C-N Coupling of Amides with Alcohols Catalyzed by N-Heterocyclic Carbene-Phosphine Iridium Complexes

Article abstract of DOI:10.1021/acs.joc.5b01324

N-Heterocyclic carbene-phosphine iridium complexes (NHC-Ir) were developed/found to be a highly reactive catalyst for N-monoalkylation of amides with alcohols via hydrogen transfer. The reaction produced the desired product in high isolated yields using a wide range of substrates with low catalyst loading and short reaction times.

Full text of DOI:10.1021/acs.joc.5b01324

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Note
C-N coupling of amides with alcohols catalyzed by N-
heterocyclic carbene-phosphine iridium complexes.
Sutthichat Kerdphon, Xu Quan, Vijay Singh Parihar, and Pher G. Andersson
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Oct 2015
Downloaded from http://pubs.acs.org on October 21, 2015
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C-N coupling of amides with alcohols catalyzed by N-heterocyclic
carbene-phosphine iridium complexes.
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Sutthichat Kerdphon,† Xu Quan,† Vijay Singh Parihar,‡ and Pher G. Andersson*,†
†Department of Organic Chemistry, Stockholm University, S-10691, Stockholm, Sweden
‡Department of Chemistry, S. P. Pune University, Pune, India
Phera@organ.su.se
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
O
O
0.5 mol% of NHC,P-Ir catalyst
R1 NH2
R2 OH
R1
N
H
R2
(0.2 e.q.) Cs2CO3, 120 oC, Toluene
43 examples
up to 98% isolated yields
ABSTRACT: N-heterocyclic carbene-phosphine iridium complexes (NHC-Ir) were developed/found to
be a highly reactive catalyst for N-monoalkylation of amides with alcohols via hydrogen transfer. The
reaction produced the desired product in high isolated yields using a wide range of substrates with low
catalyst loading and short reaction times.
N-alkylation of amides is a familiar/useful and important technique in the synthesis of natural
products, polymers and peptides.1-3 Consequently, there are general methods available for the N-
alkylation of amides with aryl and alkenyl halides.4-8 From a green chemistry perspective, alcohols
would be an attractive alternative as alkylating reagents for the C-N bond formation.9-17 Alcohols are
widespread and relatively cheap reagents, they are generally non- or less toxic and easier to handle
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when compared to other reagents used for N-alkylation of amides. However, due to the poor
electrophilicity of alcohols, either harsh conditions or extra steps are required.
9
The metal catalyzed hydrogen transfer raction is an elegant way to overcome this problem and have
been succesfully applied in N-alkylation of amines.18-21 In this reaction the alcohol is oxidized by the
metal complex to produce an electrophilic aldehyde that undergoes a condensation with the amine. The
newly generated C=N bond is finally reduced by the metal hydride complex resulting in a reaction in
which only water is generated as a by-product. Hence, the N-alkylation of amines using alcohols as an
alkylating reagent is an environmentally friendly alternative.
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The corresponding alkylation of amides, have also been studied.22-30 Due to the amide being less
nucleophilic than amines, these reactions normally require higher temperatures and/or higher catalyst
loadings. Watanabe and Jenner31,32 reported the successful use of alcohols as alkylating reagents
catalyzed by ruthenium and rhodium catalysts at high temperature in the N-alkylation of amides. Fujita
and co-workers applied iridium catalysts to develop a method for the N-alkylation of amides using
alcohols in 2009.33 This method required 5 mol% of iridium metal catalysts and a long reaction time
under reflux conditions. In 2011, Dean and co-workers reported N-alkylation of amides with alcohols
using heterogenous Ag/Mo oxides.34 In the same year, alcohols were reported as alkylating reagents in
N-alkylation catalyzed by copper35, ruthenium36 and iridium catalysts28. In 2013, Sun and co-workers
applied ruthenium/iridium dual catalyst systems in alkylation of aldoximes using alcohols to obtain the
N-monoalkylated amide products.37 Recently, N-alkylation of amides with alcohols was successful
using 5 mol% of iridium dimer catalyst under base-free conditions in a microwave reactor.38 In this
study, N-heterocyclic carbene-phosphine iridium catalysts was developed and found to be very active
catalysts for the N-monoalkylation of amides using alcohols as alkylation reagents via hydrogen
transfer.
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Table 1. Optimization of reaction conditions using NHC,P-Ir catalystsa
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9
O
O
0.5 mol% NHC,P-Ir
catalyst
NH2
OH
N
H
Base, Solvent
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Entry Base (equiv)
Catalyst Solvent
Temp (oC) Time (hour)
yield (%)b
A
A
A
Toluene
Toluene
Toluene
120
120
120
5
5
5
No conversion
1
2
3
No Base
KOtBu (0.5)
NaOtBu (0.5)
73
68
4
5
K2CO3 (0.5)
KOH (0.5)
A
A
A
A
A
A
A
B
C
D
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
120
120
120
120
80
5
67
5
80
6
Cs2CO3 (0.5)
Cs2CO3 (0.2)
Cs2CO3 (0.2)
Cs2CO3 (0.2)
Cs2CO3 (0.2)
Cs2CO3 (0.2)
Cs2CO3 (0.2)
Cs2CO3 (0.2)
5
88
7
5
84
8
12
12
12
12
12
12
11c
55c
91
31c
40c
84c
9
100
120
100
100
100
10
11
12
13
D
D
D
120
120
120
3
3
3
14
15
16
Cs2CO3 (0.2)
Cs2CO3 (0.2)
Cs2CO3 (0.2)
Toluene
DMF
96
84
78
DMSO
D
120
3
17
Cs2CO3 (0.2)
1,4-dioxane
32
BArF
BArF
BArF
N
N
R
N
N
Ir
P
N
N
Ph
Ph
Ph
Ir
P
Ph
Ir
Ph
P
Ph
Ph
Ph
Catalyst A, R = Ph
Catalyst B, R = Me
Catalyst C
Catalyst D
a Amide (0.25mmol), benzyl alcohol (0.30mmol), catalyst (0.5 mol%), base and 0.25ml of solvent, heat.
b Isolated yield. c NMR yield using 1,3,5-trimethoxybenzene as internal standard.
Initially benzamide and benzyl alcohol were chosen as model substrates for the study. The reaction
o
was carried out at 120 C in toluene with 0.5 equivalents of a base and using 0.5 mol% of an iridium
catalyst for 5 hours (Table 1, entries 2-6). The use of cesium carbonate produced the N-monoalkylated
product in the highest isolated yield (Table 1, entry 6). The quantity of cesium carbonate could be
decreased to 0.2 equivalents, without any significant loss in yield (Table 1, entry 7). An elevated
temperature (120 oC) was necessary to complete the reaction in 5 hours. At 100 C, the reaction was
o
o
incomplete with only 55% yield in 5 hours (Table 1, entry 9). A catalyst screening at 100 C was also
performed for the reaction. When the substituent on the imidazole was changed from phenyl to methyl
group, 31% of the desired product was obtained (Table 1, entries 11). The best reactivity was obtained
for catalyst D which resulted in 84% yield (Table 1, entry 13) at 100 °C and 96% isolated yield at 120
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oC (Table 1, entry 14). Toluene was found to be the best solvent for the reaction. (Table 1, entries 14-
17).
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Table 2. N-monoalkylation of benzamide with various aromatic alcohols using NHC,P-Ir
catalystsa
O
O
0.5 mol% Catalyst D
Cs2CO3, Toluene, 120 oC, 3 h
NH2
N
R
H
R
OH
yield (%)b
yield (%)b
Entry
1
Entry
9c
Product
O
Product
O
N
H
N
H
90
82
98
96
95
97
82
MeO
O
O
N
H
2
3
4
N
H
10c
Me
Br
O
O
N
H
Me
N
H
OMe
11
O
Me
O
N
H
Me
Me
Br
N
H
12
13
96
O
Me
N
H
O
5
89
91
97
83
OMe
N
H
90
96
87
O
OMe
Br
N
H
6c
7c
8c
OMe
O
O
N
H
14
N
H
O
O
N
H
N
H
15c
Me
a
Benzamide (0.25mmol) in toluene (0.25ml), alcohol (0.3mmol), catalyst D (0.5mol%), Cs2CO3
o
b
c
(0.05mmol), 120 C, 3 h. Isolated yield. Benzamide (0.25mmol) in toluene (0.25ml), alcohol
(0.3mmol), catalyst D (0.5mol%), Cs2CO3 (0.05mmol), 120 oC, 12 h.
