Expedient carbonylation of aryl halides in aqueous or neat condition

Article abstract of DOI:10.1016/j.tet.2014.09.065

An expedient and versatile, microwave-assisted procedure for the carbonylation of aryl halides with boronic acids, alcohols or amines in water or under neat conditions has been developed. The reaction is catalyzed by fluorous, oxime-based palladacycle 1 that shows an excellent recyclable property and low levels of Pd leaching. To demonstrate the usefulness of the protocol, we applied it to the preparation of compounds of pharmaceutical interest, including a precursor of the reverse transcriptase inhibitor, niacin, benzocaine and butamben.

Full text of DOI:10.1016/j.tet.2014.09.065

Tetrahedron 70 (2014) 8545e8558
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Tetrahedron
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Expedient carbonylation of aryl halides in aqueous or neat condition
,
a,
Wei Jie Ang a, Lee-Chiang Lo b , Yulin Lam
*
*
a Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
b Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2014
Received in revised form 9 September 2014
Accepted 22 September 2014
Available online 28 September 2014
An expedient and versatile, microwave-assisted procedure for the carbonylation of aryl halides with
boronic acids, alcohols or amines in water or under neat conditions has been developed. The reaction is
catalyzed by fluorous, oxime-based palladacycle 1 that shows an excellent recyclable property and low
levels of Pd leaching. To demonstrate the usefulness of the protocol, we applied it to the preparation
of compounds of pharmaceutical interest, including a precursor of the reverse transcriptase inhibitor,
niacin, benzocaine and butamben.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Carbonylation
Palladacycle
Aryl halide
Boronic acid
Alcohol
1. Introduction
medium.13 To this effort, we have previously developed a fluorous
oxime-based palladacycle 1 (Fig. 1), which was shown to be a very
Palladium-catalyzed carbonylation reactions are a versatile tool
for the synthesis of amides, esters, ketones, carbamates, etc., which
are important functional groups found in dyes, pharmaceuticals
and other industrial products. These reactions require the insertion
of CO into the substrate and are typically carried out with carbon
monoxide gas as it is readily available.1e5 During these reactions,
a constant stream of carbon monoxide gas has to be supplied into
the reaction system whose reaction times could range from 1 to
60 h, which reduces the expediency in combinatorial chemistry and
drug-discovery.3,6e9 To provide a more expedient reaction, mo-
lybdenum hexacarbonyl, Mo(CO)6, has been used as a solid carbon
monoxide source.10 With Mo(CO)6, the carbon monoxide gas is
released in situ during the reaction thus making it possible for the
reaction to be carried out in a closed vessel under microwave
irradiation.11e14 The ease of handling makes Mo(CO)6 an appealing
carbon monoxide source for lab-scale synthesis where parallel
synthesis methods are favoured especially in medicinal chemistry
applications and could be beneficial to high-throughput applica-
tions in small-scale protocols where the introduction of gaseous
reactants is problematic.
efficient and versatile precatalyst for a wide range of carbonecarbon
bond formation reactions (SuzukieMiyaura, Sonogashira, Stille,
Heck, Glaser-type and Kumada) in either aqueous or organic
medium under microwave irradiation.15e17 In addition, palladacycle
1 possessed an excellent recyclable property and produces only low
levels of Pd leaching. These features are important for medicinal
chemistry applications as the tolerance for heavy metal impurities is
very low. To date, carbonylative SuzukieMiyaura coupling and
alkoxycarbonylation reactions with Mo(CO)6 has been only carried
out in organic solvents.18,19 Therefore, in this study we further ex-
tend the use of palladacycle 1 and evaluate its performance in the
microwave-assisted carbonylative SuzukieMiyaura coupling,
alkoxycarbonylation and aminocarbonylation reactions with
Mo(CO)6 in aqueous medium. To demonstrate the usefulness of the
protocol, we applied it to the preparation of compounds of phar-
maceutical interest, including a precursor of the reverse transcrip-
tase inhibitor, niacin, benzocaine and butamben.
Recently, there has been a growing trend of performing
microwave-assisted CeC bond forming reactions in aqueous
* Corresponding authors. E-mail addresses: lclo@ntu.edu.tw (L.-C. Lo), chmlamyl@
nus.edu.sg (Y. Lam).
Fig. 1. Structure of fluorous palladacycle 1.
http://dx.doi.org/10.1016/j.tet.2014.09.065
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

8546
W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
Table 2
2. Results and discussion
Carbonylative SuzukieMiyaura coupling of aryl halides and boronic acidsa
2.1. Carbonylative SuzukieMiyaura coupling of aryl halides
and arylboronic acids
Initial assessment of the carbonylative Suzuki-Miyaura reaction
for the formation of asymmetrical biaryl ketones was conducted
using methyl 2-iodobenzoate 2a and phenylboronic acid 3a with
palladacycle 1 as precatalyst, N,N-diisopropylethylamine (DIPEA) as
base, water as solvent and Mo(CO)6 as the carbon monoxide source
under microwave irradiation at 130 ꢀC. The desired biaryl ketone 4a
was obtained after 20 min in 72% yield (Table 1, entry 1). To opti-
mize the reaction, we varied the base and found that the reaction
proceeded most efficiently with DIPEA (entries 1e6). Next, we in-
vestigated the effect of the amount of palladacycle 1 on the reaction
and found that 1 mol % Pd provided the best yield of the desired
product (entries 1, 7e9).
Entry
1
Aryl halide
R1
Time (min)
12 (12 hc)
Product (yieldb)
3a: H
2
3b: 4-Cl
3c: 3-OEt
3d: 4-Me
3a
15
Table 1
Reaction condition studyusing methyl2-iodobenzoate 2a and phenylboronic acid 3aa
3
12
Entry
Base
Temp (ꢀC)
Time (min)
Yield of 4ab (%)
4
15
1
2
3
4
DIPEA
DBU
TEA
K2CO3
KOAc
130
130
130
130
130
130
140
130
130
120
140
140
140
140
140
140
140
140
20
20
20
25
25
20
20
25
13
35
12
12
17
15
12
12
12
12
72
0
47
55
35
13
18
62
68
68
73
69
70
57
64
56
63
73
5
6
Pyridine
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
7c
5
10 (12 hc)
20 (12 hc)
20 (12 hc)
20
8d
9e
10
11
12f
13g
14h
15i
16j
17k
18l
6
3b
a
Reaction condition: methyl 2-iodobenzoate (0.6 mmol), phenylboronic acid
7
3d
(2.5 equiv), 1 (1 mol % Pd), Mo(CO)6 (1.5 equiv), base (3.0 equiv), H2O (1.0 mL).
b
Isolated yields.
Absence of palladacycle 1.
Pd (0.5 mol %).
Pd (2 mol %).
Reaction concentration 1.0 M.
Reaction concentration 0.3 M.
Phenylboronic acid (1.5 equiv).
Phenylboronic acid (2.0 equiv).
c
d
e
f
g
8
3e: 2-F
h
i
j
Mo(CO)6 (0.5 equiv) was used.
Base (2.0 equiv) was used.
TBAB (1.0 equiv) was added.
k
l
9
3a
15
We have also examined the effect of temperature on the reaction.
Lowering the temperature to 120 ꢀC lengthened the reaction time
andprovidedcompound 4ain a slightlyloweryieldwhilstincreasing
the temperature to 140 ꢀC enabled the reaction to be completed in
half the time and provided compound 4a in comparable yield (en-
tries 10 and 11). Other variations, like changing the concentrations of
2a, 3a, Mo(CO)6 or base or adding tetra-n-butylammonium bromide
(TBAB) as an additive to the reaction did not provide any significant
improvement in the yield of compound 4a (entries 12e18).
The generality of the reaction condition was examined using var-
ious aryl halides and arylboronic acids, which gave the desired biaryl
ketoneinmoderate to goodyields (Table 2). The aqueous protocol was
compatible with aryl halides bearing acidic protons (entries 9e11),
10
11
3a
20
3a
12

