Highly enantioselective Ag(I)-catalyzed [3 + 2] cycloaddition of azomethine ylides

Article abstract of DOI:10.1021/ja025969x

A highly reactive Ag(I)-catalyzed [3 + 2] cycloaddition of azomethine ylides is founded using AgOAc as the catalytic precursor and phosphines as ligands. Using a new bis-ferrocenyl amide phosphine (FAP) as the ligand, we found that high enantioselectiviti

Full text of DOI:10.1021/ja025969x

Published on Web 10/19/2002
Highly Enantioselective Ag(I)-Catalyzed [3 + 2] Cycloaddition of Azomethine
Ylides
James M. Longmire, Bin Wang, and Xumu Zhang*
Department of Chemistry, 152 DaVey Laboratory, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
Received February 18, 2002
The reaction of azomethine ylide 1,3-dipoles with olefinic dipo-
larophiles forms highly substituted five-membered ring nitrogen
heterocycles. This extremely versatile and atom economical process
has been applied toward the syntheses of substituted prolines, which
can be used as new catalysts1 and served as important motifs in
many biologically active molecules.2,3 Among the different versions
of this reaction,4 the most practical approach has been the interaction
between stabilized N-metalated azomethine ylides and π-deficient
alkenes.5,6 This method allows the cycloaddition to proceed under
mild reaction conditions and with a high degree of diastereocontrol.7
Silver(I) and lithium(I) metal cations are most commonly used to
facilitate the reaction along with an excess of base such as a tertiary
amine. The reaction is usually carried out in a stoichiometric fash-
ion, and only few reports mention the use of substoichiometric
amounts of metal salts.8
Figure 1. Chiral phosphine ligands screened for the AgOAc catalyzed
cycloaddition of 7a with dimethyl maleate.
We were intrigued by the Ag-catalyzed cycloaddition of azome-
thine ylides and the corresponding asymmetric reaction. Previous
work in this area has focused mainly on the use of chiral auxiliaries
on the dipolarophile9 or dipole10 substrates. The use of chiral transi-
tion metal catalysts is relatively unexplored.11 Grigg et al. have re-
ported ee’s up to 96% using a stoichiometric amount of Co(II) and
a chiral ephedrine ligand for the cycloaddition of R-imino esters.
In another paper, up to 70% ee has been reported by Grigg using
AgOTf and a chiral bisphosphine ligand. However, detailed reaction
conditions such as catalyst loading and substrate scope were not
reported, and a full account of this work has yet to be disclosed.
Herein we wish to report a highly reactive Ag(I)-catalyzed [3 + 2]
cycloaddition of azomethine ylides using AgOAc as the catalytic
precursor and phosphines as ligands. Using a new chiral ferrocene
phosphine as the ligand, we found that high enantioselectivities
have been achieved in the [3 + 2] cycloaddition of azomethine
ylides.
In our study, we discovered that AgOAc is an excellent catalytic
precursor and high activity can be achieved. For example, 1 mol
% AgOAc with 2 mol % PPh3 can effectively catalyze the cyclo-
addition of 7a with dimethylmaleate to yield only the endo dia-
stereomer 8a in high yield (Scheme 1).12 AgOAc has low solubility
in most organic solvents, and addition of PPh3 forms a highly
soluble catalyst. The high reactivity and diastereoselectivity of the
AgOAc/PPh3 system encouraged us to investigate a number of chiral
bisphosphine ligands to develop a highly enantioselective process.
Some of the phosphine ligands that were screened are listed in
Figure 1.
Scheme 1
the endo diastereomer under these reaction conditions. The BINAP
(1)13a and Me-DuPhos13b (3) ligands gave poor enantioselectivity
(13% ee with 1, 23% ee with 3), and poor diastereoselectivity was
observed in the case of BINAP (endo/exo ) 3:1). The PennPhos13c
(4) and BICP13d (5) ligands, developed in our laboratories, also
gave very low enantioselectivities (27% ee with 4 and 13% ee with
5). Interestingly, the Trost ligand13e (2) provided a considerably
higher enantioselectivity of 59% ee. Recently, we reported the syn-
thesis of a new bis-ferrocenyl amide phosphine (FAP),13f,g 6a, for
the Pd-catalyzed allylic alkylation reaction. This ligand is similar
to the Trost ligand; however, the ferrocene units add an additional
element of chirality and also impart different steric and electronic
properties. A significant improvement in reactivity and enantiose-
lectivity was observed with the FAP ligand (6a) for the cycload-
