Three-component synthesis of homoallylic amines promoted by carboxylic acids

Article abstract of DOI:10.1055/s-2006-942548

A highly selective, three-component reaction promoted by carboxylic acids for the synthesis of homoallylic amines has been developed. By using maleic acid or trifluoroacetic acid as a promoter, the reaction between a variety of aldehydes, aromatic amines,

Full text of DOI:10.1055/s-2006-942548

PAPER
3189
Three-Component Synthesis of Homoallylic Amines Promoted by Carboxylic
Acids
T
hree-Component
u
Synthesis of
i
Homo
-
allylic
A
l
mines ong Li, Gang Zhao*
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Feng
Lin Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: Zhaog @mail.sioc.ac.cn
Received 9 May 2006; revised 14 June 2006
OH
carboxylic acid (1 equiv)
Abstract: A highly selective, three-component reaction promoted
SnBu3
(1)
+
RCHO
by carboxylic acids for the synthesis of homoallylic amines has
been developed. By using maleic acid or trifluoroacetic acid as a
promoter, the reaction between a variety of aldehydes, aromatic
amines, and allyltin reagents proceeds smoothly to afford the corre-
sponding homoallylic amines in moderate to quantitative yields un-
der mild conditions.
R
MeCN, r.t.
SO2NHCHCO2H
(1.2–2.5 equiv)
R2
HN
R1
(2)
(3)
+ R2NH
+ R2NH
1
SnBu3
SnBu3
R CHO
+
+
2
MeCN, r.t.
R2
Key words: allylations, carboxylic acids, imines, multicomponent
reactions, tin
HN
R1
carboxylic acid (1 equiv)
MeCN, r.t.
1
R CHO
2
Scheme 1
The allylation of imines is an important method for the
synthesis of synthetically useful homoallylic amines.
Among several allylic metal reagents containing group 14 commercially available carboxylic acids (Scheme 1,
elements (e.g., Si, Ge, Sn), allyltin reagents have been the equation 3).
subject of extensive studies due to their good stability and
In an initial experiment to investigate the carboxylic acid
reactivity.1 In general, the allylation of imines with allyl-
mediated three-component reaction, we used 4-nitroben-
tributyltin is carried out in the presence of Lewis acids;2
zoic acid (1.0 equiv) as a promoter with benzaldehyde
palladium [PdCl2(PPh3)2] and platinum [PtCl2(PPh3)2]
(1.0 equiv), aniline (1.0 equiv), and allyltributyltin (1.2
complexes have also been utilized to catalyze this reac-
equiv) as the model substrates; 4-nitrobenzoic acid was
tion.3 The three-component reaction (aldehydes, amines,
selected as the promoter because it was found to be the
and allyltributyltin), which does not require the initial
best promoter for the allylation of aldehydes in acetoni-
preparation of the imine, is a convenient method for the
trile.6 The reaction proceeded rapidly and afforded ho-
synthesis of homoallylic amines. However, as we know,
moallylic amine 5a as the major product (81% yield) in
five hours, however, the corresponding homoallylic alco-
hol 4a was also observed (19% yield, Table 1, entry 5).
traditional Lewis acids are ineffective in the three-compo-
nent reaction because they decompose or lose their activ-
ity in the presence of water and amines.4 Additionally, the
In a previous report, we demonstrated clearly that the
selective allylation of imines is not so easy in the presence
acidity of the promoter is a crucial factor in the carboxylic
acid mediated allylation of aldehydes.6 Weak carboxylic
acids (pKa ≥ 4.2) are almost inactive in the allylation of al-
dehydes. Therefore, we selected various weak carboxylic
acids to improve the chemoselectivity. The results are
summarized in Table 1. It is apparent that the selectivity
of the reaction improves with increasing pKa values from
4-nitrobenzoic acid (entry 5), 4-fluorobenzoic acid (entry
3), to 4-hydroxybenzoic acid (entry 1). As expected, the
homoallylic amine was the sole product when using ben-
zoic acid as a promoter (pKa ≥ 4.2), but the yield decreased
and the reaction time was prolonged (entries 1 and 2). On
the other hand, some strong carboxylic acids (pKa £ 3.42)
were also screened in the three-component reaction. Very
high chemoselectivity was obtained when stronger acids
(pKa £ 2.98, entries 6–8) were used as promoters. The
maleic acid mediated three-component reaction provided
homoallylic amine 5a in quantitative yield, and no
homoallylic alcohol 4a was observed (by 1H NMR).
