Alternatives to N,N-diethyl-2,4-dimethoxybenzamide as a precursor for the synthesis of 6,8-dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-one

Article abstract of DOI:10.1080/00397910701557655

Although the amide group of N,N-diethyl-2,4-dimethoxybenzamide facilitates directed ortho-metallation and subsequent allylation of the aromatic ring, it is not readily hydrolyzed prior to conversion into the title isochromenone. This article describes the use of 1-(2-allyl-4,5-dimethoxybenzoyl)-4-methylpiperazine and N,N-diethyl-2-(2-hydroxypropyl)-4,6-dimethoxybenzamide as alternative substrates for conversion into 6,8-dimethoxy-3-methyl-3,4-dihydro-1H-isochromen- 1-one. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701557655

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Alternatives to
N,N‐Diethyl‐2,4‐dimethoxybenzamide
as a Precursor for the Synthesis of
6,8‐Dimethoxy‐3‐methyl‐3,4‐dihydro‐1H‐isochrom
Willem A. L. van Otterlo a , Joseph P. Michael a & Charles B. de Koning a
a Molecular Sciences Institute, School of Chemistry, University of the
Witwatersrand , Johannesburg, South Africa
Published online: 05 Oct 2007.
To cite this article: Willem A. L. van Otterlo , Joseph P. Michael & Charles B. de Koning
(2007) Alternatives to N,N‐Diethyl‐2,4‐dimethoxybenzamide as a Precursor for the Synthesis
of 6,8‐Dimethoxy‐3‐methyl‐3,4‐dihydro‐1H‐isochromen‐1‐one, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:20, 3611-3621, DOI:
10.1080/00397910701557655
To link to this article: http://dx.doi.org/10.1080/00397910701557655
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Synthetic Communicationsw, 37: 3611–3621, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701557655
Alternatives to N,N-Diethyl-2,4-
dimethoxybenzamide as a Precursor
for the Synthesis of 6,8-Dimethoxy-3-methyl-
3,4-dihydro-1H-isochromen-1-one
Willem A. L. van Otterlo, Joseph P. Michael,
and Charles B. de Koning
Molecular Sciences Institute, School of Chemistry, University of the
Witwatersrand, Johannesburg, South Africa
Abstract: Although the amide group of N,N-diethyl-2,4-dimethoxybenzamide
facilitates directed ortho-metallation and subsequent allylation of the aromatic ring,
it is not readily hydrolyzed prior to conversion into the title isochromenone. This
article describes the use of 1-(2-allyl-4,5-dimethoxybenzoyl)-4-methylpiperazine and
N,N-diethyl-2-(2-hydroxypropyl)-4,6-dimethoxybenzamide as alternative substrates
for conversion into 6,8-dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Keywords: 3,4-dihydro-1H-isochromen-1-one, directed ortho metallation, N,N-diethyl
arylamide
INTRODUCTION
3,4-Dihydroisochromenones such as the naturally occurring compound
(2)-mellein 1 are of particular interest to the scientific community as a
result of their biological activities (Fig. 1).[1] The synthesis of these types of
compounds has been achieved by many research groups.[2] Of interest to
our group is the use of directed ortho-metallation (DOM) as a key step to
accomplish their synthesis. Sibi and coworkers had previously employed
DOM methodology to construct a variety of substituted isochromanones 2
Received in Poland January 11, 2007
Address correspondence to Charles B. de Koning, Molecular Sciences Institute,
School of Chemistry, University of the Witwatersrand, PO Wits 2050, Johannesburg,
South Africa. E-mail: charles.dekoning@wits.ac.za
3611

3612
W. A. L. van Otterlo, J. P. Michael, and C. B. de Koning
Figure 1. R ¼ H, 8-OH, 5-OMe, 5-OH, and 2-OH or 6-OMe, 7-OMe, and 8-OH.
from appropriately substituted tertiary benzamides.[3] In their synthesis, the
N,N-diethylamide functional group was used for the directed ortho metalation
to introduce the allyl substituent (3a!3b). More recently, this methodology
has also been used in the synthesis of the naturally occurring isochromanone
semivioxanthin 4.[4]
As part of our program[5] directed toward the synthesis of aromatic and
heteroaromatic compounds using DOM,[6] we decided to implement this
strategy for the synthesis of target molecule 5 (Fig. 2).
RESULTS AND DISCUSSION
The initial synthetic steps involved the methylation of commercially available
2,4-dihydroxybenzoic acid 7 followed by ester hydrolysis under basic con-
ditions and conversion into the corresponding acid chloride (Scheme 1).
Treatment of the carboxylic acid chloride with diethylamine resulted in the
formation of the N,N-diethylamido compound 8 in good overall yields. Appli-
cation of the Snieckus metallation methodology[3,6] using s-BuLi, followed by
transmetalation of the lithium species with Mg and subsequent quenching with
allyl bromide, afforded compound 6 in good yield.[7]
Figure 2. Retrosynthesis of 6,8-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromene-
1-one.

