Preparation of new axially chiral bridged 2,2′-bipyridines and pyridyl monooxazolines (pymox). Evaluation in copper(i)-catalyzed enantioselective cyclopropanation

Article abstract of DOI:10.1039/b701549f

This work reports the synthesis of new axially chiral bridged 2,2′-bipyridines 1 and pyridylmonooxazolines (pymox) 2. The potential of these new axially chiral N,N-ligands was evaluated in asymmetric catalytic cyclopropanation of styrene derivatives 22a-c with diazoesters 21a,b. While 2,2′-bipyridines 1a-c afforded the corresponding cyclopropanes 23a-f in up to 65% ee, pymoxs 2a-e gave somewhat lower enantioselectivities (up to 53% ee). Both classes of ligands produced trans-cyclopropanes 23a-f as the major isomer, although with modest diasteroselectivities (56: 44 to 78: 22). A structure-stereoselectivity relationship study of ligands 1 and 2 identified the chiral biaryl axis as being mostly responsible for the enantioselective performances of these ligands. The Royal Society of Chemistry.

Full text of DOI:10.1039/b701549f

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Preparation of new axially chiral bridged 2,2ꢀ-bipyridines and pyridyl
monooxazolines (pymox). Evaluation in copper(I)-catalyzed enantioselective
cyclopropanation†
Alexis Bouet,a Barbara Heller,b Cyril Papamicae¨l,a Georges Dupas,a Sylvain Oudeyer,a Francis Marsaisa and
Vincent Levacher*a
Received 31st January 2007, Accepted 12th March 2007
First published as an Advance Article on the web 23rd March 2007
DOI: 10.1039/b701549f
This work reports the synthesis of new axially chiral bridged 2,2ꢀ-bipyridines 1 and
pyridylmonooxazolines (pymox) 2. The potential of these new axially chiral N,N-ligands was evaluated
in asymmetric catalytic cyclopropanation of styrene derivatives 22a–c with diazoesters 21a,b. While
2,2ꢀ-bipyridines 1a–c afforded the corresponding cyclopropanes 23a–f in up to 65% ee, pymoxs 2a–e
gave somewhat lower enantioselectivities (up to 53% ee). Both classes of ligands produced
trans-cyclopropanes 23a–f as the major isomer, although with modest diasteroselectivities (56 : 44 to
78 : 22). A structure-stereoselectivity relationship study of ligands 1 and 2 identified the chiral biaryl
axis as being mostly responsible for the enantioselective performances of these ligands.
Introduction
Of the many types of N,N-ligands that have been designed for
asymmetric catalysis, chiral non-racemic 2,2ꢀ-bipyridines have
emerged as an effective class of chiral inducers in a large number
of catalytic processes, such as allylic oxidation, hydrosilylation,
allylic substitution and cyclopropanation.1 Only a few examples
of 2,2ꢀ-bipyridines bearing an element of axial chirality have been
reported so far in the literature. This may be explained by the
lack of general and straightforward stereoselective methods giving
access to axially chiral 2,2ꢀ-bipyridines. The main route to these
axially chiral ligands generally required a final resolution step
by preparative chiral HPLC.15e In an original approach initially
reported by Botteghi,2 the configuration of a biaryl axis was
controlled by bridging two aryl units with a chiral appendage
derived from tartaric acid. More recently, Hayashi has developed
a similar strategy for the preparation of atropoisomeric 2,2ꢀ-
bipyridine N,Nꢀ-dioxides,3 using a chiral binaphthalene linkage
to connect the two pyridine moities (Fig. 1).
Fig. 1 Axially chiral bridged 2, 2ꢀ-bipyridines.
lactamization of biaryl keto-acids with phenylalaninol provided
axially chiral bicyclic lactams in good yields and excellent di-
astereoselectivity. In this process, the axial configuration of the
biaryl unit is subordinated to the newly generated N,O-acetal
stereocenter of the oxazolidinone ring (Scheme 1).
Pyridyl monooxazolines (pymox) represent another important
class of N,N-ligands, which have already been shown to be effective
in various asymmetric catalytic processes.4 To the best of our
knowledge, the design and evaluation in asymmetric catalysis of
pymox ligands bearing an element of axial chirality has not been
reported so far.
Scheme 1 Design of an axially chiral bridged biaryl framework by means
We have previously reported the preparation of axially chiral
bridged biaryl systems by means of Meyers’ methodology.5 The
of Meyers’ methodology.
aLaboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014,
IRCOF, CNRS, Universite´ et INSA de Rouen, B.P. 08, F-76131, Mont-
Saint-Aignan Ce´dex, France. E-mail: vincent.levacher@insa-rouen.fr;
Fax: +33(0)235522962
We reasoned that this atroposelective lactamization could
provide a useful synthetic approach for the construction of
new axially chiral ligands. In this context, we report herein the
preparation of a series of axially chiral 2,2ꢀ-bipyridines 1 and
pyridyl monooxazolines 2 based on the functionalization of these
chiral 7,5-fused bicyclic lactams (Fig. 2). A preliminary evaluation
of their potential in enantioselective cyclopropanation is also
reported (Fig. 2).
bLeibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, 18059, Rostock, Germany. E-mail: barbara.heller@
catalysis.de; Fax: +49(381)4669324
† Electronic supplementary information (ESI) available: Syntheses of
ligands 1c, 2d,e; X-ray structure of 2,2ꢀ-bipyridine 1a. See DOI:
10.1039/b701549f
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An alternative route was explored for the preparation of 2,2ꢀ-
bipyridyl ligand 1a wherein the atroposelective lactamization takes
place in the last step of the reaction sequence (Scheme 3). The 2,6-
dichloropyridine was first cross-coupled under Stille conditions
with 2-(tributylstannyl)pyridine7 to give the bipyridine 6 in 69%
yield. This coupling step required the use of a large excess of
2,6-dichloropyridine to prevent the formation of the undesired
terpyridine. Bipyridine 6 was subsequently subjected to ortho-
lithiation in the presence of LDA at −78 ◦C for 1 h. The
lithiated species was then trapped with ethyl cyanoformate to
furnish 7 in 65% yield. A Suzuki cross-coupling reaction between
this intermediate and 2-acetylphenylboronic acid furnished the
lactamization precursor 8 in 66% yield. In the presence of (R)-
phenylglycinol and under classical dehydrating conditions, the
Fig. 2 Design of new axially chiral 2,2ꢀ-bipyridines 1 and pymox 2.
1
keto-acid 8 afforded ligand 1a in 60% yield. Analysis of the H
NMR spectrum of the crude product revealed the presence of a
single diastereoisomer (Scheme 3).
