Highly selective palladium-catalyzed direct c-h α-monoarylation of carbonyl compounds using water containing the surfactant polyoxyethylene- α-tocopheryl sebacate (PTS) as a solvent

Article abstract of DOI:10.1002/adsc.201000810

Highly selective direct C-H α-monoarylation reactions of 4-chromanones, ketones and 2-phenylacetaldehyde with aryl halides have been performed in satisfactory yields by using a tris(dibenzylideneacetone) dipalladium(0)/tri-tert-butylphosphine tetrafluoroborate catalyst system, potassium bicarbonate as the base and a solvent consisting of pure water containing a small amount of polyoxyethylene-α-tocopheryl sebacate (PTS). Analogous reaction conditions have been employed in a tandem process leading to phenyl-substituted isocoumarins from carbonyl compounds and methyl 2-bromobenzoate.

Full text of DOI:10.1002/adsc.201000810

UPDATES
DOI: 10.1002/adsc.201000810
À
Highly Selective Palladium-Catalyzed Direct C H
a-Monoarylation of Carbonyl Compounds using Water
Containing the Surfactant Polyoxyethylene-a-Tocopheryl
Sebacate (PTS) as a Solvent
Marco Lessi,a Tiziana Masini,a Luca Nucara,a Fabio Bellina,a,* and Renzo Rossia,*
a
Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
Fax : (+39)-050-2219260; e-mail: bellina@dcci.unipi.itrossi@dcci.unipi.it
Received: October 26, 2010; Published online: February 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000810.
À
Abstract: Highly selective direct C H a-monoaryla-
tion reactions of 4-chromanones, ketones and 2-
phenylacetaldehyde with aryl halides have been
performed in satisfactory yields by using a tris(di-
In the context of our studies on palladium-cata-
lyzed selective direct C H arylation reactions, we
recently described the first examples of palladium-cat-
alyzed direct a-arylation reactions[4] of 4-chroma-
nones 1 with aryl bromides 2 (Scheme 1).[5] In particu-
lar, we developed procedures involving the use of a
[3]
À
ACHTUNGTRENNUNGbenzylideneacetone)dipalladium(0)/tri-tert-butyl-
phosphine tetrafluoroborate catalyst system, potas-
sium bicarbonate as the base and a solvent consist-
ing of pure water containing a small amount of
Pd2ACHTNUGTRENN(GU dba)3/ACHTUNTGRNE(NUGN t-Bu)3PHBF4 catalyst system and KHCO3
as the base that enabled the selective synthesis of iso-
flavanones 3 and 3,3-diaryl-4-chromanones 4 in satis-
factory yields. Interestingly, the relative amount of
compounds 3 versus 4 was found to be dependent on
the amount of water into the reaction medium and
the 1:2 molar ratio. In fact, isoflavanones 3, which
represent an important class of bioactive natural
products,[6] were obtained when a 4:1 mixture of diox-
polyoxyethylene-a-tocopheryl
sebacate
(PTS).
Analogous reaction conditions have been employed
in a tandem process leading to phenyl-substituted
isocoumarins from carbonyl compounds and methyl
2-bromobenzoate.
À
Keywords: C C coupling; direct arylation; isocou-
marins; ketones; palladium; water chemistry
Introduction
A general and effective strategy that emerged over
the last three decades to connect inter- and intramo-
3
À
lecularly aryl units to sp -hybridized C H bonds in
the a-position of carbonyl groups involves the transi-
tion metal-catalyzed direct coupling of aryl halides or
pseudohalides with enolates obtained in situ from the
corresponding carbonyl derivatives under basic condi-
tions.[1]
However, the strong basic conditions often required
by this process are unsuitable for the direct a-aryla-
tion of base-labile substrates, such as aldehydes,
which can give aldol condensation by-products, or 4-
chromanones, which undergo ring-opening to pheno-
late anions.[2]
Scheme 1. Pd-catalyzed direct a-arylation of 4-chromanones
1 in dioxane/H2O or in H2O.
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Marco Lessi et al.
