Synthesis and Structure–Activity Relationships of Novel Benzylamine-Type Antifungals as Butenafine-Related Antimycotics

Article abstract of DOI:10.1002/ardp.201600342

Benzylamine-type antimycotics like naftifine, butenafine, or terbinafine are a well-known class of antimycotics since the 1980s. The following paper describes the synthesis and biological evaluation of a series of novel benzylamine-type antimycotics characterized by an isooctyl side chain and various substituents at the benzylamine moiety. The compounds were prepared from benzaldehyde derivatives and 2-amino-6-methylheptane by reductive amination with sodium triacetoxyborohydride and subsequent precipitation with hydrogen chloride. The antimycotic activity of the resulting compounds was evaluated in an agar diffusion assay against the yeasts C. glabrata and Yarrowia lipolytica, the mold Aspergillus niger and the dermatophyte H. burtonii. The compounds were also tested in a microdilution assay against the yeast Candida glabrata and the dermatophyte H. burtonii to determine the minimal inhibitory concentrations (MIC). Compounds with an aromatic ether side chain or a short alkyl ether side chain showed significant antimycotic activity against C. glabrata, comparable to terbinafine or clotrimazole.

Full text of DOI:10.1002/ardp.201600342

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Full Paper
Synthesis and Structure–Activity Relationships of Novel
Benzylamine-Type Antifungals as Butenafine-Related Antimycotics
€
Jurgen Krauss
, Martina Stadler, and Franz Bracher
Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians University, Munich, Germany
Benzylamine-type antimycotics like naftifine, butenafine, or terbinafine are a well-known class of
antimycotics since the 1980s. The following paper describes the synthesis and biological evaluation of
a series of novel benzylamine-type antimycotics characterized by an isooctyl side chain and various
substituents at the benzylamine moiety. The compounds were prepared from benzaldehyde
derivatives and 2-amino-6-methylheptane by reductive amination with sodium triacetoxyborohydride
and subsequent precipitation with hydrogen chloride. The antimycotic activity of the resulting
compounds was evaluated in an agar diffusion assay against the yeasts Candida glabrata and
Yarrowia lipolytica, the mold Aspergillus niger and the dermatophyte Hyphopichia burtonii. The
compounds were also tested in a microdilution assay against the yeast C. glabrata and the
dermatophyte H. burtonii to determine the minimal inhibitory concentrations (MIC). Compounds with
an aromatic ether side chain or a short alkyl ether side chain showed significant antimycotic activity
against C. glabrata, comparable to terbinafine or clotrimazole.
Keywords: Antimicrobial activity / Antimycotics / Benzylamines / Reductive amination
Received: November 20, 2016; Revised: March 6, 2017; Accepted: March 7, 2017
DOI 10.1002/ardp.201600342
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
damaging effect on the fungal cell membranes at higher
concentrations [9].
Since the launch of terbinafine and naftifine in the 1980s, the
Introduction
allylamines have been an important class of antimycotics and
are often used in human medicine against several dermal
fungal infections [1–6]. These antimycotics target ergosterol
Results and discussion
Chemistry
biosynthesis by inhibition of squalene epoxidase resulting in a
lack of ergosterol in fungal membranes. From 1980 until now
a wide variety of derivatives of terbinafine and naftifine were
developed like the benzylamine antimycotics (e.g., butena-
fine) or benzothiophene antimycotics (Fig. 1) [7, 8]. Butena-
fine is a derivative without the allylamine partial structure
and shows a similar activity. Additionally butenafine has a
In continuation of our research in development of new
ergosterol biosynthesis inhibitors [10–13], we tried to find out
if benzylamines with an alkyl side chain similar to the
ergosterol alkenyl side chain show any antimycotic activity
and if a substitution of the benzyl moiety with bromine,
chlorine, hydroxyl, methoxy, nitro, cyano, or several aryloxy or
alkoxy substituents increases the activity.
In a first series benzaldehyde derivatives 1a–o were reacted
with (ꢀ)-2-amino-5-methylheptane (2) by a reductive amina-
tion with sodium triacetoxyborohydride [14] to give the
racemic secondary amines 3a–o in moderate yields. As by-
products, the benzyl alcohol derivatives were formed in this
reaction but they could be separated simply by flash column
chromatography.
€
Correspondence: Dr. Jurgen Krauß, Department of Pharmacy –
Center for Drug Research, Ludwig-Maximilians University,
Butenandtstr. 5–13, 81377 Munich, Germany.
E-mail: hjkra@cup.uni-muenchen.de
Fax: þ49-89-218077171
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determined in an MTT assay against HL-60 cell line [18].
The compounds showed moderate cytotoxicity against this
cell line with IC50 values between 6 and 47 mM, in the same
range as terbinafine hydrochloride (IC50 ¼ 47 mM) (Table 3).
Conclusion
A library of more than 35 new benzylamine antimycotics with
N-isooctyl side chain was prepared by reductive amination of
substituted benzaldehydes in moderate to good yields. In
order to enhance their stability, the amines were precipitated
as the corresponding hydrochlorides. N-Isooctyl benzylamines
with several substituents at the benzyl moiety like hydroxyl,
nitro or cyano showed no or only weak antimycotic activities.
Only compounds with chloro- and bromo-substituents
showed significant antimycotic activity.
On the other hand, the benzylamine derivatives with
phenoxy, benzyloxy, phenylethoxy, or alkyloxy (C4–C6)
substituents showed high antimycotic activities against C.
glabrata, Y. lipolytica, and H. burtonii in the same range as
clotrimazole and terbinafine. Ether substituents with C10
side chains or free phenolic hydroxyl groups as well as
N-methylation led to total loss of activity.
Summing up, 3- and 4-alkoxy-substituted benzylamines
bearing N-isooctyl residues as mimetics of the ergosterol side
chain are an interesting lead structure for development of
new antimycotics with a broad range of variation of the ether
substituents.
Figure 1. Potent squalene epoxidase inhibitors.
Sodium triacetoxyborohydride was chosen because it showed
no reaction with nitro or cyano substituents and it is less
poisonous than sodium cyanoborohydride. The resulting
amines 3a–o were precipitated by hydrogen chloride
gas [10] from diethyl ether to give the corresponding
hydrochlorides 4a–o (Scheme 1).
In a second series, 3- and 4-hydroxy benzaldehyde (5a, 5b)
were etherified with alkyl or arylalkyl bromides to give the
ethers 6a–r. Following the above-described procedure, these
aldehydes were converted into the secondary amines 7a–r and
precipitated to give the corresponding hydrochlorides 8a–r
(Scheme 2). Exemplarily the three compounds 7a, 7b, and 7d
were N-methylated with formaldehyde and sodium cyano
borohydride [15] to give the tertiary amines 9a, 9b, and 9d
and their corresponding hydrochlorides 10a, 10b, and 10d
(Scheme 3) because the antimycotic activity of known
benzylamines increased upon N-methylation.
Experimental
Chemistry
General
All solvents used were of HPLC grade or p.a. grade and/or
purified according to standard procedures. Chemical reagents
were purchased from Sigma–Aldrich (Schnelldorf, Germany)
and Acros (Geel, Belgium). IR-spectra: Jasco FT/IR 4600 series
with ATR (ZnS); MS: Hewlett Packard MS-Engine, electron
ionization (EI) 70 eV, chemical ionization (CI) with CH4
(300 eV); GC-MS: Shimadzu GC17A, carrier gas: He, column:
fused silica capillary column 30 m, detector: MS EI (70 eV).
LC-MS (ESI) NMR: Avance III HD 400 MHz Bruker BioSpin (1H:
400 MHz, 13C: 100 MHz); 500 MHz Avance III HD 500 MHz
Bruker BioSpin (1H: 500 MHz, 13C: 125 MHz); melting points:
Biology
The resulting compounds were tested in an agar diffusion
assay against three bacteria (gram-positive bacterium:
Staphylococcus equorum, gram-negative bacteria: Escherichia
coli, Pseudomonas marginalis) and four fungi (mold:
Aspergillus niger, yeasts: Yarrowia lipolytica, Candida
glabrata, dermatophyte: Hyphopichia burtonii). The anti
microbial activity was compared to tetracycline hydrochlo-
ride, clotrimazole, and terbinafine (Table 1). All compounds
that showed any activity in this pre-test were further
evaluated in the microdilution assay and their minimal
inhibitory concentration (MIC) was determined against C.
glabrata and H. burtonii (Table 2). Both assays were
performed according to the German industry norm
(DIN) [16]. Exemplarily the cytotoxicity of the compounds
8d, 8f, 8i, 8q, 8r and terbinafine hydrochloride was
€
Buchi Melting Point B-540 (not corrected); flash column
chromatography (FCC): silica gel 60 (230–400 mesh; E. Merck,
Darmstadt).
The InChI codes of the investigated compounds are
provided as Supporting Information.
General procedure I
In 40 mL dry THF, 4.5 mmol of the aldehyde and 6.4 mmol
of 6-methylheptan-2-amine were dissolved, and 2.76 g
(13.0 mmol) sodium triacetoxyborhydride was added. The
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Scheme 1. Synthesis of compounds 4a–o. Reagents and conditions: (a) THF, NaB(OAc)3H, (b) Et2O.
suspension was stirred under N2 atmosphere for 12 h. Then it
was quenched with 30 mL saturated aqueous NaHCO3
solution and extracted with diethyl ether (3 ꢁ 30 mL). The
combined organic layers were dried over Na2SO4 and the
solvent was evaporated. The residue was purified by flash
column chromatography (isohexane/ethyl acetate/trimethyl-
amine 2:1:0.1).
were dissolved and the suspension was refluxed for 5 h. The
solvent was evaporated and the residue was dissolved in
50 mL of diethyl ether/2 M aqueous HCl (1:1). The aqueous
layer was again extracted with diethyl ether (2 ꢁ 25 mL), and
the combined organic layers were dried over Na2SO4 and the
solvent was evaporated. The residue was purified by flash
column chromatography (isohexane/ethyl acetate 4:1).
General procedure II
General procedure IV
Of the amine, 1.0 mmol was dissolved in 20 mL dry diethyl
ether and the solution was flushed with HCl gas for 2 min. The
solvent was evaporated and the residue was suspended in dry
diethyl ether. After 5 h at 0°C the precipitate was collected
and dried in vacuo. In some cases only an oily product could be
collected after evaporation of the solvent. These oils were
dried in vacuo. If necessary the crude oil was purified by
RP-flash column chromatography (solvent: methanol).
In 15 mL acetonitrile, 5.0 mmol of the amine was dissolved, and
25 mmol formaldehyde (2 mL 37% aqueous formaldehyde
solution) and 500 mg (8.00 mmol) sodium cyanoborohydride
were added. The suspension was stirred for 15 min, then glacial
acetic acid was addedto adjust pH7 andthe mixture was stirred
foranother60 min. Thesolventwasevaporatedandtheresidue
was dissolved in 20 mL 10% aqueous potassium hydroxide
solution and 20 mL diethyl ether. The aqueous layer was
extracted with diethyl ether, the combined organic layers were
driedoverNa2SO4, andthesolventwasevaporated. Theresidue
was purified by flash column chromatography (isohexane/ethyl
acetate/trimethylamine 2:1:0.1) [15].
General procedure III
In 50 mL dry acetone, 10.0 mmol of the phenols 5a or 5b,
15.0 mmol of the alkyl bromide, and 2.8 g (20 mmol) K2CO3
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Scheme 2. Synthesis of compounds 8a–r. Reagents
and conditions: (a) acetone, (b) THF, (c) Et2O.
(ꢀ)-N-(2-Chlorobenzyl)-6-methylheptan-2-amine (3a)
The compound was prepared according General proce-
dure I from 633 mg (4.5 mmol) 2-chlorobenzaldehyde and
822 mg (6.4 mmol) 6-methylheptan-2-amine to give
455 mg (40%) of 3a as colorless oil. 1H NMR (500 MHz,
CDCl3) d 7.39 (dd, J ¼ 7.3, 1.9 Hz, 1 H, arom. CH), 7.35 (dd,
J ¼ 7.7, 1.5 Hz, 1 H, arom. CH), 7.23 (td, J ¼ 7.4, 1.6 Hz, 1 H,
arom. CH), 7.19 (td, J ¼ 7.5, 1.9 Hz, 1 H, arom. CH), 3.91 (d,
J ¼ 13.5 Hz, 1 H, CH2), 3.83 (d, J ¼ 13.6 Hz, 1 H, CH2), 2.68–
2.60 (m, 1 H, CH), 1.51 (m, 1 H, CH), 1.48–1.40 (m, 1 H, CH2),
1.34–1.27 (m, 3 H, 2 CH2), 1.12 (m, 2 H, CH2), 1.09 (d,
J ¼ 6.3 Hz, 3 H, CH3), 0.86 (d, J ¼ 7.1 Hz, 3 H, CH3), 0.86 (d,
J ¼ 7.1 Hz, 3 H, CH3). 13C NMR (125 MHz, CDCl3) d 138.10
(quat. C), 133.76 (quat. C), 130.34 (arom. CH), 129.50
(arom. CH), 128.22 (arom. CH), 126.79 (arom. CH), 52.32
(CH), 48.96 (CH2), 39.10 (CH2), 37.32 (CH2), 27.96 (CH),
23.72 (CH2), 22.65 (CH3), 22.58 (CH3), 20.37 (CH3). MS (EI):
m/z (%) ¼ 252 (Mþꢂ1, 0.8), 238 (9), 170 (60), 168 (100), 125
(ꢀ)-N-(2-Chlorobenzyl)-6-methylheptan-2-aminium
chloride (4a)
The compound was prepared according to General procedure II
from 200mg (0.8 mmol) of 3a to give 170mg (74%) of 4a as a
white solid. M.p. 124°C (diethyl ether). 1H NMR (500 MHz,
CD2Cl2) d 9.92 (s, 1 H, NH), 9.68 (s, 1 H, NH), 8.01–7.92 (m, 1 H,
arom. CH), 7.38–7.31 (m, 1 H, arom. CH), 7.28–7.17 (m, 2 H, 2
arom. CH), 4.21–3.98 (m, 2 H, CH2), 2.93 (m, 1 H, CH), 1.91–1.75
(m, 1 H, CH2), 1.61–1.49 (m, 1 H, CH), 1.41 (m,1 H, CH2), 1.34–1.24
(m,1H,CH2),1.31(d,J ¼ 6.6 Hz,3H,CH3),1.22–1.12(m,1H,CH2),
1.11–1.01 (m, 2 H, CH2), 0.77 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(125 MHz, CD2Cl2) d 134.78 (quat. C), 132.61 (arom. CH), 130.56
(arom. CH), 129.76 (arom. CH), 129.04 (quat. C), 127.46 (arom.
CH), 53.31 (CH), 43.76(CH2), 38.37(CH2), 32.89(CH2), 27.80(CH),
23.46 (CH2), 22.30 (CH3), 22.16 (CH3), 16.02 (CH3). MS: calcd. for
C
15H25Nþ: 254.1675. Found: 254.1680.
(ꢀ)-N-(4-Chlorobenzyl)-6-methylheptan-2-amine (3b)
The compound was prepared according General procedure I
from 4-chlorobenzaldehyde and 822mg (6.4 mmol)
(79). HR-MS: calcd. for
252.1502.
C15H23ClN: 252.1519. Found:
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Scheme 3. Synthesis of compounds 10a,b,d. Reagents and conditions: (a) acetonitrile, (b) diethyl ether.
Table 1. Agar diffusion assay.
P.
S.
Y.
Log P
E. coli
marginalis
equorum
lipolytica
C. glabrata
A. niger
H. burtonii
3o
3a
3b
3c
3d
3e
3f
3g
3h
3i
4.32
4.88
4.88
5.44
5.44
4.11
5.15
3.95
3.95
3.95
4.57
3.93
3.81
3.81
4.36
4.32
5.86
5.93
6.25
6.21
5.02
5.44
5.86
6.27
7.94
5.86
5.93
6.25
6.21
5.02
5.44
5.86
6.27
7.94
12
0
0
0
0
0
0
0
0
0
7
10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
27
10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
27
0
0
10
0
0
0
0
0
0
0
0
0
0
0
0
0
nt
nt
nt
nt
nt
0
0
10
7
0
0
9
0
0
9
0
8
0
0
0
10
0
0
0
0
0
0
0
19
18
nt
0
0
0
16
11
0
7
7
0
0
6
0
8
0
0
0
0
0
0
0
0
0
0
0
23
25
nt
12
nt
16
10
6
0
7
10
8 (GI)
10 (GI)
0
10 (GI)
15 (GI)
0
10
0
0
10
0
0
9
0
0
0
0
0
0
0
10
11
nt
12
nt
20
11
8
3j
3k
3l
3m
3n
3o
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
0
0
23
27
nt
11
17
15
13
8
10
7
0
0
0
0
10
nt
nt
9
14
11
13
10
0
14
11
nt
12
17
15
10
11
0
15
15
nt
10
15
15
12
14
0
15
14
nt
11
18
13
10
10
0
7l
nt
15
7m
7n
7o
7p
7q
7r
15
12
0
Tetracycline ꢂ3.85
26
0
0
0
0
HCl
(base)
5.52
(base)
5.19
Terbinafine
HCl
Clotrimazole
0
0
0
0
0
7
18
10
10 (GI)
13
35
14
14
11
Notes: 50 mg/disc, diameter of in total inhibition [mm]; GI, growth inhibition; nt, not tested; 0, no inhibition. Log P-values of the
free amines were calculated with ChemDrawProfessional 16.0.
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Table 2. MIC values against C. glabrata and H. burtonii.
MIC (mg/mL)
MIC (mg/mL)
Compound
C. glabrata
H. burtonii
Compound
C. glabrata
H. burtonii
4a
4b
4c
4d
4e
4f
4g
4h
50
50
50
38
50
nt
nt
nt
8d
8e
8f
8g
8h
8h
8i
10
38
10
12.5
3.8
25
>50
13
19
10
10
12.5
10
nt
56
44
>50
nt
5
50
12.5
>50
11
>50
>50
50
8k
8l
3i
nt
5
4j
4k
4o
8a
8b
8c
50
nt
nt
nt
25
56
10
nt
8m
8n
8o
8p
8r
10
25
10
5
10
5
2.5
5
>50
nt
>50
>50
19
50
25
2.5
>50
10
Clotrimazole
Terbinafine
Fluconazole [17]
1–4
10
6-methylheptan-2-amine to give 501 mg (44%) of 3b as a
colorless oil. H NMR (500 MHz, CDCl3) d 7.22–7.16 (m, 4 H, 4
13C NMR (125 MHz, CD2Cl2) d 135.14 (quat. C), 132.06 (2 arom.
CH), 129.45 (quat. C), 129.03 (2 arom. CH), 52.43 (CH), 46.41
(CH2), 38.38 (CH2), 32.83 (CH2), 27.82 (CH), 23.77 (CH2), 22.29
(CH3), 22.15 (CH3), 15.68 (CH3). IR (KBr): n [cmꢂ1] ¼ 3441, 2954,
1577, 1496, 1096, 968, 718. HR-MS: calcd. for C15H25ClNþ:
254.1676. Found: 254.1681.
1
aromat. CH), 3.71 (d, J ¼ 13.3 Hz, 1 H, CH2), 3.63 (d, J ¼ 13.3 Hz, 1
H, CH2), 2.57 (m, 1 H, CH), 1.50–1.41 (m, 1 H, CH), 1.39–1.20 (m, 4
H, 2 CH2), 1.08 (m, 2 H, CH2), 0.99 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.79 (d,
J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (100 MHz, CDCl3) d 139.44 (quat.
C), 132.46 (quat. C), 129.45 (2 arom. CH), 128.46 (2 arom. CH),
52.51 (CH), 50.65 (CH2), 39.14 (CH2), 37.33 (CH2), 27.95 (CH),
23.72 (CH2), 22.66 (CH3), 22.58 (CH3), 20.33 (CH3). MS (EI): m/z
(%)¼ 253 (Mþ, 0.3), 252 (Mþ, 0.4), 168 (100), 125 (96). HR-MS:
calcd. for C15H24NCl: 253.1597. Found: 253.1586.
(ꢀ)-N-(2,6-Dichlorobenzyl)-6-methylheptan-2-amine (3c)
The compound was prepared according General procedure I
from 783 mg (4.5 mmol) 2,6-dichlorobenzaldehyde and
827 mg (6.4 mmol) 6-methylheptan-2-amine to give 452 mg
(35%) of 3c as a pale yellow oil. 1H NMR (500 MHz, CDCl3) d
7.22 (d, J ¼ 8.0 Hz, 2 H, 2 arom. CH), 7.07–7.02 (m, 1 H, arom.
