Pyridylmagnesiates: Generation by bromine-metal exchange and enantioselective addition to aldehydes

Article abstract of DOI:10.1016/j.tet.2012.03.058

Butyl and dibutylmagnesiates incorporating chiral ligands have been prepared and their reactivity studied. The reagents were efficient to promote the clean bromine-magnesium exchange of azinyl bromides at room temperature and subsequent reaction with aldehydes affording pyridylcarbinols. (R,R)-TADDOL-based dibutylmagnesiate was the best reagent leading to acceptable to good enantioselectivities, depending on the substrate and on the aldehyde substitution. This is the first example of enantioselective addition of in situ generated pyridylmagnesiate to carbonyl electrophiles.

Full text of DOI:10.1016/j.tet.2012.03.058

Tetrahedron 68 (2012) 4018e4028
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pyridylmagnesiates: generation by bromineemetal exchange
and enantioselective addition to aldehydes
,
Delphine Catel a, Olivier Payen a, Floris Chevallier b, Florence Mongin b, Philippe C. Gros a
*
a
ꢀ
ꢁ
SOR, SRSMC, Universite de Lorraine, CNRS, Boulevard des Aiguillettes, 54506 Vandoeuvre-Les-Nancy, France
ˇ
b
ꢀ
ꢀ
Chimie et Photonique Moleculaires, Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS, Universite de Rennes 1, Batiment 10A, Case 1003, Campus Scientifique de Beaulieu,
35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Butyl and dibutylmagnesiates incorporating chiral ligands have been prepared and their reactivity
studied. The reagents were efficient to promote the clean bromineemagnesium exchange of azinyl
bromides at room temperature and subsequent reaction with aldehydes affording pyridylcarbinols. (R,R)-
TADDOL-based dibutylmagnesiate was the best reagent leading to acceptable to good enantioselectiv-
ities, depending on the substrate and on the aldehyde substitution. This is the first example of enan-
tioselective addition of in situ generated pyridylmagnesiate to carbonyl electrophiles.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 29 February 2012
Accepted 16 March 2012
Available online 23 March 2012
Keywords:
Organomagnesiates
Bromineemetal exchange
Pyridylcarbinols
(R,R)-TADDOL
Chirality
1. Introduction
presence of an excess of reactive butyl ligands and side reactions
such as reduction of electrophilic reagents or alkylation in the
The metallation of organic compounds using organometallates
has attracted much attention. Indeed, these reagents are able to
promote chemoselective reactions under much milder conditions
than their organolithium counterparts while allowing for direct
introduction of metals onto the aromatic rings and further cross-
coupling reactions.1 Polyalkylzincates are attractive reagents. t-
Bu4ZnLi2 has been reported by Uchiyama and co-workers to be
highly chemoselective for iodineezinc or bromineezinc exchange
in the aromatic series.2 Hevia and co-workers also reported the use
of a magnesiumezinc reagent, [(Mg2Cl3(THF)6)þ, t-Bu3Znꢀ], to be
efficient in such reaction.3 In the same time we have shown that n-
Bu4ZnLi2$TMEDA could be reacted substoichiometrically (1:3 equiv
vs substrate) at room temperature with a set of bromopyridines to
give a clean halogenemetal exchange process.4 Magnesium-based
ate complexes are also of great interest since the reactivity of the
formed aromatic organometallics is generally better than that of
the corresponding organozincates especially towards carbonyl
compounds.5 Iida and Mase have reported the magnesiation of
bromopyridines and aromatic halides using a substoichiometric
amount of n-Bu3MgLi in apolar solvent.6 At the same time, Oshima
described the stoichiometric use of n-BuMe2MgLi7 to avoid the
trapping step. The use of alkoxides as ligands in magnesiates is
a promising alternative8 for several reasons: (i) only the expected
reactive species should be transferred, (ii) the ate complex benefits
in terms of stability and gentle reaction conditions should be
maintained, and (iii) tuning of the reactivity and access to asym-
metric synthesis using appropriate ligands should be possible.
Mukaiyama reported the asymmetric alkylation of prochiral car-
bonyl derivatives using combinations of diaminoalkoxides and
Grignard reagents9 while dilithium dialkylmagnesiates derived
from lithium BINOLate has been reported by Noyori to give high
enantioselectivities in alkylation of aldehydes.10 The interest in
such an approach is to have a well-arranged bimetallic reagent with
saturated metal coordination sites avoiding side aggregation and
subsequent loss of chirality. An additional benefit effect is a poten-
tial cooperative effect of lithium and magnesium in activation of
both nucleophile and electrophile. Pyridylcarbinols are excellent
candidates as such or as precursors of chiral ligands for asymmetric
synthesis and kinetic resolution,11 and thus their preparation in
enantiomerically pure form is a critical issue to develop their syn-
thetic usefulness.12,13 The most efficient synthesis of non-racemic
pyridylalcohols reported to date is the Bolm’s multistep reaction
involving asymmetric reduction of the corresponding pyr-
idylketones by chiral borane.14 Several diastereoselective ap-
proaches have been also developed, the first being reported by
Chelucci who trapped 2-pyridyllithium intermediates with
* Corresponding author. E-mail address: philippe.gros@univ-lorraine.fr (P.C.
Gros).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.058

D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
4019
naturally occurring optically active ketones.15 So there is a lack of
straightforward method to access chiral pyridylalcohols from
a pyridine derivative and a prochiral carbonyl electrophile. The
chiral ligand-containing organomagnesiate approach thus could be
a promising alternative to create a well-shaped and robust chiral
environment (Scheme 1). Here we report that the incorporation of
chiral ligands into organomagnesiates led to efficient reagents for
room temperature bromine-magnesium exchange of sensitive
bromoazines and subsequent asymmetric transfer of the formed
azinylorganometallics to carbonyl electrophiles.
were reacted efficiently, giving the expected alcohols 2 in good
to high yields. Electron-donating or electron-withdrawing sub-
stituents at the para-position of benzaldehydes gave 50e84% yields
(runs 1e8). The alcohol bearing the CF3 group was obtained in 83%
yield (run 4).
Table 1
2-Pyridylalcohols synthesis using (BINOLate)BuMgLi
1) (BINOLate)BuMgLi (1 equiv.)
R1
THF, -5 °C to r.t., 1 h
R2
N
2b-k
2) R1COR2 (1.5 equiv.)
-60 °C to r.t., 1 h
3) Hydrolysis
N
Br
FG
Li
OH
FG
Li
L*
N
1
L*
L*
Bu
N
Br
g
M
RCHO
R
OH*
Mg
N
L*
FG
Exchange
Trapping
Run
1
R1
R2
Product, yielda,b [%]
Scheme 1. Exchange-trapping sequence considered for the synthesis of chiral pyr-
idylcarbinols from chiral ligand-containing magnesiates.
OMe
H
2a, 75
2. Results and discussion
MeO
2
3
H
H
2b, 84
2c, 66c
From the works by Noyori and co-workers on asymmetric al-
kylation of carbonyl derivatives,10 BINOL was chosen as model li-
gand and the less expensive racemic form was used for reactivity
experiments. rac-BINOL was first deprotonated using n-BuLi
(2 equiv) in THF and the formed BINOLate was reacted with n-
BuMgCl (1 equiv) in order to get putative (BINOLate)BuMgLi
(Scheme 2). 2-Bromopyridine (1) was then treated with a stoi-
chiometric amount of generated (BINOLate)BuMgLi magnesiate
and the mixture quenched with p-anisaldehyde (Scheme 3).
MeO
OMe
OMe
OMe
OMe
4
H
2d, 50
OMe
NMe2
t-Bu
NO2
CF3
5
H
H
H
H
H
H
2e, 71d
2f, 71
2g, 75
2h, 83
2i, 81
2j, 85
Li
n-BuMgCl (1 equiv.)
O
O
Bu
THF-hexanes
OLi
OLi
Mg
-5 °C, 20 min
6
racemic
(BINOLate)BuMgLi
7
Scheme 2. Preparation of (BINOLate)BuMgLi.
8
1) (BINOLate)BuMgLi (1 equiv.)
OMe
Solvent, -5 °C to r.t., 1 h
Me
N
2) p-anisaldehyde (1.5 equiv.)
Solvent , -60 °C to r.t., 1 h
3) Hydrolysis
9
N
Br
OH
in toluene: 2a, 71%
in THF: 2a, 75%
1
10
Scheme 3. Exchange of 2-bromopyridine using (BINOLate)BuMgLi followed by trap-
ping with p-anisaldehyde.
11
12
13
14
t-Bu
Et
Ph
H
2k, 58d,e
df
Me
Me
Ph
dg
A short optimization study showed that, whatever the condi-
tions, (BINOLate)BuMgLi promoted the exchange reaction, leading
to the expected alcohol 2a as main product. In a separate experi-
ment, we have checked that, in contrast with i-PrMgCl,16 n-BuMgCl
was unable to promote the exchange of 2-bromopyridine, strongly
supporting the formation of the magnesiate by contact with
BINOLate. (BINOLate)BuMgLi reagent was found efficient in ex-
changing bromine of 2-bromopyridine at room temperature and
the corresponding pyridine organometallic was readily trapped
by p-anisaldehyde. A clean reaction was obtained in toluene or THF,
leading to the pyridylcarbinol 2a in 71 and 75% yield, respectively.
The scope of the exchange-trapping sequence on 2-
bromopyridine was then investigated using a set of carbonyl elec-
trophiles (Table 1). As shown, aromatic and aliphatic aldehydes
t-Bu
2l, 60h
The conversion, determined by 1H NMR integration, was >98% except when
a
mentioned.
b
c
Isolated yield after column chromatography.
Trapping step: 19.5 h.
Trapping step: 2 h.
Sublimation of 2k occurred.
No product was formed.
Complex mixture.
d
e
f
g
h
Trapping step: 21 h.
