A new palladium-catalyzed intramolecular allylation to pyrrolidin-2- ones

Article abstract of DOI:10.1021/jo971849+

A novel palladium(0)-catalyzed cyclization to 3,4-disubstituted pyrrolidin-2-ones has been developed. The new approach relies upon the concomitant generation of stabilized acetamide enolate anions and of a π- allyl-palladium appendage, properly tethered by a nitrogen atom. Reaction conditions have been optimized for the methoxycarbonyl-stabilized model reaction [(Z)-2 → 3] and then applied to other substrates. A broad range of acetamide anion stabilizers was shown to allow the desired intramolecular C- C bond formation (MeO₂C, MeCO, NC, (EtO)₂PO, PhSO₂). The cyclizations gave exclusively 5-exo-trig ring closure, thereby affording γ-lactams. All the cyclizations gave the corresponding 3,4-disubstituted pyrrolidin-2-ones with total diastereoselection. Complete trans preference was unequivocally demonstrated for the model reaction via a NOESY experiment.

Full text of DOI:10.1021/jo971849+

804
J . Org. Chem. 1998, 63, 804-807
A New P a lla d iu m -Ca ta lyzed In tr a m olecu la r Allyla tion to
P yr r olid in -2-on es1
Giuliano Giambastiani, Barbara Pacini, Marina Porcelloni, and Giovanni Poli*
Dipartimento di Chimica Organica “Ugo Schiff” and CNR Centro de Studio sulla Chimica e la Struttura
dei Composti Eterocicli e loro Applicazioni, Via G. Capponi 9, I-50121, Firenze, Italy
Received October 7, 1997
A novel palladium(0)-catalyzed cyclization to 3,4-disubstituted pyrrolidin-2-ones has been developed.
The new approach relies upon the concomitant generation of stabilized acetamide enolate anions
and of a π-allyl-palladium appendage, properly tethered by a nitrogen atom. Reaction conditions
have been optimized for the methoxycarbonyl-stabilized model reaction [(Z)-2 f 3] and then applied
to other substrates. A broad range of acetamide anion stabilizers was shown to allow the desired
intramolecular C-C bond formation (MeO2C, MeCO, NC, (EtO)2PO, PhSO2). The cyclizations gave
exclusively 5-exo-trig ring closure, thereby affording γ-lactams. All the cyclizations gave the
corresponding 3,4-disubstituted pyrrolidin-2-ones with total diastereoselection. Complete trans
preference was unequivocally demonstrated for the model reaction via a NOESY experiment.
The γ-lactam skeleton is commonly found in molecules
Following our interest in these heterocycles,14 we wish
to report our latest results toward the synthesis of 3,4-
disubstituted γ-lactams exploiting π-allyl palladium chem-
istry.15 The synthetic plan we conceived relies on the
concomitant generation of a stabilized acetamide enolate
anion and a π-allyl appendage, properly tethered by a
nitrogen atom, so as to trigger an intramolecular allylic
alkylation.16
with great value in medicinal chemistry as psychotropic
agents,2 muscarinic acid antagonists,3 and antihyperten-
sive agents.4 Furthermore, pyrrolidones can be easily
converted into other bioactive molecules via reduction to
the corresponding pyrrolidines5 or cleavage of the amide
bond to afford open γ-amino acids such as the GABA
analogue Baclofen6 or the gastroprotective substance AI-
77-B.7 In particular, C-3 and/or C-48 substituted γ-lac-
tams are present in several biologically interesting
compounds such as in the hepatoprotective agent Clause-
namide,9 in some hypolipidemic agents,10 in conforma-
tionally constrained peptide mimics,11 in glycine antago-
nists,12 and in the neurotrophic agent lactacystin.13
Therefore, the search for new procedures for the stereo-
selective synthesis of 3,4-disubstituted γ-lactams appears
to be highly desirable.
Although such an approach is, to our knowledge, still
unexplored,17,18 it is interesting to note that keto ana-
(1) This work has been presented, in part, at the 9th IUPAC
Symposium on Organometallic Chemistry, OMCOS 9, Go¨ttingen,
Germany, J uly 20-25, 1997.
(14) (a) Poli, G.; Ciofi, S.; Maccagni, E.; Sardone, N. Tetrahedron
Lett. 1995, 36, 8669. (b) Ciofi, S.; Giambastiani, G.; Poli, G.; Reginato,
G.; Sardone, N. Tetrahedron, in press.
(15) For excellent reviews see: (a) Hegedus, L. Palladium in Organic
Chemistry. In Organometallics in Synthesis; Schlo¨sser, M., Ed.; J .
Wiley: New York, 1994; Chapter 5, pp 385-459. (b) Palladium
Reagents and Catalysis, Tsuji, J .; Ed.; Wiley: New York, 1995. (c)
Palladium Reagents in Organic Synthesis, Heck, R. F., Ed.; Academic
Press: New York, 1985.
(2) See for example: (a) Rigo, B.; Fasseur, D.; Cherepy, N.; Coutu-
rier, D. Tetrahedron Lett. 1989, 30, 7057. (b) Moody, C. M.; Young, D.
W. Tetrahedron Lett. 1994, 35, 7277.
(3) Nilsson, B. M.; Ringdahl, B.; Hacksell, U. J . Med. Chem. 1990,
33, 580.
(4) Bergmann, R.; Gericke, R. J . Med. Chem. 1990, 33, 492.
