Pd-catalyzed, Cu(I)-mediated cross-couplings of bisarylthiocyclobutenediones with boronic acids and organostannanes

Article abstract of DOI:10.1021/jo701331m

(Chemical Equation Presented) Bisarylthiocyclobutenedione 7 reacted smoothly with a variety of both organostannanes and (hetero)arylboronic acids in the presence of a catalytic amount of Pd and a stoichiometric amount of CuTC to produce symmetrical disubstituted cyclobutenediones in yields that range from 37 to 94% (18 examples).

Full text of DOI:10.1021/jo701331m

Pd-Catalyzed, Cu(I)-Mediated Cross-Couplings of
Bisarylthiocyclobutenediones with Boronic Acids
and Organostannanes
Ange´lica Aguilar-Aguilar,† Lanny S. Liebeskind,‡ and
Eduardo Pen˜a-Cabrera*,†
Starting from either 1 or 2, a wide variety of different
compounds have been prepared, including triquinanes 3,3a
angularly fused aromatic systems 4,5 bisquaryls 5,6 and 2-py-
rones 67 just to mention a few (Figure 1).
Facultad de Qu´ımica, UniVersidad de Guanajuato, Col. Noria
Alta S/N, Guanajuato, Gto. 36050, Mexico, and Department of
Chemistry, Emory UniVersity, 1515 Dickey DriVe, Atlanta,
Georgia 30322
Squaric acid derivatives have also been used as ion sensors8
and ligands9 and to prepare cyclo[n]carbons.10
Accordingly, the need for new protocols that allow for a
practical functionalization of the 3 and 4 positions becomes
evident.
eduardop@quijote.ugto.mx
To date, there are several reports in the literature describing
the introduction of simple alkyl, aryl, heteroaryl, alkynyl, and
alkenyl11 functional groups in those positions of cyclobutene-
dione. However, they require the use of highly reactive Grignard
or organolithium derivatives which limits the functional groups
that can withstand these reaction conditions. Few milder
transition-metal-mediated methods to prepare such derivatives
have been reported. Namely, Knochel et al. reported the reaction
of 3,4-dichlorocyclobutendione and zinc-copper reagents.12
Likewise, Liebeskind disclosed an efficient synthesis of 3-(tri-
n-butylstannyl)-3-cyclobutene-1,2-dione. This stannylcyclobutene-
dione underwent cross-couplings with organic iodides and
triflates catalyzed by the PhCH2ClPd(PPh3)2/CuI system.1k,6,13
The same group reported the Stille couplings of monohalocy-
clobutenediones with organostannanes.14
ReceiVed June 21, 2007
Bisarylthiocyclobutenedione 7 reacted smoothly with a
variety of both organostannanes and (hetero)arylboronic acids
in the presence of a catalytic amount of Pd and a stoichio-
metric amount of CuTC to produce symmetrical disubstituted
cyclobutenediones in yields that range from 37 to 94% (18
examples).
Against this background, we decided to explore the use of
the palladium-catalyzed, copper-mediated cross-couplings of
thioorganics with both organostannanes and boronic acids15 to
develop a mild protocol to functionalize the vinyl positions of
cyclobutenedione with both aryl and heteroaryl groups.
Over the last three decades, various research groups have
demonstrated the remarkable versatility of cyclobutenedione 1
and squaric acid ester derivatives 2 in the synthesis of organic
compounds. In particular, the groups of Liebeskind,1 Moore,2
Paquette,3 and Danheiser4 have been very active in this area.
(5) Koo, S.; Liebeskind, L. S. J. Am. Chem. Soc. 1995, 117, 3389.
(6) Liebeskind, L. S.; Yu, M. S.; Yu, R. H.; Wang, J.; Hagen, K. J. Am.
Chem. Soc. 1993, 115, 9048.
(7) Liebeskind, L. S.; Wang, J. Tetrahedron 1993, 49 (25), 5461.
(8) Frontera, A.; Orell, M.; Garau, C.; Quin˜onero, D.; Molins, E.; Mata,
I.; Morey. J. Org. Lett. 2005, 7 (8), 1347.
† Universidad de Guanajuato.
‡ Emory University.
(1) (a) Liebeskind, L. S.; Jewell, C. F., Jr. J. Organomet. Chem. 1985,
285, 305. (b) Jewell, C. F., Jr.; Liebeskind, L. S.; Williamson, M. 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.; Foster, B. S. J. Am. Chem. Soc. 1987, 109, 7908. (f) Liebeskind, L.
