1H), 1.43–1.50 (m, 1H), 1.24–1.32 (m, 1H), 0.93–0.97 (m,
6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 163.0, 162.0,
138.5, 124.9, 106.4, 93.8, 68.8, 46.5, 41.2, 25.1, 25.0, 24.6,
23.4, 22.0. MS (ESI) m/z: 277 [M ϩ Na]ϩ, 255 [M ϩ H]ϩ.
Anal. calcd for C14H22O4: C 66.12, H 8.72; found: C 66.10, H
8.65.
(E)-6-(4-(4-Chlorophenyl)-4-oxobut-1-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (16c)
According to general procedure B, oxidation of dioxinone
15c (82 mg, 0.266 mmol) for 2 h and chromatography
(hexanes–Et2O, 7:3 to 1:1) gave enone–dioxinone 16c (63 mg,
77%) as an orange oil. IR (thin film, cm–1): 1711, 1689, 1587,
1376, 1391, 1270, 1200, 1089, 1022, 985, 839, 784. 1H NMR
(400 MHz, CDCl3, ppm) ␦: 7.93–7.88 (m, 2H), 7.50–7.45 (m,
2H), 6.81 (dt, J ϭ 15.7, 7.1 Hz, 1H), 6.07 (dt, J ϭ 15.7,
1.5 Hz, 1H), 5.31 (s, 1H), 3.90 (dd, J ϭ 6.8, 1.5 Hz, 2H), 1.72
(s, 6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 195.0, 162.3,
161.7, 140.2, 134.4, 133.2, 129.6, 129.2, 125.9, 106.6, 94.7,
41.6, 25.0. MS (ESI) m/z: 309 [M(37Cl) ϩ H]ϩ, 307 [M(35Cl) ϩ
H]ϩ. HR-MS (ESI) m/z calcd for C16H16ClO4: 307.0737 [M ϩ
H]ϩ; found: 307.0732. Anal. calcd for C16H15ClO4: C 62.65, H
4.93; found: C 62.77, H 4.84.
(E)-6-(4-Hydroxy-4-mesitylbut-1-enyl)-2,2-dimethyl-4H-1,3-
dioxin-4-one (15j)
According to general procedure A, reaction of alcohol 14j
(350 mg, 1.84 mmol) and dioxinone 10 (426 mg, 2.76 mmol)
with catalyst 12 (58 mg, 0.09 mmol) for 16 h and chromatog-
raphy (hexanes–Et2O, 4:1 to 1:1) gave dioxinone 15j (377 mg,
65%) as a brown gum. IR (thin film, cm–1): 3442, 2951, 1702,
1650, 1591, 1389, 1373, 1273, 1202, 1017, 967, 851, 801. 1H
NMR (400 MHz, CDCl3, ppm) ␦: 6.84 (s, 2H), 6.64 (dt, J ϭ
15.7, 7.8 Hz, 1H), 6.02 (d, J ϭ 15.6 Hz, 1H), 5.29–5.22 (m,
2H), 2.97–2.85 (m, 1H), 2.63–2.49 (m, 1H), 2.41 (s, 6H), 2.26
(s, 3H), 2.00 (d, J ϭ 2.4 Hz, 1H), 1.71 (s, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 163.0, 162.0, 138.8, 137.0, 135.8,
135.6, 130.3, 124.6, 106.3, 93.8, 70.5, 39.0, 25.0, 24.9, 20.7.
MS (ESI) m/z: 317 [M ϩ H]ϩ. HR-MS (ESI) m/z calcd for
C19H25O4: 317.1753 [M ϩ H]ϩ; found: 317.1753. Anal. calcd
for C19H24O4: C 72.13, H 7.65; found: C 71.97, H 7.59.
(E)-6-(4-(4-Fluorophenyl)-4-oxobut-1-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (16d)
According to general procedure B, oxidation of dioxinone
15d (226 mg, 0.774 mmol) for 3 h and chromatography
(hexanes–Et2O, 7:3 to 1:1) gave enone–dioxinone 16d
(143 mg, 67%) as an orange oil. IR (thin film, cm–1): 1710,
1692, 1597, 1379, 1275, 1200, 1158, 1021, 846, 793. 1H NMR
(400 MHz, CDCl3, ppm) ␦: 8.02–7.97 (m, 2H), 7.20–7.14 (m,
2H), 6.82 (dt, J ϭ 15.5, 6.9 Hz, 1H), 6.07 (d, J ϭ 16.1 Hz,
1H), 5.30 (s, 1H), 3.90 (dd, J ϭ 1.2, 7.1 Hz, 2H), 1.72 (s, 6H).
