Silver acetate catalysed asymmetric 1,3-dipolar cycloadditions of imines and chiral acrylamides

Article abstract of DOI:10.1055/s-2003-39325

N-Metallated azomethine ylides 5 were generated by the reaction of arylidene glycine imines 1 with AgOAc and triethylamine. These azomethine ylides undergo cycloaddition to chiral acrylamides 2 with excellent diastereoselectivity. The configuration of two

Full text of DOI:10.1055/s-2003-39325

LETTER
947
Silver Acetate Catalysed Asymmetric 1,3-Dipolar Cycloadditions of Imines
and Chiral Acrylamides
Silver
Acetate
C
atalyse
i
d
A
sy
k
m
metric 1,3-
l
Dipola
ó
r
Cycloadditi
s
ons Nyerges,*a David Bendell,b Andrea Arany,b David E. Hibbs,c Simon J. Coles,d Michael B. Hursthouse,d
Paul W. Groundwater,b Otto Meth-Cohnb
a
Research Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology, Technical University of
Budapest, 1521 Budapest P.O.B. 91, Hungary
E-mail: mnyerges@mail.bme.hu
b
Institute of Pharmacy and Chemistry, School of Sciences, University of Sunderland, Sunderland, SR1 3SD, UK
c
Department of Chemistry, Cardiff University, P.O. Box 912, Cardiff, CF1 3TB, UK
d
Department of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK
Received 12 December 2002
Starting from the corresponding amines,12 acrylamides
2a,13a 2b,13b 2c,14 2d,12b were prepared by simple acylation
with acryloyl chloride in dichloromethane in the presence
of triethylamine. The acrylamide 2e was prepared by the
modification of a literature procedure15 since, in this case,
the simple acylation with acryloyl chloride led to a mix-
ture of the N-acylated 2e and N,O-diacylated products.
When acrylic acid was activated by ethyl chloroformate,
however, the secondary nitrogen of the intermediate was
acylated selectively, to give 2e as a single product.
Abstract: N-Metallated azomethine ylides 5 were generated by the
reaction of arylidene glycine imines 1 with AgOAc and triethyl-
amine. These azomethine ylides undergo cycloaddition to chiral
acrylamides 2 with excellent diastereoselectivity. The configuration
of two of the cycloadducts (3a1 and 3c1) has been confirmed by X-
ray crystallography.
Key words: cycloaddition, azomethine ylides, pyrrolidine, asym-
metric
1,3-Dipolar cycloadditions are very important tools for
the construction of five membered heterocycles.1 The ease
of generation of 1,3-dipoles, coupled with the highly re-
gio-, and stereoselective nature of their cycloaddition
reactions, has resulted in a number of syntheses which uti-
lize such a reaction as a key step.2 One of the major chal-
lenges now for 1,3-dipolar cycloadditions is the synthesis
of enantiomerically pure heterocycles.3
These dipolarophiles were then reacted with the azome-
thine ylides 5, derived from arylidene glycine imines 1 in
the presence of AgOAc and triethylamine at room temper-
ature, employing dry toluene as the solvent (Scheme 1). In
accordance with previous results,16 this metallo-azome-
thine ylide cycloaddition exhibited regio- and stereospe-
cific formation of the expected syn-endo cycloadducts,
but the diastereoselectivities and yields varied depending
upon the nature of the chiral auxillary and the substituents
on the aryl group (Table 1).17
There are three possible approaches to achieving asym-
metric 1,3-dipolar cycloadditions: i) involving the use of
chiral dipoles, ii) chiral dipolarophiles, or iii) chiral cata-
lysts. We have chosen to investigate the use of chiral di-
polarophiles (alkenes). Chiral acrylate esters and amides
have been widely evaluated in asymmetric Diels–Alder
reactions,4 but fewer examples of chiral induction in the
1,3-dipolar cycloadditions of azomethine ylides have
been reported. To date, most attention has been devoted to
the use of chiral esters (mainly menthyl-esters,5
camphorsultams6 or those with a chiral controller at the b-
position7), chiral a,b-unsaturated ketones,8 and bicyclic
lactams,9 with only one report of the use of N-acryloyl-
(S)-proline esters as the chiral alkenes.10 Thus, the wide
range of easily available and cheap homochiral amines11
and amino acids still remains unexplored as a source of
chiral auxiliaries in these cycloadditions. We wish to re-
port here selected examples of the utilization of these
chiral elements in the 1,3-dipolar cycloadditions of
azomethine ylides to acrylamides.