of an aldehyde.2e In recent years, a number of methods for
the three-component reaction have been reported,5 espe-
cially those using metal triflate salts as catalysts that are
water tolerant, which provide good results.5a,5b,5e,5f
Recently, we found that carboxylic acids are efficient pro-
moters of the allylation of aldehydes under mild condi-
tions (Scheme 1, equation 1).6 In this reaction, we
proposed that the aldehydes might be activated by a hy-
drogen bond formed with the carboxylic acid. In addition,
we reported that the polymer-supported sulfonamide of
glycine is a highly efficient promoter for the allylation of
aldehydes and it is also an efficient promoter for the three-
component reaction of aldehydes, amines, and allyltribu-
tyltin (Scheme 1, equation 2).7 Herein, we describe a de-
tailed study of the three-component reaction promoted by
SYNTHESIS 2006, No. 19, pp 3189–3194
x
x.
x
x
.
2
0
0
6
Advanced online publication: 15.08.2006
DOI: 10.1055/s-2006-942548; Art ID: F07406SS
© Georg Thieme Verlag Stuttgart · New York

3190
G.-l. Li, G. Zhao
PAPER
Table 1 The Effect of Various Carboxylic Acids on the Three-Component Reactiona
NHR2
OH
promoter (1.0 equiv)
MeCN, r.t.
SnBu3
+
PhCHO + PhNH2
+
Ph
Ph
4a
5a
1a
2a
3a
Entry
Promoter
pKa
Time
Yieldb (%)
4a
5a
1
2
3
4
5
6
7
8
4-HOC6H4CO2H
PhCO2H
4.57
4.20
4.14
4.0
19 h
<1
>79
74
c
23 h
–
4-FC6H4CO2H
4-ClC6H4CO2H
4-O2NC6H4CO2H
2-HOC6H4CO2H
1,2-C6H4(CO2H)2
maleic acid
19 h
12
18
19
69
19 h
53
3.42
2.98
2.89
1.92
5 h
81
c
30 min
30 min
30 min
–
84
c
–
98
c
–
quant.
a Ratio 1a/2a/3a = 1.0:1.0:1.2 (equiv).
b Isolated yield or determined by 1H NMR.
c No 4a was observed.
The scope of the carboxylic acid mediated three-compo- In the carboxylic acid mediated three-component reac-
nent reaction was evaluated after optimum reaction condi- tion, both aldehyde and imine could be activated by the
tions had been established; using maleic acid as a hydrogen bonding formed with the carboxylic acid (I and
promoter, a set of aldehydes was investigated. As shown II, Path A, Scheme 2). As a result, homoallylic alcohol 4
in Table 2, the electronic nature of the substituents on ar- and homoallylic amine 5 were produced simultaneously
omatic aldehydes has little influence on the reaction. High in the cases of in which 4-fluorobenzoic acid, 4-chlo-
to quantitative yields were obtained in various cases (90– robenzoic acid, and 4-nitrobenzoic acid were used as pro-
100%, entries 1–3, 6). The reaction of 2-furaldehyde also moters (3.42 £ pKa £ 4.14; Table 1, entries 3–5). On the
provided the corresponding homoallylic amine 5d in good other hand, the carboxylic acids (especially strong acids;
yield (entry 4). The three-component reaction of the cy- pKa £ 2.98; Table 1, entries 6–8) could form the iminium
clic aliphatic aldehyde cyclohexanecarbaldehyde gave 5e ion with imines selectively, and then the thus-produced
in good yield (entry 5); however, the linear aliphatic alde- iminium ion underwent nucleophilic attack by allyltin re-
hyde nonanal gave only a trace amount of the desired agents and to provide the homoallylic amine adduct 5 ex-
product and an enolization byproduct was observed by 1H clusively.9 This result could be explained by the fact that
NMR (entry 13).5i,8 A variety of amines were also tested. the activation of an iminium ion to form an imine by
Obviously, the reaction of aromatic amines bearing an strong carboxylic acid is much stronger than that by form-
electron-donating group is highly efficient and excellent ing a hydrogen bond with an aldehyde (III, Path B,
yields resulted (93–100%, entries 7, 8, 9). When 4-nitro- Scheme 2).