Having identified a reactive catalyst and optimized the reaction conditions, a range of alcohols was
investigated as electrophiles in the reaction (Table 2, entries 1-13). The benzyl alcohol derivatives
bearing electron-donating substituents in the para position on the aromatic ring afforded the desired
products in excellent yields (Table 2, entries 2 and 3). A slightly lower yield was produced when the
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substrate has an electron-withdrawing group in the para position (Table 2, entry 4). The reaction of
benzamide with benzyl alcohols bearing substituents in the meta positions were complete after 3 hours
(Table 2, entries 5-7). When benzyl alcohols having two substituents on the aromatic ring were used as
alkylating reagents, high yields of isolated products were obtained (Table 2, entries 11-13). The
napthalenemethanols also resulted in high yields (Table 2, entries 14 and 15).
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Table 3. N-monoalkylation of benzamide with various heterocyclic alcohols and butanol using
NHC,P-Ir catalystsa
O
O
0.5 mol% Catalyst D
Cs2CO3, Toluene, 120 oC, 12 h
NH2
N
R
H
R
OH
Entry
Product
yield (%)b
Entry
Product
yield (%)b
O
O
O
O
O
O
O
O
O
N
H
N
H
6c
7c
8
1
2
95
87
90
63
72
O
N
N
O
N
H
N
H
N
H
N
N
H
N
H
3
4
n.d.
70
N
Me
N
H
N
H
9c
97
98
S
S
N
H
5
a
Benzamide (0.25mmol) in toluene (0.25ml), alcohol (0.3mmol), catalyst D (0.5mol%), Cs2CO3
o
b
c
(0.05mmol), 120 C, 12 h. Isolated yield. Benzamide (0.25mmol) in toluene (0.25ml), alcohol
(0.3mmol), catalyst D (1.0mol%), Cs2CO3 (0.125mmol), 120 oC, 12 h.
Alkylation of benzamide with heterocyclic aromatic alcohols as alkylating reagents was also studied
(Table 3, entries 1-8). These alcohols showed good to excellent reactivity when applied in the reaction.
A longer reaction time was required to give high to excellent yields. The 3-pyridenemethanol and 2-
pyridenemethanol were successfully used as substrates (Table 3, entries 1-3). When
thiophenenemethanol substrates were used, excellent isolated yields of N-monoalkylated products were
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obtained (Table 3, entries 4 and 5). Alkylation of benzamide with furan alcohol substrates and aliphatic
alcohol butanol as a alkylating reagent also gave the desired N-monoalkylated product in good yields
although 1.0 mol% of catalyst loading and 0.5 equivalents of base was required (Table 3, entries 6, 7
and 9). For imidazole alcohol (Table 3, entry 8), no conversion was observed.
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Table 4. N-monoalkylation of benzamide derivatives with various alcohols using NHC,P-Ir
catalystsa
O
O
0.5 mol% Catalyst D
Cs2CO3, Toluene, 120 oC, 12 h
NH2
N
R
R
R
H
R
OH
Entry
Product
yield (%)b
Entry
5
Product
O
yield (%)b
O
O
N
N
H
H
1
93
96
Me
Me
OMe
O
N
H
N
H
2c
72
6
7
84
Me
O
O
O
N
H
N
3c
77
78
n.d.
H
Me
Br
NO2
N
H
4
a
Amide (0.25mmol) in toluene (0.25ml), alcohol (0.3mmol), catalyst D (0.5mol%), Cs2CO3
(0.05mmol), 120 oC, 12 h. b Isolated yield. c Amide (0.25mmol) in toluene (0.25ml), alcohol (0.3mmol),
catalyst D (1.0mol%), Cs2CO3 (0.125mmol), 120 oC, 12 h.
Benzamide derivatives were also studied in the N-monoalkylation resulting in the desired products in
moderate to excellent yields (Table 4). The benzamide derivatives bearing electron-donating
substituents, such as methyl and methoxy groups resulted in the desired products in good yields (Table
4, entries 1 and 5). When ortho-methyl benzamide substrate was used, a slightly lower isolated product
yield was obtained (Table 4, entry 6). Benzamides having an electron-withdrawing bromo substituent on
the aromatic ring resulted in a slightly lower yield of the isolated product (Table 4, entry 4). The ortho-
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nitrobenzamide did not result in any desired product (Table 4, entry 5). Finally, the para-toluamide
successfully reacted with aliphatic alcohols but more harsher reaction conditions were required to obtain
the products in moderate 77% and 72% isolated yields (Table 4, entries 2 and 3).
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To investigate the substrate scope further, reactions of heterocyclic and aliphatic amides with various
alcohols were studied for the N-alkylation (Table 5, entries 1-10). Nicotinamide and isonicotinamide
were reacted with benzyl alcohol to obtain excellent isolated yields (Table 5, entries 1 and 2).
Alkylation of 2-thiophenecarboxamide gave N-monoalkylated products in 96% isolated yield when
reacted with benzyl alcohol and moderate yields when reacted with 2-thiophenemethanol and butanol
(Table 5, entries 3-5). The catalyst also provided high efficiency for the alkylation of aliphatic amides,
such as butyramide, hexanoamide and pivalamide with benzyl alcohol (Table 5, entries 6, 9 and 10).
Table 5. N-monoalkylation of heterocyclic aromatic and aliphatic amides with various alcohols
using NHC,P-Ir catalystsa
0.5 mol% Catalyst D
Cs2CO3, Toluene, 120 oC, 12 h
R1 NH2
+
R2 OH
R1 HN
R2
Entry
Product
yield (%)b
Entry
Product
yield (%)b
O
O
O
7c, d
N
H
N
H
1
97
5
N
O
S
N
H
8e
2
3
N
H
94
62
N
O
O
N
H
N
H
96
73
52
9
93
89
98
S
S
S
O
O
S
N
H
N
4
10
11
H
O
O
O
S
5c
N
H
N
H
Me
O
O
O
N
H
6
86
12
95
S
Me
N
H
a
Amide (0.25mmol) in toluene (0.25ml), alcohol (0.3mmol), catalyst D (0.5mol%), Cs2CO3
o
b
c
(0.05mmol), 120 C, 12 h.
Isolated yield. Amide (0.25mmol) in toluene (0.25ml), alcohol
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d
(0.3mmol), catalyst D (1.0mol%), Cs2CO3 (0.125mmol), 120oC, 12 h. NMR yield using 1,3,5-
e
trimethoxybenzene as internal standard. Amide (0.25mmol) in toluene (0.25ml), alcohol (0.3mmol),
8
9
catalyst D (3.0mol%), Cs2CO3 (0.125mmol), 120oC, 12 h.
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The reactions were completed in 12 hours and higher than 85% of isolated yields were achieved. The
iridium catalyst was also successfully applied in N-monoalkylation of sulfonamide compounds with
alcohol, such as para-tolunesulfonamide and methanesulfonamide, to afford the target products in
excellent isolated yields (Table 5, entries 11 and 12). However, when butyramide was reacted with
butanol, it showed much lower reactivity than benzyl alcohols (Table 5, entry 7).
Table 6. Comparison of the reactivity difference between benzyl alcohol and butanol with
aliphatic amidesa
O
0.5 mol% Catalyst D
O
Cs2CO3, Toluene, 120 oC, 12 h
R2 OH
Amide
+
R1 NH2
R1
N
R2
H
yield (%)b
Entry
Product
O
O
1
86
5
NH2
N
H
O
O
2c,d
NH2
N
H
O
O
O
3
NH2
NH2
N
H
93
26
O
4c
N
H
O
O
O
5
NH2
N
H
89
O
6c
NH2
N
H
n.d.
a
Amide (0.25mmol) in toluene (0.25ml), alcohol (0.3mmol), catalyst D (0.5mol%), Cs2CO3
o
b
c
(0.05mmol), 120 C, 12 h.
