Dual role of acetanilides: Traceless removal of a directing group through deacetylation/diazotation and palladium-catalyzed C-C-coupling reactions

Article abstract of DOI:10.1021/acs.joc.5b00272

The acetamide group enables regioselective oxidative ortho-C-H activation reactions, such as Pd-catalyzed acylation. The synthetic utility of these transformations can be significantly enhanced by using the acetamide as a quasi-leaving group in a subsequent conventional Pd-catalyzed coupling or cross-coupling reaction. The concept is illustrated herein for the synthesis of o-alkenyl- and o-arylphenones, which have potential for the synthesis of arylated aromatic heterocycles.

Full text of DOI:10.1021/acs.joc.5b00272

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Featured Article
Dual role of acetanilides: traceless removal of a directing group through
deacetylation/diazotation and Pd-catalyzed C-C-coupling reactions
Bernd Schmidt, Nelli Elizarov, Uwe Schilde, and Alexandra Kelling
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00272 • Publication Date (Web): 20 Feb 2015
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Dual role of acetanilides: traceless removal of a directing group through
deacetylation/diazotation and Pd-catalyzed C-C-coupling reactions
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Bernd Schmidt*, Nelli Elizarov, Uwe Schilde and Alexandra Kelling
Universitaet Potsdam, Institut fuer Chemie, KarlꢀLiebknechtꢀStraße 24ꢀ25, Dꢀ14476 Potsdamꢀ
Golm, Germany.
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eꢀmail: bernd.schmidt@uniꢀpotsdam.de
Table of contents graphic:
Abstract: The acetamide group enables regioselective oxidative orthoꢀCꢀHꢀactivation
reactions, such as Pdꢀcatalyzed acylation. The synthetic utility of these transformations can be
significantly enhanced by using the acetamide as a quasiꢀleaving group in a subsequent
conventional Pdꢀcatalyzed coupling or cross coupling reaction. The concept is illustrated
herein for the synthesis of orthoꢀalkenylꢀ and orthoꢀarylphenones, which have potential for
the synthesis of arylated aromatic heterocycles.
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Introduction
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Since Fujiwara and Moritanis original publication on the Pdꢀmediated coupling of alkenes and
arenes1 the field of transition metal catalyzed oxidative CꢀHꢀactivation has seen tremendous
progress, which has been documented in numerous recent reviews.2ꢀ4 While the coupling
between alkenes and arenes5 has probably been studied in more detail than any other CꢀHꢀ
activation reaction, several examples of other transition metal catalyzed oxidative CꢀCꢀbond
forming reactions have recently been published.6ꢀ10 For example, transition metal catalyzed
oxidative acylation reactions have been explored over the past few years to synthesize
benzophenones and alkyl aryl ketones regioselectively. The first report in this regard was a
decarboxylative orthoꢀacylation of acetanilides using αꢀoxocarboxylic acids, an oxidant and a
Pdꢀprecatalyst.11 Shortly afterwards it was demonstrated that the αꢀoxocarboxylic acids can
be replaced by aldehydes,12ꢀ14 benzylic alcohols15 or ethers,16 styrenes,17,18 or toluene
derivatives.19ꢀ23 Like most transition metal catalyzed aromatic CꢀHꢀactivation reactions these
transformations require the presence of a coordinating functional group which will direct the
electrophilic metal (in many cases Pd2+) to the orthoꢀposition.10 Among the first functional
groups identified as effecient catalyst directing moieties were acetanilides. For example,
Horino and Inoue,24 and shortly afterwards Tremont and Rahman25 could isolate dimeric
acetateꢀbridged Pdꢀσꢀaryl complexes (depicted in monomeric form as structure 4 in scheme
1) when acetanilides were treated with Pd(OAc)2, and demonstrate that these complexes
undergo stoichiometric CꢀCꢀbond forming reactions with alkenes or alkyl halides,
respectively. Later, the former transformation evolved into a truly catalytic process by reꢀ
oxidizing Pd(0) to Pd2+, e. g. with benzoquinone.26
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Over the past few years the requirement of a catalyst directing and activating group to ensure
mild conditions and good regioselectivities has increasingly been recognized as a severe
limitation of aromatic CꢀHꢀactivation reactions, in particular when target structures without
the specific functional group or a closely related functional group are addressed.27ꢀ29
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Consequently, strategies have been developed to remove a particular directing group, e. g. by
hydrolytic cleavage or transesterification, as exemplified by a Rhꢀcatalyzed orthoꢀarylation of
phenols in the presence of phosphinite coꢀcatalysts.30 Hydrolytic removal of a catalyst
directing group (CDG) is, however, only facile if the group is attached to the molecular core
through a heteroatom. Recently, we described an approach to remove a catalyst directing
group by conversion to a leaving group suitable for Pd(0)ꢀcatalyzed coupling or cross
coupling reactions.31 In this project, acetanilides 1 were first functionalized at the orthoꢀ
position via Pd2+ꢀcatalyzed FujiwaraꢀMoritani reactions, and the resulting products 2 were
then subjected to the deacetylationꢀdiazotationꢀcoupling sequence previously developed in our
group,32ꢀ34 to furnish 1,2ꢀdisubstituted arenes 3 with high regioselectivity. The deacetylationꢀ
diazotationꢀcoupling sequence relies on the in situ formation of arene diazonium salts 5,
which are highly reactive electrophilic reagents in Pd(0)ꢀcatalyzed CꢀCꢀbond forming
reactions (Scheme 1).35ꢀ38
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Scheme 1. Consecutive Pd2+ and Pd(0)ꢀcatalyzed 1,2ꢀdifunctionalization of acetanilides
Parallel to our preliminary communication a conceptually similar sequence for the 1,2ꢀ
difunctionalization of arenes was disclosed by Huang and coworkers, who used a triazene as a
directing group for a Rhꢀcatalyzed CꢀHꢀactivation. Traceless removal of the triazene and
further functionalization were then accomplished by treatment with Brønstedꢀacids (to
generate a diazonium cation in situ) and arylation or Pdꢀcatalyzed alkenylation.39
In continuation of our studies on this field we investigated an extension of the consecutive
Pd2+/Pd(0)ꢀcatalyzed 1,2ꢀdifunctionalization outlined in scheme 1 to the synthesis of highly
functionalized aromatic ketones. These compounds are valuable synthetic intermediates for
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the synthesis of numerous heterocyclic scaffolds such as xanthones,40,41 benzodiazepines42 or
acridones.43 In addition, aromatic ketones have also been used as selective cyclooxygenaseꢀ2
inhibitors44 and for the synthesis of biologically active natural45 and nonꢀnatural46 indane
derivatives.
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Results and discussion
Synthesis of ortho-acyl acetanilides 8. We started the investigation with the synthesis of a
set of orthoꢀacyl acetanilides 8 from acetanilides 6 and aldehydes 7, using a protocol recently
developed by Novák and coworkers.14 Under the reaction conditions developed by these
authors a successful and highly regioselective orthoꢀacylation can be accomplished at ambient
or slightly elevated temperatures in aqueous medium, using a commercially available aqueous
solution of tertꢀbutylhydroperoxide as oxidant, Pd(OAc)2 as catalyst and sodium lauryl
sulphate as surfactant (Scheme 2).
Scheme 2. Synthesis of orthoꢀacyl acetanilides 8.14
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R3
O
Pd(OAc)2 (5 mol-%)
NaOSO3C12H25 (5 mol-%)
CF3CO2H (26 mol-%)
R3
O
4
5
H
7 (2.0 equiv.)
NHAc
6
7
8
9
+
t-BuOOH (aq., 70%, 2.0 equiv.)
NHAc
R2
water, 20 °C, 24 h
R1
8
R2
6
R1
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Cl
MeO
NHAc
F
O
O
O
O
NHAc
NHAc
NHAc
8a (72%)
8c (quant.)
