Chemoselective Synthesis of N -(Aminoalkyl/amidino)phenyl Naphthalene-1-carboxamides and 5,6,7,8-Tetrahydronaphthalene-1-carboxamides and Their Anticoagulant Screening

Article abstract of DOI:10.1055/s-0036-1588517

N -[(Aminoalkyl)phenyl]-1-naphthamides and N -[(aminoalkyl)phenyl]-5,6,7,8-tetrahydronaphthalene-1-carboxamides were selectively synthesized from the corresponding cyanonaphthamides by catalytic hydrogenation. N -(Amidinophenyl)-1-naphthalenecarboxamides and N -(amidinophenyl)-5,6,7,8-tetrahydronaphthalene-1-carboxamides were chemoselectively obtained from the corresponding O -acetylamidoximes or amidoximes, respectively, by catalytic hydrogenation. The products were screened for their anticoagulant effects in human plasma, as measured by the activated partial thromboplastin time and the prothrombin time in vitro. Amidines and 5,6,7,8-tetrahydronaphthamides were more active than aminoalkyl compounds and naphthamides.

Full text of DOI:10.1055/s-0036-1588517

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
T. H. Nguyen, E. Ma
Letter
Synlett
Chemoselective Synthesis of N-(Aminoalkyl/amidino)phenyl
Naphthalene-1-carboxamides and 5,6,7,8-Tetrahydronaphtha-
lene-1-carboxamides and Their Anticoagulant Screening
Thi Ha Nguyena,b
Eunsook Ma*a
H
a. H2 (40 psi), 10% Pd/C, concd HCl,
ethanol, r.t., 3 h
a
a
a
b
b
1
2
3
11
12
13
4. R' = CH2NH2·HCl (51%)
5. R' = CH2NH2·HCl (60%)
6. R' = CH2CH2NH2·HCl (48%)
13. R' = 3-amidine·HCl (87%)
14. R' = 4-amidine·HCl (82%)
15. R' = 4-amidinomethyl·HCl (90%)
O
N
R'
b.1) acetic anhydride, acetic acid,
r.t., 1–2 h
OC2H5
H
O
N
2) H2 (40 psi), 10% Pd/C,
concd HCl,ethanol, r.t., 3 h
R
b
a College of Pharmacy, Catholic University of Daegu, Hayang-ro
13-13, Hayang-eup, Gyeongsan-si, Gyeongbuk 712-702,
Republic of Korea
OC2H5
1. R = 3-CN
2. R = 4-CN
3. R = 4-CH2CN
11. R = 3-amidoxime
12. R = 4-amidoxime
masook@cu.ac.kr
b Department of Phytochemistry, National Institute of Medicinal
Materials (NIMM), Hanoi 100000, Vietnam
c. SM (0.19 mmol), H2 (45 psi),
10% Pd/C, concd HCl, Ethanol,
45 °C, 5 h
c
c
c
d
d
H
1
2
3
11
12
13
7. R' = CH2NH2·HCl (81%)
8. R' = CH2NH2·HCl (86%)
9. R' = CH2CH2NH2·HCl (76%)
16. R' = 3-amidine·HCl (83%)
17. R' = 4-amidine·HCl (88%)
18. R' = 4-amidinomethyl·HCl (86%)
O
N
13. R = 4-amidoximinomethyl
R'
d. SM (0.17 mmol), H2 (45 psi),
10% Pd/C, concd HCl, ethanol,
45 °C, 5 h
OC2H5
d
Received: 13.05.2017
Accepted after revision: 03.07.2017
Published online: 08.08.2017
thrombinase complex. FXa inhibitors are predicted to have
a lower risk of bleeding and a more-favorable safety/efficacy
ratio than heparins or warfarin.2 Many amidine-containing
and nonamidine-containing compounds possess significant
FXa and thrombin inhibitory effects and anticoagulant ac-
tivities. Although amidine-containing inhibitors demon-
strate potent in vivo anticoagulant activity, owing to their
high hydrophilicity arising from the high polarity of the
amidine group, the hydrophilicity and basicity of the ami-
dine moiety result in a decrease in oral bioavailability and
membrane permeability.3 In other words, it would appear
that an enhancement in the lipophilicity of amidine-
containing compounds might improve their oral anticoagu-
lant activities.
