Bis(2-aminobenzoimidazole)-organocatalyzed asymmetric alkylation of activated methylene compounds with benzylic and allylic alcohols

Article abstract of DOI:10.1055/s-0034-1378618

The first organocatalyzed asymmetric alkylation of activated methylene compounds using benzylic and allylic alcohols as alkylating agents through dual hydrogen bond activation in an S_N1-type reaction is reported. This green protocol employs a b

Full text of DOI:10.1055/s-0034-1378618

PAPER
▌3399
paper
Bis(2-aminobenzoimidazole)-Organocatalyzed Asymmetric Alkylation of
Activated Methylene Compounds with Benzylic and Allylic Alcohols
Organocatalyzed Asymmetric Alkylation
Paz Trillo, Alejandro Baeza,* Carmen Nájera*
Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo 99,
03080 Alicante, Spain
Fax +34(96)5903549; E-mail: alex.baeza@ua.es; E-mail: cnajera@ua.es
Received: 15.07.2014; Accepted: 18.07.2014
Nishibayashi's work
Abstract: The first organocatalyzed asymmetric alkylation of acti-
R1
OR3
OR3
R2
vated methylene compounds using benzylic and allylic alcohols as
alkylating agents through dual hydrogen bond activation in an SN1-
type reaction is reported. This green protocol employs a bis(2-ami-
nobenzoimidazole) in combination with an achiral Brønsted acid as
a bifunctional catalytic system and gives the alkylation products
with moderate to good enantioselectivities. Although the scope of
the reaction is limited, this methodology can be considered as com-
plementary to existing metal-catalyzed processes. In addition, mod-
est results were obtained in a first attempt to perform a metal-free
asymmetric Tsuji–Trost reaction using allylic alcohols. Finally, the
recovery and reusability of the organocatalyst is also achieved.
O
O
P
BOX-Cu(OTf)2
(10 mol%)
OH
P
OR3
OR3
O
O
R1
+
Ar
Ar
DCE, –20 to 25 °C
65 h
Ar
Ar
R2
high yields
up to 92% ee
our previous work
OH
R1
R2
Key words: asymmetric catalysis, alcohols, organocatalysis, car-
bocations, alkylation
CO2R3
t-BuBOX-Cu(OTf)2
O
X
+
(10 mol%)
PhMe, –78 to 25 °C
20 h
O
X
CO2R3
The asymmetric alkylation of prochiral carbon nucleop-
hiles using benzylic alcohols as alkylating agents, through
an SN1-type reaction, has emerged over the last few years
an environmentally friendly alternative route to the previ-
ously reported and well-established methodologies for en-
antioselective C–C bond formation, since this process has
perfect atom-economy and only generates water as a by-
product.1 However, the prochiral carbon nucleophiles that
have been used to date seem to be limited to the use of al-
dehydes. Since the pioneer work by Cozzy and co-work-
ers, on the organocatalyzed asymmetric α-alkylation of
aldehydes using such alcohols through an enamine activa-
tion mode,2 several examples have recently appeared, the
majority following a similar strategy.3
R1
high yields
up to 95% ee
R2
X = O or S
Scheme 1 Previous asymmetric alkylations of active methylene
compounds with benzylic alcohols
Continuing with this research7 and based on the experi-
ence of our group in organocatalyzed asymmetric reac-
tions involving activated methylene compounds in
Michael-type additions,8 we envisaged a possible metal-
free strategy through dual hydrogen bond activation
(Figure 1) that would represent the first organocatalyzed
version of this transformation. The results of this study are
presented herein.
Despite the versatility of activated methylene compounds,
such as dicarbonyl compounds, β-keto esters, α-cyanoace-
tates, α-nitroacetates, β-keto sulfones, etc., as building
blocks which are easily transformed into other functional-
ities and the multiple strategies reported for their activa-
tion employing chiral catalysts,4 reported methodologies
for their use as prochiral nucleophiles in asymmetric al-
kylations with benzylic alcohols remain rare. To the best
of our knowledge, there are only two reports in this regard
recently reported by Nishibayashi and our group, disclos-
ing the asymmetric alkylation of β-keto phosphonates5
and β-keto esters6 respectively, catalyzed by BOX–
Cu(OTf)2-type complexes (Scheme 1).
X
R2
HN
NH
chiral
scaffold
H
O
+NR1
2
EWG
HO
R
H
R
R
Figure 1 Hypothetic dual hydrogen bond activation working model
Firstly, in the search for optimal reaction conditions we
selected the reaction between bis[4-(dimethylamino)phe-
nyl]methanol (1a), which would produce a rather stable
carbocationic intermediate (E = –7.02)9 and ethyl 2-oxo-
cyclopentanecarboxylate (2a) as model reaction (Table
1). This particular reaction failed completely in our previ-
SYNTHESIS 2014, 46, 3399–3407
Advanced online publication: 04.09.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378618; Art ID: ss-2014-z0447-op
© Georg Thieme Verlag Stuttgart · New York

3400
P. Trillo et al.
PAPER
ous work when using t-Bu-BOX–copper(II) catalyst.6 ready shown its effectiveness for the conjugated addition
Thus, different catalysts derived from trans-cyclohexane- of 1,3-dicarbonyl compounds to maleimides8e,f (entries 1–
1,2-diamine I–VI (10 mol%) were studied in the presence 6). Therefore, this catalyst was selected to further refine
of trifluoroacetic acid (10 mol%) as co-catalyst, which the reaction conditions. It is important to note that in the
would allow the possible activation of the hydroxy group absence of acidic co-catalyst, the reaction only produced
according to our hypothesized working model (Figure 1) poor results at best.
using toluene as solvent and at 25 °C (Table 1). As ob-
Next a wide range of solvents with different properties
served, full conversion was achieved in all cases, but
was tested at 0 °C under the same reaction conditions, but
moderate enantioselection was only observed when using
none of them increased the results obtained with toluene
bis(2-aminobenzoimidazole) derivative V, which has al-
(53% ee, Table 1, entry 7).10 At this temperature several
Table 1 Optimization of the Reaction Conditionsa
OH
O
O
catalyst (10 mol%)
acid (10 mol%)
CO2Et
+
CO2Et
PhMe, 20 °C
Me2N
F3C
NMe2
Me2N
NMe2
NR2
1a
2a
3aa
F3C
F3C
S
S
HN
S
N
CF3
NH
NH
NMe2
NH HN
N
H
NH
NH
F3C
CF3
I
II
III R = H
IV R = Me
N
N
N
N
NH HN
R
R
V R = H
VI R = Me
Entry
Catalyst
Acid
Temp (°C)
Conv.b (%)
eec (%)
1
2
I
TFA
TFA
TFA
TFA
TFA
TFA
TFA
25
25
25
25
25
25
0
>95
>95
>95
>95
>95
>95
>95
15
rac
5
II
III
IV
V
3
rac
2
4
5
33
8
6
VI
V
7
53
32
50
52
64
67
67
67
8
V
PhCO2H
TsOH
TfOH
TFA
0
9
V
0
25
10
11
12
13
14
V
0
>95
85
V
–20
–20
–20
–20
V
TfOH
TFAd
90
Vd
Vd
50
TfOHd
58
a Reaction conditions: 1a (0.15 mmol), 2a (0.23 mmol), catalyst I–VI (10 mol%), acid (10 mol%), toluene (1.0 mL).
b Determined by 1H NMR analysis on the crude product.
c Determined by HPLC using chiral columns Daicel Chiralpak IA (see Supporting Information for details).
d The reaction was carried out using 5 mol% of V and acid.
