Synthesis of naphthalenes through three-component coupling of alkynes, fischer carbene complexes, and benzaldehyde hydrazones via isoindole intermediates

Article abstract of DOI:10.1021/ol800242n

The synthesis of naphthalene derivatives through three-component coupling of 2-alkynylbenzaldehyde hydrazones with carbene complexes and electron-deficient alkynes has been examined. The reaction involves formation of an isoindole derivative, followed by intramolecular Diels-Alder reaction, followed by nitrene extrusion. The reaction was highly regioselective using unsymmetrical alkynes.

Full text of DOI:10.1021/ol800242n

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1541-1544
Synthesis of Naphthalenes through
Three-Component Coupling of Alkynes,
Fischer Carbene Complexes, and
Benzaldehyde Hydrazones via Isoindole
Intermediates
Shaofeng Duan, Dilip K. Sinha-Mahapatra, and James W. Herndon*
Department of Chemistry & Biochemistry, New Mexico State UniVersity,
MSC 3C, Las Cruces, New Mexico 88003-8001
jherndon@nmsu.edu
Received February 1, 2008
ABSTRACT
The synthesis of naphthalene derivatives through three-component coupling of 2-alkynylbenzaldehyde hydrazones with carbene complexes
and electron-deficient alkynes has been examined. The reaction involves formation of an isoindole derivative, followed by intramolecular
Diels−Alder reaction, followed by nitrene extrusion. The reaction was highly regioselective using unsymmetrical alkynes.
Substituted naphthalene derivatives have emerged as very
important biological entities1 and frequently are employed
as starting materials for the preparation of more complex
polynuclear aromatic ring systems.2 A variety of methods
have been reported for their formation;2 however, the most
common strategy is to annulate a second aromatic ring onto
a preexisting benzene ring system. Multicomponent coupling
reactions offer an incredible level of diversity for the
production of diverse structural entities from a few simple
components.3 In this paper, a method that directly produces
substituted naphthalenes in a one-pot, three-component
coupling process will be presented.
Synthesis of substituted naphthalene derivatives (E, Scheme
1) using alkynylbenzaldehydes (A, Y ) O), Fischer carbene
complexes (B), and electron-deficient alkenes was recently
presented.4 This process involves generation of an isoben-
(1) Some representative examples from this century include: (a) Dalton
King, H.; Denhart, D. J.; Deskus, J. A.; Ditta, J. L.; Epperson, J. R.; Higgins,
M. A.; Kung, J. E.; Marcin, L. R.; Sloan, C. P.; Mattson, G. K.; Molski, T.
F.; Krause, R. G.; Bertekap, R. L.; Lodge, N. J.; Mattson, R. J.; Macor, J.
E. Bioorg. Med. Chem. Lett. 2007, 17, 5647-5651. (b) Wang, Z.; Elokdah,
H.; McFarlane, G.; Pan, S.; Antane, M. Tetrahedron Lett. 2006, 47, 3365-
3369. (c) Saeki, K.; Matsuda, T.; Kato, T.; Yamada, K.; Mizutani, T.;
Matsui, S.; Fukuhara, K.; Miyata, N. Biol. Pharm. Bull. 2003, 26, 448-
452. (d) Hartmann, R. W.; Palusczak, A.; Lacan, F.; Ricci, G.; Ruzziconi,
R. J. Enz. Inhib. Med. Chem. 2004, 19, 145-155.
(3) (a) Banfi, L.; Guanti, G.; Riva, R.; Basso, A. Curr. Opin. Drug Disc.
DeVel. 2007, 10, 704-714. (b) Ulaczyk-Lesanko, A.; Hall, D. G. Curr.
Opin. Chem. Biol. 2005, 9, 266-276.
(2) de Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L. Tetrahedron
2002, 59, 7-36.
(4) Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2, 1267-1269.
10.1021/ol800242n CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/20/2008