8b (65%)
8d (65%)
O
O
O
O
NHAc
NHAc
NHAc
NHAc
OMe
8h (45%)
8e (62%)
8f (59%)
8g (23%)
O
O
NHAc
NHAc
Cl
8j (50%)
8i (21%)
Synthesis and isolation of ortho-acyl arene diazonium salts 9. With the orthoꢀacyl
acetanilides 8 in hand, we first investigated a deacetylationꢀdiazotation sequence with a view
to isolate the functionalized arene diazonium salts 9 as their tetrafluoroborates. We have
previously developed a deacetylationꢀdiazotation protocol which relies on a deacetylation
promoted by BF3ꢀmethanol complex, followed by in situ diazotation with tertꢀbutyl
nitrite.32,47 As crucial parameters for this oneꢀflask sequence were identified the initial
substrate concentration, as lower substrate concentrations often prevent the isolation of the
diazonium tetrafluoroborate through precipitation, the temperature for the diazotation step,
and the equivalents of tertꢀbutyl nitrite. While low reaction temperatures often retard the
diazotation reaction, they reduce the solubility of the diazonium salts in the alcoholic solvent,
which in turn facilitates their isolation. The reduced rate of the diazotation step at lower
temperatures can be compensated to some extent by increasing the amount of alkyl nitrite. On
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the other hand, we found that excess of tertꢀbutyl nitrite can be disadavantageous if the
deacetylationꢀdiazotation sequence is to be extended by a Pdꢀcatalysed coupling reaction,
because alkyl nitrites partially inhibit Pd(0)ꢀcatalysed reactions, presumably due to their
oxidizing properties.33 For these reasons we aimed at a minimization of the amount of
diazotation reagent and used excess tertꢀbutyl nitrite only if necessary. The results compiled
in table 1 show that by systematic variation of the above mentioned parameters suitable
conditions for the deacetylationꢀdiazotation sequence were identified for almost all
acetanilides 8, which allow the isolation of the corresponding diazonium salts 9 as
microcrystalline powders in synthetically useful yields, with just two exceptions. The isobutyl
substituted derivative 8e is apparently completely converted to the expected diazonium salt 9e
in the deacetylationꢀdiazotation sequence, as indicated by TLC, but it does not precipitate
under any combination of reaction parameters (entry 7). In the case of benzophenone 8j, TLC
analysis shows that the deacetylation proceeds quantitatively, but the intermediate aniline
undergoes diazotation only with incomplete conversion (entry 19).
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Table 1. Deacetylationꢀdiazotation sequence of orthoꢀacyl acetanilides 8.
9 (Yield)a)
9a (n. i.)
9a (46%)
9a (90%)
9b (95%)
9c (90%)
9d (90%)
9e (n. i.)
c/mol•L−1
0.01
entry
T
n (tertꢀBuONO, equiv.)
8
1
0°C
0°C
0°C
0°C
0°C
0°C
0°C;
1.0
8a
8a
8a
8b
8c
8d
8e
2
0.01
1.5
3
0.02
1.5
4
0.01
1.0
5
0.01
1.0
6
7b)
0.01
1.0
0.01;
0.02
1.0; 1.5; 2.0
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−21°C
8
0°C
0.01;
1.0; 1.5; 2.0
9f (n. i)
8f
6
7
8
9
0.02
0.02
0.02
0.02
9
1.0
9f (n. i.)
9f (53%)
9f (96%)
9g (82%)
9g (91%)
9h (n. i)
8f
−21°C
−21°C
−21°C
0°C
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13
1.5
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8f
2.0
8f
0.02
0.02
0.01;
0.02
0.02
1.0
8g
8g
8h
0°C
1.5
0°C
1.0; 1.5; 2.0
14
15
16
17
18
19c)
1.0
9h (n. i.)
9h (69%)
9h (82%)
9i (79%)
9i (66%)
9j (n. i)
8h
8h
8h
8i
−21°C
−21°C
−21°C
0°C
0.02
0.02
1.5
2.0
0.02
0.02
0.01;
0.02
1.0
0°C
2.0
8i
0°C
1.0; 1.5; 2.0
8j
a)n. i. not isolated. b)Full conversion to diazonium salt (TLC), but not isolable with any
combination of T, c and n(tertꢀBuONO). Incomplete conversion (TLC) to diazonium salt
with any combination of T, c and n(tertꢀBuONO).
c)
Deacetylation-diazotation-coupling (DDC) sequence of o-acyl acetanilides 9. Before
investigating the envisaged extension of the oneꢀflask deacetylationꢀdiazotation sequence by a
Pdꢀcatalyzed coupling reaction, we decided to investigate the CꢀCꢀbond forming reaction
separately. To this end, the isolated arene diazonium salts 9 and methyl acrylate were coupled
in a MatsudaꢀHeck36,48 reaction. The most important parameters for the outcome of Pdꢀ
catalyzed coupling reactions involving arene diazonium salts are the solvent and the presence
or absence of a base. It is an important requirement for oneꢀflask reactions in general that the
conditions chosen for the individual steps are compatible. For this reason we had to rely on
baseꢀfree methanol as a solvent, because these conditions come closest to those of the
preceeding deacetylationꢀdiazotation sequence. Commonly used precatalysts for Matsudaꢀ
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Heck reactions are Pd2(dba)3•CHCl3 and Pd(OAc)2. For convenience we started with
Pd(OAc)2, which catalyzed gratifyingly in all cases the coupling of arene diazonium salts 9
and methyl acrylate to the expected cinnamates 10 in high yields in methanol under baseꢀfree
conditions (Table 2, conditions A). oꢀAcyl cinnamates of the general structure 10 have
previously been synthesized using, for example, a Wittig olefination,45 for a single example a
MatsudaꢀHeck reaction,49 and a Ruꢀcatalyzed oꢀalkenylation of aromatic ketones.50 With
these results in hand, we investigated a synthesis of oꢀacyl cinnamates 10 from oꢀacyl
acetanilides 8 via deacetylationꢀdiazotationꢀcoupling sequence. To this end, acetanilides 8
were treated with BF3ꢀmethanol complex at 65°C to accomplish the deacetylation, followed
by addition of tertꢀBuONO at −21°C for the diazotation. Without removal or exchange of any
solvents or byproducts, the MatsudaꢀHeck reaction of the in situ formed diazonium salts was
initiated by simply adding Pd(OAc)2 and methyl acrylate to the mixture, which was then
warmed to ambient temperature (conditions B). In all cases the MatsudaꢀHeck products 10
could be isolated, mostly in yields exceeding those obtained via the two step procedure
involving isolated arene diazonium salts. Notably, the isobutyl substituted derivative 10e,
which can not be synthesized via the twoꢀstep procedure as the corresponding arene
diazonium salt 9e could not be isolated, becomes accessible in excellent yield under
conditions B (Table 2, entry 5). Compound 10j was isolated in low yield, which can most
likely be attributed to the incomplete formation of the intermediate diazonium salt (Table 2,
entry 10; compare table 1, entry 19).
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Table 2. Comparison of oneꢀ and twoꢀstep deacetylationꢀdiazotation coupling sequence.
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entry
R
Cond. A (twoꢀstep procedure) Cond. B (oneꢀflask
3
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8
procedure
Yieldc)
R1
H
R2
H
H
H
H
H
H
H
H
H
R3
Yielda) Yieldb)
9
10
8
9
1
2
3
4
5
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8
9
10
Ph
93%
88%
93%
84%
ꢀꢀd)
84%
84%
73%
76%
ꢀꢀd)
quant.
68%
9a 10a
9b 10b
9c 10c
9d 10d
9e 10e
8a
8b
8c
8d
8e
8f
8g
8h
8i
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H
pꢀC6H4OMe
pꢀC6H4Cl
pꢀC6H4F
CH2CH(CH3)2
CH2CH2CH3
C6H5
H
quant.
quant.
96%
H
H
H
quant. 96%
60%
9f
10f
OCH3
CH3
Cl
H
88%
86%
80%
71%
80%
9g 10g
9h 10h
C6H5
56%
C6H5
quant. 79%
ꢀꢀ d) ꢀꢀ d)
quant.
30%
9i
9j
10i
10j
iꢀPr C6H5
8j
a)Yield of 10 obtained from 9 with conditions A. Calcd. yield of 10 based on 8 over two
steps. Yield of 10 obtained from 8 with conditions B. Not performed (diazonium salts 9e
and 9j not isolable).
b)
c)
d)
Investigation into heterocycle synthesis from o-acyl cinnamates. With a view towards the
synthesis of phthalazine derivatives we planned a condensationꢀconjugate addition sequence
as outlined in Scheme 3, using hydrazine as a bisnucleophile. Precedence for the formation of
phthalazine derivatives through cascade reactions involving a conjugate addition step has
been published by Grigg et al., who reported a Pdꢀcatalyzed carbonylation of iodo arenes,
followed by acylationꢀconjugate addition of the bisnucleophile hydrazine.51
Scheme 3. Proposed condensationꢀconjugate addition sequence.
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Obviously, the CꢀNꢀbond forming steps might occur in a reversed order, but in any case one
step will involve formation of a hydrazone. For less reactive carbonyl compounds, such as
benzophenones, this reaction requires normally acid catalysis and/or elevated
temperatures.52,53 For these reasons we started our investigation into the proposed
condensationꢀconjugate addition sequence by mixing equimolar amounts of 10a and
hydrazine hydrate in ethanol, which was then heated to reflux for 16 h (Table 3, entry 1).
