Iron-catalyzed N-alkylation of azoles via cleavage of an sp3 C-H bond adjacent to a nitrogen atom

Article abstract of DOI:10.1021/jo301568e

Iron-catalyzed direct C-N bond formation between azoles and amides is described. The oxidative coupling reactions of sp³ C-H bonds adjacent to a nitrogen atom in amides and sulfonamides with the N-H bond in azoles proceeded smoothly in the presence of FeCl₂ and di-tert-butyl peroxide (DTBP).

Full text of DOI:10.1021/jo301568e

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Note
Iron-Catalyzed N-Alkylation of Azoles via Cleavage
of a sp3 C-H Bond Adjacent to a Nitrogen Atom
Qinqin Xia, and Wanzhi Chen
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 01 Oct 2012
Downloaded from http://pubs.acs.org on October 7, 2012
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Page 1 of 17
The Journal of Organic Chemistry
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Iron-Catalyzed N-Alkylation of Azoles via Cleavage of a sp3 C-H
Bond Adjacent to a Nitrogen Atom
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Qinqin Xia †and Wanzhi Chen*† ‡
† Department of Chemistry, Zhejiang University, Xixi Campus, Hangzhou 310028, People’s Republic of
China. chenwzz@zju.edu.cn
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‡ State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, People’s
Republic of China.
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
SYNOPSIS TOC
R4
R1
N R3
FeCl2 (5 mol%)
DTBP (3 equiv)
H
R1
Y
R4
N
R2
Y
N
R2
NH
X
X
R3
C6H5Cl
X, Y = C or N
R3 = acyl or Sulfonyl
120 °C, 3-6 h
ABSTRACT. Iron-catalyzed direct C-N bond formation between azoles and amides is described. The
oxidative coupling reactions of sp3 C-H bonds adjacent to a nitrogen atom in amides and sulfonamides
with the N-H bond in azoles proceeded smoothly in the presence of FeCl2 and di-tert-butyl peroxide
(DTBP).
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The formation of C-N bonds is one of the most important transformations in organic chemistry owing
to the high prevalence of nitrogen-containing molecules of biological and pharmaceutical relevance.1
Transition-metal catalyzed cross-coupling reactions are among the most important methods for C-N
bond formation. However, the need of pre-installation of reactive functional groups limits their further
application. The direct C-N bond formation via C-H activation represents an extremely attractive and
efficient route, because it is straightforward and has economic advantages over present procedures
which employ prefunctionalized substrates.2 The catalytic sp3 C-H bond activation is a challenging and
powerful technology in organic synthesis.3 Recently, catalytic oxidative functionalization of a sp3 C-H
bond adjacent to a heteroatom (nitrogen or oxygen) has attracted much interest.4 Selective
functionalization of C-H bonds adjacent to a nitrogen atom in simple amines and amides is of great
importance for the synthesis of nitrogen-containing compounds. For example, Li and other groups have
reported cross-dehydrogenative coupling (CDC) of C-H bonds adjacent to a nitrogen atom to give new
C-C bonds.4a-m This reaction is more atom economical and environmentally friendly than traditional
cross-coupling reactions. Recently, Shirakawa and coworkers have reported iron-catalyzed oxidative C-
C coupling between alphatic amides and electron-rich arenes via direct sp3 C-H bond activation adjacent
to nitrogen atoms in amides.5 However, construction of new C-N bonds via oxidative functionalization
of a sp3 C-H bond adjacent to a nitrogen atom is sparse.2d,6 To the best of our knowledge, the direct
conversion of a sp3 C-H bond adjacent to a nitrogen atom into a C-N bond using azoles as the nitrogen
sources has not been reported.
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N-Alkylazoles are fundamental structural and functional units of many N-heterocyclic carbenes
(NHC)7 and ionic liquids.8 Traditionally, N-alkylazoles are prepared by nucleophilic substitution of
alkyl halides. Recently, we have reported direct C-N coupling of imidazoles and benzylic compounds
for synthesis of imidazole derivatives.9 Herein, we report iron-catalyzed N-alkylation of azoles via
oxidative activation of C-H bond adjacent to a nitrogen atom.
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The Journal of Organic Chemistry
Benzimidazole (1a) and N,N-dimethylacetamide (2a) was selected as the model substrates to establish
1
2
optimized reaction conditions (Table 1). Various iron and copper salts were tested for the proposed
reaction using di-tert-butyl peroxide (DTBP) as an oxidant in DMAc (Table 1, entries 1-6). Di-tert-butyl
peroxide is a suitable oxidant5,10 and iron is an efficient catalyst in oxidative coupling reactions.11 All
the copper and iron salts are active regardless of their oxidation states. FeCl2 showed relatively higher
catalytic efficiency than other metal salts giving a yield of 74% in the presence of 2 equiv of DTBP at
120 °C and thus was chosen as the catalyst for further optimization (entry 5). The compound 3a was
almost quantitatively obtained when the amount of DTBP was increased to 3 equiv (entry 7). When the
reaction was carried out at 100 °C, the yield was decreased to 68% (entry 8). The reaction was also
tested in C6H5Cl, comparable yields could be obtained when 4-8 equiv of DMAc were used (entries 9-
11). However, the yield of 3a was decreased to 67% in the presence of 2 equiv of DMAc (entry 12).
