Catalytic enantioselective addition of dialkylzinc to N-diphenylphosphinoylimines. A practical synthesis of α-chiral amines

Article abstract of DOI:10.1021/ja027673x

The enantioselective addition of dialkylzinc reagents to N-diphenylphosphinoylimines derived from aryl-, furyl-, and cyclopropylaldehydes is efficiently catalyzed by a copper(II) triflate/(R,R)-MeDUPHOS complex. The yields are high (51-98%), and the enant

Full text of DOI:10.1021/ja027673x

Published on Web 01/21/2003
Catalytic Enantioselective Addition of Dialkylzinc to
N-Diphenylphosphinoylimines. A Practical Synthesis of r-Chiral Amines
Alessandro A. Boezio and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
Received July 12, 2002 ; E-mail: andre.charette@umontreal.ca
Table 1. Cu(OTf)2‚L2 Catalyzed Addition of Et2Zn to
The catalytic, enantioselective addition of nucleophiles to imines
is a very important process1 due to the predominant role that
R-chiral amines play in biologically important systems. Efficient
catalysts have been developed for amine synthesis, but the nature
of the starting imine plays a prominent role for the success of these
reactions. Alkynylzinc reagents have been added to nitrones 1,2
whereas dialkylzinc reagents have been added to N-arylimines 2,3
N-sulfonylimines 3,4 and N-acylimines 45 in the presence of the
appropriate chiral catalyst or ligand. Although these methods are
highly enantioselective, harsh conditions are sometimes required
to reveal the amine functionality. A very attractive precursor to
chiral, nonracemic amines is the N-phosphinoylimine 5; however,
its lower electrophilicity has resulted in the observation that
significant amounts of ligands (0.5-1 equiv) were necessary for
obtaining high enantioselectivities.6 Conversely, the main advantage
of this approach is that the resulting R-chiral amine is readily
revealed under mild conditions, making this method very attractive
relative to those requiring oxidizing, reducing, or acidic conditions
for the cleavage. In this communication, we report that the
enantioselective addition of dialkylzinc reagents to N-diphenylphos-
phinoylimines is efficiently catalyzed by a copper(II) triflate/
diphosphine complex.7 The lower electrophilicity of the imine is
overcome by an increased nucleophilicity of the reagent imparted
by the strong donating ability of the ligand.
N-Diphenylphosphinoylimines
c
entry
liganda
conversion (%)b
ee
1
2
3
4
5
6
7
8
9
(R)-BINAP
75
61
95
81
>95
63
96
44
<10
39 (R)
5 (S)
6d
7
23 (R)
13 (S)
5 (R)
36 (R)
93 (S)
38 (S)
nd
(S,S)-DIOP (8)
9d
10
11
12
13
a Unless otherwise noted, 5.5 mol % of the ligand was used. b Conver-
sions were determined by 1H NMR. c Enantiomeric excesses (ee) were
determined by SFC and/or HPLC on chiral stationary phases. The absolute
stereochemistry was established by comparison with literature data. d 11
mol % of the ligand was used.
were significant in many cases, indicating that the ligand is involved
in the addition step. Gratifyingly, (R,R)-Me-DuPHOS (11) gave
an outstanding enantiomeric excess for the addition of diethylzinc
to the N-diphenylphosphinoylimine derived from benzaldehyde.
Quite interestingly, the rate of the reaction and the observed
enantiomeric excess decreased dramatically with more sterically
demanding ligands (compare entry 7 with 8 and 9).
The copper-catalyzed addition of dialkylzinc reagents to elec-
trophiles, which presumably proceeds via an organocopper inter-
mediate, is a well-established process. This exchange has been
successfully used in a number of asymmetric processes such as in
conjugate addition8,9 and in nucleophilic addition reactions.4 Our
interest in the development of new stereoselective methods for the
nucleophilic addition to CdN10 led us to explore new chiral copper‚
phosphine complexes in the nucleophilic addition to N-phosphi-
noylimines. Our initial efforts focused on the identification of the
optimal copper(II) catalyst in terms of both conversions and
enantiomeric ratios. Numerous mono- and bidentate phosphines
were screened, and a small sample of these results is highlighted
in Table 1. The first important conclusion was that the conversions
to the protected amine were very good in most cases. The exceptions
were with weaker donating phosphines (entries 1 and 2) and with
sterically hindered ligands (entries 8 and 9). It appears that the
catalysts based on Cu(OTf)2 and a dialkylarylphosphine or a
diarylalkylphosphine are more reactive that those involving a
triarylphosphine. More importantly, the observed enantiomeric ratios
(R,R)-Me-DuPHOS (11) was chosen as the best chiral ligand
for further optimization, and the results are shown in Table 2. An
increase in catalyst loading from 5.0 to 8.0 mol % led to an
improved enantiomeric excess (entry 1 vs 2). It is apparent in these
reactions that the copper(II) catalyst is initially reduced to a copper-
(I) species by Et2Zn because CuOTf is also a suitable catalyst
precursor. However, the enantiomeric excess is lower under these
9
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J. AM. CHEM. SOC. 2003, 125, 1692-1693
10.1021/ja027673x CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Optimization of the Reaction Conditions
These reaction conditions were then tested on other N-phosphi-
noylimines derived from aryl-, furyl-, and cyclopropyl aldehydes,
