Generation of molecular complexity from cyclooctatetraene using dienyliron and olefin metathesis methodology

Article abstract of DOI:10.1039/c2ob25636c

Transformation of the simple hydrocarbon cyclooctatetraene into a variety of polycyclic skeletons was achieved by sequential coordination to iron, reaction with electrophiles followed by allylated nucleophiles, decomplexation and olefin metathesis.

Full text of DOI:10.1039/c2ob25636c

View Online / Journal Homepage
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: DOI: 10.1039/c2ob25636c
www.rsc.org/obc
COMMUNICATION
Generation of molecular complexity from cyclooctatetraene using dienyliron
and olefin metathesis methodology†
Mohamed F. El-Mansy, Anobick Sar, Subhabrata Chaudhury, Nathaniel J. Wallock and
William A. Donaldson*
Received 28th March 2012, Accepted 16th May 2012
DOI: 10.1039/c2ob25636c
Transformation of the simple hydrocarbon cyclooctatetraene
into a variety of polycyclic skeletons was achieved by
sequential coordination to iron, reaction with electrophiles
followed by allylated nucleophiles, decomplexation and olefin
metathesis.
The ability to rapidly generate diverse molecular complexity is
one of the foundations of diversity-oriented synthesis (DOS).1
Within the general build/couple/pair (B/C/P) or functional group
pairing strategy described by Schreiber and Nielsen2a and Porco
et al.,2b the introduction of folding pathways allows for the trans-
formation of different substrates into different scaffolds using a
common reagent, while branching pathways allow for the trans-
formation of a single substrate into different scaffolds with
different reagents.1b,2c From the infancy of DOS, olefin metath-
esis has played a prominent role in folding pathways, more
recently including domino sequences of ring closing and/or ring
opening metatheses.3 The DOS approach has lead to the discov-
ery of molecules exhibiting anti-MRSA activity,4a,b or in vitro
cytotoxicity against A549 lung carcinoma.4c As part of our inter-
est in the generation of molecular complexity from simple hydro-
carbons,5 we herein report the preparation of a variety of
carbocyclic and heterocyclic structures from cyclooctatetraene
(COT) using (dienyl)iron and olefin metathesis methodology.
Tricarbonyl(cyclooctatetraene)iron 1, readily prepared from
COT,6 reacts with a variety of electrophiles to form (dienyl)iron
cations 2–4 (Scheme 1).5a,7 Reaction of 2–4 with either the
anion (5) derived from dimethyl allylmalonate, or the anion (6)
derived from (allyl)tosylamine, followed by oxidative decom-
Scheme 1 (E = CO2Me).
plexation8 gave the racemic polyenes 7–12 respectively. These
transformations may be regarded as branching pathways in diver-
bicyclo[3.2.1]octa-3,5-diene skeleton;5b signals at δ 0.65–0.75
sity oriented synthesis. The structural assignments for 7–12 are
based on their NMR spectral data.9 In particular, signals at
(1H), 1.1–1.2 (1H), 5.3–5.45 (1H), 5.6 (1H) and 6.1 ppm (1H)
1
1
δ 6.0–6.2 (1H) and 5.8–5.9 ppm (1H) in the H NMR spectra of
in the H NMR spectra of 9 and 10 are characteristic of the H-8
7 and 8 are characteristic of the olefinic protons H-6/H-7 in the
and H-8′ cyclopropane protons, and the olefinic protons H-4,
H-5, and H-6 respectively;5a while signals at δ 3.4–3.6 (1H, br m),
6.1 (1H, dd) and 6.3–6.4 ppm (1H, d) in the 1H NMR spectra of
11 and 12 are characteristic of H-6, H-8, and H-9 of a styryl-sub-
stituted cycloheptadiene.10
The presence of olefins in the free ligands 7–12 offers the
possibility of ring rearrangement metathesis (RRM).11 Ring
rearrangement metathesis occurs without the formation of a
Department of Chemistry, Marquette University, P. O. Box 1881,
Milwaukee, WI, USA. E-mail: william.donaldson@marquette.edu;
Fax: +1 414-288-7066; Tel: +1 414-288-7374
†Electronic supplementary information (ESI) available: Experimental
1
procedures and copies of H and 13C NMR spectra of new compounds.
See DOI: 10.1039/c2ob25636c
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.