W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
8547
Table 2 (continued )
a precatalyst for the alkoxycarbonylation of aryl halides to afford
esters. Using a similar aqueous condition as the carbonylative
SuzukieMiyaura reaction, iodobenzene 2c was treated with etha-
nol 5a in the presence of palladacycle 1, DIPEA, water and Mo(CO)6
under microwave irradiation at 130 ꢀC. However, we did not ob-
serve the desired ethyl benzoate 6a but instead the hydrolyzed
product, benzoic acid, was obtained in 87% yield (Table 3, entry 1).
Since water is a competitive nucleophile, we decided to explore the
reaction under solvent-free condition. Gratifyingly this gave com-
pound 6a in 94% yield (entry 2). In addition, only a simple workup
and F-SPE were required to obtain the pure compound 6a.
Entry
Aryl halide
R1
Time (min)
15
Product (yieldb)
12
3a
13
14
3a
20
Table 3
Reaction condition study using iodobenzene 2c and ethanol 5aa
3f: 4-OMe 15 (12 hc)
Entry
Base
Temp (ꢀC)
Time (min)
Yield of 6ab (%)
1c
2
3
4
5
6
7
8
DIPEA
DIPEA
TEA
DBU
Bu3N
130
130
130
130
130
130
130
130
130
130
130
130
150
110
130
130
130
130
130
15
15
15
15
15
15
15
15
15
15
15
15
8
30
15
25
8
15
15
87
94
78
85
81
82
79
61
79
96
89
55
91
86
35
81
91
93
94
15
16
3d
3a
15 (12 hc)
Pyridine
Na2CO3
K2CO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
20
9d
10e
11f
12g
13
14
15h
16i
17j
18k
19l
17
3a
3a
20
30
a
Reaction condition: iodobenzene (1.0 mmol), ethanol (5.0 equiv), 1 (1 mol % Pd),
18
Mo(CO)6 (0.5 equiv), base (1.5 equiv).
b
Isolated yields.
c
Water used as solvent, benzoic acid obtained as the sole product.
EtOH (1.2 equiv) was used.
EtOH (25 equiv) was used.
Base (3.0 equiv) was used.
a
Reaction condition: aryl halide (0.6 mmol), arylboronic acid (2.5 equiv),
d
1 (1 mol % Pd), Mo(CO)6 (1.5 equiv), DIPEA (3.0 equiv), H2O (1.0 mL).
e
b
Isolated yields.
f
c
Using Pd(OAc)2: 10 mol % Pd, Mo(CO)6, K2CO3, anisole, 140 ꢀC.18
g
Mo(CO)6 (0.2 equiv) and 3.0 equiv of base were used.
d
Using 4,40-dimethoxybenzophenone oxime palladacycle instead of 1.
h
Absence of palladacycle 1.
i
Pd (0.5 mol %).
Pd (2 mol %).
DMAP added.
TBAB (1.0 equiv) was added.
j
which eliminates the need of protecting groups and could be applied
to aryl halides and arylboronic acids containing either electron-
donating or electron-withdrawing substituents (entries 2e4, 6e8,
12 and 13). Heteroaryl iodides were also successfully employed to
provide the desired product in good yields (entries 14 and 15). In
addition,theyieldsof theproductsobtainedusingpalladacycle1were
comparable with thoseobtained with Pd(OAc)2 and anisoleascatalyst
and solvent, respectively (entries 1, 5e7, 14 and 15).18 The carbon-
ylative SuzukieMiyaura coupling reaction with this aqueous protocol
could also be easily performed with aryl bromides (entries 16e18).
ortho-Substituted substrates are known to be challenging sub-
strates and gratifyingly, we were able to apply the optimized pro-
cedure to obtain good to excellent yields of the biaryl product
(entries 1e4, 10e12). In addition, synthesis of sterically hindered
biaryl ketone by FriedeleCrafts acylation is known to be difficult
but we demonstrated that using 2b we were able to obtain the
biaryl ketone 4e in 80% yield (entry 5).
k
l
Attempts to optimize the reaction by changing the base or
varying the amounts of ethanol, base or Mo(CO)6 used did not
provide any significant improvement to the yield of compound 6a
(entries 3e12). We also varied the reaction temperature and
amount of palladacycle 1 added into the reaction mixture and it
was determined that the reaction was most efficient at 130 ꢀC and
the optimal amount of palladacycle 1 was 1 mol % Pd (entries
13e17). It was reported previously that the addition of DMAP as an
additive improved the yield of the desired ester.19 However, in our
protocol, the presence of DMAP or TBAB gave compound 6a in
comparable yields (entries 18 and 19).
The scope of the reaction was explored using various aryl and
heteroaryl iodides and bromides with alkyl and aryl alcohols, which
gave the respective esters in good to excellent yields (Table 4). Aryl
halides bearing various functionality and sensitive functional
groups were also well-tolerated by the reaction (entries 1e3,10e12,
15, 16, 21). Comparing the performance of palladacycle 1 with its
non-fluorous analogue showed that the solvent-free protocol
2.2. Alkoxycarbonylation of aryl halides and alcohols
Encouraged by the results from the carbonylative Suzu-
kieMiyaura reaction, we proceeded to use palladacycle 1 as

8548
W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
Table 4 (continued)
Table 4
Alkoxycarbonylation of aryl halides with alcoholsa
Entry
Aryl halide
R1
Time (min)
20
Product (yieldb)
13
5a: Et
Entry
1
Aryl halide
R1
Time (min)
20
Product (yieldb)
14
15
5a: Et
5a: Et
20
25
5a: Et
2
5b: Bn
15 (15c)
16
17
5c: n-Bu
5a: Et
30 (20e)
3
5c: n-Bu
5a: Et
15 (15c)
30f
4
15
18
19
20
5b: Bn
5a: Et
30f
5
5b: Bn
5c: n-Bu
5d: i-Pr
5e: i-Bu
5f: Ph
20
20
5b: Bn
5c: n-Bu
25
6
20
21
20 (15g)
7
20
a
Reaction condition: aryl halide (1.0 mmol), alcohol (5.0 equiv), 1 (1 mol % Pd),
Mo(CO)6 (0.5 equiv), DIPEA (1.5 equiv).
b
Isolated yields.
c
Using Pd/C: 5 mol % Pd, Mo(CO)6, DMAP, DIPEA, dioxane, M.W. 150 ꢀC.19
d
Using 4,40-dimethoxybenzophenone oxime palladacycle instead of 1.
Using Herrmann’s palladacycle: 5 mol % Pd, Mo(CO)6, DMAP, DIPEA, dioxane,
8
20
e
M.W. 190 ꢀC.19
f
M.W. 150 ꢀC.
g
Using Herrmann’s palladacycle: 5 mol % Pd, Mo(CO)6, DMAP, DIPEA, dioxane,
M.W. 180 ꢀC.19
9
15
proceeded more efficiently with palladacycle 1 and gave the desired
ester in significantly higher yield (entry 4).
2.3. Aminocarbonylation of aryl halides with amines
10
11
12
5a: Et
17
Encouraged by the results from the carbonylative Suzu-
kieMiyaura and alkoxycarbonylation reactions, we proceeded to
apply the reactionprotocol to the aminocarbonylation reaction using
the representative aryl iodide, 1-iodonaphthalene 2b, with n-butyl-
amine 7a. Initially the reaction was conducted under microwave ir-
radiation at 130 ꢀC, which gave the desired amide 8a after 3 min in
84% yield (Table 5, entry 1). To optimize the reaction, we varied the
temperature and tried several bases (entries 1e9) and found that the
reaction proceeded most efficiently with DIPEA at 110 ꢀC. Further
optimization by changing the amounts of palladacycle 1, base, amine
or Mo(CO)6 used did not result in any improvement in the yield of
5a: Et
15
5a: Et
15

W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
8549
Table 5
compound 8a (entries 10e15). Addition of TBAB as an additive also
provided compound 8a in the same yield (entry 16).
Reaction condition study using 1-iodonaphthalene 2b and n-butylamine 7aa
To demonstrate the versatility of the optimized reaction con-
dition, we carried out the reaction with different aryl iodides and
various aromatic and alkyl amines. The reaction proceeded well
with aryl iodides bearing different functional groups and neither
electronic nor steric properties were of much importance for the
reaction efficiency (Table 6, entries 1e13). It is worth noting that for
the aminocarbonylation of aryl iodides, only a simple workup is
needed in the purification of the compounds: F-SPE was first car-
ried out to remove palladacycle 1 followed by a partition with 2 M
HCl(aq)/ethyl acetate.
Initial attempts to apply the optimized reaction condition to aryl
bromides were unsuccessful as the reaction proceeded very slug-
gishly. When the temperature was increased to 120 ꢀC, only trace
amount of the desired product was observed. Earlier studies have
shown that (t-Bu)3P-releasing [(t-Bu)3PH]BF4 salt in combination
with microwave heating could enable an acceleration of the
Mo(CO)6-mediated aminocarbonylation reaction.20e24 Hence we
decided to investigate the reaction in the presence of 2 mol % [(t-
Bu)3PH]BF4, which furnished the desired amide in good to excellent
yields (entries 14e22). The purification procedure involved an ad-
ditional step where the crude product was pass through a short pad
of silica gel after extractive workup to remove the [(t-Bu)3PH]BF4.
Entry
Base
Temp (ꢀC)
Time (min)
Yield of 8ab (%)
1
2
3
4
5
6
7
8
DIPEA
DIPEA
DIPEA
TEA
DBU
Bu3N
Na2CO3
K2CO3
Cs2CO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
130
110
90
3
10
20
10
20
10
15
10
10
10
15
5
84
93
92
85
13
79
63
74
81
34
93
87
84
90
64
93
110
110
110
110
110
110
110
110
110
110
110
110
110
9
10c
11d
12e
13f
14g
15h
16i
10
10
10
10
a
Reaction condition: 1-iodonaphthalene (0.5 mmol), n-butylamine (5.0 equiv), 1
(1 mol % Pd), Mo(CO)6 (0.5 equiv), base (3.0 equiv), H2O (1.0 mL).
b
Isolated yields.
Absence of palladacycle 1.
Pd (0.5 mol %).
Pd (2 mol %).
Base (1.5 equiv) was used.
Mo(CO)6 (1.0 equiv) was used.
Amine (2.0 equiv) was used.
TBAB (1.0 equiv) was added.
c
d
e
2.4. Recycling of palladacycle 1
f
g
We next investigated the possibility of recycling and reusing
palladacycle 1 from the carbonylation reactions. The three different
carbonylation reactions were performed under the optimized
h
i
Table 6
Aminocarbonylation of aryl halides with aminesa
Entry
1
Aryl halide
Amine
Time (min)
10
Product (yieldb)
7a: n-BuNH2
2
3
10
10
7c: BnNH2
4
10
(continued on next page)

8550
W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
Table 6 (continued )
Entry
Aryl halide
Amine
Time (min)
Product (yieldb)
5
6
10
10
7
7a: n-BuNH2
10 (10c)
10 (1 he)
10
8
7c: BnNH2
9
7a: n-BuNH2
7a: n-BuNH2
7a: n-BuNH2
10
11
10 (15f)
10
12
13
7a: n-BuNH2
7a: n-BuNH2
10
10
14
15
7a: n-BuNH2
20g (15,h10,i15j)
7a: n-BuNH2
15g