(5) See for example: Hanessian, S.; Ratovelomanana, V. Synlett
1990, 501.
(6) (a) Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1992,
3, 1213. (b) Mazzini, C.; Labreton, J .; Alphand, V.; Furstoss, R.
Tetrahedron Lett. 1997, 38, 1195.
(7) (a) Ward R. A.; Procter, G. Tetrahedron 1995, 51, 12301. (b)
Hamada, Y.; Hara, O.; Kawai, A.; Kohno, Y.; Shioiri, T. Tetrahedron
1991, 47, 8635.
(8) See also: (a) Palomo, C.; Coss´ıo, F. P.; Cuevas, C.; Odriozola, J .
M.; Ontoria, J . M. Tetrahedron Lett. 1992, 33, 4827. (b) Palomo, C.;
Coss´ıo, F. P.; Cuevas, C. Tetrahedron Lett. 1991, 32, 3109. (c) Palomo,
C.; Coss´ıo, F. P.; Cuevas, C.; Lecea, B.; Mielgo, A.; Roma´n, P.; Luque,
A.; Mart´ınez-Ripoll, M. J . Am. Chem. Soc. 1992, 114, 9360.
(9) Hartwig, W.; Born, L. J . Org. Chem. 1987, 52, 4352.
(10) (a) Diaz, R. S.; Monreal, J .; Lucas, M. J . Neurochem. 1990, 55,
134. European Patent 393,607. Chem. Abstr. 1991, 114, 22874a. (b)
Woo, E..P.; Mullins, M. J . U.S. Patent US 4,943, 640. Chem. Abstr.
1991, 114, 23798c. (c) Toja, E.; Gorini, C.; Zirotti, C.; Barzaghi, F.;
Galliani. G. European Patent 229,566, 1987.
(11) (a) Wolf, J .-P.; Rapoport, H. J . Org. Chem. 1989, 54, 3164. (b)
Garvey, D. S.; May, P. D.; Nadzan, A. M. J . Org. Chem. 1990, 55, 936.
(12) Leeson, P. D.; Williams, B. J .; Baker, R.; Ladduwahetty, T.;
Moore, K. W.; Rowley, M. J . Chem. Soc., Chem. Commun. 1990, 1578.
(13) Uno, H.; Baldwin, J . E.; Russell, A. T. J . Am. Chem. Soc. 1994,
116, 2139.
(16) Reviews: (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989,
28, 1173; (b) Heumann, A.; Re´glier, M. Tetrahedron 1995, 51, 975. See
also (c) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113.
(17) Intramolecular ring closures to pyrrolidine derivatives via
π-allyl palladium complexes. Allylic aminations: (a) Trost, B. M.;
Geneˆt, J . P. J . Am. Chem. Soc. 1976, 98, 8516. (b) Godleski, S. A.;
Meinhart, J . D.; Miller, D. J .; Van Wallendael, S. Tetrahedron Lett.
1981, 22, 2247. (c) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988,
29, 2927. (d) Fournet, G.; Balme, G.; Barieux, J . J .; Gore, J . Tetrahe-
dron 1988, 44, 5821. (e) Ba¨ckvall, J . E. Andersson, P. J . Am. Chem.
Soc. 1990, 112, 3683. (f) Larock, R. C.; Zenner, J . M. J . Org. Chem.
1995, 60, 482. (g) Trost, B. M.; Krische, M. J .; Radinov, R.; Zanoni, G.
J . Am. Chem. Soc. 1996, 118, 6297. (h) Larock, R. C.; Hightower, T.
R.; Hasvold, L. A.; Peterson, K. P. J . Org. Chem. 1996, 61, 3584.
Metallo-ene reactions: (i) Oppolzer, W.; Birkinshaw, T. M.; Bernar-
dinelli, G. Tetrahedron Lett. 1990, 31, 6995. Pyrrolidones via allylic
amidations: (j) Yamamoto, K.; Ishida, T.; Tsuji, J . Chem. Lett. 1987,
1157. (k) Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.; Shibasaki, M.;
Mori, M. J . Org. Chem. 1995, 60, 2016. For an example of ring closure
via chloropalladation see: (l) J iang, H.; Ma, S.; Zhu, G.; Lu, X.
Tetrahedron 1996, 52, 10945. For two examples of palladium-catalyzed
amide anion intramolecular via allylic alkylation see: (m) Godleski,
S. A.; Villhauer, E. B. J . Org. Chem. 1986, 51, 486. (n) J ohnson, E. P.;
Chen, G.-P.; Fales, K. R.; Lenk, B. E.; Szendroi, R. J . Wang, X.-J .;
Carlson, J . A. J . Org. Chem. 1995, 60, 6595.
