Selective cross-couplings. Sequential Stille-Liebeskind/Srogl reactions of 3-chloro-4-arylthiocyclobutene-1,2-dione

Article abstract of DOI:10.1021/ol701628z

The synthesis and initial reactivity studies of 2 are described. It was found that it participates in Stille couplings exclusively at the C-Cl site with a number of organostannanes (58-71% yield) in the absence of Cu(I). Then, these new derivatives were f

Full text of DOI:10.1021/ol701628z

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4163-4166
Selective Cross-Couplings. Sequential
Stille Liebeskind/Srogl Reactions of
−
3-Chloro-4-arylthiocyclobutene-1,2-dione
Ange´lica Aguilar-Aguilar and Eduardo Pen˜a-Cabrera*
Facultad de Qu´ımica, UniVersidad de Guanajuato, Col. Noria Alta S/N, Guanajuato,
Gto, 36050 Mexico
eduardop@quijote.ugto.mx
Received July 11, 2007
ABSTRACT
The synthesis and initial reactivity studies of 2 are described. It was found that it participates in Stille couplings exclusively at the C
with a number of organostannanes (58 71% yield) in the absence of Cu(I). Then, these new derivatives were functionalized at the C
with boronic acids by switching to the Liebeskind Srogl reaction conditions (in the presence of a Cu(I) carboxylate) to yield the bifunctionalized
cyclobutenediones (44 90% yield).
−Cl site
−
−S site
−
−
The synthetic utility of cyclobutenedione derivatives 1 has
been extensively demonstrated.1 These types of compounds
have been used not only to prepare organic molecules with
biological relevance but also as ion sensors,2 as ligands,3 and
to prepare cyclo[n]carbons.4 One of the main features that
makes cyclobutenediones such a useful starting material is
the fact that the four-membered ring is a latent highly
substituted benzene 1a or quinone ring system 1b (Figure
1). In doing so, from the reactivity point of view, 1 goes
(1) (a) Liebeskind, L. S.; Jewell, C. F., Jr. J. Organomet. Chem. 1985,
285, 305. (b) Jewell, C. F.; Liebeskind, L. S.; Williamson, M., Jr. J. Am.
Chem. Soc. 1985, 107, 6715. (c) Liebeskind, L. S.; Baysdon, S. L.; South,
M. S.; Iyer, S.; Leeds, J. P. Tetrahedron 1985, 41, 5839. (d) Liebeskind, L.
S.; Iyer, S.; Jewell, C. F., Jr. J. Org. Chem. 1986, 51, 3065. (e) Liebeskind,
L. S. Tetrahedron 1989, 45, 3053. (f) Liebeskind, L. S.; Foster, B. S. J.
Am. Chem. Soc. 1987, 109, 7908. (g) Liebeskind, L. S.; Bombrum, A. J.
Org. Chem. 1994, 59, 6856. (h) Zhang, S.; Liebeskind, L. S. J. Org. Chem.
1999, 64, 4042. (i) Mingo, P.; Zhang, S.; Liebeskind, L. S. J. Org. Chem.
1999, 64, 2145. (j) Shi, X.; Amin, R.; Liebeskind, L. S. J. Org. Chem.
2000, 65, 1650. (k) Shi, X.; Liebeskind, L, S. J. Org. Chem. 2000, 65,
1665. (l) Pen˜a-Cabrera, E.; Liebeskind, L. S. J. Org. Chem. 2002, 67, 1689.
(m) Karlsson, J. O.; Nguyen, N. V.; Foland, L. D.; Moore, H. W. J. Am.
Chem. Soc. 1985, 107, 3392. (n) Moore, H. W.; Decker, O. H. Chem. ReV.
1986, 86, 821. (o) Tiedemann, R.; Turnbull, P.; Moore, H. W. J. Org. Chem.
1999, 64, 4030. (p) Taing, M.; Moore, H. W. J. Org. Chem. 1996, 61, 329.
(q) Lee, K. H.; Moore, H. W. J. Org. Chem. 1995, 60, 735. (r) Negri, J. T.;
Morwick, T.; Doyon, J.; Wilson, P. D.; Hickey, E. R.; Paquette, L. A. J.
Am. Chem. Soc. 1993, 115, 12189. (s) Paquette, L. A.; Morwick, T. M.;
Negri, J. T.; Rogers, R. D.; Tetrahedron 1996, 52, 3075. (t) Paquette, L.
A.; Morwick, T. M. J. Am. Chem. Soc. 1997, 119, 1230. (u) Paquette, L.
A.; Kuo, L. H.; Tae, J. J. Org. Chem. 1998, 63, 2010. (v) Geng, F.; Liu, J.;
Paquette, L. A. Org. Lett. 2002, 4, 71. (w) Danheiser, R. L.; Gee, S. K.;
Sard, H. J. Am. Chem. Soc. 1982, 104, 7670. (x) Danheiser, R. L.; Gee, S.
K. J. Org. Chem. 1984, 49, 1672. Danheiser, R. L.; Gee, S. K.; Perez, J. J.
J. Am. Chem. Soc. 1986, 108, 806.
Figure 1. Cyclobutenediones as latent aromatic or quinoid rings.
from being an electron-deficient fragment to an electron-
rich moiety (1f1a).
(2) Frontera, A.; Orell, M.; Garau, C.; Quin˜onero, D.; Molins, E.; Mata,
I.; Morey, J. Org. Lett. 2005, 7, 1347.
(3) Murakami, H.; Minami, T.; Osawa, F. J. Org. Chem. 2004, 69, 4482.
(4) Rubin, Y.; Knobler, C. B.; Diederich, F. J. Am. Chem. Soc. 1990,
112, 1607.
10.1021/ol701628z CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/14/2007

