Regioselective Heck reaction of N-vinylphthalimide: A general strategy for the synthesis of (E)-N-styrylphthalimides and phenethylamines

Article abstract of DOI:10.1002/adsc.200800074

The arylation of N-vinylphthalimide takes place at the β-position with aryl iodides, bromides and chlorides using palladium acetate [Pd(OAc) ₂] or phenone oxime-derived palladacycles as catalysts under phosphine-free conditions. The reaction is succesfully carried out in organic solvents, such as DMF, in the presence of an organic base, such as dicyclohexylmethylamine, and with TBAB as additive at 120°C under conventional or microwave heating. (E)-N-Styrylphthalimides are mainly obtained using a rather low palladium loading (0.05-1 mol%). Similar catalytic efficiency is observed using a Kaiser oxime resin-derived palladacycle, which allows reuse of the polymeric complex for three cycles. The high regioselectivity observed supports that these palladacycles work as a source of Pd(0)spec ies operating mainly through a neutral mechanism. The syntheses of 2-thienylphenethylamine and mescaline have been performed by subsequent hydrogenation with Wilkinson's catalyst and hydrazinolysis.

Full text of DOI:10.1002/adsc.200800074

FULL PAPERS
DOI: 10.1002/adsc.200800074
Regioselective Heck Reaction of N-Vinylphthalimide: A
General Strategy for the Synthesis of (E)-N-Styrylphthalimides
and Phenethylamines
Emilio Alacida and Carmen Nµjeraa,*
a
Departamento de Química Orgµnica, Facultad de Ciencias and Instituto de Síntesis Orgµnica (ISO), Universidad de
Alicante, Apartado 99, 03080 Alicante, Spain
Fax : (+34)-965-903-549; e-mail: cnajera@ua.es
Received: February 4, 2008; Published online: May 9, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The arylation of N-vinylphthalimide takes oxime resin-derived palladacycle, which allows reuse
place at the b-position with aryl iodides, bromides of the polymeric complex for three cycles. The high
and chlorides using palladium acetate [Pd(OAc)2] or regioselectivity observed supports that these pallada-
G
phenone oxime-derived palladacycles as catalysts cycles work as a source of Pd(0)species operating
under phosphine-free conditions. The reaction is suc- mainly through a neutral mechanism. The syntheses
cesfully carried out in organic solvents, such as DMF, of 2-thienylphenethylamine and mescaline have been
in the presence of an organic base, such as dicyclo- performed by subsequent hydrogenation with
hexylmethylamine, and with TBAB as additive at Wilkinsonꢀs catalyst and hydrazinolysis.
1208C under conventional or microwave heating.
(E)-N-Styrylphthalimides are mainly obtained using
a rather low palladium loading (0.05–1 mol%). Simi- Keywords: Heck reaction; palladacycles; phenethyl-
lar catalytic efficiency is observed using a Kaiser
A
Introduction
phine alkaloids O-methyldehydroisopiline and 7,7’-
bisdehydro-O-methylisopiline.[2d] Although N-vinyl-
Phenethylamines, tetrahydroisoquinolines, and other phthalimide is commercially available, the main draw-
related alkaloid derivatives are important natural and back found for this Heck acceptor is the control of
pharmaceutical compounds with a wide spectrum of the a- and b-regioselectivity,[2,3] which is due to the
biological properties.[1] Thus, natural catecholamines, competition of cationic and neutral mechanisms, re-
such as dopamine and mescaline act as neurotransmit- spectively, in electron-rich alkenes.[4] In addition, b-
ters in mammals and hallucinogens, respectively. For arylated N-vinylphthalimides are important com-
the synthesis of these families of alkaloids, phenethyl- pounds,[5] for instance, the metabolic drug I is a b2
amines are generally used as precursors. These start- adrenoceptor agonist,[6] compound II is a fungicide,[7]
ing materials are usually obtained by nitroaldol con- and III is a non-linear, optically active material[8]
densation with aromatic aldehydes followed by reduc- (Figure 2).
tion of the resulting product. An alternative strategy
is the Heck arylation of vinylamine equivalents, which electron-rich alkenes using Cy2NMe as base and
We have recently studied the Heck reaction[9] of
(OAc)2 or palladacycles 3, 4, or 5[10] (Figure 3)as
allows the introduction of different aromatic and het-
eroaromatic halides in the ethylamine moiety. Two
types of vinylamine equivalents have been used for
the latter strategy, the commercial N-vinylphthalimide
(1)[2] and 3-vinyl-4,5-diphenyl-2(3H)oxazolone (2),[3]
which can be prepared through a three-step protocol
(Figure 1).
