Conversion of cycloalk-2-enones into 2-methylcycloalkane-1,3-diones - Assessment of various Tamao-Fleming procedures and mechanistic insight into the use of the Me3SiMe2Si unit

Article abstract of DOI:10.1039/c5ob02402a

Conjugate addition of Me₃SiMe₂SiLi to cycloalk-2-en-1-ones, ketalization, Tamao-Fleming oxidation (Bu₄NF, then H₂O₂, KHCO₃), TPAP oxidation and acid hydrolysis generates 2-methyl cycloalkane-1,3-diones. Ketalization is needed in order to prevent addition of Me₃Si^- to the carbonyl. The pentamethyldisilanyl group has advantages over other silicon units that are used in Tamao-Fleming procedures.

Full text of DOI:10.1039/c5ob02402a

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Conversion of cycloalk-2-enones into
2-methylcycloalkane-1,3-diones—assessment
of various Tamao-Fleming procedures and
mechanistic insight into the use of the
Me3SiMe2Si unit†
Cite this: DOI: 10.1039/c5ob02402a
Guojun Yu and Derrick L. J. Clive*
Received 22nd November 2015,
Accepted 15th December 2015
Conjugate addition of Me3SiMe2SiLi to cycloalk-2-en-1-ones, ketalization, Tamao–Fleming oxidation
(Bu4NF, then H2O2, KHCO3), TPAP oxidation and acid hydrolysis generates 2-methyl cycloalkane-1,3-
diones. Ketalization is needed in order to prevent addition of Me3Si− to the carbonyl. The pentamethyl-
disilanyl group has advantages over other silicon units that are used in Tamao–Fleming procedures.
DOI: 10.1039/c5ob02402a
www.rsc.org/obc
Introduction
Results and discussion
In connection with studies on a natural product synthesis we
planned to convert a cyclohex-2-en-1-one substructure into the
corresponding cyclohexane-1,3-dione carrying a methyl substi-
tuent at C(2). Our plan (Scheme 1) was to effect this transform-
ation by conjugate addition of a silicon unit (1 → 2), followed
by trapping of the intermediate enolate with MeI (2 → 3). The
C(3)–Si bond would then be converted into a C–OH bond by
Tamao–Fleming oxidation, and further oxidation of the result-
ing hydroxyl was expected to give the desired 1,3-dione
(3 → 4 → 5). In this way a cyclohex-2-en-1-one (or its parent
cyclohexanone) subunit would serve as a masked 2-methyl-
cyclohexane-1,3-dione that could be liberated at a late stage of
a synthesis when its reactivity would no longer interfere with
other transformations. This approach to compounds of type 4
and 5 is more direct than one based on formation of a
2-methylcyclohex-2-en-1-one substructure from a cyclohexa-
none,1 followed by epoxidation and reductive opening of the
epoxide.2 Conjugate additions of the type we contemplated,
together with trapping of the resulting enolate by electro-
philes, are known3 and there are many examples in which a
silicon–carbon bond is replaced by a carbon–oxygen bond.4
Simple though this scheme appears, it proved to require
considerable experimentation and could not be reduced to
practice without incorporating protection–deprotection steps.
We first added the PhMe2Si group to cyclohex-2-en-1-one and
trapped the intermediate enolate with MeI (Scheme 2, 6 → 7),
as reported in the literature,3c and we then applied several of
Scheme 1 Synthetic plan.
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
E-mail: derrick.clive@ualberta.ca; Fax: +1 (780) 492 8231; Tel: +1 (780) 492 3251
†Electronic supplementary information (ESI) available: NMR spectra of new
compounds. See DOI: 10.1039/c5ob02402a
Scheme 2 Conjugate addition and methylation of cyclohex-2-en-1-
one.
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the standard methods for Tamao–Fleming oxidation that had
been used successfully with compounds containing a ketone
group.
Treatment of 7 with HBF4·OEt2 and then with m-CPBA, con-
ditions that have been used with 8,5 failed to give 9. Likewise,
treatment with Hg(OAc)2/AcOH/CF3CO2H, followed by AcOOH/
AcOH, a reagent combination that worked for 10,5 were un-
successful. A simple variation—use of Hg(OCOCF3)2 in AcOH–
CF3CO2H, followed by addition of AcOOH, which gave an 85%
yield in the case of a compound containing a cyclohexenone
substructure6—again afforded PhOH as the only product we
isolated. When we used ICl in Et2O7 on 7, followed by m-CPBA,
we obtained 11 in 12% yield, but not the desired hydroxy
ketone 9; in this last reaction, substitution of AcOOH for
m-CPBA resulted in a complex mixture.
Scheme 4 Introduction of the Ph2(EtO)Si group.
The cuprate 1414 also seemed a promising candidate
because of the ease with which the aryl group on silicon can
be replaced to initiate the Tamao–Fleming sequence, but its
generation is technically difficult and we were unsuccessful in
the single attempt that we made.
We next prepared the allylic silane 16a (Scheme 5), which was
formed in 98% yield; the required cuprate is itself being easy15
to make from chlorosilane 15.
Ketone 7 appeared to be inert to BF3·2AcOH5,8,9 at room
temperature, apart from slow epimerization at C(2).
As attempts to carry out the Tamao–Fleming oxidation on
ketone 7 were unsuccessful, we accepted that protection of the
carbonyl was necessary. Formation of the ethylene ketal
(7 → 12) was achieved, but only in 25% yield; use of CSA, ethyl-
ene glycol and MeC(OMe)3 resulted in loss of the Ph group
from the silicon unit. A brief attempt to improve the yield by
use of catalytic p-TsNHOH10,11 was unsuccessful, leading only
to recovery of starting ketone 7.
Scheme 3 Ketalization of compound 12.
A sample of 12 was treated with Br2 in AcOH and then with
AcOOH/AcOH,5 but no identifiable material was isolated.
Scheme 5 Use of Fleming’s allylic silane. Reagents and conditions: for n = 1:
(a) 15, Li, THF, 0 °C, 12 h; CuCN, 0 °C, 2 h; cyclohexenone, −78 °C, 1.5 h; MeI,
−78 °C to room temperature, 12 h, 98%. (b) BF3·2AcOH, CH2Cl2, 0 °C, 30 min,
ca. 95%. (c) 30% H2O2, NaHCO3, KF, THF–MeOH (1 : 1), 3 days, 68%. (d) HC
(OMe)3, PPTS, MeOH, 40 min, 97%. (e) TPAP, NMO, 4 Å sieves, CH2Cl2,
40 min, 91%. (f) 1 M HCl–THF (1 : 10), 99%. For n = 2: (a) 15, Li, THF, 0 °C, 12 h;
CuCN, 0 °C, 2 h; cycloheptenone, −78 °C, 1.5 h; MeI, −78 °C, 12 h, 90%. (b)
BF3·AcOH, CH2Cl2, 0 °C, 10 min, 100%. (c) 30% H2O2, NaHCO3, KF, THF–
MeOH (1 : 1), 31 h, 64%. (d) HC(OMe)3, PPTS, MeOH, 16 h, 81%. (e) TPAP,
NMO, 4 Å sieves, CH2Cl2, 40 min, 98%. (f) 1 M HCl–THF (1 : 10), 30 min, 96%.
For n = 0: (a) 15, Li, THF, 0 °C, 12 h; CuCN, 0 °C, 3 h; cyclopentenone; −78 °C,
4 h; MeI, −78 °C, 12 h, 98%. (b) BF3·2AcOH, CH2Cl2, 0 °C, 30 min, 97%. (c) 30%
H2O2, NaHCO3, KF, THF–MeOH (1 : 1), 1.5 days, 36%. a trans : cis 11.5 : 1.
b trans : cis 20 : 1. c Single trans isomer. d trans : cis 7 : 3. e trans : cis 5 : 1.
Examination of different monosilicon units
At this point we decided to examine silicon groups other than
PhMe2Si in the hope that at least one of the steps of the
Tamao–Fleming oxidation would be facilitated.
Cyclohex-2-en-1-one was therefore converted into 13 (67%
yield) by conjugate addition and alkylation.12 Treatment with
13
m-CPBA and KHF2 again gave PhOH as the only isolated
product (Scheme 4).
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Treatment of 16a with BF3·2AcOH gave 17a in ca. 95% yield. Use of the pentamethyldisilanyl group
The compound partially decomposes on silica gel, but the
During the course of our experimental work it became
desirable to impose the additional requirement that the
intermediate silane be of such a nature that a number of
further reactions could be carried out before replacing the
silicon unit by an oxygen. Both a phenyl and an allyl
group on silicon rendered the compounds rather sensitive to
acidic conditions; however, the Me3SiSiMe2– unit seemed
ideal for conferring greater stability. This group has been used
on only a few occasions13,32,33 and so its merits have not yet
been firmly established, but we applied it (Scheme 6) to the
case of cyclohex-2-en-1-one for comparison with our earlier
route, and then to cyclopent-2-en-1-one and cyclohept-2-en-
1-one.
crude material is satisfactory for the next step. Alternatively,
treatment of 16a with HBF4.OEt2 in CH2Cl2 gave the same
product 17a in 62% yield as a 3.4 : 1 trans : cis mixture of
isomers. When the fluorosilane 17a was exposed to the action
of 30% H2O2 in the presence of NaHCO3 and KF in THF–
MeOH for 3 days at room temperature we obtained the desired
hydroxy ketones 18a in 68% yield as a 20 : 1 trans : cis mixture
of stereoisomers; a four-day period gave 64% yield.
Oxidation of 3-hydroxy-2-methycyclohexan-1-one (18a) to
2-methylcyclohexane-1,3-dione (21a)
We now sought to oxidize the β-hydroxy ketones 18a to the 1,3-
diketone 21a, and for these experiments it was convenient to
make a supply of the β-hydroxy ketone (as a 3 : 1 mixture of cis
and trans isomers) by a literature method.16,17 We examined
several oxidizing agents,18 but usually obtained complex
mixtures or only a small amount of the desired β-diketone 21a.
A common observation was the early appearance (tlc) of the
desired product and its subsequent disappearance, while
much starting hydroxy ketone remained.
