Click-BINOLs: A new class of tunable ligands for asymmetric catalysis

Article abstract of DOI:10.1055/s-0031-1291009

A new class of easily tunable 1,2,3-triazole-BINOL ligands, 'click'-BINOLs, have been synthesized from readily available alkynes and several azido-BINOL derivatives using the powerful Huisgen [3+2] cycloaddition 'click' approach. The activity of these ligands in asymmetric Lewis acid catalysis has been explored for the first time in the diethylzinc addition to aldehydes. The C ₂-symmetric ligand 1d showed an interesting catalytic behavior, which suggests the non-innocent participation of the triazole units. Thus, good enantioselectivities (up to 86% ee) were obtained by both the right selection of the substitution pattern at the triazole ring and the fine tuning of the reaction conditions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1291009

2162▌
SPECIAL TOPIC
special topic
‘Click’-BINOLs: A New Class of Tunable Ligands for Asymmetric Catalysis
‘Click’-BINOLs: Tuneable Ligands for Asymmetric Catalysis
Stephan Beckendorf, Olga García Mancheño*
Institute of Organic Chemistry, Münster University, Corrensstr. 40, 48149 Münster, Germany
Fax +49(251)8333202; E-mail: olga.garcia@uni-muenster.de
Received: 26.03.2012; Accepted: 30.03.2012
azide library
Abstract: A new class of easily tunable 1,2,3-triazole-BINOL li-
commercially
available alkynes
gands, ‘click’-BINOLs, have been synthesized from readily avail-
n
N3
R2
R2
able alkynes and several azido-BINOL derivatives using the
powerful Huisgen [3+2] cycloaddition ‘click’ approach. The activ-
ity of these ligands in asymmetric Lewis acid catalysis has been ex-
plored for the first time in the diethylzinc addition to aldehydes. The
C2-symmetric ligand 1d showed an interesting catalytic behavior,
which suggests the non-innocent participation of the triazole units.
Thus, good enantioselectivities (up to 86% ee) were obtained by
both the right selection of the substitution pattern at the triazole ring
and the fine tuning of the reaction conditions.
OR1
OR1
alkyne library
R3
‘click’
BINOLs
+
n
N3
R2
R2
OR1
OR1
Sonogashira coupling
Key words: Lewis acids, asymmetric catalysis, ‘click’ chemistry,
BINOL ligands, alkynes, aldehydes, diethylzinc additions
N3
n
Figure 1 Modular approach to ‘click’-BINOL ligands
Chiral axial 1,1′-bi-2-naphthol (BINOL) represents a
privileged ligand structure in asymmetric catalysis and
therefore its derivatives have been extensively used.1 The
hydroxy basic sites of the BINOL moiety allow the incor-
poration of hard metal Lewis acids such as Ti(IV) or
Al(III), providing with chiral complexes for catalysis. On
the other hand, the substituents at the 3 and 3′ positions
can modulate the electronic and steric properties of the
generated Lewis acid complex, leading in many cases to
more active and selective catalysts. Although the chemis-
try of BINOL is well studied, permitting the easy func-
tionalization of its skeleton, often many linear synthetic
steps are required to produce a desired derivative.1 It
would be then very desirable to be able to generate in a
very efficient manner a library of such ligands from sim-
ple common precursors. In this regard, a very powerful
synthetic method is the copper-catalyzed Huisgen [3+2]
cycloaddition2,3 between an azide and an alkyne to link the
two units via a triazole moiety. Surprisingly, the combina-
tion of the high performance of BINOL ligands with this
extremely efficient transformation and the ready avail-
ability of alkynes has not yet been exploited. To easily
tune the properties of the catalysts for their application in
asymmetric catalysis, we herein propose a modular and
flexible strategy by using such ‘click’ chemistry4 to intro-
duce into BINOL derivatives a 1,2,3-triazole group as a
possible second coordination site.5 Thus, a small set of
BINOL azides will be used in combination with commer-
cially available or easy to prepare substituted terminal al-
kynes to generate a new family of ‘click’-BINOL ligands
1 (Figure 1).
The introduction of azido groups into the 3 and 3′ posi-
tions of BINOL was carried out first (Scheme 1). The
preparation in multigram scale of the BINOL azides
building blocks 2a–d was easily accomplished by a first
ortho-lithiation of MOM-protected (S)-BINOL and treat-
ment with an appropriate electrophile. Thus, methylene
azide derivatives 2a and 2b were obtained by reaction
with paraformaldehyde or DMF followed by reduction,
affording the mono- or dimethyl alcohols, respectively.
After mesylation and treatment of the crude reaction mix-
ture with NaN3, 2a and 2b were obtained in good overall
yields (3–4 steps, 47–60%; Scheme 1, left). On the other
hand, precursors 2c and 2d, having the azide group direct-
ly linked at the BINOL backbone, were prepared in a sin-
N3
N3
OMOM
OMOM
OMOM
OMOM
i)
i), ii)
2a
2c
51%
(3 steps)
59%
(1 step)
OMOM
OMOM
iii)
iv), ii)
N3
N3
iii)
OMOM
OMOM
(S)-MOM-BINOL
OMOM
OMOM
N3
N3
2b
2d
68%
63%
(4 steps)
(1 step)
Scheme 1 Synthesis of the azido-BINOL derivatives. Reagents and
conditions: i) t-BuLi, –78 °C, THF, 2 h; (HCHO)n or TosN3, –78 °C
to r.t., 12 h; ii) MeSO2Cl, Et3N, toluene–EtOAc, 0 °C, 1 h; NaN3,
DMF, 0 °C to r.t., 4 h; iii) n-BuLi, TMEDA, 0 °C to r.t., Et2O, 2 h;
DMF or TosN3, 0 °C to r.t., 4 h; iv) NaBH4, THF–EtOH, 0 °C, 6 h.
SYNTHESIS 2012, 44, 2162–2172
Advanced online publication: 25.05.2012
DOI: 10.1055/s-0031-1291009; Art ID: SS-2012-C0311-ST
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

SPECIAL TOPIC
‘Click’-BINOLs: Tuneable Ligands for Asymmetric Catalysis
2163
gle step by reaction of the corresponding lithiated species in hexanes) in toluene (0.25 M) at room temperature (23–
with TosN3 (51–68% yields; Scheme 1, right).
25 °C). Under these conditions, ligands 1a and 1b with
mono- and bis-methylene-bridged triazoles led to results
similar to the parent BINOL [85%, 54–58% ee (S) vs
84%, 53% ee (S)] (Scheme 3). Conversely, the ligands
having the triazole units directly linked to the binaphthol
backbone 1c,d showed more interesting and promising re-
sults. Whereas unsymmetrical ‘click’-BINOL 1c provid-
ed carbinol 5a in a modest 38% ee, the C2-symmetric
ligand 1d built the new stereocenter in a significantly im-
proved 72% ee. Interestingly, now the opposite enantio-
mer R was formed. For this ligand, we also observed a
strong influence of the incubation time to form the chiral
Lewis acid catalyst on the final enantioselectivity. Thus,
the stirring of 1d with Ti(Oi-Pr)4 for 15–30 minutes prior
to the addition of benzaldehyde was critical to obtain good
selectivities (66–74% ee). Moreover, shorter or longer in-
cubation times, such as overnight, led to considerable
lower or even inverse enantioselectivity. This indicates
the different participation of kinetic and thermodynamic
active catalytic species. Therefore, a study on the varia-
tion of the enantiomeric excess with the reaction time was
carried out (Scheme 3, below). In this case, after 15 min-
utes catalyst incubation, benzaldehyde was added and
stirred for another 15 minutes before the treatment with
Et2Zn. We were pleased to observe that the enantiomeric
excess did not fluctuate significantly during the course of
the reaction under these conditions [final ee = 66% (R)].
The new family of ‘click’-BINOL ligands 1a–l were then
synthesized in a divergent manner from these BINOL
azides 2 using various substituted alkynes under standard
conditions for the Huisgen [3+2] cycloaddition: combina-
tion of CuSO4 (4–8 mol%) and Na ascorbate (12–24
mol%) in a 1:1:1 mixture of t-BuOH–H2O–CH2Cl2 at
50 °C. A number of terminal alkynes, containing sterical-
ly and electronically different aryl and alkyl groups, were
employed. Finally, the obtained MOM-intermediates 3
were directly deprotected under acidic conditions (aq 12
M HCl) to give the desired OH-free ligands 1 (Scheme 2).
R2
R2
CuSO4 (4–8 mol%)
Na ascorbate
N
n N3
n
N
N
(12–24 mol%)
OMOM
OMOM
OMOM
OMOM
t-BuOH–H2O–CH2Cl2
(1:1:1), 50 °C
R1
R1
2
3
12 M HCl (aq)
CH2Cl2–MeOH (1:2).