CH), 4.01 (d, J ¼ 12.6 Hz, 1 H, CH2), 3.96 (d, J ¼ 12.6 Hz, 1 H,
CH2), 2.56 (h, J ¼ 6.1 Hz, 1 H, CH), 1.45 (dq, J ¼ 13.3, 6.6 Hz, 1 H,
CH), 1.41–1.17 (m, 4 H, 2 CH2), 1.05 (d, J ¼ 5.9 Hz, 3 H CH3),
1.08–1.04 (m, 2 H, CH2), 0.78 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(125 MHz, CDCl3) d 136.27 (quat. C), 135.90 (2 quat. C), 128.72
(arom. CH), 128.38 (2 arom. CH), 52.41 (CH), 46.19 (CH2), 39.03
(CH2), 37.20 (CH2), 27.97 (CH), 23.74 (CH2), 22.64 (CH3), 22.59
(CH3), 20.66 (CH3). MS (EI): m/z (%) ¼ 287 (Mþ, 0.33), 286 (0.5),
272 (4), 204 (64), 202 (100), 161 (55), 159 (76). HR-MS: calcd. for
(ꢀ)-N-(4-Chlorobenzyl)-6-methylheptan-2-aminium
chloride (4b)
The compound was prepared according to General procedure
II from 186 mg (0.74 mmol) of 3b to give 151 mg (71%) 4b as a
white solid. M.p. 190°C (diethyl ether). 1H NMR (400 MHz,
DMSO-d6) d 9.33 (s, 1 H, NH), 9.19 (s, 1 H, NH), 7.69 (d,
J ¼ 8.3 Hz, 2 H, 2 arom. CH), 7.56 (d, J ¼ 8.3 Hz, 2 H, 2 arom. CH),
4.37–3.98 (m, 2 H, CH2), 3.21–3.07 (m, 1 H, CH), 1.90–1.76 (m, 1
H, CH), 1.55 (dt, J ¼ 13.1, 6.5 Hz, 2 H, CH2), 1.46–1.36 (m, 1 H,
CH2), 1.33 (d, J ¼ 6.5 Hz, 3H, CH3), 1.24–1.31 (m, 1 H, CH2), 1.20
(dt, J ¼ 6.6 Hz, J ¼ 2 H, CH2), 0.91 (d, J ¼ 6.6 Hz, 6 H, 2 CH3).
C
15H23NCl2: 287.1208. Found: 287.1186.
(ꢀ)-N-(2,6-Dichlorobenzyl)-6-methylheptan-2-aminium
chloride (4c)
Table 3. IC50 values against HL-60 cell line.
The compound was prepared according to General procedure
II from 287 mg (1.0 mmol) of 3c to give 230 mg (71%) 4c as a
white solid. M.p. 126°C. 1H NMR (400 MHz, CD2Cl2) d 9.81 (s, 1
H, NH), 9.35 (s, 1 H, NH), 7.35–7.20 (m, 3 H, 3 arom. CH), 4.26
(t, J ¼ 5.7 Hz, 2 H, CH2), 3.20–3.08 (m, 1 H, CH), 1.93–1.77 (m, 1
H, CH2), 1.64–1.49 (m, 1 H, CH2), 1.44 (hept, J ¼ 6.7 Hz, 1 H, CH),
1.33 (d, J ¼ 6.6 Hz, 3 H, CH3), 1.29–1.01 (m, 4 H, 2 CH2), 0.79 (d,
Compound
IC50 (mM)
Compound
IC50 (mM)
8d
8f
8i
13
18
11
8r
8q
6
13
47
Terbinafine
HCl
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J ¼ 6.6 Hz, 6 H, 3 CH3). 13C NMR (101 MHz, CD2Cl2) d 137.09
(2 quat. C), 135.88 (quat. C), 131.39 (arom. CH), 128.66 (2
arom. CH), 55.26 (CH), 42.26 (CH2), 38.37 (CH2), 32.58 (CH2),
27.85 (CH), 23.76 (CH2), 22.32 (CH3), 22.17 (CH3), 15.85 (CH3). IR
(KBr): n [cmꢂ1] ¼ 3390, 1581, 1564, 1435, 1390, 1091, 1031, 984,
791, 766. HR-MS: calcd. for C15H24NCl2þ: 288.1286. Found:
288.1294.
J ¼ 6.3 Hz, 3H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(100 MHz, CDCl3) d 139.64 (quat. C), 132.79 (arom. CH), 130.51
(arom. CH), 128.52 (arom. CH), 127.43 (arom. CH), 124.02
(quat. C), 52.30 (CH), 51.33 (CH2), 39.10 (CH2), 37.31 (CH2),
27.96 (CH), 23.75 (CH2), 22.67 (CH3), 22.59 (CH3), 20.36 (CH3).
MS (EI): m/z (%) ¼ 299 (Mþ, 0.2), 298 (Mþꢂ1, 0.4), 297 (Mþ,
0.2), 296 (Mþꢂ1, 0.4), 214 (100), 169 (69). HR-MS: calcd. for
C15H24BrN: 297.1092. Found: 297.1058.
(ꢀ)-N-(2,3-Dichlorobenzyl)-6-methylheptan-2-amine (3d)
The compound was prepared according to General procedure
I from 783 mg (4.5 mmol) 2,3-dichlorobenzaldehyde and
827 mg (6.4 mmol) 6-methylheptan-2-amine to give 581 mg
(45%) of 3d as a colorless oil. 1H NMR (500 MHz, CDCl3) d 7.29
(dd, J ¼ 7.8, 1.5 Hz, 1 H, arom. CH), 7.25 (dd, J ¼ 7.8, 1.5 Hz, 1 H,
arom. CH), 7.10 (t, J ¼ 7.8 Hz, 1 H, arom. CH), 3.86 (d,
(ꢀ)-N-(2-Bromobenzyl)-6-methylheptan-2-aminium
chloride (4e)
The compound was prepared according to General procedure
II from 300 mg (1.0 mmol) of 3e to give 280 mg (84%) of 4e as a
solid. M.p. 92°C. 1H NMR (400 MHz, CDCl3) d 9.64 (s, 1 H, NH),
9.94 (s, 1 H, NH), 8.10 (dd, J ¼ 1.6 Hz, J ¼ 7.7 Hz, 1 H, 30-H), 7.59
(dd, J ¼ 8.0, 1.2 Hz, 1 H, 60-H), 7.37 (dt, J ¼ 7.7, 1.2 Hz, 1 H, 40-H),
7.21 (dt, J ¼ 8.0, 1.6 Hz, 1 H, 50-H), 4.26 (t, J ¼ 4.9 Hz, 2 H, CH2),
3.02 (m, 1 H, CH), 1.88–2.05 (m, 1 H, CH), 1.65 (m, 1 H), 1.61 (m,
2 H), 1.44 (d, J ¼ 6.6 Hz, 3 H, CH3), 1.55–1.45 (m, 1 H), 1.29–1.41
(m, 1 H), 1.17–1.30 (m, 1 H), 1.09–1.18 (m, 2 H, CH2), 0.84 (d,
J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (125 MHz, CDCl3) d 133.26
(arom. C), 132.50 (arom. CH), 130.84 (arom. CH), 130.47 (quat.
C), 128.33 (arom. CH), 125.06 (quat. C), 53.28 (CH), 46.59 (CH2),
38.35 (CH2), 33.03 (CH2), 27.78 (CH), 23.50 (CH2), 22.58 (CH3),
22.43 (CH3), 16.39 (CH3). HR-MS. calcd. for C15H25BrNþ:
298.1170. Found: 298.1163.
J ¼ 14.0 Hz,
1
H, CH2), 3.79 (d, J ¼ 14.0 Hz,
1 H, CH2),
2.63–2.50 (m, 1 H, CH), 1.51–1.41 (m, 1 H, CH), 1.40–1.34 (m,
1 H, CH2), 1.30–1.20 (m, 3 H, 2 CH2), 1.11–1.04 (m, 2 H, CH2),
1.02 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.79 (d, J ¼ 6.6 Hz, 6 H, 2 CH3).
13C NMR (100 MHz, CDCl3) d 140.60 (quat. C), 133.11 (quat. C),
131.85 (quat. C), 128.95 (arom. CH), 128.23 (arom. CH), 127.18
(arom. CH), 52.42 (CH), 49.53 (CH2), 39.09 (CH2), 37.32 (CH2),
27.96 (CH), 23.71 (CH2), 22.65 (CH3), 22.58 (CH3), 20.37 (CH3).
MS (EI): m/z (%) ¼ 289 (Mþ, 0.2), 288 (Mþꢂ1, 0.5), 287 (Mþ,
0.2), 286 (Mþꢂ1, 0.5), 272 (7) 274 (5), 204 (94), 202 (100), 159
(76). HR-MS: calcd. for C15H23NCl2: 287.1208. Found: 287.1198.
(ꢀ)-N-(2,3-Dichlorobenzyl)-6-methylheptan-2-aminium
chloride (4d)
(ꢀ)-N-(3-Bromobenzyl)-6-methylheptan-2-amine (3f)
The compound was prepared according to General procedure
I from 828 mg (4.5 mmol) 3-bromobenzaldehyde and 822 mg
(6.4 mmol) 6-methylheptan-2-amine to give 548 mg (41%) of
3f as a colorless oil. 1H NMR (400 MHz, CDCl3) d 7.49 (t,
J ¼ 1.6 Hz, 1 H, arom. CH), 7.37 (dt, J ¼ 7.7, 1.6 Hz, 1 H, arom.
CH), 7.25 (d, J ¼ 7.7 Hz, 1 H, arom. CH), 7.18 (t, J ¼ 7.7 Hz, 1 H,
arom. CH), 3.80 (d, J ¼ 13.4 Hz, 1 H, CH2), 3.71 (d, J ¼ 13.4 Hz, 1
H, CH2), 2.65 (tq, J ¼ 6.1 Hz, 1 H, CH), 1.53 (th, J ¼ 13.5, 6.7 Hz, 1
H, CH), 1.48–1.37 (m, 2 H, 2 CH2), 1.38–1.24 (m, 2 H, 2 CH2), 1.15
(m, 2 H, CH2), 1.07 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.87 (d, J ¼ 7.2 Hz, 6
H, 2 CH3). 13C NMR (100 MHz, CDCl3) d 143.39 (quat. C), 131.14
(arom. CH), 129.91 (arom. CH), 126.69 (arom. CH), 122.51
(arom. CH), 52.53 (CH), 50.77 (CH2), 39.14 (CH2), 37.31 (CH2),
27.96 (CH), 23.72 (CH2), 22.67 (CH3), 22.59 (CH3), 20.34 (CH3).
MS (EI): m/z (%) ¼ 299 (Mþ, 0.2), 298 (Mþꢂ1, 0.5), 297 (Mþ,
0.2), 296 (Mþꢂ1, 0.3), 284 (4), 214 (100), 169 (69). HR-MS: calcd.
for C15H24BrN: 297.1092. Found: 297.1099.
The compound was prepared according to General procedure
II from 287 mg (1.0 mmol) of 3d to give 285 mg (88%) 4d as a
white solid. M.p. 118°C. 1H NMR (400 MHz, CD2Cl2) d 9.98 (s, 1
H, NH), 9.76 (s, 1 H, NH), 7.90 (dd, J ¼ 7.9 Hz, J ¼ 1.5 Hz, 1 H,
arom. CH), 7.40 (dd, J ¼ 7.9, J ¼ 1.5 Hz, 1 H, arom. CH), 7.20 (t,
J ¼ 7.9 Hz, 1 H, arom. CH), 4.15 (m, 2 H, CH2), 2.95 (m, 1 H, CH),
1.90–1.76 (m, 1 H, CH2), 1.62–1.47 (m, 1 H, CH2), 1.42 (m, 1 H,
CH), 1.36–1.26 (m, 1 H, CH2), 1.31 (d, J ¼ 6.6 Hz, 3 H, CH3),
1.23–1.12 (m, 1 H, CH2), 1.11–0.99 (m, 2 H, CH2), 0.77 (d,
J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (100 MHz, CD2Cl2) d 133.47
(quat. C), 133.09 (quat. C), 131.36 (quat. C), 131.25 (arom. CH),
130.75 (arom. CH), 127.85 (arom. CH), 53.61 (CH), 44.50 (CH2),
38.37 (CH2), 32.89 (CH2), 27.80 (CH), 23.44 (CH2), 22.30 (CH3),
22.15 (CH3), 16.02 (CH3). HR-MS: calcd. for C15H24Cl2Nþ:
288.1286. Found: 288.1258.
(ꢀ)-N-(2-Bromobenzyl)-6-methylheptan-2-amine (3e)
The compound was prepared according to General procedure
I from 828 mg (4.5 mmol) 2-bromobenzaldehyde and 827 mg
(6.4 mmol) 6-methylheptan-2-amine to give 540 mg (40%) of
3e as a pale brown oil. 1H NMR (400 MHz, CDCl3) d 7.53 (dd,
J ¼ 7.8, 1.2 Hz, 1 H, 30-H), 7.39 (dd, J ¼ 7.7, 1.6 Hz, 1 H, 60-H),
7.27 (td, J ¼ 7.7 Hz, 1.2 Hz, 1 H, 50-H), 7.11 (td, J ¼ 7.7 Hz, 1.6 Hz,
1 H, 40-H), 3.89 (d, J ¼ 13.5 Hz, 1 H, CH2), 3.82 (d, J ¼ 13.5 Hz, 1
H, CH2), 2.65 (tq, J ¼ 6.1 Hz, J ¼ 6.1 Hz, 1 H, CH), 1.80 (s, 1 H,
NH), 1.53 (th, J ¼ 13.2, 6.6 Hz, 1 H, CH), 1.50–1.43 (m, 1 H, CH2),
1.35–1.26 (m, 3 H, 2 CH2), 1.19–1.11 (m, 2 H, CH2), 1.10 (d,
(ꢀ)-N-(3-Bromobenzyl)-6-methylheptan-2-aminium
chloride (4f)
The compound was prepared according to General procedure
II from 36 mg (0.12 mmol) of 3f to give 31 mg (78%) of 4f as a
pale brown solid. M.p. 162°C. 1H NMR (400 MHz, CD2Cl2) d
10.04 (s, 1 H, NH), 9.86 (s, 1 H, NH), 7.85 (t, J ¼ 1.8 Hz, 1 H, arom.
CH), 7.66 (d, J ¼ 7.9 Hz, 1 H, arom. CH), 7.50 (ddd, J ¼ 7.9 Hz,
J ¼ 1.8 Hz, J ¼ 0.9 Hz, 1 H), 7.30 (t, J ¼ 7.9 Hz, 1 H, arom. CH),
4.06–3.88 (m, 2 H, CH2), 3.00–2.84 (m, 1 H, CH), 1.95–1.82 (m, 1
H, CH2), 1.70–1.57 (m, 1 H, CH2), 1.51 (m, 1 H, CH), 1.43–1.33
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(m, 1 H, CH2), 1.37 (d, J ¼ 6.5 Hz, 3 H, CH3), 1.31–1.19 (m, 1 H,
CH2), 1.18–1.11 (m, 2 H, CH2), 0.85 (d, J ¼ 6.6 Hz, 3 H, CH3), 0.85
(d, J ¼ 6.6 Hz, 3 H, CH3. 13C NMR (100 MHz, CD2Cl2) d 134.75
(arom. CH), 134.28 (quat. C), 133.60 (arom. CH), 131.86 (arom.
CH), 130.61 (arom. CH), 123.93 (quat. C), 53.81 (CH), 47.79
(CH2), 39.68 (CH2), 34.14 (CH2), 29.13 (CH), 24.66 (CH2), 23.63
(CH3), 23.47 (CH3), 17.08 (CH3). HR-MS: calcd. for C15H25NBr:
298.1170. Found: 298.1181.
CH2), 2.60 (tq, J ¼ 6.1 Hz, 1 H, CH), 1.95–1.85 (m, 1 H, CH2),
1.73–1.63 (m, 1 H, CH2), 1.54–1.44 (m, 1 H, CH), 1.41 (d,
J ¼ 6.5 Hz, 3 H, CH3), 1.39–1.33 (m, 1 H, CH2), 1.27–1.18 (m, 1 H,
CH2), 1.15–1.08 (m, 2 H, CH2), 0.83 (d, J ¼ 6.6, Hz, 3 H, CH3), 0.83
(d, J ¼ 6.6 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3) d 158.43
(quat. C), 128.62 (arom. CH), 128.06 (arom. CH), 123.05 (quat.
C), 118.87 (arom. CH), 116.43 (arom. CH), 52.57 (CH), 50.04
(CH2), 39.00 (CH2), 36.95 (CH2), 27.89 (CH), 23.59 (CH2), 22.63
(CH3), 22.56 (CH3), 19.79 (CH3). MS (EI): m/z (%) ¼ 264 (Mþ,
0.1), 263 (Mþꢂ1, 0.6), 249 (6), 179 (100), 136 (64). HR-MS: calcd.
for C15H24N2O2: 264.183778. Found: 264.1846.
(ꢀ)-6-Methyl-N-(2-nitrobenzyl)heptan-2-amine (3g)
The compound was prepared according to General procedure
I from 682 mg (4.5 mmol) 2-nitrobenzaldehyde and 822 mg
(6.4 mmol) 6-methylheptan-2-amine to give 632 mg (53%) of
3g as a pale yellow oil. 1H NMR (400 Hz, CDCl3) d 7.93 (dd,
J ¼ 8.1 Hz, J ¼ 1.2 Hz, 1 H, 3-H), 7.63 (dd, J ¼ 7.7 Hz, J ¼ 1.2 Hz, 1
H, 6-H), 7.57 (td, J ¼ 7.5, 1.3 Hz, 1 H, arom. CH), 7.38 (dt,
J ¼ 7.7 Hz, J ¼ 1.7 Hz, 1 H, arom. CH), 4.06 (d, J ¼ 14.1 Hz, 1 H,
CH2), 3.97 (d, J ¼ 14.1 Hz, 1 H, CH2), 2.66 (m, 1 H, CH), 1.47 (m, 2
H, CH2), 1.43 (m, 1 H, CH), 1.28 (m, 2 H, CH2), 1.19–1.11 (m, 2 H,
CH2), 1.08 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2
CH3). 13C NMR (101 MHz, CDCl3) d 149.25 (quat. C), 136.24
(quat. C), 133.09 (arom. CH), 131.49 (arom. CH), 127.81 (arom.
CH), 124.66 (arom. CH), 52.95 (CH), 48.33 (CH2), 39.11 (CH2),
37.40 (CH2), 27.95 (CH), 23.73 (CH2), 22.66 (CH3), 22.58 (CH3),
20.42 (CH3). HR-ESI-MS: calcd. for C15H25N2O2: 265.1916.
Found: 265.1914. IR (KBr): n [cmꢂ1] ¼ 2955, 2929, 1527,
1468, 1349, 1158, 1046, 784, 728.
(ꢀ)-6-Methyl-N-(3-nitrobenzyl)heptan-2-aminium
chloride (4h)
The compound was prepared according to General procedure II
from260 mg(1.0 mmol)of3htogive245 mg(82%)4hasawhite
solid. M.p. 183°C. 1H NMR (500 MHz, CDCl3) d 10.06 (s, 1 H, NH),
9.89(s,1H,NH),8.39(t,J ¼ 1.8 Hz,1H,arom.CH),8.18–8.16(m,1
H, arom.CH), 8.15(t,J ¼ 2.0 Hz, 1H, arom.CH), 7.56(t, J ¼ 8.0 Hz,
1 H, arom. CH), 4.19–4.00 (m, 2 H, CH2), 3.01–2.73 (m, 1 H, CH),
1.89–1.79 (m, 1 H, CH), 1.67–1.56 (m, 2 H, CH2), 1.42 (dt, J ¼ 13.3,
6.6 Hz, 1 H, CH2), 1.35 (d, J ¼ 6.5 Hz, 3 H, CH3), 1.33–1.26 (m, 1 H,
CH2), 1.21–1.11 (m, 1 H, CH2), 1.09–1.02 (m, 2 H, CH2), 0.77 (dd,
J ¼ 6.6, 1.5 Hz, 6 H, 2 CH3). 13C NMR (125 MHz, CDCl3) d 148.31
(quat. C), 136.61 (arom. CH), 132.25 (quat. C), 130.39(arom.CH),
125.37 (arom. CH), 124.37 (arom. CH), 52.90 (CH), 46.54 (CH2),
38.35 (CH2), 32.91 (CH2), 27.79 (CH), 23.40 (CH2), 22.53 (CH3),
22.38 (CH3), 15.99 (CH3). IR (KBr): n [cmꢂ1] ¼ 2944, 2699, 2428,
þ
(ꢀ)-6-Methyl-N-(2-nitrobenzyl)heptan-2-aminium
1536, 1469, 1353, 734, 689. MS: calcd. for C15H25N2O2
265.1916. Found: 265.1918.
:
chloride (4g)
The compound was prepared according to General procedure
II from 264 mg (1.0 mmol) of 3g to give 271 mg (90%) of 4g as a
pale brown solid. M.p. 139°C. 1H NMR (400 MHz, CD2Cl2) d 9.87
(s, 1 H, NH), 9.62 (s, 1 H, NH), 8.15 (dd, J ¼ 8.2, 1.4 Hz, 1 H, arom.
