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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 2149–2151 2149

Cite this: Chem. Commun., 2012, 48, 2149–2151

Cu-catalyzed asymmetric [3+2] cycloaddition of a-iminoamides with

activated olefinswzMarıa Gonzalez-Esguevillas, Javier Adrio* and Juan C. Carretero*

Received 17th November 2011, Accepted 23rd December 2011

DOI: 10.1039/c2cc17149j

A variety of 2-amido pyrrolidines, includingWeinreb-type amides,

have been prepared with very high exo diastereoselectivity and

enantioselectivitiy in the reaction of a-iminoamides with activated

alkenes catalyzed by CuI–Segphos ligands.

Pyrrolidine derivatives have attracted great attention in recent

years owing to both their abundance in bioactive natural and

unnatural products,1 as well as their applications as chiral

ligands and organocatalysts in asymmetric synthesis.2 Their

importance has prompted the development of different efficient

approaches for their enantioselective synthesis.3 Among them,

the 1,3-dipolar cycloaddition of azomethine ylides with activated

alkenes has emerged as one of the most powerful and atom

economy strategies. Since the first catalytic asymmetric protocols

reported in 2002,4 a wide variety of procedures based on the

combination of a metal salt and a chiral ligand as catalyst system

have been developed.5 In addition, several organocatalytic

asymmetric methods have been recently reported.6 Despite these

impressive achievements, there are still significant limitations,

especially regarding the structural variety of the dipole precursor.

Thus, themajority of procedures deal with the use of a-iminoesters,

providing pyrrolidines with 2-carboxylate substitution. As notable

exceptions to this trend azlactones,7 a-iminophosphonates,8

a-iminonitriles,9 and N-(2-pyridylmethyl)imines10 have been very

recently incorporated into the arsenal of suitable azomethine ylide

precursors for this reaction.

In this context, surprisingly, a-iminoamides have remained

unexplored as azomethine precursors, in spite of the fact that

the expected strong metal coordination ability of the carbonyl

amide group would render this type of species very suitable

bidentate substrates in the formation of the key chiral metallo-

dipole. In addition, the resulting prolineamides are biologically

relevant compounds11 and the chemical versatility of the amide

moiety could offer novel possibilities for further transformations

on the enantioenriched pyrrolidine moiety. Herein we describe

a highly exo-diastereoselective and enantioselective catalytic

asymmetric procedure for the 1,3-dipolar cycloaddition of

a-iminoamides by using CuI/Segphos complexes as catalyst

system. Some aspects of the chemical versatility of the resulting

adducts are also presented.

As model reaction we chose the [3+2] cycloaddition

of 2-(benzylidenamino)-N,N-dimethylacetamide (1a) with

N-methylmalemide (2) in the presence of catalytic amounts

of Cu(CH3CN)PF6,12 a chiral ligand, and Et3N as base, in

THF at room temperature. Among the tested chiral ligands13

Segphos family afforded the best outcome14 (Table 1).

Gratifyingly, Segphos ligand 3a led to the pyrrolidine 4a in

excellent yield, and nearly complete exo-selectivity (>98 :o2)

and enantioselectivity (Z 99% ee) (entry 1). Under these

conditions, the catalyst loading could be reduced to 5 mol%

with similar diastereo- and enantioselectivity (entry 2). However

a further reduction to 3 mol% resulted in a much lower

enantioselectivity (Table 1, entry 3). A very similar behaviour

was observed from DM-Segphos ligand 3b (entries 4 and 5).

Interestingly, the use of the bulkier and electron rich

DTBM-Segphos ligand 3c allowed us to reduce the catalyst

loading to 1 mol% maintaining the excellent levels of enantio-

selectivity and exo-selectivity, albeit an excess of a-iminoamide

(1.5 equiv.) and longer reaction times were required (entry 7).

With these optimal reaction conditions in hand, the scope of

Table 1 Optimization studies

Entrya Ligand X t/h Yield 4ab (%) ee 4ac (%)

1 3a 10 10 91 Z 992 3a 5 10 86 Z 993 3a 3 10 88 524 3b 5 30 86 Z 995 3b 3 30 84 706d 3c 3 48 87 Z 997d 3c 1 48 85 Z 99

a Only the exo adduct was detected by 1H-NMR. b In pure adduct 4a

after column chromatography. c By HPLC, see ESI for details.d 1.5 equiv. of iminoamide 1a was used.