50 °C
R2
R2
N
n
n N
N
N
N
N
N
OH
OH
OH
OH
or
N
R2
N
Next, the optimization of the reaction conditions with the
best first generation ligand 1d and an incubation time of
30 minutes was carried out (Table 1). We found out that
the use of Ti(Oi-Pr)4 and the ratio of Lewis acid/ligand
were also crucial (Table 1, entries 1–5). Thus, the reaction
in the absence of Lewis acid delivered the product in only
18% ee (entry 2) and the use of other metal species such
as Al(Oi-Pr)3 gave 5a in a 27% ee (entry 6). On the other
hand, by decreasing (entry 3) or increasing (entries 4, 5)
the amount of Ti(Oi-Pr)4 with respect to 1d, 5a was ob-
tained in remarkably lower enantiomeric excesses. More-
over, in the case of utilizing a large excess of Ti (4:1
Ti/ligand, entry 5), the reverse S-enantiomer started to
build, although in a modest 22% ee.
n
1a n = 1, R2 = Ph (74%)
1c n = 0, R2 = Ph (72%)
1b n = 1, R2 = Ph (84%)
n = 0
R2
=
F
F
OMe
F
1d
F
1g
(39%)
1f
(87%)
1e
(41%)
(37%)
Me
N
H
Me
1k
(47%)
N
1l
(90%)
1h
(25%)
1i
(95%)
1j
(38%)
Scheme 2 Synthesis of ‘click’-BINOL ligands
The concentration of the reaction (entries 7, 8 vs 1) and
the solvent used (entries 9–11) were also essential to ob-
tain a high enantioselectivity. Hence, the initial concentra-
tion of 0.25 M and toluene turned out to be the optimal
concentration and solvent. Importantly, we observed that
the reaction in hexane gave a poor enantiomeric excess
(26% ee, entry 9). Considering that the Et2Zn that we were
employing was a 1 M solution in hexanes, in order to im-
prove the enantioselectivity we decided to use a solution
in toluene (1.1 M). As expected, the enantiomeric excess
increased substantially to 86% ee (entry 12). The effect of
the amount of Et2Zn on the asymmetric induction of the
reaction was next explored (entries 12–15). The amount
of Et2Zn could be reduced from 2 to 1.1 equivalents with-
out significant loss of enantioselectivity. However, when
only 1 equivalent was used both the reactivity and the en-
With these ‘click’-BINOL ligands 1 in hand, we decided
to explore their performance in Lewis acid catalyzed
asymmetric reactions. Among important classes of such
transformations, the asymmetric addition of diethylzinc to
aldehydes is considered as one of the benchmark reactions
for investigating the catalytic activity and potential of new
ligands.6 Moreover, this reaction leads to pharmaceutical-
ly important carbinol derivatives. Therefore, the addition
of Et2Zn to benzaldehyde 4a was chosen as the model re-
action.
Initially, the performance of the first generation of ‘click’-
(S)-BINOLs (R2 = Ph) was tested and compared with sim-
ple (S)-BINOL (Scheme 3). The reactions were performed
using the combination of 10 mol% of the ligand, 10 mol%
Ti(Oi-Pr)4 as Lewis acid, and 2 equivalents of Et2Zn (1 M
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2162–2172

2164
S. Beckendorf, O. G. Mancheño
SPECIAL TOPIC
Table 1 Optimization of the Reaction of 4a with 1da
O
OH
ligand 1d (10 mol%)
Ti(Oi-Pr)4
H
Et2Zn, solvent, r.t.
4a
5a
Entry
Ti/1d
Et2Zn
(equiv) (M)
Solvent
Yield ee (%)c
(%)b
(config)
1
2
1:1
–/1
1:4
2:1
4:1
1:1e
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0f
1.5f
1.1f
1.0f
2.0f
toluene (0.25)
74d
86
75
87
86
96
85
73
86
62
78
79d
80
68
65
40
72 (R)
18 (R)
58 (R)
0
toluene (0.25)
toluene (0.25)
toluene (0.25)
toluene (0.25)
toluene (0.25)
toluene (0.4)
toluene (0.17)
hexane (0.25)
CH2Cl2 (0.25)
Et2O (0.25)
3
4
5
22 (S)
27 (R)
28 (R)
52 (R)
26 (S)
36 (R)
18 (R)
86 (R)
83 (R)
81 (R)
63 (R)
80 (R)g
6
7
8
9
10
11
12
13
14
15
16
toluene (0.25)
toluene (0.25)
toluene (0.25)
toluene (0.25)
toluene (0.25)
Scheme 3 First generation of ‘click’-BINOLs (R2 = Ph) in the addi-
tion of Et2Zn to benzaldehyde and reaction profile with 1d
a Reaction conditions: 1d (10 mol%) and Ti(Oi-Pr)4 (10 mol%) in tol-
uene (30 min); next addition of 4a (0.25 mmol), and after 30 min ad-
dition of Et2Zn (0.50 mmol, 2 equiv, 1 M in hexanes). The reaction
was then stirred at r.t. for 24 h.
antiomeric excess sank (entry 15). Lastly, the reaction was
carried out at 0 °C. Unfortunately, the reaction was con-
siderably slower and no improvement in the ee was
achieved (entry 16).
b GC yield.
c The ee was determined by chiral HPLC.
d Isolated yield.
e Al(Oi-Pr)3 was used as Lewis acid.
f A 1.1 M solution of Et2Zn in toluene was used.
g Reaction at 0 °C for 96 h.
With these initial optimized conditions for ligand 1d [10
mol% Ti(Oi-Pr)4/1 and Et2Zn (2 equiv, 1.1 M in toluene)
in toluene (0.25 M) at r.t.], the effect of the substituents at
the triazole ring was next explored (Figure 2).
metric induction or again the reverse enantioselectivity.
This can be explained by a competitive formation of dif-
ferent Lewis acid complexes in which the triazole and this
new coordination unit, further from the chirality source,
are the principal players. All these results indicate that the
triazole unit is not an innocent group and participates in
the coordination and modulates the activity of the active
Lewis acid catalyst.7 In this sense, although complex clus-
ter metallic species can be formed,1 three simplified sce-
narios in which a different coordination with the nitrogens
or the acidic C-5 position of the triazoles can be envi-
sioned: A) the triazole also coordinates with the N-atoms
to the organometallic species; B) the C-5 position of the
triazole is metallated and participates in the formation of
a multi-metallic active catalyst;8 and C) a mixture of both
coordination modus A and B occur. In the scenario A, a
We were surprised to observe a strong decrease of enantio-
selectivity by the increase of the steric hindrance of the
aromatic substituent at the triazole ring. Thus, the 9-an-
thracenyl derivative 1e led to a poor 5% ee, whereas mes-
ityl 1f or even a fluorinated aryl-substituted triazole ligand
1g provided now the opposite S-enantiomer in low or
moderate enantioselectivities (30% or 59% ee, respective-
ly). Conversely, the unsubstituted triazole ligand 1h re-
sulted highly ineffective (racemic 5a was formed in 50%
yield). On the other hand, bulky aliphatic substituents
such as tert-butyl (1i) or 1-adamantyl (1j) worked rela-
tively well, providing carbinol 5a in good yields and 62%
ee. Finally, the introduction of a further coordination
group in the ‘click’-BINOL ligand such as a dimethyl-
amine (1k) or a 2-pyridine (1l), led to a very low asym-
Synthesis 2012, 44, 2162–2172
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
‘Click’-BINOLs: Tuneable Ligands for Asymmetric Catalysis
2165
Table 2 Asymmetric Addition of Et2Zn to Aldehydes: Substrate
2nd optimization round
R
Scopea
F
ligand 1d (10 mol%)
Ti(Oi-Pr)4 (10 mol%)
F
OMe
F
O
OH
R
H
R
Et2Zn (2 equiv; 1.1 M in toluene)
toluene (0.25 M), r.t.
4
(R)-5
F
(S)-1d
86% ee (R)
79% yield
(R)-1d
70% ee (S)
88% yield
(S)-1e
5% ee (R)
49% yield
(S)-1g
59% ee (S)
59% yield
(S)-1f
30% ee (S)
70% yield
Entry
1
R
Product 5
Yield (%)b ee (%)c
OH
Me
H
N
N
2-naphthyl
99
86
Me
(S)-1h
rac
50% yield
(S)-1i
62% ee (R)
76% yield
(S)-1j
62% ee (R)
87% yield
(S)-1k
3% ee (R)
83% yield
(S)-1l
46% ee (S)
35% yield
5b
5c
OH
C vs. N second interaction site of the triazole group
R
2
3
4
5
1-naphthyl
4-MeOC6H4
4-FC6H4
86
96
75
94
86
77
78
81
N
N
N
N
N
N
N
R
N
N
R
OH
OH
OH
OH
OH
OH
OH
N
N
N
N
N
N
MeO
R
N
N
N
5d
A
B
C
R
R
OH
Ph
Ph
N
N
N
N
1,4- vs. 1,5-triazoles
F
N
N
(S)-1d
86% ee (R)
79% yield
(S)-1d'
20% ee (S)
56% yield
OH
OH
OH
OH
5e
OH
N
N
N
N
N
N
4-ClC6H4
Cl
Ph
Ph
5f
Figure 2 Effect of the substitution at the triazole rings on the enanti-
OH
oselectivity
Cl
6
7
8
9
3-ClC6H4
2-ClC6H4
cyclohexyl
2-pyridyl
66
86
39
29
46
54
50
0
little effect on the enantioselectivity of the substituent,
which is pointing out of the coordination sphere, could be
expected. However, we observed a clear influence of this
substitution. Therefore, scenarios B or C are more likely
to generate the enantioselective active catalyst. Moreover,
in order to avoid strong steric interactions between the
substituents at the C-4 position, a dynamic interconver-
sion might take place. Thus, the rotation of the triazoles
and the different interaction can justify the lower perfor-
mance, and even the favored generation of the opposite S-
enantiomer. Therefore, after this short substitution screen-
ing, the phenyl group in 1d was taken as optimal compro-
mise.
Additionally, the regioisomeric 1,5-triazole ligand 1d′,9,10
in which the C-5 position is blocked, showed a lower re-
activity (56% yield after 16 h) and enantioselectivity in fa-
vor to the S-alcohol [20% ee (S) 1d′ vs 86% ee (R) 1d;
Figure 2, bottom]. Again, this result indicates the active
participation and influence of the triazole group in the for-
mation and asymmetric induction activity of the active
Lewis acid catalyst.
5g
Cl
OH
OH
OH
5h
5i
N
5j
a Reaction conditions: 1d (10 mol%) and Ti(Oi-Pr)4 (10 mol%) in tol-
uene (30 min); next addition of 4a (0.25 mmol), and after 30 min ad-
dition of Et2Zn (0.50 mmol, 2 equiv, 1.1 M in toluene). The reaction
was then stirred at r.t. for 15–48 h.
b Isolated yield.
c The ee was determined by chiral HPLC or GC.
