2,4-Diarylpyrrolidine-3-carboxylic Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1045
solution was concentrated in vacuum. More toluene was added
and the mixture reconcentrated until the odor of acetic acid
was gone. Ether (150 mL) was added. Cooling gave 17.88 g
of 17u : mp 122-124 °C; yield 77% in two steps based upon
16.85 g of trans-trans 11; TLC (5% HCOOH in EtOAc) was
one spot of Rf ) 0.33. The ether extracts from the basic
solution were concentrated to give recovered cis-trans ester.
This was hydrolyzed as above (refluxing for two days was
necessary) to give 17y, the structure of which was determined
by X-ray analysis. NMR (CDCl3): 17u , 0.79 (t, J ) 7 Hz, 3H),
0.85 (t, J ) 7 Hz, 3H), 1.00-1.50 (m, 8H), 2.74 (d, J ) 13 Hz,
1H), 2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, J ) 13
Hz, 1H), 3.52-3.62 (m, 1H), 3.75 (d, J ) 10 Hz, 1H), 3.78 (s,
3H), 5.93 (dd, J ) 2 Hz, 4 Hz, 2H), 6.71 (d, J ) 8 Hz, 1H),
6.81-6.89 (m, 2H), 7.03 (d, J ) 2 Hz, 1H), 7.30 (J ) 8 Hz,
2H); 17y, 0.82 (t, J ) 7 Hz, 3H), 0.90 (t, J ) 7 Hz, 3H), 1.08-
1.48 (m, 8H), 2.92-3.38 (m, 6H), 3.04 (d, J ) 13 Hz, 1H), 3.45
(d, J ) 13 Hz, 1H), 3.45-3.52 (m, 1H), 3.74 (s, 3H), 3.75-3.87
(m, 1H), 4.24 (d, J ) 10 Hz, 1H), 5.93 (s, 2H), 6.70-6.82 (m,
3H), 6.77 (d, J ) 8 Hz, 2H), 7.28 (d, J ) 8 Hz, 2H).
Met h od C. tr a n s,tr a n s-2-(4-Met h oxyp h en yl)-4-(1,3-
ben zod ioxol-5-yl)-1-[2-(2-m et h oxyet h oxy)et h yl]p yr r oli-
d in e-3-ca r boxylic Acid (14t). Compound 11 (250 mg, 0.677
mmol, pure trans-trans), 150 mg (0.820 mmol) of 2-(2-
methoxyethoxy)ethyl bromide, 175 mg of (1.356 mmol) diiso-
propylethylamine, and 1 mL of acetonitrile were refluxed for
3 h, when TLC showed that no 11 was left. Toluene was
added, and the mixture was washed with KHCO3 solution,
dried (Na2SO4), and concentrated. More toluene was added
and concentrated to get rid of the diisopropylethylamine. The
yield was 230 mg, which was used in the hydrolysis step
(method B) to give 151 mg of 14t as a white powder (57% in
two steps). TLC (5% HCOOH in EtOAc) showed one spot of
Rf ) 0.25. NMR (CD3OD): 2.90-3.90 (m, 13H), 3.81 (s, 3H),
4.49 (d, J ) 10 Hz, 1H), 5.94 (s, 2H), 6.79 (d, J ) 8 Hz, 1H),
6.89 (dd, J ) 8 Hz, 1 Hz, 1H), 7.00 (d, J ) 9 Hz, 2H), 7.05 (d,
J ) 1 Hz), 7.49 (d, J ) 9 Hz, 2H).
Other compounds synthesized by this method were
14a -d ,p -u . Either pure 11 or the mixture of 11 and 13 was
used. Compound 14c was synthesized by reacting 1-bromo-
2-hexyne30 and 11 for 1 h at 55 °C. Compound 14d was
synthesized from 4-fluorobenzyl bromide and 11 at room temp
for 3 h. Compound 14b was made from trans-1-bromo-5-
methylhex-2-ene, the preparation of which is described below.
tr a n s-1-Br om o-5-m eth ylh ex-2-en e. Diisopropyl (ethoxy-
carbonylmethyl) phosphonate (5.0 mL) in 20 mL of THF was
reacted with 0.85 g of NaH for 20 min. Isovaleraldehyde (2.0
mL) was added. After 18 h at room temperature the reaction
was worked up giving 2.10 g of trans-5-methylhex-2-enoic acid,
ethyl ester. This was reduced to trans-5-methylhex-2-en-1-ol
with diisobutyl aluminum hydride, which was brominated with
PBr3 in ether to give the title compound.
