Pd-catalyzed ring opening of oxa- and azabicyclic alkenes with aryl and vinyl halides: Efficient entry to 2-substituted 1,2-dihydro-1-naphthols and 2-substituted 1-naphthols

Article abstract of DOI:10.1021/jo060299p

An efficient syntheses of 2-substituted 1,2-dihydro-1-naphthols and 2-substituted 1-naphthols has been developed that involves the sequential palladium-catalyzed ring opening of oxabicyclic alkenes with aryl and vinyl halides followed by oxidation of with

Full text of DOI:10.1021/jo060299p

Pd-Catalyzed Ring Opening of Oxa- and Azabicyclic Alkenes with
Aryl and Vinyl Halides: Efficient Entry to 2-Substituted
1,2-Dihydro-1-naphthols and 2-Substituted 1-Naphthols
Chi-Li Chen and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas, Austin, Texas 78712
sfmartin@mail.utexas.edu
ReceiVed February 13, 2006
An efficient syntheses of 2-substituted 1,2-dihydro-1-naphthols and 2-substituted 1-naphthols has been
developed that involves the sequential palladium-catalyzed ring opening of oxabicyclic alkenes with aryl
and vinyl halides followed by oxidation of with IBX. In the first step of the sequence, a combination of
2 3
Pd(OAc) , PPh , Zn, and PMP in dry DMF was employed to catalyze the ring opening of 7-oxaben-
zonorbornadienes with aryl and vinyl halides to afford the corresponding cis-2-substituted 1,2-
dihydronaphthols in good to excellent yields. These reactions occurred under very mild conditions with
a variety of aryl halides bearing electron-withdrawing or -donating groups. Similarly, a 7-azabenzonor-
bornadiene substituted with an electron-withdrawing group on the nitrogen atom underwent facile ring-
opening reaction with aryl halides to provide cis-2-substitued (1,2-dihydro-1-naphthyl)carbamates in
excellent yields. Oxidation of the intermediate1,2-dihydro-1-naphthols using IBX yielded the corresponding
2-substituted 1-naphthols in good to excellent yields.
Introduction
SCHEME 1
In the context of developing general synthetic approaches to
1
C-aryl glycosides, we discovered a facile and efficient entry
to 1,2-dihydro-1-naphthols and 1-naphthols from benzenoid
2
precursors according to the reactions outlined in Scheme 1.
The essential features comprise the well-known Diels-Alder
reactions of benzynes 2, which are generated in situ from
suitable precursors 1, with furan to give oxabenzonorbornadienes
3. Subsequent ring opening of 3 with a variety of organometallic
reagent then furnishes substituted dihydro-1-naphthols 4 that
are transformed into the substituted 1-naphthols 5 by an
oxidation.
Although numerous procedures and various tactics for induc-
ing the ring opening of 7-oxabenzonorbornadienes 3 to give 4
are known,3
-15
most suffer from one or more limitations
associated with their efficiency, generality, and/or ease of
(
1) (a) Kaelin, D. E., Jr.; Lopez, O. D.; Martin, S. F. J. Am. Chem. Soc.
001, 123, 6937-6938. (b) Apsel, B.; Bender, J. A.; Escobar, M.; Kaelin,
D. E., Jr.; Lopez, O. D.; Martin, S. F. Tetrahedron Lett. 2003, 44, 1075-
077. (c) Kaelin, D. E., Jr.; Sparks, S. M.; Plake, H. R.; Martin, S. F. J.
Am. Chem. Soc. 2003, 125, 12994-12995.
2) For a preliminary report of some of these investigations, see: Chen,
C.-L.; Martin, S. F. Org. Lett. 2004, 6, 3581-3584.
2
1
execution. Most relevant to the present work are the findings
of Cheng, who described the ring opening of some oxabicyclic
(
10.1021/jo060299p CCC: $33.50 © 2006 American Chemical Society
4
810
J. Org. Chem. 2006, 71, 4810-4817
Published on Web 06/02/2006

2
-Substituted 1,2-Dihydro-1-naphthols and 1-Naphthols
alkenes with aryl and vinyl halides in the presence of nickel
and palladium catalysts.13 However, these reactions were not
TABLE 1. Pd-Catalyzed Ring Opening of Oxabenzonorbornadiene
7a with p-Iodoacetophenonea
general as the Pd(0)-catalyzed reaction of electron-deficient aryl
iodides with 3 gave primarily dehydration products 6 rather than
the desired ring-opened products 4.1 Transformations involv-
ing aryl and vinyl bromides as substrates typically proceeded
in low yields,1 and there were no reports of reactions of aryl
chlorides. In related work directed toward the synthesis of C-aryl
glycosides, we had discovered that reactions of 3 with glycal
iodides were sometimes inefficient, perhaps as a consequence
of the instability of the glycal iodides under the reaction
conditions.