Isolated yield. Amide (0.25mmol) in toluene (0.25ml), alcohol
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d
(0.3mmol), catalyst D (1.0mol%), Cs2CO3 (0.125mmol), 120oC, 12 h. NMR yield using 1,3,5-
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7
8
trimethoxybenzene as internal standard.
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The aliphatic amides were less reactive than aryl amides, perhaps because the alkyl substitution on the
α-carbon decreased the acidity of the amide. Additionally, in the case of the other reagent - the alcohol,
the aliphatic aldehydes generated in the reaction, might be more unstable under the reaction condition
than benzyl aldehyde. This reactivity difference was first observed using benzamide, and was much
more pronounced in the combination of an aliphatic amide and an aliphatic alcohol.
In order to shed further light on the reactivity difference, several combinations between aliphatic
amides and aliphatic alcohols were carried out and summarized in Table 6. Three alkyl amides were
chosen as the nucleophiles. Compared with the results from alkylation of benzamide with benzyl
alcohol (Table 2, entry 1) which gave 96% yield in 3 hours, aliphatic amides were less reactive and
required longer reaction time and higher catalytic loading (1.0mol%). With benzyl alcohol (Table 6,
entry 1), reaction went to completion in 12 hours with over 85% yield. However, when the butyramide
and butanol which were both poor reactants were combined (Table 6, entry 2), it completely inhibited
the alkylation reaction with only 5% of NMR yield. This reactivity difference was also observed with
other aliphatic amides such as hexanoamide and pivalamide as well (Table 6, entries 3-6). The
alkylation with butanol instead of benzyl alcohol decreased the yields from 93% to 26% (Table 6,
entries 3 and 4) for hexanoamide and 89% to 0% (Table 6, entries 5 and 6) for pivalamide, respectively.
O
O
0.5 mol% Catalyst D,
0.2 e.q. Cs2CO3
NH2
OH
N
H
8.4 ml Toluene, 120oC, 6 h
1g
1.08g (1.2 e.q)
1.6 g, 91% yield
Scheme 1. Alkylation of benzamide with benzyl alcohol in 1 g scale.
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Next, the new iridium catalytic system for the alkylation of amide was evaluated in the large-scale
reaction using 1 g of the benzamide and 0.5 mol% of the iridium catalyst D (Scheme 1). The reaction
was completed in 6 hours at 120oC and 91% of the isolated yield was obtained.
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In conclusion, we have developed an efficient NHC-Ir catalyst system for N-monoalkylation of
amides with alcohol via a hydrogen transfer reaction. Catalyst D exhibited high reactivity and good
selectivity. A variety of substrate amides were converted to the desired product with various different
alcohols in up to 98% isolated yield with low catalyst loading (only 0.5 mol%) in 3 to 12 hours. Catalyst
D also displayed high reactivity for N-monoalkylation of sulfonamides with alcohol to give the desired
product in excellent yield.
EXPERIMENTAL SECTION
General methods: Iridium catalyzed alkylation was carried out under nitrogen atmosphere. The glass
vessels were dried in the oven (160 °C) over night and cooled to room temperature under nitrogen.
Toluene and 1,4-dioxane were dried over sodium-benzophenone, distilled and stored under nitrogen.
Dimethyl formamide and dimethyl sulfoxide were dried with molecular sieve 0.4 nm, followed by
distillation under nitrogen. Amides and alcohols substrates were commercially available sources, and
purified by column chromatography or distillation. Potassium tert-butoxide, sodium tert-butoxide,
potassium carbonate, potassium hydroxide and cesium carbonate, which are sublimed grade. The thin-
layer chromatography (TLC) was performed on aluminum plates coated with Kieselgel 60 (0.20 mm,
UV 254) and visualized under ultraviolet light followed by staining with potassium
1
permanganatesolution. HNMR spectra were recorded at 400 MHz in CDCl3 and referenced internally
13
to the residual CHCl3 signal (7.26 ppm). CNMR spectra were recorded at 100 MHz in CDCl3 and
referenced to the central peak of CDCl3 (77.16 ppm). Chemical shifts were reported in ppm (δ scale),
and coupling constants (J) were reported in Hertz (Hz). IR spectra were obtained from FT-IR
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Spectrometer. High-resolution mass spectrometric (HRMS) data were obtained from the instrument with
TOF-Q instrument operated at ambient temperatures.
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Synthesis of Catalyst A: Synthesis of catalyst A has been reported by Li and Andersson in 2013.27
Synthesis of Catalyst B:
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BArF
BArF
[Ir(cod)Cl]2
KOtBu, THF
N
1)EtOH,80o
C
Cl
N
N
N
N
N
Me
Me
Me
2) NaBArF, DCM
PPh2
Ir
P
Ph2P
Ph
Ph
1
2
3
Crude
NHC,P-Ir catalyst B
53% yield
Under the argon atmosphere, commercially available 1-methylimidazole 1 (2.0 mmol) was added to
the schlock tube, followed by 2 (2.05 mmol) in ethanol (8 mL). The mixture was allowed to stir at 80 °C
for 48 hours. The ethanol was the removed under the vacuum. The crude product was dissolved in
dichloromethane (5 mL), the NaBArF (2.2 mmol) was added. After stirring the reaction mixture at room
temperature for 1 hour, the mixture was filtrated through celite and the solvent was removed under the
vacuum. The resulting residue was dissolved in dry THF (10 mL) under argon, followed by addition of
[Ir(cod)Cl]2 (1.0 mmol) and KOtBu (2.1 mmol). The mixture was stirred at room temperature for 3
hours under argon atmosphere. After the reaction was completed, the solvent was removed under
vacuum and the residual was purified by flash column chromatography on silica gel with
dichloromethane:pentane (3:1) as the eluent to obtain 1.62g of NHC,P-Ir catalyst B as red solids with
53% yields in three steps. Rf = 0.50 (DCM/Pentane = 3/1). 1H NMR (CDCl3, 400 MHz): δ 8.12 (m, 2H),
7.72 (m, 8H), 7.50-7.47 (m, 10H), 7.35-7.20 (m, 3H), 6.95-6.90 (m, 2H), 5.03 (m, 1H), 4.75 (d, J =
14Hz, 1H), 4.60 (m, 1H), 3.97 (m, 1H), 3.12 (m, 1H), 2.80 (m, 1H), 2.50 (m, 2H), 2.30 (m, 2H), 1.65-
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1.55 (m,5H), 1.26-1.12 (m, 2H). C NMR (CDCl3, 100 MHz): δ 170.1 (d, J = 11Hz), 161.9 (dd, J =
101, 50Hz), 141.2(d, J = 9Hz), 137.2, 134.8, 133.6, 131.7, 130.5 (d, J = 7Hz), 129.5-128.6 (m),
126.5,126.1, 125.8, 123.2, 122.7, 122.0, 120.7, 120.5, 117.4 (m), 86.3 (d, J = 11Hz), 82.0,80.1 (d, J =
31
13Hz), 79.7, 56.2 (d, J = 6Hz), 36.5, 36.3, 36.0, 35.7, 32.0, 31.7, 30.7,30.2, 27.0-25.4 (m). P NMR
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(CDCl3, 100 MHz): δ 2.1. IR (neat, cm-1): ν = 3060, 2924, 1610, 1354, 1278, 1125, 887, 741. HRMS
(EI) m/z: [M−BArF]+ Calcd for C31H33IrN2P 657.2006; Found 657.2025.
