Unexpected nucleophilic behaviour of free-radicals generated from α-iodoketones

Article abstract of DOI:10.1039/b901943j

The unexpected nucleophilic reactivity of free-radicals generated from α-iodoketones is reported; two different procedures, either employing tin or the more environmentally acceptable ethylsulfone-based coupling reagent 5c have been developed.

Full text of DOI:10.1039/b901943j

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Unexpected nucleophilic behaviour of free-radicals generated from
a-iodoketonesw
Corinne De Dobbeleer,a Jirı sil,a Freija De Vleeschouwer,b Frank De Proftb
Pospı
´ ´
a
´ ´
and Istvan E. Marko*
Received (in Cambridge, UK) 29th January 2009, Accepted 5th March 2009
First published as an Advance Article on the web 19th March 2009
DOI: 10.1039/b901943j
The unexpected nucleophilic reactivity of free-radicals generated
from a-iodoketones is reported; two different procedures, either
employing tin or the more environmentally acceptable ethylsulfone-
based coupling reagent 5c have been developed.
Table 1 Radical coupling partners optimization
Methodologies based upon radical species occupy an important
place in the toolbox of synthetic chemists since many trans-
formations that are not possible via ionic chemistry can be
readily accomplished using radical intermediates.1
Entry
1
Conditions
Yield (%)a
90
As part of a research programme aimed at the development
of connective strategies for the efficient assembly of medium-
and large-membered rings, a-iodo diketones such as 1 have
been prepared (Scheme 1).2 Disappointingly, the synthetic
utility of these compounds proved to be rather limited because
of their rapid Lewis and Brønsted acid- or base-mediated ring
closure to bicycle 2.2a Since the ionic conditions employed to
functionalize iodoketone 1 failed, we decided to explore the
reactivity of 1 under radical conditions.
5a (3.0 equiv.), nBu6Sn2 (1.2 equiv.),
AIBN (0.2 equiv.), benzene, 80 1C, 2.5 h
5b (1.5 equiv.), AIBN (0.2 equiv.), benzene,
80 1C, 4 h
5c (10 equiv.), AIBN (0.2 equiv.), benzene,
80 1C, 2 h
2
92
96
3b
a
b
Refers to pure, isolated compounds. 5.4 equiv. of 5c were
reisolated.
To test this hypothesis, a-iodoketone 4a was reacted with
bromoacrylate 5a (3.0 equiv.) in the presence of nBu6Sn2 and
AIBN (Table 1, entry 1).7 Gratifyingly, the desired adduct 6a
was obtained in 90% yield. The main drawback of this
method, though, lies in the formation of the dimerization
by-product 7, resulting in a rather cumbersome purification
of adduct 6a. To avoid the formation of 7, tributylstannylacrylate
5b (1.5 equiv.) was used instead of bromoacrylate 5a (Table 1,
entry 2). Pleasingly, the desired product 6a was formed in
92% yield.
In contrast to abundant literature on the intramolecular
transformations of radicals generated from a-iodoketones,3
the intermolecular reactions of the corresponding a-keto
radicals have seldom been reported.3b,4
At the onset of our work, it was thought that radicals
generated from a-iodoketones would behave as electro-
philic species5 and thus react with electron rich radicophilic
trapping agents such as enol ethers.6 Much to our surprise,
the desired adducts could not be obtained, suggesting that
a-keto radicals might display neutral or nucleophilic
properties.
Even though the introduction of ester 5b did simplify the
reaction procedure, it was decided to focus on the develop-
ment of a tin-free alternative. For this reason, sulfone 5c was
tested as a surrogate for acrylate derivative 5b (Table 1,
entry 3) and the expected product 6a was obtained in an
excellent 96% yield.8,9
Having delineated suitable reaction conditions to effect this
transformation, its scope and limitations were next explored
(Table 2).
Scheme 1 Undesired ring closure of medium-sized rings 1.