A
ACHTREUNG
N-Vinylphthalimide (1)has been used in a Heck ar-
ylation for the synthesis of different phenethyl-
amines,[2a] aminoalkylphencyclidines,[2b] and the apor- Figure 1.
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Regioselective Heck Reaction of N-Vinylphthalimide
FULL PAPERS
Results and Discussion
Initial studies were performed on the coupling of 4-
bromoacetophenone as an activated aryl bromide and
N-vinylphthalimide (1), under the previously reported
reaction Heck conditions for aryl bromides,[12,13] with
dicyclohexylmethylamine as base, tetra-n-butylammo-
nium bromide (TBAB)[14] as additive, and palladacy-
cle 4 (1 mol% Pd)as catalyst in aqueous N,N-dime-
thylacetamide (DMA)at 120 8C giving no conversion
(Scheme 1 and Table 1, entry 1). However, full con-
version and high regio- and diasteroselectivity were
observed in DMF as solvent affording product 6a in
14 h reaction time with the E-configuration in 76%
yield after recrystallization (Table 1, entry 2). Alterna-
tively, triethylamine can also be used as base afford-
ing similar results (Table 1, compare entries 2 and 3).
However, an inorganic base, such as Cs2CO3 gave
21% overall yield with 35% of the homocoupled
product, 4,4’-diacetylbiphenyl (Table 1, entry 4). In
the case of using Pd(OAc)2, lower conversion and
A
Figure 2.
yield than when using palladacycle 4 was observed
(Table 1, compare entries 2 and 5). When this reaction
was performed under microwave heating,[15] full con-
version and very good yield for compound 6a (82%)
was obtained in only 15 min reaction time (Table 1,
entry 6). The same protocol using Pd(OAc)2 gave
A
lower conversion and yield (Table 1, compare en-
tries 6 and 7). The loading of palladacycle could be
decreased down to 0.05 mol% Pd, providing 79%
conversion and 67% yield after 24 h reaction time
under conventional thermal conditions (Table 1, com-
pare entry 2 and 8). Similar regioisomeric ratio
(>95/5)was obtained in all cases and crude product
6a was formed with high diasteromeric ratio (>97/3).
On the basis of these experiments, the scope of this
arylation was studied with different types of aryl hal-
ides using dicyclohexylmethylamine as base, TBAB as
additive, and palladacycles 4 and 5 as catalysts in
Figure 3.
catalysts under phosphine-free conditions. Thus, styr- DMF as solvent (Scheme 2 and Table 2). Optimiza-
enes[11] allylic alcohols,[12] and acrolein diethyl tion reactions with iodobenzene were carried out
acetal[13] react with aryl halides giving mainly aryla- under microwave heating during 15 min at 1208C
tion at the terminal position of the double bond ac- using palladacycles and Pd(OAc)2 as catalysts. The
G
cording to a neutral mechanism. Here, we describe best yields were obtained with the palladacycles using
the appropriate reaction conditions for the regioselec- 0.1 mol% Pd (Table 2, entries 1–5). This arylation per-
tive Heck arylation of N-vinylphthalimide (1)at the
b-position.
formed under conventional heating gave compound
6b with similar yields using both palladacycles 4 and 5
in 4 and 7 h, respectively (Table 2, entries 6 and 7). 4-
Scheme 1.
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Emilio Alacid and Carmen Nµjera
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[a]
Table 1. Heck reaction of N-vinylphthalimide (1)with 4-bromoacetophenone: reaction conditions study.
