Samarium diiodide induced reactions of cyclopropyl ketones: Reductive ring cleavage and dimerization leading to 1,8-diketones - Scope, limitations, mechanisms

Article abstract of DOI:10.1002/ejoc.200500945

Reactions of the samarium diiodide/HMPA complex with alkyl cyclopropyl ketones such as 3, 5, and 7 provided dimers incorporating a 1,8-diketone moiety. The products 4, 6, and 8 were isolated in moderate to good yields. The aryl-substituted cyclopropyl ketones afforded a broader product spectrum, which results from the attack of samarium intermediates to the aryl group. Cyclopropyl phenyl ketone (13) gave dimer 14, where one cyclopropane ring was reductively cleaved, whereas the second one is still present. The reductive dimerization of cyclopropyl 2-thienyl ketone (21) furnished the product 22, which still contains two cyclopropyl groups. Further examples demonstrate the diversity of samarium diiodide induced reductions of cyclopropyl ketones. Plausible reaction mechanisms involving samarium ketyl intermediates are presented. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500945

FULL PAPER
DOI: 10.1002/ejoc.200500945
Samarium Diiodide Induced Reactions of Cyclopropyl Ketones: Reductive Ring
Cleavage and Dimerization Leading to 1,8-Diketones – Scope, Limitations,
Mechanisms
Francesca Aulenta,[a] Alexandra Hölemann,[a] and Hans-Ulrich Reißig*[a]
Keywords: Samarium diiodide / Cyclopropyl ketones / Electron transfer / Radical dimerization
Reactions of the samarium diiodide/HMPA complex with
alkyl cyclopropyl ketones such as 3, 5, and 7 provided dimers
incorporating a 1,8-diketone moiety. The products 4, 6, and
8 were isolated in moderate to good yields. The aryl-substi-
tuted cyclopropyl ketones afforded a broader product spec-
trum, which results from the attack of samarium intermedi-
ates to the aryl group. Cyclopropyl phenyl ketone (13) gave
dimer 14, where one cyclopropane ring was reductively
ductive dimerization of cyclopropyl 2-thienyl ketone (21) fur-
nished the product 22, which still contains two cyclopropyl
groups. Further examples demonstrate the diversity of sa-
marium diiodide induced reductions of cyclopropyl ketones.
Plausible reaction mechanisms involving samarium ketyl in-
termediates are presented.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
cleaved, whereas the second one is still present. The re- Germany, 2006)
Introduction
We recently reported that the samarium diiodide in-
duced[1] coupling of the carbonyl compounds 1 to meth-
oxyallene affords the 4-hydroxy-1-enol ethers 2 in moderate
to good yields,[2] thus providing a new route to these useful
intermediates[3] (Scheme 1). Although other allenes[2,4]
could also be coupled with carbonyl compounds, meth-
oxyallene proved to be the most suitable substrate. In order
to investigate further the substrate dependency of this novel
reaction, cyclopropyl methyl ketone (3) was also employed
as the carbonyl component.[5] However, instead of the ex-
pected enol ether of type 2, the 1,8-diketone 4 was isolated
in good yield (Scheme 2) – probably, as a result of a re-
ductive cyclopropane cleavage, followed by a dimerization
process. This observation motivated us to study in more de-
tail the behavior of a series of cyclopropyl ketones em-
Scheme 2.
ploying samarium diiodide as reducing reagent, which dis-
closed the high diversity of products and mechanistic path-
Results
Upon treatment of simple alkyl cyclopropyl ketones with
ways herein described.
2.2 equiv. of the samarium diiodide/HMPA complex, the
corresponding diketone dimers were always isolated in low
to good yields (Scheme 2). The reductive coupling of cy-
clopropyl methyl ketone (3) – the simplest among the sub-
strates tested – afforded decane-2,9-dione (4) in a satisfying
70% yield. The increase of the length of the aliphatic moi-
ety – as in the case of ketone 5 – led to an impoverished
efficacy of the coupling process, hence the 1,8-diketone 6
was isolated in only 20%. No other coupling products
could be identified in the reaction mixture. The expected
dimer was also obtained when bicyclo[4.1.0]heptan-2-one
(7) was subjected to the standard conditions, providing the
Scheme 1.
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
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F. Aulenta, A. Hölemann, H.-U. Reißig
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diketone 8 in 45% yield as a 1:1 mixture of diastereomers.
Disappointingly, the lower homologue bicyclo[3.1.0]hexan-
2-one led to a complex mixture of unidentified com-
pounds.[6]
Studies of the role of proton sources, amount of re-
ductive reagent and co-solvents on the outcome of the reac-
tion (carried out on ketone 3), indicated that the absence
of a proton source – such as tert-butyl alcohol – does not
significantly influence the yield of the diketone, whereas a
decrease of the amount of samarium diiodide to 1.1 equiv.
lowered the yield to 30%. In the absence of HMPA[7] the
reaction is completely inhibited.
