Seven-membered ring formation from cyclopropanated oxo- and epoxyallylsilanes

Article abstract of DOI:10.1021/jo200705u

A useful strategy for cycloheptane annulations from oxo- and epoxyallylsilanes, prepared by silylcupration of allene , has been developed, and their application to the stereoselective synthesis of 4- methylenecycloheptan-1-ols is of great potential in the

Full text of DOI:10.1021/jo200705u

NOTE
pubs.acs.org/joc
Seven-Membered Ring Formation from Cyclopropanated Oxo- and
Epoxyallylsilanes
Francisco J. Pulido,* Asunciꢀon Barbero,* and Pilar Castre~no
ꢀ
Departamento de Quimica Orgꢀanica, Universidad de Valladolid, 47011 Valladolid, Spain
S Supporting Information
b
ABSTRACT: A useful strategy for cycloheptane annulations
from oxo- and epoxyallylsilanes, prepared by silylcupration of
allenes, has been developed, and their application to the stereo-
selective synthesis of 4-methylenecycloheptan-1-ols is of great
potential in the construction of seven-membered ring natural
products presented.
uring the past decade, chemists have witnessed a rapid
development of organosilicon chemistry, which has proven
and stereoselective seven-membered ring formation by cyclopro-
D
panation of oxo- and epoxyallylsilanes, which might be of interest
in the approach to cycloheptane-containing naturally occurring
products. Although synthetic approaches to seven-membered ring
systems via cyclization reactions from acyclic substrates are
abundant and the numberof stereoselective methods for preparing
the seven-membered carbocycles has increased in the last years,12
the metal-mediated approach to the synthesis of medium-sized
rings was just recently faced.13
Oxoallylsilanes (2) and epoxyallylsilanes (3) are easily pre-
pared from 1,2-propadiene and lower-order cyanosilylcuprates
of type 1, followed by reaction of the resulting vinylcopperꢀ
allylsilane intermediate with R,β-unsaturated ketones and ulter-
ior epoxidation with sulfur ylides (Scheme 1).6a,9a,9c
Silylcupration of 1,2-propadiene is a reversible process whose
regiochemistry depends on the reaction temperature and the
nature of cuprate. Using low temperatures and lower-order
cuprates, exclusive formation of the kinetic intermediate (the
vinylcopperꢀallylsilane species) is ensured.14
to be very powerful in modern organic synthesis.1 Many valuable
natural product syntheses have been possible thanks to the
outstanding chemical behavior of silicon compounds.2 In parti-
cular, the chemistry of allylsilanes is probably the most useful and
widely used in synthesis due to the increasing number of novel
methodologies that allow relevant transformations.3 Conse-
quently, a great deal of effort has been directed to find new
routes for the preparation of these powerful intermediates.
Silylcupration of dienes and acetylenes is one of the most
attractive strategies for the efficient preparation of allyl- and
vinylsilanes, providing an easy entry to silicon-containing
products.4 Some of these developments have been summarized
in a recent review, in which we report the scope of the
silylcupration of allenes, the interest of this method for the
preparation of functionalized allylsilanes, and their application to
the synthesis of natural products.5
Functionalized allylsilanes containing electrophilic groups in
their structure are readily available from allenes by silylcupration
and further reaction with electrophiles.6 They undergo intramole-
cular allylsilane-terminated cyclizations when treated with Lewis acid,
affording carbocyclic structures of different size.6,7 Oxoallylsilanes
lead to cyclopentane annulation6 or spiro-cyclopropanation8 de-
pending on the reaction conditions, whereas epoxyallylsilanes give
methylenecyclohexanols following an unusual rearrangementꢀ
cyclization pathway.9 In a brief review, we have reported the
relevancy of the silylcuprate strategy in the synthesis of three- to
seven-membered rings.10 More recently, we published the first total
synthesis of (ꢀ)-nomadone, the principal component of the
mandibular secretion that rules the territorial behavior of the
Nomada bees, by Pd-catalyzed cross-coupling of allylsilaneꢀ
vinylcopper species and vinyl halides.11
Oxoallylsilanes 2aꢀd (Table 1) in THF were treated with
dimethylsulfonium methylide at 0 °C for 1 h. By warming up the
mixture to room temperature with additional stirring of 1 h,
epoxyallylsilanes 3aꢀd were obtained in good yield (Table 1).
Compounds 3aꢀd in DCM reacted with a mixture 2 equiv of
CH2I2 and 3 equiv of Me3Al (a modified version of the
Yamamoto reagent) at ꢀ60 °C. The mixture was left to warm
to rt and kept at this temperature for 50 h with stirring. Workup
of the crude (Et3N/H2O (1:3) at ꢀ20 °C and purification of the
residue (silica gel, EtOAc/hexane) gave the cyclopropanated
hydroxysilanes 4aꢀd (eq 1, Table 1). Formation of cyclopro-
pylhydroxysilanes 4 occurs probably by simultaneous attack of
the Yamamoto reagent to both the epoxide and the alkene
In the aim of contributing to find new routes for silicon-assisted
synthesis of natural products, we now report an unprecedented
Received: April 7, 2011
Published: May 27, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 1
Table 2. 5-Methylenecycloheptan-1-ols 6 from Silanes 4
Table 1. Cyclopropylhydroxysilanes 4 from Epoxyallylsilanes 3
a Yield from 4. Reagent used: oxalyl chloride/DMSO in DCM ꢀ78 to
0 °C. b Yield from 5. Lewis acid used: BF3 OEt2 in DCM at 0 °C.