and the results are presented in Table 3. The reaction proceeded
extremely well with a wide range of N-phosphinoylimines derived
from aldehydes containing nonenolizable protons. The enantiomeric
excesses are excellent, and the efficiency of the reaction is not
jeopardized by the presence of electron-donating or electron-
withdrawing substituents on the aromatic ring. However, the
presence of electron-donating substituents on the aromatic ring
decreases the rate of the reaction, but slightly higher enantiomeric
excesses were observed. The presence of an ortho- or a meta-
substituent on the ring is also compatible with these reaction
conditions. Other dialkylzinc reagents can also be used, providing
R-chiral amines with excellent enantiomeric excesses (entries 12
and 13).
conversion
entry
x
y
(%)a
eeb
1
2
5.0
8.0
5.5
8.5
5.5
5.5
5.0
5.0
3.0
3.0
96
96
85
86
95
88
95
93
93
96
86
96
96
96
93
95
3
2.5c
5.0
4d
5
10.0
10.0
6.0
6e
7
8
10.0
a Conversions were determined by 1H NMR. b Enantiomeric excesses
were determined by HPLC on chiral stationary phase. See the Supporting
Information for details. c (CuOTf)2‚C6H5CH3 was used. d Zn(OTf)2 (5 mol
%) was used as an additive. e Reaction was carried out at -15 °C.
In conclusion, we have reported the first practical new catalytic
system for the addition of dialkylzinc reagents to N-diphenylphos-
phinoylimines.12 Both antipodes of Me-DuPHOS are commercially
available, and the reaction conditions are quite mild. Further
applications of this methodology will be reported in due course.
Table 3. Addition of Et2Zn to N-Diphenylphosphinoylimines
Acknowledgment. This work was supported by the E. W. R.
Steacie Fund, NSERC, Merck Frosst Canada, Boehringer Ingelheim
(Canada), and the University de Montre´al. A.A.B. is grateful to
NSERC (PGF B), F.C.A.R. (B2), and Boehringer Ingelheim for
postgraduate fellowships.
Supporting Information Available: Experimental procedure and
conditions for the separation of enantiomers for analytical purposes
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Reviews: (a) Bloch, R. Chem. ReV. 1998, 98, 1407-1438. (b) Kobayashi,
S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094.
(2) Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem.
Res. 2000, 33, 373-381.
(3) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 984-985. (b) Porter, J. R.; Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 10409-10410. (c)
Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638-5639.
(4) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122,
12055-12056.
a Enantiomeric excesses were determined by HPLC on chiral stationary
phase. The absolute stereochemistry was established by comparison with
the authentic sample, except in entries 4 and 5, which were tentatively
assigned on the basis of HPLC retention times. See the Supporting
Information for details. b Absolute stereochemistry has not been established.
c (CuOTf)2‚C6H5CH3 was used in this case.
(5) Dahmen, S.; Brase, S. J. Am. Chem. Soc. 2002, 124, 5940-5941.
(6) (a) Jimeno, C.; Reddy, K. S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera,
A. Org. Lett. 2000, 2, 3157-3159. (b) Sato, I.; Kodaka, R.; Soai, K. J.
Chem. Soc., Perkin Trans. 1 2001, 2912-2914. (c) Pinho, P.; Andersson,
P. G. Tetrahedron 2001, 57, 1615-1618. (d) Zhang, H. L.; Zhang, X.
M.; Gong, L. Z.; Mi, A. Q.; Cui, X.; Jiang, Y. Z.; Choi, M. C. K.; Chan,
A. S. C. Org. Lett. 2002, 4, 1399-1402.
(7) For recent examples of Cu‚phosphine catalysts: (a) Jurkauskas, V.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 2892-2893. (b) Ferraris,
D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J.; Ryzhkov, L.; Taggi,
A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67-77.
reactions conditions presumably due to the greater sensitivity of
the catalyst precursor (entry 3). Because the enantiomeric excesses
dropped significantly with lower catalyst loadings, several additives
were tested to improve the enantioselectivities. We found that the
addition of 5 mol % of Zn(OTf)2 played a significant role at lower
loadings (entry 4). We reasoned that the increase in concentration
of EtZnOTf (through the Schlenk equilibrium between Et2Zn and
Zn(OTf)2) improved the catalytic turnovers and the regeneration
of the active copper catalyst (entry 4).9 We later found that it was
more convenient to simply use a slight excess of Cu(OTf)2 relative
to the chiral ligand (entry 5-8). The ligand loading could be
decreased to 3 mol % without any erosion of the enantiomeric
excesses (entry 8).11
(8) (a) Alexakis, A.; Mutti, S.; Normant, J. F. J. Am. Chem. Soc. 1991, 113,
6332-6334. (b) Alexakis, A.; Burton, J.; Vastra, J.; Mangeney, P.
Tetrahedron: Asymmetry 1997, 8, 3987-3990.
(9) (a) deVries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2374-2376. (b) Feringa, B. L.; Pineschi, M.; Arnold,
L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997,
36, 2620-2623.
(10) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J.
Am. Chem. Soc. 2001, 123, 11829-11830.
(11) The ligand loading could be decreased down to 1 mol % under these
conditions when the reaction is carried out on larger scale.
(12) 15a is cleaved in 95% yield and no racemization with 2 M HCl/MeOH
(room temperature, 4 h).
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