Furthermore, we found that the reaction in the presence of 5 mol% of FeCl2 gave identical result to those
of 10 mol% of FeCl2 (entry 13). Although the reaction could proceed without use of a metal catalyst, the
yield is quite poor (entry 14).
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Table 1. Optimization of Reaction Conditions a
catalyst
DTBP
DMAc
+
O
N
N
solvent (1 mL)
120 °C, 3 h
NH
N
N
2a
1a
3a
DTBP
(equiv)
2a
(equiv)
entry
Cat. (mol%)
CuBr (10)
solvent
Yield (%)
2
2
2
DMAc
DMAc
DMAc
1
2
3
4
5
6
--
--
--
66
34
41
19
74
44
CuI (10)
Cu(OTf)2 (10)
FeSO4·7H2O
FeCl2 (10)
--
--
2
2
DMAc
DMAc
Fe(acac)3 (10)
2
DMAc
--
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7
8b
FeCl2 (10)
FeCl2 (10)
--
--
8
6
4
2
4
4
3
3
3
3
3
3
3
3
DMAc
DMAc
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
97
68
93
94
96
67
96
17
1
2
3
4
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7
8
9
FeCl2 (10)
FeCl2 (10)
10
11
12
13
14
FeCl2 (10)
FeCl2 (10)
FeCl2 (5)
--
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a Reaction conditions: 1a 0.5 mmol, under N2. b 100 °C
The coupling of various azoles with DMAc 2a was investigated under the optimized conditions, and
the results were summarized in Table 2. The reaction of imidazole 1b gave a slightly lower yield (Table
2, entry 2). A moderate yield was obtained when 2-methyl imidazole 1c was applied (entry 3).
Benzoimidazole 1d having two methyl groups at its 5- and 6-positions shows relatively lower activity
compared to 1a (entry 4). 2-Substituted benzoimidazoles 1e-i having either electron-withdrawing or
electro-donating groups gave good yields (entries 5-9) indicating that the steric and electronic effect of
groups at the 2-positions has little influence on the C-N coupling. 2-Phenyl imidazole 1j shows higher
reactivity than imidazole 1b (entry 10). 4,5-Dicyanoimidazole bearing two strong electron-withdrawing
substituents gave similar yield compared to imidazole 1b (entry 11). Moreover, 3,5-dimethylpyrazole 1l
and benzotriazole 1m afforded the corresponding products 3l and 3m in satisfactory yields (entries 12
and 13).
Table 2. Reactions of Various Azoles with DMAc a
FeCl2 (5 mol%)
R1
R1
DTBP (3 equiv)
O
N
DMAc
+
NH
Y
C6H5Cl (1 mL)
120 °C, 3 h
X
Y
N
X
X, Y=C or N
1
2a
3
entry
1
product
yield (%)
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The Journal of Organic Chemistry
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2
3
4
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96
O
N
N
N
NH 1a
N
3a
5
6
7
8
O
O
N
2
3
N
72
44
N
NH 1b
N
3b
3c
N
N
NH
9
N
N
10
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1c
4
5
6
52
83
75
O
N
N
N
NH 1d
N
3d
3e
O
O
N
N
NH
N
N
N
1e
N
N
N
NH
N
N
Cl
1f
Cl
3f
O
N
NH
N
7
80
1g
3g
O
N
8
9
87
84
N
NH
N
N
CF3
CF3
1h
3h
O
N
N
NH
N
N
1i
3i
O
N
NH
N
N
N
10
81
3j
1j
CN
N
CN
NC
NC
O
11
12
13
75
76
69
N
NH
N
N
1k
1l
3k
N
O
N
NH
N
N
3l
O
N
N
N
NH 1m
N
N
N
3m
Reaction conditions: 1 0.5 mmol, 2a 2.0 mmol, FeCl2 0.025 mmol,
DTBP 1.5 mmol, C6H5Cl 1.0 mL, 120 °C, 24 h, under N2.
a
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We next examined the coupling reactions of a series of amides and sulfonamides with imidazole
(Table 3). The acyclic amides afforded the corresponding products with moderate to good yields (entries
1-8). A free N-H bond in N-methylacetamide 2b can be tolerated but a lower yield was obtained
compared to N,N-dimethylacetamide 2a (entry 1). N-Methyl-N-phenylacetamide 2c gave moderate yield
probably due to the steric effect (entry 2). Reaction of N,N-dimethylbenzamide 2d with benzoimidazole
and imidazole yielded the desired products in excellent yields (entries 3 and 4). The methylene moieties
of N-ethylacetamide, N,N-diethylacetamide, and N-butylacetamide are relatively inert than methyl in
N,N-dimethylacetamide (entries 5-7). The coupling reaction of N-butyl-N-methylacetamide 2h with 1a
took place in the presence of FeCl2 affording a mixture of 4h and 4h’ in a ratio of 2.2:1 (entry 8). The
results clearly demonstrate that C-H bonds of N-methyl are more active than those of N-methylene
group. Benzyl C-H bond in N-benzylacetamide 2i showed high reactivity giving 4i in 98% yield (entry
9). Probably the benzyl group can stabilize the proposed acyliminium cation intermediate generated by
oxidation.
