Palladium-catalyzed synthesis of benzimidazoles and quinazolinones from common precursors

Article abstract of DOI:10.1021/jo301805d

N-(o-Halophenyl)imidoyl chlorides and the corresponding imidates are easily prepared and can be utilized as complementary precursors for the synthesis of important heterocycles. The synthesis of N-substituted benzimidazoles was possible from the palladium

Full text of DOI:10.1021/jo301805d

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Featured Article
Palladium-Catalyzed Synthesis of Benzimidazoles
and Quinazolinones from Common Precursors
Jessie E. R. Sadig, Radleigh A. A. Foster, Florian Wakenhut, and Michael C. Willis
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 03 Oct 2012
Downloaded from http://pubs.acs.org on October 4, 2012
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Palladium-Catalyzed Synthesis of Benzimidazoles and Quinazolinones from Common
Precursors
†
†
‡
†, *
Jessie E.R. Sadig, Radleigh Foster, Florian Wakenhut and Michael C. Willis.
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†
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1
‡
3TA, U.K. Worldwide Medicinal Chemistry, Pfizer, Sandwich, Kent, CT13 9NJ, U.K.
michael.willis@chem.ox.ac.uk
Graphical Abstract
Quinazolinones
Common Precursor
Benzimidazoles
CO (1 atm)
Pd(OAc)2
L3
NH2R4
R2
R2
Pd(OAc)2
N
N
X
N
L3
R1
R1
R1
R2
N
Y
NH2R4
R4
N
R4
O
X = Br, Cl; Y = Cl
X = Br, Cl; Y = OR3
1
7 examples
25 examples
42-94% yield
41-90% yield
P
Me
L3
Abstract
N-(o-halophenyl)imidoyl chlorides and the corresponding imidates are easily prepared and
can be utilised as complementary substrates for the synthesis of important heterocycles. The
synthesis of N-substituted benzimidazoles was possible from the palladium-catalyzed
reaction of both class of substrate with a variety of N-nucleophiles. The use of the imidate
precursor for the synthesis of N-substituted quinazolinones by incorporation of a palladium-
catalyzed aminocarbonylation reaction has also been demonstrated. Both processes tolerate a
wide range of functional groups.
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Introduction
1
2
Nitrogen-containing heterocycles such as benzimidazoles and quinazolinones display a
wide range of pharmacological activities. Palladium catalysis has had a significant impact on
the synthesis of these important molecules as it provides notable advantages over classical
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0
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0
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,4,5
syntheses.
For example, readily available starting materials can be utilised under mild
reaction conditions to afford complex scaffolds. However, there is a continuing need to
develop ever more efficient ways of preparing these molecules. One attractive strategy is the
6
use of a single class of precursor to synthesise a variety of heterocyclic motifs. Towards this
end, we have developed substrates which when subjected to palladium or copper-catalyzed
reactions with appropriate nucleophiles undergo tandem processes to form a number of
different heterocycles. For example, 2-(2-haloalkenyl)-aryl halides 1 (Scheme 1) or the
corresponding alkenyl triflates 2 have been efficiently used to construct indoles 3 as a result
7
8,9
of tandem C-N bond forming reactions with N-nucleophiles. The use of these substrates
for the construction of 2-quinolones 4 was also possible by inclusion of a palladium-
1
0
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catalyzed alkenyl aminocarbonylation to the reaction sequence. We envisaged that the use
of structurally similar N-(o-halophenyl)imidoyl chlorides 5 or imidates 6 could be used to
synthesise benzimidazoles 7 and quinazolinones 8. This could occur via a palladium-
catalyzed coupling at the aryl halide, followed by a condensation/cyclisation or by
nucleophilic substitution at the imidoyl moiety then an intramolecular palladium-catalyzed
ring closing reaction. This reactivity difference would be determined by the susceptibility of
the imidoyl unit to undergo nucleophilic attack.
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Scheme 1. Synthesis of heterocycles from Common Precursors
Previous work:
R2
R2
R2
R3
R3
Pd or Cu
Pd, CO
R1
R1
R1
R3
Y
4
NH R
2
4
NH R
2
N
R4
10
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N
X
O
R4
1: X = Br, Cl; Y = Br, Cl,
: X = Br, Cl; Y = OTf
2
4
3
This work:
N
N
R2
N
X
R2
Pd
N
N
R4
Pd, CO
NH2R4
R1
R1
R1
R2
Y
NH2R4
R4
O
5: X = Br, Cl; Y = Cl
6: X = Br, Cl; Y = OR3
8
7
ꢀ
Results and Discussion
Initial investigations focused on the viability of N-(o-halophenyl)imidoyl chlorides 5 as
12
substrates for benzimidazoles. These substrates were prepared in a two-step process,
namely by synthesis of amides 9 and then conversion of these to imidoyl chlorides 5 using
1
3
phosphorous pentachloride (Scheme 2). Although not stable towards purification by column
chromatography, these substrates were obtained in excellent conversions and were employed
directly in the heterocycle forming transformation (see experimental section and supporting
1
13
14
2
information for H and C NMR spectra). It was found that use of SOCl
or oxalyl chloride
1
5
and 2,6-lutidine, were both less efficient methods.
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5
5
5
6
a
Scheme 2. Synthesis of imidoyl chlorides 5 from amides 9
H
N
R2
R2
NH2
X
N
X
O
a)
b)
R1
R1
R1
+
R2
O
Cl
Cl
X
0
1
2
3
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0
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0
1
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9
0
1
2
1
2
9
9
9
a: R = H; R = Ph; X = Cl
5a: R = H; R = Ph; X = Cl
1
2
1
2
b: R = 5-OMe; R = Ph; X = Cl
5b: R = 5-OMe; R = Ph; X = Cl
1
2
1
2
c: R = 4-Me; R = Ph; X = Cl
5c: R = 4-Me; R = Ph; X = Cl
1
2
1
2
9d: R = 6-Me; R = Ph; X = Cl
5d: R = 6-Me; R = Ph; X = Cl
1
2
1
2
9e: R = 4-CN; R = Ph; X = Cl
5e: R = 4-CN; R = Ph; X = Cl
1
2
1
2
9f: R = 5-COMe; R = Ph; X = Cl
5f: R = 5-COMe; R = Ph; X = Cl
1
2
1
2
9g: R = Py; R = Ph; X = Cl
5g: R = Py; R = Ph; X = Cl
1
2
1
2
9
9
9
9
9
h: R = 4-F; R = Ph; X = Cl
5h: R = 4-F; R = Ph; X = Cl
1
2
1
2
i: R = 4-Cl; R = Ph; X = Br
5i: R = 4-Cl; R = Ph; X = Br
1
2
1
2
j: R = H; R = 2-Fu; X = Cl
5j: R = H; R = 2-Fu; X = Cl
1
2
1
2
k: R = H; R = 4-Py; X = Cl
5k: R = H; R = 4-Py; X = Cl
1
2
t
1
2
t
l: R = H; R = Bu; X = Cl
5l: R = H; R = Bu; X = Cl
a
Reaction Conditions: a) 2-haloaniline (1.0 equiv), acid chloride (1.2 equiv), triethylamine
(1.1 equiv), THF, 0 °C, 3 h; b) PCl (1.1 equiv), DCM, reflux, 24 h.
5
Reaction of imidoyl chloride 5a with benzylamine (10a) in the presence of a catalyst derived
1
6
from Pd
2 3
(dba) and SPhos (L1) (see Figure 1) along with sodium tert-butoxide and toluene
at 100 °C afforded a low yield of benzimidazole 7a (entry 1). Changing the ligand to
1
7
DavePhos (L2) increased the yield (entry 2), however, use of cesium carbonate as the base
gave only a trace amount of product (entry 3). The use of an alternative palladium source,
2
namely Pd(OAc) gave an excellent yield (entry 4). Unfortunately, when this system was
applied to the more challenging electron-rich imidoyl chloride 5b, a poor yield of
benzimidazole 7b was obtained, even at an elevated reaction temperature (entry 5). When an
®
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alternative ligand was utilised, cataCXium A (L3), an increase in yield was observed
1
9
(entry 6). This reaction was then subjected to microwave irradiation with benzotrifluoride
as the solvent, which has previously been used as a toluene substitute in similar microwave
2
0
reactions. This gave only a small increase in yield (entry 7). However, increasing the
temperature to 135 °C afforded a high yield (entry 8).
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Figure 1. Structures of Ligands L1-L6.
