Screening of N,N-bidentate and N,N,Ntridentate pyridine-based ligands in the catalytic allylic oxidation of cyclic olefins

Article abstract of DOI:10.1002/aoc.3222

A variety of chiral N,N-bidentate and N,N,N-tridentate ligands based on the pyridine framework, namely C2-symmetric dipyridylmethane and terpyridine, N-(p-toluensulfinyl)iminopyridines and two kinds of iminopyridines, has been assessed in the asymmetric c

Full text of DOI:10.1002/aoc.3222

Full Paper
Received: 10 June 2014
Revised: 15 July 2014
Accepted: 24 August 2014
Published online in Wiley Online Library: 23 September 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3222
Screening of N,N-bidentate and N,N,N-
tridentate pyridine-based ligands in the
catalytic allylic oxidation of cyclic olefins
Maurizio Solinasa*, Barbara Sechia and Giorgio Cheluccib
A variety of chiral N,N-bidentate and N,N,N-tridentate ligands based on the pyridine framework, namely C2-symmetric
dipyridylmethane and terpyridine, N-(p-toluensulfinyl)iminopyridines and two kinds of iminopyridines, has been assessed in
the asymmetric copper(I)-catalysed allylic oxidation of cyclic olefins. Catalytic activity and enantioselectivity were found to be
highly dependent upon the framework of the ligands, which afforded cycloalkenyl benzoates in low to moderate yields and
enantioselectivities. The best yields (up to 70%) and enantioselectivities (up to 53% enantiomeric excess) were obtained with
an iminopyridine based on camphane and quinoline skeletons. Copyright © 2014 John Wiley & Sons, Ltd.
Keywords: allylic oxidation; N,N-bidentate ligands; N,N,N-tridentate ligands; copper; enantioselectivity
Introduction
Experimental
General Remarks
The copper-catalysed allylic oxidation of olefins with peresters to
give allylic esters (also known as the Kharasch–Sosnovsky
reaction)[1] represents a valid method for the synthesis of allylic
alcohols that may be obtained by subsequent saponification or
reduction of the esters (Scheme 1).[2] The enantioselective ver-
sion of this reaction provides access to chiral allylic alcohols,[3]
which are key intermediates in natural product synthesis.[4]
Among the ligands developed for this asymmetric process, a
variety of pyridine-based ligands have been shown to be efficient.[5]
Among them, several examples of chiral 2,2′-bipyridines,[6] 1,10-
phenanthrolines[7] and recently iminopyridines[8] have been reported.
Ligand syntheses and catalytic allylic oxidation reactions were car-
ried out under nitrogen atmosphere in oven-dried glassware with
magnetic stirring. Unless otherwise noted, all materials were ob-
tained from commercial suppliers and were used without further
purification. All solvents were of HPLC grade. 1H NMR and 13C
NMR spectra were recorded using a Varian Mercury (1H, 400.1 MHz;
13C, 100.6 MHz) with tetramethylsilane as reference. Ligands 4,[10]
5,[11] 6a–d,[12] 7a–e,[13] 8a–d[14] and 8f[13,15] were prepared according
to reported procedures.
The group of Kocovsky and Malkov reported that Cu(I) com-
plexes of chiral C2-symmetric 2,2′-bipyridines are very efficient cat-
alysts in this process. Thus, for instance, allylic oxidation of
cyclohexene with the bipyridine 1 (Fig. 1) led to cyclohexenyl ben-
zoate in 96% yield within a very short reaction time (≤30 min at
room temperature), though with a moderate enantioselectivity
Typical Procedure for Allylic Oxidation
A solution of the ligand (0.06 mmol) and Cu(OTf)2 (18 mg,
0.05 mmol) in dry acetone (4 ml) was stirred under a nitrogen atmo-
sphere at 20 °C for 1 h. Phenylhydrazine (5.9μl, 0.06 mmol) was then
added. After 10 min, the appropriate cyclic olefin (5mmol) was
added, followed by the dropwise addition of tert-butyl
peroxybenzoate (0.2ml, 1.0mmol). The progress of the reaction
was monitored using TLC (hexane–ethyl acetate= 20/1). Disappear-
ance of the peroxyester indicated the completion of the reaction.