Results and discussion
Preparation of 2,2ꢀ-bipyridyl ligands 1a,b
An initial route was investigated by functionalization of the
lactam 3 previously reported in our laboratory.5 Subsequent to
N-oxidation of lactam 3 with m-CPBA, the resulting pyridine
N-oxide 4 was treated with POCl3 providing the desired chloropy-
ridine 5a in a modest yield (30%) along with the undesired
regioisomer 5b (20%). Initial attempts to obtain ligand 1a by
a Negishi cross-coupling reaction between 5b and 2-pyridylzinc
bromide failed, leading in most cases to the recovered starting
chloropyridine 5a. Finally, a Stille cross-coupling reaction between
chloropyridine 5a and 2-(tributylstannyl)pyridine afforded the
desired C1-symmetric 2,2ꢀ-bipyridyl 1a in a modest yield of 30%.
The C2-symmetric 2,2ꢀ-bipyridyl ligand 1b was obtained by a
nickel-mediated homo-coupling reaction6 of chloropyridine 5a in
61% yield (Scheme 2).
Scheme 3 Preparation of 2,2ꢀ-bipyridine 1a by atroposelective lactamiza-
tion of 8. Reagents and conditions: (i) 2-(tributylstannyl)pyridine, toluene,
Pd(PPh3)4, reflux, 24 h (69%); (ii) LDA, THF, −78 ◦C, 1 h then ethyl
cyanoformate, −78 ◦C, 1 h (65%); (iii) 2-acetylphenylboronic acid, toluene,
K2CO3, EtOH, H2O, Pd(PPh3)4, reflux, 48 h (66%); (iv) (R)-phenylglycinol,
toluene, reflux, 6 days (60%).
Finally, the last approach investigated was the cobalt-catalyzed
[2 + 2 + 2] cycloaddition of cyanopyridine 9 and acetylene
under photochemical conditions.8 The pyridine N-oxide 4 was
subjected to the Reissert reaction conditions, affording the re-
quired cyanopyridine 9 in 97% yield. The cobalt-catalyzed [2 +
2 + 2] cycloaddition was carried out in toluene under very mild
conditions, at ambient temperature and pressure in the presence
of CpCo(cod)9 as the catalyst source. Ligand 1a was isolated in
80% yield after flash chromatography. This approach provide rapid
and straightforward access to ligand 1a in good yield. An X-ray
crystallographic analysis‡ of 1a revealed an S configuration for
the newly created N,O-acetal stereocenter and an R configuration
for the biaryl axis that connects the phenyl and the bipyridyl unit.
It was found that these two aryl moities adopt a rather flat dihedral
angle of 38◦(Scheme 4).10
Preparation of pyridylmonooxazolines (pymox) 2a–d
The preparation of the pymox ligands 2a–c was accomplished
from the cyanopyridine 9 intermediate by formation of Meyers’
oxazoline. Pymox 2a was straightforwardly obtained in 90% yield
Scheme 2 Preparation of 2,2ꢀ-bipyridines 1 by means of homo- and
cross-coupling reactions from 5a. Reagents and conditions: (i) CH2Cl2,
m-CPBA, rt (72%); (ii) CH2Cl2, NEt3, POCl3, rt, 30 min, then reflux for
1 h (30% of 5a); (iii) 2-(tributylstannyl)pyridine, toluene, Pd(PPh3)4, reflux,
24 h (30%); (iv) DMF, NiCl2 6H2O, Zn, PPh3, 60 ◦C, 4 h (61%).
‡ CCDC reference number 637822. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b701549f
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Scheme 4 Preparation of C1-symmetric 2,2ꢀ-bipyridine 1a via [2 + 2 +
2] photocycloaddition of 9 with acetylene. Reagents and conditions:
(i) (Me)2NCOCl, TMSCN, CH2Cl2, rt, 48 h (repeated twice) (97%);
(ii) toluene, [CpCo(cod)], acetylene, rt, hm (420 nm), 5 h (80%).
by reacting 2-amino-2-methylpropanol and 9 in the presence of
dry ZnCl2 in refluxing chlorobenzene.11 Attempts to apply these
reaction conditions with (R)- or (S)-phenylglycinol failed, leading
in both cases to the formation of tarry materials. We finally
succeeded via the formation of an imidate intermediate, which
was then transformed into the desired pymox 2b,c by reaction
with (R)- or (S)-phenylglycinol in refluxing chorobenzene.12 This
method could be scaled up to multigram quantities affording 2b,c
in 79% and 84% yields, respectively (Scheme 5).
Scheme 6 Preparation of pymox 2d. Reagents and conditions: (i) toluene,
Pd(PPh3)4, EtOH, KOH, 60 ◦C, 4 h (98%); (ii) (R)-phenylglycinol,
toluene, reflux, 2 days (64%); (iii) m-CPBA, CH2Cl2, rt, 72 h (81%); (iv)
(Me)2NCOCl, TMSCN, CH2Cl2, rt, 48 h (repeated twice) (58%); (v) ZnCl2,
2-amino-2-methylpropanol, chlorobenzene, reflux, 48 h (60%).
Preparation of chiral analogues 1c and 2e devoid of stereogenic axis
Finally, in order to probe the role of the chiral biaryl axis on the
performance of these ligands, the preparation of two analogues 1c
and 2e,wherein the chiral biaryl axis is replaced by a stereogenic
center, was undertaken. Ligands 1c and 2e were prepared in a
similar manner to that developed for the preparation of their
axially chiral analogues 1b and 2a by functionalization of the
bicyclic lactam 17 (Scheme 7). The 5,5-fused bicyclic lactam 17 was
obtained in 50% yield as a single diastereoisomer by lactamization
of 2-benzoylpyridine 3-carboxylic acid 16 with (R)-phenylglycinol.
Subsequent oxidation of 17 afforded pyridine N-oxide 18 in 76%
yield, which was converted to 2-chloropyridine 19 in 41% yield.
A homo-coupling reaction of 19 mediated by nickel in DMF at
60 ◦C afforded the C2-symmetric 2,2ꢀ-bipyridine 1c in 91% yield.
From pyridine N-oxide 18, pymox 2e was obtained by a Reissert
reaction (56%) followed by oxazoline formation (80%).
Scheme 5 Preparation of pymox 2a–c from cyanopyridine 9. Reagents and
conditions: (i) ZnCl2, 2-amino-2-methylpropanol, chlorobenzene, reflux,
48 h (90%); (ii) NaOMe, methanol–THF (5 : 1), rt, 24 h, then (R)- or
(S)-phenylglycinol, chlorobenzene, reflux, 24 h (79% of 2b, 84% of 2c).