Lastly, the performance of 1d for the addition of Et2Zn to
diverse aldehydes was studied (Table 2). All reactions
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2162–2172

2166
S. Beckendorf, O. G. Mancheño
SPECIAL TOPIC
7.17 (br d, J = 8.5 Hz, 2 H), 5.10 (d, J = 6.8 Hz, 2 H), 4.99 (d,
J = 6.8 Hz, 2 H), 3.15 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 152.8, 134.1, 130.0, 129.5,
lead to the formation of the R-configured carbinols 5, with
the exception of the N-coordinating 2-pyridylcarboxalde-
hyde, which provided a racemic product (entry 9). The 2-
and 1-naphthaldehydes, as well as both electron-with-
128.0, 126.4, 125.7, 124.2, 121.4, 117.4, 95.3, 56.0.
drawing and -donating para-substituted benzaldehydes HRMS (ESI): m/z [M + Na]+ calcd for C24H22O4 + Na: 397.1410;
found: 397.1412.
reacted well, giving alcohols 5b–f in similar good enantio-
selectivities (entries 1–5). On the other hand, meta- and
ortho-substituted benzaldehydes, as well as aliphatic cy-
(S)-3-(Azidomethyl)-MOM-BINOL (2a)
(S)-3-Hydroxymethyl-MOM-BINOL (6):12 (S)-MOM-BINOL
clohexyl carboxaldehyde, afforded 5g–j in significantly (6.37 g, 17.0 mmol, 1.0 equiv) was dissolved in THF (100 mL) and
the solution was cooled to –78 °C. Then, t-BuLi (11.3 mL, 1.5 M in
hexane, 17.0 mmol, 1.0 equiv) was added dropwise and the mixture
was stirred at –78 °C for 2 h. Paraformaldehyde (782 mg,
25.5 mmol, 1.5 equiv) was then added and the reaction mixture was
lower ee values (entries 6–8). These results indicate a
strong substrate-recognition dependence and face dis-
crimination by the catalysts, in which steric issues might
play again an important role.
stirred at r.t. for 12 h. The mixture was quenched with H2O (50 mL)
and extracted with EtOAc (3 × 50 mL). The combined organic lay-
ers were dried (Na2SO4), filtered, and concentrated under reduced
pressure. After flash column chromatography (pentane–EtOAc,
In conclusion, an easy and modular synthetic approach to
a new family of ‘click’-BINOL ligands from simple al-
kynes and azido-BINOL derivatives has been developed.
Among all synthesized ligands, the C2-symmetric 1,4-di-
substituted bis-triazole (S)-1d, in combination with Ti(Oi-
Pr)4 as Lewis acid, behaved as interesting chiral catalyst
in the asymmetric addition of diethylzinc to aldehydes. Its
performance suggested a non-innocent participation of
the triazole units in both the formation and reactivity of
the active Lewis acid metal catalyst.
2:1), the desired product (3.94 g, 9.74 mmol, 57%) was obtained as
a colorless resin; [α]D20 –200 (c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 8.01–7.96 (m, 2 H), 7.92–7.85 (m,
2 H), 7.60 (d, J = 9.1 Hz, 1 H), 7.43–7.33 (m, 2 H), 7.30–7.21 (m,
2 H), 7.19–7.12 (m, 2 H), 5.12 (d J = 7.0 Hz, 1 H), 5.04 (d,
J = 7.0 Hz, 2 H), 4.95 (dd, J = 12.4 Hz, 6.5 Hz, 1 H), 4.90 (dd,
J = 12.4 Hz, 6.5 Hz, 1 H), 4.69 (d, J = 6.1 Hz, 1 H), 4.48 (d,
J = 6.1 Hz, 1 H), 3.52 (t J = 6.5 Hz, 1 H), 3.25 (s, 3 H), 3.16 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 153.3, 152.9, 134.4, 133.9, 133.9,
131.2, 130.2, 129.8, 129.3, 128.1, 128.1, 127.0, 126.4, 125.8, 125.6,
125.5, 125.3, 124.4, 120.6, 116.6, 99.5, 95.0, 62.3, 57.2, 56.1.
HRMS (ESI): m/z [M + Na]+ calcd for C25H24O5 + Na: 427.1516;
found: 427.1520.
All reactions were carried out in heat-gun-dried glassware under ar-
gon atmosphere. CH2Cl2 was distilled over CaH2; and THF, Et2O,
and toluene were distilled and dried over Na. 1H, 13C and 19F NMR
spectra were recorded in CDCl3 and DMSO-d6 (reference signals:
1
1H = 7.26 ppm, 13C = 77.16 ppm, CDCl3; H = 2.50 ppm, 13C =
BINOL-azide 2a: Compound 6 (3.52 g, 8.70 mmol, 1.0 equiv) and
Et3N (4.80 mL, 34.8 mmol, 4.0 equiv) were dissolved in toluene–
EtOAc (100 mL, 1:1) and the solution was cooled to 0 °C. Then,
MsCl (1.4 mL, 17.4 mmol, 2.0 equiv) was added and the mixture
was stirred 1 h at 0 °C. After filtration through Celite, the obtained
filtrate was treated with NaN3 (5.65 g, 87.0 mmol, 10.0 equiv), pre-
viously dissolved in DMF (100 mL), and stirred at r.t. for 4 h. The
reaction mixture was then diluted with H2O (100 mL) and extracted
with Et2O (3 × 100 mL). The combined organic layers were washed
with H2O (2 × 100 mL), 1 M aq HCl (100 mL) and brine (100 mL),
dried (Na2SO4), and filtered. After removal of the solvent under re-
duced pressure, the desired product (3.30 g, 7.70 mmol, 89%) was
39.52 ppm, DMSO-d6) on a Bruker ARX-300 and a Varian AV-
300, 400 or 600 MHz spectrometers. Chemical shifts (δ) are given
in ppm and spin-spin coupling constants (J) are given in Hz. Ana-
lytical TLC was performed using silica gel 60 F254 and a solution of
KMnO4 served as staining agent. Column chromatography was per-
formed on silica gel 60 (0.040–0.063 mm). Exact masses (HRMS)
were recorded on a Bruker Daltonics MicroTof spectrometer (sam-
ples in MeOH as solvent). Melting points were measured by differ-
ential scanning calorimetry with a Ta Instruments Q20 calorimeter.
HPLC and GC analysis were performed with Agilent Technologies
1200 Series and 6890 Series spectrometers, respectively. Aldehydes
were freshly distilled for the catalytic reaction. Analytical grade sol-
vents and other commercially available reagents were used without
further purification. The structures of intermediates 6–8 are shown
in the Supporting Information.
20
obtained as a white solid; mp 129–133 °C; [α]D –52 (c 1.4,
CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.01–7.97 (m, 2 H), 7.94–7.85 (m,
2 H), 7.61 (d, J = 9.1 Hz, 1 H), 7.46–7.34 (m, 2 H), 7.32–7.23 (m, 2
H), 7.18 (br t, J = 7.3 Hz, 2 H), 5.14 (d, J = 7.0 Hz, 1 H), 5.06 (d,
J = 7.0 Hz, 1 H), 4.74 (s, 2 H), 4.64 (d, J = 5.6 Hz, 1 H), 4.52 (d,
J = 5.7 Hz, 1 H), 3.18 (s, 3 H), 3.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.0, 152.4, 134.0, 133.9, 130.8,
130.2, 129.8, 129.4, 129.1, 128.1, 128.1, 127.0, 126.7, 125.9, 125.8,
125.5, 125.4, 124.4, 120.3, 116.5, 99.5, 94.9, 57.0, 56.1, 51.1.
MOM-BINOL11
NaH (1.35 g, 60% in mineral oil, 33.8 mmol, 2.24 equiv) was sus-
pended in THF–DMF (90 mL, 2:1) and cooled to 0 °C. Then, a so-
lution of (S)- or (R)-1,1′-binaphthol (4.32 g, 15.1 mmol, 1.00 equiv)
in THF (18 mL) was added dropwise and the resulting mixture was
stirred 1 h at r.t. Chloro(methoxy)methane (3.62 mL, 47.7 mmol,
3.16 equiv) was added and the reaction mixture was stirred at r.t. for
4 h. The mixture was quenched with H2O (50 mL) and extracted
with EtOAc (3 × 50 mL). The combined organic layers were
washed with brine (30 mL), dried (Na2SO4), filtered, and concen-
trated under reduced pressure. After recrystallization from MeOH,
the desired product (5.45 g, 14.6 mmol, 97%) was obtained as a
white solid; mp 104–105 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C25H23N3O4 + Na: 452.1581;
found: 452.1582.
(S)-3,3′-Bis(azidomethyl)-MOM-BINOL (2b)
(S)-3,3′-Dicarboxyaldehyde-MOM-BINOL (7):13 (S)-MOM-BINOL
(6.00 g, 16.0 mmol, 1.0 equiv) and TMEDA (9.5 mL, 64.0 mmol,
4.0 equiv) were dissolved in THF (100 mL) and the solution was
cooled to 0 °C. n-BuLi (1.6 M solution in pentane) (25.0 mL,
40.0 mmol, 2.5 equiv) was added dropwise and the mixture was
stirred 1 h at 0 °C. DMF (6.20 mL, 80.0 mmol, 5.0 equiv) was add-
ed and the reaction mixture was stirred at r.t. for 12 h. The reaction
was quenched with H2O (50 mL) and extracted with EtOAc (3 ×
20
(S)-MOM-BINOL: [α]D –93 (c 1.0, THF); (R)-MOM-BINOL:
[α]D20 +96 (c 1.0, THF).