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Synthesis of Catalyst C and D:
BArF
BArF
[Ir(cod)Cl]2
KOtBu, THF
N
1)EtOH,80o
C
Cl
N
N
N
Ph
Ph
N
NH
2) NaBArF, DCM
PPh2
Ph
Ir
P
Ph2P
Ph
Ph
2
5
4
39% yield
NHC,P-Ir catalyst C
70% yield
BArF
N
[Ir(cod)Cl]2
KOtBu, THF
BArF
1)EtOH,80o
C
Cl
N
N
N
Ph
Ph
Ir
Ph
2) NaBArF, DCM
P
PPh2
N
N
Ph2P
Ph
Ph
7
37% yield
6
2
NHC,P-Ir catalyst D
71% yield
Under the argon atmosphere, compound 437 or 638 (0.6 mmol) was added to the schlenktube, followed
by 2 (0.5 mmol) in ethanol (5 ml). The mixture was allowed to stir at 80 °C for 12 hours. The ethanol
was then removed under the vacuum. The crude product was dissolved in dichloromethane (5ml), then
NaBArF (0.6 mmol) was added. After stirring the reaction mixture at room temperature for 1 hour, the
mixture was filtrated through celite and the solvent was removed under the vacuum. The resulting
residue was purified by column chromatography with dichloromethane:pentane (3:1) as the eluent to
obtain compounds 5 and 7 as white solids with 39% and 37% yields, respectively.
Compounds 5 or 7 (0.5mmol) was dissolved in dry THF (10ml) under argon, followed by addition of
[Ir(cod)Cl]2 (0.25 mmol) and KOtBu (0.525 mmol). The mixture was stirred at room temperature for 3
hours under argon atmosphere. After the reaction was completed, the solvent was removed under
vacuum and the residual was purified by flash column chromatography on silica gel with
dichloromethane:pentane (1:1 to 3:1) as the eluent to obtain NHC,P-Ir catalysts C and D as red solids
with 70% and 71% yields, respectively.
Compound 5. White solid, 260 mg, 39% yield. Rf = 0.50 (DCM).1H NMR (CDCl3, 400 MHz): δ
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8.19 (s, 1H), 7.82 (m, 1H), 7.72 (s, 8H), 7.72-7.49 (m, 13H), 7.26 (m, 2H), 7.21-7.18 (m, 4H), 7.10 (d, J
= 8 Hz, 2H), 7.00-6.97 (m, 4H),5.89 (s, 2H). 13C NMR (CDCl3, 100 MHz): δ 161.6 (dd, J = 99, 50 Hz),
138.1, 137.9, 137.7 (d, J = 4 Hz), 136.1, 134.8, 134.2, 134.1, 133.6 (d, J = 6 Hz), 133.4, 133.2, 131.9,
131.5 (m), 131.4, 131.3, 130.9, 130.8, 130.7, 129.7, 129.4 (m), 129.0-128.9 (m), 128.7 (m), 128.6, 128.5
(m), 125.9, 124.2, 123.1, 120.6, 117.8, 113.8, 51.4 (d, J = 22 Hz). 31P NMR (CDCl3, 100 MHz): δ -18.4.
IR (NaCl, neat, cm-1): ν = 3058, 1610, 1355, 1279, 1126, 877, 742. HRMS (EI) m/z: [M−BArF]+ Calcd
for C32H26N2P 469.1828; Found 469.1830.
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Catalyst C. Red solid, 571 mg, 70% yield. Rf = 0.50 (DCM/Pentane = 3/1). H NMR (CDCl3, 400
MHz): δ 7.76 (m, 8H), 7.52 (m, 1H), 7.43-7.34 (m, 17H), 7.29-7.21 (m, 7H), 7.17 (m, 1H), 7.02 (m,
1H), 6.55 (d, J = 7.6 Hz, 2H), 5.38 (d, J = 14.8 Hz, 1H), 4.8 (m, 1H), 4.27 (m, 1H), 3.99 (m, 1H), 3.52
(m, 1H), 2.34 (m, 2H), 2.12 (m, 2H), 1.70-1.55 (m, 2H), 1.37 (m, 1H). 13C NMR (CDCl3, 100 MHz): δ
179.5 (d, J = 9 Hz), 161.9 (dd, J = 80, 40 Hz), 140.1 (d, J = 11 Hz), 139.4, 135.7 (d, J = 9 Hz), 134.8,
132.6, 132.5, 132.4, 132.2, 132.0, 131.3, 131.2 (m), 131.1, 130.7, 131.6, 130.2, 129.9, 129.6 (m), 128.8
(m), 128.5-128.3 (m), 127.8, 126.1, 125.6, 124.9, 124.5, 123.5, 117.5, 111.7, 109.8, 88.7 (d, J = 8 Hz),
85.9 (d, J = 10 Hz), 82.2, 82.1, 52.3, 52.2, 34.6, 33.7, 28.1, 28.0. 31P NMR (CDCl3, 100 MHz): δ 4.7. IR
(NaCl, neat, cm-1): ν = 3065, 2926, 1610, 1435, 1355, 1278, 1125, 887, 743. HRMS (EI) m/z:
[M−BArF]+ Calcd for C40H37IrN2P 769.2320; Found 769.2278.
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Compound 7. Yellow solid, 255 mg, 37% yield. Rf = 0.40 (DCM). H NMR (CDCl3, 400 MHz): δ
7.71 (m, 8H), 7.70 (m, 1H), 7.67-7.54 (m, 3H), 7.49 (m, 5H), 7.45-7.39 (m, 3H), 7.32-7.17 (m, 11H),
13
7.13-7.08 (m, 4H), 6.82 (d, J = 7.6 Hz, 1H), 6.23 (d, J = 7.2 Hz, 1H), 5.13 (s, 2H). C NMR (CDCl3,
100 MHz): δ 162.0 (dd, J = 99, 49 Hz), 150.8 (d, J = 5 Hz), 137.4 (d, J = 16 Hz), 135.8, 135.4, 135.0,
134.8, 133.7 (d, J = 20 Hz), 133.3 (d, J =6 Hz), 133.0, 132.84, 131.7, 131.2, 131.0, 130.8 (d, J = 5 Hz),
130.6, 129.8, 129.3 (m), 129.0-129.1, 129.0, 128.8 (m), 128.6 (m), 128.1 (d, J = 8Hz), 127.8, 125.9,
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125.7 (m), 125.6, 123.5, 121.3, 120.9, 117.5, 110.1, 109.1, 56.0 (d, J = 17Hz). P NMR (CDCl3, 100
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MHz): δ -16.3. IR (NaCl, neat, cm-1): ν = 3054, 2986, 1659, 1609, 1354, 1278, 1127, 895, 741. HRMS
(EI) m/z: [M−BArF]+ Calcd for C36H28N2P 519.1985; Found 519.1993.
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Catalyst D. Orange solid, 597 mg, 71% yield. Rf = 0.50 (DCM/Pentane = 3/1). 1H NMR (CDCl3, 400
MHz): δ 7.77 (brs, 8H), 7.67 (m, 1H), 7.50-7.28 (m, 19H), 7.21-7.20 (m, 3H), 7.18 (m, 1H), 7.11 (m,
1H), 7.10-7.03 (m, 2H), 5.98 (m, 1H), 5.71 (d, J = 7.6 Hz, 1H), 5.34 (d, J = 14.4 Hz, 1H), 5.06 (m, 1H),
4.48 (m, 1H), 4.29 (m, 1H0, 3.56 (m, 1H), 3.26 (m, 1H), 2.27 (m, 1H), 2.14 (m, 2H), 1.81 (m, 2H). 13C
NMR (CDCl3, 100 MHz): δ 195.9, 161.5 (dd, J = 100, 50 Hz), 139.2 (d, J = 14 Hz), 138.1, 137.9, 136.2,
134.8, 133.4, 133.1, 132.5-132.2 (m), 131.8, 131.7, 131.3, 131.1, 130.9, 130.6, 130.5, 130.3 (m), 129.2-
129.0 (m), 128.9, 128.8, 128.5, 127.8, 127.3, 127.2, 125.6, 123.5, 122.9, 122.7, 122.4, 122.3, 121.3,
117.5, 107.8, 106.3, 84.5, 83.3, 82.9 (d, J = 6 Hz), 55.3, 39.7, 37.5, 34.9, 29.7, 29.3, 26.2, 25.8, 25.6,
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25.4, 24.5. P NMR (CDCl3, 100 MHz): δ - 4.6. IR (NaCl, neat, cm-1): ν = 3055, 2926, 1601, 1354,
1278, 1126, 887, 743. HRMS (EI) m/z: [M−BArF]+ Calcd for C44H39IrN2P 819.2477; Found 819.2457.
