Catalytic allylation of stabilized phosphonium ylides with primary allylic amines

Article abstract of DOI:10.1021/jo401736k

A range of ketone-stabilized phosphonium ylides were allylated with high regioselectivity by primary allylic amines in the presence of 5 mol % Pd(PPh₃)₄ and 10 mol % B(OH)₃, and subsequent one-pot Wittig olefination gave structurally diverse α,β-unsaturated ketones in good to excellent overall yields with excellent E selectivity. The one-pot allylation/olefination reaction was extended to ester- and nitrile-stabilized phosphonium ylides by replacing B(OH)₃ with TsOH, and the corresponding α,β-unsaturated esters and nitriles were obtained in moderate overall yields.

Full text of DOI:10.1021/jo401736k

Note
pubs.acs.org/joc
Catalytic Allylation of Stabilized Phosphonium Ylides with Primary
Allylic Amines
Xian-Tao Ma,† Yong Wang,† Rui-Han Dai,† Cong-Rong Liu,†,‡ and Shi-Kai Tian*,†,§
†Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
‡Department of Environmental Engineering, Nanjing Institute of Technology, Nanjing, Jiangsu 211167, China
§Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A range of ketone-stabilized phosphonium ylides
were allylated with high regioselectivity by primary allylic amines
in the presence of 5 mol % Pd(PPh3)4 and 10 mol % B(OH)3,
and subsequent one-pot Wittig olefination gave structurally
diverse α,β-unsaturated ketones in good to excellent overall yields
with excellent E selectivity. The one-pot allylation/olefination
reaction was extended to ester- and nitrile-stabilized phos-
phonium ylides by replacing B(OH)3 with TsOH, and the corresponding α,β-unsaturated esters and nitriles were obtained in
moderate overall yields.
he Tsuji−Trost reaction is powerful for the introduc-
ketone-stabilized phosphonium ylides with primary allylic amines.
Ttion of the allyl moiety to target compounds, permitting a Importantly, the resulting more highly substituted phospho-
nium ylides could be subjected to the Wittig reaction to afford a
range of structurally diverse α,β-unsaturated ketones in good to
excellent overall yields.
broad range of transformations such as oxidation, reduction,
and addition.1 While allylic halides and alcohol derivatives fre-
quently serve as electrophilic components in the Tsuji−Trost
reaction by exhibiting various reactivities and selectivities,2
allylic amines have rarely been employed directly as allylic electro-
philes because of the poor leaving ability and compatibility of
amino groups.3 However, it would be rewarding to develop the
corresponding reactions with allylic amines in regard to the
exploration of new reactivity and selectivity. Although in many
cases the synthetic routes to allylic amines are not shorter than
those to allylic halides and alcohol derivatives, allylic amines can
be readily purified in large quantities using simple extractive
procedures instead of routine chromatography because of their
basicity. Sporadic studies have shown that allylic amines can
undergo the Tsuji−Trost reaction with a few carbon,4 nitrogen,5
and sulfur nucleophiles.6,7 In most cases, secondary and tertiary
allylic amines have been employed as allylic electrophiles, and
only recently has appeared the disclosure of the Tsuji−Trost reac-
tion with primary allylic amines, which exhibits much higher atom
economy relative to that with commonly used allylic electro-
philes.4f,g,6b
The Tsuji−Trost reaction has recently been extended to the
allylation of stabilized phosphonium ylides, which affords more
highly substituted phosphonium ylides for the synthesis of
polysubstituted alkenes through the Wittig reaction.8,9 In 2010,
You and co-workers reported an elegant allylation reaction of
ester-stabilized phosphonium ylides with allylic carbonates in
the presence of [Pd(allyl)Cl]2/Trost ligand/Cs2CO3.10 In-
spired by this work, together with our interest in exploring new
reactions with allylic amines4f,g,6b and phosphonium ylides,11
we have realized a Pd(PPh3)4/B(OH)3-catalyzed allylation of
A 5 mol % loading of Pd(PPh3)4 was employed to catalyze
the allylation of phosphonium ylide 2a with primary allylic
amine 1a in acetonitrile under a nitrogen atmosphere at 100 °C,
and subsequently, the resulting mixture was treated with formal-
dehyde (formalin) at room temperature (Table 1, entry 1).
Whereas such a one-pot allylation/olefination sequence did not
give α,β-unsaturated ketone 3a at all, to our delight, addition of
10 mol % B(OH)3 to the allylation reaction mixture permitted
the synthesis of the desired product in 93% overall yield with
retention of the alkene geometry (Table 1, entry 2).4f,6b A few
other palladium catalysts, phosphine ligands, and acids were
examined, but none of them gave a better yield (Table 1,
entries 3−9). The reaction efficiency was also significantly
affected by the solvent, but a survey of common solvents
proved fruitless to improve the yield (Table 1, entries 10−15).
In the presence of 5 mol % Pd(PPh3)4 and 10 mol %
B(OH)3, a range of ketone-stabilized phosphonium ylides were
smoothly allylated by α-unbranched primary allylic amines in
an α-selective fashion, and subsequent one-pot olefination with
formaldehyde gave structurally diverse α,β-unsaturated ketones
in good to excellent overall yields with excellent E selectivity
(Table 2).12 It is noteworthy that the γ-positions of the primary
allylic amines could bear aryl, heteroaryl, and alkyl groups and
that the reaction tolerated allylic ethers (Table 2, entries 1−10).
