Direct alkynylation of thiophenes: Cooperative activation of TIPS-EBX with gold and Bronsted acids

Article abstract of DOI:10.1002/anie.201003179

United we stand! Cooperative activation of the hypervalent-iodine reagent TIPS-EBX with a gold catalyst and a Bronsted acid allowed the first direct ethynylation of thiophenes at room temperature (see scheme; TFA = trifluoroacetic acid). The obtained ethynylthiophenes are important building blocks for organic dyes and electronic materials.

Full text of DOI:10.1002/anie.201003179

Communications
DOI: 10.1002/anie.201003179
Cooperative Catalysis
Direct Alkynylation of Thiophenes: Cooperative Activation of TIPS–
EBX with Gold and Brønsted Acids**
Jonathan P. Brand and Jꢀrꢁme Waser*
Table 1: Reaction optimization and discovery of the Brønsted acid
activation.
Thiophene is a ubiquitous heterocycle in both medicinal
chemistry and materials science.[1] Oligo- and polythiophenes
play a crucial role in organic electronic materials.[2] For most
applications, extended p-electron systems are required, which
are usually prepared by cross-coupling methods.[3] Direct
arylation has recently emerged as a more step- and atom-
economic alternative.[4] However, no direct alkynylation of
thiophenes has been reported to date, even though oligo- and
poly(arylene ethynylene)s are an important class of organic
materials.[5] Consequently, more direct methods to access
ethynylthiophenes in particular would be highly desirable.
The direct alkynylation of (hetero)aromatic compounds
has become an active research area.[6,7] The direct alkynyla-
tion of thiophenes, however, remains elusive. In fact, the
extension of known alkynylation methodologies to thiophene
is not easy, because of its low reactivity.[4,8] Herein, we report
the alkynylation of thiophenes by using 1-[(triisopropyl-
silyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS–EBX; 1).
The reaction proceeded at room temperature under air
[Eq. (1)]. The discovery of a cooperative effect between a
gold catalyst and a Brønsted acid allowed the development of
the direct silylethynylation of thiophenes.
Entry
Solvent
Conc. 2a [m]
Additive[b]
Yield [%][a]
1
2
3
4
5
6
7
8
9
Et2O
0.05
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.2
–
–
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
14[c]
62
Zn(OTf)2
CH3CO2H
ClCH2CO2H
Cl3CCO2H
TFA
18
53
73
84
TsOH
0
TFA[d]
50
10
TFA
94 (83)[e]
[a] Reaction conditions: 0.20 mmol 2a, 0.24 mmol 1, and 0.01 mmol
AuCl under N2 for 12–15 h; yields determined by GC using pentadecane
as reference. [b] 1.2 equiv additive. [c] Reaction run at 608C. [d] 0.1 equiv
TFA. [e] Isolated yield; Hex=hexyl; Tf=trifluoromethanesulfonic ; Ts=
toluene-4-sulfonyl.
temperatures led to only slightly better results (Table 1,
entry 2), thus demonstrating the challenges associated with
the less reactive thiophenes. Inspired by recent examples on
the activation of benziodoxole reagents,[9g–h] we then
attempted the reaction in presence of Lewis or Brønsted
acids (Table 1, entries 3–8). The best result (84% yield) was
obtained with trifluoroacetic acid (TFA; 1 equivalent with
respect to 1). A correlation between the yield and the acid
strength was observed, but no product was obtained with
acids stronger than TFA; in this case the starting material
decomposed (Table 1, entry 8). TFA could also be used
catalytically, but the yield was lower (Table 1, entry 9). The
alkynylation reaction did not occur in the absence of AuCl. To
the best of our knowledge, this result is the first example of
the cooperative activation of a benziodoxolone reagent with a
gold catalyst and a Brønsted acid.[10] In contrast to most direct
arylation methods of thiophenes, the alkynylation did not
require heating. A reaction under more dilute conditions
(0.2m) gave the product in 94% yield (83% isolated
compound; Table 1, entry 10). Other solvents or gold catalysts
gave lower yields.[11] No product was afforded when alkyn-
yliodonium salts and bromo- or iodoalkynes were used, hence
showing the unique properties of TIPS-EBX 1.[12] On a
2 mmol scale, 3a was obtained in 84% yield by using only 1
mol% AuCl under air without drying the solvents.[13]
2-Iodobenzoic acid could be recovered in 86% yield by a
simple basic workup and could be recycled for the synthesis of
TIPS–EBX (1).[14]
Recently, our research group reported the direct alkyny-
lation of indoles and pyrroles by using AuCl and TIPS-
EBX.[7,9] Unfortunately, when the reaction was applied to
thiophenes only traces of 3a were observed under the
reaction conditions (Table 1, entry 1). An increased concen-
tration, use of acetonitrile as solvent, and higher reaction
[*] J. P. Brand, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (Switzerland)
Fax: (+41)21-693-9700
E-mail: jerome.waser@epfl.ch
Homepage: http://isic.epfl.ch/lcso
[**] EPFL is acknowledged for financial support, Prof. Holger Frauenrath
and Jan Gebers (LMOM, EPFL) for fruitful discussions, and Prof.
