An air-tolerant approach to the carbonylative suzuki-miyaura coupling: Applications in isotope labeling

Article abstract of DOI:10.1021/jo401696c

Carbonylative Suzuki-Miyaura coupling conditions have been developed that proceed without the exclusion of oxygen and in the presence of nondegassed and nondried solvents. By adapting the method to a two-chamber setup, the direct handling of carbon monoxide, produced from stable CO precursors, is avoided. The protocol afforded the desired benzophenones with excellent functional group tolerance and in good yields. Substituting the CO precursor, in the CO-producing chamber, with its carbon-13 labeled version generated the corresponding carbon-13 labeled benzophenones. Finally, the developed system was applied in the synthesis and isotope labeling of two pharmaceuticals, nordazepam and Tricor.

Full text of DOI:10.1021/jo401696c

Article
pubs.acs.org/joc
An Air-Tolerant Approach to the Carbonylative Suzuki−Miyaura
Coupling: Applications in Isotope Labeling
Andreas Ahlburg,‡ Anders T. Lindhardt,*,§ Rolf. H. Taaning,‡ Amalie E. Modvig,‡
and Troels Skrydstrup*,‡
‡Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the Interdisciplinary Nanoscience Center
(iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Central Denmark Region, Denmark
§Interdisciplinary Nanoscience Center (iNANO), Biological & Chemical Engineering, Department of Engineering, Aarhus University,
Findlandsgade 22, 8200 Aarhus N, Denmark
S
* Supporting Information
ABSTRACT: Carbonylative Suzuki−Miyaura coupling conditions have been developed that proceed without the exclusion of
oxygen and in the presence of nondegassed and nondried solvents. By adapting the method to a two-chamber setup, the direct
handling of carbon monoxide, produced from stable CO precursors, is avoided. The protocol afforded the desired
benzophenones with excellent functional group tolerance and in good yields. Substituting the CO precursor, in the CO-
producing chamber, with its carbon-13 labeled version generated the corresponding carbon-13 labeled benzophenones. Finally,
the developed system was applied in the synthesis and isotope labeling of two pharmaceuticals, nordazepam and Tricor.
is the benzophenones. Such compounds are found in sun-
blockers (benzophenone 1−9), Tricor,3 Sector,4 Evista,5 photo-
initiators in UV-curing inks, and serve as key structural
components in the benzodiazapine families (Scheme 1).9,6 The
high presence of benzophenones in target structures makes the
carbonylative Suzuki−Miyaura coupling an obvious synthetic
strategy for the R&D chemist. The majority of the literature
covering this particular cross coupling is dominated by high-
pressure protocols, and only few are found applying CO at
atmospheric pressure.7−9 However, it is interesting to note that
protocols have emerged that operate without the exclusion of
oxygen from the headspace or the reaction medium. This is
achieved by applying air-stable ligands or even ligandless
conditions. Furthermore, a few of these protocols afford the
carbonylative Suzuki−Miyaura coupling product under a simple
balloon pressure of CO.
One drawback that relates to all carbonylative reactions is the
necessity to apply carbon monoxide as the gas itself. Because CO
is a corrosive, flammable, and highly toxic gas, it must be handled
with extreme caution. This statement is further strengthened
since CO is colorless, odorless, and without taste. CO is typically
delivered in pressurized cylinders and operated in the presence of
CO detectors and in dedicated laboratories to protect the
operator.
INTRODUCTION
■
In principle, every palladium-catalyzed cross coupling holds a
carbonylative counterpart.1 In example, whereby the heter-
oatoms represent the nucleophile, this includes the direct
amination with its corresponding aminocarbonylation, as well as
the aryl ether formation and the alkoxycarbonylation. Reactions
with carbon nucleophiles including the Sonogashira, Stille, and
Suzuki−Miyaura couplings also have their carbonylative
versions. Even the Mizoroki−Heck reaction can be transformed
into a reaction where carbon monoxide (CO) is incorporated. In
this way, it is possible to prepare a vast structural diversity based
on few starting materials by performing the cross coupling
reaction under conditions with and without CO integration.
The Suzuki−Miyaura cross coupling represents one of the
most applied transition metal-catalyzed reaction in discovery
chemistry.2 A successful coupling results in the site-specific
carbon−carbon bond formation between two activated sub-
strates, typically an aryl boronic acid or derivative thereof and an
aryl halide, to form a biaryl. Furthermore, there is literature
precedence providing conditions for virtually any desirable
Suzuki−Miyaura coupling, and chemical distributors provide
large chemical catalogues of commercially available boronic acid
and aryl halide derivatives, adding to the ever-growing popularity
of this transformation.
The carbonylative version of the Suzuki−Miyaura reaction has
also been studied, although not to the same extent as its direct
version. One class of products obtained from successful coupling
Received: August 2, 2013
© XXXX American Chemical Society
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Scheme 1. Selected Examples of Benzophenone Derivatives
Scheme 2. Applications of COgen and COware
Previously, we have developed an alternative delivery method
of CO.10 This technique was based on a stable solid CO
precursor (COgen) from which a predetermined amount of CO
can be released. Upon combination of the CO release with a
sealed two-chamber system (COware), this method has proven
highly adaptable for many Pd-catalyzed carbonylations (Scheme
2).10,11 During our work, it was realized that despite the CO
release being a palladium/phosphine-catalyzed transformation,
CO could efficiently be produced under noninert conditions (i.e.,
in the presence of air and in nondegassed and nondried solvents).
Obviously, this adds to the overall applicability of the two-
chamber technique by circumventing the direct handling of CO
and not requiring an inert atmosphere or glovebox.
With a simple CO technique in hand and with existing
literature on air-tolerant carbonylative Suzuki−Miyaura coupling
conditions, we decided to investigate the potential combination
of these two areas into a new tool for the general organic
chemists. Not only would this represent a simple method for the
preparation of benzophenones, but also at the same time it would
provide a facile entry point for carbon isotope labeling, applying
isotopically labeled CO generated from 13COgen or even
14COgen. CO is an ideal source for isotope labeling, as the
conditions applied for its introduction, typically transition metal
catalysis, ensure a high functional group tolerance. This in turn
allows this particular isotope-labeled building block to be
installed in the final steps of the linear sequence toward the
target structure. This ensures a high isotope efficiency and
reduces the number of overall steps in which the labeled material
needs to be handled, a fact which is especially important when
working with radioactive isotopes such as carbon-14.3
Furthermore, CO is typically introduced by the formation of a
stable carbon−carbon bond, which is important, if the final
compound is to be applied in drug metabolism studies. Being
able to apply an identical synthetic approach for the preparation
of the test substrates and even their isotopically labeled
counterparts could significantly reduce downstream processes
in the pharmaceutical and agrochemical industry.
Here, we report on our findings on a simple and air-tolerant
carbonylative Suzuki−Miyaura coupling. CO was generated in
parallel to the carbonylative coupling based on a two-chamber
technique, and the conditions developed allowed for high
functional group tolerance in the synthesized benzophenones.