aniline was used as the substrate, we isolated two allyl-
ation products, homoallylic amine 5j and alcohol 4j (ratio
The g-adduct and syn-isomer selective results could be
understood through an acyclic antiperiplanar transition
5j/4j 1.4:1.0, entry 10); however, by using the strong acid
trifluoroacetic acid as a promoter, 5j was obtained from 4-
nitroaniline with high chemoselectivity (with no 4j) and in
81% yield (entry 11). Finally, when aliphatic amines such
as 2-phenylethanamine were used, none of the desired
product was produced (entry 13).
state.2c,2g,2h In the carboxylic acid mediated allylation of
imines, firstly, the imine was activated by the formation of
the iminium salt with a carboxylic acid. Then, of the pos-
sible geometries, the antiperiplanar (a, Figure 1) will be
the most favorable transition state, which has less steric
crowding compared with the other five possible geome-
The three-component reaction of substituted allyltin re- tries (steric crowding order: a < d <b, c, e, f.), as a result,
agents was further investigated. As shown in Table 3, all the syn-isomer was produced as the major adduct. The
the reactions of substituted allyltin reagents proceeded anti-adduct as the minor product could be explained by
smoothly and afforded the g-adduct exclusively in moder- the fact that compared with strong Lewis acids, such as
ate to high yields (entries 1–4). The reaction favored the boron trifluoride–diethyl ether complex, the proton of the
formation of the syn-isomer (ratio syn/anti ~ 3:1, entries carboxylic acid is a small Lewis acid. The very low ste-
1–3) except allyltin 3e (syn/anti = 49:51, entry 4).
reoselectivity provided by allyltin 3e may be due to the
Synthesis 2006, No. 19, 3189–3194 © Thieme Stuttgart · New York

PAPER
Three-Component Synthesis of Homoallylic Amines
3191
Table 2 The Scope of the Three-Component Reaction Promoted by Carboxylic Acidsa
R2
HN
maleic acid (1 equiv)
R1CHO + R2NH2
SnBu3
+
R1
MeCN, r.t.
1
5a–j
3a
2
Entry
1
R1
Ph
R2
Ph
Ph
Ph
Ph
Ph
Ph
Time (min)
Product 5
Yieldb (%)
100
90
30
50
50
50
50
40
50
50
50
50
50
50
3 d
5a
5b
5c
5d
5e
5f
5g
5h
5i
2
4-O2NC6H4
3
3-MeOC6H4
97
4
2-furyl
71
5
Cy
73
6
2,4-Cl2C6H3
97
7
Ph
3,4,5-(MeO)3C6H2
4-FC6H4
95
8
Ph
100
93
9
Ph
4-MeOC6H4
4-O2NC6H4
4-O2NC6H4
Ph
10
11
12
13
Ph
5j
5j
–
63c
Ph
81d
trace
n-C8H17
Ph
e
CH2CH2Ph
–
–
a Ratio 1/2/3 = 1.0:1.0:1.2 (equiv).
b Isolated yield.
c Two products were isolated, with the ratio of 5j/4j = 1.4:1.0.
d Maleic acid and TFA were used as promoters.
e No desired product was observed.
Table 3 The Three-Component Reaction of Benzaldehyde, Aniline, and Substituted Allyltin Promoted by Carboxylic Acids
Ph
carboxylic
acid
SnBu3
HN
Ph
R1
R2
PhCHO + PhNH2
+
MeCN, r.t.
R2
3b–e
R1
5k–n
1a
2a
Entry
Allyltin
3bc
R1
R2
H
H
H
Carboxylic acid
TFA
Time (h)
0.5
Product
5k
Ratioa syn/anti
73:27
Yieldb (%)
1
2
3
4
Me
quant.
97
3cd
Ph
maleic acid
maleic acid
maleic acid
1.0
5l
74:26
3de
4-MeOC6H4O
Me
2.0
5m
82:18
67
3ed
OMOM
2.0
5n
49:51
52
a Determined by 1H NMR.
b Total isolated yield.
c E/Z 85:15.
d E-Isomer.
e Z-Isomer.
