Pd(0)-catalyzed [1,5]-sigmatropic hydrogen shift of propargylic esters toward substituent naphthylamines

Article abstract of DOI:10.1021/jo1024267

A novel and convenient carboannulation method for the synthesis of highly substituted naphthylamine derivatives has been developed though a Pd(0)-catalyzed [1,5]-sigmatropic hydrogen shift and cyclization reaction of propargyl esters.

Full text of DOI:10.1021/jo1024267

NOTE
pubs.acs.org/joc
Pd(0)-Catalyzed [1,5]-Sigmatropic Hydrogen Shift of Propargylic
Esters toward Substituent Naphthylamines
Shu-Chun Zhao, Xing-Zhong Shu, Ke-Gong Ji, An-Xi Zhou, Ting He, Xue-Yuan Liu, and Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P.R. China
S Supporting Information
b
ABSTRACT: A novel and convenient carboannulation method for the
synthesis of highly substituted naphthylamine derivatives has been
developed though a Pd(0)-catalyzed [1,5]-sigmatropic hydrogen shift
and cyclization reaction of propargyl esters.
he development of catalytic reactions which involve the
cleavage of C-H bonds is one of the most challenging
Initial studies showed that substrates with the benzyl position
substituted by a nitrogen atom worked in palladium catalysis.
When we treated propargylic ester 1a (0.1 mmol), K2CO3 (0.2
mmol), Pd2(dba)3 (10 mmol %), and PPh3 (20 mmol %) in
DMF (1 mL) under argon atmosphere at 100 °C, naphthylamine
product 2a9 was isolated in 30% yield after 4 h (Table 1, entry 1).
Further investigation revealed that the reaction will benefit from
the addition of a weakly inorganic base such as KOAc, the
increase of base loading, and the higher reaction temperature
(Table 1, entries 2-9). Except for DMF, neither polar nor
nonpolar solvents gave acceptable results (Table 1, entries 10-
13). The effect of ligand should be noted. When monodentate
phosphine ligands such as P(o-tolyl)3 or P(2-furyl)3 were used,
an almost quantitative yield of desired product was obtained,
whereas bidentate phosphine ligands, like dppe and dppp, failed
to improve the yield of product 2a (Table 1, entries 14, 15 vs 16,
17). Compared with Pd2(dba)3, other precatalysts were less
effective (Table 1, entries 18-20). Thus, the use of 10 mol % of
Pd2(dba)3, 20 mol % of P(o-tolyl)3, and 3 equiv of KOAc in DMF
at 120 °C were found to be the most efficient and were used as
the standard.
Under the optimized reaction conditions, the scope of this
reaction was then examined. The results are summarized in
Table 2. Apart from the phenyl group, various aryl substituents
were tolerated at the propargylic position (Table 2, entries 1-8).
Propargylic esters with electron-rich aryl groups always gave
better yields than the ones with electron-withdrawing substitu-
ents. The electron effect also appeared in methyl-substituted
substrates 1e (para position) and 1f (ortho position), which
afforded the desired products in 71% and 59% yields, respectively
(Table 2, entries 5 vs 6). When alkyl substituents were investi-
gated, we failed to obtain any desired product (Table 2, entry 9).
Interestingly, when a methyl group was introduced to the
benzene ring, an excellent yield of naphthylamine 2j was
T
projects in organic synthesis.1 Despite significant progress in this
area, catalytic transformations of sp3 C-H bonds to C-C bonds
still remain rare.2 Among powerful methods for this purpose, the
tandem [1,5]-hydride transfer/cyclization reaction is an attrac-
tive strategy. The most typical examples of this internal redox
process involve the coupling of sp3 C-H bonds with double
bonds (Scheme 1a).3 In this process, activation of an electron-
deficient alkene by a Lewis acid triggers a 1,5-hydride transfer and
the formation of carbocation, which induces the cyclization of the
C-C bond. More recently, the strategy has been extended to the
coupling of sp3 C-H with triple bonds (Scheme 1b,c).4 How-
ever, except for limited examples when a terminal alkyne group
was used to form a metal allene intermediate to induce a 1,5-
hydride transfer (Scheme 1c),4d-4f a strong electron-withdraw-
ing group on the terminal position of the double or triple bond
was needed in almost all cases. This strongly restricts its applica-
tion, although the process has been applied in some cases, such as
the synthesis of (-)-PNU-286607.5
Very recently, we have extended the cascade [1,5]-hydride
transfer/cyclization reaction to propargylic ester via platinum
catalysis.6 The key steps involve a [1,5]-hydride transfer to allene
intermediate, which is formed by platinum-catalyzed 1,3-OAc
migration of the propargylic ester (Scheme 2a). However, the
reaction is limited in naphthalenyl acetate synthesis. Previously
introduced heteroatom groups are lost in most cases. On the
basis of our works on palladium-catalyzed transformation of
propargylic ester,7 we envisioned that the allene palladium
intermediate might also induce the [1,5]-hydride transfer in
suitable systems (Scheme 2b). Furthermore, because of the high
tendency for the C-Pd bond to participate in insertion and β-
elimination processes,8 the reaction might afford products dif-
ferent from that obtained by using a platinum catalyst. Herein, we
reported our new results in the study of the cascade [1,5]-hydride
transfer/cyclization reaction involving the propargylic ester
group via palladium catalysis.
