Intramolecular Enantioselective Palladium-Catalyzed Heck Arylation of Cyclic Enamides

Article abstract of DOI:10.1021/jo961832b

Palladium-catalyzed intramolecular cyclization of N-formyl-6-<3-(2-iodophenyl)propyl>-1,2,3,4-tetrahydropyridine (1a) and N-formyl-6-<2-(2-iodophenyl)ethyl)>-1,2,3,4-tetrahydropyridine (1b) in the presence of AsPh3 resulted in formation of the spiro compounds N-formyl-3,3',4,4'-tetrahydrospiro (2a) and N-formyl-3',4'-dihydrospiro (2b), respectively, and in the presence of PPh3 and TlOAc in the spiro compounds N-formyl-3,4,5',6'-tetrahydrospiro (3a) and N-formyl-5',6'-dihydrospiro (3b), respectively.Cyclization of N-formyl-6-(3-<2-<(trifluoromethanesulfonyl)oxy>phenyl>propyl)-1,2,3,4-tetrahydropyridine (7) in presence of a chiral (phosphinoaryl)oxazoline ((S)-8) resulted in formation of (R)-3a and (R)-N-formyl-1',3,4,6'-tetrahydrospiro ((R)-6a) in high enantiomeric excesses, 87 percent and >99percent, respectively, and in good yield.The oxazoline ligand (S)-8 furnished higher enantiomeric excesses and improved regioselectivities than (R)-BINAP.

Full text of DOI:10.1021/jo961832b

J . Org. Chem. 1997, 62, 595-602
595
In tr a m olecu la r En a n tioselective P a lla d iu m -Ca ta lyzed Heck
Ar yla tion of Cyclic En a m id es
Lena Ripa and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University,
Box 574, SE-751 23 Uppsala, Sweden
Received September 24, 1996X
Palladium-catalyzed intramolecular cyclization of N-formyl-6-[3-(2-iodophenyl)propyl]-1,2,3,4-
tetrahydropyridine (1a ) and N-formyl-6-[2-(2-iodophenyl)ethyl]-1,2,3,4-tetrahydropyridine (1b) in
the presence of AsPh3 resulted in formation of the spiro compounds N-formyl-3,3′,4,4′-tetrahy-
drospiro[naphthalene-1(2H),2′(1′H)-pyridine] (2a ) and N-formyl-3′,4′-dihydrospiro[indan-1,2′(1′H)-
pyridine] (2b), respectively, and in the presence of PPh3 and TlOAc in the spiro compounds N-formyl-
3,4,5′,6′-tetrahydrospiro[naphthalene-1(2H),2′(1′H)-pyridine] (3a) and N-formyl-5′,6′-dihydrospiro[indan-
1,2′(1′H)-pyridine] (3b), respectively. Cyclization of N-formyl-6-(3-{2-[(trifluoromethanesulfonyl)-
oxy]phenyl}propyl)-1,2,3,4-tetrahydropyridine (7) in presence of a chiral (phosphinoaryl)oxazoline
((S)-8) resulted in formation of (R)-3a and (R)-N-formyl-1′,3,4,6′-tetrahydrospiro[naphthalene-
1(2H),2′(3′H)-pyridine] ((R)-6a ) in high enantiomeric excesses, 87% and >99%, respectively, and
in good yield. The oxazoline ligand (S)-8 furnished higher enantiomeric excesses and improved
regioselectivities than (R)-BINAP.
In tr od u ction
to achieve high asymmetric inductions in asymmetric
Heck reactions of cyclic enamides.
The construction of tetrasubstituted carbon centers can
be achieved by application of intramolecular Heck reac-
tions.1 A number of complex natural products have been
prepared relying on this strategy.2 The first examples
of enantioselective intramolecular Heck reactions were
reported by Shibasaki3 and Overman.4 Grigg used ena-
mides as an olefinic counterpart in intramolecular ary-
lation reactions, for the assembly of spiro compounds
comprising a nitrogen atom in the new ring formed.5
Attachment of a chiral auxiliary to the nitrogen atom
prior to cyclization allowed highly diastereoselective
reactions to occur.6 We have previously conducted re-
giocontrolled intermolecular palladium-catalyzed aryla-
tions of cyclic enamides,7 and Ozawa and Hayashi8 have
employed the combination of aryl triflates and (R)-BINAP
Herein we report an intramolecular palladium-cata-
lyzed arylation of cyclic enamides which provides spiro
compounds accommodating an R-phenylpiperidine frag-
ment. Rigidified molecules with this fragment constitute
scaffolds, which after appropriate functionalizations should
provide valuable bioactive molecules useful in the search
for new anticonvulsants.9
Resu lts
Palladium-catalyzed intramolecular spirocyclization of
1a and 1b with triphenylarsine as ligand afforded 2a and
2b in 67% and 74% isolated yields, respectively (Scheme
1). Triphenylarsine10 was more effective than other
monodentate ligands tested11 in promoting the concomi-
tant migration of the double bond. Hydrogenation of 2a
and 2b occurred smoothly to deliver 4a and 4b, with
subsequent removal of the formyl group by methyllithium
providing the secondary amines 5a and 5b in good yields.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1997.
(1) For recent reviews see: (a) de Meijere, A.; Meyer, F. E. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2379-2411. (b) Cabri, W.; Candiani,
I. Acc. Chem. Res. 1995, 28, 2-7. (c) Ojima, I.; Tzamarioudaki, M.; Li,
Z.; Donovan, R. J . Chem. Rev. 1996, 96, 635-662.
(2) See for example: (a) Laschat, S.; Narjes, F.; Overman, L. E.
Tetrahedron 1994, 50, 347-358. (b) Overman, L. E. Pure Appl. Chem.
1994, 66, 1423-1430. (c) Negishi, E.-i.; Cope´ret, C.; Ma, S.; Liou, S.-
Y.; Liu, F. Chem. Rev. 1996, 96, 365-393.
(3) Sato, Y.; Sodoeka, M.; Shibasaki, M. J . Org. Chem. 1989, 54,
4738-4739.
(4) Carpenter, N. E.; Kucera, D. J .; Overman, L. E. J . Org. Chem.
1989, 54, 5846-5848.
Cyclizations in the presence of thallium acetate and
triphenylphosphine allowed the double bond migration
to be suppressed5c and produced less than 2% of the
undesired double bond isomers, enabling isolation of 3a
and 3b in 91% and 84% yields, respectively. Hydrogena-
tion afforded 4a and 4b. Use of silver carbonate was
equally effective in suppressing double bond isomeriza-
tion12 but produced lower yields. Attempts to prepare
the other allylic double bond isomer by use of palladium
(5) (a) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.
Tetrahedron 1989, 45, 3557-3568. (b) Grigg, R.; Sridharan, V.;
Stevenson, P.; Sukirthalingam, S.; Worakun, T. Tetrahedron 1990, 46,
4003-4018. (c) Grigg, R.; Loganathan, V.; Santhakumar, V.; Sridharan,
V.; Teasdale, A. Tetrahedron Lett. 1991, 32, 687-690. Recently the
regioselectivity of related intramolecular arylations of enamides to
provide polycyclic systems has been studied in some detail. (d) Comins,
D. L.; Baevsky, M. F.; Hong, H. J . Am. Chem. Soc. 1992, 114, 10971-
10972. (e) Comins, D. L.; J oseph, S. P.; Zhang, Y.-m. Tetrahedron Lett.
1996, 37, 793-796. (f) Gibson, S. E., (ne´e Thomas); Middleton, R. J . J .
Chem. Soc., Chem. Commun. 1995, 1743-1744. (g) Rigby, J . H.;
Hughes, R. C.; Heeg, M. J . J . Am. Chem. Soc. 1995, 117, 7834-7835.