CH), 8.01 (dd, J ¼ 7.5, 1.4 Hz, 1 H, arom. CH), 7.66 (td, J ¼ 7.5,
1.4 Hz, 1 H, arom. CH), 7.56 (ddd, J ¼ 8.2, 7.5, 1.4 Hz, 1 H, arom.
CH), 4.27 (m, 2 H, CH2), 3.12 (m, 1 H, CH). 1.93–1.81 (m, 1 H,
CH2), 1.62–1.47 (m, 2 H, CH, CH2), 1.44–1.32 (m, 1 H, CH2), 1.30
(d, J ¼ 6.6 Hz, 3 H, CH3), 1.23 (m, 1 H, CH2), 1.18 (m, 2 H, CH2),
0.88 (d, J ¼ 6.6, 3 H, CH3), 0.88 (d, J ¼ 6.6, 3 H, CH3). 13C NMR
(100 MHz, CD2Cl2) d 149.36 (quat. C), 135.03 (arom. CH), 134.46
(arom. CH), 130.93 (arom. CH), 126.88 (quat. C), 125.80 (arom.
CH), 55.56 (CH), 45.38 (CH2), 38.82 (CH2), 32.94 (CH2), 28.30
(CH), 23.96 (CH2), 22.75 (CH3), 22.58 (CH3), 16.21 (CH3). IR
(ꢀ)-6-Methyl-N-(4-nitrobenzyl)heptan-2-amine (3i)
The compound was prepared according to General procedure
I from 682 mg (4.5 mmol) 4-nitrobenzaldehyde and 822 mg
(6.4 mmol) 6-methylheptan-2-amine to give 582 mg (49%) of
3i as a pale yellow oil. 1H NMR (400 MHz, CDCl3) d 8.17 (d,
J ¼ 8.8 Hz, 2 H, 2 arom. CH), 7.51 (d, J ¼ 8.8 Hz, 2 H, 2 arom. CH),
3.93 (m, J ¼ 14.4 Hz, 1 H, CH2), 3.85 (d, J ¼ 14.4 Hz, 1 H, CH2),
2.73–2.58 (m, 1 H, CH), 1.54 (m, 1 H, CH), 1.41 (m, 1 H, CH2),
1.28 (m, 3 H, 2 CH2), 1.20–1.11 (m, 2 H, CH2), 1.08 (d, J ¼ 6.3 Hz,
3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (100 MHz,
CDCl3) d 148.99 (quat. C), 146.93 (quat. C), 128.61 (2 arom. CH),
123.57 (2 arom. CH), 52.80 (CH), 50.59 (CH2), 39.13 (CH2), 37.39
(CH2), 27.95 (CH), 23.72 (CH2), 22.65 (CH3), 22.58 (CH3), 20.40
(CH3). HR-ESI-MS: calcd. for C15H25N2O2: 265.191603. Found:
265.1914. IR (KBr): n [cmꢂ1] ¼ 2955, 2929, 2868, 1604, 1467,
1347, 1109, 857.
(KBr): n [cmꢂ1] ¼ 2951, 2869, 1572, 1529, 1469, 1345, 1127,
þ
1087, 990, 858, 792, 747, 696. HR-MS: calcd. for C15H25N2O2
265.1916. Found: 265.1915.
:
(ꢀ)-6-Methyl-N-(3-nitrobenzyl)heptan-2-amine (3h)
(ꢀ)-6-Methyl-N-(4-nitrobenzyl)heptan-2-aminium
chloride (4i)
The compound was prepared according to General procedure
I from 682 mg (4.5 mmol) 3-nitrobenzaldehyde and 822 mg
(6.4 mmol) 6-methylheptan-2-amine to give 523 mg (44%) of
3h as a pale brown oil. 1H NMR (400 MHz, CDCl3) d 8.15
(t, J ¼ 2.2 Hz, 1 H, arom. CH), 8.03 (ddd, J ¼ 8.2, 2.2, 1.1 Hz, 1 H,
arom. CH), 7.65–7.58 (m, 1 H), 7.41 (t, J ¼ 8.0 Hz, 1 H, arom.
CH), 3.86 (d, J ¼ 13.9 Hz, 1 H, CH2), 3.78 (d, J ¼ 13.8 Hz, 1 H,
The compound was prepared according to General procedure
II from 248 mg (0.93 mmol) of 3i to give 261 mg (93%) of 4i as a
pale dark white solid. M.p. 127°C (diethyl ether). 1H NMR
(400 MHz, CD2Cl2) d 10.18 (s, 1 H, NH), 10.00 (s, 1 H, NH), 8.22
(d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 7.91 (d, J ¼ 8.8 Hz, 2 H, 2 arom.
CH), 4.30–3.94 (m, 2 H, CH2), 3.07–2.75 (m, 1 H, CH), 1.93–1.83
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(m, 1 H, CH2), 1.68–1.58 (m, 1 H, CH2), 1.51 (th, J ¼ 6.6 Hz,
J ¼ 6.1 Hz, 1 H, CH), 1.43–1.33 (m, 1 H, CH2), 1.37 (d, J ¼ 6.5 Hz, 3
H, CH3), 1.30–1.18 (m, 1 H, CH2), 1.17–1.09 (m, 2 H, CH2), 0.85
(d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (100 MHz, CD2Cl2) d 149.73
(quat. C), 138.97 (quat. C), 132.90 (arom. CH), 125.21 (arom.
CH), 47.73 (CH2), 39.68 (CH2), 34.21 (CH2), 29.14 (CH), 24.68
(CH2), 23.58 (CH3), 23.44 (CH3), 17.07 (CH3). IR (KBr):
4-H), 4.02 (d, J ¼ 13.8 Hz, 1 H, CH2), 3.94 (d, J ¼ 13.9 Hz, 1 H,
CH2), 2.73 (tq, J ¼ 6.3, 6.3 Hz, 1 H, CH), 1.51 (m, 2 H, CH, CH2),
1.41–1.26 (m, 3 H, 2 CH2), 1.21–1.14 (m, 2 H, CH2), 1.14 (d,
J ¼ 6.4 Hz, 3 H, CH3), 0.87 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(100 MHz, CDCl3) d 158.43 (quat. C), 128.62 (arom. CH), 128.06
(arom. CH), 123.05 (quat. C), 118.87 (arom. CH), 116.43 (arom.
CH), 52.57 (CH), 50.04 (CH2), 39.00 (CH2), 36.95 (CH2), 27.89
(CH), 23.59 (CH2), 22.63 (CH3), 22.56 (CH3), 19.79 (CH3). MS (EI):
m/z (%) ¼ 235 (Mþ, 0.4), 220 (7), 150 (100), 107 (53). HR-ESI-MS:
calcd. for C15H26NO: 236.2014. Found: 236.2012. IR (KBr): n
[cmꢂ1] ¼ 2955, 2030, 2869, 1590, 1491, 1471, 1259, 1034, 754.
n [cmꢂ1] ¼ 2954, 2869, 1609, 1530, 1467, 1433, 1393, 1351,
þ
1340, 862, 843, 739, 681, 467. HR-MS: calcd. for C15H25N2O2
265.1916. Found: 265.1915.
:
(ꢀ)-N-(5-Chloro-2-nitrobenzyl)-6-methylheptan-2-amine
(3j)
(ꢀ)-N-(2-Hydroxybenzyl)-6-methylheptan-2-aminium
chloride (4k)
The compound was prepared according to General procedure
I from 833 mg (4.5 mmol) 5-chloro-2-nitrobenzaldehyde and
822 mg (6.4 mmol) 6-methylheptan-2-amine to give 628 mg
(47%) of 3j as a pale yellow oil. 1H NMR (400 MHz, CDCl3) d
7.85 (d, J ¼ 8.7 Hz, 1 H, 3-H), 7.66 (d, J ¼ 2.3 Hz, 1H, 6-H), 7.29
(dd, J ¼ 8.7, 2.3 Hz, 1 H, 4-H), 4.00 (d, J ¼ 15.0 Hz, 1 H, CH2), 3.92
(d, J ¼ 15.0 Hz, 1 H, CH2), 2.65–2.52 (m, 1 H, CH), 1.43 (m, 1 H,
CH), 1.34 (m, 1 H, CH2), 1.22 (m, 3 H, 2 CH2), 1.09 (m, 2 H, CH2),
1.01 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.80 (d, J ¼ 6.7 Hz, 6 H, 2 CH3).
13C NMR (125 MHz, CDCl3) d 139.68 (quat. C), 138.87 (quat. C),
131.13 (arom. CH), 127.78 (arom. CH), 126.19 (arom. CH, quat.
C), 53.15 (CH), 47.94 (CH2), 39.09 (CH2), 37.41 (CH2), 27.95 (CH),
23.75 (CH2) 22.65 (CH3), 22.57 (CH3), 20.47 (CH3). MS (EI): m/z
(%) ¼ 300 (Mþ, 0.1), 299 (Mþꢂ1, 0.3), 298 (Mþ, 0.1), 297
(Mþꢂ1, 0.3), 283 (6), 213 (100), 170 (76). HR-MS: calcd. for
The compound was prepared according to General procedure
II from 235 mg (1.0 mmol) of 3k to give 251 mg (93%) 4k as a
white solid. M.p. 144°C. 1H NMR (400 MHz, CD2Cl2) d 9.49 (s, 1
H, NH), 8.96 (s, 1 H, NH), 8.39 (s, 1 H, OH), 7.28–7.18 (m, 3 H, 3
arom. CH), 6.88 (m, 1 H, arom. CH), 4.22–3.85 (m, 2 H, CH2),
3.16–2.86 (m, 1 H, CH), 1.84–1.71 (m, 1 H, CH2), 1.58 (m, 1 H,
CH2), 1.49 (m, 1 H, CH), 1.39–1.26 (m, 1 H, CH2), 1.34 (d,
J ¼ 6.6 Hz, 3 H, CH3), 1.28–1.17 (m, 1 H, CH2), 1.15–1.07 (m, 2 H,
CH2), 0.84 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (100 MHz, CD2Cl2)
d 156.96 (quat. C), 132.81 (arom. CH), 132.31 (arom. CH),
121.90 (arom. CH), 119.04 (quat. C), 118.83 (arom. CH), 55.0
(CH), 46.30 (CH2), 39.61 (CH2), 34.47 (CH2), 29.08 (CH), 24.63
(CH2), 23.59 (CH3), 23.46 (CH3), 17.32 (CH3). IR (KBr):
n [cmꢂ1] ¼ 2956, 1607, 1530, 1470, 1436, 1161, 1034, 833.
HR-MS: calcd. for C15H26NOþ: 236.2014. Found: 236.2014.
C
15H22N2O2Cl [MþꢂH]: 297.1370. Found: 297.1330.
(ꢀ)-N-(5-Chloro-2-nitrobenzyl)-6-methylheptan-2-
aminium chloride (4j)
(ꢀ)-2-Methoxy-4-(((6-methylheptan-2-yl)amino)methyl)-
phenol (3l)
The compound was prepared according to General procedure
II from 300 mg (1.0 mmol) of 3j to give 289 mg (88%) of 4j as a
pale white solid. M.p. 169°C (diethyl ether). 1H NMR (400 MHz,
CD2Cl2) d 9.95 (s, 1 H, NH), 9.76 (s, 1 H, NH), 8.16 (d, J ¼ 8.8 Hz, 1
H, arom. CH), 8.05 (d, J ¼ 2.3 Hz, 1 H, arom. CH), 7.54 (dd,
J ¼ 8.8 Hz, J ¼ 2.3 Hz, 1 H, arom. CH), 4.27 (m, 2 H, CH2),
3.20–3.07 (m, 1 H, CH), 1.91–1.77 (m, 1 H, CH2), 1.60–1.46 (m, 2
H, CH, CH2), 1.44–1.34 (m, 1 H, CH2), 1.28 (d, J ¼ 6.6 Hz, 3 H,
CH3), 1.26–1.14 (m, 3 H, 2 CH2), 0.89 (d, J ¼ 8.7 Hz, 6 H, 2 CH3).
13C NMR (100 MHz, CD2Cl2) d 148.63 (quat. C), 141.51 (quat. C),
136.11 (arom. CH), 132.01 (arom. CH), 129.73 (quat. C), 128.32
(arom. CH), 56.81 (CH), 46.14 (CH2), 39.67 (CH2), 33.67 (CH2),
29.24 (CH), 24.84 (CH2), 23.65 (CH3), 23.48 (CH3), 17.16 (CH3). IR
(KBr): n [cmꢂ1] ¼ 2952, 1606, 1570, 1525, 1342, 1131, 1112, 913,
884, 857, 680. HR-MS: calcd. for C15H24ClN2O2þ: 299.1526.
Found: 299.1526.
The compound was prepared according to General procedure
I from 684 mg (4.5 mmol) vanillin and 822 mg (6.4 mmol)
6-methylheptan-2-amine to give 382 mg (32%) of 3l as a
colorless oil. 1H NMR (400 MHz, CDCl3) d 6.87–6.83 (m, 1 H),
6.82 (s, 1 H), 6.76 (dd, J ¼ 8.0, 1.8 Hz, 1 H), 3.85 (s, 3 H, CH3), 3.77
(d, J ¼ 12.7 Hz, 1 H), 3.67 (d, J ¼ 12.7 Hz, 1 H), 2.78–2.67 (m, 1 H,
CH), 1.51 (m, 2 H, CH2), 1.26–1.38 (m, 3 H, CH, CH2), 1.20 (m, 2
H, CH2), 1.11 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2
CH3). 13C NMR (100 MHz, CDCl3) d 146.76 (quat. C), 144.90
(quat. C), 131.43 (quat. C), 121.12 (arom. CH), 114.43 (arom.
CH), 111.04 (arom. CH), 55.79 (CH3), 52.66 (CH), 50.90 (CH2),
39.07 (CH2), 36.73 (CH2), 27.94 (CH), 23.75 (CH2), 22.65 (CH3),
22.56 (CH3), 19.77 (CH3). MS (EI): m/z (%) ¼ 265 (Mþ, 4), 180
(28), 137 (100). HR-MS: calcd. for C16H27O2N: 265.2042. Found:
265.2049. IR (KBr): n [cmꢂ1] ¼ 2954, 2930, 1517, 1466, 1279,
1158, 1037, 816.
(ꢀ)-2-(((6-Methylheptan-2-yl)amino)methyl)phenol (3k)
The compound was prepared according to General procedure
I from 540 mg (4.5 mmol) 2-hydroxybenzaldehyde and 822 mg
(6.4 mmol) 6-methylheptan-2-amine to give 645 mg (61%) of
3k as a colorless oil. 1H NMR (400 MHz, CDCl3) d 7.16 (td,
J ¼ 8.0, 1.7 Hz, 1 H, 5-H), 6.98 (dd, J ¼ 7.4, 1.3 Hz, 1 H, 3-H), 6.83
(dd, J ¼ 8.1, 1.0 Hz, 1 H, 6-H), 6.76 (td, J ¼ 7.4, 1.2 Hz, 1 H,
(ꢀ)-N-(4-Hydroxy-3-methoxybenzyl)-6-methylheptan-2-
aminium chloride (4l)
The compound was prepared according to General procedure
II from 265 mg (1.0 mmol) of 3l to give 210 mg (70%) of 4l as a
brown white solid. M.p. 104°C. 1H NMR (500 MHz, CDCl3) d
9.41 (s, 1 H, NH), 9.23 (s, 1 H, NH), 7.42 (s, 1 H, arom. CH), 6.84
(d, J ¼ 8.0 Hz, 1 H, arom. CH), 6.80 (d, J ¼ 8.0 Hz, 1 H, arom. CH),
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4.02–3.90 (m, 2 H, CH2), 3.89 (s, 3 H, OCH3), 2.79 (s, 1 H, CH),
1.81 (m, 2 H, CH2), 1.58 (m, 1 H, CH2), 1.41 (th, J ¼ 6.7 Hz,
J ¼ 6.8 Hz, 1 H, CH), 1.30 (d, J ¼ 6.5 Hz, 3 H, CH3), 1.17 (m, 1 H,
CH2), 1.04 (dt, J ¼ 6.2 Hz, J ¼ 8.5 Hz, 2 H, CH2), 0.76 (d,
J ¼ 6.7 Hz, 6 H, 2 CH3). 13C NMR (100 MHz, CDCl3) d 147.10
(quat. C), 146.47 (quat. C), 123.47 (arom. CH), 121.88 (quat. C),
114.27 (arom. CH), 112.81 (arom. CH), 56.42 (OCH3), 51.81
(CH), 47.45 (CH2), 38.35 (CH2), 32.89 (CH2), 27.78 (CH), 23.39
(CH2), 22.54 (CH3), 22.40 (CH3), 15.98 (CH3). HR-MS: calcd. for
(6.4 mmol) 6-methylheptan-2-amine to give 516 mg (47%) of
3n as a pale brown oil. 1H NMR (500 MHz, CDCl3) d 7.53 (d,
J ¼ 8.4 Hz, 2 H, 2 arom. CH), 7.38 (d, J ¼ 8.4 Hz, 1 H, 2 arom CH),
3.81 (d, J ¼ 14.1 Hz, 1 H, CH2), 3.74 (d, J ¼ 14.1 Hz, 1 H, CH2),
2.57 (tq, J ¼ 6.0 Hz, J ¼ 6.1 Hz, 1 H, CH). 1.46 (m, 1 H, CH),
1.41–1.32 (m, 1 H, CH2), 1.28–1.20 (m, 3 H, 2 CH2), 1.11–1.05 (m,
2 H, CH2), 1.00 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.80 (d, J ¼ 6.6 Hz, 6 H, 2
CH3). 13C NMR (125 MHz, CDCl3) d 146.80 (quat. C), 132.16 (2
arom. CH), 128.64 (2 arom. CH), 126.98 (quat. C), 119.03 (CN),
110.55 (quat. C), 52.73 (CH), 50.87 (CH2), 39.12 (CH2), 37.36
(CH2), 27.94 (CH2), 23.71 (CH2), 22.65 (CH3), 22.58 (CH3), 20.38
(CH3). MS (EI): m/z (%) ¼ 244 (Mþ, 0.3), 243 (0.5), 159 (100), 116
(76). HR-MS: calcd. for C16H24N2: 244.1939. Found: 244.1947. IR
(KBr): n [cmꢂ1] ¼ 3316, 2956, 2928, 2867, 2227, 1608, 1467,
1366, 1157, 1102.
C
16H28N2O2þ: 266.2120. Found: 266.2161.
(ꢀ)-2-Methoxy-5-(((6-methylheptan-2-yl)amino)methyl)-
phenol (3m)
The compound was prepared according to General procedure
I from 684 mg (4.5 mmol) 3-hydroxy-4-methoxybenzaldehyde
and 822 mg (6.4 mmol) 6-methylheptan-2-amine to give
394 mg (33%) of 3m as pale yellow oil. 1H NMR (400 MHz,
CDCl3) d 6.81 (t, J ¼ 1.1 Hz, 1 H, arom. CH), 6.72 (d, J ¼ 1.1 Hz, 2
H, 2 arom. CH), 3.79 (s, 3 H, CH3), 3.66 (d, J ¼ 12.9 Hz, 1 H, CH2),
3.57 (d, J ¼ 12.9 Hz, 1 H, CH2), 2.59 (tq, J ¼ 6.3 Hz, 1 H, CH), 1.42
(m, 1 H, CH), 1.34 (m, 1 H, CH2), 1.28–1.16 (m, 3 H, 2 CH2),
1.11–1.03 (m, 2 H, CH2), 1.00 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.79 (d,
J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (125 MHz, CDCl3) d 145.65
(quat. C), 145.62 (quat. C), 134.09 (quat. C), 119.57 (arom. CH),
114.63 (arom. CH), 110.60 (arom. CH), 55.99 (CH3), 52.28 (CH),
50.85 (CH2), 39.16 (CH2), 37.39 (CH2), 27.95 (CH), 23.66 (CH2),
22.67 (CH3), 22.59 (CH3), 20.21 (CH3). MS (EI): m/z (%) ¼ 265
(Mþ, 0.7), 180 (43), 137 (100). HR-MS: calcd. for C16H27NO2:
265.2042. Found: 265.2040.
(ꢀ)-N-(4-Cyanobenzyl)-6-methylheptan-2-aminium
chloride (4n)
The compound was prepared according to General procedure
II from 244 mg (1.0 mmol) of 3n to give 210 mg (75%) of 4n as
pale white solid. M.p. 157°C. 1H NMR (400 MHz, DMSO-d6) d
9.38 (s, 1 H, NH), 9.29 (s, 1 H, NH), 7.93 (d, J ¼ 8.5 Hz, 2 H, 2
arom. CH), 7.82 (d, J ¼ 8.4 Hz, 2 H, 2 arom. CH), 4.32–4.16 (m, 2
H, CH2), 3.19–3.06 (m, 1 H, CH), 1.75 (m, 1 H, CH), 1.57–1.44 (m,
2 H, CH2), 1.41–1.31 (m, 1 H, CH2), 1.30 (d, J ¼ 6.6 Hz, 3 H, CH3),
1.27–1.19 (m, 1 H, CH2), 1.13 (m, 2 H, CH2), 0.86 (d, J ¼ 7.7 Hz, 6
H, 2 CH3). 13C NMR (125 MHz, DMSO-d6) d 137.28 (quat. C),
131.82 (2 arom. CH), 130.33 (arom. CH), 117.92 (CN), 110.88
(quat. C), 53.01 (CH), 26.61 (CH), 21.90 (CH3), 21.72 (CH3), 14.91
(CH3). IR (KBr): n [cmꢂ1] ¼ 3419, 2956, 2746, 2238, 1583, 1449,
1390, 875, 846, 826. HR-MS: calcd. for C16H25N2þ: 245.2018.
