Mechanistic studies of highly regioselective decarboxylative-prenyl migration reactions of prenyloxycarbonyl-diketo-dioxinones

Article abstract of DOI:10.1016/j.tet.2014.06.098

Mechanistic studies of tandem regioselective decarboxylation, prenyl transfer, and aromatization reactions of prenyl dioxinone diketo-carboxylates to provide 3-prenyl-resorcylate derivatives are described. Studies of the effects of concentration and the b

Full text of DOI:10.1016/j.tet.2014.06.098

Tetrahedron 70 (2014) 5569e5579
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Tetrahedron
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Mechanistic studies of highly regioselective decarboxylative-prenyl
migration reactions of prenyloxycarbonyl-diketo-dioxinones
*
Katie Anderson, Sylvain Laclef, Anthony G.M. Barrett
Department of Chemistry, Imperial College, London SW7 2AZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2014
Received in revised form 13 June 2014
Accepted 23 June 2014
Available online 27 June 2014
Mechanistic studies of tandem regioselective decarboxylation, prenyl transfer, and aromatization re-
actions of prenyl dioxinone diketo-carboxylates to provide 3-prenyl-resorcylate derivatives are de-
scribed. Studies of the effects of concentration and the base employed as well as the results of cross-over
experiments were all found to be consistent with the reaction proceeding largely via an intermolecular
reaction pathway.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Decarboxylation
Aromatization
Intermolecular
Mechanistic
1. Introduction
2. Results and discussion
The formation of CeC bonds, particularly under mild conditions
are fundamental transformations in synthetic organic chemistry.
Frequently, such, reactions require high temperatures, or strongly
basic conditions and are sensitive to the size and electronic prop-
erties of the substrate.1,2 Developments in the use of CeC bond
construction reactions that utilize decarboxylative coupling, which
is exemplified by the decarboxylative TsujieTrost reaction,3,4 have
revolutionized such bond construction reactions.5 During our
studies on the total synthesis of resorcylate natural products, we
discovered a novel regioselective, decarboxylative, allylation, and
aromatization sequence.6 In these cases, treatment of diketo-
dioxinone esters 1 with Pd(PPh3)4 resulted in a decarboxylative-
allylation transfer reaction sequence, providing diketo-dioxinones
2, which readily underwent cyclization to afford the correspond-
ing resorcylates 3 specifically substituted at C-3. Such regioselective
transformations were successfully employed in the total synthesis
of angelicoin A (4),7,8 amorfrutin A (5),9 hericenone J (6),8 hericenol
We first sought to demonstrate that the Pd(0)-decarboxylative
prenyl transfer reaction was highly regioselective from the C-5 in
intermediate 10 to the C-3 center of the intermediate on reaction
with Pd(PPh3)4 and thence, by necessity, at the C-3 of the resor-
cylate ring 11 after aromatization. This was confirmed using X-ray
crystallography of the products 12 (Scheme 2) and 16/17 (Scheme
3), representing stable species obtained prior to and after the
decarboxylative prenyl transfer reaction. Accordingly, during our
studies into the synthesis of angelicoin A (4), cycloaromatization of
diketo-dioxinone ester 10 under basic conditions followed by
deprotection of the silyl ether 11 furnished phenol 12, in which the
prenyl carboxylate was retained (Scheme 2).7 This clearly showed
that the ester group was indeed at C-5.
As previously published, during our studies into the total syn-
thesis of amorfrutin A (5), reaction of diketo-dioxinone ester 13
with Pd(PPh3)4 and cesium carbonate resulted in decarboxylative
prenyl migration and formation of the resorcylate 16. Under these
reaction conditions, the minor branched chain isomer 14 did not
rapidly aromatize, but could be converted into the corresponding
resorcylate 17 under more forcing reaction conditions. The regio-
selectivity of the prenyl migration and the structures of both
resorcylates 16 and 17 were confirmed unambiguously by crystal
structure determinations (Scheme 3).9
A
(7),8 methyl cristatate (8),10 and mycophenolic acid (9)11
(Scheme 1).
Herein, we report results of our studies into the mechanism of
this intriguing and novel sequence for the elaboration of terpenoid
resorcylates, an extensive group of bioactive natural products.
Initially we considered that the mechanism of reaction could be
taking place through a modified TsujieCarroll transformation
(Scheme 4)3,12 of 18 via formation of the
19 followed by decarboxylation to provide diketo-dioxinone 20.
p
-allyl-palladium complex
* Corresponding author. Tel.: þ44 (0)207 5945766; e-mail address: agm.barrett@
imperial.ac.uk (A.G.M. Barrett).
http://dx.doi.org/10.1016/j.tet.2014.06.098
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
Scheme 1. Decarboxylationeallylation sequence in the synthesis of angelicoin A (4), amorfrutin A (5), hericenone J (6), hericenol (7), methyl cristatate (8), and mycophenolic
acid (9).
Scheme 2. Tricyclic resorcylate 12 and its X-ray crystal structure.
Scheme 3. Formation of resorcylates 16 and 17 and their respective crystal structures.
Subsequent allylation should then provide the prenylated diketo-
dioxinone 21, which would readily undergo aromatization.
influence of base on the reaction; (d) studies of the regioselectivity
of the allylation, to determine the reason for preference of C-3
substitution over C-5.
We began our mechanistic investigation by studying the effects
of reaction concentration on the course of the reaction. The
optimized conditions for the Pd(0)-decarboxylative-allyla-
tionearomatization sequence (0.2 M) gave the branched-diketo-
dioxinone 23 and linear resorcylate 32. Surprisingly, when the
To further probe our mechanistic hypothesis about the allyla-
tion, we decided to perform a variety of investigations: (a) con-
centration studies to define the intra- versus intermolecular
pathways of the transformation and to establish the origins of the
allyl group; (b) cross-over experiments to track the migratory allyl
on its pathway to a new molecular partner; (c) studies of the

K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
5571
Intermolecular trapping of the
p-prenyl-palladium(II) cation
complex, produced from oxidative insertion of a Pd(0) complex into
the CeO bond of ester 18, by a second molecule of diketo-dioxinone
ester 18 afforded intermediate dioxinones 26 and 28. Subsequent
aromatization resulted in the formation of the two resorcylates 34
and 36. These results are consistent with the operation of an in-
termolecular mechanism at lowconcentration inwhich diketo-ester
18 serves as both a
p-prenyl donor and acceptor. Interestingly,
diketo-dioxinones 23 and 24 were the only intermediates that did
not undergo aromatization within the reaction mixture under the
mild reaction conditions. However, during our studies into the total
synthesis of amorfrutin A it was discovered that structurally similar
intermediate 14 could be converted under more vigorous reaction
conditions with cesium carbonate in THF at reflux to furnish the
corresponding prenyl-resorcylate 17 (Scheme 3).9
Scheme 4. Observed prenyl migration and postulated reaction mechanism via
a modified TsujieCarroll transformation.
Surprisingly, at low concentration the branched-diketo-
dioxinone prenyl ester 38 or branched resorcylate 39 was not ob-
served (Fig. 1). It was postulated that this could be due to the
reaction concentration was decreased (0.014 M), two new products,
the resorcylates 34 and 36 were formed and isolated in a 1:1 ratio
and 83% overall yield. Interestingly, at this lower concentration
(0.014 M), only traces of diketo-dioxinone 23 and resorcylate 32
were isolated. Similarly, at the higher concentration (0.2 M), only
traces of resorcylates 34 and 36 were isolated (Scheme 5). The re-
action was repeated on diketo-dioxinone ester 22 showing re-
producibility of this surprising result with a different substrate.
Scheme 5 illustrates the results from the concentration studies and
proposes the intermediates (in square brackets) that were formed
throughout the reaction.13
enolate of 18/22 acting as one of the ligands co-ordinating to the p-
prenyl-palladium(II) cation complex. Co-ligand exchange of the
branched and unbranched prenyl is fast relative to CeC bond for-
mation and due to sterics this biases attack giving the non-
branched isomer 26/27.14,15
Encouraged by these findings, we sought to examine a cross-
over experiment between unlabeled and deuterium labeled com-
pounds. The study focused on the rearrangements of esters 13 and
40 at a concentration of 0.2 M (Scheme 6).
Scheme 5. Concentration studies of the Pd(0)-decarboxylative prenylation transfer with dioxinones 18 and 22.

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K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
mechanism; in other words ligand exchange of the b-diketo-diox-
inone enolate (prenyl)Pd(II) complex was faster than CeC bond
formation.
We subsequently examined the role of base in the de-
carboxylation prenyl transfer and aromatization reaction sequence.