In the light of the above findings, the β-hydroxy ketones 18a
were converted into the dimethoxy ketals 19a using HC(OMe)3
and PPTS. When TsOH was used as the catalyst the main
pathway was dehydration, but with PPTS at room
temperature only ketalization occurred and the yield was
high (97%). TPAP oxidation to 20a was also efficient and the
desired 2-methylcyclohexane-1,3-dione 21a was then liberated
almost quantitatively by hydrolysis with hydrochloric acid28
in THF.
The sequence 6a → 21a of Scheme 5 defined a route to
accomplish our aim of converting a cyclohex-2-en-1-one into a
2-methylcyclohexane-1,3-dione, and we next applied it to cyclo-
hept-2-en-1-one (6b), a ketone that was best made by Saegusa
oxidation29 from cycloheptanone.30
Conjugate addition of the Fleming allylic silyl cuprate
derived from 15 gave 16b (90% yield); no cis isomer was iso-
lated. Replacement of the allylic unit by fluorine was quanti-
tative and the second stage of the Tamao–Fleming oxidation
(17b → 18b) afforded the keto alcohol in 64% yield as the trans
isomer. Again, direct oxidation with TPAP generated some of
the desired 1,3-diketone but this disappeared while much
starting material remained. Accordingly, 18b was ketalized
(18b → 19b) and then TPAP oxidation worked well (19b → 20b,
98%). Finally, acid hydrolysis gave 21b31 (96%) which, accord-
Scheme 6 Conversion of cycloalkenones to 2-methylcycloalkane-1,3-
diones by use of the pentamethyldisilanyl group. Reagents and con-
ditions: for n = 1: (a) Me3SiSiMe3, HMPA, MeLi, 0 °C, 30 min; dilute with
THF at 0 °C over 30 min; cyclohexenone, −78 °C, 1 h; MeI, −78 °C to
room temperature, 5 h, 88%. (b) Ethylene glycol, TsOH, PhH, reflux,
Dean-Stark, 4.5 h, 91%. (c) Bu4NF, THF, 15 min; 30% H2O2, KHCO3,
MeOH, 23 h, 71%. (d) TPAP, NMO, 4 Å sieves, CH2Cl2, 20 min, 95%. (e) 1
M HCl : THF (1 : 10), 10 h, 58% (78%, corrected for recovered 25a). For
n = 2: (a) Me3SiSiMe3, HMPA, MeLi, 0 °C, 40 min; dilute with THF at 0 °C
over 40 min; cycloheptenone, −78 °C, 30 min; MeI, −78 °C, 20 min,
0 °C, 1 h, 85%. (b) Ethylene glycol, TsOH, PhH, reflux, Dean-Stark, 23 h,
83%. (c) Bu4NF, THF, 30 min; 30% H2O2, KHCO3, MeOH, 23 h, 69%. (d)
TPAP, NMO, 4 Å sieves, CH2Cl2, 25 min, 94%. (e) 1 M HCl : THF (1 : 10),
reflux, 17 h, 71% (82% corrected for recovered 25b). For n = 0: (a) Me3Si-
SiMe3, HMPA, MeLi, 0 °C, 30 min; dilute with THF at 0 °C over 40 min;
cyclopentenone, −78 °C, 1 h; MeI, −78 °C to 0 °C, 3 h, 94%. (b)
Ethylene glycol, TsOH, PhH, reflux, Dean-Stark, 6 h, 95%. (c) Bu4NF,
THF, 20 min; 30% H2O2, KHCO3, MeOH, 20 h, 70%. (d) TPAP, NMO, 4 Å
sieves, CH2Cl2, 30 min, 77%. (e) 1 M HCl : THF (1 : 10), 2.5 h, 71%.
a Compound 23a appeared (1H NMR) to be a 5 : 1 mixture of trans and cis
isomers.
1
ing to its H NMR spectrum, was in the diketo form and not
enolized.
We also applied the method of Scheme 5 to cyclopent-2-en-
1-one (6c). Formation of the conjugate addition product 16c
was very efficient (98%), as was replacement of the allylic unit
by fluorine (16c → 17c, 97%); however, the yield (36%) in the
oxidation step of the Tamao–Fleming process 17c → 18c was
too low to warrant studies on conversion to the 1,3-dione.
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An additional advantage of the Me3SiMe2Si group is that
Finally, in view of the difficulties we had met with cyclo-
formation of a cuprate is unnecessary, as the second silicon pent-2-en-1-one (see Scheme 5, 6c → 18c), we applied the
modifies the properties of the anion Me3SiMe2Si− in a way that pentamethyldisilane approach to this ketone; again all the
causes it to add 1,4 to cycloalk-2-en-1-ones.
steps worked smoothly (Scheme 6, 6c → 21c).
We generated Me3SiMe2SiLi in the manner reported in the
literature,33 although we found it was better to prolong to
30 min the initial period after addition of MeLi, and that the
subsequent dilution with THF should be done slowly32d (over
ca. 30 min). With this procedure, addition to cyclohexenone
(Scheme 6, 6a → 22a) was efficient (88% yield). Unlike the situ-
ation with PhMe2Si (cf. Scheme 3, 7 → 12) ketalization (22a →
23a) was easily achieved in the presence of TsOH, reflecting
the stability of the pentamethyldisanyl group to acid. The
Tamao–Fleming steps provided the hydroxy ketal 24a (71%),
and oxidation (95%) took the route as far as 25a. The final acid
hydrolysis (78%) was best stopped before completion, at least
when using HCl–THF, which was the only reagent we
examined.
The above sequence was not the first we tried with the
pentamethyldisilane reagent. Initially, we did not protect the
ketone and we found that in the Tamao–Fleming step three
byproducts were formed that revealed details of the mechan-
ism and established the need for ketone protection
(Scheme 7). While we did not deduce the structure of one of
these byproducts the other two were clearly 28 and 29 (of un-
determined stereochemistry), and we interpret their formation
as resulting from attack of the Me3Si− anion34 on the ketone
carbonyl (26 → 27), followed by Brook rearrangement to 28.
On the basis of this proposal we obviously had to protect
the ketone carbonyl before the Tamao–Fleming sequence. We
did examine the possibility of using acetone as a sacrificial
trap for Me3Si−, but this modification did not alter the
outcome.
Conclusions
Conversion of cycloalk-2-en-1-ones into 2-methylcycloalkane-
1,3-diones, using conjugate addition of a silicon group,
enolate trapping with MeI and Tamao–Fleming oxidation is
most reliably achieved if the intermediate β-silyl ketone is con-
verted into a ketal before applying the Tamao–Fleming con-
ditions. The presence of a silicon unit carrying a phenyl (as in
7, Scheme 3) or allyl substituent (as in 16a,b,c, Scheme 5)
renders the compounds sensitive to acids and this restricts the
types of transformations that can be carried out. The efficiency
of the Tamao–Fleming oxidation steps with the allylsilane are
comparable to the corresponding steps in the pentamethyl-
disilanyl series but the far greater stability of the Me3SiMe2Si
unit is a significant advantage, and this silicon unit deserves
to be more widely used, especially where other structural
features of the substrate are immune to attack by Me3Si−.
Experimental
Solvents used for chromatography were distilled before use.
Commercial thin layer chromatography plates (silica gel,
Merck 60F-254) were used. Silica gel for flash chromatography
was Merck type 60 (230–400 mesh). Dry solvents were prepared
under an inert atmosphere and transferred by syringe or
cannula. The symbols s, d, t and q used for 13C NMR spectra
indicate zero, one, two, or three attached hydrogens, respecti-
vely, the assignments being made from APT spectra. Solutions
were evaporated under water pump vacuum and the residue
was then kept under oil pump vacuum. High resolution
electrospray mass spectrometric analyses were done with an
orthogonal time of flight analyzer and electron ionization
mass spectra were measured with a double-focusing sector
mass spectrometer.
6-Iodo-7-methyloxepan-2-one (11)
ICl (0.43 mL, 0.43 mmol) was added to a stirred solution of 7
(50 mg, 0.21 mmol) in Et2O (1.0 mL) (Ar atmosphere). After
3 h, the reaction mixture was cooled to 0 °C and m-CPBA
(149 mg, 0.82 mmol, purified from wet commercial material)
was added, followed by a solution of Et3N (34 µL, 0.25 mmol)
in Et2O (1 mL). The ice bath was left in place, but not
recharged, and stirring was continued overnight. The mixture
was quenched with saturated aqueous Na2S2O3 (ca. 5 mL) and
saturated aqueous NaHCO3 (ca. 5 mL) and then extracted with
Et2O (2 × 20 mL). The combined organic extracts were washed
with brine, dried (MgSO4) and evaporated. Flash chromato-
graphy of the residue over silica gel (1.8 × 15 cm), using a
5–10% EtOAc–hexanes gradient, gave 11 (6 mg, 12%) as an oil:
Scheme 7 Byproducts from reaction of fluoride with 23a. Reagent: (a)
Bu4NF, THF.
We next applied the procedure to the case of cyclohept-2-
en-1-one (Scheme 6, 6b) and found that each of the steps
(6b → 21b) proceeded without incident.
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FTIR (CDCl3, cast) 2958, 1736, 1443, 1239, 1043 cm−1; 1H NMR room temperature for 24 h. The mixture was then diluted with
(500 MHz, CDCl3) δ 1.62–1.72 (m, 1 H), 1.82–1.93 (m, 1 H), Et2O (150 mL), washed with water (100 mL), and the organic
1.96 (d, J = 7.0 Hz, 3 H), 1.93–2.01 (m, 1 H), 2.22–2.29 (m, 1 H), extract was dried (MgSO4) and evaporated. Flash chromato-
2.42–2.51 (m, 1 H), 2.57–2.66 (m, 1 H), 3.93–4.01 (m, 1 H), graphy of the residue over silica gel (2.8 × 18 cm), using a
4.22–4.30 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 18.2 (t), 23.9 5–20% EtOAc–hexanes gradient, gave the trans isomer 13
(q), 27.1 (t), 29.2 (d), 29.4 (t), 84.3 (d), 170.4 (s); exact mass (906 mg, 67%) as a thick oil: FTIR (CDCl3, cast) 3069, 2972,
(ESI) m/z calcd for C7H11INaO2 (M + Na)+ 276.9696, found 1709, 1445 cm−1
;
1H NMR (500 MHz, CDCl3) δ 1.06 (d,
276.9692. Additional small signals in the 13C NMR spectrum J = 6.5 Hz, 3 H), 1.13 (t, J = 7.0 Hz, 3 H), 1.52–1.68 (m, 2 H),
suggested the presence of a second stereoisomer.