The acrylamides 2a and 2b, derived from the a-phenyl-
ethylamine reacted with only moderate diastereoselectiv-
ity (entries 1–4), but, in most cases, both pyrrolidine
isomers were readily obtained, in pure form, from these
cycloadduct mixtures after repeated recrystallisations.
The chiral dipolarophile 2c based on (R,R)-bis-a-phenyl-
ethylamine as the chiral auxillary also resulted in the for-
mation of diastereoisomeric mixtures. In contrast, the
cyclic C2-symmetric pyrrolidine, derivative 2d showed
complete diastereoselectivity in all cases.
The most promising results were achieved using (1R,2S)-
(–)-ephedrine as the chiral element – the corresponding
alkene 2e gave, in most of the cycloadditions studied, a
single diastereoisomeric product in good yield.
In the reactions involving imine 1c, a small amount of di-
dehydroaminoacid 6 was always isolated from the reac-
tion mixture. The formation of this compound has been
observed and explained in our earlier papers, Scheme 2.18
The relative configurations of the cycloadducts of series 3
and 4 were determined by NOE studies of representative
examples. The all cis configaration of these pyrrolidines
in all cases was confirmed by the observed NOE enhance-
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,0947,0950,ftx,en;D27902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

948
M. Nyerges et al.
LETTER
Scheme 1
Table 1 Synthesis of Pyrrolidines 3 and 4 from Acrylamides 2 and Glycine Imines 1
Entry
Acryl-
amide
Imine
R1
R2
R3
Products
Reaction
time
Yield
(%)
Ratio
(3:4)
1.8: 1
1: 1.8
1:1.5
1: 1
1:1.2
1:1
1
2a
2b
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
2e
1a
1a
1b
1c
1d
1a
1b
1c
1a
1b
1c
1a
1b
1e
1d
H
H
Cl
H
H
H
Cl
H
H
Cl
H
H
Cl
H
H
H
H
3a1, 4a1
3b1, 4b1
3b2, 4b2
3b3, 4b3
3b4, 4b4
3c1, 4c1
3c2, 4c2
3c3, 4c3
3d1, 4d1
3d2, 4d2
3d3, 4d3
3e1, 4e1
3e2, 4e2
3e3, 4e3
3e4, 4e4
48 h
48 h
36 h
24 h
24 h
36 h
80 h
24 h
24 h
48 h
24 h
24 h
48 h
24 h
24 h
77a
74a
70a
82a
71a
65a
51a
67a
78b
66a
85b
76b
57b
75b
81b
2
H
H
3
H
Cl
4
H
NO2
MeO
H
5
MeO
H
6
7
H
Cl
1: 2
1:1.7
1:0
8
H
NO2
H
9
H
10
11
12
13
14
15
H
Cl
1:0
H
NO2
H
1:0
H
1:0
H
Cl
10:1
1:0
H
MeO
MeO
MeO
1:0
a Isolated yield after recrystallisation.
b Isolated yield after flash chromatography.
Synlett 2003, No. 7, 947–950 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Silver Acetate Catalysed Asymmetric 1,3-Dipolar Cycloadditions
949
Scheme 2
Figure 2 Crystal structure of 3c1
Single diastereoisomers were obtained from the reaction
of the ylides with the dipolarophiles 2d and 2e.
Acknowledgement
N.M. thanks the National Foundation for Science and Research,
Hungary (OTKA Project No. T 032221) and NATO/Royal Society
for grants. We sincerely thank the EPSRC for grant in support of
AA.
References
Figure 1 Crystal structure of 3a1
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York, 1984. (c) Synthetic Applications of 1,3-Dipolar
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Tetrahedron Lett. 1996, 37, 3915. (f) Daubié, C.; Mutti, S.
Tetrahedron Lett. 1996, 37, 7743.
ments between H-2 and H-5 (2–4%) and H-5 and H-4
(3–6%). The absolute configurations of two cycloadducts,
3a1 (Figure 1) and 3c1 (Figure 2) were established by
X-ray crystallography. To compare the configurations of
the other products to those of these configurations, the cy-
cloadducts were hydrolyzed to the diacids 6 by ethanolic
hydrochloric acid and re-esterified by the means of
thionyl chloride and dry EtOH, Scheme 3. The diesters 7
were then purified by chromatography and the specific
rotations were compared.
(3) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
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H. Chem. Commun. 1999, 963. (c) Kitagawa, O.; Izawa, H.;
Taguchi, T. Tetrahedron Lett. 1997, 38, 4447.