Synthesis 2006, No. 19, 3189–3194 © Thieme Stuttgart · New York

3192
G.-l. Li, G. Zhao
PAPER
R3
O
R3
O
O
O
H
R2NH2
H
R2
H
Path A
R3CO2H
(3.42 ≤ Ka ≤ 4.14)
O
N
R1
I
H
R1
II
SnBu3
R2
R2
H
O
N
OH
HN
R1
+
+
R1
R1
H
R1
4
5
minor product
major product
R3
O
R2
H
R2
H
O
SnBu3
HN
R1
Path B
N
R3CO2H
R1
5
(pKa ≤ 2.98 )
exclusive product
III
Scheme 2
Allyltin reagents 3a,10 3b,11 3c,12 3d,13 and 3e14 were prepared ac-
cording to the reported literature. Commercially available carboxy-
lic acids and MeCN were used without purification. Other solvents
and reagents were purified under standard methods. Petroleum ether
refers to the fraction boiling in the range 60–90 °C. Flash column
chromatography was performed on silica gel (300–400 mesh,
Qingdao, China). Melting points were measured on a Mettler FP62
or WRS-1A apparatus and are uncorrected. 1H NMR and 13C NMR
spectra were recorded on EM-360A or Bruker-AM-300 300 MHz
spectrometers with TMS as an internal standard. LRMS were ob-
tained on a HP-5989A mass spectrometer. HRMS were performed
on Fingian MAT8403 mass spectrometer.
Sn
H
Sn
Ph
R1
Ph
H
H
antiperiplanar
R1
Ph
H
N
N
H
H
Ph
R'
O
R'
O
a
b
O
O
anti-5k
syn-5k
R1
H
Ph
Ph
H
H
N-(1-Phenylbut-3-enyl)aniline (5a); Typical Procedure
Benzaldehyde (53 mg, 0.5 mmol), aniline (47 mg, 0.5 mmol), ma-
leic acid (58 mg, 0.5 mmol), and allyltributyltin (198 mg, 0.6 mmol)
were added to MeCN (1.0 mL). The mixture was stirred at r.t. The
reaction was monitored by TLC and when complete it was
quenched with 2.0 M NaOH (2.0 mL) and extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure to furnish the crude product,
which was purified by chromatography (silica gel, typical eluent:
petroleum ether–EtOAc, 100:1) to afford homoallylic amine 5a5h as
a yellow oil; yield: 112 mg (100%).
R1
Sn
R'
Sn
R'
H
N
N
H
H
Ph
Ph
O
O
c
d
R1
O
O
O
synclinal
H
Ph
H
Ph
R1
H
H
O
Sn
Sn
N
N
H
H
Ph
R'
Ph
R'
O
f
e
IR (KBr, film): 3412, 3054, 2914, 1639, 1602, 1504, 1316, 920, 749
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.20 (m, 5 H), 7.10–7.04 (m,
2 H), 6.66–6.61 (m, 1 H), 6.50–6.47 (m, 2 H), 5.77–5.71 (m, 1 H),
5.21–5.12 (m, 2 H), 4.35 (s, 1 H), 4.15 (s, 1 H), 2.45–2.61 (m, 2 H).
O
Figure 1 Acyclic transition states geometries proposed for the car-
boxylic acid mediated allylation of imines.
possible hydrogen bonding between the oxygen of the a-
substituted group (adjoining tin atom) and the iminium
ion.
N-[1-(4-Nitrophenyl)but-3-enyl]aniline (5b)5h
Yellow oil.
IR (KBr, film): 3410, 3077, 3021, 2979, 2914, 2853, 1640, 1603,
1518, 1344, 1289, 1108, 993, 854, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.19–8.15 (m, 2 H), 7.55–7.51 (m,
2 H), 7.10–7.05 (m, 3 H), 6.70–6.65 (m, 1 H), 6.44–6.41 (dd,
J = 7.5, 1.5 Hz, 2 H), 5.80–5.66 (m, 1 H), 5.24–5.17 (m, 2 H), 4.47
(s, 1 H), 4.24 (s, 1 H), 2.65–2.57 (m, 2 H).
In conclusion, a highly selective three-component reac-
tion promoted by carboxylic acids has been developed for
the synthesis of homoallylic amines. By using commer-
cially available maleic acid or trifluoroacetic acid as a
promoter, the three-component reactions between a vari-
ety of aldehydes, aromatic amines, and allyltin reagents
proceed smoothly to afford the corresponding homoallyl-
ic amines in moderate to quantitative yields under mild re-
action conditions.
N-[1-(3-Methoxyphenyl)but-3-enyl]aniline (5c)7
Yellow oil.
IR (KBr, film): 3048, 3015, 2935, 1639, 1602, 1501, 1266, 750
cm–1.
