Phenoxide-mediated Sonogashira coupling of trimethylsilylalkynes and aryliodides: Practical synthesis of phenolic-hydroxy-substituted diarylethynes and 1,4-diarylbutadiynes

Article abstract of DOI:10.1016/j.tetlet.2013.01.091

We successfully synthesized phenolic-hydroxy-substituted diarylethynes and 1,4-diarylbutadiynes from trimethylsilylalkynes and aryliodides via silyl-group-migration-induced deprotection of alkynes and the usual Sonogashira coupling. The phenol moiety, which works as a desilylating agent, can be attached to any position in the coupling partner. This improvement for Sonogashira coupling would be highly effective, especially when the coupling partner has a phenol moiety. Additionally, the stability of the migrated silyl moiety on the ethynylation of 2-iodophenol is discussed.

Full text of DOI:10.1016/j.tetlet.2013.01.091

Tetrahedron Letters 54 (2013) 1761–1764
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Phenoxide-mediated Sonogashira coupling of trimethylsilylalkynes
and aryliodides: practical synthesis of phenolic-hydroxy-substituted
diarylethynes and 1,4-diarylbutadiynes
⇑
⇑
Masayuki Shigeta , Junji Watanabe, Gen-ichi Konishi
Department of Organic and Polymeric Materials, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We successfully synthesized phenolic-hydroxy-substituted diarylethynes and 1,4-diarylbutadiynes from
trimethylsilylalkynes and aryliodides via silyl-group-migration-induced deprotection of alkynes and the
usual Sonogashira coupling. The phenol moiety, which works as a desilylating agent, can be attached to
any position in the coupling partner. This improvement for Sonogashira coupling would be highly effec-
tive, especially when the coupling partner has a phenol moiety. Additionally, the stability of the migrated
silyl moiety on the ethynylation of 2-iodophenol is discussed.
Received 29 December 2012
Revised 18 January 2013
Accepted 21 January 2013
Available online 30 January 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Sonogashira coupling
Silyl migration
Phenols
Tolane
Benzofuran
Sonogashira coupling1 is a fundamental and important reaction
for the synthesis of aryl acetylene derivatives, which in turn can be
applied for preparing organic and polymeric materials,2 and bioac-
tive compounds.3 Among the various applications of this reaction,4
coupling with silylalkynes has been actively developed,5–8 for the
main reason that isolation of the unstable terminal alkyne inter-
mediates is not required. This reaction involves desilylation by
ClÀ ions in a polar solvent,5 sec-amines,5h,6 oxygen nucleophiles
such as alkoxides, siloxides, and hydroxides,7 or fluoride re-
agents,5b,8 followed by the usual Sonogashira coupling.
Phenolic-hydroxy-substituted diarylethynes and 1,4-diarylbut-
adiynes have the basic structure of liquid crystals, and they are
synthetic intermediates for polycyclic antibiotics and functional
polymers. These phenolic compounds with an alkyne functionality
are synthesized frequently via Sonogashira coupling.3,9 However,
the hydroxy group tends to undergo undesired reactions such as
O-arylation;10 in particular, the ortho hydroxy group undergoes
intramolecular cyclization to afford benzofuran.11
silylation by a phenoxide, on the basis of the above mentioned
supposition.13 In this Letter, we present the efficient syntheses of hy-
droxyl-substituted diarylethynes and 1,4-diarylbutadiynes by silyl
migration and Sonogashira coupling.
To verify the effectiveness of phenols as desilylating agents, we
carried out Sonogashira coupling using 4-(trimethylsilylethy-
nyl)phenol 1 and MOM-protected phenol 3. Trimethylsilylethynyl-
benzene
1 or 3 (1.05 equiv) was treated with iodobenzene
(1 equiv), Pd(PPh3)4 (3 mol %), CuI (3 mol %), PPh3 (3 mol %), and
K2CO3 (2 equiv) in THF, and the mixture was heated to 80 °C. Under
these conditions, the one-pot Sonogashira coupling of 3 did not
give the desired product (no conversion), but the reaction with 1
proceeded to afford the product in 79% yield (Scheme 1).