Thus, if both R1 and R2 are aryl substituents, this route
would lead to the construction of tri- (or oligo-) phenylenes
provided there is an efficient methodology to incorporate
aryl fragments at the vinyl positions of 1. Polyphenylenes
are of significant importance in the design of organic light-
emitting diodes (OLED’s).5 On the other hand, the terphenyl
motif is found in a plethora of natural products.6
We have recently developed a mild functionalization of
bisarylthiosubstituted cyclobutenediones using the Liebe-
skind-Srogl cross-coupling7 to prepare bisferrocenyl-
cyclobutenediones8 and other symmetrical bisarylcyclobutene-
diones9 (Scheme 1).
as part of either a vinyl chloride or a vinylogous acid chloride
which can be functionalized by using the Stille, Suzuki,
Heck, Sonogashira, Hiyama, or Negishi reaction,10 among
others, proVided no Cu(I) salts or hydrolytic conditions are
used (vide infra). Furthermore, 2 should presumably be
susceptible to conjugate addition/elimination reactions of
oxygen, nitrogen, or phosphorus nucleophiles and organo-
cuprates. Second, the S-bearing vinyl carbon atom will react,
as we have demonstrated,9 with either boronic acids or
organostannanes as long as a Cu(I) carboxylate is used in
stoichiometric amounts. Third, the carbonyl groups react with
Grignard or organolithium reagents as has been extensively
shown in the classical ring-opening/expansion sequence that
has been used to form benzene derivatives.1
By the aforementioned arguments, 2 may become a very
useful platform that possesses orthogonal reactivity because
it can be functionalized at will at three different reaction
centers by simply varying the reaction conditions.11
Cyclobutenedione 2 was prepared in 93% yield by treating
3,4-dichloro-3-cyclobutene-1,2-dione12 with 0.5 equiv of
p-methoxybenzenethiol and 0.5 equiv of triethylamine (eq
1).
Scheme 1. Synthesis of Symmetrical Cyclobutenediones
Building upon our results, we wish to disclose the synthesis
and initial synthetic applications of 3-chloro-4-arylthiocy-
clobutene-1,2-dione 2 (Figure 2).
Chlorothiocyclobutenedione 2 is a pale yellow solid with
excellent shelf life. It can be handled in air with no special
precautions, even after several months at room temperature,
and it shows no signs of decomposition. Once 2 was
prepared, we set forth studying its reactivity. On the grounds
of handling a more robust product after the first cross-
coupling, the Stille reaction was attempted first to introduce
an aryl group at the Cl-bearing C atom. In this fashion, the
resulting product would be stable to silica-gel chromatog-
raphy purification. The initial reaction conditions used were
similar to those that Liebeskind et al. applied for the Stille
reaction of similar substrates with organostannanes,13 i.e., a
Pd(II) catalyst and CuI as a cocatalyst. However, the results
were disappointing because a mixture of the arylated products
at both the vinyl positions was observed in addition to
unreacted 2 (eq 2).
Figure 2. Multiple reaction centers of 2.
Cyclobutenedione 2 displays three types of reaction
centers. First, the Cl-bearing carbon atom may be regarded
(5) Li, Z. H.; Wong, M. S.; Tao, Y. Tetrahedron 2005, 61, 5277 and
references cited therein.
(6) Liu, J-K. Chem. ReV. 2006, 106, 2209.
(7) (a) Liebeskind, L. S.; Srogl, J.; Savarin, C.; Polanco, C. Pure Appl.
Chem. 2002, 74, 115. (b) Kusturin, C.; Liebeskind, L. S.; Rahman, H.;
Sample, K.; Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5
(23), 4349. (c) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J. Am.
Chem. Soc. 1999, 121, 9449. (d) Savarin, C.; Srogl, J.; Liebeskind, L. S.
Org. Lett. 2001, 3 (1), 91. (e) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.;
Lebret, B.; Guillaumet, G. Org. Lett. 2003, 5, 803 (f) Yu, Y.; Liebeskind,
L. S. J. Org. Chem. 2004, 69 (10), 3554. (g) Srogl, J.; Liebeskind, L. S. J.
Am. Chem. Soc. 2000, 122, 11260. (h) Savarin, C.; Liebeskind, L. S. Org.
Lett. 2001, 3 (14), 2149. (i) Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4
(6), 979. (j) Kusturin, C. L.; Liebeskind, L. S.; Newman, W. L. Org. Lett.
2002, 4 (6), 983. (k) Egi, M.; Wittenberg, R.; Srogl, J.; Liebeskind, L. S.
Org. Lett. 2003, 5, 3033. (l) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5,
801.
These results, although not very useful from the synthetic
point of view, strongly suggest that in the presence of Cu(I)
(10) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinhein, Germany, 2004; Vols. 1-2.
(11) For an efficient example of orthogonal reactivity of thioorganics,
see ref 7a.
(8) Aguilar-Aguilar, A.; Pen˜a-Cabrera, E.; Liebeskind, L. S. ARKIVOC
2004, (i), 156.
(9) The results will be reported elsewhere.
4164
Org. Lett., Vol. 9, No. 21, 2007

