Enantioselective desymmetrization of prochiral ketones via an organocatalytic deprotonation process

Article abstract of DOI:10.1016/j.tetasy.2013.05.011

The first desymmetrization of 4-substituted cyclohexanones by organocatalytic asymmetric deprotonation at low catalyst loading is reported. The combination of N,O-bis(trimethylsilyl)acetamide (BSA) and chiral quaternary ammonium aryloxide salts has been u

Full text of DOI:10.1016/j.tetasy.2013.05.011

Tetrahedron: Asymmetry 24 (2013) 764–768
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective desymmetrization of prochiral ketones via
an organocatalytic deprotonation process
⇑
⇑
Aurélie Claraz, Sylvain Oudeyer , Vincent Levacher
Normandie Univ, COBRA, UMR 6014 & FR3038, Univ Rouen, INSA Rouen, CNRS, IRCOF, 1 Rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 April 2013
Accepted 22 May 2013
The first desymmetrization of 4-substituted cyclohexanones by organocatalytic asymmetric deprotona-
tion at low catalyst loading is reported. The combination of N,O-bis(trimethylsilyl)acetamide (BSA) and
chiral quaternary ammonium aryloxide salts has been used as an efficient organocatalytic system to pro-
vide silyl enolates in high yields and with modest ee.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
amine (30 mol %) in the presence of an achiral tridentate lithium
amide (2.4 equiv), HMPA (2.4 equiv) and DABCO (1.5 equiv) in
Due to their importance in the pharmaceutical and agrochemi-
cal fields, impressive efforts have been directed towards the devel-
opment of efficient routes to gain access to enantiopure
compounds. These strategies can be grouped into two mains cate-
gories: asymmetric synthesis or kinetic resolution (or kinetic dy-
namic resolution), the desymmetrization pathway belongs to the
first class of transformations. Historically speaking, desymmetriza-
tion reactions mediated by enzymes are preferred over chemical
catalysts because of their high levels of chemo-, regio- and stere-
oselectivities.1 Nevertheless, asymmetric catalysis by means of
metallo- or organocatalysts has benefited from huge contributions
from the chemistry community allowing asymmetric desymmetri-
zations to be achieved with high levels of enantioinduction.2
Among all of the substrates assessed in desymmetrization pro-
cesses, much attention has been devoted to prochiral ketones as
underlined by the large number of reactions in which they are in-
volved, namely enamine catalysis,3–8 Baeyer–Villiger oxidations,9
olefination reactions,10 ring expansions,11 enantioselective desym-
metrization–fragmentation reactions12 or enantioselective depro-
tonations providing transiently chiral enolates.13–18 This last class
of transformation mainly involves the use of stoichiometric
amounts of chiral lithium13,14 or magnesium amides15 to obtain
the corresponding enantioenriched silyl enol ether (upon silylation
of the transient enolate by Me3SiCl) or b-hydroxyketones16 (by
trapping the enolate with aldehydes). To the best of our knowl-
edge, only one example of a catalytic process has been reported
to date by Koga et al.17 for the desymmetrization of prochiral 4-
substituted cyclohexanones via the formation of silyl enol ethers.
The authors made use of a catalytic amount of a chiral bidentate
THF at ꢀ78 °C. By implementing these rather complex conditions,
the corresponding silyl enol ether was obtained with up to 76%
ee after quenching with TMSCl (external quench). More recently,
Simpkins et al.18 reported a study implementing competition reac-
tions between chiral and achiral lithium amides during the depro-
tonation of prochiral ketones and imides with the aim of
developing new catalytic processes. Although the results of this
study demonstrated that the presence of an achiral base, such as
LDA, does not erode the level of stereoinduction induced by the
asymmetric ODVA
R'
O
O
O
reaction
O
+
R'CHO
OH
Previous work
organocatalytic in situ generation of a chiral Brønsted base
*
N
OTMS
+
R4N
N
O
TMS
*
ArOTMS
ArO
TMS
NR4
+
Me
BSA 1a
silylating
agent
Me
Cat.
chiral Brønsted
base
O
OTMS
This
work
organocatalytic desymmetrization via
asymmetric deprotonation
+ internal quenching
R
R
2
3
⇑
Corresponding authors. Tel.: +33 (0) 235522496; fax: +33 (0) 235522962.
