A novel ferrocenyl diselenide for the catalytic asymmetric aryl transfer to aldehydes

Article abstract of DOI:10.1039/b003237i

An oxazolinyl ferrocenyl diselenide was synthesised by directed ortho-metalation and used as catalyst precursor in the asymmetric addition of diethyl- and diphenylzinc to various aldehydes, yielding synthetically useful secondary alcohols, of which some are difficult to access using other catalytic methodologies. Enantioselectivities of up to 44% for the former and up to 85% for the latter transformations were obtained.

Full text of DOI:10.1039/b003237i

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A novel ferrocenyl diselenide for the catalytic asymmetric aryl
transfer to aldehydes
Carsten Bolm,* Martin Kesselgruber, Achim Grenz, Nina Hermanns and Jens P. Hildebrand
Institut fur Organische Chemie der RW T H Aachen, Prof.-Pirlet-Str. 1, 52074 Aachen, Germany.
E-mail: Carsten.Bolm=oc.rwth-aachen.de; Fax: ]49 241 888 8391
L e t t e r
Received (in Montpellier, France) 19th April 2000, Accepted 30th May 2000
First published as an Advance Article on the web 3rd October 2000
An oxazolinyl ferrocenyl diselenide was synthesised by directed
ortho-metalation and used as catalyst precursor in the asym-
metric addition of diethyl- and diphenylzinc to various alde-
hydes, yielding synthetically useful secondary alcohols, of which
some are difficult to access using other catalytic methodologies.
Enantioselectivities of up to 44% for the former and up to 85%
for the latter transformations were obtained.
diethylzinc,12,13 leading to synthetically useful enantio-
enriched diarylmethanols with up to 98% ee.14h16
Encouraged by the fact that diselenide 2 displayed excellent
selectivities in the alkylations, we assumed that compound 4
would also be useful for the asymmetric addition of diorgano-
zinc reagents to aldehydes. Herein, we present the application
of 4 as catalyst precursor in these reactions.
The synthesis of 4 was accomplished by directed ortho-
lithiation17 of (S)-2-ferrocenyl-4-tert-butyloxazoline 5,18 fol-
lowed by addition of selenium powder (Scheme 1). Oxidation
by air for several minutes a†orded the diselenide in good yield
(69%).
Initially, 4 was used in the addition of diethylzinc to aro-
matic and aliphatic aldehydes. The most signiÐcant results are
summarised in Table 1. Although the results in the diethylzinc
Organoselenium chemistry represents an established tool in
organic synthesis.1 However, compared to sulfur, this area is
much less investigated, a fact that the reduced stability
towards oxidative conditions and light as well as the frequent-
ly encountered toxicity of selenium reagents may account for.
Extensive use of selenium in organic synthesis was initiated
with the discovery of oleÐn formation by the decomposition of
selenoxides, a reaction that proceeds under very mild condi-
tions.2 The chemistry of chiral selenium compounds is an even
more undeveloped area.3 Early articles dealing with their
application in asymmetric catalysis were published in 1996 by
Uemura and coworkers.4 Ferrocene 1, derived from UgiÏs
amine,5 showed enantioselectivities of up to 88% in the
rhodium(I)-catalysed hydrosilylation of ketones. This com-
pound was also employed in the asymmetric transfer hydro-
genation of ketones and in stoichiometric asymmetric
syntheses like selenoxide eliminations,6 [2,3]sigmatropic
rearrangements7 and intramolecular selenocyclisations.8
Wirth et al.9 demonstrated that 2 and related compounds are
highly e†ective ligands in the asymmetric addition of
diethylzinc to aromatic and aliphatic aldehydes.10 With only 1
mol% of catalyst enantioselectivities of up to 98% were
achieved for a wide range of substrates.