3
Scheme 2
a Prepared according to refs 6a and 7a (see also ref 9a). b Yield from 2
(refs 9a,9c). Reagent used: Me2SdCH2 in THF at 0 °C. c Yield from 3.
Reagent used: CH2I2/Me3Al (2:3) in DCM at ꢀ60 °C. d Diastereomeric
mixtures.
carbenoid intermediate with TFA lowers reaction times and
increases yield. The only exception to this general behavior was
2b, which upon treatment in the former acidic conditions
undergoes desilylation with concomitant cyclopropane ring
cleavage leading to 5-ethyl-4-phenylhex-3-en-2-one. Compounds
7a,cꢀf are readily epoxidated under standard conditions
(Me2SdCH2/THF/0 °C), leading to epoxycyclopropylsilanes
8a,cꢀf (Table 3). Silanes 8aꢀf cannot be obtained by the
opposite sequence (epoxidationꢀcyclopropanation) because epoxy-
allylsilanes are not stable enough in TFA conditions.
moiety. Reaction proceeds cleanly with total absence of possible
side products, resulting from a single attack of the reagent to one
of the functional groups.
Swern oxidation of cyclopropylhydroxysilanes 4aꢀd at ꢀ78 °C
affords aldehydes 5aꢀd, which under Lewis acid catalysis under-
go silicon-mediated intramolecular cyclization leading to 5-methyl-
enecycloheptan-1-ols 6aꢀd selectively (Table 2). Boron trifluoride
etherate in DCM at 0 °C is the most efficient catalyst, providing
the best yields and a high level of stereoselectivity (Table 2).
The stereochemistry shown by cycloheptanols 6b,c indicates
that the compound attains a preferred low energy conformation
(Scheme 2), where substituents OH, Ph, and iPr arrange properly
for minimal repulsions. Change of stereochemistry when 4-R
substituent is Ph (6b) or alkyl (iPr, 6c) is not unusual; it has been
previously observed for six-membered ring formation,9a,c and it is
probably due to the different bulkiness and stereoelectronic
effect of Ph and iPr.
An alternative method for cycloheptane ring formation from
oxoallylsilanes 2 could be efficiently developed by means of a
consecutive cyclopropanationꢀepoxidation process and further
cyclization. Thus, oxoallylsilanes 2a,cꢀf were treated with Et2Zn/
TFA/CH2I2 (1:1:1) in DCM at 0 °C (a recent version of the
Furukawa cyclopropanation reaction15) to give oxocyclopro-
pylsilanes 7a,cꢀf in good yield (Table 3). Activation of the
Cyclization of epoxycyclopropylsilanes 8a,cꢀf in the presence
of TiCl4 or BF3 Et2O affords 5-methylenecycloheptan-1-ols 9a,
3
cꢀf in good yield and with a high degree of stereocontrol
(Table 4). Cycloheptanols 9a,dꢀf bearing two stereocenters
are selectively obtained as trans isomers, except for 9d (cis/trans
ratio 1:10) and 9a (cis/trans ratio 1:10/BF3 or 1:15/TiCl4),
where small amounts of the cis isomer are also observed
(Table 4). The presence of Ti4Cl may improve the stereoselec-
tivity ratio; for instance, the boron-mediated cyclization of 8a
leads to the formation of a cisꢀtrans mixture of products, in a
1:10 ratio, favoring the trans isomer 9a, whereas the correspond-
ing titanium-catalyzed reaction provides an improved cisꢀtrans
disatereomeric ratio of 1:15 (Table 4). Three stereocenter
cycloheptanols as 9c are still formed with acceptable stereocon-
trol (5:1 mixture of epimers at C-2, Table 4).
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NOTE
Table 3. Epoxycyclopropylsilanes 8 from Oxoallylsilanes 2
Scheme 3
Scheme 4
preferentially, suggesting the intervention of an intermediate
oxocyclopropylsilane I (Scheme 3) with both the C-7 substituent
and the carbonyl-LA groups equatorial for minimal steric
repulsions.
a Yield from 2. Reagent used: Et2Zn/TFA/CH2I2 (1:1:1) in DCM at 0
°C. b Yield from 7. Reagent used: Me2SdCH2 in THF at
0 °C. c Diastereomeric mixture.
The substituted 5-methylenecycloheptan-1-ols 6 and 9
synthesized by this route might be excellent building blocks
for the total synthesis of cycloheptane-containing naturally
occurring terpenes. For example, 6d is very close in structure
to the natural product Karahanaenone (Scheme 4), a mono-
terpene present in hop essential oil, which is widely used in
food industry as a flavoring and stability agent in beer.16 Com-
pound 6d might be envisaged as a useful precursor for a short
and convenient synthesis of Karahanaenone. Similarly, compound
9d seems to be a near precursor of Perforenone (Scheme 4), a
sesquiterpene isolated from the extract of red alga Laurentia
perforata having multifunctional ecological roles. Many second-
ary metabolites obtained from the genus Laurentia have been
proposed to behave as antifeedant, antimicrobial, and cytotoxic
principles.17 A plausible route for the design and synthesis of this
natural sesquiterpene might involve a Robinson annelation as the
key step, followed by a short number of standard chemical
transformations.
Table 4. 5-Methylenecycloheptan-1-ols 9 from Epoxysilanes 8
In conclusion, a new and useful strategy for cycloheptane
annulations from cyclopropanated allylsilanes has been devised,
and their application to the stereoselective synthesis of methy-
lenecycloheptanols of much potential in the construction of
seven-membered ring natural products was presented.
