Palladium-Imidazolium N-Heterocyclic Carbene-Catalyzed Carbonylative Amidation with Boronic Acids, Aryl Diazonium Ions, and Ammonia

Article abstract of DOI:10.1055/s-2003-42478

Aryl diazonium tetrafluoroborates have been coupled with arylboron compounds, carbon monoxide, and ammonia to give aryl amides in high yields. A saturated N-heterocyclic carbene (NHC) ligand, H2IPr was used with palladium(II) acetate to give the active catalyst. A mechanism is proposed for this novel four-component coupling reaction.

Full text of DOI:10.1055/s-2003-42478

2886
SPECIAL TOPIC
Palladium-Imidazolium N-Heterocyclic Carbene-Catalyzed Carbonylative
Amidation With Boronic Acids, Aryl Diazonium Ions, and Ammonia
P
d-NHC-Catalyze
u
d Carbonylat
d
ive
A
midatio
a
n
o Ma,a Chun Song,b Qiang Chai,c Changqin Ma,a Merritt B. Andrus*b
a
Chemistry College of Shandong University, Shanda Road #100, Jinan, Shandong 250100, P. R. China
b
Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, Utah 84602, USA
Fax +(801)4220153; E-mail: mbandrus@chem.byu.edu
c
Shandong Academy of Medical Science, Jinan, Shandong 250062, P. R. China
Received 8 October 2003
tive aryl diazonium ions,22 as part of an effort to develop
milder, low temperature conditions for these transforma-
tions.
Abstract: Aryl diazonium tetrafluoroborates have been coupled
with arylboron compounds, carbon monoxide, and ammonia to give
aryl amides in high yields. A saturated N-heterocyclic carbene
(NHC) ligand, H2IPr was used with palladium(II) acetate to give the
active catalyst. A mechanism is proposed for this novel four-com-
ponent coupling reaction.
The NHC-palladium catalyst was formed from N,N-
bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium chlo-
ride (H2IPr HCl and palladium(II) acetate reacted in situ
(Table 1). THF was found to be the most effective solvent
which was saturated with ammonia prior to use. A sealed
autoclave containing the reaction components was
charged with the indicated pressure of CO. The substrates
used for the initial development of this reaction were phe-
nylboronic acid and o-tolyl diazonium tetrafluoroborate at
1:1 stoichiometry. Initially the reaction was plagued by
poor product distribution. In addition to the desired
amides 1 and 2, large amounts of biphenyl 3 and aryl
aniline 4 products were obtained at room temperature.
Fortunately, when the CO pressure was raised to 5 atmo-
spheres, amide 1 was obtained in 82% isolated yield with
the aryl diazonium substrate added 60 seconds after addi-
tion of all the other components. The N-aryl group is de-
rived from the aryl diazonium salt and the carbonyl aryl
group of the amide arises from the boronic acid. Under
these conditions only trace amounts of biphenyl and
aniline products were found. When the arylboronic acid
and the diazonium salt were added together under 5 atmo-
spheres CO at room temperature, again a poor product dis-
tribution was obtained. Interestingly, when the substrates
were added in this manner, a significant amount of the re-
versed amide 2 was also obtained. When the aryl diazoni-
um salt was added first followed by the boronic acid 60
seconds later, the same amide 2 yield was higher than
amide 1. The product distribution is clearly a function of
the relative rates of the individual steps of the catalytic cy-
cle where the various insertions are competing with each
other and are balanced by terminal reductive elimination
steps. Other solvents explored included dioxane, which
gave amide 1 in a lower 72% yield, and toluene, methanol,
and diethyl ether, which were all less effective. Catalyst
loading was also investigated. A 65% yield of 1 was ob-
tained using 0.1 mol% catalyst and at 1 mol%, a 76% yield
was found. Increasing the amount to 5 mol% gave an 83%
yield.
Key words: palladium cross-coupling, multi-component, carbony-
lative coupling , amides, N-heterocyclic carbene
Carbonylative coupling with sp2 halides and triflates in
the presence of carbon monoxide and an alcohol or an
amine is a convenient method for the construction of un-
saturated esters and amides.1 Many other variations of this
three component process are available including orga-
nostannanes,2 boronic acids,3 bismuth,4 magnesium,5 alu-
minum,6 silanes,7 and hypervalent iodonium salts.8
Carbonylation has also been used in conjunction with
Heck type couplings9 and as the termination step in palla-
dium-catalyzed cascade processes.10 Recent develop-
ments include carbonylative acetylene couplings11 and
use of stannyl selenides to give selenol esters.12 Alterna-
tive CO sources have also been reported including metal
carbonyls,13 formate,14 and aldehydes.15 We now report a
novel variation of carbonylative coupling using a palladi-
um N-heterocyclic carbene (NHC) catalyst with arylbo-
ronic acids and aryl diazoniun salts in a four-component
coupling process with carbon monoxide and ammonia to
give aryl amide products.
We recently reported the use of palladium NHC catalysis
for the carbonylative formation of unsymmetrical aryl ke-
tones from boronic acids and aryl diazonium salts.16 Opti-
mal ketone formation and minimal undesired biaryl
coupling product was found by using 1 atmosphere of CO
at 100 °C in dioxane. Catalyzed reactions with NHC-pal-
ladium complexes have become the subject of intense in-
terest due to their enhanced reactivity and stability.17
Successful transformations now include Heck,18 Suzuki–
Miyaura,19 Hiyama,20 and Kumada21 couplings. We have
reported base free conditions with NHC catalysts for effi-
cient Heck, Suzuki, and borylation couplings using reac-
The optimal conditions with 2 mol% palladium-NHC cat-
alyst were applied with various organoboron compounds
and three aryl diazonium tetrafluoroborates to give nu-
merous aryl amides (Table 2). The diazonium salt in each
SYNTHESIS 2003, No. 18, pp 2886–2889
Advanced online publication: 12.11.2003
DOI: 10.1055/s-2003-42478; Art ID: C14003SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
3