13C NMR (101 MHz, CDCl3, ppm) ␦: 194.7, 167.3, 163.5 (d,
J ϭ 239.3 Hz), 161.7, 133.4, 132.5, 130.9 (d, J ϭ 9.6 Hz),
125.8, 116.0 (d, J ϭ 20.9 Hz), 106.6, 94.6, 41.6, 25.0. HR-MS
(CI) m/z calcd for C16H19NO4F: 308.1298 [M ϩ NH4]ϩ;
found: 308.1301. Anal. calcd for C16H15FO4: C 66.20, H 5.21;
found: C 66.15, H 5.14.
(E)-2,2-Dimethyl-6-(4-oxo-4-phenylbut-1-enyl)-4H-1,3-
dioxin-4-one (16a)
According to general procedure B, oxidation of dioxinone
15a (329 mg, 1.21 mmol) for 3.5 h and chromatography
(hexanes–Et2O, 7:3 to 1:1) gave enone–dioxinone 16a (255 mg,
77%) as a yellow solid; mp 58–61 °C (Et2O–pentane). IR (thin
film, cm–1): 1714, 1687, 1655, 1597, 1392, 1369, 1278, 1204,
(E)-6-(4-(4-Methoxyphenyl)-4-oxobut-1-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (16e)
1
1019, 991, 905, 816. H NMR (400 MHz, CDCl3, ppm) ␦:
According to general procedure B, oxidation of dioxinone
15e (150 mg, 0.493 mmol) for 0.75 h and chromatography
(hexanes–Et2O, 7:3 to 3.5:10) gave enone–dioxinone 16e
(98 mg, 66%) as a yellow solid; mp 89–92 °C (Et2O–pentane).
IR (thin film, cm–1): 1710, 1674, 1655, 1573, 1374, 1255,
1204, 1182, 1020, 984, 967, 844, 790, 597. 1H NMR
(400 MHz, CDCl3, ppm) ␦: 7.97–7.92 (m, 2H), 6.99–6.94 (m,
8.04–7.91 (m, 2H), 7.74–7.56 (m, 1H), 7.56–7.36 (m, 2H),
6.85 (dt, J ϭ 15.7, 7.1 Hz, 1H), 6.08 (d, J ϭ 15.6 Hz, 1H), 5.31
(s, 1H), 3.93 (dd, J ϭ 7.1, 1.2 Hz, 2H), 1.73 (s, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 196.3, 162.4, 161.6, 136.2, 133.7,
133.7, 128.8, 128.2, 125.7, 106.6, 94.6, 41.7, 25.0. MS (ESI)
m/z: 273 [M ϩ H]ϩ. HR-MS (EI) m/z calcd for C16H17O4:
Published by NRC Research Press

982
Can. J. Chem. Vol. 90, 2012
2H), 6.84 (dt, J ϭ 15.4, 7.0 Hz, 1H), 6.06 (d, J ϭ 15.7 Hz,
1H), 5.30 (s, 1H), 3.89 (s, 3H), 3.87 (dd, J ϭ 7.3, 1.5 Hz, 2H),
1.72 (s, 6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 194.8,
163.9, 162.5, 161.8, 134.3, 130.6, 129.2, 125.5, 114.0, 106.5,
94.4, 55.5, 41.5, 25.0. MS (ESI) m/z: 303 [M ϩ H]ϩ. HR-MS
(ESI) m/z calcd for C17H19O5: 303.1232 [M ϩ H]ϩ; found:
303.1226. Anal. calcd for C17H18O5: C 67.54, H 6.00; found:
C 67.43, H 6.05.
812. 1H NMR (400 MHz, CDCl3, ppm) ␦: 6.68 (dt, J ϭ 15.7,
7.3 Hz, 1H), 6.00 (dt, J ϭ 15.7, 1.5 Hz, 1H), 5.31 (s, 1H), 3.34
(dd, J ϭ 7.3, 1.0 Hz, 2H), 2.37 (d, J ϭ 7.3 Hz, 2H), 2.10–2.25
(m, 1H), 1.74 (s, 6H), 0.96 (d, J ϭ 6.4 Hz, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 206.6, 162.4, 161.8, 133.3, 125.6,
106.5, 94.5, 51.9, 46.3, 25.0, 24.5, 22.5. MS (ESI) m/z: 275 [M ϩ
Na]ϩ, 253 [M ϩ H]ϩ. Anal. calcd for C14H20O4: C 66.65, H
7.99; found: C 66.74, H 7.90.