S0022-3263(97)01849-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

Palladium-Catalyzed Intramolecular Allylation
J . Org. Chem., Vol. 63, No. 3, 1998 805
Sch em e 1a
Ta ble 2. Am id a tion of (Z)-1 to 5-10 a n d Th eir
Cycliza tion s to 3,4-Disu bstitu ted P yr r olid in -2-on es
11-16a
entry
EWG
amid (%) yield (%) cycliz product yield (%)
1
2
3
4
5
6
MeCO
NC
PhSO2
PhS
(EtO)2PO (Z)-9
Cl (Z)-10
(Z)-5
(Z)-6
(Z)-7
(Z)-8
61
93
78
83
75
73
11
12
13
-
14
b
77
70
78
0
80
0
a
a
Key: (i) (Z)-1 f (Z)-5: 2,6,6-trimethyl-4H-1,3-dioxin-4-one,
toluene, 110 °C, 3 h; (Z)-1 f (Z)-6: NCCH2CO2H, DCC, THF, rt,
10 h; (Z)-1 f (Z)-7: PhSO2CH2CO2H, DCC, THF, rt, 10 h; (Z)-1
f (Z)-8: PhSCH2COCl, NEt3, CH2Cl2, 0 °C f rt, 4 h; (Z)-1 f (Z)-
9: (EtO)2POCH2CO2H, DCC, THF, rt, 10 h; (Z)-1 f (Z)-10:
ClCH2COCl, NEt3, CH2Cl2, 0 °C f rt, 4 h. (ii) All the cyclizations
have been performed in THF in the presence of Pd2(dba)3 (0.05
equiv), PPh3, (0.5 equiv), BSA (1.2 equiv), AcOK (0.1 equiv) and
Key: (i) MeO2CCH2COCl, NEt3, CH2Cl2 (74%); (ii) Pd2(dba)3,
(0.05 equiv), PPh3, (0.5 equiv), BSA (1.2 equiv), AcOK (0.1 equiv),
THF, 70 °C, 12 h, (69%); (iii) Pd2(dba)3, (0.05 equiv), PPh3, (0.5
equiv), THF, 70 °C, 12 h, (E)-2: 51%, 3: 13%). (iv) H2, (1 atm),
10% Pd/C Cat., MeOH (86%).
Ta ble 1. Stu d y of Cycliza tion of (E)-2 a n d (Z)-2
enolization
b
refluxed at 70 °C for 12 h. The acyclic 1,3-diene 15 was obtained
in 68% yield (eq 2).
entry precursor
catalyst
system
NaH
BSA/AcOK
3 (%) (E)-2 (%)
1
2
3
4
5
6
(Z)-2
(Z)-2
(Z)-2
(Z)-2
(Z)-2
(E)-2
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4 BSA/AcOK
BSA/AcOK
Pd2(dba)3
Pd2(dba)3
50a
69
70
0
(Z)-2 to (E)-2, 13% of the cyclized product 3 was also
detected. Cyclization of (E)-2, under otherwise identical
conditions (entry 6) gave essentially the same outcome
as (Z)-2. Since the rate-determining step in allylic
alkylations is expected to be the oxidative addition,22 and
given the high rate of a 5-exo-trig cyclization, we surmise
that cyclization of (Z)-2 and (E)-2 involves immediate
trapping of the anti and the syn π-allyl-palladium
complexes, respectively, as soon as they are formed.
Only the trans diasteroisomer 3 was always detected
as the cyclized product. Its stereochemistry was unam-
biguously assigned on the basis of the NOESY spectrum
of the hydrogenated product 4.23 Whether the observed
trans diastereoselectivity is attained during the C-C
bond formation or after equilibration of the cyclized
material is still a matter of investigation.24
Having in hand the optimized conditions for the
cyclization step, we next evaluated other EWG moieties
as acetamide anion stabilizers. Accordingly, the acyclic
precursors 5-10 have been prepared from (Z)-1 using
standard procedures, and then submitted to the above
cyclization conditions. The acetyl-, cyano-, phenylsulfo-
nyl-, and diethylphosphonyl moieties all were able to
promote the cyclizations (Table 2). Again, the five-
membered rings were always and exclusively obtained,
the alternative 7-endo-trig process being evidently highly
disfavored. Interestingly, this result differs from what
observed by Tsuji19 in the case of the corresponding
acyclic keto precursors. In contrast to the above results,
the sulfenyl- and the chloro-stabilized acetamides 8 and
10 failed to cyclize. Seemingly, such substrates are not
activated enough to be enolized by the BSA/AcOK system.
In the latter case oxidative addition of Pd(0) on the C-Cl
13
73
51
BSA/AcOK
a
Spectroscopic yield.
logues of amide derived from A have been reported to
cyclize giving mixtures of 5-exo-trig and 7-endo-trig
products.19
According to the envisioned synthetic plan, a model
cyclization precursor was first prepared. Benzylamine
was allylated with (Z)-1-acetoxy-4-chloro-butane20 to give
the allylic amine (Z)-1 whose acylation with methyl
malonyl chloride gave the amide (Z)-2 in high yield
(Scheme 1).
The crucial cyclization step has been studied next
(Table 1). First trials by treatment of (Z)-2 with NaH in
THF at 70 °C, in the presence of Pd2(dba)3 and PPh3, gave
1
indeed the expected cyclized product, as detected by H
NMR of the crude material. However, contamination by
some intractable byproducts did not allow a clean isola-
tion of the product (entry 1). We found later that by
using BSA/AcOK as the enolization system,21 the cycliza-
tion product was cleanly obtained in 69 and 70% yields,
by employing Pd2(dba)3 or Pd(PPh3)4 as catalysts, respec-
tively (entries 2 and 3). Further corollary experiments
were also of help for a better understanding. The
presence of palladium (entry 4) appeared essential for
the success of the cyclization, thereby confirming the true
palladium catalysis of the cyclization. However, when
the π-allyl-palladium complex was generated in the
absence of any base (entry 5), to obtain isomerization of
(18) For a related approach using radical chemistry see: Galeazzi,
R.; Geremia, S.; Mobbili, G.; Orena, M. Tetrahedron: Asymmetry 1996,
7, 3573.