UPDATES
ane and water was employed as a solvent and the 1:2
molar ratio was 2. On the contrary, the use of water
as a reaction medium and a large molar excess of 2
led to the formation of compounds 4 as the only reac-
tion products.[5]
Intrigued by the role played by water, we then de-
cided to evaluate the influence of a variety of ionic
and non-ionic organic surfactants on the efficiency
and selectivity of the a-arylation of 1 with aryl halides
2 in water.[7] On the other hand, it is well known that
organic surfactants are able to self-aggregate into
aqueous micelles able to accomodate hydrophobic
substrates and catalysts, leading to the acceleration of
organic reactions performed in water.[8]
In this update we describe a protocol for the direct
Pd-catalyzed a-monoarylation of 4-chromanones 1
with aryl bromides 2 or chlorobenzene 5a, involving
the use of a reaction medium consisting of pure water
containing a small amount of an amphiphile, which al-
lowed us to improve the synthesis of isoflavanones 3
Scheme 2. Direct a-arylation of 1a with 2a in H2O contain-
ing a surfactant.
Interestingly, the selectivity of the reaction proved
in terms of chemical yields and selectivity compared to be unrelated to the non-ionic or ionic nature of the
with our previously described procedure.[5] Efficient surfactant, but its efficiency was deeply influenced by
direct a-monoarylation reactions of ketones bearing a the chemical structure of this additive. Remarkably, a
À
C H bond in the a-position and 2-phenylacetalde- high yield of 3a was obtained when the reaction was
hyde by using reaction conditions similar to those em- carried out in the presence of 5 wt% PTS in water
ployed for the improved synthesis of compounds 3 using a 2:1 molar ratio between 1a and 2a (entry 4,
are also reported. Finally, a tandem process based on Table 1) and 3a was isolated in the highest yield when
the use of this new a-monoarylation protocol, which water containing 15 wt% PTS was used as a solvent
allowed us to prepare phenyl-substituted isocoumar- (entry 7, Table 1). On the other hand, 3a was isolated
ins is mentioned.
in lower yields when the molar excess of 1a was de-
creased while doubling the reaction time (compare
entries 5 and 6 with entry 4, Table 1).[9] A lower yield
of 3a was also obtained when the reaction tempera-
ture was lowered to 608C (compare entries 7 and 8,
Results and Discussion
We began our study by examining the outcome of the Table 1).
Pd2A(dba)3/A(t-Bu)3PHBF4-catalyzed a-arylation of 4- Good results were also obtained either by using
C
CHTUNGTRENNUNG
chromanone (1a) with bromobenzene (2a) at 1008C CTAB or SDS as the surfactant agent, but the chemi-
in the presence of 2 equivalents of of KHCO3 using cal yields resulted to be lower than those obtained
pure water containing a surfactant as a solvent using PTS (entries 1 and 2, Table 1). On the other
(Scheme 2).
hand, the low yield of 3a obtained by using Tween 80
The commercially available surfactants selected for (entry 3, Table 1) might be ascribed at least in part to
this reaction were the non-ionic amphiphiles polyoxy- protodehalogenation of 2a.[10]
ethylene-a-tocopheryl sebacate (PTS) and polyoxy-
On the basis of these results, we next examined the
ethylene-sorbitan monooleate (Tween 80), the cation- outcome of the reaction of 4-chromanones 1a–c with
ic amphiphile cetyl trimethylammonium bromide aryl bromides 2a–e and chlorobenzene (5a) under the
(CTAB), and the anionic amphiphile sodium dodecyl optimized reaction conditions of entry 7 of Table 1.
sulfate (SDS) (Figure 1).
As shown in entries 1–7 of Table 2, non-activated, de-
We had previously observed that an increase of the activated and activated aryl bromides 2, including
water/dioxane ratio resulted in an increase of the ortho- and para-substituted derivatives, were used,
4a:3a molar ratio in the crude reaction mixtures and and the required isoflavanones 3 were obtained after
that 3,3-diarylated chromanone 4a was exclusively 2–4 h at 1008C in satisfactory chemical yields and
formed when pure water was used as a solvent.[5] with selectivities higher than 95%. Interestingly, bro-
However, we found that the addition of a small mide 2d containing an acidic unprotected OH group
amount of an ionic or non-ionic surfactant to water also gave the required isoflavanone 3d in a satisfacto-
invariably drove the coupling reaction towards the ry yield (entry 4, Table 2).
formation of racemic isoflavanone 3a with selectivity
higher than 95% (entries 1–4, Table 1).
