FeCl3-catalyzed intramolecular hydroarylation of alkynes

Article abstract of DOI:10.1055/s-2008-1077954

The intramolecular hydroarylation of alkynes using a substoichiometric amount of FeCl₃ is described. When starting from tetrasubstituted substrates, products resulting from an unexpected toluene (or xylene) elimination are isolated in good yields.

Full text of DOI:10.1055/s-2008-1077954

LETTER
2033
FeCl3-Catalyzed Intramolecular Hydroarylation of Alkynes
F
eCl -Catalyzed
h
r
a
r
Hydro
i
a
rylati
s
onof
A
lky
t
nes ophe Dal Zotto, Johny Wehbe, David Virieux, Jean-Marc Campagne*
3
Institut Charles Gerhardt Montpellier, ENSCM, 8 rue de l’Ecole Normale, 34296 Montpellier, France
E-mail: jean-marc.campagne@enscm.fr
Received 16 April 2008
Abstract: The intramolecular hydroarylation of alkynes using a
FeCl3⋅6H2O
substoichiometric amount of FeCl3 is described. When starting from
(10 mol%)
tetrasubstituted substrates, products resulting from an unexpected
toluene (or xylene) elimination are isolated in good yields.
R
R
R
DCE, T
R
Key words: electrophilic aromatic substitutions, arylations, iron,
ring closure
1a (R = Tol)
2a
3a
4a
80 °C (GC yields)
r.t. (isolated yields)
2
84
52
<5
46
<5
The transition-metal-catalyzed hydroarylation of alkynes
has quite recently emerged as an efficient and atom-eco-
nomic methodology for the construction of functionalized
aromatic compounds and styrene derivatives.1–5
Scheme 2
These reactions might be considered as potential alterna-
tives to the well known Mirozoki–Heck and cross-cou-
pling reactions. Ruthenium-, rhodium-, platinum-,
gallium-, palladium-, indium-, mercury-, scandium- and
gold-catalyzed reactions have recently been described in
inter- and intramolecular hydroarylation reactions.1,2
However, the high cost and/or toxicity of such metals pre-
cludes their large-scale use. The development of this type
of atom-economic reaction with nontoxic and affordable
catalyst is thus highly desirable. As part of a program di-
rected toward the development of iron-catalyzed reac-
tions,6,7 the FeCl3-catalyzed intramolecular hydroaryl-
ation of alkynes was attempted (Scheme 1). During the
preparation of this manuscript, Lu reported the FeCl3-cat-
alyzed intermolecular hydroarylation of alkynes.8 Exam-
ples of intramolecular reactions were, however, restricted
to the synthesis of coumarins starting from phenylpropio-
lates.8 In this letter, we wish to present our preliminary re-
sults on the intramolecular hydroarylation of alkynes.
OMe
2c
82%
r.t., 0.5 h
Ph
2a
84%
r.t., 1 h
2b
72%
40 °C, 5 h
2d
86%
40 °C, 1.5 h
2e NO2
NR
2f
87%
r.t., 5 h
2g
72%
90 °C, overnight
40 °C, 5 h
Br
In the context of the synthesis of polyaromatic com-
pounds, the intramolecular hydroarylation of compound
1a was investigated (Scheme 2). Initial experiments at 80 °C
led to a complex mixture of the expected compound 2a
along with products 3a and 4a resulting from the formal
reduction and oxidation of 2a (Scheme 2). Gratifyingly,
2j
NR
80 °C, 3 h
2i
66%
r.t., 3 h
2h
68%
40 °C, 2 h
Figure 1
n
MX (cat.)
n
R1
R1
when the same reaction was carried out at room tempera-
ture, the amount of byproducts could be greatly reduced,
and compound 2a was isolated in 84% yield.
2
R2
1
R2
Scope and limitations were next explored and Figure 1
contains the results of an aromatic survey for this reaction.
The reaction with unsubstituted aromatics (compound 2b,
Figure 1) was somewhat tricky: whereas no reaction oc-
Scheme 1 Intramolecular hydroarylation of alkynes
SYNLETT 2008, No. 13, pp 2033–2035
x
x
.x
x
.2
0
0
8
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077954; Art ID: G12708ST
© Georg Thieme Verlag Stuttgart · New York

