Regiochemical control and suppression of double bond isomerization in the heck arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole

Article abstract of DOI:10.1021/jo952112s

Arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole under standard Heck reaction conditions produces a mixture of compounds. The olefin undergoes two types of palladium-catalyzed reactions: (a) arylation to provide C-3 arylated derivatives and (b) competing double bond isomerization. Addition of silver carbonate and thallium acetate fully suppressed the isomerization, and good yields of C-3 substituted compounds were achieved after arylation with aryl halides. With regard to aryl triflates as arylating agents, addition of lithium chloride was necessary to promote the Heck reaction. This additive excluded the use of silver and thallium salts, but high regioselectivity and good yields could be obtained by employing tri-2-furylphosphine as ligand. Arylation was rendered both regioselective and enantioselective (58% ee) with 1-naphthyl triflate as substrate utilizing a (R)-BINAP/thallium acetate combination. The C-3 arylated enamides were converted further into the corresponding 3-arylpyrrolidines.

Full text of DOI:10.1021/jo952112s

4756
J . Org. Chem. 1996, 61, 4756-4763
Regioch em ica l Con tr ol a n d Su p p r ession of Dou ble Bon d
Isom er iza tion in th e Heck Ar yla tion of
1-(Meth oxyca r bon yl)-2,5-d ih yd r op yr r ole
Clas Sonesson,*,† Mats Larhed,‡ Camilla Nyqvist,† and Anders Hallberg*,‡
Medicinal Chemistry Unit, Department of Pharmacology, Medicinargatan 7, S-413 90 Go¨teborg, Sweden
and Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University,
Box 574, S-751 23 Uppsala, Sweden
Received November 29, 1995X
Arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole under standard Heck reaction conditions
produces a mixture of compounds. The olefin undergoes two types of palladium-catalyzed
reactions: (a) arylation to provide C-3 arylated derivatives and (b) competing double bond
isomerization. Addition of silver carbonate and thallium acetate fully suppressed the isomerization,
and good yields of C-3 substituted compounds were achieved after arylation with aryl halides. With
regard to aryl triflates as arylating agents, addition of lithium chloride was necessary to promote
the Heck reaction. This additive excluded the use of silver and thallium salts, but high
regioselectivity and good yields could be obtained by employing tri-2-furylphosphine as ligand.
Arylation was rendered both regioselective and enantioselective (58% ee) with 1-naphthyl triflate
as substrate utilizing a (R)-BINAP/thallium acetate combination. The C-3 arylated enamides were
converted further into the corresponding 3-arylpyrrolidines.
Ch a r t 1
In tr od u ction
Regioselective palladium-catalyzed C-2 arylation of
cyclic five- and six-membered enol ethers1,2 or of en-
amides3 with aryl halides or triflates can be achieved in
good yields. In addition, cyclic five-membered allylic
compounds such as sulfolene can undergo facile aryl-
ation4 and Larock has reported relatively recently that
2,5-dihydrofuran reacts smoothly under mild reaction
conditions producing the C-3 arylated 2,3-dihydrofuran
in high yield.5 A low degree of regioselectivity is observed
in the arylation of six-membered, cyclic N-acylallyl-
amines, possessing two nonequivalent vinylic positions,
while a highly regioselective Pd-N chelate-controlled
vinylic substitution of the corresponding cyclic N-alkyl-
allylamines occurs.6 The latter reaction6 was applied to
the synthesis of the partial dopamine D2-agonist, pre-
clamol (1),7a,b currently undergoing clinical trials.7c The
arylpiperidine 2 was recently reported as a preferential
DA (dopamine) autoreceptor antagonist, with an inter-
esting pharmacological profile.8 To expand the SAR
(structure-activity relationship), access to a short and
convergent procedure was needed for the preparation of
related C-3 substituted pyrrolidines 3, as potential DA
receptor antagonists.
We herein report a regioselective palladium-catalyzed
arylation reaction of N-substituted 2,5-dihydropyrroles
4a ,b, that provides 3-aryl(heteroaryl)-2,3-dihydropyrroles
5a -j, key intermediates in this synthesis of 3-aryl-
(heteroaryl)pyrrolidines 3a -j.
Resu lts
The initial Heck arylation experiments9 were con-
ducted using iodobenzene as arylating agent. Arylation
of 1-(methoxycarbonyl)-2,5-dihydropyrrole (4a ) with iodo-
benzene under the following reaction conditions:
a
catalytic amount of palladium acetate, dppp (1,3-bis-
[diphenylphosphino]propane) as phosphine ligand, and
N,N-diisopropylethylamine as base in DMF at 100 °C,
resulted in a reaction mixture comprised of 1-(methoxy-
carbonyl)-3-phenyl-2,3-dihydropyrrole (5a ), 1-(methoxy-
carbonyl)-2-phenyl-2,3-dihydropyrrole (6a ), and 1-(meth-
† Medicinargatan 7.
‡ Uppsala University.
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) (a) Arai, I.; Daves, G. D., J r. J . Org. Chem. 1979, 44, 21. (b)
Andersson, C.-M.; Hallberg, A.; Daves, G. D., J r. J . Org. Chem. 1987,
52, 3529.
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113, 1417. (b) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.;
Nishioka, E.; Yanagi, K.; Moriguchi, K. Organometallics 1993, 12, 4188.
(c) Hillers, S.; Reiser, O. Tetrahedron Lett. 1993, 33, 5265. (d) Hillers,
S.; Reiser, O. Synlett 1995, 153.
(8) Sonesson, C.; Lin, C.-H.; Hansson, L.; Waters, N.; Svensson, K.;
Carlsson, A.; Smith, M. W.; Wikstro¨m, H. J . Med. Chem. 1994, 37,
2735.
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Ozawa, F.; Hayashi, T. J . Organomet. Chem. 1992, 428, 267. (c)
Hillers, S.; Sartori, S.; Reiser, O. J . Am. Chem. Soc. 1996, 118, 2087.
(4) Harrington, P. J .; DiFiore, K. A. Tetrahedron Lett. 1987, 28, 495.
(5) Larock, R. C.; Baker, B. E. Tetrahedron Lett. 1988, 29, 905.
(6) Nilsson, K.; Hallberg, A. J . Org. Chem. 1992, 57, 4015.
