SmI2-Mediated 3-exo-trig Cyclization of β,γ- unsaturated carbonyl compounds: Diastereoselective synthesis of cyclopropanols

Article abstract of DOI:10.1021/ol101666m

SmI₂-mediated 3-exo-trig cyclizations of β,γ- unsaturated carbonyl compounds to generate cyclopropanols are not generally observed processes. The reported examples are limited to β,γ- unsaturated carbonyl compounds that possess ester groups con

Full text of DOI:10.1021/ol101666m

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4082-4085
SmI2-Mediated 3-exo-trig Cyclization of
ꢀ,γ-Unsaturated Carbonyl Compounds:
Diastereoselective Synthesis of
Cyclopropanols
Mar Martin-Fontecha, Antonia R. Agarrabeitia, Maria J. Ortiz,* and
Diego Armesto*
Departamento de Quimica Organica I, Facultad de Ciencias Quimicas, UniVersidad
Complutense, 28040 Madrid, Spain
darmesto@quim.ucm.es; mjortiz@quim.ucm.es
Received July 19, 2010
ABSTRACT
SmI2-mediated 3-exo-trig cyclizations of ꢀ,γ-unsaturated carbonyl compounds to generate cyclopropanols are not generally observed processes.
The reported examples are limited to ꢀ,γ-unsaturated carbonyl compounds that possess ester groups conjugated with the alkene unit. The
results of the current study show that this cyclization also occurs when other substitution patterns are present on the alkene moiety, affording
(E)-cyclopropanols in good to excellent yields and in most cases with high degrees of diastereoselectivity.
A few years ago we reported the influence of electron-donor
sensitizers on the single-electron transfer (SET)-promoted
photochemical reactivity of ꢀ,γ-unsaturated aldehydes 1, 2, and
3 (Figure 1).1 These compounds undergo photochemical oxa-
di-π-methane rearrangement (ODPM), using 1,4-dimethoxy-
naphthalene as sensitizer, to afford the corresponding cyclo-
propyl aldehydes 4, 5, and 6, respectively, in addition to
products resulting from decarbonylation reactions. As such, they
represented the first examples of ODPM reactions taking place
via radical-anion intermediates.1 In this effort, we observed that
irradiation of aldehyde 3, using N,N-dimethylaniline as an SET
sensitizer, affords a variety of products including the cyclopro-
panol 7. A mechanism involving a 3-exo-trig cyclization of a
ketyl radical-anion intermediate was proposed to account for
this diastereoselective process. The involvement of this inter-
mediate was confirmed by the observation that reaction of 3
with SmI2 in t-BuOH/THF results in formation of the (E)-
cyclopropanol 7 in 61% yield.
This finding is interesting because carbonyl-alkene reductive
coupling, using SmI2 as a single-electron reducing agent, has
been extensively employed in intermolecular and intramolecular
C-C bond-forming reactions.2 The latter reactions have been
(2) For selected reviews of SmI2-mediated carbonyl-alkene reactions,
see: (a) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307–338. (b)
Skrydstrup, T. Angew. Chem., Int. Ed. 1997, 36, 345–347. (c) Molander,
G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321–3354. (d) Krief, A.; Laval,
A.-M. Chem. ReV. 1999, 99, 745–777. (e) Steel, P. G. J. Chem. Soc., Perkin
Trans. 1 2001, 2727–2751. (f) Kagan, H. B. Tetrahedron 2003, 59, 10351–
10372. (g) Edmonds, D. J.; Johnston, D.; Procter, D.-J. Chem. ReV. 2004,
104, 3371–3403. (h) Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32,
607–637. (i) Rudkin, I. M.; Miller, L. C.; Procter, D. J. Organomet. Chem.
2008, 34, 19–45. (j) Nicolau, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem.,
Int. Ed. 2009, 48, 7140–7165. (k) Procter, D. J.; Flowers, R. A. Skrydstrup,
T. Organic Synthesis Using Samarium Diiodide: A Practical Guide; Royal
Society of Chemistry: London, 2010; Chapter 5.
(1) Armesto, D.; Ortiz, M. J.; Agarrabeitia, A. R.; Martin-Fontecha, M.
Org. Lett. 2004, 6, 2261–2264.
10.1021/ol101666m  2010 American Chemical Society
Published on Web 08/13/2010