Synthesis of 6,8-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromene-1-one
3613
Scheme 1. (a) Me2SO4, K2CO3, quantitative; (b) KOH, 97%; (c) (i) SOCl2, (ii)
.
HNEt2, quantitative over two steps; (d) (i) s-BuLi, (ii) MgBr2 Et2O, (iii) allyl bro-
mide, 95%; (e) HCl or KOH, low yields of contaminated 5 obtained.[8]
With the o-allyl amide 6 in hand, we initially decided to hydrolyze the
amide 6 using the acid-catalyzed route suggested by Sibi and coworkers.[3] It
was expected that the ensuing acid would participate in an acid-induced
reaction with the internal alkene to yield the desired lactone 5, but this transform-
ation proved to be less than straightforward in our hands. Unfortunately the
hydrolysis was not always successful. When the lactone 5 was obtained it was
in low yield, along with decomposition, and the reactions were often poorly
reproducible.[8] Attempts at hydrolysis included the following procedures: (i)
6 M HCl, 908C, 96 h (isochromanone 5, 22%, recovered 6, 75%); (ii)
6 M HCl, reflux, 24 h (mainly 6), added further 6 M HCl and heated at reflux
for 60 h (decomposition); (iii) 6.6 M HCl, 2-propanol, reflux, 144 h (lactone 5
24%, recovered 6, 50%); (iv) 10% KOH, HOCH2CH2OH, 908C, 96 h (no
product, alkene isomerization observed);[9a] (v) 6 M HCl, microwave, power
25–50%, 1 min (no product, DMF as co-solvent also had no effect).[9b]
Reitz and Massey also described problems associated with the hydrolysis
of 2,6-disubstituted benzamides, which they surmise were “essentially inert to
hydrolysis except in the cases where intramolecular lactone formation is
possible.”[10] This reference seemed to confirm our fears that simple hydroly-
sis of the amide 6 and subsequent conversion into lactone 5 was going to be
problematic. The problem also appears to be exacerbated by the presence of
a methoxy substituent ortho to the tertiary amide.
Realizing that hydrolysis of the N,N-diethylamide was proving far from
trivial, we synthesized the N-methylpiperazinylamide 9,[11] as it was
reported to be easier to hydrolyze, while still allowing the use of DOM meth-
odology for the introduction of the required allyl substituent. The N-methylpi-
perazinylamide 10 was thus synthesized from carboxylic acid 11 in
quantitative yield via the acid chloride (Scheme 2). Fortunately, straight-
forward acidic hydrolysis of 10 afforded isochromanone 5 in reproducible,
moderate yields of up to 53%.

3614
W. A. L. van Otterlo, J. P. Michael, and C. B. de Koning
Scheme 2. (a) (i) SOCl2, (ii) N-methylpiperazine, quantitative over two steps; (b) (i)
.
s-BuLi, (ii) MgBr2 Et2O, (iii) allyl bromide, 70%; (c) 6 M HCl, heat, 53%.
Because the yields in converting 9 to 5 were still unsatisfactory, we
sought an alternative method to accomplish this transformation. Work done by
Watanabe et al.[12] and Salvadori et al.[7a] has demonstrated that compounds
containing an alcohol functional group can participate successfully in the intra-
molecular hydrolysis of an N,N-diethylamide group to yield a variety of functio-
nalized lactones. The alkene bond of 6 was thus oxymercurated with Hg(OAc)2
in a THF–water mixture.[13,14] Reduction of the organomercury intermediate
then afforded the secondary alcohol 12 as a 2:1 mixture of amide rotamers in
63% yield (Scheme 3).[15] It was hoped that the subsequent hydrolysis with intra-
molecular participation would be appreciably faster because of neighboring
group participation,[16] and fortunately this time alkaline hydrolysis was
highly successful. Compound 5 was isolated in 75% yield (94% based on
recovered starting material) after workup and purification by chromatography.
Scheme 3. (a) (i) Hg(OAc)2, H2O, THF, (ii) NaBH4, 63% over two steps; (b) KOH,
EtOH, D, 75% (and 20% recovered 6).