2034
C. Dal Zotto et al.
LETTER
R
Ar
R
Ar
R
FeCl3⋅6H2O
(10 mol%)
R
R
R
DCE, r.t. 1 h
R
R
R
7a R = H, 86% (1 h, r.t.)
7b R = Me, 96% (1 h, r.t.)
6a R = H
6b R = Me
5a R = H
5b R = Me
not observed
Scheme 3
curred at room temperature, at higher temperature (80 °C) References and Notes
redox byproducts 3b and 4b became predominant.
(1) For reviews, see: (a) Nevado, C.; Echavarren, A. M.
Synthesis 2005, 167. (b) Bandini, M.; Emer, E.; Tommasi,
S.; Umani-Ronchi, A. Eur. J. Org. Chem. 2006, 3527.
(2) For recent reports, see: (a) Bajracharya, G. B.; Pahadi, N.
K.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71,
6204. (b) Nakamura, I.; Mizushima, Y.; Yamamoto, Y.
J. Am. Chem. Soc. 2005, 127, 15022. (c) Yeh, M. P.; Tsao,
W. C.; Cheng, S. T. J. Org. Chem. 2008, 73, 2902.
(d) Oyamada, J.; Kitamura, T. Tetrahedron 2007, 63,
12754. (e) Saito, A.; Kanno, A.; Hanzawa, Y. Angew. Chem.
Int. Ed. 2007, 46, 3931. (f) Biffis, A.; Tubaro, C.; Buscemi,
G.; Basato, M. Adv. Synth. Catal. 2008, 350, 189. (g)Otani,
T.; Kunimatsu, S.; Nihei, H.; Abe, Y.; Saito, T. Org. Lett.
2007, 9, 5513. (h) Mamane, V.; Hannen, P.; Fuerstner, A.
Chem. Eur. J. 2004, 10, 4556. (i) Ferrer, C.; Echavarren, A.
M. Angew. Chem. Int. Ed. 2006, 45, 1105. (j) Jimenez-
Nunez, E.; Echavarren, A. M. Chem. Commun. 2007, 333.
(k) Tarselli, M. A.; Gagné, M. R. J. Org. Chem. 2008, 73,
2439. (l) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M.
Chem. Eur. J. 2007, 13, 1359. (m) Yamamoto, H.; Sasaki,
I.; Imagawa, H.; Nishizawa, M. Org. Lett. 2007, 9, 1399.
(n) Choi, D. S.; Kim, J. H.; Shin, U. S.; Deshmukh, R. R.;
Song, C. E. Chem. Commun. 2007, 3482. (o) Yoon, M. Y.;
Kim, J. H.; Choi, D. S.; Shin, U. S.; Lee, J. Y.; Song, C. E.
Adv. Synth. Catal. 2007, 349, 1725.
(3) For mechanistic issues, see: (a) Soriano, E.; Marco-
Contelles, J. Organometallics 2006, 25, 4542. (b) Nevado,
C.; Echavarren, A. M. Chem. Eur. J. 2005, 11, 3155.
(4) For the use of ICl activation, see: Worlikar, S. A.;
Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007,
72, 1347.
(5) For the synthesis of phenol from furan derivatives, see:
Hashmi, A. S. K.; Weyrauch, J. P.; Kurpejovic, E.; Frost,
T. M.; Michlich, B.; Frey, W.; Bats, J. W. Chem. Eur. J.
2006, 12, 5806; and references cited therein.
(6) (a) Michaux, J.; Terrasson, V.; Marque, S.; Wehbe, J.; Prim,
D.; Campagne, J. M. Eur. J. Org. Chem. 2007, 2601.
(b) Terrason, V.; Michaux, J.; Gaucher, A.; Wehbe, J.;
Marque, S.; Prim, D.; Campagne, J. M. Eur. J. Org. Chem.
2007, 5332. (c) Terrason, V.; Marque, S.; Gerogy, M.;
Campagne, J. M.; Prim, D. Adv. Synth. Catal. 2006, 348,
2063.
The key to success was to initiate the reaction by gentle
warming to 40 °C, and then carrying out the reaction over
five hours at this temperature to give 2b in 72% yield.
Various substituents on the aromatic ring were tolerated
(see 2c, 2d, 2f), except for strong electron-withdrawing
groups such as the nitro substituent (compound 2e), as ex-
pected for Friedel–Crafts type reactions.9 On the nucleo-
philic arene, alkyl and halogen substituents were well
tolerated and the corresponding cyclized products 2g and
2h were isolated in 72% and 68% yields, respectively
when the reaction was carried out at 40 °C. A limitation of
this methodology was observed with unsubstituted
alkynes (see 2j), where no reaction occurred.
This methodology was next extended to the cycloisomer-
ization of compounds 5a and 5b. Surprisingly, the expect-
ed compounds 6a and 6b were not observed, whereas
polyaromatic compounds 7a and 7b were isolated in 86%
and 96% yields, respectively (Scheme 3).
These products, probably resulting from the elimination
of toluene (R = H) or p-xylene (R = Me), were quite un-
expected. However, Klumpp has recently described the
elimination of a benzene group in somewhat related
Friedel–Crafts reactions.10
In conclusion, we have shown that cheap and nontoxic
iron(III) chloride is able to promote atom-economic in-
tramolecular Friedel–Crafts hydroarylation of alkynes.11
The use of alternative solvents is currently under investi-
gation: dioxane and chloroform can also be used success-
fully in these reactions. However, these solvents require a
gentle warming to initiate the reaction, and subtle modifi-
cations of the reaction conditions to minimize the amounts
of byproducts 3 and 4. Further developments are currently
under investigation in our laboratory.
Acknowledgment
We are grateful to the CNRS for financial support (ATIPE jeune
équipe) and the Institut de Chimie des Substances Naturelles for a
grant (CDZ).
Synlett 2008, No. 13, 2033–2035 © Thieme Stuttgart · New York

