Remote electronic effects in the rhodium-catalyzed nucleophilic ring opening of oxabenzonorbornadienes.

Article abstract of DOI:10.1021/jo025822o

We report the application of our rhodium-catalyzed nucleophilic ring-opening methodology to unsymmetrically arene-substituted oxabenzonorbornadienes. The regioselectivity of the ring opening was investigated using a variety of nucleophiles that led to a broad selection of dihydronaphthalene products. It was found that good to excellent regioselectivities are obtained using strongly pi-donating substituents, whereas sigma-donating and electron-withdrawing functionalities have a minimal effect. Post ring-opening manipulations of functional groups in the dihydronaphthalene products were shown to give efficient access to mono- and diamine tetrahydronaphthalene building blocks.

Full text of DOI:10.1021/jo025822o

Rem ote Electr on ic Effects in th e Rh od iu m -Ca ta lyzed Nu cleop h ilic
Rin g Op en in g of Oxa ben zon or bor n a d ien es
Mark Lautens,* Gavin A. Schmid, and Anh Chau
Davenport Research Laboratories, Department of Chemistry, University of Toronto,
Toronto, Ontario, Canada M5H 3H6
mlautens@chem.utoronto.ca
Received April 15, 2002
We report the application of our rhodium-catalyzed nucleophilic ring-opening methodology to
unsymmetrically arene-substituted oxabenzonorbornadienes. The regioselectivity of the ring opening
was investigated using a variety of nucleophiles that led to a broad selection of dihydronaphthalene
products. It was found that good to excellent regioselectivities are obtained using strongly π-donating
substituents, whereas σ-donating and electron-withdrawing functionalities have a minimal effect.
Post ring-opening manipulations of functional groups in the dihydronaphthalene products were
shown to give efficient access to mono- and diamine tetrahydronaphthalene building blocks.
SCHEME 1
In tr od u ction
Oxabicyclic compounds and particularly 7-oxabicyclo-
[2.2.1]hept-2-ene derivatives are valuable intermediates
for the synthesis of a variety of compounds of biological
interest.1 For instance, Vogel2 has described the regiose-
lective exo-addition of various electrophiles to the CdC
double bond of 7-oxabicyclo[2.2.1]hept-5-en-2-one and
closely related systems. The stereochemical outcome of
these electrophilic additions is controlled by conjugative
interactions of the carbonyl group across the bicyclic
system or by neighboring group participation of a ketal
substituent.
norbornene enabled a regioselective ring opening pro-
moted by a Lewis acid catalyst.4
The regioselective cleavage of the oxygen bridge to give
functionalized cyclohexanes is central to many synthetic
strategies. A regioselective ring opening using organo-
lithium reagents and 7-oxanorbornenes has been inves-
tigated by Arjona and Plumet3 for cases where the olefinic
moiety is directly substituted with appropriate Michael
acceptor functionalities such as a vinyl sulfone. Similarly,
methylthio substitution of the double bond of a 7-oxa-
Remote electronic effects mediated by an aromatic
π-system have been thoroughly investigated for the
transformation of substituted oxabenzonorbornadienes to
the corresponding naphthols under protic conditions.5 In
two typical examples, treatment of oxabenzonorborna-
dienes 1 and 3 under acidic conditions gave one of two
possible regioisomeric naphthol products (2 and 4) ex-
clusively, since in both cases the depicted carbocationic
intermediate is strongly favored by conjugative stabiliza-
tion (Scheme 1).6 However, the formation of the aromatic
compounds from these chiral precursors entails a loss of
all stereochemical information.
(1) For reviews on synthetic strategies involving oxabicyclic systems,
see: (a) Vogel, P.; Cossy, J .; Plumet, J .; Arjona, O. Tetrahedron 1999,
55, 13521. (b) Chiu, P., Lautens, M. Top. Curr. Chem. 1997, 190, 1. (c)
Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (d) Vogel, P.; Fattori, D.;
Gasparini, F.; Le Drian, C. Synlett 1990, 173. (e) Vogel, P. Bull. Soc.
Chim. Belg. 1990, 99, 395. (f) Lautens, M. Synlett 1993, 177.
(2) For selected references, see: (a) Cossy, J .; Ranaivosata, J .-L.;
Bellosta, V.; Ancerewicz, J .; Ferritto, R.; Vogel, P. J . Org. Chem. 1995,
60, 8351. (b) Reymond, J .-L.; Pinkerton, A. A.; Vogel, P. J . Org. Chem.
1991, 56, 2128. (c) Black, K. A.; Vogel, P. J . Org. Chem. 1986, 51, 5341.
(d) Nativi, C.; Reymond, J .-L.; Vogel, P. Helv. Chim. Acta 1989, 72,
882. (e) Gasparini, F.; Vogel, P. Helv. Chim. Acta 1989, 72, 271. (f)
Allemann, S.; Vogel, P. Synthesis 1991, 923. (g) Le Drian, C.; Vogel,
P. J . Org. Chem. 1993, 58, 2328.
(3) For selected references, see: (a) Arjona, O.; Ferna´ndez de la
Pradilla, R.; Garcia, E.; Martin-Domenech, A.; Plumet, J . Tetrahedron
Lett. 1989, 30, 6437. (b) Arjona, O.; Ferna´ndez de la Pradilla, R.; Mallo,
A.; Plumet, J .; Viso, A. Tetrahedron Lett. 1990, 31, 1475. (c) Arjona,
O.; de Dios, A.; Ferna´ndez de la Pradilla, R.; Plumet, J .; Viso, A. J .
Org. Chem. 1994, 59, 3906. (d) Arjona, O.; Borrallo, C.; Iradier, F.;
Medel, R.; Plumet, J . Tetrahedron Lett. 1998, 39, 1977.
We therefore envisaged a regioselective ring opening
of oxabenzonorbornadienes in which a remote substituent
(4) Yamamoto, I.; Narasaka, K. Chem. Lett. 1995, 1129.
(5) (a) Gavin˜a, F.; Luis, S. V.; Ferrer, P.; Costero, A. M.; Gil, P.
Tetrahedron 1986, 42, 5641. (b) Batt, D. G.; J ones, D. G.; La Greca, S.
J . Org. Chem. 1991, 56, 6704. (c) Giles, R. G. F.; Sargent, M. V.;
Sianipar, H. J . Chem. Soc., Perkin Trans. 1 1991, 1571. (d) Giles, R.
G. F.; Hughes, A. B.; Sargent, M. V. J . Chem. Soc., Perkin Trans. 1
1991, 1581. (e) Baker, R. W.; Baker, T. M.; Birkbeck, A. A.; Giles, R.
G. F.; Sargent, M. V.; Skelton, B. W.; White, A. H. J . Chem. Soc., Perkin
Trans. 1 1991, 1589.
(6) In an analogous experiment, even the weak σ-donating methyl
group gave Batt a regioselectivity of 3:1, whereas the σ-withdrawing
bromo group gave an inverted regioselectivity of 1:9 (ref 5b).
10.1021/jo025822o CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/19/2002
J . Org. Chem. 2002, 67, 8043-8053
8043

Lautens et al.
SCHEME 2a
unsymmetrically arene-substituted oxabenzonorborna-
dienes. If we could establish the necessary requirements
for highly regioselective opening, subsequent modification
of the dihydronaphthalene products promised to generate
diverse structures within the hydronaphthalene scaffold.
Resu lts a n d Discu ssion
a
Bidentate PP-ligand ) dppf, PPF-PtBu2. Nucleophile )
Syn th esis of Un sym m etr ica lly Ar en e-Su bstitu ted
Oxa ben zon or bor n a d ien es.12 We required versatile and
efficient synthetic routes leading to multigram quantities
of diversely substituted oxabenzonorbornadienes. There
exists a multitude of methods for oxabenzonorbornadiene
preparation13 that differ in the way a highly reactive
benzyne intermediate is formed. In all cases, the benzyne
intermediate reacts with furan in a [4 + 2]-cycloaddition
to form the strained oxabicyclic framework.14 We selected
three commonly used strategies of benzyne formation for
the synthesis of five known and seven novel oxaben-
zonorbornadienes for reasons of their directness and
reliability.15
Method I starts from suitable anthranilic acid deriva-
tives.16 These are treated with isoamyl nitrite in order
to obtain the corresponding benzyne via an intermediate
diazonium species. Substrates 85a and 115a,b (Table 1)
were accessed accordingly using literature procedures.
Method II starts from substituted aryl bromides with
an additional leaving group in the ortho-position, usually
a second halogen or a tosylate substituent.5c-e,17 Metal-
halogen exchange using butyllithium and the subsequent
expulsion of the second leaving group reliably gives the
benzyne intermediate at different characteristic temper-
atures. We observed immediate elimination of lithium
bromide at -78 °C, whereas lithium chloride is only
eliminated at approximately -20 °C,18 thus confirming
once again the order of elimination found by Bunnett
(I > Br > Cl > F).19 In most cases, the yields of
oxabenzonorbornadienes accessed by metal-halogen ex-
change are good and reproducible, making this the
method of choice provided that the dihalide precursor is
easily accessible and all other substituents are stable
ROH, RR′NH, phthalimide, RCOOH, dimethylmalonate.
controls which C-O bond is broken while conserving the
stereochemical information in the dihydronaphthalene
products. It was necessary to replace the deprotonation
step in an equivalent reactive intermediate by an addi-
tion of a nucleophile. The rhodium-catalyzed nucleophilic
ring opening of oxabenzonorbornadienes developed in our
group was potentially well suited to achieve this objec-
tive.7
Since we first reported the reductive and alkylative
nucleophilic ring opening of oxabenzonorbornadienes
using nickel and palladium catalysts,8 we have success-
fully extended this methodology using rhodium catalysts
and a variety of nucleophiles to include asymmetric
additions of aliphatic alcohols,9a phenols,9b,c carboxylates,9d
both aliphatic and aromatic amines,9e malonates,9e and
most recently boronic acids.10 The stereocontrolled addi-
tion of heteroatom nucleophiles to different oxabenzonor-
bornadienes of general structure 5 cleanly gives trans-
substituted dihydronaphthalene products 6 (Scheme 2),
whereas the addition of boronic acids was found to lead
to the corresponding cis-products.10
The hydronaphthalene core can be found in a variety
of natural and synthetic compounds, possessing a wide
range of biological activities.11 Given the medicinal inter-
est, our goal was to prepare a diverse range of substitu-
tional patterns on the hydronaphthalene pharmacophore
in order to investigate the regioselectivity of opening
(7) For a review, see: Lautens, M.; Fagnou, K.; Hiebert, S. Acc.
Chem. Res. Accepted for publication.
(8) (a) Lautens, M.; Rovis, T. Tetrahedron 1998, 54, 1107. (b)
Lautens, M.; Renaud, J . L.; Hiebert, S. J . Am. Chem. Soc. 2000, 122,
1804. (c) Lautens, M.; Hiebert, S.; Renaud, J .-L. J . Am. Chem. Soc.
2001, 123, 6834.
(12) For synthetic procedures of all oxabenzonorbornadienes used
in this study, see Supporting Information.
(9) (a) Lautens, M.; Fagnou, K, Rovis, T. J . Am. Chem. Soc. 2000,
122, 5650. (b) Lautens, M.; Fagnou, K.; Taylor M. Org. Lett. 2000, 2,
1677. (c) Lautens, M.; Fagnou, K.; Taylor, M.; Rovis, T. J . Organome-
tallic Chem. 2001, 624, 259. (d) Lautens, M.; Fagnou, K. Tetrahedron
2001, 57, 5067. (e) Lautens, M.; Fagnou, K. J . Am. Chem. Soc. 2001,
123, 7170.
(13) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic
Press: New York, 1967.
(14) The oxygen bridge causes a decrease in the bond angles between
the benzene ring and the bridgehead carbons from the ideal 120° to
typically 104.4 ( 0.5°, as determined by X-ray structure analysis of
compounds 1, 3, and 13 (see Supporting Information).