This approach allows the carbonylative Suzuki−Miyaura
coupling to be performed without the direct handling of CO,
and it avoids the elaborate drying and deoxygenation of both
solvents and the reaction vessel. Finally, the method was applied
for the synthesis and carbon isotope labeling of the two
pharmaceuticals, Tricor and nordazepam, clearly illustrating the
usefulness of this simple and straightforward protocol.
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a
Table 1. Optimization of the Carbonlytative Suzuki−Miyaura Coupling
b
c
entry
Pd cat (mol %)
base
conversion (%)
ratio 2:3 [yield]
1
Pd(OAc)2 (5)
Pd(OAc)2 (1)
PdCl2COD (1)
PdBr2 (1)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
KF
100
100
100
100
100
100
100
100
0
25:75
2
69:31 [67%]
71:29
3
4
84:16
5
Pd(dba)2 (1)
Pd(TFA)2 (1)
PdCl2 (1)
71:29
6
58:42
7
94:6 [81%]
89:11
8
Pd/C (1)
9
none
−
>95:5
10
11
12
13
PdCl2 (1)
13
PdCl2 (1)
87
83:17
PdCl2 (1)
100
15
83:17
PdCl2 (1)
NaOAc
>95:5
a
Conditions: Chamber A, COgen (0.75 mmol), Pd(dba)2 (5 mol %), HBF4P(tBu)3 (5 mol %), DIPEA (2.0 equiv) in anisole (3 mL). Chamber B, 4-
b
iodoacetophenone (0.5 mmol), [Pd] (x mol %), Base (3 equiv) in anisole (3 mL). Both chambers were heated to 80 °C. Determined by 1H NMR
analysis of the crude reaction mixture. Isolated yields of 2 are reported in square brackets.
c
reaction mixture (entry 7). Furthermore, an 81% isolated yield of
2 (entry 7) was shown.12 Even Pd/C was able to catalyze the
carbonylative coupling with a 89:11 selectivity for CO insertion
(entry 8).13 Omitting the Pd catalyst led to an inactive catalytic
system (entry 9).14 Finally, different bases were tested as
alternatives to K2CO3 (entries 10−13). Only KF afforded the
same high reactivity as K2CO3 but with a lowered 2:3 ratio of
83:17.2a,b Finally, by carefully mixing the PdCl2 with K2CO3 in a
mortar, a pale brown powder was obtained, which proved simple
to handle and to weigh out. This catalyst/base mixture afforded
the same results as when the two reagents were added separately,
and hence, this mixture was therefore used in the rest of the
carbonylative couplings.15 Attempts to include aryl bromides as
electrophiles did afford the desired benzophenones; however,
only low yields were obtained because of competing formation of
the benzoic acid derivatives.
RESULTS AND DISCUSSION
■
The previously developed CO-delivery system consisting of the
acid chloride 1 (COgen), Pd(dba)2, HBF4P(tBu)3, and N,N-
diisopropyl-N-ethylamine (DIPEA) as the stoichiometric base
proved able to deliver CO even in presence of an ambient
atmosphere applying nondried solvents.10 With this source of
CO in our hands and inspired by the work of Yang and Xue et al.,
who reported a benzophenone protocol applying Pd(dba)2 as the
catalyst with K2CO3 as the base in anisole delivering CO by a
balloon, we set forth to develop an equally oxygen-compatible
carbonylative Suzuki−Miyaura coupling protocol.8a Several
groups have reported that the combination of Pd(OAc)2 with
K2CO3 effectively promotes the carbonylated Suzuki−Miyaura
coupling reaction. Importantly, the use of anisole as the solvent
proved essential in order to secure high yields, whereas solvents
like DMF, toluene, and THF afforded mainly the direct biaryl
coupling products without CO insertion.7a,8a−c,9 As a model
system, we chose the coupling of 4-iodoacetophenone and
phenylboronic acid with anisole as the solvent (Table 1). 1.5
equiv of CO was applied using the two-chamber setup. All
reactions were set up using nondried solvents and with no
exchange of the headspace atmosphere with inert N2 or Ar. The
crude reaction mixtures were analyzed for the desired
benzophenone 2, the direct coupling product 4-phenyl
acetophenone (3), and the overall conversion.
Satisfied with these simple-to-perform carbonylative Suzuki−
Miyaura coupling conditions, these were then tested against a
series of different aryl iodides and aryl boronic acids, the results of
which are depicted in Table 2.16
Full conversion of the aryl iodide starting material was typically
observed, and drops in yields are ascribed to competing biaryl
coupling as observed by 1H NMR analysis of the crude reaction
mixture. Aryl iodides carrying electron-withdrawing groups such
as nitro or and amide underwent successful coupling with
phenylboronic acid providing the corresponding benzophenones
with isolated yields of 72, 93, and 59% (entries 1−3).17 The
presence of a free phenolic alcohol only afforded low conversion,
but upon its MOM or tosyl protection, the desired
benzophenones could be obtained in reasonable yields (entries
4, 5 and 15). A slight decrease in isolated yield was observed by
the introduction of a substituent in ortho-position of the aryl
iodide (entries 6, 8, 9 and 15). The presence of both protected
and free anilines did not seem to interfere with the catalytic
system, and the corresponding benzophenones were secured in
yields ranging from 71−79% (entries 9, 11−13). Even the
acetylated phenyldiazenyl iodophenol provided the desired
Applying the conditions tested by Yang and Xue, however,
using Pd(OAc)2 instead of Pd2(dba)3, afforded a clean reaction
with full conversion but with a nonideal 25:75 ratio of 2:3 (entry
1).8a Lowering the Pd(OAc)2 loading to 1 mol % afforded the
same conversion rate while increasing the formation of 2 (entry
2). This increase in the formation of 2 could be explained by the
higher CO/Pd ratio. Setting the reaction temperature to 60 °C
resulted in incomplete conversion (result not shown). Other Pd
sources were screened as shown in entries 3−8. For all of the
tested Pd sources, completion of the reactions were observed,
and gratifyingly, we found that PdCl2 afforded an excellent 94:6
1
ratio of 2:3 as measured by H NMR analysis of the crude
C
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a
Table 2. Carbonylative Suzuki−Miyaura Couplings
a
b
c
For specific reaction conditions, see Supporting Information. Isolated yields after column chromatography. Reaction repeated on 3 mmol scale
(yield in brackets).
benzophenone, although only in a 50% isolated yield after
column chromatography (entry 14). Acetal protection of the
ketone moiety in 4-iodoacetophenone prior to coupling
generated the benzophenone coupling product in 80% isolated
yield (entry 16). Also heteroaromatic aryl iodides underwent
successful coupling with isolated yields of 71, 70, and 67%
(entries 17−19). A double coupling was attempted using 1,4-
diiodobenzene as substrate affording the 1,4-dibenzoyl benzene
in 70% isolated yield (entry 10). Finally, performing the reaction
of o-iodoaniline with phenylboronic acid on a 3 mmol scale
afforded a slight increase in isolated yield to 82% (entry 9, results
in brackets).
Next, a few examples of the benzophenones depicted in Table
2 were selected for carbon-13 labeling (Scheme 3). By simply
exchanging COgen for 13COgen, applying the exact coupling
conditions as in Table 2, the desired 13C-labeled benzophenones
were obtained in yields similar to those of the unlabeled version
(Table 2, entries 3, 6, 15 and 17). Again, these couplings are
performed without careful drying or deoxygenation of solvents,
nor was oxygen excluded from the reaction vessel headspace.