The introduction of substitution ortho to the carbonyl group
such as MeO or Me did not affect the reactivity, also giving

4020
D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
high yields of, respectively, 84 and 81% (runs 2 and 9). The trime-
thoxybenzaldehydes were reacted efficiently, even in case of ste-
rically crowded 2,4,6-trimethoxybenzaldehyde provided that an
extended time for the trapping step was applied (run 3). A good
yield was also obtained with bulky 1-naphthaldehyde (run 7, 85%).
Trimethylacetaldehyde gave the corresponding alcohol 2k, which
was isolated in acceptable yield despite a marked trend to sub-
limation (run 11). Unfortunately, methyl ethyl ketone did not afford
the expected alcohol (run 12), and acetophenone gave a complex
mixture of unidentified products (run 13), results that could be in
relation with possible enolization. Indeed, from non-enolizable 2,2-
dimethylpropiophenone, we were pleased to obtain the tertiary
alcohol 2l in acceptable yield (run 14, 60%) after extending the in-
terception time to 21 h.
2-pyridylmagnesiate. Then we examined the reaction with highly
coordinated (BINOLate)Bu2MgLi2 using 0.5 equiv of this reagent
(Scheme 4). We were pleased to obtain products 8 and 9 in ac-
ceptable to excellent yields. The bromineemagnesium exchange
was complete in both cases, but slower with 4-bromopyridine (2 h
instead of 1 h for 3-bromopyridine). 3-Pyridylalcohol 8 was pro-
duced in excellent yield (87%). Thus the use of highly coordinated
magnesiate confirmed that the low yields obtained using (BINO-
Late)BuMgLi were not due to a lack of stability of the pyr-
idylmagnesiates but due to a lack of nucleophilicity of the pyridyl
ligand; the latter could be dramatically enhanced using a highly
coordinated magnesiate.
The reaction using p-anisaldehyde was also examined from
some other azine bromides (Table 2). First, it must be mentioned
that the bromoheterocycles were exchanged quantitatively using
(BINOLate)BuMgLi. The introduction of a methoxy group at the 3-
position of the pyridine substrate and thus at the position adjacent
to the metal centre in the intermediate pyridylmagnesiate did not
affect the reaction course. When the methoxy group was placed at
C-6, the conversion was complete and 6 was obtained in excellent
89% yield (run 2). Finally, 2-bromoquinoline was also involved in
the reaction, leading to the alcohol 7 in 56% yield (run 3).
Li
Li
n-BuLi (1 equiv.)
O
O
Bu
O
O
Bu
Bu
THF-hexanes
Mg
Mg
-5 °C, 20 min
Li
(BINOLate)BuMgLi
(BINOLate)Bu2MgLi2
1) (BINOLate)Bu2MgLi2
(0.5 equiv.)
THF, -5 °C to r.t., 1-2 h
OMe
4
N
N
4
2) p-anisaldehyde (1.5 equiv.)
-60 °C to r.t., 1.5 h
3
3
Br
OH
3) Hydrolysis
Table 2
3: at C-3
4: at C-4
8 (at C-3), 87%
9 (at C-4), 49%
Reaction of (BINOLate)BuMgLi with bromoazines
OMe
1) (BINOLate)BuMgLi (1 equiv.)
Scheme 4. Preparation of (BINOLate)Bu2MgLi2 and reaction with 3- and 4-
bromopyridines.
THF, -5 °C to r.t., 1 h
HetAr
HetArBr
2) p-anisaldehyde (1.5 equiv.)
OH
-60 °C to r.t., 1.5 h
5-7
3) Hydrolysis
After having demonstrated the efficiency of the exchange-
trapping sequence using rac-BINOLate as model ligand, we turned
to the asymmetric version of the reaction. Butylmagnesiates were
prepared from several chiral ligands including alkoxides, amides,
aminoalkoxides, and dialkoxides in order to examine their re-
activity and ability to induce asymmetry during the process
(Table 3). The ligands were first deprotonated using the appropriate
amount of n-BuLi (1 equiv for alcohols/amine or 2 equiv for diols) in
THF and the resulting lithiated species were reacted with n-BuMgCl
(0.5 equiv for alcohols/amine or 1 equiv for diols) in order to gen-
erate the putative magnesiates (Scheme 5). These latter were
treated with 2-bromopyridine (1) under stoichiometric conditions
to perform the BreMg exchange step. Finally, a subsequent trap-
ping step using p-anisaldehyde as electrophile allowed to obtain
the expected enantioenriched pyridylcarbinol 2a (Table 3).
Run
1
HetArBr
OMe
Br
Product, yielda [%]
5, 51 (94)b
N
2
3
4
6, 89 (>98)
7, 56 (>98)c
8, dd (27)
Br
MeO
N
N
Br
N
N
Br
Br
Interestingly, chiral alkoxides derived from menthol or borneol
led to a complete bromineemagnesium exchange with the for-
mation of the expected pyridylalcohol 2a in acceptable to excellent
yields (51% and >98%, respectively). Unfortunately, any enantio-
control was observed (runs 1 and 2). The exchange also proceeded
5
9, de
completely with
termediate did not exhibit any nucleophilicity towards p-ani-
saldehyde in the trapping step (run 3).
-Aminoalkoxides were also
a chiral amide but the organometallic in-
a
Isolated yield after column chromatography (the NMR yield is given in brackets).
Trapping step: 2 h.
Moderate yields due to purification issues.
Complex mixture impeding isolation of 8.
No alcohol formed.
b
c
b
studied. The use of 3-quinuclidinol or (1S,2R)-(þ)-N-methylephe-
drine gave good yields of pyridylalcohol (>98% and 82% yields,
respectively) with however a poor enantioselectivity (ers of 52:48
and 48:52, respectively, runs 5 and 6). Surprisingly lithium N-
methylpyrrolidinemethoxide, that was found efficient in lithiation
reactions when associated to n-BuLi,16 did not give any exchange
reaction when combined with n-BuMgCl (Run 4). The reactivity
and enantioselectivity of diols were finally examined. (R,R)-
(þ)-Hydrobenzoin, after a complete exchange, sluggishly gave 2a
in only 28% yield and in racemic form (run 7). When liganded to the
Grignard reagent, (R)- or (S)-BINOLate and (R,R)-TADDOLate
d
e
In order to examine the effect of the pyridine halogen position
on the process, 3- and 4-bromopyridine (3 and 4) were reacted
with (BINOLate)BuMgLi. While the exchange was complete with
both substrates, complex mixtures were obtained, alcohol 8 was
however formed in moderate yield while no alcohol (run 4)
was formed from 4-bromopyridine (run 5). Thus it seemed to
us that 3- and 4-pyridylmagnesiates were less nucleophilic than

D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
4021
Table 3
Chiral ligand screening in exchange-trapping sequence with magnesiatesa
1) n-BuLi (1 equiv.)
L*
L*
THF, -5 °C, 1 h
Mg Bu Li
L*H
OMe
2) n-BuMgCl (0.5 equiv.)
1) Magnesiate (1 equiv.)
-5 °C, 1 h
NR2
Toluene, -5 °C to r.t., 1 h
*
N
N
Br
2) p-anisaldehyde (1.5 equiv.)
Toluene, -60 °C to r.t., 1 h
OH
2a
L*H =
, R2NH, ROH
*
1
OH
Run
1
Ligand
Yield [%]
51c
S/Rb
1) n-BuLi (2 equiv.)
OH
OH
O
THF, -5 °C, 1 h
Li
Mg Bu
*
*
2) n-BuMgCl (1 equiv.)
50:50
O
-5 °C, 1 h
HO
Scheme 5. Preparation of chiral magnesiates.
2
3
>98c
50:50
H
OH
induced a promising level of enantioselectivity. Hence, a 61:39
enantiomeric ratio was determined by chiral GC.
Starting from this first set of experiments, chiral diols were se-
lected. Different parameters (solvent, source of magnesiate, and
trapping temperature) and several ligands based on BINOL and
TADDOL skeletons were screened (Table 4). TADDOL analogues
T1eT4 were prepared according to published procedures19e21 from
trans-dimethyl tartrate acetonide and the appropriate Grignard
reagents (Scheme 6). Monobutylmagnesiate LBuMgLi and dibu-
tylmagnesiates LBu2MgLi2 were prepared according to Scheme 7.
Two routes were investigated to generate LBu2MgLi2 species. After
deprotonation of the diol with n-BuLi (2 equiv), the resulting alk-
oxide was treated according to two different procedures: n-BuMgCl
(1 equiv) and n-BuLi (1 equiv) were added successively (Route A), or
n-Bu2Mg (1 equiv) was added (Route B). The formed magnesiate
(0.5 equiv) was then reacted with 1 and the medium subsequently
quenched by the aldehyde.
dd,e
d
H
Ph
HN
Me
df
d
OH
OH
N
4
5
6
>98d
82d
52:48
48:52
N
Ph
Me
HO
NMe2
Ph
HO
Ph
7
8
28c
50:50
50:50
Table 4
OH
Chiral diols screening in exchange-trapping sequence with magnesiates
1) LBuMgLi (1 equiv.)
or LBu2MgLi2 (0.5 equiv.)
