Formal Radical Cyclization onto Benzene Rings: A General Method and Its Use in the Synthesis of ent-Nocardione A

Article abstract of DOI:10.1021/jo030364k

An indirect method is described for effecting radical cyclization onto a benzene ring. Cross-conjugated dienones 6, which are readily prepared from phenols, undergo radical cyclization (6 → 7 → 8), and the products (8) are easily aromatized. The method ha

Full text of DOI:10.1021/jo030364k

F or m a l Ra d ica l Cycliza tion on to Ben zen e Rin gs: A Gen er a l
Meth od a n d Its Use in th e Syn th esis of en t-Noca r d ion e A
Derrick L. J . Clive,* Stephen P. Fletcher, and Dazhan Liu
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
derrick.clive@ualberta.ca
Received November 26, 2003
An indirect method is described for effecting radical cyclization onto a benzene ring. Cross-conjugated
dienones 6, which are readily prepared from phenols, undergo radical cyclization (6 f 7 f 8), and
the products (8) are easily aromatized. The method has been applied to the synthesis of
ent-nocardione A (21).
SCHEME 1
In tr od u ction
While radical cyclization onto double bonds is now a
standard synthetic method, related closures onto aro-
matic rings represent a much less developed area. Radi-
cal cyclization onto certain heterocycles is reasonably
well-known,1 and typical examples are shown in Scheme
1. In contrast, the corresponding closure onto benzene
rings (see Scheme 2) is usually a difficult process, and is
not well understood.1b,2 Such reactions can be achieved,
however, by application of xanthate-based methods, as
illustrated in Scheme 3,3-5 but these often involve quite
harsh procedures, and the development of a milder pro-
cess that operates under standard free radical cyclization
conditions (R3SnH, catalytic AIBN, refluxing PhH) would
undoubtedly be useful.
SCHEME 2
We report an indirect method for achieving the same
overall transformation as that shown in Scheme 2. Our
SCHEME 3
(1) For typical examples of cyclization onto heteroaromatic rings,
see: (a) Murphy, J . A.; Sherburn, M. S. Tetrahedron 1991, 47, 4077-
4088. (b) Beckwith, A. L. J .; Storey, J . M. D. J . Chem. Soc., Chem.
Commun. 1995, 977-978. (c) Moody, C. J .; Norton, C. L. J . Chem. Soc.,
Perkin Trans. 1 1997, 2639-2643. (d) Aldabbagh, F.; Bowman, W. R.;
Mann, E.; Slawin, A. M. Z. Tetrahedron 1999, 55, 8111-8128. (e)
Marco-Contelles, J .; Rodr´ıguez-Ferna´ndez, M. Tetrahedron Lett. 2000,
41, 381-384. (f) Escolano, C.; J ones, K. Tetrahedron Lett. 2000, 41,
8951-8955. (g) Miranda, L. D.; Cruz-Almanza, R.; Pavo´n, M.; Romero,
Y.; Muchowski, J . M. Tetrahedron Lett. 2000, 41, 10181-10184. (h)
Bowman, W. R.; Fletcher, A. J .; Potts, G. B. S. J . Chem. Soc., Perkin
Trans. 1 2002, 2747-2762. (i) Allin, S. M.; Barton, W. R. S.; Bowman,
W. R.; McInally, T. Tetrahedron Lett. 2002, 43, 4191-4193. (j) Gagosz,
F.; Zard, S. Z. Org. Lett. 2002, 4, 4345-4348. (k) Du, W.; Curran, D.
P. Org. Lett. 2003, 5, 1765-1768. (l) Flanagan, S. R.; Harrowven, D.
C.; Bradley, M. Tetrahedron Lett. 2003, 44, 1795-1798.
approach6,7 (Scheme 4) involves converting the starting
benzenoid compound into a cross-conjugated ketone (4
f 6) carrying an alkoxy substituent terminating in a
homolyzable group. The ketone readily undergoes radical
cyclization,8 and the product (8) is easily rearomatized
(8 f 9), so that the overall result is similar to that
summarized in Scheme 2.
(2) (a) Crich, D.; Hwang, J .-T. J . Org. Chem. 1998, 63, 2765-2770.
(b) Cf.: Crich, D.; Sannigrahi, M. Tetrahedron 2002, 58, 3319-3322.
(3) (a) Axon, J .; Boiteau, L.; Boivin, J .; Forbes, J . E.; Zard, S. Z.
Tetrahedron Lett. 1994, 35, 1719-1722. (b) Liard, A.; Quiclet-Sire, B.;
Saicic, R.; Zard, S. Z. Tetrahedron Lett. 1997, 38, 1759-1762. (c)
Cholleton, N.; Zard, S. Z. Tetrahedron Lett. 1998, 39, 7295-7298. (d)
Hoang-Cong, X.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1999,
40, 2125-2126. (e) Ly, T.-M.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z.
Tetrahedron Lett. 1999, 40, 2533-2536. (f) Kaoudi, T.; Quiclet-Sire,
B.; Seguin, S.; Zard, S. Z. Angew. Chem., Int. Ed. 2000, 39, 731-733.
(g) Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. J . Chem. Soc., Chem.
Commun. 2002, 1692-1693. (h) Quiclet-Sire, B.; Zard, S. Z. J . Chem.
Soc., Chem. Commun. 2002, 2306-2307. (i) Zard, S. Z. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 672-685.
(5) For methods that do not involve xanthates, see: (a) Ishibashi,
H.; Nakamura, N.; Ito, K.; Kitayama, S.; Ikeda, M. Heterocycles 1990,
31, 1781-1784. (b) Curran, D. P.; Liu, H. J . Chem. Soc., Perkin Trans.
1 1994, 1377-1393. (c) Este´vez, J . C.; Villaverde, M. C.; Este´vez, R.
J .; Castedo, L. Tetrahedron 1994, 50, 2107-2114. (d) Rosa, A. M.; Lobo,
A. M.; Branco, P. S.; Prabhakar, S. Tetrahedron 1997, 53, 285-298.
(e) Bowman, W. R.; Mann, E.; Parr, J . J . Chem. Soc., Perkin Trans. 1
2000, 2991-2999. (f) Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D.
R. Tetrahedron Lett. 2002, 43, 3185-3187. (g) Fiumana, A.; J ones, K.
Tetrahedron Lett. 2000, 41, 4209-4211.
(6) Preliminary communication: Clive, D. L. J .; Fletcher, S. P.; Zhu,
M. J . Chem. Soc., Chem. Commun. 2003, 526-527.
(7) Preliminary communication: Clive, D. L. J .; Fletcher, S. P. J .
Chem. Soc., Chem. Commun. 2003, 2464-2465.
(8) Cf.: Villar, F.; Equey, O.; Renaud, P. Org. Lett. 2000, 2, 1061-
1064.
(4) For oxidative cyclizations initiated by radical formation from
â-dicarbonyl compounds, see: Snider, B. B. Chem. Rev. 1996, 96, 339-
363.
10.1021/jo030364k CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/17/2004
3282
J . Org. Chem. 2004, 69, 3282-3293

Formal Radical Cyclization onto Benzene Rings
TABLE 1.
SCHEME 4
The cross-conjugated ketones are available (Scheme 4)
by oxidation of p-methoxyphenols in the presence of an
excess of an R,ω-halo alcohol (5), which is used as solvent.
Alternatively, the starting phenol can carry a p-alkoxy
group already bearing a homolyzable substituent, and in
that case the oxidation is done in MeOH. Typical ex-
amples of these approaches are shown in Table 1. We
generally use PhI(OAc)2 (ca 1.1 equiv) as the oxidizing
agent, but have also used DDQ (see later, Scheme 6, 28
f 29).
The intermediate quinone ketals are sensitive to acid,
and so the oxidation must be done in the presence of
K2CO3 (ca. 2.2 equiv),9 and during chromatographic
purification, a small amount of Et3N should be added
to all solvents used. In some cases the oxidation is done
with iodo alcohols (Table 1, entries 1 and 2, right-hand
columns; Table 2, entry 3), but 4-iodobutanol could not
be used since it reacts with PhI(OAc)2. Generally, chloro
alcohols are satisfactory, and the resulting chlorides can
be converted into the corresponding iodides by heating
with anhydrous NaI; yields were better when this step
is done in DME rather than in acetone. In the prepara-
tion of 12a (Table 1), evaporation of excess of 4-chlorobu-
tanol (which produces THF and HCl10) was done in the
presence of solid K2CO3.
In those cases where a phenol, bearing an ω-haloalkoxy
group in the para position, is readily available (Table 1,
entries 5-7), then oxidation in MeOH is an alternative
route that is experimentally convenient, because the
excess of solvent is easily removed. Iodides 14a and 15a
were made by alkylating hydroquinone with the appro-
priate benzylic bromide (see the Experimental Section).
Chloride 17 was chosen as a starting material simply
because its preparation is straightforward. We noticed
that the oxidation of 17 to 17a is peculiar in that it does
not work well unless a trace of EtOAc is present. This
phenomenon was observed repeatedly in a series of
experiments in which the outcome was uniformly suc-
cessful when EtOAc was added, and unsuccessful when
it was omitted. However, we did not attempt to identify
the mechanistic basis of this intriguing observation.
The examples in Table 2 establish that the general
oxidation works satisfactorily when an additional meth-
a
b
PhI(OAc)2, K2CO3. 2-Chloroethanol. c Anhydrous NaI, ace-
tone, reflux. 2-Iodoethanol. e 3-Chloropropanol. f Not optimized,
since direct route from 4 was developed. 3-Iodopropanol. 4-
Chlorobutanol. 5-Chloropentanol. 1-(Bromomethyl)-2-iodoben-
zene, DMF, K2CO3. MeOH. 2-Bromomethyl-3-iodonaphthalene,
DMF, K2CO3. 2-Chloroethanol, HCl. Anhydrous NaI, DME,
reflux.
d
g
h
i
j
k
l
m
n
oxy substituent is present. A methyl group para to the
phenolic hydroxyl is also tolerated, although in the single
example of this type (entry 3), the yield was only 48%.
The radical cyclizations proceeded without incident (see
Tables 3 and 4) when dilute toluene solutions of stannane
(0.07-0.12 M) and initiator (0.005-0.011 M) were added
over 3-5 h to a hot (85 °C) solution (0.030-0.040 M) of
the substrate in the same solvent. We arbitrarily avoided
refluxing the solvent, and suspect, on the basis of a single
experiment, that our milder conditions give a better re-
sult. Yields were generally above 75%. It appears neces-
sary to use iodides in these reactions, as in two cases
where bromides were examined [the bromide correspond-
(9) Cf.: (a) Tamura, Y.; Yakura, T.; Haruta, J .; Kita, Y. J . Org.
Chem. 1987, 52, 3927-3903. (b) Fleck, A. E.; Hobart, J . A.; Morrow,
G. W. Synth. Commun. 1992, 22, 179-187.
(10) Heine, H. W.; Siegfried, W. J . Am. Chem. Soc. 1954, 76, 489-
490.
J . Org. Chem, Vol. 69, No. 10, 2004 3283