W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
8551
Table 6 (continued )
Entry
Aryl halide
Amine
Time (min)
Product (yieldb)
16
17
7a: n-BuNH2
20g (15,h20k)
7c: BnNH2
20g (10i)
18
19
7a: n-BuNH2
7a: n-BuNH2
20g (15h)
20g
20
21
7a: n-BuNH2
7a: n-BuNH2
20g
20g
22
7c: BnNH2
20g
a
Reaction condition: aryl halide (0.5 mmol), amine (5.0 equiv), 1 (1 mol % Pd), Mo(CO)6 (0.5 equiv), DIPEA (3.0 equiv), H2O (1.0 mL).
Isolated yields.
b
c
d
e
f
Using Pd(OAc)2: 5 mol % Pd, Mo(CO)6, Na2CO3, H2O, M.W. 110 ꢀC.20
Using 4,40-dimethoxybenzophenone oxime palladacycle instead of 1.
Using Pd(OAc)2: 10 mol % Pd, 10 mol % BINAP, Mo(CO)6, Cs2CO3, toluene/ACN, 80 ꢀC.25
Using Pd/C: 10 mol % Pd, Mo(CO)6, K2CO3, diglyme, M.W. 150 ꢀC.26
g
h
i
[(t-Bu)3PH]BF4 (2 mol %) was added.
Using Herrmann’s palladacycle: 4 mol % Pd, 10 mol % BINAP, Mo(CO)6, K2CO3, diglyme, M.W. 150 ꢀC.26
Using Herrmann’s palladacycle: 5 mol % Pd, Mo(CO)6, Na2CO3, water, M.W. 170 ꢀC.27
Using Herrmann’s palladacycle: 5 mol % Pd, Mo(CO)6, Na2CO3, water, M.W. 170 ꢀC.20
Using Herrmann’s palladacycle: 5 mol % Pd, 10 mol % [(t-Bu)3PH]BF4, Mo(CO)6, Na2CO3, water, M.W. 140 ꢀC.20
j
k
reaction condition. To stabilize the Pd nanoparticles so as to avoid
(Table 8, entry 1). The synthesis of compound 4q was previously
achieved via a metalehalogen exchange reaction of n-BuLi and 2-
bromo-4-chloroanisole followed by quenching with 3,5-difluoro-
N-methoxy-N-methylbenzamide in 42% yield.33
aggregation,28e32 1 equiv of TBAB was added as an additive to the
reaction mixture and the recycling was successfully carried out
over five cycles with little loss of catalytic activity (Table 7). Re-
covery of palladacycle 1 was good and ICP-OES analysis of the crude
product indicated that the Pd leaching was low.
Next, we explored the application of the alkoxycarbonylation
reaction in the synthesis of niacin 6t. In our earlier studies, we have
obtained the ethyl ester of niacin 6n in good yield (Table 4, entry
14). In addition, we have shown that in the presence of water,
benzoic acid was obtained as the sole product (Table 3, entry 1).
With these results, we proceeded to treat 3-iodopyridine 2j with
water as the nucleophile, which gave niacin 6t in 81% yield (Table 8,
entry 2). Typical industrial methods for obtaining niacin include (i)
the oxidation of 5-ethyl-2-methylpyridine under high temperature
(230e270 ꢀC) and pressure (6e8 MPa)34 and (ii) metal-catalyzed
ammoxidation of 3-methylpyridine (350 ꢀC, 60 MPa) followed by
2.5. Application of carbonylation protocol
Finally, we proceeded to apply our optimized protocols for the
synthesis of several simple biologically relevant compounds. Firstly,
the precursor of a human immunodeficiency virus (HIV) non-
nucleosidic reverse transcriptase inhibitor (NNRTI) analogue 4q
was obtained in a single step from aryl halide 2y and boronic acid
3g in 54% yield via the carbonylative SuzukieMiyaura reaction

8552
W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
Table 7
Recycling of palladacycle 1a
Entry
Timeb (min)
Yield of productc (%)
Recovered 1d (wt %)
Pd leachinge (ppm)
1
2
3
4
5
12
15
18
21
25
73
70
66
63
60
91
87
82
78
74
<0.05
<0.05
<0.05
<0.05
<0.05
6
7
8
9
15
18
21
25
29
94
92
90
87
84
92
89
87
85
81
<0.05
<0.05
<0.05
<0.05
<0.05
10
11
12
13
14
15
10
12
14
17
20
94
92
90
87
84
95
92
88
86
81
0.09
0.08
0.08
0.09
0.09
a
Reaction condition: respective optimized reaction condition and TBAB (1.0 equiv).
Time required for reaction to reach completion using recovered palladacycle 1 from previous cycle.
Isolated yields.
Recovered by F-SPE.
Determined by ICP-OES of the crude product.
b
c
d
e
base-catalyzed hydrolysis of 3-cyanopyridine (130e150 ꢀC).35
procedure.16 Moisture-sensitive reactions were carried out under
nitrogen with commercially obtained anhydrous solvents. Analyt-
ical thin-layer chromatography (TLC) was carried out on precoated
F254 silica plates and visualized with UV light. Column chroma-
tography was performed with silica (Merck, 230e400 mesh). F-SPE
Hence compared to the industrial methods, our aqueous protocol
provides a milder and more direct synthesis of niacin.
Besides niacin, we have also applied our alkoxycarbonylation
protocol to the synthesis of benzocaine 6u and butamben 6v in 88%
and 90% yields, respectively (Table 8, entries 3 and 4). Finally, using
4-iodoaniline 2d and glycine methyl ester hydrochloride 7e, we
have also successfully applied our aminocarbonylation protocol to
the preparation of diagnostic agent, methyl aminohippurate 8t
(Table 8, entry 5).
was performed with FluoroFlashÒ silica gel (40 m). 1H and 13C
m
NMR spectra were recorded at 298 K. Chemical shifts are expressed
in terms of (ppm) relative to the internal standard tetrame-
d
thylsilane (TMS). Mass spectra were performed under EI and ESI
mode. Microwave reactions were performed on the Biotage Ini-
tiatorÔ microwave synthesizer in quartz pressure tubes. Pd
leaching values were obtained on a Dual-view Optima 5300 DV
(inductively coupled plasma) ICP-OES system.
3. Conclusion
We have reported an expedient procedure for the carbonylation
of aryl halides with various nucleophiles in aqueous or neat medium
using Mo(CO)6 as a solid carbon monoxide source under microwave
irradiation. This methodology can be applied to the syntheses of
asymmetrical biaryl ketones, esters and amides. Moreover, the ab-
senceoforganicsolvent in themethodologyand theabilitytorecycle
and reuse palladacycle 1 increases the greenness of the reaction.
4.2. Carbonylative SuzukieMiyaura coupling of aryl halide
and arylboronic acid: general procedure
A mixture of the aryl halide (0.6 mmol), arylboronic acid
(2.5 equiv), Mo(CO)6 (1.5 equiv), DIPEA (3.0 equiv), palladacycle
1 (1 mol % Pd), and water (1.0 mL) was heated in a pressure tube at
140 ꢀC under microwave irradiation. The reaction was monitored
by TLC. When the reaction has completed, the reaction mixture
was cooled to room temperature, poured into EtOAc (20 mL)
and washed successively with water (3ꢁ10 mL). The organic layer
was dried over anhydrous MgSO4, filtered and concentrated. The
crude product was then purified by column chromatography to
give pure 4.
4. Experimental
4.1. General
All chemicals purchased were used without further purification.
Palladacycle 1 was synthesized according to previously reported

