Palladium-catalyzed allylation of α -nitroacetates with propynes

Article abstract of DOI:10.1080/00397911.2014.928939

A novel way to synthesize allylated α-nitroacetates under Pd catalysis has been described. Reactions of propynes with diverse α-nitroacetates in the presence of a catalytic amount of Pd(PPh₃)₄ and HOAc in 1,4-dioxane afforded the corresponding allylated products in good yields. Compared with other known methods, this method of synthesizing allylated α-nitroacetates generated no waste and needed neither a stoichiometric amount of base nor a leaving group.

Full text of DOI:10.1080/00397911.2014.928939

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Palladium-Catalyzed Allylation of α-
Nitroacetates with Propynes
Shanshan Yao a , Jidan Liu a , Zhiyong Yang a , Qingwen Gui a , Xiang
Chen a , Ze Tan a & Ping Li a
a State Key Laboratory of Chemo/biosensing and Chemometrics ,
College of Chemistry and Chemical Engineering, Hunan University ,
Changsha , China
Accepted author version posted online: 16 Jul 2014.Published
online: 04 Sep 2014.
To cite this article: Shanshan Yao , Jidan Liu , Zhiyong Yang , Qingwen Gui , Xiang Chen , Ze
Tan & Ping Li (2014) Palladium-Catalyzed Allylation of α-Nitroacetates with Propynes, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:21, 3165-3172, DOI: 10.1080/00397911.2014.928939
To link to this article: http://dx.doi.org/10.1080/00397911.2014.928939
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Synthetic Communications1, 44: 3165–3172, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.928939
PALLADIUM-CATALYZED ALLYLATION OF
a-NITROACETATES WITH PROPYNES
Shanshan Yao, Jidan Liu, Zhiyong Yang, Qingwen Gui,
Xiang Chen, Ze Tan, and Ping Li
State Key Laboratory of Chemo=biosensing and Chemometrics, College of
Chemistry and Chemical Engineering, Hunan University, Changsha, China
GRAPHICAL ABSTRACT
Abstract A novel way to synthesize allylated a-nitroacetates under Pd catalysis has been
described. Reactions of propynes with diverse a-nitroacetates in the presence of a catalytic
amount of Pd(PPh3)4 and HOAc in 1,4-dioxane afforded the corresponding allylated
products in good yields. Compared with other known methods, this method of synthesizing
allylated a-nitroacetates generated no waste and needed neither a stoichiometric amount of
base nor a leaving group.
Keywords a-Nitroacetate; allylation; Pd catalysis; propynes; Tsuji–Trost reaction
INTRODUCTION
The palladium-catalyzed allylic alkylation (Tsuji–Trost reaction) has been
widely recognized as one of the most powerful methods for the construction of
carbon–carbon bonds.[1] Typically these allylic alkylations are carried out with an
allylic electrophile, a pronucleophile, and a stoichiometric amount of base to react
with the pronucleophile to generate the real nucleophile (-Nu). Though highly
efficient, like most other cross couplings, a leaving group (-X) is liberated in the reac-
tion and some type of salt was formed as the by-product, thus limiting the overall
atom economy. To overcome this problem, Kadota et al. have shown that the
palladium-catalyzed allylation reactions can be performed by reacting a propyne
derivative with methylmalononitrile in the presence of a catalytic amount of AcOH
[Scheme 1, Eq. (1)].[2] Not only were the allylated products obtained with excellent
Received April 7, 2014.
Address correspondence to Shanshan Yao, State Key Laboratory of Chemo=biosensing and
Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082,
P. R. China. E-mail: ztanze@gmail.com
3165

3166
S. YAO ET AL.
Scheme 1. Pd-catalyzed allylation of pronucleophiles with alkynes.
regioselectivities, but also the reaction can be adapted to an intramolecular version
to afford cyclic products. More importantly, the reaction was achieved with 100%
atom efficiency, which means no waste was generated in the process. They also
showed that the same type of allyation can be extended to pronucleophiles such as
cyanoesters and disulfonylmethanes. Later on, by using a different ligand in
combination with a catalytic amount of benzoic acid, they also demonstrated that
ketoesteres [Eq. (2)],[3,4] phenyl amines, and simple aldehydes [Eq. (3)][5] can also par-
ticipate in this type of allylation reactions. Even more impressively, when a suitable
chiral ligand was used together with the Pd catalyst, they were able to use malononi-
triles [Eq. (4)], alcohols [Eq. (5)], and amines as the pronucleophiles as well.[6] In
addition, they were also able to synthesize heterocycles and carbocycles in good to
excellent enantioselectivites (ees).[6] Building upon these results, Ni and Hu recently
also reported that fluorine-containing sulfones can be used to serve as pronucleo-
philes to allylate propyne derivatives [Eq. (6)].[7] Based on their results, Yamamoto

