Highly diastereoselective 1,3-dipolar cycloaddition via in situ formed ketimine ylides

Article abstract of DOI:10.1016/j.tetlet.2012.09.138

1,3-Dipolar cycloaddition of conjugated unsaturated ketimine ylides was disclosed. The reaction of glycine ester with a series of β,γ- unsaturated keto esters in the presence of catalytic amount of TFA was found to give structurally diverse and functionally enriched pyrrolidine derivatives 3 in up to 88% yield. These processes feature a hydrolysis of glycine ketimine. A preliminary enantioselective version of the transformation was also investigated.

Full text of DOI:10.1016/j.tetlet.2012.09.138

Tetrahedron Letters 53 (2012) 6775–6778
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Tetrahedron Letters
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Highly diastereoselective 1,3-dipolar cycloaddition via in situ formed
ketimine ylides
⇑
⇑
Yu Cheng, Ya-Nan Liu, Jia Ye, Long He , Tai-Ran Kang, Quan-Zhong Liu
Chemical Synthesis and pollution Control Key Laboratory of Sichuan Province, College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637009,
PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
1,3-Dipolar cycloaddition of conjugated unsaturated ketimine ylides was disclosed. The reaction of gly-
Received 9 August 2012
Revised 18 September 2012
Accepted 29 September 2012
Available online 12 October 2012
cine ester with a series of b,c-unsaturated keto esters in the presence of catalytic amount of TFA was
found to give structurally diverse and functionally enriched pyrrolidine derivatives 3 in up to 88% yield.
These processes feature a hydrolysis of glycine ketimine. A preliminary enantioselective version of the
transformation was also investigated.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dipolar cycloaddition
Ketimine ylides
Glycine ester
b,c-Unsaturated keto ester
1,3-Dipolar cycloaddition has received considerable interest
by NMR, HRMS, and further verified by X-ray analysis12 (Fig. 1 and
see Supplementary data).
and great achievements have been made during the past years.1
The azomethine ylide dipoles generated from aldehydes and amino
acid esters are widely employed in the cycloaddition for the prep-
aration of pyrrolidine scaffolds,2–4 which are present frequently in
natural alkaloids and pharmaceuticals with vital bioactivities.5 To
our knowledge, however, those derived from ketones have been
less studied,6 only N-(diphenylmethylidene) glycine tert-butyl es-
ter 1 was applied in the 1,3-dipolar cycloaddition.6 This limits
Since the pyrrolidine rings are inherent in numerous bioactive
natural products and medicinal agents, we sought to optimize
the above reaction conditions by varying the Brønsted acid and sol-
vent. The results are recorded in Table 1. Among the acids investi-
gated, the best results were obtained using TFA as the acid (entries
1–6). Regarding the influence of the solvent, a preliminary study
revealed that diethyl ether, chloroform, and tetrachloromethane
gave higher yield than polar solvents CH3CN, Dioxane, and THF
(entries 10–12 vs 7–9). In these cycloadditions, diethyl ether was
the application of the chemistry. b,c-Unsaturated keto esters are
electron-deficient species and widely applied in the Michael reac-
tion,7 the Aldol reaction,8 and other transformations.9 The tandem
reactions have been successfully applied in the synthesis of struc-
turally and functionally diverse organic compounds.10 Based on
employed since most b,c-unsaturated keto esters have good solu-
bility in this medium. Further optimization of the reaction condi-
tions by varying the TFA loading was also investigated. It was
found that the yield was increased to 88% by using 20 mol % of
TFA (entry 14), however, the yield could not be further improved
as the amount of acid was increased (entry 15). We surmised that
the reaction proceeded by a 1,3-dipolar cycloaddition of azome-
thine ylide (namely conjugated ketimine ylide 5, See Scheme 2)
previous reports from the literature7–10 and our11 group on b,
unsaturated keto esters, we conjectured that the reaction of b,
c
c
-
-
unsaturated keto esters 2a and N-(diphenylmethylidene) glycine
tert-butyl ester 1 in the presence of catalytic amount of acids,
would form the corresponding Michael adducts (Scheme 1, eq 1).
To our surprise, however, the unexpected functionally enriched
pyrrolidine derivative 3a was afforded in 51% yield when
10 mol % of TFA was used as catalyst (Scheme 1, eq 2).
generated in situ from b,c-unsaturated keto ester and glycinate es-
ter derived from the hydrolysis of diphenyl glycinate ester in the
presence of trace amounts of water. The hypothesis was supported
by the addition of catalytic amount of water. the reaction time was
shortened from 48 h to 24 h (entry 16). It should be noted that the
reaction exhibited excellent regioselectivity and diastereoselectiv-
ity, only one single diastereoismer was obtained in all cases. In
addition, to the best of our knowledge, this work presents the first
1,3-dipolar cycloaddition of in situ formed conjugated ketimine
ylides.
In order to establish the configuration of the observed cycload-
dition product an exhaustive characterization of 3a was elucidated
⇑
Corresponding authors.
E-mail addresses: longhe@mail.ustc.edu.cn (L. He), quanzhongliu@sohu.com
(Q.-Z. Liu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.138