’ EXPERIMENTAL SECTION
General Experimental Methods. Spectroscopic data were re-
corded as follows: 1H NMR and 13C NMR spectra were run at 300 and
75 MHz, respectively. Peak asignments were performed with the aid of
the DEPT technique and 2D-COSY spectra. Tetrahydrofuran was
distilled from sodium benzophenone. All compounds were obtained
as colorless oils except where melting points are mentioned. The
stereochemistry of the compounds has been assigned on the basis of
NOESY experiments.
Synthesis of Hydroxycyclopropylsilanes 4: To a solution of epox-
yallylsilanes 3 (1.1 mmol) in DCM (2 mL), under nitrogen atmosphere
and at 0 °C, was added 2.2 mmol of CH2I2 (0.12 mL). At ꢀ60 °C, 3.3
mmol of Me3Al (2 M in hexane, 1.65 mL) was added dropwise, and the
a Yield from 8. Lewis acid used: TiCl4 in DCM at ꢀ78 °C or BF3 OEt2
3
in DCM at 0 °C. b Yield 81% (cis/trans ratio 1:10). c Yield 78% (cis/trans
ratio 1:15). d Mixture of epimers at C-2 (ratio 5:1), the major being the
one shown in the table. e Ratio cis/trans 1:10.
Cyclization of epoxycyclopropylsilanes 8 to methylenecyclo-
heptanols 9 takes place by a tandem rearrangementꢀcyclization
process,9a with isomerization of the epoxy group to carbonyl
prior to cyclization. Reaction leads to the 1,7-trans isomer
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NOTE
reaction mixture was allowed to warm to rt and stirred for 50 h. Then,
0.5 mL of a Et3N/H2O (1/3) mixture was carefully added, and after 20
min stirring, the mixture was extracted with ether, dried, and evaporated
to dryness. The residue was purified by chromatography to give
hydroxycyclopropylsilanes 4aꢀd.
2,2,5-Trimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]hexanal
(5c): Colorless liquid (93%); 1H NMR (300 MHz, CDCl3) δ 9.42 (s,
1H), 7.60ꢀ7.27 (m, 5H), 1.79ꢀ1.67 (m, 2H), 1.40 (dd, J = 15, 3 Hz,
1H), 1.24 (d, J = 15 Hz, 1H), 1.15ꢀ1.07 (m, 1H), 1.07 (d, J = 15 Hz,
1H), 1.02 (s, 3H), 1.01 (s, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8
Hz, 3H), 0.58ꢀ0.25 (m, 3H), 0.32 (s, 3H), 0.31 (s, 3H), 0.11ꢀ0.00 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 206.9, 139.6, 133.5, 128.8, 127.7,
48.8, 45.9, 37.8, 31.9, 24.0, 22.2, 21.1, 20.7, 19.7, 14.1, 12.9, ꢀ1.4. Anal.
Calcd for C21H34SiO: C, 76.30; H, 10.37. Found: C, 76.67; H, 10.61.
2,2-Dimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]butanal
(5d): Colorless liquid (94%); 1H NMR (300 MHz, CDCl3) δ 9.14 (s,
1H), 7.55ꢀ7.27 (m, 5H), 1.43ꢀ1.37 (m, 2H), 1.02ꢀ0.94 (m, 2H), 0.87
(s, 2H), 0.84 (s, 6H), 0.21 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
206.4, 140.1, 133.5, 128.8, 127.7, 45.2, 34.2, 33.1, 23.7, 21.1, 21.0, 17.3,
14.1, 14.0, ꢀ1.8. Anal. Calcd for C18H28SiO: C, 74.94; H, 9.78. Found:
C, 75.29; H, 10.04.
2,2,4-Trimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]pentan-1-
ol (4a): Colorless oil (74%); 1H NMR (300 MHz, CDCl3) δ 7.53ꢀ7.27
(m, 5H), 3.33 (s, 2H), 1.46 (s, 2H), 1.31 (s, 2H), 1.27 (s, 1H), 1.00
(s, 6H), 0.86 (s, 6H), 0.50 (t, J = 5.4 Hz, 2H), 0.28 (s, 6H), 0.21 (t, J =
5.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 140.2, 133.4, 128.7, 127.7,
73.9, 46.5, 37.5, 36.7, 25.9, 25.8, 25.7, 20.5, 10.4, 10.3, ꢀ1.2. Anal. Calcd
for C20H34SiO: C, 75.40; H, 10.76. Found: C, 75.77; H, 11.05.
2,2-Dimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]-4-phe-
nylbutan-1-ol (4b): Colorless oil (78%); 1H NMR (300 MHz, CDCl3)
δ 7.52ꢀ7.23 (m, 10H), 3.10 (s, 2H), 2.26 (d, J = 11 Hz, 1H), 2.06 (dd,
J = 14, 11 Hz, 1H), 1.65 (d, J = 14 Hz, 1H), 1.40 (s, 1H), 1.28 (d, J =
15 Hz, 1H), 1.10 (d, J = 15 Hz, 1H), 0.86 (s, 3H), 0.73 (s, 3H), 0.33
(s, 6H), 0.46ꢀ0.29 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 144.7,
140.0, 133.6, 128.8, 128.5, 128.1, 127.8, 126.2, 71.4, 49.1, 40.1, 35.7, 25.5,
24.3, 24.1, 20.3, 13.1, 12.4, ꢀ1.2; IR (film, cmꢀ1) 3401, 2954, 1426,
1111. Anal. Calcd for C24H34SiO: C, 78.63; H, 9.35. Found: C, 78. 93;
H, 9.59.
