Nicholas reactions in the construction of cyclohepta[ de ]naphthalenes and cyclohepta[de]naphthalenones. The total synthesis of microstegiol

Article abstract of DOI:10.1021/jo102127q

The application of the Nicholas reaction chemistry of 2,7-dioxygenated naphthalenes in the synthesis of cyclohepta[de]napthalenes and in the synthesis of (±)-microstegiol (1) is presented. The substitution profile of Nicholas monosubstitution (predominantly C-1) and disubstitution reactions (predominantly 1,6-) on 2,7-dioxygenated napthalenes is reported. Application of a 1,8-dicondensation product and selected C-1 monocondensation products to the construction of cyclohepta[de]naphthalenes by way of ring closing metathesis and intramolecular Friedel-Crafts reactions, respectively, is described. Deprotection of the C-7 oxygen function to the corresponding naphthol allows tautomerization to cyclohepta[de]naphthalene-1-ones upon seven-membered-ring closure in most cases, and replacement of the C-2 oxygen function in the naphthalene by a methyl group ultimately allows the synthesis of (±)-microstegiol.

Full text of DOI:10.1021/jo102127q

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Nicholas Reactions in the Construction of Cyclohepta[de]naphthalenes
and Cyclohepta[de]naphthalenones. The Total Synthesis of Microstegiol
Rafiq A. Taj and James R. Green*
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, N9B 3P4, Canada
jgreen@uwindsor.ca
Received October 26, 2010
The application of the Nicholas reaction chemistry of 2,7-dioxygenated naphthalenes in the synthesis of
cyclohepta[de]napthalenes and in the synthesis of (()-microstegiol (1) is presented. The substitution profile
of Nicholas monosubstitution (predominantly C-1) and disubstitution reactions (predominantly 1,6-) on
2,7-dioxygenated napthalenes is reported. Application of a 1,8-dicondensation product and selected C-1
monocondensation products to the construction of cyclohepta[de]naphthalenes by way of ring closing
metathesis and intramolecular Friedel-Crafts reactions, respectively, is described. Deprotection of the C-7
oxygen function to the corresponding naphthol allows tautomerization to cyclohepta[de]naphthalene-1-
ones upon seven-membered-ring closure in most cases, and replacement of the C-2 oxygen function in the
naphthalene by a methyl group ultimately allows the synthesis of (()-microstegiol.
Introduction
including microstegiol (1),1 oxomicrostegiol (2),2 salvibretol
(3),1c and oxosalvibretol (4),1c,m have been isolated from roots
of a number of plants of the genus Salvia. These plants have
often seen use as folk remedies, and their crude extracts have
demonstrated antibacterial, anticancer, and insect antifeedant
activities.1h,k,3 Microstegiol itself has been demonstrated to have
antileukemic activity and modest antibacterial activity.1a,k,m,n
The cyclohepta[de]naphthalenes comprise a class of seven-
membered-ring compounds that has received significant atten-
tion for decades. Much of the early work centered around the
pleiadienes and acepleiadylenes and stemmed from interest in
their electronic structure. More recently, several rearranged
abietanes containing the cyclohepta[de]naphthalene nucleus,
*To whom correspondence should be addressed. Tel: (519)-253-3000, ext.
3545. Fax: (519)-973-7098
(1) (a) Ulubelen, A.; Topc-u, G.; Tan, N.; Lin, L.-J.; Cordell, G. A.
Phytochemistry 1992, 31, 2419–2421. (b) Ulubelen, A.; Topc-u, G.; Tan, N.
Phytochemistry 1992, 31, 3637–3638. (c) Topc-u, G.; Ulubelen, A. J. Nat.
€
Prod. 1996, 59, 734–737. (d) Ulubelen, A.; Topc-u, G.; Ufuk Sonmez, U.;
Choudhary, M. I.; Atta-Ur-Rahman Phytochemistry 1995, 40, 861–864. (e)
€
Ulubelen, A.; Sonmez, U.; Topc-u, G. Phytochemistry 1997, 44, 1297–1299.
(f) Ulubelen, A.; Tan, N.; Topc-u, G. Phytochemistry 1997, 45, 1221–1223. (g)
€
Sonmez, U.; Topc-u, G.; Ulubelen, A. Turk. J. Chem. 1997, 21, 376–382. (h)
Ulubelen, A.; Topc-u, G.; Chai, H.-B.; Pezzuto, J. M. Pharm. Biol. 1999, 37,
148–151. (i) Li, M.; Zhang, J.-S.; Ye, Y.-M.; Fang, J.-N. J. Nat. Prod. 2000,
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Sci. 2000, 14, 57–61. (k) Ulubelen, A.; Oksuz, S.; Kolak, U.; Bozok-
Johansson, C.; Celik, C.; Voelter, W. Planta Med. 2000, 66, 458–462. (l)
Okodil, G.; Topc-u, G.; Goren, A. C.; Voelter, W. Z. Naturforsch., B: Chem.
Sci. 2002, 57, 957–960. (m) Topc-u, G.; Altiner, E. N.; Gozcu, S.; Halfon, B.;
Aydogmus, Z.; Pezzuto, J. M.; Zhou, B.-N.; Kingston, D.G. I. Planta Med.
2003, 69, 462–464. (n) A. Kabouche, A.; Boutaghane, N.; Kabouche, Z.;
Seguin, E.; Tillequin, F.; Benlabed, K. Filoterapia 2005, 76, 450–452.
(2) Chyu, C.-F.; Lin, H.-C.; Kuo, Y.-H. Chem. Pharm. Bull. 2005, 53, 11–14.
Despite the recent upsurge in interest in the natural product
literature, none of the rearranged abietanes 1-4 have been the
subject of synthetic activity. The carbon framework of the
€
(3) (a) Topc-u, G.; Goren, A. C. Rec. Nat. Prod. 2007, 1, 1–16. (b) Ulubelen,
A. In Sage. The Genus Salvia; Kintzios, S. E., Ed.; Harwood: Amsterdam, The
Netherlands, 2000; pp 55-68.
8258 J. Org. Chem. 2010, 75, 8258–8270
Published on Web 11/11/2010
DOI: 10.1021/jo102127q
r
2010 American Chemical Society

Taj and Green
JOCArticle
cyclohepta[de]naphthalenes themselves has normally been pre-
pared by sequential Friedel-Crafts acylations of succinic anhy-
dride or some variation of that approach,4 although scattered
reports of access to this ring system by 2 þ 2 cycloaddition/ring
expansion reactions of cyclopenta[de]naphthalenes,5 malonate
intramolecular alkylation processes,6 reductive carbonyl cou-
pling reactions,7 and o-xylylene Diels-Alder cycloadditions8
have been published.9
TABLE 1. Monocondensation Reactions of 6a-f with 5a,b
Our group has a long-standing interest in the synthesis of
seven-membered-ring compounds,10 based in part on the
ability of alkynedicobalt complexes and the Nicholas reac-
tion chemistry11 of their derived propargyldicobalt cations
to allow umpolung bond constructions from reactions of
γ-carbonyl cation equivalents with electron-rich arenes, enol
derivatives, allylmetalloids, or other nucleophiles.12-17 Gi-
ven the recent interest in 1-4, the absence of synthetic work
on these compounds, and the relative paucity of methods for
the synthesis of cyclohepta[de]naphthalenes in general, we
(4) (a) Fieser, L. F.; Peters, M. A. J. Am. Chem. Soc. 1932, 54, 4347–4356.
(b) Morita, K.; Aida, T.; Morinaga, K.; Tsunetsugu, J. J. Chem. Soc., Perkin
Trans. 1 1994, 1215–1220. (c) Ashworth, G.; Barry, D.; Smith, D. C. C.
J. Chem. Soc., Perkin Trans. 1 1979, 2995–3000.
(5) (a) Gleiter, R.; Dobler, W. Chem. Ber. 1985, 118, 4725–4742. (b)
Tsunetsugu, J.; Yamaguchi, T.; Ebina, S.; Morinaga, K. J. Chem. Soc.,
entry
5
6
7 (yield, %)
8 (yield, %)
ꢀ
Perkin Trans. 1 1986, 1965–1973. (c) Sheilds, J. E.; Gavrilovoc, D.; Kopecky,
1
2
3
4
5
6
7
5a
5a
5a
5a
5a
5a
5b
6a
6b
6c
6d
6e
6f
7a (93)
7b (88)
7c (84)
7d (97)
7e (66)
J.; Hartmann, W.; Heine, H.-G. J. Org. Chem. 1974, 39, 515–520.
(6) Boekelheide, V.; Vick, G. K. J. Am. Chem. Soc. 1956, 78, 653–658.
(7) Vogel, E.; Neumann, B.; Klug, W.; Schmickler, H.; Lex, J. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1046–1048. Angew. Chem. 1985, 97,
1044-1045.
(8) Connolly, T. J.; Durst, T. Tetrahedron 1997, 53, 15969–15982.
(9) In addition, some homologues, such as the hypocrellins, have seen
recent synthetic attention: (a) O’Brien, E. M.; Morgan, B. J.; Mulrooney,
C. A.; Carroll, P. J.; Kozlowski, M. C. J. Org. Chem. 2010, 75, 57–68. (b)
O’Brien, E. M.; Li, J.; Carroll, P. J.; Kozlowski, M. C. J. Org. Chem. 2010, 75,
69–73.
8f (51)
6b
7g (71)a
aIn addition, 13% of 9g was isolated.
considered it of importance to study the applicability of
propargyldicobalt cation chemistry to this ring system, with
particular attention to microstegiol (1). Given structural char-
acteristics of 1, we consider the issues of (a) the fundamental
substitution characteristics in Nicholas reactions on 2,7-disub-
stituted naphthalenes, (b) seven-membered-ring construction
derived from Nicholas reaction adducts, (c) tautomerization to
the keto form of the 7(or 2-)- hydroxynaphthalenes, and (d)
regioselection in the constructed cycloheptane to be significant
for the methodology. This work describes in complete form our
developments in these directions, culminating in the synthesis
of (()-microstegiol (1).18
(10) Green, J. R. Eur. J. Org. Chem. 2008, 6053–6062.
(11) For recent reviews dedicated to the Nicholas reaction, see: (a) Diaz,
D. D.; Betancort, J. M.; Martin, V. S. Synlett 2007, 343–353. (b) Teobald,
B. J. Tetrahedron 2002, 58, 4133–4170. (c) Green, J. R. Curr. Org. Chem.
2001, 5, 809–826. For reviews covering Nicholas reactions in part, see ref 9
and the following: (d) Fletcher, A. J.; Christie, S. D. R. J. Chem. Soc., Perkin
Trans. 1 2000, 1657–1668. (e) Welker, M. E. Curr. Org. Chem. 2001, 5, 785–
€
807. (f) Muller, T. J. J. Eur. J. Org. Chem. 2001, 2021–2033. (g) Omae, I. Appl.
Organomet. Chem. 2007, 21, 318–344. (h) Bromfield, K. M.; Graden, H.;
Ljungdahl, N.; Kann, N. Dalton Trans. 2009, 5051–5061.
ꢀ
(12) (a) Green, J. R.; Tjeng, A. A. J. Org. Chem. 2009, 74, 7411–7416. (b)
Green, J. R. Chem. Commun. 1998, 1751–1752. (c) Vizniowski, C. S.; Green,
J. R.; Breen, T. L.; Dalacu, A. V. J. Org. Chem. 1995, 60, 7496–7502.
(13) For γ-carbonyl cation equivalents by way of cationic allyl iron
complexes, see: (a) Green, J. R.; Carroll, M. K. Tetrahedron Lett. 1991,
32, 1141–1144. (b) Zhou, T.; Green, J. R. Tetrahedron Lett. 1993, 34, 4497–
4500. (c) Charlton, M. A.; Green, J. R. Can. J. Chem. 1997, 75, 965–974. (d)
Enders, D.; Jandeleit, B.; Von Berg, S. Synlett 1997, 421–431. and references
citd therein. (e) Enders, D.; Jandeleit, B.; von Berg, S.; Raabe, G.; Runsink, J.
Organometallics 2001, 20, 4312–4332.
(14) For reviews including γ-carbonyl cation equivalents and their viny-
logous homologues by way of iron dienyl cations, see: (a) Pearson, A. J. Adv.
Met.-Org. Chem. 1988, 1, 1–49. and references cited therein. (b) Pearson,
A. J. Iron Compounds in Organic Synthesis; Academic: London, UK, 1994;
Chapter 5. (c) Donaldson, W. A.; Chaudhury, S. Eur. J. Org. Chem. 2009,
3831–3843. (d) Donaldson, W. A. Curr. Org. Chem. 2000, 4, 837–868.
(15) For γ-carbonyl cation equivalents by way of carbonyl-substituted
cyclopropanes, see: (a) Lifchits, O.; Alberico, D.; Zakharian, I.; Charette,
A. B. J. Org. Chem. 2008, 73, 6838 and references cited therein. (b) Hu, B.;
Xing, S.; Wang, Z. Org. Lett. 2008, 10, 5481–5484. (c) Yu, M.; Pagenkopf,
B. L. Tetrahedron 2005, 61, 321–347. (d) Harrington, P. A.; Kerr, M. A.
Tetrahedron Lett. 1997, 38, 5949. (e) Danishefsky, S. Acc. Chem. Res. 1979,
12, 66.
Results and Discussion
To develop a comprehensive understanding of the pattern
of reactivity of propargyldicobalt cations with naphthalene-2,7-
diol derivatives, 2,7-dimethoxynaphthalene (5a) was chosen as a
reference molecule, and its Lewis acid-mediated Nicholas reac-
tions of a number of substituted propargyl alcohol- or pro-
pargyl ether-Co2(CO)6 complexes were studied (6a-f).
Monocondensation. The condensation reactions of 6 with
2,7-dimethoxynaphthalene (5a) occurred to variable levels
of conversion in the presence of stoichiometric amounts of
BF3-OEt2, but readily to complete conversion in the presence
of 3 equiv of BF3-OEt2 (Table 1). With approximately equi-
molar amounts of 6a-f (1.1 equiv) relative to 5a, monocon-
densation products (7, 8) were formed in most cases without
(16) Forγ-carbonyl cation equivalents by way of π-allylpalladium complexes,
see: (a) Nemoto, T.; Fukuda, T.; Matsumoto, T.; Hitomi, T.; Hamada, Y. Adv.
Synth. Catal. 2005, 347, 1504–1506. (b) Nemoto, T.; Fukuda, T.; Hamada, Y.
Tetrahedron Lett. 2006, 47, 4365–4368. and references cited therein.
(17) For γ-carbonyl cation equivalents by way of neutral π-allylmolyb-
denum complexes, see: (a) Zhang, Y.; Liebeskind, L. J. Am. Chem. Soc. 2005,
127, 11258–11259. (b) Coombs, T. C.; Zhang, Y.; Garnier-Ambland, E. C.;
Liebeskind, L. J. Am. Chem. Soc. 2009, 131, 876–877.
(18) For a preliminary report of this work, see: Taj, R.;Abhayawardhana,
A.; Green, J. R. Synlett 2009, 292–296.
J. Org. Chem. Vol. 75, No. 23, 2010 8259

