Aminocarbonylations employing Mo(CO)6 and a bridged two-vial system: Allowing the use of nitro group substituted aryl iodides and aryl bromides

Article abstract of DOI:10.1021/jo302322w

A bridged two-vial system aminocarbonylation protocol where Mo(CO) ₆ functions as an external in situ solid source of CO has been developed. For the first time both nitro group containing aryl/heteroaryl iodides and bromides gave good to excellent yields in the Mo(CO) ₆-mediated and palladium(0)-catalyzed conversion to benzamides, while the identical one-vessel protocol afforded extensive reduction of the nitro functionality. The above-mentioned bridged two-compartment protocol furnished good results with both primary amines and secondary amines and sluggish aniline nucleophiles at 65-85 C reaction temperatures.

Full text of DOI:10.1021/jo302322w

Note
pubs.acs.org/joc
Aminocarbonylations Employing Mo(CO)6 and a Bridged Two-Vial
System: Allowing the Use of Nitro Group Substituted Aryl Iodides
and Aryl Bromides
Patrik Nordeman, Luke R. Odell, and Mats Larhed*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, P.O. Box
574, SE-751 23 Uppsala, Sweden
S
* Supporting Information
ABSTRACT: A bridged two-vial system aminocarbonylation protocol where Mo(CO)6 functions as an external in situ solid
source of CO has been developed. For the first time both nitro group containing aryl/heteroaryl iodides and bromides gave good
to excellent yields in the Mo(CO)6-mediated and palladium(0)-catalyzed conversion to benzamides, while the identical one-
vessel protocol afforded extensive reduction of the nitro functionality. The above-mentioned bridged two-compartment protocol
furnished good results with both primary amines and secondary amines and sluggish aniline nucleophiles at 65−85 °C reaction
temperatures.
ncorporation of the carbonyl moiety into organic molecules
using a three-component matrix with carbon monoxide
DBU to chemically liberate free CO by a ligand exchange
process7−10 or by elevating the reaction temperature without
the presence of activating additives.11 By including Mo(CO)6 in
the reaction system we have been able to carbonylate a wide
range of aryl and vinyl electrophiles, although the use of a nitro-
containing aromatic substrate has not been realized due to
concomitant Mo-mediated reduction to the corresponding
aniline group.12,13 The Ar-NO2 group is an import functionality
and a versatile synthetic handle, and we were therefore
interested in developing a nitro group compatible Mo(CO)6
carbonylation method.
Skrydstrup and co-workers have recently utilized a two-
chamber system for the Pd-activated release of CO from 9-
methyl-fluorene-9-carbonyl chloride and F−-mediated CO
liberation from methyldiphenylsilacarboxylic acid with excellent
results.14−16 In these protocols CO is released in one
compartment while the carbonylative reaction occurs in the
other vial after free diffusion of the gas. Using a two-
compartment reaction setup, the synthesis of nitro-containing
products would be possible with Mo(CO)6 as solid source of
CO. Furthermore, the workup would also be facilitated due to
the absence of complex molybdenum-containing species
formed during the reaction.
I
(CO), an organic halide, and a nucleophilic component is a
simple and diverse approach to the formation of benzoic and
cinnamyl acid derivatives, e.g., amides, esters, ketones, and
anhydrides.1−3 The most versatile method for this class of
reactions is the palladium(0)-catalyzed carbonylation reaction
employing aryl or vinyl halides (or halide surrogate), initially
disclosed by Heck in the 1970s.4 The catalytic process follows a
pathway starting with oxidative addition of palladium(0) to the
organohalide and coordination of CO to the metal center in the
organopalladium complex followed by migratory 1,1-insertion
to form an acylpalladium species, and subsequent nucleophilic
attack liberates the carbonyl-containing product and the
regenerated Pd(0) catalyst.2,5
As a result of its ability to bind to hemoglobin and inhibit
oxygen transport from the lungs, CO is highly poisonous. In
addition, the gas is odorless, invisible, and flammable.
Furthermore, the use of highly specialized equipment capable
of withstanding elevated pressure has often been necessary to
enable safe handling of CO in a standard laboratory
environment. Accordingly the development of alternative and
safer sources of CO for small scale synthesis, for example, solid
reagents that can release CO in a controlled manner, has gained
considerable interest over the past decade. In our group, we
have extensively investigated molybdenum hexacarbonyl as a
solid substitute for gaseous CO.6 The in situ CO-releasing
ability of MoCO6 has been previously demonstrated in a range
of palladium(0)-catalyzed one-pot carbonylative reactions using
Herein, we report a series of efficient palladium(0)-catalyzed
aminocarbonylations using Mo(CO)6 and a bridged two-vessel
Received: October 25, 2012
Published: December 3, 2012
© 2012 American Chemical Society
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Note
system, including examples of aryl iodides and bromides
carrying nitro group functionalities.