Intramolecular Acid-Catalyzed Cyclization of Compounds 5aꢀd:
To a solution of compounds 5 (1 mmol) in DCM (5 mL), at 0 °C and
under nitrogen atmosphere, was added dropwise BF3 Et2O (0.18 mL,
3
1.4 mmol), and the mixture was stirred for 30 min. Then, brine was
added (5 mL) and the mixture extracted with ether, dried, and
evaporated to dryness. The residue was purified by chromatography
to give methylenecycloheptanols 6aꢀd.
2,2,5-Trimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]hexan-
1-ol (4c): Colorless oil (72%); 1H NMR (300 MHz, CDCl3) δ 7.61ꢀ7.38
(m, 5H), 3.26 (s, 2H), 2.08ꢀ1.85 (m, 2H), 1.41 (d, J = 15 Hz, 1H), 1.30
(d, J = 15 Hz, 1H), 1.15ꢀ1.12 (m, 2H), 1.01ꢀ0.85 (m, 1H), 0.93 (s, 3H),
0.91 (s, 3H), 0.87 (d, J = 6.7 Hz, 6H), 0.50ꢀ0.25 (m, 4H), 0.38 (s, 3H),
0.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 140.0, 133.5, 128.8, 127.7,
72.8, 45.8, 35.5, 35.3, 32.0, 24.9, 24.7, 22.3, 22.0, 20.4, 19.9, 13.4,
12.4, ꢀ1.3, ꢀ1.4; IR (film, cmꢀ1) 3367, 1426, 1112. Anal. Calcd for
C21H36SiO: C, 75.84; H, 10.91. Found: C, 76.17; H, 11.26.
2,2,4,4-Tetramethyl-5-methylenecycloheptanol (6a): Colorless li-
1
quid (75%); H NMR (300 MHz, CDCl3) δ 4.77 (s, 1H), 4.73 (s,
1H), 3.32 (dd, J = 8, 4 Hz, 1H), 2.34ꢀ2.28 (m, 1H), 2.12ꢀ2.04 (m, 2H),
1.98ꢀ1.84 (m, 1H), 1.71 (d, J = 15.3 Hz, 1H), 1.71ꢀ1.56 (m, 2H), 1.13
(s, 3H), 1.10 (s, 3H), 0.95 (s, 3H), 0.90 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.3, 107.9, 79.4, 48.5, 38.6, 36.8, 32.0, 31.5, 29.1, 28.8, 28.0,
22.6. Anal. Calcd for C12H22O: C, 79.06; H, 12.16. Found: C, 79.39;
H, 12.35.
2,2-Dimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]butan-1-ol
(4d): Colorless oil (76%); 1H NMR (300 MHz, CDCl3) δ 7.56ꢀ7.27
(m, 5H), 3.14 (s, 2H), 1.22ꢀ1.17 (m, 2H), 1.08ꢀ1.02 (m, 2H), 0.88
(s, 2H), 0.69 (s, 6H), 0.34 (s, 6H), 0.22ꢀ0.21 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 140.3, 133.5, 128.7, 127.7, 72.0, 35.3, 34.5, 32.7,
23.8, 23.5, 23.4, 17.5, 14.2, 14.1, ꢀ1.7. Anal. Calcd for C18H30SiO: C,
74.42; H, 10.41. Found: C, 74.78; H, 10.76.
Swern Oxidation of Hydroxycyclopropylsilanes 4: To a solution of
oxallyl chloride (1.5 mmol, 0.14 mL) in DCM (5 mL) at ꢀ78 °C was
added a solution of dry DMSO (1.6 mmol, 0.1 mL) in DCM (0.5 mL),
and the mixture was stirred for 10 min. Then, a solution of hydro-
xycyclopropylsilanes 4 in DCM (1 mmol) was added and the mixture
stirred for an additional 20 min. Triethylamine (5 mmol, 2.2 mL) was
then added, the reaction allowed to warm to rt, and the mixture extracted
with ether, dried, and evaporated to dryness. The residue was purified by
chromatography to give oxocyclopropylsilanes 5aꢀd.
(1RS,4RS)-2,2-Dimethyl-5-methylene-4-phenylcycloheptanol (6b):
1
Colorless liquid (75%); H NMR (300 MHz, CDCl3) δ 7.63ꢀ7.14
(m, 5H), 4.92 (s, 1H), 4.69 (s, 1H), 3.64 (dd, J = 12.5, 4.5 Hz, 1H), 3.60
(m, 1H), 2.68 (td, J = 12.5, 2.6 Hz, 1H), 2.30 (dd, J = 14.5, 12.5 Hz, 1H),
2.27 (dq, J = 12.5, 3.0 Hz, 1H), 2.05ꢀ1.97 (m, 1H), 1.83 (tq, J = 12, 2.8
Hz, 1H), 1.38ꢀ1.27 (m, 2H), 1.05 (s, 3H), 1.02 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 154.3, 148.2, 128.3, 126.9, 125.8, 113.3, 77.1, 47.5, 39.9,
38.3, 34.5, 30.0, 29.0, 23.8. Anal. Calcd for C16H22O: C, 83.43; H, 9.63.
Found: C, 83.11; H, 9.94.
(1RS,4SR)-4-Isopropyl-2,2-dimethyl-5-methylenecycloheptanol (6c):
White solid, mp 53.3ꢀ54.2 °C (71%); 1H NMR (300 MHz, CDCl3) δ
4.89 (s, 1H), 4.66 (s, 1H), 3.24 (dd, J = 4.8, 11.3 Hz, 1H), 2.22ꢀ2.13 (m,
2H), 2.03 (dt, J = 13, 6.4 Hz, 1H), 1.91 (t, J = 13 Hz, 1H), 1.62 (m, 1H),
1.54 (sept, J = 6.8 Hz, 1H), 1.42 (d, J = 13 Hz, 1H), 1.37 (dd, J = 13 Hz,
1H), 1.45ꢀ1.29 (m, 1H), 1.01 (s, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.85 (s,
3H), 0.81 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 152.7,
112.4, 80.9, 47.6, 39.3, 37.6, 37.3, 34.0, 31.1, 31.0, 19.9, 19.7, 16.5. Anal.