DOI: 10.1055/s-0036-1588517; Art ID: st-2017-u0359-l
Abstract N-[(Aminoalkyl)phenyl]-1-naphthamides and N-[(amino-
alkyl)phenyl]-5,6,7,8-tetrahydronaphthalene-1-carboxamides were se-
lectively synthesized from the corresponding cyanonaphthamides by
catalytic hydrogenation. N-(Amidinophenyl)-1-naphthalenecarbox-
amides and N-(amidinophenyl)-5,6,7,8-tetrahydronaphthalene-1-car-
boxamides were chemoselectively obtained from the corresponding O-
acetylamidoximes or amidoximes, respectively, by catalytic hydrogena-
tion. The products were screened for their anticoagulant effects in hu-
man plasma, as measured by the activated partial thromboplastin time
and the prothrombin time in vitro. Amidines and 5,6,7,8-tetra-
hydronaphthamides were more active than aminoalkyl compounds and
naphthamides.
Among approaches for the enhancement of lipophilici-
ty, the introduction of a naphthalene ring instead of a ben-
zene ring as a skeletal structure and the subsequent conver-
sion of the naphthalene ring into a 5,6,7,8-tetrahydronaph-
thalene ring has been suggested. Nonamidine-type
compounds containing weakly basic groups, such as amino-
alkyl groups, have being also developed for the enhance-
ment of lipophilicity. However, elimination of the amidine
group causes an increase in the overall lipophilicity of the
inhibitor, which often leads to a detrimental decrease in an-
ticoagulant potency.4
Taking in consideration the presence of carboxamide
groups in many FXa inhibitors, we aimed to synthesize a set
of novel compounds as potential anticoagulant agents that
have benzamidine or less-basic amine entities in addition
to naphthalenecarboxamide or tetrahydronaphthalenecar-
boxamide as the target skeleton. Here, we describe the
chemoselective synthesis of N-[(aminoalkyl)phenyl] or
N-(amidinophenyl)naphthalene-1-carboxamides and -5,6,7,8-
tetrahydronaphthalene-1-carboxamides. All the newly syn-
thesized compounds were tested for their anticoagulant ac-
Key words reduction,
naphthamide, catalytic hydrogenation
amidines,
naphthamides,
tetrahydro-
Thromboembolic diseases continue to be a leading
cause of morbidity and mortality in the developed world,
and the use of anticoagulant drugs is a primary clinical
strategy to treat and prevent these diseases. Currently pre-
scribed anticoagulant drugs have considerable shortcoming
that limit their clinical application. Warfarin, the most
widely used oral anticoagulant, is limited by its slow onset
and offset of action, its narrow therapeutic range, and its
high degree of individual variation of response, which de-
mands frequent monitoring.1 Heparins have a rapid onset
of action, but must be administered parenterally and are in-
convenient and not cost-effective for administration after
hospital discharge.
Factor Xa, a trypsin-like serine protease located in a
central position of the intrinsic and extrinsic pathways of
the blood-coagulation cascade, catalyzes the conversion of
prothrombin into its active form, thrombin, via the pro-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
T. H. Nguyen, E. Ma
Letter
Synlett
tivity through determination of their activated partial
thromboplastin time (aPTT) and prothrombin time (PT) in
vitro.
