Iron-catalyzed benzannulation reactions of 2-alkylbenzaldehydes and alkynes leading to naphthalene derivatives

Article abstract of DOI:10.1021/ol4000394

An efficient and practical method for the synthesis of naphthalene derivatives via Fe(III)-catalyzed benzannulation of 2-(2-oxoethyl)-benzaldehydes and alkynes has been developed. The system holds the advantages of cheap catalysts, wide substrate scope, and mild reaction conditions.

Full text of DOI:10.1021/ol4000394

ORGANIC
LETTERS
2013
Vol. 15, No. 4
898–901
Iron-catalyzed Benzannulation Reactions
of 2‑Alkylbenzaldehydes and Alkynes
Leading to Naphthalene Derivatives
Shifa Zhu,* Yelin Xiao,† Zhengjiang Guo,† and Huanfeng Jiang
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China
zhusf@scut.edu.cn
Received January 6, 2013
ABSTRACT
An efficient and practical method for the synthesis of naphthalene derivatives via Fe(III)-catalyzed benzannulation of 2-(2-oxoethyl)-benzaldehydes
and alkynes has been developed. The system holds the advantages of cheap catalysts, wide substrate scope, and mild reaction conditions.
Aromatic compounds are one of the most widely dis-
tributed classes of organic compounds in nature.1 Many
applications can be found in the fields of coal chemical
industry, medicinal chemistry, and material science.2
Among different aromatic compounds, naphthalene de-
rivatives have attracted much attention in the design of chiral
catalysts3 and advanced functional materials.2e,f There-
fore, methods for the synthesis of naphthalene derivatives,
especially the polysubstituted ones, is of great importance.
Lewis acid-catalyzed benzannulations of enynals with
unsaturated compounds (alkynes, alkenes, and enols) have
been proven to be one of the most powerful and reliable
approaches to naphthalene derivatives. For example,
Yamamoto and co-workers had developed a variety of
transition metal-catalyzed benzannulations of enynals with
alkynes or enols leading to naphthalenes.4aꢀd Recently, we
reported an efficient route to polysubstituted tetrahydro-
naphthols via silver-catalyzed [4 þ 2] cyclization of 2-alkyl-
benzaldehydes and alkenes5 (Scheme 1, eq 1). It is supposed
that the reaction proceeded via DielsꢀAlder reactions of
alkenes with benzo-1,3-butadienols (also called hydroxy-o-
quinodimethanes or o-QDMs), which was generated from
the enolization of 2-(2-oxoethyl)-benzaldehydes. Inspired
by these results, also as part of our continuous efforts to
† These authors contributed equally to this work.
(1) (a) Carmona, M.; Zamarro, M. T.; Blazquez, B.; Durante-
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(2) (a) Fang, X.-L.; Tang, R. Y.; Zhang, X.-G.; Zhong, P.; Deng,
C.-L.; Li, J.-H. J. Organomet. Chem. 2011, 696, 352. (b) Meyers, A. I.;
Willemsen, J. J. Tetrahedron Lett. 1996, 37, 791. (c) Medarde, M.;
Ramos, A. C.; Caballero, E.; Lopez, J. L. Tetrahedron Lett. 1996, 37,
2663. (d) Katritzky, A. R.; Zhang, G.; Xie, L. J. Org. Chem. 1997, 62,
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W.; Diele, S.; Pelzl, G. J. Mater. Chem. 2003, 13, 2104. (f) Reddy, R. A.;
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r
10.1021/ol4000394
Published on Web 01/29/2013
2013 American Chemical Society

