Efficient access to orthoquinols and their [4 + 2] cyclodimers via SIBX-mediated hydroxylative phenol dearomatization

Article abstract of DOI:10.1021/jo0708893

(Chemical Equation Presented) SIBX, the nonexplosive formulation of the λ⁵-iodane 2-iodoxybenzioc acid (IBX), safely and efficiently mediates the hydroxylative dearomatization of various 2-alkylphenols and napthols into orthoquinols or their [4 + 2] cyclodimers. Reactions are typically run at room temperature using SIBX as a suspension in THF. Using these conditions, natural products such as the cyclodimer of the terpene carvacrol and, for the first time, the shikimate-derived (±)-grandifloracin were prepared in one step from their respective phenolic precursor.

Full text of DOI:10.1021/jo0708893

Efficient Access to Orthoquinols and Their
[4 + 2] Cyclodimers via SIBX-Mediated
Hydroxylative Phenol Dearomatization
Nathalie Lebrasseur,†,‡ Julien Gagnepain,†,‡
Aure´lie Ozanne-Beaudenon,†,‡ Jean-Michel Le´ger,§ and
Ste´phane Quideau*,†,‡
UniVersite´ de Bordeaux, Institut Europe´en de Chimie et
Biologie, 2 rue Robert Escarpit, 33607 Pessac Cedex, France,
Institut des Sciences Mole´culaires (CNRS-UMR 5255), 351
cours de la Libe´ration, 33405 Talence Cedex, France, and
Laboratoire de Pharmacochimie, 146 rue Le´o Saignat,
33076 Bordeaux Cedex, France
s.quideau@iecb.u-bordeaux.fr
ReceiVed April 27, 2007
FIGURE 1. Examples of natural nondimerizing orthoquinols and
orthoquinol-derived [4 + 2] cyclodimers.
undergo spontaneous [4 + 2] cyclodimerizations. Only when
their substitution pattern sterically blocks their [4 + 2] cycload-
dition can these species be isolated from their natural sources.1a
The structures displayed in Figure 1 exemplify both natural
nondimerizing orthoquinols [e.g., humulone (1),2 wasabidienone
B1 (2),3 and the epoxide scyphostatin (3)4] and orthoquinol-
derived cyclodimers [e.g., aquaticol (4),5 bisorbicillinol (5),6 and
grandifloracin (6)7].
Direct additions of carbon-based nucleophiles to orthoquino-
nes are of limited synthetic value to access orthoquinols because
of the difficulty in controlling the regioselectivity of this
carbon-carbon bond formation, which is further complicated
by the instability of most orthoquinones.1a A much better
strategy is based on phenol dearomatization tactics that can
instead promote the formation of the carbon-oxygen bond of
the tertiary alcohol function. Over the last 50 years, several
oxygenative dearomatizing systems have thus been examined
to generate orthoquinols from 2-alkylphenols with some suc-
cess.1 More recently, the utilization of the λ5-iodane 2-iodoxy-
benzoic acid (IBX) or its stabilized nonexplosive version (SIBX,
i.e., 49% IBX, 22% benzoic acid, 29% isophthalic acid)8 was
explored by the Pettus group9a and us,9b and these were thus
revealed as a promising general alternative to mediate hydroxy-
lative phenol dearomatization (HPD) reactions in an ortho-
selective manner. We wish to report herein our results on the
SIBX, the nonexplosive formulation of the λ5-iodane 2-io-
doxybenzioc acid (IBX), safely and efficiently mediates the
hydroxylative dearomatization of various 2-alkylphenols and
napthols into orthoquinols or their [4 + 2] cyclodimers.
Reactions are typically run at room temperature using SIBX
as a suspension in THF. Using these conditions, natural
products such as the cyclodimer of the terpene carvacrol and,
for the first time, the shikimate-derived (()-grandifloracin
were prepared in one step from their respective phenolic
precursor.