SPECIAL TOPIC
Pd-NHC-Catalyzed Carbonylative Amidation
2887
Table 2 Carbonylative Amide Formation
Table 1 Effect of CO Pressure on Product Distribution Yields (%)
Diazonium Salt\Bo-
ron Compound
Yield (%) (Time)
CO (atm)
1 (%)
23
2 (%)
3 (%)
30
4 (%)
47
83 (3 h)
86 (3 h)
89 (3 h)
82 (3 h)
83 (4.5 h)
87 (3 h)
64 (6 h)
73 (5 h)
80 (3.5 h)
1
2
–
32
–
25
42
3
46
–
37
7
5
82
–
3
trace
12
5a
5b
10
61
21
27
–
trace
12
80 (4.5 h)
67 (5.5 h)
77 (5 h)
75 (6.5 h)
58 (6 h)
21
36
62 (5.5 h)
83
trace
trace
a Boronic acid and diazonium salt were added at the same time.
b Diazonium salt added 60 s before boronic acid.
83 (3 h)
72 (3 h)
68 (6 h)
case was added last and the known products were ob-
tained and characterized following silica gel purification.
Phenylboronic acid again gave high yields after 3 hours
with phenyl and o-tolyl diazonium salt. Coupling with the
o-anisyl diazonium substrate was less successful at 64%
yield after 6 hours. 4-Methoxy and p-tolylboronic acid
also gave amides in high yield. (E)-Styrylboronic acid
coupled giving unsaturated amide products with only
slightly lower yields with longer reaction times. Phenyl-
pinacolatoborane also functioned well under these reac-
tion conditions giving amides in somewhat reduced yields
and longer times. Potassium phenyltrifluoroborate was
also effective giving products with comparable rates to the
boronic acids.
um amide 8. Transmetalation at this point would lead to
arylaniline product. CO addition to 8 gives palladium car-
bonyl 9 which would then promote transmetalation with
the arylboron reagent to give intermediate 10. Migration
of the Ar group to ligated CO would give an acylpalladi-
um intermediate (not shown) which gives amide product
upon reductive elimination and catalyst regeneration.
With lower pressures of CO (1–3 atm) carbonylation is
not favored and higher amounts of biphenyl and aryla-
niline products are obtained. The dependence of the prod-
uct distribution on the order of reagent addition is more
difficult to rationalize. Lacking a detailed picture of the
absolute rates of the individual steps under these condi-
tions, conclusions at this point are not well-supported.
When the more reactive coupling partner, the aryl diazo-
nium ion, is added first or at the same time as the boronic
acid, a mixture of products results. Conversely, by adding
the less reactive arylboronic acid substrate first, the timing
of the individual steps is more balanced and amide 1 is
highly favored. When both reagents are added at the same
time, amide 1 is still the dominant product, however all
others are present in significant amounts. In no case was
arylketone observed. This results indicates that ammonia
insertion is faster than CO incorporation in this case. In-
terestingly, arylaniline product appears to arise exclusive-
ly from the boronic acid, not from the diazonium ion. This
indicates that boronic acid can add to palladium or an am-
monia bound palladium complex and that this complex fa-
vors elimination to give arylaniline, and not addition of
the aryl diazomium at this point.
A mechanistic rationale can be offered for this new pro-
cess based on the precedent of the individual steps that
have been established (Scheme 1).9a The product distribu-
tion is a balance between the oxidative additions, inser-
tions, and elimination steps leading to the various possible
products, four of which have been observed. We and oth-
ers have previously shown that the palladium-NHC com-
plex 5 can form in situ under base free conditions.22 In this
case the excess ammonia may also function as a base to
form the free carbene leading to 5. Ammonium ion also
provides a proton source to facilitate the addition step and
the transmetalation step with arylboronic acid. Oxidative
insertion with the aryl diazonium ion will give the aryl
palladium cation 6 and nitrogen gas. Transmetalation at
this point with arylboron reagent leads to biphenyl forma-
tion. Ammonia, present in high concentration, adds to 6
and following loss of a proton the palladium amide 7 re-
sults. Bond migration and proton loss then gives palladi-
Synthesis 2003, No. 18, 2886–2889 © Thieme Stuttgart · New York