Met h od D. tr a n s,tr a n s-2-(4-Met h oxyp h en yl)-4-(1,3-
ben zod ioxol-5-yl)-1-[2-(2-p yr id yl)eth yl]p yr r olid in e-3-ca r -
boxylic Acid (20c). Compound 11 (250 mg, 0.677 mmol of
pure trans-trans), 2-vinylpyridine (355 mg, 3.38 mmol), and
one drop of acetic acid were dissolved in 1 mL of methoxy-
ethanol and stirred at 100 °C for 2.5 h. Toluene was added
and the solution was washed with KHCO3, dried (Na2SO4),
and concentrated. More toluene was added and the mixture
concentrated to get rid of the excess 2-vinylpyridine. The
residue was dissolved in heptane, filtered from a small amount
of insoluble matter, and concentrated to yield 225 mg of the
intermediate ester. This was hydrolyzed by method B to give
202 mg of 20c, mp 77-80 (from water), as the dihydrate. NMR
(CD3OD): 2.8-3.3 (m, 6H), 3.55-3.70 (m, 2H), 3.76 (s, 3H),
3.99 (d, J ) 10 Hz, 1H), 5.92 (d, J ) 1 Hz, 2H), 6.72 (d, J ) 8
Hz, 1H), 6.80 (dd, J ) 8 Hz, 1 Hz, 1H), 6.85 (d, J ) 9 Hz, 2H),
6.92 (d, J ) 1 Hz, 1H), 7.20 (d, J ) 9 Hz, 2H), 7.20-7.32 (m,
2H), 7.70-7.80 (m, 2H), 8.40 (d, J ) 4 Hz, 2H).
acid and oxalyl chloride) in 1 mL of CH2Cl2. After 2 h at room
temperature, the solution was washed with bicarbonate and
dried (Na2SO4) to give 394 mg of the intermediate ethyl ester.
This was hydrolyzed by method B to give 222 mg of 14f (63%
yield). NMR (DMSO-d6): rotational isomers, 2.92 and 3.10
(dd, J ) 11 Hz, 9 Hz, 0.5H), 3.35-3.58 (m, 2H), 3.72 and 3.76
(s, 3H), 4.05 and 4.22 (dd, J ) 10 Hz, 8 Hz, 0.5H), 4.78 and
4.90 (s, 2H), 5.00 and 5.20 (d, J ) 9 Hz, 1H), 6.00 (s, 2H), 6.6-
7.2 (m, 9H), 7.32 and 7.41 (d, J ) 8 Hz, 2H).
Compounds synthesized by a similar manner were 14e,j,k,m .
For 14m , dibutylcarbamoyl chloride31 was reacted with 11 at
45 °C for 1 h.
Met h od F . tr a n s,tr a n s-2-(4-Met h oxyp h en yl)-4-(1,3-
ben zodioxol-5-yl)-1-[(ph en ylam in o)car bon yl]pyr r olidin e-
3-ca r boxylic Acid (14g). Phenyl isocyanate (75 mg, 0.630
mmol) in 0.5 mL of THF was added to 200 mg (0.542 mmol) of
compound 11 in 0.5 mL of THF. After 1 h at room tempera-
ture, toluene was added, and the solvents were concentrated
in vacuo to remove the excess phenyl isocyanate. This
intermediate ester was hydrolyzed by method B to give 206
mg (83% of 14g, mp 209-211 °C. NMR (DMSO-d6): 3.03 (dd,
J ) 11 Hz, 9 Hz, 1H), 3.50-3.62 (m, 1H), 3.65-3.80 (m, 1H),
3.75 (s, 3H), 4.15 (dd, J ) 10 Hz, 8 Hz) 5.13 (d, J ) 9 Hz, 1H),
6.82-6.92 (m, 5H), 7.07 (s, 1H), 7.12-7.30 (m, 2H), 7.30 (d, J
) 8 Hz, 2H), 7.38 (d, J ) 8 Hz, 2H), 8.20 (s, 1H).