(h) Rigby, J . H.; Mateo, M. E. Tetrahedron 1996, 52, 10569-10582.
See also: (i) Iida, H.; Yuasa, Y.; Kibayashi, C. J . Org. Chem. 1980, 45,
2938-2942.
(8) (a) Hayashi, T.; Kubo, A.; Ozawa, F. Pure Appl. Chem. 1992,
64, 421-427. (b) Ozawa, F.; Hayashi, T. J . Organomet. Chem. 1992,
428, 267-277.
(9) (a) Bigge, C. F. Biochem. Pharmacol. 1993, 45, 1547-1561. (b)
Ornstein, P. L.; Monn, J . A.; Schoepp, D. D. Drug News Perspec. 1994,
7, 5-12.
(10) For use of triphenylarsine in Heck reaction see: (a) Zhang, H.-
C.; Daves, G. D., J r. J . Org. Chem. 1992, 57, 4690-4696. (b) Zhang,
H.-C.; Daves, G. D., J r. Organometallics 1993, 12, 1499-1500. (c) Ripa,
L.; Hallberg, A. J . Org. Chem. 1996, 61, 7147-7155.
(11) In the absence of phosphine or arsine ligands (see ref 10c) a
slow reaction was encountered. Addition of triphenylphosphine, tri-o-
tolylphosphine, or tri-2-furylphosphine gave mixtures of double bond
isomers.
(6) Grigg, R.; Dorrity, M. J . R.; Malone, J . F.; Mongkolaussavara-
tana, T.; Amilaprasadh Norbert, W. D. J .; Sridharan, V. Tetrahedron
Lett. 1990, 31, 3075-3076.
(7) Nilsson, K.; Hallberg, A. J . Org. Chem. 1990, 55, 2464-2470.
S0022-3263(96)01832-4 CCC: $14.00 © 1997 American Chemical Society

596 J . Org. Chem., Vol. 62, No. 3, 1997
Ripa and Hallberg
Sch em e 1
acetate, (R)-BINAP, and triethylamine10c gave as ex-
pected a mixture of isomers.
The rate of the 6-exo cyclizations of 1a were slower
than the 5-exo cyclization of 1b and required more of the
palladium catalyst for satisfactory conversion.13
still mixtures of double bond isomers were observed
(entries 4 and 5). Omitting calcium carbonate or tri-
ethylamine and using Pd2(dba)3 and (R)-BINAP as cata-
lytic system19 allowed isolation of a mixture of (R)-3a
(38% ee) and (R)-6a (15% ee) in 59% yield together with
(R)-2a (18% ee) in 15% yield (entry 6).
The enantiomeric excesses achieved with (R)-BINAP14
as ligand is summarized in Table 1. Cyclization of 1a
with a catalytic system prepared in situ from palladium
acetate and (R)-BINAP, and in the presence of silver
nitrate and triethylamine in acetonitrile at 80 °C, led to
a mixture of 2a , 3a and the double bond isomer 6a (entry
1).15 The enamide (R)-2a (38% ee) and a mixture of (S)-
3a (8% ee) and (R)-6a (35% ee) were isolated in 39% and
20% yields, respectively. Hydrogenation of the reaction
mixture after subjecting 1a to the cyclization conditions
afforded (R)-4a in 52% total yield in an enantiomeric
excess of 31%. Cyclization of 1b under the conditions
used for 1a led to formation of (R)-2b,16 as the major
product, in low enantiomeric excess and in low yield
(22%, 17% ee). Substitution of the silver nitrate for silver
phosphate17 and employing 1a as starting material gave
(R)-2a (42% ee) and the mixture of (R)-3a (13% ee) and
(R)-6a (20% ee), and a similar result was obtained with
calcium carbonate as base18 (entries 2 and 3). Use of
calcium carbonate and silver phosphate in more polar
solvents improved the enantiomeric excess of (R)-2a
[DMF 51% ee, dimethylacetamide (DMAA) 54% ee] but
Intramolecular cyclization of the aryl triflate 7 at 60
°C with (R)-BINAP and triethylamine as base in aceto-
nitrile led to the enamide (R)-2a (40% ee) and the mixture
of (S)-3a (19% ee) and (R)-6a (20% ee) in low yields, 30%
and 14%, respectively (entry 7). Reactions in DMF
produced similar results (entry 8). With less polar
solvents, a greater degree of asymmetric induction was
encountered, although the reactions required consider-
ably longer reaction times for completion. Thus, after
reaction in THF, at 60 °C, (R)-2a was isolated in 30%
yield and in an enantiomeric excess of 71% (entry 9). The
mixture of (S)-3a and (R)-6a was isolated in 29% yield,
and (R)-6a gave 68% ee, while (S)-3a gave only 13% ee.
A lower reaction temperature, 40 °C, had a limited
influence on the enantioselectivity and resulted in slow
conversion (entry 10). The outcome of reactions in
toluene was high enantiomeric excesses of (R)-2a (90%
ee) and of (R)-6a (89% ee), but the enantiomeric purity
of (S)-3a in this solvent was also low (8% ee) (entry 11).
Additionally, a long reaction time, 168 h, was needed for
full conversion. A comparison of entry 9 and entry 12
reveals that a similar product composition was attained
when starting from Pd2(dba)3, but this reaction required
higher temperature for a satisfactory conversion.20 The
low isolated yields encountered with the reactions using
the aryl triflate 7 is, to a large extent, due to reduction
prior to insertion, causing deoxygenation of 7.21 Inor-
ganic bases,22 which have been reported to circumvent
(12) The beneficial effect of silver additives in controlling double
bond isomerization in the Heck reaction was first observed by Over-
man’s group. (a) Abelman, M. M.; Oh, T.; Overman, L. E. J . Org. Chem.
1987, 52, 4130-4133. (b) Abelman, M. M.; Oveman, L. E. J . Am. Chem.
Soc. 1988, 110, 2328-2329. For use of silver salts in controlling double
bond isomerization in heterocycles see: (c) Larock, R. C.; Gong, W.
H.; Baker, B. E. Tetrahedron Lett. 1989, 30, 2603-2606. (d) Larock,
R. C.; Gong, W. H. J . Org. Chem. 1989, 54, 2047-2050. (e) Larock, R.
C.; Gong, W. H. J . Org. Chem. 1990, 55, 407-408. (f) Sakamoto, T.;
Kondo, Y.; Yamanaka, H. Tetrahedron Lett. 1992, 33, 6845-6848. (g)
Nilsson, K.; Hallberg, A. J . Org. Chem. 1992, 57, 4015-4017. See also
refs 7 and 10c.
(19) (a) Ashimori, A.; Overman, L. E. J . Org. Chem. 1992, 57, 4571-
4572. Applying Overman’s conditions omitting silver additives and with
1,2,2,6,6-pentamethylpiperidine as base rendered racemic products. (b)
Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J . J . Org. Chem.
1993, 58, 6949-6951.
(13) For a related example see ref 5a.
(14) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Noyori,
R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345-350.
(15) Prolonged reaction times do not alter the product distribution.
(16) (R)-2a and (R)-2b carry the aryl ring on opposite side of the
tetrahydropyridine ring. See ref 27.
(20) Ozawa and Hayashi found that the kinetic resolution process
was promoted by acetate ions displacing the olefin from the π-complex.
Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi,
K.; Moriguchi, K.-i. Organometallics 1993, 12, 4188-4196.
(21) Employing sterically hindered amine bases (1,2,2,6,6-penta-
methylpiperidine and diisopropylethylamine) reduced the formation
of the undesired reduction product but furnished lower yields and
moderate asymmetric induction of 2a (ee < 40%).