both reactive centers (C-Cl and C-S) have comparable
reactivity.14 To achieve the sought after selectivity, CuI was
eliminated from the initial Stille coupling reactions at the
risk of compromising the reactivity of the vinyl chloride
moiety (eq 3).
Table 2. Liebeskind-Srogl Cross-Coupling of 3 and 5-7
compd,
entry
Ar1
Ar2
% yielda
1
2
3
4
5
6
7
p-CH3OC6H4-
p-CH3OC6H4-
p-CH3C6H4-
p-CH3C6H4-
p-ClC6H4-
p-CH2)CHC6H4-
p-Me2NC6H4-
8, 74
9, 44
6-methoxy-2-naphthyl-
3,4-dimethoxyphenyl-
4-formylphenyl-
4-bromophenyl-
3-thienyl-
10, 50
11, 58
12, 76
13, 47
14, 56
p-ClC6H4-
To our delight, not only did the system show excellent
reactivity even in the absence of CuI but also product 3 was
obtained in 69% isolated yield at 25 °C. No evidence of any
8
2-furyl-
15, 90
1
other cross-coupling product was observed in the H NMR
spectrum of the crude material. Thus, a series of arylstan-
nanes were coupled with 2 under the reaction conditions of
eq 3. The results are presented in Table 1.
a
Isolated yields.
It tolerates a variety of functional groups that range from
electron-releasing (entries 1-4) to electron-withdrawing
(entries 5 and 6), including heterocyclic systems (entries 7
and 8).16 The functional groups attached to the aryl systems
allow further elaboration of the products. For instance,
cyclobutenedione 8 was reacted with p-iodoanisole under the
Heck conditions to yield 16 in 73% yield (eq 4).
Table 1. Stille Coupling of 2 with Organostannanes
entry
Ar
time (h)
compd
% yielda
1
2
3
4
p-CH3OC6H4-
p-CH3C6H4-
p-ClC6H4-
2
2
2
3
5
6
7
69
58
71
71
14
a
Isolated yield.
As can be observed, both electron-rich and electron-
deficient arylstannanes reacted with 2 under the Stille
conditions in good yields.15
Then, thiocyclobutenediones 3 and 5-7 were subjected
to the Liebeskind-Srogl protocol with a variety of boronic
acids to give nonsymmetric biarylcyclobutenediones9 (Table
2).
In conclusion, we have prepared chlorothiocyclobutene-
dione 2 and demonstrated its utility in the efficient synthesis
of nonsymmetrical bisarylcyclobutenediones. By using reac-
tion conditions for the Stille coupling without CuI, orga-
nostannanes react exclusively at the Cl-bearing C atom. Then,
by switching the reaction conditions to the Liebeskind-Srogl
protocol in the presence of a stoichiometric amount of CuTC,
the S-bearing C atom reacts with highly functionalized
boronic acids. The nature of the different reaction centers
of 2, and the unique methods to activate them, makes this
The Liebeskind-Srogl reactions worked efficiently to give