Synthesis of 6,8-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromene-1-one
3615
CONCLUSION
The inertness of the N,N-diethyl arylamide functionality, especially adjacent
to an ortho methoxy substituent, leads to problems with hydrolysis. These
can be overcome by using N-methylpiperazinyl benzamides as the DOM
group or by allowing the reaction to proceed by using an internal hydroxyl
nucleophile as in the transformation of 12 to 5. Using these two
methods allowed for the preparation of 6,8-dimethoxy-3-methyl-3,4-
dihydro-1H-isochromen-1-one 5 in reasonable yields.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded either on a Bruker AC-200 or
Bruker DRX 400 spectrometer at the frequency indicated. Distortionless
enhancement by polarization transfer (DEPT), carbon hydrogen (CH)-corre-
lated, and heteronuclear multiple bond correlation (HMBC) spectra were run
on some samples to enable complete assignments of all the signals. NMR spec-
troscopic assignments with the same superscript may be interchanged. Infrared
spectra were recorded on either a Bruker IFS 25 or a Bruker Vector 22 Fourier
transform spectrometer. Mass spectra were recorded on a Kratos MS 9/50, VG
70E MS, or VG 70 SEQ mass spectrometer. Macherey–Nagel kieselgel
60 (particle size 0.063–0.200 mm) was used for conventional silica-gel chrom-
atography, and Macherey–Nagel kieselgel 60 (particle size 0.040–0.063 mm)
was used for preparative flash chromatography. All solvents used for reactions
and chromatography were distilled prior to use.
Methyl 2,4-dimethoxybenzoate,[17] 2,4-dimethoxybenzoic acid,[18] and N,N-
diethyl-2,4-dimethoxybenzamide 8[3] were prepared by reported procedures.
2-Allyl-N,N-diethyl-4,6-dimethoxybenzamide 6
N,N-Diethyl-2,4-dimethoxybenzamide 8 (0.683 g, 2.88 ꢀ 1023 mol) was
dissolved in dry THF (5 cm3) and added dropwise by syringe over 5 min to
a cooled solution (2788C) of s-BuLi (5.5 cm3, 4.2 ꢀ 1023 mol) and tetra-
methylethylenediamine (TMEDA) (0.63 cm3, 4.2 ꢀ 1023 mol) in dry tetra-
hydrofuran (THF) (50 cm3). The reaction mixture was stirred at 2788C
under Ar for a further 30 min. Magnesium bromide etherate (2.23 g,
8.64 ꢀ 1023 mol) was added, and the reaction mixture was allowed to
warm slowly until all the white reagent had dissolved. The mixture was
then recooled to 2788C and stirred for 40 min, after which allyl bromide
(0.75 cm3, 8.7 ꢀ 1023 mol) was added by syringe. The reaction was then
allowed to warm to rt over 14 h, during which time it went to a milky
color. The organic solvent was washed with HCl (50 cm3, 10%), which was
extracted with CH2Cl2 (4 ꢀ 50 cm3). The combined organic extracts were

