Synthesis and application in asymmetric copper(I)-catalyzed allylic oxidation of a new chiral 1,10-phenanthroline derived from pinene

Article abstract of DOI:10.1016/S0040-4039(02)00549-X

A convenient and rapid method for the preparation of chiral C₂-symmetric 1,10-phenanthrolines is reported. As an example of this procedure the synthesis of new 1,10-phenanthroline (+)-7 and its 5,6-dihydro derivative (+)-6 from (-)-β-pinene is

Full text of DOI:10.1016/S0040-4039(02)00549-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3601–3604
Synthesis and application in asymmetric copper(I)-catalyzed
allylic oxidation of a new chiral 1,10-phenanthroline
derived from pinene
Giorgio Chelucci,a,* Giovanni Loriga,b Gabriele Murineddub and Gerard A. Pinnab
aDipartimento di Chimica, Universita` di Sassari, via Vienna 2, I-07100 Sassari, Italy
bDipartimento Farmaco Chimico Tossicologico, Universita` di Sassari, Via Muroni 23, I-07100 Sassari, Italy
Received 11 October 2001; accepted 14 March 2002
Abstract—A convenient and rapid method for the preparation of chiral C2-symmetric 1,10-phenanthrolines is reported. As an
example of this procedure the synthesis of new 1,10-phenanthroline (+)-7 and its 5,6-dihydro derivative (+)-6 from (−)-b-pinene
is described. These ligands have been assessed in asymmetric copper(I)-catalyzed allylic oxidation of cycloalkenes affording
enantioselectivities up to 71%. © 2002 Published by Elsevier Science Ltd.
Enantioselective reactions based on chiral nitrogen lig-
ands are currently an actively pursued research area and
a number of bidentate-nitrogen (N–N) ligands with
sp2-nitrogen donors have been demonstrated to be useful
auxiliaries for metal-promoted asymmetric reactions
reaching high levels of stereocontrol.1
ing the synthesis and application in asymmetric catalysis
of 2,2%-bipyridines (bpys) with both C1-2 and C2-symme-
try.3 By contrast, the use of chiral 1,10-phenanthrolines4
(phens) has been limited to C1-symmetric derivatives
owing to the difficulties associated with the preparation
of the C2-symmetric controupart.4h,j,k In fact only one
example of this kind of phens has been reported4h and
used in asymmetric catalysis.2a
In this contest, there has been considerable work involv-
Scheme 1. (a) LDA, THF, −78°C, 2 h; then 2 from −78°C to slowly rt; (b) AcOH, AcONH4, THF, reflux, 2 h; (c) 10% Pd/C,
MeOH, 3 atm; (d) Swern oxidation; (e) 10% Pd/C, decaline, reflux, 3 h.
Keywords: 1,10-phenanthrolines; copper complex; allylic oxidation; enantioselectivity.
* Corresponding author. Tel.: +39-79-229539; fax: +39-79-229559; e-mail: chelucci@ssmain.uniss.it
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00549-X

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G. Chelucci et al. / Tetrahedron Letters 43 (2002) 3601–3604
probably locked in a single conformation, whereas a
certain degree of conformational mobility is allowed to
the bpy 8 on account of the inherently high flexibility of
its backbone. An intermediate situation could be possi-
ble to find in the dihydrophen 6 in which the 3,3%-bridge
can control the relative orientation of the two pyridine
rings and thus influence the shape of the chelating
bite-angle.
Herein, we report a new approach to the synthesis of
chiral C2-symmetric phens describing the preparation of
the phen (+)-7 and of its 5,6-dihydro derivative 6 in
which the chiral auxiliary, (−)-b-pinene, is present in the
form of a cycloalkeno-condensed substituent in the 2,3-
and 8,9-positions of the heterocycle.
The synthesis of phen (+)-7 begin with racemic 2-benzyl-
oxycyclohexanone 15 (Scheme 1) whose lithium enolate,
generated by treatment with LDA (THF, −78°C, 2 h),
was treated with (1R,5R)-3-methylenenopinone (2), in
turn obtained from (−)-b-pinene,6 to give by conjugate
addition an unisolated 1,5-dicarbonyl intermediate.