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TABLE 2. Dicondensation Reactions of 6 with 5a
SCHEME 1. Mixed Dicondensation Products
SCHEME 2. Cyclohepta[de]naphthalenes by RCM
entry
5a
6
9 (yield, %)
10 (yield, %)
10a (9)
1
2
3
4
5a
5a
5a
5a
6a
6b
6c
6d
9a (63)
9b (86)
10c (86)
10d (40)a
aIn addition, 59% of 7d was isolated.
significant contamination from the products of dialkylation.
Nicholas reaction precursors (6a-d) bearing no substitution at
the propargylic site cleanly afforded C-1 substitution in good
yields, regardless of whether the remote site of the alkyne bore
no substitution (7a, 93%), or substitution by an electron-
withdrawing group (7b, 76%), an alkyl group (7c, 84%), or a
silyl group (7d, 97%). Substitution at the propargylic site by a
methyl group (6e) still allowed C-1 substitution to occur (7e,
66%), but phenyl substitution at the propargyl site (6f) resulted
in condensation to give C-3 substitution product (8f, 51%) as
the sole isolable one. Use of 2,7-dibenzyloxy-substituted 5b
gave an analogous reaction with ester-substituted complex 6b,
with the exception of giving a small amount of 1,8-dicondensa-
tion product 9g (13%) in addition to the C-1 monocondensa-
tion product 7g (71%).
Dicondensation. Increasing the amount of propargyl alcohol/
ether-Co2(CO)6 complex 6a-e to slightly over 2 equiv enabled,
in most cases, ready conversion of 2,7-dimethoxynaphthalene
(5a) to disubstituted products (9-10) (Table 2). In these cases, a
competition existed between the formation of 1,8-disubstitution
products (9) and 1,6-disubtitution products (10), which de-
pended upon the structure of the Nicholas reaction precursor
complex 6. In the case of unsubstituted 6a, 1,8-disubstitution
predominated, although not to the exclusion of 1,6-disubstitu-
tion (9a, 63%, 10a, 9%). This tendency toward 1,8-disubstitu-
tion was increased in the case of remote electron withdrawing
group substituted 6b, as9b (86%) was formed to the exclusion of
any 1,6-disubstitution product. Conversely, substitution at the
remote end of the alkyne complex with either methyl (6c) or
trimethylsilyl (6d) groups resulted in the second substitution
occurring at C-6, giving 1,6-disubstitution products 10c (86%)
and 10d (40%); in the case of 6d, the second substitution was
incomplete, despite allowing the reaction to warm to rt, and a
significant amount of 7d (59%) was also isolated.
mediated reaction with butyn-2-ol complex 6e, giving 10e in
72% yield. C-3 substituted 8f, under analogous conditions
with unsubstituted 6a, afforded 10f (50% yield).
The pattern of Nicholas reaction reactivity of 2,7-dimethoxy-
naphthalene is therefore relatively consistent. Propargyldicobalt
cations which are unsubstituted or substituted with electron-
withdrawing groups undergo C-1 monosubstitution and C-1,
C-8 disubstitution. If the cation possesses an alkynyl substi-
tutent that is not electron withdrawing, monosubstitution is at
C-1, while the second substitution occurs at C-6. Substitution of
6 with groups at the propargylic site allows C-1 monosubstitu-
tion if the group is of moderate size, while a group of sufficient
size at this site ultimately forces the initial Nicholas reaction to
occur at C-3. The dichotomy in disubstitution is reminiscent of
that of dinitration and chlorination (1,8-) versus dibromination
(1,6-) of 2,7-dimethoxynaphthalene,19 including the element
of the most electrophilic reagents being directed toward the
1,8-positions.
Application toward Cyclohepta[de]naphthalene Synthesis.
Given an understanding of the substitution patterns of 2,7-
dioxygenated naphthalenes toward propargyldicobalt cations,
three different approaches to construction of the cyclohepta-
[de]naphthalene ring system were envisaged. Use of dicondensa-
tion product 9a was the most readily apparent precursor, as it
was one of the few cases in which the naphthalene 1,8-disub-
stitution pattern incorporated within the cyclohepta[de]naph-
thalene predominated; consequently its use in the preparation of
the cyclohepta[de]naphthalene system was pursued (Scheme 2).
In addition, two of the monocondensation products were
taken and subjected to a second Nicholas reaction (Scheme 1).
C-1 substitution product 7a was subjected to BF3-OEt2
ꢀ
(19) Richer, J.-C.; Pepin, Y. Can. J. Chem. 1965, 43, 3443–3445.
8260 J. Org. Chem. Vol. 75, No. 23, 2010

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SCHEME 3. Ring Closure by Friedel-Crafts Alkylation
SCHEME 4. Ring Closure by Friedel-Crafts Acylation
Decomplexation of 9a could be accomplished with (NH4)2-
Ce(NO3)6 under carefully controlled, low-temperature condi-
tions, giving 11 (57% yield, 89% by recovered starting material
(brsm)). Other common reagents for decomplexation (Me3NO, I2)
gave poorer yields of 11 or none at all. Semihydrogenation of 11
in the presence of the Lindlar catalyst then afforded diene 1220
(89% yield, 98% brsm). Finally, ring-closing metathesis (RCM)
employing Grubbs 1 catalyst (5 mol %) gave dihydrocyclo-
hepta[de]naphthalene 13 (85% yield). While this work was in
progress, the Kotha and Chattopadhyay groups demonstrated
the accessibility of the corresponding acetates by RCM.21
Using this dipropargylation-RCM approach to cyclohep-
tanaphthalenes, however, afforded only limited possibilities
for creating unsymmetrical substitution patterns regioselectively
on both the naphthalene and cycloheptene portions of 13, due to
the incompatibility of propargyl substitution in 6 with 1,8-disub-
stitution on 5. Consequently, the applicability of monoconden-
sation product 7b toward cyclohepta[de]naphthalene construc-
tion was explored (Scheme 3). Decomplexation of the organic
unit from the Co2(CO)6 residue of 7b was readily accomplished
by treatment of iodine in THF, giving 14 in excellent yield (98%).
While hydrogenation of 14 over Pd/C was sluggish, reduction
of the triple bond to the alkanoate (15) was straightforward
in the presence of H2 and Rh/C (99% yield). Addition of excess
MeLi (7 equiv) to 15 resulted in attack on the ester function to
give tertiary alcohol 16 in high yield (90% yield) provided a
significant excess of MeLi was employed; more modest excesses
(i.e., 3 equiv) resulted in noticeable amounts of ketone 17 being
isolated in addition to 16. Subjecting tertiary alcohol 16 to
H2SO4 in CH2Cl2 induced its conversion to 7,7-dimethyltetra-
hydrocyclohepta[de]naphthalene 18 (70% yield), contaminated
with a small amount of elimination product 19 (8% yield).
As all the naturally occurring cyclohepta[de]napthalenes exist
as dehydrotetralones, and since the matter of selective deprotec-
tion of the methoxy groups of 18 is not trivial, related approaches
to these ring systems were made on phenolic acetate 20.22 The
Nicholas reaction of 20 with 6b in the presence of BF3-OEt2
occurred somewhat sluggishly (relative to 2,7-dimethoxy-
naphthalene), but ultimately afforded the product of γ-carbonyl
cation substitution ortho to the methoxy function (21) in
excellent yield (88%) (Scheme 4). Bu2BOTf has often proved
more effective in generating γ-carbonyl cation based Nicholas
reactions, and accordingly, this Lewis acid enabled the same
transformation to occur more rapidly, even in substoichio-
metric amounts, ultimately giving 21 in similar yields (90%).23
Alkyne decomplexation with I2 in THF occurred readily to
give alkynoate 22 (93%), and Pd/C catalyzed hydrogenation
of the alkyne afforded alkanoate 23 in excellent yield (93%).
From alkanoate 23, the synthesis of cyclohepta[de]naphtha-
lene systems diverged in two ways. Given the oxygenated
(22) (a) Gorelik, A. M.; Reznichenko, A. V.; Andronova, N. A.; Luk’yanets,
E. A. J. Org. Chem. USSR 1983, 19, 183–189. (b) Bell, K. H.; McCaffery, L. F.
Aust. J. Chem. 1992, 45, 1213–1224.
(20) Shorthill, B. J.; Glass, T. E. Org. Lett. 2001, 3, 577–579.
(21) (a) Kotha, S.; Mandal, K.; Tiwari, A.; Mobin, S. M. Chem.;Eur. J.
2006, 12, 8024–8038. (b) Chattopadhyay, S. K.; Ghosh, D.; Neogi, K. Synth.
Commun. 2007, 37, 1535–1543.
(23) The superiority of Bu2BOTf over BF3-OEt2 in Nicholas reactions for
substrates possessing Lewis basic groups has been observed in our group
previously: (a) Green, J. R. Chem. Commun. 1998, 1751–1752. (b) Green,
J. R.; Tjeng, A. A. J. Org. Chem. 2009, 74, 7411–7416.
J. Org. Chem. Vol. 75, No. 23, 2010 8261

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SCHEME 5. Cyclohepta[de]napthalenone Synthesis by Cycli-
zation-Tautomerization
yield (96%). Attempts at using H2 with Pd/C on 30 to effect a
one-pot conversion to 32 resulted in less clean reaction mixtures,
whichdidcontainsome32. Compound 32 was converted readily
into its triflate (33, 96%) in the presence of Tf2O/pyridine, which
was subjected to methylation. After some experimentation, it
was found that Pd2(dba)3/Cy-JohnPhos-catalyzed reaction of
33 with the DABCO-(AlMe3)2 complex (DABAL-Me3)25 gave
efficient methyl group incorporation, resulting in the formation
of both 34 (84%) and a small amount of deacetylated 35 (7%).
Each of these methylnaphthalenes could be converted into
naphthol-tertiary alcohol 36 by reaction with excess MeLi
(Scheme 7). In the case of 34, 36 was obtained in 94% yield; in
the case of 35, 36 could be isolated in 70% yield. Subjecting
36 in CH2Cl2 to H2SO4 then resulted in rapid conversion to
cyclohepta[de]naphthalenone 37 in excellent yield (87%).
The incorporation of an R-hydroxy function relative to the
ketone was briefly explored (eq 1). Exposure of a solution of 37
in DMF to NaH in air26 resulted in the disappearance of 37 and
the formation of two compounds: R-hydroxy ketone 38 (42%),
and the relatively unstable R-hydroxylated epoxide 39 (31%).
cycloheptane unit present within salvibretol, access to a
ketone function in the seven-membered ring was desired.
Consequently, saponification of 23 was accomplished, albeit
slowly, by K2CO3 in MeOH at reflux, giving 24 (76% yield).
After experimentation with several sets of acidic conditions,
it was found that exposure to polyphosphoric acid (PPA)
(CH2Cl2, reflux) gradually converted 24 to 25 (80% yield).
Compound 25 was found to exist entirely as the phenolic
tautomer, the conjugation of the aromatic system to the
ketone no doubt being in part responsible; the existence of
1-hydroxy-7,12-pleiadenedione and related compounds in
their naphthol tautomer provides additional precedent for
this observation.24
In contrast to 25, PM5 and DFT (B88-PW91 functional,
dzvp basis set) calculations suggest that without the ketone
function in the cycloheptane unit, the 1-hydroxycyclohepta-
[de]naphthalene-cyclohepta[de]naphthalen-1(7H)-one equili-
brium strongly favors the latter tautomer. As a result, 23 was
subjected to reaction with excess MeLi, to give tertiary alcohol
26 (70% yield) (Scheme 5). Subsequent addition of one drop of
H2SO4 to a CH2Cl2 solution of this phenol at 0 °C induced rapid
closure of the seven-membered ring, producing 27 (70% yield)
exclusively as its keto tautomer. This angle strain-directed tauto-
merization demonstrates the viability of the approach for pre-
paring the rearranged abietane framework of microstegiol.
Methyl Group Incorporation. In the naturally occurring
cyclohepta[de]naphthalenes, there resides a C-6 methyl func-
tion (C-2 in the source naphthalene) as opposed to an
oxygen-based one. As a strongly electron donating function
is required for viable Nicholas reaction/γ-carbonyl cation
chemistry on the naphthalene nucleus, the use of a C-2/C-7
oxygen-based function followed by its ultimate replacement
by methyl is necessary. To that end, we chose benzyl/acetyl-
protected 28, prepared from 7-benzyloxy-2-naphthol, as a
starting point for further studies (Scheme 6). Compound 28
underwent reaction with 6b only sluggishly in the presence of
BF3-OEt2 (24 h, 0 °C, 45% yield of 29, 66% brsm), but gave
29 promptly and in excellent yield in the presence of Bu2-
BOTf (1.5 h, 0 °C, 90% yield). Following uneventful decom-
plexation with I2 (30, 90% yield), hydrogenation under Rh/C
catalysis reduced the triple bond without affecting the benzyl
protecting group (31, 92% yield); subsequent treatment of 31
with H2 and Pd/C then gave phenolic acetate 32 in excellent
Synthesis of Microstegiol. With model studies for cyclohepta-
[de]naphthalene-1-one preparation, C-6 methyl group incor-
poration, and R-hydroxylation completed, the synthesis of
microstegiol could now be undertaken. 7-Benzyloxy-3-bromo-
2-naphthol (40) was chosen as the foundation compound for
this synthesis. Compound 40 has been prepared by the method
of the Diederich group from 2,7-naphthalenediol,27 by way of
dibromination/monodebromination to give 41, selective meth-
oxymethyl ether formation (42), conventional benzylation (43),
and MOM ether deprotection (Scheme 8). Incorporation of
the C-3 isopropyl group was preceded by naphthol acetylation
under standard conditions, giving 44 (96% yield).28 Suzuki-
Miyaura coupling of 44 with isopropenylboronic acid pinacol
ester gave 45 cleanly (80% yield), and reduction of the alkene
function by hydrogenation over Rh/C afforded 46 (92% yield)
(Scheme 2).
With the two arene rings of the naphthalene now posses-
sing distinctly different levels of activation toward electro-
philic substitution, the critical Nicholas reaction of γ-car-
bonyl cation equivalent 6b was attempted. In the presence of
an excess amount of BF3-OEt2 (3 equiv), compounds 46 and
6b gradually underwent reaction at 0 °C, and 47 was formed
in excellent yield (89%) (Scheme 9). In accordance with the
majority of cases in our methodological study,19 polyalkyla-
tion was not a detectable side reaction for this process.
(25) (a) Biswas, K.; Prieto, O.; Goldsmith, P. J.; Woodward, S. Angew.
Chem., Int. Ed. 2005, 44, 2232–2234. Angew. Chem. 2005, 117, 2272-2274;
(b) Cooper, T.; Novak, A.; Humphreys, L. D.; Walker, M. D.; Woodward, S.
Adv. Synth. Catal. 2006, 348, 686–690.
(26) Ishikawa, T.; Hino, K.; Yoneda, T.; Murota, M.; Yamaguchi, K.;
Watanabe, T. J. Org. Chem. 1999, 64, 5691–5695.
€
€
(27) Bahr, A.; Droz, A. S.; Puntener, M.; Neidlein, U.; Anderson, S.;
Seiler, P.; Diederich, F. Helv. Chem. Acta 1998, 81, 1931–1963.
(24) (a) Rieche, A.; Fruhwald, E. Chem. Ber. 1931, 64B, 1603–1606.
(b) Moghaddam, F. M.; Porkaleh, H.; Zali-Boeini, H. Lett. Org. Chem.
2006, 3, 123–127.
(28) Attempts to subject 41 to initial acetylation, in order to give an
expedited route to 44, were not selective for protection of the C-2 alcohol.
8262 J. Org. Chem. Vol. 75, No. 23, 2010