3a,b
3b,c
entry
catalyst, ligand (ratio)
solvent
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
10
Pd(OAc)2, PPh3 (1:2.2)
(PPh3)2PdCl2
Pd(PPh3)4
Pd(dppf)Cl2
Pd2(dba)3, dppe (1:2)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
3
4.5
12
16
16
16
16
16
18
18
8
87
91
85
32
0
2
0
0
10
3
44
95
60
90
64
Despite the ubiquity of oxidative transformations in organic
synthesis, it is perhaps surprising that examples of the oxidation
16
(PPh ) NiCl2
of dihydronaphthols are rare. During the course of work
3 2
directed toward the synthesis of C-aryl glycosides,1a we found
NiCl2, dppf (1:1)
NiCl2, dppe (1:1)
1
that oxidations of substituted dihydronaphthols 4 (R ) OMe)
Pd(OAc)2, PPh3 (1:2.2)
Pd(OAc) , PPh (1:2.2)
1
to give the corresponding aromatic compounds 5 (R ) OMe)
Tol
2
3
1
1
1
1
1
2
3
4
Pd(OAc)2, PPh3 (1:2.2)
Pd(OAc)2, PPh3 (1:2.2)
Pd(OAc)2, PPh3 (1:2.2)
Pd(OAc)2, PPh3 (1:2.2)
Pd(OAc) , PPh (1:2.2)
MeCN
DMF
DMF
DMF
DMF
were often accompanied by extensive dehydration to give 6 as
a deleterious side reaction. DDQ emerged as a useful oxidant
in some cases, but we found that such conversions were
sometimes difficult to optimize and reproduce.1 In the context
of solving various problems associated with the generality of
ring-opening reactions of oxabenzonorbornadienes 3 and the
oxidation of the resultant 1,2-dihydronaphthols 4, we developed
a reliable and efficient protocol for preparing substituted
compounds of the general form 4 and 5 from benzene derivatives
according to Scheme 1. We now report the details of these
c
3
3
3
2
d
c,e
a
15c,f
2
3
a
b
Conditions: 0.05 M of 7a, room temperature except as noted. Isolated
c
yield of product after chromatography. PMP (0.5 equiv) used as additive.
d
Et N (8 equiv) used as additive. Reaction performed at 45 °C. f Reaction
e
3
performed at 60 °C.
Results and Discussion
2
investigations.
Palladium-Catalyzed Ring-Opening Reaction. In our stud-
ies directed toward developing useful methods for the synthesis
of C-aryl glycosides, we discovered that oxabenzonorborna-
dienes underwent ring opening with glycal iodides in the
presence of PdCl2(PPh3)2, Zn, ZnCl2, and Et3N, although the
(
3) For reviews, see: (a) Chiu, P.; Lautens, M. Top. Curr. Chem. 1997,
1
3
90, 1-85. (b) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003,
6, 48-58.
(4) DIBAL-H: (a) Lautens, M.; Chiu, P.; Colucci, J. T. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 281-283. (b) Lautens, M.; Rovis, T. J. Org. Chem.
1
997, 62, 5246-5247.
5) Arylboronic acids: (a) Murakami, M.; Igawa, H. Chem. Commun.
1a,b
reactions required some experimentation to optimize. These
basic conditions, which were originally reported by Cheng,1
seemed to constitute a useful point of embarkation for the
present investigations. In the context of preparing 2-aryl
naphthol derivatives, the challenge lay in discovering milder
conditions that would be applicable to aryl halides bearing a
wide variety of substituents. In this context, those aryl halides
with electron-withdrawing substituents posed the greatest dif-
(
3a,b
2
002, 390-391. (b) Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki,
A. Org. Lett. 2002, 4, 1311-1314. (c) Lautens, M.; Dockendorff, C. Org.
Lett. 2003, 5, 3695-3698.
(6) Organozinc halide reagents: (a) Rayabarapu, D. K.; Chiou, C.-F.;
Cheng, C.-H. Org. Lett. 2002, 4, 1679-1682. (b) Li, M.; Yan, X.-X.; Hong,
W.; Zhu, X.-Z.; Cao, B.-X.; Sun, J.; Hou, X.-L. Org. Lett. 2004, 6, 2833-
2
835.
(7) Dialkylzinc reagents: (a) Lautens, M.; Renaud, J.-L.; Hiebert, S. J.
Am. Chem. Soc. 2000, 122, 1804-1805. (b) Lautens, M.; Hiebert, S.;
Renaud, J.-L. Org. Lett. 2000, 2, 1971-1973. (c) Lautens, M.; Hiebert, S.;
Renaud, J.-L. J. Am. Chem. Soc. 2001, 123, 6834-6839. (d) Bertozzi, F.;
Pineschi, M.; Macchia, F.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L.
Org. Lett. 2002, 4, 2703-2705. (e) Lautens, M.; Hiebert, S. J. Am. Chem.
Soc. 2004, 126, 1437-1447.
ficulty as premature dehydration of the intermediate dihy-
13a,b
dronaphthols was known to be a significant problem.
We
thus selected the reaction of dimethoxy oxabenzonorbornadiene
7a with p-iodoacetophenone as the test system in which to
optimize conditions for forming the ring-opened product 8a
(
8) Alkenylzirconium reagents: Wu, M.-S.; Rayabarapu, D. K.; Cheng,
C.-H. J. Org. Chem. 2004, 69, 8407-8412.
9) Organolithium reagents: Caple, R.; Chen, G. M. S.; Nelson, J. D. J.
Org. Chem. 1971, 36, 2874-2876.
10) Organomagnesium reagents: (a) Array a´ s, R. G.; Cabrera, S.;
(Table 1).
(
A variety of palladium and nickel precatalysts were screened
(
for their ability to convert 7a into 8a in the presence of activated
zinc powder (Table 1, entries 1-8). However, only Pd(OAc)2/
PPh3, (PPh3)2PdCl2, and Pd(PPh3)4 gave 8a in reasonable yields,
with Pd(OAc)2/PPh3 providing the fastest rates of reaction. The
nature of the solvent proved important, with the reactions being
slower in THF, toluene, and MeCN (entries 9-11) than in DMF.
