LETTER
Synthesis of Constrained b-Amino Esters from Norbornenes
2141
(5) Sabitha, G.; Srividya, R.; Yadav, J. S. Tetrahedron 1999, 55,
4015.
(6) Smith, P. A. S. Org. React. (NY) 1946, 3, 337.
(7) (a) Bolm, C.; Dinter, C. L.; Schiffers, I.; Defrere, L. Synlett
2001, 1875. (b) Kanaoka, S.; Grubbs, R. H. Macromolecules
1995, 28, 4707.
metathesis of alkyne bearing b-amino esters 13 and 14
were variable compared to those seen for the ene–ene
metathesis reactions. Thus, homopropargylated b-amino
ester 13 was converted into the 5,7-fused bicyclic b-amino
ester 17 in 32% yield with the mass balance being recov-
ered starting material. Tandem metathesis of 14 (contain-
ing an extra methylene unit in the alkyne tether) did not
undergo conversion into the desired 5,8-bicyclic b-amino
ester with the only isolable materials being the ring-
opened norbornene 18 and recovered staring material. At-
tempts to force ring closure of the ring-opened norbornene
18 with the Grubbs II catalyst resulted in recovery of only
unreacted starting material.
(8) Lloyd-Jones, G. C.; Margue, R. G.; de Vries, J. G. Angew.
Chem. Int. Ed. 2005, 44, 7442.
(9) (a) RRM of a structure related to 2 has been reported, see:
Maechling, S.; Norman, S. E.; Mckendrick, J. E.; Basra, S.;
Knoppner, K.; Blechert, S. Tetrahedron Lett. 2006, 47, 189.
(b) Conditions for the conversion warranted exposure of the
material to high catalyst loading (20 mol%) and ethene gas
(3 atm) for three cycles to obtain good conversion (88%).
(10) The most diagnostic peaks for the epimerization are: cis-
amino ester Heq d = 3.3 ppm and trans-amino ester Hax d =
2.6 ppm.
In summary, tandem metathesis has proven to be an effi-
cient reaction for the synthesis of highly constrained bicy-
clic b-amino esters from easily prepared norbornene
substrates. The reaction is facile when the ring being
formed is favorable (c.f. 5 and 10),12 ene–ene metathesis
has been demonstrated to be a more reliable reaction when
the size of the ring being generated in the ring-closing step
is less favorable. Ene–yne tandem metathesis reactions
were less efficient, the 5,7-bicyclic ring system was pre-
pared in low yield and attempts to furnish the 5,8-bicycle
proved to be non-productive.
(11) General Procedure for Olefin Metathesis Reactions –
Synthesis of 5.
A flask was charged with alkyne 4 (51 mg, 0.14 mmol) and
freshly distilled CH2Cl2 (50 mL). Ethene gas was then
bubbled through the solution for 20 s. Grubbs I catalyst (11
mg, 0.014 mmol) was then added and a balloon filled with
ethene gas was fitted to the flask. The reaction was allowed
to stir at r.t. overnight. The reaction mixture was concen-
trated in vacuo and subjected to column chromatography
eluting with PE–EtOAc (19:1 to 4:1) to furnish 5 as a white
solid in 96% yield (52 mg). Mp 144–146 °C. 1H NMR (250
MHz, CDCl3): d = 1.16–1.27 (m, 1 H, CH2CHCHN), 2.20–
2.28 (m, 1 H, CH2CHCHN), 2.39 (s, 3 H, CH3), 2.56–2.66
(br s, 1 H, CHCO2), 2.60 (br s, 1 H, CHCHN), 2.71–2.86 (m,
1 H, CHCHCO2), 3.68 (s, 3 H, CO2CH3), 3.76 (dt, 1 H,
NCH2, J = 18.0, 2.0 Hz), 4.45–4.92 (m, 1 H, NCH2), 4.45–
4.92 (m, 1 H, CHN), 4.92–5.17 (m, 4 H, 2 × CH=CH2) 5.42
(br s, 1 H, HC=C*), 5.58 (ddd, 1 H, HC=CH2, J = 17.5, 10.0,
7.5 Hz), 6.16 (dd, 1 H, HC=CH2, J = 18.0, 11.0 Hz), 7.28 (m,
2 H, 2 × ArH), 7.79 (m, 2 H, 2 × ArH). 13C NMR (62.5 MHz,
CDCl3): d = 21.9 (CH3), 34.7 (CHCHCO2), 36.2
(CH2CHCHN), 39.2 (NCH2), 44.2 (CHCHN), 51.1
(CHCO2), 52.5 (CO2CH3), 59.5 (CHN), 112.8 (CH=CH2),
115.8 (CH=CH2), 127.4 (2 × ArC), 129.9 (2 × ArC), 130.6
(HC=C*), 131.6 (HC=C*), 136.7 (CH=CH2) 137.8
(1 × ArC), 139.6 (CH=CH2), 143.6 (1 × ArC), 173.4 (C=O).
IR (thin film): nmax = 1163, 1345 (SO2), 1735 (C=O), 2952
(sat. C–H) cm–1. MS (CI, NH3): m/z calcd for C21H25NO4S:
387.1504; found: 387.1497 [M+].
Acknowledgment
J.E.M. and A.E.N. would like to thank the EPSRC for funding a
studentship for A.E.N.
References and Notes
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(12) Analytical data for 10: 1H NMR (250 MHz, CDCl3): d =
1.23 (ddd, 1 H, CH2CHCH=CH, J = 13.0, 8.5, 4.5 Hz), 2.24
(m, 1 H, CH2CHCH=CH), 2.40 (s, 3 H, CH3), 2.48–2.50 (br
m, 1 H, CHCH=CH), 2.66–2.74 (m, 1 H, CHCO2CH3),
2.78–2.87 (m 1 H, CHCH=CH2), 3.66 (s, 3 H, CO2CH3),
3.68–3.78 (m, 1 H, CH2N), 4.14–4.22 (m, 1 H, CH2N), 4.55
(dd, CHN, 1 H, J = 10.5, 8.0 Hz), 4.91–5.01 (m, 2 H,
CH=CH2), 5.45–5.71 (m, 2 H, CH=CH), 5.45–5.71 (m, 1 H,
CH=CH2), 7.25 (m, 2 H, 2 × ArH), 7.66 (m, 2 H, 2 × ArH).
13C NMR (62 5 MHz, CDCl3): d = 21.9 (CH3), 34.2
(CHCH=CH), 35.8 (CH2CHCH=CH), 39.8 (CH2N), 44.1
(CHCH=CH2), 50.9 (CHCO2CH3), 52.4 (CO2CH3), 59.6
(CHN), 115.6 (CH=CH2), 121.4 (HC=CH), 127.4 (2 × ArC),
129.9 (2 × ArC), 130.8 (HC=CH), 138.0 (1 × ArC), 140.0
(CH=CH2), 143.5 (1 × ArC), 173.6 (C=O). IR (thin film):
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n
max = 1164, 1345 (SO2), 1734 (C=O), 2952 (sat. C–H)
cm–1. MS (CI, NH3): m/z calcd for C19H23NO4S: 361.1348;
found: 361.1355 [M+].
Synlett 2006, No. 13, 2139–2141 © Thieme Stuttgart · New York