Found: 245.2027.
(ꢀ)-N-(3-Hydroxy-4-methoxybenzyl)-6-methylheptan-2-
aminium chloride (4m)
The compound was prepared according to General procedure
II from 265 mg (1.0 mmol) of 3m to give 190 mg (63%) of 4m as
a pale white solid. M.p.: 92°C. 1H NMR (400 MHz, CD2Cl2) d 9.29
(s, 1 H, NH), 9.13 (s, 1 H, NH), 7.24 (d, J ¼ 2.1 Hz, 1 H, arom. CH),
7.02 (dd, J ¼ 8.2 Hz, J ¼ 2.1 Hz, 1 H, arom. CH), 6.82 (d,
J ¼ 8.2 Hz, 1 H, arom. CH), 5.17 (s, 1 H, OH), 3.95 (m, 2 H,
CH2), 3.80 (s, 3 H, CH3), 2.99 (m, 1 H, CH), 1.90–1.80 (m, 1 H,
CH2), 1.68–1.56 (m, 1 H, CH2), 1.46 (th, J ¼ 13.2, 6.6 Hz, 1 H, CH),
1.43–1.29 (m, 1 H, CH2), 1.35 (d, J ¼ 6.5 Hz, 3 H, CH3), 1.20 (m, 1
H, CH2), 1.18–1.07 (m, 2 H, CH2), 0.83 (d, J ¼ 6.6, 3 H, CH3), 0.83
(d, J ¼ 6.6, 3 H, CH3). 13C NMR (125 MHz, CD2Cl2) d 149.15
(quat. C), 147.47 (quat. C), 124.58 (quat. C), 123.58 (arom. CH),
117.80 (arom. CH), 112.48 (arom. CH), 57.14 (CH3), 53.55 (CH),
48.39 (CH2), 39.68 (CH2), 34.16 (CH2), 29.11 (CH), 24.67 (CH2),
23.61 (CH3), 23.47 (CH3), 17.09 (CH3). IR (KBr): n [cmꢂ1] ¼ 3358,
2927, 1595, 1514, 1454, 1389, 1366, 1249, 1165, 1131, 1033.
HR-MS: calcd. for C16H28NO2þ: 266.2120. Found: 266.2125.
(ꢀ)-N-Benzyl-6-methylheptan-2-amine (3o)
The compound was prepared according to General procedure
I
from 497 mg (4.7 mmol) benzaldehyde and 822 mg
(6.4 mmol) 6-methylheptan-2-amine to give 728 mg (71%)
of 3o as a colorless oil. 1H NMR (400 MHz, CDCl3) d 7.31 (m, 4 H,
4 arom. CH), 7.25–7.21 (m, 1 H, arom. CH), 3.83 (d, J ¼ 12.9 Hz,
1 H, CH2), 3.74 (d, J ¼ 12.9 Hz, 1 H, CH2), 2.67 (tq, J ¼ 6.2 Hz, 1 H,
CH), 1.53 (m, 1 H, CH), 1.48–1.41 (m, 1 H, CH2), 1.30 (m, 3 H, 2
CH2), 1.19–1.11 (m, 2 H, CH2), 1.08 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.86
(d, J ¼ 6.6, 3 H, CH3), 0.86 (d, J ¼ 6.6, 3 H, CH3). 13C NMR
(100 MHz, CDCl3) d 140.92 (quat. C), 128.38 (2 arom. CH),
128.13 (2 arom. CH), 126.80 (arom. CH), 52.52 (CH), 51.45
(CH2), 39.17 (CH2), 37.35 (CH2), 27.96 (CH), 23.74 (CH2), 22.67
(CH3), 22.59 (CH3), 20.35 (CH3). MS (EI): m/z (%) ¼ 219 (Mþ,
0.4), 218 (0.4), 204 (5), 134 (100), 106 (6).
(ꢀ)-N-(Benzyl)-6-methylheptan-2-aminium chloride (4o)
The compound was prepared according to General procedure
II from 512 mg (2.34 mmol) of 3o to give 470 mg (79%) of 4o as
white solid. M.p. 131°C. 1H NMR (500 MHz, CD2Cl2) d 7.61–7.56
(m, 2 H, 2 arom. CH), 7.41–7.35 (m, 2 H, 2 arom. CH), 7.35–7.29
(ꢀ)-4-(((6-Methylheptan-2-yl)amino)methyl)benzonitrile
(3n)
The compound was prepared according to General procedure
I from 590 mg (4.5 mmol) 4-cyanobenzaldehyde and 822 mg
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(m, 1 H, arom. CH), 3.99 (d, J ¼ 13.5 Hz, 1 H, CH2), 3.91 (d,
J ¼ 13.5 Hz, 1 H, CH2), 2.86 (m, 1 H, CH), 1.86–1.76 (m, 1 H, CH2),
1.63–1.53 (m, 1 H, CH2), 1.49 (tq, J ¼ 13.3, 6.5 Hz, 1 H, CH),
1.40–1.32 (m, 1 H, CH2), 1.30 (d, J ¼ 6.5 Hz, 3 H, CH3), 1.28–1.18
(m, 1 H, CH2), 1.13 (m, 2 H, CH2), 0.85 (d, J ¼ 6.6, 3 H, CH3), 0.85
(d, J ¼ 6.6, 3 H, CH3). 13C NMR (100 MHz, CD2Cl2) d 132.87
(quat. C), 129.97 (2 arom. CH), 128.72 (2 arom. CH), 128.55
(arom. CH), 52.20 (CH), 47.87 (CH2), 38.55 (CH2), 33.73 (CH2),
27.83 (CH), 23.43 (CH2), 22.31 (CH3), 22.19 (CH3), 16.59 (CH3).
HR-MS: calcd. for C15H26Nþ: 220.2066. Found: 220.2065.
3-(Propyloxy)benzaldehyde (6e)
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 3-hydroxybenzaldehyde and 2.55 g
(15.0 mmol) n-propyl iodide to give 902 g (55%) of 6e as a
colorless oil. 1H NMR (500 MHz, CDCl3) d 9.97 (s, 1 H, CHO),
7.46–7.42 (m, 2 H, 2 arom. CH), 7.39 (d, J ¼ 2.0 Hz, 1 H, arom.
CH), 7.20–7.15 (m, 1 H, arom. CH), 3.99 (t, J ¼ 6.6 Hz, 2 H, CH2),
1.84 (tq, J ¼ 6.6 Hz, J ¼ 7.4 Hz, 2 H, CH2), 1.05 (t, J ¼ 7.4 Hz, 3 H,
CH3). 13C NMR (100 MHz, CDCl3) d 192.21 (CHO), 159.72 (quat.
C), 137.78 (quat. C), 129.99 (arom. CH), 123.29 (arom. CH),
121.96 (arom. CH), 112.80 (arom. CH), 69.80 (CH2), 22.48 (CH2),
10.49 (CH3).
3-Phenoxybenzaldehyde (6a)
The compound was purchased from Sigma–Aldrich.
3-(Butyloxy)benzaldehyde (6f)
3-Benzyloxybenzaldehyde (6b)
The compound was prepared according to General procedure
III from 488 mg (4.0 mmol) 3-hydroxybenzaldehyde and
726 mg (4.0 mmol) n-butyl iodide to give 166 mg (23%) of
6f as a colorless oil. 1H NMR (500 MHz, CDCl3) d 9.97 (s, 1 H,
CHO), 7.46–7.42 (m, 2 H, 2 arom. CH), 7.39 (d, J ¼ 2.2 Hz, 1 H,
arom. CH), 7.17 (dt, J ¼ 5.8, 2.9 Hz, 1 H, arom. CH), 4.03 (t,
J ¼ 6.5 Hz, 2 H, CH2), 1.83–1.75 (m, 2 H, CH2), 1.51 (h, J ¼ 7.4 Hz,
2 H, CH2), 0.99 (t, J ¼ 7.4 Hz, 3 H, CH3). 13C NMR (100 MHz,
CDCl3) d 192.23 (CHO), 159.73 (quat. C), 137.78 (quat. C),
129.99 (arom. CH), 123.30 (arom. CH), 121.98 (arom. CH),
112.76 (arom. CH), 68.01 (CH2), 31.18 (CH2), 19.22 (CH2), 13.83
(CH3).
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 3-hydroxybenzaldehyde and 2.57 g
(15.0 mmol) benzyl bromide to give 996 mg (47%) of 6d as a
white solid. 1H NMR (500 MHz, CDCl3) d 9.97 (s, 1 H, CHO),
7.50–7.46 (m, 2 H, 2 arom. CH), 7.46–7.43 (m, 3 H, 3 arom. CH),
7.40 (t, J ¼ 7.4 Hz, 2 H, 2 arom. CH), 7.34 (t, J ¼ 7.2 Hz, 1 H,
arom. CH), 7.27–7.23 (m, 1 H, arom. CH), 5.13 (s, 2 H, CH2).
13C NMR (125 MHz, CDCl3) d 192.06 (CHO), 159.32 (quat. C),
137.83 (quat. C), 136.31 (quat. C), 130.13 (arom. CH), 128.69 (2
arom. CH), 128.22 (arom. CH), 127.55 (2 arom. CH), 123.70
(arom. CH), 122.21 (arom. CH), 113.27 (arom. CH), 70.25 (CH2).
IR (KBr): n [cmꢂ1] ¼ 2812, 2728, 1699, 1595, 1481, 1385, 1257,
1018, 743.
3-(Pentyloxy)benzaldehyde (6g)
The compound was prepared according to General proce-
dure III from 1.22 g (10.0 mmol) 3-hydroxybenzaldehyde and
2.25 g (15.0 mmol) n-pentyl bromide to give 903 mg (47%) of
(ꢀ)-3-(1-Phenylethoxy)benzaldehyde (6c)
The compound was prepared according to General proce-
dure III from 2.77 g (15 mmol) 1-phenylethyl bromide and
1.23 g (10.0 mmol) 3-hydroxybenzaldehyde to give 1.09 g of
6c (48%) as a colorless oil. 1H NMR (500 MHz, CDCl3) d 9.89
(s, 1 H, CHO), 7.44–7.30 (m, 7 H, 7 arom. CH), 7.26 (m, 1 H,
arom. CH), 7.18–7.11 (m, 1 H, arom. CH), 5.39 (q, J ¼ 6.4 Hz, 1
H, CH), 1.66 (d, J ¼ 6.4 Hz, 3 H, CH3). 13C NMR (100 MHz,
CDCl3) d 192.05 (CO), 158.49 (quat. C), 142.39 (quat. C),
137.67 (quat. C), 129.96 (arom. CH), 128.74 (2 arom. CH),
127.71 (arom. CH), 125.57 (2 arom. CH), 123.01 (arom. CH),
122.71 (arom. CH), 115.15 (arom. CH), 76.30 (CH), 24.31
(CH3).
1
6g as a colorless oil. H NMR (400 MHz, CDCl3) d 9.97 (s, 1 H,
CHO), 7.44 (d, J ¼ 0.9 Hz, 1 H, arom. CH), 7.43 (dd, J ¼ 2.3,
0.9 Hz, 1 H, arom. CH), 7.38 (dt, J ¼ 2.0, 0.7 Hz, 1 H, arom. CH),
7.20–7.14 (m, 1 H, arom. CH), 4.01 (t, J ¼ 6.6 Hz, 2 H, CH2),
1.95–1.68 (m, 2 H, CH2), 1.56–1.29 (m, 4 H, 2 CH2), 0.94 (t,
J ¼ 7.2 Hz, 3 H, CH3).
3-(Hexyloxy)benzaldehyde (6h)
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 3-hydroxybenzaldehyde and 2.46 g
(15.0 mmol) n-hexyl bromide to give 1.13 g (55%) of 6h as a
colorless oil. 1H NMR (400 MHz, CDCl3) d 9.97 (s, 1 H, CHO), 7.44
(s, 1 H, arom. CH), 7.44–7.42 (m, 1 H, arom. CH), 7.38 (dd,
J ¼ 2.1, 0.8 Hz, 1 H, arom. CH), 7.22–7.12 (m, 1 H, arom. CH),
4.03 (7, J ¼ 6.7 Hz, 2 H, CH2), 1.84–1.63 (m, 2 H, CH2), 1.51–1.43
(m, 2 H, CH2), 1.38–1.31 (m, 4 H, 2 CH2), 0.91 (t, J ¼ 7.0 Hz, 3 H,
CH3).
3-(2-Phenylethyloxy)benzaldehyde (6d)
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 3-hydroxybenzaldehyde and 3.02 g
(15.0 mmol) (2-bromoethyl)benzene to give 973 g (43%) of 6d
as a colorless oil. 1H NMR (500 MHz, CDCl3) d 9.95 (s, 1 H, CHO),
7.51–7.12 (m, 9 H, 9 arom. CH), 4.23 (t, J ¼ 7.0 Hz, 2 H, CH2O),
3.12 (t, J ¼ 7.0 Hz, 2 H, CH2). 13C NMR (100 MHz, CDCl3) d 192.12
(CHO), 159.39 (quat. C), 137.94 (quat. C), 137.78 (quat. C),
130.05 (arom. CH), 128.99 (2 arom. CH), 128.55 (2 arom. CH),
126.62 (arom. CH), 123.49 (arom. CH), 121.93 (arom. CH),
112.92 (arom. CH), 68.93 (CH2), 35.67 (CH2).
3-(Decyloxy)benzaldehyde (6i)
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 3-hydroxybenzaldehyde and 3.30 g
(15.0 mmol) n-decyl bromide to give 2.07 g (79%) of 6i as a
pale yellow oil. 1H NMR (400 MHz, CDCl3) d 9.97 (s, 1 H, CHO),
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7.46–7.42 (m, 2 H, 2 arom. CH), 7.38 (dt, J ¼ 2.0, 0.7 Hz, 1 H,
arom. CH), 7.20–7.14 (m, 1 H, arom. CH), 4.01 (t, J ¼ 6.6 Hz, 2 H,
CH2), 1.90–1.81 (m, 2 H, CH2), 1.49–1.37 (m, 2 H, CH2),
1.36–1.21 (m, 12 H, 6 CH2), 0.88 (t, J ¼ 6.9 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3) d 192.24 (CHO), 159.73 (quat. C),
137.77 (quat. C), 129.98 (arom. CH), 123.29 (arom. CH), 121.98
(arom. CH), 112.79 (arom. CH), 68.33 (CH2), 32.86 (CH2), 31.88
(CH2), 29.51 (CH2), 29.45 (CH2), 29.29 (CH2), 28.78 (CH2), 28.19
(CH2), 22.68 (CH2), 14.11 (CH3).
4-Butyloxybenzaldehyde (6o)
The compound was prepared according to General procedure
III from 244 g (2.0 mmol) 4-hydroxybenzaldehyde and 563 g
(3.0 mmol) n-butyl bromide to give 261 mg (73%) of 6o as a
pale yellow oil. 1H NMR (500 MHz, CDCl3) d 9.88 (s, 1 H, CHO),
7.83 (d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 6.99 (d, J ¼ 8.7 Hz, 2 H, 2
arom. CH), 1.84–1.76 (m, 2 H, CH2), 1.51 (tq, J ¼ 7.4 Hz, 2H),
0.99 (t, J ¼ 7.4 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3) d 190.81
(CHO), 164.27 (quat. C), 131.98 2. arom. CH), 129.75 (quat. C),
114.75 (2 arom. CH), 68.11 (CH2), 31.09 (CH2), 19.18 (CH2),
13.80 (CH3).
4-Phenoxybenzaldehyde (6j)
The compound was purchased from Sigma–Aldrich.
4-Pentyloxybenzaldehyde (6p)
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 4-hydroxybenzaldehyde and 2.25 g
(15.0 mmol) n-pentyl bromide to give 921 mg (48%) of 6p as a
colorless oil. 1H NMR (400 MHz, CDCl3) d 9.88 (s, 1 H, CHO), 7.82
(d, J ¼ 8.9 Hz, 2 H, 2 arom. CH), 6.99 (d, J ¼ 6.8 Hz, 2 H, 2
arom. CH), 4.04 (t, J ¼ 6.6 Hz, 2 H, CH2), 1.95–1.70 (m, 2 H, CH2),
1.60–1.26 (m, 4 H, 2 CH2), 0.94 (t, J ¼ 7.2 Hz, 3 H, CH3).
4-Benzyloxybenzaldehyde (6k)
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 4-hydroxybenzaldehyde and 2.57 g
(15.0 mmol) benzyl bromide to give 1.8 g (85%) of 6k as a
white solid. All spectroscopic data were in full accordance
with lit. [19].
(ꢀ)-4-(1-Phenylethoxy)benzaldehyde (6l)
4-Hexyloxybenzaldehyde (6q)
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 4-hydroxybenzaldehyde and 2.78 g
(15.0 mmol) (ꢀ)-1-phenylethyl bromide to give 2.03 g (90%) of
6l as a colorless oil. 1H NMR (500 MHz, CDCl3) d 9.82 (s, 1 H,
CHO), 7.73 (d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 7.43–7.18 (m, 5 H,
arom. CH), 6.95 (d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 5.41 (q,
J ¼ 6.4 Hz, 1 H, CH), 1.67 (d, J ¼ 6.4 Hz, 3 H, CH3). 13C NMR
(100 MHz, CDCl3) d 190.75 (CHO), 163.06 (quat. C), 142.17
(quat.), 131.85 (2 arom. CH), 128.82 (2 arom. CH), 127.83
(arom. CH), 125.42 (2 arom. CH), 116.02 (2 arom. CH), 76.47
(CH), 24.44 (CH3). GC-MS (EI): m/z (%) ¼ 226 (Mþ, 1), 121 (7),
106 (24), 104 (100), 103 (28).
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 4-hydroxybenzaldehyde and 2.46 g
(15.0 mmol) n-hexyl bromide to give 1857 mg (90%) of 6q as a
colorless oil. 1H NMR (400 MHz, CDCl3) d 9.88 (s, 1 H, CHO), 7.82
(d, J ¼ 8.9 Hz, 2 H, 2 arom. CH), 6.99 (d, J ¼ 8.7 Hz, 2 H, 2 arom.
CH), 4.04 (t, J ¼ 6.6 Hz, 2 H, CH2), 1.87–1.76 (m, 2 H, CH2),
1.51–1.42 (m, 2 H, CH2), 1.38–1.29 (m, 4 H, 2 CH2), 0.95–0.87 (t,
J ¼ 7.0 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3) d 190.85 (CHO),
164.29 (quat. C), 132.00 (2 arom. CH), 129.72 (quat. C), 114.75
(2 arom. CH), 68.44 (CH2), 31.52 (CH2), 29.02 (CH2), 25.64 (CH2),
22.58 (CH2), 14.01 (CH3).
4-Decyloxybenzaldehyde (6r)
4-Phenethoxybenzaldehyde (6m)
The compound was prepared according to General procedure
III from 1.22 g (10 mmol) of 4-hydroxybenzaldehyde and
3.30 g (15.0 mmol) of n-decyl bromide to give 1.85 g (71%) of
1p as a colorless oil. 1H NMR (400 MHz, CDCl3) d 9.88 (s, 1 H,
CHO), 7.83 (d, J ¼ 8.7 Hz, 2 H, 2 arom. CH), 6.99 (d, J ¼ 8.7 Hz, 2
H, 2 arom. CH), 4.04 (t, J ¼ 6.6 Hz, 2 H, CH2), 1.85–1.76 (m, 2 H,
CH2), 1.51–1.41 (m, 2 H, CH2), 1.40–1.19 (m, 12 H, 6 CH2), 0.87
(t, J ¼ 7.3 Hz, 3 H, CH3). 13C NMR (125 MHz, CDCl3) d 190.85
(CHO), 164.28 (quart. C), 132.00 (2 arom. CH), 129.73 (quat. C),
114.75 (2 arom. CH), 68.44 (CH2), 31.89 (CH2), 29.55 (CH2),
29.55 (CH2), 29.34 (CH2), 29.31 (CH2), 29.06 (CH2), 25.96 (CH2),
22.68 (CH2), 14.12 (CH3).
