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U. D. Wermuth et al.
Experimental
Esterification of ( )-Bicyclo[2.2.1]hept-6-one-2-endo-carboxylic
Acid 7 with Diazomethane[14a]
General
The keto acid 7 (2.0 g, 13 mmol) was suspended in diethyl ether (10 mL)
and was titrated with ethereal diazomethane until a yellow colour per-
sisted for 30 min and no more N2 evolved upon addition of further
CH2N2.The diethyl ether was removed under vacuum to yield 14 (2.1 g,
96%) as a yellow oil which required no further purification (compound
waspurebyTLC, aswellas1Hand13CNMRspectroscopy). vmax (NaCl,
oil, neat)/cm−1 1740 (C=O, ketone and ester), 1200 (C–O, ester). δH
(CDCl3, TMS) 3.67 (3H, ester), 3.15–2.95 (1H, m), 2.85 (1H, br s),
2.75 (1H, br s), 2.25–1.65 (6H, m). δC (CDCl3, TMS) 214.7 (C=O,
ketone), 173.9 (C=O, ester), 52.0 (CH3, ester), 53.7, 44.6, 43.0, 38.9,
35.0, 31.0 (norbornane). δC (DEPT) 53.7 (CH), 44.6 (CH2), 43.0 (CH),
38.9 (CH2), 35.0 (CH), 31.0 (CH2).
Melting points were performed on a digital Gallenkamp apparatus and
are uncorrected. Solvents were distilled before use or were of analytical
grade. IR spectra were recorded on a JASCO IR-810 or on a Perkin–
Elmer 1725 XFT-IR spectrometer. NMR spectra were recorded on a
Varian 200 MHz spectrometer. ESMS spectra were recorded on a Fisons
VG Platform 8070 mass spectrometer. Thin-layer chromatography was
performed on silica-gel plates (Merck, Kieselgel 60, F254, 0.255 mm).
The spots were developed either by exposure to UV or iodine. Acrylic
acid and cyclopentadiene were obtained fromAldrich and Fluka, respec-
tively. Microanalyses were performed by the Microanalytical Service of
the Chemistry Department at the University of Queensland.
(
)-Bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic Acid 5
(
)-6-endo-Aminobicyclo[2.2.1]heptane-2-endo-carboxylic
Freshly distilled cyclopentadiene 3 (33 g, 0.5 mol) was added to acrylic
acid 4 (30 g, 0.4 mol) that was being cooled in an ice bath.When addition
was complete, the mixture was allowed to warm to room tempera-
ture and was then stirred for 12 h. Distillation of the crude residue,
bp 99.5◦C/1.2 mmHg (lit.[8] 139.0◦C/16 mmHg), gave a clear viscous
oil (50 g, 80%) that had a pungent odour.
Acid-γ-lactam-6-exo-carboxylic Acid 11 (One-pot Procedure)
Bicyclo[2.2.1]hept-6-one-2-endo-carboxylic acid 7 (1.0 g, 6.5 mmol)
was added dropwise at 0◦C to a reaction vial that contained NH4Cl
(0.4 g, 7.3 mmol) and NaCN (0.4 g, 7.3 mmol) in a solution of concen-
trated ammonia (1.3 mL) and distilled water (0.6 mL). Upon complete
addition the reaction vial was sealed and transferred to an oil bath, and
was then heated with stirring at 50◦C (bath temperature) for 5 h. The
solution was allowed to cool and the volume was reduced to about one-
third of the original. Concentrated HCl (32%, 4 mL) was then added and
the mixture was heated at reflux for 3 h. Upon cooling in an ice bath,
a white solid precipitated. This was filtered off, washed with ice-cold
water, ethanol, and diethyl ether, and dried to give 11 (0.3 g, 25%) as
a white solid. The melting point, as well as the IR and 1H NMR spec-
tra were identical to those obtained for the product from the hydrolysis
of 16.
Mixture of endo (75%) and exo Isomers (25%): Determined by
13C NMR Spectroscopy of the Methyl Ester
vmax (NaCl, neat, oil)/cm−1 3500–2400 (OH, acid), 1700 (C=O, acid).
δH (CDCl3) 11.93 (s), 6.11 (s), 3.51–1.16 (series of multiplets). δC
183.0, 181.8, 138.1, 137.8, 135.7, 132.5, 49.7, 46.7, 46.4, 45.6, 43.4,
43.2, 42.6, 41.7, 30.3, 29.1.
(
)-5-exo-Bromo-6-endo-hydroxybicyclo[2.2.1]heptane-2-endo-
carboxylic Acid-γ-lactone 6
(
)-6-endo-Aminobicyclo[2.2.1]heptane-2-endo-carboxylic Acid-γ-
A solution of the unsaturated acid mixture 5 (1.0 g, 7.24 mmol) and
sodium bicarbonate (3.0 g, 35.7 mmol) in water (45 mL) was treated
with neat bromine (1.0 mL, 3.1 g, 19.4 mmol) to give a light yellow oil
that was extracted with diethyl ether (4 × 10 mL) after 16 h. The extract
was dried over MgSO4 and filtered, and the diethyl ether was removed
under vacuum to yield a light yellow oil that crystallized upon standing.