Primary (4f) and secondary a-iodoketones 4b–d reacted
smoothly under these conditions, yielding the corresponding
adducts 6f and 6b–d in good to excellent yields (Table 2,
entries 1–3 and entry 5). More sterically hindered tertiary
a-iodoketones 4i and 4k afforded adducts 6i and 6k in 79%
and 55% yield respectively (Table 2, entries 8 and 10).
Interestingly, the tin-free method based upon the use of
sulfone 5c (method B) always provided the desired adducts 6
in somewhat higher yields, when compared to method A using
bromoacrylate 5a.10
a
´
´
Universite catholique de Louvain, Departement de Chimie,
Baˆtiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve,
Belgium. E-mail: istvan.marko@uclouvain.be; Fax: +32 1047 2788;
Tel: +32 1047 8773
b Eenheid Algemene Chemie (ALGC), Vrije Universiteit Brussel
(VUB), Faculteit Wetenschappen, Pleinlaan 2, 1050 Brussels, Belgium
w Electronic supplementary information (ESI) available: Charac-
terization data for compounds 6a–l; experimental procedures; details
of the calculations of the addition of the radicals listed in Table 3
to a series of three alkenes; Tables S-1 to S-3; discussion relating
to reference 4; full list of authors for reference 14. See DOI:
10.1039/b901943j
ꢀc
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Table 2 Allylation of radicals generated from a-iodoketones 4
Next, the functional group tolerance was investigated and
a-iodoketones 4e and 4f, bearing a terminal olefin, were
prepared (Table 2, entries 4 and 5). It was expected that the
homoallylic olefin present in 4e might react rapidly with the
in-situ generated radical. Similarly, a competitive 5-exo-trig
and/or 6-endo-trig cyclization might be observed in the
coupling of 4f. Interestingly, in both cases, only the desired
products 6e and 6f were obtained at the end of the reaction.
These observations indicate that the a-keto radical is unreactive
towards electron rich alkenes and that it possesses nucleophilic
properties, preferring to react intermolecularly with an
electron deficient partner rather than intramolecularly with
the pendant olefin.4
Yieldc
(%)
Entry Ketone
1
Methoda Adductb
A
B
85
92
2
3
A
B
70
89
A
B
71
88
Similarly, diketones 4g, 4h and 4l were submitted to the
reaction’s conditions (Table 2, entries 6, 7 and 11). In these
cases, it was expected that an undesired intramolecular
1,5-hydrogen abstraction would compete with the radical
allylation. Again, and contrary to that expectation, the
desired adducts 6g, 6h and 6l were obtained in good to
excellent yields.
4
A
B
80
86
Finally, the diastereoselectivity of this radical reaction was
studied. Thus, 2-iodo-4-tert-butylcyclohexanones 4j and 4k
were reacted with acrylates 5a and 5b (Table 2, entries 9–10).
The resulting adducts 6j and 6k were generated as single
diastereoisomers. When substituted a-iodocyclodecadione 4l
was treated with bromoacrylate 5a, the resulting adduct 6l was
obtained as a 3 : 1 mixture of the syn and anti products.
Theoretical evidence for the nucleophilic behaviour of the
radicals generated from iodoketones was obtained by com-
puting their global electrophilicities11 and the charge and spin
density on the radical centre. These properties were computed
at the B3LYP12/6-311+G(d,p)13//B3LYP/6-311+G(d,p) level
of theory and are listed in Table 3 for three selected and
prototypical radicals of the type considered in this work. All
calculations were performed using the Gaussian03 program.14
According to a classification proposed earlier on the basis of
an analysis of 35 typical organic radicals,15 all values of the
electrophilicities of these radicals indicate that they can be
considered as weakly to moderately nucleophilic (see ref. 16
for more details). This is also in line with the fact that the
radical centres bear a slightly negative atomic charge. The spin
densities reveal only a small to moderate delocalization of the
5
A
B
83
91
6
A
B
70
89
7
A
B
67
90
8d
A
B
63
79
9
A
B
72
91
Table
3
Global electrophilicity o, atomic charge q(Cꢁ) and
spin density NS(Cꢁ) on the radical centre for three prototypical
a-keto radicals
10d
A
B
16
55
Radical
oa
NS(Cꢁ)b
q(Cꢁ)b
1.939
0.835
B0.242
11
A
60
1.744
1.680
0.742
0.727
B0.078
B0.071
(syn/anti = 3 : 1)
a
Method A: 5a (3.0 equiv.), nBu6Sn2 (1.2 equiv.), AIBN (0.2 equiv.),
benzene, 80 1C, 2.5 h. Method B: 5c (10 equiv.), AIBN (0.2 equiv.),
benzene, 80 1C, 2 h. Between 4–6 equiv. of 5c were recovered after
the reaction (Method B). Refers to pure, isolated compounds.
