4762 J . Org. Chem., Vol. 61, No. 14, 1996
Sonesson et al.
7b are unknown. Elemental analyses were performed by
Mikro Kemi AB, Uppsala, Sweden. High resolution mass
spectrometry was performed by Dr. Hasse Karlsson, MS Lab,
Dept. of Medicinal Chemistry, Go¨teborg University, Sweden
(EI+). Melting points were determined with a melting point
microscope and are uncorrected. Silica gel 60 (0.040-0.063
mm, E. Merck, no. 9385) was used for flash chromatography.
The coupling reactions were run under argon, in flasks
equipped with reflux condensers. Asymmetric coupling reac-
tions were performed under nitrogen in heavy-walled and thin-
necked Pyrex tubes, sealed with a Teflon-brand stopcock.
Ma ter ia ls. Palladium(II) acetate was obtained from Sigma
Chemical Co. and was recrystallized from benzene.2b N,N-
Diisopropylethylamine was distilled from potassium hydroxide
prior to use. DMF was stored over activated 4 Å molecular
sieves and was degassed with argon before use. Tris(dibenzyl-
ideneacetone)dipalladium(0)-chloroform adduct (Pd[0]2[dba]3-
CHCl3), tri-o-tolylphosphine (P(o-tol)3), 1,3-bis(diphenylphos-
phino)propane (DPPP), 1,2-bis(diphenylphosphino)ethane
(DPPE), 1,4-bis(diphenylphosphino)butane (DPPB), (R)-
BINAP, and (S)-BINAP were obtained from Aldrich Co. and
used as supplied. Palladium(II) acetylacetonate (Pd[II]acac),
10% Pd/C, and triphenylarsine (AsPh3) were bought from Acros
Chimica. Triphenylphosphine (PPh3) was obtained from
Merck, and tri(2-furyl)phosphine (TFP) from Lancaster Syn-
thesis. 3-Pyrroline was obtained from Aldrich and contained
20-35% pyrrolidine according to GC/MS. Different concentra-
tions of the methoxycarbonyl-substituted pyrrolidine were not
found to influence the outcome of the Heck reactions. 1-Bromo-
3-methanesulfonylbenzene and the enamide 8 were prepared
as described elsewhere.10,54 Aryl triflates were prepared from
the corresponding phenols by a standard procedure using
triethylamine as base.37 The cyclohexenyltriflate was prepared
according to ref. 55. All other reagents obtained from com-
mercial sources were used as received. Compounds 4a ,56 6a ,3b
10,18 11,57 1-[3-(3-methoxyphenyl)pyrrolidin-1-yl]propan-1-
one,7a 3-(3-methoxyphenyl)-1-propylpyrrolidine,7a and 127a are
known compounds.
Hz, 3H), 2.35 (m, 2H), 4.35 (bs, 4H), 5.85-6.00 (m, 2H); 13C
NMR (CDCl3, 125.6 MHz) δ 8.6, 27.3, 52.6 and 53.0 (rotamers,
2 × CH2), 124.7 and 126.2 (rotamers, 2 × CH), 171.9. High
resolution mass spectrum calcd for C7H11NO (M+) 125.08398,
found 125.0840.
P r ep a r a tive P a lla d iu m -Ca ta lyzed Rea ction s. Gen er a l
P r oced u r e for Ar yl Ha lid es (Ta ble 1). To a stirred solution
of 30 mmol 4a (or 8 for the formation of 6a and 6b) in DMF
(10 mL) under an argon atmosphere at rt were sequentially
added i-Pr2NEt (1.55 g, 12.0 mmol), Ag2CO3 (0.580 g, 2.10
mmol), aryl halide (3.00 mmol), P(o-tol)3 (0.100 g, 0.329 mmol),
and Pd(OAc)2 (0.034 g, 0.151 mmol). GC/MS analysis of the
reaction mixture was periodically performed on small samples
taken up in diethyl ether and washed with a small quantity
of brine. The reaction was stirred and heated at 100 °C for
4-22 h and then cooled to rt, quenched with 10% Na2CO3 (40
mL) and extracted several times with diethyl ether. The
combined organic phases were dried (MgSO4) and filtered, and
the solvent was removed under reduced pressure. The excess
of 4a (or 8) was removed by bulb-to-bulb distillation conducted
with a Bu¨chi Kugelrohr (∼0.1 torr, oven temperature ∼50 °C).
