Synthesis and evaluation of new chiral nonracemic C2-symmetric and unsymmetric 2,2′-bipyridyl ligands

Article abstract of DOI:10.1039/b513286j

The synthesis of a series of chiral nonracemic and C₂-symmetric 2,2′-bipyridyl ligands (R = Me, i-Pr and Ph) as well as the syntheses of the corresponding unsymmetric 2,2′-bipyridyl ligands (R = Me and Ph) is described. These bipyridyl ligands

Full text of DOI:10.1039/b513286j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and evaluation of new chiral nonracemic C2-symmetric and
unsymmetric 2,2ꢀ-bipyridyl ligands†
Michael P. A. Lyle,‡ Neil D. Draper‡ and Peter D. Wilson*
Received 21st September 2005, Accepted 9th December 2005
First published as an Advance Article on the web 20th January 2006
DOI: 10.1039/b513286j
The synthesis of a series of chiral nonracemic and C2-symmetric 2,2ꢀ-bipyridyl ligands (R = Me, i-Pr
and Ph) as well as the syntheses of the corresponding unsymmetric 2,2ꢀ-bipyridyl ligands (R = Me and
Ph) is described. These bipyridyl ligands were prepared, in a notably direct and modular fashion, from
the readily available and corresponding 2-chloropyridine acetals (R = Me, i-Pr and Ph). The bipyridyl
ligands were evaluated in copper(I)-catalyzed cyclopropanation reactions of styrene with the ethyl and
t-butyl esters of diazoacetic acid. The stereoselectivities, as well as the yields of the cyclopropanation
reactions, were dependant on the ratio of the bipyridyl ligands and copper triflate that was employed.
The best result was obtained in the asymmetric cyclopropanation reaction of styrene and tert-butyl
diazoacetate with the C2-symmetric bipyridyl ligand (R = i-Pr). This afforded the corresponding
trans-cyclopropane in good diastereoselectivity (4 : 1) and in moderate enantioselectivity (44% ee). The
X-ray structure determination of a complex formed between the C2-symmetric 2,2ꢀ-bipyridyl ligand (R
= Ph) and copper(I) chloride showed that two bipyridyl ligands had coordinated to the copper(I) ion.
This information, along with the results of a series of cyclopropanation reactions and NMR data, led to
the conclusion that the 2,2ꢀ-bipyridyl ligands had the propensity to form catalytically inactive
bis-ligated copper(I) species in solution that were in equilibrium with catalytically active copper(I)
triflate and the desired mono-ligated copper(I) species. Moreover, it was observed that the complex of
the bipyridyl ligand (R = Ph) and copper(I) chloride had a particularly large optical rotation (sodium
D-line). The maximum positive optical rotation was subsequently found to be +1.1 × 104 at 304 nm and
the maximum negative optical rotation was −1.3 × 104 at 329 nm.
Introduction
We have recently established a new design concept for the efficient
and modular construction of chiral nonracemic auxiliaries, ligands
and catalysts for use in asymmetric synthesis.1 These novel chiral
directors can be prepared from functionalized indan-1-one deriva-
tives (as well as their heterocyclic analogues) and a series of chiral
nonracemic C2-symmetric 1,2-diols by experimentally simple acid-
Fig. 1 Chiral nonracemic 2,2ꢀ-bipyridyl ligands 1a–c (R = Me, i-Pr and
catalyzed condensation reactions. In this paper, the synthesis of
a series of chiral nonracemic and C2-symmetric 2,2ꢀ-bipyridyl
Ph) and 2a–b (R = Me and Ph). * The compound used in the following
study was the enantiomer of that indicated in the figure.
ligands 1a–c (R = Me, i-Pr and Ph) as well as the syntheses of the
corresponding unsymmetric 2,2ꢀ-bipyridyl ligands 2a–b (R = Me
cyclopropanation reactions of styrene with the ethyl and t-butyl
esters of diazoacetic acid. The observations and conclusions made
in this detailed study are of significance for the future design,
synthesis and application of new chiral nonracemic ligands in
transition metal-catalyzed asymmetric processes.
and Ph) is described (Fig. 1).2 The bipyridyl ligands were prepared
from the corresponding 2-chloropyridine acetals 3a–c (R = Me, i-
Pr and Ph) and were evaluated in copper(I)-catalyzed asymmetric
Department of Chemistry, Simon Fraser University, 8888 University Drive,
We have previously reported the six-step synthesis of the
Burnaby, British Columbia, Canada V5A 1S6. E-mail: pwilson@sfu.ca;
Fax: 1 604 291-3765; Tel: 1 604 291-5654
precursors to the chiral nonracemic ligands described in this
paper, the 2-chloropyridine acetals 3a–c (R = Me, i-Pr and
Ph), from the known 2-hydroxypyridine 4 (Scheme 1).3,4 Thise
2-hydroxypyridine was readily prepared on a multi-gram scale
(from cyclopentanone, ethyl acetoacetate and ammonium ac-
etate) and converted to the 2-chloropyridine 5 on heating with
phenylphosphonic dichloride. Subsequent oxidation with 30%
aqueous hydrogen peroxide afforded the corresponding pyridine
N-oxide that was converted to the acetate 6 on heating with acetic
anhydride. Hydrolysis of the acetate 6 with lithium hydroxide
† Electronic supplementary information (ESI) available: General ex-
perimental details, detailed experimental procedures and full product
characterization data for all of the additional compounds synthesized.
An experimental procedure for the preparation and crystallization of the
bis-2,2ꢀ-bipyridyl ligand copper(I) chloride complex 18. 1H and 13C NMR
spectra for compounds 1a–c, 2a–b and 10–15 as well as for the complex
18. See DOI: 10.1039/b513286j
‡ M. P. A. L. performed all of the synthetic work and obtained all of the
compound characterization data described herein. N. D. D. determined the
X-ray crystal structure of the bis-2,2ꢀ-bipyridyl ligand copper(I) chloride
complex 18.
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Scheme
3
Synthesis of the chiral nonracemic and unsymmetric
2,2ꢀ-bipyridyl ligands 2a–b (R = Me and Ph). Reagents and conditions:
(i) 5 mol% Pd2dba3, 10 mol% P(t-Bu)3, CsF, dioxane, reflux, 24 h, 72%
(2a), 83% (2b). * The compound used in this study was the enantiomer of
that indicated in the scheme.
Scheme 1 Synthesis of the chiral nonracemic 2-chloropyridine acetals
3a–c (R = Me, i-Pr and Ph). Reagents and conditions: (i) PhP(O)Cl2,
160 ◦C, 16 h, 83%; (ii) H2O2, H2O, AcOH, 80 ◦C, 16 h; (iii) Ac2O, room
temperature, 1 h then 100 ◦C, 4 h, 60% (over two steps); (iv) LiOH, THF,
H2O, room temperature, 16 h, 94%; (v) (COCl)2, DMSO, CH2Cl2; NEt3,
−78 ◦C to room temperature, 90%; (vi) p-TsOH (cat.), benzene, reflux,
16 h, 85% (3a), 89% (3b), 79% (3c). * The compound used in this study
was the enantiomer of that indicated in the scheme.