The solvent was removed under vacuum and the residue taken
up with CH2Cl2 (15 ml). The organic solution was washed succes-
sively with a saturated aqueous NaHCO3 solution, brine and finally
(49% enantiomeric excess, ee).[6f]
A slight increase of the
stereoselectivity (53% ee), with unchanged catalytic efficiency, was
obtained by us by the introduction of the related phenanthroline 2
(85% yield, ≤30 min)[7b] (Fig. 1). Similar results have been recently
obtained by Tan and Hayashi with iminopyridine ligands 3. The
quinoline 3a was the best performing ligand affording cyclohexenyl
benzoate in 89% yield with 51% ee (Fig. 1).[8]
In our ongoing research efforts aimed at the application of
chiral ligands based on the pyridine framework to asymmetric
catalysis,[9] and in particular to the allylic oxidation of olefins,[7]
we became interested to determine the potential of a variety
of chiral N,N-bidentate and N,N,N-tridentate ligands, included
in this category, in the asymmetric Cu(I)-catalysed allylic
oxidation of cyclic alkenes. In this paper we report the results
obtained using ligands 4–8 whose general structures are
depicted in Fig. 2.
*
Correspondence to: Maurizio Solinas, CNR, Istituto di Chimica Biomolecolare UOS
Sassari, Traversa La Crucca 3, 07100 Sassari, Italy. E-mail: maurizio.solinas@icb.
cnr.it
a CNR, Istituto di Chimica Biomolecolare UOS Sassari, Traversa La Crucca 3, 07100,
Sassari, Italy
b Dipartimento di Agraria, Università di Sassari, Viale Italia 39, 07100, Sassari, Italy
Appl. Organometal. Chem. 2014, 28, 831–834
Copyright © 2014 John Wiley & Sons, Ltd.

M. Solinas et al.
concomitant aromatization of the 1,5-dicarbonyl intermediates.
N-(p-toluensulfinyl)iminopyridines 6a–d (Fig. 3) were obtained by
condensation of commercially available (S)-(+)-N-p-toluenesulfinamide
with pyridine-2-carboxaldehyde or pyridyl ketones.[12] Iminopyridines
7a–e (Fig. 4) were formed in one step by reaction of
quinoline-8-carbaldehyde with chiral amines in
diethyl ether containing anhydrous K2CO3 at room
temperature.[13] Iminopyridines 8a–d (Fig. 5) were
obtained from chiral ketones, (1R)-(+)-camphor or
(1R)-fenchone, and aminoalkylpyridine derivatives
in the presence of a catalytic amount of BF3ꢁOEt2,[14]
while aminopyridine 8e (Fig. 5) was formed by double
alkylation with n-BuLi and MeI of the benzylic position
of 8a.[14] Ligand 8f (Fig. 5) was prepared by reaction of
8-aminoquinoline with (1R)-(+)-camphor.[13,15]
Scheme 1. General scheme for copper-catalysed allylic oxidation.
Figure 1. Examples of pyridine-based ligands applied to the enantioselective allylic
oxidation of olefins.
Cu(I)-Catalysed Asymmetric Allylic Oxidation
The reaction conditions selected to carry out the cat-
alytic oxidation are those reported for bipyridines
and iminopyridines.[6f,8] The protocol entails the re-
action of the ligand with Cu(OTf)2 to give a Cu(II)
complex which is then reduced in situ with
phenylhydrazine to the related Cu(I) species. The ox-
idation reaction is then carried out with tert-butyl
peroxybenzoate in the presence of the catalyst
(1.0 mol%) and alkene (Scheme 2). Cyclohexene
was used as a representative substrate to compare
the catalytic activity and stereodifferentiating ability
of all examined ligands.
Starting our investigation we assessed the two
C2-symmetric ligands 4[10] and 5[11] that share
with the bipyridine 1 the same chiral framework
(Fig. 2). It has been recognized that to obtain an
effective transfer of chiral information from cata-
Figure 2. N,N-bidentate and N,N,N-tridentate pyridine-based ligands employed in this work.
lyst to product it is necessary a close interaction between the sub-
strate and the chiral ligand in the intermediate metal complex.
