In vitro antifungal activity of new series of homoallylamines and related compounds with inhibitory properties of the synthesis of fungal cell wall polymers

Article abstract of DOI:10.1016/S0968-0896(02)00605-3

The synthesis, in vitro antifungal evaluation and SAR studies of 101 compounds of the 4-aryl-, 4-alkyl-, 4-pyridyl or -quinolinyl-4-N-arylamino-1-butenes series and related compounds, are reported here. Active structures showed to inhibit (1,3)-β-D-glucan and mainly chitin synthases, enzymes that catalyze the synthesis of the major fungal cell wall polymers.

Full text of DOI:10.1016/S0968-0896(02)00605-3

Bioorganic & Medicinal Chemistry 11 (2003) 1531–1550
In Vitro Antifungal Activity of New Series of Homoallylamines
and Related Compounds with Inhibitory Properties of the
Synthesis of Fungal Cell Wall Polymers
Leonor Y. Vargas M.,a Marıa V. Castelli,b Vladimir V. Kouznetsov,a,*
Juan M. Urbina G.,a Silvia N. Lopez,b Maximiliano Sortino,b Ricardo D. Enriz,c
Juan C. Ribasd and Susana Zacchinob,*
aLaboratory of Fine Organic Chemistry, School of Chemistry, Industrial University of Santander, A.A. 678, Bucaramanga, Colombia
b
´
Farmacognosia, Facultad de Ciencias Bioquımicas y Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531,
´
(2000)-Rosario, Argentina
c
´
Quımica Medicinal, Facultad de Quımica, Bioquımica y Farmacia, Chacabuco y Pedernera, (5700)-San Luis, Argentina
´
´
d
´
Instituto de Microbiologıa Bioquımica, Campus ‘Miguel de Unamuno’, Edificio Departamental (37007)- Salamanca, Spain
´
Received 8 August 2002; accepted 17 October 2002
Abstract—The synthesis, in vitro antifungal evaluation and SAR studies of 101 compounds of the 4-aryl-, 4-alkyl-, 4-pyridyl or
-quinolinyl-4-N-arylamino-1-butenes series and related compounds, are reported here. Active structures showed to inhibit (1,3)-b-d-
glucan and mainly chitin synthases, enzymes that catalyze the synthesis of the major fungal cell wall polymers.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction
arylamino-1-butenes (Fig. 1) and related tetra-
hydroquinolines and quinolines display a range of anti-
fungal properties against dermatophytes, fungi that
produce most of the dermatomycoses in humans.
Regarding their mode of action, active compounds
showed in vitro inhibitory activities against (1,3)-b-d-
glucan-synthase and mainly against chitin-synthase,
enzymes that catalyze the synthesis of the major fungal
cell wall polymers.3 Since fungal but not mammalian
cells possess a cell wall, these structures appeared as
promissory leads for the development of selective anti-
fungal compounds. From the early structure–activity
studies of these compounds,7 it became apparent that
the R moiety on the 4-position of 4-amino-1-butenes
(Fig. 1) played a crucial role in the activity, being com-
pounds with R=aryl (compounds type C in Table 1)
more active than those containing an alkyl moiety (type
A in Table 1). In addition, the types of substituents on
During the last two decades, coupled to the growing
population of immunocompromised individuals there has
been an increasing frequency of fungal infections. Among
them, superficial and subcutaneous mycoses affect the skin,
keratinous tissues and mucous membranes, usually giving
rise to debilitating effects on a person’s quality of life.1,2
Although amphotericin B, ketoconazole, and more
recently, allylamines and triazoles have been used to treat
superficial mycoses, they are very difficult to eradicate.
Many of the currently available drugs are toxic, fungistatic
but not fungicide thus producing recurrence or lead to the
rapid development of resistance. Although a combined
therapy has emerged as a good alternative for bypassing
those disadvantages, there is a real need for a next genera-
tion of more potent and safer antifungal agents.3ꢀ6
In the course of our ongoing screening program for new
and selective antifungal compounds,7ꢀ9 we have pre-
viously reported7 that a series of 4-aryl- or 4-alkyl-N-
*Corresponding authors. Fax:+54-361-4375-315; e-mail: kouznet@
epb.multi.net.co (V. Kouznetsov), szaabgil@citynet.net.ar (S. Zacchino)
Figure 1. General structure of antifungal homoallylamines.
0968-0896/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00605-3

1532
L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
Table 1. MIC values of 4-N-arylamino-1-heptenes 41–46, 4-N-arylamino-6-phenyl-1-hexenes 47–52, 4-N-arylamino-4-phenyl-1-butenes 53–61,
4-N-arylamino-4-pyridyl(8-quinolinyl)-1-butenes 62–78 4-N-benzylamino-4-pyridyl-1-butenes 79,80 and related compounds against dermatophytes
Compd
Type
R1
R2
R3
R4
R5
Pos N
M.c.
M.g.
T.m
T.r.
E.f
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
Amp.
Terb.
A
A
A
A
A
A
B
B
B
B
B
H
H
CH3O
Cl
Br
F
H
CH3
H
CH3O
Br
F
H
CH3
Br
CH3O
H
H
CH3O
CH3O
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
CH3
H
—
—
—
—
—
—
—
—
—
—
—
—
H
H
H
H
H
H
H
H
H
—
—
—
—
—
—
—
—
—
—
—
—
H
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
OH—
OH
OH
OH
OH
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
b
b
a
g
b
b
b
b
b
b
b
b
—
—
—
—
—
b
>250
>250
125
>250
>250
250
>250
>250
>250
>250
>250
>250
30
30
>250
30
>250
>250
>250
>250
250
12.5
6.25
>250
50
>250
>250
125
>250
>250
125
>250
>250
125
250
125
>250
>250
>250
>250
>250
>250
>250
30
>250
>250
30
>250
125
>250
>250
125
12.5
6.25
>250
50
>250
250
125
250
250
>250
>250
>250
>250
>250
>250
>250
>250
>250
30
>250
>250
>250
>250
>250
250
>250
>250
>250
>250
>250
>250
>250
>250
>250
30
>250
>250
30
>250
>250
>250
>250
250
50
50
250
50
50
>250
50
12.5
25
250
>250
>250
250
>250
>250
250
12.5
3.12
6.25
3.12
>250
50
H
H
H
H
B
C
C
C
C
C
C
C
C
C
D
D
D
D
D
D
D
D
D
D
D
D
E
E
E
E
E
F
F
C
C
E
H
H
CH(CH3)2
H
H
CH3O
CH3O
CH3O
H
250
250
>250
250
50
OCH2O
H
H
H
H
62.5
12.5
6.25
>250
50
50
50
50
1.5
3.12
1.5
250
12.5
>250
25
>250
50
50
H
CH3
CH3
CH3
H
H
H
H
H
H
H
50
>250
25
50
>250
50
12.5
12.5
25
25
50
>250
>250
>250
>250
>250
>250
>250
250
>250
>250
>250
50
>250
>250
>100
125
6.25
0.04
H
CH(CH3)2
25
25
25
25
50
50
6.25
12.5
6.25
250
CH3O
H
H
H
H
H
F
I
H
CH3
H
H
H
H
H
H
H
OCH2O
Br
Cl
F
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3.12
6.25
6.25
6.25
12.5
>250
>250
>250
>250
>250
>250
>250
250
>250
>250
>250
50
50
50
12.5
12.5
25
>250
>250
>250
>250
>250
250
25
CH3
CH3
CH3O
CH3CH2O
Cl
>250
>250
>250
>250
>250
250
250
125
250
>250
>250
50
>250
>250
12.5
50
H
H
H
H
H
H
—
—
COCH3
Allyl
Allyl
H
—
H
H
250
g
>250
250
>250
250
250
>250
>250
50
>250
>250
50
>250
0.3
0.004
CH3O
CH3O
CH3
CH3
Br
H
CH3
Br
—
—
—
—
—
—
—
—
—
>250
>250
>250
>250
>250
>250
50
250
6.25
0.01
H
Allyl
H
H
H
H
E
G
H
H
H
H
H
H
50
50
>250
0.01
H
CH(CH3)2
25
0.04
M.c: Microsporum canis C 112. M.g: Microsporum gypseum C 115; T.m.: Trichophyton mentagrophytes ATCC 9972; T.r.: Trichophyton rubrum C113.
E.f.: Epidermophyton floccosum C 114; Amp., Amphotericin B.; Terb., Terbinafine.

