A method for the synthesis of pyridine-based C2-symmetrical chiral nucleophilic organocatalysts via Pd-catalyzed coupling

Article abstract of DOI:10.1016/j.tetasy.2012.11.007

A one step Pd-catalyzed coupling methodology involving a reaction between a chiral diamine and a 2-bromo-4-(alkylamino)pyridine, was developed for the synthesis of novel C₂-symmmetrical chiral compounds with chemical yields of up to 87%. The or

Full text of DOI:10.1016/j.tetasy.2012.11.007

Tetrahedron: Asymmetry 23 (2012) 1694–1699
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A method for the synthesis of pyridine-based C -symmetrical chiral nucleophilic
2
organocatalysts via Pd-catalyzed coupling
⇑
Emre Y. Yazıcıo g˘ lu, Cihangir Tanyeli
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 November 2012
Accepted 13 November 2012
A one step Pd-catalyzed coupling methodology involving a reaction between a chiral diamine and a
2
2-bromo-4-(alkylamino)pyridine, was developed for the synthesis of novel C -symmmetrical chiral com-
pounds with chemical yields of up to 87%. The organocatalytic performance was tested as an alternative
to the enzymatic kinetic resolution of 1-phenylethanol and a promising result of 76% ee was obtained. We
observed that the catalysts synthesized had their own characteristics in terms of enantioselectivity; for
example, non-nucleophilic heterogeneous auxiliary bases and ether solvents proved to be more efficient.
Ó 2012 Elsevier Ltd. All rights reserved.
1
. Introduction
The demand for environmentally friendly procedures for the
the pyridine rings are placed in proximity to each other thus provid-
ing chiral information by blocking one face of the acyl group of 1 to-
ward nucleophilic attack of the alcohol by the other pyridine ring
(iii) second amine functionality is substituted at C-2 on the pyridine
ring and so might increase the nucleophilicity of the reactive pyri-
dine nitrogen and thus increase turnover (Fig. 1). These advantages
prompted us to develop a methodology for the synthesis of these
catalyst systems and evaluate their efficiency.
production of optically active materials has given rise to an impor-
tant increase in work on asymmetric organocatalysis over the last
few decades. As a subgroup, chiral dialkylaminopyridines, which
are used as acyl-transfer reagents and catalysts, have gained con-
siderable attention due to their acylase enzyme-mimicking func-
1
2
3
tion. Intense work on this subject has resulted in catalysts such as
those presented in the pioneering works of Fu and Fuji et al., and
which provide high enantiomeric purity with reasonable reaction
rates for a broad substrate range.2 In the recent literature, studies
have focused on lowering the amount of catalyst used while keep-
ing the efficiency, by decreasing the number of steps required for
the synthesis of such catalysts. An important contribution to the
field was made by Yamada et al.5
2
2
. Results and discussion
,4
2
.1. Pd-Catalyzed bis-DMAP coupling of C -symmetrical chiral
diamines
A commercially available set of C
2
-symmetrical chiral dia-
6
mines 3–6 were chosen as templates. For the synthesis of the de-
Herein we attempt to solve this problem by exchanging the
aforementioned multistep methodologies with a single step cou-
pling approach for chiral catalyst synthesis, which should grant
direct access to many different catalyst systems. The initial syn-
thetic plan was to couple a 4-(dimethylamino)pyridine (DMAP)
signed organocatalysts, different retrosynthetic strategies were
devised. Our first plan was to couple the C
2
-symmetrical chiral
diamine (9R,10R,11S,12S)-9,10-dihydro-9,10-ethanoanthracene-11,
1
4
2-diamine 3 directly with a pyridine derivative such as a
7
-hydroxypyridin-2-yl trifluoromethanesulfonate.
