Palladium(0)-catalyzed allylic alkylation of diketoester-dioxinones with allyl acetates under neutral conditions: Synthesis of hexasubstituted benzene derivatives

Article abstract of DOI:10.1021/jo300340c

Intermolecular palladium(0)-catalyzed allylic alkylation of diketoester-dioxinones was performed under neutral conditions with 2-alkenyl and 2-cycloalkenyl acetates. Subsequent aromatization using cesium carbonate gave rise to isopropylidene-protected hexasubstituted resorcylates.

Full text of DOI:10.1021/jo300340c

Article
pubs.acs.org/joc
Palladium(0)-Catalyzed Allylic Alkylation of Diketoester−Dioxinones
with Allyl Acetates under Neutral Conditions: Synthesis of
Hexasubstituted Benzene Derivatives
Jens Cordes, Sylvain Laclef, Andrew J. P. White, and Anthony G. M. Barrett*
Department of Chemistry, Imperial College, London SW7 2AZ, England
S
* Supporting Information
ABSTRACT: Intermolecular palladium(0)-catalyzed allylic
alkylation of diketoester−dioxinones was performed under
neutral conditions with 2-alkenyl and 2-cycloalkenyl acetates.
Subsequent aromatization using cesium carbonate gave rise to
isopropylidene-protected hexasubstituted resorcylates.
Scheme 1. Palladium-Catalyzed Migratory Allylation and
Aromatization Sequences5−7
INTRODUCTION
■
The construction of new C−C bonds by palladium-catalyzed
reactions of allylic compounds via the formation of π-allyl
palladium complexes is a powerful synthetic method that is
widely used in organic chemistry.1 Soft carbon-centered
nucleophiles2 such as the carbanions derived from malonates
and acetoacetates as well as enamines can react in such Tsuji−
Trost reactions with Pd(0) complexes, which are accessible
from various allylic precursors.
The reaction of allyl acetates, which are most widely used,
usually requires a strong base in order to generate the required
stabilized carbanion intermediates and to neutralize the acetic
acid formed during the reaction. Generally, sodium hydride,
alkali metal alkoxides, or hydroxides are used, and these may
cause problems when base-labile functionalities are present.
The first allylation of β-ketoesters using allylic acetates under
neutral conditions was described by Giambastiani and Poli
demonstrating that the acetate anion can deprotonate
substrates of suitable pKa.3
We recently reported palladium-catalyzed decarboxylative
prenyl or geranyl migration and aromatization reactions
(Scheme 1),4 which were successfully employed in the total
synthesis of the terpenoid resorcylates angelicoin A (4),5,6
hericenone J (5),6 hericenol A (6),6 and amorfrutin A (7)7
(Figure 1). Such resorcylate natural products display interesting
biological activities, for example, as antitumor, antimicrobial, or
immunosuppressant agents.8
Herein, we report an extension of this chemistry for the
concise and practically simple synthesis of hexasubstituted
resorcylates, which should be useful to generate novel diverse
pharmacophores.
Figure 1. Resorcylate natural products that are accessible via the
transformation of dioxinones 1 to resorcylates 3.
two sequential acylations of dioxinone 13 with acyl chlorides 12
and 14.
Such hexafunctionalized arenes are usually tedious to
synthesize9 via long sequences using transition-metal-mediated
cyclizations of appropriately functionalized enynes10 and
Diels−Alder cycloadditions of furans.11 We considered that
hexasubstituted benzenes like 8 (Scheme 2) should be available
from diketoester−dioxinone 10 via 9 by selective C-3 allylation
using π-allyl palladium chemistry and in situ aromatization.12
The diketoester−dioxinone 10 should be readily accessed by
RESULTS AND DISCUSSION
Deprotonation of dioxinone 13 with lithium hexamethyldisila-
zide and Claisen condensation reaction with the commercially
■
Received: February 16, 2012
Published: March 15, 2012
© 2012 American Chemical Society
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ethyl esters were prepared during this study, this reaction
should be of general utility for various esters, as the necessary
acid chlorides 14 can be prepared from the corresponding
alcohol (R1OH) and Meldrum’s acid in two steps.6
Scheme 2. Retrosynthetic Analysis of the Hexasubstituted
Resorcylate 8
The second Claisen condensation reaction was carried out
regioselectively in the presence of magnesium chloride and
pyridine. By varying the acid chloride 12, a series of eight
different diketoesters 10a−h was prepared from β-ketoesters
11a and 11b (42−80%, Table 1). The resultant diketoesters
10a−h were subsequently allowed to react with allyl acetate
catalyzed by Pd(PPh3)4 to afford the allyl-substituted
diketoesters 9, which were smoothly aromatized with cesium
carbonate, providing the isopropylidene-protected resorcylates
8a−h (Table 1). The regioselectivity of the allylation step was
unambiguously proven in the case of 8c (Table 1, entry 3) by a
single-crystal X-ray structure determination.13
The best results were obtained by using initial Pd(0)-
catalyzed allylation in the absence of base, indicating that
substrates containing a diketoester−dioxinone unit are
sufficiently acidic to be deprotonated by the acetate anion
generated as part of the palladium catalytic cycle. After
allylation, cesium carbonate was added to catalyze aromatiza-
tion providing the corresponding isopropylidene-protected
isophthalate esters 8. For sterically hindered substituents on
position R2, the cyclization did not proceed upon addition of
cesium carbonate but could be accomplished by subsequent
reaction with silica (Table 1, entries 5 and 6). The yields for α-
branched ketones (R2 = isopropyl, cyclopropyl, phenyl, or
furan-2-yl), however, were considerably lower (42−59%, Table
1, entries 5−8) than in the case of less substituted moieties like
methyl, ethyl, and 2-phenethyl (83−90%, Table 1, entries 1−
4).
available acyl chlorides 14a or 14b gave ketoester−dioxinones
11a and 11b (64−75%, Scheme 3). Although only methyl and
Scheme 3. Synthesis of the β-Ketoesters 11a and 11b
The diketoester−dioxinones 10a−c were also allowed to
react with more functionalized 2-alkenyl and 2-cycloalkenyl
Table 1. Synthesis of Allyl-Substituted Resorcylates 8a−h
a
b
Isolated yield. Silica was used for cyclization.
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Table 2. Synthesis of Hexasubstituted Resorcylates 16a−o with Substituted Allyl Side Chains
a
b
Isolated yield. Longer reaction time (24 h) required for (i).
acetates (Table 2). Although the yields of arenes were generally
lower, the reaction proceeded in all cases, and it is noteworthy
that the substitution on the allyl moiety has less impact on the
efficiency of the synthesis of the isophthalates 16 than
substitutions on the diketoester−dioxinone (R2). Substitution
at C-1 of the allyl donor resulted in slightly lower yields (58−
76%; Table 2, entries 1−5), although it is clear that the method
proceeds easily for allyl acetates with up to two substituents on
different positions of the allyl core. The reaction of geranyl
acetate required longer reaction times and proceeded in lower
yield (47−52%, Table 2, entries 10 and 11), probably due to
steric hindrance, but resulted only in the formation of the linear
and not the branched geranyl isophthalate. In all cases that
could result in product mixtures (Table 2, entries 8−15), only
linear allylated arenes were isolated. This indicates a mechanism
occurring through an attack of the enol or enolate of
diketoester 10 on a π-allyl palladium complex at C-1 of the
allyl ligand. Indeed, cinnamylations using cinnamyl acetate are
known to provide excellent linear to branched ratios,3,14 and
since the resorcylates 16h and 16i were isolated without any
branched side products, a mechanism proceeding via an O-
allylation followed by a subsequent Claisen rearrangement to
form the observed C−C bonds is unlikely to have occurred.
