First syntheses of 2,2-dimethyl-7-(2′-methylbut-3′-en-2′- yl)-2H-chromen-6-ol and 2-(3′-methylbut-2′-enyl)-5-(2′- methylbut-3′-en-2′-yl)-1,4-benzoquinone, novel prenylated quinone derivatives from the New Zealand brown alga Perithalia capillaris

Article abstract of DOI:10.1021/jo801057x

(Chemical Equation Presented) The first syntheses of 2,2-dimethyl-7- (2′-methylbut-3′-en-2′-yl)-2H-chromen-6-ol (1) and 2-(3′-methylbut-2′-enyl)-5-(2′-methylbut-3′-en-2′- yl)-1,4-benzoquinone (2), novel prenylated quinone derivatives from the New Zealand

Full text of DOI:10.1021/jo801057x

First Syntheses of 2,2-Dimethyl-7-(2′-methylbut-3′-en-2′-yl)-2H-
chromen-6-ol and 2-(3′-Methylbut-2′-enyl)-5-(2′-methylbut-3′-en-2′-
yl)-1,4-benzoquinone, Novel Prenylated Quinone Derivatives from
the New Zealand Brown Alga Perithalia capillaris
Catherine L. Coombes and Christopher J. Moody*
School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham NG7 2RD, United Kingdom
c.j.moody@nottingham.ac.uk
ReceiVed May 16, 2008
The first syntheses of 2,2-dimethyl-7-(2′-methylbut-3′-en-2′-yl)-2H-chromen-6-ol (1) and 2-(3′-methylbut-
2′-enyl)-5-(2′-methylbut-3′-en-2′-yl)-1,4-benzoquinone (2), novel prenylated quinone derivatives from
the New Zealand brown alga Perithalia capillaris, are reported, in which the key steps are consecutive
Claisen rearrangements that proceed with both high chemo- and regioselectivity.
Introduction
us in the synthesis of other naturally occurring quinones.6-8
Hence it was envisaged that both structures could be accessed
from the same advanced intermediate 3 by divergent path-
ways involving two consecutive Claisen rearrangements (CR),
exhibiting both chemoselectivity (CR 1 occurs before CR 2)
and regioselectivity (CR 2 proceeds to C-5 rather than C-3)
(Scheme 1).
Quinones are ubiquitous in Nature and exhibit wide-ranging
properties.1-3 Not only do they constitute a large group of
natural pigments, although surprisingly their contribution to
natural coloring is relatively small, but they also participate in
a range of important biological redox processes. One particular
group of compounds is the isoprenoid benzoquinones, some of
which such as the ubiquinones and the phyllaquinones have
important roles in living organisms. Recently, two bis-prenylated
derivatives, the chromenyl hydroquinone 1 and the related
quinone 2 (Figure 1), were isolated from Perithalia capillaris,
a seaweed found growing on the northern coasts of New Zealand
by Perry and co-workers.4 Despite their relative simplicity, these
substances are novel structures, and both display antiproliferative
activity in human leukemia cells. 2-(3′-Methylbut-2′-enyl)-5-
(2′-methylbut-3′-en-2′-yl)-1,4-benzoquinone (2) is only the
second example of a naturally occurring bis-prenylated quinone,5
and it is the first example containing an inverse prenyl group.
These novel structures were envisaged to be accessible via
the Claisen rearrangement methodology previously used by
Results and Discussion
The synthesis of the advanced intermediate 3 was relatively
straightforward. The monoacetate 4 of hydroquinone9 was
alkylated with dimethylpropargyl chloride, using a copper-
mediated coupling,10 to form propargyl ether 5 (Scheme 2).
Deprotection of the acetate and alkylation of the resulting
phenol under standard conditions led to an efficient synthesis
of the prenylated alkyne intermediate 3 (Scheme 2). The
literature contains many examples of Claisen rearrangements
involving both dimethylpropargyl and dimethylallyl (prenyl)
groups;11-13 however, to our knowledge, this is the first
instance of rearrangement of both groups in the same
(1) Thomson, R. H. Naturally Occurring Quinones, 2nd ed.; Academic Press:
London, UK, 1971.
(2) Thomson, R. H. Naturally Occurring Quinones III. Recent adVances, 3rd
ed.; Chapman and Hall: London, UK, 1987.
(3) Thomson, R. H. Naturally Occurring Quinones IV. Recent adVances, 4th
ed.; Blackie: London, UK, 1997.
(4) Sansom, C. E.; Larsen, L.; Perry, N. B.; Berridge, M. V.; Chia, E. W.;
Harper, J. L.; Webb, V. L. J. Nat. Prod. 2007, 70, 2042–2044.
(5) Permana, D.; Lajis, N. H.; Mackeen, M. M.; Ali, A. M.; Aimi, N.;
Kitajima, M.; Takayama, H. J. Nat. Prod. 2001, 64, 976–979.
(6) Davis, C. J.; Hurst, T. E.; Jacob, A. M.; Moody, C. J. J. Org. Chem.
2005, 70, 4414–4422.
(7) Jacob, A. M.; Moody, C. J. Tetrahedron Lett. 2005, 46, 8823–8825.
(8) McErlean, C. S. P.; Moody, C. J. J. Org. Chem. 2007, 72, 10298–10301.