Synthesis 2014, 46, 3399–3407
© Georg Thieme Verlag Stuttgart · New York

PAPER
Organocatalyzed Asymmetric Alkylation
3401
Brønsted acids, aside from trifluoroacetic acid, were also amount of reactants did not produce any improvement in
evaluated (entries 8–10). As result of this study, it was ob- the results.
served that trifluoromethanesulfonic acid behaved simi-
larly to trifluoroacetic acid (entries 7 and 10). However,
benzoic acid and 4-toluenesulfonic acid gave inferior re-
Once the optimal reaction conditions were established, 10
mol% catalyst V, 10 mol% trifluoroacetic acid or trifluo-
romethanesulfonic acid as co-catalyst, toluene, –20 °C,
sults (entries 8 and 9). It is important to note that chiral
we decided firstly to examine the use of other β-keto es-
Brønsted acids (a Binol-phosphoric acid derivative and
ters using alcohol 1a as the alkylating agent (Table 2). As
previously mentioned, the alkylation of keto ester 2a pro-
ceeded in high yields and good enantioselectivities under
CSA) were also tested, but unfortunately no synergistic
effect was observed. Moreover, with the use of 20 mol%
of acid, the enantioselectivity decreased dramatically. Fi-
these reaction conditions with either acid co-catalyst (en-
nally, with the two acid co-catalysts in hand, we tried to
tries 1 and 2). It is important to note that the optical purity
increase the enantioselectivity of the process by lowering
of 3aa further increased to 82% ee by crystallization in
hexanes (entry 2). Next, the six-membered β-keto ester 2b
was tested, and we were pleased to observe high yields
and enantioselectivities when the reaction was performed
the temperature. Thus, at –20 °C the enantioselectivity of
3aa increased to 64% and 67% ee when using trifluoro-
acetic acid and trifluoromethanesulfonic acid, respective-
ly, as co-catalysts (entries 11 and 12). At this point, we
at 0 °C using trifluoroacetic acid (entry 3). In contrast, the
decided to reduce the amount of catalyst to 5 mol%, in this
reaction failed when trifluoromethanesulfonic acid was
case only moderate conversions were observed but the en-
the co-catalyst regardless the temperature employed (en-
try 4). The corresponding benzocondensed analogues 2c
and 2d were also evaluated, but unfortunately the reaction
antioselectivity remained approximately the same in both
cases (entries 13 and 14).
In addition, the use of dry reaction conditions (by per- was unsuccessful or if it did proceed then racemic mix-
forming the reaction under and argon atmosphere and us- tures were obtained. High yields, although with low enan-
ing dry solvents) or other changes in the concentration and tioselectivities, were obtained when using lactone 2e as
Table 2 Asymmetric Alkylation of β-Keto Esters with 1aa
R1
O
OH
O
V (10 mol%)
acid (10 mol%)
CO2R3
R2
CO2R3
R1
+
PhMe, –20 °C
20 h
R2
Me2N
NMe2
Me2N
NMe2
2a–d
1a
3aa–af
O
O
O
O
O
CO2Et
CO2Et
CO2Et
O
Ph
n
n
2a n = 0
2b n = 1
2c n = 0
2d n = 1
2e
2f
Entry
Acid
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
TFA
3aa
3aa
3ab
3ab
3ae
3ae
3af
3af
85
64
TfOH
TFAe
TfOH
TFA
90 (76)d
70
67 (82)d
90
10
rac
16
77
TfOH
TFA
81
26
70
38
TfOH
40
37
a Reaction conditions: 1a (0.15 mmol), 2 (0.23 mmol, 1.5 equiv), catalyst V (10 mol%), acid (10 mol%), toluene (1.0 mL), –20 °C, unless oth-
erwise stated.
b Isolated yield after preparative TLC.
c Determined by HPLC using chiral columns Daicel Chiralpak IA (see Supporting Information for details).
d Yield and ee after crystallization (hexanes).
e The reaction was performed at 0 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3399–3407

3402
P. Trillo et al.
PAPER
substrate in both cases (entries 5 and 6). Finally, several phenyl)methanol (1d), which had already turned out to be
linear β-keto esters were also examined, but among these excellent alkylating agents in the copper-catalyzed asym-
2f was the only success, producing 3af with modest enan- metric version.5,6 Thus, 9H-xanthen-9-ol (1b) and 9H-thi-
tioselectivity and trifluoroacetic acid gave the best yield oxanthen-9-ol (1c) along with 1d were allowed to react
(entries 7 and 8). This last particular case allowed us to as- with activated methylene compounds 2a–j under the opti-
sume an S-configuration for the new created stereogenic mal reaction conditions. However, despite the good yields
center by comparison with our previous work.6
obtained in the majority of cases, only the reaction be-
tween 9H-thioxanthen-9-ol (1c) and keto ester 2a and β-
keto sulfone 2j at room temperature proceeded in an enan-
tioselective manner. In the first case, trifluoroacetic acid
afforded the best results in terms of yield, but with poor
enantioselectivity (18 and 30% ee, respectively) with both
acids (Scheme 3). However, moderate yields and high en-
antioselectivities, 83% and 97% ee, were obtained in the
case of β-keto sulfone 2j when trifluoroacetic acid and tri-
fluoromethanesulfonic acid, respectively, were employed
(Scheme 3). Other attempts to obtain enantioenriched al-
kylation products using these benzylic alcohols and acti-
vated methylene compounds by changing temperature,
catalyst loading, or other reaction parameters were inef-
fective.
Next, the scope of the reaction towards the use of other
prochiral activated methylene compounds was studied.