To evaluate the release of carbon monoxide from solid
Mo(CO)6, a model reaction was set up using the bridged two-
vial system depicted in Figure 1. Etherous solvents have been
Table 1. Optimization of Reaction Conditions for the
Aminocarbonylation of 4-iodoanisole with Mo(CO)6 and
DBU in the CO-Producing Vial (C1)
a
n
time (h) Pd(PPh3)4 (mol %) Mo(CO)6 (equiv) yield (%)
1
15
15
5
5
5
3
5
5
5
3
1
5
1
94
95
61
88
52
69
75
2
3
0.5
0.5
0.3
0.3
0.5
1
4
15
5
5
6
5
7
15
15
15
Figure 1. Schematic representation of the two-compartment vessel
used; C1 is the CO-producing chamber and C2 is the CO-accepting
chamber. X = I or Br.
9
0.5
14
b
10
0.5
92
a
Isolated yield, >95% purity (GC−MS and 1H NMR). Reaction
conditions: One of the H-shaped vial chambers (C1) was loaded with
Mo(CO)6. The other chamber (C2) was loaded with 4-iodoanisole
(0.5 mmol) and Pd(PPh3)4. 1,4-Dioxane (6 mL, 3 mL in each
chamber) was added to the two chambers, and to C2 were added Et3N
(1 mmol) and n-butylamine (1 mmol). After capping, DBU (0.75
mmol) was added to C1, and the two chambers were heated at 65 °C
proven to be appropriate solvents for carbonylation reactions,
and 1,4-dioxane (bp 101 °C) was chosen as solvent in both
chambers, due to its relatively high boiling point.17 This may be
important since the two compartments are interconnected and
transport of solvents may cause uneven distribution of solvent
and ultimately alter the reaction properties. CO-releasing vessel
C1 was charged with Mo(CO)6, and the reaction vial C2 was
charged with 1 equiv of 4-iodoanisole using 2 equiv of n-
butylamine as the nucleophile and 2 equiv of Et3N as the base
(Figure 1). The Pd/triphenylphosphine catalytic system has
previously served as a general catalyst for aminocarbonylations
of aryl iodides, and tetrakis(triphenylphosphine)palladium(0)
was selected for this reason.18,19 Next, both vials were sealed,
DBU was added through the septa to C1, and both vials were
placed into a heating block. Gratifyingly full conversion of the
aryl iodide was observed after 15 h of heating at 65 °C using 0.5
equiv of Mo(CO)6 and 5% Pd(PPh3)4, furnishing an excellent
95% isolated yield of aryl amide 1 (Table 1, entry 2). The
addition of 1 equiv of Mo(CO)6 gave similar results (94%), but
when 0.3 equiv of Mo(CO)6 was used, the yield decreased
slightly to 88%. A reduction in reaction time from 15 to 5 h
gave only 52% of 1. Because a shorter reaction time or
decreased catalyst loading led to incomplete conversion, the
conditions for entry 2 were chosen for further evaluation. A
reaction on a 2 mmol scale was also performed, giving 92%
yield (Table 1, entry 10).20
b
for 5−15 h. The reaction was performed on a 2.0 mmol scale.
Table 2. Bridged Two-Vial Aminocarbonylation of Aryl
Iodides and Nitro-Substituted Aryl Iodides; All Yields Are
Isolated Yields
Next we sought to examine the scope and limitations of the
new two-chamber method using various aryl iodides and amine
nucleophiles. As can be seen from Table 2, primary amines
performed well, and the secondary benzamide products were
isolated in good to excellent yields (81−97%, 1−11); however,
when secondary amines and aniline were used, low conversions
were observed. Inspired by the work by Odell et al. the
nucleophilic catalyst 4-dimethylaminopyridine (DMAP) was
added to the reaction mixture.21 This resulted in full
consumption of the starting material, and good isolated yields
of the desired products were observed (69−89%, 12−20),
although in the case of aniline the temperature had to be
increased to 85 °C. Notably, aryl iodides containing electron-
donating or electron-withdrawing substituents were found to be
suitable substrates. In addition, full chemoselectivity was
observed in the reaction of 1-bromo-4-iodobenzene, and no
traces of product arising from oxidative addition to the Ar−Br
a
b
All reagents were placed in a single vial. The reaction was performed
c
d
on a 2 mmol scale. 85 °C. 1 mmol of DMAP was added to C2.
bond were detected. Finally, a one-pot, one-vessel reaction was
performed that resulted in only modest conversion and low
isolated yield (20% of 1). This result implies that the two-
compartment reaction is a much more efficient process, and the
presence of Mo(CO)6 may in fact impede the catalytic
carbonylation reaction at these moderate temperatures.22
As mentioned above, the reductive properties of Mo(CO)6
has precluded the use of nitro group containing substrates in
Mo(CO)6-mediated aminocarbonylations.12,13 For example, a
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Note
one-pot reaction using Mo(CO)6, 1-iodo-4-nitrobenzene, and
n-butylamine at 65 °C resulted in the formation of a complex
mixture of aniline derived side products, yielding only 12% of
the desired nitro containing benzamide 7. Using the two-
chamber methodology, the reactions of mononitroaryl iodides
instead proceeded smoothly for all isomers with isolated yields
ranging from 71% to 92% (7−9). The use of the less reactive
aniline nucleophiles, furnished good yields of the amino-
carbonylations products when DMAP was used (15−17).