Beginning with a positive control, ethyl ester 44 was allowed to
react with allyl chloride as an electrophile in the presence of
Pd(PPh3)4 in THF. Interestingly, no product was formed and starting
material was recovered confirming that a base is required for this
transformation to take place (Scheme 7). Furthermore, when re-
action of diketo-dioxinone prenyl ester 18 and Pd(PPh3)4 was car-
Fig. 1. Branched-diketo-dioxinone prenyl ester 38 and branched-prenyl resorcylate 39.
Scheme 6. Cross-over experiment between non-deuterated diketo-dioxinone ester 13 and deuterated ester 40.
Four resorcylates 41, 16, 42, and 43 were obtained from the
cross-over experiment, with esters 41 and 16 being isolated to-
gether in a 35% yield and 1:1 ratio and esters 42 and 43 also isolated
together in a 35% yield and 1:1 ratio.16 These results are consistent
with the prenyl moiety migration occurring via an intermolecular
ried out in the absence of cesium carbonate at 0.2 M, the yield of
diketo-dioxinone 23 and resorcylate 32 decreased to 5% and 18%,
respectively, indicating that the cesium carbonate played a key role
in the reaction. We sought to establish if cesium carbonate was
catalyzing the aromatization step or the decarboxylation and
Scheme 7. Reactions between ethyl ester 44 and allyl chloride.

K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
5573
allylation step, or both steps. Several intermediates generated
during the course of the reaction including an enolate or a carbox-
ylate could be acting as a general base.
Finally, in a cross-over experiment between esters 13 and 50 at
0.2 M, only two products were obtained namely the resorcylates
53 (40%) and 54 (40%).19 This result is consistent with the ethyl
diketo-ester 50 being a more reactive prenyl acceptor than prenyl
diketo-ester 13 possibly due to the improved chelation/stabiliza-
tion provided by ethyl diketo-ester 50 at the C-3 position
(Scheme 9).
To investigate the topic further ethyl ester 44 was allowed to
react with allyl chloride and cesium acetate at 0.2 M, which
resulted in the formation of the hexa-substituted resorcylate 46
(82%) (Scheme 7). In this case, cesium carbonate was added into the
reaction mixture following consumption of intermediate 44 in or-
der to aid aromatization to take place.17 Reaction using cesium
carbonate in place of cesium acetate at 0.2 M resulted in the for-
mation of the same resorcylate 46 (81%, Scheme 7). We have re-
cently utilized this allylation reaction in the synthesis of diverse
hexa-substituted benzene derivatives, whereby the acetate anion
was generated in situ and acted as a base in the reaction.18 The
results from the transformations in Scheme 7 are further evidence
for an intermolecular reaction pathway. Interestingly, the reaction
did proceed in the presence of other non-cesium bases such as 4-
methylmorpholine, however, these bases gave lower yields after
longer reaction times.
The next approach was to investigate the regioselectivity of the
reaction and to understand why the migratory nature of the ally-
lation occurred. In order to examine this we decided to allow the
diketo-dioxinone 47 to react with allyl acetate catalyzed by
Pd(PPh3)4 at 0.2 M and to ascertain the regioselectivity of the
allylation reaction. High regioselectivity in the allyl transfer step
was observed providing diketo-dioxinone 48, which underwent
aromatization to give resorcylate 49 (82%) (Scheme 8).
Following with the results of these experiments, we propose the
following mechanism (Scheme 10). Diketo-dioxinone prenyl ester
55 enters the catalytic manifold through the formation of a 4-
coordinate square planar palladium complex 56 (lower in en-
ergy), reducing the nucleophilicity at the C-5 center (where X can
be either CO2R2 or H). This complex can reversibly become the
three-coordinate20 palladium complex 57 (higher in energy), which
can undergo rapid ligand exchange with another diketo-dioxinone
ester 55. Following the addition of a base, the three-coordinate
palladium complex 58 (higher in energy) can undergo linear prenyl
migration to give complex 59. The prenyl three-coordinate palla-
dium complex 59 (higher in energy) can then undergo ligand ex-
change giving diketo-dioxinone 60. If X¼CO2R2 the Pd can insert
into the allylic CeO bond causing decarboxylation to occur and
providing linear isomer 61 (which readily aromatizes giving
resorcylate 62). The three-coordinate palladium complex 58
(higher in energy) can also undergo branched prenyl migration but
at a lower rate, due to steric congestion to form the branched iso-
mer 64 (which requires more forcing conditions in order to un-
dergo aromatization, see Scheme 3).
Scheme 8. Allylation and aromatization of phenyl-diketo-dioxinone 47 with allyl acetate.
The experiment indicated that decarboxylation could be oc-
curring before or after prenylation (allylation). This is consistent
with the regioselectivity not being driven by decarboxylation. We
conclude that the regioselectivity could be due to the more acidic C-
Resorcylates 65 and 66 (shown in blue) were isolated when the
reaction was carried out at low concentration. Under these condi-
tions the cyclization reaction to form resorcylate 65 and
prenylated-resorcylate 66 proceeded faster than the allylation re-
actions to form prenyl-diketo-dioxinone 61, which rely on an in-
termolecular reaction with Pd(0)/base to facilitate deallylation and
decarboxylation.
3 position, and better chelation and stabilization for the Pdep-allyl
complex at C-3 compared to C-5 or indeed C-1 (Schemes 8 and 9).
The regioselective mechanistic study is consistent with an in-
termolecular reaction manifold.
Scheme 9. Cross-over experiment between prenyl ester 13 and ethyl ester 50.

5574
K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
Scheme 10. Proposed mechanism.
We considered that the cyclization reaction, which is a unim-
from Na/Ph2CO, CaH2, CaH2, and Mg turnings/I2, respectively.
Hexanes refer to petroleum spirit with a bp range of 40e60 ꢀC.
Chromatography was carried out on silica gel, using flash tech-
niques (eluants are given in parenthesis). Analytical thin layer
chromatography was performed on pre-coated silica gel F254
aluminum plates with visualization under UV light or by staining
using either acidic vanillin, anisaldehyde or ninhydrin spray
reagents. Melting points were obtained using a hot stage appa-
ratus and are uncorrected. Infrared data were carried out neat as
films unless otherwise stated. Indicative features of each spec-
trum are given with adsorptions reported in wavenumbers
(cmꢁ1). 1H and 13C NMR spectra were, respectively, recorded at
olecular reaction, was preferred to the bimolecular ligand exchange
reaction with reduction in concentration.21 Unfortunately, NMR
experiments, conducted in order to seek to detect the respective
intermediate were inconclusive.
3. Conclusions
In conclusion, mechanistic studies on the conversion of dioxi-
nones 1 to resorcylates 3 via prenyl transfer, decarboxylation, and
aromatization are consistent with an intermolecular reaction
manifold, meaning that the ‘migrating’ allyl groups may originate
from different molecules. These studies have indicated that a gen-
eral base is required for the transformation, which could be acetate,
an enolate, and/or a carboxylate. Finally, we observed the same
regioselectivity of reaction for both the prenylation (allylation) of
diketo-dioxinones as well as diketo-dioxinone esters indicating
that the regioselectivity was not controlled during the de-
carboxylation step. We are currently examining decarbox-
ylationeallyl rearrangement reactions and related transformations
in the total synthesis of other natural products.
400 or 500 MHz and 100 MHz with chemical shifts (d) quoted in
parts per million (ppm) and coupling constants (J) recorded in
hertz (Hz).
