Para-selective gold-catalyzed direct alkynylation of anilines

Article abstract of DOI:10.1021/ol203289v

A method for the para-selective alkynylation of anilines is reported using AuCl as catalyst and triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) as an electrophilic acetylene equivalent. Para-alkynyl anilines substituted at positions 2 or 3 w

Full text of DOI:10.1021/ol203289v

ORGANIC
LETTERS
2012
Vol. 14, No. 3
744–747
Para-Selective Gold-Catalyzed Direct
Alkynylation of Anilines
ꢀ ^
Jonathan P. Brand and Jerome Waser*
Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and
ꢀ ꢀ
Engineering, Ecole Polytechnique Federale de Lausanne, EPFL SB ISIC LCSO,
BCH 4306, 1015 Lausanne, Switzerland
jerome.waser@epfl.ch
Received December 9, 2011
ABSTRACT
A method for the para-selective alkynylation of anilines is reported using AuCl as catalyst and triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one
(TIPS-EBX) as an electrophilic acetylene equivalent. Para-alkynyl anilines substituted at positions 2 or 3 were obtained in one step from simple
anilines under mild conditions (room temperature to 60 °C) under air. The methodology could also be extended to the alkynylation of
trimethoxybenzenes.
Heteroarylacetylenes are important structures in both
organic synthesis and material sciences.1 They are versatile
building blocks thanks to the large number of transforma-
tions available based on the functionalization of the triple
bond. In addition, both aromatics and acetylenes have
been successfully used in extended π systems for organic
electronic materials.2 To access heteroarylacetylenes, the
Sonogashira reaction is one of the most popular methods
for sp2ꢀspbond formation.3 However, the main drawback
of this method is the required prefunctionalization of the
sp2 carbon. Numerous methods have been developed in the
field of CꢀH arylation to avoid this prefunctionalization
of aromatics.4 Surprinsingly, reports of direct alkynyla-
tions were scarce up to 2009.5 Since then, important break-
throughs have been realized and several groups reported
new CꢀH alkynylation methods.6 Our group especially
focused on the functionalization of electron-rich hetero-
cycles such as indoles, pyrroles and thiophenes using
triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one
(TIPS-EBX (1)) as an electrophilic alkynylation reagent
and AuCl as catalyst.7 The focus on the synthesis of
silylated acetylenes is motivated by their simple deprotec-
tion to access the synthetically highly versatile terminal
alkynes.
(1) Diederich, F.; Stang, P. J.; Tykwinski, R. R. Acetylene Chemistry:
Chemistry, Biology and Material Science; Wiley-VCH: Weinheim, 2005.
(2) (a) Tour, J. M. Acc. Chem. Res. 2000, 33, 791. (b) Tour, J. M.
Chem. Rev. 1996, 96, 537. (c) Moore, J. S. Acc. Chem. Res. 1997, 30, 402.
(d) Haley, M. M.; Pak, J. J.; Brand, S. C. Top. Curr. Chem. 1999, 201, 81.
(e) Youngs, W. J.; Tessier, C. A.; Bradshaw, J. D. Chem. Rev. 1999, 99,
3153. (f) Haley, M. M. Synlett 1998, 557. (g) Pinto, M. R.; Schanze, K. S.
Synthesis 2002, 1293. (h) Yamamoto, T. Synlett 2003, 425. (i) Tobe, Y.;
Sonoda, M. In Modern Cyclophane Chemistry; Gleiter, R., Hopf, H., Eds.;
Wiley VCH: Weinheim, 2004; p 1. (j) Swager, T. M.; Semiconducting
Poly(arylene ethylene)s. In Acetylene Chemistry: Chemistry, Biology and
Material Science; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-
VCH: Weinheim, 2005. (k) James, D. K.; Tour, J. M. Top. Curr. Chem. 2005,
257, 33.
Presently, there are only two reports for the alkynylation
of anilines by Yamaguchi and Chatani,5b,6j with both
(4) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174. (b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (c)
Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269. (d) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792.
(5) (a) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am. Chem.
Soc. 2002, 124, 8528. (b) Amemiya, R.; Fujii, A.; Arisawa, M.;
Yamaguchi, M. J. Organomet. Chem. 2003, 686, 94. (c) Seregin, I. V.;
Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. For non
catalytic methods, see: (d) Trofimov, B. A.; Stepanova, Z. V.; Sobenina,
L. N.; Mikhaleva, A. I.; Ushakov, I. A. Tetrahedron Lett. 2004, 45, 6513.
(e) Kalinin, V. N.; Pashchenko, D. N.; She, F. M. Mendeleev Commun.
1992, 60.
(3) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Sonogashira, K. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002;
p 493. (c) Sonogashira, K. J. Organomet. Chem. 2002, 653.
r
10.1021/ol203289v
Published on Web 01/19/2012
2012 American Chemical Society