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Scheme 3. Synthesis of 13C-Isotope Labeled Benzophenones
Scheme 4. Synthesis and 13C-Labeling of Nordazepam and Tricor
Attention was then turned toward more advanced applications
of this method in order to prove its utility in the synthesis of
biologically relevant structures. The basic idea was to apply a
carbonylative coupling in which CO was incorporated into the
core of the final structure. From the family of benzodiazepines
and used in the treatment of anxiety, nordazepam was chosen as
the first target structure. To this end, 4-chloro-2-iodoaniline was
attempted coupled with phenyl boronic acid. Using the
developed conditions from Table 1 only afforded the target
As a final example, the synthesis of Tricor, a cholesterol and
triglyceride regulator, was chosen. The starting iodide 25 for the
carbonylative coupling was obtained from iodophenol via a
Barganelli reaction (acetone, KOH, and chloroform), followed
by Fischer esterification in isopropyl alcohol. Gratifyingly, the
coupling of 25 with 4-chlorophenyl boronic acid, applying the
developed conditions, afforded Tricor (26) and 13C-labeled
Tricor (13C-26) in 84 and 85% isolated yields, respectively
(Scheme 4). We have previously reported the synthesis of 14C-
Tricor (27) using the same conditions introducing this
radioactive label in the final step of the synthesis, however,
applying 14CO as the limiting reagent on a 0.1 mmol scale
(Scheme 4, bottom reaction).3,19 The successful synthesis and
labeling of Tricor under near identical conditions, only
substituting the CO precursor, applying the same two-chamber
reaction vessel for all transformations proves the overall strength
and simplicity of the developed carbonylative Suzuki−Miyaura
protocol.
1
benzophenone 23 in low yield. H NMR analysis of the crude
reaction mixture showed full consumtion of the aryl iodide with
the formation of the biaryl without CO insertion. Lowering the
amount of phenyl boronic acid to an equimolar amount (0.5
mmol) increased the selectivity toward the benzophenone
moiety. Decreasing the palladium loading further improved the
selectivity toward 23 but at the expence of an incomplete
reaction. Finally, increasing the temperature of the reaction to
120 °C in combination with 0.1 mol % of PdCl2 catalyst allowed
for a 62% isolated yield of 23 after column chromatography. In a
similar manner 13C-23 could be obtained in 68% isolated yield.
Acetylation of both 23 and 13C-23 applying 2-bromoacetyl
bromide in the presence of sodium bicarbonate followed by
treatment with aqueous ammonia in a one-pot manner affoded
nordazepam (24) and 13C-labeled nordazepam (13C-24) in 55
and 63% isolated yields, respectively (Scheme 4).18
CONCLUSION
■
In conclusion, carbonylative Suzuki−Miyaura coupling con-
ditions have been developed in combination with CO being
delivered from a CO precursor in a two-chamber system. All
reactions were performed using nondried solvents and with no
exclusion of air from the reactor headspace significantly
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(59% yield) of the title compound as a colorless solid: 1H NMR (400
MHz, CDCl3) δ (ppm) 8.07 (d, 1H, J = 0.6 Hz,), 7.98 (d, J = 7.7 Hz,
1H), 7.85 (dd, 1H, J = 7.8, 0.6 Hz), 7.81−7.79 (m, 2H), 7.63 (dt, 2H, J =
7.6, 0.6 Hz), 7.51 (dt, 2H, J = 7.7, 1.6 Hz); 13C NMR (100 MHz, CDCl3)
δ (ppm) 195.2, 138.3, 136.7, 133.1, 133.0, 131.0 (q, J = 32.7 Hz), 130.0,
128.9, 128.8 (q, J = 3.6 Hz), 128.5, 126.7 (q, J = 3.8 Hz), 126.7 (q, J =
270.6 Hz); 19F NMR (376.8 MHz, CDCl3) δ (ppm) −62.8 (s, 3F);
HRMS C14H9F3O [M + Na+]; calculated 273.0498, found 273.0500, [M
+ H+]; calculated 251.0678, found 251.0679.
simplifying the reaction setup. Several benzophenones were
synthesized with high functional group tolerance and good to
excellent isolated yields. The method was further extrapolated to
include isotope labeling using 13CO simply by exchanging the
carbon monoxide precursor to its carbon-13 labeled counterpart.
Finally, the synthesis of both nordazepam and Tricor and their
labeled versions was performed using the developed method on
key transformations introducing the carbonyl moiety onto
advanced reaction intermediates. The simplicity of the developed
approach will provide the synthetic chemistry community with a
straightforward tool for performing carbonylative Suzuki−
Miyaura couplings without the need of handling CO or
drying/degassing solvents and reactor headspace.
[13C]-Phenyl-(3-(trifluoromethyl)phenyl)methanone (13C-6).
General method with 3-(trifluoromethyl)-iodobenzene (136.0 mg,
0.50 mmol) and phenylboronic acid (73.2 mg, 0.60 mmol). 13C-Labeled
9-methyl-fluorene-9-carbonyl chloride (182.8 mg, 0.75 mmol) in
chamber B. Flash column chromatography (pentane to CH2Cl2). This
gave 78.3 mg (62% yield) of the title compound as a colorless solid: 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.07 (t, 1 H, J = 1.8 Hz), 7.98 (dd, 1
H, J = 7.7, 3.7 Hz), 7.85 (dd, 1H, J = 1.0 Hz, 0.5 Hz), 7.84−7.78 (m, 2H),
7.63 (dt, 2H, J = 7.5, 0.5 Hz), 7.52 (dt, 2H, J = 7.6, 0.5 Hz); 13C NMR
(100 MHz, CDCl3) δ (ppm) 194.9 (13CO), 138.3 (d, J = 50.0 Hz), 136.7
(d, J = 60.0 Hz), 133.1 (d, J = 1.0 Hz), 133.0 (d, J = 1.0 Hz), 131.3 (dd, J
= 32.6, 4.1 Hz), 130.0 (d, J = 4.0 Hz), 128.9 (d, J = 5.0 Hz), 128.8 (q, J =
3.6 Hz), 128.6 (d, J = 7.0 Hz), 126.7 (q, J = 4.0 Hz), 123.8 (q, J = 270.6
Hz); HRMS [M + H+]; calculated 252.0712, found 252.0709.
Methyl 2-methoxy-5-(4-methoxybenzoyl)benzoate (7). Gen-
eral method with methyl 5-iodo-2-methoxybeonzoate (146.0 mg, 0.50
mmol) and 4-methoxyphenylboronic acid (67.1 mg, 0.55 mmol). Flash
column chromatography (10−40% EtOAc/pentane) gave 78.5 mg
(52% yield) of the title compound as a colorless solid: 1H NMR (400
MHz, CDCl3) δ (ppm) 8.24−8.24 (m, 1H), 7.97−7.94 (m, 1H), 7.80−
7.76 (m, 2H), 7.07−7.05 (m, 1H), 6.99−6.95 (m, 2H), 3.98−3.98 (m,
3H), 3.88−3.88 (m, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.6,
166.0, 163.2, 162.0, 135.5, 134.0, 132.3, 130.2, 130.2, 119.8, 113.7, 111.7,
56.4, 55.6, 53.3; HRMS m/z calculated for C17H16O5H+ [M + H+]
301.1071, found 301.1072.