In summary, N-metallated azomethine ylides 5 were gen-
erated by the reaction of arylidene glycine imines 1 with
AgOAc and triethylamine. These azomethine ylides un-
dergo cycloaddition to chiral acrylamides 2 to give chiral
pyrrolidines, 3 and 4, with excellent diastereoselectivity.
(d) Waldmann, H. Liebigs Ann. Chem. 1990, 671.
Scheme 3
Synlett 2003, No. 7, 947–950 ISSN 1234-567-89 © Thieme Stuttgart · New York

950
M. Nyerges et al.
LETTER
(5) (a) Barr, D. A.; Dorrity, M. J.; Grigg, R.; Hargreaves, S.;
Malone, J. F.; Montgomery, J.; Redpath, J.; Stevenson, P.;
Thornton-Pett, M. Tetrahedron 1995, 51, 273. (b) Keller,
E.; De Lange, B.; Rispens, M. T.; Feringa, B. L. Tetrahedron
1993, 49, 8899.
(6) (a) Karlsson, S.; Högberg, H.-E. Tetrahedron: Asymmetry
2001, 12, 1977. (b) Ling, R.; Ekhato, I. V.; Rubin, R.;
Wustrow, D. J. Tetrahedron 2001, 57, 6579.
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Sakurai, T. J. Org. Chem. 1991, 56, 4473. (b) Annunziata,
R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Pilati, T.
Tetrahedron: Asymmetrie 1991, 2, 1329.
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(b) Kopach, M. E.; Fray, A. H.; Meyers, A. I. J. Am. Chem.
Soc. 1996, 118, 9876.
(10) (a) Waldmann, H.; Blaeser, E.; Jansen, M.; Letschert, H. P.
Chem.–Eur. J. 1995, 1, 150. (b) Waldmann, H.; Blaeser, E.;
Jansen, M.; Letschert, H. P. Angew. Chem., Int. Ed. Engl.
1994, 33, 1329.
(11) O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439.
(12) All amines were purchased from Sigma-Aldrich Chemical
Co. except for the precursor of 2d which was prepared by a
known literature procedure: (a) Chong, M. J.; Clark, I. S.;
Koch, I.; Olbach, P.; Taylor, N. J. Tetrahedron: Asymmetry
1995, 6, 409. (b) Useful note on the original method: Taber,
D. F.; Gorski, G. J.; Liable-Sands, L. M.; Rheingold, A. L.
Tetrahedron. Lett. 1997, 38, 6317.
1090, 1050, 1019 cm–1. MS (CI): m/z (rel. intensity, %) =
477 (4)[M+], 463 (12), 435 (base peak), 401 (15), 361 (14),
262 (17), 140 (20), 105 (34). HRMS: Calcd 434.1164 for
C22H24Cl2N2O3. Found: 434.1152. (R,R,R,R,R)-Ethyl-5-
phenyl-4-{[bis(1¢-phenyl-ethyl)]carbamoyl}-pyrrolidine-
2-carboxylate (3c1). Colourless needles; mp 172–173 °C.
[a]D23 = –158 (c 0.96, CHCl3). 1H NMR (270 MHz, CDCl3):
d = 7.31–7.02 (m, 11 H, Ph), 6.77–6.71 (m, 4 H, Ph), 5.31
(broad d, 1 H, J = 6.6 Hz, PhCH), 4.70 (q, 1 H, J = 7.3 Hz,
PhCH), 4.23 (dq, 2 H, J = 1.9 and 7.3 Hz, OCH2), 3.95 (d, 1
H, J = 7.3 Hz, H-5), 3.87 (t, 1 H, J = 8.6 Hz, H-2), 3.43 (dd,
1 H, J = 5.3 Hz and 7.3 Hz, H-4), 2.53–2.02 (m, 2 H, H2-3),
1.46 (d, 3 H, J = 7.3 Hz, CH3), 1.42 (d, 3 H, J = 7.3 Hz, CH3),
1.29 (t, 3 H, J = 7.3 Hz, CH3). 13C NMR: d = 173.9 (C=O),
173.1 (C=O), 141.1 (2 × Ph-1¢C), 138.7 (Ph-1¢C), 128.4,
128.3, 128.0, 127.8, 127.2, 126.9 (15 × CH, overlapping),
67.4, 61.0, 52.4, 52.1, 47.2, 36.9, 30.0, 19.5, 16.9, 14.3. IR
(nujol): 1737, 1627, 1604, 1453, 1293, 1262, 1195, 1177,
1102, 1025, 949 cm–1. MS (CI): m/z (rel. intensity, %) = 471
(base peak) [M+], 397 (10), 367 (15), 280 (12), 246 (9), 105
(22). HRMS: Calcd 470.2569 for C30H34N2O3. Found:
470.2573. (R,R,R,R,R)-Ethyl-5-(4-nitrophenyl)-4-[(2¢,5¢-
trans-diphenylpyrrolidinyl)-1-carbonyl]-pyrrolidine-2-
carboxylate (3d3). White powder; mp 222–223 °C.
