Arylation of allyl alcohols in organic and aqueous media catalyzed by oxime-derived palladacycles: Synthesis of β-arylated carbonyl compounds

Article abstract of DOI:10.1002/adsc.200700301

A 4-hydroxyacetophenone oxime-derived palladacycle catalyzes the Mizoroki-Heck reaction of allyl alcohols with aryl iodides, bromides, and chlorides in aqueous and organic solvents. The reaction takes place in the presence of dicyclohexylmethylamine or cesium carbonate as bases, the addition of tetrabutylammonium bromide (TBAB) as additive for aryl bromides and chlorides being necessary. Under these reaction conditions, β-arylated aldehydes and ketones are mainly obtained using a rather low loading of palladium (0.1-1 mol%). Similar catalytic activity is shown by a Kaiser oxime resin-derived palladacycle, which allows one to perform recycling and reusing experiments with low Pd leaching. The high regio- and chemoselectivity observed supported that these palladacycles, working as a source of Pd(0) species, operates mainly through a neutral mechanism. This methodology has been applied to the synthesis of important β-arylated carbonyl compounds, such as 4-phenylbutan-2-one, 4-(4-hydroxyphenyl)butan-2-one, dihydrochalcones, the anti-inflamatory nabumetone, and the fragance β-lilial. γ-Arylation is observed in the reactions of allyl alcohol and but-3-en-2-ol with 2-iodoaniline giving mainly the corresponding quinolines. The same tendency is observed in the case of 1,1-dimethylallyl alcohol affording either γ-arylated alcohols or (E)-1-arylisoprenes.

Full text of DOI:10.1002/adsc.200700301

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DOI: 10.1002/adsc.200700301
Arylation of Allyl Alcohols in Organic and Aqueous Media
Catalyzed by Oxime-Derived Palladacycles: Synthesis of
b-Arylated Carbonyl Compounds
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: June 22, 2007; Published online: November 21, 2007
Dedicated to Prof. Jan Bäckvall on the occasion of his 60th birthday.
Abstract: A 4-hydroxyacetophenone oxime-derived a source of Pd(0)species, operates mainly through a
palladacycle catalyzes the Mizoroki–Heck reaction neutral mechanism. This methodology has been ap-
of allyl alcohols with aryl iodides, bromides, and plied to the synthesis of important b-arylated carbon-
chlorides in aqueous and organic solvents. The reac- yl compounds, such as 4-phenylbutan-2-one, 4-(4-hy-
tion takes place in the presence of dicyclohexylme- droxyphenyl)butan-2-one, dihydrochalcones, the
thylamine or cesium carbonate as bases, the addition anti-inflamatory nabumetone, and the fragance b-
of tetrabutylammonium bromide (TBAB)as additive
lilialꢀ. g-Arylation is observed in the reactions of
for aryl bromides and chlorides being necessary. allyl alcohol and but-3-en-2-ol with 2-iodoaniline
Under these reaction conditions, b-arylated alde- giving mainly the corresponding quinolines. The
hydes and ketones are mainly obtained using a same tendency is observed in the case of 1,1-dime-
rather low loading of palladium (0.1–1 mol%). Simi- thylallyl alcohol affording either g-arylated alcohols
lar catalytic activity is shown by a Kaiser oxime or (E)-1-arylisoprenes.
resin-derived palladacycle, which allows one to per-
form recycling and reusing experiments with low Pd
leaching. The high regio- and chemoselectivity ob- Keywords: allyl alcohols; carbonyl compounds; Heck
served supported that these palladacycles, working as reaction; palladacycles; polymeric reagents
Introduction
nal.[1] In addition, b-lilial,ꢀ 3-(4-tert-butylphenyl)-2-
methylpropanal, is a common fragrance and an inter-
b-Arylated saturated aldehydes and ketones are im- mediate in the production of the biodegradable fungi-
portant products as well as useful intermediates for cide fenpropimorph (Corbelꢀ).[11]
the synthesis of valuable pharmaceuticals, natural
One of the most direct and general strategies for
products, and fragrances. Some of these interesting the preparation of these b-arylated saturated carbonyl
ketones are 4-phenylbutan-2-one, an enzyme inhibi- compounds is the Pd-catalyzed arylation of allyl alco-
tor,[1] 4-(4-hydroxyphenyl)butan-2-one, the precursor hols.[12] Allyl alcohols are inexpensive and very con-
of an anticancer agent,[2] and dihydrochalcones,[3] venient starting materials to perform the Mizoroki–
which have shown antifungal, antibacterial,[4] anti- Heck reaction. However, there are problems associat-
cancer,[5] antioxidant,[6] and food sweetener[7] proper- ed with the regioselectivity of this process giving a-
ties. Dihydrochalcones have been used as appropriate and b-arylated carbonyl compounds and also, b- and
intermediates for the synthesis of flavenes[8] and an- g-arylated allyl alcohols with E or Z configuration
thocyanin-derived dyes.[9] Nabumetone, 4-(6’-me- (Scheme 1 and Scheme 2).
thoxy-2’-naphthyl)butan-2-one, has shown good non-
In the case of g-unsubstituted primary and secon-
steroidal anti-inflammatory activity like the a-arylpro- dary allyl alcohols of the type 1, b- and a-arylated sa-
pionic acids, ibuprofen and naproxen.[10] Representa- turated aldehydes or ketones 2 and 3 are predomi-
tive examples of b-arylated saturated aldehydes with nantly formed (Scheme 1), whereas another secon-
similar enzymatic inhibition activity as 4-phenylbutan- dary product can be the unsaturated ketones 4 when
2-one are dihydrocinnamaldehyde and 3-phenylbuta- working under air[13] or in the presence of Cu
(OTf)2
A
[14]
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Scheme 1.
Scheme 2.