addition to aldehydes are highly unsatisfying (ee \ 44% in
max
the reaction with benzaldehyde), it is interesting to note that a
structurally very similar compound, phenyloxazolinyl dis-
elenide 6,9 devoid of the metal fragment, gives 1-
phenylpropanol with only 8% ee in 1% yield.19 The element
of planar chirality present in 4 seems to have a decisive inÑu-
ence on both the enantioselectivity and yield of the reaction.20
Superior results were obtained in the asymmetric aryl trans-
fer to aldehydes using a zinc reagent prepared by mixing
diphenylzinc and diethylzinc in a 1 : 2 ratio. Compared to the
addition of dialkylzincs, this reaction gave eeÏs of up to 85%
Recently, we developed a new catalytic system for the asym-
metric addition of dialkylzinc reagents to aldehydes11 based
on 2-ferrocenyloxazoline, 3, which is capable of inducing
enantioselectivities up to 97% ee.12 Even higher ee values
were obtained in the analogous phenyl transfer reaction with
a zinc reagent prepared in situ from diphenylzinc and
Scheme 1 Synthesis of ligand 4
Table 1 Addition of diethylzinc to aldehydes in the presence of 2.5
mol% of 4
Entry
R
Yield/%
ee/%
Abs. conÐg.
1
2
3
Phenyl
4-Chlorophenyl
Hexyl
68
66
79
44
44
20
R
R
n.d.a
a n.d. \ not determined.
DOI: 10.1039/b003237i
New J. Chem., 2001, 25, 13È15
13
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2001

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radical prior to use. 1H- and 13C-NMR spectra were recorded
on a Varian Gemini 300 spectrometer at 300 and 75 MHz,
respectively, in CDCl , chemical shifts are given in ppm. All
3
experiments were conducted at least twice to ensure repro-
ducibility.
Preparation of compound 4
and uniformly high yields between 65 and 96% (Table 2). Ali-
phatic aldehydes were less suitable substrates, resulting in an
enantiomeric excess of only 65% for 2,2-dimethyl-1-phenyl-
propanol. The catalytically active species is believed to be
formed by heterolytic cleavage of the SeÈSe bond of diselenide
4 (Scheme 2).9
Most likely, zinc selenides such as 4a or 4b serve as cata-
lysts. Based on the results by Wirth et al.9 who demonstrated
the inferiority of selenoethers in diethylzinc additions as con-
cerns the rate and enantioselectivity compared to selenols, we
believe that 4c and 4d play only a minor role in the stereoche-
mical outcome of the catalysis.
In summary we have introduced a new catalyst for asym-
metric addition reactions, capable of inducing moderate to
high eeÏs with a zinc reagent prepared by mixing diethyl- and
diphenylzinc. Further studies concerning the inÑuence of the
chalcogenide atom and the mechanistic details of the reaction
are currently in progress.
A solution of 5 (700 mg, 2.25 mmol) in 15 ml of THF is cooled
to [78 ¡C and treated with s-BuLi (1.9 ml, 2.48 mmol). The
resulting dark red solution is stirred for 30 min at this tem-
perature, and then selenium powder (216 mg, 2.70 mmol) is
added in one portion. The mixture is stirred for a further 10
min at [78 ¡C and subsequently warmed to room tem-
perature within 15 min. After quenching with 30 ml of deion-
ised water and extraction with dichloromethane (3 ] 20 ml),
air is bubbled through the combined organic layers for 5 min.
The solution is dried over MgSO and Ðltered. The solvent is
evaporated and the product puriÐed by column chromatog-
4
raphy (pentaneÈdiethyl ether, 2 : 1) to a†ord 600 mg of 4 as an
orange solid (69% yield). Mp: 192 ¡C (dec.). [a] \ [1270
D
[c \ 1.0, CHCl ]. 1H NMR: d 1.05 (s, 18H), 3.99 (dd, J \ 9.9
3
Hz, 7.4 Hz, 2H), 4.16 (s, 10H), 4.22È4.29 (m, 6H), 4.65È4.68 (m,
4H). 13C NMR: d \ 25.9, 33.6, 69.2, 69.4, 70.2, 71.6, 72.0, 73.7,
76.7, 79.7, 165.2. MS (EI, 70 eV): m/z (%) 780.3 (7, M`), 713.2
(6), 511.2 (16), 390.2 (100), 309.3 (35), 254.3 (38). IR (KBr):
l \ 3435, 3108, 2956, 2186, 1655 cm~1. Anal. calcd. for
Experimental
C
H
Fe N O Se : C, 52.47%; H, 5.18%; N, 3.60%;
34 40
2 2 2 2
All manipulations except workup and puriÐcation were con-
ducted under an inert atmosphere of Ar using standard
Schlenk techniques. s-BuLi was purchased from Fluka as a 1.3
N solution in hexane. Diphenylzinc was obtained from Strem
and handled in a glovebox under Ar. Tetrahydrofuran and
toluene were distilled from sodium/benzophenone ketyl
Found: C, 52.34%; H, 4.84%; N, 3.46%.