When the γ-substituent was a benzyloxymethyl group, E to Z
Received: August 7, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401736k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Optimization of the Reaction Conditions
Table 2. Allylation of Ketone-Stabilized Phosphonium Ylides
with Primary Allylic Amines Followed by the Wittig
Reaction with Formaldehyde
a b
,
b
entry
[Pd]
ligand (mol %)
acid
none
solvent yield (%)
1
2
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]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
none
none
none
PPh3
PPh3
dppb
none
none
none
none
none
none
none
none
none
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
dioxane
DMSO
DMF
0
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
ZnCl2
93
31
37
86
83
92
80
87
42
52
62
trace
69
trace
c
entry
1
R1
2
R2
3
yield (%)
3
1
2
1a
1b
1c
1d
1e
1f
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
Ph
3a
3b
3c
3d
3e
3f
93
83
73
95
97
94
87
97
66
4
4-MeOC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5
3
4-Me2NC6H4
6
4
4-CF3C6H4
7
5
2-MeOC6H4
8
HOAc
6
1-naphthyl
9
TsOH
7
1g
1h
1i
3-pyridinyl
3g
3h
3i
10
11
12
13
14
15
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
8
3-thienyl
nPr
9
d
nPrOH
toluene
DCE
10
1j
BnOCH2
H
3j
68
e
11
1k
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
3k
3l
75
84
79
89
80
83
80
84
85
84
62
12
13
14
15
16
17
18
19
20
Ph
4-MeOC6H4
4-FC6H4
Ph
3m
3n
3o
3p
3q
3r
3s
3t
a
Reaction conditions: (1) amine 1a (0.36 mmol), phosphonium ylide
Ph
4-ClC6H4
4-O2NC6H4
2-MeC6H4
2-naphthyl
2-furyl
2a (0.30 mmol), [Pd] (5 mol %; for entries 3, 5, and 6, 2.5 mol %),
ligand (if any, 20 mol %; for entry 6, 10 mol %), acid (if any,
10 mol %), solvent (0.50 mL), 100 °C (oil bath), 10 h; (2) HCHO
Ph
Ph
b
Ph
2g
2h
2i
(3.0 equiv), rt, 6 h. Isolated yields (two steps).
Ph
Ph
2-thienyl
isomerization of the original allyl carbon−carbon double bond
was observed (Table 2, entry 10). Such a geometric isomeriza-
tion could be attributed to the coordination between the alkoxy
group and palladium in the π-allylpalladium intermediate
generated from the palladium catalyst and the allylic amine
(see below). Nevertheless, the reaction was not applicable to
α-unbranched primary allylic amines with β,γ- or γ,γ′-disubstitution
because of poor reactivity.13 On the other hand, suitable
nucleophiles include aryl, heteroaryl, alkenyl, and alkyl ketone-
stabilized phosphonium ylides (Table 2, entries 12−21).
In contrast, γ-selectivity was observed with an α-substituted
terminal allylic amine. For example, phosphonium ylide 2a was
allylated by α-phenyl allylamine (4) in a γ-selective fashion, and
subsequent one-pot olefination gave α,β-unsaturated ketone 3a
in 97% overall yield with exclusive E selectivity (eq 1). Such
Ph
2j
(E)-PhCHCH
f
21
Ph
2k
tBu
3u
a
Reaction conditions: (1) amine 1 (0.36 mmol), phosphonium ylide 2
(0.30 mmol), Pd(PPh3)4 (5 mol %), B(OH)3 (10 mol %), acetonitrile
(0.50 mL), 100 °C (oil bath), 10 h; (2) HCHO (3 equiv), rt, 6 h.
b
Unless otherwise stated, the product was obtained with >99:1 E/Z.
c
d
e
Isolated yields (two steps). 92:8 E/Z. The reaction of step 1 was
f
run in a sealed tube. The reaction of step 1 was run at 120 °C.
(42% or 40%) relative to primary allylic amine 1a (93%;
Table 2, entry 1).
The one-pot allylation/olefination sequence was extended to
ester- and nitrile-stabilized phosphonium ylides, but the desired
electron-poor alkenes were obtained in much lower yields.
To our delight, the yields could be significantly improved by
replacing B(OH)3 with TsOH, and consequently, the correspond-
ing α,β-unsaturated esters and nitriles were obtained in moderate
overall yields with retention of the alkene geometry (eq 3).
regioisomerization could be attributed to the selective attack
of phosphonium ylide 2a on the π-allylpalladium intermediate
generated from the palladium catalyst and the allylic amine
(see below). Probably as a result of steric hindrance, sluggish
reactions were observed with α,γ-disubstituted allylamines such
as (E)-4-phenylbut-3-en-2-amine.
Replacement of the NH2 group with a bulkier amino group
as the leaving group significantly decreased the reaction rate
for the allylation of ketone-stabilized phosphonium ylides
with allylic amines. As shown in eq 2, either secondary allylic
amine 1aa or tertiary allylic amine 1ab underwent one-pot
allylation/olefination under the same reaction conditions to
give α,β-unsaturated ketone 3a in a much lower overall yield
On the basis of our experimental results and previous mecha-
nistic studies,4f,6b,10 we propose the reaction pathway depicted
B
dx.doi.org/10.1021/jo401736k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2H), 7.56−7.49 (m, 1H), 7.45−7.40 (m, 2H), 7.37−7.34 (m, 2H),
7.30−7.26 (m, 2H), 7.22−7.16 (m, 1H), 6.50 (d, J = 15.6 Hz, 1H),
6.29 (dt, J = 15.6, 6.8 Hz, 1H), 5.93 (d, J = 0.8 Hz, 1H), 5.70 (d, J =
0.8 Hz, 1H), 3.37 (dd, J = 6.8, 0.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 197.7, 146.6, 137.7, 137.4, 132.5, 132.3, 129.5, 128.6, 128.3,
127.3, 126.7, 126.6, 126.2, 35.5; HRMS (EI) calcd for C18H16O (M)
248.1201, found 248.1196.