Importantly, no reduced products were detected in the crude
reaction mixture from any example in Table 2 as observed by
°C reaction temperature, only trace amounts of aniline derived
byproducts from concomitant reduction of aromatic nitro
moieties were detected. Unfortunately, low yields were
obtained with 2-bromobiphenyl and sluggish 2-bromopyridine
due to low conversion and competitive dehalogenation
(according to GC−MS), respectively.
Conclusions. A number of CO gas-free two-chamber
methods have been developed to synthesize benzamides
containing EWG/EDG or heterocycles via palladium(0)-
catalyzed aminocarbonylation reactions of aryl/heteroaryl
iodides and bromides using Mo(CO)6 as a solid CO releasing
solid reagent. CO gas was released in one of the bridged
reaction vials by chemical liberation with DBU. After release
the gas was able to diffuse to a second accepting vial where it
could participate in the aminocarbonylation reaction. Impor-
tantly, nitro group containing benzamide products were
synthesized in good to excellent yields with only negligible
formation of aniline byproducts arising from nitro group
reduction.
1
GC−MS, LC−MS and H NMR.
The preparative scope of the two-vial carbonylation method
was further expanded to include aryl bromides (Table 3), an
Table 3. Bridged Two-Vial Aminocarbonylation of Aryl
Bromides and Nitro-Substituted Aryl Bromides; All Yields
Are Isolated Yields
EXPERIMENTAL SECTION
■
General Information. Palladium catalysts were purchased from
Sigma-Aldrich. Analytical thin-layer chromatography was performed
on silica gel 60 F-254 plates and visualized with UV light. Flash
column chromatography was performed on silica gel 60 (40−63 μm).
1H and 13C NMR spectra were recorded at 400 and 101 MHz,
respectively, using MeOD, DMSO-d6 or CDCl3 as a solvent. Chemical
1
shifts for H and 13C are referenced via the residual solvent signal.
Caution! The closed-vessel carbonylation reactions described in this paper
should not be repeated on a larger scale or at higher temperatures than
reported as this could result in an explosion unless an appropriate pressure
relief device is used.
General Procedure for the Aminocarbonylation Using Aryl
Iodies Yielding 1−20. Chamber two (C2) was loaded with aryl
iodide (0.5 mmol), Pd(PPh3)4 (29 mg, 5 mol %), Et3N (139 μL, 1
mmol), and the corresponding nucleophilic amine (1 mmol). For
carbonylations using aryl iodides with secondary amines or aniline,
DMAP (61 mg, 0.5 mmol) was added to C2. To chamber one (C1)
was added Mo(CO)6 (66 mg, 0.25 mmol), and thereafter 1,4-dioxane
(3 + 3 mL) was added to C1 and C2. The two chambers were capped
with a gastight cap, and DBU (112 μL, 0.75 mmol) was added to C1.
The sealed double vial was heated in a heat block at 65 °C (85 °C for
nucleophilic anilines) for 15 h with vigorous stirring.
a
b
All reagents were placed in the same chamber. 5 mol % of
c
d
Pd(PPh3)4 was used. Without nitrogen flush prior to heating.
mmol of DMAP was added to C2.
1
General Procedure for the Aminocarbonylation Using Aryl
Bromides Yielding 21−35. Chamber two (C2) was loaded with aryl
bromide (0.5 mmol), Pd(dppf)Cl2 (18 mg, 5 mol %), Et3N (139 μL, 1
mmol), and the corresponding nucleophilic amine (1 mmol). For
carbonylations using aryl bromides with aniline, DMAP (61 mg, 0.5
mmol) was added to C2. To chamber one (C1) was added Mo(CO)6
(66 mg, 0.25 mmol), and thereafter 1,4-dioxane (3 + 3 mL) was added
to C1 and C2. The two chambers were capped with a gastight cap and
flushed with nitrogen for 2 min after which DBU (112 μL, 0.75 mmol)
was added to C1. The sealed double vial was heated in a heat block at
85 °C for 15 h with vigorous stirring.
improvement in terms of both costs and commercial
availability. Aryl bromides are less prone to undergo oxidative
addition than iodides, thus demanding higher temperatures and
a more active catalytic system. When 4-bromoanisole and n-
hexylamine were reacted with Pd(PPh3)4 at a slightly elevated
temperature (85 °C), the corresponding carbonylated product
was isolated in 55% yield (21). However, upon changing the
precatalyst to [1,1′-bis(diphenylphosphino)ferrocene]-
dichloropalladium (Pd(dppf)Cl2), full conversion was observed
and the corresponding product was isolated in 72% yield. Small
amounts of N,N′-dihexylurea originating from the nucleophile
were detected in the reaction mixture, suggesting that
competition from a Pd(II)-catalyzed carbonylation had
occurred.23 Flushing the vial with nitrogen prior to heating
solved this problem and yielded product 21 in an improved
88% yield. The reaction was again found to be robust and
highly chemoselective as aryl bromides equipped with a set of
different functional groups as well as primary, secondary, and
aniline nucleophiles all performed well. Notably, formyl-
substituted compound 30 underwent a clean reaction without
reduction to the benzyl alcohol. Rewardingly and despite the 85
Workup Procedure for 1−35. After careful evacuation of excess
CO, the crude mixture from C2 was evaporated to dryness. The
residue was dissolved in small amount of DCM and purified by
column chromatography, eluted with n-pentane/EtOAc (7:1−2:1) or
CHCl3/MeOH (20:1) to yield products 1−35. (In the case of aniline
and 4-nitroaniline, the crude mixture was evaporated, taken up in 20
mL of DCM, washed with 3 × 10 mL 3 M HCl, and evaporated prior
to purification).