General procedure for the addition of diethylzinc to aldehydes
A solution of 4 (20 mg, 0.025 mmol) in toluene (2 ml) is treated
with diethylzinc (0.25 ml, 2.5 mmol) at room temperature.
After stirring for 30 min the dark orange solution is cooled to
0 ¡C and the aldehyde (1 mmol) is added neat in one portion.
Stirring is continued at this temperature for 24 h, then the
mixture is quenched by addition of a saturated aqueous solu-
tion of ammonium chloride (5 ml) and extracted with diethyl
ether (3 ] 10 ml). The collected organic layers are dried over
Table 2 Asymmetric phenyl transfer to aldehydes in the presence of
5 mol% of 4
MgSO and the solvent is evaporated. The crude product is
4
puriÐed by column chromatography (pentaneÈdiethyl ether)
and subjected to HPLC or GLC analysis.
General procedure for the enantioselective phenyl transfer to
aldehydes
Entry
R
Yield/%
ee/%
Abs. conÐg.
1
2
3
4
5
6
4-Chlorophenyl
2-Naphthyl
4-Biphenyl
2-Bromophenyl
4-Tolyl
85
96
86
65
80
85
84
76
85
77
76
65
R
R
Ra
R
Ra
S
In a glovebox a well-dried Schlenk Ñask is charged with
diphenylzinc (36 mg, 0.16 mmol). The Ñask is sealed and
removed from the glovebox. Freshly distilled toluene (3 ml) is
added followed by diethylzinc (33 ll, 0.33 mmol). After stirring
at room temperature for 30 min ferrocene 4 (10 mg, 0.013
mmol) is added, and then the resulting clear solution is cooled
to 10 ¡C. Stirring is continued for an additional 10 min at this
temperature; the aldehyde (0.25 mmol) is then added neat in
one portion. The Schlenk Ñask is sealed and the reaction
mixture stirred at 10 ¡C overnight. Quenching with water is
followed by extraction of the mixture with diethyl ether. The
tert-Butyl
a Tentatively assigned by assumption of an identical reaction
pathway.
combined organic layers are dried over MgSO and the
4
solvent is evaporated. The product is puriÐed by column chro-
matography using silica gel (pentaneÈdiethyl ether).
HPLC analysis: 1-phenyl-1-propanol [Chiralcel OD-H,
heptaneÈPriOH \ 96 : 4, 0.5 ml min~1, (R): 16.7, (S): 18.7
min]; 1-(4-chlorophenyl)-1-propanol [Chiralcel OD, heptaneÈ
PriOH \ 97 : 3, 0.5 ml min~1, (S): 23.0, (R): 24.8 min]; a-(4-
chlorophenyl)phenylmethanol [Chiralcel OB, heptaneÈ
PriOH \ 80 : 20, 0.8 ml min~1, (R): 8.8, (S): 13.3 min]; a-(2-
naphthyl)phenylmethanol
PriOH \ 90 : 10, 0.8 ml min~1, (S): 20.4, (R): 23.7 min]; a-(4-
biphenyl)phenylmethanol [Chiralcel OD, heptaneÈ
PriOH \ 98 : 2, 1.0 ml min~1, (R): 65.9, (S): 75.5 min]; a-(2-
[Chiralcel
OD,
heptaneÈ
Scheme 2 Cleavage of the SeÈSe bond in 4
14
New J. Chem., 2001, 25, 13È15

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10 Reviews on diorganozinc additions to aldehydes: K. Soai and S.