Both TLC and NMRꢀspectroscopy of the crude reaction mixture revealed the formation of a
complex mixture of products. The same outcome was observed in ethanol/water and in acetic
acid under reflux (entries 2 and 3). Performing reactions under microwave irradiation often
reduces reaction times significantly and may lead to higher selectivities.54 This prompted us to
investigate the projected reaction of hydrazine and 10a in a microwave reactor using various
solvents such as ethanol, ethanol/water, ethyl acetate and toluene (entries 4 – 8). In all cases
the results were very similar to those observed under conventional heating conditions. In
particular, it was not possible to identify a major reaction product. Eventually, ethylene glycol
was tested (entries 9 and 10). This solvent has a very high loss factor55 and should therefore
ensure particularly efficient conversion of microwave energy into heat. Indeed, TLC indicated
the formation of a main product and a significantly reduced number of side products.
Irrespective of the reaction time, the isolated yield of the major product 14, obtained after
column chromatography on silica, is rather low, which might at least in part be explained by
loss of material due to the high polarity of the product.
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Table 3. Conditions for condensationꢀconjugate addition sequence of 10a and hydrazine.
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8
entry Solvent
Heating method
time
Product (yield)
9
(temperature)
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ethanol
Conventional (78°C)
Conventional (78°C)
Conventional (118°C)
ꢀꢀwave irradiation (180°C)
16 h
72 h
72 h
0.5 h
ꢀꢀa)
ꢀꢀa)
ꢀꢀa)
ꢀꢀa)
Ethanol/water (1:1)
Acetic acid
ethanol
5
Ethanol/water (1:1)
Ethyl acetate
toluene
0.5 h
0.5 h
0.3 h
0.5 h
0.5 h
1.0 h
ꢀꢀa)
ꢀꢀwave irradiation (180°C)
ꢀꢀwave irradiation (180°C)
ꢀꢀwave irradiation (180°C)
ꢀꢀwave irradiation (250°C)
ꢀꢀwave irradiation (250°C)
ꢀꢀwave irradiation (250°C)
6
ꢀꢀa)
7
ꢀꢀa)
8
toluene
ꢀꢀa)
9
Ethylene glycol
Ethylene glycol
14 (20%)b)
14 (20%)b)
10
a)Complex mixture of products, no major product identified. Major product 14 is formed
along with several minor products.
b)
The spectroscopic data of the isolated product 14 were not in agreement with the structure of
phthalazine 13 or a dihydrophthalazine 12. In particular, HRMS leads to a molecular formula
of C16H12O2N, which suggests the incorporation of one equivalent of hydrazine and
1
condensation of one equivalent of water and methanol. HꢀNMR spectroscopy shows the
presence of two singlets at 5.83 and 6.22 ppm, which are connected to two tertiary carbon
atoms at 82.2 and 65.9 ppm, respectively. Further NMRꢀspectroscopical analysis, in particular
based on twoꢀdimensional Hꢀ13Cꢀcorrelation spectroscopy, remained ambigous but pointed
1
towards the structure of a benzoannellated tricyclic pyrazol derivative. Gratifyingly, we
succeeded in obtaining a crystal suitable for single crystal Xꢀray structure analysis. The
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molecular structure of product 14 can be described as a pyrazoloꢀisoindole derivative and is
shown in Figure 1. Beyond the molecular structure, crystal structure analysis reveals that the
two enantiomers of 14 form a centrosymmetric dimer through hydrogen bonding in the solid
state. Intermolecular Hꢀbonds were observed between the OHꢀgroup of one molecule and both
Nꢀatoms of the other molecule, as illustrated in the packing diagram (see supporting
information for further details).
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Figure 1. Molecular structure of compound 14 (only Rꢀenantiomer shown)
A tentative mechanism for the formation of the tricyclic condensation product 14 is outlined
below. Cinnamate 10a reacts with hydrazine in a conjugate addition and subsequent
condensation of methanol to the pyrazolidinone 15. Literature precedence for this type of
additionꢀcondensation sequence exists.56,57 In the next step, 15 cyclizes to a hemiaminal 16,
which eventually undergoes a sequence of deprotonation, 1,3ꢀhydride shift and dehydration.
An alternative scenario starting with the formation of a hydrazone from 10a and subsequent
conjugate additionꢀmethanol condensation would also be conceivable. In any case, however, a
1,3ꢀhydride shift must be involved (Scheme 4).
Scheme 4. Tentative mechanism for the formation of pyrazoloꢀisoindole 14.
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Matsuda-Heck-reaction of of o-acyl arene diazonium salts 9 with styrenes. The stilbene
pattern is present in important bioactive natural products,58,59 synthetic drugs60 and fluorescent
dyes.61 Scattered examples for the synthesis of stilbenes via MatsudaꢀHeck arylation of
styrenes have been reported over the years,35,62,63 but systematic investigations have not been
performed until recently.34,64,65 For example, Felpin and coꢀworkers reported good yields and
high Eꢀselectivities of stilbene products at very low catalyst loadings for the Pdꢀcatalyzed
arylation of styrenes substituted with an electron withdrawing group, i. e. aryl acrylates.64 In
contrast, we found that simple styrenes are often surprisingly unreactive towards electron rich
methoxyarene diazonium salts, in particular under baseꢀfree conditions, resulting in low yields
and undesired side reactions such as hydrodediazonation.34 This observation prompted us to
investigate the MatsudaꢀHeck reaction of styrenes and electronꢀdeficient oꢀacyl arene
diazonium salts 9 for comparison. Diazoniums salts 9aꢀc,f,g,i and styrene (17a), 4ꢀ
chlorostyrene (17b) and 4ꢀmethoxystyrene (17c), respectively, were chosen for this study. In
all experiments, the precatalyst Pd(OAc)2 and the baseꢀfree conditions established previously
for the coupling with methyl acrylate were used (Table 4).
Table 4. MatsudaꢀHeck reaction of diazonium salts 9 and styrenes 17.
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entry
1
R1
H
R2
R3
18 (Yield)
18aa (96%)
18ab (95%)
18ac (ꢀꢀa))
18ba (86%)
18bb (86%)
18bc (ꢀꢀa))
18ca (78%)
18cb (80%)
18cc (ꢀꢀa))
9
17
Ph
H
9a
9a
9a
9b
9b
9b
9c
9c
9c
9f
9f
9f
9g
9g
9g
9i
17a
17b
17c
17a
17b
17c
17a
17b
17c
17a
17b
17c
17a
17b
17c
17a
17b
17c
2
H
Ph
Cl
3
H
Ph
OMe
H
4
H
pꢀC6H4OMe
pꢀC6H4OMe
pꢀC6H4OMe
pꢀC6H4Cl
pꢀC6H4Cl
pꢀC6H4Cl
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
Ph
5
H
Cl
6
H
OMe
H
7
H
8
H
Cl
9
H
OMe
H
10
11
12
13
14
15
13
14
15
H
18fa (57%)
18fb (63%)
18fc (ꢀꢀa))
H
Cl
H
OMe
H
OMe
OMe
OMe
Cl
Cl
Cl
18ga (70%)
18gb (75%)
18gc (ꢀꢀa))
18ia (80%)
18ib (75%)
18ic (ꢀꢀa))
Ph
Cl
Ph
OMe
H
Ph
Ph
Cl
9i
Ph
OMe
9i
a)Complex mixture of products; hydrodediazonation product detected by GCꢀMS.
All MatsudaꢀHeck reactions of oꢀacyl arene diazonium salts 9 and 4ꢀmethoxystyrene (17c)
were unsuccessful and resulted in the formation of complex mixtures. Via GCꢀMS analysis of
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the crude reaction mixtures we could identify the hydrodediazonation product as one
component. In contrast, the less electronꢀrich styrene (17a) and 4ꢀchlorostyrene (17b)
underwent the coupling with all oꢀacyl arene diazonium salts tested in good to excellent yields
and Eꢀselectivities higher than 95 : 5. Notably, the isolated yields of these transformations
significantly exceeded those previously reported by us34 for the reactions of 17a,b with the
more electron rich oꢀ, mꢀ, and pꢀmethoxy arene diazonium salts.
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Suzuki-Miyaura-coupling of o-acyl arene diazonium salts 9 with arene trifluoroborates.