(19) Tsuji, J .; Kobayashi, Y.; Kataoka, H.; Takahashi, T. Tetrahedron
Lett. 1980, 21, 1475.
(22) Trost, B. M. Verhoeven, T. R. J . Am. Chem. Soc. 1980, 102,
4730.
(23) Direct assignment of the relative stereochemistry on compound
3 turned out to be unfeasible owing to signal overlaps in the 1H-NMR
spectrum.
(20) Nystrom, J . E.; Rein, T.; Ba¨ckvall, J . E. Org. Synth. 1988, 67,
105.
(21) Trost, B. M.; Murphy, D. J . Organometallics 1985, 4, 1143.
(24) Since in the isomerization of (Z)-2 to (E)-2 (Table 1, entry 5),
where a potentially enolizing base is absent and 3 was again obtained
in trans stereochemistry, we favor the first hypothesis.

806 J . Org. Chem., Vol. 63, No. 3, 1998
Giambastiani et al.
bond did not compete,25 and clean elimination to the
8), a n d (Z)-4-[Ben zyl(2-ch lor oa cetyl)a m in o]bu t-2-en yl
Aceta te ((Z)-10). To a solution of (Z-1) (1.0 mmol) in CH2Cl2
(11 mL) are dropwise added at 0 °C NEt3 (0.21 mL, 1.5 mmol)
and the proper acid chloride (1.5 mmol) sequentially. After 6
h stirring at rt, the reaction mixtures are treated with water
(5 mL) and extracted with CH2Cl2. The collected organic layers
are dried and evaporated in vacuo. Flash chromatography of
the crude products (AcOEt:hexanes) gives the pure amides as
oils ((Z)-2, 74%, (Z)-8, 83%, (Z)-10, 73%). (Z)-2: 1H NMR
(CDCl3): δ ) 7.37-7.17 (5H), 5.78-5.43 (2H), 4.62-4.42 (4H),
4.10 (d, 2H, 55%, J ) 5.9 Hz), 3.93 (d, 2H, 45%, J ) 5.9 Hz),
3.76 (s, 3H, 45%), 3.72 (s, 3H, 55%), 3.53 (s, 2H, 45%), 3.48 (s,
2H, 55%), 2.03 (s, 3H, 45%), 2.00 (s, 3H, 55%). 1H NMR
(DMSO, 70 °C, 300 MHz): δ ) 7.40-7.19 (5H), 5.63-5.51 (2H),
4.53 (s, 2H), 4.49 (d, 2H, J ) 6.3 Hz), 3.98 (d, 2H, J ) 6.2 Hz),
3.65 (s, 3H), 3.11 (s, 2H), 1.99 (s, 3H). 13C NMR (CDCl3): δ )
20.70, 20.74, 40.99, 42.59, 44.70, 48.45, 51.16, 52.38, 59.37,
59.72, 126.50, 127.32, 127.43, 127.54, 127.89, 128.09, 128.63,
128.87, 129.00, 129.23, 135.84, 136.66, 166.19, 166.37, 167.90,
168.07, 170.55, 170.60. IR (CDCl3): 3007, 2955, 2856, 1733,
1643 cm-1. Anal. Calcd for C17H21NO5: C, 63.94; H, 6.63; N,
4.39. Found: C, 64.01; H, 6.60; N, 4.51. (Z)-8: 1H NMR
(CDCl3): δ ) 7.53-7.17 (10H), 5.77-5.50 (2H), 4.60-4.43 (4H),
4.07 (d, 2H, 50%, J ) 4.3 Hz), 3.98 (d, 2H, 50%, J ) 3.9 Hz),
3.82 (s, 2H, 50%), 3.76 (s, 2H, 50%), 2.04 (s, 3H, 50%), 1.99 (s,
3H, 50%). Anal. Calcd for C21H23NO3S: C, 68.27; H, 6.27; N,
3.79. Found: C, 68.19; H, 6.21; N, 3.82. (Z)-10: 1H NMR
(CDCl3): δ ) 7.38-7.18 (5H), 5.78-5.50 (2H), 4.60-4.48 (4H),
4.14-4.00 (4H), 2.04 (s, 3H, 50%), 2.00 (s, 3H, 50%). 13C NMR
(CDCl3): δ ) 20.80, 41.26, 42.97, 44.39, 48.75, 50.95, 59.43,
59.76, 126.54, 127.67, 127.80, 128.08, 128.20, 128.45, 128.78,
129.13, 129.25, 133.72, 133.91. IR (CHCl3): 3006, 2945, 1737,
1650 cm-1. Anal. Calcd for C15H18NO3Cl: C, 60.91; H, 6.13;
N, 4.74. Found: C, 60.97; H, 6.21; N, 4.67.
corresponding 1,3-diene26 15 was observed.
In conclusion, we have illustrated a new and stereo-
selective intramolecular cyclization to 3,4-disubstituted
pyrrolidin-2-ones based on π-allyl-palladium chemistry.
The method is flexible enough to encompass a broad
range of acetamide anion stabilizers. Given the mild
conditions required and the high yields and selectivities
attained, this new approach appears to be synthetically
attractive and a useful alternative to the existing meth-
ods.17,18 Asymmetric modifications of the methodology
are currently underway.