4.2. Experimental procedures
4.2.1. (E)-1-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-(hydroxy((3-
methylbut-2-en-1-yl)oxy)methylene)pentane-2,4-dione
(18). 3-
Methylbut-2-enyl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-
oxobutanoate7e9 (570 mg, 1.92 mmol, 1.0 equiv), pyridine (0.5 mL,
5.18 mmol, 2.7 equiv), and MgCl2 (457 mg, 4.80 mmol, 2.5 equiv)
were stirred in CH2Cl2 (15 mL) at 0 ꢀC for 30 min. AcCl (0.21 mL,
2.88 mmol, 1.5 equiv) was added dropwise and the mixture stirred
at 0 ꢀC for 30 min. The reaction was quenched with brine (100 mL),
and the mixture extracted with EtOAc (2ꢂ200 mL), dried (MgSO4),
rotary evaporated, and chromatographed (1:1:10 EtOAc/CH2Cl2/
hexanes) to give (E)-1-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-
4. Experimental
4.1. General procedures
All reactions were carried out in oven-dried glassware under
N2, using commercially supplied solvents and reagents unless
otherwise stated. THF, CH2Cl2, Et3N, and MeOH were redistilled

K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
5575
(hydroxy((3-methylbut-2-en-1-yl)oxy)methylene)pentane-2,4-
dione (18) (500 mg, 80%) as a pale yellow oil: Rf 0.7 (2:1:5 EtOAc/
CH2Cl2/hexanes); IR (neat) nmax 1728, 1706, 1638, 1566, 1390, 1373,
trimethyl-4H-benzo[d][1,3]dioxin-4-one (36) was characterized as
described earlier.22
1270, 1251, 1201, 1073 cmꢁ1
;
1H NMR (500 MHz, C6D6)
d
18.00 (s,
4.2.3. (R)-3-(Benzyloxy)butanoic
acid
(69). (R)-Methyl
3-
1H), 5.27 (app. t quin., J¼7.3, 1.4 Hz, 1H), 5.20 (s, 1H), 4.54 (d,
hydroxybutanoate (2.0 g, 17.0 mmol, 1.0 equiv) was stirred in cy-
clohexane (113 mL) and CH2Cl2 (56 mL) and benzyl 2,2,2-
trichloroacetimidate (8.56 g, 33.9 mmol, 2.0 equiv) followed by
J¼7.4 Hz, 2H), 3.38 (s, 2H), 2.03 (s, 3H), 1.53 (s, 3H), 1.45 (s, 3H), 1.31
(s, 6H); 13C NMR (125 MHz, C6D6)
d 195.9, 194.2, 165.9, 164.4, 159.6,
139.6, 118.6, 108.8, 106.7, 97.3, 61.6, 43.1, 25.6, 25.1, 24.7 (2C), 17.8;
HRMS (ESI) calcd for C17H23O7, requires 339.1444, found 339.1440
TsOH$H2O (10 mL, 0.85 mmol, 0.1 equiv) were added and the mix-
ture stirred at 25 ꢀC for 18 h. Reaction was quenched with saturated
aqueous NaHCO3 (100 mL) and the solution extracted with CH2Cl2
(3ꢂ100 mL), dried (MgSO4), rotary evaporated, and chromato-
graphed (1:9 EtOAc/hexanes) to afford benzyl-protected alcohol 68
(2.66 g, 76%) as a clear oil, which was used without further purifi-
cation. Methyl ester 68 was stirred in NaOH (1 M, 22.0 mL,
22.1 mmol, 1.8 equiv) and THF (20 mL) for 72 h. The mixture was
acidified to pH 3 using 1 M HCl, extracted with CH2Cl2 (3ꢂ200 mL),
the organic extracts combined, washed with brine (150 mL), dried
(
D
¼ꢁ1.2 ppm). Anal. Calcd for C17H22O7: C, 60.35, H, 6.55. Found: C,
60.43; H, 6.50.
4.2.2. 5-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-6,6-dimethyloct-7-
ene-2,4-dione (23), 7-hydroxy-2,2,5-trimethyl-8-(3-methylbut-2-
enyl)-4H-benzo[d][1,3]dioxin-4-one (32), 3-methylbut-2-enyl 7-
hydroxy-2,2,5-trimethyl-8-(3-methylbut-2-enyl)-4-oxo-4H-benzo[d]
[1,3]dioxine-6-carboxylate (34), and 7-hydroxy-2,2,5-trimethyl-4H-
benzo[d][1,3]dioxin-4-one (36). 3-Methylbut-2-enyl 2-acetyl-4-(2,2-
dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (18) (480 mg,
1.42 mmol, 1.0 equiv), Pd(PPh3)4 (164 mg, 0.142 mmol, 0.1 equiv),
and Cs2CO3 (1.4 g, 4.26 mmol, 3.0 equiv) were stirred in THF (7.1 mL
for a concentration of 0.2 M and 100 mL for a concentration
of 0.014 M) at 0 ꢀC for 3 h. The reaction was quenched with
saturated aqueous NH4Cl (10 mL) and the solution extracted
with EtOAc (2ꢂ50 mL), dried (MgSO4), rotary evaporated, and
chromatographed (1:1:10 to 1:1:5 CH2Cl2/EtOAc/hexanes) to give
5-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-6,6-dimethyloct-7-ene-
2,4-dione (23) (42 mg, 10% at 0.2 M, 2 mg, 0.5% at 0.014 M) as
a yellow oil, 7-hydroxy-2,2,5-trimethyl-8-(3-methylbut-2-enyl)-4H-
benzo[d][1,3]dioxin-4-one (32) (195 mg, 50% at 0.2 M, 12 mg, 3% at
0.014 M) as a white solid, 3-methylbut-2-enyl 7-hydroxy-2,2,5-
trimethyl-8-(3-methylbut-2-enyl)-4-oxo-4H-benzo[d][1,3]dioxine-
6-carboxylate (34) (11 mg, 2% at 0.2 M, 231 mg, 42% at 0.014 M) as a
clear oil and 7-hydroxy-2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-
one (36) (9 mg, 3% at 0.2 M, 121 mg, 41% at 0.014 M) as a colorless
(MgSO4), and rotary evaporated to afford carboxylic acid 69 (1.94 g,
25
83%) as a clear oil: Rf 0.4 (1:9 MeOH/CH2Cl2); [
a
]
ꢁ0.83 (c 0.113,
D
CHCl3); IR (neat) nmax 3029 (br), 1706, 1454, 1377, 1305, 1204, 1134,
1075 cmꢁ1; 1H NMR (500 MHz, C6D6)
d
7.25e7.24 (m, 2H), 7.17e7.14
(m, 2H), 7.08e7.05 (m, 1H), 4.27 (q, J¼13.0 Hz, 2H), 3.80e3.74 (m,
1H), 2.44 (dd, J¼15.0, 7.0 Hz, 1H), 2.13 (dd, J¼15.0, 5.0 Hz, 1H), 0.96
(d, J¼6.0 Hz, 3H); 13C NMR (125 MHz, C6D6)
d 177.3, 139.1, 128.2
(2C), 128.0, 127.8 (2C), 71.7, 70.8, 41.8, 19.6; HRMS (CI) calcd for
C
11H18NO, requires 212.1287, found 212.1297 (
D
¼þ4.7 ppm); Anal.
Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 68.13; H, 7.14.
4.2.4. (5R)-3-Methylbut-2-enyl 5-(benzyloxy)-2-(2-(2,2-dimethyl-4-
oxo-4H-1,3-dioxin-6-yl)acetyl)-3-oxohexanoate (22). Oxalyl chlo-
ride (0.45 mL, 5.04 mmol, 3.0 equiv) and two drops of DMF were
added with stirring to carboxylic acid 69 (490 mg, 2.52 mmol,
1.5 equiv) in CH2Cl2 (10 mL) at 0 ꢀC. After 30 min, the mixture was
rotary evaporated to afford acid chloride 67, which was used
without further purification. Keto-dioxinone prenyl ester
707(500 mg, 1.68 mmol, 1.0 equiv), MgCl2 (352 mg, 3.7 mmol,
2.2 equiv), and pyridine (0.4 mL, 4.54 mmol, 2.7 equiv) were stirred
in CH2Cl2 (10 mL) for 30 min. Acid chloride 67 in CH2Cl2 (5 mL) was
added and the mixture stirred for 30 min at 0 ꢀC. Reaction was
quenched with brine (50 mL), and the resultant mixture extracted
with EtOAc (2ꢂ100 mL), dried (MgSO4), rotary evaporated, and
chromatographed (1:1:4 CH2Cl2/EtOAc/hexanes) to give diketo-
dioxinone prenyl ester 22 (500 mg, 65%) as a pale yellow oil: Rf
oil.