(17) The counter anion of the silver salts has been reported to
influence the chiral induction in asymmetric Heck reactions. (a) Sato,
Y.; Sodoeke, M.; Shibasaki, M. Chem. Lett. 1990, 1953-1954. (b)
Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1993, 34,
4965-4968. (c) Sato, Y.; Nukui, S.; Sodeoka, M.; Shibasaki, M.
Tetrahedron 1994, 50, 371-382.
(18) A combination of silver phosphate and calcium carbonate was
used by Shibasaki to obtain high enantiomeric excess, see ref 17a.
(22) The bases tested were KOAc, NaOAc, TlOAc, NaHCO3, and K2-
CO3.

Palladium-Catalyzed Heck Arylation of Cyclic Enamides
J . Org. Chem., Vol. 62, No. 3, 1997 597
Ta ble 1. En a n tiom er ic Excesses in In tr a m olecu la r P a lla d iu m -Ca ta lyzed Ar yla tion of 1a a n d 7 w ith (R)-BINAP a s
Liga n d
a
b
The reactions were conducted under argon atmosphere in sealed heavy-walled Pyrex tubes. The enantiomeric excess was determined
by GLC analysis on a chiral capillary column. See ref 29. c The isomer ratio was determined by GLC and double bond isomers were
assumed to have the same response factors. Isolated yields (not optimized) by column chromatography. e DMAA ) dimethylacetamide.
d
f See ref 19.
Sch em e 2
this problem,23 had a deleterious effect on the reaction
rate, although the competing reduction was eliminated.
At higher reaction temperatures (80-120 °C) the cata-
lytic system decomposed before satisfactory conversion
was achieved.
Recently Pfaltz24 reported the successful use of the
chiral (phosphinoaryl)oxazoline (S)-825 (Scheme 2) as
ligand in the Heck arylation of 2,3-dihydrofuran with
phenyl triflate at 60 °C in THF. (R)-2-Phenyl-2,5-
dihydrofuran was produced in an enantiomeric excess of
97%, and the double bond isomer 2-phenyl-2,3-dihydro-
furan was not detected.24a Applying Pfaltz’s reaction
conditions to the triflate 7 resulted in a slow reaction,
furnishing only minute amounts of product after 48 h.
However, after raising the temperature to 110 °C, isola-
tion of a 2:1 mixture of (R)-3a (86% ee) and (R)-6a (>99%
ee) was allowed. A higher regioselectivity was obtained
with a more nonpolar solvent (toluene), which afforded
71% yield of a 6:1 mixture of (R)-3a (87% ee) and (R)-6a
(>99% ee) after 48 h (Scheme 2).26
(23) Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci, F.;
Penco, S.; Santi, R. J . Org. Chem. 1991, 56, 5796-5800. See also ref
2a.
(24) (a) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed.
Engl. 1996, 35, 200-202. See also: (b) Pfaltz, A. Acta Chem. Scand.
1996, 50, 189-194.
(25) The systematic name of (S)-8 is (-)-(S)-4-tert-butyl-2-[2-(di-
phenylphosphino)phenyl]-4,5-dihydrooxazole. (a) Koch, G.; Lloyd-J ones,
G. C.; Loiseleur, O.; Pfaltz, A.; Pre´toˆt, R.; Schaffner, S.; Schnider, P.;
von Matt, P. Recl. Trav. Chim. Pays-Bas 1995, 114, 206-210. (b) Peer,
M.; de J ong, J . C.; Kiefer, M.; Langer, T.; Rieck, H.; Schell, H.;
Sennhenn, P.; Sprintz, J .; Steinhagen, H.; Wiese, B.; Helmchen, G.
Tetrahedron 1996, 52, 7547-7583.

598 J . Org. Chem., Vol. 62, No. 3, 1997
Ripa and Hallberg
Sch em e 3
F igu r e 1. π-Complexes 11S and 11R. The binaphthylene group
in the (R)-BINAP ligand is omitted for clarity. See ref 34.
The absolute configurations of 2a and 2b were assigned
based on empirical force-field calculations (MM2-91) and
by analyses of the circular dichroism spectra.27 Isolation
of the pure enantiomers of 3a and 6a was achieved by
HPLC, using a chiral stationary phase.28 Compounds
(+)-3a and (-)-6a were, after reduction to 4a and
subsequent comparison on a chiral GLC-column29 with
a sample of (S)-4a , assigned to be the (S)-3a and (R)-6a
enantiomers, respectively.30
Sta r tin g Ma ter ia ls. Compounds 1a and 1b were
prepared from the corresponding enamidines10c by hy-
drolysis in 77% and 80% yield, respectively. In an
analogous reaction sequence the N-(N′-tert-butylformim-
idoyl)-1,2,3,4-tetrahydropyridine31 was alkylated with 9
to give 10 after subsequent hydrolysis of the enamidine
function, and 10 was converted thereafter to the triflate
7 as outlined in Scheme 3.
Asym m etr ic Ar ylation s with (R)-BINAP as Ligan d.
The results reported by Ozawa and Hayashi, where
phenyl triflate was employed in asymmetric inter-
molecular arylations of 1-(alkoxycarbonyl)-2,3-dihydro-
pyrroles, afforded (R)-1-(alkoxycarbonyl)-2-phenyl-2,3-
dihydropyrroles in 64-73% ee, as the major products.8b
The regioisomers 1-(alkoxycarbonyl)-2-phenyl-2,5-dihy-
dropyrroles had the opposite, (S), configuration and were
produced with lower enantiomeric excesses.8b The mech-
anism proposed by the authors involves a catalytic kinetic
resolution process.33 The related intramolecular spiro-
cyclizations of 7 reported here provided 2a and 3a with
a preference for enantiomers with the same absolute
configuration as obtained by Ozawa and Hayashi, in their
intermolecular arylations, (R) and (S), respectively. The
third regioisomer 6a was produced with a preference for
the (R) configuration. We believe that the enantiomeric
excesses of the three products, formed either from the
triflate 7 or from the iodide 1a in combination with silver
salts, can be accounted for by involvement of a kinetic
resolution process similar to that suggested by Ozawa
and Hayashi in the intermolecular reaction.
Discu ssion
For the preparation of compounds 2a and 2b , tri-
phenylarsine was employed to enhance the reaction rate.
Triphenylarsine, with the characteristic feature of sta-
bilizing Pd(0) while binding less strongly to Pd(II),32 is
less prone than phosphine ligands to compete with the
olefin for the coordination sites of the hydrido-palladium
π-complexes, thus facilitating the double bond migration.
The oxidative addition is followed by a selection of
enantiofaces, generating two π-complexes, 11S and 11R,
the former being more sterically crowded (Figure 1).
After insertion and â-hydrogen elimination, hydrido-
palladium π-complexes are formed (Scheme 4). One of
the phenyl groups of (R)-BINAP in the π-complex 12R
suffers from a considerable steric repulsion from the
phenyl group of the rigid spirosystem according to a
molecular model analysis.34 Rotation of the palladium-
olefin bond, a prerequisite for the double bond migration,
releases the steric strain and consecutive readdition and
â-hydrogen elimination provides the (R) enantiomers 2a
and 6a . In contrast, the rotation of the olefin-palladium
bond in 12S is disfavored due to steric reasons. Decom-
plexation of 12S dominates and delivers the (S) enanti-
omer of 3a .
(26) Using (S)-8 as ligand in cyclization reactions starting from aryl
iodide 1a in DMAA with silver phosphate resulted in racemic 3a as
the major product.
(27) Ripa, L.; Hallberg, A.; Sandstro¨m, J . Manuscript in preparation.
(28) Compounds 3a and 6a were resolved on columns packed with
swollen microcrystalline triacetylcellulose (TAC), packed and provided
by Dr Roland Isaksson, Department of Analytical Pharmaceutical
Chemistry, Box 574, Uppsala University, BMC, SE-751 23 Uppsala,
Sweden, see: Isaksson, R.; Erlandsson, P.; Hansson, L.; Holmberg, A.;
Berner, S. J . Chromatogr. 1990, 498, 257-280.
