Regioselective double Suzuki couplings of 4,5-dibromothiophene-2-carboxaldehyde

Article abstract of DOI:10.1016/j.tetlet.2007.09.114

Conditions have been identified that enable the one-pot double Suzuki coupling of 4,5-dibromothiophene-2-carboxaldehyde to proceed in good yield. The key to success in these reactions is the use of minimal amounts of water to avoid significant amounts of

Full text of DOI:10.1016/j.tetlet.2007.09.114

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Tetrahedron Letters 48 (2007) 8108–8110
Regioselective double Suzuki couplings
of 4,5-dibromothiophene-2-carboxaldehyde
Scott T. Handy* and Diyar Mayi
Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA
Received 20 August 2007; revised 7 September 2007; accepted 18 September 2007
Available online 21 September 2007
Abstract—Conditions have been identified that enable the one-pot double Suzuki coupling of 4,5-dibromothiophene-2-carboxalde-
hyde to proceed in good yield. The key to success in these reactions is the use of minimal amounts of water to avoid significant
amounts of dehalogenation during the first coupling.
Ó 2007 Elsevier Ltd. All rights reserved.
Stepwise Approach
1. Halogenate
Cross-coupling reactions are a well established family of
reactions that find great use in the preparation of substi-
tuted aromatic compounds.1 Through these reactions,
C–C, C–N, C–O, and even C–S bonds can be formed
with a high degree of control and functional group tol-
erance. As a result, it is hardly surprising that cross-cou-
pling chemistry is one of the main methods employed in
the synthesis of substituted aromatics.
R
R
1. Halogenate
2. Cross-couple
2. Cross-couple
R'
4 steps
One-pot Approach
R
1. Dihalogenate
2. Double
R'
Cross-couple
2 steps
At the same time, the use of cross-coupling chemistry to
introduce more than one substituent is inherently less
than ideal. For each substituent to be installed, a halo-
genation and a coupling reaction are required. Thus, a
minimum of two steps are needed to introduce each
new group. If multiple groups are to be installed, this
results in a very linear sequence (Scheme 1).
Scheme 1. Stepwise vs one-pot cross-coupling methods.
Our earliest efforts developing the polycoupling route to
polysubstituted aromatics focussed on the pyrrole nu-
cleus.2a,b Particularly successful results were obtained
with dibromopyrrole aldehyde 1.2a (Scheme 2) Thus,
the use of palladium acetate as the catalyst provided
excellent selectivity for coupling at C5, with no compet-
ing coupling at C4. By simple addition of a phosphine
ligand with the second boronic acid, though, coupling
at C4 occurred to afford the dicoupled material in good
overall yield.
In an effort to render the use of cross-coupling reactions
to introduce multiple substituents more efficient, we
have been interested in developing the regioselective,
one-pot polycoupling reaction of polyhaloaromatics.2,3
In this case, multiple halogens are introduced in one step
and then, in the second step, different substituents are
introduced via sequential cross-coupling reactions. The
regiocontrol in these cross-coupling reactions is deter-
mined by the electronic differences between the different
halogenated sites and is highly predictable.4
In light of this success, an obvious extension to consider
was related heteroaromatic aldehydes. One such system
pMeOC6H4B(OH)2
Et
N
Et
N
Pd(OAc)2, K2CO3
Br
Br
pMeOC6H4
pFC6H4
CHO
CHO
DMF, 100 ºC, 3-6 h
then
pFC6H4B(OH)2
tBu3P/HBF4
aq Na2CO3, 14 h
2
58%
1
Keywords: Regioselective; Suzuki coupling; Thiophenes; One-pot;
Dehalogenation.
*
Corresponding author. Tel.: +1 615 904 8114; fax: +1 615 898
2956; e-mail: shandy@mtsu.edu
Scheme 2. Pyrrole aldehyde 1 double couplings.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.114

S. T. Handy, D. Mayi / Tetrahedron Letters 48 (2007) 8108–8110
8109
Table 1. Catalyst studies
ArB(OH)2
catalyst
base
S
S
S
Br
Br
Ar
Br
CHO
Ar
CHO
CHO
+
solvent
90 ºC, 12 h
5
3
4
Ar = pMeOC6H4
Entry
Catalyst
Base
Solvent
DMF
EtOH/toluene (1:3 v/v)
DMF
EtOH/toluene (1:3 v/v)
EtOH/toluene (1:3 v/v)
DMF
Product
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2, tBu3P/HBF4
Pd(OAc)2, tBu3P/HBF4
Pd(OAc)2, tBu3P/HBF4
Pd(OAc)2, tBu3P/HBF4
aq K2CO3
aq Na2CO3
K2CO3
aq Na2CO3
Cs2CO3
aq Cs2CO3
Cs2CO3
4 (75%)
Complex mixture
No rxn
4 (82%)
5 (42%)
5 (58%) 4 (38%)
No rxn
Dioxane
is thiophene aldehyde 3.5 Despite the apparent similari-
ties, application of the conditions used for regioselective
couplings of pyrrole aldehyde 1 to aldehyde 3 failed to
afford any significant quantities to the desired double
coupling product.
