Synthesis of highly functionalized arene systems. Novel selectivities of intra- and intermolecular Friedel-Crafts reactions

Article abstract of DOI:10.1081/SCC-120006014

The intermolecular Friedel-Crafts acylation of electron-rich aromatic rings can be difficult in the presence of easily ionized groups. During these studies directed toward the synthesis of colchicine, it was observed that the stability of the cation is ke

Full text of DOI:10.1081/SCC-120006014

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SYNTHESIS OF HIGHLY FUNCTIONALIZED ARENE
SYSTEMS. NOVEL SELECTIVITIES OF INTRA- AND
INTERMOLECULAR FRIEDEL–CRAFTS REACTIONS
Mark C. McMills a , Dennis L. Wright b & R. Matt Weekly a
a Department of Chemistry and Biochemistry , Ohio University , Athens, OH, 45701, U.S.A.
b Department of Chemistry , University of Florida , Gainesville, FL, 32611, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Mark C. McMills , Dennis L. Wright & R. Matt Weekly (2002) SYNTHESIS OF HIGHLY FUNCTIONALIZED ARENE
SYSTEMS. NOVEL SELECTIVITIES OF INTRA- AND INTERMOLECULAR FRIEDEL–CRAFTS REACTIONS, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:15, 2417-2425, DOI: 10.1081/
SCC-120006014
To link to this article: http://dx.doi.org/10.1081/SCC-120006014
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 15, pp. 2417–2425, 2002
SYNTHESIS OF HIGHLY
FUNCTIONALIZED ARENE SYSTEMS.
NOVEL SELECTIVITIES OF
INTRA- AND INTERMOLECULAR
FRIEDEL–CRAFTS REACTIONS
,y
*
Mark C. McMills, Dennis L. Wright,
and R. Matt Weekly
*
Department of Chemistry and Biochemistry,
Ohio University, Athens, OH 45701, USA
ABSTRACT
The intermolecular Friedel–Crafts acylation of electron-rich
aromatic rings can be difficult in the presence of easily ionized
groups. During these studies directed toward the synthesis of
colchicine, it was observed that the stability of the cation is
key to controlling alternative competing processes.
Key Words: Friedel-Crafts reaction; Cyclization; Indane
During efforts directed toward the synthesis of colchicine and colchi-
cine analogs,[1] it became necessary to synthesize a highly substituted diazo-
ketone 1 as a precursor for a carbonyl ylide cycloaddition with the allylic
*Corresponding authors. Fax: 352-846-0296; E-mail: dwright@chem.ufl.edu
yCurrent address: Department of Chemistry, University of Florida, Gainesville, FL
32611, USA.
2417
DOI: 10.1081/SCC-120006014
Copyright & 2002 by Marcel Dekker, Inc.
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2418
MCMILLS, WRIGHT, AND WEEKLY
Scheme 1.
Scheme 2.
acetate functioning as a dipolarophile. Ketoester 2 was seen as a convenient
precursor that could in turn be prepared directly from arene 3. To accom-
plish this goal, it was anticipated that a Friedel–Crafts acylation[2] reaction
could place the necessary functionality onto 3 under relatively mild con-
ditions (Scheme 1).
The precursor allylic acetate 3 was synthesized from trimethoxy-
phenyl proprionic acid by standard methods[3] (see experimental section
for details). Exposure of acetate 3 to an appropriate acid chloride[4]
(ClCOCH2CH2CO2CH3) and SnCl4 as a Lewis acid catalyst in either
dichloromethane or nitromethane failed to generate the acylated
product 2. Surprisingly, a highly substituted indane 4 had been cleanly
formed in very good yield (Scheme 2).
Indane 4 was envisioned to arise from an initial intramolecular capture
of an allylic cation initiated through acetate ionization.[5] Subsequent inter-
molecular Friedel–Crafts acylation followed to prepare the hexasubstituted
arene. In an attempt to prevent ionization, alternate protecting groups such
as a pivalate ester or silyl ether were prepared, but found to be ineffective as
well, resulting only in the quantitative recovery of the starting aromatic
nucleus. Despite the electron rich nature of 3, the aromatic may suffer
from steric congestion at the unsubstituted phenyl position, exacerbated
in part by the steric bulk of the alcohol protecting group. This possibility
was supported by further studies regarding the reactivity of 3.