(9) Lee, Y.-S.; Kim, B.-T.; Min, Y.-K.; Park, N.-K.; Kim, K.-H.; Kim, K.-
S. United States Patent 2204/0260114, 2004.
(10) Godfrey, J. D.; Mueller, R. H.; Sedergran, T. C.; Soundararajan, N.;
Colandrea, V. J. Tetrahedron Lett. 1994, 35, 6405–6408.
(11) Rhoads, S. H.; Raulins, N. R. Org. React. 1975, 22, 1–252.
6758 J. Org. Chem. 2008, 73, 6758–6762
10.1021/jo801057x CCC: $40.75 2008 American Chemical Society
Published on Web 08/06/2008

NoVel Prenylated Quinone DeriVatiVes from Perithalia capillaris
occurring at temperatures as low as 110 °C.16,17 In the event,
our predictions were well founded, and heating the Claisen
substrate 3 to 150 °C in DMF for 3 h in a microwave reactor
resulted in selective rearrangement of the propargyl ether to
give the desired chromene 6 in good yield. As expected, the
second Claisen rearrangement was less facile and required a
higher temperature. Also, it is known that heating γ,γ-
disubstituted allyl groups often results in formation of the
so-called abnormal Claisen product, whereby the initial
phenolic product undergoes further rearrangement.11,18 The
formation of the abnormal Claisen product can be prevented
by trapping the initial phenol with an acylating agent under
basic conditions,16,19 and hence the rearrangement of the
dimethylallyl ether 6 was carried out in N,N-diethylaniline
in the presence of acetic anhydride at 200 °C, and allowed
the isolation of the desired product as its acetate derivative
7 in modest yield. However, the reaction was complicated
by competing cleavage of the prenyl group at the high
temperature, a process observed previously,20,21 to give 2,2-
dimethyl-2H-chromen-6-yl acetate. Nevertheless, the desired
rearrangement proceeded with complete regioselectivity to
the less hindered 7-position, and none of the regioisomer was
FIGURE 1. Structures of 2,2-dimethyl-7-(2′-methylbut-3′-en-2′-yl)-
2H-chromen-6-ol (1) and 2-(3′-methylbut-2′-enyl)-5-(2′-methylbut-3′-
en-2′-yl)-1,4-benzoquinone (2), novel quinone derivatives from the New
Zealand brown alga Perithalia capillaris.
SCHEME 1. Retrosynthetic Analysis of 1 and 2 Revealing
Two Claisen Rearrangements
1
observed by H NMR spectroscopy. More conveniently, the
two sequential Claisen rearrangements can be effected in N,N-
diethylaniline in the same reaction vessel simply by initial
heating to 160 °C for 18 h, followed by addition of acetic
anhydride and raising the temperature to 200 °C for a
prolonged period. This gave the chromenyl acetate 7 in 38%
yield (Scheme 2), which was again accompanied by the
product from cleavage of the prenyl group (10% yield).
Although the reaction times for the conversion of 3 into 7
could be shortened under microwave irradiation, the reaction
was lower yielding and less clean. Finally, the synthesis was
completed by deprotection of the acetate to give 2,2-dimethyl-
7-(2′-methylbut-3′-en-2′-yl)-2H-chromen-6-ol (1), whose spec-
troscopic properties matched those of the natural product.4
It was originally planned to use the same intermediate 3 to
access the second natural product, the quinone 2, but attempts
to hydrogenate the alkyne to the corresponding alkene over
quinoline-poisoned Lindlar’s catalyst resulted in recovery of the
alkyne. However, the Lindlar hydrogenation of acetate 5
proceeded smoothly to give the allyl ether 8. Deprotection of
the acetate group and alkylation with dimethylallyl bromide gave
the required precursor 9 for the 2-fold Claisen rearrangement
(Scheme 3). As in the case of substrate 3 we required the two
Claisen rearrangements to occur sequentially, with the second
one proceeding regioselectively. In this case, there was some
precedent to suggest that owing to the gem-dimethyl effect an
inverted prenyl ether (ArOCMe2CHdCH2) would rearrange in
preference to a prenyl ether (ArOCH2CHdCMe2), presumably
due to relief of steric compression in the transition state.22 This
indeed proved to be the case, and heating the bis-allyl ether 9
to 160 °C resulted in a selective Claisen rearrangement to give
SCHEME 2. Synthesis of 2,2-Dimethyl-7-(2′-methylbut-3′-
en-2′-yl)-2H-chromen-6-ol (1)
substrate. Notwithstanding the report that inverted prenyl
ethers (ArOCMe2CHdCH2) undergo Claisen rearrangement
in preference to their propargyl counterparts (ArOCMe2Ct
CH),14 we reasoned that in our case the positioning of the
two methyl groups on the terminus of the alkene would favor
the Claisen rearrangement of the dimethylpropargyl group.
Support for this view comes from detailed kinetic studies
that show a significant rate enhancement in the rearrangement
of aryl propargyl ethers due to the gem-dimethyl group,15
and the fact there are examples of such rearrangements
(16) Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1984, 1333–1337.
(17) Kolokythas, G.; Kostakis, I. K.; Pouli, N.; Marakos, P.; Kletsas, D.;
Pratsinis, H. Bioorg. Med. Chem. 2003, 11, 4591–4598.