Entry
Cat. [mol% Pd]
Base
Solvent
t
Yield [%][b]
Ratio [%][c] 6a/7a
Product 6a E/Z[c]
1
2
3
4
5
6
7
8
4 [1]
4 [1]
4 [1]
4 [1]
Cy2NMe
Cy2NMe
Et3N
Cs2CO3
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
DMA/H2O[d]
DMF
DMF
DMF
DMF
DMF
DMF
DMF
14 h
14 h
14 h
16 h
0
-
-
99 (76)95/5
91 (70)96/4
21[e]
77 (54)95/5
99 (82)96/4
88 (65)95/5
79 (67)95/5
98/2
98/2
-
-
Pd
4 [1]
Pd(OAc)2 [1]
4 [0.05]
A
14 h
98/2
98/2
97/3
98/2
15 min[f]
15 min[f]
24 h
C
[a]
Reaction conditions: 4-bromoacetophenone (199 mg, 1 mmol), N-vinylphthalimide (175 mg, 1 mmol), Pd catalyst (see
column), base (1.5 mmol), TBAB (322 mg, 1 mmol), solvent (2 mL) at 1208C in a pressure tube.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR. In parenthesis product 6a isolated after recrystallization from EtOH.
1
Determined by H NMR in the crude products.
4:1.
35% of 4,4’-diacetylbiphenyl was also obtained.
Under microwave irradiation at 1208C (30 W, 0.5 bar).
Scheme 2.
Table 2. Heck reaction of 1 in the presence of palladacycles 4 and 5. Synthesis of products 6.[a]
Entry ArX
Cat.
[mol% Pd]
t
Ratio [%][b] Product 6
6/7
Yield
[%][c]
No. Product
G
E/Z[b]
1
PhI
4 [0.1]
5 [0.1]
15 min[d] 98/2
97/3
86
6b
2
3
15 min[d] 98/2
97/3
97/3
81
59
6b
6b
Pd(OAc)2
G
15 min[d] 97/3
[0.1]
4 [0.05]
4
5
15 min[d] 97/3
15 min[d] 97/3
97/3
97/3
65
51
6b
6b
Pd(OAc)2
A
[0.05]
4 [0.1]
5 [0.1]
6
7
4 h
7 h
98/2
97/3
97/3
97/3
81
69
6b
6b
8
4 [0.1]
3 h
98/2
97/3
74[e]
6c
9
5 [0.1]
4 [0.1]
5 [0.1]
6 h
3 h
6 h
98/2
97/3
95/5
96/4
95/5
95/5
68[e]
69
6c
6d
6d
10
11
64
12
13
14
4 [0.1]
5 [0.1]
4 [1]
3 h
98/2
98/2
89/11
96/4
97/3
95/5
83
79
74
6e
6e
6f
6 h
14 h
15
16
4 [0.1]
5 [1]
15 min[d] 90/10
14 h 89/11
95/5
95/5
82
67
6f
6f
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Regioselective Heck Reaction of N-Vinylphthalimide
Table 2. (Continued)
FULL PAPERS
Entry ArX
Cat.
[mol% Pd]
t
Ratio [%][b] Product 6
6/7
Yield
[%][c]
No. Product
A
E/Z[b]
17
18
19
20
4 [1]
14 h
14 h
14 h
100/0
99.5/0.5
96/4
99/1
99/1
98/2
72
77
74
6g
6g
6a
5 [1]
4 [0.1]
5 [1]
4 [1]
5 [1]
14 h
14 h
14 h
95/5
97/3
95/5
97/3
97/3
96/4
68
84
72
6a
6b
6b
21
22
PhBr
23
24
25
26
4 [1]
5 [1]
4 [1]
5 [1]
10 h
14 h
14 h
14 h
100/0
100/0
99/1
97/3
95/5
99/1
98/2
79
61
61
55
6h
6h
6i
97/3
6i
27
4 [1]
8 h
100/0
95/5
71
6j
28
4 [1]
14 h
99/1
96/4
86
6k
29
30
4 [0.5]
5 [1]
15 min[d] 98/2
96/4
96/4
67
59
6k
6k
14 h
14 h
24 h
98/2
98/2
97/3
31
32
4 [1]
5 [1]
98/2
98/2
42
44
6l
6l
33
4 [1]
24 h[f]
97/3
95/5
96/4
32
6a
34
35
36
4 [2]
4 [1]
40 h
96/4
95/5
95/5
57
73
46
6a
6a
6a
20 min[d,f] 97/3
20 min[d,f] 96/4
Pd
A
[1]
37
38
4 [1]
4 [1]
4 [1]
30 min[d,f] 99/1
30 min[d,f] 99/1
30 min[d,f] 99/1
98/2
97/3
98/2
82
71
66
6c
6d
6e
39
[a]
Reaction conditions: aryl halide (1 mmol), N-vinylphthalimide (175 mg, 1 mmol), Pd catalyst (see column), Cy2NMe
(0.320 mL, 1.5 mmol), TBAB (322 mg, 1 mmol), DMF (2 mL) at 1208C in a pressure tube.