Met h od G. tr a n s,tr a n s-2-(4-Met h oxyp h en yl)-4-(1,3-
ben zod ioxol-5-yl) -1-[(d ibu tyla m in o)a cetyl]p yr r olid in e-
3-ca r boxylic Acid (14n ). To 152 mg (0.813 mmol) of N,N-
dibutylglycine32 in 0.75 mL of THF was added 138 mg (0.852
mmol) 1,1-carbonyldiimidazole. The solution was kept at 50
°C for 30 min. Compound 11 (250 mg, 0.678 mmol) was added
and the solution kept at 45 °C for 1 h. The product was
chromatographed on silica gel, eluting with 1:1 hexane-EtOAc
to give 306 mg (84%) of the intermediate ethyl ester, which
was hydrolyzed by method B to yield 14n in 92% yield, as a
white powder. TLC (5% HCOOH in EtOAc) showed one spot
of Rf ) 0.15. NMR (CDCl3): rotational isomers, 0.75 and 0.85
(t, J ) 7 Hz, 3H), 1.05-1.50 (m, 8H), 2.65-3.20 (m, 6H), 3.43-
3.70 (m, 3H), 3.72 (s, 3H), 3.87 (d, J ) 15 Hz, 1H), 4.49 (dd, J
) 12 Hz, 6 Hz) and 5.23 (dd, J ) 12 Hz, 8 Hz, 2H), 5.90 (dd,
J ) 2 Hz, 4 Hz, 2H), 6.63-6.78 (m, 3H), 6.86 and 7.04 (d, J )
9 Hz, 2H), 7.22 (d, J ) 9 Hz, 2H).
Met h od H . tr a n s,tr a n s-2-(4-Met h oxyp h en yl)-4-(1,3-
ben zod iolol-5-yl)-1-[2-(eth ylsu lfin yl)eth yl]p yr r olid in e-3-
ca r boxylic Acid (20a ). To the 64:36 mixture of 11 and 13
(100 mg, 0.27 mmol) in 6 mL acetonitrile were added 67.5 mg
(0.50 mmol) of 2-chloroethyl ethyl sulfide, 375 mg of diiso-
proplyethyamine, and 10 mg of KI. The mixture was refluxed
for 4 h. The solvents were removed in vacuum and the residue
chromatographed on silica gel eluting with 4:1 hexane-EtOAc
to give 93 mg of the intermediate 1-(ethylthio)ethyl compound.
To this compound dissolved in 5 mL of CH2Cl2 was added 68
mg of 3-chloroperoxybenzoic acid. The mixture was stirred
for 40 min in an ice bath and then for 3 h at room temperature.
After washing with NaHCO3 and drying, the solution was
concentrated and the residue chromatographed on silica gel
eluting with EtOAc to give 62 mg (65%) of the sulfoxide, ethyl
ester. This was hydrolyzed by method B to give 20a as a
mixture of diastereoisomers. NMR (CDCl3): 1.25 and 1.32 (t,
J ) 7 Hz, 3H), 2.45-2.75 (m, 4H), 2.84-2.96 (m, 3H), 3.02-
3.08 (m, 1H), 3.32 and 3.36 (d, J ) 3 Hz, 1H), 3.47-3.58 (m,
2H), 3.65 and 3.68 (d, J ) 8 Hz, 1H), 3.76 and 3.80 (s, 3H),
5.94 (s, 2H), 6.72 (d, J ) 8 Hz, 1H), 3.84-3.89 (m, 3H), 7.02
(d, J ) 6 Hz, 1H), 7.30 and 7.34 (d, J ) 8 Hz, 2H).
tr a n s,tr a n s-Eth yl 2-(4-Meth oxyp h en yl)-4-(1,3-ben zo-
dioxol-5-yl)-1-(2-br om oeth yl)pyr r olidin e-3-car boxylate (20,
R ) Et, X ) Br ). Compound 11 (2.00 g, 5.42 mmol), 2 mL of
diisopropylethylamine, and 200 mg of NaI were stirred in 18
mL of 1,2-dibromoethane at 100 °C for l h. Toluene was added,
and the mixture was washed with bicarbonate. The solvents
were concentrated, and the black residue was chromato-
graphed on silica gel, eluting with 4:1 hexane-EtOAc to yield
2.22 g (87%) of product. NMR (CDCl3): 1.11 (t, J ) 7 Hz, 3H),
2.48-2.56 (m, 1H), 2.80-3.00 (m, 3H), 3.31-3.42 (m, 3H),
3.48-3.55 (m, 1H), 3.70 (d, J ) 9 Hz, 1H), 3.70 (s, 3H), 4.05
(q, J ) 7, 2H), 5.95 (s, 2H), 6.72 (d, J ) 7 Hz, 1H), 6.82 (d, J
Met h od E . tr a n s,tr a n s-2-(4-Met h oxyp h en yl)-4-(1,3-
ben zod ioxol-5-yl)-1-(4-flu or op h en oxya cetyl)p yr r olid in e-
3-ca r boxylic Acid (14f). To compound 11 (300 mg, 0.813
mmol of pure trans-trans) and 165 mg of triethylamine in 2
mL of CH2Cl2 cooled in an ice bath was added 183 mg (0.973
mmol) of (4-flourophenoxy)acetyl chloride (prepared from the