There are
derivative with a C
2
-symmetrical chiral diamine template at the
many examples in the literature where a primary amine is directly
coupled with a trifluoromethanesulfonyl bearing pyridine deriva-
2
-position of the pyridine ring to obtain a nucleophilic catalyst,
8
where the DMAP rings are mounted onto each amino group. In
the kinetic resolution of racemic secondary alcohols via esterifica-
tion with an acid anhydride, such a design should have advantages
such as: (i) protic hydrogen on the amine functionality of the cata-
lyst would restrict the free rotation of the acyl group of the formed
acyl pyridinium intermediate 1 over the course of the reaction; (ii)
tive by heating. In the next step, the phenolic hydroxyl group
would be substituted with chlorine and then dimethyl amine
moieties, respectively. The coupling of chiral diamine 3 and
4
-hydroxypyridin-2-yl trifluoromethanesulfonate was performed
under thermal conditions. For this purpose, two compounds were
mixed in a high boiling solvent (mesitylene), after which the mix-
ture was heated gradually starting from 45 °C to its boiling point,
1
50 °C. The molar ratio of pyridine derivative:chiral diamine 3 was
2
:1. The reaction was monitored by TLC. However, no new product
⇑
Corresponding author. Tel.: +90 312 210 3222; fax: +90 312 210 3200.
E-mail address: tanyeli@metu.edu.tr (C. Tanyeli).
formation was observed.
0
957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.007

E. Y. Yazıcıo g˘ lu, C. Tanyeli / Tetrahedron: Asymmetry 23 (2012) 1694–1699
1695
N
N
N
N
N
N
NH
HN
+
NH
HN
X
N
N
N
N
R2
O
O
N
N
HO
N
N
+
O
H
NH
R1
N
O
NH
HN
OH
R1
R2
1
Figure 1. Retrosynthetic plan for novel catalyst systems and their presumed mode of function.
As a result, we turned our attention to metal catalyzed coupling
reactions carried out with CuBr9 or various Pd complexes. Our
nitrogen and thus activate the ring for nucleophilic attack. In a
sealed polytetrafluoroethylene (PTFE) of microwave, the com-
pounds were mixed in ethanol and the mixture was heated to
160 °C for 10 min. Again, no trace of product formation was ob-
served at the end of the reaction period. The last trial was carried
out under similar conditions as the first, except that the solvent
and reactor were changed; this time a microwave was used as
the driving force for the reaction. Compounds were mixed in
benzotrifluoride (BTF) and the mixture was heated up to 150 °C
for 10 min. Again, no product formation was observed.
10
retrosynthetic approach involved
whereby a 2-halopyridine was coupled with C
a
multistep transformation
-symmetrical chiral
2
diamine 3. The optimal pyridine derivative was 2-bromo-4-nitro-
pyridine since the 4-nitro group would decrease the electron
density in the aromatic ring and thus make it easier for metal
insertion and nucleophilic attack by the amine species. The last
step of the synthesis was the replacement of the nitro group with
a dimethyl amino unit. Three different conditions were screened.
Throughout the reactions, the molar ratio of 3 and 2-bromo-
After screening various Pd-coupling conditions,12
a Pd-
4
-nitropyridine was 1:2. The first screen was similar to a relevant
catalyzed Buchwald-Hartwig amination method proved to be the
most efficient (Scheme 1). Initially, the bis-DMAP coupling of
1
1
13
literature procedure, which involved conventional heating and
adding 5% molar equivalent of CuBr, with the same stoichiometric
chiral diamine 3 was performed by using 2-bromo-4-(dimethyl-
0
0
14
amount of ligand N-benzyldinaphtho[2,1-d:1 ,2 -f][1,3,2]dioxapho-
sphepin-4-amine in dry DMF. The best base was Cs CO due to its
high organic solubility compared with other bases. However, after
4 h, no product formation was observed. In the next trial, a
amino)pyridine 2 as the DMAP source in the presence of catalytic
2
3
2
amounts of Pd(dba) and racemic BINAP ligand, with excess
amounts of strong base (NaOtBu) in toluene at reflux. The conver-
2
sion was monitored by TLC and 87% conversion was achieved after
1
13
microwave assisted coupling was carried out in ethanol under
acidic conditions. It was presumed that the introduction of a cat-
alytic amount of PTSA (1 mol %) may coordinate to the pyridine
12 h. The H and C NMR spectra confirmed the presence of a
-symmetrical structure 7 (Fig. 2). We also decided to study the
Pd-catalyzed bis-DMAP coupling condition with the most
C
2
N
4
mol% Pd(dba)2
R1
R2
*
R1
*
R2
4 mol% BINAP
00 mol% NaOtBu
N
6
+
*
HN
*
HN
H N
NH2
toluene, reflux 12 h
2
Br
N
N
N
2
20 mol%
2
N
H N
NH2
2
R1
*
R2
*
NH2
H N
2
NH2
NH2
=
H N
2
NH
H N
NH2
2
2
87%
56%
76%
14%
3
4
5
6
Scheme 1. Synthesis of organocatalyst systems.