Table 2. Dioxane/water studies
ArB(OH)2
Pd(Ph3P)4
S
S
S
Br
Br
Ar
Br
CHO
Ar
CHO
CHO
K2CO3
+
solvent
90 ºC, 12 h
5
3
4
Ar = pMeOC6H4
In an effort to determine the source of this failure, inves-
tigation of just the first coupling at C5 was undertaken.
One complication that was quickly noted was the
appearance of a significant by-product 4 in many of
the reactions. This apparent product of coupling fol-
lowed by dehalogenation was difficult to separate from
the mono-coupled product 5.6,7 As can be seen, varia-
tion in solvent when using palladium acetate as the cat-
alyst did not avoid this dehalogenation (Table 1, entries
1 and 4). Curiously, attempts to use anhydrous reaction
conditions did shut down the dehalogenation, but re-
sulted in no reaction (Table 1, entry 3).
Entry
Ratio (H2O/dioxane)
% Yield of 5
% Yield of 4
1
2
3
1:4
1:6
1:8
35
95
35a
55
3
0
a Remainder was covered starting material.
tional base and the second boronic acid needed to be
added. Interestingly, no particular care needed to be ta-
ken to exclude oxygen and these reactions were per-
formed under a simple atmosphere of air rather than
nitrogen or argon.
Next, more active palladium catalysts were examined,
but even bis(tri-tert-butylphosphine)palladium(II) ace-
tate failed to improve the coupling results.8 Choice of
base or solvent made little difference, although again at-
tempts to use anhydrous conditions failed to afford any
coupling or dehalogenation (Table 1, entry 7).
With reaction conditions in hand, the application to a
variety of boronic acids was explored.9,10 (Table 3)
Not unexpectedly, the reaction worked best with elec-
tron-rich boronic acids. Still, electron-deficient and even
alkenyl boronic acids worked at modestly reduced yields
(Table 3, entries 2, 3, and 6). Finally, steric hindrance
From these results, it appeared that the presence of
water was both crucial for the coupling but also in-
volved in the dehalogenation. Indeed, using tetrakis(tri-
phenylphosphine) palladium(0) as the catalyst with
potassium carbonate as the base in a mixture of dioxane
and water supported this hypothesis (Table 2). Thus, in
a 4:1 solvent mixture, dehalogenation was the major
product, while in an 8:1 mixture the reaction failed to
proceed to completion within 24 h. Selecting a value be-
tween these two (6:1) was a good compromise, affording
complete conversion within 5 h, but minimizing the
Table 3. Double coupling results
ArB(OH)2
Pd(Ph3P)4
K2CO3
Dioxane/H2O
90 ºC, 12 h
S
S
Br
Br
CHO
Ar
Ar'
CHO
Ar'B(OH)2
K2CO3
90 ºC, 12 h
3
6
1
amount of dehalogenation (<10% as determined by H
NMR).
Entry
Ar
Ar0
% Yield
1
2
3
4
5
6
p-MeOC6H4
p-FC6H4
Ph
Ph
Ph
p-FC6H4
3,4-DiMeOC6H4
Ph
p-MeOC6H5
97
82
56
80
25
41
Fortunately, the second coupling also proceeded under
these same conditions, enabling a simple one-pot double
coupling method using tetrakis(triphenylphosphine)
palladium(0) and potassium carbonate. The catalyst
remained active for the second coupling, so only addi-
Ph
o-MeOC6H4
trans-Heptenyl

8110
S. T. Handy, D. Mayi / Tetrahedron Letters 48 (2007) 8108–8110
shaker. At this point, the second boronic acid (0.45 mmol)
and more potassium carbonate (0.66 mmol) were added
and the reaction was shaken and heated for an additional
12 h. The reaction was then cooled to room temperature
and partitioned between ether and water. The organic
layer was dried with magnesium sulfate, filtered, and
concentrated in vacuo. The crude residue was purified by
column chromatography using 20% ether/hexanes as the
eluent to afford the double-coupled product.
also decreased the efficiency, but an ortho substituted
boronic acid did afford the coupled product (Table 3,
entry 5).