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HIGHLY FUNCTIONALIZED ARENE SYSTEMS
2419
Scheme 3.
The conversion of 3 to 4 required the overall consumption of two
equivalents of Lewis acid. Limiting the amount of Lewis acid available to
1 equivalent, in the presence of the acid chloride, produced only vinyl indane
5.[6] Subsequent addition of a second equivalent of Lewis acid to the reac-
tion mixture resulted in conversion of indane 5 to the acylated indane 4.
Moreover, if the reaction was quenched at 0ꢀC, even in the presence of
excess Lewis acid, indane 5 was produced exclusively, indicating that acyla-
tion can occur only after cyclization removes the steric constraint of the
freely rotating side chain. The isolated indane 5 could also be converted to 4
upon re-exposure to the reaction conditions.
Concurrent with these studies, an alternative cycloaddition approach
to colchicine that utilized an acetylenic dipolarophile was considered.
Therefore, it was necessary to examine the behavior of the propargylic
acetate[3] 6a under the same cyclization conditions used previously
(Scheme 3).
Propargylic acetate 6a was expected from previous observations to
cyclize to the alkynyl indane 8 upon exposure to a Lewis acid. In contrast
to the prior results, treatment of acetate 6a with tin tetrachloride produced a
complex mixture of products. The recovered mixture was determined to be
primarily tetralone 7 along with small quantities of indane 8 (conversion
based on crude NMR and GC-MS data). The appearance of the tetralone
was surprising and was surmised to be formed through an acid catalyzed
cyclization of the internal carbon atom of the alkyne to initially produce an
exo-methylene derivative 9. Acid catalyzed isomerization to the endocyclic
olefin would produce enol acetate 10, that could further undergo hydrolysis
to 7 upon aqueous work-up. The protic acid required for this process would

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2420
MCMILLS, WRIGHT, AND WEEKLY
Scheme 4.
Scheme 5.
conceivably arise through the initial formation of indane 8. Subjecting pro-
pargyl alcohol 6b to the same conditions resulted in the clean production of
tetralone 7 in 81% isolated yield. The more efficient synthesis of 7 would be
due to the generation of HCl from initial reaction of tin tetrachloride with a
free hydroxyl group.
It was presumed that the cyclization was facilitated by allylic stabiliza-
tion of a carbocationic intermediate derived from 3 and that a less reactive
acetate might survive the conditions needed for the acylation. To investigate
this possibility, two additional acetates were prepared by the same synthetic
route[3] and subjected to the cyclization conditions found to be effective in
the prior indane forming reactions (Scheme 4).
Exposure of secondary acetate 11a to Lewis acid conditions failed to
produce any of the saturated indane. Similarly, primary acetate 11b also
failed to produce any product resulting from intramolecular cyclization, but
instead a nearly quantitative yield of the starting material was recovered.
The stability of propylacetate 11b towards Lewis acid afforded an opportunity
to prepare the key synthetic intermediate 3 targeted for a synthesis of colchi-
cine (Scheme 5).
Gratifyingly, it was found that Friedel–Crafts acylation of primary
acetate 11b can be carried out (1.1 eq. SnCl4, CH2Cl2, reflux 24 h, 95%) in
excellent overall yield to prepare acetate 12. The primary acetate is
completely stable to the acylation conditions and even survives the more