3616
W. A. L. van Otterlo, J. P. Michael, and C. B. de Koning
dried (MgSO4) and removed in vacuo to give a crude product, which was
purified by silica-gel chromatography (50% EtOAc/hexane) to yield the
product 6 as a yellow oil (0.76 g, 95%). The spectra of this compound
compared well with those published in the literature.[4a]
6,8-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-one 5
Method 1
Arylamide 6 (0.20 g, 7.2 ꢀ 1024 mol) was dissolved in a solution of
1-propanol (10 cm3) and concentrated HCl (15 cm3) and heated under reflux
for 6 d. After cooling, H2O (50 cm3) was added, and the crude organic
compound was extracted with Et2O (3 ꢀ 10 cm3). The organic solvent was
dried (MgSO4) and removed under vacuum to give an impure residue. The
desired compound 5 was obtained as a clear oil, which slowly became a
semisolid (0.039 g, 24%) after silica-gel preparative layer chromatography
(50% EtOAc/hexane). Unreacted starting material 6 (0.099 g, 50%) was
1
also recovered. H NMR (200 MHz; CDCl3) dH 6.42 (1H, d, J 2.3, 5-H),
6.31 (1H, d, J 2.3, 7-H), 4.61–4.44 (1H, m, 3-H), 3.93 (3H, s, OCH3), 3.87
(3H, s, OCH3), 2.88–2.79 (2H, m, 4-H), 1.47 (3H, d, J 6.3, 3-CH3); 13C
NMR (50 MHz; CDCl3) dC 164.3 (C55O), 163.2, 162.7 (C-8 and C-6),
143.9 106.8 (C-8a and C-4a), 103.8 (C-5), 97.8 (C-7), 73.5 (C-3), 56.1, 55.6
(2 ꢀ OCH3), 36.6 (C-4), 20.7 (CH3); IR (thin film) nmax/cm21 1717
(C55O), 1603 (ArC55C); m/z (EI) Mþ (93%) 222.0901 (C12H14O4 requires
222.0892), 205 (13), 178 (100), 161 (40), 148 (34), 135 (34), 120 (18), 77
1
(22), 43 (13). The H NMR spectrum of this compound compared well with
that published in the literature.[19]
Method 2
Arylamide 9 (0.050 g, 1.6 ꢀ 1024 mol) was dissolved in a solution of
1-propanol (5 cm3) and concentrated hydrochloric acid (7.5 cm3) and heated
under reflux for 4 d. H2O (50 cm3) was added, and a crude organic
compound was extracted with CH2Cl2 (3 ꢀ 10 cm3). The organic solvent
was dried (MgSO4) and removed under vacuum to give an impure residue.
The product 5 was obtained as a clear oil (0.019 g, 53%), which slowly
became a semisolid, after silica-gel preparative layer chromatography (50%
EtOAc/hexane) of the crude material. Spectral data for this compound were
identical to that obtained in the previous experiment.
Method 3
Alcohol 12 (0.074 g, 2.5 ꢀ 1024 mol) was dissolved in a mixture of EtOH
(2 cm3) and aqueous NaOH solution (2 cm3 H2O, 1.0 g NaOH) and heated

Synthesis of 6,8-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromene-1-one
3617
at reflux for 144 h. The solvent was removed in vacuo, and the residue was
acidified with concentrated HCl at 08C. The aqueous layer was extracted
with EtOAc (4 ꢀ 10 cm3) and CH2Cl2 (2 ꢀ 10 cm3). The combined organic
extracts were washed with H2O (10 cm3), dried (MgSO4), and removed in
vacuo. The residue was purified by silica-gel preparative layer chromato-
graphy (30% EtOAc/hexane) to afford isochromanone 5 (0.042 g, 75%),
which slowly became a semisolid, and starting material 12 (0.015 g, 20%).
The NMR spectra of compound 5 obtained in this experiment were
identical to those obtained earlier.
1-(2,4-Dimethoxybenzoyl)-4-methylpiperazine 10
SOCl2 (0.96 cm3, 1.32 ꢀ 1022 mol, 1.2 mol equiv.) was added dropwise over
15 min to 2,4-dimethoxybenzoic acid 11 (2.00 g, 1.10 ꢀ 1022 mol) dissolved
in C6H6 (100 cm3) and DMF (0.25 cm3). The reaction mixture was heated at
reflux for 2 h under an Ar atmosphere. After cooling to rt using an ice bath,
N-methylpiperazine (3.65 cm3, 3.29 ꢀ 1022 mol) was added, and the
reaction mixture became cloudy as a precipitate formed. The mixture was
stirred for a further 2 h, after which H2O (100 cm3) was added. The organic
layer was then extracted with Et2O (3 ꢀ 50 cm3). Subsequent drying
(MgSO4) and removal of the solvent in vacuo resulted in the crude material,
which afforded the product 10 (2.90 g, quantitative) as a yellow oil after silica-
gel column chromatography (50% EtOAc/hexane). 1H NMR (200 MHz;
CDCl3) dH 7.17 (1H, d, J 8.2, 60-H), 6.53–6.45 (2H, m, 30-H and 50-H),
3.80 (6H, br s, 2 ꢀ OCH3), 3.35–3.28 (4H, m, 4 ꢀ 2-H), 2.48–2.35 (4H,
m, 4 ꢀ 3-H), 2.30 (3H, br s, NCH3); 13C NMR (50 MHz; CDCl3) dC 167.3
(C55O), 161.2, 156.2 (C-20 and C-40), 128.7 (C-60), 117.8 (C-10), 104.5 (C-
50), 97.9 (C-30), 55.0, 54.9, 54.7, 54.2 (2 ꢀ OCH3 and 2 ꢀ C-2), 46.3, 45.5
(2 ꢀ C-3)a, 41.0 (NCH3)a; IR (thin film) nmax/cm21 1633 (C55O), 1616
(ArC55C); m/z (EI) Mþ (26%) 264.1475 (C14H20N2O3 requires 264.1474),
207 (33), 194 (25), 182 (17), 165 (100), 99 (94), 83 (65), 70 (60), 56 (32).
1-(2-Allyl-4,5-dimethoxybenzoyl)-4-methylpiperazine 9
Amide 10 (1.80 g, 6.81 ꢀ 1023 mol) was dissolved in dry THF (20 cm3) and
added dropwise over 5 min to a cooled solution (–788C) of s-BuLi (18.1 cm3,
0.75 M, 1.36 ꢀ 1022 mol, 2 mol equiv.) and TMEDA (2.05 cm3,
1.36 ꢀ 1022 mol, 2 mol equiv.) in dry THF (100 cm3). The reaction was
.
stirred at –788C under Ar for a further 30 min. MgBr2 Et2O (5.3 g,
2.0 ꢀ 1022 mol) was added, and the reaction mixture was allowed to warm
slowly until all the inorganic reagent had dissolved. The mixture was then
cooled to –788C and stirred for 40 min, after which allyl bromide
(1.80 cm3, 2.0 ꢀ 1022 mol) was added by syringe. The reaction was then