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The lactams also underwent the C-N coupling with benzoimidazole 1a (entries 10-15). When 1-
methylpyrrolidin-2-one 2j was used, two products 4j and 4j’ were formed in an overall yield of 97%.
Unlike the chain amides described above, the functionalization of the CH2 group adjacent to nitrogen
atom in the ring is more facile than that of the N-Me group (entry 10). However, when 1-methylazepan-
2-one 2k was used, 1-((1H-benzo[d]imidazol-1-yl)methyl)azepan-2-one 4k was isolated as the only
product, and no functionalization product occurred at the ring was found (entry 11). Again, the free N-H
bond can be tolerated but 2l and 2m shows lower activities than N-methyllactams (entries 12 and 13).
Interestingly, reactions of 1-phenylpyrrolidin-2-one 2n and 1-phenylazepan-2-one 2o showed
remarkable difference (entries 14 and 15). We speculate that the methylene C-H bonds of 5-membered
lactams are more reactive than those of 7-membered lactams (entries 10, 11, 14 and 15). We further
found that sulfonamides were also suitable for the direct C-N bond coupling (entries 16 and 17).
Table 3. Reactions of Azoles with Various Amides and Sulfonamides a
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The Journal of Organic Chemistry
FeCl2 (5 mol%)
R4
N R3
R1
N
R1
1
2
3
4
R4
DTBP (3 equiv)
R2
N
R3
NH
N
C6H5Cl (1 mL)
120 °C, 3 h
N
R2
R3 = acyl or Sulfonyl
5
6
1
2
4
7
8
9
entry
1
product
yield (%)
1
2
10
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O
75
44
1a
1a
O
N
N
H
N
HN
2b
2c
4a
4b
O
N
O
O
N
N
2
N
O
N
N
N
3
4
95
96
1a
N
2d
2d
4c
O
O
N
N
N
N
1b
4d
O
O
5
6
7
55
75
47
1a
1a
1a
O
O
N
H
N
N
2e
HN
4e
4f
N
N
N
N
2f
O
O
N
H
N
N
N
2g
HN
4g
O
N
N
82
(4h:4h’ =
2.2:1)
O
8
1a
N
4h
2h
2i
O
N
N
N
4h’
O
N
H
9
98
1a
1a
N
O
N
HN
N
4i
O
97
(4i:4i’ =
3.1:1)
O
10
N
N
N
4j
2j
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1
2
3
4
5
6
7
8
9
N
O
O
N
N
4j’
4k
O
N
N
11
79
1a
N
N
2k
10
11
12
13
14
15
16
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O
H
N
12 b
13 b
46
53
O
1a
1a
NH2l
N
N
N
N
4l
O
O
HN
NH
2m
4m
O
N
N
14
15
92
42
1a
1a
N
O
N
2n
4n
O
N
N
N
N
2o
O
4o
4p
4q
O
S
O
N
N
16
17
N
65
68
1a
1j
N
N
S
O
2p
O
O
N
O
S
N
N
S
O
O
2p
a
Reaction conditions: 1 0.5 mmol, 2 2.0 mmol, FeCl2 0.025 mmol, DTBP
1.5 mmol, C6H5Cl 1.0 mL, 120 °C, 3 h. b 6 h.
The mechanism of FeCl2-catalyzed direct C-N coupling was briefly investigated. The oxidation of
alkylamides with an oxygen-based oxidant to give α-alkoxylamides has been known.5,12 Based on this
fact, the following control experiments were performed. As shown in Scheme 1, treatment of N,N-
dimethylbenzamide 2d with 2 equiv of DTBP gave N-(tert-butoxymethyl)-N-methylbenzamide 5 in
45% yield in the presence of FeCl2. Further reaction of benzoimidazole 1a with isolated 5 afforded 4c in
82% yield when 5 mol% FeCl3 was used. When the reaction was carried out under metal free condition,
only a trace amount of 4c was observed. Obviously, iron catalyst is crucial for the formation of both N-
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The Journal of Organic Chemistry
(tert-butoxymethyl)-N-methylbenzamide
5
and
N-((1H-benzo[d]imidazol-1-yl)methyl)-N-
1
2
3
methylbenzamide 4c.