E-mail addresses: sylvain.oudeyer@univ-rouen.fr (S. Oudeyer), vincent.leva-
Figure 1. Organocatalytic in situ generation of chiral quaternary ammonium amide
cher@insa-rouen.fr (V. Levacher).
salts.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.011

A. Claraz et al. / Tetrahedron: Asymmetry 24 (2013) 764–768
765
Table 1
O
OTMS
CD+1, MeOC6H4O- (10 mol%)
BSA 1a (1.5 equiv)
Screening of catalysts (R4ꢁN+, 4-MeOC6H4Oꢀ) and silylated bases (BTMS)
*
R4N+, 4-MeOC6H4O-
O
THF, -78°C, 2h
(S)
OTMS
TMSO
B
(x mol%)
t-Bu
BTMS (1.5 equiv)
t-Bu
+
2a
3a
THF, -78°C, 2h
Conva: 81% ; 6% eeb
t-Bu
t-Bu
t-Bu
N
Ph
2a
4a-e
3a
OH
*
R4N+, 4-MeOC6H4O-
BTMS
N
CD+1
R1
N
OTMS
R = CH3, 1a
R = CF3, 1b
Scheme 1. Preliminary result. aDetermined by GC-FID analysis of the crude
R2O
TMS
mixture. bMeasured by GC-FID analysis using a chiral column (see Section 4).
R
N
TMS
R3
N
N
H
1c
1d
chiral amide, no catalytic version has been reported so far.
Recently, we reported the catalytic in situ generation of chiral
quaternary ammonium amide salts from N,O-bis(trimethyl-
silyl)acetamide (BSA) 1a and quaternary ammonium aryloxides
(Fig. 1, middle part). This system was successfully applied to an
anti-selective organocatalytic direct vinylogous aldol (ODVA)
reaction of (5H)-furan-2-one derivatives with both aliphatic or
R1=R2=H, R3=Ph:CN+1
N
1
2
3
QD+1
Me
Me
OTMS
R = OMe, R =H, R =Ph:
OMe
R1
OTMS
Me
1e
N
OR2
(hetero)aromatic aldehydes to afford several 5-(10-hydroxy)-
c-
R3
butenolides in good diastereomeric ratios (up to 95/5) and with
excellent enantioselectivities (up to 94%) (Fig. 1, upper part).19
We postulated that this catalytic system could be extrapolated
to the desymmetrization of prochiral cycloalkanones 2 (Fig. 1, bot-
tom part). After deprotonation of the ketone by the chiral quater-
nary ammonium amide salt, the resulting enolate could be
silylated by ArOTMS generated during the catalytic cycle, thus
avoiding the use of an external silylating agent.
N
R1=R2=H, R3=Ph: CD+1
R1=OMe, R2=H, R3=Ph: QN+1
R1=OMe, R2=Bn, R3=Ph: QN+2
1
2
3
QN+3
R =OMe, R =H, R =2-FC6H4:
R1=OMe, R2=R3=H: QN+4
QN+5
1
2
3
R =OMe, R =H, R =3,5-(BnO)2C6H3:
R1=OMe, R2=H, R3=anthracenyl: QN+6
2. Results and discussion
Entry
BTMS
R4⁄N+
x (mol %)
Conversiona (%)
3a/4
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
CD+1
CN+1
QD+1
QN+1
10
10
10
10
5
81
85
92
90
91
80
41
75
95
84
94
0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
70/30
85/15
6
ꢀ4
With this basic idea in mind, several quaternary ammonium
aryloxide salts derived from Cinchona alkaloids were synthesized
according to known procedures19,20 and, among them, the readily
accessible CD+1, ArOꢀ was evaluated in the desymmetrization of
4-tert-butylcyclohexanone, used as a model substrate in the pres-
ence of BSA (Scheme 1).