This protocol could also be applied to the synthesis of various
diarylacetylenes, by the coupling of 1 with various aryl iodides.
The results are summarized in Table 1. The electron-donating
4-(1-hexyloxy)iodobenzene 4b and electron-withdrawing 4-nitro-
iodobenzene 4c underwent the coupling smoothly to afford the
desired products in 82% (entry 2) and 76% yields (entry 3), respec-
tively. However, 4-iodobromobenzene 4d was alkynylated only at
the iodide position, and the Br–C bond was not cleaved (entry 4). 3-
Trimethylsilyliodobenzene 4e was converted into diarylacetylene
2e in 64% yield, and the desilylated product 2a was not detected
in the crude mixture by 1H NMR (entry 5).14 The proposed protocol
could be extended to diarylbutadiyne derivatives as well, under the
same conditions. 4-(Trimethylsilylbutadiynyl)phenol 5 was cou-
pled with iodobenzene 4a to give the desired product in quantita-
To solve these problems, we supposed that if the silyl group on an
alkyne migrates to the phenol moiety, Sonogashira coupling can be
carried out without the risk of the aforementioned undesired reac-
tions. Recently, inspired by Mukaiyama’s report,12 we developed
the monoarylation of 1,3-bis(trimethylsilyl)butadiyne via monode-
⇑
Corresponding authors. Tel.: +81 3 5734 2321; fax: +81 3 5734 2888.
E-mail addresses: mshigeta@polymer.titech.ac.jp (M. Shigeta), konishi.g.aa@m.
titech.ac.jp (G. Konishi).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.091

1762
M. Shigeta et al. / Tetrahedron Letters 54 (2013) 1761–1764
Scheme 1. Sonogashira coupling with unprotected and protected trimethylsilylethynylphenol.
Table 1
Scope of coupling 4-(trimethylsilylalkynyl)phenol 5 and various aryliodides
Entry
1
n
Ar-I
Yield (%)
1
79 (2a)
2
3
4
1
1
1
82 (2b)
76 (2c)
95 (2d)
5
1
64 (2e)a
6
7
8
9
2
2
2
2
Quant (6a)
68 (6b)
97 (6c)
64 (6d)
a
The desilylated product 2a was not detected in the crude mixture by 1H NMR.
Table 2
Scope of coupling 4-iodophenol with various aryltrimethylsilylalkynes
Entry
Yield (%)
1
2
63 (2a)
81 (2b)
3
4
Quant (2f)
99 (6d)

M. Shigeta et al. / Tetrahedron Letters 54 (2013) 1761–1764
1763
Table 3
Scope of coupling 4-(trimethylsilylbutadiynyl) bromobenzene 7e and iodophenols 8
Entry
Iodophenol
Additives
Yield (%)
1
2
3
4
5
6
7
4-Iodophenol (8a)
3-Iodophenol (8b)
2-Iodophenol (8c)
8c
8c
8c
8c
—
—
—
72 (2a)
85 (2g)
72 (9)
69 (9)
74 (9)
a
Cs2CO3
AgOTf (2 equiv)
NaHa
54 (2h)
87 (2h)
MS4 Å (0.9 g/mmol)
a
These bases were utilized instead of K2CO3.
in moderate yields (72–85%), 2-iodophenol 8c gave benzofuran 9 in
72% yield instead of the diarylalkyne. Diarylethynylene 2h could not
be effectively isolated when Cs2CO3 was used instead of K2CO3 or
when AgOTf was added (entries 4, 5) but was successfully isolated
in 54% and 87% yields, respectively, when using NaH or adding
molecular sieve 4 Å (MS4A) (entries 6, 7).