The compound was prepared according to General procedure
III from 1.22 g (10 mmol) of 4-hydroxybenzaldehyde and
2.78 g (15.0 mmol) of 2-phenylethyl bromide to give 1.89 g
(84%) of 1o as a colorless oil. 1H NMR (400 MHz, CDCl3) d 9.86
(s, 1 H, CHO), 7.81 (d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 7.39–7.22 (m,
5 H, 5 arom. CH), 6.98 (d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 4.24 (t,
J ¼ 7.0 Hz, 2 H, CH2), 3.12 (t, J ¼ 7.0 Hz, 2 H, CH2). 13C NMR
(100 MHz, CDCl3) d 190.84 (CO), 163.91 (quat. C), 137.81 (quat.
C), 132.03 (2 arom. CH), 129.98 (2 arom. CH), 129.07 (2 arom.
CH), 128.66 (quat. C), 126.77 (arom. CH), 114.87 (2 arom. CH),
69.02 (CH2), 35.60 (CH2).
4-Propyloxybenzaldehyde (6n)
(ꢀ)-6-Methyl-N-(3-(phenoxy)benzyl)heptan-2-amine (7a)
The compound was prepared according General procedure I
from 673 mg (3.4 mmol) of 6a and 617mg (4.8 mmol)
6-methylheptan-2-amine to give 650 mg (61%) of 7a as a pale
yellowoil. 1H NMR (500MHz, CDCl3) d 7.35–7.30(m, 2 H, 2 arom.
CH), 7.30–7.24(m, 1H,arom.CH), 7.12–7.04(m, 2H, 2arom.CH),
7.03–6.97(m,3H,3arom.CH),6.87(dd,J ¼ 8.1,2.4 Hz,1H,arom.
CH), 3.80 (d, J ¼ 13.3 Hz, 1 H, CH2), 3.71 (d, J ¼ 13.3 Hz, 1 H, CH2),
The compound was prepared according to General procedure
III from 1.22 g (10.0 mmol) 4-hydroxybenzaldehyde and 2.55 g
(15.0 mmol) n-propyl iodide to give 869 mg (53%) of 6n as a
colorless oil. 1H NMR (400 MHz, CDCl3) d 9.88 (s, 1 H, CHO), 7.83
(d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 6.99 (d, J ¼ 8.8 Hz, 2 H, 2 arom.
CH), 4.01 (t, J ¼ 6.5 Hz, 2 H, CH2), 1.85 (h, J ¼ 7.2 Hz, 2 H, CH2),
1.06 (t, J ¼ 7.4 Hz, 3 H, CH3).
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2.65 (h, J ¼ 6.1 Hz, 1 H, CH), 1.59–1.47 (m, 1 H, CH), 1.47–1.37 (m,
1 H, CH2), 1.34–1.22 (m, 3 H, 2 CH2), 1.18–1.11 (m, 2 H, CH2), 1.06
(d, J ¼ 6.3 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, CH3). 13C NMR
(125 MHz, CDCl3) d 157.32 (2 quat. C), 143.17 (quat. C), 129.63 (2
arom. CH), 129.61 (arom. CH), 123.13 (arom. CH), 122.96 (arom.
CH), 118.84 (2 arom. CH), 118.56 (arom. CH), 117.24 (arom. CH),
52.44 (CH), 51.08 (CH2), 39.17 (CH2), 37.33 (CH2), 27.95 (CH),
23.70 (CH2), 22.68 (CH3), 22.60 (CH3), 20.35 (CH3). IR (KBr): n
[cmꢂ1] ¼ 2954, 2927, 1584, 1488, 1252, 1216, 692. GC-MS
(EI) ¼ 311 (Mþ, 0.21), 226 (88), 183 (100). HR-MS (ESI): calcd.
for C21H30NO: 312.2327. Found: 312.2325.
(500 MHz, CD2Cl2) d 11.96 (s, 2 H, NH2), 7.51–7.14 (m, 8 H,
arom. CH), 6.95 (dd, J ¼ 8.1, 2.4 Hz, 1 H, arom. CH), 5.11 (s, 2 H,
CH2), 4.07 (d, J ¼ 13.5 Hz, 1 H, CH2), 3.99 (d, J ¼ 13.5 Hz, 1 H,
CH2), 2.98–2.88 (m, 1 H, CH), 2.04–1.83 (m, 2 H, CH2), 1.72–1.58
(m, 2 H, CH2), 1.55–1.45 (m, 1 H, CH), 1.38–1.14 (m, 5 H, CH3,
CH2), 0.85 (d, J ¼ 6.6 Hz, 6 H, 2 CH3).
(ꢀ)-6-Methyl-N-(3-(1-phenylethoxy)benzyl)heptan-2-
amine (7c) (diastereomeric mixture)
The compound was prepared according to General proce-
dure I from 763 mg (3.4 mmol) of 6c and 617 mg (4.8 mmol)
6-methylheptan-2-amine to give 983 mg (85%) of 7d as a
pale yellow oil. 1H NMR (400 MHz, CDCl3) d 7.41–7.28 (m, 4 H,
4 arom. CH), 7.23 (m, 1 H, arom. CH), 7.12 (t, J ¼ 7.8 Hz, 1 H,
arom. CH), 6.86 (dt, J ¼ 4.2, 1.9 Hz, 1 H, arom. CH), 6.83 (s, 1 H,
arom. CH), 6.71 (d, J ¼ 8.2 Hz, 1 H, arom. CH), 5.32 (q,
J ¼ 6.5 Hz, 1 H, CH), 3.73 (dd, J ¼ 13.2, J ¼ 3.3 Hz, 1 H, CH2),
3.64 (d, J ¼ 13.1 Hz, 1 H, CH2), 2.60 (dq, J ¼ 11.8, 6.0 Hz, 1 H,
CH), 1.62 (d, J ¼ 6.5 Hz, 3 H, CH3), 1.59–1.45 (m, 3 H, 2 CH2),
1.45–1.36 (m, 1 H, CH), 1.32–1.22 (m, 3 H, 2 CH2), 1.19–1.09
(m, 2 H, CH2), 1.02 (dd, J ¼ 10.7, 6.3 Hz, 3 H, CH3), 0.87 (d,
J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (100 MHz, CDCl3) d 158.05
(quat. C), 143.27 (quat. C), 142.39 (quat. C), 129.21 (arom.
CH), 128.56 (2 arom. CH), 127.36 (arom. CH), 125.56 (2 arom.
CH), 120.39 (arom. CH), 115.86 (arom. CH), 114.07 (arom. CH),
75.84/75.78 (CHO), 52.34/52.21 (CH), 51.23/51.21 (CH2), 39.17/
39.16 (CH2), 37.31 (CH2), 27.95 (CH), 24.41/24.38 (CH3), 23.71/
23.68 (CH2), 22.67 (CH3), 22.59 (CH3), 20.27 (CH3). GC-MS (EI):
m/z (%) ¼ 339 (Mþ, 0.21), 338 (0.4), 324 (4), 254 (100), 211
(38), 150 (22). HR-MS: calcd. for C23H33NO (Mþꢂ1): 338.2484.
Found: 338.2476.
6-Methyl-N-(3-phenoxybenzyl)heptan-2-aminium
chloride (8a)
The compound was prepared according to General procedure II
from 500mg (1.6 mmol) of 7a to give 540mg (97%) of 8a as a
pale brown solid. M.p (diethyl ether): 107°C. 1H NMR (400 MHz,
CD2Cl2) d 10.04 (s, 1 H, NH), 9.86 (s, 1 H, NH), 7.49 (d, J ¼ 7.7 Hz, 1
H, arom. CH), 7.42–7.35 (m, 3 H, 3 arom. CH), 7.34–7.31 (m, 1 H,
arom. CH), 7.20–7.14 (m, 1 H, arom. CH), 7.05 (dd, J ¼ 8.2, 1.6 Hz,
2 H, arom. CH), 6.99 (ddd, J ¼ 8.2, 2.4, 0.9 Hz, 1 H, arom. CH),
4.14–3.90(m, 2 H, CH2), 3.07–2.93(m, 1 H, CH), 1.99–1.88(m, 1 H,
CH2), 1.73–1.62 (m, 1 H, CH2), 1.54 (dp, J ¼ 13.3, 6.7 Hz, 1 H, CH),
1.48–1.40 (m, 1 H, CH2), 1.41 (d, J ¼ 6.5 Hz, 3 H, CH3),
1.34–1.21 (m, 1 H, CH2), 1.21–1.14 (m, 2 H, CH2), 0.89 (d,
J ¼ 6.6 Hz,6H,2CH3).IR(KBr):n[cmꢂ1] ¼ 2952,2866,1585,1489,
1259, 1219, 783, 698. HR-MS: calcd. for C21H30NOþ: 312.2327.
Found: 312.2323.
(ꢀ)-6-Methyl-N-(3-(benzyloxy)benzyl)heptan-2-amine (7b)
The compound was prepared according to General proce-
dure I from 721 mg (3.4 mmol) of 6b and 617 mg (4.8 mmol)
6-methylheptan-2-amine to give 751 mg (68%) of 7b as a
pale yellow oil. 1H NMR (500 MHz, CDCl3) d 7.43 (d,
J ¼ 7.3 Hz, 2 H, 2 arom. CH), 7.38 (t, J ¼ 7.3 Hz, 2 H, 2 arom.
CH), 7.32 (t, J ¼ 7.3 Hz, 1 H, arom. CH), 7.23 (t, J ¼ 7.8 Hz, 1 H,
arom. CH), 6.98 (t, J ¼ 1.9 Hz, 1 H, arom. CH), 6.92 (d,
J ¼ 7.3 Hz, 1 H, arom. CH), 6.85 (dd, J ¼ 8.1, 1.9 Hz, 1 H, arom.
CH), 5.07 (s, 2 H, CH2), 3.80 (d, J ¼ 13.1 Hz, 1 H, CH2), 3.71 (d,
J ¼ 13.1 Hz, 1 H, CH2), 2.67 (p, J ¼ 5.9 Hz, 1 H, CH), 1.57–1.48
(m, 1 H, CH), 1.47–1.39 (m, 2 H, CH2), 1.34–1.24 (m, 2 H, CH2),
1.18–1.12 (m, 2 H, CH2), 1.07 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.87 (d,
J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (125 MHz, CDCl3) d 129.38
(arom. CH), 128.54 (2 arom. CH), 127.90 (arom. CH), 127.48
(2 arom. CH), 120.69 (arom. CH), 114.59 (arom. CH), 113.14
(arom. CH), 69.92 (CH2), 52.43 (CH), 51.33 (CH2), 39.17 (CH2),
37.34 (CH2), 27.95 (CH), 23.73 (CH2), 22.67 (CH3), 22.58
(CH3), 20.33 (CH3). IR (KBr): n [cmꢂ1] ¼ 2954, 2927, 1487,
1454, 1261, 738, 695. HR-MS: calcd. for C22H32NO: 326.2484.
Found: 326.2483.
(ꢀ)-6-Methyl-N-(3-(1-phenylethoxy)benzyl)heptan-2-
aminium chloride (8c) (diastereomeric mixture)
The compound was prepared according to General procedure
II from 500 mg (1.6 mmol) of 7c to give 544 mg (91%) of 8c as a
pale brown viscous oil. 1H NMR (500 MHz, CD2Cl2) d 9.89–9.23
(m, 2 H, 2 NH), 7.51–6.66 (m, 9 H, 9 arom. CH), 5.46 (m, 1 H, CH),
4.00–3.81 (m, 2 H, CH2), 2.85–2.68 (m, 1 H, CH), 1.94–1.03 (m,
13 H, CH, 2 CH3, 3 CH2), 0.91–0.77 (m, 6 H, 2 CH3). 13C NMR
(100 MHz, CD2Cl2) d 158.29 (d, quat. C), 142.97 (d, quat. C),
131.70 (d, quat. C), 129.80 (d, arom. CH), 128.50 (d, 2 arom.
CH), 127.40 (d, arom. CH), 125.90 (d, 2 arom. CH), 117.40 (d,
arom. CH), 117.00 (d, arom. CH), 116.90 (d, arom. CH), 75.78 (d,
CH), 52.00 (d, CH), 47.29 (d, CH2), 38.39 (d, CH2), 32.87 (d, CH2),
27.80 (d, CH), 24.15 (d, CH3), 24.05 (d, CH2), 23.28 (d, CH3),
22.15 (d, CH3), 15.68 (d, CH3). HR-MS: calcd. for C23H34NOþ:
340.2640. Found: 340.2613.
(ꢀ)-6-Methyl-N-(3-(phenylethoxy)benzyl)heptan-2-amine
(7d)
N-(3-(Benzyloxy)benzyl)-6-methylheptan-2-aminium
chloride (8b)
The compound was prepared according to General procedure
II from 500 mg (1.6 mmol) of 7b to give 549 mg (95%) of 8b as a
pale white solid. M.p. 235°C (decomposition). 1H NMR
The compound was prepared according to General procedure
I from 768 mg (3.4 mmol) of 6d and 617 mg (4.8 mmol)
6-methylheptan-2-amine to give 749 mg (65%) of 7d as a
pale yellow oil. 1H NMR (500 MHz, CDCl3) d 7.34–7.27 (m, 4 H, 4
arom. CH), 7.24–7.18 (m, 2 H, 2 arom. CH), 6.90–6.87 (m, 2 H, 2
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arom. CH), 6.80–6.76 (m, 1 H, arom. CH), 4.17 (t, J ¼ 7.1 Hz, 2 H,
CH2), 3.78 (d, J ¼ 13.1 Hz, 1 H, CH2), 3.69 (d, J ¼ 13.1 Hz, 1 H,
CH2), 3.09 (t, J ¼ 7.1 Hz, 2 H, CH2), 2.66 (h, J ¼ 6.1 Hz, 1 H, CH),
1.52 (dp, J ¼ 13.2, 6.7 Hz, 1 H, CH), 1.47–1.39 (m, 1 H, CH2),
1.36–1.29 (m, 3 H, 2 CH2), 1.18–1.11 (m, 2 H, CH2), 1.06 (d,
J ¼ 6.3 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(125 MHz, CDCl3) d 158.95 (quat. C), 142.59 (quat. C), 138.28
quat. C), 129.33 (arom. CH), 129.00 (2 arom. CH), 128.46 (2
arom. CH), 126.45 (arom. CH), 120.48 (arom. CH), 114.27
(arom. CH), 112.89 (arom. CH), 68.59 (CH2), 52.46 (CH), 51.36
(CH2), 39.16 (CH2), 37.34 (CH2), 35.85 (CH2), 27.94 (CH), 23.74
(CH2), 22.66 (CH3), 22.58 (CH3), 20.33 (CH3). GC-MS (EI): m/z
(%) ¼ 310 (Mþꢂ2 ꢁ CH3, 0.3), 266 (5), 226 (87), 183 (100), 168
(6). IR (KBr): n [cmꢂ1] ¼ 2955, 2928, 1602, 1585, 1455, 1262,
1155, 782, 750, 699. HR-MS: calcd. for C23H33NO: 339.2562.
Found: 339.2562.
6-Methyl-N-(3-propoxybenzyl)heptan-2-aminium chloride
(8e)
The compound was prepared according to General procedure
II from 500 mg (1.6 mmol) of 7e to give 431 mg (86%) of 8e as a
1
pale brown solid. M.p.: 71°C. H NMR (500 MHz, DMSO-d6) d
9.20 (s, 1 H, NH), 9.05 (s, 1 H, NH), 7.32 (t, J ¼ 7.9 Hz, 1 H, arom.
CH), 7.25 (s, 1 H, arom. CH), 7.11 (d, J ¼ 7.1 Hz, 1 H, arom. CH),
6.95 (dd, J ¼ 8.3, 2.0 Hz, 1 H, arom. CH), 4.10 (m, 2 H, CH2), 3.95
(t, J ¼ 6.5 Hz, 2 H, CH2O), 3.11–3.03 (m, 1 H, CH), 1.78–1.69 (m, 2
H, CH2), 1.52–1.35 (m, 3 H, 2 CH2, CH), 1.27 (d, J ¼ 6.5 Hz, 3 H,
CH3), 1.26–1.18 (m, 2 H, 2 CH2), 1.18–1.10 (m, 2 H, CH2), 0.98 (t,
J ¼ 7.4 Hz, 3 H, CH3), 0.85 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(125 MHz, DMSO-d6) d 159.21 (quat. C), 134.07 (quat. C),
130.19 (arom. CH), 122.33 (arom. CH), 116.42 (arom. CH),
115.31 (arom. CH), 69.47 (CH2O), 53.52 (CH), 47.42 (CH2), 38.49
(CH2), 32.62 (CH2), 27.68 (CH), 23.07 (CH2), 22.97 (CH3), 22.80
(CH3), 22.46 (CH2), 16.01 (CH3), 10.88 (CH3). HR-MS: calcd. for
6-Methyl-N-(3-phenethoxybenzyl)heptan-2-aminium
chloride (8d)
C18H32NO: 278.2484. Found: 278.2454.
The compound was prepared according to General procedure
II from 500 mg (1.6 mmol) of 7d to give 571 mg (95%) of 8d as
a pale yellow oil. 1H NMR (500 MHz, CD2Cl2) d 9.93 (s, 1 H, NH),
9.72 (s, 1 H, NH), 7.34–7.19 (m, 7 H, 7 arom. CH), 7.13 (d,
J ¼ 7.6 Hz, 1 H, arom. CH), 6.85 (dd, J ¼ 8.2, 2.0 Hz, 1 H, arom.
CH), 4.20 (t, J ¼ 6.9 Hz, 2 H, CH2), 4.02–3.86 (m, 2 H, CH2), 3.06
(t, J ¼ 6.9 Hz, 2 H, CH2), 2.96–2.86 (m, 1 H, CH), 1.93–1.82 (m, 1
H, CH2), 1.73–1.55 (m, 2 H, CH2), 1.53–1.45 (m, 1 H, CH), 1.35 (d,
J ¼ 6.5 Hz, 3 H, CH3), 1.28–1.16 (m, 1 H, CH2), 1.16–1.09 (m, 2 H,
CH2), 0.84 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (125 MHz, CD2Cl2)
d 159.19 (quat. C), 138.50 (quat. C), 132.11 (quat. C), 129.87
(arom. CH), 129.02 (2 arom. CH), 128.35 (2 arom. CH), 126.35
(arom. CH), 122.48 (arom. CH), 113.45 (arom. CH), 112.79
(arom. CH), 68.60 (CH2O), 52.16 (CH), 47.04 (CH2), 38.38 (CH2),
35.56 (CH2), 32.86 (CH2), 27.80 (CH), 23.36 (CH2), 22.30 (CH3),
22.15 (CH3), 15.74 (CH3). HR-MS: calcd. for C23H34NOþ:
340.2640. Found: 340.2654.
6-Methyl-N-(3-(butyloxy)benzyl)heptan-2-amine (7f)
The compound was prepared according to General procedure
I from 476 mg (2.67 mmol) of 6f and 483 mg (3.7 mmol)
6-methylheptan-2-amine to give 343 mg (44%) of 7f as a pale
1
yellow oil. H NMR (400 MHz, CDCl3) d 7.21 (t, J ¼ 8.0 Hz, 1 H,
arom. CH), 6.90–6.85 (m, 2 H, arom. CH), 6.77 (ddd, J ¼ 8.2, 2.4,
0.8 Hz, 1 H, arom. CH), 3.96 (t, J ¼ 6.5 Hz, 2 H, CH2), 3.79 (d,
J ¼ 13.1 Hz, 1 H, CH2), 3.70 (d, J ¼ 13.1 Hz, 1 H, CH2), 2.66 (h,
J ¼ 6.1 Hz, 1 H, CH), 1.81–1.70 (m, 2 H, CH2), 1.57–1.40 (m, 5 H,
CH, 2 CH2), 1.34–1.27 (m, J ¼ 4.6 Hz, 2 H, CH2), 1.20–1.11 (m, 2
H, CH2), 1.07 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.97 (t, J ¼ 7.4 Hz, 3 H,
CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (125 MHz, CDCl3)
d 159.31 (quat. C), 142.36 (quat. C), 129.32 (arom. CH), 120.25
(arom. CH), 114.28 (arom. CH), 112.86 (arom. CH), 67.58 (CH2),
52.43 (CH), 51.33 (CH2), 39.16 (CH2), 37.28 (CH2), 31.39 (CH2),
29.71 (CH), 23.75 (CH2), 22.66 (CH3), 22.58 (CH3), 20.27 (CH3),
19.27 (CH2), 13.88 (CH3). HR-MS: calcd. for C19H33NO:
291.2562. Found: 291.2556.
6-Methyl-N-(3-(propyloxy)benzyl)heptan-2-amine (7e)
The compound was prepared according to General procedure
I from 558 mg (3.4 mmol) of 6e and 617 mg (4.8 mmol) 6-
methylheptan-2-amine to give 650 mg (69%) of 7e as a pale
N-(3-Butoxybenzyl)-6-methylheptan-2-aminium chloride
(8f)
The compound was prepared according to General procedure
II from 500 mg (1.6 mmol) of 7f to give 434 mg (83%) of 8f as a
pale yellow oil. 1H NMR (500 MHz, CD2Cl2) d 9.95 (s, 1 H, NH),
9.74 (s, 1 H, NH), 7.31 (d, J ¼ 5.9 Hz, 1 H, arom. CH), 7.29–7.25
(m, 1 H, arom. CH), 7.18–7.06 (m, 1 H, arom. CH), 6.91–6.82 (m,
1 H, arom. CH), 3.98 (t, J ¼ 6.7 Hz, 2 H, CH2), 4.04–3.89 (m, 2 H,
CH2), 3.00–2.84 (m, 1 H, CH), 1.93–1.83 (m, 1 H, CH2), 1.80–1.57
(m, 2 H, CH2), 1.56–1.42 (m, 3 H, CH, 2 CH2), 1.36 (d, J ¼ 6.5 Hz, 3
H, CH3), 1.30–1.18 (m, 2 H, CH2), 1.14 (p, J ¼ 6.6 Hz, 2 H, CH2),
0.97 (t, J ¼ 7.4 Hz, 3 H, CH3), 0.84 (d, J ¼ 6.6 Hz, 3 H, CH3), 0.84
(d, J ¼ 6.6 Hz, 3 H, CH3). 13C NMR (100 MHz, CD2Cl2) d 159.59
(quat. C), 132.05 (quat. C), 129.81 (arom. CH), 122.15 (arom.