Whereas the reactions of alkyl cyclopropyl ketones oc-
curred in an apparently uniform manner, as illustrated in
Scheme 2, the coupling of the aryl-substituted cyclopropyl
ketones proceeded in a more complex fashion. In the case
of ketone 9 – bearing a phenyl group at C-2 of the cyclopro-
pane ring – the dimerization product 10 (isolated in 22%
yield as a single diastereomer) was accompanied by 5-phen-
ylpentan-2-one (11) and styrene (12) in 19% and 10% yield,
respectively (Scheme 3). The formation of 11 can be ration-
alized as the result of a simple reductive opening of 9 with-
out dimerization, whilst an unclear fragmentation reaction
might lead to 12. We cannot exclude that similar side reac-
tions also took place during the transformations of 3, 5
and 7 (Scheme 2) generating volatile products, and hence
explaining the reduced mass balances of these reactions.
Scheme 4.
molecule. The reductive coupling of cyclopropyl 2-thienyl
ketone (21) disclosed another manner of dimerization,
wherein the product 22 retained the two cyclopropyl groups.
Scheme 5.
Finally, we carried out some experiments in order to trap
possible intermediates of this reductive dimerization reac-
tion. As during the reductive coupling of cyclopropyl
methyl ketone (3) the most likely intermediate – before
aqueous workup – is a samarium dienolate species (see
Scheme 7), we performed the reaction in the presence of
methyl iodide. Indeed, we were very pleased to isolate the
Scheme 3.
Upon the treatment of cyclopropyl phenyl ketone (13)
with the samarium diiodide/HMPA complex, a dimeriza-
tion product 14 was indeed formed as the sole product in
very good yield (Scheme 4). However, in this case, the dimer
was the result of the reductive cleavage of one cyclopropyl
ring only, and subsequent attack of this species at the para
position of the phenyl ring of a second molecule. When the
para position was blocked by the bulky tert-butyl group
(precursor 15), the related coupling product 18 was formed
from the attack of the ring-opened intermediate at the ortho
position of the aryl moiety. However, together with the
ketone 18, the tertiary alcohol 17 and 1-(4-tert-butylphenyl)-
butan-1-one (16) were also formed in similar yields.
dialkylated product 23 in
a
satisfying 55% yield
(Scheme 6).[8] Other trapping experiments, performed on
ketone 3 in the presence of allyl bromide, chlorotrimethylsil-
ane, acetone or benzaldehyde, were not successful; instead,
complex mixtures of products were observed. Experiments
employing cyclopropyl phenyl ketone (13) as a precursor
were also carried out in the presence of potential trapping
reagents (acetophenone, benzonitrile, anisole, toluene).
However, none of these compounds were incorporated into
the products isolated; instead, the regular dimerization
product 14 was formed, albeit in strongly reduced yields (14
to 36%).
The reaction of methyl 1-methylcyclopropyl ketone (19)
with the samarium diiodide/HPMA complex furnished the
δ-hydroxy ketone 20 as a mixture of diastereomers
(Scheme 5) in moderate yield – a compound analogous to
the tertiary alcohol 17. It is generated by the attack of a
ring-opened intermediate to the carbonyl group of a second Scheme 6.
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Samarium Diiodide Induced Reactions of Cyclopropyl Ketones
FULL PAPER
shifts the equilibria to the product sides, thus favoring the
progress of the reactions. We can not exclude that dimeric
species bridged by O–Sm–O moieties are involved in the C–
C bond-forming processes. This (speculative) template ef-
fect may lead to the observed, surprisingly high efficacy of
several of the radical dimerization reactions, and it may also
influence the stereoselectivity (see below).
The regiochemistry of the cyclopropane ring cleavage is
also a remarkable feature of these reactions. The formation
of the 1,8-diketone 8 from the bicyclic compound 7 pro-
ceeds via the primary radical generated by the cleavage of
the “external” proximal cyclopropane C–C bond. The con-
ceivable secondary cycloheptyl radical – derived from 7 by
the cleavage of the “internal” cyclopropane bond – is either
not formed, or it is not sufficiently reactive for a dimeriza-
tion to occur, as a consequence of its higher steric hin-
drance.[10] Most probably, the radical derived from 9 is sta-
bilized by the phenyl group, hence delivering dimer 10 and
compound 11, either by protonation of the samarium inter-
mediate D, or by hydrogen abstraction of the benzylic radi-
cal equivalent to C. The pathway that in this experiment
leads to the formation of styrene is not yet clear.