(18) Lauer, W. M.; Filbert, W. F. J. Am. Chem. Soc. 1936, 58, 1388–1392.
(19) Karanewsky, D. S.; Kishi, Y. J. Org. Chem. 1976, 41, 3026–3030.
(20) Daskiewicz, J. B.; Depeint, F.; Viornery, L.; Bayet, C.; Comte.Sarrazin,
G.; Comte, G.; Gee, J. M.; Johnson, I. T.; Ndjoko, K.; Hostettmann, K.; Barron,
D. J. Med. Chem. 2005, 48, 2790–2804.
(12) Bennett, G. B. Synthesis 1977, 589–606.
(13) Castro, A. M. M. Chem. ReV. 2004, 104, 2939–3002.
(14) Tisdale, E. J.; Vong, B. G.; Li, H. M.; Kim, S. H.; Chowdhury, C.;
Theodorakis, E. A. Tetrahedron 2003, 59, 6873–6887.
(21) Ito, F.; Fusegi, K.; Kumamoto, T.; Ishikawa, T. Synthesis 2007, 1785–
1796.
(22) Murray, R. D. H.; Ballantyne, M. M.; Hogg, T. C.; McCabe, P. H.
Tetrahedron 1975, 31, 2960–2965.
(15) Harfenist, M.; Thom, E. J. Org. Chem. 1972, 37, 841–848.
J. Org. Chem. Vol. 73, No. 17, 2008 6759

Coombes and Moody
SCHEME 3. Synthesis of 2-(3′-Methylbut-2′-enyl)-5-(2′-me-
thylbut-3′-en-2′-yl)-1,4-benzoquinone (2)
(4.51 g, 80%); mp 35.5-37.5 °C; νmax (CHCl3)/cm-1 3305, 3011,
2992, 1755, 1501, 1370, 1191, 1136, 1014; δH (400 MHz; CDCl3)
7.21 (2H, d, J ) 9.1 Hz), 7.00 (2H, d, J ) 9.1 Hz), 2.57 (1H, s),
2.29 (3H, s), 1.64 (6H, s); δC (100 MHz; CDCl3) 169.6 (C), 153.0
(C), 146.0 (C), 122.3 (CH), 121.7 (CH), 85.9 (C), 74.0 (CH), 72.7
(C), 29.5 (Me), 21.1 (Me). (Found: M + Na+, 241.0847. C13H14O3
+ Na+ requires 241.0835.) (Found: C, 71.7; H, 6.5. C13H14O3
requires C, 71.5; H, 6.5.)
4-(2′-Methylbut-3′-yn-2′-yloxy)phenol. To a stirred solution of
4-(2′-methylbut-3′-yn-2′-yloxy)phenyl acetate (5) (1.50 g, 6.87
mmol) in methanol (35 mL) at room temperature was added
potassium carbonate (1.14 g, 8.25 mmol). The reaction mixture was
stirred for 30 min, water was added (60 mL), and the reaction
mixture was acidified to pH 3-4 with hydrochloric acid (2 M).
The reaction mixture was concentrated under reduced pressure to
60 mL and extracted with ether (3 × 150 mL). The combined
organic extracts were washed with water (3 × 200 mL), dried
(MgSO4), and concentrated under reduced pressure to yield the title
compound as an off-white powder (1.20 g, 99%); mp 125-127 °C
(lit.23 mp 132-134 °C); νmax (CHCl3)/cm-1 3600, 3305, 2992, 2939,
1506, 1178, 1137; δH (400 MHz; CDCl3) 7.08 (2H, d, J ) 9.0
Hz), 6.75 (2H, d, J ) 9.0 Hz), 4.74 (1H, s), 2.53 (1H, s), 1.60 (6H,
s); δC (100 MHz; CDCl3) 151.7 (C), 148.9 (C), 123.9 (CH), 115.3
(CH), 86.3 (C), 73.6 (CH), 73.1 (C), 29.5 (Me). (Found: M + H+,
177.0899. C11H12O2 + H+ requires 177.0910.) (Found: C, 74.7;
H, 6.8. C11H12O2 requires C, 75.0; H, 6.9.)