EXPERIMENTAL SECTION
■
General Materials and Methods. All purchased chemicals were
used as received without further purification. Flash chromatography was
carried out on silica gel 60 (230−400 mesh). The chemical shifts are
reported in ppm relative to solvent residual peak.20 1H NMR spectra
were recorded at 400 MHz, 13C NMR spectra were recorded at 100
MHz, and 19F NMR were recorded at 376.8 MHz. MS spectra were
recorded on a LC TOF (ES) apparatus.
General Method. Aryl halide (0.50 mmol, 1.0 equiv), arylboronic
acid (0.55−0.75 mmol, 1.1−1.5 equiv), K2CO3 (1.5 mmol, 3 equiv), and
PdCl2 (0.005 mmol, 0.01 equiv) were added to chamber A of a COware
system. 9-Methyl-fluorene-9-carbonyl chloride (0.75 mmol, 1.5 equiv),
P(tBu)3HBF4 (0.0375 mmol, 0.075 equiv), and Pd(dba)2 or PdCl2(cod)
(0.0375 mmol, 0.075 equiv) were added to chamber B. To both
chambers was added anisole (3.0 mL). Finally, DIPEA (1.5 mmol, 3
equiv) was added to chamber B, and both chambers were fitted with a
Teflon-sealed screwcap. Both reaction chambers were heated overnight
at 80 °C. The crude of chamber A was evaporated onto silica gel and
purified with flash column chromatography to yield the desired product.
1-(4-Benzoylphenyl)ethanone21 (2). General method with 1-(4-
iodophenyl)ethanone (123.0 mg, 0.50 mmol) and phenylboronic acid
(91.0 mg, 0.75 mmol). Flash column chromatography (10% EtOAc in
pentane). This gave 91.2 mg (81% yield) of the title compound as a
Methyl 5-benzoyl-2-(methoxymethoxy)benzoate (8). General
method with methyl 5-iodo-2-(methoxymethoxy)benzoate (161.0 mg,
0.50 mmol) and phenylboronic acid (91.4 mg, 0.75 mmol). Flash
column chromatography (0−5% EtOAc/CH2Cl2) gave 101.4 mg (68%
1
yield) of the title compound as a colorless oil: H NMR (400 MHz,
1
CDCl3) δ (ppm) 8.25 (d, 1H, J = 2.3 Hz), 7.92 (dd, 1H, J = 8.7, 2.3 Hz),
7.76−7.73 (m, 2H), 7.58−7.54 (m, 1H), 7.48−7.44 (m, 2H), 7.27 (d,
1H, J = 8.8 Hz), 5.32 (s, 2H), 3.87 (s, 3H), 3.51 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 194.7, 165.8, 159.8, 137.5, 135.3, 133.9, 132.4,
130.6, 129.8, 128.4, 121.0, 115.2, 94.7, 56.6, 52.3; HRMS m/z calculated
for C17H16O5H+ [M + H+] 301.1071, found 301.1070.
colorless solid: H NMR (400 MHz, CDCl3) δ (ppm) 8.05−8.02 (m,
2H), 7.86−7.83 (m, 2H), 7.80−7.77 (m, 2H), 7.62−7.58 (m, 1H),
7.50−7.46 (m, 2H), 2.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 197.6, 196.0, 141.4, 139.6, 137.0, 133.1, 130.2, 130.1, 128.5,
128.2, 27.0; HRMS m/z calculated for C15H12O2H+ [M + H+] 225.0910,
found 225.0911.
(4-Nitrophenyl)(phenyl)methanone22 (4). General method with
1-iodo-4-nitrobenzene (124.5 mg, 0.50 mmol) and phenylboronic acid
(67.1 mg, 0.55 mmol). Flash column chromatography (50% CH2Cl2/
pentane) gave 81.6 mg (72% yield) of the title compound as a colorless
solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 8.34 (d, 2H, J = 8.6 Hz),
7.94 (d, 2H, J = 8.5 Hz), 7.80 (d, 2H, J = 7.1 Hz), 7.68−7.63 (m, 1H),
7.55−7.51 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 194.9,
149.9, 143.0, 136.4, 133.6, 130.8, 130.2, 128.8, 123.7; HRMS m/z
calculated for C13H10NO3H+ [M + H+] 228.0655, found 228.0654.
3-Benzoyl-N-(6-methylpyridin-2-yl)benzamide (5). General
method with 3-methyl-N-(6-methylpyridin-2-yl)benzamide (169.1
mg, 0.50 mmol) and phenylboronic acid (91.5 mg, 0.75 mmol). Flash
column chromatography (25% EtOAc/pentane) gave 147.5 mg (93%
Dibenzo[b,d]furan-4-yl(4-methoxyphenyl)methanone (9).
General method with 4-iodoanisole (117.0 mg, 0.50 mmol) and
dibenzo[b,d]furan-4-ylboronic acid (116.6 mg, 0.75 mmol). Flash
column chromatography (5% EtOAc/pentane) gave 88.9 mg (59%
yield) of the title compound as a colorless solid: 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.12 (dd, 1H, J = 7.7, 1.2 Hz), 8.00−7.97 (d, 1H), 7.92
(d, 2H, J = 9.0 Hz), 7.68 (dd, 1H, J = 7.6, 1.3 Hz), 7.54 (d, 1H, J = 8.2
Hz), 7.48−7.42 (m, 2H), 7.39−7.35 (m, 1H), 8.96 (d, 2H, J = 8.9 Hz),
3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 192.6, 163.9, 156.4,
153.7, 132.8, 130.4, 128.3, 127.8, 125.5, 123.9, 123.7, 123.5, 123.2, 122.6,
120.8, 113.7, 112.2, 55.6; HRMS m/z calculated for C20H14O3H+ [M +
H+] 303.1016, found 303.1018.
(4-Methoxyphenyl)(phenyl)methanone21 (10). General meth-
od with 4-iodoanisole (117.0 mg, 0.50 mmol) and phenylboronic acid
(91.4 mg, 0.75 mmol). Flash column chromatography (50% CH2Cl2/
pentane) gave 98.3 mg (93% yield) of the title compound as a colorless
solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.83 (d, 2H, J = 8.9 Hz),
7.77−7.74 (m, 2H), 7.58−7.54 (m, 1H), 7.49−7.44 (m, 2H), 6.96 (d,
2H, J = 8.9 Hz), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
195.6, 163.3, 138.3, 132.6, 131.9, 130.2, 129.8, 128.2, 113.6, 55.5; HRMS
m/z calculated for C14H12O2H+ [M + H+] 213.0910, found 213.0911.