We then turned our interest to the synthesis of pymox 2d; the
main structural distinction between pymox 2a and 2d being an
inversion of the chiral appendage connecting the biaryl system
(Scheme 6). By comparison of their performance in asymmetric
catalytic cyclopropanation, we expected to gain insight into the
individual contribution of both the chiral appendage and chiral
biaryl axis on the enantioselective properties of this type of
ligands. Ligand 2d was prepared from the available 2-chloro-3-
acetylpyridine 1013 and the boronic ester 1114 by a Suzuki coupling
reaction, affording the cyclization precursor 12 in 98% yield.
Lactamization of 12 upon heating at reflux in toluene with (R)-
phenylglycinol proceeded smoothly, giving rise to the formation of
the bicyclic lactam 13 in 64% yield as a single diastereoisomer. The
synthesis of 2d was then completed by oxazolidine construction
at C-2 of the pyridine ring, following the classical sequence of
N-oxidation (81%), Reissert reaction (58%) and oxazoline-ring
formation (60%).
Evaluation of the ligands in catalytic asymmetric cyclopropanation
With 2,2ꢀ-bipyridyl ligands 1a–c and pymox 2a–e in hand, their
evaluation in Cu(I)-catalyzed asymmetric cyclopropanation of
styrene derivatives with diazoesters was undertaken. While the
use of chiral 2,2ꢀ-bipyridine ligand in cyclopropanation is well
documented,1,15 chiral pymoxs have received less attention.4a This
study was carried out under standard conditions using 1.2 mol%
of the ligand and 1 mol% of copper(II) triflate in CH2Cl2 at room
temperature. The standard procedure involves the slow addition
of the diazoester by means of a syringe pump to the reaction
mixture. Phenylhydrazine generates in situ the active copper(I)
catalyst by reduction of the copper(II) triflate catalyst precursor.
This reduction was accompanied by a change in color from light
green to deep red, indicating the presence of the catalytically active
species. Styrene, p-methoxystyrene and p-chlorostyrene derivatives
22a–c were used to survey the influence of the electronic nature of
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Table 1 Catalytic asymmetric cyclopropanation of styrene derivatives 22
and diazoesters 21 with 2,2ꢀ-bipyridyl ligands 1a–c and copper(I)
Scheme 7 Preparation of non-axially chiral 2,2ꢀ-bipyridine 1c and pymox
2e analogues. Reagents and conditions: (i) (R)-phenylglycinol, toluene,
reflux, 48 h (50%); (ii) m-CPBA, CH2Cl2, rt, 72 h (76%) (iii) POCl3,
NEt3, reflux, 12 h (41%); (iv) DMF, NiCl2, 6H2O, Zn, PPh3, 60 ◦C, 4 h
(91%);(v) (Me)2NCOCl, TMSCN, CH2Cl2, rt, 48 h (repeated twice) (56%);
(vi) ZnCl2, 2-amino-2-methylpropanol, chlorobenzene, reflux, 48 h (80%).
Diazoester
21
Styrene
22
Yield
(%)
Ratioa
(trans/cis)
Eeb
(trans/cis)
Entry
Ligand
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
21a
21b
21a
21b
21a
21b
21a
21b
21a
21b
21a
21b
21b
22a
22a
22b
22b
22c
22c
22a
22a
22b
22b
22c
22c
22a
67
90
75
50
68
66
84
64
80
75
87
65
65
23a, 60 : 40
23b, 75 : 25
23c, 62 : 38
23d, 69 : 31
23e, 64 : 36
23f, 76 : 24
23a, 66 : 34
23b, 75 : 25
23c, 60 : 40
23d, 73 : 27
23e, 62 : 38
23f, 78 : 22
23b, 72 : 28
57 : 46
65 : 64
nd : 42
nd : 54
nd : 52
nd : 58
26 : 10
31 : 14
nd : 6
nd : 20
nd : 17
nd : 13
15 : 0
the para-substituent on the enantioselectivity of the cyclopropana-
tion. The steric demand of the diazoester generally influences the
trans/cis ratio, the trans isomer being obtained as major product
when sterically hindered diazoesters are used. Ethyl and t-butyl
diazoacetates 21a,b, commonly employed as standard substrates
in asymmetric cyclopropanation, were selected to evaluate these
new ligands (Scheme 8).
a Determined by GC. b Enantiomers of the trans-cyclopropanes 23c–f
reaction products could not be separated by chiral GC (Chiraldex CB
25 m × 0.25 mm).
and enantioselectivity of the reaction (Table 1, Entries 1, 3
and 5). The C2-symmetric 2,2ꢀ-bipyridyl ligand 1b furnished 23a–f
in much lower enantioselectivity (up to 31%) (Table 1, Entries 7–
12). This result is surprizing in that it has been frequently shown
that C2-symmetric bipyridyl ligands are capable of providing high
ee’s.15 Additionally, when compared with C1-symmetric bipyridyl
analogues, it is apparent that C2-symmetric bipyridyl ligands
usually give rise to higher levels of enantioselection.15f In our case,
although its efficiency remains rather modest, the C1-symmetric
bipyridyl ligand 1a turned out to be more efficient than the C2-
symmetric ligand 1b. Interestingly, the incapability of ligand 1c to
induce a substantial enantioselectivity during cyclopropanation of
styrene 22a with t-butyl diazoacetate 21b seems to designate the
chiral biaryl axis as an important element of chirality in the design
of these ligands (Table 1, Entry 13).
Scheme 8 Catalytic asymmetric cyclopropanation. Reagents and condi-
tions: (i) CH2Cl2, rt, PhNHNH2, Cu(OTf)2.
Evaluation of 2,2ꢀ-bipyridyl ligands 1a–c
As can be seen from Table 1, cyclopropanes 23a–f were obtained in
fair to good yields (50–90%). In accordance with what is generally
observed in the literature, the trans-isomer was obtained as the ma-
jor product in all cases, however, with modest diastereoselectivities
ranging from 60 : 40 to 78 : 22. As expected, the trans/cis selectivity
was somewhat improved in favor of the trans-isomer by using the
bulky t-butyl diazoacetate 21b. The nature of the bipyridyl ligand
1a–c has no significant effect on the trans/cis ratio. In contrast,
the enantioselectivity was highly influenced by the nature of the
ligands 1a–c ranging from 0 to 65% ee. Ligand 1a proved to be the
most effective affording 23a–f in 42% to 65% ee (Table 1, Entries 1–
6). One can notice that the electronic nature of the para-substituent
in styrenes 22a–c exerts only a limited effect on both the diastereo-
Evaluation of pymox ligands 2a–e
As can be seen from Table 2, pymox 2a–e showed mostly similar
trends to those observed with bipyridyl ligands 1a–c in terms of
yields (49–100%) and trans/cis selectivities (56 : 44 to 77 : 23).