OMe
OH
OH
74d
Solvent, -5 °C to r.t., 1 h
*
N
2) p-anisaldehyde (1.5 equiv.)
solvent, T °C, 1 h
N
Br
OH
2a
1
3) Hydrolysis
Run
Ligand
Reagenta
Solvent, T [ꢁC]
2ab,c [%]
S/Rd
OH
OH
9
88d
50:50
61:39
1
2
3
4
5
6
7
8
(R,R)-TADDOL
(R,R)-TADDOL
(R,R)-TADDOL
(R,R)-TADDOL
(R,R)-TADDOL
(R,R)-TADDOL
T1
T2
T3
T4
L
L
L
L
L
L
L
L
L
L
L
L
L
L
*
*
*
*
*
*
*
*
*
*
*
*
*
*
BuMgLi
BuMgLi
BuMgLi
BuMgLi
PhMe, ꢀ60 to rt
PhMe, ꢀ60
ꢀ60
59
55
56
93
64
68
11
64
56
47
68
79
54
38
61:39
58:42
63:37
60:40
73:27
70:30
58:42
66:34
50:50
50:50
54:46
28:72
17:83
88:12
rt
Ph
Bu2MgLi2
Bu2MgLi2
Bu2MgLi2
Bu2MgLi2
Bu2MgLi2
Bu2MgLi2
Bu2MgLi2
Bu2MgLi2
Bu2MgLi2
Bu2MgLi2
ꢀ60
Ph
OH
ꢀ60
O
10
59,c 65d
ꢀ60
ꢀ60
OH
Ph Ph
O
9
ꢀ60
10
11
12
13
14
ꢀ60
a
(R)-BINOL
(R)-BIPHEN H2
(R)-BIPHEN H2
(R,R)-TADDOL
ꢀ60
A solution of 2-bromopyridine in toluene (C¼0.21 M) was added to the mixture
containing the magnesiate, then p-anisaldehyde in solution in toluene (C¼0.63 M)
was added. The bromineemetal exchange was complete except when otherwise
stated.
ꢀ60
ꢀ100
ꢀ100
er determined by chiral GC using as reference known (S) compound.18
b
a
All the LBu2MgLi2 magnesiates were prepared according to Route A (see Scheme
7) except in run 6 (Route B).
c
Yield determined by GC.
Determined by 1H NMR integration.
p-Anisaldehyde was recovered.
The exchange reaction did not proceed, and the reaction was thus stopped be-
d
b
The bromineemetal exchange was complete.
e
c
Yield determined by GC.
f
d
er determined by chiral GC using as reference known (S) compound.18
fore adding p-anisaldehyde.
afforded alcohol 2a in good yields (59e88%) after complete
bromine-metal exchange (runs 8e10). Whereas BINOLate
ligands afforded racemic 2a, (R,R)-TADDOLate,17 a ligand pos-
sessing two stereogenic carbon centres as source of chirality,
As a first result, all experiments led to a complete bromi-
neemagnesium exchange. When (R,R)-TADDOL was used in
L BuMgLi reagent by performing the trapping step at lower tem-
*
perature (ꢀ60 ꢁC) than previously defined (see Table 3, run 10)

4022
D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
TADDOL (run 8). The naphthyl group in T3, while allowing 2a to be
prepared in acceptable yield, led to a racemic product (run 9). Fi-
nally, methyls instead of phenyl groups in (R,R)-TADDOL (T4) were
unable to operate any enantiofacial selection, leading to racemic
product in however acceptable yield (run 10). (R)-BINOL was also
compared under the same conditions, leading to poor enantiose-
lectivity (54:46) but good yield (run 11). We were pleased to see
that another axially chiral diol, BIPHEN H2, was able to give 2a in
79% yield and 28:72 er (run 12). Interestingly, the opposite enan-
tiomer was obtained in this case. An additional decrease of the
trapping temperature to ꢀ100 ꢁC was found to improve the enan-
tiocontrol, leading to 17:83 er with BIPHEN H2 (run 13) and 88:12
with (R,R)-TADDOL (run 14). (R,R)-TADDOL ligand in the dibu-
tylmagnesiate leading to the best enantioselectivity, we further
studied the process involving ((R,R)-TADDOLate)Bu2MgLi2 mag-
nesiate species with the aim to improve the enantiocontrol using
different solvents and additives (Table 5).
O
O
O
O
R R
R R
MeO
OMe
RMgX (excess)
HO
OH
THF or Et2O
reflux then r.t.
O
O
t-Bu
T1, R=
T2, R=
, 33% T3, R=
, 56%
, 49%
Me
Scheme 6. Preparation of TADDOL analogues.
T4, R= Me, 80%
Me
Route A
Li
Mg
L*BuMgLi
n-BuMgCl (1 equiv.)
O
THF-hexanes
Bu
n-BuLi (1 equiv.)
THF-hexanes
-5 °C, 20 min
Table 5
Additive and solvent effects
*
-5 °C, 20 min
O
Ph
1) n-BuLi (2 equiv.)
Solvent, -5 °C, 1 h
2) n-BuMgCl (1 equiv.)
-5 °C, 1 h
Ph
Ph
Ph
Li
Mg
Li
Ph
OH
Li
Bu
Bu
O
O
O
O
O
OLi
Bu
Bu
O
n-Bu2Mg (1 equiv.)
THF-hexanes, -5 °C, 1 h
- LiCl
O
OH
Ph
Mg
*
*
3) n-BuLi (1 equiv.)
Ph
OLi
Ph
O
-5 °C, 1 h
Li
L*Bu2MgLi2
(R,R)-TADDOL
((R,R)-TADDOLate)Bu2MgLi
2
Route B
1) ((R,R)-TADDOLate)Bu2MgLi
(0.5 equiv),
OH OH
2
t-Bu
t-Bu
OMe
Additive, -5 °C to r.t., 1 h
L = (R,R)-TADDOL, T1, T2, T3, T4,
N
2) p-anisaldehyde (1.5 equiv.)
T °C, 1 h
N
Br
OH
2a
3) Hydrolysis
(R)-BIPHEN H2
Scheme 7. Preparation of putative LBuMgLi and LBu2MgLi2.
1
Run
Additive (equiv)
Solvent
T [ꢁC]
2aa [%]
S/Rb
1
d
THF
THF
THF
Et2O
THF
THF
THF
1:1 THF/DME
7:2 THF/DME
20:3 THF/DME
ꢀ60
ꢀ60
64
43
14
Traces
38
73:27
63:37
56:44
d
2c
3
d
TMEDA (0.5)
d
ꢀ60
under the best experimental conditions (exchange step: toluene at
ꢀ5 ꢁC to room temperature for 1 h; trapping step: toluene at ꢀ60 ꢁC
to room temperature for 1 h), 2a was obtained in similar yield and
enantioselectivity (55% yield and 58:42 er with trapping step per-
formed at ꢀ60 ꢁC compared to 59% yield and 61:39 er from ꢀ60 ꢁC
to rt) (Table 4, runs 1 and 2). Keeping the temperature of the
trapping step at ꢀ60 ꢁC and removing toluene as solvent in the
exchange and trapping step (run 3) has only little effect on the
reactivity (56% yield without toluene compared to 55% with it) and
the enantioselectivity (63:37 er without toluene compared to 58:42
with it). As no benefit was showed in the enantioselectivity, toluene
was discarded for the rest of the study. The increase of the trapping
step temperature from ꢀ60 ꢁC (run 3) to room temperature (run 4)
gave pyridylcarbinol 2a in excellent yield (93%) however with
a somewhat lowered enantiomeric ratio of 60:40 (run 4). Conse-
quently low trapping temperature conditions were applied to the
next experiments. A much better enantiocontrol was made possible
4
5
6
7
8
9
10
ꢀ60
d
LiCl (2)d
ꢀ100
ꢀ100
ꢀ100
ꢀ100
ꢀ100
ꢀ100
88:12
82:18
84:16
d
21
BF3$OEt2 (1)e
18
d
d
d
df
0
27
d
83:17
a
Yields determined by GC. The bromineemetal exchange was complete except
when otherwise stated.
b
c
er determined by chiral GC using as reference known (S) compound.18
Magnesiate of 1 equiv was used.
d
LiCl (related to the ligand) of 2 equiv was used to prepare a LiCl solution in THF
and (R,R)-TADDOL was dissolved in the resulting solution to perform the deproto-
nation reaction with n-BuLi.
e
BF3$OEt2 (1 equiv related to 1) was added at ꢀ100 ꢁC just before the aldehyde.
f
Exchange reaction did not proceed.
At first, an attempt to use a double amount of magnesiate
(1 equiv related to 2-bromopyridine) decreased the yield and the
enantiomeric ratio (43% yield and 63:37 er with 1 equiv of mag-
nesiate compared to 64% yield and 73:27 er with 0.5 equiv) (runs 1
and 2). TMEDA, expected to activate organometallic species via
metal coordination was added to the reagent but the yield dropped
dramatically (14%) as well as er (56:44) (run 3). When the solvent
was switched from THF to Et2O the reaction did not proceed (run 4).
This could be explained by an inefficient stabilization of in-
termediates by Et2O. Then the temperature was decreased to
ꢀ100 ꢁC. Such experimental conditions (Table 4, run 14 and Table 5,
run 5), without the use of any additive, have already exhibited the
using the L Bu2MgLi2 magnesiate since a 73:27 er could be mea-
*
sured (run 5), and pyridylcarbinol 2a was obtained in 64% yield in
this case.
As expected, the structure of the ligand had a critical impact on
the process. The introduction of an electron-donating and bulky t-
Bu substituent on the phenyl group of the ligand T1, was found
seriously deleterious for both the yield and asymmetric process,
suggesting repulsive interactions with the aldehyde during the
trapping step. Indeed, 2a was formed only in 11% yield with a poor
58:42 er (run 7). The methyl groups in T2 were found to play
a benign role since results were similar to that obtained with (R,R)-

D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
4023
best enantiodiscrimination (88:12 er). Since better ers were
obtained when the magnesiate was formed according to Route A
(Scheme 7), i.e., in which LiCl was formed, an excess of this salt was
added. This resulted in a slight decrease of both the yield (21%) and
er (82:18) (run 6). The effect of a Lewis acid was also examined
expecting an activation of the carbonyl group and a better yield of
the trapping step by the aldehyde. However, no improvement was
noted (18% yield and 84:16 er) (run 7). Mixtures of solvents were
finally used combining THF and DME in various ratios. Ratios of 1:1
(no exchange occurred in this case, run 8) and 1:0.28 did not give
any product, while a lower amount of DME (1:0.15 ratio) led to
a result close to those obtained with THF alone (run 10). Conse-
quently, an enantiomeric ratio of 88:12 was reached, which is our
best result obtained under conditions involving the generation of
((R,R)-TADDOLate)Bu2MgLi2 magnesiate in THF using Route A (see
Scheme 7), then the exchange step with 2-bromopyridine (1)
without adding solvent, and the trapping step at ꢀ100 ꢁC with p-
anisaldehyde (see Table 5, run 5).
