Enantioselective synthesis of arylamines through Zr-catalyzed addition of dialkylzincs to imines. Reaction development by screening of parallel libraries [5]

Full text of DOI:10.1021/ja003747y

984
J. Am. Chem. Soc. 2001, 123, 984-985
Parallel libraries were constructed to establish the appropriate
reaction parameters. Imines derived from condensation of ben-
zaldehyde and benzylamine, aminodiphenylmethane, aniline,
2-aminophenol, o-anisidine, and 2,4-dimethoxyaniline constituted
the initial substrate pool. Toluene was chosen as the solvent, since
its low volatility leads to more reliable data from ligand screening
(minimum concentration variation of library samples). Com-
mercially available Et2Zn was used as the alkylating agent. The
following metal salts were screened: CuCN, Cu(OAc)2, CuOTf,
Ti(Oi-Pr)4, Zr(Oi-Pr)4‚HOi-Pr, BF3‚Et2O, ZnCl2, AlBr3, Sc(OTf)3.
Since both early and late transition metals were incorporated
within our search, the phenol-based Schiff base derived from
naphthaldehyde (1) and (2-diphenylphosphino) benzaldehyde8 (2)
served as preliminary chiral ligands (both aldehydes are com-
mercially available). L-Val was positioned at the AA1 site, and
L-Phe served as the AA2, as these two amino acids are relatively
inexpensive. We judged that, if necessary, positional optimization
would be carried out at the Schiff base and AA1 and AA2 sites
for enhanced enantioselectivities.7b-e
Enantioselective Synthesis of Arylamines Through
Zr-Catalyzed Addition of Dialkylzincs to Imines.
Reaction Development by Screening of Parallel
Libraries
James R. Porter, John F. Traverse, Amir H. Hoveyda,* and
Marc L. Snapper*
Department of Chemistry, Merkert Chemistry Center
Boston College, Chestnut Hill, Massachusetts 02467
ReceiVed October 23, 2000
Efficient and asymmetric preparation of amines is an important
objective in organic synthesis.1 Myriad chiral auxiliaries2 and
ligands (stoichiometric)3 have thus been reported that allow the
enantioselective addition of alkylmetals to CdN bonds. The
groups of Denmark4 and Tomioka5 have accomplished the
catalytic addition of alkyllithiums to imines, where appreciable
levels of enantioselectivity are detected (up to 82% ee) in the
presence of 10-20 mol % of amine chiral ligands. We are
interested in the possibility of a catalytic asymmetric approach
to the addition of dialkylzincs to imines (eq 1).6 Our preference
Screening studies (20 mol % metal and ligand) indicate that
the Zr and Ti salts provide higher levels of reactivity and
selectivity in conjunction with phenolic Schiff base ligands when
o-anisidine derivatives are used as substrates (25-98% conversion
and 40-75% ee). With the remaining substrates and metal salts,
<5% conversion and ee is detected. The phosphine-based ligand
provided less conversion and <5% ee with all metals and
electrophiles. Further examination of the above parameters
indicated that Zr(Oi-Pr)4‚HOi-Pr delivers more selective and
efficient additions than Ti(Oi-Pr)4 (88% ee, >98% conversion
vs 62% ee, 43% conversion).9 Positional optimizations at the
Schiff base, AA1, and AA2 sites (∼20 ligands screened) were
carried out subsequently. These studies established that, as shown
in entry 1 of Table 1, with 10 mol % 3 and 10 mol % Zr(Oi-
Pr)4‚HOi-Pr at 0-22 °C, amine 4 is obtained from the corre-
sponding o-anisidyl arylimine10 in 93% ee and 84% isolated yield.
As depicted in entry 2, with 1 mol % 3, reaction efficiency and
selectivity suffer (81% ee, 10% conversion, 24 h). When the
amount of the chiral ligand 3 is reduced to 1 mol % but that of
the less valuable Zr salt is increased to 20 mol % (entry 3),
catalytic alkylation proceeds efficiently and enantioselectively
(95% ee, >98% conversion). Remarkably, even in the presence
of 0.1 mol % 3 and 20 mol % Zr(Oi-Pr)4‚HOi-Pr, the asymmetric
alkylation takes place rapidly to afford 4 in 93% ee (entry 4).11
As the data summarized in Table 1 illustrate, Zr-catalyzed
addition of an Et group to a variety of imines proceeds to >98%
conversion within 24 h (except for entries 4-6, requiring 48 h)
to afford the desired chiral amines in >88% ee and >62% yield.A
number of additional issues merit mention: (1) As the result in
entry 7 indicates, where the Schiff base from 2-naphthalene
carboxaldehyde is used as the electrophile, reactions involving
for alkylzincs is partly because of their functional group tolerance.