Synthesis 2006, No. 19, 3189–3194 © Thieme Stuttgart · New York

PAPER
Three-Component Synthesis of Homoallylic Amines
3193
1H NMR (300 MHz, CDCl3): d = 7.26–7.24 (m, 2 H), 7.11–7.05 (m,
2 H), 6.97–6.92 (m, 2 H), 6.78–6.75 (m, 1 H), 6.66–6.61 (m, 1 H),
6.51–6.47 (m, 1 H), 5.81–5.71 (m, 1 H), 5.22–5.12 (m, 2 H), 4.31
(q, J = 5.1, 2.7, 5.3 Hz, 1 H), 4.13 (m, 1 H), 3.80 (s, 3 H), 2.63–2.56
(m, 1 H), 2.52–2.45 (m, 1 H).
4-Nitro-N-(1-phenylbut-3-enyl)aniline (5j)5i
Pale yellow solid; mp 102–104 °C.
IR (KBr, film): 3351, 3080, 3001, 2874, 1641, 1601, 1533, 1483,
1304, 1282, 1111, 991, 831 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.53–2.66 (m, 2 H), 4.49 (t,
J = 7.2, 5.4 Hz, 1 H), 4.95 (br s, 1 H), 5.18–5.25 (m, 2 H), 5.67–5.80
(m, 1 H), 6.42 (d, J = 6.9 Hz, 2 H), 7.25–7.37 (m, 5 H), 7.96 (d,
J = 8.8 Hz, 2 H).
N-[1-(2-Furyl)but-3-enyl]aniline (5d)5h
Pale yellow oil.
IR (KBr, film): 3411, 3035, 2921, 1640, 1603, 1504, 922, 749 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34 (s, 1 H), 7.16–7.11 (m, 2 H),
6.67 (t, J = 7.5 Hz, 1 H), 6.59 (d, J = 7.3 Hz, 2 H), 6.27 (d, J = 1.8
Hz, 1 H), 6.15 (s, 1 H), 5.79–5.70 (m, 1 H), 5.11 (t, J = 8.9, 15.9 Hz,
2 H), 4.53 (t, J = 6.0 Hz, 1 H), 3.98 (s, 1 H), 2.63 (t, J = 4.1, 7.1 Hz,
2 H).
N-(2-Methyl-1-phenylbut-3-enyl)aniline (5k)2c
Pale yellow oil.
IR (KBr, film): 3414, 3054, 2967, 1930, 2872, 1638, 1602, 1504,
1452, 1317, 1282, 919, 748, 701 cm–1.
1H NMR (300 MHz, CDCl3) (mixture of syn- and anti-isomers):
d = 0.97 (d, J = 7.1 Hz, 3 H), 2.48–2.55 (m, 0.27 H) (anti), 2.64–
2.71 (m, 0.73 H) (syn), 4.06 (d, J = 6.9 Hz, 0.27 H) (anti), 4.20 (br
s, 1 H), 4.33 (d, J = 4.4 Hz, 0.73 H) (syn), 5.10–5.21 (m, 2 H),
5.675.79 (m, 1 H), 6.45 (d, J = 8.2 Hz, 2 H), 6.58 (t, J = 7.3 Hz, 1
H), 7.02–7.07 (m, 2 H), 7.19–7.36 (m, 5 H).
N-(1-Cyclohexylbut-3-enyl)aniline (5e)5i
Pale yellow oil.
IR (KBr, film): 3412, 3053, 2961, 2926, 2853, 1640, 1601, 1505,
1259, 1005, 789, 691 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.16 (td, J = 2.1, 5.2, 1.1 Hz, 2 H),
6.65–6.54 (m, 3 H), 5.85–5.73 (m, 1 H), 5.08–5.02 (m, 2 H), 3.52
(s, 1 H), 3.28 (q, J = 5.4, 6.9, 5.3 Hz, 1 H), 2.37–2.32 (m, 1 H),
2.22–2.12 (m, 1 H), 1.85–1.04 (m, 11 H).
N-(1,2-Diphenylbut-3-enyl)aniline (5l)
White solid; mp 81–83 °C; Rf = 0.70 (petroleum ether–EtOAc, 8:1).
IR (KBr, film): 3404, 3083, 3053, 3022, 2869, 1636, 1601, 1501,
1452, 1311, 1265, 1076, 934, 747, 696 cm–1.