(Scheme 1). The formation of g-arylated allyl alcohols ligand free Pd(OAc)2 or the Herrmannꢂs catalyst in
E
R
H
C
A
T
G
5 as major products has been observed by Jeffery in moderate yields.[3]
the reaction of secondary allyl alcohols 1 with aryl io-
Similarly, g-substituted allyl alcohols 7 can suffer g-
dides when stoichiometric amount of a silver salt was and b-arylation with or without double bond isomeri-
used as additive,[15] or in the case of using Cs2CO3 as zation to afford carbonyl compounds 8 and 9 or allyl
base.[16] Similar results have been described when alcohols 10 and 11, respectively (Scheme 2). Caló and
using aryl triflates[17] or iodonium salts.[18] In the case colleagues have found that when working in TBAB as
of the reaction of primary and secondary allyl alco- solvent and using NaHCO3 as base, carbonyl com-
hols 1 with aryl bromides, mainly b-arylated allyl alco- pounds 8 and 9 were formed. However, allylic alco-
hols 5 and a-arylated by-products 6 were formed even hols 10 and 11 were chemoselectively obtained when
in the absence of silver salts[19] (Scheme 1). More re- using TBAA as solvent and base.[21]
cently, Caló and colleagues have reported that the ar-
For Heck reactions with electron-rich alkenes it has
ylation of primary and secondary allyl alcohols 1 with been proposed that the b-arylation occurred through
aryl bromides in ionic liquids, such as tetra-n-butylam- an ionic pathway and the g-arylation takes place via a
monium bromide (TBAB), and NaHCO3 as base gave neutral mechanism, although steric effects can also be
mainly carbonyl compounds 2 as well as a-arylated responsible.[21–24] The ionic pathway is mainly ob-
compounds 3 as by-products.[20] However, using tetra- served when the halide anion is not bonded to Pd(II).
n-butylammonium acetate (TBAA)as ionic liquid
This is the case when silver or thallium salts are
and base, g- and b-arylated allyl alcohols 5 and 6 were added, when employing triflates as arylating reagents,
chemoselectively obtained.[21] Moreover, working in when using halide-free ionic liquids as solvents, or
1-butyl-3-methylimidazolium
tetrafluoroborate when adding diphosphines, such as 1,3-bis(diphenyl-
[bmim]BF4 as ionic liquid and 1,3-bis(diphenylphos- phosphino)propane or 1,1’-bis(diphenylphosphino)fer-
phino)propane (dppp) as ligand, mainly g-arylation of rocene.[24] On the other hand, the isomerization pro-
allyl alcohol with aryl bromides has been observed.[22] cess can be avoided by working in halide-free ionic
Furthermore, the regioselective formation of b-arylat- liquids to give g-arylated allyl alcohols, such as 5 and
ed carbonyl compounds with aryl bromides can be 10.[21]
achieved by using the tetraphosphine Tedicyp as
In our laboratory we have been working on the use
ligand in DMF and with K2CO3 as base with high of oxime-derived palladacycles as a source of highly
turnover numbers (TON).[23] Deactivated aryl bro- active zero-valent palladium nanoparticles for phos-
À
mides have been used for the g-arylation and applied phine-free C C bond forming reactions, Heck,
to the synthesis of a variety of dihydrochalcones using Suzuki, Stille, Ullmann, Cassar–Heck–Sonogashira,
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Figure 1.
Glaser, Hiyama and alkoxycarbonylation reactions of Results and Discussion
alkynes, in organic and aqueous media.[25–28] In this
work the application of the dimeric oxime-derived For the preliminary studies, iodobenzene and but-3-
palladacycles 12–14 and the Kaiser oxime resin deriv- en-2-ol (1a)[29,30] were allowed to react in H2O at
ative 15 (Figure 1)as precatalysts in the chemo- and
1208C in a pressure tube with different bases and pre-
regioselective arylation of allyl alcohols in organic catalysts (0.1 mol% Pd loading)(Scheme 3 and
and aqueous solvents, focused to the synthesis of b- Table 1). Initially, dicyclohexylmethylamine was
arylated saturated aldehydes, and ketones, is de- chosen as base, because previous results in Heck reac-
scribed.
tions have shown that this tertiary amine gives better
results than triethylamine.[26l,28] Different palladacyles
Scheme 3.
[a]
Table 1. Heck reactions of but-3-en-1-ol (1a)with iodo- and bromobenzene: reaction conditions study.
Entry PhX
Cat. [mol% Pd] Base
Solvent
Additive
t
Yield [%][b] Ratio[c] 2aa/3aa/5aa/6aa
1
2
3
4
5
6
7
8
PhI
12 [0.1]
13 [0.1]
13 [0.1]
14 [0.1]
15 [0.1]
Cy2NMe H2O
Cy2NMe H2O
Cy2NMe H2O
Cy2NMe H2O
Cy2NMe H2O
Cy2NMe H2O
-
-
-
-
-
-
-
-
6 h
6 h
0
-
98 (89)44/15/3.5/1
10 min[d] 81
28/1.5/3/1
45/1.5/2.5/1
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
93
99 (92)44/1.5/3.5/1
Pd
A
75
76
65
67
68
29/1/2.5/1
13 [0.1]
15 [0.1]
Cs2CO3
Cs2CO3
H2O
H2O
33/1/1.5/1.5
3271/8/1.5
44/1.5/3.5/1
35/1/12.5/2
9
PhBr 13 [1]
13 [1]
Cy2NMe H2O
Cs2CO3 H2O
TBAB[e]
TBAB[e]
10
11
12
13
14
15
13 [1]
13 [1]
Cy2NMe DMA:H2O[f] TBAB[e]
96 (83)46/1/2.5/1
Cs2CO3
DMA:H2O[f] TBAB[e]
94
44
81
48
36/1/12/1.5
Pd
A
Cy2NMe DMA:H2O[f] TBAB[e]
30/2/1/0
45/2/2/1
34/1/13/2
15 [1]
15 [1]
Cy2NMe DMA:H2O[f] TBAB[e]
Cs2CO3
DMA:H2O[f] TBAB[e]
[a]
Reaction conditions: phenyl halide (1 equiv.), but-3-en-1-ol (1.5 equivs.), Pd catalyst (see column), base (1.5 equivs.), sol-
vent at 1208C in a pressure tube.
Determined by H NMR by using N,N-diphenylformamide as internal standard. In parenthesis yield of compound 2 after
[b]
1
flash chromatography.
Determined by GC in the crude products.
Under microwave irradiation at 1208C (80 W).
1 equiv.
4/1.
