Catalytic, Three-Component Assembly Reaction for the Synthesis of Pyrrolidines

Article abstract of DOI:10.1021/ol035292y

Equation presented. Copper(I) salts catalyze the three-component assembly reaction between an α-diazo ester, an imine, and various alkenes and alkynes to form substituted pyrrolidines with excellent to good diastereoselectivities in high yields. The transition metal-catalyzed decomposition of the α-diazo compound in the presence of the imine likely generates a transient azomethine ylid that undergoes addition with various dipolarophiles in a highly convergent manner.

Full text of DOI:10.1021/ol035292y

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3487-3490
Catalytic, Three-Component Assembly
Reaction for the Synthesis of
Pyrrolidines
Chris V. Galliford, Melissa A. Beenen, SonBinh T. Nguyen, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208
scheidt@northwestern.edu
Received July 13, 2003
ABSTRACT
Copper(I) salts catalyze the three-component assembly reaction between an r-diazo ester, an imine, and various alkenes and alkynes to form
substituted pyrrolidines with excellent to good diastereoselectivities in high yields. The transition metal-catalyzed decomposition of the r-diazo
compound in the presence of the imine likely generates a transient azomethine ylid that undergoes addition with various dipolarophiles in a
highly convergent manner.
Pyrrolidines are an important class of heterocycles found in
numerous natural products and medicinal structures. Con-
sequently, the efficient construction of these molecules has
received significant attention.1 A powerful method for the
synthesis of these compounds involves the 1,3-dipolar
cycloaddition of an azomethine ylid to an unsaturated partner.
Although many cycloaddition strategies for the construction
of substituted pyrrolidines have been explored, a convergent,
one-pot approach to generate a reactive azomethine ylid in
the presence of a suitable dipolarophile has not fully emerged.
Herein, we report a catalytic, three-component assembly of
pyrrolidines that utilizes a convenient copper(I) catalyst to
generate an azomethine ylid in situ that undergoes subsequent
addition to alkenes and alkynes (Scheme 1).