In short, we have identified conditions that are effective
for the regioselective double Suzuki coupling of
thiophene aldehyde 3. This sequential, one-pot reaction
affords the double-coupled products in generally good
yield and is expected to be of great utility in the prepa-
ration of substituted thiophenes for a variety of applica-
tions. Efforts are currently underway to extend these
dicoupling conditions to furfural and other thiophenes.
10. All new compounds exhibited spectral properties consis-
tent with the assigned structures. 5-(40-Methoxyphenyl)-4-
phenylthiophene-2-carboxaldehyde: Brown oil. IR (cmꢀ1
,
neat) 2860, 2820, 1665, 1435 1252, 1176, 1043, 831; 1H
NMR (360 MHz, CDCl3) 9.89 (s, 1H), 7.77 (s, 1H), 7.34–
7.24 (m, 7H), 6.82 (d, J = 6.8 Hz, 2H), 3.81 (s, 3H); 13C
NMR (90 MHz, CDCl3) 183.0, 160.2, 149.2, 140.7, 139.6,
138.9, 135.5, 130.6, 129.1, 128.8, 127.7, 125.5, 114.3, 55.4.
HRMS (EI) Calcd for C18H14O2S 402.0784; found,
Acknowledgments
Financial support by the NIH (GM074662-01) and a
gift of boronic acids from Frontier Scientific are grate-
fully acknowledged.
402.0785.
5-(40-Fluorophenyl)-4-phenylthiophene-2-car-
boxaldehyde: Tan solid. Mp 78–79 °C. IR (cmꢀ1, neat)
1
2860, 2820, 1645, 1375, 1236, 1159, 1038, 835; H NMR
(360 MHz, CDCl3) 9.92 (s, 1H), 7.79 (s, 1H), 7.59 (d,
J = 6.8 Hz, 2H), 7.44 (t, J = 6.8 Hz, 2H), 7.34–7.24 (m,
3H), 7.00 (t, J = 8.6 Hz, 2H); 13C NMR (90 MHz, CDCl3)
182.9, 166.3, 147.5, 141.5, 139.8, 139.2, 135.0, 131.1 (d,
J = 34 Hz), 130.7, 129.1 (d, J = 60 Hz), 128.9, 127.9, 116.0
(d, J = 54 Hz). HRMS (EI) Calcd for C17H11OS 390.0515;
found, 390.0515. 4-(40-Fluorophenyl)-5-phenylthiophene-2-
carboxaldehyde: Brown oil. IR (cmꢀ1, neat) 2860, 2820,
1650, 1480, 1232, 1162, 1041, 829; 1H NMR (360 MHz,
CDCl3) 9.92 (s, 1H), 7.77 (s, 1H), 7.34–7.18 (m, 7H), 7.01
(t, J = 9.2 Hz, 2H); 13C NMR (90 MHz, CDCl3) 182.9,
164.0, 160.7, 148.8, 141.6, 138.9, 138.5, 133.0, 131.2, 130.8
(d, J = 32 Hz), 129.2 (d, J = 100 Hz), 128.8, 115.8 (d,
J = 86 Hz). HRMS (EI) Calcd for C17H11FOS 390.0515;
found, 390.0517. 4-(30,40-Dimethoxyphenyl)-5-phenylthi-
ophene-2-carboxaldehyde: Tan solid. Mp 152–155 °C. IR
(cmꢀ1, neat) 2860, 2820, 1668, 1513, 1465, 1432, 1251,
References and notes
1. Handbook of Organopalladium Chemistry for Organic
Chemistry; Negishi, E., Ed.; John Wiley & Sons: New
York, 2002; Vol. 1.
2. (a) Handy, S. T.; Sabatini, J. J. Org. Lett. 2006, 8, 1537–
1539; (b) Handy, S. T.; Zhang, Y. Synthesis 2007, 3883–
3887; (c) Handy, S. T.; Wilson, T.; Muth, A. J. Org. Chem.
72, in press.
3. For examples from other groups, see: (a) Kaswasaki, I.;
Yamashita, M.; Ohta, S. Chem. Commun. 1994, 2085–
2086; (b) Beletskaya, I. P.; Tsvetkov, A. V.; Tsvetkov, P.