[13C]-(4-Methoxyphenyl)(phenyl)methanone (13C-10). Gener-
al method with 4-iodoanisole (117.0 mg, 0.50 mmol) and phenylboronic
acid (91.4 mg, 0.75 mmol). 13C-labeled 9-methyl-fluorene-9-carbonyl
chloride (182.8 mg, 0.75 mmol) in chamber B. Flash column
1
yield) of the title compound as a colorless oil: H NMR (400 MHz,
CDCl3) δ (ppm) 9.01 (s, 1H), 8.30−8.29 (m, 1H), 8.15−8.10 (m, 2H),
7.95−7.92 (m, 1H), 7.76−7.74 (m, 2H), 7.61−7.54 (m, 3H), 7.47−7.43
(m, 2H), 6.87 (d, 1H, J = 7.4 Hz), 2.33 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 195.6, 164.9, 156.9, 150.7, 138.8, 138.1, 136.9, 134.7,
133.3, 132.9, 131.1, 130.0, 128.9, 128.6, 128.5, 119.7, 111.2, 23.9; HRMS
m/z calculated for C20H16N2O2Na+ [M + Na+] 339.1104, found
339.1107.
Phenyl-(3-(trifluoromethyl)phenyl)methanone23 (6). General
method with 3-(trifluoromethyl)-iodobenzene (136.0 mg, 0.50 mmol)
and phenylboronic acid (73.2 mg, 0.60 mmol). Flash column
chromatography (pentane to dichloromethane). This gave 73.5 mg
F
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chromatography (50% CH2Cl2/pentane) gave 96.7 mg (91% yield) of
the title compound as colorless solid: H NMR (400 MHz, CDCl3) δ
(97.9 mg, 0.55 mmol). Flash column chromatography (CH2Cl2) gave
100.5 mg (50% yield) of the title compound as a yellow oil: 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.13−8.10 (m, 2H), 7.92−7.87 (m, 2H),
7.80−7.78 (m, 2H), 7.54−7.45 (m, 5H), 7.38−7.35 (m, 1H) 2.02 (s,
3H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.9, 169.1,
157.3, 152.5, 150.5, 149.8, 134.5, 132.6, 131.6, 130.1, 129.3, 125.8, 125.7,
125.3, 124.2, 123.1, 35.4, 31.2, 20.7; HRMS m/z calculated for
C25H24N2O3H+ [M + H+] 401.1860, found 401.1865.
1
(ppm) 7.85−7.80 (m, 2H), 7.76−7.73 (m, 2H), 7.57−7.54 (m, 1H),
7.48−7.44 (m, 2H), 6.96 (d, 2H, J = 8.8 Hz), 3.87 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 195.6 (13C), 163.3, 138.4 (d, J = 54.0 Hz),
132.6 (d, J = 3.0 Hz), 132.0, 130.2 (d, J = 57.0 Hz), 129.8 (d, J = 3.0 Hz),
128.3 (d, J = 4.0 Hz), 113.6 (d, J = 4.0 Hz), 55.6; HRMS m/z calculated
for C1313CH12O2H+ [M + H+] 214.0944, found 214.0947.
(2,4-Dimethoxyphenyl)(4-methoxyphenyl)methanone24
(11). General method with iodo-2,4-dimethoxybenzene (132.0 mg, 0.50
mmol) and 4-methoxyphenylboronic acid (114.0 mg, 0.75 mmol). Flash
column chromatography (30% EtOAc/toluene) gave 107.1 mg (79%
yield) of the title compound as a colorless solid: 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.78 (d, 2H, J = 9.0 Hz), 7.34 (d, 1H, J = 8.4 Hz), 6.90
(d, 2H, J = 9.0 Hz), 6.55−6.51 (m, 2H), 3.86−3.86 (m, 6H), 3.72 (m,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 194.3, 163.2, 162.9, 159.1,
132.1, 131.5, 131.4, 121.9, 113.3, 104.5, 98.8, 55.6, 55.5, 55.4; HRMS m/
z calculated for C16H16O4Na+ [M + Na+] 295.0941, found 295.0946.
(2-Aminophenyl)(phenyl)methanone25 (12). General method
with 2-iodoaniline (109.5 mg, 0.50 mmol) and phenylboronic acid (67.1
mg, 0.55 mmmol). Flash column chromatography (CH2Cl2) gave 81.2
mg (71% yield) of the title compound as a yellow solid. Repeating this
reaction on a 6 mmol scale afforded 12 in an isolated yield of 82%: 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.66−7.63 (m, 2H), 7.55−7.50 (m,
1H), 7.48−7.43 (m, 3H), 7.29 (ddd, 1H, J = 8.3, 7.1, 1.6 Hz), 6.74 (ddd,
1H, J = 8.2, 1.1, 0.3 Hz), 6.60 (ddd, 1H, J = 9.16, 7.1, 1.1 Hz), 6.10 (br,
2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 199.2, 151.0, 140.2, 134.7,
134.3, 131.1, 129.2, 128.2, 118.3, 117.1, 115.6; HRMS m/z calculated for
C13H11NOH+ [M + H+] 198.0913, found 198.0915.
2-(4-Vinylbenzoyl)phenyl 4-methylbenzenesulfonate (18).
General method with 2-iodophenyl 4-methylbenzenesulfonate (187.1
mg, 0.50 mmol) and 4-vinylphenylboronic acid (111.0 mg, 0.75 mmol).
Flash column chromatography (CH2Cl2) gave 99.2 mg (52% yield) of
the title compound as a colorless solid: 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.59 (d, 2H, J = 1.8 Hz), 7.55−7.50 (m, 1H), 7.46 (d, 2H, J = 8.4
Hz), 7.43−7.34 (m, 5H), 7.11 (d, 2H, J = 8.0 Hz), 6.75 (dd, 1H, J = 17.6,
10.9 Hz), 5.88 (d, 1H, J = 17.6 Hz), 5.41 (d, 1H, J = 10.9 Hz), 2.32 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 192.6, 146.5, 145.6, 142.3,
136.0, 135.9, 133.2, 132.1, 132.0, 130.6, 130.5, 129.7, 128.5, 127.0, 126.0,
124.0, 117.1, 21.8; HRMS m/z calculated for C22H18O4H+ [M + H+]
379.0999, found 379.1001.
(4-Chlorophenyl)(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-
methanone (19). General method with 2-(4-iodophenyl)-2-methyl-
1,3-dioxolane (145.0 mg, 0.50 mmol) and 4-chlorophenylboronic acid
(86.0 mg, 0.55 mmol). Flash column chromatography (CH2Cl2) gave
122.3 mg (81% yield) of the title compound as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ (ppm) 7.76−7.72 (m, 4H), 7.59 (d, 2H, J = 8.6
Hz), 7.44 (d, 2H, J = 8.6 Hz), 4.10−4.01 (m, 2H), 3.82−3.74 (m, 2H),
1.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 195.2, 148.2, 139.0,
136.8, 135.9, 131.5, 130.1, 128.7, 125.5, 108.6, 64.7, 27.6; HRMS m/z
calculated for C17H15ClO3H+ [M + H+] 303.0782, found 303.0783.