(29) Analytical separations of the enantiomers were achieved by gas
chromatography, on a chiral capillary column (10 m × 0.32 mm) with
H2 as carrier gas and a flame ionization detector. Compounds 2a , 3a ,
4a , and 6a were separated on a column coated with 50% heptakis(6-
O-tert-butyldimethylsilyl-2,3-di-O-methyl)-â-cyclodextrin in OV 1701
and compound 2b on a column coated with 20% octakis(2,6-di-O-
methyl-3-O-pentyl)-γ-cyclodextrin in OV 1701, prepared and developed
by Prof. W. A. Ko¨nig, Institut fu¨r Organische Chemie, Universita¨t
Hamburg, D-201 46 Hamburg, Germany.
(30)
Asym m etr ic Ar yla tion s w ith (S)-8 a s Liga n d .
With the (phosphinoaryl)oxazoline ligand (S)-8 two oxi-
dative addition complexes are conceivable. The thermo-
dynamically most stable complex is likely to have the soft
aryl group trans to the harder nitrogen, and the soft
phosphine, with a large trans effect,35 trans to the leaving
(33) For the related intermolecular arylation of 2,3-dihydrofuran,
see: (a) Ozawa, F.; Kubo, A.; Hayashi, T. J . Am. Chem. Soc. 1991,
113, 1417-1419. (b) Ozawa, F.; Kubo, A.; Hayashi, T. Tetrahedron Lett.
1992, 33, 1485-1488. See also ref 19.
(31) Meyers, A. I.; Edwards, P. D.; Bailey, T. R.; J agdmann, G. E.
J . J . Org. Chem. 1985, 50, 1019-1026.
(32) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585-
9595.
(34) The molecular model analyses were based on the X-ray struc-
ture of PdCl2[(R)-BINAP], see ref 20.
(35) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994,
33, 497-526.

Palladium-Catalyzed Heck Arylation of Cyclic Enamides
J . Org. Chem., Vol. 62, No. 3, 1997 599
Sch em e 4
F igu r e 2. Diastereomeric π-complexes 14S, 14R, 15S, and 15R.
See ref 38.
isolated in fair to good yields. Triphenylarsine was a
suitable ligand for the promotion of double bond migra-
tion while thallium acetate efficiently retarded the double
bond migration process. With (R)-BINAP, addition of
silver additives, or alternatively employment of a phenyl
triflate, leads to moderate to high enantioselectivities,
although the yields are low. Employment of (phosphi-
noaryl)oxazoline (S)-8 as ligand rendered good isolated
yield of spiro compounds as well as high enantiomeric
excesses.
triflate.36 Olefin coordination to the fourth coordination
site enables formation of four diastereomeric π-complexes
(Figure 2). Complexes of the type 14, with the aryl
groups trans to the nitrogen, are less prone to migratory
insertion than complexes such as 15, and isomerization
of 14 to 15 may occur before insertion takes place.37
Examination of molecular models38 of complexes 14 and
15 suggests that both the complexes giving the spiro
product with R configuration (14R and 15R) are the
sterically least hindered. The higher enantiomeric excess
for (R)-6a (>99%) as compared to (R)-3a 87% can be
interpreted by assuming involvement of a kinetic resolu-
tion process as discussed previously (Scheme 4). The
rotation of the palladium in complex 13S should be
strongly disfavored due to steric interactions between (S)-
3a and both the tert-butyl group and one of the phenyl
groups in the ligand.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 270 and 67.8 MHz, respectively. Spectra were recorded at
ambient temperature with CDCl3 as solvent and tetrameth-
ylsilane as internal standard. The 1H NMR spectra of the
N-formyl compounds show (with the exeption of compounds
4a , 4b, and 6a ) the existence of two rotamers in an ap-
proximately 96:4 ratio. Shift values are given only for the
major isomer. Peak assignments of the spiro compounds were
made by 13C-13C and 1H-13C correlation experiments. Cou-
pling constants are given as absolute values. Low-resolution
electron-impact MS spectra were measured at an ionization
potential of 70 eV. The mass detector was interfaced with a
gas chromatograph, equipped with a HP-1 (25 m × 0.20 mm)
column. Isomers were assumed to have the same response
factors. Infrared spectra were recorded on a FTIR spectro-
photometer as solutions in CDCl3 unless otherwise noted.
Elemental analyses were performed by Mikro Kemi AB,
Uppsala, Sweden, or by Analytische Laboratorium, Prof. Dr.
H. Malissa and G. Reuter GmbH, Gummersbach, Germany.
The high resolution MS analysis was performed by Einar
Nilsson, Instrumentstationen, Kemicentrum, Lund. Melting
points were determined in open capillary tubes in a melting
point microscope and are uncorrected. All palladium-catalyzed
cyclization reactions were carried out in heavy-walled Pyrex
tubes, sealed with a screw cap fitted with a Teflon gasket. Thin
layer chromatography (TLC) was carried out on aluminum
sheets precoated with silica gel 60 F254 (0.2 mm, E. Merck).
Column chromatography was performed on silica using kisel-
gel 60 (0.032-0.063 mm, E. Merck, or 0.015-0.040 mm (fine),
E. Merck). Preparative HPLC was performed on a Dynamax
60-A 21.4 × 250 mm, 8-µm silica column. A dynamax UV-1
UV detector (254 nm) and a Gilson 305 piston pump (1% EtOH
in isohexane at a flow rate of 13 mL/min) were used.
Con clu sion
We have demonstrated that intramolecular cyclization
of enamides with aryl iodides provides an entry to rigid
R-phenyl piperidines with the double bond restored for
further manipulations. These spiro compounds were
(36) For a discussion of hard and soft acids and bases coordinating
to soft Pd(II), see: (a) Davies, J . A.; Hartley, F. R. Chem. Rev. 1981,
81, 79-90. See also: (b) Clark, G. R.; Palenik, G. J . Inorg. Chem. 1970,
9, 2754-2760. (c) Dekker, G. P. C. M.; Buijs, A.; Elsevier, C. J .; Vrieze,
K.; van Leeuwen, P. W. N. M.; Smeets, W. J . J .; Spek, A. L.; Wang, Y.
F.; Stam, C. H. Organometallics 1992, 11, 1937-1948.
(37) van Leeuwen, P. W. N. M.; Roobeek, C. F.; van der Heijden, H.
J . Am. Chem. Soc. 1994, 116, 12117-12118. See also ref 36c.
(38) The molecular model analyses were based on the X-ray struc-
ture of a π-allyl palladium complex with a similar ligand published
previously. Sprinz, J .; Kiefer, M.; Helmchen, G.; Reggelin, M.; Hutter,
G.; Walter, O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523-1526.

600 J . Org. Chem., Vol. 62, No. 3, 1997
Ripa and Hallberg
Ma ter ia ls. Triethylamine was distilled from potassium
hydroxide, and THF and diethyl ether were distilled from
sodium/benzophenone prior to use. Acetonitrile (CH3CN) was
stored over activated 3 Å molecular sieves and degassed with
argon before use. Triphenylphosphine (PPh3) (Merck) was
recrystallized from 95% ethanol. Pd(OAc)2 (Merck), Pd(dba)2
(Lancaster), Pd2(dba)3 (Aldrich), triphenylarsine (AsPh3) (Acros
Chimica), and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaph-
thyl ((R)-BINAP) (Aldrich) were used as supplied. The ligand
(S)-8 was prepared according to the procedure reported by
Pfaltz,25a and the spectroscopic data was consistent with data
reported.25b Compound 9 was prepared according to a syn-
thetic strategy described elsewhere39 from 2-allylphenol (Acros
Chimica). N-(N′-tert-Butylformimidoyl)-6-[2-(2-iodophenyl)-
ethyl]-1,2,3,4-tetrahydropyridine and N-(N′-tert-butylformim-
idoyl)-6-[3-(2-iodophenyl)propyl]-1,2,3,4-tetrahydropyridine were
prepared as described elsewhere10c from N-(N′-tert-butyl-
formimidoyl)-1,2,3,4-tetrahydropyridine.31 All other reagents
were obtained from commercial sources and used as received.