methods affording exclusively ortho-alkynylated products.
This selectivity was rationalized by a mechanism involving
a directing effect of the nitrogen functional group. As the
gold-catalyzed alkynylation did not require a directing
group, we hypothesized that para-selective functionaliza-
tion could be realized (Scheme 1). Herein, we report the
development of the first para-selective alkynylation of ani-
lines using TIPS-EBX (1) as acetylene-transfer reagent,
which proceeds under mild conditions (room temperature
to 60 °C, ambient atmosphere).
anilines would constitute an important advance, not only
in the field ofacetylene chemistrybut alsofor gold catalysis
in general, especially in light of nitrogen-containing groups
being reported to deactivate gold catalysts in several
cases.14
To investigate the alkynylation of protected anilines
with TIPS-EBX (1),15 we decided to use N,N-benzylaniline
(5a) as model compound since it is more nucleophilic than
the corresponding carbamate and the benzyl groups are
easily removed by hydrogenation. Unfortunately, the re-
action conditions previously optimized for indoles7a only
afforded a 14% yield employing N,N-dibenzylaniline (5a)
as substrate (Table 1, entry 1) due to low conversion. The
outcome of the reaction was highly dependent on the
Scheme 1. Direct Alkynylation of Anilines
i
solvent, with PrOH giving the best result (entries 2ꢀ4).
No ortho alkynylation was observedfor aniline 5a. Theuse
of 1.4 equiv of TIPS-EBX (1) was optimal (entries 4ꢀ6).
The use of a higher concentration did not improve the yield
(entry 7). Best results were obtained when the reaction was
not pushed to full conversion to prevent the formation of
Para-alkynyl anilines are widely used in material
sciences, especially as strong electron donors in pushꢀpull
chromophores for applications in optoelectronic devices
(Figure 1).8 For example, tetraalkyne 2 has shown easily
tunable photochromic properties.8f The tetraethynylene 3
(TEES) has molecular photoswitch properties.8d Further-
more, ethynylanilines are used as starting materials for the
synthesis of chromophores based on core structure 4 via
[2 þ 2]-cycloaddition with tetracyanoethene followed by
retro-electrocyclization.8e Consequently, an efficient ac-
cess to para-alkynylated anilines would lead to a more
straightforward synthesis of electronic organic materials.
(6) Reviews: (a) Dudnik, A. S.; Gevorgyan, V. Angew. Chem. Int., Ed.
2010, 49, 2096. (b) Messaoudi, S.; Brion, J. D.; Alami, M. Eur. J. Org.
Chem. 2010, 6495. Selected examples: (c) Matsuyama, N.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2009, 11, 4156. (d) Kawano, T.;
Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2010, 75, 1764. (e) Kitahara, M.; Hirano, K.; Tsurugi, H.; Satoh, T.;
Miura, M. Chem.;Eur. J. 2010, 16, 1772. (f) Matsuyama, N.; Kitahara,
M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2358. (g)
Besselievre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553. (h)
Berciano, B. P.; Lebrequier, S.; Besselievre, F.; Piguel, S. Org. Lett. 2010,
12, 4038. (i) Kim, S. H.; Chang, S. Org. Lett. 2010, 12, 1868. (j) Tobisu,
M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. (k) Gu, Y. H.; Wang,
X. M. Tetrahedron Lett. 2009, 50, 763. (l) de Haro, T.; Nevado, C. J. Am.
Chem. Soc. 2010, 132, 1512. (m) Yang, L.; Zhao, L. A.; Li, C. J. Chem.
Commun. 2010, 46, 4184.
(7) (a) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed.
2009, 48, 9346. (b) Brand, J. P.; Waser, J. Angew. Chem., Int. Ed. 2010,
49, 7304. (c) Brand, J. P.; Chevalley, C.; Waser, J. Beilstein J. Org. Chem.
2011, 7, 565. First synthesis of TIPS-EBX (1): (d) Zhdankin, V. V.;
Kuehl, C. J.; Krasutsky, A. P.; Bolz, J. T.; Simonsen, A. J. J. Org. Chem.
1996, 61, 6547.
(8) Selected examples: (a) Kivala, M.; Diederich, F. Acc. Chem. Res.
2009, 42, 235. (b) Gobbi, L.; Elmaci, N.; Luthi, H. P.; Diederich, F.
ChemPhysChem 2001, 2, 423. (c) Bosshard, C.; Spreiter, R.; Gunter, P.;
Tykwinski, R. R.; Schreiber, M.; Diederich, F. Adv. Mater. 1996, 8, 231.
(d) Gobbi, L.; Seiler, P.; Diederich, F. Angew. Chem., Int. Ed. 1999, 38,
674. (e) Reutenauer, P.; Kivala, M.; Jarowski, P. D.; Boudon, C.;
Gisselbrecht, J. P.; Gross, M.; Diederich, F. Chem. Commun. 2007,
4898. (f) Marsden, J. A.; Miller, J. J.; Shirtcliff, L. D.; Haley, M. M.
J. Am. Chem. Soc. 2005, 127, 2464.
(9) (a) Li, Z. G.; Capretto, D. A.; Rahaman, R. O.; He, C. J. Am.
Chem. Soc. 2007, 129, 12058. (b) Gu, L.; Neo, B. S.; Zhang, Y. Org. Lett.
2011, 13, 1872.
(10) Shi, Z. J.; He, C. J. Am. Chem. Soc. 2004, 126, 13596.
(11) Selected examples: (a) Reetz, M. T.; Sommer, K. Eur. J. Org.
Chem. 2003, 3485. (b) Shi, Z. J.; He, C. J. Org. Chem. 2004, 69, 3669. (c)
Reich, N. W.; Yang, C. G.; Shi, Z. J.; He, C. Synlett 2006, 1278. (d) Jean,
M.; van de Weghe, P. Tetrahedron Lett. 2011, 52, 3509.
Figure 1. Para-alkynyl anilines in material sciences.
(12) Kar, A.; Mangu, N.; Kaiser, H. M.; Beller, M.; Tse, M. K. Chem.
Commun. 2008, 386.
Gold catalysis has recently been investigated for the
direct functionalization of benzene rings via amination,9
alkylation,10 hydroarylation,11 and arylation.12 Only one
example of the catalytic use of gold for the alkynylation of
benzene rings has been reported, but no anilines were used
in that work.6l,13 Moreover, there are only two single
examples of gold-catalyzed direct functionalization of
anilines for amination9b and hydroarylation.11d Conse-
quently, the extension of the alkynylation reaction to
(13) For the stoichiometric use of gold, see: Fuchita, Y.; Utsunomiya,
Y.; Yasutake, M. J. Chem. Soc., Dalton Trans. 2001, 2330.
(14) (a) Belot, S.; Vogt, K. A.; Besnard, C.; Krause, N.; Alexakis, A.
Angew. Chem., Int. Ed. 2009, 48, 8923. (b) Monge, D.; Jensen, K. L.;
Franke, P. T.; Lykke, L.; Jorgensen, K. A. Chem.;Eur. J. 2010, 16,
9478. (c) Loh, C. C. J.; Badorrek, J.; Raabe, G.; Enders, D. Chem.;Eur.
J. 2011, 17, 13409.
(15) Our work has been focused on TIPS-EBX (1) to afford easy to
deprotect silyl acetylenes. Furthermore, a bulky silyl group was shown to
be essential for the success of the reaction, see ref 7. Indeed, no product
was obtained using phenylethynyl-1,2-benziodoxol-3(1H)-one as acet-
ylene transfer reagent.
Org. Lett., Vol. 14, No. 3, 2012
745

