Monoamine Oxidase-Catalyzed Rearrangement
J . Org. Chem., Vol. 61, No. 25, 1996 8965
Ta ble 4. GHMBC Da ta (C-H Lon g-Ra n ge Cor r ela tion s)
for th e Meta bolite fr om MAO-Ca ta lyzed Oxid a tion of 3
(in p p m )a
with lithium aluminum hydride (1.2 g, 37 mmol) in 25 mL of
anhydrous THF at reflux under a positive pressure of nitrogen
for 4 h followed by quenching with water in THF. Aqueous
20% sodium hydroxide (4 mL) was added to remove the
aluminate salts. The THF solution was extracted with 2 N
HCl (3 × 10 mL), the acid extracts were back-extracted with
ether (10 mL), the aqueous solution was evaporated to dryness,
and the residue was crystallized with ethanol-ethyl acetate
to give 1.9 g (85%) of 3: NMR (CDCl3) δ 8.26 (br, 2 H), 7.2-
7.3 (m, 5 H), 3.42 (dd, 1 H), 3.11 (s, 3 H), 2.6-2.8 (br, 2 H),
2.06 (t, 1 H), 1.90 (dd, 1 H). Anal. Calcd for C11H16ClNO: C,
61.82; H, 7.49; N, 6.56; Cl, 16.63. Found: C, 61.50; H, 7.49;
N, 6.50; Cl, 16.83.
7.48 T 125.0, 125.5, 128.9
7.32 T 136.3, 128.9, 125.1
7.29 T 126.2, 128.3, 137.0
7.23 T 126.2, 128.4
7.14 T 125.1
7.19 T 128.3
7.07 T 125.0, 121.9, 106.6
6.78 T 125.0, 117.6, 106.6
6.44 T 117.6, 121.9
a
The symbol T denotes which protons correlate with which
t r a n s,t r a n s-2-Me t h oxy-3-p h e n ylc yc lop r op a n e c a r -
boxylic Acid (6). Compound 4a (1.0 g, 4.5 mmol) was
saponified by the addition of 1.5 g of potassium hydroxide in
10 mL of ethanol at rt with stirring for 4 h. After acidification
with 15 mL of 3 N HCl, 6 (0.79 g, 90%) was obtained by
extraction into ether followed by evaporation: NMR (CDCl3)
δ 7.2-7.4 (m, 5 H), 3.89 (dd, 1 H), 3.35 (s, 3 H), 2.78 (t, 1 H),
2.20 (dd, 1 H); HRMS calcd 192.0786, found 192.0798, m/z 192
(192, 162, 147, 131, 115, 103, 91, 77, 51).
carbons. See Figure 6.
Sch em e 3
tr a n s,tr a n s-2-Meth oxy-3-p h en ylcyclop r op a n eca r boxa -
m id e (5). A second procedure for the synthesis of 5 is as
follows: To a stirred mixture of the compound 6 (192 mg, 1.0
mmol) and N-hydroxysuccinimide (138 mg, 1.2 mmol) in
methylene chloride (10 mL) at 0 °C was added N,N′-dicyclo-
hexylcarbodiimide (247 mg, 1.2 mmol). The reaction mixture
was stirred for 1.5 h under the same conditions, and 30%
aqueous ammonia (166 µL) was added to the stirred solution.
The reaction mixture was allowed to continue to stir for 1 h.
Dicyclohexylurea, which precipitated during the reaction, was
filtered off. The filtrate was evaporated under reduced pres-
sure to dryness, giving 5 (150 mg, 78%).