An advantage of the above attribute is that modular peptide-based
ligands (e.g., 1, below) can be used to effect enantioselective
catalysis.7 Herein, we disclose efficient Zr-catalyzed imine
alkylations promoted by peptide-based chiral ligands that afford
arylimines in 84-98% ee and 60-98% isolated yield.
(1) Federsel, H.-J.; Collins, A. N.; Sheldrake, G. N.; Crosby, J. Chirality
in Industry II; John Wiley and Sons: Chichester, 1997; pp 225-244.
(2) For example, see: Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999,
121, 268-269.
(3) For representative examples of addition of dialkylzincs to imines
(stoichiometric ligand), see: (a) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem.
Soc., Chem. Commun. 1992, 1097-1098. (b) Andersson, P. G.; Guijarro, D.;
Tanner, D. J. Org. Chem. 1997, 62, 7364-7375. (c) Franz, D. E.; Faessler,
R.; Carreira, E. M. J. Am. Chem. Soc. 1999, 121, 11245-11246. (d) Jimeno,
C.; Reddy, K. S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A. Org. Lett.
2000, 2, 3157-3159. For related processes involving other alkylmetals, see:
(e) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111, 8266-
8268. (f) Weber, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1992, 31,
84-86. (g) Itsuno, S.; Sasaki, M.; Kuroda, S.; Ito, K. Tetrahedron: Asymmetry
1995, 6, 1507-1510. (h) Inoue, I.; Shindo, M.; Koga, K.; Kanai, M.; Tomioka,
K. Tetrahedron: Asymmetry 1995, 6, 2527-2533. For related reviews, see:
(i) Bloch, R. Chem. ReV. 1998, 98, 1407-1438. (j) Denmark, S. E.; Nicaise,
O. J.-C. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; pp 924-958.
(4) (a) Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65, 5875-5878.
(b) Denmark, S. E.; Nakajima, N.; Nicaise, O. J.-C. J. Am. Chem. Soc. 1994,
116, 8797-8798. For a related review, see: (c) Denmark, S. E.; Nicaise, O.
J.-C. Chem. Commun. 1996, 999-1004.
(5) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett. 1991,
32, 3095-3098.
(6) For a review on catalytic asymmetric additions to imines, see:
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094.
(7) For other catalytic asymmetric C-C bond-forming processes promoted
by peptidic Schiff base ligands, see the following. Ti-catalyzed addition of
CN to aldehydes: (a) Nitta, H.; Yu, D.; Kudo, M.; Mori, A.; Inoue, S. J. Am.
Chem. Soc. 1992, 114, 7969-7975. Ti-catalyzed CN addition to epoxides:
(b) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668-1671.
(c) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.; Snapper, M.
L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1704-1707. Ti-
catalyzed CN addition to imines: (d) Krueger, C. A.; Kuntz, K. W.; Dzierba,
C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 1999, 121, 4284-4285. (e) Porter, J. R.; Wirschun, W. G.;
Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122,
2657-2658.
(8) This class of peptide-based phosphine ligands promotes catalytic
enantioselective conjugate addition of dialkylzincs to cyclic enones: Degrado,
S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc., in press.
(9) Use of other Zr-based salts (e.g., Zr(OEt)4 led to lower selectivity.
(10) For use of o-anisidyl imines in other transformations, see: Saito, S.;
Hatanaka, K.; Yamamoto, H. Org. Lett. 2000, 2, 1891-1894. (b) Adrian, J.
C., Jr.; Barkin, J. L.; Hassib, L. Tetrahedron Lett. 1999, 40, 2457-2460.
(11) Similar effects have been observed in the Ti-catalyzed enantioselective
addition of alkylzinc reagents to aldehydes: Takahashi, H.; Kawakita, T.;
Ohno, M.; Yoshioka, M.; Kobayashi, S. Tetrahedron 1992, 48, 5691-5700.
10.1021/ja003747y CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/13/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 5, 2001 985
Table 1. Zr-Catalyzed Enantioselective Ethyl Addition to
Table 2. Zr-Catalyzed Enantioselective Additions to Arylimines
Aryliminesa
Promoted by Amine-Peptide Ligandsa
a Conditions: (entries 1, 2) 15 equiv of Me2Zn, toluene, 10 mol %
Zr(Oi-Pr)4‚HOi-Pr and ligand, 0 f 22 °C, 48 h; (entry 3) 6 equiv of
(octyl)2Zn at +4 °C. b By 1H NMR analysis. c Isolated yield. d By chiral
HPLC in comparison with authentic material (Chiralcel OD).
aforementioned transformations proceed to <15% conversion.