By performing the reaction in THF at ꢀ78 °C for 2 h, we ob-
served the formation of the corresponding silyl enol ether 3a of
4-tert-butylcyclohexanone with good conversion, as a slightly
enantioenriched mixture.21 This result prompted us to perform a
survey of other catalysts and silylated bases using THF at ꢀ78 °C
as the optimized solvent and temperature. The results are reported
in Table 1.
First, all of the N-benzyl ammonium backbones derived from
Cinchona alkaloids (i.e. quininium QN+, quinidinium QD+, cinchon-
inium CN+ and cinchonidinium CD+) were evaluated (Table 1, en-
tries 1–4) revealing that catalysts in the quininium series
provided a higher enantioselection (34% ee, Table 1, entry 4).22
We thus paid attention to the catalyst charge and found that no
erosion of the enantiomeric excess occurred with a catalyst loading
as low as 2 mol %, thus indicating the efficiency of the catalytic pro-
cess (Table 1, entries 4–6). Next, we decided to explore the influ-
ence of modification of the quininium pattern on the
enantioselectivity of the reaction (Table 1, entries 7–11). All of
the modifications made resulted in a decrease in the enantiomeric
excesses. Moreover, it is noteworthy that substitution of the nitro-
gen by an anthracenyl group led to an inversion of the enantiose-
lectivity (Table 1, entry 11). We then studied other N- or O-
silylated bases (Table 1, entries 12–15).23 All other N-silylated
bases 1b–c (Table 1, entries 12 and 13) gave lower conversions
than BSA 1a (Table 1, entry 4). Lastly, attempts to use O-silylated
ꢀ12
34c
34
32
20
25
0
24
ꢀ6
nd
0
2
QN+2
QN+3
QN+4
QN+5
QN+6
QN+1
10
10
10
10
10
10
10
10
10
1b
1c
1d
1e
36
91
93
ꢀ35
ꢀ6
nd: not determined.
a
Measured by GC-FID analysis.
Measured by GC-FID analysis using a chiral column (see Section 4).
No variation of the ee was observed over the course of the reaction.
b
c
bases such as 1d, which were revealed to be more nucleophilic,
led to the formation of a 70/30 mixture of 3a/4d, with 3a being ob-
tained with the same level of enantioselectivity as previously ob-
tained from BSA 1a, but with the opposite configuration. The
chemoselectivity could be slightly enhanced by using 1e instead
of 1d but at the expense of the enantioselectivity (Table 1, entry
14 vs 15).
With the optimized conditions in hand, we next examined the
scope of the reaction (Table 2).
Several 4-substituted cyclohexanone derivatives 2a–f were
tested (Table 2, entries 1–6). All substrates led to high levels of
conversion providing silyl enolates 3a–f with fair to good isolated

766
A. Claraz et al. / Tetrahedron: Asymmetry 24 (2013) 764–768
Table 2
OTMS
TMS
OTMS
Me
Ar = 4-MeOC6H4
Desymmetrization of the prochiral 4-substituted cyclohexanone derivatives 2a–f
N
*
1a
R4N, ArO
QN+1, 4-MeOC6H4O-
O
OTMS
(5 mol%)
R
BSA 1a (1.5 equiv)
ArOTMS
3
THF, -78°C
TMS
O
N
R
R
*
Me
O
R4N
2a-f
3a-f
A
*
O
R
R4N
R
2
ArOTMS
Entry
R
2
3
Yielda (Conv.) (%)
ee (%)b
O
Me
TMS
1
2
3
4
5
6
t-Bu
Me
n-Pr
i-Pr
Ph
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
79 (91)
75 (88)
84 (96)
73 (85)
68 (78)
70 (81)
34
24
22
26
25
25c
N
H
B
1f
Figure 2. Proposed catalytic cycle.