2-Alkynylphenols tend to isomerize into benzofurans via a ring-
closing reaction under basic conditions and in the presence of a
transition-metal catalyst.11 However, in our experiments, benzofu-
ran 9 was obtained, although the phenol moiety should have been
protected by the trimethylsilyl group,12,13 suggesting the possible
removal of the silyl group by a base. Iodide ion originated from aryl
iodide acts as a base for desilylation.17 However, the results of reac-
tions performed using Cs2CO318 and AgOTf19 indicated that the io-
dide ion did not play any role in the desilylation (Table 3, entries
4, 5). Hence, we guessed that H2O, which is a degradate of KHCO3,20
worked as a desilylating agent (Fig. 1). Since both NaH and MS4 Å
aided the isolation of 2h (entries 6, 7), we concluded that the tri-
methylsilyl group was transferred to the phenol moiety and re-
moved in the presence of a little water. Further, removal of the
trimethylsilyl group could be prevented by adding a dehydrating
agent or by using an alkali hydride instead of an alkali carbonate.
In conclusion, we successfully synthesized phenolic-hydroxy-
substituted diarylethynes and 1,4-diarylbutadiynes from trim-
ethylsilylalkynes and aryliodides via silyl-group-migration-induced
deprotection of alkynes and the usual Sonogashira coupling. The
phenol moiety, which works as a desilylating agent, can be attached
to any position in the coupling partner. Silylation of the phenolic
group helps in preventing unwanted side reactions. Various func-
tional groups in the aryl moiety—alkoxy (electron donating), nitro
(electron withdrawing), bromo, and trimethylsilyl—showed good
reactivity under the reaction conditions. Removal of the migrated
trimethylsilyl group could be prevented by adding a dehydrating
agent or by using an alkali hydride instead of an alkali carbonate.
This protocol is a strong tool for Sonogashira coupling using a pheno-
lic-hydroxy-substituted reagent and is expected to be applicable for
the synthesis of bioactive compounds and functional materials.
Figure 1. Plausible mechanism of removal of the trimethylsilyl group when using
K2CO3.
tive yield (entry 6). Other aryl iodides (4b–d) could also be coupled
with 5 to yield the desired products in moderate-to-good yields
(entries 7–9).
The aforementioned results confirmed that alkynylphenols act as
a desilylating agent for trimethylsilylalkynes. Next, we investigated
whether the reaction proceeds if a phenol moiety is attached to the
aryl iodide and carried out the reaction of 4-iodophenol with various
trimethylsilylethynylbenzene and trimethylsilylbutadiynylben-
zene derivatives (Table 2). With trimethylsilylethynylbenzene 7a,
the reaction proceeded at 80 °C to afford the product in 63% yield
(entry 1).15 4-(1-Hexyloxy)-1-(trimethylsilylethynyl)benzene 7b
was also transformed into the coupling product 2b in 81% yield
(entry 2). 2-Trimethylsilylethynylthiophene 7c, too, afforded the
coupled product 2f in quantitative yield, although the intermediate,
2-ethynylthiophene, was highly unstable (entry 3).16 Coupling with
4-bromo-1-(trimethylsilylbutadiynyl)benzene 7d was also success-
ful, and the product was obtained in excellent (99%) yield (entry 4).
We next investigated the effect of the substitution position of the
hydroxyl group in the iodobenzene moiety (Table 3). In this regard,
we performed coupling reactions of 4-(trimethylsilylethynyl)bro-
mobenzene 7e with iodophenols 8a–c under the same conditions.
While 8a, b were smoothly transformed into the coupling products
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.
091.

1764
M. Shigeta et al. / Tetrahedron Letters 54 (2013) 1761–1764
7. (a) Denmark, S. E.; Tymonko, S. A. J. Org. Chem. 2003, 68, 9151–9154; (b) Wu,
References and notes
M.-J.; Wei, L.-M.; Lin, C.-F.; Leou, S.-P.; Wei, L.-L. Tetrahedron 2001, 57, 7839–
7844; (c) Halbes, U.; Pale, P. Tetrahedron Lett. 2002, 43, 2039–2042; (d) Mio, M.
