Regioselective Synthesis of Substituted Naphthalenes: A Novel de Novo Approach Based on a Metal-Free Protocol for Stepwise Cycloaddition of o-Alkynylbenzaldehyde Derivatives with Either Alkynes or Alkenes

Article abstract of DOI:10.1021/ol035691t

(Equation presented) Iodonium ions, o-alkynyl-substituted carbonyl compounds, and alkynes react to give 1-iodonaphthalene derivatives featuring interesting substitution patterns. The reaction with alkenes instead of acetylenes affords related naphthyl ketone derivatives. These two metal-free processes are conducted at room temperature and furnish products in a regioselective manner.

Full text of DOI:10.1021/ol035691t

ORGANIC
LETTERS
2
003
Vol. 5, No. 22
121-4123
Regioselective Synthesis of Substituted
Naphthalenes: A Novel de Novo
Approach Based on a Metal-Free
Protocol for Stepwise Cycloaddition of
o-Alkynylbenzaldehyde Derivatives with
Either Alkynes or Alkenes
4
Jos e´ Barluenga,* Henar V a´ zquez-Villa, Alfredo Ballesteros, and Jos e´ M. Gonz a´ lez
Instituto UniVersitario de Qu ´ı mica Organomet a´ lica “Enrique Moles”-Unidad Asociada
al C.S.I.C., UniVersidad de OViedo, Juli a´ n ClaVeria, 8, 33006 OViedo Spain
barluenga@sauron.quimica.unioVi.es
Received September 4, 2003
ABSTRACT
Iodonium ions, o-alkynyl-substituted carbonyl compounds, and alkynes react to give 1-iodonaphthalene derivatives featuring interesting
substitution patterns. The reaction with alkenes instead of acetylenes affords related naphthyl ketone derivatives. These two metal-free processes
are conducted at room temperature and furnish products in a regioselective manner.
The reactivity of carbon-metal bonds has been largely
exploited for the regioselective elaboration of substituted
naphthalenes. Thus, at the same time the basic aromatic core
Scheme 1
1
is assembled, a site-selective functionalization of naphthalene
is achieved, rendering straightforward access to otherwise
2
difficult substitution patterns. Recently, we have shown that
iodonium ions are a simple alternative to metal compounds
3
to accomplish valuable C-C bond forming reactions. Here-
in, we present recent findings on the preparation of substi-
tuted naphthalene compounds upon treatment of o-(alkynyl)-
benzaldehyde derivatives 1 with bis(pyridine) iodonium
4
tetrafluoroborate (IPy
BF
2 4
) and subsequent addition of either
an alkyne 2 or an alkene 5 (Scheme 1).
The cocyclization of acetylenic aldehydes 1 with different
mixing reagents at 0 °C, allowing the reaction mixture to
rise up to room temperature before adding 2a, and further
stirring the mixture for 1 h. Variable amounts of naphthyl
alkynes 2 mediated by IPy
resentative data are summarized in Scheme 2.
In a standard protocol, HBF is added to generate in
2 4
BF was initially explored. Rep-
5
(1) For recent examples, see: (a) Yasukawa, T.; Satoh, T.; Miura, M.;
4
Nomura, M. J. Am. Chem. Soc. 2002, 124, 12680. (b) Asao, N.; Takahashi,
K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,
solution a reactive form of the iodonium ion, by neutralizing
pyridine ligands. On this basis, a facile and regioselective
1
2650. (c) Viswanathan, G. S.; Wang, M.; Li, C.-J. Angew. Chem., Int. Ed.
6
2002, 41, 2138. (d) Huang, Q.; Larock, R. C. Org. Lett. 2002, 4, 2505. (e)
assembling of iodinated naphthalenes 3 was noticed upon
Miura, T.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 518.
1
0.1021/ol035691t CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/02/2003