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HIGHLY FUNCTIONALIZED ARENE SYSTEMS
2421
severe conditions needed to promote acylation. Conversion to arene 3
can be accomplished in four step reaction sequence starting with primary
acetate 12.[7]
This work represents the first step toward the synthesis of highly
functionalized arenes that are to be utilized for tandem diazodecomposition
reactions applied to the synthesis of colchicine analogs.
EXPERIMENTAL
General
1H (250 MHz) and 13C (62.5 MHz) NMR were recorded on a Bruker
AC-250 NMR. GC-MS data was obtained on a Hewlett Packard 5890
Series II Gas Chromatograph with MSD detector. IR spectra were recorded
using a Perkin-Elmer 1600 Series FT-IR. Dichloromethane and nitro-
methane were distilled from phosphorus pentoxide prior to use, all other
compounds were used without further purification.
Synthesis of Acetates 3, 6a, 11a, 11b
3-(3,4,5-trimethoxyphenyl)propionic acid (5.0 g, 20.8 mmol) was added
to 100 mL of dry THF and cooled to 0ꢀC. A dropping funnel was attached
and charged with borane–THF (31.2 mL, 31.2 mmol). The borane solution
was added over a 15 min period and the resulting solution was allowed to
warm to room temperature. The cloudy solution was allowed to stir for an
additional 12 h at ambient temperature and then re-cooled to 0ꢀC. The reac-
tion was quenched by the addition of saturated NH4Cl (100 mL) and allowed
to stir for 30 min. The layers were separated and the organic layer extracted
(3 ꢁ 20 mL) with ether. The layers were washed (NaCl), dried (MgSO4), and
concentrated to give a clear oil. The residue was purified by flash chromatog-
raphy with ether/petroleum ether (5 : 1) as the eluent to give 4.66 g (98%) of
3-(3,4,5-trimethoxyphenyl) propanol as a clear oil. TLC Rf ¼ 0.49 (ether/pet
1
ether ¼ 5 : 1); H NMR (250 MHz, CDCl3) ꢀ 6.33 (s, 2H) 3.76 (s, 6H), 3.73
(s, 3H), 3.59 (t, J ¼ 6.4 Hz, 2H), 2.57 (t, J ¼ 7.5 Hz, 2H), 1.91 (bs, 1H), 1.79
(m, 2H); 13C NMR (62.5 MHz, CDCl3) ꢀ 152.9, 137.6, 135.9, 105.2, 62, 60.7,
55.9, 34.1, 32.4; IR(neat) 3422, 3058, 2940, 1590, 1504, 1454, 1422; MS (70 eV)
m/z (Mþ) 226, 181, 151. Anal. calcd. for C12H18O4: C, 63.70; H, 8.02. Found:
C, 63.52; H, 8.04.
A flask containing a solution of pyridinium chlorochromate (1.11 g,
5.18 mmol) and 4 A molecular sieves (2.22 g) in dry dichloromethane

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2422
MCMILLS, WRIGHT, AND WEEKLY
(50 mL) was cooled to 0ꢀC, fitted with a pressure equalizing dropping funnel,
then charged with a solution of 3-(3,4,5-trimethoxy phenyl) propanol
(780 mg, 3.45 mmol) in dichloromethane (25 mL) and added over 15 min.
The black solution was allowed to stir at room temperature until the reaction
was judged complete by TLC (typically 3–4 h.). Celite was added and the
resulting solution filtered through a 1 inch pad of celite. The dark solution
was concentrated to one-half volume and an equal portion of toluene added.
The solution was filtered through a 2 inch pad of silica gel and the pad washed
with solvent (1 : 1 ether/toluene). The solution was concentrated to give an
oily residue that was purified by flash column chromatography with hexa-
ne/ethyl acetate (1 : 1) to give 3-(3,4,5-trimethoxyphenyl) propanal (626 mg,
81%) as a light yellow oil. TLC Rf ¼ 0.26 (hexane/ethyl acetate ¼ 1 : 1);
1H NMR (250 MHz, CDCl3) ꢀ 9.75 (t, J ¼ 1.3 Hz, 1H), 6.33 (s, 2H), 3.76 (s,
6H), 3.74 (s, 3H), 2.83 (dt, J ¼ 6.9, 1.3 Hz, 2H), 2.69 (t, J ¼ 6.9 Hz, 2H);
13C NMR (62.5 MHz, CDCl3) ꢀ 201.4, 153.2, 136.4, 105.2, 99.2, 60.7, 55.9,
45.3, 28.4; IR(neat) 3058, 2942, 2825, 2719, 1719, 1584, 1454, 1419; MS (70 eV)
m/z (Mþ)224, 196, 181, 151. Anal. calcd. for C12H15O4 ꢂ 0.5 H2O: C, 61.79; H,
7.34. Found: C, 62.17; H, 6.99.
General Procedure for Grignard Addition
To a solution of the aldehyde (200 mg, 0.89 mmol) in dry THF (10 mL)
at 0ꢀC was added the alkyl magnesium bromide (1.07 mmol) as a solution in
THF. The ice bath was removed and the solution allowed to stir at room
temperature for 6 h. At that time, NH4Cl(sat) was added and the solution
allowed to stir for 10 min, extracted (3 ꢁ 10 mL) with ether and the combined
layers washed with NaHCO3(sat) then NaCl(sat), dried (Na2SO4) and concen-
trated in vacuo. The residue was subjected to flash column chromatography
with ether/pet ether (5 : 1) as the eluent to give the alcohol as a colorless oil.
General Procedure for Acetate Formation
To a stirred solution of the alcohol (1.0 mmol) in dry dichloromethane
(10 mL) was added DMAP (catalytic), pyridine (5.0 mmol) and acetic
anhydride (5.0 mmol). The yellow solution was allowed to stir for 24 h,
quenched by the addition of NH4Cl(sat), extracted (3 ꢁ 5 mL) with dichloro-
methane and the combined organic layers are washed with NaCl(sat), dried
(Na2SO4) and concentrated. The residue was purified by column chromatog-
raphy with ether/pet ether (5 : 1) as the eluent to give the acetate as a clear oil.

