Synthesis of Medium-Ring-Sized Benzolactams by Using Strong Electrophiles and Quantitative Evaluation of Ring-Size Dependency of the Cyclization Reaction Rate

Article abstract of DOI:10.1021/acs.joc.9b02843

Benzolactams with medium-sized rings were synthesized via the electrophilic aromatic substitution reaction of carbamoyl cations (R₁R₂N⁺═C═O) in good to high yields without dilution. These reactions were utilized to quantitatively examine the extent of retardation of medium-sized ring formation, compared to five- or six-membered ring formation. The order of reaction rates of formation of cyclic benzolactams is six- > five- > seven- > eight- > nine-membered ring at 25 °C. The present reaction provides a route to eight- A nd nine-membered benzolactams.

Full text of DOI:10.1021/acs.joc.9b02843

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Article
Synthesis of Medium-Ring-sized Benzolactams by Using
Strong Electrophiles and Quantitative Evaluation of
Ring-size Dependency of the Cyclization Reaction Rate
Hiroaki Kurouchi, and Tomohiko Ohwada
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02843 • Publication Date (Web): 04 Dec 2019
Downloaded from pubs.acs.org on December 8, 2019
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Page 1 of 52
The Journal of Organic Chemistry
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Synthesis of Medium-Ring-sized Benzolactams by Using Strong Electrophiles and
Quantitative Evaluation of Ring-size Dependency of the Cyclization Reaction Rate
§
,†
,†
Hiroaki Kurouchi, and Tomohiko Ohwada*
§
Research Foundation Itsuu Laboratory, C1232, Kanagawa Science Park R&D Building, 3-2-1 Sakado,
†
Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan Graduate School of Pharmaceutical Sciences, The
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
1
1
1
1
1
1
1
1
1
1
2
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0
1
2
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5
6
7
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0
1
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3
4
5
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0
1
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0
1
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9
0
*
E-mail: ohwada@mol.f.u-tokyo.ac.jp
n
O
OMe
R
N
X
R
N
medium sized
ring formation
Y
X
X
Y
CF
3
SO
3
H
Y
O
n
C
n
O
O
CH
2
Cl
2
N
r.t.
O
R
X = H, Me, 3,4-diOMe, Ph
Y = CH , O
R = Me, Et, i-Pr, i-Bu, n-Octyl
n = 1-3
~
96% yield
2
Relative cyclization rates
2 x 10-8
2 x 10-6
1 x 10-4 7 x 10-4
1 (standard)
<
k
cyclization
9
N
8
6
N
R
O
7
5
N R
N
O
N
R
R
R
O
O
O
The most favorable
ABSTRACT: Benzolactams with medium-sized rings were synthesized via electrophilic aromatic
+
substitution reaction of carbamoyl cations (R
1
R
2
N =C=O) in good to high yields without dilution. These
reactions were utilized to quantitatively examine the extent of retardation of medium-sized ring
formation, compared to 5- or 6-membered ring formation. The order of reaction rates of formation of
cyclic benzolactams is 6- > 5- > 7- > 8- > 9-membered ring at 25 ºC. The present reaction provides a
route to 8- and 9-membered benzolactams
Introduction
1
Benzolactam structures are important moieties of bioactive compounds, and are frequently
found in natural products and pharmaceuticals. Recently, medium-sized benzolactams have attracted
2
attention as a new type of scaffold for bioactive compounds. Benzolactams contain benzoyl
functionalities, and ring closure reactions under various conditions have been employed for the
3
synthesis of benzolactam derivatives containing 5-, 6- and 7-membered rings. However, direct ring
4
formation of benzolactams containing medium-sized rings has not been studied systematically, and no
synthetic method via intramolecular electrophilic aromatic substitution (IEAS) reaction has been
reported. Instead, ring expansion reactions have frequently been used for the synthesis of benzolactams
with 8- and 9-membered rings, even though the low regioselectivity of the rearrangement generally
5
results in poor yields of the desired products.
Indeed, medium-sized ring formation via intramolecular electrophilic aromatic substitution reactions is a
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challenging area of chemistry. Intramolecular Friedel-Crafts acylation was reported as the first example,
and the applicability of this reaction to formation of rings of various sizes was examined by Huisgen
1
2
3
4
5
6
7
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
6
and his coworkers. Their research revealed that medium- to large-sized benzoketones (8- to
1
9-membered rings) can be synthesized by means of IEAS reaction, but careful control of the substrate
concentration is necessary. Very recently, Friedel-Crafts alkylation was also reported to give cyclic
7
compounds with 8- and 9-membered rings, although the yields were moderate to low. In spite of the
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
long-standing history of IEAS reactions in organic synthesis, there have been few studies of
medium-sized ring formation by means of IEAS reactions.
O
OMe
O
OMe
H
O
R
N
CF SO H
(TfOH)
R
N
3
3
O
X
X
CH Cl2
r.t.
2
O
O
1
Intramolecular
Hydrogen Bonding-Assisted
Activation
R
N
C
N
R
X
O
O
Carbamoyl Cation
2
Scheme 1. Intramolecular hydrogen bonding-assisted activation of carbamate
Recently, we developed a system to activate carbamate compounds (1), which is applicable to
highly efficient cyclization of phenethylcarbamates to afford 6-membered dihydroisoquinolone
8
derivatives (2) in high yields. We found that when ortho-methyl salicylate was used as a leaving group
in carbamates, steady cleavage of the C-O bond occurred under mild conditions (at 20 °C in the
3 3
presence of trifluoromethanesulfonic acid (CF SO H, TfOH)) to generate carbamoyl cations, and these
systems offered considerable substrate generality (Scheme 1). Kinetic and computational studies
indicated that the rate-determining step of this reaction is not the cyclization step but the C-O (o-methyl
salicylate) bond cleavage step to generate carbamoyl cations. After generation of the carbamoyl cation,
the reactive species immediately transforms to the cyclized product. We expected that this highly
efficient reaction under mild conditions would be applicable to medium-sized ring formation. Further,
we also expected that we could utilize the reaction rates as a quantitative scale to evaluate the ring-size
dependency of the activation free energy of IEAS reaction.
Results and Discussion
First, we examined the formation of benzolactams with 8-membered rings. The reaction
conditions were screened and optimized (Supporting Information), and we found that carbamate
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substrates bearing ortho-methyl salicylate as a leaving group gave 8-membered benzolactams in good
yields under TfOH-activated conditions. By this method, various 8- and 9-membered benzolactams can
be obtained from a simple amine compound (Scheme 2 (a) (b)).
1
2
3
4
5
6
7
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)
MeO
O
O
OMe
O
O
O
OMe
R2
N
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
H
N
Y
R2
O
Y
O
n
X
n
R1
X
R1
O
THF
3
∆
1
X = H, Me, 3,4-diOMe etc., Y = CH , O
R = H or alkyl group, R = alkyl group
n = 1, 2, 3
2
1
2
(
b)
n
O
OMe
R2
N
Y
CF SO H
R2
3
3
Y
O
(TfOH)
X
Y
N
n
R1
C
X
n
R1
N
R2
O
CH2Cl2
r.t.
X
O
R1
O
1
2
Scheme 2. Formation of benzolactams with medium-sized rings from simple amine compounds (a
and b)
Table 1. Substrate generality of medium-sized ring formation
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Entry[a]
Substrate
Product
Yield[b]
Entry[a]
6
Substrate
Product
Me
Yield[b]
87%
Entry[a]
Substrate
Product
Yield[b]
41%
1
2
3
4
5
6
7
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
8-membered ring formation
Me
Me
9-membered ring formation
O
N
O
1
O
MeO
O
N
MeO
MeO
Me
MeO Me
1
2
N
Me
O
O
N
6
1%
3
3
1f
O
OMe
Me
N
Me
O
O
N
Me
MeO
2
f
O
O
O
OMe
OMe
O
O
O
OMe 2a
O
O
1l
2l
1a
MeO
MeO
O
O
9
6%
MeO
MeO
6
8%
O
MeO
N
O
MeO
MeO
N
7
8
9
MeO
OMe
N
Me
13
N
N
6
4%
2
3
N
Me
O
O
O
N
Et
1
g
2g
O
Et
1m
1n
2m
2n
OMe 2b
1
b
MeO
MeO
MeO
MeO
MeO
MeO
Me
O
O
7
6
3%
8
6%
4%
14 MeO
MeO
N
O
O
O
65%
74%
73%
N
O
O
N
Me
Me
3
7
N
N
N
O
O
O
N
N
N
1h Me
OMe
OMe
O
O
O
OMe
2h
2i
O
O
O
O
O
O
OMe
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
2c
1
c
O
O
O
N
O
O
62%
75%
N
Me
7
3
O
N
15
Me
N
O
O
Me
1o
O
2o
O
1i
OMe
O
Me
4
5
O
OMe
O
O
O
N
2
d
O
1d
N
O
1
6
3
8
6%
1
0
O
O
N
Me
O
O
N
OMe
1
p
O
2p
1
j
O
O
OMe
OMe
O
Me
Me
2j
10-membered ring formation
O
Ph
O
Me
O
O
MeO
MeO
Me
2e
Me
17 MeO
MeO
80%
6%
1
e
OMe
11
N
N
Me
O
Ph
N
4
N
1k Me
O
Me
O
OMe
O Me
2q
2
k
1q
[
a] General procedure: Substrate (0.60 mmol) was dissolved in dichloromethane (3.0 mL) and TfOH (10 equiv.) was
added at 0 ºC. The reaction mixture was stirred at 20-25 °C (r.t.) for 1-6 hrs. [b] Isolated yields.
The substrate generality of this reaction was investigated under these optimized conditions
(
Table 1). The reactions proceeded in good to high yields without dilution. Examples of 8-membered
ring formation are shown in entries 1-11. For compounds with non-substituted aromatic rings,
8-membered ring products (2a-2d) were obtained in good to high yields (Entries 1-4). Interestingly,
higher yields were obtained as the size of the alkyl group on the nitrogen atom became larger. Possible
explanations for this include: (1) the Thorpe-Ingold effect, and (2) protection of the carbamoyl cation
from the attack of triflate anion, which would result in formation of amine by-products (for evidence of
counter anion attack, see Supporting Information). In the absence of an alkyl group on the nitrogen atom,
the reaction afforded a complex mixture (data not shown).
Electron-donating groups were favorable for the cyclization (Entries 5-7). On the other hand, a methoxy
group at the para-position with respect to the alkyl chain prevented the cyclization (data not shown),
presumably because it is at the meta position with respect to the bond-forming carbon atom, leading to
deactivation of the cyclization. A methyl group (1h) at the α-position of the nitrogen atom did not
greatly affect the reaction (Entry 8). Substrates tethered by an oxygen-containing carbon chain (1i-1k)
were also examined (Entries 9-11) and they afforded cyclized products in good yields.
Nine-membered ring formation reactions were also investigated (Entries 12-16). Electron-rich
aromatic rings were required for this ring size. Introduction of methoxy groups improved the reaction
efficiency, affording the cyclized product in 41 % yield (Entry 12). As the steric bulkiness of the alkyl
group on the nitrogen atom was increased, the reaction yield also increased (68 and 63 % in Entries 13,
1
4, respectively). This 9-membered ring formation reaction was also quite effective for naphthol
derivative 1o (Entry 15). When the size of the alkyl group on the nitrogen atom was increased (1p,
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The Journal of Organic Chemistry
Entry 16), the reaction yield increased, reaching 75%. To examine the limitations of the reaction, the
formation of a 10-membered ring was also investigated (Entry 17). Although the yield was low, the
1
2
3
4
5
6
7
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
1
0-membered ring product 2q could be obtained.
Next, we quantitatively compared the reaction rates of formation of normal-size (5, 6 and 7 members)
and medium-size rings (8 and 9 members).
In a previous study, it was found that the rate-determining step is not the cyclization reaction,
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
8
but generation of the carbamoyl cation. So, direct measurement of cyclization rates is impossible.
However, relative cyclization rates can be obtained by means of competition experiments. We designed
and prepared substrates 1r-x (Table 2) that bear two aromatic rings connected to a nitrogen atom,
tethered by two alkyl chains of different lengths; with these compounds, the relative ratios of the
9
products of different ring sizes can be used to evaluate the relative reaction rates of the cyclizations.
Table 2. Competition experiments to measure relative cyclization rates.
X2
m-4
X1
X1
N
n-4
-m
n-4
X1
O
2
O
m-4
N
TfOH (10 eq.)
CH Cl
m-4
N
O
+
X1
C
O
n-4
2
2
n-4
O
OMe
N
2
5ºC, 1 hr
m-4
-n
X2
X2
1
X2
O
2
[a]
[b]
Entry
Substrate X
1
X
2
m
n
Product Ratio
Total
[
c]
2
-m : 2-n
Yield
1
2
1r
1s
H
6
6
6
6
86.5 : 13.5
98.5 : 1.5
90%
Cl
Cl
72%
Cl
3
4
5
6
7
8
1t
Cl
H
H
H
Cl
H
H
H
6
5
7
5
6
8
5
7
5
8
5
9
77.4 : 22.6
86.7 : 13.3
97.6 : 2.4
59.4 : 40.6
83%
84%
81%
55%
95%
53%
1u
1v
1w
1x
1y
H
Cl
H
[
d]
100 : 0
[d]
H
100 : 0
[a] General procedure: Substrate (0.40 mmol) was dissolved in dichloromethane (2.0 mL) and slowly
dropped into a mixture of TfOH (10 equiv.) and dichloromethane (2.0 mL) at 25 ºC in an isothermal
1
bath. The reaction mixture was stirred at 25 ºC for 1 hr under argon atmosphere. [b] H NMR integration
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ratio. Average values of two independent experiments. [c] Average values of the yield of the mixture
1
2
3
4
5
6
7
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
1
of the two products in two independent experiments. [d] H NMR integration ratio obtained from one
experiment. The 9-membered-ring product 2x-n was not detected.
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
To estimate the size effect on ring formation rates, a solution of substrate in dichloromethane
was dropped into a mixture of TfOH and dichloromethane at 25 ºC and the product ratio was determined
after 1 hr. All of the reactions were completed within one hour. The main reason of the loss of starting
material mass, the total product yield did not reach 100%, is that the carbamoyl cation is not only
trapped by tethered aromatic ring but also trapped by triflate anion to afford amine product (See
supporting information). The intermolecular reaction was not observed based on the product analysis.
The attempt of quantitative comparison of the rate of 6- and 5-membered ring formation was
difficult because 6-membered ring formation dominated (Entry 7). To make the product ratios
1
measurable by means of H-NMR, i.e., to avoid highly biased selectivity of cyclization reactions, the
magnitude of the activation enthalpy was tuned by introduction of a deactivating 4-chloro group or
4-chlorophenyl group on the aromatic rings (see Table 2).
Introduction of a 4-chlorophenyl group decreased the cyclization rate by about one-sixth (1r,
Entry 1). Introduction of a 4-chloro group decreased the reaction rate to greater extent (1s, Entry 2). The
reaction rate of 6-membered ring formation (2t-m) for compounds with a 4-chloro-substituted benzene
ring was about three times faster than 5-membered ring formation (2t-n) for compounds with a
non-substituted benzene ring (Entry 3). In this context, 6-membered ring formation occurs more readily
than 5-membered ring formation in the present reaction. This trend has also been observed in various
1
0
Friedel-Crafts-type alkylation reactions.
The reaction rate of 5-membered ring formation for compounds with a non-substituted benzene
ring (2u-m) was six times faster than that of 7-membered ring formation for compounds with a
non-substituted benzene ring (2u-n) (Entry 4). The reaction rate of 7-membered ring formation for
compounds with a non-substituted benzene ring (2v-m) was forty times faster than that of 5-membered
ring formation for compounds with a chloro-substituted benzene ring (2v-n) (Entry 5). The reaction rate
of 5-membered ring formation of 4-chloro-substituted compounds (2w-m) was revealed to be 1.5 times
faster than 8-membered ring formation of non-substituted compounds (2w-n) (Entry 6). Finally,
9-membered ring formation (2y-n) was not detected in compounds with the present combinations of the
substituents (Entry 8). This result indicated that 9-membered ring formation is significantly slower
than 8-membered ring formation.
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
log krel -∆∆G‡
(kJ/mol)
6 N
krel = 1
Standard
0
0
R
O
6 N
krel = 2 x 10-1
krel = 2 x 10-3
krel = 7 x 10-4
R
O
1
0
Cl
6 N
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
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
Cl
R
O
5
N R
O
2
0
7
krel = 1 x 10-4
N
R
O
-5
30
5
N R
krel = 3 x 10-6
Cl
O
8
krel = 2 x 10-6
N
R
O
4
0
(lower than here)
9
N
krel < 2 x 10-8
(assumed)
R
O
Figure 1. Relative reaction rates (errors: within ±3% for each competition experiment at maximum) and
free energies of each ring formation and relative Gibbs free energy of activation (kJ/mol) at 25 ºC.
Based on these results (Table 2), we obtained relative reaction rates for formation of
‡
various-sized rings (Figure 1), and relative differences of Gibbs free energy of activation (∆∆G298K
)
1
1
were calculated based on transition state theory.
-4
The results indicate that the rate of 5-membered ring formation is 7 x 10 times slower than
-
4
6-membered ring formation, and the 7-membered ring formation was 1 x 10 times slower than
6
-membered ring formation. These results indicate that the Gibbs free energy of activation for the 5- and
-membered ring formations are unfavorable by approximately 20 kJ/mol over the 6-membered ring
7
-
6
formation. In addition, 8-membered ring formation was 2 x 10 times slower than 6-membered ring
formation, that is, the former is energetically more unfavorable than 6-membered ring formation by
approximately 30 kJ/mol. Because 9-membered ring formation is much slower than 8-membered ring
formation, the relative Gibbs free energy of activation should be larger than approximately 40 kJ/mol at
minimum in comparison with 6-membered ring formation (this value was derived from the product ratio
of 100: 1 at 25 ºC, within the limits of experimental error). In order to overcome this energy barrier,
activation of the aromatic ring is effective for formation of medium-sized benzolactams.
Conclusion
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This work provides a facile method for the synthesis of medium-sized benzolactams, which are
important substructures of bioactive compounds. Compounds containing non-substituted or activated
benzene rings react with electrophile to afford 8- and 9-membered benzolactams in good to high yields.
The method is also tolerant of atom replacement in the linker chain. These results are expected to be
useful reference data for estimation of the difficulty of medium-sized ring formation in other IEAS
reactions. However, the reaction mechanism of this cyclization is not as simple as that of usual IEAS
1
2
3
4
5
6
7
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
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
1
2
reactions. Further mechanistic study to assess path bifurcation is under way.
Experimental Section
I. General methods
Melting points were determined with a Yanaco micro melting point apparatus without
1
13
correction. H (400 MHz) – and C (100 MHz) -NMR spectra were recorded on a Bruker Avance400.
