Asymmetric alkylation of aromatic aldehydes with diethylzinc catalyzed by a fluorous BINOL-Ti complex in an organic and fluorous biphase system

Article abstract of DOI:10.1016/S0040-4039(99)01999-1

Fluorous chiral BINOL ((R)-FBINOL) was prepared by short reaction steps in good overall yield and was applied to the catalytic asymmetric alkylation in a toluene and FC-72 biphase system. The (R)-FBINOL-Ti complex in the FC-72 phase was consecutively reus

Full text of DOI:10.1016/S0040-4039(99)01999-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 57–60
Asymmetric alkylation of aromatic aldehydes with diethylzinc
catalyzed by a fluorous BINOL–Ti complex in an organic and
fluorous biphase system
Yutaka Nakamura,a Seiji Takeuchi,a,∗ Yoshiaki Ohgo a and Dennis P. Curran b,∗
aNiigata College of Pharmacy, 5-13-2 Kamishin’ei cho, Niigata 950-2081, Japan
bDepartment of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
Received 13 September 1999; revised 14 October 1999; accepted 18 October 1999
Abstract
Fluorous chiral BINOL ((R)-FBINOL) was prepared by short reaction steps in good overall yield and was applied
to the catalytic asymmetric alkylation in a toluene and FC-72 biphase system. The (R)-FBINOL–Ti complex in the
FC-72 phase was consecutively reused in the biphase system and the enantioselectivity was still higher than 80%
ee at the 5th reaction. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: fluorine; fluorine compounds; asymmetric; catalysis; alkylation.
Transition metal catalysts in which fluorous ligands are coordinated to the metal ion can partition
exclusively to a fluorous solvent such as FC-72 (F3C(CF2)4CF3) in an organic–fluorous biphase system
(FBS). The characteristic nature of the fluorous catalysts enables reactions to proceed consecutively in
FBS. After the completion of a reaction, the organic phase in which the organic products are contained
is removed and a new organic solution of the reactants is added to the fluorous phase to continue the
reaction. The reaction can thus be repeated as long as the catalyst remains intact in the fluorous phase.1
This is a liquid–liquid biphase version of a catalytic reaction in a liquid–solid biphase flow reactor system
by metal complexes in which polymer-supported or polymeric ligands are coordinated to the metal ions
and is expected to complement the drawbacks of the polymer catalysts.
Very recently, Gladysz and co-workers have reported hydroboration of alkenes and alkynes catalyzed
by a fluorous rhodium complex in a toluene and CF3C6F11 biphase system. The organoboron products
were isolated or oxidized to the corresponding alcohols after separation from the catalyst in CF3C6F11.
The yields were high and the overall TON values of the catalytic reaction turned out higher than
10000/cycle.2
To our knowledge, however, only a few reports have been published on catalytic asymmetric reactions
using the fluorous chiral catalysts3 in spite of the successful attempts with chiral polymer catalysts.4 This
is simply attributable to the lack of useful fluorous analogues of popular chiral ligands such as BINOL
or BINAP. Therefore, we have attempted to synthesize such fluorous ligands and succeeded in preparing
∗
Corresponding authors.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)01999-1