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JOCArticle
SCHEME 6. C-2 Methyl Group Incorporation
SCHEME 7. Preparation of Cyclohepta[de]naphthalenone 37
SCHEME 8. Differentially Protected C-3 Isopropyl-2,7-naphtha-
lenediol Preparation
Decomplexation of 47 was straightforward in the pres-
ence of I2/THF (48, 87% yield). With the four-carbon
unit incorporated, replacement of the benzyloxy function
with a methyl group was facilitated by the observation
that in the presence of H2 and Pd/C, alkyne reduction was
accompanied by hydrogenolytic removal of the benzyl
ether, giving 49 in 84% yield. The naphthol function of
49 was then readily converted into its triflate in the
presence of Tf2O and pyridine, with 50 being obtained in
83% yield. Cross coupling of the methyl organometallic
was accomplished by the palladium-catalyzed reaction
with DABAL-Me3,23 providing 51 in excellent (91%) yield
(Scheme 10).
Formation of the tautomerized cyclohepta[de]naphthol
was pursued following the methodology developed for 23
(Scheme 10). The ester function of 51 was cleanly converted
into 3° alcohol 52 in the presence of excess MeLi (52, 92%
yield). In a manner analogous to our model compound (26),
a CH2Cl2 solution of 52, when exposed to 1 drop of H2SO4,
underwent ring closure in conjunction with tautomeriza-
tion of the naphthol function to a cyclohexenone, giving 53
(81% yield).
material was spectroscopically identical with that isolated
from Salvia microstegia.1a
Incorporation of the alcohol function R to the keto function
remained the sole requirement for the synthesis of microstegiol.
Fortunately, the addition of NaH to a DMF solution of 53, with
exposure to an oxygen atmosphere, resulted in the clean forma-
tion of (()-microstegiol 1 (64% yield) (eq 2). The synthetic
In summary, a systematic study of Nicholas reaction-based
γ-carbonyl cation chemistry on 2,7-dioxygenated naphthalenes
J. Org. Chem. Vol. 75, No. 23, 2010 8263

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SCHEME 9. Nicholas Reaction of 46 and Triflate Incorporation
distilled and stored under nitrogen. All reactions were conducted
under a nitrogen atmosphere unless otherwise noted. Flash chro-
matography was performed as described by Still using silica gel 60
(230-400 mesh).29 Compounds 5b,30 6a,31 6b,32 6c,33 6d,34 6e,35
6f,31and 2022 were prepared by literature procedures and are >95%
1
pure as determined by H and 13C NMR spectroscopy. All new
compounds are >95% pure as determined by 1H and 13C NMR
spectroscopy. NMR spectra were run at 500 or 300 MHz for 1Hand
125 or 75 MHz for 13C in CDCl3; chemical shifts are given in ppm
and coupling constants (J) are given in Hz. High-resolution
mass spectra were run by time-of-flight mass spectroscopy, in EI
mode, at 70 eV.
Hexacarbonyl[μ-η4-(2,7-dimethoxy-1-(prop-2-ynyl)naphthal-
ene)]dicobalt (7a): Method 1. To a solution of 2,7-dimethoxy-
naphthalene 5a (0.050 g, 0.27 mmol) in CH2Cl2 (15 mL) was added
propargyl alcohol complex 6a (0.100 g, 0.292 mmol). BF3-OEt2
(101 μL, 0.797 mmol) was added dropwise at 0 °C. After 3 h of con-
tinuous stirring, NH4Cl(aq) was added and the mixture was subjected
to a conventional extractive workup (CH2Cl2). The residue was
subjected to flash chromatography (50:1 petroleum ether:Et2O) to
give 7a (0.127 g, 93%) as a red brown solid: IR (KBr) υmax 3003,
2960, 2090, 2055 cm-1; 1H NMR δ 7.71 (d, J = 8.9, 1H), 7.70 (d,
J = 8.9, 1H), 7.22 (d, J = 2.4, 1H), 7.10 (d, J = 8.9, 1H), 7.04 (dd,
J = 8.9, 2.4, 1H), 5.95 (s, 1H), 4.60 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H);
13C NMR 199.9, 158.4, 154.7, 133.9, 130.2, 128.6, 124.6, 120.1, 116.1,
109.7, 101.6, 96.1, 73.5, 55.4, 55.1, 29.5; MS 484 (Mþ - CO), 456
(Mþ - 2CO), 428 (Mþ - 3CO), 372 (Mþ - 5CO); HRMS m/e for
C21H14Co2O8 calcd (Mþ - 2CO) 455.9454, found 455.9441.
Hexacarbonyl[μ-η4-(2,7-dimethoxy-1-(3-carbomethoxyprop-
2-ynyl)naphthalene)]dicobalt (7b).Subjecting 5a (0.210 g, 1.12 mmol),
6a (0.508 g, 1.23 mmol), and BF3-OEt2 (425 μL, 3.35 mmol) to
Method 1 gave product 7b (0.560 g,, 88% yield) following flash
chromatography (5:1 petroleum ether:Et2O) as red brown solid: IR
(KBr) υmax 3003, 2951, 2097, 2063, 2028, 1708; 1H NMR δ 7.72 (d,
J=8.9,1H),7.68(d,J= 8.9, 1H), 7.18 (d, J=2.3,1H),7.10(d,J=
8.9, 1H), 7.02 (dd, J= 8.9, 2.3, 1H), 4.64 (s, 2H), 3.96 (s, 3H), 3.95 (s,
3H), 3.53 (s, 3H); 13C NMR 198.4, 170.7, 158.5, 154.7, 133.9, 130.2,
128.8, 124.4, 119.1, 116.2, 109.4, 101.1, 99.4, 79.3, 55.2, 54.9, 52.4,
29.1; MS m/e 570 (Mþ), 542 (Mþ - 1CO), 514 (Mþ - 2CO), 486
(Mþ - 3CO), 458 (Mþ - 4CO), 430 (Mþ - 5CO), 402 (Mþ
- 6CO); HRMS m/e for C23H16Co2O10 calcd (Mþ - CO) 541.9458,
found 541.9455.
SCHEME 10. Methyl Incorporation and Cycloheptane Formation
Hexacarbonyl[μ-η4-(2,7-dimethoxy-1-(but-2-ynyl)naphtha-
lene)]dicobalt (7c). Subjecting 5a (0.0960 g, 0.511 mmol), 6c (0.200 g,
0.562 mmol), and BF3-OEt2 (196 μL, 1.55 mmol) to Method 1
gave product 7c (0.225 g, 84% yield) following flash chromatogra-
phy (100:1 petroleum ether:Et2O) as red brown solid: IR (KBr)
υ
max 2941, 2086, 2044, 2015, 1629 cm-1; 1H NMR δ 7.73 (d, J =
9.0, 1H), 7.71 (d, J = 9.0, 1H), 7.26 (d, J = 2.2, 1H), 7.12 (d, J =
8.9, 1H), 7.03 (dd, J = 8.9, 2.2, 1H), 4.61 (s, 2H), 3.98 (s, 3H), 3.96
(s, 3H), 2.42 (s, 3H); 13C NMR 200.1, 158.4, 154.7, 133.8, 130.2,
128.5, 124.5, 119.6, 116.1, 109.5, 101.6, 98.1, 94.2, 55.3, 55.0, 29.5,
21.0; MS m/e442 (Mþ - 3CO), 414 (Mþ - 4CO), 386 (Mþ - 5CO),
358 (Mþ - 6CO); HRMS m/e for C22H16Co2O8 calcd (Mþ - CO)
497.9560, found 497.9583.
Hexacarbonyl[μ-η4-(2,7-dimethoxy-1-(3-trimethylsilylprop-
2-ynyl)naphthalene)]dicobalt (7d). Subjecting 5a (0.0433 g,
0.230 mmol), 6d (0.1092 g, 0.264 mmol), and BF3-OEt2 (87 μL,
has established the pattern of monosubstitution and disubstitu-
tion reactions. With use of selected condensation products, three
different methods for generation of the cyclohepta[de]naphtha-
lene ring system have been developed. Selective C-3 functionaliza-
tion and replacement of the C-7 oxygen-based function by a
methyl group has allowed the synthesis of (()-microstegiol (1) in
15 steps and 7.2% overall yield from 2,7-dihydroxynaphthalene.
(29) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
(30) Haraldsson, G. G.; Baldwin, J. E. Tetrahedron 1997, 53, 215–224.
(31) D’Agostino, M. F.; Frampton, C. S.; McGlinchey, M. J. Organo-
metallics 1990, 9, 2972–2984.
(32) Tjeng, A. A.; Green, J. R. J. Org. Chem. 2009, 74, 7411–7416.
(33) (a) Vessieres, A.; Jaouen, G.; Gruselle, M.; Rossignol, J. L.; Savignac,
M.; Top, S.; Greenfield, S. J. Steroid Biochem. 1988, 30, 301–305. (b) Lang, H.;
Experimental Section
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Kohler, K.; Emmerich, C. Z. Naturforsch., B: Chem. Sci. 1995, 50, 923–930.
(34) Kuhn, O.; Rau, D.; Mayr, H. J. Am. Chem. Soc. 1998, 120, 900–907.
(35) Connor, R. E.; Nicholas, K. M. J. Am. Chem. Soc. 1987, 109, 5749–5759.
General Methods. All reaction solvents were used after passage
through a solvent purification system. Commercial BF3-OEt2 was
8264 J. Org. Chem. Vol. 75, No. 23, 2010