sideproducts. Inthiscase, the starting materialcouldeasily
be recovered. The obtained yields are in the same range as
those obtained in the current state-of-the-art direct para-
functionalizations of anilines.16
Table 2. Scope of the Para-alkynylation of Anilinesa
Table 1. Optimization of the Para-alkynylation of Anilines
entry
solvent
TIPS-EBX (1) equivalents
yielda (%)
1
2
3
4
5
6
7c
Et2O
1.2
1.2
1.2
1.2
1.4
1.6
1.4
14
CH2Cl2
CH3CN
iPrOH
iPrOH
iPrOH
iPrOH
49
51
58
73 (84)b
55
68 (81)b
a Reaction conditions: 0.20 mmol N,N-dibenzylaniline (5a), 0.01 mmol
i
AuCl in 4 mL PrOH at 23 °C under air. Isolated yield after column
chromatography. b Yield based on recovered starting material (brsm).
c Two milliliters of iPrOH.
We then focused our attention on the scope of the
reaction (Table 2). In addition to benzyl (entry 1), butyl,
ethyl and methyl groups were tolerated as nitrogen sub-
stituents, but led to lower yields (entries 2ꢀ4). Smaller
alkyl groups led to a complex mixture of side products,
including 8% of the orthoꢀpara disubstituted product for
R = Me (entry 4). These results indicate that the process
has the regioselectivity of an aromatic electrophilic sub-
stitution. It is in line with our previous highly SEAr
regioselective methodologies for the alkynylation of in-
doles, pyrroles, and thiophenes.7a,b
Ortho-methyl, -phenyl, and -methoxy groups were tol-
erated for monoprotected anilines (entries 5ꢀ7).17 This
result also demonstrated that the method was tolerant
toward a free NH bond on the aniline. The alkynylation
reaction was even successful in the case of the less reactive
dibenzyl 2-aminonaphthalene (5h), although full conver-
sion could not be achieved in this case (entry 8).
Importantly, alkynylation was also possible for alkyl,
methoxy, chloro and bromo groups in the meta position,
giving more sterically hindered 1,3,4-substituted anilines
(entries 9ꢀ13). In addition, the tolerance to chloro and
bromo substituents demonstrated the orthogonality of the
method to classical Pd cross-couplings. Low yields of
ortho-alkynylated products were obtained using para-
substituted anilines.18 In the case of 4-methyl-N,N-
dimethyl aniline (5n), one of the main products obtained
was the sp3 coupling product on the methyl substituent of
a Reaction conditions: 0.40 mmol 5, 0.56 mmol 1, 0.02 mmol AuCl
i
in 8 mL PrOH at 23 °C under air. Isolated yields. b Yields based on
recovered starting materials are given in parentheses. c At 60 °C in 2 mL
of iPrOH. d Orthoꢀpara disubstituted product.
the nitrogen (eq 1). This reaction can easily be achieved
with free acetylenes and metal catalysts under oxidative
conditions.19 Consequently, it could indicate that this
product results from the relatively high oxidation capacity
of TIPS-EBX (1).
(19) For sp3 alkynylation of dimethylaniline (5d), see: (a) Li, Z. P.; Li,
C. J. J. Am. Chem. Soc. 2004, 126, 11810. (b) Volla, C. M. R.; Vogel, P.
Org. Lett. 2009, 11, 1701. (c) Liu, P.; Zhou, C. Y.; Xiang, S.; Che, C. M.
Chem. Commun. 2010, 46, 2739. For cyanation of dimethylaniline (5d)
using hypervalent iodine, see: (d) Zhdankin, V. V.; Kuehl, C. J.;
Krasutsky, A. P.; Bolz, J. T.; Mismash, B.; Woodward, J. K.; Simonsen,
A. J. Tetrahedron Lett. 1995, 36, 7975. For sp3 cyanation of dimethylani-
line (5d) using a gold complexe, see: (e) Zhang, Y.; Peng, H.; Zhang, M.;
Cheng, Y. X.; Zhu, C. J. Chem. Commun. 2011, 47, 2354.
(16) Ciana, C. L.; Phipps, R. J.; Brandt, J. R.; Meyer, F. M.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2011, 50, 458.
(17) Ortho substituted N,N-disubstituted anilines were not reactive,
probably because of the deconjugation of the nitrogen for steric reasons.
(18) 4-Methyl-N,N-dibenzylaniline was ortho alkynylated in 18%
yield.
746
Org. Lett., Vol. 14, No. 3, 2012

