Nucleophilic Partners in the Tandem Conjugate Addition-Dieckmann Condensation Reaction: 1. Synthesis of 1,2,3-Trisubstituted Naphthalenes

Article abstract of DOI:10.1021/jo035342c

The scope and limitations of the tandem conjugate addition-Dieckmann condensation for the construction of 1,2,3-trisubstituted naphthalenes is defined. Viable nucleophilic partners in this methodology include organocuprates, active methylenes, and a variety of heteroatom initiators.

Full text of DOI:10.1021/jo035342c

TABLE 1.
Nu cleop h ilic P a r tn er s in th e Ta n d em
Con ju ga te Ad d ition -Dieck m a n n
Con d en sa tion Rea ction : 1. Syn th esis of
1,2,3-Tr isu bstitu ted Na p h th a len es
Aaron D. Martinez, J ay P. Deville, J oel L. Stevens, and
Victor Behar*
entry
nucleophile
Me2CuLi
Bu2CuLi
time (h)
product
yield (%)
87
Department of Chemistry MS-60 Rice University,
Houston, Texas 77251-1892
1
2
3
1
2.5
4
2a
2b
2c
80
(Bu3Sn)2CuLi
recovered
starting
material
behar@rice.edu
4
5
6
7
8
NaCH(CO2Me)2
NaCH2NO2
NaOPh
p-MeOPhONa
p-ClPhONa
CH2CHCH2ONa
NaOAc
4
3
3
4
2.5
4
2d
2e
2f
2g
2h
2i
70
62
65
36
Received September 11, 2003
Abstr a ct: The scope and limitations of the tandem conju-
gate addition-Dieckmann condensation for the construction
of 1,2,3-trisubstituted naphthalenes is defined. Viable nu-
cleophilic partners in this methodology include organocu-
prates, active methylenes, and a variety of heteroatom
initiators.
53
9
10
complex mix
recovered
starting
material
75
53
67
84
4
2j
11
12
13
14
HCCCH2ONa
NaN3
PhSNa
1.5
3
12
3.5
2k
2l
2m
2n
(CuH‚Ph3P)6
Since the formal introduction of the Michael-induced
ring-closing (MIRC) reaction concept by Little in 1980,1
numerous accounts have appeared related to the utility
of tandem reactions initiated by Michael addition to
construct multicyclic arrays with remarkable atom
economy.2-5 We previously described the tandem conju-
gate addition-Dieckmann condensation strategy to ac-
cess type II polyketide structures tetracenomycin A26 and
the lactonamycin ABCD-ring system.7 The applicability
of this reaction sequence to the construction of highly
substituted naphthalenes was immediately recognized.
Aside from traditional synthetic sequences to substituted
naphthalenes such as the Stobbe condensation/Friedel-
Crafts cyclization,8 a recent method employing an anion-
accelerated electrocyclization to construct 1-naphthols
has been reported.9 The general approach to substituted
naphthalenes described herein involves the addition of
a nucleophile to an appropriately substituted phenyl
alkynyl ester with an ortho-disposed carbomethoxym-
ethylene group (Figure 1). Dieckmann condensation and
tautomerization affords fully aromatized 3-naphthol
products.
The model substrate, diester 1, has been previously
described and was considered appropriate for studying
the scope of the method. Initial experiments focused on
the addition of carbon-based nucleophiles. As seen in
Table 1, simple Gilman cuprate reagents10 (entries 1 and
2) participate quite well in the reaction. Unfortunately,
the corresponding stannyl cuprate reagents (entry 3)
failed to give the desired cyclization product. Indeed,
complete recovery of the starting material even under
forcing conditions led to the conclusion that such nucleo-
philes were too hindered to participate in the reaction.
In general, however, soft nucleophilic partners such as
active methylene compounds add in smoothly as exempli-
fied by addition of the anion of dimethylmalonate (entry
4) as well as the anion derived from nitromethane (entry
5).
Oxygen-based nucleophiles presented a significant
challenge (entries 6-11). Phenolic anions initiate the
cyclization in modest yields (entries 6-8). Access to biaryl
ether structures by this method provides an interesting
mild alternative to traditional Ullmann-type methods.11
Harder oxygen nucleophiles (allyloxy anion, entry 9)
failed to initiate the reaction presumably due to compet-
ing enolization of the benzylic ester and also in part due
to active transesterification processes. Acetate (entry 10)
was also a poor nucleophile for affecting cyclization.
Success was finally achieved utilizing the alkoxide of a
propargyl alcohol anion12 (entry 11), and this reaction
proceeded remarkably cleanly to afford cyclization adduct
2k in 75% yield. Presumably the greater acidity of
propargyl alcohol relative to its allyl counterpart provides
With the promise of generating unnatural analogues
of these polyketide structures, it was deemed necessary
to define the scope and limitations of this tandem
sequence.
(1) Little, R. D.; Dawson, J . R. Tetrahedron Lett. 1980, 21, 2609-
2612.
(2) Bunce, R. A. Tetrahedron 1995, 51, 13103-13159.
(3) Amputch, M. A.; Matamoros, R.; Little, R. D. Tetrahedron 1994,
50, 5591-5614.
(4) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131-163.
(5) Posner, G. H. Chem. Rev. 1986, 86, 831-844.
(6) Kozhinov, D.; Behar. V. J . Org. Chem. 2003, in press.
(7) Deville, J . P.; Behar, V. Org. Lett. 2002, 4, 1403.
(8) Bloomer, J . L.; Stagliano, K. W.; Gazzillo, J . A. J . Org. Chem.
1993, 58, 7906.
(9) Makra, F.; Rohloff, J . C.; Muehldorf, A. V.; Link, J . O. Tetrahe-
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2000, 2, 3967.
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10.1021/jo035342c CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/14/2004
J . Org. Chem. 2004, 69, 991-992
991