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 9.0 Hz, 2 H), 7.88 (d,
J = 8.2 Hz, 2 H), 7.59 (d, J = 9.0 Hz, 2 H,), 7.35 (ddd, J = 8.0 Hz,
6.7 Hz, 1.3 Hz, 2 H), 7.23 (ddd, J = 8.0 Hz, 6.7 Hz, 1.3 Hz, 2 H),
Synthesis 2012, 44, 2162–2172
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
‘Click’-BINOLs: Tuneable Ligands for Asymmetric Catalysis
2167
50 mL). The combined organic layers were dried (Na2SO4), filtered,
and concentrated under reduced pressure. After flash column chro-
matography (pentane–EtOAc, 3:1), the desired product (5.99 g,
13.9 mmol, 87%) was obtained as a yellow solid; mp 118–119 °C.
lized from a EtOAc solution (30 mL) overlayed with pentane
(400 mL) and kept for 2 days at –20 °C. After filtration, the desired
product (7.3 g, 17.6 mmol, 59%) was obtained as a white solid; mp
85–89 °C; [α]D20 –45 (c 1.5, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 10.55 (s, 2 H), 8.61 (s, 2 H) 8.07
(dd, J = 8.1 Hz, 2 H), 7.61–7.47 (m, 2 H), 7.47–7.34 (m, 2 H), 7.24–
7.19 (m, 2 H), 4.73 (d, J = 6.2 Hz, 2 H), 4.68 (d, J = 6.2 Hz, 2 H),
2.87 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 190.8, 154.2, 136.8, 132.4, 130.4,
130.2, 129.8, 129.0, 126.4, 126.2, 126.0, 100.7, 57.2.
1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J = 8.5 Hz, 1 H), 7.72 (d,
J = 8.1 Hz, 1 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.54 (s, 1 H), 7.46 (d,
J = 9.1 Hz, 1H), 7.30–7.07 (m, 3 H), 7.07–7.00 (m, 3 H), 5.01 (d,
J = 7.0 Hz, 1 H), 4.91 (d, J = 7.0 Hz, 1 H), 4.66 (d, J = 5.7 Hz, 1 H),
4.59 (d, J = 5.7 Hz, 1 H), 3.06 (s, 3 H), 2.59 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 152.9, 145.7, 133.9, 133.3, 131.5,
131.1, 130.1, 129.6, 128.0, 127.9, 126.8, 126.8, 126.1, 125.9, 125.8,
125.6, 124.2, 119.9, 117.4, 116.4, 99.0, 94.9, 56.6, 56.0.
HRMS (ESI): m/z [M + Na]+ calcd for C26H22O6 + Na: 453.1309;
found: 453.1319.
HRMS (ESI): m/z [M + Na]+ calcd for C24H21N3O4 + Na: 438.1424;
found: 438.1424.
(S)-3,3′-Dihydroxymethyl-MOM-BINOL (8):14 Compound
7
(4.30 g, 10.0 mmol, 1.0 equiv) was dissolved in MeOH (50 mL)
and the solution was cooled to 0 °C. Then, NaBH4 (907 mg,
24.0 mmol, 2.4 equiv) was added and the resulting mixture was
stirred 1 h at r.t. The reaction was quenched with H2O (50 mL) and
extracted with CH2Cl2 (3 × 75 mL). The combined organic layers
were dried (Na2SO4) and filtered. After removal of the solvent un-
der reduced pressure, the desired product (4.15 g, 9.60 mmol, 96%)
3,3′-Diazido-MOM-BINOL (2d)
(S)-MOM-BINOL (5.00 g, 13.4 mmol, 1.0 equiv) and TMEDA
(8.00 mL, 53.4 mmol, 4.0 equiv) were dissolved in Et2O (300 mL)
and the solution was cooled to 0 °C. n-BuLi (23.0 mL, 1.6 M in
pentane, 36.7 mmol, 2.75 equiv) was added dropwise and the re-
sulting mixture was stirred for 1 h at r.t. The reaction mixture was
cooled to 0 °C and TosN3 (7.90 g, 40.1 mmol, 3.0 equiv) was added
dropwise. The resulting mixture was stirred for 1 h at 0 °C and for
further 3 h at r.t. The reaction was quenched with H2O (50 mL) and
extracted with CH2Cl2 (3 × 100 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. After flash column chromatography (gradient of pentane–
EtOAc–CH2Cl2, 30:2:1 → 20:2:1), the desired product (3.84 g,
8.41 mmol, 63%) was obtained as a slightly brown solid; mp 81–
84 °C.
20
was obtained as a white solid; mp >268 °C (dec.); [α]D +224
(c 0.3, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.03 (s, 2 H), 7.90 (d, J = 8.1 Hz,
2 H), 7.46–7.38 (m, 2 H), 7.30–7.22 (m, 2 H), 7.19–7.12 (m, 2 H),
4.99 (d, J = 12.6 Hz, 2 H), 4.85 (d, J = 12.6 Hz, 2 H), 4.48 (d, J =
6.2, 2 H), 4.45 (d, J = 6.2 Hz, 2 H), 3.18 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 153.2, 134.6, 133.8, 131.0, 129.8,
128.2, 126.9, 125.8, 125.5, 125.2, 99.4, 61.9, 57.2.
HRMS (ESI): m/z [M + Na]+ calcd for C26H26O6 + Na: 457.1622;
found: 457.1626.
20
20
(S)-2d: [α]D +24 (c 0.50, CHCl3); (R)-2d: [α]D –23 (c 0.25,
CHCl3).
BINOL-azide 2b: Compound 8 (4.15 g, 9.50 mmol, 1.0 equiv) and
Et3N (10.6 mL, 76.0 mmol, 8.0 equiv) were dissolved in toluene–
EtOAc (100 mL, 1:1) and the solution was cooled to 0 °C.
MeSO2Cl (3.0 mL, 38.0 mmol, 4.0 equiv) was added and the mix-
ture was stirred at 0 °C for 2 h. After filtration of the mixture
through Celite, the obtained filtrate was treated with NaN3 (6.18 g,
95.0 mmol, 10.0 equiv), previously dissolved in DMF (100 mL),
and stirred for 4 h at r.t. The mixture was diluted with H2O
(100 mL) and extracted with Et2O (3 × 100 mL). The combined or-
ganic layers were washed with H2O (2 × 100 mL), 1 M aq HCl
(100 mL), and brine (100 mL), dried (Na2SO4), and filtered. After
removal of the solvent under reduced pressure, the desired product
(3.12 g, 7.70 mmol, 81%) was obtained as a colorless oil; [α]D
+166 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.03 (s, 2 H) 7.93 (d, J = 8.1 Hz,
2 H), 7.49–7.41 (m, 2 H), 7.35 –7.27 (m, 2 H), 7.22–7.15 (m, 2 H),
4.81 (d, J = 14.1 Hz, 2 H), 4.69 (d, J = 14.1 Hz, 2 H), 4.54 (d, J =
5.9 Hz, 2 H), 4.49 (d, J = 5.9 Hz, 2 H), 3.02 (s, 6 H).
1H NMR (300 MHz, CDCl3): δ = 7.64 (d, J = 8.2 Hz, 2 H), 7.52 (s,
2 H), 7.26 (ddd, J = 8.2, 6.7, 1.3 Hz, 2 H), 7.10–7.04 (m, 2 H), 6.98
(d, J = 8.6 Hz, 2 H), 4.71 (d, J = 5.9 Hz, 2 H), 4.59 (d, J = 5.9 Hz,
2 H), 2.47 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 145.8, 133.2, 131.4, 130.9, 127.3,
126.8, 126.5, 126.2, 126.1, 117.8, 99.0, 56.5.
HRMS (ESI): m/z [M + Na]+ calcd for C24H20N6O4 + Na: 479.1444;
found: 479.1440.
Copper-Catalyzed Cycloaddition of Azides 2 with Alkynes
(CuAAC);3 General Procedure
20
A mixture of azide 2 (7.70 mmol, 1.0 equiv), the corresponding al-
kyne [1.5 equiv for mono-N3 (2a and 2d) or 3.0 equiv for di-N3 (2b
and 2d), respectively], 0.04 M aq CuSO4 (4–8 mol%), and 0.12 M
aq sodium ascorbate (12–24 mol%) in 1:1:1 mixture of CH2Cl2–t-
BuOH–H2O (15–30 mL, H2O solvent from the CuSO4 and Na
ascorbate stock solutions) was stirred vigorously at 50 °C under ar-
gon in a pressure Schlenk flask. After completion of the reaction
(followed by TLC), the mixture was diluted with H2O (8 mL) and
extracted with CH2Cl2 (3 × 8 mL). The combined organic layers
were washed with 25% aq ammonia (3 × 8 mL) and brine (8 mL),
dried (Na2SO4) and concentrated under reduced pressure. The de-
sired products were obtained by crystallization, precipitation, or
flash column chromatography of the crude product.
13C NMR (100 MHz, CDCl3): δ = 152.6, 134.1, 130.7, 130.0, 129.4,
128.3, 127.3, 126.1, 125.7, 125.5, 99.6, 57.0, 51.0.
HRMS (ESI): m/z [M + Na]+ calcd for C26H24N6O4 + Na: 507.1751;
found: 507.1749.
(S)-3-Azido-MOM-BINOL (2c)
(S)-MOM-BINOL (11.23 g, 30.0 mmol, 1.0 equiv) was dissolved
in THF (200 mL) and the solution was cooled to –78 °C. Then, t-
BuLi (20.0 mL, 1.5 M in pentane, 30.0 mmol, 1.0 equiv) was added
dropwise and the resulting mixture was stirred for 2 h at –78 °C. Af-
ter the addition of TosN3 (7.11 g, 36 mmol, 1.2 equiv), the reaction
mixture was warmed up to r.t. and stirred further for 6 h. The reac-
tion was quenched with H2O (50 mL) and extracted with EtOAc (3
× 100 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. After removal of
the excess of TosN3 by flash column chromatography (pentane–
EtOAc, 12:1), the obtained crude product (yellow oil) was crystal-
(S)-3-{[1H-(4-Phenyl)-1,2,3-triazol-1-yl]methyl}-MOM-BINOL
(3a)
Following the general CuAAC procedure, azide 2a (3.30 g,
7.70 mmol, 1.0 equiv) was reacted with phenylacetylene (1.30 mL,
11.6 mmol, 1.5 equiv) for 18 h using 4 mol% CuSO4. The desired
product (3.67 g, 6.90 mmol, 90%) was obtained as a white solid by
precipitation (Et2O–pentane) of the crude product; mp >152 °C
(dec.); [α]D20 –44 (c 0.1, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.99 (s, 1 H) 7.93–
7.79 (m, 5 H), 7.62 (d, J = 9.1 Hz, 1 H), 7.47–7.10 (m, 9 H), 6.01
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2162–2172

2168
S. Beckendorf, O. G. Mancheño
SPECIAL TOPIC
(d, J = 15.0 Hz, 1 H), 5.93 (d, J = 15.0 Hz, 1 H), 5.10 (d, J = 7.0 Hz,
1 H), 5.05 (d, J = 7.0 Hz, 1 H), 4.66 (d, J = 5.9 Hz, 1 H), 4.51 (d, J =
5.9 Hz, 1 H), 3.18 (s, 3 H), 3.13 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.9, 152.2, 134.2, 133.8, 130.9,
130.8, 130.4, 129.7, 129.5, 128.9, 128.5, 128.2, 128.2, 127.1, 127.0,
125.9, 125.8, 125.7, 125.6, 125.2, 124.4, 119.8, 116.3, 99.8, 94.9,
57.3, 56.1, 50.5.