Xile Hu (LSCI, EPFL) for proofreading this manuscript. TIPS–
EBX=[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003179.
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The scope of the reaction was then examined. 2-Alkyl-
substituted thiophenes were alkynylated in good yields
(Table 2, entries 1–2). Monoalkynylation of thiophene (2c)
was achieved when thiophene was used as a solvent without
TFA (Table 2, entry 3). 2-Methoxythiophene (2d) was also
alkynylated without TFA (Table 2, entry 4).[15] The reaction
was tolerant towards functional groups such as alcohols,
carbamates, esters, and amides, including a protected amino
acid (Table 2, entries 5–9). The reaction was slower in the
presence of protected amines or esters, and full conversion
could not be achieved under standard conditions. Fortunately,
the use of 10 mol% of catalyst, two equivalents of TIPS–
EBX, and a higher concentration of TFA afforded the desired
products in moderate to good yields (Table 2, entries 7–9).
Only traces of product were observed for less nucleophilic
substrates with electron-withdrawing groups directly attached
to the thiophene.[16]
Table 2: Scope of the ethynylation of thiophenes.
Entry Substrate
Product
Yield
[%][a]
We then turned to 2-aryl thiophenes, because substrates
with extended p systems are more useful for applications in
materials science (Table 2, entries 10–12). Gratifyingly,
full conversion could be achieved (Table 2, entries 10–11).
4-Bromophenylthiophene (2k) could be successfully alkyny-
lated, thus demonstrating the orthogonality of the method to
classical cross-coupling reactions (Table 2, entry 11). The
alkynylation of 2,2’-bithiophenes gave useful building blocks
for the elaboration of oligothiophenes (Table 2, entries 13–
15).[2] 3-Methoxythiophene (2p) was selectively alkynylated
at the 2 position (Table 2, entry 16). 3,4-Ethylene-dioxythio-
phene (EDOT, 2q) could be either mono- or bisalkynylated,
depending on the reaction stoichiometry (Table 2, entries 17–
18). Reaction of 2,5-methylthiophene (2r) furnished the
3-substituted alkynylated product 3s in 48% yield (Table 2,
entry 19). Less reactive benzothiophenes were then inves-
tigated; gratifyingly, full conversion was obtained with 5
mol% of AuCl for benzothiophene (2s), but no regioselec-
tivity was observed (Table 2, entry 20).[17] Finally, reaction of
3-methylbenzothiophene (2t) afforded 3v in 73% yield
(Table 2, entry 21).
1
2
R=Hexyl 2a
R=Methyl 2b
3a
3b
3c
3d
3e
3 f
83
80
73
68
50
65
81
55
62
3[b,c] R=H 2c
4[c]
5
R=OMe 2d
R=CH2OH 2e
R=CH2CH2OH 2 f
R=CH2NHCbz 2g
R=CH2CO2Et 2h
6
7[d]
8[d]
9[d]
3g
3h
R=C2H4NH(CbzVal) 3i
2i
10[d] R=Phenyl 2j
3j
3k
3l
70
67
67
11[d] R=4-BrPhenyl 2k
12
R=4-MeOPhenyl 2l
13
R2 =Hexyl 2m
3m
3n
3o
68
73
61
14[e] R2 =Methyl 2n
15[d] R2 =Bromo 2o
Our methodology allowed rapid access to oligothiophenes
(Scheme 1). 2-Hexylthiophene (2a) was alkynylated under
standard conditions and deprotected to afford acetylene 4 in
16
63
17[f]
70
18[g]
19
71
48
Scheme 1. Straightforward synthesis of terthiophene 5. Reaction con-
ditions: a) 1 (1.2 equiv), TFA (1.2 equiv), 5 mol% AuCl, CH3CN, RT;
b) tetra-n-butylammonium fluoride (TBAF; 1.2 equiv)), THF, 08C,
78% over 2 steps; c) Cu(OAc)2, (2 equiv), CH3CN, 808C, then
Na2S·3H2O (4 equiv), 808C, 18 h, 86%.
