Silver salt-promoted direct cross-coupling reactions of alkynylsilanes with aryl iodides: Synthesis of aryl-substituted alkynylamides

Article abstract of DOI:10.1016/S0040-4039(00)00167-2

A direct cross-coupling reaction of 5-trimethylsilyl-4-pentynamides (alkynylsilanes) 1 with aryl iodides, promoted by silver carbonate in the presence of palladium catalyst, afforded aryl-substituted alkynylamides 2, which readily underwent cyclization to form benzylidenelactams 3. This coupling reaction proved to be a useful for synthesis of aryl-substituted alkynes. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00167-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2377–2380
Silver salt-promoted direct cross-coupling reactions of
alkynylsilanes with aryl iodides: synthesis of aryl-substituted
alkynylamides
Yuji Koseki, Kunio Omino, Shinobu Anzai and Tatsuo Nagasaka ∗
Tokyo University of Pharmacy & Life Science, School of Pharmacy, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 24 November 1999; revised 17 January 2000; accepted 21 January 2000
Abstract
A direct cross-coupling reaction of 5-trimethylsilyl-4-pentynamides (alkynylsilanes) 1 with aryl iodides, pro-
moted by silver carbonate in the presence of palladium catalyst, afforded aryl-substituted alkynylamides 2, which
readily underwent cyclization to form benzylidenelactams 3. This coupling reaction proved to be a useful for
synthesis of aryl-substituted alkynes. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: alkynes; coupling reactions; silicon and compounds; palladium catalyst.
Palladium cross-coupling reactions between alkynylorganometallic compounds and aryl halides and
related compounds are widely used in organic synthesis.1 Many of such coupling reactions involving
alkynylorganometallic compounds, such as zinc, magnesium, boron, stannane, and copper have been
reported.1 However, these alkynylorganometallic compounds are often unstable. In contrast, alkynylsi-
lanes are versatile synthetic intermediates in organic synthesis that are stable and have been primarily
used to protect terminal alkynes from organometallic reagents.2 Nevertheless, there have only been a
few reported examples of such direct coupling reactions of alkynylsilanes with aryl halides being carried
out in the presence of F– for activation of Si–C bonds as in Hiyama et al.3 or under basic conditions
as in Rossi et al.4 and Huang et al.5 Other examples of the one-pot desilylation/coupling reaction
including a coupling reaction of alkynylsilanes with acid halides by catalyzed CuCl6 and dimerization of
alkynylsilanes by CuCl7 or CuOTf8 have been reported.
Recently, as an example of such a copper(I) salt-mediated coupling reaction, a direct Pd(0)-cross-
coupling reaction of alkynylsilanes with aryl trifrates in the presence of CuCl in DMF was reported by
Hiyama et al.9
In
a
previous paper, we reported that palladium cross-coupling reaction of 2-
(trimethylsilylethynyl)benzamide derivatives with 3,4-(methylenedioxy)phenyl iodide in the presence of
silver carbonate was a key-step in lennoxamine synthesis.10 The efficacy of this cross-coupling method
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00167-2
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2378
led us to an attempt to apply it to conversion of 5-trimethylsilyl-4-pentynamides 1 (alkynylsilanes) into
aryl-substituted 4-pentynamides 2, which readily underwent cyclization to form benzylidenelactams 3
(Scheme 1).11
Scheme 1.
Sonogashira’s procedure is the most useful method for the induction of aryl groups into a terminal
alkyne.12 However, Jacobi et al. reported that Sonogashira-type coupling reactions of 4-pentynamide
derivatives with iodopyrroles (Pd(Ph3P)4, CuI, Et3N in DMF) required the use of DMF as a solvent under
strict anaerobic conditions in order to prevent formation of diynes arising from oxidative dimerization of
4-pentynamides.13
In the present paper, we focused on silver mediated direct coupling reaction of 5-trimethylsilyl-4-
pentynamides 414 with aryl iodides under very mild conditions without fluoride ion or inorganic bases.
And also, the coupling of alkyl- and phenylalkyne derivatives (5, 6 respectively), was examined. The
results are summarized in Table 1.
