Hydrolytic deallylation of N-allyl amides catalyzed by PdII complexes

Article abstract of DOI:10.1002/ejoc.200800771

Hydrolytic deallylation of N-allyl amides to give amides and propanal can be achieved with Pd^II catalysts. The optimized catalyst consists of Pd(OCOCF₃)₂ and 1,3-bis(diphenylphosphanyl) propane (DPPP). Several kinds of open-chain N-allyl amides and N-allyl lactams undergo hydrolytic deallylation to give the corresponding amides and lactams in good to high yield. A mechanism which includes isomerization to enamides and subsequent hydrolysis is proposed. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800771

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800771
Hydrolytic Deallylation of N-Allyl Amides Catalyzed by PdII Complexes
Naoya Ohmura,[a] Asami Nakamura,[a] Akiyuki Hamasaki,[a] and Makoto Tokunaga*[a]
Keywords: Amides / Allylic compounds / Hydrolysis / Homogeneous catalysis / Palladium
Hydrolytic deallylation of N-allyl amides to give amides and
propanal can be achieved with PdII catalysts. The optimized
catalyst consists of Pd(OCOCF3)2 and 1,3-bis(diphenylphos-
phanyl)propane (DPPP). Several kinds of open-chain N-allyl
amides and N-allyl lactams undergo hydrolytic deallylation
to give the corresponding amides and lactams in good to high
yield. A mechanism which includes isomerization to en-
amides and subsequent hydrolysis is proposed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
which the complex also catalyzes both the isomerization
step to enamides and the oxidative cleavage step with stoi-
chiometric KIO4.[7] This method is applicable for a wide
range of substrates to provide the products in high yields,
however, alkene or diol functional groups may be oxidized
at the same time. Since we have focused on utilizing water
and alcohols as reagent for organic reactions,[8] we have ex-
plored the possibilities of hydrolytic deallylation of N-allyl
amides. This paper describes the first one-pot deallylation
of N-allyl amides using PdII catalysts employing water as
reagent which possess high atom efficiency.
Introduction
The allyl group is one of the most versatile protecting
groups in organic synthesis. This group is used for the pro-
tection of various functional groups such as alcohols, phe-
nols, carboxylic acids, phosphoric acids, amines and amides
because of its stability towards both acidic and basic condi-
tions.[1] A traditional approach for deprotection of the allyl
group is isomerization to the 1-propenyl group and subse-
quent hydrolysis or oxidation.[1] In recent decades, several
single-step mild deprotection procedures have been devel-
oped including Pd-catalyzed Tsuji–Trost reaction-based
methods,[2] Rh-[2c] and Ru-catalyzed[3] hydrolysis or
alcoholysis. However, in spite of the importance of amides
and lactams in pharmacology and natural product chemis-
try, there are only few single-step procedures for the cleav-
age of the allyl group from nitrogen. In a pioneering work
for using the allyl group for the protection of nitrogen in a
β-lactam synthesis, it took four steps for the removal.[4] The
use of current ruthenium chemistry allows a two-step se-
quence:[5] isomerization to the 1-propenyl isomer with a
Grubbs-type catalyst, then cleavage leading to the N–H
form by NaIO4 oxidation with RuCl3 as a catalyst.[5c,5d]
More recently, two types of one-pot deallylation methods
have been reported.[6,7] Zacuto et al. developed a one-pot
deallylation method using unadorned RhCl3 as catalyst and
1-propanol as reagent.[6] The key to success in this case is
the dual function of RhCl3 in alcohol solvents, which pro-
vides an active rhodium hydride species that catalyzes the
isomerization of N-allyl amides to the corresponding en-
amides but also generates HCl to hydrolyze to amides. Cad-
ierno et al. developed a RuIV-complex-catalyzed method in
Results and Discussion
The hydrolysis of N-allyl amides was examined with sev-
eral Pd precursors and ligands. N-Allyl-N-methylbenzamide
(1) was chosen for the screening, 1 mol-% of catalyst and
20 equiv. of water in MeCN were stirred at 80 °C for 20–24
h (Table 1). When PdCl2(MeCN)2 was used as palladium
source, reactions in the absence of ligand gave almost no
conversion of 1 (Table 1, entry 1), and the addition of 5,5Ј-
dimethylbipyridine did not improve the catalytic activity
(Table 1, entry 2). However, the hydrolyzed amide was ob-
tained in 41% yield when PPh3 was added as ligand
(Table 1, entry 3). When Pd(OCOMe3)2 was used, the sub-
strate 1 remained intact under the examined conditions
(Table 1, entries 4 and 5). Generally higher conversions
were observed when Pd(OCOCF3)2 was used as catalyst
precursor. In the absence of a ligand, the product was ob-
tained in 2% yield (Table 1, entry 6), addition of pyridine
derivatives decreased the activity (Table 1, entries 7 and 8).