It should also be noted that the use of the water/
PTS solvent system allowed the synthesis of com-
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Highly Selective Palladium-Catalyzed Direct C H a-Monoarylation of Carbonyl Compounds
Figure 1. Chemical structures of PTS, Tween-80, CTAB and SDS.
Table 1. Effect of the surfactant on the direct a-arylation of 1a with 2a in H2O.
Entry[a]
1a:2a ratio
KHCO3 [equiv.]
Surfactant [wt%]
Reaction time [h][b]
Yield [%] of 3a[c]
1
2
3
4
5
2:1
2:1
2:1
2.0
2.0
2.0
2.0
1.2
1.2
2.0
2.0
CTAB (5)
SDS (5)
Tween 80 (5)
PTS (5)
PTS (5)
PTS (5)
PTS (15)
PTS (15)
4
2.5
3.5
2
2
4
67
61
20
70
56
59
83
67
2:1
1.2:1
1.2.1
2:1
6
7
2
7
8[d]
2:1
[a]
Unless otherwise stated, the reactions were performed at 1008C (oil bath) by treatment of 2a (1.0 mmol) with 1a (1.2 or
2.0 mmol) in the presence of 2.5 mol% Pd2A(dba)3, 10 mol% (t-Bu)3PHBF4 in water (5 mL).
The reactions were stopped when the amount of 2a in the reaction mixture was less than 5% (GLC).
Isolated yield.
The reaction was performed at 608C (oil bath).
CTHUNGTRENNUNG
[b]
[c]
[d]
pounds 3 in higher yields than those previously ob-
The results reported in Table 3 concerning a-aryla-
tained by using a mixture of dioxane and water as the tion reactions of ketones 6 with aryl bromides deserve
reaction solvent[5] (see entries 1–6 of Table 2). More- some comments. The reaction of acetophenone (6a)
over, this protocol proved suitable for the synthesis of with PhBr (2a) (entry 1, Table 3), unexpectedly gave a
3a from 1a and chlorobenzene (5a), although a reac- mixture of benzyl phenyl ketone (7a) and the a,a-di-
tion time (24 h) longer than that employed in the syn-
ACHTUNGTRENaNGNU rylated derivative 8a in which the latter compound
thesis involving bromide 2a was necessary to com- was the main component. However, the use of ortho-
plete the reaction (entry 8, Table 2) and the yield was substituted bromides 2e–g resulted in the selective
significantly lower than that obtained in entry 1 of formation of the required a-monoarylated ketones
Table 2.
7b–d (entries 2–4, Table 3).[11] Selective monoarylation
Encouraged by the results obtained in the direct a- reactions were found also to occur when two typical
arylation of the base-labile 4-chromanone moiety, we a-substituted ketones, 1- and 2-tetralone (6b, 6c),
subsequently tested the Pd2ACHTNUTRGNEN(UG dba)3/AHCTUNGTREN(NUNG t-Bu)3PHBF4/ were used (entries 5 and 6, Table 3).
KHCO3/PTS/H2O system for the direct a-arylation of
carbonyl derivatives different from 1 that included an Pd
The a-arylation protocol involving the use of the
2A(dba)3/A(t-Bu)3PH/KHCO3/PTS/H2O system was
G
CHTUNGTRENNUNG
À
aldehyde and some ketones bearing a C H bond in next tested for the a-monoarylation of aldehydes, a
the a-position.
class of challenging substrates that can give rise to
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Marco Lessi et al.
UPDATES
Table 2. Pd-catalyzed a-arylation of 4-chromanones 1 with aryl halides 2 or 5a in PTS/H2O.