Chemical shifts were calibrated with tetramethylsilane as an internal standard or with the solvent peak,
and are shown in ppm values, and coupling constants are shown in hertz (Hz). The following
abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd =
doublet of double doublet, dt = double triplet, dq = double quartet, h = heptet, m = multiplet, and brs =
broad singlet. The NMR spectra are measured at 25 ºC if not mentioned. Electron spray ionization
time-of-flight mass spectra (ESI-TOF MS) were recorded on a Bruker micrOTOF-05 to give
high-resolution mass spectra (HRMS). HPLC separation was performed on HITACHI LaChrom Elite
HPLC systems containing of following: pump, L-2130;
detector, L-2400. All of the
trifluoromethanesulfonic acid promoted cyclization reactions were performed using heat gun-dried or
oven-dried glassware. Trifluoromethanesulfonic acid (TfOH) was dried with trifluoromethanesulfonic
acid anhydride and purified with vacuum distillation prior to use. Other commercially available
compounds and solvents were used as received. All microwave reactions were carried out in a
TM
single-mode microwave (Biotage Initiator Eight Synthesizer programmed to heat constantly at the
specified power). Reaction temperatures were determined using the built-in, on-line IR-sensor. The
reaction temperature of the competition reactions was implemented in water bath; the temperature was
kept at 25 ºC using HAAKE DC5 immersion circulator. Other heating reaction was conducted in oil
bath.
II. Synthesis of substrates
Synthesis of dimethyl 2,2'-(carbonylbis(oxy))dibenzoate
This compound was synthesized according to our previous literature.
8
Synthesis of methyl 2-((methyl(4-phenylbutyl)carbamoyl)oxy)benzoate (1a)
To a solution of (4-bromobutyl)benzene (854 mg, 4.00 mmol) in methanol (2.0 mL),
methylamine (40% solution in methanol) (5.0 mL) was added at room temperature. The reaction
mixture was stirred at room temperature for 6 hrs. The solvent was removed in vacuo and the crude
residue was dissolved in dichloromethane. The solution was washed with aqueous sodium hydroxide
(2M) (10 mL), dried over sodium sulfate and the solvent was evaporated under reduced pressure to give
N-methyl-4-phenylbutan-1-amine (3a) as colorless oil (668 mg, 4.09 mmol, 102% crude yield). The
amine was used without further purification.
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.28-7.25 (m, 2H), 7.18-7.15 (m, 3H), 2.64-2.56 (m, 4H), 2.41 (s,
13
3
1
3
H), 1.69-1.61 (m, 2H), 1.56-1.48 (m, 2H), 1.29 (brs, 1H). C-NMR (100 MHz, CDCl ) δ (ppm): 142.4,
+
+
28.3, 128.2, 125.6, 52.0, 36.5, 35.8, 29.5, 29.1.ESI-HRMS: Calcd for C11H18N [M+H] : 164.14338.
Found: 164.14161.
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The Journal of Organic Chemistry
A solution of 3a (386 mg, 2.37 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (668
mmol) in tetrahydrofuran (5.0 mL) was stirred at room temperature for 13 hrs. The solvent of the
reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 5 ~ 1 : 4) to afford methyl
2-((methyl(4-phenylbutyl)carbamoyl)oxy)benzoate 1a as colorless oil (590 mg, 1.80 mmol, 89% yield
2
3
4
5
6
7
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
(
based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))).
1
H-NMR (400 MHz, CDCl
3
), two rotamers (A and B) with respect to the amide bond were observed
(approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.96 (dd, J = 7.6, 1.6 Hz, 1H, rotamer A and B),
7
3
.53-7.49 (m, 1H, rotamer A and B), 7.28-7.08 (m, 7H, rotamer A and B), 3.81 (s, 1.3H, rotamer B),
.79 (s, 1.7H, rotamer A), 3.48 (t, J = 6.8 Hz, 0.9H, rotamer B), 3.38 (t, J = 6.8 Hz, 1.1H, rotamer A),
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
3.09 (s, 1.7H, rotamer A), 2.98 (s, 1.3H, rotamer B), 2.70-2.64 (m, 2H, rotamer A and B), 1.73-1.66 (m,
4H, rotamer A and B). C-NMR (100 MHz, CDCl
observed, δ (ppm): 165.2, 154.5, 154.3, 151.3, 151.1, 142.2, 142.0, 133.4, 131.4, 128.4, 128.3, 128.2,
1
3
3
), two rotamers with respect to the amide bond were
1
2
25.74, 125.66, 125.2, 124.1, 124.0, 123.8, 123.7, 51.9, 49.12, 49.08, 35.5, 34.8, 34.4, 28.4, 28.3, 27.4,
6.9. ESI-HRMS: Calcd for C20H23NNaO [M+Na] : 364.1519. Found: 364.1509.
4
+
+
Synthesis of methyl 2-((ethyl(4-phenylbutyl)carbamoyl)oxy)benzoate (1b)
To a stirred solution of 4-phenylbutan-1-amine (753 mg, 5.04 mmol) and triethylamine (1.0
mL) in dry dichloromethane (10 mL), acyl chloride (405 mg, 5.16 mmol) was added dropwise slowly at
0
ºC. The temperature was raised to 25 ºC and the mixture was stirred for 30 min. The reaction was
quenched with 10 mL of ice water and the whole was extracted with dichloromethane (30 mL). The
organic layer was washed with aqueous hydrogen chloride (1M, 5.0 mL), dried over sodium sulfate and
the solvent was removed under reduced pressure to give crude oil which contains
N-(4-phenylbutyl)acetamide (3b) (known compound) (1056 mg, 5.52 mmol, 109% crude yield). The
crude product was used without further purification.
1
H-NMR (400 MHz, CDCl
.8 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.94 (s, 3H), 1.68-1.60 (m, 2H), 1.55-1.48 (m, 2H). C-NMR (100
MHz, CDCl ) δ (ppm): 170.0, 142.0, 128.3, 128.2, 125.7, 39.4, 35.4, 29.1, 28.6, 23.2. ESI-HRMS:
Calcd for C12
3
) δ (ppm): 7.29-7.25 (m, 2H), 7.19-7.15 (m, 3H), 5.82 (brs, 1H), 3.23 (q, J =
1
3
6
3
+
+
H
17NNaO [M+Na] : 214.1202. Found: 214.1218.
A solution of the crude compound that contains 3b (627 mg) and lithium aluminum hydride
(307 mg, 8.09 mmol) in tetrahydrofuran (20 mL) was stirred at 60 ºC for 20 hrs. Then the reaction
solution was cooled to 0 ºC and quenched with sodium sulfate decahydrate (10 g) and ethyl acetate (50
mL). Then the solution was filtered and the solvent was removed in vacuo to give crude oil, which
contains N-ethyl-4-phenylbutylamine (4b) (known compound) (565 mg, 3.19 mmol, 97% crude yield).
The amine was used directly in the next step without further purification.
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.28-7.25 (m, 2H), 7.18-7.15 (m, 3H), 2.64-2.60 (m, 6H),
1
3
1.69-1.61 (m, 2H), 1.56-1.49 (m, 2H), 1.29 (brs, 1H), 1.09 (t, J = 7.2 Hz, 3H). C-NMR (100 MHz,
CDCl ) δ (ppm): 142.4, 128.3, 128.2, 125.6, 49.7, 44.1, 35.8, 29.8, 29.2, 15.3. ESI-HRMS: Calcd for
C
3
+
+
12
H
20N [M+H] : 178.1590. Found: 178.1601.
A solution of 4b (407 mg, 2.30 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (660 mg,
2
.00 mmol) in tetrahydrofuran (5.0 mL) was stirred at 50 ºC for 2 days. The solvent of the reaction
mixture was evaporated under reduced pressure to give a crude oil. The crude product was purified by
column chromatography (eluent: ethyl acetate : n-hexane = 1 : 4) to afford methyl
2
-((ethyl(4-phenylbutyl)carbamoyl)oxy)benzoate 1b as colorless oil (596 mg, 1.68 mmol, 84% yield
(
based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))).
1
H-NMR (400 MHz, CDCl
approximately 1 : 1 ratio at 25 ºC), δ (ppm): 7.95 (d, J = 7.6 Hz, 1H), 7.52-7.48 (m, 1H), 7.23-7.22 (m,
H), 7.19-7.10 (m, 4H), 3.80 (s, 1.5H), 3.78 (s, 1.5H), 3.49-3.42 (m, 2H), 3.38-3.33 (m, 2H), 2.67-2.63
3
), two rotamers with respect to the amide bond were observed
(
3
1
3
(m, 2H), 1.76-1.66 (m, 4H), 1.26 (t, J = 6.8 Hz, 1.5H), 1.18 (t, J = 6.8 Hz, 1.5H). C-NMR (100 MHz,
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CDCl
1
5
3
), two rotamers with respect to the amide bond were observed, δ (ppm): 165.3, 154.2, 153.9,
51.04, 151.01, 142.2, 142.0, 133.3, 131.4, 128.32, 128.29, 128.22, 128.18, 125.7, 125.6, 125.2, 124.0,
1.9, 47.1, 46.9, 42.6, 42.2, 35.50, 35.48, 28.5, 28.4, 28.1, 27.6, 13.7, 13.0. ESI-HRMS: Calcd for
1
2
3
4
5
6
7
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
+
+
21 4 4
C H25NNaO [M+Na] : 378.1676. Found: 378.1666. Anal. Calcd. for C21H25NO : C, 70.96; H, 7.09; N,
3.94. Found: C, 71.03; H, 7.07; N, 4.07.
Synthesis of methyl 2-((isobutyl(4-phenylbutyl)carbamoyl)oxy)benzoate (1c)
To a stirred solution of 4-phenylbutan-1-amine (753 mg, 5.04 mmol) and triethylamine (1.0
mL) in dry dichloromethane (10 mL), isobutyryl chloride (541 mg, 5.08 mmol) was added dropwise
slowly at 0 ºC. The temperature was raised to 25 ºC and the mixture was stirred for 30 min. The reaction
was quenched with 10 mL of ice water and the whole was extracted with dichloromethane (30 mL). The
organic layer was washed with aqueous hydrogen chloride (1M, 5.0 mL), dried over sodium sulfate and
the solvent was removed under reduced pressure to give N-(4-phenylbutyl)isobutyramide (3c) as
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
colorless oil (1091 mg, 4.98 mmol, 99% yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.28-7.24 (m, 2H), 7.18-7.14 (m, 3H), 5.81 (brs, 1H), 3.23 (q, J =
6
1
.8 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 2.32 (h, J = 7.2 Hz, 1H), 1.67-1.60 (m, 2H), 1.55-1.48 (m, 2H),
.12 (d, J = 6.8 Hz, 6H). C-NMR (100 MHz, CDCl ) δ (ppm): 177.0, 142.2, 128.4, 128.3, 125.8, 39.2,
3
1
3
+
+
35.6, 35.5, 29.3, 28.7, 19.7. ESI-HRMS: Calcd for C14H21NNaO [M+Na] : 242.1515. Found: 242.1527.
A solution of N-(4-phenylbutyl)isobutyramide (588 mg, 2.68 mmol) and lithium aluminum
hydride (241 mg, 6.35 mmol) in tetrahydrofuran (15 mL) was stirred at 60 ºC for 7 hrs. Then the
reaction solution was cooled to 0 ºC and quenched with sodium sulfate decahydrate (10 g) and ethyl
acetate (50 mL). Then the solution was filtered and the solvent was removed in vacuo to give crude oil,
which contains N-isobutyl-4-phenylbutan-1-amine (4c) (known compound) (532 mg). The amine was
used directly in the next step without further purification.
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.29-7.25 (m, 2H), 7.19 -7.15 (m, 3H), 2.64-2.58 (m, 4H), 2.39 (d,
J = 6.8 Hz, 2H), 1.73 (h, J = 6.8 Hz, 1H), 1.68-1.59 (m, 2H), 1.56-1.49 (m, 2H), 1.06 (brs, 1H), 0.89 (d,
13
J = 6.4 Hz, 6H). C-NMR (100 MHz, CDCl
9.8, 29.2, 28.3, 20.7. ESI-HRMS: Calcd for C14
A solution of 4c (409 mg, 1.99 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (597 mg,
3
) δ (ppm): 142.5, 128.4, 128.2, 125.6, 58.2, 50.0, 35.9,
H24N [M+H] : 206.1903. Found: 206.1878.
+
+
2
1.81 mmol) in tetrahydrofuran (5.0 mL) was stirred at 50 ºC for 42 hrs. The solvent of the reaction
mixture was evaporated under reduced pressure to give a crude oil. The crude product was purified by
column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 3) to afford methyl
2
-((isobutyl(4-phenylbutyl)carbamoyl)oxy)benzoate 1c as colorless oil (547 mg, 1.43 mmol, 79% yield
(
based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))).
H-NMR (400 MHz, CDCl
1
3
), two rotamers with respect to the amide bond were observed
(approximately 1 : 1 ratio at 25 ºC), δ (ppm): 7.96-7.93 (m, 1H, rotamer A and B), 7.52-7.47 (m, 1H),
7.28-7.12 (m, 7H), 3.81 (s, 1.5H), 3.77 (s, 1.5H), 3.44 (t, J = 6.8 Hz, 1H), 3.34 (t, J = 6.8 Hz, 1H), 3.24
(d, J = 7.6 Hz, 1H), 3.12 (d, J = 7.6 Hz, 1H), 2.69-2.63 (m, 2H), 2.14-1.94 (m, 1H), 1.79-1.66 (m, 4H),
1
3
0
.97 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). C-NMR (100 MHz, CDCl
3
), two rotamers with
respect to the amide bond were observed, δ (ppm): 165.3, 154.5, 1510, 151.0, 142.2, 142.0, 133.3, 133.2,
1
5
31.4, 131.3, 128.32, 128.30, 128.22, 128.18, 125.7, 125.6, 125.2, 124.1, 124.03, 123.99, 123.9, 55.1,
4.6, 51.9, 48.0, 47.8, 35.6, 35.5, 28.6, 28.5, 27.8, 27.5, 27.11, 27.09, 20.1, 20.0. ESI-HRMS: Calcd for
+
+
23 4 4
C H29NNaO [M+Na] : 406.1989. Found: 406.1983. Anal. Calcd. for C23H29NO : C, 72.04; H, 7.62; N,
3.65. Found: C, 72.04; H, 7.54; N, 3.73.
Synthesis of methyl 2-((isopropyl(4-phenylbutyl)carbamoyl)oxy)benzoate (1d)
To a solution of (4-bromobutyl)benzene (551 mg, 2.59 mmol) in tetrahydrofuran (2.0 mL),
isopropylamine (4.0 mL) was added at room temperature. The reaction mixture was stirred at room
temperature for 24 hrs. The solvent was removed in vacuo and crude residue was dissolved in ethyl
acetate. The solution was washed with aqueous sodium hydroxide (2M) (5 mL), washed with brine (10
1
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The Journal of Organic Chemistry
mL), dried over sodium sulfate and the solvent was evaporated under reduced pressure to give
1
2
3
4
5
6
7
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
N-isopropyl-4-phenylbutan-1-amine (3d) as colorless oil (489 mg, 2.56 mmol, 99% yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.28-7.25 (m, 2H), 7.18-7.15 (m, 3H), 2.76 (h, J = 6.4Hz, 1H),
2
.64-2.58 (m, 4H), 1.69-1.62 (m, 2H), 1.56-1.48 (m, 2H), 1.04 (d, J = 6.0 Hz, 6H), 0.86 (brs, 1H).
1
3
C-NMR (100 MHz, CDCl
3
) δ (ppm): 142.5, 128.4, 128.2, 125.6, 48.7, 47.4, 35.9, 30.2, 29.3, 23.0.
+
+
ESI-HRMS: Calcd for C13 22N [M+H] : 192.1747. Found: 192.1760.
H
A solution of 3d (463 mg, 2.42 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (1016 mg,
3
.07 mmol) in tetrahydrofuran (4.0 mL) was stirred at 50 ºC for 16 hrs. The solvent of the reaction
mixture was evaporated under reduced pressure to give a crude oil. The crude product was purified by
column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 4) to afford methyl
2-((isopropyl(4-phenylbutyl)carbamoyl)oxy)benzoate 1d (703 mg, 1.90 mmol, 79% yield (based on
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-isopropyl-4-phenylbutan-1-amine)) as colorless oil.
1
3
H-NMR (400 MHz, CDCl ), two rotamers (A and B) with respect to the amide bond were observed
(
(
approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.95 (d, J = 7.6 Hz, 1H, rotamer A and B), 7.51
ddd, J = 7.6, 7.6, 1.6 Hz, 1H, rotamer A and B), 7.27-7.23 (m, 3H, rotamer A and B), 7.18-7.06 (m, 4H,
rotamer A and B), 4.42-4.35 (m, 0.4H, rotamer B), 4.25-4.19 (m, 0.6H, rotamer A), 3.81 (s, 3H, rotamer
A and B), 3.32 (t, J = 7.2 Hz, 1.2H, rotamer A), 3.24 (t, J = 6.8 Hz, 0.8H, rotamer B), 2.68-2.64 (m, 2H,
rotamer A and B), 1.79-1.66 (m, 4H, rotamer A and B), 1.28 (d, J = 6.8 Hz, 2.4H, rotamer B), 1.21 (d, J
1
3
= 6.8 Hz, 3.6H, rotamer A). C-NMR (100 MHz, CDCl
3
), two rotamers with respect to the amide bond
were observed, δ (ppm): 165.5, 154.0, 151.1, 142.1, 133.4, 131.5, 128.33, 128.26, 125.7, 125.2, 124.2,
1
C
24.1, 124.0, 52.0, 48.7, 48.4, 43.5, 35.6, 35.5, 29.8, 29.3, 28.8, 21.1, 20.4. ESI-HRMS: Calcd for
H27NNaO [M+Na] : 392.1832. Found: 392.1829. Anal. Calcd. for C22H27NO : C, 71.52; H, 7.37; N,
22 4 4
+
+
3
.79. Found: C, 71.59; H, 7.30; N, 3.82.
Synthesis of methyl 2-((methyl(4-(p-tolyl)butyl)carbamoyl)oxy)benzoate (1e)
A solution of 4-(p-tolyl)butanoic acid (532 mg, 2.99 mmol) in SOCl (1.0 mL) was stirred at 60
2
ºC for 4 hours. Then the solvent was removed under reduced pressure to afford crude oil. The oil was
dissolved in dry dichloromethane (4.0mL) and the solution was added dropwise to methylamine (40%
solution in methanol) (2.5 mL) under stirring at 0 ºC. The temperature was raised to 25 ºC and the
reaction mixture was stirred for 5 min. Then 10 mL of aqueous hydrogen chloride (1M) was added and
the whole was extracted with dichloromethane (20 mL). The organic layer was washed with aqueous
sodium carbonate (2M, 10 mL) and dried over sodium sulfate. The solvent was removed in vacuo to
afford N-methyl-4-(p-tolyl)butanamide (3e) as white solid (562 mg, 2.94 mmol, 98% yield).