The coupling of 4a with 4-iodoanisole performed with 0.5 equiv. of Ag2CO3 (1 equiv. as Ag+) and 5
mol% of Pd catalyst (A) in the presence of Bu4NCl gave a coupling product 7 in 81% yield (run 1).15
In the absence of Ag2CO3, no coupled product was detected under similar conditions, after isolating
5
the starting material. In addtion, the use of K2CO3 instead of Ag2CO3 was completely ineffective.
Furthermore, the use of a catalytic amount of Ag2CO3 (0.2 equiv.) produced only a low yield. The effects
of other silver salts have been examined. The use of Ag2O16 instead of Ag2CO3 under similar conditions
was also equally effective (77%), while AgNO3 and AgI resulted in recovery of the starting material.
The coupling with 4-chloroiodobenzene, heteroaromatic iodides such as 2-iodopyridine, 2-iodothiophen,
or 3,4-(methylenedioxy)phenyl iodide successfully proceeded under similar conditions (runs 2–7). It is
important to note that 4c and 5, which have a fluoride ion and a basic medium-sensitive functional group,
respectively, showed smooth coupling with aryl iodides without any loss of the TBDMS-group. The
couplings afforded their corresponding aryl-substituted alkynes in good yield (runs 8 and 9). The coupling
of 1-phenyl-2-(trimethylsilyl)acetylene 6 also proceeded in a similar manner to give the corresponding
diarylalkyne 14 in high yield (run 10).
In all cases, oxidative homo-coupling17 of alkynylsilanes afforded only a trace amount of corres-
ponding symmetrical diynes, accompanied by the desired products. This may have been due to homo-
coupling of 4, 5 or 6 with whatever trace oxygen was present. In particular, with 2-iodopyridine in
the presence of Pd-catalyst (A), an increase in the ratio of diyne formation was observed (run 3,
product/diyne=91:9). Many palladium catalysts, such as (PPh3)2PdCl2 (catalyst B) and Pd2(dba)3·CHCl3
(catalyst C) were used in an attempt to minimize formation of diyne. However, none proved to be
satisfactory (runs 4 and 5). In addition, the coupling of 6 with aryl bromide (4-bromoanisole) afforded
only the homo-coupled product (run 11).
The reaction mechanism underlying the present coupling reaction remains to be clarified. When
coupling of 4a with 4-iodoanisole was allowed to proceed under the same conditions aside from the
absence of Pd catalyst no coupled product 7 was observed, but the corresponding desilylated terminal
alkyne was given in quantitative yield. Therefore, we concluded that the role of Ag2CO3 is a base
for desilylation of trimethylsilyl group on terminal alkynes in the presence of Bu4NCl.18 Consistent

2379
Table 1
Direct cross-coupling reaction of alkynylsilanes with aryl iodides
with this notion, previous studies have reported generation of silver acetylides through desilylation of
alkynylsilanes in the presence of silver salts19,20 and a coupling reaction of vinyl triflates with terminal
alkynes using Pd–Ag catalytic system.21 However, no successful isolation of silver acetylides as an
intermediate in this system have been reported. Furthermore, no evidence has been obtained for the
transmetallation between silver acetylides and organopalladium species.22

2380
The aryl coupled products 7–11 could readily be cyclized to aryl-substituted 5-methylidene-2-
pyrrolidinones 3 by utilizing a LiN(TMS)2:AgOTf (=2:1) catalytic system in toluene.23
In conclusion, a new method for direct coupling reactions of alkynylsilanes with aryl iodides to the
corresponding aryl coupled product have been developed. The mild reaction conditions utilized for the
present Ag2CO3 and Pd catalyst system should have widespread applicability for other alkynylsilanes as
a general method. Work is now in progress to clarify the mechanism underlying this coupling reaction
and to modify it in order to utilize a catalytic amount of Ag salt.
References
1. (a) Sonogashira, K. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: New York, 1991;
Vol. 3, pp. 521–549. (b) Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester, 1995; pp. 168–171.
2. Weber, W. P. Silicon Reagents for Organic Synthesis; Springer Verlag: Berlin, Heidelberg, New York, 1983; pp. 129–158.
3. (a) Hatanaka, Y.; Matsui, K.; Hiyama, T. Tetrahedron Lett. 1989, 30, 2403–2406. (b) Hatanaka, Y.; Hiyama, T. J. Synth. Org.