W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
8553
Table 8
129.9,129.4,129.3,129.1,129.1,127.6, 52.0, 21.5. HRMS (EI): calcd for
16H14O3 254.0943, found 254.0940.
Application of palladacycle 1 catalyzed carbonylation to the synthesis of biologically
relevant compounds
C
Entry Aryl halide Nucleophile
Time (min)
20
Product (yielda)
4.2.5. Naphthalen-1-yl(phenyl)methanone (4e).18 White solid. 1H
NMR (500 MHz, CDCl3)
d
8.10 (d, J¼8.5 Hz, 1H), 8.01 (d, J¼8.4 Hz,
1H), 7.94e7.91 (m, 1H), 7.88 (dd, J¼8.3, 1.3 Hz, 2H), 7.61e7.58 (m,
2H), 7.56e7.50 (m, 3H), 7.48e7.44 (m, 2H). 13C NMR (126 MHz,
1b
CDCl3)
d 198.0, 138.2, 136.4, 133.7, 133.2, 131.2, 131.0, 130.4, 128.4,
128.4, 127.7, 127.2, 126.5, 125.9, 124.3. HRMS (EI): calcd for C17H12O1
232.0888, found 232.0881.
4.2.6. (4-Chlorophenyl)(phenyl)methanone (4f).18 White solid. 1H
2c
3d
4d
H2O
20
12
12
10
NMR (500 MHz, CDCl3)
7.51e7.44 (m, 4H). 13C NMR (126 MHz, CDCl3)
135.8, 132.6, 131.4, 129.9, 128.6, 128.4. HRMS (EI): calcd for
13H9O315Cl1 216.0342, found 216.0340.
d
7.82e7.73 (m, 4H), 7.60 (t, J¼7.4 Hz, 1H),
d
195.4, 138.8, 137.2,
C
5a: EtOH
5c: n-BuOH
4.2.7. Phenyl(p-tolyl)methanone (4g).18 Yellow solid. 1H NMR
(500 MHz, CDCl3)
7.79 (d, J¼7.9 Hz, 2H), 7.73 (d, J¼8.1 Hz, 2H), 7.57
(t, J¼7.5 Hz, 1H), 7.50e7.45 (m, 2H), 7.28 (d, J¼8.0 Hz, 2H), 2.44 (s,
3H). 13C NMR (126 MHz, CDCl3)
196.4, 143.2, 137.9, 134.9, 132.1,
d
d
130.3, 129.9, 128.9, 128.2, 21.6. HRMS (EI): calcd for C14H12O1
196.0888, found 196.0883.
4.2.8. (2-Fluorophenyl)(phenyl)methanone (4h).18 Yellow oil. 1H
NMR (500 MHz, CDCl3)
7.47 (t, J¼7.8 Hz, 2H), 7.26 (td, J¼7.5, 1.0 Hz, 1H), 7.16 (t, J¼9.1 Hz,
1H). 13C NMR (126 MHz, CDCl3)
d
7.84 (d, J¼8.4 Hz, 2H), 7.61e7.50 (m, 3H),
5e
d
193.4, 160.0 (d, J¼253 Hz), 137.4,
133.3, 133.0 (d, J¼8.3 Hz), 130.7 (d, J¼2.8 Hz), 129.7, 128.4, 127.0 (d,
J¼14.7 Hz), 124.2 (d, J¼3.7 Hz), 116.2 (d, J¼22 Hz). HRMS (EI): calcd
for C13H9O1F1 200.0637, found 200.0632.
a
Isolated yields.
b
Reaction condition: 2y (0.6 mmol), 3g (2.5 equiv), 1 (1 mol % Pd), Mo(CO)6
(1.5 equiv), DIPEA (3.0 equiv), H2O (1.0 mL), M.W. 140 ꢀC.
c
Reaction condition: 2j (1.0 mmol), water (1.0 mL), 1 (1 mol % Pd), Mo(CO)6
4.2.9. (4-Aminophenyl)(phenyl)methanone (4i).38 White solid. 1H
(0.5 equiv), DIPEA (1.5 equiv), M.W. 130 ꢀC.
d
Reaction condition: 2d (1.0 mmol), 5a or 5e (5.0 equiv), 1 (1 mol % Pd), Mo(CO)6
NMR (500 MHz, CDCl3)
d
7.71 (dd, J¼5.1, 3.6 Hz, 4H), 7.55e7.48 (m,
(0.5 equiv), DIPEA (1.5 equiv), M.W. 130 ꢀC.
1H), 7.45 (t, J¼7.4 Hz, 2H), 6.67 (d, J¼8.6 Hz, 2H), 4.16 (s, 2H). 13
C
e
Reaction condition: 2d (0.5 mmol), 7e (5.0 equiv), 1 (1 mol % Pd), Mo(CO)6
NMR (126 MHz, CDCl3)
d 195.3, 150.9, 138.9, 132.9, 131.4, 129.5,
(0.5 equiv), DIPEA (3.0 equiv), H2O (1.0 mL), M.W. 110 ꢀC.
128.0, 127.4, 113.6. HRMS (EI): calcd for C13H11O1N1 197.0841, found
197.0837.
4.2.1. Methyl 2-benzoylbenzoate (4a).18 White solid. 1H NMR
(500 MHz, CDCl3)
7.63 (td, J¼7.5, 1.2 Hz, 1H), 7.58e7.52 (m, 2H), 7.44e7.39 (m, 3H),
3.60 (s, 3H). 13C NMR (126 MHz, CDCl3)
197.0, 166.3, 141.6, 137.1,
133.0, 132.3, 130.0, 129.6, 129.2, 129.1, 128.4, 127.7, 52.1. HRMS (EI):
calcd for C15H12O3 240.0786, found 240.0779.
d
8.04 (dd, J¼7.8, 0.9 Hz, 1H), 7.76e7.73 (m, 2H),
4.2.10. (2-Hydroxyphenyl)(phenyl)methanone
solid. 1H NMR (500 MHz, CDCl3)
12.02 (s, 1H), 7.68 (d, J¼7.2 Hz,
(4j).39 Colourless
d
d
2H), 7.61e7.58 (m, 2H), 7.51 (t, J¼7.7 Hz, 3H), 7.08 (d, J¼8.4 Hz, 1H),
6.89 (d, J¼8.0 Hz, 1H). 13C NMR (126 MHz, CDCl3)
d 201.6, 163.2,
137.9, 136.3, 133.6, 131.9, 129.2, 128.3, 119.2, 118.6, 118.4. HRMS (EI):
calcd for C13H10O2 198.0681, found 198.0676.
4.2.2. Methyl 2-(4-chlorobenzoyl)benzoate (4b).36 Colourless solid.
1H NMR (500 MHz, CDCl3)
d
8.04 (d, J¼7.8 Hz, 1H), 7.68 (d, J¼8.6 Hz,
4.2.11. (2-Aminophenyl)(phenyl)methanone (4k).38 Brown solid. 1H
2H), 7.63 (td, J¼7.5, 1.2 Hz, 1H), 7.56 (td, J¼7.7, 1.3 Hz, 1H), 7.38 (dd,
NMR (500 MHz, CDCl3)
d
7.65 (dd, J¼8.2, 1.3 Hz, 2H), 7.54e7.50 (m,
J¼11.1, 4.4 Hz, 3H), 3.64 (s, 3H). 13C NMR (126 MHz, CDCl3)
d
195.7,
1H), 7.46 (ddd, J¼7.1, 3.4, 1.4 Hz, 3H), 7.29 (ddd, J¼8.5, 7.1, 1.6 Hz,
166.1,141.2,139.4,135.5,132.5,130.5,130.1,129.7,128.9,128.8,127.5,
52.2. HRMS (EI): calcd for C15H11O335Cl1 274.0397, found 274.0396.
1H), 6.73 (dd, J¼8.3, 0.9 Hz, 1H), 6.60 (ddd, J¼8.1, 7.2, 1.1 Hz, 1H),
6.07 (s, 2H). 13C NMR (126 MHz, CDCl3)
d 199.0, 150.9, 140.1, 134.5,
134.2, 131.0, 129.0, 128.0, 118.1, 116.9, 115.4. HRMS (EI): calcd for
C13H11O1N1 197.0841, found 197.0839.
4.2.3. Methyl 2-(3-ethoxybenzoyl)benzoate (4c). White solid. 1H
NMR (500 MHz, CDCl3)
d
8.02 (d, J¼7.8 Hz,1H), 7.61 (t, J¼7.5 Hz,1H),
7.54 (td, J¼7.7, 1.2 Hz, 1H), 7.40e7.35 (m, 2H), 7.28 (d, J¼7.8 Hz, 1H),
7.18 (d, J¼7.7 Hz, 1H), 7.06 (dd, J¼8.2, 2.6 Hz, 1H), 4.04 (q, J¼7.0 Hz,
2H), 3.61 (s, 3H), 1.39 (t, J¼7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3)
4.2.12. Ethyl 2-(2-benzoylphenyl)acetate (4l).40 Yellow oil. 1H NMR
(500 MHz, CDCl3)
7.82 (d, J¼8.3 Hz, 2H), 7.57 (t, J¼7.4 Hz, 1H),
d
7.46 (q, J¼7.8 Hz, 3H), 7.40e7.31 (m, 3H), 4.02 (q, J¼7.2 Hz, 2H), 3.88
d
196.7, 166.3, 159.0, 141.6, 138.4, 132.3, 130.0, 129.5, 129.4, 129.2,
(s, 2H), 1.11 (t, J¼7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 198.0,
127.7, 122.1, 120.0, 113.7, 63.6, 52.1, 14.6. HRMS (EI): calcd for
17H16O4 284.1049, found 284.1049.
171.2, 138.3, 137.8, 134.0, 132.9, 131.7, 130.8, 130.3, 129.9, 128.2,
126.4, 60.8, 38.9, 14.0. HRMS (EI): calcd for C17H16O3 268.1099,
found 268.1093.
C
4.2.4. Methyl 2-(4-methylbenzoyl)benzoate (4d).37 White solid. 1H
NMR (500 MHz, CDCl3)
8.02 (d, J¼7.7 Hz, 1H), 7.64 (d, J¼8.1 Hz,
d
4.2.13. (4-Methoxyphenyl)(thiophen-2-yl)methanone (4m).18 White
2H), 7.61 (td, J¼7.6, 1.1 Hz, 1H), 7.54 (t, J¼7.6 Hz, 1H), 7.38 (d,
solid. 1H NMR (500 MHz, CDCl3)
d
7.92e7.89 (m, 2H), 7.69 (d,
J¼0.9 Hz, 1H), 7.65e7.64 (m, 1H), 7.16 (d, J¼4.0 Hz, 1H), 6.99e6.96
(m, 2H), 3.89 (s, 3H). 13C NMR (126 MHz, CDCl3)
186.8, 163.1, 143.8,
J¼7.5 Hz, 1H), 7.21 (d, J¼8.1 Hz, 2H), 3.60 (s, 3H), 2.38 (s, 3H). 13
C
NMR (126 MHz, CDCl3)
d
196.6, 166.3, 143.8, 141.8, 134.6, 132.2,
d