20[h]
65
73
78% yield. Instead of the reported two-step sequence,[18] we
developed a one-pot procedure that involves a copper-
mediated dimerization and cyclization with Na2S to give
terthiophene 5 in 86% yield.
21[h]
Our research group[7] and others[6k] have proposed that the
gold-catalyzed alkynylation could proceed either through an
AuIII acetylide complex or by p activation of the triple bond.
A mechanism that involves a reaction at the iodine atom or a
single-electron transfer[19] (SET) appeared less probable, as it
would be difficult to rationalize the role of the metal catalyst.
However, this possibility cannot be excluded at this stage. The
cooperative effect observed here with Brønsted acids is
[a] Reaction conditions: 0.40 mmol 2 (0.2m in CH3CN), 0.48 mmol 1, 5
mol% AuCl, 0.48 mmol TFA, RT, 12–60 h. Yields of isolated products are
shown.[b] Thiophene used as solvent. [c] Without TFA. [d] 2 equiv 1 and
TFA, 10 mol% AuCl, 2 (0.4m in CH3CN). [e] Product was shown to be
85% pure by NMR spectroscopy. [f] Without TFA, 1 equiv 1, 3 equiv 2q.
[g] 2.2 equiv 1 and TFA. [h] 1.5 equiv 1 and TFA; Cbz=carboxybenzyl;
Val =valine.
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(Eds.: F. Diederich, P. J. Stang, R. R. Tykwinski), Wiley-VCH,
Weinheim, 2005; b) D. K. James, J. M. Tour, Top. Curr. Chem.
2005, 257, 33.
particularly intriguing. TFA could promote the 2-auration
of thiophene.[20] However, no product was obtained when
2-[(triphenylphosphine)gold]thiophene[21] was treated with 1
in the presence or absence of TFA. TIPS-EBX could also be
activated by TFA.[9g–h] No product was observed when using
the trifluoromethanesulfonic acid (TfOH) adduct of TIPS-
EBX, but a 54% yield (determined by GC) was obtained
when using the TFA adduct.[22] At this point, it is not clear if
the latter TFA adduct represented an activated form of the
reagent, or just served as a source of TFA during the reaction.
Stoichiometric mixtures of AuCl and 1 gave 2-iodobenzoic
acid and 1,4-bis(triisopropylsilyl)buta-1,3-diyne; no strong
effect of the TFA was observed.[23] No gold-containing
intermediate could be detected, hence these results did not
allow us to discriminate with certitude between an oxidative
or a p-activation mechanism. Further investigations will be
needed to understand the mechanism of the reaction and the
Brønsted acid effect.
[6] For a review, see: a) A. S. Dudnik, V. Gevorgyan, Angew. Chem.
2010, 122, 2140; Angew. Chem. Int. Ed. 2010, 49, 2096. For
selected examples, see: b) K. Kobayashi, M. Arisawa, M.
Yamaguchi, J. Am. Chem. Soc. 2002, 124, 8528; c) M. Tobisu,
Y. Ano, N. Chatani, Org. Lett. 2009, 11, 3250; d) I. V. Seregin, V.
Ryabova, V. Gevorgyan, J. Am. Chem. Soc. 2007, 129, 7742; e) N.
Matsuyama, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2009, 11,
4156; f) F. Besseliꢁvre, S. Piguel, Angew. Chem. 2009, 121, 9717;
Angew. Chem. Int. Ed. 2009, 48, 9553; g) S. H. Kim, S. Chang,
Org. Lett. 2010, 12, 1868; h) B. A. Trofimov, Z. V. Stepanova,
L. N. Sobenina, A. I. Mikhaleva, I. A. Ushakov, Tetrahedron
Lett. 2004, 45, 6513; i) Y. H. Gu, X. M. Wang, Tetrahedron Lett.