OTBS
a
Measured by GC-FID analysis.
Measured by GC-FID analysis using a chiral column unless otherwise indicated
b
QN+1, Cl- (10 mol%)
4-MeOC6H4ONa (10 mol%)
1a (1.5 equiv)+1f (1 equiv)
(see Section 4).
c
OTMS
O
Determined by the specific rotation (see Section 4).
OTMS
1f (1.5 equiv)
THF, -78° C, 2 h
THF, -78° C, 2 h
yields after careful work-up. Modest enantioselectivities of
approximately about 25% were obtained whatever the substituents
at the C-4 position (alkyl, aryl or OTBS). It should be noted that de-
spite those rather modest levels of stereoinduction, the reaction is
very clean and reaches completion within 2 h with only 5 mol % of
catalyst, which represents so far the first example of a low-loading
catalytic system for this reaction (with respect to the 30 mol % re-
quired in Koga’s procedure).
(b)
(a)
t-Bu
( )-3a
t-Bu
t-Bu
2a
3a
Conva: 90%
31% eeb
Conva: 52%
Scheme 3. Control experiments. aDetermined by GC-FID analysis of the crude
mixture. bMeasured by GC-FID analysis using a chiral column.
In order to facilitate the implementation of the procedure, we
looked at the possibility of generating in situ the quaternary
ammonium aryloxide salt by means of an ionic metathesis reaction
between the corresponding quaternary ammonium halide and so-
dium aryloxide salts (Scheme 2).
sumed to be formed during the activation step of BSA). When
BSA was used as the silylating agent, GC–MS analysis showed
no detectable traces of compound 3a after 5 min. When using
4-MeOC6H4OTMS as the silylating agent, a low but significant
(28%) conversion into compound 3a was observed after 5 min.
Although this last experiment strongly argues in favour of 4-
MeOC6H4OTMS as the silylating agent, a single step concerted
mechanism involving all partners of the reaction, namely the chi-
ral ammonium aryloxide, BSA and the prochiral ketone cannot be
ruled out. Regarding these results, the following catalytic cycle
was proposed (Fig. 2).
First, desilylation of BSA 1a triggered by the ammonium phen-
oxide catalyst would give the active chiral Brønsted base interme-
diate A along with ArOTMS. Then, deprotonation of ketone 2 by the
chiral base A would occur to provide the protonated BTMS 1f and
the enantioenriched ammonium enolate B which upon silylation,
likely by ArOTMS, would furnish the corresponding silyl enol ether
3 with concomitant regeneration of the catalyst. Given that 1f gen-
erated during the reaction was also found to be effective in the for-
mation of the silyl enol ether 3 as a racemic mixture (Scheme 3a),
we ascertained that the presence of 1f from the start of the reac-
tion did not lead to an erosion of the enantioselectivity
(Scheme 3b). This control experiment showed that 1f does not
compete with the putative reactive catalyst A in the deprotonation
step and consequently is not responsible for the modest enantiose-
lectivities observed.
Starting the reaction from the corresponding QN+1, Clꢀ and 4-
MeOC6H4ONa (1 M solution in THF), the same level of enantiose-
lectivity to that obtained with the preformed catalyst (Table 1, en-
try 4) could be achieved, thus avoiding the preparation of the
quaternary ammonium aryloxide salt, which can be sometimes dif-
ficult to isolate.