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JOCArticle
0.69 mmol) to Method 1 gave product 7d (0.1308 g, 97% yield)
following flash chromatography (50:1 petroleum ether:Et2O)
Dodecacarbonyl[μ-η4-(2,7-dimethoxy-1,8-di(prop-2-ynyl)naph-
thalene)]tetracobalt (9a) and Dodecacarbonyl[μ-η4-(2,7-di-
methoxy-1,6-di(prop-2-ynyl)naphthalene)]tetracobalt (10a): Method
2. To a solution of 2,7-dimethoxynaphthalene 5a (0.100 g, 0.531
mmol) in CH2Cl2 (10 mL) was added propargyl alcohol complex 6a
(0.393 g, 1.149 mmol), followed by the dropwise addition of
BF3-OEt2 (202 μL, 1.59 mmol) at 0 °C. After 3 h of continuous
stirring, NH4Cl(aq) was added and the mixture was subjected to a
conventional extractive workup. The residue was purified by flash
chromatography (10:1 petroleum ether:Et2O) to give, in order of
elution, 10a (0.040 g, 9% yield) and 9a (0.280 g, 63% yield) as red
brown solids. 9a: IR (KBr) υmax 2917, 2090, 2051, 2021 cm-1; 1H
NMR δ 7.70 (d, J = 8.9, 2H), 7.12 (d, J = 8.9, 2H), 5.83 (s, 2H),
5.22 (d, J=16.4, 2H), 4.50 (d, J=16.4, 2H), 3.99 (s, 6H); 13C NMR
199.6, 156.1, 131.9, 130.7, 126.5, 121.3, 110.1, 97.5, 73.8, 55.9, 30.6;
MS m/e 808 (Mþ-1CO), 780 (Mþ-2CO), 752 (Mþ-3CO), 724
(Mþ-4CO), 696 (Mþ-5CO), 668 (Mþ-6CO), 640 (Mþ-7CO),
612 (Mþ - 8CO); HRMS m/e for C30H16Co4O14 calcd (Mþ - CO)
807.7917, found 807.7904. 10a: IR (KBr) υmax 2922, 2091, 2048,
2016 cm-1; 1H NMR δ 7.67 (d, J = 8.5, 1H), 7.57 (s, 1H), 7.19 (s,
1H), 7.08(d, J=8.5, 1H), 6.05 (s, 1H), 5.86 (s, 1H), 4.59 (s, 2H), 4.26
(s, 2H), 3.97 (s, 3H), 3.96 (s, 3H); 13C NMR 199.8, 156.5, 154.4,
133.2, 130.4, 128.2, 127.8, 124.4, 120.0, 110.0, 100.9, 97.9, 96.1, 73.8,
as red brown solid: IR (KBr) υmax 2959, 2083, 2042, 2013, 1629 cm-1
;
1H NMR δ7.73 (d, J=8.8, 1H), 7.72 (d, J=8.8, 1H), 7.26 (d, J=2.3,
1H), 7.12 (d, J=8.9, 1H), 7.05 (dd, J=8.9, 2.3, 1H), 4.72 (br s, 2H),
3.96 (s, 3H), 3.95 (s, 3H), 0.06 (s, 9H); 13C NMR 200.6, 158.7, 154.8,
134.0, 130.3, 128.7, 124.8, 120.0, 115.8, 110.6, 109.8, 102.5, 79.3,
55.3, 55.2, 30.6, 0.3; MS m/e 556 (Mþ-CO), 528 (Mþ-2CO), 500
(Mþ -3CO), 444 (Mþ -5CO); HRMS for C24H22Co2O8Si calcd
(Mþ-3CO) 499.9900, found 499.9898.
Hexacarbonyl[μ-η4-(2,7-dibenzyloxy-1-(3-carbomethoxyprop-2-
ynyl)naphthalene)]dicobalt (7g) and Dodecacarbonyl[μ-η4-(2,7-di-
benzyloxy-1,8-di(3-carbomethoxyprop-2-ynyl)naphthalene)]tetra-
cobalt (9g). Subjecting 2,7-dibenzyloxynaphthalene (5b) (0.754 g,
2.21 mmol), 6b (1.009 g, 2.437 mmol), and BF3-OEt2 (842 μL,
6.64 mmol) to Method 1 gave, in order of elution, 7g (1.133 g,
71% yield) as a red brown solid, and 9g (0.3210 g, 13% yield),
following flash chromatography (5:1 petroleum ether:Et2O) as
red brown viscous oil. 7g: IR (KBr) υmax 3039, 2957, 2098,
2031, 1706 cm-1; 1H NMR δ 7.81 (dd, J = 8.9, 2.4, 2H), 7.66
(d, J = 7.1, 2H), 7.62 (d, J = 7.1, 2H), 7.45-7.59 (m, 7H), 7.28
(dd, J = 8.7, 1.9, 1H), 7.26 (d, J = 8.8, 1H), 5.39 (s, 2H), 5.33 (s,
2H), 4.81 (br s, 2H), 3.56 (s, 3H); 13C NMR 198.3, 170.5, 157.7,
154.1, 137.0, 134.0, 130.2, 128.8, 128.5, 127.9, 127.6, 127.4,
124.8, 120.0, 116.5, 111.5, 103.1, 99.0, 79.6, 70.7, 69.6, 52.4,
29.5; MS m/e 610 (Mþ - 4CO), 554 (Mþ - 6CO); HRMS for
C35H24Co2O10 calcd (Mþ - 6CO) 554.0339, found 554.0354.
9g: IR (KBr) υmax 2951, 2097, 2063, 2030, 1709 cm-1; 7.67 (d,
J=8.9, 2H), 7.51 (d, J=7.3, 4H), 7.40 (apparent t, J=7.3, 4H),
7.33 (t, J=7.1, 2H), 7.16 (d, J=8.9, 2H), 5.35 (d, J=16.7, 2H),
5.30 (1/2 ABquartet, J=12.2, 2H), 5.22 (1/2 ABquartet, J=
12.2, 2H), 4.82 (d, J=16.6, 2H), 3.36 (s, 6H); 13C NMR 198.2,
170.4, 155.6, 137.0, 132.2, 130.8, 128.5, 127.9, 127.2, 126.8,
121.4, 112.0, 99.6, 80.2, 71.0, 52.3, 31.0. Anal. Calcd for C46H28-
Co4O18: C, 50.02; H, 2.56. Found: C, 49.87, H, 2.52.
73.4, 55.5, 54.7, 39.3, 29.7; MS m/e 640 (Mþ - 6CO), 612 (Mþ
-
7CO), 584 (Mþ-8CO), 500 (Mþ-12CO); HRMS m/e for C30H16-
Co4O14 calcd (Mþ - 7CO) 639.8224, found 639.8223.
Dodecacarbonyl[μ-η4-(2,7-dimethoxy-1,8-di(3-carbomethoxy-
prop-2-ynyl)naphthalene)]tetracobalt (9b). Subjecting a solution of
2,7-dimethoxynaphthalene 5a (0.0258 g, 0.137 mmol), propargyl
ether complex 6b (0.1314 g, 0.317 mmol), and BF3-OEt2 (115 μL,
0.91 mmol) to Method 2 gave 9b (0.1117 g, 86%) following flash
chromatography (5:1 petroleum ether:Et2O) as red brown solid: IR
(KBr) υmax 3004, 2950, 2097, 2067, 1710 cm-1; 1H NMR δ 7.71 (d,
J = 9.0, 2H), 7.10 (d, J = 9.0, 2H), 5.19 (d, J = 16.5, 2H), 4.69 (d,
J = 16.5, 2H), 3.94 (s, 6H), 3.46 (s, 6H); 13C NMR 198.2, 170.5,
156.0, 132.0, 130.9, 126.3, 120.2, 109.7, 99.8, 80.2, 55.6, 52.3, 30.8;
MS m/e 896 (Mþ - 2CO), 840 (Mþ - 4CO), 784 (Mþ - 6CO), 728
(Mþ - 8CO), 700 (Mþ - 9CO). Anal. Calcd for C34H20Co4O18: C,
42.88; H, 2.12. Found: C, 43.12; H, 2.10.
Hexacarbonyl[μ-η4-(2,7-dimethoxy-1-(1-methylprop-2-ynyl)-
naphthalene)]dicobalt (7e). Subjecting 5a (0.0498 g, 0.264 mmol), 6e
(0.0880 g, 0.247 mmol), and BF3-OEt2 (105 μL, 0.829 mmol) to
Method 1 gave product 7e (0.0920 g, 66% yield) following flash
chromatography (40:1 petroleum ether:Et2O) as red brown solid:
IR (KBr) υmax 3039, 2957, 2098, 2031, 1706 cm-1; 1H NMR (58:42
mixture of rotamers) δ 7.66-7.70 (m, 2H, both), 7.60 (d, J = 2.3,
1H minor), 7.35 (d, J=1.9, 1H major), 7.10 (d, J=8.9, 1H, minor),
7.08 (d, J = 8.8, 1H, major), 7.03 (dd, J = 8.8, 2.3, 1H, major), 7.02
(dd, J=8.9, 1.9, 1H minor), 6.09 (s, 1H, both), 5.65 (q, J = 7.5, 1H,
minor), 5.04 (q, J=6.9, 1H, major), 3.99 (s, 3H, minor), 3.97 (s, 3H,
major), 3.96 (s, 3H, minor), 3.93 (s, 3H, major), 1.89 (d, J=6.9, 3H,
major), 1.88 (d, J=7.5, 3H, minor); 13C NMR 200.3, 199.9, 158.7,
157.1, 156.3, 154.1, 133.5, 133.3, 130.6, 130.4, 128.9, 128.8, 125.4,
124.9, 124.7, 124.4, 116.1, 115.5, 111.0, 110.3, 104.6, 102.4, 101.8,
101.0, 74.1, 72.6, 56.1, 55.3, 55.2, 55.0, 37.7, 35.3, 22.4, 21.5; MS m/e
Dodecacarbonyl[μ-η4-(2,7-dimethoxy-1,6-di(but-2-ynyl)naph-
thalene)]tetracobalt (10c). Subjecting 5a (0.1000 g, 0.5314 mmol), 6c
(0.400 g,1.123 mmol), and BF3-OEt2 (202 μL, 1.59 mmol) to
Method 2 gave product 10c (0.3950 g, 86% yield) following flash
chromatography (100:1 petroleum ether:Et2O) as red brown solid:
IR (KBr) υmax 2949, 2085, 2000, 1631 cm-1; 1H NMR δ 7.71 (d,
J= 8.9, 1H), 7.60 (s, 1H), 7.27 (s, 1H), 7.13 (d, J= 8.9, 1H), 4.62 (s,
2H), 4.30 (s, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 2.55 (s, 3H), 2.44 (s, 3H);
13C NMR 200.1, 156.6, 154.6, 133.3, 130.4, 128.3, 127.4, 124.4,
119.6, 109.8, 100.7, 99.3, 98.2, 94.3, 55.3, 54.7, 34.8, 29.7, 21.0, 20.4;
MS m/e 808 (Mþ - 2CO), 780 (Mþ - 3CO), 724 (Mþ - 5CO), 640
(Mþ - 8CO), 612 (Mþ - 9CO); HRMS m/e for C32H20Co4O14
calcd (Mþ - 3CO) 779.8334, found 779.8342.
498 (Mþ - CO), 470 (Mþ - 2CO), 442 (Mþ - 3CO), 414 (Mþ
-
4CO), 386 (Mþ - 5CO); HRMS m/efor C22H16Co2O8 calcd (Mþ -
2CO) 469.9611, found 469.9608.
Dodecacarbonyl[μ-η4-(2,7-dimethoxy-1,6-di(3-trimethylsilyl-
prop-2-ynyl)naphthalene)]tetracobalt (10d). Subjecting 5a (0.050 g,
0.266 mmol), 6d (0.242 g, 0.585 mmol), and BF3-OEt2 (118 μL,
0.931 mmol) to Method 2, with the exception that the reaction
mixture was additionally warmed to room temperature for 5 h,
with flash chromatography (50:1 petroleum ether:Et2O) gave, in
order of elution, 10d (0.105 g, 40% yield) as a red-brown solid,
and 7d (0.091 g, 59%). 10d: IR (KBr) υmax 2960, 2089, 2050, 2023,
1632 cm-1; 1H NMR δ 7.70 (d, J=8.9, 1H), 7.61 (s, 1H), 7.21 (s,
1H), 7.12 (d, J=8.9, 1H), 4.70 (br s, 2H), 4.38 (s, 2H), 3.97 (s, 3H),
3.94 (s, 3H), 0.25 (s, 9H), 0.12 (s, 9H); 13C NMR 200.3., 156.6, 154.9,
133.4, 131.1, 128.3, 127.6, 124.5, 119.9, 112.7, 110.6, 110.0, 100.7,
79.4, 79.2, 55.3, 54.6, 34.9, 30.7, 0.5, 0.4; MS m/e 952 (Mþ - CO),
924 (Mþ-2CO), 896 (Mþ-3CO), 840 (Mþ-5CO), 784 (Mþ-
7CO); HRMS (electrospray, negative ion) m/e for C36H32Co4O14Si2
calcd (M - Hþ) 978.8580, found 978.8584.
Hexacarbonyl[μ-η4-(2,7-dimethoxy-3-(1-phenylprop-2-ynyl)-
naphthalene)]dicobalt (8f). Subjecting 5a (0.0560 g, 0.298 mmol), 6f
(0.1500 g, 0.3588 mmol), and BF3-OEt2 (113 μL, 0.892 mmol) to
Method 1 gave product 8f (0.0900 g, 51% yield) following flash
chromatography (10:1 petroleum ether:Et2O), as red brown solid:
IR (KBr) υmax 2922, 2089, 2050, 2014, 1632 cm-1; 1H NMR δ 7.78
(s, 1H), 7.62 (d, J = 8.9, 1H), 7.48 (d, J = 7.3, 2H), 7.26 (m, 2H),
7.18 (t, J = 7.3, 1H), 7.02 (obscured d, J = 2.5, 1H), 7.01 (s, 1H),
6.98 (dd, J = 8.9, 2.5, 1H), 6.46 (s, 1H), 6.01 (s, 1H), 3.93 (s, 3H),
3.89 (s, 3H); 13C NMR 199.5, 158.1, 155.5, 144.2, 134.9, 131.4,
129.1, 128.4, 127.9, 126.9, 123.8, 116.2, 105.0, 104.8, 100.5, 74.1,
55.4, 55.2, 48.7; MS m/e 532 (Mþ - 2CO), 476 (Mþ - 4CO), 448
(Mþ - 5CO), 420 (Mþ - 6CO); HRMS m/e for C27H18Co2O8
calcd (Mþ - 4CO) 475.9869, found 475.9853.
J. Org. Chem. Vol. 75, No. 23, 2010 8265