Scheme 1. Proposed Reaction Pathway
(E)-5-(4-Methoxyphenyl)-2-methylene-1-phenylpent-4-en-1-one
(3b). Colorless oil (69.2 mg, 83% yield); 1H NMR (400 MHz, CDCl3)
δ 7.76 (dd, J = 8.4, 1.6 Hz, 2H), 7.54−7.49 (m, 1H), 7.44−7.39 (m,
2H), 7.30−7.25 (m, 2H), 6.84−6.80 (m, 2H), 6.44 (d, J = 15.6 Hz,
1H), 6.14 (dt, J = 15.6, 7.2 Hz, 1H), 5.91 (d, J = 0.8 Hz, 1H), 5.68 (d,
J = 0.8 Hz, 1H), 3.77 (s, 3H), 3.34 (dd, J = 7.2, 0.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 197.8, 159.0, 146.9, 137.8, 132.2, 131.9, 130.2,
129.5, 128.2, 127.3, 126.5, 124.3, 114.0, 55.3, 35.5; HRMS (EI) calcd
for C19H18O2 (M) 278.1307, found 278.1301.
(E)-5-(4-(Dimethylamino)phenyl)-2-methylene-1-phenylpent-4-
en-1-one (3c). Colorless oil (63.6 mg, 73% yield); 1H NMR (400 MHz,
CDCl3) δ 7.77−7.74 (m, 2H), 7.55−7.50 (m, 1H), 7.45−7.40 (m,
2H), 7.25 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 6.41 (d, J =
15.6 Hz, 1H), 6.07 (dt, J = 15.6, 7.2 Hz, 1H), 5.91 (d, J = 0.8 Hz, 1H),
5.66 (d, J = 0.8 Hz, 1H), 3.33 (dd, J = 7.2, 0.8 Hz, 2H), 2.93 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 198.0, 149.9, 147.2, 137.8, 132.4,
in Scheme 1 for the allylation of stabilized phosphonium ylides
with primary allylic amines. The NH2 group in allylic amine 1 is
activated by B(OH)3, and the allylic carbon−nitrogen bond is
cleaved by palladium(0) to give π-allylpalladium 8,4f,6b the
allylic carbon of which is selectively attacked by phosphonium
ylide 2 to give phosphonium salt 9. Proton transfer of phosphonium
salt 9 gives phosphonium ylide 10 and ammonia14 and con-
currently regenerates palladium(0) and B(OH)3 to continue
the catalytic cycle. The subsequent one-pot Wittig reaction of
phosphonium ylide 10 with formaldehyde gives α,β-unsaturated
ketone 3.8
In summary, we have developed an unprecedented allylation
reaction of stabilized phosphonium ylides with allylic amines.
In the presence of 5 mol % Pd(PPh3)4 and 10 mol % B(OH)3, a
range of ketone-stabilized phosphonium ylides were smoothly
allylated by primary allylic amines in a highly regioselective
fashion, and subsequent one-pot Wittig olefination gave struc-
turally diverse α,β-unsaturated ketones in good to excellent
overall yields with excellent E selectivity. The one-pot allylation/
olefination reaction was extended to ester- and nitrile-stabilized
phosphonium ylides by replacing B(OH)3 with TsOH, and the
corresponding α,β-unsaturated esters and nitriles were obtained
in moderate overall yields.
132.2, 129.5, 128.2, 127.1, 126.3, 122.2, 112.6, 40.6, 35.5; HRMS (EI)
calcd for C20H21NO (M) 291.1623, found 291.1625.
(E)-2-Methylene-1-phenyl-5-(4-(trifluoromethyl)phenyl)pent-4-
1
en-1-one (3d). White solid (90.3 mg, 95% yield); mp 72−73 °C; H
NMR (400 MHz, CDCl3) δ 7.78−7.74 (m, 2H), 7.57−7.52 (m, 3H),
7.48−7.42 (m, 4H), 6.54 (d, J = 15.6 Hz, 1H), 6.40 (dt, J = 15.6, 6.4
Hz, 1H), 5.95 (d, J = 0.8 Hz, 1H), 5.74 (d, J = 0.8 Hz, 1H), 3.41 (d,
J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 197.5, 146.1, 140.8,
137.6, 132.3, 131.2, 129.6, 129.5, 128.3, 127.1, 126.3, 125.5 (q, J =
7.6 Hz), 35.5; HRMS (EI) calcd for C19H15OF3 (M) 316.1075, found
316.1061.