L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1533
ring a showed to be important for activity. Tetra-
hydroquinolines or quinolines obtained by cyclization
of some homoallylamines showed to be active as well.
following objectives: (1) synthesize diverse cyclic analo-
gues (2-alkyl or aryl substituted tetrahydroquinolines)
of corresponding 4-amino-1-heptenes and 4-amino-1-
butenes and (2) prepare some aminoalcohols related to
the same aminoalkenes. This attempt resulted in the
formation of a mixture of 1,2,3,4-tetrahydroquinolines
and aminoalcohols, which were separated by alumina
column chromatography (Scheme 3).
The interesting antifungal properties displayed by these
homoallylamines, tetrahydroquinolines and quinolines
prompted us to synthesize new members of the previously
reported series, a new one including 4-N-arylamino-1-
butenes containing the pyridyl or quinolinyl moieties at
C-4 and other related compounds, in order to find new
antifungal structures with inhibitory properties of the
fungal cell wall synthesis and to establish their struc-
ture–activity relationships. In this work, we report the
synthesis and antifungal evaluation of 101 compounds,
most of them not reported in the literature up to date.
In the case of aminobutenes 53 and 54, we were able to
separate both 4-aminobutanols 86 and 87 and cyclic
products 90 and 91,7 respectively. However, in the case
of aminoalkenes 45, 55, and 57, we isolated in pure form
only the corresponding 4-aminobutanols 85, 88, and 89
in moderate yields. Finally, after the acid cyclization of
aminoheptenes 41, 42, and 46, the corresponding 2-n-
propyl-tetrahydroquinolines 92–94 were obtained in 21–
73% yields. The presence of hydroxyl and amino groups
in compounds 85–89 was established by both physical
(mainly IR) and chemical (acetylation of compound 87
yielded derivative 95) methods. One of the isolated tet-
rahydroquinolines (92) was aromatised with DDQ13
affording quinoline 96 (Scheme 3).
Homoallylamines and derivatives 41–89, tetra-
hydroquinolines 90–94 and 96–107, quinolines 95, 96,
and 108–119, and related compounds 120–141 were tes-
ted for antifungal properties with the agar dilution
method against a panel of standardized dermatophytes.
Based on the results obtained in this screen, a SAR
study including computational analysis was performed
with the aim of explaining the influence of the different
substituents on the antifungal activity. Then, to gain
insight into the capacity of active compounds to inter-
fere with the biosynthesis of fungal cell wall, active
compounds were tested for their in vitro inhibitory
activity on (1,3)-b-d-glucan- and chitin-synthases.
Results and Discussion
Chemistry
The starting N-arylaldimines 1–38 and N-benzylaldi-
mines 39 and 40 needed in our investigation were read-
ily prepared from commercially available aldehydes
(butyraldehyde, cinnamaldehyde, benzaldehyde, iso-
Scheme 1. Preparation of N-substituted aminoalkenes: (a) ArNH2,
EtOH (benzene or toluene), reflux; (b) BnNH2, benzene, reflux; (c)
allylmagnesium bromide/Et2O, 10–24 ꢁC, then H2O/NH4Cl/ice.
meric
pyridinecarboxyaldehydes
or
quinoline
8-carboxyaldehyde) and substituted anilines or benzyla-
mine, according to literature procedures.7,10 Both series
of obtained aldimines were converted into the requisite
N-substituted unsaturated amines. Using the nucleo-
philic addition of allylmagnesium bromide to the C¼N
bond of these imines, we obtained corresponding 4-N-
arylamino-1-heptenes 41–46, 4-N-arylamino-6-phenyl-1-
hexenes 47–52, 4-N-arylamino-4-phenyl-1-butenes 53–61,
4-N-arylamino-4-pyridyl(8-quinolinyl)-1-butenes 62–78
and 4-N-benzylamino-1-butenes 79 and 80, which were
isolated as stable oils in 59–85% yields (Scheme 1). All
these reactions were run in dry diethyl ether at 20–34 ꢁC.
Scheme 2. Transformation of 4-N-arylamino-4-phenyl (8-quinolinyl)-
1-butenes: (a) Ac2O/Et3N(cat), ꢀ; (b) allylbromide, K2CO3, acetone,
reflux; (c) BF.3Et2O, reflux.
Acetamide 81 was prepared from aminobutene 56 in the
usual way for amine acetylation (Ac2O/Et3N). N-Allyla-
tion of aminobutene 56 and its pyrido analogue 7411 was
carried out with allyl bromide/K2CO3 in dry acetone
affording derivatives 82 and 83, respectively. Compound
83 was further used in the amino-Claisen rearrangement to
afford quinoline aminobutene 8412 as shown in Scheme 2.
Treatment of selected unsaturated amines 41, 42, 45, 46,
53–55, and 57 with 75% H2SO4 (60 ꢁC, 8 h) had two
Scheme 3. Transformation of aminoheptenes and aminobutenes: (a)
H2SO4 (75%), 60 ꢁC, 8 h; (b) Ac2O, Et3N(cat), ꢀ; (c) DDQ, benzene.

1534
L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
Scheme 4. Transformation of 4-methyl-(tetrahydro)quinolines. (a) H2SO4 (85%), CHCl3, 90 ꢁC, 10–12 h; (b) S, 270–300 ꢁC, 10–20 min; (c) HNO3,
H2SO4, ꢀ8 ꢁC; (d) NaBH4, Pd/C, MeOH, rt.
Next, a series of 4-N-arylamino-1-butenes with a pyri-
dine ring at C-4 62–73 was used in the preparation of its
cyclic analogues 97–107 in good yields. Tetra-
hydroquinolines 97–101 and 103–107 were prepared
using 85% H2SO4 (90 ꢁC, 10–15 h) meanwhile methoxy
tetrahydroquinoline derivative 102 was obtained with
PPA (95 ꢁC, 12 h) (Scheme 4).
Finally, we prepared diverse series of N-(1-allylcyclo-
alkyl)arylamines 122–141. These 4,4-disubstituted ana-
logues of 4-aryl (hetaryl)-4-N-arylamino-1-butenes are
readily available from corresponding ketimines and
allylmagnesium bromide21ꢀ23 (Scheme 6).
Antifungal assays and structure–activity relationships
Since the obtained tetrahydroquinoline derivatives have
two asymmetric carbons, they could contain a couple of
diastereomers. GC–MS study of the crude of reaction
showed that these tetrahydroquinolines are formed
either as a unique diastereoisomer (106 or 107) or as a
diastereoisomeric mixture (all other compounds), which
differ in the arrangement of the methyl group at C-4 and
of pyridyl ring at C-2. Its ratio varies considerably and
depends on the chemical nature of N-arylamino frag-
ment in the aminobutenes.14 Based on our previous
reports15,16 and on the NMR data as well as COSY and
NOESY techniques, we assume that the major isomers
have the cis form (2e,4e orientation of groups), while
minor isomers possess a 2e,4a disposition. Purification
process (column chromatography on alumina) allowed
us to obtain the cis isomer as the sole product for sev-
eral tetrahydroquinolines 97, 98, and 100. However, we
were unable to separate diastereoisomeric mixtures for
other tetrahydroquinolines. These results coincided with
those found in new 2-n-propyl substituted tetra-
hydroquinolines 92–94 and reported 2-phenyl-tetra-
hydroquinolines 90 and 91.7
To study the structure–activity relationships, different
type of structures and the effects of structural changes in
different regions of the molecules were considered: (a)
Change of the R substituent in the general structure of
Figure 1 by alkyl (compounds type A in Table 1); phe-
nylalkyl (type B); phenyl (type C); or alternative ring
systems, pyridyl (type D) and quinolinyl (type E). (b)
Introduction of a methylene between Nand ring a
(compounds type F). (c) Elimination of the double bond
of the allyl radical (types G and H). (d) Introduction of
different substituents on ring a and on the Natom in
different type of compounds. (e) Cyclization of com-
pounds type A, C, and D to tetrahydroquinolines types
I, J, M, and quinolines types L and N.
A panel of dermatophytes including Microsporum canis,
Microsporum gypseum, Trichophyton mentagrophytes,
Trichophyton rubrum, and Epidermophyton floccosum
were used for the antifungal evaluation of homo-
allylamines 41–84, allyl-reduced derivatives 85–89, tet-
rahydroquinolines 90–94 and 96–107, quinolines 95, 96,
and 108–119 and related compounds 120–141 with the
agar dilution method. Concentrations up to 250 mg/mL
of each compound were added to growth media accord-
ing to reported procedures.24 Compounds producing no
inhibition at 250 mg/mL were considered inactive.
Conversion of the prepared tetrahydroquinolines into
the corresponding quinolines 108–116 was carried out
by heating with powdered sulfur17 in good yields. Final
quinolines 109 and 110 were subjected to electrophilic
nitration reaction using a nitric and sulfuric acid mix-
ture to produce regioselectively 5-nitroquinoline deriva-
tives 117 and 118. Amino derivative 119 was reduced
smoothly upon treatment with NaBH4 with Pd/C in
methanol18 (Scheme 4).
Results of the antifungal assays are shown in Tables 1–
3. Regarding 4-alkyl- and 4-arylalkyl-4-N-arylamino-1-
butenes (41–52, types A and B), results showed that they
did not possess any significant antifungal activity, and
that neither the presence of donor or acceptor sub-
stituents on ring a nor their position produced any sig-
nificant variation in the activity. These results confirm
our previous findings obtained with a lower number of
compounds.7
Analogous electrophilic intramolecular cyclization of
N-benzyl substituted 4-amino-1-butenes 79 and 80
afforded tetrahydro-[2]benzazepines 120 and 121 con-
taining pyridyl ring19,20 (Scheme 5).
Scheme 6. Preparation of N-(1-allylcycloalkyl)arylamines and their
derivatives: (a) ArNH2, benzene or toluene, reflux; (b) allylmagnesium
bromide, Et2O, 10–24 ꢁC, then H2O, NH4Cl, ice; (c) Ac2O, Et3N(cat),
ꢀ; (c) DDQ, benzene.
Scheme 5. Transformation of 4-N-benzylamino-4-pyridyl-1-butenes.
(a) H2SO4 concd, CHCl3, 85–90 ꢁC, 10–12 h.

