Phosphine-free Palladium-catalyzed allene carbopalladation/allylie alkylation domino sequence: A new route to 4-(α-Styryl) γ-lactams

Article abstract of DOI:10.1002/chem.200900184

The original regio and stereoselective heterocycle synthesis by a phosphine-free Pd-catalyzed allene carbopalladation/allylic alkylation sequence and its application to the synthesis of a new aza analogue of naturally occurring (+)-oxo-parabenzlactone was

Full text of DOI:10.1002/chem.200900184

DOI: 10.1002/chem.200900184
Phosphine-Free Palladium-Catalyzed Allene Carbopalladation/Allylic
Alkylation Domino Sequence: A New Route to 4-(a-Styryl) g-Lactams
Claire Kammerer, Guillaume Prestat,* David Madec, and Giovanni Poli*[a]
Dedicated to our friend and colleague Professor Max Malacria on the occasion of his 60th birthday
In recent decades, allene chemistry has gained a tremen-
dous importance, in particular in the field of transition-
metal catalysis.[1] Effective and straightforward methods for
the synthesis of carbo- and heterocycles have emerged,[2]
due to the unique reactivity of allenes toward arylpalladium
Scheme 1. Palladium-catalyzed carbopalladation/allylic alkylation domino
species. Indeed, the carbopalladation of a 1,2-diene takes
sequence toward the synthesis of 4-(a-styryl) g-lactams. EWG=electron-
place regioselectively, generating a transient p-allyl inter-
withdrawing group; PG=protecting group.
mediate,[3] which can in turn be trapped by an internal nu-
cleophile. The overall process usually requires phosphine li-
gands, which are generally associated with some major
drawbacks, such as air-sensitivity, toxicity, and high cost.
Nevertheless, allenes tethered to carbon nucleophiles or het-
eronucleophiles have been intensively used as linear precur-
sors of carbo-[4] and heterocycles[5] respectively. However,
the synthesis of heterocycles from allene-tethered carbon
nucleophiles has only been scarcely reported.[6]
Our ongoing research is focussed on the development of
new transition-metal-catalyzed domino processes,[7] with a
particular interest in the synthesis of pyrrolidin-2-ones.[8] Ac-
cordingly, we envisioned that a Pd-catalyzed carbopallada-
tion/allylic alkylation sequence would be an efficient way to
obtain 4-(a-styryl) g-lactams starting from a linear allenyl
amide precursor (Scheme 1). This pure domino process[9]
allene carbopalladation/allylic alkylation sequence, and its
application to the synthesis of a new aza analogue of natu-
rally occurring (+)-oxo-parabenzlactone.
The sodium enolate of allenyl malonamide 1 and 4-iodo-
toluene (1.2 equivalents) were chosen as model coupling
partners to test the carbopalladation/allylic alkylation se-
quence (Table 1). Catalytic systems based on palladium di-
acetate (10 mol%) and biphosphine ligands (20 mol%) such
as 4-bis(diphenyl
ACHTUNGTRENUNpNG hosphanyl)ethane (dppe) or 9,9-dimethyl-
4,5-bis(diphenylphosphanyl)xanthene (xantphos) did not
AHCTUNGTRENNUNG
lead to the expected lactam. Instead, partial decomposition
of the starting allene occurred upon heating in THF at 558C
for 1.5 h (Table 1, entries 1 and 2). Encouragingly, use of Pd-
AHCTUNGRTEG(NUNN OAc)2 with 1,1’-bis(diphenylphosphanyl)ferrocene (dppf)
ꢀ
would allow the formation of two new C C bonds in a
single synthetic operation, along with the installation of two
contiguous stereocenters.
as a ligand afforded regioselectively the desired 4-styrylpyr-
rolidin-2-one as a single trans diastereoisomer in 38% yield
and 64% conversion (Table 1, entry 3). Increasing the reac-
tion time to 5 h allowed complete conversion of the starting
material and increased the yield to 58% (Table 1, entry 4).
In agreement with results reported by Ma and Zhao,[10] the
addition of a catalytic amount of tetrabutylammonium bro-
mide (20 mol%) led to a dramatic reaction rate enhance-
ment, affording an increased yield of 64% in only 1.5 h
(Table 1, entry 5). The influence of the solvent was next
studied. 1,4-Dioxane appeared slightly less effective than
THF (58% vs. 64%; Table 1, entry 6), whereas nonpolar sol-
vents, such as toluene and dichloromethane, led to dimin-
ished yields of 28% and 20%, respectively (Table 1, en-
tries 7 and 8). Acetonitrile led to almost complete degrada-
Herein we report an original regio- and stereoselective
heterocycle synthesis by
a phosphine-free Pd-catalyzed
[a] C. Kammerer, Dr. G. Prestat, Dr. D. Madec, Prof. G. Poli
Institut Parisien de Chimie Molꢀculaire UMR CNRS 7201, FR2769
Institut de Chimie Molꢀculaire
UPMC Universitꢀ Paris 06, 4 Place Jussieu, case 183
75005, Paris (France)
Fax : (+33)144274287
E-mail: guillaume.prestat@upmc.fr
giovanni.poli@upmc.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900184.
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Chem. Eur. J. 2009, 15, 4224 – 4227