This intermediate underwent azaanellation with con-
comitant aromatization (AcONH4, AcOH, reflux, 2 h)
to afford the pyridine 3 (23% overall yield). Catalytic
hydrogenolysis of this benzyl derivative (Pd/C at 3 atm)
gave the carbinol 4 (92%) which was oxidized under
Swern conditions to ketone 5 (93%). Starting from this
key intermediate, the 5,6-dihydrophen (+)-67 was pre-
pared by building up the second pyridine ring in a
similar manner to that used to prepare 3 from 1 (35%
overall yield). Dehydrogenation by using a catalytic
amount of palladium on charcoal in refluxing decaline
completes the synthesis of (+)-77 (93%).
On the basis of these considerations, it appeared inter-
esting to exploit 6 and 7 as catalysts for the asymmetric
copper(I)-catalyzed allylic oxidation of cycloalkenes.8
The reaction conditions selected to carry out the cata-
lytic oxidation of cycloalkenes were those used by
Kocovsky for bpy ligands.3a,b The protocol entails the
reaction of the ligand with Cu(OTf)2 to give a Cu(II)
complex, which is then reduced in situ with phenylhy-
drazine to the corresponding Cu(I) species.9 The oxida-
tion reaction is then carried out with tert-butyl
peroxybenzoate as the oxidant in the presence of the
catalyst (1.0 mol%) and of the cycloalkene.10 The
results of the catalytic reactions are reported in Table 1.
Recently, Kocovsky et al. have reported the use of the
bipyridine (bpy) (+)-8 in the asymmetric copper(I)-cata-
lyzed allylic oxidation of cycloalkenes obtaining enan-
tioselectivities up to 62% ee in the case of cycloheptene
(75% ee at 0°C).3a,b The structure of this bpy is closely
related to those of dihydrophen 6 and phen 7, but a
distinct catalytic activity for each of these ligands could
be expected as they differ in their coordinating proper-
ties. In fact, the five-membered chelate ring resulting
from the coordination to the metal of phen 7 is most
The catalytic activity showed by ligands 6 and 7 was
greatly dependent on the ring size of the cycloalkene.
Thus, the oxidations of cyclopentene, cyclohexene and
cycloheptene were complete within <30 min at room
temperature giving the corresponding benzoate esters in
good yields. It should be noted that the reaction time
Table 1. Asymmetric allylic oxidation of cycloalkanes catalyzed by Cu(I)–L* complexesa
Entry
Olefin
Ligand
Time (h)
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
Cyclopentene
Cyclopentene
Cyclohexene
Cyclohexene
Cycloheptene
Cycloheptene
Cyclooctene
Cyclooctene
(+)-6
(+)-7
(+)-6
(+)-7
(+)-6
(+)-7
(+)-6
(+)-7
0.5
0.5
0.5
0.5
0.5
0.5
168
168
78
86
82
85
81
91
–
47
57
50
53
63
71
–
–
–
a The reaction were carried out at room temperature in Me2CO in the presence of the catalyst (1 mol%), generated in situ by reduction of
Cu(OTf)2 with PhNHNH2.10
b Isolated yields.
c Determined by chiral HPLC.10 The assignment of the absolute configuration is based on the sign of the optical rotation: Ref. 12.

G. Chelucci et al. / Tetrahedron Letters 43 (2002) 3601–3604
3603
recorded with these alkenes was significantly shorter
than most of the catalysts reported so far.9,11 On the
other hand, cyclooctene was substantially unreactive, in
fact only a trace of the reaction product was detected
after a week.
Lett. 2000, 2, 3047; (c) Wong, H. L.; Tian, Y.; Chan, K.
S. Tetrahedron Lett. 2000, 41, 7723; (d) Rios, R.; Liang,
J.; Lo, M. M.-C.; Fu, G. C. Chem. Commun. 2000, 377;
(e) Chelucci, G.; Culeddu, N.; Saba, A.; Valenti, R.
Tetrahedron: Asymmetry 1999, 10, 3537; (f) Fletcher, N.