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JOCArticle
Dodecacarbonyl[μ-η4-(6-(but-3-yn-2-yl)-2,7-dimethoxy-1-(prop-
2-ynyl)naphthalene)]tetracobalt (10e). Subjecting 7a (0.0300 g,
0.0585 mmol), 6e (0.0330 g, 0.0926 mmol), and BF3-OEt2 (25 μL,
0.20 mmol) to Method 1 gave product 10e (0.0360 g, 72% yield)
following flash chromatography (100:1 petroleum ether:Et2O) as red
brown solid: IR (KBr) υmax 2935, 2089, 2050, 2018, 1627 cm-1; 1H
NMR δ 7.69 (d, J = 8.9, 1H), 7.63 (s, 1H), 7.22 (s, 1H), 7.09 (d, J =
8.9, 1H), 6.02 (s, 1H), 5.90 (s, 1H), 4.80 (q, J = 7.1, 1H), 4.66 (1/2
ABquartet, J=15.3, 1H), 4.57 (1/2 ABquartet, J=15.3, 1H), 4.01 (s,
3H), 3.97 (s, 3H), 1.77 (d, J=7.1,3H);13C NMR 199.9, 156.1, 154.5,
133.0, 132.8, 128.5, 126.8, 124.4, 119.9, 110.0, 105.4, 101.0, 96.2, 74.1,
73.5, 55.5, 54.9, 35.3, 30.0, 22.1; MS m/e822 (Mþ - CO), 794(Mþ -
2CO), 766 (Mþ - 3CO), 738 (Mþ - 4CO), 710 (Mþ - 5CO), 682
give 13 (0.0130 g, 0.0541 mmol, 85%): mp 95-96 °C; IR (KBr)
υmax 7.58 (d, J = 9.0, 2H), 7.10 (d, J = 9.0, 2H), 6.19 (m, 2H), 4.02
(d, J = 5.6, 4H), 3.92 (s, 6H); 13C NMR 154.0, 134.8, 130.9, 128.3,
126.8, 120.2, 112.0, 57.3, 24.3; MS m/e 240 (Mþ), HRMS m/e for
C16H16O2 calcd (Mþ) 240.1150, found 240.1150.
2,7-Dimethoxy-1-(3-carbomethoxyprop-2-ynyl)naphthalene (14):
Method 3. To a solution of 7b (0.446 g, 0.782 mmol) in THF
(50 mL) at room temperature was added an excess of iodine (I2).
The solution was stirred for 3 h. Following the addition of aqueous
sodium bisulfate, the mixture was subjected to a conventional
extractive workup (Et2O). Purification by preparative TLC (1:1
petroleum ether:Et2O) gave 14 (0.218 g, 98% yield): mp 80-81 °C;
IR (KBr) υmax 2956, 2233, 1712, 1628; 1H NMR δ 7.72 (d, J = 9.0,
1H), 7.69 (d, J = 8.9, 1H), 7.22 (d, J = 2.4, 1H), 7.11 (d, J = 9.0,
1H), 7.05 (dd, J = 8.9, 2.4, 1H), 4.11 (s, 2H), 3.97 (s, 3H), 3.96 (s,
3H), 3.70 (s, 3H); 13C NMR 158.4, 154.6, 154.0, 133.7, 129.9, 128.9,
124.3, 116.1, 113.6, 110.1, 101.2, 87.7, 71.9, 56.1, 55.0, 52.2, 14.5; MS
m/e 284 (Mþ). Anal. Calcd for C17H16O4: C, 71.82; H, 5.67. Found:
C, 71.72; H, 5.47.
2,7-Dimethoxy-1-(3-carbomethoxypropyl)naphthalene (15). To a
solution of 14 (0.210 g, 0.739 mmol) in MeOH (20 mL) under H2
was added Rh/C (excess) at room temperature. The solution was
stirred for 6 h with monitoring by TLC. The suspension was filtered
and the solvent was removed under reduced pressure. Preparative
TLC (2:1 petroleum ether:Et2O) to give 15 (0.211 g, 99% yield): bp
170-175 °C (0.5 Torr); IR (KBr) υmax 2954, 1740, 1628; 1H NMR
δ 7.69 (d, J = 8.9, 1H), 7.66 (d, J = 8.9, 1H), 7.32 (d, J = 2.0, 1H),
7.12 (d, J = 8.9, 1H), 7.03 (dd, J = 8.9, 2.0, 1H), 3.98 (s, 3H), 3.93
(s, 3H), 3.70 (s, 3H), 3.11 (t, J = 7.6, 2H), 2.44 (t, J = 7.1, 2H), 2.00
(m, 2H); 13C NMR 174.1, 158.2, 155.0, 134.3, 129.9, 127.4, 124.7,
121.4, 115.7, 110.5, 101.9, 56.1, 55.1, 51.2, 33.5, 24.4, 24.2; MS m/e
288 (Mþ); HRMS m/e for C17H20O4 calcd (Mþ) 288.1362, found
288.1360.
1-(4-Hydroxy-4-methylpentyl)-2,7-dimethoxynaphthalene (16).
To a solution of 15 (0.114 g, 0.396 mmol) in Et2O (10 mL) at 0 °C
was added MeLi (1.9 mL, 1.5 M, 2.9 mmol). The solution was
stirred for 3 h, at which time aqueous NH4Cl was added and a
conventional extractive workup (Et2O) performed. The volatiles
were removed under reduced pressure. Purification by prepara-
tive TLC (1:1 petroleum ether:Et2O) gave 15 (0.103 g, 0.356
mmol, 90% yield): mp 45-46 °C; IR (KBr) υmax 3422 br, 2966,
1627 cm-1; H NMR δ 7.70 (d, J = 8.9, 1H), 7.66 (d, J = 8.9, 1H),
7.24 (d, J = 2.3, 1H), 7.13 (d, J = 8.9, 1H), 7.03 (dd, J = 8.9, 2.3,
1H), 3.952 (s, 3H), 3.945 (s, 3H), 3.07 (t, J = 7.6, 2H), 1.74 (m,
2H), 1.69 (m, 2H), 1.38 (br s, 1H), 1.23 (s, 6H); 13C NMR 158.0,
154.8, 134.1, 130.0, 127.1, 124.8, 122.6, 115.5, 110.8, 102.0, 70.9,
56.3, 55.1, 43.8, 29.1, 25.4, 24.4; MS m/e 288 (Mþ); HRMS m/e
for C18H24O3 calcd (Mþ) 288.1725, found 288.1713.
1,6-Dimethoxy-7,7-dimethyl-7,8,9,10-tetrahydrocyclohepta[de]-
naphthalene (18) and 2,7-Dimethoxy-1-(4-methylpent-3-enyl)naph-
thalene (19). To a solution of 16 (0.0750 g, 0.260 mmol) in CH2Cl2
(10 mL) was added one drop of H2SO4. The solution was refluxed
for 24 h. Water was added and a conventional extractive workup
performed CH2Cl2. Purification by preparative TLC (4:1 hexanes:
CH2Cl2) gave, in order of elution, 18 (0.0490 g, 70% yield) and 19
(0.0056 g, 8% yield) as a mixture. 18: mp 101 °C; IR (KBr) υmax
2929, 1612; 1H NMR δ 7.54 (d, J = 8.9, 1H), 7.52 (d, J = 8.8, 1H),
7.09 (d, J= 8.9, 1H), 7.06 (d, J= 8.8, 1H), 3.94 (s, 3H), 3.91 (s, 3H),
3.00 (br m, 2H), 1.95 (m, 2H), 1.69 (m, 2H), 1.52 (s, 6H); 13C NMR
158.8, 154.5, 137.6, 131.7, 127.3, 126.9, 125.4, 122.9, 112.1, 111.6,
57.4, 56.0, 41.1, 39.4, 25.5, 22.1; MS m/e 270 (Mþ); HRMS
m/e for C18H22O2 calcd (Mþ) 270.1620, found 270.1614. 19: 55-
56 °C; 1H NMR δ 7.69 (d, J = 9.4, 1H), 7.66 (d, J = 9.4, 1H), 7.25
(d, J=2.1, 1H), 7.13 (d, J = 8.7, 1H), 7.02 (dd, J=8.7, 2.1, 1H), 5.36
(t,J=7.2,1H),3.95(s,6H),3.05(m,2H),2.31(m,2H),1.73(s,3H),
1.61 (s, 3H); 13C NMR 158.1, 155.0, 134.2, 131.8, 130.0, 127.2, 124.8,
124.6, 122.7, 115.7, 110.9, 102.0, 56.5, 55.2, 28.2, 25.7, 25.5, 17.6;
HRMS m/e for C18H22O2 calcd (Mþ) 270.1620, found 270.1606.
(Mþ - 6CO), 654 (Mþ - 7CO), 626 (Mþ - 8CO), 598 (Mþ
-
9CO); HRMS m/e for C31H18Co4O14 calcd (Mþ - 4CO) 737.8228,
found 737.8201.
Dodecacarbonyl[μ-η4-(2,7-dimethoxy-6-(1-phenylprop-2-ynyl)-1-
(prop-2-ynyl)naphthalene)]tetracobalt (10f). Subjecting 8f (0.0372 g,
0.0632 mmol), 6a (0.0238 g, 0.0695 mmol), and BF3-OEt2 (24 μL,
0.19 mmol) to Method 1 gave product 10f (0.0380 g, 65% yield)
following flash chromatography (10:1 petroleum ether:Et2O) as
red brown viscous oil: IR (KBr) υmax 2929, 2089, 2049, 2018,
1629 cm-1; 1H NMR δ 7.80 (s, 1H), 7.66 (d, J=9.0, 1H), 7.51 (d,
J=7.6, 2H), 7.27-7.31 (apparent t, J=7.6, 2H), 7.21 (t, J=7.4,
1H), 7.17 (d, J=1.0, 1H), 7.07 (d, J=9.0, 1H), 6.46 (s, 1H), 6.05
(s, 1H), 5.88 (s, 1H), 4.60 (1/2 AB quartet, J=15.4, 1H), 4.52 (1/2
ABquartet, J = 15.4, 1H), 3.97 (s, 3H), 3.95 (s, 3H); 13C NMR
199.4, 155.7, 154.5, 144.0, 132.8, 131.4, 128.9, 128.6, 128.4, 126.9,
124.2, 119.8, 110.0, 101.1, 100.4, 96.0, 74.0, 73.5, 55.4, 55.2, 48.5,
29.6; MS m/e 884 (Mþ - CO), 856 (Mþ - 2CO), 828 (Mþ - 3CO),
800 (Mþ - 4CO); HRMS for C36H20Co4O14, calcd (Mþ - 4CO)
799.8384, found 799.8414.
2,7-Dimethoxy-1,8-di(prop-2-ynyl)naphthalene (11). To a solu-
tion of 9a (0.0970 g, 0.116 mmol) in acetone (30 mL) with silica gel
(0.600 g) was added ceric ammonium nitrate (0.360 g) at -78 °C.
The reaction was stirred for 4 h, followed by the addition of H2O
and filtration through Celite. After a conventional aqueous work-
up, the mixture was filtered through Celite and concentrated under
reduced pressure. Preparative TLC (10:1 petroleum ether:Et2O)
afforded, in order of elution, 9a (0.0350 g, 36% recovery) and 11
(0.0175 g, 57%, 89% based on recovered starting material). 11: mp
144-145 °C;IR(KBr) υmax 3291, 2932, 2107, 1618 cm-1;1HNMR
δ 7.72 (d, J = 9.0, 2H), 7.18 (d, J = 9.0, 2H), 4.31 (d, J = 2.6, 4H),
4.03 (s, 6H), 2.16 (t, J = 2.6, 2H); 13C NMR 156.7, 133.5, 130.1,
126.2, 117.3, 111.0, 84.7, 69.1, 56.9, 17.3; MS m/e 264 (Mþ);HRMS
m/e for C18H16O2 calcd (Mþ) 264.1150, found 264.1153.
1,8-Diallyl-2,7-dimethoxynaphthalene (12). To a solution of
11 (0.0200 g, 0.0758 mmol) in 20 mL of a mixture of ethyl
acetate:1-hexene:pyridine (10:1:1) was added Lindlar catalyst
(5 mol %) at room temperature. The reaction was stirred under
an H2 atmosphere for 3 h. The reaction mixture was filtered
through Celite, and the filtrate was concentrated under reduced
pressure. The residue was purified by preparative TLC (5:1
petroleum ether:Et2O) to give, in order of elution, 12 (0.0180 g,
0.0671 mmol, 89% yield, 98% based on recovered starting material)
and 11 (0.0018 g). 12: mp 93-94 °C (lit.20 mp 189.4-194 °C); IR
(KBr) υmax 3077, 2934, 1614 cm-1; 1H NMR δ 7.72 (d, J = 8.9,
2H), 7.18 (d, J= 8.9, 2H), 6.22 (m, 2H), 5.09 (dd J= 10.3, 1.9, 2H),
4.84 (dd, J = 17.3, 1.9, 2H), 3.93 (s, 6H), 3.91 (br s, 4H); 13C NMR
155.7, 139.0, 134.9, 129.4, 126.3, 120.4, 114.5, 111.0, 56.8, 30.9; MS
m/e 268 (Mþ); HRMS m/e for C18H20O2 calcd (Mþ) 268.1463,
found 268.1466.
(Z)-1,6-Dimethoxy-7,10-dihydrocyclohepta[de]naphthalene (13).
To a solution of 12 (0.0170 g, 0.0634 mmol) in CH2Cl2 (2 mL) was
added Grubbs’ 1 Catalyst (0.0027 g, 5 mol %) at room tempera-
ture. After 6 h, the mixture was filtered through Celite. The filtrate
was concentrated under reduced pressure and the crude product
was purified by preparative TLC (100:1 petroleum ether:Et2O) to
8266 J. Org. Chem. Vol. 75, No. 23, 2010