Clive et al.
TABLE 2.
TABLE 3.
a
2-Chloroethanol, PhI(OAc)2, K2CO3. b Anhydrous NaI, acetone,
reflux. c 3-Chloropropanol, PhI(OAc)2, K2CO3. 2-Iodoethanol,
d
PhI(OAc)2, K2CO3.
ing to 14b, and the bromide corresponding to 37 (see
Scheme 7)], cyclization did not occur (the 14b analog11)
or was a minor pathway (the 37 analog), and we suspect
that preferential reduction of the dienone system takes
place. Of all the iodides listed in Tables 3 and 4, only
13b failed to undergo radical cyclization.
The last step of the overall sequence is acid-catalyzed
aromatization, and in all the examples we examined the
methoxy group is expelled in preference to the hetero-
cyclic oxygen; in entry 3 of Table 4, where no methoxy
group is present, the heterocyclic ring opens. TsOH‚H2O
is usually satisfactory, but HCO2H and AcOH can also
be used (see 31 f 32), and yields for the aromatization
are generally above 87%. The crude products from the
radical cyclization can be used directly without purifica-
tion (Table 3, entry 1). The aromatization of 17c (Table
3) and 20b (Table 4) was initially problematic, and the
expected phenols could not be isolated. However, in situ
acetylation, achieved by acid treatment in the presence
of Ac2O, overcomes the problems and delivers the acetates
17d and 20c in 89% and 69% yield, respectively. The
aromatization of 18c and 19c was arbitrarily done in the
presence of 4 Å molecular sieves.
a
Bu3SnH, AIBN, PhMe, 85 °C, except for entry 1, where
Ph3SnH was used. TsOH, PhMe. c TsOH, acetone, CH2Cl2. T-
b
d
sOH, 4 Å molecular sieves, CH2Cl2. e TsOH, Ac2O.
always chromatographed in the presence of Et3N, but this
precaution was arbitrarily not taken for the examples in
Table 5.
Ma n ip u la tion of th e Ra d ica l Cycliza tion
P r od u cts befor e Ar om a tiza tion
As illustrated in Tables 3 and 4, our general process
affords phenols; it can, however, be modified easily so as
to produce products with hydrogen, alkyl, or aryl groups
in place of the normal phenolic hydroxyl.
Reduction of the radical cyclization products with
NaBH4 in the presence of CeCl3‚7H2O proceeds normally
and aromatization of the resulting alcohols results in loss
of the hydroxyl group (Table 5, entries 1, 4, and 5). In
the case of entry 5, aromatization occurs so easily that
silica chromatography of the reduction product 19e gives
some of the aromatized product 19f, while corresponding
treatment of 18e is devoid of such complications. The
prearomatization substrates shown in Table 3 were
Acid treatment of 18g and 19g (Table 5, entries 6-9)
gives results that depend on the precise conditions. In
the presence of 4 Å molecular sieves, aromatization and
formation of an intermediate enone occurs (18g f 18h
+ 18i; 19g f 19h + 19i) and both the aromatized methyl
ethers (18h , 19h ) and the enones (18i, 19i) can be
isolated. In the absence of molecular sieves, the normal
aromatization products (18h , 19h ) are formed along with
the corresponding phenols (18j, 19j) resulting from arom-
atization of the enone (18i, 19i). The enones can them-
selves be aromatized (18i f 18j, 89%; 19i f 19j, 81%).
When the radical cyclization products are treated with
a Grignard reagent, a tertiary alcohol is, of course, formed
(Table 5, entries 2, 3, 6, and 8), and aromatization gives
(11) (2-Bromophenyl)methanol was isolated.
3284 J . Org. Chem., Vol. 69, No. 10, 2004

Formal Radical Cyclization onto Benzene Rings
TABLE 4.
problems, but it seemed clear that the compound should
be accessible by our radical methodology, and its con-
struction would be a more demanding test than the
examples we had examined so far. It would also represent
a worthwhile synthetic target on account of its potentially
important biological properties. In the event, we prepared
ent-nocardione A in 22% overall yield from juglone.
Nocardione A is produced by a microorganism tenta-
tively identified as the Gram-positive bacterium Nocardia
sp TP-A0248.12 The compound is a cdc25B tyrosine
phosphatase inhibitor, a property that is noteworthy
because 50% of cancers of the head and neck15 and 32%
of breast cancers16 are associated with elevated expres-
sion of cdc25B tyrosine phosphatase. The general class
of protein tyrosine phosphatases are key enzymes in the
signal transduction pathway of a wide range of cellular
processes,17 and inhibitors of such enzymes merit study
as leads in drug design and as tools to elucidate the role
of phosphorylation pathways.18 Nocardione A also has
moderate antifungal and cytotoxic activity,12 and causes
cell death with characteristics of apoptosis in U937
human myeloid leukemia cell lines.12
products carrying an alkyl or aryl group originating from
the Grignard reagent.
Previous synthetic work13 on nocardione A initially
relied on deprotection of the congener nocardione B (22),
but attempts to effect the required demethylation caused
epimerization at C(2). The successful route13 was based
on O-benzyl protection and use of a Mitsunobu displace-
ment to generate the delicate dihydrofuran unit (19%).
Surprisingly, the debenzylation needed to release the
phenolic hydroxyl proved difficult (50%).
After extensive exploratory work, we settled on the
route summarized in Scheme 6 (which leads to ent-
nocardione A).7 J uglone (23) was protected as its allyl
ether (Ag2O, allyl bromide, 79%) and then reduced to the
hydroquinone level (Na2S2O4) (23 f 24 f 25). The
hydroquinone could be alkylated (25 f 26) with the
trifluoromethanesulfonate prepared19 from (-)-ethyl lac-
tate.20 This step required some optimization and, al-
though a systematic survey of reaction conditions was
not made, we did investigate a number of solvents
(acetone, DMF, DMSO, CH2Cl2), bases (K2CO3, Cs2CO3),
and ethyl lactate derivatives (mesylate and trifluo-
romethanesulfonate), using the O-benzyl (35a ), O-meth-
Another modification to the normal sequence that can
be made is to trap the intermediate radical arising from
the closure step,8 and this was done in the case of iodide
14b (Scheme 5). When the iodide was heated with
allyltributyltin and AIBN, radical 14i underwent Keck
allylation, ultimately giving 14k , after acid treatment.
R-Keto radicals, such as 14i, appear to react only at
carbon, and we later found (see Scheme 6, compound 30)
a case where reaction at oxygen, while geometrically
favorable, did not occur at all.
The results summarized in the above tables and
schemes show clearly that the present radical cyclization
method is a very effective route to benzo-fused oxygen
heterocycles and gives access to substitution patterns not
easily accessible by other methods.
We have also applied our method to the synthesis of a
sensitive natural product, as described in the next
section.
Ap p lica tion to Na tu r a l P r od u ct Syn th esis:
Syn th esis of Noca r d ion e A
During the course of the above work the o-quinone (-)-
nocardione A (21)12 came to our attention. The prior
oxymethyl (35b), and allyl (25) hydroquinones. We also
(15) Gasparotto, D.; Maestro, R.; Piccinin, S.; Vukosavljevic, T.;
Barzan, L.; Sulfaro, S.; Boiocchi, M. Cancer Res. 1997, 57, 2366-2368.
(16) Galaktionov, K.; Lee, A. K.; Eckstein, J .; Draetta, G.; Meckler,
J .; Loda, M.; Beach, D. Science 1995, 269, 1575-1577.
(17) Dunphy, W. G.; Kumagai, A. Cell 1991, 67, 189-196.
(18) (a) Blaskovich, M. A.; Kim, H. O. Expert Opin. Ther. Pat. 2002,
12, 871-905. (b) Walton, K. M.; Dixon, J . E. Annu. Rev. Biochem. 1993,
62, 101-120.
synthesis of optically pure material13,14 had revealed that
the structure presents a number of difficult synthetic
(12) Isolation: Otani, T.; Sugimoto, Y.; Aoyagi, Y.; Igarashi, Y.;
Furumai, T.; Saito, N.; Yamada, Y.; Asao, T.; Oki, T. J . Antibiot. 2000,
53, 337-344.
(19) (a) Effenberger, F.; Burkard, U.; Willfahrt, J . Liebigs Ann.
Chem. 1986, 314-333. (b) Effenberger, F.; Burkard, U.; Willfahrt, J .
Angew. Chem., Int. Ed. Engl. 1983, 95, 65-66.
(13) Synthesis of optically pure material: Tanada, Y.; Mori, K. Eur.
J . Org. Chem. 2001, 4313-4319.
(14) Synthesis of racemic material: Yang, H.; Lu, W.; Bao, J . X.;
Aisa, H. A.; Cai, J . C. Chinese Chem. Lett. 2001, 12, 883-886; Chem.
Abstr. 2002, 136, 102216.
(20) Commercial samples of ethyl (-)-lactate are probably ca. 97%
ee. See: Overman, L. E.; Bell, K. L.; Ito, F. J . Am. Chem. Soc. 1984,
106, 4192-4201 and references therein.
J . Org. Chem, Vol. 69, No. 10, 2004 3285

Clive et al.
TABLE 5.
SCHEME 5
SCHEME 6 a
a
Reagents and conditions: (a) allyl bromide, Ag2O, CH2Cl2,
reflux, 11 h, 79%; (b) Na2S2O4, ether-water, 40 min, 100%; (c)
triflate of ethyl (-)-lactate, Cs2CO3, CH2Cl2, -78 °C, 18 h, 50%,
88% corrected for recovered 25; (d) LiAlH4, THF, 10 min, 100%;
(e) Ph3P, imidazole, I2, THF, 12 h, 89%; (f) DDQ, MeOH, K2CO3,
4 min, 87%; (g) Bu3SnH and AIBN (addition over 9 h), heat 6 h
more, PhMe, 85 °C, 82%; (h) AcOH, CHCl3, 2 h, 88%; (i)
[PhSe(O)]2O, THF, 12 min, 96%, 82% after recrystallization; (j)
10 mol % of Pd(PPh3)4, dimedone, THF, 4 min, 74%.
examined a Mitsunobu reaction between 35a and ethyl
lactate, but the yield of coupling product was poor and
extensive amounts of quinone were generated. These
experiments guided us to the conditions summarized in
Scheme 6, and we accepted the modest yield (50%) for
the alkylation (25 f 26) since much hydroquinone could
be recovered, so that the corrected yield was 88%. In
addition, alkylation occurred only at the required phe-
nolic hydroxyl under the optimized conditions, and the
process appeared to work with clean inversion of the
a
NaBH4, CeCl3‚7H2O, MeOH. b TsOH‚acetone, CHCl3. c MeMgCl,
THF. TsOH, CH2Cl2. e PhMgBr, THF. f TsOH, 4 Å molecular
sieves, CH2Cl2.
d
3286 J . Org. Chem., Vol. 69, No. 10, 2004