Exp er im en ta l Section
Gen er a l Meth od s. THF and toluene were dried by distil-
lation from sodium/benzophenone under nitrogen atmosphere,
and CH2Cl2 was dried by distillation from CaH2. All moisture
and air-sensitive reactions were carried out in predried
glassware under a positive nitrogen atmosphere. Final prod-
uct solutions were dried over Na2SO4, filtered, and evaporated
under reduced pressure on a rotary evaporator.
(Z)-4-(Ben zyla m in o)bu t-2-en yl Aceta te ((Z)-1). To a
solution of (Z)-2-butene-1,4-diol (0.607 g, 6.89 mmol) in CH2Cl2
(40 mL) are added sequentially triethylamine (0.72 mL, 5.17
mmol) and acetic anhydride (0.49 mL, 5.17 mmol). After 6 h
stirring, the mixture is treated with H2O (10 mL), the organic
phase is separated and the aqueous phase is extracted with
CH2Cl2 (3 × 20 mL). The organic phases are collected, washed
with a small portion of H2O, and dried, and the solvent is
evaporated. To the resulting crude monoacetate are added
pyridine (1.67 mL, 20.67 mmol) and thionyl chloride (1.50 mL,
20.67 mmol), and stirring is continued for 3 h. After treatment
with saturated aqueous Na2CO3 (15 mL), the reaction mixture
is extracted with CH2Cl2 (3 × 10 mL), and the collected organic
phases are dried and evaporated in vacuo. The resulting
monoacetate monochloride is then immediately dissolved in
acetonitrile (20 mL), benzylamine (1.13 mL, 10.34 mmol) is
added, and the mixture is brought to reflux for 12 h. The
mixture is then treated with saturated aqueous Na2CO3 (10
mL) and submitted to standard extractive workup with CH2Cl2
(3 × 10 mL). Flash chromatography (hexanes:ethyl acetate:
triethylamine 75:25:4%) gives the pure amine amine (Z)-1 (237
mg, 39%, starting from the diol 69% considering the recovered
diol), and the corresponding (Z)-diacetate AcOCH2CHd
CHCH2OAc (67 mg, 11%). 1H NMR (CDCl3): δ ) 7.33-7.27
(5H), 5.85-5.56 (2H), 4.60 (d, 2H, J ) 6.4 Hz), 3.79 (s, 2H),
3.34 (d, 2H, J ) 6.4 Hz), 2.05 (s, 3H). 13C NMR (CDCl3,
selected data): δ ) 20.93, 45.65, 53.42, 60.25, 125.56, 127.07,
128.18, 128.47, 133.06, 140.01. IR (CDCl3): 3005, 2930, 1731
cm-1. Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39.
Found: C, 71.47; H, 7.96; N, 6.17.
Gen er a l P r oced u r e for th e Syn th esis of (Z)-4-[Ben zyl-
(cya n oa cet yl)a m in o]b u t -2-en yl Acet a t e ((Z)-6), (Z)-4-
[Ben zyl[(p h en ylsu lfon yl)a cet yl]a m in o]b u t -2-en yl Ac-
et a t e ((Z)-7), (Z)-4-[Ben zyl[(d iet h ylp h osp h on o)a cet yl]-
a m in o]bu t-2-en yl Aceta te ((Z)-9). To a solution of (Z)-1 (0.5
mmol) and the proper carboxylic acid (0.5 mmol) in THF (32
mL) is added DCC (0.122 g, 0.60 mmol), and the resulting
mixture is stirred for 15 h. Hexane (15 mL) is then added so
as to precipitate most of the formed dicyclohexyl urea. The
reaction mixture is then filtered on a Celite pad washing with
hexanes. Evaporation of the solvent gives the crude products
which are purified by flash chromatography (AcOEt:hexanes)
to give the pure amides as oils ((Z)-6, 93%; (Z)-7, 78%; (Z)-9,
75%). (Z)-6 and (Z)-7 are obtained slightly contaminated by
small traces of the dicyclohexylurea byproduct. However, this
impurity does not affect the subsequent reactivity of the
substrates. (Z)-6: 1H NMR (CDCl3): δ ) 7.40-7.15 (5H),
5.80-5.40 (2H), 4.61-4.47 (4H), 4.14 (d, 2H, 50%, J ) 6.6 Hz),
3.96 (d, 2H, 50%, J ) 5.5 Hz), 3.59 (s, 2H, 50%), 3.48 (s, 2H,
50%), 2.04 (s, 3H, 50%), 2.00 (s, 3H, 50%). 13C NMR (CDCl3):
δ ) 20.80, 25.19, 43.63, 44.85, 49.55, 51.26, 59.27, 59.65,
113.82, 114.07, 126.23, 128.03, 128.27, 128.38, 128.47, 128.89,
129.38, 134.99, 135.97, 156.72, 162.23, 166.05, 170.73. IR
(CHCl3): 3009, 2937, 2858, 2261, 1734, 1665 cm-1 (Z)-7: 1H
NMR (CDCl3): δ ) 7.92 (2H), 7.68-7.53 (3H), 7.37-7.14 (5H),
5.68 (m, 1H), 5.57 (m, 1H), 4.71-4.47 (4H), 4.31-4.04 (4H),
2.05 (s, 3H, 50%), 1.99 (s, 3H, 50%) 13C NMR (CDCl3, 200
MHz): δ ) 20.82, 24.93, 25.60, 33.92, 43.23, 45.27, 49.15,
51.46, 59.49, 59.72, 59.83, 60.00, 126.41, 127.71, 127.78,
127.87, 128.13, 128.20, 128.40, 128.58, 128.76, 129.02, 129.16,
129.20, 134.24, 134.30, 135.61, 136.21, 138.85, 166.66, 170.71.