Calcd for C13H24O: C, 79.53; H, 12.32. Found: C, 79.88; H, 12.61.
2,2-Dimethyl-5-methylenecycloheptanol (6d): Colorless liquid (72%);
1H NMR (300 MHz, CDCl3) δ 4.72 (s, 1H), 4.68 (s, 1H), 3.40ꢀ3.14 (m,
1H), 2.45ꢀ1.40 (m, 9H), 0.98 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 142.6, 109.8, 79.5, 36.0, 32.5, 30.8, 29.2, 27.6, 22.6. Anal. Calcd for
C10H18O: C, 77.87; H, 11.76. Found: C, 78.08; H, 12.05.
Synthesis of Oxocyclopropylsilanes 7aꢀf: To a solution of Et2Zn
(1 M in hexane, 2 mmol, 2 mL) in dry DCM (2 mL), under nitrogen and
at 0 °C, was added a solution of trifluoroacetic acid (2 mmol, 0.15 mL) in
DCM (1 mL), and the mixture was stirred for 40 min. Then, CH2I2 (2
mmol, 0.16 mL) was added dropwise and stirred for an additional 35 min
before a solution of the oxoallylsilane 2 (1 mmol) in DCM (1 mL) was
added. The reaction mixture was stirred at 0 °C for 30 min and then at rt
for 4 h. The mixture was quenched with saturated NH4Cl, extracted with
ether, dried, and evaporated to dryness. The residue was purified by
chromatography to give oxocyclopropylsilanes 7aꢀf.
2,2,4-Trimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]pentanal
(5a): Colorless liquid (94%); 1H NMR (300 MHz, CDCl3) δ 9.51 (s,
1H), 7.54ꢀ7.27 (m, 5H), 1.80 (s, 2H), 1.29 (s, 2H), 1.11 (s, 6H), 0.76
(s, 6H), 0.47 (t, J = 5.4 Hz, 2H), 0.30 (s, 6H), 0.24 (t, J = 5.4 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 207.0, 139.9, 133.4, 128.8, 127.7, 47.9,
46.7, 37.1, 25.8, 25.2, 25.1, 24.1, 24.0, 20.5, 10.3, 10.2, ꢀ1.2. Anal. Calcd
for C20H32SiO: C, 75.88; H, 10.19. Found: C, 75.51; H, 10.48.
2,2-Dimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]-4-phe-
nylbutanal (5b): Colorless liquid (92%); 1H NMR (300 MHz, CDCl3)
δ 9.05 (s, 1H), 7.49ꢀ7.06 (m, 10H), 2.20 (d, J = 11 Hz, 1H), 2.20 (dd,
J = 13, 11 Hz, 1H), 1.80 (d, J = 13 Hz, 1H), 1.18 (d, J = 15 Hz, 1H), 1.03
(d, J = 15 Hz, 1H), 0.91 (s, 3H), 0.89 (s, 3H), 0.61ꢀ0.53 (m, 1H),
0.43ꢀ0.33 (m, 1H), 0.31ꢀ0.24 (m, 2H), 0.30 (s, 3H), 0.29 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 205.0, 142.7, 139.8, 133.6, 128.7, 128.1,
127.8, 126.6, 48.7, 45.8, 39.9, 23.3, 23.2, 21.1, 21.0, 12.9, 11.7, ꢀ1.2,
ꢀ1.3. Anal. Calcd for C24H32SiO: C, 79.06; H, 8.85. Found: C, 79.41;
H, 9.17.
5853
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The Journal of Organic Chemistry
NOTE
4-Methyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]pentan-2-one
(7a): Colorless liquid (92%); 1H NMR (300 MHz, CDCl3) δ 7.53ꢀ7.35
(m, 5H), 2.47 (s, 2H), 2.14 (s, 3H), 1.29 (s, 2H), 0.90 (s, 6H), 0.50 (t, J =
5.3 Hz, 2H), 0.30 (s, 6H), 0.24 (t, J = 5.3 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 209.6, 139.8, 133.4, 128.8, 127.8, 52.2, 37.0, 32.7, 24.5, 24.0,
20.3, 9.6, 9.5, ꢀ1.3. Anal. Calcd for C18H28SiO: C, 74.94; H, 9.78. Found:
C, 75.31; H, 10.06.
127.6, 56.7, 54.4, 49.7, 37.0, 31.3, 22.2, 20.7, 20.2, 20.1, 19.4, 14.4, 11.5,
0.86, ꢀ1.4.
2-Methyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]-1,2-epox-
ybutane (8d): Colorless liquid (75%); 1H NMR (300 MHz, CDCl3) δ
7.58ꢀ7.36 (m, 5H), 2.45 (d, J = 5 Hz, 1H), 2.37 (d, J = 5 Hz, 1H),
1.58ꢀ1.41 (m, 2H), 1.22 (t, J = 8.7 Hz, 2H), 1.12 (s, 3H), 0.92 (d, J = 15
Hz, 1H), 0.85 (d, J = 15 Hz, 1H), 0.40 (s, 6H), 0.28ꢀ0.25 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 140.1, 133.5, 128.8, 127.7, 56.8, 53.7, 34.2,
33.9, 23.8, 20.8, 17.0, 14.2, 14.1, ꢀ1.7; IR (film, cmꢀ1) 3068, 2956, 1427,
1248, 1111. Anal. Calcd for C17H26SiO: C, 74.39; H, 9.55. Found: C,
74.71; H, 9.84.