ene-2,4-dione (23): Rf¼0.5 (1:1:6 EtOAc/CH2Cl2/hexanes); IR (neat)
nmax 1740, 1395, 1365, 1217, 1222, 1019 cmꢁ1 1H NMR (500 MHz,
C6D6)
5-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-6,6-dimethyloct-7-
;
d
16.0 (br s, 1H), 5.91 (dd, J¼17.0, 11.0 Hz,1H), 5.52 (s, 1H), 5.04
(s,1H), 4.88 (dd, J¼11.0, 2.0 Hz,1H), 4.85 (dd, J¼17.0, 2.0 Hz,1H), 2.60
(s, 1H), 1.50 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H), 1.04 (s, 3H), 1.04 (s, 3H);
13C NMR (125 MHz, C6D6)
d
192.1, 188.7, 166.3, 159.8, 145.1, 122.4,
106.4, 101.7, 97.6, 62.5, 40.4, 25.7, 25.4, 25.3, 24.4, 23.4; HRMS (ESI)
calcd for 16H23O5, requires 295.1545, found 295.1540
C
0.60 (1:1:6 CH2Cl2/EtOAc/hexanes); [
a
]
25 ꢁ40.95 (c 0.61, CHCl3); IR
D
(
D
¼ꢁ1.7 ppm). 7-Hydroxy-2,2,5-trimethyl-8-(3-methylbut-2-enyl)-
(neat) nmax 1728, 1638, 1564, 1374, 1271, 1250, 1202, 1126, 1065,
4H-benzo[d][1,3]dioxin-4-one (32): mp 121e124 ꢀC (pentane);
Rf¼0.55 (1:1:6 EtOAc/CH2Cl2/hexanes); IR (neat) nmax 3213, 1689,
1015 cmꢁ1; 1H NMR (500 MHz, C6D6)
d 17.50 (s, 1H), 7.25e7.23 (m,
3H), 7.07 (tt, J¼7.5, 1.0 Hz, 2H), 5.29 (app. t of quin., J¼7.0, 0.5 Hz,
1H), 5.2 (s, 1H), 4.56e4.53 (m, 2H), 4.34 (d, J¼12.0 Hz, 1H), 4.25 (d,
J¼12.0 Hz, 1H), 3.91e3.87 (m, 1H), 3.34 (s, 2H), 3.15 (dd, J¼14.0,
3.0 Hz, 1H), 2.65 (dd, J¼14.0, 5.5 Hz, 1H), 1.51 (d, J¼0.5 Hz, 3H), 1.45
(d, J¼0.5 Hz, 3H), 1.31 (s, 6H), 1.04 (d, J¼6.0 Hz, 3H); 13C NMR
1605, 1518, 1378, 1324, 1296, 1279, 1240, 1167, 1048 cmꢁ1 1H NMR
;
(500 MHz, C6D6)
d
5.94 (s, 1H), 5.63 (s, 1H), 5.29 (t quin., J¼7.0,
2.0 Hz, 1H), 3.36 (d, J¼7.0 Hz, 2H), 2.70 (s, 3H), 1.65 (d, J¼0.5 Hz, 3H),
1.58 (d, J¼0.5 Hz, 3H), 1.33 (s, 6H); 13C NMR (125 MHz, C6D6)
d 160.6,
159.8, 156.6, 142.6, 132.6, 122.2, 113.7, 113.5, 106.0, 104.6, 30.4, 25.54
(2C), 22.3, 22.2, 17.8; HRMS (ESI) calcd for C16H21O4, requires
(125 MHz, C6D6) d 195.8, 193.5, 166.1, 164.2, 159.6, 139.9, 139.1, 127.5
(2C), 127.3 (3C), 118.6, 110.1, 106.7, 97.4, 72.6, 70.8, 61.8, 44.6, 42.9,
25.6 (2C), 24.7, 20.0,17.8; HRMS (ESI) calcd for C26H32O8Na, requires
277.1440, found 277.1437 (
D
¼ꢁ1.1 ppm). Anal. Calcd for C16H20O4: C,
69.54, H, 7.30. Found: C, 68.01; H, 7.53. 3-Methylbut-2-enyl
7-hydroxy-2,2,5-trimethyl-8-(3-methylbut-2-enyl)-4-oxo-4H-benzo
[d][1,3]dioxine-6-carboxylate (34): Rf¼0.85 (1:1:6 EtOAc/CH2Cl2/
hexanes); IR (neat) nmax 1736, 1654, 1586, 1447, 1376, 1266, 1226,
495.1995, found 495.1993 (
C, 66.09; H, 6.83. Found: C, 66.22; H, 6.74.
D
¼ꢁ0.4 ppm). Anal. Calcd for C26H32O8:
4.2.5. 3-Methylbut-2-en-1-yl (R)-5-(2-(benzyloxy)propyl)-7-
hydroxy-2,2-dimethyl-8-(3-methylbut-2-en-1-yl)-4-oxo-4H-benzo
[d][1,3]dioxine-6-carboxylate (35), (R)-5-(2-(benzyloxy)propyl)-7-
hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (33), and (R)-
5-(2-(benzyloxy)propyl)-7-hydroxy-2,2-dimethyl-8-(3-methylbut-2-
enyl)-4H-benzo[d][1,3]dioxin-4-one (37). Diketo-dioxinone prenyl
1034 cmꢁ1 1H NMR (500 MHz, C6D6)
; d 12.48 (s, 1H), 5.43 (t quin.,
J¼7.0, 1.5 Hz, 1H), 5.25 (t quin., J¼7.0, 1.5 Hz, 1H), 4.54 (d, J¼7.0 Hz,
2H), 3.50 (d, J¼7.0 Hz, 2H), 3.06 (s, 3H), 1.75 (d, J¼1.0 Hz, 3H), 1.65 (d,
J¼1.0 Hz, 3H), 1.46 (d, J¼1.0 Hz, 3H), 1.39 (d, J¼1.0 Hz, 3H), 1.30 (s,
6H); 13C NMR (125 MHz, C6D6)
d 171.9, 165.2, 159.4, 158.5, 147.1,
140.3, 131.8, 122.1, 118.14, 115.7, 110.8, 107.3, 104.3, 62.6, 25.8 (2C),
25.5 (2C), 22.4, 20.5 (2C), 17.9; HRMS (ESI) calcd for C22H29O6, re-
ester 22 (100 mg, 0.21 mmol, 1.0 equiv), Pd(PPh3)4 (12 mg, 10 mmol,
5 mol %), and Cs2CO3 (205 mg, 0.63 mmol, 3.0 equiv) in THF (15 mL)
quires 389.1964, found 389.1960 (D¼ꢁ1.0 ppm). 7-Hydroxy-2,2,5-
were stirred at 0 ꢀC for 30 min. The mixture was allowed to warm to

5576
K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
25 ꢀC and stirred for 18 h. Reaction was quenched with saturated
aqueous NH4Cl (50 mL) and the mixture extracted with EtOAc
(2ꢂ50 mL), dried (MgSO4), rotary evaporated, and chromato-
graphed (1:1:4 CH2Cl2/EtOAc/hexanes) to afford resorcylate 35
(24 mg, 33%) as a colorless gum, resorcylate 33 (35 mg, 32%) as
a colorless oil, and prenyl-resorcylate 37 (2 mg, 2%) as a white solid
(traces of diketo-dioxinone 24 could be seen by crude NMR but could
mixture was filtered and the filtrate concentrated by rotary evap-
oration. The resulting residue was redissolved in CH2Cl2 (300 mL)
and washed with NaOH (0.5 M) (3ꢂ150 mL) followed by phosphate
buffer pH 9 (2ꢂ250 mL). The organic phases were combined, dried
(MgSO4), and rotary evaporated to give 3-methylbut-2-enyl-1,1-d2-
3-(1H-benzo[d][1,2,3]triazol-1-yl)-3-oxopropanoate (72) (2.27 g,
73%) as a yellow oil: Rf¼0.70 (1:1:6 CH2Cl2:EtOAc:hexanes); IR
(neat) nmax 1732, 1375, 1226, 1271, 1203, 1154 cmꢁ1; 1H NMR (C6D6,
not be isolated): Prenyl-prenylester-resorcylate 35: Rf 0.90 (1:1:6
25
CH2Cl2/EtOAc/hexanes); [
a]
ꢁ33.3 (c 0.46, CHCl3); IR (neat) nmax
400 MHz)
1H), 6.96e6.92 (m, 1H), 5.29 (s, 1H), 4.04 (s, 2H), 1.50 (s, 3H), 1.41 (s,
3H); 13C NMR (C6D6, 100 MHz)
165.7, 165.6, 146.5, 139.4, 131.0,
130.1, 125.9, 120.1, 118.2, 114.4, 61.7, 42.6, 25.3, 17.5; HRMS (ESI)
calcd for 14H13D2N3O3, requires 276.1317; found 276.1306
¼4.0 ppm).