Increased activity was observed in the presence of phos-
phane ligands (Table 1, entries 9–23). Among the tested
monodentate ligands, S-Phos showed the highest activity
and the product was obtained in 81% yield (Table 1, entry
12). On the other hand, bidentate phosphanes were also
effective for the reaction. In both cases, P/Pd = 2 exhibited
the best performance in this reaction. When P/Pd was lower
[a] Department of Chemistry, Graduate School of Science, Kyushu
University
6-10-1, Hakozaki, Higashi-ku 812-8581, Japan
Fax: +81-92-642-7528
E-mail: mtok.scc@mbox.nc.kyushu-u.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Catalyzed Hydrolytic Deallylation of N-Allyl Amides
than 2, rapid formation of Pd-black was observed, however, 1–4). However, the four-, five- and six-membered cyclic sub-
when the ratio was larger than 2, the reaction became slug- strates 5–7 were found to have lower reactivity. Using higher
gish. Among the examined bidentate ligands, DPPP was catalyst loadings (5 mol-%), 7 was hydrolyzed to give the de-
found to be most effective and afforded the hydrolyzed sired product in 99% yield, however, 5 and 6 gave the prod-
product in 92% yield (Table 1, entry 17). DPPP in combina- uct only in moderate yield and mainly 1-propenyl amides
tion with a different Pd source, such as PdCl2(MeCN)2 and remained unhydrolyzed (Table 3, entries 5–7). Lactam sub-
Pd(OCOMe)2, was examined but yields were low (Table 1, strates having a seven- (8), or eight-membered ring (9) readily
entries 18 and 19), therefore we conclude that Pd(OCOCF3)2/ underwent the hydrolysis reaction (Table 3, entries 8 and 9).
DPPP is the optimized catalyst system.
The reactions with the N-allylcarbamates 10 and 11 afforded
the products in good yield (100 and 90%, Table 3, entries 10
Table 1. Pd-catalyzed hydrolytic deallylation of 1.[a]
Entry Catalyst
Ligand
Time [h] Yield [%]
1
2
3
4
5
6
7
8
PdCl2(MeCN)2 none
20
20
20
20
20
24
24
24
20
20
20
20
20
20
20
20
20
20
20
20
24
24
20
1
0
41
0
0
2
PdCl2(MeCN)2 5,5Ј-dimethylbipyridine[b]
[c]
PdCl2(MeCN)2 PPh3
Pd(OCOMe)2
Pd(OCOMe)2
none
PPh3
[c]
Pd(OCOCF3)2 none
Pd(OCOCF3)2 5,5Ј-dimethylbipyridine[b]
3
0
Pd(OCOCF3)2 pyridine[c]
[c]
9
Pd(OCOCF3)2 PPh3
Pd(OCOCF3)2 P(4-CF3C6H4)3
Pd(OCOCF3)2 P(cyclohexyl)3
67
18
7
81
12
5
38
58
92
34
1
83
43
36
32
Table 2. Solvent effect on the Pd-catalyzed hydrolytic deallylation
[c]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
of 1.[a]
[c]
Pd(OCOCF3)2 S-Phos[c,d]
Pd(OCOCF3)2 BINAP[b,e]
Pd(OCOCF3)2 XANTPHOS[b,f]
Pd(OCOCF3)2 DPPM[b, g]
Pd(OCOCF3)2 DPPE[b,h]
Pd(OCOCF3)2 DPPP[b,i]
PdCl2(MeCN)2 DPPP[b,i]
Entry
Solvent
Yield [%]
1
2
3
4
5
THF
DME
1,4-dioxane
2-propanol
MeCN
18
26
26
50
92
Pd(OCOMe)2
DPPP[b,i]
Pd(OCOCF3)2 DPPB[b,j]
Pd(OCOCF3)2 DPPPent[b,k]
Pd(OCOCF3)2 DPPHex[b,l]
Pd(OCOCF3)2 DPPF[b,m]
[a] The reactions were carried out on 1-mmol scale and the yield
was determined by GC analysis.
[a] The reactions were carried out on 1-mmol scale and the yield
was determined by GC analysis. [b] 1 mol-% of ligand was used. [c]
2 mol-% of ligand was used. [d] S-Phos: 2-dicyclohexylphosphanyl-
2Ј,6Ј-dimethoxy-1,1Ј-biphenyl. [e] BINAP: 2,2Ј-bis(diphenylphos-
phanyl)-1,1Ј-binaphthyl. [f] XANTPHOS: 4,5-bis(diphenylphos-
phanyl)-9,9-dimethylxanthene. [g] DPPM: 1,1-Bis(diphenylphos-
phanyl)methane. [h] DPPE: 1,2-Bis(diphenylphosphanyl)ethane. [i]
DPPP: 1,3-Bis(diphenylphosphanyl)propane. [j] DPPB: 1,4-Bis(di-
phenylphosphanyl)butane. [k] DPPPent: 1,5-Bis(diphenylphos-
phanyl)pentane. [l] DPPHex: 1,6-Bis(diphenylphosphanyl)hexane.