L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1535
In turn, among compounds type C, those possessing
none or a sole substituent in the para position of ring a
(53–56), showed strong activity against E. floccosum and
moderate activity against the rest of dermatophytes.
The presence of a bulky substituent in the o-position
(57), the change of position of a methoxy group to the
meta position (56!58) or the presence of more than one
substituent on ring a (59–61) drastically diminished the
activity. The introduction of a substituent on the N
atom (56!81 or 82) and the saturation of the allyl
moiety (compare compounds 53/86; 54/87; 55/88; 57/
89), rendered almost inactive compounds.
Regarding the activity showed by homoallyalmines
with 4-b-pyridyl moieties, structures with an halogen in
the p-position (69–71) displayed the best antifungal
activities (MICs 1.5–25 mg/mL). The non-substituted
and the p-methyl substituted compounds 62 and 63,
inhibited all the dermatophytes, with higher MICs
(12.5–50 and 6.25–50 mg/mL respectively) being M.
canis, T. mentagrophytes and T. rubrum the most sus-
ceptible species (MICs<20 mg/mL). It is noteworthy
that when the p-substituent is a methoxy or a 3,4-
methylenedioxy group (structures 67 and 68), the activ-
ity falls down, with all MICs ꢂ25 mg/mL. These results
show a clear difference with 4-aryl derivatives 53–56,
where the p-OCH3 phenyl derivative was the most active
compound.
In contrast with these weak antifungal properties, the
change of phenyl ring by alternative heterocycle rings
such as a-, b-, or g-pyridyl (compounds type D) or qui-
nolinyl (type E) displayed a variety of activities, many
compounds of the series inhibiting all the tested fungi at
low concentrations.
Another structure–activity feature observed in homo-
allylamines containing a b-pyridyl moiety is that the
activity against E. floccosum is severely affected when ring
Table 2. MICs values of tetrahydroquinolines, quinolines and related compounds acting against dermatophyes
Compd
Type
Ro
R1
R2
R3
R4
R5
NPosition
M.c.
M.g.
T.m
T.r.
E.f
90
91
92
93
94
95
96
97
I
I
J
J
J
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
H
CH3
H
H
F
CH3
H
H
CH3
CH3
CH3
H
CH3O
Br
Cl
F
F
H
H
CH 3
CH 3
CH 3
H
Br
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
—
—
—
—
—
—
—
—
—
—
—
b
b
b
g
b
b
b
b
b
b
b
b
b
a
g
b
b
b
b
b
b
a
b
b
g
50
50
125
>250
100
50
>250
62.5
250
25
50
50
62.5
62.5
25
25
62.5
25
25
25
25
50
25
25
12.5
12.5
62.5
250
125
>250
>250
50
25
50
50
25
125
25
6.25
25
50
25
50
25
12.5
12.5
>250
6.25
25
12.5
12.5
250
>250
12.5
125
250
—
—
—
COCH3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
125
250
125
>250
>250
50
250
25
25
50
125
50
25
50
50
50
25
25
125
125
125
>250
>250
62.5
250
12.5
25
25
25
125
12.5
25
125
25
50
25
6.25
25
>250
12.5
25
125
250
125
>250
>250
62.5
250
50
50
25
125
25
12.5
50
50
12.5
50
50
12.5
25
50
12.5
25
25
50
>250
>250
25
250
250
—
K
L
COCH3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
M
M
M
M
M
M
M
M
M
M
M
N
N
N
N
N—
N
N
N
N
ONN
ONN
HNN
O
98
99
H
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
H
CH(CH3)2
H
H
H
H
F
I
H
H
H
H
50
25
6.25
62.5
62.5
12.5
50
12.5
62.5
>250
12.5
62.5
25
H
CH(CH
)
3 2
—
—
—
—
H
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
F
F
CH3
CH3
CH3
H
12.5
25
25
25
>250
>250
25
25
>250
>250
12.5
>250
>250
>250
>250
25
>250
>250
2
2
2
—
—
—
—
—
250
250
O
H
M.c: Microsporum canis C 112. M.g: Microsporum gypseum C 115; T.m.: Trichophyton mentagrophytes ATCC 9972; T.r.: Trichophyton rubrum C113.
E.f.: Epidermophyton floccosum C 114.

1536
L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
a possess a substituent in the ortho position (compare
compounds 62/66 and 71/72).
and 121, analogues of tetrahydroquinolines but with a
bigger saturated ring, did not show any significative
activity neither. a-Pyridyl quinoline 110 displayed better
activities than tetrahydroquinoline 99, and the activities
of g-pyridyl quinoline 64 were similar than those of
tetrahydroquinoline 53.
In addition, it is interesting to note that when the
b-pyridyl changes to a- or g-pyridyl (63!64 or 65,
respectively) the antifungal activity decreased and this
decrease is higher in the a isomer.
In contrast, when the most active homoallylamines
possessing a 4-b-pyridyl moiety in their structures were
cyclised to tetrahydroquinolines, less active structures
were obtained in most cases (compare MICs of com-
pounds 62/97; 63/98; 69/103; 70/104; 71/105). The oxi-
dation of b-pyridyl substituted tetrahydroquinolines to
the corresponding quinolines did not introduce homo-
genous changes in the antifungal properties, although
an enhancement in the activity was observed in most
compounds (compare 97/108; 98/109; 103/113; 105/115;
106/116). Quinolines 117–119, obtained by introducing
a nitro group to structures 98 and 99 were devoid of
activity, this effect having been already observed in
homoallylamines.
The introduction of a flexible chain between ring a and
the Natom in b- or g-pyridyl derivatives (compounds
type F, 79 and 80) rendered inactive compounds (com-
pare 62 with 79).
Quinolinyl derivatives with different types of sub-
stituents in ring a (74–78, 83, and 84) were devoid of
activity in all tested fungi.
Regarding the cyclization of 4-alkyl derivatives 41, 42,
and 46 to tetrahydroquinolines 92–94, it is interesting to
note an enhancement of activity against almost all der-
matophytes tested although none of them possess a sig-
nificative activity. The oxidation of 92 to quinoline 96
led to a complete loss of activity. The same enhance-
ment trend is observed by cyclization of 4-aryl deriva-
tives 53 and 54 to tetrahydroquinolines 90 and 91, with
the difference that the activity in this type of compounds
was enhanced when tetrahydroquinolines were oxidized
to quinolines (see ref 7).
Another type of homoallylamines, possessing a spiro
atom (122–141), were tested in order to widen the
insight about activities of homoallyamines. Although
with low MICs, compounds 122–125 and 137–141 dis-
played antifungal activities and some interesting SAR
could be extracted: Unsubstituted compounds (122–125)
were the most active of this series and within them, the size
of the spiro ring seemed to play a role in the antifungal
activity, (123) with n=2 (MICs=50–125 mg/mL) or 124
with n=3 (MICs=50–250 mg/mL) being the most active
compounds. Within substituted compounds with n=2,
In turn, a-pyridyl tetrahydroquinoline 99 showed better
activities than the corresponding open derivative 64 and
4-g-pyridyl derivative 100 showed similar activities than
the corresponding homoallylamine 65. Compounds 120
Table 3. MICs values of N-(1-allylcycloalkyl)arylamines 122–141
Compd
Type
R1
R2
R3
R4
n
M.c.
M.g.
T.m
T.r.
E.f
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
H
H
H
H
H
H
H
H
H
H
H
CH3O
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
F
H
F
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
2
H
H
H
H
H
H
H
H
H
1
2
3
4
1
1
2
250
2
2
3
3
4
4
4
2
2
3
100
50
62.5
100
250
250
>250
>250
>250
>250
>250
>250
>250
100
>250
100
100
100
100
125
50
50
250
62.5
125
125
>250
>250
125
125
250
>250
>250
>250
>250
>250
>250
>250
100
100
100
125
>250
62.5
50
25
>250
250
250
250
250
>250
>250
>250
>250
>250
100
>250
100
100
250
125
250
>250
250
250
>250
>250
>250
250
>250
>250
>250
>250
>250
125
>250
100
125
125
100
CH3O
CH3O
OCH2O
Cl
H
Cl
H
H
CH3O
Cl
CH3CH2O
CH3O
CH3O
CH3O
CH3CH2O
250
>250
>250
>250
>250
>250
250
>250
250
100
H
100
50
100
100
50
100
H
H
COCH3
COCH3
2
2
H
>250
250
M.c: Microsporum canis C 112. M.g: Microsporum gypseum C 115; T.m.: Trichophyton mentagrophytes ATCC 9972; T.r.: Trichophyton rubrum C113.
E.f.: Epidermophyton floccosum C 114.