1,4-Dibenzoylbenzen26 (13). General method with 1,4-diiodo-
benzene (82.5 mg, 0.25 mmol) and phenylboronic acid (91.5 mg, 0.75
mmol). Flash column chromatography (CH2Cl2). This gave 50.4 mg
[
13C]-(4-Chlorophenyl)(4-(2-methyl-1,3-dioxolan-2-yl)-
phenyl)methanone (13C-19). General method with 2-(4-iodophen-
yl)-2-methyl-1,3-dioxolane (145.0 mg, 0.50 mmol) and 4-chlorophe-
nylboronic acid (86.0 mg, 0.55 mmol). 13C-labeled 9-methyl-fluorene-9-
carbonyl chloride in chamber B. Flash column chromatography
(CH2Cl2) gave 116.0 mg (76% yield) of the title compound as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.76−7.72 (m, 4H),
7.59 (d, 2H, J = 8.6), 7.44 (d, 2H, J = 8.6), 4.10−4.01 (m, 2H), 3.83−
3.74 (m, 2H), 1.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
195.1 (13C), 148.3, 139.0, 136.9 (d, J = 55.0 Hz), 135.9 (d, J = 55.0 Hz),
131.5 (d, J = 3.0 Hz), 130.1 (d, J = 3.0 Hz), 128.7 (d, J = 4.0 Hz), 125.5
(d, J = 4.0 Hz), 108.6, 64.7, 27.6; HRMS m/z calculated for
C1613CH15ClO3H+ [M + Na+] 304.0816, found 304.0817.
1
(70% yield) of the title compound as a colorless solid: H NMR (400
MHz, CDCl3) δ (ppm) 7.89 (s, 4H), 7.86−7.83 (m, 4H), 7.65−7.60
(m, 2H), 7.53−7.49 (m, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm)
196.1, 140.8, 137.0, 133.1, 130.2, 129.8, 128.6; HRMS m/z calculated for
C20H14O2H+ [M + H+] 287.1067, found 287.1068.
(4-Aminophenyl)(4-methoxyphenyl)methanone27 (14). Gen-
eral method with 4-iodoaniline (109.5 mg, 0.50 mmol) and 4-
methoxyphenylboronic acid (114.0 mg, 0.75 mmol). Flash column
chromatography (10% EtOAc/CH2Cl2) gave 76.8 mg (68% yield) of
the title compound as a colorless solid: 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.75 (d, 2H, J = 8.9 Hz), 7.67 (d, 2H, J = 8.6 Hz), 6.94 (d, 2H, J =
8.9 Hz), 6.65 (d, 2H, J = 8.7 Hz), 4.21 (s, 2H), 3.86 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 194.4, 162.5, 150.8, 132.7, 132.0, 131.4,
127.9, 113.7, 113.4, 55.5; HRMS m/z calculated for C14H13NO2Na+ [M
+ Na+] 250.0838, found 250.0838.
Thiophen-2-yl (p-tolyl)methanone28 (20). General method with
2-iodothiophene (105.0 mg, 0.50 mmol) and p-tolylboronic acid (74.8
mg, 0.55 mmol). Flash column chromatography (50% CH2Cl2/
pentane) gave 71.5 mg (71% yield) of the title compound as a colorless
solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.79 (d, 2h, J = 8.1 Hz),
7.70 (dd, 1H, J = 4.9, 1.1 Hz), 7.64 (dd, 1H, J = 3.8, 1.1 Hz), 7.31−7.28
(m, 2H), 7.17−7.14 (m, 1H), 2.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 188.1, 143.9, 143.2, 135.5, 134.6, 134.0, 129.5, 129.2,
128.0, 21.8; HRMS m/z calculated for C12H10OSH+ [M + H+]
203.0525, found 203.0524.
tert-Butyl 4-(4-chlorobenzoyl)phenylcarbamate (15). General
method with tert-butyl 4-iodophenylcarbarbamate (159.6 mg, 0.50
mmol) and 4-chlorophenylboronic acid (86.0 mg, 0.55 mmol). Flash
column chromatography (5% EtOAc/pentane) gave 130.9 mg (79%
yield) of the title compound as a colorless solid: 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.76 (d, 2H, J = 8.8 Hz), 7.70 (d, 2H, J = 8.7 Hz), 7.49
(d, 2H, J = 8.8 Hz), 7.44 (d, 2H, J = 8.7 Hz), 1.52 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 194.5, 152.2, 142.8, 138.5, 136.3, 131.7,
131.4, 131.2, 128.5, 117.4, 81.4, 28.3; HRMS m/z calculated for
C18H18ClNO3Na+ [M + Na+] 354.0867, found 354.0872.
(4-Amino-3,5-dichlorophenyl)(4-tert-butylphenyl)-
methanone (16). General method with 2,6-dichloro-4-iodoaniline
(144.0 mg, 0.50 mmol) and 4-tert-butyl phenylboronic acid (97.9 mg,
0.55 mmol). Flash column chromatography (30% CH2Cl2/pentane)
gave 119.1 mg (74% yield) of the title compound as a colorless solid: 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.75 (s, 2H), 7.68 (d, 2H, J = 8.6
Hz), 7.50 (d, 2H, J = 8.6 Hz), 1.37 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 193.1, 156.0, 143.9, 134.9, 130.5, 129.7, 127.6, 125.5,
118.7, 35.2, 31.3; HRMS m/z calculated for C17H17Cl2NOH+ [M + H+]
322.0760, found 322.0762.
N-(5-Benzoylpyridin-2-yl)cyclopropanecarboxamide (21).
General method with N-(5-iodopyridin-2-yl)cyclopropanecarboxamide
(144.0 mg, 0.50 mmol) and phenylboronic acid (67.1 mg, 0.55 mmol).
Flash column chromatography (20% EtOAc/pentane) gave 93.5 mg
(70% yield) of the title compound as a colorless solid: 1H NMR (400
MHz, CDCl3) δ (ppm) 8.73 (d, 1H, J = 1.7 Hz), 8.62 (br, 1H), 8.32 (d,
1H, J = 8.7 Hz), 8.15 (dd, 1H, J = 8.7, 2.3 Hz), 7.79−7.77 (m, 2H), 7.62
(m, 1H), 7.53−7.49 (m, 2H), 1.64−1.58 (m, 1H), 1.17−1.13 (m, 2H),
0.97−0.92 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 194.1,
172.8, 154.1, 150.6, 140.5, 137.3, 132.9, 129.9, 129.1, 128.7, 113.0, 16.2,
9.1; HRMS m/z calculated for C16H14N2O2Na+ [M + Na+] 289.0947,
found 289.0950.
[13C]-N-(5-Benzoylpyridin-2-yl)cyclopropanecarboxamide
(
13C-21). General method with N-(5-iodopyridin-2-yl)-
cyclopropanecarboxamide (144.0 mg, 0.50 mmol) and phenylboronic
acid (67.1 mg, 0.55 mmol). 13C-Labeled 9-methyl-fluorene-9-carbonyl
chloride in chamber B. Flash column chromatography (20% EtOAc/
(E)-4-(4-tert-Butylbenzoyl)-2-(phenyldiazenyl)phenyl acetate
(17). General method with (E)-4-iodo-2-(phenyldiazenyl)phenyl
acetate (183.1 mg, 0.50 mmol) and 4-tert-butyl phenylboronic acid
G
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pentane) gave 105.6 mg (79% yield) of the title compound as a white
solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 8.73 (s, 1H), 8.66 (s, 1H),
8.32 (d, 1H, J = 8.3 Hz), 8.16−8.14 (m, 1H), 7.79−7.76 (m, 2H), 7.61
(t, 1H, J = 7.4 Hz), 7.50 (t, 2H, J = 7.4 Hz), 1.66−1.58 (m, 1H), 1.17−
1.13 (m, 2H), 0.97−0.92 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 194.0 (13C), 172.8, 154.1, 150.4 (d, J = 4.0 Hz), 140.5 (d, J = 3.0
Hz), 137.3 (d, J = 55.0 Hz), 132.9, 129.9 (d, J = 3.0 Hz), 129.1 (d, J =
57.0 Hz), 128.7 (d, J = 4.0 Hz), 113.0 (d, J = 3.0 Hz), 16.2, 9.1; HRMS
m/z calculated for C1513CH14N2O2Na+ [M + Na+] 290.0981, found
290.0985.