N-Butyl-4-methoxybenzamide (1).24 Brown solid (98 mg,
1
95%); H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.8 Hz, 2H),
6.89 (d, J = 8.8 Hz, 2H), 6.17 (brs, 1H), 3.83 (s, 3H), 3.52−3.33 (m,
2H), 1.64−1.48 (m, 2H), 1.45−1.32 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 167.1, 162.0, 128.6, 127.1, 113.7, 55.4,
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Note
39.8, 31.8, 20.1, 13.8; MS (ESI) calcd for C12H17NO2 [M + H]+ m/z
208, found m/z 208.
(m, 2H), 1.78−1.52 (m, 4H), 1.52−1.36 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 162.9, 138.0, 127.9, 126.4, 126.2, 51.6, 33.3, 23.9;
HRMS calcd for C10H13NOS [M + H]+ m/z 196.0796, found m/z
196.0798.
N-Butyl-3-methoxybenzamide (2). Brown oil (94 mg, 91%); 1H
NMR (400 MHz, CD3OD) δ 7.40−7.30 (m, 3H), 7.09−7.03 (m, 1H),
3.82 (s, 3H), 3.36 (t, J = 7.2 Hz, 2H), 1.63−1.54 (m, 2H), 1.47−1.33
(m, 2H), 0.96 (t, J = 7.4 Hz, 1H); 13C NMR (101 MHz, CD3OD) δ
167.1, 162.0, 128.6, 127.1, 113.7, 55.4, 39.8, 31.8, 20.1, 13.8; HRMS
(ESI) calcd for C12H17NO2 [M + H]+ m/z 208.1338, found m/z
208.1340.
4-Methoxy-N-phenylbenzamide (12).27 White crystals (99 mg,
87%); mp 169−171 °C, lit.25 Mp 171 °C); H NMR (400 MHz,
1
CDCl3) δ 7.85 (d, J = 8.9 Hz, 2H), 7.78 (brs, 1H), 7.63 (d, J = 8.7 Hz,
2H), 7.40−7.33 (m, 2H), 7.31−7.25 (m, 1H), 7.14 (t, J = 7.4 Hz, 1H),
6.97 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
165.4, 162.7, 138.2, 129.2, 129.0, 127.3, 124.6, 120.4, 114.2, 55.6 ; MS
(ESI) calcd for C14H13NO2 [M + H]+ m/z 228, found m/z 228.
N-(p-Methoxybenzoyl)pyrrolidine (13).28 Brown solid (79 mg,
N-Butyl-2-methoxybenzamide (3). Brown oil (95 mg, 92%); 1H
NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 7.8, 1.8 Hz, 1H), 7.83 (brs,
1H), 7.42 − 7.34 (m, 1H), 7.03 (td, J = 7.6, 1.0 Hz, 1H), 6.93 (d, J =
9.1 Hz, 1H), 3.91 (s, 3H), 3.51−3.38 (m, 2H), 1.65−1.50 (m, 2H),
1.47−1.27 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 165.2, 157.4, 132.5, 132.2, 121.8, 121.3, 111.3, 56.0, 39.5,
31.7, 20.3, 13.8; HRMS calcd for C12H17NO2 [M + H]+ m/z 208.1338,
found m/z 208.1336.
1
77%); H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 8.9 Hz, 2H),
6.95 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H), 3.49−3.39 (m, 4H), 1.94−1.66
(m, 4H); 13C NMR (101 MHz, CDCl3) δ 167.9, 160.3, 129.2, 129.1,
113.3, 55.2, 49.1, 46.0, 26.1, 23.9; MS (ESI) calcd for C12H15NO2 [M
+ H]+ m/z 206, found m/z 206.
(4-Nitrophenyl)(pyrrolidin-1-yl)methanone (14).28 Beige solid
N-Butyl-[1,1′-biphenyl]-4-carboxamide (4). Light brown solid
1
1
(123 mg, 97%); H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.6 Hz,
(95 mg, 86%); H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz,
2H), 7.63 (d, J = 8.6 Hz, 2H), 7.61−7.57 (m, 2H), 7.49−7.42 (m,
2H), 7.41−7.34 (m, 1H), 6.33 (brs, 1H), 3.56−3.38 (m, 2H), 1.69−
1.53 (m, 2H), 1.52−1.35 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 167.3, 144.2, 140.2, 133.6, 129.0, 128.0, 127.5,
127.3, 40.0, 31.9, 20.3, 13.9; HRMS calcd for C17H19NO [M + H]+ m/
z 254.1545, found m/z 254.1552.