In order to get more insight into the trapping step, the influence
of the pyridylalkoxide intermediate formed upon reaction with the
aldehyde was studied. Yield versus enantioselectivity was thus
measured under the following conditions: ((R,R)-TADDOLate)
Bu2MgLi2 was prepared according to Scheme 7 (Route A), treated
with 2-bromopyridine and then with the aldehyde at ꢀ100 ꢁC
(Table 4, run 14). The reaction was hydrolyzed after various contact
times and the crude product was analyzed by GC to determine
yields and enantiomeric ratios (Table 6). As shown, the maximum
enantiomeric ratio was fastly reached after 5 min where the yield in
2a was only of 8% and remained constant for 2 h. From this study it
can be seen that the formed pyridylalkoxide intermediate did not
have neither deleterious nor beneficial effect on the enantiose-
lectivity. This is in agreement with the fast formation of stable
transition state. As shown, the reaction of the pyridylmagnesium
intermediate with the aldehyde was slow, 40% yield could be
reached after 2 h.
lower than in the usual mode (Table 4, run 14). A competitive
coordination of metal by the pyridine nitrogen could be involved
in this case.
The best conditions determined in Table 4, run 14 were
then applied to the reaction with various carbonyl derivatives
(Table 7). Various methoxybenzaldehydes were examined. When
the methoxy group was moved from the para to the ortho position
(run 2), a decrease of er was observed (73:27). The introduction of
an additional methoxy group at the other ortho position (run 3)
induced a substantial increase of the er (84:16). In contrast, when
the methoxy groups were placed far from the aldehyde like in
3,4,5-trimethoxybenzaldehyde (run 4), the product was obtained
in its racemic form. This first set of experiments showed the
influence of coordination in the enantioselective process.
Table 7
Pyridylcarbinols from 2-bromopyridine using ((R,R)TADDOLate)Bu2MgLi2
1) ((R,R)-TADDOLate)Bu2MgLi
(0.5 equiv.)
2
R1
R2
OH
2a-l
THF, -5 °C to r.t., 1h
N
2) R1COR2 (1.5 equiv.)
-100 °C, 1 h
N
Br
1
3) Hydrolysis
Run
1
R1
R2
H
Yielda [%]
S/Rb
OMe
2a, 35
88:12
73:27
MeO
2
3
H
H
2b, 24
2c, 21c
MeO
OMe
84:16
49:51
OMe
OMe
Table 6
Evolution of er versus yielda
OMe
4
H
2d, 28
Run
Reaction time (min)
2ab [%]
S/Rc
1
2
3
4
5
30
60
8
19
28
40
86:14
87:13
88:12
87:13
OMe
t-Bu
5
6
H
H
2f, 30
2g, 53
78:22
50:50
120
a
((R,R)-TADDOLate)Bu2MgLi2 was prepared according to Route A (see Scheme 7).
The bromineemetal exchange was complete.
NO2
CF3
b
Yields determined by GC.
c
er determined by chiral GC using as reference known (S) compound.18
7
8
H
H
2h, 25
2i, 36
53:47
68:32
In order to examine the effect of both substrate and
electrophile on the process, the role of each partner was reversed.
Thus 4-iodoanisole was the halogenated substrate while 2-
pyridylcarboxaldehyde was the carbonyl electrophile (Scheme 8).
After a quantitative iodineemagnesium exchange, as checked by
TLC, the reaction with the aldehyde led to the expected alcohol
2a in 42% GC yield. The enantiomeric ratio (62:38) was found
Me
9
H
2j, 31
71:29
10
t-Bu
t-Bu
H
Ph
2k, 16
2l, 0
50:50
d
11d
1) ((R,R)-TADDOLate)Bu2MgLi
(0.5 equiv.), THF
2
OMe
a
OMe
Isolated yield after column chromatography.
er determined by GC or HPLC. All chiral products found with major (S) config-
-5 °C to r.t., 1 h
b
N
uration based on 1H NMR of Mosher esters.22,23
2)
(1.5 equiv.)
-100 °C, 1 h
I
c
OH
2a, 42%, er: 62:38
Scheme 8. Preparation of 2a by magnesiation of 4-iodoanisole.
The trapping step time was extended up to 2 h.
Under the reported conditions, no product was obtained. The temperature of
d
N
CHO
the trapping step was increased from ꢀ100 ꢁC to ꢀ60 ꢁC and to ꢀ35 ꢁC. Product 2l
was only formed when the trapping step was carried out at ꢀ35 ꢁC, with a moderate
yield of 44% and in a racemic form.

4024
D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
When electron-releasing sterically hindered tert-butyl group
metal. For clarity, only one Py is shown in Scheme 10. After this
exchange step the aldehyde approach is conditioned by the ge-
ometry of the diarylmethoxide. Thus the pseudo axially oriented
aryl group forces the aldehyde to minimize interactions with this
substituent offering its Re-face for attack of the carbonyl by the
pyridine ligands. Consequently the major enantiomer was obtained
with the S configuration while the R enantiomer was the minor one.
From the proposed transition state it could be easily understood
why changing the phenyl groups of TADDOL into methyls (Table 4,
run 10, ligand T4) led to a racemic mixture by absence of steric
effects. With naphthyl substituents, a restricted rotation around the
C-naphthyl bond freezing a specific conformation, i.e., leading to
a face-on instead of edge-on for the axial naphthyl substituent
could be responsible for the absence of enantioselection upon the
aldehyde approach.26
was present (run 5), a 78:22 er was measured for alcohol 2f. In
contrast, when electron-withdrawing groups such as NO2 (run 6) or
CF3 (run 7) were present, products 2f and 2g were found racemic.
These results could be explained by considering the impact of
electronic effects on the coordination of the aldehyde oxygen to the
metal in chiral magnesiate complex. When electron-releasing
substituents are present on the aldehyde, the coordination ability
of the oxygen is exalted leading to a better stabilization of the
transition state favouring the enantiocontrol. The reverse effect
is obtained with electron-withdrawing moieties. Switching
from methoxy to methyl group at the ortho position decreased
the er to 68:32 (run 8). A 71:29 er was measured using 1-
naphthaldehyde with a moderate yield of 31% (run 9). Piv-
alaldehyde led to a racemic alcohol indicating that aromatic alde-
hydes are essential to ensure enantiodiscrimination (run 10).
Finally, 2,2-dimethylpropiophenone could not react under the
conditions used, probably due to a strong steric hindrance (run 11).
The temperature of the trapping step had to be increased from
ꢀ100 ꢁC to ꢀ35 ꢁC to observe a moderate reactivity and to form the
desired alcohol 2l in 44% yield, however in racemic form.
Finally we examined the effect of substitution of the pyridine
ring as well as the position of nitrogen (Scheme 9). As shown when
methoxy groups were introduced at C-3 or C-6, the alcohols 5 and 6
were formed in low yields and found racemic. When 3-
bromopyridine (3) was used as substrate, some enantioselection
occurred but with a 56:44 er for 8. This result strongly contrasted
with those obtained from 2-bromopyridine. This could be related to
the absence of cooperative pyridine nitrogen coordination for sta-
bilization of the formed magnesium alkoxide. Thus the enantiose-
lective process appeared to be highly sensitive to the substrate
structure.
Ph Ph
O
Ph Ph
O
Li
Mg
Li
2-PyBr
(2 equiv.)
Li
Mg
Li
Bu
Bu
O
O
Py
Py
O
O
O
O
Ph Ph
Ph Ph
((R,R)-TADDOLate)Bu2MgLi2
((R,R)-TADDOLate)Py2MgLi2
H
O
Ar
O
attack of Re face
O
Ar
(S)
O
O
N
Mg
major
OH
Li
N
OMe
OMe
OMe
Ar
N
O
H
N
Br
1) ((R,R)-TADDOLate)Bu2MgLi
(0.5 equiv.)
OH
2
O
5 (2-MeO), 11%, rac
6 (6-MeO), 14%, er: 53:47
attack of Si face
O
(R) Ar
O
-5°C to r.t., 1 h
O
N
Mg
2) p-anisaldehyde (1.5 equiv.)
-100°C, 1 h
minor
OH
Li
OMe
N
3) Hydrolysis
N
N
Br
OH
3
8, 14%, 56:44
Scheme 10. Proposed transition states to explain the enantioselectivity and preference
for the S enantiomer.
Scheme 9. Metallation of various bromopyridines using ((R,R)-TADDOLate)Bu2MgLi2.