Discussion
Since the spectrum of products generated under these coup-
ling conditions is remarkably broad, and the mass balances
of several transformations are low to moderate, the mech-
anistic discussion is complex and in part speculative. Never-
theless, examples of samarium diiodide induced reactions
reported in the literature,[9,10] lend support to our mechan-
istic suggestions. A plausible pathway is presented in
Scheme 7 that explains the formation of the dimers 4, 6, 8,
and 10 as well as that of 17 and 20. Addition of 1 equiv. of
samarium diiodide (the HMPA ligands in Schemes 7, 8 and
9 are omitted for clarity and simplicity) to the cyclopropyl
ketone A furnishes the expected samarium ketyl B which
can undergo a fast ring cleavage,[11] that leads to the homo-
allylic radical C, which incorporates a samarium enolate
moiety. A simple dimerization of this radical C to dienolate
E, followed by protonation of this intermediate should af-
ford the 1,8-diketones G. Because the dienolate E could be
trapped by methyl iodide (Scheme 6), we consider this
mechanism conceivable. However, we cannot strictly ex-
clude that a Lewis acid assisted ring opening[12] of cyclopro-
pyl ketone A [samarium() or samarium() species being
More speculative are the mechanistic routes that – from
the activator] with the samarium species D as nucleophile, aryl-substituted cyclopropyl ketone of type I – lead to the
formed by reaction of the radical C with a second equiva- formation of the products 14, 16, 17 and 20. In contrast
lent of samarium diiodide, may also furnish E. Whereas we with the case of alkyl cyclopropyl ketones of type A, the
believe that the involvement of D in the formation of E is considerably higher stability of the ketyl radical J (also rep-
rather unlikely, this species can add to the carbonyl group resented by the mesomeric formula JЈ) in comparison with
of A to produce intermediate F, which, after protonation, that of the homoallylic radical K, shifts the equilibrium
provides compounds of general structure H. Alternatively, towards the first, hence rendering this radical species more
F may be generated by addition of the samarium ketyl B to abundant. The combination of J with K may provide M,
homoallyl radical C. All these coupling reactions require and finally coupling products N, found in two cases (17 and
only 1 equiv. of samarium diiodide; however, we believe that 20). However, intermediate K can also be further trans-
the improved efficacy of the coupling process in the pres- formed into the disamarium species L, whose nucleophilic
ence of 2 equiv. of samarium diiodide is because of the addition to I may also provide the intermediate M. Al-
higher concentration of the intermediates B, C, or D, which though the experiments aimed at confirming the proposed
Scheme 7.
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F. Aulenta, A. Hölemann, H.-U. Reißig
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Scheme 8.
tonation. Similar observations have been made in the sa-
marium diiodide induced dimerization of aromatic alde-
hydes, from which rearomatized addition products are also
isolated, or in related cyclizations of γ-aryl ketones.[10,13]
The samarium ketyl O, derived from cyclopropyl 2-thi-
enyl ketone (21), is particularly stable, and the correspond-
ing homoallylic radical is apparently not formed or not par-
ticipating in the coupling reaction. “Head-to-tail” dimeriza-
tion of O/OЈ leads to the intermediate P which, after pro-
tonation and oxidation during workup, furnishes the ad-
duct 22. Similar reactions of ketyls derived from 2-thio-
phenecarbaldehyde are literature-known.[14]
The formation of dimer 8 occurs apparently without
stereoselection (1:1) as the two possible approaches of the
primary radicals are essentially identical. On the other
hand, the conversion of 9 into 10 proceeds apparently with
perfect stereoselectivity. The resulting product should be the
/ diastereomer because a dimerization of the stabilized
secondary radical would probably involve more steric repul-
sions of the larger substituents (Scheme 10). However, this
assignment is tentative and literature precedence is not con-
clusive for comparable cases.[15] Compound 20 was formed
unselectively as a mixture of two diastereomers. This is to
be expected as the stereogenic center next to the carbonyl
group is too far from the reactive carbon atom to influence
the C–C bond-forming step.
Scheme 9.
mechanism – by trapping of the intermediates – failed to
afford the expected products, we believe that this last mech-
anistic route is the most likely to take place.
The formation of 14 and 16 could be explained by the
addition of the homoallylic radical K to the aromatic ring
of the ketyl J. This addition occurs preferentially at the ste-
rically less congested para position or – when this is not
available – at the less favorable ortho position. The interme-
diates thus formed – incorporating samarium enolate moie-
ties in conjugation with cyclohexadiene subunits – have to
be rearomatized. This event occurs probably during the
workup of the reaction mixtures by oxygenation and pro- Scheme 10.
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Samarium Diiodide Induced Reactions of Cyclopropyl Ketones
FULL PAPER
the solvent was removed under reduced pressure to give the crude
mixture.
Conclusion
In this report we demonstrate that several reaction path-
ways are opened for samarium ketyl intermediates derived
from cyclopropyl ketones. Whereas the alkyl cyclopropyl
ketones provide compounds with 1,8-diketone moieties by
ring cleavage of both participating cyclopropane rings, the
reductive dimerizations of the aryl-substituted cyclopropyl
ketones strongly depend on the substitution pattern. Prod-
ucts with one or two intact cyclopropyl rings are formed by
a so far unpredictable reaction pathway.