ALLYLATION OF a-NITROACETATES WITH PROPYNES
3167
believed that these reactions go through hydropalladation–dehydropalladation–
rehydropalladation of the propyne to give a p-allylpalladium intermediate, which
subsequently react with the pronucleophile to give the desired allylated product.
Inspired by these results, we wondered if other nucleophiles can also be used to par-
ticipate in this type of allylation. Herein we report that in the presence of Pd catalyst
and a catalytic amount of AcOH, nitroacetate can also be used to react with pro-
pynes to give allylated nitroacetates [Eq. (7)].[8]
RESULTS AND DISCUSSION
2-Substituted nitroacetates constitute a class of valuable intermediates for the
synthesis of a large variety of organic compounds, particularly for the synthesis of
amino acids.[9–11] They are frequently prepared from the parent nitroacetates by
the classical alkylation procedure, the SN2 reaction.[9,10] Among the various alkyla-
tions, allylation stands out from the rest because allylations are much more favorable
and generally can be run under relatively mild conditions. Inspired by Yamamoto’s
results and the fact that nitroacetates can also be used to participate in the classical
Tsuji–Trost reaction,[12,13] we attempted to use propyne to allylate nitroacetates
under Yamamoto’s condition. At the outset of our study, we decided to use the
reaction of 1-phenyl-1-propyne (1a) with ethyl 2-nitrobutanoate (2a) as our model
reaction. When we treated 1-phenyl-1-propyne with 1 equiv of ethyl 2-nitrobutano-
ate in the presence of Pd(PPh3)4 (10 mol%) and acetic acid (50 mol%) in dioxane at
80 ꢀC for 12 h, much to our delight, the desired product (E)-ethyl 2-ethyl-2-nitro-
5-phenylpent-4-enoate (3a) was isolated in 53% yield (Table 1, entry 1). It should
be noted that the addition took place on the propargyl position only and the stereo-
chemistry of the double was exclusively E, based on the large coupling constant
observed for the two olefinic hydrogens. When the temperature was elevated to
100 ꢀC, the yield was increased to 77% (Table 1, entry 2). In contrast, the reaction
was rather sluggish when the reaction was run at 60 ꢀC (Table 1, entry 3). When
the Pd source was switched to either Pd(OAc)2 or Pd2(dba)3, 3a was only isolated
in <10% yield (Table 1, entries 4 and 5). The use of PdCl2(PPh3)2 instead of
Pd(PPh3)4 also led to much lower yield (Table 1, entry 6). These results showed
the use of Pd(0) catalyst in combination with a ligand is essential for achieving good
yield. Next we tried to examine the reaction using other solvents. Unfortunately, the
use of solvents such as CH3CN, dimethylsulfoxide (DMSO), and dimethylforma-
mide (DMF) all resulted in disappointing yields (Table 1, entries 7–9). Moreover,
increasing the amount of acetic acid in the reaction did not affect the yield much
(Table 1, entries 10 and 11). On the other hand, lowering the amount of AcOH
used led to much lower yield of 3a (Table 1, entries 12 and 13). In addition, we
found that when AcOH was substituted with benzoic acid, the reaction of 1a with
2a only gave 3a in 23% yield (Table 1, entry 14) We also found that no product
was formed when no acetic acid was added to the reaction mixture (Table 1, entry
15). Control reaction also indicated no reaction took place in the absence of Pd cata-
lyst (Table 1, entry 16). On the basis of these results, we decided to run the reaction
in 1,4-dioxane at 100 ꢀC for 15 h with propyne (1 equiv), nitroacetate (1 equiv),
Pd(PPh3)4 (10 mol%), and acetic acid (50 mol%) under a balloon of nitrogen as our
standard condition.