Departamento de Quımica Organica, Facultad de Ciencias,Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid,Spain. E-mail: javier.adrio@uam.es, juancarlos.carretero@uam.es;Fax: +34914973966w This article is part of the ChemComm ‘Chirality’ web themed issue.z Electronic supplementary information (ESI) available: Experimentalprocedures, spectroscopic data and NMR spectra. CCDC 846895. ForESI and crystallographic data in CIF or other electronic format seeDOI: 10.1039/c2cc17149j

ChemComm Dynamic Article Links

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2150 Chem. Commun., 2012, 48, 2149–2151 This journal is c The Royal Society of Chemistry 2012

the 1,3-dipolar cycloaddition with regard to the substitution at

the azomethine ylide was investigated (Table 2). All aryl

substituted dipole precursors afforded a single diastereomer

with excellent enantiocontrol regardless of the electronic

nature of the substituent (entries 1–6). However, bulkier

aromatic substrates showed lower reactivity, a higher catalyst

loading (5 mol%) being required to obtain good chemical

yields (entries 7–9). The procedure can be also applied to

heteroaryl substituted glycine derivatives (entry 10) and a,b-unsaturated imines (entry 11) with complete diastereoselectivity

and similar levels of enantioselectivity. The stereochemical and

configurational assignment of 4c was unequivocally established

by X-ray diffraction analysis.15 To further explore other struc-

tural possibilities of this methodology, the influence of the

substitution at the amide on the reactivity and selectivity was

also studied. The procedure tolerates the presence of aromatic

substitution without erosion in the reactivity or selectivity (entry

12). Moreover, we found that the appealing glycine-derived

Weinreb amides16 1n and 1o afforded, under similar conditions,

the corresponding pyrrolidines with excellent yields and enantio-

selectivities (entries 13 and 14).

We next studied other dipolarophiles in this asymmetric

[3+2] cycloaddition of a-iminoamides 1 catalyzed by

CuI–Segphos chiral ligands (Table 3). Monosubstituted

activated alkenes, such as acrylates 5 and 6 and phenylvinyl-

sulfone 7, proved to be excellent dipolarophiles for this

cycloadditon furnishing the corresponding pyrrolidines with

excellent exo-selectivities17 and asymmetric inductions, with

both the N,N-dimethylamide 1a (entries 1 and 4) and the

Weinreb-type amide 1n (entries 2, 3 and 5). In addition, the

enantiopurity of 13n can be enhanced to Z 99% ee by simple

recrystallization with isopropanol (entry 5). On the contrary,

we did not observe reaction under similar conditions, when

(E)-b-nitrostyrene (8) or trans-chalcone (9) were used as

dipolarophiles (entries 6 and 9). Interestingly, this drawback

was overcome using the less sterically hindered Segphos ligand

3a, which afforded the desired pyrrolidines 14a, 14n and 15 in

high yield and enantioselectivity (entries 7, 8 and 10), albeit a

non-complete exo-selectivity was observed when nitrostyrene

was used as dipolarophile (entries 7 and 8).

Table 2 Cu(CH3CN)4PF6/DTBM-Segphos catalyzed 1,3-dipolarcycloaddition of a-iminoamides 1 with N-methylmaleimide

Entrya R1 R2 Product Yieldb (%) eec (%)

1 p-CF3C6H4 Me 4b 98 982 p-BrC6H4 Me 4c 92 993 p-ClC6H4 Me 4d 94 Z 994 p-MeOC6H4 Me 4e 67 965 p-NO2C6H4 Me 4f 86 Z 996 m-MeC6H4 Me 4g 86 967d o-MeC6H4 Me 4h 83 988d 2-Naphtyl Me 4i 76 Z 999d 3-Thienyl Me 4j 95 Z 9910d 5-Br-2-thienyl Me 4k 82 Z 9911 CHQCHPh Me 4l 60 9812 Ph p-FC6H4 4m 83 Z 9913 Ph OMe 4n 71 9814 p-BrC6H4 OMe 4o 79 96

a Only the exo aduct was detected by 1H-NMR. b In pure product

after column chromatography. c By HPLC, see ESI for details.d 5 mol% of catalyst was used.