L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1537
the activity lowers down according with the following
order of substitution of ring a: compounds with donor
substituents in the 4-position (137 and 138) displayed
better activities than structures with donor substituents in
the 3,4 positions (128 and 129), which in turn are better
than compounds with acceptor substituents (130–133). In
contrast, substitution in the Natom ( 140 and 141) seems
not to play an important role in the activity.
energy one or that topographically congruent with other
active compounds in this series.
Once obtained the relevant conformations for the dif-
ferent homoallylamines and derivatives, we evaluated
the electronic aspects of the molecules using Molecular
Electrostatic Potentials (MEPs) in an attempt to find the
potentially reactive sites. MEPs are of particular value
for this purpose, since they allow the visualization of the
To a better understanding of experimental antifungal
results, we conducted a computer-assisted conforma-
tional and electronic study on the most representative
molecules which could aid in the finding of the poten-
tially reactive centers for these compounds. Before
computing its electronic properties, it was necessary to
define the three-dimensional geometry of the relevant
conformation of the molecules which could be a low-
electron density of a molecular system, strongly
depending on the molecule conformation. Indeed, each
three-dimensional arrangement of atoms in a molecule
correspond to a different electronic distribution and
hence a different MEP.
Conformational analysis were conducted according
with the Computational Analysis Section within the
Figure 2. MEPS calculated using the RHF/3-21G optimized geometries for compounds: (a) 53, (b) 62, (c) 68, (d) 69, (e) 70, and (f) 71.

1538
L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
Experimental. Electronic studies were carried out from
MEPs using ab initio RHF/3-21G calculations. As seen
above and in a previous paper,7 experimental results
showed that the most active homoallylamines possessed
aryl or mainly b-pyridyl b-rings. Compounds possessing
only an aromatic ring (a) were inactive (41–52) or dis-
played very low activity (122–141).
catalyze the synthesis of the major polymers of the fun-
gal cell-wall, (1,3)-b-d-glucan and chitin, respectively.
Results on the in vitro assays are listed in Table 4.
Regarding the activity against chitin synthase-1, homo-
allylamines 63 and 69–71, substituted in ring a, exhib-
ited strong inhibitory activities at 20 mg/assay
(inhibition ranging from 89 to 96%). Serial dilutions of
them (1, 2, 5, 10, and 20 mg/assay) were tested for
enzyme inhibition and their average inhibitory effects
were calculated (Fig. 3). The IC50 values were all ꢃ0.17
mg/mL, possessing compound 63, with a donor sub-
stituent, a higher IC50 value (=0.17 mg/mL) than com-
pounds with acceptor subsituents 69–71 (IC50=0.04–
0.09 mg/mL). Compound 62, without any substituent on
ring a, was a very weak inhibitor of chitin synthase with
40% inhibition at 20 mg/assay.
In accordance with these results, computational studies
were carried out with the active homoallylamines 53, 62,
and 68–71 (Fig. 2a–f).
The analyses of MEPs showed four regions with nega-
tive potential for all compounds: (1) a region generated
by the aryl a; (2) a region generated by ring b; and (3
and 4) two small regions generated by both the NH
group and the double bond of the allyl moiety, which
are shallower than those due to aromatic rings.
Results obtained from (1,3)-b-d-glucan synthase assays
showed the same pattern of activity, with non-sub-
Figure 2 showed that (a) all compounds possessing both
aromatic rings a and b (Fig. 2a–f) showed negative
regions around them, which seems to be necessary but
not sufficient by itself to produce antifungal effect (a
great number of compounds having two aromatic rings
were devoid of antifungal activity). (b) Negative poten-
tial in zones 3 and 4 seemed not to contribute to the
activity: Compounds possessing electro-donating
groups such as methylenedioxy (68) (Fig. 2c) show clear
negative zones 3 and 4. In contrast, the most active
compounds (69–71) (Fig. 2d–f, respectively) show a neat
diminution of the negative potential on zones 3 and 4,
suggesting that the characteristic electronic features for
compounds of these series to display antifungal activ-
ities would be both the presence of negatives zones
around rings a and mainly b, and a very weak negative
potential in zones 3 and 4.
Figure 3. Effect of different concentrations of 4-N-arylamino-4-pyr-
idyl-1-butenes 63 and 69–71 on the in vitro incorporation of [14C]-N-
acetylglucosamine into insoluble chitin, expressed as % of residual
activity of the enzyme chitin synthase-1.
Mode of action studies
To gain insight into the mode of action of the most
active compounds, we tested 4-N-arylamino-4-b-pyr-
idyl-1-butenes 62, 63, and 69–71 for their capacity of in
vitro inhibiting the Saccharomyces cerevisiae (1,3)-b-d-
glucan synthase25 or chitin synthase-1,26 enzymes that
Table 4. (1,3)-b-d-glucan and chitin synthase inhibitory capacity
expressed as % of inhibition and IC50 values (mg/mL)
Compd (1,3)-b-d-Glucan synthase assay
Chitin synthase assay
% Ia
ICb
% Ic
ICb
50
50
62
63
69
70
43.44Æ1.6
73.00Æ2.28
93.83Æ0.1
75.65Æ0.04
76.30Æ3.97
98.83Æ1.94
>0.50
0.21
0.17
0.14
0.27
0.02
0.10
40.00Æ2.0
92.44Æ2.8
91.25Æ1.7
89.1Æ0.06
96.52Æ2.3
98.59Æ2.0
>0.50
0.17
0.09
0.06
0.04
0.01
71
104
Pap
Nik
0.0006d
Pap, Papulacandin B; Nik, Nikkomicin.
a% of inhibition at 20 mg/assay (total volume: 40 mL): meanÆSEM.
bConcentration (mg/mL) that produces 50% of inhibition.
c% of inhibition at 20 mg/assay (total volume: 50 mL): meanÆSEM.
dValue obtained from ref 39.
Figure 4. Effect of different concentrations of 4-N-arylamino-4-pyr-
idyl-1-butenes 63 and 69–71 on the in vitro incorporation of [14C]-
glucose into insoluble (1,3)-b-d-glucan, expressed as % of residual
activity of the enzyme (1,3)-b-d-glucan synthase.