J.; Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.; Hull, K. L.; Brisbois, R. G.;
Markworth, C. J.; Grieco, P. A. Org. Lett. 2002, 4, 3199–3202; (e) Severin, R.;
Reimer, J.; Doye, S. J. Org. Chem. 2010, 75, 3518–3521.
1. (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–49; (b) Sonogashira, K.;
Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467–4470; (c) Takahashi, S.;
Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 627–630; (d)
Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084–5121; (e) Chinchilla, R.;
Najera, C. Chem. Rev. 2007, 107, 874–922.
8. (a) Denmark, S. E.; Wehrli, D. Org. Lett. 2000, 2, 565–568; (b) Chang, S.; Yang, S.
H.; Lee, P. H. Tetrahedron Lett. 2001, 42, 4833–4835; (c) Bertus, P.; Halbes, U.;
Pale, P. Eur. J. Org. Chem. 2001, 4391–4393; (d) Halbes, U.; Bertus, P.; Pale, P.
Tetrahedron Lett. 2001, 42, 8641–8644; (e) Merkul, E.; Urselmann, D.; Müller, T.
J. J. Eur. J. Org. Chem. 2011, 238–242.
9. (a) Mihalcik, D. J.; Zhang, T.; Ma, L.; Lin, W. Inorg. Chem. 2012, 51, 2503–2508;
(b) Mann, J. A.; Rodríguez-López, J.; Abruña, H. D.; Dichtel, W. R. J. Am. Chem.
Soc. 2011, 133, 17614–17617; (c) Weibel, N.; Mishchenko, A.; Wandlowski, T.;
Neuburger, M.; Leroux, Y.; Mayor, M. Eur. J. Org. Chem. 2009, 6140–6150.
10. (a) Chang, J. W. W.; Mak, S.; Chee, S.; Buranaprasertsuk, P.; Chavasiri, W.; Chan,
P. W. H. Tetrahedron Lett. 2008, 49, 2018–2022; (b) Ito, H.; Sensui, H.; Arimoto,
K.; Miura, K.; Hosomi, A. Chem. Lett. 1997, 26, 639–640; For reviews, see: (c)
Sawyer, J. S. Tetrahedron 2000, 56, 5045–5065; (d) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
11. (a) Barton, T. J.; Groh, B. L. J. Org. Chem. 1985, 50, 158–166; (b) Buckle, D. R.;
Rockell, C. J. M. J. Chem. Soc., Perkin Trans. 1 1985, 2443–2446; (c) Arcadi, A.;
Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280–
9288; (d) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett. 2006, 8,
2803–2805; (e) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.
Tetrahedron 2008, 64, 53–60; (f) Kálai, T.; Schindler, J.; Balog, M.; Fogassy, E.;
Hideg, K. Tetrahedron 2008, 64, 1094–1100; (g) Fiandanese, V.; Bottalico, D.;
Marchese, G.; Punzi, A. Tetrahedron 2008, 64, 7301–7306; (h) Tsuji, H.; Mitsui,
C.; Ilies, L.; Sato, Y.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 11902–11903; (i)
Mitsui, C.; Soeda, J.; Miwa, K.; Tsuji, H.; Takeya, J.; Nakamura, E. J. Am. Chem.
Soc. 2012, 134, 5448–5451; (j) Tsuji, H.; Mitsui, C.; Sato, Y.; Nakamura, E. Adv.
Mater. 2009, 21, 3776–3779.
2. (a) Bunz, U. H. F. Chem. Rev. 2000, 100, 1605–1644; (b) Kim, J.; Swager, T. M.