This can be obtained by a careful ligand design that would involve,
among various factors, the change of the chelate ring size of the
metal complex and consequently the ligand bite angle. As these
parameters increase, the substituents on the stereocentres are
pushed towards the substrate and so the chiral recognition is
generally enhanced. As an example of this strategy, we prepared
the dipyridylmethane 4 by introducing an isopropylidene back-
bone between the two pyridine rings of the bipyridine 1.[10]
with water. The organic solution was dried over anhydrous Na2SO4
and the solvent was evaporated. The residue was purified by chro-
matography on silica gel (petroleum ether–ethyl acetate = 20/1).
The ee was determined by HPLC (Phenomenex Lux5u Cellulose-3
column), hexane 100, 0.5 ml minꢀ1. tr: 16.3 min, (R)-cyclopent-2-
en-1-yl benzoate; 17.9 min, (S)-cyclopent-2-en-1-yl benzoate;
17.8 min, (R)-cyclohex-2-en-1-yl benzoate, 18.9min, (S)-cyclohex-2-
en-1-yl benzoate; 19.2 min, (R)-cyclohept-2-en-1-yl benzoate;
20.4 min, (S)-cyclohept-2-en-1-yl benzoate; 23.7min, (R)-cyclooct-
2-en-1-yl benzoate; 25.5min, (S)-cyclooct-2-en-1-yl benzoate.
Results and Discussion
Synthesis of Ligands
Dipyridylmethane 4[10] and terpyridine 5[11] (Fig. 2) were prepared
by reaction of the lithium enolates of methyl ketones with
(1R,5R)-3-methylenenopinone, followed by azaanellation with
Figure 4. Iminopyridines based on 2-quinoline framework employed in
Figure 3. N-(p-toluensulfinyl)iminopyridines used in this work.
this work.
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Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 831–834

Pyridine-based ligands for catalytic allylic oxidation
Table 1. Asymmetric allylic oxidation of cycloalkenes catalysed by Cu
(I)–L* complexesa (Scheme 2)
Entry Olefin Ligand Time (h) Yield (%)b ee (%)c Configurationd
1
11b
11b
11b
11b
11b
11b
11b
11b
11b
11b
11b
11b
11b
11b
11b
11b
11b
11a
11c
11d
4
168
168
48
48
120
96
48
24
24
48
24
24
24
48
24
48
24
24
24
24
38
—
51
23
30
52
44
77
69
65
71
51
57
37
65
37
63
70
44
24
3
—
6
S
—
R
2
5
3
6a
6b
6c
6d
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
8f
4
5
R
5
3
R
6
0
—
—
S
7
0
8
5
Figure 5. Iminopyridines based on (1R)-(+)-camphor and (1R)-fenchone
employed in this work.
9
22
3
S
10
11
12
13
14
15
16
17
18
19
20
R
9
S
14
3
S
S
5
S
15
0
R
—
S
51
40
53
34
8f
S
8f
S
Scheme 2. Copper-catalysed asymmetric allylic oxidation of cyclic olefins.
8f
S
aSee experimental section for details of the allylic oxidation reactions.
bIsolated yields are based on the converted tert-butyl peroxybenzoate.
cDetermined using chiral HPLC (see experimental section for details).
dThe assignment is based on the sign of the optical rotation.[17]
Unfortunately, this ligand gives a Cu(I) complex that shows very
low catalytic activity in the allylic oxidation of cyclohexene,
affording almost racemic cyclohexenyl benzoate in 38% yield after
a week (Table 1). A poorer result is obtained with the N,N,N-
tridentate terpyridine 5 that provides the related Cu(I) species de-
void of any catalytic activity even after a prolonged reaction time
(168 hours). The results obtained with these ligands are rather dis-
appointing considering that the structurally related bis(oxazoline)
9 and pyridinebis(oxazoline) 10 ligands (Fig. 2) are very active cata-
lysts in this reaction.[16]
The transfer of chiral information in the iminopyridine ligands
3 is due to the presence of a stereogenic carbon bonded to the
imino nitrogen. In analogy, we decided to test in this process
the structural analogue N-(p-toluensulfinyl)iminopyridines 6[12]
in which a stereogenic sulfur replaces the chiral carbon on the
imino group (Fig. 3). The simple ligand 6a affords cyclohexenyl
benzoate in 51% yield with very low ee (6%) after 48 h. In order
to determine the effect of the modification of the ligand frame-
work on the catalytic activity, we examined ligands 6b–d
obtained by introducing methyl or phenyl substituents on the
imino carbon and on the 6-position of the pyridine ring of the
basic structure of 6a. The increased stiffness of these ligands,
pursued to limit the conformational mobility in their Cu com-
plexes, does not improve yield and stereoselectivity (Table 1).