IR (CDCl3): 3072, 3034, 2936, 2858, 1732, 1652 cm-1 (Z)-9:
1H NMR (CDCl3): δ ) 7.36-7.16 (5H), 5.75-5.46 (2H), 4.66
(s, 2H, 50%), 4.61 (s, 2H, 50%), 4.50 (d, 2H, J ) 5.9 Hz), 4.23-
4.07 (6H), 3.11 (d, 2H, 50%), 3.04 (d, 2H, 50%), 2.03 (s, 3H,
50%), 1.99 (s, 3H, 50%), 1.32 (t, 6H, J ) 6.9 Hz). 13C NMR
(CDCl3): δ ) 16.25, 16.36, 20.80, 32.25, 32.36, 34.89, 35.00,
42.86, 45.10, 48.65, 51.44, 59.56, 59.80, 62.62, 126.45, 127.34,
127.51, 127.82, 127.98, 128.64, 129.00, 129.11, 129.49, 136.17,
136.77, 165.34, 165.45, 170.69. IR (CDCl3): 3032, 2983, 2931,
Gen er a l P r oced u r e for th e Syn th esis of (Z)-[Ben zyl-
(m a lon yl)a m in o]bu t-2-en yl Aceta te ((Z)-2), (Z)-4-[Ben -
zyl[2-(p h en ylth io)a cetyl]a m in o]bu t-2-en yl Aceta te ((Z)-
(25) (a) Mori, M.; Kanda, N.; Oda, I.; Ban, Y. Tetrahedron 1985, 41,
5474. (b) Mori, M.; Kubo, Y.; Ban, Y. Tetrahedron Lett. 1985, 26, 1519.
(26) (a) Tsuji, J .; Yamakawa, T.; Kaito, M.; Mandai, T. Tetrahedron
Lett. 1978, 19, 2075. (b) Trost, B. M.; Verhoeven, T. R.; Fortunak, J .
M. Tetrahedron Lett. 1979, 20, 2301. (c) Trost, B. M.; Fortunak, J . M.
J . Am. Chem. Soc. 1980, 102, 2841. (d) Yamamoto, K., Suzuki, S.; Tsuji,
J . Bull. Chem. Soc. J pn. 1981, 54, 2541. (e) Trost, B. M.; Fortunak, J .
M. Tetrahedron Lett. 1981, 22, 2301. (f) See also: Takacs, J . M.;
Lawson, E. C.; Clement, F. 213th ACS National Meeting, San
Francisco, 1997, abstract 633.

Palladium-Catalyzed Intramolecular Allylation
J . Org. Chem., Vol. 63, No. 3, 1998 807
1735, 1643 cm-1. Anal. Calcd for C19H28NO6P: C, 57.42; H,
7.10; N, 3.52. Found: C, 57.37; H, 7.12; N, 3.47
(M + 1+, 4); 200 (47); 91 (100); 77 (28). Anal. Calcd for
C
19H19NO3S: C, 66.84; H, 5.61; N, 4.10. Found: C, 66.83; H,
(Z)-4-[Ben zyl(3-oxobu tyr yl)a m in o]bu t-2-en yl Aceta te
((Z)-5). A solution of (Z)-1 (1.0 mmol) (0.026 g, 0.119 mmol)
and 2,6,6-trimethyl-4H-1,3-dioxin-4-one (0.019 mL, 0.142 mmol)
in toluene (6.0 mL) is heated at reflux. After 3 h stirring,
water (3 mL) is added, and the mixture is extracted with Et2O.
The collected organic layers are dried, and the solvent is
evaporated in vacuo. Flash chromatography (CH2Cl2: MeOH
100:3%) gives pure 5 as an oil.
5.85; N, 4.22. 14: 1H NMR (CDCl3): δ ) 7.38-7.21 (5H), 5.78
(ddd, 1H, J ) 17.2 Hz, J ) 9.7 Hz, J ) 7.1 Hz), 5.11 (d, 1H, J
) 17 Hz), 5.05 (d, 1H, J ) 9.1 Hz), 4.46 (s, 2H), 4.30-4.09
(4H), 3.56 (dd, 1H, J ) 9 Hz, J ) 8.1 Hz), 3.24 (m, 1H), 2.98
(m, 1H), 2.83 (dd, 1H, J ) 22 Hz, J ) 5.2 Hz), 1.33 (t, 3H, J )
6.6 Hz), 1.32 (t, 3H, J ) 6.6 Hz). 13C NMR (CDCl3): δ ) 16.36,
37.15, 45.81, 46.87, 48.62, 62.29, 62.42, 63.15, 116.13, 127.73,
128.11, 128.73, 135.86, 138.03, 168.60. IR (CDCl3): 2986, 2932,
1686 cm-1. MS m/z (%): 337 (M+, 9); 200 (27), 91 (100). Anal.