N-F or m yl-6-[3-(2-iod op h en yl)p r op yl]-1,2,3,4-t et r a h y-
d r op yr id in e (1a ). A solution of N-(N′-tert-butylformimidoyl)-
6-[3-(2-iodophenyl)propyl]-1,2,3,4-tetrahydropyridine10c (89 mg,
0.22 mmol) and KOH (85 mg, 1.5 mmol) in MeOH (1.8 mL)
and water (0.7 mL) was heated at 55 °C under argon until
TLC indicated complete consumption of the formamidine.
Upon cooling, the solvent was removed under reduced pres-
sure, and the residue was dissolved in CH2Cl2 (3 mL). The
organic layer was washed with saturated aqueous NaHCO3
(3 × 1 mL) and brine (2 mL), dried (K2CO3), and concentrated.
Purification by column chromatography (SiO2, pentane/EtOAc
4:1, Rf 0.33) gave 1a (60 mg, 77%). 1H NMR δ 8.53 (s, 1H),
7.81 (dd, 1H), 7.31-7.14 (m, 2H), 6.89 (app dt, 1H), 4.94 (t, J
) 3.9 Hz, 1H), 3.67 (app t, 2H), 2.73 (app t, 2H), 2.45 (app t,
2H), 2.13-2.07 (m, 2H), 1.85-1.63 (m, 4H); 13C NMR δ 159.0,
139.5, 144.0, 135.5, 129.3, 128.4, 127.9, 108.8, 100.5, 40.1, 39.4,
32.0, 27.8, 22.5, 21.5; IR (CDCl3) 1647 cm-1; MS [IP 70 eV;
m/z (% rel int)] 355 (M+, 32), 228 (9), 125 (67), 97 (100). Anal.
Calcd for C15H18INO: C, 50.72; H, 5.11; N, 3.94. Found: C,
50.8; H, 5.2; N, 3.9.
dropwise BH3‚THF (28 mL, 28 mmol, 1 M in THF) at 0 °C,
and the resulting mixture was stirred at room temperature
for 2 h. The reaction mixture was quenched with water (12
mL) followed by 10% aqueous NaOH (12 mL) and 30% aqueous
H2O2 (7 mL) at 0 °C and thereafter stirred for additional 3 h
at 0 °C, acidified with 5% HCl to pH 4, and extracted with
diethyl ether (2 × 100 mL). The organic layers were washed
with saturated aqueous NaHCO3 (50 mL) and brine (50 mL),
dried (Na2SO4), and concentrated to yield 7.64 g of the crude
alcohol. To a solution of the alcohol in benzene (100 mL) at 0
°C were added imidazole (4.8 g, 70 mmol), PPh3 (16.8 g, 64
mmol), and I2 (14.2 g, 56 mmol), and the reaction mixture was
stirred for 1.5 h at room temperature. An 10% aqueous
Na2S2O3 solution (130 mL) was added, and the mixture was
extracted with EtOAc (2 × 70 mL), dried (Na2SO4), and
concentrated. Purification by column chromatography (SiO2,
pentane, Rf 0.33) gave 6 (6.6 g, 62%). 1H NMR δ 7.15 (app dt,
1H), 7.08 (dd, 1H), 6.89 (app dt, 1H), 8.80 (dd, 1H), 3.19 (t, J
) 6.9 Hz, 2H), 2.70 (app t, 2H), 2.17-2.09 (m, 2H), 1.03 (s,
9H), 0.25 (s, 6H); 13C NMR δ 153.5, 130.9, 130.3, 127.2, 121.0,
118.4, 33.4, 31.5, 25.8, 18.2, 6.7, -4.1; MS [IP 70 eV; m/z (%
rel int)] 376 (M+, 1), 319 (77), 191 (100). Anal. Calcd for
C15H25IOSi: C, 47.87; H, 6.70. Found: C, 47.9; H, 6.6.
N-F or m yl-6-[3-(2-h yd r oxyp h en yl)p r op yl]-1,2,3,4-t et -
r a h yd r op yr id in e (10). To a solution of N-(N′-tert-butyl-
formimidoyl)-1,2,3,4-tetrahydropyridine31 (1.7 g, 10 mmol) in
diethyl ether/THF 4:1 (20 mL) was slowly added t-BuLi (9.3
mL, 13 mmol, 1.4 M in hexane) at -78 °C. The yellow solution
was stirred at -20 °C until a white solid had precipitated (2
h). The reaction mixture was cooled to -78 °C, after which
compound 9 (5.6 g, 15 mmol) was added and the reaction
mixture was stirred at -20 °C overnight. The reaction
mixture was poured into saturated NH4Cl (100 mL) and
extracted with diethyl ether (3 × 50 mL). The combined ether
layers were washed with brine (40 mL), dried over K2CO3/Na2-
SO4 1:1, and concentrated to a yellow oil. The crude product
(5.8 g) was dissolved in MeOH (70 mL), KOH (3.9 g, 70 mmol)
in water (30 mL) was added, and the mixture was heated at
60 °C for 2 h. Upon cooling, the solvent was removed under
reduced pressure, and the residue was dissolved in CH2Cl2 (200
mL). The organic layer was washed with saturated aqueous
NaHCO3 (3 × 50 mL) and brine (50 mL), dried (NaHCO3), and
concentrated. Purification by column chromatography (SiO2,
pentane/EtOAc 1:1, Rf 0.45) gave 10 (1.4 g, 5.6 mmol, 56%) as
a white solid, mp 97-98 °C. 1H NMR δ 8.47 (s, 1H), 7.09-
7.04 (m, 2H), 6.85-6.76 (m, 2H), 6.45 (broad s, 1H), 4.94 (t, J
) 3.8 Hz, 1H), 3.68-3.63 (m, 2H), 2.66 (t, J ) 7.4 Hz, 2H),
2.40 (t, J ) 7.4 Hz, 2H), 2.09-2.05 (m, 2H), 1.90-1.72 (m, 4H);
13C NMR δ 159.7, 154.1, 136.0, 130.3, 127.7, 127.3, 120.3,
115.3, 109.0, 39.6, 32.2, 29.9, 27.3, 22.5, 21.5; IR (CDCl3) 3599,
3300-3150, 1615 cm-1; MS [IP 70 eV; m/z (% rel int)] 245 (M+,
20), 227 (21), 138 (76), 97 (100). Anal. Calcd for C15H19NO2:
C, 73.44; H, 7.81; N, 5.71. Found: C, 73.6; H, 7.9; N, 5.8.
N -F or m yl-6-(3-{2-[(t r iflu or om e t h a n e su lfon yl)oxy]-
p h en yl}p r op yl)-1,2,3,4-t et r a h yd r op yr id in e (7). Com-
pound 10 (0.96 g, 3.9 mmol) was mixed with N-phenylbis-
(trifluoromethane)sulfonimide (2.8 g, 7.8 mmol) and triethyl-
amine (0.6 mL, 3.4 mmol) in CH2Cl2 (40 mL). The solution
was stirred at 20 °C for 48 h, diluted with CH2Cl2 (50 mL),
washed with 10% aqueous K2CO3 (3 × 40 mL), dried (Na2-
SO4), and concentrated. Purification by column chromatog-
raphy (SiO2, pentane/EtOAc 3:1, Rf 0.23) gave 7 (1.3 g, 87%).