[c]
[d]
[e]
[f]
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[31]
12–15 and Pd
(OAc)2 were evaluated as precatalysts the addition of 1 equiv. of TBAB[33] was necessary in
A
during 6-h reaction times. Under these aqueous condi- order to achieve good conversions in a 6-h reaction
tions, the 4,4’-dichlorobenzophenone oxime-derived time (Table 1, entries 9 and 10). Similar studies in a
palladacycle 12 failed (Table 1, entry 1). However, 4- 1:4 mixture of aqueous N,N-dimethylacetamide
hydroxyacetophenone oxime palladacycle 13 gave (DMA)and in the presence of TBAB and with palla-
products in 98% crude yield, the arylation taking dacycles 13 or 15 (Table 1, entries 11, 12, 14, and 15)
place at the g-position of the allylic alcohol 1a. A 15:1 afforded higher overall yields than when using Pd-
ratio of the b-substituted ketone 2aa and allyl alcohol
A
5aa was regioselectively obtained, whereas only a ditions dicyclohexylmethylamine gave the highest
very small proportion of a-products 3aa and 6aa were ratio of 4-phenylbutan-2-one (2aa)whereas, as above-
[16]
formed (Table 1, entry 2). When this reaction was per- mentioned for iodobenzene, Cs2CO3
favored the
formed under microwave heating,[32] a lower overall formation of allyl alcohol 5aa (Table 1, entries 12 and
yield of 81% and similar regioisomeric ratio were ob- 15).
tained (Table 1, entry 3). Similar results were ob-
served when using dimeric and polymeric palladacy- cluded that dicyclohexylmethylamine is the base of
cles 14 and 15, whereas Pd(OAc)2 gave the lowest choice in order to get mainly the b-arylated ketone, 4-
On the basis of these experiments it can be con-
AHCTREUNG
yield (Table 1, compare entry 2 with entries 4–6). The phenylbutan-2-one (2aa), either with iodo- or bromo-
dimeric palladacycle 14 was chemically characterized benzene. These results indicate that Cs2CO3 promotes
by reduction with sodium cyanoborodeuteride to the to some extent the ionic mechanism facilitating the
corresponding 2-deuteriophenyl 4-nitrophenyl ketone displacement of the halogen atom bonded to the in-
oxime.
Polystyrene-supported
palladacycle
15 termediate ArPdX.[21] In the first case, the process can
(12.5 mggÀ1 of polymer)was prepared from commer-
be performed in neat water and in the case of bromo-
cially available Kaiser oxime resin by treatment with benzene TBAA must be used as additive and aqueous
Li2PdCl4 in MeOH and NaOAc as base.[28] However, DMA as solvent. Concerning the catalyst, similar re-
when Kaiser oxime resin was treated with a solution sults were obtained using dimeric and polymeric pal-
of Li2PdCl4 in the absence of NaOAc as base, the re- ladacycles with relative low loadings of Pd, whereas
sulting polymer gave products 2aa, 3aa, 5aa, and 6aa Pd
ACHTREUNG
in only 16% overall yield working under the same re-
action conditions as complex 15 (Table 1, entry 5). the Heck reaction of secondary (1a,b)and primary
The use of inorganic bases, such as KOH, K2CO3, (1c,d)allyl alcohols with different aryl halides using
K3PO4, and NaOAc in the presence of palladacycle 13 dimeric and polymeric palladacycles 13–15 as precata-
provided lower yields and increased the proportion of lysts (Scheme 4 and Table 2). The arylation of but-3-
g-arylated allyl alcohol 5aa.[16] The best inorganic base en-1-ol (1a)was performed with iodobenzene
was Cs2CO3 which, in the presence of complexes 13 (Table 1, entries 2 and 5)and 4-iodophenol using dicy-
and 15, gave Heck products in 76 and 65% yield, re- clohexylmethylamine as base in H2O as solvent
spectively, with ca. 65:30 ratio of 2aa:5aa and 5% of (Table 2, entries 1 and 2)and with palladacycles 13
products 3aa and 6aa resulting from the b-arylation of and 15 as precatalyst in order to prepare 4-phenylbu-
1a (Table 1, entries 7 and 8).
tan-2-one (2aa)[1] and the precursor of an anticancer
When the coupling experiments were performed agent 4-(4-hydroxyphenyl)butan-2-one (2ab),[2] re-
using deactivated bromobenzene in the presence of spectively, in very good yields. The arylation with the
palladacycle 13 (1 mol% Pd loading)and dicyclohex-
highly deactivated 4-iodophenol needed the addition
ylmethylamine or Cs2CO3 as bases in H2O as solvent, of TBAB and to increase to 1 mol% the loading of
Scheme 4.
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Pd, taking place without protection of the OH group formed. The synthesis of 2be in moderate yields was
as occurred in the case of the arylation in ionic liq- also performed with 2-bromophenol, increasing the
uids.[20] In this case the proportion of allyl alcohol 5ab loading of palladacycles 13 and 15 to 3 mol% of Pd
was higher than in the former case for 5aa.
(Table 2, entries 17 and 18), similar results being ob-
The synthesis of 4-phenylbutan-2-one (2aa)[1] and tained in DMA as solvent (Table 2, entry 19). In these
the anti-inflamatory nabumetone (2ac)[10] was per- couplings 10% of 2-hydroxychalcone (4be)was also
formed by the Heck reaction of but-3-en-2-ol (1a) formed.
with bromobenzene (Table 1, entry 11)and 6-me-
The presence of an additional OH group in the aryl
thoxy-2-bromonaphthalene (Table 2, entry 3), respec- bromide, as in 3-hydroxy-6-bromophenol, transforms
tively, under the reaction conditions described in it into a complicated coupling partner. It has been
Table 1. These arylations were performed in aqueous coupled previously with 1-phenylprop-2-en-1-ol (1b)
DMA using TBAB as additive and 0.5 mol% loading by using 3 mol% of Herrmannꢂs phosphapalladacycle
of palladacycle 13. In the case of nabumetone (2ac), at 1408C to give ketone 2bf in 45% yield.[3] In our
less than 3% of allyl alcohol 5ac was obtained and case, the developed palladacycles 13–15 were assayed
the ketone could be isolated in 82% yield. Similar re- for this arylation reaction under the typical reaction
sults were obtained by using dimeric and polymeric conditions for aryl bromides: dicyclohexylmethyl-
palladacycles 14 and 15, respectively (Table 2, en- amine, TBAB in aqueous DMA at 1208C (Table 2,
tries 4 and 5). The Pd loading could be decreased to entries 20–22). The same results were obtained in all
0.5 mol% in the case of catalyst 13, the reaction time cases and the dihydrochalcone 2bf was isolated in
being increased from to 9 h to 1 d (Table 2, compare 33% yield (Table 2, entry 20).