Furthermore, direct C-allylation catalyzed by acetate anion
was supported by the fact that allyl chloride 17, which produces
the less basic chloride anion, did not react with diketoester−
dioxinone 10a in the presence of Pd(PPh3)4. Nevertheless,
when the same reaction was carried out using cesium carbonate
as base, both isophthalate 8a and resorcylate 18, resulting from
the cyclization of the starting diketoester−dioxinone 10a, were
produced (Scheme 4). The same reaction carried out in the
absence of Pd(PPh3)4 did not provide the arene 8a.
Scheme 4. Synthesis of Resorcylates by Using Allyl Chloride
CONCLUSION
■
In conclusion, we describe Pd(0)-catalyzed allylic alkylations of
diketoester−dioxinones using allylic acetates under neutral
conditions and subsequent aromatization to produce diverse
tetrasubstituted isophthalates in four steps with good overall
yields. The reaction, which is suitable for delicate substrates, is
currently being applied in total synthesis and medicinal
chemistry.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out in oven-dried
glassware under Ar using commercially supplied solvents and reagents
unless otherwise stated. THF was redistilled from Na−Ph2CO.
Hexanes refers to petroleum spirits 40−60 °C. Column chromatog-
raphy was carried out on silica gel using flash techniques (eluents are
given in parentheses). Analytical TLC was performed on precoated
silica gel F254 aluminum plates with visualization under UV light or by
staining with acidic vanillin, anisaldehyde, or ninhydrin spray reagents.
1H and 13C NMR spectra were respectively recorded at 400 and 100
MHz with chemical shifts (δ) quoted in ppm. Data are reported as
follows: s = singlet, d = duplet, t = triplet, q = quartet, mc = symmetric
multiplet (center is given), m = unsymmetric multiplet (shift range is
given).
General Procedure for the Synthesis of β-Ketoester−
Dioxinones 11a,b. n-BuLi (2.5 M in hexanes; 50.5 mL, 126 mmol,
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3.6 equiv) was added with stirring to (Me3Si)2NH (26.3 mL, 105
mmol, 3.6 equiv) in THF (200 mL) at −78 °C. After 1 h, dioxinone
13 (14.9 g, 105 mmol, 3.0 equiv) in THF (45 mL) and, after an
additional 1 h, acyl chloride 14a,b (35.1 mmol, 1.0 equiv) in THF (20
mL) were each added dropwise. After a further 1 h at −78 °C, the
reaction was quenched at this temperature by the addition of saturated
aqueous NH4Cl (150 mL), and the mixture was allowed to warm to
room temperature. The aqueous layer was acidified to pH 3 with 1 M
HCl and was extracted with EtOAc (3 × 250 mL). The combined
organic extracts were washed with brine (25 mL), dried (MgSO4),
rotary evaporated, and chromatographed (hexanes/EtOAc 100:1, 10:1,
5:1, 4:1, 3:2) to give β-keto ester dioxinones 11a,b.
(CDCl3, 400 MHz) δ 5.31 (s, 1H), 4.25 (q, 2H, J = 7.1 Hz), 3.66 (s,
2H), 2.71 (q, 2H, J = 7.4 Hz), 1.66 (s, 6H), 1.32 (t, 3H, J = 7.2 Hz),
1.16 (t, 3H, J = 7.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 199.7, 191.9,
166.3, 165.2, 160.6, 108.2, 107.1, 96.2, 61.1, 42.5, 31.1, 24.8 (2C), 14.1,
9.6; HRMS-ESI (m/z) calcd for C15H21O7 (M + H+) 313.1287, found
313.1283.
Ethyl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetyl)-4-
methyl-3-oxopentanoate (10e): colorless oil; 42%; Rf 0.42 (Et2O/
1
hexanes 1:1); IR 1713, 1373, 1271, 1249, 1201, 1092, 1063 cm−1; H
NMR (CDCl3, 400 MHz) δ 5.34 (s, 1H), 4.27 (q, 2H, J = 7.1 Hz),
3.64 (s, 2H), 3.20 (sept., 1H, J = 6.8 Hz), 1.69 (s, 6H), 1.34 (t, 3H, J =
7.2 Hz), 1.18 (d, 6H, J = 6.7 Hz); 13C NMR (CDCl3, 100 MHz) δ
201.7, 192.3, 166.6, 165.0, 160.7, 107.9, 107.2, 96.4, 61.3, 42.6, 34.5,
24.9 (2C), 19.4 (2C), 14.1; HRMS-ESI (m/z) calcd for C16H23O7 (M
+ H+) 327.1444, found 327.1446.
Methyl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobuta-
noate (11a): yellow oil; 64%; Rf 0.36 (hexanes/EtOAc 1:1); IR
1
1724, 1637, 1438, 1391, 1332, 1273, 1204 cm−1; H NMR (CDCl3,
Ethyl 2-(cyclopropanecarbonyl)-4-(2,2-dimethyl-4-oxo-4H-1,3-di-
oxin-6-yl)-3-oxobutanoate (10f): colorless oil; 80%; Rf 0.43 (Et2O/
hexanes 1:1); IR 1726, 1708, 1637, 1390, 1374, 1272, 1252, 1203,
1098, 1064, 1015 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.35 (s, 1H),
4.30 (q, 2H, J = 7.2 Hz), 3.65 (s, 2H), 2.50 (tt, 1H, J = 7.9, 4.6 Hz),
1.68 (s, 6H), 1.35 (t, 3H, J = 7.1 Hz), 1.30 (mc, 2H), 1.08 (mc, 2H);
13C NMR (CDCl3, 100 MHz) δ 199.3, 189.9, 166.8, 165.4, 160.8,
108.8, 107.1, 96.2, 61.1, 42.2, 24.9 (2C), 16.6, 14.2, 12.9 (2C); HRMS-
ESI (m/z) calcd for C16H21O7 (M + H+) 325.1287, found 325.1281.
Ethyl 2-benzoyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxo-
butanoate (10g): colorless oil; 73%; Rf 0.23 (Et2O:hexanes 1:1); IR
1728, 1640, 1601, 1391, 1376, 1273, 1245, 1204, 1015 cm−1; 1H NMR
(CDCl3, 400 MHz) mixture of several keto−enol tautomers, two sets of
signals are dominating this mixture: keto−enol tautomer 1 (ca. 40%) δ
7.58−7.40 (m, 5H), 5.40 (s, 1H), 3.94 (q, 2H, J = 7.1 Hz), 3.75 (s,
2H), 1.70 (s, 6H), 0.84 (t, 3H, J = 7.2 Hz); keto−enol tautomer 2 (ca.