Moreover, significant amounts of the naphthalene byproduct
arising from the dehydration of 8a were observed when MeCN
was used as solvent. Two tertiary amines 1,2,2,6,6,-pentameth-
ylpiperidine (PMP, entry 12) and Et3N (entry 13) were examined
as additives. Use of PMP, which has been employed to
Carretero, J. C. Org. Lett. 2003, 5, 1333-1336. (b) Nakamura, M.; Matsuo,
K.; Inoue, T.; Nakamura, E. Org. Lett. 2003, 5, 1373-1375.
(11) Phenylstannanes: Fugami, K.; Hagiwara, S.; Oda, H.; Kosugi, M.
Synlett 1998, 477-478.
12) Aryl triflates: Moinet, C.; Fiaud, J.-C. Tetrahedron Lett. 1995, 36,
051-2052.
13) Aryl halides: (a) Duan, J.-P.; Cheng, C.-H. Tetrahedron Lett. 1993,
(
2
(
3
1
4, 4019-4022. (b) Duan, J.-P.; Cheng, C.-H. Organometallics 1995, 14,
608-1618. (c) Feng, C.-C.; Nandi, M.; Sambaiah, T.; Cheng, C.-H. J.
Org. Chem. 1999, 64, 3538-3543.
(
14) Thiols: Leong, P.; Lautens, M. J. Org. Chem. 2004, 69, 2194-
196.
15) Alcohols and amines: Lautens, M.; Fagnou, K.; Rovis, T. J. Am.
Chem. Soc. 2000, 122, 5650-5651.
16) For the oxidative coupling of dihydronaphthols to give binaphthyl
2
(
17
advantage in Heck reations, resulted in improved yields of
(
8
a to 95%, whereas the yield using Et3N was lower, in part
diols, see: Fillion, E.; Tr e´ panier, V. E.; Mercier, L. G.; Remorova, A. A.;
Carson, R. J. Tetrahedron Lett. 2005, 46, 1091-1094.
owing to formation of naphthalene products via dehydration of
J. Org. Chem, Vol. 71, No. 13, 2006 4811

Chen and Martin
TABLE 2. Pd-Catalyzed Ring Opening of 7a and 7b with Aryl and Vinyl Halidesa
a
b
Conditions: 0.05 M of 7a or 7b in DMF, RX (1.2 equiv), Pd(OAc)2 (5 mol %), PPh3 (11 mol %), PMP (0.5 equiv), Zn (10 equiv). Oil bath temperature.
c
Isolated yield of product after chromatography. Pd(OAc)2 (10 mol %), PPh3 (20 mol %). e Pd(OAc)2 (15 mol %), PPh3 (30 mol %).
d
4812 J. Org. Chem., Vol. 71, No. 13, 2006

2
-Substituted 1,2-Dihydro-1-naphthols and 1-Naphthols
TABLE 3. Pd-Catalyzed Ring Opening of 7c with Aryl Halidesa
the intermediate 1,2-dihydro-1-naphthols. Increasing the tem-
perature also tended to reduce the yields by increasing the
amount of dehydration as a side reaction (entries 14 and 15).
After extensive screening of various combinations of palladium
and nickel precatalysts, solvents, amine bases, and temperatures,
we eventually discovered that the combination of Pd(OAc)2,
PPh3, PMP, and Zn in DMF was highly effective for promoting
the ring opening of 7a.
Having identified optimal conditions for effecting the pal-
ladium-catalyzed ring opening of 7a with 8a, it remained to
vary the nature of the aryl halide and the oxabenzonorbornadiene
to explore the scope of this process. Toward this end, a series
of electron-rich and electron-deficient aryl iodides were screened
and found to serve as excellent partners in ring-opening reactions
with 7a and 7b to give the corresponding products 8a-15a and
1
8a-20a with high stereoselectivity and in good to excellent
yields (Table 2). Under the mild conditions employed, only
small amounts of dehydration products were observed, and the
corresponding trans-1,2-dihydro-1-naphthols were not detected
1
in the H NMR spectra of the crude reaction mixtures. Aryl
bromides bearing electron-withdrawing and electron-donating
groups underwent facile reaction with 7a or 7b, albeit at higher
temperatures than the corresponding aryl iodides, to provide
the expected ring-opened products 8a, 9a, 11a, and 16a-18a
(Table 2). The difference in reactivity of aryl iodides and
bromides is sufficient that it may be exploited as exemplified
by selective formation of 13a from o-bromoiodobenzene. As is
typical of most palladium-catalyzed cross-coupling processes,
reactions involving electron-rich halides required higher tem-
a
Conditions: 0.05 M of 7c in DMF, RX (1.2 equiv), Pd(OAc)2 (5 mol
b
%
), PPh3 (11 mol %), PMP (0.5 equiv), Zn (10 equiv). Oil bath
temperature. Isolated yield of product after chromatography. Pd(OAc)2
10 mol %), PPh3 (20 mol %).
c
d
1
8
peratures than the corresponding electron-deficient halides.
(
Furthermore, mesityliodide and 2-iodothiophene required higher
temperatures in order to obtain good yields of products,
suggesting that these couplings may sensitive to steric and
coordination effects.19
conditions yielded only trace amounts of the desired 2-aryl-1-
naphthol 11b, and little starting 11a was recovered (Eq 1). We
We also briefly explored the ring-opening reactions of the
7-azabenzonorbornadiene 7c and discovered that the same
conditions that had been developed for 7a and 7b were effective.