have focused predominantly on thermal ring-opening of
aziridines,3 deprotonation of R-imino esters,4 and exposure
of R-silylammonium salts to fluoride.5 A very attractive and
mild method for accessing azomethine ylids is the combina-
tion of a metallocarbenoid species with an imine (1, Scheme
1). The 1,3-dipole intermediate A generated in situ can then
be employed in a cycloaddition process when an appropriate
dipolarophile (3) is present.6 Related strategies have been
successful involving rhodium(II)-catalyzed intramolecular
cycloadditions of R-diazo carbonyl compounds.7 However,
the intermolecular, three-component strategy has not received
the same attention. Our current investigations of new catalytic
reactions led us to explore this process, thereby differentiating
Dipolar cycloadditions utilizing azomethine ylids and
related species are important and concise methods for the
stereoselective synthesis of nitrogen-containing five-mem-
bered rings.2 Past approaches to generate 1,3-dipolar species
Scheme 1. Catalytic, Three-Component Assembly of
Pyrrolidines
(1) (a) Pichon, M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927-
964. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435-446 and references
therein. (c) Broggini, G.; Zecchi, G. Synthesis 1999, 905-917. (d) Pearson,
W. H. Pure Appl. Chem. 2002, 74, 1339-1347. (e) Pearson, W. H.; Stoy,
P. Synlett 2003, 903-921.
10.1021/ol035292y CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/21/2003

the positions of the pyrrolidine ring simultaneously in a
convergent, one-pot reaction.8
dichoromethane (entry 2, 91%), 1,2-dichloroethane (entry 3,
40%), and chloroform (entry 4, 71%). The reaction per-
formed in diethyl ether proceeds in 75% yield (entry 5) but
does not afford the desired product in more coordinating
ethereal solvents such as THF and DME (entries 6 and 7),
possibly due to interactions with the copper(I) catalyst. When
hydrocarbon solvents such as hexanes (entry 8) or toluene
(entry 9) are employed, the yield of 4a is moderate (58 and
54%, respectively). In all solvents we examined, the di-
astereoselectivity of the reaction (eq 1) was determined to
be exclusively the 2,5-trans-pyrrolidine stereoisomer by 1H
NMR (500 MHz, >20:1) analysis of the unpurified reaction
mixtures.9
We began the exploration of this cycloaddition process
by surveying different potential catalysts and solvents in the
presence of N-benzylidene imine (1a), dimethyl acetylene-
dicarboxylate (DMAD, 3a), and ethyl diazoacetate (EDA,
2a) (Table 1, eq 1). Gratifyingly, both copper(I) trifluo-
Table 1. Catalytic, Three-Component Coupling of
N-Benzylidine Imine (1a), EDA (2a) and DMAD (3a) (Eq 1)
The effect of catalyst loading was then determined using
the same reaction conditions (Table 2, eq 2). Although
copper(I) triflate is commercially available as the dimer‚
benzene complex, we observe higher yields with catalyst
prepared in our laboratory.10 The reaction proceeds well with
10 mol % (entry 1, 91% yield) and 5 mol % (entry 2, 60%
yield) [Cu(OTf)]. However, the yield decreases to less than
20% after the catalyst loading is reduced to 2.5 and 1 mol
% (entries 3 and 4).
time (h),
entry
catalyst
solvent
CH2Cl2
temp (°C) yield (%)
b
1
2
3
4
5
6
7
8
9
Rh2OAc4
13.5, 40
4, 40
62
91
40
71
75
nre
nr
[Cu(SO3CF3)]c CH2Cl2
d
[Cu(SO3CF3)]
[Cu(SO3CF3)]
[Cu(SO3CF3)]
[Cu(SO3CF3)]
[Cu(SO3CF3)]
[Cu(SO3CF3)]
[Cu(SO3CF3)]
CHCl3
ClCH2CH2Cl
Et2O
4, 60
4, 60
6, 38
THF
DME
hexanes
toluene
14, 60
13.5, 60
6, 65
Table 2. Effect of Catalyst Loading and R-Diazo Ester
Substitution on Catalytic Pyrrolidine Synthesis (Eq 2)a
58
54
6, 65
a Diastereomeric ratios determined by H NMR (500 MHz) spectra of
unpurified reaction mixtures. Relative stereochemistry of 4a was assigned
by analogy to 10 (X-ray structure, see Figure 1). b EDA (2a, l equiv) in
CH2Cl2 (2.5 mL) was added over 2 h to a solution of imine (1a, 3 equiv),
DMAD (3a, 3 equiv), and Rh2OAc4 (1 mol %) in CH2Cl2 (5 mL) then
heated at reflux for 12 h. c Reaction conditions: a solution of EDA (2a, 3
equiv) in CH2Cl2 (2.5 mL) was added via syringe pump over 3 h to a
solution of imine (1a, 3 equiv), DMAD (3a, 1 equiv), and [Cu(OTf)]2‚C6H6
(10 mol %) in CH2Cl2 (5 mL) with heating at the indicated temperature.
The reaction was stirred for an additional hour; the solvent was removed,
and the residue was purified on SiO2. d Passed through Al2O3 immediately
prior to use. e No reaction.
1
entry mol % [CuOTf] diazo ester yield (%)
drb
compd
1
2
3
4
5
10
5
2.5
1
10
2a
2a
2a
2a
2b
91
60
18
12
83
20:1
20:1
20:1
20:1
20:1
4a
4a
4a
4a
4b
a Reaction conditions: a solution of diazo ester (2a,b, 3 equiv) in CH2Cl2
(2.5 mL) was added via syringe pump over 3 h to a solution of imine (1a,
3 equiv), DMAD (3a, 1 equiv), and [Cu(OTf)]2‚C6H6 in the indicated
amounts in CH2Cl2 (5 mL) with heating at reflux. b Diastereomeric ratios
determined by 1H NMR (500 MHz) spectra of unpurified reaction mixtures.