The residue was further purified by flash chromatography in
an appropriate solvent.
1-(Meth oxycar bon yl)-3-ph en yl-2,3-dih ydr opyr r ole (5a).
Colorless oil, 0.41 g (68%); eluent hexane/diethyl ether (2/1,
v/v): MS m/z (relative intensity, 70 eV) 203 (M+, 100), 144
1
(79), 128 (83), 115 (44), 104 (78); H NMR (CDCl3, 300 MHz)
δ 3.68 (m, 4H, OCH3 + NCHH), 4.11 (m, 2H, NCHH + ArCH),
5.08 and 5.12 (rotamers, m, 1H, NCHdCH), 6.61 and 6.75
(rotamers, m, 1H, NCHdCH), 7.05-7.35 (m, 5H, Ar); 13C NMR
(CDCl3, 75.4 MHz) δ 47.1 and 48.3 (rotamers), 52.7, 53.9, 112.2
and 112.5 (rotamers), 127.0, 127.2 (2 × CH), 128.7 (2 × CH),
129.5 and 130.4 (rotamers), 143.8, 152.3 and 153.4 (rotamers).
High resolution mass spectrum calcd for C12H13NO2 (M+)
203.0946, found: 203.0937.
1-(M e t h o x y c a r b o n y l)-2,4-d i p h e n y l-2,5-d i h y d r o -
p yr r ole (7a ). A second fraction from the chromatographic
separation of 5a was obtained (0.10 g, 12%) and was found to
be the diphenylated compound (7a ): MS m/z (relative inten-
sity, 70 eV) 279 (M+, 78), 264 (70), 220 (50), 202 (100), 115
(81); 1H NMR (CDCl3, 500 MHz) δ 3.60 and 3.72 (rotamers, s,
3H, OCH3), 4.76-4.81 and 4.82-4.87 (rotamers, ddd, J ) 15
Hz, 4 Hz, 2 Hz, 1H, NCHH), 4.81-4.86 and 4.90-4.94
(rotamers, app dt, J ) 15 Hz, 2 Hz, 1H, NCHH), 5.72 and 5.81
(rotamers, ddd, J ) 4 Hz, 2 Hz, 2 Hz, 1H, PhCH), 6.20 and
6.25 (rotamers, app. q, J ) 2 Hz, 1H, CHdC), 7.20-7.46 (m,
10 H, Ar); 13C NMR (CDCl3, 75.4 MHz) δ 52.5, 53.9 and 54.5
(rotamers), 68.7 and 69.2 (rotamers), 124.5-128.7 (10 × CH
(Ar) + 1 × CdC), 132.8, 136.3 and 136.6 (rotamers), 141.1 and
141.7 (rotamers), 155.0 and 155.5 (rotamers). High resolution
mass spectrum calcd for C18H17NO2 (M+) 279.1258, found:
279.1287.
1-(Me t h o x y c a r b o n y l)-3-(1-n a p h t h y l)-2,3-d ih y d r o -
p yr r ole (5b). Light yellow oil, 0.44 g (58%); eluent hexane/
diethyl ether (2/1, v/v): MS m/z (relative intensity, 70 eV) 253
(M+, 100), 238 (35), 178 (46), 166 (34), 165 (89); 1H NMR
(CDCl3, 300 MHz) δ 3.60-3.81 (m, 4H, OCH3 + NCHH), 4.39
(dd, J ) 11.7 Hz, 1H, NCHH), 4.9 (br m, 1H, ArCH), 5.3 (br
m, 1H, NCHdCH), 6.79 and 6.94 (rotamers, br m, 1H,
NCHdCH), 7.34-7.60 (m, 4H, Ar), 7.75 (d, J ) 8.8 Hz, 1H,
Ar), 7.9 (d, J ) 8.7 Hz, 1H, Ar), 8.0 (d, J ) 7.8 Hz, 1H, Ar);
13C NMR (CDCl3, 75.4 MHz) δ 42.9 and 44.0 (rotamers), 52.6
and 52.7 (rotamers), 53.3 and 53.4 (rotamers), 110.8 and 111.1
(rotamers), 123.2-129.0 (7 × CH (Ar)), 129.1 and 130.2
(rotamers), 131.3, 134.0, 139.6, 152.4 and 153.5 (rotamers).