1H NMR δ 8.49 (s, 1H), 7.37-7.22 (m, 4H), 4.93 (t, J ) 3.8 Hz,
1H), 3.68-3.64 (m, 2H), 2.74 (app t, 2H), 2.43 (t, J ) 7.3 Hz,
2H), 2.10-2.05 (m, 2H), 1.91-1.73 (m, 4H); 13C NMR δ 158.9,
147.9, 135.1, 134.2, 130.9, 128.5, 128.1, 121.4, 118.5 (q), 109.3,
N-F or m yl-6-[2-(2-iod op h en yl)eth yl]-1,2,3,4-tetr a h yd r o-
p yr id in e (1b). Compound 1b was synthesized from N-(N′-
ter t-bu t ylfor m im idoyl)-6-[2-(2-iodoph en yl)et h yl]-1,2,3,4-
tetrahydropyridine10c (3.5 g, 8.8 mmol) as described above for
the synthesis of 1a . Purification by column chromatography
(SiO2, pentane/EtOAc 3:1, Rf 0.41) gave 1b (2.4 g, 80%). 1H
NMR δ 8.70 (s, 1H), 7.82 (dd, 1H), 7.28 (app dt, 1H), 7.16 (dd,
1H), 6.91 (app dt, 1H), 4.90 (t, J ) 3.9 Hz, 1H), 3.70-3.66 (m,
2H), 2.92 (app t, 2H), 2.63 (app t, 2H), 2.07-2.04 (m, 2H),
1.82-1.68 (m, 2H); 13C NMR δ 159.0, 143.1, 134.9, 139.4, 129.4,
128.3, 128.1, 109.4, 100.0, 39.4, 38.9, 32.9, 22.4, 21.3; IR
(CDCl3) 1648 cm-1; MS [IP 70 eV; m/z (% rel int)] 341 (M+, 2),
340 (3), 214 (100), 186 (83), 141 (48). Anal. Calcd for C14H16
-
INO: C, 49.29, H, 4.73, N, 4.10. Found: C, 49.5; H, 5.1; N,
4.1.
3-{2-[(ter t-Bu tyld im eth ylsilyl)oxy]p h en yl}-1-iod op r o-
p a n e (9).39 2-Allylphenol (13.4 g, 0.10 mol) was mixed with
tert-butyldimethylsilyl chloride (16.6 g, 0.11 mol), triethyl-
amine (15.2 g, 0.15 mol), and 4-(dimethylamino)pyridine (1.2
g, 0.01 mol) in CH2Cl2 (300 mL) and stirred at room temper-
ature until TLC indicated complete consumption of the alcohol.
The reaction mixture was washed consecutively with brine
(140 mL), water (140 mL), and brine (140 mL) and was
thereafter dried (MgSO4) and concentrated. Purification by
column chromatography (SiO2, pentane, Rf 0.64) gave a llyl-
1
2-[(ter t-bu tyld im eth ylsilyl)oxy]ben zen e (22.4 g, 90%). H
NMR δ 7.17-7.04 (m, 2H), 6.89 (app dt, 1H), 6.79 (dd, 1H),
6.03-5.93 (m, 1H), 5.08-5.05 (m, 1H), 5.04-5.00 (m, 1H), 3.37
(d, J ) 6.6 Hz, 2H), 1.01 (s, 9H), 0.24 (s, 6H); 13C NMR δ 153.3,
137.0, 130.7, 130.1, 127.0, 121.1, 118.4, 115.4, 34.4, 25.8, 18.2,
-4.1; MS [IP 70 eV; m/z (% rel int)] 248 (M+, 3), 191 (100),
163 (55). Anal. Calcd for C15H24OSi: C, 72.52; H, 9.74.
Found: C, 72.4; H, 9.6. To a solution of the protected
2-allylphenol (7.0 g, 28 mmol) in THF (50 mL) was added
39.4, 32.0, 29.2, 27.2, 22.5, 21.4; IR (CDCl3) 1673, 1642 cm-1
;
MS [IP 70 eV; m/z (% rel int)] 377 (M+, 18), 216 (5), 125 (47),
97 (100). Anal. Calcd for C16H18F3NO4S‚1/2H2O: C, 49.74; H,
4.96; N, 3.63. Found: C, 49.9; H, 4.9; N, 3.7.
N -F o r m y l-3,3′,4,4′-t e t r a h y d r o s p ir o [n a p h t h a le n e -
1(2H),2′(1′H)-p yr id in e] (2a ). Pd(OAc)2 (7.2 mg, 0.032 mmol)
and AsPh3 (39.2 mg, 0.13 mmol) were mixed in CH3CN (20
mL) under a stream of argon. Triethylamine (80 mg, 0.8
mmol) and 1a (142 mg, 0.40 mmol) were added to the mixture.
The reaction mixture was stirred and heated at 80 °C for 120
(39) Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J . Am.
Chem. Soc. 1993, 115, 8477-8478.

Palladium-Catalyzed Heck Arylation of Cyclic Enamides
J . Org. Chem., Vol. 62, No. 3, 1997 601
h. After cooling, the mixture was poured out on saturated
aqueous NaHCO3 (60 mL) and extracted with EtOAc (3 × 40
mL), and the combined organic layers were washed with brine
(2 × 40 mL), dried (K2CO3), and concentrated. The crude
product was purified by column chromatography (SiO2 (fine),
pentane/EtOAc 4:1, Rf 0.37) to yield 2a (61 mg, 67%) as a white
solid, mp 74-75 °C. 1H NMR δ 7.80 (s, 1H, CHO), 7.33-7.09
(m, 5H, Ar-H and H-6′), 5.29-5.22 (m, 1H, H-5′), 2.92-2.75
1(2H),2′(3′H)-p yr id in e] (6a ). Compound 6a was prepared
from 1a (533 mg, 1.5 mmol), Pd(OAc)2 (16.8 mg, 3.0 mmol),
TFP (69 mg 0.30 mmol), and triethylamine (304 mg, 3.0 mmol)
in CH3CN (45 mL) as described above for the peparation of
2a from 1a (80 °C, 14 h). Purification by column chromatog-
raphy (SiO2, pentan/EtOAc 4:1 to 2:1) gave 2a (104 mg, 31%)
and a mixture of 3a and 6a (166 mg, 49%). The mixture of
3a (tR 139 min) and 6a (tR 131 min) was further purified on
preperative HPLC to yield 6a (36 mg, 11%), mp 96-98 °C. 1H
NMR δ 7.72 (d, J ) 1.1 Hz, 1H, CHO), 7.42-7.37 (m, 1H, Ar-
H), 7.25-7.14 (m, 3H, Ar-H), 5.93-5.80 (m, AB spectra, 2H,
H-4′ and H-5′), 4.56-4.47 (m, 1H, H-6′), 3.63-3.54 (m, 1H,
H-6′), 3.00-2.93 (m, 1H, H-3′), 2.84-2.80 (m, 2H, H-4), 2.26-
2.16 (m, 2H, H-2 and H-3′), 1.85-1.52 (m, 3H, H-2 and H-3);
13C NMR δ 163.7 (CHO), 138.6, 136.5 (C-9 and C-10), 129.8,
128.2, 127.8, 126.7 (C-5, C-6, C-7 and C-8), 123.5, 122.4 (C-4′
and C-5′), 57.1 (C-1), 39.8 (C-6′), 38.6 (C-3′), 33.4 (C-2), 30.1
(C-4), 18.4 (C-3); IR (CDCl3) 1632 cm-1; MS [IP 70 eV; m/z (%
rel int)] 227 (M+, 80), 198 (47), 182 (100), 167 (57), 145 (49),
128 (83). HRMS (EI) m/z calcd for C15H17NO 227.1310, found
227.1314.