Coupling of Cyclopropyl Methyl Ketone (3) To Afford Decane-2,9-
dione (4): According to the general procedure above, cyclopropyl
methyl ketone (3) (84 mg, 1.00 mmol) afforded 4 as a colorless solid
(60 mg, 70%) after column chromatography on neutral alumina
(hexane/ethyl acetate, 5:1), m.p. 51–53 °C (ref.[19] 56–58 °C). 1H
NMR (CDCl3, 250 MHz): δ = 1.26–1.32 (m, 4 H, 5-H, 6-H), 1.51–
1.62 (m, 4 H, 4-H, 7-H), 2.13 (s, 6 H, 1-H, 10-H), 2.42 (t, 3J =
7.4 Hz, 4 H, 3-H, 8-H) ppm. 13C NMR (CDCl3, 126 MHz): δ =
23.4 (t, C-5, C-6), 28.7 (t, C-4, C-7), 29.7 (t, C-3, C-8), 43.4 (q, C-
1, C-10), 208.8 (s, C-2, C-9) ppm. IR (KBr): ν = 2930, 2905, 2850
˜
(C–H), 1700 (C=O) cm–1. Decane-2,9-dione (4) was then converted
into the corresponding bis(2,4-dinitrophenylhydrazone) derivative,
m.p. 195–197 °C (ref.[20] 199 °C).
Experimental Section
Coupling of 1-Cyclopropylpentan-1-one (5) To Afford Hexadecane-
5,12-dione (6): According to the general procedure above, ketone 5
(252 mg, 2.00 mmol) afforded 6 as a colorless solid (50 mg, 20%)
after column chromatography on neutral alumina (hexane/ethyl
acetate, 5:1), m.p. 77–79 °C (ref.[21] 73 °C). 1H NMR (CDCl3,
General Experimental Procedures: Reactions were generally per-
formed under argon in flame-dried flasks, and solvents and rea-
gents were added by syringes. The reagents used in the trapping
experiments were purified and stored under argon: acetone and
allyl bromide were distilled from calcium hydride and stored over
molecular sieves (4 Å). 1,2-Diiodoethane was purified by sublima-
tion under vacuum (0.2 mbar, 50 °C). Tetrahydrofuran (THF) was
freshly distilled from sodium/benzophenone under argon for all re-
actions. Hexamethylphosphoramide (HMPA) was distilled from
calcium hydride (130 °C, 12 mbar) and stored over molecular sieves
(4 Å) under argon. Argon was purged through the solution to elim-
inate residual oxygen prior to use. Products were purified by flash
chromatography on silica gel (230–400 mesh, Merck) or neutral
alumina (activity III, Fluka). Preparative HPLC was carried out
on a nucleosil 50-5 column and detected with a Knauer variable
UV detector (λ = 255 nm) and a Knauer refractometer. Unless
otherwise stated, yields refer to analytically pure samples. The
starting materials bicyclo[4.1.0]heptan-2-one,[16] butyl cyclopropyl
ketone,[17] 1-(2-phenylcyclopropyl)ethanone[16,18] were synthesized
according to literature procedures. Other reagents were purchased
and were used as received without purification unless otherwise
stated. 1H [CHCl3 (δ = 7.25 ppm) or TMS (δ = 0.00 ppm) as in-
ternal standard] and 13C NMR spectra [CDCl3 (δ = 77.0 ppm) as
internal standard] were recorded with Bruker AC 250 (250 MHz),
AC 500 (500 MHz) and Joel Eclipse 500 (500 MHz) instruments
in CDCl3 solutions. Integrals are in accordance with assignments;
coupling constants are given in Hz. IR spectra were measured with
an FT-IRD spectrometer Nicolet 5 SXC. MS and HRMS analyses
were performed with Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT
CH7A (EI, 80 eV, 3 kV) instruments. Elemental analyses were car-
ried out with an “Elemental-Analyzer” (Perkin–Elmer). Melting
points were measured with a Reichert apparatus and are uncor-
rected.
3
500 MHz): δ = 0.89 (t, J = 7.4 Hz, 6 H, CH3), 1.24–1.33 (m, 8 H,
2-H, 8-H, 9-H, 15-H), 1.50–1.57 (m, 8 H, 3-H, 7-H, 10-H, 14-H),
3
2.37 (t, J = 7.4 Hz, 8 H, 4-H, 6-H, 11-H, 13-H) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 13.8 (q, CH3), 22.4 (t, C-8, C-9), 23.6 (t,
C-2, C-15), 25.9 (t, C-7, C-10), 29.0 (t, C-3, C-14), 42.5 (t, C-4, C-
13), 42.6 (t, C-6, C-11), 211.4 (s, C-5, C-12) ppm. IR (KBr): ν =
˜
2995, 2930, 2900, 2865 (C–H), 1705 (C=O) cm–1. MS (EI, 80 eV,
60 °C): m/z (%) = 254 (3) [M]+, 197 (8) [M – C4H9]+, 85 (100)
[C5H9O]+, 57 (71) [C4H9]+. HRMS (EI, 80 eV, 60 °C): calcd. for
C16H30O2 254.22458; found 254.22533.