b
a
Values in eV; for theoretical background and computational details,
b
see ref. 15. Values in a.u. obtained using NPA atomic charges or spin
c
d
populations.16
Refluxed for 4.5 h.
ꢀc
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H. Shinokubo and K. Oshima, Synlett, 2002, 674; M. P. Sibi and
N. A. Porter, Acc. Chem. Res., 1999, 32, 163.
2 (a) C. De Dobbeleer, A. Ates and I. E. Marko, Tetrahedron Lett.,
2005, 46, 3889; (b) I. E. Marko and A. Ates, Synlett, 1999, 7, 1033.
3 (a) C.-K. Sha, T. S. Jean and D. C. Wang, Tetrahedron Lett., 1990,
31, 3745; (b) C. K. Sha, K. C. Santhosh, C.-T. Tseng and C.-T. Lin,
Chem. Commun., 1998, 397; (c) C.-K. Sha, F.-K. Lee and
C.-J. Chang, J. Am. Chem. Soc., 1999, 121, 9875; (d) C.-K. Sha,
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A. Bhattacharyya and C.-K. Sha, Org. Lett., 2007, 9, 3241.
4 Although ketone functions have been reported as an efficient
stabilizing group for radicals, the subsequent addition of a-keto
radicals has seldom been reported. Huang states that ‘‘ketones do
not add homolytically to olefins generally’’ (R. L. Huang,
S. H. Goh and S. H. Ong, in The Chemistry of Radicals, Edvard
Arnold, London, 1974, p. 153). In contrast, Nikishin describes the
addition of cyclopentanone to 1-decene, in the presence of TBHP,
with up to 78% yield (G. I. Nikishin, G. V. Somov and
A. D. Petrov, Izvest. Akad. Nauk., 1961, 2065). See also ESIw.
5 (a) L. C. Stella and J. N. Harvey, in Radicals in Organic Synthesis,
ed. P. Renaud and M. P. Sibi, Wiley-VCH, Weinheim, 2001, vol. 2,
p. 360; (b) I. Fleming, Frontier Orbitals and Organic Chemical
Reactions, Wiley, New York, 1976.
Scheme 2 Adducts 6 as useful synthetic intermediates.
single electron, indicating a low conjugation of the radical to
the carbonyl group, which explains the non-electrophilic
behaviour of these compounds.
The activation barriers and reaction energies of these three
radicals for their addition to a series of three alkenes (a neutral
one: propene, an electron rich derivative: methoxyethylene
and an electron poor substrate: methyl vinyl ketone) have also
been computed (Table S-3w).
From the synthetic point of view, adducts such as 6 are
useful synthetic intermediates that might be easily converted
into interesting building blocks (Scheme 2). For example,
compound 6a was transformed into exo-methylene lactone
817 and ketone 6i into the spiro derivative 9. This spirocyclic
structure is rather similar to the core of various natural
products such as agarospirol and hinesol.18
6 For selected examples, see Table S-1w.
7 For the reaction optimization, see Table S-2w.
8 For the use of Etꢁ as a radical chain promoter see: (a) F. Bertrand,
F. Le Guyader, L. Liguori, G. Ouvry, B. Quiclet-Sire, S. Seguin
and S. Z. Zard, C. R. Acad. Sci., 2001, 4, 547; (b) S. Kim and
C. J. Lim, Angew. Chem., Int. Ed., 2002, 41, 3265. For the use of
sulfones see M. P. Bertrand, Org. Prep. Proced. Int., 1994, 26, 257.