Calcd for C17H24NO4P: C, 60.53; H, 7.17; N, 4.15. Found: C,
60.59; H, 7.17; N, 4.17
1H NMR (CDCl3): δ ) 7.40-7.15 (5H), 5.76-5.43 (2H),
4.61-4.43 (4H), 4.10 (d, 2H, 50%, J ) 5.8 Hz), 3.90 (d, 2H,
50%, J ) 5.8 Hz), 3.63 (s, 2H, 50%), 3.55 (s, 2H, 50%), 2.30 (s,
3H, 50%), 2.25 (s, 3H, 50%), 2.03 (s, 3H, 50%), 2.00 (s, 3H,
50%). 13C NMR (CDCl3): δ ) 20.83, 22.01, 30.37, 42.59, 44.77,
48.51, 49.85, 49.94, 51.18, 59.48, 59.78, 126.47, 127.32, 127.49,
127.63, 127.98, 128.10, 128.72, 129.01, 129.09, 129.38, 135.97,
136.66, 166.90, 167.08, 170.71, 202.3, 203.5. IR (CDCl3): 3012,
2970, 2943, 1728, 1667 cm-1. Anal. Calcd for C17H21NO4: C,
67.31; H, 6.98; N, 4.62. Found: C, 67.28; H, 7.02; N, 4.67
Cycliza tion s of th e Aceta tes. Gen er a l P r oced u r e for
th e Syn th esis of (3,4-tr a n s)-1-Ben zyl-3-(m eth oxyca r bo-
n yl)-4-vin ylp yr r olid in -2-on e (3), (3,4-tr a n s)-3-Acetyl-1-
ben zyl-4-vin ylp yr r olid in -2-on e (11), (3,4-tr a n s)-1-Ben zyl-
3-cyan o-4-vin ylpyr r olidin -2-on e (12), (3,4-tr a n s)-1-Ben zyl-
3-(p h en ylsu lfon yl)-4-vin ylp yr r olid in -2-on e (13), a n d (3,4-
tr a n s)-1-Ben zyl-3-(d ieth ylp h osp h or yl)-4-vin ylp yr r olid in -
2-on e (14). To a solution of the acyclic substrate (1.0 mmol)
in THF (20 mL) are added bis(trimethylsilyl)acetamide (0.3
mL, 1.2 mmol) and AcOK (10 mg, 0.1 mmol) sequentially with
stirring, under nitrogen atmosphere. In a separate flask
Pd2(dba)3 (45 mg, 0.05 mmol) and PPh3 (130 mg, 0.5 mmol)
are weighed and added to the reaction vessel, and the resulting
mixture is brought to reflux for 12 h. After this period, a
saturated aqueous solution of NH4Cl is added and the organic
phase is extracted with Et2O. The collected organic phases
are dried, and the solvent is removed in vacuo. Flash
chromatography (hexanes:AcOEt) gives the pure compounds
as oils (3, 69% from (Z)-2 73% from (E)-2), 11, 77%, 12, 70%,
13, 78%, 14, 80%). 3: 1H NMR (CDCl3): δ ) 7.34-7.20 (m,
5H), 5.72 (m, 1H), 5.14 (d, 1H, J trans ) 10.7 Hz), 5.07 (d, 1H,
J cis ) 4.1 Hz), 4.46 (s, 2H), 3.80 (s, 3H), 3.44-3.34 (3H), 3.01
(m, 1H). 13C NMR (CDCl3): δ ) 40.85, 47.42, 50.48, 53.22,
54.77, 117.88, 128.31, 128.65, 129.29, 136.24, 136.68, 169.45,
(E)-[Ben zyl(m a lon yl)a m in o]bu t-2-en yl Aceta te ((E)-2).
To a solution of the methyl ester (Z)-2 (0.120 g, 0.376 mmol)
in THF (10 mL) are added Pd2(dba)3 (0.017 g, 0.019 mmol)
and PPh3 (0.049 g, 0.188 mmol), and the resulting mixture is
brought to reflux for 12 h. A saturated aqueous solution of
NH4Cl is then added, and the organic phase is extracted with
Et2O. The collected organic phases are dried, and the solvent
is removed in vacuo. Flash chromatography (hexanes:AcOEt
60:40) gave pure (E)-2 as an oil (51%) together with a small
amount of the cyclized product 3 (13%). 1H NMR (CDCl3): δ
) 7.40-7.11 (5H), 5.73-5.62 (2H), 4.63-4.46 (4H), 4.03 (d,
2H, 45%, J ) 3.1 Hz), 3.84 (2H, 55%), 3.76 (s, 3H, 55%), 3.72
(s, 3H, 45%), 3.50 (s, 2H, 55%), 3.48 (s, 2H, 45%), 2.05 (s, 3H,
55%), 2.04 (s, 3H, 45%). 13C NMR (CDCl3): δ ) 20.70, 20.73,
40.99, 41.03, 46.70, 48.33, 48.40, 51.17, 52.39, 63.36, 63.76,
126.36, 127.22, 127.47, 127.58, 127.91, 128.19, 128.53, 128.68,
129.08, 134.84, 135.86, 136.36, 166.19, 167.93, 170.55. IR
(CHCl3): 3006, 2957, 1738, 1642 cm-1. Anal. Calcd for C17H21
-
NO5: C, 63.94; H, 6.63; N, 4.39. Found: C, 63.81; H, 6.67; N,
4.47.