2888
Y. Ma et al.
SPECIAL TOPIC
N-(2-Methoxyphenyl)benzamide
1H NMR (CDCl3): = 3.76 (s, 3 H), 7.02–7.93 (m, 8 H), 8.65 (s, 1
H).
13C NMR (CDCl3): = 57.2, 120.5, 121.7, 125.7, 125.9, 126.3,
127.8, 132.4, 136.2, 145.2, 165.3.
MS (EI): m/z = 227.
4-Methoxy-N-phenylbenzamide
1H NMR (CDCl3): = 3.88 (s, 3 H), 6.68 (d, J = 8.6 Hz, 2 H), 7.15–
7.91 (m, 8 H).
13C NMR (CDCl3): = 56.6, 119.7, 120.6, 121.3, 121.7, 126.5,
128.0, 131.2, 132.5, 136.7, 164.7.
MS (EI): m/z = 227.
4-Methoxy-N-(2-methylphenyl)benzamide
1H NMR (CDCl3): = 2.32 (s, 3 H), 3.86 (s, 3 H), 6.70 (d, J = 8.6
Hz, 2 H), 7.12–7.90 (m, 7 H).
Scheme 1
13C NMR (CDCl3): = 19.6, 57.8, 119.3, 120.2, 121.5, 121.9, 126.3,
128.5, 132.2, 132.7, 137.2, 164.5.
In summary a new four-component carbonylative amide
forming reaction has been developed. Various aryl amides
were selectively formed in high yield from organoboron
compounds and aryl diazonium ions using pressurized CO
in a THF solution saturated with ammonia. Factors that ef-
fect the distribution of the reaction products have been
identified.
MS (EI): m/z = 241.
4-Methoxy-N-(2-methoxyphenyl)benzamide
1H NMR (CDCl3): = 3.78 (s, 3 H), 3.87 (s, 3 H), 6.68 (d, J = 8.6
Hz, 2 H), 7.17–7.90 (m, 6 H), 8.63 (s, 1 H).
13C NMR (CDCl3): = 56.8 57.2, 119.7, 120.5, 121.2, 121.7, 125.5,
126.1,126.7, 128.2, 132.0, 133.2, 135.5, 137.3, 146.2 165.0.
MS (EI): m/z = 257.
1
All commercial reagents were used as supplied. H and 13C NMR
4-Methyl-N-phenylbenzamide
spectra were recorded on a 400 MHz spectrometer. Chemical shifts
are reported in ppm from tetramethylsilane with the solvent reso-
nance used as the internal standard (CDCl3, = 7.26). Coupling re-
actions were performed in a flame-dried autoclave. Solvents were
distilled from sodium metal or CaH2 prior to use.
1H NMR (CDCl3): = 2.41 (s, 3 H), 7.41–8.07 (m, 10 H).
13C NMR (CDCl3): = 36.5, 122.3, 125.2, 125.7, 127.4, 127.8,
128.6, 128.9, 129.1, 132.5, 135.7, 138.1,163.1.
MS (EI): m/z = 211.
Pd-NHC-Catalyzed Carbonylative Amidation; General Proce-
dure
4-Methyl-N-(2-methyphenyl)benzamide
1H NMR (CDCl3): = 2.30 (s, 3 H), 2.42 (s, 3 H), 7.27–8.11 (m, 9
H).
Boronic acid (1.25 mmol), Pd(OAc)2 (4.5 mg, 0.01 mmol, 2 mol%)
and dihydroimidazolium chloride, H2IPr·HCl (8.5 mg, 0.02 mmol,
4 mol%) were added to THF saturated with ammonia (10 mL) in a
autoclave fitted with an inlet to regulate CO (5 atm) at r.t. After 1
