Facile formation of iodocyclobutenes by a ruthenium-catalyzed enyne cycloisomerization

Article abstract of DOI:10.1039/b708903a

Enynes bearing an iodide (bromide) at their alkyne terminus react with catalytic amounts of [Cp*Ru(MeCN)₃]PF₆ in DMF to give strained iodo(bromo)cyclobutene derivatives in good to excellent yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/b708903a

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Facile formation of iodocyclobutenes by a ruthenium-catalyzed enyne
cycloisomerization{
Alois Fu¨rstner,* Andreas Schlecker and Christian W. Lehmann
Received (in Cambridge, UK) 13th June 2007, Accepted 25th July 2007
First published as an Advance Article on the web 9th August 2007
DOI: 10.1039/b708903a
Enynes bearing an iodide (bromide) at their alkyne terminus
react with catalytic amounts of [Cp*Ru(MeCN)3]PF6 in DMF
to give strained iodo(bromo)cyclobutene derivatives in good to
excellent yields.
During our ongoing investigations on noble metal catalyzed
skeletal rearrangement reactions,1,2 we noticed that the brominated
enyne 1, on treatment with catalytic amounts of AuCl in toluene at
80 uC, furnished the tricyclic bromocyclobutene derivative 2 in
Scheme 2 Reagents and conditions: (a) complex 4 (5 mol%), RT, 94%
87% yield (Scheme 1). However, this particular outcome remained
unique and analogous cyclizations of related substrates could not
be achieved under the chosen conditions.3,4
(DMF), 75% (THF).
chromatography; in pure form, the compound is stable for weeks
when kept cold (218 uC). The constitution of this and related
products was unambiguously proven by extensive NMR investiga-
tions (see ESI{). The structure of the amide analogue 16 in the
solid state{ is depicted in Fig. 1, which represents the first example
of a tricyclic skeleton of this type.
Despite the many impressive advances in the field of gold and
platinum catalysis, a mechanistic analysis shows that such
transformations usually exploit the pronounced carbophilicity of
these noble metals but do not involve conventional redox cycles.5
Cyclobutene 2, however, likely originates from an oxidative
cyclization of the enyne followed by reductive elimination of the
resulting metallacycle. Therefore it seemed reasonable to focus on
more redox active transition metals in the quest for a catalyst
system that allows the scope of this novel mode of cycloisomeriza-
tion to be extended.
The selected examples compiled in Tables 1 and 2 illustrate the
scope of the method. Specifically, enynes incorporating an ether or
an amido group in the tether between the olefin and the
haloalkyne unit are converted with high efficiency into the
corresponding cyclobutenes, irrespective of whether the backbone
of the substrates is aromatic or aliphatic; purely carbocyclic
products form equally well (entry 10, Table 1). The fact that not
only the produced alkenyl iodide but also a pre-existing aryl
bromide entity (entries 7 and 8, Table 1) is compatible with the
reaction conditions shows that oxidative insertion of the catalyst
into such reactive C–X bonds does not compete with the proposed
Metallacyclic intermediates are believed to dominate the
behavior of CpRu(II) and Cp*Ru(II) templates.6,7 In line with this
notion, [Cp*Ru(MeCN)3]PF6 (4), a readily prepared and also
commercially available complex with a truly remarkable track
record in catalysis,6–10 turned out to effect cycloisomerizations of
this kind with exceptional ease. As shown in Scheme 2, the model
substrate 3 converts within minutes at ambient temperature into
the desired iodocyclobutene 5 when exposed to catalytic amounts
of 4 in THF or DMF as the preferred solvents, presumably via a
metallacycle of type A as the key reactive intermediate. Product 5
was isolated in excellent yield, provided that either neutral
alumina or Florisil1 were used as stationary phase for flash
Scheme 1 Lead finding on a novel mode of enyne cycloisomerization.
Max-Planck-Institut fu¨r Kohlenforschung, D-45470, Mu¨lheim/Ruhr,
Germany. E-mail: fuerstner@mpi-muelheim.mpg.de;
Fax: +49 208 306 2994; Tel: +49 208 306 2342
{ Electronic supplementary information (ESI) available: Experimental
part, including analytical and spectroscopic data of all new compounds.
See DOI: 10.1039/b708903a
Fig. 1 Molecular structure of 16 from single-crystal X-ray structure
determination. Anisotropic displacement parameter ellipsoids are shown
at 50% probability and hydrogen atoms have been omitted.
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Table 1 Cycloisomerization of 1-haloenynes with aromatic back-
bones into iodo(bromo)cyclobutene derivatives catalyzed by complex
Table 2 Cycloisomerization of 1-iodoenynes with aliphatic back-
bones into the corresponding iodocyclobutene derivatives catalyzed by
complex 4a
4a
Entry
Product
Yield (%)
Entry
Product
Yield (%)
1
2
3
6
7
8
81 (X = I)
78 (X = Br)c
0 (X = Cl)