8554
W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
134.0, 133.4, 131.6, 130.7, 127.7, 113.7, 55.5. HRMS (EI): calcd for
12H10O322S1 218.0402, found 218.0396.
133.8, 133.4, 131.4, 130.3, 128.9, 128.6, 128.5, 128.2, 127.8, 126.9,
126.2, 125.8, 124.4, 66.7. HRMS (EI): calcd for C18H14O2 262.0994,
found 262.0986.
C
4.2.14. Pyridin-3-yl(p-tolyl)methanone (4n).18 White solid. 1H NMR
(500 MHz, CDCl3)
8.82 (d, J¼1.9 Hz, 1H), 8.59 (dd, J¼5.4, 1.4 Hz,
1H), 7.90 (dd, J¼4.7, 3.2 Hz, 1H), 7.43e7.41 (m, 2H), 7.36e7.32 (m,
3H), 2.44 (s, 3H). 13C NMR (126 MHz, CDCl3)
204.4, 153.0, 152.8,
d
4.3.4. Butyl 1-naphthoate (6d).19 Pale orange oil. 1H NMR
(500 MHz, CDCl3)
d
8.93 (d, J¼8.7 Hz,1H), 8.19 (d, J¼7.2 Hz,1H), 8.01
d
(d, J¼8.1 Hz,1H), 7.88 (d, J¼8.2 Hz,1H), 7.65e7.60 (m,1H), 7.56e7.47
(m, 2H), 4.44 (td, J¼6.6, 0.7 Hz, 2H), 1.87e1.78 (m, 2H), 1.57e1.53
(m, 2H), 1.02 (td, J¼7.4, 0.8 Hz, 3H). 13C NMR (126 MHz, CDCl3)
139.3, 138.4, 135.5, 132.9, 130.2, 127.0, 124.7, 21.2. HRMS (EI): calcd
for C13H11O1N1 197.0841, found 197.0845.
d
167.7, 133.8, 133.1, 131.3, 130.0, 128.5, 127.6, 127.5, 126.1, 125.8,
4.2.15. Anthracen-9-yl(phenyl)methanone (4o).41 Yellow solid. 1H
124.5, 64.9, 30.8, 19.3, 13.7. HRMS (EI): calcd for C15H16O2 228.1150,
found 228.1149.
NMR (500 MHz, CDCl3)
d
8.57 (s, 1H), 8.07 (d, J¼8.5 Hz, 2H), 7.83 (d,
J¼7.5 Hz, 2H), 7.73 (d, J¼8.7 Hz, 2H), 7.58 (t, J¼7.4 Hz, 1H), 7.50e7.45
(m, 2H), 7.40 (dd, J¼15.0, 7.4 Hz, 4H). 13C NMR (126 MHz, CDCl3)
4.3.5. Benzyl benzoate (6e).45 Pale yellow liquid. 1H NMR (500 MHz,
d
200.2, 138.2, 134.0, 133.9, 131.0, 130.1, 128.8, 128.6, 128.4, 128.3,
CDCl3)
d
8.13 (d, J¼7.4 Hz, 2H), 7.58 (t, J¼7.4 Hz, 1H), 7.43 (ddt,
126.5, 125.5, 125.3. HRMS (EI): calcd for C21H14O1 282.1045, found
282.1040.
J¼20.4, 13.9, 7.3 Hz, 7H), 5.41 (s, 2H). 13C NMR (126 MHz, CDCl3)
d
166.3, 136.0, 132.9, 130.0, 129.6, 128.5, 128.3, 128.1, 128.1, 66.6.
HRMS (EI): calcd for C14H12O2 212.0837, found 212.0838.
4.2.16. 2-(Naphthalen-2-yl)-1-phenylethanone (4p).42 White solid.
1H NMR (500 MHz, CDCl3)
d
8.06 (d, J¼7.4 Hz, 2H), 7.84e7.78 (m,
4.3.6. Butyl benzoate (6f).46 Colourless liquid. 1H NMR (500 MHz,
3H), 7.73 (s, 1H), 7.56 (t, J¼7.4 Hz, 1H), 7.46 (dd, J¼9.4, 5.7 Hz, 4H),
CDCl3)
d
8.05 (d, J¼7.1 Hz, 2H), 7.54 (t, J¼7.4 Hz, 1H), 7.43 (t,
7.41 (dd, J¼8.4, 1.7 Hz, 1H), 4.45 (s, 2H). 13C NMR (126 MHz, CDCl3)
J¼7.7 Hz, 2H), 4.33 (t, J¼6.6 Hz, 2H), 1.79e1.72 (m, 2H), 1.52e1.44
d
197.6, 136.6, 133.6, 133.2, 132.4, 132.1, 128.6, 128.3, 128.1, 127.7,
(m, 2H), 0.98 (t, J¼7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 166.6,
127.6, 127.6, 126.1, 125.7, 45.7. HRMS (EI): calcd for C18H14O1
246.1045, found 246.1038.
132.7, 130.5, 129.5, 128.2, 64.7, 30.7, 19.2, 13.7. HRMS (EI): calcd for
C11H14O2 178.0994, found 178.0986.
4.2.17. (5-Chloro-2-methoxyphenyl)(3,5-difluorophenyl)methanone
4.3.7. Isopropyl benzoate (6g).47 Colourless liquid. 1H NMR
(4q).33 White solid. 1H NMR (500 MHz, CDCl3)
d
7.45 (dd, J¼8.9,
(500 MHz, CDCl3) 8.05 (d, J¼7.1 Hz, 2H), 7.53 (t, J¼7.4 Hz, 1H), 7.42
(t, J¼7.7 Hz, 2H), 5.27 (dq, J¼12.5, 6.3 Hz, 1H), 1.37 (d, J¼6.3 Hz, 6H).
13C NMR (126 MHz, CDCl3)
166.0, 132.6, 130.8, 129.4, 128.2, 68.2,
d
2.7 Hz, 1H), 7.34 (d, J¼2.7 Hz, 1H), 7.30e7.27 (m, 2H), 7.01 (tt, J¼8.4,
2.4 Hz, 1H), 6.94 (d, J¼8.9 Hz, 1H), 3.72 (s, 3H). 13C NMR (126 MHz,
d
CDCl3)
d
192.4, 162.8 (dd, J¼11.3, 251 Hz), 155.9, 140.4, 132.3, 129.3,
21.9. HRMS (EI): calcd for C10H12O2 164.0837, found 164.0835.
128.8, 126.0, 112.9, 112.4 (dd, J¼6.3, 20.1 Hz), 108.4 (t, J¼25.2 Hz),
55.9. HRMS (EI): calcd for C14H9O325Cl1F2 282.0259, found 282.0251.
4.3.8. tert-Butyl benzoate (6h).48 Yellow liquid. 1H NMR (500 MHz,
CDCl3)
d
8.00 (d, J¼7.2 Hz, 2H), 7.52 (t, J¼7.4 Hz, 1H), 7.41 (t,
4.3. Alkoxycarbonylation of aryl halide and alcohol: general
procedure
J¼7.8 Hz, 2H), 1.60 (s, 9H). 13C NMR (126 MHz, CDCl3)
d 165.7, 132.4,
132.0, 129.4, 128.1, 80.9, 28.2. HRMS (EI): calcd for C11H14O2
178.0994, found 178.0992.
A mixture of the aryl halide (1.0 mmol), alcohol (5.0 equiv),
Mo(CO)6 (0.5 equiv), DIPEA (1.5 equiv) and palladacycle 1 (1 mol %
Pd) was heated in a pressure tube at 130 ꢀC under microwave irra-
diation. The reaction was monitored by TLC. When the reaction has
completed, the reaction mixture was cooled to room temperature
and the alcohol was removed. The crude mixture was subjected to F-
SPE to remove palladacycle 1 (see general procedure for the recy-
cling of palladacycle 1) and the solution of crude product was con-
centrated, diluted with EtOAc (20 mL) and washed successively with
2 M HCl (2ꢁ10 mL) and water (10 mL). The organic layer was dried
over anhydrous MgSO4, filtered and concentrated to give pure 6.
4.3.9. Phenyl benzoate (6i).49 White solid. 1H NMR (500 MHz,
CDCl3)
d
8.29 (s, 2H), 7.69 (t, J¼7.4 Hz,1H), 7.57 (t, J¼7.7 Hz, 2H), 7.49
(t, J¼7.8 Hz, 2H), 7.33 (t, J¼7.4 Hz, 1H), 7.29 (d, J¼8.4 Hz, 2H). 13
C
NMR (126 MHz, CDCl3)
d 165.1, 150.9, 133.5, 130.1, 129.5, 129.4,
128.5, 125.8, 121.6. HRMS (EI): calcd for C13H10O2 198.0681, found
198.0674.
4.3.10. Ethyl 4-acetylbenzoate (6j).50 White solid. 1H NMR
(500 MHz, CDCl3)
d
8.11 (d, J¼8.4 Hz, 2H), 7.98 (d, J¼8.4 Hz, 2H),
4.39 (q, J¼7.1 Hz, 2H), 2.62 (s, 3H), 1.40 (t, J¼7.1 Hz, 3H). 13C
NMR (126 MHz, CDCl3)
d 197.5, 165.7, 140.1, 134.2, 129.7, 128.1,
4.3.1. Ethyl benzoate (6a).43 Colourless liquid. 1H NMR (300 MHz,
61.4, 26.8, 14.2. HRMS (EI): calcd for C11H12O3 192.0786, found
192.0779.
CDCl3)
d
8.04 (d, J¼7.1 Hz, 2H), 7.53 (t, J¼7.3 Hz,1H), 7.41 (t, J¼7.5 Hz,
2H), 4.37 (q, J¼7.1 Hz, 2H), 1.38 (t, J¼7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3)
d
166.5, 132.7, 130.4, 129.4, 128.2, 60.8, 14.2. HRMS (EI): calcd
4.3.11. Ethyl 4-nitrobenzoate (6k).51 Pale yellow solid. 1H NMR
for C9H10O2 150.0681, found 150.0680.
(500 MHz, CDCl3)
d
7.84 (d, J¼8.7 Hz, 2H), 6.62 (d, J¼8.7 Hz, 2H),
4.30 (q, J¼7.1 Hz, 2H), 1.35 (t, J¼7.2 Hz, 3H). 13C NMR (126 MHz,
4.3.2. Ethyl methyl phthalate (6b).44 Colourless liquid. 1H NMR
CDCl3) d 166.7, 150.8, 131.4, 119.8, 113.7, 60.2, 14.3. HRMS (EI): calcd
(500 MHz, CDCl3)
d
7.77e7.68 (m, 2H), 7.53 (dd, J¼5.7, 3.3 Hz, 2H),
for C9H9O4N1 195.0532, found 195.0530.
4.37 (q, J¼7.1 Hz, 2H), 3.90 (s, 3H), 1.37 (t, J¼7.1 Hz, 3H). 13C NMR
(126 MHz, CDCl3)
d
168.1, 167.5, 132.1, 132.0, 131.0, 128.9, 128.8, 61.7,
4.3.12. Ethyl 4-cyanobenzoate (6l).52 White solid. 1H NMR
52.5, 14.1. HRMS (EI): calcd for C11H12O4 208.0736, found 208.0738.
(500 MHz, CDCl3)
d
8.14 (d, J¼8.2 Hz, 2H), 7.74 (d, J¼8.2 Hz, 2H),
4.45e4.39 (m, 2H), 1.40 (d, J¼7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
4.3.3. Benzyl 1-naphthoate (6c).19 Yellow oil. 1H NMR (500 MHz,
d 164.9, 134.3, 132.2, 130.0, 118.0, 116.3, 61.8, 14.2. HRMS (EI): calcd
CDCl3)
d
9.01 (d, J¼8.6 Hz, 1H), 8.27 (dd, J¼7.3, 1.2 Hz, 1H), 8.03
for C10H9O2N1 175.0633, found 175.0629.
(d, J¼8.2 Hz, 1H), 7.90 (d, J¼8.2 Hz, 1H), 7.64 (ddd, J¼8.5, 6.9,
1.4 Hz, 1H), 7.57e7.50 (m, 4H), 7.46e7.41 (m, 2H), 7.40e7.38 (m,
4.3.13. Ethyl thiophene-2-carboxylate (6m).53 Yellow liquid. 1H
1H), 5.50 (s, 2H). 13C NMR (126 MHz, CDCl3)
d
167.2, 136.1,
NMR (500 MHz, CDCl3)
d
7.79 (dd, J¼3.7, 1.2 Hz, 1H), 7.53 (dd, J¼5.0,