nitrogen of a pyrrole or isoindole ring contains an amino
group, then azanorbornenes produced in the Diels-Alder
reactions can undergo nitrene extrusion reactions to directly
afford aromatic systems.6 Aminoisoindoles have limited
precedent in cycloaromatization reactions.7
Scheme 1
The three-component coupling of hydrazone 1a, methyl-
carbene complex 2a, and DMAD (3a) was tested initially
(Table 1, entry A-1). This reaction led to the naphthalene
derivative 4a in high yield as the exclusive product of the
reaction. The reaction was next attempted with the less
activated alkyne ethyl propiolate (entries B-1, 2). This
cycloaddition reaction was considerably lower yielding but
was completely regioselective for the depicted isomer, 4b.
The yield was not improved by the addition of a larger excess
of ethyl propiolate (3b). The regiochemistry was easily
assigned based on the appearance of isolated doublets (J )
8.3 Hz) at δ 7.77 and δ 7.68. Use of ethanol as the solvent
led to the deep red Michael addition product 6b and not the
cycloaddition/nitrene extrusion product 4b (entry B-3). This
reaction pathway has been observed primarily for pyrrole
derivatives and in a few cases for isoindoles.8 Both N-
aminopyrroles and N-aminoisoindoles however engage pri-
marily in cycloaddition reactions with acetylenic esters.9 A
similar reaction using DMAD in ethanol also led to the
Michael addition product 6a as a mixture of stereoisomers
(entry A-2). Formation of 4 and 6 in the different solvents
likely reflects solvent polarity. The nonpolar Diels-Alder
reaction occurs in dioxane and the polar Michael addition
pathway in ethanol. The alkynyl ketone derivative 3c
underwent a similar cycloaddition reaction in higher yield
than the corresponding ester (see entry C). The silylated
alkyne analogue 3d, however, was not a suitable dienophile
zofuran (C) and Diels-Alder reaction to afford oxano-
bornene derivatives (D), which can subsequently transform
to naphthalenes through either dehydration (using alkene
dienophiles) or reduction (using alkyne dienophiles). High
product yields were limited to systems involving compara-
tively stable arylisobenzofuran intermediates (R2 ) Ph),
which offer sufficient lifetimes such that the carbene-alkyne
coupling and Diels-Alder reactions can be conducted in
separate events. In theory, if the isobenzofuran intermediate
could be stabilized, the versatility of a carbene complex-
based naphthalene synthesis could be improved substantially.
One potential solution is to employ isoindoles (C, Y ) NR)
in place of isobenzofurans. Isoindoles offer increased stability
relative to isobenzofurans yet still offer a high level of
reactivity in cycloaddition processes.5 In cases where the
Table 1. Three-Component Coupling of Benzaldehyde Hydrazones, Carbene Complexes, and Alkynes
entrya,b
reactants
R1
R2
EWG
R3
solventc
yield of 4d (%)
yield of 6 (%)
A-1
A-2
B-1
B-2Ie
B-3
C
D
E
F
G
1a + 2a + 3a
1a + 2a + 3a
1a + 2a + 3b
1a + 2a + 3b
1a + 2a + 3b
1a + 2a + 3c
1a + 2a + 3d
1a + 2b + 3a
1b + 2b + 3a
1a + 2c + 3a
1a + 2d + 3a
1a + 2a + 3e
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
H
Me
Me
Me
Me
Me
Me
Me
E
E
E
E
H
H
H
H
TMS
E
E
E
dioxane
ethanol
dioxane
dioxane
ethanol
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
90 (98)
0
30
10
0
72
0
72
75
95 (46)
86
85
79
COOEt
COOEt
COOEt
COPh
COPh
E
E
E
65
1-cyclohexenyl
1-cyclohexenyl
Ph
-(CH2)2CHdCH2
Me
TMS
TMS
TMS
H
I
E
E
CHdCHCOOEt
COOEt
a Table entry letters correlate with substituent identifiers for compounds 4-6. b Unless otherwise stated, the hydrazone, carbene complex, and dienophile
were used in a 1.0:1.3:5.0 ratio. c Reactions in dioxane were conducted at 80 °C; reactions in ethanol at reflux. d The yield in parentheses is the yield for
hydrolysis to form ketone 5. e In this experiment, 20 equiv of ethyl propiolate was employed.
1542
Org. Lett., Vol. 10, No. 8, 2008