L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1539
negative potential in the zones of the NH group and the
double bond of the allyl moiety.
Regarding their mode of action, substituted homo-
allylamines with b-pyridyl moieties might act by inhi-
biting the biosynthesis of the major polymers of the
fungal cell wall as one mechanism of action. They inhi-
bit both (1,3)-b-d-glucan and mainly chitin synthases.
In contrast, although active in cellular assays, non-sub-
stituted homoallylamine with b-pyridyl ring b, seems
not to act by this mechanism.
Experimental
Chemistry
Figure 5. Comparative values of the inhibitory activities of antifungal
4-N-arylamino-4-pyridyl-1-butenes 63 and 69–71, against (1,3)-b-d-
glucan synthase and chitin synthase-1, expressed as % of residual
activity.
All reagents were purchased from Aldrich, commercial
grade. IR spectra were recorded on a Nicolet Avatar
360-FT spectrophotometer. 1H NMR spectra were
recorded on a Bruker AM-400, Bruker AC-300, or on a
Bruker AC-200 spectrometer. Chemical shifts are
reported in ppm (d) relative to the solvent peak (CHCl3
in CDCl3 at 7.26 ppm for protons and at 77.0 ppm for
carbons). Signals are designated as follows: s, singlet; d,
doublet; dd, doublet of doublets; ddd, doublet of doub-
lets of doublets; t, triplet; dt, doublet of triplets; td, tri-
plet of doublets; q, quartet; quin., quintet; quin-d,
quintet double; sext., sextet; sept, septet; m, multiplet;
br, broad. A Hewlett Packard 5890a Series II Gas
Chromatograph interfaced to an HP 5972 Mass Selec-
tive Detector (MSD) with an HP MS ChemStation
Data system was used for MS identification at 70 eV
using a 60 m capillary column coated with HP-5 [5%-
phenylpoly(dimethylsiloxane)]. Elemental analyses were
performed on a Leco CHN-600 or on a Perkin-Elmer
2400 Series II analyzers. Column chromatography was
carried out on columns packed with SiO2 or Al2O3.
stituted homoallylamine 62 possessing a weak capacity
of inhibiting the enzyme with a IC50 >0.50 mg/mL. In
contrast, compounds 63 and 69–71 were very good
inhibitors of this enzyme (IC50 between 0.14 and 0.27
mg/mL) (Fig. 4).
From these results, we can deduce that substituted
homoallylamines with b-pyridyl moieties might act by
inhibiting the biosynthesis of the major polymers of the
fungal cell wall as one of their antifugal mechanism of
action. They inhibit both (1,3)-b-d-glucan and mainly
chitin synthases as it is clearly shown in the comparative
Figure 5.
In contrast, although active in cellular assays, non-sub-
stituted homoallylamine 62 seems not to act by this
mechanism.
The aldimine formation was performed according to
literature reports.7,10 Aldimines were obtained with
nearly quantitative yields. The imine structure was con-
firmed by IR spectroscopy. Starting imines were used in
subsequent synthesis without further purification. Gen-
eral procedure for the synthesis of N-arylaminoalquenes
(41–78) have been reported in ref 7.
Conclusions
In this article, we report the synthesis and fungistatic
effects of new series of homoallylamines and related
compounds acting against dermatophytes, the struc-
ture–activity relationships and studies of their mechan-
ism
of
action.
Among
compounds
tested,
homoallyalmines with a 4-b-pyridyl as ring b and an
halogen in the p-position of ring a, displayed the best
antifungal activities (MICs 1.5–25 mg/mL). When the
most active homoallylamines were cyclized to tetra-
hydroquinolines, less active structures were obtained in
most cases. The oxidation of b-pyridyl substituted tet-
rahydroquinolines to the corresponding quinolines, did
not introduce homogenous changes in the antifungal
properties, although an enhancement in the activity was
observed in most compounds.
4-N-Arylamino-1-heptenes (41–46)
Compound 41 has been reported previously in ref 7.
4-N-(2-Methylphenyl)amino-1-heptene (42). Yellowish
oil. Yield 87%. IR (film) n 3430 cmꢀ1 (s, NH). 1H N MR
(400 MHz) d0.81 (3H, t, J=7.1 Hz, 7-H), 1.22–1.42 (4H,
m, 5- and 6-H), 1.99 (3H, s, CH3), 2.19 (2H, sept.,
J=5.7 Hz, 3-H), 3.23 (1H, br. s., H-N), 3.36 (1H, t,
J=6.0 Hz, 4-H), 4.94 (1H, dd, J=5.4, 1.3 Hz, 1-HA),
4.97 (1H, s, 1-HB), 5.64–5.76 (1H, m, 2-H), 6.47 (1H, d,
J=7.8 Hz, 6-HAr), 6.50 (1H, d, J=7.1 Hz, 4-HAr), 6.89
(1H, d, J=7.2 Hz, 3-HAr) 6.99 (1H, td, J=8.3, 1.2 Hz,
5-HAr); 13C NMR (100 MHz) d 14.0, 17.3, 19.1, 36.6,
38.5, 51.5, 109.9, 116.2, 117.3, 121.4, 126.7, 130.1, 134.9,
145.4. MS m/z (EI) 203 (M+, 10%), 162 (MꢀC3H5,
The analyses of Molecular Electrostatic Potential
(MEPs) strongly suggested that the characteristic elec-
tronic features for compounds of these series to display
antifungal activities would be both the presence of
negatives zones around rings a and b, and a very weak