View Online
Scheme 2 (G-I = (PCy3)2Cl2RuvCHPh).
Scheme 3 (E = CO2Me; G-I = (PCy3)2Cl2RuvCHPh).
Scheme 4 (E = CO2Me; G-I = (PCy3)2Cl2RuvCHPh).
by-product olefin, and as such these reactions may be considered
an equilibrium between two isomeric structures. For this reason,
substrates which undergo successful RRM reactions generally
embody a degree of strain; this strain energy is released upon the
rearrangement. To this end, reaction of 7 or 8 with Grubbs’ 1st
generation catalyst led exclusively to the RRM products 13 or 14
respectively (Scheme 2). Epimerization at C-10 of 13 or 14,
under the reaction conditions or during spectroscopic character-
ization, was not observed. The structural assignments for these
products are based on their NMR spectral data. In particular,
signals at δ 41.4, 51.3, and 62.1 ppm in the 13C NMR spectrum
of 13 are characteristic of the C-2, C-5, and C-1 carbons of a
substituted dimethyl 3-cyclopentene-1,1-dicarboxylate,12 while
the signals at δ ∼3.4 ppm (t) in the 1H NMR spectrum of 13 and
14 are characteristic of H-9.13
Similarly, exposure of 9 to Grubbs’ 1st generation catalyst
gave the ring rearranged product 15 (Scheme 3). The presence of
the substituted dimethyl 3-cyclopentene-1,1-dicarboxylate ring is
evident by comparison to the 13C NMR spectral data for 13. In
addition, signals at δ 6.04 (dt, J = 0.9, 10.9 Hz) and 6.71 (dddd,
J = 0.9, 10.2, 11.3, 16.7 Hz) are characteristic of H-2 and H-3 of
a 1,3-Z-butadien-5-yl sidechain.14 In contrast, reaction of 10
with Grubbs’ 1st or 2nd generation catalyst gave only self-
metathesis dimer 16, as an inseparable mixture of dl- and meso-
diastereomers. The structure of 16 was assigned on the basis of
its NMR spectral data. In particular many of the signals in the
1H NMR spectrum of 16 are remarkably similar to those of 8,
the primary difference being the absence of signals correspond-
ing to a mono-substituted olefin and the appearance of a narrow
multiplet at δ 5.80–5.85 (2H) corresponding to the new 1,2-dis-
ubstituted double bond. In addition, the presence of a signal at
δ 130.5 ppm in the 13C NMR spectrum of 16 (instead of a signal
at ca. δ 117–119 ppm) indicated the presence of the self-meta-
thesis olefin.
Scheme 5 (E = CO2Me2; G-I = (PCy3)2Cl2RuvCHPh; G-II = (PCy3)-
(IMes)Cl2RuvCHPh).
particularly effective as an activator for initiating relay ring-
closing metathesis (RRCM).15 These authors suggested that the
rate-determining step in some RRCM reactions is the decom-
plexation of the product olefin (i.e. a cyclopentene ring), and that
this decomplexation was more rapid for a cyclopentene ring with
a sterically bulky dicarboxylate substitution pattern. In the
present case initiation generates the Ru-carbene A (Scheme 4).
Two pathways are available to this intermediate: either reversible
intramolecular equilibration to afford intermediate E, or irreversible
self-metathesis dimerization. According to Hoye’s proposal, the
rate of decomplexation of D [X = C(CO2Me)2] is rapid (i.e. koff
is fast), and thus E reacts with 9 to give the ring rearranged
product 15 and regenerate intermediate A. Conversely, inter-
mediate D [X = NTs] undergoes decomplexation at a slower rate
leading to the eventual irreversible self metathesis and concomi-
tant formation of ethylene via the methylene carbene complex
[(Cy3P)Cl2RuvCH2].
The substrates 11 or 12 contain a number of potential sites for
olefin metathesis. In contrast to the reactions of 7–10, exposure
of 11 to Grubbs’ 1st generation catalyst led to the ring-closed
product 17 (Scheme 5). The structural assignment for this
product as the Δ6,7 isomer is based on its NMR spectral data. In
The difference in reactivity between 9 and 10 toward G-I cata-
lyst may be rationalized on the basis of the allylmalonate group
of 9 compared to the (allyl)tosylamine group of 10. Hoye and
co-workers have previously noted that the allylmalonate group is
1
particular, the H NMR spectrum of 17 integrates to 18 Hs; five
of which are olefinic. Furthermore, the 13C NMR spectrum of 17
consisted of 15 signals with five olefinic methine carbons and
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2012