romethanesulfonate, (C6H6)‚[Cu(OTf)]2, and rhodium(II)
acetate dimer are catalysts for the reaction, with copper(I)
being superior in terms of yield and reliability. The cyclo-
addition is highest yielding in chlorinated solvents such as
(2) (a) Harwood, L. M.; Vickers, R. J. In The Chemistry of Heterocyclic
Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products.; Padwa, A., Pearson, W. H.,
Eds.; Wiley: New York, 2002; Vol. 59, pp 169-252. (b) Doyle, M. P.;
Yan, M.; Hu, W. H.; Gronenberg, L. S. J. Am. Chem. Soc. 2003, 125, 4692-
4693 and references therein.
(3) (a) Heine, H. W.; Peavy, R. Tetrahedron Lett. 1965, 3123-3126.
(b) Padwa, A.; Hamilton, L. Tetrahedron Lett. 1965, 4363-4367. (c)
Huisgen, R.; Scheer, W.; Szeimies, G.; Huber, H. Tetrahedron Lett. 1966,
397-404. (d) Bartnik, R.; Mloston, G. Tetrahedron 1984, 40, 2569-2576.
(e) DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem. 1985, 50, 2309-
2315. (f) Wenkert, D.; Ferguson, S. B.; Porter, B.; Qvarnstrom, A.; McPhail,
A. T. J. Org. Chem. 1985, 50, 4114-4119.
(4) (a) Grigg, R.; Kemp, J.; Sheldrick, G.; Trotter, J. Chem. Commun.
1978, 109-111. (b) Grigg, R.; Kemp, J. Tetrahedron Lett. 1980, 21, 2461-
2464.
To differentiate the resulting esters from the reaction for
future synthetic endeavors, various R-diazo esters were
utilized in the reaction (Table 2). As indicated earlier,
commercial ethyl diazoacetate affords high yields of the
desired pyrrolidine 4a (Table 1). Additionally, use of tert-
butyl diazoacetate (entry 5) produces the substituted pyrro-
lidine (4b) in 83% yield.
(7) (a) Padwa, A. Top. Curr. Chem. 1997, 189, 121-158 and references
therein. (b) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda,
C.; Watanabe, N.; Hashimoto, S.-i. J. Am. Chem. Soc. 1999, 121, 1417-
1418.
(8) During the last stage of preparation of our manuscript, a related
approach to pyrrolidines using Ru(CO)porphyrin catalysts appeared in the
literature: Li, G.-Y.; Chen, J.; Yu, W.-Y.; Hong, W.; Che, C.-M. Org. Lett.
2003, 5, 2153-2156.
(9) See Supporting Information for details.
(10) Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95, 1889-
1897. Yield (eq 1) with 10 mol % commercial [CuOTf]: 10-25%
(5) Vedejs, E.; West, F. G. Chem. ReV. 1986, 86, 941-955 and references
therein.
(6) This process has been observed previously in the catalytic synthesis
of aziridines from imines: (a) Bartnik, R.; Mloston, G. Tetrahedron 1984,
40, 2569-2576. (b) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. Engl. 1995, 34, 676-678.
3488
Org. Lett., Vol. 5, No. 19, 2003

Encouraged by the results from optimizing this initial
reaction, we examined the scope of this process regarding
substitution on the nitrogen atom (Table 3). As with our
earlier optimization studies, dimethyl acetylene-dicarboxy-
late (DMAD, 3a) was employed as the dipolarophile, ethyl
diazoacetate (EDA, 2a) as the carbenoid source, and 10 mol
% [CuOTf] as the catalyst. As the data from Table 3 indicate,
the reaction proceeds with halogen or alkoxy substitution
on the N-phenyl ring (entries 2 and 3), but not with an
electron-withdrawing nitro group (entry 4). Surprisingly, the
reaction with the more basic N-benzyl imine of benzaldehyde
(1e, entry 5) generated the N-benzyl pyrrolidine (7), although
only in 43% yield.