(15) For selected references concerning alternative and more recent
methods of benzyne generation, see: (a) Kitamura, T.; Meng, Z.;
Fujiwara, Y. Tetrahedron Lett. 2000, 41, 6611. (b) Birkett, M. A.;
Knight, D. W.; Little, P. B.; Mitchell, M. B. Tetrahedron 2000, 56, 1013.
(c) Kitamura, T.; Yamane, M.; Inoue, K.; Todaka, M.; Fukatsu, N.;
Meng, Z.; Fujiwara, Y. J . Am. Chem. Soc. 1999, 121, 11674. (d)
Effenberger, F.; Daub, W. Chem. Ber. 1991, 124, 2113. (e) Furukawa,
N.; Shibutani, T.; Fujihara, H. Tetrahedron Lett. 1987, 28, 2727. (f)
Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
(16) (a) Stiles, M.; Miller, R. G. J . Am. Chem. Soc. 1960, 82, 3802.
(b) Stiles, M.; Miller, R. G.; Burckhardt, U. J . Am. Chem. Soc. 1963,
85, 1792. (c) Gompper, R.; Seybold, G.; Schmolke, B. Stiles, M.; Miller,
R. G. Angew. Chem., Int. Ed. Engl. 1968, 7, 389. (d) Logullo, F. M.;
Seitz, D. F.; Friedman, L. Organic Syntheses; Wiley: New York, 1973;
Collect. Vol. V, p 54.
(10) Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett.
2002, 4, 1311.
(11) For selected references, see: (a) Saito, M.; Kayama, Y.; Wa-
tanabe, T.; Fukushima, H.; Hara, T.; Koyano, K.; Takenaka, A.; Sasada,
Y. J . Med. Chem. 1980, 23, 1364. (b) Freeman, J . P.; Michalson, E. T.;
D’Andrea, S. V.; Baczynskyj, L.; Von Voigtlander, P. F.; Lahti, R. A.;
Smith, M. W.; Lawson, C. F.; Scahill, T. A.; Mizsak, S. A. J . Med. Chem.
1991, 34, 1891. (c) J ones, J . H.; Anderson, P. S.; Baldwin, J . J .;
Clineschmidt, B. V.; McClure, D. E.; Lundell, G. F.; Randall, W. C.;
Martin, G. E.; Williams, M.; Hirshfield, J . M. J . Med. Chem. 1984, 27,
1607. (d) New, J . S.; Yevich, J . P.; Eison, M. S.; Taylor, D. P.; Eison,
A. S.; Riblet, L. A.; VanderMaelen, C. P.; Temple, D. L., J r. J . Med.
Chem. 1986, 29, 1476. (e) Welch, W. M.; Kraska, A. R.; Sarges, R.;
Koe, B. K. J . Med. Chem. 1984, 27, 1508. (f) Wyrick, S. D.; Booth, R.
G.; Myers, A. M.; Owens, C. E.; Kula, N. S.; Baldessarini, R. J .;
McPhail, A. T.; Mailman, R. B. J . Med. Chem. 1993, 36, 2542. (g)
J ohansson, A. M.; Arvidsson, L.-E.; Hacksell, U.; Nilsson, J . L.;
Svensson, K.; Carlsson, A. J . Med. Chem. 1987, 30, 602. (h) Snyder,
S. E.; Aviles-Garay, F. A.; Chakraborti, R.; Nichols, D. E.; Watts, V.
J .; Mailman, R. B. J . Med. Chem. 1995, 38, 2395. (i) Perrone, R.;
Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Tortorella, V.; Fiorentini,
F.; Olgiati, V.; Ghiglieri, A.; Govoni, S. J . Med. Chem. 1995, 38, 942.
(17) Caster, K. C.; Keck, C. G.; Walls, R. D. J . Org. Chem. 2001, 66,
2932.
(18) Pansegrau, P. D.; Rieker, W. F.; Meyers, A. I. J . Am. Chem.
Soc. 1988, 110, 7178.
(19) Bunnett, J . F.; Kearley, F. J ., J r. J . Org. Chem. 1971, 36, 184.
Elimination of LiF takes place at approximately 0 °C; see: Clark, R.
D.; Caroon, J . M. J . Org. Chem. 1982, 47, 2804.
8044 J . Org. Chem., Vol. 67, No. 23, 2002

Nucleophilic Ring Opening of Oxabenzonorbornadienes
TABLE 1. Regioselectivity of th e Rin g-Op en in g Rea ction Usin g Meth a n ol a s a Nu cleop h ile
b
c
c
b
entrya
substrate
R1
R2
R3
R4
products 17 + 18
yieldd of 17 + 18 (ratioe)
1
2
3
4
5
6
7
8
9
10
H
H
H
OCH3
H
OCH3
OCH3
OCH3
H
Ac
H
H
H
H
H
H
H
H
H
H
H
H
CF3
H
Br
H
H
CH3
H
Ac
H
H
Cl
H
H
H
H
a
b
c
d
e
f
g
h
i
83% (1.05:1)
86% (1.05:1)
84% (1.05:1)
62% (1.1:1)
75% (1.8:1)
81% (3.5:1)
82% (3.9:1)
82% (4.9:1)
89% (12:1)
115a-b,15c
12
13
85a
15d,20e
14
H
Cl
15
35d
OCH3
OCH3
N(CH3)Ph
10
11
165d,21
9
OCH3
H
j
k
80%f (>25:1)
58%f (>25:1)
a
b
d
In the order of increasing regioselectivity. Proximal positions. c Distal positions. Yield of purified material. Conditions: 2.5 mol %
[Rh(cod)Cl]2/5 mol % dppf, THF/MeOH 1:1, reflux, 0.2 M in substrate. e Determined by crude 1H NMR and confirmed by isolated yields
for all cases where regioisomers were separable by column chromatography. f Only one regioisomer was observed.
SCHEME 3a
SCHEME 4
be possible using the mild procedure described by Sterzy-
cki23 (PPTS in wet acetone, 60 °C). It is noteworthy that
the otherwise acid-sensitive oxabenzonorbornadienes are
sufficiently stable to these reaction conditions.
a
Reaction conditions: (a) 1.2 equiv of pyrrolidine, 1.4 equiv of
NaOtBu, 7 mol % Pd(OAc)2, 14 mol % L, toluene (1 M in aryl halide
8), 60 °C, 15 h. (b) 1.2 equiv of N-methylaniline, 1.4 equiv of
NaOtBu, 5 mol % Pd2(dba)3, 10 mol % L, toluene (1 M in aryl halide
8), 60 °C, 19 h.
Regioselectivity of th e Rh od iu m -Ca ta lyzed Rin g-
Op en in g Rea ction . With a representative selection of
unsymmetrically substituted oxabenzonorbornadiene sub-
strates in hand, a standard set of ring-opening reaction
conditions9c was employed (Scheme 4), enabling a direct
comparison of the regioselectivities for almost all sub-
strates (Table 1).24 Methanol was chosen as the standard
nucleophile, since it can easily be used in large excess
while being small enough not to dominate the Rf in the
ring-opened products, thus generally facilitating chro-
matographic separation of regioisomers. Though the
nature of the respective nucleophiles (e.g., nucleophilicity,
ability to act as a ligand to rhodium, solubility, and
necessity for additives) brings minor variations in reac-
tivity for a given oxabenzonorbornadiene substrate, the
regioselectivity has been found to be largely substrate-
dominated. The catalyst system employed also strongly
affects the outcome of these reactions, and we screened
a variety of systems for regioselectivity by variation of
the catalyst precursor,25a the phosphine ligand,25b and the
remaining ligands25c on the rhodium(I) center. Though
some catalyst systems such as [Rh(CO)2Cl]2 gave signifi-
cantly higher regioselectivities than others, reactions
with this catalyst were accompanied by a greater number
of byproducts. In many cases (e.g., using monodentate
ligands), intractable mixtures of unidentified products
were obtained. Our studies demonstrated that the origi-
toward butyllithium. Substrates 3,5d 10, and 12 (Table
1) were prepared using this methodology.
Method III starts from substituted anisoles containing
a leaving group in the meta-position and takes advantage
of the ortho-directing properties of the methoxy group.20
Thus, treatment of suitably substituted anisoles with
LDA efficiently generates the corresponding benzynes via
ortho-lithiation and the subsequent elimination of the
adjacent leaving groups. Substrates 15d,20e and 13-165d,21
(Table 1) were reliably prepared in one-step procedures
following this strategy, the yields ranging from 46 to 76%.
While significantly expanding the scope of methods II
and III, we also showed that manipulation of the sub-
stituents on an oxabenzonorbornadiene was possible.
Thus, the Buchwald-Hartwig amination methodology22
was employed to access nitrogen-substituted oxaben-
zonorbornadienes 7 and 9 from bromo-substituted 8
(Scheme 3). None of the aforementioned direct methods
had been successful in delivering nitrogen substitution.
Also, deprotection of the ketal functionality in the
synthetic precursors to substrates 10 and 13 proved to
(20) (a) Slocum, D. W.; J ennings, C. A. J . Org. Chem. 1976, 41, 3653.
(b) Carre´, M.-C.; Gregoire, B.; Caubere, P. J . Org. Chem. 1984, 49,
2050. (c) Apeloig, Y.; Arad, D.; Halton, B.; Randall, C. J . J . Am. Chem.
Soc. 1986, 108, 4932. (d) Sims, C. G.; Wege, D. Aust. J . Chem. 1992,
45, 1983. (e) J ung, M. E.; Lowen, G. T. Tetrahedron Lett. 1986, 27,
5319. (f) Clive, D. L. J .; Khodabocus, A.; Vernon, P. G.; Angoh, A. G.;
Bordeleau, L.; Middleton, D. S.; Lowe, C.; Kellner, D. J . Chem. Soc.,
Perkin Trans. 1 1991, 1433.
(21) Tochtermann, W.; Strickler, R.; Klein, H. A.; Biegi, E. Chem.
Ber. 1977, 110, 2456.
(22) For selected references, see: (a) Yang, B. H.; Buchwald, S. L.
J . Organomet. Chem. 1999, 576, 125. (b) Wolfe, J . P.; Tomori, H.;
Sadighi, J . P.; Yin, J .; Buchwald, S. L. J . Org. Chem. 2000, 65, 1158.
(c) Ali, M. H.; Buchwald, S. L. J . Org. Chem. 2001, 66, 2560 and
references therein.
(23) Sterzycki, R. Synthesis 1979, 724.
(24) The ring opening of the pyrrolidinyl-substituted substrate 7
(scheme 3) with methanol gives a product that proved to be unstable
under standard ring-opening reaction conditions. However, ring open-
ing with N-methylaniline gives one regioisomer exclusively in 86%
yield.
(25) (a) [Rh(CO)2Cl]2, [Rh(cod)Cl]2. (b) Monodentate: PPh3, P(OiPr)3,
P(2-furyl)3, (o-biphenyl)P(tBu)2, 2-dicyclohexylphosphino-2′-(N,N-di-
methylamino)-biphenyl. Bidentate: dppm, dppe, dppp, dppb, dpppe,
dppf. (c) Cl-, I-, CO, solvent molecule.
J . Org. Chem, Vol. 67, No. 23, 2002 8045

Lautens et al.
nal catalyst system9a (2.5 mol % [Rh(cod)Cl]2/5 mol %
dppf) proved to be the most reliable for the ring openings,
generally giving reproducible yields and regioselectivities,
although the catalyst formed with dppf proved to be far
less active than the Rh-J OSIPHOS complexes used in
asymmetric ring openings (ARO).9
SCHEME 5
Table 1 gives the results of the standard ring-opening
experiments in the order of increasing regioselectivity,
using methanol as a nucleophile. The structural assign-
ment of the two regioisomers was accomplished by X-ray
structure analysis26 of the major regioisomers 17f and
17i containing both proximal and distal27 methoxy sub-
stitution (entries 6 and 9). For all other entries, the
comparison of the 1H NMR data of the two respective
regioisomers with the data recorded for entries 6 and 9
enabled an unambiguous assignment of substituent
positioning. The 1H NMR signals of the aromatic and
olefinic protons revealed characteristic coupling patterns
and relative chemical shifts for both proximal and distal
substitution.