Thus, different 1,3-diketones, α-cyanoacetates, β-keto
phosphonates, α-nitroacetates, and β-keto sulfones were
tested using alcohol 1a as substrate (Scheme 2). As ob-
served, benzoylacetone (2g) afforded the corresponding
product 3ag in good yield and with 87% ee when trifluo-
romethanesulfonic acid was the acid co-catalyst and the
reaction was carried out at –50 °C. Encouraged by this re-
sult several diketones were tested, but disappointingly
only low enantioselectivity was obtained at best when the
five-membered diketone 2h was employed. As men-
tioned, α-cyanoacetates and β-keto phosphonates were
also evaluated, but no enantioselection was observed. The
alkylation product 3ai was obtained in good yield, but low Finally, allylic alcohols, which also would produce a rath-
enantioselectivity, when either acid was used as co-cata- er stable carbocationic intermediates after dehydration,11
lyst with ethyl nitroacetate (2i). Finally, β-keto sulfone 2j were also examined, since their use as alkylating agents
gave the corresponding product 3aj in moderate yield and would be very attractive because it would represent a
enantioselectivity when the reaction was performed at metal-free asymmetric Tsuji–Trost-type reaction.12 Thus,
room temperature using trifluoromethanesulfonic acid as activated methylene compounds 2a,b,f,g,i,j, which af-
co-catalyst.
forded the best results in terms of enantioselection in their
reaction with benzylic alcohols, were subjected to the op-
timized reaction conditions using allylic alcohols 4a and
In order to extend this methodology to other benzylic al-
cohols we thought to use xanthenols and bis(4-methoxy-
R1
O
OH
O
V (10 mol%)
acid (10 mol%)
R2
EWG
EWG
R1
+
PhMe, –20 °C
20 h
R2
Me2N
NMe2
O
Me2N
NMe2
2g–j
1a
3ag–aj
O
O
Ph
O
Me2N
NMe2
Me2N
NMe2
3ag
3ah
TFA 70% yield, 25% ee
TfOH 95% yield, 87% ee (–50 °C)
TFA 60% yield, 10% ee
TfOH 60% yield, 18% ee
O
O
O
O
NO2
EtO
S
Me
Ph
Me2N
NMe2
Me2N
NMe2
3ai
3aj
TFA 71% yield, 26% ee
TfOH 70% yield, 21% ee
TFA 55% yield, 10% ee (23 °C)
TfOH 51% yield, 48% ee (23 °C)
Scheme 2 Asymmetric alkylation of activated methylene compounds with 1a
Synthesis 2014, 46, 3399–3407
© Georg Thieme Verlag Stuttgart · New York

PAPER
Organocatalyzed Asymmetric Alkylation
3403
O
ing the temperature (–78 °C) and increasing the amount of
catalyst to 20 mol% (entry 3). Unfortunately, under these
new conditions, trifluoromethanesulfonic acid produced
inferior results (entry 4). Next, β-keto ester 2b was also
tested and under the optimal reaction conditions and it
gave the corresponding product 5bb in modest yield and
low diastereo- and enantioselectivity in its best result with
either acid (entries 5 and 6). Further changes in the reac-
tion conditions in order to improve these results were un-
successful. In addition, as already mentioned, the reaction
between 4b and 2f,g,i produced the desired products in
high yields, but as racemic mixtures; the reaction with 2j
failed.
OH
V (10 mol%)
acid (10 mol%)
CO2Et
O
+
CO2Et
PhMe, 23 °C
20 h
S
S
3ca
1c
2a
TFA 70% yield, 18% ee
TfOH 30% yield, 30% ee
O
O
O
S
OH
Ph
V (10 mol%)
acid (10 mol%)
O
O
O
+
S
Ph
PhMe, 23 °C
20 h
S
S
Table 3 Asymmetric Alkylation of 4b with Active Methylene Com-
poundsa
1c
2j
3cj
TFA 55% yield, 83% ee
TfOH 69% yield, 97% ee
Entry Acid
Temp (°C) Product Yieldb (%) drc
eed (%)
Scheme 3 Asymmetric alkylation of activated methylene com-
pounds with 9H-thioxanthen-9-ol
1
2
3
4
5
6
TFA
–50
–50
–78
5ba
5ba
5ba
5ba
5bb
5bb
64
72
72
30
67
55
70:30 26:24
25:75 40:30
73:27 48:12
55:45 30:28
TfOH
TFAe
4b as electrophiles (Scheme 4). With alcohol 4a, which
forms highly reactive carbocationic intermediate (E =
2.70),9 excellent yields, although with almost no enanti-
oselection (<10% ee), were observed in most cases de-
spite the use of different temperatures and catalyst
loading. Slightly better results, which could be ascribed to
the formation of a more stable allylic carbocation after de-
hydration (E = –1.45)9 were observed with (E)-1,3-bis(4-
methoxyphenyl)prop-2-en-1-ol (4b), although from all
the methylene compounds 2a,b,f,g,i,j examined, cyclic β-
keto esters were the only substrates that yielded the corre-
sponding enantioenriched allylation products (Scheme 4
and Table 3). Thus, the reaction between 4b and keto ester
2a gave 5ba in good yields and modest diastereo- and
enantioselectivity employing either acid when the reac-
tion was carried out at –50 °C (Table 3, entries 1 and 2). It
is remarkable that depending on the acid employed the op-
posite diastereomeric ratio was observed for product 5ba.
After several attempts we were able to slightly increase
the enantioselectivity of one of the diastereomers in the
case of using trifluoroacetic acid (up to 50% ee) by lower-
TfOHe –78
TFA
–20
–20
63:37
52:48
5:10
5:25
TfOH
a Reaction conditions: 4b (0.15 mmol), 2 (0.23 mmol, 1.5 equiv), cat-
alyst V (10 mol%), acid (10 mol%) toluene (1.0 mL), unless other-
wise stated.
b Isolated yield after preparative TLC.
c Determined by 1H NMR analysis of crude product.
d Determined by HPLC using chiral columns (see Supporting Infor-
mation for details).
e 20 mol% of catalyst V and acid were employed.