(E)-6-(4-(Furan-2-yl)-4-oxobut-1-enyl)-2,2-dimethyl-4H-1,3-
dioxin-4-one (16f)
(E)-6-(4-Mesityl-4-oxobut-1-enyl)-2,2-dimethyl-4H-1,3-
dioxin-4-one (16j)
According to general procedure B, oxidation of dioxinone
15f (94 mg, 0.356 mmol) for 2 h and chromatography (hex-
anes–Et2O, 7:3 to 1:1) gave enone–dioxinone 16f (35 mg,
38%) as a yellow oil. IR (thin film, cm–1): 1721, 1675, 1655,
2-Iodoxybenzoic acid (842 mg, 2.94 mmol) was added with
stirring to dioxinone 15j (310 mg, 0.981 mmol) in EtOAc
(7 mL) open to the air at 80 °C for 2 h. The mixture was
filtered through Celite and rotary evaporated. Chromatography
(hexanes–Et2O, 4:1 to 1:1) of the residue gave enone–
dioxinone 16j as a 2:1 mixture of the ␤,␦-enone: ␣,␤-enone
(207 mg, 67%) as a yellow oil. IR (thin film, cm–1): 1713,
1698, 1603, 1373, 1268, 1200, 1148, 1017, 978, 852, 802, 602.
␤,␦-Enone: 1H NMR (400 MHz, CDCl3, ppm) ␦: 6.87 (s, 2H),
6.78 (dt, J ϭ 15.6, 7.8 Hz, 1H), 6.04 (d, J ϭ 15.7 Hz, 1H), 5.31
(s, 1H), 3.63 (dd, J ϭ 7.1, 1.2 Hz, 2H), 2.30 (s, 3H), 2.21 (s, 6H),
1.73 (s, 6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 206.5, 162.4,
161.8, 138.7, 133.8, 132.8, 132.5, 128.6, 125.8, 106.6, 94.7, 47.8,
25.0, 21.1, 19.2. ␣,␤-Enone: 1H NMR (400 MHz, CDCl3, ppm)
␦: 6.87 (s, 2H), 6.47–6.29 (m, 2H), 5.22 (s, 1H), 3.16 (d, J ϭ
6.4 Hz, 2H), 2.30 (s, 3H) 2.14 (s, 6H), 1.66 (s, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 206.5, 162.4, 161.8, 141.6, 138.7,
136.1, 133.8, 132.5, 128.4, 106.6, 94.5, 36.3 25.0, 21.1, 19.2. MS
(CI) m/z: 332 [M ϩ H2O]ϩ, 315 [M ϩ H]ϩ. Anal. calcd for
C19H22O4: C 72.59, H 7.05; found: C 72.44, H 6.95.
1
1466, 1392, 1376, 1275, 1204, 1019. H NMR (400 MHz,
CDCl3, ppm) ␦: 7.63 (d, J ϭ 1.0 Hz, 1H), 7.28–7.25 (m, 1H),
6.76 (dt, J ϭ 15.6, 7.3 Hz, 1H), 6.58 (dd, J ϭ 3.4, 1.5 Hz, 1H),
6.12–6.04 (m, 1H), 5.30 (s, 1H), 3.78 (dd, J ϭ 7.3, 1.5 Hz,
2H), 1.71 (s, 6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 185.1,
162.4, 161.8, 152.0, 146.9, 132.9, 125.9, 117.9, 112.6, 106.6,
94.6, 41.6, 25.0. MS (ESI) m/z: 263 [M ϩ H]ϩ. HR-MS (ESI)
m/z calcd for C14H15O5: 263.0919 [M ϩ H]; found: 263.0912.
Anal. calcd for C14H14O5: C 64.12, H 5.38; found: C 60.65,
H 5.34.
(E)-2,2-Dimethyl-6-(4-oxopent-1-enyl)-4H-1,3-
dioxin-4-one (16g)
According to general procedure B, oxidation of dioxinone
15g (145 mg, 0.684 mmol) for 1.25 h and chromatography
(pentane–Et2O, 1:1 to 2:3) gave enone–dioxinone 16g (78 mg,
54%) as a yellow oil. IR (thin film, cm–1): 1711, 1654, 1593,
1390, 1274, 1273, 1251, 1200, 1158, 1016, 968, 903, 859, 808.
1H NMR (400 MHz, CDCl3, ppm) ␦: 6.67 (dt, J ϭ 15.7,
7.3 Hz, 1H), 6.00 (dt, J ϭ 15.6, 1.5 Hz, 1H), 5.32 (s, 1H), 3.39
(dd, J ϭ 7.3, 1.0 Hz, 2H), 2.24 (s, 3H), 1.74 (s, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 204.5, 162.4, 161.8, 132.9, 125.8,
106.6, 94.7, 46.7, 30.1, 25.0. MS (ESI) m/z: 233 [M ϩ Na]ϩ,
211 [M ϩ H]ϩ. HR-MS (ESI) m/z calcd for C11H15O4:
211.0965 [M ϩ H]ϩ; found: 211.0966.