phenol 10 in good yield. As before, the second Claisen
rearrangement required a higher temperature, and was again
conducted in the presence of acetic anhydride to avoid the
formation of abnormal rearrangement products. Again this was
conducted in a one-pot procedure by heating the bis-allyl ether
in N,N-diethylaniline to 160 °C for 3 h, followed by addition
of acetic anhydride and prolonged heating at 200 °C, although
in this case no loss of the prenyl group was observed. This gave
the hydroquinone diacetate 11 in 58% yield with no evidence
for the formation of the regioisomeric Claisen rearrangement
product (Scheme 3). The reaction time could be shortened
considerably by conducting the reaction under microwave
irradiation. Treatment of 11 with an excess of lithium aluminum
hydride cleaved both acetates, and the resulting hydroquinone
underwent oxidation to give 2-(3′-methylbut-2′-enyl)-5-(2′-
methylbut-3′-en-2′-yl)-1,4-benzoquinone (2), whose spectro-
scopic data matched those of the natural product.4
1-(3′-Methylbut-2′-enyloxy)-4-(2′-methylbut-3′-yn-2′-yloxy)ben-
zene, 3. To a stirred solution of 4-(2′-methylbut-3′-yn-2′-yloxy)phe-
nol (1.10 g, 6.24 mmol) in DMF (31 mL) under argon at 0 °C was
added sodium hydride (60% dispersion in mineral oils, 275 mg,
6.87 mmol) portionwise. After stirring for 5 min, light was excluded
from the reaction and 3,3-dimethylallyl bromide (0.87 mL, 7.49
mmol) was added dropwise. The reaction mixture was warmed to
room temperature and stirred for 3 h. Saturated ammonium chloride
solution (50 mL) was added and the mixture was extracted with
ether (3 × 100 mL). The combined organic extracts were washed
with water (4 × 100 mL), dried (MgSO4), and concentrated under
reduced pressure to yield the title compound as a yellow oil (1.55
g, 100%), which was used without further purification; νmax
(CHCl3)/cm-1 3305, 3011, 2990, 2936, 2871, 1676 (w), 1504, 1466,
1448, 1383, 1364, 1287, 1138; δH (400 MHz; CDCl3) 7.12 (2H, d,
J ) 9.1 Hz), 6.83 (2H, d, J ) 9.1 Hz), 5.51 (1H, m), 4.48 (2H, d,
J ) 6.7 Hz), 2.53 (1H, s), 1.81 (3H, s), 1.75 (3H, s), 1.61 (6H, s);
δC (100 MHz; CDCl3) 155.1 (C), 148.8 (C), 138.0 (C), 123.6 (CH),
119.8 (CH), 114.6 (CH), 86.4 (C), 73.5 (CH), 72.9 (C), 65.0 (CH2),
29.5 (Me), 25.8 (Me), 18.2 (Me); m/z (ESI) 267 ([M + Na]+, 73%),
245/246 ([M + H]+, 83/15), 234 (29), 200 (42), 189 (35), 177 (69).
(Found: M + H+, 245.1524. C16H20O2 + H+ requires 245.1536.)
(Found: C, 78.8; H, 8.6. C16H20O2 requires C, 78.7; H, 8.3.)
2,2-Dimethyl-6-(3′-methylbut-2′-enyloxy)-2H-chromene, 6. A
stirred solution of 1-(3′-methylbut-2′-enyloxy)-4-(2′-methylbut-3′-
yn-2′-yloxy)benzene (3) (50 mg, 0.20 mmol) in DMF (5 mL) in a
sealed tube was subjected to microwave irradiation (300 W) at 150
°C for 3 h. Water (25 mL) was added and the mixture was extracted
with ethyl acetate (3 × 100 mL). The combined organic extracts
were then washed with water (4 × 100 mL), dried (MgSO4), and
concentrated under reduced pressure and the residue was subjected
to flash chromatography with dichloromethane and light petroleum
(1:9) to yield the title compound as a yellow oil (36 mg, 72%);
In summary, we have described the first syntheses of two
unusual bis-prenylated marine natural products using routes that
demonstrate both high chemoselectivity and regioselectivity in
the key Claisen rearrangement steps.
Experimental Section
4-(2′-Methylbut-3′-yn-2′-yloxy)phenyl Acetate, 5. To a stirred
solution of 4-acetoxyphenol (4) (5.0 g, 32.9 mmol), prepared by
the literature method,9 in anhydrous acetonitrile (165 mL) under
argon at 0 °C was added copper(II) chloride dihydrate (5.6 mg,
0.032 mmol) followed by DBU (5.0 mL, 32.9 mmol) dropwise.
To this mixture was added 3-chloro-3-methyl-1-butyne (3.32 mL,
29.6 mmol) dropwise, and the reaction mixture was stirred at 0 °C
for 18 h. The reaction mixture was then concentrated under reduced
pressure. The residue was partitioned between toluene (300 mL)
and water (200 mL), and the water was extracted with toluene (3
× 100 mL). The combined organic extracts were washed with
hydrochloric acid (2 M; 3 × 300 mL), aqueous sodium hydroxide
(2 M; 2 × 300 mL), saturated sodium hydrogen carbonate (200
mL), and brine (200 mL). The organic layer was dried (MgSO4)
and concentrated under reduced pressure and the residue was
subjected to flash chromatography with use of ether and light
petroleum (5:95) to yield the title compound as a crystalline solid
ν
max (CHCl3)/cm-1 3011, 2979, 2928, 2858, 1576, 1491, 1439, 1384,
1362, 1305, 1258, 1167, 1120, 1105, 1010, 959; δH (400 MHz;
CDCl3) 6.73-6.67 (2H, m), 6.58 (1H, d, J ) 2.1 Hz), 6.29 (1H, d,
J ) 9.8 Hz), 5.64 (1H, d, J ) 9.8 Hz), 5.49 (1H, m), 4.45 (2H, d,
J ) 6.7 Hz), 1.80 (3H, s), 1.74 (3H, s), 1.42 (6H, s); δC (100 MHz;
CDCl3) 152.9 (C), 146.7 (C), 138.0 (C), 131.6 (CH), 122.4 (CH),
121.8 (C), 119.9 (CH), 116.7 (CH), 115.0 (CH), 112.3 (CH), 75.7
(23) Brown, P. E.; Lewis, R. A.; Waring, M. A. J. Chem. Soc., Perkin Trans.
1 1990, 2979–2988.