1-naphthalenecarboxylic acid with a Ni catalyst leads to se-
lective reduction of the more-electron-rich part to yield
5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid and, fur-
thermore, a nitrile group was reduced more slowly than a
naphthalene ring attached to an electron-withdrawing
group.10 This report suggests that it might be difficult to
obtain N-[(aminoalkyl)phenyl]-1-naphthamides without
hydrogenation of the naphthalene ring. The N-[(amino-
alkyl)phenyl]-5,6,7,8-tetrahydro-1-naphthylamides 7–9 were
chemoselectively obtained in yields of 81, 86, and 76%, re-
spectively, from the corresponding nitrile compounds 1–3
by extension of reaction time for the hydrogenation [1–3
(0.19 mmol) 10% Pd/C (12 mg), H2 (40 psi), concd HCl (6.93
mg), ethanol (15 mL), 45 °C, 5 h] (Scheme 1).
The amidine functional group is found in a wide variety
of biologically active molecules. Therefore, several synthetic
strategies have been developed for the synthesis of ami-
dines. The most common methods for amidine synthesis
commence with amides, nitriles, or thioamides.11 Generally,
alkyl nitriles are converted into amidines in a two-step pro-
cess involving reaction with HCl/EtOH to afford an imidate
salt (the Pinner reaction), followed by reaction with NH4-
Cl/EtOH to give the desired amidine salt. This method is
also the most widely used procedure for the preparation of
unsubstituted amidines.12
We followed the Pinner/ammonolysis procedure in an
attempt to synthesize the amidino naphthamides 13–15
from nitriles 1–3, but <1% of the corresponding amidines
were obtained. In accord with Garigipati’s procedure,13 the
nitriles 1–3 were treated with chloro(methyl)aluminum
amide in toluene and then treated with H2O in an single
step, but the corresponding amidines were not obtained.
Therefore, other methods were attempted. Nitriles 1–3
were converted into amidines 13–15 via the corresponding
amidoximes 10–12 by 10% palladium-catalyzed hydro-
genation, but mixtures of amidino-1-naphthamides and
-5,6,7,8-tetrahydronaphthalene-1-carboxamides were ob-
All the synthetic methods used in this study are shown
in Schemes 1 and 2. Scheme 1 shows the synthesis of N-
[(aminoalkyl)phenyl]naphthalene-1-carboxamides 4–6 and
N-[(aminoalkyl)phenyl]-5,6,7,8-tetrahydronaphthalene-1-
carboxamides 7–9 from the corresponding nitriles 1–3.
Coupling of 2-ethoxy-1-naphthoyl chloride with 3- or 4-
aminobenzonitrile or (4-aminophenyl)acetonitrile to give
nitriles 1–3. Generally, nitriles can be reduced to primary
amines by using a variety of hydride reducing agents, such
as LiAlH4, LiBH3NH2,5 NiCl2/NaBH4,6 InCl3/NaBH4,7 or
NaBH4/I2.8 However, we observed that the reduction of ni-
triles 1–3 with LiAlH4, NiCl2/NaBH4, or InCl3/NaBH4 did not
afford the corresponding aminoalkyl derivatives 4–6.
According to a report by Bagal and Bhanage,9 selective
hydrogenation of cyano groups to aminoalkyl groups by us-
ing Pd/C is difficult, and secondary or tertiary amine deriv-
atives are frequently obtained as byproducts. To prevent the
formation of these amine derivatives and to obtain the final