N-[1-(2,4-Dichlorophenyl)but-3-enyl]aniline (5f)
Pale yellow oil; Rf = 0.79 (petroleum ether–EtOAc, 50:1).
1H NMR (300 MHz, CDCl3) (mixture of syn- and anti-isomers):
d = 3.51 (t, J = 8.5 Hz, 0.26 H) (anti), 3.66 (t, J = 7.3, 8.1 Hz, 0.74
H) (syn), 4.13 (br s, 0.74 H) (syn), 4.47 (d, J = 7.8 Hz, 0.26 H)
(anti), 4.58 (d, J = 6.9 Hz, 0.74 H) (syn), 4.92–5.26 (m, 2 H), 5.91–
6.03 (m, 0.74 H) (syn), 6.11–6.23 (m, 0.24 H) (anti), 6.39–6.64 (m,
3 H), 6.98–7.29 (m, 12 H).
13C NMR (75 MHz, CDCl3) (mixture of syn- and anti-isomers): d =
57.2 (syn), 58.4 (anti), 62.0 (syn), 62.4 (anti), 113.8, 117.6, 117.7,
118.2, 127.2, 127.3, 127.4, 127.9, 128.2, 128.2, 128.5, 128.6, 128.7,
128.7, 129.1, 129.2, 137.8 (syn), 138.7 (anti), 140.3 (syn), 140.8
(anti), 141.4 (syn), 142.0 (anti), 147.2 (syn), 147.4 (anti).
IR (KBr, film): 3414, 3079, 3053, 3020, 2979, 2918, 1639, 1603,
1588, 1500, 1468, 1315, 1266, 1046, 819, 749, 692 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.32–2.42 (m, 1 H), 2.62–2.71 (m,
1 H), 4.16 (d, J = 3.7 Hz, 1 H), 4.74–4.80 (m, 1 H), 5.17–5.25 (m, 2
H), 5.69–5.81 (m, 1 H), 6.39 (d, J = 8.6 Hz, 2 H), 6.64 (t, J = 7.7,
7.1 Hz, 1 H), 7.05–7.17 (m, 3 H), 7.35–7.40 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 40.7, 53.4, 113.4, 118.0, 119.0,
127.6, 128.7, 129.3, 129.6, 133.2, 133.3, 134.0, 139.1, 146.6.
LRMS (ESI): m/z = 292.0 (M+).
LRMS (ESI): m/z = 300.2 (M + 1)+.
HRMS (MALDI): m/z calcd for C22H22N+: 300.1740; found
HRMS (EI): m/z calcd for C16H15Cl2N: 291.0582; found: 291.0581.
3,4,5-Trimethoxy-N-(1-phenylbut-3-enyl)aniline (5g)7
300.1746.
Pale yellow solid; mp 63–65 °C.
N-[2-(4-Methoxyphenoxy)-1-phenylbut-3-enyl]aniline (5m)
Pale yellow oil; Rf = 0.57 (petroleum ether–EtOAc, 8:1).
IR (KBr): 3384, 3062, 2998, 2934, 2840, 1639, 1611, 1510, 1453,
1237, 1127, 1010, 911, 732 cm–1.
IR (KBr, film): 3412, 3052, 3024, 2951, 2906, 2833, 1602, 1504,
1453, 1314, 1224, 1180, 1105, 1036, 993, 826, 750, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39–7.21 (m, 5 H), 5.84–5.73 (m,
1 H), 5.72 (s, 2 H), 5.23–5.15 (m, 2 H), 4.30 (q, J = 4.8, 3.2, 5.1 Hz,
1 H), 4.09 (s, 1 H), 3.70 (s, 3 H), 3.66 (s, 6 H), 2.63–2.56 (m, 1 H),
2.52–2.45 (m, 1 H).
1H NMR (300 MHz, CDCl3) (mixture of syn- and anti-isomers):
d = 3.73 (s, 3 H), 4.58 (br 1 H), 4.65 (s, 1 H), 4.83 (t, J = 5.2, 3.8
Hz, 1 H), 5.27–5.36 (m, 2 H), 5.65–5.81 (m, 0.82 H) (syn), 5.86–
5.92 (m, 0.18 H) (anti), 6.50–6.85 (m, 7 H), 7.04 (t, J = 8.2, 7.3 Hz,
2 H), 7.23–7.41 (m, 5 H).
4-Fluoro-N-(1-phenylbut-3-enyl)aniline (5h)5h
Pale yellow oil.