P
Me
PCy2
PCy2
NMe2
MeO
OMe
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11
12
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L2
L3
L1
P(iPr)2
OMe
t
Bu P.HBF
Ph P
2
PPh2
3
4
L4
L5
L6
a
Table 1. Optimisation of Reaction Conditions using imidoyl chlorides 5a and 5b
Pd catalyst (5 mol%)
ligand (7 mol%)
R1
N
Ph
R1
N
N
+
NH2
Ph
10a
t
Ph
Ph
NaO Bu, solvent
Cl
Cl
temperature, 18 h
1
1
5
5
a: R = H
7a: R = H
1
1
b: R = OMe
7b: R = OMe
ꢀ
Entry
Imidoyl
chloride
5a
Catalyst
Ligand Temperature Solvent
(°C)
Product
Yield
(%)
23
1
2
Pd
Pd
Pd
2
2
2
(dba)
(dba)
(dba)
3
3
3
L1
L2
L2
L2
L2
L3
L3
L3
100
100
100
100
120
120
120
135
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
7a
7a
7a
7a
7b
7b
7b
7b
5a
63
b
3
5a
trace
98
4
5
6
5a
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
5b
18
5b
30
c
d
7
5b
BTF
38
c,e
d
8
5b
BTF
80
a
Reaction Conditions: N-(o-chlorophenyl)imidoyl chloride 5 (1.0 equiv), 10a (1.5 equiv), Pd
b
catalyst (5.0 mol%), Ligand (7.0 mol%), base (3.0 eq), solvent, 18 h. Cs
2
CO
3
used as base.
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5
5
5
5
5
5
6
c
d
e
Reaction conducted with microwave irradiation for 2 h. BTF = Benzotrifluoride. 2.2 equiv
of base used.
0
1
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8
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0
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0
Small amounts of amidine 11 had been isolated during the reaction optimisation, and so in
order to probe the reaction mechanism, and establish if amidine 11 was an intermediate,
imidoyl chloride 5b was reacted with amine 10a in the absence of a palladium catalyst
(
Scheme 3). This afforded amidine 11 in a 65% yield. Exposure of amidine 11 to the
optimised reaction conditions led to the formation of benzimidazole 7b (together with 41% of
recovered amidine 11). Therefore, we postulate that the reaction mechanism involves initial
nucleophilic substitution by the amine at the imidoyl chloride to afford an amidine
intermediate, followed by intramolecular palladium-catalyzed amination.
Scheme 3. Synthesis of benzimidazole 7b from imidoyl chloride 5b via amidine 11
Pd(OAc) (6 mol%)
2
MeO
N
Ph
10a
MeO
N
Ph
Ph
MeO
L3 (12 mol%)
N
N
Ph
t
HN
Cl
t
Cl
NaO Bu, PhMe
r.t., 24 h
NaO Bu, PhMe
Cl
120 ϒC, 3 h, µw
Ph
b: 54%
5
b
11: 65%
7
With these optimised conditions in hand, we then explored the variety of N-nucleophiles (10)
and imidoyl chloride substrates (5) which could be utilised in this reaction (Table 2). Entries
1-5 illustrate the effectiveness of primary amines as coupling partners in this reaction, as
generally high yields of N-alkyl benzimidazoles 7c-7g were obtained. Unfortunately, the
reactivity of anilines proved to be less successful with only moderate yields of N-aryl
benzimidazoles 7i-7j obtained (entries 6-8). Similarly, hydrazine 10i gave poor yield (entry
9
). Entries 10 and 11 demonstrate the successful incorporation of electron-donating
substituents on the imidoyl chloride substrate. Electron-withdrawing moieties were also
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tolerated as shown in entries 12 and 13. Entry 14 demonstrates the application of these
reactions conditions for the successful synthesis of aza-benzimidazole 7o. A fluorine atom
was tolerated affording halogenated heterocycle 7p in a high 75% yield (entry 15). Use of N-
10
11
12
13
14
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17
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(
2-bromo-4-chlorophenyl)imidoyl chloride 5i successfully afforded chloro-substituted
benzimidazole 7q in a good 67% yield (entry 16). This is a useful substituent as it allows a
8
e
handle for further functionalization. Both furan and pyridine substituents could be
incorporated successfully at the 2-position of the benzimidazole product (entries 17 and 18).
The latter, however, required a higher catalyst loading and a prolonged reaction time in order
to obtain a good conversion of the intermediate imidamide to the heterocycle. A sterically
demanding tert-butyl group afforded the corresponding 2-alkyl benzimidazole 7t in an
excellent yield (entry 19).
Table 2. Palladium-catalyzed preparation of benzimidazoles from N-(o-
a
halophenyl)imidoyl chlorides 5
Pd(OAc) (5 mol%)
R2
2
N
X
N
N
R3
L3 (7 mol%)
R1
R1
R2
3
+
H N R
2
t
Cl
NaO Bu, BTF
o
1
35 C, 2 h, µw
5
10
7
ꢀ
Entry
Imidoyl
chloride
N-nucleophile
Product
Yield (%)
69
N
N
1
10a
7c
Ph
Me
5
c
Ph
N
2
5c
NH2
7d
75
73
Ph
N
Me
1
0b
Ph
N
3
5c
Me
NH2
7e
Ph
1
0c
N
Me
C H
8
17
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
b
b
N
N
4
5c
5c
7f
94
48
Ph
NH2
Me
1
0d
N
N
5
NH2
7g
Ph
S
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
1
0e
S
b
NH2
N
N
6
7
5c
5c
7h
7i
53
46
45
Ph
Me
Me
10f
Me
b
NH2
N
N
Ph
Me
MeO
1
0g
OMe
b
b
F
NH2
N
N
8
5c
5c
7j
Ph
Me
F
F
1
0h
F
N
N
9
7k
7l
47
91
O
N NH2
Ph
Me
1
0i
N
O
b
Me
Me
10
10a
N
Ph
N
N
Ph
Cl
Cl
5d
Ph
MeO
N
Ph
MeO
1
1
10a
10a
10a
N
N
7b
7m
7n
80
46
71
Ph
Cl
Cl
5
b
Ph
b
N
Ph
N
1
2
Ph
Cl
N
NC
NC
Cl
5
e
Ph
b
O
O
13
N
Ph
N
N
Me
Me
Ph
Cl
Cl
5
f
Ph
b
N
Ph
N
1
4
10a
7o
50
Ph
Cl
N
N
N
Cl
5
g
Ph
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b
c
N
Ph
N
N
1
5
10a
7p
7q
7r
75
67
80
Ph
Cl
F
F
Cl
5
h
Ph
N
Ph
N
1
6
10a
Ph
Cl
N
Cl
Cl
Br
10
11
12
13
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5
i
Ph
N
17
10a
10a
N
O
N
O
Cl
Cl
Ph
5
j
d
N
N
1
1
8
N
7s
7t
72
84
N
N
Cl
Cl
Ph
5k
N
b
tBu
N
N
9
10a
tBu
Cl
Cl
5l
Ph
a
Conditions: N-(o-halophenyl)imidoyl chloride 5 (1.0 equiv), N-nucleophile 10 (1.5 equiv),
t
b
Pd(OAc)
2
(5.0 mol%), L3 (7.0 mol%), NaO Bu (2.2 equiv), BTF, 135 °C, 2 h, µw. Reaction
c
carried out at 50 °C, 0.5 h, µw then 135 °C, 2 h, µw. Reaction carried out at 50 °C, 0.5 h, µw
d
then 120 °C, 2 h, µw. Reaction carried out with Pd(OAc)
2
(10 mol%), L3 (14 mol%) at
5
0 °C, 0.5 h, µw then 135 °C, 4 h, µw.
We next turned our attention to the use of N-(o-halophenyl)imidates 6 in this process. These
substrates were readily synthesised either by the acid-catalyzed reaction of 2-haloanilines
2
1
with ortho-esters following literature precedent (p-TSA, PhMe, reflux,Condition A), or by
heating 2-haloanilines with an excess of ortho-esters to 90-110 °C (Condition B) (Scheme
22
4
).
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Scheme 4. Synthesis of imidates 6
NH2
X
N
X
R2
OMe
OMe
OMe
(A) or (B)
R1
R2
R1
+
OMe
1
2
1
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6a: R = 4-Me; R = Ph; X = Cl
6i: R = 5-OMe; R = Ph; X = Br
1
2
1
2
6
6
6
6
6
6
6
b: R = 5-OMe; R = Ph; X = Cl
6j: R = 4-CO Me; R = Ph; X = Br
2
1
2
1
2
c: R = Py; R = Ph; X = Cl
6k: R = Py; R = Ph; X = Br
1
2
1
2
d: R = 4-F; R = Ph; X = Cl
6l: R = 4-F; R = Ph; X = Br
1
2
n
1
2
e: R = H; R = Bu; X = Cl
6m: R = 4-Cl; R = Ph; X = Br
1
2
1
2
n
f: R = H; R = Bn; X = Cl
6n: R = H; R = Bu; X = Br
1
2
1
2
g: R = H; R = Ph; X = Br
6o: R = H; R = Bn; X = Br
1
2
h: R = 4,6-di-Me; R = Ph; X = Br
a
Reaction Conditions: (A) 2-haloaniline (1.0 equiv), ortho-ester (1.1-2.0 equiv), p-TSA (cat.),
PhMe, reflux, 3 h. or (B) 2-haloaniline (1.0 equiv), ortho-ester (1.1-2.0 equiv), 90-110 °C,
9-53 h.