N-F or m yl-3,4-d ih yd r osp ir o[n a p h th a len e-1(2H),2′-p ip -
er id in e] (4a ). Compound 2a (21 mg, 0.09 mmol) and 10%
Pd/C (10 mg, 0.009 mmol) were mixed in absolute ethanol (2
mL) under H2 (1 atm) for 16 h. The mixture was filtered
through Celite and concentrated to yield 4a (21 mg, 98%) as a
white solid, mp 90-91 °C. Compound 4a (17 mg, 84%) was
prepared in the same way from compound 3a (20 mg, 0.09
mmol). 1H NMR δ 7.70 (s, 1H, CHO), 7.45-7.42 (m, 1H, Ar-
H), 7.39-7.05 (m, 3H, Ar-H), 4.42 (ddd, J ) 13.9, 4.6 and 2.3
Hz, 1H, H-6′), 3.75-2.70 (m, 3H, H-4 and H-6′), 2.32-2.06 (m,
1H, H-2), 2.05-2.00 (m, 1H) and 1.96-1.51 (m, 8H) (H-2, H-3,
H-3′, H-4′ and H-5′); 13C NMR δ 164.1 (CHO), 138.2, 138.0 (C-9
and C-10), 129.6, 127.9, 127.4, 126.6 (C-5, C-6, C-7 and C-8),
58.5 (C-1), 36.8 (C-6′), 32.1 (C-2), 30.0 (C-4), 39.2, 24.8, 20.1,
18.4 (C-3, C-3′, C-4′ and C-5′); IR (CDCl3) 1641 cm-1; MS [IP
70 eV; m/z (% rel int)] 229 (M+, 82), 200 (72), 128 (100). Anal.
Calcd for C15H19NO: C, 78.57; H, 8.35; N, 6.11. Found: C,
78.38; H, 8.19; N, 6.19.
N-F or m ylsp ir o[in d a n -1,2′-p ip er id in e] (4b). Compound
4b was prepared from 2b (55 mg, 0.26 mmol), as described
above for the preparation of 4a from 2a to yield (48 mg, 87%)
as a white solid, mp 105-106 °C. Compound 4b (57 mg, 82%)
was prepared in the same way from compound 3b (68 mg, 0.32
mmol).1H NMR δ 7.63 (s, 1H, CHO), 7.33-7.23 (m, 4H, Ar-
H), 4.58-4.49 (m, 1H, H-6′), 3.00-2.74 (m, 3H, H-3 and H-6′),
2.41-2.32 (m, 1H, H-2), 2.20-1.52 (m, 7H, H-2, H-3′, H-4′ and
H-5′); 13C NMR δ 161.7 (CHO), 144.0, 142.8 (C-8 and C-9),
128.8, 127.0, 125.4, 124.4 (C-4, C-5, C-6 and C-7), 68.8 (C-1),
38.0 (C-6′), 36.0 (C-2), 30.0 (C-3), 37.7, 24.9, 21.3 (C-3′, C-4′
and C-5′); IR (CDCl3) 1646 cm-1; MS [IP 70 eV; m/z (% rel
int)] 215 (M+, 34), 186 (50), 170 (65), 158 (43), 144 (56), 130
(83), 128 (78), 115 (100). Anal. Calcd for C14H17NO: C, 78.11;
H, 7.96; N, 6.50. Found: C, 78.0; H, 7.7; N, 6.4.
3,4-Dih ydr ospir o[n aph th alen e-1(2H),2′-piper idin e] (5a).
Compound 4a (17 mg, 0.074 mmol) was dissolved in dry THF
(0.5 mL), and MeLi (0.12 mL, 0.18 mmol) was added slowly at
0 °C. The reaction mixture was kept at 0 °C for additional 45
min after which water (1 mL) was added. The reaction
mixture was acidified by adding 3 N HCl and washed with
diethyl ether (3 × 0.5 mL). The aqueous layer was made
alkaline with 10% aqueous K2CO3 and extracted with diethyl
ether (4 × 1 mL). The combined organic layers were dried
(K2CO3) and concentrated to yield 5a (11 mg, 71%) as a white
solid, mp 49-50 °C. Spectroscopic data was consistent with
data described elsewhere.10c
(m, 2H, H-4), 2.31-1.70 (m, 8H, H-2, H-3, H-3′ and H-4′); 13
C
NMR δ 161.0 (CHO), 138.0, 137.7 (C-9, C-10), 129.5, 127.6,
127.3, 127.0, 121.8 (C-5, C-6, C-7, C-8 and C-6′), 108.6 (C-5′),
57.4 (C-1), 30.0 (C-4), 36.0, 33.3, 19.8, 18.3 (C-2, C-3, C-3′ and
C-4′); IR (CDCl3) 1660 cm-1; MS [IP 70 eV; m/z (% rel int)]
227 (M+, 78), 198 (6), 129 (100). Anal. Calcd for C15H17NO:
C, 79.26; H, 7.54; N, 6.16. Found: C, 79.2; H, 7.5; N, 6.2.
N -F o r m y l-3′,4′-d ih y d r o s p ir o [in d a n -1,2′(1′H )-p y r i-
d in e] (2b). 2b was prepared from 1b (171 mg, 0.50 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol), AsPh3 (31 mg, 0.10 mmol), and
triethylamine (101 mg, 1.0 mmol) in CH3CN (25 mL) as
described above for the preparation of 2a from 1a (80 °C, 64
h). Purification by column chromatography (SiO2 (fine), pen-
tane/EtOAc 4:1, Rf 0.37) gave 2b (79 mg, 74%) as a white solid,
mp 65-66 °C. 1H NMR δ 7.65 (s, 1H, CHO), 7.35-7.14 (m,
5H, Ar-H and H-6′), 5.32-5.25 (m, 1H, H-5′), 3.10-2.88 (m,
2H, H-3), 2.42-2.10 (m, 5H, H-2, H-3′ and H-4′), 1.85-1.76
(m, 1H, H-4′); 13C NMR δ 159.5 (CHO), 143.9, 143.0 (C-8 and
C-9), 128.9, 127.5, 125.2, 123.5, 121.9 (C-4, C-5, C-6, C-7 and
C-6′), 109.5 (C-5′), 67.2 (C-1), 37.8 (C-2), 33.4 (C-3′), 29.1 (C-
3), 20.1 (C-4′); IR (CDCl3) 1655 cm-1; MS [IP 70 eV; m/z (% rel
int)] 213 (M+, 33), 168 (100), 129 (67). Anal. Calcd for C14H15
-
NO: C, 78.84; H, 7.09; N, 6.56. Found: C, 78.9; H, 6.9; N,
6.4.
N -F o r m y l-3,4,5′,6′-t e t r a h y d r o s p ir o [n a p h t h a le n e -
1(2H),2′(1′H)-p yr id in e] (3a ). Pd(OAc)2 (3.6 mg, 0.016 mmol),
PPh3 (16.8 mg, 0.064 mmol), and TlOAc (58 mg, 0.22 mmol)
were mixed in CH3CN (10 mL) under a stream of argon.
