Modification and optimization of the bis-picolylamide-based relay protection for carboxylic acids to be cleaved by unusual complexation with Cu2+ salts

Article abstract of DOI:10.1021/jo301349t

A simple modification of our recently published protection scheme for carboxylic acids as amides resulted in a new protecting group with significantly improved properties. It requires shorter reaction times for deprotection and allows us to replace Cu(OTf)₂ by CuCl₂, indicating at the same time the importance of the nature of the anion of the Cu²⁺ source. Since the new scheme fulfills all criteria required for an ideal protection group it should find widespread application in synthetic organic chemistry.

Full text of DOI:10.1021/jo301349t

Article
pubs.acs.org/joc
Modification and Optimization of the Bis-picolylamide-Based Relay
Protection for Carboxylic Acids to be Cleaved by Unusual
Complexation with Cu2+ Salts
Stephan Mundinger, Uwe Jakob, Plamen Bichovski, and Willi Bannwarth*
Institut fur Organische Chemie und Biochemie, Albert-Ludwigs-Universitat Freiburg, Albertstraße 21, 79104 Freiburg, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A simple modification of our recently published
protection scheme for carboxylic acids as amides resulted in a
new protecting group with significantly improved properties. It
requires shorter reaction times for deprotection and allows us
to replace Cu(OTf)2 by CuCl2, indicating at the same time the
importance of the nature of the anion of the Cu2+ source.
Since the new scheme fulfills all criteria required for an ideal
protection group it should find widespread application in
synthetic organic chemistry.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The preparation of complex organic molecules in most cases
encompasses the need for protecting groups.1,2 Common
requirements for them are straightforward introduction and
robustness to a variety of reaction conditions combined with
the possibility for selective and efficient cleavage, preferably
under mild conditions. There is only a small number of
protection schemes fulfilling all these criteria.
Recently, we reported on two new linker systems for solid-
phase chemistry which are based on chelating amides.3,4 These
activities led us to the development of a relay protection
scheme for carboxylic acids 1a as amides of bispicolylamine
(bpa, 2) (Scheme 1).5 The protection group is easily removed
from amide 3 by treatment with Cu(OTf)2 in MeOH, which
leads to quantitative formation of methyl ester 4. The reaction
is based on the unusual involvement of the amide nitrogen in
the complexation to Cu2+ leading to a weakening of the amide
bond which makes it accessible to the nucleophilic attack by
MeOH.
To widen the scope of the new protection scheme and to
overcome the disadvantage of the long reaction times we
carried out a systematic investigation of the influence of
pendant coordinating groups on the rate of methanolysis of
amides. Therefore, we prepared an array of variants to the
original bpa entity (Scheme 2). The modifications involved the
replacement of one or both pyridine rings of bis-picolylamine
(bpa) by other coordinating entities, as well as variations of the
distances between the pyridyl donor sites.9,10
Compounds 6−25 were then submitted to a cleavage process
using Cu(OTf)2 in MeOH at rt for 24 h. The amount of the
released benzoic acid methyl ester was quantified by HPLC
using phenol as standard. As a benchmark for the methanolysis
we used the transformation of the original bpa-protected
benzoic acid amide 5 to its methyl ester (Table 1).
Omitting one pyridine ring and hence omitting one
coordination site as in 6 led only to a marginal cleavage rate,
indicating that at least three coordinating sites are necessary to
obtain decent methanolysis rates. Replacing one pyridine ring
by other heterocycles was to no avail as well. Of all investigated
compounds, derivatives 9, 10, and 25 revealed quantitative
cleavage and were superior compared to the benchmark amide
5. Since the parent amine of derivative 9 is most easily
obtained, very robust and structurally very simple, we focused
on the application of amine 9a namely dimethylaminoethyl-
picolylamine (dmepa) for the protection of carboxylic acids.
For this reason, we performed a side by side evaluation of 9
with the bpa amide 5 using Cu(OTf)2 as copper source. In the
methanolysis of 9 at rt a quantitative conversion was already
observed after about 5 h compared to the more than 30 h
Alternatively, the methanolysis was performed in the
presence of Ba(OH)2·8H2O6−8 which yielded after acidic
workup the pertinent carboxylic acid 1b.
Compared to the commonly used protection of carboxylic
acids as esters, the protection as amides shows a significantly
higher stability due to the high resonance energy of about 80
kJ/mol. Despite its robustness it allowed for a cleavage under
mild conditions. In addition, the cleavage process was
orthogonal to most conditions employed for the deprotection
of esters. Furthermore, bpa protection could be successfully
applied to aliphatic, aromatic, and amino acids. A disadvantage
though was the relatively long reaction time required for the
methanolysis step which took between 16 and about 30 h and
the use of the rather expensive Cu(OTf)2 as copper source
which had to be used in equimolar amounts.
Received: July 13, 2012
© XXXX American Chemical Society
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Scheme 1. Principle of the bpa-Based Protection for Carboxylic Acids As Chelating Amides
needed for derivative 5. Variations of the experimental
conditions led to further enhancements. Addition of
by the much more effective and significantly cheaper CuCl2.
The new protection scheme works for aromatic as well as
aliphatic carboxylic acids, and complete methanolysis can be
achieved in both cases in less than 1 h. Thus, the newly
developed protecting group for carboxylic acids fulfills virtually
all requirements for an ideal protection scheme: The synthesis
of the parent dmep-amine 9a comprises only one step starting
from cheap starting materials. The protection of carboxylic
acids is easily performed using TBTU as coupling reagent,11 the
protection itself is very robust, the rather fast cleavage is
performed under mild conditions with high yields and leads
optionally to the methyl ester or the free carboxylic acid, and
the procedure for cleavage is orthogonal to most deprotection
schemes for carboxylic acids. Hence, we believe that the newly
developed protection scheme should find widespread applica-
tion in synthetic organic chemistry.
diisopropylethylamine (DIEA, Hunig’s base) turned out to
̈
have a positive effect on the cleavage rate which was also true
for elevated temperatures. Hence, we also carried out the
comparison at 50 °C and in the presence or absence of Hunig’s
̈
base (Figure 1).
Quantitative cleavage of 9 was now possible within about 1 h.
Next we investigated the cleavage rate of an aliphatic amide.
For this purpose, benzoylpropionic acid was first coupled to the
parent dimethylaminoethylpicolylamine (dmepa) 9a using
TBTU as coupling reagent (Scheme 3). The resulting amide
27 was then subjected to the methanolysis reactions and
compared to the one of 26.
It turned out that formation of the expected methyl ester was
at rt significantly slower than for the aromatic amide 9. Again,
increasing the temperature to 50 °C and/or adding DIEA led to
much faster cleavage of the amide and complete conversion was
achieved within 2−3 h (Figure 2).
EXPERIMENTAL SECTION
■
General Methods. All reactions with air- and moisture-sensitive
compounds were carried out under an argon atmosphere. All solvents
were analytical grade or better. Dry DCM and 1,2-DCE were distilled
from CaH2. 1H NMR and 13C NMR spectra were recorded with Me4Si
as internal reference. Mass spectrometry was carried out using
chemical ionization (CI) methods. High-resolution masses were
recorded with a double-focusing sector-field as analyzer (mass
resolution up to 50.000) or an orbitrap as mass analyzer (HRMS of
compounds 17, 19, and 23).
No differences were observed in the methanolysis rate of 28
and 29 (Scheme 4) applying CuCl2 when compared to the one
of 9. This indicated that electronic factors on the aromatic
system had virtually no influence on this reaction.
A previous kinetic study involving bpa-amide 5 with either
Cu(OTf)2 and CuCl2 had revealed that the reaction with the
former proceeded much faster. For this reason, we had
originally devised Cu(OTf)2 as source for the Cu2+ being
aware of the fact that this salt is rather expensive and that this
would become an issue especially in large-scale synthesis
employing equimolar amounts. To our delight, we discovered
that the order of reactivity concerning the Cu source is reversed
for the new derivative 9 (Figure 3). Complete transfer into the
methyl ester was observed with CuCl2 at rt already after about 1
h. This result emphasizes the importance of the nature of the
anion of the Cu2+ source, a topic of ongoing investigations.
Application of Ba(OH)2·8H2O in combination with the Cu2+
salt, furnished after acidic workup the carboxylic acid.
General Procedure for Reductive Aminations (General
Procedure a). The amino compound (1.0 equiv) and the aldehyde
(1.0 equiv) were dissolved in dry 1,2-DCE and then treated with solid
sodium triacetoxyborohydride (1.5 equiv). The reaction mixture was
stirred at room temperature, and completion of the reaction was easily
monitored by TLC (using DCM/MeOH 9:1). Most of the reactions
were already complete after 2 or 3 h. The reaction mixture was then
quenched with saturated sodium hydrogen carbonate solution which
was then extracted three times with DCM. The combined organic
phases were dried over sodium sulfate, and the solvent was removed
under reduced pressure with a rotatory evaporator. The products were
purified either via distillation (parent secondary amines of compounds
9, 14, and 22) or via column chromatography (parent secondary
amines of compounds 6−8, 10, 13, 15−21, 25) or used without
further purification (parent amines of 11, 12, 23, and 24) in the
following acylation reaction.
General Procedure for the Acylation with TBTU and the
Carboxylic Acid (General Procedure b). The carboxylic acid (1.5
equiv, either benzoic acid or 3-benzoyl propionic acid) and TBTU (1.4
equiv) were suspended in DCM, and DIEA (6.0 equiv) was added.
After 10 min, the secondary amine (1.0 equiv) was added. After
stirring overnight at rt, the mixture was washed with water 2× and
dried over Na2SO4. The organic solvent was evaporated, and the crude
product was purified via flash chromatography (silica gel using
CH2Cl2/MeOH 98:2 → 85:15 or aluminum oxide with CH/EE
mixtures).
