Synthesis of tri- and tetraynes using a butadiynyl synthon

Article abstract of DOI:10.1039/b816177a

Using a one-pot protocol, triynes and tetraynes are formed from the reaction of a dibromovinyl triflate and a terminal alkyne under palladium-catalyzed cross-coupling conditions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b816177a

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Synthesis of tri- and tetraynes using a butadiynyl synthonw
Khalid Azyat, Eike Jahnke, Trent Rankin and Rik R. Tykwinski*
Received (in College Park, MD, USA) 16th September 2008, Accepted 16th October 2008
First published as an Advance Article on the web 13th November 2008
DOI: 10.1039/b816177a
Using a one-pot protocol, triynes and tetraynes are formed from
the reaction of a dibromovinyl triflate and a terminal alkyne
under palladium-catalyzed cross-coupling conditions.
Conjugated polyynes are useful building blocks for conjugated
structures,1,2 and they show significant potential for new
optical materials.3 They are also commonly isolated as natural
products with significant biological activity.4 While the con-
jugated acetylenic framework of an unsymmetrical 1,3-diyne
Scheme 1 Attempted formation of 2.
can be formed through a plethora of different transforma-
tions,5 that of 1,3,5-hexatriyne is typically more difficult to
achieve. Two methods are commonly employed, the Cadiot–
Chodkiewicz coupling6 and the Fritsch–Buttenberg–Wiechell
(FBW) rearrangement,7,8 while other protocols also exist.9,10
To broaden the scope of the FBW rearrangement toward
polyyne formation, the use of vinyl triflate 1 as a butadiynyl
synthon was explored,11 and a general method was sought
toward the formation of 1,1-dibromoolefins 2 (Scheme 1). In
the course of subjecting 1 to Sonogashira coupling condi-
tions12 in the presence of a terminal alkyne, we have discov-
ered that the product of the reaction was not the expected
olefin 2, but rather the triyne 3. It was immediately clear that
this transformation offered a route to polyynes not accessible
though a typical elimination reaction because the formation of
3 did not require the use of a strong base. Herein, the results of
an initial study to optimize this protocol are presented.
The requisite precursor 1 is readily available from dibromo-
olefin 413 via deprotonation with LiHMDS followed by quench-
ing the resultant enolate with either N-phenyltriflamide or triflic
anhydride (Scheme 2). Yields in both cases are quite good, and
the reaction could be scaled to several grams without a decrease
of yield.14
Scheme 2 Synthesis of dibromovinyl triflate 1.
was isolated in 37% yield under the same conditions after 12 h
(entry 2). Several additional attempts with P(p-tolyl)3 and
other acetylenes revealed that the yields were typically low
(e.g., entry 7), although a 60% yield was obtained in the case
of triyne 3d (entry 10).
Switching to the even more active phosphine ligand,
P(Cy)3,15 significantly improved the yield of 3a, and, at the
same time, reduced the reaction time to only 2 h at r.t. (entry 3).
Finally, the use of P(tBu)3 gave a comparable yield to that
found for P(Cy)3, but further reduced the reaction time to
30 min (entry 4) and allowed for a reduction of the excess of
the terminal acetylenes to 2 equivalents. The trend of compar-
able yields and shorter reaction times for P(tBu)3 vs. P(Cy)3
was maintained for a number of different polyynes, including
electron rich (entries 6 and 16) and electron deficient aromatic
substituents (entries 9, 12 and 14). It is worth noting that
triynes 3c–h have not previously been available via a FBW
rearrangement because either the electrophilic aryl substituent
was not tolerant to the strong base required (3c–e and 3h) or
the aniline substituent hampered the formation of the requisite
dibromoolefin (3f and 3g). Reactions of both trimethylsilyl-
acetylene and its more polar analogue (entry 20) have so far
been unsuccessful but are subject to further investigations.16
With a reasonably optimized set of conditions in hand,z this
one-pot reaction was tested with several terminal diynes,
and unsymmetrical tetraynes 3k–m were, thus, produced
(entries 21–23). The formation of 3l is particularly noteworthy
because it demonstrates the compatibility of this reaction with
an acetylene terminated with the acetone adduct, a commonly
used alkyne protecting group.17
Initial attempts toward the Sonogashira coupling of triflate
1 to form 2 utilized typical conditions with either PdCl2(PPh3)2
or Pd(PPh3)4 in the presence of a variety of bases. These
exploratory reactions led only to mixtures of products result-
ing from an indiscriminate cross-coupling of the alkyne with
both the triflate and dibromoolefin groups.
As the reactivity of 1 was explored further, a catalyst system
of Pd(OAc)2 (10 mol%), and PPh3 (20 mol%) was attempted
in DMF, using an excess (4 equiv.) of phenylacetylene at
70 1C. A trace of triyne 3a was formed (Table 1, entry 1),
and when the phosphine ligand was changed to P(p-tolyl)3, 3a
Department of Chemistry, University of Alberta, Edmonton, Alberta,
Canada. E-mail: rik.tykwinski@ualberta.ca; Fax: +1 780 492 8231;
Tel: +1 780 492 5307
w Electronic supplementary information (ESI) available: Experimental
and spectroscopic details; 1H and 13C NMR spectra for new com-
pounds. CCDC 700679. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b816177a
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Chem. Commun., 2009, 433–435 | 433