Received: December 16, 2010
Published: February 11, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
obtained, whereas chloro-substituted substrate only gave 21%
yield of product 2k (Table 2, entries 10 and 11).
product, demonstrating the fact that the acyl substituent is
required to activate the R C(sp3)-H bond adjacent to the
nitrogen in the [1,5]-hydride transfer/cyclization reaction. When
the nitrogen atom was protected by one acyl substituent, like
substrate 1p, the corresponding naphthylamine 2p was obtained
in only 30% yield, compared with 70% yield of 2l synthesized
from methyl-substituted amide 1l. This might be due to that the
amide with low electron density in nitrogen will benefit the 1,5-
hydride transfer as shown in Scheme 3.
Furthermore, to expand the scope of this reaction, we also
investigated a range of propargylic esters 1l-p with different R3
and R4 groups. It was found that under the optimized conditions,
the substrates 1l-n with an electron-withdrawing acyl substitu-
ent were transferred into naphthylamines 2l-n in moderate to
good yields, as depicted in Table 3. However, the substrate like
1o with two methyl groups cannot afford the corresponding
Additionally, we also investigated a range of propargylic
carbonates 1q-t, as depicted in Table 4. It was found that
Scheme 1. General Groups Used for Tandem [1,5]-Hydride
Transfer/Cyclization Reactions
Scheme 2. Propargylic Ester Applied for Tandem [1,5]-Hy-
dride Transfer/Cyclization Reactions
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
Pd2(dba)3
base (equiv)
ligand (mol %)
solvent
T (°C)
yield (%)b
1
2
K2CO3 (2)
Cs2CO3 (2)
KOt-Bu (2)
NaOAc (2)
Et3N (2)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
P(2-furyl)3 (20)
P(o-tolyl)3(20)
dppe (10)
dppp (10)
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
THF
100
100
100
100
100
100
100
100
120
100
100
100
100
120
120
120
120
100
100
100
30
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd2(dba)3 3 CH3Cl
Pd(OAc)2
15
Dc
3
4
26
5
NRd
30.8
49
6
DMAP (2)
KOAc (2)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (3)
7
8
67
9
75
10
11
12
13
14
15
16
17
18
19
20
NRd
NRd
20
NMP
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
40
95
98
23
49
20
PPh3 (20)
32
PPh3 (30)
18
a Unless otherwise specified, the reaction was carried out by using 1a (0.20 mmol), Pd catalysts (10 mol %), and bases in solvent (2 mL) under Ar
atmosphere for 2 h . b Isolated yield. c Decomposed. d No reaction.
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The Journal of Organic Chemistry
NOTE
Table 2. Scope Studies of Pd-Catalyzed Synthesis of
Naphthylamine 2a
Table 3. Scope Studies of Pd-Catalyzed Synthesis of
Naphthylamine 2a
a Unless otherwise specified, the reaction was carried out by using 1 (0.2
mmol), Pd2(dba)3 (10 mol %), P(o-tolyl)3 (20 mol %), and KOAc (3
equiv) in DMF (2 mL), at 120 °C under argon atmosphere. b Isolated
yield. c Decompose.
a Unless otherwise specified, the reaction was carried out by using 1 (0.2
mmol), Pd2(dba)3 (10 mol %), P(o-tolyl)3 (20 mol %), and KOAc (3
equiv) in DMF (2 mL), at 120 °C under argon atmosphere. b Isolated
yield. c No reaction.