d
8.19e8.16 (m, 1H), 7.80 (d, J¼8.0 Hz, 1H), 7.10e7.07 (m,
D
1730, 1655, 1585, 1452, 1376, 1266, 1207, 1118, 1042 cmꢁ1; 1H NMR
(500 MHz, CDCl3) 11.30 (br s, 1H), 7.22e7.17 (m, 3H), 7.10e7.04 (m,
d
d
2H), 5.43 (app. t of quin., J¼7.0, 0.5 Hz, 1H), 5.20 (app. t of quin.,
J¼7.0, 0.5 Hz, 1H), 4.80 (d, J¼7.0 Hz, 2H), 4.40 (d, J¼12.0 Hz, 1H), 4.19
(d, J¼12.0 Hz, 1H), 4.10 (q, J¼7.0, 1H), 3.75 (br s, 1H), 3.54 (br s, 1H),
3.31 (d, J¼7.0, 2H), 1.78 (s, 6H), 1.74 (br s, 3H), 1.70 (br s, 3H), 1.62
(br s, 3H), 1.53 (br s, 3H), 1.21 (d, J¼7.0 Hz, 3H); 13C NMR (125 MHz,
C
(D
4.2.8. 3-Methylbut-2-enyl-1,1-d2-4-(2,2-dimethyl-4-oxo-4H-1,3-
dioxin-6-yl)-3-oxobutanoate (71). 2,2,6-Trimethyl-4H-1,3-dioxin-
4-one (2.38 mL, 17.4 mmol, 3.0 equiv) was added dropwise with
stirring to LiN(SiMe3)2 (1 M; 20.3 mL, 20.3 mmol, 3.5 equiv) in THF
(250 mL) at ꢁ78 ꢀC. After 2 h at ꢁ78 ꢀC, 3-methylbut-2-enyl-1,1-d2-
3-(1H-benzo[d][1,2,3]triazol-1-yl)-3-oxopropanoate (72) (1.6 g,
5.8 mmol, 1 equiv) in THF (20 mL) was added dropwise with stir-
ring. After a further 2 h at ꢁ78 ꢀC, the mixture was allowed to warm
to 25 ꢀC and stirring was continued for 18 h. The mixture was
poured into saturated aqueous NH4Cl (300 mL), acidified to pH 3
with 1 M HCl, and extracted with EtOAc (3ꢂ200 mL). The organic
extracts were combined, washed with brine (1ꢂ100 mL), dried
(MgSO4), rotary evaporated, and chromatographed (7:3 hexanes/
Et2O) to give 3-methylbut-2-enyl-1,1-d2-4-(2,2-dimethyl-4-oxo-
4H-1,3-dioxin-6-yl)-3-oxobutanoate (71) (1.54 g, 89%) as a yellow
oil: Rf¼0.31 (2:1 Et2O/hexanes); IR (neat) nmax 1736, 1733, 1641,
1376, 1274, 1226, 1213, 1205, 1017 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
CDCl3)
d 171.3, 163.5, 160.4, 157.8, 146.7, 140.7, 138.9, 132.2, 128.3,
128.0 (2C), 127.7, 127.3 (2C), 121.2, 117.5, 115.7, 104.4 (2C), 76.5, 70.5,
62.7, 36.3, 26.5 (2C), 25.8, 24.8, 22.0, 19.9, 18.1, 17.8; HRMS (ESI)
calcd for
C31H39O7 requires 523.2696, found 523.2701
(D
¼þ1.0 ppm). Prenyl-resorcylate 33: mp 72e74 ꢀC (pentane); Rf 0.6
(1:1:6 CH2Cl2/EtOAc/hexanes); [
a
]
D
25 ꢁ31.5 (c 0.21, CHCl3); IR (neat)
nmax 3264 (br), 1724, 1693, 1606, 1419, 1376, 1285, 1207, 1166,
1108 cmꢁ1; 1H NMR (500 MHz, C6D6)
d 7.18e7.15 (m, 2H), 7.12e7.09
(m, 2H), 7.04e7.01 (m, 1H), 6.36 (s, 1H), 6.31 (s, 1H), 5.37 (app. t of
quin., J¼7.0, 0.5 Hz, 1H), 4.45 (d, J¼12.0 Hz, 1H), 4.29 (d, J¼12.0 Hz,
1H), 4.01e3.95 (m, 1H), 3.52 (dd, J¼12.0, 4.0 Hz, 1H), 3.43 (d,
J¼7.0 Hz, 2H), 3.28 (dd, J¼12.0, 7.0 Hz, 1H), 1.69 (d, J¼0.5 Hz, 3H),
1.61 (d, J¼¼0.5 Hz, 3H), 1.33 (s, 6H), 1.29 (d, J¼6.0 Hz, 3H); 13C NMR
(125 MHz, C6D6) d 160.7, 159.8, 156.8, 143.5, 139.6, 132.2, 129.2 (2C),
128.6, 127.4 (2C), 122.4, 115.1, 114.7, 105.6, 104.6, 76.3, 70.9, 42.3,
25.6, 22.4, 21.5, 20.4 (2C), 17.8; HRMS (ESI) calcd for C25H31O5, re-
quires 411.2157, found 411.2171 (
(1:1:6 CH2Cl2/EtOAc/hexanes); [
nmax 1738, 1366, 1217 cmꢁ1 1H NMR (500 MHz, C6D6)
D
a
¼ꢁ1.5 ppm). Resorcylate 37: Rf 0.4
d
5.40 (s, 1H), 5.32 (s, 1H), 3.53 (s, 2H), 3.52 (s, 2H), 1.78 (s, 3H), 1.75
25
]
ꢁ3.0 (c 0.3, CHCl3); IR (neat)
(s, 6H), 1.71 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
195.9, 166.6, 164.0,
D
;
d
7.21e7.19
161.1, 126.1, 117.5, 115.04, 97.1, 49.2, 47.0, 25.8, 25.00 (2C), 24.91,
18.0; HRMS (ESI) calcd for C15H19D2O6, requires 299.1385; found
299.1383 (
(m, 2H), 7.13e7.10 (m, 2H), 7.05e7.02 (m, 1H), 6.28 (d, J¼2.5 Hz, 1H),
6.24 (d, J¼2.5 Hz, 1H), 5.74 (s, 1H), 4.47 (d, J¼12.0 Hz, 1H), 4.30 (d,
J¼12.0 Hz, 1H), 3.97e3.91 (m, 1H), 3.48 (dd, J¼12.0, 6.0 Hz, 1H), 3.30
(dd, J¼12.0, 3.0 Hz, 1H), 1.30 (s, 3H), 1.29 (s, 3H), 1.26 (d, J¼6.0 Hz,
D¼0.6 ppm).
4.2.9. 3-Methylbut-2-enyl-1,1-d2-2-(2-(2,2-dimethyl-4-oxo-4H-1,3-
dioxin-6-yl)acetyl)-5-(4-methoxyphenyl)-3-oxopentanoate (40). 3-
Methylbut-2-enyl-1,1-d2-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-
yl)-3-oxobutanoate (71) (100 mg, 0.34 mmol, 1.0 equiv), MgCl2
(64 mg, 0.67 mmol, 2.0 equiv), and pyridine (0.08 mL, 0.92 mmol,
2.7 equiv) were stirred in CH2Cl2 (15 mL) at 0 ꢀC for 30 min. 3-(4-
Methoxyphenyl)propanoyl chloride (81 mg, 0.41 mmol, 1.2 equiv)
was added to the reaction mixture and stirring continued for 1 h at
3H); 13C NMR (125 MHz, C6D6)
d 161.9, 160.2, 159.5, 147.0, 139.7,
128.5 (2C), 127.5, 127.4 (2C), 115.4, 105.5, 104.7, 102.1, 76.0, 70.9,
42.3, 25.6, 25.2, 20.3; HRMS (ESI) calcd for C20H23O5, requires
343.1545, found 343.1552 (
D
¼þ2.0 ppm).
4.2.6. 3-(3-Methyl-2-buten-1-yl-1,1-d2)malonate (73). [1-2H2]-3-
23
Methylbut-2-en-1-ol-1,1-d2 (12.4 g, 141 mmol, 1.5 equiv) and
2,2-dimethyl-1,3-dioxane-4,6-dione (13.56 g, 94 mmol, 1.0 equiv)
were stirred at 120 ꢀC for 12 h. The reaction mixture was poured
into saturated aqueous NaHCO3 (400 mL) and washed with EtOAc
(3ꢂ200 mL). The aqueous layer was acidified to pH 3.0 using 1 N
HCl and extracted with EtOAc (2ꢂ400 mL). The organic extracts
were combined, dried (MgSO4), and rotary evaporated to give 3-(3-
methyl-2-buten-1-yl-1,1-d2)malonate (73) (14.75 g, 90%) as a pale
yellow oil: Rf¼0.40 (1:9 MeOH/CH2Cl2); Rf¼0.40 (1:9 MeOH/
CH2Cl2); IR (neat) nmax 1714, 1415, 1378, 1339, 1311, 1277, 1151,
0
ꢀC and 2 h at 25 ꢀC. Reaction was quenched with brine (20 mL)
and the mixture extracted with EtOAc (2ꢂ50 mL). The organic ex-
tracts were combined, dried (MgSO4), rotary evaporated, and
chromatographed (2:8 Et2O/hexanes to Et2O) to give 3-methylbut-
2-enyl-1,1-d2-2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)ace-
tyl)-5-(4-methoxyphenyl)-3-oxopentanoate (40) (106 mg, 68%) as
a yellow oil: Rf¼0.67 (2:1 Et2O/hexanes); IR (neat) nmax 1730, 1708,
1640, 1514, 1500, 1392, 1375, 1273, 1246, 1205, 1177, 1038, 942,
902 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
7.11 (d, J¼8.5 Hz, 2H), 6.83
1048 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
3.46 (s, 2H), 1.79 (s, 3H), 1.74 (s, 3H); 13C NMR (CDCl3, 100 MHz)
171.6, 167.0, 140.5, 117.5, 40.8, 25.8, 22.3, 18.1; HRMS (ESI) calcd for
C8H9D2O4, requires 173.0783, found 173.0788 (
¼2.9 ppm).