Concerning the reaction mechanism for benzylic alcohols,
an SN1-type mechanism was immediately assumed from
the fact that as soon as alcohol 1a was added to the solu-
tion containing the catalyst and the acid, it turned deep
blue, indicating the formation of the corresponding cat-
ionic specie (Michler’s hydrol blue),9 remaining this color
until the reaction went to completion. In addition, the
R1
O
O
V (10 mol%)
acid (10 mol%)
R2
OH
EWG
EWG
R1
+
PhMe, 20 h
R2
R
R
R
R
2
5
4a R = H
4b R = OMe
O
O
O
CO2Et
EtO2C
NO2
EWG
SO2Ph
Ph
n
2i
2j
2f EWG = CO2Et
2a n = 0
2b n = 1
2g EWG = C(O)Me
Scheme 4 Asymmetric allylation of activated methylene compounds with allylic alcohols 1d and 1e
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3399–3407

3404
P. Trillo et al.
PAPER
V
+
CF3XO2H
X = C, SO
CF3
O
X
–
O
H
N
O
H
N
H
EWG
Ar
R1
Ar
O
NH
N
+N
1)
EWG
OH
R1
N
H
A
2)
Ar
X
Ar
CF3
O
–
O
H
H
H
N
N
H
N
N
H
N
N
N
H
N
N
N+
H
H
N+
H
H
+N
H
O
O
–
EWG
–
R1
EWG
H
R1
O
–
CF3XO2
Ar
+
Ar
Ar
Ar
C
B
H2O
Scheme 5 Proposed reaction mechanism for benzylic alcohols
comparison of HPLC chart of compound 3af with our pre- after the work-up, the aqueous phase was treated with sat-
vious copper-catalyzed work (in which R-configuration urated aqueous sodium hydrogen carbonate until basic
was assumed)6 points towards the S-configured product pH, recovering the organocatalyst V in 62% yield after ex-
3af when (R,R)-V was used. These facts, along with pre- traction in dichloromethane. The catalyst was again re-
vious experimental and computational studies carried out used without further purification in the same reaction, and
in our group on the use of organocatalyst catalyst V in the no apparent loss of catalytic activity was observed.
presence of an acid for the Michael addition of 1,3-dicar-
In summary, the first metal-free asymmetric alkylation of
bonyl compounds to maleimides,8e,f led us to propose a
activated methylene compounds with benzylic alcohols
catalytic cycle as shown in Scheme 5. Thus, after mixing
pre-catalyst V and equimolecular amounts of the corre-
sponding acid, the bifunctional catalytic species A is
formed through protonation of the most basic iminic nitro-
can be performed using C2 symmetric bis(2-aminobenzo-
imidazole) V as a bifunctional organocatalyst. The corre-
sponding alkylated products were obtained generally in
good yields and with moderate to high enantioselectivi-
gen. Subsequent addition of activated methylene com-
ties. Despite the fact that the reaction seems to be almost
pound and benzylic alcohol would give rise to the
exclusively limited to highly activated alcohols, the meth-
formation of intermediate B, through dual hydrogen bond
odology presented here can be considered as complemen-
activation. After dehydration, presumably an ionic pair is
tary to the metal-catalyzed processes which was only
formed which would react in an enantioselective fashion
useful with xanthenols. According to our observations,
with the methylene compound (intermediate C), releasing
apparently the reaction proceeds through a dual hydrogen-
bond activation, in an SN1-type mechanism, in which the
the product and recovering the catalytic species A.
According to the above-proposed reaction mechanism, af- activated methylene compound reacts in an enantioselec-
ter the reaction takes place, the catalyst V remains proton- tive manner with the in situ formed benzylic carbocation.
ated. Therefore, taking advantage on this purported fact, In addition, we have demonstrated that the organocatalyst
we studied the possible recovery and reutilization of the V can be recovered and reused without any loss of activi-
(R,R)-bis(2-aminobenzoimidazole) catalyst V. Thus, we ty. Finally, the basis for an asymmetric organocatalyzed
performed a 1-mmol scale model reaction (Scheme 1) and
Synthesis 2014, 46, 3399–3407
© Georg Thieme Verlag Stuttgart · New York

PAPER
Organocatalyzed Asymmetric Alkylation
3405
MS (IE): m/z (%) = 408 [M+, 3], 254 (100), 237 (14), 210 (25), 134
(15), 126 (12).
HRMS (ESI+): m/z [M+ + H] calcd for C25H33N2O3: 409.2491;
Tsuji–Trost-type reaction with allylic alcohols is estab-
lished.
found: 409.2491.
All reagents were purchased from commercial sources and used
without further purification. Substrates which were not commer-
cially available were synthesized according to known literature pro-
cedures.13 Catalysts II–VI were synthesized as described in the
literature and the spectroscopic data fully agreed with the reported
values.8b,e Melting points were determined with a Reichert Thermo-
var hot plate apparatus and are uncorrected. IR spectra were record-
ed on a Jasco FT-IR 4100 LE (Pike Miracle ATR) and only the
structurally most relevant peaks are listed. NMR spectroscopy was
performed on a Bruker AC-300 or a Bruker Avance-400 using CD-
Cl3 as solvent and TMS as internal standard unless otherwise stated.
LR-MS (EI) were obtained at 70 eV on an Agilent GC/MS-5973N
instrument equipped with a HP-5MS column (Agilent Technolo-
gies, 30 m × 0.25 mm) and HRMS (ESI) were obtained on a Waters
LCT Premier XE instrument equipped with a time-of-flight (TOF)
analyzer and the samples were ionized by ESI techniques and intro-
duced through an ultra-high pressure liquid chromatography
(UPLC) model Waters Acquity H Class. Optical rotations were
measured on a Jasco P-1030 polarimeter with a 5-cm cell (c given
in g/100 mL). Enantioselectivities were determined by HPLC anal-
ysis (Agilent 1100 Series HPLC) equipped with a G1315B diode ar-
ray detector and a Quat Pump G1311A equipped with the
corresponding Daicel chiral column. Analytical TLC was per-
formed on Merck silica gel plates and the spots were visualized with
UV light at 254 nm. Silica gel 60 F254 containing gypsum was em-
ployed for preparative layer chromatography.
Ethyl 1-{Bis[4-(dimethylamino)phenyl]methyl}-2-oxocyclohex-
anecarboxylate (3ab)
Colorless oil; yield: 44 mg (70%); 90% ee; Rf = 0.27 (hexane–
EtOAc, 4:1). Chiral HPLC analysis (Chiralcel IA column, hexane–
i-PrOH, 97:3, flow rate = 1 mL/min, λ = 254 nm): tR = 14.7 (major),
17.0 min (minor).
[α]D20 +292.4 (c 1.4, CHCl3).
IR (ATR): 1127, 1163, 1199, 1229, 1346, 1444, 1478, 1518, 1561,
1611, 1710, 2340, 2358, 2798.2, 2863, 2935 cm–1.
1H NMR (300 MHz): δ = 0.96 (t, J = 7.1 Hz, 3 H), 1.20–1.30 (m, 2
H), 1.60–1.78 (m, 3 H), 2.37–2.44 (m, 2 H), 2.62–2.67 (m, 1 H),
2.87 (s, 12 H), 3.77–3.83 (m, 1 H), 3.89–3.95 (m, 1 H), 4.89 (s, 1
H), 6.60 (d, J = 8.8 Hz, 4 H), 7.22–7.27 (m, 4 H).