30%): δ 13.28 (s, 1H), 7.79−7.77 (m, 2H), 7.58−7.40 (m, 3H), 5.37
(s, 1H), 4.11 (q, 2H, J = 7.2 Hz), 3.33 (s, 2H), 1.60 (s, 6H), 0.96 (t,
3H, J = 7.1 Hz); 13C NMR (CDCl3, 100 MHz) keto−enol tautomer 1: δ
191.0, 173.7, 167.2, 164.8, 160.7, 136.2, 132.0, 128.3 (2C), 127.5 (2C),
108.6, 107.2, 96.5, 61.2, 41.6, 24.9 (2C), 13.3; keto−enol tautomer 2: δ
190.2, 170.9, 167.2, 165.1, 160.5, 138.6, 133.2, 128.8 (2C), 128.4 (2C),
107.3, 107.1, 95.8, 61.5, 37.2, 24.8 (2C), 13.5; HRMS-ESI (m/z) calcd
for C19H21O7 (M + H+) 361.1287, found 361.1284.
400 MHz,) δ 5.37 (s, 1H), 3.76 (s, 3H), 3.53 (s, 2H), 3.49 (s, 2H),
1.71 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 195.5, 166.7, 163.4,
160.4, 107.4, 97.1, 52.6, 48.8, 46.9, 24.9 (2C); MS (ES) m/z 243 (M +
H+); HRMS (ES) calcd for C11H15O6 (M + H+) 243.0863, found
243.0869. Anal. Calcd for C11H14O6: C, 54.54; H, 5.83. Found: C,
54.65; H, 5.75.
Ethyl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate
(11b): white solid; 75%; mp 42−45 °C (hexanes); Rf 0.48 (hexanes/
EtOAc 1:1); IR 1746, 1717, 1393, 1377, 1336, 1275, 1263, 1202, 1028,
1015 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.33 (s, 1H), 4.18 (q, J =
7.2 Hz, 2H), 3.48 (s, 4H), 1.68 (s, 6H), 1.25 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 195.7, 166.3, 163.5, 160.4, 107.2, 97.0,
61.7, 49.0, 46.9, 24.9 (2C), 14.0; HRMS-ESI (m/z) calcd for
C12H17O6 (M + H+) 257.1020, found 257.1020. Anal. Calcd for
C12H16O6: C, 56.24; H, 6.29. Found: C, 56.24; H, 6.35.
General Procedure for the Synthesis of Diketoester−
Dioxinones 10a−h. Ketoester dioxinone 11a,b (3.4 mmol, 1.0
equiv) in CH2Cl2 (10 mL) was added with stirring to MgCl2 (640 mg,
6.7 mmol, 2.0 equiv) and pyridine (0.8 mL, 9.2 mmol, 2.7 equiv) in
CH2Cl2 (100 mL) at 0 °C. After 30 min, acyl chloride 12a−h (4.1
mmol, 1.2 equiv) was added. After the mixture was stirred for 1 h at 0
°C, the reaction was quenched with brine (100 mL) and the mixture
extracted with EtOAc (2 × 200 mL). The combined organic layers
were dried (MgSO4) and rotary evaporated, and the residue was
chromatographed (Et2O/hexanes 1:4 to 100% Et2O) to afford
diketoester−dioxinone 10a−h.
Methyl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2-(furan-2-car-
bonyl)-3-oxobutanoate (10h): yellow oil; 69%; Rf 0.21 (Et2O/
hexanes 1:1); IR 1721, 1391, 1376, 1273, 1248, 1200, 1013, 903, 859,
Methyl 2-acetyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxo-
butanoate (10a): colorless oil; 71%; Rf 0.48 (AcOEt/hexanes 3:7); IR
1714, 1637, 1564, 1436, 1390, 1374, 1270, 1251, 1200, 1081, 1013,
1
766, 728 cm−1; H NMR (CDCl3, 400 MHz) mixture of several keto−
enol tautomers, two sets of signals are dominating this mixture: keto−enol
tautomer 1 (ca. 45%): δ 7.58−7.49 (m, 1H), 7.22 (d, 1H, J = 3.4 Hz),
6.59−6.51 (m, 1H), 5.35 (s, 1H), 3.75 (s, 3H), 3.54 (s, 2H), 1.64 (s,
6H); keto−enol tautomer 2 (ca. 30%): δ 13.05 (s, 1H), 7.58−7.49 (m,
1H), 7.13 (d, 1H, J = 3.5 Hz), 6.59−6.51 (m, 1H), 5.32 (s, 1H), 3.69
(s, 3H), 3.27 (s, 2H), 1.55 (s, 6H); 13C NMR (CDCl3, 100 MHz)
keto−enol tautomer 1: δ 188.9, 173.4, 164.5, 160.5, 147.8, 147.1, 119.1,
112.7, 107.1, 106.9, 96.4, 52.3, 40.9, 24.7 (2C); keto−enol tautomer 2: δ
193.3, 174.1, 167.1, 164.8, 148.4, 146.9, 118.9, 112.6, 106.7, 106.4,
95.7, 53.2, 36.9, 24.6 (2C); HRMS-ESI (m/z) calcd for C16H17O8 (M
+ H+) 337.0923, found 337.0929.
1
959, 901 cm−1; H NMR (CDCl3, 400 MHz) δ 5.31 (s, 1H), 3.79 (s,
3H), 3.71 (s, 2H), 2.40 (s, 3H), 1.67 (s, 6H); 13C NMR (CDCl3, 100
MHz) δ 196.0, 193.8, 166.6, 165.1, 160.7, 108.1, 107.1, 96.3, 51.8,
43.2, 25.5, 24.8 (2C); HRMS-ESI (m/z) calcd for C13H17O7 (M + H+)
285.0969, found 285.0964.
Ethyl 2-acetyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxo-
butanoate (10b): colorless oil; 76%; Rf 0.54 (AcOEt/hexanes 3:7);
IR 1725, 1637, 1565, 1373, 1271, 1251, 1201, 1078, 1013, 901 cm−1;
1H NMR (CDCl3, 400 MHz) δ 5.31 (s, 1H), 4.26 (q, J = 7.2 Hz, 2H),
3.71 (s, 2H), 2.40 (s, 3H), 1.67 (s, 6H), 1.32 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 195.8, 193.5, 166.2, 165.2, 160.7, 108.4,
107.1, 96.3, 61.0, 43.1, 25.5, 24.8 (2C), 14.1; HRMS-ESI (m/z) calcd
for C14H19O7 (M + H+) 299.1131, found 299.1137.
General Procedure for the Synthesis of Resorcylates 8a−h
and 16a−o. Diketoester-dioxinone 10a−h (0.30 mmol, 1.0 equiv)
and allyl acetate 15 (0.33 mmol, 1.1 equiv) in THF (0.5 mL) were
added with stirring to Pd(PPh3)4 (8.7 mg, 0.008 mmol, 2.5 mol %) in
THF (1 mL). After 5 h (24 h in the case of geranyl acetate) at 25 °C,
Cs2CO3 (294 mg, 0.90 mmol, 3.0 equiv) was added, and the resulting
mixture was stirred for 12 h at 25 °C. Reaction was quenched by
addition of brine (20 mL) and the mixture acidified to pH 3 with 1 M
HCl and extracted with EtOAc (2 × 50 mL). The organic extracts
were combined, dried (MgSO4), filtered, rotary evaporated, and
(unless noted otherwise) chromatographed (hexanes/EtOAc 9:1) to
provide resorcylate 8a−h (R3 = allyl) or 16a−o (R3 = 2-alkenyl or 2-
cycloalkenyl).
