Synthesis of α-methyl ketones by a selective, iridium-catalyzed cyclopropanol ring-opening reaction

Article abstract of DOI:10.1016/j.tetlet.2010.10.067

A mild method for synthesizing α-methyl ketones from substituted cyclopropanols is reported. This process, catalyzed by [CpIrCl₂] ₂, cleaves cyclopropanol rings regioselectively and more efficiently than the other conditions examined. While tertiary cyclopropanols afford α-methyl ketones, secondary cyclopropanols and cyclopropyl silyl ethers are less reactive and yield other isomerization products.

Full text of DOI:10.1016/j.tetlet.2010.10.067

Tetrahedron Letters 51 (2010) 6726–6729
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Tetrahedron Letters
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Synthesis of
a-methyl ketones by a selective, iridium-catalyzed
cyclopropanol ring-opening reaction
⇑
Daniel T. Ziegler, Andrew M. Steffens, Timothy W. Funk
Department of Chemistry, Gettysburg College, 300 N Washington St., Gettysburg, PA 17325, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild method for synthesizing a-methyl ketones from substituted cyclopropanols is reported. This pro-
Received 26 August 2010
Revised 8 October 2010
Accepted 12 October 2010
Available online 20 October 2010
cess, catalyzed by [Cp*IrCl2]2, cleaves cyclopropanol rings regioselectively and more efficiently than the
other conditions examined. While tertiary cyclopropanols afford -methyl ketones, secondary cycloprop-
anols and cyclopropyl silyl ethers are less reactive and yield other isomerization products.
a
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropane
Cyclopropanol
Ring-opening
Iridium
Carbon–carbon bond cleavage
Cyclopropanes are versatile synthetic intermediates and a large
number of ring-opening processes affording a wide variety of prod-
ucts have been reported. Within the broad field of cyclopropane
chemistry lies the reactions of cyclopropanes substituted with
electron-donating heteroatoms1; the most common substituents
are alkoxy and silyloxy presumably because they are easily synthe-
sized from vinyl ethers by Simmons–Smith cyclopropanations.2
Ring-opening reactions of these substituted cyclopropanes
generally occur regioselectively. The development of a titanium-
mediated coupling of esters and Grignard reagents to access
substituted cyclopropanols in a single step has been followed by
explorations of their ring-opening reactions.1a,3 In particular, we
were interested in the ring-opening isomerization of cyclopropa-
Scheme 1. Synthesis of
cyclopropanols.
a
-methyl ketones from unsymmetrical ketones or
in alcohol), which may destroy sensitive functionality in the mole-
cule.1a,b,5 Two metal-catalyzed reactions have been reported: a Pd/
C process done under a hydrogen atmosphere6 and a platinum-
catalyzed ring-opening using Zeise’s dimer ([Pt(C2H4)Cl2]2).7 Both
methods have been applied only to the opening of the cyclopropa-
nol ring of substituted bicyclo[4.1.0]heptanes. We chose to use the
latter process as a starting point largely due to its mild reaction
conditions and procedural simplicity.
nols to
a-methyl ketones because they are common structural
features in organic molecules. Traditionally
a-methyl ketones have
been synthesized by C-methylations of enolates, but this method
can lead to mixtures of regioisomers when an unsymmetrical
ketone is used.4 To avoid this issue, the
a-methyl ketone could
be accessed from the appropriate cyclopropanol by a ring-opening
isomerization (Scheme 1).
The 1,2-disubstituted cyclopropanol 1a was synthesized as a
racemate using a modified Kulinkovich reaction8 and was treated
with Zeise’s dimer using the published reaction conditions (Table 1,
We were interested in developing a simple, mild, regioselective,
transition metal-catalyzed synthesis of
a-methyl ketones from
cyclopropanols. In order to take full advantage of this approach,
the cyclopropanol ring-opening must occur selectively at the less
substituted carbon–carbon bond. The conditions most commonly
used to afford the desired regioisomer are strongly basic (hydroxide
entry 1).7 The desired
a-methyl ketone product 2a formed with
none of the linear regioisomer 3a was observed in the crude 1H
NMR spectrum. The linear ketone 3a would form if cleavage oc-
curred at the more substituted C–C bond (bond b). In addition to
2a, a small amount of alkene 4a was present.9,10 Encouraged by
these results, we examined other transition metal dimers for reac-
tivity and selectivity in the ring-opening of 1a. The two ruthenium
⇑
Corresponding author. Tel.: +1 717 337 6348; fax: +1 717 337 6270.
E-mail address: tfunk@gettysburg.edu (T.W. Funk).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.067