Table 3 1,3-dipolar cycloaddition of a-iminoamides 1 with other dipolarophiles

Entrya Amide Dipolarophile R1 R2 R3 R4 Ligand Product exo/endo Yieldb (%) eec (%)

1 1a 5 CO2tBu H H Me 3c 11a >98/o2 82 94

2 1n 5 CO2tBu H H OMe 3c 11n >98/o2 50 Z 99

3 1n 6 CO2Me H H OMe 3c 12 >98/o2 60 984 1a 7 SO2Ph H H Me 3c 13a >98/o2 85 Z 995 1n 7 SO2Ph H H OMe 3c 13n >98/o2 95 90 (Z 99)d

6 1a 8 NO2 H Ph Me 3c — — — —7 1a 8 NO2 H Ph Me 3a 14a 85/15 80 918 1n 8 NO2 H Ph OMe 3a 14n 88/12 87 899 1a 9 COPh H Ph Me 3c — — — —10 1a 9 COPh H Ph Me 3a 15 >98/o2 58 8911 1a 10 CO2Me H CO2Me Me 3c — — — —12 1a 10 CO2Me H CO2Me Me 3a 16a 80/20 78 6113 1a 10 CO2Me H CO2Me Me 3b 16a 85/15 50 7014 1m 10 CO2Me H CO2Me p-FC6H4 3a 16m 80/20 73 7115 1a 11 CO2Me CO2Me H Me 3c — — — —16 1a 11 CO2Me CO2Me H Me 3a 17a >98/o2 70 4117 1a 11 CO2Me CO2Me H Me 3b 17a 90/10 68 94

a By 1H-NMR from the crude reaction mixtures. b In pure product after column chromatography. c By HPLC, see ESI for details. d ee after

recrystallization.

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 2149–2151 2151

The cycloadditions of 1 with acyclic diactivated alkenes,

such as dimethyl fumarate (9) and dimethyl maleate (10), were

also conducted. Only traces of adduct were formed in the

reaction with 9 or 10 using CuI/DTBM-Segphos as catalyst

system (entries 11 and 15). Again, in these cases we found a

strong beneficial effect on the reactivity when the less bulkier

Segphos ligand 3a was used. Under these conditions the

reaction with fumarate 9 took place with good yield and

reasonable exo-selectivity but moderate enantioselectivity

(61% ee, entry 12). The enantioselectivity could be slightly

enhanced to 70% ee using DM-Segphos as ligand (entry 13) or

the iminoamide 1m as dipole precursor (entry 14). On the

other hand, in the reaction with dimethyl maleate Segphos

ligand 3a provided the pyrrolidine 17a with complete exo-

selectivity but low enantioselectivity (41% ee, entry 16).

Interestingly, a great enhancement in the enantioselectivity

was achieved in the presence of DM-Segphos ligand (94% ee,

entry 17).

The synthetic usefulness of this methodology to the

preparation of substituted pyrrolizidines was next demon-

strated.18 The reaction of the enantiopure Weinreb amide

pyrrolidine 13n with acetyl chloride gave rise to the N-acetyl

pyrrolidine 18 in 97% yield. Subsequent treatment

with LiHMDS led to the straightforward formation of the

pyrrolizidine 1,3-dione19 which was in situ reduced to the

alcohol 19 (NaBH4, EtOH) due to its instability. Finally,

the reductive elimination of the sulfonyl group provided the

hydroxypyrrolizidine 20 in 70% yield20 (Scheme 1).

In summary, we have developed an efficient protocol for the

catalytic asymmetric [3+2] cycloaddition of a-iminoamides,

including Weinreb-type amides. This procedure relies on

the use of CuI/Segphos as catalyst system, providing

2-amidopyrrolidines usually with excellent levels of exo

diastereoselectivity and enantiocontrol (up to Z 99% ee) in

the reaction with a variety of activated alkenes. This

methodology offers a new entry to the enantioselective

construction of pyrrolidine containing structures, such as

pyrrolizidines.

Financial support of this work by the Ministerio de Ciencia

e Innovacion of Spain (MICINN, CTQ2009-07791), CAM

(project AVANCAT; S2009/PPQ-1634) and CAM-UAM

(CCG-10-UAM/PPQ-5853) is gratefully acknowledged.

M.G.-E. thanks the MICINN for a predoctoral fellowship.

We thank Takasago Company (Dr Taichiro Touge) for generous

loans of Segphos chiral ligands.

Notes and references

1 Five membered nitrogen heterocycles are present in about 9000natural products: W. Hess and J. W. Burton, Chem.–Eur. J., 2010,16, 12306.

2 For reviews, see: (a) C. Grondal, M. Jeanty and D. Enders, Nat.Chem., 2010, 2, 167; (b) special feature issue on organocatalysis,Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 20618.

3 For recent selected references, see: (a) A. Z. Gonzalez, D. Benitez,E. Tkatchouk,W. A. Goddard III and F. D. Toste, J. Am. Chem. Soc.,2011, 133, 5500; (b) K. X.-K. Liu, S. Qiu, Y.-G. Xiang, Y.-P. Ruan,X. Zheng and P.-Q. Huang, J. Org. Chem., 2011, 76, 4952.