CONCLUSIONS
■
In summary, by investigating a number of structural variants of
our original bpa protecting group for carboxylic acids we have
developed a new and more versatile protecting group in which
one pyridine entity of bpa was replaced by a simple tertiary
amine and which we have dubbed as “dmepa” protecting group.
The synthesis of the parent amine 9a was performed by a
simple reductive amination between pyridine-2-carboxaldehyde
and N,N-dimethylethylenediamine, both of which are commer-
cially available. The methanolysis reaction of pertinent
carboxylic acid amides was significantly faster compared to
the one resulting from bpa and it could be further increased by
running the reactions at 50 °C or in the presence of DIEA.
Furthermore, the commonly used Cu(OTf)2 could be replaced
General Procedure for the Acylation Using Benzoyl Chloride
and NEt3 (General Procedure c). The secondary amine (1.0 equiv)
and NEt3 (3.0 equiv) were dissolved in DCM and cooled to 0 °C.
B
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Scheme 2. Overview of Synthesized Chelating Amides
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Scheme 2. continued
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Scheme 2. continued
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Scheme 2. continued
a
Key: (a) NaBH(OAc)3 (1.40 equiv), 1,2-DCE, rt; (b) TBTU (1.40 equiv), benzoic acid (1.40 equiv), DIEA (6.00 equiv), DCM, rt; (c) benzoyl
chloride (3.00 equiv), NEt3 (3.00 equiv), DCM, rt; (d) NH4Cl (2.00 equiv), MeOH/water, reflux; (e) hydroxylammonium hydrochloride (1.00
equiv), rt; (f) Zn (5.00 equiv), HCl (2 M), reflux; (g) DMAP (0.09 equiv), DCC (1.00 equiv), MeOH (3.00 equiv), DCM, rt; (h) pyridinium-2-
carboxaldehyde (1.30 equiv), CuI (0.10 equiv), NEt3 (0.40 equiv), MeCN, rt; (i) MeLi (1.00 equiv), Et2O, −78 °C to rt; KMnO4, acetone, 2 h, rt;
(j) SeO2 (1.50 equiv), dioxane, reflux; (k) diethyl malonate (1.55 equiv), NaH (1.04 equiv), toluene, 120 °C; (l) H2SO4 (50%), 120 °C; (m) I2 (1.00
equiv), TFA (3.00 equiv), t-BuI (0.40 equiv), DMSO, 170 °C; (n) H2 (1 bar), Pd/C (10%), MeOH/toluene (1:2), rt; (o) n-BuLi (1.00 equiv), n-
pentane, 1 h, −78 °C; 1 h, 0 °C; 1 h, rt.
Table 1. Yield of Methanolysis Product after 24 h at rt
methanolysis (%) after 24 h
at rt
methanolysis (%) after 24 h
at rt
compd
compd
5
89
4
16
17
18
19
20
21
22
23
24
25
5
1
6
7
3
0
8
16
100
100
1
22
24
75
25
0
9
10
11
12
13
14
15
14
1
5
59
77
100
Benzoyl chloride (3.0 equiv) was then added dropwise within 15 min.
After removal of the ice bath, the reaction mixture was stirred at room
temperature overnight. The reaction was then quenched with water,
and the organic phase was washed with water one more time. After the
mixture was dried over sodium sulfate, the solvent was removed under
reduced pressure and the compounds were purified via column
chromatography (over silica gel using CH2Cl2/MeOH 98:2 → 85:15
or over basic aluminum oxide using CH/EE 4:1→ EE → EE/EtOH
98:2).
General Procedure of the Cleavage of the Chelating Amide
to the Methyl Ester with Cu(OTf)2 at rt. To a solution of the
chelating amide (1.0 equiv) in MeOH (volume was added in order to
get a concentration of 0.28 M) was added Cu(OTf)2 (1.1 equiv), and
the resulting mixture was stirred at rt. During the reaction, samples for
HPLC measurements were taken with Hamilton syringes (10 μL,
diluted with 100 μL of phenol standard solution and 180 μL of
MeOH). Alternatively, the reaction was performed at 50 °C and/or in
the presence of DIEA (1.1 equiv). The samples for the HPLC
measurements were taken in an analytical way.
Figure 1. (a) Methanolysis of benzamide 5 at rt, at 50 °C or/and in
the presence of DIEA. (b) Methanolysis of benzamide 9 at rt, at 50 °C
or/and in the presence of DIEA.
Analytical Data. Benzylbis[(2-pyridyl)methyl]amine (5). Benza-
mide 5 was synthesized according to the general procedure b described
above. The resulting dark oil was purified via column chromatography
(silica gel, DCM/MeOH 98:2 → DCM/MeOH 95:5). The resulting
yellow gum (0.97 g, 3.2 mmol, 80%) crystallized overnight.
N-Propyl-N-pyridin-2-ylmethylbenzamide (6). The precursor
amine 6a was synthesized by the general procedure a described
above. A yellow liquid (0.93 g, 6.2 mmol, 72%) with the following
analytical data was obtained after purification with column
chromatography (silica gel, DCM/MeOH 98:2 → DCM/MeOH
80:20).
1
Benzylbis[(2-pyridyl)methyl]amine (5): mp 58−59 °C; H NMR
(CDCl3, 300 MHz) δ = 4.70 (s, 2H), 4.90 (s, 2H), 7.15 − 7.20 (m,
3H), 7.32−7.45 (m, 4H), 7.53 −7.57 (m, 2H), 7.66 (m, 2 H), 8.55 (m,
2H); 13C NMR (CDCl3, 100 MHz) δ = 50.5, 54.6, 121.4, 122.4, 122.5,
127.0, 128.5, 129.8, 136.0, 136.8, 149.4, 149.9, 156.8, 157.2, 172.6
ppm, MS (CI, NH3): m/z = 304.1 (100) [(M + 1)+]; HRMS (CI,
NH3) m/z [(M + 1)+] calcd for C19H17N3O 303.13716, found
303.13720. Anal. Calcd for C19H17N3O: C, 75.23; H, 5.65; N, 13.85.
Found: C, 75.06; H, 5.62; N, 13.81.
N-((Pyridin-2-yl)methyl)propan-1-amine (6a):12 1H NMR (CDCl3,
300 MHz) δ = 0.95 (t, 3H, J = 7.4 Hz), 1.59−1.73 (m, 2H), 2.76 (t,
2H, J = 7.4 Hz), 4.07 (s, 2H), 7.22 (mc, 1H), 7.33 (d, 1H, J = 7.7 Hz),
7.69 (ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.8 Hz), 8.57 (mc, 1H); 13
C
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Scheme 3. Synthetic Steps for the Preparation of Aliphatic Amides 26 and 27
Figure 2. Methanolysis of 26 and 27 in the presence of Cu(OTf)2 at rt
or at 50 °C in the presence of Cu(OTf)2 and DIEA.
Figure 3. Comparison of the cleavage rate of 5 and 9 with CuCl2 and
Cu(OTf)2 at rt.
m/z = 255.1 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M + 1)+]
calcd for C16H18N2O 255.14974, found 255.14930.
NMR (CDCl3, 100 MHz) δ = 11.8, 23.1, 51.5, 55.1, 121.9, 122.3,
136.5, 149.3, 159.6; MS (CI, NH3) m/z = 151.1 (100) [(M + 1)+];
HRMS (CI, NH3) m/z [(M + 1)+] calcd for C9H14N2 151.12352,
found 151.12370.
N-(2-Methoxyethyl)-N-pyridin-2-ylmethylbenzamide (7). The pre-
cursor amine 7a was synthesized according to the general procedure a)
described above. A yellow liquid (0.79 g, 4.7 mmol, 50%) with the
following analytical data was obtained after purification with column
chromatography (silica gel, DCM/MeOH 98:2 → DCM/MeOH
90:10).
Amine 6a was then acylated according to literature procedure b, and
benzamide 6 was obtained as a yellow gum (0.74 g, 2.9 mmol, 48%)
after purification via column chromatography (silica gel, DCM/MeOH
99:1 → DCM/MeOH 98:2).
2-Methoxy-N-((pyridin-2-yl)methyl)ethanamine (7a):13 1H NMR
(CDCl3, 300 MHz) δ = 2.64 (br s, 1H), 2.87 (t, 2H, J = 5.2 Hz), 3.36
(s, 3H), 3.55 (t, 2H, J = 5.2 Hz), 3.93 (s, 2H), 7.16 (mc, 1H), 7.32 (d,
1H, J = 7.7 Hz), 7.63 (ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.8 Hz),
8.55 (mc, 1H); 13C NMR (CDCl3, 100 MHz) δ = 49.0, 55.2, 59.0,
72.0, 122.1, 136.6, 159.4, 159.6; MS (CI, NH3) m/z = 167.1 (100)
[(M + 1)+].
1
N-Propyl-N-pyridine-2-ylmethyl-benzamide (6): H NMR (CDCl3,
300 MHz) δ = 0.63−1.00 (m, 3H), 1.48−1.77 (m, 2H), 3.19−3.54 (m,
2H), 4.58−4.96 (m, 2H), 7.20 (mc, 1H), 7.29−7.47 (m, 6H), 7.68
(ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.5 Hz), 8.55 (mc, 1H); 13C NMR
(CDCl3, 100 MHz) δ = 11.2, 21.6, 47.1, 50.2, 51.2, 54.4, 121.1, 122.4,
126.5, 128.4, 129.4, 136.5, 136.9, 149.3, 157.4, 172.3; MS (CI, NH3)
Scheme 4. Benzamide 9 and Structurally Related Benzamides
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Amine 7a was then acylated according to literature procedure c, and
benzamide 7 was obtained as a brown gum (0.67 g, 2.5 mmol, 85%)
after purification via column chromatography (silica gel, DCM/MeOH
98:2).