Aryl iodides bearing electron-donating and -withdrawing groups
as well as simple aryl bromides could be used in these cross-
couplings to give the expected cis-2-substitued (1,2-dihydro-
1
-naphthyl)carbamates in excellent yields (Table 3). No dehy-
then examined numerous oxidants to effect this transformation,
but the naphthol 11b was invariably isolated in poor yield
together with the dehydration product and/or recovered starting
material as well as several unidentified products. For example,
oxidation of 11a with Dess-Martin periodinane, PCC, Swern
droamination to give naphthalene byproducts was observed
under the conditions employed.
Oxidation of 1,2-Dihydronaphthols. Having established the
generality of the cross-couplings of the 7-oxabenzonorborna-
dienes 7a and 7b, we turned our attention to developing
conditions for effecting the oxidation of the intermediate
dihydronaphthols to give naphthols. Oxidation of alcohols to
give ketones is one of the most frequently used reactions in
organic synthesis, but other than our previous work,
are few examples of oxidations leading to substituted 1-naph-
thols. For example, we recently reported that glycal-substituted
cis-1,2-dihydronaphthols could be oxidized to the corresponding
C-aryl glycosides under carefully defined conditions using
recrystallized DDQ.1 However, oxidation of 11a under these
2
0
reagent, Pd(OAc)2/pyridine/O2/toluene, Pd(OAc)2/NaHCO3/
2
1
22
O2/DMSO, Pd(PPh3)4/PhBr/DMF/K2CO3 or NaH, or IBX/
2
3
H2O/acetone/â-cyclodextrin did not furnish the naphthol 11b
in more than about 30% yield, and simple dehydration was the
major reaction in all of these experiments. Other oxi-
dants including TPAP, DMSO/NEt3/py-SO3, MnO2, p-chloranil,
1
a,b
there
16
24
25
Pd(nbd)Cl2/sparteine/O2, NCS/DMS/Et3N, and DMDO were
similarly ineffective, giving only trace amounts of 11b together
a,b
(20) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999,
6
4, 6750-6755.
21) Peterson, K. P.; Larock, R. C. J. Org. Chem. 1998, 63, 3185-3189.
(22) Tamaru, Y.; Yamada, Y.; Inoue, K.; Yamamoto, Y.; Yoshida, Z.-I.
(
(
17) For a discussion of use of different bases for Heck reactions, see:
Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945-2964.
18) For example, see: (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem.
Soc. 2000, 122, 4020-4028. (b) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc.
001, 123, 6989-7000.
19) For example, see: (a) Duan, J.-P.; Cheng, C.-H. J. Chin. Chem.
J. Org. Chem. 1983, 48, 1286-1292.
(
(23) Surendra, K.; Krishnaveni, N. S.; Reddy, M. A.; Nageswar, Y. V.
D.; Rao, K. R. J. Org. Chem. 2003, 68, 2058-2059.
(24) Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B. M. Org. Lett. 2003, 5,
835-837.
2
(
Soc. 1994, 41, 749-754. (b) Schuman, M.; Lopez, X.; Karplus, M.;
Gouverneur, V. Tetrahedron 2001, 57, 10299-10307.
(25) (a) Murray, R. W.; Singh, M.; Rath, N. J. Org. Chem. 1997, 62,
8794-8799. (b) Lee, J. S.; Fuchs, P. L. Org. Lett. 2003, 5, 2247-2250.
J. Org. Chem, Vol. 71, No. 13, 2006 4813

Chen and Martin
TABLE 4. Oxidation of 2-Substituted 1,2-Dihydro-1-naphthols with IBX
a
Oil bath temperature. b Isolated yield of product after chromatography. c IBX (1.5 equiv). d IBX (2 equiv).
with several unidentified products and/or recovered starting
material. Gratifyingly, we eventually discovered that oxidation
of 11a with IBX26 (3 equiv) in EtOAc at 60 °C for 14 h afforded
naphthol 11b in 94% yield. This reaction also proceeded at 80
4814 J. Org. Chem., Vol. 71, No. 13, 2006

2
-Substituted 1,2-Dihydro-1-naphthols and 1-Naphthols
improved route to C-aryl glycosides such as 32.1a,b Thus,
reaction of 7a with glycal iodide 30 provided a mixture (4:1)
of diastereomeric cis-dihydronaphthols 31a and 31b (Scheme
SCHEME 2
2
). Subsequent oxidation of this mixture with IBX cleanly
provided the C-aryl glycoside 32 in with no dehydration of the
intermediate dihydronaphthols 31a and 31b being observed.
Summary
We have developed a general and efficient method for the
synthesis of 2-substituted 1,2-dihydro-1-naphthols and 2-sub-
stituted 1-naphthols from oxabenzonorbornadienes, which are
readily accessed by the Diels-Alder reactions of benzynes with
furan. The procedure involves sequential palladium-catalyzed
ring opening of these oxabenzonorbornadienes with aryl or vinyl
halides followed by oxidation of the intermediate dihydronaph-
thols with IBX. The palladium-catalyzed reaction is conducted
under mild conditions and is applicable to aryl iodides and
bromides with both electron-withdrawing and -donating groups,
as well as to glycal iodides. The formation of naphthalene
byproducts, which are otherwise commonly observed, is sup-
pressed under the conditions of these reactions.