6760 J. Org. Chem. Vol. 73, No. 17, 2008

NoVel Prenylated Quinone DeriVatiVes from Perithalia capillaris
(C), 65.3 (CH2), 27.6 (Me), 25.8 (Me), 18.2 (Me); m/z (ESI) 267/
268 ([M + Na]+, 100/19%), 245 ([M + H]+, 38), 243 (18), 227
(24), 223 (15), 207 (11), 198 (47), 177 (72), 175 (51), 149 (15).
(Found: M + Na+, 267.1359. C16H20O2 + Na+ requires 267.1356.)
(Found: C, 78.8; H, 8.3. C16H20O2 requires C, 78.7; H, 8.3.)
2,2-Dimethyl-7-(2′-methylbut-3′-en-2′-yl)-2H-chromen-6-yl Ac-
etate, 7. A stirred solution of 1-(3′-methylbut-2′-enyloxy)-4-(2′-
methylbut-3′-yn-2′-yloxy)benzene (3) (500 mg, 2.05 mmol) in N,N-
diethylaniline (15 mL) under argon was heated to 160 °C and stirred
at this temperature for 18 h, after which complete disappearance
of starting material was observed. Acetic anhydride (15 mL) was
added and the temperature of the mixture was raised to 200 °C.
The mixture was stirred at this higher temperature for 6 days, cooled
to room temperature, and poured into ice-water. After being stirred
for 15 min, the mixture was extracted with ether (3 × 150 mL)
and the combined organic extracts were further washed with water
(4 × 150 mL), hydrochloric acid (2 M; 4 × 150 mL), water (150
mL), saturated sodium hydrogen carbonate (4 × 150 mL), and brine
(150 mL) and dried (MgSO4). The filtrate was concentrated under
reduced pressure and the residue subjected to flash chromatography
with ether and light petroleum (5:95) to give the title compound
and a degradation product in a 4:1 ratio (429 mg). The products
were then separated by using HPLC (gradient increase up to 55:45
acetonitrile and water) to yield the title compound as a colorless
solid (225 mg, 38%); mp 73-75 °C; νmax (CHCl3)/cm-1 3011, 2976,
2935, 1750, 1640, 1621, 1495, 1465, 1421, 1361, 1188, 1157, 1112,
1050, 1010; δH (400 MHz; CDCl3) 6.81 (1H, s), 6.61 (1H, s), 6.24
(1H, d, J ) 9.7 Hz), 5.97 (1H, dd, J ) 17.4, 10.6 Hz), 5.59 (1H,
d, J ) 9.7 Hz), 5.00 (1H, dd, J ) 17.4, 1.5 Hz), 4.95 (1H, dd, J )
10.6, 1.5 Hz), 2.18 (3H, s), 1.44 (6H, s), 1.40 (6H, s); δC (100
MHz; CDCl3) 169.8 (C), 150.1 (C), 147.0 (CH), 142.3 (C), 140.1
(C), 130.8 (CH), 121.3 (CH), 121.2 (CH), 119.6 (C), 114.9 (CH),
109.8 (CH2), 76.4 (C), 40.2 (C), 28.2 (Me), 27.5 (Me), 21.7 (Me);
m/z (ESI) 309/310 ([M + Na]+, 100/18), 304 (M + NH4+, 11),
287/288 ([M + H+], 34/7), 251 (10), 250 (13), 245 (11), 227 (6),
223 (6), 219 (7), 177 (7). (Found: M + Na+, 309.1447. C18H22O3
+ Na+ requires 309.1461.) (Found: C, 75.6; H, 7.7. C18H22O3
requires C, 75.5; H, 7.7.)
evacuated and stirred under a hydrogen atmosphere for 3.7 h. The
mixture was then filtered through Celite, washed with ethyl acetate
(3 × 100 mL), and concentrated under reduced pressure. The
residue was then subjected to flash chromatography with ether and
light petroleum (1:9) to yield the title compound as a pale yellow
oil (602 mg, 99%); νmax (CHCl3)/cm-1 3011, 2985, 2933, 1749,
1501, 1415, 1370, 1192, 1129, 1013; δH (400 MHz; CDCl3)
7.00-6.92 (4H, m), 6.12 (1H, dd, J ) 17.7, 10.8 Hz), 5.17 (1H,
dd, J ) 17.7, 1.0 Hz), 5.14 (1H, dd, J ) 10.8, 1.0 Hz), 2.28 (3H,
s), 1.44 (6H, s); δC (100 MHz; CDCl3) 169.7 (C), 153.5 (C), 145.4
(C), 144.1 (CH), 122.4 (CH), 121.6 (CH), 113.6 (CH2), 79.7 (C),
26.9 (Me), 21.1 (Me); m/z (ESI) 243/244 ([M + Na]+, 100/14),
153 (C8H9O3, 21). (Found: M + Na+, 243.0998. C13H16O3 + Na+
requires 243.0992.) (Found: C, 71.1; H, 7.4. C13H16O3 requires C,
70.9; H, 7.3.)
4-(2′-Methylbut-3′-en-2′-yloxy)phenol. To a stirred solution of
4-(2′-methylbut-3′-en-2′-yloxy)phenyl acetate (8) (400 mg, 1.8
mmol) in methanol (9 mL) under argon at 0 °C was added
potassium carbonate (301 mg, 2.2 mmol). After the solution was
stirred for 10 min, water was added (20 mL) and the reaction
mixture was acidified to pH 3-4 with hydrochloric acid (2 M).
