Synthesis of non-racemic nitrogen-containing diselenides as efficient precursor catalysts in the diethylzinc addition to benzaldehyde

Article abstract of DOI:10.1016/S0957-4166(99)00090-7

Short synthetic procedures for the preparation of new chiral, non- racemic nitrogen-containing diselenides are described. Only 1 mol% of these diselenides can very efficiently catalyze the diethylzinc addition to benzaldehydes affording the secondary alcohols in high enantiomeric purities (up to 97% ee).

Full text of DOI:10.1016/S0957-4166(99)00090-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1019–1023
Synthesis of non-racemic nitrogen-containing diselenides as
efficient precursor catalysts in the diethylzinc addition to
benzaldehyde
Claudio Santi a and Thomas Wirth b,∗
aIstituto di Chimica Organica Università degli Studi, I-06123 Perugia, Italy
bInstitut für Organische Chemie der Universität Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Received 23 February 1999; accepted 10 March 1999
Abstract
Short synthetic procedures for the preparation of new chiral, non-racemic nitrogen-containing diselenides are
described. Only 1 mol% of these diselenides can very efficiently catalyze the diethylzinc addition to benzaldehydes
affording the secondary alcohols in high enantiomeric purities (up to 97% ee). © 1999 Elsevier Science Ltd. All
rights reserved.
The enantioselective addition of dialkylzinc reagents to aldehydes can be catalyzed by a large variety
of chiral compounds affording optically active secondary alcohols.1 Detailed mechanistic studies have
also been performed.2 Diols, diamines and amino alcohols were found to be highly efficient catalysts for
this reaction. Recently, it has been shown that both sulfur-3 and selenium-containing4 amines are also
able to catalyze diethylzinc addition reactions.
We observed a positive nonlinear relationship (asymmetric amplification) between the enantio-
meric excesses of the catalyst generated from nitrogen-containing diselenides and the product.4c This
phenomenon5 was subsequently also observed in the corresponding sulfur-containing compounds.3e By
NMR studies we demonstrated that the catalyst derived from 1 is aggregated and acts as a bidentate
ligand.4c
In this paper we report on efficient and simple routes for the synthesis of new chiral non-racemic
nitrogen-containing diselenides as procatalysts for diethylzinc addition to benzaldehyde.
∗
Corresponding author. E-mail: wirth@ubaclu.unibas.ch
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00090-7

1020
C. Santi, T. Wirth / Tetrahedron: Asymmetry 10 (1999) 1019–1023
Having investigated diselenides of type 1 in detail, we prepared compound 2 with a second
ortho-substituent. Chiral diselenide 26 was prepared in a few steps from commercially available 1-
phenylethylamine 6. After alkylation, the first ortho-deprotonation was achieved by treatment with t-
BuLi.7 By addition of trimethylsilyl chloride, 7 was obtained in quantitative yield. Compound 7 was
then converted into a mixture of triselenide 8 and diselenide 2 by treatment with t-BuLi and elemental
selenium. Reduction of this mixture with NaBH4 in ethanol was followed by reoxidation in an ammonium
chloride solution to convert 8 into 2. Diselenide 2 was obtained in 67% overall yield. When the
reoxidation was performed in 2 N HCl, the corresponding salt 9 was obtained in 55% yield as pale
yellow crystals.
To study the influence of the side chain, the nitrogen-containing diselenide 38 was prepared starting
from hydroxy diselenide 10 using a one-pot procedure. Diselenide 10 was transformed in situ to the
corresponding tosylate by treatment with p-TsCl and KOH at −15°C. After addition of dimethylamine,
diselenide 3 was obtained in 30% yield (60% conversion) after flash chromatography.
Diselenide 4 is readily accessible starting from (1S,2S)-1,2-diphenylethylenediamine through a two-
step procedure as reported recently.9 The electronically modified diselenide 510 was synthesized starting
from 2-bromo-5-nitro-acetophenone 11.11 This compound was enantioselectively reduced with (−)-
diisopinocampheylchloroborane [(−)-Ipc2BCl]. The resulting chiral alcohol was tosylated and substituted