Genêt and coꢀworkers described the first SuzukiꢀMiyaura coupling of arene diazonium salts,
using boronic acids as coupling partners and Pd(OAc)2 as the catalyst under baseꢀ and ligandꢀ
free conditions.66 They discovered that high yields can be obtained in dioxane, while the
yields in methanol are only mediocre. In contrast, Sengupta and Bhattacharyya reported
almost simultaneously that methanol is a suitable solvent for the coupling of arene diazonium
salts and arene boronic acids, although significantly higher catalyst loadings had to be
applied.67 Other reports describing the suitability of alcohols as solvents were published
afterwards.68ꢀ70 Briefly after their seminal report, Genêt and coꢀworkers found that
organotrifluoroborates71ꢀ75 are superior coupling reagents under otherwise identical
conditions.76 More recently, we investigated the SuzukiꢀMiyaura coupling of
organotrifluoroborates and a 4ꢀmethoxybenzene diazonium salt in comparison with 4ꢀphenol
diazonium salt, and found that coupling reactions of the latter were advantageously performed
in methanol rather than dioxane.77
We started this part of the investigation by comparing the SuzukiꢀMiyaura coupling of oꢀ
benzoyl benzene diazonium salt 9a with phenyl boronic acid (19a') and with potassium
phenyltrifluoroborate (19a), respectively (Scheme 5). With 19a' in methanol the expected
biphenyl 20aa was formed together with a considerable amount of methyl ether 21, which
was identified by comparison of its spectroscopic data with those reported previously in the
literature.78 The formation of this solvolysis product was fully suppressed when the analogous
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potassium organotrifluoroborate 19a was used. Performing the coupling of 9a and 19a in
dioxane instead of methanol worked equally well and gave 20aa in comparable selectivity.
Scheme 5. SuzukiꢀMiyaura coupling of 9a and phenylboron reagents 19a and 19a'
9
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We applied the conditions established for the cross coupling of 9a and 19a to other oꢀacyl
diazonium salts 9 and organotrifluoroborates 19 (Table 5). In most cases good yields and
selectivities of biaryl products 20 were obtained in methanol and in dioxane.
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Table 5. SuzukiꢀMiyaura coupling of oꢀacyl diazonium salts 9 and organotrifluoroborates 19
4
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entry
1
R1
H
R2
R3
Solvent
methanol 20aa (91%)
dioxane 20aa (93%)
methanol 20ba (78%)
dioxane 20ba (91%)
methanol 20ca (77%)
dioxane 20ca (66%)
methanol 20fa (79%)
dioxane 20fa (59%)
methanol 20ga (87%)
dioxane 20ga (73%)
methanol 20ia (55%)
20 (yield)
9
19
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
9a
9a
9b
9b
9c
9c
9f
9f
9g
9g
9i
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19b
19c
19d
2
H
C6H5
3
H
pꢀC6H4OMe
pꢀC6H4OMe
pꢀC6H4Cl
pꢀC6H4Cl
CH2CH2CH3
CH2CH2CH3
C6H5
4
H
5
H
6
H
7
H
8
H
9
OMe
OMe
Cl
Cl
H
10
11
12
13
14
15
C6H5
C6H5
C6H5
dioxane
pꢀC6H4OMe dioxane
20ia (78%)
20cb (quant.)
20cc (87%)
20cd (96%)
9i
pꢀC6H4Cl
pꢀC6H4Cl
pꢀC6H4Cl
9c
9c
9c
H
pꢀC6H4F
dioxane
dioxane
H
2ꢀnaphthyl
Conclusions
In summary, we report the efficient recycling of a catalyst directing group for oxidative Pd2+ꢀ
catalyzed CꢀHꢀactivation reactions by conversion into a leaving group for subsequent nonꢀ
oxidative Pd(0)ꢀcatalyzed coupling reactions. Specifically, an acetamide group was used to
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enable a regioselective orthoꢀacylation through CꢀHꢀactivation, which was then converted into
a diazonium group by a deacetylationꢀdiazotation sequence. Pd(0)ꢀcatalyzed coupling of the
arene diazonium salts thus formed proceeds effectively with styrenes, acrylates and
organotrifluoroborates. The sequence disclosed in this work leads eventually to structurally
diverse orthoꢀsubstituted aromatic ketones from simple acetanilides.
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Experimental Section
General methods. All experiments were conducted in dry reaction vessels under an
1
atmosphere of dry nitrogen. Solvents were purified by standard procedures. H NMR spectra
were obtained at 300 MHz in CDCl3 with CHCl3 (δ = 7.26 ppm) as an internal standard.
Coupling constants are given in Hz. All 13C NMR spectra were recorded with broadband
decoupling at 75 MHz in CDCl3 with CDCl3 (δ = 77.0 ppm) as an internal standard.
Whenever the solubility of the sample was insufficient in CDCl3, DMSOꢀd6 was used
1
(DMSOꢀd5 as internal standard for H NMR spectroscopy, δ = 2.50 ppm, DMSOꢀd6 as
internal standard for 13C NMR spectroscopy, δ = 39.5 ppm). IR spectra were recorded as
ATRꢀFTIR spectra. Wavenumbers (ν
) are given in cm−1. The peak intensities are defined as
strong (s), medium (m) or weak (w). Lowꢀ and high resolution mass spectra were obtained by
EIꢀTOF or ESIꢀTOF. Microwave reactions were carried out in an AntonꢀPaarꢀmonowaveꢀ300
reactor at 150 °C (monowave, maximum power 850 W, temperature control via IRꢀsensor,
vial volume: 20 mL). oꢀAcyl acetanilides 8aꢀd and 8fꢀj14 and diazonium salt 9h79 have
previously been described in the literature. Diazonium salts 9a,80 9b,81 and 9f82 were
mentioned in previous publications, but not characterized.
N-(2-(3-Methylbutanoyl)phenyl)acetamide (8e). Acetanilide 6a (3.00 g, 22.2 mmol) was
suspended in water (20 mL) and Pd(OAc)2 (249 mg, 5 molꢀ%), Naꢀlaurylsulfate (320 mg, 5
molꢀ%) and CF3COOH (0.44 mL, 5.7 mmol, 0.26 equiv.) were added. To this mixture were
added isovaleraldehyde (6.30 mL, 44.4 mmol, 2.0 equiv.) and tertꢀBuOOH (70 wtꢀ% solution
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in water, 5.72 g, 44.4 mmol), it was stirred for 24 h at ambient temperature and then extracted
with ethyl acetate (three times 20 mL each). The combined organic extracts were washed with
water, dried with MgSO4, filtered and evaporated. The residue was purified by
9
chromatography on silica using a hexaneꢀethyl acetate mixture (1 : 1) to furnish 8e (3.00 g,
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1
13.7 mmol, 62%). Colourless solid, mp 73 °C; H NMR (300 MHz, CDCl3)
δ 11.47 (s, 1H),
8.45 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 8.1, 1.3 Hz, 1H), 7.17 (ddd, J = 8.6, 8.6, 1.3Hz, 1H),
6.76 (ddd, J = 8.1, 8.1, 1.0 Hz, 1H), 2.55 (d, J = 6.8 Hz, 2H), 1.94 (sept., J = 6.7 Hz, 1H), 1.91
(s, 3H), 0.72 (d, J = 6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3)
131.0, 122.2, 121.8, 120.7, 48.8, 25.5, 25.4, 22.8; IR (ATR)
δ
204.6, 169.1, 141.2, 134.7,
ν
2951 (m), 1518 (s), 1449 (s),
1360 (s), 761 (s); HRMS (EI) calcd for C13H17O2N [M+]: 219.1254, found: 219.1259; MS (EI)
m/z 219 (18%), 162 (100%), 144 (18%), 120 (74%), 92 (21%). Anal. Calcd. for C13H17NO2
(219.28): C, 71.2; H, 7.8; N, 6.4. Found: C, 71.1; H, 7.7; N, 6.5.
General procedure for the synthesis and isolation of arene diazonium salts 9. To a
solution of acetanilide 8 (1.0 mmol) in dry and degassed methanol (5.0 mL) was added
BF3•CH3OH (3.0 mmol). The solution was heated to reflux for 16 h, and then cooled to 0°C
or −21°C, as indicated in table 1. tertꢀBuONO (103 mg, 1.0 mmol; 155 mg, 1.5 mmol; 206
mg, 2.0 mmol as indicated in table 1) was added, and stirring at the respective temperature
was continued for 2 h. The resulting precipitate of the corresponding arene diazonium salt 9
was filtered through a Büchnerꢀfunnel, washed with a minimum amount of cold MTBE, and
dried in vacuo.
2-Benzoylbenzenediazonium tetrafluoroborate (9a).80 Following the general procedure, 8a
(119 mg, 0.50 mmol) was converted to 9a (134 mg, 0.46 mmol, 90%). Orange solid; 1H NMR
(500 MHz, DMSOꢀd6)
δ 9.03 (dd, J = 8.2, 1.1 Hz, 1H), 8.37 (ddd, J = 7.7, 7.7, 1.1 Hz, 1H),
8.27 (ddd, J = 8.0, 8.0, 1.2 Hz, 1H), 8.19 (dd, J = 7.8, 1.1 Hz, 1H), 7.89 (dm, J = 8.2 Hz, 2H),
7.83 (tm, J = 7.5 Hz), 7.68 (dd, J = 8.2, 7.5 Hz); 13C NMR (126 MHz, DMSOꢀd6)
δ
189.9,
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140.2, 137.1, 136.2, 134.6, 134.3, 133.9, 133.7, 130.7, 128.9, 115.6; IR (ATR) ν 3114 (w),
2290 (m), 1660 (m), 1274 (s), 1036 (s); HRMS (ESI) calcd for C13H9N2O [M+]: 209.0715,
found: 209.0721; MS (ESI) m/z 196 (41%), 181 (100%), 144 (15%), 98 (31%).