entries 3 and 6). Similar results were observed using
DMA as solvent with palladacycles 13 and 15, giving iodides in water as solvent (Table 2, entries 23–34).
nabumetone (2ac)in very good yields (Table 2, en- Thus, allyl alcohol (1c)reacted with iodobenzene in
Primary alcohols 1c and 1d were arylated with aryl
tries 7 and 8). An activated aryl chloride, such as 4-tri- water in the presence of palladacycles 13 or 15 (0.1
fluoromethyl-1-chlorobenzene could also be used as mol% Pd loading)giving mainly 3-phenylpropanal
arylating reagent of 1a with palladacycles 13 or 15 (1 (2ca)in good yields (Table 2, entries 23–26). In gener-
mol% of Pd)working in neat DMA and in the pres-
al, product 2ca could be obtained in a higher propor-
ence of TBAB in 1 d reaction time, giving exclusively tion using dicyclohexylmethylamine as base than with
compounds 2ad and 5ad in 13/1 or 9/1 ratio, respec- Cs2CO3 (Table 2, compare entries 23 and 24 with 25
tively, in moderate yields (Table 2, entries 9 and 10). and 26). When this coupling was performed with
In these last two cases, 8% of the homocoupling phenyl bromide, similar results were obtained with
product 4,4’-bis(trifluoromethyl)biphenyl and 8% of precatalysts 13 and 15 (1 mol% Pd), working in aque-
the a,b-unsaturated ketone (E)-4-(4-trifluoromethyl- ous DMA (Table 2, entries 27 and 28). Methallyl alco-
phenyl)but-3-en-2-one (4ad)were also obtained.
hol (1d)was coupled with 4- tert-butylphenyl iodide
Next, the synthesis of dihydrochalcones by Heck re- and bromide in order to synthesize 3-(4-tert-butyl-
action, recently described by Mioskowski and collea- phenyl)-2-methylpropanal (2dg)or b-lilial.ꢀ The ary-
gues,[3] was attempted by performing the arylation of lations with the iodide were performed in water as
the secondary alcohol 1-phenylprop-2-en-1-ol (1b) solvent using complexes 13–15 (0.1 mol% Pd load-
with different aryl iodides and bromides (Table 2, en- ing), affording exclusively the expected product 2dg
tries 11–22). In the case of iodobenzene, 1,4-diphenyl- in high yields (Table 2, entries 29–31). Alternatively,
propan-2-one (2ba)was formed with a high chemo-
4-tert-butylphenyl bromide can be used for the prepa-
and regioselectivity when using water as solvent in ration of 2dg increasing the Pd loading to 1 mol%
the presence of low loading (0.1 mol% of Pd)of 13 and after addition of TBAB, DMA being the best sol-
or 15 with (Table 2, entries 11 and 12). We also at- vent (Table 2, compare entries 32–34).
tempted a difficult coupling partner under Heck con-
A one-pot synthesis of quinolines via vinylation or
ditions, such as 2-iodophenol.[3] In our hands, when indoles by sequential N-allylation-vinylation[34,35] was
the reaction with 1b was performed in H2O in the attempted by coupling of 2-iodoaniline with but-3-en-
presence of TBAB as additive, a 68% yield of a mix- 2-ol (1a)and allyl alcohol ( 1c)in water or aqueous
ture of 2be/3be/5be/6be in a 10/1/2/1 ratio was ob- DMA using palladacycles 13 and 15 (1 mol% Pd)as
tained (Table 2, entry 13). In the absence of TBAB precatalysts (Scheme 5 and Table 3). In the case of al-
lower yields were obtained using both Pd complexes cohol 1c, a ca. 4/1 mixture of quinoline (16c) and 3-
13 and 15 (Table 2, entries 14 and 17). The best results methylindole (17c)was obtained either in water or in
were obtained working in aqueous DMA as solvent aqueous DMA using K2CO3 or dicyclohexylmethyla-
and in the presence of TBAB, giving product 2be in mine as bases (Table 3, entries 1–6). In addition, the
the highest ratio and with 87% overall yield (Table 2, dimeric compound 18 was also formed, probably by
entry 16). In all these experiments, a 12% yield of the 1,4-conjugate addition of intermediate 1,2-dihydroqui-
b-arylated a,b-unsaturated ketone 4be was also noline to quinoline. When but-3-en-2-ol (1a)was al-
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Scheme 5.
Table 3. Heck reactions of allyl alcohol (1c)and but-3-en-1-ol ( 1a)with 2-iodoaniline. [a]
Entry Allyl Alco-
hol
Cat. Base
Solvent
Additive t
Conv.
Ratio[c] 16/ Yield 16
17
Yield 18
[h] [%][b]
[%][d]
[%][d]
1
2
3
4
1c
1c
1c
1c
1c
1c
1a
1a
13
13
15
13
15
15
13
15
K2CO3
Cy2NMe H2O
Cy2NMe H2O
H2O
-
-
-
24 76
14 82
24 74
4/1
6/1
4/1
4/1
5/1
6/1
9/1
8/1
36
20
41 (34)24 (18)
33
39
43
19
16
15
19
Cy2NMe DMA:H2O[e] TBAB
Cy2NMe DMA:H2O[e] TBAB
Cy2NMe DMA:H2O[e] TBAB
Cy2NMe DMA:H2O[e] TBAB
Cy2NMe DMA:H2O[e] TBAB
8
80
5
20 81
20 82
6[f]
7
45
8
79
52[g] (44)-
49[h]
8
16 82
-
[a]
Reaction conditions: 2-iodoaniline (1 mmol), allyl alcohol (1.5 mmol), Pd catalyst (1 mol%), base (1.5 mmol), TBAB
(1 mmol), H2O (2 mL)or DMA:H O (5 mL)at 120 8C in a pressure tube.