Although the enantioselective performances of pymox 2a remain
moderate (up to 52% ee), these results are similar to those obtained
with previously reported pymox.4a The effect of an additional
stereogenic center at the oxazoline moities of pymox 2b–c was then
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Table 2 Catalytic asymmetric cyclopropanation of styrene derivatives 22
and diazoesters 21 with pymox ligands 2a–e and copper(I)
Conclusions
The synthesis of new axially chiral biaryl N,N-ligands in 2,2ꢀ-
bipyridyl and pymox series has been developed. Their preparation
is essentially based on an atroposelective lactamization of keto-
ester biaryl systems and subsequent functionalization of the
resulting 7,5-fused bicyclic lactam 3. By this modular approach,
ligands were obtained in three to five steps from lactam 3 and
could be prepared on a multi-gram scale. A preliminary evaluation
of these bidentate N,N-ligands has been investigated in catalytic
asymmetric cyclopropanation. Whereas 2,2ꢀ-bipyridyl ligands 1
afforded cypropropanes 23 in up to 65% ee, enantioselectivities
did not exceed 53% ee with pymox ligands 2. Diverse modular
modifications of the ligands gave some evidence that, among
the multiple elements of chirality present in the structure, the
chiral biaryl axis plays a crucial role in their enantioselective
properties. The potential of these bidentate ligands is presently
being evaluated for other catalytic asymmetric processes.
Experimental
Diazoester
21
Styrene
22
Yield
(%)
Ratioa
(trans/cis)
Eeb
(trans/cis)
Entry
Ligand
General methods
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2a
2a
2a
2a
2a
2a
2b
2c
2d
2d
2d
2d
2d
2d
2e
21a
21b
21a
21b
21a
21b
21b
21b
21a
21b
21a
21b
21a:
21b
21b
22a
22a
22b
22b
22c
22c
22a
22a
22a
22a
22b
22b
22c
22c
22a
62
80
82
77
96
71
74
85
100
90
83
64
66
49
94
23a: 64 : 36
23b: 72 : 28
23c: 62 : 38
23d: 67 : 33
23e: 56 : 44
23f: 77 : 23
23b: 61 : 39
23b: 72 : 38
23a: 64 : 36
23b: 71 : 29
23c: 62 : 38
23d: 70 : 30
23e: 64 : 36
23f: 77 : 23
23b: 76 : 24
46 : 40
52 : 44
nd : 42
nd : 44
nd : 44
nd : 40
53 : 32
7 : 5
46 : 47
50 : 40
nd : 44
nd : 39
nd : 48
nd : 45
0 : 0
Chemicals were purchased and used without further
purification.1H and 13C were recorded on a Bruker Avance 300 with
chloroform-d1 (d 7.26, 1H; d 77.0, 13C) as internal standard unless
otherwise indicated. Melting points were determined on a Kofler
block. Optical rotations were recorded in CH2Cl2. The [a]D values
are given in 10−1deg cm−3 g−1. The IR spectra were recorded on
a Perkin Elmer Paragon 500. Elemental analyses were performed
by the University of Rouen Microanalytical Service Laboratory
on a Carlo Erba 1160. Mass spectrometry was performed by
the University of Rouen Spectroscopy Center. Electron impact
(EI) and chemical ionization (IC) spectra were performed on
a Jeol JMS AX-500 spectrometer. Routine monitoring of the
reaction was performed by TLC, using 0.2 Kieselgel 60 F254
precoated aluminium sheets, commercially available from Merck.
Flash chromatography was performed on Gerudan SI-60 (70–230
mesh ASTM) from Merck. Tetrahydrofuran (THF) was distilled
on sodium benzophenone ketyl under nitrogen. The following
compounds were prepared according literature methods: lactam
3;5 2-(tributylstannyl)pyridine;7 2-chloro-3-acetylpyridine 10;13
and boronic ester 11.14
a Determined by GC. b Enantiomers of the trans-cyclopropanes 23d–f
reaction products could not be separated by chiral GC (Chiraldex CB
25 m × 0.25 mm).
investigated. While the performance of pymox 2b proved compa-
rable to that of 2a (Table 2, Entries 2 and 7), the performance of
pymox 2c was drastically affected by the presence of this additional
chiral element (Table 2, entries 2 and 8). Thus, whereas a mismatch
effect was observed with (S)-phenylglycinol, no assistance of a
match effect, that would have improved the enantioselectivity,
was recorded with (R)-phenylglycinol. Comparison of the results
obtained with pymox 2a and 2d indicates that an inversion of
the chiral lactam appendage linking the biaryl system has only a
limited effect on the enantio- and diastereoselective outcome of the
reaction (Table 2, Entries 1–6, 9–14). This may be explained by the
fact that the chiral appendage is too far from the catalytic site to
influence the stereochemical course of the reaction. Thus, it could
be concluded from these results that in both pymox 2a and 2d, the
chiral biaryl axis is the main element of chirality responsible for
the stereochemical outcome of the cyclopropanation. As earlier
observed for the 2,2ꢀ-bipyridyl ligands series, the replacement of
this chiral axis with a stereogenic center in pymox 2e provokes a
disastrous effect on the enantioselective properties of the ligand
(Table 2, Entry 15).
Trans-(3R,13bS,aS)-methyl-3-phenyl-2,3-dihydro-13bH-benz-
[c]oxazolo[3,2-a]-N-oxide-pyrido[2,3-e]azepin-5-one (4). To a so-
lution of lactam 3 (700 mg, 2.04 mmol) in CH2Cl2 (10 mL)
was added m-CPBA (70%, 1.51 g, 6.13 mmol). The mixture was
stirred for 48 hours at room temperature. A cold 40% aqueous
NaOH solution (2 mL) was added, and this suspension was stirred
for a further 1 hour at room temperature. Water (10 mL) and
dichloromethane (10 mL) were added. The organic layer was
separated, dried with magnesium sulfate, filtered and solvents were
removed to afford a pale yellow oil. Flash chromatography on
silica gel of the residue (eluent used was EtOAc–cyclohexane 95 :
5) provided (3R,13bS,aS)-4 (530 mg, 72%) as a white solid. Mp
110 ◦C. 1H NMR 300 MHz, (CDCl3) d 8.47 (d, J = 6.1 Hz, 1H),
8.40 (dd, J = 8.6 and 1.1 Hz, 1H), 7.73–7.67 (m, 2H), 7.54–7.29
(m, 8H), 5.43 (d, J = 6.0 Hz, 1H), 4.42 (dd, J = 6.4 and 2.0 Hz,
1H), 4.33 (dd, J = 8.7 and 1.0 Hz, 1H), 1.69 (s, 3H). 13C NMR
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75 MHz, (CDCl3) d 161.5, 145.3, 143.0, 142.5, 140.4, 134.4, 132.6,
131.0, 129.2 (2 C), 128.3, 127.8, 127.4 (2 C), 125.8, 124.9, 122.6,
94.3, 71.4, 61.8, 26.9. IR tmax cm−1 (KBr): 1643, 1428, 1395, 1247,
1217, 1037, 747, 700. Anal. Calc. for C22H18N2O3: C, 73.73; H,
5.06; N, 7.82. Found: C, 73.82; H, 5.13; N, 7.81. [a]2D0 = −83.66
(c = 3.55, CH2Cl2).