COMMUNICATION
Table 1. Optimization of the reaction conditions.[a]
tams 5, 6, and 7 in 81%, 88%,
and 81% (57:43 mixture of
atropoisomers) yields, respec-
tively.
The effect of electron-with-
drawing substituents was next
investigated (Scheme 2). Reac-
tions of 4-nitro-, 4-trifluoro-
methyl-, 4-acetyl-, and 4-(me-
Entry
Catalytic system
Solvent
Conversion [%][b]
Yield [%][c]
thoxycarbonyl)iodobenzene
1
2
3
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
THF
THF
THF
THF
THF
1,4-dioxane
toluene
CH2Cl2
CH3CN
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
64
76
64
100
100
100
100
26
Traces
0
38
gave satisfactory yields of 71%
(8), 77% (9), 80% (10), and
78% (11), respectively. When
4-bromoiodobenzene was used
as coupling partner, pyrrolidin-
2-one 12 was obtained as the
sole product in 81% yield. 5-
Iodo-1,3-benzodioxole and the
sterically hindered 9-iodophe-
nanthrene yielded the expected
lactams 13 and 14 in 67% and
61% (59:41 mixture of atro-
poisomers) yields, respectively.
Heteroaromatic iodides also
gave satisfactory results. 3-Io-
dothiophene and 3-iodopyri-
dine reacted smoothly, afford-
ing the expected products 15
and 16 in 82% and 69%
4[d]
5[e]
6[e]
7[e]
8[e]
9[e]
10[e]
11[e]
12[e]
13[e]
14[e]
15
58
64
58
28
20
0
76
88
11
90
64
62
[f]
88
100
100
32
100
100
100
ACHTUNGTRENNUNG[Pd CHTUNGTRENNUNG
T
N
N
CHTUNGTRENNUNG
R
CHTUNGTRENNUNG
[a] Reagents and reaction conditions: allenyl malonamide 1 (0.1 mmol), 4-iodotoluene (0.12 mmol), NaH
(0.12 mmol), Pd(OAc)2 (0.01 mmol), [Pd2A(dba)3] (0.005 mmol), or [PdCl2A(CH3CN)2] (0.01 mmol), phosphine
ligand or nBuLi (0.02 mmol) in the appropriate solvent (2 mL) at 558C for 1.5 h. [b] Consumption of 1 as de-
termined by H NMR spectroscopy. [c] Based on H NMR spectroscopy, with butadiene sulfone as internal ref-
erence. [d] The reaction was stirred at 558C for 5 h. [e] nBu4NBr (0.02 mmol) was added. [f] The reaction mix-
ture was heated at reflux.
A
G
CHTUNGTRENNUNG
1
1
tion of the starting allene (Table 1, entry 9). DMF and
DMSO greatly improved the yield of the g-lactam to 76%
and 88%, respectively (Table 1, entries 10 and 11). As sulf-
oxides are able to coordinate to transition metals, and espe-
cially palladium species,[11] we reasoned that DMSO could
play a dual role, behaving simultaneously as a solvent and
as a ligand for palladium. To test this hypothesis, the catalyt-
yields, respectively.
In all the cases studied, the carbopalladation/allylic alkyla-
tion sequence yielded the desired 3,4-disubstituted lactam as
a sole trans diastereoisomer. Such a stereochemical outcome
was unambiguously assigned for compound 8, whose X-ray
crystal structure showed a 3,4-trans configuration of the pyr-
rolidin-2-one (Figure 1),[14] extended by analogy to all the
other lactams described in Scheme 2.
ic system Pd
ACHTUNGTRENNUNG
free Pd0 complex [Pd
C
A mechanistic proposal for the carbopalladation/allylic al-
kylation domino sequence is depicted in Scheme 3. Oxida-
tive addition of the aryl iodide on Pd0 affords the aryl palla-
dium species I. Coordination of one of the allene double
bonds to the electrophilic complex I and subsequent carbo-
palladation affords the p-allyl species II. Trapping of II by
the internal active methylene affords the 5-exo cyclization
product thereby releasing the active catalytic species.
The domino sequence was next applied to the synthesis of
the racemic aza analogue 19 of (+)-oxo-parabenzlactone, a
naturally occurring lignan (Scheme 4).[15] The pyrrolidin-2-
one 13 was first submitted to demethoxycarbonylation[16] to
yield the expected g-lactam 17 in 92% yield. Functionaliza-
tion at position 3 using lithium 2,2,6,6-tetramethylpiperidide
(LiTMP), hexamethylphosphoramide (HMPA), and piper-
onyl bromide afforded the expected benzylated lactam 18 in
75% yield as a single trans diastereoisomer.[17,18] Finally, a
ruthenium tetroxide-mediated oxidative cleavage[19] afforded
the desired oxo-parabenzlactone aza analogue 19 in 75%
