Rapid Sonogashira cross-coupling of iodoferrocenes and the unexpected cyclo-oligomerization of 4-ethynylphenylthioacetate

Article abstract of DOI:10.1039/c3cc43116a

A systematic study into the Sonogashira cross-coupling of 1,1′-diiodoferrocene (fcI₂) confirms that the Pd(0)-P( ^tBu)₃ system provides a remarkable rate increase over Pd(0)-(PPh₃)₂. Attempts to couple 4- ethynylphenylthioacetate (2) with fcI₂ instead produced a novel cyclic trimer of the former, from syn addition of S-Ac across CC.

Full text of DOI:10.1039/c3cc43116a

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Rapid Sonogashira cross-coupling of iodoferrocenes
and the unexpected cyclo-oligomerization of
4-ethynylphenylthioacetate†
Cite this: DOI: 10.1039/c3cc43116a
Received 26th April 2013,
Accepted 13th May 2013
Michael S. Inkpen, Andrew J. P. White, Tim Albrecht* and Nicholas J. Long*
DOI: 10.1039/c3cc43116a
www.rsc.org/chemcomm
A
systematic study into the Sonogashira cross-coupling of
1,10-diiodoferrocene (fcI2) confirms that the Pd(0)–P(tBu)3 system
provides a remarkable rate increase over Pd(0)–(PPh3)2. Attempts
to couple 4-ethynylphenylthioacetate (2) with fcI2 instead pro-
duced a novel cyclic trimer of the former, from syn addition of S–Ac
Scheme 1 Model reaction used to study the Sonogashira cross-coupling of
iodoferrocenes and terminal alkynes.
R
across C C.
Whilst large quantities of pure iodo-1 and 1,10-diiodoferrocene2
can now easily be obtained, the full synthetic exploitation of It appeared that normally outstanding catalytic systems might
these useful starting materials may only be realized through offer little or no benefit over the use of PPh3-ligated complexes in
optimizing onward reaction conditions (enabling high product Sonogashira reactions with iodoferrocenes.
yields). Towards this end, increasing the typically low/moderate
We were accordingly motivated to explore the reaction
reactivity of iodoferrocenes3 (versus aryliodides/bromides) between fcI2 and phenylacetylene as a model in an attempt to
under Sonogashira cross-coupling conditions was considered a optimise the Sonogashira cross coupling of iodoferrocenes and
primary target. Convenient and widely applicable, this reaction terminal alkynes in general (Scheme 1). Concentration, tem-
(from Fc–I containing materials) has been used to construct perature, phosphine (14 examples), solvent (3 examples), time
compounds for molecular4 and organic5 electronics, the study of and the phenylacetylene/fcI2 ratio were systematically varied to
intramolecular electron transfer,6 photo-7 and electro-chemical examine their individual effects. Product yields were deter-
1
sensing,8 catalysis (pincer complexes),9 and artificial bio- mined via H NMR spectroscopy of crude reaction mixtures.
receptors.10 It is worth noting that just two years after the
As shown in Fig. S2 (ESI†), overall reaction yields were found
seminal 1975 papers concerning aryl iodides by Heck,11 to increase substantially with substrate concentration (using
Cassar12 and Sonogashira et al.,13 cross-coupling of iodoferrocenes PdCl2(PPh3)2 at 80 1C). The effect of phosphine ligand on reaction
was under investigation.14
yields was subsequently explored by employing PdCl2(MeCN)2
In the reports referenced above, syntheses have usually at room temperature – PR3 was added separately to form
employed the convenient PdCl2(PPh3)2 precatalyst in DIPA/ PdCl2(PR3)2 in situ. Though PPh3 was found to be the best ligand
THF. However, variances in substrate structure and reagent within its local steric/electronic landscape (10% yield 1b, Fig. 1),
stoichiometry make it difficult to ratify the superiority of any the PdCl2(MeCN)2–P(tBu)3 combination provided an exceptional
particular set of conditions. Of particular significance, one rate improvement (93% yield 1b). Furthermore, whilst all reactions
paper15 describes unsuccessful attempts with Buchwald and were run for 20 h, with P(tBu)3 a large exotherm, and rapid and
Fu’s Pd(PhCN)2Cl2–P(tBu)3 combination – utilized to rapidly complete precipitate formation was observed after B15 min. Such
cross-couple electron-rich aryl-bromides at room temperature.16 observations eliminate any previous doubt15 as to the superior
reactivity of bulky, electron-rich phosphines16,17 in this context.
In comparison, other variables provided only small changes
in yields. It was additionally noted that hydrodehalogenation
reactions (Fc–I - Fc–H) occur under these conditions (limiting
yields in some cases), attributed to adventitious water. Full
experimental details may be found in the ESI.†
Department of Chemistry, Imperial College London, London, SW7 2AZ, UK.
E-mail: n.long@imperial.ac.uk, t.albrecht@imperial.ac.uk;
Tel: +44 (0)20 7594 5781
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, tables of data for all catalytic runs, discussion of hydrodehalo-
genation reactions, 1H/13C{1H} NMR spectra, crystallographic information. CCDC
927952. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc43116a
Intrigued as to why previous reactions using PdCl2(PhCN)2–
P(tBu)3 had proven unsuccessful, we noted that in these attempts
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Fig. 2 The crystal structure of one (4-A) of the three independent molecules
present in the crystals of 4.
Fig. 1 A 3D map of the effect of phosphine ligand on reaction conversion –
plotted on the z-axis where the height of black bars = % 1a, blue bars = % 1b
(nel = Tolman electronic parameter, y = Tolman cone angle).