In addition to the obvious electronic effects, there also
exists a small steric component in the cases of proximal
substitution that seems to inhibit the catalyst’s approach
to the C-O bond that will be broken en route to the
electronically favored product. In this sense, the elec-
tronically “wrong” regioisomer is (minimally) favored by
the overriding steric effect in the case of the weak
σ-donating methyl group (entry 2), whereas the difference
in regioselectivity shown in entries 6 and 9, where a
single methoxy group is placed in the proximal and distal
positions, respectively, may be at least partially at-
tributed to the stronger steric hindrance exerted by the
proximal substitution. Steric effects also cause a rise in
regioselectivity going from entry 6 to entry 7, since we
would expect a decrease due to the unfavorable 1,4-
relationship of the two substituents. Entry 8, on the other
hand, illustrates the increase in regioselectivity seen for
the corresponding 1,3-substituents.
Chromatographic separation of the regioisomers is
generally easy with substrates having proximal substitu-
tion, whereas distal substitution results in little differ-
ence in the Rf. In all but two cases (entries 1 and 2),
where the regioselectivity is reversed, the major product
has a higher Rf and can be isolated in high purity,
whereas the minor component can be accompanied by
significant amounts of impurities.
An aliphatic amine substituent was found to be the
most effective in obtaining high regioselectivity, activat-
ing the bicyclic system so strongly that most dihy-
dronaphthalene products are no longer stable to the
reaction conditions. To compare the ring opening of
substrate 7 with that of the other substrates, it was
therefore necessary to change to N-methylaniline as a
nucleophile (Scheme 5), since the corresponding products
generally are more stable.28 Entries 1-3 of Table 2 give
the regioselectivities for the ring opening of the three
most selective systems. The results show that two meth-
oxy groups placed in a reinforcing 1,3-relationship (entry
1) are approximately equal to one aromatic nitrogen
substituent (entry 2). Aliphatic nitrogen substitution
(entry 3) clearly gives the highest selectivity, though the
dihydronaphthalene product 19c is very acid-sensitive.29
Strongly activated dihydronaphthalene products such as
19c must be reduced to the corresponding tetrahy-
dronaphthalene if they are to be stored over a longer
period of time (see below). Finally, it must be noted that
strong π-donating groups are a necessary condition in
order to obtain synthetically useful regioselectivities
(>10:1).
The results (Table 1) clearly show that substrates with
strong π-donating substituents, containing either oxygen
or nitrogen atoms, lead to high regioselectivity (entries
6-11), whereas π-withdrawing groups (e.g., acetyl group,
entry 1), σ-withdrawing groups (CF3 group, entry 3), and
σ-donating groups (methyl group, entry 2) have practi-
cally no effect on regioselectivity. Even the weak σ-donat-
ing methyl group had shown significant regioselectivity
for the conversion of substrate 11 to the corresponding
naphthols.5b,6 In our study, however, only the π-with-
drawing acetyl group and the methyl group were able to
reverse the regioselectivity observed in all other entries.
Significantly, the CF3 group minimally favors the same
regioisomer as a methoxy group, indicating that its
σ-withdrawing properties do not influence this process.
Moreover, an acetyl group, placed in a para-position to a
methoxy group, not only fails to enhance regioselectivity,
as is characteristic for electrophilic aromatic substitution
reactions, but almost completely counteracts the influ-
ence of the methoxy group (entry 4). Halogen substituents
have a small but distinct influence on regioselectivity by
virtue of their poor π-donating ability, as seen from entry
5 or by comparison of entries 6-8. Again, it is particularly
noteworthy that bromo substitution (entry 5) favors the
same regioisomer as the analogous methoxy substitution
(entry 9), clearly indicating that π-donating abilities
overwhelmingly dominate the rhodium-catalyzed reac-
tion. In stark contrast to this result, the ionic reaction
pathway of naphthol formation under protic conditions
gave Batt the reversed regioselectivity for proximal
bromo-substitution.5b,6 Finally, the rhodium-catalyzed
nucleophilic ring opening has proven to be sufficiently
chemoselective to allow for bromo substitution on the
aromatic ring.
(26) Data were collected on a Nonius Kappa CCD diffractometer
using a combination of φ and ω scans with κ offsets. Data were
integrated and scaled using the Denzo-SMN package [Otwinowski, Z.;
Minor, W. Methods in Enzymology; Academic Press: London, 1997,
307.]. The structure was solved and refined using SHELXTL V6.12.
The full-matrix least-squares refinement was based on F2 [Sheldrick,
G. M. SHELXTL/PC, version 6.12 for Windows NT. Bruker AXS, Inc.:
Madison, WI; 2001.]. See Supporting Information.
(28) N-Methylaniline is the most versatile nucleophile and reacts
with all the substrates examined to date. The regioselectivity using
N-methylaniline is always slightly below the regioselectivity observed
with methanol.
(29) The silica used for column chromatography had to be thoroughly
neutralized with triethylamine prior to purification. Otherwise, 19c
was cleanly converted to its corresponding naphthol in 89% overall
yield.
(27) In this paper, the positions of R1 and R4 within the structures
of Scheme 3 will be termed proximal in relation to the dihydrofuran
moiety. The positions of R2 and R3 will be termed distal.
8046 J . Org. Chem., Vol. 67, No. 23, 2002

Nucleophilic Ring Opening of Oxabenzonorbornadienes
TABLE 2. Regioselectivity of th e Rin g-Op en in g Rea ction Usin g th e Most Selective Su bstr a tes w ith Differ en t
Nu cleop h iles
entrya
substrate
R1
R3
nucleophile (NuH)
products 19 + 20
yieldb of 19 (ratioc)
1
2
3
4
5
6
7
16
9
7
16
16
16
16
OCH3
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
N-methylaniline
N-methylaniline
N-methylaniline
dibenzylamine
phenol
dimethylmalonate
4-hydroxyacetophenone
a
b
c
d
e
f
84% (11:1)
N(CH3)Ph
N(C4H8)
OCH3
OCH3
OCH3
80% (11:1)
86%d (>25:1)
77% (11:1)
74%d (>25:1)
55%d (>25:1)
50% (18:1)
OCH3
g
a
b
In the order of increasing regioselectivity (entries 1-3) or decreasing yield (entries 4-7). Yield of purified material. Conditions: 2.5
mol % [Rh(cod)Cl]2/5 mol % dppf, THF reflux, 0.4 M in substrate, 5 equiv of nucleophile, 2.5 equiv of ammonium iodide (entries 4 and 6).
c Determined by crude 1H NMR and confirmed by isolated yields for all cases where regioisomers were separable by column chromatography.
d
Only one regioisomer was observed.
There are no spectroscopic parameters with which to
predict the regioselectivity of a given substrate with
certainty, though selective systems often give distinctly
different chemical shifts for the 1H-signals corresponding
to the bridgehead positions (typically 5.60-6.00 ppm).
Even the two C-O bond lengths30 within the bicyclic
moiety have been shown to be equal within experimental
error.
Usin g Ot h er Nu cleop h iles on High ly Act iva t ed
System s. The dimethoxy-substituted oxabenzonorbor-
nadiene 165d,21 was chosen for a study on the use of other
nucleophiles (Scheme 5) because it is easily prepared
from 5-chloro-1,3-dimethoxybenzene on a multigram
scale while giving synthetically useful regioselectivities.
At the same time, substrate 16 leads to regioisomers that
are easily separated thanks to proximal substitution.
Entries 4-7 in Table 2 are listed in order of decreasing
yield.31 The nature of the nucleophile has a very limited
influence on regioselectivity, whereas the yield of the
ring-opened product strongly depends on the nucleophi-
licity and the tendency of NuH to be eliminated from the
dihydronaphthalene products, giving the substituted
naphthol derivatives. Thus, the adduct from the more
easily eliminated 4-hydroxyacetophenone is isolated in
lower yield than the corresponding phenol-derived dihy-
dronaphthalene (entries 5 and 7). The benzoic acid-
derived product could only be isolated with great care.31
Dimethylmalonate (entry 6) and pyrrolidine31 are best
used as nucleophiles with ammonium iodide as an
additive.9e In the case of strongly activated systems, the
reduced stability of the substrate and products becomes
the limiting factor. Fortunately, dibenzylamine efficiently
gives the desired product 19d in good yield and excellent
purity. Ammonium iodide (2.5 equiv) was added to
facilitate the dissociation of the amine from the rhodium
center.
shown to give products that are prone to decomposition
under the reaction conditions.
In tr od u cin g Am in o F u n ction a lities to Rin g-
Op en ed Dih yd r on a p h th a len es. Our next goal became
the development of post ring-opening strategies suitable
for the preparation of nitrogen-substituted tetrahy-
dronaphthalenes including 22, 24, 27, and 28 (Scheme
6). Finding suitable conditions for the selective reduction
of the olefin in the substituted dihydronaphthalenes
proved to be challenging in some cases. For instance,
catalytic hydrogenation using either Pd/C or Pt/C led to
over-reduction at benzylic positions. In addition, an azide
was considered as a likely intermediate in our routes so
that selective olefin reductions were of interest.
1-Amino-tetrahydronaphthalene 22 was obtained by
standard H2/Pt/C reduction33 of ring-opened intermediate
17j, followed by Mitsunobu-type inversion of the hydroxy
group in 21 using DPPA as an azide source34 and H2/
Pd/C reduction35 of the corresponding (cis)-azide inter-
mediate.36 Since the benzylic position in 21 is highly
activated, the Mitsunobu-reaction was conducted in
toluene at -20 °C in order to minimize the competing
elimination process while at the same time completely
inhibiting epimerization observed at 0 °C, which led to
the formation of the corresponding (trans)-azide.36 The
2-amino-tetrahydronaphthalene 24 was prepared by a
very efficient diimide reduction37 of 19d , followed by
double deprotection of 23 using ammonium formate to
act as a catalytic hydrogen transfer agent.38 Deprotection
of 23 was completed in 15 min, and compound 24 was
best isolated as its hydrochloride by simple extraction of
the product with 2 M HCl and concentration of the
resulting aqueous solution. Hydrogenation of 23 using
(33) For a review on olefin reductions, see: Siegel, S. Comprehensive
Organic Synthesis; Pergamon Press: Oxford, 1991, p 417 and refer-
ences therein.
(34) Imamura, H.; Ohtake, N.; Shimizu, A.; Sato, H.; Sugimoto, Y.;
Sakuraba, S.; Nagano, R.; Nakano, M.; Abe, S.; Suzuki-Sato, C.;
Nishimura, I.; Kojima, H.; Tsuchiya, Y.; Yamada, K.; Hashizume, T.;
Morishima, H. Bioorg. Med. Chem. 2000, 8, 1969.
In conclusion, a representative member of each class
of nucleophiles32 used in previous publications9 was tried
on the highly activated system of substrate 16. Moderate
to good yields were obtained in each case with the
exception of the carboxylate family, which has been
(35) Luke, G. P.; Holt, D. A. Tetrahedron: Asymmetry 1999, 10,
4393.
(36) 1H NMR presents a valuable tool for the determination of the
relative configuration of 1,2-disubstituted tetrahydronaphthalenes,
since the cis-configuration invariably gives a smaller vicinal coupling
constant than the corresponding trans-configuration. Thus, the (cis)-
azide intermediate gave a 1H NMR signal of H(1) ) 4.61 (d, J ) 3.6
Hz), whereas the corresponding (trans)-azide showed a 1H NMR signal
of H(1) ) 4.44 (d, J ) 6.3 Hz). Analogously, (trans)-azide 25 gave a 1H
NMR signal of H(1) ) 4.53 (d, J ) 9.7 Hz) with an even larger vicinal
coupling constant.
(30) As determined by X-ray structure analysis of compounds 1, 3,
and 13 (cf. ref 26).