(Scheme 3).8,9 In the first instance, it was found that these 2-
chloropyridine acetals reacted exceedingly slowly under stan-
dard Stille coupling reaction conditions, when tetrakis(triphenyl-
phosphine)palladium(0) was employed as the catalyst on heating
at reflux in benzene or toluene with potassium carbonate.10
However, the coupling reactions proceeded smoothly on employ-
ment of the conditions recently reported by Fu and co-workers
to afford the unsymmetric 2,2ꢀ-bipyridyl ligands 2a–b in good
yield (72 and 83%, respectively).11 These reaction conditions
involved heating a mixture of the 2-chloropyridine acetals 3a
and 3c with 2-(tri-n-butylstannyl)pyridine and anhydrous cesium
fluoride in dioxane at reflux in the presence of catalytic amounts
of tris(dibenzylideneacetone)dipalladium(0) and tri-t-butyl phos-
phine.
afforded the corresponding alcohol 7 and subsequent Swern
oxidation afforded the 2-chloroketone 8.5 The 2-chloropyridine
acetals 3a–c (R = Me, i-Pr and Ph) were then prepared in
good yield on condensation of the 2-chloroketone 8 with the
corresponding chiral nonracemic C2-symmetric 1,2-diols 9a–c
(R = Me, i-Pr and Ph) by heating these reaction partners at
reflux in benzene with a catalytic amount of para-toluenesulfonic
acid.6
Results and discussion
The direct and modular synthesis of the C2-symmetric 2,2ꢀ-
bipyridyl ligands 1a–c (R = Me, i-Pr and Ph) and the unsymmetric
2,2ꢀ-bipyridyl ligands 2a–b (R = Me and Ph) further demonstrated
the versatility of the corresponding 2-chloropyridine acetals 3a–
c as building blocks for the construction of new chiral ligands.3
However, the formation of a significant quantity of the reductively
dehalogenated product 10 in the nickel(0)-mediated homocou-
pling reaction of the 2-chloropyridine acetal 3a (R = Me) was
problematic because it occurred in the last step of the synthetic
sequence, after the valuable chiral portion of the molecule had
been installed. In order to circumvent this problem, it was
decided to prepare the corresponding 2-bromopyridine acetal 15
(Scheme 4). In this case, it was considered that the higher reactivity
of a pyridyl–bromide bond would lead to an improvement in
the yield of the desired 2,2ꢀ-bipyridyl ligand 1a (R = Me). The
lower reactivity of aryl–chloride bonds relative to aryl–bromide
bonds in metal-catalyzed coupling reactions is generally attributed
to their reluctance to undergo oxidative addition to the metal
catalyst.12 This is in agreement with the bond dissociation energies
of aryl halide bonds [at 298 K, Ph–Cl (96 kcal mol−1) > Ph–
Br (81 kcal mol−1)].13 The mechanism by which reduction of the
aryl–chloride bond occurred, in the case of the reaction of the 2-
chloropyridine acetal 3a (R = Me), is not obvious. However, if this
coupling reaction proceeds via radical intermediates, the reaction
solvent (tetrahydrofuran) or the reagent (tetraethylammonium
iodide) could have acted as sources of the hydrogen atoms as this
reaction was performed under strictly anhydrous conditions. The
observation that the reduction process only occurred during the
homocoupling reaction of the 2-chloropyridine acetal 3a (R =
Me) can be attributed to the fact that this is a less sterically
encumbered molecule and so it is presumably more reactive than
the 2-chloropyridine acetals 3b,c (R = i-Pr and Ph).
Synthesis of the 2,2ꢀ-bipyridyl ligands
The chiral nonracemic and C2-symmetric 2,2ꢀ-bipyridyl ligands
1a–c (R = Me, i-Pr and Ph) were prepared from the corresponding
2-chloropyridine acetals 3a–c by a nickel(0)-mediated homocou-
pling reaction upon heating in tetrahydrofuran with dibromo-
bis(triphenylphosphine)nickel(II), zinc dust and tetraethylammo-
nium iodide (Scheme 2).7 The reactions of the 2-chloropyridine
acetals 3b–c (R = i-Pr and Ph) both afforded the corresponding
2,2ꢀ-bipyridyl ligands 1b–c in good yield (72 and 73%, respectively).
However, in the case of the reaction of the 2-chloropyridine
acetal 3a (R = Me), a significant amount of the reductively
dehalogenated product 10 (35% yield) was obtained along with the
desired and corresponding 2,2ꢀ-bipyridyl ligand 1a (41% yield).
Scheme
2
Synthesis of the chiral nonracemic and C2-symmetric
2,2ꢀ-bipyridyl ligands 1a–c (R = Me, i-Pr and Ph). Reagents and conditions:
(i) NiBr2(PPh3)2, Zn, Et4NI, THF, 60 ◦C, 72 h, 41% (1a) and 35% (10), 72%
(1b), 73% (1c). * The compound used in this study was the enantiomer of
that indicated in the scheme.
The chiral nonracemic and unsymmetric 2,2ꢀ-bipyridyl ligands
2a–b (R = Me and Ph) were prepared from the correspond-
ing 2-chloropyridine acetals 3a and 3c by palladium-catalyzed
Stille coupling reactions with 2-(tri-n-butylstannyl)pyridine
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yield (54%, over two steps). Hydrolysis of the acetate 12 with
lithium hydroxide afforded the corresponding alcohol 13 that
was efficiently oxidized under Swern conditions to afford the
2-bromoketone 14. Condensation of this 2-bromoketone with
(2R,3R)-2,3-butanediol 9a (R = Me) in the presence of a catalytic
amount of p-toluenesulfonic acid monohydrate in benzene at
reflux afforded the 2-bromopyridine acetal 15 in high yield
(89%). This acetal was then subjected to the nickel(0)-mediated
homocoupling reaction to afford the 2,2ꢀ-bipyridyl ligand 1a (R =
Me) in good yield (83%). In this case, and as anticipated, none of
the reductively dehalogenated product 10 was detected.
Evaluation of the bipyridyl ligands
With a series of three chiral nonracemic and C2-symmetric
2,2ꢀ-bipyridyl ligands 1a–c (R = Me, i-Pr and Ph) as well as
two unsymmetric 2,2ꢀ-bipyridyl ligands 2a–b (R = Me and Ph)
in hand, the evaluation of these ligands in copper(I)-catalyzed
asymmetric cyclopropanation reactions of styrene with the ethyl
and t-butyl esters of diazoacetic acid 16a–b (R = Et and t-Bu) was
undertaken (Table 1). These catalytic reactions were performed
under a standard set of reaction conditions.14 Of note, the study
of copper(I)-catalyzed asymmetric cyclopropanation reactions of
styrene and diazoacetates constitutes a standard (“benchmark”)
method for the evaluation of new chiral nonracemic 2,2ꢀ-bipyridyl
ligands.2,14
The active copper catalysts in these reactions were generated
by reduction of the complexes formed between 1.25 mol% of
copper(II) triflate and 1.3 or 2.6 mol% of the 2,2ꢀ-bipyridyl ligands
1a–c and 2a–b with phenylhydrazine.15 In all cases, the solutions
of the copper(II) complexes formed between copper(II) triflate and
the bipyridyl ligands were light green in colour that turned deep red
Scheme 4 Synthesis of the C2-symmetric 2,2ꢀ-bipyridyl ligand 1a (R =
Me) from the 2-bromopyridine acetal 15. Reagents and conditions: (i)
PBr3, reflux, 12 h, 52%; (ii) H2O2, H2O, AcOH, 80 ◦C, 16 h; (iii) Ac2O,
room temperature, 1 h then 100 ◦C, 4 h, 54% (over two steps); (iv) LiOH,
THF, H2O, room temperature, 16 h, 95%; (v) (COCl)2, DMSO, CH2Cl2;
NEt3, −78 ◦C to room temperature, 90%; (vi) (2R,3R)-2,3-butanediol 9a,
p-TsOH (cat.), benzene, reflux, 20 h, 89%; (vii) NiBr2(PPh3)2, Zn, Et4NI,
THF, 60 ◦C, 72 h, 83%.