(E)-5-(2-Methoxyphenyl)-2-methylene-1-phenylpent-4-en-1-one
(3e). Colorless oil (80.9 mg, 97% yield); 1H NMR (400 MHz, CDCl3)
δ 7.79−7.76 (m, 2H), 7.55−7.50 (m, 1H), 7.45−7.40 (m, 3H), 7.21−
7.16 (m, 1H), 6.92−6.81 (m, 3H), 6.29 (dt, J = 16.0, 6.8 Hz, 1H), 5.94
(d, J = 0.8 Hz, 1H), 5.69 (d, J = 0.8 Hz, 1H), 3.83 (s, 3H), 3.39 (dd,
J = 6.8, 0.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 198.0, 156.6,
147.0, 137.9, 132.3, 129.7, 128.4, 128.3, 127.3, 126.8, 126.5, 120.8,
111.0, 55.6, 35.9; HRMS (EI) calcd for C19H18O2 (M) 278.1307,
found 278.1310.
(E)-2-Methylene-5-(naphthalen-1-yl)-1-phenylpent-4-en-1-one
1
(3f). White solid (84.1 mg, 94% yield); mp 68−69 °C; H NMR
(400 MHz, CDCl3) δ 8.08 (dd, J = 6.8, 2.4 Hz, 1H), 7.83−7.72 (m,
4H), 7.56−7.38 (m, 7H), 7.24 (d, J = 15.6 Hz, 1H), 6.29 (dt, J = 15.6,
6.8 Hz, 1H), 5.98 (s, 1H), 5.73 (s, 1H), 3.50 (d, J = 6.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 197.8, 146.7, 137.7, 135.2, 133.7, 132.3,
131.2, 129.9, 129.6, 128.5, 128.3, 127.7, 126.7, 126.0, 125.8, 125.7,
124.0, 123.8, 35.9; HRMS (EI) calcd for C22H18O (M) 298.1358,
found 298.1352.
EXPERIMENTAL SECTION
■
General Information. 1H NMR and 13C NMR spectra were
recorded using tetramethylsilane as an internal reference. Chemical
shifts (δ) and coupling constants (J) were expressed in parts per
million and hertz, respectively. High-resolution mass spectrometry
(HRMS) was performed on an LC-TOF spectrometer using electron
impact (EI) techniques. Melting points were uncorrected. All of the
starting allylic amines and phosphonium ylides are known compounds,
and they were prepared according to known procedures.4f,6b,11d
General Procedure for the Allylation of Stabilized Phos-
phonium Ylides with Primary Allylic Amines Followed by the
Wittig Reaction with Formaldehyde. A mixture of primary allylic
amine 1 (0.36 mmol), phosphonium ylide 2 (0.30 mmol), B(OH)3
(1.9 mg, 10 mol %), and Pd(PPh3)4 (17.3 mg, 5 mol %) in acetonitrile
(0.50 mL) was heated under nitrogen at 100 °C for 10 h. After the
reaction mixture was cooled to room temperature, formalin (37% w/w
HCHO in water, 0.068 mL, 0.90 mmol) was added, and the resulting
mixture was stirred for 6 h. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel chromatography,
eluting with ethyl acetate/petroleum ether (0:100−1:5), to give
compound 3.
(E)-2-Methylene-1-phenyl-5-(pyridin-3-yl)pent-4-en-1-one (3g).
1
White solid (65.1 mg, 87% yield); mp 51−52 °C; H NMR (400 MHz,
CDCl3) δ 8.59 (s, 1H), 8.45 (d, J = 3.6 Hz, 1H), 7.77 (dd, J = 8.4, 1.2
Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.58−7.53 (m, 1H), 7.47−7.42 (m,
2H), 7.25−7.21 (m, 1H), 6.50 (d, J = 16.0 Hz, 1H), 6.38 (dt, J = 16.0,
6.8 Hz, 1H), 5.96 (d, J = 0.8 Hz, 1H), 5.75 (d, J = 0.8 Hz, 1H), 3.41
(dd, J = 6.8, 0.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 197.5,
148.2, 148.0, 146.0, 137.6, 132.8, 132.3, 129.5, 129.4, 129.2, 128.8,
128.3, 127.1, 123.5, 35.6; HRMS (EI) calcd for C17H15NO (M)
249.1154, found 249.1142.
(E)-2-Methylene-1-phenyl-5-(thiophen-3-yl)pent-4-en-1-one (3h).
1
Colorless oil (74.2 mg, 97% yield); H NMR (400 MHz, CDCl3) δ
7.77−7.73 (m, 2H), 7.55−7.50 (m, 1H), 7.45−7.40 (m, 2H), 7.24−
7.16 (m, 2H), 7.10−7.08 (m, 1H), 6.52 (d, J = 15.6 Hz, 1H), 6.14 (dt,
J = 15.6, 7.2 Hz, 1H), 5.92 (d, J = 0.8 Hz, 1H), 5.70 (d, J = 0.8 Hz,
1H), 3.34 (dd, J = 7.2, 0.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
197.7, 146.6, 139.9, 137.7, 132.2, 129.5, 128.3, 126.8, 126.5, 125.9,
(E)-2-Methylene-1,5-diphenylpent-4-en-1-one (3a). Colorless oil
1
(69.4 mg, 93% yield); H NMR (400 MHz, CDCl3) δ 7.78−7.74 (m,
C
dx.doi.org/10.1021/jo401736k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
125.0, 121.3, 35.4; HRMS (EI) calcd for C16H14OS (M) 254.0765,
found 254.0763.