Ethyl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetyl)-3-oxo-
5-phenylpentanoate (10c): colorless oil; 78%; Rf 0.54 (AcOEt/
hexanes 2:8); IR 1726, 1710, 1637, 1560, 1389, 1374, 1271, 1250,
1201, 1071, 1014 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.19−7.31 (m,
5H), 5.34 (s, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.69 (s, 2H), 3.05 (m,
2H), 2.97 (m, 2H), 1.69 (s, 6H), 1.32 (t, J = 7.2 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 197.5, 192.4, 166.1, 165.0, 160.7, 140.2, 128.5
(2C), 128.2 (2C), 126.3, 108.6, 107.1, 96.4, 61.2, 42.8, 39.2, 31.6, 24.9
(2C), 14.1; HRMS-ESI (m/z) calcd for C21H25O7 (M + H+) 389.1600,
found 389.1602.
Ethyl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetyl)-3-oxo-
Methyl 8-allyl-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-benzo[d][1,3]-
dioxine-6-carboxylate (8a): white solid; 84%; mp 59−60 °C
(hexanes); Rf 0.69 (EtOAc/hexanes 1:9); IR 1730, 1657, 1583,
pentanoate (10d): colorless oil; 71%; Rf 0.42 (Et2O/hexanes 1:1);
1
IR 1725, 1390, 1373, 1271, 1251, 1202, 1071, 1015 cm−1; H NMR
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1436, 1377, 1330, 1265, 1234, 1208, 1139, 1029, 992, 977, 914 cm−1;
Ethyl 8-allyl-7-hydroxy-2,2-dimethyl-4-oxo-5-phenyl-4H-benzo-
[d][1,3]dioxine-6-carboxylate (8g): white solid; 53%; mp 84−86 °C
(CH2Cl2); Rf 0.33 (Et2O/hexanes 1:3); IR 1739, 1268, 1237, 1205,
1H NMR (CDCl3, 400 MHz) δ 11.86 (s, 1H), 5.88 (m, 1H), 5.02−
4.97 (m, 2H), 3.99 (s, 3H), 3.37 (d, J = 6.2 Hz, 2H), 2.88 (s, 2H), 1.69
(s, 6H); 13C NMR (CDCl3, 100 MHz) δ 172.0, 164.7, 160.1, 158.4,
147.3, 135.0, 115.0, 113.5, 110.4, 106.5, 104.7, 52.7, 26.8, 25.7 (2C),
20.2; HRMS-ESI (m/z) calcd for C16H19O6 (M + H+) 307.1176,
found 307.1175. Anal. Calcd for C16H18O6: C, 62.74; H, 5.92. Found:
C, 62.84; H, 6.01.
1
1189, 1172, 1009, 921, 742 cm−1; H NMR (CDCl3, 400 MHz) δ
11.88 (s, 1H), 7.37−7.33 (m, 3H), 7.15−7.10 (m, 2H), 5.94 (ddt, 1H,
J = 16.3, 10.0, 6.3 Hz), 5.08 (dq, 1H, J = 17.1, 1.8 Hz), 5.04 (dq, 1H, J
= 10.0, 1.6 Hz), 3.88 (q, 2H, J = 7.1 Hz), 3.45 (dt, 2H, J = 6.3, 1.4 Hz),
1.73 (s, 6H), 1.73 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 100 MHz) δ
170.9, 164.3, 158.4, 158.2, 147.7, 140.0, 134.7, 127.7 (2C), 127.4 (2C),
127.0, 115.3, 115.0, 109.9, 104.9, 61.4, 26.8, 25.8 (2C), 12.8; HRMS-
ESI (m/z) calcd for C22H23O6 (M + H+) 383.1495, found 383.1494.
Methyl 8-allyl-5-(furan-2-yl)-7-hydroxy-2,2-dimethyl-4-oxo-4H-
benzo[d][1,3]dioxine-6-carboxylate (8h): white solid; 42%; mp 78−
80 °C (CHCl3); Rf 0.27 (Et2O/hexanes 1:3); IR 1746, 1666, 1581,
Ethyl 8-allyl-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-benzo[d][1,3]-
dioxine-6-carboxylate (8b): colorless oil; 90%; Rf 0.71 (EtOAc/
hexanes 1:9); IR 1725, 1637, 1565, 1373, 1271, 1251, 1201, 1078,
1
1013, 901 cm−1; H NMR (CDCl3, 400 MHz) δ 11.93 (s, 1H), 5.87
(m, 1H), 5.00−4.95 (m, 2H), 4.45 (q, J = 7.2 Hz, 2H), 3.35 (d, J = 6.2
Hz, 2H), 2.88 (s, 3H), 1.68 (s, 6H), 1.42 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 171.4, 164.7, 160.1, 158.3, 147.2, 135.0,
115.0, 113.5, 110.5, 106.4, 104.7, 62.3, 26.7, 25.7 (2C), 20.3, 14.1;
HRMS-ESI (m/z) calcd for C17H21O6 (M + H+) 321.1338, found
321.1349.
1
1432, 1380, 1335, 1268, 1243, 1204, 1146, 997, 916 cm−1; H NMR
(CDCl3, 400 MHz) δ 11.51 (s, 1H), 7.54 (d, 1H, J = 2.1 Hz), 6.49
(dd, 1H, J = 1.9, 3.3 Hz), 6.26 (d, 1H, J = 3.6 Hz), 5.08 − 5.01 (m,
2H), 5.91 (ddt, 1H, J = 16.3, 10.0, 6.2 Hz), 3.63 (s, 3H), 3.44 (dt, 2H,
J = 6.1, 1.4 Hz), 1.74 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 170.9,
163.8, 158.2, 158.1, 148.9, 142.0, 134.9, 134.4, 116.6, 115.5, 111.1,
110.5, 108.9, 106.8, 105.3, 53.0, 26.9 (2C), 25.8; HRMS-ESI (m/z)
calcd for C19H19O7 (M + H+) 359.1131, found 359.1122.
Ethyl 8-allyl-7-hydroxy-2,2-dimethyl-4-oxo-5-phenethyl-4H-
benzo[d][1,3]dioxine-6-carboxylate (8c): white solid; 84%; mp 63−
65 °C (hexanes); Rf 0.78 (EtOAc/hexanes 1:9); IR 1730, 1647, 1595,
1
1580, 1377, 1274, 1263, 1233, 1214, 1137, 1046, 1015, 914 cm−1; H
Methyl 8-(cyclohex-2-enyl)-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-
benzo[d][1,3]dioxine-6-carboxylate (16a): white solid; 63%; mp
76−78 °C (hexanes); Rf 0.74 (EtOAc/hexanes 1:9); IR 1731, 1720,
1656, 1573, 1436, 1375, 1360, 1302, 1262, 1229, 1217, 1118, 1025,
NMR (CDCl3, 400 MHz) δ 11.89 (s, 1H), 7.32−7.22 (m, 4H), 7.16
(m, 1H), 5.87 (m, 1H), 4.98 (m, 2H), 4.46 (q, J = 7.2 Hz, 2H), 3.76
(m, 2H), 3.35 (d, J = 6.2 Hz, 2H), 2.88 (m, 2H), 1.63 (s, 6H), 1.38 (t,
J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 171.2, 164.8, 159.7,
158.6, 150.2, 141.9, 134.9, 128.4 (2C), 128.3 (2C), 125.9, 115.1, 114.1,
110.2, 105.7, 104.5, 62.5, 37.0, 33.1, 26.8, 25.7 (2C), 14.2; HRMS-ESI
(m/z) calcd for C24H27O6 (M + H+) 411.1802, found 411.1790. Anal.