6-Alkyl-6-hydroxycyclohexa-2,4-dienone derivatives are com-
monly referred to as orthoquinols, for they can be viewed as
deriving from orthoquinones in which one of the two carbonyl
groups is replaced by a tertiary alcohol function. Such an
arrangement of a chiral carbon center adjacent to a conjugated
dienone unit within a six-membered ring system makes ortho-
quinols attractive intermediates for the rapid construction of
complex structural architectures.1 Evidence of such a synthetic
potential can be gleaned from the chemistry of several naturally
occurring substances that either feature an orthoquinol moiety
or biosynthetically derive from an orthoquinol intermediate
(Figure 1).1 Natural orthoquinols are not often identified as such,
because of the propensity of their hydroxydienone system to
(2) (a) Goese, M.; Kammhuber, K.; Bacher, A.; Zenk, M. H.; Eisenreich,
W. Eur. J. Biochem. 1999, 263, 447-454. (b) Stevens, R. Chem. ReV. 1967,
67, 19-71.
(3) Soga, O.; Iwamoto, H.; Takuwa, A.; Takata, T.; Tsugiyama, Y.;
Hamada, K.; Fujiwara, T.; Nakayama, M. Chem. Lett. 1988, 1535-1536.
(4) Saito, S.; Tanaka, N.; Fujimoto, K.; Kogen, H. Org. Lett. 2000, 2,
505-506.
(5) Su, B.-N.; Zhu, Q.-X.; Jia, Z.-J. Tetrahedron Lett. 1999, 40, 357-
358.
(6) (a) Abe, N.; Murata, T.; Hirota, A. Biosci. Biotechnol. Biochem. 1998,
62, 661-666. (b) Nicolaou, K. C.; Simonsen, K. B.; Vassilikogiannakis,
G.; Baran, P. S.; Vidali, V. P.; Pitsinos, E. N.; Couladouros, E. A. Angew.
Chem., Int. Ed. 1999, 38, 3555-3559.
(7) Liao, Y.-H.; Xu, L.-Z.; Yang, S.-H.; Dai, J.; Zhen, Y.-S.; Zhu, M.;
Sun, N.-J. Phytochemistry 1997, 45, 729-732.
(8) (a) Ozanne, A.; Pouyse´gu, L.; Depernet, D.; Franc¸ois, B.; Quideau,
S. Org. Lett. 2003, 5, 2903-2906. (b) Depernet, D.; Franc¸ois, B. WO, 02/
057210 A1, U.S. 2002/0107416, PCT/FR02/00189.
† Institut Europe´en de Chimie et Biologie.
‡ Institut des Sciences Mole´culaires.
§ Laboratoire de Pharmacochimie.
(1) (a) Quideau, S. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
VCH: Weinheim, 2002; pp 539-573. (b) Quideau, S.; Pouyse´gu, L. Org.
Prep. Proced. Int. 1999, 31, 617-680. (c) Magdziak, D.; Meek, S. J.; Pettus,
T. R. R. Chem. ReV. 2004, 104, 1383-1429.
10.1021/jo0708893 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/12/2007
6280
J. Org. Chem. 2007, 72, 6280-6283

TABLE 1. SIBX-Mediated HPD of 2-Alkylphenols
treatment of 7a with SIBX in THF furnished 9a in 96% yield
(Table 1, entry 1), after treating the reaction mixture with TFA
(1.0 equiv). Similarly, the 2,4,6-trimethylated phenol 7b was
converted into dimer 9b10a,12 in 94% yield (Table 1, entry 2).