2H), 7.67 (d, J = 8.8 Hz, 2H), 3.66 (t, J = 6.9 Hz, 2H), 3.37 (t, J = 6.6
Hz, 2H), 2.05−1.86 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 167.5,
148.5, 143.3, 128.3, 123.8, 49.6, 46.5, 26.5, 24.5; MS (ESI) calcd for
C11H12N2O3 [M + H]+ m/z 221, found m/z 221.
3-Nitro-N-phenylbenzamide (15).27 Yellow solid (91 mg, 75%);
1H NMR (400 MHz, DMSO-d6) δ 10.58 (brs, 1H), 8.79 (s, 1H),
8.51−8.36 (m, 2H), 7.84 (t, J = 8.0 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H),
7.38 (t, J = 7.9 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H); 13C NMR (101
MHz, DMSO-d6) δ 163.3, 147.7, 138.7, 136.3, 134.2, 130.2, 128.7,
126.1, 124.1, 122.4, 120.6; MS (ESI) calcd for C13H10N2O3 [M + H]+
m/z 243, found m/z 243.
N-Butyl-2-methylbenzamide (5).25 Brown oil (79 mg, 83%); 1H
NMR (400 MHz, DMSO-d6) δ 8.19 (brs, 1H), 7.33−7.26 (m, 2H),
7.24−7.17 (m, 2H), 3.27−3.17 (m, 2H), 2.32 (s, 3H), 1.55−1.43 (m,
2H), 1.40−1.28 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (101
MHz, DMSO-d6) δ 169.0, 137.6, 134.9, 130.3, 129.0, 126.9, 125.4,
38.5, 31.2, 19.7, 19.3, 13.7; MS (ESI) calcd for C12H17NO [M + H]+
m/z 192, found m/z 192.
3-Nitro-N-(4-nitrophenyl)benzamide (16). Yellow solid (102
mg, 71%); 1H NMR (400 MHz, DMSO-d6) δ 11.15 (brs, 1H), 8.79 (t,
J = 2.0 Hz, 1H), 8.47−8.38 (m, 2H), 8.26 (d, J = 9.2 Hz, 2H), 8.05 (d,
J = 9.2 Hz, 2H), 7.84 (t, J = 8.0 Hz, 1H); 13C NMR (101 MHz,
DMSO-d6) δ 164.2, 147.8, 145.0, 142.9, 135.6, 134.5, 130.4, 126.7,
124.9, 122.7, 120.3; HRMS (ESI) calcd for C13H9N3O5 [M + H]+ m/z
288.0620, found m/z 288.0627.
N-Butyl-4-cyanobenzamide (6).24 Off-white solid (82 mg, 81%);
1H NMR (400 MHz, CD3OD) δ 7.94 (d, J = 8.7 Hz, 2H), 7.82 (d, J =
8.7 Hz, 2H), 3.39 (t, J = 7.2 Hz, 2H), 1.66−1.53 (m, 2H), 1.50−1.33
(m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CD3OD) δ
168.3, 140.1, 133.5, 129.1, 119.1, 115.9, 40.9, 32.5, 21.2, 14.1; MS
(ESI) calcd for C12H14N2O [M + H]+ m/z 203, found m/z 203.
N-Butyl-4-nitrobenzamide (7).26 Brown crystals (102 mg, 92%);
4-Nitro-N-(4-nitrophenyl)benzamide (17).29 Yellow solid (111
1
mg, 77%); H NMR (400 MHz, DMSO-d6) δ 11.10 (brs, 1H), 8.40
mp 99−101 °C, lit.27 100−101 °C; H NMR (400 MHz, CDCl3) δ
1
(d, J = 9.0 Hz, 2H), 8.30 (d, J = 9.4 Hz, 2H), 8.21 (d, J = 9.0 Hz, 2H),
8.07 (d, J = 9.4 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 164.7,
149.5, 144.9, 142.9, 139.8, 129.5, 124.9, 123.6, 120.1; LC−MS (ESI)
calcd for C13H9N3O5 [M + H]+ m/z 288, found m/z 288.
8.25 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 6.38 (brs, 1H), 3.46
(td, J = 7.2, 5.7 Hz, 2H), 1.66−1.54 (m, 2H), 1.48−1.28 (m, 2H), 0.95
(t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.6, 149.6,
140.6, 128.2, 123.9, 40.3, 31.7, 20.3, 13.9; MS (ESI) calcd for
C11H14N2O3 [M + H]+ m/z 223, found m/z 223.
(4-(4-Phenylpiperidine-1-carbonyl)benzonitrile (18). White
1
solid (129 mg, 89%); H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J
1
N-Butyl-3-nitrobenzamide (8). Brown solid (92 mg, 83%); H
= 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.33−7.25 (m, 4H), 7.22−
7.16 (m, 1H), 4.70−4.58 (m, 1H), 3.57−3.46 (m, 1H), 3.25−3.10 (m,
1H), 2.94−2.75 (m, 2H), 1.90−1.78 (m, 1H), 1.75−1.55 (m, 3H); 13C
NMR (101 MHz, DMSO-d6) δ 167.3, 145.5, 141.0, 132.6, 128.4,
127.6, 126.8, 126.2, 118.4, 111.9, 47.5, 42.0, 41.7, 33.0, 32.6; HRMS
(ESI) calcd for C19H18N2O [M + H]+ m/z 291.1497, found m/z
291.1498.