[a]D23 = +34 (c 0.17, CHCl3). 1H NMR (270 MHz, CDCl3):
d = 8.09 (d, 2 H, J = 8.6 Hz, Ar), 7.44–7.31 (m, 5 H, Ar), 7.18
(d, 2 H, J = 6.6 Hz, Ar), 7.07 (t, 1 H, J = 7.3 Hz, Ar), 6.95 (t,
2 H, J = 7.3 Hz, Ar), 6.52 (d, 2 H, J = 7.3 Hz, Ar), 5.25 (d, 1
H, J = 7.3 Hz, CHPh), 5.16 (d, 1 H, J = 7.3 Hz, CHPh), 4.24
(d, 1 H, J = 7.3 Hz, H-5), 4.20 (q, 2 H, J = 7.3 Hz, OCH2),
3.69 (t, 1 H, J = 8.6 Hz, H-2), 3.25 (ddd, 1 H, J = 3.3 Hz, 4.6
Hz and 7.9 Hz, H-4), 2.51–2.19 (m, 2 H, CH2), 2.01 (ddd, 1
H, J = 4.6 Hz, 7.3 Hz and 13.2 Hz, H2-3), 1.88–1.72 (m, 2 H,
CH2), 1.58 (dd, 1 H, J = 5.3 Hz and 11.9 Hz, CH2), 1.27 (t, 3
H, J = 7.3 CH3). 13C NMR: d = 172.9 (C=O), 172.2 (C=O),
147.1 (q), 146.2 (q), 143.6 (q), 142.6 (q), 129.0 (2 × CH),
127.9 (2 × CH), 127.8 (2 × CH), 127.7 (2 × CH), 126.6 (CH),
125.4 (2 × CH), 125.1 (2 × CH), 123.6 (2 × CH), 66.1, 63.2,
62.0, 61.1, 60.2, 47.8, 36.3, 33.4, 30.0, 14.2. IR (nujol):
1736, 1611, 1511, 1416, 1353, 1309, 1272, 1187, 1171,
1063, 1028 cm–1. MS (CI): m/z (rel. intensity, %) = 514 (base
peak) [M+1], 484 (12), 440 (8), 278 (10), 237 (12). HRMS:
Calcd 513.2264 for C30H31N3O5. Found: 513.2239.
(13) (a) Cardillo, G.; Hashem, A.; Tomasini, C. J. Chem. Soc.,
Perkin Trans. 1 1990, 1487. (b) Benovsky, P.; Stephenson,
G. A.; Stille, J. R. J. Am. Chem. Soc. 1998, 2493.
(14) Gutiérrez-García, V. M.; López-Ruiz, H.; Reyes-Rangel, G.;
Juaristi, E. Tetrahedron 2001, 57, 6487.
(15) Blaschke, G. Chem. Ber. 1974, 107, 237.
(16) (a) Nyerges, M.; Rudas, M.; Tóth, G.; Herényi, B.; Bitter, I.;
Tõke, L. Tetrahedron 1995, 51, 13321. (b) Pak, C. S.;
Nyerges, M. Synlett 1999, 1271. (c) Nyerges, M.; Fejes, I.;
Tõke, L. Synthesis 2002, 1823.
(17) Silver Acetate Catalysed Cycloaddition Reactions -
General procedure: A mixture of imine (1.2 equiv) AgOAc
(1.5 equiv), appropriate dipolarophile (1 equiv) and Et3N in
dry toluene (5 mL for 1 mmol of imine) protected from the
light with aluminium foil was stirred at r.t. for 12–48 h. The
reaction was then quenched by addition of sat. aq NH4Cl
solution and Et2O. The mixture was filtered through a pad of
Celite®. The organic layer was separated, washed with H2O,
brine and dried over MgSO4, filtered and the solvent
evaporated. The residue was purified by flash
(R,R,R,R,S)-Ethyl-4-[(2¢-hydroxy-1¢-methyl-2¢-phenyl-
ethyl)carbamoyl]-5-(2,4-dichlorophenyl)-pyrrolidine-2-
carboxylate (3e1). White powder; mp 182–183 °C.