[m] DPPF: 1,1Ј-Bis(diphenylphosphanyl)ferrocene.
Table 3. Pd-catalyzed hydrolytic deallylation from N-allyl amides.[a]
Entry
Sub-
strate
Catalyst loadings
[mol-%]
Time
[h]
Yield
[%]
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
9
2[b]
2[b]
2[b]
2[b]
5[c]
5[c]
5[c]
2[b]
2[b]
2[b]
2[b]
20
20
20
20
24
24
24
24
20
17
23
100
99
100
100
40
53
99
100
100
100
90
Table 2 displays solvent effects on this reaction. Several
water-miscible solvents were tested and acetonitrile was
found to be the best solvent (Table 2, entry 5, cf. entries 1–
4). In this study, the reactions were generally conducted un-
der N2 atmosphere, while slight decrease of the product yield
was observed when the reactions were carried out under air
atmosphere. Then substrate generality was explored with an
optimized catalyst system. Several kinds of N-allyl amides
9
10
11
10
11
(1–11)
were
examined
with
2–5 mol-%
Pd-
(OCOCF3)2/DPPP catalyst (Table 3). The reactions with
open-chain substrates 1–4 proceeded smoothly and afforded
[a] The reactions were carried out on 1-mmol scale and the yield
was determined by GC analysis. [b] 2 mol-% of ligand was used.
the hydrolyzed product almost quantitatively (Table 3, entries [c] 5 mol-% of ligand was used.
Eur. J. Org. Chem. 2008, 5042–5045
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. Ohmura, A. Nakamura, A. Hamasaki, M. Tokunaga
SHORT COMMUNICATION
and 11). Then optically pure compounds 12 and 13 were
examined in order to examine the stability of the stereochem-
ical center (Scheme 1). In both cases, the enantiomeric excess
of the amides did not change during the reactions. In ad-
dition, Boc and methyl ester groups stayed intact under the
reaction condition. A previous two-step deallylation method
needs 6  HCl under reflux conditions for 2 hours to hy-
drolyze an enamide.[1f] Under these conditions, Boc protect-
ing groups or methyl ester functions will not be tolerated.
Scheme 2. Hydrolytic deallylation on 30 mmol scale.
amides and allyl alcohols via the formation of a π-allyl
complex. Facile formation of π-allyl Pd complexes is gen-
erally recognized and a number of nucleophilic reagents
have been developed.
Scheme 3. Possible pathways of Pd-catalyzed hydrolytic deal-
lylation of N-allyl amides.
To the best of our knowledge, addition of water to π-
allyl Pd complexes has not been reported except for the bu-
tadiene telomerisation which includes bis(π-allyl)Pd inter-
mediates.[9] In addition, Zacuto et al. mentioned that Pd0
complexes did not give any products in their preliminary
investigation of deallylation.[6] In our Pd-catalyzed reaction,
propanal was detected by GC and GC-MS in each run,
the molar amounts of which are close to the corresponding
amides (Scheme 4). Additionally, when H218O was used as
hydrolysis reagent, 18O was incorporated into the aldehyde
which was confirmed by GC-MS analysis.
Scheme 1. Hydrolytic deallylation of optically active N-allyl amides.
The described catalytic hydrolysis reaction has a wide
substrate scope, but there are a few limitations: N-allyl
amides and imides of type 14–18 afford the desired products
only in very low yields (Ͻ 20%). Substrates 14–16 seem to
undergo further hydrolysis and give several by-products. In
contrast, 17 does not undergo hydrolysis but gives an iso-
merized compound (1-propenyl imide, suggested by GC-
MS). The substrate 18 bearing a formyl group does not re-
act.
Scheme 4. Pd-catalyzed hydrolytic deallylation of 8 with 18O-lab-
eled water.