Isopropyl 3-hydroxybiphenyl-2-carboxylate (17a)
According to general procedure C, aromatization of enone–
dioxinone 16a (50 mg, 0.184 mmol) and chromatography
(hexanes–Et2O, 100:0 to 19:1) gave salicylate 17a (26 mg,
55%) as a colorless solid; mp 53–55 °C (Et2O–pentane). IR
(thin film, cm–1): 1650, 1606, 1597, 1441, 1370, 1278, 1225,
1178, 1097, 922, 897, 814. 1H NMR (400 MHz, CDCl3, ppm)
␦: 10.96 (s, 1H), 7.48–7.30 (m, 4H), 7.30–7.12 (m, 2H), 7.01
(dd, J ϭ 8.3, 1.0 Hz, 1H), 6.78 (dd, J ϭ 7.3, 1.0 Hz, 1H),
5.05–4.85 (m, 1H), 0.86 (d, J ϭ 6.4 Hz, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 170.4, 161.5, 145.0, 143.2, 133.3,
128.3, 127.6, 126.6, 122.4, 116.6, 112.6, 69.1, 20.9. HR-MS
(EI) m/z calcd for C16H17O3: 257.1178 [M ϩ H]ϩ; found:
257.1168. Anal. calcd for C16H16O3: C 74.98, H 6.29; found:
C 74.90, H 6.37.
(E)-2,2-Dimethyl-6-(4-oxohex-1-enyl)-4H-1,3-
dioxin-4-one (16h)
According to general procedure B, oxidation of dioxinone
15h (60 mg, 0.265 mmol) for 0.75 h and chromatography
(hexanes–Et2O, 1:1) gave enone–dioxinone 16h (47 mg, 79%)
as a yellow oil. IR (thin film, cm–1): 1711, 1630, 1586, 1460,
1391, 1376, 1276, 1252, 1200, 1096, 1017, 973, 903, 812. 1H
NMR (400 MHz, CDCl3, ppm) ␦: 6.66 (dt, J ϭ 15.6, 6.8 Hz,
1H), 5.98 (dt, J ϭ 15.7, 1.5 Hz, 1H), 5.29 (s, 1H), 3.34 (dd,
J ϭ 7.3, 1.5 Hz, 2H), 2.50 (q, J ϭ 7.3 Hz, 2H), 1.71 (s, 6H), 1.08
(t, J ϭ 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3, ppm) ␦:
207.3, 162.4, 161.7, 133.3, 125.6, 106.5, 94.5, 45.5, 36.1, 25.0,
7.6. MS (ESI) m/z: 247 [M ϩ Na]ϩ, 225 [M ϩ H]ϩ.
Isopropyl 4=-bromo-3-hydroxybiphenyl-2-carboxylate (17b)
According to general procedure C, aromatization of enone–
dioxinone 16b (100 mg, 0.29 mmol) and chromatography
(hexanes–Et2O, 100:0 to 9:1) gave salicylate 17b (43 mg,
45%) as a colorless solid; mp 79–83 °C (Et2O–pentane). IR
(thin film, cm–1): 1663, 1600, 1575, 1492, 1444, 1363, 1314,
1273, 1209, 1173, 1100, 1066, 918, 807. 1H NMR (400 MHz,
CDCl3, ppm) ␦: 11.04 (s, 1H), 7.54–7.46 (m, 2H), 7.40 (t, J ϭ
8.1 Hz, 1H), 7.14–7.06 (m, 2H), 7.02 (dd, J ϭ 8.3, 1.0 Hz,
1H), 6.73 (dd, J ϭ 7.3, 1.0 Hz, 1H), 4.98 (spt, J ϭ 6.2 Hz, 1H),
0.91 (d, J ϭ 6.4 Hz, 6H). 13C NMR (101 MHz, CDCl3, ppm)
␦: 170.1, 161.8, 143.6, 142.2, 133.5, 130.6, 130.0, 122.2,
120.7, 117.1, 112.2, 69.5, 21.0. MS (CI) m/z: 354 [M(81Br) ϩ
H2O]ϩ, 352 [M(79Br) ϩ H2O]ϩ, 337 [M(81Br) ϩ H]ϩ, 335
(E)-2,2-Dimethyl-6-(6-methyl-4-oxohept-1-enyl)-4H-1,3-
dioxin-4-one (16i)
According to general procedure B, oxidation dioxinone 15i
(151 mg, 0.594 mmol) for 1.25 h and chromatography
(pentane–Et2O, 7:3 to 1:1) gave enone–dioxinone 16i (101 mg,
67%) as a yellow oil. IR (thin film, cm–1): 1707, 1655, 1594,
1451, 1392, 1373, 1277, 1204, 1105, 1019, 979, 906, 864, 849,
Published by NRC Research Press

Blencowe and Barrett
983
[M(79Br) ϩ H]ϩ. HR-MS (CI) m/z calcd for C16H16BrO3:
335.0283 [M ϩ H]ϩ; found: 335.0274. Anal. calcd for
C16H15BrO3: C 57.33, H 4.51; found: C 57.25, H 4.56.