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Sanchez, D.; Wikstro¨m, H.; Lindberg, P.; Hjorth, S.; Carlsson, A. J .
Med. Chem. 1981, 24, 1475. (b) Hjorth, S.; Carlsson, A.; Clark, D.;
Svensson, K.; Wikstro¨m, H.; Sanchez, D.; Lindberg, P.; Hacksell, U.;
Arvidsson, L.-E.; J ohansson, A.; Nilsson, J . L. G. Psychopharmacology
1983, 81, 89. (c) Tamminga, C. A.; Cascella, N. G.; Lahti, R. A.;
Lindberg, M.; Carlsson, A. J . Neural Transm. [GenSect] 1992, 88, 165.
(9) For reviews on the Heck reaction see; (a) Heck, R. F. Org React.
1982, 27, 345. (b) Trost, B. M.; Verhoeven, T. R. Comprehensive
Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W.,
Eds.; Pergamon Press: Oxford, 1982; Vol. 8, pp 854. (c) Heck, R. F.
Palladium Reagents in Organic Synthesis; Academic Press; London,
1985; pp 276. (d) Heck, R. F. Comprehensive Organic Synthesis; Trost,
B. M., Flemming, I., Eds.; Pergamon Press: Oxford 1991; Vol. 4, pp
833. (e) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl.
1994, 33, 2379. (f) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28,
2. (g) For Heck arylation of heteroatom-substituted double bonds see
Tsuji, J . Palladium Reagents and Catalysts: Innovations in Organic
Chemistry; J ohn Wiley & Sons: Chichester, 1995; pp 125-163. (h)
Daves, G. D., J r.; Hallberg, A. Chem. Rev. 1989, 89, 1433.
S0022-3263(95)02112-8 CCC: $12.00 © 1996 American Chemical Society

Heck Arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole
J . Org. Chem., Vol. 61, No. 14, 1996 4757
Ta ble 1. P a lla d iu m -Ca ta lyzed Regioselective Rea ction
of 4a w ith Ar yl Ha lid es
oxycarbonyl)-2,4-diphenyl-2,5-dihydropyrrole (7a ) as the
major products, all formed in yields higher than 10% (eq
1). In addition, a considerable amount of 4a had isomer-
ized to the enamide 8.10 This isomerization continued
even after complete consumption of the aryl halide. The
compounds 5-8 were also the major components, to-
gether with the deoxygenated naphthalene, when 1-naph-
thyl triflate was employed under similar reaction condi-
tions. The naphthyl derivatives 5b and 6b were formed
in equal amounts (eq 1) We observed that separation of
the two regioisomers 5 and 6, or separation of their
saturated counterparts, was not facile by standard
chromatographic procedures, and it was therefore es-
sential for our preparative purposes to have access to
methods providing a high 5/6 ratio.
The olefin 4a undergoes two types of palladium-
catalyzed reactions: (a) arylation to provide 5 and (b)
double bond isomerization. These processes are competi-
tive and subsequent arylation of the isomerized double
bond furnishes the undesired compound 6. Thus, our
primary objective was the suppression of the isomeriza-
tion process and secondly, were this to prove unrealizable,
to find conditions disfavoring arylation of the isomeriza-
tion product 8 relative to the 2,5-dihydropyrrole 4a .
Iod oben zen e a s Ar yla tin g Agen t. The beneficial
effect of silver additives in controlling double bond
migration in intramolecular Heck-reactions was first
observed by Overman’s group.11a,b Although we realized
that the isomerization in our system precedes the aryl-
ation, we assumed that a similar type of catalytic species
could be involved in both reactions. We therefore decided
to examine the effect of silver additives on the undesired
conversion of the allylamide to the enamide. Addition
of 0.7 equiv of silver carbonate12 to reactions using
Furthermore, we did not observe isomerization of the
olefin 4a to the enamide 8 under these reaction condi-
tions. To minimize the undesired diarylation, the main
cause of the moderate yields of 5, an excess of the olefin
was required (an olefin/iodobenzene ratio of 10/1 was
sufficient). These conditions gave less than 10-20% of
7, depending on the arylating substrate used, and 7 could
be separated easily from 5 by chromatography. A 56%
yield of 7a was isolated after employing an olefin/
iodobenzene ratio of 1/2, reflecting the importance of
conducting the reaction with an excess of olefin.
13
iodobenzene (1.0 equiv) as arylating agent and P(o-tol)3
as ligand suppressed the formation of 6a completely.
1-Na p h th yl Tr ifla te a s Ar yla tin g Agen t. Employ-
ing PPh3 or P(o-tol)3 instead of the bidentate ligand dppp
led only to small amounts of product with 1-naphthyl
triflate remaining. Addition of lithium chloride was
required to promote the reaction.14,15 This additive also
strongly suppressed the undesired reduction of the naph-
thyl triflate,16 but the unsatisfactory isomer ratio, derived
from the olefin isomerization, remained as an obstacle.
(10) We recently reported that 8 was conveniently prepared from
4a under Heck reaction conditions omitting aryl halide. Sonesson, C.;
Hallberg, A. Tetrahedron Lett. 1995, 36, 4505.
(11) (a) Abelman, M. M.; Oh, T.; Overman, L. E. J . Org. Chem. 1987,
52, 4130. (b) Abelman, M. M.; Overman, L. E. J . Am. Chem. Soc. 1988,
110, 2328. For recent applications of silver additives in intramolecular
Heck reactions see: (c) Ahimori, A.; Overman, L. E. J . Org. Chem.
1992, 57, 4571. (d) Larock, R. C. Pure Appl. Chem. 1990, 62, 653. (e)
Sato, Y.; Watanabe, S.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2589.
(f) Sato, Y.; Honda, T.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2593.
(g) Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1993, 34,
4965. (h) Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H. J .
Chem. Soc., Perkin Trans. 1 1993, 1941. (i) J in, Z.; Fuchs, P. L.
Tetrahedron Lett. 1993, 34, 5205. (j) Tietze, L. F.; Schimpf, R. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1089. (k) Steinig, A. G.; Bra¨se, S.; de
Meijere, A. 8th IUPAC Symposium on Organo-Metallic Chemistry
directed towards Organic Synthesis, Santa Barbara, 1995, Abstr. No.