HRMS (ESI): m/z [M + Na]+ calcd for C40H32N6O4 + Na: 683.2377;
found: 683.2367.
(S)-3,3′-Bis(5-phenyl-1H-1,2,3-triazol-1-yl)-MOM-BINOL
(3d′)9
Azide 2d (114 mg, 0.25 mmol, 1.0 equiv) and phenylacetylene
(84 μL, 0.75 mmol, 3.0 equiv) were dissolved in DMSO (1 mL).
Then, a 0.45 M solution of KOH in DMSO–H2O (3:1, 111 μL,
0.05 mmol, 20 mol%) was added and the resulting mixture was
stirred for 16 h at r.t. The desired product (135 mg, 0.20 mmol,
82%) was obtained after flash column chromatography (gradient
CH2Cl2–EtOAc, 1:0 → 3:1) as a slightly yellow solid; mp >88 °C
(dec.); [α]D20 –143.7 (c 0.19, CH2Cl2).
HRMS (ESI): m/z [M + Na]+ calcd for C33H29N3O4 + Na: 554.2050;
found: 554.2058.
(S)-3,3′-Bis[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-MOM-
BINOL (3b)
Following the general CuAAC procedure, azide 2b (3.12 g,
6.50 mmol, 1.0 equiv) was reacted with phenylacetylene (2.10 mL,
20.0 mmol, 3.0 equiv) for 48 h using 5 mol% CuSO4. The desired
product (4.01 g, 5.80 mmol, 90%) was obtained as a white solid by
precipitation (Et2O–pentane) of the crude product; mp 114–116 °C;
[α]D20 –44 (c 0.1, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 7.99 (s, 2 H), 7.89–7.85 (m, 2 H)
7.85–7.82 (m, 4 H), 7.45–7.37 (m, 7 H), 7.36–7.27 (m, 5 H), 7.18
(d, J = 8.5 Hz, 2 H), 6.02 (d, J = 15.1 Hz, 2 H), 5.90 (d, J = 15.1 Hz,
2 H), 4.45 (d, J = 6.0 Hz, 2 H), 4.40 (d, J = 6.0 Hz, 2 H), 3.07 (s,
6 H).
13C NMR (100 MHz, CDCl3): δ = 152.4, 148.3, 134.1, 132.2, 130.8,
130.7, 130.2, 129.0, 129.0, 128.9, 128.5 128.4, 128.3, 127.7, 126.0,
125.7 125.3, 120.1, 99.9, 57.3, 50.3.
HRMS (ESI): m/z [M + Na]+ calcd for C42H36N6O4 + Na: 711.2690;
found: 711.2688.
1H NMR (400 MHz, CDCl3): δ = 8.18 (s, 2 H), 7.92 (s, 2 H), 7.91
(d, J = 8.9 Hz, 2 H), 7.49 (ddd, J = 8.1, 6.8, 1.2 Hz, 2 H), 7.37–7.26
(m, 12 H), 7.03 (br s, 2 H), 4.19 (d, J = 5.7 Hz, 2 H), 4.11 (br d,
J = 5.7 Hz, 2 H), 2.35 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 148.2, 140.4, 134.1, 132.7, 130.2,
130.1, 129.4, 129.3, 129.0, 128.5, 128.2, 128.2, 127.1, 126.7, 126.5,
126.3, 99.0, 56.2.
HRMS (ESI): m/z [M + Na]+ calcd for C40H32N6O4 + Na: 683.2377;
found: 683.2371.
MOM-Deprotection (MOM-D) of BINOL Derivatives 3; Gener-
al Procedure
MOM-protected BINOL derivative 3 (1.00 mmol, 1 equiv) was dis-
solved in CH2Cl2–MeOH (1:2, 33.0 mL) in a pressure tube. Then,
12 M aq HCl (38 equiv) was added and the reaction mixture was
stirred for 12 h at 50 °C. The mixture was neutralized with sat. aq
NaHCO3 and extracted with CH2Cl2 (3 × 30 mL). The combined or-
ganic layers were concentrated under reduced pressure followed by
precipitation (CH2Cl2–pentane) and filtration to obtain the desired
product 1.
(S)-3-(4-Phenyl-1H-1,2,3-triazol-1-yl)-MOM-BINOL (3c)
Following the general CuAAC procedure, azide 2c (11.31 g,
27.0 mmol, 1.0 equiv) was reacted with phenylacetylene (4.50 mL,
41.0 mmol, 1.5 equiv) for 18 h using 4 mol% CuSO4. The desired
product (10.7 g, 22.7 mmol, 84%) was obtained as a white solid by
precipitation (Et2O–pentane) of the crude product; mp 82–86 °C;
[α]D20 –103 (c 0.1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 8.53 (s, 1 H), 8.41 (s, 1 H), 8.04–
7.93 (m, 4 H), 7.90 (d, J = 8.1 Hz, 1 H), 7.63 (d, J = 9.1 Hz, 1 H),
7.54–7.22 (m, 9 H), 5.19 (d, J = 7.0 Hz, 1 H), 5.08 (d, J = 7.0 Hz,
1 H), 4.47 (d, J = 5.5 Hz, 1 H), 4.40 (d, J = 5.6 Hz, 1 H), 3.20 (s,
3 H), 2.58 (s, 3 H).
(S)-3-[(4-Phenyl-1H-1,2,3-triazol-1-yl)methyl]-BINOL (1a)
Following the MOM-D procedure, the deprotection of 3a (1.45 g,
2.72 mmol) gave compound 1a (992 mg, 2.23 mmol, 82%) as a
white solid; mp 269–273 °C; [α]D20 –79 (c 0.5, DMSO).
1H NMR (300 MHz, DMSO-d6): δ = 9.41 (s, 1 H), 8.64 (s, 1 H),
8.59 (s, 1 H), 7.94–7.82 (m, 5 H), 7.73 (s, 1 H), 7.48–7.40 (m, 2 H),
7.37–7.14 (m, 6 H), 6.91 (d, J = 13.7 Hz, 1 H), 6.89 (d, J = 13.8 Hz,
1 H), 5.84 (s, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 154.0, 150.8, 146.3, 134.3,
133.9, 130.9, 129.6, 128.9, 128.5, 128.4, 128.1, 128.0, 128.0, 127.8,
126.3, 126.1, 125.2, 125.2, 124.4, 124.0, 123.1, 122.4, 121.8, 118.8,
116.3, 113.1, 49.9.
HRMS (ESI): m/z [M + Na]+ calcd for C29H21N3O2 + Na: 466.1526;
found: 466.1530.
13C NMR (100 MHz, CDCl3): δ = 153.0, 147.9, 145.9, 133.8, 133.8,
130.6, 130.6, 130.5, 130.5, 129.7, 129.0, 128.6, 128.3, 128.2, 127.9,
127.7, 127.2, 126.4, 126.0, 125.9, 125.4, 125.2, 124.5, 122.4, 119.4,
116.4, 99.6, 94.9, 56.7, 56.1.
HRMS (ESI): m/z [M + Na]+ calcd for C32H27N3O4 + Na: 540.1899;
found: 540.1886.
(S)-3,3′-Bis[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-BINOL
(1b)
Following the MOM-D procedure, the deprotection of 3b (1.42 g,
2.06 mmol) gave compound 1b (1.05 g, 1.74 mmol, 93%) as a
white solid; mp 253–256 °C; [α]D20 –96 (c 0.2, DMSO).
1H NMR (300 MHz, DMSO-d6): δ = 8.88 (s, 2 H), 8.53 (s, 2 H),
7.94–7.80 (m, 8 H), 7.46–7.39 (m, 4 H), 7.36–7.26 (m, 4 H), 7.26–
7.18 (m, 2 H), 6.90 (d, J = 8.3 Hz, 2 H), 5.86 (d, J = 17.4 Hz, 2 H),
5.81 (d, J = 17.4 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 152.1, 146.1, 134.2, 130.9,
130.2, 128.9, 128.3, 128.2, 127.8, 126.7, 125.1, 124.9, 124.0, 123.3,
121.7, 114.2, 49.9.
3,3′-Bis(4-phenyl-1H-1,2,3-triazol-1-yl)-MOM-BINOL (3d)
Following the general CuAAC procedure, azide 2d (0.50 g,
1.10 mmol, 1.0 equiv) was reacted with phenylacetylene (370 μL,
3.30 mmol, 3.0 equiv) for 60 h using 8 mol% CuSO4. The desired
product (636 mg, 0.96 mmol, 87%) was obtained as a white solid by
flash column chromatography (CH2Cl2–EtOAc, 20:1) followed by
precipitation (CH2Cl2–pentane); mp >153 °C (dec.).
20
20
(S)-3d: [α]D –53 (c 0.1, CH2Cl2); (R)-3d: [α]D –159.6 (c 0.8,
CH2Cl2).