Nonetheless, the results obtained with these ligands are similar
to those of the iminopyridines 3 with a chiral carbon on the
imino group.[12]
five-membered chelate ring with the metal, but differ in the orien-
tation of the N¼C double bond, which is directed forward of the
pyridine ring in ligands 3 and in the opposite manner in ligands
8. The iminopyridines 8a and 8b, derived from (1R)-(+)-camphor
and (1R)-fenchone, respectively, give moderately reactive Cu(I) cat-
alysts requiring 24 h at room temperature to convert cyclohexene
into cyclohexenyl benzoate in 51 and 57% yields, respectively,
but only 8a gives a detectable stereoselectivity (14% ee; Table 1).
On this basis, we examined the iminopyridines 8c–e obtained by
modification the basic structure of 8a. In order to realize ring-size
control in the allylic oxidation, ligand 8c that contains a further
methylene unit between the pyridine ring and the imino nitrogen
was assessed. Moreover, in order to increase the reaction activity
by stiffening the framework, we examined ligands 8d and 8e that
include a methyl group on ligand 8a at the 6-position of the pyri-
dine ring or two methyl groups on the bridged methylene carbon,
respectively. However, no substantial increase in the catalytic
activity and stereoselectivity is achieved with these ligands. On
the other hand, a marked improvement of the stereoselectivity is
seen with ligand 8f in which the bridged carbon is enclosed in a
benzo-fused ring to the pyridine, forming in this way a rigid struc-
ture. With this ligand, cyclohexenyl benzoate is formed in 63% yield
and with 51% ee (Table 1).
Based on the results obtained by Hayashi and Tan with
iminopyridine ligands 3, we aimed to assess in this process the
iminoquinoline ligands 7a–e (Fig. 4), which form six-membered
chelate ring copper complexes in a rather rigid structure.[13] Unfor-
tunately, disappointing results are obtained with these ligands.
Thus, neither the yield nor the stereoselectivity is improved
compared to 3 with the exception of ligand 7c which gives
(S)-cyclohex-2-en-1-yl benzoate with 22% ee (Table 1).
Based on the above results, we finally examined the asymmetric
allylic oxidation of three other cyclic olefins, namely cyclopentene,
cycloheptene and cyclooctene, employing the best performing
ligand, 8f. The results summarized in Table 1 show that among
the examined olefins only cycloheptene affords the related oxida-
tion product with slightly higher ee (53%), although in lower yield
(44%) than cyclohexene.
We next examined iminopyridine ligands 8a–f. It should be
noted that both these ligands (n = 0) and iminopyridine 3 form a
Appl. Organometal. Chem. 2014, 28, 831–834
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M. Solinas et al.
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Conclusions
In this study we have determined for the first time the activity of a
series of chiral N,N-bidentate and N,N,N-tridentate ligands based on
the pyridine framework, namely the C2-symmetric dipyridylmethane
4 and terpyridine 5, N-(p-toluensulfinyl)iminopyridines 6 and two
kinds of iminopyridines, 7 and 8, in the asymmetric Cu(I)-catalysed
allylic oxidation of cyclic alkenes. We have demonstrated that an
increase of the chelate ring size passing from the 2,2′-bipyridine 1
to the related dipyridylmethane 4 reduces the activity of the Cu(I)
complex, which afforded low yield and stereoselectivity. The results
for terpyridine 5 also showed that it is not suitable for this catalytic
process. Unsatisfactory results were also obtained with N-(p-
toluensulfinyl)iminopyridines 6, which afforded Cu(I) complexes with
activity similar to that of the iminopyridines 3 with a chiral carbon on
the imino group. The Cu(I) complexes of iminopyridines 7 and 8 gave
also negligible outcomes. On the other hand, the Cu(I) complex of the
iminopyridine 8f, including the 2-quinoline moiety in a rigid structure,
catalyses the asymmetric allylic oxidation of various cycloolefins with
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Financial support from the Fondazione Banco di Sardegna is grate-
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