A highly selective cascade approach to diverse aromatic ring systems from simple aromatic aldehydes and propiolates

Article abstract of DOI:10.1021/ol060143b

A new triethylamine-catalyzed cascade reaction of aromatic aldehydes with propiolates has been developed. This serial multi-bond-forming process furnishes diverse polycyclic aromatic hydrocarbons, including naphthalenes, phenanthrenes, benzofurans, and 2,3,9,9a-tetrahydronaphtha-[2,3-b]furans. The chemical outcome of the process depends on the reaction temperature and can be tailored selectively by an appropriate choice of experimental conditions.

Full text of DOI:10.1021/ol060143b

ORGANIC
LETTERS
2
006
Vol. 8, No. 6
241-1244
A Highly Selective Cascade Approach to
Diverse Aromatic Ring Systems from
Simple Aromatic Aldehydes and
Propiolates
1
Yan-Guang Wang,* Sun-Liang Cui, and Xu-Feng Lin
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, P. R. China
orgwyg@zju.edu.cn
Received January 17, 2006
ABSTRACT
A new triethylamine-catalyzed cascade reaction of aromatic aldehydes with propiolates has been developed. This serial multi-bond-forming
process furnishes diverse polycyclic aromatic hydrocarbons, including naphthalenes, phenanthrenes, benzofurans, and 2,3,9,9a-tetrahydronaphtha-
[2,3-b]furans. The chemical outcome of the process depends on the reaction temperature and can be tailored selectively by an appropriate
choice of experimental conditions.
Cascade reaction has emerged as a powerful tool to create
molecular complexity from simple starting materials.
able and an economical synthetic method for introducing
1
,2
1
chemical and structural complexity. Recently, Garc ´ı a-
2
Unlike stepwise bond formation toward a target molecule,
such process has the advantages of greatly enhanced synthetic
efficiency, while generating less waste and minimizing the
excessive handling. Particularly when catalytic possibility
exists, this type of transformation becomes extremely valu-
Tellado et al. reported that a triethylamine-catalyzed cascade
reaction of aliphatic aldehydes with methyl propiolate
afforded either enol-protected functionalized propargylic
alcohols (at 0 °C) or 1,3-dioxolanes (at -78 °C). As a part
of our research program aiming at developing multicompo-
nent cascade reactions for the synthesis of substituted
3
(
1) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (b) Seigal, B. A.;
Fajardo, C.; Snapper, M. L. J. Am. Chem. Soc. 2005, 127, 16329-16332.
c) Ohno, H.; Yamamoto, M.; Iuchi, M.; Tanaka, T. Angew. Chem., Int.
aromatic compounds, we herein report a new triethylamine-
catalyzed cascade reaction of aromatic aldehydes with
terminal conjugated acetylenes, which furnishes diverse
polycyclic aromatic hydrocarbons, including naphthalenes,
phenanthrenes, benzofurans, and 2,3,9,9a-tetrahydronaphtha-
[2,3-b]furans. The chemical outcome of the process depends
on the reaction temperature, and it can be tailored selectively
by an appropriate choice of experimental conditions.
As shown in Scheme 1, benzaldehydes 1 (0.67 equiv)
reacted with propiolates 2 (1.0 equiv) in the presence of a
(
Ed. 2005, 44, 5103-5106. (d) Kusama, H.; Yamabe, H.; Onizawa, Y.;
Hoshino, T.; Iwasawa, N. Angew. Chem., Int. Ed. 2005, 44, 468-470. (e)
de Meijere, A.; von Zezschwitz, P.; Br a¨ se, S. Acc. Chem. Res. 2005, 38,
4
13-422. (f) von Wangelin, J. A.; Neumann, H.; G o¨ rdes, D.; Klaus, S.;
Str u¨ bing, D.; Beller, M. Chem.sEur. J. 2003, 9, 4286-4294. (g) Neumann,
H.; von Wangelin, J. A.; Klaus, S.; Str u¨ bing, D.; G o¨ rdes, D.; Beller, M.
Angew. Chem., Int. Ed. 2003, 42, 4503-4507. (h) Ashfeld, B. L.; Miller,
K. A.; Smith, A. J.; Tran, K.; Martin, S. F. Org. Lett. 2005, 7, 1661-1663.
(
2
i) Fedou, N. M.; Parsons, P. J.; Viseux, E. M. E.; Whittle, A. J. Org. Lett.
005, 7, 3179-3182.
2) (a) Tejedor, D.; Garc ´ı a-Tellado, F.; Marrero-Tellado, J. J.; de Armas,
(
P. Chem.sEur. J. 2003, 9, 3122-3131. (b) de Armas, P.; Garc ´ı a-Tellado,
F.; Marrero-Tellado, J. J.; Tejedor, D.; Maestro, M. A.; Gonzalez-Platas, J.
Org. Lett. 2001, 3, 1905-1908.
(3) Cui, S. L.; Lin, X. F.; Wang, Y. G. J. Org. Chem. 2005, 70, 2866-
2869.
1
0.1021/ol060143b CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/22/2006

