Zirconocene-mediated synthesis of cyclobutabenzenes

Article abstract of DOI:10.1021/ol801652h

(Chemical Equation Presented) A new, mild, one-pot method for the synthesis of cyclobutabenzenes by the zirconium-promoted cross-coupling reaction of aryllithium compounds and alkenyl bromides is reported. Formation of an arynezirconocene complex and its regioselective coupling with an alkenyl bromide are the key steps of the process. This method allows the regio- and diastereoselective synthesis of functionalized cyclobutabenzene derivatives from simple and easily available starting materials.

Full text of DOI:10.1021/ol801652h

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4469-4471
Zirconocene-Mediated Synthesis of
Cyclobutabenzenes†
´
Jose´ Barluenga,* Jona´s Calleja, Mar´ıa J. Anto´n, Luc´ıa Alvarez-Rodrigo,
Fe´lix Rodr´ıguez, and Francisco J. Fan˜ana´s
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, Unidad
Asociada al CSIC, UniVersidad de OViedo, Julia´n ClaVer´ıa 8, 33006-OViedo, Spain
barluenga@unioVi.es
Received July 21, 2008
ABSTRACT
A new, mild, one-pot method for the synthesis of cyclobutabenzenes by the zirconium-promoted cross-coupling reaction of aryllithium compounds
and alkenyl bromides is reported. Formation of an arynezirconocene complex and its regioselective coupling with an alkenyl bromide are the
key steps of the process. This method allows the regio- and diastereoselective synthesis of functionalized cyclobutabenzene derivatives from
simple and easily available starting materials.
Cyclobutabenzenes (benzocyclobutanes) are very interest-
ing compounds because of their structural features and
important reactivity profile.1 They serve as synthons for
o-xylylenes upon thermal activation2 and as building blocks
for the synthesis of some natural products and drugs,3 and
they are beginning to find application in polymer chemistry
and material science.4 Although several methods have been
described for the synthesis of functionalized cyclobutaben-
zenes in the last three decades, many of these methods
involve (a) multistep routes, (b) unusual starting materials,
(c) low overall yields, or (d) special apparatus.5
Since a few years ago, we have been involved in the
development of a project regarding the reactivity of zir-
conocene complexes and heterosubstituted alkenes.6 In
particular, we are interested in the reactivity of enol ethers
and alkenyl halides.7 In this context, we found that cy-
clobutene derivatives could be obtained, under particular
conditions, by the reaction of alkyne-zirconocene complexes
and alkenyl bromides.8
† Dedicated to John M. Birmingham, one of the pioneers in organozir-
conium chemistry, on the occasion of his 80th birthday.
Taking into account that aryne-zirconocene complexes
could be considered as a particular class of alkyne-
zirconocene complexes, we reasoned that cyclobutaben-
(1) (a) Mychellys, P.-Y.; Pellissier, H.; Santelli, M. Org. Prep. Proced.
Int. 1996, 28, 545. (b) Segura, J. L.; Martin, N. Chem. ReV. 1999, 99, 3199.
(c) Mehta, G.; Kohta, S. Tetrahedron 2001, 57, 625.
(2) For reviews, see: (a) Nemoto, H.; Fukumoto, K. Tetrahedron 1998,
54, 5425. (b) Sadana, A. K.; Saini, R. K.; Billups, W. E. Chem. ReV. 2003,
103, 1539.
´
(6) Barluenga, J.; Rodr´ıguez, F.; Alvarez-Rodrigo, L.; Fan˜ana´s, F. J.
(3) For recent examples, see: (a) Mychellys, P.-Y.; Maurin, P.; Toupet,
L.; Pellissier, H.; Santelli, M. J. Org. Chem. 2001, 66, 115. (b) Yamamoto,
K.; Hentemann, M. F.; Allen, J. G.; Danishefsky, S. J. Chem.sEur. J. 2003,
9, 3242. (c) Matsuya, Y.; Masuda, S.; Itoh, T.; Murai, T.; Nemoto, H. J.
Org. Chem. 2005, 70, 6898. (d) Port, M.; Lett, R. Tetrahedron Lett. 2006,
47, 4677.
Chem. Soc. ReV. 2005, 34, 762.
´
(7) (a) Barluenga, J.; Alvarez-Rodrigo, L.; Rodr´ıguez, F.; Fan˜ana´s, F. J.;
Sordo, T. L.; Campomanes, P. Angew. Chem., Int. Ed. 2007, 46, 2607. (b)
´
Barluenga, J.; Alvarez-Rodrigo, L.; Rodr´ıguez, F.; Fan˜ana´s, F. J. Org. Lett.
´
2007, 9, 3081. (c) Barluenga, J.; Alvarez-Rodrigo, L.; Rodr´ıguez, F.;
Fan˜ana´s, F. J. Angew. Chem., Int. Ed. 2006, 45, 6362. (d) Barluenga, J.;
´
(4) (a) Jiang, T.; Rigney, J.; Jones, M.-C. G.; Markoski, L. J.; Spilman,
G. E.; Mielewski, D. F.; Martin, D. C. Macromolecules 1995, 28, 3301.
(b) Chino, K.; Takata, T.; Endo, T. Macromolecules 1995, 28, 5947. (c)
Kla¨rner, F.-G.; Lobert, M.; Naatz, U.; Bandmann, H.; Boese, R.
Chem.sEur. J. 2003, 9, 5036.
Ferna´ndez, A.; Alvarez-Rodrigo, L.; Rodr´ıguez, F.; Fan˜ana´s, F. J. Synlett
´
2005, 2513. (e) Barluenga, J.; Alvarez-Rodrigo, L.; Rodr´ıguez, F.; Fan˜ana´s,
F. J. Angew. Chem., Int. Ed. 2004, 43, 3932. (f) Barluenga, J.; Rodr´ıguez,
´
F.; Alvarez-Rodrigo, L.; Zapico, J. M.; Fan˜ana´s, F. J. Chem.sEur. J. 2004,
10, 109.
´
(5) Jakiela, D. J.; Helquist, P.; Jones, L. D. Organic Syntheses; Wiley:
New York, 1990; Collect. Vol. 7, p 326, and references therein.
(8) Barluenga, J.; Rodr´ıguez, F.; Alvarez-Rodrigo, L.; Fan˜ana´s, F. J.
Chem.sEur. J. 2004, 10, 101.
10.1021/ol801652h CCC: $40.75
Published on Web 09/19/2008
2008 American Chemical Society