compound as a hydrochloride salt, we chose to use acidic
conditions under high pressure in Pd/C hydrogenation. As a
result, we found that nitriles 1–3 were converted into the
corresponding N-[(aminoalkyl)phenyl]-1-naphthamide de-
rivatives 4–6 by hydrogenation with a 10% Pd/C catalyst [re-
action conditions: 1–3 (0.19 mmol) 10% Pd/C (12 mg), H2
(40 psi), r.t., 3 h] (Scheme 1). However, the isolated yields of
4–6 were moderate (51, 60, and 48%, respectively), and the
residual starting materials were recovered. Fortunately,
however, secondary and tertiary amine derivatives were
not obtained. In every hydrogenation reaction that we
tried, mixtures of the desired products 4–6, unwanted
5,6,7,8-tetrahydronaphthalene-1-carboxamides 7–9, and
starting material 1–3 were always obtained in various
yields under a range of 10% Pd/C-catalyzed hydrogenation
conditions. It has been reported that the hydrogenation of
O
O
7 : R = 3-CH2NH2 HCl (81%)
8 : R = 4-CH2NH2 HCl (86%)
9 : R = 4-CH2CH2NH2 HCl (76%)
OH
HN
OC2H5
R
OC2H5
SOCl2
H2 (45 psi), 10% Pd/C
concd HCl, ethanol,
45 °C, 5 h
O
O
O
R
H2 (40 psi), 10% Pd/C
Et3N
+
H2N
HN
HN
concd HCl, ethanol,
r.t., 3 h
Cl
OC2H5
dichloromethane
R
R
OC2H5
OC2H5
4 : R = 3-CH2NH2 HCl (51%)
5 : R = 4-CH2NH2 HCl (60%)
6 : R = 4-CH2CH2NH2 HCl (48%)
1 : R = 3-CN (90%)
2 : R = 4-CN (88%)
3 : R = 4-CH2CN (79%)
Scheme 1 Synthesis of N-[(aminoalkyl)phenyl]naphthalene-1-carboxamides 4–6 and N-[(aminoalkyl)phenyl]-5,6,7,8-tetrahydronaphthalene-1-
carboxamide derivatives 7–9
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
T. H. Nguyen, E. Ma
Letter
Synlett
1 : R = 3-CN
2 : R = 4-CN
O
3 : R = 4-CH2CN
HN
R
OC2H5
NH2OH HCl, Et3N
dichloromethane
reflux
H2 (45psi), 10% Pd/C
concd HCl, ethanol, 45 °C, 5 h
1. acetic anhydride,
acetic acid
O
O
O
HN
HN
2. H2 (40 psi), 10% Pd/C
concd HCl, ethanol,
r.t., 3 h
HN
R
OC2H5
R
R
OC2H5
OC2H5
16 : R = 3-amidine HCl (83%)
17 : R = 4-amidine HCl (88%)
18 : R = 4-methylamidine HCl (86%)
13 : R = 3-amidine HCl (87%)
14 : R = 4-amidine HCl (82%)
15 : R = 4-methylamidineHCl (90%)
10 : R = 3-amidoxime (80%)
11 : R = 4-amidoxime (87%)
12 : R = 4-methylamidoxime (90%)
Scheme 2 Synthesis of N-(amidinophenyl)naphthalene-1-carboxamides 13–15 and -5,6,7,8-tetrahydronaphthalene-1-carboxamides 16–18.
tained regardless of the amount of catalyst, the reaction
temperature, or the reaction time. It has been reported that
amidoximes can be reduced to the desired amidines treat-
ment with triethylsilane and PdCl2 in acetic acid.14 Howev-
er, when the amides 10–12 were treated by this method,
the corresponding (amidinophenyl)naphthamides 13–15
Table 1 Reaction Conditions and Yields in the Conversion of Nitriles and O-Acetylamidoximes or Amidoximes into the Corresponding Alkylamines and
Amidines
R2
H
O
N
OC2H5
R1
H
4–6
13–15
O
N
OC2H5
R2
H
O
N
OC2H5
1–3
10–12
7–9
16–19
Substrate
R1
3-CN
Reaction conditionsa
Product
R2
Yield (%)
1
2
A
A
A
B
3-CH2NH2·HCl
51
60
48
81
86
76
87
82
90
83
88
86
4-CN
5
6
4-CH2NH2·HCl
3
4-CH2CN
4-CH2CH2NH2·HCl
3-CH2NH2·HCl
1
3-CN
7
2
4-CN
B
8
4-CH2NH2·HCl
3
4-CH2CN
B
9
4-(CH2)2NH2·HCl
3-C(=NH)NH2·HCl
4-C(=NH)NH2·HCl
4-CH2C(=NH)NH2·HCl