13C NMR (75 MHz): δ = 13.6, 22.7, 26.7, 34.4, 40.6, 40.7, 41.9,
61.1, 66.4, 77.2, 112.1, 112.2, 127.5, 129.3, 129.5, 130.8, 131.2,
147.9, 148.8, 149.1, 170.9, 206.9.
MS (EI): m/z (%) = 422 [M+, 4], 254 (100), 253 (79), 237 (14), 210
(25), 126 (13), 118 (11).
HRMS (ESI+): m/z [M+ + H] calcd for C26H35N2O3: 423.2648;
found: 423.2648.
3-Acetyl-3-{bis[4-(dimethylamino)phenyl]methyl}tetrahydro-
furan-2-one (3ae)
Yellow oil; yield: 46 mg (81%); 26% ee; Rf = 0.25 (hexane–EtOAc,
4:1). Chiral HPLC analysis (Chiralcel IA column, hexane–EtOH,
96:4, flow rate = 1 mL/min, λ = 254 nm): tR = 22.0 (major), 56.6 min
(minor).
1H NMR (300 MHz): δ = 1.98–2.42 (m, 1 H), 2.45(s, 3 H), 2.73–
2.84 (m, 1 H), 2.89 (s, 6 H), 2.92 (s, 6 H), 3.57–3.62 (m, 1 H), 4.02–
4.08 (m, 1 H), 5.18 (s, 1 H), 6.58–6.64 (m, 4 H), 6.97–7.00 (m, 4 H).
13C NMR (75 MHz): δ = 23.6, 25.3, 40.4, 52.7, 66.5, 67.3, 112.3,
112.6, 127.1, 127.8, 129.4, 130.1, 149.2, 149.4, 175.5, 199.9, 201.9.
MS (EI): m/z (%) = 380 [M+, 6], 255 (17), 254 (100), 253 (78), 237
Asymmetric Alkylation of Activated Methylene Compounds
with Alcohols; General Procedure
In an open-air flask the corresponding acid co-catalyst TFA or
TfOH (0.015 mmol, 10 mol%) was added to a solution of bis(2-am-
inobenzoimidazole) V (0.015 mmol, 10 mol%) in technical grade
toluene (0.5 mL). After 5 min the turbid solution became transpar-
ent. Next, the flask was placed in a cooling bath at the correspond-
ing temperature, and then the activated methylene compound (0.23
mmol, 1.5 equiv) was added and after an additional 5 min, a solution
of the corresponding alcohol (0.15 mmol) in toluene (0.5 mL) was
finally added by syringe. The mixture was stirred for 20 h. After this
time, H2O (5 mL) and EtOAc (5 mL) were added at r.t. The aqueous
layer was re-extracted (2 × 5 mL), and the combined organic phases
were dried (MgSO4) and evaporated under reduced pressure. Final-
ly, the reaction crude was purified by preparative TLC (hexanes–
EtOAc).
(14), 210 (26), 134 (15), 126 (10).
Ethyl 2-Benzoyl-3,3-bis[4-(dimethylamino)phenyl]propanoate
(3af)6
Brown solid; yield: 44.7 mg (70%); 38% ee; mp 179–180 °C. Chiral
HPLC analysis (Chiralcel ODH column, hexane–i-PrOH, 96:4,
flow rate = 0.8 mL/min, λ = 254 nm): tR = 17.70 (major), 20.75 min
(minor).
For the recovery of the organocatalyst V, after the reaction work-up,
the aqueous phase was treated with sat. aq NaHCO3 until basic pH.
The aqueous phase was then extracted with CH2Cl2 (3 × 5 mL),
dried (MgSO4) and evaporated to afford V in 62% yield.
[α]D20 –11.78 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.97 (t, J = 7.1 Hz, 3 H), 2.79 (s,
6 H), 2.88 (s, 6 H), 3.89–3.94 (m, 2 H), 4.91 (d, J = 11.7 Hz, 1 H),
5.31 (d, J = 11.7 Hz, 1 H), 6.57 (d, J = 8.4 Hz, 2 H), 6.69 (d, J = 8.4
Hz, 2 H), 7.08 (d, J = 8.7 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H), 7.42–
7.45 (m, 3 H), 8.00–8.04 (m, 2 H).
13C NMR (75 MHz): δ = 13.8, 40.6, 49.2, 60.1, 61.3, 112.8, 112.9,
128.1, 128.5, 128.7, 130.6, 133.2, 136.9, 149.0, 149.3, 168.1, 193.3.
Ethyl 1-{Bis[4-(dimethylamino)phenyl]methyl}-2-oxocyclopen-
tanecarboxylate (3aa)
Yellow solid; yield: 55 mg (90%); 82% ee (after recrystallization);
mp 207–210 °C (hexanes); Rf = 0.25 (hexane–EtOAc, 4:1). Chiral
HPLC analysis (Chiralcel IA column, hexane–EtOH, 92:8, flow
rate = 1 mL/min, λ = 254 nm): tR = 24.5 (minor), 31.1 min (major).
[α]D20 +129.6 (c 0.95, CHCl3).
MS (EI): m/z (%) = 444 [M+, 1], 255 (18), 254 (100), 253 (79), 237
(15), 210 (25), 134 (15).
IR (KBr): 1100, 1134, 1222, 1348, 1444, 1519, 1644, 2088, 3442
cm–1.
2-{Bis[4-(dimethylamino)phenyl]methyl}-1-phenylbutane-1,3-
dione (3ag)
Yellow oil; yield: 59 mg (95%); 87% ee; Rf = 0.56 (hexane–EtOAc,
4:1). Chiral HPLC analysis (Chiralcel IA column, hexane–EtOH,
92:8, flow rate = 1 mL/min, λ = 254 nm): tR = 32.71 (minor), 35.92
min (major).
1H NMR (300 MHz): δ = 0.91 (t, J = 7.1 Hz, 3 H), 1.55–1.59 (m, 2
H), 1.67–1.78 (m, 2 H), 2.22–2.27 (m, 2 H), 2.87 (s, 6 H), 2.89 (s, 6
H), 3.86–4.02 (m, 2 H), 5.07 (s, 1 H), 6.56 (d, J = 8.7 Hz, 2 H), 6.63
(d, J = 8.7 Hz, 2 H), 6.95 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2
H).