Coupling of Bicyclo[4.1.0]heptan-2-one (7) To Afford 3-[2-(3-Oxocy-
clohexyl)ethyl]cyclohexanone (8): According to the general pro-
cedure above, ketone 7 (110 mg, 1.00 mmol) afforded 8 as a color-
less solid, as a 1:1 mixture of diastereomers (50 mg, 45%) after
column chromatography on silica gel (gradient elution: hexane/
ethyl acetate from 9:1 to 7:3), m.p. 62–64 °C. 1H NMR (CDCl3,
500 MHz): δ = 1.23–1.33 (m, 6 H, 4-H, 6ЈЈ-H, 1Ј-Ha, 2Ј-Ha), 1.62
3
(mc, 2 H, 5-Ha, 5ЈЈ-Ha), 1.71 (mc, 2 H, 1ЈЈ-H, 3-H), 1.87 (br. d, J
Ϸ 13.3 Hz, 2 H, 1Ј-Hb, 2Ј-Hb), 1.95–2.20 (m, 4 H, 2-Ha, 2ЈЈ-Ha, 5-
Hb, 5ЈЈ-Hb), 2.23 (dt, 3J = 5.9 Hz, 2J = 13.8 Hz, 2 H, 4ЈЈ-Ha, 6-
2
2
Ha), 2.33 (br. d, J Ϸ 13.8 Hz, 2 H, 4ЈЈ-Hb, 6-Hb), 2.39 (br. d, J
Ϸ 13.7 Hz, 2 H, 2-Hb, 2ЈЈ-Hb) ppm. 13C NMR (CDCl3, 126 MHz):
δ = 25.1 (t, C-4, C-6ЈЈ), 31.2 (t, C-5, C-5ЈЈ), 33.5 (t, C-1Ј, C-2Ј),
33.6 (t, C-1Ј, C-2Ј), 39.0, 39.2 (2 d, C-1ЈЈ, C-3), 41.3 (t, C-4ЈЈ, C-
6), 48.0 (t, C-2, C-2ЈЈ), 211.5 (s, C-1, C-3ЈЈ) ppm. IR (KBr): ν =
˜
2955, 2930, 2860 (C–H), 1705 (C=O) cm–1. MS (EI, 80 eV, 60 °C):
m/z (%) = 222 (9) [M]+, 97 (100) [C6H9O]+. HRMS (EI, 80 eV,
60 °C): calcd. for C14H22O2 222.16199; found 222.16322. C14H22O2
(222.3): calcd. C 75.63, H 9.97; found C 75.97, H 10.02.
General Procedure for SmI2-Induced Coupling Reactions: Samarium
(2.4–2.5 equiv.) and 1,2-diiodoethane (2.2 equiv.) were suspended
in THF (25 mL/2.20 mmol SmI2) under argon and stirred at room
temperature until the color of the suspension turned into dark blue
(approximately 2 h). The flask was then evacuated, purged with
argon and HMPA (18 equiv.) was added. The cyclopropyl ketone
(1 equiv.) was dissolved in THF (15 mL/mmol of cyclopropyl
ketone), argon was purged through for 10 min, and the solution
was then added to the deep violet solution of SmI2 in THF/HMPA.
The mixture was stirred at room temperature for 16 h and then
quenched by addition of a satd. aq. NaHCO3 solution (15 mL).
The aqueous phase was extracted with diethyl ether (3×20 mL),
and the combined organic layers were washed once with distilled
water and twice with brine, then dried with MgSO4, filtered and
Conversion of 1-(2-Phenylcyclopropyl)ethanone (9) into 5-Phen-
ylpentan-2-one (11), 5,6-Diphenyldecane-2,9-dione (10) and Styrene
(12): According to the general procedure above, ketone 9 (160 mg,
1.00 mmol) afforded after column chromatography on silica gel
(hexane/ethyl acetate, 6:1) 11 as a colorless oil (30 mg, 19%), 10 as
a colorless solid (35 mg, 22%) and 12 as a colorless oil (10 mg,
10%). The spectroscopic data of 10 and 12 are in agreement with
those reported in the literature.[22,23] 10: M.p. 127–129 °C. 1H NMR
(CDCl3, 500 MHz): δ = 1.60 (mc, 4 H, 4-H, 7-H), 1.86 (s, 6 H,
CH3), 2.06 (mc, 4 H, 3-H, 8-H), 2.69 (mc, 2 H, 5-H, 6-H), 7.17 (d,
4
3
3J = 7.2 Hz, 4 H, Ph), 7.23 (tt, J = 1.2 Hz, J = 7.2 Hz, 2 H, Ph),
3
7.32 (t, J = 7.2 Hz, 4 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz):
δ = 28.5 (t, C-4, C-7), 29.7 (q, C-1, C-10), 41.7 (t, C-3, C-8), 51.5
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(d, C-5, C-6), 126.6, 128.3, 128.6, 143.1 (3 d, s, Ph), 208.7 (s, C-2,
140 °C): m/z (%) = 404 (14) [M]+, 337 (4) [M – C4H9]+, 229 (100)
[M – C12H15O]+, 176 (42) [C12H16O]+, 161 (74) [C11H13O]+, 69 (29)
[C4H5O]+, 57 (52) [C4H9]+. HRMS (EI, 80 eV, 140 °C): calcd. for
C-9) ppm. IR (KBr): ν = 3080, 3055, 3025, 3000, 2955, 2885, 2870
˜
(=CH, C–H), 1710 (C=O) cm–1. MS (EI, 80 eV, 170 °C): m/z (%)
= 322 (0.4) [M]+, 161 (48) [M/2]+, 43 (100) [COCH3]+. HRMS (EI, C28H36O2 404.27155; found 404.27362.