Procedure for iridium catalyzed alkylation of amides: To the oven-dried pressure a microwave vial
(5 mL, tapered style) with magnetic stirring bar, Cs2CO3 (16.3 mg, 0.05mmol) and NHC,P-Ir catalyst D
(2.10 mg, 5 mol%) and amide reagent (0.25 mmol) were added. Under the nitrogen, alcohol (0.3mmol)
and toluene (0.25ml) were added, followed degassing that used a vacuum pump and refilled with
nitrogen 3 times. The reaction mixture was stirred for 3 or 12 hours under 120 oC and then the mixture
was cooled to ambient temperature. The solvent was then removed under vacuum and the residue was
purified by column chromatography (EtOAc/Pentane).
Table 2 – Entry 1. White solid, 50.7 mg, 96% yield. Spectral data match those previously reported.37
1H NMR (CDCl3, 400 MHz): δ 7.79 (d, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.37-7.35
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(m = 4H), 7.32-7.28 (m, 1H), 6.44 (s, 1H), 4.65 (d, J = 5.7 Hz, 2H). C NMR (CDCl3, 100 MHz): δ
7
8
167.4, 138.2, 134.3, 131.5, 128.7, 128.5, 127.9, 127.6, 126.9, 44.1.
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Table 2 – Entry 2. White solid, 53.4 mg, 95% yield. Spectral data match those previously reported.37
1H NMR (CDCl3, 400 MHz): δ 7.78 (d, J = 7.3 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz,
2H), 7.25 (d, J = 4.3 Hz, 2H), 7.16 (d, J = 4.3 Hz, 2H), 6.39 (s, 1H), 4.60 (d, J = 5.7 Hz, 2H), 2.34 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 167.2, 159.2, 134.5, 131.5, 130.2, 129.3, 128.6, 126.9, 114.2, 55.3,
43.7.
Table 2 – Entry 3. Yellow solid, 58.6 mg, 97% yield. Spectral data match those previously reported.37
1H NMR (CDCl3, 400 MHz): δ 7.91 – 7.62 (m, 2H), 7.56 – 7.44 (m, 1H), 7.39 (td, J = 7.6, 2.2 Hz, 2H),
7.29 – 7.21 (m, 2H), 6.90 – 6.81 (m, 2H), 6.59 (d, J = 22.6 Hz, 1H), 4.54 (dd, J = 5.6, 2.9 Hz, 2H), 3.78
(d, J = 1.7 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 167.4, 159.2, 134.5, 131.6, 130.43, 130.40, 129.35,
128.6, 127.1, 127.0, 114.2, 55.4, 43.7.
Table 2 – Entry 4. White solid, 59.4 mg, 82% yield. Spectral data match those previously reported.37
1H NMR (CDCl3, 400 MHz): δ 7.85 – 7.66 (m, 2H), 7.56 – 7.45 (m, 1H), 7.41 (td, J = 8.5, 6.8 Hz, 4H),
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7.22 – 7.12 (m, 2H), 6.86 – 6.69 (m, 1H), 4.54 (d, J = 5.8 Hz, 2H). C NMR (CDCl3, 100 MHz): δ
167.6, 137.5, 134.2, 131.9, 131.8, 129.6, 128.7, 127.1, 121.5, 43.5.
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Table 2 – Entry 5. Yellow solid, 50.0 mg, 89% yield. Spectral data match those previously reported.41
1H NMR (CDCl3, 400 MHz): δ 7.83 – 7.77 (m, 2H), 7.52 – 7.46 (m, 1H), 7.41 (dd, J = 8.2, 6.7 Hz, 2H),
7.28 – 7.21 (m, 1H), 7.17 – 7.08 (m, 2H), 6.59 (s, 1H), 4.59 (d, J = 5.6 Hz, 2H), 2.34 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 167.4, 138.6, 138.2, 134.5, 131.6, 128.8, 128.6, 128.4, 127.1, 125.0, 44.2, 21.5.
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Table 2 – Entry 6. Yellow solid, 54.8 mg, 91% yield. Spectral data match those previously reported.41
1H NMR (CDCl3, 400 MHz): δ 7.82 – 7.75 (m, 2H), 7.54 – 7.46 (m, 1H), 7.41 (ddd, J = 8.7, 4.9, 1.8
Hz, 2H), 7.30 – 7.23 (m, 1H), 6.97 – 6.87 (m, 2H), 6.83 (dd, J = 8.3, 2.5 Hz, 1H), 6.50 (s, 1H), 4.61 (d,
J = 5.8 Hz, 2H), 3.79 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 167.5, 160.1, 139.9, 134.5, 131.7, 129.9,
128.7, 127.1, 120.2, 113.6, 113.2, 55.4, 44.2.
Table 2 – Entry 7; N-(3-bromobenzyl)benzamide. 70.0 mg, 97% yield. white solid; Rf = 0.54
o
1
(EtOAc/Pentane = 3/7), mp 104 – 105 C. H NMR (CDCl3, 400 MHz): δ 7.83 – 7.74 (m, 2H), 7.55 –
7.47 (m, 2H), 7.47 – 7.38 (m, 3H), 7.32 – 7.26 (m, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.55 (s, 1H), 4.61 (d, J
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= 5.8 Hz, 2H). C NMR (CDCl3, 100 MHz): δ 167.5, 140.7, 134.2, 131.9, 130.9, 130.8, 130.5, 128.8,
127.1, 126.6, 122.9, 43.6. IR (NaCl, neat, cm-1): IR: ν = 3293, 3080, 2931, 1638, 1576, 1546, 1416,
1351, 1255, 990, 750, 695. HRMS (EI) m/z: [M+H]+ Calcd for C14H13BrNO 290.0175; Found
290.0161.
Table 2 – Entry 8. White solid, 46.7 mg, 83% yield. Spectral data match those previously reported.42
1H NMR (CDCl3, 400 MHz): δ 7.81 – 7.76 (m, 2H), 7.53 – 7.47 (m, 1H), 7.45 – 7.39 (m, 2H), 7.32 –
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7.28 (m, 1H), 7.24 – 7.17 (m, 3H), 6.30 (s, 1H), 4.64 (d, J = 5.3 Hz, 2H), 2.37 (s, 3H). C NMR
7
8
(CDCl3, 100 MHz): δ 167.3, 136.8, 135.9, 134.5, 131.6, 130.8, 128.8, 128.7, 128.0, 127.1, 126.4, 42.5,
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Table 2 – Entry 9. White solid, 54.0 mg, 90% yield. Spectral data match those previously reported.43
1H NMR (CDCl3, 400 MHz): δ 7.77 – 7.74 (m, 2H), 7.2 – 7.48 (m, 4H), 6.96 – 6.90 (m, 3H), 6.62 (s,
1H), 4.64 (d, J = 5.4 Hz, 2H), 3.89 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 167.2, 157.7, 134.8, 131.4,
129.0, 128.6, 127.0, 120.8, 110.5, 55.5, 40.1.
Table 2 – Entry 10; N-(2-bromobenzyl)benzamide. 59.5 mg, 82% yield. white solid; Rf = 0.67
(EtOAc/Pentane = 3/7), mp 105 – 107 oC. 1H NMR (CDCl3, 400 MHz): δ 7.84 – 7.74 (m, 2H), 7.57 (dd,
J = 7.9, 1.3 Hz, 1H), 7.54 – 7.39 (m, 4H), 7.29 (td, J = 7.5, 1.3 Hz, 1H), 7.16 (td, J = 7.7, 1.8 Hz, 1H),
6.69 (s, 1H), 4.71 (d, J = 6.0 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 167.4, 137.4, 134.4, 133.0, 131.8,
130.8, 129.4, 128.7, 127.9, 127.1, 124.0, 44.5. IR (NaCl, neat, cm-1): IR: ν = 3268, 3061, 2925, 1641,
1535, 1498, 1306, 1026, 746, 692. HRMS (EI) m/z: [M+H]+ Calcd for C14H13BrNO 290.0175; Found
290.0171.