C. Santi, T. Wirth / Tetrahedron: Asymmetry 10 (1999) 1019–1023
1021
by pyrrolidine to give compound 12. The following reaction with Na2Se2 led to diselenide 5 which was
purified by flash chromatography.
Diselenides 1–5 and 9 have been investigated as procatalysts in the enantioselective addition of
diethylzinc to benzaldehyde. The reaction was carried out in toluene at −15°C using 1.25 equiv.
diethylzinc, 1 equiv. freshly distilled benzaldehyde and 1 mol% of the diselenide. The reaction mixture
was stirred at −15°C overnight and then quenched with 2 N HCl. The secondary alcohol was purified
by flash chromatography and the enantiomeric purities and absolute configurations are reported in
Table 1. Because we have previously shown that a variety of aldehydes can be used successfully in
this reaction,4b,c we are discussing herein only the results obtained with benzaldehyde.
Table 1
Diethylzinc addition to benzaldehyde using 1 mol% diselenide as procatalyst
We have already reported that diselenide 1, using the conditions described above, is an efficient catalyst
producing alcohol 13 in 92% enantiomeric excess (entry 1).4c A similar level of selectivity is observed
for diselenide 3 (entry 2) with an aminopropyl instead of an aminoethyl side chain. After electronic
modification of the aromatic ring by a nitro group in position 4 (diselenide 5) the enantiomeric excess as
well as the chemical yield decreases (entry 3). Diselenide 4 containing an additional stereogenic center
in the five-membered ring is more efficient in generating product 13 with 97% ee (entry 4).
Particularly interesting is the comparison between the enantiomeric excesses obtained with diselenide
2 (entries 5+6) and the data reported for 1 (entry 1). Diselenide 2 bears a second ortho-substituent
with respect to the chiral moiety. The higher selectivity observed with diselenide 2 (96% ee) might
indicate that the presence of the second ortho-substituent is pushing the nitrogen moiety of the chiral
side chain towards the selenium atom in facilitating the coordination to zinc as shown below. This
selectivity, however, was completely lost when hydrochloride 9 was employed as a procatalyst in the
addition reaction (entry 7).