zene derivatives could be easily available from simple
aryllithium compounds and alkenyl bromides as depicted
in Scheme 1. Details on the development of this strategy
are given in this paper.
and the reaction of both of the Csp2 of the alkenyl bromide.
This transformation is accomplished through non conven-
tional reactions of the starting materials: functionalization
of an aromatic C-H bond, substitution of a bromine atom
in an alkenyl bromide or a formal and net [2 + 2]
cycloaddition reaction between an aryllithium reagent and
an alkenyl bromide.
To expand the synthetic possibilities of this reaction, we
carried out a set of experiments adding different electrophiles
at the end of the reaction. Thus, the reaction of aryllithium
compounds 1 and zirconocene methyl chloride followed by
treatment with bromoalkene 2a and further reaction with
appropriate electrophiles led to the formation of the new
cyclobutabenzene derivatives 3h-n substituted at the 7- and
8-positions (Scheme 3 and Table 2). Notably, products 3h-n
Scheme 1
.
Proposal for the Zirconocene-Mediated Synthesis of
Cyclobutabenzene Derivatives
We initiated our study with the reaction of different
aryllithium compounds 1 with zirconocene methyl chloride
and bromoalkenes 2 using THF as solvent. Thus, after
heating the mixture at 80 °C in a sealed tube during 14 h
the reaction was quenched with H2O to obtain the function-
alized cyclobutabenzene derivatives 3a-g (Scheme 2 and
Scheme 3. Synthesis of Cyclobutabenzenes 3h-n from
Aryllithium Compounds 1, Alkenyl Bromide 2a, and
Electrophiles
Scheme 2. Synthesis of Cyclobutabenzenes 3a-g from
Aryllithium Compounds 1 and Alkenyl Bromides 2 Mediated by
were obtained as single regio- and cis-diastereoisomers.
Those examples where the reaction with the electrophile
implies the formation of a new carbon-carbon bond should
be remarked (reactions with phenyl iodide, allyl chloride,
and 2-cyclohexenone as electrophiles).
Zirconocene
Table 2. Cyclobutabenzenes 3h-n from Aryllithium
Compounds 1, Alkenyl Bromide 2a, and Electrophiles
Table 1). These compounds 3a-g were obtained in all cases
as single regioisomers. We only observed the formation of
that isomer in which the R1 group is far away from the R3
group.
1
R1 R2
E+
E
3
yielda (%)
1a Me
1a Me
1c OMe
1c OMe
1c OMe
H
H
H
H
H
H
H
allyl chlorideb
allyl
3h
76
74d
64
62
75
75
72
2-cyclohexenonec 3-oxocyclohexyl 3i
D2O
D
3j
3k
3l
3m
3n
allyl chlorideb
PhIe
allyl
Ph
D
Table 1. Cyclobutabenzene Derivatives 3a-g from Aryllithium
Compounds 1 and Bromoalkenes 2 Mediated by Zirconocene
1f
1f
H
H
D2O
allyl chlorideb
allyl
1
R1
R2
2
R3
3
yielda (%)
a Isolated yield based on starting 1. b CuCl (5 mol %) was also added.
The reaction was stirred at 60 °C for 6 h. c CuCl (5 mol %), LiCl (1 equiv)
and TMSCl (2 equiv) were also added. The reaction was stirred at 60 °C
for 6 h. d 4: 1 mixture of diastereoisomers. Isomers at the stereogenic center
of the cyclohexyl moiety. e CuCl (1.5 equiv), LiCl (1 equiv), and Pd(PPh3)4
(5 mol %) were also added. The reaction was stirred at 60 °C for 6 h.
1a
1b
1c
1c
1d
1d
1e
Me
Et
OMe
OMe
Ph
H
H
H
H
H
H
2ab
2ab
2ab
2bc
2ab
2cc
2ab
Me
Me
Me
Decd
Me
Bn
3a
3b
3c
3d
3e
3f
76
72
60
70
65
79
62
Ph
-(CH)4-
To gain further insight into the mechanism of formation
of cyclobutabenzenes 3, we performed the reaction of
organolithium 1d with zirconocene methyl chloride, and we
treated the reaction mixture with both 2a (cis-isomer) and
trans-2a followed by addition of a solution of DCl in D2O
(Scheme 4). As expected, the reaction with 2a led to cis-3o
in high yield. However, the reaction with trans-2a exclu-
Me
3g
a Isolated yield based on starting 1. b cis-Isomer. c trans-Isomer. d Dec
) decyl.
Noteworthy, this process supposes an easy functionaliza-
tion of two adjacent positions of the initial aromatic ring
4470
Org. Lett., Vol. 10, No. 20, 2008