1.68–1.80 (m, 1 H), 1.99 (br d, J = 16.0 Hz, 1 H), 2.06–2.15 (m,
1 H), 2.15–2.30 (m, 2 H), 2.38 (br d, J = 13.5 Hz, 1 H), 3.60–3.70
(m, 2 H), 7.38–7.50 (m, 6 H), 7.60–7.69 (m, 4 H); 13C NMR
(125 MHz, CDCl3) δ 15.2 (q), 18.2 (q), 26.6 (t), 30.0 (t), 33.3 (d),
42.0 (t), 45.7 (d), 59.4 (t), 127.9 (d), 128.0 (d), 130.0 (d), 130.1
(d), 133.3 (s), 133.5 (s), 135.1 (d), 135.2 (d), 214.3 (s); exact
mass (ESI) m/z calcd for C21H26NaO2Si (M + Na)+ 338.1702,
found 338.1707.
Dimethyl[trans-6-methyl-1,4-dioxaspiro[4,5]decan-7-yl]-
phenylsilane (12)
(Me3SiOCH2)2 (340 mg, 1.65 mmol) in CH2Cl2 (2 mL) and
CF3SO2OSiMe3 (8.0 μL, 0.045 mmol) were added sequentially
to a stirred and cooled (−78 °C) solution of 7 in CH2Cl2 (3 mL)
(Ar atmosphere). Stirring was continued for 4 h and the reac-
tion mixture was quenched with saturated aqueous NaHCO3
(ca. 15 mL) and extracted with Et2O (3 × 15 mL). The combined
organic extracts were dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (1.8 × 15 cm),
using 3% EtOAc–hexanes, gave 12 (33 mg, 25%) as an oil: FTIR
trans-2-Methyl-3-{[(2Z)-2-methylbut-2-en-1-yl]diphenylsilyl}-
cyclohexan-1-one (16a)
A solution of the allyl silyl cuprate reagent was prepared
as follows: lithium wire (65.5 mg, 9.5 mmol) was cut into
strips (ca. 1 cm), washed with dry hexane, blotted and
weighed. The strips were quickly cut into pieces (1–2 mm) and
transferred into a cooled (0 °C) round-bottomed flask contain-
ing chloro[(2Z)-2-methylbut-2-en-1-yl]diphenylsilane (15)15
(717.5 mg, 2.5 mmol) in THF (5 mL) (Ar atmosphere). The reac-
tion mixture was stirred overnight to produce a deep dark
green solution.
Dry CuCN (kept for 12 h under oilpump vacuum, 112 mg,
1.25 mmol) was added to another flask containing THF (1 mL)
and the mixture was stirred and cooled (0 °C) (Ar atmosphere).
The silyllithium solution was taken up into a syringe and
added dropwise over ca. 5 min to the stirred CuCN mixture.
1
(CDCl3, cast) 3068, 2975, 2879, 1878 cm−1; H NMR (500 MHz,
CDCl3) δ 0.28 (s, 3 H), 0.31 (s, 3 H), 0.81 (d, J = 6.5 Hz, 3 H),
1.05–1.18 (m, 2 H), 1.31 (td, J = 13.5, 4.0 Hz, 1 H), 1.43–1.53
(m, 1 H), 1.56–1.63 (m, 1 H), 1.63–1.72 (m, 2 H), 1.75–1.82 (m,
1 H), 3.84–4.00 (m, 4 H), 7.30–7.36 (m, 3 H), 7.46–7.52 (m,
2 H); 13C NMR (125 MHz, CDCl3) δ −3.0 (q), −2.9 (q), 14.3 (q),
25.5 (t), 27.7 (t), 29.6 (d), 35.3 (t), 41.7 (d), 65.0 (t), 65.1 (t),
110.8 (s), 127.6 (d), 128.6 (d), 133.8 (d), 139.7 (s); exact mass
(EI) calcd for C17H26O2Si (M)+ 290.1702, found 290.1705.
trans-3-(Ethoxydiphenylsilyl)-2-methylcyclohexan-1-one (13)
A solution of the dimethylaminodiphenylsilyl cuprate reagent After the addition, stirring was continued at 0 °C for 2 h to
was prepared as follows: lithium wire (113 mg, 16.4 mmol) was generate the cuprate reagent.
cut into strips (ca. 1 cm long), washed with dry hexane, blotted
The solution of the cuprate reagent was cooled to −78 °C,
and weighed. The strips were quickly cut into small pieces and cyclohex-2-en-1-one (0.10 mL, 1.0 mmol) was added drop-
(1–2 mm) and transferred to a round-bottomed flask contain- wise (Ar atmosphere). Stirring was continued for 1.5 h at
ing Me2NPh2SiCl (2.16 mL, 8 mmol) in THF (16 mL) (Ar atmos- −78 °C. MeI (0.62 mL, 10 mmol) was then added, the cold
phere). The mixture was stirred vigorously for 5 min and then bath was left in place, but not recharged, and stirring was con-
at 0 °C for 4 h to generate a dark green solution.
tinued overnight, by which time the mixture had reached
Dry CuCN (kept for 12 h under oilpump vacuum, 358 mg, room temperature. The mixture was then quenched with satu-
4.0 mmol) was added to another flask containing THF (4 mL) rated aqueous NH4Cl (ca. 15 mL) and stirring was continued
and HMPA (6 mL) and the mixture was stirred and cooled for 15 min. The mixture was then extracted with Et2O (3 ×
(0 °C) (Ar atmosphere). The silyllithium solution was taken up 30 mL) and the combined organic extracts were washed with
into a syringe and added dropwise over ca. 5 min to the stirred brine, dried (MgSO4) and evaporated. Flash chromatography of
CuCN mixture. After the addition, stirring was continued at the residue over silica gel (2.3 × 18 cm), using 10% EtOAc–
0 °C for 0.5 h and then at −78 °C for 4.5 h to generate the hexanes, gave the trans isomer 16a (355 mg, 98%) as an oil:
cuprate reagent.
FTIR (CDCl3, cast) 3069, 2933, 1709, 1108 cm−1 1H NMR
;
Cyclohex-2-en-1-one (0.43 mL, 4 mmol) in THF (5.0 mL) (500 MHz, CDCl3) δ 0.96 (d, J = 7.0 Hz, 3 H), 1.08 (d, J = 6.5 Hz,
was added dropwise to the cooled (−78 °C) cuprate solution 3 H), 1.47 (s, 3 H), 1.70–1.60 (m, 2 H), 1.82–1.70 (m, 1 H), 2.12
and stirring was continued for 1.5 h. MeI (2.5 mL, 40 mmol) (d, J = 4.0 Hz, 2 H), 2.25–2.00 (m, 4 H), 2.39 (br d, J = 13.0 Hz,
was added and stirring at −78 °C was continued overnight 1 H), 4.94 (q, J = 6.5 Hz, 1 H), 7.45–7.32 (m, 6 H), 7.62–7.54 (m,
(large silvered Dewar filled with dry ice/acetone). The mixture 4 H); 13C NMR (125 MHz, CDCl3) δ 13.5 (q), 15.7 (q), 19.4 (t),
was then quenched with a slurry of saturated aqueous NH4Cl 26.5 (q), 27.5 (t), 30.1 (t), 33.0 (d), 41.9 (t), 46.7 (d), 118.6 (d),
(2.14 g, 40 mmol) in absolute ethanol (10 mL) and stirred at 127.6 (d), 127.8 (d), 129.4 (d), 129.5 (d), 132.0 (s), 133.9 (s),
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134.3 (s), 135.50 (d), 135.52 (d), 214.1 (s); exact mass (ESI) CDCl3) δ 0.93 (d, J = 7.0 Hz, 3 H), 1.28–1.39 (m, 1 H), 1.39–1.52
calcd for C24H30NaOSi (M + Na)+ 385.1958, found 385.1961.
(m, 2 H), 1.52–1.65 (m, 3 H), 1.65–1.72 (m, 1 H), 2.22 (dq, J =
10.5, 6.0 Hz, 1 H), 3.16 (s, 3 H), 3.18 (s, 3 H), 3.94 (ddd, J =
10.5, 9.5, 4.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 7.8 (q),
18.9 (t), 26.3 (t), 28.8 (t), 40.4 (d), 47.2 (q), 47.7 (q), 70.3 (d),
103.3 (s); exact mass (EI) calcd for C9H18O3 (M)+ 174.1256,
found 174.1257.
trans-3-(Fluorodiphenylsilyl)-2-methylcyclohexan-1-one (17a)
BF3·2AcOH (0.51 mL, 1.98 mmol) was added to a stirred and
cooled (0 °C) solution of 16a (240 mg, 0.66 mmol) in CH2Cl2
(12 mL) (Ar atmosphere). Stirring was continued for 30 min,
and the reaction mixture was quenched with saturated
aqueous NaHCO3 (ca. 20 mL) and extracted with CH2Cl2 (3 ×
30 mL). The combined organic extracts were dried (MgSO4)
and evaporated to give the trans isomer 17a (196 mg, 95%) as
3,3-Dimethoxy-2-methylcyclohexan-1-one (20a)
N-Methylmorpholine N-oxide (129 mg, 1.11 mmol), powdered
4 Å molecular sieves (369 mg) and Pr4NRuO4 (26 mg,
0.074 mmol) were added sequentially to a stirred solution of
19a (128 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) (Ar atmosphere).