Table 2 – Entry 11; N-(3,5-dimethylbenzyl)benzamide. 58.6 mg, 98% yield. white solid; Rf = 0.69
(EtOAc/Pentane = 3/7), mp 66 – 67 oC. 1H NMR (CDCl3, 400 MHz): δ 7.84 – 7.77 (m, 2H), 7.53 – 7.46
(m, 1H), 7.42 (ddt, J = 8.3, 6.5, 1.3 Hz, 2H), 6.97 (d, J = 1.6 Hz, 2H), 6.94 (s, 1H), 6.51 (s, 1H), 4.56 (d,
13
J = 5.6 Hz, 2H), 2.31 (d, J = 0.8 Hz, 6H). C NMR (CDCl3, 100 MHz): δ 167.4, 138.5, 138.2, 134.6,
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131.6, 129.3, 128.7, 127.1, 125.9, 44.2, 21.4. IR (NaCl, neat, cm-1): IR: ν = 3312, 3061, 3020, 2919,
1645, 1605, 1538, 1490, 1308, 848, 695. HRMS (EI) m/z: [M+Na]+ Calcd for C16H17NONa 262.1202;
Found 262.1191.
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Table 2 – Entry 12. White solid, 57.4 mg, 96% yield. Spectral data match those previously reported.44
1H NMR (CDCl3, 400 MHz): δ 7.78 (dd, J = 7.9, 1.5 Hz, 2H), 7.52 – 7.46 (m, 1H), 7.42 (td, J = 7.3, 1.3
13
Hz, 2H), 7.17 – 7.02 (m, 3H), 6.38 (s, 1H), 4.58 (dd, J = 5.5, 1.5 Hz, 2H), 2.26 (s, 6H). C NMR
(CDCl3, 100 MHz): δ 167.4, 137.2, 136.2, 135.7, 134.6, 131.6, 130.1, 129.5, 128.7, 127.1, 125.6, 44.1,
19.9, 19.6.
O
OMe
OMe
Table 2 – Entry 13. White solid, 61.0 mg, 90% yield. Spectral data match those previously reported.43
1H NMR (CDCl3, 400 MHz): δ 7.82 – 7.75 (m, 2H), 7.53 – 7.45 (m, 1H), 7.45 – 7.37 (m, 2H), 6.58 (d, J
= 5.9 Hz, 1H), 6.49 (d, J = 2.3 Hz, 2H), 6.37 (t, J = 2.2 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H), 3.76 (s, 6H).
13C NMR (CDCl3, 100 MHz): δ 167.5, 161.2, 140.7, 134.4, 131.6, 128.7, 127.1, 105.9, 104.6, 99.5,
55.5, 44.3.
Table 2 – Entry 14. White solid, 62.6 mg, 96% yield. Spectral data match those previously reported.37
1H NMR (CDCl3, 400 MHz): δ 7.89 – 7.74 (m, 6H), 7.56 – 7.39 (m, 6H), 6.51 (s, 1H), 4.81 (d, J = 5.6
Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 167.5, 135.7, 134.5, 133.5, 133.0, 131.7, 128.8, 128.8, 127.9,
127.8, 127.1, 126.7, 126.5, 126.2, 126.1, 44.4.
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Table 2 – Entry 15. White solid, 56.8 mg, 87% yield. Spectral data match those previously reported.37
1H NMR (CDCl3, 400 MHz): δ 8.13 – 8.04 (m, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.84 (dt, J = 8.2, 1.1
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Hz, 1H), 7.78 – 7.72 (m, 2H), 7.61 – 7.33 (m, 7H), 6.39 (s, 1H), 5.09 (d, J = 5.3 Hz, 2H). C NMR
(CDCl3, 100 MHz): δ 167.3, 134.4, 134.1, 133.5, 131.7, 131.6, 129.0, 128.9, 128.8, 128.7, 127.1, 126.9,
126.2, 125.6, 123.6, 42.7.
Table 3 – Entry 1. Yellow oil, 50.4 mg, 95% yield. Spectral data match those previously reported.42 1
H
NMR (CDCl3, 400 MHz): δ 8.62 – 8.45 (m, 2H), 7.84 – 7.78 (m, 2H), 7.72 (d, J = 7.9 Hz, 1H), 7.53 –
7.46 (m, 1H), 7.41 (tt, J = 7.2, 1.8 Hz, 2H), 7.27 (d, J = 6.7 Hz, 1H), 7.08-6.88 (m, 1H), 4.63 (dt, J =
5.7, 3.6 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 167.7, 149.0, 148.6, 136.3, 134.5, 134.1, 131.9, 128.8,
127.2, 123.9, 41.6.
Table 3 – Entry 2. Yellow oil, 46.1 mg, 87% yield. Spectral data match those previously reported.42 1
H
NMR (CDCl3, 400 MHz): δ 8.56 (dt, J = 5.0, 1.3 Hz, 1H), 7.90 – 7.84 (m, 2H), 7.73 – 7.57 (m, J = 8.0,
2.3 Hz, 2H), 7.54 – 7.47 (m, 1H), 7.47 – 7.40 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.21 (ddd, J = 7.5, 5.0,
1.1 Hz, 1H), 4.76 (d, J = 4.7 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 167.5, 156.3, 149.1, 137.0, 134.5,
131.6, 128.7, 127.2, 122.6, 122.3, 44.8.
O
N
H
N
Me
Table 3 – Entry 3; N-((6-methylpyridin-3-yl)methyl)benzamide. 50.9 mg, 90% yield. white solid; Rf
o
1
= 0.38 (EtOAc/Pentane = 3/7), mp 103 – 105 C. H NMR (CDCl3, 400 MHz): δ 8.50 (d, J = 2.3 Hz,
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1H), 7.82 – 7.75 (m, 2H), 7.64 (dd, J = 8.0, 2.3 Hz, 1H), 7.54 – 7.48 (m, 1H), 7.44 (ddt, J = 8.2, 6.6, 1.3
Hz, 2H), 7.16 (d, J = 7.9 Hz, 1H), 6.49 (s, 1H), 4.63 (d, J = 5.8 Hz, 2H), 2.56 (s, 3H). 13C NMR (CDCl3,
100 MHz): δ 167.7, 157.7, 148.5, 136.5, 134.2, 131.8, 131.2, 128.8, 127.1, 123.4, 41.3, 24.1. IR (NaCl,
neat, cm-1): IR: ν = 3263, 3061, 2924, 1641, 1603, 1577, 1539, 1490, 1297, 1032, 705. HRMS (EI) m/z:
[M+H]+ Calcd for C14H15N2O 227.1179; Found 227.1186.
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Table 3 – Entry 4; N-(thiophen-3-ylmethyl)benzamide. 52.7 mg, 97% yield. white solid; Rf = 0.50
o
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(EtOAc/Pentane = 3/7), mp 103 – 105 C. H NMR (CDCl3, 400 MHz): δ 7.82 – 7.73 (m, 2H), 7.52 –
7.45 (m, 1H), 7.45 – 7.36 (m, 2H), 7.30 (dd, J = 5.0, 2.9 Hz, 1H), 7.19 (qd, J = 3.0, 2.0, 1.3 Hz, 1H),
13
7.07 (dd, J = 4.9, 1.4 Hz, 1H), 6.60 (s, 1H), 4.62 (d, J = 5.4 Hz, 2H). C NMR (CDCl3, 100 MHz): δ
167.4, 139.1, 134.4, 131.7, 128.7, 127.5, 127.08, 127.07, 126.59, 126.57, 122.6, 77.5, 77.2, 76.8, 39.4.
IR (NaCl, neat, cm-1): IR: ν = 3301, 3053, 2933, 1637, 1543, 1422, 1333, 1254, 987, 760, 690. HRMS
(EI) m/z: [M+H]+ Calcd for C12H12NOS 218.0634; Found 218.0626.