241.
(14) (a) Echavarren, A. M. and Stille, J . K. J . Am. Chem. Soc. 1987,
109, 5478. (b) Amatore, C.; Azzabi, M.; J utand, A. J . Am. Chem. Soc.
1991, 113, 8375. (c) Amatore, C.; J utand, A.; Suarez, A. J . Am. Chem.
Soc. 1993, 115, 9531. (d) J utand, A.; Mosleh, A. Organometallics 1995,
14, 1810. (e) Larhed, M.; Andersson, C.-M.; Hallberg, A. Tetrahedron
1994, 50, 285. (f) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G.
P. J . Org. Chem. 1993, 58, 5434.
(15) No conversion of the aryl triflate occurred with dppp in presence
of chloride, as expected from recent findings. See refs 16 and 35d.
(16) Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci, F.;
Penco, S.; Santi, R. J . Org. Chem. 1991, 56, 5796.
(12) A 0.7 equiv amount of silver carbonate was the minimum
amount needed to fully suppress the formation of 6a .
(13) In
a screening of ligands we found that the monodentate
ligands, and in particular P(o-tol)3, were superior to the bidentate
ligands with regard to regioselectivity and yield.

4758 J . Org. Chem., Vol. 61, No. 14, 1996
Sonesson et al.
Ta ble 2. P a lla d iu m -Ca ta lyzed Regioselective Rea ction
of 4a w ith Ar yl- or Vin yl Tr ifla tes
reported to be a good ligand for nicotine receptors in
vitro,18 and to the preparation of the partial dopamine
agonist USDA 19, 127a (eq 4).
Asym m etr ic Rea ction s. In 1989, Shibasaki19 and
Overman20 independently reported the first examples of
an intramolecular asymmetric Heck reaction. The first
example of an intermolecular asymmetric Heck reaction
was reported in 1991 by Hayashi,2a who performed C-2
arylations of 2,3-dihydrofuran2a,b and N-substituted 2,3-
dihydropyrroles3b with aryl triflates in high enantiomeric
excess. The enantioselectivity was even better with
alkenyl triflates,21 while no or only a low ee was experi-
enced with iodoarenes.2a-c,3a,22 The potential use of 3-aryl
substituted cyclic enamides as precursors for 3 encour-
aged us to briefly study asymmetric arylation of 4a . It
is important to emphasize that this olefin contains two
vinylic carbon atoms interrelated by a C2-axis. We are
only aware of one example of chiral induction of analo-
gous olefins, namely in the arylation of 4,7-dihydro-1,3-
dioxepin and some of its analogs (which furnished up to
75% ee).23
The chloride addition precluded the use of silver and
thallium ions, but by employing the weakly palla-
dium(II)-coordinating TFP (tri[2-furyl]phosphine)17 as
ligand, a satisfactory 5b/6b ratio (98/2) was achieved.
To prove the generality of the Ag/P(o-tol)3 conditions
with organohalides and the chloride/TFP procedure with
organotriflates, we selected eleven different arylating
reagents and one vinyl triflate. The preparative results
are summarized in Table 1 and Table 2. Fair isolated
yields of coupled products were obtained with both
electron-rich and electron-poor organopalladium precur-
sors, including the pyridyl triflate. The arylated cyclic
enamides 5a -j tended to decompose slowly upon isola-
tion, and full characterization, including elemental analy-
ses, were therefore conducted after the subsequent
hydrogenation reaction. The hydrogenated products
3a -j were converted to the secondary amines 9a -e by
hydrolysis (eq 2).
We focussed on 1-naphthyl triflate as arylating agent,
since the N-propyl substituted 9b had exhibited interest-
ing pharmacological properties in an initial receptor
binding study.24 The reactions were performed with a
(18) (a) Dukat, N.; Damaj, M. I.; Glassco, W.; Dumas, D.; May, E.
L.; Martin, B. R. Med. Chem. Res. 1994, 4, 131. (b) Ber. Dtsch. Chem.
Ges. B 1938, 71, 1276.
(19) (a) Sato, Y.; Sodeoka, M.; Shibasaki, M. J . Org. Chem. 1989,
54, 4738. (b) Ohrai, K.; Kondo, K.; Sodeoka, M.; Shibasaki, M. J . Am.
Chem. Soc. 1994, 116, 11737. (c) Kondo, K.; Sodeoka, M.; Shibasaki,
M. J . Org. Chem. 1995, 60, 4322.
(20) (a) Carpenter, N. E.; Kucera, D. J .; Overman, L. E. J . Org.
Chem. 1989, 54, 5846. (b) Ashimori, A.; Matsuura, T.; Overman, L.
E.; Poon, D. J . J . Org. Chem. 1993, 58, 6949.
(21) Ozawa, F.; Kobatake, Y.; Hayashi, T. Tetrahedron Lett. 1993,
34, 2505.
(22) Asymmetric arylation of the cyclic vinyl ether 4H-1,3-dioxin
with (R)-BINAP as ligand has been achieved in 43% ee utilizing
iodobenzene/silver carbonate. Sakamoto, T.; Kondo, Y.; Yamanaka,
H. Tetrahedron Lett. 1992, 33, 6845.
(23) Koga, Y.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1994,
35, 1227.
We have applied the arylation-hydrogenation proce-
dure to the preparation of isonicotine, 10 (eq 3), recently
(24) Sonesson, C.; Wikstro¨m, H.; Smith, M. W.; Svensson, K.;
Carlsson, A.; Waters, N. Bioorg. Med. Chem. Lett., to be submitted.
(17) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.