After 40 min, the reaction mixture was filtered through a short
pad of silica gel and the filtrate was evaporated to give 20a
(115 mg, 91%) as an oil: FTIR (CDCl3, cast) 2957, 2832, 1716,
an oil: FTIR (CDCl3, cast) 3071, 2935, 1709, 1160 cm−1 1H
;
NMR (500 MHz, CDCl3) δ 1.06 (d, J = 6.5 Hz, 3 H), 1.62–1.82
(m, 3 H), 1.88–1.89 (m, 1 H), 2.10–2.20 (m, 1 H), 2.24–2.34 (m,
1 H), 2.37–2.48 (m, 2 H), 7.34–7.54 (m, 6 H), 7.60–7.74 (m,
4 H); 13C NMR (125 MHz, CDCl3) δ 14.99 (q), 15.01 (q), 26.41
(t), 26.43 (t), 29.9 (t), 33.8 (d), 33.9 (d), 41.9 (t), 45.2 (d), 128.3
(d), 130.85 (d), 130.88 (d), 131.9 (s), 132.0 (s), 132.2 (s), 132.3
(s), 134.3 (d), 134.36 (d), 134.39 (d), 134.4 (d), 213.0 (s); exact
mass (EI) calcd for C19H21OFSi (M)+ 312.1346, found 312.1344.
1175 cm−1 1H NMR (500 MHz, CDCl3) δ 1.14 (d, J = 7.5 Hz,
;
3 H), 1.56–1.67 (m, 1 H), 1.76–1.86 (m, 2 H), 1.93–2.01 (m,
1 H), 2.18–2.26 (m, 1 H), 2.46 (ddd, J = 15.0, 13.0, 7.0 Hz, 1 H),
2.75 (qt, J = 7.5, 1.5 Hz, 1 H), 3.16 (s, 3 H), 3.17 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 13.4 (q), 19.2 (t), 26.0 (t), 36.1 (t),
47.5 (q), 47.8 (q), 51.8 (d), 103.6 (s), 211.9 (s); exact mass (EI)
calcd for C9H16O3 (M)+ 172.1099, found 172.1096.
3-Hydroxy-2-methylcyclohexan-1-one (18a)35 from (17a)
KF (53 mg, 0.90 mmol), NaHCO3 (214 mg, 2.55 mmol) and
H2O2 (30 wt% in water, 0.25 mL, 2.40 mmol) were added
sequentially to a stirred solution of 17a (94 mg, 0.30 mmol) in
THF (2 mL) and MeOH (2 mL) (Ar atmosphere). Stirring was
continued for 72 h. Without aqueous workup, silica gel
(ca. 1 g) was added to the reaction mixture and the solvent was
evaporated in vacuo at room temperature (rotary evaporator,
water pump). The residue was added to the top a column of
flash chromatography silica gel (1.3 × 15 cm) made up with
hexanes. Flash chromatography, using a 10–30% acetone-
hexanes gradient, gave 18a (26 mg, 68%) as an oil which was a
20 : 1 mixture of trans and cis isomers. The material had: FTIR
3-Hydroxy-2-methylcyclohex-2-en-1-one (21a)17 from (20a)
A solution of 20a (115 mg, 0.67 mmol) in a 1 : 10 mixture
(3.5 mL) of hydrochloric acid (1 M) and THF was stirred for
3.5 h. Evaporation of the solvent gave 21a (84 mg, 99%) as a
solid: 1H NMR (500 MHz, DMSO-d6) δ 1.53 (s, 3 H), 1.80
(quintet, J = 6.5 Hz, 2 H), 2.28 (br s, 4 H), 10.3 (br s, 1 H); 13C
NMR (125 MHz, DMSO-d6) δ 7.2, 20.5, 30.2 (br s), 109.5.
trans-2-Methyl-3-{[(2Z)-2-methylbut-2-en-1-yl]diphenylsilyl}-
cycloheptan-1-one (16b)
(CDCl3, cast) 3428, 2937, 2873, 1708, 1035 cm−1 1H NMR
;
A solution of the allyl silyl cuprate reagent was prepared as
follows: lithium wire (196.6 mg, 28.5 mmol) was cut into strips
(ca. 1 cm), washed with dry hexane, blotted and weighed. The
strips were quickly cut into pieces (1–2 mm) and transferred to
a cooled (0 °C) round-bottomed flask containing allyl silane 15
(2.15 g, 7.5 mmol) in THF (5 mL) (Ar atmosphere). The
mixture was stirred overnight to produce a dark green
solution.
(500 MHz, CDCl3) (signals of major isomer only) δ 1.17 (d, J =
6.5 Hz, 3 H), 1.48–1.60 (m, 1 H), 1.69–1.80 (m, 2 H), 1.96–2.06
(m, 1 H), 2.21–2.12 (m, 1 H), 2.23–2.33 (m, 1 H), 2.34–2.46 (m,
2 H), 3.44–3.54 (m, 1 H); 13C NMR (125 MHz, CDCl3) (signals
of major isomer only) δ 10.8 (q), 20.8 (t), 33.8 (t), 40.4 (t), 53.9
(d), 75.9 (d), 210.4 (s); exact mass (EI) calcd for C7H12O2 (M)+
128.0837, found 128.0837.
Dry CuCN (kept for 12 h under oilpump vacuum, 336 mg,
3.75 mmol) was added to another flask containing THF (1 mL)
3,3-Dimethoxy-2-methylcyclohexan-1-ol (19a)
Pyridinium p-toluenesulfonate (287 mg, 1.14 mmol) and and the mixture was stirred and cooled (0 °C) (Ar atmosphere).
CH(OMe)3 (0.84 mL, 7.6 mmol) were added sequentially to a The silyl lithium solution was taken up into a syringe and
stirred solution of 18a (97 mg, 0.76 mmol) in MeOH (4.5 mL) added dropwise over ca. 5 min to the stirred CuCN mixture.
(Ar atmosphere). After 40 min, the reaction mixture was After the addition, stirring was continued at 0 °C for 2 h to
quenched with saturated aqueous NaHCO3 (ca. 10 mL) and generate the cuprate reagent.
stirring was continued for 5 min. The mixture was extracted
The solution of the cuprate reagent was cooled to −78 °C,
with Et2O (3 × 20 mL) and the combined organic extracts were and cyclohept-2-en-1-one (347.4 mg, 3.0 mmol) was added
dried (MgSO4) and evaporated to afford 19a (128 mg, 97%) as dropwise (Ar atmosphere). Stirring was continued for 1.5 h at
an oil which was a 5 : 1 mixture of trans and cis isomers. A −78 °C, MeI (1.89 mL, 30 mmol) was then added and stirring
small sample of the trans isomer was separated; it had: FTIR at −78 °C was continued overnight (large silvered Dewar filled
1
(CDCl3, cast) 3421, 2951, 2829, 1067 cm−1; H NMR (500 MHz, with dry ice/acetone). The mixture was then quenched with
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saturated aqueous NH4Cl (ca. 25 mL) and stirring was contin- H), 1.42–1.54 (m, 1 H), 1.56 (d, J = 5.0 Hz, 1 H), 1.68–1.97 (m, 5
ued for 15 min. The mixture was extracted with Et2O (3 × H), 2.42–2.55 (m, 2 H), 2.66–2.74 (m, 1 H), 3.57–3.64 (m, 1 H);
75 mL) and the combined organic extracts were washed with 13C NMR (125 MHz, CDCl3) δ 14.6 (q), 24.2 (t), 24.7 (t), 37.2 (t),
brine, dried (MgSO4) and evaporated. Flash chromatography of 42.6 (t), 54.3 (d), 73.7 (d), 214.2 (s); exact mass (EI) calcd for
the residue over silica gel (2.8 × 18 cm), using a 5–10% EtOAc– C8H14O2 (M)+ 142.0994, found 142.0995.
hexanes gradient, gave 16b (1.02 g, 90%) as an oil which was
trans-3,3-Dimethoxy-2-methylcycloheptan-1-ol (19b)
;
1445 cm−1 1H NMR (500 MHz, CDCl3) δ 0.90 (d, J = 7.0 Hz, Pyridinium p-toluenesulfonate (155 mg, 0.62 mmol) and
the trans-isomer: FTIR (CDCl3, cast) 3069, 2929, 2857, 1701,
3 H), 1.00–1.12 (m, 1 H), 1.19 (d, J = 6.5 Hz, 3 H), 1.26–1.34 (m, CH(OMe)3 (1.8 mL, 16.4 mmol) were added sequentially to a
1 H), 1.36–1.46 (m, 2 H), 1.52 (s, 3 H), 1.84–2.00 (m, 2 H), stirred solution of 18b (58 mg, 0.41 mmol) in MeOH (6 mL)
2.06–2.20 (m, 3 H), 2.22–2.30 (m, 1 H), 2.60 (dq, J = 10.5, (Ar atmosphere). After 16 h, the reaction mixture was
7.0 Hz, 1 H), 2.75 (td, J = 10.5, 3.0 Hz, 1 H), 5.01 (q, J = 6.5 Hz, quenched with Et3N (0.17 mL, 1.23 mmol) and stirring was
1 H), 7.30–7.42 (m, 6 H), 7.50–7.60 (m, 4 H); 13C NMR continued for 15 min. The solution was applied directly to the
(125 MHz, CDCl3) δ 13.7 (q), 18.7 (t), 19.2 (q), 26.2 (t), 26.6 (q), top of a column (1.3 × 18 cm) of flash chromatography silica
28.5 (d), 30.0 (t), 32.1 (t), 39.2 (t), 49.9 (d), 118.6 (d), 127.7 (d), gel made up with 3% Et3N in hexanes. Flash chromatography,
127.8 (d), 129.4 (d), 129.5 (d), 132.3 (s), 134.7 (s), 134.8 (s), using 10% acetone–hexanes, gave 19b (63 mg, 81%) as an oil
135.4 (d), 135.5 (d), 216.7 (s); exact mass (ESI) calcd for which was the trans isomer: FTIR (CDCl3, cast) 3526, 2942,
1
C25H32NaOSi (M + Na)+ 399.2115, found 399.2119.