Table 4. Catalytic, Three-Component Coupling of EDA (2a),
DMAD (3a), and Various N-Phenyl Imines (Eq 4)a
entry
R
yield (%)
drc
compd
1
2
3
4
5
6
7
8
9
Ph
91
86
nrd
79
77
74
94
54
51
35
20:1
20:1
4a
8
9
10
11
12
13
14
15
16
4-CH3Ph
4-NO2Ph
4-BrPh
4-ClPh
2-ClPh
20:1
20:1
20:1
20:1
20:1
20:1
20:1
2-Furyl
Table 3. Effect of Nitrogen Substitution of Imine on Catalytic
Pyrrolidine Synthesis (Eq 3)a
4-OMePh
3-OMePh
cyclohexyl
10
a Reaction conditions: a solution of EDA (2a, 3 equiv) in CH2Cl2 (2.5
mL) was added via syringe pump over 3 h to a solution of imine (3 equiv),
DMAD (3a, 1 equiv) and [CuOTf] (10 mol %) in CH2Cl2 (5 mL) heating
at the indicated temperature. The reaction was stirred for an additional hour,
the solvent was removed and the residue was purified on SiO2.
b [Cu(OTf)]2•C6H6. c Diastereomeric ratios determined by 1H NMR (500
MHz) spectra of unpurified reaction mixtures. d No reaction.
entry
R
yield (%)
drc
compd
1
2
3
4
5
Ph (1a )
91
75
43
nrd
43
>20:1
>20:1
>20:1
4a
5
6
4-ClPh (1b)
4-OMePh (1c)
4-NO2Ph (1d )
PhCH2 (1e)
(Figure 1). The relative stereochemistry of 10 was determined
to be trans with respect to the 2 and 5 positions of the
pyrrolidine ring.13
>10:1e
7
a Reaction conditions: a solution of EDA (2a, 3 equiv) in CH2Cl2 (2.5
mL) was added via syringe pump over 3 h to a solution of imine (1a-e, 3
equiv), DMAD (3a, 1 equiv), and CuOTf (10 mol %) in CH2Cl2 (5 mL)
with heating at the indicated temperature. b [Cu(OTf)]2‚C6H6. c Diastereo-
meric ratios determined by 1H NMR (500 MHz) spectra of unpurified
reaction mixtures. Relative stereochemistry of 5-7 were assigned by analogy
to 10 (X-ray structure, see Figure 1). d No reaction. e As determined by
gas chromatography.
The impact of substitution on the benzylidene portion of
N-phenyl imines on the cycloaddition process was also
explored. We again employed dimethyl acetylene-dicar-
boxylate (DMAD, 3a) as the dipolarophile and ethyl di-
azoacetate (EDA, 2a) as the carbenoid source with 10 mol
% [CuOTf] as the catalyst. As Table 4 indicates, the reaction
tolerates electron-withdrawing substituents (entries 4-6).
Interestingly, inclusion of a nitro group in the substrate
produces no reaction (entry 3). This deleterious effect of a
nitro group on pyrrolidine formation was previously observed
(Table 3, entry 4), and we postulate that the nitro group is
deactivating the copper catalyst in both cases.11 Electron-
donating groups decrease the yield of the reaction (entries 8
and 9), but substantial quantities of product are still isolated.
Cyclohexyl-N-phenyl imine was also utilized in the reaction
(entry 10, 35% yield).12
Figure 1. ORTEP representation of the crystal structure of
substituted pyrrolidine 10. Thermal ellipsoids are drawn at 50%
probability.
Crystallization of 10 (Table 4, entry 4) from ether yielded
single crystals that were analyzed by X-ray crystallography
We have also examined the scope of our three-component
coupling with regard to the dipolarophile structure (Table
5). Electron-deficient alkenes undergo cyclization readily to
(11) For an example of a nitro group binding to copper(I), see: Yokota,
S.; Tachi, Y.; Nishiwaki, N.; Ariga, M.; Itoh, S. Inorg. Chem. 2001, 40,
5316-5317.