NMR (400 MHz, DMSO-d6) δ 8.81 (brs, 1H), 8.68−8.65 (m, 1H),
8.38−8.33 (m, 1H), 8.29−8.25 (m, 1H), 7.76 (t, J = 8.0 Hz, 1H),
3.34−3.25 (m, 2H), 1.58−1.47 (m, 2H), 1.40−1.25 (m, 2H), 0.90 (t, J
= 7.3 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 163.9, 147.8, 136.0,
133.6, 130.1, 125.7, 121.9, 39.1, 31.1, 19.7, 13.7; HRMS (ESI) calcd
for C11H14N2O3 [M + H]+ m/z 223.1083, found m/z 223.1082.
N-Butyl-2-nitrobenzamide (9). Light brown solid (87 mg, 78%);
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 1H), 7.66−7.60
(m, 1H), 7.57−7.51 (m, 1H), 7.47 (dd, J = 7.4, 1.5 Hz, 1H), 6.00 (brs,
1H), 3.45−3.37 (m, 2H), 1.64−1.54 (m, 2H), 1.46−1.43 (m, 2H),
0.95 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.6, 146.5,
133.8, 133.3, 130.4, 128.8, 124.6, 40.1, 31.4, 20.2, 13.9; HRMS (ESI)
calcd for C11H14N2O3 [M + H]+ m/z 223.1083, found m/z 223.1081.
N-Cyclopentyl-4-methoxybenzamide (10). Brown solid (101
(4-Bromophenyl)(4-methylpiperidin-1-yl)methanone (19).
1
Brown solid (97 mg, 69%); H NMR (400 MHz, CDCl3) δ 7.53 (d,
J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 4.64 (brs, 1H), 3.66 (brs,
1H), 2.97 (brs, 1H), 2.76 (brs, 1H), 1.85−1.54 (m, 3H), 1.30−1.01
(m, 2H), 0.97 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
169.4, 135.5, 131.8, 128.7, 123.8, 48.2, 42.7, 34.8, 33.9, 31.3, 21.8;
HRMS (ESI) calcd for C13H16BrNO [M + H]+ m/z 282.0494, found
m/z 282.0493.
(4-Nitrophenyl)(4-(4-nitrophenyl)piperazin-1-yl)methanone
(20). Yellow solid (132 mg, 74%); 1H NMR (400 MHz, DMSO-d6) δ
8.30 (d, J = 8.9 Hz, 2H), 8.07 (d, J = 9.5 Hz, 2H), 7.74 (d, J = 8.9 Hz,
2H), 7.01 (d, J = 9.5 Hz, 2H), 3.79 (s, 2H), 3.63 (s, 2H), 3.47 (s, 4H);
13C NMR (101 MHz, DMSO-d6) δ 167.3, 154.3, 147.9, 141.9, 137.2,
1
mg, 92%); H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.9 Hz, 1H),
6.88 (d, J = 8.9 Hz, 1H), 6.07 (brs, 1H), 4.46−4.26 (m, 1H), 3.82 (s,
3H), 2.15−1.98 (m, 2H), 1.77−1.57 (m, 4H), 1.52−1.40 (m, 2H); 13C
NMR (101 MHz, CDCl3) δ 166.8, 162.1, 128.7, 127.3, 113.7, 55.5,
51.7, 33.4, 23.9; HRMS calcd for C13H17NO2 [M + H]+ m/z 220.1338,
found m/z 220.1332.
128.4, 125.7, 123.8, 112.8, 46.3, 46.1, 45.7, 41.2; HRMS (ESI) calcd
for C17H16N4O5 [M + H]+ m/z 357.1199, found m/z 357.1196.
N-Hexyl-4-methoxybenzamide (21).14 Light brown solid (104
N-Cyclopentylthiophene-3-carboxamide (11). Off-white crys-
1
tals (85 mg, 87%); mp 141−143 °C; H NMR (400 MHz, CDCl3) δ
1
7.83 (dd, J = 3.0, 1.3 Hz, 1H), 7.37 (dd, J = 5.1, 1.3 Hz, 1H), 7.30 (dd,
J = 5.1, 3.0 Hz, 1H), 6.08 (brs, 1H), 4.45−4.22 (m, 1H), 2.15−1.97
mg, 88%); H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 2H),
6.88 (d, J = 8.8 Hz, 2H), 6.27 (brs, 1H), 3.82 (s, 3H), 3.40 (td, J = 7.3,
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Note
5.7 Hz, 2H), 1.64−1.47 (m, 2H), 1.40−1.24 (m, 6H), 0.87 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.1, 162.1, 128.7, 127.3,
113.7, 55.5, 40.2, 31.6, 29.8, 26.8, 22.7, 14.1.; MS (ESI) calcd for
C14H21NO2 [M + H]+ m/z 236, found m/z 236.