Determined by H NMR in the crude products.
[b]
[c]
[d]
[e]
[f]
1
After recrystallization from EtOH.
Under microwave irradiation at 1208C (30 W, 0.5 bar).
10% of 4,4’-bis(trifluoromethyl)biphenyl was also isolated.
At 1408C.
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(Trifluoromethyl)-1-iodobenzene reacted under con- ing N-styrylphthalimides 6h and 6i were obtained in
ventional thermal conditions using both catalysts (0.1 55–79% yields (Table 2, entries 23–26). It is worthy of
mol% Pd)in 3 and 6 h, respectively, providing
note that the latter compound 6i, which is the main
ACHTREUNG
tion, and also the corresponding homocoupled prod- high regio- and diastereoselectivity (up to 99/1). The
uct, 4,4’-bis(trifluoromethyl)biphenyl, in 10% yield activated 4-nitrobromobenzene furnished the insolu-
(Table 2, entries 8 and 9). Deactivated 4-methyl- and ble product 6j, which precipitated in the reaction
4-methoxyiodobenzenes gave similar results under the medium and was isolated in 71% yield (Table 2,
typical reaction conditions, furnishing b-arylated vi- entry 27). The Heck reaction with 3,4,5-trimethoxy-
nylphthalimides (E)-6d and (E)-6e in 69 and 83% bromobenzene and 2-bromothiophene was also evalu-
yields, respectively (Table 2, entries 10–13). The ated for the synthesis of mescaline (8k)and 2-(2-thi-
ortho-substituted 2-methoxyiodobenzene needed 1
A
mol% Pd loading, providing products with lower re- afforded product 6k with very high regioselectivity
gioselectivity (6f/7f ratio ca. 9/1)than the para-sub- (99/1)and with higher (86%)yield than with polymer
stitued iodoanisole, although the b-arylated product 5 as catalyst (Table 2, entries 28 and 30). Alternative-
6f was isolated in good yields (67 and 74%)particu-
ly, the Pd loading can be decreased from 1 to 0.5
larly under microwave heating, which gave an 82% mol% working under microwave heating to give 6k in
yield using a lower loading of 4 (0.1 mol% Pd) 67% yield (Table 2, entry 29). For the reaction of 1
(Table 2, entries 14–16). These results are better than with 2-bromothiophene, product 6l was obtained in
those previously described using a higher loading of moderate yields of 42 and 44% (Table 2, entries 31
Pd, 1 mol% Pd(OAc)2 and (o-Tol)3P as catalyst, tri- and 32).
G
A
Concerning the use of aryl chlorides as coupling
afforded 41% of product 6f and 8% of 7f.[3] In the partners, the arylation of N-vinylphthalimide (1)has
case of the arylation of 1 with 2-bromoiodobenzene, to be performed at a higher temperature of 1408C
product 6g was obtained with very high regioselectivi- (Table 2, entries 33–39). Thus, the reaction with 4-
ty (up to 99/1)and in 72 and 77% yield after recrys-
tallization (Table 2, entries 17 and 18).
chloroacetophenone under microwave heating afford-
ed product 6a with higher yield than when conven-
Optimized reaction conditions were employed for tional heating was used (Table 2, entries 33–35). Sur-
the Heck reaction of N-vinylphthalimide (1)with dif- prisingly, good yields of products 6 were obtained
ferent aryl bromides using dimeric and polymeric pal- under microwave heating with only 1 mol% of Pd,
ladacycles 4 and 5, respectively, as precatalysts, gener- not only with activated aryl chlorides, such as 4-chlo-
ally with 1 mol% Pd loading in 14 h reaction time
A
(Scheme 2 and Table 2). For the arylation of 1 with 4- zene (Table 2, entries 35 and 37, respectively)but also
bromoacetophenone, palladacycle 4 (0.1 mol% Pd) with deactivated ones, such as 4-methyl- and 4-me-
gave better performance than the polymer 5, which thoxychlorobenzene (Table 2, entries 38 and 39). The
needed 1 mol% Pd loading (Table 2 entries 19 and reaction of 1 with 4-chloroacetophenone can be also
20). Bromobenzene afforded product 6b in 84 and performed with Pd(OAc)2, affording product 6a in
G
72% yield (Table 2, entries 21 and 22). In the case of lower yield than when using palladacycle 4 (Table 2,
methyl 4- and 3-bromophenylacetates the correspond- compare entries 35 and 36).