1540
L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
100%). Found: C, 82.57; H, 10.68; N, 6.65; calcd for
C14H21N: C, 82.76; H, 10.34; N, 6.90.
2.19 (2H, m, 3-H), 2.70 (2H, t, J=7.3 Hz, 6-H), 3.40
(1H, m, 4-H), 4.89 (2H, m, 1-H), 5.65 (1H, m, 1-H),
6.09–7.15 (10H, m, HAr); 13C NMR (100 MHz) d 32.3,
35.9, 38.5, 51.6, 113.1 (2C), 116.8, 117.4, 125.7, 128.1
(2C), 128.5 (2C), 129.2 (2C), 134.5, 141.6, 147.3. MS
m/z (EI) 251 (M+, 5%), 91 (MꢀC11H14N, 100%).
Found: C, 86.23; H, 8.65; N, 5.23; calcd for C18H21N:
C, 86.05; H, 8.37; N, 5.58.
4-N-(4-Methoxylphenyl)amino-1-heptene (43). Yellowish
oil. Yield 75%. IR (film) n 3399 cmꢀ1 (s, NH). 1H N MR
(400 MHz) d 0.80 (3H, t, J=7.0 Hz, 7-H), 1.28–1.35
(4H, m, 5- and 6-H), 2.15 (2H, td, J=4.2, 0.9 Hz, 3-H),
3.05 (1H, br. s., H–N), 3.21 (1H, t, J=5.8 Hz, 4-H),
3.57 (3H, s, CH3O), 4.93 (1H, dt, J=6.5, 2.2 Hz, 1-HA),
4.96 (1H, s, 1-HB), 5.66–5.72 (1H, m, 2-H), 6.41 (2H, d,
J=8.9 Hz, 2(6)-HAr), 6.64 (2H, d, J=8.9 Hz, 3(5)-HAr);
13C NMR (100 MHz) d 14.0, 19.0, 36.5, 38.3, 52.9, 55.4,
114.2 (2C), 114.7 (2C), 117.1, 134.9, 141.9, 151.6. MS m/
z (EI) 219 (M+, 9%), 178 (MꢀC3H5, 100%). Found: C,
76.43; H, 9.96; N, 6.21; calcd for C14H21NO: C, 76.71;
H, 9.59; N, 6.39.
4-N-(4-Methylphenyl)amino-6-phenyl-1-hexene (48).
Yellowish oil. Yield 79%. IR (film) n 3403 cmꢀ1 (s,
1
NH). H NMR (400 MHz) d 1.54–1.63 (1H, m, 5-HA),
1.67–1.74 (1H, m, 5-HB), 2.09 (3H, s, CH3), 2.11–2.17
(2H, m, 3-H), 2.48–2.62 (2H, m, 6-H), 3.10 (1H, br. s.,
H–N), 3.24 (1H, td, J=6.4, 1.6 Hz, 4-H), 4.89 (2H, dd,
J=7.9, 1.7 Hz, 1-HA), 4.93 (1H, s, 1-HB), 5.58–5.69
(1H, m, 2-H), 6.30 (2H, d, J=8.3 Hz, 2(6)-HAr), 6.81
(2H, d, J=8.3 Hz, 3(5)-HAr), 6.99 (1H, d, J=8.1 Hz, 4-
HPh), 7.02 (2H, dd, J=7.0, 1.0 Hz, 2(6)-HPh), 7.10 (2H,
dd, J=7.0, 1.5 Hz, 3(5)-HPh); 13C NMR (100 MHz) d
20.3, 32.2, 35.8, 38.4, 51.9, 113.4 (2C), 117.5, 125.7,
125.9, 127.9 (2C), 128.6 (2C), 129.7 (2C), 134.6, 141.9,
145.2. MS m/z (EI) 265 (M+, 10%), 224 (MꢀC3H5,
100%). Found: C, 85.67; H, 8.96; N, 5.35; calcd for
C19H23N: C, 86.04; H, 8.68; N, 5.28.
4-N-(4-Chlorophenyl)amino-1-heptene (44). Dark yel-
lowish oil. Yield 86%. IR (film) n 3418 cmꢀ1 (s, NH).
1H NMR (400 MHz) d 0.78 (3H, t, J=7.5 Hz, 7-H),
1.24–1.29 (4H, m, 5- and 6-H), 1.92–1.98 (2H, m, 3-H),
3.29 (1H, t, J=6.1 Hz, 4-H), 4.96–5.02 (2H, m, 1-H),
5.62–5.76 (1H, m, 2-H), 6.39 (2H, d, J=8.8 Hz, 2(6)-
HAr), 6.99 (2H, d, J=8.8 Hz, 3(5)-HAr); 13C N MR
(100 MHz) d 13.7, 19.2, 36.5, 38.4, 52.3, 114.4 (2C),
117.6, 126.7, 128.7 (2-C), 134.6, 146.4. MS m/z (EI) 223
(M+ for 35Cl, 8%), 182 (MꢀC3H5, 100%). Found: C,
69.60; H, 8.29; N, 6.20; calcd for C13H18ClN: C, 69.80;
H, 8.05; N, 6.27.
4-N-(2-Methylphenyl)amino-6-phenyl-1-hexene (49).
Transparent oil. Yield 89%. IR (film) n 3430 cmꢀ1 (s,
1
NH). H NMR (400 MHz) d 2.01–2.09 (2H, m, 5-H),
2.28 (3H, s, CH3), 2.53–2.55 (2H, m, 3–H), 2.87–2.95
(2H, m, 6-H), 3.71 (1H, t, J=7.6 Hz, 4-H), 5.25 (2H, d,
J=8.4 Hz, 1-HA), 5.29 (2H, s, 1-HB), 5.96–6.03 (1H, m,
2-H), 6.72 (1H, d, J=7.6 Hz, 6-HAr), 6.81 (1H, t, J=7.3
Hz, 4-HAr), 7.22–7.47 (7H, m, 3(5)-HAr and HPh); 13C
NMR (100 MHz) d 17.4, 32.3, 36.0, 38.4, 51.4, 110.0,
116.3, 117.7, 121.7 (2C), 125.8, 127.0 (2C), 128.3 (2C),
130.3, 134.6, 141.8, 145.3. MS m/z (EI) 265 (M+, 8%).
Found: C, 85.79; H, 8.96; N, 5.19; calcd for C19H23N:
C, 86.04; H, 8.68; N, 5.28.
4-N-(4-Bromophenyl)amino-1-heptene (45). Yellowish
oil. Yield 91%. IR (film) n 3412 cmꢀ1 (s, NH). 1H N MR
(400 MHz) d 0.79 (3H, t, J=7.1 Hz, 7-H), 1.20–1.41
(4H, m, 5- and 6-H), 2.09–2.18 (2H, m, 3-H), 3.23 (1H,
t, J=5.9 Hz, 4-H), 3.33 (1H, br. s., H–N), 4.94 (1H,
ddd, J=8.4, 3.2, 1.5 Hz, 1-HA), 4.96 (1H, s, 1-HB),
5.60–5.71 (1H, m, 2-H), 6.29 (2H, d, J=8.8 Hz, 2(6)-
HAr), 7.07 (2H, d, J=8.8 Hz, 3(5)-HAr); 13C N MR
(100 MHz) d 14.0, 19.0, 38.3, 40.8, 52.0, 107.9, 114.5
(2C), 117.2, 131.7 (2C), 134.5, 146.7. MS m/z (EI) 267
(M+ for 79Br, 9%), 226 (MꢀC3H5, 100%). Found: C,
58.05; H, 6.85; N, 5.36; calcd for C13H18BrN: C, 58.21;
H, 6.72; N, 5.22.
4-N-(4-Methoxyphenyl)amino-6-phenyl-1-hexene (50).
Brown oil. Yield 90%. IR (film) n 3400 cmꢀ1 (s, NH).
1H NMR (400 MHz) d 1.78–2.67 (6H, m, 3-, 5- and 6-
H), 3.18 (1H, br. s., H–N), 3.31 (1H, br. t, J=8.9 Hz,
4-H), 3.58 (3H, s, CH3O), 4.81–4.88 (2H, m, 1-H), 5.47–
5.59 (1H, m, 2-H), 6.32 (2H, d, J=8.7 Hz, 2(6)-HAr),
6.34 (2H, d, J=8.7 Hz, 3(5)-HAr), 6.59–7.14 (5H, m,
HPh); 13C NMR (100 MHz) d 32.3, 35.8, 36.4, 52.6, 55.5,
114.6 (2C), 114.9 (2C), 117.6, 125.9, 128.1 (2C), 128.4
(2C), 134.6, 141.6, 142.0, 151.6. MS m/z (EI) 281 (M+,
11%), 240 (MꢀC3H5, 100%). Found: C, 81.38; H, 8.48;
N, 4.67; calcd for C19H23NO: C, 81.14; H, 8.19; N, 4.98.
4-N-(4-Fluorophenyl)amino-1-heptene (46). Dark yellow-
1
ish oil. Yield 82%. IR (film) n 3414 cmꢀ1 (s, NH). H
NMR (400 MHz) d0.79 (3H, t, J=7.1 Hz, 7-H), 1.26–
1.34 (4H, m, 5- and 6-H), 2.10–2.14 (2H, m, 3-H), 3.20
(1H, t, J=5.8 Hz, 4-H), 4.92 (1H, ddd, J=9.0, 3.0, 1.5
Hz, 1-HA), 4.96 (1H, d, J=0.9 Hz, 1-HB), 5.62–5.73
(1H, m, 2-H), 6.35 (2H, dd, J=8.3, 4.5 Hz, 2(6)-HAr),
6.72 (2H, t, J=8.3 Hz, 3(5)-HAr); 13C NMR (100 MHz)
d 13.7, 19.0, 39.5, 39.6, 52.6, 113.9 (2C), 115.3 (2C),
117.3, 134.7, 144.2, 156.5 (d, J=ꢀ8 Hz). MS m/z (EI)
207 (M+, 6%), 166 (Mꢀ, 100%). Found: C, 75.66; H,
8.86; N, 6.45; calcd for C13H18FN: C, 75.36; H, 8.70; N,
6.76.
4-N-(4-Bromophenyl)amino-6-phenyl-1-hexene (51). Yel-
lowish oil. Yield 79%. IR (film) n 3410 cmꢀ1 (s, NH).
1H NMR (400 MHz) d 1.58–1.66 (1H, m, 5-HA), 1.69–
1.78 (1H, m, 5-HB), 2.14–2.17 (2H, m, 3-H), 2.50–2.62
(2H, m, 6-H), 3.23 (1H, td, J=6.4, 1.2 Hz, 4-H), 3.38
(1H, br. s., H-N), 4.91–4.99 (2H, m, 1-H), 5.58–5.69
(1H, m, 2-H), 6.23 (2H, dd, J=6.8, 2.0 Hz, 2(6)-HAr),
7.05 (2H, dd, J=6.8, 2.0 Hz, 3(5)-HAr), 7.01–7.17 (5H,
m, HPh); 13C NMR (100 MHz) d 32.1, 35.8, 38.7, 51.6,
108.2, 114.7 (2C), 117.7, 125.9, 128.2 (2C), 128.7 (2C),
4-N-Arylamino-6-phenyl-1-hexenes (47–52)
6-Phenyl-4-N-phenylamino-1-hexene (47). Yellowish oil.
1
Yield 67%. IR (film) n 3410 cmꢀ1 (s, NH). H N MR
(400 MHz) d 1.65 (1H, m, 5-HA), 1.77 (1H, m, 5-HB),