Calcd for C24H26O6: C, 70.23; H, 6.38. Found: C, 70.32; H, 6.28.
Ethyl 8-allyl-5-ethyl-7-hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d]-
[1,3]dioxine-6-carboxylate (8d): white solid; 83%; mp 82−84 °C
(CH2Cl2); Rf 0.68 (Et2O/hexanes 1:3); IR 1732, 1654, 1582, 1264,
1214, 1182, 1038 cm−1; 1H NMR (CDCl3, 400 MHz) δ 11.91 (s, 1H),
5.88 (ddt, 1H, J = 16.3, 10.0, 6.3 Hz), 5.03 − 4.96 (m, 2H), 4.46 (q,
2H, J = 7.1 Hz), 3.45 (q, 2H, J = 7.2 Hz), 3.36 (dt, 2H, J = 6.3, 1.4
Hz), 1.67 (s, 6H), 1.44 (t, 3H, J = 7.2 Hz), 1.26 (t, 3H, J = 7.2 Hz);
13C NMR (CDCl3, 100 MHz) δ 171.4, 164.8, 159.5, 158.6, 153.0,
1
962 cm−1; H NMR (CDCl3, 500 MHz) δ 11.21 (s, 1H), 5.80 (m,
1H), 5.54 (bd, J = 10.0 Hz, 1H), 3.97 (s, 1H), 2.81 (s, 3H), 2.09 (bs,
2H), 1.90−1.75 (m, 4H), 1.69 (s, 3H), 1.65 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 171.5, 163.8, 160.2, 158.4, 146.0, 130.0, 126.9,
118.5, 111.9, 106.7, 104.5, 52.6, 32.1, 27.4, 26.0, 25.1, 24.7, 22.9, 20.0;
HRMS-ESI (m/z) calcd for C19H23O6 (M + H+) 347.1489, found
347.1486. Anal. Calcd for C19H22O6: C, 65.88; H, 6.40. Found: C,
65.79; H, 6.47.
Ethyl 8-(cyclohex-2-enyl)-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-
benzo[d][1,3]dioxine-6-carboxylate (16b): white solid; 76%; mp
39−41 °C (hexanes); Rf 0.68 (EtOAc/hexanes 1:9); IR 1728, 1647,
1
1561, 1445, 1378, 1301, 1266, 1232, 1218, 1185, 1029, 913 cm−1; H
NMR (CDCl3, 400 MHz) δ 5.75 (m, 1H), 5.50 (bd, J = 10.0 Hz, 1H),
4.42 (q, J = 7.2 Hz, 2H), 3.94 (bs, 1H), 2.80 (s, 3H), 2.05 (m, 2H),
1.86−1.74 (m, 4H), 1.66 (s, 3H), 1.63 (s, 3H), 1.39 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 171.0, 163.9, 160.1, 158.3,
146.0, 129.9, 126.6, 118.5, 111.7, 106.6, 104.3, 62.1, 31.9, 27.2, 25.9,
24.9, 24.6, 22.8, 20.0, 14.0; HRMS-ESI (m/z) calcd for C20H25O6 (M
+ H+) 361.1646, found 361.1639. Anal. Calcd for C20H24O6: C, 66.65;
H, 6.71. Found: C, 66.71; H, 6.86.
Ethyl 8-(cyclohex-2-enyl)-7-hydroxy-2,2-dimethyl-4-oxo-5-phe-
nethyl-4H-benzo[d][1,3]dioxine-6-carboxylate (16c): colorless oil;
58%; Rf 0.72 (EtOAc/hexanes 1:9); IR 1730, 1653, 1577, 1388, 1377,
1299, 1265, 1230, 1220, 1044, 1021, 916 cm−1; 1H NMR (CDCl3, 400
MHz) δ 10.95 (s, 1H), 7.35−7.28 (m, 4H), 7.19 (m, 1H), 5.85 (m,
1H), 5.59 (m, 1H), 4.48 (q, J = 7.2 Hz, 2H), 3.99 (m, 1H), 3.64 (m,
2H), 2.92 (s, 2H), 2.11 (m, 2H), 1.92−1.81 (m, 4H), 1.68 (s, 3H),
1.64 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
170.6, 163.5, 159.8, 158.5, 148.6, 142.0, 129.8, 128.5 (2C), 128.3 (3C),
127.5, 125.9, 118.9, 105.8, 104.3, 62.4, 37.0, 33.5, 32.1, 27.4, 26.0, 25.1,
24.7, 22.8, 14.3; HRMS-ESI (m/z) calcd for C27H31O6 (M + H+)
451.2115, found 451.2111.
(E)-Methyl 7-hydroxy-2,2,5-trimethyl-4-oxo-8-(pent-3-en-2-yl)-
4H-benzo[d][1,3]dioxine-6-carboxylate (16d): white solid; 68%; mp
48−50 °C (hexanes); Rf 0.73 (EtOAc/hexanes 1:9); IR 1726, 1656,
1573, 1441, 1378, 1310, 1267, 1234, 1032, 1074, 1017, 967, 924 cm−1;
1H NMR (CDCl3, 400 MHz) δ 11.73 (s, 1H), 5.81 (ddd, J = 15.2, 7.2,
1.5 Hz, 1H), 5.50 (dqd, J = 15.2, 6.5, 1.5 Hz, 1H), 4.06 (quint, J = 7.2
Hz, 1H), 4.00 (s, 3H), 2.85 (s, 3H), 1.72 (s, 3H), 1.71 (s, 3H), 1.35
(d, J = 6.5 Hz, 3H), 1.65 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 172.0, 164.1, 160.2, 158.1, 146.5, 133.8, 124.2, 119.4, 111.0,
106.8, 104.4, 52.6, 32.2, 25.8, 25.5, 20.2, 18.5, 17.8; HRMS-ESI (m/z)
calcd for C18H23O6 (M + H+) 335.1495, found 335.1498. Anal. Calcd
for C18H22O6: C, 64.66; H, 6.63. Found: C, 64.75; H, 6.56.
135.0, 115.1, 113.8, 109.9, 105.5, 104.4, 62.3, 26.8, 25.7, 24.9 (2C),
15.4, 13.9.; HRMS-ESI (m/z) calcd for C18H23O6 (M + H+) 335.1495,
found 335.1487.