5-Methyl-4-[1-(dimethylphenylsilyl)methyl)cyclopropyl]hexan-2-one
(7c): Colorless liquid (74%); 1H NMR (300 MHz, CDCl3) δ 7.56ꢀ7.27
(m, 5H), 2.41ꢀ2.37 (m, 2H), 2.12 (s, 3H), 1.79ꢀ1.64 (m, 1H), 1.17 (d,
J = 15 Hz, 1H), 1.13ꢀ1.07 (m, 1H), 1.00 (d, J = 15 Hz, 1H), 0.91 (d, J =
6.7 Hz, 3H), 0.75 (d, J = 6.7 Hz, 3H), 0.47ꢀ0.38 (m, 2H), 0.30 (s, 3H),
0.29 (s, 3H), 0.29ꢀ016 (m, 1H), 0.09ꢀ0.03 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 208.6, 139.7, 133.4, 128.8, 127.7, 49.3, 46.4,
2-Ethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]-1,2-epoxybutane
(8e): Colorless liquid (75%); 1H NMR (300 MHz, CDCl3) δ 7.57ꢀ7.27
(m, 5H), 2.46 (d, J = 4.7 Hz, 1H), 2.31 (d, J = 4.7 Hz, 1H), 1.58 (t, J = 8.5
Hz, 2H), 1.44 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 8.5 Hz, 2H), 0.87 (s, 2H),
0.83 (t, J = 7.5 Hz, 3H), 0.37 (s, 3H), 0.36 (s, 3H), 0.28ꢀ0.24 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 140.1, 133.4, 128.7, 127.7, 59.9, 51.8,
33.8, 31.2, 26.9, 23.7, 17.1, 14.1, 8.7, ꢀ1.8. Anal. Calcd for C18H28SiO:
C, 74.94; H, 9.78. Found: C, 75.29; H, 9.49.
2-Isopropyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]-1,2-
epoxybutane (8f): Colorless liquid (76%); 1H NMR (300 MHz,
CDCl3) δ 7.56ꢀ7.27 (m, 5H), 2.44 (d, J = 4.6 Hz, 1H), 2.27 (d, J =
4.6 Hz, 1H), 1.74ꢀ1.52 (m, 1H), 1.58 (t, J = 7 Hz, 2H), 1.20ꢀ0.79 (m,
4H), 0.89 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H), 0.37 (s, 3H), 0.35
(s, 3H), 0.30ꢀ0.23 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 140.1,
133.4, 128.7, 127.7, 62.2, 50.1, 33.1, 32.2, 28.0, 23.8, 18.2, 17.8, 17.1,
14.1, 14.0, ꢀ1.6. Anal. Calcd for C19H30SiO: C, 75.43; H, 10.00. Found:
C, 75.76; H, 10.29.
31.4, 30.3, 21.7, 20.8, 20.6, 18.7, 15.5, 10.7, ꢀ1.42; IR (film, cmꢀ1
)
3100, 2956, 1720, 1430, 1110. Anal. Calcd for C19H30SiO: C, 75.43; H,
10.00. Found: C, 75.78; H, 10.31.
4-[1-(Dimethylphenylsilylmethyl)cyclopropyl]butan-2-one (7d):
Colorless liquid (77%); 1H NMR (300 MHz, CDCl3) δ 7.56 ꢀ7.33 (m,
5H), 2.30 (t, J = 7.9 Hz, 2H), 1.92 (s, 3H), 1.40 (t, J = 7.9 Hz, 2H), 0.87
(s, 2H), 0.36 (s, 6H), 0.35ꢀ0.24 (m, 4H); 13C NMR (75 MHz, CDCl3)
δ 208.7, 140, 133.4, 128.8, 127.8, 41.0, 33.0, 29.6, 23.8, 16.7, 14.1, 14.0, ꢀ1.9;
IR (film, cmꢀ1) 3070, 2955, 1718, 1426, 1111. Anal. Calcd for C16H24SiO:
C, 73.79; H, 9.29. Found: C, 74.06; H, 9.53.
1-[1-(Dimethylphenylsilylmethyl)cyclopropyl]pentan-3-one (7e):
Colorless liquid (82%); 1H NMR (300 MHz, CDCl3) δ 7.57ꢀ7.34 (m,
5H), 2.34 (t, J = 8 Hz, 2H), 2.21 (q, J = 7.3 Hz, 2H), 1.43 (t, J = 8 Hz,
2H), 0.98 (t, J = 7.3 Hz, 3H), 0.87 (s, 2H), 0.37 (s, 6H), 0.30ꢀ0.27 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 211.7, 140.0, 133.5, 129.0, 127.8,
39.7, 35.6, 33.1, 23.8, 16.7, 14.1, 14.0, 7.7, ꢀ1.8. Anal. Calcd for
C17H26SiO: C, 74.39; H, 9.55. Found: C,74.71; H, 9.88.
4-Methyl-1-[1-(dimethylphenylsilylmethyl)cyclopropyl]pentan-3-one
(7f): Colorless liquid (72%); 1H NMR (300 MHz, CDCl3) δ 7.55ꢀ7.33
(m, 5H), 2.43ꢀ2.35 (m, 1H), 2.35 (t, J = 7.9 Hz, 2H), 1.42 (t, J = 7.9 Hz,
2H), 1.00 (d, J = 6.9 Hz, 6H), 0.87 (s, 2H), 0.36 (s, 6H), 0.34ꢀ0.23 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 214.7, 140.0, 133.4, 128.7, 127.7,
40.6, 37.7, 33.0, 23.9, 18.3, 18.2, 16.7, 14.1, 14.0, ꢀ1.9. Anal. Calcd for
C18H28SiO: C, 74.94; H, 9.78. Found: C, 75.32; H, 10.06.