6776
Y. Cheng et al. / Tetrahedron Letters 53 (2012) 6775–6778
Ph
O
O
O
Ph
∗
∗
Ph
N
O
OMe
OMe
OMe
+
+
TFA, 10 mol%
CH2Cl2
O
Ph
Ph
Ph
N
Expected product
Ph
O
O
O
O
O
2a
1
COCO2Me
CO2Me
Ph
Ph
TFA, 10 mol%
CH2Cl2
O
Observed product
Ph
N
NH
Ph
3a
O
O
2a
1
O
Scheme 1. Brønsted acid catalyzed reaction of diphenyl glycinate 1 and b,
c
-unsaturated keto ester 2a.
Ph
O
Ph
N
O
1
COCO2Me
CO2Me
H+/H2O
Ph
NH
Ph
O
O
O
O
O
H2N
OMe
4
3a
O
COCO2Me
CO2Me
2a
Ph
NH
Ph
O
Figure 1. X-ray crystal structure of 3a.
O
O
N
O
endo-3a
OMe
Table 1
Optimization of the reactiona
2a
5
O
COCO2Me
CO2Me
O
Ph
Scheme 2. The plausible mechanism for the reaction.
Ph
OMe
+
Acid
O
Ph
NH
Ph
Ph
N
O
O
Solvent
O
O
because of the poor solubility of esters in diethyl ether. Fortu-
nately, mixed solvent systems consisting of Et2O/CHCl3 led to high-
er yield. When N-(diphenylmethylidene)glycinate methyl ester
was employed in the tandem reaction, the corresponding pyrroli-
dine 3l was also obtained in 78% yield with 10:1 dr.
1
2a
Entry
3a
Acid
Solvent
Temp
Time (h)
Yieldb(%)
1
2
3
4
5
6
7
8
TFA
TFA
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH3CN
Dioxane
THF
CHCl3
CCl4
Et2O
CH2Cl2
Et2O
Et2O
25
50
50
50
50
50
25
25
25
25
25
25
25
25
25
25
50
36
69
50
50
33
—
—
—
48
51
50
62
63
73
51
88
87
88
TsOH
TfOH
HAc
PhCO2H
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
Based on the experimental results, a plausible mechanistic se-
quence is proposed for this TFA-catalyzed cycloaddition reaction
(Scheme 2). Diphenyl glycinate ester imine 1 was hydrolyzed to
the glycinate ester 4 which reacted with unsaturated keto ester
2a forming the azomethine ylide, then in situ generated unsatu-
rated conjugate ketimine dipole underwent a 1,3-dipolar cycload-
dition with another molecule of 2a forming the corresponding
pyrrolidine endo-3a. We believed that the slow delivering of gly-
cinate ester 4 by the hydrolysis of 1 was helpful for achieving good
yield of the cycloaddition product 3, under identical conditions, the
reaction of N-(diphenylmethylene) glycine tert-butyl ester 1 and
2a in diethyl ether provided 88% yield (entry 10, Table 1), while
that of glycinate ester 4 only afforded 30% yield. So slow addition
60
120
120
94
120
41
48
72
60
29
9
10e
11
12
13
14c
15d
16c,e
48
48
24
TFA
Et2O
a
All reactions were carried out with 2a (0.2 mmol) and 1 (0.1 mmol) in the
presence of 10 mol % Brønsted acid in the solvent unless indicated otherwise.
b
of glycinate ester
cycloaddition.
4
might be beneficial for 1,3-dipolar
Isolate yield and >95/5 dr was observed unless indicated otherwise.
20 mol % of TFA was used.
30 mol % of TFA was used.
20 mol % of water added.
c
d
Since the reaction proceeded via a 1,3-dipolar cycloaddition of
in situ generated azomethine ylide, we envisaged that the direct
e
reaction of b,c-unsaturated keto ester 2a and glycinate 4 would
also generate the pyrrolidine 3a. To testify the hypothesis, a mix-
ture of ester 2a and glycinate ester 4 was stirred at room temper-
ature for 12 h in the presence of 20 mol % TFA using chloroform as
the solvent. The corresponding pyrrolidine derivative 3a was ob-
tained in 30% yield in combination with an unexpected product 6
resulting from the intramolecular Michael addition of b,
The cycloaddition can be extended to other substrates and the
results were summarized in Table 2. Among the esters investi-
gated, methyl ester provided better yields than ethyl and isopropyl
ester (entries 1–3), this maybe resulted from the steric hindrance
of the ester group. Other substituted esters on the aromatic ring
of b,c-unsaturated keto esters afforded less satisfactory results
c-unsaturated imine 7.