(31) Ring opening with triethylammonium benzoate gave the cor-
responding (very unstable) dihydronaphthalene product in only 25%
yield (9:1 ratio). It was not fully characterized. Ring opening with
pyrrolidine/ammonium iodide gave complete decomposition under
standard reaction conditions.
(32) Alcohols, phenols, aliphatic and aromatic amines, carboxylates,
and malonates.
(37) Stafford, J . A.; Valvano, N. L. J . Org. Chem. 1994, 59, 4346.
(38) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.
J . Org. Chem, Vol. 67, No. 23, 2002 8047

Lautens et al.
SCHEME 6a
a
Reaction conditions: (a) [Rh(cod)Cl]2, dppf, THF/MeOH reflux. (b) H2, Pt/C. (c) PPh3, DEAD, DPPA, toluene, -20 °C. (d) H2, Pd/C. (e)
[Rh(cod)Cl]2, dppf, HNBn2, THF reflux. (f) HNdNH. (g) Method I: EtOAc/MeOH, 1500psi H2, 5d. Method II: HCO2NH4, Pd/C, MeOH/
EtOAc, 15 min reflux. (h) MsCl/TEA, NaN3 in DMF. (i) H2, Pd/C. (j) BOC2O, TEA. (k) HCO2NH4, Pd/C, MeOH. (l) HCO2NH4, Pd/C,
MeOH.
SCHEME 7
H2/Pd/C39 was very clean but sluggish, and the addition
of acetic or formic acid also led to partial epimerization
at the benzylic position.
Treating the dibenzylamino-alcohol 23 under various
Mitsunobu-type reaction conditions was not as successful
as in the case of its methoxy counterpart 21, possibly
because of the steric bulk of the dibenzylamine function-
ality. A combination of in situ mesylation40 and subse-
quent double-SN2 reaction using a DMF solution of
sodium azide as a source of nucleophile41 to open the
cationic aziridium intermediate finally gave the antici-
pated (trans)-azide 25 with clean retention of configura-
tion.36 The neighboring group participation of the diben-
zylamino group in this transformation was confirmed by
X-ray structure analysis26 of compound 25. Complete
reduction of azide 25 under the aforementioned catalytic
hydrogen transfer conditions38 directly gives (trans)-
diamine 28. However, the reduction can also be inter-
rupted at the N2,N2-dibenzyl-protected diamine 26 by
using standard H2/Pd/C reduction,35 allowing for an
exchange of protecting groups,38,42 to give the N1-BOC-
palladium-catalyzed ring opening using organozinc
nucleophiles,8c we do not have any direct evidence for the
ring-opening reaction using Rh catalysts and heteroatom-
containing nucleophiles. However, the results obtained
with unsymmetrical substrates are in agreement with a
pathway that is triggered by coordination to the bridging
oxygen (and perhaps the alkene) followed by regioselec-
tive insertion into the bridging C-O bond to give III,
Scheme 7. Bond b in intermediate II should be more
prone to cleavage as a result of the stabilization of
positive charge that results following ionization. We
cannot rule out a direct displacement (pathway A) or
stepwise ionization in analogy with the reactions de-
scribed in Scheme 1, but the observation of a steric effect
(in cases of proximal substitution) suggests that pathway
B is the dominant process. Nucleophilic attack on the
σ-enyl or π-allyl form of III would yield IV and ultimately
the observed product and the regenerated catalyst.
protected diamine 27, now leaving the 2-amino-group free
for further derivatization. With the two monoprotected
diamines 26 and 27 in hand, virtually any further
derivatization of the amino groups can be envisaged, thus
making these compounds potentially valuable building
blocks for tetrahydronaphthalene-based biologically ac-
tive agents.11
P r op osed Ca ta lytic Cycle. While we were able to
obtain detailed information on the mechanism of the
(39) (a) Gray, B. D.; J effs, P. W. J . Chem. Soc., Chem. Commun.
1987, 1329. (b) ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.;
Means, G. E. J . Org. Chem. 1979, 44, 3442. (c) Hartung, W. H.;
Simonoff, R. Org. React. 1953, VII, 263.
(40) Fu¨rst, A.; Koller, F. Helv. Chim. Acta 1947, 30, 1454.
(41) Iwasawa, Y.; Shibata, J .; Nonoshita, K. Tetrahedron 1996, 52,
13881.
(42) Ponnusamy, E.; Fotadar, U.; Spisni, A.; Fiat, D. Synthesis 1986,
48.
8048 J . Org. Chem., Vol. 67, No. 23, 2002

Nucleophilic Ring Opening of Oxabenzonorbornadienes
7.00 (dd, J ) 5.5, 1.7 Hz, 1H), 6.95 (dd, J ) 5.5, 1.7 Hz, 1H),
6.67 (d, J ) 1.9 Hz, 1H), 6.04 (dd, J ) 8.0, 2.2 Hz, 1H), 5.67-
5.65 (m, 1H), 5.63-5.61 (m, 1H), 3.28-3.22 (m, 4H), 2.01-
1.93 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 150.8, 146.1, 143.9,
141.8, 134.5, 120.8, 106.7, 105.9, 82.8, 82.4, 48.1, 25.6. HRMS
calcd for C14H15NO (M+): 213.1154. Found: 213.1155.
6-(Meth ylp h en yla m in o)-1,4-d ih yd r o-1,4-ep oxid on a p h -
th a len e (9). A Schlenk flask was flame-dried under a stream
of nitrogen. The flask was charged with aryl bromide 8 (1.08
g, 4.84 mmol), anhydrous toluene (5 mL), Pd2(dba)3 (221 mg,
5 mol %), (o-biphenyl)P(tBu)2 (159 mg, 11 mol %), sodium
t-butoxide (0.65 g, 1.4 equiv), and N-methylaniline (0.63 mL,
1.2 equiv). The resulting dark reaction mixture was heated to
60 °C for 19 h, diluted with diethyl ether (100 mL), filtered
through Celite, and concentrated. The resulting crude product
was purified by flash chromatography (10% ethyl acetate/
hexane), yielding adduct 9 (712 mg, 59%) as a brown oil that
Con clu sion s
A representative selection of unsymmetrically arene-
substituted oxabenzonorbornadienes was synthesized.
The regioselectivity of their rhodium-catalyzed nucleo-
philic ring opening was investigated using a variety of
nucleophiles. It was found that good to excellent regio-
selectivities are obtained using strongly π-donating sub-
stituents containing either oxygen or nitrogen donor
atoms, whereas σ-donating and electron-withdrawing
functionalities only have a minimal effect. The dominance
of π-donating abilities in controlling regioselectivity is in
stark contrast to other reactions such as electrophilic
aromatic substitution reactions and the conversion of
oxabenzonorbornadienes to their corresponding naph-
thols. Distal arene substitution generally gives higher
regioselectivity when compared to an equivalent proximal
substitution (steric effect). Whereas the regioselectivity
is largely substrate-controlled, the yield in ring-opened
dihydronaphthalenes depends on the leaving-group prop-
erties of NuH.
solidified upon refrigeration: mp 83-84 °C; IR (CHCl3, cm-1
)
1592 (m), 1495 (s), 1470 (m); 1H NMR (400 MHz, CDCl3) δ
7.25 (t, J ) 7.7 Hz, 2H), 7.15 (d, J ) 7.7 Hz, 1H), 7.04-6.89
(m, 6H), 6.60 (dd, J ) 7.6, 1.7 Hz, 1H), 5.68 (s, 1H), 5.61 (s,
1H), 3.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.4, 149.1,
146.5, 143.2, 142.3, 141.8, 129.2, 120.8, 120.7, 119.7, 116.6,
115.4, 82.5, 82.2, 40.8. HRMS calcd for
249.1154. Found: 249.1165.
C
17H15NO (M+):
Subsequent modifications of the ring-opened dihy-
dronaphthalenes were shown to quickly lead to interest-
ing tetrahydronaphthalene building blocks. In particular,
vicinal (trans)-diamines are readily accessible from the
corresponding oxabenzonorbornadienes.
(tr a n s)-6-Acetyl-2-m eth oxy-1,2-d ih yd r on a p h th a len -1-
ol (17a ). Following the general procedure, starting from
oxabenzonorbornadiene 10 and using the nucleophile metha-
nol, a 1.05:1 mixture of regioisomers 17a and 18a was obtained
that was inseparable by flash chromatography (20% ethyl
acetate/hexane; 83% combined yield). A small sample of the
pure major regioisomer was isolated, giving adduct 17a as a
colorless solid: mp 103-104 °C; IR (CHCl3, cm-1) 3587 (w),
1683 (s), 1427 (w), 1279 (m), 1267 (m), 1200 (m), 1112 (m); 1H
NMR (300 MHz, CDCl3) δ 7.85 (dd, J ) 8.0, 1.6 Hz, 1H), 7.70
(d, J ) 8.0 Hz, 1H), 7.66 (d, J ) 1.6 Hz, 1H), 6.51 (dd, J )
10.0, 1.9 Hz, 1H), 6.13 (dd, J ) 9.9, 1.9 Hz, 1H), 4.94 (dd, J )
11.0, 2.7 Hz, 1H), 4.14 (ddd, J ) 11.0, 2.1, 2.1 Hz, 1H), 3.53
(s, 3H), 2.95 (d, J ) 3.3 Hz, 1H), 2.60 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 198.0, 141.4, 136.8, 132.6, 128.4, 128.3, 127.7,
125.8, 125.2, 82.4, 72.8, 57.1, 26.9. HRMS calcd for C13H14O3
(M+): 218.0943. Found: 218.0950.
(tr a n s)-2-Meth oxy-8-m eth yl-1,2-d ih yd r on a p h th a len -1-
ol (17b). Following the general procedure, starting from
oxabenzonorbornadiene 11 and using the nucleophile metha-
nol, a 1.05:1 mixture of regioisomers 17b and 18b was
obtained. Separation by flash chromatography (25% ethyl
acetate/hexane) yielded adducts 17b and 18b as colorless oils
(86%). 17b: IR (CHCl3, cm-1) 3592 (w), 2930 (w), 1586 (w), 1467
(w), 1100 (m), 1085 (s); 1H NMR (300 MHz, CDCl3) δ 7.19 (dd,
J ) 7.5, 7.4 Hz, 1H), 7.11 (d, J ) 7.3 Hz, 1H), 7.01 (d, J ) 7.4
Hz, 1H), 6.69 (d, J ) 9.6 Hz, 1H), 6.12 (dd, J ) 9.6, 5.2 Hz,
1H), 4.97-4.92 (m, 1H), 4.01 (ddm, J ) 5.2, 1.9 Hz, 1H), 3.39
(s, 3H), 2.46 (s, 3H), 1.59 (br s, 1H); 13C NMR (75 MHz, CDCl3)
δ 137.7, 132.9, 131.5, 131.3, 131.0, 128.9, 126.0, 123.8, 76.7,
65.9, 56.6, 18.4. HRMS calcd for C12H14O2 (M+): 190.0994.
Found: 190.0994.
Exp er im en ta l Section
All flasks were flame-dried under a stream of nitrogen
before use. Solvents were freshly distilled prior to their use.
Reactions were conducted using standard inert atmosphere
techniques. Yields are given for purified products only unless
otherwise stated. Regioisomer ratios were determined by crude
1H NMR and confirmed by isolated yields for all cases where
regioisomers were separable by column chromatography.
Gen er a l P r oced u r e for th e Rh -Ca ta lyzed Rin g-Op en -
in g Rea ction . A round-bottom flask was equipped with a
reflux condenser, flame-dried under a stream of nitrogen, and
charged with an oxabenzonorbornadiene substrate (1 mmol)
that was dissolved in anhydrous THF (2.5 mL). [Rh(cod)Cl]2
(2.5 mol %) and dppf (5 mol %) were added simultaneously
before immediately heating the resulting dark orange solution
to reflux. As soon as boiling was observed, the nucleophile
methanol (2.5 mL) was added and the reaction mixture was
stirred under nitrogen at reflux temperature until the starting
oxabenzonorbornadiene was consumed, as determined by TLC
(typically 1-3 h). Nonvolatile nucleophiles were used in
smaller excess (5 equiv). If the additive ammonium iodide was
used (2.5 equiv), it was added together with the catalyst. After
completion, the reaction mixture was concentrated and the
crude product was purified by flash chromatography. When
carboxylic acids or phenols were employed as nucleophiles,
chromatography was preceded by an extractive workup using
dichloromethane and 2 M aqueous NaOH.