d
10.54 (br s,1H), 5.36 (s,1H),
(d, J¼8.5 Hz, 2H), 5.37 (br s, 1H), 5.34 (s, 1H), 3.79e3.78 (m, 4H),
3.68 (s, 2H), 3.00e2.97 (m, 2H), 2.92e2.89 (m, 2H),1.75 (d, J¼0.5 Hz,
3H), 1.71 (d, J¼0.5 Hz, 3H), 1.69 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d
D
d 197.5, 192.5,166.3, 165.1, 160.7, 158.2,140.5,132.4,129.3 (2C), 117.7,
114.0 (2C), 108.7, 107.2, 96.4, 55.3, 42.8, 39.6, 31.0, 29.7, 25.7, 24.9
(2C), 18.1; HRMS (ESI) calcd for C25H29D2O8, requires 461.2139,
found 461.2137 (
4.2.7. 3-Methylbut-2-enyl-1,1-d2-3-(1H-benzo[d][1,2,3]triazol-1-yl)-
3-oxopropanoate (72). SOCl2 (0.84 mL, 11.6 mmol, 1.0 equiv) was
added dropwise with stirring to benzotriazole (4.4 g, 36.6 mmol,
3.0 equiv) in CH2Cl2 (47 mL) at 25 ꢀC. After 1 h, 3-(3-methyl-2-
buten-1-yl-1,1-d2)malonate (73) (2 g, 11.6 mmol, 1.0 equiv) in
CH2Cl2 (20 mL) was added and stirring continued for 24 h. The
D¼0.4 ppm).
4.2.10. 7-Hydroxy-2,2-dimethyl-8-(3-methylbut-2-enyl-1,1-d2)-5-
phenethyl-4H-benzo[d][1,3]dioxin-4-one (41) and 7-hydroxy-2,2-
dimethyl-8-(3-methylbut-2-enyl)-5-phenethyl-4H-benzo[d][1,3]

K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
5577
dioxin-4-one (16) and 7-hydroxy-5-(4-methoxyphenethyl)-2,2-
dimethyl-8-(3-methylbut-2-enyl-1,1-d2)-4H-benzo[d][1,3]dioxin-4-
one (42) and 7-hydroxy-5-(4-methoxyphenethyl)-2,2-dimethyl-8-(3-
one (32) (15 mg, 18%) as a white solid. Both samples were identical
with samples prepared above.
methylbut-2-enyl)-4H-benzo[d][1,3]dioxin-4-one
(43). 3-
4.2.12. Ethyl 8-allyl-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-benzo[d]
[1,3]dioxine-6-carboxylate (46). Method 1. Ethyl 2-acetyl-4-(2,2-
dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (44)18 (90
mg, 0.3 mmol, 1.0 equiv), allyl chloride (0.027 mL, 0.33 mmol,
1.1 equiv), Pd(PPh3)4 (35 mg, 0.03 mmol, 0.1 equiv), and CsOAc
(64 mg, 0.33 mmol,1.1 equiv) were stirred in THF (1.5 mL) at 0 ꢀC for
30 min. After consumption of the starting material by TLC, Cs2CO3
(108 mg, 0.33 mmol, 1.0 equiv) was added and the solution was
allowed to warm to 25 ꢀC. After 1 h, saturated aqueous NH4Cl
(15 mL) was added and the mixture extracted with Et2O (2ꢂ20 mL).
The combined organic extracts were dried (MgSO4), rotary evapo-
rated, and chromatographed (1:9 EtOAc/pentane) to give ethyl 8-
allyl-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-benzo[d][1,3]dioxine-6-
carboxylate (46) (82 mg, 85%) as a colorless oil. Ethyl 8-allyl-7-
hydroxy-2,2,5-trimethyl-4-oxo-4H-benzo[d][1,3]dioxine-6-
Methylbut-2-enyl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)
acetyl)-3-oxo-5-phenylpentanoate (13)9 (186 mg, 0.43 mmol,
1.0 equiv), 3-methylbut-2-enyl-1,1-d2-2-(2-(2,2-dimethyl-4-oxo-
4H-1,3-dioxin-6-yl)acetyl)-5-(4-methoxyphenyl)-3-oxopentanoate
(40) (200 mg, 0.43 mmol, 1.0 equiv), Pd(PPh3)4 (25 mg, 0.02 mmol,
0.05 equiv), and Cs2CO3 (42 mg, 0.13 mmol, 3 equiv) were stirred in
THF (2 mL) at 0 ꢀC. The resulting mixture was allowed to warm to
25 ꢀC and stirring continued for 12 h. Reaction was quenched with
saturated aqueous NH4Cl (10 mL) and the mixture extracted with
Et2O (2ꢂ10 mL). The combined organic extracts were dried
(MgSO4), rotary evaporated, and chromatographed (1:9 EtOAc/
hexanes) to give 7-hydroxy-2,2-dimethyl-8-(3-methylbut-2-enyl-
1,1-d2)-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one (41) and 7-
hydroxy-2,2-dimethyl-8-(3-methylbut-2-enyl)-5-phenethyl-4H-
benzo[d][1,3]dioxin-4-one (16) (110 mg, 70%) in a 1:1 ratio as
carboxylate (46) was characterized as described earlier.18
a
white solid and 7-hydroxy-5-(4-methoxyphenethyl)-2,2-
dimethyl-8-(3-methylbut-2-enyl-1,1-d2)-4H-benzo[d][1,3]dioxin-
4-one (42) and 7-hydroxy-5-(4-methoxyphenethyl)-2,2-dimethyl-
4.2.13. Ethyl 8-allyl-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-benzo[d]
[1,3]dioxine-6-carboxylate (46). Method 2. Ethyl 2-acetyl-4-(2,2-
8-(3-methylbut-2-enyl)-4H-benzo[d][1,3]dioxin-4-one
(43)
dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate
(44)18
(119 mg, 70%) as a 1:1 ratio as a white solid. 7-Hydroxy-2,2-
dimethyl-8-(3-methylbut-2-enyl-1,1-d2)-5-phenethyl-4H-benzo[d]
[1,3]dioxin-4-one (41) and 7-hydroxy-2,2-dimethyl-8-(3-methylbut-
(96 mg, 0.32 mmol, 1.0 equiv), allyl chloride (0.029 mL,
0.35 mmol, 1.1 equiv), Pd(PPh3)4 (37 mg, 0.032 mmol, 0.1 equiv),
and Cs2CO3 (105 mg, 0.32 mmol, 1.1 equiv) were stirred in THF
(1.6 mL) at 0 ꢀC and allowed to warm to 25 ꢀC. After 1 h, saturated
aqueous NH4Cl (15 mL) was added and the mixture extracted with
Et2O (2ꢂ20 mL). The combined organic extracts were dried
(MgSO4), rotary evaporated, and chromatographed (1:9 EtOAc/
pentane) to give ethyl 8-allyl-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-
benzo[d][1,3]dioxine-6-carboxylate (46)18 (90 mg, 88%) as a color-
less oil. Ethyl 8-allyl-7-hydroxy-2,2,5-trimethyl-4-oxo-4H-benzo[d]
[1,3]dioxine-6-carboxylate (46) was characterized as described
earlier.18
2-enyl)-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one
(16):
mp
119e120 ꢀC (hexanes); Rf¼0.81 (3:1 EtOAc/hexanes); IR (neat) nmax
1689, 1593, 1512, 1419, 1300, 1213, 909 cmꢁ1 1H NMR (CDCl3,
;
400 MHz) d 7.29e7.28 (m, 8H), 7.22e7.17 (m, 2H), 6.43 (s, 2H), 6.30
(s, 2H), 5.22 (s, 2H), 3.35 (d, J¼8.0 Hz, 2H), 3.31e3.29 (m, 4H),
2.91e2.87 (m, 4H), 1.83 (s, 6H), 1.77 (s, 6H), 1.71 (s, 6H); 13C NMR
(CDCl3, 100 MHz)
d 166.9, 160.9, 144.5, 140.2, 128.6, 126.4, 124.6,
120.4, 112.8, 110.2, 106.7, 101.7, 96.6, 62.5, 40.5, 39.5, 31.7, 27.6, 25.9
(2C), 25.8, 25.6, 24.7. Compound 41: HRMS (ESI) calcd for
C
23H24D2O4, requires 369.1957, found 369.1957 (
compound 16: HRMS (ESI) calcd for C23H26O4, requires 367.1909,
found 367.1914 (
D
¼0.0 ppm);
4.2.14. 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-1-phenylbutane-
1,3-dione (47). n-BuLi in hexanes (2.5 M; 3.6 mL, 8.4 mmol,
2.4 equiv) was added dropwise with stirring to iso-Pr2NH (1.2 mL,
8.4 mmol, 2.4 equiv) in THF (20 mL) at ꢁ78 ꢀC. After 20 min, 2,2-
dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one24 (0.74 g, 4.0
mmol, 1.0 equiv) in THF (2.0 mL) was added dropwise at ꢁ78 ꢀC.