(6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(4-
methoxyphenyl)methanone29 (22). General method with 3-iodo-6-
methoxy-2-(4-methoxyphenyl)benzo[b]-thiophene (198.1 mg, 0.50
mmol) and 4-methoxyphenylboronic acid (63.6 mg, 0.55 mmol).
Flash column chromatography (10−40% EtOAc/pentane) gave 139.2
mg (67% yield) of the title compound as a yellow amorphous solid: 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.78 (d, 2H, J = 8.9 Hz), 7.53 (d, 1H,
J = 8.9 Hz), 7.35 (d, 2H, J = 8.8 Hz), 7.31 (d, 1H, J = 2.4 Hz), 6.96 (dd,
1H, J = 8.9, 2.4 Hz), 6.76 (dd, 2H, J = 9, 2.5 Hz), 3.88 (s, 3H), 3.79 (s,
3H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 193.4, 163.8,
159.9, 157.8, 142.6, 140.2, 134.1, 132.5, 130.7, 130.5, 130.4, 126.2, 124.2,
114.9, 114.2, 113.8, 104.6, 55.8, 55.5, 55.4; HRMS m/z calculated for
C24H20O4SNa+ [M + Na+] 427.0975, found 427.9080.
(0.75 mL) at 0 °C. The reaction mixture was gradually warmed to rt and
heated to reflux overnight. The reaction was cooled, concentrated in
vacuo, and purified by flash column chromatography (2:0.5:7.5−3:4:3
CH2Cl2/ethyl acetate/pentane). The solid was recrystallized in
benzene. This gave 212.2 mg (55% yield) of the title compound as a
1
colorless solid: H NMR (400 MHz, CDCl3) δ (ppm) 9.62 (s, 1H),
7.54−7.51 (m, 2H), 7.49−7.44 (m, 2H), 7.42−7.36 (m, 2H), 7.30 (d,
1H, J = 2.4), 7.15 (d, 1H, J = 8.64), 4.33 (b, 2H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 172.0, 169.8, 138.8, 137.4, 131.8, 130.7, 130.6, 129.6,
128.8, 128.5, 128.4, 122.7, 56.6; HRMS C15H11ClN2O [M + H+];
calculated 271.0633, found 271.0632.
[13C]-7-Chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one
(13C-24). Sodium bicarbonate (30.3 mg, 0.36 mmol) was added to 13C-
23 (40.0 mg, 0.17 mmol) in chloroform (1 mL). The reaction was
cooled to 0 °C, and bromoacetyl bromide (17.0 μL, 0.21 mmol) in
chloroform (0.2 mL) was added dropwise. The reaction was stirred
overnight. The reaction was quenched with ice−water, separated,
extracted with chloroform, washed with water and sodium bicarbonate,
dried over sodium sulfate, filtered, and concentrated in vacuo. The
concentrate was added to a closed vial and dissolved in chloroform.
Saturated ammonia in methanol (0.68 mL, 4.74 mmol) taken directly
from the freezer was added. The closed vial was warmed to 60 °C and
left overnight. The product was purified by flash column chromatog-
raphy (4:1:15−3:4:3 CH2Cl2/ethyl acetate/pentane) and (9:1 CH2Cl2/
ethyl acetate/pentane to ethyl acetate). The product was again
attempted to purify by flash column chromatography with Al2O3
(1:3:6 + 1 ‰ triethyl amine CH2Cl2/acetone/pentane − acetone + 1
‰ triethylamine). This gave 29.2 mg (63% yield) of the title compound
as a colorless solid. 13C NMR shows two minor carbon-impurities at
(2-Amino-5-chlorophenyl)(phenyl)methanone30 (23). 4-
Chloro-2-iodoaniline (133.7 mg, 0.50 mmol), phenylboronic acid
(67.0 mg, 0.55 mmol), PdCl2 (17.7 mg, 0.1 mmol) and K2CO3 (207.3
mg, 1.50 mmol) were added to chamber A of a COware system. 9-
Methyl-fluorene-9-carbonyl chloride (182.0 mg, 0.75 mmol), P-
(tBu)3HBF4 (10.9 mg, 0.0375 mmol) and PdCl2(cod) (21.4 mg, 0.05
mmol) were added to chamber B. To both chambers anisole (3.0 mL)
was added before DIPEA (260 μL, 1.5 mmol) was added to chamber B,
and both chambers were fitted with a Teflon-sealed screwcap. The
reaction was heated overnight at 120 °C. The crude was evaporated onto
silica gel and purified by flash column chromatography (1:1 pentane/
CH2Cl2 to dichloromethane). This gave 73.3 mg (63% yield) of the title
compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63
(dd, 2H, J = 7.5, 0.6 Hz), 7.57−7.53 (m, 1H), 7.47 (t, 2H, J = 7.9 Hz,),
7.41 (d, 1H, J = 2.5 Hz), 7.23 (ddd, 1H, J = 8.8, 2.5, 0.6 Hz), 6.68 (d, 1H,
J = 8.8 Hz), 6.09 (b, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 198.0,
149.4, 139.3, 134.2, 133.2, 131.5, 129.1, 128.3, 119.9, 118.7, 118.5;
HRMS C13H10ClNO [M + H+]; calculated 232.0524, found 232.0525.
(2-Amino-5-chlorophenyl)(phenyl)methanone (13C-23). 4-
Chloro-2-iodoaniline (133.7 mg, 0.50 mmol), phenylboronic acid
(67.0 mg, 0.55 mmol), PdCl2 (17.7 mg, 0.1 mmol), and K2CO3 (207.3
mg, 1.50 mmol) were added to chamber A of a COware system. 13C-
Labeled 9-methyl-fluorene-9-carbonyl chloride (182.0 mg, 0.75 mmol),
P(tBu)3HBF4 (10.9 mg, 0.0375 mmol) and PdCl2(cod) (21.4 mg, 0.075
mmol) were added to chamber B. To both chambers anisole (3.0 mL)
was added before DIPEA (260 μL, 1.5 mmol) was added to chamber B,
and both chambers were fitted with a Teflon-sealed screwcap. The
COware was heated overnight at 120 °C. The crude was A was
evaporated on silica gel and purified by flash column chromatography
(1:1 pentane/CH2Cl2 to CH2Cl2). This gave 78.9 mg (68% yield) of the
title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ (ppm)
7.65−7.62 (m, 2H), 7.56 (t, 1H, J = 8.7 Hz), 7.48 (t, 2H, J = 7.4 Hz),
7.43−7.41 (m, 1H), 7.26−7.21 (m, 1H), 6.68 (dt, 1H, J = 8.8, 1.0 Hz),
6.09 (b, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 198.0 (13C), 149.4,
139.4 (d, J = 54.7 Hz), 134.2, 133.2 (d, J = 5.0 Hz), 131.5, 129.1 (d, J =
3.0 Hz), 128.3 (d, J = 5.0 Hz), 119.9 (d, J = 7.0 Hz), 118.7 (d, J = 55.0
Hz), 118.5 (d, J = 3.0 Hz); HRMS C1213C H10ClNO [M + H+];
calculated 233.0557, found 233.0557.