1
696
E. Y. Yazıcıo g˘ lu, C. Tanyeli / Tetrahedron: Asymmetry 23 (2012) 1694–1699
N
N
N
N
N
N
H
N
N
H
N
N
N
N
N
N
N
NH
HN
HN
NH
NH HN
N
N
N
9
10
BINAPHTRADAP
7
8
ANTRADAP
CYTRADAP
DIPHETRADAP
N
N
N
N
N
NH
N
N
cat-11
Figure 2. Catalyst structures obtained.
demanding chiral backbones (1R,2R)-cyclohexane-1,2-diamine 4,
referred to as a DMAP derivative, a different nomenclature was fol-
lowed in our study. Due to hydrogen bonding and the presence of
one more electron-donor amino group, the catalytic behavior of a
2-alkylamino-4-(dimethylamino)pyridine might have different
properties than the other aforementioned DMAP derivatives,
which bear only one amine functionality on the pyridine ring, in
the kinetic resolution of secondary alcohols. The structures synthe-
sized were named as ‘trialkyldiaminopyridine’ (TRADAP) in general
and to distinguish the catalysts from each other, the initial letters
of the diamine skeleton were taken to name the catalyst (e.g. CYTR-
ADAP for 1,2-cyclohexanediamine) (Fig. 2).
0
(
1R,2R)-1,2-diphenylethane-1,2-diamine 5, and (R)-1,1 -binaph-
0
thyl-2,2 -diamine 6. The C
2
-symmetrical chiral diamines 4 and 5
afforded moderate chemical yields, 56 and 76%, respectively. When
R)-BINAM 6 was used as the starting material, the yield was signif-
(
icantly lower due to the formation of a side product whereby one
of the BINAM amino groups was doubly substituted with DMAP
and the other amino group was mono substituted with a DMAP
unit (see 11). The yield of this side product was 47% (Fig. 2).
Although Rabalakos and Wulff15 (which was noticed during the
course of this research) described a similar structure, which was
Table 1
Kinetic resolution of 1-phenylethanol.
O
OH
0
.7 eq base
O
CH3
OH
O
O
2 ml solvent
0
.02 eq catalyst
*
*
+
+
H C
O
CH3
3
RT, 24 h
1
eq
0.7 eq
Entry
Cat.
Base
Solvent
ee (%) a
Conv. (%)b
1
2
3
4
5
6
7
8
7
8
9
10
7
7
7
7
8
7
NEt
NEt
NEt
NEt
3
3
3
3
CH
CH
CH
CH
CH
CH
THF
THF
THF
THF
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
4 (R)
4 (R)
0
3 (R)
0
22 (S)
40 (S)
8 (S)
8 (R)
76 (S)
<5
<5
<5
<5
2
19
40
20
25
26
DIEA
Cs
Cs
—
2
CO
3
3
2
CO
9
Cs
Cs
2
CO
CO
3
3
c
1
0
2
a
The enantiomeric excess of the major acetate ester enantiomer was determined by HPLC analysis by employing a Diacel Chiralcel OJ-H column. The absolute configu-
rations denoted in parenthesis were determined according to the specific rotations reported in the literature.16
b
Conversion calculated from the ee values of the acetate and the remaining alcohol, for ee values lower than the 5% conversion was calculated from the mass of the
17
acetate.
c
Reaction conducted at ꢀ60 °C.

E. Y. Yazıcıo g˘ lu, C. Tanyeli / Tetrahedron: Asymmetry 23 (2012) 1694–1699
1697
N
N
N
N
N
4
mol% Pd(dba)2
NH
4
mol% BINAP
HN
3
+
600 mol% NaOtBu
toluene, reflux 12 h
Br
N
1
eq
2.2 eq
70% yield
12
Scheme 2. Catalyst derived from 2-bromo-4-(pyrrolidin-1-yl)pyridine and 3.