Mp. 60 - 61 ºC (colorless needles, recrystallized from CHCl
3
/hexane)
1
H-NMR (400 MHz, CDCl
t, J = 7.6 Hz, 2H), 2.31 (s, 3H), 2.16 (t, J = 7.6 Hz, 2H), 1.98-1.90 (m, 2H). C-NMR (100 MHz,
CDCl ) δ (ppm): 173.4, 138.4, 135.3, 129.0, 128.3, 35.7, 34.7, 27.2, 26.2, 20.9. ESI-HRMS: Calcd for
3
) δ (ppm): 7.09-7.04 (m, 4H), 5.63 (brs, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.60
1
3
(
3
+
+
C
12
H
17NNaO [M+Na] : 214.1202. Found: 214.1198.
A solution of 3e (483 mg, 2.53 mmol) and lithium aluminum hydride (195 mg, 5.14 mmol) in
tetrahydrofuran (10 mL) was stirred at 65 ºC for 4 hrs. Then the reaction solution was cooled to 0 ºC and
quenched with sodium sulfate decahydrate (10 g) and ethyl acetate (50 mL). Then the solution was
filtered and the solvent was removed in vacuo to give crude oil which contains
N-methyl-4-(p-tolyl)butan-1-amine (4e) (452 mg, 2.55 mmol, 101% crude yield). The amine was used
directly in the next step without further purification.
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.09-7.05 (m, 4H), 2.60-2.56 (m, 4H), 2.41 (s, 3H), 2.31 (s, 3H),
1
3
1
1
1
3
.67-1.59 (m, 2H), 1.55-1.47 (m, 2H), 1.14 (brs, 1H). C-NMR (100 MHz, CDCl ) δ (ppm): 139.4,
+
+
35.0, 128.9, 128.2, 52.0, 36.5, 35.3, 29.6, 29.2, 20.9. ESI-HRMS: Calcd for C12
78.1590. Found: 178.1589.
H20N [M+H] :
A solution of 4e (418 mg, 2.36 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (670 mg,
2
.03 mmol) in tetrahydrofuran (5.0 mL) was stirred at 50 ºC for 2 hrs. The solvent of the reaction
mixture was evaporated under reduced pressure to give a crude oil. The crude product was purified by
1
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column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 3) to afford methyl
-((methyl(4-(p-tolyl)butyl)carbamoyl)oxy)benzoate 1e (670 mg, 1.89 mmol, 93% yield (based on
dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))) as colorless oil.
1
2
3
4
5
6
7
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
2
1
H-NMR (400 MHz, CDCl
(approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.96 (dd, J = 7.6, 1.6 Hz, 1H, rotamer A and B),
.52-7.48 (m, 1H, rotamer A and B), 7.24 (dd, J = 7.6, 7.6 Hz, 1H, rotamer A and B), 7.15-7.07 (m, 5H,
3
), two rotamers (A and B) with respect to the amide bond were observed
7
rotamer A and B), 3.80 (s, 1.4H, rotamer B), 3.79 (s, 1.6H, rotamer A), 3.47 (t, J = 6.8 Hz, 0.9H,
rotamer B), 3.37 (t, J = 6.8 Hz, 1.1H, rotamer A), 3.08 (s, 1.6H, rotamer A), 2.97 (s, 1.4H, rotamer B),
2
.65-2.60 (m, 2H, rotamer A and B), 2.30 (s, 3H, rotamer A and B), 1.71-1.64 (m, 4H, rotamer A and B).
C-NMR (100 MHz, CDCl ), two rotamers with respect to the amide bond were observed, δ (ppm):
3
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
1
3
165.2, 154.4, 154.3, 151.2, 151.1, 139.1, 138.9, 135.1, 135.0, 133.4, 131.4, 128.89, 128.86, 128.2, 125.2,
124.1, 124.0, 123.8, 123.7, 51.9, 49.1, 35.0, 34.8, 34.4, 28.4, 28.3, 27.3, 26.9, 20.9. ESI-HRMS: Calcd
+
+
for C21
H
25NNaO
4
[M+Na] : 378.1679. Found: 378.1657. Anal. Calcd. for C21
4
H25NO : C, 70.96; H,
7
.09; N, 3.94. Found: C, 71.02; H, 7.09; N, 4.00.
Synthesis of methyl 2-(((4-(2,5-dimethylphenyl)butyl)(methyl)carbamoyl)oxy)benzoate (1f)
1
3
4
-(2,5-dimethylphenyl)-4-oxobutanoic acid was synthesized according to the literature.
A mixture of methyl 4-(2,5-dimethylphenyl)-4-oxobutanoic acid (1483 mg, 7.19 mmol) and
tetraethylsilane (3316 mg, 28.5 mmol) was added trifluoroacetic acid (15 mL) at 0 ºC. The temperature
was raised to room temperature and the reaction solution was stirred for 1 day. The reaction was
quenched with aqueous sodium hydroxide (1M, 100 mL). The whole was washed with dichloromethane
(50 mL). The water layer was acidified with aqueous hydrogen chloride (2M, 20 mL) and extracted with
ethyl acetate (50 mL x 2). The organic layer was washed with brine (10 mL), dried over sodium sulfate
and the solvent was removed under reduced pressure to give white powder which contains
4-(2,5-dimethylphenyl)butanoic acid (3f) (known compound) (1458 mg, 7.58 mmol, 105% crude yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 10.77 (brs, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.93 (s, 1H), 6.92 (d, J
=
7.6 Hz, 1H), 2.64-2.60 (m, 2H), 2.42 (t, J = 7.6 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.95-1.87 (m, 2H).
13
C-NMR (100 MHz, CDCl
0.9, 18.7.
3
) δ (ppm): 180.2, 139.2, 135.3, 132.7, 130.2, 129.7, 126.8, 33.7, 32.4, 25.1,
2
2
The crude mixture that contains 3f (1279 mg) was dissolved in SOCl (3 mL), and the solution was
stirred at 70 ºC for 30 min. Then the solvent was removed under reduced pressure to afford crude oil.
The oil was added methylamine (40% solution in methanol) (5.0 mL) under stirring at -78ºC. The
temperature was raised to 25 ºC and the reaction mixture was stirred for 1 hour. Then 10 mL of aqueous
hydrogen chloride (1M) was added and the whole was extracted with dichloromethane (50 mL). The
organic layer was washed with aqueous sodium carbonate (2M, 10 mL) and dried over sodium sulfate.
The solvent was removed in vacuo to afford crude oil. The crude oil was purified by column
chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 2) to afford
4-(2,5-dimethylphenyl)-N-methylbutanamide (4f) as white powder (941 mg, 4.58 mmol, 73% yield for 3
steps, the yield was calculated based on methyl 4-(2,5-dimethylphenyl)-4-oxobutanoic acid).
Mp. 77 - 78 ºC (colorless needles, recrystallized from CHCl
3
/hexane)
) δ (ppm): 7.01 (d, J = 7.6 Hz, 1H), 6.94-6.90 (m, 2H), 5.40 (brs, 1H), 2.80
d, J = 4.8 Hz, 3H), 2.60 (t, J = 7.6 Hz, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.22 (t, J = 7.6 Hz, 2H),
1
H-NMR (400 MHz, CDCl
3
(
1
1
3
3
.95-1.87 (m, 2H). C-NMR (100 MHz, CDCl ) δ (ppm): 173.3, 139.5, 135.3, 132.8, 130.1, 129.7,
+
+
126.7, 36.1, 32.6, 26.3, 26.0, 20.9, 18.8. ESI-HRMS: Calcd for C13
Found: 228.1370.
H19NNaO [M+Na] : 228.1359.
A solution of 4f (878 mg, 4.27 mmol) and lithium aluminum hydride (421 mg, 11.1 mmol) in
tetrahydrofuran (20 mL) was stirred at 40 ºC for 10 hrs. Then the reaction solution was cooled to 0 ºC
and quenched with sodium sulfate decahydrate (10 g) and ethyl acetate (50 mL). Then the solution was
filtered and the solvent was removed in vacuo to give 4-(2,5-dimethylphenyl)-N-methylbutan-1-amine
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The Journal of Organic Chemistry
(
5f) as crude oil (777 mg, 4.06 mmol, 95%).
1
2
3
4
5
6
7
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
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.01 (d, J = 7.6 Hz, 1H), 6.94 (s, 1H), 6.89 (d, J = 7.6 Hz, 1H),
1
3
2
(
.62-2.53 (m, 4H), 2.43 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 1.61-1.55 (m, 4H), 1.04 (brs, 1H). C-NMR
100 MHz, CDCl ) δ (ppm): 140.5, 135.1, 132.6, 130.0, 129.6, 126.4, 52.1, 36.6, 33.2, 30.0, 28.1, 20.9,
18.8. ESI-HRMS: Calcd for C13
3
+
+
H
22N [M+H] : 192.1747. Found: 192.1737.
A solution of 5f (763 mg, 3.99 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (1262 mg,
.82 mmol) in dichloromethane (5.0 mL) was stirred at room temperature for 3 days. The solvent of the
3
reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 7) to afford methyl
2-(((4-(2,5-dimethylphenyl)butyl)(methyl)carbamoyl)oxy)benzoate 1f as colorless oil (1086 mg, 2.94
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
mmol, 77% yield (based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))).
1
H-NMR (400 MHz, CDCl
3
), two rotamers (A and B) with respect to the amide bond were observed
(approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.96 (dd, J = 8.0, 1.6 Hz, 1H, rotamer A and B),
7
8
.52-7.49 (m, 1H, rotamer A and B), 7.26 (ddd, J = 7.6, 7.6, 0.4 Hz, 1H, rotamer A and B), 7.14 (d, J =
.0 Hz, 0.6H, rotamer A), 7.10 (d, J = 8.0 Hz, 0.4H, rotamer A and B), 7.00 (d, J = 7.6 Hz, 1H, rotamer
A and B), 6.95 (s, 1H, rotamer A and B), 6.90 (d, J = 7.6 Hz, 1H, rotamer A and B), 3.82 (s, 1.2H,
rotamer B), 3.79 (s, 1.8H, rotamer A), 3.50 (t, 0.8H, J = 7.2 Hz, rotamer B), 3.39 (t, 1.2H, J = 7.2 Hz,
rotamer A), 3.11 (s, 1.8H, rotamer A), 3.00 (s, 1.2H, rotamer B), 2.65-2.59 (m, 2H, rotamer A and B),
2
.27 (s, 2.4H, rotamer B), 2.26 (s, 3.6H, rotamer A), 1.80-1.59 (m, 4H, rotamer A and B).
13
3
C-NMR (100 MHz, CDCl ), two rotamers with respect to the amide bond were observed, δ (ppm):
1
1
1
65.2, 154.5, 151.3, 151.2, 140.2, 140.0, 135.1, 133.4, 132.5, 131.4, 130.03, 129.98, 129.63, 129.55,
26.54, 126.47, 125.2, 124.1, 124.0, 123.9, 123.8, 51.9, 49.2, 34.9, 34.4, 32.9, 27.8, 27.3, 27.2, 20.9,
+
+
8.8. ESI-HRMS: Calcd for C22
4
H27NNaO [M+Na] : 392.1832. Found: 392.1803. Anal. Calcd. for
22 4
C H27NO
: C, 71.52; H, 7.37; N, 3.79. Found: C, 71.36; H, 7.16; N, 3.73.
Synthesis of methyl 2-(((4-(3,4-dimethoxyphenyl)butyl)(methyl)carbamoyl)oxy)benzoate (1g)
A suspension of succinic anhydride (3329 mg, 33.3 mmol), aluminum chloride (8556 mg, 64.0
mmol) in dry dichloromethane (40 mL) was stirred at 0 ºC. To the suspension, 1,2-dimethoxybenzene
(3005 mg, 21.8 mmol) was added dropwise and the temperature was raised to room temperature (25 ºC).
The mixture was stirred for 2 hours. The reaction was quenched with 100 mL of ice water. Then the
whole was extracted with dichloromethane (100 mL x 2). The organic layer was washed with brine (100
mL), dried over sodium sulfate and the solvent was removed under reduced pressure to give crude
mixture, which contains 4-(3,4-dimethoxyphenyl)-4-oxobutanoic acid (known compound) (3443 mg).
The crude mixture (3443 mg) and potassium carbonate (4201 mg) in acetone (20 mL) was
added methyl iodide (2.0 mL). The reaction mixture was stirred at room temperature for 20 hours. To
the reaction solution, acetone (20 mL), methyl iodide (2.0 mL), potassium carbonate (1567 mg) and
dimethylformamide (10 mL) were added and the solution was stirred for 6 hours. The reaction was
quenched with 30 mL of water and acetone was removed under reduced pressure. The whole was
extracted with ethyl acetate : hexane = 1 : 1 (100 mL x 2). The organic layer was dried over sodium
sulfate and the solvent was removed under reduced pressure to give crude oil. The crude oil was purified
by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 4) to afford methyl
4
-(3,4-dimethoxyphenyl)-4-oxobutanoate (3g) as white powder (known compound) (2574 mg, 10.2
mmol, 34% yield for 2 steps).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.89 (d, J
=
8.8 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.71 (s, 3H), 3.29 (t, J = 6.8 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H).
1
3
C-NMR (100 MHz, CDCl
1.7, 32.8, 28.1.
3
) δ (ppm): 196.5, 173.4, 153.3, 148.9, 129.7, 122.6, 110.0, 110.0, 56.0, 55.9,
5
A mixture of 3g (2311 mg, 9.16 mmol) and tetraethylsilane (4229 mg, 36.4 mmol) was added
trifluoroacetic acid (20 mL) at 0 ºC. The temperature was raised to room temperature and the reaction
solution was stirred for 2 days. The reaction was quenched with 50 mL of ice water and the whole was
1
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extracted with dichloromethane (50 mL x 2). The organic layer was dried over sodium sulfate and the
solvent was removed under reduced pressure to give crude oil. The crude oil was purified by column
chromatography (eluent: ethyl acetate : n-hexane = 1 : 8 ~ 1 : 2) to afford methyl
1
2
3
4
5
6
7
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
4
-(3,4-dimethoxyphenyl)butanoate (4g) (known compound) as colorless oil (1890 mg, 7.93 mmol, 87%
yield).
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 6.81-6.78 (m, 1H), 6.73-6.71 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H),
.68 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 2.35 (t, J = 7.6 Hz, 2H), 1.94 (p, J = 7.6 Hz, 2H). C-NMR (100
1
3
3
3
MHz, CDCl ) δ (ppm): 174.5, 148.8, 147.2, 134.0, 120.3, 111.8, 111.3, 55.9, 55.7, 51.6, 34.6, 33.3,
2
6.6.
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
To a solution of 4g (1087 mg, 4.56 mmol) in methylamine (40% solution in methanol) (5.0
mL) was added at room temperature. The reaction mixture was stirred at room temperature for 24 hrs.
The solvent was removed in vacuo and crude residue was dissolved in dichloromethane (50 mL). The
solution was washed with brine (10 mL), dried over sodium sulfate and the solvent was evaporated
under reduced pressure to give 4-(3,4-dimethoxyphenyl)-N-methylbutanamide (5g) as colorless oil
(
1013 mg, 4.27 mmol, 94% yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 6.79-6.77 (m, 1H), 6.71-6.69 (m, 2H), 5.65 (brs, 1H), 3.86 (s, 3H),
3
.85 (s, 3H), 2.79 (d, J = 5.2 Hz, 3H), 2.59 (t, J = 7.6 Hz, 2H), 2.17 (t, J = 7.6 Hz, 2H), 1.95 (p, J = 7.6
1
3
Hz, 2H). C-NMR (100 MHz, CDCl
55.7, 35.7, 34.8, 27.2, 26.1. ESI-HRMS: Calcd for C13
60.1278.
A solution of 5g (953 mg, 4.01 mmol) and lithium aluminum hydride (382 mg, 10.1 mmol) in
3
) δ (ppm): 173.3, 148.8, 147.2, 134.1, 120.2, 111.7, 111.2, 55.8,
+
+
H
3
19NNaO [M+Na] : 260.1257. Found:
2
tetrahydrofuran (20 mL) was stirred at 50 ºC for 20 hrs. Then the reaction solution was cooled to 0 ºC
and quenched with sodium sulfate decahydrate (10 g) and ethyl acetate (50 mL). Then the solution was
filtered and the solvent was removed in vacuo to give crude oil, which contains
4-(3,4-dimethoxyphenyl)-N-methylbutan-1-amine (6g) (802 mg, 3.59 mmol, 90% crude yield). The
amine was used directly in the next step without further purification.
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 6.78 (d, J = 8.4 Hz, 1H), 6.73-6.70 (m, 2H), 3.87 (s, 3H), 3.85 (s,
13
3
H), 2.61-2.56 (m, 4H), 2.42 (s, 3H), 1.68-1.48 (m, 5H). C-NMR (100 MHz, CDCl
3
) δ (ppm): 148.8,
1
C
47.1, 135.2, 120.2, 111.8, 111.2, 55.9, 55.8, 52.1, 36.6, 35.5, 29.6, 29.4. ESI-HRMS: Calcd for
+
+
13
H
22NO
2
[M+H] : 224.1645. Found: 224.1635.
A solution of 6g (778 mg, 3.49 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (997 mg,
3.02 mmol) in dichloromethane (5.0 mL) was stirred at room temperature for 22 hrs. The solvent of the
reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 2) to afford methyl
2
-(((4-(3,4-dimethoxyphenyl)butyl)(methyl)carbamoyl)oxy)benzoate 1g (831 mg, 2.07 mmol, 69%
yield (based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))) as colorless oil.
1
3
H-NMR (400 MHz, CDCl ), two rotamers (A and B) with respect to the amide bond were observed
(approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.96 (dd, J = 7.6, 1.6 Hz, 1H, rotamer A and B),
7.51 (dd, J = 7.6, 7.6 Hz, 1H, rotamer A and B), 7.28-7.24 (m, 1H, rotamer A and B), 7.15 (d, J = 7.6
Hz, 0.6H, rotamer A), 7.09 (d, J = 7.6 Hz, 0.4H, rotamer B), 6.79-6.71 (m, 3H, rotamer A and B), 3.85
(s, 6H, rotamer A and B), 3.82 (s, 1.2H, rotamer B), 3.78 (s, 1.8H, rotamer A), 3.49 (t, J = 6.8Hz, 0.9H,
rotamer B), 3.39 (t, J = 6.4 Hz, 1.1H, rotamer A), 3.10 (s, 1.7H, rotamer A), 2.99 (s, 1.3H, rotamer B),
1
3
2
3
.64-2.59 (m, 2H, rotamer A and B), 1.71-1.66 (m, 4H, rotamer A and B). C-NMR (100 MHz, CDCl ),
two rotamers with respect to the amide bond were observed, δ (ppm): 165.22, 154.5, 154.34, 151.29,
151.2, 148.8, 147.2, 147.1, 134.9, 134.7, 133.4, 131.4, 125.2, 124.1, 124.0, 123.9, 123.8, 120.2, 111.8,
1
11.7, 111.2, 55.9, 55.8, 51.9, 49.2, 49.1, 35.1, 35.0, 34.9, 34.4, 28.6, 28.4, 27.4, 26.8. ESI-HRMS:
+
+
6 6
Calcd for C22H27NNaO [M+Na] : 424.1731. Found: 424.1717. Anal. Calcd. for C22H27NO : C, 65.82;
H, 6.78; N, 3.49. Found: C, 65.75; H, 6.95; N, 3.48.