C.; Keene, F. R.; Ziegler, M.; Stoeckli-Evans, H.;
Viebrock, H.; von Zelewsky, A. Helv. Chim. Acta 1996,
79, 119; (g) Ito, K.; Yoshitake, M.; Katsuki, T. Tetra-
hedron 1996, 3905; (h) Ito, K.; Katsuki, T. Chem. Lett.
1994, 1857; (i) Chelucci, G.; Falorni, M.; Giacomelli, G.
Tetrahedron 1992, 48, 3653; (j) Ito, K.; Tabuchi, S.;
Katsuki, T. Synlett 1992, 575; (k) Ito, K.; Tabuchi, S.;
Katsuki, T. Tetrahedron Lett. 1992, 575; (l) Bolm, C.;
Zehnder, M.; Bur, D. Angew. Chem., Int. Ed. Engl. 1990,
29, 205.
The stereoselectivity was also dependent on the struc-
ture of the cycloalkene. Thus, the enantiomeric excess
obtained in the oxidation of cyclopentene and cyclohex-
ene was modest (47–57% ee), while that afforded by
cycloheptene was moderately high (63–71% ee).
A comparison among the data obtained with ligands
6–8 appear to indicate that the increase of the stiffness
of the structure of the ligand passing from the bpy 8 to
the phen 7 has a beneficial effect on the enantioselectiv-
ity of the reaction. This fact is particularly evident
employing cycloheptene as the alkene. In this case the
enantiomeric excess of 62% obtained with the bpy 8
was substantially lower than that found with the phen 7
(71% ee).3a,b
4. (a) Gladiali, S.; Chelucci, G.; Madadu, M. T.; Gastaut,
M. G.; Thummel, R. P. J. Org. Chem. 2001, 66, 400; (b)
Chelucci, G.; Pinna, G. A.; Saba, A.; Sanna, G. J. Mol.
Catal. A 2000, 159, 423; (c) Chelucci, G.; Saba, A.;
Sanna, G.; Soccolini, F. Tetrahedron: Asymmetry 2000,
11, 3427; (d) Chelucci, G.; Thummel, R. P. Synth. Com-
mun. 1999, 29, 1665; (e) O’Neill, D.; Helquist, P. Org.
Lett. 1999, 1, 1659; (f) Riesgo, E. C.; Credi, A.; De Cola,
L.; Thummel, R. P. Inorg. Chem. 1998, 37, 2145; (g)
Chelucci, G.; Saba, A. Tetrahedron: Asymmetry 1998, 9,
2575; (h) Pen˜a-Cabrera, E.; Norrby, P.-A.; Sjgo¨ren, M.;
Vitagliano, A.; De Felice, V.; Oslob, J.; Ishii, S.; O’Neill,
In summary, we have described a general procedure for
the preparation of C2-symmetric phens preparing the
new dyhydrophen (+)-6 and phen (+)-7 from (−)-b-
pinene. The preliminary results obtained with the
[Cu(I)-7] complex indicate that phens are good catalysts
in asymmetric-catalyzed allylic oxidation of cycloalke-
nes. Further studies aimed at the synthesis of other
C2-symmetric phens with the hope to obtain a very
effective enantioselective catalytic system are in
progress.
,
D.; Akermark, B.; Helquist, P. J. Am. Chem. Soc. 1996,
118, 4299; (i) Gladiali, S.; Pinna, L.; Delogu, G.; De
Martin, S.; Zassinovich, G.; Mestroni, G. Tetrahedron:
Asymmetry 1990, 1, 635; (j) Kandzia, C.; Steckhan, E.;
Knoch, F. Tetrahedron: Asymmetry 1993, 4, 39; (k)
Chelucci, G.; Falorni, M.; Giacomelli, G. Tetrahedron
1992, 48, 3653; (l) Gladiali, S.; Chelucci, G.; Soccolini, F.;
Delogu, G.; Chessa, G. J. Organomet. Chem. 1989, 370,
285; (m) Gladiali, S.; Chelucci, G.; Chessa, G.; Delogu,
G.; Soccolini, F. J. Organomet. Chem. C 1987, 327, 15.
5. Wu, Y.-J.; Ding, W.-L.; Du, C.-X. Tetrahedron: Asymme-
try 1998, 9, 4035.