Recrystallization from EtOAc/hexane gave clear white crystals of 6
(0.5 g, 35%), mp 64–66◦C (lit.[9] 64.8–65.9◦C). vmax (KBr)/cm−11770
(C=O, lactone). δH (CDCl3) 4.95 (1H, d, J 4.9), 3.87 (1H, d, J 2.3),
3.25 (1H, m), 2.68–2.55 (1H, m), 2.60 (1H, br s), 2.45–2.30 (1H, m),
2.55–2.05 (1H, m), 2.90–1.70 (2H, m). δC (CDCl3) 179.2 (C=O, lac-
tone), 87.8 (C6), 53.6 (C5), 46.0, 45.7, 37.7, 35.9, 34.1 (norbornane).
δC (DEPT) 87.8 (CH), 53.6 (CH), 46.0 (CH), 45.7 (CH), 37.7 (CH),
35.9 (CH2), 34.1 (CH2).
lactam-6-exo-carboxylic Acid 11 (with Isolation of Aminonitrile 16)
Ketoester 14(5.9 g, 35.3 mmol)wasdissolvedin50%aqueousmethanol
(30 mL)inapressureflaskandthenasolutionofKCN(3.6 g, 56.1 mmol,
1.6 equiv.) and NH4Cl (3.1 g, 57.9 mmol, 1.6 equiv.) in 50% aqueous
methanol (30 mL) was added to it.The flask was sealed and incubated in
an oil bath at 80◦C (bath temperature) with stirring for 8 h. The cooled
mixture was transferred to a round-bottomed flask and the methanol was
removed under vacuum. The aqueous residue was extracted with diethyl
ether (6 × 30 mL), the extract was dried over MgSO4, filtered, and the
solvent was removed under vacuum to give crude 16 (2.3 g, 33%). vmax
(NaCl, oil, neat)/cm−1 3300 (N–H), 2220 (CN), 1740 (C=O, unreacted
ketone), 1720 (C=O, ester), 1700 (C=O, free acid).
Thecrudeaminonitrile16(2.3 g, 11.9 mmol, calculatedaspureester)
was dissolved in 6 M HCl (55 mL, 27.6 equiv.), the solution was placed
in a pressure flask, and this was then sealed and incubated at 124◦C
(bath temperature) for 12 h with stirring. The solution was cooled, the
solvent was removed under vacuum, and the aqueous residue was acid-
ified to pH 1 with concentrated HCl to give, after drying, 11 as a white,
analytically pure solid (1.0 g, 46%), mp 302–305◦C (dec.) (lit.[30] 298–
300◦C) (Found: C 59.5, H 6.2, N 7.7. C9H11NO3 requires C 59.6, H 6.1,
N 7.7%). vmax (KBr)/cm−1 3600–2400 (OH, acid), 3200 (N–H), 2980
(CH), 1720 (C=O, acid), 1640 (C=O, lactam). δH [(CD3)2SO] 7.88
(1H, s), 4.00–3.20 (integration uncertain but approx. 1H, br s, possibly
due to carboxylate hydrogen), 3.05–1.30 (9H, m). δC [(CD3)2SO] 180.1
(C=O, acid), 174.5 (C=O, lactam), 66.3 (C6), 52.0, 42.6, 42.3, 37.8,
37.3, 33.6. δC (DEPT) 52.0 (CH), 42.6 (CH2), 42•.3 (CH), 37.8 (CH),
37.3 (CH2), 33.6 (CH2). m/z (ESI) 182 ([M + 1]+ ), 180 ([M − 1]+•).
This procedure worked equally well on a large scale.
(
)-Bicyclo[2.2.1]hept-6-one-2-endo-carboxylic Acid 7
Bromolactone 6 (88 g, 0.4 mol) was dissolved in MeOH (820 mL), and
an ice-cold solution of KOH (67 g, 1.2 mol) in distilled water (125 mL)
was added in five portions with vigorous stirring. The mixture was then
refluxed for 6 h, allowed to cool, and the MeOH was removed under
vacuum. The aqueous residue was carefully neutralized with concen-
trated HCl, stirred at room temperature over NoritA charcoal (to remove
a brown oil), filtered, and acidified to pH 1. The acidified solution was
extracted with diethyl ether (4 × 200 mL), the extract was dried over
MgSO4, filtered, and the solvent was removed under vacuum to yield
a light yellow oil in which crystals formed upon standing. Recrystal-
lization from CH2Cl2 yielded a first crop. Two further crops were also
collected from reduced volumes. Colourless, well formed crystals of 7
were obtained (29 g, 45%), mp 102–104◦C (lit.[10] 102–103◦C). vmax
(KBr)/cm−1 3600–2400 (OH, acid), 1740 (C=O, ketone), 1700 (C=O,
acid). δH (CDCl3) 9.90 (1H, br s, acid), 3.30–1.70 (9H, m). δC (CDCl3)
216.0 (weak, br, C=O, ketone), 178.5 (C=O, acid), 53.4, 44.6, 42.8,
38.8, 35.4, 31.5 (norbornane). δC (DEPT) 53.4 (CH), 44.6 (CH2), 42.8
(CH), 38.8 (CH2), 35.4 (CH), 31.5 (CH2).
(
)-Bicyclo[2.2.1]heptane-2-endo-carboxylic Acid-6-spiro-
5ꢀ- hydantoin 15
A solution of (NH4)2CO3 (14 g, 145.5 mmol, 4.1 equiv.) in 50% aqueous
EtOH (50 mL) was placed into a 100 mL round-bottomed flask. A solu-
tion of keto ester 14 (5.8 g, 35.0 mmol) in 50% aqueous EtOH (12 mL)
was then added followed by a solution of KCN (4.7 g, 72.30 mmol, 2.0