The 2-bromopyridine acetal 15 was prepared in a similar
manner as to that used in the preparation of the corresponding
2-chloropyridine acetal 3a (R = Me). This involved conversion
of the 2-hydroxypyridine 4 to the 2-bromopyridine 11, in reason-
able yield, on heating with phosphorus tribromide. Subsequent
treatment of the 2-bromopyridine 11 with 30% aqueous hydrogen
peroxide in glacial acetic acid at 80 ◦C for 16 h afforded the
corresponding pyridine N-oxide. This compound was then heated
in acetic anhydride to afford the acetate 12 in good overall
Table 1 Asymmetric copper(I)-catalyzed cyclopropanation reactions of styrene with the ethyl and t-butyl esters of diazoacetic acid 16a–b (R = Et and
t-Bu)
Entry
L*
R
L* : Cu Ratio
Producta
trans : cis Ratiob
Yield (%)c
Ee (%)d
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
2a
2b
Et
t-Bu
Et
t-Bu
Et
t-Bu
Et
t-Bu
Et
Et
Et
Et
1 : 1
1 : 1
2 : 1
2 : 1
1 : 1
1 : 1
2 : 1
2 : 1
1 : 1
2 : 1
1 : 1
1 : 1
ent-17a
ent-17b
ent-17a
ent-17b
17a
3 : 2
4 : 1
1 : 1
7 : 3
7 : 3
4 : 1
7 : 3
3 : 1
3 : 2
—
55
67
48
47
62
59
53
57
58
0
9
7
24
38
25
44
34
42
0
—
2
3
17b
17a
17b
(
—
)-17a
10
11
12
ent-17a
17a
3 : 2
3 : 2
75
74
a The absolute stereochemistry of the trans- and cis-diastereoisomers of cyclopropane reaction products were determined by comparison of the optical
rotations with literature values.17 b The ratios of the trans- and cis-diastereoisomers of the cyclopropane reaction products were determined by analysis
of the 1H NMR spectra (400 MHz, CDCl3) of the crude reaction mixtures. c Combined yields of the chromatographically separated trans- and cis-
cyclopropane reaction products. d The enantioselectivities were determined by analytical chiral HPLC (Daicel Chiralcel OD column) following reduction
of the trans-cyclopropane reaction products to the corresponding primary alcohol with lithium aluminum hydride.
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instantaneously when phenylhydrazine was added to the reaction
mixture. This indicated that reduction to the copper(I) complexes
had occurred. The asymmetric cyclopropanation reactions were
carried out at room temperature in dichloromethane and involved
the slow addition (over ca. 3 h) of the ethyl and t-butyl esters of
diazoacetic acid 16a–b (R = Et and t-Bu) to a solution of 2.2
equivalents of styrene and the preformed catalyst. It was found
that both the yields and stereoselectivities of the cyclopropanation
reactions were highly dependant on which bipyridyl ligand was
employed as well as on the ratio of the ligand and copper(II) triflate.
The reaction of styrene with ethyl diazoacetate 16a (R = Et)
using a 1 : 1 ratio of the bipyridyl ligand 1a (R = Me), that was
derived from (2R,3R)-2,3-butanediol 9a, and copper(II) triflate
afforded the cyclopropane ent-17a in a trans : cis ratio of 3 :
2 and in low enantioselectivity (9% ee) (Table 1, entry 1).16
Employment of the larger reaction substrate, t-butyl diazoacetate
16b (R = t-Bu) (under identical reaction conditions), afforded
the cyclopropane ent-17b in an improved trans : cis ratio (4 : 1).
However, the enantioselectivity of the reaction remained low (7%
ee) (Table 1, entry 2). The absolute stereochemistry of the major
trans-cyclopropane reaction products ent-17a–b (R = Et and t-
Bu) were determined to be (1R,2R) and the corresponding minor
cis-cyclopropane reaction products ent-17a–b were determined to
be (1S,2R) by comparison of the optical rotations with literature
values.17 These initial results led to the consideration that the
bipyridyl ligand 1a was not completely bound to the copper(I)
salt (or that a bis-ligated copper(I) species had formed which
would imply that copper(I) triflate was present in the reaction
mixtures).18 Thus, to attempt to improve the stereoselectivities of
these initial experiments, the above reactions were repeated using
a 2 : 1 ratio of the bipyridyl ligand 1a and copper(II) triflate. It was
found that the reactions, with ethyl and t-butyl diazoacetate 16a–b,
afforded the corresponding cyclopropanes ent-17a–b in improved
enantioselectivities (24 and 38% ee, respectively) (Table 1, entries
3 and 4). Similar trends were observed on evaluation of the
pseudo-enantiomeric bipyridyl ligand 1b (R = i-Pr) that was
derived from (1S,2S)-1,2-diisopropyl-1,2-ethanediol 9b. The use
of a 1 : 1 ratio of the bipyridyl ligand 1b and copper(II) triflate, in
the cyclopropanation reaction of styrene with ethyl and t-butyl
diazoacetate 16a–b, afforded the corresponding cyclopropanes
17a–b in higher enantioselectivities (25 and 44% ee, respectively)
(Table 1, entries 5 and 6). Of note, and as was expected for these
latter reactions with this pseudo-enantiomeric bipyridyl ligand, the
major trans-cyclopropanes 17a–b (R = Et and t-Bu) had (1S,2S)
stereochemistry and the corresponding minor cis-cyclopropanes
17a–b had (1R,2S) stereochemistry.17 The use of a 2 : 1 ratio of the
bipyridyl ligand 1b and copper(II) triflate with ethyl diazoacetate
16a resulted in a further improvement in the enantioselectivity of
the reaction (34% ee) (entry 7). However, the enantioselectivity of
the reaction remained essentially the same (42% ee) when t-butyl
diazoacetate 16b was employed as the reaction substrate (Table 1,
entry 8). This is in contrast to what was found for the bipyridyl
ligand 1a (R = Me) when the latter set of reaction conditions was
employed.
16a resulted in the isolation of the cyclopropane ( )-17a in racemic
form (Table 1, entry 9). This was a surprising result in that it was
expected that the ligand 1c (R = Ph) would be the most efficient
chiral director in view of the relatively large size of the cyclic acetal
moiety. Moreover and remarkably, no reaction occurred when the
above reaction was repeated with a 2 : 1 ratio of the bipyridyl
ligand 1c and copper(II) triflate (Table 1, entry 10).
The unsymmetric 2,2ꢀ-bipyridyl ligands 2a–b (R = Me and Ph)
were also evaluated in the cyclopropanation reaction of styrene
with ethyl diazoacetate 16a. In these instances, on employment of
a 1 : 1 ratio of the bipyridyl ligands 2a–b and copper(II) triflate,
the cyclopropanes ent-17a and 17a were isolated in good yield but
in very low enantiomeric excess (2 and 3%, respectively) (Table 1,
entries 11 and 12). The low enantioselectivities obtained here are
presumably due to the lack of sufficient steric bulk on one side of
these ligands and so no further experiments were conducted.
Crystallographic studies of the bis-2,2ꢀ-bipyridyl ligand copper(I)
chloride complex (18)
In order to probe the structure of the species involved in the
asymmetric cyclopropanation reactions with the C2-symmetric
2,2ꢀ-bipyridyl ligands 1a–c (R = Me, i-Pr and Ph), a crystallo-
graphic study was undertaken.§ The bipyridyl ligand 1c (R = Ph)
was selected for this study in light of the interesting results that had
been obtained in this case. Due to the air and moisture sensitivity of
copper(I) triflate complexes, the corresponding copper(I) chloride
complex of the bipyridyl ligand 1c was prepared. This involved the
reaction of equimolar quantities of the ligand 1c and anhydrous
copper(I) chloride in a mixture of ethanol and dichloromethane (1 :
1). Bright red X-ray quality crystals of the resultant complex 18,
which was formed quantitatively, were obtained by recrystalliza-
tion from a mixture of ether and dichloromethane (1 : 1) on slow
evaporation of the solvent. Analysis of the X-ray data revealed
that two bipyridyl ligands were coordinated, in a geometry that
was somewhat distorted from tetrahedral, to the copper(I) centre.
In addition, the chloride counterion that had been displaced
from the coordination sphere of the complex had combined with
the remaining copper(I) chloride to form a copper(I) dichloride
counterion (CuCl2−).19 An ORTEP representation of complex 18
is shown below (Fig. 2). Around the copper(I) centre, the following
bond angles were determined: N1–Cu1–N2 = 82.2◦ and N2–Cu1–
◦
˚
N1* = 131.2 . The N1–Cu1 bond length was 2.057 A and the
20
˚
N2–Cu1 bond length was 2.052 A.