°
C in 3 h to provide 11b in similar yield. Although acetone
and THF were also found to be suitable solvents, DMSO, which
is frequently used as solvent in IBX oxidations,2 was not
satisfactory because the naphthol products underwent more rapid
decomposition, presumably by oxidation, in DMSO than in the
other solvents. For example, when a homogeneous solution of
Experimental Section
7
General Procedure for Palladium-Catalyzed Ring Opening
of Bicyclic Alkenes. 1,2,2,6,6-Pentamethylpiperidine (PMP) (67
µL, 0.37 mmol) was added to a mixture of bicyclic alkene (0.74
2
mmol), aryl or vinyl halide (0.88 mmol), Pd(OAc) (9 mg, 5 mol
1
1b in DMSO containing IBX was stirred at room temperature
%), PPh (21 mg, 11 mol %), and activated Zn (480 mg, 7.4 mmol)
3
for 2 h, less than 10% of 11b was recovered.
in DMF (14.7 mL) under argon. The resulting mixture was heated
Having discovered that IBX was an effective oxidant for
converting 11a into 11b, we then surveyed its utility as an
oxidant of other substituted dihydronaphthols to give the
corresponding 1-naphthols, and these results are summarized
in Table 4. Yields were generally good to excellent with only
small amounts of the corresponding naphthalenes being observed
in the crude reaction mixtures. Because the product 1-naphthols
were found to be somewhat unstable toward excess IBX, the
yields in these oxidations were found to depend critically upon
temperatures, reaction times, solvents, and the number of
equivalents of IBX. Some experimentation was thus necessary
to optimize the yield for oxidizing a given dihydronaphthol.
For example, the oxidations of 8a and 12a in EtOAc to give
at the indicated bath temperature (see Tables 2 and 3) with stirring
until the starting bicyclic alkene was fully consumed as indicated
by TLC. The reaction was allowed to cool to room temperature,
5
0% EtOAc/hexanes (60 mL) was added, and the mixture was
filtered through a pad of Celite. The filtrate was washed with
), and
saturated aqueous NaCl (4 × 10 mL), dried (MgSO
4
concentrated under reduced pressure. The crude residue was purified
by flash chromatography, eluting with EtOAc/hexanes in the ratio
given to provide the 2-substituted 1,2-dihydro-1-naphthol derivatives
(8a-20a, 21-25).
cis-1,2-Dihydro-5,8-dimethoxy-2-mesityl-1-naphthol (14a). 15%
1
EtOAc/hexanes; white solid; mp 117-118 °C; H NMR (250 MHz,
CDCl ) δ 6.95 (dd, J ) 9.8, 3.4 Hz, 1 H), 6.89 (s, 2 H), 6.82 (d,
3
J ) 8.9 Hz, 2 H), 6.76 (d, J ) 8.9 Hz, 1 H), 6.21 (ddd, J ) 9.8,
.4, 1.2 Hz, 1 H), 5.16 (ddd, J ) 5.5, 4.2, 1.2 Hz, 2 H), 4.13-4.02
m, 1 H), 3.82 (s, 3 H), 3.80 (s, 3 H), 2.48 (s, 3 H), 2.34 (s, 3 H),
.26 (s, 3 H), 1.65 (d, J ) 4.2 Hz, 1 H); 13C NMR (62.5 MHz,
CDCl ) δ 150.9, 149.4, 139.2, 136.7, 135.9, 133.2, 131.9, 130.7,
29.0, 124.4, 122.7, 117.5, 111.1, 109.9, 62.7, 56.1, 55.9, 42.3,
1.4, 20.9, 20.6; IR (CDCl ) 3597, 2939, 1598, 1482, 1262, 1086
3
(
2
8
8
b and 12b proceeded in 51% and 60% yields, respectively, at
0 °C, whereas the corresponding yields were 88% and 80%
when the reactions were performed at 60 °C. Although ethyl
acetate was frequently the solvent of choice, oxidations of 9a
and 10a proceeded in higher yields in acetone because 9b and
3
1
2
3
-
1
1
0b appeared to be less stable toward IBX in EtOAc. It is
cm ; mass spectrum (CI) m/z 325.1802 [C H O (M + H)
requires 325.1804], 307 (base), 205.
cis-1,2-Dihydro-5,8-dimethoxy-2-(2-thienyl)-1-naphthol (15a).
21
25
3
noteworthy that this oxidation is not limited to the production
of 2-aryl-1-naphthols, as IBX may also be used to oxidize
1
2
-alkyl-1,2-dihydronaphthols to give 2-alkyl-1-naphthols as
3
25% EtOAc/hexanes; orange liquid; H NMR (250 MHz, CDCl )
δ 7.27-7.24 (m, 1 H), 7.12-7.09 (m, 1 H), 7.07-7.00 (comp, 2
H), 6.82 (d, J ) 9.1 Hz, 1 H), 6.78 (d, J ) 9.1 Hz, 1 H), 6.07
exemplified by the oxidations of 26a-29a. However, in
preliminary experiments, the cis-2-substitued (1,2-dihydro-1-
naphthyl)carbamates 21-25 did not undergo clean oxidation
to the corresponding protected naphthylamines using IBX.