5
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8
9
2-(4-Methoxybenzoyl)benzenediazonium tetrafluoroborate (9b).81 Following the general
procedure, 8b (269 mg, 1.00 mmol) was converted to 9b (309 mg, 0.95 mmol, 95%). Yellow
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solid; 1H NMR (500 MHz, DMSOꢀd6)
δ 9.00 (dd, J = 8.2, 1.1 Hz, 1H), 8.35 (ddd, J = 7.7, 7.7,
1.2 Hz, 1H), 8.24 (ddd, J = 8.0, 8.0, 1.2 Hz, 1H), 8.19 (dd, J = 7.8, 1.1 Hz, 1H), 7.89 (dm, J =
8.9 Hz, 2H), 7.20 (dm, J = 8.9 Hz), 3.91 (s, 3H); 13C NMR (126 MHz, DMSOꢀd6)
δ
188.1,
3110
164.4, 140.1, 138.0, 136.1 133.9, 133.4, 133.3, 126.5, 115.7, 114.4, 55.9; IR (ATR)
ν
(w), 2293 (m), 1587 (s), 1269 (s), 1041 (s); HRMS (ESI) calcd for C14H11N2O2 [M+]:
239.0821, found: 239.0822; MS (ESI) m/z 239 (13%), 213 (79%), 211 (100%), 196 (18%).
2-(4-Chlorobenzoyl)benzenediazonium tetrafluoroborate (9c). Following the general
procedure, 8c (1.50 g, 5.4 mmol) was converted to 9c (1.60 g, 4.9 mmol, 90%). Colourless
solid; 1H NMR (500 MHz, DMSOꢀd6)
δ 9.02 (dd, J = 8.1, 1.2 Hz, 1H), 8.37 (ddd, J = 7.7, 7.7,
1.3 Hz, 1H), 8.27 (ddd, J = 7.9, 7.9, 1.3 Hz, 1H), 8.20 (dd, J = 7.7, 1.2 Hz, 1H), 7.89 (dm, J =
8.5 Hz, 2H), 7.75 (dm, J = 8.5 Hz, 2H); 13C NMR (126 MHz, DMSOꢀd6)
δ
188.9, 140.2,
139.5, 136.9, 136.2, 134.4, 133.6, 132.8, 132.6, 129.1, 115.5; IR (ATR)
ν 3100 (w), 2284 (m),
1658 (s), 1285 (s), 1027 (s); HRMS (ESI) calcd for C13H8N2OCl [M+]: 243.0352, found:
243.0331; MS (ESI) m/z 243 (8%), 217 (41%), 215 (100%), 196 (23%).
2-(4-Fluorobenzoyl)benzenediazonium tetrafluoroborate (9d). Following the general
procedure, 9d (1.50 g, 5.8 mmol) was converted to 9d (1.65 g, 5.2 mmol, 90%). Colourless
solid; 1H NMR (300 MHz, DMSOꢀd6)
δ 9.02 (dd, J = 8.1, 1.1 Hz, 1H), 8.37 (ddd, J = 7.7, 7.7,
1.2 Hz, 1H), 8.26 (ddd, J = 7.9, 7.9, 1.3 Hz, 1H), 8.20 (dd, J = 7.7, 1.2 Hz, 1H), 8.17–7.92 (m,
2H), 7.51 (ddm, J = 8.8, 8.8 Hz, 2H); 13C NMR (126 MHz, DMSOꢀd6)
δ
188.8, 165.8 (d, J =
254.2 Hz), 140.4, 137.3, 136.4, 134.4, 134.0 (d, J = 9.9 Hz), 133.8, 130.8, 116.3 (d, J = 22.3
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Hz), 115.6; F NMR (282 MHz, DMSOꢀd6) δ −103.3 (s), −148.2 (s); IR (ATR) ν 3100 (w),
2284 (m), 1658 (s), 1285 (s), 1027 (s); HRMS (ESI) calcd for C13H8N2OF [M+]: 227.0621,
found: 227.0610; MS (ESI) m/z 227 (10%), 201 (26%), 199 (100%), 196 (36%).
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2-Butyrylbenzenediazonium tetrafluoroborate (9f).82 Following the general procedure, 8f
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(103 mg, 0.50 mmol) was converted to 9f (126 mg, 0.48 mmol, 96%). Colourless solid; H
NMR (500 MHz, DMSOꢀd6)
δ 8.94 (dd, J = 8.1, 1.0 Hz, 1H), 8.62 (dd, J = 7.6, 0.7 Hz, 1H),
8.40 (ddd, J = 7.8, 7.8, 1.1 Hz, 1H), 8.23 (ddd, J = 8.1, 8.1, 1.0 Hz, 1H), 3.20 (t, J = 7.0 Hz,
2H), 1.69 (sext., J = 7.3 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz, DMSOꢀd6)
δ
196.5, 140.8, 136.2, 135.9, 134.8, 132.3, 113.9, 16.5, 13.4; IR (ATR)
ν 3111 (w), 1700 (m),
1211 (m), 1042 (s), 786 (m); HRMS (ESI) calcd for C10H11N2O [M+]: 175.0871, found:
175.0876; MS (ESI) m/z 175 (100%), 161 (14%), 147 (48%), 122 (32%).
2-Benzoyl-5-methoxybenzenediazonium tetrafluoroborate (9g). Following the general
procedure, 8g (1.00 g, 3.7 mmol) was converted to 9g (1.20 g, 3.6 mmol, 97%). Colourless
solid; 1H NMR (500 MHz, DMSOꢀd6)
(dd, J = 8.8, 2.7 Hz, 1H), 7.85 – 7.78 (m, 3H), 7.67 (dd, J = 7.8, 7.8 Hz, 2H), 4.04 (s, 3H); 13C
δ 8.73 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.9
NMR (126 MHz, DMSOꢀd6)
δ
189.3, 162.0, 135.4, 134.4, 134.3, 130.4, 129.5, 128.9, 124.7,
3099 (w), 2280 (m), 1654 (m), 1593 (m), 1255 (s); HRMS
121.6, 117.2, 57.5; IR (ATR)
ν
(ESI) calcd for C14H11N2O2 [M+]: 239.0821, found: 239.0828.
2-Benzoyl-5-methylbenzenediazonium tetrafluoroborate (9h).79 Following the general
procedure, 8h (100 mg, 0.40 mmol) was converted to 9h (100 mg, 0.33 mmol, 82%).
1
Colourless solid; H NMR (500 MHz, DMSOꢀd6)
δ 8.87 (s, 1H), 8.18 (dm, J = 8.1 Hz, 1H),
8.09 (d, J = 8.0 Hz, 1H), 7.86 (dm, J = 8.0 Hz, 2H), 7.82 (tm, J = 7.5 Hz, 1H), 7.67 (dd, J =
13
7.8, 7.8 Hz, 2H), 2.61 (s, 3H); C NMR (126 MHz, DMSOꢀd6)
δ
190.6, 146.5, 141.4, 136.6,
135.6, 135.3, 134.9, 134.5, 131.4, 129.8, 116.3, 21.7; IR (ATR)
ν 3111 (w), 2282 (m), 1652
(m), 1274 (m), 1021 (s); HRMS (ESI) calcd for C14H11N2O [M+]: 223.0866, found: 223.0864.
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2-Benzoyl-5-chlorobenzenediazonium tetrafluoroborate (9i). Following the general
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procedure, 8i (100 mg, 0.37 mmol) was converted to 9i (95 mg, 0.29 mmol, 79%). Colourless
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solid; H NMR (500 MHz, DMSOꢀd6)
δ 9.24 (d, J = 2.1 Hz, 1H), 8.47 (dd, J = 8.4, 2.2 Hz,
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1H), 8.19 (d, J = 8.4 Hz, 1H), 7.88 (dm, J = 8.3 Hz, 2H), 7.83 (tm, J = 7.5 Hz, 1H), 7.68 (dd,
J = 8.2, 7.5, 2H); 13C NMR (126 MHz, DMSOꢀd6)
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δ
189.0, 140.2, 137.9, 135.9, 135.0, 134.8,
134.7, 133.7, 130.7, 129.3, 117.4; IR (ATR)
ν 3104 (w), 2288 (m), 1653 (m), 1282 (m), 1019
(s); HRMS (ESI) calcd for C13H8N2OCl [M+]: 243.0320, found: 243.0315.
