Application of Enantiopure 1-(Aminoalkyl)naphthols and 2-(Aminoalkyl) phenols in the Enantioselective Addition of Organozinc to ,-Unsaturated Carbonyl Compounds

Article abstract of DOI:10.1080/00397910902737148

Several enantiopure 1-(aminoalkyl)naphthols and a 2-(aminoalkyl)phenol were tested as ligands in the Nickel-catalyzed enantioselective addition of organozinc to chalcones.

Full text of DOI:10.1080/00397910902737148

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Application of Enantiopure 1-
(Aminoalkyl)naphthols and 2-
(Aminoalkyl)phenols in the
Enantioselective Addition of
Organozinc to α,β-Unsaturated
Carbonyl Compounds
Cristina Cimarelli a , Davide Fratoni a & Gianni
Palmieri a
a University of Camerino, Department of Chemical
Sciences , Camerino, Italy
Published online: 03 Aug 2009.
To cite this article: Cristina Cimarelli , Davide Fratoni & Gianni Palmieri (2009)
Application of Enantiopure 1-(Aminoalkyl)naphthols and 2-(Aminoalkyl)phenols in the
Enantioselective Addition of Organozinc to α,β-Unsaturated Carbonyl Compounds,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:17, 3184-3190, DOI: 10.1080/00397910902737148
To link to this article: http://dx.doi.org/10.1080/00397910902737148
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Synthetic Communications1, 39: 3184–3190, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902737148
Application of Enantiopure
1-(Aminoalkyl)naphthols and
2-(Aminoalkyl)phenols in the Enantioselective
Addition of Organozinc to a,b-Unsaturated
Carbonyl Compounds
Cristina Cimarelli, Davide Fratoni, and Gianni Palmieri
University of Camerino, Department of Chemical Sciences,
Camerino, Italy
Abstract: Several enantiopure 1-(aminoalkyl)naphthols and a 2-(aminoalkyl)
phenol were tested as ligands in the Nickel-catalyzed enantioselective addition
of organozinc to chalcones.
Keywords: 1-(Aminoalkyl)naphthols, 2-(aminoalkyl)phenols, chalcones, enantio-
selective conjugated addition
Carbon–carbon bond formation through conjugated addition of organo-
metallic reagents to a,b-unsaturated carbonyl compounds is an efficient
method for the synthesis of b-substituted carbonyl compounds. Because
this reaction often produces a stereogenic center, the search for efficient
and enantioselective methods has been privileged.
Methods employing stoichiometric amounts of chiral reagents were
developed, using sparteine[1] or 1,4-(dialkylamino)-2,3-dimethoxybutane[2]
as chiral ligands. Other methods used N-alkylprolinol[3] or phosphorous
chiral ligands[4] in the presence of organocopper reagents or copper salts.
Received November 21, 2008.
Address correspondence to Cristina Cimarelli, Department of Chemical
Sciences, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy.
E-mail: cristina.cimarelli@unicam.it
3184