In order to gain insight into the mechanism of this organocat-
alytic desymmetrization process, several control experiments
were conducted. First, we sought to determine which species
was responsible for the silylation of the transient enolate. In or-
der to do so, we generated the tetramethylammonium enolate
derived from ketone 2a by desilylation of the corresponding silyl
enolate 3a with Me4NF. Next, we attempted to trap this enolate
by adding 3 equiv of either BSA 1a or 4-MeOC6H4OTMS (pre-
QN+1,Cl-
(5 mol%)
O
OTMS
4-MeOC6H4ONa (5 mol%)
BSA 1a (1.5 equiv)
(S)
THF, -78°C, 2 h
t-Bu
2a
t-Bu
3a
Conva: 88%; 33% eeb
3. Conclusion
Scheme 2. The in situ generation of chiral quaternary ammonium aryloxide:
simplification of the procedure. aDetermined by GC-FID analysis of the crude
mixture. bMeasured by GC-FID analysis using a chiral column (see Section 4).
In conclusion, we have developed the first organocatalytic
asymmetric desymmetrization reaction of 4-substituted prochiral

A. Claraz et al. / Tetrahedron: Asymmetry 24 (2013) 764–768
767
ketones 2 by an asymmetric deprotonation–silylation sequence
providing the corresponding silyl enol ethers 3 in good yields
and with modest ee values. However, the modest ee values are
counterbalanced by the low charge of catalyst required and by
the ease of implementation in comparison with the only previous
catalytic example reported in the literature.17 The use of a silylated
base (that acts both as a base and a silylating agent) in association
with a chiral ammonium phenoxide catalyst could be advanta-
geous to the combination of an achiral lithium amide, chiral amine
and TMSCl previously reported by Koga et al.17 in terms of atom
economy. Further developments of this catalytic in situ generation
of chiral quaternary ammonium amides to other reactions are cur-
rently under investigation.
2.35 (m, 3H), 2.82–3.01 (m, 1H), 3.02–3.12 (m, 1H), 3.60 (s, 3H),
3.60–3.69 (m, 2H), 4.09 (s, 3H), 4.32–4.48 (s, 1H), 4.18–4.39 (m,
1H), 4.69–4.84 (m, 1H), 4.92–5.02 (m, 1H), 5.68–5.76 (m, 2H),
6.55–6.60 (m, 6H), 7.03 (s, 1H), 7.54–7.66 (m, 4H), 7.77–7.81 (m,
2H), 8.01–8.09 (m, 2H), 8.21–8.25 (m, 2H), 8.54–8.65 (m, 2H),
8.80–8.86 (m, 2H). 13C NMR (75 MHz, CD3OD, d): 22.6, 26.2, 27.3,
39.7, 54.0, 56.3, 56.4, 57.4, 63.0, 66.8, 71.0, 102.8, 115.8, 117.6,
118.6, 119.0, 121.9, 123.1, 124.7, 125.2, 126.6, 126.7, 127.5,
129.4, 129.5, 131.1, 131.4, 131.9, 133.0, 133.1, 133.8, 134.6,
138.6, 144.7, 146.8, 148.4, 152.1, 158.2, 160.0. IR (ATR, cmꢀ1):
832, 1028, 1227, 1465, 1513, 1618. HRMS (ESI+) calcd for
[C35H34N2O2]+ m/z 514.2605, found: 514.2608. HRMS (ESIꢀ) calcd
for [C7H7O2]ꢀ m/z 123.0446, found: 123.0445.
4.3. Organocatalytic enantioselective deprotonation of
prochiral cyclohexanones
4. Experimental
4.1. General
4.3.1. General procedure II
To a solution of cyclohexanone 2a–f (0.25 mmol) and QN+1, 4-
MeOC6H4Oꢀ (0.0125 mmol, 7 mg) in THF (0.25 mL) at ꢀ78 °C was
MeOH was distilled from CaH2. THF was distilled from Na/ben-
zophenone. All reagents were used as received unless otherwise
indicated. The NMR spectra were recorded on a Bruker AVANCE
300 at 300 MHz (1H) and 75 MHz (13C) using CDCl3 (d 7.26, 1H; d
77.16, 13C) or MeOD (d 3.31, 1H; d 49.00, 13C) as solvent. Chemical
shifts are reported in ppm and calibrated using residual solvent
peaks: CHCl3 (d 7.26, 1H; d 77.16, 13C), MeOH (d 3.31, 1H; d 49.00,
13C). Melting points are uncorrected. Flash chromatography was
added BSA (0.375 mmol, 92 lL) as a solution in THF (0.25 mL).