2832, 1461, 1043 cm−1; H NMR (500 MHz, CDCl3) δ 0.93 (d,
J = 7.5 Hz, 3 H), 1.40–1.66 (m, 3 H), 1.70–1.90 (m, 5 H),
2.38–2.46 (m, 1 H), 3.16 (s, 3 H), 3.26 (s, 3 H), 3.69–3.74 (m, 1
H), 3.76 (d, J = 9.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 14.3
(q), 19.5 (t), 21.1 (t), 28.7 (t), 30.7 (t), 42.2 (d), 47.7 (q), 48.3 (q),
72.6 (d), 106.7 (s); exact mass (ESI) calcd for C10H20NaO3
(M + Na)+ 211.1305, found 211.1305.
trans-3-(Fluorodiphenylsilyl)-2-methylcycloheptan-1-one (17b)
BF3·2AcOH (0.13 mL, 0.91 mmol) was added to a stirred and
cooled (0 °C) solution of 16b (114 mg, 0.30 mmol) in CH2Cl2
(5 mL) (Ar atmosphere). After 10 min, the reaction mixture was
quenched with saturated aqueous NaHCO3 (ca. 10 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried (MgSO4) and evaporated to afford 17b
(99 mg, 100%) as an oil which was the trans-isomer: FTIR
3,3-Dimethoxy-2-methylcycloheptan-1-one (20b)
N-Methylmorpholine N-oxide (66 mg, 0.57 mmol), powdered
4 Å molecular sieves (113 mg) and Pr4NRuO4 (8.0 mg,
0.023 mmol) were added sequentially to a stirred solution of
19b (43 mg, 0.23 mmol) in CH2Cl2 (2 mL) (Ar atmosphere).
After 40 min, the solution was applied directly onto a column
of flash chromatography silica gel (1.3 × 8 cm) made up with
hexanes. Flash chromatography, using 10% acetone-hexanes,
gave 20b (41 mg, 98%) as an oil: FTIR (CDCl3, cast) 2947, 2831,
1
(CDCl3, cast) 3072, 2927, 1702, 1122 cm−1; H NMR (500 MHz,
CDCl3) δ 1.13 (dd, J = 7.0, 1.0 Hz, 3 H), 1.04–1.20 (m, 1 H),
1.30–1.52 (m, 3 H), 1.84–1.98 (m, 2 H), 2.03 (dd, J = 15.0, 5.5 Hz,
1 H), 2.28–2.38 (m, 1 H), 2.67 (dq, J = 11.0, 7.0 Hz, 1 H), 2.75
(td, J = 12.0, 2.5 Hz, 1 H), 7.38–7.46 (m, 4 H), 7.46–7.52 (m,
2 H), 7.60–7.66 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 18.57
(q), 18.59 (q), 26.0 (t), 28.11 (t), 28.13 (t), 29.0 (d), 29.1 (d), 31.6
(t), 39.4 (t), 48.6 (d), 128.25 (d), 128.27 (d), 130.87 (d), 130.90
(d), 131.4 (s), 131.5 (s), 132.4 (s), 132.5 (s), 134.43 (d), 134.44
(d), 134.5 (d), 216.2 (s); exact mass (ESI) calcd for
C20H23FNaOSi (M)+ 349.1394, found 349.1401.
1694, 1109 cm−1 1H NMR (500 MHz, CDCl3) δ 1.22 (d, J =
;
8.0 Hz, 3 H), 1.48–1.56 (m, 1 H), 1.67–1.89 (m, 4 H), 1.98–2.06
(m, 1 H), 2.54–2.64 (m, 2 H), 2.92–3.01 (m, 1 H), 3.14 (s, 3 H),
3.20 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 13.1 (q), 23.0 (t),
24.0 (t), 32.0 (t), 43.4 (t), 47.7 (q), 48.1 (q), 53.8 (d), 101.9 (s),
212.7 (s); exact mass (ESI) calcd for C10H18NaO3 (M + Na)+
209.1148, found 209.1146.
trans-3-Hydroxy-2-methylcycloheptan-1-one (18b)36
KF (51 mg, 0.87 mmol), NaHCO3 (208 mg, 2.48 mmol) and
H2O2 (30 wt% in water, 0.24 mL, 2.32 mmol) were added
2-Methylcycloheptan-1,3-dione (21b)31 from (20b)
sequentially to a stirred solution of 17b (95 mg, 0.29 mmol) in A 1 : 10 mixture (0.2 mL) of hydrochloric acid (1 M) and THF
a mixture of THF (2 mL) and MeOH (2 mL) (Ar atmosphere). was added to a stirred solution of 20b (41.5 mg, 0.22 mmol) in
Stirring was continued for 31 h. The reaction was quenched THF (2 mL). After 30 min, the solvent was evaporated to afford
1
with solid Na2S2O3 (2.30 g, 14.6 mmol) and stirring was contin- 21b (30 mg, 96%) as an oil: H NMR (500 MHz, CDCl3) δ 1.23
ued for a further 15 min. Without aqueous workup, silica gel (d, J = 7.0 Hz, 3 H), 1.84–1.94 (m, 2 H), 2.00–2.10 (m, 2 H),
(ca. 2 g) was added to the reaction mixture and the solvent was 2.46–2.55 (m, 2 H), 2.55–2.64 (m, 2 H), 3.73 (q, J = 7.0 Hz, 1 H);
evaporated in vacuo at room temperature (rotary evaporator, 13C NMR (125 MHz, CDCl3) δ 11.2 (q), 25.8 (t), 43.4 (t), 60.9 (d),
water pump). The residue was added to the top of a column of 208.0 (s).
flash chromatography silica gel (1.8 × 18 cm) made up with
trans-2-Methyl-3-{[(2Z)-2-methylbut-2-en-1-yl]diphenylsilyl}-
hexanes. Flash chromatography, using a 10–15% acetone–
cyclopentan-1-one (16c)
hexanes gradient, gave 18b (26.5 mg, 64%) as an oil which was
the trans isomer: FTIR (CDCl3, cast) 3431, 2934, 2863, 1695, A solution of the allyl silyl cuprate reagent was prepared as
1
1036 cm−1; H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 7.0 Hz, 3 follows: lithium wire (196.6 mg, 28.5 mmol) was cut into strips
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(ca. 1 cm), washed with dry hexane, blotted and weighed. The 3-Hydroxy-2-methylcyclopentan-1-one (18c)16
strips were quickly cut into small pieces (1–2 mm) and trans-
KF (191 mg, 3.30 mmol), NaHCO3 (785 g, 9.35 mmol) and
ferred into a cooled (0 °C) round-bottomed flask containing
the allyl silane 15 (2.15 g, 7.5 mmol) in THF (15 mL) (Ar atmos-
phere). The mixture was stirred overnight to produce a dark
green solution.
Dry CuCN (kept for 12 h under oilpump vacuum, 336 mg,
3.75 mmol) was added to another flask containing THF (5 mL)
and the mixture was stirred and cooled (0 °C) (Ar atmosphere).
The silyl lithium solution was taken up into a syringe and
added dropwise over ca. 5 min to the stirred CuCN mixture.
After the addition, stirring was continued at 0 °C for 3 h to
generate the cuprate reagent.
H2O2 (30 wt% in water, 0.90 mL, 8.80 mmol) were added
sequentially to a stirred solution of 17c (328 mg, 1.10 mmol)
in THF (5 mL) and MeOH (5 mL) (Ar atmosphere), and stirring
was continued for 39 h. Without aqueous workup, silica gel
(ca. 2 g) was added to the reaction mixture and the solvent was
evaporated in vacuo at room temperature (rotary evaporator,
water pump). The residue was added to the top of a column of
flash chromatography silica gel (1.8 × 18 cm) made up with
hexanes. Flash chromatography, using a 10–15% acetone–
hexanes gradient, gave 18c (44.8 mg, 36%) as an oil which was a
7 : 3 mixture of trans and cis isomers. The material had: FTIR
The solution of the cuprate reagent was cooled to −78 °C,
and cyclopent-2-en-1-one (383.5 mg, 3.38 mmol) was added
dropwise (Ar atmosphere). Stirring was continued for 4 h at
−78 °C, MeI (1.89 mL, 30 mmol) was then added and stirring
at −78 °C was continued overnight (large silvered Dewar filled
with dry ice/acetone). The mixture was then quenched with
saturated aqueous NH4Cl (ca. 20 mL) and stirring was contin-
ued for 15 min. The mixture was filtered through a short pad
of Celite, and then extracted with Et2O (3 × 75 mL). The com-
bined organic extracts were washed with brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over
silica gel (2.8 × 18 cm), using a 3–10% EtOAc–hexanes gradi-
ent, gave 16c (1.15 g, 98%) as an oil which was the trans
1
(CDCl3, cast) 3440, 2969, 2877, 1741 cm−1; H NMR (500 MHz,
CDCl3) δ 1.11 (d, J = 7.0 Hz, 0.9 H), 1.14 (d, J = 7.0 Hz, 2.1 H),
1.46 (d, J = 7.5 Hz, 0.3 H), 1.80 (d, J = 7.5 Hz, 0.7 H),
1.81–1.90 (m, 0.7 H), 2.00–2.45 (m, 3.6 H), 2.51 (qdd, J = 9.5, 3.5,
1.5 Hz, 0.7 H), 3.96–4.04 (m, 0.7 H), 4.50 (br s, 0.3 H); 13C NMR
(125 MHz, CDCl3) δ 7.8 (q), 11.8 (q), 29.8 (t), 30.0 (t), 33.9 (t), 36.1
(t), 50.0 (d), 52.5 (d), 72.7 (d), 76.6 (d), 217.5 (s), 218.7 (s); exact
mass (EI) calcd for C6H10O2 (M)+ 114.0681, found 114.0680.