L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1541
131.9 (2C), 134.2, 141.6, 146.5. MS m/z (EI) 331 (M+
for 81Br, 3%). Found: C, 65.23; H, 6.35; N, 4.13; calcd
for C18H20BrN: C, 65.46; H, 6.06; N, 4.24.
HAr), 6.10 (1H, s, 2-HAr), 6.52 (1H, d, J=8.1 Hz, 5-
HAr), 7.23–7.45 (5H, m, HPh). MS m/z (EI) 283 (M+,
4%), 242 (MꢀC3H5, 100%). Found: C, 76.29; H, 7.47
N, 5.31; calcd for C18H21NO2: C, 76.33; H, 7.42; N,
4.95.
4-N-(4-Fluorophenyl)amino-6-phenyl-1-hexene (52). Yel-
lowish oil. Yield 69%. IR (film) n 3411 cmꢀ1 (s, NH).
1H NMR (400 MHz) d 1.58–1.65 (1H, m, 5-HA), 1.68–
1.78 (1H, m, 5-HB), 2.13 (1H, dd, J=13.5, 7.0 Hz, 3-
HA), 2.16 (1H, dd, J=13.5, 7.9 Hz, 3-HB), 2.50–2.62
(2H, m, 6-H), 3.20 (1H, quin., J=5.6 Hz, 4-H), 4.90–
4.99 (2H, m, 1-H), 5.59–5.69 (1H, m, 2-H), 6.29 (2H, dd,
J=8.7, 4.5 Hz, 2(6)-HAr), 6.71 (2H, t, J=8.7 Hz, 3(5)-
HAr), 7.00 (1H, d, J=8.2 Hz, 4-HPh), 7.06 (2H, d,
J=7.6 Hz, 2(6)-HPh), 7.13 (2H, t, J=7.6 Hz, 3(5)-HPh);
13C NMR (100 MHz) d 32.7, 35.9, 38.3, 52.3, 114.1
(2C), 115.7 (2C), 117.7, 125.8, 128.0 (2C), 128.6 (2C),
134.4, 141.8, 143.9, 156.6 (d, J=ꢀ233.0 Hz). MS m/z
(EI) 269 (M+, 5%). Found: C, 80.11; H, 7.63; N, 5.31;
calcd for C18H20FN: C, 80.30; H, 7.44; N, 5.20.
4-N-(2,4-Dimethoxyphenyl)amino-4-phenyl-1-butene (60).
Reddish oil. Yield 93%. IR (film) n 3421 cmꢀ1 (s, NH).
1H NMR (400 MHz) d 2.55–2.68 (2H, m, 3-H), 3.56
(3H, s, OCH3), 3.73 (3H, s, OCH3), 4.20 (1H, dd,
J=7.6, 5.5 Hz, 4-H), 4.35 (1H, br. s., H–N), 5.16 (1H, d,
J=10.3 Hz, 1-HA), 5.22 (1H, d, J=17.1 Hz, 1-HB),
5.78–5.88 (1H, m, 2-H), 6.10 (2H, s, 3(5)-HAr), 6.33 (1H,
s, 6-HAr), 7.24–7.41 (5H, m, HPh); 13C NMR (100 MHz)
d 43.3, 55.4, 55.5, 57.8, 99.0, 103.5, 111.2, 117.9, 126.3,
126.8 (2C), 128.4 (2C), 131.6, 134.7, 143.9, 147.8, 151.6.
MS m/z (EI) 283 (M+, 9%), 242 (MꢀC3H5, 100%).
Found: C, 76.34; H, 7.50; N, 4.78; calcd for C18H21NO2:
C, 76.33; H, 7.42; N, 4.95.
4-N-(3,4-Methylenedioxyphenyl)amino-4-phenyl-1-butene
(61). Dark oil. Yield 79%. IR (film) n 3409 cmꢀ1 (s,
NH). H NMR (400 MHz) d 2.34–2.41 (1H, m, 3-HA),
4-Aryl-4-N-arylamino-1-butenes (53–61)
Compounds 53–56 have been previously reported.7
1
2.47–2.53 (1H, m, 3-HB), 3.89 (1H, br. s., H–N), 4.20
(1H, dd, J=8.0, 4.0 Hz, 4-H), 5.05 (2H, t, J=8.0 Hz, 1-
H), 5.69 (2H, s, O–CH2–O), 5.83 (1H, d, J=8.0 Hz, 6-
HAr), 6.05 (1H, s, 2-HAr), 6.46 (1H, d, J=8.0 Hz, 5-
HAr), 7.13–7.27 (5H, m, HPh); 13C NMR (100 MHz) d
43.3, 57.9, 96.4, 100.4, 105.1, 108.4, 118.3, 126.2, 126.7
(2C), 128.6 (2C), 134.6, 139.4, 143.1, 143.5, 148.0. MS
m/z (EI) 267 (M+, 5%), 226 (M–C3H5, 100%). Found:
C, 76.19.; H, 6.63.; N, 5.12; calcd for C17H17NO2: C,
76.40; H, 6.37; N, 5.24.
4-Phenyl-4-N-(2-isopropylphenyl)amino-1-butene
(57).
Dark yellowish oil. Yield 85%. IR (film) n 3439 cmꢀ1
1
(s, NH). H NMR (400 MHz) d 1.18 (3H, d, J=6.8 Hz,
CH3-i-Pr), 1.22 (3H, d, J=6.8 Hz, CH03-i-Pr), 2.40 (1H,
m, 3-HA), 2.52 (1H, m, 3-HB), 2.84 (1H, quin., J=6.8
Hz, H–C-i-Pr), 4.25 (1H, br. s., H–N), 4.30 (1H, dd,
J=8.1, 4.7 Hz, 4-H), 5.04 (1H, td, J=7.8, 1.5 Hz, 1-
HA), 5.11 (1H, t, J=1.5 Hz, 1-HB), 5.61–5.72 (1H, m, 2-
H), 6.20 (1H, dd, J=8.0, 0.8 Hz, 6-HAr), 6.54 (1H, td,
J=7.5, 1.1 Hz, 4-HAr), 6.77 (1H, td, J=7.8, 1.5 Hz, 5-
HAr), 7.00 (1H, dd, J=7.5, 1.5 Hz, 3-HAr), 7.06–7.25
(5H, m, HPh); 13C NMR (100 MHz) d 22.4, 27.4, 43.7,
56.7, 111.8, 117.1, 118.3, 124.7, 126.1, 126.5, 126.8 (2C),
128.5 (2C), 131.9 (2C), 134.9, 143.6, 143.7. MS m/z (EI)
265 (M+, 4%), 224 (MꢀC3H5, 100%). Found: C, 85.77;
H, 8.93; N, 5.31; calcd for C19H23N: C, 86.04; H, 8.68;
N, 5.28.
4-N-Arylamino-4-pyridyl-1-butenes (62–74).
4-N-Phenylamino-4-(3-pyridyl)-1-butene (62). Beige
crystals. Mp 57 ꢁC. Yield 88%. IR (KBr) n 3257 cmꢀ1
1
(s, NH). H NMR (300 MHz) d 2.51 (1H, quin., J=5.6
Hz, 3-HB), 2.61 (1H, quin., J=4.9 Hz, 3-HA), 4.18 (1H,
br.s, H–N), 4.44 (1H, br.s, 4-H), 5.17 (1H, s, 1-Htrans),
5.21 (1H, d, J=7.1 Hz, 1-Hcis), 5.70–5.80 (1H, dddd,
J=15.4, 7.1, 7.1, 5.5 Hz, 2-H), 6.48 (2H, d, J=5.8 Hz,
2(6)-HAr), 6.67 (1H, t, J=5.3 Hz, 4-HAr), 7.09 (2H, t,
J=5.3 Hz, 3(5)-HAr), 7.23 (1H, t, J=5.8 Hz, 5-HPy), 7.67
(1H, d, J=5.8 Hz, 4-HPy), 8.50 (1H, d, J=3.0 Hz,
6-HPy), 8.65 (1H, s, 2-HPy); 13C NMR (75 MHz) d 43.1,
55.0, 113.6 (2C), 118.0, 119.2, 123.7, 129.3 (2C), 133.8,
134.0, 139.0, 146.8, 148.7, 148.8. MS m/z (EI) 224 (M+,
3%), 183 (MꢀC3H5, 100%). Found: C, 80.09; H, 7.35;
N, 12.56; calcd for C15H16N2: C, 80.36; H, 7.14; N,
12.50.
4-N-(3-Methoxyphenyl)amino-4-phenyl-1-butene
(58).
Yellowish oil. Yield 94%. IR (film) n 3410 cmꢀ1 (s,
1
NH). H NMR (400 MHz) d 2.48–2.56 (1H, m, 3-HA),
2.59–2.68 (1H, m, 3-HB), 3.83 (3H, s, OCH3), 4.48 (1H,
dd, J=7.8, 5.3 Hz, 4-H), 5.19 (1H, d, J=17.2 Hz, 1-
HA), 5.20 (1H, d, J=10.3 Hz, 1-HB), 5.75–5.84 (1H, m,
2-H), 6.11 (1H, br.t, J=2.1 Hz, 2-HAr), 6.24 (1H, br.dd,
J=8.1, 1.7 Hz, 6-HAr), 6.32 (1H, d, J=1.6 Hz, 4-HAr),
7.17 (1H, t, J=8.1 Hz, 5-HAr), 6.29–6.38 and 7.25–7.43
(5H, m, HPh); 13C NMR (100 MHz) d 43.0, 54.8, 57.1,
99.3, 102.4, 106.4, 118.2, 126.1, 126.9 (2C), 128.5 (2C),
129.7, 134.5, 143.4, 148.6, 160.4. MS m/z (EI) 253 (M+,
4%), 212 (MꢀC3H5, 100%). Found: C, 80.78; H, 7.43;
N, 5.38; calcd for C17H19NO: C, 80.63; H, 7.51; N, 5.53.
4-N-(4-Methylphenyl)amino-4-(3-pyridyl)-1-butene (63).
Yellow crystals. Mp 84–85 ꢁC. Yield 94%. IR (KBr) n
1
3256 cmꢀ1 (s, NH). H NMR (300 MHz) d 2.20 (3H, s,
CH3), 2.50 (1H, quin., J=5.8 Hz, 3-HB), 2.57–2.65 (1H,
m, 3-HA), 4.10 (1H, br.s, H–N), 4.41 (1H, t, J=4.7 Hz,
4-H), 5.17 (1H, d, J=0.6 Hz, 1-Htrans), 5.20 (1H, dd,
J=6.3, 1.1 Hz, 1-Hcis), 5.70–5.81 (1H, m, 2-H), 6.42
(2H, dt, J=6.3, 1.9 Hz, 2(6)-HAr), 6.91 (2H, d, J=6.3
Hz, 3(5)-HAr), 7.23 (1H, dd, J=5.8, 3.6 Hz, 5-HPy), 7.68
(1H, dt, J=5.8, 1.4 Hz, 4-HPy), 8.50 (1H, dd, J=3.6, 1.4
4-N-(3,4-Dimethoxyphenyl)amino-4-phenyl-1-butene (59).
1
Pink oil. Yield 44%. IR (film) n 3392 cmꢀ1 (s, NH). H
NMR (400 MHz) d 2.48–2.65 (2H, m, 3-H), 3.54 (3H, s,
OCH3), 3.76 (3H, s, OCH3), 4.31 (1H, dd, J=7.4, 4.8
Hz, 4-H), 4.36 (1H, br. s., H–N), 5.15–5.21 (1H, m, 1-
H), 5.73–5.86 (1H, m, 2-H), 5.80 (1H, d, J=8.1 Hz, 6-