The reaction mixture was then concentrated under reduced pressure
to 20 mL and extracted with ether (3 × 50 mL). The combined
organic extracts were then washed with water (3 × 100 mL), dried
(MgSO4), and concentrated under reduced pressure and the residue
was subjected to flash chromatography with ether and light
petroleum (2:8) to yield the title compound as a yellow crystalline
solid (230 mg, 71%); mp 72-75 °C (lit.24 mp 34-37 °C); νmax
(CHCl3)/cm-1 3600, 3011, 2984, 1506, 1177, 1129; δH (400 MHz;
CDCl3) 6.86 (2H, d, J ) 9.0 Hz), 6.68 (2H, d, J ) 9.0 Hz), 6.11
(1H, dd, J ) 17.5, 10.8 Hz), 5.30 (1H, br s), 5.15-5.09 (2H, m),
1.40 (6H, s); δC (100 MHz; CDCl3) 151.4 (C), 148.7 (C), 144.0
(CH), 124.2 (CH), 115.3 (CH), 113.6 (CH2), 79.7 (C), 26.6 (Me);
m/z (ESI) 201 (27), 171 (11), 159 (14), 157 (8), 149 (17). (Found:
M + Na+, 201.0897. C11H14O2 + Na+ requires 201.0886.) (Found:
C, 74.4; H, 8.0. C11H14O2 requires C, 74.1; H, 7.9.)
1-(3′-Methylbut-2′-enyloxy)-4-(2′-methylbut-3′-en-2′-yloxy)ben-
zene, 9. To a stirred solution of 4-(2′-methylbut-3′-en-2′-yloxy)phe-
nol (200 mg, 1.12 mmol) in DMF (6 mL) under argon at 0 °C was
added sodium hydride (60% dispersion in mineral oils, 49 mg, 1.23
mmol) portionwise. After 5 min of stirring, light was excluded from
the reaction and 3,3-dimethylallyl bromide (0.16 mL, 1.35 mmol)
was added dropwise. The reaction mixture was then warmed to
room temperature and stirred for 1 h. Saturated ammonium chloride
solution (50 mL) was added and the mixture was extracted with
ether (3 × 50 mL). The combined organic extracts were further
washed with water (4 × 100 mL), dried (MgSO4), and concentrated
under reduced pressure to yield the title compound as a yellow oil
(280 mg, 100%) that was used without further purification; νmax
(CHCl3)/cm-1 3008, 2983, 2931, 2859, 1503, 1468, 1380, 1240,
1129, 1002; δH (400 MHz; CDCl3) 6.91 (2H, d, J ) 9.1 Hz), 6.78
(2H, d, J ) 9.1 Hz), 6.12 (1H, dd, J ) 17.5, 10.8 Hz), 5.50 (1H,
m), 5.13 (1H, dd, J ) 17.5, 0.9 Hz), 5.11 (1H, dd, J ) 10.8, 0.9
Hz), 4.46 (2H, d, J ) 6.7 Hz), 1.80 (3H, s), 1.74 (3H, s), 1.40 (6H,
s); δC (100 MHz; CDCl3) 154.6 (C), 149.1 (C), 144.3 (CH), 138.0
(C), 123.8 (CH), 119.9 (CH), 114.6 (CH), 113.4 (CH2), 79.3 (C),
65.1 (CH2), 26.7 (Me), 25.8 (Me), 18.2 (Me); m/z (ESI) 269/270
([M + Na]+, 100/17), 251 (23), 250 (21), 247/248 ([M + H]+,
39/7), 242 (9), 227 (16), 223 (13), 200/201 (48/7), 191 (16), 177
(7). (Found: M + Na+, 269.1502, C16H22O2 + Na+ requires
269.1512.)
The degradation product was identified as 2,2-dimethyl-2H-
chromen-6-yl acetate (43 mg, 10%); δH (400 MHz; CDCl3)
6.83-6.77 (1H, m), 6.77-6.71 (2H, m), 6.27 (1H, d, J ) 9.7 Hz),
5.64 (1H, d, J ) 9.7 Hz), 2.27 (3H, s), 1.43 (6H, s).