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Table 1 One-pot synthesis of tri-and tetraynes by Pd-catalyzed
reactions between 1 and terminal alkynes
PR3 (20
Product mol%)
Yield
T/1C t/h (%)
Entry
R
1
2
3
4
3aa
3aa
3aa
3ab
PPh3 70 24 Trace
P(p-tolyl)3 70 12 37
Fig. 1 ORTEP drawing of triyne 3d.
P(Cy)3
P(tBu)3
r.t.
r.t.
2 57
0.5 62
5
6
3ba
3bb
P(Cy)3
P(tBu)3
r.t. 16 50
62
r.t.
1
7
8
9
3ca
3ca
3cb
P(p-tolyl)3 70
6
2
1
31
52
59
P(Cy)3
r.t.
r.t.
P(tBu)3
10
11
12
3da
3da
3db
P(p-tolyl)3 70
6
2
2
60
70
68
P(Cy)3
r.t.
r.t.
P(tBu)3
13
14
3ea
3eb
P(Cy)3
P(tBu)3
r.t. 24 48
r.t. 12 53
Scheme 3 Synthesis of polyynes bearing a dibromovinyl moiety.
15
16
3fa
3fb
P(Cy)3
P(tBu)3
r.t. 24 32
r.t.
further elaboration. Specifically, in the case of 6a–c, a sub-
sequent FBW reaction,7 could be used to form penta- and
hexaynes terminated with triisopropyl groups. While the yields
of these transformations tended to be somewhat lower
(ca. 30–50%) than those in Table 1, the rapid formation of
advanced polyyne intermediates still make this an attractive
alternative to the stepwise approach used in the past.
In summary, we have presented an efficient new synthetic
route toward polyynes by using a Pd-catalyzed cross-coupling
reaction of terminal alkynes with an a,a-dibromovinyl triflate.
A variety of triyne and tetrayne derivatives were prepared to
demonstrate that this protocol is a valuable alternative to a
traditional FBW rearrangement, because it tolerates base
sensitive functional groups. Further studies toward elucidating
the scope and mechanism19 of this reaction are currently in
progress.
6
33
17
18
3ga
3hb
P(Cy)3
P(tBu)3
r.t. 24 48
r.t. 12 40
19
3ib
P(tBu)3
r.t.
4
31
0
20
21
3jb
P(tBu)3
P(tBu)3
r.t. 24
3kb
r.t. 24 26
22
3lb
P(tBu)3
P(tBu)3
r.t. 24 45
r.t. 24 15
This work has been generously supported by the University
of Alberta, the Natural Sciences and Engineering Research
Council of Canada (NSERC) through the Discovery grant
program, and the German Academic Exchange Service
(DAAD, Postdoctoral Fellowship E. Jahnke). We thank
Dr. Michael J. Ferguson for the crystallographic characteriza-
tion of 3d.
23
3mb
a
Reaction was run with R–CRCH (4 equiv.), Pd(OAc)2 (10 mol%),
PR3 (20 mol%), CuI (20 mol%), Pr2NH (4 equiv.), under nitrogen.
i
b
Reaction was run with R–CRCH (2 equiv.), Pd(OAc)2 (10 mol%),
PR3 (20 mol%), CuI (20 mol%), Pr2NH (4 equiv.), under nitrogen.
i
Notes and references
z General procedure for the Pd-catalyzed cross coupling reaction of a
terminal alkyne with a,a-dibromovinyl triflate 1: To compound 1
(0.5 mmol) dissolved in 10 ml of DMF was added the appropriate
terminal alkyne (1 to 2 mmol) and iPr2NH (2 mmol). The solution was
deoxygenated for 1 h, and P(tBu)3 (0.25M solution in toluene), CuI
(20 mol%), and Pd(OAc)2 (10 mol%) were added. After stirring at r.t.
for the time specified, a saturated aqueous solution of NH4Cl was
added, and the resulting mixture was extracted with ethyl acetate
(3 ꢁ 10 mL). The combined organic layers were washed with brine
(10 mL) and dried over anhydrous MgSO4. Evaporation of the solvent
followed by purification via silica-gel column chromatography gave
the corresponding polyyne.
Spectroscopic analysis of all tri- and tetraynes were consis-
tent with their proposed structures and with data that was
previously reported (e.g., 3c). Definitive proof of polyyne
formation was also provided by X-ray crystallographic char-
acterization of 3d (Fig. 1).y As observed with other polyynes in
the solid state,18 the triyne segments of 3d takes on a gentle
bowing conformation, with bond angles of 177–1781.
To extend the potential usefulness of this procedure toward
even longer polyynes, the reaction of 1 with substrates 5a–d
bearing a 1,1-dibromovinyl moiety was explored (Scheme 3).
The products of this reaction, 6, might then be suitable for
y Crystal data for 3d: C21H25NO2Si, M = 351.51; monoclinic crystal
system; space group P21/c (no. 14), a = 20.1591(16), b = 7.3496(6),
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434 | Chem. Commun., 2009, 433–435

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c = 14.2110(11) A, b = 107.9480(10)1, V = 2003.1(3) A3, Z = 4;
Dc = 1.166 g cmꢂ3; 2ymax = 55.001; m = 0.130 mmꢂ1; T = ꢂ80 1C;
total data collected = 16 620; Final R1(F) = 0.0411 [4074 observations
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Chem. Commun., 2009, 433–435 | 435