Formal Radical Cyclization onto Benzene Rings
SCHEME 7
was recrystallized (82% yield after recrystallization) and
treated with (Ph3P)4Pd in the presence of dimedone to
remove the allyl protecting group and release ent-
nocardione A (74%).
As already indicated, in preliminary work along similar
lines to those of our optimized route summarized in
Scheme 6, we had used O-benzyl protection, but removal
of the O-benzyl group in the last step of the synthesis
could be achieved in only 43% yield. We also explored
O-MOM protection, but found that reduction of the ester
unit (cf. 26 f 27) then gave variable yields, and at the
end of the sequence (cf. 33 f 34) the MOM group could
not be removed without opening the dihydrofuran ring.
Therefore, we tried the O-allyl group, and found that it
was satisfactory, as described above. Its use, in combina-
tion with the radical cyclization methodology, allows
construction of ent-nocardione A in overall yield of 22%
from juglone (23).
SCHEME 8
lactate stereochemistry (as judged by 19F NMR examina-
tion of the Mosher ester derived from alcohol 27). This
mechanistic outcome requires that ethyl (+)-R-lactate be
used to make natural nocardione A, but we decided to
go ahead with the very much cheaper S-isomer.
The ester was then reduced (Scheme 6, LiAlH4, 100%,
26 f 27); surprisingly, reduction of the corresponding
ester in the methoxymethyl series (derived from 35b)
gave erratic results. With alcohol 27 in hand, iodide 28
was easily obtained by reaction with Ph3P, I2, and
imidazole (89%). At this point, oxidation with DDQ in
MeOH afforded (87%) the substrates 29 required for the
key radical cyclization. Our choice of DDQ, as opposed
to PhI(OAc)2, was based on earlier studies in the benzyl
series, where the corresponding transformation (see
Scheme 7, 36 f 37) was very inefficient when PhI(OAc)2
was used as the oxidant.
An alternative method for making cross-conjugated
ketones such as 29 was investigated briefly: the hydro-
quinone O-methyl ether 38 (Scheme 8) was treated with
DDQ in neat ethyl lactate, but we did not isolate the
expected product and obtained instead the mixed acetal
39.
Radical cyclization of 29 (Scheme 6) under standard
conditions (slow addition of a dilute solution of stannane
and initiator to a dilute solution of the substrate at 85
°C) gave the desired product 31 in 82% yield; evidently,
the intermediate radical 30 is quenched by stannane
rather than undergoing closure through oxygen onto the
double bond of the allyl group. Quantitative rearomati-
zation to 32 occurred on storing the cyclization product
in CDCl3; use of HCO2H gave some 32, but an appreciable
amount of the cyclic ether 40 (as a mixture of two
Con clu sion
The radical methodology described in this article repre-
sents a powerful method for making benzo-fused oxygen
heterocycles; the approach is amenable to a number of
modifications, and has been applied in the synthesis of
ent-nocardione A.
Exp er im en ta l Section
4-(2-Ch lor oet h oxy)-4-m et h oxycycloh exa -2,5-d ien on e
(10a ). PhI(OAc)2 (143 mg, 0.443 mmol) and K2CO3 (122 mg,
0.886 mmol) were tipped into a flask that was then closed by
a septum and flushed with N2. The flask was placed in an ice
bath and the contents were stirred. After 5 min 2-chloroethanol
(1 mL) was injected and, after a further 10 min, a solution of
4 (50 mg, 0.40 mmol) in 2-chloroethanol (1 mL) was added
dropwise over ca. 6 min. A further portion of 2-chloroethanol
(1 mL) was used as a rinse, which was added rapidly. Stirring
was continued for 50 min and the reaction was quenched with
saturated aqueous NaHCO3 (5 mL). The mixture was parti-
tioned between water and Et2O. The aqueous phase was
extracted with Et2O, and the combined organic extracts were
washed with water and brine, dried (MgSO4), and evaporated.
The residue was kept under oil pump vacuum (0.3 mmHg) for
50 min to remove the excess of 2-chloroethanol. Flash chro-
matography of the residue over silica gel (1 × 24 cm), using
1:10:90 to 1:20:80 Et3N-EtOAc-hexane, gave 10a (68.0 mg,
84%) as an oil: FTIR (CHCl3, cast) 2962, 1689, 1674, 1638
1
cm-1; H NMR (CDCl3, 300 MHz) δ 3.39 (s, 3 H), 3.61 (t, J )
5.9 Hz, 2 H), 3.81 (t, J ) 5.9 Hz, 2 H), 6.23-6.25 (m, 1 H),
6.27-6.29 (m, 1 H), 6.77-6.79 (m, 1 H), 6.81-6.83 (m, 1 H)
(strictly an AA′BB′ system); 13C NMR (CDCl3, 100 MHz) δ 42.7
(t), 50.7 (q), 60.1 (t), 92.6 (s), 130.1 (d), 142.8 (d), 184.9 (s);
exact mass m/z calcd for C9H1135ClO3 204.03673, found
204.03697.
4-(2-Iodoeth oxy)-4-m eth oxycycloh exa-2,5-dien on e (10b).
Acetone (1 mL, dried over K2CO3) was added to a mixture of
10a (37.0 mg, 0.183 mmol) and anhydrous NaI (85.2 mg, 0.568
mmol). The mixture was stirred and refluxed for 45 h, cooled,
and evaporated. The residue was partitioned between water
and Et2O, and the aqueous phase was extracted with Et2O.
The combined organic extracts were washed with brine, dried
(Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel (26 × 1.2 cm), using first hexane and
then EtOAc-hexane mixtures up to 1:10 EtOAc-hexane, gave
10b (38.4 mg, 71%) as an oil: FTIR (CH2Cl2, cast) 2940, 2832,
isomers) was also formed. Treatment of 31 with DBU in
refluxing PhMe (12 h) caused no change, but satisfactory
rearomatization (31 f 32) was easily achieved by using
AcOH in CHCl3 at room temperature (88%).
The naphthol 32 was next converted (96%) into the
(21) Barton, D. H. R.; Brewster, A. W.; Ley, S. V.; Read, C. M.;
Rosenfeld, M. N. J . Chem. Soc., Perkin Trans. 1 1981, 1473-1476.
o-quinone 33 by the action of [PhSe(O)]2O.21 The quinone
J . Org. Chem, Vol. 69, No. 10, 2004 3287

Clive et al.
1
1688, 1638, 1617, cm-1; H NMR (CDCl3, 300 MHz) δ 3.35 (t,
solid: mp 43-44 °C; 1H NMR (CDCl3, 400 MHz) δ 2.01-2.06
(m, 2 H), 2.85 (t, J ) 6.8 Hz, 2 H), 4.22 (t, J ) 5.2 Hz, 2 H),
6.86 (d, J ) 8.2 Hz, 1 H), 7.26-7.34 (m, 3 H), 7.38-7.42 (m, 2
H), 7.52-7.55 (m, 2 H); 13C NMR (CDCl3, 100.6 MHz) δ 22.4
(t), 25.0 (t), 66.6 (t), 117.0 (d), 122.4 (s), 126.0 (d), 126.5 (d),
126.7 (d), 128.4 (d), 128.6 (d), 133.3 (s), 141.0 (s), 154.6 (s);
exact mass m/z calcd for C15H14O 210.10446, found 210.10445.
4a-Meth oxy-1,2,6,10b-tetr ah ydr o-4aH-ben zo[c]ch r om en -
2-ol (14e). CeCl3‚7H2O (76.7 mg, 0.206 mmol) and then NaBH4
(23.4 mg, 0.618 mmol) were added to a stirred and cooled (-78
°C) solution of 14c (47.7 mg, 0.206 mmol) in dry MeOH (5 mL).
After the addition the cooling bath was removed and stirring
was continued for 55 min. Water was added and the mixture
was extracted with CHCl3. The combined organic extracts were
dried (MgSO4) and evaporated. Flash chromatography of the
residue over silica gel, using 1:15:35 Et3N-EtOAc-hexane,
gave 14e (35.9 mg, 75%) as an oil [which was a single isomer
J ) 6.8 Hz, 2 H), 3.42 (s, 3 H), 3.84 (t, J ) 6.8 Hz, 2 H), 6.25-
6.32 (m, 2 H), 6.78-6.88 (m, 2 H) (strictly an AA′BB′ system);
13C NMR (CDCl3, 75.5 MHz) δ 2.3 (t), 50.9 (q), 63.8 (t), 92.6
(s), 130.1 (d), 143.0 (d), 184.9 (s); exact mass m/z calcd for
C9H11IO3 293.97531, found 293.97605. If we were to do this
experiment again we would use DME as the reaction solvent,
and Et3N during the chromatography.
4-(2-Iodoeth oxy)-4-m eth oxycycloh exa-2,5-dien on e (10b).
PhI(OAc)2 (143 mg, 0.443 mmol) and K2CO3 (122 mg, 0.886
mmol) were tipped into a flask that was then closed by a
septum and flushed with N2. The flask was placed in an ice
bath and the contents were stirred. After 5 min, 2-iodoethanol
(1 mL) was injected and, after a further 5 min, a solution of 4
(52.3 mg, 0.422 mmol) in 2-iodoethanol (1 mL) was added
dropwise over ca. 7 min. A further portion of 2-iodoethanol
(0.5 mL) was used as a rinse, which was added rapidly.
Stirring was continued for 1.5 h and the reaction was quenched
with saturated aqueous NaHCO3 (5 mL). The mixture was
diluted with water and extracted with Et2O. The combined
organic extracts were washed with 1 N aqueous Na2S2O3,
water, and brine, dried (MgSO4), and evaporated. The residue
was kept under oil pump vacuum (0.3 mmHg) for 24 h to
remove the excess of 2-iodoethanol. Flash chromatography of
the residue over silica gel (1 × 28 cm), using 1:10:90 Et3N-
EtOAc-hexane, gave 10b (89.7 mg, 72%) as an oil.
2,3-Dih yd r oben zofu r a n -5-ol (10d ). A solution of Ph3SnH
(0.07 mL, 0.27 mmol) and AIBN (4.8 mg, 0.030 mmol) in PhMe
(5 mL) was added over 4 h (syringe pump) to a stirred and
heated (85 °C) solution of 10b (47.8 mg, 0.163 mmol) in PhMe
(10 mL). Heating was continued for 2 h after the addition, the
mixture was cooled to room temperature, and TsOH‚H2O (5
mg) was added. Stirring was continued for 30 min and the
mixture was partitioned between water and Et2O. The aqueous
phase was extracted with Et2O and the combined organic
extracts were washed with brine, dried (MgSO4), and evapo-
rated. Flash chromatography of the residue over silica gel,
using 1:4 EtOAc-hexane, gave the 10d 22 (17.4 mg, 79%) as a
white solid: mp 108-110 °C.
8a -Me t h o x y -6-p h e n y l-3,4,4a ,5,6,8a -h e x a h y d r o -2H -
ch r om en -6-ol (11e). PhMgBr (0.60 mL, 0.60 mmol, 1 M in
THF) was added at a fast dropwise rate to a stirred solution
of 11c (55.0 mg, 0.302 mmol) in THF (5 mL). Stirring was
continued for 2 h and the mixture was then cooled to 0 °C and
quenched with water. The solvent was evaporated and the
residue was partitioned between water and Et2O. The aqueous
phase was extracted with Et2O and the combined organic
extracts were washed with brine, dried (Na2SO4), and evapo-
rated. Flash chromatography of the residue over silica gel,
using 1:20:30 Et3N-EtOAc-hexane, gave 11e (59.5 mg, 75%)
as a colorless solid: mp 131-133 °C; FTIR (CH2Cl2 cast) 3406,
3033, 2862, 1490, 1274, 1012 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.22-1.32 (m, 2 H), 1.68-1.81 (m, 3 H), 1.96-2.06 (m, 1 H),
2.19 (s, 1 H), 2.44 (t, J ) 13.2 Hz, 1 H), 3.36 (s, 3 H), 3.60-
3.68 (m, 2 H), 5.85 (dd, J ) 5.2, 2 Hz, 1 H), 6.07 (d, J ) 5.2, 1
H), 7.23-7.27 (m, 3 H), 7.47 (d, J ) 7.6 Hz, 2 H); 13C NMR
(CDCl3, 100.6 MHz) δ 20.2 (t), 24.4 (t), 33.5 (d), 42.5 (t), 48.0
(q), 61.5 (t), 74.8 (s), 96.0 (s), 126.0 (d), 126.8 (d), 127.4 (d),
128.2 (d), 135.6 (d), 144.6 (s); exact mass m/z calcd for C16H20O3
260.14124, found 260.14086.
(1H NMR)]: FTIR (CH2Cl2, cast) 3378, 2942, 2858, 1496 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 1.76 (dt, J ) 10.5, 13.3 Hz, 1 H),
2.17-2.23 (m, 1 H), 2.15 (br s, 1 H), 2.82 (dd, J ) 13.5, 3.0 Hz,
1 H), 3.38 (s, 3 H), 4.41 (q, J ) 4.9 Hz, 1 H), 4.75 (AB q, J )
15.0 Hz, ∆νAB ) 13.2 Hz, 2 H), 6.01 (apparent AB q, J ) 10.5
Hz, ∆νAB ) 7.8 Hz, 2 H), 6.98 (d, J ) 7.2 Hz, 1 H), 7.13-7.22
(m, 3 H); 13C NMR (CDCl3, 125 MHz) δ 40.4 (d), 41.2 (t), 49.1
(q), 62.8 (t), 67.86 (d), 67.87 (d), 95.8 (s), 123.5 (d), 125.2 (d),
126.2 (d), 126.8 (d), 128.8 (d), 132.2 (s), 135.0 (s), 136.5 (d);
exact mass m/z calcd for C14H16O3 232.10994, found 232.11016.
6H-Ben zo[c]ch r om en e (14f). TsOH‚H2O (35.1 mg, 0.201
mmol) was added to a stirred solution of 14e (35.9 mg, 0.155
mmol) in a mixture of CHCl3 (10 mL) and acetone (1 mL), and
stirring was continued overnight [TLC control (silica, hexane
or 5% EtOAc-hexane) suggested the reaction was over within
4 min]. The mixture was evaporated and the residue was
partitioned between hexane and water. The combined organic
extracts were dried (Na2SO4) and evaporated. Flash chroma-
tography of the residue over silica gel, using 1:20 CH2Cl2-
hexane, gave 14f24 (23.7 mg, 85%) as an oil.
1-Allyl-4a -m et h oxy-6,10b -d ih yd r o-1H ,4a H -b en zo[c]-
ch r om en -2-on e (14j). AIBN (10 mg, 0.061 mmol) and allyl-
tributyltin (170 mg, 0.512 mmol) were added to a stirred
solution of 14b (83.5 mg, 0.256 mmol) in PhMe (5 mL), and
the mixture was then refluxed for 34 h, cooled, and evaporated.
Flash chromatography of the residue over silica gel, using 1:5:
45 Et3N-EtOAc-hexane, gave a solid, which appeared to be
a mixture of isomers corresponding to the desired product (14j)
(1H NMR). TLC analysis (silica, 30% EtOAc-hexane), showed
two close spots. The crude material was used directly for the
next step.
1-Allyl-6H-ben zo[c]ch r om en -2-ol (14k ). TsOH‚H2O (20
mg, 0.11 mmol) was added to a stirred solution of 14j (mixture
of isomers) in CH2Cl2 (4 mL). After 45 min, acetone (10 mL)
was added and stirring was continued overnight, since it was
not clear from TLC examination (silica, 30% EtOAc-hexane)
of the mixture if the reaction was over. Evaporation of the
solvent and flash chromatography of the residue over silica
gel, using 20% EtOAc-hexane, gave 14k (44.1 mg, 72%) as
an oil: FTIR (CH2Cl2, cast) 3418, 3076, 2976, 2835, 1635, 1571
cm-1; 1H NMR (CDCl3, 500 MHz) δ 3.71 (apparent dt, J ) 2.3,
2.1 Hz, 2 H), 4.81-4.85 (br m, 1 H), 4.89 (s, 2 H), 5.24 (dq, J
) 17.3, 1.6 Hz, 1 H), 5.35 (dq, J ) 10.3, 1.8 Hz, 1 H), 6.25-
6.34 (m, 1 H), 6.80 (d, J ) 8.6 Hz, 1 H), 6.89 (d, J ) 8.6 Hz, 1
H), 7.23 (br d, J ) 6.4 Hz, 1 H), 7.28 (td, J ) 7.3, 1.1 Hz, 1 H),
7.33 (td, J ) 7.5, 1.4 Hz, 1 H), 7.62 (d, J ) 7.7 Hz, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 33.0 (t), 69.3 (t), 116.2 (d), 116.6
(d), 117.2 (t), 121.3 (s), 124.8 (s), 124.9 (d), 126.0 (d), 127.2 (d),
127.9 (d), 130.3 (s), 134.0 (s), 135.6 (d), 150.0 (s), 150.5 (s);
exact mass m/z calcd for C16H14O2 238.09938, found 238.09982.
4-(3-Iod on a p h th a len -2-ylm eth oxy)p h en ol (15a ). A solu-
tion of 2-bromomethyl-3-iodonaphthalene (0.23 g, 0.66 mmol)
in THF (3 mL) was added dropwise over 25 min to a stirred
6-P h en ylch r om a n (11f). TsOH‚H2O (10 mg) was added to
a stirred solution of 11e (47.8 mg, 0.184 mmol) in CH2Cl2 (10
mL), and stirring was continued for 1 h. The mixture was then
partitioned between water and CH2Cl2. The aqueous phase was
extracted with CH2Cl2 and the combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated. Flash
chromatography of the residue over silica gel, using 1:4
CH2Cl2-hexane, gave 11f23 (30.5 mg, 79%) as a colorless
(22) Benbow, J . W.; Katoch-Rouse, R. J . Org. Chem. 2001, 66, 4965-
4972.
(23) Deady, L. W.; Topsom, R. D.; Vaughan, J . J . Chem. Soc. 1965,
5718-5724.
(24) Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919-1926.
3288 J . Org. Chem., Vol. 69, No. 10, 2004