1
Exploratory palladium-catalyzed reactions revealed that under similar reaction conditions to
those used for the imidoyl chloride substrates, these precursors gave high yields of the
desired heterocycle only when an aniline nucleophile was employed, demonstrating
complementary reactivity to the corresponding imidoyl chloride substrates. The scope of both
the N-nucleophile (10) and imidate substrate (6) were explored (Table 3). The use of
electron-rich anilines gave excellent yields of N-aryl benzimidazoles 7h and 7i (entries 1 and
2). However, moderate yields were obtained for electron-poor aniline 10h (entry 3) and
hydrazine 10i (entry 4). Entries 5-10 show that a variety of functional groups (methoxy,
pyridyl, fluoro, alkyl and benzyl) can be tolerated on the substrate back-bone. In addition,
comparison of entries 8 and 9 demonstrates the increased reactivity of aryl bromide substrates
relative to aryl chlorides, as an excellent yield of benzimidazole 7x was obtained in a shorter
reaction time and at a lower reaction temperature when the bromide substrate was employed.
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Table 3. Palladium-catalyzed preparation of benzimidazoles from N-(o-halophenyl)
a
imidates 6
Pd(OAc) (5 mol%)
R2
2
N
X
N
N
R3
L3 (7 mol%)
R1
3
R1
R2
+
H N R
2
t
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OMe
NaO Bu, BTF
o
150 C, 3 h, µw
6
10
7
ꢀ
Entry
Imidate
6a
N-nucleophile
Product
Yield (%)
1
2
3
4
5
10f
10g
10h
10i
7h
7i
7j
7k
N
87
86
42
43
42
6a
6a
6a
MeO
N
Ph
OMe
MeO
10f
7u
Ph
N
Cl
6b
Me
Ph
N
Ph
OMe
N
N
6
7
8
10f
10f
10f
10f
10f
7v
7w
7x
7x
7y
80
80
64
94
76
N
N
Cl
6
c
Me
N
Ph
N
N
Ph
OMe
F
F
Cl
6
d
Me
N
nBu
N
N
nBu
OMe
Cl
6e
Me
b
nBu
N
N
N
9
nBu
OMe
Br
6
n
Me
N
N
1
0
Ph
OMe
N
Ph
Cl
6
f
Me
1
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1
1
1
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Conditions: N-(o-halophenyl)imidate 6 (1.0 equiv), N-nucleophile 10 (1.5 equiv), Pd(OAc)
2
t
b
(
5.0 mol%), L3 (7.0 mol%), NaO Bu (2.2 equiv), BTF, 150 °C, 3 h, µw. Reaction carried out
at 135 °C, 2 h, µw.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Having demonstrated the use of both substrate classes in the palladium-catalyzed synthesis of
benzimidazoles, we then focused on their use in quinazolinone synthesis. Investigations
began with the reaction of N-(o-bromophenyl)imidoyl chloride 5m with benzylamine (10a)
utilising the catalyst system developed for benzimidazole synthesis in a two-step process
(Scheme 5). The reaction was initially carried out at 55 °C for 0.5 h to allow formation of an
amidine intermediate, which was then subjected to a balloon atmosphere of carbon monoxide.
The desired quinazolinone heterocycle 8a was obtained in a 30% yield as a result of a
palladium-catalyzed aminocarbonylation reaction; however, benzimidazole 7a was also
isolated. Evaluation of a variety of reaction parameters did not result the identification of a
selective set of conditions for the preparation of quinazolinones from the imidoyl chloride
precursors.
Scheme 5. Palladium-catalyzed synthesis of quinazolinone 8a from imidoyl chloride 5m
Pd(OAc) (6 mol%)
2
N
Ph
N
Ph
N
N
L3 (18 mol%)
Ph
Ph
+
10a
+
Cl
N
Ph
Cs CO , PhMe
Br
2
3
55 ϒC, 0.5 h
then CO (1 atm)
85 ϒC, 18 h
O
5
m
8a: 30%
7a: 40%
We postulated that the use of the imidate precursor should provide a more effective route to
quinazolinones. An initial palladium-catalyzed aminocarbonylation reaction should occur at
2
3
the aryl halide, forming an amide intermediate, which could then undergo base induced
cyclisation. Additionally, a two-step one-pot process should no longer be required. In order to
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test this we investigated the coupling of imidate 6g with aniline 10f under a balloon
t
atmosphere of carbon monoxide (Table 4). The use of NaO Bu, K
2
CO
3
or Cs
2
CO
3
(entries 1-
3
2 3
) as the base revealed Cs CO to be the most successful, as quinazolinone 8b was obtained
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
in 75% yield. Reduction of the catalysts and ligand loadings gave a lower conversion (entry
4), as did the use of ligands which have been successfully used in our earlier quinolone
1
1
synthesis (entries 5-7).
a
Table 4. Optimisation of reaction conditions using imidate 6g
Pd(OAc) (6 mol%)
ligand (18 mol%)
2
N
Ph
OMe
N
Ph
+
10f
+
CO (1 atm)
N
base, PhMe
Br
o
8
5 C, 18 h
O
Me
6
g
8b
Entry Ligand
Base
Yield (%)
t
1
2
3
L3
L3
L3
L3
L4
L5
L6
NaO Bu
65
62
75
2 3
K CO
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
b
c
4
37
33
c
5
6
7
46
c
18
a
Reaction conditions: 6g (1.0 equiv), 10f (1.5 equiv), Pd(OAc)
2
(6.0 mol%), ligand (18
(4.0 mol%), L3 (12
b
mol%), CO (1 atm), base (3.0 equiv), PhMe, 85 °C, 18 h. Pd(OAc)
2
c
1
mol%) used. Conversion determined from H NMR spectrum of crude reaction mixture.
We then explored the variety of N-nucleophiles (10) and imidates (6) that could be
incorporated in this process (Table 5). The use of aniline nucleophiles bearing a range of
substituents delivered quinazolinones in high yields (entries 1-4). When alkyl amines were
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
employed, it was found that greater yields of N-alkyl quinazolinones 8a and 8e-h, were
observed when the reaction temperature was raised and more of equivalents of amine (3
equiv) used (entries 5-8). Allyl amine 10k afforded the expected product in only a moderate
yield under the standard reaction conditions (entry 9). Both electron-donating (entries 10 and
11) and electron-withdrawing substituents (entry 12) on the aryl ring of the substrate were
successfully incorporated. Entry 13 demonstrates the use of a pyridyl substrate to synthesise
pyrimidinone 8m in an excellent yield. Fluoro- and chloro-substituted quinazolinones 8n and
8o were also prepared in good yields from corresponding imidates 6l and 6m, respectively
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(entries 14 and 15). 2-Alkyl substituted quinazolinones can also be prepared using this
method (entries 16 and 17). Finally, entry 18 highlights the difficulties associated with using
unactivated aryl chlorides in aminocarbonylation reactions.
Table 5. Palladium-catalyzed preparation of quinazolinones from N-(o-halophenyl)
a
imidates 6
Pd(OAc) (6 mol%)
2
R2
R2
N
N
L3 (18 mol%)
R1
R1
3
+
H N R
2
+
CO (1 atm)
N
OMe
Cs CO , PhMe
2
3
R3
Br
o
8
5 C, 18 h
O
6
10
8
Entry
Imidate
N-nucleophile
Product
Yield
%)
(
N
Ph
1
2
3
6g
10f
8b
75
65
89
N
O
Me
N
Ph
6g
6g
10g
10h
8c
N
O
OMe
N
Ph
8d
N
F
O
F
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7
8
9
b
c
NH2
N
O
Ph
4
6g
8e
76
N
N
N
1
0j
10a
N
Ph
5
6g
6g
8a
8f
59
72
N
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
c
N
Ph
6
10b
N
O
Ph
c
c
N
Ph
7
8
6g
6g
10d
10e
8g
8h
54
67
N
O
N
Ph
N
O
S
N
Ph
9
6g
8i
8j
41
81
NH2
N
1
0k
O
d
Me
Me
1
1
0
1
10f
N
Ph
OMe
N
Ph
N
Me
Br
Me
O
6
h
Me
d
MeO
N
Ph
OMe
MeO
N
Ph
10f
10f
8k
8l
71
76
N
Br
O
6
i
Me
N
Ph
OMe
N
Ph
12
MeO
MeO
N
Br
O
O
O
Me
6j
N
Ph
OMe
N
O
Ph
1
1
1
1
3
4
5
6
10f
10f
10f
10f
8m
8n
8o
90
58
74
71
N
N
Br
N
6k
Me
N
Ph
OMe
N
Ph
N
F
Br
F
O
6
l
Me
N
Ph
OMe
N
Ph
N
Cl
Br
Cl
O
6
m
Me
N
nBu
OMe
N
O
nBu
8p
N
Br
6
n
Me
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N
N
1
7
10f
8q
67
0
Ph
Ph
OMe
N
O
Br
6
o
Me
e
N
Ph
18
6a
10f
N
Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
Me
a
Conditions: N-(o-halophenyl)imidate 6 (1.0 equiv), N-nucleophile 10 (1.5 equiv), Pd(OAc)
2
b
(6.0 mol%), L3 (18 mol%), Cs
2
CO
3
(3.0 equiv), CO (1 atm), PhMe, 85 °C, 18 h. Reaction
c
d
carried out at 90 °C. Reaction carried out using 10 (3.0 equiv) and at 95 °C. Reaction
e
carried out at 90 °C. Reaction carried out at 120 °C.