These first two examples demonstrate the excellent level of
ortho-oxygenation control brought about by the use of the
stabilized IBX reagent. This regioselectivity is a consequence
of the initial step of the reaction during which the hypervalent
iodine(V) center of IBX probably exchanges one of its oxygen
ligands with the reacting phenol through a condensation event
(i.e., 1 equiv of H2O is generated).8a,9 The resulting phenyloxy-
λ5-iodanyl species can then rearrange in a sigmatropic-like
manner by forming a single oxygen-carbon bond at either
available methylated ortho-carbon center of the starting phenol,
with concomitant reduction of the iodine(V) center into the
iodine(III) center of a 2-iodosobenzoic acid (IBA) unit then still
linked at the ortho-carbon center undergoing the sp2 f sp3
hybridation change. In support of this sequence of events is
our observation of 2,6-di-tert-butylphenol that remained refrac-
tory to these HPD reaction conditions, probably because the
steric bulk of the two tert-butyl groups either masks the phenolic
hydroxy group or prevents the intramolecular oxygenation of
their carbon bearers.
The high yields of conversion of 7a and 7b into cyclodimers
9a and 9b were not totally unexpected, since the two ortho-
positions of these symmetrically substituted phenols are equiva-
lent. We then submitted the 2,6-dimethylphenols 7c and 7d,
which also bear either a methyl or a methoxy group at their
3-position, to the same reaction conditions. Hydroxylation
cleanly and solely occurred at both methylated ortho-positions
to about the same extent. Interestingly, in each case, only the
orthoquinol resulting from oxygenation at the methylated
6-position of the starting phenol dimerized to give either 9c13a
or 9d (Table 1, entries 3 and 4). Indeed, the presence of a small
alkyl or alkoxy group at the 5-position of an orthoquinol is
known to block the Diels-Alder process.13 Hence, when
oxygenation takes place at the methylated 2-position of 7c or
7d, the resulting orthoquinols 8c13a and 8d are also isolated as
such (Table 1, entries 3 and 4).
a Reactions run in THF using SIBX (1.1 equiv) at rt for 24 h. b Isolated
yield after chromatography. c Isolated yield after chromatography and
crystallization. d The methyl enol ether of the bridge unit of the expected
dimer suffered hydrolysis during processing to furnish the triketone 9d.
We then wondered about what could happen when using
phenols featuring an alkyl group at only one of its two ortho-
positions. Is the inductive electron release of an alkyl group
enough to direct oxygenation exclusively at its carbon bearer?
The answer is negative in contrast to what is observed with
phenols singly ortho-substituted by a conjugating electron-
releasing alkoxy group.8a,14 Thus, treatment of 2,5-dimethylphe-
nol (7e) with SIBX under the same reaction conditions furnished
dimer 9e,10c together with an unstable orthoquinone (not shown)
resulting from oxygenation at the free ortho-position. A reduc-
tive step was then added to the workup procedure using Na2S2O4
in the aim of isolating the corresponding catechol, but this was
also found to be unstable during standard silica gel chroma-
tography.15 Dimer 9e was then the sole product isolated from
this reaction in 49% yield after crystallization (Table 1, entry
5). Similarly, 5-tert-butyl-2-methylphenol (7f) gave rise to the
expected dimer 9f9b in 39% yield (Table 1, entry 6). Again, the
use of SIBX to convert directly, cleanly, and safely 2-alkylated
phenols and naphthols into orthoquinols or their corresponding
[4 + 2] cyclodimers.
The first phenol that was submitted to the SIBX-mediated
HPD reaction was 2,6-dimethylphenol (7a). The resulting
orthoquinol dimerizes spontaneously to furnish the known [4
+ 2] cyclodimer 9a10a,b,11 (Table 1). This dimer was previously
obtained in 51% yield by using standard IBX in DMF, followed
by a reductive (Na2S2O4) workup.9a Gratifyingly, we found that
(9) (a) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus,
T. R. R. Org. Lett. 2002, 4, 285-288. (b) Quideau, S.; Pouyse´gu, L.;
Deffieux, D.; Ozanne, A.; Gagnepain, J.; Fabre, I.; Oxoby, M. ARKIVOC
2003, 6, 106-119.
(10) (a) Adler, E.; Dahlen, J.; Westin, G. Acta Chem. Scand. 1960, 14,
1580-1596. (b) Karlsson, B.; Pilotti, A.-M.; Wiehager, A.-C. Acta Chem.