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HIGHLY FUNCTIONALIZED ARENE SYSTEMS
2423
3-Acetoxy-5-(3,4,5-trimethoxyphenyl) pentene (3): Colorless oil (96%
yield); TLC Rf ¼ 0.55 (ether/pet ether ¼ 5 : 1); 1H NMR (250 MHz, CDCl3) ꢀ
6.33 (s, 2H), 5.75 (ddd, J ¼ 6.2, 10.6, 19.8 Hz, 1H), 5.23 (dd, J ¼ 1.3, 19.8 Hz,
1H), 5.22 (q, J ¼ 6.2 Hz, 1H), 5.03 (dd, J ¼ 1.3, 10.6 Hz, 1H), 3.78 (s, 6H),
3.75 (s, 3H), 2.54 (m, 2H), 2.0 (s, 3H), 1.89 (m, 2H); 13C NMR (62.5 MHz,
CDCl3) ꢀ 219.9, 170, 152.9, 136.5, 136.1,105.1, 73.9, 60.5, 55.8, 38.5, 31.6,
20.9; IR(neat) 3002, 2919, 1725, 1584, 1500; MS (70 eV) m/z (Mþ)294, 181,
167, 151. Anal. calcd for C16H21O5 ꢂ 0.5 H2O: C, 65.07; H, 7.88. Found: C,
65.47; H, 7.75.
3-Acetoxy-5-(3,4,5-trimethoxyphenyl) pentyne (6a): Colorless oil (96%
yield); TLC Rf ¼ 0.55 (ether/pet ether ¼ 5:1); 1H NMR (250 MHz, CDCl3) ꢀ
6.36 (s, 2H), 5.33 (dt, J ¼ 2.2, 7.5 Hz, 1H), 3.81 (s, 6H), 3.78 (s, 3H), 2.69
(t, J ¼ 7.5 Hz, 2H), 2.49 (d, J ¼ 2.2 Hz, 1H), 2.05 (s, 3H), 2.1 (m, 2H);
13C NMR (62.5 MHz, CDCl3) ꢀ 169.7, 153.1, 136.3, 136.1, 105.2, 80.8,
73.9, 63.1, 60.7, 55.9, 35.9, 31.4, 20.8; IR(neat) 2931, 2108, 1737, 1589,
1502, 1465; MS (70 eV) m/z (Mþ)292, 250, 217, 201, 181, 167, 151, 43.
Anal. calcd for C16H19O5 ꢂ 0.5 H2O: C, 65.51; H, 7.22. Found: C, 65.46;
H, 7.41.
3-Acetoxy-5-(3,4,5-trimethoxyphenyl) pentane (11a): Colorless oil
(91% yield) TLC Rf ¼ 0.17 (ether/pet ether ¼ 1 : 1); 1H NMR (250 MHz,
CDCl3) ꢀ 6.38 (s, 2H), 4.88 (dt, J ¼ 5.8, 6.5 Hz, 1H), 3.84 (s, 6H), 3.81 (s,
3H), 2.55 (m, 2H),1.83 (m, 2H), 1.56 (d, J ¼ 7.6 Hz, 2H), 0.89 (t, J ¼ 7.6 Hz,
3H) ; 13C NMR (62.5 MHz, CDCl3) ꢀ 170.9, 153.1, 137.4, 136.2, 105.2, 74.9,
60.8, 56.1, 35.4, 32.3, 27.1, 21.2, 9.5; IR(neat) 3055, 2926, 1732, 1588, 1248;
MS (70 eV) m/z (Mþ)296, 236, 221, 207, 181, 151, 43. Anal. calcd for
C16H21O4 ꢂ 0.5 H2O: C, 63.86; H, 8.80. Found: C, 63.63; H, 8.73.
1-Acetoxy-5-(3,4,5-trimethoxyphenyl) propane (11b): Colorless oil
(96% yield from 3-(3,4,5-trimethoxyphenyl) propanol); TLC Rf ¼ 0.51
1
(ether/pet ether ¼ 5 : 1); H NMR (250 MHz, CDCl3) ꢀ 6.32 (s, 2H), 4.02
(t, J ¼ 6.6 Hz, 2H), 3.75 (s, 6H), 3.73 (s, 3H), 2.55 (t, J ¼ 7.6 Hz, 2H), 1.97
(s, 3H), 1.83 (m, 2H); 13C NMR (62.5 MHz, CDCl3) ꢀ 171, 153, 136.9, 136.1,
105.2, 63.7, 60.7, 55.9, 32.5, 30.1, 20.8; IR(neat) 3064, 2937, 1737, 1591, 1509,
1462; MS (70 eV) m/z (Mþ)268, 193, 181, 151, 43. Anal. calcd for C14H20O5:
C, 62.67; H, 7.51. Found: C, 62.44; H, 7.45.
4-Oxo-4-(5,6,7-trimethoxy-1-vinyl-indan-4-yl)-butyric acid methyl ester
(4): To allylic acetate 3 (80 mg, 0.27 mmol) in dry nitromethane (3 mL, 0ꢀC)
was added 3-carbomethoxypropionyl chloride (36 mL, 0.30 mmol, Aldrich
Chemical) and tin tetrachloride (0.680 mL, 0.68 mmol, 1.0 M in dichloro-
methane). The mixture was allowed to stir at 0ꢀC for 15 min, then at room
temperature for an additional 30 min. Water (3 mL) was added, the solution
was extracted with dichloromethane (3 ꢁ 3 mL), washed with NaHCO3 and
brine. The solution was dried (Na2SO4) and concentrated under reduced