2
.2. Performance of C
2
-symmetrical chiral compounds 7–10 as
high chemical yields (56–87%) except BINAM (14%). The same cou-
pling approach can be applied to many other diamine systems. The
organocatalytic performance of all catalyst systems was evaluated
in racemic alcohol resolutions and ANTRADAP-7 showed a promis-
ing enantioselectivity (76% ee). Further applications of organocata-
lysts are currently under investigation.
organocatalysts in racemic alcohol resolutions
It is well-known that certain organic molecules can function as
enzymes, and thus provide ‘green’ routes to many synthetic prob-
lems. Our novel DMAP based C
2
-symmetrical chiral molecules
7
–10 could serve as a versatile catalyst due to existence of two
DMAP units in the context of nucleophilic organocatalysts. In order
to evaluate the performance of compounds 7–10 as organocata-
lysts, rac-1-phenylethanol was resolved as a model secondary alco-
hol, using acetic anhydride. In addition to the catalyst, the solvent,
auxiliary base and temperature were also screened as reaction
parameters. Table 1 shows the catalysts’ performance in some se-
lected examples. The initial reaction conditions which employed
4
. Experimental
The H and 13C NMR spectra were recorded in CDCl
1
on a Bruker
3
Spectrospin Advance DPX 400 spectrometer and the chemical
shifts are expressed in ppm relative to CDCl (d 7.26 and 77.0 for
H and C NMR, respectively) as the internal standard. Standard
3
1
13
COSY, HETCOR and DEPT experiments were performed to establish
NMR assignments. Infrared spectra were obtained on Varian 1000
3
NEt as the base and dichloromethane as the solvent gave very
ꢀ1
poor results both in terms of ee and yield for all catalysts, as seen
in entries 1–4. Due to the higher availability of the starting amine
and higher synthetic yield, 7 was used for most of the later trials.
FT-IR spectrophotometer and are reported in cm . HRMS data
were obtained via LC–MS analysis performed with a Waters Synapt
mass spectrometer at the central laboratory of Middle East Techni-
cal University. Optical rotations were measured a 1 dm cell using a
Rudolph research analytical, Autopol III automatic polarimeter.
HPLC measurements were performed with a Thermo Separation
Products, Inc., P1500-SN-4000-UV2000 instrument using a Chiral-
cel OJ-H analytical column (250 ꢁ 4.60 mm). Flash column chro-
matography was performed on silica gel (60-mesh, Merck). The
reactions were monitored by thin layer chromatography using
Merck 0.2 mm silica gel 60 F254 analytical aluminum plates. Melt-
ing points were obtained on a Thomas Hoover capillary melting
point apparatus and are uncorrected.
2 3
After screening various bases, we observed that Cs CO gave the
best results. Homogeneous (soluble) bases such as diisopropyleth-
ylamine gave poor results while non-nucleophilic heterogeneous
bases were relatively better. The reason for this may be the inter-
ference of these amine bases with the possible hydrogen bonding
between the –NH proton of the catalyst and the carbonyl oxygen
as a competing electron pair donor. The catalyst also works in
the absence of the base as can be seen in entry 8. This may be
the result of the formation of a bifunctional catalyst system where-
by one of the pyridine units is functionalized as an acetate salt by
the reaction of the acetic acid that is formed over the course of the
reaction. Under identical conditions, ether solvents generally in-
creased the efficiency of the catalyst. The overall catalytic inactiv-
ity of DIPHETRADAP 9 may be due to the insolubility of the
compound in common organic solvents and/or lower the rigidity
of the molecule due to less restricted rotation, which give rise to
poor face discrimination and, as a result, no enantioselectivity.