Formal Radical Cyclization onto Benzene Rings
mixture of hydroquinone (0.364 g, 3.30 mmol) and K2CO3
(0.229 g, 1.66 mmol) in THF (10 mL). A further portion of THF
(1 mL) was used as a rinse, which was added quickly. The
flask was transferred to an oil bath, and stirring was continued
overnight at 60 °C. The mixture was cooled, poured into water,
neutralized with 10% hydrochloric acid, and extracted with
Et2O. The combined organic extracts were washed with brine,
dried (Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel, using 1:4 EtOAc-hexane, gave 15a
(0.1637 g, 65%) as a solid: mp 124-126 °C; FTIR (CH2Cl2 cast)
(m, 1 H), 7.84-7.88 (m, 1 H), 8.05 (s, 1 H); 13C NMR (CDCl3,
100.6 MHz) δ 69.0 (t), 109.9 (d), 116.6 (d), 118.5 (d), 120.9 (d),
123.2 (d), 123.8 (s), 126.2 (two coincident d), 127.5 (d), 128.0
(s), 128.1 (d), 130.6 (s), 132.9 (s), 133.5 (s), 149.4 (s), 150.6 (s);
exact mass m/z calcd for C17H12O2 248.08372, found 248.08336.
4-(2-Ch lor oet h oxy)-4-m et h oxy-4H -n a p h t h a len -1-on e
(17a ). A solution of 1725 in EtOAc was evaporated and the
residue was kept for 10 min (and no longer) under oil pump
vacuum (0.1 mmHg). When material that had been too
thoroughly dried was used, the following experiment did not
work and a blue color developed.
3368, 3051, 1204, 1053 cm-1 1H NMR (CDCl3, 400 MHz) δ
;
4.68 (s, 1 H), 5.09 (s, 2 H), 6.76-6.79 (m, 2 H), 6.89-6.93 (m,
2 H), 7.46-7.50 (m, 2 H), 7.69-7.72 (m, 1 H), 7.77-7.80 (m, 1
H), 7.93 (s, 1 H), 8.39 (s, 1 H); 13C NMR (CDCl3, 100.6
MHz) δ 74.8 (t), 94.2 (s), 116.1 (d), 116.3 (d), 126.5 (d), 126.7
(d), 126.8 (d), 127.4 (d), 128.0 (d), 132.7 (s), 134.3 (s), 135.4
(s), 138.6 (d), 149.9 (s), 152.7 (s); exact mass m/z calcd for
C17H13IO2 375.99603, found 375.99672.
PhI(OAc)2 (110 mg, 0.342 mmol) and K2CO3 (95.0 mg, 0.688
mmol) were tipped into a flask that was then closed by a
septum and flushed with N2. The flask was placed in an ice
bath and the contents were stirred. After 5 min, freshly
distilled MeOH (10 mL) was injected and, after a further 10
min, a solution of 17 (69.8 mg, 0.314 mmol) in MeOH (5 mL)
was added dropwise over ca. 3 min. Stirring was continued
for 25 min and the reaction was quenched with saturated
aqueous NaHCO3 (5 mL). The mixture was partitioned be-
tween water and Et2O, and the aqueous phase was extracted
with Et2O. The combined organic extracts were washed with
water and brine, dried (MgSO4), and evaporated. The residue
was kept under oil pump vacuum (0.3 mmHg) overnight. Flash
chromatography of the residue over silica gel, using 2% Et3N-
hexane and then 1:10:40 Et3N-EtOAc-hexane, gave 17a (60.7
mg, 76%) as an oil: FTIR (CHCl3, cast) 2963, 1678, 1631, 1601,
4-(3-Iodon aph th alen -2-ylm eth oxy)-4-m eth oxycycloh exa-
2,5-d ien on e (15b). PhI(OAc)2 (0.164 g, 0.510 mmol) and
K2CO3 (0.140 g, 1.02 mmol) were tipped into a flask that was
then closed by a septum and flushed with N2. The flask was
placed in an ice bath and the contents were stirred. MeOH (6
mL) was added, and a solution of 15a (0.16 g, 0.43 mmol) in
MeOH (4 mL) was injected dropwise over ca. 5 min. A further
portion of MeOH (2 mL) was used as a rinse, which was added
rapidly. Stirring was continued for 2 h and the reaction was
quenched with saturated aqueous NaHCO3. The mixture was
partitioned between water and Et2O, and the combined organic
extracts were washed with water and brine, dried (Na2SO4),
and evaporated. Flash chromatography of the residue over
silica gel, using 2:15:90 Et3N-EtOAc-hexane, gave 15b
(0.1471 g, 86%) as an oil: FTIR (CH2Cl2 cast) 3053, 1638, 1383,
1
1457 cm-1; H NMR (CDCl3, 500 MHz) δ 3.19 (s, 3 H), 3.44-
3.49 (m, 1 H), 3.52-3.60 (m, 2 H), 3.66-3.71 (m, 1 H), 6.58
(dd, J ) 10.5, 0.8 Hz, 1 H), 6.92 (dd, J ) 10.5, 0.5 Hz, 1 H),
7.49 (apparent t, J ) 7.7 Hz, 1 H), 7.65 (apparent t, J ) 7.3
Hz, 1 H), 7.74 (apparent d, J ) 7.9 Hz, 1 H), 8.06 (apparent d,
J ) 7.9 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 42.6 (t), 51.3
(q), 63.8 (t), 94.9 (s), 126.4 (d), 126.8 (d), 129.5 (d), 131.4 (s),
132.6 (d), 133.6 (d), 139.5 (s), 143.6 (d), 183.6 (s); exact mass
m/z calcd for C12H1035ClO2 (M - OMe) 221.03693, found
221.03698.
1
1105, 1066 cm-1; H NMR (CDCl3, 500 MHz) δ 3.45 (s, 3 H),
4.74 (s, 2 H), 6.32 (dt, J ) 10, 1.5 Hz, 2 H), 6.95 (dt, J ) 10,
1.5 Hz, 2 H), 7.44-7.50 (m, 2 H), 7.66-7.69 (m, 1 H), 7.76-
7.79 (m, 1 H), 7.84 (s, 1 H), 8.34 (s, 1 H); 13C NMR (CDCl3,
125 MHz) δ 50.9 (q), 68.8 (t), 93.0 (s), 94.3 (s), 126.5 (d), 126.76
(d), 126.82 (d), 127.3 (d), 127.9 (d), 130.1 (d), 132.7 (s), 134.3
(s), 135.8 (s), 138.6 (d), 143.2 (d), 185.1 (s); exact mass m/z
calcd for C18H15IO3 406.00659, found 406.00562.
4-(2-Iodoeth oxy)-4-m eth oxy-4H-n aph th alen -1-on e (17b).
DME (10 mL, dried over Na/Ph2CO) was added to a stirred
mixture of 17a (70.0 mg, 0.275 mmol) and anhydrous NaI (412
mg, 2.75 mmol). The mixture was stirred and refluxed for 22
h, cooled, and poured into water. The aqueous phase was
extracted with Et2O and the combined organic extracts were
washed with Na2S2O3, saturated aqueous NaHCO3, and brine,
dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel, using 1:10:90 Et3N-EtOAc-hexane,
gave 17b (72.8 mg, 77%) as an oil: FTIR (CHCl3, cast) 2937,
4a -Me t h oxy-6,12b -d ih yd r o-1H ,4a H -n a p h t h o[2,3-c]-
ch r om en -2-on e (15c). A solution of Bu3SnH (0.117 mL, 0.422
mmol) and AIBN (7.1 mg, 0.042 mmol) in PhMe (10 mL) was
added over 3 h (by syringe pump) to a stirred and heated (80
°C) solution of 15b (0.143 g, 0.352 mmol) in PhMe (50 mL).
Heating at 80 °C was continued overnight. Evaporation of the
solvent and flash chromatography of the residue over silica
gel, using 2:20:80 Et3N-EtOAc-hexane, gave 15c (0.070 g,
70%) as an oil: FTIR (CH2Cl2 cast) 3053, 1631, 1270, 1164
1
1673, 1630, 1600 cm-1; H NMR (CDCl3, 500 MHz) δ 3.15-
3.23 (m, 2 H), 3.20 (s, 3 H), 3.47 (apparent dt, J ) 10.2, 6.1
Hz, 1 H), 3.69 (apparent dt, J ) 9.8, 6.7 Hz, 1 H), 6.58 (d, J )
10.5 Hz, 1 h), 6.93 (d, J ) 10.5 Hz, 1 H), 7.50 (apparent dt, J
) 7.3, 1.3 Hz, 1 H), 7.66 (apparent dt, J ) 7.3, 1.4 Hz, 1 H),
7.76 (apparent dq, J ) 7.8, 0.6 Hz, 1 H), 8.06 (apparent dq, J
) 7.9, 0.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 2.4 (t), 51.4
(q), 64.4 (t), 94.8 (s), 126.4 (d), 126.8 (d), 129.5 (d), 131.4 (s),
132.6 (d), 133.7 (d), 139.6 (s), 143.7 (d), 183.7 (s); exact mass
m/z calcd for C13H13IO3 343.99094, found 343.99073.
1
cm-1; H NMR (CDCl3, 500 MHz) δ 2.81 (dd, J ) 16.5, 5, 0.5
Hz, 1 H), 2.90 (dd, J ) 16.5, 10.5 Hz, 1 H), 3.49 (s, 3 H), 3.53
(dd, J ) 10.5, 5 Hz, 1 H), 5.03 (d, J ) 2.5 Hz, 2 H), 6.10 (d, J
) 10, 0.5 Hz, 1 H), 6.94 (d, J ) 10.5 Hz, 1 H), 7.40-7.44 (m,
2 H), 7.54 (s, 1 H), 7.60 (s, 1 H), 7.73-7.78 (m, 2 H); 13C NMR
(CDCl3, 125 MHz) δ 41.8 (q), 43.2 (t), 49.6 (d), 63.6 (t), 95.8
(s), 122.6 (d), 125.9 (d), 126.1 (d), 126.2 (d), 127.3 (d), 127.5
(d), 130.4 (d), 130.8 (s), 132.2 (s), 132.7 (s), 132.7 (s), 143.1 (d),
197.9 (s); exact mass m/z calcd for C18H16O3 280.10995, found
280.10993.
9b-Meth oxy-2,3,3a ,9b-tetr a h yd r o-4H-n a p h th o[1,2-b]fu -
r a n -5-on e (17c). A solution of Bu3SnH (0.08 mL, 0.3 mmol)
and AIBN (10 mg, 0.061 mmol) in PhMe (5 mL) was added
over 3 h (syringe pump) to a stirred and heated (95 °C) solution
of 17b (72.8 mg, 0.212 mmol) in PhMe (15 mL). Heating was
continued for 30 min after the addition. Evaporation of the
solvent and flash chromatography of the residue over silica
gel, using 1:10:40 Et3N-EtOAc-hexane, gave 17c (37.7 mg,
82%) as an oil [which was a single isomer (1H NMR)]: FTIR
6H-Na p h th o[2,3-c]ch r om en -2-ol (15d ). TsOH‚H2O (5 mg)
was added to a stirred mixture of 15c (68.0 mg, 0.243 mmol)
and 4 Å molecular sieves (ca. 100 mg) in CH2Cl2 (7 mL), and
stirring was continued for 1 h. The mixture was diluted with
CH2Cl2 and washed with saturated aqueous NaHCO3. The
organic extract was dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel, using 1:20
EtOAc-CH2Cl2, gave 15d (52.7 mg, 87%) as a colorless solid:
mp 200-201 °C; FTIR (CH2Cl2 cast) 3452, 3048, 1489, 1194
cm-1; 1H NMR (CDCl3, 500 MHz) δ 4.55 (s, 1 H), 5.19 (s, 2 H),
6.74 (dd, J ) 9, 3 Hz, 1 H), 6.91 (d, J ) 8.5 Hz, 1 H), 7.38 (d,
J ) 3 Hz, 1 H), 7.42-7.48 (m, 2 H), 7.60 (s, 1 H), 7.76-7.80
1
(CHCl3, cast) 2947, 2893, 1692, 1600 cm-1; H NMR (CDCl3,
500 MHz) δ 1.73-1.79 (m, 1 H), 2.35-2.42 (m, 1 H), 2.69 (dd,
J ) 16.0, 8.7 Hz, 1 H), 2.82 (dd, J ) 16.0, 5.7 Hz, 1 H), 3.06-
3.12 (m, 1 H), 3.20 (s, 3 H), 4.06 (dt, J ) 8.3, 5.8 Hz, 1 H), 4.17
(25) Laatsch, H. Liebigs Ann. Chem. 1980, 140-157.
J . Org. Chem, Vol. 69, No. 10, 2004 3289

