Synthesis of (Z)-R-Alkylidene-γ-butyrolactams
TABLE 1. Cyclization of N-(Z)-(4′-X-2′-butenyl)-2-butynamides (X
) leaving group)a
SCHEME 1
substrate
entrya
R
X
time (h)
productb
yield (%)c,d
1
2
3
4
5
6
7
H
OBz
OBz
OBz
OAc
OBz
OAc
OBz
1a
1b
1c
1c′
1d
1d′
1e
24
28
23
23
45
42
24
2a
2b
2c
2c
2d
2d
2e
e
70
90
90
80
82
e
Me
Bn
Bn
Ts
Ts
Boc
TABLE 2. Cyclization of
N-(Z)-(4′-Benzoyloxybut-2′-enyl)butynamides in the Absence of the
Nitrogen Ligands
a Reaction conditions: A mixture of 1 (0.5 mmol), Pd(OAc)2 (0.025
mmol), and bpy (0.038 mmol) in HOAc (2.0 mL) was stirred at 80 °C; the
reaction was monitored by TLC. b The products were identified by 1H NMR,
IR, MS, and elemental analysis or HRMS. c Isolated yield. d Z/E > 97:3
e No anticipated product was observed
entrya
substrate R
productb
yield (%)c,d
has been developed in which the acetoxy anion served as the
nuleophile and the nitrogen-containing ligands were employed
to inhibit the â-hydride elimination reaction.10 The stoichio-
metric reactions strongly demonstrated that the nitrogen-
containing ligands, like halides, serve to favor â-heteroatom
elimination over â-hydride elimination.10 Also a similar strategy
was used in the cycloisomerization of the electron-rich 1,6-
enynes.11 The asymmetric version of this acetoxypalladation-
initiated enyne-coupling reaction was achieved while chiral
nitrogen-containing ligands were employed.10 Herein we wish
to report the asymmetric construction of R-alkylidene-γ-
butyrolactams from palladium(II)-catalyzed intramolecular enyne
cyclization of N-allylic 2-alkynamides based on the above
methodology.
1
2
3
Me
Bn
Ts
1b
1c
1d
2b
2c
2d
37
45
24
a Reaction conditions: A mixture of 1 (0.5 mmol) and Pd(OAc)2 (0.025
mmol) in HOAc (2.0 mL) was stirred at 80 °C and the reaction was
monitored by TLC. b The products were identified by H NMR, IR, MS,
1
and elemental analysis. c Isolated yield. d Z/E > 97:3
Further experiments were carried out to study the difference
of the cyclization of allylic alkynoates and N-allylic alkyna-
mides. As mentioned in the acetoxypalladation-initiated cy-
clization of allylic butynoates,10a,b the cyclization reaction can
occur only in the presence of bipyridine as the ligands. When
the reaction was carried out in the absence of the nitrogen
ligands, only the hydroacetoxylation byproduct was observed
(Scheme 1),10 while in the case of N-allylic alkynamides, the
cyclization product could be isolated in noticeable yield even
in the absence of the nitrogen ligands (Table 2). Combined with
the electronic effect of the substituents on nitrogen atom
mentioned above, these results revealed that the nitrogen atom
of the N-allylic alkynamides, to some extent, may also play the
role of nitrogen-containing ligand in stabilizing the carbon-
palladium bond, inhibiting the â-hydride elimination and
promoting the â-heteroatom elimination.10b,c,13
Results and Discussion
We initially examined the reaction of N-(Z)-(4′-X-2′-butenyl)-
2-butynamides (X ) leaving group) using the reaction conditions
for the corresponding esters10 (Table 1).
Most of the reactions proceeded smoothly to afford the
γ-butyrolactams in high yields with high stereoselectivity with
respect to the exocyclic double bonds (Z/E > 97:3).12 The
variation of leaving groups has little influence on the â-hetero-
atom elimination reaction, which is similar to the reaction
initiated by halopalladation.12b Change of the substituents on
the nitrogen atom of the N-allylic 2-alkynamides influenced the
cyclization greatly on the yield of the reaction (Table 1, entries
1-3, and 5). The alkynamides with electron-withdrawing
substituents on the nitrogen atom required longer reaction time
and gave lower yield than those with electron-donating sub-
stituents (Table 1, compare entry 3 with 5, and entry 4 with 6).
N-Benzyl-substituted amides led to the best results. However,
no product could be isolated when N-Boc is the substituent
(Table 1, entry 7) or there is no substituent on the nitrogen atom
of the N-allylic 2-alkynamides (Table 1, entry 1).
Variation of the substituted group R1 on the alkyne of the
N-allylic 2-alkynamides influenced the cyclization moderately
on the yield of the reaction. However, attempts to cyclize the
N-(Z)-(4′-acetoxy-2′-butenyl)propynamide (1f) met with failure,
which was in accord with Pd(OAc)2-catalyzed hydroacetoxy-
lation of 2-alkynoates14 and might be attributed to the possible
formation of (alkynyl)palladium species15 (Table 3, entry 1).
When R1 is methyl, the yield of the enyne-coupling product is
the highest (Table 3, entry 2). For larger R1 groups, the yield is
(13) Similar results related to stabilizing the carbon-transition metal bond
and inhibiting the â-hydride elimination by coordination have been
reported: (a) Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto´, J. M.; Delgado,
A. J. Am. Chem. Soc. 1994, 116, 12133. (b) Devasagayaraj, A.; Stu¨demann,
T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2723. (c) Giovannini,
R.; Stu¨demann, T.; Dussin, G.; Knochel, P. Angew. Chem., Int. Ed. 1998,
37, 2387. (d) Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120,
11186. (e) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
(14) Lu, X.; Zhu, G.; Ma, S. Tetrahedron Lett. 1992, 33, 7205.
(10) (a) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604. (b) Zhang,
Q.; Lu, X.; Han, X. J. Org. Chem. 2001, 66, 7676. (c) Lu, X.; Zhang, Q.
Pure Appl. Chem. 2001, 73, 247.
(11) Zhang, Q.; Xu, W.; Lu, X. J. Org. Chem. 2005, 70, 1505.
(12) Zhu, G.; Lu, X. Organometallics 1995, 14, 4899.
J. Org. Chem, Vol. 71, No. 10, 2006 3855