Scheme 2
Table 1. Iodonaphthalene Derivatives 3
entry
product
R2
R3
t (h)
yield (%)a
1b
2b
3b
4b
5b
3a
3b
3c
3d
3e
Ph
n-Pr
4-MeO-C6H4
Ph
Ph
H
H
H
Me
CO Et
1
1
0.5
0.5
3
68
60
42
65
42
a
Yield based on the combined isolated amount of pure com-
2
b
pounds 3 and 4. Based on GC analysis of the crude reaction
mixture.
a
Isolated yield for compounds 3, referenced to 1b (1 mmol scale). b In
all cases the crude reaction mixture contained variable amounts of the
corresponding ketone 4 (see Scheme 1). Entry (GC ratio 3:4) from crude
reaction mixture: 1 (10:1), 2 (8:1), 3 (2.5:1), 4 (15:1), 5 (17:1).
ketone derivatives 4 were found as byproduct in this new
reaction. Initial studies addressed the influence that the
amount of acid has over the reaction outcome. As depicted,
no appreciable influence over the product distribution was
the transformation is more prone toward the formation of
compounds of type 3, as proved by higher values for the
ratio 3:4 in crude reaction mixtures. Thus, though pure 3e
was obtained in only moderate yield in a yet unoptimized
process, no significant amounts of the related naphthyl
ketones were isolable after chromatographic purification of
the crude reaction mixture.
1
noticed for R ) Ph, and only a slight increase in the
1
combined yield was observed. However, for R ) n-Bu,
higher selectivity in the synthesis of 3a is possible. Interest-
ingly, this selectivity was greatly increased when 2 equiv of
HBF were added. Consequently, 1b and addition of 2 equiv
4
of the acid were routinely employed to further investigate
other features of this uncommon iodo-benzannulation se-
quence. Some important results are summarized in Table 1.
Entries 1 and 2 show both aryl-2a and alkyl-substituted
terminal alkynes 2b can be selectively cross-coupled with
A mechanistic proposal accounting for the observed
products is outlined in Scheme 3. An initial attack of the
Scheme 3
1b to give compounds 3a and 3b, respectively. These re-
actions gave the desired iodinated compounds in satisfactory
isolated yield and, interestingly, proceeded in a regioselective
7
manner. Internal alkynes were also tested (see entries 4 and
5) and reacted according to a similar trend, opening a
convenient entry to a selective and direct elaboration of 1,2,3-
trisusbstituted naphthalenes. For the case of internal alkynes,
(2) To this aim, not only organometallic transformations but also
thermally and photochemically driven reactions have been reported. For
illustrative examples, see: (a) Rodr ´ı guez, D.; Navarro-V a´ zquez, A.; Castedo,
L.; Dom ´ı nguez, D.; Sa a´ , C. J. Org. Chem. 2003, 68, 1938. (b) Takahashi,
T.; Li, Y.; Stepnicka, P.; Kitamura, M.; Liu, Y.; Nakajima, K.; Kotora, M.
J. Am. Chem. Soc. 2002, 124, 576. (c) Rodr ´ı guez, D.; Navarro-V a´ zquez,
A.; Castedo, L.; Dom ´ı nguez, D.; Sa a´ , C. J. Am. Chem. Soc. 2001, 123,
8
iodonium ion to the alkyne moiety assisted by the neighbor-
9
178. (d) Bowles, D. M.; Anthony, J. E. Org. Lett. 2000, 2, 85. (e)
ing carbonyl functionality leads to the reactive benzo[c]-
pyrilium cation A. As earlier proposed for the AuCl -
3
catalyzed synthesis of naphthyl ketone derivatives, stepwise
cycloaddition of the alkyne onto the pyrilium system would
render intermediate C that determines the regioselectivity
of the process. From there, loss of iodonium ion affords the
minor reaction product 4, in a formally catalytic process.
Competitive retro [4 + 2] cycloaddition gives access to the
Yoshikawa, E.; Yamamoto, Y. Angew. Chem., Int. Ed. 2000, 39, 173. (f)
Pe n˜ a, D.; P e´ rez, D.; Guiti a´ n, E.; Castedo, L. J. Am. Chem. Soc. 1999, 121,
5
827. (f) de Frutos, OÄ ; Echavarren, A. M. Tetrahedron Lett. 1997, 38, 7941.
g) Takahashi, T.; Hara, R.; Nishihara, Y.; Kotora, M. J. Am. Chem. Soc.
996, 118, 5154. (h) Bradford, C.; Fleming, S. A.; Ward, S. C. Tetrahedron
Lett. 1995, 36, 4189.
3) Barluenga, J.; V a´ zquez-Villa, H.; Ballesteros, A.; Gonz a´ lez, J. M. J.
Am. Chem. Soc. 2003, 125, 9028.
4) For a recent synthetic application of this commercially available
9
(
1
10
(
(
reagent, see: Barluenga, J.; Trincado, M.; Rubio, E.; Gonz a´ lez, J. M. Angew.
Chem., Int. Ed. 2003, 42, 2406.
(
5) The structures for compounds 3 and 4 are based on their spectroscopic
and analytical data. For the case of 3d and 3e, 2D-NMR experiments
HMBC) confirmed the depicted structures (see Supporting Information).
(8) (a) Barluenga, J.; Rodr ´ı guez, M. A.; Campos, P. J J. Org. Chem.
1990, 55, 3104. (b) Barluenga, J.; Llorente, I.; Alvarez-Garc ´ı a, L. J.;
Gonz a´ lez, J. M.; Campos, P. J.; D ´ı az, M. R.; Garc ´ı a-Granda, S. J. Am.
Chem. Soc. 1997, 119, 6933. (c) See also ref 3.
(
For compounds 4, satisfactory comparison with already published data was
possible for some compounds (see characterization data in ref 1b).
(
6) See for instance: Barluenga, J.; Campos, P. J.; Gonz a´ lez, J. M.;
Su a´ rez, J. L.; Asensio, G. J. Org. Chem. 1991, 56, 2234.
7) No evidences for the formation of other regioisomers of compound
were obtained from GC analysis of crude reaction mixtures.
(9) For related intermediate species triggered by gold salts instead of
iodonium ions, see ref 1b.
(10) For the chemistry of this class of compounds, see: Kuznetsov, E.;
Shcherbakova, I. V.; Balaban, A. T. AdV. Heterocycl. Chem. 1990, 50, 157.
(
3
4122
Org. Lett., Vol. 5, No. 22, 2003