6-(P yr r olid in -1-yl)-1,4-d ih yd r o-1,4-ep oxid on a p h t h a -
len e (7). A Schlenk flask was flame-dried under a stream of
nitrogen. The flask was charged with aryl bromide 8 (513 mg,
2.30 mmol), anhydrous toluene (2.3 mL), Pd(OAc)2 (36 mg, 7
mol %), (o-biphenyl)P(tBu)2 (96 mg, 14 mol %), sodium t-
butoxide (0.31 g, 1.4 equiv), and pyrrolidine (0.23 mL, 1.2
equiv). The resulting dark reaction mixture was heated to 60
°C for 15 h, diluted with diethyl ether (50 mL), filtered through
Celite, and concentrated. The resulting crude product was
purified by flash chromatography (10% ethyl acetate/hexane),
yielding adduct 7 (309 mg, 63%) as a brown oil that solidified
upon refrigeration: mp 79-83 °C; IR (CHCl3, cm-1) 2973 (w),
1622 (m), 1605 (w), 1582 (w), 1494 (m), 1479 (s), 1461 (s), 1372
(s); 1H NMR (300 MHz, CDCl3) δ 7.08 (d, J ) 8.0 Hz, 1H),
(tr a n s)-2-Meth oxy-7-tr iflu or om eth yl-1,2-d ih yd r on a p h -
th a len -1-ol (17c). Following the general procedure, starting
from oxabenzonorbornadiene 12 and using the nucleophile
methanol, a 1.05:1 mixture of regioisomers 17c and 18c was
obtained. Separation by flash chromatography (20% ethyl
acetate/hexane) yielded adducts 17c and 18c, which each
crystallized from dichloromethane as colorless needles (84%).
17c: mp 115-116 °C; IR (CHCl3, cm-1) 3595 (w), 1619 (w),
1437 (w), 1327 (s), 1266 (m), 1192 (m), 1167 (s), 1129 (s), 1093
1
(m), 1074 (s); H NMR (300 MHz, CDCl3) δ 7.87 (s, 1H), 7.49
(dm, J ) 8.0 Hz, 1H), 7.16 (d, J ) 8.0 Hz, 1H), 6.48 (dd, J )
9.9, 2.2 Hz, 1H), 6.18 (dd, J ) 10.0, 2.1 Hz, 1H), 4.93 (d, J )
11.0 Hz, 1H), 4.14 (ddd, J ) 11.0, 2.2, 2.1 Hz, 1H), 3.53 (s,
3H), 2.98 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 137.0, 135.4
(q, J ) 1.4 Hz), 129.9 (q, J ) 33 Hz), 129.8, 127.3, 126.4, 125.0
J . Org. Chem, Vol. 67, No. 23, 2002 8049

Lautens et al.
(q, J ) 3.7 Hz), 124.3 (q, J ) 272 Hz), 122.2 (q, J ) 3.7 Hz),
82.5, 72.4, 57.1; 19F NMR (282 MHz, CDCl3) δ -62.92. HRMS
calcd for C12H11F3O2 (M+): 244.0711. Found: 244.0717.
hexane) yielded both adducts 17h and 18h as colorless oils
(82%). Only the major regioisomer 17h crystallized from
dichloromethane as white needles: mp 140-142 °C; IR (CHCl3,
cm-1) 3589 (w), 1626 (w), 1589 (w), 1570 (m), 1462 (s), 1423
(tr a n s)-8-Acetyl-2,5-dim eth oxy-1,2-dih ydr on aph th alen -
1-ol (17d ). Following the general procedure, starting from
oxabenzonorbornadiene 13 and using the nucleophile methanol
(12 h reflux), a 1.1:1 mixture of the regioisomers 17d and 18d
was obtained. Separation by flash chromatography (40% ethyl
acetate/hexane) yielded both adducts 17d and 18d (62%). 17d
(white solid): mp 88-89 °C (CHCl3); IR (CHCl3, cm-1) 3502
(w, br), 1663 (m), 1573 (s), 1485 (w), 1464 (w), 1437 (w), 1264
(s); 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J ) 8.8 Hz, 1H),
7.14 (d, J ) 9.9 Hz, 1H), 6.84 (d, J ) 8.8 Hz, 1H), 6.27 (ddd,
J ) 9.9, 5.5, 1.1 Hz, 1H), 4.86-4.82 (m, 1H), 4.26 (d, J ) 3.8
Hz, 1H), 4.07 (dd, J ) 5.5, 1.6 Hz, 1H), 3.89 (s, 3H), 3.39 (s,
3H), 2.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.2, 158.7,
137.4, 131.32, 131.30, 124.7, 123.2, 121.6, 109.5, 75.3, 65.6,
56.6, 55.9, 28.6. HRMS calcd for C14H16O4 (M+): 248.1049.
Found: 248.1049.
(tr a n s)-2-Meth oxy-7-br om o-1,2-d ih yd r on a p h th a len -1-
ol (17e). Following the general procedure, starting from
oxabenzonorbornadiene 8 and using the nucleophile methanol,
a 1.8:1 mixture of regioisomers 17e and 18e was obtained.
Separation by flash chromatography (10% ethyl acetate/
hexane) yielded both adducts 17e and 18e as white solids
(75%). Adduct 17e crystallized from chloroform as white
needles: mp 119-120 °C; IR (CHCl3, cm-1) 3593 (w), 1590 (w),
1478 (m), 1192 (s), 1110 (s), 1092 (s); 1H NMR (300 MHz,
CDCl3) δ 7.74 (s, 1H), 7.35 (dd, J ) 8.0, 1.8 Hz, 1H), 6.93 (d,
J ) 8.1 Hz, 1H), 6.40 (dd, J ) 10.0, 2.0 Hz, 1H), 6.07 (dd, J )
10.0, 2.1 Hz, 1H), 4.87 (br d, J ) 10.6 Hz, 1H), 4.08 (ddd, J )
10.6, 2.2, 2.2 Hz, 1H), 3.51 (s, 3H), 2.78 (d, J ) 2.9 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 138.2, 131.1, 131.0, 128.5, 127.8,
1
(m), 1276 (s), 1111 (s), 1101 (s), 1049 (s); H NMR (300 MHz,
CDCl3) δ 7.23-7.21 (m, 1H), 6.79-6.77 (m, 1H), 6.76 (dd, J )
10.3, 2.1 Hz, 1H), 6.03 (dd, J ) 10.2, 2.2 Hz, 1H), 4.80 (br d,
J ) 11.0 Hz, 1H), 4.06 (ddd, J ) 11.0, 2.2, 2.2 Hz, 1H), 3.82 (s,
3H), 3.50 (s, 3H), 2.72 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ
155.5, 138.9, 134.4, 126.1, 121.8, 119.4, 117.9, 111.0, 82.1, 72.6,
57.0, 56.0. HRMS calcd for
Found: 240.0555.
C
12H13ClO3 (M+): 240.0553.
(tr a n s)-2,7-Dim eth oxy-1,2-dih ydr on aph th alen -1-ol (17i).
Following the general procedure, starting from oxabenzonor-
bornadiene 3 and using the nucleophile methanol, a 12:1
mixture of the regioisomers 17i and 18i was obtained. Puri-
fication by flash chromatography (33% ethyl acetate/hexane)
yielded adduct 17i (89%) as a white solid which crystallized
from cyclohexane/dichloromethane as colorless needles, which
were used for X-ray structure analysis: mp 94-95 °C; IR
(CHCl3, cm-1) 3590 (w), 1632 (w), 1606 (s), 1516 (w), 1496 (s),
1480 (m), 1464 (m), 1448 (m), 1432 (m), 1275 (s), 1155 (s), 1110
(s), 1032 (s); 1H NMR (300 MHz, CDCl3) δ 7.17 (d, J ) 2.6 Hz,
1H), 7.01 (d, J ) 8.2 Hz, 1H), 6.75 (ddm, J ) 8.2, 2.6 Hz, 1H),
6.41 (dd, J ) 9.9, 2.1 Hz, 1H), 5.92 (dd, J ) 10.0, 2.2 Hz, 1H),
4.86 (br dd, J ) 10.3, 3.5 Hz, 1H), 4.09 (ddd, J ) 10.4, 2.2, 2.2
Hz, 1H), 3.83 (s, 3H), 3.50 (s, 3H), 2.70 (d, J ) 3.7 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 159.8, 137.9, 127.9, 127.8, 125.2,
124.3, 113.1, 111.1, 82.5, 72.8, 56.9, 55.6. HRMS calcd for
C
12H14O3 (M+): 206.0943. Found: 206.0938.
(tr a n s)-2,5,7-Tr im et h oxy-1,2-d ih yd r on a p h t h a len -1-ol
(17j). Following the general procedure, starting from oxaben-
zonorbornadiene 16 and using the nucleophile methanol,
adduct 17j was obtained as a single regioisomer. Purification
by flash chromatography (25% ethyl acetate/hexane) yielded
adduct 17j (80%) as a white solid: mp 71-73 °C (CHCl3); IR
(CHCl3, cm-1) 3586 (w), 1623 (w), 1605 (s), 1576 (w), 1487 (w),
1464 (m), 1149 (s), 1047 (s); 1H NMR (300 MHz, CDCl3) δ 6.79
(d, J ) 2.2 Hz, 1H), 6.75 (dd, J ) 10.0, 2.0 Hz, 1H), 6.35 (d,
J ) 2.2 Hz, 1H), 5.89 (dd, J ) 10.2, 2.2 Hz, 1H), 4.79 (d, J )
10.4 Hz, 1H), 4.06 (ddd, J ) 10.4, 2.2, 2.2 Hz, 1H), 3.83 (s,
3H), 3.79 (s, 3H), 3.49 (s, 3H), 2.89 (br s, 1H); 13C NMR (75
MHz, CDCl3) δ 160.7, 156.2, 138.8, 122.9, 122.3, 114.2, 101.8,
97.9, 82.3, 72.9, 56.8, 55.7, 55.6. HRMS calcd for C13H16O4
(M+): 236.1049. Found: 236.1053.
(tr a n s)-2-Met h oxy-7-(m et h ylp h en yla m in o)-1,2-d ih y-
d r on a p h th a len -1-ol (17k ). Following the general procedure,
starting from the oxabenzonorbornadiene 9 and using the
nucleophile methanol, adduct 17k was obtained as a single
regioisomer. Purification by flash chromatography (15% ethyl
acetate/hexane, containing 2% triethylamine; silica was thor-
oughly neutralized with triethylamine/hexane before applica-
tion of crude product) yielded adduct 17k (58%) as a brown
oil; IR (CHCl3, cm-1) 3590 (w), 1612 (m), 1593 (s), 1557 (w),
1495 (s), 1111 (s); 1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m,
3H), 7.11-6.93 (m, 4H), 6.79 (dd, J ) 8.2, 2.5 Hz, 1H), 6.41
(dd, J ) 9.8, 1.5 Hz, 1H), 5.90 (dd, J ) 9.9, 2.5 Hz, 1H), 4.82
(d, J ) 10.2 Hz, 1H), 4.08 (ddd, J ) 10.0, 2.4, 1.9 Hz, 1H),
3.49 (s, 3H), 3.33 (s, 3H), 2.67 (br s, 1H); 13C NMR (75 MHz,
CDCl3) δ 149.0, 148.7, 137.3, 129.5, 128.2, 127.4, 124.5, 123.7,
122.6, 122.3, 117.6, 115.7, 82.3, 72.7, 56.9, 40.5. HRMS calcd
for C18H19NO2 (M+): 281.1416. Found: 281.1423.
127.7, 127.5, 122.0, 82.4, 72.3, 57.1. HRMS calcd for C11H11
-
BrO2 (M+): 253.9942. Found: 253.9939.