Clive et al.
(dt, J ) 8.4, 6.0 Hz, 1 H), 7.43 (t of m, J ) 7.3 Hz, 1 H), 7.64
(td, J ) 7.2, 1.4 Hz, 1 H), 7.70 (dq, J ) 7.9, 0.5 Hz, 1 H), 7.91
(dq, J ) 8.1, 0.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 30.4
(t), 39.0 (d), 40.6 (t), 51.2 (q), 67.3 (t), 105.8 (s), 126.0 (d), 127.5
(d), 129.0 (d), 131.8 (s), 134.4 (d), 140.2 (s), 196.7 (s); exact
mass m/z calcd for C13H14O3 218.09430, found 218.09453.
Acetic Acid 2,3-Dih yd r on a p h th o[1,2-b]fu r a n -5-yl Ester
(17d ). Ac2O (ca 1 mL) was added with stirring to 17c (16.0
mg, 0.0734 mmol), followed by TsOH‚H2O (5 mg). A yellow
color developed immediately. Stirring was continued for 3.5
h, the Ac2O was evaporated under oil pump vacuum, and the
residue was taken up in Et2O. The solution was washed with
saturated aqueous NaHCO3 and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica
gel, using 1:20 EtOAc-hexane, gave 17d 26 (14.7 mg, 89%) as
an oil.
(5 mL), and stirring was continued for 1 h. The mixture was
diluted with CH2Cl2 and washed with saturated aqueous
NaHCO3. The combined organic extracts were dried (Na2SO4)
and evaporated. Flash chromatography of the residue over
silica gel, using 1:20 EtOAc-CH2Cl2, gave 18d 22 (12.2 mg,
1
81%) as a solid: 110-111 °C; H NMR (CDCl3, 300 MHz) δ
3.15 (t, J ) 8.7 Hz, 2 H), 3.80 (s, 3 H), 4.57 (t, J ) 8.7, 2 H),
5.09 (s, 1 H), 6.30-6.34 (m, 2 H).
7-Meth oxy-5-m eth yl-2,3-d ih yd r oben zofu r a n (18h ) a n d
5-Meth yl-2,3,3a,7a-tetr ah ydr o-4H-ben zofu r an -7-on e (18i).
TsOH‚H2O (5 mg) was added to a stirred mixture of 18g (98.0
mg, 0.429 mmol) and 4 Å molecular sieves (ca. 100 mg) in
CH2Cl2 (15 mL), and stirring was continued for 1 h. The
mixture was diluted with CH2Cl2 and washed with water. The
organic extract was dried (Na2SO4) and evaporated. Flash chro-
matography of the residue over silica gel, using 5:1 EtOAc-
hexane, gave 18h (41.3 mg, 51%) as a colorless solid and 18i
(33.1 mg, 37%) as an oil. Compound 18h data: mp 46-48 °C;
4-(2-Ch lor oe t h oxy)-3,4-d im e t h oxycycloh e xa -2,5-d i-
en on e (18a ). PhI(OAc)2 (0.230 g, 0.714 mmol) and K2CO3
(0.197 g, 1.43 mmol) were tipped into a flask that was then
closed by a septum and flushed with N2. After 5 min,
2-chloroethanol (1 mL) was injected and, after a further 10
min, a solution of 18 (100 mg, 0.649 mmol) in 2-chloroethanol
(2.5 mL) was added dropwise over ca. 6 min. A further portion
of 2-chloroethanol (1 mL) was used as a rinse, which was added
rapidly. Stirring was continued for 1 h and the reaction was
quenched with saturated aqueous NaHCO3 (5 mL). The
mixture was partitioned between water and CH2Cl2, and the
aqueous phase was extracted with CH2Cl2. The combined
organic extracts were washed with water and brine, dried
(Na2SO4), and evaporated. The residue was kept under oil
pump vacuum overnight to remove the excess of 2-chloro-
ethanol. Flash chromatography of the residue over silica gel,
using 1:40:60 Et3N-EtOAc-hexane, gave 18a (0.151 g, 68%)
as a yellow oil: FTIR (CH2Cl2 cast) 3076, 2942, 1308, 1174
1
FTIR (CH2Cl2 cast) 2935, 1620, 1203 cm-1; H NMR (CDCl3,
400 MHz) δ 2.27 (s, 3 H), 3.16 (t, J ) 8.4 Hz, 2 H), 3.83 (s, 3
H), 4.57 (t, J ) 8.4 Hz, 2 H), 6.53 (s, 1 H), 6.62 (s, 1 H); 13C
NMR (CDCl3, 100.6 MHz) δ 21.1 (q), 30.6 (t), 55.9 (q), 71.6 (t),
111.9 (d), 117.4 (d), 127.9 (s), 130.6 (s), 144.0 (s), 146.1 (s);
exact mass m/z calcd for C10H12O2 164.08372, found 164.08344.
Compound 18i data: FTIR (CH2Cl2 cast) 2976, 1484, 1252
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.70-1.74 (m, 1 H), 1.90
(s, 3 H), 2.19-2.26 (m, 2 H), 2.39-2.46 (m, 1 H), 2.64-2.66
(m, 1 H), 3.44 (s, 3 H), 3.94-4.05 (m, 2 H), 5.84 (s, 1 H); 13C
NMR (CDCl3, 100.6 MHz) δ 24.3 (s), 30.4 (t), 33.6 (t), 43.5 (q),
51.9 (q), 67.3 (t), 101.4 (s), 125.3 (d), 160.0 (s), 192.4 (s); exact
mass m/z calcd for C10H14O3 182.09430, found 182.09465.
7-Meth oxy-5-m eth yl-2,3-d ih yd r oben zofu r a n (18h ) a n d
5-Meth yl-2,3-d ih yd r oben zofu r a n -7-ol (18j). TsOH‚H2O (5
mg) was added to a stirred solution of 18g (28.0 mg, 0.138
mmol) in CH2Cl2 (5 mL), and stirring was continued for 1 h.
The mixture was diluted with CH2Cl2 and washed with
saturated aqueous NaHCO3. The organic extract was dried
(Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel, using 3:1 EtOAc-hexane, gave 18h (12.0 mg,
52%) and 18j (6.8 mg, 36%) as colorless solids. Compound 18j
data: mp 95-97 °C; FTIR (CH2Cl2 cast) 3361, 3031, 1718, 999
1
cm-1; H NMR (CDCl3, 400 MHz) δ 3.27 (s, 3 H), 3.52-3.56
(m, 2 H), 3.67-3.72 (m, 5 H), 5.55 (d, J ) 2 Hz, 1 H), 6.22 (dd,
J ) 10.4, 2 Hz, 1 H), 6.52 (d, J ) 10.4 Hz, 1 H); 13C NMR
(CDCl3, 100.6 MHz) δ 42.5 (t), 51.5 (q), 56.0 (q), 64.1 (t), 93.8
(s), 104.0 (d), 131.0 (d), 140.1 (d), 168.8 (s), 185.9 (s); exact
mass m/z calcd for C10H13ClO4 232.05023, found 232.05016.
4-(2-I o d o e t h o x y )-3,4-d im e t h o x y c y c lo h e x a -2,5-d i-
en on e (18b). Dry acetone (10 mL) was added to a stirred
mixture of 18a (0.42 g, 1.8 mmol) and anhydrous NaI (2.71 g,
18.1 mmol) and the mixture was refluxed for 48 h, cooled, and
partitioned between water and CH2Cl2. The aqueous phase was
extracted with CH2Cl2 and the combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated. Flash
chromatography of the residue over silica gel, using 1:1
EtOAc-hexane, gave 18b (510.8 mg, 87%) as a yellow oil,
which was used directly in the next step.
1
cm-1; H NMR (CDCl3, 400 MHz) δ 2.23 (s, 3 H), 3.18 (t, J )
8.8 Hz, 2 H), 4.57 (t, J ) 8.8 Hz, 2 H), 4.96 (s, 1 H), 6.40 (s, 1
H), 6.57 (s, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 20.9 (q), 30.5
(d), 71.9 (d), 115.6 (d), 117.2 (d), 127.7 (s), 131.1 (s), 139.7 (s),
144.4 (s); exact mass m/z calcd for C9H10O2 150.06808, found
150.06840.
5-Meth yl-2,3-d ih yd r oben zofu r a n -7-ol (18j). TsOH‚H2O
(5 mg) was added to a stirred solution of 18i (30.0 mg, 0.165
mmol) in CH2Cl2 (5 mL), and stirring was continued for 1 h.
The mixture was diluted with CH2Cl2 and washed with
saturated aqueous NaHCO3. The organic extract was dried
(Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel, using 1:3 EtOAc-hexane, gave 18j (22.1 mg,
89%) as a colorless solid, spectroscopically identical with
material obtained previously.
4-(2-Iodoeth oxy)-4-m eth ylcycloh exan -2,5-dien on e (20a).
PhI(OAc)2 (529 mg, 1.64 mmol) and K2CO3 (452 mg, 3.28 mmol)
were tipped into a flask that was then closed by a septum and
flushed with N2. The flask was placed in an ice bath and the
contents were stirred. After 5 min, 2-iodoethanol (2 mL) was
injected and, after a further 5 min, a solution of freshly
distilled p-cresol (20) (162 mg, 1.49 mmol) in 2-iodoethanol (2
mL) was added dropwise over ca. 5 min. A further portion of
2-iodoethanol (1 mL) was used as a rinse, which was added
rapidly. Stirring was continued for 130 min and the reaction
was quenched with saturated aqueous NaHCO3 (5 mL). The
mixture was partitioned between water and Et2O, and the
aqueous phase was extracted with Et2O. The combined organic
extracts were washed with 1 N aqueous Na2S2O3, saturated
aqueous NaHCO3, water, and brine, dried (MgSO4), and
evaporated. The residue was kept under oil pump vacuum (0.4
7,7a -Dim eth oxy-2,3,3a ,7a -tetr a h yd r o-4H-ben zofu r a n -
5-on e (18c). A solution of Bu3SnH (0.956 mL, 3.55 mmol) and
AIBN (58.3 mg, 0.355 mmol) in PhMe (15 mL) was added over
3 h (by syringe pump) to a stirred and heated (85 °C) solution
of 18b (960 mg, 2.96 mmol) in PhMe (40 mL). Heating at 85
°C was continued overnight. Evaporation of the solvent and
flash chromatography of the residue over silica gel, using 2:98
Et3N in EtOAc, gave 18c (0.417 g, 70%) as a yellow oil: FTIR
(CH2Cl2 cast) 2944, 2834, 1664, 1612, 1317 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.69-1.80 (m, 1 H), 2.20-2.28 (m, 1 H),
2.37 (dd, J ) 16.4, 7.4 Hz, 1 H), 2.54 (dd, J ) 16.4, 7.4 Hz, 1
H), 2.78 (quintet, J ) 6.8 Hz, 1 H), 3.37 (s, 3 H), 3.71 (s, 3 H),
4.00-4.10 (m, 2 H), 5.31 (s, 1 H); 13C NMR (CDCl3, 100.6 MHz)
δ 30.3 (t), 38.8 (t), 40.9 (d), 51.3 (q), 56.1 (q), 68.1 (t), 102.9
(d), 103.7 (s), 171.3 (s), 196.6 (s); exact mass m/z calcd for
C
10H14O4 198.08920, found 198.08962.
7-Meth oxy-2,3-d ih yd r oben zofu r a n -5-ol (18d ). TsOH‚
H2O (3 mg) was added to a stirred mixture of 18c (18.0 mg,
0.0910 mmol) and 4 Å molecular sieves (ca 100 mg) in CH2Cl2
(26) Semmelhack, M. F.; Bozell, J . J . Tetrahedron Lett. 1982, 23,
2931-2934.
3290 J . Org. Chem., Vol. 69, No. 10, 2004