CH), 115.98 (arom. CH), 115.44 (arom. CH), 67.91 (CH2), 52.05
(CH), 47.06 (CH2), 38.37 (CH2), 32.87 (CH2), 31.26 (CH2), 27.80
(CH), 23.36 (CH2), 22.29 (CH3), 22.14 (CH3), 19.25 (CH2), 15.75
1
yellow oil. H NMR (500 MHz, CDCl3) d 7.21 (t, J ¼ 8.0 Hz, 1 H,
arom. CH), 6.89–6.87 (m, 2 H, 2 arom. CH), 6.78 (ddd, J ¼ 8.1,
2.5, 0.8 Hz, 1 H, arom. CH), 3.92 (t, J ¼ 6.6 Hz, 2 H, CH2), 3.80 (d,
J ¼ 13.0 Hz, 1 H, CH2), 3.71 (d, J ¼ 13.0 Hz, 1 H, CH2), 2.73–2.60
(m, 1 H, CH), 1.80 (tt, J ¼ 6.4, 7.6 Hz, 2 H, CH2), 1.58–1.48 (m, 1
H, CH), 1.47–1.36 (m, 2 H, 2 CH2), 1.34–1.22 (m, 2 H, 2 CH2), 1.17
(m, 2 H, CH2), 1.07 (d, J ¼ 6.3 Hz, 3 H, CH3), 1.03 (t, J ¼ 7.6 Hz, 3
H, CH3), 0.86 (d, J ¼ 6.6 Hz, 3 H, CH3), 0.85 (d, J ¼ 6.6 Hz, 3 H,
CH3). 13C NMR (100 MHz, CDCl3) d 159.30 (quat. C), 142.52
(quat. C), 129.31 (arom. CH), 120.24 (arom. CH, 114.27 (arom.
CH), 112.84 (arom. CH), 69.42 (CH2O), 52.43 (CH), 51.39 (CH2),
39.17 (CH2), 37.35 (CH2), 27.96 (CH), 23.76 (CH2), 22.65 (CH2),
22.58 (2 CH3), 20.33 (CH3), 10.56 (CH3). HR-MS: calcd. for
C
18H31NO: 277.2406. Found: 277.2401.
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(CH3), 13.64 (CH3). HR-MS: calcd. for C19H34NO: 292.2640.
Found: 292.2640.
37.11 (CH2), 31.61 (CH2), 29.28 (CH2), 27.94 (CH), 25.74 (CH2),
23.73 (CH2), 22.66 (CH3), 22.61 (CH2), 22.58 (CH3), 20.10 (CH3),
14.04 (CH3). HR-MS: calcd. for C21H36NO (Mþꢂ1): 318.2797.
Found: 318.2776.
6-Methyl-N-(3-(pentyloxy)benzyl)heptan-2-amine (7g)
The compound was prepared according to General procedure
I from 653 mg (3.4 mmol) of 6g and 617 mg (4.8 mmol)
6-methylheptan-2-amine to give 591 mg (57%) of 7g as a
pale yellow oil. 1H NMR (400 MHz, CDCl3) d 7.21 (t, J ¼ 8.0 Hz, 1
H, arom. CH), 6.90–6.85 (m, 2 H, 2 arom. CH), 6.77 (ddd, J ¼ 8.0,
2.5, 0.9 Hz, 1 H, arom. CH), 3.95 (t, J ¼ 6.6 Hz, 2 H, CH2), 3.80 (d,
J ¼ 13.1 Hz, 1 H, CH2), 3.70 (d, J ¼ 13.1 Hz, 1 H, CH2), 2.67 (h,
J ¼ 6.2 Hz, 1 H, CH), 1.82–1.73 (m, 2 H, CH2), 1.53 (dq, J ¼ 13.3,
6.6 Hz, 1 H, CH), 1.43 (m, 6 H, 3 CH2), 1.30 (m, 3 H, CH2),
1.18–1.11 (m, 2 H, CH2), 1.07 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.93 (t,
J ¼ 7.1 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(125 MHz, CDCl3) d 159.31 (quat. C), 142.41 (quat. C), 129.31
(arom. CH), 120.24 (arom. CH), 114.26 (arom. CH), 112.85
(arom. CH), 67.88 (CH2), 52.41 (CH), 51.33 (CH2), 39.16 (CH2),
37.30 (CH2), 29.03 (CH2), 28.24 (CH2), 27.96 (CH), 23.75 (CH2),
22.66 (CH3), 22.59 (CH3), 22.46 (CH2), 20.28 (CH3), 14.04 (CH3).
HR-MS: calcd. for C20H35NO: 305.2719. Found: 305.2733.
N-(3-(Hexyloxy)benzyl)-6-methylheptan-2-aminium
chloride (8h)
The compound was prepared according to General procedure II
from 638mg (2.0 mmol) of 7h to give 667 mg (94%) of 8h as a
white waxysolid. M.p. 48°C. 1H NMR(400 MHz, CD2Cl2) d 9.73(s,
1 H, NH), 9.54 (s, 1 H, NH), 7.35–7.29 (m, 2 H, 2 arom. CH), 7.16
(d, J ¼ 7.8 Hz, 1 H, arom. CH), 6.91 (dd, J ¼ 8.3, 2.5 Hz, 1 H, arom.
CH), 4.00 (t, J ¼ 6.5 Hz, 2 H, CH2), 3.13 (d, J ¼ 14.1 Hz, 2 H),
2.98 (dd, J ¼ 9.4, 4.8 Hz, 1 H), 1.98–1.86 (m, 1 H, CH2),
1.84–1.74 (m, 2 H, CH2), 1.71–1.60 (m, 1 H, CH2), 1.59–1.49 (m,
1 H, CH), 1.48–1.40 (m, 7 H, 4 CH2), 1.40 (d, J ¼ 6.5 Hz, 3 H, CH3),
1.34–1.20(m,1H,CH2),1.21–1.13(m,2H,CH2),0.96(t,J ¼ 7.1 Hz,
3 H, CH3), 0.88 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (100 MHz,
CD2Cl2) d 159.60 (quat. C), 131.94 (quat. C), 129.88 (arom. CH),
122.11 (arom. CH), 116.01 (arom. CH), 115.46 (arom. CH), 68.25
(CH2O), 52.21 (CH), 47.19 (CH2), 38.36 (CH2), 32.86 (CH2), 31.62
(CH2), 29.19 (CH2), 27.79 (CH), 25.71 (CH2), 23.35 (CH2), 22.60
(CH2), 22.29 (CH3), 22.14 (CH3), 15.79 (CH3), 13.80 (CH3). HR-MS:
calcd. for C21H38NOþ: 320.2953. Found: 320.3017.
6-Methyl-N-(3-(pentyloxy)benzyl)heptan-2-aminium
chloride (8g)
The compound was prepared according to General procedure II
from 610mg (2.0 mmol) of 7g to give 627 mg (92%) of 8g as a
colorlessoil.1HNMR(400MHz, CD2Cl2)d9.73(s, 1H,NH),9.54(s,
1H,NH),7.35–7.26(m, 2H,2arom.CH), 7.16(dt,J ¼ 7.7,1.2 Hz, 1
H, arom. CH), 6.91 (ddd, J ¼ 8.3, 2.5, 0.9 Hz, 1 H, arom. CH), 4.00
(t, J ¼ 6.5 Hz, 2 H,CH2),3.18–3.09(m, 2H, CH2),3.03–2.91(m, 1H,
CH), 1.98–1.86 (m, 1 H, CH2), 1.85–1.74 (m, 2 H, CH2), 1.72–1.59
(m,1H,CH2),1.53(dt,J ¼ 13.2, 6.6 Hz,1H,CH),1.49–1.41(m,5H,
3 CH2), 1.33–1.21 (m, 1 H, CH2), 1.21–1.12 (m, 2 H, CH2), 1.40 (d,
J ¼ 6.5 Hz, 3 H, CH3), 0.96 (t, J ¼ 7.1 Hz, 3 H, CH3), 0.88 (d,
J ¼ 6.6 Hz, 3 H, CH3), 0.88 (d, J ¼ 6.6 Hz, 3 H, CH3). 13C NMR
(100 MHz, CD2Cl2) d 159.60 (quat. C), 131.98 (quat. C), 129.88
(arom. CH), 122.10 (arom. CH), 115.93 (arom. CH), 115.47 (arom.
CH), 68.21 (CH2), 52.10 (CH), 47.18 (CH2), 38.35 (CH2), 32.86
(CH2), 28.92 (CH2), 28.19 (CH2), 27.79 (CH), 23.33 (CH2), 22.49
(CH2), 22.29 (CH3), 22.14 (CH3), 15.79 (CH3), 13.79 (CH3). HR-MS:
calcd. for C20H36NOþ: 306.2797. Found: 306.2767.
N-(3-(Decyloxy)benzyl)-6-methylheptan-2-amine (7i)
The compound was prepared according to General procedure
I
from 1.18 g (4.5 mmol) 3-(decyloxy)benzaldehyde and
827 mg (6.4 mmol) 6-methylheptan-2-amine to give 552 mg
(33%) of 7i as a colorless oil. 1H NMR (500 MHz, CDCl3) d 7.21 (t,
J ¼ 8.1 Hz, 1 H, arom. CH), 6.89–6.85 (m, 2 H, 2 arom. CH),
6.79–6.74 (m, 1 H, arom. CH), 3.95 (t, J ¼ 6.6 Hz, 2 H, CH2), 3.79
(d, J ¼ 13.1 Hz, 1 H, CH2), 3.70 (d, J ¼ 13.1 Hz, 1 H, CH2), 2.67 (h,
J ¼ 6.1 Hz, 1 H, CH), 1.81–1.71 (m, 2 H, CH2), 1.60–1.49 (m, 6 H, 3
CH2), 1.49–1.40 (m, 3 H, CH, CH2), 1.37–1.22 (m, 10 H, 5 CH2),
1.18–1.12 (m, 2 H, CH2), 1.07 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.89 (t,
J ¼ 6.8 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.5 Hz, 3 H, CH3), 0.86 (d,
J ¼ 6.5 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3) d 159.31 (quat.
C), 142.51 (quat. C), 129.30 (arom. CH), 120.22 (arom. CH),
114.26 (arom. CH), 112.83 (arom. CH), 67.91 (CH2), 52.44 (CH),
51.39 (CH2), 39.17 (CH2), 37.35 (CH2), 31.91 (CH2), 29.60 (CH2),
29.57 (CH2), 29.43 (CH2), 29.35 (CH2), 29.33 (CH2), 27.96 (CH),
26.08 (CH2), 23.76 (CH2), 22.69 (CH2), 22.67 (CH3), 22.59 (CH3),
20.33 (CH3), 14.13 (CH3). HR-MS: calcd. for C25H45NO (Mþ):
375.3501. Found: 375.3497.
N-(3-(Hexyloxy)benzyl)-6-methylheptan-2-amine (7h)
The compound was prepared according to General procedure
I
from 927 mg (4.5 mmol) 3-hexyloxybenzaldehyde and
826 mg (6.4 mmol) 6-methylheptan-2-amine to give 703 mg
(49%) of 7h as a colorless oil. 1H NMR (400 MHz, CDCl3) d 7.22
(t, J ¼ 8.1 Hz, 1 H, arom. CH), 6.89 (m, 2 H, 2 arom. CH), 6.78 (m,
1 H, arom. CH), 3.95 (t, J ¼ 6.6 Hz, 2 H, CH2), 3.82 (d, J ¼ 13.1 Hz,
1 H, CH2), 3.72 (d, J ¼ 13.1 Hz, 1 H, CH2), 2.69 (qt, J ¼ 6.0 Hz, 1 H,
CH), 1.82–1.71 (m, 2 H, CH2), 1.53 (m, 1 H, CH), 1.48–1.40 (m, 3
H, 2 CH2), 1.39–1.21 (m, 8 H, 4 CH2), 1.21–1.14 (m, 3 H, 2 CH2),
1.09 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.90 (t, J ¼ 6.9 Hz, 3 H, CH3), 0.86
(d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (100 MHz, CDCl3) d 158.61
(quat. C), 132.35 (quat. C), 129.33 (2 arom. CH), 114.42 (2
arom. CH), 68.03 (CH2), 52.35 (CH), 50.64 (CH2), 39.13 (CH2),
N-(3-(Decyloxy)benzyl)-6-methylheptan-2-aminium
chloride (8i)
The compound was prepared according to General procedure
II from 335 mg (0.89 mmol) of 7i to give 369 mg (100%) of 8i as
a white solid. M.p. 72°C. 1H NMR (500 MHz, CD2Cl2) d 9.95 (s, 1
H, NH), 9.76 (s, 1 H, NH), 7.32–7.29 (dd, J ¼ 1.8, 1.7 Hz, 1 H,
arom. CH), 7.29–7.25 (dd, J ¼ 7.7, 7.7 Hz, 1 H, arom. CH), 7.13
(d, J ¼ 7.7 Hz, 1 H, arom. CH), 6.86 (dd, J ¼ 7.7, 1.8 Hz, 1 H,
arom. CH), 4.04–3.89 (m, 2 H, CH2), 3.96 (t, J ¼ 6.5 Hz, 3 H, CH2),
2.91 (h, J ¼ 8.8, 7.4 Hz, 1 H, CH), 1.94–1.84 (m, 1 H, CH2),
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1.79–1.70 (m, 2 H, CH2), 1.68–1.58 (m, 1 H, CH2), 1.55–1.45 (m, 1
H, CH), 1.46–1.39 (m, 2 H, CH2), 1.36 (d, J ¼ 6.5 Hz, 3 H, CH3),
1.34–1.20 (m, 14 H, 7 CH2), 1.17–1.07 (m, 2 H, CH2), 0.88 (t,
J ¼ 6.8 Hz, 3 H, CH3), 0.84 (d, J ¼ 6.6 Hz, 3 H, CH3), 0.84 (d,
J ¼ 6.6 Hz, 3 H, CH3). 13C NMR (100 MHz, CD2Cl2) d 159.58
(quat. C), 132.06 (quat. C), 129.80 (arom. CH), 122.15 (arom.
CH), 116.01 (arom. CH), 115.43 (arom. CH), 68.24 (CH2), 52.05
(CH), 47.06 (CH2), 38.38 (CH2), 32.86 (CH2), 31.91 (CH2), 29.60
(CH2), 29.58 (CH2), 29.46 (CH2), 29.33 (CH2), 29.25 (CH2), 27.79
(CH), 26.06 (CH2), 23.36 (CH2), 22.68 (CH2), 22.30 (CH3), 22.15
(CH3), 15.75 (CH3), 13.86 (CH3). HR-MS: calcd. for C25H46NOþ:
376.3579. Found: 376.3583.
2 arom. CH), 7.38 (t, J ¼ 7.3 Hz, 2 H, 2 arom. CH), 7.35–7.29 (m, 1
H, arom. CH), 7.23 (d, J ¼ 8.6 Hz, 2 H, arom. CH), 6.93 (d,
J ¼ 8.6 Hz, 2 H, 2 arom. CH), 5.05 (s, 2 H, CH2), 3.76 (d,
J ¼ 12.8 Hz, 1 H, CH2), 3.67 (d, J ¼ 12.8 Hz, 1 H, CH2), 2.66 (h,
J ¼ 6.0 Hz, 1 H, CH), 1.52 (tq, J ¼ 6.7, 6.7 Hz, 1 H, CH), 1.48–1.37
(m, 2 H, CH2), 1.35–1.24 (m, 4 H, CH2), 1.20–1.10 (m, 2 H, CH2),
1.07 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.7 Hz, 3 H, CH3), 0.86
(dd, J ¼ 6.7 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3) d 157.74
(quat. C), 137.13 (quat. C), 133.37 (quat. C), 129.29 (2 arom.
CH), 128.56 (2 arom. CH), 127.90 (arom. CH), 127.45 (2 arom.
CH), 114.77 (2 arom. CH), 70.05 (CH2), 52.46 (CH), 50.84 (CH2),
39.17 (CH2), 37.34 (CH2), 27.96 (CH), 23.75 (CH2), 22.68 (CH3),
22.60 (CH3), 20.35 (CH3). MS (EI): m/z (%) ¼ 325 (Mþ, 0.3), 383
(Mþꢂ1, 0.324), 280 (7), 240 (31), 197 (100), 107 (10). HR-MS:
calcd. for C22H31NO: 325.2406. Found: 325.2399.
6-Methyl-N-(4-phenoxybenzyl)heptan-2-amine (7j)
The compound was prepared according to General procedure
I from 891 mg of 6j (4.5 mmol) and 827 mg (6.4 mmol) of
6-methylheptan-2-amine to give 1.272 g (91%) of 7j as a
colorless oil. 1H NMR (500 MHz, CDCl3) d 7.32 (dd, J ¼ 8.6,
7.4 Hz, 2 H, 2 arom. CH), 7.28 (d, J ¼ 8.6 Hz, 2 H, 2 arom. CH),
7.08 (t, J ¼ 7.4 Hz, 1 H, arom. CH), 7.02–6.98 (m, 2 H, 2 arom.
CH), 6.97 (d, J ¼ 8.6 Hz, 2 H, 2 arom. CH), 3.80 (d, J ¼ 12.9 Hz, 1
H, CH2), 3.71 (d, J ¼ 12.9 Hz, 1 H, CH2), 2.67 (tq, J ¼ 6.1 Hz, 1 H,
CH), 1.54 (m, 1 H, CH), 1.46 (m, 1 H, CH2), 1.36–1.26 (m, 3 H, 3
CH2), 1.17 (t, J ¼ 7.2 Hz, 2 H, CH2), 1.08 (d, J ¼ 6.3 Hz, 3 H, CH3),
0.87 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR (125 MHz, CDCl3) d
157.50 (quat. C), 155.95 (quat. C), 135.91 (quat. C), 129.75 (2
arom. CH), 129.51 (2 arom. CH), 123.02 (arom. CH), 119.00 (2
arom. CH), 118.61 (2 arom. CH), 52.59 (CH), 50.85 (CH2), 39.17
(CH2), 37.33 (CH2), 27.96 (CH), 23.75 (CH2), 22.68 (CH3), 22.61
(CH3), 20.37 (CH3). HR-MS: calcd. for C21H29NO: 311.2249.
Found: 311.2236.
N-(4-(Benzyloxy)benzyl)-6-methylheptan-2-aminium
chloride (8k)
The compound was prepared according to General procedure
II from 611 mg (1.88 mmol) of 7k to give 598 mg (88%) of 8k as
a white solid. M.p. 168°C. 1H NMR (500 MHz, CD2Cl2) d 9.82 (s,
1 H, NH), 9.65 (s, 1 H, NH), 7.57 (d, J ¼ 8.7 Hz, 2 H, 2 arom. CH),
7.39–7.25 (m, 5 H, 5 arom. CH), 7.00–6.93 (d, J ¼ 8.7 Hz, 2 H, 2
arom. CH), 4.95 (s, 2 H, CH2), 3.89 (m, 2 H, CH2), 2.91 (m, 1 H,
CH), 1.94–1.83 (m, 1 H, CH2), 1.67–1.57 (m, 1 H, CH2), 1.50 (ts,
J ¼ 7.3, 6.9 Hz, 1 H, CH), 1.43–1.33 (m, 1 H, CH2), 1.35 (d,
J ¼ 6.5 Hz, 3 H, CH3), 1.28–1.18 (m, 1 H, CH), 1.17–1.11 (m, 2 H,
CH2), 0.85 (d, J ¼ 6.6 Hz, 3 H, CH3), 0.84 (d, J ¼ 6.6 Hz, 3 H, CH3).