(tr a n s)-2,5-Dim eth oxy-1,2-dih ydr on aph th alen -1-ol (17f).
Following the general procedure, starting from oxabenzonor-
bornadiene 1 and using the nucleophile methanol, a 3.5:1
mixture of regioisomers 17f and 18f was obtained. Separation
by flash chromatography (25% ethyl acetate/hexane) yielded
both adducts 17f and 18f as colorless oils (81%). Only the major
regioisomer 17f crystallized from cyclohexane as colorless
crystals, which were used for X-ray structure analysis: mp
73-74 °C; IR (CHCl3, cm-1) 3588 (w), 1626 (w), 1598 (w), 1577
(w), 1474 (s), 1460 (m), 1267 (s), 1109 (s); 1H NMR (300 MHz,
CDCl3) δ 7.26-7.18 (m, 2H), 6.86 (dd, J ) 10.2, 1.9 Hz, 1H),
6.82-6.78 (m, 1H), 6.03 (dd, J ) 10.2, 2.2 Hz, 1H), 4.84 (dd,
J ) 10.4, 3.6 Hz, 1H), 4.08 (ddd, J ) 10.4, 2.2, 2.2 Hz, 1H),
3.85 (s, 3H), 3.53 (s, 3H), 2.76 (br s, 1H); 13C NMR (75 MHz,
CDCl3) δ 155.0, 137.5, 129.0, 125.7, 122.5, 120.7, 117.6, 110.3,
82.0, 72.7, 56.9, 55.8. HRMS calcd for C12H14O3 (M+): 206.0943.
Found: 206.0937.
(tr a n s)-8-Ch lor o-2,5-dim eth oxy-1,2-dih ydr on aph th alen -
1-ol (17g). Following the general procedure, starting from
oxabenzonorbornadiene 14 and using the nucleophile metha-
nol, a 3.9:1 mixture of regioisomers 17g and 18g was obtained.
Separation by flash chromatography (25% ethyl acetate/
hexane) yielded both adducts 17g and 18g as colorless oils
(82%). 17g: IR (CHCl3, cm-1) 3593 (w), 1635 (w), 1586 (w),
1576 (w), 1471 (s), 1463 (s), 1440 (m), 1284 (s), 1263 (s), 1193
1
(m), 1105 (m), 1083 (s); H NMR (300 MHz, CDCl3) δ 7.24 (d,
J ) 8.8 Hz, 1H), 7.11 (d, J ) 9.9 Hz, 1H), 6.79 (d, J ) 8.9 Hz,
1H), 6.16 (dd, J ) 9.8, 5.4 Hz, 1H), 5.14 (s, 1H), 4.01 (ddd,
J ) 5.5, 1.9, 0.5 Hz, 1H), 3.82 (s, 3H), 3.40 (s, 3H), 2.04 (br s,
1H); 13C NMR (75 MHz, CDCl3) δ 154.5, 133.2, 129.6, 126.5,
123.99, 123.98, 122.3, 112.5, 75.6, 65.8, 56.7, 56.1. HRMS calcd
for C12H13ClO3 (M+): 240.0553. Found: 240.0555.
(tr a n s)-5,7-Dim eth oxy-2-(m eth ylp h en yla m in o)-1,2-d i-
h yd r on a p h th a len -1-ol (19a ). Following the general proce-
dure, starting from oxabenzonorbornadiene 16 and using the
nucleophile N-methylaniline, a 11:1 mixture of the regioiso-
mers 19a and 20a was obtained. Separation by flash chroma-
tography (20% ethyl acetate/hexane) yielded adducts 19a and
20a as colorless, viscous oils (92%). 19a : IR (CHCl3, cm-1) 3584
(w), 1730 (w), 1599 (s), 1576 (m), 1503 (s), 1464 (m), 1149 (s);
1H NMR (300 MHz, CDCl3) δ 7.26-7.19 (m, 2H), 6.95-6.90
(m, 2H), 6.86 (dd, J ) 10.0, 2.5 Hz, 1H), 6.79-6.73 (m, 1H),
(tr a n s)-7-Ch lor o-2,5-dim eth oxy-1,2-dih ydr on aph th alen -
1-ol (17h ). Following the general procedure, starting from
oxabenzonorbornadiene 15 and using the nucleophile metha-
nol, a 4.9:1 mixture of regioisomers 17h and 18h was obtained.
Separation by flash chromatography (20% ethyl acetate/
8050 J . Org. Chem., Vol. 67, No. 23, 2002

Nucleophilic Ring Opening of Oxabenzonorbornadienes
6.74 (d, J ) 2.2 Hz, 1H), 6.36 (d, J ) 2.3 Hz, 1H), 5.74 (dd,
J ) 10.0, 2.9 Hz, 1H), 4.97 (d, J ) 10.3 Hz, 1H), 4.67 (ddd,
J ) 10.3, 2.7, 2.6 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 2.82 (s,
3H), 2.49 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 160.7, 156.3,
150.5, 139.5, 129.4, 123.8, 123.6, 118.1, 114.8, 114.2, 102.2,
97.9, 70.6, 63.4, 55.7, 55.6, 33.4. HRMS calcd for C19H21NO3
(M+): 311.1521. Found: 311.1513.
1604 (s), 1587 (m), 1579 (m), 1495 (s), 1464 (m), 1456 (m), 1429
(m), 1149 (s); 1H NMR (300 MHz, CDCl3) δ 7.32-7.24 (m, 2H),
7.00-6.92 (m, 3H), 6.85 (d, J ) 2.3 Hz, 1H), 6.79 (d, J )
10.4 Hz, 1H), 6.37 (d, J ) 2.2 Hz, 1H), 5.85 (dm, J ) 10.2 Hz,
1H), 5.10-5.03 (m, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.72 (br s,
1H); 13C NMR (75 MHz, CDCl3) δ 160.9, 157.6, 156.4, 138.5,
129.9, 123.0, 122.4, 121.5, 116.0, 114.1, 102.0, 98.0, 79.2, 72.9,
55.8, 55.7. HRMS calcd for C18H18O4 (M+): 298.1205. Found:
298.1210.
(tr a n s)-2,7-Bis-(m eth ylp h en yla m in o)-1,2-dih ydr on a ph -
th a len -1-ol (19b). Following the general procedure, starting
from oxabenzonorbornadiene 9 and using the nucleophile
N-methylaniline, a 11:1 mixture of regioisomers 19b and 20b
was obtained. Purification by flash chromatography (10% ethyl
acetate/hexane, containing 2% triethylamine; silica was thor-
oughly neutralized with triethylamine/hexane before applica-
tion of crude product) yielded adduct 19b as a brown oil (80%);
IR (CHCl3, cm-1) 3582 (w), 1611 (m), 1594 (s), 1556 (w), 1495
(tr a n s)-5,7-Dim eth oxy-2-(d im eth oxyca r bon ylm eth yl)-
1,2-d ih yd r on a p h th a len -1-ol (19f). Following the general
procedure, starting from oxabenzonorbornadiene 16 and using
both the nucleophile dimethylmalonate and the additive
ammonium iodide, a >25:1 mixture of regioisomers was
obtained from which the major adduct 19f was isolated (55%)
as a colorless oil by means of flash chromatography (33% ethyl
acetate/hexane): IR (CHCl3, cm-1) 1751 (m), 1732 (s), 1606
1
(s); H NMR (300 MHz, CDCl3) δ 7.32-6.92 (m, 11H), 6.82-
1
6.74 (m, 2H), 6.51 (dd, J ) 9.7, 2.4 Hz, 1H), 5.75 (dd, J ) 9.6,
3.0 Hz, 1H), 5.00 (d, J ) 9.9 Hz, 1H), 4.69 (ddd, J ) 9.9, 2.7,
2.7 Hz, 1H), 3.33 (s, 3H), 2.83 (s, 3H), 2.36 (br s, 1H); 13C NMR
(75 MHz, CDCl3) δ 150.5, 149.1, 148.7, 138.0, 129.54, 129.46,
129.42, 127.5, 124.7, 124.5, 122.7, 122.5, 118.1, 117.6, 115.8,
114.8, 70.5, 63.7, 40.5, 33.5. HRMS calcd for C24H24N2O (M+):
356.1889. Found: 356.1896.
(m), 1577 (w), 1492 (w), 1150 (s); H NMR (400 MHz, CDCl3)
δ 6.82 (dd, J ) 9.9, 1.3 Hz, 1H), 6.57 (d, J ) 2.0 Hz, 1H), 6.37
(d, J ) 2.2 Hz, 1H), 5.76 (dd, J ) 9.9, 4.0 Hz, 1H), 4.57 (br dd,
J ) 6.1, 6.0 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H),
3.70 (s, 3H), 3.49 (d, J ) 8.1 Hz, 1H), 2.43 (br d, J ) 6.6 Hz,
1H), 3.31-3.25 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 169.0,
168.7, 160.7, 156.4, 138.2, 122.5, 122.3, 114.2, 103.6, 98.2, 70.9,
55.7, 55.6, 52.8, 52.7, 52.6, 42.1. HRMS calcd for C17H20O7
(M+): 336.1209. Found: 336.1212.
(tr a n s)-2-(Meth ylp h en yla m in o)-7-(p yr r olid in -1-yl)-1,2-
d ih yd r on a p h th a len -1-ol (19c). Following the general pro-
cedure, starting from oxabenzonorbornadiene 7 and using the
nucleophile N-methylaniline, adduct 19c was obtained as a
single regioisomer. Purification by flash chromatography (10%
ethyl acetate/hexane, containing 2% triethylamine; silica was
thoroughly neutralized with triethylamine/hexane before ap-
plication of crude product) yielded adduct 19c as a light brown
oil (89%): IR (CHCl3, cm-1) 3586 (w), 1611 (s), 1599 (s), 1551
(w), 1503 (s), 1487 (m), 1448 (m), 1377 (s); 1H NMR (300 MHz,
CDCl3) δ 7.28-7.21 (m, 2H), 7.00-6.92 (m, 3H), 6.80-6.73 (m,
2H), 6.51 (dd, J ) 9.8, 2.5 Hz, 1H), 6.41 (dd, J ) 8.2, 2.5 Hz,
1H), 5.62 (dd, J ) 9.6, 3.3 Hz, 1H), 4.97 (d, J ) 9.3 Hz, 1H),
4.67 (ddd, J ) 9.1, 2.8, 2.7 Hz, 1H), 3.37-3.25 (m, 4H), 2.81
(s, 3H), 2.32 (br s, 1H), 2.06-1.93 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 150.6, 148.0, 138.0, 129.9, 129.4, 128.0, 121.6, 120.1,
117.9, 114.6, 110.3, 109.5, 70.7, 63.3, 47.8, 33.3, 25.6. HRMS
calcd for C21H24N2O (M+): 320.1889. Found: 320.1883.
(tr a n s)-2-(4-Acet ylp h en oxy)-5,7-d im et h oxy-1,2-d ih y-
d r on a p h th a len -1-ol (19g). Following the general procedure,
starting from the oxabenzonorbornadiene 16 and using the
nucleophile 4-hydroxyacetophenone, a >25:1 mixture of re-
gioisomers was obtained from which the major adduct 19g was
isolated (50%) by means of flash chromatography (33% ethyl
acetate/hexane; silica was neutralized with triethylamine/
hexane before application of crude product). 19g (white
solid): mp 123-124 °C (CH2Cl2); IR (CHCl3, cm-1) 3601 (w),
1731 (w), 1674 (m), 1599 (s), 1576 (m), 1507 (m), 1487 (w),
1250 (s); 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J ) 8.6 Hz,
2H), 6.96 (d, J ) 8.8 Hz, 2H), 6.85 (d, J ) 2.0 Hz, 1H), 6.84
(dd, J ) 10.2, 1.6 Hz, 1H), 6.39 (d, J ) 1.8 Hz, 1H), 5.80 (dd,
J ) 10.1, 1.8 Hz, 1H), 5.14 (dm, J ) 10.4 Hz, 1H), 5.09 (dd,
J ) 10.4, 3.3 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 2.86 (d, J )
3.8 Hz, 1H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.0,
161.7, 161.1, 156.6, 138.3, 130.92, 130.86, 123.7, 121.2, 115.4,
114.0, 102.3, 98.1, 79.4, 72.7, 55.8, 55.7, 26.5. HRMS calcd for
(tr a n s)-2-Dib en zyla m in o-5,7-d im et h oxy-1,2-d ih yd r o-
n a p h th a len -1-ol (19d ). Following the general procedure,
starting from the oxabenzonorbornadiene 16 and using both
the nucleophile dibenzylamine and the additive ammonium
iodide, a 11:1 mixture of regioisomers was obtained from which
the major adduct 19d was isolated (77%) by means of flash
chromatography (5% ethyl acetate/hexane, containing 2%
triethylamine; silica was neutralized with the eluent before
application of crude product). Compound 19d crystallized from
dichloromethane as colorless crystals: mp 105-106 °C; IR
(CHCl3, cm-1) 3488 (w, br), 1603 (s), 1574 (w), 1494 (w), 1485
C
20H20O5 (M+): 340.1312. Found: 340.1319.