Y. Cheng et al. / Tetrahedron Letters 53 (2012) 6775–6778
6777
Table 2
1,3 Dipolar cycloaddition of N-(diphenylmethylene) glycine tert-butyl ester 1 and b,
c
-unsaturated keto esters 2a
R1
COCO2R2
CO2R2
O
Ph
OR2
+
OR3
TFA, 20 mol%
Ph
N
NH
R
R3O
1
O
Et2O
O
O
3
1
R1
R3
2
Entry
product
R1
R2
Yieldb
1
2
3
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
Me
Et
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
88
78
61
76
73
70
87
63
69
66
70
78e
iPr
4c
5c
6c
7c
8c
9c
10c
11c
12d
3-OMe
3-Br
3-Cl
4-Me
4-OMe
4-F
4-Cl
4-Br
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
3j
3k
3l
a
b
c
All reactions were carried out with 1 (0.1 mmol), 2 (0.2 mmol), 20 mol % TFA, and 20 mol % of water in 1 mL of solvent at rt for 24–72 h.
Isolate yield and >95/5 dr was observed unless indicated otherwise.
Mixed solvent (CHCl3/Et2O = 1:1) was used.
N-(Diphenylmethylidene) glycine methyl ester was used.
10/1 dr.
d
e
COCO2Me
O
CO2Me
OMe
OMe
+
O
TFA 20 mol%
CHCl3, RT
H2N
2
NH
O
O
O
O
2a
4
3a
78%
O
O
Ph
H
N
TFA 20 mol%
CHCl3, RT
O
+
O
H N
O
2.5
N
2
O
O
O
O
6
2a
4
79%
t-BuO
O
N
O
H
N
OBu-t
O
7
Scheme 3. Direct reaction of unsaturated keto ester 2a with glycinate ester 4.
The reaction pathway could be altered by the variation of molar
and the intramolecular Michael addition product 6 were obtained
in 78% yield with 52% ee and in 79% yield with 56% ee, respectively
(Scheme 4). The discovery would undoubtedly give useful clues for
the enantioselective transformation.
In conclusion, we described a dipolar cycloaddition reaction of
azomethine ylide generated in situ from b,c-unsaturated keto es-
ters and glycinate ester which was delivered in the hydrolysis of
diphenyl glycinate ester. Varieties of keto esters can be applied
for the preparation of functional enriched pyrrolidine in moderate
yield. The reaction pathway alteration according to molar ratio of
reactants and procedure. The enantioselective 1,3-dipolar cycload-
dition and intramolecular Michael addition were also carried out
and moderate enantioselectivities were obtained. The preliminary
results shed light on the catalytic asymmetric transformation
employing chiral Brønsted acids as the catalysts.
ratio of reactants and procedure. Based on the above mentioned
mechanism, slow addition of 4 (1 equiv) to the solution of keto ester
2a (2 equiv) and catalytic amount of TFA in chloroform would result
in the formation of compound 3a in 78% yield. On the contrary, the
slow dropwise addition of keto ester 2a (1 equiv) to the solution of
glycinate 4 (2.5 equiv) in chloroform would lead to the formation of
the intramolecular Michael addition product 6 in 79% yield
(Scheme 3). It should be addressed that compound 6 is a precursor
for unnatural amino acid, and upon the deprotection of compound 6
would yield a b-amino acid derivative which may find application
in protein engineering as well as in pharmaceutical.13
Investigation of the enantioselective version of the reactions
was also attempted. When 10 mol % of chiral phosphoric acid 8
and 9 was used as and the catalyst, the cycloaddition product 3a