Heck Arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole
J . Org. Chem., Vol. 61, No. 14, 1996 4759
catalyst generated in situ from Pd(OAc)2 and (R)-BINAP25
as cocatalyst, since it is known that the active Pd(0)
catalyst is generated under similar conditions.2b,19b,26 Our
initial experiments revealed that DMF as solvent was
superior to the less polar benzene27 and toluene with N,N-
diisopropylethylamine as the base. Although chiral
induction was achieved with (R)-BINAP, the use of this
bidentate ligand: as was the case with dppp (eq 1), was
accompanied by a low 5b/6b ratio. We found that the
presence of acetate, weakly coordinating to Pd(II),19b,28
was beneficial both for the 5b/6b ratio29 and for the
enantiomeric enrichment, while the addition of LiCl
ruined the chiral induction.30 Even a catalytic amount
of acetate tended to exhibit a positive effect on the
product distribution and substitution of Pd(OAc)2 for
20b,31
Pd(0)2(dba)3-CHCl3
or Pd(II)acac as precatalysts
phenyl triflate and 2-naphthyl triflate. Equally disap-
pointing results were encountered with 1-iodonaphtha-
lene after the addition of silver carbonate or thallium
acetate, which was expected to provide a similar cationic
π-complex as suggested in aryl triflate reactions.9e,f,36 The
relatively low yield in the asymmetric arylation of 4a is
probably mainly attributable to an inefficient coordina-
tion-insertion step9f,30 and not to a slow oxidative addi-
tion of 1-naphthyl triflate, which proved to be an efficient
process as deduced by the large amounts of naphthalene
formed.16,37
In addition, enantiomerically enriched 5b was allowed
to react with 2 equiv of 1-naphthyl triflate, employing
similar conditions used for the racemic reactions in Table
2 (eq 5). A complete chirality transfer (100%) was
encountered, and 7b was isolated in 48% yield (58% ee).
furnished a mixture of almost equal amounts of 5b and
6b. The addition of 0.5-2.0 mol equiv of acetic acid,
generating ammonium acetate in the system, provided
a 5b/6b selectivity of 95/532,33 and an enantiomeric excess
of 50-60%.34
However, for efficient synthesis of 9b in enantiomeric
excess, a 5b/6b ratio higher than 95/5 was desired.
Addition of thallium acetate35 fulfilled this requirement.
In fact, it was found that the presence of 1.0 equiv of
thallium acetate, replacing acetic acid, allowed the
synthesis of isomerically pure 5b (5b/6b > 99/1) in 58%
ee and 34% isolated yield (eq 5). Unfortunately, sub-
stantial chiral induction was realized only in the case of
1-naphthyl triflate, despite several attempts with both
(25) 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl. See. Noyori, R.;
Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(26) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177.
(27) DMF was also found to be superior to benzene in the asym-
metric arylation of 4H-1,3-dioxin. See ref 22.
(28) The acetate ion is considered to possess an intermediately
strong dissociating ability to Pd(II), with respect to the easily dissoci-
ated triflate ion and the more strongly complexed halide ions. See
refs 16 and 35d.
(29) (a) Suppression of double bond migration by acetate addition
in Heck reactions has been reported. See, Laschat, S.; Narjes, F.;
Overman, L. E. Tetrahedron 1994, 50, 347. See also ref 2b and 5. (b)
It is also noteworthy that the chemoselectivity was improved (5b/6b
) 99/1, 32% yield) utilizing the racemic combination Pd(OAc)2/DPPP/
KOAc (2.0 equiv).
(30) PhPdCl complexes of dippb (1,4-bis[diisopropylphosphino]-
butane), a nonasymmetric bidentate ligand with a four-carbon tether
(same as BINAP), is found to exist in both the η1 coordination mode
and in the chelating mode. Portnoy, M.; Ben-David, Y.; Rousso, I.;
Milstein, D. Organometallics 1994, 13, 3465.
Discu ssion
R ea ct ion s w it h Neu t r a l Ar ylp a lla d iu m H a lid e
Sp ecies. Although we have made no detailed studies
which permit the evaluation of the reaction mechanism
for the formation of 5-8, we suggest the catalytic cycle
in Scheme 1. Initial reduction of palladium(II) to the
active zero-valent state is facile under the conditions used
with the olefin, amine, or phosphine acting as reducing
agent.38 With regard to the isomerization39 of 4a to 8
we observed, under Heck reaction conditions omitting
iodobenzene, that Pd(OAc)2 was active as a catalyst.
However, omission of the phosphine and the amine (both
capable of reducing palladium(II) from the reaction
mixture) afforded a completely inactive isomerization
catalyst. It has been demonstrated that Pd/C catalyzes
the transformation of N-acyl-1,2,5,6-tetrahydropyridines
to enamides.40 Pd/C in the absence of phosphine/amine
exhibits isomerization capacity also in our catalytic
system.
(31) (a) Sato, Y.; Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron
1994, 50, 371. (b) Tsuda, T.; Kiyoi, T.; Saegusa, T. J . Org. Chem. 1990,
55, 3388.
(32) To examine the effect of acetate concentration three competitive
experiments with equal concentration (5.0 equiv) of 4a and 8 were
performed in DMF. 1-Naphthyl triflate (1.0 equiv) was used as
arylating agent, and i-Pr2NEt (4.0 equiv) and three different catalytic
systems, Pd(0)2(dba)3-CHCl3/(R)-BINAP, Pd(OAc)2/(R)-BINAP, and
Pd(OAc)2/(R)-BINAP/HOAc (1.0 equiv) were employed. All three
reactions at 80 °C afforded after 18 h an almost identical 11/89 mixture
of 5b and 6b, demonstrating the higher reactivity of 8 irrespective of
the acetate concentration. This result corroborate the proposal that
the increased 5b/6b ratio in the asymmetric arylation is due to acetate-
mediated suppression of isomerization.
(33) Regrettably, the acetate/P(o-tol)3 combination was found to be
inferior to silver carbonate/P(o-tol)3 in controlling the regioselectivity
with aryl halides.
(34) A high (R)-BINAP/Pd ratio (2.2/1) was needed for enantiomeric
induction, which might be due to the consumption of BINAP in the
reduction of Pd(II). See ref 26. Prereduction of Pd(OAc)2 with
cyclohexene in the presence of base and BINAP did not improve the
ee. See ref 31a.
(35) Thallium(I) salts have been introduced and proved to be very
useful in Pd-catalyzed reactions. (a) Grigg, R.; Loganathan, V.;
Sukirthalingam, S.; Sridharan, V. Tetrahedron Lett. 1990, 31, 6573.
(b) Grigg, R.; Loganathan, V.; Santhakumar, V.; Sridharan, V.;
Teasdale, A. Tetrahedron Lett. 1991, 32, 687. (c) Carfagna, C.; Musco,
A.; Sallese, G.; Santi, R. and Fiorani, T. J . Org. Chem. 1991, 56, 261.
(d) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J . Org.