1
2
18
19
63 (X = O)
63 (X = NTs)
4
9
45
3
4
5
a
20
21
22
70
5
6
5
10
94 (X = I)
43 (X = Br)
79
7
8
11
12
90 (X = I)
89 (X = Br)c
60 + 20b
9
13
86
All reactions were carried out with 5 mol% of 4 in DMF at
b
ambient temperature. 60% of major isomer (depicted) + 20% of
diastereomer.
10
11
12
14
15
16
82 (X = CH2)b,c
88 (X = NTs)
74 (X = NAc)
chlorides, as evident from a comparison of entries 1 and 3 in
Table 1. While cyclobutenyl iodide 6 was obtained in excellent
yield, the analogous chloride 8 would not form under the standard
conditions. Likewise, enynes 25–27 featuring either a terminal or
an internal alkyne unit remained unchanged. The exact role
exerted by the iodine moiety, however, which is obviously not
merely electronic in nature, remains to be elucidated.
13
17
63
Even though the cyclobutenyl iodides produced by this novel
route are fairly labile due to the strain inherent to their polycyclic
frames,11 they are amenable to further functionalization
(Scheme 3). This includes conventional palladium catalyzed cross
couplings as exemplified by the Sonogashira reaction12 affording
compound 28 and the Suzuki coupling13 leading to 29, which was
performed according to the ‘‘9-MeO-9-BBN-variant’’14 of this
venerable transformation. Gratifyingly, iodides 6 and 15 also react
with Grignard reagents under iron catalysis as a benign alternative
to the established methods for cross coupling.15–18 BuLi alkylates
substrates of this type even without any further additive, although
the yield was low in the case of product 32 (n = 1). Subsequent
electrocyclic ring opening afforded diene 33 that is amenable to
further manipulation, suggesting that the novel mode of enyne
cycloisomerization described herein may pave the way to a host of
valuable product structures and should therefore qualify for
(diversity oriented) synthetic endeavours. Some possibilities along
these lines are presently pursued in this laboratory and will be
reported in due course.
a
Unless stated otherwise, all reactions were carried out with 5 mol%
of 4 in DMF at ambient temperature. In THF. 4 (10 mol%).
b
c
oxidative cyclization pathway thought to be responsible for the
formation of the cyclobutene ring.
A comparison of entries 1, 4 and 5 in Table 1, however,
indicates a subtle effect of the substrate’s electronic properties on
the efficiency of cyclization. The view that more electron rich
substrates seem to be preferred is supported by the fact that enyne
23 carrying an electron withdrawing nitro group essentially failed
to afford the corresponding cyclobutene, whereas acrylate 24 was
decomposed. It is also important to note that the substituent on
the alkyne plays a pre-eminent role in the cyclization process.
Thus, alkynyl bromides tend to react less readily than the
corresponding iodides and require a higher catalyst loading to
reach full conversion (entries 2, 6 and 8, Table 1). Even more
striking is the difference between alkynyl iodides and alkynyl
Generous financial support by the MPG and the Fonds
der Chemischen Industrie is gratefully acknowledged. We
thank Dr R. Mynott and Ms P. Philipps for expert NMR
assistance and Umicore AG & Co KG, Hanau, for a gift of noble
metal salts.
4278 | Chem. Commun., 2007, 4277–4279
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T. Gress, J. Am. Chem. Soc., 2005, 127, 8244; (b) A. Fu¨rstner and
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Scheme 3 Reagents and conditions: (a) Me3SiCMCH, CuI (20 mol%),
(Ph3P)2PdCl2 (10 mol%), Et3N, 77%; (b) PhMgBr, 9-MeO-9-BBN,
(dppf)PdCl2 (5 mol%), Ph3As (10 mol%), THF, 60–80 uC, 56%; (c)
MeMgBr, [(C2H4)4Fe][Li(tmeda)]2 (10 mol%), THF, 220 uC, 55%; (d)
nBuLi, THF–Et2O, 278 uC A RT, 72%; (e) hexylmagnesium bromide,
[(C2H4)4Fe][Li(tmeda)]2 (10 mol%), THF, 220 uC, 51% (n = 3); (f) nBuLi,
THF–Et2O, 278 uC A RT, 31% (n = 1); (g) toluene, reflux, 88%.
Notes and references
{ Crystal data for 16: [C13H12INO], Mr = 325.14, colourless, crystal size:
0.03 6 0.05 6 0.07 mm; monoclinic, space group Cc (no. 9), a =
˚
24.4838(8), b = 8.0709(3), c = 12.1166(4) A, b = 104.469(2)u, U =
2318.4(1) A , T = 100 K, Z = 8, Dc = 1.86 g cm23, F(000) = 1264, Bruker-
3
˚
21
˚
AXS X8-Proteum diffractometer, l(Cu-Ka) = 1.54178 A, m = 21.52 mm ,
9921 measured and 2821 independent reflections (Rint = 0.037), 2474 with
I . 2s(I), hmax = 63.26u, apparent Tmin/max = 0.4362 (SADABS), direct
2
methods (SHELXS-97) and least-squares refinement (SHELXL-97) on Fo
,
programs from G. Sheldrick, University of Go¨ttingen, 1997. Two
crystallographically independent molecules. Chebyshev type weights,
290 parameters, R1 = 0.032 (I . 2s(I)), wR2 = 0.081 (all data),
23
˚
˚
˚
Drmax/min = 1.5/20.7 e A (1.0 A from I2/0.95 A from I1). CCDC
650426. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b708903a
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Chem. Commun., 2007, 4277–4279 | 4279