7.8 Hz, 1H), 7.03 (dd, J ϭ 8.3, 1.0 Hz, 1H), 6.95 (dd, J ϭ 7.3,
1.0 Hz, 1H), 6.47 (dd, J ϭ 3.4, 2.0 Hz, 1H), 6.40 (d, J ϭ
2.9 Hz, 1H), 5.13 (spt, J ϭ 6.3 Hz, 1H), 1.12 (d, J ϭ 6.4 Hz,
6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 170.0, 161.2,
154.2, 141.7, 133.5, 132.8, 122.3, 118.0, 112.7, 111.1, 107.1,
69.3, 21.5. MS (CI) m/z: 247 [M ϩ H]ϩ. HR-MS (CI) m/z
calcd for C14H15O4: 247.0970 [M ϩ H]ϩ; found: 247.0972.
Isopropyl 4=-chloro-3-hydroxybiphenyl-2-carboxylate (17c)
According to general procedure C, aromatization of enone-
dioxinone 16c (69 mg, 0.23 mmol) and chromatography
(hexanes–Et2O, 100:0 to 97:3) gave salicylate 17c (32 mg, 49%)
as a colorless solid; mp 73–76 °C (CHCl3). IR (thin film, cm–1):
1665, 1601, 1576, 1492, 1444, 1363, 1314, 1272, 1172, 1101,
807. 1H NMR (400 MHz, CDCl3, ppm) ␦: 11.04 (s, 1H), 7.40
(t, J ϭ 7.8 Hz, 1H), 7.37–7.30 (m, 2H), 7.20–7.12 (m, 2H),
7.02 (dd, J ϭ 8.6, 1.2 Hz, 1H), 6.73 (dd, J ϭ 7.6, 1.2 Hz, 1H),
4.98 (spt, J ϭ 6.3 Hz, 1H), 0.91 (d, J ϭ 6.4 Hz, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 170.1, 161.8, 143.6, 141.7, 133.5,
132.7, 129.6, 127.7, 122.3, 117.1, 112.3, 69.4, 21.0. MS (CI)
m/z: 310 [M(37Cl) ϩ H2O]ϩ, 308 [M(35Cl) ϩ H2O]ϩ, 293
[M(37Cl) ϩ H]ϩ, 291 [M(35Cl) ϩ H]ϩ. HR-MS (CI) m/z calcd
for C16H16ClO3: 291.0788 [M ϩ H]ϩ; found: 291.0786. Anal.
calcd for C16H15ClO3: C 66.10, H 5.20; found: C 65.98, H 5.24.
Isopropyl 2-hydroxy-6-methylbenzoate (17g)
According to general procedure C, aromatization of enone–
dioxinone 16g (73 mg, 0.348 mmol) and chromatography
(pentane–Et2O, 100:0 to 98:2) gave salicylate 17g (45 mg,
67%) as a colorless oil. IR (thin film, cm–1): 1727, 1650, 1606,
1580, 1459, 1439, 1365, 1291, 1251, 1212, 1165, 1100, 1078,
1
1034, 965, 911, 863, 806, 756, 702. H NMR (400 MHz,
CDCl3, ppm) ␦: 11.43 (s, 1H), 7.27 (t, J ϭ 7.8 Hz, 1H), 6.84
(d, J ϭ 8.3 Hz, 1H), 6.71 (d, J ϭ 7.3 Hz, 1H), 5.34 (spt, J ϭ
6.2 Hz, 1H), 2.56 (s, 3H), 1.43 (d, J ϭ 6.4 Hz, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 171.2, 162.8, 141.3, 133.9, 122.9,
115.6, 112.7, 69.7, 24.2, 22.0. MS (ESI) m/z: 212 [M ϩ
H2O]ϩ, 195 [M ϩ H]ϩ. Anal. calcd for C11H14O3: C 68.02, H
7.27; found: C 67.87, H 7.21.