Hz), 7.58 (ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.9 Hz), 7.62 (ddd, 1H,
J = 7.7 Hz, J = 7.7 Hz, J = 1.9 Hz), 8.53 (mc, 2H); 13C NMR (CDCl3,
100 MHz) δ = 22.9, 53.1, 59.2, 121.1, 121.9, 122.0, 122.3, 136.4, 136.6,
149.2, 149.3, 159.7, 164.4; MS (CI, NH3) m/z = 214.2 (100) [(M +
1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd for C13H15N3
214.13442, found 214.13420.
This amine was then acylated according to general procedure b, and
10 was obtained as a yellow gum (1.29 g, 4.05 mmol, 83%) after
purification via column chromatography (silica gel, DCM/MeOH 98:2
→ DCM/MeOH 90:10). The yellow gum crystallized after several
days.
N-(2-Methoxyethyl)-N-pyridin-2-ylmethylbenzamide (7): 1H NMR
(CDCl3, 300 MHz) δ = 3.14−3.27 (m, 2H), 3.30−3.43 (m, 2H),
3.47−3.79 (m, 3H), 4.69−5.02 (m, 2H), 7.19 (mc, 1H), 7.28−7.75 (m,
7H), 8.56 (mc, 1H); 13C NMR (CDCl3, 100 MHz) δ = 45.3, 49.1,
50.7, 55.7, 58.9, 70.0, 122.5, 127.0, 128.4, 129.6, 136.4, 172.6; MS (CI,
NH3) m/z = 271.2 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M +
1)+] calcd for C16H18N2O2 271.14520, found 271.14465.
N-(2-Methylsulfanylethyl)-N-pyridine-2-ylmethylbenzamide (8).
The precursor amine 8a was synthesized according to the general
procedure a described above. A dark yellow liquid (0.210 g, 1.14
mmol, 41%) with the following analytical data was obtained after
purification with column chromatography (silica gel, DCM/MeOH
98:2 → DCM/MeOH 90:10).
N-(1-Pyridin-2-yl)ethyl)-N-((pyridin-2-yl)methyl)benzamide (10):
1H NMR (CDCl3, 400 MHz) δ = 1.58 (d, 3H, J = 5.5 Hz), 4.32−6.10
(m, 3H), 6.90−7.70 (m, 11H), 8.47 (mc, 2H); 13C NMR (CDCl3, 100
MHz) δ = 17.7, 47.8, 59.3, 121.6, 121.7, 122.4, 126.7, 128.7, 129.6,
136.5, 148.7, 149.5, 158.5, 172.9; MS (CI, NH3) m/z = 318.2 (100)
[(M + 1)+]. Anal. Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24.
Found: C, 75.60; H, 6.14; N, 13.32.
2-(Methylthio)-N-((pyridin-2-yl)methyl)ethanamine (8a):14 1H
NMR (CDCl3, 300 MHz) δ = 2.09 (s, 3H), 2.41 (br s, 1H), 2.71
(t, 2H, J = 6.5 Hz), 2.89 (t, 2H, J = 6.5 Hz), 3.96 (s, 2H), 7.16 (mc,
1H), 7.33 (d, 1H, J = 7.7 Hz), 7.65 (dd, 1H, J = 7.7 Hz, J = 7.7 Hz),
8.56 (d, 1H, J = 4.3 Hz); 13C NMR (CDCl3, 100 MHz) δ = 15.4, 34.4,
48.7, 54.9, 122.2, 136.5, 149.5, 159.6; MS (CI, NH3) m/z = 183.1
(100) [(M + 1)+].
N-(1-Methyl-1H-imidazol-4-ylmethyl)-N-pyridin-2-ylmethylben-
zamide (11). The precursor amine 11a was synthesized according to
the general procedure a described above. The pale yellow liquid 11a
was then acylated according to the general procedure b, and 11 was
obtained as a brown gum (0.27 g, 0.8 mmol, 83% over two steps) after
purification via column chromatography (silica gel, DCM/MeOH 98:2
→ DCM/MeOH 90:10). N-(1-Methyl-1H-imidazol-4-ylmethyl)-N-
This amine was then acylated according to the general procedure c,
and benzamide 8 was obtained as a brown gum (0.26 g, 0.92 mmol,
79%) after purification via column chromatography (silica gel, DCM/
MeOH 98:2 → DCM/MeOH 95:5).
1
pyridin-2-ylmethylbenzamide (11): H NMR (CDCl3, 300 MHz) δ =
3.64 (s, 3H), 4.36−4.67 (m, 2H), 4.67−4.95 (m, 2H), 6.70−6.99 (m,
1H), 7.14−7.25 (m, 1H), 7.28−7.51 (m, 6H), 7.64−7.72 (m, 2H),
8.51−8.59 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ = 33.5, 42.6,
49.6, 118.5, 119.3, 121.45, 122.3, 127.0, 127.4, 128.4, 129.4, 136.8,
138.0, 138.3, 149.2, 149.8; MS (CI, NH3) m/z = 307.2 (100) [(M +
1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd for C18H18N4O
307.15589, found 307.15570.
N-Pyridin-2-ylmethyl-N-quinolin-2-ylmethylbenzamide (12). The
precursor amine 12a was synthesized according to the general
procedure a described above. Amine 12a was then acylated according
to literature procedure b, and 12 was obtained as a brown gum (0.44 g,
1.23 mmol, 46% over two steps) after purification via column
chromatography (silica gel, DCM/MeOH 98:2 → DCM/MeOH
97:3). N-Pyridin-2-ylmethyl-N-quinolin-2-ylmethylbenzamide (12):
1H NMR (CDCl3, 300 MHz) δ = 4.69−4.90 (m, 2H), 4.94−5.11
(m, 2H), 7.15 (mc, 1H), 7.17−7.28 (m, 1H), 7.28−7.39 (m, 3H), 7.45
(mc, 1H), 7.48−7.73 (m, 6H), 7.80 (dd, 1H, J = 8.1 Hz, J = 1.4 Hz),
7.99−8.05 (m, 1H), 8.09−8.16 (m, 1H), 8.52 (mc, 1H); 13C NMR
(CDCl3, 100 MHz) δ = 48.9, 49.2, 52.7, 53.2, 117.2, 118.5, 119.6,
120.4, 120.7, 124.5, 125.1, 125.5, 125.7, 126.5, 127.3, 127.6, 127.8,
134.2, 134.8, 135.0, 147.4, 147.9, 170.9; MS (CI, NH3) m/z = 354.1
(100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd for
C23H19N3O 354.16064, found 354.16080.
1
N-(2-Methylsulfanylethyl)-N-pyridin-2-ylmethylbenzamide (8): H
NMR (300 MHz, CDCl3): δ = 1.96 (mc, 3H), 2.70 (mc, 2H), 3.63 (mc,
2H), 4.79 (mc, 2H), 7.12−7.24 (m, 1H), 7.27−7.66 (m, 6H), 7.66−
7.84 (m, 1H), 8.57 (mc, 1H); 13C NMR (100 MHz, CDCl3): δ = 15.5,
32.5, 45.0, 48.9, 50.3, 55.3, 122.9, 126.9, 128.6, 129.8, 134.6, 149.9,
136.2, 157.0, 172.4; MS (CI, NH3) m/z = 287.0 (100) [(M + 1)+];
HRMS (CI, NH3) m/z [(M + 1)+] calcd for C16H18N2OS 287.12180,
found 287.12181.
N-(2-Dimethylaminoethyl)-N-pyridin-2-ylmethylbenzamide (9).
The precursor amine 9a was synthesized by the general procedure a
described above. A liquid with the following analytical data was
−2mbar
obtained after distillation (bp6.5*10
liquid (2.42 g, 13.5 mmol, 58%).
= 95−100 °C) as a yellow
N1,N1-Dimethyl-N2-((pyridin-2-yl)methyl)ethane-1,2-diamine
(9a):15 1H NMR (CDCl3, 300 MHz) δ = 2.28 (s, 6H), 2.58 (t, 2H, J =
6.2 Hz), 2.82 (t, 2H, J = 6.2 Hz), 3.96 (s, 2H), 7.16 (ddd, 1H, J = 7.7
Hz, J = 4.8 Hz, J = 1.2 Hz), 7.32−7.34 (m, 1H), 7.64 (ddd, 1H, J = 7.7
Hz, J = 7.7 Hz, J = 1.8 Hz), 8.54 (mc, 1H); 13C NMR (CDCl3, 100
MHz) δ = 45.7, 47.0, 55.5, 59.3, 122.0, 122.3, 136.5, 149.3, 159.9; MS
(CI, NH3) m/z = 180.2 (100) [(M + 1)+]; HRMS (CI, NH3) m/z
[(M + 1)+] calcd for C10H17N3 180.15007, found 180.15020.
Amine 9a was then acylated according to the general procedure b,
and benzamide 9 was obtained as a yellow gum (0.54 g, 1.9 mmol,
57%) after purification with column chromatography (silica gel,
DCM/MeOH 98:2 → DCM/MeOH 80:20).
N-Furan-2-yl-methyl-N-pyridin-2-ylmethylbenzamide (13). The
precursor amine 13a was synthesized according to the general
procedure a described above. A brown liquid (0.80 g, 4.25 mmol, 46%)
with the following analytical data was obtained after purification with
column chromatography (silica gel, DCM/MeOH 98:2 → DCM/
MeOH 85:15).
N-(2-Dimethylamino-ethyl)-N-pyridine-2-ylmethylbenzamide (9):
1H NMR (CDCl3, 300 MHz) δ = 1.94−2.36 (m, 6H), 2.35−2.70
(m, 2H), 3.32−3.71 (m, 2H), 4.64−4.99 (m, 2H), 7.19 (mc, 1H),
7.29−7.43 (m, 4H), 7.44−7.47 (m, 2H), 7.67 (m, 1H), 8.55 (mc, 1H);
13C NMR (CDCl3, 100 MHz) δ = 45.7, 122.6, 126.9, 128.5, 129.6,
137.0, 172.5; MS (CI, NH3) m/z = 284.2 (100) [(M + 1)+]; HRMS
(CI, NH3) m/z [(M + 1)+] calcd for C17H21N3O 284.17629, found
284.17640.