W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
8555
1.2 Hz, 1H), 7.08 (dd, J¼4.9, 3.8 Hz, 1H), 4.34 (q, J¼7.1 Hz, 2H), 1.37 (t,
131.5, 120.2, 113.9, 64.2, 30.9, 19.3, 13.7. HRMS (EI): calcd for
C11H15O2N1 193.1103, found 193.1103.
J¼7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d
162.2, 134.1, 133.2, 132.1,
127.6, 61.1, 14.3. HRMS (EI): calcd for C7H8O322S1 156.0245, found
156.0246.
4.4. Aminocarbonylation of aryl halide and amine: general
procedure
4.3.14. Ethyl nicotinate (6n).54 Pale yellow liquid. 1H NMR
(500 MHz, CDCl3)
d
9.19 (d, J¼1.7 Hz,1H), 8.73 (dd, J¼4.8,1.7 Hz,1H),
A mixture of the aryl halide (0.5 mmol), amine (5.0 equiv),
Mo(CO)6 (0.5 equiv), DIPEA (3.0 equiv), palladacycle 1 (1 mol % Pd),
[(t-Bu)3PH]BF4 (2 mol %, for aryl bromides only) and water (1.0 mL)
was heated in a pressure tube at 110 ꢀC (for aryl iodides) or 120 ꢀC
(for aryl bromides) under microwave irradiation. The reaction was
monitored by TLC. When the reaction has completed, the reaction
mixture was cooled to room temperature.
8.26 (dt, J¼7.9, 1.9 Hz, 1H), 7.35 (dd, J¼7.9, 4.9 Hz, 1H), 4.38 (q,
J¼7.1 Hz, 2H), 1.37 (t, J¼7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d
165.2, 153.2, 150.8, 136.9, 126.3, 123.2, 61.3, 14.2. HRMS (EI): calcd
for C8H9O2N1 151.0633, found 151.0627.
4.3.15. Ethyl 4-methoxybenzoate (6o).55 Colourless liquid. 1H
NMR (500 MHz, CDCl3)
J¼9.0 Hz, 2H), 4.35 (q, J¼7.1 Hz, 2H), 3.86 (s, 3H), 1.38 (t, J¼7.1 Hz,
3H). 13C NMR (126 MHz, CDCl3)
166.4, 163.2, 131.5, 123.0, 113.5,
60.6, 55.4, 14.4. HRMS (EI): calcd for C10H12O3 180.0786, found
180.0782.
d
8.00 (d, J¼9.0 Hz, 2H), 6.91 (d,
4.4.1. Workup and purification for aryl iodide. Water was removed
and the crude mixture was subjected to F-SPE to remove pallada-
cycle 1 (see general procedure for the recycling of palladacycle 1).
The solution of crude product was concentrated, diluted with EtOAc
(20 mL) and washed successively with 2 M HCl (2ꢁ10 mL) and
water (10 mL). The organic layer was dried over anhydrous MgSO4,
filtered and concentrated to give pure 8.
d
4.3.16. Butyl 4-methoxybenzoate (6p).19 Yellow oil. 1H NMR
(500 MHz, CDCl3)
d
8.00 (d, J¼8.9 Hz, 2H), 6.91 (d, J¼8.8 Hz, 2H),
4.29 (t, J¼6.6 Hz, 2H), 3.86 (s, 3H), 1.77e1.71 (m, 2H), 1.47 (dq,
J¼14.8, 7.4 Hz, 2H), 0.98 (t, J¼7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3)
4.4.2. Workup and purification for aryl bromide. The reaction mix-
ture was poured into EtOAc (20 mL) and washed successively with
water (3ꢁ10 mL). The organic layer was dried over anhydrous
MgSO4, filtered and concentrated. The crude product was then
passed through a short pad of silica (eluent is hexane/EtOAc) to give
pure 8.
d
166.5, 163.2, 131.5, 123.0, 113.5, 64.5, 55.4, 30.8, 19.3, 13.8. HRMS
(EI): calcd for C12H16O3 208.1099, found 208.1097.
4.3.17. Ethyl 2-(naphthalen-2-yl)acetate (6q).56 White solid. 1H
NMR (500 MHz, CDCl3)
7.48e7.42 (m, 3H), 4.19e4.15 (m, 2H), 3.78 (s, 2H), 1.27 (t, J¼7.1 Hz,
3H). 13C NMR (126 MHz, CDCl3)
171.5, 133.4, 132.4, 131.6, 128.1,
d
7.82 (dt, J¼6.4, 4.3 Hz, 3H), 7.74 (s, 1H),
d
4.4.2.1. N-Butyl-1-naphthamide (8a).20 Colourless solid. 1H NMR
127.9, 127.6, 127.6, 127.3, 126.1, 125.7, 60.9, 41.6, 14.1. HRMS (EI):
calcd for C14H14O2 214.0994, found 214.0995.
(500 MHz, CDCl3)
d
8.23 (dd, J¼5.9, 3.7 Hz, 1H), 7.87e7.79 (m, 2H),
7.48 (ddd, J¼6.0, 5.0, 1.6 Hz, 3H), 7.36 (dd, J¼8.2, 7.1 Hz, 1H), 6.26 (s,
1H), 3.42 (dd, J¼13.1, 7.1 Hz, 2H), 1.55 (dt, J¼14.9, 7.5 Hz, 2H), 1.38
(dq, J¼14.6, 7.3 Hz, 2H), 0.94 (t, J¼7.4 Hz, 3H). 13C NMR (126 MHz,
4.3.18. Benzyl 2-(naphthalen-2-yl)acetate (6r).57 White solid. 1H
NMR (500 MHz, CDCl3)
(m, 2H), 7.46 (dd, J¼8.5, 1.5 Hz, 1H), 7.36 (s, 5H), 5.20 (s, 2H), 3.87
(s, 2H). 13C NMR (126 MHz, CDCl3)
171.3, 135.8, 133.5, 132.5,
d
7.87e7.81 (m, 3H), 7.77 (s, 1H), 7.52e7.48
CDCl3) d 169.5, 134.7, 133.5, 130.2, 130.0, 128.1, 126.8, 126.2, 125.3,
124.6, 124.6, 39.6, 31.6, 20.0, 13.7. HRMS (EI): calcd for C15H17O1N1
227.1310, found 227.1306.
d
131.4, 128.5, 128.2, 128.2, 128.0, 127.7, 127.6, 127.4, 126.1, 125.8,
123.5, 66.7, 41.5. HRMS (EI): calcd for C19H16O2 276.1150, found
276.1148.
4.4.2.2. N-Cyclohexyl-1-naphthamide (8b).61 White solid. 1H
NMR (500 MHz, CDCl3)
d
8.27 (d, J¼8.3 Hz, 1H), 7.87 (dd, J¼15.1,
7.8 Hz, 2H), 7.58e7.49 (m, 3H), 7.43 (dd, J¼8.1, 7.1 Hz, 1H), 5.92 (d,
J¼6.8 Hz, 1H), 4.08 (tdt, J¼12.2, 8.2, 3.9 Hz, 1H), 2.14e2.07 (m, 2H),
1.79e1.75 (m, 2H), 1.70e1.63 (m, 1H), 1.51e1.41 (m, 2H), 1.30e1.17
4.3.19. Butyl 4-(trifluoromethyl)benzoate (6s).19 Colourless oil. 1H
NMR (500 MHz, CDCl3)
d
8.15 (d, J¼8.4 Hz, 2H), 7.70 (d, J¼8.3 Hz,
2H), 4.36 (t, J¼6.6 Hz, 2H), 1.80e1.74 (m, 2H), 1.48 (dq, J¼14.8,
(m, 3H). 13C NMR (126 MHz, CDCl3)
d 168.7, 135.0, 133.6, 130.3,
7.4 Hz, 2H), 0.99 (t, J¼7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d
165.5,
130.0, 128.2, 127.0, 126.3, 125.3, 124.7, 124.7, 48.7, 33.2, 25.5, 24.9.
HRMS (EI): calcd for C17H19O1N1 253.1467, found 253.1459.
134.3 (d, J¼33.0 Hz), 133.8, 129.9, 125.4 (q, J¼3.7 Hz), 123.7 (d,
J¼274 Hz), 65.4, 30.7, 19.2, 13.7. HRMS (EI): calcd for C12H13F3O2
246.0868, found 246.0870.
4.4.2.3. N-Benzyl-1-naphthamide (8c).62 White solid. 1H NMR
(500 MHz, CDCl3)
d
8.30 (dd, J¼7.0, 2.7 Hz, 1H), 7.89e7.82 (m, 2H),
4.3.20. Nicotinic acid (6t).58 White solid. 1H NMR (500 MHz,
7.51 (ddd, J¼6.5, 5.9, 4.9 Hz, 3H), 7.35 (dd, J¼9.3, 6.3 Hz, 5H), 7.30
DMSO)
1.7 Hz, 1H), 8.25 (dt, J¼7.9, 2.0 Hz, 1H), 7.51 (ddd, J¼7.9, 4.9,
0.7 Hz, 1H). 13C NMR (126 MHz, DMSO)
166.4, 153.3, 150.3, 137.1,
d
13.41 (s, 1H), 9.07 (dd, J¼2.1, 0.6 Hz, 1H), 8.76 (dd, J¼4.8,
(dd, J¼8.8, 4.3 Hz, 1H), 6.59 (s, 1H), 4.63 (d, J¼5.8 Hz, 2H). 13C NMR
(126 MHz, CDCl3)
d 169.3, 138.1, 134.1, 133.5, 130.5, 130.0, 128.6,
d
128.2, 127.7, 127.4, 127.0, 126.3, 125.3, 124.8, 124.5, 43.9. HRMS (EI):
calcd for C18H15O1N1 261.1154, found 261.1149.
126.7, 123.8. HRMS (EI): calcd for C6H5O2N1 123.0320, found
123.0321.
4.4.2.4. Naphthalen-1-yl(pyrrolidin-1-yl)methanone
4.3.21. Ethyl 4-aminobenzoate (6u).59 White solid. 1H NMR
(8d).63 Yellow oil. 1H NMR (500 MHz, CDCl3)
d 7.87e7.82 (m, 3H),
(500 MHz, CDCl3)
d
7.84 (d, J¼8.7 Hz, 2H), 6.62 (d, J¼8.7 Hz, 2H),
7.52e7.42 (m, 4H), 3.77 (t, J¼7.0 Hz, 2H), 3.09 (t, J¼6.7 Hz, 2H),
4.32e4.27 (m, 2H), 3.94 (s, 2H), 1.34 (t, J¼7.1 Hz, 3H). 13C NMR
2.01e1.92 (m, 2H), 1.83e1.75 (m, 2H). 13C NMR (126 MHz, CDCl3)
(126 MHz, CDCl3)
d
166.7, 150.8, 131.4, 119.8, 113.7, 60.2, 14.3. HRMS
d 169.1, 135.7, 133.4, 129.0, 128.9, 128.3, 126.8, 126.1, 125.1, 124.7,
(EI): calcd for C9H11O2N1 165.0790, found 165.0790.
123.6, 48.4, 45.5, 25.9, 24.5. HRMS (EI): calcd for C15H15O1N1
225.1154, found 225.1147.
4.3.22. Butyl 4-aminobenzoate (6v).60 Off-white solid. 1H NMR
(500 MHz, CDCl3)
d
7.85 (d, J¼8.7 Hz, 2H), 6.64 (d, J¼8.7 Hz, 2H),
4.4.2.5. Methyl 2-(1-naphthamido)acetate (8e).64 Beige solid. 1H
4.26 (t, J¼6.6 Hz, 2H), 3.89 (s, 2H), 1.75e1.68 (m, 2H), 1.50e1.42 (m,
NMR (500 MHz, CDCl3)
1H), 7.85e7.82 (m, 1H), 7.61 (d, J¼7.0 Hz, 1H), 7.55e7.47 (m, 2H),
d
8.32 (d, J¼8.3 Hz, 1H), 7.89 (d, J¼8.2 Hz,
2H), 0.97 (t, J¼7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 166.7, 150.5,