IR (KBr, film): 3415, 3062, 3030, 2977, 2912, 2855, 1639, 1613,
1509, 1221, 1315, 819, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.37–2.56 (m, 2 H), 3.98 (br s, 1
H), 4.21–4.25 (m, 1 H), 5.06–5.14 (m, 2 H), 5.62–5.75 (m, 1 H),
6.31–6.36 (m, 2 H), 6.67–6.74 (m, 2 H), 7.15–7.31 (m, 5 H).
13C NMR (75 MHz, CDCl3) (mixture of syn and anti isomers): d =
55.7, 55.7, 61.1, 62.1, 83.4, 84.4, 113.9, 114.0, 114.6, 114.7, 117.7,
118.0, 118.1, 118.9, 119.1, 127.6, 127.6, 127.9, 128.5, 128.5, 129.2,
133.7, 135.5, 139.5, 140.5, 147.2, 147.5, 151.9, 152.2, 154.5, 154.6.
LRMS (ESI): m/z 346.2 (M + 1)+.
+
HRMS (MALDI): m/z calcd for C23H23NO2 : 346.1811; found
346.1801.
4-Methoxy-N-(1-phenylbut-3-enyl)aniline (5i)5c
Pale yellow oil.
IR (KBr, film): 3403, 3061, 2999, 2831, 1639, 1512, 1452, 1239,
1037, 819, 702 cm–1.
N-[4-(Methoxymethoxy)-2-methyl-1-phenylbut-3-enyl]aniline
(5n)
Pale yellow oil; Rf = 0.60 (petroleum ether–EtOAc, 8:1).
1H NMR (300 MHz, CDCl3): d = 2.44–2.62 (m, 2 H), 3.67 (s, 3 H),
3.92 (br s, 1 H), 4.28–4.33 (m, 1 H), 5.12–5.21 (m, 2 H), 5.72–5.78
(m, 1 H), 6.44–6.48 (m, 2 H), 6.66–6.69 (m, 2 H), 7.20–7.38 (m, 5
H).
IR (KBr, film): 3412, 3025, 2960, 2929, 2828, 1663, 1602, 1504,
1452, 1314, 1159, 1036, 922, 749, 693 cm–1.
Synthesis 2006, No. 19, 3189–3194 © Thieme Stuttgart · New York

3194
G.-l. Li, G. Zhao
PAPER
1H NMR (300 MHz, CDCl3) (mixture of syn- and anti-isomers):
d = 0.82 (d, J = 6.8 Hz, 0.51 H) (anti), 0.97 (d, J = 6.9 Hz, 0.49 H)
(syn), 2.91–3.02 (m, 0.51 H), 3.25–3.32 (m, 0.49 H) (syn), 3.42 (d,
J = 5.9 Hz, 3 H) (anti), 3.86 (d, J = 8.7 Hz, 0.51 H) (anti), 4.21–
4.27 (m, 0.49 H) (syn), 4.32 (d, J = 3.9 Hz, 0.49 H) (syn), 4.42–4.48
(m, 0.51 H) (anti), 4.58 (br s, 1 H), 4.83 (s, 2 H), 6.20 (q, J = 6.2, 1
H), 6.41 (t, J = 8.8 Hz, 2 H), 6.55–6.60 (m, 1 H), 6.99 (t, J = 7.2, 8.6
Hz, 2 H), 7.19–7.40 (m, 5 H).
13C NMR (75 MHz, CDCl3) (mixture of syn- and anti-isomers): d =
17.9, 18.2, 34.9, 36.8, 56.0, 56.0, 62.5, 64.2, 96.6, 110.1, 112.1,
113.1, 113.2, 116.7, 116.9, 126.9, 127.0, 127.6, 127.9, 127.9, 128.3,
129.0, 129.0, 140.7, 143.2, 143.3, 143.7, 147.5, 148.1.
(3) Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Am. Chem. Soc.
1996, 118, 6641.
(4) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett.
1995, 36, 5773.
(5) (a) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem.
Commun. 1998, 19. (b) Aspinall, H. C.; Greeves, N.;
McIver, E. G. Tetrahedron Lett. 1998, 39, 9283.