H NMR (300 MHz, CDCl3): δ = 8.54 (s, 2 H), 8.45 (s, 2 H), 8.03 (d,
J = 8.1 Hz, 2 H), 7.99– 7.93 (m, 4 H), 7.61–7.51 (m, 2 H), 7.52–
7.29 (m, 10 H), 4.51 (d, J = 5.8 Hz, 2 H), 4.41 (d, J = 5.8 Hz, 2 H),
2.57 (s, 6 H).
HRMS (ESI): m/z [M + Na]+ calcd for C38H28N6O2 + Na: 623.2166;
13C NMR (100 MHz, CDCl3): δ = 148.2, 146.5, 133.7, 130.5, 130.4,
130.3, 129.1, 128.8, 128.5, 128.4, 126.9, 126.8, 126.4, 126.2, 125.9,
122.1, 99.7, 56.7.
found: 623.2157.
Synthesis 2012, 44, 2162–2172
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
‘Click’-BINOLs: Tuneable Ligands for Asymmetric Catalysis
2169
(S)-3-(4-Phenyl-1H-1,2,3-triazol-1-yl)-BINOL (1c)
HRMS (ESI): m/z [M + Na]+ calcd for C52H32N6O2 + Na: 795.2479;
found: 795.2476.
Following the MOM-D procedure, the deprotection of 3c
(4.44 mmol, 2.30 g) gave compound 1c (1.64 g, 3.82 mmol, 86%)
as a white solid; mp 254–256 °C; [α]D20 –147 (c 0.2, DMSO).
(S)-3-(4-Mesityl-1H-1,2,3-triazol-1-yl)-BINOL (1f)
Following the general CuAAC procedure, azide 2d (201 mg,
0.44 mmol, 1.0 equiv) was reacted with 2-ethynyl-1,3,5-trimethyl-
benzene (190 mg, 1.32 mmol, 3.0 equiv) for 4 days using 8 mol%
CuSO4. Due to the low reactivity, additional CuSO4 (8 mol%) and
sodium ascorbate (24 mol%) were added and the reaction mixture
was stirred for further 6 days at 70 °C. The MOM-‘click’ product
was obtained by flash column chromatography (CH2Cl2–EtOAc
20:1). Subsequent deprotection by using the MOM-D procedure
(16 h) afforded the desired product 1f (118 mg, 0.18 mmol, 41%
1H NMR (300 MHz, DMSO-d6): δ = 9.60 (br s, 1 H), 9.18 (br s,
1 H), 9.08 (s, 1 H), 8.38 (s, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 8.04–
7.99 (m, 2 H), 7.96 (d, J = 8.9 Hz, 1 H), 7.94–7.89 (m, 1 H), 7.54–
7.46 (m, 2 H), 7.44–7.22 (m, 6 H), 7.07–6.94 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 154.0, 146.3, 146.2, 134.2,
133.8, 130.6, 129.9, 129.0, 128.5, 128.3, 128.2, 128.1, 127.5, 127.3,
127.0, 126.4, 125.4, 124.7, 124.6, 124.1, 124.0, 123.6, 122.6, 118.9,
118.8, 113.0.
20
over two steps) as a white solid; mp >268 °C (dec.); [α]D +16
(c 0.3, DMSO).
HRMS (ESI): m/z [M + Na]+ calcd for C28H19N3O2 + Na: 452.1369;
found: 452.1362.
1H NMR (300 MHz, CDCl3): δ = 9.59 (br s, 2 H), 8.25 (br s, 4 H),
7.95 (d, J = 7.7 Hz, 2 H), 7.48–7.33 (m, 4 H), 7.28 (d, J = 8.7 Hz,
2 H), 6.99 (s, 4 H), 2.35 (s, 6 H), 2.19 (s, 12 H).
13C NMR (75 MHz, CDCl3): δ = 145.3, 138.8, 137.9, 137.9, 133.3,
128.7, 128.7, 128.6, 128.1, 128.0, 126.1, 125.2, 124.9, 122.1, 120.1,
118.6, 21.3, 20.9.
3,3′-Bis(4-phenyl-1H-1,2,3-triazol-1-yl)-BINOL (1d)
Following the MOM-D procedure, the deprotection of 3d (315 mg,
0.48 mmol) gave compound 1d (275 g, 0.48 mmol, quant) as a
white solid; mp 174–177 °C.
20
20
(S)-1d: [α]D +18 (c 0.6, DMSO); (R)-1d: [α]D –16 (c 0.25,
DMSO).
HRMS (ESI): m/z [M + Na]+ calcd for C42H36N6O2 + Na: 679.2792;
found: 679.2799.
1H NMR (300 MHz, DMSO-d6): δ = 9.57 (s, 2 H), 9.04 (s, 2 H),
8.46 (s, 2 H), 8.11 (br d, J = 8.5 Hz, 2H), 8.03–7.97 (m, 4 H), 7.54–
7.43 (m, 5 H), 7.43–7.34 (m, 5 H), 7.09–7.03 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 147.2, 146.3, 133.8, 130.5,
129.1, 128.7, 128.1, 127.8, 127.7, 127.3, 125.5, 125.4, 124.2, 124.2,
123.4, 116.5.
(S)-3,3′-Bis[4-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-1H-1,2,3-
triazol-1-yl]-BINOL (1g)
Following the general CuAAC procedure, azide 2d (201 mg,
0.44 mmol, 1.0 equiv) was reacted with 1-ethynyl-2,3,5,6-tetrafluo-
ro-4-methoxybenzene (269 mg, 1.32 mmol, 3.0 equiv) for 4 days
using 8 mol% CuSO4. Due to the low reactivity, additional CuSO4
(8 mol%) and sodium ascorbate (24 mol%) were added and the re-
action mixture was stirred for further 4 days at 60 °C. The MOM-
‘click’ product was obtained by flash column chromatography
(CH2Cl2–EtOAc, 30:1). Subsequent deprotection by using the
MOM-D protocol afforded the desired product 1g (130 mg,
0.17 mmol, 39% (over two steps)) as a white solid; mp >90 °C
(dec.); [α]D20 +56 (c 0.2, DMSO).
HRMS (ESI): m/z [M + Na]+ calcd for C36H24N6O2 + Na: 595.1853;
found: 595.1852.
(S)-3,3′-Bis(5-phenyl-1H-1,2,3-triazol-1-yl)-BINOL (1d′)
Following the MOM-D procedure, the reaction of 3d′ (86 mg,
0.13 mmol) gave compound 1d′ (70 mg, 0.12 mmol, 92%) as a pur-
ple solid; mp 175 °C; [α]D20 –213 (c 0.19, DMSO).
1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 2 H), 7.73 (d, J = 8.1 Hz,
2 H), 7.64 (s, 2 H), 7.39–7.23 (m, 16 H), 6.99 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 147.5, 139.6, 133.9, 132.5, 129.5,
129.0, 128.8, 128.6, 128.3, 128.2, 128.2, 127.0, 125.8, 125.1, 124.5,
115.8.
1H NMR (300 MHz, DMSO-d6): δ = 9.66 (s, 2 H), 8.92 (s, 2 H),
8.53 (s, 2 H), 8.12 (d, J = 8.0 Hz, 2 H), 7.49–7.34 (m, 4 H), 7.06 (d,
J = 8.0 Hz, 2 H), 4.12 (t, J = 1.4 Hz, 6 H).
13C NMR (75 MHz, DMSO-d6): δ = 147.1, 145.8–145.3 (m), 142.6–
142.1 (m), 139.4–139.0 (m), 137.8–137.3 (m), 133.9, 133.8–133.5
(m), 128.8, 127.9, 127.7, 127.3 (t, J = 3.9 Hz), 126.9, 125.7, 124.3
(d, J = 8.2 Hz), 116.1, 104.1 (t, J = 16.0 Hz), 62.4 (t, J = 3.6 Hz).
19F NMR (282 MHz, DMSO-d6): δ = –142.16 to –142.31 (m),
–157.79 to –158.09 (m).
HRMS (ESI): m/z [M + Na]+ calcd for C38H20F8N6O4 + Na:
799.1310; found: 799.1307.
HRMS (ESI): m/z [M + Na]+ calcd for C36H24N6O2 + Na: 595.1853;
found: 595.1847.
(S)-3,3′-Bis[4-(anthracen-9-yl)-1H-1,2,3-triazol-1-yl]-BINOL
(1e)
Following the general CuAAC procedure, azide 2d (150 mg,
0.33 mmol, 1.0 equiv) was reacted with 9-ethynylanthracene
(169 mg, 0.83 mmol, 2.5 equiv) for 72 h using 8 mol% CuSO4. Due
to the low reactivity, additional CuSO4 (8 mol%) and sodium ascor-
bate (24 mol%) were added and the reaction mixture was stirred for
further 48 h at 55 °C. The MOM-‘click’ product was obtained by
flash column chromatography (gradient CH2Cl2–EtOAc, 30:1 →
5:1). Subsequent deprotection by using the MOM-D procedure (48
h) afforded the desired product 1e (93 mg, 0.12 mmol, 37% over
two steps) as a slightly brown solid; mp >106 °C (dec.); [α]D20 –458
(c 0.1, DMSO).