Formal Radical Cyclization onto Benzene Rings
mmHg) for 18 h to remove the excess of 2-iodoethanol. Flash
chromatography of the residue over silica gel (24 × 1.8 cm2),
using 1:10:90 Et3N-EtOAc-hexane, gave 20a (198.9 mg, 48%)
as an oil: FTIR (CHCl3, cast) 2977, 2928, 1674, 1631, 1605
cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.42-1.45 (m, 3 H), 3.15-
3.20 (m, 2 H), 3.48-3.53 (m, 2 H), 6.24-6.29 (m, 2 H), 6.75-
6.80 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 3.5 (t), 26.3 (q),
66.3 (t), 72.6 (s), 130.2 (d), 151.0 (d), 184.8 (s); exact mass m/z
calcd for C9H11IO2 277.98038, found 277.98014.
5-(Allyloxy)n a p h t h a len e-1,4-d iol (25). A solution of
Na2S2O4 (1.92 g, 11.0 mmol) in water (10 mL) was added to a
solution of 24 (0.7871 g, 3.678 mmol) in Et2O (50 mL), and
the mixture was stirred for 40 min. Water (20 mL) was added
and the aqueous phase was extracted twice with Et2O. The
combined organic extracts were washed with brine, dried
(MgSO4), and evaporated to give 25 (0.7926 g, 100%) as beige
flakes: mp 133-134 °C; FTIR (CHCl3, cast) 3400, 3196, 2938,
1
1636, 1608 cm-1; H NMR (CDCl3, 400 MHz) δ 4.76 (dt, J )
4.9, 1.3 Hz, 2 H), 4.89 (s, 1 H), 5.40 (dq, J ) 10.4, 1.0 Hz, 1 H),
5.49 (dq, J ) 17.2, 1.3 Hz, 1 H), 6.09-6.18 (m, 1 H), 6.72 (AB
q, J ) 8.2 Hz, ∆νAB ) 19.9 Hz, 2 H), 6.82 (d, J ) 7.7 Hz, 1 H),
7.31 (t, J ) 7.9 Hz, 1 H), 7.74 (dd, J ) 8.6, 0.9 Hz, 1 H), 9.03
(s, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 70.3 (t), 106.3 (d),
109.4 (d), 110.9 (d), 115.8 (s), 115.9 (d), 119.8 (t), 125.2 (d),
126.9 (s), 131.8 (d), 143.7 (s) 148.4 (s) 155.1 (s); exact mass
m/z calcd for C13H12O3 216.07864, found 216.07872.
7a -Met h yl-2,3,3a ,7a -t et r a h yd r o-4H -b en zofu r a n -5-on e
(20b). A solution of Bu3SnH (0.09 mL, 0.3 mmol) and AIBN
(10 mg, 0.061 mmol) in PhMe (5 mL) was added over 3 h
(syringe pump) to a stirred and heated (95 °C) solution of 20a
(74.9 mg, 0.269 mmol) in PhMe (10 mL). Heating was
continued for 20 min after the addition. The solvent was
evaporated under water pump vacuum (the product is volatile),
and flash chromatography of the residue over silica gel, using
1:10:90 Et3N-EtOAc-hexane (and evaporation of appropriate
fractions under water pump vacuum), gave 20b (27.3 mg, 67%)
as an oil. A distilled sample (Kugelrohr oven at 120 °C, 40
mmHg) solidified at ca. 0 °C, but the solid melted below room
(2R)-2-[[5-(Allyloxy)-4-h yd r oxyn a p h t h a len -1-yl]oxy]-
p r op ion ic Acid Eth yl Ester (26). A solution of (S)-2-[(tri-
fluoromethanesulfonyl)oxy]propionic acid ethyl ester19 (3.50 g,
14.0 mmol) in CH2Cl2 (10 mL) was added over 10 min to a
stirred and cooled (-78 °C) mixture of 25 (0.6117 g, 3.045
mmol) and Cs2CO3 (0.9945 g, 3.045 mmol) in CH2Cl2 (15 mL).
Stirring at -78 °C was continued arbitrarily for 18 h. The
progress of the reaction was monitored by TLC (silica, 1:3
EtOAc-hexane); no further change seemed to occur after ca.
3 h. The mixture was quenched with saturated aqueous
NH4Cl (10 mL) and partitioned between water and CH2Cl2.
The aqueous phase was extracted with CH2Cl2 and the
combined organic extracts were dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (23 × 2.4
cm), using 1:10 to 1:5 EtOAc-hexane mixtures, gave 26
[0.4789 g, 50% or 88% after correction for recovered 25 (0.2448
g, 40%)] as a clear, colorless oil: FTIR (CHCl3, cast) 3415, 2984,
1
temperature: FTIR (CH2Cl2, cast) 2970, 2878, 1683 cm-1; H
NMR (CDCl3, 500 MHz) δ 1.43 (s, 3 H), 1.69-1.78 (m, 1 H),
2.14-2.21 (m, 1 H), 2.40-2.46 (m, 1 H), 2.59 (apparent d, J
4.0 Hz, 2 H), 3.76 (sextet, J ) 4.5 Hz, 1 H), 3.86 (q, J ) 8.0
Hz, 1 H), 5.88 (d, J ) 10.2 Hz, 1 H), 6.52 (dd, J ) 10.2, 1.8 Hz,
1 H); 13C NMR (CDCl3, 125 MHz) δ 23.7 (q), 31.6 (t), 38.1 (t),
43.3 (d), 66.0 (t), 78.9 (s), 128.0 (d), 152.7 (d), 197.6 (s); exact
mass m/z calcd for C9H12O2 152.08372, found 152.08378.
Acetic Acid 3-(2-Acetoxyeth yl)-4-m eth ylp h en yl Ester
(20c). TsOH‚H2O (5 mg, 0.03 mmol) was added to a stirred
solution of 20b (13.9 mg, 0.0914 mmol) in a mixture of
CH2Cl2 (2 mL) and Ac2O (1 mL), and stirring was continued
for 160 min. The flask was fitted with a condenser and then
lowered into an oil bath preset at 110 °C. After 2 h, the mixture
was cooled and the excess of Ac2O was removed under oil pump
vacuum. The mixture was partitioned between water and
Et2O, and the combined organic extracts were washed with
saturated aqueous NaHCO3 and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica
gel, using hexane-CH2Cl2 mixtures from 100% hexane to
100% CH2Cl2, gave 20c (14.9 mg, 69%) as an oil: FTIR (CHCl3,
1750, 1632, 1609, 1513 cm-1 1H NMR (CDCl3, 400 MHz) δ
;
1.21 (t, J ) 7.2 Hz, 3 H), 1.68 (d, J ) 6.8 Hz, 3 H), 4.19 (q, J
) 7.1 Hz, 2 H), 4.75 (dt, J ) 5.6, 1.8 Hz, 2 H), 4.78 (q, J ) 6.8
Hz, 1 H), 5.39 (dq, J ) 10.4, 1.2 Hz, 1 H), 5.48 (dq, J ) 17.2,
1.5 Hz, 1 H), 6.08-6.18 (m, 1 H), 6.7 (s, 2 H), 6.83 (dd, J )
7.8, 0.7 Hz, 1 H), 7.31 (dd, J ) 7.8, 8.5 Hz, 1 H), 7.92 (dd, J )
8.6, 1.0 Hz, 1 H), 9.04 (s, 1 H); 13C NMR (CDCl3, 100.6 MHz)
δ 14.2 (q), 18.7 (q), 61.2 (t), 70.4 (t), 74.1 (s), 106.4 (d), 108.9
(d), 109.5 (d), 115.9 (s), 116.7 (d), 119.8 (t), 125.3 (d), 128.6 (s),
131.8 (d), 146.2 (s), 149.0 (s), 154.9 (s), 172.5 (s); exact mass
m/z calcd for C18H20O4 316.13107, found 316.13089.
cast) 2959, 1761, 1739, cm-1 1H NMR (CDCl3, 500 MHz) δ
;
2.03 (s, 3 H), 2.26 (s, 3 H), 2.29 (s, 3 H), 2.91 (t, J ) 7.2 Hz, 2
H), 4.24 (t, 7.2 Hz, 2 H), 6.83-6.87 (m, 2 H), 7.13 (d, J ) 7.8
Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 18.9 (q), 21.0 (q), 21.2
(q), 32.4 (t), 63.6 (t), 119.6 (d), 122.3 (d), 131.0 (d), 133.9 (s),
137.1 (s), 148.7 (s), 169.5 (s), 170.8 (s); exact mass m/z calcd
for C13H16O4 236.10486, found 236.10471.
8-Allyloxy-4-[(1R)-2-h yd r oxy-1-m eth yleth oxy]n a p h th a -
len -1-ol (27). LiAlH4 (0.0149 g, 0.392 mmol) was added to a
stirred solution of 26 (0.1661 g, 0.5223 mmol) in THF (15 mL).
After 10 min, aqueous sodium potassium tartrate (20% w/v, 5
mL) was added. The mixture was stirred for a further 20 min,
and then partitioned between water and Et2O. The aqueous
phase was extracted twice with Et2O and the combined organic
extracts were washed with brine, dried (MgSO4), and evapo-
rated. Flash chromatography of the residue over silica gel (21
× 2.3 cm), using 1:1 EtOAc-hexane, gave 27 (146.9 mg, 100%)
as clear, light green flakes: mp 76-78 °C; FTIR (CHCl3, cast)
5-(Allyloxy)-1,4-n aph th oqu in on e (24). Allyl bromide (1.82
g, 1.30 mL, 15.0 mmol) and silver(I) oxide (2.61 g, 11.3 mmol)
were added to a stirred solution of juglone (23) (1.31 g, 7.52
mmol) in CH2Cl2 (20 mL), and stirring was continued for 20
h. Additional portions of allyl bromide (0.84 g, 0.60 mL, 6.9
mmol) and silver(I) oxide (1.8 g, 7.8 mmol) were added, and
the mixture was then refluxed for 11 h. The mixture was cooled
and partitioned between water and CH2Cl2, and the aqueous
phase was extracted with CH2Cl2. The combined organic
extracts were washed with saturated aqueous NaHCO3 and
water, dried (MgSO4), and evaporated. Flash chromatography
of the residue over silica gel (25 × 2.8 cm), using 1:4 EtOAc-
hexane, gave 24 (1.28 g, 79%) as a yellow-orange solid: mp
54-56 °C; FTIR (CHCl3, cast) 1659, 1613, 1583 cm-1; 1H NMR
(CDCl3, 400.1 MHz) δ 4.66 (dt, J ) 4.8, 1.7 Hz, 2 H), 5.31 (dq,
J ) 10.7, 1.6 Hz, 1 H), 5.60 (dq, J ) 17.4, 1.6 Hz, 1 H), 6.03
(apparent q of t, J ) 10.7, 4.7 Hz, 1 H), 6.80 (AB q, J ) 2.0,
10.2 Hz, ∆νAB ) 6.3 Hz, 2 H), 7.22 (dd, J ) 8.2, 1.3 Hz, 1 H),
7.58 (t, J ) 8.2 Hz, 1 H), 7.65 (dd, J ) 6.3, 1.3 Hz, 1 H); 13C
NMR (CDCl3, 100.6 MHz) δ 69.7 (t), 117.9 (t), 119.2 (d), 119.3
(d), 120.0 (s), 131.9 (d), 134.0 (s), 134.7 (d), 136.0 (d), 140.8
(d), 158.5 (s), 184.0 (s), 185.1 (s); exact mass m/z calcd for
3414, 2975, 2932, 1630, 1609, 1512 cm-1 1H NMR (CDCl3,
;
400.1 MHz) δ 1.30 (d, J ) 6.5, 3 H), 3.78-3.85 (m, 2 H), 4.50-
4.59 (m, 1 H), 4.77 (dt, J ) 5.6, 1.4 Hz, 2 H), 5.41 (dq, J )
10.3, 1.2 Hz, 1 H), 5.50 (dq, J ) 17.3, 1.2 Hz, 1 H), 6.10-6.20
(m, 1 H), 6.83 (br d, J ) 7.5, 1 H), 6.84 (AB q, J ) 8.6 Hz,
∆νAB ) 148.2 Hz, 2 H), 7.30 (AB q, J ) 7.8 Hz, ∆νAB ) 3.6 Hz,
1 H), 7.84 (dd, J ) 8.5, 0.9 Hz, 1 H), 9.06 (s, 1 H), OH signal
not observed in this spectrum; 13C NMR (CDCl3, 100.5 MHz)
δ 16.2 (q), 66.6 (t), 70.4 (t), 76.6 (d), 106.2 (d), 109.3 (d), 111.3
(d), 115.8 (s), 116.1 (d), 119.7 (t), 125.2 (d), 129.3 (s), 131.7 (d),
145.7 (s), 148.7 (s), 155.0 (s); exact mass m/z calcd for C16H18O4
274.12051, found 274.12067.
8-Allyloxy-4-[(1R)-2-iod o-1-m eth yleth oxy]n a p h th a len -
1-ol (28). Ph3P (0.3337 g, 1.272 mmol) and then imidazole
(0.0914 g, 1.34 mmol) were added to a stirred solution of 27
(0.1255 g, 0.4547 mmol) in THF (10 mL) (Ar atmosphere). The
C
13H10O3 214.06299, found 214.06276.
J . Org. Chem, Vol. 69, No. 10, 2004 3291