(KBr): 2887, 1635, 1408. HRMS IC calc. for C27H22N3O2: m/z =
420.1712. Found: (MH)+ m/z = 420.1704.
By atroposelective lactamization of keto-ester 8 with (R)-
phenylglycinol. Keto-ester
8 (1.56 g, 4.5 mmol) and (R)-
phenylglycinol (617 mg, 4.5 mmol) were dissolved in toluene
(50 mL) in a Dean–Stark apparatus. The mixture was stirred at
reflux for 6 days and then cooled to room temperature. Toluene
was removed under vacuum, flash chromatography of the residue
(eluent used was EtOAc–CH2Cl2–cylohexane 2 : 7 : 1) provided
ligand 1a (1.80 g, 60%) as a white solid.
By Co-cyclotrimerization of acetylene and cyanopyridine 9. A
thermostated (25 ◦C) reaction vessel, equipped with a very effective
quill spin bar, was loaded with 500 mg (1.36 mmol) of 2-
cyanopyridine 9 and 2.7 mg (0.011 mmol) of CpCo(cod). Toluene
(10 mL) was added to the mixture, and the vessel was connected
to an acetylene delivering and measuring device providing a
constant pressure of acetylene. Alternatively, acetylene may simply
be bubbled through the solution. The mixture was irradiated by
two 460 W Phillips HPM-12 lamps (420 nm) for 5 h. The reaction
was quenched by switching off the lamps and simultaneously
introducing air. The obtained reaction mixture was filtered and
chromatographed on silica gel (eluent used was toluene–EtOAc
5 : 1) to give ligand 1a (456 mg, 80%) as a white solid.
Trans-(3R,13bS,aS)-13b-methyl-3-phenyl-2,3-dihydro-13bH-
benz[c]oxazolo[3,2-a](6-chloropyrido)[2,3-e]azepin-5-one (5a). To
a solution of dry N-oxide 4 (200 mg, 0.55 mmol) in CH2Cl2 (5 mL)
were added triethylamine (94 lL, 0.67 mmol) and phosphorus
oxychloride (62 lL, 67 mmol). The mixture was stirred for 30 min,
refluxed for 1 hour and then cooled to room temperature. The
solution was neutralized with a 2M NaOH aqueous solution.
After phase separation, the aqueous layer was extracted twice with
CH2Cl2. The combined organic layers were dried over MgSO4 and
solvent was evaporated under vacuum. Flash chromatography of
the residue on silica gel (eluent used was EtOAc–cyclohexane 1 : 9)
provided 2-chloropyridine 5a (63 mg, 30%) and 4-chloropyridine
5b (36 mg, 20%). Compound 5a was obtained as a white solid.
◦
1
Mp 82 C. H NMR 300 MHz, (CDCl3) d 8.07 (d, J = 7.9 Hz,
1H), 8.02 (m, 1H), 7.60 (m, 1H), 7.45 (m, 4H), 7.17–7.34 (m,
4H), 5.32 (d, J = 5.6 Hz, 1H), 4.34 (dd, J = 8.7 Hz and 6.0 Hz,
1H), 4.23 (d, J = 8.7 Hz, 1H), 1.54 (s, 3H). 13C NMR 75 MHz,
(CDCl3) d 162.7, 154.3, 153.8, 142.3, 142.2, 140.7, 134.4, 132.3,
130.8, 129.4, 129.1, 128.6, 128.3, 127.5, 123.8, 122.6, 94.1, 71.4,
62.5, 27.3. IR tmax cm−1 (KBr): 1635, 1571, 1409, 1183, 1092, 764,
698. Anal. Calc. for C22H17ClN2O2: C, 70.12; H, 4.55; N, 7.43.
Found: C, 70.25; H, 4.58; N, 7.48. [a]2D0 = +48.1(c = 0.77, CH2Cl2).
Compound 5b was obtained as a white solid. Mp 68 ◦C. 1H NMR
300 MHz, (CDCl3) d 8.59 (d, J = 8.0 Hz, 1H), 8.03 (m, 1H), 7.57
(m, 1H), 7.18–7.46 (m, 8H), 5.49 (d, J = 6.4 Hz, 1H), 4.39 (dd, J =
6.8 Hz and 9.0 Hz, 1H), 4.22 (dd, J = 9.0 Hz and 1.1 Hz, 1H), 1.50
(s, 3H). 13C NMR 75 MHz, (CDCl3) d 160.8, 155.0 151.4, 144.6,
142.9, 140.61 135.3, 131.9, 130.5, 129.4, 129.1, 129.0, 128.1, 126.6,
124.7, 122.8, 94.6, 71.5, 61.0, 26.7. IR tmax cm−1 (KBr): 2924, 2361,
1645, 1384, 1038, 758. Anal. Calc. for C22H17ClN2O2: C, 70.12; H,
4.55; N, 7.43. Found: C, 69.94; H, 4.38; N, 7.51. [a]2D0 = −16.7 (c =
0.12, CH2Cl2).
6,6ꢀ-Bis(trans-(3R,13bS,aS)-13b-methyl-3-phenyl-2,3-dihydro-
13bH-benz[c]oxazolo[3,2-a]pyrido[2,3-e]azepin-5-one
(1b). To
a stirred solution of nickel(II) chloride hexahydrate (64 mg,
0.27 mmol) and triphenylphosphine (283 mg, 1.08 mmol) in dry,
degassed DMF (1 mL) was added zinc dust (<10 lm, 23 mg,
0.35 mmol). The resulting suspension was heated at 60 ◦C for
1 hour. A solution of 2-chloropyridine 5a (100 mg, 0.27 mmol)
in dry, degassed DMF (1 mL) was then added. The resultant
mixture was heated at 60 ◦C for 4 hours. The reaction mixture
was then allowed to cool to room temperature and was poured
into 10% aqueous ammonium hydroxide (50 mL). The resultant
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined
organic phases were dried over MgSO4 and concentrated in vacuo.