3-C(=NH)NH2·HCl
4-C(=NH)NH2·HCl
4-CH2C(=NH)NH2·HCl
10
11
12
10
11
12
3-C(NH2)=NOH
4-C(NH2)=NOH
4-CH2C(NH2)=NOH
3-C(NH2)=NOH
4-C(NH2)=NOH
4-CH2C(NH2)=NOH
C
C
C
D
D
D
13
14
15
16
17
18
a Reaction conditions: A: 1–3 (0.19 mmol), 10% Pd/C (12 mg), H2 (40 psi), concd HCl (6.93 mg), ethanol (15 mL), r.t., 3 h; B: 1–3 (0.19 mmol), 10% Pd/C (12 mg),
H2 (45 psi), 45 °C, 5 h; C: 10–12 (0.34 mmol), acetic anhydride (1 mL), acetic acid (1 mL), r.t., 1–3 h; then 10% Pd/C (12 mg), H2 (40 psi), concd HCl (5.48 mg),
ethanol (15 mL), r.t., 3 h; D: 10–12 (0.17 mmol), 10% Pd/C (12 mg), H2 (45 psi), ethanol (15mL), 45 °C, 5 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
T. H. Nguyen, E. Ma
Letter
Synlett
were not obtained. Nadrah and Dolenc15 have reported that
amidines can be prepared by reducing acetylated amidox-
imes with potassium formate. A published study16 found
that substituted benzonitriles could be converted into in-
termediate benzamidoximes, which were then successfully
reduced to benzamidines by palladium-catalyzed hydroge-
nolysis in acetic acid–acetic anhydride in situ; however,
compounds with a naphthalene skeleton were not used in
this study.
Scheme 2 illustrated the synthesis of N-[(amidino)phe-
nyl]naphthalene-1-carboximides 13–15 and N-[(amidi-
no)phenyl]-5,6,7,8-tetrahydronaphthalene-1-carboxamides
16–18. Nitriles 1–3 were selectively converted into the cor-
responding amidine derivatives 13–15 in yields of 87, 82,
and 90%, respectively, by treatment with hydroxylamine,
followed by acetylation with acetic anhydride and acetic ac-
id, and subsequent palladium-catalyzed hydrogenation of
the resulting O-acetylamidoxime derivatives [acetylami-
doxime, 10% Pd/C (10 mg), concd HCl (5.48 mg), ethanol (15
mL), H2 (40 psi), r.t., 3 h].
N-[(Amidino)phenyl]-5,6,7,8-tetrahydronaphthalene-1-
carboxamides 16–18 were chemoselectively synthesized
from intermediate amidoximes 10–12 by palladium-cata-
lyzed hydrogenolysis [reaction condition: amidoxime (0.17
mmol), 10% Pd/C (12 mg), H2 (45 psi), concd HCl (6.2 mg),
ethanol (15 mL), 45 °C, 5 h]. The benzamidines were effi-
ciently precipitated as their HCl salts by addition of cold dry
diethyl ether to residues in ethanol, obtained after filtra-
tion, and then recrystallized.
Collectively, the hydrogenation time, reaction tempera-
ture, and amount of 10% Pd/C catalyst were the decisive fac-
tors in the chemoselective reduction. Reaction conditions
and yields for the chemoselective hydrogenations are sum-
marized in Table 1.
N-{3-[Amino(imino)methyl]phenyl}-2-ethoxy-5,6,7,8-
tetrahydronaphthalene-1-carboxamide (16) was the most
active compound (aPTT: 64.6 s) in both the aPTT and PT as-
says. N-{3-[Amino(imino)methyl]phenyl}-2-ethoxynaph-
thalene-1-carboxamide (13), N-{4-[amino(imino)meth-
yl]phenyl}-2-ethoxy-5,6,7,8-tetrahydronaphthalene-1-car-
boxamide (17), N-[3-(aminomethyl)phenyl]-2-ethoxy-
5,6,7,8-tetrahydronaphthalene-1-carboxamide (7), and N-
{4-[amino(imino)methyl]phenyl}-2-ethoxynaphthalene-1-
carboxamide (14) displayed high aPTT values (53.2, 52.6,
46.9, and 43.8 s, respectively) compared with the control.