F IGURE 1. Tandem conjugate addition.
the softer nucleophilic character in its alkoxide required
for desired conjugate addition rather than to compete
with enolization. Confident in a method to introduce an
oxygen-based nucleophile to gain access to phenolic
structures, our attention turned to nitrogen nucleophilic
sources. Addition of azide (entry 12) provides access to
nitrogen-substituted naphthalenes in modest isolated
yield. Compromised yields are observed due to the
instability of the azide product upon silica gel chromato-
graphic purification. As expected, thiolate (entry 13) adds
in quite well as does the hydride-donating Stryker
reagent (entry 14).13
The utility of this sequence in the construction of
highly diverse naphthalene systems is realized by the
ready conversion of the 3-substituted phenolic products
to the corresponding triflate, which allows one to enter
the manifold of a variety of palladium-catalyzed cross-
coupling reactions.14-24 Additionally, the resultant ester
functionality at the 2-position gives access to a variety
of latent functional groups. Finally, in addition to gen-
erating type II polyketide analogues by this methodology,
the expansion of the tandem sequence to access a variety
of substituted heteroaromatic systems, including indoles,
quinolines, benzofurans, and benzothiophenes, is under
investigation. The results of this work will be reported
in due course.
Ack n ow led gm en t. This work was partially sup-
ported by a grant from the Robert A. Welch Foundation
(C-14189) and William Marsh Rice University. The
National Science Foundation (CHEM 0075728) provided
partial funds for the 400 MHz NMR instrument. A.D.M.
is supported by A.G.E.P. through a National Science
Foundation Cooperative Agreement (HRD-9817555).
Su p p or tin g In for m a tion Ava ila ble: Genereal procedures
and preparation of all compounds 2a ,b,d -h ,k -n , as well as
1
copies of H and 13C NMR. This material is available free of
(13) Chiu, P.; Li, Z.; Fung, K. C. M. Tetrahedron Lett. 2002, 44, 455.
(14) Shenglof, M.; Gelman, D.; Heymer, B.; Schumann, H.; Molan-
der, G. A.; Blum, J . Synthesis 2003, 302-306.
(15) Hanamoto, T.; Handa, K.; Mido, T. Bull. Chem. Soc. J pn. 2002,
75, 2497-2502.
charge via the Internet at http://pubs.acs.org.
J O035342C
(16) Wang, J .-Q.; Harvey, R. G. Tetrahedron 2002, 58, 5927-5931.
(17) Han, J . W.; Tokunaga, N.; Hayashi, T. Synlett 2002, 871-874.
(18) Molander, G. A.; Yun, C.-S. Tetrahedron 2002, 58, 1465-1470.
(19) Rao, M. L. N.; Yamazaki, O.; Shimada, S.; Tanaka, T.; Suzuki,
Y.; Tanaka, M. Org. Lett. 2001, 3, 4103-4105.
(20) Blum, J .; Katz, J . A.; J aber, N.; Michman, M.; Schumann, H.;
Schutte, S.; Kaufmann, J .; Wassermann, B. C. J . Mol. Catal. 2001,
165, 97-102.
(21) Garcia Martinez, A.; Osio Barcina, J .; del Rosario Colorado
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Bolm, C.; Hildebrand, J . P.; Rudolph, J . Synthesis 2000, 911-913.
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992 J . Org. Chem., Vol. 69, No. 3, 2004