Flash chromatography of the residue on silica gel (eluent used
was EtOAc–cyclohexane 1 : ◦4) provided ligand 1b (55 mg, 61%)
1
as a white powder. Mp 312 C. H NMR 300 MHz, (CDCl3) d
Trans-(3R,13bS,aS)-13b-methyl-3-phenyl-2,3-dihydro-13bH-
8.70 (d, J = 8.3 Hz, 2H), 8.36 (d, J = 8.3 Hz, 2H), 8.31 (dd, J =
1.9 Hz and 7.5 Hz, 2H), 7.72 (dd, J = 7.5 Hz and 1.5 Hz, 2H),
7.53–7.66 (m, 8H), 7.30–7.45 (m, 6H), 5.45 (d, J = 5.6 Hz, 2H),
4.47 (dd, J = 8.7 Hz and 6.0 Hz, 2H), 4.33 (d, J = 8.6 Hz, 2H),
1.62 (s, 6H). 13C NMR 75 MHz, (CDCl3) d 163.6, 157.3, 153.2,
142.3, 141.0, 140.6, 135.8, 132.4, 130.4, 130.2, 129.3, 129.1, 128.2,
127.6, 122.6, 120.9, 94.2, 62.5, 27.4. IR tmax cm−1 (KBr): 2367,
1637, 1406, 1037, 696. Anal. Calcd. for C44H34N4O4: C, 77.40; H,
5.02; N, 8.21. Found: C, 77.24; H, 5.17; N, 8.16. [a]2D0 = −51.4
(c = 1.09, CH2Cl2).
benz[c]oxazolo[3,2-a]-6-(2-pyridyl)pyrido[2,3-e]azepin-5-one (1a).
By Stille cross-coupling reaction of 2-chloropyridine 5a with
2-(tributylstannyl)pyridine. To a solution of 2-chloropyridine
5a (752 mg, 2 mmol) and 2-(tributylstannyl)pyridine (736 mg,
2 mmol) in toluene (15 mL) was added Pd[(PPh3)]4 (0.167 g,
0.136 mmol). The resulting solution was refluxed for 24 h, after
which the solution was filtered and evaporated under vacuum
to afford a brown solid. The residue was purified by flash
chromatography on silica gel (eluent used was EtOAc–cyclohexane
1 : 5) to give ligand 1a (250 mg, 30%) as a white solid. Mp 216 ◦C.
1H NMR 300 MHz, (CDCl3) d 8.65 (d, J = 4.9 Hz, 1H), 8.56 (d,
J = 7.8 Hz, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.28 (d, J = 8.3 Hz,
1H), 8.2 (m, 1H), 7.80 (dt, J = 7.9 and 1.5 Hz, 1H), 7.65 (m,
1H), 7.50 (m, 4H), 7.30 (m, 4H), 5.40 (d, J = 8.9 Hz, 1H), 4.40
(d, J = 8.9 Hz, 1H), 4.25 (d, J = 8.9 Hz, 1H), 1.60 (s, 3H). 13C
NMR 75 MHz, (CDCl3) d 163.7, 158.1, 155.6, 152.9, 149.7, 142.3,
140.9, 140.4, 137.4, 136.0, 132.2, 130.2, 129.6, 129.2, 129.1, 128.1,
127.5, 124.9, 122.5, 122.2, 120.1, 94.2, 71.4, 62.4, 27.3. IR tmax cm−1
6-Chloro-2,2ꢀ-bipyridine (6). To a solution of 2,6-dichloro-
pyridine (6.03 g, 40.76 mmol) and 2-(tributylstannyl)-
pyridine (5 g, 13.58 mmol) in degassed toluene (50 mL) was added
Pd[(PPh3)]4 (0.784 g, 0.679 mmol). The resulting solution was
refluxed for 24 h under nitrogen, after which the solution was
filtered and evaporated under vacuum to afford a brown solid.
The residue was purified by flash chromatography on silica gel
(eluent used was EtOAc–cyclohexane 1 :◦5) to give 2,2ꢀ-bipyridine
1
6 (1.78 g, 69%) as a white solid. Mp 62 C. H NMR 300 MHz,
1402 | Org. Biomol. Chem., 2007, 5, 1397–1404
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(CDCl3) d 8.57 (d, J = 4.1 Hz, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.25
(d, J = 7.9 Hz, 1H), 7.72 (t, J = 4.1 Hz, 1H), 7.67 (t, J = 7.9 Hz,
1H), 7.24–7.20(m, 2H). 13CNMR75 MHz, (CDCl3) d 157.2, 154.9,
151.3, 149.6, 139.9, 124.65, 124.6, 121.8, 119.8. IR tmax cm−1 (KBr):
3061, 1583, 1427, 1135. Anal. Calc. for C10H7ClN2: C, 63.01; H,
3.70; N, 14.70. Found: C, 63.03; H, 3.74; N, 14.66.
a 10% K2CO3 aqueous solution. After phase separation, the
aqueous phase was extracted with CH2Cl2 (2 × 5 mL). The
combined dichloromethane layers were dried (MgSO4) and rotary
evaporated. Flash chromatography of the residue (eluent used was
EtOAc–cycloh◦exane 1 : 1) provided 9 as a white solid (198 mg,
1
97%). Mp 91 C. H NMR 300 MHz, (CDCl3) d 8.20 (d, J =
7.9 Hz, 1H), 8.02 (m, 1H), 7.60 (m, 2H), 7.44 (m, 4H), 7.25 (m,
3H), 5.31 (d, J = 5.7 Hz, 1H), 4.33 (dd, J = 9.0 Hz and 6.0 Hz,
1H), 4.22 (d, J = 9.0 Hz, 1H), 1.48 (s, 3H). 13C NMR 75 MHz,
(CDCl3) d 161.4, 154.5, 141.8, 140.2, 139.8, 135.2, 133.4, 131.9,
130.7, 129.0, 128.6, 127.8, 126.9, 126.6, 122.2, 116.5, 93.4, 70.9,
62.0, 27.0. IR tmax cm−1 (KBr): 1640, 1416, 1240, 1037, 765, 699.
Anal. Calc. for C23H17N3O2: C, 75.19; H, 4.66; N, 11.44. Found:
C, 75.26; H, 4.65; N, 11.26. [a]2D0 = +35.9 (c = 0.39, CH2Cl2).