Mechanistic aspects of the cyclopropanation reactions
Based on the above structure determination, the results of the
cyclopropanation reactions (i.e. the dependence of the enantios-
electivity of reaction as a function of the ratio of the bipyridyl
ligand and copper reagent employed in the process) can be
rationalized. It is proposed that the bipyridyl ligands 1a–c (R =
Me, i-Pr and Ph) have the propensity to form bis-ligated copper(I)
complexes in solution and that an equilibrium is established
between copper(I) triflate, the mono-ligated copper(I) triflate
complexes 19, and the bis-ligated copper(I) triflate complexes
20 (Fig. 3). The latter bis-ligated complexes 20 are presumably
Particularly interesting and surprising results were obtained
when the (1S,2S)-1,2-diphenyl-1,2-ethanediol 9c derived bipyridyl
ligand 1c (R = Ph) was employed in these cyclopropanation
reactions. Employment of a 1 : 1 ratio of the bipyridyl ligand 1c and
copper(II) triflate in the reaction of styrene with ethyl diazoacetate
§ CCDC reference number 293622. For crystallographic data in CIF
format see DOI: 10.1039/b513286j
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corresponding bis-ligated complex 20. This would account for the
additional fact that the cyclopropanation reaction was completely
shut down in this instance. The relative kinetic and thermodynamic
stability of this particular complex could be the result of favourable
p–p interactions (between one of the phenyl rings of each of the
four chiral acetal moieties and both aromatic rings of the two
bipyridyl moieties) or that the two bipyridyl ligands are rigidly
interlocked once they are positioned around the copper ion (see
Fig. 2).
Optical rotary dispersion spectrum of the bis-2,2ꢀ-bipyridyl ligand
copper(I) chloride complex (18)
In the process of obtaining full spectroscopic data for the bis-
2,2ꢀ-bipyridyl ligand copper(I) chloride complex 18, it was noted
that this compound had a particularly large specific rotation
([a]2D0 −1300 [c 0.0030, chloroform]). Pfaltz and co-workers have
20
436
reported a similar optical rotation ([a] −1574 [c 0.01, ethanol])
for a bis-ligated copper(II) semicorrin complex.18 This result led
us to record an optical rotary dispersion spectrum on a dilute
solution of the complex 18 (1.9 × 10−5 M) in chloroform (Fig. 4).
Remarkably, the maximum positive specific optical rotation was
+1.1 × 104 at a wavelength of 304 nm and the maximum
negative specific rotation was −1.3 × 104 at 329 nm. To put these
values in context, the classic hydrocarbons—the helicenes—have
extraordinarily high specific rotations ([a]D) that range from 3640
for [6]-helicene to 9620 for [13]-helicene.22 A UV-vis spectrum of
the complex 18 was also recorded. Strong absorptions at 287 nm
(e = 3.8 × 104 M−1 cm−1), 309 (e = 3.9 × 104 M−1 cm−1) and 472 nm
(e = 6.2 × 103 M−1 cm−1) were observed. The absorbance at 472 nm
is in the blue-visible region of the electromagnetic spectrum which
accounts for the intense red colour of the complex.
Fig. 2 ORTEP representation of the bis-2,2ꢀ-bipyridyl ligand copper(I)
chloride complex 18. The thermal ellipsoids are drawn at a 25%
probability level and the atoms of the incorporated solvent molecule
(dichloromethane) as well as the hydrogen atoms have been removed for
clarity.
Fig. 3 Proposed equilibrium established in solution between copper(I)
triflate and the C2-symmetric 2,2ꢀ-bipyridyl ligands (L*).
inactive cyclopropanation catalysts since all coordination sites
on the copper centre are blocked. However, copper(I) triflate
and the mono-ligated copper(I) triflate complexes 19 would be
active catalysts and so the enantioselectivities observed in the
cyclopropanation reactions are a result of the relative rates of
catalysis by these two species.21 It is also possible that the desired
mono-ligated copper(I) triflate complexes 19 [derived from the C2-
symmetric 2,2ꢀ-bipyridyl ligands 1a–b (R = Me and i-Pr)] could be
very effective chiral directors in asymmetric cyclopropanation re-
actions. However, in the cases that were studied, the free copper(I)
triflate in solution had compromised the overall enantioselectivity
of the reactions. In the case of the bipyridyl ligand 1c (R =
Ph), the results of the cyclopropanation reactions suggested that
the corresponding bis-ligated complex was the major complex in
solution. This conclusion is further supported by the fact that
the 1H and 13C NMR spectra of the bis-2,2ꢀ-bipyridyl ligand
copper(I) chloride complex 18 in deuterated chloroform were well-
resolved and no free ligand was observed. Thus, when a 1 : 1
ratio of the ligand 1c and copper(II) triflate was employed in the
cyclopropanation reaction, the two species in solution would have
been catalytically active copper(I) triflate and the corresponding
catalytically inactive bis-ligated complex 20. This would account
for the fact that the cyclopropane reaction product ( )-17a was
isolated in racemic form. When the cyclopropanation reaction
was performed with a 2 : 1 ratio of the ligand 1c and copper(II)
triflate, the copper ions would have been entirely sequestered as the
Fig. 4 Optical rotary dispersion spectrum of the bis-2,2ꢀ-bipyridyl ligand
copper(I) chloride complex 18. The spectrum was recorded at 20 ◦C in
chloroform [c 0.0030 (g per 100 mL)].
Stereochemical interpretation of the asymmetric cyclopropanation
reactions
The stereochemical outcome of the asymmetric cyclopropanation
reactions of the copper(I) complexes of the C2-symmetric 2,2ꢀ-
bipyridyl ligands 1a–b (R = Me and i-Pr) can be rationalized
in terms of the minimization of steric interactions between the
reacting species. A schematic representation, that depicts the
proposed low and high energy modes for the reaction of styrene
with the copper–carbenoid intermediates [for the bipyridyl ligand
1a (R = Me) and the diazoacetates 16a–b (R = Et and t-Bu)]
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that would lead to the four possible stereoisomeric cyclopropane
reaction products, is shown below (Fig. 5).
(R = i-Pr) was employed. This afforded the corresponding
trans-cyclopropane reaction product 17b (R = t-Bu) in good
diastereoselectivity (4 : 1) and in moderate enantioselectivity
(44% ee). An X-ray structure determination of the complex 18
formed between the C2-symmetric 2,2ꢀ-bipyridyl ligand 1c (R =
Ph) and copper(I) chloride showed that two bipyridyl ligands had
coordinated to the copper(I) ion. This information, along with
the results from the cyclopropanation reactions and NMR data,
led to the conclusion that the 2,2ꢀ-bipyridyl ligands 1a–c (R =
Me, i-Pr and Ph) had the propensity to form catalytically inactive
bis-ligated copper(I) species in solution that were in equilibrium
with catalytically active copper(I) triflate and the desired mono-
ligated copper(I) species. It was also inferred that the mono-
ligated copper(I) species could possibly be very selective in the
asymmetric cyclopropanation reactions and that the observed
enantioselectivities were significantly eroded by free copper(I)
triflate in solution. For this reason, future studies with these
ligands will involve their application in asymmetric reactions
which are catalyzed by copper(II) species or by transition metals
other than copper. The bis-2,2ꢀ-bipyridyl ligand copper(I) chloride
complex 18 was found to have a particularly large optical rotation
(sodium D-line). Moreover, the maximum positive optical rotation
was +1.1 × 104 at 304 nm and the maximum negative optical
rotation was −1.3 × 104 at 329 nm. In view of these exceptionally
high values, a future study will involve the use of the bipyridyl
ligand 1c (R = Ph) for the detection of trace quantities of metal
ions by optical rotation measurements. To further demonstrate the
versatility of the design concept employed in the synthesis of these
bipyridyl ligands, the 2-chloropyridine acetals 3a–c (R = Me, i-Pr
and Ph) will also be used to construct additional chiral nonracemic
ligands and catalysts for evaluation in asymmetric synthesis.
