A one-pot synthesis of 1-arylalka-1,3-diynes by sequential acetylene zipper and Sonogashira reactions

Article abstract of DOI:10.1016/S0040-4039(02)02496-6

1,3-Diynes, formed in situ by base-induced acetylene zipper reactions, following anion quenching with water, undergo smooth Sonogashira-type couplings with functionalized aryl iodides, to give good overall yields of 1-arylalka-1,3-diynes.

Full text of DOI:10.1016/S0040-4039(02)02496-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 107–109
A one-pot synthesis of 1-arylalka-1,3-diynes by sequential
acetylene zipper and Sonogashira reactions
Irina A. Balova,a,* Svetlana N. Morozkina,a David W. Knightb and Sergei F. Vasilevskyc
aDepartment of Chemistry, St. Petersburg State University, Universitetskij pr. 26, 198904 St. Petersburg, Russia
bChemistry Department, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
cInstitute of Chemical Kinetics & Combustion of Russian Academy of Sciences, Institutskaya Str., 3 Novosibirsk 630090, Russia
Received 27 September 2002; accepted 1 November 2002
Abstract—1,3-Diynes, formed in situ by base-induced acetylene zipper reactions, following anion quenching with water, undergo
smooth Sonogashira-type couplings with functionalized aryl iodides, to give good overall yields of 1-arylalka-1,3-diynes. © 2002
Elsevier Science Ltd. All rights reserved.
Since the discovery of the Pd–Cu-catalyzed cross-cou-
pling reactions of terminal acetylenes with aryl iodides
or bromides, now commonly referred to as the Sono-
gashira reaction,1 these have enjoyed many applications
in organic synthesis especially in the preparation of a
very wide range of aryl- and heteroarylacetylenes.2
Indeed, this reaction is probably one of the most fre-
quently used CꢀC bond forming processes in organic
chemistry. However, there are very few examples
known of similar couplings with 1,3-diynes in general,
most likely due to difficulties associated with the syn-
thesis and especially the stability of such intermediates.3
Hence, Cadiot–Chodkiewicz couplings are often used to
obtain unsymmetrical diynes, including 1-(hetero) aryl-
1,3-diynes. However this reaction often leads to a mix-
ture of the target and by-products of symmetrical
couplings and delivers moderate isolated yields.4
A commonly used tactic when intermediates are
unstable or difficult to handle is to generate such spe-
cies in situ and carry out a subsequent reaction without
isolation. Herein, we report that just such a strategy is
highly effective for the elaboration of 1-arylalka-1,3-
diynes by a combination of the Sonogashira method
with a preceeding multi-positional prototropic isomer-
ization (‘acetylene zipper’ reaction) of a disubstituted
diyne. In this remarkably rapid zipper reaction, a disub-
stituted alkyne is typically treated with an alkaline
metal amide of an a,v-alkanediamine (K,5a Na5b or
Li5c), and the multiple isomerizations concluded by
formation of a much more stable 1-acetylide. This
isomerization is also applicable to disubstituted alka-
diynes when the product is the lithium salt of the
corresponding alka-1,3-diyne.6 Therefore, by quenching
the latter salts using water, solutions of the free alka-
1,3-diynes are obtained. We have found that these are
Scheme 1.
* Corresponding author.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02496-6