(Furan-2-yl)-N-((pyridin-2-yl)methyl)methanamine (13a): 1H
NMR (CDCl3, 300 MHz) δ = 2.78 (br s, 1H), 3.85 (s, 2H), 3.93
(s, 2H), 6.20 (dd, 1H, J = 3.1 Hz, J = 0.7 Hz), 6.30 (dd, 1H, J = 3.1 Hz,
J = 1.8 Hz), 7.16 (mc, 1H), 7.28 (d, 1H, J = 7.7 Hz), 7.37 (dd, 1H, J =
1.8 Hz, J = 0.7 Hz), 7.63 (ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.8 Hz),
8.56 (mc, 1H); 13C NMR (CDCl3, 100 MHz) δ = 45.8, 54.1, 107.3,
110.2, 122.3, 136.6, 142.0, 149.4, 153.6, 159.4; MS (CI, NH3): m/z =
189.2 (100) [(M + 1)+].
N-(1-Pyridin-2-yl)ethyl)-N-((pyridin-2-yl)methyl)benzamide (10).
The precursor amine 10a was synthesized according to the general
procedure a described above. A brown liquid (2.08 g, 9.6 mmol, 96%)
with the following analytical data was obtained without further
purification.
Amine 13a was then acylated according to literature procedure b,
and 13 was obtained as a brown gum (0.59 g, 2.0 mmol, 95%) after
purification via column chromatography (silica gel, DCM/MeOH 98:2
→ DCM/MeOH 90:10).
1-(Pyridin-2-yl)-N-((pyridin-2-yl)methyl)ethanamine (10a):16 1H
NMR (CDCl3, 400 MHz) δ = 1.43 (d, 3H, J = 6.7 Hz), 3.10 (br s,
1H), 3.77 (s, 2H, CH2), 3.94 (q, 1H, J = 6.7 Hz), 7.08−7.14 (m, 2H),
7.25 (d, 1H, J = 7.7 Hz), 7.36 (ddd, 1H, J = 7.8 Hz, J = 7.8 Hz, J = 1.1
N-Furan-2-yl-methyl-N-pyridin-2-ylmethyl-benzamide (13): 1H
NMR (CDCl3, 300 MHz) δ = 4.58 (mc, 2H), 4.80 (mc, 2H), 6.15−
6.32 (m, 2H), 7.20 (dd, 1H, J = 7.4 Hz, J = 4.9 Hz), 7.31−7.76 (m,
H
dx.doi.org/10.1021/jo301349t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
8H), 8.57 (mc, 1H); 13C NMR (CDCl3, 100 MHz) δ = 46.4, 49.7,
109.2, 110.4, 122.4, 127.1, 128.3, 129.8, 132.9, 135.9, 142.7, 149.2; MS
(CI, NH3) = 293.0 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M +
1)+] calcd for C18H16N2O2 293.12950, found 293.12900.
N-(Pyridin-2-yl)-N-((pyridin-2-yl)methyl)benzamide (14). The pre-
cursor amine 14a was synthesized by the general procedure a
described above. A yellow liquid (1.53 g, 8.27 mmol, 75%) with the
following analytical data was obtained after purification with column
chromatography (silica gel, DCM/MeOH 98:2 → DCM/MeOH
95:5).
NH3) m/z [(M + 1)+] calcd for C20H19N3O 318.16064, found
318.16050.
N,N-Bis(2-(pyridin-2-yl)ethyl)benzamide (16). The parent secon-
dary amine of benzamide 16 was prepared according to a literature
process23 in a two-step reaction. In the first step, hydroxylammonium
hydrochloride was added to 2-vinylpyridine. The hydroxylamine
derivative 16a (2.17 g, 9.11 mmol, 31%) was obtained after
recrystallization (n-hexane/DCM) as a brown solid.
Bis[2-(pyridin-2-ylethyl)]hydroxylamine (16a): mp 100 °C; 1H
NMR (CDCl3, 400 MHz) δ = 3.10 (s, 8H), 7.06 (ddd, 2H, J = 6.2 Hz,
J = 5.0 Hz, J = 1.2 Hz), 7.12 (ddd, 2H, J = 7.8 Hz, J = 1.0 Hz, J = 1.0
Hz), 7.53 (ddd, 2H, J = 7.7 Hz, J = 7.7 Hz, J = 1.9 Hz), 8.44 (ddd, 2H,
J = 4.9 Hz, J = 1.9 Hz, J = 1.0 Hz); 13C NMR (CDCl3, 100 MHz) δ =
36.0, 60.0, 121.2, 123.5, 136.5, 148.9, 160.4 ppm.
N,N-(2-Pyridyl)(2-pyridylmethyl)amine (14a):17,18 1H NMR
(CDCl3, 400 MHz) δ = 4.63 (s, 2H), 4.76 (s, 1H), 6.46 (d, 1H, J =
8.5 Hz), 6.58 (ddd, 1H, J = 6.1 Hz, J = 5.2 Hz, J = 0.9 Hz), 6.77 (s,
1H), 7.36 (d, 1H, J = 7.7 Hz), 7.42 (ddd, 1H, J = 8.6 Hz, J = 7.4 Hz, J
= 2.0 Hz), 7.64 (ddd, 1H, J = 7.6 Hz, J = 7.6 Hz J = 1.8 Hz), 8.02 (mc,
1H), 8.55 (mc, 1H); 13C NMR (CDCl3, 100 MHz) δ = 47.4, 108.2,
113.1, 121.8, 122.3, 136.8, 138.0, 148.6, 149.2, 157.9, 158.1 ppm.
This amine was then acylated according to the general procedure c
and 14 was obtained as a crystalline powder (0.82 g, 2.84 mmol, 70%)
after purification via column chromatography (aluminum oxide, CH/
EE 4:1).
In the second step, 16a was reduced to the corresponding amine
with zinc and hydrochloric acid. After the solution was stirred at 95 °C
for 90 min, the suspension was allowed to cool down and made basic
with a solution of sodium hydroxide. The secondary amine 16b was
obtained after extraction with DCM (3×) as yellow oil (0.70 g, 2.35
1
mmol, 97%): H NMR (CDCl3, 400 MHz) δ = 2.16 (br s, 1H), 3.00
(t, 4H, J = 6.5 Hz), 3.08 (t, 4H, J = 6.5 Hz), 7.10 (dd, 2H, J = 5.8 Hz, J
= 5.8 Hz), 7.15 (d, 2H, J = 7.7 Hz), 7.57 (ddd, 2H, J = 7.8 Hz, J = 7.8
Hz, J = 1.8 Hz), 8.49 (d, 2H, J = 4.8 Hz); 13C NMR (CDCl3, 100
MHz) δ = 49.2, 121.4, 123.4, 136.5, 149.4, 160.2 ppm.
N-(Pyridin-2-yl)-N-((pyridin-2-yl)methyl)benzamide (14): 1H
NMR (CDCl3, 400 MHz) δ = 5.45 (s, 2H), 6.92 (ddd, 1H, J = 8.1
Hz, J = 8.1 Hz, J = 0.9 Hz), 6.99 (ddd, 1H, J = 7.5 Hz, J = 4.9 Hz, J =
1.0 Hz), 7.13 (mc, 1H), 7.19−7.24 (m, 2H), 7.28−7.33 (m, 1H),
7.39−7.44 (m, 3H), 7.46 (ddd, 1H, J = 7.9 Hz, J = 7.9 Hz, J = 1.0 Hz),
7.63 (ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.8 Hz), 8.36 (ddd, 1H, J =
4.9 Hz, J = 1.9 Hz, J = 0.9 Hz), 8.50 (ddd, 1H, J = 4.1 Hz, J = 1.9 Hz, J
= 1.0 Hz); 13C NMR (CDCl3, 100 MHz) δ = 53.6, 121.0, 122.0, 122.1,
128.1, 128.8, 130.4, 136.0, 136.7, 137.3, 148.8, 149.2, 156.2, 157.7; MS
(CI, NH3) m/z = 290.1 (100) [(M + 1)+]. Anal. Calcd for
C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found: C, 74.50; H, 5.24;
N, 14.50.
Benzamide 16 was then synthesized according to general procedure
b. Compound 16 was obtained as a yellow oil (0.32 g, 0.97 mmol,
57%) after purification via column chromatography (silica gel, DCM/
MeOH 99:1 → 97:3).
1
N,N-Bis(2-(pyridin-2-yl)ethyl)benzamide (16): H NMR (CDCl3,
400 MHz) δ = 3.41 (mc, 8H), 6.90 (br s, 1H), 7.04−7.20 (m, 4H),
7.26−7.36 (m, 4H), 7.58 (mc, 2H), 8.47 (mc, 2H); MS (CI, NH3) m/z
= 332.2 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd
for C21H21N3O 332.17629, found 332.17630.
N-(2-(Pyridin-2-yl)ethyl)-N-((pyridin-2-yl)methyl)benzamide (15).
Benzamide 15 was synthesized via a multistep reaction. The first step
was the addition of ammonium chloride to 2-vinylpyridine which was
commercially available.19 The primary amine 15a was obtained as a
4-[5-[(Benzoylpyridin-2-ylmethylamino)methyl][1,2,3]triazol-1-
yl]benzoic Acid Methyl Ester (17). Benzamide 17 was synthesized in a
multistep reaction. Its triazol unit was built up via a [2 + 3]-
cycloaddition. The propargyl amine 17a was synthesized by a reductive
amination step according to the general procedure a. The propargyl
amine was a dark brown oil (0.91 g, 6.23 mmol, 33%) purified via
column chromatography (silica gel, DCM/MeOH 98:2 → 90:10).