V.; Latyshev, G. V.; Lukashev, N. V. Russ. Chem. Bull.
2005, 54, 215–219; (c) Duan, X. F.; Li, X. H.; Li, F. Y.;
Huang, C. H. Synthesis 2004, 2614–2616.
4. Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299–301.
5. No previous efforts have been reported on the regioselec-
tive coupling of thiophene aldehyde 3, although one report
has investigated 3,5-dibromothiophene-2-carboxaldehyde
Kodani, T.; Matsude, K.; Yamada, T.; Kobatake, S.; Irie,
M. J. Am. Chem. Soc. 2000, 122, 9631–9637.
6. Interestingly, the formation of 4 does not appear to be the
result of dehalogenation of 5, since resubjection of 5 to the
reaction conditions, but in the absence of a boronic acid,
does not result in the formation of 4 and resubjection of 5
to the reaction conditions in the presence of a boronic acid
only affords the product of a second Suzuki coupling.
7. The identity of compound 4 was confirmed by comparison
to the spectral data for this compound reported in the
literature Alson, D. A.; Najera, C.; Pacheco, M. C. J. Org.
Chem. 2002, 67, 5588–5594, Hydrogenolysis of 5 also
affords compound 4, thereby confirming the regioselectiv-
ity of the first coupling.
1
1027, 845; H NMR (360 MHz, CDCl3) 9.92 (s, 1H), 7.80
(s, 1H), 7.36–7.30 (m, 5H), 6.86 (d, J = 6.8 Hz, 1H), 6.85
(s, 1H), 6.68 (d, J = 6.8 Hz, 1H), 3.89 (s, 3H), 3.63 (s, 3H);
13C NMR (90 MHz, CDCl3) 182.9, 148.8, 141.3, 139.4,
138.9, 129.4, 128.9, 128.8, 127.7, 121.3, 119.2, 112.3, 111.5,
111.2, 110.4, 55.9, 55.7. HRMS (EI) Calcd for C19H16O3S
432.0820; found, 432.0818. 5-(20-Methoxyphenyl)-4-phe-
nylthiophene-2-carboxaldehyde: Tan wax. Mp 77–78 °C.
IR (cmꢀ1, neat) 2860, 2820, 1164, 1460, 1248, 1025, 831;
1H NMR (360 MHz, CDCl3) 9.94 (s, 1H), 7.85 (s, 1H),
7.28–7.22 (m, 6H), 7.08–7.00 (m, 1H), 6.93 (t, J = 6.8 Hz,
1H), 6.86 (d, J = 6.8 Hz, 1H), 3.49 (s, 3H); 13C NMR
(90 MHz, CDCl3)183.1, 156.7, 142.0, 141.2, 138.1, 136.2,
132.0, 131.5, 130.7, 128.4, 128.0, 127.4, 120.8, 120.6, 111.6,
55.2. HRMS (EI) Calcd for C18H14O2S 402.0784; found,
402.0783. 5-(trans-Heptenyl)-4-(40-methoxyphenyl)thio-
phene-2-carboxaldehyde: Yellow solid. Mp 74–75 °C. IR
(cmꢀ1, neat) 2860, 2820, 1164, 1508, 1437, 1289, 1246,
1177, 835, 741; 1H NMR (360 MHz, CDCl3) 9.83 (s, 1H),
7.63 (s, 1H), 7.30 (d, J = 6.6 Hz, 2H), 6.98 (d, J = 6.6 Hz,
2H), 6.54 (d, J = 14.4 Hz, 1H), 6.36 (dt, J = 6.7, 14.4 Hz,
1H), 3.86 (s, 3H), 2.18 (q, 2H), 1.46–1.24 (m, 6H), 0.89 (t,
3H); 13C NMR (90 MHz, CDCl3) 182.8, 159.3, 147.2,
139.5, 139.2, 139.0, 137.1, 130.2, 128.5, 122.2, 114.2, 55.4,
33.3, 31.5, 28.7, 22.6, 14.1. HRMS (EI) Calcd for
C19H22OS 406.1391; found, 406.1390.
8. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295–
4298.
9. Representative procedure: To a solution of dibromothio-
phene aldehyde 3 (0.3 mmol) in 4 mL of dioxane/water
(6:1 v/v) was added boronic acid (0.33 mmol), potassium
carbonate (0.6 mmol), and tetrakis(triphenylphosphine)
palladium(0) (0.015 mmol). The reaction mixture was
heated to 90 °C overnight (12 h) and shaken on an orbital