1022
C. Santi, T. Wirth / Tetrahedron: Asymmetry 10 (1999) 1019–1023
In conclusion, we have prepared new chiral nitrogen-containing diselenides by using simple pro-
cedures. The selectivities in diethylzinc addition to benzaldehyde, catalyzed by these diselenides as
procatalysts, were investigated with respect to the steric and electronic features of these compounds.
The results should give useful information for the design of new catalysts for these kinds of reactions.
Acknowledgements
This work was supported by the Schweizer Nationalfonds and by the Treubel-Fonds (fellowship
for T.W.). We thank Professors B. Giese and M. Tiecco for their generous support. This research
was performed under MURST National Project ‘Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni’ (C.S.).
References
1. (a) Devant, R. M.; Radunz, H. E. In Houben-Weyl, Methoden der Organischen Chemie; Helmchen, G.; Hoffman, R.W.;
Mulzer, J.; Schaumann, E., Eds. Thieme: Stuttgart, 1995; Vol. E21b, pp. 1314–1334. (b) Soai, K.; Niwa, S. Chem. Rev.
1992, 92, 833–856.
2. (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071–6072. (b) Noyori, R.; Kitamura,
M. Angew. Chem. 1991, 103, 34–55; Angew. Chem., Int. Ed. Engl. 1991, 30, 49–69. (c) Kitamura, M.; Suga, S.; Niwa,
M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 4832–4842. (d) Bolm, C.; Schlingloff, G.; Harms, K. Chem. Ber. 1992, 125,
1191–1203.
3. (a) Fitzpatrick, K.; Hulst, R.; Kellog, R. M. Tetrahedron: Asymmetry 1995, 6, 1861–1864. (b) Gibson, C. L. J. Chem. Soc.,
Chem. Commun. 1996, 645–646. (c) Kellog, R. M.; Hof, R. P. J. Chem. Soc., Perkin Trans. 1 1996, 1651–1657. (d) Fulton,
D. A.; Gibson, C. L. Tetrahedron Lett. 1997, 38, 2019–2022. (e) Rijnberg, E.; Hovestad, N. J.; Kleij, A. W.; Jastrzebski, J.
T. B. H.; Boersma, J.; Janssen, M. D.; Spek, A. L.; van Koten, G. Organometallics 1997, 16, 2847–2857.
4. (a) Fukuzawa, S.; Tsudzuki, K. Tetrahedron: Asymmetry 1995, 6, 1039–1042. (b) Wirth, T. Tetrahedron Lett. 1995, 36,
7849–7852. (c) Wirth, T.; Kulicke, K. J.; Fragale, G. Helv. Chim. Acta 1996, 79, 1957–1966. (d) Wirth, T. Tetrahedron
1999, 55, 1–28.
5. Girard, C.; Kagan, H. B. Angew. Chem. 1998, 110, 3088–3127; Angew. Chem., Int. Ed. Engl. 1998, 37, 2922–2959.
6. Selected spectroscopic data of diselenide 2: 1H NMR: δ 7.93 (dd, 1H, J=1.1, 7.9 Hz), 7.28 (dd, 1H, J=1.1, 7.3 Hz), 7.03
(dd, 1H, J=7.3, 7.9 Hz), 3.66 (q, 1H, J=6.7 Hz), 2.30 (s, 6H), 1.53 (d, 3H, J=1.5 Hz), 0.35 (s, 9H). 13C NMR: δ 151.3,
138.3, 134.0, 133.4, 132.3, 127.8, 67.2, 43.6, 19.8, 2.4. 77Se NMR: δ 463.5 (broad 250 Hz). FAB-MS m/z (rel. int.) 601
(11), 300 (100), 254 (3), 149 (4), 73 (77), 44 (9).
7. Ito, Y.; Nakatsuka, M.; Saegusa, T. J. Am. Chem. Soc. 1982, 104, 7609–7622.
8. Selected spectroscopic data of diselenide 3: 1H NMR: δ 7.81 (dd, 1H, J=7.4, 1.3 Hz), 7.2–7.0 (m, 3H), 3.48 (t, 1H, J=7.5
Hz), 2.29 (s, 6H), 1.91 (quint, 2H, J=7.5 Hz), 0.84 (t, 3H, J=7.5 Hz). 13C NMR: δ 141.8, 133.5, 131.6, 127.7, 127.6, 125.7,
71.0, 42.1, 22.5, 11.4. 77Se NMR: δ 444.5. FAB-MS m/z (rel. int.) 485 (15), 242 (100), 197 (12), 86 (20), 69 (11), 57 (21),
44 (30).
9. Santi, C.; Fragale, G.; Wirth, T. Tetrahedron: Asymmetry 1998, 9, 3625–3628.

C. Santi, T. Wirth / Tetrahedron: Asymmetry 10 (1999) 1019–1023
1023
10. Selected spectroscopic data of diselenide 5: 1H NMR: δ 8.07 (t, 1H, J=1.5 Hz), 7.88 (d, 2H, J=1.5 Hz), 3.85 (q, 1H, J=6.8
Hz), 2.64 (m, 4H), 1.86 (m, 4H), 1.52 (d, 3H, J=6.8 Hz). 13C NMR: δ 146.6, 146.1, 141.3, 131.6, 122.1, 121.2, 63.0, 50.5
(2C), 23.8 (2C), 17.5. 77Se NMR: δ 483.0. FAB-MS m/z (rel. int.) 599 (8), 299 (100), 283 (12), 138 (20), 98 (41), 70 (92),
55 (35).
11. Meisenheimer, J.; Zimmermann, P.; von Kummer, U. Justus Liebigs Ann. Chem. 1926, 446, 205–228.