Scand. 1973, 27, 2945-2954. (c) Adler, E.; Holmberg, K. Acta Chem.
Scand. 1974, B28, 465-472.
(11) This dimer is a metabolite of the bacterial degradation of 7a. See:
Kneifel, H.; Poszich-Busher, C.; Rittich, S.; Breitmaier, E. Angew. Chem.,
Int. Ed. 1991, 30, 202-203.
(12) Siegel, A.; Wessely, F.; Stockhammer, P.; Antony, F.; Klezl, P.
Tetrahedron 1958, 4, 49-67.
(13) (a) Andersson, G. Acta Chem. Scand. 1976, B30, 64-70. (b)
Andersson, G. Acta Chem. Scand. 1976, B30, 403-406.
(14) Quideau, S.; Pouyse´gu, L.; Looney, M. A. J. Org. Chem. 1998, 63,
9597-9600.
J. Org. Chem, Vol. 72, No. 16, 2007 6281

TABLE 2. SIBX-Mediated HPD of 2-Alkylnaphthols
excess of SIBX dissolved in DMSO instead of suspended in
THF (Table 2, entry 1).19 Also, the same reaction performed
on 1-naphthol (not shown) led to the stable 1,2-naphthoquinone
in 99% yield (Supporting Information). Naphthols, as well as
phenols, bearing electron-withdrawing groups are usually refrac-
tory to iodane-mediated oxidative transformations.8a,20 Neverthe-
less, the naphtholic ester 11c could here be converted into
orthoquinol 13 in 74% yield after 7 days in EtOAc at 50 °C
(Table 2, entry 2). More complex naphthol-derived orthoquinols
were then targeted in the context of our ongoing efforts toward
the synthesis of natural angucyclines bearing oxygen atoms at
the two AB ring fusion positions of their ABCD benz[a]-
anthracenic ring system.21 Orthoquinols 14 and 15 can serve as
useful models to explore different tactics for the construction
of angucycline AB ring systems, such as that of aquayamy-
cin.21,22 These two orthoquinols were obtained in high yields
from naphthols 11d and 11e (Table 2, entries 3 and 4, and
Supporting Information).
a Reactions run in THF using SIBX (1.1 equiv) at rt for 14 h, unless
otherwise noted. b Isolated yields. c Reaction run using SIBX (2.5 equiv)
in DMSO at rt for 2 h. d Reaction run in EtOAc at 50 °C for 7 days.
No treatment of reaction mixtures with TFA was necessary
in these cases of nondimerizing naphthoid orthoquinols (Table
2). However, the advantage of treating reaction mixtures with
an organic acid such as TFA in the case of dimerizing benzoid
orthoquinols (Table 1) deserves additional comments. In fact,
when these reactions are performed using IBX, the resulting
cyclodimers still bear IBA units at their two oxygenated
tetrahedral carbon centers. This was first evidenced by Pettus
and co-workers, who isolated such a dimer from 7a.9a It thus
catechol byproduct could not be isolated. Next, the terpenoid
2-alkylphenols carvacrol (7g) and thymol (7h) were efficiently
converted into their corresponding dimers 9g16 and 9h17 (Table
1, entries 7 and 8) in yields much higher than those previously
obtained using sodium periodate or iodic acid as the oxidizing
agent (48-50% vs 12-30%).16b,17 Of particular note is the fact
that the carvacrol-derived dimer 9g has been isolated from the
heartwood of Callitris macleayana.16a In these two last runs,
the catechol 10g could be isolated in 24 and 14% yields,
respectively. The last 2-alkylphenol that was submitted to our
HPD reaction conditions was 2-hydroxybenzyl benzoate (7i),
which gave rise to (()-grandifloracin (9i) in 30% yield, after
purification by silica gel chromatography and crystallization
(Table 1, entry 9). This is the first reported synthesis of this
natural product isolated from the plant UVaria grandiflora.7
Overall, considering that the maximum possible yield of
orthoquinol-derived cyclodimers from nonsymmetrically sub-
stituted ortho-alkylated phenols is 50%, the yields we obtained
ranging from 30 to 50%, after purification, are very satisfying
(Table 1, entries 3-9). The remarkable level of regio- and
stereoselectivities observed in these Diels-Alder reactions (i.e.,
only one dimer is in each case produced out of 16 possible
dimeric racemates)10c has been rationalized in the context of
the first total synthesis of (+)-aquaticol (4).18
appears that the acidity of any unreacted IBX (pKaH O ) 2.4)23
2
is not strong enough to mediate in situ the hydrolytic cleavage
of these IBA units. When SIBX is used, this cleavage sometimes
occurs as observed for the naphthoid orthoquinols (Table 2).