Nature 2001, 411, 1030–1034; (c) Langhals, H.; Esterbauer, A. J.; Walter, A.;
Riedle, E.; Pugliesi, I. J. Am. Chem. Soc. 2010, 132, 16777–16782; (d) Jana, D.;
Ghorai, B. K. Tetrahedron Lett. 2012, 53, 196–199; (e) Fukumoto, H.; Yamane, K.;
Kase, Y.; Yamamoto, T. Macromolecules 2010, 43, 10366–10375; (f) Wang, C.;
Pålsson, L.; Batsanov, A. S.; Bryce, M. R. J. Am. Chem. Soc. 2006, 128, 3789–3799;
(g) Doi, Y.; Chiba, J.; Morikawa, T.; Inouye, M. J. Am. Chem. Soc. 2008, 130, 8762–
8768; (h) Abe, H.; Masuda, N.; Waki, M.; Inouye, M. J. Am. Chem. Soc. 2005, 127,
16189–16196; (i) Maeda, H.; Maeda, T.; Mizuno, K.; Fujimoto, K.; Shimizu, H.;
Inouye, M. Chem. Eur. J. 2006, 12, 824–831; (j) Ulrich, G.; Ziessel, R. Synlett 2004,
439–444; (k) Arakawa, Y.; Nakajima, S.; Ishige, R.; Uchimura, M.; Kang, S.;
Konishi, G.; Watanabe, J. J. Mater. Chem. 2012, 22, 8394–8398; (l) Arakawa, Y.;
Nakajima, S.; Kang, S.; Shigeta, M.; Konishi, G.; Watanabe, J. J. Mater. Chem.
2012, 22, 13908–13910; (m) Arakawa, Y.; Nakajima, S.; Kang, S.; Konishi, G.;
Watanabe, J. J. Mater. Chem. 2012, 22, 14346–14348; (n) Asai, K.; Konishi, G.;
Nakajima, Y.; Kawauchi, S.; Ozawa, F.; Mizuno, K. J. Organomet. Chem. 2011,
696, 1266–1271; (o) Uchimura, M.; Kang, S.; Ishige, R.; Watanabe, J.; Konishi, G.
Chem. Lett. 2010, 39, 513–515; (p) Arakawa, Y.; Nakajima, S.; Kang, S.; Shigeta,
M.; Watanabe, J.; Konishi, G. Liq. Cryst. 2012, 39, 1063–1069; (q) Yamaji, M.;
Maeda, H.; Minamida, K.; Maeda, T.; Asai, K.; Konishi, G.; Mizuno, K. Res. Chem.
Intermed. 2013, 39, 321–345.
3. (a) Takiguchi, H.; Ohmori, K.; Suzuki, K. Chem. Lett. 2011, 40, 1069–1071; (b)
Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2010, 132,
1236–1327; (c) Nicolaou, K. C.; Peng, X. S.; Sun, Y. P.; Polet, D.; Zou, B.; Lim, C.
S.; Chen, D. Y. K. J. Am. Chem. Soc. 2009, 131, 10587–10597; (d) Miyazaki, T.;
Yokoshirna, S.; Simizu, S.; Osada, H.; Tokuyama, H.; Fukuyama, T. Org. Lett.
2007, 9, 4737–4740; (e) Suzuki, M.; Kambe, M.; Tokuyama, H.; Fukuyama, T. J.
Org. Chem. 2004, 69, 2831–2843; (f) Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am.
Chem. Soc. 2003, 125, 8798–8805; (g) Sasaki, T.; Inoue, M.; Hirama, M.
Tetrahedron Lett. 2001, 42, 5299–5303; (h) Tatsuta, K.; Takano, S.; Sato, T.;
Nakano, S. Chem. Lett. 2001, 172–173.
12. Kitazawa, T.; Minowa, T.; Mukaiyama, T. Chem. Lett. 2006, 35, 1002–1003.
13. Shigeta, M.; Watanabe, J.; Konishi, G. Asian J. Org. Chem. 2012, 1, 43–46.
14. Desilylation rate might be related to their pKa. Aryl proton (ꢀ43) is much
higher than alkynyl proton (ꢀ23).