Conclusion
In summary, we have demonstrated the use of N-(o-halophenyl)imidoyl chlorides and the
corresponding imidates as useful precursors for the synthesis of N-heterocycles by palladium-
catalyzed reactions with a variety of N-nucleophiles. Significant variation of the substrates
allowed for the preparation of structurally diverse benzimidazole and quinazolinone products.
Identification of a single catalyst system has proved to be general for the synthesis of both
heterocycles from either precursor. Finally, the ease of the synthesis of these precursors from
readily available starting materials makes them attractive building blocks for heterocycle
preparation.
Experimental Section
General Experimental Methods All reactions were conducted under a positive pressure of
dry argon in glassware that had been oven-dried prior to use. Microwave reactions were
carried out in a CEM Discover® S microwave using 10 mL CEM microwave tubes. The
reaction temperatures were measured by infrared detector during microwave heating. All
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reagents and solvents were purchased and used without further purification or drying. Thin
layer chromatography (TLC) was performed using pre-coated silica gel plates. Flash column
chromatography was performed with silica gel. Infrared spectra were recorded on a Fourier
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
13
Transform spectrometer. H and C nuclear magnetic resonance spectra (NMR) were
recorded in the order: chemical shift, integration, multiplicity in ppm (δ) downfield of TMS
(
3
δ = 0) in CDCl . Signal splitting patterns were described as singlet (s), doublet (d), triplet (t),
quartet (q), quintet (quin), sextet (sex), broad (br), or multiplet (m), with coupling constants
(J) in hertz and are rounded to the nearest 0.1 Hz. High resolution mass spectra (HRMS) were
performed on an electron spray injection (ESI) TOF mass spectrometer.
General procedure A for the Synthesis of Amides 9 (Scheme 2). To a solution of 2-
haloaniline (1.0 equiv) and triethylamine (1.1 equiv) in anhydrous THF (0.3 M) at 0 °C was
added drop wise acid chloride (1.2 equiv). The solution was stirred at this temperature for 3 h
then quenched with brine and the aqueous phase extracted with diethyl ether. The combined
4
organic phases were dried (MgSO ) and concentrated in vacuo. Purification was conducted
by column chromatography or recrystallization.
N-(2-Chlorophenyl)benzamide 9a. General procedure A was followed using 2-chloroaniline
(
10.0 g, 78.0 mmol) and benzoyl chloride (11.0 mL, 94.0 mmol). Recrystallization from
dichloromethane afforded 9a as a white crystalline solid (15.4 g, 85 %). Spectral data are
2
4
consistent with those in the literature.
N-(2-Chloro-5-methoxyphenyl)benzamide 9b. General procedure A was followed using 2-
chloro-5-methoxyaniline (2.0 g, 13.0 mmol) and benzoyl chloride (1.8 mL, 15.0 mmol).
Column chromatography (petrol/diethyl ether 4:1) afforded 9b as a white crystalline solid
-1
(
2.6 g, 78%); mp: 82-83 °C; IR: (KBr, νmax/cm ) 3223, 3012, 2956, 2835, 1776, 1636, 1600,
1
1
7
579, 1519, 1481; H NMR: (400 MHz, CDCl
3
) δ 8.48 (1H, br. s), 8.32-8.29 (1H, m), 7.95-
.91 (2H, m), 7.63-7.57 (1H, m), 7.56-7.50 (2H, m), 7.32-7.26 (1H, m), 6.69-6.64 (1H, m),
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
3
.88-3.85 (3H, m); C NMR: (100 MHz, CDCl
3
) δ 165.3, 159.1, 135.4, 134.6, 132.3, 129.2,
+
1
29.0, 127.0, 114.1, 111.4, 106.2, 55.7; HRMS: (ESI) found m/z 284.0447 [M+Na] ,
3
5
C
14 2
H12 ClNNaO requires 284.0449.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-(2-Chloro-4-methylphenyl)benzamide 9c. General procedure A was followed using 2-
chloro-4-methylaniline (5.0 g, 35.0 mmol) and benzoyl chloride (4.9 mL, 42.0 mmol).
Recrystallization from ethanol afforded 9c as a white crystalline solid (7.5 g, 87%). Spectral
2
5
data are consistent with those in the literature.
N-(2-Chloro-6-methylphenyl)benzamide 9d. General procedure A was followed using 2-
chloro-6-methylaniline (0.5 g, 3.5 mmol) and benzoyl chloride (0.5 mL, 4.2 mmol). Column
chromatography (petrol/diethyl ether 3:1) afforded 9d as a white solid (0.7 g, 86%). Spectral
2
6
data are consistent with those in the literature.
N-(2-Chloro-4-cyanophenyl)benzamide 9e. General procedure A was followed using
methyl 4-amino-3-chlorobenzonitrile (3.0 g, 20.0 mmol) and benzoyl chloride (2.7 mL, 24.0
mmol). Recrystallization from ethanol afforded 9e as an orange crystalline solid (2.6 g, 51%).
-
1
mp: 136-137 °C; IR: (neat, νmax/cm ) 3429, 3412, 3065, 2224, 1686, 1596, 1578, 1508, 1494,
1
1464; H NMR: (400 MHz, CDCl
3
) δ 8.81 (1H, d, J 8.7 Hz), 8.64 (1H, br. s), 7.95-7.91 (2H,
13
m), 7.74 (1H, d, J 1.8 Hz), 7.67-7.61 (2H, m), 7.59-7.53 (2H, m); C NMR: (100 MHz,
CDCl
3
) δ 165.3, 138.9, 133.7, 132.9, 132.5, 132.1, 129.2, 127.2, 122.8, 121.0, 117.5, 107.7;
+
35
HRMS: (ESI) found m/z 257.0481 [M+H] , C14
H
2
10 ClN O requires 257.0476.
N-(5-Acetyl-2-chlorophenyl)benzamide 9f. General procedure A was followed using
methyl 1-(3-amino-4-chlorophenyl)ethanone (1.0 g, 6.0 mmol) and benzoyl chloride (0.8 mL,
7
.0 mmol). Recrystallization from ethanol afforded 9f as a light yellow crystalline solid (0.4
-1
g, 26%); mp: 114-116 °C; IR: (neat, νmax/cm ) 3282, 1681, 1655, 1574, 1524, 1491, 1450,
1
1408, 1355; H NMR: (400 MHz, CDCl
3
) δ 9.20 (1H, d, J 2.1 Hz), 8.51 (1H, br. s), 7.97-7.92
(
2H, m), 7.71 (1H, dd, J 8.4 Hz, J 2.1 Hz), 7.64-7.60 (1H, m), 7.58-7.50 (3H, m), 2.66 (3H,
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s); C NMR: (100 MHz, CDCl
3
) δ 197.1, 165.4, 136.6, 135.0, 134.1, 132.5, 129.3, 129.1,
+
1
27.6, 127.1, 124.0, 121.7, 26.7; HRMS: (ESI) found m/z 296.0447 [M+Na] ,
3
5
C
15 2
H12 ClNNaO requires 296.0449.
10
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N-(2-Chloropyridin-3-yl)benzamide 9g. General procedure A was followed using 3-amino-
2-chloropyridine (3.0 g, 23.0 mmol) and benzoyl chloride (3.3 mL, 28.0 mmol).
Recrystallization from ethanol afforded 9g as a light pink crystalline solid (3.4 g, 63%).
2
7
Spectral data are consistent with those in the literature.
N-(2-Chloro-4-fluorophenyl)benzamide 9h. General procedure A was followed using 2-
chloro-4-fluoroaniline (2.0 g, 14.0 mmol) and benzoyl chloride (1.9 mL, 17.0 mmol).