D. T. Ziegler et al. / Tetrahedron Letters 51 (2010) 6726–6729
6727
Table 1
Potential catalysts for regioselective cyclopropanol ring-opening
Entry
Catalyst (mol %)
Conversion (%)a
Product distributiona
2a (%) 3a (%)
1a (%)
4a (%)
1b
2
3
4
5
[Pt(C2H4)Cl2]2 (2.5)
Shvo’s catalyst (4)
[(p-Cymene)RuCl2]2 (2.5)
[Cp*RhCl2]2 (2.5)
[Cp*IrCl2]2 (2.5)
[Cp*IrCl2]2 (2.5) + PPh3 (5)
[Cp*IrCl2]2 (2.5) + pyridine (5)
[Cp*IrCl2]2 (2.5)
HCl (10)
>99
>99
>99
>99
>99
>99
74
>99
>99
74
0
0
0
0
0
0
26
0
0
26
85
97
73
79
83
97
91
56
96
58
62
7
0
27
21
13
3
9
18
4
3
0
0
4
0
0
0
0
0
0
0
6
7
8c
9
42
12
8
10
—
—
11c
15
a
b
c
Determined by 1H NMR spectroscopy of the crude reaction mixture; no other compounds were observed.
Reaction run in Et2O at rt.
Reaction run at 80 °C. Shvo’s catalyst = {[Ph4(g l-H); Cp* = pentamethylcyclopentadienyl.
5-C4CO)]2H}Ru2(CO)4(
compounds examined isomerized 1a but with lower selectivity for
the desired regioisomer (Table 1, entries 2 and 3). Selectivity for 2a
increased when a rhodium dimer was used (Table 1, entry 4) and
was excellent in the presence of [Cp*IrCl2]2 (Table 1, entry 5).
The addition of ligands to [Cp*IrCl2]2 decreased the formation of
2a (Table 1, entries 6 and 7). Decreasing the temperature to 80 °C
had an insignificant effect on the selectivity of the ring-opening
reaction (Table 1, entry 8). With the exception of Shvo’s catalyst,
all the transition metal dimers explored contained chloride ligands.
We treated cyclopropanol 1a with HCl to determine if residual HCl
formed in solution was catalyzing the reaction (Table 1, entry 9),
and the ring opening was largely unselective. At elevated temper-
ature there was a background reaction that generated 2a preferen-
tially, but at 80 °C that process was slowed significantly (Table 1,
entries 10 and 11).
was used. We initially proceeded forward with Zeise’s dimer but
discovered that the reaction was not as efficient as with other
cyclopropanols (Table 2, entries 2 and 3). While none of the linear
regioisomer was observed in either reaction, unreacted cyclopro-
panol A was present in addition to the alkene product from oxida-
tive ring-opening (C). Presumably
C formed by b-hydrogen
elimination from a platinum(II)-alkyl species, which generated an
unreactive platinum(0) species upon reductive elimination of
HCl.11 The formation of a catalytically inactive platinum compound
explains the incomplete conversions.
Fortunately when other cyclopropanols were treated with
[Cp*IrCl2]2, the ring-openings occurred cleanly and selectively to
form the desired a-methyl ketones (Table 3). Only the cyclopropa-
nol ring of a cyclopropyl-substituted compound was opened (Ta-
ble 3, entry 2), illustrating the selectivity and mildness of the
reaction conditions. A variety of other substituents on the cyclo-
propanol ring were tolerated, including protected alcohols (Table 3,
entries 6–8) and alkyl bromides (Table 3, entries 9 and 10). Toluene
was ultimately selected as the reaction solvent, but it also occurred
cleanly in ethanol and acetonitrile at 80 °C with 2.5 mol % of the
iridium dimer. When the catalyst loading was decreased to
0.5 mol %, the reaction did not go to completion in toluene (94%
conversion for substrate 1b), and unidentified impurities and large
amounts of unreacted cyclopropanol were present in ethanol and
acetonitrile. The successful ring-opening isomerization of tertiary
Based on the results presented in Table 1, the ring-opening
isomerization was most selective when Zeise’s dimer or [Cp*IrCl2]2
Table 2
Product distribution of cyclopropanol ring-openings using [Pt(C2H4)Cl2]2
cyclopropanols to
a-methyl ketones encouraged us to explore sec-
ondary cyclopropanols (Table 3, entry 11). While the desired
a-
methyl aldehyde 2k was the major product, a large amount of
unreacted cyclopropanol 1k remained in addition to small
amounts of the linear regioisomer 3k and the alkene 4k. Silyl
cyclopropyl ether 1l afforded no 2-methylcyclohexanone; instead,
an undetermined mixture of unreacted 1l and alkene 2l was
formed (Table 3, entry 12). Alkene 2l was generated in high yield
when 1l was treated with Zeise’s dimer.7,12
The proposed mechanism for the reaction is illustrated in
Scheme 2. The cyclopropanol coordinates to a monomeric iridium
species and loses H+ to form D. Regioselective b-carbon elimination
cleaves the less sterically hindered cyclopropanol C–C bond and af-
Entry Cyclopropanol
Conversion (%)a
Product distributiona
Unreacted A (%) B (%) C (%)
1
2
>99
95
0
5
(94)
90
3
5
3
79
21
76
3
fords an iridium-alkyl species (E) that is protonated to yield the a-
methyl ketone and regenerate the catalyst. We believe that the
a
Determined by 1H NMR spectroscopy of the crude reaction mixture; no other
compounds were observed. Values in parentheses are isolated yields.
reaction does not occur through a radical mechanism because an