2
[b]
[c]
[d]
[e]
[f]
Determined by GC in the crude products.
1
Determined by H NMR in the crude product.
1
Determined by H NMR. In parenthesis yield after flash chromatography.
Under microwave irradiation at 1208C (80 W).
4/1.
The reaction was performed in a flask with a reflux condenser.
A 6% of 2-methyl-1,2,3,4-tetrahydroquinoline was also obtained.
A 11% of 2-methyl-1,2,3,4-tetrahydroquinoline was also obtained.
[g]
[h]
[i]
lowed to react with 2-iodoaniline in aqueous DMA a iodobenzene in water in the presence of complexes 13
9/1 mixture of 2-methylquinoline (16a)and 2,3-dime-
thylindole (17a)was mainly obtained together with
small amounts (6–11%)of 2-methyl-1,2,3,4-tetrahy-
and 15 (0.1 mol% Pd)gave a ca. 4:1 mixture of alco-
hol 20a and arylated isoprene 21a (Table 4, entries 1
and 2). Diene 21a was exclusively obtained after
droisoquinoline (Table 3, entries 7 and 8). All these treatment of the reaction mixture with 2M HCl for
compounds could be isolated after flash chromatogra- 5 min (Table 4, entries 3 and 4). When the same aryla-
phy.
tion was carried out in aqueous DMA, similar results
The former tendency to vinylation has also been were obtained (Table 4, entries 5–7). In the absence
observed in the Heck coupling of 1,1-dimethylallyl al- of TBAB, the ratio 20a/21a increased up to 11:1
cohol (19)[34,36] with iodobenzene and 2-iodoaniline (Table 4, entry 6). However, the coupling of dimethyl-
(Scheme 6 and Table 4). Thus, the arylation of 19 with allyl alcohol (19)with 2-iodoaniline in water failed
Scheme 6.
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Table 4. Heck reactions of 2-methylbut-3-en-2-ol (19)with aryl iodides. [a]
Entry
R
Cat. [mol% Pd]
Solvent
Additive
t [h]
Ratio[b] 20/21
Yield [%][c]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
2-NH2
2-NH2
2-NH2
2-NH2
2-NH2
13 [0.1]
15 [0.1]
13 [0.1]
15 [0.1]
13 [0.1]
13 [0.1]
15 [0.1]
13 [1]
14 [1]
15 [1]
13 [1]
13 [1]
H2O
H2O
H2O
H2O
-
-
-
-
6
6
6
6
3
4
4
8
20
10
14
24
4/1
3/1
76
71 (62)
72 (65)[e]
61[e]
61
71
0/100[d]
0/100[d]
7/3
DMA:H2O[f]
DMA:H2O[f]
DMA:H2O[f]
DMA:H2O[f]
DMA:H2O[f]
DMA:H2O[f]
DMA:H2O[f]
DMA:H2O[f]
TBAB
-
-
TBAB
TBAB
TBAB
-
-
12/1
8/1
-
-
-
74
88 (70)[g]
72[h]
9
10
11
12
81[h]
1/13
1/12
51 (38)[i]
62[j]
[a]
Reaction conditions: aryl iodide (1 mmol), allyl alcohol 19 (1.5 mmol), Pd catalyst (see column), Cy2NMe (1.5 mmol),
TBAB (1 mmol), H2O (2 mL)or DMA:H O (5 mL)at 120 8C in a pressure tube.
2
[b]
[c]
[d]
[e]
[f]
Determined by GC in the crude products.
1
Determined by H NMR. In parenthesis yield of compound 20 after flash chromatography.
Acid work up (2M HCl).
Only compound 21b was obtained.
4:1.
For compound 21b. A 35% of homocoupled 2,2’-biphenyldiamine and 5% of compound 20b were also obtained.
For compound 21b.
For compound 21b.
[g]
[h]
[i]
[j]
A 21% of homocoupled 2,2’-biphenyldiamine and 5% of compound 20b were also obtained.
and in aqueous DMA gave mainly the diene 21b was chosen as the first model reaction (Table 6, en-
(Table 4, entries 8–12). This methodology is a good tries 1–10). After 4 runs at 1208C and 0.1 mol% load-
strategy for the stereoselective synthesis of (E)-1-aryl- ing of Pd the yield decreased until 44% and the reac-
isoprenes.[37,38]
tion time increased from 7 to 36 h. Lowering the tem-
When crotyl alcohol (7a) , ag-substituted allylic al- perature down to 808C under 1 mol% Pd loading, al-
cohol, was cross-coupled with iodobenzene under lowed us to keep the yield in the range 81–88%
water reflux in the presence of dicyclohexylmethyl- during 5 runs, the reaction time being increased from
amine or Cs2CO3 as bases, products 8aa, 9aa, 10aa, 4 to 24 h (Table 6, entries 5–10). In the sixth run the
and 11aa were formed (Scheme 7 and Table 5). The yield decreased to 61% after 24 h reaction time, and
best yields and isomer ratios for the b-arylated alde- the Pd contents in the polymer was determined to be
hyde 8aa were observed when dicyclohexylmethyla- 51% with respect to the starting complex (ICP-OES),
mine was used as base (Table 5, compare entries 1 which means that the average leaching of Pd per
with 2 and 4 with 5), palladacycle 14 giving the high- cycle was around 8%. For the coupling of 2-bromo-6-
est yield (Table 5, entry 3). When the arylation was methoxynaphthalene with 1a to give nabumetone
performed with phenyl bromide, a higher loading of (2ac), DMA was used as solvent with 1 mol% of Pd
Pd (1 mol%), aqueous DMA as solvent, and TBAB at 1208C (Table 5, entries 11–14). The polymeric pre-
as additive were used (Table 5, entries 6 and 7). Allyl catalyst was active during 3 runs and started to dimin-
alcohols 10aa and 11aa were obtained in very low ish the activity in the fourth cycle, the Pd loading of
ratio and with E-configuration.
the polymer being 80%. The temperature and the
For the recycling studies of the polymeric complex long reaction times seem to deteriorate the polymeric
15, the coupling of iodobenzene with but-3-en-1-ol complex, especially in organic solvents as it was de-
(1a)in water to provide 4-phenylbutan-2-one ( 2aa) scribed before with electron-poor alkenes.[28]
Scheme 7.