The dimethylamino groups of the pyridine rings of ANTRADAP
were exchanged with pyrrolidino groups in order to obtain struc-
ture 12 through a similar coupling reaction between 2-bromo-4-
4
.1. General procedure for the synthesis of organocatalysts via
Pd-catalyzed coupling
Chiral diamine (2.67 mmol), 2-bromo-4-alkylaminopyridine
(
5.88 mmol), NaOtBu (16 mmol), BINAP (0.11 mmol), and
Pd(dba) .CHCl (0.11 mmol) were mixed in 45 mL of toluene
which was distilled under Ar over Na-benzophenone) under an in-
2
3
(
ert atmosphere. The mixture was heated to 110 °C for 12 h,
brought to rt, and transferred to a separatory funnel. The toluene
phase was washed with 50 mL of water, after which the two
phases were separated. The remaining water phase was washed
(
pyrrolidin-1-yl)pyridine and 3. When the same reaction
conditions as shown in Table 1 were applied and 12 was used as
the catalyst, 24 ee and 9% conversion were observed (Scheme 2).
2 2
with CH Cl and the combined organic phases were concentrated
under vacuum. The mixture was purified by flash chromatography;
the solvent polarity was gradually changed from pure EtOAc to
3
. Conclusion
2
0:1 EtOAc:NEt
3
with each 100 mL mobile phase portion.
In conclusion, we have described a novel and practical method-
2
2
0
ology for the synthesis of five TRADAP based chiral nucleophilic
organocatalysts via Pd-catalyzed coupling reactions. Commercially
available and demanding chiral diamines were chosen as tem-
plates. Although the chosen chiral diamines possess different back-
bones, all afforded the desired bis-DMAP coupling product with
4.1.1. N ,N -((9R,10R,11S,12S)-9,10-Dihydro-9,10-ethanoanthra-
4
4
cene-11,12-diyl) bis (N ,N -dimethylpyridine-2,4-diamine) (9R,
10R,11S,12S)-ANTRADAP-(ꢀ)-7
Compound (S,S)-3 was used as the starting diamine. This com-
pound was obtained as a yellow foam (87% yield). Mp: 143 °C.

1
698
E. Y. Yazıcıo g˘ lu, C. Tanyeli / Tetrahedron: Asymmetry 23 (2012) 1694–1699
2
D
7
1
½
a
ꢂ
¼ ꢀ46 (c 0.2, CHCl
3
). H NMR (400 MHz, 70:30 CDCl
d 7.59 (d, J = 6.2 Hz, 2H), 7.34–7.25 (m, 4H), 7.14–7.07 (m, 4H), 5.86
dd, J = 6.2, 2.2 Hz, 2H), 5.52 (d, J = 2.0 Hz, 2H), 4.51 (s, 2H), 4.38 (d,
3
+ CCl
4
):
126.7, 125.8, 125.5, 125.0, 124.6, 124.3, 124.12, 123.4, 122.7,
120.5, 100.5, 98.5, 90.1, 37.4, 37.1. IR (neat) 2924, 2360, 1602,
1540, 1486, 1443, 1427, 1373, 1337, 1279, 1163, 1125, 1063,
(
1
3
J = 2.4 Hz, 2H), 3.62 (d, J = 7.5 Hz, 2H), 2.73 (s, 12H). C NMR
101 MHz, 70:30 CDCl + CCl ): d 168.2, 155.7, 154.1, 138.8,
37.0, 124.6, 124.5, 124.1, 122.2, 97.0, 86.0, 58.0, 47.3, 36.9. IR
neat) 3244, 2961 1600, 1526, 1486, 1446, 1370, 1288, 1260,
164, 1107, 892, 808, 760 cm . HRMS (APCI) calcd for C30
76.2688, found 477.2744 [M+H] .
1011, 984, 807, 774, 746 HRMS (APCI) calcd for
644.3376, found 645.3469 [M+H] .
C
41
H
40
N
8
+
(
1
(
1
3
4
4.1.6. (9R,10R,11S,12S)-N11,N12-Bis(4-(pyrrolidin-1-yl)pyridin-
2-yl)-9,10-dihydro-9,10-ethanoanthracene-11,12-diamine,
(9R,10R,11S,12S)-(ꢀ)-12
ꢀ1
H
32
N
6
+
4
Compound (S,S)-3 was used as the starting diamine. This com-
pound was obtained as a yellow foam (70% yield). Mp: 159 °C.