S. Tetrahedron 1989, 45, 3053. (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.
(2) (a) Karlsson, J. O.; Nguyen, N. V.; Foland, L. D.; Moore, H. W. J.
Am. Chem. Soc. 1985, 107, 3392. (b) Moore, H. W.; Decker, O. H. Chem.
ReV. 1986, 86, 821. (c) Lee, K. H.; Moore, H. W. J. Org. Chem. 1995, 60,
735. (d) Taing, M.; Moore, H. W. J. Org. Chem. 1996, 61, 329. (e)
Tiedemann, R.; Turnbull, P.; Moore, H. W. J. Org. Chem. 1999, 64, 4030.
(3) (a) Negri, J. T.; Morwick, T.; Doyon, J.; Wilson, P. D.; Hickey, E.
R.; Paquette, L. A. J. Am. Chem. Soc. 1993, 115, 12189. (b) Paquette, L.
A.; Morwick, T. M.; Negri, J. T.; Rogers, R. D. Tetrahedron 1996, 52,
3075. (c) Paquette, L. A.; Morwick, T. M. J. Am. Chem. Soc. 1997, 119,
1230. (d) Paquette, L. A.; Kuo, L. H.; Tae, J. J. Org. Chem. 1998, 63,
2010. (e) Geng, F.; Liu, J.; Paquette, L. A. Org. Lett. 2002, 4, 71.
(4) (a) Danheiser, R. L.; Gee, S. K.; Sard, H. J. Am. Chem. Soc. 1982,
104, 7670. (b) 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.
(9) Murakami, H.; Minami, T.; Osawa, F. J. Org. Chem. 2004, 69, 4482.
(10) Rubin, Y.; Knobler, C. B.; Diederich, F. J. Am. Chem. Soc. 1990,
112 (4), 1607.
(11) Mukkanti, A.; Periasami, M. ARKIVOC 2005, (xi), 48 and references
therein.
(12) Sidduri, A.; Budries, N.; Laine, R. M.; Knochel, P. Tetrahedron
Lett. 1992, 33, 7515.
(13) (a) Liebeskind, L. S.; Zhang, J. J. Org. Chem. 1991, 56, 6379. (b)
Liebeskind, L. S.; Yu, M. S.; Fengl, R. W.; Hagen, K. S. J. Org. Chem.
1993, 58, 3543.
(14) Liebeskind, L. S.; Wang, J. Tetrahedron Lett. 1990, 31, 4293.
(15) (a) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J. Am. Chem.
Soc. 1999, 121, 9449. (b) Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc.
2000, 122, 11260. (c) Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3
(14), 2149. (d) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3
(1), 91. (e) Liebeskind, L. S.; Srogl, J.; Savarin, C.; Polanco, C. Pure Appl.
Chem. 2002, 74 (1), 115. (f) Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4
(6), 979. (g) Kusturin, C. L.; Liebeskind, L. S.; Newman, W. L. Org. Lett.
2002, 4 (6), 983. (h) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample,
K.; Schweitzer, B.; Srogl, J.; Neumann Org. Lett. 2003, 5 (23), 4349. (i)
Egi, M.; Wittenberg, R.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2003, 5,
3033. (j) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801. (k) Alphonse,
F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org. Lett.
2003, 5, 803. (l) Aguilar-Aguilar, A.; Pen˜a-Cabrera, E.; Liebeskind, L. S.
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10.1021/jo701331m CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/25/2007
J. Org. Chem. 2007, 72, 8539-8542
8539

SCHEME 2. Short Survey of Organostannanes in the
Liebeskind-Sro1gl Cross-Coupling
FIGURE 1. Examples of organic compounds prepared from either 1
or 2.
SCHEME 1. Synthesis of Thiocyclobutenediones 7-9
It was necessary to use a 2-fold excess of the stannane to
compensate for the formation of the homocoupled biaryl
byproduct present in all of these reactions. The yields for
electron-rich substituents (OMe, Me) were moderate. The p-Cl
derivative was somewhat unstable to aqueous saturated KF
treatment17 to eliminate the tin byproducts, hence its low yield.
As in the majority of cross-couplings reactions where orga-
nostannanes are involved, the removal of tin byproducts was
tedious and time-consuming. Thus, the need for a better and
more practical procedure became clear.