Prop-2-ynylpyridin-2-ylmethylamine (17a):24 1H NMR (CDCl3, 300
MHz) δ = 2.12 (br s, 1H), 2.24 (t, 1H, J = 2.4 Hz), 3.51 (d, 2H, J = 2.4
Hz), 4.01 (s, 2H), 7.17 (mc, 1H), 7.33 (d, 1H, J = 7.7 Hz), 7.64 (ddd,
1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.8 Hz), 8.56 (mc, 1H); 13C NMR
(CDCl3, 100 MHz) δ = 37.8, 53.7, 71.7, 81.9, 122.4, 136.5, 149.5,
159.2; MS (CI, NH3) m/z = 147.1 (100) [(M + 1)+].
colorless liquid (1.76 g, 14.3 mmol, 29%) after distillation (bp16mbar
=
88 °C).
2-(Pyridin-2-yl)ethanamine (15a):20 1H NMR (CDCl3, 400 MHz)
δ = 1.54 (s, 2H), 2.91 (t, 2H, J = 6.7 Hz), 3.10 (t, 2H, J = 6.7 Hz), 7.09
(ddd, 1H, J = 7.5 Hz, J = 6.1 Hz, J = 1.1 Hz), 7.14 (ddd, 1H, J = 7.9
Hz, J = 0.9 Hz, J = 0.9 Hz), 7.57 (ddd, 1H, J = 7.6 Hz, J = 7.2 Hz, J =
1.9 Hz), 8.51 (ddd, 1H, J = 4.9 Hz, J = 1.9 Hz, J = 1.0 Hz); 13C NMR
(CDCl3, 100 MHz) δ = 41.9, 121.2, 123.3, 136.3, 149.3, 160.0; MS
(CI, NH3) m/z = 123.1 (100) [(M + 1)+].
The secondary amine 15b was then synthesized via the general
procedure a described above. 2-Pyridine-carboxaldehyde was used as
the carbonyl compound. The secondary amine was obtained as a
yellow liquid (1.47 g, 6.95 mmol, 97%) without further purification.
2-(Pyridin-2-yl)-N-((pyridin-2-yl)methyl)ethanamine (15b):21,22
1H NMR (CDCl3, 400 MHz) δ = 2.01 (s, 1H), 3.16 (m, 4H), 4.10
(s, 2H), 7.13−7.22 (m, 3H), 7.37 (ddd, 1H, J = 7.7 Hz, J = 1.0 Hz),
7.62 (ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.8 Hz), 7.67 (ddd, 1H, J =
7.7 Hz, J = 7.7 Hz, J = 1.8 Hz), 8.51 (ddd, J = 4.9 Hz, J = 1.8 Hz, J =
0.9 Hz), 8.54 (ddd, 1H, J = 4.9 Hz, J = 1.8 Hz, J = 0.9 Hz); 13C NMR
(CDCl3, 100 MHz) δ = 35.8, 48.3, 55.7, 121.8, 122.8, 122.9, 123.5,
136.8, 136.9, 149.1, 149.5, 156.3, 159.4; MS (CI, NH3) m/z = 214.1
(100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd for
C13H15N3 214.13442, found 214.13430.
The azido building block 17b was prepared via a methylester
formation using the commercially available carboxylic acid (1.0 equiv),
dry MeOH, DMAP (0.09 equiv), and DCC (1.0 equiv). The reaction
mixture was stirred at rt for 4 h. The methyl ester was isolated as a
yellow solid (2.02 g, 11.4 mmol, 93%) after purification via column
chromatography (silica gel, DCM/MeOH 99:1).
1
4-Azido-benzoic acid methyl ester (17b): H NMR (CDCl3, 300
MHz) δ = 3.91 (s, 3H), 7.06 (mc, 2H), 8.03 (mc, 2H); 13C NMR
(CDCl3, 100 MHz) δ = 35.0, 52.2, 118.9, 126.9, 131.5, 144.8, 166.4
ppm.
The [2 + 3]-cycloaddition resulting in amine 17c was achieved by
stirring azide 17b (1.3 equiv) and propargyl amine 17a (1.0 equiv) in
CH3CN in the presence of CuI (0.1 equiv) and NEt3 (0.4 equiv) for
48 h. Amine 17c was obtained as a brown gum (0.15 g, 0.45 mmol,
51%) after purification via column chromatography (silica gel, DCM/
MeOH 99:1 → DCM/MeOH 90:10).
The secondary amine 15b was then acylated according to general
procedure b. The benzamide 15 was obtained as yellow gum (0.55 g,
1.74 mmol, 62%) after purification via column chromatography (silica
gel, DCM/MeOH 98:2 → DCM/MeOH 97:3).
4-[5-[[(Pyridin-2-ylmethyl)amino]methyl][1,2,3]triazol-1-yl]-
1
benzoic acid methyl ester (17c): H NMR (CDCl3, 300 MHz) δ =
2.53 (s, 1H), 3.96 (s, 3H), 4.04 (s, 2H), 4.11 (s, 2H), 7.18 (mc, 1H),
7.34 (d, 1H, J = 7.7 Hz), 7.66 (ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.8
Hz), 7.84 (mc, 2H), 8.12 (s, 1H), 8.19 (mc, 2H), 8.57 (mc, 1H); 13C
NMR (CDCl3, 100 MHz) δ = 44.3, 52.5, 54.5, 119.9, 120.0, 122.2,
122.5, 130.2, 130.7, 131.4, 136.6, 140.3, 148.0, 149.5, 159.0, 166.0; MS
(CI, NH3) m/z = 324.0 (100) [(M + 1)+].
N-(2-(Pyridin-2-yl)ethyl)-N-((pyridin-2-yl)methyl)benzamide
(15): 1H NMR (CDCl3, 400 MHz) δ = 3.12 (mc, 2H), 3.84 (mc, 2H),
4.70 (mc, 2H), 6.84−7.71 (m, 11H), 8.50 (mc, 2H); 13C NMR
(CDCl3, 100 MHz) δ = 35.6, 37.0, 45.9, 49.4, 50.2, 55.0, 121.1, 121.7,
122.4, 124.0, 126.7, 128.2, 128.5, 129.5, 129.9, 136.4, 136.7, 149.0,
149.8; MS (CI, NH3) m/z = 318.2 (100) [(M + 1)+]; HRMS (CI,
I
dx.doi.org/10.1021/jo301349t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Amine 17c was then acylated according to the general procedure c,
and benzamide 17 was isolated as a brown solid (0.12 g, 0.28 mmol,
77%) after purification via column chromatography (silica gel, DCM/
MeOH 98:2 → DCM/MeOH 95:5).
4-[5-[(Benzoyl-pyridin-2-ylmethylamino)methyl][1,2,3]triazol-1-
yl]benzoic acid methyl ester (17): mp 107 °C; 1H NMR (CDCl3, 300
MHz) δ = 3.97 (s, 3H), 4.75 (s, 2H), 4.85 (s, 2H), 7.24 (mc, 1H),
7.31−7.89 (m, 7H), 7.87 (mc, 2H), 8.21 (mc, 2H), 8.29 (s, 1H), 8.63
(mc, 1H); 13C NMR (CDCl3, 100 MHz) δ = 41.0, 52.5, 54.5, 119.9,
121.9, 122.0, 127.3, 128.5, 130.1, 131.4, 135.6, 136.9, 140.2, 145.2,
150.0, 156.4, 166.0, 172.7; MS (CI, NH3) m/z = 428.2 (100) [(M +
1)+]; HRMS (APCI, MeOH) m/z [(M + 1)+] calcd for C24H22N5O3
428.17226, found 428.17220.
sequence. In the first step, malonic acid diethylester was added
dropwise to a suspension of sodium hydride (1.1 equiv). The resulting
white suspension was then stirred for 30 min at 120 °C. Then, 2-
chloro-5-nitropyridine (1.0 equiv) in toluene was added dropwise, and
the reaction mixture stirred for 8 h at 120 °C. After the mixture was
cooled to rt, the solvent was removed at reduced pressure using the
rotatory evaporator. The oily residue was then resolved in sulfuric acid
(50%), and the reaction mixture was refluxed for 8 h. After the mixture
was cooled to rt and water was added, a concentrated sodium
hydroxide solution was added slowly at 0 °C. Furthermore, a solution
of saturated NaHCO3 was added. After the water phases were
extracted with Et2O, the organic layers were dried over sodium sulfate
and the picoline derivative 19a was obtained as a pink solid (2.15 g,
15.6 mmol, 39%) after purification via column chromatography (silica
gel, DCM).
N-((Pyridin-2-yl)methyl)-N-(6-(pyridine-2-yl)pyridin-2-yl)methyl)-
benzamide (18). Benzamide 18 was synthesized in a multistep
reaction using commercially available 2,2′-bipyridine as starting
material. 2,2′-Bipyridine was methylated according to a literature
process,25 and 18a was obtained as a yellow gum (1.83 g, 10.6 mmol,
30%) after purification via column chromatography (silica gel, DCM/
MeOH 97:3).
2-Methyl-5-nitropyridine (19a):27 mp 102 °C; H NMR (CDCl3,
1
300 MHz) δ = 2.70 (s, 3H), 7.34 (d, 1H, J = 8.6 Hz), 8.36 (dd, 1H, J =
2.7 Hz, J = 8.6 Hz), 9.33 (d, 1H, J = 2.7 Hz); 13C NMR (CDCl3, 100
MHz) δ = 24.9, 123.4, 131.3, 144.8, 165.5; MS (CI, NH3) m/z = 139.1
(100) [(M + 1)+]. Anal. Calcd for C6H6N2O2: C, 52.17; H, 4.38; N,
20.28. Found: C, 52.34; H, 4.47; N, 20.00.
2-Methyl-6-(pyridin-2-yl)pyridine (18a): 1H NMR (CDCl3, 400
MHz) δ = 2.61 (s, 3H), 7.13 (d, 1H, J = 7.7 Hz), 7.23−7.29 (m, 1H),
7.66 (t, 1H, J = 7.8 Hz), 7.74−7.81 (m, 1H), 8.15 (d, 1H, J = 7.6 Hz),
8.38 (m, 1H), 8.64−8.67 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ =
24.6, 118.1, 121.2, 123.3, 123.5, 136.8, 137.1, 149.2, 155.6, 156.5, 157.9
ppm.