4 (a) J. M. Longmire, B. Wang and X. Zhang, J. Am. Chem. Soc.,2002, 124, 13400; (b) A. S. Gothelf, K. V. Gothelf, R. J. Hazell andK. A. Jørgensen, Angew. Chem., Int. Ed., 2002, 41, 4236.

5 For recent reviews, see: (a) J. Adrio and J. C. Carretero, Chem.Commun., 2011, 47, 6784; (b) C. Najera and J. M. Sansano, Top.Heterocycl. Chem., 2008, 12, 117; (c) L. M. Stanley and M. P. Sibi,Chem. Rev., 2008, 108, 2887; (d) H. Pellisier, Tetrahedron, 2007,63, 3235. For a very recent reference, see: (e) M. Wang, Z. Wang,Y.-H. Shi, X.-X. Shi, J. S. Fossey and W.-P. Deng, Angew. Chem.,Int. Ed., 2011, 50, 4897 and references therein.

6 For a very recent reference see: J.-F. Bai, L.-L. Wang, L. Peng,Y.-L. Guo, J.-N. Ming, F.-Y. Wang, X.-Y. Xu and L.-X. Wang,Eur. J. Org. Chem., 2011, 4472.

7 A. D. Melhado, M. Luparia and F. D. Toste, J. Am. Chem. Soc.,2007, 129, 12638.

8 Y. Yamashita, X.-X. Guo, R. Takashita and S. Kobayashi, J. Am.Chem. Soc., 2010, 132, 3262.

9 R. Robles-Machın, I. Alonso, J. Adrio and J. C. Carretero,Chem.–Eur. J., 2010, 16, 5286.

10 S. Padilla, R. Tejero, J. Adrio and J. C. Carretero,Org. Lett., 2010,12, 5608.

11 For applications in medicinal chemistry, see for example:K. K.-C. Liu, B. A. Lefker, M. A. Dombroski, P. Chiang,P. Cornelius, T. A. Patterson, Y. Zeng, S. Santucci, E. Tomlinson,C. P. Gibbons, R. Marala, J. A. Brown, J. X. Kong, E. Lee,W. Werner, Z. Wenzel, C. Giragossian, H. Chen and S. B. Coffey,Bioorg. Med. Chem. Lett., 2010, 20, 2365.

12 The use of other metal complexes such as AgOAc, Zn(OAc)2 orCu(OAC)2 afforded poorer results than Cu(CH3CN)4PF4.

13 For the use of Segphos ligands in catalytic asymmetric 1,3-dipolarcycloadditions of azomethine ylides, see: (a) Y. Yamashita,T. Imaizumi and S. Kobayashi, Angew. Chem., Int. Ed., 2011,50, 4893; (b) R. Robles-Machın, M. Gonzalez-Esguevillas, J. Adrioand J. C. Carretero, J. Org. Chem., 2010, 75, 233; (c) A. Lopez-Perez,J. Adrio and J. C. Carretero, Angew. Chem., Int. Ed., 2009, 48, 340;(d) Y. Oderaotoshi, W. Cheng, S. Fujitomi, Y. Kasano, S. Minakataand M. Komatsu, Org. Lett., 2003, 5, 5043. See also ref. 8.

14 A variety of structurally diverse chiral ligands were tested in thiscycloaddition, see ESIz for details.

15 CCDC 846895z.16 For a review on the synthetic utility of Weinreb amides, see:

J. S. Balasubramaniam and I. S. Aidhen, Synthesis, 2008, 3707.17 The exo configuration of the 2-amidopyrrolidines 13n and 14n was

established by chemical correlations to known pyrrolidines-2-carboxylate esters, see ESIz.

18 The pyrrolizidine structural motif is present in a wide variety ofpolyhydroxylated alkaloids with important biological activitiesand potential therapeutic use, such as anti-HIV or anticanceragents. J. P. Michael, Nat. Prod. Rep., 2007, 24, 191.

19 It has been reported that this kind of cyclization cannot be achievedfrom methyl N-acetylprolinate. The competitive deprotonation at thea position of the ester is the main process, resulting in racemization ofthe starting material, see: A. Murray, G. R. Proctor and P. J. Murray,Tetrahedron, 1996, 52, 3757.

20 A nOe experiment was used to establish the stereochemistry at thecarbinol center in 20, see ESIz for details. A similar diastereofacialselectivity has been previously described in the reduction of relatedpyrrolizin-1,3-diones: N. Galeotti, J. Poncet, L. Chiche andP. Jouin, J. Org. Chem., 1993, 58, 5370. See also ref. 19.

Scheme 1 Application to enantioselective pyrrolizidine synthesis.

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