Acknowledgements
Thanks are due to Mr. Mauro Mucedda for experimen-
tal assistance. Financial support by M.U.R.S.T. and by
Regione
acknowledged.
Autonoma
Sardegna
is
gratefully
6. Gianini, M.; Von Zelewsky, A. Synthesis 1996, 702.
7. All compounds showed satisfactory spectroscopic and
analytical data. Compound (+)-6: mp 116–118°C; [h]D20
1
+111.5 (c 1.1 CHCl3); H NMR (CDCl3): l 7.26 (s, 2H),
References
3.29 (t, 2H, J=5.7 Hz); 3.00–279 (m, 8H); 2.69 (m, 2H);
2.29 (m, 2H); 1.40 (s, 6H); 1.30 (d, 2H, J=9.6 Hz); 0.69
(s, 6H). Compound (+)-7: mp 104–106°C; [h]2D0 +68.2 (c
1.2 CHCl3); 1H NMR (CDCl3): l 7.91 (s, 2H); 7.63 (s,
2H), 3.58 (t, 2H, J=5.7 Hz); 3.17 (m, 4H); 2.80 (m, 2H);
2.28 (m, 2H); 1.46 (s, 6H); 1.42 (d, 2H, J=9.9 Hz); 0.71
(s, 6H).
1. Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M.
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2. (a) Chelucci, G.; Gladiali, S.; Sanna, M. G.; Brunner, H.
Tetrahedron: Asymmetry 2000, 11, 3419; (b) Chelucci, G.;
Gladiali, S.; Saba, A.; Sanna, G.; Soccolini, F. Tetra-
hedron: Asymmetry 2000, 11, 3427; (c) Chelucci, G.;
Pinna, G. A.; Saba, A. Tetrahedron: Asymmetry 1998, 9,
531; (d) Collomb, P.; von Zelewsky, A. Tetrahedron:
Asymmetry 1998, 9, 3911; (e) Duboc-Toia, C.; Me´nage,
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Malkov, A. V.; Bella, M.; Langer, V.; Kocovsky, P. Org.
10. Typical procedure for allylic oxidation: a solution of the
ligand (0.06 mmol) and Cu(OTf)2 (18 mg, 0.05 mmol) in
acetone (4 ml) was stirred under a nitrogen atmosphere at
20°C for 1 h. Phenylhydrazine (5.9 ml, 0.06 mmol) was

3604
G. Chelucci et al. / Tetrahedron Letters 43 (2002) 3601–3604
then added. After 10 min, the cycloalkene was added,
perature 25°C); retention time: 18.6 min [(R)-2-
cyclopentenyl-1-benzoate] and 18.1 min [(S)-2-cyclopen-
tenyl-1-benzoate]. (b) 2-Cyclohexenyl-1-benzoate (Chiral-
cel OJ; hexane, flow 0.3 ml/min, temperature 25°C);
retention time: 32.6 min [(R)-2-cyclohexenyl-1-benzoate]
and 35.3 min [(S)-2-cyclohexenyl-1-benzoate]. (c) 2-
Cycloheptenyl-1-benzoate (Chiralcel OJ; hexane/iso-
propanol=99.7/0.3, flow 0.5 ml/min, temperature 25°C);
retention time: 17.5 min [(R)-2-cycloheptenyl-1-benzoate]
and 18.1 min [(S)-2-cycloheptenyl-1-benzoate].
followed by the dropwise addition of tert-butyl peroxy-
benzoate (0.2 ml, 1.0 mmol). The progress of reaction
was monitored by TLC (hexane/ethyl acetate=9/1). Dis-
appearance 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 successively with a saturated
aqueous NaHCO3 solution, brine and finally with water.
The organic solution was dried over anhydrous Na2SO4
and the solvent was evaporated. The residue was purified
by chromatography on silica gel (petroleum ether/ethyl
acetate=20/1). The enantiomeric excess was determined
by HPLC: (a) 2-cyclopenten-1-benzoate: (Chiralcel OD-
H; hexane/isopropanol=99.8/0.2, flow 1.0 ml/min, tem-
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Tetrahedron Lett. 1995, 361831.
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