Ethyl 8-Allyl-7-hydroxy-5-isopropyl-2,2-dimethyl-4-oxo-4H-
benzo[d][1,3]dioxine-6-carboxylate (8e). After the aqueous workup,
the resultant oil was dissolved in Et2O (10 mL), and silica (1 g) was
added. After the mixture was stirred at 20 °C for 18 h, the solvent was
evaporated and the product was isolated by chromatography: white
solid; 43%; mp 95−96 °C (CH2Cl2); Rf 0.68 (Et2O/hexanes 1:3); IR
1732, 1578, 1376, 1298, 1265, 1211, 1183, 1134, 1048, 1019 cm−1; 1H
NMR (CDCl3, 400 MHz) δ 9.93 (s, 1H), 5.87 (ddt, 1H, J = 16.5, 10.1,
6.3 Hz), 5.06 − 4.99 (m, 2H), 4.44 (q, 2H, J = 7.2 Hz), 4.03 (sept.,
1H, J = 7.1 Hz), 3.36 (dt, 2H, J = 6.3, 1.3 Hz), 1.67 (s, 6H), 1.44 (t, J =
7.2 Hz, 3H), 1.41 (d, 6H, J = 7.0 Hz); 13C NMR (CDCl3, 100 MHz) δ
171.1, 161.5, 159.6, 158.0, 154.9, 135.0, 115.4, 113.7, 113.1, 106.9,
104.3, 62.4, 31.8, 27.1, 25.6 (2C), 21.2 (2C), 13.9; HRMS-ESI (m/z)
calcd for C19H25O6 (M + H+) 349.1646, found 349.1645.
Ethyl 8-Allyl-5-cyclopropyl-7-hydroxy-2,2-dimethyl-4-oxo-4H-
benzo[d][1,3]dioxine-6-carboxylate (8f). After the aqueous workup,
the resultant oil was dissolved in Et2O (10 mL), and silica (1 g) was
added. After the mixture was stirred at 20 °C for 18 h, the solvent was
evaporated and the product was isolated by chromatography: white
solid; 59%; mp 130−132 °C (CH2Cl2); Rf 0.48 (Et2O/hexanes 1:3);
IR 1740, 1659, 1581, 1266, 1236, 1209, 1019 cm−1; 1H NMR (CDCl3,
400 MHz) δ 11.03 (s, 1H), 5.84 (ddt, 1H, J = 16.5, 10.0, 6.3 Hz), 5.01
− 4.94 (m, 2H), 4.41 (q, 2H, J = 7.1 Hz), 3.33 (d, 2H, J = 6.3), 2.49
(tt, 1H, J = 8.6, 6.0 Hz), 1.66 (s, 6H), 1.39 (t, 3H, J = 7.0 Hz), 1.07
(mc, 2H), 0.30 (mc, 2H); 13C NMR (CDCl3, 100 MHz) δ 171.0,
162.6, 158.9, 157.5, 151.5, 134.9, 115.1, 113.8, 112.8, 109.0, 104.9,
62.1, 26.8, 25.6 (2C), 16.9, 13.9, 10.0 (2C); HRMS-ESI (m/z) calcd
for C19H23O6 (M + H+): 347.1495, found: 347.1498.
3528
dx.doi.org/10.1021/jo300340c | J. Org. Chem. 2012, 77, 3524−3530

The Journal of Organic Chemistry
Article
(E)-Ethyl 7-hydroxy-2,2-dimethyl-4-oxo-8-(pent-3-en-2-yl)-5-phe-
nethyl-4H-benzo[d][1,3]dioxine-6-carboxylate (16e): colorless oil;
62%; Rf 0.76 (EtOAc/hexanes 1:9); IR 1729, 1653, 1575, 1496, 1452,
26.6, 25.7 (2C), 25.6, 21.7, 20.2, 17.6, 16.1, 14.1; HRMS (ESI) m/z
calcd for C24H33O6 (M + H+) 417.2277, found 417.2271.
(E)-Ethyl 8-(3,7-dimethylocta-2,6-dienyl)-7-hydroxy-2,2-dimeth-
yl-4-oxo-5-phenethyl-4H-benzo[d][1,3]dioxine-6-carboxylate (16k):
colorless oil; 47%; Rf 0.80 (EtOAc/hexanes 1:8); IR 1733, 1655, 1584,
1454, 1377, 1300, 1267, 1235, 1048, 1020, 916 cm−1; 1H NMR
(CDCl3, 400 MHz) δ 11.80 (s, 1H), 7.35−7.27 (m, 4H), 7.19 (m,
1H), 5.16 (m, 1H), 5.06 (m, 1H), 4.49 (q, J = 7.2 Hz, 2H), 3.76 (m,
2H), 3.33 (d, J = 7.2 Hz, 2H), 2.91 (m, 2H), 2.04 (m, 2H), 1.97 (m,
2H), 1.77 (s, 3H), 1.67 (s, 6H), 1.64 (s, 3H), 1.57 (s, 3H), 1.41 (t, J =
7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 171.3, 164.7, 159.8,
158.4, 149.7, 142.0, 136.0, 131.4, 128.5 (2C), 128.3 (2C), 125.9, 124.1,
120.8, 116.1, 110.4, 105.7, 104.4, 62.5, 39.7, 37.1, 33.2, 26.6, 25.7 (2C),
25.6, 21.9, 17.7, 16.2, 14.3; HRMS-ESI (m/z) calcd for C31H39O6 (M
+ H+) 507.2741, found 507.2747.
Ethyl 8-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-
methyl)-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-benzo[d][1,3]dioxine-
6-carboxylate (16l): white solid; 67%; mp 84−86 °C (CH2Cl2); Rf
0.39 (Et2O/hexanes 1:9); IR 1733, 1655, 1584, 1378, 1265, 1232,
1211, 1031 cm−1; [α]25D −43.1 (c = 1.02, CH2Cl2); 1H NMR (CDCl3,
400 MHz) δ 11.78 (s, 1H), 4.89 (mc, 1H), 4.45 (q, 2H, J = 7.1 Hz),
3.29 (dq, 1H, J = 15.5, 2.0 Hz), 3.16 (dq, 1H, J = 15.5, 2.0 Hz), 2.89
(s, 3H), 2.33 (dt, 1H, J = 8.5, 5.6 Hz), 2.19 (dq, 1H, J = 17.4, 2.0 Hz),
2.13 − 2.02 (m, 3H), 1.66 (s, 6H), 1.43 (t, 3H, J = 7.1 Hz), 1.24 (s,
3H), 1.14 (d, 1H, J = 8.6 Hz), 0.78 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 171.4, 164.9, 160.3, 158.5, 146.9, 145.2, 115.6, 113.1, 110.5,
106.2, 104.5, 62.2, 46.1, 40.9, 38.1, 31.5, 31.1, 29.4, 26.3, 25.8, 25.6,
20.8, 20.3, 14.1; HRMS-ESI (m/z) calcd for C24H31O6 (M + H+)
415.2121, found 415.2108.