Scheme 1
Table 2. Triethylamine-Catalyzed Synthesis of Polysubstituted
Naphthalenes 4 and 5
product/yield (%)a
entry
R
Z
4
5
1
2
3
4
5
6
7
1a
1c
1d
1e
1f
2a
2a
2b
2a
2b
2a
2a
4a
4b
4c
4d
4e
4f
21
28
29
27
26
27
24
5a
5b
5c
5d
5e
5f
35
40
42
43
37
38
34
1g
1i
4g
5g
a
Isolated yield refers to propiolate.
crowded naphthalenes 3i and 3j (Route A) or 4g and 5g
(Route B), as structurally shown in Scheme 2. It was also
Scheme 2
catalytic amount of triethylamine (0.5 equiv) to give a
naphthalene derivative 3 in 45-66% yield when the reaction
was carried out in ClCH CH Cl at -20 to -10 °C for 5 h
2 2
and then at reflux for 8 h (Route A) (Table 1). When the
Table 1. Triethylamine-Catalyzed Synthesis of Polysubstituted
Naphthalenes 3
entry
R
Z
product yield (%)a
1
2
3
4
5
6
7
8
9
H (1a)
2-Me (1b)
4-Me (1c)
4-Et (1d)
CO2Et (2a)
CO2Me (2b)
3a
3b
3c
3d
3e
3f
3g
3h
3i
45
53
66
65
63
60
56
56
52
57
2a
2b
2a
2b
2a
2a
2a
4-Ph (1e)
found that 1-naphthaldehyde (1k) afforded a phenanthrene
derivative 3k in 58% yield (Scheme 3), and furan-2-
carbaldehyde (1l) gave a benzofuran derivative 3l (53%
yield) (Scheme 4, Route A) or 4h (30% yield) and 5h (21%
yield) (Scheme 4, Route B), respectively.
4-MeO (1f)
4-PhCH2O (1g)
4-TsO (1h)
3,4-dimethyl (1i)
1
0
3,4-OCH2O- (1j) 2a
3j
a
Isolated yield refers to propiolate.
Scheme 3
2 2
reaction was performed in CH Cl at -20 to -10 °C for 5
h and then at 25 °C for 8 h, products 4 and 5 instead of 3
were isolated in 56-71% total yields (Route B) (Table 2).
In all cases, no Z-isomers of the products were detected. The
syn and anti configurations of the products 4 and 5 were
4
assigned from NMR evidence, namely, JH1-H2. Trioctyl-
amine was also found to be able to promote this reaction
(see the Supporting Information).
It is noteworthy that presumably because of steric reasons
asymmetric benzaldehydes 1i and 1j furnished only the less
We subsequently performed analogous reactions using
electron-deficient benzaldehydes, such as 4-bromobenz-
aldehyde, and other terminal alkynes, such as 3-butyn-2-
one and ethynyl p-tolyl sulfone, but did not observe any of
the corresponding naphthalene derivatives.
(4) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982,
1
6
3, 1-115. (b) Fringuelli, F.; Piermatti, O.; Pizzo, F. J. Org. Chem. 1995,
0, 7006-7009.
1242
Org. Lett., Vol. 8, No. 6, 2006