To explore this possibility, we have extended the study to
include the methyl and phenyl ketones 8 and 9 that are
structurally related to aldehyde 3. Treatment of these substrates
with SmI2, under the same conditions used for aldehyde 3, leads
to exclusive formation of the corresponding (E)-cyclopropanols
10 and 11 in 29% and 48% yield, respectively (Scheme 2). A
conventional mechanism is proposed to account for these
cyclization reactions (Scheme 2).
Scheme 2
.
SmI2-Mediated 3-exo-trig Cyclization of Fluorene
Derivatives 3, 8, and 9
Figure 1. Starting aldehydes (1-3) and photoproducts (4-7) from
our previous study.1
studied extensively by Molander and co-workers, who dem-
onstrated that the SmI2-mediated cyclization of ω-unsaturated
carbonyl compounds in the presence of an alcohol as proton
source in THF produces cyclopentanols, cyclohexanols, and
cyclooctanols in good yields and with high degrees of stereose-
lectivity.3 The process is general since both aldehydes and ketones
can be used as coupling partners with both activated and unacti-
vated alkenes. More recently, this method was applied to the
synthesis of nine-, ten-, and eleven-membered carbocycles.4
However, to date formation of 4- or 3-membered rings
by using this method is limited to substrates that contain
ester-activated alkenes, as exemplified by the cyclobutanol-5
and cyclopropanol-forming6 reactions shown in Scheme 1.
The stereochemistry of the products of these reactions was
determined by using 1D NOESY experiments (see Support-
ing Information). In each case, the stereochemical outcome
matches those observed in the formation of five- to seven-
membered cycloalkanols by using this method and that has
been attributed to a stereoelectronically driven strong prefer-
ence for an antiparallel relationship of the ketyl radical and
the alkene moiety.3
To evaluate whether other unactivated ꢀ,γ-unsaturated car-
bonyl compounds also undergo the 3-exo-trig cyclization, the
reactivity of aldehyde (E)-12 was examined. Indeed, reaction
of (E)-12 with SmI2 leads to formation of the corresponding
(E)-cyclopropanol 13 in 43% yield. This finding demonstrates
that this process is not limited to fluorene derivatives. Moreover,
two new substances, identified as aldehyde 14 and cyclic
hemiacetal 15, were also generated in this reaction in 9% and
11% yield, respectively (Scheme 3).
Scheme 1. Previously Reported SmI2-Mediated Carbonyl-Alkene
Cyclization To Form Cyclobutanols5 and Cyclopropanols6
Scheme 3. Treatment of Aldehyde 12 with SmI2
Nevertheless, the reaction of 3 with SmI2 that affords
cyclopropanol 7 in good yield suggests that other ꢀ,γ-
unsaturated carbonyl compounds, not containing ester-
activated alkene moieties, could participate in 3-exo-trig
cyclizations to generate cyclopropanols.
(3) (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57, 3132–
3139. (b) Molander, G. A.; McKie, J. A. J. Org. Chem. 1994, 59, 3186–
3192. (c) Molander, G. A.; McKie, J. A. J. Org. Chem. 1995, 60, 872–882.
(4) Saadi, J.; Lentz, D.; Reissig, H.-U. Org. Lett. 2009, 11, 3334–3337.
(5) Edmons, D. J.; Kenneth, W. M.; Procter, D. J. J. Org. Chem. 2003,
68, 3190–3198, and references therein.
Org. Lett., Vol. 12, No. 18, 2010
4083