15. By 4-bromophenol in the same condition, Glaser coupling was proceeded.
4. (a) Ahmed, M. S. M.; Mori, A. Org. Lett. 2003, 5, 3057–3060; (b) Mori, A.; Ahmed,
M. S. M.; Sekiguchi, A.; Masui, K.; Koike, T. Chem. Lett. 2002, 756–757; (c)
Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org. Lett. 2002, 4,
1691–1694; (d) Mori, A.; Shimada, T.; Kondo, T.; Sekiguchi, A. Synlett 2001,
649–651; (e) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.; Hirabayashi, K.;
Nishihara, Y. Org. Lett. 2000, 2, 2935–2937.
5. (a) Akita, Y.; Kanekawa, H.; Kawasaki, T.; Shiratori, I.; Ohta, A. J. Heterocycl.
Chem. 1988, 25, 975–977; (b) Hatanaka, Y.; Matsui, K.; Hiyama, T. Tetrahedron
Lett. 1989, 30, 2403–2406; (c) Nishihara, Y.; Ikegashira, K.; Mori, A.; Hiyama, T.
Chem. Lett. 1997, 26, 1233–1234; (d) Nishihara, Y.; Ikegashira, K.; Hirabayashi,
K.; Ando, J.; Mori, A.; Hiyama, T. J. Org. Chem. 2000, 65, 1780–1787; (e) Ito, H.;
Arimoto, K.; Sensul, H.; Hosomi, A. Tetrahedron Lett. 1997, 38, 3977–3980; (f)
Koseki, Y.; Omino, K.; Anzai, S.; Nagasaka, T. Tetrahedron Lett. 2000, 41, 2377–
2380; (g) Marshall, J. A.; Chobanian, H. R.; Yanik, M. M. Org. Lett. 2001, 3, 4107–
4110; (h) Yang, C.; Nolan, S. P. Organometallics 2002, 21, 1020–1022; (i) Gil-
Moltó, J.; Nájera, C. Adv. Synth. Catal. 2006, 348, 1874–1882; (j) Nishihara, Y.;
Inoue, E.; Ogawa, D.; Okada, Y.; Noyori, S.; Takagi, K. Tetrahedron Lett. 2009, 50,
4643–4646; (k) Nishihara, Y.; Noyori, S.; Okamoto, T.; Suetsugu, M.; Iwasaki, M.
Chem. Lett. 2011, 40, 972–974.
16. 2-Ethynylthiophenes are so unstable that it is difficult to isolate. See: Khan, M.
S.; Al-Suti, M. K.; Shah, H. H.; Al-Humaimi, S.; Al-Battashi, F. R.; Bjernemose, J.
K.; Male, L.; Raithby, P. R.; Zhang, N.; Köhler, A.; Warren, J. E. Dalton Trans.
2011, 40, 10174–10183.
17. Voronkov, M. G.; Tsyrendorzhieva, I. P.; Rakhlin, V. I. Russ. J. Org. Chem. 2009,
45, 1621–1622.
18. Cs+ ion is superior to K+ for iodide trapping. See: (a) Beronius, P.; Pataki, L. J. Am.
Chem. Soc. 1970, 92, 4518–4521; (b) Marlow, A. L.; Davis, J. T. Tetrahedron Lett.
1999, 40, 3539–3542.
19. Ag+ is an efficient reagent to rapidly remove iodide ion. See 3rd paragraph of
the follow reference: Eaborn, C.; Happer, D. A. R. J. Chem. Soc., Chem. Commun.
1991, 1608–1609.
6. Alonso, D. A.; Nájera, C.; Pacheco, M. Adv. Synth. Catal. 2003, 345, 1146–
1158.
20. Hisatsune, I. C.; Adl, T. J. Phys. Chem. 1970, 74, 2875–2877.