a hydrogen atom to furnish the aryne-zirconocene complex
5 and a molecule of methane.9 The insertion reaction of the
corresponding alkenyl bromide 2 and complex 5 generates
the intermediates cis-6 or trans-6 depending on the structure
of the alkenyl bromide 2. It is important to note that the
insertion process is doubly regioselective: insertion occurs
at the zirconium-carbon bond of 5 which is far away from
the R1 group. Also, the double bond of the alkenyl bromide
2 is oriented during the insertion step so that the bromine
atom is close to the zirconocene moiety. An intramolecular
migratory insertion process is proposed to explain the
formation of the cyclobutene core observed in the final
products.10 This reaction leads to cis-7 from cis-6 and trans-7
from trans-6.
Scheme 4. Cyclobutabenzenes cis-3o and trans-3o by the
Zirconocene-Mediated Reaction of Aryllithium 1d with
Bromoalkenes 2a and trans-2a, Respectively
Regarding the diastereoselectivity of the reaction, it should
be noted that the migratory insertion process leading to cis-7
or trans-7 occurs with inversion of the configuration of the
carbon initially substituted by the bromine atom (SN2 like
process). Finally, the reaction of intermediate cis-7 or trans-7
with the corresponding electrophile leads, after the hydrolysis
step, to the final benzocyclobutane derivatives cis-3 or
trans-3 respectively (Scheme 5).
In summary, we have developed a new zirconocene-
mediated method for the selective synthesis of cyclobuta-
benzene derivatives through a three-component one-pot
coupling reaction of an aryllithium compound, an alkenyl
bromide, and an electrophile. The method is broad in scope,
and it offers the option of varying the substituents of both
the aryl moiety and the cyclobutene ring. This method
implies nonconventional transformations of simple starting
materials, providing an elegant synthesis of highly function-
alized cyclobutabenzenes not easily available by other
procedures. The key steps of the process are the formation
of an aryne-zirconocene complex and a doubly regioselec-
tive insertion reaction of an alkenyl bromide.
sively led to trans-3o. The structure of these products was
assigned on the basis of different NMR studies including
HSQC-NOESY experiments performed on trans-3o and the
totally hydrogenated compound 3e.
All these results allow us to propose the mechanism shown
in Scheme 5 for the formation of cyclobutabenzenes 3. In
Scheme 5
.
Proposed Mechanism of Formation of
Benzocyclobutenes 3
Acknowledgment. Financial support for this work was
provided by the Ministerio de Educacio´n y Ciencia of Spain
(CTQ2007-61048/BQU and predoctoral grants to L.A.-R. and
J.C.).
Supporting Information Available: Experimental pro-
cedures and characterization data. Copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
first place, the transmetalation reaction of the organolithium
compounds 1 and the zirconocene methyl chloride leads to
the formation of the new aryl-zirconocene complex 4. These
complexes are known to evolve through a ꢀ-abstraction of
OL801652H
(10) For an excellent account on zirconium-mediated migratory insertion
processes, see: (a) Dixon, S.; Whitby, R. J. In Titanium and Zirconium in
Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; p 86.
See also: (b) Kasatkin, A.; Whitby, R. J. Tetrahedron 2003, 59, 9857.
(9) Buchwald, S. L.; Nielsen, R. B. Chem. ReV. 1988, 88, 1047.
Org. Lett., Vol. 10, No. 20, 2008
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