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Hexacarbonyl[μ-η4-(7-acetoxy-2-methoxy-1-(3-carbomethoxy-
prop-2-ynyl)naphthalene)]dicobalt (21). Subjecting 20 (0.249 g,
1.152 mmol), 6b (0.525 g, 1.27 mmol), and BF3-OEt2 (440 μL, 3.5
mmol) to Method 1 afforded 21 (0.609 g, 1.018 mmol, 88% yield),
following flash chromatographic purification (2:1 petroleum ether:
Et2O), as a viscous red-brown oil: IR (KBr) υmax 3004, 2952, 2099,
2063, 2029,1765, 1709; 1H NMR δ 7.82 (d, J = 9.0, 1H), 7.81 (d,
J = 8.8, 1H), 7.62 (d, J = 2.2, 1H), 7.25 (d, J = 9.0, 1H), 7.11 (dd,
J= 8.8, 2.2, 1H), 4.60(s, 2H), 3.95(s, 3H), 3.76(s, 3H), 2.33(s, 3H);
13C NMR 198.3, 170.7, 169.6, 155.0, 149.5, 133.4, 130.0, 129.0,
127.0, 120.2, 118.8, 114.3, 112.0, 98.7, 94.1, 55.4, 52.7, 28.4, 21.0;
MS m/e 542 (Mþ-2CO), 514 (Mþ-3CO), 486 (Mþ-4CO), 458
(Mþ-5CO), 430 (Mþ-6CO); HRMS m/e for C24H16Co2O11 calcd
(Mþ - 3CO) 513.9509, found 513.9511.
7-Acetoxy-2-methoxy-1-(3-carbomethoxyprop-2-ynyl)naph-
thalene (22). Subjecting 21 (0.284 g, 0.475 mmol) to Method
3 followed by recrystallization from Et2O afforded 22 (0.138 g,
93% yield): mp 132-133 °C; IR (KBr) υmax 2917, 2234, 1761,
1712; 1H NMR δ 7.80 (d, J = 8.9, 1H), 7.78 (d, J = 8.9, 1H), 7.61
(d, J = 1.9, 1H), 7.23 (d, J = 8.9, 1H), 7.14 (dd, J = 8.9, 1.9, 1H),
4.07 (s, 2H), 3.96 (s, 3H), 3.70 (s, 3H), 2.38 (s, 3H); 13C NMR 169.4,
154.7, 154.0, 149.5, 133.1, 129.9, 129.2, 126.9, 118.8, 114.8, 113.7,
112.7, 87.4, 72.0, 56.3, 52.3, 21.0, 14.6; MS m/e 312 (Mþ); HRMS
m/e for C18H16O5 calcd (Mþ) 312.0998, found 312.0991.
8.10 (br s, 1H), 7.65 (d, J = 8.8, 1H), 7.61 (d, J = 8.9, 1H), 7.33 (d,
J = 2.2, 1H), 7.08 (d, J = 8.9, 1H), 7.01 (dd, J = 8.8, 2.2, 1 H), 3.91
(s, 3H),2.95(brt, J= 7.0, 2H), 2.60 (br s, 1H), 1.65 (m, 4H), 1.21 (s,
6H); 13C NMR 154.6, 154.5, 134.4, 130.3, 127.3, 124.5, 122.1, 115.6,
110.7, 105.3, 72.0, 56.4, 43.5, 29.0, 25.4, 24.3; MS m/e 274 (Mþ);
HRMS m/e for C17H22O3 calcd 274.1569, found 274.1574.
6-Methoxy-10,10-dimethyl-8,9,10,10a-tetrahydrocyclohepta-
[de]naphthalen-1(7H)-one (27). To a solution of 26 (0.0625 g,
0.228 mmol) in CH2Cl2 (10 mL) was added one drop of H2SO4
at 0 °C. After 0.5 h of stirring, a conventional extractive workup
(CH2Cl2) followed by preparative TLC (10:1 petroleum ether:
Et2O) afforded 27 (0.0410 g, 70% yield): mp 85-87 °C; IR (KBr)
υ
max 2934, 1653, 1615 cm-1; 1H NMR δ 7.29 (d, J=9.7, 1H), 7.13
(d, J=8.4, 1H), 6.79 (d, J=8.4, 1H), 5.97 (d, J=9.7, 1H), 3.84
(s, 3H), 3.63 (s, 1H), 3.36 (m, 1H), 2.42 (m, 1H), 1.84 (m, 1H), 1.51
(m, 1H), 1.38 (m, 1H), 1.27 (m, 1H), 1.17 (s, 3H), 0.66 (s, 3H); 13
C
NMR 203.2, 157.7, 145.5, 140.8, 129.4, 127.9, 124.4, 123.5, 108.9,
58.3, 55.7, 43.2, 37.0, 27.5, 24.3, 21.5, 20.2; MS m/e 256 (Mþ);
HRMS m/e for C17H20O2 calcd 256.1463, found 256.1457.
2-Acetoxy-7-benzyloxynaphthalene (28). To a solution of
7-benzyloxy-2-naphthol (2.000 g, 7.991 mmol) in CH2Cl2
(50 mL) were added Et3N (2 mL, excess) and acetic anhydride
(2 mL, excess). After 1 h of stirring, the mixture was subjected to
a conventional extractive workup. Recrystallization from Et2O
afforded 28 (2.1958 g, 94% yield) as a white crystalline solid: mp
121 °C; IR (KBr) υmax 2938, 1751 cm-1; 1H NMR δ 7.78 (d, J=
8.9, 1H), 7.76 (d, J=8.9, 1H), 7.49 (d, J=7.4, 2H), 7.45 (d, J=2.2,
1H), 7.42 (apparent t, J = 7.5, 2H), 7.36 (t, J = 7.5, 1H), 7.22 (dd,
J = 8.8, 2.2, 1H), 7.19 (d, J = 2.2, 1H), 7.10 (dd, J = 9.0, 2.2, 1H),
5.19 (s, 2H), 2.36 (s, 3H); 13C NMR 169.5, 157.3, 149.0, 136.7,
135.0, 129.3, 129.1, 128.6, 128.0, 127.5, 127.0, 118.8, 118.7, 117.5,
107.1, 70.0, 21.1; MS m/e 292 (Mþ); HRMS for C19H16O3 calcd
292.1099, found 292.1097.
7-Acetoxy-1-(3-carbomethoxypropyl)-2-methoxynaphthalene (23).
To a solution of 22 (0.157 g, 0.503 mmol) in MeOH (15 mL) under
H2 was added Pd/C (excess). The solution was stirred for 6 h, follow-
ing which the suspension was filtered and the filtrate concentrated
under reduced pressure. Preparative TLC (1:1 petroleum ether:Et2O)
gave 23 (0.148 g, 93% yield) as colorless solid: mp 125 °C; IR (KBr)
υ
max 3067, 2950, 1759, 1734; 1H NMR δ 7.79 (d, J = 8.8, 1H), 7.72
(d, J = 9.0, 1H), 7.65 (d, J = 2.0, 1H), 7.22 (d, J = 9.0, 1H), 7.11
(dd, J=8.8, 2.0, 1H), 3.92(s, 3H), 3.68(s, 3H), 3.09(t, J=7.5, 2H),
2.42 (t, J = 7.5, 2H), 2.37 (s, 3H), 1.98 (m, 2H); 13C NMR 173.9,
169.5, 154.9, 149.1, 133.6, 129.9, 127.6, 127.1, 122.3, 118.4, 114.0,
112.7, 56.1, 51.2, 33.5, 24.7, 24.0, 21.1; MS m/e 316 (Mþ); HRMSm/
e for C18H20O5 calcd (Mþ) 316.1311, found 316.1316.
1-(3-Carboxypropyl)-7-hydroxy-2-methoxynaphthalene (24). To
a solution of 23 (0.117 g, 0.370 mmol) in methanol (20 mL) was
added an excess of sodium hydroxide. Following heating to reflux
for 18 h, the mixture was acidified (3 M HCl) and a conventional
extractive workup performed (Et2O). Recrystallization from CH2-
Cl2 afforded product 24 (0.0730 g, 76% yield): mp 164-165 °C;
IR (KBr) υmax 3385 br, 2924, 1703, 1626; 1H NMR (acetone-d6) δ
7.63 (d, J = 8.8, 1H), 7.62 (d, J = 9.0, 1H), 7.28 (br s, 1H), 7.11 (d,
J = 9.0, 1H), 6.93 (dd, J = 8.8, 2.1, 1H), 3.87 (s, 3H), 2.99 (t, J =
7.7, 2H), 2.35 (m, 2H), 1.85 (m, 2H); 13C NMR (acetone-d6) 174.5,
156.0, 155.1, 134.8, 130.2, 127.7, 124.5, 120.7, 115.7, 110.3, 104.8,
55.8, 33.3, 24.8, 24.1; MS m/e 260 (Mþ); HRMS m/e for C15H16O4
calcd (Mþ) 260.1049, found 260.1045.
6-Hydroxy-1-methoxy-9,10-dihydrocyclohepta[de]naphthalen-
7(8H)-one (25). A solution of polyphosphoric acid (PPA, ca. 0.1 g,
excess) and 24 (0.100 g, 0.385 mmol) in CH2Cl2 (20 mL) was heated
to reflux for 36 h. Water was added and the mixture was subjected to
a conventional extractive workup (CH2Cl2). Preparative TLC (2:1
petroleum ether:Et2O) gave 25 (0.075 g, 80% yield): mp 90 °C; IR
(KBr) λmax 3009, 2970, 1616 cm-1;1HNMRδ12.73 (s, 1H), 7.71 (d,
J = 8.9, 1H), 7.63 (d, J = 8.8, 1H), 7.12 (d, J = 8.8, 1H), 6.93 (d,
J=8.9,1H), 3.95(s, 3H), 3.01(t,J= 7.1, 2H), 2.71 (t, J=7.4, 2H),
2.39 (m, 2H); 13C NMR 207.4, 162.5, 157.3, 136.2, 135.7, 128.6,
123.2, 122.4, 116.5, 115.2, 110.3, 56.2, 42.3, 29.5, 25.4; MS m/e 242
(Mþ); HRMS for C15H14O3 calcd (Mþ) 242.0943, found 242.0931.
7-Hydroxy-1-(4-hydroxy-4-methylpentyl)-2-methoxynaphthalene
(26). To a solution of 23 (0.1030 g, 0.3259 mmol) in Et2O at 0 °C
was added MeLi (0.76 mL, 1.1 mmol, 1.5 M in Et2O). After 4 h of
stirring, aqueous NH4Cl was added. A conventional workup and
preparative TLC (1:1 petroleum ether:Et2O) gave 26 (0.0625 g,
70% yield): mp 140 °C;IR(KBr) υmax 3358, 2967 cm-1;1HNMRδ
Hexacarbonyl[μ-η4-(7-acetoxy-2-benzyloxy-1-(3-carbomethoxy-
prop-2-ynyl)naphthalene)]dicobalt (29).To a solution of 28 (0.2000 g,
0.6849 mmol) in CH2Cl2 (10 mL) was added 6b (0.3120 g, 0.7534
mmol) and Bu2BOTf (479 μL, 0.479 mmol) was added dropwise at
0 °C. After 1 h of continuous stirring, NH4Cl(aq) was added and the
mixture was subjected to a conventional extractive workup. The
residue was purified by flash chromatography (2:1 petroleum ether:
Et2O) to give 29 (0.4150 g, 90% yield) as a red brown solid: IR (KBr)
υ
max 2953, 2113, 2063, 2031, 1765, 1708 cm-1; 1H NMR δ 7.80 (d,
J = 8.8, 1H), 7.78 (d, J = 9.0, 1H), 7.65 (d, J = 2.1, 1H), 7.46 (d,
J = 7.2, 2H), 7.39 (apparent t, J = 7.2, 2H), 7.33 (t, J = 7.2, 1H),
7.31 (d, J = 9.0, 1H), 7.14 (dd, J = 8.8, 2.1, 1H), 5.28 (s, 2H), 4.68
(br s, 2H), 3.64 (s, 3H), 2.34 (s, 3H); 13C NMR 198.2, 170.5, 169.5,
154.2, 149.5, 136.8, 133.5, 130.1, 128.9, 128.6, 128.0, 127.34, 127.25,
121.0, 119.0, 114.6, 113.9, 98.3, 78.8, 70.9, 52.6, 28.9, 21.0; MS m/e
618 (Mþ - 2CO), 590 (Mþ - 3CO), 506 (Mþ - 6CO); HRMS m/e
for C30H20Co2O11 calcd (Mþ - 2CO) 617.9771, found 617.9773.
7-Acetoxy-2-benzyloxy-1-(3-carbomethoxyprop-2-ynyl)naph-
thalene (30). Subjecting 29 (0.3630 g, 0.5385 mmol) to Method
3 gave the crude reaction product, which upon recrystallization
from methanol gave 30 (0.1880 g, 90% yield): mp 144 °C; IR (KBr)
υ
max 2956, 2234, 1761, 1712 cm-1;1HNMRδ7.79 (d, J= 8.8, 1H),
7.75 (d, J = 9.0, 1H), 7.67 (d, J = 1.5, 1H), 7.49 (d, J = 7.5, 2H),
7.43 (apparent t, J= 7.5, 2H), 7.36 (t, J= 7.5, 1H), 7.26 (d, J=9.0,
1H), 7.17 (dd, J = 8.8, 1.5, 1H), 5.25 (s, 2H), 4.13 (s, 2H), 3.72 (s,
3H), 2.39 (s, 3H); 13C NMR 169.5, 154.14, 154.09, 149.6, 136.8,
133.3, 130.1, 129.3, 128.6, 128.1, 127.3, 119.2, 116.0, 114.4, 114.1,
87.4, 72.3, 71.4, 52.4, 21.2, 15.1; MS m/e 388 (Mþ); HRMS m/e for
C24H20O5 calcd 388.1311, found 388.1298.
7-Acetoxy-2-benzyloxy-1-(3-carbomethoxypropyl)naphthalene
(31). To a solution of 30 (0.2000 g, 0.5154 mmol) in ethyl acetate
(20 mL) under H2 was added Rh/C (excess) at room temperature.
The solution was stirred for 18 h with monitoring by TLC. The
suspension was filtered and the solvent was removed under
reduced pressure. Preparative TLC (2:1 petroleum ether:Et2O)
J. Org. Chem. Vol. 75, No. 23, 2010 8267