Entry[a]
Reagents
2, 5
Reaction time [h][b]
Product[c]
1
R1
R2
3
Yield [%][d]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1a
1a
H
H
H
2a
2b
2c
2d
2a
2a
2e
5a
H
4-OMe
4-CF3
4-OH
H
H
2-Me
H
2
4
2
4
3
3
3
24
3a
3b
3c
3d
3e
3f
3g
3a
83 (71)
79 (55)
67 (40)
66 (44)
65 (58)
86 (81)
68
H
Cl
Me
H
H
47
[a]
All reactions were performed at 1008C (oil bath) with 1 (2.0 mmol) and 2 or 5a (1.0 mmol) in the presence of 2.5 mol%
Pd2A(dba)3, 10 mol% (t-Bu)3PHBF4, 2.0 equiv. of KHCO3 in water (5 mL) containing 15 wt% PTS.
The reactions were stopped when the amount of 2 or 5a in the reaction mixture was less than 5% (GLC).
The amount of 3,3-diaryl-4-chromanone 4 in the crude reaction mixture was less than 5% (GLC).
Isolated yields. The yields reported in parenthesis were obtained by using a 4:1 mixture of dioxane and H2O as a sol-
vent.[5]
CHTUNGTRENNUNG
[b]
[c]
[d]
Table 3. Pd-catalyzed a-arylation of ketones 6 with aryl halides 2 in PTS/H2O.
Entry[a]
Reagents
Reaction time [h][b]
7:8
Product
Yield [%][c]
ArBr (2)
GLC ratio
7, 8
1
2
3
4
C6H5Br (2a)
2
2
2
2
38:62
90:10
98:2
7a, 8a
7b
19, 40
46
2-MeC6H4Br (2e)
2-bromobiphenyl (2f)
2-MeOC6H4Br (2g)
7c
43
90:10
7d
68
5
C6H5Br (2a)
C6H5Br (2a)
4
100:0
100:0
7e
74
54
6
24
[a]
All reactions were performed at 1008C (oil bath) with 1 mmol ArBr 2, 2.0 mmol of ketone 6 in the presence of 2.5 mol%
Pd2A(dba)3, 10 mol% (t-Bu)3PHBF4, 2.0 equiv. of KHCO3 in water (5 mL) containing 15 wt% PTS.
The reactions were stopped when the amount of 2 in the reaction mixture was less than 5% (GLC).
CHTUNGTRENNUNG
[b]
[c]
Isolated yields.
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Highly Selective Palladium-Catalyzed Direct C H a-Monoarylation of Carbonyl Compounds
Table 4. Pd-catalyzed a-arylation of 2-phenylacetaldehyde 9 with aryl bromides 2 in PTS/H2O.
Entry[a]
ArBr (2)
10:aldol by-products (GLC ratio)
Product
Yield [%][b]
10
1[c]
2
3
4
5
C6H5Br (2a)
C6H5Br (2a)
4-MeOC6H4Br (2g)
2-MeC6H4Br (2e)
4-F3CC6H4 (2c)
60:40
83:17
80:20
87:13
53:47
10a
10a
10b
10c
10d
48
51
42
59
24
[a]
Unless otherwise stated, the reactions were performed at 1008C (oil bath) for 2 h with 1 mmol ArBr 2 and 1.2 mmol 9 in
the presence of 2.5 mol% Pd2ACHTUGNTRNE(NUNG dba)3, 10 mol% (t-Bu)3PHBF4, 2.0 equiv. of KHCO3 in water (5 mL) containing 15 wt%
PTS.
Isolated yields.
The reaction was performed by using 2.0 mmol 9.