We then employed these new protocols for converting
oxabenzonorbornadienes into 1-naphthols in developing an
(
ddd, J ) 9.8, 2.4, 1.4 Hz, 1 H), 5.17-5.10 (m, 1 H), 4.12-4.05
(
m, 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 1.83 (d, J ) 5.4 Hz, 1 H);
1
3
3
C NMR (62.5 MHz, CDCl ) δ 150.7, 149.6, 143.1, 128.5, 126.8,
1
4
25.6, 124.3, 124.2, 122.2, 122.0, 111.5, 111.1, 64.5, 56.1, 56.0,
-1
2.7; IR (CDCl
3
) 3594, 2938, 1602, 1486, 1259, 1087 cm ; mass
S requires 288.0820], 271
spectrum (CI) m/z 288.0831 [C16
base).
cis-1,2-Dihydro-5,8-dimethoxy-2-(2-methyl-propenyl)-1-naph-
16 3
H O
(
26) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
(
(27) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-
8
022. (b) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org.
1
Chem. 1995, 60, 7272-7276. (c) Wirth, T. Angew. Chem., Int. Ed. 2001,
thol (17a). 20% EtOAc/hexanes; orange liquid; H NMR (250 MHz,
4
0, 2812-2814.
CDCl
3
) δ 6.91 (dd, J ) 9.8, 3.1 Hz, 1 H), 6.79 (d, J ) 9.0 Hz, 1
J. Org. Chem, Vol. 71, No. 13, 2006 4815

Chen and Martin
H), 6.74 (d, J ) 9.0 Hz, 1 H), 5.80-5.71 (m, 1 H), 5.62-5.53 (m,
H); 13C NMR (62.5 MHz, CDCl
129.2, 126.9, 121.3, 120.6, 115.5, 112.0, 103.7, 102.5, 56.5, 55.7,
26.5, 19.7; IR (CDCl ) 3586, 2937, 1597, 1483, 1259, 1088 cm ;
3
mass spectrum (CI) m/z 259.1329 [C16H O (M + H) requires
19 3
259.1334] (base).
5,8-Dimethoxy-2-(tert-butyl)-1-naphthol (28b). 10% EtOAc/
3
) δ 151.0, 150.3, 150.1, 135.5,
1
3
6
H), 4.93 (ddd, J ) 6.4, 4.7, 1.2 Hz, 1 H), 3.81 (s, 3 H), 3.79 (s,
H), 3.34-3.24 (m, 1 H), 1.80 (d, J ) 1.1 Hz, 3 H), 1.77 (d, J )
.4 Hz, 1 H), 1.69 (d, J ) 1.3 Hz, 3 H); 13C NMR (62.5 MHz,
-
1
CDCl
3
) δ 150.5, 149.5, 134.4, 130.6, 125.2, 122.4, 122.3, 120.8,
11.1, 110.6, 63.6, 56.1, 56.0, 39.6, 25.9, 18.2; IR (CDCl ) 3586,
937, 1597, 1483, 1259, 1088 cm-1; mass spectrum (CI) m/z
60.1400 [C16 requires 260.1412], 243 (base).
Methyl N-[cis-1,2-Dihydro-2-(4-acetylphenyl)-1-naphthyl]car-
bamate (21). 30% EtOAc/hexanes; yellow solid; mp 112-113 °C;
1
2
2
3
1
hexanes; yellow solid; mp 109-110 °C; H NMR (250 MHz,
H
20
O
3
CDCl ) δ 10.06 (s, 1 H), 7.61 (d, J ) 8.9 Hz, 1 H), 7.45 (d, J )
3
8.9 Hz, 1 H), 6.63 (d, J ) 8.4 Hz, 1 H), 6.55 (d, J ) 8.4 Hz, 1 H),
4.00 (s, 3 H), 3.91 (s, 3 H), 1.47 (s, 9 H); 13C NMR (62.5 MHz,
1
H NMR (250 MHz, CDCl
comp, 6 H), 6.71 (dd, J ) 9.6, 1.5 Hz, 1 H), 6.11 (d, J ) 9.6, 4.8
Hz, 1 H), 5.35 (dd, J ) 10.3, 7.0 Hz, 1 H), 4.66 (d, J ) 10.3 Hz,
3
) δ 7.85-7.77 (m, 2 H), 7.32-7.13
CDCl
3
) δ 152.7, 150.2, 150.1, 131.2, 127.0, 126.0, 116.0, 111.9,
) 3364, 2958, 1607,
1515, 1399, 1252 cm ; mass spectrum (CI) m/z 261.1491
21 3
[C16H O (M + H) requires 261.1491] (base).
(
103.2, 101.9, 56.4, 55.7, 34.8, 29.5; IR (CDCl
3
-
1
13
1
(
1
4
H), 3.96-3.85 (m, 1 H), 3.60 (s, 3 H), 2.54 (s, 3 H); C NMR
62.5 MHz, CDCl ) δ 197.4, 156.3, 143.1, 136.0, 134.4, 134.0,
32.7, 129.0, 128.8, 128.3, 128.2, 127.9, 126.4, 125.4, 52.6, 52.1,
3
cis-1,2-Dihydro-5,8-dimethoxy-2-(n-butyl)-1-naphthol (26a).
n-BuLi (1.67 mL, 2.20 M solution in pentane, 3.68 mmol) was
added to a solution of oxabenzonorbornadiene 7a (150 mg, 0.74
mmol) and TMEDA (222 µL, 1.47 mmol) in THF (7.4 mL) under
argon at -78 °C over 5 min. After 40 min of stirring at -78 °C,
EtOH (1 mL) was added. The resulting mixture was allowed to
warm to room temperature, and then water (10 mL) and hexane
(80 mL) were added. The organic layer was separated, and the
aqueous layer was extracted with hexane (2 × 15 mL). The
combined organic layers were washed with saturated aqueous NaCl
-
1
4.6, 26.3; IR (CDCl
3
) 3320, 2952, 1721, 1681, 1519, 1269 cm
;
mass spectrum (CI) m/z 322.1445 [C20
22.1443] (base), 247.