dition of 7a providing endo-8a in 94% isolated yield and 76% ee.
Further improvement in enantioselectivity to 86% ee was achieved
by replacing the phenyl groups in 6a to 3,5-dimethylphenyl (xylyl-
FAP, 6b).
Using ligand 6b, we investigated a variety of R-iminoester
substrates (Table 1). A number of R-(arylimino)esters were cyclized
in good yields and high enantioselectivities (up to 97% ee) (entries
1-11). On the other hand, R-(alkylimino)esters are less reactive,
requiring prolonged reaction times at room temperature and yielding
cycloaddition products of slightly lower enantioselectivity (entries
12 and 13). Again, only the endo products were observed.
To perform the Ag-catalyzed asymmetric reaction, the cycload-
dition was carried out in toluene using 3 mol % AgOAc, 3.3 mol
% ligand, and 10 mol % i-Pr2NEt at room temperature. With the
exception of BINAP (1), all ligands that were screened gave only
* To whom correspondence should be addressed. E-mail: xumu@chem.
psu.edu.
9
13400
J. AM. CHEM. SOC. 2002, 124, 13400-13401
10.1021/ja025969x CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Variation of the R-Substituent on 7 for the Cycloaddition
with Dimethylmaleate
tion. Up to four stereogenic centers can be established in this
multicomponent coupling reaction from readily available materials
such as aldehydes, aminoesters, and dienophiles. Further work
toward exploring the asymmetric intramolecular azomethine ylide
[3 + 2] cycloaddition reaction and rapid synthesis of biologically
active compounds will be forthcoming.
Acknowledgment. This work was supported by a Camille and
Henry Dreyfus Teacher-Scholar Award and a NSF grant.
endo-8
entrya
7, R
)
time (h)
% yieldc
% eed
Supporting Information Available: Experimental procedures,
spectral data for all compounds, and stereochemical proofs (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
1
2
3
4
5
6
7
8
9
10
11
12b
13b
Ph (7a)
7
7
7
7
7
7
7
7
7
14
7
48
48
87
93
98
96
96
90
96
97
73
98
98
82
82
87
88
92
92
90
96
86
90
85
97
84
70
81
p-toluyl (7b)
p-anisole (7c)
4-chlorophenyl (7d)
4-fluorophenyl (7e)
4-cyanophenyl (7f)
2-chlorophenyl (7g)
o-toluyl (7h)
1-naphthyl (7i)
2-naphthyl (7j)
3-pyridyl (7k)
i-Pr (7l)
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cyclohexyl (7m)
a Conditions: imine (1.0 equiv), dimethyl maleate (1.2 equiv), AgOAc
i
(3 mol %), ligand 6b (3.3 mol %), Pr2NEt (10.0 mol %), toluene (3 mL)
at 0 °C, unless indicated otherwise. b Reactions were run at room temper-
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A variety of dipolarophiles were explored in the cycloaddition
with 7a as outlined in Table 2. Only the endo products were isolated
in all cases. With dimethyl fumarate, the enantioselectivity is
considerably reduced as compared with dimethyl maleate (52% ee
versus 86% ee). Much lower enantioselectivity was also observed
with methyl acrylate (60% ee). The most interesting result is the
markedly improved enantioselectivity on going from methyl acrylate
to a bulky tert-butyl acrylate, 60 and 93% ee, respectively. A fused
bicyclic pyrrolidine was also synthesized in good yield and
enantioselectivity using N-methyl maleimides as the dipolarophile.
Following is our working model: Coordination of the R-imi-
noester to the chiral Ag(I) catalyst, followed by deprotonation with
i-Pr2NEt, forms the reactive metal-bound azomethine ylide dipole.
Chiral ligand 6b effectively blocks one enantiotopic face of the
azomethine ylide, providing pyrrolidine products with high enan-
tioselectivity. The higher ee observed with dimethyl maleate versus
dimethyl fumarate and tert-butyl acrylate versus methyl acrylate
can be explained by the endo-transition state model. More steric
interaction between these substrates and the chiral ligand results
in better enantiodescrimination. This can explain the improved
enantioselectivity observed with xylyl-FAP (6b) as compared to
FAP (6a). The 3,5-dimethyl substitution extends the steric environ-
ment of the ligand and effectively blocks one of the enantiotopic
faces of the azomethine ylide.
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In conclusion, we have developed a highly enantioselective Ag-
(I)-catalyzed azomethine ylide [3 + 2] cycloaddition reaction. These
results demonstrate that FAP ligands are unique for this transforma-
JA025969X
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J. AM. CHEM. SOC. VOL. 124, NO. 45, 2002 13401