Fig. 5 Rationalization of the stereochemical outcome of the asymmetric
cyclopropanation reactions of styrene and the diazoacetates 16a–b (R =
Et and t-Bu) with the C2-symmetric 2,2ꢀ-bipyridyl ligand 1a (R = Me).
The lower energy mode would result from minimization of
steric interactions between the substituents (R) of the chiral
acetal moieties and styrene. In addition, the favoured approach
of styrene (from the accessible front face of the complex, as
drawn) along reaction pathway (a) would lead to the major
trans-cyclopropane reaction products (1R,2R)-17a–b (due to
minimization of additional interactions with the ester moiety).
Conversely, approach along reaction pathway (b) (again from
the front face of the complex) would lead to the minor cis-
cyclopropane reaction products (1S,2R)-17a–b. Approach from
the front face of the complex along reaction pathways (a) and
(b) in the higher energy mode would lead to the enantiomeric
major trans-cyclopropane reaction products (1S,2S)-17a–b and
the minor cis-cyclopropane reaction products (1R,2S)-17a–b.
In this mode, the steric interactions between the substituents
(R) of the chiral acetal moieties and styrene are more severe.
Moreover, from this schematic representation, the relationship of
the observed diastereoselectivity of the reaction to the size of the
ester moiety can also be realized.
Experimental
4,4ꢀ-Dimethyl-6,6ꢀ,7,7ꢀ-tetrahydro-5H,5ꢀH-2,2ꢀ-bi([1]pyridinyl)-
7,7ꢀ-dione-(1S,2S)-1,2-diphenyl-1,2-ethanediolbisacetal (1c).
Representative procedure for the preparation of the 2,2ꢀ-bipyridyl
ligands (1a–c) from the 2-chloropyridine acetals (3a–c)
To a stirred solution of dibromobis(triphenylphosphine)nickel(II)
(743 mg, 1.00 mmol) in degassed tetrahydrofuran (15 mL) were
added zinc dust (<10 lm, 197 mg, 3.02 mmol) and tetraethylam-
monium iodide (517 mg, 2.01 mmol). The reaction mixture was
stirred at room temperature for 30 min and then a solution of
the 2-chloropyridine acetal 3c23 (760 mg, 2.01 mmol) in degassed
tetrahydrofuran (12 mL) was added via a cannula. The resultant
mixture was heated at 60 ◦C for 72 h and then was allowed to
cool to room temperature. The reaction mixture was then poured
into an aqueous solution of ammonium hydroxide (10% w/w, 300
mL) and was extracted with ether (3 × 50 mL). The combined
organic extracts were washed with water (2 × 20 mL), dried over
anhydrous sodium sulfate and concentrated in vacuo to afford the
crude product. Flash chromatography using hexanes–ether (6 :
1) as the eluant afforded the title compound 1c (502 mg, 73%)
Conclusions
The direct and modular synthesis of a series of chiral nonracemic
and C2-symmetric 2,2ꢀ-bipyridyl ligands 1a–c (R = Me, i-Pr and
Ph) as well as the syntheses of the corresponding unsymmetric 2,2ꢀ-
bipyridyl ligands 2a–b (R = Me and Ph) from the 2-chloropyridine
acetals 3a–c (R = Me, i-Pr and Ph) have been developed. These
bipyridyl ligands were evaluated for use in asymmetric synthesis
in copper(I)-catalyzed cyclopropanation reactions of styrene with
the ethyl and t-butyl esters of diazoacetic acid 16a–b (R = Et
and t-Bu). The catalytic species in these reactions were generated
by reduction of the complexes formed between 1.25 mol% of
copper(II) triflate and 1.3 or 2.6 mol% of the bipyridyl ligands
with phenylhydrazine in dichloromethane. It was found that the
stereoselectivities, as well as the yields of the reactions, were
dependant on the ratio of the bipyridyl ligands and copper(II)
triflate employed. The best result was obtained in the asymmetric
cyclopropanation reaction of styrene with t-butyl diazoacetate
16b (R = t-Bu) when the C2-symmetric bipyridyl ligand 1b
◦
as a white crystalline solid. Mp 214–215 C, hexanes–ether; [a]D20
1
+250 (c 1.00, chloroform); H NMR (400 MHz, CDCl3) d 2.39
(6H, s, ArCH3), 2.70–2.84 (4H, m, ArCH2CH2), 2.97–3.07 (4H,
m, ArCH2), 4.95 (2H, d, J = 8.5 Hz, CH), 5.79 (2H, d, J =
8.5 Hz, CH), 7.28–7.45 (16H, m, ArH), 7.65–7.78 (4H, m, ArH),
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8.39 (2H, s, ArH); 13C NMR (101 MHz, CDCl3) d 18.7, 24.3, 36.1,
86.0, 86.5, 115.7, 122.5, 127.0, 128.0, 128.4, 128.5, 136.0, 136.6,
137.8, 145.0, 156.7, 161.0; IR (KBr) mmax 2366, 2341, 1594, 1498,
1436, 1422, 1326, 1195, 1159, 1141, 1099, 1023, 938, 916, 761,
700 cm−1; MS (MALDI-TOF) m/z 686 (M + H); Anal. calcd for
C46H40N2O4: C, 80.68; H, 5.89; N, 4.09. Found: C, 80.50; H, 5.77;
N, 4.06.
865 cm−1; MS (CI) m/z (rel. intensity) 213 [M(81Br) + H, 97], 211
[M(79Br) + H, 100]; Anal. calcd for C9H10NBr: C, 50.97; H, 4.75;
N, 6.60. Found: C, 50.66; H, 4.73; N, 6.39.
(7R,S)-7-Acetoxy-2-bromo-4-methyl-6,7-dihydro-5H-[1]pyridine
(12)
To a stirred solution of the 2-bromopyridine 11 (2.20 g, 10.4 mmol)
in glacial acetic acid (20 mL) was added an aqueous solution of
hydrogen peroxide (30% w/w, 5.0 mL, 49 mmol). The resultant
solution was heated at 80 ◦C for 20 h and then was allowed to
cool to room temperature. The reaction mixture was concentrated
in vacuo and the residue was taken up in water (100 mL). The
resultant slightly acidic mixture was neutralized by the careful
addition of solid potassium carbonate which was then extracted
with chloroform (3 × 50 mL). The combined organic extracts were
dried over anhydrous sodium sulfate and concentrated in vacuo to
afford the pyridine N-oxide (2.35 g, 99%) as a white crystalline
solid. This material was taken up in acetic anhydride (20 mL) and
4-Methyl-2-(2ꢀ-pyridyl)-6,7-dihydro-5H-[1]pyridin-7-one-(1S,2S)-
1,2-diphenyl-1,2-ethanediol acetal (2b). Representative procedure
for the preparation of the unsymmetric 2,2ꢀ-bipyridyl ligands
(2a–b) from the 2-chloropyridine acetals (3a and 3c)
To a stirred solution of the 2-chloropyridine acetal 3c23 (261 mg,
0.690 mmol) and 2-(tri-n-butylstannyl)pyridine8a (472 mg, 0.759
mmol) in anhydrous, degassed dioxane (5 mL) at room tempera-
ture were added tris(dibenzylideneacetone)dipalladium(0) (16 mg,
17 lmol), a solution of tri-t-butylphosphine in tetrahydrofuran
(0.10 M, 0.69 mL, 69 lmol) and anhydrous cesium fluoride
(231 mg, 1.52 mmol). The resultant solution was heated at reflux
for 24 h and then was allowed to cool to room temperature. The
reaction mixture was filtered through a pad of silica gel using ethyl
acetate as the eluant and the filtrate was then concentrated in vacuo
to afford the crude product. Flash chromatography using hexanes–
ether (4 : 1) as the eluant afforded the title compound 2b (242 mg,
83%) as a white crystalline solid. Mp 120–121 ◦C, hexanes–ether;
◦
the reaction mixture was heated slowly to 100 C over 2 h. The
◦
resultant mixture was heated at 100 C for 2 h and then allowed
to cool to room temperature. The reaction mixture was then
concentrated in vacuo and purified by flash chromatography using
hexanes–ether (1 : 1) as the eluant to afford the title compound 12
(1.50 g, 54% over two steps) as a light orange oil which crystallized
upon standing. Mp 68–69 ◦C; 1H NMR (400 MHz, CDCl3) d 2.00–
2.11 (4H, m, ArCH2CHH and CH3CO), 2.26 (3H, s, ArCH3),
2.68–2.69 (1H, m, ArCH2CHH), 2.69–2.80 (1H, m, ArCHH),
2.87–2.98 (1H, m, ArCHH), 5.98–6.02 (1H, m, CHOAc), 7.22
(1H, s, ArH); 13C NMR (101 MHz, CDCl3) d 18.7, 21.5, 26.3,
30.6, 122.9, 136.9, 141.5, 147.2, 160.8, 170.8; IR (KBr) mmax 2363,
2337, 1734, 1653, 1635, 1559, 1541, 1507, 1370, 1337, 1235, 1094,
1036, 856 cm−1; MS (CI) m/z (rel. intensity) 272 [M(81Br) + H,
97], 270 [M(79Br) + H, 100], 212 (30), 101 (35); Anal. calcd for
C11H12NO2Br: C, 48.91; H, 4.48; N, 5.19. Found: C, 48.63; H,
4.43; N, 5.32.