the corresponding products from moderate to excellent yields.
(12) Yamamoto, Y.; Shirasaki, Y.; Eguchi, S. J. Chem. Soc. 1993, 263.
(13) Liebeskind, L. S.; Wang, J. Tetrahedron Lett. 1990, 31, 4293.
(14) It has been reported in the literature that in cross-couplings or
thioorganics with organostannanes the Cu(I) additive need not be a Cu(I)
carboxylate. See ref 7e.
(15) Typical experimental procedure: In an oven-dried Schlenk tube,
2 (50.0 mg, 0.19 mmol) and p-methylphenyltributylstannane (95.0 mg, 0.23
mmol) were dissolved in anhyd. CH3CN (3 mL) under N2. Then, the mixture
was purged with N2 for 5 min whereupon (CH3CN)2PdCl2 (2.5 mg, 0.009
mmol) was added, and the reaction mixture was stirred at rt for 2 h. The
mixture then was washed with hexanes (4 × 3 mL) to remove the tin
byproducts, and the remaining CH3CN phase was concentrated in vacuo.
The final product (yellow solid, 17.2 mg, 58%) was purified by flash
chromatography (SiO2-gel, EtOAc/hexanes gradient).
(16) Typical experimental procedure: In an oven-dried Schlenk tube,
5 (50.0 mg, 0.16 mmol) and 6-methoxynaphthaleneboronic acid (81.0 mg,
0.4 mmol) were dissolved in dry THF (4 mL) under N2. Then, the mixture
was purged with N2 for 5 min whereupon Pd2bda3 (1.47 mg, 0.001 mmol),
TFP (1.1 mg, 0.004 mmol), and CuTC (91.8 mg, 0.48 mmol), were added.
The reaction mixture was heated at 50 °C for 20 h, cooled to rt, and then
quenched with satd. aq. NH4Cl saturada. Then, it was extracted with EtOAc
(3 × 10 mL), dried over CaCl2, and filtered, and the volatiles were removed
under reduced pressure. The product (yellow solid, 26.0 mg, 50%) was
purified by flash chromatography (SiO2-gel, EtOAc/hexanes gradient).
Org. Lett., Vol. 9, No. 21, 2007
4165

substrate amenable to other (both transition-metal-catalyzed
and non-transition-metal-catalyzed) tandem processes that
may be combined with the Liebeskind-Srogl reaction to
yield more elaborate products. These studies and the anchor-
ing of solid resins and fluorinated tags to the vinyl chloride
moiety of 2 are underway in our laboratory and will be
published in due course.
2004-C01-45970/A1). A.A.-A. wishes to thank CONACyT
for a graduate scholarship.
Supporting Information Available: A complete descrip-
tion of all of the experimental procedures as well as the
characterization of all of the compounds in the paper. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by CONA-
CyT (CIAM program grant 2005-C02-51833/A-1 and SEP-
OL701628Z
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Org. Lett., Vol. 9, No. 21, 2007