Isopropyl 4=-fluoro-3-hydroxybiphenyl-2-carboxylate (17d)
According to general procedure C, aromatization of enone–
dioxinone 16d (35 mg, 0.21 mmol) and chromatography
(hexanes–Et2O, 19:1) gave salicylate 17d (17 mg, 51%) as a
colorless solid; mp 85–87 °C (Et2O–pentane). IR (thin
film, cm–1): 1650, 1606, 1513, 1445, 1367, 1280, 1227, 1213,
Isopropyl 2-hydroxy-6-ethylbenzoate (17h)
According to general procedure C, aromatization of enone-
dioxinone 16h (76 mg, 0.339 mmol) and chromatography
(pentane–Et2O, 100:0 to 19:1) gave salicylate 17h (41 mg,
58%) as a colorless oil. IR (thin film, cm–1): 1727, 1654, 1606,
1577, 1447, 1363, 1308, 1295, 1245, 1207, 1167, 1102, 931,
908, 816. 1H NMR (400 MHz, CDCl3, ppm) ␦: 11.33 (s, 1H),
7.30 (t, J ϭ 8.1 Hz, 1H), 6.85 (dd, J ϭ 8.3, 1.5 Hz, 1H), 6.74
(d, J ϭ 7.3 Hz, 1H), 5.36 (spt, J ϭ 6.3 Hz, 1H), 2.96 (q, J ϭ
7.3 Hz, 2H), 1.43 (d, J ϭ 6.4 Hz, 6H), 1.23 (t, J ϭ 7.3 Hz, 3H).
13C NMR (101 MHz, CDCl3, ppm) ␦: 171.0, 162.6, 147.4,
134.1, 121.7, 115.6, 112.2, 69.7, 29.6, 21.8, 16.5. MS (ESI)
m/z: 231 [M ϩ Na]ϩ, 209 [M ϩ H]ϩ. Anal. calcd for
C12H16O3: C 69.21, H 7.74; found: C 69.18, H 7.64.
1
1177, 1093, 842, 815. H NMR (400 MHz, CDCl3, ppm) ␦:
11.01 (s, 1H), 7.40 (t, J ϭ 7.8 Hz, 1H), 7.22–7.16 (m, 2H),
7.10–7.03 (m, 2H), 7.01 (dd, J ϭ 8.3, 1.5 Hz, 1H), 6.74 (dd,
J ϭ 7.6, 1.2 Hz, 1H), 4.98 (spt, J ϭ 6.3 Hz, 1H), 0.91 (d, J ϭ
6.4 Hz, 6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 170.3,
161.7, 143.8, 139.2 133.4, 129.8, 122.5, 116.9, 114.5, 114.3,
112.5, 69.3, 21.0. MS (CI) m/z: 275 [M ϩ H]ϩ. HR-MS (CI)
m/z calcd for C16H16FO3: 275.1083 [M ϩ H]ϩ; found:
275.1081. Anal. calcd for C16H15FO3: C 70.06, H 5.51; found:
C 70.00, H 5.60.
Isopropyl 2-hydroxy-6-isobutylbenzoate (17i)
Isopropyl 3-hydroxy-4=-methoxybiphenyl-
According to general procedure C, aromatization of enone–
dioxinone 16i (78 mg, 0.310 mmol) and chromatography
(pentane–Et2O, 100:0 to 19:1) gave salicylate 17i (31 mg,
45%) as a colorless oil. IR (thin film, cm–1): 1651, 1606, 1577,
1478, 1363, 1308, 1294, 1250, 1229, 1202, 1164, 1097, 1062,
911, 833, 803, 763, 709. 1H NMR (400 MHz, CDCl3, ppm) ␦:
11.35 (s, 1H), 7.28 (t, J ϭ 7.8 Hz, 1H), 6.86 (dd, J ϭ 8.3,
1.5 Hz, 1H), 6.66 (dd, J ϭ 7.6, 1.2 Hz, 1H), 5.37 (spt, J ϭ
6.3 Hz, 1H), 2.82 (d, J ϭ 7.3 Hz, 2H), 1.76–1.91 (m, 1H), 1.43
(d, J ϭ 6.4 Hz, 6H), 0.89 (d, J ϭ 6.4 Hz, 6H). 13C NMR
(101 MHz, CDCl3, ppm) ␦: 171.2, 162.8, 144.5, 133.5, 123.7,
115.8, 112.5, 69.6, 45.5, 30.0, 22.5, 21.8. MS (ESI) m/z: 259
[M ϩ Na]ϩ, 237 [M ϩ H]ϩ. Anal. calcd for C14H20O3: C
71.16, H 8.53; found: C 71.08, H 8.45.