3168
S. YAO ET AL.
Table 1. Reaction condition optimizationa
Entry
Pd catalyst
Solvent
Acid (equiv)
Temperature (ꢀC)
Yield (%)b
1
2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
—
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
CH3CN
DMSO
HOAc (0.5)
HOAc (0.5)
HOAc (0.5)
HOAc (0.5)
HOAc (0.5)
HOAc (0.5)
HOAc (0.5)
HOAc (0.5)
HOAc (0.5)
HOAc (0.7)
HOAc (1.0)
HOAc (0.1)
HOAc (0.3)
PhCOOH (0.5)
—
80
100
60
53
77
3
16
9
4
100
100
100
100
100
100
100
100
100
100
100
100
100
5
4
24
6
7
45
33
8
9
DMF
25
75
10
11
12
13
14
15
16
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
73
21
39
23
Trace
Trace
HOAc (0.5)
aUnless specified otherwise, all reactions were carried out under a balloon of nitrogen by treating 1a
(1 equiv) with 2a (1 equiv), Pd(PPh3)4 (10 mol%) in dioxane (3 mL) at 100 ꢀC for 15 h.
bIsolated yields.
With the optimized protocol in hand, we next set out to explore the scope
and limitation of the reaction. We first tried to test the allylation reaction on the
2-unsubstituted 2-nitroacetate. When we treated ethyl 2-nitroacetate with 1-phenyl-
1-propyne under our standard condition, we found that both mono-allylated and dia-
llylated products were formed in 65% yield with a ratio of 2.2=1. Because the selectivity
is rather poor, we focused our study using 2-substituted 2-nitroacetates to avoid the
diallylation problem and the results are summarized in Table 2. As we expected, the
reaction worked satisfactorily for various substituted 1-phenyl-1-propynes and nitroa-
cetates. From the table, we can see substituents such as methoxy and ethoxy were well
tolerated on the benzene ring (Table 2, entries 3–10). Gratifyingly, we found that sub-
strates with electron-withdrawing groups such as acetyl and pentanoyl on the benzene
ring also reacted satisfactorily, affording the desired products in 65–78% yields
(Table 2, entries 11–18). In addition, the substituent on the a-carbon of 2-nitroacetates
can also be replaced by different groups such as methyl, n-butyl, and benzyl groups,
affording the desired allylated products in good yields. From the table, we do see
slightly better yields were obtained with electron-donating groups such as methoxy
or ethoxy groups than electron-withdrawing groups. We can also see a gradual yield
drop as the substituent size on the a-carbon of 2-nitroacetates was increased. This is
probably due to the increasing steric hindrance on the reaction site.
To see whether propargyl ether and amine derivatives are suitable substrates,
we synthesized substrates bearing methoxy, benzyloxy, and dimethylamino groups

ALLYLATION OF a-NITROACETATES WITH PROPYNES
3169
Table 2. Pd-catalyzed allylation of ethyl 2-nitroacetates with 1-phenyl-1-propynesa
Entry
1
Substrate
Product Yield (%)b (dr)c Entry
Substrate
Product Yield (%)b (dr)c
=
=
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
H
3b
3c
3d
3e
3f
82 (—)
87 (—)
80 (—)
87 (—)
84 (—)
90 (—)
80 (—)
92 (—)
89 (—)
95 (—)
68 (—)
12
13
14
15
16
17
18
19
20
21
22
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
H
3m
3n
3o
3p
3q
3r
70 (—)
69 (—)
67 (—)
72 (—)
78 (—)
76(—)
1
1
=
=
H
CH3
CH3CO
=
C2H5
2
2
=
=
=
H
2
3
H
1
1
=
=
H
n-C4H9
CH3CO
=
n-C4H9
2
2
=
=
=
H
H
1
1
=
=
MeO
CH3
CH3CO
=
PhCH2
2
2
=
=
=
H
4
H
1
1
=
=
MeO
C2H5
n-C4H9CO
=
CH3
2
2
=
=
=
H
5
H
1
1
=
=
MeO
n-C4H9
n-C4H9CO
=
C2H5
2
2
=
=
=
H
6
H
3g
3h
3i
1
1
=
=
MeO
PhCH2
n-C4H9CO
=
n-C4H9
2
2
=
=
=
H
7
H
3s
71(—)
1
1
=
=
EtO
CH3
n-C4H9CO
=
PhCH2
2
2
=
=
=
1
8
H
OCH3
3t
39 (1.7:1)
35 (1.1:1)
27 (1:1)
25 (1.1:1)
1
=
=
H
EtO
C2H5
2
2
=
=
CH3
OCH3
=
=
1
9
H
3j
3u
3v
3w
1
=
=
H
EtO
n-C4H9
2
2
=
=
C2H5
OCH2Ph
=
=
10
11
H
3k
3l
1
1
=
=
H
EtO
PhCH2
2
2
=
=
CH3
=
=
H
OCH2Ph
1
1
=
=
H
CH3CO
CH3
2
2
=
=
C2H5
aAll reactions were carried out under dry nitrogen atmosphere using 10 mol% Pd(PPh3)4 and 50 mol%
HOAc in dioxane (3 mL) at 100 ꢀC for 15 h.
bIsolated yields.
cThe diastereomeric ratios were determined from the 1H NMR spectra of the isolated product mixtures.
on the 3-position of 1-phenyl-1-propyne accordingly. Under the standard reaction
conditions, propargyl amine derivative failed to react with 2a. This might be because
the amine has reacted with AcOH to form the corresponding ammonium salt, thus
shutting down the isomerization reaction pathway (see the mechanism discussion
part). On the other hand, propargyl ether derivative did react with 2a to deliver
the desired products 3t–3w in 25–39% yields (Table 2, entries 19–22). From the