Compounds 7, 14, 16, and 17 showed prolongation of the
PT. However, N-(4′-amidinomethylphenyl)-2-ethoxynaph-
thalene-1-carboxamide (15) and N-(4′-amidinomethylphe-
nyl)-2-ethoxy-5,6,7,8-tetrahydronaphthalene-1-carboxamide
(18) did not prolong the aPTT or the PT. The anticoagulant
activities of 13, 16, and 17 were about one-third or a quar-
ter of that of heparin in vitro, and these compounds have
low molecular weights. Therefore, the 5,6,7,8-tetra-
hydronaphthalene substructure appears to be effective in
inducing anticoagulant activity.
In conclusion, by using various 10% Pd/C-catalyzed hy-
drogenation conditions, N-[(aminoalkyl)phenyl]naphtha-
lene-1-carboxamides18 and -5,6,7,8-tetrahydronaphtha-
lene-1-carboxamides were synthesized from the corre-
sponding nitriles, and N-(amidino)phenyl-1-naphthamides
and -5,6,7,8-tetrahydronaphthalene-1-carboxamides were
chemoselectively synthesized from the corresponding O-
acetylamidoximes and amidoximes, respectively. The N-
(amidinophenyl)-5,6,7,8-tetrahydronaphthalene-1-carbox-
amide derivatives 16 and 17 showed more active than the
Table 2 Anticoagulant Activities of 4–9 and 13–18 at 30 μg/mL
We then examined the effect of the lipophilicity en-
hancement on the anticoagulant activities of the product.
Values of the aPTT and the PT were determined by using a
Thrombotimer (Behnk Elektronik, Norderstedt, Germany),
according to the manufacturer’s instructions, as described
previously.17 The PT results are expressed in seconds and as
international normalized ratios (INRs), and the aPTT results
are expressed in seconds. [INR = (PT sample/PT control)ISI,
ISI = international sensitivity index]. The anticoagulant ef-
fects of the three nonamidinol naphthamides 4–6 and tet-
rahydronaphthamides 7–9, the three amidino 1-naphtha-
mides 13–15, and the three amidino 5,6,7,8-tetrahydro-
naphthalene-1-carboxamide 16–18 were screened in aPTT
and PT assays at a concentration of 30 μg/mL in vitro by us-
ing human plasma (Table 2). The nonamidines 4–6, 8, and 9
did not exhibit a prolongation of the aPTT or the PT in vitro.
These results were slightly surprising, because these com-
pounds contain a less-polar surrogate for the amidine group
(phenylamine or benzylamine), and more lipophilic non-
amidine groups have been reported to improve oral avail-
ability and anticoagulant activity.
Compound
aPTT
PT
11.1
nPTa
DMSOa
39.0
–
4
39.4
11.6
1.05
5
36.0
11.4
1.03
1.01
1.34
1.13
1.21
1.18
1.26
1.19
1.50
1.35
1.09
–
6
39.8
11.2
7
46.9
14.9
8
36.2
12.5
9
40.5
13.4
13
53.2
13.1
14
43.8
14.0
15
35.5
13.2
16
64.6
16.6
17
52.6
15.0
18
38.6
12.1
heparinb
85 (30 μM)
34 (30 μM)
a nPT = PTtested/PTvehicles
.
b DMSO was used as the negative control.
c The molecular weight of the heparin used as a positive control was 3500.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
T. H. Nguyen, E. Ma
Letter
Synlett
N-(amidinophenyl)naphthalene-1-carboxamide derivatives
13 and 14. Compounds 7, 16, and 17 also showed a PT pro-
longation effect. This result suggests that the enhancement
of the lipophilicity of these compounds might prolong their
in vitro aPTT and PT.
(8) Prasad, A. S. B.; Kanth, J. V. B.; Periasamy, M. Tetrahedron 1992,
48, 4623.
(9) Bagal, D. M.; Bhanage, B. M. Adv. Synth. Catal. 2015, 357, 883.