80 eV, 170 °C): calcd. for C22H26O2 322.19327; found 322.19422.
Coupling of 1-(1-Methylcyclopropyl)ethanone (19) To Afford 6-Hy-
Coupling of Cyclopropyl Phenyl Ketone (13) To Afford 4-[4-(Cy-
clopropylcarbonyl)phenyl]-1-phenylbutan-1-one (14): According to
the general procedure above, ketone 13 (146 mg, 1.00 mmol) af-
forded 14 as a colorless solid[24] (119 mg, 81%) after column
chromatography on silica gel (hexane/ethyl acetate, 4:1), m.p. 91–
droxy-3-methyl-6-(1-methylcyclopropyl)heptan-2-one (20): Accord-
ing to the general procedure above, ketone 19 (98 mg, 1.00 mmol)
afforded 20 as a colorless oil (45 mg, 45%, ca. 1:1.5 mixture of
diastereomers) after column chromatography on neutral alumina
(hexane/ethyl acetate, 5:1). 1H NMR (CDCl3, 250 MHz): δ = 0.10–
0.17, 0.50–0.55, 0.69–0.74 (3 m, 2 H, 1 H, 1 H, cyclopropane-H),
1
93 °C. H NMR (CDCl3, 500 MHz): δ = 1.00 (mc, 2 H, cyclopro-
pane-H), 1.21 (mc, 2 H, cyclopropane-H), 2.10 (quint, 3J = 7.4 Hz,
3
1.03 (s, 3 H, CH3), 1.10 (d, J = 6.4 Hz, CH3), 1.16 (s, 3 H, CH3),
3
2 H, 3-H), 2.65 (mc, 1 H, cyclopropane-H), 2.77 (t, J = 7.4 Hz, 2
1.44–1.55 (m, 3 H, 4-Ha, 5-H), 1.72–1.86 (m, 1 H, 4-Hb), 2.15 (s, 3
H, CH3), 2.51 (mc, 1 H, 3-H) ppm. The signal corresponding to the
hydroxy proton was not observed. 13C NMR (CDCl3, 126 MHz): δ
= 8.8, 8.9, 9.9 (3 t, CH2-cyclopropane), 16.4, 21.5 (2 q, CH3), 22.8
(s, C-7), 25.4, 25.5 (2 q, CH3), 26.7, 26.8 (2 t, C-4), 28.0 (q, CH3),
37.3, 37.4 (2 t, C-5), 47.4, 47.5 (2 d, CH), 76.7 (s, C–OH), 212.8 (s,
3
3
H, 2-H), 2.98 (t, J = 7.4 Hz, 2 H, 4-H), 7.30 (d, J = 8.2 Hz, 2 H,
Ar), 7.43 (t, 3J = 7.6 Hz, 2 H, Ph), 7.54 (tt, 4J = 1.2 Hz, 3J =
7.6 Hz, 1 H, Ph), 7.91 (d, 3J = 8.2 Hz, 2 H, Ar), 7.94 (dd, 4J =
1.3 Hz, J = 8.2 Hz, 2 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz):
3
δ = 11.4 (t, CH2-cyclopropane), 16.9 (t, C-3), 25.2 (t, C-4), 35.1 (t,
C-2), 37.4 (d, CH-cyclopropane), 127.9, 128.2, 128.5, 128.6, 133.0,
136.0, 136.8, 147.0 (5 d, 3 s, Ph), 199.7, 200.1 ppm (2 s, CO) ppm.
CO) ppm. IR (KBr): ν = 3490 (O–H), 3080, 3000, 2960, 2935, 2875
˜
(C–H), 1705 (C=O) cm–1. MS (EI, 80 eV, 30 °C): m/z (%) = 198
(Ͻ1) [M]+, 183 (4) [M – CH3]+, 170 (15) [M – C2H4]+, 143 (6)
[MH – C4H8]+, 43 (100) [C2H3O]+. HRMS (EI, 80 eV, 30 °C):
calcd. for C12H22O2 198.16199; found 198.16200.