2-carboxylate (17e)
According to general procedure C, aromatization of enone–
dioxinone 16e (37 mg, 0.12 mmol) and chromatography
(hexanes–Et2O, 100:0 to 19:1) gave salicylate 17e (17 mg, 48%)
as a yellow solid; mp 42–45 °C (Et2O). IR (thin film, cm–1):
1655, 1602, 1515, 1446, 1369, 1271, 1243, 1218, 1175, 1094,
1034, 807. 1H NMR (400 MHz, CDCl3, ppm) ␦: 10.86 (s, 1H),
7.38 (t, J ϭ 7.8 Hz, 1H), 7.18–7.11 (m, 2H), 6.98 (dd, J ϭ 8.3,
1.0 Hz, 1H), 6.94–6.87 (m, 2H), 6.77 (dd, J ϭ 7.3, 1.0 Hz,
1H), 4.97 (spt, J ϭ 6.3 Hz, 1H), 3.86 (s, 3H), 0.91 (d, J ϭ
6.4 Hz, 6H). 13C NMR (101 MHz, CDCl3, ppm) ␦: 170.5,
161.4, 158.7, 144.6, 135.7, 133.3, 129.4, 122.6, 116.3, 113.0,
112.8, 69.1, 55.4, 21.1. MS (CI) m/z: 304 [M ϩ H2O]ϩ, 287
[M ϩ H]ϩ. HR-MS (CI) m/z calcd for C17H19O4: 287.1283 [M
ϩ H]ϩ; found: 287.1275. Anal. calcd for C17H18O4: C 71.31,
H 6.34; found: C 68.02, H 6.55.
Supplementary data
Supplementary data are available with the article through
the journal Web site http://nrcresearchpress.com/doi/suppl/
10.1139/v2012-071.
Isopropyl 2-(furan-2-yl)-6-hydroxybenzoate (17f)
According to general procedure C, aromatization of enone–
dioxinone 16f (30 mg, 0.12 mmol) and chromatography
(hexanes–Et2O, 100:0 to 19:1) gave salicylate 17f (13 mg, 46%)
as a colorless oil. IR (thin film, cm–1): 1664, 1606, 1572, 1453,
Acknowledgements
1
1374, 1275, 1222, 1178, 1103. H NMR (400 MHz, CDCl3,
We would like to thank GlaxoSmithKline for the generous
endowment (to A.G.M.B.) and the Thorpe Bequest (Imperial
ppm) ␦: 10.67 (s, 1H), 7.47 (d, J ϭ 1.0 Hz, 1H), 7.40 (t, J ϭ
Published by NRC Research Press

984
Can. J. Chem. Vol. 90, 2012
(17) Harris, T. M.; Harris, C. M. Tetrahedron 1977, 33 (17), 2159.
doi:10.1016/0040-4020(77)80001-X.
(18) Navarro, I.; Basset, J.-F.; Hebbe, S.; Major, S. M.; Werner, T.;
Howsham, C.; Bräckow, J.; Barrett, A. G. M. J. Am. Chem. Soc.
2008, 130 (31), 10293. doi:10.1021/ja803445u.
(19) Gebauer, J.; Blechert, S. J. Org. Chem. 2006, 71 (5), 2021.
doi:10.1021/jo052421a.
(20) Hoffman, R. V.; Kim, H.; Wilson, A. L. J. Org. Chem. 1990, 55
(9), 2820. doi:10.1021/jo00296a047.
(21) Hathaway, S. J.; Paquette, L. A. J. Org. Chem. 1983, 48 (19),
3351. doi:10.1021/jo00167a047.
(22) Wasylenko, W. A.; Kebede, N.; Showalter, B. M.; Matsunaga,
N.; Miceli, A. P.; Liu, Y.; Ryzhkov, L. R.; Hadad, C. M.;
Toscano, J. P. J. Am. Chem. Soc. 2006, 128 (40), 13142.
doi:10.1021/ja062712g.
(23) Homoallylic alcohols such as 14a have been shown to have
rate-increasing effects due to hydrogen bonding with ruthenium
cross metathesis catalysts; see Hoveyda, A. H.; Lombardi, P. J.;
O’Brien, R. V.; Zhugralin, A. R. J. Am. Chem. Soc. 2009, 131
(24), 8378. doi:10.1021/ja9030903.
College) for studentship support (to P.S.B.). We also thank
P.R. Haycock and R.N. Sheppard for NMR spectroscopy
services and J. Barton for mass spectra.
References
(1) Ekinci, D.; S¸entürk, M.; Küfreviogˇlu, O. I. Expert Opin. Ther.
Pat. 2011, 21 (12), 1831. doi:10.1517/13543776.2011.636354.
(2) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R.
J. Org. Chem. 1997, 62 (23), 8188. doi:10.1021/jo971556g.
(3) Jansen, R.; Kunze, B.; Reichenbach, H.; Höfle, G. Eur. J. Org.
Chem. 2000, 2000 (6), 913. doi:10.1002/(SICI)1099-
0690(200003)2000:6Ͻ913::AID-EJOC913Ͼ3.0.CO;2-L.