4
5
6
7
8
Scheme 1. Proposed mechanism
9
O
N
O
N
10
11
12
13
14
15
16
17
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59
60
FeCl2 (5 mol%)
DTBP (2 equiv)
O
tBu
120 °C, 24 h
2d
5
45%
O
N
FeCl3 (5 mol%)
N
82%
N
C6H5Cl (1 mL)
120 °C, 1.5 h
O
N
4c
+
O
tBu
N
NH
No Metal
O
N
N
trace
0.5 mmol
0.6 mmol
N
C6H5Cl (1 mL)
120 °C, 1.5 h
1a
5
4c
Therefore, a possible mechanism is proposed in Scheme 2. The reaction is initiated by iron assisted
oxidation to form radical A from the H abstraction of DMAc. The radical A could be further oxidized to
acyliminium ion B through a single-electron transfer process. The acyliminium ion B reacts with t-
BuOH to give tert-butoxyamide 6, and subsequent nucleophilic reaction of benzimidazole with tert-
butoxyamide 6 assisted by Fe(III) ion would form the product 3a. Another possibility is that
benzimidazole directly reacts with acyliminium ion B to yield 3a.
Scheme 2. A possible mechanism of oxidative C-N coupling.
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tBuOOtBu
+
1
2
3
+
3a
tBuOH
FeIICl2
O
N
4
5
6
N
NH
tBuOH
N
7
8
9
tBu
HN
tBuO-FeIICl
tBuO-FeIII Cl2
O
O
3a
O
N
10
11
12
13
14
15
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N
O
+
N
tBuOH
tBuOH
Cl
6
A
B
In summary, we have developed an efficient method for the synthesis of azole derivatives by an iron
catalyzed direct C-N coupling of azoles and amides. The chemistry has several methodological
advantages: (i) The catalyst-oxidant system is inexpensive and readily available. (ii) The C-N bonds can
be formed directly from C-H bonds. (iii) A wide range of amides and sulfonamides can be used as
substrate for N-alkylation of azoles.
Experimental Section
General procedure for the synthesis of products 3 or 4: An oven-dried Schlenk tube equipped with
a magnetic stir bar was charged with azole 1 (0.5 mmol), FeCl2 (3.2 mg, 0.025 mmol), and amide 2 (2.0
mmol). The tube was evacuated and refilled with N2, and this process was repeated three times. Then di-
tert-butyl peroxide (220 mg, 1.5 mmol) in chlorobenzene (1.0 mL) was added. The resulting mixture
was stirred at 120 °C for 3 h. After completion of the reaction, the resulting solution was cooled to room
temperature. The reaction mixture was then filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate/ethanol,
10:1) to afford the corresponding product.
N-((1H-benzo[d]imidazol-1-yl)methyl)-N-methylacetamide (3a).13 Light yellow oil (97 mg, 96%);
1H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.21 (t,
13
J = 3.8 Hz, 2H), 5.63 (s, 2H), 2.91 (s, 3H), 2.03 (s, 3H); C NMR (100 MHz, CDCl3): δ 171.4, 143.5,
143.4, 133.1, 123.5, 122.6, 120.1, 110.3, 55.0, 35.0, 21.7; HRMS (TOF MS EI+): m/z calcd for
C11H13N3O 203.1059, found 203.1061.
1
N-((1H-imidazol-1-yl)methyl)-N-methylacetamide (3b). Light yellow oil (55 mg, 72%); H NMR
(400 MHz, CDCl3): δ 7.59 (s, 1H), 6.99 (d, J = 8.0 Hz, 2H), 5.38 (s, 2H), 2.97 (s, 3H), 2.05 (s, 3H); 13C
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NMR (100 MHz, CDCl3): δ 171.5, 137.3, 129.3, 119.1, 57.1, 35.0, 21.6; HRMS (TOF MS EI+): m/z
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calcd for C7H11N3O 153.0902, found 153.0901.
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N-methyl-N-((2-methyl-1H-imidazol-1-yl)methyl)acetamide (3c). Light yellow oil (37 mg, 44%);
1H NMR (400 MHz, CDCl3): δ 6.97 (s, 1H), 6.90 (s, 1H), 5.44 (s, 2H), 2.99 (s, 3H), 2.44 (s, 3H), 2.14
(s, 3H); 13C NMR (100 MHz, CDCl3): δ171.1, 144.8, 127.3, 119.6, 55.8, 34.5, 21.7, 12.9; HRMS (TOF
MS EI+): m/z calcd for C8H13N3O 167.1059, found 167.1061.
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N-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-N-methylacetamide (3d). Yellow oil (60 mg,
52%); 1H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.50 (s, 1H), 7.28 (s, 1H), 5.62 (s, 2H), 2.93 (s, 3H),
2.33 (s, 3H), 2.31 (s, 3H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.3, 142.7, 142.0, 132.7,
131.6, 131.5, 120.1, 110.3, 54.9, 34.8, 21.7, 20.5, 20.1; HRMS (TOF MS EI+): m/z calcd for C13H17N3O
231.1372, found 231.1373.
N-methyl-N-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)acetamide (3e). Yellow oil (90 mg, 83%);
1H NMR (400 MHz, CDCl3): δ 7.59-7.57 (m, 1H), 7.36-7.34 (m, 1H), 7.15-7.13 (m, 2H), 5.62 (s, 2H),
2.77 (s, 3H), 2.55 (s, 3H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.0, 151.7, 142.2, 134.7,
122.6, 122.3, 118.9, 109.7, 53.1, 33.8, 21.8, 13.9; HRMS (TOF MS EI+): m/z calcd for C12H15N3O
217.1215, found 217.1213.