Cyclization of Epoxycyclopropylsilanes 8aꢀf: BF3 OEt2 (1.2 mmol)
3
or TiCl4 (0.7 mmol) was slowly added to a solution of the epoxycyclo-
propylsilane 8 (1 mmol) in DCM (10 mL) under nitrogen. After stirring
for 30 min at the corresponding temperature (0 or ꢀ78 °C), 2 mL of
MeOH was added and the mixture was allowed to warm to room
temperature. The organic layer was washed with brine and dried over
MgSO4. The solvent was evaporated and the residue purified by chro-
matography to give methylenecycloheptanols 9aꢀf. The relative stereo-
chemistry of cyclic products was determined by extensive NMR
experiments and in particular with COSY and NOESY data.
Synthesis of Epoxycyclopropylsilanes 8aꢀf: To a solution of tri-
methylsulfonium iodide (1 mmol, 208 mg) in dry THF (5 mL) was added
dropwise BuLi (1 mmol, 1.6 M n-BuLi in hexanes), and the mixture was
stirred for 5 min at 0 °C. Then, a solution of the oxocyclopropylsilane
(0.8 mmol) in THF (1 mL) was added. After stirring for an additional
30 min at 0 °C and 1 h at rt, brine (10 mL) was added and the mixture
extracted with ether, dried, and evaporated to dryness. The residue was
purified by chromatography to give epoxycyclopropylsilanes 8aꢀf.
2,2,4-Trimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]-1,2-
epoxypentane (8a): Colorless liquid (76%); 1H NMR (300 MHz,
CDCl3) δ 7.52ꢀ7.27 (m, 5H), 2.64 (d, J = 4.8 Hz, 1H), 2.58 (d, J = 4.8
Hz, 1H), 1.96 (d, J = 14.2 Hz, 1H), 1.44 (d, J = 14.2 Hz, 1H), 1.40 (s,
3H), 1.27 (s, 2H), 0.90 (s, 3H), 0.84 (s, 3H), 0.53ꢀ0.44 (m, 2H), 0.29
(s, 6H), 0.27ꢀ0.20 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 139.9,
133.4, 128.7, 127.7, 56.0, 55.0, 46.8, 36.4, 25.1, 25.0, 24.6, 23.6, 20.2,
10.0, 9.7, ꢀ1.2. Anal. Calcd for C19H30SiO: C, 75.43; H, 10.00. Found:
C, 75.76; H, 10.32.
(1SR,2SR)-2,4,4-Trimethyl-5-methylenecycloheptanol (9a): Color-
less liquid (81%); H NMR (300 MHz, CDCl3) δ 4.80 (s, 2H), 3.20
1
(td, J = 9.7, 5.0 Hz, 1H), 2.27ꢀ2.08 (m, 3H), 1.56 (t, J = 14.1 Hz, 1H),
1.55 (d, J = 14.1 Hz, 1H), 1.46 (dd, J = 9.3, 6.6 Hz, 1H), 1.43ꢀ1.25 (m,
2H), 1.14 (s, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.99 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.0, 109.3, 78.5, 46.6, 40.8, 38.4, 36.5, 32.1, 29.9, 27.4,
20.8; IR (film, cmꢀ1) 3426, 2962, 1721, 1456. Anal. Calcd for C11H20O:
C, 78.51; H, 11.98. Found: C, 78.83; H, 12.31.
(1SR,2SR,4SR)-4-Isopropyl-2-methyl-5-methylenecycloheptanol (9c):
Colorless liquid (75%); 1H NMR (300 MHz, CDCl3) δ 4.88 (s, 1H), 4.68
(s, 1H), 3.16 (td, J = 9.7, 5 Hz, 1H), 2.26ꢀ1.83 (m, 5H), 1.68ꢀ1.28 (m,
5H), 1.04 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.82 (d, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 152.6, 112.9, 78.8, 51.6, 40.9, 38.7,
35.3, 33.0, 29.1, 20.7, 20.6, 19.8. Anal. Calcd for C12H22O: C, 79.06; H,
12.16. Found: C, 79.40; H, 12.37.
(1SR,2SR)-2-Methyl-5-methylenecycloheptanol (9d): Colorless liq-
uid (74%); 1H NMR (300 MHz, CDCl3) δ 4.70 (s, 1H), 4.67 (s, 1H),
3.31 (td, J = 8.8, 3.3 Hz, 1H), 2.45ꢀ2.38 (m, 2H), 2.32 (d, J = 13.5 Hz,
1H), 2.26 (d, J = 13.5 Hz, 1H), 1.92 (tt, J = 10.8, 3 Hz, 1H), 1.74ꢀ1.50
(m, 4H), 1.36ꢀ1.23 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 150.6, 109.6, 78.3, 42.2, 35.6, 34.1, 31.4, 30.6, 19.8.
Anal. Calcd for C9H16O: C, 77.09; H, 11.50. Found: C, 77.43; H, 11.79.