1
[a]2D0 −98.4 (c 1.00, chloroform); H NMR (400 MHz, CDCl3) d
2.40 (3H, s, ArCH3), 2.68–2.82 (2H, m, ArCH2CH2), 2.96–3.03
(2H, m, ArCH2), 4.92 (1H, d, J = 8.5 Hz, CH), 5.77 (1H, d, J =
8.5 Hz, CH), 7.29–7.37 (9H, m, ArH), 7.61–7.66 (2H, m, ArH),
7.80–7.86 (1H, m, ArH), 8.30 (1H, s, ArH), 8.52–8.56 (1H, m,
ArH), 8.67–8.71 (1H, m, ArH); 13C NMR (101 MHz, CDCl3) d
18.5, 24.3, 36.1, 86.1, 86.5, 115.6, 121.4, 122.2, 123.6, 126.9, 127.9,
128.4, 128.5, 128.5, 136.5, 137.1, 137.5, 145.4, 149.0, 156.7, 161.2;
IR (KBr) mmax 1586, 1564, 1492, 1441, 1381, 1351, 1320, 1289,
1253, 1210, 1185, 1164, 1103, 1056, 1021, 936, 920, 796, 761, 751,
700 cm−1; MS (CI) m/z (rel. intensity) 421 (M + H, 90), 314 (2),
225 (100); Anal. calcd for C28H24N2O2: C, 79.98; H, 5.75; N, 6.66.
Found: C, 79.64; H, 6.02; N, 6.30.
(7R,S)-2-Bromo-4-methyl-6,7-dihydro-5H-[1]pyridin-7-ol (13)
A stirred solution of the acetate 12 (1.50 g, 5.55 mmol) and lithium
hydroxide monohydrate (932 mg, 22.2 mmol) in tetrahydrofuran
(15 mL) and water (5 mL) was stirred at room temperature
for 5 h. The reaction mixture was then diluted with water (25
mL) and extracted with chloroform (3 × 25 mL). The combined
organic extracts were dried over anhydrous sodium sulfate and
concentrated in vacuo to afford the crude product. Flash chro-
matography using hexanes–ether (1 : 1) as the eluant afforded the
title com◦pound 13 (1.20 g, 95%) as a white crystalline solid. Mp
110–111 C, hexanes–ether; 1H NMR (400 MHz, CDCl3) d 1.99–
2.12 (1H, m, ArCH2CHH), 2.26 (3H, s, ArCH3), 2.48–2.59 (1H,
m, ArCH2CHH), 2.63–2.75 (1H, m, ArCHH), 2.87–2.97 (1H, m,
ArCHH), 5.18 (1H, apparent t, J = 7.2 Hz, CHOH), 7.19 (1H, s,
ArH); 13C NMR (101 MHz, CDCl3) d 18.6, 25.8, 32.2, 74.8, 127.6,
135.2, 141.0, 147.3, 165.1; IR (KBr) mmax 3258, 2361, 1733, 1717,
1700, 1684, 1653, 1636, 1559, 1541, 1507, 1187, 1090, 863 cm−1;
MS (CI) m/z (rel. intensity) 230 [M(81Br) + H, 22], 228 [M(79Br) +
H, 22], 201 (100), 173 (25), 118 (18), 91 (53), 77 (36), 65 (36), 51
(33), 39 (42); Anal. calcd for C9H10NOBr: C, 47.39; H, 4.42; N,
6.14. Found: C, 47.61; H, 4.45; N, 5.98.
2-Bromo-4-methyl-6,7-dihydro-5H-[1]pyridine (11)
A solution of the 2-hydroxypyridine 44,15a (3.00 g, 20.1 mmol) in
phosphorus tribromide (4.5 mL, 47 mmol) was heated at reflux
for 12 h. The reaction mixture was then allowed to cool to room
temperature and was poured into an ice-cold aqueous solution
of sodium hydroxide (2 M, 300 mL). The resultant mixture was
extracted (gentle agitation to avoid emulsification) with ethyl
acetate (3 × 200 mL). The combined organic extracts were dried
over anhydrous sodium sulfate and concentrated in vacuo to afford
the crude product. Flash chromatography using chloroform as
the eluant afforded the title compound 11 (2.20 g, 52%) as a
colourless oil which crystallized upon standing. Mp 35–36 ◦C;
1H NMR (400 MHz, CDCl3) d 2.04–2.16 (2H, m, ArCH2CH2),
2.21 (3H, s, ArCH3), 2.80 (2H, apparent t, J = 7.5 Hz, ArCH2),
2.99 (2H, apparent t, J = 7.8 Hz, ArCH2), 7.05 (1H, s, ArH); 13
C
NMR (101 MHz, CDCl3) d 18.7, 25.9, 32.31, 74.9, 127.7, 135.3,
141.1, 147.4, 165.2; IR (KBr) mmax 2356, 2337, 1733, 1717, 1700,
1684, 1653, 1558, 1507, 1458, 1419, 1375, 1305, 1261, 1186, 1090,
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2-Bromo-4-methyl-6,7-dihydro-5H-[1]pyridin-7-one (14)
tetrahydrofuran (6 mL) was added via a cannula. The reaction
mixture was then heated at 60 ◦C for 72 h. The resultant mixture
was allowed to cool to room temperature and was then poured into
an aqueous solution of ammonium hydroxide (10% w/w, 150 mL).
The resultant mixture was extracted with a mixture of ether and
benzene (1 : 1, 3 × 100 mL). The combined organic extracts were
washed with water (2 × 20 mL), dried over anhydrous sodium
sulfate and concentrated in vacuo to afford the crude product.
Flash chromatography using chloroform as the eluant afforded
the title compound 1a (364 mg, 83%) as a white crystalline solid.
The spectroscopic data for this compound were in agreement with
that recorded for the material prepared from the 2-chloropyridine
acetal 3a (refer to the electronic supplementary information).