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2424
MCMILLS, WRIGHT, AND WEEKLY
pressure. The residue was purified (flash column chromatography 1 : 1
ether : petroleum ether as eluent) to give 4 (66 mg, 70%) as a pale yellow
1
oil. H NMR (250 MHz, CDCl3) ꢀ 5.95(ddd, J ¼ 7.5, 10, 17.2 Hz, 1H), 5.0
(dd, J ¼ 1.2, 17.2 Hz, 1H), 4.9 (dd, J ¼ 1.2, 10 Hz, 1H), 3.83–3.85 (m, 1H),
3.91 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.70 (s, 3H), 3.20 (t, J ¼ 6.6 Hz, 2H),
2.90 (t, J ¼ 6.6 Hz), 2.15–2.3 (m, 8 lines, 2H), 1.96–1.84 (m, 8 lines, 2H);
13C NMR (62.5 MHz, CDCl3) ꢀ 202.2, 173.4, 152.2, 153.4, 144.3, 141.2,
140.7, 133.9, 126.2, 113.4, 62, 61.9, 61.3, 51.3, 38.1, 33.4, 31.2, 28.5, 27.3;
IR(neat) 2938, 1740, 1684, 1576, 1455, 1403, 1332; MS (70 eV) m/z 348(Mþ),
261, 233, 115. Anal. calcd for C19H26O6: C, 65.50; H, 6.94. Found: C, 65.73;
H, 7.21.
6,7,8-Trimethoxy-1-methyl-3,4-dihydro-1H-naphthalen-2-one (7): T o a
solution of propargyl alcohol 11b (70 mg, 0.28 mmol) in dry nitromethane
(3 mL, 0ꢀC) was added tin tetrachloride (420 mL, 0.42 mmol, 1.0 M in
dichloromethane). The mixture was allowed to stir at 0ꢀC for 30 min,
water (3 mL) was added, the solution extracted (3 ꢁ 3 mL) with dichloro-
methane then washed with NaHCO3(sat) and brine. The solution was
dried (Na2SO4) and concentrated under reduced pressure. The resulting
residue was purified (flash column chromatography 1 : 1 ether:petroleum
1
ether as eluent) to give 7 (65 mg, 81%) as a colorless oil. H NMR (C6D6)
ꢀ 6.23 (s, 1H), 3.89 (q, J ¼ 7.5 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 3.44
(s, 3H), 2.74 (ddd, J ¼ 15.1, 12.2, 4.4 Hz, 1H), 2.53 (ddd, J ¼ 12.6, 4.4,
3.5 Hz, 1H) 2.41 (ddd, J ¼ 12.2, 6, 3.5 Hz, 1H), 2.16 (ddd, J ¼ 15.1, 12.6,
6 Hz, 1H), 1.42 (d, J ¼ 7.5 Hz, 3H); 13C NMR (62.5 MHz, CDCl3) ꢀ 211.3,
152.7, 151.8, 141.7, 131.4, 125.5, 107.6, 60.7, 60.4, 55.7, 42.6, 38, 28.2,
19.5; IR(neat) 2936, 1712, 1602, 1501; MS (70 eV) m/z 250(Mþ), 235,
207, 176. Anal. calcd for C14H18O4: C, 67.18; H, 7.25. Found: C, 67.37;
H, 7.33.
4-[6-(3-Acetoxy-propyl)-2,3,4-trimethoxy-phenyl]-4-oxo-butyric acid
methyl ester (12):. To a solution of acetate 11b (900 mg, 2.35 mmol) in
dry dichloromethane (20 mL, 0ꢀC) was added 3-carbomethoxyproprio-
nyl chloride (451 mL, 3.69 mmol) and tin tetrachloride (5.04 mL, 1.0 M in
dichloromethane, 5.04 mmol) dropwise. The mixture was heated at reflux
for 24 h, water (20 mL) was added and the solution was extracted
(3 ꢁ 10 mL) with dichloromethane then washed with NaHCO3(sat) and
brine. The solution was dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified (flash column chromatography 1 : 5
ether : petroleum ether as eluent) to give 12 (1.22 g, 95%) as a yellow oil.
1H NMR (250 MHz, CDCl3) ꢀ 6.43 (s, 1H), 3.99 (t, J ¼ 6.4 Hz, 2H), 3.78
(s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.67 (s, 3H), 3.02 (t, J ¼ 6.6 Hz, 2H),
2.61 (t, J ¼ 6.6 Hz, 2H), 2.45 (t, J ¼ 7.8 Hz, 2H), 1.96 (s, 3H), 1.91–1.75
(m, 2H); 13C NMR (62.5 MHz, CDCl3) ꢀ 203.9, 172.9, 170.8, 154.1,