13C NMR (75 MHz): δ = 13.7, 19.8, 29.2, 38.8, 40.5, 40.7, 53.5,
61.5, 79.8, 112.2, 112.5, 129.0, 129.5, 130.7, 148.9, 168.0, 214.3.
[α]D20 –10.7 (c 1.1, CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3399–3407

3406
P. Trillo et al.
PAPER
IR (ATR): 1062, 1166, 1261, 1276, 1446, 1480, 1519, 1612, 1674,
1720, 2361, 2801, 2852, 2923, 2987, 3005 cm–1.
HRMS (ESI+): m/z [M+ + H] calcd for C26H31N2O3S: 451.2055;
found: 451.2043.
1H NMR (300 MHz): δ = 2.04 (s, 3 H), 2.79 (s, 6 H), 2.89 (s, 6 H),
4.93 (d, J = 12.0 Hz, 1 H), 5.51 (d, J = 12.0 Hz, 1 H), 6.50 (d, J =
8.7 Hz, 2 H), 6.65 (d, J = 8.7 Hz, 2 H), 7.06 (d, J = 8.7 Hz, 2 H),
7.20 (d, J = 8.8 Hz, 2 H), 7.41 (m, 2 H), 7.50–7.55 (m, 1 H), 7.91–
8.00 (m, 2 H).
13C NMR (75 MHz): δ = 27.5, 40.6, 49.8, 69.7, 112.8, 112.9, 127.8,
128.1, 128.2, 128.6, 128.6, 128.8, 133.3, 195.3, 201.0.
Ethyl 2-Oxo-1-(9H-thioxanthen-9-yl)cyclopentanecarboxylate
(3ca)6
Yellow solid; yield: 37 mg (70%); 18% ee; mp 73–74 °C; Rf = 0.37
(hexane–EtOAc, 4:1). Chiral HPLC analysis (Chiralcel IA column,
hexane–EtOH, 99.5:0.5, flow rate = 1 mL/min, λ = 254 nm): tR =
17.03 (minor), 18.10 min (major).
1H NMR (300 MHz): δ = 1.15 (t, J = 7.2 Hz, 3 H), 1.26–1.29 (m, 1
H), 1.62–1.78 (m, 3 H), 2.18–2.38 (m, 1 H), 2.57–2.83 (m, 1 H),
3.93–4.01 (m, 2 H), 5.23 (s, 1 H), 7.02–7.63 (m, 8 H).
MS (EI): m/z (%) = 414 [M+, 1], 255 (18), 254 (100), 253 (78), 237
(15), 210 (28), 134 (17), 126 (13), 118 (11).
13C NMR (75 MHz): δ = 13.9, 19.7, 28.7, 37.5, 50.2, 61.8, 69.6,
126.2, 126.6, 126.8, 127.2, 130.2, 131.3, 132.6.
MS (EI): m/z (%) = 352 [M+, 2], 198 (16), 197 (100), 165 (8).
HRMS (ESI+): m/z [M+ + H] calcd for C27H31N2O2: 415.2386;
found: 415.2386.
2-Acetyl-2-{bis[4-(dimethylamino)phenyl]methyl}cyclopentan-
one (3ah)
Colorless oil; yield: 34 mg (60%); 18% ee; Rf = 0.55 (hexane–
EtOAc, 4:1). Chiral HPLC analysis (Chiralcel ASH column,
hexane–i-PrOH, 97/3, flow rate = 1 mL/min, λ = 254 nm): tR = 6.78
(minor), 7.81 min (major).
1H NMR (300 MHz): δ = 1.63–1.75 (m, 2 H), 2.00–2.17 (m, 2 H),
2.10 (s, 3 H), 2.33–2.42 (m, 2 H), 2.86 (s, 6 H), 2.88 (s, 6 H), 5.17
(s, 1 H), 6.55–7.04 (m, 6 H), 7.73–7.78 (m, 2 H).
13C NMR (75 MHz): δ = 20.2, 25.8, 26.1, 27.3, 40.5, 53.8, 62.7,
128.2, 128.5, 128.7, 129.3, 129.4, 129.5, 130.4, 149.0, 190.5, 203.4.
1-(Phenylsulfonyl)-1-(9H-thioxanthen-9-yl)propan-2-one (3cj)
White solid; yield: 41 mg (69%); 97% ee; mp 153–154 °C; Rf = 0.58
(hexane–EtOAc, 4:1). Chiral HPLC analysis (Chiralcel ODH col-
umn, hexane–i-PrOH, 92:8, flow rate = 1 mL/min, λ = 254 nm): tR =
13.98 (minor), 26.47 min (major).
[α]D20 +6.96 (c 1, CHCl3).
IR (ATR): 1073, 1083, 1146, 1272, 1307, 1325, 1358, 1443, 1464,
1584, 1721, 2162, 2192, 2341, 2336, 2931, 2970, 3011, 3063 cm–1.
1H NMR (300 MHz): δ = 1.79 (s, 3 H), 5.13 (d, J = 11.0 Hz, 1 H),
5.31 (d, J = 11.0 Hz, 1 H), 7.06–7.30 (m, 7 H), 7.32–7.46 (m, 4 H),
7.63–7.66 (m, 2 H).
13C NMR (75 MHz): δ = 33.1, 48.3, 69.0, 126.9, 127.2, 127.3,
127.5, 127.6, 127.7, 128.7, 130.1, 131.6, 133.1, 133.8.
MS (EI): m/z (%) = 394 [M+, 2], 198 (15), 197 (100), 165 (10).
MS (EI): m/z (%) = 378 [M+, 0.5], 281 (35), 254 (64), 253 (69), 237
(13), 208 (21), 207 (100), 191 (15), 134 (12).
Ethyl 3,3-Bis[4-(dimethylamino)phenyl]-2-nitropropanoate
(3ai)
Yellow oil; yield: 41 mg (71%); 26% ee; Rf = 0.32 (hexane–EtOAc,
4:1). Chiral HPLC analysis (Chiralcel ADH column, hexane–
i-PrOH, 96:4, flow rate = 1 mL/min, λ = 254 nm): tR = 30.89 (mi-
nor), 41.31 min (major).
HRMS (ESI+): m/z [M+ + Na] calcd for C22H18O3S2Na: 417.0595;
found: 417.0596.
Ethyl (E)-1-[1,3-Bis(4-methoxyphenyl)allyl]-2-oxocyclopen-
tanecarboxylate (5ba)
IR (ATR): 1061, 1096, 1130, 1162, 1311, 1351, 1444, 1518, 1559,
1611, 1746, 2341, 2360, 2802, 2851, 2921, 2975 cm–1.