After 40 min, Et2Zn in hexanes (1.0 M, 8.4 mL, 8.4 mmol, 2.4 equiv)
was added slowly and, after a further 20 min, the reaction mixture
was allowed to warm to ꢁ20 ꢀC. N-Methoxy-N-methylbenzamide
(0.33 g, 2.0 mmol, 0.5 equiv) in THF (3.0 mL) was added and the
mixture stirred at ꢁ10 ꢀC. After 2 h, reaction was quenched with
saturated aqueous NH4Cl (30 mL) and 1.0 M HCl (10 mL), and the
aqueous layer acidified to pH 1e2 using 1 M aqueous HCl. The
mixture was extracted with EtOAc (75 mL, 25 mL) and the com-
bined organic extracts dried (MgSO4), rotary evaporated, and
chromatographed (hexanes/EtOAc 5:1 to 2:1) to give 4-(2,2-
dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-1-phenylbutane-1,3-dione
(47) (0.44 g, 76%) as a pale yellow solid: mp 59e60 ꢀC (hexanes);
Rf¼0.71 (1:1 EtOAc/hexane); IR (neat) nmax 1722, 1593, 1571, 1492,
1455, 1390, 1271, 1252, 1014, 927 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
D
¼1.4 ppm). 7-Hydroxy-5-(4-methoxyphenethyl)-
2,2-dimethyl-8-(3-methylbut-2-enyl-1,1-d2)-4H-benzo[d][1,3]dioxin-
4-one (42) and 7-Hydroxy-5-(4-methoxyphenethyl)-2,2-dimethyl-8-
(3-methylbut-2-enyl)-4H-benzo[d][1,3]dioxin-4-one
(43):
mp
84e86 ꢀC (pentane); Rf¼0.43 (1:4 EtOAc/hexanes); IR (neat) nmax
1718, 1625, 1592, 1512, 1416, 1393, 1351, 1291, 1244, 1038 cmꢁ1; 1H
NMR (CDCl3, 400 MHz):
4H), 6.42 (s, 2H), 6.37 (s, 2H), 5.21 (br s, 2H), 3.80 (s, 6H), 3.34 (d,
d
7.19 (d, J¼8.5 Hz, 4H), 6.82 (d, J¼8.5 Hz,
J¼8.0 Hz, 2H), 3.24 (m, 4H), 2.82 (m, 4H), 1.80 (s, 6H), 1.74 (s, 6H),
1.68 (s, 12H); 13C NMR (CDCl3, 100 MHz):
d 160.6, 160.0, 157.8, 156.2,
146.5, 134.9, 134.1, 129.6 (2C), 120.9, 113.7 (2C), 113.1, 105.0, 104.7,
55.3, 37.0, 36.5, 25.8 (2C), 25.7, 22.0,17.9. Compound 42: HRMS (ESI)
calcd for C24H26D2O5, 399.2135, found 399.2131 (
compound 43: HRMS (ESI) calcd for C24H28O5, requires 397.2015,
found 397.1999 (
¼4.0 ppm).
D¼1.0 ppm);
D
4.2.11. 5-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-6,6-dimethyloct-
7-ene-2,4-dione (23) and 7-hydroxy-2,2,5-trimethyl-8-(3-methylbut-
2-enyl)-4H-benzo[d][1,3]dioxin-4-one (32). 3-Methylbut-2-enyl 2-
acetyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate
(18) (100 mg, 0.3 mmol, 1.0 equiv) and Pd(PPh3)4 (44 mg,
0.03 mmol, 0.1 equiv) were stirred in THF (1.5 mL) at 0 ꢀC for 3 h.
The reaction was quenched with saturated aqueous NH4Cl (5 mL)
and the mixture extracted with EtOAc (2ꢂ20 mL). The
combined organic extracts were dried (MgSO4), rotary evaporated,
and chromatographed (1:1:10 to 1:1:5 CH2Cl2/EtOAc/hexanes) to
give 5-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-6,6-dimethyloct-7-
ene-2,4-dione (23) (4.5 mg, 5%) as a yellow oil and 7-hydroxy-
2,2,5-trimethyl-8-(3-methylbut-2-enyl)-4H-benzo[d][1,3]dioxin-4-
d
15.73 (s, 1H), 7.87 (d, J¼7.5 Hz, 2H), 7.57 (t, J¼7.5 Hz, 1H), 7.47 (t,
J¼7.5 Hz, 2H), 6.21 (s, 1H), 5.45 (s, 1H), 3.36 (s, 2H), 1.71 (s, 6H);
13C NMR (CDCl3, 100 MHz)
190.2, 182.4, 165.0, 160.7, 133.7,
d
132.9, 128.8 (2C), 127.0 (2C), 107.2, 96.4, 96.4, 44.1, 24.9 (2C);
HRMS (ESI) calcd for C16H17O5, requires 289.1076, found 289.1086
(D¼3.4 ppm).
4.2.15. 8-Allyl-7-hydroxy-2,2-dimethyl-5-phenyl-4H-benzo[d][1,3]
dioxin-4-one (49). 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-1-
phenylbutane-1,3-dione (47) (200 mg, 0.69 mmol, 1.0 equiv), allyl

5578
K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
acetate (69 mg, 0.69 mmol, 1.0 equiv) and Pd(PPh3)4 (20 mg,
0.017 mmol, 0.025 equiv) were stirred in THF (3.5 mL) at 25 ꢀC for
2 h. After consumption of the starting material by TLC, Cs2CO3
(678 mg, 2.07 mmol, 3.0 equiv) was added and stirring continued
for 12 h. Reaction was quenched with saturated aqueous NH4Cl
(20 mL) and the mixture extracted with EtOAc (2ꢂ30 mL). The
combined organic extracts were dried (MgSO4), rotary evaporated,
and chromatographed (1:9 EtOAc/hexanes) to give 8-allyl-7-
hydroxy-2,2-dimethyl-5-phenyl-4H-benzo[d][1,3]dioxin-4-one
(49) (148 mg, 69%) as a white solid: mp 72e75 ꢀC (pentane);
Rf¼0.55 (1:3 EtOAc/hexane); IR (neat) nmax 3233, 1735, 1695, 1591,
7.26e7.22 (m, 4H), 7.17e7.15 (m, 1H), 6.44 (d, J¼2.5 Hz,1H), 6.37 (d,
J¼2.5 Hz, 1H), 3.33e3.31 (m, 2H), 2.90e2.87 (m, 2H), 1.68 (s, 6H);
13C NMR (CDCl3, 100 MHz)
d 162.6, 161.4, 159.2, 149.4, 141.6, 128.6
(2C), 128.3 (2C), 125.9, 113.6, 105.1, 104.1, 102.0, 37.2, 36.8, 25.5
(2C); HRMS (ESI) calcd for C18H19O4, requires 299.1278, found
299.1279
(
D
¼0.3 ppm). Ethyl 7-hydroxy-2,2-dimethyl-8-(3-
methylbut-2-enyl)-4-oxo-5-phenethyl-4H-benzo[d][1,3]dioxine-6-
carboxylate (54): Rf¼0.76 (1:9 EtOAc/hexanes); IR (neat) nmax 1729,
1654, 1581, 1376, 1264, 1223, 1185, 1047, 1018 cmꢁ1 1H NMR
;
(CDCl3, 500 MHz)
d 11.80 (s, 1H), 7.35e7.27 (m, 4H), 7.19 (m, 1H),
5.16 (m, 1H), 4.49 (q, J¼7.0 Hz, 2H), 3.76 (m, 2H), 3.33 (d, J¼7.0 Hz,
1574, 1490, 1378, 1273, 1203, 1118, 1003, 911, 863 cmꢁ1
(CDCl3, 400 MHz)
;
1H NMR
2H), 2.91 (m, 2H), 1.78 (s, 3H), 1.68 (s, 3H), 1.67 (s, 6H), 1.41 (t,
d
7.85e7.83 (m, 2H), 7.55 (t, J¼7.5 Hz, 1H), 7.47 (t,
J¼7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 171.3, 164.7, 159.7,
J¼7.5 Hz, 2H), 6.21 (s, 1H), 5.67e5.60 (m, 1H), 5.51 (s, 1H), 5.16 (d,
158.4, 149.7, 142.0, 132.3, 128.5 (2C), 128.3 (2C), 125.9, 121.0, 116.1,
110.4, 105.7, 104.4, 62.4, 37.1, 33.2, 30.9, 25.7 (2C), 22.0, 17.9, 14.3;
HRMS (ESI) calcd for C26H31O6, requires 439.2115, found 439.2104
J¼8.0 Hz, 2H), 2.64 (d, J¼8.0 Hz, 2H), 1.65 (s, 6H); 13C
NMR (CDCl3, 100 MHz)
d 170.8, 160.9, 135.2, 133.7, 132.7, 131.3,
128.8 (2C), 126.9 (2C), 120.0, 115.9, 106.8, 95.6, 95.1, 94.2, 35.2, 25.0
(2C); HRMS (ESI) calcd for C19H18O4, requires 311.1283, found
(
D
¼2.5 ppm).