[a]D23 = –101 (c 1.0, CHCl3). 1H NMR (270 MHz, CDCl3):
d = 7.40–7.15 (m, 8 H, Ar), 4.61 (d, 1 H, J = 6.6 Hz, CHOH),
4.40 (d, 1 H, J = 4.0 Hz, H-5), 4.27 (dq, 2 H, J = 1.9 and 7.3
Hz, OCH2), 4.10 (broad m, 2 H, OH + CH-CH3), 3.84 (t, 1
H, J = 7.9 Hz, H-2), 3.57 (ddd, 1 H, J = 4.0 Hz, 7.3 Hz and
10.7 Hz, H-4), 2.80 (m, 1 H, H2-3), 2.47 (s, 3 H, NMe), 2.35
(m, 1 H, H2-3), 1.33 (t, 3 H, J = 7.3 Hz, CH3), 0.72 (d, 3 H,
J = 7.3 Hz, CH3). 13C NMR: d = 173.6 (C=O), 172.8 (C=O),
141.7, 134.7, 133.7, 133.2, 129.2, 128.5, 127.9 (2 × CH),
127.3, 127.1, 126.1 (2 × CH), 76.5, 62.3, 59.8, 56.8, 43.5,
34.8, 32.5, 14.2, 11.4. IR (KBr): 3377, 2987, 1736, 1621,
1476, 1449, 1413, 1374, 1206, 1104, 1048 cm–1. MS (CI):
m/z (rel. intensity, %) = 479 (base peak) [M+], 463 (20), 314
(31), 280 (15), 176 (10), 148 (52), 135 (22), 107 (25).
HRMS: Calcd 478.1426 for C24H28Cl2N2O4. Found:
chromatography and/or recrystallisation to afford the
cycloadducts. Selected data for representative examples:
(S,S,S,R)-Ethyl-5-(2,4-dichlorophenyl)-4-[(1¢-phenyl-
ethyl)carbamoyl]-pyrrolidine-2-carboxylate (4b2). White
powder; mp 171–172 °C. [a]D23 = +116 (c 1.2, CHCl3). 1H
NMR (270 MHz, CDCl3): d = 7.51 (d, 1 H, J = 7.9 Hz, Ar),
7.33–7.12 (m, 5 H, Ar), 6.93 (dd, 1 H, J = 1.8 Hz and 7.9 Hz,
Ar), 6.42 (d, 1 H, J = 1.8 Hz, Ar), 4.73 (m, 1 H, CHCH3),
4.57 (d, 1 H, J = 6.0 Hz, H-5), 4.29 (q, 2 H, OCH2), 3.96 (dd,
1 H, J = 6.1 Hz and 9.5 Hz, H-2), 3.35 (ddd, 1 H, J = 3.2 Hz,
6.0 Hz and 6.7 Hz, H-4), 2.70 (br s, 1 H, NH), 2.53 (ddd, 1
H, J = 6.7 Hz, 9.5 Hz and 13.8 Hz, H2-3), 2.35 (ddd, 1 H, J
= 3.2 Hz, 6.1 Hz and 13.8 Hz, H2-3), 1.29 (t, 3 H, J = 7.3 Hz,
Me), 1.08 (d, 3 H, J = 8.6 Hz, Me). 13C NMR: d = 173.4
(C=O), 170.9 (C=O), 143.0 (q), 134.5 (q), 133.8 (q), 133.3
(q), 129.1 (2 × CH), 128.6 (2 × CH), 127.6 (CH), 127.6
(CH), 126.4 (CH), 125.9 (CH), 62.6, 61.2, 58.1, 47.3, 33.6,
21.0, 14.2, IR (nujol): 3306, 1734, 1644, 1527, 1213, 1123,
478.1409.
(18) (a) Groundwater, P. W.; Sharif, T.; Arany, A.; Hibbs, D. E.;
Hurthouse, M. B.; Nyerges, M. Tetrahedron Lett. 1998, 38,
1433. (b) Groundwater, P. W.; Sharif, T.; Arany, A.; Hibbs,
D. E.; Hurthouse, M. B.; Garnett, I.; Nyerges, M. J. Chem.
Soc., Perkin Trans. 1 1998, 2837.
Synlett 2003, No. 7, 947–950 ISSN 1234-567-89 © Thieme Stuttgart · New York