Table 3 – Entry 5. Yellow solid, 53.2 mg, 98% yield. Spectral data match those previously reported.42
1H NMR (CDCl3, 400 MHz): δ 7.83 – 7.74 (m, 2H), 7.54 – 7.47 (m, 1H), 7.43 (dd, J = 8.3, 6.8 Hz, 2H),
7.27 – 7.23 (m, 1H), 7.05 (dd, J = 3.4, 1.1 Hz, 1H), 6.97 (dd, J = 5.1, 3.4 Hz, 1H), 6.46 (s, 1H), 4.82 (d,
J = 5.5 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 167.2, 140.9, 134.3, 131.8, 128.8, 127.1, 126.4, 125.5,
39.0.
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Table 3 – Entry 6; N-(furan-3-ylmethyl)benzamide. 31.7 mg, 63% yield. brown solid; Rf = 0.44
(EtOAc/Pentane = 3/7), mp 68 – 70 oC. 1H NMR (CDCl3, 400 MHz): δ 7.80 – 7.75 (m, 2H), 7.54 – 7.47
(m, 1H), 7.47 – 7.39 (m, 4H), 6.43 (dd, J = 1.9, 0.9 Hz, 1H), 6.24 (s, 1H), 4.50 (dd, J = 5.6, 0.9 Hz, 2H).
13C NMR (CDCl3, 100 MHz): δ 167.5, 143.8, 140.5, 134.5, 131.7, 128.8, 127.0, 122.3, 110.5, 35.2. IR
(NaCl, neat, cm-1): IR: ν = 3309, 3058, 2940, 1636, 1545, 1491, 1311, 1262, 1156, 991, 777, 692.
HRMS (EI) m/z: [M+H]+ Calcd for C12H12NO2 202.0863; Found 202.0857.
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Table 3 – Entry 7. Yellow solid, 36.2 mg, 72% yield. Spectral data match those previously reported.46
1H NMR (CDCl3, 400 MHz): δ 7.82 – 7.74 (m, 2H), 7.54 – 7.46 (m, 1H), 7.46 – 7.39 (m, 2H), 7.38 (dd,
J = 1.9, 0.8 Hz, 1H), 6.42 (s, 1H), 6.35 (dd, J = 3.3, 1.9 Hz, 1H), 6.32 – 6.29 (m, 1H), 4.65 (d, J = 5.5
Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 167.3, 151.3, 142.5, 134.3, 131.8, 128.7, 127.1, 110.7, 107.9,
37.2.
Table 3 – Entry 9. Yellow oil, 31.0 mg, 70% yield. Spectral data match those previously reported.37 1H
NMR (CDCl3, 400 MHz): δ 7.79 – 7.72 (m, 2H), 7.52 – 7.45 (m, 1H), 7.45 – 7.39 (m, 2H), 6.14 (s,
1H), 3.50 – 3.38 (m, 2H), 1.71 – 1.53 (m, 2H), 1.42 (h, J = 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C
NMR (CDCl3, 100 MHz): δ 167.6, 135.0, 131.4, 128.7, 126.9, 39.9, 31.9, 20.3, 13.9.
Table 4 – Entry 1. White solid, 52.4 mg, 93% yield. Spectral data match those previously reported.37
1H NMR (CDCl3, 400 MHz): δ 7.72 – 7.67 (m, 2H), 7.35 (d, J = 4.4 Hz, 4H), 7.32 – 7.27 (m, 1H), 7.22
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(d, J = 7.9 Hz, 2H), 6.48 (s, 1H), 4.63 (d, J = 5.7, 1.0 Hz, 2H), 2.39 (s, 3H). C NMR (CDCl3, 100
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MHz): δ 167.4, 142.1, 138.4, 131.6, 129.3, 128.9, 128.0, 127.7, 127.1, 44.2, 21.6.
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Table 4 – Entry 2; 4-methyl-N-(3-phenylpropyl)benzamide. 45.6 mg, 72% yield. Yellow solid; Rf =
0.63 (EtOAc/Pentane = 3/7), mp 64 – 66 oC. 1H NMR (CDCl3, 400 MHz): δ 7.63 – 7.52 (m, 2H), 7.33 –
7.27 (m, 3H), 7.25 – 7.16 (m, 5H), 6.06 (s, 1H), 3.50 (td, J = 7.1, 5.8 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H),
13
2.38 (s, 4H), 2.03 – 1.88 (m, 2H). C NMR (CDCl3, 100 MHz): δ 167.5, 141.8, 141.7, 132.0, 129.3,
128.7, 128.5, 126.9, 126.2, 39.9, 33.7, 31.3, 21.6. IR (NaCl, neat, cm-1): IR: ν = 3308, 3027, 2925, 1634,
1547, 1505, 1453, 1306, 1187, 838, 750, 699. HRMS (EI) m/z: [M+H]+ Calcd for C17H20NO 254.1539;
Found 254.1535.
Table 4 – Entry 3. Yellow oil, 36.8 mg, 77% yield. Spectral data match those previously reported.47 1H
NMR (CDCl3, 400 MHz): δ 7.69 – 7.62 (m, 2H), 7.24 – 7.19 (m, 2H), 6.12 (s, 1H), 3.44 (td, J = 7.1, 5.7
13
Hz, 2H), 2.38 (s, 3H), 1.64 – 1.53 (m, 2H), 1.48 – 1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). C NMR
(CDCl3, 100 MHz): δ 167.6, 141.8, 132.2, 129.3, 126.9, 39.9, 31.9, 21.5, 20.30, 13.9.
Table 4 – Entry 4. White solid, 56.6 mg, 78% yield. Spectral data match those previously reported.37
1H NMR (CDCl3, 400 MHz): δ 7.69 – 7.62 (m, 2H), 7.58 – 7.51 (m, 2H), 7.39 – 7.27 (m, 5H), 6.47 (s,
1H), 4.62 (d, J = 5.7 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 166.5, 138.0, 133.3, 131.9, 129.0, 128.7,
128.07, 127.9, 126.4, 44.4.
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Table 4 – Entry 5. Yellow solid, 58.0 mg, 96% yield. Spectral data match those previously reported.41
1H NMR (CDCl3, 400 MHz): δ 7.41 – 7.37 (m, 1H), 7.35 (d, J = 4.4 Hz, 4H), 7.32 – 7.27 (m, 3H), 7.03
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(dt, J = 6.9, 2.5 Hz, 1H), 6.50 (s, 1H), 4.63 (d, J = 5.7 Hz, 2H), 3.83 (s, 3H). C NMR (CDCl3, 100
MHz): δ 167.3, 160.0, 138.3, 136.0, 129.7, 128.9, 128.0, 127.7, 118.8, 117.9, 112.5, 55.6, 44.3.
Table 4 – Entry 6. White solid, 47.3 mg, 84% yield. Spectral data match those previously reported.48
1H NMR (CDCl3, 400 MHz): δ 7.39 – 7.27 (m, 7H), 7.24 – 7.15 (m, 2H), 6.10 (s, 1H), 4.62 (d, J = 6.0
13
Hz, 2H), 2.46 (s, 3H). C NMR (CDCl3, 100 MHz): δ 170.0, 138.3, 136.4, 136.3, 131.2, 130.1, 128.9,
128.0, 127.7, 126.8, 125.8, 44.0, 20.0.
Table 5 – Entry 1. White solid, 51.5 mg, 97% yield. Spectral data match those previously reported.48
1H NMR (CDCl3, 400 MHz): δ 8.94 (d, J = 2.6 Hz, 1H), 8.67 (q, J = 3.1, 2.0 Hz, 1H), 8.12 (dq, J = 8.0,
13
1.9 Hz, 1H), 7.42 – 7.25 (m, 6H), 6.75 (s, 1H), 4.64 (dd, J = 6.0, 2.6 Hz, 2H). C NMR (CDCl3, 100
MHz): δ 165.6, 152.4, 148.0, 137.8, 135.3, 130.2, 129.0, 128.1, 127.9, 123.6, 44.3.