N-((2-chloro-1H-benzo[d]imidazol-1-yl)methyl)-N-methylacetamide (3f). Yellow oil (89 mg, 75%);
1H NMR (400 MHz, CDCl3): δ 7.70-7.63 (m, 2H), 7.31-7.29 (m, 2H), 5.87 (s, 2H), 2.98 (s, 3H), 2.16 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 171.4, 141.4, 140.2, 134.2, 123.9, 123.3, 119.2, 111.1, 53.7, 34.0,
21.8; HRMS (TOF MS EI+): m/z calcd for C11H12ClN3O 237.0669, found 237.0674.
N-methyl-N-((2-phenyl-1H-benzo[d]imidazol-1-yl)methyl)acetamide (3g). White solid (112 mg,
80%); Mp 155-156 °C; 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 7.2 Hz, 1H), 7.65-7.60 (m, 3H), 7.51
(s, 3H), 7.30-7.27 (m, 2H), 5.93 (s, 2H), 2.42 (s, 3H), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
171.1, 154.3, 142.8, 134.3, 130.0, 129.8, 129.6, 128.9, 123.5, 123.0, 119.7, 111.4, 53.8, 33.1, 21.6;
HRMS (TOF MS EI+): m/z calcd for C17H17N3O 279.1372, found 279.1371.
N-methyl-N-((2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)acetamide (3h). Yellow oil
(118 mg, 87%); 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.37-
13
7.31 (m, 2H), 5.91 (s, 2H), 2.81 (s, 3H), 2.13 (s, 3H); C NMR (100 MHz, CDCl3): δ 171.4, 140.8,
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140.5 (q, JC-F = 37.9 Hz), 134.5, 126.0, 124.1, 121.4, 118.9 (q, JC-F = 269.9 Hz), 111.9, 54.1, 33.1, 21.8;
HRMS (TOF MS EI+): m/z calcd for C12H12F3N3O 271.0932, found 271.0931.
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N-((2-isopropyl-1H-benzo[d]imidazol-1-yl)methyl)-N-methylacetamide (3i). White solid (103 mg,
84%); Mp 121-122 °C; 1H NMR (400 MHz, CDCl3): δ 7.74-7.72 (m, 1H), 7.43-7.40 (m, 1H), 7.23-7.21
(m, 2H), 5.78 (s, 2H), 3.33-3.26 (m, 1H), 2.81 (s, 3H), 2.12 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 171.0, 160.4, 142.3, 134.6, 122.7, 122.4, 119.3, 109.5, 52.4, 33.4, 26.0, 21.8, 21.8;
HRMS (TOF MS EI+): m/z calcd for C14H19 N3O 245.1528, found 245.1528.
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N-methyl-N-((2-phenyl-1H-imidazol-1-yl)methyl)acetamide (3j). Light yellow oil (93 mg, 81%); H
NMR (400 MHz, CDCl3): δ 7.47-7.38 (m, 5H), 7.10 (s, 1H), 7.04 (s, 1H), 5.51 (s, 2H), 2.56 (s, 3H),
1.98 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.4, 148.1, 130.1, 129.4, 129.1, 128.9, 128.7, 120.2,
56.5, 34.4, 21.6; HRMS (TOF MS EI+): m/z calcd for C13H15N3O 229.1215, found 229.1213.
N-((4,5-dicyano-1H-imidazol-1-yl)methyl)-N-methylacetamide (3k). Light yellow oil (76 mg, 75%);
1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 5.56 (s, 2H), 3.24 (s, 3H), 2.13 (s, 3H); C NMR (100
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MHz, CDCl3): δ 172.6, 143.0, 122.7, 111.5, 111.4, 108.1, 58.6, 36.9, 21.5; HRMS (TOF MS EI+): m/z
calcd for C9H9N5O 203.0807, found 203.0810.
N-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylacetamide (3l). Light yellow oil (69 mg, 76%);
1H NMR (400 MHz, CDCl3): δ 5.74 (s, 1H), 5.48 (s, 2H), 3.00 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H), 2.03
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.7, 148.0, 139.9, 105.9, 58.0, 34.6, 21.8, 13.3, 10.8; HRMS
(TOF MS EI+): m/z calcd for C9H15N3O 181.1215, found 181.1216.
N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-N-methylacetamide (3m).14 White solid (70 mg, 69%);
Mp 74-75 °C; 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.50 (t,
J = 7.8 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 6.22 (s, 2H), 3.11 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 171.5, 146.0, 132.3, 127.8, 124.3, 119.5, 111.0, 57.4, 34.8, 21.6; HRMS (TOF MS EI+): m/z
calcd for C10H12N4O 204.1011, found 204.1008.