Ethyl 8-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-
methyl)-7-hydroxy-2,2-dimethyl-4-oxo-5-phenethyl-4H-benzo[d]-
[1,3]dioxine-6-carboxylate (16m): white solid; 64%; mp 81−83 °C
(CH2Cl2); Rf 0.41 (Et2O/hexanes 1:9); IR 1726, 1666, 1583, 1275,
1228, 1050, 1021, 792, 752 cm−1; [α]25D (c = 1.00, CH2Cl2) = −33.3;
1H NMR (CDCl3, 400 MHz) δ 11.71 (s, 1H), 7.34−7.27 (m, 4H),
7.21−7.17 (m, 1H), 4.91 (mc, 1H), 4.49 (q, 2H, J = 7.1 Hz), 3.82 (mc,
2H), 3.32 (dq, 1H, J = 15.5, 2.0 Hz), 3.20 (dq, 1H, J = 15.5, 2.0 Hz),
2.92 (mc, 2H), 2.89 (s, 3H), 2.36 (dt, 1H, J = 8.5, 5.6 Hz), 2.20 (dq,
1H, J = 17.4, 2.0 Hz), 2.16−2.05 (m, 3H), 1.65 (s, 3H), 1.64 (s, 3H),
1.42 (t, 3H, J = 7.1 Hz), 1.27 (s, 3H), 1.17 (d, 1H, J = 8.6 Hz), 0.81 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 171.4, 164.9, 160.3, 158.5,
146.9, 145.2, 115.6, 113.1, 110.5, 106.2, 104.5, 62.2, 46.1, 40.9, 38.1,
31.5, 31.1, 29.4, 26.3, 25.8, 25.6, 20.8, 20.3, 14.1; HRMS-ESI (m/z)
calcd for C31H37O6 (M + H+) 505.2590, found: 505.2580.
(S)-Ethyl 7-hydroxy-2,2,5-trimethyl-4-oxo-8-((4-(prop-1-en-2-yl)-
cyclohex-1-enyl)methyl)-4H-benzo[d][1,3]dioxine-6-carboxylate
(16n): white solid; 70%; mp 73−75 °C (CH2Cl2); Rf 0.40 (Et2O/
hexanes 1: 9); IR 1734, 1655, 1584, 1377, 1304, 1266, 1233, 1214,
1031 cm−1; [α]25D (c = 1.00, CH2Cl2) = −45.0; 1H NMR (CDCl3, 400
MHz) δ 11.81 (s, 1H), 5.28 (s, 1H), 4.67 (d, 2H, J = 5.0 Hz), 4.45 (q,
2H, J = 7.2 Hz), 3.24 (s, 2H), 2.88 (s, 3H), 2.11−2.00 (m, 4H), 1.92−
1.74 (m, 2H), 1.70 (s, 3H), 1.67 (s, 3H), 1.66 (s, 3H), 1.48−1.38 (m,
4H); 13C NMR (CDCl3, 100 MHz) δ 171.4, 164.8, 160.3, 158.6,
150.0, 146.9, 135.0, 120.7 (2C), 113.9, 110.6, 108.4, 106.4, 104.6, 62.2,
41.0, 30.7, 29.9, 29.1, 27.9, 25.7, 20.7, 20.3, 14.1; HRMS-ESI (m/z)
calcd for C24H31O6 (M + H+) 415.2121, found 415.2109.
(S)-Ethyl 7-hydroxy-2,2-dimethyl-4-oxo-5-phenethyl-8-((4-(prop-
1-en-2-yl)cyclohex-1-enyl)methyl)-4H-benzo[d][1,3]dioxine-6-car-
boxylate (16o): white solid; 68%; mp 82−84 °C (CH2Cl2); Rf 0.62
(Et2O/hexanes 1:3); IR 1731, 1654, 1583, 1377, 1301, 1267, 1233,
1212 cm−1; [α]25D (c = 1.00, CH2Cl2) = −36.0; 1H NMR (CDCl3, 400
MHz) δ 11.75 (s, 1H), 7.34−7.27 (m, 4H), 7.21−7.17 (m, 1H), 5.30
(s, 1H), 4.70 (d, 2H, J = 5.0 Hz), 4.50 (q, 2H, J = 7.2 Hz), 3.80 (mc,
2H), 3.28 (s, 2H), 2.93 (mc, 2H), 2.88 (s, 3H), 2.13−2.06 (m, 4H),
1.96−1.78 (m, 2H), 1.72 (s, 3H), 1.64 (s, 6H), 1.51−1.41 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ 171.2, 164.9, 159.8, 158.9, 149.9,
1
1416, 1389, 1376, 1264, 1226, 1046, 1013, 966, 927 cm−1; H NMR
(CDCl3, 400 MHz) δ 11.65 (s, 1H), 7.36−7.28 (m, 4H), 7.19 (m,
1H), 5.82 (ddd, J = 15.2, 7.2, 1.5 Hz, 1H), 5.50 (dqd, J = 15.2, 6.5, 1.5
Hz, 1H), 4.49 (q, J = 7.2 Hz, 2H), 4.06 (quint, J = 7.2 Hz, 1H), 3.71
(m, 2H), 2.91 (m, 2H), 1.68 (d, J = 6.5 Hz, 3H), 1.67 (s, 6H), 1.41 (t,
J = 7.2 Hz, 3H), 1.35 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 171.2, 164.1, 159.8, 158.3, 149.4, 142.0, 133.8, 128.5 (2C),
128.3 (2C), 125.9, 124.3, 119.9, 111.0, 106.1, 104.2, 62.5, 37.0, 33.3,
32.3, 25.8, 25.5, 18.5, 17.9, 14.3; HRMS-ESI (m/z) calcd for C26H31O6
(M + H+) 439.2115, found 439.2124.
Methyl 7-hydroxy-2,2,5-trimethyl-8-(2-methylallyl)-4-oxo-4H-
benzo[d][1,3]dioxine-6-carboxylate (16f): white solid; 74%; mp =
42−43 °C (hexanes); Rf 0.76 (EtOAc/hexanes 1:9); IR 1730, 1656,
1583, 1437, 1377, 1328, 1307, 1265, 1232, 1207, 1174, 1126, 1028,
1
979, 913, 889 cm−1; H NMR (CDCl3, 400 MHz) δ 11.83 (s, 1H),
4.71 (bs, 1H), 4.51 (bs, 1H), 3.98 (s, 3H), 3.30 (s, 2H), 2.87 (s, 3H),
1.76 (s, 3H), 1.67 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 171.9,
164.9, 160.2, 158.7, 147.2, 143.2, 113.5, 110.4 (2C), 110.2, 104.7, 52.6,
30.4, 25.6 (2C), 22.7, 20.2; HRMS-ESI (m/z) calcd for C17H21O6 (M
+ H+) 321.1338, found 321.1342. Anal. Calcd for C17H20O6: C, 63.74;
H, 6.29. Found: C, 63.65; H, 6.27.
Ethyl 7-hydroxy-2,2-dimethyl-8-(2-methylallyl)-4-oxo-5-pheneth-
yl-4H-benzo[d][1,3]dioxine-6-carboxylate (16g): white solid; 78%;
mp = 61−63 °C (hexanes); Rf 0.74 (EtOAc/hexanes 1:9); IR 1718,
1660, 1583, 1373, 1303, 1271, 1226, 1207, 1164, 1118, 1050, 1017,
1
1007, 912, 890 cm−1; H NMR (CDCl3, 400 MHz) δ 11.85 (s, 1H),
7.34−7.27 (m, 4H), 7.19 (m, 1H), 4.74 (bs, 1H), 4.53 (bs, 1H), 4.49
(q, J = 7.2 Hz, 2H), 3.81 (m, 2H), 3.33 (s, 2H), 2.92 (m, 2H), 1.79 (s,
3H), 1.65 (s, 6H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 171.2, 165.0, 159.8, 158.9, 150.3, 143.2, 141.9, 128.5 (2C),
128.3 (2C), 125.9, 114.2, 110.2 (2C), 105.7, 104.5, 62.5, 37.1, 33.1,
30.5, 25.6 (2C), 22.8, 14.3; HRMS-ESI (m/z) calcd for C25H29O6 (M
+ H+) 425.1964, found 425.1982. Anal. Calcd for C25H28O6: C, 70.74;
H, 6.65. Found: C, 70.84; H, 6.56.