(10) Granik, V. G. Russ. Chem. Rev. 1983, 52, 377.
(11) Aly, A. A.; Nour-El-Din, A. M. ARKIVOC 2008, (i), 153.
(12) (a) Roger, R.; Neilson, D. G. Chem. Rev. 1961, 61, 179.
(b) Schaefer, F. C.; Peters, G. A. J. Org. Chem. 1961, 26, 412.
(c) Schaefer, F. C.; Krapcho, A. P. J. Org. Chem. 1962, 27, 1255.
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(14) Mahajan, U. S.; Godinde, R. R.; Mandhare, P. N. Synth. Commun.
2011, 41, 2195.
Funding Information
This research was supported by the Basic Science Research Program
through the National Research Foundation of Korea (NRF), funded by
(15) Nadrah, K.; Dolenc, S. M. Synlett 2007, 1257.
(16) Brian, D. J.; Allen, D. G.; Cook, T. A.; Evans, B.; Sardharwala, T. E.
Synth. Commun. 1996, 26, 4351.
the Ministry of Education, Science, and Technology (2010-0013516)
N
oaitn
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u
n
d
oaitnofKore
a
2(
0
1
0-0
0
1
3
5
1
6)
(17) Kim, T. H.; Gu, S. K.; Bae, J. S. J. Cell. Biochem. 2012, 113, 2877.
(18) N-[(Aminoalkyl)phenyl]-2-ethoxynaphthalene-1-carboxam-
ide Hydrochlorides 4–6; General Procedure
Supporting Information
Supporting information for this article is available online at
10% Pd/C (12 mg) and concd HCl (6.93 mg, 0.19 mmol) were
added to a solution of the appropriate nitrile 1–3 (0.19 mmol)
in absolute EtOH (15 mL), and the mixture was hydrogenated
(40 psi) at r.t. for 3 h. The mixture was filtered through a Celite
pad that was washed with cold EtOH. The filtrate was evapo-
rated under reduced pressure to give a beige solid that was crys-
tallized from EtOH–Et2O to give pure white or pale-yellow crys-
tals.
https://doi.org/10.1055/s-0036-1588517.
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N-[3-(Aminomethyl)phenyl]-2-ethoxy-1-naphthamide
Hydrochloride (4)
White solid; yield: 31 mg (51%); mp 88–89 °C. 1H NMR (400
MHz, DMSO-d6): δ = 10.57 (s, 1 H, NH), 8.25 (br s, 3 H, NH2·HCl),
8.03 (d, J = 9.2 Hz, 1 H, H-8), 8.00 (s, 1 H, H-2′), 7.93 (d, J = 8.4 Hz,
1 H, H-5), 7.69 (d, J = 8.4 Hz, 1 H, H-4), 7.63 (d, J = 8.0 Hz, 1 H, H-
6′), 7.47–7.55 (m, 2 H, H-3,7), 7.35–7.44 (m, 2 H, H-6,5′), 7.26 (d,
J = 7.2 Hz, 1 H, H-4′), 4.24 ( q, J = 6.8 Hz, 2 H, OCH2), 3.96 (s, 2 H,
CH2) 1.29 (t, J = 6.8 Hz, 3 H, CH3). 13C NMR (100 MHz, DMSO-d6):
δ = 165.5 (C=O), 152.6 (C-2), 139.7 (C-3′), 136.0 (C-1′), 131.0 (C-
4), 130.9 (C-5′), 130.6 (C-7), 129.1 (C-8a), 128.2 (C-5), 128.1 (C-
4a), 127.3 (C-6), 124.0 (C-4′), 123.8 (C-3), 123.6 (C-8), 122.0 (C-
6′), 119.2 (C-2′), 115.4 (C-1), 64.8 (OCH2), 42.6 (CH2), 15.0 (CH3).
DIP-MS (EI): m/z = 320 [M – HCl]+. HRMS (FAB): m/z [M + H]+
calcd for C20H20N2O2: 321.1603; found: 321.1621.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E