The reaction mixture was stirred at the same temperature for
2 h. The conversion was measured by GC-FID. Next, 100 L of a sat-
l
urated solution of NaHCO3 was added at ꢀ78 °C. The reaction mix-
ture was dried over Na2SO4, filtered and concentrated. The crude
product 3a–f was purified on silica gel by using petroleum ether/
Et2O (95:5) as eluent and then subjected to GC-FID analysis using
chiral column in order to determine the enantiomeric excess.
performed with silica gel (70–230
Gas chromatographies with an achiral column were performed on
lm) unless otherwise indicated.
a Varian 3900 using a DB-5 column (30 m ꢂ 0.25 mm ꢂ 0.25
lm)
4.3.2. (4-tert-Butylcyclohex-1-enyloxy)trimethylsilane 3a
equipped with FID detector (carrier gas: He (1 mL minꢀ1), starting
temperature: 50 °C [hold 2 min], rate of temperature increase:
25 °C minꢀ1 up to 250 °C [hold 15 min]). Enantiomeric excesses
were determined by gas chromatographies using a chiral column
The title compound was obtained in 91% conversion according
to general procedure II (GC analysis using
a DB-5 column:
tR = 7.7 min (2a), tR = 8.4 min (3a)) and isolated as a colourless oil
(79% yield). 1H NMR (300 MHz, CDCl3, d): 0.17 (s, 9H), 0.86 (s,
9H), 1.18–1.28 (m, 2H), 1.77–1.84 (m, 2H), 1.96–2.08 (m, 3H),
4.82–4.86 (m, 1H). ee = 35% (GC analysis using a Supelco-Beta-
Dex 120Ò column: conditions, carrier gas: He (20 psi), isotherm
105 °C, tR = 32.97 min (major, S), tR = 33.64 min (minor, R)).
Supelco-Beta-Dex 120Ò column (30 m ꢂ 0.25 mm ꢂ 0.25
lm) on
a Varian 3900 equipped with FID detector unless otherwise indi-
cated. All experiments were conducted under a nitrogen atmo-
sphere in oven-dried glassware with magnetic stirring using
standard Schlenk techniques. ½a D20
ꢃ
are reported in mL dmꢀ1 gꢀ1
as follows: (c, solvent) with c = concentration in g/100 mL.
4.3.3. (4-Methylcyclohex-1-enyloxy)trimethylsilane 3b
The title compound was obtained in 88% conversion according
4.2. Preparation of the catalysts
to general procedure II (GC analysis using
a DB-5 column:
tR = 5.8 min (2b), tR = 6.8 min (3b)) and isolated as a colourless oil
(75% yield). 1H NMR (300 MHz, CDCl3, d): 0.17 (s, 9H), 0.95 (d,
J = 6.3 Hz, 3H), 0.95–1.37 (m, 1H), 1.56–1.72 (m, 3H), 1.91–2.09
(m, 3H), 4.81–4.82 (m, 1H). ee = 24% (GC analysis using a Supe-
lco-Beta-Dex 120Ò column: conditions, carrier gas: He (20 psi),
50 °C [hold 0 min], rate of temperature increase: 2 °C minꢀ1 up to
130 °C [hold 0 min], tR = 21.89 min (major, S), tR = 22.11 min (min-
or, R)).