8556
W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
7.40 (dd, J¼8.2, 7.1 Hz, 1H), 6.70 (s, 1H), 4.23 (d, J¼5.4 Hz, 2H), 3.76
(s, 3H). 13C NMR (126 MHz, CDCl3)
170.3, 169.6, 133.5, 133.4, 130.8,
130.0, 128.2, 127.1, 126.3, 125.3, 125.2, 124.6, 52.3, 41.5. HRMS (EI):
calcd for C14H13O3N1 243.0895, found 243.0896.
4.4.2.14. N-Butyl-4-methoxybenzamide (8n).20 White solid. 1H
NMR (500 MHz, CDCl3)
d
d
7.72 (d, J¼8.8 Hz, 2H), 6.85 (d, J¼8.8 Hz,
2H), 6.50 (s, 1H), 3.79 (s, 3H), 3.37 (dd, J¼12.9, 7.1 Hz, 2H), 1.53 (dd,
J¼14.8, 7.6 Hz, 2H), 1.35 (dd, J¼15.1, 7.5 Hz, 2H), 0.90 (t, J¼7.4 Hz,
3H). 13C NMR (126 MHz, CDCl3)
d 167.1, 161.9, 128.6, 127.0, 113.5,
4.4.2.6. N-Phenyl-1-naphthamide (8f).65 White solid. 1H NMR
55.2, 39.7, 31.7, 20.1, 13.7. HRMS (EI): calcd for C12H17O2N1 207.1259,
found 207.1258.
(500 MHz, CDCl3)
d
8.36e8.30 (m, 1H), 7.93 (d, J¼8.2 Hz, 1H),
7.91e7.82 (m, 2H), 7.68 (d, J¼4.0 Hz, 3H), 7.54 (dd, J¼6.3, 3.2 Hz, 2H),
7.45 (t, J¼7.6 Hz, 1H), 7.38 (t, J¼7.6 Hz, 2H), 7.18 (t, J¼7.3 Hz, 1H). 13
C
4.4.2.15. N-Butylanthracene-9-carboxamide (8o).70 Yellow solid.
NMR (126 MHz, CDCl3)
d
167.6,138.0,134.4,133.7,131.0,130.0,129.1,
1H NMR (500 MHz, CDCl3)
d
8.40 (s, 1H), 8.00 (d, J¼8.7 Hz, 2H), 7.95
128.4, 127.3, 126.5, 125.2, 125.1, 124.7, 124.6, 120.0. HRMS (EI): calcd
for C17H13O1N1 247.0997, found 247.0994.
(d, J¼7.6 Hz, 2H), 7.48e7.43 (m, 4H), 6.22 (s, 1H), 3.58 (dd, J¼13.1,
7.2 Hz, 2H), 1.64 (dt, J¼14.9, 7.5 Hz, 2H), 1.43 (dq, J¼14.7, 7.4 Hz, 2H),
0.97 (t, J¼7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 169.3, 132.1,
4.4.2.7. N-Butylbenzamide (8g).20 Pale yellow oil. 1H NMR
131.0, 128.4, 127.9, 127.9, 126.5, 125.3, 125.0, 39.8, 31.6, 20.1, 13.7.
HRMS (EI): calcd for C19H19O1N1 277.1467, found 277.1464.
(500 MHz, CDCl3)
d
7.75 (d, J¼7.3 Hz, 2H), 7.42 (t, J¼7.4 Hz, 1H), 7.33
(t, J¼7.8 Hz, 2H), 6.81 (s, 1H), 3.37 (dd, J¼13.1, 7.1 Hz, 2H), 1.58e1.49
(m, 2H), 1.33 (dq, J¼14.6, 7.3 Hz, 2H), 0.89 (d, J¼7.3 Hz, 3H). 13C NMR
4.4.2.16. N-Butyl-4-methylbenzamide (8p).20 White solid. 1H
(126 MHz, CDCl3)
d
167.6, 134.7, 131.0, 128.2, 126.8, 39.7, 31.5, 20.0,
NMR (500 MHz, CDCl3)
d
7.65 (d, J¼8.2 Hz, 2H), 7.19 (d, J¼7.9 Hz,
13.6. HRMS (EI): calcd for C11H15O1N1 177.1154, found 177.1149.
2H), 6.29 (s, 1H), 3.43e3.39 (m, 2H), 2.37 (s, 3H), 1.56 (d, J¼7.2 Hz,
2H), 1.41e1.37 (m, 2H), 0.92 (d, J¼7.4 Hz, 3H). 13C NMR (126 MHz,
4.4.2.8. N-Benzylbenzamide (8h).25 White solid. 1H NMR
CDCl3) d 167.5, 141.5, 131.9, 129.1, 126.8, 39.7, 31.7, 21.3, 20.1, 13.7.
(500 MHz, CDCl3)
d
7.79 (d, J¼7.4 Hz, 2H), 7.48 (t, J¼7.4 Hz, 1H), 7.39
HRMS (EI): calcd for C12H17O1N1 191.1310, found 191.1304.
(t, J¼7.7 Hz, 2H), 7.32 (d, J¼4.5 Hz, 4H), 7.30e7.26 (m, 1H), 6.86 (s,
1H), 4.59 (d, J¼5.7 Hz, 2H). 13C NMR (126 MHz, CDCl3)
d
167.4, 138.2,
4.4.2.17. N-Benzyl-4-methylbenzamide (8q).20 White solid. 1H
134.3, 131.4, 128.6, 128.4, 127.7, 127.4, 126.9, 43.9. HRMS (EI): calcd
for C14H13O1N1 211.0997, found 211.0991.
NMR (500 MHz, CDCl3)
d
7.69 (d, J¼8.1 Hz, 2H), 7.32 (d, J¼4.4 Hz,
4H), 7.29e7.24 (m, 1H), 7.18 (d, J¼8.2 Hz, 2H), 6.73 (s, 1H), 4.59 (d,
J¼5.7 Hz, 2H), 2.37 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 167.3, 141.8,
4.4.2.9. 4-Amino-N-butylbenzamide (8i).66 Yellow solid. 1H NMR
(500 MHz, CDCl3)
138.3, 131.4, 129.1, 128.6, 127.7, 127.4, 126.9, 43.9, 21.3. HRMS (EI):
calcd for C15H15O1N1 225.1154, found 225.1149.
d
7.57 (d, J¼8.6 Hz, 2H), 6.58 (d, J¼8.6 Hz, 2H),
6.34 (s, 1H), 3.92 (s, 2H), 3.35 (dd, J¼13.0, 7.2 Hz, 2H), 1.55e1.48
(m, 2H), 1.33 (dq, J¼14.6, 7.3 Hz, 2H), 0.89 (t, J¼7.4 Hz, 3H). 13C NMR
4.4.2.18. N-Butyl-4-cyano-3-methylbenzamide(8r). Yellow oil. 1H
NMR (500 MHz, CDCl3) d 7.70 (s, 1H), 7.61 (s, 2H), 6.52 (s, 1H), 3.41
(126 MHz, CDCl3)
d
167.3, 149.5, 128.5, 124.0, 113.9, 39.5, 31.7,
20.0, 13.7. HRMS (EI): calcd for C11H16O1N2 192.1263, found
192.1254.
(dd, J¼13.1, 7.1 Hz, 2H), 2.54 (s, 3H), 1.56 (d, J¼6.8 Hz, 2H), 1.38e1.34
(m, 2H), 0.92 (t, J¼7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 166.0,
142.4,138.6,132.6,128.8,124.5,117.3,115.1, 39.9, 31.5, 20.0,19.2,13.6.
HRMS (EI): calcd for C13H16O1N2 216.1263, found 216.1259.
4.4.2.10. 4-Acetyl-N-butylbenzamide (8j).26 White solid. 1H NMR
(500 MHz, CDCl3)
d
7.88 (d, J¼8.5 Hz, 2H), 7.80 (d, J¼8.5 Hz, 2H),
6.88 (s, 1H), 3.39 (dd, J¼13.0, 7.2 Hz, 2H), 2.55 (s, 3H), 1.59e1.52 (m,
4.4.2.19. N-Benzylquinoline-3-carboxamide
solid. 1H NMR (500 MHz, CDCl3)
(8s).71 Colourless
9.26 (s, 1H), 8.59 (d, J¼2.1 Hz, 1H),
2H), 1.34 (dq, J¼14.7, 7.4 Hz, 2H), 0.89 (d, J¼7.3 Hz, 3H). 13C NMR
d
(126 MHz, CDCl3)
d
197.5, 166.6, 138.7, 138.7, 128.2, 128.2, 39.9. 31.5,
8.07 (d, J¼8.4 Hz, 1H), 7.75 (dt, J¼8.3, 4.8 Hz, 2H), 7.55 (t, J¼7.5 Hz,
26.6, 20.0, 13.6. HRMS (EI): calcd for C13H17O2N1 219.1259, found
219.1257.
1H), 7.41e7.23 (m, 6H), 4.67 (d, J¼5.7 Hz, 2H). 13C NMR (126 MHz,
CDCl3)
d 165.6, 148.9, 148.1, 137.8, 135.8, 131.2, 129.0, 128.7, 128.7,
127.8, 127.6, 127.4, 126.8, 126.8, 44.1. HRMS (EI): calcd for
4.4.2.11. N-Butyl-4-cyanobenzamide (8k).67 Colourless solid. 1H
C17H14O1N2 262.1106, found 262.1104.
NMR (500 MHz, CDCl3)
d
7.85 (d, J¼8.4 Hz, 2H), 7.67 (d, J¼8.5 Hz,
2H), 6.65 (s, 1H), 3.41 (dd, J¼13.0, 7.2 Hz, 2H), 1.57 (dd, J¼14.6,
4.4.2.20. Methyl 2-(4-aminobenzamido)acetate (8t).72 Orange
7.2 Hz, 2H), 1.37 (dt, J¼15.0, 7.4 Hz, 2H), 0.91 (t, J¼7.4 Hz, 3H). 13
C
solid. 1H NMR (500 MHz, CDCl3)
d
7.64 (d, J¼8.6 Hz, 2H), 6.65 (d,
NMR (126 MHz, CDCl3)
d
165.7, 138.7, 132.2, 127.6, 118.0, 114.7, 40.0,
J¼8.6 Hz, 2H), 6.52 (s, 1H), 4.21 (d, J¼5.1 Hz, 2H), 3.78 (s, 3H). 13
C
31.4, 20.0, 13.6. HRMS (EI): calcd for C12H14O1N2 202.1106, found
202.1099.
NMR (126 MHz, CDCl3) d 170.8, 167.2, 149.9, 123.2, 114.1, 52.3, 41.6.
HRMS (EI): calcd for C10H12O3N2 208.0848, found 208.0845.
4.4.2.12. N-Butylthiophene-2-carboxamide (8l).68 Pale yellow
4.5. Recycling of palladacycle 1: general procedure
solid. 1H NMR (500 MHz, CDCl3)
d
7.53 (dd, J¼3.7, 1.1 Hz, 1H), 7.41
(dd, J¼5.0, 1.1 Hz, 1H), 7.01 (dd, J¼5.0, 3.7 Hz, 1H), 6.52 (s, 1H),
3.40e3.34 (m, 2H), 1.55e1.51 (m, 2H), 1.37 (dd, J¼15.1, 7.5 Hz, 2H),
Recycling experiments were carried out on a 1.36 mmol scale for
the carbonylative SuzukieMiyaura reaction and 1.50 mmol scale for
both alkoxy- and aminocarbonylation reactions using the general
procedures described above. The crude product was first diluted
with THF/H2O¼8:2 (1.0 mL) and loaded into an F-SPE fluorous silica
column (column diameter: 2.20 cm; amount of fluorous silica re-
quired: 10% of crude product by weight). The crude product was
then eluted using THF/H2O¼8:2 (30 mL) as eluent and the palla-
dacycle 1 (see Table 7 for amount of recovered 1) was subsequently
eluted with THF (20 mL). The fluorous silica was regenerated and
reused (five times) after washing with acetone (10 mL). For ele-
mental analysis of Pd leaching, a small volume of a solution of the
crude product was concentrated and analysed by ICP-OES. To
0.89 (d, J¼7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 162.0, 139.3,
129.5, 127.7, 127.4, 39.7, 31.6, 20.0, 13.6. HRMS (EI): calcd for
C9H13O1N312S1 183.0718, found 183.0716.
4.4.2.13. N-Butylnicotinamide (8m).69 Yellow oil. 1H NMR
(500 MHz, CDCl3)
d
8.94 (s, 1H), 8.62 (d, J¼3.5 Hz, 1H), 8.08 (d,
J¼7.9 Hz, 1H), 7.31 (dd, J¼7.8, 4.9 Hz, 1H), 6.91 (s, 1H), 3.40 (d,
J¼6.7 Hz, 2H), 1.57 (dd, J¼14.8, 7.1 Hz, 2H), 1.37e1.32 (m, 2H), 0.89
(t, J¼7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 165.6, 151.7, 147.8,
135.1, 130.5, 123.4, 39.8, 31.5, 20.0, 13.6. HRMS (EI): calcd for
C
10H14O1N2 178.1106, found 178.1098.