(entry D). The Do¨tz benzannulation reaction10 does not
compete as noted by the successful three-component cou-
plings using R,â-unsaturated carbene complexes 2b,c (entries
E-G) and no formation of naphthalenes 8 or 9 (Figure 1).
Scheme 3
conducted (Scheme 3). If the reaction was performed without
a dienophile additive, several products were obtained after
an attempted chromatographic purification. The major and
only identifiable product was the N-aminolactam derivative
15 (35% yield), obtained through auto-oxidation of the
isoindole intermediate 14.12
Figure 1. Hypothetical side products from the reactions in
Table 1.
Acid-catalyzed hydrolysis of the DMAD adducts in Table
1 leads to compounds containing multiple carbonyl groups
(5). The DMAD-adduct 5a was examined in condensation
reactions to test for the possible formation of additional ring
system (Scheme 4). Reaction of 5a with sodium methoxide
Use of the γ,δ-unsaturated carbene complex 2d led to none
of the intramolecular Diels-Alder adduct 10; however, the
isoindole could be efficiently trapped using DMAD (entry
H). Use of the enyne diester dienophile 3e led to the
naphthalene derivative 4i in high yield as a single regioisomer
(entry I). Although the directly attached ester is intuitively
the stronger electron-withdrawing group, in related Diels-
Alder processes using enyne 3e the alkene acts as the stronger
electron-withdrawing group.11 This regiochemical assignment
was based on the appearance of a cross-correlation for the
naphthalene singlet (HA) and a carbonyl group in the HMBC
spectrum. Although unactivated alkynes were not suitable
dienophiles for the three-component naphthalene synthesis,
their use in intramolecular couplings was successful (Scheme
2). Coupling of alkynylphenylcarbene complex 11 with
alkyne hydrazone 1a led to the chrysene derivative 13.
Scheme 4
Scheme 2
led only to the lactonization product 17a and none of the
Claisen condensation product, phenanthrenediol derivative
18. Apparently enolate generation occurs exclusively at the
more acidic13 benzylic position and thus none of the
anticipated thermodynamic product 18 arising from depro-
tonation of the methyl ketone group of 5a was ever observed.
(6) Schultz, A. G.; Shen, M. Tetrahedron Lett. 1979, 20 2969-2972.
(7) Hart, H.; Lai, C. Y.; Nwokogu, G. C.; Shamouilian, S. Tetrahedron
1987, 43, 5203-24.
(8) Simons, S. S., Jr.; Ammon, H. L.; Doherty, R.; Johnson, D. F. J.
Org. Chem. 1981, 46, 4739-4744.
(9) Schultz, A. G.; Shen, M. Tetrahedron Lett. 1979, 20 2969-2972.
(10) Reviews of carbene complex-alkyne couplings: (a) Dotz, K. H.;
Tomuschat, P. Chem. Soc. ReV. 1999, 28, 187-198. (b) Wulff, W.D. In
ComprehensiVe Organic Synthesis; Trost, B.M., Fleming, I., Eds.; Perga-
mon: Oxford, 1991; Vol. 5, pp 1065-1113. (c) Barluenga, J.; Ferna´ndez-
Rodr´ıguez, M. A.; Aguilar, E. J. Organomet. Chem. 2005, 690, 539-587.
(11) Dai, M.; Sarlah, D.; Yu, M.; Danishefsky, S. J.; Jones, G. O.; Houk,
K. N. J. Am. Chem. Soc. 2007, 129, 645-657.
Simple isoindoles are typically unstable and difficult to
isolate. An attempt to isolate the isoindole intermediate was
(5) (a) Donohoe, T. J. Product class 14: 1H- and 2H isoindoles. Sci.
Synth. 2001, 10, 653-692. Recent examples have appeared. (b) Chen, Y.
L.; Lee, M. H.; Wong, W.; Lee, A. W. M. Synlett 2006, 2510-2512. (c)
Chen, Z. H.; Muller, P.; Swager, T. M. Org. Lett. 2006, 8, 273-276.
(12) Stobaugh, J. F.; Repta, A. J.; Sternson, L. A. J. Org. Chem. 1984,
49, 4306-4309.
Org. Lett., Vol. 10, No. 8, 2008
1543

Similarly, treatment of 5a with benzylamine led only to the
pyridone derivative 17b. The 2-azapyridine ring system has
been evaluated for cytotoxic and antiinflammatory proper-
ties.14 This represents a potentially diverse route to this ring
system.15
In summary, a new three-component coupling reaction for
the synthesis of naphthalene derivatives has been presented.
The reaction provides richly functionalized naphthalenes that
can undergo further annulation reactions to afford 2-aza-
phenanthrene ring system. The reaction can be diverted
toward the production of stable isoindole derivatives through
a change of the solvent from dioxane to ethanol. Reactions
employing alkynylated carbene complexes afford chrysene
rings in a single step in a net [5 + 5]-cycloaddition-nitrene
extrusion process.
(13) The experimental pKa in DMSO for phenylacetone is 19.9 and
acetone is 26.5. (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
(b) Fu, Y.; Liu, L.; Li, R. Q.; Liu, R.; Guo, Q.X. J. Am. Chem. Soc. 2004,
126, 814-822.
(14) (a) Chuang, T. H.; Lee, S. J.; Yang, C. W.; Wu, P. L. Org. Biomol.
Chem. 2006, 4, 860-867. (b) Anikina, L.V.; Vikharev, Yu. B.; Safin, V.
A.; Gorbunov, A. A.; Shklyaev, Yu. V.; Karmanov, V. I. Pharm. Chem. J.
2002, 36, 72-76.
(15) Synthetic approaches to this ring system have been the focus of
several investigations. (a) Carme Pampin, M.; Estevez, J. C.; Estevez, R.
J.; Maestro, M.; Castedo, L. Tetrahedron 2003, 59, 7231-7243. (b) Li,
A.; Kindelin, P. J.; Klumpp, D. A. Org. Lett. 2006, 8, 1233-1236. (c)
Arisvaran, V.; Ramesh, M.; Rajendran, S. P.; Shanmugam, P. Synthesis
1981, 821-823.
Acknowledgment. This research project was funded by
the SCORE program of NIH. We thank Prof. Dennis Johnson
for assistance in acquiring the 2D NMR spectra.
Supporting Information Available: Complete experi-
mental procedures and compound characterization data for
compounds 4a-c,d-i, 5a,g, 13, 15, and 17a,b. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL800242N
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Org. Lett., Vol. 10, No. 8, 2008