TABLE 1. Reactivity of Thiocyclobutenediones 7-9 in the
Liebeskind-Sro1gl Cross-Coupling
We then turned our attention to explore the scope of the
reaction with boronic acids. The reaction was first optimized
by varying the reaction conditions as shown in Table 2. The
Pd sources and external ligands used are shown below.
entry
M
R
% yield of 11a
1
2
3
4
5
6
B(OH)2
B(OH)2
B(OH)2
SnBu3
SnBu3
SnBu3
p-MeOC6H4
p-MeC6H4
n-Bu
p-MeOC6H4
p-MeC6H4
n-Bu
70
62
trace amt
61
51
trace amt
a Isolated yield.
Bisthiocyclobutenediones 7-9 where prepared in order to
study the influence of the substituent on sulfur in the cross-
couplings. Thus, the corresponding thiols were reacted with 3,4-
dichlorocyclobutene-1,2-dione16 10 in the presence of triethy-
lamine (Scheme 1).
Thiocyclobutenediones 7-9 were obtained in a straightfor-
ward manner as stable yellow powders which could be handled
in air with no evident signs of decomposition even after several
weeks. With 7-9 in hand, their reactivity was assessed with
phenylboronic acid and with tributylphenylstannane as illustrated
in Table 1. Since thiocyclobutenediones 7-9 may be regarded
as vinylogous thiol esters, the initial reactions conditions chosen
were based upon those reported for the cross-couplings of thiol
esters with organostannanes and boronic acids.15b,i
Aromatic substituents on sulfur gave the best results presum-
ably because once the oxidative addition takes place, the
negative charge on sulfur may be better stabilized onto the
aromatic ring. Due to its ease of formation, excellent shelf life,
and higher reactivity in the cross-couplings, thiocyclobutene-
dione 7 was chosen as the starting material for the reaction with
boronic acids and organostannanes.
Even though the aim of this report is to emphasize the scope
of the cross-coupling reaction with boronic acids by virtue of
their availability and nontoxicity, a few organostannanes were
surveyed (Scheme 2).
Initial testing with a slight excess of the boronic acid only
produced incomplete conversions and rather complex crude
mixtures (entries 1-5) using a variety of Pd sources and external
ligands in THF at 55 °C. The formation of 16 was never avoided
even with rigorous deoxygenation and slow addition of the
boronic acid. Addition of an increased amount of boronic acid
to compensate for the formation of the homocoupled byproduct
16 showed improvement only when used in the presence of Pd-
(PPh3)4 in THF (entry 7). Complete conversion and a 69% yield
of 14 were obtained. Finally, similar results were observed with
either Pd2(dba)3/TFP or Pd(PPh3)4 in THF when 4 equiv of the
boronic acid were added (entries 8 and 9). In light of the slightly
higher efficiency displayed (77% vs 75%) and better shelf life,
the combination Pd2(dba)3/TFP was chosen to study the scope
and limitations of the reaction. The results are summarized in
Table 3.
In general, the reaction furnished the desired products with
boronic acids containing strong electron-donating groups (entries
3, 6, and 7) in moderate to good yields. Arylboronic acids with
milder electron donors (entries 1, 4, 5, and 10) gave the
corresponding disubstituted cyclobutenediones in moderate
(16) Yamamoto, Y.; Shirasaki, Y.; Eguchi, S. J. Chem. Soc. 1993, 263.
(17) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org. Chem.
1993, 58, 5434.
8540 J. Org. Chem., Vol. 72, No. 22, 2007

TABLE 2. Optimization of the Cross-Coupling of 7 with
MeC6H4B(OH)2
TABLE 3. Scope and Limitations of the Liebeskind-Sro1gl
Cross-coupling
a
RB(OH)2
entry
1
% Pd
% PR3
(equiv)
resultb
2.5% A 7.5% E
2.5
similar amounts of 7, 14,
15, and 16 were observed
as in entry 1
2
3
4
2.5% D
5% B
2.5% C 5% F
2.5
2.5
2.5
1:1 (7:14)
similar amounts of 7, 14,
and 15
5
6
7
8
9
5% A
5% D
5% B
2.5% A 7.5% E
5% B
5% G
2.5
3.0
3.0
4.0
4.0
only 7 and 16 were observed
complex mixture
14 (69%) + traces of 16
14 (77%) + traces of 16
14 (75%) + traces of 16
a A 25% excess of CuTC was used with respect to the boronic acid.
b The results were obtained from the 1H NMR spectrum of the crude
material.