3. Conclusion
Despite moderate yields, essentially due to low temperature of
the trapping step, acceptable to good enantioselectivities were
obtained. ((R,R)-TADDOLate)Bu2MgLi2 was able to concomitantly
effect clean bromineemagnesium exchange and to transfer its
chiral ligand to pyridine organometallics then inducing enantio-
selective addition. All the formed enantioenriched pyridylcarbinols
had the (S) configuration. This is in agreement with the model
proposed by Seebach and co-workers,24 showing the critical effect
of the so-called ‘magic’ diarylhydroxymethyl groups that control
the topicity of the nucleophile attack on carbonyl coumpounds.25 In
Scheme 10, is proposed a plausible mechanism for enantioselective
addition of pyridylmagnesiates to aldehydes. Upon reaction of
((R,R)-TADDOLate)Bu2MgLi2 with bromopyridine, butyl groups are
transferred to give the exchange leading to a liganded pyr-
idylmagnesiate. Since the exchange reaction proceeded quantita-
tively with 0.5 equiv of the dibutylmagnesiate it was assumed that
two pyridyl moieties (Py) had replaced the two butyl chains on the
Several combinations of chiral ligands and butylmagnesiates
have been prepared and applied to the synthesis of enantioen-
riched pyridylcarbinols via bromineemagnesium exchange of 2-
bromopyridine. At first the replacement of one or several butyl
chains by ligands in magnesiates led to efficient reagents for bro-
mineemagnesium exchange that could be performed at room
temperature when alcohols, aminoalcohols and diols were used as
ligands. Concerning the enantioselective addition of the formed
pyridyl organometallics to aldehydes, (R,R)-TADDOLate-containing
dibutylmagnesiates used in substoichiometric amount (0.5 equiv)
were found to be the best reagents. Interesting enantioselectivities
were obtained with a range of aldehydes while all other ligands
tried led to racemic products. The enantiomeric ratios were found
dependent of the trapping step temperature (ꢀ100 ꢁC) and of
the aldehyde substitution pattern. This concomitant pyridyl or-
ganometallic generation and enantioselective addition to carbonyl

D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
4025
derivatives using organomagnesiates is a new promising route to
(62.5 MHz, CDCl3):
d
161.3, 159.4, 147.9, 136.9, 135.6, 128.5, 122.4,
chiral alcohols. Works are in progress to get more insight into
structural features of the intermediates involved in the chiral
event.
121.4, 114.1, 74.7, 55.4. HRMS calcd for C13H14NO2 [MþH]þ: 216.102.
Found: 216.103. Anal. Calcd for C13H13NO2 (215.25): C, 72.54; H,
6.09; N, 6.51. Found: C, 72.71; H, 6.21; N, 6.30.
4. Experimental section
4.1. General
4.2.1.2. (2-Methoxyphenyl)(pyridin-2-yl)methanol (2b).27 2-Bro-
mopyridine (100 mL, 1.05 mmol, 1 equiv), o-anisaldehyde (218 mg,
1.6 mmol,1.5 equiv) as a THF solution (2 mL), trapping step reaction
time: t¼1 h. Yield: 84% (190 mg). White powder, mp¼67e68 ꢁC.
Rf¼0.31 (cyclohexane/ethyl acetate: 5:4). 1H NMR (250 MHz,
All reactions were carried out under argon atmosphere. All
glassware was flame-dried before use. All reagents, ligands (except
T1,19 T2,19 T320 and T421) and aldehydes were commercially avail-
able and used as received. Toluene and THF were purified by
a solvent purification device. Column chromatography was per-
CDCl3):
d
8.53 (d, JHH¼4.8 Hz, 1H), 7.59 (td, JHH¼7.8, 1.5 Hz, 1H),
7.33e7.10 (m, 4H), 6.97e6.86 (m, 2H), 6.20 (s, 1H), 5.20 (br s, 1H),
3.86 (s, 3H). 13C NMR (62.5 MHz, CDCl3):
d
161.3, 156.8, 147.8, 136.8,
131.8, 128.8, 127.9, 122.3, 121.3, 121.1, 110.9, 69.3, 55.6. HRMS calcd
for C13H13NNaO2 [MþNa]þ: 238.084. Found: 238.086. Anal. Calcd
for C13H13NO2 (215.25): C, 72.54; H, 6.09; N, 6.51. Found: C, 72.65; H,
6.04; N; 6.19.
formed on silica gel Si 60 (63e200 mm). Solvents were used as
purchased. Thin-layer chromatography (TLC) was performed on
silica gel 60 with fluorescent indicator UV254 (0.2 mm) with UV
detection. 1H and 13C NMR spectra were obtained on 250 or
400 MHz spectrometers. 1H and 13C NMR chemical shifts (
d) are
4.2.1.3. (Pyridin-2-yl)(2,4,6-trimethoxyphenyl)methanol (2c). 2-
reported relative to Me4Si used as an internal standard. 19F NMR
chemical shifts are reported relative to CFCl3 used as external ref-
erence. Coupling constants are reported in hertz (Hz). Melting
points were measured with a Totoli apparatus and are given
without correction. Yields for reactions performed in asymmetric
version as well as enantiomeric ratios were measured with a gas
Bromopyridine (100 mL, 1.05 mmol, 1 equiv), 2,4,6-trimethoxyben-
zaldehyde (308 mg, 1.6 mmol, 1.5 equiv) as a THF solution (6 mL),
trapping step reaction time: t¼19.5 h. Yield: 66% (190 mg). White
powder, mp¼104e106 ꢁC. Rf¼0.23 (cyclohexane/ethyl acetate: 3:7).
1H NMR (250 MHz, CDCl3):
d
8.54 (d, JHH¼4.8 Hz, 1H), 7.56 (td,
JHH¼8.0,1.5 Hz,1H), 7.21 (d, JHH¼8.0 Hz,1H), 7.14e7.05 (m,1H), 6.30
chromatograph equipped with
a
CP-Chirasil-DexCB column
(s, 1H), 6.13 (s, 2H), 3.80 (s, 3H), 3.69 (s, 6H). 13C NMR (62.5 MHz,
(5 mꢂ0.25 mm) using helium as carrier gas (injection port tem-
perature: 250 ꢁC, detector temperature: 275 ꢁC). HPLC were re-
alized using Chiracel OD-H or Chiralpak ASH columns. Yields are
given using internal standard method. Enantiomeric ratios were
confirmed by the use of a racemic reference. Optical rotations of
CDCl3): d 163.1, 161.1, 159.3, 147.9, 136.1, 121.3, 120.1, 112.2, 91.4, 67.3,
55.9, 55.4. HRMS calcd for C15H17NNaO4 [MþNa]þ: 298.105. Found:
298.104. Anal. Calcd for C15H17NO4 (275.30): C, 65.44; H, 6.22; N,
5.09. Found: C, 65.62; H, 6.26; N, 5.04.
enantiomers (
l
¼589 nm, T¼29 ꢁC) were measured by an MCP 300
4.2.1.4. (Pyridin-2-yl)(3,4,5-trimethoxyphenyl)methanol (2d). 2-
Bromopyridine (100 mL, 1.05 mmol, 1 equiv), 3,4,5-trimethoxyben-
Anton Paar Polarimeter.
zaldehyde (308 mg, 1.6 mmol, 1.5 equiv) as a THF solution (6 mL),
trapping step reaction time: t¼10 h. Yield: 47% (mg). White pow-
der, mp¼104e106 ꢁC. Rf¼0.29 (cyclohexane/ethyl acetate: 1:4). 1H
4.2. Synthesis
4.2.1. General procedure for BreMg exchange reaction using (rac-
BINOLate)BuMgLi and synthesis of pyridylcarbinols (2ael). In
a Schlenk tube, flushed under argon, rac-BINOL (0.3 g, 1.05 mmol,
1 equiv) was dissolved in anhydrous THF (7.5 mL). n-BuLi (1.6 M in
hexanes, 1.3 mL, 2.1 mmol, 2 equiv) was slowly added at ꢀ5 ꢁC.
After stirring at this temperature for 1 h, n-BuMgCl (2 M in THF,
0.52 mL, 1.05 mmol, 1 equiv) was added at ꢀ5 ꢁC and the resulting
solution was stirred for additional 1 h at the same temperature.
The 2-bromopyridine derivative (1 equiv) was then added at
ꢀ5 ꢁC. The mixture was warmed to room temperature and stirred
for 1 h. The reaction was monitored by TLC (eluent: cyclohexane/
ethyl acetate 8:2.5). The medium was then cooled to ꢀ60 ꢁC and
the electrophile (1.5 equiv) was added. The mixture was warmed
to room temperature and stirred for a time t. The reaction was
quenched with a saturated aqueous solution of NH4Cl. The aque-
ous layer was extracted with ethyl acetate and acidified (pH¼3e4)
using a 0.4 M hydrochloric acid aqueous solution. The aqueous
solution was then extracted with ethyl acetate (3ꢂ15 mL). The
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. The crude product was then purified
by silica gel column chromatography, leading to products 2ael
and 5e7.
NMR (250 MHz, CDCl3):
d
8.55 (dd, JHH¼4.6 Hz, JHH¼0.8 Hz, 1H),
7.64 (td, JHH¼7.6, 1.6 Hz, 1H), 7.18 (d, JHH¼7.6 Hz, 2H), 6.59 (s, 2H),
5.66 (s, 1H), 3.81 (d, 9H). 13C NMR (62.5 MHz, CDCl3):
d
160.7, 153.4,
147.8, 138.8, 137.5, 136.9, 122.6, 121.3, 104.0, 75.1, 60.8, 56.1. HRMS
calcd for C15H17NNaO4 [MþNa]þ: 298.105. Found: 298.104. Anal.
Calcd for C15H17NO4 (275.30): C, 65.44; H, 6.22; N, 5.09. Found: C,
65.06; H, 6.13; N, 5.01.
4.2.1.5. (4-Dimethylaminophenyl)(pyridin-2-yl)methanol (2e).28
2-Bromopyridine (100 mL, 1.05 mmol, 1 equiv), 4-(dimethylamino)
benzaldehyde (234 mg, 1.6 mmol, 1.5 equiv) as a THF solution
(2 mL), trapping step reaction time: t¼2 h. Yield: 71% (170 mg).
Yellow powder, mp¼95e97 ꢁC. Rf¼0.17 (cyclohexane/ethyl acetate:
6:4). 1H NMR (250 MHz, CDCl3):
d
8.54 (d, JHH¼4.5 Hz, 1H), 7.59 (td,
JHH¼1.5, 7.8 Hz, 1H), 7.27e7.10 (m, 4H), 6.69 (d, JHH¼8.7 Hz, 2H),
5.68 (s, 1H), 5.08 (br, 1H), 2.92 (s, 6H). 13C NMR (62.5 MHz, CDCl3):
d
161.8, 150.4, 147.8, 136.8, 131.3, 128.2, 122.2, 121.5, 112.7, 74.9, 40.7.