Table 3. Recycling experiments for the Heck reaction of N-vinylphthalimide (1)with 4-bromoacetophenone catalyzed by pal-
ladacycle 5.[a]
Entry
Run
Solvent
t [h]
Yield [%][b]
Pd leaching [ppm][c]
Pd leaching [mg Pd/g product][c]
1
2
3
4
5
6
1
2
3
1
2
3
DMF
DMF
DMF
PhMe
PhMe
PhMe
14
24
24
7
14
24
86
72
1.68
1.06
1.26
0.44
0.17
0.12
0.35
0.35
0.47
0.21
0.07
0.08
46
71[d]
78[e]
48[f]
[a]
Reaction conditions: 4-bromoacetophenone (199 mg, 1 mmol), N-vinylphthalimide (175 mg, 1 mmol), 5 (1 mol% Pd),
Cy2NMe (0.320 mL, 1.5 mmol), TBAB (322 mg, 1 mmol), solvent (2 mL) at 1208C in a pressure tube.
For the mixture of 6a and 7a determined by 1H NMR using diphenylmethane as internal standard.
Determined in the crude product by ICP-OES, mg Pd/1 L 1% HNO3 aqueous solution.
20% of 4,4’-diacetylbiphenyl was also isolated.
[b]
[c]
[d]
[e]
[f]
18% of 4,4’-diacetylbiphenyl was also isolated.
10% of 4,4’-diacetylbiphenyl was also isolated.
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Regioselective Heck Reaction of N-Vinylphthalimide
FULL PAPERS
Scheme 3.
For the recycling experiments, the reaction of 4- allows the isolation of pure (E)-N-styrylphthalimides
bromoacetophenone and N-vinylphthalimide (1)was just by simple recrystallization from ethanol. For the
performed using the polymeric palladacycle 5 at synthesis of phenethylamines, such as mescaline and
1208C (Table 3). From these studies in DMF, it was 2-(2-thienyl)ethylamine, it has been found that
found that the reaction gave compound 6a in good Wilkinsonꢀs catalyst performs better for the hydroge-
yields (86 and 72%)only in the two first runs, since
only 46% yield was achieved in the third run. A mod-
erate Pd leaching was observed in the final products
nation step.
according to ICP-OES analyses (Table 3, entries 1–3). Experimental Section
These results are probably due to partial decomposi-
tion of the resin working at this rather high tempera- General Procedure for Heck Coupling of Aryl
ture. When the reaction was performed in toluene at Halides and N-Vinylphthalimide under Conventional
reflux, a lower Pd leaching was detected, but competi- Thermal or Microwave Heating
tive homocoupling of 4-bromoacetophenone to give
4,4’diacetylbiphenyl was observed (Table 3, entries 4–
A mixture of aryl halide (1 mmol), N-vinylphthalimide
(175 mg, 1.01 mmol), Cy2NMe (0.320 mL, 1.5 mmol), TBAB
6).
When the synthesis of phenethylamines was intend-
ed, the first step was the hydrogenation of styryl-
phthalimides of the type 6. This reduction has been
(0.322 g, 1 mmol)and the palladium catalyst (see Tables)in
DMF (2 mL)was heated at 120 8C (oil bath temperature)in
a pressure tube and the reaction progress was monitored by
GLC. When using the microwave reactor, the pressure tube
was sealed and the heating program was started at 30 W
(1208C or 1408C, see Tables)and with air stream cooling at
20 psi. After the reaction was completed, the mixture was
cooled at room temperature and poured into 15 mL of tolu-
ene. The crude was percolated through celite and then con-
centrated under vacuum (0.1 torr). The product was precipi-
tated by adding 5 mL of ethanol, filtered off and washed
with several portions of ethanol (5”2 mL). The solid was re-
crystallized with ethanol to afford the E-product 6.