trans-2-Methyl-3-(pentamethyldisilan-1-yl)cyclohexan-1-one
(22a)
MeLi (1.6 M in Et2O, 1.88 mL, 3.0 mmol) was added slowly to
a stirred and cooled (0 °C) solution of Me3SiSiMe3 (1.25 mL,
6.0 mmol) in HMPA (4.0 mL) (Ar atmosphere). After 30 min,
the reaction mixture was diluted in a dropwise manner with
THF (12.0 mL) over 30 min and the solution was then cooled
to −78 °C. Cyclohex-2-en-1-one (0.16 mL, 1.5 mmol) was added
dropwise over 30 min, and stirring was continued for 1 h. MeI
(1.02 mL, 15.0 mmol) in THF (3 mL) was then added slowly to
the reaction mixture, the cold bath was left in place, but not
recharged, and stirring was continued for 5 h during which
time the mixture reached room temperature. The mixture was
quenched with saturated aqueous NH4Cl (ca. 3 mL) and stirr-
ing was continued for 5 min. The mixture was then washed
with water (20 mL) and extracted with Et2O (3 × 30 mL). The
combined organic extracts were dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (2.8 ×
18 cm), using a 5–10% EtOAc–hexanes gradient, gave 22a
(321 mg, 88%) as an oil which was the trans-isomer: FTIR
isomer: FTIR (CDCl3, cast) 3069, 2965, 1737, 1427 cm−1 1H
;
NMR (500 MHz, CDCl3) δ 1.03 (d, J = 7.0 Hz, 3 H), 1.15 (d, J =
6.5 Hz, 3 H), 1.53 (s, 3 H), 1.59–1.74 (m, 2 H), 1.78–1.86 (m,
1 H), 2.04–2.28 (m, 5 H), 4.99 (q, J = 6.5 Hz, 1 H), 7.32–7.47 (m,
6 H), 7.54–7.62 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 13.6 (q),
15.3 (q), 18.2 (t), 23.0 (t), 26.5 (q), 29.8 (d), 37.6 (t), 46.2 (d),
118.4 (d), 127.7 (d), 127.9 (d), 129.65 (d), 129.71 (d), 131.8 (s),
133.3 (s), 133.7 (s), 135.6 (d), 222.0 (s); exact mass (ESI) calcd
for C23H28NaOSi (M + Na)+ 371.1802, found 371.1801.
3-(Fluorodiphenylsilyl)-2-methylcyclopentan-1-one (17c)
BF3·2AcOH (0.96 mL, 6.78 mmol) was added to a stirred and
cooled (0 °C) solution of 16c (0.79 g, 2.26 mmol) in CH2Cl2
(15 mL) (Ar atmosphere). After 30 min, the reaction mixture
was quenched with saturated aqueous NaHCO3 (ca. 30 mL)
and extracted with CH2Cl2 (3 × 30 mL). The combined organic
extracts were dried (MgSO4) and evaporated to afford 17c
(657 mg, 97%) as an oil which was an 11.5 : 1 mixture of trans
and cis isomers. The material had: FTIR (CDCl3, cast) 3071,
(CDCl3, cast) 2948, 2894, 1711 cm−1 1H NMR (500 MHz,
;
CDCl3) δ 0.06–0.18 (m, 15 H), 1.06 (d, J = 6.5 Hz, 3 H),
1.00–1.08 (m, 1 H), 1.57 (qd, J = 12.5, 4.0 Hz, 1 H), 1.73 (qt, J =
12.5, 4.0 Hz, 1 H), 1.82–1.90 (m, 1 H), 2.12–2.20 (m, 1 H),
2.27–2.39 (m, 2 H), 2.39–2.46 (dm, J = 13.0 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ −3.8 (q), −3.6 (q), −1.3 (q), 15.2 (q), 28.3
(t), 30.5 (t), 35.1 (d), 41.9 (t), 47.3 (d), 214.3 (s); exact mass (EI)
calcd for C11H23OSi2 (M − CH3)+ 227.1288, found 127.1285.
1
2966, 1739, 1122 cm−1; H NMR (500 MHz, CDCl3) (signals of
major isomer only) δ 1.07 (d, J = 7.0 Hz, 3 H), 1.66–1.90 (m,
2 H), 2.02–2.22 (m, 3 H), 2.32 (dd, J = 16.5, 9.0 Hz, 1 H),
7.36–7.55 (m, 6 H), 7.63–7.74 (m, 4 H); 13C NMR (125 MHz,
CDCl3) (signals of major isomer only) δ 14.80 (q), 14.81 (q),
22.0 (t), 22.1 (t), 30.6 (d), 30.7 (d), 37.61 (t), 37.62 (t), 45.0 (d),
128.28 (d), 128.32 (d), 131.01 (d), 131.02 (d), 131.03 (d), 131.04
(d), 131.4 (s), 131.5 (s), 131.7 (s), 131.9 (s), 134.30 (s), 134.32
1,1,1,2,2-Pentamethyl-2-[trans-6-methyl-1,4-dioxaspiro[4,5]-
decan-7-yl]disilane (23a)
(d), 134.4 (d), 134.5 (d), 220.94 (s), 220.95 (s); exact mass (ESI) Ethylene glycol (0.46 mL, 8.16 mmol) and TsOH (7.0 mg,
calcd for C18H19FNaOSi (M + Na)+ 321.1081, found 321.1079.
0.04 mmol) were added sequentially to a solution of 22a
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(99 mg, 0.41 mmol) in C6H6 (4 mL). The solution was refluxed 3-Hydroxy-2-methylcyclohex-2-en-1-one (21a)17 from (25a)
for 4.5 h, using a Dean-Stark apparatus. The solution was
A 1 : 10 mixture (0.3 mL) of hydrochloric acid (1 M) and THF
cooled, quenched with saturated aqueous NaHCO3 (ca. 20 mL)
was added to a stirred solution of 25a (51 mg, 0.30 mmol) in
and extracted with Et2O (3 × 30 mL). The combined organic
THF (3 mL) and stirring was continued for 10 h. Without
extracts were dried (MgSO4) and evaporated to afford 23a
aqueous workup, silica gel (ca. 1 g) was added to the reaction
(107 mg, 91%) as an oil which was a 5 : 1 mixture of trans and
mixture and the solvent was evaporated in vacuo at room temp-
erature (rotary evaporator, water pump). The residue was
cis isomers. The material had: FTIR (CDCl3, cast) 2943, 2882,
1245 cm−1 1H NMR (500 MHz, CDCl3) (signals of major
;
added to the top of a column of flash chromatography silica
gel (1.5 × 15 cm) made up with hexanes. Flash chromato-
graphy, using a 10–20% acetone–hexanes gradient, gave 21a
isomer only) δ 0.01–0.18 (m, 15 H), 0.87–0.94 (m, 3 H),
0.94–1.01 (m, 1 H), 1.07–1.20 (m, 1 H), 1.33 (td, J = 13.5,
4.0 Hz, 1 H), 1.44–1.55 (m, 1 H), 1.64–1.76 (m, 3 H), 1.81 (br d,
J = 13.0 Hz, 1 H), 3.87–4.03 (m, 4 H); 13C NMR (125 MHz,
CDCl3) (signals of major isomer only) δ −3.6 (q), −3.4 (q), −1.2
(q), 14.4 (q), 25.7 (t), 28.6 (t), 30.1 (d), 35.4 (t), 42.5 (d), 64.9 (t),
65.1 (t), 110.8 (s); exact mass (EI) calcd for C13H27O2Si2
(M − CH3)+ 271.1550, found 271.1550.
1
[22.2 mg, 58%, 78% corrected for recovered 25a (12.9 mg)]: H
NMR (500 MHz, DMSO-d6) δ 1.53 (s, 3 H), 1.80 (quintet, J =
6.5 Hz, 2 H), 2.28 (br s, 4 H), 10.3 (br s, 1 H); 13C NMR
(125 MHz, DMSO-d6) δ 7.2, 20.5, 30.2 (br s), 109.5.
trans-2-Methyl-3-(pentamethyldisilan-1-yl)cycloheptan-1-one
(22b)
6-Methyl-1,4-dioxaspiro[4,5]decan-7-ol (24a)37
MeLi (1.6 M in Et2O, 4.45 mL, 7.12 mmol) was added slowly to
a stirred and cooled (0 °C) solution of Me3SiSiMe3 (2.97 mL,
14.2 mmol) in dry HMPA (9.5 mL) (Ar atmosphere). After
40 min, the reaction mixture was diluted over 40 min in a
dropwise manner with THF (12.0 mL) and the solution was
cooled to −78 °C. Cyclohept-2-en-1-one (392 mg, 3.56 mmol)
was added slowly and stirring was continued for 30 min. MeI
(2.24 mL, 35.6 mmol) in THF (7 mL) was added slowly and,
after 20 min, the cooling bath was replaced with an ice bath
and stirring was continued for 1 h. The reaction mixture was
quenched with saturated aqueous NH4Cl (ca. 5 mL) and stir-
ring was continued for 5 min. The mixture was diluted with
water (40 mL) and extracted with Et2O (3 × 50 mL). The com-
bined organic extracts were dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (2.8 ×
18 cm), using a 1–5% EtOAc–hexanes gradient, gave 22b
(779 mg, 85%) as an oil which was the trans isomer: FTIR
Bu4NF (1.0 M in THF, 1.80 mL, 1.80 mmol) was added slowly
to a stirred solution of 23a (85.8 mg, 0.30 mmol) in THF
(5.0 mL) (Ar atmosphere) and stirring was continued for
15 min. MeOH (5.0 mL), H2O2 (30 wt% in water, 0.73 mL,
7.18 mmol) and KHCO3 (119.7 mg, 1.20 mmol) were added
sequentially and stirring was continued for 23 h. Without
aqueous workup, silica gel (ca. 2 g) was added to the reaction
mixture and the solvent was evaporated in vacuo at room temp-
erature (rotary evaporator, water pump). The residue was
added to the top a column of flash chromatography silica gel
(1.8 × 18 cm) made up with hexanes. Flash chromatography,
using a 3–10% acetone–hexanes gradient, gave 24a (37 mg,
71%) as an oil which was the trans isomer containing a trace
of the cis isomer: FTIR (CDCl3, cast) 3415, 2940, 2883,
1040 cm−1 1H NMR (500 MHz, CDCl3) δ 1.01 (d, J = 7.0 Hz,
;
3 H), 1.34–1.45 (m, 2 H), 1.45–1.56 (m, 1 H), 1.67–1.81 (m,
3 H), 1.81–1.88 (m, 1 H), 2.33 (br s, 1 H), 3.53–3.61 (m, 1 H),
3.88–4.00 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 11.1 (q), 19.2
(t), 31.9 (t), 32.8 (t), 45.8 (d), 64.6 (t), 64.8 (t), 73.6 (d), 111.0 (s);
exact mass (EI) calcd for C9H16O3 (M)+ 172.1099, found
172.1100.