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gave 31 (0.1880 g, 93% yield): bp 180-185 °C (0.15 Torr); IR
(KBr) υmax 2956, 1763, 1731 cm-1; 1H NMR δ 7.81 (d, J = 8.8,
1H), 7.73 (d, J = 2.1, 1H), 7.72 (d, J = 8.9, 1H), 7.50 (d, J = 7.4,
2H), 7.44 (apparent t, J = 7.4, 2H), 7.37 (t, J = 7.4, 1H), 7.29 (d,
J = 8.9, 1H), 7.16 (dd, J = 8.8, 2.1, 1H), 5.22 (s, 2H), 3.64(s, 3H),
3.20 (t, J = 7.7, 2H), 2.46 (t, J = 7.4, 2H), 2.40 (s, 3H), 2.05 (m,
2H); 13C NMR 173.8, 169.5, 154.0, 149.0, 137.2, 133.6, 129.8,
128.4, 127.7, 127.5, 127.3, 127.0, 123.0, 118.6, 114.2, 114.1, 70.9,
51.2, 33.6, 24.7, 24.3, 21.0; MS m/e 392 (Mþ); HRMS m/e for
C24H24O5 calcd 392.1624, found 392.1610.
gave product 36 (0.0306 g, 94% yield): mp 145-146 °C; IR (KBr)
υ
max 3312 (br), 2968, 1635 cm-1; 1H NMR δ (DMSO-d6) 9.57 (s,
1H), 7.67 (d, J = 8.8, 1H), 7.51 (d, J = 8.3, 1H), 7.25 (d, J = 2.1,
1H), 7.07 (d, J = 8.3, 1H), 6.99 (dd, J = 8.8, 2.1, 1H), 4.09 (s, 1H),
2.87 (m, 2H), 2.41 (s, 3H), 1.57 (m, 4H), 1.08 (s, 6H); 13C NMR
(DMSO) 155.4, 133.7, 133.3, 132.4, 129.8, 126.8, 125.8, 125.5,
116.9, 105.1, 68.7, 44.0, 29.3, 28.8, 24.3, 19.8; MS m/e 258 (Mþ);
HRMS for C17H22O2 calcd (Mþ) 258.1620, found 258.1620.
6,10,10-Trimethyl-8,9,10,10a-tetrahydrocyclohepta[de]naphtha-
len-1(7H)-one (37). To a solution of 36 (0.0260 g, 0.101 mmol) in
CH2Cl2 (10 mL) was added H2SO4 (1 drop) and the solution was
stirred for 4 h. A conventional extractive workup (CH2Cl2) followed
by preparative TLC (1:4 hexanes:CH2Cl2) afforded product
37 (0.0210 g, 87% yield): mp 73-74 °C; IR (KBr) υmax 2955,
1654 cm-1; 1H NMR δ 7.33 (d, J = 9.8, 1H), 7.11 (1/2 AB quartet,
J=7.7, 1H), 7.08 (1/2 ABquartet, J=7.7, 1H), 6.05 (d, J=9.8, 1H),
3.66 (s, 1H), 2.99 (m, 1H), 2.70 (m, 1H), 2.36 (s, 3H), 1.90 (m, 1H),
1.55 (m, 1H), 1.32 (m, 1H), 1.21 (s, 3H), 1.19 (m, 1H), 0.67 (s, 3H);
13C NMR 203.6, 145.7, 138.9, 136.9, 128.9, 128.1, 126.6, 125.9, 58.2,
42.3, 37.4, 29.7, 26.8, 25.6, 24.9, 20.4, 19.9; MS m/e 240 (Mþ);
HRMS m/e for C17H20O calcd 240.1514, found 240.1518.
7-Acetoxy-1-(3-carbomethoxypropyl)-2-hydroxynaphthalene
(32). To a solution of 31 (0.1900 g, 0.4846 mmol) in ethyl acetate
(20 mL) under H2 was added Pd/C (excess) at room temperature.
The solution was stirred for 4 h with monitoring by TLC. The
suspension was filtered and the solvent was removed under
reduced pressure. Preparative TLC (1:1 petroleum ether:Et2O)
afforded 32 (0.1400 g, 96% yield): mp 80-81 °C; IR (KBr) υmax
3425 br, 2952, 1759, 1733 cm-1; 1H NMR δ 7.75 (d, J = 8.8, 1H),
7.572 (d, J = 8.8, 1H), 7.565 (d, J = 2.3, 1H), 7.25 (br, 1H), 7.073
(d, J = 8.8, 1H), 7.069 (dd, J = 8.8, 2.3, 1H), 3.74 (s, 3H), 3.02 (t,
J = 7.8, 2H), 2.43 (t, J = 6.8, 2H), 2.38 (s, 3H), 1.96 (m, 2H); 13
C
10a-Hydroxy-6,10,10-trimethyl-8,9,10,10a-tetrahydrocyclohepta-
[de]naphthalen-1(7H)-one (38) and (2R*,3R*,10aS*)-10a-Hydroxy-
6,10,10-trimethyl-8,9,10,10a-tetrahydrocyclohepta[de]naphthalen-
1(7H)-one 2,3-Oxide (39). To a solution of 37 (0.0200 g, 0.0833
mmol) in dry DMF (3 mL) was added NaH (0.0024 g, 0.10 mmol).
After the reaction mixture was stirred for 3 h in open air, it was
subjected to a conventional extractive workup (Et2O). Prepar-
tive TLC (1:1 hexanes:CH2Cl2) gave, in order of elution, 38
(0.0090 g, 42% yield) and 39 (0.0070 g, 31% yield). 38: mp
102 °C; IR (KBr) υmax 3450, 2959, 1657 cm-1; 1H NMR δ 7.29
(d, J = 9.8, 1H), 7.10 (d, J = 7.6, 1H), 6.95 (d, J = 7.6, 1H),
6.20 (d, J = 9.8, 1H), 4.40 (s, 1H), 3.64 (m, 1H), 2.79 (m, 1H),
2.34 (s, 3H), 2.33 (m, 1H), 1.83 (m, 1H), 1.45 (m, 1H), 1.29 (m,
1H), 0.82 (s, 6H); 13C NMR 205.6, 148.0, 143.5, 140.4, 138.8,
130.2, 128.8, 127.3, 123.1, 84.4, 42.4, 39.0, 27.9, 26.8, 23.2, 22.0,
21.5; MS m/e 256 (Mþ); HRMS m/e for C17H20O2 calcd
256.1463, found 256.1473. 39: mp 110-111 °C IR (KBr) υmax
3456, 2924, 1698 cm-1; 1H NMR δ 7.15 (1/2 AB quartet, J =
7.7, 1H), 7.11 (1/2 AB quartet, J = 7.7, 1H), 4.37 (s, 1H), 4.21 (d,
J = 4.2, 1H), 3.95 (d, J = 4.2, 1H), 3.46 (dd, J = 14.3, 14.3, 1H),
2.87 (dd, J= 14.3, 5.9, 1H), 2.49 (m, 1H), 2.35 (s, 3H), 1.78 (m, 1H),
1.58 (m, 1H), 1.26 (m, 1H), 1.03 (s, 3H), 0.84 (s, 3H); 13C NMR
212.1, 143.9, 139.3, 138.3, 130.2, 127.5, 127.2, 85.2, 59.5, 54.4, 43.7,
39.5, 28.7, 27.8, 25.7, 23.4, 21.7; MS m/e 272 (Mþ); HRMS m/e for
NMR 175.6, 170.0, 152.5, 149.0, 133.7, 130.0, 127.7, 127.1, 118.3,
118.2, 117.7, 113.7, 51.9, 32.6, 24.3, 23.8, 21.2; MS m/e 302 (Mþ);
HRMS m/e for C17H18O5 calcd 302.1154, found 302.1141.
7-Acetoxy-1-(3-carbomethoxypropyl)-2-(trifluoromethylsulfonyl-
oxy)naphthalene (33). To a solution of 32 (0.1700 g, 0.5629 mmol)
in CH2Cl2 (20 mL) were added pyridine (136 μL,1.69 mmol) and
Tf2O (105 μL, 0.625 mmol) sequentially. The reaction mixture was
stirred for 0.5 h. Following a coventional extractive workup
(CH2Cl2), preparative TLC (1:1 petroleum ether:Et2O) afforded
33 (0.2347 g, 96% yield) as a viscous oil: IR (KBr) υmax 2955, 1765,
1738 cm-1; 1H NMR δ 7.91 (d, J = 8.9, 1H), 7.86 (d, J = 2.1, 1H),
7.80 (d, J = 9.1, 1H), 7.37 (d, J = 9.1, 1H), 7.35 (dd, J = 8.9, 2.1,
1H), 3.72 (s, 3H), 3.17 (m, 2H), 2.48 (t, J = 7.3, 2H), 2.40 (s, 3H),
2.03 (m, 2H); 13C NMR 173.4, 169.4, 149.8, 145.5, 133.2, 130.7,
130.3, 129.8, 128.8, 122.2, 119.1, 118.5 (q, JCF=319.8), 115.9, 51.6,
33.4, 25.6, 24.8, 21.1; MS m/e 434 (Mþ); HRMS m/e for C18H17-
F3O7S calcd 434.0647, found 434.0641.
7-Acetoxy-1-(3-carbomethoxypropyl)-2-methylnaphthalene (34)
and 1-(3-Carbomethoxypropyl)-7-hydroxy-2-methylnaphthalene
(35). To a solution of Pd2(dba)3 (0.0058 g, 0.0063 mmol) and (2-
biphenyl)dicyclohexylphosphine (0.0045 g, 0.013 mmol) in anhy-
drous THF (20 mL) were added DABAL-Me3 (0.0987 g, 0.385
mmol in THF) and 33 (0.1860 g, 0.4281 mmol, in THF (2 mL))
sequentially. After 0.5 h of stirring, dilute HCl (1 M) was added.
After conventional extractive workup (Et2O), the residue was
subjected to preparative TLC, which afforded, in order of elution
(1:1 petroleum ether:Et2O), 34 (0.1080 g, 84% yield) and 35
(0.0080 g, 7% yield). 34: colorless crystals, mp 48 °C; (KBr)
1
C17H20O3 calcd 272.1412, found 272.1404. H NOESY spectral
studies showing cross peaks between the 0.84 ppm (methyl) and
4.37 ppm (hydroxy) resonances, along with cross peaks between
1.03 ppm (methyl) and both the 3.95 and 4.21 ppm (epoxide CH)
resonances support a cis-relationship between the OH and epoxy
functions.
3-Bromonaphthalene-2,7-diol (41). 41 was prepared according
to the method of Diederich:36 mp 187-188 °C (lit.36 mp
191-192 °C). This compound has >95% purity as determined
by 1H and 13C NMR spectroscopy.
6-Bromo-7-(methoxymethoxy)naphthalen-2-ol (42). 42 was
prepared according to the method of Diederich:27 mp 109-
110 °C (lit.27 107-108 °C). This compound has >95% purity as
determined by 1H and 13C NMR spectroscopy.
6-(Benzyloxy)-2-bromo-3-(methoxymethoxy)naphthalene (43).
43 was prepared according to the method of Diederich:27 mp
114-115 °C (lit.27 mp 114-115 °C). This compound has >95%
purity as determined by 1H and 13C NMR spectroscopy.
7-(Benzyloxy)-3-bromonaphthalen-2-ol (40). 40 was prepared
according to the method of Diederich:27 mp 153-154 °C (lit.27 mp
1
υmax 2951, 1769, 1736 cm-1; H NMR δ 7.81 (d, J = 9.0, 1H),
7.73 (d, J = 2.0, 1H), 7.63 (d, J = 8.5, 1H), 7.29 (d, J = 8.5, 1H),
7.19 (dd, J = 9.0, 2.0, 1H), 3.72 (s, 3H), 3.06 (m, 2H), 2.51 (s, 3H),
2.50 (t, J = 7.0, 2H), 2.39 (s, 3H), 1.96 (m, 2H); 13C NMR 173.8,
169.8, 148.6, 134.5, 133.9, 132.6, 130.6, 129.9, 129.0, 126.1, 119.7,
114.6, 51.5, 33.9, 28.0, 24.8, 21.2, 20.1; MS m/e 300 (Mþ); HRMS
m/e for C18H20O4 calcd 300.1362, found 300.1351. 35: viscous oil;
(KBr) υmax 3395 br, 2953, 1736 cm-1; 1H NMR δ 7.70 (d, J = 9.0,
1H), 7.56 (d, J = 8.5, 1H), 7.44 (d, J = 2.3, 1H), 7.14 (d, J = 9.0,
1H), 7.08 (dd, J = 8.5, 2.3, 1H), 3.76 (s, 3H), 3.01 (m, 2H), 2.52 (t,
J = 7.0, 2H), 2.47 (s, 3H), 1.95 (m, 2H); 13C NMR 174.4, 153.9,
133.6, 133.5, 133.1, 130.4, 127.9, 126.8, 126.1, 116.4, 105.9, 51.7,
33.9, 28.2, 24.5, 20.1; MS m/e 258 (Mþ); HRMS m/e for C16H18O3
calcd 258.1256, found 258.1259.
7-Hydroxy-1-(4-hydroxy-4-methylpentyl)-2-methylnaphthalene
(36). To a solution of 34 (0.0380 g, 0.127mmol)inEt2Oat0 °Cwas
added MeLi (0.59 mL, 1.5 M in Et2O, 0.89 mmol). After 4 h of
stirring, aqueous NH4Cl was added. After a conventional extrac-
tive workup (Et2O), preparative TLC (1:1 petroleum ether:Et2O)
(36) Martinborough, E.; Denti, T. M.; Castro, P. P.; Wyman, T. B.;
Knobler, C. B.; Diederich, F. Helv. Chim. Acta 1995, 78, 1037–1066.
8268 J. Org. Chem. Vol. 75, No. 23, 2010