For recycling experiments the catalyst 5 was filtered off in
a porous plate (G4, 1 cm diameter and 8 cm height)and
washed successively with toluene (4”2 mL), THF (4”
2 mL), THF/methanol 1/1 (4”2 mL) and methanol (4”
2 mL). The crude product was treated as above. For ICP-
OES analyses, the solution of the crude product was evapo-
rated without purification and analyzed.
ACHTREUNG
performed with Pd on charcoal when the substituents
in the aryl group have no electron-donating proper-
ties.[2a] However, for electron-rich aryl groups Crab-
treeꢀs catalyst {[Ir
N
N
used.[2d] We have found that the hydrogenation with
Wilkinsonꢀs catalyst in ethanol under reflux at 4 atm
H2 gave the corresponding saturated phthalimides in
91 and 90% yield, respectively. These compounds were
submitted to hydrazinolysis without previous purifica-
tion, affording 2-(3,4,5-trimethoxyphenyl)ethanamine
(mescaline)( 8k)and 2-(2-thienyl)ethanamine ( 8l)in 56
and 67% overall yields, respectively (Scheme 3).
Conclusions
Experimental details and yields for compounds 6 are de-
scribed in Table 1, Table 2, and Table 3. Physical, spectro-
scopic, and analytical data are available in the Supporting
Information.
We conclude that N-vinylphthalimide can be regio-
and diastereoselectively b-arylated using appropiate
Heck reaction conditions not only with aryl iodides
and bromides, but for the first time also with chlor-
ides under conventional and microwave heating in
DMF as solvent. The dimeric and polymeric oxime-
Experimental Procedure for the Synthesis of
Phenethylamines 8
derived palladacycles and also Pd(OAc)2 under
ligand-free conditions using a tertiary amine as base
and TBAB as additive seems to work under a neutral
A
A suspension of (E)-2-(arylvinyl)isoindoline-1,3-dione 6k or
6l (0.78 mmol)and Wilkinsonꢀs catalyst (29 mg, 4 mol%)in
ethanol (25 mL)was charged in a Parr shaker hydrogenator
mechanism. This protocol and the simple work-up which was filled with H2 at 4 bar and heated at 65–708C
Adv. Synth. Catal. 2008, 350, 1316 – 1322
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Emilio Alacid and Carmen Nµjera
FULL PAPERS
during 48 h. The progress of reaction was analyzed by GC
until 100% conversion. Then, the reaction mixture was con-
centrated under vacuum, dissolved in toluene, and the crude
was percolated through 5 cm of flash silica. Finally, the sol-
vent was eliminated under vacuum (0.1 torr)to obtain a
solid product that was hydrolyzed without further purifica-
tion. To the crude product was added ethanol (5 mL)and
the suspension was stirred at À788C during 5 min, then an
80% aqueous solution of hydrazine (0.342 mL, 5.3 mmol)
was added and the mixture was allowed to reach room tem-
perature. The resuting reaction mixture was heated under
reflux during 14 h with vigorous stirring. Then, the mixture
was cooled at 258C and the precipitate was filtered off. The
filtrate was diluted with 2M HCl (10 mL)and washed with
dichloromethane (10 mL). Potassium carbonate was added
to the aqueous layer until pH 10 and the product was ex-
tracted with ethyl acetate (5”10 mL). The organic layers
were evaporated to afford pure products 8, which are com-
mercially available.
[5] L. J. Goosssen, M. Blanchot, C. Brinkmann, K. Goos-
sen, R. Karch, A. Rivas-Nass, J. Org. Chem. 2006, 71,
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[6] A. D. Brown, M. E. Bunnage, C. A. L. Lane, R. A.
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Acknowledgements
This work was financially supported by the Dirección Gener-
al de Investigación of the Ministerio de Educación y Ciencia
of Spain (Grants CTQ2004–00808/BQU, CTQ2007–62771/
BQU, and Consolider INGENIO 2010 CSD2007–00006), the
Generalitat Valenciana (GV05/157) and the University of Ali-
cante. E. A. thanks the Ministerio de Educación y Ciencia of
Spain for a predoctoral fellowship.
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