6728
D. T. Ziegler et al. / Tetrahedron Letters 51 (2010) 6726–6729
Table 3
Substrate scope of iridium-catalyzed cyclopropanol ring-opening
Entry
1
Substrate
Product(s)
Isolated yield (%)a
84
2
93
3
4
86
90
5
86
6
7
72
71
78
71
92
8
9
10
1k: (77)
2k: (17)
3k: (4)
4k: (2)
11b
12c
nd
Reaction conditions: cyclopropanol (1 equiv) and [CpÃIrCl2]2 (0.025 equiv) in toluene (0.25 M in cyclopropanol) heated to 80 °C for 18 h.
a
Values in parentheses are product distributions determined by 1H NMR spectroscopy.
b
From the 1H NMR spectrum of the crude reaction mixture.
c
nd = not determined.
unpaired electron on the alcohol carbon of substrate 1b would
fragment the appended cyclopropane ring.13 There is no evidence
of cyclopropane ring-opening in the crude 1H NMR spectrum of
the reaction of [Cp*IrCl2]2 with 1b. While we propose the above
mechanism because of its similarity to alcohol oxidations with
[Cp*IrCl2]2,14 we cannot rule out a mechanism involving oxidative
addition of a cyclopropyl C–C bond to afford a metallacyclobutane
intermediate.15
In summary, we have developed a selective, simple, mild synthe-
sis of a-methyl ketones from cyclopropanols using [Cp*IrCl2]2. This

D. T. Ziegler et al. / Tetrahedron Letters 51 (2010) 6726–6729
6729
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Acknowledgment
The authors thank Gettysburg College for financial support.
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Supplementary data (experimental procedures and spectral
data for new compounds) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2010.10.067.
References and notes
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