Table 2. Naphthyl Ketone Derivatives 4
Scheme 4
yield
t (h) (%)a
entry alkene product
R1
Ph
n-Bu Ph
R2
R3
1
2
3
4
5
6
5a
5a
5b
5c
5d
5e
4a
4b
4e
4f
4g
4h
Ph
H
H
H
Me
1
2
2
1
19
2
78
70
73
65
74
70
Ph
Ph
Ph
Ph
n-Bu
Ph
Ph
CO2Me
-CH2CH2CH2CH2-
enter in this approach to access ketones 4 (see entry 6). This
is a remarkable feature, because the resulting compound 4h
cannot be easily targeted from alternative approaches based
on simple alkynes.
a
Isolated yield for compounds 4, referenced to 1 (1 mmol scale).
major component 3. To support this mechanism, the quench-
ing of the reaction mixture with 1-octanol was investigated.
Interestingly, besides the desired naphthalene compounds,
significant amounts of octylpentanoate were found also to
be present in the crude reaction mixture, providing an
additional evidence for the participation of C in the formation
of iodonaphthalenes 3. Furthermore, differences between
C-Au and C-I bonds might account for a distinctive
reaction manifold, as observed for these approaches to the
construction of substituted naphthalene rings.
In terms of a plausible mechanistic interpretation for this
reaction and based on the previous observations for the parent
alkyne transformation, a related intermediate D can be
assumed. Loss of a proton would produce compound E, and
elimination of HI with concomitant aromatization easily
furnish 4 (Scheme 4).
In summary, new metal-free protocols for the synthesis
of different types of substituted naphthalenes have been
presented. The combination of 1, iodonium ions, and either
alkynes 2 or the convenient alkenes 5 drives complex reaction
sequences in a predictable manner and with attractiveness
for preparative purposes. In this synthetic scenario, the
adventage offered by a sole triggering element such as iodine
is unique. It suggests further developments, specially offering
valuable alternatives to transition-metal-mediated transforma-
tions.
We attempted to expand the scope of this iodonium-trig-
gered chemistry to allow for a synthetic entry to compounds
4. In this regard, we decided to explore the related process
using alkenes instead of alkynes in cyclization reactions with
compounds 1. Our preliminary results are summarized in
Table 2. A fast process takes place, resulting in an efficient
preparation of the target naphthyl ketone, as sole reaction
product. This new reaction offers a nice selectivity for the
Acknowledgment. This research was funded by DGI
(Grant BQU-2001-3853) and FYCYT (Grant PR-01-GE-09).
Predoctoral fellowship (MCYT) to H.V.-V. is gratefully
acknowledged. Generous support from Merck Sharp &
Dohme (UK) is gratefully acknowledged.
1
assayed alkenes 5. With respect to R in 1, both aliphatic
and aromatic substituents gave satisfactory results (entries
1
and 2). Both aliphatic- and aromatic-substituted terminal
alkenes are adequate components for this benzannulation
chemistry, though a longer reaction time (2 h) was required
for the former to raise a similar yield of the corresponding
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 3 and 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
4. Disubstituted alkenes (entries 4 and 5) offer an interesting
alternative to prepare 2,3-disubstituted 1-naphthyl ketones
in a very simple process, both in terms of the chemicals and
simplicity of the operational protocol. Cyclic alkenes also
OL035691T
Org. Lett., Vol. 5, No. 22, 2003
4123