[b]
[c]
aldol-type products under the basic conditions usually 51% yield (entry 2, Table 4). The reaction conditions
employed for Pd-catalyzed a-arylation reactions.[12] used in this entry were then employed for the synthe-
We found that the reaction of 2-phenylacetaldehyde sis of compounds 10b, 10c and 10d in 42, 59 and 24%
(9) with 2 equivalents of 2a gave 2,2-diphenylacetal- yield, respectively (entries 3–5, Table 4). It should be
dehyde (10a) in 48% yield (entry 1, Table 4).
noted that, in order to avoid the slow oxidative cleav-
On the other hand, GLC and GC-MS analyses age of aldehydes 10 in open air,[13] the work-up of the
showed the presence of significant amounts of by- crude reaction mixtures of these syntheses was per-
products derived from aldol-type reactions in the formed under a nitrogen atmosphere.
crude reaction mixture. Nevertheless, we found that
Finally, we found that when 0.5 equivalents of
the amount of these undesired by-products could be methyl 2-bromobenzoate (2h) were used for the aryla-
decreased by reducing the molar excess of aldehyde tion of acetophenone (6a) or 2-phenylacetaldehyde
from 2.0 to 1.2 equiv. and 10a could be isolated in (9), isocoumarins 11 and 12, derived from a base-
Scheme 3. Pd-catalyzed synthesis of isocoumarins 11 and 12.
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Marco Lessi et al.
UPDATES
were filtered over silica gel and quickly concentrated under
reduced pressure in a nitrogen atmosphere. The resulting
residues were purified by flash chromatography on silica gel.
This procedure was employed to prepare aldehydes 10a–d.
mediated a-arylation–spontaneous lactonization se-
quence, were obtained in 24 and 41% yield, respec-
tively (Scheme 3).[14]
3-Phenylisocoumarin
(11):
Pd
G
(22.9 mg,
0.025 mmol), (t-Bu)3PHBF4 (29.0 mg, 0.1 mmol), and
KHCO3 (200 mg, 2.0 mmol) were placed in a reaction vessel
containing a magnetic stir bar under an argon atmopshere.
The reaction vessel was fitted with a silicon septum, evacu-
ated and back-filled with argon, and this sequence was re-
peated thrice. A deaerated solution of 15 wt% PTS in H2O
(5 mL), acetophenone 6a (0.234 mL, 240 mg, 2.0 mmol) and
methyl 2-bromobenzoate 2h (0.140 mL, 215 mg, 1.0 mmol)
were sequentially added by syringe and the resulting mix-
ture was stirred at 1008C under argon for 24 h. The reaction
mixture was then allowed to cool to room temperature and
diluted with AcOEt (25 mL), filtered over silica gel and con-
centrated under reduced pressure. The resulting residue was
purified by flash chromatography on silica gel using a mix-
ture of petroleum ether (bp 40–608C) and AcOEt (85/15 v/
v) as eluant to give 11 as a colorless solid; yield: 52.4 mg
(24%); mp 84–878C (lit.[15] 88–898C); EI-MS: m/z (%)=223
(17) [M+ +1], 222 (100) [M+], 194 (75), 165 (63), 105 (19),
Conclusions
In summary, we have demonstrated that the use of
water containing a small amount of PTS as the reac-
tion solvent and KHCO3 as the base allows for direct
highly selective Pd2ACHTUNGRTENNUG(dba)3/ACHTUNTGREN(NUGN t-Bu)3PHBF4-catalyzed a-
monoarylation reactions of carbonyl derivatives, in-
cluding base-labile 4-chromanones, ketones and alde-
À
hydes bearing a C H bond in the a-position, with
aryl halides. Due to the use of a very mild base this
method represents an important alternative to other
established procedures for the direct a-monoarylation
of carbonyl derivatives that, requiring strong bases
such as KHMDS,[4b,d] t-BuOK,[4p] or MeONa,[4d,m]
suffer a reduced chemoselectivity. This protocol,
which provides better results in terms of selectivity
and yields than those obtained by using our previous-
ly reported procedure for the a-arylation of 4-chro-
manones,[5] may be a useful tool for the synthesis of
relevant synthetic targets.