Synthesis of methyl 2-(((5-(3,4-dimethoxyphenyl)pentan-2-yl)(methyl)carbamoyl)oxy)benzoate
(1h)
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The Journal of Organic Chemistry
1
4
1
-bromo-2-(3,4-dimethoxyphenyl)ethane was synthesized according to the literature.
1
2
To the solution of potassium tert-butoxide (1353 mg, 12 mmol) in dry tetrahydrofuran (20 mL),
methyl acetoacetate (1513 mg, 13 mmol) was added under stirring at 0 ºC. The solution was stirred at 0
ºC for 30 min under argon atmosphere. To the stirring solution,
3
4
5
6
7
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
1-bromo-2-(3,4-dimethoxyphenyl)ethane (2463 mg, 10.0 mmol) in tetrahydrofuran (10 mL) was added
slowly and refluxed for 21 hours. Then the reaction mixture was cooled to 0 ºC and 40 mL of water was
added to quench the reaction. Then the whole was extracted with ethyl acetate (50 mL x 2) and the
organic layer was washed with brine, and dried over Na SO . The solvent was removed under reduced
2 4
pressure to afford crude oil. The crude oil was purified by column chromatography (eluent: ethyl
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
acetate : n-hexane = 1 : 4 ~ 1 : 3) to afford methyl 2-acetyl-4-(3,4-dimethoxyphenyl)butanoate (3h) as
colorless oil (1347 mg, 4.80 mmol, 48% yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 6.81 (dd, J = 8.4, 1.2 Hz, 1H), 6.73-6.71 (m 2H), 3.89 (s, 3H),
3
.87 (s, 3H), 3.76 (s, 3H), 3.46 (t, J = 7.2 Hz, 1H), 2.65-2.52 (m, 2H), 2.22 (s, 3H), 2.19-2.14 (m, 2H).
13
3
C-NMR (100 MHz, CDCl ) δ (ppm): 202.8, 170.2, 148.9, 147.5, 133.1, 120.4, 111.8 , 111.3, 58.6,
+
+
5
3
5.9, 55.8, 52.4, 32.9, 29.8, 28.9. ESI-HRMS: Calcd for C15
03.1176.
5
H20NaO [M+H] : 303.1203. Found:
The solution of 3h (652 mg, 2.33 mmol) and triethylbenzylammonium chloride (8.1 mg) in
tetrahydrofuran (7 mL), aqueous sodium hydroxide (2M) (3 mL) was added at room temperature. The
mixture was stirred at 50 ºC for 27 hours. And the reaction solution was acidified with 10 mL of
aqueous hydrogen chloride (1M). The mixture was heated at 50 ºC for 1 hour and the reaction solution
was basified with 10 mL of aqueous sodium carbonate (2M). Then the whole was extracted with
dichloromethane (50 mL x 2) and the organic layer was dried over Na
under reduced pressure to afford crude oil. The crude oil was purified by column chromatography
eluent: ethyl acetate : n-hexane = 1 : 4) to afford 5-(3,4-dimethoxyphenyl)pentan-2-one (4h) (known
compound) (360.5 mg, 1.62 mmol, 70% yield for 2 steps).
2 4
SO . The solvent was removed
(
1
H-NMR (400 MHz, CDCl
.57 (t, J = 7.6 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 2.12 (s, 3H), 1.89 (p, J = 7.6 Hz, 2H). C-NMR (100
MHz, CDCl ) δ (ppm): 208.7, 148.9, 147.3, 134.2, 120.2, 111.7, 111.2, 55.9, 55.8, 42.8, 34.6, 29.9,
5.3.
3
) δ (ppm): 6.80-6.78 (m, 1H), 6.71-6.69 (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H),
1
3
2
3
2
To a mixture of sodium borohydride (208 mg, 5.49 mmol) and dichloromethane (10.0 mL),
acetic acid (1.0 mL, 17.5 mmol) was added at 0 ºC. The mixture was stirred at room temperature for 30
min to form sodium triacetoxyborohydride. The solution was added 4h (509 mg, 2.29 mmol),
methylamine (40% solution in methanol) (1.5 mL) dichloromethane (8.0 mL) and stirred at room
temperature for 24 hrs. To the reaction solution, ethyl acetate (20 mL) was added and the amine
compounds are back-extracted in aqueous hydrogen chloride (1M) (20 mL). The water layer was
basified with aqueous sodium hydroxide and extracted with ethyl acetate (30 mL x 2). The organic layer
was dried over sodium sulfate and the solvent was removed under reduced pressure to give crude oil.
The crude oil was purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 2) to afford
5-(3,4-dimethoxyphenyl)-N-methylpentan-2-amine (5h) as colorless oil (206 mg, 0.867 mmol, 38%
yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 6.78 (d, J = 8.4 Hz, 1H), 6.73-6.71 (m, 2H), 3.87 (s, 3H), 3.85 (s,
3
H), 2.58-2.51 (m, 3H), 2.39 (s, 3H), 1.66-1.58 (m, 2H), 1.54-1.45 (m, 1H), 1.37-1.28 (m, 1H), 1.04
1
3
(
brs, 1H), 1.03 (d, J = 6.0 Hz, 3H). C-NMR (100 MHz, CDCl
11.8, 111.2, 55.9, 55.8, 54.8, 36.5, 35.7, 33.9, 28.0, 19.8. ESI-HRMS: Calcd for C14
238.1802. Found: 238.1807.
3
) δ (ppm): 148.8, 147.1, 135.2, 120.1,
+
+
1
2
H24NO [M+H] :
A solution of 5h (390 mg, 1.64 mmol) and dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (778
mg, 2.36 mmol) in dichloromethane (3.0 mL) was stirred at room temperature 31 hrs. Then five drops of
ethylenediamine was added to decompose excess dimethyl 2,2'-(carbonylbis(oxy))dibenzoate). The
solvent of the reaction mixture was evaporated under reduced pressure to give a crude oil. The crude
product was purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 3) to
afford methyl 2-(((5-(3,4-dimethoxyphenyl)pentan-2-yl)(methyl)carbamoyl)oxy)benzoate 1h (501 mg,
1
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1
.20 mmol, 73% yield (based on 5-(3,4-dimethoxyphenyl)-N-methylpentan-2-amine) as colorless oil.
1
2
3
4
5
6
7
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
1
H-NMR (400 MHz, CDCl
approximately A : B = 2 : 1 ratio at 25 ºC), δ (ppm): 7.97-7.94 (m, 1H, rotamer A and B), 7.54-7.48 (m,
3
), two rotamers (A and B) with respect to the amide bond were observed
(
1
H, rotamer A and B), 7.25 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H, rotamer A and B), 7.15 (d, J = 8.0 Hz, 0.6H,
rotamer A), 7.09 (d, J = 8.0 Hz, 0.4H, rotamer B), 6.77 (d, J = 8.8 Hz, 1H, rotamer A and B), 6.73-6.72
m, 2H, rotamer A and B), 4.46-4.41 (m, 0.3H, rotamer B), 4.38-4.30 (m, 0.7H, rotamer A), 3.85 (s, 4H,
(
rotamer A), 3.84 (s, 2H, rotamer B), 3.81 (s, 1H, rotamer B), 3.76 (s, 2H, rotamer A), 2.92 (s, 2H,
rotamer A), 2.82 (s, 1H, rotamer B), 2.68-2.52 (m, 2H, rotamer A and B), 1.70-1.40 (m, 4H, rotamer A
and B), 1.25 (d, J = 6.8 Hz, 1H, rotamer B), 1.18 (d, J = 6.8Hz, 2H, rotamer A). C-NMR (100 MHz,
CDCl ), two rotamers with respect to the amide bond were observed, δ (ppm): 165.2, 154.6,154.4, 151.3,
151.0, 148.7, 147.14, 147.05, 134.9, 134.7, 133.34, 133.25, 131.4, 125.2, 124.2, 124.0, 123.9, 123.8,
120.2, 111.8, 111.7, 111.2, 55.9, 55.8, 51.9, 51.8, 51.4, 51.1, 35.1, 35.0, 33.4, 33.1, 28.2, 28.1, 27.7,
1
3
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
3
+
+
2
7.6, 18.4, 18.1. ESI-HRMS: Calcd for C23
6
H29NNaO [M+Na] : 438.1887. Found: 438.1894. Anal.
Calcd. for C23 : C, 66.49; H, 7.04; N, 3.37. Found: C, 66.60; H, 7.00; N, 3.38.
H29NO
6
Synthesis of methyl 2-((methyl(3-phenoxypropyl)carbamoyl)oxy)benzoate (1i)
A mixture of phenol (529.0 mg, 5.62 mmol), 1,3-dibromopropane (3067 mg, 15.2 mmol),
potassium carbonate (1988 mg) in acetone (5.0 mL) was stirred at room temperature for 28 hrs. Then
the reaction solution was filtered and the solvent was removed in vacuo to give crude oil. The oil was
chromatographed on silica gel (eluent: ethyl acetate : n-hexane = 1 : 10) to afford mixture of
(3-bromopropoxy)benzene and 1,3-dibromopropane as colorless oil (2278 mg). The oil was dissolved in
methylamine (40% solution in methanol) (100 mL) and stirred at room temperature for 24 hrs. The
solvent was removed in vacuo and crude residue was dissolved in dichloromethane (20 mL). The
organic phase was back-extracted with aqueous hydrogen chloride (1M) (20 mL). The water layer was
basified with aqueous sodium hydroxide and extracted with ethyl acetate (30 mL x 2). The organic layer
was dried over sodium sulfate and the solvent was removed under reduced pressure to give crude oil,
which contains N-methyl-3-phenoxypropan-1-amine (3i) (known compound) (665 mg, 4.02 mmol, 72%
yield for two steps).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.20-7.25 (m, 2H), 6.95-6.89 (m, 3H), 4.03 (t, J = 6.4 Hz, 2H),
2
.77 (t, J = 6.8 Hz, 2H), 2.45 (s, 3H), 2.00-1.94 (m, 2H), 1.86 (brs, 1H). ESI-HRMS: Calcd for
+
+
C
10
H
16NO [M+H] : 166.12264. Found: 166.12157.
A solution of 3i (506 mg, 3.06 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (792 mg,
2
.40 mmol) in tetrahydrofuran (2.8 mL) was stirred at 50 ºC for 4 hrs. The solvent of the reaction
mixture was evaporated under reduced pressure to give a crude oil. The crude product was purified by
column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 3) to afford methyl
2
-((methyl(3-phenoxypropyl)carbamoyl)oxy)benzoate 1i as colorless oil (679 mg, 1.98 mmol, 82%
yield (based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))).
1
H-NMR (400 MHz, CDCl
(approximately A : B = 1 : 1 ratio at 25 ºC), δ (ppm): 7.97-7.95 (m, 1H), 7.52-7.45 (m, 1H), 7.28-7.22
m, 3H), 7.12 (d, J = 8.0 Hz, 0.5H), 7.01 (d, J = 8.0 Hz, 0.5H), 6.95-6.90 (m, 3H), 4.09-4.04 (m, 2H),
3
), two rotamers (A and B) with respect to the amide bond were observed
(
3
1
.83 (s, 1.5H), 3.81 (s, 1.5H), 3.69 (t, J = 7.2 Hz, 1H), 3.55 (t, J = 6.8 Hz, 1H), 3.15 (s, 1.6H), 3.03 (s,
.4H), 2.21-2.08 (m, 2H). C-NMR (100 MHz, CDCl ), two rotamers with respect to the amide bond
3
13
were observed, δ (ppm): 165.1, 158.7, 154.5, 154.4, 151.3, 151.1, 133.42, 133.37, 131.4, 129.3, 125.3,
1
24.1, 123.9, 123.7, 123.6, 120.7, 120.6, 114.43, 114.40, 65.1, 64.9, 51.9, 46.7, 46.4, 35.2, 35.0, 27.8,
+
+
5
27.3. ESI-HRMS: Calcd for C19H21NNaO [M+Na] : 366.1312. Found: 366.1294. Anal. Calcd. for
C H21NO : C, 66.46; H, 6.16; N, 4.08. Found: C, 66.71; H, 6.32; N, 4.10.
19 5
Synthesis of methyl 2-((methyl(3-(naphthalen-2-yloxy)propyl)carbamoyl)oxy)benzoate (1j)
The mixture of naphthalen-2-ol (1074 mg, 7.45 mmol), 1,3-dibromopropane (4615 mg, 22.9
mmol), potassium carbonate (2073 mg) in acetone (20 mL) was stirred at room temperature for 3 days.
Then the reaction was quenched with water (30 mL) and the whole was extracted with ethyl acetate (50
1
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mL x 2). The organic layer was washed with brine and dried over sodium sulfate. Then the solvent was
removed in vacuo to give crude oil. The oil was dissolved in methanol and filtered to remove
1
2
3
4
5
6
7
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
1
,3-bis(naphthalen-2-yloxy)propane. Then the filtrate was evaporated under reduced pressure to afford
mixture of 2-(3-bromopropoxy)naphthalene and 1,3-dibromopropane as colorless oil (2434 mg). The oil
was dissolved in methylamine (40% solution in methanol) (10 mL) and stirred at room temperature for
2
4 hrs. The solvent was removed in vacuo and crude residue was dissolved in aqueous HCl (1M, 10
mL). The whole was extracted with dichloromethane (50 mL x 2). The organic phase was washed with
aqueous sodium hydroxide (2M, 10 mL) and the organic layer was dried over sodium sulfate. The
solvent was removed under reduced pressure to give crude oil. The oil was dissolved in n-hexane and
filtered to remove impurities. Then the filtrate was evaporated under reduced pressure to afford crude oil
pale yellow crude oil, which contains N-methyl-3-(naphthalen-2-yloxy)propan-1-amine (3j) (known
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
compound) (1065 mg, 4.95 mmol, 66% crude yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.76-7.70 (m, 3H), 7.44-7.40 (m, 1H), 7.34-7.30 (m, 1H),
7
1
1
.16-7.12 (m, 2H), 4.16 (t, J = 6.4 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.48 (s, 3H), 2.07-1.99 (m, 2H),
13
.28 (brs, 1H). C-NMR (100 MHz, CDCl
3
) δ (ppm): 156.9, 134.6, 129.3, 128.9, 127.6, 126.7, 126.3,
+
+
23.5, 118.9, 106.6, 66.3, 49.1, 36.6, 29.6. ESI-HRMS: Calcd for C14
H
18NO [M+H] : 216.1383.
Found: 216.1399.
A solution of the crude oil which contains 3j (854 mg) and dimethyl 2,2'-(carbonylbis(oxy))dibenzoate)
1478 mg, 4.47 mmol) in tetrahydrofuran (5.0 mL) was stirred at room temperature for 2 days. The
(
solvent of the reaction mixture was evaporated under reduced pressure to give a crude oil. The crude
product was purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 2) to
afford 1j as colorless oil (1009 mg, 2.56 mmol, 43% yield for 3 steps (based on naphthalen-2-ol)).
1
3
H-NMR (400 MHz, CDCl ), two rotamers (A and B) with respect to the amide bond were observed
(approximately A : B = 1 : 1 ratio at 25 ºC), δ (ppm): 7.95 (dd, J = 7.6, 7.6 Hz, 1H), 7.75-7.69 (m, 3H),
.51-7.46 (m, 0.5H), 7.43-7.39 (m, 1.5H), 7.31 (dd, J = 7.6, 7.6 Hz, 1H), 7.26-7.19 (m, 1H), 7.15-7.11
m, 2.5H), 6.99 (d, J = 8.0 Hz, 0.5H), 4.21-4.15 (m, 2H), 3.82 (s, 1.5H), 3.79 (s, 1.5H), 3.72 (t, J = 6.8
7
(
13
Hz, 1H), 3.59 (t, J = 6.8 Hz, 1H), 3.16 (s, 1.5H), 3.04 (s, 1.5H), 2.27-2.14 (m, 2H). C-NMR (100 MHz,
CDCl ), two rotamers with respect to the amide bond were observed, δ (ppm): 165.1, 156.7, 154.6,
54.4, 151.3, 151.1, 134.50, 134.46, 133.45, 133.4, 131.4, 129.33, 129.28, 128.9, 127.5, 126.6, 126.2,
125.29, 125.26, 124.1, 123.9, 123.7, 123.6, 123.53, 123.48, 118.8, 106.7, 65.3, 65.1, 51.9, 46.7, 46.5,
3
1
+
+
35.3, 35.1, 27.8, 27.3. ESI-HRMS: Calcd for C23
5
H23NNaO [M+Na] : 416.1468. Found: 416.1453.
Anal. Calcd. for C23 : C, 70.21; H, 5.89; N, 3.56. Found: C, 70.21; H, 6.10; N, 3.62.
H23NO
5
Synthesis of methyl 2-(((3-([1,1'-biphenyl]-4-yloxy)propyl)(methyl)carbamoyl)oxy)benzoate (1k)
The mixture of [1,1'-biphenyl]-4-ol (1015 mg, 5.96 mmol), 1,3-dibromopropane (3602 mg,
17.8 mmol), potassium carbonate (1718 mg) in acetone (20 mL) was stirred at room temperature for 3
days. Then the reaction was quenched with water (30 mL) and the whole was extracted with ethyl
acetate (50 mL x 2). The organic layer was washed with brine and dried over sodium sulfate. Then the
solvent was removed in vacuo to give crude mixture of 4-(3-bromopropoxy)-1,1'-biphenyl and
1
,3-dibromopropane as colorless oil (2870 mg). The oil was dissolved in methylamine (40% solution in
methanol) (10 mL) and stirred at room temperature for 21 hrs. The solvent was removed in vacuo and
crude residue was dissolved in HCl aq (1M, 10 mL). The whole was extracted with dichloromethane (50
mL x 2). The organic phase was washed with aqueous sodium hydroxide (2M, 10 mL) and the organic
layer was dried over sodium sulfate. The solvent was removed under reduced pressure to give pale
yellow crude oil. The oil was dissolved in n-hexane and filtered to remove impurities. Then the filtrate
was evaporated under reduced pressure to afford crude oil, which contains
3
-([1,1'-biphenyl]-4-yloxy)-N-methylpropan-1-amine (3k) (1111 mg, 4.60 mmol, 77% crude yield for 2
steps).