yield.
Unfortunately, these conditions led to a poor yield (11%;
Table 1, entry 12). As dba is known to be a non-innocent
ligand,[12] a dba-free system was also studied. Accordingly, a
phosphine-free Pd0 complex was generated in DMSO from
[PdCl2ACHTUNGTRENNUNG(CH3CN)2], by using nBuLi (2 equiv) as an in situ re-
ducing agent.[13] The desired product was obtained in 90%
yield, thereby demonstrating the catalytic efficiency of this
phosphine-free system (Table 1, entry 13). Finally, omission
of either nBuLi or nBu4NBr, as shown by control experi-
ments, lowered the yields to 64% and 62%, respectively
(Table 1, entries 14 and 15).
Using the optimized phosphine-free conditions, the scope
of the domino sequence was next examined on a 0.5 mmol
scale, with various aryl iodides (Scheme 2). 4-Iodotoluene
and 3-iodotoluene afforded the pyrrolidin-2-ones 2 and 3,
isolated in 88% and 80% yields, respectively. The use of
simple iodobenzene led to the lactam 4, which was isolated
in 85% yield. Electron-rich 4-, 3-, and 2-iodoanisoles all re-
acted smoothly, affording the expected corresponding lac-
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G. Prestat, G. Poli et al.
Scheme 3. Mechanistic proposal for the carbopalladation/allylic alkyla-
tion domino sequence.
Scheme 2. Scope of the domino sequence (all reactions were run on a
0.5 mmol scale, yields refer to isolated product).
Scheme 4. Synthesis of the oxo-parabenzlactone aza analogue (ꢁ)-19:
a) NaCl, H2O, DMSO, microwave, 2008C, 1 h, 92%; b) LiTMP, HMPA,
THF, ꢀ788C, 2 h then piperonyl bromide, ꢀ788C, 3 h then ꢀ788C!RT,
overnight, 75%; c) RuCl3·ACTHUNGTERNN(GNU H2O)n, NaIO4, CH3CN/CCl4/H2O, RT, 1 h30,
75%.
In conclusion, we have developed a phosphine-free carbo-
palladation/allylic alkylation sequence allowing the synthesis
of 4-(a-styryl) g-lactams. High yields were obtained for elec-
tron-rich as well as electron-poor aryl iodides. The domino
sequence is completely regio- and stereoselective in favor of
the 5-exo trans product. Finally, the sequence was applied to
the synthesis of a new aza analogue of oxo-parabenzlactone.
Experimental Section
General procedure for the domino sequence: Sodium hydride (24 mg,
0.6 mmol, 1.2 equiv, 60% dispersion in mineral oil) was added to a solu-
tion of allenyl malonamide 1 (144 mg, 0.5 mmol) in freshly distilled
DMSO (8 mL) under an argon atmosphere. In another flask, nBuLi
(50 mL, 0.1 mmol, 20 mol%, 2.0m solution in hexanes) was added drop-
Figure 1. X-Ray crystal structure of compound 8 (see Scheme 2) with
thermal ellipsoids set at 50% probability and hydrogen atoms partially
omitted for clarity.
wise to a solution of [PdCl2ACHTUNTRGNE(NUG MeCN)2] (13 mg, 50 mmol, 10 mol%) in dis-
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Phosphine-Free Palladium-Catalyzed Allene Carbopalladation/Allylic Alkylation
COMMUNICATION
tilled DMSO (2 mL) under an argon atmosphere. The appropriate aro-
matic iodide (0.6 mmol, 1.2 equiv) and nBu4NBr (32 mg, 0.1 mmol,
20 mol%) were successively introduced, and the solution containing the
enolate of 1 was added through a cannula. The resulting mixture was
stirred at 558C and the completion of the reaction was monitored by
TLC. The reaction was quenched with a saturated solution of NH4Cl and
the aqueous layer was extracted with dichloromethane. The combined or-
ganic layers were washed with a saturated solution of NaCl, dried on
MgSO4 and concentrated in vacuo. The crude product was purified by
flash column chromatography on silica gel.
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Acknowledgements
CNRS and UPMC are acknowledged for financial support. The sponsor-
ship of COST Action D40 “Innovative Catalysis: New Processes and Se-
lectivities” is kindly acknowledged.
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Received: January 21, 2009
Published online: March 19, 2009
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