(12) Yield suffers presumably due to the instability of the starting material
imine under the reaction conditions.
(13) Crystallographic data for 10 have been deposited with the Cambridge
Crystallographic Data Centre. See Supporting Information for details.
Org. Lett., Vol. 5, No. 19, 2003
3489

Table 5. Three-Component Assembly Reaction of
N-Benzylidene Imine (1a), EDA (2a), and Dipolarophiles
Catalyzed by [CuOTf]a
Figure 2. Proposed model for the three-component assembly of
2,5-trans-pyrrolidines.
azomethine ylid intermediate with the carbenoid carbon cis
to the benzylidene substituent. We are currently engaged in
determining whether this transient species is interacting with
the metal center. The rate of (E)-(Z) isomerization of the
azomethine ylid is apparently slower than the rate of the
cycloaddition since only 2,5-trans stereochemistry of the
resulting substituted pyrrolidine is observed. In addition, the
dipolarophile alkene geometry is directly translated to the
cycloaddition products: trans-alkenes (Table 4, entries 1,
3, and 5) give 3,4-trans products, and cis-alkenes (entries 2)
afford 3,4-cis products. The factors that govern the endo and
exo facial selectivity (with respect to the benzylidene
substituent) of the azomethine ylid are currently under
investigation.
In summary, the combination of an R-diazo ester and an
imine in the presence of a copper(I) catalyst generates a
transient azomethine ylid. This 1,3-dipole, generated in situ,
undergoes diastereoselective cycloadditions with activated
dipolarophiles to afford highly substituted pyrrolidines in a
convergent, three-component assembly reaction. Notably, this
process is capable of generating four contiguous stereogenic
centers in one operation by employing a readily available
catalyst. Our current efforts are focused on the development
of the analogous asymmetric three-component coupling
reaction and the utilization of these processes toward the
synthesis of bioactive natural products.
a Reaction conditions: a solution of EDA (2a, 3 equiv) in CH2Cl2 (2.5
mL) was added via syringe pump over 3 h to a solution of imine (1a, 3
equiv), dipolarophile (3b-e, 1 equiv) and 10 mol % [Cu(OTf)]2‚C6H6 in
CH2Cl2 (5 mL). The reaction was stirred for an additional hour; the solvent
was removed, and the residue was purified on SiO2. b Diastereomeric ratios
determined by 1H NMR (500 MHz) spectra of unpurified reaction mixtures.
Minor products (not shown) possess inverted stereocenters at C3 and C4.
Relative stereochemistry of products were assigned by analogy to the X-ray
crystal structure of 10 (Figure 1) and known compound 23; see Supporting
Information for details. c EDA (2a, 1 equiv), imine (1a, 1 equiv), di-
polarophile (3f-h, 6 equiv).
Acknowledgment. Support for this research has been
provided by Northwestern University. M.A.B. thanks North-
western University for a Summer Undergraduate Research
Grant. We thank Dr. B. Ramirez and Dr. C. Stern of the
Analytical Services Laboratory (NU) for assistance with
NMR experiments and single-crystal X-ray diffraction,
respectively.
afford the desired substituted pyrrolidines (entries 1-7). In
some cases, an excess of the less-reactive dipolarophile was
required (entries 5-7) to minimize competitive cycloaddition
with fumarate (3b), which results from Cu(I)-catalyzed EDA
dimerization. In the reactions employing unsymmetrical
dipolarophiles (entries 5 and 7), no regioisomers were
observed.
Our current working model of this reaction is shown in
Figure 2). The combination of copper(I) and diazo com-
pounds produces the corresponding metallocarbenoid. The
presence of an imine during this process generates an
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds, as well
as X-ray crystallographic data for 10 in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035292Y
3490
Org. Lett., Vol. 5, No. 19, 2003