Triethylamine (40 mg, 0.4 mmol) and 1a (71 mg, 0.2 mmol)
were added to the mixture. The reaction mixture was stirred
and heated at 80 °C for 50 h. After cooling, the black mixture
was poured out on saturated aqueous NaHCO3 (60 mL) and
extracted with EtOAc (3 × 40 mL), and the combined organic
layers were washed with brine (2 × 40 mL), dried (K2CO3),
and concentrated. The crude product was purified by column
chromatography (SiO2 (fine), pentane/EtOAc 2:1, Rf 0.26) to
yield 3a (41 mg, 91%) as a white solid, mp 111-112 °C. 1H
NMR δ 7.66 (s, 1H, CHO), 7.23-7.07 (m, 4H, Ar-H), 6.01-
5.95 (m, 1H, H-4), 5.55 (ddd, J ) 10.1, 2.7 and 1.1 Hz, 1H,
H-3′), 4.62 (app dd, 1H, H-6′), 2.97-2.72 (m, 3H, H-4 and H-6′),
2.46-2.32 (m, 1H, H-5′), 2.20-2.04 (m, 2H, H-2 and H-5′),
1.90-1.64 (m, 3H, H-2 and H-3); 13C NMR δ 163.3 (CHO),
138.0, 135.7 (C-9 and C-10), 134.4 (C-3′), 129.3, 128.8, 127.9,
126.8 (C-5, C-6, C-7 and C-8), 124.3 (C-4′), 58.9 (C-1), 34.3 (C-
2), 33.9 (C-6′), 29.3 (C-4), 24.7 (C-3′), 17.9 (C-3); IR (CDCl3)
1637 cm-1; MS [IP 70 eV; m/z (% rel int)] 227 (M+, 63), 198
(48), 170 (100). Anal. Calcd for C15H17NO: C, 79.26; H, 7.54;
N, 6.16. Found: C, 79.1; H, 7.4; N, 6.0.
N -F o r m y l-5′,6′-d ih y d r o s p ir o [in d a n -1,2′(1′H )-p y r i-
d in e] (3b). Compound 3b was prepared from 1b (171 mg,
0.50 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), PPh3 (26 mg, 0.10
mmol), TlOAc (145 mg, 0.55 mmol), and triethylamine (101
mg, 1.0 mmol) in CH3CN (25 mL) as described above for the
preparation of 3a from 1a (80 °C, 19 h). Purification by column
chromatography (SiO2 (fine), pentane/EtOAc 3:1, Rf 0.25) gave
3b (90 mg, 84%) as a white solid, mp 96-98 °C. 1H NMR δ
7.56 (s, 1H, CHO), 7.29-7.14 (m, 4H, Ar-H), 6.02-5.97 (m,
1H, H-4′), 5.58 (ddd, J ) 10.0, 2.7 and 1.2 Hz, 1H, H-3′), 4.58
(dd, J ) 10.3 and 5.2 Hz, 1H, H-6′), 3.05-2.89 (m, 3H, H-3
and H-6′), 2.44-2.27 (m, 1H, H-5′), 2.30 (app t, 2H, H-2), 2.22-
2.11 (m, 1H, H-5′); 13C NMR δ 161.3 (CHO), 144.4, 142.6 (C-8
and C-9), 132.1 (C-3′), 128.9, 127.4, 125.2, 125.0, 124.7 (C-4,
C-5, C-6, C-7 and C-4′), 68.4 (C-1), 39.3 (C-2), 35.4 (C-6′), 29.6
(C-3), 24.5 (C-3′); IR (CDCl3) 1647 cm-1; MS [IP 70 eV; m/z (%
rel int)] 213 (M+, 61), 184 (36), 168 (100). Anal. Calcd for
C14H15NO: C, 78.84; H, 7.09; N, 6.56. Found: C, 79.1; H, 7.3;
N, 6.5.
Sp ir o[in d a n -1,2′-p ip er id in e] (5b). Compound 5b was
prepared from 4b (22 mg, 0.1 mmol), as described above for
the preparation of 5a from 4a , to yield 5b (16 mg, 83%).
Spectroscopic data was consistent with data described else-
where.10c
Gen er a l P r oced u r e for Asym m etr ic Cycliza tion . Cy-
cliza tion of 1a . Pd(OAc)2 (0.1 equiv), (R)-BINAP (0.2 equiv),
and AgNO3 (1.0 equiv) were mixed in well degassed solvent
(5 mL) under a stream of argon. Triethylamine (2.0 equiv)
and 1a (0.10 mmol) were added to the mixture. The reaction
N -F o r m y l-1′,3,4,6′-t e t r a h y d r o s p ir o [n a p h t h a le n e -

602 J . Org. Chem., Vol. 62, No. 3, 1997
Ripa and Hallberg
mixture was stirred and heated at 60-80 °C for 24-168 h until
GLC indicated complete consumption of 1a . After cooling, the
mixture was poured out on saturated aqueous NaHCO3 (10
mL) and extracted with EtOAc (3 × 5 mL), and the combined
organic layers were washed with brine (2 × 5 mL), dried (K2-
CO3), and concentrated. The crude product was purified by
column chromatography (SiO2, pentane/EtOAc 4:1-2:1) to
yield 2a and a mixture of 3a and 6a . The enantiomeric
excesses was determined by enantioselective GLC.29
Cycliza tion of 7. Pd(OAc)2 (0.1 equiv) and (R)-BINAP (0.2
equiv) were mixed in well degassed solvent (5 mL) under a
stream of argon. Triethylamine (2.0 equiv) and 7 (0.10 mmol)
were added to the mixture. The reaction mixture was stirred
and heated to 60-80 °C for 24-168 h until GLC indicated
complete consumption of 7. Workup and purification as
described for the cyclization of 1a .
Deter m in a tion of Absolu te Con figu r a tion s of Com -
p ou n d s 2a , 2b, 3a , a n d 6a . Gen er a l. The absolute configu-
rations of compounds 2a and 2b were assigned based on
empirical force-field calculations (MM2-91) and by analyses
of the circular dichroism spectra and are descibed elsewhere.27
Compounds 3a and 6a were resolved on two TAC28 columns
(600 × 10 mm i.d.) in series at a flow rate of 1.0 mL min-1. A
1.1 mL loop was employed to introduce the samples. Detection
was carried out at 254 nm with a variable wavelength detector.
The mobile phase consisted of ethanol/water 96:4 and was
degassed with He prior to use. The collected fractions of each
enantiomer were concentrated, dissolved in 7 mL of diethyl
ether, dried (K2CO3), and concentrated.
4, 3.5 mL) and filtered. Four injections were made. The first
eluted band, (+)-3a , was found to be optically pure, but the
second eluted band, (-)-3a , was reinjected. The fractions were
optically pure according to GLC.29 (+)-3a , [R]23D +10.1 (c 0.74,
absolute ethanol), (-)-3a , [R]23 -10.9 (c 0.68, absolute etha-
D
nol).
Ch r om a toga p h ic En a n tiom er Sep a r a tion of 6a . Ra-
cemic 6a (15 mg) was dissolved in degassed ethanol/water (96:
4, 0.9 mL) and filtered. One injection was made. The first
eluted band, (+)-6a , was not pure (95% according to GLC),
but the second eluted band, (-)-6a , was found to be optically
pure.29 (+)-6a , [R]23D +18.8 (c 0.67, absolute ethanol), (-)-6a ,
[R]23 -28.5 (c 0.60, absolute ethanol).
D
Cor r ela tion of 3a a n d 6a w ith (R)-2a by Hyd r ogen a -
tion to 4a . Compound (R)-2a 27 (6.0 mg, 0.026 mmol) and 10%
Pd/C (2.8 mg, 0.0022 mmol) were mixed in absolute ethanol
(0.5 mL) under H2 (1 atm) for 15 h. The mixture was filtered
through Celite and concentrated to yield (S)-4a (6.0 mg, 99%).
Compound (+)-3a was hydrogenated in the same way to
yield (R)-4a , [R]23 -24.1 (c 0.65, absolute ethanol) and
D
compound (-)-6a to yield (S)-4a , [R]23D +24.2 (c 0.43, absolute
ethanol). The absolute configurations were determined by
comparison of the products on a chiral GLC-column.29
Ack n ow led gm en t. The authors are grateful to the
Swedish Natural Science Research Council for financial
support.
Ch r om a toga p h ic En a n tiom er Sep a r a tion of 3a . Ra-
cemic 3a (60 mg) was dissolved in degassed ethanol/water (96:
J O961832B