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Table 5. Heck reactions of (E)-but-2-en-1-ol (7a)with iodo- and bromobenzene. [a]
Entry PhX
Cat. [mol% Pd] Base
Additive Solvent
t [h] Ratio [%][b] 8aa/9aa/10aa/11aa Yield [%][c]
1
2
3
4
5
6
7
PhI
PhI
PhI
PhI
PhI
PhBr 13 [1]
PhBr 15 [1]
13 [0.1]
13 [0.1]
14 [0.1]
15 [0.1]
15 [0.1]
Cs2CO3
-
-
-
-
-
H2O
H2O
H2O
H2O
H2O
14
9
10
14
10
20/1/3/1
14/1/1/0
16/1/1/0
45/1.5/2.5/1
15/1.5/1/0
16/1/1/0
11/1/1/0
65
79
88
63
83 (74)
74 (60)
61
Cy2NMe
Cy2NMe
Cs2CO3
Cy2NMe
Cy2NMe TBAB
Cy2NMe TBAB
DMA:H2O[d] 10
DMA:H2O[d] 19
[a]
Reaction conditions: halobenzene (1 mmol), (E)-but-2-en-1-ol (7a) (1.5 mmol), Pd catalyst (see column), base (1.5 mmol),
TBAB (1 mmol), H2O (2 mL)or DMA/H O (5 mL)at 120 8C in a pressure tube.
2
[b]
[c]
Determined by GC in the crude products.
1
Determined by H NMR by using N,N-diphenylformamide as internal standard. In parenthesis yield of compound 8aa
after flash chromatography.
4:1.
[d]
Table 6. Recycling experiments for the heck reaction of but-3-en-1-ol (1a)with iodobenzene or 2-bromo-6-methoxynaphtha-
lene catalyzed by palladacycle 15.[a]
Entry
Run
mol% Pd
Solvent
T [8C]
Additive
t [h]
Ratio[c] 2/3/5/6
Yield [%][b]
Product 2
1
2
3
4
5
6
7
8
1
2
3
4
1
2
3
4
5
6
1
2
3
4
0.1
0.1
0.1
0.1
1
1
1
1
1
1
1
1
1
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
DMA
DMA
DMA
DMA
120
120
120
120
80
80
80
80
80
-
-
-
-
7
58/3/4/1
89/5/5/1
43/3.5/2.5/1
19/3/1/1
91/0/8/1
90/3/6/1
45/1/3/1
23/2/1/1
37/1/2/0
17/1/1/1
24/1/0/0
97/2/1/0
49/1/0/0
28/1/0/1
98
84
85
44
83
88
86
84
81
62
86
81
76
38
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2ac
2ac
2ac
2ac
14
24
36
4
6
10
15
24
24
8
14
24
24
9
10
11
12
13
14
80
120
120
120
120
TBAB[d]
TBAB[d]
TBAB[d]
TBAB[d]
1
[a]
Reaction conditions: aryl halide (1 equiv.), but-3-en-1-ol (1.5 equivs.), 15 (see column), dicyclohexylmethylamine
(1.5 equiv.), TBAB (see column), solvent, in a pressure tube.
Determined by H NMR by using N,N-diphenylformamide as internal standard.
Determined by GC in the crude products.
1 equiv.
[b]
[c]
[d]
1
Conclusions
tone and b-lilial.ꢀ In the case of 2-iodoaniline, vinyla-
tion followed by dehydrogenation took place prefer-
In conclusion, we have found that dimeric and poly- entially instead of N-allylation-vinylation to afford
meric oxime-derived palladacycles are appropriate mainly quinolines. The same tendency to vinylation
precatalysts for the synthesis of b-arylated ketones or was observed in the reaction of 1,1-dimethylallyl alco-
aldehydes using a Heck reaction with allyl alcohols, hol to give g-arylated alcohols, which suffer easy dia-
employing dicyclohexylmethylamine better than stereoselective dehydration to the corresponding (E)-
Cs2CO3 as base at 1208C. However, Pd
lower yields under the same reaction conditions. Aryl electron-rich alkenes employing these Pd nanoparti-
iodides can be coupled with 0.1 mol% of Pd in water cle-generating palladacycles,[28] support
neutral
(OAc)2 gave 1-arylisoprenes. The results in the Heck reaction, with
a
as solvent, and aryl bromides in aqueous DMA in the mechanism for this process. The Kaiser oxime resin
presence of TBAB as additive with higher Pd loading derivative 15 has been reused when working in water
(1 mol%). These reaction conditions are very conven- and in DMA as solvents, giving the best performance
ient for the synthesis of 4-phenylbutan-2-one, 4-(4-hy- in water at 808C with relative low leaching of Pd.
droxyphenyl)butan-2-one, dihydrochalcones, nabume-
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13C NMR (75 MHz, DMSO-d6): d=123.4, 126.8, 128.5,
128.6, 130.5 (ArCH), 128.9 (t, J=31.0 Hz, ArC-D), 129.3,
135.5, 140.4, 147.3 (ArC), 153.8 (C=N); MS: m/z (%)=243
(M+, 100), 226 (40), 196 (10), 180 (52), 166 (20), 78 (26);
anal. calcd.: C 64.19, H 4.56, N 11.52; found: C 63.85, H
4.52, N 11.26%.
Experimental Section
General Remarks
The reagents and solvents were obtained from commercial
sources and were generally used without further purifica-
tion. Flash chromatography was performed on silica gel 60
(0.040–0.063 mm, Merck). Thin layer chromatography was
perfomed on Polygramꢀ SIL G/UV254 plates. Melting points
were determined on a Reichert Thermovar apparatus. Gas
chromatographic analyses were performed on a HP-6890 in-
strument equipped with a WCOT HP-1 fused silica capillary
column. IR data were collected on a Nicolet Impact-400D-
FT spectrophotometer in cmÀ1. 1H NMR spectra were re-
corded on Bruker AC-300 (300 MHz)and Bruker AC-400
(400 MHz). Chemical shifts are reported in ppm using tetra-
methylsilane (TMS, 0.00 ppm)as internal standard.