General procedure for the synthesis of of o-acyl cinnamates 10 from arene diazonium
salts 9 (conditions A). To a solution of the appropriate arene diazonium salt 9 (1.0 mmol) in
anhydrous methanol (3 mL) was added Pd(OAc)2 (11.2 mg, 5 molꢀ%). The solution was
stirred for 0.25 h at ambient temperature, followed by addition of methyl acrylate (172 mg,
2.0 mmol). Stirring was continued at this temperature for 12 h. Water (15 mL) was added, and
the mixture was extracted three times with ethyl acetate (20 mL for each extraction). The
combined organic layers were dried with MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography on silica using hexanesꢀMTBE
mixtures as eluent.
General procedure for the synthesis of of o-acyl cinnamates 10 from acetanilides 8 via
deacetylation-diazotation-coupling (conditions B). To a solution of the appropriate oꢀacyl
acetanilide 8 (1.0 mmol) in dry and degassed methanol (6 mL) was added BF3•CH3OH (3.0
mmol, 324 ꢁL). The solution was stirred at 65°C for 16 h, and then cooled to 0°C (iceꢀwater
bath) or −21°C (iceꢀsaltꢀbath) as indicated in table 1. tertꢀBuONO (103 mg, 1.0 mmol; 155
mg, 1.5 mmol; 206 mg, 2.0 mmol as indicated in table 1) was added, and stirring at the
respective temperature was continued for 0.5 h, followed by addition of Pd(OAc)2 (5 molꢀ%,
11.2 mg) and warming to ambient temperature. After stirring for 0.25 h, methyl acrylate (172
mg, 2.0 mmol) was added and the solution was stirred for 12 h at ambient temperature. Water
(15 mL) was added and the mixture was extracted three times with ethyl acetate (20 mL for
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each extraction). The combined organic layers were dried with MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by column chromatography on
silica, using hexanesꢀMTBE mixtures as eluent.
9
(E
)-Methyl-3-(2-benzoylphenyl)acrylate (10a).49 Conditions A: following the general
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procedure, 9a (100 mg, 0.34 mmol) was converted to 10a (84 mg, 0.32 mmol, 93%).
Conditions B: following the general procedure, 8a (239 mg, 1.00 mmol) was converted to 10a
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(260 mg, 0.98 mmol, quant.). Yellowish oil; H NMR (300 MHz, CDCl3)
δ 7.80 – 7.68 (m,
4H), 7.57 (tm, J = 7.4 Hz, 1H), 7.50 (m, 1H), 7.47 – 7.36 (4H), 6.36 (d, J = 15.9 Hz, 1H), 3.69
(s, 3H); 13C NMR (75 MHz, CDCl3)
δ
197.1, 166.7. 142.0, 139.4, 137.3, 133.9, 133.5, 130.7,
130.3, 129.2, 129.1, 128.5, 127.3, 120.5, 51.7; IR (ATR)
ν 3062 (w), 2950 (w), 1715 (s), 1267
(s), 1172 (s); HRMS (ESI): calcd for C17H15O3 [M+H]+: 267.1021, found: 267.1022.
(E)-Methyl-3-(2-benzoyl-4-methoxyphenyl)acrylate (10b). Conditions A: following the
general procedure, 9b (100 mg, 0.31 mmol) was converted to 10b (80 mg, 0.27 mmol, 88%).
Conditions B: following the general procedure, 8b (269 mg, 1.00 mmol) was converted to 10b
1
(202 mg, 0.21 mmol, 68%). Yellow solid, mp 108 °C; H NMR (300 MHz, CDCl3)
δ 7.80
(dm, J = 9.0 Hz, 2H), 7.78 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 15.9 Hz, 1H), 7.53 (dd, J = 7.5,
7.5 Hz, 1H), 7.47 (ddm, J = 7.5, 7.5 Hz, 1H), 7.41 (dm, J = 7.5 Hz, 1H), 6.95 (dm, J = 9.0 Hz,
2H), 6.40 (d, J = 15.9 Hz, 1H), 3.90 (s, 3H), 3.75 (s, 3H); 13C NMR (75 MHz, CDCl3)
195.9, 166.9, 164.2, 142.2, 140.3, 133.6, 133.0, 130.5, 130.3, 129.4, 128.9, 127.3, 120.6,
114.1, 55.8, 51.9; IR (ATR) 2951 (w), 2840 (w), 1595 (s), 1253 (s), 1149 (s); HRMS (ESI)
δ
ν
calcd for C18H17O4 [M+H]+: 297.1127, found: 297.1100; MS (ESI) m/z 297 (100%), 294
(13%), 265 (10%), 196 (18%). Anal. Calcd. for C18H16O4 (296.32): C, 73.0; H, 5.4. Found: C,
73.0; H, 5.2.
(E)-Methyl-3-(2-benzoyl-4-chlorophenyl)acrylate (10c). Conditions A: following the
general procedure, 9c (93 mg, 0.28 mmol) was converted to 10c (79 mg, 0.26 mmol, 93%).
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Conditions B: following the general procedure, 8c (273 mg, 1.00 mmol) was converted to 10c
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(294 mg, 0.98 mmol, quant.). Yellow solid, mp 98 – 100°C; H NMR (300 MHz, CDCl3)
δ
7
8
9
7.77 – 7.68 (m, 4H), 7.53 (ddm, J = 7.5, 7.5 Hz, 1H), 7.48 – 7.34 (m, 4H), 6.36 (d, J = 15.9
Hz, 1H), 3.72 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ
196.1, 166.9, 141.9, 140.4, 139.1, 135.9,
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134.1, 131.9, 131.2, 129.5, 129.3, 129.2, 127.6, 121.0, 51.9; IR (ATR)
ν 3211 (w), 2951 (w),
1719 (s), 1582 (s), 1163 (s); HRMS (ESI) calcd for C17H14O3Cl [M+H]+: 301.0631, found:
301.0628; MS (ESI) m/z 301 (36 %), 202 (51 %), 196 (100 %), 176 (64 %). Anal. Calcd. for
C17H13ClO3 (300.74): C, 67.9; H, 4.4. Found: C, 67.8; H, 4.3.
(E)-Methyl-3-(2-benzoyl-4-fluorophenyl)acrylate (10d). Conditions A: following the
general procedure, 9d (100 mg, 0.32 mmol) was converted to 10d (76 mg, 0.27 mmol, 84%).
Conditions B: following the general procedure, 9d (257 mg, 1.00 mmol) was converted to 10d
1
(280 mg, 0.98 mmol, quant.). Yellowish oil; H NMR (300 MHz, CDCl3)
δ 7.87 – 7.76 (m,
2H), 7.72 (d, J = 15.9 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.52 (ddd, J = 7.5, 7.5, 1.6 Hz, 1H),
7.43 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 7.38 (dd, J = 7.5, 1.5 Hz, 1H), 7.22 (ddm, J = 9.0, 9.0 Hz,
2H), 6.36 (d, J = 15.9 Hz, 1H), 3.71 (s, 3H); 13C NMR (75 MHz, CDCl3)
166.2 (J = 255 Hz), 164.5, 141.9, 139.3, 134.0, 133.9, 133.2 (J = 9.0 Hz), 131.0, 129.3 (J =
21.8 Hz), 127.5, 120.9, 116.0 (J = 21.8 Hz), 51.9; IR (ATR) 2951 (w), 1716 (s), 1595 (s),
δ 195.7, 166.9,
ν
1270 (s), 1148 (s); HRMS (ESI) calcd for C17H13O3F [M+H]+: 285.0927, found: 285.0918;
MS (ESI) m/z 383 (100%), 294 (20%), 285 (72%), 196 (59%).
(E)-Methyl-3-(2-(3-methylbutanoyl)phenyl)acrylate (10e). Conditions B: following the
general procedure, 8e (100 mg, 0.45 mmol) was converted to 10e (108 mg, 0.44 mmol,
1
quant.). Yellow solid, mp 181 – 184°C; H NMR (300 MHz, CDCl3)
δ 8.03 (d, J = 15.9 Hz,
1H), 7.64 (dd, J = 7.5, 1.5 Hz, 1H), 7.57 (dd, J = 7.5, 1.4 Hz, 1H), 7.47 (ddd, J = 7.5, 7.5, 1.4
Hz, 1H), 7.42 (ddd, J = 7.5, 7.5, 1.4 Hz, 1H), 6.27 (d, J = 15.9 Hz, 1H), 3.77 (s, 3H), 2.76 (d,
J = 6.9 Hz, 2H), 2.25 (nonet, J = 6.7 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz,
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CDCl3)
δ
203.6, 166.9, 143.8, 139.3, 134.4, 131.5, 129.4, 128.4, 128.2, 120.4, 51.7, 50.5,
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25.2, 22.7; IR (ATR)
ν 2955 (m), 1716 (s), 1682 (s), 1273 (s), 1170 (s); HRMS (EI) calcd for
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8
C15H18O3 [M+]: 246.1256, found: 246.1242; MS (EI) m/z 246 (23%), 187 (100%), 145 (27%),
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115 (23%). Anal. Calcd. for C15H18O3 (246.30): C, 73.2; H, 7.4. Found: C, 72.8; H, 7.3.