N-((1H-benzo[d]imidazol-1-yl)methyl)acetamide (4a). White solid (71 mg, 75%); Mp 159-160 °C; 1H
NMR (400 MHz, CDCl3): δ 8.25 (br, 1H), 7.82 (s, 1H), 7.68 (t, J = 4.2 Hz, 1H), 7.56 (t, J = 4.6 Hz, 1H),
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7.29-24 (m, 2H), 5.55 (d, J = 6.8 Hz, 2H), 1.96 (s, 3H); C NMR (100 MHz, CDCl3): δ 171.0, 143.2,
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143.1, 132.8, 123.5, 122.7, 119.7, 110.2, 48.2, 22.8; HRMS (TOF MS EI+): m/z calcd for C10H11N3O
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189.0902, found 189.0905.
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N-((1H-benzo[d]imidazol-1-yl)methyl)-N-phenylacetamide (4b). White solid (58 mg, 44%); Mp 146-
147 °C; 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.38-7.20 (m, 6H), 6.85
(d, J = 7.2 Hz, 2H), 6.00 (s, 2H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.0, 143.6, 143.5,
140.4, 132.9, 130.2, 129.0, 128.1, 123.3, 122.5, 120.1, 110.5, 56.0, 22.4; HRMS (TOF MS EI+): m/z
calcd for C16H15N3O 265.1215, found 265.1214.
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N-((1H-benzo[d]imidazol-1-yl)methyl)-N-methylbenzamide (4c). Light yellow oil (126 mg, 95%); 1H
NMR (400 MHz, CDCl3): δ 8.18 (s,1H), 7.82 (d, J = 6.4 Hz, 1H), 7.66 (s, 1H), 7.37-7.28 (m, 7H), 5.87
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(s, 2H), 2.92 (s, 3H); C NMR (100 MHz, CDCl3): δ 172.1, 143.6, 143.3, 134.5, 133.2, 130.4, 128.5,
127.0, 123.7, 122.8, 120.3, 110.2, 55.4, 36.2; HRMS (TOF MS EI+): m/z calcd for C16H15N3O 265.1215,
found 265.1212.
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N-((1H-imidazol-1-yl)methyl)-N-methylbenzamide (4d). Light yellow oil (103 mg, 96%); H NMR
(400 MHz, CDCl3): δ 7.69 (s, 1H), 7.35 (s, 5H), 7.12 (s, 1H), 7.02 (s, 1H), 5.51 (s, 2H), 2.89 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 172.1, 137.6, 134.5, 130.4, 129.6, 128.5, 127.0, 119.4, 57.3, 36.2;
HRMS (TOF MS EI+): m/z calcd for C12H13N3O 215.1059, found 215.1058.
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N-(1-(1H-benzo[d]imidazol-1-yl)ethyl)acetamide (4e). Yellow oil (56 mg, 55%); H NMR (400 MHz,
CDCl3): δ 8.51 (br, 1H), 7.80 (s, 1H), 7.72-7.63 (m, 2H), 7.32-7.25 (m, 2H), 6.55-6.48 (m, 1H), 1.95 (s,
3H), 1.82 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 170.0, 143.1, 140.2, 132.6, 123.4, 122.7,
119.6, 111.1, 56.6, 22.8, 20.2; HRMS (TOF MS EI+): m/z calcd for C11H13N3O 203.1059, found
203.1059.
N-(1-(1H-benzo[d]imidazol-1-yl)ethyl)-N-ethylacetamide (4f). White solid (87 mg, 75%); Mp 135-
136 °C; 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H),
7.31-7.26 (m, 3H), 3.17-3.10 (m, 2H), 2.16 (s, 3H), 1.90 (d, J = 7.2 Hz, 3H), 0.74 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 170.6, 143.4, 139.8, 133.4, 123.6, 122.8, 120.2, 110.8, 58.8, 37.2, 21.6,
17.6, 15.3; HRMS (TOF MS EI+): m/z calcd for C13H17 N3O 231.1372, found 231.1371.
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N-(1-(1H-benzo[d]imidazol-1-yl)butyl)acetamide (4g). Light yellow oil (54 mg, 47%); H NMR (400
MHz, CDCl3): δ 7.82 (s, 1H), 7.70-7.68 (m, 1H), 7.58-7.56 (m, 1H), 7.39 (br, 1H), 7.25-7.21 (m, 2H),
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6.30 (q, J = 8.0 Hz, 1H), 2.11-2.03 (m, 2H), 1.91 (s, 3H), 1.39-1.26 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 170.0, 143.0, 140.6, 132.7, 123.4, 122.7, 119.8, 111.0, 60.0, 35.9, 22.9,
18.8, 13.3; HRMS (TOF MS EI+): m/z calcd for C13H17N3O 231.1372, found 231.1368.
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N-((1H-benzo[d]imidazol-1-yl)methyl)-N-butylacetamide (4h). Light yellow oil (69 mg, 56%); 1H
NMR (400 MHz, CDCl3) : δ 8.07 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.33-7.28
(m, 2H), 5.73 (s, 2H), 3.22 (t, J = 7.8 Hz, 2H), 2.14 (s, 3H), 1.50-1.44 (m, 2H), 1.33-1.26 (m, 2H), 0.91
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.3, 143.5, 143.4, 133.2, 123.4, 122.4, 120.2,
110.0, 52.7, 47.1, 30.5, 21.3, 19.9, 13.5; HRMS (TOF MS EI+): m/z calcd for C14H19N3O 245.1528,
found 245.1530.