These observations are consistent with the proposed role of metal
hydrides in the in situ formation of ligands such as 9.14 As shown
in entry 3 of Table 2, catalytic asymmetric addition of (octyl)2Zn
can be carried out efficiently and enantioselectively (98% ee) in
the presence of 15. When ligands 9 and 3 are employed to promote
the formation of 14, ∼65% of the reaction mixture again consists
of the reduced amine product.
The resulting o-anisidine amines constitute a building block
in a number of medicinally important agents.15,16 Moreover, as
the representative example in eq 2 illustrates,17 optically enriched
a Conditions: 3 equiv of Et2Zn, toluene, 0 f 22 °C, 24 h except for
entries 4 and 6 (48 h); 5 equiv of Et2Zn used in entry 4. b By 1H NMR
analysis. c Isolated yield. d By chiral HPLC in comparison with
authentic material (Chiralcel OD for entries 1-8, 10, 11; Chiralcel OJ
for entry 9). e Carried out at +4 °C.
more sterically demanding substrates occur efficiently and with
high asymmetric induction. (2) In contrast to reactions illustrated
in entries 1-7 of Table 1, when ligand 3 is employed in the
catalytic alkylation of electron-deficient imines (entries 8, 9), the
reduced amine product is formed predominantly (10-50%). This
finding suggests that the active chiral ligand may be the derived
peptidic amine and not the original Schiff base. That is, an EtZr
or EtZn complex might undergo rapid â-H elimination to afford
a metal hydride that effects CdN bond reduction. We surmised
that competitive reduction of the highly reactive substrate imine
might preclude the in situ generation of the active amine ligand.12
Accordingly, amine ligand 9 was prepared and used in the
catalytic alkylations depicted in entries 8 and 9 (Table 1). In the
presence of 10 mol % 9 and 11 mol % Zr(Oi-Pr)4‚HOi-Pr (+4
°C), ethyl addition products 8 and 10 are generated efficiently
(95% conversion) in 88% and 90% ee, respectively. (3) As
depicted in entry 10 (Table 1), catalytic formation of 11 from
the corresponding electron-rich imine, promoted by ligand 3, takes
place selectively (82% ee) but slowly (57% conversion, 24 h).
When amine ligand 9 is used, however (entry 11), reaction
efficiency is enhanced (95% conversion, 24 h) and enantioselec-
tivity is increased to 91% ee.13
arylamines can be accessed through oxidative removal of the
anisido group.18
Acknowledgment. This work is dedicated to the memory of our late
colleague Professor George Vogel. Financial support was provided by
the NIH (GM-57212) and DuPont (to A. H. H.). We are grateful to
Professor J. C. Adrian, Jr., K. W. Kuntz, and Dr. H. Mizutani for helpful
suggestions. M.L.S. is a Camille Dreyfus Tecaher-Scholar and a Glaxo-
Wellcome Young Investigator.
Supporting Information Available: Experimental procedures and
spectral and analytical data for all recovered starting materials and reaction
products (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA003747Y
(13) In entries 10, 11, <2% reduced products are detected.
(14) Metal hydride generation likely requires the presence of a â-hydride
within the alkylmetal precursor; use of Me2Zn thus preempts the generation
of such hydrides. Generation of metal hydrides is less facile with â-methylenes
(vs â-Me). For example, see: Negishi, E.; Nguyen, T.; Maye, J. P.; Choueiri,
D.; Suzuki, N.; Takahashi, T. Chem. Lett. 1992, 2367-2370.
(15) While this paper was under review, a report concerning catalytic
asymmetric addition of Et2Zn to imines appeared: Fujihara, H.; Nagai, K.;
Tomioka, K. J. Am. Chem. Soc. 2000, 122, 0000.
As the data in entries 1 and 2 of Table 2 illustrate, with 10
mol % 9 and Zr(Oi-Pr)4‚HOi-Pr, asymmetric addition of Me2Zn
affords 12 and 13 in 88% ee (79% yield) and 84% ee (98% yield),
respectively. Under identical conditions, but with ligand 3, the
(16) For example, see: Annunziata, R.; Cinquini, M.; Cozzi, F.; Molteni,
V.; Schupp, O. Tetrahedron 1997, 53, 9715-9726.
(17) (a) Bhattarai, K.; Cainelli, G.; Panunzio, M. Synlett 1990, 229-230.
(b) Reference 10a.
(12) Preliminary studies indicate that Schiff base ligands are partially
reduced in situ in the presence of Et2Zn and the Zr salt (<2% Et addition to
the CdN bond of ligands).
(18) Significantly lower yields (<20%) are observed when CAN is used
as the oxidant. Kobayashi, S.; Ishitani, H. Ueno, M. J. Am. Chem. Soc. 1998,
120, 431-432.