9 For the reaction optimization see Table S-3w.
In summary, we have uncovered an unexpected nucleophilic
behaviour of radicals generated from a-iodoketones. Importantly,
a tin-free modification of a coupling process with a substituted
acrylate was also established. Calculations, both of the
chemical properties of the isolated a-keto radicals and of the
barriers and reaction energies of their addition to neutral,
electron poor and electron rich alkenes, confirm their classification
as non-electrophilic radicals.
10 Recent examples: (a) D. S. Masterson and J. P. Shackleford,
Synlett, 2007, 1302; (b) J. Y. Lee, Y.-T. Hong and S. Kim, Angew.
Chem., Int. Ed., 2006, 45, 6182; (c) S. Kim and C. J. Lim, Angew.
Chem., Int. Ed., 2004, 43, 5378.
11 (a) R. G. Parr, L. Von Szentpaly and S. Liu, J. Am. Chem. Soc.,
1999, 121, 1922; (b) P. K. Chattaraj, U. Sarkar and D. R. Roy,
Chem. Rev., 2006, 106, 2065.
12 (a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648; (b) C. Lee,
W. Yang and R. G. Parr, Phys. Rev. B: Condens. Matter Mater.
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C. F. Chabalowski and M. J. Frisch, J. Phys. Chem., 1994, 98,
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13 For a detailed account of these types of basis sets, see e.g.
W. J. Hehre, L. Radom, P. v. R. Schleyer and J. A. Pople,
Ab initio Molecular Orbital Theory, Wiley, New York, 1986.
14 M. J. Frisch et al., GAUSSIAN 03 (Revision D.01), Gaussian, Inc.,
Wallingford, CT, 2004.
We are grateful to Prof. Chin-Kang Sha (National Tsing
Hua University) for insightful discussions about the reactivity
of a-iodoketones. Financial support of this work by the
Universite catholique de Louvain, the Fonds pour la Recherche
dans l’Industrie et l’Agriculture (F.R.I.A., studentships to
C.D.), the Fond de la Recherche Scientific (Charge de
Recherche F.N.R.S.) and Merck Sharp & Dohme (unrestricted
grant to I.E.M.) is gratefully acknowledged. FDV and FDP
wish to acknowledge financial support from a Research
Program of the Research Foundation-Flanders (FWO)
(G.0464.06).
15 F. De Vleeschouwer, V. Van Speybroeck, M. Waroquier,
P. Geerlings and F. De Proft, Org. Lett., 2007, 9, 2721.
16 (a) A. E. Reed, R. B. Weinstock and F. A. Weinhold, J. Chem.
Phys., 1985, 83, 735; (b) A. E. Reed, L. A. Curtiss and
F. Weinhold, Chem. Rev., 1988, 88, 899.
17 E. Ghera, T. Yechezkel and A. Hassner, J. Org. Chem., 1990, 55,
5977.
18 For reviews on the preparation of spirocyclic compounds, see:
(a) M. Sannigrahi, Tetrahedron, 1999, 55, 9007; (b) J. A. Marshall,
S. F. Brady and N. H. Andersen, Fortschr. Chem. Org. Naturst.,
1974, 31, 283. For a recent synthesis of agarospirol and hinesol
accomplished in our laboratory see N. Maulide, J.-C. Vanherck
and I. E. Marko, Eur. J. Org. Chem., 2004, 3962.
Notes and references
1 (a) Recent reviews about radical chemistry in: Radicals in Organic
Synthesis, ed. P. Renaud and M. P. Sibi, Wiley-VCH, Weinheim,
2001, vol. 2; (b) A. Gansauer, T. Lauterbach and S. Narayan,
Angew. Chem., Int. Ed., 2003, 42, 5556; (c) H. Yorimitsu,
ꢀc
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2144 | Chem. Commun., 2009, 2142–2144