(E)-2-Methylene-1-(naphthalen-2-yl)-5-phenylpent-4-en-1-one
(3q). White solid (71.3 mg, 80% yield); mp 56−57 °C; 1H NMR (400
MHz, CDCl3) δ 8.27 (s, 1H), 7.95−7.84 (m, 4H), 7.61−7.49 (m, 2H),
7.37 (d, J = 7.6 Hz, 2H), 7.31−7.27 (m, 2H), 7.23−7.17 (m, 1H), 6.55
(d, J = 15.6 Hz, 1H), 6.34 (dt, J = 15.6, 7.2 Hz, 1H), 5.97 (s, 1H), 5.76
(s, 1H), 3.43 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
197.7, 146.8, 137.4, 135.3, 134.9, 132.6, 132.3, 131.1, 129.4, 128.6,
128.3, 128.2, 127.8, 127.3, 126.8, 126.6, 126.5, 126.2, 125.5, 35.6;
HRMS (EI) calcd for C22H18O (M) 298.1358, found 298.1365.
(E)-1-(Furan-2-yl)-2-methylene-5-phenylpent-4-en-1-one (3r).
(E)-2-Methylene-1-phenyloct-4-en-1-one (3i). Colorless oil (42.7 mg,
66% yield); 1H NMR (400 MHz, CDCl3) δ 7.77−7.73 (m, 2H), 7.55−
7.51 (m, 1H), 7.45−7.41 (m, 2H), 5.85 (d, J = 0.8 Hz, 1H), 5.62 (d,
J = 0.8 Hz, 1H), 5.57−5.42 (m, 2H), 3.15 (d, J = 6.4 Hz, 2H), 2.03−
1.96 (m, 2H), 1.43−1.35 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 198.1, 147.5, 137.9, 133.6, 132.2, 129.6, 128.3,
126.3, 125.8, 35.2, 34.7, 22.6, 13.7; HRMS (EI) calcd for C15H18O
(M) 214.1358, found 214.1364.
1
Colorless oil (60.0 mg, 84% yield); H NMR (400 MHz, CDCl3) δ
(E)-6-(Benzyloxy)-2-methylene-1-phenylhex-4-en-1-one (3j). Ob-
tained as a 92:8 mixture of E and Z isomers; colorless oil (59.6 mg,
68% yield); 1H NMR (400 MHz, CDCl3) δ 7.76−7.73 (m, 2H), 7.55−
7.50 (m, 1H), 7.44−7.40 (m, 2H), 7.36−7.25 (m, 5H), 5.89−5.65
(m, 4H), 4.50 (s, 2H), 4.01 (dd, J = 6.4, 0.8 Hz, 2H), 3.24 (d, J =
7.64 (dd, J = 1.6, 0.8 Hz, 1H), 7.36−7.14 (m, 6H), 6.53 (dd, J = 3.2,
1.6 Hz, 1H), 6.46 (d, J = 15.6 Hz, 1H), 6.24 (dt, J = 15.6, 7.2 Hz, 1H),
6.06 (d, J = 0.8 Hz, 1H), 5.84 (d, J = 0.8 Hz, 1H), 3.34 (dd, J = 7.2, 0.8
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 183.6, 152.0, 147.1, 146.3,
137.3, 132.5, 128.5, 127.3, 126.4, 126.2, 124.7, 119.9, 112.0, 35.4;
HRMS (EI) calcd for C16H14O2 (M) 238.0994, found 238.1007.
(E)-2-Methylene-5-phenyl-1-(thiophen-2-yl)pent-4-en-1-one (3s).
1
6.4 Hz, 2H); partial H NMR for the minor Z isomer δ 4.53 (s, 2H),
4.15 (d, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 197.6, 146.4,
138.4, 137.7, 132.2, 130.3, 129.5, 129.2, 128.4, 128.2, 127.8, 127.6,
126.6, 72.0, 70.5, 34.9; HRMS (EI) calcd for C20H20O2 (M) 292.1463,
found 292.1467.
1
Colorless oil (64.8 mg, 85% yield); H NMR (400 MHz, CDCl3) δ
7.70−7.63 (m, 2H), 7.37−7.17 (m, 5H), 7.13−7.09 (m, 1H), 6.48 (d,
J = 15.6 Hz, 1H), 6.26 (dt, J = 15.6, 7.2 Hz, 1H), 5.88 (d, J = 0.8 Hz,
1H), 5.81 (d, J = 0.8 Hz, 1H), 3.35 (dd, J = 7.2, 0.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 189.1, 147.0, 143.4, 137.3, 134.1, 133.9,
132.6, 128.5, 127.9, 127.3, 126.3, 126.2, 123.9, 35.8; HRMS (EI) calcd
for C16H14OS (M) 254.0765, found 254.0772.
2-Methylene-1-phenylpent-4-en-1-one (3k).15 Colorless oil
1
(38.9 mg, 75% yield); H NMR (400 MHz, CDCl3) δ 7.77−7.74
(m, 2H), 7.56−7.51 (m, 1H), 7.46−7.42 (m, 2H), 5.97−5.81 (m, 2H),
5.67 (s, 1H), 5.17−5.07 (m, 2H), 3.22 (d, J = 6.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 197.8, 146.5, 137.8, 135.0, 132.3, 129.6, 128.3,
126.5, 117.2, 36.3.
(1E,6E)-4-Methylene-1,7-diphenylhepta-1,6-dien-3-one (3t).