Enantioselective Alkylation of Enones
3185
Anyway, catalytic enantioselective methodologies were developed to
improve the efficiency of the reaction and minimize the amounts of
unrecoverable chiral catalysts and metals.
Organolithium, Grignard reagents, and organozinc compounds
were used in the presence of copper, rhodium, heterobimetal, or nickel
catalysts.[5] Recently chiral b-aminoalcohols derived from (S)-leucine
gave very high ee, up to 92%.[6]
In the past, diastereoselective syntheses of 1-(aminoalkyl)naphthols[7]
and 2-(aminoalkyl)phenols[8] were developed, and these compounds were
revealed to be good catalysts in the enantioselective addition of diethyl-
zinc to aldehydes.[8,9] Consequently the study of their efficacy as chiral
ligands was extended to catalyzed enantioselective conjugated addition.
In this article, the results of the application of chiral ligands 2a–e in
the nickel catalyzed enantioselective addition of organozinc reagents to
a,b-unsaturated carbonyl compounds 1a–g are presented (Scheme 1).
Addition of diethylzinc to chalcone 1a afforded 1,3-diphenyl-pentan-
1-one 3a in 63–97% yield, with a certain selectivity to the R enantiomer.
The better compromise between ee and yield for this reaction was
achieved with a metal=ligand=substrate ratio of 1=15=100. The reaction
was performed in acetonitrile, which was revealed to be the better solvent
for this reaction.[10] The use of tetrahydrofuran (THF), also in mixture
with acetonitrile, reduces significantly both yields (40%) and ee (11%).
The formation of the complex catalyst needs at least 1 h of reflux of
Ni(acac)2 in the presence of chiral ligands 2a–e. Better enantioselectivities
were obtained by performing the subsequent addition step at ꢀ30ꢁC. In
the standard conditions (see Experimental), several chiral ligands were
tested, with the results reported in Table 1.
Different dialkylzinc reagents were added to chalcone 1a in the pre-
sence of ligand 2b: in the standard experimental conditions, dibuthylzinc
Scheme 1. Enantioselective catalyzed addition of organozinc reagents to chalcone 1a.

3186
C. Cimarelli, D. Fratoni, and G. Palmieri
Table 1. Enantioselective addition of diethylzinc to chalcone
1a using ligands 2a–e
Entry
2
R
3 yield (%)a
3 ee (%)b
1
2
3
4
5
6
7
2a
Et
Et
But
Me
Et
3a (92)
3a (99)
3g (92)
3h (53)
3a (94)
3a (96)
3a (95)
71
57
33
12
53
45
7
2bc
2b
2b
2cd
2dc
2ec
Et
Et
aYield of the pure isolated enantiomers mixture.
bDetermined by HPLC analysis. The absolute configuration
of the major enantiomer is (R).
cRef. 6.
dRef. 7.
and dimethylzinc afforded the corresponding addition products 3g and
3h, but with less yields with respect to diethylzinc (Table 1, entries 3,4).
When performing diethylzinc addition on chalcone 1a in the presence
of mixtures of (R,R)-2a and (S,R)-2a in different rates, a nonlinear depen-
dence of the ee of the resulting ketone on the diastereomeric purity of the
catalyst is observed. The results are shown in Fig. 1.
Figure 1. Diethylzinc addition to chalcone 1a using mixtures at different ratios of
ligand 2a diastereomers.

Enantioselective Alkylation of Enones
3187
Scheme 2. Enantioselective catalyzed addition of organozinc reagents to
chalcones 1b–g using chiral ligands 2a–b.
The conjugated addition was extended to substituted chalcones 1b–f
using ligands 2a and 2b, with less satisfactory results (yield 15–99%, ee
14–64%), as described in Scheme 2 and Table 2.
The reaction of substrate 1g resulted in poor yield of the alkylation
product 3g (Y ¼ 43%) because of the contemporary formation of a
comparable amount of the corresponding allylic alcohol 2,2-dimethyl-5-
phenyl-4-penten-3-ol[11] (yield 44%).
EXPERIMENTAL
General Methods
Optical rotations were measured in a 1-dm cell at 20ꢁC. Enantiomeric
purities (% ee) were determined by high-performance liquid chromato-
graphic (HPLC) analyses, performed with an Agilent 1100 workstation
Table 2. Enantioselective addition of diethylzinc to chalcones 1b–g using ligand
2a and 2b
Entry
1
2
R1
R2
3 yield (%)a
3 ee (%)b
1
2
3
4
5
6
7
8
9
1b 2a
1c 2a
1d 2a
1e 2a
1f 2a
1b 2b
1c 2b
1d 2b
1e 2b
Ph
Ph
Ph
Me
p-Cl-Ph
p-MeO-Ph
Ph
3b (57)
3c (41)
3d (58)
3e (65)
3f (93)
3b (54)
3c (15)
3d (99)
3e (97)
3f (97)
3g (43)
19 (R)c
63 (R)c
59 (S)c
64 (R)c
33 (R)c
14 (R)c
26 (R)c
28 (S)c
29 (R)c
30 (R)c
26 (R)c
p-Cl-Ph
p-MeO-Ph Ph
Ph
Ph
Ph
p-Cl-Ph
Me
p-Cl-Ph
p-MeO-Ph
Ph
10
11
1f 2b
1g 2b
p-MeO-Ph Ph
Ph
But
aYield of the pure isolated enantiomer mixture.
bDetermined by HPLC analysis (see Experimental).
cAbsolute configuration of the major isomer.