(CDCl3, cast) 2948, 2852, 1703 cm−1 1H NMR (500 MHz,
;
CDCl3) δ 0.02–0.16 (m, 15 H), 0.69 (t, J = 10.0 Hz, 1 H), 0.96–1.07
(m, 1 H), 1.11 (d, J = 7.0 Hz, 3 H), 1.23–1.35 (m, 1 H), 1.44 (qt,
J = 13.0, 3.0 Hz, 1 H), 1.76–1.98 (m, 3 H), 2.22–2.32 (m, 1 H),
2.46 (dq, J = 10.5, 7.0 Hz, 1 H), 2.69 (td, J = 12.0, 3.0 Hz, 1 H);
13C NMR (125 MHz, CDCl3) δ −4.5 (q), −3.2 (q), −1.4 (q),
19.1 (q), 26.1 (t), 29.6 (d), 30.1 (t), 32.1 (t), 39.2 (t), 50.2 (d), 216.9
(s); exact mass (EI) calcd for C12H25OSi2 (M − CH3)+ 241.1444,
found 241.1444.
6-Methyl-1,4-dioxaspiro[4,5]decan-7-one (25a)38
N-Methylmorpholine N-oxide (96.7 mg, 0.83 mmol), powdered
4 Å molecular sieves (275 mg) and Pr4NRuO4 (19.3 mg,
0.055 mmol) were added sequentially to a stirred solution of
24a (94.8 mg, 0.55 mmol) in CH2Cl2 (8 mL) (Ar atmosphere).
After 20 min, the solution was applied directly to a column of
1,1,1,2,2-Pentamethyl-2-[trans-6-methyl-1,4-dioxaspiro[4,6]-
undecan-7-yl]disilane (23b)
flash chromatography silica gel (1.3 × 8 cm) made up with Ethylene glycol (0.70 mL, 12.3 mmol) and TsOH (10.6 mg,
hexanes. Flash chromatography, using 10% acetone–hexanes, 0.062 mmol) were added sequentially to a solution of 22b
gave 25a (89.3 mg, 95%) as an oil: FTIR (CDCl3, cast) 2948, (158 mg, 0.616 mmol) in C6H6 (6 mL) and the mixture was
2884, 1716 cm−1 1H NMR (500 MHz, CDCl3) δ 1.05 (d, J = refluxed for 23 h, using a Dean-Stark apparatus. The solution
;
6.5 Hz, 3 H), 1.68–1.91 (m, 3 H), 1.99–2.02 (m, 1 H), 2.22–2.32 was cooled, quenched with saturated aqueous NaHCO3
(m, 1 H), 2.40–2.48 (m, 1 H), 2.73 (q, J = 7.0 Hz, 1 H), 3.88–4.03 (ca. 10 mL) and water (20 mL), and extracted with Et2O (3 ×
(m, 4 H); 13C NMR (125 MHz, CDCl3) δ 7.5 (q), 20.0 (t), 34.0 (t), 30 mL). The combined organic extracts were dried (MgSO4)
39.9 (t), 54.4 (d), 65.3 (t), 65.6 (t), 111.9 (s), 209.3 (s); exact and evaporated. Flash chromatography of the residue over
mass (EI) calcd for C9H14O3 (M)+ 170.0943, found 170.0941.
silica gel (1.8 × 15 cm), using a 1–5% EtOAc–hexanes gradient,
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gave 23b (154 mg, 83%) as an oil which was the trans isomer: added to the top of a column of flash chromatography silica
1
FTIR (CDCl3, cast) 2945, 2683, 1244 cm−1; H NMR (500 MHz, gel (1.5 × 10 cm) made up with hexanes. Flash chromato-
CDCl3) δ −0.10–0.20 (m, 15 H), 0.52–0.64 (m, 1 H), 1.01 (d, J = graphy, using a 5–10% acetone–hexanes gradient, gave 21b
7.0 Hz, 3 H), 1.08–1.20 (m, 1 H), 1.42–1.58 (m, 2 H), 1.58–1.68 [22 mg, 71% or 82% corrected for recovered 25b (5.4 mg)] as
1
(m, 3 H), 1.80–1.92 (m, 3 H), 3.80–3.95 (m, 4 H); 13C NMR an oil: H NMR (500 MHz, CDCl3) δ 1.23 (d, J = 7.0 Hz, 3 H),
(125 MHz, CDCl3) δ −4.5 (q), −3.9 (q), −1.3 (q), 20.6 (q), 23.6 1.84–1.94 (m, 2 H), 2.00–2.10 (m, 2 H), 2.46–2.55 (m, 2 H),
(t), 28.9 (t), 31.8 (d), 32.6 (t), 33.3 (t), 42.4 (d), 63.5 (t), 64.4 (t), 2.55–2.64 (m, 2 H), 3.73 (q, J = 7.0 Hz, 1 H); 13C NMR
114.4 (s); exact mass (EI) calcd for C14H29O2Si2 (M − CH3)+ (125 MHz, CDCl3) δ 11.2 (q), 25.8 (t), 43.4 (t), 60.9 (d), 208.0 (s).
285.1706, found 285.1699.
trans-2-Methyl-3-(pentamethyldisilan-1-yl)cyclopentan-1-one
(22c)
trans-6-Methyl-1,4-dioxaspiro[4,6]undecan-7-ol (24b)
Bu4NF (1.0 M in THF, 2.56 mL, 2.56 mmol) was slowly added
MeLi (1.6 M in Et2O, 1.88 mL, 3.0 mmol) was added slowly to
to a stirred solution of 23b (133 mg, 0.44 mmol) in THF
a stirred and cooled (0 °C) solution of Me3SiSiMe3 (1.25 mL,
(4.0 mL) (Ar atmosphere) and stirring was continued for
6.0 mmol) in dry HMPA (4.0 mL) (Ar atmosphere). After
30 min. MeOH (4.0 mL), H2O2 (30 wt% in water, 1.08 mL,
30 min, the reaction mixture was diluted over 40 min in a
10.6 mmol) and KHCO3 (176 mg, 1.76 mmol) were added
dropwise manner with THF (12.0 mL) and the orange solution
sequentially and stirring was continued for 23 h. The reaction
was then cooled to −78 °C. Cyclopent-2-en-1-one (0.15 mL,
mixture was evaporated. Et2O (ca. 10 mL) and silica gel
1.5 mmol) was added dropwise over ca. 5 min and stirring was
(ca. 2 g) were added and the solvent was evaporated in vacuo at
continued for 1 h. MeI (1.02 mL, 15.0 mmol) in THF (3 mL)
room temperature (rotary evaporator, water pump). The
was added slowly, the cold bath was left in place, but not
residue was added to the top a column of flash chromato-
recharged, and stirring was continued for 3 h during which
graphy silica gel (1.5 × 15 cm) made up with hexanes. Flash
time the mixture reached room temperature. The mixture was
chromatography, using a 10–15% acetone–hexanes gradient,
quenched with saturated aqueous NH4Cl (ca. 3 mL) and stir-
gave 24b (56.8 mg, 69%) as an oil which was the trans isomer:
ring was continued for 5 min. The mixture was then diluted
FTIR (CDCl3, cast) 3434, 2933, 2692, 1458 cm−1 1H NMR
;
with water (30 mL) and extracted with Et2O (3 × 30 mL). The
combined organic extracts were dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (2.8 ×
18 cm), using 10% EtOAc–hexanes, gave 22c (322 mg, 94%) as
an oil which was the trans isomer: FTIR (CDCl3, cast) 2952,
(500 MHz, CDCl3) δ 1.04 (d, J = 7.0 Hz, 3 H), 1.44–1.57 (m,
2 H), 1.61–1.74 (m, 2 H), 1.74–1.94 (m, 4 H), 2.04–2.14 (m,
1 H), 3.03 (d, J = 7.0 Hz, 1 H), 3.64 (d, J = 6.0 Hz, 1 H),
3.84–4.04 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 14.1 (q), 20.8
(t), 22.0 (t), 33.3 (t), 33.4 (t), 47.6 (d), 64.1 (t), 64.6 (t), 76.8 (d),
113.8 (s); exact mass (EI) calcd for C10H18O3 (M)+ 186.1256,
found 186.1257.
2894, 1740 cm−1 1H NMR (500 MHz, CDCl3) δ 0.06–0.14 (m,
;
15 H), 1.00–1.10 (m, 1 H), 1.11 (d, J = 7.0 Hz, 3 H), 1.54–1.66
(m, 1 H), 1.91 (sextet, J = 6.5 Hz, 1 H), 1.99–2.08 (m, 1 H),
2.08–2.18 (m, 1 H), 2.33 (dd, J = 19.0, 8.5 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ −5.5 (q), −4.9 (q), −1.5 (q), 15.1 (q), 23.9
(t), 31.6 (d), 38.2 (t), 46.7 (d), 222.6 (s); exact mass (EI) calcd for
C11H24OSi2 (M)+ 228.1366, found 228.1365.
6-Methyl-1,4-dioxaspiro[4,6]undecan-7-one (25b)
N-Methylmorpholine N-oxide (44.4 mg, 0.38 mmol), powdered
4 Å molecular sieves (127 mg) and Pr4NRuO4 (8.9 mg,
0.025 mmol) were added sequentially to a stirred solution of
24b (47.2 mg, 0.253 mmol) in CH2Cl2 (5 mL) (Ar atmosphere).