1
White solid (69.3 mg, 84% yield); mp 75−76 °C; H NMR (400 MHz,
(E)-1-(4-Methoxyphenyl)-2-methylene-5-phenylpent-4-en-1-one
(3l). White solid (70.4 mg, 84% yield); mp 38−39 °C; 1H NMR
(400 MHz, CDCl3) δ 7.84−7.79 (m, 2H), 7.36−7.33 (m, 2H), 7.30−
7.25 (m, 2H), 7.21−7.17 (m, 1H), 6.94−6.90 (m, 2H), 6.49 (d, J =
15.6 Hz, 1H), 6.28 (dt, J = 15.6, 7.2 Hz, 1H), 5.82 (d, J = 0.8 Hz, 1H),
5.61 (d, J = 0.8 Hz, 1H), 3.84 (s, 3H), 3.36 (dd, J = 7.2, 0.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 196.5, 163.2, 146.8, 137.4, 132.4,
CDCl3) δ 7.68 (d, J = 15.6 Hz, 1H), 7.60−7.55 (m, 2H), 7.41−7.17
(m, 9H), 6.47 (d, J = 15.6 Hz, 1H), 6.26 (dt, J = 15.6, 7.2 Hz, 1H),
6.13 (s, 1H), 5.88 (t, J = 1.6 Hz, 1H), 3.31 (dd, J = 7.2, 0.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 191.4, 148.4, 144.0, 137.4, 134.9,
132.3, 130.4, 128.9, 128.5, 128.4, 127.2, 127.0, 126.2, 124.4, 121.7,
34.8; HRMS (EI) calcd for C20H18O (M) 274.1358, found 274.1366.
(E)-2,2-Dimethyl-4-methylene-7-phenylhept-6-en-3-one (3u).
132.0, 130.1, 128.5, 127.3, 126.7, 126.2, 124.5, 113.6, 55.5, 35.9;
HRMS (EI) calcd for C19H18O2 (M) 278.1307, found 278.1305.
(E)-1-(4-Fluorophenyl)-2-methylene-5-phenylpent-4-en-1-one
(3m). Colorless oil (63.0 mg, 79% yield); 1H NMR (400 MHz,
CDCl3) δ 7.84−7.78 (m, 2H), 7.38−7.34 (m, 2H), 7.31−7.26 (m,
2H), 7.23−7.18 (m, 1H), 7.14−7.08 (m, 2H), 6.50 (d, J = 15.6 Hz,
1H), 6.27 (dt, J = 15.6, 7.2 Hz, 1H), 5.91 (s, 1H), 5.66 (s, 1H), 3.36
(dd, J = 7.2, 0.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 196.2, 165.3
(d, J = 252.2 Hz), 146.6, 137.3, 133.8 (d, J = 3.1 Hz), 132.6, 132.1 (d,
J = 9.0 Hz), 128.6, 127.3, 126.3, 126.2, 126.1, 115.4 (d, J = 21.7 Hz),
35.6; HRMS (EI) calcd for C18H15FO (M) 266.1107, found 266.1108.
(E)-1-(4-Chlorophenyl)-2-methylene-5-phenylpent-4-en-1-one
(3n). White solid (75.0 mg, 89% yield); mp 51−52 °C; 1H NMR (400
MHz, CDCl3) δ 7.73−7.68 (m, 2H), 7.44−7.18 (m, 7H), 6.50 (d, J =
15.6 Hz, 1H), 6.26 (dt, J = 15.6, 7.2 Hz, 1H), 5.94 (s, 1H), 5.67 (d, J =
0.4 Hz, 1H), 3.36 (dd, J = 6.8, 0.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 196.4, 146.5, 138.7, 137.3, 135.9, 132.7, 130.9, 128.6, 127.4,
126.7, 126.3, 126.2, 35.4; HRMS (EI) calcd for C18H15OCl (M)
282.0811, found 282.0815.
1
Colorless oil (42.4 mg, 62% yield); H NMR (400 MHz, CDCl3) δ
7.36−7.18 (m, 5H), 6.42 (d, J = 15.6 Hz, 1H), 6.17 (dt, J = 15.6,
7.2 Hz, 1H), 5.53 (s, 1H), 5.48 (t, J = 1.2 Hz, 1H), 3.14 (dd, J = 7.2,
1.2 Hz, 2H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 210.8,
146.9, 137.4, 132.5, 128.5, 127.3, 126.6, 126.1, 118.3, 44.1, 37.5, 27.8;
HRMS (EI) calcd for C16H20O (M) 228.1514, found 228.1519.
(E)-Ethyl 2-Methylene-5-phenylpent-4-enoate (6a).10 Colorless
1
oil (34.4 mg, 53% yield); H NMR (400 MHz, CDCl3) δ 7.37−7.18
(m, 5H), 6.44 (d, J = 16.0 Hz, 1H), 6.23 (dt, J = 16.0, 7.2 Hz, 1H),
6.22 (s, 1H), 5.61 (d, J = 0.8 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.21
(dd, J = 7.2, 0.8 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 167.0, 139.6, 137.5, 132.2, 128.6, 127.3, 126.9, 126.2,
125.4, 60.8, 35.2, 14.3.
(E)-2-Methylene-5-phenylpent-4-enenitrile (6b).16 Colorless oil
1
(29.4 mg, 58% yield); H NMR (400 MHz, CDCl3) δ 7.40−7.22 (m,
5H), 6.53 (d, J = 15.6 Hz, 1H), 6.15 (dt, J = 15.6, 6.8 Hz, 1H), 5.92
(s, 1H), 5.80 (t, J = 1.6 Hz, 1H), 3.14 (dd, J = 6.8, 1.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 136.6, 134.2, 130.8, 128.6, 127.8, 126.4,
123.2, 121.8, 118.5, 37.7.