Table 4. Study the Scope of Propargylic Carbonate 1q-ta
under the optimized conditions, only substrate 1q afforded
the naphthylamine 2a in moderate yield (entry 1). Other
propargylic carbonates 1r-t gave only modest results (entries
2-4).
The deuterium-labeling experiments (Scheme 3) showed that
the deuterium on the benzyl position transferred into the C5
position of the ester after reaction. This observation is consistent
with our proposed mechanism, as depicted in Scheme 3. This
plausible mechanism involves the following key steps: (a) Pd(0)-
catalyzed transformation of the propargylic compound D-1u
generates allenylpalladium intermediate B. (b) Then the 1,5-D
transfer process, which might be promoted by the nitrogen atom,
affords the intermediate C.3-6 (c) Finally the direct 6π cycliza-
tion of compound C leads to the intermediate E, which under-
goes a 1,3-H shift10 and a hydrogen elimination affording the final
product D-2u (path I). Alternatively, the intermediate G may
also be formed after a 1,3-palladium shift of the intermediate C.11
The insertion of the C-Pd bond, following hydrogen elimina-
tion, affords the product D-2u (path II).
a Unless otherwise specified, the reaction was carried out by using 1 (0.2
mmol), Pd2(dba)3 (10 mol %), P(o-tolyl)3 (20 mol %), and KOAc (3
equiv) in DMF (2 mL), at 120 °C under argon atmosphere. b Isolated
yield.
In conclusion, we have developed a novel and convenient
carboannulation method for the synthesis of highly substituted
naphthylamine derivatives through Pd(0)-catalyzed [1,5]-sigma-
tropic hydrogen shift of propargyl esters. The study of details of
the reaction mechanism is in progress.
chromatography, the reaction mixture was allowed to cool to room
temperature and quenched by a saturated aqueous solution of ammo-
nium chloride. After being extracted with ethyl acetate, the combined
organic extracts were washed with water and saturated brine and dried
over Na2SO4. Solvents were evaporated under reduced pressure. The
residue was purified by chromatography on silica gel, using hexane-
ethyl acetate (4:1), to afford 2a (54.3 mg, 98%) as a solid. Mp 169-
172 °C; 1H NMR (400 MHz, CDCl3) δ 7.93-7.89 (m, 2 H), 7.78-7.76
(d, J = 8.0 Hz, 1 H), 7.59-7.39 (m, 8 H), 3.52-3.46 (m, 1 H), 3.12-
3.05 (m, 1 H), 2.70-2.61 (m, 1 H), 2.50-2.41 (m, 1 H), 2.19-2.04 (m,
1 H), 1.89-1.79 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 176.4,
139.4, 138.2, 133.9, 132.0, 130.1, 128.7, 128.6, 128.5, 128.4, 128.0, 127.7,
127.4, 126.4, 122.8, 49.9, 31.1, 19.4; IR (neat, cm-1) 3359, 3054, 2923,
2889, 1681, 1410; (ESI)HRMS found m/z 288.1378, calcd for
C20H17NO (M þ H)þ 288.1383.
’ EXPERIMENTAL SECTION
General Procedure for the Palladium-Catalyzed 1,5-Hy-
dride Shift and Cyclization Reaction of Propargylic Ester
1a. A mixture of 3-(2-((2-oxopyrrolidin-1-yl)methyl)phenyl)-1-phe-
nylprop-2-ynyl acetate 1a (69.5 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg,
10% mmol), KOAc (58.8 mg, 0.6 mmol), P(o-tolyl)3 (12.2 mg, 20%
mmol), and DMF(2 mL) was placed in a 20 mL tube under argon
atmosphere. The resulting mixture was then heated at 120 °C. When the
reaction was considered complete as determined by thin-layer
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The Journal of Organic Chemistry
NOTE
Scheme 3. Deuterium-Labeling Experiments and Proposed
Mechanism
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determined by X-ray crystallography, for details see the Supporting
Information.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dure and copies of H NMR and 13C NMR spectra of all
1
compounds and X-ray data of 2a in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: liangym@lzu.edu.cn.
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’ ACKNOWLEDGMENT
We are grateful for the National Science Foundation (NSF-
21072080) for financial support. We acknowledge the National
Basic Research Program of China (973 Program,
2010CB833203).
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