Methyl 8-cinnamyl-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-benzo-
[d][1,3]dioxine-6-carboxylate (16h): colorless oil; 73%; Rf 0.71
(EtOAc/hexanes 1:9); IR 1729, 1656, 1584, 1437, 1377, 1328, 1309,
1
1265, 1233, 1208, 1125, 1029, 966, 915 cm−1; H NMR (CDCl3, 400
MHz) δ 11.92 (s, 1H), 7.31−7.24 (m, 4H), 7.16 (m, 1H), 6.39 (d, J =
15.6 Hz, 1H), 6.25 (dt, J = 15.6, 6.5 Hz, 1H), 3.99 (s, 2H), 3.52 (d, J =
6.5 Hz, 2H), 2.89 (s, 3H), 1.70 (s, 6H); 13C NMR (CDCl3, 100 MHz)
δ 172.0, 164.7, 160.1, 158.4, 147.3, 137.4, 130.6, 128.4 (2C), 127.0,
126.8, 125.9 (2C), 113.6, 110.4, 106.5, 104.8, 52.7, 26.0, 25.8 (2C),
20.2; HRMS-ESI (m/z) calcd for C22H23O6 (M + H+) 383.1489,
found 383.1479.
Ethyl 8-cinnamyl-7-hydroxy-2,2-dimethyl-4-oxo-5-phenethyl-4H-
benzo[d][1,3]dioxine-6-carboxylate (16i): colorless oil; 71%; Rf 0.72
(EtOAc/hexanes 1:9); IR 1728, 1654, 1581, 1495, 1452, 1417, 1377,
1265, 1229, 1208, 1181, 1046, 1017, 964 cm−1; 1H NMR (CDCl3, 400
MHz) δ 11.98 (s, 1H), 7.23−7.35 (m, 8H), 7.19 (m, 2H), 6.41 (d, J =
15.8 Hz, 1H), 6.26 (dt, J = 15.7, 6.6 Hz, 1H), 4.49 (q, J = 7.2 Hz, 2H),
3.80 (m, 2H), 3.53 (d, J = 6.6 Hz, 2H), 2.92 (m, 2H), 1.67 (s, 6H),
1.41 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 171.2, 164.8,
159.6, 158.6, 150.3, 141.9, 137.4, 130.6, 128.4 (5C), 128.3 (2C), 127.0,
126.7, 125.9 (2C), 114.3, 110.2, 105.8, 104.5, 62.5, 37.0, 33.2, 26.1,
25.7 (2C), 14.2; HRMS-ESI (m/z) calcd for C30H31O6 (M + H+)
487.2115, found 487.2111.
(E)-Ethyl 8-(3,7-dimethylocta-2,6-dienyl)-7-hydroxy-2,2,5-tri-
methyl-4-oxo-4H-benzo[d][1,3]dioxine-6-carboxylate (16j): color-
less oil; 52%; Rf 0.22 (hexanes/Et2O 9:1); IR 1732, 1654, 1583,
1
1377, 1298, 1264, 1233, 1223, 1185, 1028 cm−1; H NMR (CHCl3,
400 MHz) δ 11.86 (s, 1H), 5.13 (mc, 1H), 5.04 (mc, 1H), 4.44 (q, 2H,
J = 7.1 Hz), 3.30 (d, 2H, J = 7.3 Hz), 2.87 (s, 3H), 2.09−1.93 (m, 4H),
1.75 (s, 3H), 1.68 (s, 6H), 1.62 (s, 3H), 1.55 (s, 3H), 1.42 (t, 3H, J =
7.1 Hz); 13C NMR (CHCl3, 100 MHz) δ 171.5, 164.6, 160.2, 158.0,
146.6, 135.7, 131.3, 124.1, 120.9, 115.4, 110.6, 106.4, 104.5, 62.2, 39.7,
141.9, 135.0, 128.5 (2C), 128.3 (2C), 125.9, 120.8, 114.5, 110.3, 108.4,
105.7, 104.4, 62.5, 41.0, 37.1, 33.1, 30.7, 30.1, 29.1, 27.9, 25.7, 20.8,
14.2; HRMS-ESI (m/z) calcd for C31H37O6 (M + H+) 505.2590,
found 505.2592.
3529
dx.doi.org/10.1021/jo300340c | J. Org. Chem. 2012, 77, 3524−3530

The Journal of Organic Chemistry
Article
Synthesis of Resorcylates 8a and 18 Using Allyl Chloride.
Pd(PPh3)4 (9.5 mg, 0.008 mmol, 2.5 mol %) and Cs2CO3 (323 mg,
0.99 mmol, 3.0 equiv) were stirred in THF (1 mL) for 10 min at 0 °C.
A mixture of diketoester−dioxinone 10a (94 mg, 0.33 mmol, 1.0
equiv) and allyl chloride 17 (28 mg, 0.36 mmol, 1.1 equiv) in THF (1
mL) was added with stirring, and after 12 h at 25 °C, reaction was
quenched with brine (20 mL), acidified to pH 3 utilizing 1 M HCl,
and extracted with EtOAc (2 × 50 mL). The organic extracts were
combined, dried (MgSO4), filtered, rotary evaporated, and chromato-
graphed (hexanes/EtOAc 9:1) to give the isophthalate 8a (53 mg,
52%) and resorcylate 18 (34 mg, 39%) as a colorless oil: Rf 0.62
(EtOAc/hexanes 1:9); IR 1718, 1663, 1582, 1435, 1310, 1269, 1210,
1176, 1154, 1032, 920 cm−1; 1H NMR (CDCl3, 400 MHz) δ 11.63 (s,
1H), 6.41 (s, 1H), 3.99 (s, 3H), 2.91 (s, 3H), 1.70 (s, 6H); 13C NMR
(CDCl3, 100 MHz) δ 171.5, 167.1, 160.9, 159.7, 150.3, 110.8, 106.6,
104.9, 103.1, 52.7, 25.7 (2C), 20.3; HRMS-ESI (m/z) calcd for
C13H15O6 (M + H+) 267.0869, found 267.0876.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 8a−h, 10a−h, 11a,b,
16a−o, and 18, as well as X-ray structural data for 8c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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(13) CCDC 854173, see the Supporting Information for details.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: agm.barrett@imperial.ac.uk.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the European Research Council (ERC) and the Swiss
National Science Foundation (SNF, to S.L.) for generous grant
support, GlaxoSmithKline for the Glaxo endowment (to
A.G.M.B.), and P. R. Haycock and R. N. Sheppard (Imperial
College London) for high-resolution NMR spectroscopy.
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