(E)-2-Methylene-1-(4-nitrophenyl)-5-phenylpent-4-en-1-one (3o).
1
Light-yellow solid (70.3 mg, 80% yield); mp 78−79 °C; H NMR
Isolation of Phosphonium Ylide 10a. A mixture of primary
allylic amine 1a (47.9 mg, 0.36 mmol), phosphonium ylide 2a (114.0 mg,
0.30 mmol), B(OH)3 (1.9 mg, 10 mol %), and Pd(PPh3)4 (17.3 mg,
5 mol %) in acetonitrile (0.50 mL) was heated under nitrogen at 100 °C
for 10 h. After the reaction mixture was cooled to room temperature, the
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel chromatography, eluting with methanol/
dichloromethane (0:100 to 1:10), to give compound 10a (80.3 mg,
(400 MHz, CDCl3) δ 8.29 (dd, J = 6.8, 2.0 Hz, 2H), 7.86 (dd, J =
6.8, 2.0 Hz, 2H), 7.40−7.20 (m, 5H), 6.53 (d, J = 15.6 Hz, 1H), 6.27
(dt, J = 15.6, 7.2 Hz, 1H), 6.09−6.07 (m, 1H), 5.73 (s, 1H), 3.39 (dd,
J = 7.2, 0.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 195.7, 149.7,
146.4, 143.1, 137.1, 133.0, 130.2, 128.9, 128.6, 127.5, 126.2, 125.8,
123.5, 34.9; HRMS (EI) calcd for C18H15NO3 (M) 293.1052, found
293.1053.
1
(E)-2-Methylene-5-phenyl-1-(o-tolyl)pent-4-en-1-one (3p). Color-
54% yield) as a white solid. Mp 168−169 °C; H NMR (400 MHz,
1
less oil (65.0 mg, 83% yield); H NMR (400 MHz, CDCl3) δ 7.41−
CDCl3) δ 7.69 (dd, J = 12.4, 8.0 Hz, 6H), 7.62 (d, J = 7.6 Hz, 2H),
7.54−7.50 (m, 3H), 7.45−7.41 (m, 6H), 7.35−7.22 (m, 5H), 7.14 (dd,
J = 17.2, 7.6 Hz, 3H), 6.01 (dt, J = 15.6, 5.2 Hz, 1H), 5.92 (d, J = 15.6
Hz, 1H), 2.98 (dd, J = 22.0, 5.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 186.8 (d, J = 5.6 Hz), 142.7 (d, J = 12.5 Hz), 138.0, 133.7
(d, J = 9.6 Hz), 133.0, 131.6 (d, J = 2.8 Hz), 129.1, 128.6 (d, J = 12.1
Hz), 128.4, 128.1, 127.8, 127.7, 127.4, 126.7 (d, J = 13.3 Hz), 126.0,
7.17 (m, 9H), 6.51 (d, J = 15.6 Hz, 1H), 6.30 (dt, J = 15.6, 7.2 Hz,
1H), 6.00 (d, J = 0.8 Hz, 1H), 5.68 (d, J = 0.8 Hz, 1H), 3.36 (dd, J =
7.2, 0.8 Hz, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.9,
148.0, 138.8, 137.4, 136.2, 132.5, 130.8, 129.9, 129.8, 128.6, 128.0,
127.3, 126.7, 126.2, 125.1, 34.0, 19.7; HRMS (EI) calcd for C19H18O
(M) 262.1358, found 262.1367.
D
dx.doi.org/10.1021/jo401736k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
64.0 (d, J = 102.4 Hz), 31.8 (d, J = 13.1 Hz); HRMS (EI) calcd for
C35H29OP (M) 496.1956, found 496.1980.
(8) For reviews, see: (a) Maercker, A. Org. React. 1965, 14, 270−490.
(b) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863−927.
(c) Edmonds, M.; Abell, A. In Modern Carbonyl Olefination; Takeda,
T., Ed.; Wiley-VCH: Weinheim, Germany, 2004; pp 1−17. (d) Ju, Y.
In Modern Organic Reactions; Hu, Y.-F., Lin, G.-Q., Eds.; Chemical
Industry Press: Beijing, China, 2008; Vol. 3, pp 413−460 (in Chinese).
(e) Gu, Y.; Tian, S.-K. Top. Curr. Chem. 2012, 327, 197−238.
(9) For examples of conventional allylation of phosphonium ylides
with allyl halides, see: (a) Bestmann, H. J.; Schulz, H. Chem. Ber. 1962,
95, 2921−2927. (b) Scholz, D.; Weber-Roth, S.; Macoratti, E.;
Francotte, E. Synth. Commun. 1999, 29, 1143−1156. (c) Baldwin, J. E.;
Moloney, M. G.; Parsons, A. F. Tetrahedron 1992, 48, 9373−9384.
(d) Amonkar, C. P.; Tilve, S. G.; Parameswaran, P. S. Synthesis 2005,
2341−2344. (e) Boeckman, R. K., Jr.; Song, X.; Pero, J. E. J. Org.
Chem. 2006, 71, 8969−8972.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H NMR and 13C NMR spectra for products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tiansk@ustc.edu.cn.