Possible mechanistic pathways for formation of 14 and 15
involve the intermediacy of the radical-anion 16, which gener-
ates radical 17 by protonation. Reduction of 17 by a second
molecule of SmI2, followed by protonation of the samarium
derivative 18, affords aldehyde 14 (Scheme 4, path a).
The formation of alkenes 21 in this process is consistent
with the involvement of the alkylsamarium intermediate 26,
resulting from R-cleavage of the ketyl radical 24 and
subsequent reduction of radical 25 by a second molecule of
SmI2 (Scheme 6). The intermediate 26 can also be respon-
Scheme 6
Scheme 4
sible for the formation of the alcohol 22, through nucleophilic
addition of oxygen. Diene 23 most probably arises by
spontaneous dehydration of 22.
The results obtained in studies with aldehydes 1 show that
monophenyl or diphenyl substitution on the alkene moiety
does not provide the stabilization required to promote the
carbonyl-alkene reductive coupling process. As a result,
alternative reaction pathways via ketyl radical intermediates,
such as fragmentations and oxidations, are observed.
Although SmI2 has been previously employed to mediate
C-C bond fragmentations,7 to the best of our knowledge,
the reaction documented above represents the first example
of a decarbonylation process taking place in ꢀ,γ-unsaturated
aldehydes promoted by this reagent. It is noteworthy that
this process, reminiscent of the well-known photochemical
Norrish type I reaction, has also been observed when radical-
anion intermediates of ꢀ,γ-unsaturated aldehydes are gener-
ated photochemically using SET-sensitizers.1
Alternatively, oxidation of 18 by nucleophilic addition of
molecular oxygen generates the δ-hydroxyaldehyde 19,
which undergoes intramolecular cyclization to 15 (Scheme
4, path b). This mechanistic hypothesis is supported by the
results of previously described reactions of organosamarium
species with molecular oxygen.3a
To explore the scope of the 3-exo-trig cyclization, the
study was extended to include simple acyclic aldehydes 1,
with monophenyl and diphenyl substitution on the double
bond. However, treatment of aldehyde (E)-1a with SmI2 does
not provide the expected cyclopropanol but rather yields
alcohol (E)-20a (12%), resulting from direct reduction of
the carbonyl group, along with the alkene (E)-21a (16%)
(Scheme 5). Similarly, aldehyde 1b affords alcohol 20b and
A study of the reactivity of the 4-cyanophenyl substituted
aldehyde 27 and ketone 28 was carried out to determine if
the presence of a cyano group attached to the phenyl ring
would provide sufficient activation of the alkene unit to
promote intramolecular reductive coupling. Treatment of 27
and 28 with SmI2 promotes formation of the corresponding
cyclopropanols 29 and 30 in 54% and 23% yield, respectively
(Scheme 7). Therefore, conjugation of the alkene moiety with
a 4-cyanophenyl group promotes the 3-exo-trig cyclization.
The reaction of phenyl ketone 28 also affords the alcohol
31 (19%) resulting from reduction of the carbonyl group.
Interestingly, cyclopropanol 29 was isolated as a 1:1
mixture of Z/E diastereomers, whereas cyclization of phenyl
ketone 29 yields the (E)-cyclopropanol 30 selectively. The
reasons for the lack of diasteroselectivity observed in the
reaction of aldehyde 27 are unclear at this point.
Scheme 5. Treatment of Aldehydes 1 with SmI2
Finally, the reactivity of ketones 32 and 33,8 possessing
two cyano groups directly bound to the alkene unit, was
alkene 21b in 12% and 7% yield, respectively, in addition
to the tertiary alcohol 22 (9%) and the 1,3-diene 23 (11%)
when treated with SmI2.
(7) Williams, D. B. G.; Blann, K.; Caddy, J. Org. Prep. Proc. 2001,
33, 565–602.
(6) (a) Bezzenine-Lafolle´e, S.; Guibe´, F.; Villar, H.; Zriba, R. Tetra-
hedron 2004, 60, 6931–6944. (b) Zriba, R.; Bezzenine-Lafolle´e, S.; Guibe´,
F.; Guillerez, M.-G. Synlett 2005, 2362–2366. (c) Zriba, R.; Bezzenine-
Lafolle´e, S.; Guibe´, F.; Magnier-Boubier, C. Tetrahedron Lett. 2007, 48,
8234–8237.
(8) Efforts made to synthesize the aldehyde analogue (4,4-dicyano-2,2-
dimethyl-3-butenal) by deprotection of its corresponding acetal or thioacetal,
as well as by reduction of methyl 4,4-dicyano-2,2-dimethylbut-3-enoate,
failed.
4084
Org. Lett., Vol. 12, No. 18, 2010

reported in the literature include compounds bearing an ester
group attached to the alkene unit. However, the current effort
demonstrates that this reaction can also take place when other
electron-withdrawing groups, such as cyano and 4-cyanophe-
nyl, are present, affording the corresponding cyclopropanols
in good to excellent yields. Interestingly, aromatic moieties,
such as fluororene and indene, also promote the cyclization
process, probably owing to the enhanced stability of the
cyclopropyl intermediates. In contrast, monophenyl or di-
phenyl substitution do not provide the necessary stabilization
required for the cyclization to occur, thus opening new
reaction pathways for the ketyl radical intermediates, such
as fragmentations to yield alkenes, and oxidation.
Scheme 7. SmI2-Mediated 3-exo-trig Cyclization of
4-Cyanophenyl-Substituted Compounds 27 and 28
The results outlined above increase considerably the
synthetic potential of the 3-exo-trig cyclizations of ꢀ,γ-
unsaturated carbonyl compounds, a method that enables the
synthesis of differently functionalized cyclopropanols that
can be present in a wide range of natural products and
synthetic building blocks.9
investigated. Reactions of 32 and 33 with SmI2 yield the
respective (E)-cyclopropanols 34 (37%) and 35 (93%)
(Scheme 8).
Acknowledgment. We thank the Spanish Ministerio de
Ciencia e Innovacio´n (MICINN, CTQ2008-02820) and the
Universidad Complutense de Madrid (Grant No. GR58/08)
for financial support. We acknowledge the support provided
by the Centro de Resonancia Magnetica Nuclear and the
Centro de Microana´lisis of the Universidad Complutense de
Madrid.
Scheme 8. SmI2-Mediated 3-exo-trig Cyclization of
Dicyano-Substituted Ketones 32 and 33
Supporting Information Available: Experimental pro-
cedures for the preparation of ꢀ,γ-unsaturated carbonyl
compounds 8, 9, 27, 28, and 33 and general procedure for
the reactions with SmI2. Analytical and spectroscopic data
and copies of 1H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
These results described above show that the 3-exo-trig
cyclization of ꢀ,γ-unsaturated carbonyl compounds occurs
not only with ester groups at the γ-position, as has been
previously reported, but also with other electron-withdrawing
substituents, such as cyano and 4-cyanophenyl groups.
In summary, the SmI2-mediated 3-exo-trig cyclization of
ꢀ,γ-unsaturated carbonyl compounds to produce cyclopro-
panols has been observed only infrequently.6 The examples
OL101666M
(9) Kulinkovich, O. G. Chem. ReV. 2003, 74, 2597–2632.
Org. Lett., Vol. 12, No. 18, 2010
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