3188
C. Cimarelli, D. Fratoni, and G. Palmieri
equipped with binary pump, diode array detector, and autosampler
system, using the chiral column LiChroCART1 250-4 (S,S)-Whelk-01
(5 mm) and a mixture of hexane=isopropanol in 99=1 ratio as eluent.
Dialkyklzinc reagents were commercially available as 1 M solution in
toluene (Aldrich). All the other reagents were commercially available,
purchased at the highest quality and purified by distillation when neces-
sary. Ligands 2a–e[7,8] were prepared according to the literature methods.
General Procedure for the Addition of Organozinc
Reagents to Chalcones
Ligands 2a–e (3 mmol) were poured in a three-necked, round-bottom
flask with Ni(acac)2 (0.2 mmol, 0.052 g) in CH3CN (30 mL) at reflux
for 1 h under an inert atmosphere. Then the mixture was allowed to reach
room temperature and chalcones 1 (20 mmol) were added. The mixture
was then cooled to ꢀ30ꢁC, and the organozinc reagent (30 mmol,
30 mL 1 M solution in toluene) was added. An instantaneous change of
color from green to brown was observed. The mixture was then allowed
to reach room temperature in 4 h, and then HCl solution (50 mL 2 M
solution) was added and extracted with CH2Cl2 (3 ꢂ 30 mL). The organic
layer was dried with anhydrous sodium sulfate, then the solvent was eva-
porated under reduced pressure. The residue was then submitted to flash
chromatography on silica gel with n-hexane=ethyl acetate 90=10 as
solvent. The products 3 were isolated as pure enantiomers mixture, then
submitted to HPLC analysis to determine the ee. Products 3 were identi-
fied, and their absolute configuration were attributed by comparison
with literature data.[12–20] The ligand was recovered in 78% yield with
unaltered absolute configuration, then reused.
REFERENCES
1. Kretchmer, R. A. 1,4-Addition of organometallic reagents to a,b-unsaturated
ketones in the presence of (ꢀ)-sparteine. J. Org. Chem. 1972, 37, 2744–2747.
2. Langer, W.; Seebach, D. Enantioselective 1,4-additions of organometallic
compounds to conjugated systems in a chiral 1,4-bis(dimethylamino)-23-
dimethoxybutane medium. Helv. Chim. Acta 1979, 62, 1710–1722.
3. Leyendecker, F.; Jesser, F.; Laucher, D. Ligand effects in enantioface-
differentiating 1,4-addition to 1,3-diphenyl-2-propen-1-one. Tetrahedron
Lett. 1983, 24, 3513–3516.
4. Alexakis, A.; Mutti, S.; Normant, F. New chiral ligand for the asymmetric
conjugate addition of organocopper reagents to enones. J. Am. Chem. Soc.
1991, 113, 6332–6334.