1H NMR (300 MHz): δ = 1.05 (t, J = 7.1 Hz, 3 H), 2.88 (s, 12 H),
4.05 (qd, J = 7.1, 2.7 Hz, 2 H), 4.83 (d, J = 12 Hz, 1 H), 5.82 (d, J =
12 Hz, 1 H), 6.63 (dd, J = 8.8, 4.2 Hz, 4 H), 7.13 (m, 4 H).
13C NMR (75 MHz): δ = 13.6, 40.4, 40.5, 62.7, 77.2, 91.8, 112.7,
112.8, 125.8, 126.6, 127.9, 128.7, 149.7, 149.8, 163.5.
MS (EI): m/z (%) = 385 [M+, 4], 255 (17), 254 (100), 253 (81), 237
Colorless oil; yield: 44 mg (72%); 48% and 12% ee obtained as
diastereomeric mixture 73:27 dr; Rf = 0.38 (hexane–EtOAc, 4:1).
Chiral HPLC analysis (Chiralcel IA column, hexane–EtOH, 96:4,
flow rate = 1 mL/min, λ = 230 nm): tR = 13.97 (minor), 16.88 (ma-
jor), 15.17 (major), 18.72 min (minor).
IR (ATR): 1103, 1137, 1265, 1402, 1420, 1462, 1607, 1718, 1748,
2835, 2932, 2957 cm–1.
1H NMR (400 MHz): δ = 1.10 (t, J = 7.1 Hz, 3 H), 1.19 (t, J = 7.1
Hz, 3 H), 1.65–1.89 (m, 4 H), 2.05–2.25 (m, 4 H), 2.35–2.42 (m, 2
H), 2.68–2.73 (m, 2 H), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.77 (s, 3 H),
3.78 (s, 3 H), 3.79 (s, 3 H), 3.98–4.18 (m, 4 H), 4.35 (m, 1 H), 4.49
(m, 1 H), 6.22–6.28 (m, 3 H), 6.44 (d, J = 15.7 Hz, 1 H), 6.79–6.83
(m, 8 H), 7.19–7.27 (m, 8 H).
13C NMR (100 MHz): δ = 13.9, 14.2, 19.6, 19.8, 28.4, 29.9, 38.9,
39.0, 51.4, 52.1, 55.2, 55.3, 61.6, 61.8, 66.3, 66.6, 113.7, 113.8,
113.84, 113.9, 125.5, 126.3, 127.5, 127.51, 128.2, 128.3, 128.5,
128.6, 129.5, 129.7, 129.8, 129.9, 130.7, 131.7, 131.9, 132.0, 132.2,
158.5, 159.1, 169.2, 213.6, 213.7.
MS (EI): m/z (%) = 408 [M+, 1], 355 (17), 354 (100), 339 (13), 308
(12), 281 (14), 207 (10), 177 (20).
HRMS (ESI+): m/z [M+ + Na] calcd for C25H28O5Na: 431.1834;
found: 431.1843.
(12), 210 (25), 207 (14), 134 (17), 126 (13).
HRMS (ESI+): m/z [M+ + H] calcd for C21H28N3O4: 386.2080;
found: 386.2080.
4,4-Bis[4-(dimethylamino)phenyl]-3-(phenylsulfonyl)butan-2-
one (3aj)
Brown solid; yield: 37 mg (51%); 48% ee; mp 202–204 °C; Rf =
0.57 (hexane–EtOAc, 4:1). Chiral HPLC analysis (Chiralcel IA col-
umn, hexane–EtOH, 70:30, flow rate = 1 mL/min, λ = 254 nm): tR =
19.32 (major), 81.42 min (minor).
[α]D20 +7.3 (c 0.6, CHCl3).
IR (ATR): 1135, 1245, 1294, 1348, 1447, 1516, 1608, 1720, 2339,
2355, 2796, 2852, 2922, 2948 cm–1.
1H NMR (300 MHz): δ = 2.23 (s, 3 H), 2.84 (s, 12 H), 4.53 (d, J =
12.2 Hz, 1 H), 5.04 (d, J = 12.2 Hz, 1 H), 6.38 (d, J = 8.8 Hz, 2 H),
6.54 (d, J = 8.8 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.05 (d, J = 8.8
Hz, 2 H), 7.26–7.46 (m, 5 H).
13C NMR (75 MHz): δ = 29.7, 40.4, 40.6, 49.5, 80.5, 112.7, 112.8,
127.3, 128.2, 128.4, 128.5, 128.6, 133.0, 139.6, 149.4, 149.5, 199.6.
MS (EI): m/z (%) = 450 [M+, 2], 255 (18), 254 (100), 253 (80), 237
Ethyl (E)-1-[1,3-Bis(4-methoxyphenyl)allyl]-2-oxocyclohexane-
carboxylate (5bb)
Yellow oil; yield: 42 mg (67%); 5% and 10% ee obtained as diaste-
reomeric mixture 63:37 dr; Rf = 0.40 (hexane–EtOAc, 4:1). Chiral
HPLC analysis (Chiralcel IA column, hexane–EtOH, 98:2, flow
rate = 1 mL/min, λ = 254 nm): tR = 12.78 (major), 15.51 (minor),
14.24 (minor), 18.18 min (major).
(15), 210 (24), 134 (16), 126 (15), 118 (11).
Synthesis 2014, 46, 3399–3407
© Georg Thieme Verlag Stuttgart · New York

PAPER
Organocatalyzed Asymmetric Alkylation
3407
IR (ATR): 1092, 1131, 1176, 1202, 1248, 1299, 1365, 1441, 1463,
1509, 1578, 1607, 1710, 2835, 2863, 2935, 3030 cm–1.
J.; Vorholt, A. J.; Ostrowski, K. A.; Behr, A.; Christmann,
M. Chem. Eur. J. 2012, 18, 9496.
(4) Organocatalytic Enantioselective Conjugate Addition
Reactions; Vicario, J. L.; Badia, D.; Carrillo, L.; Reyes, E.,
Eds.; RSC: Cambridge, 2010.
(5) Shibata, M.; Ikeda, M.; Motoyama, K.; Miyake, Y.;
Nishibayashi, Y. Chem. Commun. 2012, 48, 9528.
(6) Trillo, P.; Baeza, A.; Nájera, C. Adv. Synth. Catal. 2013,
355, 2815.
(7) For recent contributions from our group about allylic
substitution using free alcohols as alkylating agents, see:
(a) Giner, X.; Trillo, P.; Nájera, C. J. Organomet. Chem.
2010, 696, 357. (b) Trillo, P.; Baeza, A.; Nájera, C. Eur. J.
Org. Chem. 2012, 2929. (c) Trillo, P.; Baeza, A.; Nájera, C.