2,2-Dimethyl-7-(2′-methylbut-3′-en-2′-yl)-2H-chromen-6-ol, 1. To
a stirred solution of 2,2-dimethyl-7-(2′-methylbut-3′-en-2′-yl)-2H-
chromen-6-yl acetate (7) (30 mg, 0.11 mmol) in methanol (1 mL)
at room temperature was added potassium carbonate (18 mg, 0.13
mmol). After the reaction mixture had been stirred for 1 h, saturated
ammonium chloride was added (20 mL), the reaction mixture was
extracted with ethyl acetate (3 × 20 mL), and the combined organic
extracts were washed with water (4 × 20 mL), dried (MgSO4),
and concentrated under reduced pressure to give a green solid (37
mg). Trituration with light petroleum gave the title compound as a
colorless crystalline solid (16 mg, 63%); mp 89-91 °C (lit.4 yellow
oil); νmax (CHCl3)/cm-1 3485 (br), 2976, 2934, 1640, 1494, 1437,
1363, 1322, 1264, 1253, 1163, 1112, 949, 929, 909, 881; δH (400
MHz; CDCl3) 6.72 (1H, s), 6.51 (1H, s), 6.26 (1H, d, J ) 9.8 Hz),
6.17 (1H, dd, J ) 17.8, 10.5 Hz), 5.60 (1H, d, J ) 9.8 Hz), 5.42
(1H, s), 5.33 (1H, d, J ) 17.8 Hz), 5.29 (1H, dd, J ) 10.5, 0.9
Hz), 1.43 (6H, s), 1.42 (6H, s); δC (100 MHz; CDCl3) 148.4 (C),
147.6 (CH), 146.4 (C), 132.9 (C), 131.1 (CH), 121.8 (CH), 120.6
(C), 115.0 (CH), 113.9 (CH), 113.4 (CH2), 75.8 (C), 40.4 (C), 27.8
(Me), 26.9 (Me); m/z (ESI) 267/268 ([M + Na]+, 100/24), 251
(45), 250 (21), 245/246 (55/10), 242 (15), 227 (29), 223 (26), 217
(9), 178 (10), 177 (12), 164 (23). (Found: M + Na+, 267.1360.
C16H20O2 + Na+ requires 267.1356.)
2-(3′-Methylbut-2′-enyl)-4-(3′-methylbut-2′-enyloxy)phenol, 10.
A solution of 1-(3′-methylbut-2′-enyloxy)-4-(2′-methylbut-3′-en-
2′-yloxy)benzene (9) (60 mg, 0.24 mmol) in N,N-diethylaniline (2
mL) was stirred under argon at 160 °C for 2 h. After this time, the
reaction mixture was cooled, poured into ice-water, and stirred
4-(2′-Methylbut-3′-en-2′-yloxy)phenyl Acetate, 8. To a solution
of 4-(2′-methylbut-3′-yn-2′-yloxy)phenyl acetate (5) (600 mg, 2.75
mmol) in ethyl acetate (43 mL) was added Lindlar catalyst (99
mg) and quinoline (2.8 mL). The reaction mixture was then
(24) Lantero, D. R.; Welker, M. E. J. Organomet. Chem. 2002, 656, 217–
227.
J. Org. Chem. Vol. 73, No. 17, 2008 6761

Coombes and Moody
for 15 min. The aqueous was extracted with ether (3 × 50 mL)
and the combined organic extracts were further washed with water
(4 × 50 mL), hydrochloric acid (2 M; 3 × 50 mL), water (50 mL),
saturated sodium hydrogen carbonate (50 mL), and brine (50 mL)
and dried (MgSO4). The filtrate was concentrated under reduced
pressure and the residue subjected to flash chromatography with
ether and light petroleum (1:9) to yield the title compound as a
yellow oil (44 mg, 73%), νmax (CHCl3)/cm-1 3603, 3469 (br), 3011,
2976, 2917, 1496, 1440, 1383, 1174; δH (400 MHz; CDCl3)
6.75-6.65 (3H, m), 5.50 (1H, m), 5.32 (1H, m), 4.83 (1H, br s),
4.45 (2H, d, J ) 6.8 Hz), 3.33 (2H, d, J ) 7.3 Hz), 1.80 (3H, s),
1.78 (6H, s), 1.74 (3H, s); δC (100 MHz; CDCl3) 152.9 (C), 148.1
(C), 137.9 (C), 134.7 (C), 128.0 (C), 121.6 (CH), 120.0 (CH), 116.6
(CH), 116.1 (CH), 112.8 (CH), 65.3 (CH2), 29.8 (CH2), 25.79 (Me),
25.76 (Me), 18.1 (Me), 17.8 (Me); m/z (ESI) 269/270 ([M + Na]+,
100/17), 251 (9), 250 (8), 247/248 (19/3), 200 (11), 191 (9), 177
(4). (Found: M + Na+, 269.1501. C16H22O2 + Na+ requires
269.1512.)
(b) A stirred solution of 1-(3′-methylbut-2′-enyloxy)-4-(2′-
methylbut-3′-en-2′-yloxy)benzene (9) (36 mg, 0.15 mmol) in N,N-
diethylaniline (1 mL) in a sealed tube was subjected to microwave
irradiation (300 W) at 160 °C for 1 h. Acetic anhydride was added
(1 mL) and the reaction mixture was again stirred and subjected to
microwave irradiation at 200 °C for 17 h. The reaction mixture
was cooled, poured into ice-water, and stirred for 15 min. The
aqueous mixture was extracted with ether (3 × 50 mL) and the
combined organic extracts were washed with water (4 × 50 mL),
hydrochloric acid (2 M; 3 × 100 mL), water (100 mL), saturated
sodium hydrogen carbonate (100 mL), and brine (100 mL) and dried
(MgSO4). The filtrate was concentrated under reduced pressure and
the residue subjected to flash chromatography with ether and light
petroleum (1:9) to yield the title compound as a yellow solid (28
mg, 60%), identical with the material from the previous experiment.