Niwa, Chem. Rev., 1992, 92, 833; R. Noyori and M. Kitamura,
Angew. Chem., Int. Ed. Engl., 1991, 30, 49; K. Soai and T.
Shibata, Comprehensive Asymmetric Catalysis, eds. E. N. Jacob-
sen, A. Pfaltz and H. Yamamoto, Springer, Berlin, Germany,
1999, vol. 2, p. 911.
11 (a) C. Bolm, K. MunizÈFernandez, A. Seger and G. Raabe,
Synlett, 1997, 1051; (b) C. Bolm, K. MunizÈFernandez, A. Seger,
G. Raabe and K. Gunther, J. Org. Chem., 1998, 63, 7860; (c) C.
Bolm, K. Muniz and J. P. Hildebrand, Org. L ett., 1999, 1, 491.
12 C. Bolm and K. Muniz, Chem. Commun., 1999, 1295; C. Bolm, N.
Hermanns, J. P. Hildebrand and K. Muniz, Angew, Chem., in
press.
bromophenyl)phenylmethanol [Chiralcel OD, heptaneÈ
PriOH \ 90 : 10, 0.9 ml min~1, (R): 11.6, (S): 14.9 min]; a-(4-
tolyl)phenylmethanol [Chiralcel OB, heptaneÈPriOH \ 98 : 2,
0.9 ml min~1, (S): 35.8, (R): 38.5 min]; 2,2-dimethyl-1-phenyl-
propanol [Chiralcel OD, heptaneÈPriOH \ 98 : 2, 1.0 ml
min~1, major: 11.0, minor: 16.7 min].
GLC analysis: 3-nonanol as triÑuoroacetate derivative
(Lipodex G; 50 m ] 0.25 mm, 40È170 ¡C, minor: 93.5, major:
95.1 min).
13 Use of a combination of ZnPh and ZnMe in the addition to
Acknowledgements
2
2
aldehydes has been described before. For example, aryl transfer
to nicotinaldehyde catalysed by N,N-diethylnorephedrine results
in phenyl transfer with 20 : 1 selectivity to give 3-phenylpyridyl-
methanol in 70% ee. J. Blacker, in T hird International Conference
on the Scale Up of Chemical Processes (Conference Proceedings),
ed. T. Laird, ScientiÐc Update, UK, 1998, p. 74.
We are grateful to the Deutsche Forschungsgemeinschaft
(DFG) within the Collaborative Research Center (SFB) 380
“Asymmetric Synthesis by Chemical and Biological MethodsÏ
and the Fonds der Chemischen Industrie for Ðnancial support.
M. K. acknowledges DFG for a predoctoral fellowship
(Graduiertenkolleg), and we thank Witco and Degussa-Huls
for donations of chemicals. We also thank Dr. J. Blacker
(Avecia) for pointing out reference 13 to us, and I. Schi†ers for
performing GLC analyses.
14 For other catalytic systems for the asymmetric addition of
diphenylzinc to aldehydes see: (a) E. I. Dosa, J. C. Ruble and
G. C. Fu, J. Org. Chem., 1997, 62, 444; (b) W.-S. Huang, Q.-S. Hu
and L. Pu, J. Org. Chem., 1999, 64, 7940; (c) W.-S. Huang and L.
Pu, T etrahedron L ett., 2000, 41, 145.
15 For reports of additions to aldehydes employing in situ-generated
ZnPh from ZnCl and a Grignard precursor, see: (a) enantio-
2
2
selective: K. Soai, Y. Kawase and A. Oshio, J. Chem. Soc., Perkin
T rans. 1, 1991, 1613; (b) diastereoselective: J. Hubscher and R.
Barner, Helv. Chim. Acta, 1990, 73, 1068. It appears as if these
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2
16 Enantiomerically enriched diarylmethanols can also be synthe-
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New J. Chem., 2001, 25, 13È15
15