108
I. A. Balo6a et al. / Tetrahedron Letters 44 (2003) 107–109
then suitable for subsequent Sonogashira couplings,
especially as these are carried out in the presence of an
organic amine base and hence the residual a,v-diamine
does not interfere, thereby obviating the need to isolate
the sensitive alka-1,3-diynes. The method is summa-
rized in Scheme 1.
Although most examples of aryl iodides in this present
study are relatively electron poor and hence particularly
well suited to Sonogashira coupling reactions, the
finding that 1-amino-2-iodobenzene (cf. 4) also partici-
pates very efficiently indicates that this ‘one-pot’
method should be widely applicable to a range of both
aryl and heteroaryl halides.
For example, starting with dodeca-5,7-diyne 1b, treat-
ment with three equivalents of lithium 2-aminoethyl-
amide (LAETA) at 16–18°C for 10 min results in
Acknowledgements
complete isomerization, following which,
a small
amount of water is added to release the free alka-1,3-
diyne 3b from the salt 2b. This is followed by the
addition of an aryl iodide, palladium(II) acetate,
triphenylphosphine, triethylamine and copper(I) iodide
in this order, to set up the catalyst system usually
associated with the Sonogashira coupling reaction.1 In
all cases, these final coupling reactions took place under
very mild conditions, either at ambient temperature or
slightly above (35–45°C) during 3–8 h. A routine work-
up and chromatography then delivered the isolated
yields of the representative 1-arylalka-1,3-diynes 4–8.7
We gratefully acknowledge financial support from
INTAS, Grant 97-31999 and RFBR Grant 02-03-
32229.
References
1. (a) Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetra-
hedron Lett. 1975, 16, 4467; (b) Dieck, H. A.; Heck, R. F.
J. Organomet. Chem. 1975, 93, 259; (c) Cassar, L. J.
Organomet. Chem. 1975, 93, 253.
2. (a) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced.
Int. 1995, 27, 127; (b) Brandsma, L.; Vasilevsky, S. F.;
Verkruiisse, H. D. Application of Transition Metal Cata-
lysts in Organic Synthesis; Springer: New York, 1998; p.
179; (c) Bunz, U. H. F. Chem. Rev. 2000, 100, 1605.
3. (a) Schvartsberg, M. A.; Vasilevsky, S. F.; Prihod’ko, T.
A. Izv. Acad. Nauk., Ser. Khim. 1982, 11, 2524; (b) Boese,
R.; Green, J. R.; Mittendorf, J.; Mohler, D. L.; Vollhardt,
K. P. C. Angew. Chem., Int. Ed. Engl. 1992, 31, 1963; (c)
Vasilevsky, S. F.; Tretyakov, E. V. Liebigs Ann. 1995, 775;
(d) Liao, H.-Y.; Cheng, Ch. H. J. Org. Chem. 1995, 60,
3711.
4. (a) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763;
(b) Siemsen, P.; Livingston, R. C.; Diederick, F. Angew.
Chem., Int. Ed. 2000, 39, 1643.
5. (a) Brown, C. A.; Yamishita, A. J. Am. Chem. Soc. 1975,
97, 891; (b) Macaulay, S. R. J. Org. Chem. 1980, 45, 734;
(c) Remizova, L. A.; Krukov, A. V.; Balova, I. A.;
Favorskaja, I. A. Zh. Org. Khim. (Russ.) 1985, 21, 1001.
6. (a) Balova, I. A.; Remizova, L. A.; Favorskaja, I. A. Zh.
Org. Khim. (Engl. Transl.) 1988, 24, 2523; (b) An improved
method for the ‘acetylene zipper’ reaction was used.
Balova, I. A.; Moprozkina, S. N.; Voskresenskij, S. V.;
Remozova, L. A. Zh. Org. Khim. (Russ.) 2000, 36, 1466.
7. Full spectroscopic and analytical data has been obtained
for all compounds reported herein. For example, 2-
(dodeca-1,3-diynyl)aniline (4b): lH (300 MHz, CDCl3):
0.88 (3H, t, J=7 Hz, Me), 1.21–1.42 (10H, 5×CH2), 1.57
(2H, p, J=7 Hz, CH2), 2.37 (2H, t, J=7 Hz, CH2C), 4.47
(2H, s, NH2), 6.67–6.75 (2H, m), 7.12 (1H, t, J=7 Hz,
Ar-H) and 7.28 (1H, t, J=7 Hz, Ar-H); lC (75 MHz,
CDCl3): 14.5 (Me), 20.1 (CH2C), 23.1, 28.7, 29.3 29.5,
29.6, 32.3 (all CH2), 65.4, 72.0, 80.0, 86.4 (all C), 107.1,
114.8, 118.4, 130.6 133.5, and 149.6 (all ArC), m/z 253
(C18H23N=253). Anal. found: C, 85.24; H, 9.12; N, 5.63.
C18H23N requires: C, 85.32; H, 9.15; N, 5.53%.
In our initial experiments, a 10% excess of the aryl
iodide relative to the diyne 3b was used. Under these
conditions, between 4 and 10% of the dehydrodimeriza-
tion product 9b was formed as a by-product. With a
view to reducing this amount, we investigated the effect
of varying the stoichiometry of the diyne and the aryl
iodide and found the best yields of the aryl-1,3-diynes
4–8 were obtained using a molar ratio of 1.2:1 of these
two reactants, that is, slightly less aryl iodide than
formally required to react with all of the diyne. It is
also important that the copper(I) iodide is added last.
Given these two conditions, yields of the tetrayne by-
products 9 were reduced from levels of ca. 10% to
2–4%.8 It is also worth noting that, under the mild
coupling conditions used, no intramolecular cyclization
products were formed during the synthesis of the ortho-
aminoarylalka-1,3-diynes 4 and 7.
8. Typical experimental procedure: LAETA was obtained by
the reaction of Li (53 mg, 7.5 mmol) with absolute EDA
(0.6 ml, 7.5 mmol) in dry THF (1.8 ml) under Ar. After
the addition of benzene (1.8 ml) and hexane (1.8 ml), the

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109
suspension of LAETA was cooled to 16°C, the diacetylenic
hydrocarbon (2.5 mmol) added and the resulting mixture
stirred for 10 min. After this, 0.5 ml of water was added to
the dark-brown reaction mixture. The aryl iodide (2 mmol),
Pd(OAc)2 (22.4 mg, 0.1 mmol), PPh3 (52.5 mg, 0.2 mmol),
Et3N (5 ml) and CuI (57 mg, 0.3 mmol) were then added
subsequently in this order to the stirred reaction mixture.
TLC was used to monitor the reaction. When the reaction
was complete, the mixture was poured into ice–water and
the resulting mixture extracted with CH2Cl2 (4×25 ml). The
combined organic extracts were washed with water and
dried over MgSO4. After solvent evaporation, the product
was isolated by flash chromatography on silica gel, eluting
with hexane, then hexane/CH2Cl2 mixtures.