The picoline derivative 19a was dissolved in DMSO, and iodine
(1.0 equiv), tert-butyliodine (0.4 equiv), and TFA (3.0 equiv) were
added. The resulting reaction mixture was then stirred for 3 h at 170
°C. After cooling down to rt, a NaHCO3 solution (10%) and a
Na2S2O3 solution (1 M) were added. The combined water phases
were extracted with DCM several times, and the combined organic
phases were dried over sodium sulfate. The carbaldehyde 19b was
obtained as yellow crystals (1.11 g, 7.23 mmol, 56%) after purification
via column chromatography (silica gel, DCM).
Compound 18a was then oxidized to the corresponding
carboxaldehyde 18b according to literature.26 Carboxaldehyde 18b
was then isolated as yellow powder (1.06 g, 5.76 mmol, 56%) after
purification via column chromatography (silica gel, DCM/EE 90:10).
6-(Pyridin-2-yl)pyridin-2-carbaldehyde (18b): 1H NMR (CDCl3,
400 MHz) δ = 7.36 (ddd, 1H, J = 7.7 Hz, J = 4.8 Hz, J = 1.1 Hz), 7.87
(ddd, 1H, J = 7.8 Hz, J = 7.8 Hz, J = 1.8 Hz), 7.95−8.02 (m, 2H), 8.55
(ddd, 1H, J = 7.8 Hz, J = 7.8 Hz, J = 1.0 Hz), 8.66 (dd, 1H, J = 6.7 Hz,
J = 2.3 Hz), 8.71 (ddd, 1H, J = 4.7 Hz, J = 1.8 Hz, J = 0.9 Hz), 10.17
(d, 1H, J = 0.7 Hz); 13C NMR (CDCl3, 100 MHz) δ = 121.4, 121.5,
124.4, 125.3, 137.2, 138.0, 149.3, 152.4, 155.0, 156.7, 193.7; MS (CI,
NH3): m/z = 184.0 (100) [(M + 1)+].
5-Nitropyridine-2-carbaldehyde (19b):28 mp 55 °C, 1H NMR
(CDCl3, 300 MHz) δ = 8.16 (dd, 1H, J = 8.5 Hz, J = 0.6 Hz), 8.66
(dd, 1H, J = 8.5 Hz, J = 2.4 Hz), 9.59 (d, 1H, J = 2.4 Hz), 10.18 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ = 121.8, 132.6, 145.8, 146.1,
155.8, 191.3; MS (CI, NH3) m/z = 153.1 (100) [(M + 1)+]. Anal.
Calcd for C6H4N2O3: C, 47.38; H, 2.65; N, 18.42. Found: C, 46.91; H,
2.67; N, 18.76.
The secondary amine 19c was prepared according to the general
procedure a, and 19c was obtained as a dark brown gum (0.15 g, 0.61
mmol, 52%) after purification via column chromatography (silica gel,
DCM/MeOH 98:2 → DCM/MeOH 90:10).
The secondary amine was then prepared via a reductive amination
step according to general procedure a, and amine 18c was obtained as
a brown oil (1.04 g, 3.75 mmol, 68%) without further purification.
(Pyridin-2-yl)-N-((6-(pyridin-2-yl)pyridin-2-yl)methyl)-
(5-Nitropyridine-2-ylmethyl)pyridin-2-ylmethylamine (19c): 1H
NMR (CDCl3, 300 MHz) δ = 4.02 (s, 2H), 4.14 (s, 2H), 7.19 (mc,
1H), 7.32 (d, 1H, J = 7.8 Hz), 7.62−7.70 (m, 2H), 8.44 (dd, 1H, J =
8.6 Hz, J = 2.5 Hz), 8.58 (mc, 1H), 9.38 (d, 1H, J = 2.5 Hz); 13C NMR
(CDCl3, 100 MHz) δ = 54.6, 60.5, 122.3, 122.4, 131.6, 136.7, 143.2,
144.8, 149.5, 159.1, 166.9 ppm.
1
methanamine (18c): H NMR (CDCl3, 400 MHz) δ = 3.33 (br s,
1H), 4.07 (s, 2H), 4.09 (s, 2H), 7.16 (dd, 1H, J = 7.7 Hz, J = 4.9 Hz),
7.28 (ddd, 1H, J = 7.5 Hz, J = 4.8 Hz, J = 1.2 Hz), 7.35 (d, 1H, J = 7.8
Hz), 7.38 (d, 1H, J = 7.8 Hz), 7.64 (ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J
= 1.8 Hz), 7.73−7.82 (m, 2H), 8.26 (d, 1H, J = 7.9 Hz), 8.45 (ddd,
1H, J = 8.0 Hz, J = 8.0 Hz, J = 1.0 Hz), 8.57 (ddd, 1H, J = 4.8 Hz, J =
1.5 Hz, J = 0.8 Hz), 8.66 (ddd, 1H, J = 4.8 Hz, J = 1.7 Hz, J = 0.9 Hz);
13C NMR (CDCl3, 100 MHz) δ = 54.5, 54.6, 119.5, 121.3, 122.2,
122.3, 122.4, 123.7, 136.6, 136.9, 137.5, 149.2, 149.4, 155.7, 156.2,
158.4, 159.2; MS (CI, NH3): m/z = 277.2 (100) [(M + 1)+].
Amine 18c was then acylated according to the general procedure c.
Benzamide 18 was obtained as a yellow gum (0.98 g, 2.57 mmol, 66%)
after purification via column chromatography (aluminum oxide, CH/
EE 4:1 → CH/EE 1:1).
N-((Pyridin-2-yl)methyl)-N-(6-(pyridine-2-yl)pyridin-2-yl)methyl)-
benzamide (18): 1H NMR (CDCl3, 400 MHz) δ = 4.79 (s, 2H), 4.97
(d, 2H, J = 10.8 Hz), 7.10−7.53 (m, 10H), 7.66 (ddd, 1H, J = 7.7 Hz, J
= 7.7 Hz, J = 1.9 Hz), 7.73−7.86 (m, 2H), 8.31 (d, 1H, J = 7.8 Hz),
8.36−8.46 (dd, 1H, J = 18.8 Hz, J = 8.0 Hz), 8.49−8.59 (m, 1H), 8.67
(ddd, 1H, J = 4.8 Hz, J = 1.8 Hz, J = 0.9 Hz); 13C NMR (CDCl3, 100
MHz) δ = 50.5, 50.8, 54.6, 77.3, 119.6, 119.8, 121.3, 121.7, 122.5,
122.6, 123.0, 123.7, 124.0, 149.2, 127.0, 127.1, 128.4, 129.8, 136.2,
137.1, 137.7, 149.1, 149.9; MS (CI, NH3) m/z = 381.2 (100) [(M +
1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd for C24H18N4O
381.17154, found 381.17130.
Benzamide 19 was prepared according to the general procedure c.
Benzamide 19 was obtained as a brown gum (0.18 g, 0.52 mmol, 92%)
after purification via column chromatography (silica gel, DCM/MeOH
98:2).
N-(5-Nitropyridin-2-ylmethyl)-N-pyridin-2-ylmethylbenzamide
1
(19): H NMR (CDCl3, 300 MHz) δ = 4.74−4.86 (m, 2H), 4.87−
4.97 (m, 2H), 7.20 (mc, 2H), 7.28−7.73 (m, 8H), 8.44 (mc, 1H), 9.35
(mc, 1H); 13C NMR (CDCl3, 100 MHz) δ = 50.9, 55.4, 121.8, 122.9,
127.2, 128.7, 130.2, 131.7, 135.5, 136.9, 143.4, 144.8, 150.0, 156.3,
164.0; MS (CI, NH3) m/z = 349.2 (100) [(M + 1)+]; HRMS (APCI,
MeOH) m/z [(M + 1)+] calcd for C19H16N4O3 349.13007, found
349.13000. Anal. Calcd for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08.
Found: C, 65.12; H, 4.71; N, 16.18.
Benzamide 20 was prepared via a hydrogenation of benzamide 19.
Benzamide 20 was dissolved in MeOH/toluene (1:2) and Pd/C was
added. The resulting black suspension was then stirred for 24 h in a
hydrogen atmosphere (1 bar). The suspension was then filtrated over
kieselguhr and washed with MeOH. After the solvent was removed
under reduced pressure and purification via column chromatography
(silica gel, DCM/MeOH 98:2 → DCM/MeOH 95:5), 20 was
obtained as yellow gum (0.25 g, 0.78 mmol, 63%).
N-(5-Nitropyridin-2-ylmethyl)-N-pyridin-2-ylmethylbenzamide
(19) and N-(5-Aminopyridin-2-ylmethyl)-N-pyridin-2-ylmethylben-
zamide (20). Benzamide 19 was prepared in a multistep reaction
N-(5-Aminopyridin-2-ylmethyl)-N-pyridin-2-ylmethylbenzamide
1
(20): H NMR (CDCl3, 300 MHz) δ = 3.56 (br s, 2H), 4.53 (mc,
J
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2H), 4.74 (mc, 2H), 6.82−6.94 (m, 2H), 7.07−7.62 (m, 8 H) 7.94
(mc, 1H), 8.47 (mc, 1H); 13C NMR (CDCl3, 100 MHz) δ = 50.1, 59.1,
66.3, 122.3, 127.0, 128.4, 129.7, 136.2, 136.8, 137.2, 141.8, 145.7,
146.5, 149.3, 149.8, 156.8, 157.3; MS (CI, NH3) m/z = 319.2 (100)
[(M + 1)+], HRMS (CI, NH3) m/z [(M + 1)+] calcd for C19H18N4O
319.15589, found 319.15660.
steps) after purification via column chromatography (aluminum oxide,
EE → EE/EtOH 98:2).