Scheme 4
Figure 1. X-ray of compound 6b.
On the other hand, refluxing 4b and 5b in the presence of
triethylamine in ClCH CH Cl also yielded 3c (95%) and 1c.
2 2
In the absence of triethylamine, however, 4b, 5b, and 6b
are stable even at refluxing temperature. These results suggest
that compound 3 was formed by a retro-aldol reaction from
4 or 5, which in turn was generated from 6.
As the next step, we obtained intermediates 6 of this
cascade process by quenching the reaction with dilute acid
at -40 °C (Table 3). The structure of compound 6b was
Scheme 5
Table 3. Triethylamine-Catalyzed Synthesis of
2
,3,9,9a-Tetrahydronaphtha[2,3-b]furans 6
Further insight into the reaction mechanism was gained
by conducting a deuterium-labeling experiment, that is, the
yield (%)a
entry
R
product
reaction of C
6 5
H C(O)D ([D]1a) (98% D) with 1b (Scheme
1
2
3
4
1a
1c
1d
6a
6b
6c
6d
63
65
66
55
6
). The deuterated products [D]3a, [D]4a, [D]5a, and [D]6a
were isolated in 52, 21, 33, and 61% yields, respectively.
Herein we propose a plausible mechanism presented in
Scheme 7. Triethylamine as a nucleophile triggers the
cascade sequence and forms the enol-protected propargyl
4-t-Bu (1m)
a
Isolated yield refers to ethyl propiolate.
2,5
alcohol II. II then undergoes a Michael-type addition with
the acetylide I to produce III, which adds to benzaldehyde.
Intramolecular hydroarylation of the resulting IV, followed
by an intramolecular Michael addition, protonation, and a
triethylamine-catalyzed isomerization leads to intermediate
unambiguously established by X-ray crystallographic analysis
Figure 1) (see Supporting Information). Thus, triethylamine
alone is able to catalyze the formation of up to five new
C-C bonds and two new C-O bonds in one operation.
To understand the mechanism of our cascade process, we
examined the relationships between products 3-6 (Scheme
). It was found that compound 6b could be transformed to
naphthalene 3c (90%) along with 4-methylbenzaldehyde (1c)
by refluxing with triethylamine in ClCH CH Cl, while 4b
33%) and 5b (60%) were obtained by stirring 6b and
triethylamine in CH Cl at room temperature (Scheme 6).
(
6
. Furan ring of 6 is opened by triethylamine to give a
mixture of 4 and 5 at 25 °C. At higher temperature, further
transformation into 3 by a retro-aldol reaction ensues.
In summary, we have demonstrated that triethylamine
catalyzes the condensation of aromatic aldehydes with
5
2
2
(
(5) Tejedor, D.; Santos-Exp o´ sito, A.; Gonz a´ lez-Cruz, D.; Marrero-
2
2
Tellado, J. J.; Garc ´ı a-Tellado, F. J. Org. Chem. 2005, 70, 1042-1045.
Org. Lett., Vol. 8, No. 6, 2006
1243

Scheme 6
Scheme 7
propiolates to furnish diverse polycyclic aromatic hydrocar-
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (No. 20272051) and the Natural
Science Foundation of Zhejiang Province (R404109).
bons, including naphthalenes, phenanthrenes, benzofurans,
and 2,3,9,9a-tetrahydronaphtha[2,3-b]furans. The chemical
outcome of this serial multi-bond-forming process depends
on the reaction temperature, and it can be tailored selectively
by the appropriate choice of the experimental conditions. This
cascade process exhibits high bond-forming efficiency and
high regioselectivity. Studies to synthesize biologically
important aromatic compounds using this approach are in
progress and will be reported in due course.
Supporting Information Available: Detailed experi-
1
mental procedures, characterization data, copies of H and
1
3
C NMR spectra for all products and crystallographic
information files (CIF) for compound 6b. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL060143B
1244
Org. Lett., Vol. 8, No. 6, 2006