13C NMR (100 MHz, CD2Cl2) d 160.71 (quat. C), 138.10 (quat. C),
133.34 (2 arom. CH), 129.81 (2 arom. CH), 129.31 (arom. CH),
128.84 (2 arom. CH), 124.20 (quat. C), 116.32 (2 arom. CH),
71.26 (CH2), 53.30 (CH), 47.87 (CH2), 39.72 (CH2), 34.17 (CH2),
29.13 (CH), 24.68 (CH2), 23.63 (CH3), 23.49 (CH3), 17.04 (CH3). IR
(KBr): n [cmꢂ1] ¼ 2950, 1613, 1584, 1516, 1455, 1379, 1250,
1182, 1026, 815, 727, 692, 515. HR-MS: calcd. for C22H32NOþ:
326.2484. Found: 326.2460.
6-Methyl-N-(4-phenoxybenzyl)heptan-2-aminium
chloride (8j)
The compound was prepared according to General procedure
II from 311 mg (1.0 mmol) of 7j to give 319 mg (92%) of 8j as a
white solid. M.p. 146°C. 1H NMR (500 MHz, CD2Cl2) d 9.70 (s, 1
H, NH), 9.52 (s, 1 H, NH), 7.54 (d, J ¼ 8.7 Hz, 2 H, 2 arom. CH),
7.28–7.21 (m, 2 H, 2 arom. CH), 7.08–7.03 (m, 1 H, arom. CH),
6.92–6.86 (m, 4 H, 4 arom. CH), 3.99–3.83 (m, 2 H, CH2), 2.87 (m,
1 H, CH), 1.86–1.76 (m, 1 H, CH2), 1.61–1.51 (m, 1 H, CH2),
1.47–1.37 (m, 1 H, CH), 1.30–1.29 (m, 1 H, CH2), 1.29 (d,
J ¼ 6.5 Hz, 3 H, CH3), 1.21–1.11 (m, 1 H, CH2), 1.09–1.02 (m, 2 H,
CH2), 0.77 (d, J ¼ 6.6 Hz, 2 H, CH3), 0.76 (d, J ¼ 6.6 Hz, 2 H, CH3).
13C NMR (125 MHz, CD2Cl2) d 158.35 (quat. C), 156.25 (quat. C),
132.18 (2 arom. CH), 129.85 (2 arom. CH), 125.02 (quat. C),
123.89 (arom. CH), 119.44 (2 arom. CH), 118.40 (2 arom. CH),
52.10 (CH), 46.59 (CH2), 38.38 (CH2), 32.85 (CH2), 27.81 (CH),
23.35 (CH2), 22.31 (CH3), 22.17 (CH3), 15.77 (CH3). HR-MS:
calcd. for C21H30NOþ 312.2327. Found: 312.2312.
(ꢀ)-6-Methyl-N-(4-(1-phenylethoxy)benzyl)heptan-2-
amine (7l)
The compound was prepared according to General procedure I
from1.02g(4.5 mmol)of4-(1-phenylethoxy)benzaldehydeand
822mg (6.4 mmol) 6-methylheptan-2-amine to give 1.26mg
(83%) of 7l as a pale brown oil. 1H NMR (500MHz, CDCl3) d 7.36
(d,J ¼ 7.6 Hz,2H,2arom.CH),7.32(t,J ¼ 7.6 Hz,2H,2arom.CH),
7.25–7.21(m, 1 H, arom. CH), 7.13(d, J ¼ 8.6 Hz, 2 H, 2 arom. CH),
6.80 (d, J ¼ 8.6 Hz, 2 H, 2 arom. CH), 5.28 (q, J ¼ 6.4 Hz, 1 H, CH),
3.69 (d, J ¼ 12.7 Hz, 1 H, CH2), 3.60 (d, J ¼ 12.7 Hz, 1 H, CH2), 2.63
(h, J ¼ 6.1 Hz, 1 H, CH), 1.62(d, J ¼ 6.4 Hz, 3 H, CH3), 1.56–1.47(m,
1 H, CH), 1.46–1.36 (m, 1 H, CH2), 1.31–1.23 (m, 3 H, 2 CH2),
1.16–1.10 (m, 2 H, CH2), 1.04 (d, J ¼ 6.2 Hz, 3 H, CH3), 0.87–0.84
(m, 6 H, 2 CH3). 13C NMR (125MHz, CDCl3) d 156.90 (quat. C),
143.29 (quat. C), 132.98 (quat. C), 129.13 (2 arom. CH), 128.57 (2
arom. CH), 127.37 (arom. CH), 125.56 (2 arom. CH), 115.85 (2
arom. CH), 75.97 (CH), 52.50(CH), 50.83(CH2), 39.16(CH2), 37.29
(CH2), 27.95 (CH), 24.46 (CH3), 23.72 (CH2), 22.67 (CH3), 22.59
(CH3), 20.31 (CH3). IR (KBr): n [cmꢂ1] ¼ 3353, 2954, 2927, 1586,
N-(4-(Benzyloxy)benzyl)-6-methylheptan-2-amine (7k)
The compound was prepared according to General procedure
I from 954 mg (4.5 mmol) of 7k and 827 mg (6.4 mmol)
6-methylheptan-2-amine to give 1.34 g (92%) of 7k as a
colorless oil. 1H NMR (500 MHz, CDCl3) d 7.43 (d, J ¼ 7.3 Hz, 2 H,
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1508, 1467, 1238, 1170, 1014, 698. GC-MS (EI): m/z (%)¼ 339
131.94 (2 arom. CH), 128.94 (2 arom. CH), 128.38 (2 arom.
CH), 126.41 (arom. CH), 122.61 (quat. C), 114.69 (2 arom.
CH), 68.61 (CH2), 51.87 (CH), 46.52 (CH2), 38.39 (CH2), 35.56
(CH2), 32.83 (CH2), 27.80 (CH), 23.35 (CH2), 22.30 (CH3),
22.16 (CH3), 15.69 (CH3). IR (KBr): n [cmꢂ1] ¼ 2953, 2866,
2770, 1613, 1585, 1518, 1468, 1454, 1431, 1384, 1247, 1184,
1037, 819, 750, 699, 603, 538. HR-MS: calcd. for C23H34NOþ:
340.2640. Found: 340.2634.
(Mþ, 0.2), 228 (0.2), 254 (18), 107 (100). HR-MS: calcd. for
C23H33NO: 339.2562. Found: 339.2561.
(ꢀ)-6-Methyl-N-(4-(1-phenylethoxy)benzyl)heptan-2-
aminium chloride (8l)
The compound was prepared according to General proce-
dure II from 776 mg (2.29 mmol) of 7l to give 854 mg (99%) of
1
8l as a colorless oil. H NMR (400 MHz, CD2Cl2) d 9.67 (s, 1 H,
NH), 9.45 (s, 1 H, NH), 7.45 (d, J ¼ 8.7 Hz, 2 H, 2 arom. CH),
7.39–7.19 (m, 5 H, 5 arom. CH), 6.85 (d, J ¼ 8.7 Hz, 2 H, 2 arom.
CH), 5.22 (q, J ¼ 6.5 Hz, 1 H, CH), 3.89–3.77 (m, 2 H, CH2),
2.93–2.82 (m, 1 H, CH), 1.55 (d, J ¼ 6.5 Hz, 3 H, CH3), 1.37–0.88
(m, 10 H, CH, 3 CH2, CH3), 0.90–0.79 (m, 6 H, 2 CH3). 13C NMR
(125 MHz, DMSO-d6) d 157.91 (quat. C), 142.80 (quat. C),
131.46 (2 arom. CH), 128.55 (2 arom. CH), 127.49 (arom. CH),
125.74 (2 arom. CH), 123.93 (quat. C), 115.84 (2 arom. CH),
74.79 (CH), 53.21 (CH), 46.50 (CH2), 38.00 (CH2), 32.16 (CH2),
27.29 (CH), 24.13 (CH3), 22.65 (CH2), 22.46 (CH3), 22.27 (CH3),
20.70 (CH3). HR-MS: calcd. for C23H34NOþ: 340.2640. Found:
340.2636.
6-Methyl-N-(4-propoxybenzyl)heptan-2-amine (7n)
The compound was prepared according to General procedure
I from 558 mg (3.4 mmol) of 6n and 617 mg (4.8 mmol)
6-methylheptan-2-amine to give 518 mg (55%) of 7n as a
pale yellow oil. 1H NMR (500 MHz, CDCl3) d 7.22 (d, J ¼ 8.6 Hz, 2
H, 2 arom. CH), 6.85 (d, J ¼ 8.6 Hz, 2 H, 2 arom. CH), 3.94 (t,
J ¼ 6.6 Hz, 2 H, CH2), 3.76 (d, J ¼ 12.8 Hz, 1 H, CH2), 3.67 (d,
J ¼ 12.8 Hz, 1 H, CH2), 2.67 (h, J ¼ 6.1 Hz, 1 H, CH), 1.81–1.70 (m,
2 H, CH2), 1.56–1.43 (m, 4 H, 2 CH2, CH), 1.34–1.25 (m, 3 H, 2
CH2), 1.17–1.11 (m, 2 H, CH2), 1.08 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.97
(t, J ¼ 7.4 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.7 Hz, 3 H, CH3), 0.86 (d,
J ¼ 6.7 Hz, 3 H, CH3). 13C NMR (125 MHz, CDCl3) d 158.49 (quat.
C), 129.84 (2 arom. CH), 128.56 (quat. C), 114.50 (2 arom. CH),
69.51 (CH2O), 52.09 (CH), 49.58 (CH2), 38.95 (CH2), 36.02 (CH2),
27.89 (CH), 23.65 (CH2), 22.63 (CH2), 22.58 (CH3), 22.53 (CH3),
19.02 (CH3), 10.51 (CH3). HR-MS: calcd. for C18H30NO (MþꢂH):
276.2327. Found: 276.2334.
6-Methyl-N-(4-phenethoxybenzyl)heptan-2-amine (7m)
The compound was prepared according to General procedure
I from 1.017 g (4.5 mmol) 2-phenylethoxybenzaldehyde and
822 mg (6.4 mmol) 6-methylheptan-2-amine to give 485 mg
1
(32%) of 7m as a pale brown oil. H NMR (500 MHz, CDCl3) d
7.35–7.27 (m, 5 H, 5 arom. CH), 7.23 (d, J ¼ 8.6 Hz, 2 H, 2 arom.
CH), 6.86 (d, J ¼ 8.6 Hz, 2 H, 2 arom. CH), 4.16 (t, J ¼ 7.1 Hz, 2 H,
CH2), 3.77 (d, J ¼ 12.7 Hz, 1 H, CH2), 3.68 (d, J ¼ 12.7 Hz, 1 H,
CH2), 3.09 (t, J ¼ 7.2 Hz, 2 H, CH2), 2.74–2.61 (m, 1 H, CH), 1.56
(m, 1 H, CH), 1.28 (m, 4 H, 2 CH2), 1.17 (m, 2 H, CH2), 1.09 (d,
J ¼ 6.2 Hz, 3 H, CH3), 0.87 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(125 MHz, CDCl3) d 157.58 (quat. C), 138.26 (quat. C), 132.13
(quat. C), 129.44 (2 arom. CH), 129.00 (2 arom. CH), 128.48 (2
arom. CH), 126.48 (arom. CH), 114.51 (2 arom. CH), 68.71
(CH2), 52.36 (CH), 50.49 (CH2), 39.13 (CH2), 38.79 (CH2), 35.82
(CH2), 27.95 (CH), 23.74 (CH2), 22.68 (CH3), 22.60 (CH3), 20.02
(CH3). MS (EI): m/z (%) ¼ 339 (Mþ, 0.4), 338 (Mþꢂ1, 0.6), 254
(31), 211 (100), 105 (76). HR-MS: calcd. for C23H33NO: 339.2562.
Found: 339.2560.
6-Methyl-N-(4-propoxybenzyl)heptan-2-aminium chloride
(8n)
The compound was prepared according to General procedure
II from 260 mg (0.94 mmol) of 7n to give 270 mg (91%) of 8n as
a white solid. M.p. 170°C. 1H NMR (500 MHz, CD2Cl2) d 9.73 (s,
1 H, NH), 9.53 (s, 1 H, NH), 7.54 (d, J ¼ 8.7 Hz, 2 H, 2 arom. CH),
6.89 (d, J ¼ 8.7 Hz, 2 H, 2 arom. CH), 3.99 (d, J ¼ 13.7 Hz, 1 H,
CH2), 3.92 (d, J ¼ 13.7 Hz, 1 H, CH2), 3.85 (t, J ¼ 6.3 Hz, 2 H, CH2),
2.92 (m, 1 H, CH), 1.93–1.83 (m, 2 H, CH2), 1.75 (qt, J ¼ 6.3,
7.4 Hz, 2 H, CH2), 1.52–1.45 (m, 1 H, CH), 1.44–1.17 (m, 2 H,
CH2), 1.36 (d, J ¼ 6.6 Hz, 3 H, CH3), 1.16–1.09 (m, 2 H, CH2), 0.99
(t, J ¼ 7.4 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 3 H, CH3), 0.85 (d,
J ¼ 6.6 Hz, 3 H, CH3). 13C NMR (125 MHz, DMSO-d6) d 159.52
(quat. C), 132.00 (2 arom. CH), 124.26 (quat. C), 114.94 (2
arom. CH), 69.47 (CH2O), 53.26 (CH), 47.04 (CH2), 38.50 (CH2),
32.72 (CH2), 27.78 (CH), 23.04 (CH2), 22.97 (CH3), 22.80 (CH3),
22.43 (CH2), 16.03 (CH3), 10.83 (CH3). IR (KBr): n [cmꢂ1] ¼ 2951,
2867, 1614, 1516, 1469, 1255, 1183, 983, 818. HR-MS: calcd. for
6-Methyl-N-(4-phenethoxybenzyl)heptan-2-aminium
chloride (8m)
The compound was prepared according to General proce-
dure II from 63 mg (0.19 mmol) of 7m to give 75 mg (100%)
of 8m as a dark white solid. M.p. 129°C (diethyl ether).
1H NMR (400 MHz, CD2Cl2) d 9.81 (s, 1 H, NH), 9.63 (s, 1 H,
NH), 7.58 (d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 7.39–7.21 (m, 5 H, 5
arom. CH), 6.92 (d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 4.13 (t,
J ¼ 6.9 Hz, 2 H, CH2), 3.92 (m, 2 H, CH2), 3.07 (t, J ¼ 6.9 Hz, 2
H, CH2), 2.92 (m, 1 H, CH), 1.96–1.84 (m, 1 H, CH2), 1.72–1.58
(m, 1 H, CH2), 1.53 (th, J ¼ 13.3, 6.6 Hz, 1 H, CH), 1.43 (m, 1 H,
CH2), 1.38 (d, J ¼ 6.5 Hz, 3H, CH3), 1.32–1.20 (m, 1 H, CH2),
1.14 (m, 2 H, CH2), 0.88 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(125 MHz, CD2Cl2) d 159.41 (quat. C), 138.29 (quat. C),
C
18H32NO: 278.2484. Found: 278.2504.
N-(4-Butoxybenzyl)-6-methylheptan-2-amine (7o)
The compound was prepared according to General procedure
I from 605 mg (3.4 mmol) of 6o and 617 mg (4.8 mmol) 6-
methylheptan-2-amine to give 544 mg (55%) of 7o as pale
yellow oil. 1H NMR (500 MHz, CDCl3) d 7.22 (d, J ¼ 8.6 Hz, 2 H, 2
arom. CH), 6.85 (d, J ¼ 8.6 Hz, 2 H, 2 arom. CH), 3.94 (t,
J ¼ 6.5 Hz, 2 H, CH2O), 3.76 (d, J ¼ 12.8 Hz, 1 H, CH2), 3.67 (d,
J ¼ 12.8 Hz, 1 H, CH2), 2.67 (h, J ¼ 6.2 Hz, 1 H, CH), 1.80–1.71 (m,
2 H, CH2), 1.57–1.42 (m, 4 H, 2 CH2), 1.34–1.23 (m, 3 H, CH2, CH),
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1.17–1.11 (m, 2 H, CH2), 1.08 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.97 (t,
J ¼ 7.4 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 3 H, CH3), 0.86 (d,
J ¼ 6.6 Hz, 3 H, CH3). 13C NMR (125 MHz, CDCl3) d 158.17 (arom.
CH), 132.34 (quat. C), 129.33 (2 arom. CH), 114.42 (2 arom. CH),
67.70 (CH2), 52.35 (CH), 50.63 (CH2), 39.13 (CH2), 37.11 (CH2),
31.37 (CH2), 27.94 (CH), 23.73 (CH2), 22.66 (CH3), 22.58 (CH3),
20.10 (CH3), 19.26 (CH2), 13.87 (CH3). HR-MS: calcd. for
C19H32NO: 290.2484. Found: 290.2473.
CH2), 1.27 (d, J ¼ 6.5 Hz, 3 H, CH3), 1.25–1.20 (m, 2 H, CH2),
1.16–1.08 (m, 2 H, CH2), 0.89 (t, J ¼ 7.2 Hz, 3 H, CH3), 0.85 (d,
J ¼ 6.6 Hz, 3 H, CH3), 0.85 (d, J ¼ 6.6 Hz, 3 H, CH3). 13C NMR
(101 MHz, DMSO-d6) d 159.46 (quat. C), 132.05 (2 arom. CH),
124.26 (quat. C), 114.87 (2 arom. CH), 67.95 (CH2), 53.12
(CH), 46.92 (CH2), 38.50 (CH2), 32.63 (CH2), 28.76 (CH2),
28.15 (CH2), 27.68 (CH), 23.08 (CH2), 22.97 (CH3), 22.79
(CH3), 22.34 (CH2), 15.94 (CH3), 14.38 (CH3). HR-MS: calcd.
for C20H36NOþ: 306.2797. Found: 306.2828.
N-(4-Butoxybenzyl)-6-methylheptan-2-aminium chloride
(8o)
N-(4-(Hexyloxy)benzyl)-6-methylheptan-2-amine (7q)
The compound was prepared according to General procedure
I from 700 mg (3.4 mmol) of 6q and 617 mg (4.8 mmol)
6-methylheptan-2-amine to give 748 mg (69%) of 7q as a
pale yellow oil. 1H NMR (400 MHz, CDCl3) d 7.22 (d, J ¼ 8.6 Hz, 2
H, 2 arom. CH), 6.84 (d, J ¼ 8.6 Hz, 2 H, 2 arom. CH), 3.93 (t,
J ¼ 6.6 Hz, 2 H, CH2), 3.77 (d, J ¼ 12.8 Hz, 1 H, CH2), 3.67 (d,
J ¼ 12.8 Hz, 1 H, CH2), 2.67 (h, qt ¼ 6.3 Hz, 1 H, CH), 1.82–1.71
(m, 2 H, CH2), 1.53 (m, 1 H, CH), 1.48–1.40 (m, 2 H, CH2), 1.32
(m, 8 H, 4 CH2), 1.20–1.11 (m, 2 H, CH2), 1.07 (d, J ¼ 6.3 Hz, 3 H,
CH3), 0.89 (t, J ¼ 6.9 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2
CH3). 13C NMR (101 MHz, CDCl3) d 158.17 (quat. C), 132.35
(quat. C), 129.33 (2 arom. CH), 114.42 (2 arom. CH), 68.03
(CH2), 52.35 (CH), 50.64 (CH2), 39.13 (CH2), 37.11 (CH2), 31.61
(CH2), 29.28 (CH2), 27.94 (CH), 25.74 (CH2), 23.73 (CH2), 22.66
(CH3), 22.61 (CH2), 22.58 (CH3), 20.10 (CH3), 14.04 (CH3). MS
(EI): m/z (%) ¼ 319 (Mþ, 0.3), 318 (Mþꢂ1, 0.8), 317 (2), 274 (31),
191 (100), 107 (72). HR-MS: calcd. for C21H37NO (MþꢂH):
319.2875. Found: 319.2885.
The compound was prepared according to General procedure
II from 275 mg (0.95 mmol) of 7o to give 312 mg (100%) of 8o
as a white solid. M.p. 180°C. 1H NMR (400 MHz, methanol-d4) d
7.41 (d, J ¼ 8.8 Hz, 2 H, 2 arom. CH), 6.98 (d, J ¼ 8.8 Hz, 2 H, 2
arom. CH), 4.21–4.06 (m, 2 H, CH2), 4.00 (t, J ¼ 6.4 Hz, 2 H, CH2),
3.28–3.20 (m, 1 H, CH), 1.86–1.71 (m, 3 H, 2 CH2), 1.63–1.46 (m,
4 H, CH, 2 CH2), 1.47–1.30 (m, 2 H, 2 CH2), 1.37 (d, J ¼ 6.6 Hz, 3
H, CH3), 1.27–1.19 (m, 2 H, CH2), 0.98 (t, J ¼ 7.4 Hz, 3 H, CH3),
0.91 (d, J ¼ 6.6 Hz, 3 H, CH3), 0.91 (d, J ¼ 6.6 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3) d 159.78 (quat. C), 131.87 (quat. C),
121.87 (2 arom. CH), 114.83 (2 arom. CH), 67.96 (CH2), 51.87
(CH), 46.82 (CH2), 38.37 (CH2), 32.86 (CH2), 28.85 (CH2), 28.14
(CH2), 27.76 (CH), 23.41 (CH2), 22.55 (CH3), 22.41 (CH3), 15.87
(CH3), 14.00 (CH3). HR-MS: calcd. for C19H34NOþ: 292.2640.