yields. Boronic acids with electron-withdrawing substituents
(entries 2, 11, 12, and 14) also reacted smoothly to give the
desired products in acceptable yields. The heteroaryl boronic
acids evaluated in this study displayed variable behavior. For
reasons that are not clear at the moment, 3-pyridylboronic failed
to react under the standard conditions. Variations that included
the use of Pd(PPh3)4 and the addition of an additive (Zn(OAc)2)
failed as well.15i Dibenzofurylboronic acid (entry 15) produced
the expected product albeit in low yield. The fact that in this
case all of the starting material is consumed, suggests a degree
of instability of the final product. 3-Thienylboronic acid (entry
13) gave the product in excellent yield. Ferrocenylboronic acid
showed good reactivity and gave the product in 71% yield
(entry 7).
It is worth mentioning that the products of entries 9 and 12,
since they bear either a vinyl group or a Br atom in the para
position of the aromatic ring, respectively, can participate in
further Pd-catalyzed cross-coupling reactions, thereby yielding
more elaborate derivatives. As an example, bis(p-styryl)-
cyclobutenedione was reacted with p-iodoanisole under Heck
conditions18 to give monofunctionalized product 17 in 77% yield
(eq 1).
a Isolated yield after column chromatography.
with 1 equiv of phenylboronic acid to introduce only one phenyl
group failed, giving the disubstituted product and unreacted 7
(eq 2).
In conclusion, we have developed a mild and efficient method
to incorporate aryl, heteroaryl, and organometallic functional
groups at the vinylic positions of cyclobutenedione under mild
and nonbasic reaction conditions. Some of these derivatives
would be difficult to obtain using the reported methods to
functionalize cyclobutenediones. Even though Knochel’s orga-
nocuprate method allows the introduction of two different groups
at the vinyl positions, the methodology presented here uses
readily available reagents and catalysts that are air stable.
Bisthiocyclobutenedione 7 reacts smoothly with both arylstan-
nanes and (hetero)arylboronic acids to furnish the corresponding
symmetric cyclobutenediones in modest to excellent yields.19
Limitations of this methodology include the failed reaction with
Finally, our efforts focused on the possibility of synthesizing
nonsymmetric cyclobutenediones. Attempts to cross-couple 7
(18) Reiser, O.; Reichow, S.; de Meijere, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1277.
J. Org. Chem, Vol. 72, No. 22, 2007 8541

and CuTC (66.6 mg, 0.35 mmol) were added, and the reaction
mixture was heated to 50 °C for 18 h. The heating bath was
removed, and the volatiles were eliminated in vacuo. The crude
material was purified by flash chromatography (SiO2 gel, ethyl
acetate/hexanes gradient) to give the products as yellow solids. The
remaining tin impurities were removed by partitioning the product
between MeCN (2 mL) and hexanes (2 mL) and washing the MeCN
phase with fresh hexanes (5 × 2 mL). The MeCN was removed in
vacuo to give the pure product (yellow solid, 12.0 mg, 65%): TLC
pyridylboronic acid and the inability to synthesize nonsym-
metrical derivatives. Further studies of the reactivity of 7 toward
alkylboronic acids and other unsaturated boronic acids and
organostannanes (vinyl, alkynyl, allyl, etc.), as well as with
organozinc, organocopper, and organomagnesium derivatives
are being currently pursued in our laboratory and will be
reported in due course.
1
(30% EtOAc/hexanes, Rf ) 0.75); H NMR (200 MHz, CDCl3) δ
Experimental Section
8.00 (d, J ) 7.0 Hz, 2H), 7.36 (d, J ) 7 Hz, 2H), 2.45 (s, 3H); 13
C
NMR (75.5 MHz, CDCl3) δ 196.6, 186.8, 144.6, 130.2, 128.5,
3,4-Bis(p-methoxythiophenoxy)-3-cyclobutene-1,2-dione 7. To
a cool (0 °C) THF (10 mL) solution of dichlorodione 10 (250 mg,
1.6 mmol) was added p-methoxythiophenol (0.4 mL, 3.3 mmol)
dropwise via syringe under N2, followed by the addition of
triethylamine (0.43 mL, 3.3 mmol). The reaction mixture gradually
reached 25 °C and after 6 h was quenched with an equivalent
volume of aq NH4Cl. Then, it was extracted with CH2Cl2 (3 ×
30 mL), dried (anhyd MgSO4), and filtered. The solvent was
removed in vacuo to give a yellow solid. The remaining solid was
triturated in hexanes and used directly in the following reactions
(515 mg, 90%). For characterization purposes, the product was
crystallized from hexane/EtOAc: TLC (Rf ) 0.3, silica gel, 20%
EtOAc/hexane); mp 133 °C; IR (KBr) 2939 (m), 2840 (m), 2366
(m), 1787 (s), 1807 (m) 1761 (s), 1740 (m), 1590 (s), 1571 (s); 1H
NMR (200 MHz, CDCl3) δ 7.50 (d, J ) 8.94 Hz, 2H), 6.90 (d, J
) 8.89 Hz, 2H), 3.80 (s, J ) 1.8 Hz, 3H); 13C NMR (50 MHz,
CDCl3) 188.2, 186.7, 161.7, 136.4, 115.0, 66.1, 55.7. Anal. Calcd
for C18H14O4S2: C, 60.32; H, 3.94; S, 17.89. Found: C, 59.99; H,
3.92; S, 17.58.