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.56-7.49 (m, 4H), 7.42-7.39 (m, 2H), 7.31-7.27 (m, 1H),
1
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1
1
.98-6.96 (m, 2H), 4.08 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.46 (s, 3H), 2.02-1.96 (m, 2H),
1
2
3
4
5
6
7
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
13
.06 (brs, 1H). C-NMR (100 MHz, CDCl
14.8, 66.4, 49.1, 36.6, 29.6. ESI-HRMS: Calcd for C16
3
) δ (ppm): 158.6, 140.8, 133.7, 128.7, 128.1, 126.7, 126.6,
+
+
H
20NO [M+H] : 242.15394. Found: 242.15578.
A
solution of the crude oil which contains 3k (752 mg) and dimethyl
2
,2'-(carbonylbis(oxy))dibenzoate) (1106 mg, 3.35 mmol) in tetrahydrofuran (5.0 mL) was stirred at
room temperature for 2 days. The solvent of the reaction mixture was evaporated under reduced
pressure to give a crude oil. The crude product was purified by column chromatography (eluent: ethyl
acetate
-((methyl(3-(naphthalen-2-yloxy)propyl)carbamoyl)oxy)benzoate 1k as colorless oil (794 mg, 1.89
mmol, 47% yield for 3 steps (based on [1,1'-biphenyl]-4-ol)).
:
n-hexane
=
1
:
6
~
1
:
2)
to
afford
methyl
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
2
1
H-NMR (400 MHz, CDCl
3
), two rotamers (A and B) with respect to the amide bond were observed
(approximately A : B = 1 : 1 ratio at 25 ºC), δ (ppm): 7.96 (dd, J = 6.0, 6.0 Hz, 1H), 7.54-7.38 (m, 7H),
7
3
.30-7.20 (m, 2H), 7.12 (d, J = 8.0 Hz, 0.5H), 7.01-6.96 (m, 2.5H), 4.13-4.08 (m, 2H), 3.83 (s, 1.5H),
.81 (s, 1.5H), 3.70 (t, J = 6.8 Hz, 1H), 3.56 (t, J = 6.8 Hz, 1H), 3.16 (s, 1.5H), 3.04 (s, 1.5H), 2.23-2.10
1
3
(m, 2H). C-NMR (100 MHz, CDCl
3
), two rotamers with respect to the amide bond were observed, δ
(ppm): 165.1, 158.4, 154.5, 154.4, 151.3, 151.1, 140.7, 133.8, 133.7, 133.5, 133.4, 131.4, 128.6, 128.0,
126.6, 125.3, 124.1, 124.0, 123.7, 123.6, 114.8, 65.4, 65.2, 51.9, 46.7, 46.4, 35.2, 35.1, 27.8, 27.4.
ESI-HRMS: Calcd for C25
C H25NO
25 5
+
+
H
25NNaO
5
[M+Na] : 442.1625. Found: 442.1632. Anal. Calcd. for
: C, 71.58; H, 6.01; N, 3.34. Found: C, 71.69; H, 6.25; N, 3.36.
Synthesis of methyl 2-(((5-(3,4-dimethoxyphenyl)pentyl)(methyl)carbamoyl)oxy)benzoate (1l)
A suspension of glutaric anhydride (2279 mg, 19.9 mmol), aluminum chloride (5735 mg, 43.0
mmol) in dry dichloromethane (30 mL) was stirred at 0 ºC. To the suspension, 1,2-dimethoxybenzene
(3005 mg, 21.8 mmol) was added dropwise and the temperature was raised to room temperature (25 ºC).
The mixture was stirred for 2 hours. The reaction was quenched with 100 mL of ice water and 10 g of
citric acid was added. Then the solution was basified with 200 mL of aqueous sodium hydroxide (2M)
and the whole was washed with dichloromethane (50 mL x 2) to remove impurities. The water layer was
acidified with aqueous hydrogen chloride (1M, 200 mL) and extracted with ethyl acetate (100 mL x 2).
The organic layer was washed with brine (100 mL), dried over sodium sulfate and the solvent was
removed under reduced pressure to give 5-(3,4-dimethoxyphenyl)-5-oxopentanoic acid (3l) as pale
yellow solid (known compound) (3572 mg, 14.2 mmol, 71% yield).
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 11.10 (brs, 1H), 7.59 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 2.0
Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.04 (t, J = 7.2 Hz, 2H), 2.51 (t, J = 7.2 Hz,
13
3
2H), 2.08 (p, J = 7.2 Hz, 2H). C-NMR (100 MHz, CDCl ) δ (ppm): 198.0, 179.1, 153.3, 149.1, 130.0,
1
22.7, 110.2, 110.0, 56.1, 56.0, 36.9, 33.1, 19.4.
A mixture of 3l (3304 mg, 13.1 mmol) and potassium carbonate (2569 mg) in acetone (40 mL)
was added methyl iodide (1.5 mL). The reaction mixture was stirred at room temperature for 14 hours.
To the reaction solution, acetone (60 mL) and methyl iodide (2.0 mL) were added and the solution was
stirred for 9 hours. The reaction was quenched with 50 mL of water and the whole was extracted with
dichloromethane (50 mL x 2). The organic layer was dried over sodium sulfate and the solvent was
removed under reduced pressure to give methyl 5-(3,4-dimethoxyphenyl)-5-oxopentanoate 4l as white
powder (known compound) (2584 mg, 9.70 mmol, 74% yield).
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.89 (d, J
= 8.4 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.68 (s, 3H), 3.01 (t, J = 7.2 Hz, 2H), 2.45 (t, J = 7.2 Hz, 2H),
1
3
3
2.07 (p, J = 7.2 Hz, 2H). C-NMR (100 MHz, CDCl ) δ (ppm): 198.0, 173.7, 153.2, 149.0, 130.1, 122.6,
1
10.1, 110.0, 56.0, 55.9, 51.4, 36.9, 33.1, 19.7.
A mixture of 4l (2446 mg, 9.18 mmol) and tetraethylsilane (2985 mg, 25.7 mmol) was added
trifluoroacetic acid (10 mL) at 0 ºC. The temperature was raised to room temperature and the reaction
solution was stirred for 16 hours. The reaction was quenched with 50 mL of water and the whole was
extracted with dichloromethane (50 mL x 2). The organic layer was dried over sodium sulfate and the
1
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solvent was removed under reduced pressure to give crude oil. The crude oil was purified by column
chromatography (eluent: ethyl acetate n-hexane 4) to afford methyl
-(3,4-dimethoxyphenyl)pentanoate (5l) as colorless oil (known compound) (2303 mg, 9.13 mmol, 99%
1
2
3
4
5
6
7
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
:
=
1
:
5
yield).
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 6.78 (d, J = 8.4 Hz, 1H), 6.72-6.70 (m, 2H), 3.87 (s, 3H), 3.85 (s,
H), 3.66 (s, 3H), 2.58 (t, J = 7.2 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H), 1.71-1.60 (m, 4H). C-NMR (100
1
3
3
3
MHz, CDCl ) δ (ppm): 174.3, 148.8, 147.1, 134.8, 120.2, 111.8, 111.3, 55.9, 55.8, 51.5, 35.1, 33.9, 31.0,
+
+
2
4.5. ESI-HRMS: Calcd for C14
4
H20NaO [M+Na] : 275.1254. Found: 275.1242.
The compound 5s (1183 mg, 4.69 mmol) was dissolved in methylamine (40% solution in
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
methanol) (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 17
hrs. The solvent was removed in vacuo and crude residue was dissolved in chloroform (100 mL). The
solution was washed with water (20 mL), dried over sodium sulfate and the solvent was evaporated
under reduced pressure to give 5-(3,4-dimethoxyphenyl)-N-methylpentanamide (6l) as colorless oil
(
1023 mg, 4.07 mmol, 87% yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 6.79-6.77 (m, 1H), 6.71-6.69 (m, 2H), 5.62 (brs, 1H), 3.86 (s, 3H),
3
4
.84 (s, 3H), 2.78 (d, J = 4.8 Hz, 3H), 2.57 (t, J = 7.2 Hz, 2H), 2.18 (t, J = 7.2 Hz, 2H), 1.72-1.58 (m,
H). C-NMR (100 MHz, CDCl ) δ (ppm): 173.5, 148.7, 147.0, 134.8, 120.1, 111.7, 111.2, 55.9, 55.8,
3
1
3
36.4, 35.2, 31.2, 26.2, 25.3.
A solution of 6l (679 mg, 2.70 mmol) and lithium aluminum hydride (289 mg, 7.48 mmol) in
tetrahydrofuran (15 mL) was stirred at 50 ºC for 18 hrs. Then the reaction solution was cooled to 0 ºC
and quenched with sodium sulfate decahydrate (10 g) and ethyl acetate (50 mL). Then the solution was
filtered and the solvent was removed in vacuo to give crude oil, which contains
5
-(3,4-dimethoxyphenyl)-N-methylpentan-1-amine (7l) (known compound) (425 mg, 1.79 mmol, 66%
crude yield). The amine was used directly in the next step without further purification.
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 6.78 (d, J = 8.8 Hz, 1H), 6.72-6.70 (m, 2H), 3.87 (s, 3H), 3.85 (s,
+
+
3
1
H), 2.58-2.54 (m, 4H), 2.42 (s, 3H), 1.69-1.25 (m, 7H). ESI-HRMS: Calcd for C12
78.15903. Found: 178.15904.
H20N [M+H] :
A solution of the crude oil of 7l (425 mg) and dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (661
mmol, 2.00 mmol) in dichloromethane (3.5 mL) was stirred at room temperature for 2 days. The solvent
of the reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product
was purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 4 ~ 1 : 2) to afford
methyl 2-(((5-(3,4-dimethoxyphenyl)pentyl)(methyl)carbamoyl)oxy)benzoate 1l as colorless oil (393
mg, 0.946 mmol, 35% yield for two steps (based on 5-(3,4-dimethoxyphenyl)-N-methylpentanamide)).
1
H-NMR (400 MHz, CDCl
approximately 1 : 1 ratio at 25 ºC), δ (ppm): 7.96 (dd, J = 8.0, 1.2 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz,
H), 7.26 (t, J = 7.6, 7.6 Hz, 1H), 7.14 (d, J = 8.0 Hz, 0.5H), 7.11 (d, J = 8.0 Hz, 0.5H), 6.77 (d, J = 7.6
3
), two rotamers with respect to the amide bond were observed
(
1
HZ, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 3.85 (s, 3H), 3.84 (s, 6H), 3.46 (t, J = 7.2 Hz, 1H), 3.35
(t, J = 7.2 Hz, 1H), 3.11 (s, 1.5H), 3.00 (s, 1.5H), 2.60-2.55 (m, 2H), 1.77-1.61 (m, 4H), 1.45-1.35 (m,
1
3
2H). C-NMR (100 MHz, CDCl
3
), two rotamers with respect to the amide bond were observed, δ
(ppm): 165.3, 154.5, 154.4, 151.3, 151.2, 148.8, 147.1, 135.2, 135.1, 133.4, 131.5, 125.3, 124.2, 124.0,
1
2
23.9, 123.8, 120.1, 111.8, 111.2, 55.9, 55.8, 52.0, 49.4, 49.3, 35.5, 34.9, 34.5, 31.4, 30.9, 27.7, 27.3,
+
+
6.3. ESI-HRMS: Calcd for C23
6
H29NNaO [M+Na] : 438.1887. Found: 438.1865. Anal. Calcd. for
23 6
C H29NO
: C, 66.49; H, 7.04; N, 3.37. Found: C, 66.26; H, 6.98; N, 3.35.
Synthesis of methyl 2-(((5-(3,4-dimethoxyphenyl)pentyl)(isopropyl)carbamoyl)oxy)benzoate (1m)
To a solution of 5s (1930 mg, 7.65 mmol) in methanol (10 mL), 5 mL of aqueous sodium
hydroxide (2M) was added and stirred at room temperature for 2 days. Then the reaction solution was
acidified by 20 mL of aqueous hydrogen chloride (1M) and the whole was extracted by
dichloromethane (50 mL x 2). The organic phase was dried over sodium sulfate and the solvent was
removed under reduced pressure to afford 5-(3,4-dimethoxyphenyl)pentanoic acid (3m) (known
compound) as white solids (1564 mg, 6.56 mmol, 86% yield).
1
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2
A mixture of 3m (847 mg, 3.55 mmol), SOCl (0.5 mL) in toluene (4 mL) was stirred at 60 ºC
1
2
3
4
5
6
7
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
for 1 hr. The reaction mixture was cooled to room temperature and the reaction solution was added
dropwise into a solution of isopropylamine (2.0 mL) in dry dichloromethane (10 mL) under stirring at 0
ºC. The temperature was raised to 25 ºC and the reaction mixture was stirred for 10 min. Then 20 mL of
water was added and the whole was extracted with dichloromethane (50 mL x 2). The organic phase
was dried over sodium sulfate; the solvent was removed in vacuo to afford crude oil. The crude product
was purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 1) to afford
5
-(3,4-dimethoxyphenyl)-N-isopropylpentanamide (4m) as white solid (832 mg, 2.98 mmol, 84%
yield).
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
Mp. 80 - 81 ºC (colorless needles, recrystallized from CHCl
3
/hexane)
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 6.78 (d, J = 8.4 Hz, 1H), 6.71-6.69 (m, 2H), 5.41 (brs, 1H),
4.11-4.03 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.15 (t, J = 6.8 Hz, 2H),
1
3
1
1
C
.65-1.62 (m, 4H), 1.12 (d, J = 6.4 Hz, 6H). C-NMR (100 MHz, CDCl
3
) δ (ppm): 171.9, 148.7, 147.0,
34.9, 120.1, 111.7, 111.2, 55.8, 55.7, 41.1, 36.7, 35.2, 31.2, 25.3, 22.7. ESI-HRMS: Calcd for
+
+
16
H
25NNaO
3
[M+Na] : 302.17266. Found: 302.17383.
A solution of 4m (745 mg, 2.67 mmol) and lithium aluminum hydride (213 mg, 5.62 mmol) in
tetrahydrofuran (10 mL) was stirred at 50 ºC for 18 hrs. Then the reaction solution was cooled to 0 ºC
and quenched with large amount of sodium sulfate decahydrate and ethyl acetate. Then the solution was
filtered and the solvent was removed in vacuo to give crude oil, which contains
-(3,4-dimethoxyphenyl)-N-isopropylpentan-1-amine (5m) (661 mg, 2.49 mmol, 93% yield). The amine
was used directly in the next step without further purification.
5
1
H-NMR (400 MHz, CDCl
H), 2.81-2.75 (m, 1H), 2.60-2.54 (m, 4H), 1.66-1.33 (m, 7H), 1.05 (d, J = 6.4 Hz, 6H). C-NMR (100
MHz, CDCl ) δ (ppm): 148.7, 147.0, 135.3, 120.0, 111.7, 111.1, 55.8, 55.7, 48.7, 47.4, 35.4, 31.5, 30.2,
27.0, 22.9. ESI-HRMS: Calcd for C16
solution of the crude oil which contains 5m (585 mg) and dimethyl
3
) δ (ppm): 6.78 (d, J = 8.4 Hz, 1H), 6.72-6.70 (m, 2H), 3.87 (s, 3H), 3.85 (s,
1
3
3
3
+
+
H
2
28NO [M+H] : 266.2115. Found: 266.2118.
A
2
5
,2'-(carbonylbis(oxy))dibenzoate) (935 mmol, 2.83 mmol) in tetrahydrofuran (5.0 mL) was stirred at
0 ºC for 13 hrs. The solvent of the reaction mixture was evaporated under reduced pressure to give a
crude oil. The crude product was purified by column chromatography (eluent: ethyl acetate : n-hexane =
: 6 ~ 1 : 2) to afford methyl 2-(((5-(3,4-dimethoxyphenyl)pentyl)(isopropyl)carbamoyl)oxy)benzoate
1
1m as colorless oil (580 mg, 1.31 mmol, 55% yield for
2
steps (based on
5-(3,4-dimethoxyphenyl)-N-isopropylpentanamide))).
1
H-NMR (400 MHz, CDCl
approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.98 (d, J = 8.0 Hz, 1H, rotamer A and B),
.56-7.52 (m, 1H, rotamer A and B), 7.28 (dd, J = 7.6, 7.6 Hz, 1H, rotamer A and B), 7.16-7.14 (m, 1H,
rotamer A and B), 6.81-6.71 (m, 3H, rotamer A and B), 4.47-4.36 (m, 0.4H, rotamer B), 4.36-4.23 (m,
.6H, rotamer A), 3.88-3.86 (m, 9H, rotamer A and B), 3.31 (t, J = 8.0 Hz, 1.2H, rotamer A), 3.22 (t, J
3
), two rotamers (A and B) with respect to the amide bond were observed
(
7
0
= 8.0 Hz, 0.8H, rotamer B), 2.61-2.56 (m, 2H, rotamer A and B), 1.81-1.62 (m, 4H, rotamer A and B),
1.44-1.35 (m, 2H, rotamer A and B), 1.32 (d, J = 6.4 Hz, 2.4H, rotamer B), 1.26 (d, J = 6.8 Hz, 3.6H,
1
3
rotamer A). C-NMR (100 MHz, CDCl
3
), two rotamers with respect to the amide bond were observed,
δ (ppm): 165.4, 154.0, 151.1, 151.0, 148.7, 147.0, 135.2, 135.1, 133.3, 133.2, 131.4, 125.1, 124.1, 124.0,
1
20.1, 111.7, 111.2, 55.9, 55.7, 52.0, 48.6, 48.3, 43.5, 35.4, 31.3, 30.1, 29.4, 26.7, 21.0, 20.4.
+
+
6
ESI-HRMS: Calcd for C25H33NNaO [M+Na] : 466.2200. Found: 466.2207.
Synthesis of methyl 2-(((5-(3,4-dimethoxyphenyl)pentyl)(octyl)carbamoyl)oxy)benzoate (1n)
A mixture of 4t (649 mg, 2.72 mmol), SOCl (0.4 mL) in toluene (3 mL) was stirred at 60 ºC
2
for 3 hrs. The reaction mixture was cooled to room temperature and added dropwise to a solution of
octan-1-amine (1275 mg, 9.85 mmol) in dry dichloromethane (10 mL) under stirring at 0 ºC. The
temperature was raised to 25 ºC and the reaction mixture was stirred for 10 min. Then 20 mL of water
was added and the whole was extracted with dichloromethane (50 mL x 2). The organic phase was dried
over sodium sulfate; the solvent was removed in vacuo to afford crude oil. The crude product was
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purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 2) to afford
-(3,4-dimethoxyphenyl)-N-octylpentanamide (3n) as white solid (777 mg, 2.22 mmol, 82% yield).