4.2.1. General procedure I
Ammonium phenoxides were prepared according to the follow-
ing general procedure I previously reported.19,20 Ion-exchange re-
sin Amberlyst A-26 (OHꢀ) (1.0 g) was added to a stirred solution
of ammonium halide (1 mmol) in dry methanol (10 mL) at room
temperature. The mixture was stirred for 10 h at the same temper-
ature, filtered and washed with methanol. 4-Methoxyphenol
(1 mmol, 124 mg) was added to the filtrate, and the resulting mix-
ture was co-evaporated three times with toluene. Crystallization of
the residue with diethyl ether and filtration afforded the ammo-
nium phenoxide which can be used without further purification.
Spectroscopic data of ammonium phenoxides CN+1, 4-
MeOC6H4Oꢀ, CD+1, 4-MeOC6H4Oꢀ, QD+1, 4-MeOC6H4Oꢀ, QN+1-5,
4-MeOC6H4Oꢀ were in agreement with those previously
reported.19
4.3.4. (4-n-Propylcyclohex-1-enyloxy)trimethylsilane 3c
The title compound was obtained in 96% conversion according
to general procedure II (GC analysis using
a DB-5 column:
tR = 7.3 min (2c), tR = 8.0 min (3c)) and isolated as a colourless oil
(84% yield). 1H NMR (300 MHz, CDCl3, d): 0.17 (s, 9H), 0.88 (t,
J = 7.0 Hz, 3H), 1.19–1.42 (m, 6H), 1.60–1.73 (m, 2H), 1.96–2.10
(m, 3H), 4.94–4.96 (m, 1H). ee = 22% (GC analysis using a Supe-
lco-Beta-Dex 120Ò column: conditions, carrier gas: He (20 psi), iso-
therm 95 °C, tR = 30.96 min (major, S), tR = 31.53 min (minor, R)).
4.2.2. N-(90-Anthracenylmethyl)quininium 4-
methoxyphenoxide (QN+6, 4-MeOC6H4Oꢀ)
Compound QN+6, 4-MeOC6H4Oꢀ (535 mg, 99% yield) was pre-
pared according to the general procedure I from the corresponding
ammonium chloride (451 mg, 1 mmol) and was obtained as a yel-
4.3.5. (4-iso-Propylcyclohex-1-enyloxy)trimethylsilane 3d
The title compound was obtained in 85% conversion to general
procedure II (GC analysis using a DB-5 column: tR = 7.3 min (2d),
tR = 8.0 min (3d)) and isolated as a colourless oil (73% yield). 1H
NMR (300 MHz, CDCl3, d): 0.17 (s, 9H), 0.88 (dd, J = 6.6, 3.0 Hz,
low solid (mp: 151–151 °C). ½a D20
ꢃ
¼ ꢀ145:0 (c 0.50, CHCl3). 1H NMR
(300 MHz, CD3OD, d): 1.54–1.57 (m, 3H), 1.90–1.91 (m, 1H), 2.04–

768
A. Claraz et al. / Tetrahedron: Asymmetry 24 (2013) 764–768
Rios, R. Chem. Eur. J. 2009, 15, 6564–6568; (h) Diaba, F.; Bonjoch, J. Org. Biomol.
Chem. 2009, 7, 2517–2519; (i) Aitken, D. J.; Bernard, A. M.; Capitta, F.; Frongia,
A.; Guillot, R.; Ollivier, J.; Piras, P. P.; Secci, F.; Spiga, M. Org. Biomol. Chem. 2012,
10, 5045–5048.
6H), 1.20–1.35 (m, 2H), 1.42–1.54 (m, 1H), 1.71–1.81 (m, 2H),
1.93–2.08 (m, 3H), 4.83–4.84 (m, 1H). ee = 26% (GC analysis using
a Supelco-Beta-Dex 120Ò column: conditions, carrier gas: He
(20 psi), isotherm 105 °C, tR = 32.59 min (major, S), tR = 33.40 min
(minor, S)).