Methyl N-[cis-1,2-Dihydro-2-(3-ethoxycarbonylphenyl)-1-
naphthyl]carbamate (22). 25% EtOAc/hexanes; pale yellow solid;
H20NO
3
(M + H) requires
3
1
mp 126-127 °C; H NMR (250 MHz, CDCl ) δ 7.93-7.86 (m, 1
3
H), 7.80 (s, 1 H), 7.33-7.13 (comp, 6 H), 6.71 (dd, J ) 9.6, 1.6
Hz, 1 H), 6.12 (dd, J ) 9.6, 4.7 Hz, 1 H), 5.31 (dd, J ) 10.0, 7.1
Hz, 1 H), 4.69 (d, J ) 10.0 Hz, 1 H), 4.32 (q, J ) 7.1 Hz, 2 H),
(2 × 20 mL), dried (MgSO
pressure. The crude residue was purified by flash chromatography,
eluting with Et N/EtOAc/hexanes (0.1:1:5) to give 26a (190 mg,
4
), and concentrated under reduced
1
3
3
.96-3.87 (m, 1 H), 3.59 (s, 3 H), 1.34 (t, J ) 7.1 Hz, 3 H); C
NMR (62.5 MHz, CDCl
3
) δ 166.3, 156.5, 138.1, 134.2, 133.2,
3
1
13
1
1
1
32.9, 130.6, 130.2, 129.5, 128.8, 128.5, 128.4, 128.3, 128.0, 126.5,
25.6, 60.9, 52.8, 52.2, 44.7, 14.2; IR (CDCl ) 3337, 2981, 1717,
522, 1283 cm ; mass spectrum (CI) m/z 352.1541 [C21
98%) as a colorless oil whose H and C NMR spectral data were
consistent with those reported.2
3
-
1
H22NO
4
cis-1,2-Dihydro-5,8-dimethoxy-2-benzyl-1-naphthol (27a). A
solution of benzyllithium, which had been generated from n-BuLi
(0.89 mL, 2.10 M solution in pentane, 1.88 mmol) and toluene (6
mL) containing TMEDA (226 µL) at 0 °C, was added to a solution
of oxabenzonorbornadiene 7a (153 mg, 0.75 mmol) in toluene (10
mL) under argon at 0 °C over 1 min. After 3 min of stirring at 0
(
M + H) requires 352.1549] (base), 277.
General Procedure for IBX Oxidation of 2-Substituted 1,2-
Dihydro-1-naphthol. IBX (0.66 mmol) was added to a solution
of 2-substituted 1,2-dihydro-1-naphthol (8a-20a, 26a-29a) (0.22
mmol) in EtOAc (3.3 mL). The resulting suspension was then
heated with vigorous stirring in an oil bath at the indicated
temperature (see Table 4) until the starting material was fully
consumed (TLC). The reaction was then allowed to cool to room
temperature and diluted with 30% EtOAc/hexanes (15 mL). The
mixture was filtered through a pad of Celite, and the filtrate was
concentrated under reduced pressure. The crude residue was purified
by flash chromatography, eluting with EtOAc/hexanes in the ratio
given to provide the 2-substituted 1-naphthols (8b-20b, 26b-29b).
°C, H
warm to room temperature, and water (10 mL) and Et
were added. The organic layer was separated, and the aqueous layer
was extracted with Et
O (2 × 15 mL). The combined organic layers
were washed with saturated aqueous NaCl (2 × 20 mL), dried
(MgSO ), and concentrated under reduced pressure. The crude
residue was purified by flash chromatography, eluting with Et N/
EtOAc/hexanes (0.1:1:5) to give 27a (194 mg, 87%) as a white
2
O (1 mL) was added. The resulting mixture was allowed to
2
O (80 mL)
2
4
3
2
1
13
5
,8-Dimethoxy-2-mesityl-1-naphthol (14b). 10% EtOAc/hex-
solid (mp 89-90 °C; lit. mp 89-90 °C) whose H and C NMR
1
spectral data were consistent with those reported.2
3
anes; white solid; mp 134-135 °C; H NMR (250 MHz, CDCl )
δ 9.60 (s, 1 H), 7.76 (d, J ) 8.5 Hz, 1 H), 7.17 (d, J ) 8.5 Hz, 1
H), 6.95 (s, 2 H), 6.70 (d, J ) 8.4 Hz, 1 H), 6.65 (d, J ) 8.4 Hz,
cis-1,2-Dihydro-5,8-dimethoxy-2-(tert-butyl)-1-naphthol (28a).
t-BuLi (1.08 mL, 1.70 M solution in pentane, 1.84 mmol) was added
to a solution of oxabenzonorbornadiene 7a (150 mg, 0.74 mmol)
in THF (7.4 mL) under argon at -78 °C over 5 min. After 30 min
of stirring at -78 °C, EtOH (1 mL) was added. The resulting
mixture was allowed to warm to room temperature, and water (10
mL) and hexane (80 mL) were added. The organic layer was
separated, and the aqueous layer was extracted with hexane (2 ×
15 mL). The combined organic layers were washed with saturated
1
H), 3.98 (s, 3 H), 3.96 (s, 3 H), 2.31 (s, 3 H), 2.02 (s, 6 H); 13
C
NMR (62.5 MHz, CDCl
3
) δ 150.5, 150.3, 150.2, 136.6, 135.1,
1
2
29.6, 128.0, 127.6, 123.2, 115.7, 112.8, 103.5, 102.7, 56.3, 55.7,
-
1
1.1, 20.3; IR (CDCl
3
) 3381, 2918, 1612, 1511, 1391, 1252 cm
;
mass spectrum (CI) m/z 323.1648 [C21
23.1647] (base).