Chem. 1992, 57, 1481.
(36) In solution the triflate anion is not coordinated to palladium(II).
See ref 14d and Decker, G. P. C. M.; Elsevier, C. J .; Vrieze, K.; van
Leeuwen, P. W. N. M. Organometallics 1992, 11, 1598.
(37) Saa´, J . M.; Dopico, M.; Martorell, G.; Garc´ıa-Raso, A. J . Org.
Chem. 1990, 55, 991.
(38) For olefin as reducing agent see: (a) Trost, B. M.; Murphy, D.
J . Organometallics 1985, 4, 1143. For amine as reducing agent see:
(b) McCrindle, R.; Ferguson, G.; Arsenault, G.; McAlees, A. J . J . Chem.
Soc., Chem. Commun. 1983, 571. For phosphine as reducing agent
see; (c) Amatore, C.; J utand, A.; M’Barki, M. A. Organometallics 1992,
11, 3009. (d) Amatore, C.; Carre´, E.; J utand, A.; M’Barki, M. A.
Organometallics 1995, 14, 1818. (e) Mandai, T.; Matsumoto, T.; Tsuji,
J . Tetrahedron Lett. 1993, 34, 2513. See also ref 26.
(39) (a) Parshall, G. W.; Ittel, S. D. Homogeneous Catalysis; J ohn
Wiley & Sons Inc: New York, 1992; p 8. (b) For Pd(II)-catalyzed olefin
isomerization see: Sen, A.; Lai, T.-W. Inorg. Chem. 1984, 23, 3257. (c)
For isomerization of N-allylamides catalyzed by other transition metal
complexes see: Stille, J . K.; Becker, Y. J . Org. Chem. 1980, 45, 2139.
(40) (a) Wanner, K. Th.; Ka¨rtner, A. Heterocycles 1987, 26, 917. (b)
Wanner, K. Th.; Ka¨rtner, A. Arch. Pharm. (Weinheim) 1987, 320, 1050.

4760 J . Org. Chem., Vol. 61, No. 14, 1996
Sonesson et al.
Sch em e 1
Sch em e 2
a neutral π-complex is formed, and the olefin 4a inserts
into the Pd-aryl bond, eventually providing 5 (cycle A).
The isomerization product 8 competes favorably with 4a
for the arylpalladium halide species, leading to the
formation of the regioisomer 6 (cycle B). Surprisingly,
only the enamide 5 seemed prone to further arylation,
and we were only able to detect traces of product derived
from a second arylation of 6. This result, probably of
steric origin, is unexpected considering the elegant ap-
proach to trans-2,5-diaryltetrahydrofurans, based on
diarylation of 2,3-dihydrofuran, reported by Larock43 and
Hayashi.44
Rea ction s w ith Ca tion ic Ar yl P a lla d iu m Sp ecies.
A likely mechanism for the Heck reaction performed in
the presence of silver carbonate (aryl halides) or thallium
acetate (asymmetric arylation of 1-naphthyl triflate) is
presented in Scheme 2. In this catalytic cycle, halide
abstraction by silver carbonate or dissociation of the
labile triflate or acetate ligand generates cationic pal-
ladium intermediates. An explanation for the complete
suppression of the isomerization process (providing a 5/6
ratio higher than 99/1) after addition of 0.7 equiv of silver
carbonate to reactions of aryl halides is not obvious.
Double bond migration in the arylation of certain cyclic11
and acyclic45 alkenes is also suppressed by silver addi-
tives.46 We have conducted one experiment where iodo-
(41) Negishi, E.; Takahashi, T.; Akiyoshi, K. J . Chem. Soc., Chem.
Commun. 1986, 1338.
(42) Recently, Hartwig et al. have reported that oxidative addition
of aryl halides to Pd[P(o-tol)3]2 in benzene results in dimeric products
{Pd[P(o-tol)3](Ar)(X)}2. See: (a) Paul, F.; Hartwig, J . F. J . Am. Chem.
Soc. 1995, 117, 5373. (b) Paul, F.; Patt, J .; Hartwig, J . F. Organo-
metallics 1995, 14, 3030.
(43) Larock, R. C.; Gong, W. H. J . Org. Chem. 1990, 55, 407.
(44) Ozawa, F.; Kubo, A.; Hayashi, T. Tetrahedron Lett. 1992, 33,
1485.
Reaction of the aryl halide or triflate with an anionic
acetate-palladium(0)-phosphine complex38c or a stabi-
lized chloropalladium(0)-phosphine compound,14b,41 re-
sults in an oxidative addition complex.42 In the next step
(45) (a) J effery, T. Tetrahedron Lett. 1991, 32, 2121. (b) J effery, T.
Tetrahedron Lett. 1993, 34, 1133.

Heck Arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole
J . Org. Chem., Vol. 61, No. 14, 1996 4761
benzene was not initially included in the reaction mix-
ture, but was added after 20 h. Arylation occurred,
proving that the active palladium catalyst formed in this
Pd(0)/Ag(I) system is able to undergo oxidative addition
to the aryl halide, but not capable of acting as an
isomerization catalyst. We observed that silver triflate47
did not suppress the double bond isomerization, and
arylation of 4a with iodobenzene yielded the C-2 arylated
derivative 6a as the major product. Silver nitrate
exhibited only a weak suppressive effect on the isomer-
ization rate.48 Addition of thallium acetate to a reaction
mixture with iodobenzene in the presence of dppp pro-
vided an almost identical product pattern to that found
after silver carbonate addition, and the olefin isomeriza-
tion was fully suppressed.
strongly palladium-coordinated dppp is due to a slow
arylation of 4a and a faster arylation of the more reactive
enamide 8. The fact that TFP/Cl- was preferable in the
reactions of aryl triflates indicates that the phosphine
ligand displacement is important also in this case.
Con clu sion
In summary, we have developed three different sets
of reaction conditions which allow fully controlled regio-
selectivity and high yields of C-3 arylated 2,3-dihydro-
pyrroles: (1) the use of the silver carbonate/P(o-tol)3
combination with aryl halides, (2) the lithium chloride/
TFP procedure with aryl triflates, and finally, (3) the
thallium acetate/BINAP system in the asymmetric aryl-
ation reaction.