HRMS calcd for C14H16N2NaO [MþNa]þ: 251.115. Found: 251.114.
Anal. Calcd for C14H16N2O (228.29): C, 73.66; H, 7.06; N, 12.27.
Found: C, 73.49; H, 6.75; N, 12.35.
4.2.1.6. (4-tert-Butylphenyl)(pyridin-2-yl)methanol (2f). 2-Bro-
mopyridine (100
mL, 1.05 mmol, 1 equiv), 4-tert-butylbenzalde-
4.2.1.1. (4-Methoxyphenyl)(pyridin-2-yl)methanol (2a).4 2-Bro-
hyde (263 mL, 1.6 mmol, 1.5 equiv), trapping step reaction time:
mopyridine (100
m
L, 1.05 mmol, 1 equiv), p-anisaldehyde (191
mL,
t¼1 h. Yield: 71% (180 mg). White powder, mp¼86e89 ꢁC. Rf¼0.23
1.6 mmol, 1.5 equiv), trapping step reaction time: t¼1 h. Yield: 75%
(cyclohexane/ethyl acetate: 7:3). 1H NMR (250 MHz, CDCl3):
d 8.55
(170 mg). Yellow powder, mp¼124e126 ꢁC. Rf¼0.26 (cyclohexane/
(d, JHH¼3.8 Hz, 1H), 7.67e7.55 (m, 1H), 7.39e7.24 (m, 4H), 7.22e7.12
ethyl acetate: 5:5). 1H NMR (250 MHz, CDCl3):
d
8.55 (d, JHH¼4.8 Hz,
(m, 2H), 5.73 (s, 1H), 5.21 (br, 1H), 1.29 (s, 9H). 13C NMR (62.5 MHz,
1H), 7.61 (td, JHH¼7.8,1.8 Hz,1H), 7.28 (d, JHH¼8.8 Hz, 2H), 7.22e7.10
CDCl3): d 161.2, 150.8, 147.9, 140.3, 136.9, 126.9, 125.6, 122.5, 121.5,
(m, 2H), 6.86 (d, JHH¼8.8 Hz, 2H), 5.71 (s, 1H), 3.78 (s, 3H). 13C NMR
74.9, 34.6, 31.5. HRMS calcd for C16H20NO [MþH]þ: 242.154. Found:

4026
D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
242.153. Anal. Calcd for C16H19NO (241.34): C, 79.63; H, 7.94; N,
5.80. Found: C, 79.89; H, 7.99; N, 5.68.
4.2.1.12. 2,2-Dimethyl-1-(pyridin-2-yl)-1-(phenyl)-1-propanol
(2l). 2-Bromopyridine (100 L, 1.05 mmol, 1 equiv), 2,2-
dimethylpropiophenone (263 L, 1.6 mmol, 1.5 equiv), trapping
m
m
4.2.1.7. (4-Nitrophenyl)(pyridin-2-yl)methanol (2g).29 2-Bromo-
pyridine (100 mL, 1.05 mmol, 1 equiv), p-nitrobenzaldehyde
(237 mg, 1.6 mmol, 1.5 equiv) as a THF solution (2 mL), trapping
step reaction time: t¼1 h. Yield: 75% (180 mg). Yellow powder,
mp¼109e112 ꢁC. Rf¼0.22 (cyclohexane/ethyl acetate: 5:5). 1H NMR
step reaction time: t¼21 h. Yield: 60% (150 mg). White powder,
mp¼81e82 ꢁC. Rf¼0.20 (pentane/diethyl ether: 1:0.1). 1H NMR
(250 MHz, CDCl3):
d
8.51 (d, JHH¼4.8 Hz, 1H), 7.84e7.64 (m, 4H),
7.34e7.14 (m, 4H), 6.42 (br, 1H), 1.07 (s, 9H). 13C NMR (62.5 MHz,
CDCl3):
d 162.5, 146.9, 144.3, 136.2, 128.3, 127.3, 126.6, 123.0, 122.2,
(250 MHz, CDCl3):
d
8.59 (d, JHH¼4.8 Hz, 1H), 8.19 (d, JHH¼8.5 Hz,
81.4, 39.9, 27.1. HRMS calcd for C16H20NO [MþH]þ: 242.154. Found:
242.154. Anal. Calcd for C16H19NO (241.33): C, 79.63; H, 7.94; N,
5.80. Found: C, 79.64; H, 8.07; N, 5.54.
2H), 7.67 (td, JHH¼7.8, 1.8 Hz, 1H), 7.59 (d, JHH¼8.5 Hz, 2H),
7.30e7.21 (m,1H), 7.16 (d, JHH¼8.0 Hz,1H), 5.85 (s,1H), 5.37 (br,1H).
13C NMR (62.5 MHz, CDCl3):
d 159.4, 150.5, 148.4, 147.6, 137.4, 127.8,
123.9, 123.2, 121.3, 74.3. HRMS calcd for C12H10N2NaO3 [MþNa]þ:
253.058. Found: 253.059. Anal. Calcd for C12H10N2O3 (230.22): C,
62.60; H, 4.38; N, 12.17. Found: C, 62.65; H, 4.45; N, 12.16.
4.2.1.13. (4-Methoxyphenyl)-(3-methoxypyridin-2-yl)methanol
(5). 2-Bromo-3-methoxypyridine (197 mg, 1.05 mmol, 1 equiv) as
a THF solution (2 mL), p-anisaldehyde (191 mL, 1.6 mmol, 1.5 equiv),
trapping step reaction time: t¼1.5 h. Yield: 51% (130 mg). White
powder, mp¼124e127 ꢁC. Two purifications by silica gel column
chromatography were performed using first cyclohexane/ethyl
acetate (6:4) as eluent (Rf¼0.28) and then cyclohexane/ethyl ace-
4.2.1.8. (Pyridin-2-yl)(4-(trifluoromethyl)phenyl)methanol (2h).4,30
2-Bromopyridine (100
benzaldehyde (215
mL, 1.05 mmol, 1 equiv), p-(trifluoromethyl)
m
L, 1.6 mmol, 1.5 equiv), trapping step reaction
time: t¼1 h. Yield: 83% (220 mg). White powder, mp¼66e68 ꢁC.
tate (2:8) (Rf¼0.61). 1H NMR (250 MHz, CDCl3):
d 8.17 (d,
Rf¼0.29 (cyclohexane/ethyl acetate: 5:5). 19F NMR (235 MHz, CDCl3):
JHH¼4.5 Hz, 1H), 7.28 (d, JHH¼8.5 Hz, 2H), 7.23e7.15 (m, 1H),
7.14e7.07 (m, 1H), 6.81 (d, JHH¼8.5 Hz, 2H), 5.90 (s, 1H), 5.41 (br,
d
ꢀ62.5 (s). 1H NMR (250 MHz, CDCl3):
8.58 (d, JHH¼4.8 Hz, 1H), 7.65
d
(d, JHH¼7.8, 1.8 Hz, 1H), 7.60 (d, JHH¼8.2 Hz, 2H), 7.52 (d, JHH¼8.2 Hz,
2H), 7.27e7.19 (m, 1H), 7.14 (d, JHH¼8.0 Hz, 1H), 5.80 (s, 1H), 5.34 (br,
1H), 3.75 (s, 3H), 3.74 (s, 3H). 13C NMR (62.5 MHz, CDCl3):
d 158.9,
152.3, 150.7, 139.4, 135.6, 128.3, 123.3, 117.9, 113.6, 70.0, 55.4, 55.3.
HRMS calcd for C14H16NO3 [MþH]þ: 246.112. Found: 246.112. Anal.
Calcd for C14H15NO3 (245.27): C, 68.56; H, 6.16; N, 5.71. Found: C,
68.77; H, 6.22; N, 5.66.
1H). 13C NMR (62.5 MHz, CDCl3):
d 160.0, 148.1, 147.1, 137.1, 130.0 (q,
2JCF¼32 Hz), 127.3, 125.5 (q, 3JCF¼3.8 Hz), 124.1 (q, 1JCF¼272 Hz), 122.8,
121.3, 74.4. HRMS calcd for C13H11F3NO [MþH]þ: 254.079. Found:
254.079. Anal. Calcd for C13H10F3NO (253.22): C, 61.66; H, 3.98; N,
5.53. Found: C, 61.65; H, 4.06; N, 5.36.
4.2.1.14. (4-Methoxyphenyl)-(6-methoxypyridin-2-yl)methanol
(6). 2-Bromo-6-methoxypyridine (129
a THF solution (2 mL), p-anisaldehyde (191
m
L, 1.05 mmol, 1 equiv) as
4.2.1.9. (Pyridin-2-yl)(o-tolyl)methanol (2i).23 2-Bromopyridine
mL, 1.6 mmol, 1.5 equiv),
(100
m
L, 1.05 mmol, 1 equiv), o-tolualdehyde (182
m
L, 1.6 mmol,
trapping step reaction time: t¼2 h. Yield: 89% (230 mg). Orange oil.
1.5 equiv), trapping step reaction time: t¼1 h. Yield: 81% (170 mg).
Rf¼0.12 (cyclohexane/dichloromethane: 1:9). 1H NMR (250 MHz,
White powder, mp¼59e60 ꢁC. Rf¼0.25 (cyclohexane/ethyl acetate:
CDCl3):
d 7.56e7.44 (m, 1H), 7.35e7.24 (m, 2H), 6.93e6.81 (m, 2H),
7:3). 1H NMR (250 MHz, CDCl3):
d
8.58 (d, JHH¼4.5 Hz, 1H), 7.59 (td,
6.71e6.57 (m, 2H), 5.63 (d, JHH¼4.2 Hz, 1H), 4.90 (d, JHH¼4.2 Hz,
JHH¼7.8, 1.5 Hz, 1H), 7.27e7.12 (m, 5H), 7.02 (d, JHH¼7.8 Hz,1H), 5.96
1H), 3.99 (s, 3H), 3.79 (s, 3H). 13C NMR (62.5 MHz, CDCl3):
d
163.3,
(s,1H), 5.18 (br,1H), 2.33 (s, 3H). 13C NMR (62.5 MHz, CDCl3):
d
161.1,
159.3, 159.2, 139.6, 135.6, 128.4, 114.0, 113.8, 109.2, 74.4, 55.4, 53.6.