1H NMR (600 MHz, CDCl3): δ = 8.53 (s, 2 H), 8.05–8.02 (m, 4 H),
8.00 (s, 2 H), 7.96 (d, J = 8.5 Hz, 2 H), 7.72–7.68 (m, 2 H), 7.56 (d,
J = 8.6 Hz, 2 H), 7.52–7.48 (m, 4 H), 7.40 (ddd, J = 8.2, 6.6, 1.1 Hz,
2 H), 7.34–7.29 (m, 4 H), 7.15 (d, J = 7.4 Hz, 2 H), 7.11–7.05 (m,
2 H), 7.00–6.97 (m, 2 H), 6.40 (d, J = 8.4 Hz, 2 H).
(S)-3,3′-Bis(1H-1,2,3-triazol-1-yl)-BINOL (1h)
Following the general CuAAC procedure, azide 2d (201 mg,
0.44 mmol, 1.0 equiv) was reacted with ethynyltrimethylsilane
(0.5 mL, 3.5 mmol, 8.0 equiv) for 6 days using 8 mol% CuSO4. The
corresponding MOM-‘click’ product was obtained by flash column
chromatography (gradient pentane–EtOAc, 6:1 → 3:1). Subsequent
deprotection by using the MOM-D protocol gave a complex mix-
ture due to the partial cleavage of the trimethylsilyl group. Finally,
the crude reaction mixture was treated with 1 M aq KOH (2 mL) for
12 h at r.t. to afford 1j (56 mg, 0.11 mmol, 25% over two steps) as
a white solid; mp >144 °C (dec.); [α]D20 –56 (c 0.3, DMSO).
1H NMR (300 MHz, DMSO-d6): δ = 9.50 (s, 2 H), 8.57 (d, J = 1.1
Hz, 2 H), 8.42 (s, 2 H), 8.09 (d, J = 7.6 Hz, 2 H), 7.99 (d, J = 1.1 Hz,
2 H), 7.47–7.31 (m, 4 H), 7.01 (d, J = 8.3 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 147.0, 133.6, 133.4, 128.7,
127.7, 127.6, 127.3, 126.9, 125.2, 124.2, 124.1, 116.2.
13C NMR (150 MHz, CDCl3): δ = 145.7, 135.3, 134.9, 132.3, 130.5,
130.3, 130.1, 130.1, 129.0, 128.0, 127.9, 127.4, 127.1, 126.5, 126.4,
126.2, 124.8, 124.6, 124.3, 124.1, 124.0, 124.0, 123.5, 123.2, 118.8,
115.4.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2162–2172

2170
S. Beckendorf, O. G. Mancheño
SPECIAL TOPIC
HRMS (ESI): m/z [M + Na]+ calcd for C24H16N6O2 + Na: 443.1227;
found: 443.1232.
over two steps) as a slightly olive colored solid; mp >113 °C (dec.);
[α]D20 +39 (c 0.2, DMSO).
1H NMR (300 MHz, DMSO-d6): δ = 9.61 (s, 2 H), 8.99 (s, 2 H),
8.64 (s, 2 H), 8.52 (s, 2 H), 8.17 (d, J = 8.1 Hz, 2 H), 8.12 (d, J = 7.7
Hz, 2 H), 7.96 (t, J = 7.5 Hz, 2 H), 7.51–7.32 (m, 6 H), 7.09 (d,
J = 8.3 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 149.8, 149.7, 147.2, 147.0,
137.4, 133.7, 128.8, 127.8, 127.7, 127.2, 125.4, 125.0, 124.3, 124.2,
123.3, 119.7, 116.3.
(S)-3,3′-Bis[4-(tert-butyl)-1H-1,2,3-triazol-1-yl]-BINOL (1i)
Following the general CuAAC procedure, azide 2d (201 mg,
0.44 mmol, 1.0 equiv) was reacted with 3,3-dimethylbut-1-yne
(324 μL, 2.64 mmol, 6.0 equiv) for 2.5 days using 8 mol% CuSO4.
The MOM-‘click’ product was obtained by flash column chroma-
tography (CH2Cl2–EtOAc, 20:1). Subsequent deprotection by using
the MOM-D procedure afforded the desired product 1i (223 mg,
0.42 mmol, 95% over two steps) as a white solid; mp >163 °C
(dec.); [α]D20 –29 (c 0.6, DMSO).
1H NMR (300 MHz, DMSO-d6): δ = 9.49 (s, 2 H), 8.41 (s, 2 H),
8.35 (s, 2 H), 8.06 (d, J = 8.1 Hz, 2 H), 7.45–7.30 (m, 4 H), 7.00 (d,
J = 8.4 Hz, 2 H), 1.37 (s, 18 H).
13C NMR (75 MHz, DMSO-d6): δ = 156.2, 146.8, 133.4, 128.6,
127.8, 127.5, 127.3, 124.5, 124.1, 121.6, 121.6, 116.4, 30.6, 30.3.
HRMS (ESI): m/z [M + Na]+ calcd for C34H22N8O2 + Na: 597.1758;
found: 597.1745.
Addition of Et2Zn to Aldehydes 4: General Procedure
3,3′-Bis(4-phenyl-1H-1,2,3-triazol-1-yl)-BINOL (1d; 14.3 mg,
0.025 mmol, 10 mol%) and a 0.05 M Ti(Oi-Pr)4 solution in toluene
(0.5 mL, 0.025 mmol, 10 mol%) were combined in a heat-gun-
dried Schlenk tube (5 mL) under argon atmosphere and stirred for
30 min at r.t. (20–25 °C). The corresponding aldehyde 4 (0.25
mmol, 1.0 equiv) was added and the resulting mixture was stirred
for further 30 min. Then, Et2Zn (0.46 mL, 1.1 M in toluene,
0.5 mmol, 2.0 equiv) was added. The reaction was monitored by
GC-MS and quenched with H2O (1 mL) after consumption of the
corresponding aldehyde 4 (15–48 h). The mixture was extracted
with EtOAc (3 × 3 mL) and the combined organic layers were dried
(MgSO4) and filtered. The crude product was adsorbed on silica gel
and alcohols 5 were obtained after purification by flash column
chromatography.
HRMS (ESI): m/z [M + Na]+ calcd for C32H32N6O2 + Na: 555.2488;
found: 555.2488.
(S)-3,3′-Bis[4-(adamantan-1-yl)-1H-1,2,3-triazol-1-yl]-BINOL
(1j)
Following the general CuAAC procedure, azide 2d (60 mg,
0.13 mmol, 1.0 equiv) was reacted with 1-ethynyladamantane
(45 mg, 0.28 mmol, 2.1 equiv) for 2.5 days using 8 mol% CuSO4.
The MOM-‘click’ product was obtained by flash column chroma-
tography (CH2Cl2–EtOAc, 15:1). Subsequent deprotection by using
the MOM-D protocol afforded the desired product 1j (35 mg,
0.05 mmol, 38% over two steps) as a white solid; mp >273 °C
(dec.); [α]D20 –9 (c 0.2, DMSO).
1-Phenylpropan-1-ol (5a)
Following the general procedure (15 h), after flash column chroma-
tography (pentane–EtOAc, 3:1), 5a was obtained as an oil (28 mg,
0.206 mmol, 82%).
1H NMR (300 MHz, CDCl3): δ = 9.92 (s, 2 H), 8.08 (s, 2 H), 8.03
(s, 2 H), 7.86 (d, J = 8.1 Hz, 2 H), 7.41–7.27 (m, 4 H), 7.21 (dd,
J = 8.4, 1.3 Hz, 2 H), 2.09 (s, 6 H), 2.03 (s, 12 H), 1.80 (s, 12 H).
13C NMR (75 MHz, CDCl3): δ = 158.1, 145.5, 133.2, 128.4, 127.9,
127.8, 124.9, 124.9, 124.8, 119.3, 118.8, 118.1, 42.5, 36.7, 32.9,
28.5.
HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (97.5:2.5), flow
rate 1.0 mL/min, 210 nm; tR = 13.8 min (R-isomer) and 15.2 min (S-
isomer).
1H NMR (300 MHz, CDCl3): δ = 7.31–7.16 (m, 5 H), 4.51 (dd,
J = 7.2, 6.0 Hz, 1 H), 1.88 (s, 1 H), 1.85–1.57 (m, 2 H), 0.84 (t,
J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 144.7, 128.5, 127.6, 126.1, 76.1,
32.0, 10.3.
HRMS (ESI): m/z [M + Na]+ calcd for C9H12O + Na: 159.0780;
found: 159.0780.
HRMS (ESI): m/z [M + Na]+ calcd for C44H44N6O2 + Na: 711.3418;
found: 711.3409.
(S)-3,3′-Bis{4-[(dimethylamino)methyl]-1H-1,2,3-triazol-1-yl}-
BINOL (1k)
Following the general CuAAC procedure, azide 2d (201 mg,
0.44 mmol, 1.0 equiv) was reacted with N,N-dimethylprop-2-yn-1-
amine (142 μL, 1.32 mmol, 3.0 equiv) for 12 h using 8 mol%
CuSO4. The MOM-‘click’ product was obtained by flash column
chromatography (CH2Cl2–MeOH, 2:1). Subsequent deprotection by
using the MOM-D procedure afforded the desired product 1k
(111 mg, 0.21 mmol, 47% over two steps) as an olive colored solid;
mp >223 °C (dec.); [α]D20 +942 (c 0.1, DMSO).
1-(Naphthalen-2-yl)propan-1-ol (5b)
Following the general procedure (19 h), after flash column chroma-
tography (pentane–EtOAc, 10:1), 5b was obtained as a white solid
(46 mg, 0.247 mmol, 99%); mp 37–38 °C.
HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (90:10), flow rate
0.8 mL/min, 210 nm; tR = 12.1 min (S-isomer) and 13.1 min (R-iso-
mer).
1H NMR (300 MHz, CDCl3): δ = 7.89–7.80 (m, 3 H), 7.79–7.77 (m,
1 H), 7.54–7.43 (m, 3 H), 4.77 (t, J = 6.6 Hz, 1 H), 2.01–1.77 (m,
2 H), 1.98 (br s, 1 H) 0.95 (t, J = 7.4 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6): δ = 8.75 (s, 2 H), 8.36 (s, 2 H),
7.96 (d, J = 7.8 Hz, 2 H), 7.23 (ddd, J = 8.0, 6.7, 1.3 Hz, 2 H), 7.16
(ddd, J = 8.3, 6.7, 1.5 Hz, 2 H), 7.01 (d, J = 1.2 Hz, 2 H), 3.82 (s,
4 H), 2.34 (s, 12 H).
13C NMR (100 MHz, DMSO-d6): δ = 151.9, 141.7, 133.6, 129.0,
128.6, 126.1, 126.0, 126.0, 125.16, 122.3, 122.2, 119.2, 53.0, 44.0.