6-Chloro-2,2ꢀ-bipyridine-5-carboxylic acid ethyl ester (7). To
a solution of diisopropylamine (156 mg, 1.54 mmol) in dry THF
(3 mL) was added under nitrogen at 0 ◦C a solution of butyllithium
in hexanes (0.62 mL, 2.5 M, 1.54 mmol). The resulting solution
was stirred for 15 min before being added to a solution of 2,2ꢀ-
bipyridine 6 (100 mg, 0.516 mmol) in THF (3 mL) at −78 ◦C. The
solution was stirred at this temperature for 1 h, after which a
solution of ethyl cyanoformate (205 mg, 2.06 mmol) in dry THF
(8 mL) was added. After being stirred for 2 h at −78 ◦C, the
solution was quenched with water (10 mL). After phase separation,
the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried (MgSO4), and the solvent
was evaporated under vacuum. The resulting brown solid was
recrystallized from methanol–water (1 : 1) to afford white crystals
(83 mg, 65%). Mp 98 ◦C. 1H NMR 300 MHz, (CDCl3) d 8.62 (d,
J = 4.5 Hz, 1H), 8.40–8.34 (m, 2H), 8.21 (d, J = 7.9 Hz, 1H), 7.77
(t, J = 7.9 Hz, 1H), 7.30 (t, J = 4.5 Hz, 1H), 4.38 (q, J = 7.2 Hz,
2H), 1.37 (t, J = 7.2 Hz, 3H). 13C NMR 75 MHz, (CDCl3) d 165.0,
158.8, 154.0, 149.8, 141.65, 137.5, 125.3, 122.5, 119.4, 62.4, 14.6.
IR tmax cm−1 (KBr): 3050, 1731, 1585, 1435, 1151. Anal. Calc. for
C13H11ClN2O2: C, 59.44; H, 4.22; N, 10.66. Found: C, 59.42; H,
4.15; N, 10.54.
Trans-(3R,13bS,aS)-13b-methyl-3-phenyl-2,3-dihydro-13bH-
benz[c]oxazolo[3,2-a](6-(4,5-dihydro-4,4-dimethyloxazol-2-yl))-
pyrido[2,3-e]azepin-5-one (2a) (procedure B). To a solution of dry
ZnCl2 (5.6 mg, 0.04 mmol) in chlorobenzene (5 mL) was added
under nitrogen cyanopyridine 9 (150 mg, 0.41 mmol) and 2-amino-
2-methylpropanol (40 mg, 0.45 mmol). The mixture was refluxed
for 2 days under nitrogen and then cooled to room temperature.
Water (10 mL) was added. After phase separation, the aqueous
phase was extracted with CH2Cl2 (2 × 20 mL). The organic phase
was dried (MgSO4) and the solvent evaporated under vacuum.
Flash chromatography on silica gel (eluent used was EtOAc–
cyclohexane 3 : 7) furnished ligand 2a as a white powder (162 mg,
◦
1
90%). Mp 95 C. H NMR 300 MHz, (CDCl3) d 8.29 (d, J =
1.9 Hz, 1H), 8.13–8.17 (m, 2H), 7.65 (m, 1H), 7.50–7.56 (m, 4H),
7.32–7.42 (m, 3H), 5.43 (d, J = 5.6 Hz, 1H), 4.44 (dd, J = 8.6 Hz
and 4.0 Hz, 1H), 4.32 (d, J = 8.7 Hz, 1H), 4.25 (s, 2H), 1.58 (s,
3H), 1.45 (s, 3H), 1.42 (s, 3H). 13C NMR 75 MHz, (CDCl3) d 163.1,
161.2, 153.7, 149.3, 142.1, 140.7, 140.0, 135.4, 132.6, 131.1, 130.3,
129.5, 129.1, 128.2, 127.5, 123.1, 122.3, 94.2, 80.2, 71.4, 68.6, 62.4,
30.6, 28.8, 27.3. IR tmax cm−1 (KBr): 1638, 1415, 1364, 1086, 733.
Anal. Calc. for C27H25N3O3: C, 73.78; H, 5.73; N, 9.56. Found: C,
73.83; H, 5.80; N, 9.45. [a]2D0 = +15.8 (c = 0.38, CH2Cl2).
6-(2-Acetylphenyl)-2,2ꢀ-bipyridine-5-carboxylic acid ethyl ester
(8). To a solution of 2,2ꢀ-bipyridine 7 (150 mg, 0.57 mmol) in
toluene (15 mL) and ethanol (1.2 mL), 2-acetylphenylboronic acid
(103 mg, 0.63 mmol) and K2CO3 aqueous solution (0.414 g in
1.5 mL of water) were added. The mixture was degassed under a N2
flow for 30 min. After adding Pd[(PPh3)]4 (58 mg, 5%) the mixture
was degassed under a N2 flow for a further 15 min. The mixture
was stirred at reflux under an inert atmosphere for 48 h, cooled
to room temperature and filtered through a plug of celite. Toluene
was removed, Et2O (100 mL) was added and the organic layer
was extracted with water (50 mL). After drying over MgSO4, the
solvents were removed under vacuum, and the residue was purified
by flash chromatography (eluent used was EtOAc–cyclohexane 1 :
1) to afford 8 (130 mg, 66%) as a yellow oil. 1H NMR 300 MHz,
(CDCl3) d 8.60 (d, J = 4.2 Hz, 1H), 8.40 (d, J = 8.3 Hz, 1H),
8.28 (m, 2H), 7.70 (m, 2H), 7.43 (m, 2H), 7.22 (m, 2H), 4.08 (q,
J = 7.2 Hz, 2H), 2.18 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR
75 MHz, (CDCl3) d 201.6, 166.8, 159.8, 155.2, 149.6, 141.2, 137.5,
124.8, 122.5, 119.4, 61.7, 30.1, 14.6. Anal. Calc. for C21H18N2O3:
C, 72.82; H, 5.24; N, 8.09. Found: C, 72.77; H, 5.30; N, 8.06.
Trans-(3R,13bS,aS)-13b-methyl-3-phenyl-2,3-dihydro-13bH-
benz[c]oxazolo[3,2-a]-6-[(R)-4,5-dihydro-4-phenyloxazol-2-yl]-
[2,3-e]azepin-5-one (2b) (procedure C). To
a solution of
methanol–THF (6 mL, 5 : 1) was added cyanopyridine 9 (200 mg,
0.54 mmol) and sodium methylate (8.8 mg, 0.16 mmol). The
mixture was stirred at room temperature for one day. Water
(10 mL) was added and after phase separation, the aqueous phase
was extracted with CH2Cl2 (15 mL). The organic solvents were
evaporated under vacuum. To the resulting residue was added (R)-
phenylglycinol (164 mg, 1.2 mmol) and chlorobenzene (10 mL)
and the mixture was refluxed for 24 hours. After evaporation of
the solvent, flash chromatography of the crude product (eluent
used was cyclohexane–EtOAc 7 : 3) provided ligand 2b (210 mg,
Trans-(3R,13bS,aS)-13b-methyl-3-phenyl-2,3-dihydro-13bH-
benz[c]oxazolo[3,2-a](6-cyanopyrido)[2,3-e]azepin-5-one (9) (proce-
dure A). To a solution of N-oxide 4 (200 mg, 0.56 mmol)
in CH2Cl2 (2 mL) was added trimethylsilyl cyanide (61 mg,
0.61 mmol) and dimethylcarbamoyl chloride (53 lL, 0.55 mmol).