High resolution mass spectrum calcd for C16H15NO2 (M+)
253.1103, found: 253.1099.
P r ep a r a tive P a lla d iu m -Ca ta lyzed Rea ction s. Gen er a l
P r oced u r e for Ar yl Tr ifla tes (Ta ble 2). To a stirred
solution of 30 mmol of 4a in DMF (10 mL) under an argon
atmosphere at rt were sequentially added i-Pr2NEt (1.55 g,
12.0 mmol), LiCl (0.38 g, 9.0 mmol), triflate (3.00 mmol), TFP
(0.077 g, 0.332 mmol), and Pd(OAc)2 (0.034 g, 0.151 mmol).
GC/MS analysis of the reaction mixture was periodically
performed on small samples taken up in diethyl ether and
washed with a small quantity of brine. The reaction was
stirred and heated at 100 °C for 4-18 h. After the completion
1-(Meth oxyca r bon yl)-2,5-d ih yd r op yr r ole (4a ).56 To a 2
L round bottom flask was added 3-pyrroline (25.0 g, 65% pure,
236 mmol of 3-pyrroline), powdered potassium carbonate (97.5
g, 707 mmol), and methylene chloride (800 mL). The mixture
was stirred at 0 °C. Methyl chloroformate (30.8 mL, 398
mmol) dissolved in methylene chloride (300 mL) was added
dropwise over a period of 30 min. The reaction mixture was
allowed to reach rt. After an additional 60 min at rt the
reaction mixture was filtered through a pad of Celite and was
washed with two portions of 10% Na2CO3, dried (MgSO4),
filtered, and concentrated by evaporation. Distillation (50-
55 °C, 0.1 torr) of the residual liquid afforded 34.5 g (76%) as
a colorless oil containing 34% of the corresponding pyrrolidine
(GC/MS): MS m/z (relative intensity, 70 eV) 127 (70, M+), 112
1
(100), 68 (38), 67 (49), 59 (38); H NMR (CDCl3, 300 MHz) δ
3.62 and 3.74 (rotamers, s, 3H), 4.05-4.20 (m, 4H), 5.69-5.81
(m, 2H); 13C NMR (CDCl3, 75.4 MHz) δ 52.2, 52.7 and 53.2
(rotamers, 2 × CH2), 124.8 (2 × CH), 158.6.
1-(Eth ylca r bon yl)-2,5-d ih yd r op yr r ole (4b). A solution
of 3-pyrroline (25.0 g, 65% pure, 236 mmol of 3-pyrroline) and
triethylamine (40.2 g, 362 mmol) in methylene chloride (100
mL) was cooled to 0 °C an atmosphere of argon. Then
propionyl chloride (40.4 g, 398 mmol) dissolved in methylene
chloride (50 mL) was added dropwise over a period of 30 min.
The reaction mixture was allowed to reach rt. After an
additional 120 min at rt the reaction mixture was washed with
two portions of 10% Na2CO3 and two portions of 10% HCl,
dried (MgSO4), filtered, and concentrated by evaporation. The
residue was further purified by silica gel flash-chromatography
(EtOAc) to yield pure 4b as a colorless oil (20.6 g, 70%): MS
m/z (relative intensity, 70 eV) 125 (40, M+), 69 (54), 68 (100),
1
57 (28), 53 (5); H NMR (CDCl3, 300 MHz) δ 1.25 (t, J ) 7.6
(54) Sonesson, C.; Lindborg, J . Tetrahedron Lett. 1994, 35, 9063.
(55) Stang, P. J .; Treptow, W. Synthesis 1980, 283.
(56) Armande, J . C. L.; Pandit, U. K. Tetrahedron Lett. 1977, 11,
897.
(57) Arvidsson, L.-E.; Carlsson, A.; Hacksell, U.; Hjort, S.; Lindberg,
P.; Nilsson, L. G.; Sanchez, D.; Svensson, U.; Wikstro¨m, H. EP
30526A1, 1981. Chem. Abstr. 96 (1982) 122637r.