(tr a n s)-2,5,7-Tr im eth oxy-1,2,3,4-tetr ah ydr on aph th alen -
1-ol (21). 5% Pt/C (416 mg, 10 mol %) was added to a solution
of dihydronaphthalene 17j (252 mg, 1.07 mmol) in ethyl
acetate (4 mL). The flask was purged with nitrogen, fitted with
a double balloon of hydrogen, and stirred at room temperature
for 14 h. The black suspension was filtered through Celite,
and the resulting crude was purified by flash chromatography
(33% ethyl acetate/hexane), yielding the adduct 21 (198 mg,
1
(m), 1463 (s), 1453 (s), 1429 (m), 1148 (s), 1044 (s); H NMR
78%) as a white solid: mp 80-82 °C (CHCl3); IR (CHCl3, cm-1
)
(400 MHz, CDCl3) δ 7.32-7.27 (m, 8H), 7.26-7.20 (m, 2H),
6.83 (dd, J ) 10.2, 2.9 Hz, 1H), 6.72 (d, J ) 2.0 Hz, 1H), 6.30
(d, J ) 2.4 Hz, 1H), 5.99 (dd, J ) 10.1, 2.3 Hz, 1H), 4.89 (d,
J ) 12.3 Hz, 1H), 3.97 (d, J ) 13.6 Hz, 2H), 3.78 (s, 3H), 3.76
(s, 3H), 3.62 (ddd, J ) 12.5, 2.7, 2.4 Hz, 1H), 3.58 (d, J ) 13.7
Hz, 2H), 3.23 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 160.7,
156.1, 139.8, 139.3, 129.1, 128.7, 127.4, 123.6, 121.4, 114.0,
3587 (w), 1610 (m), 1597 (m), 1489 (m), 1464 (m), 1456 (m),
1200 (s), 1147 (s), 1052 (s); 1H NMR (300 MHz, CDCl3) δ 6.71
(d, J ) 2.2 Hz, 1H), 6.35 (d, J ) 2.5 Hz, 1H), 4.60 (dd, J ) 7.6,
2.9 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.49 (s, 3H), 3.39 (ddd,
J ) 10.4, 7.7, 3.3 Hz, 1H), 2.83 (ddd, J ) 17.6, 6.0, 4.1 Hz,
1H), 2.68 (d, J ) 3.6 Hz, 1H), 2.53 (dddm, J ) 17.6, 10.4, 6.0
Hz, 1H), 2.24 (dddd, J ) 13.2, 5.8, 3.6, 3.3 Hz, 1H), 1.64 (dddd,
J ) 13.0, 10.6, 10.6, 6.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
159.5, 157.8, 138.6, 117.1, 102.1, 97.9, 82.1, 72.9, 56.8, 55.6,
55.5, 23.8, 21.3. HRMS calcd for C13H18O4 (M+): 238.1205.
Found: 238.1215.
(cis)-2,5,7-Tr im et h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -
1-yla m in e (22). Diethyl azodicarboxylate (DEAD, 0.89 mL,
2.1 equiv) and diphenylphosphoryl azide (DPPA, 1.23 mL, 2.1
equiv) were added dropwise to a cooled solution of tetrahy-
dronaphthalene 21 (640 mg, 2.69 mmol) and triphenylphos-
phine (1.57 g, 2.2 equiv) in toluene (10 mL, -20 °C). The
colorless solution was kept at -20 °C for 30 min and then left
101.4, 97.7, 69.5, 62.5, 55.7, 55.6, 54.9. HRMS calcd for C26H27
-
NO3 (M+): 401.1991. Found: 401.2006.
(tr a n s)-5,7-Dim et h oxy-2-(p h en oxy)-1,2-d ih yd r on a p h -
th a len -1-ol (19e). Following the general procedure, starting
from oxabenzonorbornadiene 16 and using the nucleophile
phenol, a >25:1 mixture of regioisomers was obtained from
which the major adduct 19e was isolated (74%) by means of
flash chromatography (5% ethyl acetate/hexane, containing 2%
triethylamine; silica was neutralized with triethylamine/
hexane before application of crude product). 19e (white
solid): mp 123-124 °C (CHCl3); IR (CHCl3, cm-1) 3595 (w),
J . Org. Chem, Vol. 67, No. 23, 2002 8051

Lautens et al.
to warm to room temperature over a period of 30 min, at which
time the reaction was quenched with excess 2-propanol/
triethylamine. After an additional 15 min at room tempera-
ture, the solution was diluted with diethyl ether and washed
with brine. The crude product was then purified by flash
chromatography (5% ethyl acetate/hexane), giving the corre-
sponding intermediate (cis)-azide (559 mg, 79%) as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 6.42-6.40 (m, 2H), 4.61 (d,
J ) 3.6 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.66 (ddd, J ) 9.2,
4.4, 3.6 Hz, 1H), 3.49 (s, 3H), 2.86 (ddd, J ) 17.6, 5.5, 4.7 Hz,
1H), 2.50 (ddd, J ) 17.3, 9.1, 7.3 Hz, 1H), 2.09-1.93 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 159.2, 158.3, 133.9, 117.9, 104.6,
98.7, 78.7, 61.7, 56.6, 55.6, 55.5, 22.8, 21.3. 10% Pd/C (225 mg,
10 mol %) was added to a solution of the previously obtained
(cis)-azide (559 mg, 2.12 mmol) in ethyl acetate (30 mL). The
flask was purged with nitrogen, fitted with a double-balloon
of hydrogen, and stirred at room temperature for 18 h. The
black suspension was filtered through Celite, and the filter
was washed with dichloromethane. The amine product was
then extracted with 0.5 M aqueous HCl. The aqueous phase
was washed four times with dichloromethane, basified with 2
M aqueous NaOH, and reextracted with dichloromethane,
yielding adduct 22 (423 mg, 84%) as a colorless oil: IR (CHCl3,
cm-1) 2938 (m), 1610 (s), 1595 (s), 1490 (m), 1464 (s), 1454
(m), 1199 (s), 1148 (s), 1093 (s); 1H NMR (400 MHz, CDCl3) δ
6.57 (d, J ) 2.2 Hz, 1H), 6.33 (d, J ) 2.0 Hz, 1H), 4.03 (d, J )
3.7 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.49 (ddd, J ) 9.9, 3.4,
3.2 Hz, 1H), 3.45 (s, 3H), 2.80 (ddd, J ) 17.6, 5.3, 5.3 Hz, 1H),
2.49 (ddd, J ) 17.5, 9.3, 6.6 Hz, 1H), 2.02-1.93 (m, 1H), 1.92-
1.84 (m, 1H), 1.65 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ
159.1, 158.0, 140.2, 117.4, 104.5, 97.6, 79.5, 56.3, 55.6, 55.5,
51.7, 21.9, 21.2. HRMS calcd for C13H19NO3 (M+): 237.1365.
Found: 237.1369.
6.0 Hz, 1H), 2.04 (dddd, J ) 13.0, 6.2, 3.1, 3.1 Hz, 1H), 1.79
(br s, 3H), 1.62 (dddd, J ) 13.0, 11.4, 11.2, 6.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 159.3, 157.9, 139.9, 117.4, 101.7,
97.6, 75.8, 55.6, 55.5, 54.5, 30.2, 22.1. HRMS calcd for C12H17
-
NO3 (M+): 223.1208. Found: 223.1208. Meth od II. 10% Pd/C
(321 mg, 30 mol %) and ammonium formate (318 mg, 5 equiv)
were added to a solution of tetrahydronaphthalene 23 (408 mg,
1.01 mmol) in ethyl acetate (3.5 mL)/methanol (7 mL). The
black suspension was refluxed for 15 min, treated with
triethylamine (3.5 mL), and filtered through Celite. The filter
was washed thoroughly with 10% triethylamine/methanol, and
the resulting crude was dried under high vacuum, dissolved
in 2 M aqueous HCl, and washed three times with dichlo-
romethane. Concentration of the aqueous solution gave adduct
24 (236 mg, 90%) as a white solid (hydrochloride salt): mp
223-225 °C (dec.); 1H NMR (300 MHz, CD3OD) δ 6.73 (d, J )
2.2 Hz, 1H), 6.42 (d, J ) 2.2 Hz, 1H), 4.91 (s, 4H), 4.61 (br d,
J ) 9.3 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.23 (ddd, J ) 12.1,
9.3, 3.0 Hz, 1H), 2.87 (ddd, J ) 17.6, 6.0, 2.5 Hz, 1H), 2.59
(dddm, J ) 17.6, 11.6, 6.1 Hz, 1H), 2.25 (dddd, J ) 12.9, 6.3,
3.0, 2.8 Hz, 1H), 1.86 (dddd, J ) 12.4, 12.2, 12.2, 6.2 Hz, 1H);
13C NMR (75 MHz, CD3OD) δ 161.1, 159.2, 140.1, 117.1, 103.2,
98.5, 71.8, 56.0, 55.9, 55.7, 26.3, 22.5.
(tr a n s)-(1-Azido-5,7-dim eth oxy-1,2,3,4-tetr ah ydr on aph -
th a len -2-yl)-d iben zyla m in e (25). Triethylamine (3.41 mL,
2.4 equiv) and methanesulfonyl chloride (1.59 mL, 2.0 equiv)
were added consecutively to a cooled solution of tetrahy-
dronaphthalene 23 (4.15 g, 10.3 mmol) in dichloromethane
(190 mL). The resulting reaction mixture was kept at 0 °C for
30 min, at which time a saturated solution of sodium azide in
anhydrous DMF (190 mL), freshly prepared at room temper-
ature using 3.3 g (5 equiv) of sodium azide, was added. The
reaction mixture was left to warm to room temperature and
was stirred for an additional 3 h, after which it was diluted
with diethyl ether and washed three times with water and
once with brine. Flash chromatography (2% ethyl acetate/
hexane) yielded the (trans)-azide 25 (3.75 g, 85%). Adduct 25
crystallized from dichloromethane to give colorless crystals,
which were used for X-ray structure analysis: mp 108-109
°C; IR (CHCl3, cm-1) 2100 (s), 1610 (m), 1599 (m), 1493 (m),
1464 (m), 1455 (m), 1149 (s); 1H NMR (400 MHz, CDCl3) δ
7.45 (d, J ) 7.5 Hz, 4H), 7.31 (dd, J ) 7.5, 7.5 Hz, 4H), 7.22 (t,
J ) 7.2 Hz, 2H), 6.57 (d, J ) 2.2 Hz, 1H), 6.30 (d, J ) 2.2 Hz,
1H), 4.53 (d, J ) 9.7 Hz, 1H), 3.92 (d, J ) 13.5 Hz, 2H), 3.77
(s, 3H), 3.73 (s, 3H), 3.54 (d, J ) 13.7 Hz, 2H), 3.02 (ddd, J )
11.9, 10.1, 2.5 Hz, 1H), 2.89 (ddd, J ) 17.0, 4.8, 2.2 Hz, 1H),
2.30 (ddd, J ) 17.0, 12.3, 4.9 Hz, 1H), 2.22 (dm, J ) 12.8 Hz,
1H), 1.61 (dddd, J ) 12.4, 12.3, 12.3, 5.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 159.2, 157.8, 139.6, 137.0, 129.0, 128.5,
127.2, 118.8, 103.5, 97.8, 62.7, 60.1, 55.6, 55.5, 54.2, 22.8, 21.2.