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(R)-6,60-bis[tris(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silyl]-1,10 -binaphth-2,20-diol ((R)-FBINOL)
in good yield on a practical scale by the following route.
(R)-6,60-Dibromo-2,20-dimethoxymethoxy-1,10 -binaphthlene (I) was prepared from commercially
available (R)-6,60-dibromo-1,10-binaphth-2,2-diol by Pu’s method.5 (R)-6,60-Bis[tris(3,3,4,4,5,5,6,6,7,7,
8,8,8-tridecafluorooctyl)silyl]-2,20 -dimethoxymethoxy-1,10 -binaphthalene (II) was obtained in 91%
yield via lithiation at the 6 and 60-positions of (I) and then reaction with (C6F13CH2CH2)3SiBr6
according to Curran’s method (Scheme 1).7 (R)-FBINOL (III) was isolated in 97% yield after removing
the MOM groups.8
Scheme 1.
The approximate partition coefficients of III was determined by a simple method described in the
footnote to Table 1, and the results are summarized in Table 1.
Table 1
Partition coefficients of (R)-FBINOL in organic solvent and FC-72a
Nakai and Chan have independently reported the asymmetric alkylation of aromatic aldehydes with
diethylzinc catalyzed by a BINOL–Ti complex.9 We chose the reaction for the toluene and FC-72 biphase
system to examine usefulness of (R)-FBINOL, because the reaction brought about a high percentage ee
and yield by a simple procedure and with the use of commercially available reagents.10
When Ti(O-iPr)4 was added to the solution of (R)-FBINOL in FC-72, the reaction mixture became
a light-red homogeneous solution, and then a colorless oily material was separated out on the surface
of the FC-72 solution (Fig. 1). To the reaction mixture was added 1 M solution of Et2Zn in hexane.
After cooling the reaction mixture to 0°C, a benzaldehyde solution in toluene was added. The toluene
phase (actually toluene and hexane phase; organic phase) became pale yellow-brown and the FC-72
phase remained light-red. The reaction mixture was stirred vigorously at 0°C for 2 h, and then the
organic phase was withdrawn with a syringe and was quenched with 1.0 N-hydrochloric acid to ensure
removal of (R)-FBINOL from the Ti complex. The product and (R)-FBINOL were simply and cleanly
separated with 1H,1H,2H,2H-perfluorooctyldimethylsilyl binded silica gel (fluorous reverse phase silica
gel; FRP silica gel)11 by washing successively with acetonitrile and FC-72. The product alcohol from
the acetonitrile eluate was purified by preparative TLC, and (R)-FBINOL was recovered from the FC-72
eluate in pure form. The enantioselectivity (83% ee) of the product was similar to that reported by Nakai
and co-workers. To the fluorous layer new Ti(O-iPr)4, the Et2Zn solution and benzaldehyde solution were

59
Figure 1.
Table 2
Asymmetric catalytic alkylation of benzaldehyde with diethylzinc using a (R)-FBINOL–Ti complex
in FC-72/organic solvent biphase system
added, and the reaction was carried out in the same way. Thus, the reaction was repeated five times and
the results are summarized in Table 2.
As seen in Table 2, the enantioselectivity was still higher than 80% at the 5th experiment (run 5).
However, about 10% (0.02 mmol) of (R)-FBINOL was recovered from the organic phase in every
experiment. Therefore, it was considered that the chiral catalyst was in the organic phase and asymmetric
reaction occurred only in that phase. The fact that the organic phase had a pale brown color also led us
to this conclusion. Thus, we carried out the reaction separately in the organic phase and in the toluene-
FC-72 biphase system. The procedure was the same until the reaction mixture was cooled to 0°C after
the addition of Et2Zn solution. Toluene was added to the reaction mixture and the two phases were
separated. To the organic phase was added the benzaldehyde solution and the reaction was carried out as
described above. To the FC-72 phase, the Et2Zn solution and the benzaldehyde solution were added and
the reaction was carried out in the same way. From the organic phase the product was obtained in 73% ee
(88% yield) and 10% of (R)-FBINOL was recovered. From the toluene-FC-72 biphase system the product
was obtained in 77% ee (81% yield) and 88% of (R)-FBINOL was recovered. Therefore, it is clear that
some of the chiral complex was actually in the organic phase but that the amount of the complex was too
little to give an enantioselectivity higher than 83% ee. On the other hand, the enantioselectivity in the