N-(2-Dimethylaminoethyl)-N-(1-methyl-1H-imidazol-4-ylmethyl)-
1
benzamide (23): H NMR (CDCl3, 300 MHz) δ = 1.90−2.29 (m,
6H), 2.29−2.56 (m, 2H), 3.26−3.57 (m, 2H), 3.58 (s, 3H), 4.31−4.62
(m, 2H), 6.59−6.94 (m, 1H), 7.2−7.38 (m, 5H), 7.38−7.51 (m, 1H);
13C NMR (CDCl3, 100 MHz) δ = 42.6, 45.6, 46.9, 47.7, 56.6, 57.6,
Methyl 6-((N-((Pyridine-2-yl)methyl)benzamido)methyl)pyridine-
3-carboxylate (21). Benzamide 21 was prepared via a multistep
reaction beginning with the oxidation of 6-methyl-nicotinic acid
leading to carbaldehyde 21a. Carbaldehyde 21a was obtained as a pale
yellow solid (1.54 g, 9.28 mmol, 62%) after purification via column
chromatography (silica gel, CH/EE 3:1).
117.9, 119.0, 126.6, 126.9, 128.3, 129.3, 136.8, 137.8, 138.8, 171.8; MS
(pos ESI) m/z = 287.3 (100) [(M + 1)+]; HRMS (APCI, MeOH/
NH4) m/z [(M + 1)+] calcd for C16H22N4O 287.18730, found
287.18719.
N-(2-Dimethylaminoethyl)-N-quinolin-2-ylmethylbenzamide
(24). Benzamide 24 was prepared via a reductive amination step
according to general procedure a followed by an acylation according to
general procedure b. Benzamide 24 was then obtained as a brown gum
(0.16 g, 0.48 mmol, 20% over two steps) after purification via column
chromatography (silica gel, DCM/MeOH 98:2 → DCM/MeOH
85:15).
Methyl 6-formylpyridin-3-carboxylate (21a):29 mp 107 °C; 1H
NMR (CDCl3, 400 MHz) δ = 4.00 (s, 3H), 8.03 (dd, 1H, J = 8.1 Hz, J
= 0.9 Hz), 8.46 (ddd, 1H, J = 8.1 Hz, J = 2.0 Hz, J = 0.9 Hz), 9.36 (dd,
1H, J = 2.0 Hz, J = 0.9 Hz), 10.14 (d, 1H, J = 0.9 Hz); 13C NMR
(CDCl3, 100 MHz) δ = 52.9, 121.2, 129.3, 138.4, 151.3, 155.0, 164.9,
192.7; MS (CI, NH3) m/z = 166.0 (100) [(M + 1)+].
N-(2-Dimethylaminoethyl)-N-quinolin-2-ylmethylbenzamide (24):
A reductive amination step according to the general procedure a
using 21a as carbonyl compound and 2-picolylamine as amine lead to
the secondary amine 21b which was obtained as dark brown oil (0.41
g, 1.59 mmol, 93%) without further purification.
1H NMR (CDCl3, 300 MHz) δ = 2.71−2.86 (m, 2H), 3.41 (s, 6H),
3.97−4.15 (m, 1H), 4.88−5.06 (m, 2H) 7.12−7.31 (m, 3H), 7.23−
7.57 (m, 4H), 7.68−7.74 (m, 1H), 7.76−7.82 (m, 1H), 8.01−8.10 (m,
2H); 13C NMR (CDCl3, 100 MHz) δ = 29.1, 40.9, 43.5, 53.6, 55.1,
62.7, 120.1, 126.6, 126.7, 126.8, 127.3, 127.6, 127.7, 128.3, 128.9,
129.8, 130.0, 135.3, 137.1, 147.6, 156.0, 173.4; MS (CI, NH3) m/z =
334.2 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd for
C21H23N3O 334.19194, found 334.19250.
Methyl 6-(((pyridine-2-yl)methylamino)methyl)pyridine-3-carbox-
1
ylate (21b): H NMR (CDCl3, 400 MHz) δ = 3.94 (s, 3H), 4.01 (s,
2H), 4.07 (s, 2H), 7.17 (ddd, 1H, J = 7.5 Hz, J = 4.9 Hz, J = 1.2 Hz),
7.33 (d, 1H, J = 7.9 Hz), 7.47 (dd, 1H, J = 8.2 Hz, J = 0.8 Hz), 7.64
(ddd, 1H, J = 7.7 Hz, J = 7.7 Hz, J = 1.9 Hz), 8.24 (dd, 1H, J = 8.1 Hz,
J = 2.2 Hz), 8.56 (ddd, 1H, J = 4.8 Hz, J = 1.7 Hz, J = 0.8 Hz), 9.15
(dd, 1H, J = 2.2 Hz, J = 0.8 Hz); 13C NMR (CDCl3, 100 MHz) δ =
52.4, 54.5, 54.6, 121.8, 122.3, 122.5, 124.6, 136.6, 137.7, 149.5, 150.7,
159.0, 164.0, 165.9 ppm.
The secondary amine 21b was the acylated according to the general
procedure c, and 21 was obtained as a pale yellow gum (0.33 g, 0.91
mmol, 58%) after purification via column chromatography (silica gel,
DCM/MeOH 97:3).
N-(2-Dimethylaminophenyl)-N-pyridin-2-ylmethylbenzamide
(25). The precursor amine was synthesized by the general procedure a
described above. A yellow liquid (0.58 g, 2.6 mmol, 71%) with the
following analytical data was obtained after column chromatography
(silica gel, CH/EE 5:1 → CH/EE 2:1).
1
N,N-Dimethyl-N-pyridin-2-ylmethylbenzene-1,2-diamine (25a): H
NMR (CDCl3, 300 MHz) δ = 2.70 (s, 6H), 4.50 (s, 2H), 6.52 (dd, 1H,
J = 8.0 Hz, J = 1.4 Hz), 6.68 (ddd, 1H, J = 7.6 Hz, J = 7.6 Hz, J = 1.4
Hz), 6.93 (dddd, 1H, J = 7.4 Hz, J = 7.4 Hz, J = 1.5 Hz, J = 0.5 Hz),
7.05 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.14 (m, 1H), 7.34 (m, 1H), 7.61
(ddd, 1H, J = 7.6 Hz, J = 7.6 Hz, J = 1.8 Hz), 8.58 (mc, 1H); 13C NMR
(CDCl3, 100 MHz) δ = 44.2, 50.0, 110.6, 117.0, 119.2, 121.2, 122.1,
124.8, 136.8, 140.7, 142.9, 149.4, 159.8; MS (CI, NH3) m/z = 228.2
(100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd for
C14H17N3 228.15007, found 228.14970.
The secondary amine 25a was then acylated according to the
general procedure b, and 25 was isolated as a yellow gum (0.24 g, 0.7
mmol, 65%) after purification via column chromatography (silica gel,
DCM/MeOH 98:2 → 97:3).
N-(2-Dimethylaminophenyl)-N-pyridin-2-ylmethylbenzamide (25):
1H NMR (CDCl3, 300 MHz) δ = 2.52 (s, 6H), 4.26 (d, 1H, J = 15.2
Hz), 5.89 (d, 1H, J = 15.2 Hz), 6.78 (dd, 1H, J = 8.2 Hz, J = 1.4 Hz),
6.84 (dddd, 1H, J = 7.4 Hz, J = 7.4 Hz, J = 1.5 Hz, J = 0.3 Hz), 7.07
(dddd, 1H, J = 7.4 Hz, J = 7.4 Hz, J = 1.6 Hz, J = 0.7 Hz), 7.10−7.23
(m, 5H), 7.38−7.42 (m, 2H), 7.50−7.54 (m, 1H), 7.67 (ddd, 1H, J =
7.7 Hz, J = 7.7 Hz, J = 1.8 Hz), 8.58 (mc, 1H); 13C NMR (CDCl3, 100
MHz) δ = 42.8, 54.7, 120.1, 122.1, 122.4, 122.5, 127.1, 127.9, 128.3,
182.8, 129.5, 136.2, 136.8, 148.5, 149.2, 158.1, 171.2; MS (CI, NH3)
m/z = 332.2 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M + 1)+]
calcd for C21H21N3O 332.17629, found 332.17640.
4-Oxo-4-phenyl-N,N-bis-pyridin-2-ylmethylbutyramide (26).
Amine 2 was acylated according to the general procedure b, and the
aliphatic amide 26 was obtained as a brown gum (0.52 g, 1.44 mmol,
82%) after purification with column chromatography (silica gel,
DCM/MeOH 98:2 → DCM/MeOH 90:10).
Methyl 6-((N-((pyridine-2-yl)methyl)benzamido)methyl)pyridine-
1
3-carboxylate (21): H NMR (CDCl3, 400 MHz) δ = 3.95 (s, 3H),
4.71 (br s, 1H), 4.80 (br s, 1H), 4.92 (br s, 2H), 7.13−7.59 (m, 8H),
7.70 (ddd, 1H, J = 6.5 Hz, J = 6.5 Hz, J = 3.3 Hz), 8.25 (mc, 1H), 8.54
(mc, 1H), 8.54 (d, 1H, J = 12.4 Hz), 9.13 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ = 48.7, 50.5, 52.8, 53.0, 119.2, 119.7, 120.1, 120.7, 125.0,
125.2, 126.6, 128.0, 133.8, 134.9, 135.9, 148.0, 148.7, 149.1, 154.6,
159.3, 159.8; MS (CI, NH3) m/z = 362.1 (100) [(M + 1)+]; HRMS
(CI, NH3) m/z [(M + 1)+] calcd for C23H21N3O 362.15047, found
362.15040.