311.1280 (D¼ꢁ1.0 ppm).
Acknowledgements
4.2.16. Ethyl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)ace-
We thank the Engineering and Physical Sciences Research
Council (to K.A.) and the Swiss National Science Foundation (to S.L.)
for grant support, GlaxoSmithKline for the Glaxo endowment (to
A.G.M.B.), P.R. Haycock and R.N. Sheppard (Imperial College Lon-
don) for high-resolution NMR spectroscopy and A.J.P. White (Im-
perial College London) for X-ray Crystallography.
tyl)-3-oxo-5-phenylpentanoate (50). Ethyl 4-(2,2-dimethyl-4-
oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate18 (2 g, 7.8 mmol,
1.0 equiv), MgCl2 (1.46 g, 15.6 mmol, 2.0 equiv), and pyridine
(1.8 mL, 21.1 mmol, 2.7 equiv) were stirred in CH2Cl2 (150 mL) at
0
ꢀC for 30 min. 3-Phenylpropanoyl chloride (1.3 g, 9.36 mmol,
1.2 equiv) in CH2Cl2 (10 mL) was added dropwise and the mixture
allowed to warm to 25 ꢀC. After 2 h, reaction was quenched with
saturated aqueous NH4Cl (100 mL) and the mixture extracted
with EtOAc (2ꢂ150 mL). The combined organic extracts were
dried (MgSO4), rotary evaporated, and chromatographed (1:2
EtOAc/hexanes) to give ethyl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-
dioxin-6-yl)acetyl)-3-oxo-5-phenylpentanoate (50) (2.4 g, 71%)
as a yellow oil: Rf¼0.54 (2:8 EtOAc/hexane); IR (neat) nmax
1726, 1710, 1637, 1560, 1389, 1374, 1271, 1250, 1201, 1071,
Supplementary data
1H and 13C NMR spectra for compounds 18, 22e23, 32e37,
40e43, 47, 49e50, 53e54, 69, and 71e7325 are provided. X-ray
crystallographic data of compounds 12, 16, and 17 are available free
of charge from the Cambridge Crystallographic Data Centre (CCDC)
as 839523 (SANSIL, 10.1021/ol202320m), 843948 (NAQBIS, 10.1016/
1014 cmꢁ1 1H NMR (CDCl3, 400 MHz):
; d 7.19e7.31 (m, 5H), 5.34
j.tetlet.2011.11.019)
and
843949
(NAQBOY,
10.1016/j.tet-
let.2011.11.019), respectively. Supplementary data associated with
this article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2014.06.098.
(s, 1H), 4.26 (q, J¼7.0 Hz, 2H), 3.69 (s, 2H), 3.05 (m, 2H), 2.97 (m,
2H), 1.69 (s, 6H), 1.32 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d
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) calcd for 21H25O7, requires 389.1600, found
389.1602 (
¼0.5 ppm).
C
References and notes
D
1. Jana, R.; Partridge, J. J.; Tunge, J. A. Angew. Chem., Int. Ed. 2011, 50,
5157e5161.
4.2.17. 7-Hydroxy-2,2-dimethyl-5-phenethyl-4H-benzo[d][1,3]di-
oxin-4-one (53) and ethyl 7-hydroxy-2,2-dimethyl-8-(3-methylbut-
2-enyl)-4-oxo-5-phenethyl-4H-benzo[d][1,3]dioxine-6-carboxylate
2. de Meijer, A. Metal Catalyzed Cross Coupling Reactions, 2nd ed.; Wiley-VCH:
Weinheim, Germany, 2004; pp 531e583; (2006 printing).
3. Shimizu, L.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21, 3199e3202.
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6381e6384.
(54). 3-Methylbut-2-enyl
2-(2-(2,2-dimethyl-4-oxo-4H-1,3-
dioxin-6-yl)acetyl)-3-oxo-5-phenylpentanoate (13) (339 mg,
0.44 mmol, 1.0 equiv) and ethyl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-
dioxin-6-yl)acetyl)-3-oxo-5-phenylpentanoate (50) (187 mg,
0.44 mmol, 1.0 equiv), Pd(PPh3)4 (12.6 mg, 0.011 mmol,
0.025 equiv) and Cs2CO3 (426 mg, 1.32 mmol, 3.0 equiv) in THF
(2 mL) were stirred at 0 ꢀC. The mixture was allowed to warm to
25 ꢀC and stirred for 12 h, when reaction was quenched with H2O
(5 mL) and the resultant mixture acidified to pH 3 using 1 M HCl.
The aqueous phase was extracted with EtOAc (2ꢂ50 mL) and the
combined organic extracts were dried (MgSO4), rotary evaporated,
and chromatographed (1:2 EtOAc/hexanes) to give 7-hydroxy-2,2-
5. (a) Trost, B. M.; Krische, M. J.; Berl, V.; Grenzer, E. Org. Lett. 2002, 4, 2005e2008;
(b) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846e2847; (c) Trost, B. M.;
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Eur. J. Org. Chem. 2002, 9, 1461e1471; (e) Burger, E. C.; Tunge, J. A. Org. Lett.
2004, 22, 4113e4115; (f) Behenna, D. C.; Stolz, B. M. J. Am. Chem. Soc. 2004, 126,
15044e15045; (g) Sherden, N. H.; Behenna, D. C.; Virgil, S. C.; Stoltz, B. M.
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Lett. 2007, 9, 2763e2766.
6. Calo, F.; Richardson, J.; Barrett, A. G. M. Org. Lett. 2009, 11, 4910e4913.
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2011, 13, 5748e5750.
8. Cordes, J.; Calo, F.; Anderson, K.; Pfaffeneder, T.; Laclef, S.; White, A. J. P.; Barrett,
A. G. M. J. Org. Chem. 2012, 77, 652e657.
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dimethyl-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one
(53)
10. George, N. S.; Anderson, K. E.; Barrett, A. G. M. Eur. J. Org. Chem. 2013,
7604e7610.
11. Brookes, P. A.; Cordes, J.; White, A. J. P.; Barrett, A. G. M. Eur. J. Org. Chem. 2013,
7313e7319.
(86 mg, 68%) as a white solid and ethyl 7-hydroxy-2,2-dimethyl-8-
(3-methylbut-2-enyl)-4-oxo-5-phenethyl-4H-benzo[d][1,3]diox-
ine-6-carboxylate (54) (130 mg, 68%) as a colorless oil. 7-Hydroxy-
2,2-dimethyl-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one (53): mp
93e95 ꢀC (hexane); Rf¼0.34 (2:8 EtOAc/hexanes); IR (neat) nmax
3219, 1726, 1691, 1613, 1583, 1498, 1391, 1360, 1271, 1210, 1173,
12. Carroll, M. F. J. Chem. Soc. 1940, 704e706.
13. The total yield of intermediates 23, 32, 34, and 36 at 0.2 M is 65% and the total
yield of intermediates of 24, 33, 35, and 37 is 68%. Decomposition pathways of
the starting material and intermediates under the reaction conditions can ac-
count for the loss of material.
1055, 970 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 7.53 (br s, 1H),

K. Anderson et al. / Tetrahedron 70 (2014) 5569e5579
5579
14. Another potential reason could be due to the different kinetic reaction orders
between the branched and the linear -prenyl-palladium(II) cation complexes.
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25. Intermediates 67, 68, 69, 70, 71, 72, and 73:
16. Yield is based on using 1 equiv of 13 and 1 equiv of 40.
17. Additional cesium carbonate was added to bring about consumption of diketo-
dioxinone ethyl ester 44 in order to accelerate the aromatization step (aro-
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3524e3530.
19. Yield is based on using 1 equiv of 13 and 1 equiv of 50.
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