2
2
0
4
4
4
.1.2. N ,N -((1R,2R)-Cyclohexane-1,2-diyl)bis(N ,N -dimethyl-
2
D
3
1
pyridine-2,4-diamine) (1R,2R)-CYTRADAP-(ꢀ)-8
½
aꢂ
¼ ꢀ93:9 (c 1.0, CHCl
3 3 4
). H NMR (400 MHz, CDCl + CCl ): d
Compound (R,R)-4 was used as the starting diamine. This com-
ppm 7.59 (d, J = 5.9 Hz, 2H), 7.37–7.21 (m, 4H), 7.16–7.02 (m,
4H), 5.70 (dd, J = 5.9, 1.8 Hz, 2H), 5.31 (d, J = 1.9 Hz, 2H), 4.34 (d,
J = 2.5 Hz, 2H), 4.09–4.02 (m, 2H), 3.58 (d, J = 9.8 Hz, 2H), 3.08–
2.99 (m, 4H), 2.99–2.86 (m, 4H), 1.89–1.66 (m, 8H). 13C NMR
pound was obtained as a yellowish-white solid (56% yield). Mp:
2
D
7
1
1
7
65 °C. ½
aꢂ
¼ ꢀ41 (c 1.0, CHCl
3 3
). H NMR (400 MHz, CDCl ): d
.68 (d, J = 6.1 Hz, 2H), 5.84 (dd, J = 6.1, 2.3 Hz, 2H), 5.25 (d,
J = 1.9 Hz, 2H), 4.70 (s, 2H), 3.69 (d, J = 3.3 Hz, 2H), 2.80 (s, 12H),
3 4
(101 MHz, CDCl + CCl ): d 156.1, 151.3, 145.9, 139.1, 137.3,
2
1
1
2
1
C
.14 (d, J = 13.1 Hz, 2H), 1.71–1.65 (m, 2H), 1.41–1.32 (m, 2H),
.28–1.20 (m, 2H). C NMR (101 MHz, CDCl ): d 158.6, 154.7,
3
124.6, 124.5, 124.0, 122.4, 97.3, 86.2, 58.2, 47.7, 44.7, 23.2. IR
(neat): 2964, 2840, 2360, 2342, 1601, 1541, 1521, 1480, 1457,
1
3
ꢀ1
45.7, 98.0, 87.8, 54.6, 38.1, 32.4, 31.9, 23.7. IR (neat) 3244, 2932,
849, 2360, 2343, 1601, 1526, 1490, 1447, 1364, 1338, 1288,
1380, 1353, 1280, 1248, 1220, 772 cm . HRMS (APCI) calcd for
+
34 36 6
C H N 528.6898, found 529.3080 [M+H] .
ꢀ
1
263, 1220, 1162, 979, 770 cm
. HRMS (APCI) calcd for
+
20
30
H N
6
354.2532, found 355.2624 [M+H] .
4.2. General procedure for the resolution of secondary alcohols
2
2
0
4
4
4
.1.3. N ,N -((1R,2R)-1,2-Diphenylethane-1,2-diyl)bis(N ,N -
Representative procedure for reactions with 7. In a 10 mL
Schlenk flask, 0.02 equiv of organocatalyst (10 mg) and if solid,
0.7 equiv of base were added and the flask then sealed with a rub-
ber septum. The flask was kept under vacuum with a Teflon plug
and flushed with Ar with a cannula through the septum several
times. Next, 1 mL of solvent and 1 equiv of rac-methylbenzyl alco-
hol were added. If the base was liquid at room temperature, it was
also added in this step. Finally 0.7 equiv of anhydride was added
and the walls of the flask were washed with 1 mL of solvent, after
which the rubber septum was exchanged with a glass stopper and
the mixture was stirred for 24 h with a magnetic stirrer. The reac-
tion was monitored by TLC using p-anisaldehyde as the stain. After
dimethylpyridine-2,4-diamine) (1R,2R)-DIPHETRADAP-(+)-9
Compound (R,R)-5 was used as the starting diamine. This com-
pound was obtained as a yellow solid (76% yield). Mp: 201 °C.