We suspect that this hydrolytic capability is due to some residual
HCl left in the SIBX formulation after its preparation process.8b
We then performed a series of reactions on 7a using IBX with
or without different acids, including the benzoic acids used in
its stabilized formulation (Supporting Information, Table 3). We
thus found that the HPD reaction proceeds at a faster rate with
SIBX (12 h) than with IBX (48 h), but that the addition of a
H2O
strong organic acid such as TFA (pKa
) 0.30) to the IBX-
containing reaction mixture significantly accelerates the reaction
rate (1 h) to furnish directly the free dimer 9a. Nevertheless,
for safety reasons, we recommend the use of SIBX, followed
by a treatment of the reaction mixture with TFA before working
it up.
In conclusion, this work demonstrates the value of our SIBX-
mediated HPD reaction to access safely and cleanly orthoquinols
or their [4 + 2] cyclodimers, including natural products, in one
step from their phenolic precursors.
Having thus established the value of our SIBX-mediated HPD
reaction to generate orthoquinols from 2-alkylphenols, we turned
our attention toward 2-alkylnaphthols. 2-Methylnaphthol (11a)
was thus converted quantitatively into the orthoquinol 12 (Table
2, entry 1). It is worth noting that this HPD reaction can also
be performed on the silylated 2-methylnaphthol 11b using an
Experimental Section
General Procedure A for SIBX-Mediated HPD of 2,6-
Dimethylphenols. To a solution of starting 2,6-dimethylphenol (10
mmol) in THF (25 mL) was added SIBX (6.875 g, i.e., 11 mmol
of IBX) as a solid in one portion. The resulting suspension was
stirred at room temperature for 24 h, after which time TFA (780
(15) For reaction and purification conditions better suited for the
preparation of catechols via IBX-mediated oxygenation of phenols, see:
(a) Pezzella, A.; Lista, L.; Napolitano, A.; d’Ischia, M. Tetrahedron Lett.
2005, 46, 3541-3544. (b) Saeed, M.; Zahid, M.; Rogan, E.; Cavalieri, E.
Steroids 2005, 70, 173-178.
(16) (a) Carman, R. M.; Lambert, L. K.; Robinson, W. T.; Van Dongen,
J. M. A. M. Aust. J. Chem. 1986, 39, 1843-1850. (b) Paknikar, S. K.;
Patel, J.; Ramanamma, C. V. Proc. 11th Int. Congr. Essent. Oils, Fragrances
FlaVours 1989, 5, 105-111.
(17) Falshaw, C. P.; Franklinos, A. J. Chem. Soc., Perkin Trans. 1 1984,
95-100.
(18) Gagnepain, J.; Castet, F.; Quideau, S. Angew. Chem., Int. Ed. 2007,
46, 1533-1535.
(19) Wu, Y.; Huang, J.-H.; Shen, X.; Hu, Q.; Tang, C.-J.; Li, L. Org.
Lett. 2002, 4, 2141-2144.
(20) Ozanne-Beaudenon, A.; Quideau, S. Angew. Chem., Int. Ed. 2005,
44, 7065-7069.