After 25 min, the solution was applied directly to the top of a
column of flash chromatography silica gel (1.3 × 8 cm) made
1,1,1,2,2-Pentamethyl-2-[trans-6-methyl-1,4-dioxaspiro[4,4]-
nonan-7-yl]disilane (23c)
up with hexanes. Flash chromatography, using 10% acetone– Ethylene glycol (1.24 mL, 22.1 mmol) and TsOH (19 mg,
hexanes, gave 25b (44 mg, 94%) as an oil: FTIR (CDCl3, cast) 0.11 mmol) were added sequentially to a solution of 22c
1
2980, 2886, 1703 cm−1; H NMR (500 MHz, CDCl3) δ 1.14 (d, (253 mg, 1.11 mmol) in C6H6 (10 mL). The solution was
J = 7.0 Hz, 3 H), 1.60–1.86 (m, 5 H), 1.92–2.02 (m, 1 H), refluxed for 6 h, using a Dean-Stark apparatus. The solution
2.48–2.64 (m, 2 H), 2.96 (q, J = 7.0 Hz, 1 H), 3.86–4.02 (m, 4 H); was cooled, quenched with saturated aqueous NaHCO3
13C NMR (125 MHz, CDCl3) δ 11.6 (q), 23.9 (t), 24.0 (t), 37.6 (t), (ca. 20 mL) and water (ca. 10 mL) and extracted with Et2O (3 ×
43.1 (t), 55.6 (d), 64.7 (t), 65.1 (t), 109.4 (s), 212.4 (s); exact 30 mL). The combined organic extracts were dried (MgSO4)
mass (EI) calcd for C10H16O3 (M)+ 184.1099, found 184.1099.
and evaporated to afford 23c (285 mg, 95%) as an oil which
was the trans isomer: FTIR (CDCl3, cast) 2951, 2879,
2-Methylcycloheptane-1,3-dione (21b)31 from (25b)
1
1245 cm−1; H NMR (500 MHz, CDCl3) δ 0.02–0.12 (m, 15 H),
A 1 : 10 mixture (1.0 mL) of hydrochloric acid (1 M) and THF 0.86–1.00 (m, 1 H), 0.93 (d, J = 7.0 Hz, 3 H), 1.40–1.51 (m, 1 H),
was added to a stirred solution of 25b (40.7 mg, 0.22 mmol) in 1.68–1.81 (m, 3 H), 1.84–1.92 (m, 1 H), 3.82–3.98 (m, 4 H); 13C
THF (3 mL). The mixture was refluxed for 17 h and then NMR (125 MHz, CDCl3) δ −5.7 (q), −4.8 (q), −1.5 (q), 14.5 (q),
cooled to room temperature. Silica gel (ca. 1 g) was added to 24.4 (t), 30.4 (d), 36.2 (t), 43.5 (d), 64.6 (t), 64.8 (t), 119.2 (s);
the mixture and the solvent was evaporated in vacuo at room exact mass (EI) calcd for C12H25O2Si2 (M − CH3)+ 257.1393,
temperature (rotary evaporator, water pump). The residue was found 257.1393.
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trans-6-Methyl-1,4-dioxaspiro[4.4]nonan-7-ol (24c)37
experimental details on the preparation of 3-hydroxy-2-
methylcyclohexanone.
Bu4NF (1.0 M in THF, 1.10 mL, 1.10 mmol) was slowly added
to a stirred solution of 23c (50.1 mg, 0.184 mmol) in THF
(4.0 mL) (Ar atmosphere). After 20 min MeOH (4.0 mL), H2O2
(30 wt% in water, 0.45 mL, 4.42 mmol) and KHCO3 (74 mg, Notes and references
0.74 mmol) were added sequentially and stirring was contin-
1 Cf. (a) D. J. Burns, S. Hachisu, P. O’Brien and
ued for 20 h. Without aqueous workup, silica gel (ca. 1 g) was
added to the reaction mixture and the solvent was evaporated
in vacuo at room temperature (rotary evaporator, water pump).
The residue was added to the top a column of flash chromato-
graphy silica gel (1.3 × 15 cm) made up with hexanes. Flash
chromatography, using a 10–20% acetone–hexanes gradient,
gave 24c (20.6 mg, 70%) as an oil which was the trans isomer:
R. J. K. Taylor, Org. Biomol. Chem., 2012, 10, 7666–7668;
(b) G. Toribio, G. Marjanet, R. Alibés, P. de March, J. Font,
P. Bayón and M. Figueredo, Eur. J. Org. Chem., 2011, 1534–
1543.
2 Cf. (a) L. Engman and D. Stern, J. Org. Chem., 1994, 59,
5179–5183; (b) X.-L. Qi, J.-T. Zhang, J.-P. Feng and
X.-P. Cao, Org. Biomol. Chem., 2011, 9, 3817–3824.
3 Examples of conjugate addition of a silicon unit to a
cycloalk-2-en-1-one and trapping of the resulting enolate:
(a) W. C. Still, J. Org. Chem., 1976, 41, 3063–3064;
(b) D. J. Ager, I. Fleming and S. K. J. Patel, Chem. Soc.,
Perkin Trans. 1, 1981, 2520–2526; (c) W. Engel, I. Fleming
and R. H. Smithers, Chem. Soc., Perkin Trans. 1, 1986, 1637–
1641; (d) J. Clayden, K. R. Hebditch, B. Read and
M. Helliwell, Tetrahedron Lett., 2007, 48, 8550–8553;
(e) Z. Tang, B. Mathieu, B. Tinant, G. Dive and L. Ghosez,
Tetrahedron, 2007, 63, 8449–8462; (f) M. A. Hatcher,
K. Borstnik and G. H. Posner, Tetrahedron Lett., 2003, 44,
5407–5409; (g) P. Cuadrado, A. M. González, B. González
and F. J. Pulido, Synth. Commun., 1989, 19, 275–283;
(h) H. Nishiyama, K. Sakuta, N. Osaka, H. Arai,
M. Matsumoto and K. Itoh, Tetrahedron, 1988, 44, 2413–
2426.
1
FTIR (CDCl3, cast) 3425, 2968, 1457 cm−1; H NMR (500 MHz,
CDCl3) δ 0.97 (d, J = 7.0 Hz, 3 H), 1.56–1.66 (m, 1 H), 1.81
(ddd, J = 13.5, 10.0, 7.0 Hz, 1 H), 1.88–2.00 (m, 2 H), 2.02–2.15
(m, 2 H), 3.81 (br s, 1 H), 3.85–3.96 (m, 4 H); 13C NMR
(125 MHz, CDCl3) δ 11.5 (q), 30.9 (t), 31.1 (t), 49.0 (d), 64.4 (t),
64.8 (t), 77.5 (d), 116.8 (s); exact mass (EI) calcd for C8H14O3
(M)+ 158.0943, found 158.0943.
6-Methyl-1,4-dioxaspiro[4.4]nonan-7-one (25c)39
N-Methylmorpholine N-oxide (67.6 mg, 0.58 mmol), powdered
4 Å molecular sieves (193 mg) and Pr4NRuO4 (TPAP, 13.5 mg,
0.0385 mmol) were added sequentially to a stirred solution of
24c (60.9 mg, 0.385 mmol) in CH2Cl2 (6 mL) (Ar atmosphere).
After 30 min, the solution was applied directly to the top of a
column of flash chromatography silica gel (1.5 × 6 cm) made
up with hexanes. Flash chromatography, using 15% acetone–
hexanes, gave 25c (46.5 mg, 77%) as an oil: FTIR (CDCl3, cast)
1
4 Reviews on Tamao–Fleming oxidation: (a) I. Fleming,
Chemtracts: Org. Chem., 1996, 9, 1–64; (b) G. R. Jones and
Y. Landais, Tetrahedron, 1996, 52, 7599–7662.
5 I. Fleming, R. Henning, D. C. Parker, H. E. Plaut and
P. E. J. Sanderson, J. Chem. Soc., Perkin Trans. 1, 1995, 317–
337.
2979, 2886, 1748 cm−1; H NMR (500 MHz, CDCl3) δ 1.05 (d,
J = 7.0 Hz, 3 H), 2.04 (dt, J = 13.5, 10.5 Hz, 1 H), 2.12–2.20 (m,
1 H), 2.30–2.40 (m, 1 H), 2.42–2.51 (m, 2 H), 3.97–4.07 (m,
4 H); 13C NMR (125 MHz, CDCl3) δ 7.2 (q), 32.1 (t), 36.6 (t),
51.6 (d), 65.2 (t), 65.4 (t), 114.4 (s), 215.5 (s); exact mass (EI)
calcd for C8H12O3 (M)+ 156.0786, found 156.0787.
6 H. C. Kolb, S. V. Ley, A. M. Z. Slawin and D. J. Williams,
J. Chem. Soc., Perkin Trans. 1, 1992, 2735–2762.
7 Cf. (a) G. Félix, J. Dunoguès, F. Pisciotti and R. Calas,
Angew. Chem., Int. Ed. Engl., 1977, 76, 488–489;
(b) M. Murakami, M. Suginome, K. Fujimoto,
H. Nakamura, P. G. Andersson and Y. Ito, J. Am. Chem. Soc.,
1993, 115, 6487–6498.
8 H.-J. Knölker and G. Wanzl, Synlett, 1995, 378–
382.
9 S. Kim, G. Emeric and P. L. Fuchs, J. Org. Chem., 1992, 57,
7362–7364.
3-Hydroxy-2-methylcyclopent-2-en-1-one (21c)40
A 1 : 10 mixture (1.0 mL) of hydrochloric acid (1 M) and THF
was added to a stirred solution of 25c (40.5 mg, 0.26 mmol) in
THF (5 mL) and stirring was continued for 2.5 h. Without
aqueous workup, silica gel (ca. 1 g) was added to the reaction
mixture and the solvent was evaporated in vacuo at room temp-
erature (rotary evaporator, water pump). The residue was
added to the top of a column of flash chromatography silica
gel (1.3 × 10 cm) made up with hexanes. Flash chromato-
graphy, using a 30–50% acetone–hexanes gradient, gave 21c
(20.6 mg, 71%) as a solid: mp 208–210 °C (lit.40 214–216 °C);
1H NMR (500 MHz, DMSO-d6) δ 1.46 (s, 3 H), 2.33 (s, 4 H); 13C
NMR (125 MHz, DMSO-d6) δ 5.8, 30.0, 111.5.
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Acknowledgements
We thank NSERC for financial support and Professor M. Lopp
(Department of Chemistry, Tallinn Technical University) for
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