Recrystallization from dichloromethane afforded 9h as a light pink crystalline solid (3.1 g,
-
1
9
1
0%); mp: 110-112 °C; IR: (KBr, νmax/cm ) 3201, 3095, 2833, 2678, 1988, 1818, 1778,
1
647, 1595, 1579, 1519, 1493, 1390; H NMR: (400 MHz, CDCl
3
) δ 8.47 (1H, dd, J 9.1 Hz, J
5.7 Hz), 8.33 (1H, br. s), 7.91 (2H, d, J 7.5 Hz), 7.60-7.56 (1H, m), 7.52-7.49 (2H, m), 7.16
1
3
(
1H, dd, J 8.0 Hz, J 2.8 Hz), 7.07-7.02 (1H, m); C NMR: (100 MHz, CDCl
3
) δ 165.3, 158.5
(d, J 247.3 Hz), 134.3, 132.3, 131.2 (d, J 3.3 Hz), 128.9, 127.1, 123.9 (d, J 10.3 Hz), 122.9
1
9
(d, J 8.2 Hz), 116.3 (d, J 25.9 Hz), 114.7 (d, J 21.7 Hz); F NMR: (376 MHz, CDCl
3
) δ
+
35
−
116.0 (1F, s); HRMS: (ESI) found m/z 272.0249, [M+Na] , C13
H ClFNNaO requires
9
2
72.0249.
N-(2-Bromo-4-chlorophenyl)benzamide 9i. General procedure A was followed using 2-
bromo-6-chloroaniline (2.5 g, 12.0 mmol) and benzoyl chloride (1.7 mL, 14.0 mmol).
Recrystallization from ethanol afforded 9i as a white crystalline solid (3.1 g, 84%). Spectral
2
8
data are consistent with those in the literature.
N-(2-Chlorophenyl)furan-2-carboxamide 9j. General procedure A was followed using 2-
chloroaniline (2.0 g, 15.7 mmol) and 2-furoyl chloride (1.9 mL, 19.0 mmol).
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Recrystallization from ethanol afforded 9j as a white crystalline solid (1.4 g, 41%). Spectral
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data are consistent with those in the literature.
N-(2-Chlorophenyl)isonicotinamide 9k. General procedure A was followed using 2-
chloroaniline (2.4 g, 19.0 mmol) and isonicotinoyl chloride hydrochloride (4.0 g, 22.0 mmol).
Recrystallization from ethanol afforded 9k as a yellow crystalline solid (0.6 g, 11%). Spectral
0
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2
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8
9
0
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2
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8
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8
9
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2
3
4
5
6
7
8
9
0
3
0
data are consistent with those in the literature.
N-(2-Chlorophenyl)pivalamide 9l. General procedure A was followed using 2-chloroaniline
(3.0 g, 24.0 mmol) and pivaloyl chloride (3.6 mL, 29.0 mmol). Recrystallization from ethanol
afforded 9l as a white crystalline solid (5.0 g, 99%). Spectral data are consistent with those in
3
1
the literature.
General procedure B for the Synthesis of Imidoyl Chlorides 5 from Amides 9 (Scheme
). To amide 9 (1.0 equiv), in anhydrous DCM (0.2 M) was added PCl (1.1 equiv). The
reaction was refluxed for 24 h before cooling to room temperature. The resulting solution was
2
5
3
1
stirred and heated at 50 °C under reduced pressure until P NMR confirmed the complete
removal of all phosphoryl trichloride. No further purification was carried out and %
conversions are given. Full characterisation data was unattainable due to low stability of these
13, 15
molecules.
(
Z)-N-(2-Chlorophenyl)benzimidoyl chloride 5a. General procedure Bꢀwas followed using
1
amide 9a (5.0 g, 21.5 mmol), affording 5a as a pale green liquid (99% conversion); H NMR:
(
400 MHz, CDCl
dd, J 7.8, J 1.4 Hz), 7.16 (1H, dd, J 7.8, J 1.4 Hz), 7.00 (1H, dd, J 8.0, J 1.4 Hz); C NMR:
100 MHz, CDCl ) δ 146.2, 145.3, 135.0, 132.5, 129.8, 129.6, 128.5, 127.2, 125.8, 124.8,
21.1.
3
) δ 8.24 (2H, d, J 7.8 Hz), 7.58-7.62 (1H, m), 7.48-7.54 (3H, m), 7.33 (1H,
1
3
(
3
1
(Z)-N-(2-Chloro-5-methoxyphenyl)benzimidoyl chloride 5b. General procedure Bꢀ was
followed using amide 9b (0.6 g, 3.8 mmol), affording 5b as a yellow oil (98% conversion);
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H NMR: (400 MHz, CDCl
3
) δ 8.21 (2H, d, J 7.6 Hz), 7.61-7.55 (1H, m), 7.54-7.48 (2H, m),
7
.35 (1H, d, J 8.8 Hz), 6.71 (1H, dd, J 8.8 Hz, J 2.9 Hz), 6.53 (1H, d, J 2.9 Hz), 3.82 (3H, s);
1
3
C NMR: (100 MHz, CDCl
3
) δ 158.7, 146.5, 145.9, 134.9, 132.5, 130.2, 129.6, 128.5, 116.1,
10
11
12
13
14
15
16
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18
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
11.6, 106.6, 55.6.
(Z)-N-(2-Chloro-4-methylphenyl)benzimidoyl chloride 5c. General procedure Bꢀ was
followed using amide 9c (1.0 g, 4.1 mmol), affording 5c as an amorphous yellow solid (100%
1
conversion); H NMR: (400 MHz, CDCl
3
) δ 8.21 (2H, d, J 7.7 Hz), 7.59-7.56 (1H, m), 7.52-
1
3
7.48 (2H, m), 7.29 (1H, s), 7.12 (1H, d, J 8.0 Hz), 6.90 (1H, d, J 8.0 Hz), 2.37 (3H, s); C
NMR: (100 MHz, CDCl ) δ 145.8, 142.6, 135.9, 135.1, 132.3, 130.2, 129.6, 128.5, 127.9,
24.6, 120.9, 20.8.
Z)-N-(2-Chloro-6-methylphenyl)benzimidoyl chloride 5d. General procedure Bꢀ was
3
1
(
followed using amide 9d (0.4 g, 1.4 mmol), affording 5d as an amorphous yellow solid
1
(100% conversion); H NMR: (400 MHz, CDCl
3
) δ 7.95-7.90 (2H, m), 7.59-7.52 (1H, m),
1
3
7
.49-7.43 (2H, m), 7.29 (1H, dd, J 6.7 Hz, J 2.0 Hz), 7.18-7.13 (2H, m), 2.29 (3H, s); C
NMR: (100 MHz, CDCl
127.5, 127.0, 19.0.
3
) δ 138.2, 133.9, 132.8, 132.0, 131.5, 129.3, 128.7, 127.9, 127.5,
(
Z)-N-(2-Chloro-4-cyanophenyl)benzimidoyl chloride 5e. General procedure Bꢀ was
followed using amide 9e (2.0 g, 3.3 mmol), affording 5e as a colourless oil (100%
1
conversion); H NMR: (400 MHz, CDCl
3
) δ 8.20 (2H, d, J 7.8 Hz), 7.78-7.76 (1H, m), 7.65-
13
7
1
3
.58 (2H, m), 7.53 (2H, t, J 7.7 Hz), 7.06 (1H, d, J 8.2 Hz); C NMR: (100 MHz, CDCl ) δ
49.4, 148.2, 134.4, 133.5, 133.2, 131.2, 129.7, 128.7, 125.8, 121.9, 117.7, 109.4.
(
Z)-N-(5-Acetyl-2-chlorophenyl)benzimidoyl chloride 5f. General procedure Bꢀ was
followed using amide 9f (0.4 g, 1.5 mmol), affording 5f as an orange oil (98% conversion);
1
3
H NMR: (400 MHz, CDCl ) δ 8.21 (2H, d, J 7.6 Hz), 7.74 (1H, dd, J 8.3 Hz, J 1.8 Hz),
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5
5
5
5
5
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13
7
1
.63-7.48 (5H, m), 2.61 (3H, s); C NMR: (100 MHz, CDCl
3
) δ 196.6, 147.5, 145.6, 136.2,
34.6, 132.8, 130.2, 130.1, 129.6, 128.6, 125.5, 121.1, 26.7.
(
Z)-N-(2-Chloropyridin-3-yl)benzimidoyl chloride 5g. General procedure Bꢀwas followed
0
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2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
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9
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2
3
4
5
6
7
8
9
0
using amide 9g (1.0 g, 4.3 mmol), affording 5g as an amorphous yellow oil (98%
1
conversion); H NMR: (400 MHz, CDCl
3
) δ 8.27 (1H, dd, J 4.5 Hz, J 1.9 Hz), 8.22 (2H, d, J
1
3
7
.9 Hz), 7.64-7.59 (1H, m), 7.56-7.48 (2H, m), 7.37-7.29 (2H, m); C NMR: (100 MHz,
3
CDCl ) δ 148.4, 145.5, 142.3, 141.9, 134.5, 132.9, 129.7, 129.5, 128.7, 122.7.