3170
S. YAO ET AL.
Scheme 2. Possible mechanism for the Pd(0)=HOAc-catalyzed allylation of a-nitroacetates with propynes.
results, we do see yields are generally much lower than the parent alkynes, which
might be due to the large steric hindrance imposed by the methoxy and benzyloxy
groups. Additionally, the diastereomeric ratios observed are between 1:1 to 1.7:1,
showing that the diastereoselectivities are quite poor.
Based on previous literature reports,[2–5,7] a plausible mechanism for this allyla-
tion was proposed and is illustrated in Scheme 2. The initial step would be hydropal-
ladation of 4 with the hydridopalladium species 6 generated from Pd0 and acetic acid
(catalytic cycle I). The resultant vinyl palladium species 7 next underwent dehydro-
metallation to produce phenyl allene 8 and Pd-hydride 6. Next, rehydropalladation
of 8 with 6 would give the p-allylpalladium intermediate 9, which subsequently
reacted with nitroacetate to give the desired product 5 along with Pd(0) catalyst, thus
completing the catalytic cycle II.
In summary, we have developed a novel way of synthesizing allylated 2-nitroa-
cetates from 1-phenyl-1-propynes and ethyl 2-nitroacetates. By treating 1-phenyl-1-
propynes and ethyl 2-nitroacetates with Pd(PPh3)4 and acetic acid in 1,4-dioxane at
100 ꢀC for 15 h, a variety of allylated nitroacetates were synthesized in good yields. It
is important to point out that this reaction requires neither a stoichiometric amount
of base nor a leaving group. Detailed mechanistic investigation on this reaction is
still ongoing and the results will be reported in due course.
EXPERIMENTAL
All solvents and reagents were purchased from the suppliers and used without
further purification.1H NMR and 13C NMR were recorded in CDCl3 at room
1
temperature on the Varian Inova-400 spectrometer (400 MHz H) and Bruker spec-
1
trometer (400 MHz H). The chemical-shift scale is based on internal tetramethyl-
silane (TMS). All reactions were carried out under a dry nitrogen atmosphere.
General Reaction Procedure
Acetic acid (14 mL, 0.5 mmol) was added to a mixture of 1-phenyl-1-propyne
(1a, 1.0 mmol), ethyl 2-nitrobutanoate (2a, 1.0 mmol), and Pd(PPh3)4(116 mg,

ALLYLATION OF a-NITROACETATES WITH PROPYNES
3171
0.1 mmol) in dry dioxane (3 mL), and the mixture was stirred at 100 ꢀC for 15 h under
a balloon of nitrogen. After cooling to room temperature, the reaction mixture was
diluted with dichloromethane (25 mL) and water (25 mL). The aqueous layer was
extracted with dichloromethane (3 ꢁ 25 mL) and washed with brine. The organic
layers were combined, dried with MgSO4, and filtered, and the solvent was removed
under reduced pressure. The residue was purified by flash column chromatography
on silica gel (petroleum ether=ethyl acetate ¼ 50:1) to afford the desired product
(E)-ethyl 2-ethyl-2-nitro-5-phenylpent-4-enoate (3a) in 77% yield.
(E)-Ethyl 2-Ethyl-2-nitro-5-phenylpent-4-enoate (3a)[14]
1
Yield: 77%; yellow oil. H NMR (CDCl3, 400 MHz,) d7.32–7.25 (m, 5H), 6.50
(d, J ¼ 15.6 Hz, 1H), 5.96 (dt, J ¼ 15.6 Hz, 7.4 Hz, 1H), 4.28 (q, J ¼ 6.4 Hz, 2H),
3.15–3.04 (m, 2H), 2.36–2.20 (m, 2H), 1.28 (t, J ¼ 7.0 Hz, 3H), 0.96 (t, J ¼ 6.8 Hz,
3H); 13C NMR (CDCl3, 100 MHz) d 166.48, 136.38, 135.70, 128.56, 127.88,
126.34, 120.58, 96.18, 62.66, 37.07, 27.02, 13.90, 7.93; MS (m=z, %): 277 [Mþ]; IR
= cmꢂ1: 2939, 1749 (COO), 1608 (C C), 1554 (NO2).
=
FUNDING
Z. T. thanks the National Science Foundation of China (No. J1210040) and the
Fundamental Research Fund for the Central Universities, Hunan University, for
financial support.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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