W.J. Ang et al. / Tetrahedron 70 (2014) 8545e8558
8557
determine the amount of product formed after each recycling ex-
periment, the solution of crude product was concentrated, diluted
with EtOAc (20 mL) and washed with water (10 mL). The organic
layer was dried over anhydrous MgSO4, filtered, concentrated and
purified.
(15.0 mL) was added hydroxylamine hydrochloride (575 mg,
8.28 mmol). The mixture was refluxed with a DeaneStark apparatus
for 16 h and then concentrated to dryness. Citric acid of 5% was
added and the resulting mixture was extracted with EtOAc. The
organic phase was washed consecutively with 5% citric acid, 5%
NaHCO3, H2O and brine, dried over anhydrous MgSO4, filtered and
concentrated. The desired product 13 (1.11 g, 87%) was obtained as
a white solid after purification by column chromatography. 1H NMR
4.5.1. Sample preparation for metal analysis. Sample was digested
with HNO3/HCl and topped-up to 10 mL with H2O.
(500 MHz, acetone-d6)
J¼8.8 Hz, 2H), 7.04 (d, J¼8.8 Hz, 4H), 6.93 (d, J¼8.8 Hz, 4H),
d
10.09 (s, 1H), 7.39 (d, J¼8.8 Hz, 2H), 7.33 (d,
4.6. Synthesis of palladacycle 116
4.6.1. Bis(4-(allyloxy)phenyl)methanone (10). To a solution of 4,40-
dihydroxybenzophenone (5.0 g, 23.3 mmol) in DMF (50 mL) were
added KOH (6.5 g, 116.7 mmol) and allyl bromide (5.1 mL,
58.4 mmol). The reaction mixture was stirred at room temperature
for 24 h, quenched with H2O (10 mL) and consecutively washed
with EtOAc (100 mLꢁ3). The organic layers were combined, washed
with brine (50 mLꢁ3), dried over anhydrous MgSO4, filtered and
concentrated. The desired product 10 (6.77 g, 99%) was obtained as
a white crystal after purification by column chromatography. 1H
4.23e4.21 (m), 4.19e4.16 (m), 2.57e2.42 (m, 4H), 2.19e2.11 (m, 4H).
13C NMR (125 MHz, acetone-d6)
160.3, 159.7, 155.2, 132.8, 131.8,
131.3, 129.8, 127.1, 115.0, 114.7, 67.1, 67.1, 66.5, 28.5e28.1 (m), 21.3.
HRMS (ESI): calcd for C35H21O3F34N 1149.0979; found 1150.1051
(Mþþ1).
d
4.6.5. Palladacycle (1). To
a suspension of oxime 13 (2.3 g,
2.0 mmol) in acetone (26 mL) were added anhydrous sodium acetate
(0.165 g, 2.0 mmol) and Li2PdCl4 (0.524 g, 2.0 mmol). The mixture
was stirred under reflux for 1 day. After which, water (10 mL) was
added and the precipitate, which formed was filtered off and dried
under reduced pressure over P2O5 to give the desired product 1
NMR (500 MHz, CDCl3)
d
7.77 (d, J¼8.9 Hz, 8H), 6.96 (d, J¼8.9 Hz,
8H), 6.06 (m, 2H), 5.44 (dd, J¼10.8, 1.3 Hz, 2H), 5.32 (dd, J¼10.7,
1.3 Hz, 2H), 4.61 (d, J¼5.1 Hz, 4H). 13C NMR (125 MHz, CDCl3)
d
194.3, 161.8, 132.6, 132.1, 130.8, 118.1, 114.1, 68.8. HRMS (EI): calcd
(2.33 g, 90%) as a brown solid. 1H NMR (500 MHz, acetone-d6)
d 10.9
for C19H18O3 294.1256; found 294.1259.
(s,1H), 7.49e7.49 (m), 7.42 (d, J¼8.85 Hz, 4H), 7.12 (d, J¼8.85 Hz, 4H),
6.66 (d, J¼8.15 Hz,1H), 6.49e6.47 (m), 4.28e4.26 (m), 4.10e4.08 (m),
2.57e2.41 (m, 4H), 2.19e2.07 (m, 4H). 13C NMR (125 MHz, acetone-
4.6.2. Bis(4-(perfluorooctyl-2-iodopropoxy)phenyl)methanone
(11). Compound 10 (0.59 g, 2.0 mmol) was dissolved in di-
chloroethane (1.2 mL) and C8F17I (1.3 mL, 4.8 mmol) and AIBN
(65.6 mg, 0.4 mmol) were added. The reaction flask was equipped
with a condenser, and the apparatus was purged and filled with Ar,
stirred at 85 ꢀC for 18 h and then concentrated to dryness. The
desired product 11 (2.06 g, 74%) was obtained as a pale yellow solid
after purification by column chromatography. 1H NMR (500 MHz,
d6) d 163.7, 160.5, 158.0, 155.0, 137.4, 131.4, 128.0, 123.3, 121.8, 119.9,
115.1, 110.0, 67.3, 66.8, 55.4, 28.6e28.0 (m), 21.2. IR (KBr): v¼3429,
2961, 2762, 1578, 1246, 1206, 1025 cmꢂ1. MALDI HR: calcd for
C
35H19O3F34NPd 1288.9624; found 1287.9540 (Mþꢂ1). Elemental
analysis: calcd C, 32.58; H, 1.56; N, 1.09; Cl, 2.75; F, 50.06. Found: C,
32.70; H, 1.90; N, 1.56; Cl, 2.70; F, 50.05.
CDCl3)
(m), 4.39e4.36 (m), 4.30e4.26 (m), 3.23e3.12 (m, 2H), 2.91e2.79
(m, 2H). 13C NMR (125 MHz, CDCl3)
194.1, 160.8, 132.3, 131.7, 114.3,
d
7.80 (d, J¼8.9 Hz, 4H), 6.98 (d, J¼8.9 Hz, 4H), 4.59e4.54
Acknowledgements
d
This research is supported by grants from the Ministry of Edu-
cationdSingapore (MoE Tier 2: R-143-478-112 to Y.L.) and National
Science Council Taiwan (NSC 101-2113-M-002-007, NSC 102-2113-
M-002-004-MY3 to L.-C.L.).
72.7, 37.9 (t, J¼21.0 Hz), 12.1. HRMS (ESI): calcd for C35H18O3F34 2
I
1385.8802; found 1408.8695 (MþþNa).
4.6.3. Bis(4-(perfluorooctylpropoxy)phenyl)methanone
(12). Compound 11 (20.8 g, 15.0 mmol) was dissolved in di-
chloroethane (80 mL) and Bu3SnH (10.5 mL, 39.0 mmol) and AIBN
(0.49 mg, 3.0 mmol) were added. The reaction flask was equipped
with a condenser, and the apparatus was purged and filled with Ar.
The reaction mixture was stirred at 85 ꢀC for 18 h and then con-
centrated to dryness. The desired product 12 (15.19 g, 89%) was
obtained as a white solid after purification by column chromatog-
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.09.065.
References and notes
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13C NMR (125 MHz, 50 ꢀC, CDCl3)
194.1, 161.9, 132.2, 131.4, 114.1,
d
7.79 (d, J¼8.8 Hz, 8H), 6.96 (d,
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