HRMS calcd for C14H15NNaO3 [MþNa]þ: 268.094. Found: 268.095.
Anal. Calcd for C14H15NO3 (245.27): C, 68.56; H, 6.16; N, 5.71. Found:
C, 68.67; H, 6.19; N, 5.62.
147.9, 140.8, 136.9, 136.4, 131.0, 128.2, 128.0, 126.3, 122.4, 121.3, 73.0,
19.6. HRMS calcd for C13H13NNaO [MþNa]þ: 222.089. Found:
222.089. Anal. Calcd for C13H13NO (199.25): C, 78.36; H, 6.58; N,
7.03. Found: C, 78.70; H, 6.63; N, 6.73.
4.2.1.15. (4-Methoxyphenyl)(quinolin-2-yl)methanol
Bromoquinoline (218 mg, 1.05 mmol, 1 equiv) as a THF solution
(2 mL), p-anisaldehyde (191 L, 1.6 mmol, 1.5 equiv), trapping step
(7).33 2-
4.2.1.10. (1-Naphthyl)(pyridin-2-yl)methanol
pyridine (100 L, 1.05 mmol, 1 equiv), 1-naphthaldehyde (213
(2j).31 2-Bromo-
L,
m
m
m
1.6 mmol, 1.5 equiv), trapping step reaction time: t¼1 h. Yield: 85%
reaction time: t¼1.5 h. Yield: 56% (160 mg). Yellow oil. Two puri-
fications by silica gel column chromatography were performed
using first cyclohexane/ethyl acetate (7:3) as eluent (Rf¼0.36) and
then cyclohexane/ethyl acetate (8:2) (Rf¼0.17). 1H NMR (250 MHz,
(200 mg). White powder, mp¼75e77 ꢁC. Rf¼0.33 (cyclohexane/
ethyl acetate: 5:4). 1H NMR (250 MHz, CDCl3):
d
8.59 (d, JHH¼4.0 Hz,
1H), 8.15e8.05 (m, 1H), 7.88e7.75 (m, 2H), 7.54e7.36 (m, 5H),
7.20e7.10 (m, 1H), 7.02 (d, JHH¼7.8 Hz,1H), 6.41 (s, 1H), 5.25 (br, 1H).
CDCl3):
d
8.14 (d, JHH¼8.5 Hz, 1H), 8.05 (d, JHH¼8.5 Hz, 1H),
13C NMR (62.5 MHz, CDCl3):
d
161.1, 147.9, 138.2, 137.0, 134.3, 131.3,
7.84e7.71 (m, 2H), 7.59e7.51 (m, 1H), 7.31 (d, JHH¼8.5 Hz, 2H), 7.16
(d, JHH¼8.5 Hz, 1H), 6.87 (d, JHH¼8.5 Hz, 2H), 6.00 (br, 1H), 5.83 (s,
128.9, 128.8, 126.2, 125.7, 125.4, 124.5, 122.5,121.5, 73.6. HRMS calcd
for C16H13NNaO [MþNa]þ: 258.089. Found: 258.090. Anal. Calcd for
C16H13NO (235.28): C, 81.68; H, 5.57; N, 5.95. Found: C, 81.70; H,
5.19; N, 5.73.
1H), 3.78 (s, 3H). 13C NMR (62.5 MHz, CDCl3):
d 160.9, 159.6, 146.1,
137.1, 135.2, 130.1, 129.0, 128.9, 127.7, 126.7, 119.5, 114.2, 74.8, 55.4.
HRMS calcd for C17H16NO2 [MþH]þ: 266.118. Found: 266.118. Anal.
Calcd for C17H15NO2 (265.31): C, 76.96; H, 5.70; N, 5.28. Found: C,
76.72; H, 5.91; N, 5.04.
4.2.1.11. 2,2-Dimethyl-1-(pyridin-2-yl)-1-propanol (2k).32 2-Bro-
mopyridine (100
(171
mL, 1.05 mmol, 1 equiv), trimethylacetaldehyde
m
L, 1.6 mmol, 1.5 equiv), trapping step reaction time: t¼2 h.
4.2.2. Procedure for BreMg exchange of 3- and 4-bromopyridine
involving racemic (BINOLate)Bu2MgLi2. In a Schlenk tube, flushed
under argon, rac-BINOL (0.3 g, 1.05 mmol, 1 equiv) was dissolved in
anhydrous THF (7.5 mL). n-BuLi (1.5 M in hexanes, 1.4 mL,
2.1 mmol, 2 equiv) was slowly added at ꢀ5 ꢁC. After stirring at this
temperature for 1 h, n-BuMgCl (2.1 M in THF, 0.50 mL, 1.05 mmol,
1 equiv) was added at ꢀ5 ꢁC and the resulting solution was stirred
for additional 1 h at the same temperature. n-BuLi (1.5 M in hex-
anes, 0.7 mL, 1.05 mmol, 1 equiv) was added at ꢀ5 ꢁC and the
Yield: 58% (100 mg). Orange solid, mp¼51e54 ꢁC. Rf¼0.25 (cyclo-
hexane/ethyl acetate: 7:3). 1H NMR (250 MHz, CDCl3):
d 8.55
(d, JHH¼4.0 Hz, 1H), 7.63 (td, JHH¼7.5, 1.5 Hz, 1H), 7.23e7.14 (m, 2H),
4.34 (s, 2H), 0.92 (s, 9H). 13C NMR (62.5 MHz, CDCl3):
d
160.0,
148.0, 135.6, 123.0, 122.4, 80.4, 36.4, 26.0. HRMS calcd for
C10H16NO [MþH]þ: 166.123. Found: 166.122. Anal. Calcd for
C10H15NO (165.23): C, 72.69; H, 9.15; N, 8.48. Found: C, 72.73; H,
8.94; N, 8.34.

D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
4027
mixture was stirred for 20 min at ꢀ5 ꢁC. 3- or 4-Bromopyridine
4.2.3.2. Compound (S)-2b. Yield: 24%. er: 73:27. [
a
]
29 þ90.4 (c 1,
D
(200
m
L, 2.1 mmol, 2 equiv) was then added at ꢀ5 ꢁC. The mix-
CHCl3). Chiral GC conditions: (137 ꢁC, pressure¼50 kPa, flow rate:
50 mL/min), tR1¼7.88 min, tR2¼8.40 min (major enantiomer).
Mosher ester, 1H NMR (200 MHz, CDCl3): dH6 8.62 (R,S) (major),
8.45 (R,R).
ture was warmed to room temperature and stirred for 1 h. The
reaction was monitored by TLC (eluent: cyclohexane/ethyl acetate
8:2.5). The medium was then cooled to ꢀ60 ꢁC and p-anisaldehyde
(381 mL, 3.1 mmol, 3 equiv) was added. The mixture was warmed
to room temperature and stirred for 1 h. The reaction was
quenched with a saturated aqueous solution of NH4Cl. The aqueous
layer was extracted with ethyl acetate and acidified to reach a pH
value of 3e4 using a 0.4 M hydrochloric acid aqueous solution. The
aqueous solution was then extracted with ethyl acetate (3ꢂ15 mL).
The combined organic layers were dried over MgSO4 and con-
centrated under reduced pressure. The crude product was then
purified by silica gel column chromatography, leading to products
8 and 9.
4.2.3.3. Compound (S)-2c. Yield: 21%. er: 84:16. [
a
]
29 þ74.4 (c 1,
D
CHCl3). Chiral HPLC conditions: Chiracel OD-H column (i-PrOH/
hexane (8:92), 1 mL/min, 232.6 nm), tR1¼64.45 min (major enan-
tiomer), tR2¼72.51 min. Mosher ester, 1H NMR (200 MHz, CDCl3):
dH6 8.60 (R,S) (major), 8.39 (R,R).
4.2.3.4. Compound rac-2d. Yield: 22%. er: 49:51. Chiral GC con-
ditions: (140 ꢁC, pressure¼50 kPa, flow rate: 50 mL/min),
tR1¼59.43 min, tR2¼63.96 min.
4.2.2.1. (4-Methoxyphenyl)(pyridin-3-yl)methanol (8).4 Yellow
powder, mp¼70e72 ꢁC. Rf¼0.30 (cyclohexane/ethyl acetate: 1:4).
4.2.3.5. Compound (S)-2f. Yield: 30%. er: 78:22. [
a
]
29 þ25.3 (c 1,
D
CHCl3). Chiral GC conditions: (145 ꢁC, pressure¼50 kPa, flow rate:
50 mL/min), tR1¼12.80 min (major enantiomer), tR2¼14.10 min.
Mosher ester, 1H NMR (200 MHz, CDCl3): dH6 8.56 (R,S) (major), 8.41
(R,R).
1H NMR (250 MHz, CDCl3):
d 8.52 (s, 1H), 8.39 (s, 1H), 7.71 (d,
JHH¼7.8 Hz, 1H), 7.27 (d, JHH¼8.2 Hz, 3H), 6.88 (d, JHH¼8.6 Hz, 2H),
5.81 (s, 1H), 3.81 (s, 3H), 3,64 (br, 1H). 13C NMR (62.5 MHz, CDCl3):
d
159.2, 148.1, 147.9, 139.9, 135.5, 134.3, 127.9, 123.4, 114.0, 73.4, 55.3.
HRMS calcd for C13H14NO2 [MþH]þ: 216.102. Found: 216.103. Anal.
Calcd for C13H13NO2 (215.25): C, 72.54; H, 6.09; N, 6.51. Found: C,
72.40; H, 6.16; N, 6.37.