Mp. 67 - 68 ºC (colorless cotton like crystals, recrystallized from CHCl /hexane)
) δ (ppm): 6.78 (d, J = 8.8 Hz, 1H), 6.71-6.69 (m, 2H), 5.51 (brs, 1H), 3.86
(s, 3H), 3.85 (s, 3H), 3.22 (dt, J = 6.8, 6.8 Hz, 2H), 2.57 (t, J = 7.2 Hz, 2H), 2.17 (t, J = 7.2 Hz, 2H),
1
2
3
4
5
6
7
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
5
3
1
H-NMR (400 MHz, CDCl
3
1
3
1
.70-1.60 (m, 4H), 1.49-1.45 (m, 2H), 1.27-1.26 (m, 10H), 0.88 (t, J = 6.4 Hz, 3H). C-NMR (100
MHz, CDCl ) δ (ppm): 172.7, 148.8, 147.1, 134.9, 120.1, 111.7, 111.2, 55.9, 55.8, 39.5, 36.6, 35.2, 31.7,
1.2, 29.6, 29.2, 29.1, 26.9, 25.4, 22.6, 14.0. ESI-HRMS: Calcd for C21
Found: 372.2497.
3
+
+
3
3
H35NNaO [M+Na] : 372.2509.
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
A solution of 3n (686 mg, 1.96 mmol) and lithium aluminum hydride (218 mg, 5.74 mmol) in
tetrahydrofuran (8.0 mL) was stirred at 50 ºC for 15 hrs. Then the reaction solution was cooled to 0 ºC
and quenched with large amount of sodium sulfate decahydrate and ethyl acetate. Then the solution was
filtered and the solvent was removed in vacuo to give crude oil, which contains
N-(5-(3,4-dimethoxyphenyl)pentyl)octan-1-amine (4n) (570 mg, 1.70 mmol, 87% crude yield). The
amine was used directly in the next step without further purification.
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 6.81 (d, J = 8.4 Hz, 1H), 6.74-6.72 (m, 2H), 3.89 (s, 3H), 3.87 (s,
3
H), 2.63-2.56 (m, 6H), 1.70-1.60 (m, 2H), 1.58-1.47 (m, 4H), 1.42-1.26 (m, 13H), 0.90 (t, J = 6.8 Hz,
1
3
3H). C-NMR (100 MHz, CDCl
50.1, 35.5, 31.8, 31.6, 30.2, 30.1, 29.5, 29.2, 27.4, 27.0, 22.6, 14.1. ESI-HRMS: Calcd for C21
3
) δ (ppm): 148.8, 147.0, 135.4, 120.1, 111.8, 111.2, 55.9, 55.8, 50.2,
+
H38NO
2
+
[M+H] : 336.2897. Found: 336.2897.
A solution of the crude oil which contains N-(5-(3,4-dimethoxyphenyl)pentyl)octan-1-amine
482 mg) and dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (808 mmol, 2.44 mmol) in tetrahydrofuran
4.0 mL) was stirred at 50 ºC for 19 hrs. The solvent of the reaction mixture was evaporated under
(
(
reduced pressure to give a crude oil. The crude product was purified by column chromatography (eluent:
ethyl acetate n-hexane 2) to afford methyl
-(((5-(3,4-dimethoxyphenyl)pentyl)(octyl)carbamoyl)oxy)benzoate 1n as colorless oil (466 mg, 0.907
mmol, 55% yield for 2 steps (based on 5-(3,4-dimethoxyphenyl)-N-octylpentanamide)).
:
=
1
:
6
~
1
:
2
1
H-NMR (400 MHz, CDCl
approximately 1 : 1 ratio at 25 ºC), δ (ppm): 7.95 (dd, J = 7.6, 1.6 Hz, 1H), 7.51 (dd, J = 7.6, 7.6 Hz,
H), 7.25 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H), 7.13 (d, J = 8.0 Hz, 0.5H), 7.11 (d, J = 7.6 Hz, 0.5H),
3
), two rotamers with respect to the amide bond were observed
(
1
6.79-6.76 (m, 1H), 6.71-6.69 (m, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.43-3.38 (m, 2H),
3.32-3.27 (m, 2H), 2.60-2.54 (m, 2H), 1.78-1.61 (m, 6H), 1.44-1.24 (m, 12H), 0.89-0.86 (t, J = 6.8 Hz,
1
3
3
H). C-NMR (100 MHz, CDCl
3
), two rotamers with respect to the amide bond were observed, δ
(ppm): 165.4, 154.24, 154.20, 151.1, 148.8, 147.1, 147.0, 135.2, 135.1, 133.3, 131.4, 125.2, 124.1,
1
2
5
24.0, 120.1, 111.7, 111.2, 55.9, 55.7, 51.9, 48.0, 47.9, 47.7, 47.5, 35.4, 31.7, 31.4, 29.3, 29.2, 28.6,
+
+
8.4, 27.9, 27.8, 26.9, 26.8, 26.43, 26.41, 22.6, 14.0. ESI-HRMS: Calcd for C30
6
H43NNaO [M+Na] :
36.2983. Found: 536.2981. Anal. Calcd. for C30 : C, 70.15; H, 8.44; N, 2.73. Found: C, 70.00;
H
43NO
6
H, 8.41; N, 2.76.
Synthesis of methyl 2-((methyl(4-(naphthalen-2-yloxy)butyl)carbamoyl)oxy)benzoate (1o)
A mixture of 2-naphtol (1513 mg, 10.5 mmol), 1,4-dibromobutane (6747 mg, 31.2 mmol),
potassium carbonate (2837 mg) in dry acetone (20 mL) was stirred at room temperature for 2 days. Then
the reaction solution was filtered and the solvent was removed in vacuo to give crude oil. The oil was
chromatographed on silica gel (eluent: ethyl acetate : n-hexane = 0 : 1 ~ 1 : 50) to afford
2-(4-bromobutoxy)naphthalene 3o as white solids (known compound) (2144 mg, 7.68 mmol, 73%
yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.77-7.70 (m, 3H), 7.45-7.41 (m, 1H), 7.34-7.30 (m, 1H),
7
2
1
.14-7.12 (m, 2H), 4.11 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 2.15-2.08 (m, 2H), 2.03-1.97 (m,
1
3
H). C-NMR (100 MHz, CDCl
18.9, 106.6, 66.8, 33.4, 29.5, 27.9.
To a solution of 3o (744 mg, 2.67 mmol) in tetrahydrofuran (5.0 mL), methylamine (40%
3
) δ (ppm): 156.8, 134.5, 129.4, 129.0, 127.6, 126.7, 126.4, 123.6,
2
1
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solution in methanol) (5.0 mL) was added at room temperature. The reaction mixture was stirred at
room temperature for 16 hrs. The solvent was removed in vacuo and crude residue was dissolved in
ethyl acetate. The solution was washed with aqueous sodium hydroxide (2M) (20 mL), washed with
brine (10 mL), dried over sodium sulfate and the solvent was evaporated under reduced pressure to give
N-methyl-4-(naphthalen-2-yloxy)butan-1-amine (4o) as colorless oil (614 mg, 2.68 mmol, 100% crude
1
2
3
4
5
6
7
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
yield).
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.76-7.70 (m, 3H), 7.42 (dd, J = 7.2, 7.2 Hz, 1H), 7.33-7.30 (m,
1
2
1
C
H), 7.15-7.12 (m, 2H), 4.09 (t, J = 6.4 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 2.46 (s, 3H), 1.92-1.86 (m,
1
3
H), 1.74-1.67 (m, 2H), 1.40 (brs, 1H). C-NMR (100 MHz, CDCl
3
) δ (ppm): 157.0, 134.6, 129.3,
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
28.9, 127.6, 126.7, 126.3, 123.5, 119.0, 106.6, 67.7, 51.7, 36.5, 27.0, 26.5. ESI-HRMS: Calcd for
+
+
15
H
20NO [M+H] : 230.1539. Found: 230.1540.
A solution of 4o (516 mg, 2.25 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (1004 mg,
3
.04 mmol) in tetrahydrofuran (10 mL) was stirred at 50 ºC for 20 hrs. The solvent of the reaction
mixture was evaporated under reduced pressure to give a crude oil. The crude product was purified by
column chromatography (eluent: ethyl acetate : n-hexane = 1 : 5 ~ 1 : 1) to afford methyl
2
-((methyl(4-(naphthalen-2-yloxy)butyl)carbamoyl)oxy)benzoate 1o as colorless oil (732 mg, 1.80
mmol, 80% yield (based on N-methyl-4-(naphthalen-2-yloxy)butan-1-amine)).
1
H-NMR (400 MHz, CDCl
(approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.97-7.95 (m, 1H, rotamer A and B), 7.75-7.68 (m,
H, rotamer A and B), 7.53-7.47 (m, 1H, rotamer A and B), 7.41 (dd, J = 7.6, 7.6 Hz, 1H, rotamer A
3
), two rotamers (A and B) with respect to the amide bond were observed
3
and B), 7.31 (dd, J = 7.6, 7.6 Hz, 1H, rotamer A and B), 7.24 (dd, J = 7.6, 7.6 Hz, 1H, rotamer A and
B), 7.16-7.12 (m, 3H, rotamer A and B), 4.11 (t, J = 6.0 Hz, 2H, rotamer A and B), 3.83 (s, 3H, rotamer
A and B), 3.57 (brs, 0.8H, rotamer B), 3.46 (t, J = 6.8 Hz, 1.2H, rotamer A), 3.14 (s, 1.8H, rotamer A),
1
3
3
.03 (s, 1.2H, rotamer B), 1.92-1.85 (m, 4H, rotamer A and B). C-NMR (100 MHz, CDCl
3
), two
rotamers with respect to the amide bond were observed, δ (ppm): 165.2, 156.9, 154.6, 154.3, 151.3,
1
1
51.1, 134.5, 133.4, 131.4, 129.30, 129.25, 128.9, 127.5, 126.6, 126.2, 125.3, 124.1, 124.0, 123.8, 123.7,
23.5, 123.4, 118.8, 106.6, 67.4, 67.3, 52.0, 9.0, 48.9, 34.9, 34.4, 26.4, 26.2, 24.7, 24.1. ESI-HRMS:
+
+
5 5
Calcd for C24H25NNaO [M+Na] : 430.1625. Found: 430.1622. Anal. Calcd. for C24H25NO : C, 70.74;
H, 6.18; N, 3.44. Found: C, 70.68; H, 6.42; N, 3.44.
Synthesis of methyl 2-((isopropyl(4-(naphthalen-2-yloxy)butyl)carbamoyl)oxy)benzoate (1p)
To a solution of 3v (755 mg, 2.71 mmol) in tetrahydrofuran (5.0 mL), isopropylamine (5.0 mL)
was added at room temperature. The reaction mixture was stirred at room temperature for 15 hrs. The
solvent was removed in vacuo and crude residue was dissolved in ethyl acetate (50 mL). The solution
was washed with aqueous sodium hydroxide (2M) (20 mL), washed with brine (10 mL), dried over
sodium sulfate and the solvent was evaporated under reduced pressure to give
N-isopropyl-4-(naphthalen-2-yloxy)butan-1-amine (3p) as pale brown oil (684 mg, 2.66 mmol, 98%
yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.75-7.69 (m, 3H), 7.44-7.39 (m, 1H), 7.33-7.29 (m, 1H),
7
.14-7.12 (m, 2H), 4.08 (t, J = 6.4 Hz, 2H), 2.83-2.77 (m, 1H), 2.68 (t, J = 7.2 Hz, 2H), 1.92-1.85 (m,
13
2H), 1.72-1.65 (m, 2H), 1.06 (d, J = 6.4 Hz, 6H), 0.92 (brs, 1H). C-NMR (100 MHz, CDCl
3
) δ (ppm):
1
57.0, 134.6, 129.3, 128.9, 127.6, 126.6, 126.2, 123.4, 118.9, 106.5, 67.7, 48.7, 47.2, 27.2, 27.1, 23.0.
+
+
ESI-HRMS: Calcd for C17H24NO [M+H] : 258.1852. Found: 258.1860.
A solution of 3p (659 mg, 2.56 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (992 mg,
3.00 mmol) in tetrahydrofuran (5.0 mL) was stirred at 50 ºC for 17 hrs. The solvent of the reaction
mixture was evaporated under reduced pressure to give a crude oil. The crude product was purified by
column chromatography (eluent: ethyl acetate : n-hexane = 1 : 5 ~ 1 : 1) to afford methyl
2
-((isopropyl(4-(naphthalen-2-yloxy)butyl)carbamoyl)oxy)benzoate 1p as colorless oil (891 mg, 2.05
mmol, 80% yield (based on N-isopropyl-4-(naphthalen-2-yloxy)butan-1-amine)).
1
H-NMR (400 MHz, CDCl
3
), two rotamers (A and B) with respect to the amide bond were observed
(approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.95 (d, J = 8.0 Hz, 1H, rotamer A and B),
2
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7
.75-7.70 (m, 3H, rotamer A and B), 7.57-7.39 (m, 2H, rotamer A and B), 7.31 (t, J = 7.6 Hz, 1H,
1
rotamer A and B), 7.26-7.21 (m, 1H, rotamer A and B), 7.14-7.12 (m, 3H, rotamer A and B), 4.42 (h, J
6.8 Hz, 0.4H, rotamer B), 4.26 (h, J = 6.8 Hz, 0.6H, rotamer A), 4.13-4.10 (m, 2H, rotamer A and B),
.82 (s, 3H, rotamer A and B), 3.41 (t, J = 6.8 Hz, 1.2H, rotamer A), 3.33 (t, J = 6.8 Hz, 0.8H, rotamer
B), 1.98-1.88 (m, 4H, rotamer A and B), 1.32 (d, J = 6.8 Hz, 2.4H, rotamer B), 1.25 (d, J = 6.8 Hz,
2
3
4
5
6
7
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
=
3
1
3
3
.6H, rotamer A). C-NMR (100 MHz, CDCl
3
), two rotamers with respect to the amide bond were
observed, δ (ppm): 165.4, 156.8, 154.1, 154.0, 151.03, 150.95, 134.5, 133.3, 131.4, 129.3, 128.9, 127.6,
1
2
4
26.6, 126.2, 125.2, 124.2, 124.04, 123.96, 123.5, 118.9, 118.8, 106.6, 67.5, 52.0, 48.7, 48.4, 43.3, 27.0,
+
+
6.8, 26.7, 26.3, 21.1, 20.4. ESI-HRMS: Calcd for C26
5
H29NNaO [M+Na] : 458.1938. Found:
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
58.1922. Anal. Calcd. for C26 : C, 71.70; H, 6.71; N, 3.22. Found: C, 71.58; H, 6.89; N, 3.31.
H29NO
5
Synthesis of methyl 2-(((6-(3,4-dimethoxyphenyl)hexyl)(methyl)carbamoyl)oxy)benzoate (1q)
A stirring mixture of dimethyl adipate (5782 mg, 33.2 mmol) and 1,2-dimethoxybenzene (2134
mg, 15.4 mmol) was added TfOH (10 mL) at 0 ºC and the temperature was raised to room temperature
(
25 ºC). The mixture was stirred for 16 hours. The reaction was quenched with 100 mL of ice water and
the whole was extracted with dichloromethane (50 mL x 2) The organic layer was washed with brine
10 mL x 2), dried over sodium sulfate and the solvent was removed under reduced pressure to give
(
crude oil. The crude oil was purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 5
~ 1 : 3) to give methyl 6-(3,4-dimethoxyphenyl)-6-oxohexanoate (3q) as colorless oil (known
compound) (2146 mg, 7.66 mmol, 50% yield).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.59 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.88 (d, J
=
1
1
8.4 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.67 (s, 3H), 2.96 (t, J = 7.2 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H),
1
3
.82-1.69 (m, 4H). C-NMR (100 MHz, CDCl
10.2, 110.0, 56.1, 56.0, 51.5, 37.6, 33.9, 24.7, 24.0.
A mixture of 3q (1548 mg, 5.52 mmol) and tetraethylsilane (2019 mg, 17.4 mmol) was added
3
) δ (ppm): 198.5, 173.9, 153.2, 149.1, 130.2, 122.6,
trifluoroacetic acid (5 mL) at 0 ºC. The temperature was raised to room temperature and the reaction
solution was stirred for 13 hours. The reaction was quenched with 50 mL of water and the whole was
extracted with dichloromethane (50 mL x 2). The organic layer was dried over sodium sulfate and the
solvent was removed under reduced pressure to give crude oil. The crude mixture was dissolved in
methylamine (40% solution in methanol) (40 mL) at room temperature. The reaction mixture was stirred
at room temperature for 24 hrs. The solvent was removed in vacuo to give crude oil. The crude oil was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 1) to give
6
-(3,4-dimethoxyphenyl)-N-methylhexanamide (4q) as white powder (1027 mg, 3.87 mmol, 70% yield
for 2 steps).
Mp. 80 - 81 ºC (colorless needles, recrystallized from CHCl
3
/hexane)
1
H-NMR (400 MHz, CDCl
.85 (s, 3H), 2.79 (d, J = 4.8 Hz, 3H), 2.55 (t, J = 7.6 Hz, 2H), 2.16 (t, J = 7.6 Hz, 2H), 1.70-1.58 (m,
3
) δ (ppm): 6.80-6.77 (m, 1H), 6.71-6.69 (m, 2H), 5.45 (brs, 1H), 3.87 (s, 3H),
3
1
3
4H), 1.39-1.32 (m, 2H). C-NMR (100 MHz, CDCl
111.2, 55.9, 55.8, 36.6, 35.3, 31.3, 28.8, 26.2, 25.5. ESI-HRMS: Calcd for C15
88.1570. Found: 288.1554.
The mixture of 4q (1027 mg, 3.87 mmol) and 12 mL of borane-tetrahydrofuran complex
0.92M solution in tetrahydrofuran) was stirred under reflux for 10 hrs under argon atmosphere. Then
3
) δ (ppm): 173.6, 148.8, 147.1, 135.2, 120.1, 111.8,
+
+
H
3
23NNaO [M+Na] :
2
(
the reaction solution was cooled to 0 ºC and quenched with aqueous hydrogen chloride (1M, 10 mL).
Then the solution was heated at 50 ºC for 10 min and then cooled to 0 ºC. The solution was basified by
aqueous sodium hydroxide (2M, 10 mL) and the whole was extracted with dichloromethane (50 mL x 2).
The organic phase was dried over sodium sulfate and the solvent was removed in vacuo to give
6
-(3,4-dimethoxyphenyl)-N-methylhexan-1-amine (5q) as colorless oil (959 mg, 3.82 mmol, 99% crude
yield). The amine was used directly in the next step without further purification.
1
H-NMR (400 MHz, CDCl
H), 2.57-2.53 (m, 4H), 2.42 (s, 3H), 1.64 -1.33 (m, 9H). C-NMR (100 MHz, CDCl
147.0, 135.5, 120.1, 111.7, 111.2, 55.9, 55.8, 52.2, 36.6, 35.5, 31.6, 29.9, 29.2, 27.2. ESI-HRMS: Calcd
3
) δ (ppm): 6.78 (d, J = 8.4 Hz, 1H), 6.72-6.70 (m, 2H), 3.87 (s, 3H), 3.85 (s,
1
3
3
3
) δ (ppm): 148.7,
2
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+
+
for C15
H
26NO
2
[M+H] : 252.1958. Found: 252.1953.