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JOCArticle
153-154 °C). This compound has >95% purity as determined by
1H and 13C NMR spectroscopy.
136.8, 131.7, 128.5, 128.4, 127.8, 127.8, 127.3, 126.1, 120.5,
115.5, 113.4, 98.4, 78.7, 70.7, 52.5, 28.9, 27.6, 23.02, 22.95,
20.8; MS m/e 716 (Mþ); HRMS m/e for C33H26O11Co2 calcd
(Mþ - 6CO) 548.0473, found 548.0486.
2-Acetoxy-7-benzyloxy-3-bromonaphthalene (44). To a solu-
tion of 44 (1.500 g, 4.573 mmol) in CH2Cl2 (50 mL) was added
Et3N (1 mL, excess) and acetic anhydride (1 mL, excess). After
0.5 h, the reaction mixture was concentrated under reduced
pressure. Recrystallization from CH2Cl2:petroleum ether gave
44 as a colorless crystalline solid (1.624 g, 4.390 mmol, 96%): mp
125-126 °C (CH2Cl2-petroleum ether); IR (KBr) υmax 2940,
1773 cm-1; 1H NMR δ 8.03 (s, 1H), 7.65 (d, J = 9.0, 1H), 7.52
(d, J = 7.5, 2H), 7.51 (s, 1H), 7.46 (t, J = 7.5, 2H), 7.41 (t, J =
7.5, 1H), 7.25 (dd, J = 9.0, 2.5, 1H), 7.13 (dd, J = 2.5, 1H), 5.15
(s, 2H), 2.45 (s, 3H); 13C NMR 168.7, 157.3, 145.7, 136.3, 133.8,
131.7, 128.5, 128.3, 128.3, 128.0, 127.9, 127.4, 120.0, 112.0,
106.6, 69.8, 20.7; MS m/e 370 (Mþ); HRMS m/e for C19H15BrO3
calcd (Mþ) 370.0205, found 370.0193.
2-Acetoxy-7-benzyloxy-3-(prop-1-en-2-yl)naphthalene (45).
To a solution of Na2CO3 (0.746 g, 5.405 mmol) in degassed
water (3 mL) was added a solution of 44 (0.500 g, 1.351 mmol),
isopropenylboronic acid pinacol ester (508 μL, 2.70 mmol),
[Pd(PPh3)4] (0.078 g, 0.067 mmol), and LiCl (0.172 g, 4.054
mmol) in DME (20 mL). The resulting solution was stirred for
12 h at 80 °C before it was diluted with water. The crude product
was extracted from aqueous phase with Et2O. The organic
extract was dried over MgSO4, the solvent was evaporated to
obtain pure product 45 (0.359 g, 1.081 mmol, 80%) as a colorless
crystalline solid following flash chromatography (petroleum
ether:Et2O, 5:1): mp 91-92 °C; IR (KBr) υmax 2921, 1762,
1633 cm-1; 1H NMR δ 7.80 (obscured d, J=8.9, 1H), 7.79 (s,
1H), 7.56 (d, J = 7.3, 2H), 7.51 (s, 1H), 7.49 (apparent t, J = 7.6,
2H), 7.43 (t, J = 7.2, 1H), 7.31 (dd, J = 8.9, 2.5, 1H), 7.23 (dd,
J = 2.5, 1H), 5.37 (s, 1H), 5.28 (s, 1H), 5.21 (s, 2H), 2.40 (s, 3H),
2.28 (s, 3H); 13C NMR 169.3, 157.0, 146.5, 141.6, 136.6, 134.0,
133.1, 129.1, 128.4, 127.8, 127.7, 127.3, 127.0, 119.0, 118.6,
115.8, 106.4, 69.8, 23.4, 20.9; MS m/e 332 (Mþ); HRMS m/e
for C22H20O3 calcd (Mþ) 332.1412, found 332.1409.
Methyl 4-(7-Acetoxy-2-(benzyloxy)-6-isopropylnaphthalen-1-
yl)but-2-ynoate (48). To a solution of 47 (0.830 g, 1.16 mmol) in
THF (50 mL) was added I2 (excess). After 1 h, aqueous sodium
bisulfite was added. After a conventional workup (Et2O) and
removal of volatiles under reduced pressure, the resulting colorless
solid was recrystallizedfrommethanoltogive48 as colorless crystals
(0.435 g, 1.01 mmol, 87% yield): mp 92-93 °C;IR(KBr) υmax 2962,
2233, 1757, 1712 cm-1; 1H NMR δ 7.74 (d, J = 9.0, 1H), 7.71 (s,
1H), 7.59 (s, 1H), 7.48 (d, J = 7.3, 2H), 7.41 (apparent t, J = 7.4,
2H), 7.34 (t, J = 7.3, 1H), 7.26 (d, J =9.0, 1H), 5.25 (s, 2H), 4.12 (s,
2H), 3.72 (s, 3H), 3.11 (septet, J = 6.9, 1H), 2.43 (s, 3H), 1.33 (d,
J = 6.9, 6H); 13C NMR 169.7, 154.1, 153.4, 148.2, 137.6, 136.8,
131.6, 128.9, 128.6, 128.0, 127.3, 127.2, 126.2, 115.5, 115.1, 114.6,
87.6, 72.2, 71.4, 52.4, 27.7, 23.0, 21.0, 15.0; MS m/e 430 (Mþ);
HRMS m/e for C27H26O5 calcd (Mþ) 430.1780, found 430.1797.
Methyl 4-(7-Acetoxy-2-hydroxy-6-isopropylnaphthalen-1-yl)-
butanoate (49). To a solution of 48 (0.530 g, 1.23 mmol) in
ethyl acetate (20 mL) was added excess Pd/C. The reaction
mixture was stirred for 15 h under an H2 atmosphere. The
mixture was filtered and the volatiles were removed under
reduced pressure to give a residue that was further subjected
to preparative TLC (petroleum ether:Et2O, 1:1) to give 49 as a
viscous oil (0.356 g, 1.03 mmol, 84%): IR (KBr) υmax 3427 br,
2962, 1756, 1735 cm-1; 1H NMR δ 7.67 (s, 1H), 7.56 (d, J=8.8,
1H), 7.50 (s, 1H), 7.12 (br s, 1H), 7.05 (d, J=8.8, 1H), 3.75 (s,
3H), 3.09 (septet, J = 6.8, 1H), 3.00 (t, J = 7.6, 2H), 2.42
(obscured m, 2H), 2.42 (s, 3H), 1.96 (m, 2H), 1.32 (d, J=6.8,
6H); 13C NMR 175.2, 170.3, 151.5, 147.4, 135.7, 132.0, 127.5,
127.0, 126.0, 118.1, 117.8, 114.7, 77.2, 51.5, 32.7, 27.4, 24.3, 23.7,
22.9, 20.8; MS m/e 344 (Mþ); HRMS m/e for C20H24O5 calcd
(Mþ) 344.1624, found 344.1622.
Methyl 4-(7-Acetoxy-6-isopropyl-2-(trifluoromethylsulfony-
loxy)naphthalen-1-yl)butanoate (50). To solution of 49 (0.346
g, 1.01 mmol) in CH2Cl2 (20 mL) were added (F3CSO2)2O
(204 μL, 1.21 mmol) and pyridine (204 μL, 3.02 mmol) at room
temperature. The solution was stirred for 0.5 h. After a conven-
tional extractive workup (CH2Cl2), the volatiles were removed
under reduced pressure to give a crude product, which was
subjected to preparative TLC (petroleum ether:Et2O, 5:1) to give
50 (0.396 g, 0.832 mmol, 83%) as a viscous oil: IR (KBr) υmax 2967,
1763, 1739 cm-1; 1H NMR δ 7.80 (s, 1H), 7.79 (s, 1H), 7.76 (d, J =
9.1, 1H), 7.34 (d, J = 9.1, 1H), 3.71 (s, 3H), 3.12-3.18 (m, 3H),
2.46 (t, J = 7.1, 2H), 2.44 (s, 3H), 2.03 (m, 2H), 1.33 (d, J = 6.9,
6H); 13C NMR 173.1, 169.2, 148.4, 144.8, 140.8, 131.3, 131.1,
129.2, 128.3, 126.3, 118.7, 118.4 (d, JCF = 319 Hz), 116.9, 51.1,
33.1, 27.7, 25.3, 24.7, 22.5, 20.6; MS m/e 476 (Mþ); HRMS m/e for
C21H23F3O7S calcd (Mþ) 476.1117, found 476.1115.
2-Acetoxy-7-benzyloxy-3-isopropylnaphthalene (46). To a so-
lution of 45 (0.500 g, 1.506 mmol) in ethyl acetate (25 mL) was
added Rh/C (0.0050 g). The reaction was stirred for 2 h under an
H2 atmosphere, with monitoring by TLC. The reaction mixture
was filtered and the solvents evaporated under reduced pressure to
afford a colorless solid, which upon recrystallization (petroleum
ether-Et2O) to give 46 as a colorless crystalline solid (0.463 g,
1.386 mmol, 92% yield): mp 91-92 °C; IR (KBr) υmax 2963, 1759
cm-1; 1H NMR δ 7.79 (d, J = 9.0, 1H), 7.77 (s, 1H), 7.55 (d, J =
7.2, 2H), 7.484 (apparent t, J = 7.3, 2H), 7.476 (s, 1H), 7.41 (t, J =
7.3, 1H), 7.28 (dd, J = 9.0, 2.5, 1H), 7.22 (dd, J = 2.5, 1H), 5.21 (s,
2H), 3.21 (septet, J = 6.9, 1H), 2.45 (s, 3H), 1.41 (d, J = 6.9, 6H);
13C NMR 169.6, 156.6, 147.5, 137.0, 136.7, 133.2, 128.9, 128.5,
127.9, 127.5, 127.4, 125.2, 118.8, 118.4, 106.5, 69.8, 27.7, 23.0,
20.9; MS m/e 334 (Mþ); HRMS m/e for C22H22O3 calcd (Mþ)
334.1569, found 334.1563.
Methyl 4-(7-Acetoxy-6-isopropyl-2-methylnaphthalen-1-yl)buta-
noate (51). To a solution of 50 (0.390 g, 0.819 mmol) in THF
(20 mL) were added Pd2(dba)3 (0.011 g, 0.012 mmol), dicyclohexyl-
(2-phenylphenyl)phosphane (0.0090 g, 0.026 mmol), and DABAL-
Me3 (0.168 g, 0.656 mmol). The reaction mixture was heated to
reflux for 1 h, followed by the addition of a dilute HCl solution.
After a conventional extractive workup (Et2O) and evaporation of
the volatiles under reduced pressure, the crude product was sub-
jected to preparative TLC (petroleum ether:Et2O, 5:1) to give 51
(0.255 g, 0.7456 mmol, 91%) as a viscous oil: IR (KBr) υmax 2962,
1760, 1737 cm-1; 1H NMR δ 7.75 (s, 1H), 7.72 (s, 1H), 7.63 (d, J =
8.2, 1H), 7.28 (d, J = 8.2, 1H), 3.74 (s, 3H), 3.16 (septet, J = 6.9,
1H), 3.07 (m, 2H), 2.52 (obscured m, 2H), 2.52 (s, 3H), 2.45 (s, 3H),
1.99 (m, 2H), 1.38 (d, J = 6.9, 6H); 13C NMR 173.6, 169.7, 147.2,
137.9, 134.0, 132.7, 131.0, 130.9, 128.8, 125.9, 125.6, 115.7, 51.3,
33.7, 27.8, 27.6, 24.8, 22.9, 20.9, 19.8; MS m/e342 (Mþ);HRMSm/e
for C21H26O4 calcd (Mþ) 342.1831, found 342.1824.
Hexacarbonyl[μ-η4-(methyl
4-(7-acetoxy-2-(benzyloxy)-6-
isopropylnaphthalen-1-yl)but-2-ynoate)]dicobalt (47). To a solu-
tion of 46 (0.600 g, 1.80 mmol) in CH2Cl2 (30 mL) was added
cobalt complex 6b (0.818 g, 1.98 mmol) and BF3-OEt2 (680 μL,
5.39 mmol) at 0 °C. The mixture was stirred for 4 h under
nitrogen and then NH4Cl(aq) was added. After a conventional
workup the volatiles were evaporated under reduced pressure
to give reddish brown solid, which was subjected to column
chromatography (petroleum ether:Et2O, 10:1) to give product
47 (1.145 g, 1.599 mmol, 89% yield) as a reddish brown solid:
mp 115 °C dec; IR (KBr) υmax 2964, 2095, 2058, 2031, 1759,
1706 cm-1; 1H NMR δ; 7.76 (d, J = 9.0, 1H), 7.72 (s, 1H), 7.62
(s, 1H), 7.48 (d, J = 7.3, 2H), 7.41 (apparent t, J = 7.4, 2H), 7.34
(t, J = 7.3, 1H), 7.30 (d, J = 9.0, 1H), 5.27 (s, 2H), 4.68 (br s,
2H), 3.66 (s, 3H), 3.14 (septet, J = 6.8, 1H), 2.39 (s, 3H), 1.35 (d,
J = 6.8, 6H); 13C NMR 198.2, 170.5, 169.6, 153.5, 148.1, 137.4,
J. Org. Chem. Vol. 75, No. 23, 2010 8269

Taj and Green
JOCArticle
8-(4-Hydroxy-4-methylpentyl)-3-isopropyl-7-methylnaphthalen-
2-ol (52). To a solution of 51 (0.221 g, 0.646 mmol) in Et2O
(20 mL) was added MeLi (1.5 M in Et2O, 3.0 mL, 4.5 mmol) at
0 °C. The reaction mixture was stirred for 6 h at which time
NH4Cl(aq) was added. The mixture was subjected to conventional
extractive workup (Et2O). The volatiles were evaporated under
reduced pressure to give a crude product, which was subjected to
preparative TLC (petroleum ether:Et2O, 1:1) to give 52 (0.178 g,
0.593 mmol, 92%) as a colorless solid: mp 141-142 °C; IR (KBr)
10a-Hydroxy-2-isopropyl-6,10,10-trimethyl-8,9,10,10a-tetra-
hydrocyclohepta[de]naphthalen-1(7H)-one ((()-Microstegiol)
(1). To a solution of 53 (0.052 g, 0.18 mmol) in DMF (10 mL)
was added NaH (0.0067 g, 0.28 mmol). The reaction mixture
was stirred for 12 h under oxygen. After a conventional
extractive workup (Et2O) and evaporation of volatiles under
reduced pressure, the crude product was subjected to prepara-
tive TLC (petroleum ether:Et2O, 50:1) to give 1 (0.035 g, 64%)
as a colorless solid: mp 57-58 °C (lit.1a (enantiomerically pure
υ
max 3348 br, 2963, 1630 cm-1; 1H NMR δ 7.61 (s, 1H), 7.54 (d,
material) mp 69-70 °C); IR (KBr) υmax 3443, 2962, 1654 cm-1
;
J = 8.3, 1H), 7.39 (br s, 1H), 7.33 (s, 1H), 7.13 (d, J = 8.3, 1H),
3.41 (septet, J = 6.9, 1H), 2.96 (m, 2H), 2.60 (br s, 1H), 2.46 (s,
3H), 1.73 (m, 4H), 1.37 (d, J = 6.9, 6H), 1.25 (s, 6H); 13C NMR
152.8, 135.8, 133.4, 132.0, 131.6, 128.0, 126.4, 125.6, 125.5, 105.8,
72.0, 43.8, 29.3, 29.1, 27.2, 24.4, 22.7, 20.1; MS m/e 300 (Mþ);
HRMS m/e for C20H28O2 calcd (Mþ) 300.2089, found 300.2085.
2-Isopropyl-6,10,10-trimethyl-8,9,10,10a-tetrahydrocyclohepta-
[de]naphthalen-1(7H)-one (53). To a solution of 52 (0.170 g,
0.566 mmol) in CH2Cl2 was added one drop of concentrated
H2SO4 at room temperature. The reaction mixture was stirred for
1 h. After a conventional extractive workup (CH2Cl2) and
evaporation of the volatiles under reduced pressure, the crude
product was subjectedtopreparative TLC(petroleum ether:Et2O,
20:1) to give 53 (0.130 g, 0.461 mmol, 81%) as a colorless solid: mp
46-47 °C; IR (KBr) υmax 2958, 1655 cm-1; 1H NMR δ 7.06 (m,
3H), 3.66 (s, 1H), 3.04 (apparent septet, J = 6.9, 1H), 2.96 (m,
1H), 2.67 (m, 1H), 2.34 (s, 3H), 1.87 (m, 1H), 1.49 (m, 1H), 1.36
(m, 1H), 1.25 (m, 1H), 1.17 (s, 3H), 1.16 (d, J = 6.9, 3H), 1.14 (d,
J = 6.9, 3H), 0.62 (s, 3H); 13C NMR 203.0, 143.0, 138.9, 138.6,
138.2, 135.4, 128.9, 128.7, 126.0, 58.3, 43.2, 37.3, 27.3, 26.4, 25.8,
24.3, 22.0, 21.8, 20.4, 20.3; MS m/e 282 (Mþ); HRMS m/e for
C20H26O calcd (Mþ) 282.1984, found 282.1991.
1H NMR δ 7.07 (d, J = 7.5, 1H), 6.97 (s, 1H), 6.91 (d, J = 8.0,
1H), 4.52 (s, 1H), 3.61 (apparent t, J = 13.1, 1H), 3.00 (apparent
septet, J = 6.9, 1H), 2.79 (ddd, J = 14.1, 6.4, 2.3, 1H), 2.37 (m,
1H), 2.33 (s, 3H), 1.82 (m, 1H), 1.47 (m, 1H), 1.29 (m, 1H), 1.21
(d, J = 6.0, 3H), 1.16 (d, J = 6.9, 3H), 0.80 (s, 3H), 0.79 (s, 3H);
13C NMR 206.1, 143.3, 141.0, 140.9, 139.3, 137.4, 130.1, 129.0,
126.7, 84.4, 42.9, 39.0, 28.0, 27.0, 26.8, 23.5, 22.1, 21.7; MS m/e
298 (Mþ); HRMS m/e for C20H26O2 calcd (Mþ) 298.1933,
found 298.1940.
Acknowledgment. The authors are grateful to NSERC
(Canada), the Canada Foundation for Innovation (CFI),
and the Ontario Innovation Trust (OIT) for support of this
research. The authors acknowledge Anusha Abhayaward-
hana for preliminary work on the substitution chemistry of
2,7-dioxygenated naphthalenes.
Supporting Information Available: 1H and 13C NMR spec-
tra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
8270 J. Org. Chem. Vol. 75, No. 23, 2010