,8-Dimethoxy-2-(2-thienyl)-1-naphthol (15b). 10% EtOAc/
23 3
H O
(M + H) requires
3
5
1
hexanes; pale reddish solid; mp 106-107 °C; H NMR (250 MHz,
CDCl ) δ 10.42 (s, 1 H), 7.77 (d, J ) 8.9 Hz, 1 H), 7.71 (d, J )
.9 Hz, 1 H), 7.63 (dd, J ) 3.7, 1.1 Hz, 1 H), 7.34 (dd, J ) 5.0,
.1 Hz, 1 H), 7.12 (dd, J ) 5.0, 3.7 Hz, 1 H), 6.72 (d, J ) 8.5 Hz,
aqueous NaCl (2 × 20 mL), dried (MgSO
reduced pressure. The crude residue was purified by flash chro-
matography, eluting with Et N/EtOAc/hexanes (0.1:1:5) to give 28a
(184 mg, 95%) as a white solid; mp 112-113 °C; H NMR (250
MHz, CDCl
4
), and concentrated under
3
8
1
1
3
1
13
H), 6.64 (d, J ) 8.5 Hz, 1 H), 4.04 (s, 3 H), 3.94 (s, 3 H);
) δ 150.3, 150.2, 150.1, 140.0, 127.3,
26.8, 126.7, 125.1, 125.0, 116.7, 116.1, 113.2, 104.4, 103.3, 55.6,
5.7; IR (CDCl
) 3318, 2917, 1611, 1506, 1395, 1251 cm-1; mass
S (M + H) requires
C
3
) δ 6.96 (dd, J ) 10.0, 3.2 Hz, 1 H), 6.74 (s, 2 H),
NMR (62.5 MHz, CDCl
3
6.09-6.01 (m, 1 H), 5.25 (ddd, J ) 8.5, 4.2, 1.4 Hz, 1 H), 3.82 (s,
1
5
3 H), 3.78 (s, 3 H), 2.10-2.04 (m, 1 H), 1.42 (d, J ) 8.5 Hz, 1 H),
13
3
1.17 (s, 9 H); C NMR (62.5 MHz, CDCl
3
) δ 149.9, 149.4, 128.4,
spectrum (CI) m/z 287.0734 [C16
87.0742] (base).
,8-Dimethoxy-2-(2-methyl-propenyl)-1-naphthol (17b). 10%
H
15
O
3
126.1, 122.4, 121.4, 110.8, 110.3, 62.3, 56.1, 55.9, 49.6, 32.3, 28.6;
IR (CDCl ) 3590, 2959, 1598, 1482, 1261, 1086 cm ; mass
3
spectrum (CI) m/z 262.1570 [C16H O requires 262.1569], 245,
22 3
189 (base).
cis-1,2-Dihydro-2-(tert-butyl)-1-naphthol (29a). t-BuLi (1.22
mL, 1.70 M solution in pentane, 2.08 mmol) was added to a solution
of oxabenzonorbornadiene 7b (120 mg, 0.83 mmol) in THF (8.3
-
1
2
5
1
EtOAc/hexanes; orange solid; mp 75-77 °C; H NMR (250 MHz,
CDCl ) δ 9.77 (s, 1 H), 7.64 (d, J ) 8.6 Hz, 1 H), 7.32 (d, J ) 8.6
3
Hz, 1 H), 6.66 (d, J ) 8.4 Hz, 1 H), 6.59 (d, J ) 8.4 Hz, 1 H),
6
.43 (s, 1H), 3.99 (s, 3 H), 3.92 (s, 3 H), 1.95 (s, 3 H), 1.82 (s, 3
4816 J. Org. Chem., Vol. 71, No. 13, 2006

2
-Substituted 1,2-Dihydro-1-naphthols and 1-Naphthols
mL) under argon at -78 °C over 5 min. After 30 min of stirring at
78 °C, EtOH (1 mL) was added. The resulting mixture was
allowed to warm to room temperature, and water (10 mL) and Et
Acknowledgment. We thank the National Institutes of
Health (GM 31077), the Robert A. Welch Foundation, Pfizer,
Inc., and Merck Research Laboratories for their generous support
of this research.
-
2
O
(
80 mL) were added. The organic layer was separated, and the
aqueous layer was extracted with Et
2
O (2 × 15 mL). The combined
organic layers were washed with saturated aqueous NaCl (2 × 20
mL), dried (MgSO ), and concentrated under reduced pressure. The
crude residue was purified by flash chromatography, eluting with
Et N/EtOAc/hexanes (0.1:1:7) to give 29a (157 mg, 93%) as a white
Supporting Information Available: Summary of general
4
1
experimental practices and copies of H NMR spectra for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
3
9
1
13
solid (mp 75-76 °C; lit. mp 75-76 °C) whose H and C NMR
spectral data were consistent with those reported.9
JO060299P
J. Org. Chem, Vol. 71, No. 13, 2006 4817