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(E)-Methyl-3-(2-butyrylphenyl)acrylate (10f). Conditions A: following the general
procedure, 9f (70 mg, 0.27 mmol) was converted to 10f (61 mg, 0.26 mmol, quant.).
Conditions B: following the general procedure, 8f (103 mg, 0.50 mmol) was converted to 10f
(70 mg, 0.30 mmol, 60%). Yellowish oil; 1H NMR (300 MHz, CDCl3)
δ 8.03 (d, J = 15.9 Hz,
1H), 7.66 (dd, J = 7.3, 1.4 Hz, 1H), 7.56 (dd, J = 7.3, 1.5 Hz, 1H), 7.48 (ddd, J = 7.3, 7.3, 1.3
Hz, 1H), 7.42 (ddd, J = 7.3, 7.3, 1.4 Hz, 1H), 6.26 (d, J = 15.9 Hz, 1H), 3.78 (s, 3H), 2.87 (t, J
= 7.3 Hz, 2H), 1.73 (sext., J = 7.3 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3)
δ
203.8, 166.9, 143.9, 138.9, 134.5, 131.5, 129.4, 128.4, 128.2, 120.4, 51.7, 43.5,
2959 (w), 1716 (s), 1682 (s), 1273 (s), 1169 (s); HRMS (EI) calcd for
17.8, 13.8; IR (ATR)
ν
C14H16O3 [M+]: 232.1099, found: 232.1105; MS (EI) m/z 232 (15%), 173 (100%), 131 (14%),
151 (14%). Anal. Calcd. for C14H16O3 (232.28): C, 72.4; H, 6.9. Found: C, 71.9; H, 6.5.
(E)-Methyl-3-(2-benzoyl-5-methoxyphenyl)acrylate (10g). Conditions A: following the
general procedure, 9g (100 mg, 0.31 mmol) was converted to 10g (80 mg, 0.27 mmol, 88%).
Conditions B: following the general procedure, 8g (134 mg, 0.50 mmol) was converted to 10g
1
(118 mg, 0.40 mmol, 80%). Orangeꢀyellow solid, mp 100 – 104°C; H NMR (300 MHz,
CDCl3)
δ 7.89 (d, J = 15.9 Hz, 1H), 7.74 (dm, J = 8.5 Hz, 1H), 7.55 (tt, J = 7.4, 1.3 Hz, 1H),
7.51 – 7.35 (m, 3H), 7.17 (d, J = 2.5 Hz, 1H), 6.91 (dd, J = 8.5, 2.5 Hz, 1H), 6.34 (d, J = 15.9
Hz, 1H), 3.38 (s, 3H), 3.72 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ
196.3, 166.7, 161.6, 142.8,
138.1, 137.1, 132.9, 132.4, 131.5, 130.2, 128.4, 120.6, 114.3, 112.7, 55.6, 51.7; IR (ATR)
ν
2949 (w), 1715 (s), 1596 (s), 1227 (s), 1169 (s); HRMS (EI) calcd for C18H16O4 [M+]:
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296.1049, found: 296.1033; MS (EI) m/z 296 (13%), 237 (100%), 194 (12%), 165 (10%).
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Anal. Calcd. for C18H16O4 (296.32): C, 72.9; H, 5.4. Found: C, 72.9; H, 5.4.
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(E)-Methyl-3-(2-benzoyl-5-methylphenyl)acrylate (10h). Conditions A: following the
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general procedure, 9h (100 mg, 0.32 mmol) was converted to 10h (77 mg, 0.27 mmol, 86%).
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Conditions B: following the general procedure, 8h (253 mg, 1.00 mmol) was converted to 10h
1
(158 mg, 0.56 mmol, 56%). Yellow solid, mp 118 – 122°C; H NMR (300 MHz, CDCl3)
δ
7.79 (d, J = 15.9 Hz, 1H), 7.75 (dm, J = 8.4 Hz, 2H), 7.55 (tm, J = 7.4 Hz, 1H), 7.51 (s, 1H),
7.43 (dd, J = 8.4, 7.4 Hz, 2H)), 7.32 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.35 (d, J =
15.9 Hz, 1H), 3.71 (s, 3H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3)
141.2, 137.7, 136.5, 134.3, 133.3, 130.3, 129.8, 129.7, 128.5, 127.9, 120.2, 51.7, 21.5; IR
(ATR) 2950 (w), 1716 (s), 1655 (s), 1274 (s), 1170 (s); HRMS (EI) calcd for C18H16O3
δ 197.1, 166.8, 142.4,
ν
[M+]: 280.1099, found: 280.1093; MS (EI) m/z 280 (23%), 222 (13%), 221 (100%), 178
(10%). Anal. Calcd. for C18H16O3 (280.32): C, 77.1; H, 5.8. Found: C, 76.8; H, 5.7.
(E)-Methyl-3-(2-benzoyl-5-chlorophenyl)acrylate (10i). Conditions A: following the
general procedure, 9i (100 mg, 0.30 mmol) was converted to 10i (89 mg, 0.29 mmol, quant.).
Conditions B: following the general procedure, 8i (273 mg, 1.00 mmol) was converted to 10i
(295 mg, 0.98 mmol, quant.). Colourless solid, mp 108 – 113°C; 1H NMR (300 MHz, CDCl3)
δ
7.75 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 15.8 Hz, 1H), 7.68 (s, 1H), 7.59 (t, J = 7.4 Hz, 1H),
7.45 (dd, J = 7.7, 7.7 Hz, 2H), 7.42 – 7.31 (m, 2H), 6.35 (d, J = 15.9 Hz, 1H), 3.71 (s, 3H);
13C NMR (75 MHz, CDCl3)
δ
196.2, 166.5, 140.9, 137.7, 137.3, 136.2, 133.9, 130.9, 130.5,
129.3, 128.9, 128.9, 127.5, 121.9, 52.0; IR (ATR)
ν 2951 (w), 1721 (s), 1661 (s), 1279 (s),
1196 (s); HRMS (EI) calcd for C17H13O3Cl [M+]: 300.0553, found: 300.0550; MS (EI) m/z
300 (8%), 285 (23%), 241 (100%), 178 (23%). Anal. Calcd. for C17H13O3Cl (300.74): C, 67.9;
H, 4.4. Found: C,: 67.9; H, 4.1.
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(E
)-Methyl-3-(2-benzoyl-4-isopropylphenyl)acrylate (10j). Conditions B: following the
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general procedure, 8j (100 mg, 0.36 mmol) was converted to 10j (33 mg, 0.11 mmol, 30%).
Yellowish oil; 1H NMR (300 MHz, CDCl3)
δ
7.79 (d, J = 7.3 Hz, 2H), 7.71 (d, J = 15.9 Hz,
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1H), 7.65 (d, J = 8.2 Hz, 1H), 7.58 (tm, J = 7.4 Hz, 1H), 7.46 (dd, J = 7.7, 7.7 Hz, 2H), 7.37
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(dm, J = 8.2 Hz, 1H), 7.24 (s, 1H), 6.32 (d, J = 15.9 Hz, 1H), 3.69 (s, 3H), 2.92 (sept., J = 6.9
13
Hz, 1H), 1.23 (d, J = 6.9 Hz, 6H); C NMR (75 MHz, CDCl3)
δ 197.5, 166.9, 150.5, 141.9,
139.6, 137.4, 133.5, 131.3, 130.4, 128.9, 128.5, 127.3, 127.2, 119.5, 51.6, 33.9, 23.6; IR
2960 (m), 1718 (s), 1268 (s), 1170 (s), 721 (s); HRMS (EI) calcd for C20H20O3 [M+]:
(ATR)
ν
308.1412, found: 308.1414; MS (EI) m/z 308 (28%), 249 (100%), 233 (10%), 77 (10%).
8-Phenyl-3 ,8-dihydro-3 -pyrazolo[5,1- ]isoindol-2-ol (14). Compound 10a (100 mg, 0.37
a
H
a
mmol) and hydrazine (24 mg of 80wtꢀ% solution in water, 0.37 mmol) were dissolved in
ethylene glycol (5 mL) and irradiated for 0.5 h at 250°C in a dedicated microwave reactor.