Clive et al.
mixture was transferred to an ice bath (continued stirring),
and I2 (0.2620 g, 1.032 mmol) was added in one portion. After
2.5 h, the ice bath was removed and stirring was continued
overnight. The mixture was partitioned between water and
EtOAc. The aqueous phase was extracted with EtOAc, and the
combined organic extracts were washed with aqueous Na2S2O3
(10% w/v), water, and dilute hydrochloric acid (5%), dried
(MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (24 × 2.8 cm), using first hexane and then
EtOAc-hexane mixtures up to 1:6 EtOAc-hexane, gave 28
(0.1568 g, 89%) as an oil: FTIR (CHCl3, cast) 3414, 2977, 2930,
for both isomers reported, as extensive overlapping prevents
allocation of signals to individual isomers) δ 21.4 (q), 22.6 (q),
37.7 (t), 39.4 (t), 39.9 (d), 40.8 (d), 43.4 (t), 44.5 (t), 50.4 (q),
51.3 (q), 69.47 (t), 69.48 (t), 75.2 (d), 75.4 (d), 105.6 (s), 106.6
(s), 113.2 (d), 113.4 (d), 117.5 (two coincident t), 119.5 (d), 119.7
(d), 122.3 (s), 122.4 (s), 132.40 (d), 132.44 (d), 134.1 (d), 134.5
(d), 142.6 (s), 142.8 (s), 156.4 (s), 156.9 (s), 196.2 (s), 196.4 (s);
exact mass m/z calcd for C17H20O4 288.13617, found 288.13558.
(2R)-6-Allyloxy-2-m eth yl-2,3-d ih yd r on a p h th o[1,2-b]fu -
r a n -5-ol (32). AcOH (ca. 0.3 mL) was added to a stirred
solution of 31 (0.0733 g, 0.253 mmol) in CHCl3 (5 mL), and
stirring was continued for 2 h. Evaporation of the solvent at
room temperature (oil pump vacuum) and flash chromatog-
raphy of the residue over silica gel (22 × 2.8 cm), using 1:10
EtOAc-hexane, gave 32 (57.6 mg, 88%) as a white solid: mp
77-78 °C; FTIR (CHCl3, cast) 3423, 2972, 2928, 1641, 1605,
1
1631, 1608 cm-1; H NMR (CDCl3, 300 MHz) δ 1.50 (d, J )
6.0, 3 H), 3.35-3.47 (m, 2 H), 4.32-4.42 (m, 1 H), 4.76 (dt, J
) 5.6, 1.3 Hz, 2 H), 5.40 (dq, J ) 10.5, 1.2 Hz, 1 H), 5.49
(dq, J ) 17.2, 1.2 Hz, 1 H), 6.07-6.21 (m, 1 H), 6.72-6.84
(m, 3 H), 7.30 (AB q, J ) 7.8 Hz, ∆νAB ) 3.6 Hz, 1 H), 7.86
(dd, J ) 8.6, 0.9, 1 H), 9.06 (s, 1 H); 13C NMR (CDCl3, 125
MHz) δ 10.4 (t), 20.3 (q), 70.3 (t), 74.6 (d), 106.3 (d), 109.2 (d),
111.1 (d), 115.9 (s), 116.5 (d), 119.7 (t), 125.3 (d), 129.3 (s),
131.7 (d), 145.3 (s), 148.9 (s), 154.9 (s); exact mass m/z calcd
for C16H17IO3 384.02225, found 384.02247.
1
1524 cm-1; H NMR (CDCl3, 500 MHz) δ 1.50 (d, J ) 6.3 Hz,
3 H), 2.92 (apparent dd, J ) 16.0, 7.6 Hz, 1 H), 3.41 (apparent
dd, J ) 15.4, 8.9 Hz, 1 H) (formally part of an ABX system),
4.74 (apparent d, J ) 5.6 Hz, 2 H), 4.99-5.06 (m, 1 H), 5.38
(dq, J ) 10.5, 1.1 Hz, 1 H), 5.48 (dq, J ) 17.3, 1.4 Hz, 1 H),
6.13 (ddt, J ) 17.3, 10.5, 5.6 Hz, 1 H), 6.71 (d, J ) 7.6 Hz, 1
H), 6.73 (s, 1 H), 7.23 (t, J ) 8.2 Hz, 1 H), 7.48 (dd, J ) 8.4,
0.8 Hz, 1 H), 9.00 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 21.9
(q), 38.4 (t), 70.2 (t), 79.6 (d), 105.1 (d), 107.1 (d), 114.2 (s),
115.6 (d), 119.6 (t), 121.6 (s), 121.9 (s), 125.1 (d), 131.8 (d),
147.5 (s), 148.3 (s), 155.2 (s); exact mass m/z calcd for C16H16O3
256.10995, found 256.10936.
8-Allyloxy-4-[(1R)-2-iod o-1-m eth yleth oxy]-4-m eth oxy-
4H-n a p h th a len -1-on e (29). DDQ (0.0878 g, 0.388 mmol),
followed immediately by K2CO3 (0.0534 g, 0.387 mmol), was
added to a stirred solution of 28 (0.0995 g, 0.258 mmol) in
MeOH. After 4 min, aqueous Na2S2O3 (2 mL, 10% w/v) and
water (10 mL) were added. The mixture was partitioned
between EtOAc and water, and the aqueous phase was
extracted with EtOAc. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (21 × 2 cm),
using 1:4 EtOAc-hexane, gave 29 (0.0938 g, 87%) as an oil
[ca. 1:1.15 mixture of diastereoisomers (1H NMR)]: FTIR
In another experiment, an NMR sample (43.2 mg, 0.149
mmol) was left overnight in CDCl3, and evaporation of the
solvent, followed by flash chromatography, gave 32 (37.1 mg,
97%).
(2R)-6-Allyloxy-2-m eth yl-2,3-d ih yd r on a p h th o[1,2-b]fu -
r a n -4,5-d ion e (33). [PhSe(O)]2O21 (70%, 0.1859 g, 0.5162
mmol) was added in one portion to a stirred solution of 32
(0.0666 g, 0.258 mmol) in THF (10 mL). After 12 min, water
(20 mL) was added and the mixture was extracted with EtOAc
(2 × 20 mL). The combined organic extracts were washed with
saturated aqueous NaHCO3, dried (MgSO4), and evaporated.
Flash chromatography of the residue over silica gel (22 × 2.2
cm), using 3:7 to 1:1 EtOAc-hexane mixtures, gave 33 (0.0676
g, 96%) as a red powder. Recrystallization from CHCl3-hexane
(dissolution in CHCl3 and addition of hexane) gave 33 (0.574
g, 82%) as orange-red needles: mp 118-120 °C; FTIR (CHCl3,
cast) 2978, 1683, 1647, 1621, 1576 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.54 (d, J ) 6.4, 3 H), 2.70 (apparent dd, J ) 15.3, 7.3
Hz, 1 H), 3.24 (apparent dd, J ) 15.3, 9.8 Hz, 1 H) (formally
part of an ABX system), 4.68 (dt, J ) 4.4, 1.8 Hz, 2 H), 5.15-
5.24 (m, 1 H), 5.34 (dq, J ) 10.7, 1.6 Hz, 1 H), 5.74 (dq, J )
17.2, 1.7 Hz, 1 H), 5.99-6.08 (m, 1 H), 7.11 (d, J ) 8.6 Hz, 1
H), 7.26 (dd, 7.4, 0.8 Hz, 1 H), 7.53 (dd, 8.6, 7.5 Hz, 1 H); 13C
NMR (CDCl3, 100 MHz) δ 21.9 (q), 33.5 (t), 69.4 (t), 84.0 (d),
114.5 (s), 117.4 (d), 117.7 (t), 117.9 (d), 118.3 (s), 129.5 (s), 131.5
(d), 135.5 (d), 160.7 (s), 169.2 (s), 175.5 (s), 180.0 (s); exact mass
m/z calcd for C16H14O4 270.08920, found 270.08915.
(CHCl3, cast) 3396, 2924, 1659, 1608, 1582 cm-1 1H NMR
;
(CDCl3, 300 MHz, signals for both isomers reported, as
extensive overlapping prevents allocation of signals to indi-
vidual isomers) δ 1.23 (d, J ) 6.2, 1.4 H), 1.35 (d, J ) 6.1 Hz,
1.6 H), 2.90 (dd, J ) 10.0, 7.3 Hz, 0.6 H), 3.01 (dd, J ) 10.0,
3.8 Hz, 0.4 H), 3.10 (s, 1.6 H), 3.13 (s, 1.4 H), 3.20-3.33 (m, 1
H), 3.72-3.86 (m, 1 H), 4.66-4.70 (m, 2 H), 5.35 (apparent
dt, J ) 10.7, 1.5 Hz, 1 H), 5.68 (apparent dq, J ) 17.2, 1.7 Hz,
1 H), 6.04-6.17 (m, 1 H), 6.47 (apparent dd, J ) 10.4, 1.5 Hz,
1 H), 6.75 (d, J ) 10.5 Hz, 0.5 H), 6.81 (d, J ) 10.5 Hz, 0.5 H),
7.01 (dd, J ) 8.3, 2.8 Hz, 1 H), 7.42 (dd, J ) 7.8, 2.9, 1.0 Hz,
1 H), 7.58 (td, J ) 8.1, 1.8 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 11.6 (t), 13.08 (t), 21.6 (q), 22.4 (q), 51.3 (q), 51.4 (q),
68.9 (d), 69.3 (d), 69.6 (two coincident t), 95.3 (s), 95.4 (s), 114.1
(d), 114.2 (d), 117.6 (t), 117.7 (t), 119.7 (d), 119.8 (d), 120.5 (s),
120.6 (s), 132.25 (d), 132.28 (d), 133.9 (d), 134.0 (d), 134.4 (two
coincident d), 139.9 (d), 140.5 (d), 143.0 (s), 143.2 (s), 158.7
(s), 158.8 (s), 183.14 (s), 183.15 (s); exact mass m/z calcd for
C
17H19IO4 414.03281, found 414.03241.
(2R)-6-Allyloxy-9b-m eth oxy-2-m eth yl-2,3,3a,9b-tetr ah y-
d r o-4H -n a p h t h o[1,2-b]fu r a n -5-on e (31).
A solution of
Bu3SnH (0.19 mL, 0.70 mmol) and AIBN (0.010 g) in PhMe (5
mL) was added over 9 h (syringe pump) to a stirred and heated
(85 °C) solution of 29 (0.2246 g, 0.5399 mmol) in PhMe (10
mL). Heating at 85 °C was continued for 6 h after the addition.
The solvent was evaporated, and flash chromatography of the
residue over silica gel (26 × 2.8 cm), using 1:20:30 Et3N-
EtOAc-hexane, gave 31 (0.1286 g, 82%) as an oil: FTIR
(2R)-6-Hyd r oxy-2-m eth yl-2,3-d ih yd r on a p h th o[1,2-b]fu -
r a n -4,5-d ion e [en t-Noca r d ion e A] (34). Dimedone (0.0623
g, 0.444 mmol) and then Pd(PPh3)4 (0.0259 g, 0.0223 mmol)
were added to a stirred solution of 33 (0.0574 g, 0.211 mmol).
Stirring was continued for 4 min, and the mixture was then
evaporated (rotary evaporator) at room temperature. Flash
chromatography of the reside over silica gel (24 × 1.8 cm),
using 0.1:10:90 HCO2H-EtOAc-CHCl3, gave a crude red
powder (0.0557 g). (Use of acid in the solvent is essential for
effective purification, but recrystallization is still necessary.)
Recrystallization from EtOAc-hexane gave 34 [(R)-(+)-nocar-
dione A, ent-nocardione A] (0.0359 g, 74%) in the form of curled
red needles: mp 168-169 °C [if the crystalline material is
dissolved in a solvent and the solution evaporated to leave a
powder, the powder changes to needles (mp 168-169 °C) at
or below 158 °C]; [R]25 +36.8 (c 1.0 CHCl3, 10 cm cell); [R]25
1
(CHCl3, cast) 2968, 2934, 1694, 1593 cm-1; H NMR (CDCl3,
300 MHz, signals for both isomers reported, as extensive
overlapping prevents allocation of signals to individual iso-
mers) δ 1.26 (d, J ) 6.2 Hz, 1.5 H), 1.40 (d, J ) 6.2 Hz, 1.5 H),
1.87-1.96 (m, 0.5 H), 2.01-2.12 (m, 0.5 H), 2.39-2.49 (m, 0.5
H), 2.62-2.86 (m, 2 H), 3.00-3.14 (m, 1 H), 3.13 (s, 1.5 H),
3.15 (s, 1.5 H), 4.34-4.51 (m, 1 H), 4.54-4.69 (m, 2 H), 5.31
(apparent dt, J ) 10.6, 1.5 Hz, 1 H), 5.56 (dm, J ) 17.2 Hz, 1
H), 5.99-6.12 (m, 1 H), 6.94 (br d, J ) 8.3 Hz, 1 H), 7.32
(apparent d of quintets, J ) 8.6, 0.9 Hz, 1 H), 7.52 (apparent
sextet, J ) 4.2 Hz, 1 H); 13C NMR (CDCl3, 125 MHz, signals
D
D
+49.5 (c 0.97 CHCl3, 1 cm cell) {lit.13 [R]21 -56.0 (c 0.97
D
3292 J . Org. Chem., Vol. 69, No. 10, 2004