Table 5 – Entry 2. Yellow oil, 49.9 mg, 94% yield. Spectral data match those previously reported.49 1H
NMR (CDCl3, 400 MHz): δ 8.74 – 8.63 (m, 2H), 7.65 – 7.56 (m, 2H), 7.41 – 7.28 (m, 5H), 6.74 (s, 1H),
13
4.63 (d, J = 5.5 Hz, 2H). C NMR (CDCl3, 100 MHz): δ 165.6, 150.7, 141.6, 137.6, 129.0, 128.1,
128.0, 121.0, 44.4.
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Table 5 – Entry 3. White solid, 52.2 mg, 96% yield. Spectral data match those previously reported.50
1H NMR (CDCl3, 400 MHz): δ 7.51 (dd, J = 3.9, 1.1 Hz, 1H), 7.47 (dd, J = 5.0, 1.2 Hz, 1H), 7.35 (d, J
= 4.4 Hz, 4H), 7.32 – 7.27 (m, 1H), 7.06 (dd, J = 5.0, 3.7 Hz, 1H), 6.34 (s, 1H), 4.62 (d, J = 5.8 Hz, 2H).
13C NMR (CDCl3, 100 MHz): δ 161.9, 138.9, 138.2, 130.1, 128.9, 128.3, 128.1, 127.8, 127.8, 44.2.
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Table 5 – Entry 4. Yellow solid, 40.7 mg, 73% yield. Spectral data match those previously reported.44
1H NMR (CDCl3, 400 MHz): δ 7.53 – 7.45 (m, 2H), 7.27 – 7.22 (m, 1H), 7.10 – 7.03 (m, 2H), 6.97 (dd,
13
J = 5.1, 3.5 Hz, 1H), 6.32 (s, 1H), 4.79 (d, J = 5.7 Hz, 1H). C NMR (CDCl3, 100 MHz): δ 161.6,
140.7, 138.6, 130.3, 128.5, 127.8, 127.1, 126.5, 125.6, 38.8.
Table 5 – Entry 5. White solid, 23.8 mg, 52% yield. Spectral data match those previously reported.47
1H NMR (CDCl3, 400 MHz): δ 7.48 (dq, J = 3.6, 1.1 Hz, 1H), 7.45 (dt, J = 5.0, 1.1 Hz, 1H), 7.06 (ddd,
J = 5.0, 3.7, 1.3 Hz, 1H), 5.99 (s, 1H), 3.52 – 3.37 (m, 2H), 1.73 – 1.52 (m, 2H), 1.47 – 1.33 (m, 2H),
13
0.95 (td, J = 7.3, 1.5 Hz, 3H). C NMR (CDCl3, 100 MHz): δ 162.0, 129.7, 127.9, 127.7, 39.9, 31.9,
20.3, 13.9.
Table 5 – Entry 6. White solid, 38.1 mg, 86% yield. Spectral data match those previously reported.37
1H NMR (CDCl3, 400 MHz): δ 7.37 – 7.30 (m, 2H), 7.27 (dd, J = 7.1, 2.7 Hz, 3H), 5.81 (s, 1H), 4.43 (d,
13
J = 5.7 Hz, 2H), 2.23 – 2.13 (m, 2H), 1.69 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). C NMR
(CDCl3, 100 MHz): δ 172.9, 138.6, 128.8, 127.9, 127.6, 43.7, 38.8, 19.3, 13.93.
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Table 5 – Entry 8; N-(thiophen-2-ylmethyl)butyramide. 17.0 mg, 37% yield. Brown solid; Rf = 0.37
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(EtOAc/Pentane = 3/7), mp 53 – 55 C. H NMR (CDCl3, 400 MHz): δ 7.22 (dd, J = 4.9, 1.5 Hz, 1H),
6.99 – 6.92 (m, 2H), 5.76 (s, 1H), 4.62 (d, J = 5.6 Hz, 2H), 2.18 (t, J = 7.4 Hz, 2H), 1.68 (h, J = 7.4 Hz,
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2H), 0.95 (t, J = 7.4 Hz, 3H). C NMR (CDCl3, 100 MHz): δ 172.7, 141.3, 127.0, 126.1, 125.3, 38.7,
38.4, 19.2, 13.9. IR (NaCl, neat, cm-1): IR: ν = 3289, 3053, 2963, 2931, 1646, 1545, 1424, 1366, 1265,
1219, 738, 701. HRMS (EI) m/z: [M+Na]+ Calcd for C9H13NOS 206.0610; Found 206.0609.
Table 5 – Entry 9. White solid, 47.7 mg, 93% yield. Spectral data match those previously reported.52
1H NMR (CDCl3, 400 MHz): δ 7.37 – 7.31 (m, 2H), 7.31 – 7.24 (m, 3H), 5.70 (s, 1H), 4.44 (d, J = 5.7
Hz, 2H), 2.26 – 2.12 (m, 2H), 1.72 – 1.57 (m, 2H), 1.40 – 1.19 (m, 4H), 0.94 – 0.84 (m, 3H). 13C NMR
(CDCl3, 100 MHz): δ 173.1, 138.6, 128.9, 128.0, 127.6, 43.8, 36.9, 31.6, 25.60, 22.5, 14.1.
O
N
H
Table 5 – Entry 10. Yellow solid, 42.6 mg, 89% yield. Spectral data match those previously reported.29
1H NMR (CDCl3, 400 MHz): δ 7.23-7.40 (m, 5H), 5.93 (br, 1H), 4.43 (d, J = 5.6Hz, 2H), 1.23 (s, 9H);
13C NMR (CDCl3, 100 MHz): δ 27.5 (3C), 38.6, 43.4, 127.2, 127.5 (2C), 128.5 (2C), 138.6, 178.2.
Table 5 – Entry 11. White solid, 64.0 mg, 98% yield. Spectral data match those previously reported.36
1H NMR (CDCl3, 400 MHz): δ 7.76 (dd, J = 8.3, 1.7 Hz, 2H), 7.33 – 7.23 (m, 5H), 7.19 (dd, J = 7.5, 2.1
Hz, 2H), 4.79 (t, J = 6.4 Hz, 1H), 4.12 (d, J = 5.9 Hz, 2H), 2.44 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
143.7, 137.0, 136.4, 129.9, 128.8, 128.0, 128.0, 127.3, 47.4, 21.7.
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Table 5 – Entry 12. White solid, 44.0 mg, 95% yield. Spectral data match those previously reported.36
1H NMR (CDCl3, 400 MHz): δ 7.39 – 7.28 (m, 5H), 4.92 (s, 1H), 4.30 (d, J = 6.2 Hz, 2H), 2.84 (s, 3H).
13C NMR (CDCl3, 100 MHz): δ 136.8, 129.0, 128.2, 128.0, 47.3, 41.2.
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Table 6 – Entry 4. Yellow oil, 11.1 mg, 26% yield. Spectral data match those previously reported.53 1H
NMR (CDCl3, 400 MHz): δ 5.42 (s, 1H), 3.24 (td, J = 7.1, 5.7 Hz, 2H), 2.20 – 2.08 (m, 2H), 1.76 – 1.55
(m, 2H), 1.56 – 1.42 (m, 2H), 1.40 – 1.19 (m, 6H), 0.95 – 0.88 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ
173.2, 39.3, 37.0, 31.9, 31.6, 25.7, 22.6, 20.2, 14.1, 13.9.
ACKNOWLEDGMENT
This project was supported by Swedish Research Council (VR), Stiftelsen Olle Engkvist
Byggmästare, the Swedish Energy Agency, the Knut and Alice Wallenberg Foundation, The Swedish
Government Agency for Innovation Systems (VINNOVA) through the Berzelii Center EXSELLENT on
porous Materials and SYNFLOW (FP7) supported this work. We also thank Dr. T. Singh for
proofreading and corrections suggested and Mr. B. Peters for the useful discussions.
Supporting Information
13
1
1H and C NMR spectra for new compounds, H NMR spectra for known N-monoalkylated amides.
This material is available free of charge via the Internet at http://pubs.acs.org.
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