Dieth yl P h en ylsu ccin a te. To a 25-mL round bottom flask
fitted with a Dean-Stark trap were added phenylsuccinic acid
(1.0 g, 5.15 mmol), ethyl alcohol (5 mL), p-toluenesulfonic acid
(50 mg), and benzene (10 mL). Following overnight reflux,
the benzene solution was washed with saturated sodium
bicarbonate (2 × 5 mL) and water (2 × 5 mL) and dried over
sodium sulfate. Removal of the solvent resulted in a colorless
oil (1.1 g, 86%): 1H NMR (CDCl3) δ 7.30 (m, 5 H), 4.13 (m, 5
H), 3.18 (dd,1 H), 2.68 (dd, 1 H), 1.21 (m, 6 H), agrees with
the spectrum reported.8
Sch em e 4
Rea ction of 3 w ith 2-P h en ylsu ccin a ld eh yd e. To a
stirred solution of diethyl phenylsuccinate (1.0 g, 4.02 mmol)
in dry toluene (10 mL) at -78 °C was added a -78 °C solution
of 1.5 M diisobutylaluminum hydride (DIBAL) in toluene (10
mL) via cannula. The rate of addition was adjusted so as to
keep the internal temperature below -65 °C over the ca. 45
min addition time. The 2-phenylsuccinaldehyde produced was
too unstable to isolate. The reaction mixture was stirred for
an additional 3 h at -78 °C, and then the reaction was
quenched by slow addition of 200 mg (1 mmol) of compound 3
in 3 mL of anhydrous methanol at -78 °C, again so as to keep
the internal temperature below -65 °C. The resulting white
emulsion was allowed to warm to rt and was poured into 50
mL of 1 N HCl with swirling over 15 min. The aqueous
mixture was then extracted with methylene chloride (3 × 50
mL). The combined organic layers were washed with brine
(50 mL), dried over Na2SO4, filtered, and concentrated in vacuo
to give 50 mg of crude product as a yellow oil (4%). The
Exp er im en ta l Section
Rea gen ts. Compounds 4a and 4b were synthesized as
reported.7 All reagents were purchased from Aldrich Chemical
Co.
(5) (a) Newcomb, M.; Le Tadic-Biadatti, M.-H.; Chestney, D. L.;
Roberts, E. S.; Hollenberg, P. F. J . Am. Chem. Soc. 1995, 117, 12085-
12091. (b) Atkinson, J . K.; Hollenberg, P. F.; Ingold, K. U.; J ohnson,
C. C.; Le Tadic, M.-H.; Newcomb, M.; Putt, D. A. Biochemistry 1994,
33, 10630-10637. (c) Martin-Esker, A. A.; J ohnson, C. C.; Horner, J .
H.; Newcomb, M. J . Am. Chem. Soc. 1994, 116, 9174-9181.
(6) (a) Silverman, R. B.; Zhou, J . P.; Eaton, P. E. J . Am. Chem. Soc.
1993, 115, 8841-8842. (b) Silverman, R. B.; Lu, X.; Zhou, J . J . P.;
Swihart, A. J . Am. Chem. Soc. 1994, 116, 11590-11591. (c) Silverman,
R. B.; Zhou, J . J . P.; Ding, C. Z.; Lu, X. J . Am. Chem. Soc. 1995, 117,
12895-12896.
tr a n s,tr a n s-2-Meth oxy-3-p h en ylcyclop r op a n eca r boxa -
m id e (5). Ammonium hydroxide (20 mL) was added to 4a
(1.0 g, 4.5 mmol), and the mixture was stirred at rt overnight.
The precipitate that formed was washed with hexane to give
a pale yellow solid (0.78 g, 90%): 1H NMR (CDCl3) δ 7.2-7.4
(m, 5 H), 5.71 (br, 1 H), 5.59 (br, 1 H), 3.86 (dd, 1 H), 3.28 (s,
3 H), 2.71 (t, 1 H), 2.04 (dd, 1 H); HRMS calcd 191.0946, found
191.0930, m/z 191 (191, 159, 147, 131, 115, 103, 91, 77, 51).
tr a n s,tr a n s-1-(Am in om et h yl)-2-m et h oxy-3-p h en ylcy-
clop r op a n e (3). Compound 5 (2.0 g, 10.5 mmol) was reduced
(7) Newcomb, M.; Chestney, D. L. J . Chem. Soc., Perkin Trans. 2
1996, 1467-1473.
(8) Chadha, V. K.; Leidal, K. G.; Plapp, B. V. J . Med. Chem. 1985,
28, 36-40.