A solution of 5q (959 mg, 3.82 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (1172 mg,
.55 mmol) in tetrahydrofuran (5 mL) was stirred under reflux for 6 hrs. Then the solvent of the reaction
1
2
3
4
5
6
7
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
3
mixture was evaporated under reduced pressure to give a crude oil. The crude product was purified by
column chromatography (eluent: ethyl acetate : n-hexane = 1 : 4 ~ 1 : 1) to afford 1q as colorless oil
(
1294 mg, 3.01 mmol, 85% yield (based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))).
1
H-NMR (400 MHz, CDCl
approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.97 (dd, J = 7.6, 1.6 Hz, 1H, rotamer A and B),
.54-7.49 (m, 1H, rotamer A and B), 7.27-7.24 (m, 1H, rotamer A and B), 7.15 (d, J = 7.6 Hz, 0.6H,
3
), two rotamers (A and B) with respect to the amide bond were observed
(
7
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
rotamer A), 7.12 (d, J = 8.0 Hz, 0.4H, rotamer B), 6.79-6.77 (m, 1H, rotamer A and B), 6.71-6.70 (m,
2H, rotamer A and B), 3.86 (s, 3H, rotamer A and B), 3.85 (s, 3H, rotamer A and B), 3.83 (s, 3H,
rotamer A and B), 3.45 (t, J = 7.6 Hz, 0.8H, rotamer B), 3.34 (t, J = 7.6 Hz, 1.2H, rotamer A), 3.11 (s,
1
4
.8H, rotamer A), 3.02 (s, 1.2H, rotamer B), 2.56 (t, J = 6.8 Hz, 2H, rotamer A and B), 1.67-1.62 (m,
H), 1.40-1.38 (m, 4H). C-NMR (100 MHz, CDCl ), two rotamers with respect to the amide bond
3
13
were observed, δ (ppm): 165.2, 154.41, 154.35, 151.3, 151.2, 148.7, 147.0, 135.4, 135.2, 133.4, 131.4,
1
3
25.2, 124.1, 124.0, 123.9, 123.7, 120.0, 111.7, 111.2, 55.9, 55.7, 51.9, 49.4, 49.3, 35.4, 34.8, 34.4,
+
+
1.53, 31.49, 28.9, 27.8, 27.3, 26.6, 26.4. ESI-HRMS: Calcd for C24
H
31NNaO
6
[M+Na] : 452.2044.
Found: 452.2053. Anal. Calcd. for C24
3.30.
H31NO : C, 67.11; H, 7.27; N, 3.26. Found: C, 66.94; H, 7.24; N,
6
Synthesis
of
methyl
2
-(((2-(4'-chloro-[1,1'-biphenyl]-4-yl)ethyl)(phenethyl)carbamoyl)oxy)benzoate (1r)
A solution of 2-phenylethan-1-amine (1886 mg, 15.6 mmol) in tetrahydrofuran (5 mL) was
added 1-bromo-4-(2-bromoethyl)benzene (1325 mg, 5.02 mmol) and stirred at 25 ºC for 40 hrs. The
reaction solution was cooled to room temperature and was added 40 mL of water. The whole was
extracted with dichloromethane (30 mL x 2). The organic phase was dried over sodium sulfate and the
solvent was evaporated under reduced pressure to give a crude oil. The crude product was roughly
purified by column chromatography (eluent: acetone : n-hexane = 1 : 4) to afford
N-(4-bromophenethyl)-2-phenylethanamine (3r) as pale yellow oil (853 mg, 2.80 mmol, 56% yield).
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.39-7.35 (m, 2H), 7.29-7.25 (m, 2H), 7.22-7.18 (m, 1H),
7.16-7.14 (m, 2H), 7.03-7.00 (m, 2H), 2.90-2.84 (m, 4H), 2.77 (t, J = 7.2 Hz, 2H), 2.72 (t, J = 7.2 Hz,
1
3
3
2H), 0.96 (brs, 1H). C-NMR (100 MHz, CDCl ) δ (ppm): 139.9, 139.0, 131.5, 130.4, 128.6, 128.4,
+
+
1
3
26.1, 119.9, 51.0, 50.8, 36.3, 35.7. ESI-HRMS: Calcd for C16
04.0705.
A solution of 3r (821 mg, 2.70 mmol) and N,N-dimethylpyridin-4-amine (7.1 mg) in dry
H19BrN [M+H] : 304.0695. Found:
tetrahydrofuran (10 mL) was added triethylamine (2.0 mL) and di-tert-butyl dicarbonate 716 mg, 3.28
mmol) at 0 ºC. The reaction mixture was stirred at 25 ºC for 3.5 hours. Then the reaction solution was
evaporated under reduced pressure and the residue was dissolved in 50 mL of dichloromethane. The
solution was washed with aqueous hydrogen chlorode (0.1M, 50 mL) and dried over sodium sulfate.
The solvent was evaporated under reduced pressure to give a crude oil. The crude product was purified
by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 12) to afford tert-butyl
4
-bromophenethyl(phenethyl)carbamate (4r) as colorless oil (663 mg, 1.64 mmol, 61% yield).
1
H-NMR (400 MHz, CDCl
3
), two rotamers with respect to the amide bond were observed, δ (ppm): 7.37
(
d, J = 8.0 Hz, 2H), 7.27 (dd, J = 7.6, 7.6 Hz, 2H), 7.20-7.13 (m, 3H), 7.03-6.98 (m, 2H), 3.32-3.28 (m,
1
3
4H), 2.81-2.66 (m, 4H), 1.42 (s, 9H). C-NMR (100 MHz, CDCl
3
), two rotamers with respect to the
amide bond were observed, δ (ppm): 155.1, 139.1, 138.2, 131.4, 130.5, 128.7, 128.4, 126.2, 119.9, 79.3,
+
+
4
9.8, 49.4, 49.1, 35.2, 34.6, 33.9, 28.3. ESI-HRMS: Calcd for C21
2
H26BrNNaO [M+Na] : 426.1039.
Found: 426.1025.
A mixture of 4r (605 mg, 1.50 mmol), (4-chlorophenyl)boronic acid (310 mmol, 1.98 mmol),
potassium carbonate (406 mg, 2.94 mmol), tetraethyl ammonium bromide (71 mg, 0.33 mmol) and
palladium acetate (17 mg, 0.073 mmol, 4.9 mol%) was added to a 20-mL Biotage microwave bial with a
2
4
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Teflon coated stirring bar. The reagents are dissolved in degassed ethanol (10.0 mL) and water (8.0 mL).
The bial was sealed and heated at 120 ºC for 15 min. After cooling, the reaction solution was added 20
mL of water and extracted with 50 mL of ethyl acetate. The organic phase was washed with brine (20
mL) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a crude
oil. The crude product was roughly purified by column chromatography (eluent: ethyl acetate : n-hexane
1
2
3
4
5
6
7
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
=
(
1 : 10) to afford mixture of 4-bromophenethyl(phenethyl)carbamate (starting material) and tert-butyl
2-(4'-chloro-[1,1'-biphenyl]-4-yl)ethyl)(phenethyl)carbamate (569 mg). Because we could not separate
these compounds, the Suzuki coupling reaction was conducted again. A mixture of the crude compound
569 mg), (4-chlorophenyl)boronic acid (151 mmol, 0.966 mmol), potassium carbonate (290 mg, 2.10
(
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
mmol), tetraethyl ammonium bromide (40 mg, 0.19 mmol) and palladium acetate (9.7 mg, 0.043 mmol)
was added to a 20-mL Biotage microwave bial with a Teflon coated stirring bar. The reagents are
dissolved in degassed ethanol (8.0 mL) and water (5.0 mL). The bial was sealed and heated at 120 ºC
for 10 min. After cooling, the reaction solution was added 20 mL of water and extracted with 80 mL of
ethyl acetate. The organic phase was washed with brine (20 mL) and dried over sodium sulfate. The
solvent was evaporated under reduced pressure to give a crude oil. The crude product was purified by
column chromatography (eluent: ethyl acetate : n-hexane = 1 : 10) to afford tert-butyl
(2-(4'-chloro-[1,1'-biphenyl]-4-yl)ethyl)(phenethyl)carbamate (5r) as colorless oil (512 mg, 1.17 mmol,
78% yield).
1
3
H-NMR (400 MHz, CDCl ), two rotamers with respect to the amide bond were observed, δ (ppm):
7
.45-7.42 (m, 4H), 7.33 (d, J = 8.4 Hz, 2H), 7.27-7.24 (m, 3H), 7.19-7.13 (m, 4H), 3.39-3.32 (m, 4H),
13
3
2.82-2.75 (m, 4H), 1.43 (s, 9H). C-NMR (100 MHz, CDCl ), two rotamers with respect to the amide
bond were observed, δ (ppm): 155.1, 139.3, 139.2, 138.7, 137.7, 133.0, 129.3, 128.9, 128.7, 128.3,
1
28.0, 126.8, 126.1, 79.2, 49.7, 49.6, 49.3, 35.2, 34.8, 34.6, 34.2, 28.3. ESI-HRMS: Calcd for
+
+
C
27
H
30ClNNaO
2
[M+Na] : 458.1857. Found: 458.1853.
To a solution of 5r (480 mg, 1.10 mmol) in dry dichloromethane (5.0 mL), trifluoroacetic acid
1.0 mL) was added at 0 ºC under stirring. The temperature was raised to room temperature (20 ºC) and
(
the reaction solution was stirred for 21 hours. Then aqueous sodium carbonate (2M, 10 mL) was added
to quench the reaction and the whole was extracted with dichloromethane (50 mL). The organic layer
was dried over sodium sulfate and the solvent was removed under reduces pressure to afford
2
-(4'-chloro-[1,1'-biphenyl]-4-yl)-N-phenethylethanamine (6r) as pale yellow solids (363 mg, 1.08
mmol, 98% yield).
Mp. 70 - 71 ºC (colorless plates, recrystallized from CHCl
3
/hexane)
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.47-7.40 (m, 4H), 7.35 (d, J = 8.4 Hz, 2H), 7.26-7.14 (m, 7H),
13
2
.92-2.85 (m, 4H), 2.81-2.74 (m, 4H), 1.12 (brs, 1H). C-NMR (100 MHz, CDCl
3
) δ (ppm): 139.9,
1
39.5, 139.3, 137.7, 133.0, 129.1, 128.8, 128.6, 128.3, 128.1, 126.9, 126.0, 50.94, 50.85, 36.3, 35.9.
+
+
ESI-HRMS: Calcd for C22H23ClN [M+H] : 336.1514. Found: 336.1524.
A solution of 6r (337 mg, 1.00 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (330 mg,
1.00 mmol) in tetrahydrofuran (2.0 mL) was added to a 5-mL Biotage microwave bial with a Teflon
coated stirring bar. The bial was sealed and heated at 100 ºC for 2 hrs. After cooling, the solvent of the
reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 8 ~ 1 : 4) to afford methyl
2
-(((2-(4'-chloro-[1,1'-biphenyl]-4-yl)ethyl)(phenethyl)carbamoyl)oxy)benzoate 1r as colorless oil (483
mg, 0.940 mmol, 94% yield).
1
3
H-NMR (400 MHz, CDCl ), two rotamers with respect to the amide bond were observed
(approximately 1 : 1 ratio at 25 ºC), δ (ppm): 8.00-7.98 (m, 1H, rotamer A and B), 7.55-7.48 (m, 5H,
rotamer A and B), 7.41-7.38 (m, 2H, rotamer A and B), 7.32-7.22 (m, 8H, rotamer A and B), 7.03 (d, J
=
8.0 Hz, 0.6H, rotamer A), 6.97 (d, J = 8.4 Hz, 0.4H, rotamer B), 3.86 (s, 3H, rotamer A and B),
3
.68-3.63 (m, 2H, rotamer A and B), 3.53-3.49 (m, 2H, rotamer A and B), 3.03-2.92 (m, 4H, rotamer A
1
3
and B). C-NMR (100 MHz, CDCl
ppm): 165.0, 154.1, 154.0, 150.94, 150.91, 139.2, 139.1, 138.8, 138.4, 137.9, 137.8, 133.3, 133.1,
133.0, 131.3, 129.4, 129.3, 128.8, 128.73, 128.70, 128.40, 128.37, 128.0, 126.90, 126.86, 126.3, 126.2,
3
), two rotamers with respect to the amide bond were observed, δ
(
2
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1
C
25.3, 123.92, 123.88, 123.7, 51.9, 50.3, 50.2, 49.9, 49.8, 35.0, 34.6, 34.2, 33.8. ESI-HRMS: Calcd for
1
2
3
4
5
6
7
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
+
+
31
H
28ClNNaO
4
[M+Na] : 536.1599. Found: 536.1594.
Synthesis
of
methyl
2-(((2-(4'-chloro-[1,1'-biphenyl]-4-yl)ethyl)(4-chlorophenethyl)carbamoyl)oxy)benzoate (1s)
A solution of 2-(4-chlorophenyl)ethan-1-amine (4500 mg, 28.9 mmol) in tetrahydrofuran (10
mL) was added 1-bromo-4-(2-bromoethyl)benzene (2552 mg, 9.67 mmol) and stirred at 50 ºC for 46 hrs.
The reaction solution was cooled to room temperature and was added 40 mL of aqueous sodium
hydroxide (0.5M, 40 mL). The whole was extracted with dichloromethane (30 mL x 2). The organic
phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give a
crude oil. The crude product was roughly purified by column chromatography (eluent: acetone :
n-hexane = 1 : 4 ~ 1 : 3) to afford N-(4-bromophenethyl)-2-(4-chlorophenyl)ethan-1-amine (3s) as pale
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
yellow oil (2527 mg, 7.46 mmol, 77% yield).
1
H-NMR (400 MHz, CDCl
.02 (d, J = 8.0 Hz, 2H), 2.86-2.83 (m, 4H), 2.74-2.69 (m, 4H), 0.91 (brs, 1H). C-NMR (100 MHz,
CDCl ) δ (ppm): 138.9, 138.4, 131.9, 131.5, 130.4, 129.9, 128.5, 119.9, 50.8, 50.7, 35.7, 35.6.
ESI-HRMS: Calcd for C16
3
) δ (ppm): 7.34-7.37 (m, 2H), 7.24-7.22 (m, 2H), 7.07 (d, J = 8.4 Hz, 2H),
13
7
3
+
+
H
18BrClN [M+H] : 338.0306. Found: 338.0301.
The amine compound 3s (2493 mg, 7.36 mmol) was dissolved in dry dichloromethane (10 mL)
and the solution was added triethylamine (1.0 mL) and di-tert-butyl dicarbonate (1280 mg, 5.86 mmol)
at 0 ºC. The reaction mixture was stirred at 25 ºC for 21 hours. The reaction was quenched with aqueous
sodium carbonate (0.5M, 20 mL) and the whole was extracted with dichloromethane (30 mL x 2). The
organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure to
give a crude oil. The crude product was roughly purified by column chromatography (eluent: ethyl
acetate : n-hexane = 1 : 8) to afford tert-butyl (4-bromophenethyl)(4-chlorophenethyl)carbamate (4s)
(2242 mg, 5.11 mmol, 87%based on di-tert-butyl dicarbonate) as colorless oil.
1
H-NMR (400 MHz, CDCl
H), 3.32 (brs, 2H), 3.24 (brs, 2H), 2.76 (brs, 2H), 2.70 (brs, 2H), 1.42 (s, 9H). C-NMR (100 MHz,
CDCl ) δ (ppm): 155.1, 138.1, 137.6, 132.0, 131.4, 130.5, 130.1, 128.5, 120.0, 79.5, 49.5, 49.1, 34.6,
3.9, 28.3. ESI-HRMS: Calcd for C21
A mixture of 4s (873 mg, 1.99 mmol), (4-chlorophenyl)boronic acid (790 mmol, 5.05 mmol),
3
) δ (ppm): 7.40 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.09-7.00 (m,
1
3
4
3
+
+
3
2
H25BrClNNaO [M+Na] : 460.0649. Found: 460.0648.
potassium carbonate (877 mg, 6.35 mmol), tetraethyl ammonium bromide (194 mg, 0.923 mmol) and
palladium acetate (59 mg, 0.262 mmol, 13 mol%) was added to a 20-mL Biotage microwave bial with a
Teflon coated stirring bar. The reagents are dissolved in degassed ethanol (8.0 mL) and water (8.0 mL).
The bial was sealed and heated at 120 ºC for 15 min. After cooling, the reaction solution was extracted
with 80 mL of ethyl acetate. The organic phase was washed with water (20 mL) and then brine (20 mL)
and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a crude oil.
The crude product was purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 10 ~
1 : 6) to afford tert-butyl (2-(4'-chloro-[1,1'-biphenyl]-4-yl)ethyl)(4-chlorophenethyl)carbamate 5s as
colorless oil (688 mg, 1.46 mmol, 73% yield).
1
H-NMR (400 MHz, CDCl
3
), two rotamers with respect to the amide bond were observed, δ (ppm):
7
3
.47-7.44 (m, 4H), 7.37-7.35 (m, 2H), 7.24-7.19 (m, 4H), 7.10 (brs, 1H), 7.05 (brs, 1H), 3.36 (brs, 2H),
13
3
.31 (brs, 2H), 2.78 (brs, 4H), 1.42 (s, 9H). C-NMR (100 MHz, CDCl ), two rotamers with respect to
the amide bond were observed, δ (ppm): 155.1, 139.3, 138.6, 137.9, 137.7, 133.1, 132.0, 130.1, 129.3,
1
28.8, 128.5, 128.1, 126.9, 79.4, 49.5, 49.3, 34.8, 34.6, 34.2, 33.9, 28.3. ESI-HRMS: Calcd for
+
+
C
27
H
29Cl
2
NNaO
To a solution of 5s (1347 mg, 2.86 mmol) in dry dichloromethane (5.0 mL), trifluoroacetic acid
2.0 mL) was added at 0 ºC under stirring. The temperature was raised to room temperature and the
2
[M+Na] : 492.1468. Found: 492.1479.
(
reaction solution was stirred for 4 hours. Then aqueous sodium carbonate (2M, 20 mL) was added to
quench the reaction and the whole was extracted with dichloromethane (30 mL x 2). The organic layer
was dried over sodium sulfate and the solvent was removed under reduces pressure to afford
2-(4'-chloro-[1,1'-biphenyl]-4-yl)-N-(4-chlorophenethyl)ethanamine (6s) as colorless oil (998 mg, 2.69
2
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The Journal of Organic Chemistry
mmol, 94% yield).