1
89 (22); H NMR (300 MHz, CDCl3): d=8.26 (m, 1H), 7.85
(m, 2H), 7.42 (m, 6H), 6.89 (s, 1H); 13C NMR (75.5 MHz,
CDCl3): d=162.2, 153.4, 137.4, 134.8, 131.8, 129.9, 129.8
(2C), 128.8, 128.1, 126.0, 125.1 (2C), 120.4, 101.8. GLC anal-
ysis showed that 11 was 98% chemically pure. The spectral
properties of this compound were in agreement with those
previously reported.[15]
4-Phenyl-isocoumarin
(12):
Pd
G
(22.9 mg,
Experimental Section
0.025 mmol), (t-Bu)3PHBF4 (29.0 mg, 0.1 mmol), and
KHCO3 (200 mg, 2.0 mmol) were placed in a reaction vessel
containing a magnetic stir bar under a stream of argon. The
reaction vessel was fitted with a silicon septum, evacuated
and back-filled with argon, and this sequence was repeated
thrice. A deaerated solution of 15 wt% PTS in H2O (5 mL)
was added by syringe, and to the resulting dark brown mix-
ture 2-phenylacetaldehyde 9 (0.234 mL, 240 mg, 2.0 mmol)
and methyl 2-bromobenzoate 2h (0.140 mL, 215 mg,
1.0 mmol) were added by syringe, and the resulting mixture
was stirred at 1008C under argon for 5 h. The reaction mix-
ture was then allowed to cool to room temperature and di-
luted with AcOEt (25 mL), filtered over silica gel and con-
centrated under reduced pressure. The resulting residue was
purified by flash chromatography on silica gel using toluene
as eluant to give 12 as a colorless solid; yield: 91.2 mg
(41%); mp 94–968C (lit[16] 94–958C); EI-MS: m/z (%)=223
(12) [M+ +1], 222 (73) [M+], 194 (79), 165 (100), 139 (10),
General Procedure for the Pd-Catalyzed a-Mono-
arylation of 4-Chromanones 1, Ketones 6 or 2-
Phenylacetaldehyde (9) with Aryl Bromides 2 or
Chlorobenzene (5a)
Pd2ACHTUNGTRENNUNG(dba)3 (22.9 mg, 0.025 mmol), (t-Bu)3PHBF4 (29.0 mg,
0.1 mmol), and KHCO3 (200 mg, 2.0 mmol) were placed in a
reaction vessel containing a magnetic stir bar under an
argon atmosphere. The reaction vessel was fitted with a sili-
con septum, evacuated and back-filled with argon, and this
sequence was repeated thrice. A deaerated solution of
15 wt% PTS in H2O (5 mL), a 4-chromanone 1 (2.0 mmol),
a
ketone
6
(2.0 mmol) or 2-phenylacetaldehyde (9)
(1.0 mmol) or 5a
(1.2 mmol), and an aryl halide
2
(1.0 mmol) were then sequentially added under argon. The
reaction vessel was placed in an oil bath heated to 1008C
and after a few minutes at this temperature the color of the
reaction mixture changed from dark brown to pale green.
The mixture was then maintained at 1008C for the period of
time reported in Table 2, Table 3 and Table 4 and periodical-
ly monitored by GLC, GLC-MS and TLC analyses of its
samples extracted with AcOEt. It was then allowed to cool
to room temperature and diluted with AcOEt (25 mL). The
reaction mixtures derived from reactions involving 4-chro-
manones 1 or ketones 6 were filtered over silica gel, concen-
trated under reduced pressure, and the resulting residues
were purified by flash chromatography on silica gel. This
procedure was employed to prepare isoflavanones 3a–g and
ketones 7a–f. On the other hand, the crude reaction mix-
tures of the couplings involving 2-phenylacetaldehyde (9)
1
82 (13); H NMR (300 MHz, CDCl3): d=8.36 (m, 1H), 7.52
(m, 8H), 7.20 (s, 1H); 13C NMR (75.5 MHz, CDCl3): d=
161.9, 142.1, 136.6, 134.6, 132.9, 129.9, 129.7 (2C), 128.8
(2C), 128.5, 128.4, 124.54, 121.2, 120.5; GLC analysis
showed that 12 was chemically pure; anal. calcd. for
C15H10O2 (222.24): C 81.07, H 4.54; found C 80.96, H 4.57.
Supporting Information
General information and compound characterization data
for compounds 3a–g, 7a–f, 8a, and 10a–d are available as
Supporting Information.
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Highly Selective Palladium-Catalyzed Direct C H a-Monoarylation of Carbonyl Compounds
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