(Z)-N-(2-Chloro-4-fluorophenyl)benzimidoyl chloride 5h. General procedure Bꢀ was
followed using amide 9h (1.0 g, 4.0 mmol), affording 5h as an amorphous white solid (98%
1
conversion); H NMR: (400 MHz, CDCl
3
) δ 8.22-8.20 (2H, m), 7.61-7.58 (1H, m), 7.53-7.49
1
3
(
2H, m), 7.28-7.22 (1H, m), 7.08-7.03 (1H, m), 7.00-6.96 (1H, m); C NMR: (100 MHz,
3
CDCl ) δ 159.7 (d, J 247.0 Hz), 146.8, 141.6 (d, J 3.3 Hz), 134.9, 132.6, 129.6, 128.6, 125.8
1
9
(d, J 10.3 Hz), 122.0 (d, J 8.7 Hz), 117.1 (d, J 25.6 Hz), 114.4 (d, J 22.4 Hz); F NMR: (376
MHz, CDCl ) δ −116.5 (1F, s).
Z)-N-(2-Bromo-4-chlorophenyl)benzimidoyl chloride 5i. General procedure Bꢀ was
3
(
followed using amide 9i (1.0 g, 3.4 mmol), affording 5i as an amorphous yellow solid (99%
1
conversion); H NMR: (400 MHz, CDCl
3
) δ 8.21 (2H, d, J 7.2 Hz), 7.66 (1H, d, J 2.0 Hz),
7
.62-7.57 (1H, m), 7.54-7.48 (2H, m), 7.34 (1H, dd, J 8.5 Hz, J 2.0 Hz), 6.93 (1H, d, J 8.5
1
3
Hz); C NMR: (100 MHz, CDCl
28.1, 121.9, 115.3.
Z)-N-(2-Chlorophenyl)furan-2-carbimidoyl chloride 5j. General procedure Bꢀ was
3
) δ 146.7, 145.3, 134.8, 132.7, 132.4, 130.7, 129.6, 128.6,
1
(
followed using amide 9j (1.0 g, 4.5 mmol), affording 5j as a brown oil (100% conversion);
1
3
H NMR: (400 MHz, CDCl ) δ 7.68 (1H, s), 7.46 (1H, d, J 8.0 Hz), 7.33-7.25 (2H, m), 7.17-
1
3
3
7.12 (1H, t, J 7.7 Hz), 6.99 (1H, d, J 7.9 Hz), 6.56 (1H, s); C NMR: (100 MHz, CDCl ) δ
1
48.0, 147.2, 144.5, 134.9, 129.8, 127.2, 126.1, 125.2, 121.5, 119.0, 112.5.
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(
Z)-N-(2-Chlorophenyl)isonicotinimidoyl chloride 5k. General procedure Bꢀwas followed
using amide 9k (0.5 g, 4.3 mmol), affording 5k as an amorphous yellow solid (100%
1
conversion); H NMR: (500 MHz, CDCl
3
) δ 8.95 (2H, d, J 6.5 Hz), 8.49 (2H, d, J 6.5 Hz),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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49
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59
60
7
.53 (1H, dd, J 8.1 Hz, J 1.3 Hz), 7.38 (1H, td, J 7.8 Hz, J 1.3 Hz), 7.30-7.24 (1H, m), 7.06
1
3
(1H, dd, J 7.9 Hz, J 1.5 Hz); C NMR: (125 MHz, CDCl
3
) δ 146.7, 144.4, 143.5, 141.8,
1
30.2, 127.6, 127.4, 125.3, 125.2, 120.5.
(
Z)-N-(2-Chlorophenyl)pivalimidoyl chloride 5l. General procedure Bꢀwas followed using
1
amide 9l (2.0 g, 9.5 mmol), affording 5l as a yellow oil (98% conversion); H NMR: (400
3
MHz, CDCl ) δ 7.40 (1H, d, J 8.0 Hz), 7.26-7.22 (1H, m), 7.08 (1H, td, J 7.7 Hz, J 1.2 Hz),
1
3
6
1
.82 (1H, dd, J 7.9 Hz, J 1.2 Hz), 1.42 (9H, s); C NMR: (100 MHz, CDCl
3
) δ 158.3, 145.1,
29.7, 127.1, 125.7, 124.2, 120.9, 44.0, 28.3.
(
Z)-N-Benzyl-N'-(2-chloro-5-methoxyphenyl)benzimidamide 11 (Scheme 3). To a 5 mL
microwave vial was added (Z)-N-(2-chloro-5-methoxyphenyl)benzimidoyl chloride 5b (150
mg, 0.5 mmol) and sodium t-butoxide (77 mg, 0.9 mmol). This was capped and purged with
2
N three times and then toluene (1.5 mL) and benzylamine 10a (90 µL, 0.9 mmol) were
added. The reaction mixture was heated at room temperature for 24 h. The reaction mixture
was then diluted with diethyl ether (2 mL) and filtered through a Celite pad, washing with
diethyl ether (40 mL) and concentrated in vacuo. Column chromatography (petrol/diethyl
ether 3:1) afforded 11 as yellow crystalline solid (123 mg, 65%); mp: 88-91 °C; νmax
-1
1
(
neat/cm ) 3423, 1625, 1586, 1513, 1471, 1289, 1130; H NMR: (400 MHz, CDCl
3
) δ 7.55-
7
.49 (2H, m), 7.45-7.28 (8H, m), 7.15 (1H, d, J 8.7 Hz), 6.42-6.36 (1H, m), 6.23-6.16 (1H,
1
3
m), 5.18 (1H, br. s), 4.75 (2H, br. s), 3.63 (3H, s); C NMR: (100 MHz, CDCl
3
) δ 158.4,
1
57.9, 138.7, 135.0, 129.5, 129.0, 128.7 (2C), 128.3, 128.1, 127.9, 127.4, 118.8, 109.4, 108.7,
+
35
2
55.3, 46.1; HRMS (ESI) found m/z 351.1252 [M+H] , C21H20 ClN O requires 351.1259.
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1
-Benzyl-5-methoxy-2-phenyl-1H-benzo[d]imidazole 7b (Scheme 3). To a 5 mL
microwave vial was added amidine 11 (100 mg, 0.3 mmol), palladium (II) acetate (3.8 mg,
.02 mmol), L3 (12.0 mg, 0.03 mmol) and sodium t-butoxide (86 mg, 0.9 mmol). This was
capped and purged with N three times and anhydrous toluene (1.0 mL) and benzylamine 10a
0
0
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8
9
0
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2
3
4
5
6
7
8
9
0
2
(45 µL, 0.5 mmol) were then added. This was heated in a microwave for 3 h at 120 °C. After
cooling to room temperature the reaction mixture was diluted with diethyl ether (5 mL) and
filtered through a Celite pad, washing with diethyl ether (40 mL). This was then concentrated
in vacuo. Column chromatography (petrol/diethyl ether 1:3) afforded 7b as a pale yellow
32
crystalline solid (60 mg, 54%). Spectral data are consistent with those in the literature.
Amidine 11 (41mg, 41%) was also recovered. Data as reported previously.
General procedure D for the synthesis of Imidates 6 (Scheme 4) (Condition A).ꢀ A
mixture of 2-haloaniline (1.0 equiv), ortho-ester (1.1-2.0 equiv) and p-toluenesulfonic acid
(cat.) in anhydrous toluene (0.3 M) was heated under reflux for 3 h with the aid of Dean-
Stark apparatus. The mixture was cooled and concentrated in vacuo. The residue was re-
dissolved in diethyl ether, washed with a saturated aqueous solution of sodium bicarbonate
and then brine. This was then dried (MgSO
conducted by column chromatography.
4
) and concentrated in vacuo. Purification was
General procedure E for the synthesis of Imidates 6 (Scheme 4) (Condition B).ꢀA mixture
of 2-haloaniline (1,0 equiv) and ortho-ester (1.1-2.0 equiv) was heated at 90-110 °C for 9-53
h with the aid of Dean-Stark apparatus. Purification was conducted by column
chromatography.
(
Z)-Methyl N-2-chloro-4-methylphenylbenzimidate 6a. General procedure Eꢀwas followed
using 2-chloro-4-methylaniline (1.6 mL, 13.0 mmol) and trimethyl orthobenzoate (4.7 mL,
27.0 mmol) and heated at 90 °C for 53 h. Column chromatography (petrol/diethyl ether 12:1)
-
1
afforded 6a as a yellow oil and as a single isomer (3.1 g, 93%); IR: (neat, νmax/cm ) 3026,
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985, 1667, 1609, 1493, 1435, 1285; H NMR: (400 MHz, CDCl
3
) δ 7.35-7.29 (3H, m), 7.25-
.22 (2H, m), 7.14-7.12 (1H, m), 6.84 (1H, dd, J 8.0 Hz, J 1.1 Hz), 6.54 (1H, d, J 8.0 Hz),
1
3
.03 (3H, s), 2.25 (3H, s); C NMR: (100 MHz, CDCl
3
) δ 160.2, 143.1, 133.3, 131.6, 130.0,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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28
29
30
31
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
30.0, 128.6, 128.0, 128.0, 125.3, 122.4, 54.3, 20.5; HRMS: (ESI) found m/z 282.0652
+
35
[M+Na] , C15
H14 ClNNaO requires 282.0656.