To a stirred solution of oxalylchloride (415 lL, 4.76 mmol) in
dichloromethane (40 mL) at −78 ◦C was added dimethylsulfoxide
(1.10 mL, 14.2 mmol) dropwise over ca. 5 min. The resultant
solution was stirred for 10 min and then a solution of the alcohol
13 (900 mg, 3.95 mmol) in anhydrous dichloromethane (15 mL)
was added via a cannula. After an additional 10 min, triethylamine
(2.80 mL, 20.1 mmol) was added and the reaction mixture was then
allowed to warm to room temperature. The resultant mixture was
diluted with dichloromethane (50 mL) and was washed with brine
(20 mL), dried over anhydrous sodium sulfate and concentrated
in vacuo to afford the crude product. Flash chromatography using
dichloromethane as the eluant afforded the 2-bromoketone 14
(804 mg, 90%) as a white crystalline solid. Mp 188–189 ◦C,
General procedure for the copper(I)-catalyzed enantioselective
cyclopropanation reactions of styrene with the ethyl and t-butyl
esters of diazoacetic acid (16a–b)
1
dichloromethane; H NMR (400 MHz, CDCl3) d 2.39 (3H, s,
ArCH3), 2.74–2.80 (2H, m, ArCH2CH2), 2.97–3.02 (2H, m,
ArCH2), 7.46 (1H, s, ArH)]; 13C NMR (101 MHz, CDCl3) d 17.5,
21.9, 34.7, 132.0, 143.9, 148.9, 149.0, 154.2, 203.5; IR (KBr) mmax
2360, 1719, 1684, 1653, 1559, 1540, 1521, 1094 cm−1; MS (CI) m/z
(rel. intensity) 228 [M(81Br) + H, 100], 226 [M(79Br) + H, 100];
Anal. calcd for C9H8NOBr: C, 47.82; H, 3.57; N, 6.20. Found: C,
47.71; H, 3.48; N, 6.22.
To a stirred solution of copper(II) triflate (9.0 mg, 25 lmol)
in dichloromethane (4 mL) was added the 2,2ꢀ-bipyridyl ligand
1a–c or the unsymmetrical 2,2ꢀ-bipyridyl ligand 2a–b (26 lmol
or 52 lmol) and the resultant solution was stirred at room
temperature for 30 min. Phenylhydrazine (3.0 lL, 30 lmol) and
styrene (0.50 mL, 4.4 mmol) were then added. A solution of the
ethyl or t-butyl ester of diazoacetic acid 16a–b (2.00 mmol) in
dichloromethane (3 mL) was then added over ca. 3 h via syringe
pump. After the addition was complete, the reaction mixture was
stirred for an additional 12 h and then was concentrated in vacuo
to afford the crude product. The ratios of the trans- and cis-
isomers of the cyclopropane reaction products 17a–b were then
determined by 1H NMR spectroscopy. Flash chromatography
using petroleum ether–ethyl acetate (96 : 4) as the eluant afforded
the pure trans-cyclopropanes 17a–b and the corresponding cis-
cyclopropanes. The enantiomeric purities of the major trans-
isomers of the cyclopropane reaction products were determined
following reduction with lithium aluminum hydride.
2-Bromo-4-methyl-6,7-dihydro-5H-[1]pyridin-7-one-(2R,3R)-2,3-
butanediol acetal (15)
A solution of the 2-bromoketone 14 (650 mg, 2.87 mmol), (2R,3R)-
2,3-butanediol 9a (0.33 mL, 3.6 mmol) and p-toluenesulfonic
acid monohydrate (82 mg, 0.43 mmol) in anhydrous benzene (15
mL) was heated at reflux in a Dean–Stark trap for 20 h. The
reaction mixture was then allowed to cool to room temperature
and potassium carbonate (200 mg) was added. After 10 min,
the reaction mixture was filtered and concentrated in vacuo to
afford the crude product. Flash chromatography using hexanes–
ethyl acetate (2 : 1) as the eluant afforded the title compound
15 (760 mg, 89%) as a white crystalline solid. Mp 128–129 ◦C,
hexanes–ethyl acetate; [a]2D0 − 25.8 (c 1.07, chloroform); 1H NMR
(400 MHz, CDCl3) d 1.31 (3H, d, J = 6.1 Hz, CHCH3), 1.41 (3H,
d, J = 6.1 Hz, CHCH3), 2.22 (3H, s, ArCH3), 2.35–2.40 (2H,
m, ArCH2CH2), 2.72–2.78 (2H, m, ArCH2), 3.72–3.90 (1H, m,
CHCH3), 4.35–4.43 (1H, m, CHCH3), 7.19 (1H, s, ArH); 13C
NMR (101 MHz, CDCl3) d 16.6, 17.1, 18.1, 23.9, 35.9, 79.2,
79.7, 113.6, 128.4, 135.0, 141.8, 147.1, 162.4; IR (KBr) mmax 2985,
2933, 2361, 2331, 1588, 1441, 1376, 1314, 1263, 1204, 1107, 1077,
931, 865 cm−1; MS (CI) m/z (rel. intensity) 300 [M(81Br) + H,
97], 298 [M(79Br) + H, 100], 226 (21), 115 (53); Anal. calcd for
C13H16NO2Br: C, 52.36; H, 5.41; N, 4.70. Found: C, 52.25; H,
5.47; N, 4.61.
trans-2-Phenyl-cyclopropane-1-carboxylic acid ethyl ester (17a).
1H NMR (400 MHz, CDCl3) d 1.25–1.34 (4H, m, CH3 and CHH),
1.56–1.63 (1H, m, CHH), 1.87–1.93 (1H, m, CHCO2Et), 2.52
(1H, ddd, J = 10.2, 6.4, 4.1 Hz, CHPh), 4.17 (2H, q, J = 7.2 Hz,
CH2CH3), 7.07–7.14 (2H, m, ArH), 7.17–7.23 (1H, m, ArH), 7.24–
7.32 (2H, m, ArH); 13C NMR (101 MHz, CDCl3) d 14.4, 17.2,
24.3, 26.3, 60.8, 126.3, 126.6, 128.6, 140.3, 173.5; IR (neat) mmax
2988, 1721, 1603, 1496, 1411, 1189, 1040, 1019, 847, 761, 722,
701 cm−1; MS (CI) m/z (rel. intensity) 191 (M + H, 100). Analytical
chiral HPLC analysis of the corresponding primary alcohol using
a Daicel Chiralcel OD column [hexanes–isopropanol (90 : 10),
flow rate at 0.5 mL min−1, detection at k = 220 nm, t1 = 15.4 min,
t2 = 25.2 min].
Preparation of 4,4ꢀ-dimethyl-6,6ꢀ,7,7ꢀ-tetrahydro-5H,5ꢀH-2,2ꢀ-
bi([1]pyridinyl)-7,7ꢀ-dione-(2R,3R)-butanediolbisacetal (1a) from
the 2-bromopyridine acetal (15)
trans-2-Phenyl-cyclopropane-1-carboxylic acid t-butyl ester
(17b). 1H NMR (400 MHz, CDCl3) d 1.23 (1H, m, CHH), 1.47
(9H, s, t-Bu), 1.50–1.56 (1H, m, CHH), 1.84 (1H, m, CHCO2t-
Bu), 2.44 (1H, m, CHPh), 7.06–7.12 (2H, m, ArH), 7.16–7.22 (1H,
m, ArH), 7.24–7.31 (2H, m, ArH); 13C NMR (101 MHz, CDCl3)
d 17.4, 25.6, 26.1, 28.5, 80.9, 126.4, 126.7, 128.7, 140.9, 172.9;
IR (neat) mmax 2977, 1715, 1606, 1498, 1403, 1367, 1343, 1222,
1152, 936, 844, 783, 761, 744 cm−1; MS (CI) m/z (rel. intensity)
219 (M + H, 18), 163 (100). Analytical chiral HPLC analysis of
To a stirred solution of dibromobis(triphenylphosphine)nickel(II)
(224 mg, 0.302 mmol) in degassed tetrahydrofuran (15 mL) were
added zinc dust (<10 lm, 197 mg, 3.02 mmol) and tetraethylam-
monium iodide (517 mg, 2.01 mmol). The resultant mixture was
stirred at room temperature for 30 min and then a solution of
the 2-bromopyridine acetal 15 (600 mg, 2.01 mmol) in degassed
884 | Org. Biomol. Chem., 2006, 4, 877–885
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the corresponding primary alcohol using a Daicel Chiralcel OD
column [hexanes–isopropanol (90 : 10), flow rate at 0.5 mL min−1,
detection at k = 220 nm, t1 = 15.4 min, t2 = 25.2 min].
and W. J. Scott, Org. React., 1997, 50, 1; (c) T. N. Mitchell, in Metal
Catalyzed Cross-Coupling Reactions, ed. F. Diederich and P. J. Stang,
Wiley-VCH, New York, 1998, ch. 4.