6778
Y. Cheng et al. / Tetrahedron Letters 53 (2012) 6775–6778
O
O
O
O
O
O
P
P
OH
OH
9
8
COCO2Me
CO2Me
O
8
O
10 mol%
CHCl3
OMe
H2N
+
2
NH
O
O
O
O
4
2a
3a
78%, 52% ee
O
O
Ph
H
O
OMe
O
N
+
9
10 mol%
O
2.5
N
H2N
O
CHCl3, RT
O
O
4
O
6
2a
79%, 56% ee
Scheme 4. Enantioselective 1,3-dipolar cyclo addition of in situ formed conjugated ketimine ylides.
S.; Tejero, R.; Adrio, J.; Carretero, J. C. Org. Lett. 2010, 12, 5608; (e) Antonchick,
A. P.; Gerding-Reimers, C.; Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.;
Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735.
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (21102116, 20772097), Sichuan Pro-
vincial Science Foundation for the Outstanding Youth (05ZQ026-
008) and China West Normal University (11B004).
5. For selected reviews, see:s (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63,
12247; (b) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484;
(c) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765; (d) Sardina, F. J.;
Rapoport, H. Chem. Rev. 1825, 1996, 96; (e) Pearson, W. H. In Studies in
Natural Product Chemistry; Atta-Ur-Rahman, Ed.; Elsevier: Amsterdam, 1998;
p 323. Vol. 1.
6. For selected examples, see: (a) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem.
Soc. 2007, 129, 5364; Tsubogo, T.; Saito, S.; Seki, M.; Yamashita, Y.; Kobayashi,
S. J. Am. Chem. Soc. 2008, 130, 13321; (c) Xue, M.-X.; Zhang, X.-M.; Gong, L.-Z.
Synlett 2008, 691; (d) March, P. D.; Elias, L.; Figueredo, M.; Font, J. Tetrahedron
2002, 58, 2667.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.138.
7. For selected example, see: Zhou, L.; Lin, L.-L.; Wang, W.-T.; Ji, J.; Liu, X.-H.; Feng,
X.-M. Chem. Commun. 2010, 46, 3601.
8. For selected example, see: Li, P.-F.; Zhao, J.-L.; Li, F.-B.; Chan, A. S. C.; Kwong, F.
Y. Org. Lett. 2010, 12, 5616.
References and notes
9. For selected example, see: (a) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.;
Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593; (b) Yao, W.-J.; Pan, L.-J.; Wu, Y.-
H.; Ma, C. Org. Lett. 2010, 12, 2422; (c) Faita, G.; Mella, M.; Toscanini, M.;
Desimoni, G. Tetrahedron 2010, 66, 3024; (d) Cao, C.-L.; Chun, X.-L.; Kang, Y.-B.;
Tang, Y. Org. Lett. 2007, 9, 4151.
10. (a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (b) Zhu, J.;
Bienayme, H. Multicomponent reactions; Wiley-VCH: Weinheim, 2005. 468; (c)
Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471; (d) Dömling, A. Chem. Rev.
2006, 106, 17; (e) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
1. Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; John Wiley & Sons Inc:
New York, 2002.
2. For reviews, see: (a) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156; (b)
Kobayashi, S.; Yamashita, Y. Acc. Chem. Res. 2011, 44, 58; (c) Fu, G.-C. Acc. Chem.
Res. 2006, 39, 853; (d) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505;
(e) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484.
3. For selected examples, see: (a) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J.Am.
Chem. Soc. 2008, 130, 5652; (b) He, L.; Chen, X.-H.; Wang, D.-N.; Luo, S.-W.;
Zhang, W.-Q.; Yu, J.; Ren, L.; Gong, L.-Z. J. Am. Chem. Soc. 2011, 133, 13504; (c)
Kim, H. Y.; Li, J.-Y.; Kim, S.; Oh, K. J. Am. Chem. Soc. 2011, 133, 20750; (d) Na, R.;
Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.; Wang, M.; Benitez, D.;
Tkatchouk, E.; Goddard, W. A.; Guo, H.; Kwon, O. J. Am. Chem. Soc. 2011, 133,
13337; (e) Gonzalez-Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Commun.
2012, 48, 2149; (f) Liu, T.-L.; He, Z.-L.; Li, Q.-H.; Tao, H.-Y.; Wang, C.-J. Adv.
Synth. Catal. 2011, 353, 1713; (g) Arai, T.; Yokoyama, N.; Mishiro, A.; Sato, H.
Angew. Chem., Int. Ed. 2010, 49, 7895.
11. Kang, T.-R.; Cheng, Y.; He, L.; Ye, J.; Liu, Q.-Z. Tetrahedron Lett. 2012, 53,
2552.
12. The relative configuration of 3a was confirmed by X-ray crystallography
experiments: CCDC 857133 contains the supplementary crystallographic data
for this Letter. These data can be obtained free of charge via www.ccdc.can.
ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Center, 12
Union Road, CambridgeCB21EZ, UK; Fax: (+44)1223-336033; or deposit@c
cdc.cam.ac.uk.
13. Lu, L.-Q.; Zhang, J.-J.; Li, F.; Cheng, Y.; Ji, A.; Chen, J.-R.; Xiao, W.-J. Angew. Chem.,
Int. Ed. 2010, 49, 4495–4498.
4. (a) Schreiber, S. L. Science 1964, 2000, 287; (b) Hernandez-Toribio, J.; Arrayás, R.
G.; Martin-Matute, B.; Carretero, J. C. Org. Lett. 2009, 2, 393; (c) Arai, T.; Mishiro,
A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem. Soc. 2010, 132, 5338; Padilla,