3618
W. A. L. van Otterlo, J. P. Michael, and C. B. de Koning
allowed to warm to rt over 14 h, during which time the amide started to pre-
cipitate out of solution. The reaction mixture was made basic with careful
addition of an aqueous NaOH solution (10%) and was then extracted with
CH2Cl2 (3 ꢀ 50 cm3). The combined organic extracts were dried (MgSO4)
and concentrated under vacuum. The residue was purified by silica-gel
column chromatography (50–100% EtOAc/hexane) to afford the product 9
1
as a pale yellow oil (1.45 g, 70%). H NMR (200 MHz; CDCl3) dH 6.38
(1H, d, J 2.2, 30-H)a, 6.33 (1H, d, J 2.2, 50-H)a, 5.99–5.79 (1H, m,
CH2CH55CH2), 5.13–5.02 (2H, m, CH2CH55CH2), 3.83–3.77 (2H, m,
NCH2)b, 3.79 (3H, s, OCH3), 3.77 (3H, s, OCH3), 3.36–3.18 (4H, m,
CH2CH55CH2 and NCH2)b, 2.53–2.78 (4H, m, 2 ꢀ NCH2), 2.30 (3H, br s,
NCH3); 13C NMR (50 MHz; CDCl3) dC 166.8 (C55O), 160.5, 156.4 (C-40
and C-60), 138.7 (C-20), 136.0 (CH2CH55CH2), 117.7 (C-10), 115.9
(CH2CH55CH2), 105.7 (C-30), 95.8 (C-50), 55.0, 55.0, 54.8, 54.3
(2 ꢀ OCH3 and 2 ꢀ NCH2), 46.0, 45.7 (2 ꢀ NCH2), 40.8 (NCH3)c, 37.1
(CH2CH55CH2)c; IR (thin film) nmax/cm21 1630 (C55O), 1606 (ArC55C);
m/z (EI) Mþ (35%) 304.1796 (C17H24N2O3 requires 304.1787), 247 (5),
205 (100), 177 (16), 99 (91), 85 (27), 83 (41), 70 (50), 56 (29).
N,N-Diethyl-2-(2-hydroxypropyl)-4,6-dimethoxybenzamide 12
Arylamide
6
(0.200 g, 7.21 ꢀ 1024 mol) and Hg(OAc)2 (0.23 g,
7.2 ꢀ 1024 mol) were dissolved in a THF (10 cm3)/water (3 cm3) mixture
to yield a yellow solution. The mixture was stirred for 18 h, during which
time the color faded gradually. An aqueous NaOH solution (5 cm3, 3 M)
was added, followed by NaBH4 in a NaOH solution (3 cm3, 3 M in 3 M
NaOH). The reaction mixture was stirred for 30 min, after which the
mercury was allowed to settle. Saturated NaCl solution (10 cm3) was added,
and the organic layer was decanted carefully. The organic solvent was dried
(MgSO4), removed in vacuo, and purified by silica-gel preparative layer
chromatography (50% EtOAc/hexane) to yield the product 12 as a clear oil
(0.133 g, 63%). The product was a mixture of diastereomers (ratio 67:33)
due to the hindered rotation about the amide C-N bond. 1H NMR
(200 MHz; CDCl3, assignments for major diastereomer) dH 6.39 (1H, d, J
2.1, 3-H)a, 6.32 (1H, d, J 2.1, 5-H)a, 4.53 (1H, br s, D2O exchangeable,
OH), 3.95–3.85 (1H, m, 20-H), 3.80 (3H, s, OCH3), 3.76 (3H, s, OCH3),
3.58 (2H, q, J 7.2, NCH2CH3), 3.25–3.05 (2H, m, NCH2CH3), 2.71 (1H,
dd, J 13.6 and 3.5, 10-H), (1H, dd, J 13.6 and 6.5, 10-H), 2.39 (1H, dd, J
13.6 and 10.0, 10-H), 1.27–1.15 (3H, m, CH3), (1.02), (1.00) (3H, 2 ꢀ t, J
7.2, CH2CH3); 1H NMR (200 MHz; CDCl3, assignments for minor diastereo-
mer indicating only different signals) 6.40 (1H, d, J 2.1, 3-H)a, 6.35 (1H, d, J
2.1, 5-H)a, 4.21–4.05 (1H, m, 20-H), 2.54 (1H, dd, J 13.6 and 3.5, 10-H);
13C NMR (50 MHz; CDCl3, assignments in for major diastereomer) dC 169.2
(C55O), 160.9, 156.2 (C-40 and C-60), 139.2 (C-2), 119.1 (C-1), 105.7 (C-3),