(21) Krohn, K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127-195.
(22) Lebrasseur, N.; Fan, G.-J.; Oxoby, M.; Looney, M. A.; Quideau, S.
Tetrahedron 2005, 61, 1551-1562.
(23) Gallen, M. J.; Goumont, R.; Clark, T.; Terrier, F.; Williams, C. M.
Angew. Chem., Int. Ed. 2006, 45, 2929-2934.
6282 J. Org. Chem., Vol. 72, No. 16, 2007

1
µL, 10 mmol) was added, and the mixture was further stirred for
12 h. The reaction mixture was then diluted with CH2Cl2 (100 mL)
and H2O (50 mL), then neutralized with aqueous 1 M solution of
NaOH at 0 °C. The aqueous phase was extracted with CH2Cl2 (2
× 20 mL). The combined organic phases were washed with aqueous
1 M NaOH (40 mL), H2O (50 mL), and brine (2 × 50 mL), dried
over Na2SO4, filtered, and evaporated to furnish products of good
to excellent purity. Further purification and/or product separation
was carried out by column chromatography (Supporting Informa-
tion).
General Procedure B for SIBX-Mediated HPD of 2-Alky-
lphenols. To a solution of 2-alkylphenol (10 mmol) in THF (25
mL) was added SIBX (6.875 g, i.e., 11 mmol of IBX) as a solid in
one portion. The resulting suspension was stirred at room temper-
ature for 24 h, after which time TFA (780 µL, 10 mmol) was added,
and the mixture was further stirred for 12 h. The reaction mixture
was then diluted with CH2Cl2 (100 mL) and H2O (50 mL). An
aqueous 1 M solution of NaOH was added slowly and continuously
with vigorous shaking until all solid material dissolved. The aqueous
phase was extracted with CH2Cl2 (3 × 20 mL). The combined
organic phases were washed with aqueous 1 M NaOH (40 mL),
H2O (50 mL), and brine (2 × 50 mL), then shaken vigorously with
a saturated aqueous solution of Na2S2O4 (100 mL), washed again
with brine (50 mL), dried over Na2SO4, filtered, and evaporated at
room temperature to give a residue, which was then purified by
column chromatography.
(()-Grandifloracin (9i). To an ice-cooled solution of salicylic
alcohol (124 mg, 1 mmol) in CH2Cl2 (5 mL) were added Et3N (144
µL, 1 mmol) and benzoyl chloride (117 µL, 1 mmol). The resulting
mixture was stirred at room temperature for 24 h, after which time
it was quenched with a saturated aqueous solution of NH4Cl (20
mL), washed with brine (20 mL), dried over MgSO4, filtered, and
evaporated to give a crude brown oil (250 mg). Purification by
column chromatography, eluting with hexanes/acetone from (10:
1) to (3:1), gave 2-hydroxybenzyl benzoate (7i)24 as a colorless oil
(93 mg, 41%). This phenolic benzoate 7i (456 mg, 2 mmol gathered
from several runs) was then submitted to the SIBX-mediated HPD
reaction according to the general procedure B apart from the fact
that a saturated aqueous solution of Na2CO3 was used instead of
an aqueous 1 M solution of NaOH during the workup. Purification
by column chromatography, eluting with hexanes/acetone (3:1),
afforded a solid residue that was then crystallized from a mixture
of CH2Cl2 and hexanes to give pure (()-grandifloracin (9i) as white
fines crystals (146 mg, 30%). mp 188-188.5 °C (lit.7 mp 161-
163 °C); Rf ) 0.20 [hexanes/acetone, (3:1)]; IR (NaCl, neat) 3450,
1720, 1711, 1683, 1620 cm-1; 1H NMR (CDCl3, 300 MHz) δ 3.20-
3.35 (m, 3H), 3.69 (d, J ) 6.8 Hz, 1H), 4.23 (d, J ) 12.0 Hz, 1H),
4.40-4.43 (m, 2H), 4.46 (d, J ) 12.0 Hz, 1H), 6.00 (t, J ) 6.7
Hz, 1H), 6.20 (d, J ) 9.8 Hz, 1H), 6.43 (t, J ) 7.2 Hz, 1H), 6.58
(dd, J ) 3.6, 10.0 Hz, 1H), 7.92 (d, J ) 7.3 Hz, 2H), 8.05 (d, J )
7.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 208.1, 198.1, 166.6,
165.8, 146.7, 135.1, 133.4, 133.3, 129.8, 129.7, 129.3, 129.2, 128.5,
128.5, 128.4, 128.0, 75.4, 74.4, 71.8, 68.1, 52.1, 41.0, 39.9, 37.3;
ESIMS (MeOH) m/z (relative intensity) 511 [MNa+, 100]; HRMS
(ESIMS) calcd for C28H24O8Na+ 511.1369, found 511.1365.