Notes
(10) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Chem.Eur. J. 2010,
The authors declare no competing financial interest.
16, 7376−7379.
(11) (a) Liu, D.-N.; Tian, S.-K. Chem.Eur. J. 2009, 15, 4538−4542.
(b) Dong, D.-J.; Li, H.-H.; Tian, S.-K. J. Am. Chem. Soc. 2010, 132,
5018−5020. (c) Dong, D.-J.; Li, Y.; Wang, J.-Q.; Tian, S.-K. Chem.
Commun. 2011, 47, 2158−2160. (d) Fang, F.; Li, Y.; Tian, S.-K. Eur. J.
Org. Chem. 2011, 1084−1091. (e) Jin, Y.-H.; Fang, F.; Zhang, X.; Liu,
Q.-Z.; Wang, H.-B.; Tian, S.-K. J. Org. Chem. 2011, 76, 4163−4167.
(12) Replacing formaldehyde with benzaldehyde only gave trace
amounts of α,β-unsaturated ketones.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (21232007, 21202154,
and 21172206), the National Basic Research Program of China
(973 Program, 2010CB833300), and the Program for
Changjiang Scholars and Innovative Research Team in
University (IRT1189).
(13) Sluggish reactions were observed with (E)-2-methyl-3-phenyl-
prop-2-en-1-amine and (E)-3,7-dimethylocta-2,6-dien-1-amine under
the standard conditions.
REFERENCES
■
(14) Phosphonium ylide 10a (R1 = R2 = Ph) was isolated in 54%
yield from the reaction mixture of phosphonium ylide 2a and allylic
amine 1a.
(1) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part B:
Reactions and Synthesis, 5th ed.; Springer: New York, 2007.
(2) For reviews, see: (a) Tsuji, J. Acc. Chem. Res. 1969, 2, 144−152.
(b) Trost, B. M. Tetrahedron 1977, 33, 2615−2649. (c) Trost, B. M.;
Van Vranken, D. L. Chem. Rev. 1996, 96, 395−422. (d) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921−2943. (e) Kazmaier, U.;
Pohlman, M. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany,
2004; pp 531−583.
(15) Kaszynski, P.; Friedli, A. C.; Michl, J. J. Am. Chem. Soc. 1992,
114, 601−620.
(16) Liu, H.-J.; Wynn, H. Tetrahedron Lett. 1982, 23, 3151−3154.
(3) Although the C(sp3)−N bonds of allylic amines can be cleaved
by certain metals and strong bases, they have rarely been employed to
couple directly with nucleophiles. For reviews, see: (a) Greene, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; Wiley:
New York, 1999. (b) Escoubet, S.; Gastaldi, S.; Bertrand, M. Eur. J.
Org. Chem. 2005, 3855−3873. (c) Gu, Y.; Tian, S.-K. Synlett 2013, 24,
1170−1185.
(4) (a) Murahashi, S.-I.; Makabe, Y.; Kunita, K. J. Org. Chem. 1988,
́
53, 4489−4495. (b) Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org.
Chem. 1993, 58, 6109−6113. (c) Trost, B. M.; Spagnol, M. D. J. Chem.
Soc., Perkin Trans. 1 1995, 2083−2096. (d) Mukherjee, S.; List, B. J.
Am. Chem. Soc. 2007, 129, 11336−11337. (e) Zhao, X.; Liu, D.; Guo,
H.; Liu, Y.; Zhang, W. J. Am. Chem. Soc. 2011, 133, 19354−19357.
(f) Li, M.-B.; Wang, Y.; Tian, S.-K. Angew. Chem., Int. Ed. 2012, 51,
2968−2971. (g) Li, M.-B.; Li, H.; Wang, J.; Liu, C.-R.; Tian, S.-K.
Chem. Commun. 2013, 49, 8190−8192.
(5) (a) Trost, B. M.; Keinan, E. J. Org. Chem. 1980, 45, 2741−2746.
(b) Bricout, H.; Carpentier, J.-F.; Mortreux, A. Chem. Commun. 1997,
1393−1394. (c) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J.
Am. Chem. Soc. 2002, 124, 3669−3679. (d) Watson, I. D. G.; Yudin, A.
K. J. Am. Chem. Soc. 2005, 127, 17516−17529.
(6) (a) Kunakova, R. V.; Gaisin, R. L.; Sirazova, M. M.; Dzhemilev,
U. M. Izv. Akad. Nauk SSSR Ser. Khim. 1983, 32, 157−160; Bull. Acad.
Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1983, 32, 133−136. (b) Wu,
X.-S.; Chen, Y.; Li, M.-B.; Zhou, M.-G.; Tian, S.-K. J. Am. Chem. Soc.
2012, 134, 14694−14697.
(7) For the use of other alkylamines as carbon electrophiles, see:
(a) Murahashi, S.-I.; Yano, T. J. Am. Chem. Soc. 1980, 102, 2456−
2458. (b) Omura, K.; Furukawa, J. Chem. Lett. 1982, 1633−1636.
(c) Geng, W.; Zhang, W.-X.; Hao, W.; Xi, Z. J. Am. Chem. Soc. 2012,
134, 20230−20233. (d) Xie, Y.; Hu, J.; Wang, Y.; Xia, C.; Huang, H. J.
Am. Chem. Soc. 2012, 134, 20613−20616.
E
dx.doi.org/10.1021/jo401736k | J. Org. Chem. XXXX, XXX, XXX−XXX