Effect of Liga n d s in Rea ction s w ith Neu tr a l
Ar ylp a lla d iu m Ha lid e Sp ecies. The regioselectivity
in the reaction with iodobenzene (in the absence of metal
additives) was affected by the choice of phosphine ligand.
While the use of the bidentate ligand dppp resulted in a
low 3-aryl/2-aryl ratio (80/20), a much higher selectivity
and increased yields were achieved with the monodentate
ligands PPh3 (92/8) and P(o-tol)3 (95/5). We considered
three factors that might explain the inferior selectivity
with dppp: (a) a dppp-induced rate enhancement of the
olefin isomerization, or (b) a lower rate of arylation of
the allylic amide 4a with dppp, or (c) a higher preference
for the enamide 8 as substrate with dppp as ligand. An
experiment employing 4a and omitting iodobenzene
showed that both monodentate ligands in comparison to
dppp were similarly effective in promoting the double
bond isomerization. However, the arylation reactions
with monodentate ligands were considerably faster (es-
pecially with poor palladium(II) ligands17,49 such as TFP,
AsPh3, and P(o-tol)3) than reactions where bidentate
ligands (dppe, dppp, and dppb) were employed. This
suggests that olefin coordination occurs by phosphine
rather than halide displacement from the oxidative
addition complex,9e,f both with mono- and bidentate
ligands. The 5/6 ratio appears to be an inverse function
of the coordinating ability of the phosphine ligand.49
Competitive experiments with iodobenzene and an excess
of an equal amount of the two olefins 4a and 8 revealed
that the enamide 8 was the preferred substrate,50 but
also that the substrate selectivity was slightly influenced
by the choice of ligand. While use of P(o-tol)3 gave a
2-aryl/3-aryl ratio of 80/20, the corresponding ratio when
employing dppp was 88/12. 1-Naphthyl iodide showed
even higher preference for the enamide 8 as substrate,
especially pronounced with dppp as ligand. Thus, we
conclude that the low regioselectivity obtained with the
The arylated cyclic enamides isolated can in principle
undergo further regiocontrolled functionalizations both
in the R-positions and â-positions to the nitrogen atom.40b,51
Subsequent hydrogenation of the arylated enamides
offers an alternative route to 3-arylpyrrolidines, and this
competes favorably with other existing methods.52
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra were recorded in CDCl3
at 300 MHz and 75.4 MHz, respectively, or at 270 MHz and
1
67.8 MHz, respectively. In addition, the H NMR spectra for
compounds 5f, 7a , and 11 were recorded at 500 MHz and the
1H-NMR spectra for compound 7b was recorded at 400 MHz.
13C-NMR spectra for compound 4b were recorded at 125.6
MHz. Resolution enhancements were performed with the
routine software installed in the machine (7a and 7b). Chemi-
cal shifts were reported as δ values (ppm) relative to an
1
internal standard (tetramethylsilane). The H and 13C NMR
spectra for the enamides and amides show, when recorded in
CDCl3 at rt, the existence of two rotamers in an approximately
1/1 ratio, except compound 11 which displays a 1/3 ratio. The
spectra for the secondary amines were recorded as the HCl
salts, except compound 9a which was recorded as the free base.
Low resolution mass spectra were recorded on a instrument
operating at an ionization potential of 70 eV. The mass
detector was interfaced with a gas chromatograph equipped
with a fused silica column (11 m × 0.22 mm) coated with cross
linked SE-54 (film thickness 0.3 µm, He gas, flow ∼40 cm/s).
The column temperature was 70-300 °C (initial time 2 min,
gradient 20 °C/min). 1-(Methoxycarbonyl)pyrrolines 4a and
8 and aryl-substituted isomers 5 and 6, respectively, were
assumed to have the same GC/MS response factor. Samples
for chiral GLC-analysis were taken up in CH2Cl2 and washed
with water before being subjected to small scale flash chro-
matography. Separation of the enantiomers (5a , 5b, 5g) was
achieved with a gas chromatograph, equipped with a capillary
column (20 m × 0.32 mm), coated with 50% heptakis(6-O-tert-
butyldimethylsilyl-2,3-di-O-methyl)-â-cyclodextrin in OV 170153
and connected to a flame ionization detector. The column
temperature was 145-165 °C and H2 was used as the carrier
gas at a flow rate of ∼60 cm/s. Peak areas were determined
by means of an HP 3396 Series 2 integrator. The ee of 7b
was determined by HPLC analysis: DAICEL CHIRALCEL
OD, hexane/2-propanol/diethylamine (90/10/0.1), 0.5 mL/min,
UV monitor (254 nm). The absolute configurations of 5b and
(46) (a) Karabelas, K.; Hallberg, A. Tetrahedron Lett. 1985, 26, 3131.
(b) Karabelas, K.; Westerlund, C.; Hallberg, A. J . Org. Chem. 1985,
50, 3896. (c) Karabelas, K.; Hallberg, A. J . Org. Chem. 1986, 51, 5286.
(d) Karabelas, K.; Hallberg, A. J . Org. Chem. 1989, 54, 1773. (e) For
a positive effect of AgBF4 in olefin insertion. into the palladium-aryl
bond, see; Kawataka, F.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc.
J pn. 1995, 68, 654.
(47) AgOTf was also found by Overman’s group to be less efficient
in the suppression of alkene isomerization, see ref 11a.
(48) Shibasaki et al. have suggested that the interaction between
Pd(II) and counterions such as AgCO3- is weak. In contrast, the
interactions between non silver containing monovalent counterions is
expected to be stronger. See ref 31a.
(49) (a) Reaction with a Pt(II)-complex and P(o-tol)3 or AsPh3 results
in a low displacement energy. Manzer, L. M.; Tolman, C. A. J . Am.
Chem. Soc. 1975, 97, 1955. (b) A palladacycle acting as an efficient
catalyst was recently prepared from Pd(OAc)2 and P(o-tol)3. Herrmann,
W. A.; Brossmer, C.; O¨ fele, K.; Reisinger, C. P.; Priermeier, T.; Beller,
M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1844.
(50) Irrespective if the reaction follows a neutral or cationic pathway,
olefin 8 is more reactive than 4a . For a more general discussion, see
ref 9f.