The reaction mixture was concentrated under reduced pressure, and the residue was purified
by comlumn chromatography on silica using hexane / ethylacetate (1:1) to furnish 14 (20 mg,
1
0.08 mmol, 20%). Pale red solid, mp 215°C; H NMR (500 MHz, DMSOꢀd6) δ 9.99 (s, 1H),
7.66 (d, J = 7.5 Hz, 1H), 7.40 (ddd, J = 8.2, 8.2, 1.8 Hz, 1H), 7.38 ꢀ 7.24 (m, 5H), 7.08 (d, J =
7.0 Hz, 2H), 6.22 (s, 1H), 5.83 (s, 1H); 13C NMR (75 MHz, DMSOꢀd6) δ 164.6, 145.1, 144.9,
138.6, 129.9, 128.7, 128.3, 128.0, 127.3, 126.9, 123.7, 120.1, 82.2, 65.9; IR (ATR) ν 2922
(m), 1489 (s), 1088 (w), 747 (s), 697 (m); HRMS (ESI) calcd for C16H12ON2 [M+]: 248.0950,
found: 248.0947; MS (EI) m/z 248 (100%), 220 (21%), 189 (22%), 165 (18%).
General procedure for the synthesis of stilbenes 18. To a solution of the corresponding
arene diazonium salt 9 (1.0 equiv.) in anhydrous MeOH (15 mL per mmol of 9) was added
Pd(OAc)2 (5.0 molꢀ%). The mixture was stirred at ambient temperature for 0.25 h, and the
appropriate styrene 17 (1.2 equiv.) was added. The solution was stirred for 16 h at ambient
temperature and water (15 mL) was added. The mixture was extracted three times with ethyl
acetate (20 mL each), and the combined organic layers were dried with MgSO4, filtered and
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concentrated under reduced pressure. The residue was purified by column chromatography on
silica using hexanes / MTBE (10 : 1) as eluent.
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7
8
(E)-Phenyl-(2-styrylphenyl)methanone (18aa). Following the general procedure, 9a (100
9
mg, 0.34 mmol) and 17a (47 µL, 0.41 mmol) were converted to 18aa (93 mg, 0.33 mmol,
96%). Yellow oil; 1H NMR (300 MHz, CDCl3)
7.08 (d, J = 16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3)
10
11
12
13
14
15
16
17
18
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45
46
47
48
49
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δ
7.90 – 7.81 (m, 3H), 7.65 – 7.21 (m, 12H),
δ
198.5, 138.2, 138.1, 137.3, 136.8,
133.5, 131.5, 130.8, 130.5, 129.3, 128.8, 128.7, 128.1, 127.0, 126.9, 126.2, 126.1; IR (ATR)
ν
3059 (w), 1656 (s), 1490 (m), 1268 (s), 1086 (s); HRMS (EI) calcd for C21H16O [M+]:
284.1201, found: 284.1213; MS (EI) m/z 284 (57%), 207 (38%), 178 (100%), 105 (68%), 77
(76%).
(E)-(2-(4-Chlorostyryl)phenyl)-(phenyl)methanone (18ab). Following the general
procedure, 9a (100 mg, 0.34 mmol) and 17b (51 µL, 0.41 mmol) were converted to 18ab (102
mg, 0.32 mmol, 95%). Yellow oil; 1H NMR (300 MHz, CDCl3)
7.21 (m, 10H), 7.18 (d, J = 16.2 Hz, 1H), 6.98 (d, J = 16.2 Hz, 1H); 13C NMR (75 MHz,
δ
7.85 – 7.75 (m, 3H), 7.62 –
CDCl3)
δ
198.4, 138.1, 138.0, 136.6, 135.8, 133.7, 133.5, 130.9, 130.5, 130.1, 129.4, 128.9,
3058 (w), 1657 (s), 1596 (m), 1448 (s), 1273
128.7, 128.1, 127.2, 126.9, 126.2; IR (ATR)
ν
(s); HRMS (EI) calcd for C21H15OCl [M+]: 318.0811, found: 318.0804; MS (EI) m/z 318
(26%), 207 (22%), 178 (48%), 105 (49%), 77 (100%).
(E)-(4-Methoxyphenyl)-(2-styrylphenyl)methanone (18ba). Following the general
procedure, 9b (100 mg, 0.31 mmol) and 17a (42 µL, 0.37 mmol) were converted to 18ba (83
1
mg, 0.26 mmol, 86%). Yellow oil; H NMR (300 MHz, CDCl3)
δ 7.88 – 7.80 (m, 3H), 7.52
(ddd, J = 8.0, 8.0, 2.2 Hz, 1H), 7.42 – 7.20 (m, 7H), 7.20 (d, J = 16.2 Hz, 1H), 7.08 (d, J =
16.2 Hz, 1H), 6.95 (dm, J = 8.9 Hz, 2H), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ
197.2,
164.0, 138.8, 137.3, 136.3, 132.9, 131.2, 130.9, 130.3, 128.8, 128.7, 128.0, 127.1, 126.9,
126.2, 126.0, 114.0, 55.7; IR (ATR) 2956 (w), 1651 (m), 1594 (s), 1252 (s), 1148 (s);
ν
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HRMS (EI) calcd for C22H18O2 [M+]: 314.1307, found: 314.1306; MS (EI) m/z 314 (100%),
237 (18%), 206 (24%), 178 (12%), 108 (22%). Anal. Calcd. for C22H18O2 (314.38): C, 84.0;
H, 5.8. Found: C, 83.5; H, 5.8.
9
(E)-(2-(4-Chlorostyryl)phenyl)-(4-methoxyphenyl)methanone (18bb). Following the
10
11
12
13
14
15
16
17
18
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general procedure, 9b (100 mg, 0.31 mmol) and 17b (47 µL, 0.37 mmol) were converted to
18bb (92 mg, 0.26 mmol, 86%). Colourless solid, mp 95–96°C; 1H NMR (300 MHz, CDCl3)
δ
7.87 – 7.77 (m, 3H), 7.51 (ddd, J = 8.0, 8.0, 2.2 Hz, 1H), 7.42 – 7.20 (m, 6H), 7.18 (d, J =
16.2 Hz, 1H), 7.02 (d, J = 16.2 Hz, 1H), 6.95 (dm, J = 8.9 Hz, 2H), 3.88 (s, 3H); 13C NMR
(75 MHz, CDCl3)
δ
197.0, 164.1, 138.8, 136.1, 135.8, 133.6, 132.9, 130.8, 130.4, 129.9,
2927 (w), 1651 (m), 1594
128.9, 128.9, 128.1, 127.2, 128.8, 126.0, 113.9, 55.7; IR (ATR)
ν
(s), 1491 (m), 1253 (s); HRMS (EI) calcd for C22H17O2Cl [M+]: 348.0917, found: 348.0925;
MS (EI) m/z 348 (100%), 240 (18%), 108 (46%). Anal. Calcd. for C22H17ClO2 (348.83): C,
75.7; H, 4.9. Found: C, 75.2; H, 4.8.
(E)-(4-Chlorophenyl)-(2-styrylphenyl)methanone (18ca). Following the general procedure,
9c (100 mg, 0.30 mmol) and 17a (42 µL, 0.36 mmol) were converted to 18ca (75 mg, 0.24
1
mmol, 78%). Orangeꢀyellow oil; H NMR (300 MHz, CDCl3)
δ 7.86 – 7.75 (m, 3H), 7.51
(ddd, J = 8.0, 8.0, 2.2 Hz, 1H), 7.45 (dm, J = 8.7 Hz, 2H), 7.42 – 7.24 (7H), 7.21 (d, J = 16.3
Hz, 1H), 7.07 (d, J = 16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ
197.2, 140.0, 137.6, 137.1,
136.8, 136.4, 131.8, 131.8, 131.0, 129.1, 129.0, 128.8, 128.2, 127.1, 126.9, 126.4, 125.9;
IR(ATR) 3058 (w), 1658 (m), 1585 (s), 1271 (m), 1089 (s); HRMS (EI) calcd for
ν
C21H15OCl [M+]: 318.0811, found: 318.0809; MS (EI) m/z 318 (100%), 241 (33%), 206
(26%), 178 (20%). Anal. Calcd. for C21H15OCl (318.80): C, 79.1; H, 4.7. Found: C, 79.0; H,
4.7.
(E)-(4-Chlorophenyl)-(2-(4-chlorostyryl)phenyl)methanone (18cb). Following the general
procedure, 9c (100 mg, 0.30 mmol) and 17b (42 µL, 0.36 mmol) were converted to 18cb (85
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