Formal Radical Cyclization onto Benzene Rings
CHCl3; lit.12 [R]26 -85.4 (c 1.0 CHCl3)}; FTIR (CHCl3, cast)
cial support, Dr. X. Lu and H. Lachance for HPLC
measurements, and M. Zhu for preliminary studies.
S.P.F. holds an NSERC Postgraduate Scholarship.
D
2961, 2925, 1643, 1615, 1589, 1499 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.56 (d, J ) 6.3, 3 H), 2.72 (apparent dd, J ) 15.4, 7.2
Hz, 1 H), 3.25 (apparent dd, J ) 15.3, 9.8 Hz, 1 H) (formally
part of an ABX system), 5.19-5.27 (m, 1 H), 7.11 (dd, J ) 8.7,
0.9 Hz, 1 H), 7.18 (br d, J ) 6.7 Hz, 1 H), 7.53 (dd, J ) 8.6, 7.3
Hz, 1 H), 11.93 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ 21.9
(q), 33.4 (t), 84.5 (d), 113.4 (s), 115.1 (s), 117.4 (d), 123.2 (d),
127.4 (s), 137.5 (d), 164.4 (s), 169.1 (s), 175.0 (s), 185.4 (s); exact
mass m/z calcd for C13H10O4 230.05791, found 230.05774.
HPLC conditions for measurement of ee: column, chiralcell
AD-RHCD-CC012 column (0.46 cm × 15 cm); eluant 2:1
water-MeCN; flow rate 0.6 mL/min; detection at 230 nm;
temperature 25 °C; sample concentration and injection value
1 mL/mg in MeCN × 0.5 µL. Under these conditions (S)-(-)-
nocardione A was detected at Rt 40.31 min, and (R)-(+)-
nocardione A was detected at Rt 42.82 min. Our synthetic (R)-
nocardione A had 98.55% ee.
Note Ad d ed a fter ASAP P ostin g. There was a bond
missing in the structure of compounds 21 and 22 in the
version posted ASAP April 17, 2004; the corrected version
was posted April 20, 2004.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
10a -c, 11a -c,e, 12a -c, 13a ,b, 14c-e,g,k , 2-bromomethyl-
3-iodonaphthalene, 15a -d , 17a -c, 18a ,c,e,g-j, 19a -e,g,i,
20a -c, 24-29, and 31-34, and experimental general tech-
niques and procedures for 10c, 11a -d , 12a -d , 13a ,b ,
14a -d ,g-h , 2-bromomethyl-3-iodonaphthalene, 18e-g, and
19a -j. This material is available free of charge via the Internet
at http://pubs.acs.org.
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada for finan-
J O030364K
J . Org. Chem, Vol. 69, No. 10, 2004 3293