(4) Kwon, H. K.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. J. Am.
Chem. Soc. 2006, 128 (5), 1622. doi:10.1021/ja0558948.
(5) Dekker, K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.; Sakakibara,
T.; Suzuki, Y.; Thompson, J. F.; Yamauchi, Y.; Kojima, N. J.
Antibiot. 1998, 51 (1), 14. doi:10.7164/antibiotics.51.14.
(6) Tyman, J. H. P. Chem. Soc. Rev. 1979, 8 (4), 499. doi:10.1039/
cs9790800499.
(7) Bohlmann, F.; Tsankova, E.; Jakupovic, J. Phytochemistry
1984, 23 (5), 1103. doi:10.1016/S0031-9422(00)82618-7.
(8) Lindsey, A. S.; Jeskey, H. Chem. Rev. 1957, 57 (4), 583.
doi:10.1021/cr50016a001.
(24) Graves, C. R.; Zeng, B. S.; Nguyen, S. B. T. J. Am. Chem. Soc.
2006, 128 (39), 12596. doi:10.1021/ja063842s.
(25) Yin, J.; Gallis, C. E.; Chisholm, D. J. Org. Chem. 2007, 72 (18),
7054. doi:10.1021/jo0711992.
(9) Mohan, R.; Kates, S. A.; Dombroski, M. A.; Snider, B. B.
Tetrahedron Lett. 1987, 28 (8), 845. doi:10.1016/S0040-
4039(01)81004-2.
(10) Langer, P.; Köhler, V. Chem. Commun. (Camb.) 2000, (17):
1653. doi:10.1039/b004387g.
(11) García-García, P.; Fernández-Rodríguez, M. A.; Aguilar, E.
Angew. Chem. Int. Ed. 2009, 48 (30), 5534. doi:10.1002/
anie.200901269.
(26) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35 (43),
8019. doi:10.1016/0040-4039(94)80038-3.
(27) More, J. D.; Finney, N. S. Org. Lett. 2002, 4 (17), 3001.
doi:10.1021/ol026427n.
(28) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48 (22), 4155.
doi:10.1021/jo00170a070.
(29) Attempts to isolate the ene–dione ester intermediate by silica
gel chromatography resulted in decomposition.
(12) Danishefsky, S.; Singh, R. K.; Gammill, R. B. J. Org. Chem.
1978, 43 (2), 379. doi:10.1021/jo00396a060.
(30) Harris, C. M.; Harris, T. M. J. Org. Chem. 1971, 36 (15), 2181.
doi:10.1021/jo00814a032.
(13) (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102
(10), 3534. doi:10.1021/ja00530a038; (b) Langer, P.; Bose, G.
Angew. Chem. Int. Ed. 2003, 42 (34), 4033. doi:10.1002/
anie.200351263; (c) Brownbridge, P.; Chan, T. H.; Brook,
M. A.; Kang, G. J. Can. J. Chem. 1983, 61 (4), 688. doi:
10.1139/v83-127.
(31) Basset, J.-F.; Leslie, C.; Hamprecht, D.; White, A. J. P.; Barrett,
A. G. M. Tetrahedron Lett. 2010, 51 (5), 783. doi:10.1016/
j.tetlet.2009.11.134.
(32) Denmark, S. E.; Nguyen, S. T. Org. Lett. 2009, 11 (3), 781.
doi:10.1021/ol8028725.
(33) Thadani, A. N.; Batey, R. A. Org. Lett. 2002, 4 (22), 3827.
doi:10.1021/ol026619i.
(34) Li, G.-L.; Zhao, G. J. Org. Chem. 2005, 70 (11), 4272. doi:
10.1021/jo050186q.
(35) Tan, X.-H.; Shen, B.; Deng, W.; Zhao, H.; Liu, L.; Guo, Q.-X.
Org. Lett. 2003, 5 (11), 1833. doi:10.1021/ol034267p.
(36) Singh, S.; Kumar, S.; Chimni, S. S. Tetrahedron Asymmetry
2002, 13 (24), 2679. doi:10.1016/S0957-4166(02)00743-7.
(14) Holtz, E.; Albrecht, U.; Langer, P. Tetrahedron 2007, 63 (16),
3293. doi:10.1016/j.tet.2007.02.062.
(15) Scott, A. I.; Guilford, H.; Ryan, J. J.; Skingle, D. Tetrahedron
1971, 27 (14), 3025. doi:10.1016/S0040-4020(01)98096-2.
(16) Harris, T. M.; Murray, T. P.; Harris, C. M.; Gumulka, M. J.
Chem. Soc. Chem. Commun. 1974, 10 (10), 362. doi:10.1039/
c39740000362.
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