2
D
7
1
½
a
ꢂ
¼ þ35:6 (c 1.0, CHCl
3
). H NMR (400 MHz, 90:10 DMSO-
d
6
+ CDCl
3
): d 7.69 (d, J = 6.0 Hz, 2H), 7.13–7.01 (m, 10H), 5.82
(
2
dd, J = 6.1, 2.2 Hz, 2H), 5.21 (d, J = 1.6 Hz, 2H), 4.88 (d, J = 2.6 Hz,
H), 2.71 (s, 12H). 1 C NMR (101 MHz, 90:10 DMSO-d
3
6 3
+ CDCl ):
d 157.8, 155.5, 144.9, 141.6, 127.6, 127.5, 126.5, 99.2, 88.3, 60.2,
8.8. IR (neat): 3213, 2927, 2360, 2343, 1602, 1553, 1526, 1495,
452, 1436, 1370, 1293, 1166, 980, 804, 783, 696 cm . HRMS
32 6
APCI) calcd for C28H N 452.2688, found 453.2784 [M+H] .
3
1
(
ꢀ1
+
2
4 h, methanol was added to quench the reaction, and the mixture
2
2
0
0
0
4
4
4
.1.4. (R)-N ,N -([1,1 -Binaphthalene]-2,2 -diyl)bis(N ,N -dimeth-
was purified by column chromatography.
ylpyridine-2,4-diamine) (R)-BINAPHTRADAP-(+)-10
Compound (R)-6 was used as the starting diamine. This com-
pound was obtained as a brown solid (14% yield). Mp: 146 °C.
4.2.1. (S)-1-Phenyethyl acetate
2
6
23
D
½
a
ꢂ
¼ ꢀ59:2 (c 0.5, CHCl
3
) for 76% ee, in lit. ½aꢂ
¼ þ108:7
D
22
1
16
½
aꢂ
¼ þ232:8 (c 0.5, CHCl
3
).
H
NMR (400 MHz, 70:30
3
(c 1.0, CHCl ) for the (R)-enantiomer with 99% ee. The enantio-
D
CDCl
3
+ CCl
4
): d 7.93 (d, J = 9.0 Hz, 2H), 7.85 (d, J = 9.0 Hz, 2H),
meric purity of the product was determined by HPLC analysis
7
7
.79 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 6.0 Hz, 2H), 7.33–7.23 (m, 2H),
.16 (ddd, J = 8.1, 6.8, 1.2 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 5.83
(Daicel Chiralcel OJ-H column, hexane/i-PrOH 99:1, flow rate =
ꢀ1
1.0 mL min
,
k = 254 nm),
t
R
= 11.35 min [(R)-isomer],
R
t =
1
3
(
dd, J = 6.2, 2.3 Hz, 2H), 5.61 (d, J = 2.2 Hz, 2H), 2.73 (s, 12H).
C
13.15 min [(S)-isomer] in comparison with a racemic sample.
3
NMR (101 MHz, CDCl ): d 154.9, 132.9, 129.6, 128.2, 127.1, 125.9,
1
1
24.2, 123.5, 120.9, 99.5, 88.8, 38.1. IR (neat): 3053, 2923, 1601,
ꢀ1
Acknowledgement
541, 1507, 1486, 1443, 1427, 1337, 1280, 1260, 1163, 804 cm
.
+
HRMS (APCI) calcd for C34
H
32
N
6
524.2688, found 525.2755 [M+H] .
We are indebted to the Department of Chemistry (Middle East
Technical University).
2
2
0
4
.1.5. (R)-N -(4-(Dimethylamino)pyridin-2-yl)-N -(2 -((4-(dimeth-
0
4
ylamino)pyridin-2-yl)amino)-[1,1 -binaphthalen]-2-yl)-(N ,
4
N -dimethylpyridine-2,4-diamine (R)-(ꢀ)-11
References
Compound (R)-6 was used as the starting diamine. This com-
pound was obtained as a white solid (47% yield). Mp: 179 °C.
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D
2
1
½
a
ꢂ
¼ ꢀ35:5 (c 1.0, CHCl
3 3 4
). H NMR (400 MHz, CDCl + CCl ) d
323–345.
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1
1
2
.32–7.24 (m, 1H), 7.20 (d, J = 7.3 Hz, 2H), 7.12–7.03 (m,
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(
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7.
4-Hydroxypyridin-2-yl trifluoromethanesulfonate was prepared from
1
36.6, 132.2, 131.4, 130.2, 129.5, 127.6, 127.5, 127.1, 126.9,
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1699
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003.
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84–787.