cm-1; H NMR (CDCl3, 300 MHz) δ 3.69 (s, 3H), 6.12 (d, J )
9.8 Hz, 1H), 6.73 (d, J ) 9.8 Hz, 1H), 7.26 (d, J ) 7.5 Hz, 1H),
7.39 (dt, J ) 0.7, 7.5 Hz, 1H), 7.62 (dt, J ) 1.1, 7.5 Hz, 1H), 7.98
(d, J ) 7.5 Hz, 1H); 13C NMR (CDCl3, 75.5 MHz) δ 196.6, 169.7,
137.5, 135.5, 129.7, 129.0, 128.8, 128.1, 127.8, 127.5, 77.8, 53.7;
EIMS m/z (relative intensity) 218 (M+, 21), 159 (30), 131 (100);
HRMS (EI) calcd for C12H10O4 218.0579, found 218.0591.
2-Hydroxy-2-[(2-methyloxiran-2-yl)methyl]naphthalen-1(2H)-
one (14). To a solution of naphthol 11d (60 mg, 0.28 mmol) in
THF (2 mL) at 0 °C was added SIBX (176 mg, 0.31 mmol) as a
solid in one portion. The resulting suspension was stirred at 0 °C
for 14 h, after which time it was poured into ice-cold water (2
mL). This mixture was treated with aqueous 1 M NaOH, which
was added dropwise until pH near 9 was reached, and separated,
and the aqueous phase was extracted with EtOAc (20 mL). The
combined organic phases were washed with water (20 mL), dried
over Na2SO4, and evaporated to afford orthoquinol 14 (65 mg,
100%) as a mixture (∼50:50) of two diastereoisomers: IR (NaCl,
neat) 3428, 1716 cm-1; H NMR (CDCl3, 400 MHz) δ 1.40 (s,
1
3H), 1.39 (s, 3H), 1.75 (d, J ) 14.2 Hz, 1H), 1.88 (d, J ) 14.2 Hz,
1H), 2.00 (d, J ) 14.1 Hz, 1H), 2.17 (d, J ) 14.4 Hz, 1H), 2.50 (s,
2H), 2.54 (d, J ) 4.6 Hz, 1H), 2.67 (d, J ) 4.6 Hz, 1H), 3.62 (s,
1H), 3.62 (s, 1H), 6.31-6.38 (m, 2H), 6.48-6.51 (m, 2H), 7.19
(dd, J ) 3.0, 7.1 Hz, 2H), 7.34 (t, J ) 7.6 Hz, 2H), 7.56 (t, J ) 7.6
Hz, 2H), 7.91 (t, J ) 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ
203.80, 203.77, 137.5, 137.3, 136.0, 135.8, 135.1, 135.1, 128.4,
128.3, 127.5, 127.3, 127.2, 127.0, 124.8, 124.8, 74.4, 54.9, 54.6,
54.4, 54.2, 48.3, 47.9, 22.9, 22.6; EIMS m/z (relative intensity) 230.2
(M+, 3), 213 (6), 131 (100); HMRS (EI) calcd for C14H14O3
230.0943, found 230.0951.