substrates had featured thioacetyl and pyridyl functionalities.15
This prompted investigation into the apparently straightforward,
though as yet unreported, Sonogashira cross-coupling reaction
between 4-ethynylphenylthioacetate (2) and fcI2. The intended
product, 1,10-bis[(4-thioacetylbenzene)ethynyl]ferrocene (3), has
previously been prepared via Stille coupling.18
Remarkably, all attempts to synthesise 3 via Sonogashira
coupling failed – 1H NMR spectroscopy of the crude product
mixture indicated that the fcI2 had not appreciably reacted even
after 24 h (PdCl2(PPh3)2, 55 1C). However, upon closer inspection
it became apparent that resonances attributable to 2 had dis-
appeared, and new peaks were observed at approximately d 2.3,
6.4 and 7.0 ppm (intensities 3: 1: 4). Column chromatography led
to the isolation of a bright yellow solid, the identity of which was
unambiguously confirmed by X-ray crystallography‡ as that of the
novel cyclic trimer (4, 24%; Scheme 2 and Fig. 2). A material with
matching spectral features was produced using PdCl2(MeCN)2–
P(tBu)3 in an analogous procedure at room temperature.
Overall this reaction may be described as cyclo-oligomerization
of 2, generating 4 via the intermolecular syn addition of acetyl and
thiolate moieties to CRC (accompanied by cleavage of the S–Ac
bond, and reduction to CQC). Whereas 4 comprises all-Z linkages,
reaction between monofunctional analogues of 2 (S-phenylthio-
acetate and phenylacetylene) yielded the known compound 519 in
80% yield as a mixture of Z (81%) and E (19%) isomers (Scheme 3).
Sequential elimination of components showed that PdCl2(PPh3)2,
CuI and DIPEA were all necessary for the reaction to occur in THF
at a reasonable rate (proceeding sluggishly in the absence of CuI,
Scheme 3 Monofunctional analogues of 4-ethynylphenylthioacetate react
under Sonogashira conditions to form the addition product 5.
and not at all without PdCl2(PPh3)2); fcI2 is not required in any
case. Based on studies by other groups,20 we propose a reaction
mechanism such as that shown in Scheme 4. (Tokuyama et al.
previously isolated a series of 1-alkynyl ketones via an analogous
process, using an excess of CuI to trap the thiolate anion.20a Under
more forcing conditions, Minami et al. used a similar Pd/Cu
catalysed reaction to prepare 2,3-dihydrothiopyran-4-one deriva-
tives, isolating and reacting key intermediates to demonstrate the
reaction pathway.20b) In the absence of Cu(I), it is speculated that
an alkyne insertion step may occur in place of transmetallation.21
It was of additional interest to identify where Fc–I sits within
the well-established aryl halides/triflate rate series,22 and the
observation that 4 forms even in the presence of fcI2 is
particularly revealing. From the above discussion it is certainly
evident that k(Ar–I) c k(Fc–I), as aryl iodides will rapidly cross-
couple with terminal alkynes under most circumstances (resulting
in high to quantitative yields, even at room temperature).13 Noting
also that aryl bromides are readily cross-coupled in the presence
of thioacetate moieties,23 it is inferred that rates of oxidative
addition to Pd(0) follow the series: k(Ar–I) > k(Ar–OTf) > k(Ar–Br)
>
k(S–Ac) > k(Fc–I) (assuming oxidative addition to Pd(0) is always
the rate-limiting step).
In conclusion, a systematic study into the Sonogashira cross-
coupling of iodoferrocenes indicates that yields are maximised by
employing high reagent concentrations and reaction tempera-
tures. Though not immediately apparent given prior reports
utilising iodoferrocenes,15 we have shown that superior reactivity
can be obtained in this context using the PdCl2(MeCN)2–P(tBu)3
combination. Utilisation of such conditions may prove invaluable
when attempting cross-couplings of iodoferrocenes at room tem-
perature or lower concentrations (Fig. S2, ESI†), for example when
working with temperature-sensitive substrates or small quantities
of advanced intermediates (following multi-step syntheses).
It was further demonstrated that the cross-coupling of
terminal alkynes and iodoferrocenes is impracticable in the
Scheme 2 An unexpected product (4) is formed via cyclo-oligomerization of
4-ethynylphenylthioacetate (2) under Sonogashira conditions.
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Scheme 4 A proposed reaction mechanism: producing cross-coupled acetyl-alkyne and thiolate products that subsequently react under basic conditions to produce
R1C(O)CHQC(R2)S(R3)-type compounds (interpreted from work by Tokuyama and Minami et al.20).
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presence of thioacetate moieties. This is presumably due to a
competing Pd-catalysed reaction between the thioacetate group
and terminal alkyne(s), effectively blocking oxidative addition
of Fc–I to Pd(0). Whilst the bifunctional ligand 2 yielded an
isolable cyclic trimer (4), it is considered that systems of higher
complexity have previously formed unexpected, potentially poly-
meric, product mixtures under Sonogashira conditions. Future
work in our laboratories will explore these Fc–I and S–Ac based
catalytic processes in more detail, the latter being important for
biological applications (e.g. functionalization of SAc-terminated
bioconjugates,24 modification of biologically-relevant small
molecules25) and the syntheses of novel chelates, redox-active
materials and conducting polymers with b-thioketone linkages.
We are most grateful to the EPSRC and the Leverhulme
Trust for funding.
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