Enantioselective Alkylation of Enones
3189
5. Krause, N.; Hoffmann-Ro¨der, A. Recent advances in catalytic enantioselec-
tive Michael additions. Synthesis 2001, 2, 171–196.
6. Wakimoto, I.; Tomioka, Y.; Kawanami, Y. Catalytic enantioselective
conjugate addition of diethylzinc to chalcones using chiral amino alcohol–
nickel complexes. Tetrahedron 2002, 58, 8095–8097.
7. Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. Solvent-free asymmetric
aminoalkylation of electron-rich aromatic compounds: Stereoselective
synthesis of aminoalkylnaphthols by crystallization-induced asymmetric
transformation. J. Org. Chem. 2001, 66, 4759–4765.
8. Palmieri, G. Synthesis of enantiopure 2-hydroxybenzylamines by stereoselec-
tive reduction of 2-imidoylphenols: Application in the catalytic enantioselec-
tive addition of diethylzinc to aldehydes. Eur. J. Org. Chem. 1999, 805–811.
9. Palmieri, G. A practical o-hydroxybenzylamines promoted enantioselective
addition of dialkylzincs to aldehydes with asymmetric amplification. Tetrahe-
dron: Asymmetry 2000, 11, 3361–3373.
10. Soai, K.; Hayasaka, T.; Ugajin, S. Asymmetric synthesis of optically active b-
substituted ketones by highly enantioselective catalytic conjugate addition of
dialkylzinc reagents to enones using a catalyst system of nickel(II)–chiral
ligand–achiral ligand in acetonitrile=toluene. J. Chem. Soc., Chem. Commun.
1989, 516–517.
11. Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei, Y.; Muniz, K.;
Noyori, R. Asymmetric hydrogenation of tert-alkyl ketones. J. Am. Chem.
Soc. 2005, 127, 8288–8289.
12. Hajra, A.; Yoshikai, N.; Nakamura, E. Aminohydroxyphosphine ligand for
the copper-catalyzed enantioselective conjugate addition of organozinc
reagents. Org. Lett. 2006, 8, 4153–4156.
13. Leitereg, T. J.; Cram, D. J. Studies in stereochemistry, XXXVII: Open-chain
models for 1,3-asymmetric induction in stereospecific addition polymeriza-
tion. J. Am. Chem. Soc. 1968, 90, 4011–4018.
14. Ito, K.; Eno, S.; Saito, B.; Katsuki, T. Enantioselective conjugate addition of
diethylzinc to acyclic enones using a copper phosphino-phenol complex as
catalyst. Tetrahedron Lett. 2005, 46, 3981–3986.
15. Huttenloch, O.; Spieler, J.; Waldmann, H. Chiral bicyclic phosphorami-
dites—A new class of ligands for asymmetric catalysis. Chem. Europ. J.
2001, 7, 671–675.
16. Shi, M.; Wang, C.-J.; Zhang, W. Enantioselective conjugate addition of di-
alkylzinc and diphenylzinc to enones catalyzed by a chiral copper(I)
binaphthylthiophosphoramide or binaphthylselenophosphoramide ligand
system. Chem. Europ. J. 2004, 10 (21), 5507–5516.
17. Soai, K.; Okudo, M.; Okamoto, M. Enantioselective conjugate addition of
diethylzinc to enones using chiral b-aminoalcohol as chiral catalyst or ligand.
Tetrahedron Lett. 1991, 32 (1), 95–96.
18. Takahashi, Y.; Yamamoto, Y.; Katagiri, K.; Danjo, H.; Yamaguchi, K.;
Imamoto, T. P-Chiral o-phosphinophenol as a P=O hybrid ligand: Prepara-
tion and use in Cu-catalyzed asymmetric conjugate addition of diethylzinc
to acyclic enones. J. Org. Chem. 2005, 70 (22), 9009–9012.

3190
C. Cimarelli, D. Fratoni, and G. Palmieri
19. Ahlbrecht, H.; Sommer, H. Chiral homoenolate equivalents, III:
Asymmetric synthesis of 3-substituted 3-phenyl ketones via metalated
(S)-methoxymethylpyrrolidine (SMP)-allylamines. Chem. Ber. 1990, 123 (4),
829–836.
20. Brienne, M. J.; Ouannes, C.; Jacques, J. 3-Asymmetric induction, I: Prepara-
tion of various ketones with an asymmetric center in the b- and c-position
and of known configuration. Bull. Soc. Chim Fr. 1967, 32 (2), 613–623.