Next, a 30 mmol scale reaction with 8 was carried out
Based on these observations, the enamide pathway (1)
with Pd(OCOCF3)2/DPPP as catalyst. The reaction pro- seems to be plausible in this reaction like with other RhI-
ceeded smoothly to give the product in 100% GC yield and catalyzed reactions.[1b,1c,d,e,2c,6] In the case of the RhI-cata-
in 91% isolated yield by silica-gel column chromatography lyzed allyl isomerization to 1-propenyl group, Rh–H species
(Scheme 2).
are expected to catalyze the first isomerization step. On the
A brief mechanistic study on the Pd-catalyzed hydrolysis other hand, for the Pd-catalyzed reaction, although there are
reaction was carried out. Scheme 3 illustrates the possible examples of PdII-catalyzed allyl amides and Pd/C-catalyzed
two pathways of the reaction. Pathway (1) involves isomer- allylamines isomerization to enamides[1f] and enamines[1h]
ization of N-allyl amides to give enamides and subsequent respectively, the detail mechanism of this isomerization step
hydrolysis to amides and aldehydes, while pathway (2) gives is unclear and requires investigations in the future.
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Eur. J. Org. Chem. 2008, 5042–5045

Catalyzed Hydrolytic Deallylation of N-Allyl Amides
RALCEL OD-H, eluent: hexane/2-propanol = 20:1, 1 mL/min); N-
(1-phenylethyl)acetamide [5.00 min: (R)-isomer, 8.15 min: (S)-iso-
mer], methyl 2-tert-butoxycarbonylamino-3-phenylpropionate [7.83
min: (R)-isomer, 8.86 min: (S)-isomer].
An intermediate enamide substrate 19 prepared from 8
with a Ru-catalyst was easily hydrolyzed under the same
conditions used for the Pd-catalyzed hydrolytic deallylation
of 9 [Scheme 5, Equation (5)]. In addition, the N-vinyl
amide substrate 20, which cannot afford π-allyl intermedi-
ate, was also hydrolyzed to give amide and acetaldehyde by
use of the same Pd catalyst system [Scheme 5, Equation
(6)]. We think the mechanism of hydrolysis step is similar
Supporting Information (see also the footnote on the first page of
this article): Detailed preparation and spectroscopic data of N-allyl
amide substrates are presented.
to the Pd-complex-catalyzed vinyl ester hydrolysis,[8d] which Acknowledgments
contains side-on coordination of C=C bond of vinyl group
The present work was supported by a Grant-in-Aid for Global
to the Pd center. There is also the possibility of catalysis by
small amounts of Brønsted acid generated by the catalyst
like in other RhI-catalyzed reactions.[6] Actually, hydrolysis
of 19 with 4 mol-% HCl under the similar condition gave
the product quantitatively. In this case we cannot conclude
which is responsible for the second hydrolysis step. For the
somewhat related vinyl ether hydrolysis and alcoholysis re-
actions, we were able to achieve Pd-catalyzed kinetic resolu-
tion of chiral substrates with high selectivity.[8e] Therefore,
although the substrates are readily hydrolyzed with
Brønsted acids in this case, the Pd-catalyzed mechanism is
still operative under the reaction conditions. Further studies
toward elucidation of the mechanism are running.
Centers of Excellence (G-COE) program, “Kyushu University, Sci-
ence for Future Molecular Systems” from the Ministry of Educa-
tion, Culture, Science, Sports and Technology of Japan. This work
is also supported by the New Energy and Industrial Technology
Development Organization (NEDO), Industrial Technology Re-
search Program (project ID 05A47001d). We thank Professor Kat-
suki and his group for permission to use their NMR equipment.
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Scheme 5. Hydrolytic deallylation of N-1-propenyl and N-vinyl
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Conclusions
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A one-pot hydrolytic deallylation procedure for N-allyl
amides has been realized with Pd(OCOCF3)2/DPPP cata-
lyst system. The reaction possesses high atom efficiency and
can be performed under mild conditions. Since the catalyst
consists of a Pd-precursor and phosphanes, there is some
potential to apply the reaction in asymmetric synthesis.
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Experimental Section
Typical Procedure for the Hydrolytic Deallylation of N-Allyl
Amides: Under N2 atmosphere, a 20 mL Schlenk tube was charged
with Pd complex (0.01 mmol), phosphane (P/Pd = 2), acetonitrile
(1 mL), H2O (360 µL), diglyme (35 µL, internal standard). The
mixture was stirred at room temperature for 10 min. Then N-allyl
amide (1 mmol) was introduced and stirring continued at 80 °C for
17–24 h. After cooling to room temperature, the yield of the prod-
uct was determined by GC analysis. For the reactions of 12, 13 and
a 30 mmol scale reaction of 8, the product was purified by silica-
gel column chromatography. Enantiomeric excess of the products
amides were determined by HPLC analysis (DAICEL CHI-
[9] K. E. Atkins, W. E. Walker, R. M. Manyik, J. Chem. Soc.,
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Received: August 6, 2008
Published Online: September 16, 2008
Eur. J. Org. Chem. 2008, 5042–5045
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www.eurjoc.org
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