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HIGHLY FUNCTIONALIZED ARENE SYSTEMS
2425
150.5, 139.6, 134.3, 127.8, 108.5, 63.6, 61.4, 60.6, 55.8, 51.5, 39.5, 32.5,
32.3, 27.8, 20.6; IR(neat) 2940, 1733, 1732, 1701, 1541, 1442; MS (70 eV)
m/z 382(Mþ), 351, 294, 253, 235, 207, 115. Anal. calcd for C19H24O8: C,
59.68; H, 6.85. Found: C, 59.47; H, 6.81.
ACKNOWLEDGMENTS
The authors would like to thank the Donors of the Petroleum
Research Fund of the American Chemical Society (28135-G1) for financial
support.
REFERENCES
1. Li, Ling; Wright, D.L.; McMills, M.C. Manuscript in Preparation.
2. (a) Olah, G.A. Friedel–Crafts and Related Reactions; John-Wiley and
Sons: New York, 1964; Vol. 2; (b) Roberts, R.M. and Khalaf, A.A.
Friedel–Crafts Alkylation Chemistry: A Century of Discovery. Marcel
Dekker: New York, 1984.
3. Commercially available trimethoxyphenyl proprionic acid was con-
verted to the aldehyde by a reduction/oxidation sequence followed by
addition of the appropriate Grignard reagent and acylation. See experi-
mental section for details.
4. Hagmann, W.K.; O’Grady, L.A.; Dorn, C.P.; Springer, J.P.
J. Heterocyclic Chem. 1986, 23, 673–677.
5. For an intermolecular example with an acetate see: Niederl, J.B.; Smith,
R.A.; McGreal, M.E. J. Am. Chem. Soc. 1931, 53, 3390.
6. The structure of 5 was established by 1H NMR, 13C NMR, IR, and MS.
7. Acetate 12 can be converted to the allylic acetate 3 through the follow-
ing sequence; (i) K2CO3 (5 eq.), MeOH–H2O, RT, 30 min, 92% (ii)
TPAP (5 mole %), NMO (1.6 eq.), molecular sieves, CH2Cl2, 81% (iii)
CH2CHMgBr, Et2O, ꢃ78ꢀC to RT, 8 h, 84% (iv) Ac2O, pyridine, 95%.
Received in the USA August 8, 2001

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