J. Org. Chem. 2012, 77, 7344. (d) Trillo, P.; Baeza, A.;
Nájera, C. ChemCatChem 2013, 5, 1538.
1H NMR (300 MHz): δ = 1.06–1.112 (m, 6 H), 1.54–1.77 (m, 8 H),
1.93–1.95 (m, 2 H), 2.42–2.46 (m, 4 H), 2.56–2.59 (m, 2 H), 3.76
(s, 3 H), 3.77 (s, 3 H), 3.78 (s, 3 H), 3.79 (s, 3 H), 3.90–4.15 (m, 6
H), 6.28–6.34 (m, 2 H), 6.48–6.57 (m, 2 H), 6.78–6.82 (m, 8 H),
7.24–7.33 (m, 8 H).
13C NMR (75 MHz): δ = 13.9, 13.97, 22.7, 26.7, 27.0, 33.7, 34.9,
42.0, 52.4, 52.9, 55.1, 55.2, 55.3, 58.6, 60.4, 61.3, 65.9, 65.97, 66.1,
113.3, 113.4, 113.8, 114.8, 116.0, 126.9, 127.4, 127.5, 130.1, 130.2,
130.9, 131.1, 131.4, 131.5, 131.9, 132.3, 158.3, 158.4, 158.9, 159.0,
170.9, 191.6, 206.7, 206.9, 206.93.
MS (EI): m/z (%) = 422 [M+, 0.3], 404 (18), 254 (22), 253 (100),
145 (23), 121 (12).
HRMS (ESI+): m/z [M+ + H] calcd for C26H30O5: 423.2171; found:
423.2171.
(8) For selected recent publications from our group dealing with
the use of activated methylene compounds in
enantioselective reactions, see: (a) Tarí, S.; Chinchilla, R.;
Nájera, C. Tetrahedron: Asymmetry 2009, 20, 2651.
(b) Almaşi, D.; Alonso, D. A.; Gómez-Bengoa, E.; Nájera,
C. J. Org. Chem. 2009, 74, 6163. (c) Tarí, S.; Chinchilla, R.;
Nájera, C. Tetrahedron: Asymmetry 2010, 21, 2872.
(d) Tarí, S.; Chinchilla, R.; Nájera, C.; Yus, M. ARKIVOC
2011, 7, 116; http://www.arkat-usa.org/home. (e) Gómez-
Torres, E.; Alonso, D. A.; Gómez-Bengoa, E.; Nájera, C.
Org. Lett. 2011, 13, 6106. (f) Gómez-Torres, E.; Alonso, D.
A.; Gómez-Bengoa, E.; Nájera, C. Eur. J. Org. Chem. 2013,
1434; and references therein.
Acknowledgment
Spanish Ministerio de Ciencia e Innovación (MICINN) (projects
CTQ2010-20387 and Consolider Ingenio 2010, CSD2007-00006),
FEDER, the Generalitat Valenciana (PROMETEO 2009/039) and
the University of Alicante are gratefully acknowledged for financial
support. A.B. would also like to thank University of Alicante (Pro-
ject GRE12-03).
Supporting Information for this article is available online
(9) The E values (electrophilicity parameters in Mayr’s scale)
are related with carbocation stability and hence with the
reactivity. Thus, lower E value implies higher stability and
lower reactivity. E (1a+) = –7.02; E (1b+) = +0.47; E (1d+) =
0; E (4a) = +2.70; E (4b) = –1.45. Extracted from:
(a) Minegishi, S.; Mayr, H. J. Am. Chem. Soc. 2003, 125,
286. (b) Ammer, J.; Nolte, C.; Mayr, H. J. Am. Chem. Soc.
2012, 134, 13902. For selected reviews on this topic, see:
(c) Mayr, H.; Ofial, A. R. Pure Appl. Chem. 2005, 77, 1807.
(d) Mayr, H.; Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584.
(e) Cozzi, P. G.; Benfatti, F. Angew. Chem. Int. Ed. 2010, 49,
256.
(10) See Supporting Information for further experiments and
details.
(11) For recent reviews about the use of free allylic alcohols in
enantioselective processes, see: (a) Bandini, M. Angew.
Chem. Int. Ed. 2011, 50, 994. (b) Bandini, M.; Cera, G.;
Chiarucci, M. Synthesis 2012, 44, 504.
(12) Very recently a metal-free Tsuji–Trost type reaction has
been published using chiral phosphoric acids as the
organocatalyst: Wang, P.-S.; Zhou, X.-L.; Gong, L.-Z. Org.
Lett. 2014, 16, 976.
(13) (a) Galliford, C. V.; Scheidt, K. A. Chem. Commun. 2008,
1926. (b) House, H. O.; Hudson, C. B. J. Org. Chem. 1979,
35, 647. (c) Bowman, W. R.; Westlake, P. J. Tetrahedron
1992, 48, 4027.
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
m
o
nr
i
References
(1) For reviews about the use of free alcohols in substitution
reactions, see: (a) Muzart, J. Eur. J. Org. Chem. 2007, 3077.
(b) Emer, E.; Sinisi, R.; Guiteras-Capdevila, M.;
Petruzzielo, D.; De Vicentiis, F.; Cozzi, P. G. Eur. J. Org.
Chem. 2011, 647. (c) Biannic, B.; Aponick, A. Eur. J. Org.
Chem. 2011, 6605. (d) Baeza, A.; Nájera, C. Synthesis 2014,
46, 25.
(2) Cozzi, P. G.; Benfatti, F.; Zoli, L. Angew. Chem. Int. Ed.
2009, 48, 1313.
(3) For recent selected examples, see: (a) Bergonzini, G.; Vera,
S.; Melchiorre, P. Angew. Chem. Int. Ed. 2010, 49, 9685.
(b) Stiller, J.; Márques-López, E.; Herrera, R. P.; Frölich, R.;
Strohmann, C.; Christmann, M. Org. Lett. 2011, 13, 70.
(c) Xiao, J.; Zhao, K.; Loh, T.-P. Chem. Asian J. 2011, 6,
2890. (d) Wilcke, D.; Herdtweck, E.; Bach, T. Synlett 2011,
1235. (e) Xiao, J.; Zhao, K.; Loh, T.-P. Chem. Commun.
2012, 48, 3548. (f) Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-
P.; Peng, Y.-G.; Guo, Q.-X. Angew. Chem. Int. Ed. 2012, 51,
1059. (g) Trifonidou, M.; Kokotos, C. G. Eur. J. Org. Chem.
2012, 1563. (h) Xiao, J. Org. Lett. 2012, 14, 1716. (i) Stiller,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3399–3407