IR (KBr): ν = 3080, 3050, 3020, 2930, 2885 (=CH, C–H), 1685,
˜
1660 (C=O) cm–1. MS (EI, 80 eV, Ͼ260 °C): m/z (%) = 292 (14)
[M]+, 251 (Ͻ1) [M – C3H5]+, 173 (69) [M – C8H7O]+, 145 (3) [M –
C10H11O]+, 120 (41) [C8H7O]+, 105 (59) [C7H5O]+, 77 (76) [Ph]+,
69 (22) [C4H5O]+, 44 (100), 41 (21) [C3H5]+. HRMS (EI, 80 eV,
Ͼ260 °C): calcd. for C20H20O2 292.14633; found 292.14548.
C20H20O2 (292.4) calcd. C 82.16, H 6.89; found C 81.78, H 6.81.
Coupling of Cyclopropyl(2-thienyl)methanone (21) To Afford
Cyclopropyl{5-[cyclopropyl(hydroxy)(2-thienyl)methyl]-2-thienyl}-
methanone (22): According to the general procedure above, ketone
21 (152 mg, 1.00 mmol) afforded 22 as a colorless oil (58 mg, 38%)
after column chromatography on silica gel (hexane/ethyl acetate,
7:3) and preparative HPLC (hexane/ethyl acetate, 21:4, 64 mL/ min,
47 bar). 1H NMR (CDCl3, 500 MHz): δ = 0.59–0.61, 0.61–0.65,
1.00, 1.21, 1.74 (2 m, 3 mc, 1 H, 3 H, 2 H, 2 H, 1 H, cyclopropane-
H), 2.43 (s, 1 H, OH), 2.49 (mc, 1 H, cyclopropane-H), 6.96 (dd,
Coupling of (4-tert-Butylphenyl)cyclopropylmethanone (15) To Af-
ford 1-(4-tert-Butylphenyl)butan-1-one (16), 1,5-Bis(4-tert-butyl-
phenyl)-5-cyclopropyl-5-hydroxypentan-1-one (17) and 4-[5-tert-
Butyl-2-(cyclopropylcarbonyl)phenyl]-1-(4-tert-butylphenyl)butan-1-
one (18): According to the general procedure above, ketone 15
(606 mg, 2.99 mmol) afforded after column chromatography on sil-
ica gel (hexane/ethyl acetate, 4:1) 16 as a colorless oil (200 mg,
33%), 17 as a colorless solid (169 mg, 28%) and 18 as a colorless
oil (155 mg, 26%). The spectroscopic data of 16 are in agreement
with those reported in the literature.[25] 17: M.p. 88–90 °C. 1H
NMR (CDCl3, 250 MHz): δ = 0.28–0.36 (m, 2 H, 7-Ha, 8-Ha),
0.37–0.52 (m, 2 H, 7-Hb, 8-Hb), 1.01–1.20 (m, 1 H, 6-H), 1.23 (s, 9
H, tBu), 1.26 (s, 9 H, tBu), 1.64–2.01 (m, 5 H, OH, 3-H, 4-H), 2.89
(t, 3J = 6.8 Hz, 2 H, 2-H), 7.30–7.44 (m, 6 H, Ar), 7.85 (d, 3J =
8.2 Hz, 2 H, Ar) ppm. 13C NMR (CDCl3, 126 MHz): δ = 0.6 (t,
C-7), 1.2 (t, C-8), 18.5 (t, C-3), 21.7 (d, C-6), 30.1, 31.3, 38.4, 41.7
(2 q, 2 s, tBu), 34.2 (t, C-4), 34.9 (t, C-2), 74.5 (s, C-5), 124.7, 125.1,
125.3, 127.9, 134.0, 143.2, 149.0, 156.4 (4 d, 4 s, Ar), 200.0 (s, CO)
3
3J = 5.1 Hz, 3.8 Hz, 1 H, Ar), 7.03 (d, J = 4.0 Hz, 1 H, Ar), 7.06
3
4
3
4
(dd, J = 2.5 Hz, J = 1.2 Hz, 1 H, Ar), 7.26 (dd, J = 3.8 Hz, J
= 1.2 Hz, 1 H, Ar), 7.67 (d, J = 4.0 Hz, 1 H, Ar) ppm. 13C NMR
3
(CDCl3, 126 MHz): δ = 2.2, 2.7, 11.3, 17.8, 23.8 (3 t, 2 d, cyclopro-
pane), 74.4 (s, C–OH), 125.1, 125.2, 125.4, 125.5, 126.6, 143.4,
150.6, 160.0 (5 d, 3 s, Ar), 193.1 (s, CO) ppm. IR (KBr): ν = 3440
˜
(O–H), 3090, 3010, 2955, 2925, 2850 (=CH, C–H), 1635 (C=O)
cm–1. MS (EI, 80 eV, 90 °C): m/z (%) = 304 (21) [M]+, 263 (59)
[M – C3H5]+, 235 (27) [M – C4H5O]+, 111 (100), 69 (59)
[C4H5O]+, 41 (39) [C3H5]+. HRMS (EI, 80 eV, 90 °C): calcd. for
C16H16O2S2 304.05917; found 304.05844.