4. For examples of Michael-type additions, see: (a) Luo, S.; Zhang, L.; Mi, X.; Qiao,
Y.; Cheng, J.-P. J. Org. Chem. 2007, 72, 9350–9352; (b) Chen, J.-R.; Lai, Y.-Y.; Lu,
H.-H.; Wang, X.-F.; Xiao, W.-J. Tetrahedron 2009, 65, 9238–9243.
5. For example of hydroxylation reactions, see: Ramachary, D. B.; Barbas, C. F. Org.
Lett. 2005, 7, 1577–1580.
6. For examples of alkylation reactions, see: (a) Zhang, L.; Cui, L.; Li, X.; Li, J.; Luo,
S.; Cheng, J.-P. Chem. Eur. J. 2010, 16, 2045–2049; (b) Zhang, L.; Cui, L.; Li, X.; Li,
J.; Luo, S.; Cheng, J.-P. Eur. J. Org. Chem. 2010, 4876–4885; (c) Weng, Z.-T.; Li, Y.;
Tian, S.-K. J. Org. Chem. 2011, 76, 8095–8099.
4.3.6. (4-Phenylcyclohex-1-enyloxy)trimethylsilane 3e
The title compound was obtained in 78% conversion according
to general procedure II (GC analysis using a DB-5 column:
tR = 9.5 min (2e), tR = 10.1 min (3e)) and isolated as a colourless
oil (68% yield). 1H NMR (300 MHz, CDCl3, d): 0.21 (s, 9H), 1.82–
2.29 (m, 6H), 2.73–2.75 (m, 1H), 4.94–4.96 (m, 1H), 7.20–7.31
(m, 5H). ee = 25% (GC analysis using a Supelco-Beta-Dex 120Ò col-
umn: conditions, carrier gas: He (20 psi), 50 °C [hold 0 min], rate of
temperature increase: 2 °C minꢀ1 up to 130 °C [hold 30 min],
tR = 110.58 min (major, S), tR = 112.18 min (minor, R)).
7. For an example of a ring expansion reaction, see: Capitta, F.; Frongia, A.;
Ollivier, J.; Piras, P. P.; Secci, F. Synlett 2011, 89–93.
8. For examples of Friedländer condensations, see: (a) Li, L.; Seidel, D. Org. Lett.
2010, 12, 5064–5067; (b) Li, L.; Seidel, D. Synthesis 2011, 1853–1858.
9. (a) Murahashi, S.-I.; Ono, S.; Imada, Y. Angew. Chem., Int. Ed. 2002, 41, 2366–
2368; (b) Watanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43,
4481–4485; (c) Bolm, C.; Frison, J.-C.; Zhang, Y.; Wulff, W. D. Synlett 2004,
´
1619–1621; (d) Malkov, A. V.; Friscourt, F.; Bell, M.; Swarbrick, M. E.; Kocꢀovsky,
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4.3.7. (4-tert-Butyldimethylsilyloxy-1-enyloxy)trimethylsilane
3f
The title compound was obtained in 81% conversion according
to general procedure II (GC analysis using a DB-5 column:
tR = 8.5 min (2f), tR = 9.4 min (3f)) and isolated as a colourless oil
(70% yield). 1H NMR (300 MHz, CDCl3, d): 0.05 (s, 6H), 0.17 (s,
9H), 0.88 (s, 9H), 1.25–1.77 (m, 2H), 1.97–2.11 (m, 3H), 2.16–
2.23 (m, 1H), 3.84–3.89 (m, 1H), 4.69–4.71 (m, 1H). ee = 25%
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{½a 2D0
ꢃ
¼ ꢀ9:0 (c 0.2, CHCl3) corresponding to ee = 25% (S). Lit.24
½ ꢃ
a 2D0
(S) = ꢀ28.8 (c 0.3, CHCl3, 80% ee)}.
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Acknowledgements
This work was supported by CNRS, University and INSA of Rou-
en, the Région Haute-Normandie and the Labex SynOrg (ANR-11-
LABX-0029). A. C. thanks the CRUNCH network for a Grant.
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