2-(3′-Methylbut-2′-enyl)-5-(2′-methylbut-3′-en-2′-yl)-1,4-benzo-
quinone, 2. To a stirred solution of lithium aluminum hydride (5
mg, 0.12 mmol) in anhydrous THF (1 mL) under argon at 0 °C
was added 2-(3′-methylbut-2′-enyl)-5-(2′-methylbut-3′-en-2′-yl)-1,4-
hydroquinone diacetate (11) (20 mg, 0.06 mmol) dissolved in
anhydrous THF (1 mL). After 3 h only the monoacetate was
observed by TLC and mass spectrometry, more LiAlH4 was added
(20 mg), and the reaction mixture was warmed to room temperature
and stirred under an oxygen atmosphere overnight. Ethyl acetate
(10 mL) was added to destroy the unreacted LiAlH4, the mixture
was diluted with distilled water (15 mL), and the organic solvents
were removed in vacuo. The aqueous residue was extracted with
dichloromethane (4 × 10 mL), and the combined organic extracts
were further washed with water (20 mL) and brine (2 × 20 mL)
and dried (MgSO4). The filtrate was concentrated under reduced
pressure and the residue subjected to flash chromatography with
ether and light petroleum (1:9) to yield the title compound as a
yellow crystalline solid (8 mg, 54%); mp 27.5-29 °C (lit.,4 yellow
oil); νmax (CHCl3)/cm-1 3011, 2971, 2930, 1652, 1599, 1379, 1339,
1240, 916; δH (400 MHz; CDCl3) 6.61 (1H, s), 6.43 (1H, t, J )
1.8 Hz), 6.08 (1H, dd, J ) 17.5, 10.7 Hz), 5.14 (1H, m), 5.05 (1H,
dd, J ) 10.7, 0.8 Hz), 5.00 (1H, dd, J ) 17.5, 0.8 Hz), 3.09 (2H,
d, J ) 7.4 Hz), 1.76 (3H, d, J ) 0.9 Hz), 1.64 (3H, s), 1.38 (6H,
s); δC (100 MHz; CDCl3) 188.6 (C), 187.6 (C), 154.2 (C), 146.9
(C), 145.3 (CH), 136.2 (C), 134.2 (CH), 132.3 (CH), 118.0 (CH),
112.7 (CH2), 40.4 (C), 26.8 (Me and CH2), 25.7 (Me), 17.8 (Me);
m/z (ESI) 267/268 ([M + Na]+, 100/18), 251 (82), 245 ([M + H]+,
41), 227 (98), 223 (46), 217 (15), 185 (18), 171 (47), 158 (26),
157 (31), 149 (23), 141 (14). (Found: M + Na+, 267.1363. C16H20O2
+ Na+ requires 267.1356.)
2-(3′-Methylbut-2′-enyl)-5-(2′-methylbut-3′-en-2′-yl)-1,4-hydro-
quinone Diacetate, 11. (a) A stirred solution of 1-(3′-methylbut-
2′-enyloxy)-4-(2′-methylbut-3′-en-2′-yloxy)benzene (9) (100 mg,
0.41 mmol) in N,N-diethylaniline (4 mL) under argon was heated
to 160 °C and stirred at this temperature for 3 h, when complete
disappearance of starting material was observed. Acetic anhydride
(4 mL) was added and the temperature of the reaction was raised
to 200 °C. The reaction was then stirred at this higher temperature
for 10 days, after which time the reaction mixture was cooled to
room temperature and poured into ice-water. After being stirred
for 15 min, the mixture was extracted with diethyl ether (3 × 50
mL) and the combined organic extracts were further washed with
water (4 × 50 mL), hydrochloric acid (2 M; 8 × 50 mL), water
(50 mL), sodium hydrogen carbonate (50 mL), and brine (50 mL)
and dried (MgSO4). The filtrate was concentrated under reduced
pressure and the residue subjected to flash chromatography with
ether and light petroleum (1:9) to yield the title compound as a
yellow solid (78 mg, 58%); mp 57-58 °C, νmax (CHCl3)/cm-1 3011,
2973, 2933, 1758, 1496, 1370, 1160; δH (400 MHz; CDCl3) 7.02
(1H, s), 6.83 (1H, s), 5.97 (1H, dd, J ) 17.5, 10.6 Hz), 5.21 (1H,
m), 5.01 (1H, dd, J ) 17.5, 1.2 Hz), 4.97 (1H, dd, J ) 10.6, 1.2
Hz), 3.19 (2H, d, J ) 7.2 Hz), 2.31 (3H, s), 2.20 (3H, s), 1.74 (3H,
d, J ) 1.0 Hz), 1.68 (3H, s), 1.41 (6H, s); δC (100 MHz; CDCl3)
169.4 (C), 169.3 (C), 146.8 (CH), 146.5 (C), 146.1 (C), 138.2 (C),
133.6 (C), 132.5 (C), 125.1 (CH), 121.1 (CH), 121.0 (CH), 110.1
(CH2), 40.0 (C), 28.3 (CH2), 27.4 (Me), 25.7 (Me), 21.7 (Me), 20.9
(Me), 17.8 (Me); m/z (ESI) 353/354 ([M + Na]+, 100/20), 348/
349 ([M + NH4]+, 90/18), 331 ([M + H]+, 3), 289 (C18H24O3 +
H]+, 5). (Found: M + Na+, 353.1715. C20H26O4 + Na+ requires
353.1723.) (Found: C, 72.5; H, 7.9. C20H26O4 requires C, 72.7; H,
7.9.)
Supporting Information Available: General experimental
details and copies of 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO801057X
6762 J. Org. Chem. Vol. 73, No. 17, 2008