The mixture was stirred at room temperature for 2 days, after
which the same amount of dimethylcarbamoyl chloride and
cyanotrimethylsilane were added and the solution was allowed
to stir for a further 2 days. The mixture was treated with
◦
1
79%) as a white solid. Mp 94 C. H NMR 300 MHz, (CDCl3)
d 8.34–8.19 (m, 3H), 7.68 (m, 1H), 7.57–7.51 (m, 4H), 7.43–7.29
(m, 8H), 5.53–5.44 (m, 2H), 4.94 (dd, J = 10.4 and 8.7 Hz, 1H),
4.46 (m, 2H), 4.34 (dd, J = 10.9 and 0.8 Hz, 1H), 3.10 (s, 3H).
13C NMR 75 MHz, (CDCl3) d 163.9, 163.1, 153.8, 148.9, 142.2,
142.0, 140.7, 140.2, 135.3, 132.5, 131.4, 130.4, 129.6, 129.3, 129.1,
128.3, 128.2, 127.5, 127.3, 123.4, 122.4, 94.2, 76.0, 71.4, 70.9, 62.4,
27.4. IR tmax cm−1 (KBr): 2926, 1638, 1417, 1367. HRMS calc. for
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C31H26N3O3 [MH+]: 488.1973, found: 488.1973. [a]2D0 = +60.6 (c =
Notes and references
1.04, CH2Cl2).
1 For reviews on the preparation and applications in asymmetric catalytic
synthesis of 2,2ꢀ-bipyridyl ligands, see: (a) N. C. Fletcher, J. Chem. Soc.,
Perkin Trans. 1, 2002, 1831; (b) G. Chelucci and R. P. Thummel, Chem.
Rev., 2002, 102, 3129.
2 C. Botteghi, A. Schionato and O. De Lucchi, Synth. Commun., 1991,
21, 1819.
Trans-(3R,13bS,aS)-13b-methyl-3-phenyl-2,3-dihydro-13bH-
benz[c]oxazolo[3,2-a]-6-[(S)-4,5-dihydro-4-phenyloxazol-2-yl]-
[2,3-e]azepin-5-one (2c). Prepared as described for 2b according
to procedure C from cyanopyridine 9 (200.0 mg, 0.54 mmol) and
(S)-phenylglycinol (82.2 mg, 0.60 mmol). Flash chromatography
(eluent used was EtOAc–cyclohexane 3 : 7) of the crude product
afforded ligand 2c (223 mg, 84%) as a white solid. Mp 106 ◦C.
1H NMR 300 MHz, (CDCl3) d 8.34–8.19 (m, 3H), 7.67 (m, 1H),
7.57 (m, 4H), 7.43–7.30 (m, 8H), 5.51 (dd, J = 10.1 and 9.0 Hz,
1H), 5.45 (d, J = 6.0 Hz, 1H), 4.96 (dd, J = 10.3 and 8.9 Hz,
1H), 4.48–4.40 (m, 2H), 4.33 (d, J = 8.7 Hz, 1H), 1.62, (s, 3H).
13C NMR 75 MHz, (CDCl3) d 163.8, 163.1, 153.8, 148.9, 142.2,
142.0, 140.7, 140.2, 135.3, 132.5, 131.4, 130.4, 129.6, 129.3, 129.1,
128.3, 128.2, 127.5, 127.3, 123.4, 122.4, 94.2, 76.0, 71.4, 70.9, 62.5,
27.4. IR tmax cm−1 (KBr): 2924, 2851, 1635, 1416, 1366. Calcd. for
C31H25N3O3: C, 76.37; H, 5.17; N, 8.62. Found: C, 76.30; H, 5.29;
N, 8.54. [a]2D0 = −28.6 (c = 0.28, CH2Cl2).
General procedure for asymmetric cyclopropanation catalyzed by
ligand–Cu(I) complexes. A solution of the ligand (0.03 mmol)
and Cu(TfO)2 (9 mg, 0.025 mmol) in CH2Cl2 (1 mL) was stirred
under a nitrogen atmosphere at 20 ◦C for 1 hour. Phenylhydrazine
(3 lL, 0.03 mmol) was then added, and the color of the
solution changed from light green to deep red. After 10 min,
alkene (4.37 mmol) was added. A solution of the corresponding
diazoester (ethyldiazoacetate or t-butyldiazoacetate) (2.5 mmol)
in dry CH2Cl2 was added over ca. 5 hours via a syringe pump.
After the addition was complete, the reaction was stirred for an
additional 12 h. The reaction was then concentrated in vacuo
to afford the crude product. Conversion was determined by
1H NMR. Flash chromatography of the residue (Eluent used
was EtOAc–cyclohexane 1 : 24) provided a mixture of trans/cis
isomers. The trans/cis ratio and enantiomeric excess of each
isomer were determined by chiral GC (Chiraldex CB 25 m ×
0.25 mm) after filtration on silica gel.
3 T. Shimada, A. Kina and T. Hayashi, J. Org. Chem., 2003, 68, 6329.
4 For recent investigations of pymox ligands in asymmetric catalytic pro-
cesses, see: (a) G. Chelucci, M. G. Sanna and S. Gladiali, Tetrahedron,
2000, 56, 2889; (b) W. Xu, A. Kong and X. Lu, J. Org. Chem., 2006, 71,
3854; (c) D. W. Dodd, H. E. Toews, F. D. S. Carneiro, M. C. Jennings
and N. D. Jones, Inorg. Chim. Acta, 2006, 359, 2850; (d) H. Brunner,
H. B. Kagan and G. Kreutzer, Tetrahedron: Asymmetry, 2003, 14, 2177;
(e) Q. Zhang, X. Lu and X. Han, J. Org. Chem., 2001, 66, 7676; (f) H.
Brunner, R. Sto¨riko and F. Rominger, Eur. J. Inorg. Chem., 1998, 6,
771.
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10 Crystal, X-ray data collection and refinement parameters for 1a‡.
Formula: C27H21N3O2; chemical formula weight: 419.47 g mol−1; crystal
system: orthorhombic; space group: P212121; unit-cell dimensions: a =
3
˚
˚
˚
˚
10.052(2) A, b = 15.052(3) A, c = 42.205(8) A, V = 6386(2) A ; T (K) =
rt; Zꢀ = 3; F(000) = 2640 e−; l = 0.084 mm−1; number of independent
reflexions : 8869; Rint = 0.0339, R1 = 0.0684 & wR2 = 0.1820 for 6491
reflections with I > 2rI.
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Acknowledgements
We thank the CNRS, the re´gion Haute-Normandie and the
CRIHAN for financial and technical support. A. B. thanks the
MRT for a grant.
1404 | Org. Biomol. Chem., 2007, 5, 1397–1404
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