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N-(1-(1H-benzo[d]imidazol-1-yl)butyl)-N-methylacetamide (4h’). Light yellow oil (32 mg, 26%); H
NMR (400 MHz, CDCl3) : δ 8.13 (s, 1H), 7.82-7.79 (m, 1H), 7.58-7.56 (m, 1H), 7.32-7.30 (m, 2H),
7.14 (t, J = 7.6 Hz, 1H), 2.69 (s, 3H), 2.45-2.21 (m, 2H), 2.14 (s, 3H), 1.52-1.46 (m, 2H), 1.07 (t, J = 7.4
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Hz, 3H); C NMR (100 MHz, CDCl3): δ 171.1, 143.3, 140.1, 133.4, 123.5, 122.7, 120.0, 111.0, 61.9,
32.0, 28.7, 22.1, 18.5, 13.5; HRMS (TOF MS EI+): m/z calcd for C14H19N3O 245.1528, found 245.1535.
N-((1H-benzo[d]imidazol-1-yl)(phenyl)methyl)acetamide (4i). White solid (130 mg, 98%); Mp 173-
175 °C; 1H NMR (400 MHz, CDCl3): δ 8.72 (br, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.26-
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7.10 (m, 8H), 1.93 (s, 3H); C NMR (100 MHz, CDCl3): δ 170.0, 143.3, 141.6, 135.6, 132.7, 129.2,
129.0, 126.4, 123.4, 122.8, 119.9, 111.0, 62.2, 22.8; HRMS (TOF MS EI+): m/z calcd for C16H15N3O
265.1215, found 265.1214.
5-(1H-benzo[d]imidazol-1-yl)-1-methylpyrrolidin-2-one (4j). White solid (77 mg, 72%); Mp 146-147
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°C; H NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.86-7.83 (m, 1H), 7.35-7.28 (m, 3H), 5.96-5.93 (m,
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1H), 2.80-2.63 (m, 3H), 2.70(s, 3H), 2.37-2.29 (m, 1H); C NMR (100 MHz, CDCl3): δ 173.8, 144.6,
141.1, 131.5, 123.8, 123.0, 121.0, 109.8, 71.9, 29.1, 27.3, 25.3; HRMS (TOF MS EI+): m/z calcd for
C12H13N3O 215.1059, found 215.1056.
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1-((1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-2-one (4j’). Light yellow oil (27 mg, 25%); H
NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.82-7.80 (m, 1H), 7.62-7.59 (m, 1H), 7.35-7.29 (m, 2H), 5.65
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(s, 2H), 3.34 (t, J = 7.0 Hz, 2H), 2.42 (t, J = 8.0 Hz, 2H), 1.99 (quint, J = 7.7 Hz, 2H); C NMR (100
MHz, CDCl3): δ 175.4, 143.6, 143.0, 133.0, 123.6, 122.7, 120.3, 110.1, 51.1, 45.7, 30.3, 17.4; HRMS
(TOF MS EI+): m/z calcd for C12H13N3O 215.1059, found 215.1058.
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1-((1H-benzo[d]imidazol-1-yl)methyl)azepan-2-one (4k). Light yellow oil (96 mg, 79%); H NMR
(400 MHz, CDCl3): δ 8.02 (s, 1H), 7.74-7.72 (m, 1H), 7.56-7.53 (m, 1H), 7.25-7.23 (m, 1H), 5.67 (s,
2H), 3.37-3.34 (m, 2H), 2.49-2.48 (m, 2H), 1.53-1.52 (m, 2H), 1.20 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 176.4, 143.5, 143.3, 133.0, 123.4, 122.5, 120.1, 110.5, 55.6, 48.5, 36.8, 29.4, 28.0, 22.9;
HRMS (TOF MS EI+): m/z calcd for C14H17N3O 243.1372, found 243.1372.
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5-(1H-benzo[d]imidazol-1-yl)pyrrolidin-2-one (4l). White solid (46 mg, 46%); Mp 133-134 °C; H
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NMR (400 MHz, CDCl3): δ 7.87 (s, 1H), 7.74-7.72 (m, 1H), 7.30-7.20 (m, 4H), 6.02-6.00 (m, 1H),
2.72-2.28 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 177.2, 144.3, 140.3, 131.6, 123.5, 122.9, 120.6,
109.9, 66.1, 28.7, 27.9; HRMS (TOF MS EI+): m/z calcd for C11H11N3O 201.0902, found 201.0903.