9 The corresponding chiral nonracemic unsymmetric 2,2ꢀ-bipyridyl lig-
and (R = i-Pr) was not prepared because of the relatively limited
quantity of the chloropyridine acetal 3b (R = i-Pr) at hand as well as in
view of the results from the preliminary evaluation of the unsymmetric
2,2ꢀ-bipyridyl ligands 2a–b (R = Me and Ph) in copper(I)-catalyzed
asymmetric cyclopropanation reactions.
Acknowledgements
We are grateful to the Natural Sciences and Engineering Research
Council of Canada (NSERC) and Simon Fraser University for
financial support. We also wish to acknowledge the Canadian
Foundation for Innovation (CFI), the British Columbia Knowl-
edge Development Fund (BCKDF) and AstraZeneca Canada,
Inc. for support of our research program. M. P. A. L. thanks
Simon Fraser University for an entrance scholarship and graduate
research fellowships. Professor D. B. Leznoff (SFU) is also thanked
for advice in regard to the X-ray structure determination.
10 A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc., 1987, 109, 5478.
11 A. F. Littke, L. Schwarz and G. C. Fu, J. Am. Chem. Soc., 2002, 124,
6343.
12 V. V. Grushin and H. Alper, Chem. Rev., 1994, 94, 1047.
13 J. D. Cox and G. Pilcher, Thermochemistry of Organic and Organometal-
lic Compounds, Academic Press, London, 1970.
14 (a) M. P. Doyle and D. C. Forbes, Chem. Rev., 1998, 98, 911; (b) M. P.
Doyle and M. N. Protopopova, Tetrahedron, 1998, 54, 7919.
15 For recent and illustrative examples of the use of these reaction
conditions, see: (a) M. P. A. Lyle and P. D. Wilson, Org. Lett., 2004,
6, 855; (b) A. V. Malkov, D. Pernazza, M. Bell, M. Bella, A. Massa, F.
Teply´, P. Meghani and P. Kocˇovsky´, J. Org. Chem., 2003, 68, 4727.
16 The enantioselectivity of the reactions were only determined for the
major trans-cyclopropane reaction products. The enantiomeric purities
of the minor cis-cyclopropane reaction products were not determined
as the enantiomers of the corresponding primary alcohol could not be
resolved by analytical chiral HPLC (Daicel Chiralcel OD column).
17 T. Niimi, T. Uchida, R. Irie and T. Katsuki, Adv. Synth. Catal., 2001,
343, 79.
References
1 A. A. Narine and P. D. Wilson, Can. J. Chem., 2005, 83, 413.
2 For recent reviews on chiral 2,2ꢀ-bipyridyl ligands and their application
in catalytic asymmetric synthesis, see: (a) A. V. Malkov and P.
Kocˇovsky´, Curr. Org. Chem., 2003, 7, 1737; (b) G. Chelucci and R. P.
Thummel, Chem. Rev., 2002, 102, 3129; (c) N. C. Fletcher, J. Chem.
Soc., Perkin Trans. 1, 2002, 1831.
18 H. Fritschi, U. Leutenegger, K. Siegmann and A. Pfaltz, Helv. Chim.
Acta, 1988, 71, 1541.
3 M. P. A. Lyle, A. A. Narine and P. D. Wilson, J. Org. Chem., 2004,
69, 5060. In this instance, the chloropyridine acetals 3a–c were used to
prepare a series of chiral nonracemic P,N-ligands that were evaluated
in asymmetric palladium(II)-catalyzed allylic substitution reactions of
a racemic allylic acetate and dimethylmalonate (up to 90% ee).
4 A. Sakurai and H. Midorikawa, Bull. Chem. Soc. Jpn., 1968, 41,
165.
5 The 2-chloroketone 8 can be readily prepared on a multi-gram scale. In
this instance, only the acetate precursor 6 requires purification by flash
chromatography.
6 The diols 9a and 9c (R = Me and Ph) are commercially available in both
enantiomeric forms. However, (2R,3R)-2,3-butanediol 9a (R = Me) is
significantly less expensive than the corresponding (2S,3S)-enantiomer
and so it was employed in these studies. The non-commercially available
(1S,2S)-ethanediol 9b (R = i-Pr) was synthesized from (2R,3R)-(+)-
tartaric acid ethyl ester according to a five-step literature procedure,
see: (a) X. Wang, S. D. Erickson, T. Iimori and W. C. Still, J. Am.
Chem. Soc., 1992, 114, 4128; (b) D. S. Matteson, E. C. Beedle and
A. A. Kandil, J. Org. Chem., 1987, 52, 5034. The (1S,2S)-ethanediol 9c
(R = Ph) was also was prepared by the Sharpless asymmetric dihydroxy-
lation reaction of (E)-stilbene, see: (c) K. B. Sharpless, Y. Amberg, G.
Bannani, J. Crispino, K. Hartung, H. Jeong, K. Kwong, Z. Morikawa,
D. Wang, X. Xu and X.-L. Zhang, J. Org. Chem., 1992, 57, 2768.
7 (a) E. V. Dehmlow and A. Sleegers, Liebigs Ann. Chem., 1992, 953;
(b) M. Iyoda, H. Otsuka, K. Sato, N. Nisato and M. Oda, Bull. Chem.
Soc. Jpn., 1990, 63, 80.
19 Although the corresponding copper(I) triflate complex was not
prepared (because of the inherent practical difficulties in handling
copper(I) triflate), the copper(I) chloride complex 18 can be considered
to be a good model for the actual species that is formed on reduction
of the complex formed between the bipyridyl ligand 1c (R = Ph)
and copper(II) triflate with phenylhydrazine. In the cyclopropanation
reactions attempted with this ligand, the triflate counterion would also
have been displaced from the coordination sphere of the resultant
complex.
20 Empirical formula, C93H82Cl4Cu2N4O8; FW (g mol−1), 1648.35; tempe-
˚
rature (K), 293; wavelength (Cu Ka, A), 1.54180; crystal system, ortho-
˚
˚
rhombic; space group, P21212; a (A), 14.7325(4); b (A), 15.2366(2);
3
˚
˚
c (A), 19.0213(3); a (deg), 90; b (deg), 90; c (deg), 90; Z, 2; U (A ),
4269.77(15); Dcalc (g cm−3), 1.285; 2h limits (deg), 4.65–144.25; re-
flections collected, 28285; independent reflections, 6828; reflections
observed [I = 2.5r(I)], 4566; goodness-of-fit on F, 0.601; R1 and Rw [I =
2.5r(I)], 0.0532 and 0.750.
21 Of note, when a 2 : 1 ratio of ligands 1a–b and copper(II) triflate were
employed in the cyclopropanation reactions the isolated yields of prod-
ucts were lower. This indicated that less of the two catalytically active
species [copper(I) triflate and the mono-ligated copper(I) complexes]
were present in these instances and that more of the catalytically inactive
bis-ligated copper(I) complexes were formed.
22 For a review on the synthesis of helicenes and their physical prop-
erties, see: H. Hopf, Classics in Hydrocarbon Chemistry, Wiley-VCH,
Weinheim, 2000, pp. 321–368.
8 2-(Tri-n-butylstannyl)pyridine was prepared from 2-bromopyridine ac-
cording to a literature procedure, see: (a) W. R. McWhinnie, R. C. Poller
and M. Thevarasa, J. Organomet. Chem., 1968, 11, 499. For reviews
on the Stille coupling reaction, see: (b) V. Farina, V. Krishnamurthy
23 Full experimental details regarding the preparation of the 2-
chloropyridines acetals 3a–c have been reported (ref. 3,15a).
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