1
198.9 and 197.5 (both unidentified): H NMR (400 MHz, CDCl3) δ
(ppm) 8.73 (s, 1H), 7.52−7.39 (m, 6H), 7.31 (dd, 1H, J = 2.44, 2.08
Hz), 7.10 (dd, 1H, J = 8.64, 0.68 Hz), 4.33 (br, 2H); 13C NMR (100
MHz, CDCl3) δ (ppm) 172.1, 169.8 (13C), 138.9 (d, J = 62.1 Hz), 137.4,
131.8, 130.7 (d, J = 2.4 Hz), 130.6, 129.6, 128.9 (d, J = 4.8 Hz), 128.6 (d,
J = 50.1 Hz), 128.5 (d, J = 4.2 Hz), 122.8, 56.7; HRMS C1413CH11ClN2O
[M + H+]; calculated 272.0666, found 272.0670.
Isopropyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropa-
noate3 (26). General method with isopropyl 2-(4-iodophenoxy)-2-
methylpropanoate (174.1 mg, 0.50 mmol) and p-chlorophenylboronic
acid (86.0 mg, 0.55 mmol). Flash column chromatography (10−100%
CH2Cl2/pentane) gave 153.4 mg (84% yield) of the title compound as a
colorless solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.73 (d, 2H, J =
8.9 Hz), 7.70 (d, 2H, J = 8.7 Hz), 7.45 (d, 2H, J = 8.6 Hz), 6.86 (d, 2H, J
= 8.9 Hz), 5.09 (hep, 1H, J = 6.3 Hz), 1.66 (s, 6H), 1.20 (d, 6H, J = 6.3
Hz); 13C NMR (400 MHz, CDCl3) δ (ppm) 194.5, 173.3, 160.0, 138.6,
136.7, 132.2, 131.4, 130.5, 128.8, 117.5, 79.7, 69.6, 25.7, 21.8; HRMS
C20H21ClO4 [M+Na+]; calculated 383.1021, found 383.1021.
[13C]-Isopropyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-
propanoate (13C-26). General method with isopropyl 2-(4-
iodophenoxy)-2-methylpropanoate (174.1 mg, 0.50 mmol) and p-
chlorophenylboronic acid (86.0 mg, 0.55 mmol). 13C-Labeled 9-methyl-
fluorene-9-carbonyl chloride in chamber B. Flash column chromatog-
raphy (10−100% CH2Cl2/pentane) gave 155.2 mg (85% yield) of the
1
title compound as a colorless solid: H NMR (400 MHz, CDCl3) δ
(ppm) 7.74−7.68 (m, 4H), 7.44 (d, 2H, J = 8.3 Hz), 6.86 (d, 2H, J = 8.7
Hz), 5.08 (hep, 1H, J = 6.2 Hz), 165.7 (s, 6H), 1.20 (d, 6H, J = 6.2 Hz);
13C NMR (100 MHz, CDCl3) δ (ppm) 194.4 (13C), 173.2, 159.9, 138.5,
136.6 (d, J = 55.0 Hz), 132.1 (d, J = 3.0 Hz), 131.3 (d, J = 3.0 Hz), 130.3
(d, J = 57.0 Hz), 128.7 (d, J = 2.0 Hz), 117.4 (d, J = 4.0 Hz), 79.6, 69.5,
25.5, 21.7; HRMS C1913CH21ClO4 [M+Na+]; calculated 384.1054,
found 384.1058.
7-Chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one31
(24). Sodium bicarbonate (266.5 mg, 3.20 mmol) was added to 23
(350.0 mg, 1.50 mmol) in chloroform (5 mL). The reaction was cooled
to 0 °C, and bromoacetyl bromide (160 μL, 1.81 mmol) in chloroform
(0.8 mL) was added dropwise. The reaction was stirred overnight. The
reaction was quenched with ice−water, separated, extracted with
chloroform, washed with water and sodium bicarbonate, dried over
sodium sulfate, filtered, and concentrated in vacuo. The concentrate was
dissolved in chloroform and added to saturated ammonia in methanol
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR, 19F NMR, and 13C NMR spectra for the Suzuki−
Miyaura coupling products and nordazepam. This material is
available free of charge via the Internet at http://pubs.acs.org.
H
dx.doi.org/10.1021/jo401696c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Skrydstrup, T. J. Org. Chem. 2012, 77, 6155. (e) Gøgsig, T. M.; Nielsen,
D. U.; Lindhardt, A. T.; Skrydstrup, T. Org. Lett. 2012, 14, 2536. (f) Friis,
S. D.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J. Am. Chem. Soc.
2011, 133, 18114. (g) Broncour, C.; Fukuyama, T.; Mukai, Y.;
Skrydstrup, T.; Ilhyong, R. Org. Lett. 2013, 15, 2794.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: lindhardt@chem.au.dk.
*E-mail: ts@chem.au.dk.
(12) Combination of all reagents from both chambers in one reaction
chamber afforded a complex reaction mixture with only trace of the
desired benzophenone derivative 2.
Notes
The authors declare no competing financial interest.
(13) (a) Lu, G.; Franzen
46, 4255.
́
, R.; Zhang, Q.; Xu, Y. Tetrahedron Lett. 2005,
ACKNOWLEDGMENTS
■
We are deeply appreciative for the generous financial support
from the Danish National Research Foundation, the Danish
Council for Independent Research: Technology and Production
Sciences, the Carlsberg Foundation, the Lundbeck Foundation,
the Villum Foundation, and Aarhus University.
(14) Arvela, R. K.; Leadbeater, N. E.; Sangri, M. S.; Williams, V. A.;
Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161.
(15) The source of K2CO3 turned out to have an effect on the
selectivity of the reaction, causing a drop in selectivity of 2:3 to 80:20
when repeating the coupling of entry 7 in Table 1. The best results were
obtained using K2CO3 purchased from VWR, product number
26724.291. The reason for this effect is currently not understood.
(16) In a few of the examples in Table 2, the loading of arylboronic acid
was reduced to compete with the direct coupling. For exact reaction
conditions, see the Supporting Information.
(17) For the effects of electron-donating and -withdrawing groups on
the COincorporation ontoorganopalladium complexes, see: (a)Garrou,
P. E.; Heck, R. F. J. Am. Chem. Soc. 1976, 98, 4115. (b) Ishiyama, T.;
Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N. J. Org. Chem. 1998, 63,
4726.
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I
dx.doi.org/10.1021/jo401696c | J. Org. Chem. XXXX, XXX, XXX−XXX