HRMS calcd for C26H29N4O2 (M+ + 1): 429.2291. Found:
429.2274.
(tr a n s)-2-Diben zylam in o-5,7-dim eth oxy-1,2,3,4-tetr ah y-
d r on a p h th a len -1-ol (23). Sodium periodate (9.9 g, 10 equiv)
was added in portions at 0 °C to a solution of dihydronaph-
thalene 19d (1.88 g, 4.67 mmol) and hydrazine monohydrate
(8.9 mL, 40 equiv) in ethanol (50 mL)/THF (15 mL)/water (15
mL). The resulting suspension was slowly heated to 75 °C
(open reflux condenser, nitrogen formation!) and kept at this
temperature until a light yellow solution was obtained (3 h).
The reaction mixture was diluted with dichloromethane and
washed three times with 2 M aqueous NaOH and once with
brine. Concentration yielded adduct 23 (1.89 g, 100%) as a pale
brown solid: mp 132-134 °C; IR (CHCl3, cm-1) 3464 (w, br),
1609 (s), 1596 (m), 1489 (m), 1465 (s), 1455 (m), 1431 (m), 1197
(s), 1148 (s); 1H NMR (400 MHz, CDCl3) δ 7.33-7.28 (m, 8H),
7.26-7.21 (m, 2H), 6.72 (d, J ) 2.4 Hz, 1H), 6.30 (d, J ) 2.4
Hz, 1H), 4.71 (d, J ) 9.9 Hz, 1H), 3.93 (d, J ) 13.4 Hz, 2H),
3.78 (s, 3H), 3.75 (s, 3H), 3.68 (s, 1H), 3.47 (d, J ) 13.4 Hz,
2H), 2.92 (ddd, J ) 17.3, 5.8, 1.5 Hz, 1H), 2.80 (ddd, J ) 12.5,
10.1, 2.6 Hz, 1H), 2.43 (dddm, J ) 17.3, 12.3, 6.0 Hz, 1H), 2.19
(dm, J ) 12.6 Hz, 1H), 1.63 (dddd, J ) 12.6, 12.4, 12.4, 5.9
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.2, 157.7, 140.1,
139.4, 129.1, 128.7, 127.4, 116.4, 101.4, 97.5, 68.5, 61.4, 55.5,
(tr a n s)-N2,N2-Diben zyl-5,7-d im eth oxy-1,2,3,4-tetr a h y-
d r on a p h th a len e-1,2-d ia m in e (26). 10% Pd/C (156 mg, 10
mol %) was added to a solution of the previously obtained
(trans)-azide 25 (626 mg, 1.46 mmol) in ethyl acetate (30 mL).
The flask was purged with nitrogen, fitted with a double-
balloon of hydrogen, and stirred at room temperature for 17
h. The black suspension was filtered through Celite, and the
filter was thoroughly washed with 10% triethylamine/metha-
nol. The resulting crude product was purified by flash chro-
matography (20% ethyl acetate/hexane, containing 2% trieth-
ylamine), yielding adduct 26 (458 mg, 78%), which crystallized
from dichloromethane to give colorless crystals: mp 149-150
°C; IR (CHCl3, cm-1) 2937 (m), 1606 (s), 1594 (s), 1494 (m),
55.4, 53.7, 23.2, 19.0. HRMS calcd for
403.2147. Found: 403.2144.
C
26H29NO3 (M+):
(tr a n s)-2-Am in o-5,7-dim eth oxy-1,2,3,4-tetr ah ydr on aph -
th a len -1-ol (24): Meth od I. 10% Pd/C (128 mg, 10 mol %)
was added to a solution of tetrahydronaphthalene 23 (488 mg,
1.21 mmol) in ethyl acetate (6 mL)/methanol (6 mL). The black
suspension was placed in a hydrogenation bomb equipped with
a manometer, purged three times with 1000 psi of hydrogen,
and then stirred at room temperature under 1500 psi hydrogen
for 5 days. The black suspension was filtered through Celite,
and the filter was washed with methanol, giving adduct 24
(262 mg, 97%) as a white solid (free amine): mp 152-156 °C
(dec.); IR (CHCl3, cm-1) 1608 (m), 1594 (m), 1489 (m), 1463
1
1488 (m), 1463 (s), 1454 (s), 1200 (s), 1146 (s); H NMR (400
MHz, CDCl3) δ 7.35-7.26 (m, 8H), 7.23-7.18 (m, 2H), 6.84
(d, J ) 2.2 Hz, 1H), 6.28 (d, J ) 2.4 Hz, 1H), 3.89 (d, J ) 9.6
Hz, 1H), 3.88 (d, J ) 13.2 Hz, 2H), 3.76 (s, 3H), 3.73 (s, 3H),
3.41 (d, J ) 13.2 Hz, 2H), 2.94 (ddd, J ) 17.0, 5.2, 2.0 Hz,
1H), 2.49 (ddd, J ) 12.1, 10.2, 2.5 Hz, 1H), 2.36 (dddm, J )
17.0, 12.6, 5.6 Hz, 1H), 2.21 (dm, J ) 12.5 Hz, 1H), 1.79 (br s,
1
(m), 1456 (m), 1145 (s); H NMR (400 MHz, CDCl3) δ 6.73 (d,
J ) 2.4 Hz, 1H), 6.35 (d, J ) 2.4 Hz, 1H), 4.30 (br d, J ) 8.5
Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.91-2.83 (m, 1H), 2.79
(ddd, J ) 17.4, 6.0, 2.9 Hz, 1H), 2.55 (dddm, J ) 17.4, 11.2,
8052 J . Org. Chem., Vol. 67, No. 23, 2002

Nucleophilic Ring Opening of Oxabenzonorbornadienes
2H), 1.54 (dddd, J ) 12.4, 12.4, 12.4, 5.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 158.9, 157.5, 141.7, 139.9, 129.1, 128.4,
127.1, 117.4, 102.4, 97.0, 63.0, 55.6, 55.5, 54.0, 52.3, 23.6, 19.8.
HRMS calcd for C26H31N2O2 (M+ + 1): 403.2386. Found:
403.2389.
methanol (9 mL). The black suspension was refluxed for 25
min and filtered through Celite. The filter was thoroughly
washed with 10% triethylamine/methanol, and the resulting
crude was purified by flash chromatography (50% ethyl
acetate/hexane, containing 2% triethylamine; 5% triethyl-
amine/methanol). Removal of silica by dissolving the product
in dichloromethane and filtering through cotton gave adduct
28 (202 mg, 73%) as a colorless oil: IR (CHCl3, cm-1) 2938
(m), 1607 (s), 1592 (s), 1488 (m), 1464 (s), 1456 (m), 1199 (s),
1146 (s); 1H NMR (300 MHz, CDCl3) δ 6.68 (d, J ) 2.5 Hz,
1H), 6.33 (d, J ) 2.2 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.48
(d, J ) 8.0 Hz, 1H), 2.82-2.70 (m, 2H), 2.54 (dddm, J ) 17.0,
10.3, 6.0 Hz, 1H), 2.05 (dddd, J ) 13.1, 6.3, 3.7, 3.5 Hz, 1H),
1.82 (br s, 4H), 1.62 (dddd, J ) 13.1, 10.4, 10.2, 5.9 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 159.1, 157.9, 141.7, 117.6, 102.8,
96.8, 58.4, 55.6, 55.5, 55.0, 30.0, 21.5. HRMS calcd for
(tr a n s)-N1-BOC-5,7-Dim eth oxy-1,2,3,4-tetr a h yd r on a ph -
th a len -1,2-d ia m in e (27). Triethylamine (4.7 mL, 5.0 equiv)
and di-tert-butyl dicarbonate (2.96 g, 2.0 equiv) were added
consecutively to a solution of diamine 26 (2.73 g, 6.78 mmol)
in ethyl acetate/methanol/dichloromethane (25 mL each), and
the resulting solution was stirred for 30 min at room temper-
ature. After the addition of diethylamine (2 mL) and further
stirring for 30 min at room temperature, the solution was
concentrated. The resulting crude intermediate was dried
under high vacuum and dissolved in methanol (50 mL)/ethyl
acetate (25 mL). After the addition of 10% Pd/C (2.2 g, 30 mol
%) and ammonium formate (4.3 g, 10 equiv), the resulting
black suspension was refluxed for 15 min and filtered through
Celite. The filter was thoroughly washed with 10% triethyl-
amine/methanol, and the resulting crude product was tritu-
rated in refluxing ethyl acetate (50 mL) for 1 h. Half of the
solvent was then evaporated; ice-cold hexane was added (100
mL), and the solid was filtered off and washed with cold
hexane, giving adduct 27 (1.88 g, 86% overall yield) as a fine
white powder: mp 173-174 °C; IR (CHCl3, cm-1) 3435 (w),
3369 (w), 1708 (s), 1610 (m), 1596 (m), 1499 (s), 1490 (s), 1464
C
12H18N2O2 (M+): 222.1368. Found: 222.1363.
Ack n ow led gm en t. We thank AstraZeneca (Mont-
real), NSERC, the ORDCF, Solvias, and the University
of Toronto for the funding of this research. G.S. thanks
the Swiss National Science Foundation for a Postdoc-
toral Fellowship. A.C. thanks NSERC for a Summer
Scholarship. We also thank Dr. Alan Lough for X-ray
structure determination and Keith Fagnou for helpful
discussions regarding the ring-opening methodology.
1
(m), 1455 (m); H NMR (300 MHz, CD3OD) δ 6.38-6.36 (m,
2H), 4.84 (s, 3H), 4.38 (d, J ) 8.7 Hz, 1H), 3.77 (s, 3H), 3.74
(s, 3H), 2.87 (ddd, J ) 10.7, 8.9, 3.1 Hz, 1H), 2.77 (ddd, J )
17.5, 5.5, 4.1 Hz, 1H), 2.50 (dddm, J ) 17.7, 10.5, 6.3 Hz, 1H),
2.07 (dddd, J ) 13.1, 5.9, 3.9, 3.1 Hz, 1H), 1.64 (dddd, J )
13.0, 10.7, 10.5, 5.7 Hz, 1H), 1.51 (s, 9H); 13C NMR (75 MHz,
CD3OD) δ 160.6, 159.4, 159.3, 139.5, 118.8, 104.1, 97.9, 80.5,
58.7, 55.9, 55.7, 52.9, 30.1, 29.0, 22.4. HRMS calcd for
Su p p or tin g In for m a tion Ava ila ble: Preparation of the
oxabenzonorbornadiene substrates 1, 3, 10, 12, 13 and 14-
16; spectral data for all oxabenzonorbornadiene substrates and
all minor isomers 18 and 20, which were obtained in g7%
yield; 1H NMR spectra for all new compounds described in the
Experimental Section, including all novel oxabenzonorborna-
diene substrates; and X-ray crystallographic data for com-
pounds 1, 3, 13, 17f, 17i, and 25 (CIF and ORTEP). This
material is available free of charge via the Internet at
http://pubs.acs.org.
C
17H26N2O4 (M+): 322.1893. Found: 322.1890.
(tr a n s)-5,7-Dim eth oxy-1,2,3,4-tetr a h yd r on a p h th a len -
1,2-d ia m in e (28). 10% Pd/C (396 mg, 30 mol %) and am-
monium formate (0.96 g, 10 equiv) were added to a solution of
(trans)-azide 25 (534 mg, 1.25 mmol) in ethyl acetate (4.5 mL)/
J O025822O
J . Org. Chem, Vol. 67, No. 23, 2002 8053