2009, 50, 763; j) T. Hamada, X. Ye, S. S. Stahl, J. Am. Chem. Soc.
2008, 130, 833; k) T. de Haro, C. Nevado, J. Am. Chem. Soc.
2010, 132, 1512; l) Y. Wei, H. Q. Zhao, J. Kan, W. P. Su, M. C.
Hong, J. Am. Chem. Soc. 2010, 132, 2522.
[7] J. P. Brand, J. Charpentier, J. Waser, Angew. Chem. 2009, 121,
9510; Angew. Chem. Int. Ed. 2009, 48, 9346.
In summary, we have reported the first direct alkynylation
of thiophenes mediated by gold and TFA at room temper-
ature. The scope of the reaction included deactivated
conjugated systems, such as aryl thiophenes, bithiophenes,
and benzothiophenes, which are important for organic
materials. The unique reactivity of TIPS-EBX is crucial for
the success of the reaction. Activation by both the gold
catalyst and the Brønsted acid was required; the discovery of
this cooperative effect is expected to significantly expand the
scope of benziodoxolone-based alkynylation reactions. Inves-
tigations on the mechanism and the extension of the scope of
the reaction are currently under way in our laboratory.
[8] H. Mayr, A. R. Ofial, J. Phys. Org. Chem. 2008, 21, 584.
[9] For general reviews on hypervalent iodine, see: a) “Hypervalent
Iodine Chemistry: Modern Developments in Organic Synthe-
sis”: T. Wirth, M. Ochiai, V. V. Zhdankin, G. F. Koser, H. Tohma,
Y. Kita, Topics of Current Chemistry, Vol. 224, Springer, Berlin,
2003; b) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008, 108, 5299;
for selected examples of heterocycle functionalization using
hypervalent iodine, see: c) N. R. Deprez, D. Kalyani, A. Krause,
M. S. Sanford, J. Am. Chem. Soc. 2006, 128, 4972; d) R. J. Phipps,
M. J. Gaunt, Science 2009, 323, 1593; e) E. A. Merritt, B.
Olofsson, Angew. Chem. 2009, 121, 9214; Angew. Chem. Int.
Ed. 2009, 48, 9052. For uses of benziodoxol(on)es, see: f) I.
Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. 2007, 119, 768;
Angew. Chem. Int. Ed. 2007, 46, 754; g) R. Koller, K. Stanek, D.
Stolz, R. Aardoom, K. Niedermann, A. Togni, Angew. Chem.
2009, 121, 4396; Angew. Chem. Int. Ed. 2009, 48, 4332; h) A. E.
Allen, D. W. C. MacMillan, J. Am. Chem. Soc. 2010, 132, 4986;
i) S. Nicolai, S. Erard, D. Gonzalez Fernandez, J. Waser, Org.
Lett. 2010, 12, 384.
Received: May 26, 2010
Published online: August 20, 2010
Keywords: alkynes · cooperative catalysis · direct alkynylation ·
.
heterocycles · hypervalent iodine
[10] The effect of the Brønsted acid described here is different from
the reported acceleration of a proto-deauration step; see:
A. S. K. Hashmi, Catal. Today 2007, 122, 211.
[11] See the Supporting Information.
[12] The success of TIPS-EBX 1 is probably caused by steric
shielding, which prevents side reactions.
[1] The Chemistry of Heterocyclic Compounds, Vol. 44, Wiley-
Interscience, New York, 1994.
[2] a) A. R. Murphy, J. M. J. Frechet, Chem. Rev. 2007, 107, 1066;
b) S. Allard, M. Forster, B. Souharce, H. Thiem, U. Scherf,
Angew. Chem. 2008, 120, 4138; Angew. Chem. Int. Ed. 2008, 47,
4070; c) A. Mishra, C. Q. Ma, P. Bꢀuerle, Chem. Rev. 2009, 109,
1141.
[13] For comparison, the corresponding TMS acetylene was obtained
in two steps and 72% yield from 2-hexylthiophene (2a) by using
a bromination–Sonogashira sequence: A. van Breemen, P. T.
Herwig, C. H. T. Chlon, J. Sweelssen, H. F. M. Schoo, S.