HRMS (ESI) calcd for C13H15NO2 [M + H]+ m/z 218.1181, found m/
z 218.1179.
N-(4-Chlorobenzyl)-4-nitrobenzamide (31). Off-white crystals
(118 mg, 81%); mp 169−171 °C; 1H NMR (400 MHz, DMSO-d6) δ
9.39 (brs, 1H), 8.32 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H),
7.45−7.29 (m, 4H), 4.49 (d, J = 5.9 Hz, 2H); 13C NMR (101 MHz,
DMSO-d6) δ 164.7, 149.1, 139.8, 138.2, 131.5, 129.2, 128.8, 128.3,
123.6, 42.2; HRMS (ESI) calcd for C14H11ClN2O3 [M + H]+ m/z
291.0536, found m/z 291.0534.
1
N-Hexyl-3-nitrobenzamide (22). White solid (98 mg, 78%); H
NMR (400 MHz, CDCl3) δ 8.57 (td, J = 1.9, 0.8 Hz, 1H), 8.31 (ddd, J
= 8.2, 2.3, 1.1 Hz, 1H), 8.15 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H), 7.65−7.57
(m, 1H), 6.66 (brs, 1H), 3.52−3.40 (m, 2H), 1.69−1.55 (m, 2H),
1.43−1.22 (m, 6H), 0.87 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 165.2, 148.2, 136.6, 133.4, 129.9, 126.0, 121.8, 40.6, 31.6,
29.6, 26.8, 22.6, 14.1; HRMS (ESI) calcd for C13H18N2O3 [M + H]+
m/z 251.1396, found m/z 251.1397.
N-((Tetrahydrofuran-2-yl)methyl)picolinamide (32). White
1
solid (42 mg, 41%); H NMR (400 MHz, CDCl3) δ 8.55 (ddd, J =
4.8, 1.7, 0.9 Hz, 1H), 8.33 (brs, 1H), 8.18 (dt, J = 7.8, 1.2 Hz, 1H),
7.83 (td, J = 7.8, 1.7 Hz, 1H), 7.40 (ddd, J = 7.8, 4.8, 1.2 Hz, 1H), 4.09
(qd, J = 7.0, 3.7 Hz, 1H), 3.96−3.87 (m, 1H), 3.83−3.68 (m, 2H),
3.50−3.39 (m, 1H), 2.13−1.96 (m, 1H), 1.95−1.86 (m, 2H), 1.68−
1.58 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 164.6, 150.0, 148.3,
137.4, 126.2, 122.3, 77.9, 68.4, 43.3, 28.9, 26.0; HRMS (ESI) calcd for
C11H14N2O2 [M + H]+ m/z 207.1134, found m/z 207.1130.
1
N-Hexyl-2-nitrobenzamide (23). Brown oil (69 mg, 55%); H
NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.2, 1.3 Hz, 1H), 7.60 (td, J
= 7.5, 1.3 Hz, 1H), 7.53−7.47 (m, 1H), 7.42 (dd, J = 7.5, 1.5 Hz, 1H),
6.25 (brs, 1H), 3.39−3.28 (m, 2H), 1.60−1.50 (m, 2H), 1.38−1.20
(m, 6H), 0.91−0.83 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 166.6,
146.5, 133.7, 133.2, 130.3, 128.8, 124.5, 40.3, 31.5, 29.2, 26.6, 22.6,
14.1; HRMS (ESI) calcd for C13H18N2O3 [M + H]+ m/z 251.1396,
found m/z 251.1398.
N-Benzylfuran-3-carboxamide (33). Brown crystals (79 mg,
79%); mp 117−119 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H),
7.41−7.36 (m, 1H), 7.35−7.23 (m, 5H), 6.64 (s, 1H), 6.59 (brs, 1H),
4.55−4.48 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 162.8, 145.0,
143.8, 138.3, 128.8, 127.9, 127.6, 122.5, 108.5, 43.6; HRMS (ESI)
calcd for C12H11NO2 [M + H]+ m/z 202.0868, found m/z 202.0872.
(4-Chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)-
N-Hexyl-4-nitrobenzamide (24). Off-white crystals (101 mg,
81%); mp 62−64 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.9
Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H), 6.39 (brs, 1H), 3.45 (td, J = 7.3, 5.7
Hz, 2H), 1.68−1.54 (m, 2H), 1.41−1.27 (m, 6H), 0.88 (t, J = 6.9 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 165.6, 149.6, 140.6, 128.2,
123.9, 40.6, 31.6, 29.6, 26.8, 22.7, 14.1; HRMS (ESI) calcd for
C13H18N2O3 [M + H]+ m/z 251.1396, found m/z 251.1395.
N-Hexyl-2-naphthamide (25). Yellow crystals (119 mg, 93%);
1
methanone (34). White solid (136 mg, 74%); H NMR (400 MHz,
CDCl3) δ 7.43−7.36 (m, 4H), 7.22−7.13 (m, 2H), 6.93 (dd, J = 7.7,
1.8 Hz, 1H), 3.94 (s, 2H), 3.60 (s, 2H), 3.17−2.92 (m, 4H); 13C NMR
(101 MHz, CDCl3) δ 169.6, 150.6, 136.1, 134.4, 134.1, 129.0, 128.8,
127.9, 127.7, 125.5, 118.9, 51.8, 51.4, 48.2, 42.6; HRMS (ESI) calcd
for C17H15Cl3N2O [M + H]+ m/z 369.0328, found m/z 369.0329.