2-Hydroxy-2-[(2-tert-butyldimethylsilyloxy-3-cyano)propyl]-
naphthalen-1(2H)-one (15). To a solution of naphthol 11e (46 mg,
0.135 mmol) in THF (2 mL) at 0 °C was added SIBX (85 mg,
0.15 mmol) as a solid in one portion. The resulting suspension was
stirred at 0 °C for 14 h, after which time it was poured into ice-
cold water (2 mL). This mixture was treated with aqueous 1 M
NaOH, which was added dropwise until pH near 9 was reached,
and separated, and the aqueous phase was extracted with EtOAc
(20 mL). The combined organic phases were washed with water
(20 mL), dried over Na2SO4, and evaporated to afford orthoquinol
15 as a mixture (∼60:40) of two diastereoisomers (40 mg, 83%):
IR (NaCl, neat) 3461, 2252, 1689 cm-1; H NMR (CDCl3, 400
1
MHz) δ 7.91 (bt, 1H), 7.59 (bt, 1H), 7.36 (bd, 1H), 7.20 (bd, 1H),
6.51 (d, J ) 10 Hz, 1H, minor), 6.47 (d, J ) 9.8 Hz, 1H, major),
6.31 (d, J ) 9.8 Hz, 1H, minor), 6.27 (d, J ) 9.8 Hz, 1H, major),
4.25 (m, 1H, minor), 4.11 (m, 1H, major), 2.79-2.52 (m, 2H),
2.18-1.76 (m, 1H), 0.86 (s, 9H, minor), 0.82 (s, 9H, major), 0.10
(s, 3H, minor), 0.06 (s, 3H, minor), 0.05 (s, 3H, major), -0.06 (s,
3H, major); 13C NMR (CDCl3, 100 MHz) δ 203.7, 203.5, 137.34,
137.31, 136.3, 135.42, 135.39, 135.36, 128.55, 128.45, 128.2,
127.49, 127.45, 127.3, 125.1, 124.9, 117.7, 117.4, 65.5, 64.7, 47.4,
46.5, 27.7, 27.3, 25.6, 0.97, -4.66, -4.74, -4.85, -4.89; HMRS
(ESI) calcd for C20H27NO3Si 357.1760, found 357.1773.
Acknowledgment. We thank the Institut Universitaire de
France, the Ministe`re de la Recherche, the Centre National de
la Recherche Scientifique (“Jeunes Chercheurs” ATIP Grant
2005-2007), the Association Nationale de la Recherche Tech-
nique (CIFRE Grant No. 301/2002), and Simafex for their
financial support.
Methyl 1,2-Dihydro-2-hydroxy-1-oxonaphthalene-2-carboxy-
late (13). To a solution of naphthol 11c (50 mg, 0.25 mmol) in
EtOAc (1.5 mL) was added SIBX (310 mg, 0.52 mmol) as a solid
in one portion. The resulting suspension was stirred at 50 °C for 7
days, after which time it was diluted with EtOAc (20 mL), washed
with saturated aqueous NaHCO3 (3 × 5 mL) and brine (5 mL),
dried over Na2SO4, filtered, and evaporated to give an oily residue
(109 mg). This residue was then purified by column chromatog-
raphy, eluting with cyclohexane/acetone (1:2), to furnish orthoquinol
13 (37 mg, 74%) as an orange oil. IR (NaCl) 3491, 1748, 1224
Supporting Information Available: Additional experimental
details, characterization data and H and 13C NMR spectra for all
1
compounds, ORTEP diagrams of all new X-ray crystal structures
(9b, 9c, 9e, 9h, CCDC 640072-75), and their corresponding CIFs.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Sekine, M.; Kume, A.; Hata, T. Tetrahedron Lett. 1981, 22, 3617-
3620.
JO0708893
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