(51) (a) Amino, Y.; Nishi, S.; Izawa, K. Bull. Chem. Soc. J pn. 1991,
64, 620. (b) Wistrand, L. G. J anssen Chim. Acta, 1986, 4, 34 and
references cited therein.
(52) (a) Ebeno¨ther, A.; Hasspacher, K. Swiss Patent 526,536, 1972.
Chem. Abstr. 1972, 77, 164454s. (b) Bettoni, G.; Cellucci, C.; Tortorella,
V. J . Heterocycl. Chem. 1976, 13, 1053. (c) Tseng, C. C.; Terashima,
S.; Yamada, S. I. Chem. Pharm. Bull. 1977, 25, 166. (d) Laborde, E.
Tetrahedron Lett. 1992, 33, 6607. (e) Meyers, A. I.; Snyder, L. J . Org.
Chem. 1993, 58, 36. (f) Adkins, H.; Coonradt, H. J . Am. Chem. Soc.
1941, 63, 1563.
(53) Prepared and developed by Prof. W. A. Ko¨nig, Institut fu¨r
Organische Chemie, Universita¨t Hamburg, D-20146 Hamburg (Ger-
many).

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.

Heck Arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole
J . Org. Chem., Vol. 61, No. 14, 1996 4763
the reaction mixture was allowed to cool and was purified as
described in Preparative Palladium-Catalyzed Reactions. Gen-
eral Procedure for Aryl Halides.
87%): mp 124-128 °C (lit.7a 128-129 °C); free base MS m/z
(relative intensity, 70 eV) 205 (M+, 10), 177 (18), 176 (100),
147 (12), 84 (21); 1H NMR (CD3OD, HBr salt, 300 MHz) δ 1.1
(t, 3H), 1.85 (m, 2H), 2.1-2.35 (m, 1H), 2.5 (m, 1H), 3.1-4.0
(m, 7H), 6.75 (dd, J ) 8.0 Hz, 1.8 Hz, 1H), 6.82-6.87 (m, 2H),
7.2 (t, J ) 7.9 Hz, 1H).
Gen er al Meth od for Catalytic Hydr ogen ation . 1-(Meth -
oxyca r bon yl)-3-p h en ylp yr r olid in e (3a ). The synthesis of
the parent 3a is typical. Compound 5a (0.40 g, 1.97 mmol)
was dissolved in methanol (25 mL). Solid ammonium formate
(0.25 g, 3.94 mmol) and Pd/C (30 mg 10%) were added. The
resulting mixture was heated to reflux under a nitrogen
atmosphere for 4 h and then filtered through a pad of Celite.
The solvent was evaporated in vacuo, and the residue was
redissolved in 10% Na2CO3 (15 mL). The aqueous phase was
extracted several times with methylene chloride, and the
combined organic phases were dried (MgSO4), filtered and
evaporated to dryness. The crude product was purified by
flash chromatography (hexane/diethyl ether (9/1, v/v), affording
3a (0.36 g, 89%) as a colorless oil: MS m/z (relative intensity,
70 eV) 205 (M+, 37), 190 (46), 130 (29), 117 (46), 101 (100); 1H
NMR (CDCl3, 300 MHz) δ 1.92-2.08 (m, 1H), 2.24-2.35 (m,
1H), 3.30-3.95 (m, 8H), 7.21-7.38 (m, 5H); 13C NMR (CDCl3,
75.4 MHz) δ 32.4 and 33.3 (rotamers), 43.2 and 44.2 (rotam-
ers), 45.7 and 46.2 (rotamers), 52.1 and 52.3 (rotamers), 52.4,
126.8, 127.0 (2 × CH), 128.6 (2 × CH), 141.2, 155.5. Anal.
Calcd. for C12H15NO2: C, 70.2; H, 7.4; N, 6.8. Found: C, 70.0;
H, 7.2; N, 6.7.
Gen er a l P r oced u r e for P r ep a r a t ion of Secon d a r y
Am in es. The carbamate (3a -d and 3g) was dissolved in 5
mL of methanol or ethanol. To the solution was added 8 N
HCl (15 mL). The mixture was refluxed and after one or two
days, the conversion was complete (monitored by GLC). The
reaction mixture was evaporated to dryness and the excess of
HCl and water was distilled azeotropically with 99.5% ethanol.
The remaining salt was recrystallized from an appropriate
solvent.
Asym m etr ic Syn th esis of 5b. A mixture of Pd(OAc)2
(0.0225 g, 0.100 mmol) and (R)-BINAP (0.137 g, 0.220 mmol)
were dissolved in DMF (5 mL) under a stream of nitrogen. To
the solution were added in the following order: i-Pr2NEt (0.52
g, 4.00 mmol), 1-naphthyl triflate (0.276 g, 1.00 mmol), 4a (10
mmol), and TlOAc (0.263 g, 1.00 mmol). The reaction mixture
was heated to 60 °C in an oil bath for 16 h. GC/MS analysis
of the reaction mixture was periodically performed on small
samples taken up in methylene chloride and washed with a
small quantity of brine. An unexpected finding, according to
GC/MS, was the presence of PPh3 in the reaction mixture.14e,58
The product 5b was purified as described in Preparative
Palladium-Catalyzed Reactions. General Procedure for Aryl
Halides. Yellow oil, 0.087 g (34%), 58% ee: [R]20 ) +80° (c
D
) 1.0, CHCl3).
Syn th esis of En a n tiom er ica lly En r ich ed 1-(Meth oxy-
ca r bon yl)-2,4-d i(1-n a p h th yl)-2,5-d ih yd r op yr r ole (7b). A
solution consisting of Pd(OAc)2 (0.00185 g, 0.0082 mmol) and
TFP (0.00422 g, 0.0182 mmol) in 0.5 mL of DMF was stirred
for 5 min under a nitrogen atmosphere. Each of the remaining
reactants were added together with 0.5 mL of DMF under
nitrogen in the following order: LiCl (0.021 g, 0.49 mmol),
1-naphthyl triflate (0.091 g, 0.330 mmol), i-Pr2NEt (0.085 g,
0.658 mmol), and 5b (0.042 g, 0.166 mmol). The flask was
closed, and the content was stirred for 20 h at 100 °C. The
product was purified according to Preparative Palladium-
Catalyzed Reactions. General Procedure for Aryl Halides.