13C NMR (75 MHz, CDCl3): δ = 142.0, 133.4, 133.1, 128.4, 128.1,
127.8, 126.2, 125.9, 124.9, 124.3, 76.3, 31.9, 10.3.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14O + Na: 209.0937;
HRMS (ESI): m/z [M + H]+ calcd for C30H30N8O2: 535.2564; found:
535.2555.
found: 209.0942.
(S)-3,3′-Bis[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]-BINOL (1l)
Following the general CuAAC procedure, azide 2d (730 mg,
1.60 mmol, 1.0 equiv) was reacted with 2-ethynylpyridine (363 mg,
3.52 mmol, 2.2 equiv) for 16 h using 4 mol% CuSO4. The MOM-
‘click’ product was obtained by flash column chromatography
(CH2Cl2–MeOH, 40:1). Subsequent deprotection, by using the
MOM-D procedure and direct filtration of the neutralized reaction
mixture, afforded the desired product 1l (829 mg, 1.44 mmol, 90%
1-(Naphthalen-1-yl)propan-1-ol (5c)
Following the general procedure (18 h), after flash column chroma-
tography (pentane–EtOAc, 11:1), 5c was obtained as an oil (40 mg,
0.215 mmol, 86%).
HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (90:10), flow rate
0.8 mL/min, 210 nm; tR = 10.4 min (S-isomer) and 17.7 min (R-iso-
mer).
Synthesis 2012, 44, 2162–2172
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
‘Click’-BINOLs: Tuneable Ligands for Asymmetric Catalysis
2171
1H NMR (300 MHz, CDCl3): δ = 8.16–8.07 (m, 1 H), 7.94–7.85 (m,
1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.63 (d, J = 7.2 Hz, 1 H), 7.57–7.44
(m, 3 H), 5.38 (dd, J = 7.4, 5.0 Hz, 1 H), 2.11 (s, 1 H), 2.08–1.84
(m, 2 H), 1.04 (t, J = 7.4 Hz, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.29–7.25 (m, 1 H), 7.23–7.16 (m,
2 H), 7.16–7.11 (m, 1 H), 4.50 (t, J = 6.5 Hz, 1 H), 1.87 (br s, 1 H),
1.80–1.58 (m, 2 H), 0.84 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 146.8, 134.4, 129.8, 127.7, 126.3,
124.3, 75.5, 32.1, 10.1.
13C NMR (75 MHz, CDCl3): δ = 140.3, 133.9, 130.6, 129.0, 128.0,
126.0, 125.6, 125.5, 123.4, 123.02, 72.7, 31.2, 10.7.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14O + Na: 209.0937;
HRMS (ESI): m/z [M + Na]+ calcd for C9H11ClO + Na: 193.0391;
found: 193.8396.
found: 209.0942.
1-(2-Chlorophenyl)propan-1-ol (5h)
Following the general procedure (20 h), after flash column chroma-
tography (pentane–EtOAc, 20:1), 5h was obtained as an oil (37 mg,
0.217 mmol, 87%).
1-(4-Methoxyphenyl)propan-1-ol (5d)
Following the general procedure (15 h), after flash column chroma-
tography (pentane–EtOAc, 8:1), 5d was obtained as an oil (40 mg,
0.241 mmol, 96%).
HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (99:1), flow rate
0.5 mL/min, 210 nm; tR = 35.2 min (S-isomer) and 36.8 min (R-iso-
mer).
1H NMR (300 MHz, CDCl3): δ = 7.47 (dd, J = 7.7, 1.8 Hz, 1 H),
7.25 (dd, J = 7.7, 1.4 Hz, 1 H), 7.22–7.18 (m, 1 H), 7.12 (td, J = 7.6,
1.8 Hz, 1 H), 4.99 (dd, J = 7.6, 4.9 Hz, 1 H), 1.94 (s, 1 H), 1.85–
1.57 (m, 2 H), 0.91 (t, J = 7.4 Hz, 3 H).
HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (97.5:2.5), flow
rate 1.0 mL/min, 210 nm; tR = 20.0 min (R-isomer) and 23.6 min (S-
isomer).
1H NMR (300 MHz, CDCl3): δ = 7.30–7.23 (m, 2 H), 6.92–6.84 (m,
2 H), 4.53 (t, J = 6.7 Hz, 1 H), 3.80 (s, 3 H), 1.88 (br s, 1 H), 1.87–
1.64 (m, 2 H), 0.89 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.1, 136.9, 127.3, 113.9, 75.8,
55.4, 31.9, 10.4.
13C NMR (75 MHz, CDCl3): δ = 142.1, 132.1, 129.5, 128.5, 127.3,
127.1, 72.1, 30.6, 10.2.
HRMS (ESI): m/z [M + Na]+ calcd for C10H14O2 + Na: 189.0881;
found: 189.0886.
HR-MS (ESI): m/z [M + Na]+ calcd for C99H11ClO + Na: 193.0391;
found: 193.0391.
1-(4-Fluorophenyl)propan-1-ol (5e)
1-Cyclohexylpropan-1-ol (5i)
Following the general procedure (15 h), after flash column chroma-
tography (pentane–EtOAc, 9:1), 5e was obtained as an oil (29 mg,
0.188 mmol, 75%).
Following the general procedure (48 h), after flash column chroma-
tography (pentane–EtOAc, 20:1), 5i was obtained as an oil (14 mg,
0.098 mmol, 39%).
HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (99.5:0.5), flow
rate 0.4 mL/min, 210 nm; tR = 84.1 min (S-isomer) and 89.5 min (R-
isomer).
1H NMR (300 MHz, CDCl3): δ = 7.27–7.18 (m, 2 H), 7.00–6.90 (m,
2 H), 4.50 (t, J = 6.6 Hz, 1 H), 1.88 (br s, 1 H), 1.82–1.54 (m, 2 H),
0.82 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.3 (d, J = 245.0 Hz), 140.4 (d,
J = 3.1 Hz), 127.7 (d, J = 8.0 Hz), 115.3 (d, J = 21.3 Hz), 75.5, 32.1,
10.2.
Chiral GC: β-dex 225, (30 m × 0.25 mm × 0.25 μm), isotherm
90 °C; tR = 28.9 min (R-isomer) and 30.6 min (S-isomer).
1H NMR (400 MHz, CDCl3): δ = 3.27 (ddd, J = 8.5, 5.4, 3.8 Hz,
1 H), 1.86–1.70 (m, 3 H), 1.70–1.60 (m, 2 H), 1.60–1.49 (m, 1 H),
1.46–0.97 (m, 8 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 77.8, 43.3, 29.5, 27.9, 27.0, 26.7,
26.5, 26.4, 10.4.
HR-MS (ESI): m/z [M + Na]+ calcd for C9H18O + Na: 165.1250;
found: 165.1252.
19F NMR (282 MHz, CDCl3): δ = –115.32.
HRMS (ESI): m/z [M + Na]+ calcd for C9H11FO + Na: 177.0686;
1-(Pyridin-2-yl)propan-1-ol (5j)
Following the general procedure (19 h), after flash column chroma-
tography (pentane–EtOAc, 2:1) 5j was obtained as an oil (10 mg,
0.073 mmol, 29%).
found: 177.0687.
1-(4-Chlorophenyl)propan-1-ol (5f)
Following the general procedure (15 h), after flash column chroma-
tography (pentane–EtOAc, 10:1), 5f was obtained as an oil (40 mg,
0.234 mmol, 94%).
HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH, 95:5, flow rate
1.0 mL/min, 210 nm; tR = 8.5 min (R-isomer) and 9.1 min (S-iso-
mer).
HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH, 97.5/2.5, flow
rate 1.0 mL/min, 210 nm; tR = 12.8 min (S-isomer) and 13.9 min (R-
isomer).
1H NMR (300 MHz, CDCl3): δ = 7.27–7.17 (m, 4 H), 4.51 (t, J = 6.5
Hz, 1 H), 1.82 (br s, 1 H), 1.80–1.56 (m, 2 H), 0.83 (t, J = 7.4 Hz,
3 H).
1H NMR (300 MHz, CDCl3): δ = 8.55 (d, J = 4.7 Hz, 1 H), 7.70 (td,
J = 7.8, 1.7 Hz, 1 H), 7.27 (d, J = 7.8 Hz, 1 H), 7.22 (ddd, J = 7.3,
4.7, 0.9 Hz, 1 H), 4.71 (dd, J = 7.2, 4.6 Hz, 1 H), 1.98–1.82 (m,
1 H), 1.81–1.64 (m, 1 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.0, 148.0, 137.0, 122.4, 120.6,
73.8, 31.5, 9.5.
13C NMR (75 MHz, CDCl3): δ = 143.1, 133.2, 128.6, 127.5, 75.4,
HR-MS (ESI): m/z [M + H]+ calcd for C8H11NO: 138.0913; found:
32.1, 10.1.
138.0910.
HRMS (ESI): m/z [M + Na]+ calcd for C9H11ClO + Na: 193.0391;
found: 193.0392.
Acknowledgment
1-(3-Chlorophenyl)propan-1-ol (5g)
The Deutsche Forschungsgemeinschaft and the Fonds der Chemi-
schen Industrie are gratefully acknowledged for financial support.
S. B. thanks the Deutsche Forschungsgemeinschaft within the SFB
858 for a predoctoral contract.
Following the general procedure (18 h), after flash column chroma-
tography (pentane–EtOAc, 10:1), 5g was obtained as an oil (28 mg,
0.164 mmol, 66%).
HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (96:4), flow rate
0.5 mL/min, 210 nm; tR = 17.0 min (S-isomer) and 18.7 min (R-iso-
mer).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2162–2172

2172
S. Beckendorf, O. G. Mancheño
SPECIAL TOPIC
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Synthesis 2012, 44, 2162–2172
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