Synthesis of 6,8-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromene-1-one
3619
96.4 (C-5), 68.7, (C-20), 55.3, 55.2 (2 ꢀ OCH3), 43.1, 42.9 (2 ꢀ NCH2), 39.1,
(C-10), 24.7, (C-30), 13.9, 12.7 (2 ꢀ CH2CH3); 13C NMR (50 MHz; CDCl3,
assignments for minor diastereomer) dC 168.2 (C55O), 160.0, 157.6 (C-40
and C-60), 137.2 (C-2), 119.2 (C-1), 107.0 (C-3), 96.4 (C-5), 66.6 (C-20),
55.3, 55.2 (2 ꢀ OCH3), 42.7 42.1 (2 ꢀ NCH2), 38.8 (C-10), 22.7 (C-30),
13.7, 12.7 (2 ꢀ CH2CH3); IR (thin film) nmax/cm–1 3396br (OH), 1630
(C55O), 1607 (ArC55C); m/z (EI) Mþ (2%) 295.1789 (C16H25NO4 requires
295.1777), 277 (2), 251 (27), 236 (100), 223 (23), 220 (16), 205 (49), 195
(48), 179 (63), 177 (7), 162 (3).
ACKNOWLEDGMENTS
This material is based upon work supported by the National Research Foun-
dation under grant number 2053652. Support from the University of the
Witwatersrand (University Research Council) is also gratefully acknowl-
edged. W. A. L. V. O thanks African Explosives and Chemical Industries
(AECI) (Modderfontein, South Africa) for a postgraduate fellowship.
REFERENCES
¨
1. Krohn, K.; Bahramsari, R.; Florke, U.; Ludewig, K.; Kliche-Spory, C.; Michel, A.;
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Isolation, structure elucidation, circular dichroism and biological activity. Phyto-
chemistry 1997, 45, 313–320.
2. See, for example, (a) Kendall, J. K.; Fisher, T. H.; Schultz, H. P.; Schultz, T. P. An
improved synthesis of 6,8-dimethoxy-3-methylisocoumarin, a fungal metabolite
precursor. J. Org. Chem. 1989, 54, 4218–4220, and references cited therein;
(b) Carpenter, T. A.; Evans, G. E.; Leeper, F. J.; Staunton, J.; Wilkinson, M. R.
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Lett. 2004, 45, 5117–5120.

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W. A. L. van Otterlo, J. P. Michael, and C. B. de Koning
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3621
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