(4-Methylpiperidin-1-yl)(4-vinylphenyl)methanone (35). Yel-
low oil (89 mg, 78%); 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.3
Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 6.75−6.65 (m, 1H), 5.77 (dd, J =
17.6, 0.7 Hz, 1H), 5.29 (dd, J = 10.9, 0.7 Hz, 1H), 4.65 (s, 1H), 3.73
(s, 1H), 3.05−2.68 (m, 2H), 1.78−1.54 (m, 3H), 1.27−1.06 (m, 2H),
0.96 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.1, 138.7,
136.2, 135.8, 127.3, 126.2, 115.1, 48.1, 42.6, 34.8, 33.9, 31.3, 21.8;
HRMS (ESI) calcd for C15H19NO [M + H]+ m/z 230.1545, found m/
z 230.1541.
1
mp 96−98 °C; H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.87−
7.79 (m, 4H), 7.55−7.44 (m, 2H), 6.75 (brs, 1H), 3.46 (q, J = 7.2, 6.6
Hz, 2H), 1.67−1.56 (m, 2H), 1.40−1.25 (m, 6H), 0.88 (t, J = 6.6 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 167.7, 134.7, 132.7, 132.2,
128.9, 128.3, 127.7, 127.5, 127.4, 126.6, 123.8, 40.4, 31.6, 29.7, 26.8,
22.6, 14.1; HRMS (ESI) calcd for C17H21NO [M + H]+ m/z 256.1701,
found m/z 256.1706.
4-Cyano-N-hexylbenzamide (26). White solid (102 mg, 89%);
1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.7 Hz, 2H), 7.68 (d, J =
8.7 Hz, 2H), 6.62 (brs, 1H), 3.46−3.35 (m, 2H), 1.57 (q, J = 7.8 Hz,
2H), 1.38−1.22 (m, 6H), 0.89−0.82 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 165.8, 138.9, 132.4, 127.8, 118.1, 114.8, 40.5, 31.5, 29.5,
26.7, 22.6, 14.1; HRMS (ESI) calcd for C14H18N2O [M + H]+ m/z
231.1497, found m/z 231.1493.
ASSOCIATED CONTENT
■
S
* Supporting Information
N-Hexyl-2-methylbenzamide (27). Off-white solid (57 mg,
1H and 13C NMR spectra and chromatograms. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
52%); H NMR (400 MHz, CDCl3) δ 7.33−7.26 (m, 2H), 7.21−
7.14 (m, 2H), 5.82 (brs, 1H), 3.52−3.31 (m, 2H), 2.42 (s, 3H), 1.63−
1.50 (m, 2H), 1.43−1.26 (m, 6H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 170.2, 137.0, 136.0, 131.0, 129.8, 126.7, 125.8,
39.9, 31.6, 29.8, 26.7, 22.7, 19.8, 14.1; HRMS (ESI) calcd for
C14H21NO [M + H]+ m/z 220.1701, found m/z 220.1699.
AUTHOR INFORMATION
Corresponding Author
*Phone: +46-18-4714667. Fax: +46-18-4714474. E-mail: mats.
larhed@orgfarm.uu.se.
■
N-Hexyl-[1,1′-biphenyl]-2-carboxamide (28). White solid (44
1
mg, 32%); H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 7.5, 1.6 Hz,
Notes
1H), 7.47 (td, J = 7.5, 1.6 Hz, 1H), 7.43−7.33 (m, 7H), 5.16 (brs, 1H),
3.20−3.06 (m, 2H), 1.28−1.08 (m, 6H), 1.04−0.94 (m, 2H), 0.85 (t, J
= 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.4, 140.5, 139.5,
136.1, 130.3, 130.1, 129.0, 128.9, 128.8, 127.9, 127.7, 40.0, 31.6, 29.0,
26.5, 22.6, 14.2; HRMS (ESI) calcd for C19H23NO [M + H]+ m/z
282.1858, found m/z 282.1859.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Swedish Research Council and the Knut and
Alice Wallenberg Foundation for financial support.
■
N-Phenylbenzamide (29).30 Yellow crystals (82 mg, 83%); mp
162−164 °C (lit.29 163−164 °C); H NMR (400 MHz, CDCl3) δ
1
REFERENCES
7.88−7.85 (m, 2H), 7.85 (brs, 1H), 7.67−7.63 (m, 2H), 7.58−7.52
(m, 1H), 7.52−7.45 (m, 2H), 7.41−7.34 (m, 2H), 7.19−7.12 (m, 1H);
13C NMR (101 MHz, CDCl3) δ 165.9, 138.1, 135.2, 132.0, 129.2,
128.9, 127.1, 124.7, 120.3; MS (ESI) calcd for C13H11NO [M + H]+
m/z 198, found m/z 198.
■
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