H-NMR (400 MHz, CDCl
1
2
3
4
5
6
7
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
1
3
) δ (ppm): 7.50-7.47 (m, 2H), 7.46-7.43 (m, 2H), 7.40-7.37 (m, 2H),
7
2
.22-7.20 (m, 4H), 7.09-7.07 (m, 2H), 2.93-2.86 (m, 4H), 2.81 (t, J = 7.2 Hz, 2H), 2.75 (t, J = 7.2 Hz,
H), 1.09 (brs, 1H). C-NMR (100 MHz, CDCl ) δ (ppm): 139.4, 139.3, 138.4, 137.9, 133.2, 131.9,
3
1
3
+
2
130.0, 129.2, 128.9, 128.5, 128.2, 127.0, 50.83, 50.77, 35.9, 35.6. ESI-HRMS: Calcd for C22H22Cl N
+
[
M+H] : 370.1124. Found: 370.1130.
A solution of 6s (813mg, 2.20 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (669 mg,
2
.02mmol) in tetrahydrofuran (4.0 mL) was added to a 5-mL Biotage microwave bial with a Teflon
coated stirring bar. The bial was sealed and heated at 100 ºC for 3 hrs. After cooling, the solvent of the
reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 8 ~ 1 : 6) to afford methyl
2-(((2-(4'-chloro-[1,1'-biphenyl]-4-yl)ethyl)(4-chlorophenethyl)carbamoyl)oxy)benzoate 1s (999 mg,
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
1
.82 mmol, 90% yield (based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))).
Mp. 113 - 114 ºC (colorless needles, recrystallized from CHCl /n-hexane)
), two rotamers with respect to the amide bond were observed
approximately 1 : 1 ratio at 25 ºC), δ (ppm): 8.04-8.01 (m, 1H), 7.60-7.51 (m, 5H), 7.43 (dd, J = 8.4,
.8 Hz, 2H), 7.36-7.28 (m, 5H), 7.23-7.19 (m, 2H), 7.05 (d, J = 8.0 Hz, 0.5H), 7.00 (d, J = 8.0 Hz,
3
1
H-NMR (400 MHz, CDCl
3
(
2
1
3
0.5H), 3.90 (s, 3H), 3.70-3.64 (m, 2H), 3.56-3.50 (m, 2H), 3.07-2.93 (m, 4H). C-NMR (100 MHz,
CDCl ), two rotamers with respect to the amide bond were observed, δ (ppm): 165.1, 154.2, 151.0,
39.3, 138.4, 138.2, 138.1, 137.4, 133.51, 133.47, 133.3, 133.2, 132.3, 132.2, 131.4, 130.3, 130.2, 129.5,
29.4, 128.88, 128.85, 128.64, 128.60, 128.2, 127.1, 127.0, 125.5, 124.0, 123.8, 52.0, 50.4, 50.3, 50.0,
3
1
1
4
5
+
+
9.9, 34.7, 34.5, 34.0, 33.7. ESI-HRMS: Calcd for C31
70.1238.
2 4
H27Cl NNaO [M+Na] : 570.1209. Found:
Synthesis of methyl 2-((benzyl(4-chlorophenethyl)carbamoyl)oxy)benzoate (1t)
A solution of 2-(4-chlorophenyl)ethan-1-amine (771 mg, 4.95 mmol) in triethylamine (1.0 mL)
was added benzyl bromide (347 mg, 2.15 mmol) and stirred at 25 ºC for 15 hrs. The reaction solution
was cooled to room temperature and was added 40 mL of aqueous sodium hydroxide (0.5M, 40 mL).
The whole was extracted with dichloromethane (30 mL x 2). The organic phase was dried over sodium
sulfate and the solvent was evaporated under reduced pressure to give a crude oil. The crude product
was roughly purified by column chromatography (eluent: acetone : n-hexane = 1 : 8) to afford
N-benzyl-2-(4-chlorophenyl)ethan-1-amine (3t) as colorless oil (355 mg, 1.45 mmol, 67% yield).
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.33-7.22 (m, 7H), 7.13-7.11 (m, 2H), 3.79 (s, 2H), 2.87 (t, J =
13
6
1
.8 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 1.30 (brs, 1H). C-NMR (100 MHz, CDCl
3
) δ (ppm): 140.2,
+
38.5, 131.9, 130.0, 128.5, 128.4, 128.0, 126.9, 53.9, 50.3, 35.7. ESI-HRMS: Calcd for C15
H
17ClN
+
[M+H] : 246.1044. Found: 246.1034.
A solution of 3t (931 mg, 3.79 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (854 mg,
2.59 mmol) in tetrahydrofuran (4.0 mL) was added to a 5-mL Biotage microwave bial with a Teflon
coated stirring bar. The bial was sealed and heated at 100 ºC for 3 hrs. After cooling, the solvent of the
reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 8 ~ 1 : 4) to afford methyl
2
-((benzyl(4-chlorophenethyl)carbamoyl)oxy)benzoate 1t as colorless oil (1028 mg, 2.43 mmol, 94%
yield (based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))).
1
H-NMR (400 MHz, CDCl
(approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.99-7.97 (m, 1H, rotamer A and B), 7.55-7.50 (m,
H, rotamer A and B), 7.36-7.23 (m, 8H, rotamer A and B), 7.14-7.10 (m, 2.4H, rotamer A and B), 7.04
d, J = 7.6 Hz, 0.6H, rotamer A), 4.63 (s, 0.8H, rotamer B), 4.49 (s, 1.2H, rotamer A), 3.83 (s, 1.2H,
rotamer B), 3.78 (s, 1.8H, rotamer A), 3.61 (t, J = 7.6 Hz, 1.2H, rotamer A), 3.49 (t, J = 7.6 Hz, 0.8H,
3
), two rotamers (A and B) with respect to the amide bond were observed
1
(
1
3
rotamer B), 2.93 (t, J = 7.6 Hz, 1.2H, rotamer A), 2.87 (t, J = 7.6 Hz, 0.8H, rotamer B). C-NMR (100
MHz, CDCl ), two rotamers with respect to the amide bond were observed, δ (ppm): 165.1, 154.8, 154.2,
151.00, 150.95, 137.44, 137.40, 137.3, 137.2, 133.48, 133.45, 132.2, 132.1, 131.5, 130.22, 130.19,
3
2
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1
3
28.59, 128.55, 128.1, 127.58, 127.55, 127.5, 125.5, 124.00, 123.97, 123.8, 52.0, 51.5, 51.2, 49.1, 48.3,
4.0, 33.3. ESI-HRMS: Calcd for C24H22ClNNaO [M+Na] : 446.1130. Found: 446.1156.
4
1
2
3
4
5
6
7
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
+
+
Synthesis of methyl 2-((benzyl(3-phenylpropyl)carbamoyl)oxy)benzoate (1u)
A solution of benzoyl chloride (713 mg, 5.07 mmol) in 5 mL of dichloromethane was added
dropwise to a solution of 3-phenylpropan-1-amine (663 mg, 4.90 mmol) and triethylamine (1.0 mL) in
dry dichloromethane (5 mL) under stirring at -78ºC. The temperature was raised to 25 ºC and the
reaction mixture was stirred for 30 min. Then 20 mL of water was added and the whole was extracted
with dichloromethane (30 mL x 2). The organic phase was dried over sodium sulfate and the solvent
was removed in vacuo to afford N-(3-phenylpropyl)benzamide (3u) as white powder (known
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
compound) (1155 mg, 4.83 mmol, 98%).
1
H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.67-7.65 (m, 2H), 7.50-7.46 (m, 1H), 7.42-7.38 (m, 2H),
7
2
.32-7.28 (m, 2H), 7.23-7.19 (m, 3H), 6.06 (brs, 1H), 3.51 (dt, J = 6.8, 6.8 Hz, 2H), 2.74 (t, J = 7.6 Hz,
H), 2.02-1.94 (m, 2H). ESI-HRMS: Calcd for C16
+
+
H17NNaO [M+Na] : 262.1202. Found: 262.1202.
A solution of N-(3-phenylpropyl)benzamide (903 mg, 3.77 mmol) and lithium aluminum
hydride (337 mg, 8.88 mmol) in tetrahydrofuran (14 mL) was stirred at 50 ºC for 12 hrs. Then the
reaction solution was cooled to 0 ºC and quenched with large amount of sodium sulfate decahydrate and
ethyl acetate. Then the solution was filtered and the solvent was removed in vacuo to give
N-benzyl-3-phenylpropan-1-amine (4u) (known compound) (835 mg, 3.71 mmol, 98% crude yield) as
colorless oil. The amine was used directly in the next step without further purification.
1
3
H-NMR (400 MHz, CDCl ) δ (ppm): 7.31-7.14 (m, 10H), 3.76 (s, 2H), 2.67-2.63 (m, 4H), 1.86-1.79
13
3
(m, 2H), 1.38 (brs, 1H). C-NMR (100 MHz, CDCl ) δ (ppm): 142.1, 140.5, 128.30, 128.30, 128.2,
+
+
1
2
28.0, 126.8, 125.7, 53.9, 48.9, 33.6, 31.7. ESI-HRMS: Calcd for C16
26.1577.
H20N [M+H] : 226.1590. Found:
A solution of 4u (818 mg, 3.63 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (997 mmol,
3
.02 mmol) in tetrahydrofuran (4.0 mL) was added to a 5-mL Biotage microwave bial with a Teflon
coated stirring bar. The bial was sealed and heated at 100 ºC for 3 hrs. After cooling, the solvent of the
reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 6 ~ 1 : 4) to afford methyl
2
-((benzyl(3-phenylpropyl)carbamoyl)oxy)benzoate 1u as colorless oil (1161 mg, 2.88 mmol, 95%
yield (based on dimethyl 2,2'-(carbonylbis(oxy))dibenzoate))).
1
H-NMR (400 MHz, CDCl
3
), two rotamers (A and B) with respect to the amide bond were observed
(approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.99-7.96 (m, 1H, rotamer A and B), 7.56-7.50 (m,
1
0
H, rotamer A and B), 7.35-7.26 (m, 8H, rotamer A and B), 7.19-7.12 (m, 4H, rotamer A and B), 4.71 (s,
.8H, rotamer B), 4.55 (s, 1.2H, rotamer A), 3.81 (s, 1.2H, rotamer B), 3.77 (s, 1.8H, rotamer A), 3.45 (t,
J = 7.6 Hz, 1.2H, rotamerA), 3.78 (t, J = 7.6 Hz, 0.8H, rotamer B), 2.64 (t, J = 7.6 Hz, 2H, rotamer A
and B), 2.05-1.91 (m, 2H, rotamer A and B). C-NMR (100 MHz, CDCl ), two rotamers with respect to
3
the amide bond were observed, δ (ppm): 165.3, 154.9, 154.3, 151.0, 141.6, 141.3, 137.5, 137.4, 133.4,
131.5, 131.4, 128.52, 128.46, 128.31, 128.28, 128.23, 128.19, 128.16, 127.5, 127.42, 127.37, 125.9,
1
3
1
25.8, 125.40, 125.36, 124.03, 123.97, 52.0, 50.9, 50.8, 47.0, 46.5, 33.0, 32.9, 29.5, 29.0. ESI-HRMS:
+
+
4 4
Calcd for C25H25NNaO [M+Na] : 426.1676. Found: 426.1654. Anal. Calcd. for C25H25NO : C, 74.42;
H, 6.25; N, 3.47. Found: C, 74.22; H, 6.33; N, 3.45.
Synthesis of methyl 2-(((4-chlorobenzyl)(3-phenylpropyl)carbamoyl)oxy)benzoate (1v)
A solution of 3-phenylpropan-1-amine (1458mg, 10.8 mmol) in tetrahydrofuran (5 mL) was
added 4-chlorobenzyl bromide (829 mg, 4.04 mmol) and stirred at 25 ºC for 45 hrs. The reaction
solution was added 50 mL of dichloromethane and the whole was washed with aqueous hydrogen
chloride (1M, 10 mL x 2) and then aqueous sodium hydroxide (2M, 10 mL). The organic phase was
dried over sodium sulfate and the solvent was evaporated under reduced pressure to give a crude oil.
The crude product was purified by column chromatography (eluent: acetone : n-hexane = 1 : 4 ~ 1 : 3)
to afford N-(4-chlorobenzyl)-3-phenylpropan-1-amine (3v) as colorless oil (729 mg, 2.81 mmol, 69%
2
8
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Page 29 of 52
The Journal of Organic Chemistry
yield).
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H-NMR (400 MHz, CDCl
3
) δ (ppm): 7.29-7.24 (m, 6H), 7.22-7.15 (m, 3H), 3.73 (s, 2H), 2.67-2.62 (m,
1
3
4H), 1.82 (p, J = 7.2 Hz, 2H), 1.19 (brs, 1H). C-NMR (100 MHz, CDCl
3
) δ (ppm): 142.1, 139.0, 132.5,
+
+
129.4, 128.4, 128.34, 128.30, 125.8, 53.2, 48.8, 33.6, 31.7. ESI-HRMS: Calcd for C16
H
19ClN [M+H] :
260.1201. Found: 260.1204.
A solution of 3v (636 mg, 2.45 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (1015
mmol, 3.07 mmol) in tetrahydrofuran (4.0 mL) was stirred at 50 ºC for 22 hrs. The solvent of the
reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 4) to afford methyl
0
1
2
3
4
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0
1
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0
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0
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0
2
-(((4-chlorobenzyl)(3-phenylpropyl)carbamoyl)oxy)benzoate 1v as colorless oil (612 mg, 1.40 mmol,
57% yield (based on N-(4-chlorobenzyl)-3-phenylpropan-1-amine))).
1
H-NMR (400 MHz, CDCl
3
), two rotamers (A and B) with respect to the amide bond were observed
(approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.98-7.95 (m, 1H, rotamer A and B), 7.53-7.47 (m,
1
1
0
H), 7.32-7.23 (m, 7H), 7.20-7.09 (m, 4H), 4.64 (s, 0.8H, rotamer B), 4.48 (s, 1.2H, rotamer A), 3.80 (s,
.2H, rotamer B), 3.77 (s, 1.8H, rotamer A), 3.42 (t, J = 7.2 Hz, 1.2H, rotamer A), 3.34 (t, J = 7.2 Hz,
1
3
.8H, rotamer B), 2.63 (t, J = 7.6 Hz, 2H, rotamer A and B), 2.04-1.89 (m, 2H). C-NMR (100 MHz,
), two rotamers with respect to the amide bond were observed, δ (ppm): 165.0, 154.9, 154.1,
CDCl
3
151.0, 150.9, 141.4, 141.2, 136.0, 135.9, 133.4, 133.1, 131.4, 129.4, 128.9, 128.6, 128.5, 128.29, 128.26,
128.1, 125.9, 125.8, 125.4, 123.93. 124.86, 123.8, 51.9, 50.3, 50.2, 47.0, 46.5, 32.9, 32.8, 29.4, 28.9.
ESI-HRMS: Calcd for C25
+
+
4
H24ClNNaO [M+Na] : 460.1286. Found: 460.1299. Anal. Calcd. for
C
25
H
24ClNO : C, 68.57; H, 5.52; N, 3.20. Found: C, 68.71; H, 5.72; N, 3.18.
4
Synthesis of methyl 2-(((4-chlorobenzyl)(4-phenylbutyl)carbamoyl)oxy)benzoate (1w)
A solution of 4-phenylbutan-1-amine (896 mg, 6.00 mmol) in tetrahydrofuran (5 mL) was
added 4-chlorobenzyl bromide (621 mg, 3.02 mmol) and stirred at 25 ºC for 24 hrs. The reaction
solution was added 50 mL of dichloromethane and the whole was washed with aqueous sodium
hydroxide (2M, 10 mL). The organic phase was dried over sodium sulfate and the solvent was
evaporated under reduced pressure to give a crude oil. The crude product was purified by column
chromatography (eluent: acetone
:
n-hexane
=
1
:
4
~
1
:
2) to afford
N-(4-chlorobenzyl)-4-phenylbutan-1-amine (3w) as colorless oil (559 mg, 2.04 mmol, 68% yield).
1
H-NMR (400 MHz, CDCl
4H), 1.69-1.62 (m, 2H), 1.57-1.50 (m, 2H), 1.15 (brs, 1H). C-NMR (100 MHz, CDCl
39.1, 132.5, 129.4, 128.4, 128.3, 125.7, 53.3, 49.2, 35.8, 29.7, 29.1. ESI-HRMS: Calcd for C17H21ClN
3
) δ (ppm): 7.29-7.22 (m, 6H), 7.19-7.15 (m, 3H), 3.73 (s, 2H), 2.63-2.59 (m,
1
3
3
) δ (ppm): 142.4,
+
1
+
[M+H] : 274.1357. Found: 274.1357.
A solution of 3w (526 mg, 1.92 mmol), dimethyl 2,2'-(carbonylbis(oxy))dibenzoate) (661
mmol, 2.00 mmol) in tetrahydrofuran (6.0 mL) was added to a Biotage microwave bial with a Teflon
coated stirring bar. The bial was sealed and heated at 80 ºC for 3 hrs. After cooling, the solvent of the
reaction mixture was evaporated under reduced pressure to give a crude oil. The crude product was
purified by column chromatography (eluent: ethyl acetate : n-hexane = 1 : 4) to afford methyl
2
8
-(((4-chlorobenzyl)(4-phenylbutyl)carbamoyl)oxy)benzoate 1w as colorless oil (718 mg, 1.59 mmol,
3% yield (based on N-(4-chlorobenzyl)-4-phenylbutan-1-amine))).
1
H-NMR (400 MHz, CDCl
approximately A : B = 6 : 4 ratio at 25 ºC), δ (ppm): 7.98-7.95 (m, 1H, rotamer A and B), 7.52-7.47 (m,
3
), two rotamers (A and B) with respect to the amide bond were observed
(
1
H, rotamer A and B), 7.33-7.20 (m, 7H, rotamer A and B), 7.18-7.08 (m, 4H, rotamer A and B), 4.63 (s,
0.8H, rotamer B), 4.48 (s, 1.2H, rotamer A), 3.76 (s, 3H, rotamer A and B), 3.42-3.33 (m, 2H, rotamer
1
3
A and B), 2.64-2.60 (m, 2H, rotamer A and B), 1.70-1.63 (m, 4H, rotamer A and B). C-NMR (100
MHz, CDCl ), two rotamers with respect to the amide bond were observed, δ (ppm): 165.1, 154.9, 154.2,
51.1, 150.9, 142.1, 141.9, 136.0, 133.5, 133.2, 131.5, 131.4, 129.4, 128.9, 128.7, 128.6, 128.31, 128.25,
25.8, 125.7, 125.5, 125.4, 124.0, 123.90, 123.85, 51.9, 50.2, 50.0, 47.0, 46.8, 35.41, 35.36, 28.4, 28.3,
3
1
1
2
+
+
4
7.5, 26.9. ESI-HRMS: Calcd for C26H26ClNNaO [M+Na] : 474.1443. Found: 474.1429.
2
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