N,N-Bis(2-dimethylaminoethyl)benzamide (22). Compound 22a
was prepared according to a literature procedure30 followed by
distillation (bp16mbar = 90 °C) to obtain a colorless liquid (1.72 g, 10.8
mmol, 83%).
1
N,N,N′,N′-Tetramethyldiethylamine (22a): H NMR (CDCl3, 300
MHz) δ = 2.22 (s, 12H), 2.41 (t, 4H, J = 6.4 Hz), 2.71 (t, 4H, J = 6.4
Hz); 13C NMR (CDCl3, 100 MHz) δ = 45.7, 47.8, 59.4; MS (CI,
NH3) m/z = 160.2 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M +
1)+] calcd for C8H21N3 160.18150, found 160.18137.
Benzamide 22 was prepared out of amine 22a according to the
general procedure b. Benzamide 22 was obtained as a yellow gum
(0.57 g, 2.2 mmol, 65%) after purification via bulb to bulb distillation
−2
(bp6.8*10
= 240 °C).
mbar
N,N-Bis(2-dimethylaminoethyl)benzamide (22): 1H NMR (CDCl3,
300 MHz) δ = 1.98−2.35 (m, 12H), 2.35−2.64 (m, 4H), 3.29−3.69
(m, 4H), 7.39 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ = 45.7, 47.0,
55.5, 59.3, 122.0, 122.3, 136.5, 149.3, 159.9; MS (CI, NH3) m/z =
264.2 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd for
C15H25N3O 264.20810, found 264.20759.
4-Oxo-4-phenyl-N,N-bis-pyridin-2-ylmethyl-butyramide (26): 1H
NMR (CDCl3, 300 MHz) δ = 2.93 (t, 2H, J = 6.4 Hz), 3.41 (t, 2H,
J = 6.4 Hz), 4.78 (s, 2H), 4.82 (s, 2H), 7.14 (ddd, 1H, J = 7.6 Hz, J =
4.9 Hz, J = 1.2 Hz), 7.18 (ddd, 1H, J = 7.6 Hz, J = 4.9 Hz, J = 1.2 Hz),
7.31 (mc, 2H), 7.41−7.47 (m, 2H), 7.51−7.56 (m, 2H), 7.62 (td, 1H, J
= 7.7 Hz, J = 1.8 Hz), 7.69 (td, 1H, J = 7.7 Hz, J = 1.8 Hz), 7.98−8.02
(m, 2H), 8.48 (mc, 1H), 8.56 (mc, 1H); 13C NMR (CDCl3, 100 MHz)
δ = 27.6, 34.1, 51.9, 53.2, 120.9, 122.3, 122.4, 128.1, 128.7, 133.0,
N-(2-Dimethylamino-ethyl)-N-(1-methyl-1H-imidazol-4-
ylmethyl)benzamide (23). The secondary amine 23a was prepared
according to the general procedure a and than the secondary amine
23a was acylated according to the general procedure b. The benzamide
23 was obtained as a yellow gum (0.07 g, 0.2 mmol, 30% over two
K
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136.9, 149.2, 149.9, 156.8, 157.4, 172.8, 199.2; MS (CI, NH3) m/z =
360.2 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M + 1)+] calcd for
C22H21N3O2 360.17120, found 360.17100.
sample of the starting material for the synthesis of compound
25.
N-(2-Dimethylaminoethyl)-4-oxo-4-phenyl-N-pyridin-2-ylmethyl-
butyramide (27). Amine 9a was acylated according to the general
procedure b, and the aliphatic amide 27 was obtained as a brown gum
(0.42 g, 1.22 mmol, 56%) after purification with column
chromatography (silica gel, DCM/MeOH 98:2 → DCM/MeOH
80:20).
REFERENCES
■
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Stuttgart, 2003.
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ski, P. J. Protecting Groups, 3rd ed.; Georg Thieme:
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Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.
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̈
̈
N-(2-Dimethylaminoethyl)-4-oxo-4-phenyl-N-pyridin-2-ylmethyl-
1
Chem., Int. Ed. 2011, 50.
butyramide (27): H NMR (CDCl3, 300 MHz) δ = 2.23−2.27 (m,
(4) Kramer, R. A.; Brohmer, M. C.; Forkel, N. V.; Bannwarth, W. Eur.
̈
6H), 2.45 (t, 1H, J = 7.4 Hz), 2.55 (t, 1H, J = 7.3 Hz), 2.83 (t, 1H, J =
6.4 Hz), 2.91 (t, 2H, J = 6.4 Hz), 3.37 (t, 1H, J = 6.4 Hz), 3.43 (t, 1H,
J = 6.4 Hz), 3.53−3.61 (m, 2H), 4.74−4.80 (m, 2H), 7.13−7.23 (m,
1H), 7.25−7.38 (m, 1H), 7.42−7.48 (m, 2H), 7.52−7.58 (m, 1H),
7.61−7.73 (m, 1H), 7.98−8.04 (m, 2H), 8.49−8.59 (m, 1H); 13C
NMR (CDCl3, 100 MHz) δ = 27.0, 27.5, 33.7, 33.9, 44.6, 45.6, 45.8,
46.5, 51.8, 53.8, 56.9, 57.8, 120.8, 122.2, 122.6, 128.1, 128.6, 133.1,
136.8, 137.1, 149.2, 149.8, 157.2, 158.0, 172.2, 172.5, 199.2; MS (CI,
NH3) m/z = 340.2 (100) [(M + 1)+]; HRMS (CI, NH3) m/z [(M +
1)+] calcd for C20H25N3O2 340.20250, found 340.20260.
J. Org. Chem. 2009, 4273−4283.
(5) Brohmer, M. C.; Bannwarth, W. Eur. J. Org. Chem. 2008, 4412−
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4415; Synfacts 2008, 11, 1226−1226.
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G.; Lamboley, S. Tetrahedron Lett. 1995, 51, 9467−9486.
(8) Nambu, M.; White, J. D. Chem. Commun. 1996, 1619−1620.
(9) This compound was obtained from Prof. Xile Hu, University of
Lausanne.
(10) Csok, Z.; Vechorkin, O.; Harkins, S. B.; Scopelliti, R.; Hu, X. L.
4-Cyano-N-(2-dimethylaminoethyl)-N-(2-iminobut-3-enyl)-
benzamide (28). Amine 9a was acylated according to the general
procedure b, and benzamide 28 was obtained as a yellow gum (0.22 g,
0.7 mmol, 40%) after purification with column chromatography (silica
gel, DCM/MeOH/Et3N 99:1:0.1 → DCM/MeOH/Et3N 97:3:0.1).
4-Cyano-N-(2-dimethylaminoethyl)-N-(2-iminobut-3-enyl)-
J. Am. Chem. Soc. 2008, 130, 8156−8157.
(11) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D.
Tetrahedron Lett. 1989, 30, 1927−1930.
(12) Bandyopadhyay, P.; Jha, S.; Imran Ali, S. K. J. Agric. Food Chem.
2009, 57, 9780−9786.
1
benzamide (28): H NMR (CDCl3, 300 MHz) δ = 1.96−2.32 (m,
(13) Sundaravel, K.; Suresh, E.; Saminathanc, K.; Palaniandavar, M.
Dalton Trans. 2011, 40, 8092−8107.
6H), 2.32−2.62 (m, 2H), 3.30−3.67 (m, 2H), 4.56−4.97 (m, 2H),
7.07−7.46 (m, 1H), 7.22 (ddd, 1H), 7.55−7.76 (m, 5H), 8.58 (mc,
1H); 13C NMR (CDCl3, 100 MHz) δ = 45.7, 113.4, 118.3, 122.7,
127.8, 132.3, 136.9, 141.0, 170.4; MS (CI, NH3) m/z = 309.2 (100)
[(M + 1)+]; HRMS (APCI, MeOH) m/z [(M + 1)+] calcd for
C18H20N4O 309.17154, found 309.17090.
(14) Bebout, D. C.; Lai, W.; Stamps, S. M.; Berry, S. M.; Butcher, R.
J. Polyhedron 2008, 27, 1591−1600.
(15) Bhattacharya, S.; Snehalatha, K.; Kumar, V. P. J. Org. Chem.
2003, 68, 2741−2747.
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(17) Blank, B.; Madalska, M.; Kempe, R. Adv. Synth. Catal. 2008, 350,
749−758.
N-(2-Dimethylaminoethyl)-4-methoxy-N-pyridin-2-ylmethylben-
zamide (29). Amine 9a was acylated according to the general
procedure b and benzamide 29 was obtained as a yellow gum (0.31 g,
1.0 mmol, 37%) after purification with column chromatography (silica
gel, DCM/MeOH/Et3N 99:1:0.1 → DCM/MeOH/Et3N 97:3:0.1).
N-(2-Dimethylaminoethyl)-4-methoxy-N-pyridin-2-ylmethylbenza-
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ASSOCIATED CONTENT
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S
* Supporting Information
1H and 13C NMR spectra and theoretical calculation data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
*Fax: +49-761-203-8705. E-mail: willi.bannwarth@organik.
chemie.uni-freiburg.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. M. Keller, M. Schonhardt, and F. Reinbold for
measurements of the NMR spectra and Dr. J. Worth and C.
Warth for the measurements of the mass spectra. We also thank
Prof. Xile Hu (University of Lausanne, Switzerland) for a
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dx.doi.org/10.1021/jo301349t | J. Org. Chem. XXXX, XXX, XXX−XXX