Yellow oil, 0.030 g (48%); eluent diethyl ether/pentane (1/3,
v/v): MS m/z (relative intensity, 70 eV) 379 (M+, 100), 364
3-P h en ylp yr r olid in e (9a ). Prepared from compound 3a
(0.35 g, 1.71 mmol) using ethanol as cosolvent and refluxed
for two days. The resulting HCl salt was basified with 10%
Na2CO3 (10 mL) and extracted several times with methylene
chloride. The combined organic phases were dried (MgSO4),
filtered, and evaporated to dryness. The free amine was
converted to the fumarate salt and recrystallized from ethanol/
isopropyl ether (0.35 g 78%); mp 139-141 °C (fumarate); MS
m/z (relative intensity, 70 eV) 147 (M+, 100), 117 (59), 115 (38),
1
(25), 320 (33), 252 (34), 165 (30); H NMR (CDCl3, 400 MHz)
δ 3.55 and 3.74 (rotamers, s, 3H, OCH3), 4.85-5.12 (m, 2H,
NCH2), 6.18 and 6.20 (rotamers, m, 1H, CHdC), 6.64 and 6.71
(rotamers, m, 1H, ArCH), 7.38-7.60 (m, 8H, Ar), 7.75-7.93
(m, 4H, Ar), 8.05 (t, J ) 7 Hz, 1H, Ar), 8.22 (dd, J ) 21 Hz, 8
Hz, 1H, Ar); 13C NMR (CDCl3, 67.8 MHz) δ 52.8, 57.3, and
57.8 (rotamers), 66.0 and 66.7 (rotamers), 122.5-137.9 (22 ×
CH), 155.3 and 155.8 (rotamers). High resolution mass
spectrum calcd for C26H21NO2 (M+) 379.1572, found: 379.1565.
1
91 (37), 51 (35); H NMR (free base, CDCl3, 300 MHz) δ 2.1
(m, 1H), 2.45 (m, 1H), 3.25 (m, 1H), 3.4-3.9 (m, 4H), 4.7 (br s,
1H, NH), 7.2-7.4 (m, 5H); 13C NMR (CDCl3, 75.4 MHz) δ 32.4,
43.6, 45.2, 50.6, 127.1 (2 × CH), 127.6 (2 × CH), 129, 138.3.
Anal. Calcd for C14H17NO4‚0.1H2O: C, 63.4; H, 6.5; N, 5.3.
Found: C, 63.8; H, 6.8; N, 5.2.
58% ee: [R]20 ) -48° (c ) 1.1, CHCl3).
D
Ack n ow led gm en t . Clas Sonesson and Camilla
Nyqvist wish to thank the Upjohn Company, Kalama-
zoo, MI, for support, and Mats Larhed and Anders
Hallberg thank the Swedish Natural Science Research
Council for support. We also thank Dr. Per-A° ke J ovall
for his kind help with the high resolution NMR experi-
ment.
3-(3-Meth oxyp h en yl)-1-p r op ylp yr r olid in e.7a A solution
of 1-[3-(3-methoxyphenyl)pyrrolidin-1-yl]propan-1-one (0.35 g,
1.50 mmol) in dry diethyl ether (30 mL) was cooled to 0 °C.
Solid LiAlH4 (0.20 g, 5.3 mmol) was then added in small
portions. The reaction mixture was then allowed to reach rt
and refluxed for 2 h. The reaction was then quenched by the
addition of 0.2 mL of water, 0.2 mL 15% sodium hydroxide
solution, and 0.6 mL of water. The resulting mixture was
filtered through a Celite pad in a F sintered glass suction filter,
the Celite pad was washed with diethyl ether, and the
combined organic phases were dried (MgSO4) and evaporated
to dryness. The residue was purified by chromatography on
silica column with methylene chloride/methanol (19/1, v/v) as
eluent. The solvents from the collected fractions containing
pure reduced product were evaporated yielding 0.30 g (92%)
as an oil. MS m/z (relative intensity, 70 eV) 219 (M+, 10), 191
(19), 190 (100), 84 (23), 57 (12); 1H NMR (CDCl3, 300 MHz) δ
0.9 (t, 3H), 1.55 (sext, 2H), 1.9 (m, 1H), 2.2-2.7 (m, 5H), 2.85
(q, 1H), 3.1 (t, 1H), 3.4 (q, 1H), 3.8 (s, 3H), 6.75 (dd, J ) 8.2
Hz, 2.0 Hz, 1H), 6.87 (m, 2H), 7.2 (t, J ) 7.8 Hz, 1H).
Su p p or tin g In for m a tion Ava ila ble: Experimental details
and characterization data for compounds 3b-j, 5c-j, 6b, 9b-
e, 10, 11, and 1-[3-(3-methoxyphenyl)pyrrolidin-1-yl]propan-
1-one and 1H and/or 13C-NMR spectra for 4b, 5a -5j, 7a -b,
and 11 (34 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O952112S
(58) This might be a result of the migration of phenyl groups of
BINAP from phosphorus to Pd. Similar phenomena have been
observed in nonasymmetric Heck coupling reactions. See: (a) Herr-
mann, W. A.; Brossmer, C.; O¨ fele, K.; Beller, M.; Fischer, H. J .
Organomet. Chem. 1995, 491, C1-C4. (b) Kelkar, A. A.; Hanaoka, T.;
Kubota, Y.; Sugi, Y. J . Mol. Cat. 1994, 88, L113. Exchange of metal-
and phosphine-bound aryls has also been observed in Pd-catalyzed
Stille and Suzuki coupling reactions. (c) Morita, D. K.; Stille, J . K.;
Norton, J . R. J . Am. Chem. Soc. 1995, 117, 8576 and references cited
therein.
3-(1-P r opylpyr r olidin -3-yl)ph en ol (12, USDA 19).7a 3-(3-
Methoxyphenyl)-1-propylpyrrolidine (0.30 g, 1.29 mmol) was
converted to the corresponding hydrochloride salt and then
dissolved in 48% hydrobromic acid (15 mL). The solution was
stirred at 120 °C for 3 h under an atmosphere of argon. After
completion, the solvent was removed and azeotropically dis-
tilled with absolute ethanol in vacuo followed by recrystalli-
zation from methanol/ether affording pure 12‚HBr (0.34 g,