Chem. Jpn. 1990, 48, 834–843.
4. Rossi, R.; Carpita, A.; Lezzi, A. Tetrahedron 1984, 40, 2773–2779.
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12. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467–4470.
13. (a) Jacobi, P. A.; Brielmann, H. L.; Hauck, S. I. J. Org. Chem. 1996, 61, 5013–5023. (b) Jacobi, P. A.; Rajeswari, S.
Tetrahedron Lett. 1992, 33, 6235–6238.
14. Preparation of alkynylsilanes 4: Treatment of 4-pentynamides with 2 equiv. of LDA followed by 2.5 equiv. of TMSCl
afforded 4 in 93–95% yield.
15. Preparation of 10 (general procedure for 7–14): To the THF suspension (2.5 ml) of 4a (300 mg, 1.04 mmol), 2-iodothiophen
(283 mg, 1.35 mmol), Ag2CO3 (143 mg, 0.52 mmol) and Bu4NCl (288 mg, 1.04 mmol) was added the THF solution (1
ml) of PPh3 (54 mg, 0.11 mmol) and Pd(OAc)2 (12 mg, 0.028 mmol) under Ar followed by degassed procedure. The
reaction mixture was heated at 60–65°C for 2 h. The resulting black suspension was quenched with ice-water and diluted
with AcOEt (Et2O for 14) (10 ml), subsequently filtered with suction. The filtrate was extracted with AcOEt (or Et2O),
washed with sat. NaCl, dried over MgSO4 and evaporated to give the crude product, which was purified by silica gel column
chromatography (chloroform:acetone=20:1) to afford N-(3-methoxybenzyl)-5-(2-thienyl)-4-pentynamide 10 (277 mg, 89%).
Recrystallization from t-BuOMe/hexane gave a colorless crystal, mp 72–73°C. 1H NMR (300 MHz, CDCl3) δ: 2.48 (t, J=7.2
Hz, 2H), 2.76 (t, J=7.2 Hz, 2H), 3.74 (s, 3H), 4.40 (d, J=5.6 Hz, 2H), 6.28 (b, 1H), 6.76–7.20 (m, 7H, Ar-H). 13C NMR
(75 MHz, CDCl3) δ: 16.2, 35.4, 43.7, 55.1, 74.8, 92.3, 112.9, 113.3, 119.9, 123.4, 126.3, 126.8, 129.7, 131.4, 140.0, 159.8,
170.8. EIMS m/z 299 (M+). Anal. calcd for C17H17NO2S: C, 68.19, H; 5.72, N; 4.68. Found: C; 68.18, H; 5.95, N; 4.76.
16. Hirabayashi, K.; Kawashita, J.; Nishihara, Y.; Mori, A.; Hiyama, T. Org. Lett. 1999, 1, 299–301.
17. For Pd(0)–Cu(I)- or Pd(0)-catalyzed self-coupling of terminal alkynes, see: (a) Liu, Q.; Burton D. J. Tetrahedron Lett. 1997,
38, 4371–4374. (b) Vlassa, M.; Ciocan-Tarta, I.; Margineanu, F.; Oprean, I. Tetrahedron 1996, 52, 1337–1342. (c) Rossi,
R.; Carpita, A.; Bigelli, C. Tetrahedron Lett. 1985, 26, 523–526.
18. In Hiyama’s work on Ag2O/Pd-catalyzed cross-coupling of silanols with aryl iodides, the suggestion concerning the role of
Ag2O has been reported, see: Ref. 16.
19. Schimdt, H. M.; Arens, J. F. Rec. Trav. Chim. 1967, 86, 1138–1142.
20. Lang, H.; Kohler, K.; Rheinwald, G. Organometallics 1999, 18, 598–605.
21. Bertus, P.; Pale, P. J. Organomet. Chem. 1998, 567, 173–180.
22. For information about recent advances in elucidating the mechanism of the related transmetallation between copper
acetylides and palladium complexes; see: Osakada, K.; Sakata, R.; Yamamoto, T. Organometallics 1997, 16, 5354–5364.
23. Concerning cyclization of 7, see: Ref. 11. Detailed results for cyclization of other aryl-substituted alkynylamides 8–11 will
appear in a full paper.