4.2.3.6. Compound rac-2g. Yield 53%. er: 50:50. Chiral GC con-
ditions: (110 ꢁC, pressure¼80 kPa, flow rate: 60 mL/min),
tR1¼24.98 min, tR2¼25.48 min.
4.2.2.2. (4-Methoxyphenyl)(pyridin-4-yl)methanol (9).34 White
powder, mp¼134e136 ꢁC. Rf¼0.23 (cyclohexane/ethyl acetate: 1:4).
4.2.3.7. Compound rac-2h. Yield 25%. er: 53:47. Chiral GC con-
ditions: (80 ꢁC, pressure¼70 kPa, flow rate: 45 mL/min),
tR1¼16.57 min, tR2¼17.15 min.
1H NMR (250 MHz, CDCl3):
d
8.46 (d, JHH¼5.0 Hz, 2H), 7.34 (d,
JHH¼5.2 Hz, 2H), 7.28 (d, JHH¼8.8 Hz, 2H), 6.90 (d, JHH¼8.4 Hz, 2H),
5.78 (s, 1H), 3.83 (s, 3H). 13C NMR (62.5 MHz, CDCl3):
d
159.3, 153.5,
4.2.3.8. Compound (S)-2i. Yield: 36%. er: 68:32. [
a
]
29 þ45.0 (c 1,
D
149.2, 135.2, 128.1, 121.3, 114.0, 74.2, 55.2. HRMS calcd for
C13H14NO2 [MþH]þ: 216.102. Found: 216.101. Anal. Calcd for
C13H13NO2 (215.25): C, 72.54; H, 6.09; N, 6.51. Found: C, 72.13; H,
6.11; N, 6.34.
CHCl3). Chiral GC conditions: (115 ꢁC, pressure¼50 kPa, flow rate:
50 mL/min), tR1¼17.70 min (major enantiomer), tR2¼19.72 min.
Mosher ester, 1H NMR (200 MHz, CDCl3): dH6 8.55 (R,S) (major),
8.40 (R,R).
29
4.2.3. Procedure for BreMg exchange reaction using ((R,R)-TADDO-
Late)Bu2MgLi2 and synthesis of enantioenriched pyridylcarbinols
(method A, see Table 7). In a Schlenk tube, flushed under argon,
(R,R)-TADDOL (0.47 g, 1.05 mmol, 1 equiv) was dissolved in an-
hydrous THF (C¼0.14 M). n-BuLi (1.5 M in hexanes, 2 equiv) was
slowly added at ꢀ5 ꢁC. After stirring at this temperature for
20 min, n-BuMgCl (2 M in THF, 1 equiv) was added at ꢀ5 ꢁC and
the resulting solution was stirred for additional 20 min at the
same temperature. n-BuLi (1.5 M in hexanes, 1 equiv) was finally
added at ꢀ5 ꢁC and the mixture was stirred for 20 min at ꢀ5 ꢁC.
2-Bromopyridine (2 equiv) was then added at ꢀ5 ꢁC. The mixture
was warmed to room temperature and stirred for 1 h. The re-
action was monitored by TLC (eluent: cyclohexane/ethyl acetate
8:2.5). The medium was then cooled to ꢀ100 ꢁC and the aldehyde
(3 equiv) was added. The mixture was left at ꢀ100 ꢁC and stirred
for 1 h. The reaction was quenched with a saturated aqueous
solution of NH4Cl. The aqueous layer was extracted with ethyl
acetate and acidified (pH¼of 3e4) using a 0.4 M hydrochloric acid
aqueous solution. The aqueous solution was then extracted
with ethyl acetate (3ꢂ15 mL). The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure. The
crude product was then purified on column chromatography
and analyzed by chiral GC or HPLC to determine enantiomeric
ratios.
4.2.3.9. Compound (S)-2j. Yield: 39%. er: 71:29. [
a
]
þ54.4 (c
D
0.01, CHCl3). Chiral GC conditions: (155 ꢁC, pressure¼50 kPa, flow
rate:
50 mL/min),
tR1¼17.12 min
(major
enantiomer),
tR2¼17.97 min. Mosher ester, 1H NMR (200 MHz, CDCl3): dH6 8.60
(R,S) (major), 8.40 (R,R).
4.2.3.10. Compound rac-2k. Yield 16%. er: 50:50. Chiral GC
conditions: (80 ꢁC, pressure¼10 kPa, flow rate: 20 mL/min),
tR1¼14.75 min, tR2¼15.15 min.
4.2.3.11. Compound rac-5. Yield 11%. er: 50:50. Chiral GC con-
ditions: (120 ꢁC, pressure¼30 kPa, flow rate: 50 mL/min),
tR1¼66.41 min, tR2¼68.61 min.
4.2.3.12. Compound rac-6. Yield 11%. er: 53:47. Chiral GC con-
ditions: (80 ꢁC, pressure¼70 kPa, flow rate: 45 mL/min),
tR1¼23.97 min, tR2¼24.64 min.
29
4.2.3.13. Compound 8. Yield: 14%, er: 56:44, [
a]
ꢀ11.6 (c 0.5,
D
CHCl3). Chiral HPLC conditions: Chiralpak ASH column (i-PrOH/
hexane (10:90), 1 mL/min, 243.8 nm), tR1¼50.38 min (major enan-
tiomer), tR2¼59.67 min. The yield and er were too low to determine
the absolute configuration accurately.
4.2.4. General procedure for esterification of chiral pyridinylcarbinols
with R-MPA.23 The alcohol was dissolved in dry CH2Cl2 (concen-
tration equal to 0.033 M). (R)-Methoxyphenylacetic acid ((R)-MPA)
(4 or 5 equiv), DMAP (0.2 equiv), and dicyclohexylcarbodiimide
(2 equiv) were added to the solution in a Schlenk tube under argon.
The resulting mixture was stirred for 15 h at room temperature.
4.2.3.1. Compound (S)-2a.18 Yield: 35%. er: 88:12. [
a]
29 þ44.0 (c
D
1, CHCl3). Chiral GC conditions: (137 ꢁC, pressure¼50 kPa, flow rate:
50 mL/min), tR1¼15.34 min (major enantiomer), tR2¼16.57 min.
Absolute configuration deduced from optical rotation sense com-
pared with the known (S) compound.

4028
D. Catel et al. / Tetrahedron 68 (2012) 4018e4028
9. (a) Sato, T.; Soai, K.; Suzuki, K.; Mukaiyama, T. Chem. Lett. 1978, 601e604; (b)
Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979,
101, 1455e1460; (c) Mukaiyama, T. Tetrahedron 1981, 37, 4111e4119; (d) Weber,
B.; Seebach, D. Tetrahedron 1994, 50, 6117e6128.
After the solvent was removed, the crude residue was directly
analysed by NMR. It consisted in a mixture of (R,S) and (R,R) di-
astereoisomers. 1H NMR in CDCl3 showed a specific chemical shift
for the H6 proton of pyridine in each diasteroisomer, the most
shielded corresponding to the (R,R) form.22,23 For each ester, the
absolute configuration of the major diastereoisomer was (R,S). It is
deduced for each alcohol that the configuration of the major en-
antiomer was (S). The chemical shifts of the H-6 protons in di-
astereoisomers are given in chiral product characterization.
10. Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M. Pure Appl. Chem. 1988, 60,
1597e1606.
11. (a) Drury, W. J.; Zimmerman, N.; Keenan, M.; Hayashi, M.; Kaiser, S.; Goddard,
R.; Pfaltz, A. Angew. Chem., Int. Ed. 2004, 43, 70e74; (b) Kang, J.; Kim, H. Y.; Kim,
J. P. Tetrahedron: Asymmetry 1999, 10, 2523e2533; (c) Vedejs, E.; Chen, X. J. Am.
Chem. Soc. 1996, 118, 1809e1810.
12. Fort, Y.; Gros, P. C.; Rodriguez, A. L. Tetrahedron: Asymmetry 2001, 12,
2631e2635.
13. Catel, D.; Chevallier, F.; Mongin, F.; Gros, P. C. Eur. J. Org. Chem. 2012, 53e57.
14. (a) Bolm, C.; Zehnder, M.; Bur, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 205e207;
(b) Ohkuma, T.; Koizumi, M.; Makato, Y.; Noyori, R. Org. Lett. 2000, 2,
1749e1751; (c) Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett. 2000, 41,
9277e9280.
15. (a) Chelucci, G.; Soccolini, F. Tetrahedron: Asymmetry 1992, 3, 1235e1238; (b)
Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron: Asymmetry 1997, 8,
1869e1876; (c) Kwong, H.-L.; Lee, W.-S. Tetrahedron: Asymmetry 1999, 10,
3791e3801.
Acknowledgements
The authors gratefully acknowledge the financial support
of Agence Nationale de la Recherche (ACTIVATE program) to D.C.
and O.P.
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16. Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Queguiner, G. Tet-
rahedron Lett. 1999, 40, 4339e4342.
Supplementary data
17. Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92e138 and
references cited therein.
18. Heller, B.; Redkin, D.; Gutnov, A.; Fischer, C.; Bonrath, W.; Karge, R.; Hapke, M.
Synthesis 2008, 69e74.
Copies of 1H NMR and 13C NMR spectra for all compounds.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2012.03.058.
19. For T1 and T2 see Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D.
€
A.; Kuhnle, F. N. M. J. Org. Chem. 1995, 60, 1788e1799.
20. For T3 see Du, H.; Zhao, D.; Ding, K. Chem.dEur. J. 2004, 10, 5964e5970.
21. For T4 see Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonnacott, A.
Helv. Chim. Acta 1987, 70, 954e974.
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23. Maerten, E.; Agbossou-Nidercorn, F.; Castanet, Y.; Mortreux, A. Tetrahedron
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24. Seebach, D.; Plattner, D. A.; Beck, A. K.; Wang, Y. M.; Hunziker, D.; Petter, W.
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