13C NMR spectra were recorded at 75 or 100 MHz. EI-MS
were measured on a Mass Selective Detector G2579 A from
Agilent Technologies 5973N in m/z (rel. intensity in% of
base peak). The catalysts were weighed up in an electronic
microscale (Sartorius, XM1000P)with precision of 1 mg.
ICP-OES analyses were performed in a Perkin–Elmer
Optima 4300 spectrometer. Microwave reactions were per-
formed with a CEM Discover Synthesis Unit in glass vessels
(10 mL)sealed with a septum under magnetic stirring. Palla-
dacycles 12 and 13 and Kaiser oxime resin are commercially
available.
Synthesis of Kaiser Oxime-Derived Complex 15
To a suspension of Kaiser oxime resin (1.4 g, 1.5 mmol)and
NaOAc (0.124 g, 1.5 mmol)in MeOH (4 mL)was added a
0.5M methanolic solution of Li2PdCl4 (3 mL, 1.5 mmol).
The mixture was stirred during 7 d at 258C. After adding
water (10 mL), the corresponding polymer was filtered off
and dried over P2O5 to give 1.4 g of a brown solid. The pal-
ladium content was determined by ICP-OES: 12.5 mg Pd/g
of polymer. For the ICP-OES analyses, the resin was decom-
posed with HNO3. When the palladation was performed in
the absence of NaOAc the resulting polymer had 73 mg Pd/
g of polymer.
Typical Experimental Procedure for the Heck
Reaction of Aryl Iodides and Allyl Alcohols in Water
A
mixture of allyl alcohol (1.5 mmol)and the base
(1.5 mmol)in water (2 mL)was stirred during 15 min at
room temperature. Then, the catalyst (see Tables 1–6)and
the aryl iodide (1 mmol)were added, the bath temperature
was raised to 1208C in a pressure tube and the reaction was
monitored by GC. After the reaction was completed, it was
cooled at room temperature and an aqueous solution of 2M
HCl (5 mL)was added to the reaction mixture and stirred
for 10 min. Then, the reaction crude was poured into ethyl
acetate (40 mL)and the organic layer washed with brine
Synthesis of Palladacycle 14
A methanolic solution (2 mL)of the corresponding oxime
(0.484 g, 2 mmol)and NaOAc (0.165 g, 2 mmol)was added
over a solution of Li2PdCl4 (0.524 g, 2 mmol)in MeOH
(4 mL). Then, the solution was stirred for 3 days at room
temperature. After adding water (10 mL), the resulting pre-
cipitate was filtered off (G-3)and dried under reduced pres-
sure over P2O5 to give the title compound 14; yield: 0.723 g
(3”20 mL)and dried over MgSO . The solution was evapo-
4
rated (15 mm Hg)and the residue was purified by flash
chromatography in hexane/ethyl acetate.
(94%); yellow solid; mp 245 8C; IR (KBr): n=3307 (OH),
1612 (C=N), 1518, and 1352 (N=O)cm
Typical Experimental Procedure for Heck Reaction
of Iodobenzene and But-3-en-2-ol (1a) under
Microwave Irradiation
À1
;
1H NMR
(300 MHz, DMF-d7): d=6.75 (d, 1H, J=4.35 Hz), 7.04 (m,
2H), 7.78 (m, 1H), 7.95 (d, 2H, J=8.6 Hz), 8.50 (d, 2H, J=
8.3 Hz), 11.15 (br s, 1H); 13C NMR (75 MHz, DMF-d7): d=
124.2, 124.9, 127.7, 128.6, 131.2, 136.6, 142.8 (ArC), 149.0
(C=N); anal. calcd.: C 40.76, H 2.37, N 7.31; found: C 41.98,
H 2.39, N 7.16%.
A pressure glass vessel (10 mL)was charged with allyl alco-
hol 1a (0.090 mL, 0.75 mmol)and Cy 2NMe (0.160 mL,
0.75 mmol)in water (1 mL)and the reaction mixture was
stirred during 10 min at 258C. Then, the complex 13 (0.1
mol% Pd, 0.145 mg)and iodobenzene (0.055 mL, 0.5 mmol)
were added and the pressure tube was sealed with a septum,
starting the microwave heating (40 W, 3.5 bar, 1208C, 10 min
with air-stream cooling). The product was extracted with di-
ethyl ether (5”10 mL), the combined organic layers were
washed with aqueous solutions of 2M HCl (2”25 mL), and
water (2”20 mL). Finally, the organic layer was dried over
MgSO4 and the solvents were removed under vacuum
(15 mm Hg)to give an oil.
Reduction of Palladacycle 14; Synthesis of 2-
Deuteriophenyl 4-Nitrophenyl Ketone Oxime
To a solution of complex 14 (77 mg, 0.1 mmol)in THF
(5 mL)and MeOH (1 mL)was added sodium cyanoboro-
deuteride (26 mg, 0.4 mmol)at 0 8C and the mixture was
stirred for 1 h while being allowed to warm to room temper-
ature. The black precipitate was filtered off and the filtrate
was evaporated (15 mm Hg). To the residue was added H2O
and the solution was extracted with EtOAc. The organic
layer was dried and evaporated to give a solid, which was
purified by recrystallization to give the title compound;
yield: 44 mg (91%); green solid; mp 133–135 8C; IR (KBÀr)1:
Typical Experimental Procedure for the Heck
Reaction of Aryl Bromides or Chlorides and Allyl
Alcohols in Organic Solvents
n=3300 (OH), 1612 (C=N), 1532, 1338 (N=O)cm
;
A mixture of allyl alcohol (1.5 mmol), Cy2NMe (0.320 mL,
1.5 mmol)or Cs 2CO3 (0.488 g, 1.5 mmol)and TBAB
(0.322 g, 1 mmol)was stirred for 15 min in DMA (3 mL)or
1H NMR (300 MHz, DMSO-d6): d=7.39 (m, 4H), 7.59 (d,
J=7.5 Hz, 2H), 8.31 (d, J=8.7 Hz, 2H), 11.70 (s, 1H);
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Synthesis of b-Arylated Carbonyl Compounds
4/1 DMA/H2O (5 mL)in a pressure tube at room tempera-
ture. Then, the catalyst (see Tables 1–6)and aryl halide
(1 mmol)were added, the temperature was increased to
1208C and the progress of reaction was analyzed by GC.