(
Z)-Methyl N-2-chloro-5-methoxyphenylbenzimidate 6b. General procedure D was
followed using 2-chloro-5-methoxyaniline (1.0 g, 6.3 mmol) and trimethyl orthobenzoate (2.3
mL, 13.0 mmol). Column chromatography (petrol/diethyl ether 12:1) afforded 6b as a
-
crystalline colourless solid as a single isomer (1.0 g, 59 %); mp: 67-69 °C; IR: (neat, νmax/cm
1
1
)
3006, 2950, 1666, 1593, 1573, 1493, 1479, 1461, 1445, 1434, 1399, 1317; H NMR: (400
MHz, CDCl
3
) δ 7.39-7.31 (3H, m), 7.28-7.22 (2H, m), 7.18 (1H, d, J 8.8 Hz), 6.48 (1H, dd, J
13
8
.8 Hz, J 2.9 Hz), 6.27 (1H, d, J 2.9 Hz), 4.03 (3H, s), 3.67 (3H, s); C NMR: (100 MHz,
3
CDCl ) δ 160.2, 158.7, 146.5, 131.4, 130.3, 130.0, 128.5, 128.0, 117.3, 109.6, 108.0, 55.4,
+
35
5
4.4; HRMS: (ESI) found m/z 276.0795 [M+H] , C15
Z)-Methyl N-2-chloropyridin-3-ylbenzimidate 6c. General procedure D was followed
using 3-amino-2-chloropyridine (2.0 g, 16.0 mmol) and trimethyl orthobenzoate (2.9 mL,
7.0 mmol). Column chromatography (petrol/ethyl acetate 10:1) afforded 6c as an orange oil
2
H15 ClNO requires 276.0786.
(
1
-
1
and as a single isomer (1.2 g, 31%); IR: (neat, νmax/cm ) 3057, 2946, 1721, 1656, 1601,
1
1580, 1554, 1493, 1443, 1396; H NMR: (400 MHz, CDCl
3
) δ 8.02 (1H, dd, J 4.7 Hz, J 1.8
Hz), 7.37-7.22 (5H, m), 7.03 (1H, dd, J 7.8 Hz, J 4.7 Hz), 6.95 (1H, dd, J 7.8 Hz, J 1.8 Hz),
1
3
4
1
.05 (3H, s); C NMR: (100 MHz, CDCl
3
) δ 161.6, 143.6, 143.3, 142.6, 130.8, 130.6, 130.3,
+
35
28.5, 128.3, 122.8, 54.7; HRMS: (ESI) found m/z 247.0633 [M+H] , C13
H
2
12 ClN O
requires 247.0633.
(Z)-Methyl N-2-chloro-4-fluorophenylbenzimidate 6d. General procedure D was followed
using 2-chloro-4-fluoroaniline (2.0 g, 14.0 mmol) and trimethyl orthobenzoate (2.6 mL, 15.0
2
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8
9
1
1
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2
2
2
2
2
2
2
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2
3
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4
4
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4
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5
5
5
5
5
5
5
6
mmol). Column chromatography (petrol/ethyl acetate 20:1) afforded 6d as a yellow oil and as
-
1
a single isomer (1.2 g, 32%); IR: (neat, νmax/cm ) 2989, 2946, 1737, 1662, 1661, 1579, 1518,
1
1
485, 1458, 1447, 1434; H NMR: (400 MHz, CDCl
3
) δ 7.36-7.31 (3H, m), 7.29-7.24 (2H,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
m), 7.10 (1H, dd, J 8.4 Hz, J 2.8 Hz), 6.82-6.76 (1H, m), 6.62 (1H, dd, J 8.8 Hz, J 5.6 Hz),
1
3
4.05 (3H, s); C NMR: (100 MHz, CDCl
3
) δ 160.2 (d, J 155.8 Hz), 157.0, 142.3 (d, J 3.2
Hz), 131.3, 130.3, 128.6, 128.1, 126.1 (d, J 10.4 Hz), 123.2 (d, J 8.3 Hz), 116.7 (d, J 25.3
1
9
Hz), 114.3 (d, J 22.1 Hz), 54.4; F NMR: (376 MHz, CDCl
3
) δ −119.7 (1F, s); HRMS: (ESI)
12 ClFNO requires 264.0586.
Z)-Methyl N-2-chlorophenylpentanimidate 6e. General procedure D was followed using
+
35
found m/z 264.0591 [M+H] , C14
H
(
2
-chloroaniline (1.0 g, 7.8 mmol) and trimethyl orthovalerate (1.4 mL, 8.6 mmol). Column
chromatography (petrol/ethyl acetate 20:1) afforded 6e as colourless oil and as a single
-1
isomer (1.5 g, 83%); IR: (neat, νmax/cm ) 2962, 1713, 1670, 1589, 1437, 1360, 1267, 1220;
1
3
H NMR: (400 MHz, CDCl ) δ 7.37 (1H, dd, J 8.0 Hz, J 1.3 Hz), 7.18 (1H, td, J 7.6 Hz, J 1.3
Hz), 6.97 (1H, td, J 7.8 Hz, J 1.5 Hz), 6.80 (1H, dd, J 7.8 Hz, J 1.5 Hz), 3.85 (3H, s), 2.12
(2H, t, J 7.7 Hz), 1.51 (2H, quin, J 7.6 Hz), 1.24 (2H, sex, J 7.4 Hz), 0.83 (3H, t, J 7.3 Hz);
1
3
3
C NMR: (100 MHz, CDCl ) δ 165.4, 145.9, 129.7, 127.2, 125.6, 123.7, 122.6, 53.5, 30.0,
+
35
2
2
7.9, 22.3, 13.7; HRMS: (ESI) found m/z 226.0992 [M+H] , C12H17 ClNO requires
26.0993.
(Z)-Methyl N-2-chlorophenyl-2-phenylacetimidate 6f. General procedure E was followed
using 2-chloroaniline (0.3 g mL, 1.7 mmol) and (2,2,2-trimethoxyethyl)benzene (0.7 g, 3.3
mmol) and was heated at 90 °C for 22 h. Column chromatography (petrol/diethyl ether 18:1)
-
1
afforded 6f as a colourless oil and as a single isomer (0.62 g, 73%); IR: (neat, νmax/cm )
1
3
063, 3029, 2986, 2945, 2842, 1651, 1603, 1588, 1495, 1474, 1455; H NMR: (400 MHz,
CDCl
3
) δ 7.42 (1H, d, J 8.0 Hz), 7.32-7.19 (4H, m), 7.14 (2H, d, J 7.3 Hz), 7.05-7.00 (1H,
1
3
m), 6.84 (1H, dd, J 7.8 Hz, J 1.4 Hz), 3.89 (3H, s), 3.50 (2H, s); C NMR: (100 MHz,
2
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CDCl
3
) δ 163.0, 145.6, 135.2, 129.8, 129.1, 128.4, 127.3, 126.7, 125.7, 124.1, 122.9, 54.0,
+
35
3
6.8; HRMS: (ESI) found m/z 260.0841 [M+H] , C15
H15 ClNO requires 260.0837.
(
Z)-Methyl N-2-bromophenylbenzimidate 6g. General procedure D was followed using 2-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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28
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58
59
60
bromoaniline (2.0 g, 12.0 mmol) and trimethyl orthobenzoate (2.3 mL, 13.0 mmol). Column
chromatography (petrol/ethyl acetate 25:1) afforded 6g as colourless oil and as a single
-
1
isomer (3.0 g, 89%); IR: (neat, νmax/cm ) 3055, 2986, 2947, 1721, 1667, 1602, 1584, 1493,
1
1
469, 1447; H NMR: (400 MHz, CDCl
3
) δ 7.53 (1H, dd, J 8.0 Hz, J 1.4 Hz), 7.36-7.30 (3H,
m), 7.28-7.22 (2H, m), 7.09 (1H, td, J 7.7 Hz, J 1.4 Hz), 6.83 (1H, td, J 7.7 Hz, J 1.5 Hz),
13
6
1
3
3
.64 (1H, dd, J 7.9 Hz, J 1.5 Hz), 4.05 (3H, s); C NMR: (100 MHz, CDCl ) δ 159.9, 147.1,
32.7, 131.3, 130.2, 128.7, 128.0, 127.9, 123.8, 122.5, 116.3, 54.4; HRMS: (ESI) found m/z
+
79
11.9996 [M+Na] , C14H12 BrNNaO requires 311.9994.