4-[Ben zyl(ch lor oa cetyl)a m in o]bu ta -1,3-d ien e (15). The
same reaction conditions as those above-described for the
cyclizations of compounds 2 and 5-10 to give, respectively 3,
and 11-14 were applied. Flash chromatography (hexanes:
AcOEt 50:50) gives the pure diene 15 as an oil (68%). 1H NMR
(CDCl3): δ ) 7.34-7.22 (5H), 6.25-5.94 (3H), 5.36 (dd, 1H, J
) 16.1 Hz, J ) 2.58 Hz), 5.24 (d, 1H, J ) 9.68 Hz), 4.68 (s,
2H), 4.06 (s, 2H). 13C NMR (CDCl3): δ ) 42.17, 51.60, 122.57,
126.74, 127.78, 128.60, 128.80, 129.24, 131.18, 136.03, 166.27.
IR (CDCl3): 3034, 2929, 1666 cm-1. MS m/z (%): 235 (M+, 7);
237 (M+, 2); 91 (100). Anal. Calcd for C13H14NOCl: C, 66.24;
H, 5.99; N, 5.94. Found: C, 66.31; H, 6.07; N, 5.91.
170.27. IR (CHCl3): 3005, 2958, 1738, 1688 cm-1
. MS m/z
(%): 259 (M+, 37); 200 (55); 146 (19); 119 (42); 91 (100). Anal.
Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.23; H, 6.66; N, 5.16. 11: 1H NMR (CDCl3): δ ) 7.39-7.17
(5H), 5.70 (m, 1H), 5.10 (d, 1H, J ) 9.5 Hz), 5.03 (d, 1H, J )
4.2 Hz), 4.43 (s, 2H), 3.48-3.35 (3H), 2.99 (m, 1H), 2.46 (s,
3H). 13C NMR (CDCl3): δ ) 30.65, 37.18, 46.87, 49.78, 61.27,
116.84, 127.83, 128.13, 128.84, 135.79, 137.14, 169.09, 202.92.
IR (CHCl3): 3092, 3036, 2927, 1715, 1685 cm-1. MS m/z (%):
243 (M+, 12), 200 (47), 91 (100). Anal. Calcd for C15H17NO2:
C, 74.05; H, 7.04; N, 5.76. Found: C, 74.12; H, 7.07; N, 5.69.
12: 1H NMR (CDCl3): δ ) 7.41-7.21 (5H), 5.73 (ddd, 1H, J )
17.2 Hz, J ) 10.2 Hz, J ) 6.9 Hz), 5.30 (d, 1H, J ) 17.4 Hz),
5.24 (d, 1H, J ) 9.7 Hz), 4.56-4.37 (2H), 3.46-3.02 (4H). 13C
NMR (CDCl3): δ ) 39.93, 42.28, 47.34, 49.60, 119.64, 120.19,
128.25, 128.34, 129.04, 133.15, 133.70, 165.23. IR (CHCl3):
2928, 2248, 1710 cm-1. MS m/z (%): 226 (M+, 59), 199 (3), 91
(100). Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38.
Found: C, 74.39; H, 6.27; N, 12.47. 13: 1H NMR (CDCl3): δ
) 7.98 (2H), 7.75-7.53 (3H), 7.36-7.15 (5H), 5.78 (ddd, 1H, J
) 16.8 Hz, J ) 10.4 Hz, J ) 7.2 Hz), 5.14 (d, 1H, J trans ) 16.8
Hz), 5.13 (d, 1H, J cis ) 10.2 Hz), 4.45 (s, 2H), 3.84 (d, 1H, J )
4.4 Hz), 3.67-3.54 (2H), 3.02 (d, 1H, J ) 9 Hz). 13C NMR
(CDCl3): δ ) 36.09, 47.05, 49.87, 71.19, 117.35, 127.94, 128.05,
128.85, 129.05, 129.44, 134.30, 135.21, 136.54, 137.83, 164.79.
IR (CDCl3): 3070, 3035, 2928, 1699 cm-1. MS m/z (%): 342
(3,4-tr a n s)-1-Ben zyl-4-eth yl-3-(m eth oxyca r bon yl)p yr -
r olid in -2-on e (4). To a suspension of 10% Pd/C (2 mg) in
MeOH (2.0 mL) is added a solution of compound 3 (0.022 g,
0.085 mmol) in MeOH (3.0 mL) under nitrogen atmosphere.
Hydrogen atmosphere is then introduced by means of a three-
way tap, and vigorous stirring is started. After 4 h the reaction
is filtered through a Celite plug and evaporated. Flash
chromatography (hexanes:AcOEt 60:40) gives pure 4 as an oil
(76%). 1H NMR (CDCl3): δ ) 7.34-7.20 (5H), 4.46 (s, 2H),
3.79 (s, 3H), 3.42 (dd, 1H, J ) 9.5 Hz, J ) 8 Hz), 3.19 (d, 1H,
J ) 7.7 Hz), 2.86 (dd, 1H, J ) 9.5 Hz, J ) 7 Hz), 2.62 (m, 1H),
1.47 (2H), 0.86 (t, 3H, J ) 7.3 Hz). 13C NMR (CDCl3): δ )
11.38, 26.75, 37.89, 46.90, 50.60, 52.64, 54.82, 127.74, 128.12,
128.78, 135.95, 169.62, 170.74. IR (CDC3): 2927, 1714, 1687
cm-1. MS m/z (%): 261 (M+, 20), 202 (12), 119 (23), 91 (100).
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36.
Found: C, 69.02; H, 7.37; N, 5.21.
Ack n ow led gm en t. This work was supported in part
by grants from Consiglio Nazionale delle Ricerche (CNR
Roma) and Ministero dell′Universita` e della Ricerca
Scientifica e Tecnologica (MURST, Roma).
J O971849+