Found: 292.2645.
6-Methyl-N-(4-(pentyloxy)benzyl)heptan-2-amine (7p)
The compound was prepared according to General procedure
I from 653 mg (3.4 mmol) of 6p and 617 mg (4.8 mmol)
6-methylheptan-2-amine to give 529 mg (51%) of 7p as a
colorless oil. 1H NMR (400 MHz, CDCl3) d 7.22 (d, J ¼ 8.6 Hz, 2 H,
2 arom. CH), 6.84 (d, J ¼ 8.6 Hz, 2 H, 2 arom. CH), 3.93 (t,
J ¼ 6.6 Hz, 2 H, CH2), 3.77 (d, J ¼ 12.8 Hz, 1 H, CH2), 3.67 (d,
J ¼ 12.8 Hz, 1 H, CH2), 2.66 (m, 1 H, CH), 1.81–1.71 (m, 2 H, CH2),
1.52 (m, 1 H, CH), 1.48–1.40 (m, 3 H, CH2), 1.38–1.25 (m, 9 H,
CH2), 1.15 (m, 3 H, CH2), 1.07 (d, J ¼ 6.3 Hz, 3 H, CH3), 0.89 (t,
J ¼ 7.2 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(101 MHz, CDCl3) d 158.12 (quat. C), 132.64 (quat. C), 129.25 (2
arom. CH), 114.40 (2 arom. CH), 68.00 (CH2), 52.39 (CH), 50.77
(CH2), 39.14 (CH2), 37.24 (CH2), 29.17 (CH2), 28.41 (CH2), 27.84
(CH), 23.54 (CH2), 22.41 (CH2), 22.57 (CH3), 22.47 (CH3), 20.23
(CH3), 14.02 (CH3). MS (EI): m/z (%) ¼ 305 (Mþ, 0.3), 304 (0.5),
220 (19), 177 (100), 107 (68). HR-MS: calcd. for C20H35NO:
305.2719: Found: 305.2719.
N-(4-(Hexyloxy)benzyl)-6-methylheptan-2-aminium
chloride (8q)
The compound was prepared according to General proce-
dure II from 250 mg (0.78 mmol) of 7q to give 258 mg (93%)
of 8q as a white solid. M.p.: 163°C. 1H NMR (400 MHz,
CD2Cl2) d 9.80 (s, 1 H, NH), 9.63 (s, 1 H, NH), 7.53 (d,
J ¼ 8.7 Hz, 2 H, 2 arom. CH), 6.87 (d, J ¼ 8.7 Hz, 2 H, 2 arom.
CH), 3.98–3.85 (m, 2 H, CH2), 3.86 (t, J ¼ 6.6 Hz, 2 H, CH2),
2.97–2.83 (m, 1 H, CH), 1.93–1.83 (m, 1 H, CH2), 1.76–1.67 (m,
2 H, CH2), 1.67–1.55 (m, 2 H, CH2), 1.50 (dt, J ¼ 13.2, 6.6 Hz, 1
H, CH), 1.44–1.36 (m, 3 H, 2 CH2), 1.35 (d, J ¼ 6.6 Hz, 3 H,
CH3), 1.33–1.27 (m, 4 H, 2 CH2), 1.13 (dt, J ¼ 9.2, 7.1 Hz, 2 H,
CH2), 0.92–0.88 (t, J ¼ 6.7 Hz, 3 H, CH3), 0.85 (d, J ¼ 6.6, Hz, 3
H, CH3), 0.85 (d, J ¼ 6.6 Hz, 3 H, CH3). 13C NMR (100 MHz,
CD2Cl2) d 159.79 (quat. C), 131.90 (2 arom. CH), 122.28
(quat. C), 114.61 (2 arom. CH), 68.04 (CH2), 51.91 (CH), 46.56
(CH2), 38.40 (CH2), 32.83 (CH2), 31.56 (CH2), 29.13 (CH2),
27.80 (CH), 25.63 (CH2), 23.36 (CH2), 22.59 (CH3), 22.30
(CH3), 22.16 (CH2), 15.70 (CH3), 13.78 (CH3). HR-MS. calcd.
for C21H38NO (Mþ): 320.2953. Found: 320.2949. HR-MS:
calcd. for C21H38NOþ: 320.2953. Found: 320.2956.
6-Methyl-N-(4-(pentyloxy)benzyl)heptan-2-aminium
chloride (8p)
The compound was prepared according to General proce-
dure II from 610 mg (2 mmol) of 7p to give 607 mg (89%) of
8p as
a
white solid. M.p. 152°C. 1H NMR (500 MHz,
DMSO-d6) d 9.23 (s, 1 H, NH), 9.07 (s, 1 H, NH), 7.51 (d,
J ¼ 8.7 Hz, 2 H, 2 arom. CH), 6.96 (d, J ¼ 8.7 Hz, 2 H, 2 arom.
CH), 4.10–3.99 (m, 2 H, CH2), 3.97 (t, J ¼ 6.5 Hz, 2 H, CH2),
3.08–2.90 (m, 1 H, CH), 1.83–1.74 (m, 1 H, CH2), 1.74–1.66 (m,
2 H, 2 CH2), 1.56–1.43 (m, 2 H, CH, CH2), 1.42–1.30 (m, 4 H, 2
N-(4-(Decyloxy)benzyl)-6-methylheptan-2-amine (7r)
The compound was prepared according to General procedure
I
from 1.18 g (4.5 mmol) 4-(decyloxy)benzaldehyde and
827 mg (6.4 mmol) 6-methylheptan-2-amine to give 811 mg
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Arch. Pharm. Chem. Life Sci. 2017, 350, e1600342
Benzylamine-Type Antifungals as Butenafine-Related Antimycotics
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(48%) of 7r as a colorless oil. 1H NMR (500 MHz, CDCl3) d 7.23
(d, J ¼ 8.5 Hz, 2 H, 2 arom. CH), 6.85 (d, J ¼ 8.6 Hz, 2 H, 2 arom.
CH), 3.93 (t, J ¼ 6.6 Hz, 2 H, CH2), 3.78 (d, J ¼ 12.8 Hz, 1 H, CH2),
3.69 (d, J ¼ 12.8 Hz, 1 H, CH2), 2.69 (qt, J ¼ 6.3, 5.9 Hz, 1 H, CH),
1.76 (tt, J ¼ 14.5, 6.6 Hz, 2 H, CH2), 1.57–1.39 (m, 5 H, 2 CH2,
CH), 1.39–1.23 (m, 14 H, 7 CH2), 1.14 (m, 2 H, CH2), 1.10 (d,
J ¼ 6.3 Hz, 3 H, CH3), 0.89 (t, J ¼ 6.8 Hz, 3 H, CH3), 0.86 (d,
J ¼ 6.7 Hz, 6 H, 2 CH3). 13C NMR (100 MHz, CDCl3) d 158.28
(quat. C), 129.47 (2 arom. CH), 114.46 (2 arom. CH), 68.05
(CH2), 52.28 (CH), 50.33 (CH2), 39.07 (CH2), 36.82 (CH2), 31.90
(CH2), 29.59 (CH2), 29.57 (CH2), 29.42 (CH2), 29.33 (CH2), 29.31
(CH2), 27.93 (CH), 26.06 (CH2), 23.70 (CH2), 22.69 (CH2), 22.65
(CH3), 22.57 (CH3), 19.82 (CH3), 14.12 (CH3). HR-MS: calcd. for
N-(3-(Benzyloxy)benzyl)-N,6-dimethylheptan-2-amine
(9b)
The compound was prepared according to General procedure
III from 98 mg (0.30 mmol) of 7b to give 63 mg (62%) of 9b as a
pale yellow oil. 1H NMR (400 MHz, CDCl3) d 7.44 (d, J ¼ 7.4 Hz, 2
H, 2 arom. CH), 7.38 (t, J ¼ 7.3 Hz, 2 H, 2 arom. CH), 7.34–7.28
(m, 1 H, arom. CH), 7.23–7.18 (m, 1 H, arom. CH), 7.02 (s, 1 H,
arom. CH), 6.92 (d, J ¼ 7.5 Hz, 1 H, arom. CH), 6.84 (dd, J ¼ 8.2,
2.6 Hz, 1 H, arom. CH), 5.05 (s, 2 H, CH2O), 3.55 (d, J ¼ 13.5 Hz, 1
H, CH2), 3.43 (d, J ¼ 13.5 Hz, 1 H, CH2), 2.68 (h, J ¼ 6.6 Hz, 1 H,
CH), 2.13 (s, 3 H, CH3), 1.60–1.48 (m, 2 H, CH2), 1.41–1.30 (m, 2
H, CH2), 1.30–1.20 (m, 1 H, CH), 1.20–1.12 (m, 2 H, CH2), 0.97 (d,
J ¼ 6.5 Hz, 3 H, CH3), 0.88 (d, J ¼ 6.6 Hz, 6 H, CH3). 13C NMR
(100 MHz, CDCl3) d 158.89 (quat. C), 142.42 (quat. C), 137.22
(quat. C), 129.07 (arom. CH), 128.53 (2 arom. CH), 127.86
(arom. CH), 127.54 (2 arom. CH), 121.30 (arom. CH), 114.95
(arom. CH), 113.12 (arom. CH), 69.88 (CH2), 57.71 (CH), 57.52
(CH2), 39.20 (CH2), 36.72 (CH3), 34.12 (CH2), 28.01 (CH), 24.76
(CH2), 22.72 (CH3), 22.69 (CH3), 13.56 (CH3). IR (KBr): n
[cmꢂ1] ¼ 2956, 2930, 1598, 1585, 1487, 1455, 1381, 1366,
1264, 1152, 1041, 1029, 737, 695. MS (EI): m/z (%) ¼ 339 (Mþ,
0.43), 324 (4), 254 (100), 197 (28). HR-MS: calcd. for C23H33NO:
339.2562. Found: 339.2557.
C
25H45NO: 375.350114. Found: 375.3499.
N-(4-(Decyloxy)benzyl)-6-methylheptan-2-aminium
chloride (8r)
The compound was prepared according to General procedure
II from 132 mg (0.35 mmol) of 7r to give 124 mg (86%) of 8r as
a white solid. M.p. 157°C (diethyl ether). 1H NMR (400 MHz,
CD2Cl2) d 9.81 (s, 1 H, NH), 9.62 (s, 1 H, NH), 7.53 (d, J ¼ 8.7 Hz, 2
H, 2 arom. CH), 6.87 (d, J ¼ 6.7 Hz, 2 H, 2 arom. CH), 3.94–3.80
(m, 2 H, CH2), 3.86 (t, J ¼ 6.6 Hz, 2 H, CH2), 3.03–2.75 (m, 1 H,
CH), 1.95–1.83 (m, 1 H, CH2), 1.76–1.67 (m, 2 H, CH2), 1.67–1.55
(m, 2 H, CH2), 1.49 (tq, J ¼ 13.2, 6.7 Hz, 1 H, CH), 1.44–1.37 (m, 2
H, CH2), 1.35 (d, J ¼ 6.5 Hz, 3 H, CH3), 1.33–1.22 (m, 13 H, 7 CH2),
1.17–1.09 (m, 2 H, CH2), 0.92–0.86 (t, J ¼ 6.8 Hz, 3 H, CH3), 0.85
(d, J ¼ 6.6 Hz, 3 H, CH3), 0.85 (d, J ¼ 6.6 Hz, 3 H, CH3). 13C NMR
(101 MHz, CD2Cl2) d 161.13 (quat. C), 133.23 (2 arom. CH),
123.61 (quat. C), 115.94 (2 arom. CH), 69.38 (CH2), 53.24 (CH),
47.89 (CH2), 39.73 (CH2), 34.16 (CH2), 33.23 (CH2), 30.91 (CH2),
30.89 (CH2), 30.72 (CH2), 30.65 (CH2), 30.51 (CH2), 29.13 (CH2),
27.30 (CH), 24.69 (CH2), 24.01 (CH2), 23.63 (CH3), 23.49
(CH3), 17.03 (CH3), 15.20 (CH3). HR-MS: calcd. for C25H46NOþ:
376.3579. Found: 376.3555.
N,6-Dimethyl-N-(3-phenethoxybenzyl)heptan-2-amine
(9d)
The compound was prepared according to General procedure
III from 170 mg (0.5 mmol) of 7d to give 106 mg (60%) of 9d.
1H NMR (400 MHz, CDCl3) d 7.34–7.26 (m, 4 H, 4 arom. CH),
7.25–7.21 (m, 1 H, arom. CH), 7.19 (t, J ¼ 7.8 Hz, 1 H, arom. CH),
6.92 (d, J ¼ 2.0 Hz, 1 H, arom. CH), 6.89 (d, J ¼ 7.5 Hz, 1 H, arom.
CH), 6.76 (dd, J ¼ 7.9, 2.8 Hz, 1 H, arom. CH), 4.17 (t, J ¼ 7.2 Hz,
2 H, CH2), 3.53 (d, J ¼ 13.4 Hz, 1 H, CH2), 3.41 (d, J ¼ 13.4 Hz, 1 H,
CH2), 3.09 (t, J ¼ 7.2 Hz, 2 H, CH2), 2.67 (h, J ¼ 6.6 Hz, 1 H, CH),
2.12 (s, 3 H, CH3), 1.57–1.47 (m, 2 H, CH2), 1.39–1.29 (m, 2 H,
CH2), 1.27–1.20 (m, 1 H, CH), 1.19–1.12 (m, 2 H, CH2), 0.97 (d,
J ¼ 6.5 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2 CH3). 13C NMR
(125 MHz, chloroform-d) d 158.87 (quat. C), 142.24 (quat. C),
138.33 (quat. C), 129.07 (arom. CH), 129.02 (2 arom. CH),
128.44 (2 arom. CH), 126.42 (arom. CH), 121.12 (arom. CH),
114.60 (arom. CH), 112.95 (arom. CH), 68.55 (CH2), 57.64
(CH), 57.48 (CH2), 39.14 (CH2), 36.65 (CH3), 35.87 (CH2), 34.04
(CH2), 27.98 (CH), 24.71 (CH2), 22.67 (CH3), 22.64 (CH3), 13.49
(CH3). IR (KBr): n [cmꢂ1] ¼ 2955, 2929, 1600, 1585, 1455, 1383,
1365, 1265, 1153, 1038, 750, 698. HR-MS: calcd. for C24H35NO:
353.2719. Found: 353.2753.
N,6-Dimethyl-N-(3-phenoxybenzyl)heptan-2-amine (9a)
The compound was prepared according to General procedure
III from 109 mg (0.35 mmol) of 7a to give 74 mg (65%) of 9a as
a colorless oil. 1H NMR (500 MHz, CDCl3) d 7.34–7.29 (m, 2 H, 2
arom. CH), 7.25 (t, J ¼ 7.8 Hz, 1 H, arom. CH), 7.10–7.05 (m, 2 H,
arom. CH), 7.03 (s, 1 H, arom. CH), 7.02–6.98 (m, 2 H, 2 arom.
CH), 6.86 (dd, J ¼ 7.7, 2.1 Hz, 1 H, arom. CH), 3.55 (d,
J ¼ 13.6 Hz, 1 H, CH2), 3.43 (d, J ¼ 13.6 Hz, 1 H, CH2), 2.67 (h,
J ¼ 6.6 Hz, 1 H, CH), 2.13 (s, 3 H, CH3), 1.55–1.46 (m, 2 H, CH2),
1.37–1.27 (m, 2 H, CH2), 1.27–1.19 (m, 1 H, CH), 1.18–1.10 (m, 2
H, CH2), 0.96 (d, J ¼ 6.5 Hz, 3 H, CH3), 0.86 (d, J ¼ 6.6 Hz, 6 H, 2
CH3). 13C NMR (126 MHz, CDCl3) d 157.46 (quat. C), 157.06
(quat. C), 142.91 (quat. C), 129.63 (2 arom. CH), 129.32 (arom.
CH), 123.59 (arom. C), 122.94 (arom. CH), 119.26 (arom. CH),
118.66 (2 arom. CH), 117.15 (arom. CH), 57.70 (CH), 57.30
(CH2), 39.14 (CH2), 36.65 (CH3), 34.08 (CH2), 27.93 (CH), 24.67
(CH2), 22.67 (2 CH3), 13.52 (CH3). HR-MS: calcd. for C22H31NO:
325.2406. Found: 325.2413.
N,6-Dimethyl-N-(3-phenoxybenzyl)heptan-2-aminium
chloride (10a)
The compound was prepared according to General procedure II
from 98 mg (0.3 mmol) of 9a to give 90mg (83%) of 10a as a
white solid. M.p. 148°C (diethyl ether). 1H NMR (500 MHz,
methylene chloride-d2) d 12.26 (d, J ¼ 55.4 Hz, 1 H, NH),
7.56–7.49 (m, 1 H, arom. CH), 7.38–7.19 (m, 4 H, 4 arom. CH),
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Arch. Pharm. Chem. Life Sci. 2017, 350, e1600342
J. Krauss et al.
Archiv der Pharmazie
7.07 (t, J ¼ 7.3 Hz, 1 H, arom. CH), 6.95 (d, J ¼ 7.9 Hz, 3 H, 3 arom.
CH), 4.14–3.86(m,2H,CH2),3.13(q, J ¼ 7.6 Hz, 1H,CH), 2.51(dd,
J ¼ 9.0, 4.6 Hz, 3 H, CH3), 1.82–1.73 (m, 1 H, CH2), 1.44 (dt,
J ¼ 13.2, 6.4 Hz, 1 H, CH), 1.35 (d, J ¼ 7.0 Hz, 3 H, CH3),
1.33–1.24 (m, 1 H, CH2), 1.20 (m, 2 H, CH2), 1.14–1.03 (m, 2 H,
CH2), 0.78(d, J ¼ 4.6 Hz, 6 H, 2 CH3). 13CNMR(125MHz, CD2Cl2) d
157.81(quat. C), 156.56(quat. C),131.32(quat.C),130.77(arom.
CH), 130.05 (2 arom. CH), 125.97 (arom. CH), 123.96 (arom. CH),
121.32(arom.CH),119.64(arom. CH), 119.35(2arom. CH),58.44
(CH), 56.35 (CH2), 38.32 (CH2), 35.23 (CH3), 31.45 (CH2), 27.78
(CH), 24.10 (CH2), 22.31 (CH3), 22.11 (CH3), 14.50 (CH3). HR-MS:
calcd. for C22H32NOþ: 326.2484. Found: 326.2444.
IC50 values, as the concentration of compound that reduces
cell growth by 50% versus untreated control cells [18].
The authors have declared no conflicts of interest.
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C), 130.03 (arom. CH), 128.44 (2 arom. CH), 127.93 (arom. CH),
127.84 (2 arom. CH), 123.16 (arom. CH), 116.93 (arom. CH),
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The compound was prepared according to General procedure
II from 247 mg (0.7 mmol) of 9d to give 235 mg (86%) of 10d as
a white brown waxy oil. 1H NMR (500 MHz, methylene
chloride-d2) d 12.17–11.75 (m, 1 H, NH), 7.50 (m, 1 H, arom.
CH), 7.34–7.28 (m, 5 H, 5 arom. CH), 7.22 (m, 1 H, arom. CH),
7.16 (m, 1 H, arom. CH), 6.94 (m, 1 H, arom. CH), 4.27 (m, 2 H,
CH2), 4.17–3.93 (m, 2 H, CH2), 3.25–3.15 (m, 1 H, CH), 3.10
(t, J ¼ 6.8 Hz, 2 H, CH2), 2.59 (m, 3 H, CH3), 2.08 (m, 1 H, CH2),
1.92–1.81 (m, 1 H, CH2), 1.56–1.12 (m, 8 H, CH3, CH, 2 CH2), 0.85
(m, 6 H, 2 CH3). HR-MS: calcd. for C24H36NOþ: 354.2797. Found:
354.2782.
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Biology
Cellular toxicity of selected compounds was determined using
the colorimetric MTT-based assay on HL-60 cell line after
incubation at 37°C for 24 h in the presence of increasing
concentrations of compounds. The results are expressed as
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ß 2017 Deutsche Pharmazeutische Gesellschaft
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(20 of 20) e1600342