(
Z)-Methyl N-2-bromo-4,6-dimethylphenylbenzimidate 6h. General procedure D was
followed using 2-bromo-4,6-dimethylaniline (2.0 g, 10.0 mmol) and trimethyl orthobenzoate
1.9 mL, 11.0 mmol). Column chromatography (petrol/ethyl acetate 50:1) afforded 6h as a
(
-
1
colourless oil and as a single isomer (2.6 g, 81%); mp: 39-42 °C; IR: (neat, νmax/cm ) 3052,
1
2941, 1663, 1601, 1493, 1438, 1317, 1298, 1264; H NMR: (400 MHz, CDCl
3
) δ 7.39-7.31
(3H, m), 7.27-7.22 (2H, m), 7.18 (1H, s), 6.84 (1H, s), 4.05 (3H, s), 2.23 (3H, s), 2.02 (3H, s);
1
3
3
C NMR: (100 MHz, CDCl ) δ 159.0, 142.8, 133.0, 132.1, 130.7, 130.3, 130.3, 129.2, 128.0,
+
79
128.0, 115.2, 54.3, 20.4, 18.9; HRMS: (ESI) found m/z 318.0491 [M+H] , C16H17 BrNO
requires 318.0488.
(
Z)-Methyl N-2-bromo-5-methoxyphenylbenzimidate 6i. General procedure D was
followed using 2-bromo-5-methoxyaniline (0.8 g, 4.0 mmol) and trimethyl orthobenzoate
1.3 mL, 7.5 mmol). Column chromatography (petrol/ethyl acetate 18:1) afforded 6i as white
(
-
1
crystalline solid and as a single isomer (1.0 g, 70%); mp: 76-78 °C; IR: (neat, νmax/cm )
1
3
025, 3006, 2966, 2835, 1662, 1585, 1570, 1492, 1476, 1443; H NMR: (400 MHz, CDCl
3
) δ
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.39-7.31 (4H, m), 7.28-7.23 (2H, m), 6.43 (1H, dd, J 8.8 Hz, J 2.9 Hz), 6.23 (1H, d, J 2.9
1
3
Hz), 4.03 (3H, s), 3.65 (3H, s); C NMR: (100 MHz, CDCl
3
) δ 159.9, 159.4, 147.9, 133.0,
1
31.3, 130.2, 128.6, 128.0, 110.1, 107.9, 107.0, 55.4, 54.4; HRMS: (ESI) found m/z 320.0280
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
79
[
2
M+H] , C15H15 BrNO requires 320.0281.
(Z)-Methyl 3-bromo-4-(methoxy(phenyl)methyleneamino)benzoate 6j. General procedure
D was followed using methyl 4-amino-3-bromobenzoate (0.4 g, 1.7 mmol) and trimethyl
orthobenzoate (0.3 mL, 1.9 mmol). Column chromatography (petrol/ethyl acetate 18:1)
-
1
afforded 6j as a thick colourless oil and as a single isomer (0.4 g, 70%); IR: (neat, νmax/cm )
1
3
062, 2991, 2948, 2842, 1718, 1659, 1591, 1548, 1494, 1433, 1391; H NMR: (400 MHz,
CDCl
.22 (2H, m), 6.66 (1H, d, J 8.3 Hz), 4.05 (3H, s), 3.87 (3H, s); C NMR: (100 MHz, CDCl
δ 165.9, 159.9, 151.7, 134.3, 130.8, 130.6, 129.5, 128.6, 128.2, 125.5, 122.0, 116.0, 54.7,
3
) δ 8.22 (1H, d, J 1.8 Hz), 7.77 (1H, dd, J 8.3 Hz, J 1.8 Hz), 7.37-7.30 (3H, m), 7.27-
1
3
7
3
)
+
79
52.1; HRMS: (ESI) found m/z 370.0044 [M+Na] , C16
3
H14 BrNNaO requires 370.0049.
(
Z)-Methyl N-2-bromopyridin-3-ylbenzimidate 6k. General procedure D was followed
using 3-amino-2-bromopyridine (0.6 g, 3.5 mmol) and trimethyl orthobenzoate (0.7 mL, 3.8
mmol). Column chromatography (petrol/ethyl acetate 10:1) afforded 6k as an orange oil and
-1
as a single isomer (0.6 g, 61%); IR: (neat, νmax/cm ) 3460, 3322, 3187, 2947, 1720, 1653,
1
1
601, 1580, 1549, 1493; H NMR: (400 MHz, CDCl
3
) δ 7.99 (1H, dd, J 4.6 Hz, J 1.6 Hz),
7.37-7.22 (5H, m), 7.03 (1H, dd, J 7.8 Hz, J 4.6 Hz), 6.86 (1H, dd, J 7.8 Hz, J 1.6 Hz), 4.05
13
3
(3H, s); C NMR: (100 MHz, CDCl ) δ 161.5, 144.5, 143.7, 136.8, 130.7, 130.6, 129.6,
+
79
1
28.6, 128.3, 123.1, 54.7; HRMS: (ESI) found m/z 312.9939 [M+Na] , C13
requires 312.9947.
Z)-Methyl N-2-bromo-4-fluorophenylbenzimidate 6l. General procedure E was followed
2
H11 BrN NaO
(
using 2-bromo-4-fluoroaniline (0.6 mL, 5.0 mmol) and trimethyl orthobenzoate (1.8 mL, 10.0
mmol) and was heated at 100 °C for 19 h. Column chromatography (petrol/diethyl ether 30:1)
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-1
afforded 6l as a colourless oil and as a single isomer (1.2 g, 79%); IR: (neat, νmax/cm ) 3065,
1
2
7
981, 2945, 2840, 1723, 1658, 1599, 1580, 1493, 1447; H NMR: (400 MHz, CDCl
3
) δ 7.37-
1
3
.24 (6H, m), 6.85-6.79 (1H, m), 6.56 (1H, dd, J 8.8 Hz, J 5.5 Hz), 4.04 (3H, s); C NMR:
) δ 160.1 (d, J 138.7 Hz), 156.9, 143.6 (d, J 3.2 Hz), 131.2, 130.3, 128.6,
128.1, 122.8 (d, J 8.1 Hz), 119.6 (d, J 25.2 Hz), 116.1 (d, J 21.9 Hz), 114.9 (d, J 21.9 Hz),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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36
37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(100 MHz, CDCl
3
1
9
5
4.5; F NMR: (376 MHz, CDCl
3
) δ −119.9 (1F, s); HRMS: (ESI) found m/z 308.0083
+
79
[
M+H] , C14H12 BrFNO requires 308.0081.
(Z)-Methyl N-2-bromo-4-chlorophenylbenzimidate 6m. General procedure E was followed
using 2-bromo-4-chloroaniline (1.0 g mL, 4.8 mmol) and trimethyl orthobenzoate (1.7 mL,
9
3
3
.6 mmol) and was heated at 110 °C for 24 h. Column chromatography (petrol/diethyl ether
-
1
0:1) afforded 6m as an orange oil and as a single isomer (0.9 g, 57%); IR: (neat, νmax/cm )
1
055, 2944, 1654, 1601, 1580, 1493, 1433, 1381, 1283; H NMR: (400 MHz, CDCl
3
) δ 7.53
(1H, d, J 2.2 Hz), 7.38-7.24 (5H, m), 7.06 (1H, dd, J 8.5 Hz, J 2.2 Hz), 6.54 (1H, d, J 8.5 Hz),
1
3
4
.04 (3H, s); C NMR: (100 MHz, CDCl
3
) δ 160.5, 146.0, 132.2, 131.0, 130.4, 128.6, 128.2,
+
1
28.1, 128.0, 123.1, 116.7, 54.6; HRMS: (ESI) found m/z 323.9790 [M+H] ,
7
9
35
C
14
H12 Br ClNO requires 323.9785.
(
Z)-Methyl N-2-bromophenylpentanimidate 6n. General procedure D was followed using
-bromoaniline (2.0 g, 11.6 mmol) and trimethyl orthovalerate (2.2 mL, 13.0 mmol). Column
2
chromatography (petrol/ethyl acetate 20:1) afforded 6n as a yellow oil and as a single isomer
-1
(
2.5 g, 78%); IR: (neat, νmax/cm ) 2960, 2872, 1715, 1668, 1586, 1466, 1435, 1357, 1313,
1
1
267; H NMR: (400 MHz, CDCl
3
) δ 7.55 (1H, dd, J 8.0 Hz, J 1.1 Hz), 7.23 (1H, td, J 7.6
Hz, J 1.1 Hz), 6.90 (1H, td, J 7.7 Hz, J 1.5 Hz), 6.78 (1H, dd, J 7.8 Hz, J 1.5 Hz), 3.86 (3H,
s), 2.11 (2H, t, J 7.7 Hz), 1.51 (2H, quin, J 7.6 Hz), 1.24 (2H, sex, J 7.6 Hz), 0.83 (3H, t, J
1
3
3
7.3 Hz); C NMR: (100 MHz, CDCl ) δ 165.2, 147.2, 132.7, 127.9, 123.9, 122.3, 116.1,
2
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