(1SR,2SR)-2-Ethyl-5-methylenecycloheptanol (9e): Colorless liquid
(72%); 1H NMR (300 MHz, CDCl3) δ 4.69 (s, 1H), 4.67 (s, 1H), 3.51
(td, J = 8.1, 3.4 Hz, 1H), 2.47ꢀ2.38 (m, 2H), 2.30ꢀ2.18 (m, 2H), 1.93ꢀ
1.83(m, 1H), 1.79ꢀ1.55(m, 3H), 1.53ꢀ1.50(m, 2H), 1.45ꢀ1.24 (m, 2H),
2,5-Dimethyl-4-[1-(dimethylphenylsilylmethyl)cyclopropyl]-1,2-
epoxyhexane (8c): Colorless liquid obtained as a 1:1 mixture of
1
diastereoisomers A þ B (76%). A: H NMR (300 MHz, CDCl3) δ
7.59ꢀ7.36 (m, 5H), 2.62ꢀ2.56 (m, 2H), 1.91ꢀ1.72 (m, 2H), 1.29
(s, 3H), 1.21ꢀ1.05 (m, 2H), 0.98ꢀ0.92 (m, 8H), 0.38 (s, 6H),
0.34ꢀ0.31 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 139.7, 133.4,
129.2, 127.8, 56.5, 54.8, 51.2, 37.2, 31.3, 22.1, 21.6, 21.1, 19.9, 18.1, 14.2,
1
11.4, 0.86, ꢀ1.3. B: H NMR (300 MHz, CDCl3) δ (recognizable
signals) 1.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 139.8, 133.0, 128.9,
5854
dx.doi.org/10.1021/jo200705u |J. Org. Chem. 2011, 76, 5850–5855

The Journal of Organic Chemistry
NOTE
0.92 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 151.0, 110.0,
75.5, 48.1, 35.5, 33.9, 30.3, 26.8, 25.3, 11.0. Anal. Calcd for C10H18O: C,
77.87; H, 11.76. Found: C, 78.54; H, 12.07.
(9) (a) Barbero, A.; Castre~no, P.; Pulido, F. J. Org. Lett. 2003,
5, 4045. (b) Barbero, A.; Castre~no, P.; Fernꢀandez, G.; Pulido, F. J. J. Org.
Chem. 2005, 70, 10747. (c) Barbero, A.; Castre~no, P.; Pulido, F. J. Eur.
J. Org. Chem. 2010, 70, 1307.
(1SR,2RS)-2-Isopropyl-5-methylenecycloheptanol (9f): Colorless liq-
uid (76%); 1H NMR (300 MHz, CDCl3) δ 4.68 (s, 1H), 4.66 (s, 1H),
3.61 (td, J = 8.2, 3.7 Hz, 1H), 2.47 (ddd, J = 15, 6.6, 3 Hz, 1H), 2.38 (ddd,
J = 14.5, 8.9, 1.4 Hz, 1H), 2.23ꢀ2.14 (m, 2H), 2.08 (td, J = 6.9, 3.6 Hz,
1H), 1.96ꢀ1.87 (m, 1H), 1.74ꢀ1.61 (m, 3H), 1.33ꢀ1.22 (m, 1H),
1.19ꢀ1.13 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 151.0, 109.6, 73.7, 52.2, 36.7, 35.2, 30.3,
27.7, 22.3, 21.0, 16.6. Anal. Calcd for C11H20O: C, 78.51; H, 11.98.
Found: C, 78.85; H, 12.26.
(10) Barbero, A.; Pulido, F. J. Beilstein J. Org. Chem. 2007, 3, 16.
ꢀ
(11) Pulido, F. J.; Barbero, A.; Garcia, C. Tetrahedron 2009, 65, 5535.
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(13) See among others: (a) Zou, Y.; Garayalde, D.; Wang, Q.;
Nevado, C.; Goeke, A. Angew. Chem., Int. Ed. 2008, 47, 10110. (b)
Saito, S.; Komagawa, S.; Azumaya, I.; Masuda, M. J. Org. Chem. 2007,
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Cuerva, J. M.; Bu~nuel, E.; Cꢀardenas, D. J. J. Am. Chem. Soc. 2005,
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
ꢀ
127, 14911. (d) Barluenga, J.; Alonso, J.; Fa~nanꢀas, F. J.; Borge, J.; Garcia-
the new compounds 4aꢀd, 5aꢀd, 6aꢀd, 7a,cꢀf, 8a,cꢀf, and 9a,
cꢀf. This material is available free of charge via the Internet at
http://pubs.acs.org.
Granda, S. Angew. Chem., Int. Ed. 2004, 43, 5510. (e) Dzwiniel, T. L.;
Stryker, J. M. J. Am. Chem. Soc. 2004, 126, 9184. (f) Hanna, I.; Ricard, L.
Org. Lett. 2000, 2, 2651. (g) Yet, L. Chem. Rev. 2000, 100, 2963.
(14) For a recent recompilation on silylcuprates, see: Pulido, F. J.
Barbero, A. Silyl and Stannyl Derivatives of Organocopper Compounds.
In The Chemistry of Organocopper Compounds. Patai Series: The Chemistry
of Functional Groups; Rappoport, Z., Marek, I., Eds; Wiley: Chichester,
UK, 2009; Part 2, pp 775ꢀ857.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: pulido@qo.uva.es.
(15) Lorenz, J.; Long, J.; Yang, Z.; Xue, S.; Xie, Y.; Shi, Y. J. Org.
Chem. 2004, 69, 327.
’ ACKNOWLEDGMENT
(16) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Linares, P. Tetrahedron
1994, 50, 13239.
(17) Wright, A. D.; Goclik, E.; K€onig., G M. J. Nat. Prod. 2003,
66, 435.
We thank the Ministry of Science and Tecnology of Spain
(CTQ2009-09302) and the “Junta de Castilla y Leꢀon” (VA074A08
and GIE-2009/GR170) for financial support.
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