LETTER
FeCl3-Catalyzed Intramolecular Hydroarylation of Alkynes
2035
(7) (a) For an authoritative review on iron-catalyzed reactions,
see: Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev.
2004, 104, 6217. (b) Fürstner, A.; Majima, K.; Martin, R.;
Krause, H.; Kattnig, E.; Goddard, R.; Lehmann, C. W. J. Am.
Chem. Soc. 2008, 130, 1992. (c) Bistri, O.; Correa, A.;
Bolm, C. Angew. Chem. Int. Ed. 2008, 47, 586. (d) Casey,
C. P.; Guan, H. J. Am. Chem. Soc. 2007, 129, 5816. (e) Li,
Z.; Cao, L.; Li, C. J. Angew. Chem. Int. Ed. 2007, 46, 6505.
(f) Volla, C. M. R.; Vogel, P. Angew. Chem. Int. Ed. 2008,
47, 1305. (g) Shaikh, N. S.; Enthaler, S.; Junge, K.; Beller,
M. Angew. Chem. Int. Ed. 2008, 47, 2497.
effect of the nitro group which kills the Lewis acidity of
FeCl3.
(10) Li, A.; Kindelin, P. J.; Klumpp, D. A. Org. Lett. 2006, 8,
1233.
(11) General Procedure: To a solution of alkyne (0.2 mmol) in
1,2-dichloroethane (8 mL) under nitrogen was added
iron(III) chloride hexahydrate (0.02 mmol, finely ground).
The mixture was then stirred at r.t. until completion of the
reaction (TLC monitoring). The mixture was concentrated
under vacuum and the crude material was loaded onto a
silica gel column and chromatographed with heptane to give
the cyclization product.
(8) Li, R.; Wang, S. R.; Lu, W. Org. Lett. 2007, 9, 2219.
(9) As pointed out by a referee, the lack of reactivity in
compound 2e can also be explained by some poisoning
Synlett 2008, No. 13, 2033–2035 © Thieme Stuttgart · New York