View Online
4 (a) E. E. Wyatt, S. Fergus, W. R. J. D. Galloway, A. Bender, D. J. Fox,
A. T. Plowright, A. S. Jessiman, M. Welch and D. R. Spring, Chem.
Commun., 2006, 3296; (b) G. L. Thomas, R. J. Spandl, F. G. Glansdorp,
M. Welch, A. Bender, J. Cockfield, J. A. Lindsay, C. Bryant,
D. F. J. Brown, O. Loiseleur, H. Tudyk, M. Ladlow and D. R. Spring,
Angew. Chem., Int. Ed., 2008, 47, 2828; (c) S. K. Ko, H. J. Jang, E. Kim
and S. B. Park, Chem. Commun., 2006, 2962.
5 (a) N. J. Wallock and W. A. Donaldson, J. Org. Chem., 2004, 69, 2997;
(b) S. Chaudhury, S. Lindeman and W. A. Donaldson, Tetrahedron Lett.,
2007, 48, 7849.
6 Y. Shvo and E. Hazum, J. Chem. Soc., Chem. Commun., 1975, 829.
7 (a) A. Davison, W. McFarlane, L. Pratt and G. Wilkinson, J. Chem. Soc.,
1962, 4821; (b) M. Brookhart, E. R. Davis and D. L. Harris, J. Am.
Chem. Soc., 1972, 94, 7853; (c) A. D. Charles, P. Diversi,
B. F. G. Johnson and J. Lewis, J. Chem. Soc., Dalton Trans., 1981, 1906;
(d) K. Broadley, N. G. Connelly, R. M. Mills, M. Whiteley and
P. Woodward, J. Chem. Soc., Dalton Trans., 1984, 683.
8 Ceric ammonium nitrate [CAN] in methanol or acetonitrile was used as
the standard oxidative decomplexation conditions. The formation of 10
required the use of DDQ as oxidant.
one quaternary olefinic carbon. The reaction of 12 with Grubbs’
1st generation catalyst led to a complex mixture of products; use
of Grubbs’ 2nd generation catalyst gave the 2-azabicyclo[4.4.1]-
undeca-5,7,9-triene 18, which slowly underwent decomposition
in solution. Olefin isomerization has previously been observed
as a competitive side reaction of Ru-catalyzed olefin metath-
esis.16 Presumably the thermodynamically more stable Δ6,7
isomers 17/18 are formed by isomerization of the initially
formed Δ7,8 isomer 19.
In summary, diverse molecular complexity may be generated
in 5–6 steps by sequential reaction of (COT)Fe(CO)3 with an
electrophile, followed by an allylated nucleophile and decom-
plexation (branching pathways), and olefin metathesis (folding
pathway). The outcome of these reactions depends on the nature
of the electrophile and nucleophile used. Applications of this
methodology to target molecule synthesis will be reported in due
course.
9 See ESI† for spectral data and copies of original spectra.
10 H. M. L. Davies, T. J. Clark and H. D. Smith, J. Org. Chem., 1991, 56,
3817.
11 O. Arjona, A. G. Csaky, M. C. Murica and J. Plumet, Tetrahedron Lett.,
2000, 41, 9777; A. Ruckert, D. Reisel and S. Blechert, Tetrahedron Lett.,
2001, 42, 5245; H. Hagiwara, T. Katsumi, S. Endou, T. Hoshi and
T. Suzuki, Tetrahedron, 2002, 58, 6651; A. E. Nadany and
J. E. Mckendrick, Synlett, 2007, 1663; H. Clavier, J. Broggi and
S. P. Nolan, Eur. J. Org. Chem., 2010, 937.
12 (a) S. Sinha, T. Bhaumik and S. Ghosh, ARKIVOC, 2005, xi, 24; (b) K.
L. Bray, G. C. Lloyd-Jones, M. Paza Munoz, P. A. Slatford, E. H. P. Tan,
A. R. Tyler-Mahon and P. A. Worthington, Chem.–Eur. J., 2006, 12,
8650; (c) S. Schornshusen and J. Heck, Organometallics, 2007, 26,
5386.
Acknowledgements
This work was supported by the National Science Foundation
(CHE-0415771 and CHE-0848870) and NSF instrumentation
grants (CHE-0521323). High-resolution mass spectra were
obtained at the University of Nebraska-Center for Mass Spec-
trometry and the COSMIC lab at Old Dominion University.
13 W. Boland and L. Jaenicke, J. Org. Chem., 1979, 44, 4819;
L. A. Paquette, G. D. Crouse and A. K. Sharma, J. Am. Chem. Soc.,
1982, 104, 4411.
14 S. P. Gunasekera, M. Gunasekera and R. E. Longley, J. Org. Chem.,
1990, 55, 4912; W. A. Donaldson and L. Shang, Tetrahedron Lett., 1995,
36, 1575.
15 T. R. Hoye, J. Jeon and M. A. Tennakoon, Angew. Chem., Int. Ed., 2011,
50, 2141.
16 M. B. Dinger and J. C. Mol, Organometallics, 2003, 22, 1089; S.
H. Hong, D. P. Sanders, C. W. Lee and R. H. Grubbs, J. Am. Chem. Soc.,
2005, 127, 17160; F. C. Courchay, J. C. Sworen, I. Ghiviriga,
K. A. Abboud and K. B. Wagener, Organometallics, 2006, 25, 6074.
Notes and references
1 (a) M. D. Burke, E. M. Berger and S. L. Schreiber, Science, 2003, 302,
613; (b) M. Dow, M. Fisher, T. James, F. Marchetti and A. Nelson, Org.
Biomol. Chem., 2012, 10, 17.
2 (a) T. E. Nielsen and S. L. Schreiber, Angew. Chem., Int. Ed., 2008, 47,
48; (b) E. Comer, E. Rohan, L. Deng and J. A. Porco, Jr, Org. Lett.,
2007, 9, 2123; (c) M. D. Burke and S. L. Schreiber, Angew. Chem., Int.
Ed., 2004, 43, 46.
3 (a) R. J. Spandl, H. Rudyk and D. R. Spring, Chem. Commun., 2008,
3001; (b) D. Morton, S. Leach, C. Cordier, S. Warriner and A. Nelson,
Angew. Chem., Int. Ed., 2009, 48, 104.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.