(c) Manabe, K.; Mori, Y.; Kobayashi, S. Tetrahedron 2001,
57, 2537. (d) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. S. R.;
Shesha Rao, M. Tetrahedron Lett. 2002, 43, 6245.
(e) Choudary, B. M.; Chidara, S.; Sekhar, C. C. V. Synlett
2002, 1694. (f) Aspinall, H. C.; Bissett, J. S. B.; Greeves, N.;
Levin, D. Tetrahedron Lett. 2002, 43, 323. (g) Yadav, J. S.;
Reddy, B. V. S.; Raju, A. K.; Gnaneshwar, D. Adv. Synth.
Catal. 2002, 344, 938. (h) Yadav, J. S.; Reddy, B. V. S.;
Raju, A. K. Synthesis 2003, 883. (i) Shibata, I.; Nose, K.;
Sakamoto, K.; Yasuda, M.; Baba, A. J. Org. Chem. 2004, 69,
2185.
LRMS (ESI): m/z 298.2 (M + 1)+.
HRMS (MALDI): m/z calcd for C19H23NO2Na+: 320.1628; found
320.1621.
References
(6) (a) Li, G.-l.; Zhao, G. J. Org. Chem. 2005, 70, 4272. (b) Li,
G.-l.; Zhao, G. Synlett 2005, 2540.
(1) For recent reviews, see: (a) Davies, A. G. Organotin
Chemistry; Wiley-VCH: Weinheim, 2004. (b) Hisashi, Y.;
Koichiro, O. Main Group Metals in Organic Synthesis, Vol.
2; Wiley-VCH: Weinheim, 2004, 621–720. (c) Junzo, O.
Modern Carbonyl Chemistry; Wiley-VCH: Weinheim,
2000. (d) Marshall, J. A. Chem. Rev. 2000, 100, 3163.
(e) Marshall, J. A. Chem. Rev. 1996, 96, 31. (f) Yamamoto,
Y.; Asao, N. Chem. Rev. 1993, 93, 2207. (g) Nishigaichi,
Y.; Takuwa, A.; Naruta, Y.; Maruyama, K. Tetrahedron
1993, 49, 7395.
(2) Using Lewis acids as promoters or catalysts, see: (a) Keck,
G. E.; Enholm, E. J. J. Org. Chem. 1985, 50, 146. (b)Trost,
B. M.; Bonk, P. J. J. Am. Chem. Soc. 1985, 107, 1778.
(c) Yamamoto, Y.; Nishii, S.; Maruyama, K. J. Org. Chem.
1985, 50, 3115. (d) Bellucci, C.; Cozzi, P. G.; Umani-
Ronchi, A. Tetrahedron Lett. 1995, 36, 7289.
(7) (a) Li, G.-l.; Zhao, G. Org. Lett. 2006, 8, 633. (b) Li, G.-l.;
Zhao, G. Org. Lett. 2006, 8, 1011.
(8) Bloch, R. Chem. Rev. 1998, 98, 1407.
(9) Benzaldehyde (16 mg, 0.15 mmol), aniline (14 mg, 0.15
mmol), and maleic acid (18 mg, 0.15 mmol) were added
successively to CD3CN (0.5 mL), and the mixture was
monitored by 1H NMR. It was obvious that the
corresponding iminium salt was produced and aniline had
disappeared completely.
(10) Jones, W. J.; Davies, W. Z.; Bowden, S. T.; Edwards, C.;
Daris, V. V.; Thomas, L. H. J. Chem. Soc. 1947, 1446.
(11) Hoffmann, R. W.; Feussner, G.; Zeiss, H.-J.; Schulz, S. J.
Organomet. Chem. 1980, 18, 321.
(12) Gyldenfeldt, F.; Marton, D.; Tagliavini, G. Organometallics
1994, 13, 906.
(13) Micalizio, G. C.; Pinchuk, A. N.; Roush, W. R. J. Org.
Chem. 2000, 65, 8730.
(e) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1997,
119, 10049. (f) Kobayashi, S.; Iwamoto, S.; Nagayama, S.
Synlett 1997, 1099. (g) Andrade, C. K. Z.; Oliveira, G. R.
Tetrahedron Lett. 2002, 43, 1935. (h) Andrade, C. K. Z.;
Azevedo, N. R.; Oliveira, G. R. Synthesis 2002, 928.
(14) Pratt, A. J.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1
1989, 1521.
Synthesis 2006, No. 19, 3189–3194 © Thieme Stuttgart · New York