After the reaction was completed, it was cooled at room
temperature and an aqueous solution of 2M HCl (5 mL)
was added to the reaction mixture, stirring for 10 min. Then,
the reaction crude was poured into ethyl acetate (40 mL)
and washed with brine (3”20 mL). The organic layer dried
over MgSO4, evaporated (15 mm Hg)and the residue was
purified by flash chromatography in hexane/ethyl acetate.
1H), 6.75 (m, 1H) 6.78 (d, J=16.4 Hz, 1H), 7.05 (m, 1H),
7.32 (d, J=7.7 Hz, 1H); 13C NMR (CDCl3). d=18.7 (CH3),
116.3 (CH2), 117,2, 119.2, 123.9, 124.0 (ArCH), 127.7, 128.5
(CH=CH), 133.4 (ArC), 142.3 (C=CH2), 143.9 (C-N); MS:
m/z (%)=160 (M+ +1, 7), 159 (M+, 60), 158 (M+-1, 62), 144
(100), 143 (63), 128 (15), 127 (15), 115 (14); HR-MS: m/z=
159.1052, calcd. for C11H13N: 159.1048.
Acknowledgements
We thank DGES of the Spanish Ministerio de Educación y
Ciencia (MEC) (grants: CTQ2004–00808/BQU, CTQ2007–
62771/BQU, and Consolider INGENIO 2010 CSD2007–
00006), the Generalitat Valenciana (grant: GRUPOS05/11),
and the University of Alicante for financial support. E. A.
thanks MEC for a predoctoral fellowship.
Typical Experimental Procedure for the Heck
Reaction with Allyl Alcohols and Aromatic Halides;
Recycling Experiments
The reaction was performed under the previously described
conditions: aromatic halide (1 mmol), allylic alcohol
(1.5 mmol), Cy2NMe (0.320 mL, 1.5 mmol), catalyst 15 (0.1–
1 mol%, 8.2–82 mg), solvent H2O (2 mL)or DMA (4 mL)
and TBAB (0.322 g, 1 mmol, see Tables), heating at the cor- References
responding temperature (see, Table 5). When the reaction
was finished, the catalyst was filtered off (G-4, 1 cm diame-
ter and 8 cm height), washed with ethyl acetate and dried
under vacuum for 20 min. Work-up of the crude was per-
formed as has been described before.
The compounds 2aa, 2ab, 2ac, 2ca, 2dg, 8aa, 16a, 16c, 17a,
17c and 20a are commercially available and compounds
2ad,[39] 2be,[40] 2bf[3] and 21a[37,38] have been previously re-
ported.
[1] Y. V. S. N. Murthy, Y. Meah, V. Massey, J. Am. Chem.
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[2] S. Ducki, J. A. Hadfield, L. A. Hepworth, N. J. Law-
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[4] J. B. Harbone, H. Baxter, in: The Handbook of Natural
Flavoids, Wiley, New York, 1999, vol. 2.
3’,4’-Dihydro-2H-1,4’-biquinoline (18): Yellow solid; mp
95–978C; Rf 0.17 (hexane/AcOEt, 5/1); IR (film): n=3058
[5] M. Kobori, H. Shinmoto, T. Tsushida, K. Shinohara,
À1
1H NMR
Cancer Lett. 1997, 119, 207–212.
À
À
(=C H), 1615 (C=C), 1308 (C N)cm
;
(400 MHz, CDCl3): d=02.09–2.30 (m, 2H), 2.70–2.80 (m,
1H), 2.90–3.05 (m, 1H), 4.67 (dd, J=11.9 and 4.4 Hz, 1H),
6.62 (d, J=10.4 Hz, 1H), 6.70 (t, J=7.2 Hz, 1H), 6.95–7.10
(m, 2H), 7.54 (t, J=7.5 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H),
7.80 (d, J=8.2 Hz, 1H), 8.05–8.15 (m, 2H), 8.93 (m, 1H);
13C NMR (100 MHz, CDCl3): d=26.2 (NCH2), 31.0
(NCHCH2), 54.2 (NCHCH2), 114.4, 120.9 (CH=CH), 117.9,
127.0, 127.2, 127.9, 128.1, 129.2, 129.4, 129.5 (ArCH), 133.4,
137.5, 144.3, 147.8 (ArC), 150.2 (CH=N); MS: m/z (%)=
262 (M+ +2, 1), 261 (M+ +1, 16), 260 (M+, 100), 259 (M+À1,
33), 256 (61), 132 (39), 130 (31); HR-MS: m/z=260.1305,
calcd. for C18H16N2: 260.1313.
[6] a)L. Mathiesen, K. E. Malterud, R. B. Sund, Free
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189–191.
(E)-3-(2-Aminophenyl)-1-methylbut-3-en-2-ol
(20b):
White solid; mp 92–938C; Rf 0.30 (hexane/AcOEt, 1/1); IR
(film): n=3389, 3307 (NH2), 3223 (OH), 2969 (CH3), 1649,
1
1602 (C=C), 1492 (C C), 1158–1141 (C O)cm À1; H NMR
(400 MHz, CDCl3): d=1.39 (s, 6H), 3.21 (br s, 3H), 6.19,
6.63 (2d, J=15.9 Hz, 2H), 6.66 (m, 1H), 6.74 (t, J=7.5 Hz,
1H), 7.06 (dt, J=7.6, 1.5 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=30.1 (2CH3), 71.3 (CO),
À
À
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À1
À
(NH2), 3076 (=C H), 1626, 1616 (C=C)cm
;
1H NMR
(300 MHz, CDCl3): d=1.97 (s, 3H), 3.75 (br s, 2H), 5.06,
5.09 (2 s, 2H), 6.58 (d, J=15.9 Hz, 1H), 6.68 (d, J=7.9 Hz,
Adv. Synth. Catal. 2007, 349, 2572 – 2584
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2583

DEDICATED CLUSTER
FULL PAPERS
Emilio Alacid and Carmen Nµjera
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presence
of
tetra-n-butylammonium
chloride
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R
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N
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2584
asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2572 – 2584