Setayesh, W. M. Hardeman, C. A. Martin, D. M. de Leeuw,
J. J. P. Valeton, C. W. M. Bastiaansen, D. J. Broer, A. R. Popa-
Merticaru, S. C. J. Meskers, J. Am. Chem. Soc. 2006, 128, 2336.
[14] V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, J. T. Bolz, A. J.
Simonsen, J. Org. Chem. 1996, 61, 6547. The synthesis of 1
proceeded in 79% yield over 2 steps from 2-iodobenzoic acid on
a 30 g scale. This compound will soon be commercially available.
[15] For electron-rich thiophenes, the higher reactivity observed in
presence of TFA is sometimes counterbalanced by the acid-
mediated decomposition. In some cases, better yields are
obtained without TFA. The optimal conditions are given in
Table 2.
[3] Metal-Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: A.
De Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004.
[4] a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107,
174; b) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36,
1173; c) L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem.
2009, 121, 9976; Angew. Chem. Int. Ed. 2009, 48, 9792; For
selected examples involving thiophenes, see: d) T. Okazawa, T.
Satoh, M. Miura, M. Nomura, J. Am. Chem. Soc. 2002, 124, 5286;
e) K. Masui, H. Ikegami, A. Mori, J. Am. Chem. Soc. 2004, 126,
5074; f) A. Battace, M. Lemhadri, T. Zair, H. Doucet, M.
Santelli, Adv. Synth. Catal. 2007, 349, 2507; g) S. Yanagisawa, K.
Ueda, H. Sekizawa, K. Itami, J. Am. Chem. Soc. 2009, 131,
14622. For a metal-free approach, see: h) Y. Kita, K. Morimoto,
M. Ito, C. Ogawa, A. Goto, T. Dohi, J. Am. Chem. Soc. 2009, 131,
1668.
[16] 2-Bromo-3-hexyl-, 2-formyl- and 3-acetyl- thiophenes were
tested.
[17] The low regioselectivity observed for benzothiophene could not
yet be rationalized.
[5] a) “Semiconducting Poly(arylene ethylene)s”: T. M. Swager in
Acetylene Chemistry: Chemistry, Biology and Material Science
[18] J. Kagan, S. K. Arora, J. Org. Chem. 1983, 48, 4317.
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[19] a) V. V. Grushin, Acc. Chem. Res. 1992, 25, 529; b) T. Dohi, M.
Ito, N. Yamaoka, K. Morimoto, H. Fujioka, Y. Kita, Angew.
Chem. 2010, 122, 3406; Angew. Chem. Int. Ed. 2010, 49, 3334.
When the reaction was carried out in the presence of 3,5-di-tert-
butyl-4-hydroxytoluol (BHT), full conversion was observed, but
the reaction was impeded by the addition of 2,2,6,6-tetrame-
thylpiperidine-1-oxyl (TEMPO). However, the result obtained
with TEMPO could also be caused by the oxidative degradation
of the catalyst.
J. Organomet. Chem. 2009, 694, 592 – 597. For a selected review
on gold catalysis, see: d) A. S. K. Hashmi, Chem. Rev. 2007, 107,
3180.
[21] F. Bonati, A. Burini, B. R. Pietroni, R. Galassi, Gazz. Chim. Ital.
1993, 123, 691. [AuPPh3Cl] itself was a viable catalyst for the
reaction, although less efficient than AuCl (see the Supporting
Information).
[22] The TfOH adduct of 1 is a well-behaved solid compound that
could be fully characterized (see the Supporting Information). In
contrast, the TFA adduct gave an oil upon evaporation of the
solvent; further studies to determine its structure are under way.
[23] 1,4-Bis(triisopropylsilyl)buta-1,3-diyne and 2-iodo benzoic acid
À
[20] For selected examples of auration of aromatic C H bonds, see:
a) Z. G. Li, D. A. Capretto, R. O. Rahaman, C. He, J. Am. Chem.
Soc. 2007, 129, 12058; b) P. F. Lu, T. C. Boorman, A. M. Z.
Slawin, I. Larrosa, J. Am. Chem. Soc. 2010, 132, 5580. For
examples of reactions of organogold intermediates with oxi-
dants, see: c) A. S. K. Hashmi, T. D. Ramamurthi, F. Rominger,
1
were detected as the major products by H NMR spectroscopy
and GC–MS, but could not be separated from other impurities
formed during the reaction.
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