min, aryl diazonium tetrafluoroborate (1.25 mmol) was added and
the CO pressure was adjusted again to 5 atm. The resulting suspen-
sion was stirred at r.t. for the indicated time. The reaction mixture
was removed from the autoclave, poured into H2O (25 mL) and ex-
tracted with EtOAc (10 × 2 mL). The combined EtOAc fractions
were washed with sat. aq NaHCO3 (3 × 10 mL), brine (10 mL) and
dried (MgSO4). The solvent was removed and the products were pu-
rified by silica gel chromatography using 10–20% EtOAc–hexane
(Table 2).
13C NMR (CDCl3): = 18.9, 22.3, 120.5, 121.7, 122.5, 125.7, 125.9,
127.4, 128.7, 131.5, 132.7, 135.6, 165.1.
MS (EI): m/z = 225.
4-Methyl-N-(2-methoxyphenyl)benzamide
1H NMR (CDCl3): = 2.42 (s, 3 H), 3.80 (s, 3 H), 7.03–7.87 (m, 8
H), 8.66 (s, 1 H).
13C NMR (CDCl3): = 18.8, 56.7, 120.3, 121.7, 122.5, 123.0, 127.6,
127.9, 129.1, 132.5, 132.8, 135.2, 145.1, 165.2.
MS (EI): m/z = 241.
(E)-N,3-Diphenylacrylamide
N-Phenylbenzamide
1H NMR (CDCl3): = 5.46 (d, J = 8.2 Hz, 2 H), 7.03–7.92 (m, 11
1H NMR (CDCl3): = 7.05–7.98 (m).
H).
13C NMR (CDCl3): = 120.2, 121.7, 126.5, 126.3, 127.3, 132.2,
132.5, 138.2, 162.7.
13C NMR (CDCl3): = 118.2, 119.3, 121.2, 121.5, 121.9, 123.5,
125.7, 126.3, 127.9, 129.5, 131.6, 133.6, 136.2, 139.5, 164.3.
MS (EI): m/z = 197.
MS (EI): m/z = 223.
N-(2-Methylphenyl)benzamide
(E)-N-(2-Methylphenyl)-3-phenylacrylamide
1H NMR (CDCl3): = 2.31 (s, 3 H), 7.03–7.89 (m, 9 H).
1H NMR (CDCl3): = 5.46 (d, J = 8.2 Hz, 1 H), 7.03–7.92 (m, 11
MS (EI): m/z = 211.
H).
13C NMR (CDCl3): = 118.2, 119.3, 121.2, 121.5, 121.9, 123.5,
125.7, 126.3, 127.9, 129.5, 131.6, 133.6, 136.2, 139.5, 164.3.
Synthesis 2003, No. 18, 2886–2889 © Thieme Stuttgart · New York

SPECIAL TOPIC
Pd-NHC-Catalyzed Carbonylative Amidation
2889
MS (EI): m/z = 223.
(8) (a) Kang, S.-K.; Kim, W.-Y.; Lee, Y.-T.; Ahn, S.-K.; Kim,
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1H NMR (CDCl3): = 3.77 (s, 3 H), 5.78 (d, 1 H, J = 8.2 Hz), 6.82–
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129.8, 132.1, 135.3, 147.7, 164.2.
MS (EI): m/z = 253.
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Acknowledgments
We are grateful for the support provided by Brigham Young Uni-
versity, The Chemistry College of Shandong University, and the
National Institutes of Health (GM57275 to MBA).
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Synthesis 2003, No. 18, 2886–2889 © Thieme Stuttgart · New York