Table 1. Optimized Reaction Conditionsa
Scheme 1
entry
cat.
1a:2a
sol.
time
5 h
yieldb
1
AgOTf
AgNTf2
AgBF4
AgSbF6
AgSbF6
AgSbF6
ZnCl2
1.0:5.0
1.0:5.0
1.0:5.0
1.0:5.0
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
87%
90%
92%
99%
98%
96%c
96%
98%c
trace
72%
trace
trace
trace
NR
2
5 h
3
5 h
4
5 h
5
5 h
6
20 min
20 min
20 min
5 h
7
develop the methods for the synthesis of benzannulated
structures, we envisaged that this method might be applied
to synthesize 1,4-dihydronaphthol A when alkynes were
used as the substrates instead (Scheme 1, eq 2).
8
FeCl3
CuCl2
FeCl3
9
10
11
12
13
14
15
5 h
FeCl3
5 h
We initiated our study with the benzannulation of 2-(2-
oxoethyl)-benzaldehyde 1a and phenylacetylene 2a upon
treatment with various Lewis acids. First, four different
silver salts were chosen as the catalysts because they were
the catalysts of choice for the corresponding alkenes
parterners.5 As summarized in Table 1, when the reactions
were conducted in DCE at room temperature by using 5.0
equivalents of phenylacetylene 2a, excellent yields can be
achieved with all four silver salts being tested (entries 1ꢀ4).
The decarboxylated naphthalene 3a, not 1,4-dihydro-
naphthols A, was obtained instead. Among four different
silver salts, AgSbF6 gave the product 3a in almost quanti-
tative yield (entry 4). Further experiments indicated that
the reaction can occur smoothly even with 1.1 equivalents
of phenylacetylene 2a at room temperature to afford 3a in
90% yield after 5 h (entry 5). More surprisingly, it was
found that the reaction actually completed in only 20 min
(entry 6). Except silver salts, Zn6 and Fe7 based catalysts
were also tested for this transformation owing to their
abundance, affordability, and environmental friendliness.8
When the reaction was treated with a catalytic amount
of ZnCl2 and FeCl3 in DCE, the desired naphthalene 3a
could be obtained in excellent yields as well (entries 7ꢀ8).
It is important to note that almost quantitative yield was
obtained in the case of FeCl3 system (entry 8). Interest-
ingly, only trace product was detected when CuCl2 was
used as the catalyst (entry 9). The reaction worked equally
well in DCM (entry 10). The coordinating solvents, such
as THF, EtOAc, or toluene, were not suitable for this
FeCl3
EtOAc
Toluene
DCE
DCE
5 h
FeCl3
5 h
5 h
TfOH
5 h
trace
a [1a] = 0.25 M. b NMR yield. c Isolated yield.
transformation (entries 11ꢀ13). The control reac-
tions indicated that the metal salts were essential for the
reactions (entry 14). Furthermore, only trace product
was detected when TsOH was used instead (entry 15),
which implied that the reaction was not a proton-catalyzed
reaction.
As shown in Table 1, the reaction could be efficiently
catalyzed by silver salts, ZnCl2, or FeCl3. In consideration
of the obvious advantages of iron,7,8 the substrate scope
was then examined by using FeCl3 as catalyst (Scheme 2).
As summarized in Scheme 2, the catalytic process could be
successfully applied to a variety of 2-ethanone benzalde-
hydes 1 and different kinds of alkynes substrates 2. For
example, when the analogues of 2-ethanone benzaldehyde
1a were used instead, the reactions proceeded efficiently as
well (3aꢀ3e, Scheme 2). Both electron-donating and electron-
withdrawing groups on the phenyl rings had little effects
upon the product yields. The yields of the products derived
from 2-ethanone benzaldehydes substituted with electron-
donating groups are generally lower than those with
electron-withdrawing groups. The reactions typically com-
pleted in 1ꢀ2 h at 60 °C. In addition to phenylacetylene 2a,
various terminal aromatic alkynes derivatives could be
effectively reacted with 1a as well (3fꢀ3i). The same trends
of the reaction yields were observed for different substituted
groups on the phenyl rings of phenylacetylene derivatives.
For example, the yield for 4-MeO-substitued phenylacety-
lene was 73% (3f); however, the yield for 3,5-ditrifluoro-
methyl-phenyl-acetylene was almost quantitative (3i). Term-
inal aliphatic alkynes, including linear (3j) and branched
ones (3k, 3l), were also successfully converted into the
desired products (63ꢀ92%). In addition to terminal alkynes,
internal alkynes (both symmetric and dissymmetric) could
(6) (a) Malosh, C. F.; Ready, J. M. J. Am. Chem. Soc. 2004, 126,
10240. (b) Patil, N. T.; Singh, V. Chem. Commun. 2011, 47, 11116. (c)
Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Angew. Chem., Int. Ed.
2011, 50, 11446.
(7) For recent reviews of iron catalysis, see: (a) Bolm, C.; Legros, J.;
Paih, J. L.; Zani, L. Chem. Rev. 2004, 104, 6217. (b) Enthaler, S.; Junge,
K.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 3317. (c) Sherry, B. D.;
€
Furstner, A. Acc. Chem. Res. 2008, 41, 1500. (d) Czaplik, W. M.; Mayer,
ꢀ
M.; Cvengros, J.; Wangelin, A. J. V. ChemSusChem. 2009, 2, 396. (e)
Iron Catalysis in Organic Chemistry; Plietker, B., Ed.; Wiley-VCH:
Weinheim, 2008.
(8) Senadi, G. C.; Hu, W.-P.; Hsiao, J.-S.; Vandavasi, J. K.; Chen,
C.-Y.; Wang, J.-J. Org. Lett. 2012, 14, 4478.
Org. Lett., Vol. 15, No. 4, 2013
899