125.9, 22.2; MS (EI) m/z calcd 262, found 262.21
Typical Experimental Procedure for the Cross-Coupling
Reactions with Boronic Acids. Synthesis of 3,4-Bis(3-thienyl)-
3-cyclobuten-1,2-dione. A 50 mL Schlenk flask under N2 was
charged with 7 (35 mg, 0.098 mmol, 1 equiv), 3-thienylboronic
acid (50 mg, 0.4 mmol, 4 equiv), and anhyd THF (5 mL), and the
resulting yellow solution was deoxygenated by bubbling N2 for 5
min. Then, CuTC (93 mg, 0.5 mmol, 5 equiv), Pd2(dba)3 (2.3 mg,
2.4 × 10-3 mmol), and trifurylphosphine (1.8 mg, 7.3 × 10-3
mmol) were added. The reaction mixture was heated to 55 °C for
18 h, the heating bath was removed, and the volatiles were
eliminated in vacuo. The crude material was purified by flash
chromatography (SiO2 gel, ethyl acetate/hexanes gradient) to give
the product as a yellow solid (22.6 mg, 94%): TLC (30% EtOAc/
hexanes, Rf ) 0.7); mp ) 149-150 °C; IR (KBr, cm-1) 1754.8
(s), 1569.3 (s), 1514.8 (m), 1437.8 (m), 1221.1 (m), 1124.0 (m);
1H NMR (200 MHz, CDCl3) δ 8.58 (dd, 1.4 Hz, J ) 1.2 Hz, 1H),
7.78 (dd, J ) 1.0, 1.0 Hz, 1H), 7.58 (dd, J ) 3.0, 2.8 Hz, 1H); 13
C
NMR (75.5 MHz, CDCl3) δ 195.8, 178.4, 132.6, 129.6, 128.0,
Typical Experimental Procedure for the Cross-Coupling
Reactions with Organostannanes. Synthesis of Dione 14. A
50 mL Schlenk flask under N2 was charged with 7 (25.0 mg,
0.07 mmol, 1 equiv), tributyl-p-tolylstannane (106.0 mg, 0.28 mmol,
4 equiv), and anhyd THF (5 mL). The resulting solution was
deoxygenated by bubbling N2 for 10 min. Then Pd2(dba)3 (1.6 mg,
1.7 × 10-3 mmol), trifurylphosphine (1.2 mg, 5.2 × 10-3 mmol),
126.3; HRMS (C12H6O2S2) calcd 245.9809, found 245.9813.
Acknowledgment. This work was generously supported by
CONCyTEG (Grant No. GTO-2003-C02-11921), CONACyT
(CIAM program Grant No. 2005-C02-51833/A-1), and the NIH
(Grant No. GM066153). A.A.-A. thanks CONACyT for a
graduate scholarship.
(19) After a reviewer’s suggestion, dichlorocyclobutenedione 10 was
reacted with p-tolylboronic acid under the Suzuki conditions (1% Pd(OAc)2,
2.5% S-Phos, 2 equiv of K3PO4, toluene, 90 °C).20 However, only traces
of 18 were observed.
(20) Walter, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871-1876.
(21) Yang, N. C.; Jeong, J. K.; Choi, S. J.; Rhee, T. H.; Suh, D. H.
Macromol. Rapid Commun. 1999, 20 (11), 586-590.
Supporting Information Available: Experimental procedures
and compound characterization data and copies of the NMR spectra
of the compounds prepared. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO701331M
8542 J. Org. Chem., Vol. 72, No. 22, 2007