In conclusion, we have developed the first para-
selective direct alkynylation of anilines using gold
chloride as catalyst and TIPS-EBX (1) as acetylene-
transfer reagent. The method allowed a new and
efficient access to important building blocks in syn-
thetic chemistry and material sciences under mild
reaction conditions and at ambient atmosphere. We
demonstrated that a wide range of anilines could be
alkynylated regioselectively using the developed meth-
odology. Investigations toward the elucidation of the
reaction mechanism are currently ongoing in our
laboratory.
In addition to anilines, the reaction could also be
applied toward the alkynylation of trimethoxybenzenes
(Figure 2). Up to now, the only report for the alkynyla-
tion of this class of substrates was limited to the use of
more electron-deficient propiolic acid derivatives.6l
The use of TIPS-EBX (1) allowed access to an easily
deprotectible nonelectron-deficient acetylene.
Acknowledgment. We thank the EPFL for funding,
F. Hoffmann-La Roche Ltd for an unrestricted research
grant and Dr. Fides Benfatti (EPFL) and Reto Frei
(EPFL) for proofreading this manuscript.
Supporting Information Available. Experimental pro-
cedures, analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 2. Alkynylation of trimethoxybenzenes. Reaction condi-
tions: 0.40 mmol trimethoxybenzene, 0.56 mmol 1, 0.02 mmol
AuCl in 2 mL iPrOH at 60 °C under air. Isolated yields. Yields
based on recovered starting materials under parentheses.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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