Scheme 2. FeCl3-catalyzed Benzannulation of 2-(2-Oxoethyl)-
Benzaldehydes with Alkynesa
Scheme 3. FeCl3ꢀCatalyzed Benzannulation of 2-(2-Oxoethyl)-
Benzaldehydes with Dialkynes
and unstable substrate, could be used as substrate as well.
In this case, the desired TMS-substituted product 3z was
obtained in 87% yield.
Scheme 4. FeCl3-catalyzed Benzannulation of 2-(2-Oxoethyl)-
Benzaldehydes with Trialkynes
a Without other noted, the reaction was performed at rt using 5 mol %
FeCl3 under N2. R1 = Ph, [1] = 0.25 M. Yields refer to isolated yield.
60 °C.
be used as efficient substrates as well (3mꢀ3o). Haloaro-
matic compounds are extremely valuable not only as pre-
cursors of aryl-metals but also as substrates for transition
metal-catalyzed cross coupling reactions. When bromoalk-
ynes were used as the substrates, bromonaphthalenes (3pꢀ3s)
were obtained in 60ꢀ80% yields. The bromine atoms would
allow for further useful transformations.
Having established the reaction of 2-ethanone benzal-
dehydes 1 and alkynes 2 as a reliable and efficient synthetic
process, we are curious about the possibility to apply this
system to diynes or triynes. Two diynes 2u, 2v were then
prepared for this purpose (Scheme 3). As expected, under
the similar reaction conditions, both diynes could furnish
the benzannulation products 3u and 3v in good yields
(Scheme 3). In addition to diynes, triynes were also in-
vestigated. As shown in Scheme 4, terminal alkyne (2w),
internal alkyne (2x), and tribromoalkyne (2y) could afford
the desired products 3w, 3x, 3y in good to excellent yields.
Notably, three bromine atoms could be introduced when
tribromoalkyne 2y was used as substrate, a paddle wheel-
type molecule 3y was formed in 56% yield. More interest-
ingly, the TMS-protected trialkyne 2z, which is a fragile
900
Org. Lett., Vol. 15, No. 4, 2013

Scheme 5. Applications of Bromonaphthalene Derivatives
Scheme 6. Proposed Mechanism
benzannulation of 2-(2-oxoethyl)-benzaldehydes 1 and
alkynes 2. In addition to the simple alkynes, this system
could be successfully applied to different bromoalkynes,
diynes, and triynes. This system holds the advantages
of wide substrate scope and mild reaction conditions.
Furthermore, the obvious merits of FeCl3 employed in
this system make this system even more appealing for
construction of different types of naphthalene deriva-
tives. Further synthetic applications are underway in our
laboratory.
As mentioned above, bromine atoms could be intro-
duced into the naphthalene skeleton when bromoalkynes
were used as substrates. With the bromo-naphthalenes in
hands, we then explored the further chemical transforma-
tions. Taking 3p and 3y as examples, different applications
were then performed (Scheme 5). For instance, the 2-bro-
monaphthalene 3p could be efficiently converted into the
corresponding naphthalene derivatives 3m, 4, and5through
the well-established palladium-catalyzed Suzuki coupling
reaction, Sonogashira coupling reaction, and Buchwald
amination reaction in excellent yields (Scheme 5). Fur-
thermore, the trinaphthalenylbenzene 3x could also be
accessed through the Suzuki coupling reaction from 3y
in 60% yield.
A plausible mechanism as outlined in Scheme 6 was
proposed on the basis of our previous work.5 The reaction
commenced with the enolization of 1 to form the dienol I,
which then underwent an intramolecular nucleophilic attack
to form the hemiketal II. The hemiketal II was trapped by
alkyne 2 leading to the corresponding bridge intermediate
III. Driven by aromatization, the desired naphthalene pro-
duct 3 was then formed, accompanying with a carboxylic
acid (RCOOH) being released.
Acknowledgment. We are grateful to the National
NSFC (20902028 and 21172077), the Program for New
Century Excellent Talents in University (NCET-10-0403),
Guangdong NSF (10351064101000000), and The National
Basic Research Program of China (973) (2011CB808600)
for financial support. This project was also sponsored by
the Scientific Research Foundation for the Returned Over-
seas Chinese Scholars, State Education Ministry and The
Fundamental Research Funds for the Central Universities,
SCUT (2012ZZ0038).
Supporting Information Available. Typicalexperimental
procedure and characterization for all products. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
In summary, we have developed a very efficient method
for the synthesis of naphthalene derivatives via iron-catalyzed
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
901