3,8-Dimethyldecane-2,9-dione (23): Samarium (720 mg, 4.40 mmol)
ppm. IR (KBr): ν = 3515 (O–H), 3085, 2960, 2905, 2865 (=CH,
and 1,2-diiodoethane (1.24 g, 4.40 mmol) were suspended in THF
˜
C–H), 1680 (C=O) cm–1. MS (EI, 80 eV, 140 °C): m/z (%) = 406 (50 mL) under argon and stirred at room temperature until the
(Ͻ1) [M]+, 405 (Ͻ1) [M – H]+, 391 (Ͻ1) [M – CH3]+, 365 (6) [M – color of the suspension turned into dark blue (approximately 2 h).
C3H5]+, 349 (Ͻ1) [M – C4H9]+, 231 (10) [M – C12H15O]+, 203 (100),
176 (20) [C12H16O]+, 57 (43) [C4H9]+, 41 (14) [C3H5]+. HRMS (EI,
80 eV, 140 °C): calcd. C28H37O2 [M – H]+ 405.27936; [M – CH3]+
391.26370; found [M – H]+ 405.27866, [M – CH3]+ 391.26465. 18:
The flask was then evacuated and HMPA (6.40 mL, 32.0 mmol)
was added. Argon was purged for 10 min through a solution of
cyclopropyl methyl ketone (3) (168 mg, 2.00 mmol) and methyl io-
dide (0.37 mL, 6.00 mmol) in THF (30 mL), this mixture was
1H NMR (CDCl3, 250 MHz): δ = 0.96–1.00, 1.04–1.24 (2 m, 1 H, added to the deep violet solution of SmI2/HMPA. The resulting
2 H, cyclopropane-H), 1.30 (s, 9 H, tBu), 1.98 (s, 9 H, tBu), 2.04
(q, J = 7.5 Hz, 2 H, 3-H), 2.41 (sept, J = 4.2 Hz, 1 H, cyclopro- quenched by addition of a satd. aq. NaHCO3 solution (15 mL).
solution was stirred at room temperature for 16 h and then
3
3
pane-H), 2.96 (mc, 4 H, 2-H, 4-H), 7.27–7.30 (m, 2 H, Ar), 7.45
The aqueous phase was extracted with diethyl ether (3×30 mL)
and the combined organic layers were washed once with water and
twice with brine, then dried with MgSO4, filtered and the solvent
was removed under reduced pressure to leave the crude product.
Compound 23[26] was obtained as a colorless oil (108 mg, 55%)
after column chromatography on alumina (hexane/ethyl acetate,
3
3
(d, J = 8.7 Hz, 2 H, Ar), 7.70 (d, J = 8.0 Hz, 1 H, Ar), 7.87 (d,
3J = 8.7 Hz, 2 H, Ar) ppm. 13C NMR (CDCl3, 126 MHz): δ = 11.7
(t, CH2-cyclopropane), 20.6 (t, C-3), 26.5 (t, C-4), 31.0 (q, tBu),
33.2 (d, CH-cyclopropane), 33.2 (q, tBu), 34.7, 35.0 (2 s, tBu), 38.1
(t, C-2), 122.8, 125.4, 127.9, 128.6, 134.5, 136.7, 140.8, 154.2, 156.4
1
3
(5 d, 4 s, Ar), 199.8, 204.5 (2 s, CO) ppm. IR (KBr): ν = 3480,
5:1). H NMR (CDCl3, 500 MHz): δ = 1.06 (d, J = 7.0 Hz, 6 H,
˜
2965, 2905, 2870 (=CH, C–H), 1670 (C=O) cm–1. MS (EI, 80 eV, 3-CH3, 8-CH3), 1.12–1.26 (m, 4 H, 5-H, 6-H), 1.26–1.35 (m, 2 H,
1738
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1733–1739

Samarium Diiodide Induced Reactions of Cyclopropyl Ketones
FULL PAPER
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H), 2.49 (sext, 3J = 7.0 Hz, 2 H, 3-H, 8-H) ppm. 13C NMR (CDCl3,
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˜
cm–1. MS (EI, 80 eV, 40 °C): m/z (%) = 198 (5) [M]+, 180 (1) [M –
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C12H22O2 198.16199; found 198.16223.
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Acknowledgments
The authors thank the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie (Kekulé fellowship for A. H.) and
the Schering AG for generous support of this research. We thank
Dr. R. Zimmer for his assistance during the preparation of this
manuscript.
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Received: December 2, 2005
Published Online: February 3, 2006
Eur. J. Org. Chem. 2006, 1733–1739
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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