60
toluene-FC-72 biphase system was somewhat higher in spite of the lack of excess amount of Ti(O-iPr)4.
The presence of excess amount of Ti(O-iPr)4 is reported to be indispensable for the reaction to result in
high enantioselectivity and yield.9a
When a similar experiment was carried out by using an Et2Zn solution in toluene (1.1 M), the
enantioselectivity was 78% ee in the biphase system. However, the enantioselectivity in the separated
toluene phase was dramatically reduced to 30% ee (49% yield) and the recovery of (R)-FBINOL from
the phase was negligible.
Judging from the results, it is concluded that both phases are necessary to get enantioselectivity
higher than 83% ee in the biphase system, and hexane plays an important role to bring about the high
enantiomeric excess.
Acknowledgements
This work was partially supported by a grant-in-aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan.
References
1. (a) Curran, D. P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1174–1196. (b) Horváth, I. T. Acc. Chem. Res. 1998, 31, 641–650.
2. Juliette, J. J. J.; Rutherford, D.; Horváth, I. T.; Gladysz, J. A. J. Am. Chem. Soc. 1999, 121, 2696–2704.
3. (a) Pozzi, G.; Cinato, F.; Montanari, F.; Quici, S. Chem. Commun. 1998, 877–878. (b) Takeuchi, S.; Nakamura, Y.; Ohgo,
Y.; Curran, D. P. Tetrahedron Lett. 1998, 39, 8691–8694. (c) Pozzi, G.; Cavazzini, M.; Cinato, F.; Montanari, F.; Quici, S.
Eur. J. Org. Chem. 1999, 1947–1955. (d) Klose, A.; Gladysz, J. A. Tetrahedron: Asymmetry 1999, 10, 2665–2674 (fluorous
chiral phosphine and its rhodium and iridium complexes are described). (e) Kleijn, H.; Rijnberg, E.; Jastrzebski, J. T. B. H.;
van Koten, G. Org. Lett. 1999, 1, 853–855 (a catalytic asymmetric reaction in fluorous biphase system of similar strategy
to ours is described in the communication. It was published while our manuscript was submitted to Tetrahedron Lett.).
4. Review: Pu, L. Tetrahedron: Asymmetry 1998, 9, 1457–1477. Letters and articles: (a) Annis, D. A.; Jacobsen, E. N. J.
Am. Chem. Soc. 1999, 121, 4147–4154. (b) Simonsen, K. B.; Jørgensen, K. A.; Hu, Q.-S.; Pu, L. Chem. Commun. 1999,
811-812 and references cited therein.
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7. Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997, 62, 2917–2924.
8. The detailed preparation procedures will be published elsewhere. (R)-FBINOL (III) was a colorless syrup which gradually
crystallized: mp 80–81°C, [α]D26 −16.9 (c 0.463, FC-72); IR (KBr) 3500, 2946, 1614, 1470, 1207, 1144, 1071, 1019, 900,
844, 746, 708, cm−1; 1H NMR (200 MHz) δ 1.00–1.30 (m, 12H, -SiCH2-), 1.80–2.20 (m, 12H, -CF2CH2-), 5.14 (s, 2H,
-OH), 7.22 (d, 2H, ArH, J=8.3 Hz), 7.31 (d, 2H, ArH, J=8.3 Hz), 7.47 (d, 2H, ArH, J=9.0 Hz), 7.99 (s, 2H, ArH), 8.04
(d, 2H, ArH, J=9.0 Hz); MS (EI) m/z (relative intensity) 2422 (M+, 100). Anal. calcd for C68H36F78O2Si2: C, 33.71; H,
1.50; F, 61.16. Found: C, 33.12; H, 1.25; F, 60.93. The enantiomeric excess (ee) of the product was determined to be >99%
by HPLC analysis using a chiral column (DAICEL CHIRALCEL OD, hexane:2-propanol=95:5, flow rate=1.0 mL/min):
tR=8.9 min.
9. (a) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233–6236. (b) Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C.
Tetrahedron: Asymmetry 1997, 8, 585–589.
10. At the outset, a uniphase reaction was carried out under the same conditions as those reported except that (R)-FBINOL
and BTF (CF3C6H5) were used as the chiral ligand and the solvent. The work-up procedure was similar to that described
in the text. The enantioselectivities and the yields for several aromatic aldehydes were as follows: benzaldehyde (84%
ee, 92%); 3-methoxybenzaldehyde (85% ee, 95%), 4-methoxybenzaldehyde (80% ee, 97%), 1-naphthylaldehyde (91% ee,
98%), 2-naphthylaldedehyde (78% ee, 93%). (R)-FBINOL was recovered quantitatively and was reusable.
11. Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714–6715.
12. Soai, K.; Watanabe, M. Tetrahedron: Asymmetry 1991, 2, 97–100.