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7-(1H-benzo[d]imidazol-1-yl)azepan-2-one (4m). White solid (61 mg, 53%); Mp 173-174 °C; H
NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.81-7.78 (m, 1H), 7.47-7.45 (m, 1H), 7.47-7.43 (m, 1H),
7.36-7.29 (m, 2H), 6.41 (s, 1H), 5.83-5.79 (m, 1H), 2.66-2.44 (m, 3H), 2.34-2.31 (m, 1H), 2.18-2.15 (m,
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1H), 2.01-1.98 (m, 1H), 1.87-1.69 (m, 2H); C NMR (100 MHz, CDCl3): δ 175.3, 143.8, 140.2, 132.0,
123.6, 123.0, 120.7, 110.3, 65.8, 37.1, 35.3, 27.7, 22.5; HRMS (TOF MS EI+): m/z calcd for C13H15N3O
229.1215, found 229.1213.
5-(1H-benzo[d]imidazol-1-yl)-1-phenylpyrrolidin-2-one (4n). White solid (127 mg, 92%); Mp 163-
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164 °C; H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.72-7.70 (m, 1H), 7.32-7.03 (m, 8H), 6.41-6.38
(m, 1H), 2.90-2.70 (m, 3H), 2.37-2.32 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 173.3, 144.4, 141.0,
135.7, 131.3, 129.3, 127.0, 123.7, 123.4, 122.9, 120.9, 109.9, 71.7, 29.9, 25.6; HRMS (TOF MS EI+):
m/z calcd for C17H15N3O 277.1215, found 277.1214.
7-(1H-benzo[d]imidazol-1-yl)-1-phenylazepan-2-one (4o). White solid (62 mg, 42%); Mp 170-171
°C; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.45-7.11 (m, 6H), 6.77 (d, J
= 7.2 Hz, 2H), 6.34 (d, J = 9.2 Hz, 1H), 3.07-3.01 (m, 1H), 2.92-2.87 (m, 1H), 2.76-2.71 (m, 1H), 2.49-
2.45 (m, 1H), 2.19-1.96 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 173.9, 143.1, 140.5, 138.3, 132.8,
129.2, 128.3, 127.8, 123.6, 122.9, 120.6, 109.7, 70.3, 36.7, 33.0, 26.0, 22.4; HRMS (TOF MS EI+): m/z
calcd for C19H19N3O 305.1528, found 305.1527.
N-((1H-benzo[d]imidazol-1-yl)methyl)-N-methylmethanesulfonamide (4p). Yellow oil (78 mg,
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65%); H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H),
7.39–7.31 (m, 2H), 5.62 (s, 2H), 2.98 (s, 3H), 2.71 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 143.6,
143.0, 133.2, 124.0, 123.0, 120.5, 110.0, 58.4, 38.4, 34.1; HRMS (TOF MS EI+): m/z calcd for
C10H13N3O2S 239.0728, found 239.0724.
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N-methyl-N-((2-phenyl-1H-imidazol-1-yl)methyl)methanesulfonamide (4q). Yellow oil (90 mg,
68%); 1H NMR (400 MHz, CDCl3): δ 7.53–7.51 (m, 2H), 7.47–7.44 (m, 3H), 7.25 (d, J = 1.2 Hz, 1H),
7.15 (d, J = 1.2 Hz, 1H), 5.45 (s, 2H), 2.67 (s, 3H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 148.2,
130.0, 129.4, 129.3, 129.2, 128.8, 120.5, 59.8, 38.6, 33.4; HRMS (TOF MS EI+): m/z calcd for
C12H15N3O2S 265.0885, found 265.0885.
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General procedure for the synthesis of products 5: An oven-dried Schlenk tube equipped with a
magnetic stir bar was charged with FeCl2 (25 mg, 0. 2 mmol), and amide 2 (20 mmol). The tube was
evacuated and refilled with N2, and this process was repeated three times. Then di-tert-butyl peroxide
(8.76 g, 60 mmol) was added. The resulting mixture was stirred at 120 °C for 3 h. After completion of
the reaction, the resulting solution was cooled to room temperature. The reaction mixture was then
filtered and the solvent was removed under reduced pressure. The residue was purified by flash column
chromatography on silica gel (ethyl acetate/ petroleum ether, 1:3) to afford the corresponding product.
N-(tert-butoxymethyl)-N-methylbenzamide (5). Light yellow oil (2.0 g, 45%); Isolated as two
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rotamers of 3/1 ratio in H NMR; H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 7.2 Hz, 2H), 7.37–7.35
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(m, 3H), 4.54/5.02 (s, 2H), 3.09/2.94 (s, 3H), 1.11/1.28 (s, 3H); C NMR (100 MHz, CDCl3): δ 172.0,
171.1, 136.1, 135.5, 129.9, 129.6, 128.2, 128.0, 127.4, 126.8, 74.8, 74.2, 73.0, 70.7, 35.5, 32.8, 27.9,
27.6; HRMS (TOF MS EI+): m/z calcd for C13H19NO2 221.1416, found 221.1413.
ACKNOWLEDGMENT. The project is supported by Natural Science Foundation of China (No.
21072170).
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Supporting Information Available. Copies of H and C NMR spectra for 3a-m, 4a-q and 5. This
material is available free of charge via the Internet at http://pubs.acs.org.
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