1542
L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
Hz, 6-HPy), 8.65 (1H, d, J=1.7 Hz, 2-HPy); 13C N MR
(75 MHz) d 20.5, 43.2, 55.3, 113.7 (2C), 119.1, 123.7,
127.1, 129.8 (2C), 134.0, 134.0, 139.2, 144.6, 148.6,
148.8. MS m/z (EI) 238 (M+, 4%), 197 (M-C3H5,
100%). Found: C, 80.77; H, 7.80; N, 11.43; calcd for
C16H18N2: C, 80.67; H, 7.56; N, 11.77. Compound 64
has been reported previously in ref 16.
10 mm Hg. Yield 12%. IR (KBr) n 3297 cmꢀ1 (s, NH).
1H NMR (400 MHz) d 2.39 (1H, quin., J=8.1 Hz, 3-
HB), 2.61 (1H, quin., J=6.0 Hz, 3-HA), 3.98 (1H, br.s,
H–N), 4.30 (1H, dd, J=8.1, 5.5 Hz, 4-H), 5.10 (1H, s, 1-
Htrans), 5.14 (1H, d, J=4.5 Hz, 1-Hcis), 5.64–5.70 (1H,
m, 2-H), 5.74 (2H, d, J=1.2 Hz, O–CH2–O), 5.84 (1H,
dd, J=8.6, 2.0 Hz, 6-HAr), 6.07 (1H, d, J=2.0 Hz, 2-
HAr), 6.50 (1H, d, J=8.6 Hz, 5-HAr), 7.18 (1H, dd,
J=7.6, 4.5 Hz, 5-HPy), 7.62 (1H, d, J=7.6 Hz, 4-HPy),
8.44 (1H, d, J=4.5 Hz, 6-HPy), 8.57 (1H, s, 2-HPy); 13C
NMR (100 MHz) d 42.8, 55.6, 96.5, 100.5, 105.1, 108.4,
119.0, 123.5, 133.7, 134.0, 138.9, 139.7, 142.6, 148.1,
148.4, 148.5. MS m/z (EI) 268 (M+, 8%), 227
(MꢀC3H5, 100%). Found: C, 71.57; H, 6.34; N, 10.56;
calcd for C16H16N2O2: C, 71.64; H, 5.97; N, 10.45.
4-N-(4-Methylphenyl)amino-4-(4-pyridyl)-1-butene (65).
White crystals. Mp 95 ꢁC. Yield 73%. IR (KBr) n 3273
cmꢀ1 (s, NH). 1H NMR (400 MHz) d 2.18 (3H, s, CH3),
2.45 (1H, quin., J=7.6 Hz, 3-HB), 2.56 (1H, quin-d,
J=5.0, 1.0 Hz, 3-HA), 4.07 (1H, br.s, H–N), 4.32 (1H,
dd, J=7.6, 5.0 Hz, 4-H), 5.16 (1H, s, 1-Htrans), 5.19 (1H,
d, J=8.1 Hz, 1-Hcis), 5.66–5.74 (1H, m, 2-H), 6.36 (2H,
d, J=8.1 Hz, 2(6)-HAr), 6.89 (2H, d, J=8.1 Hz, 3(5)-
HAr), 7.29 (2H, d, J=5.5 Hz, 3(5)-HPy), 8.53 (2H, dd,
J=5.5, 1.5 Hz, 2(6)-HPy); 13C NMR (100MHz) d 20.3,
42.4, 56.4, 113.4 (2C), 119.1, 121.6 (2C), 127.1, 129.6 (2C),
133.6, 144.3, 150.0 (2C), 152.9. MS m/z (EI) 238 (M+,
100%), 197 (MꢀC3H5, 100%). Found: C, 80.44; H, 7.87;
N, 11.69; calcd for C16H18N2: C, 80.67; H, 7.56; N , 11.77.
4-N-(4-Bromophenyl)amino-4-(3-pyridyl)-1-butene (69).
Yellow crystals. Mp 79–80 ꢁC. Yield 32%. IR (KBr) n
1
3255 cmꢀ1 (s, NH). H NMR (400 MHz) d 2.40 (1H,
quin., J=6.5 Hz, 3-HB), 2.47 (1H, quin-d, J=5.8, 0.9
Hz, 3-HA), 3.52 (1H, br.s, H–N), 4.28 (1H, d, J=6.5
Hz, 4-H), 5.02 (1H, t, J=1.0 Hz, 1-Htrans), 5.06 (1H, dd,
J=3.1, 1.0 Hz, 1-Hcis), 5.54–5.63 (1H, m, 2-H), 6.23
(2H, dt, J=8.9, 2.0 Hz, 2(6)-HAr), 7.02 (2H, dd, J=8.9,
2.0 Hz, 3(5)-HAr), 7.10 (1H, dd, J=7.9, 4.8 Hz, 5-HPy),
7.50 (1H, dt, J=7.9, 1.6 Hz, 4-HPy), 8.37 (1H, dd,
J=4.9, 1.6 Hz, 6-HPy), 8.49 (1H, d, J=2.1 Hz, 2-HPy);
13C NMR (100 MHz) d 42.5, 54.7, 109.1, 116.4 (2C),
119.0, 123.6, 131.6 (2C), 133.2, 133.7, 138.1, 145.5,
148.2, 148.3. MS m/z (EI) 302 (M+ for 79Br, 4%), 261
(MꢀC3H5, 100%). Found: C, 59.11; H, 5.05; N, 9.43;
calcd for C15H15BrN2: C, 59.41; H, 4.95; N, 9.24.
4-N-(2-Isopropylphenyl)amino-4-(3-pyridyl)-1-butene
(66). Yellow transparent oil. Bp 195–200 ꢁC/10 mm Hg.
n2D0 1.5704. Yield 78%. IR (film) n 3434 cmꢀ1 (s, NH).
1H NMR (400 MHz) d 1.30 (3H, d, J=6.6 Hz, CH3-i-
Pr), 1.33 (3H, d, J=6.6 Hz, CH03-i-Pr), 2.54 (1H, quin.,
J=8.1 Hz, 3-HB), 2.69 (1H, quin., J=5.0 Hz, 3-HA),
2.96 (1H, sept., J=6.6 Hz, H-C-i-Pr), 4.28 (1H, s, H–
N), 4.49 (1H, dd, J=8.1, 5.0 Hz, 4-H), 5.23 (1H, s, 1-
Hcis), 5.25 (1H, d, J=26.4 Hz, 1-Htrans), 5.73–5.84 (1H,
m, 2-H), 6.25 (1H, d, J=8.1 Hz, 6-HAr), 6.70 (1H, t,
J=7.5 Hz, 4-HAr), 6.92 (1H, ddd, J=8.1, 7.6, 1.5 Hz, 5-
HAr), 7.15 (1H, d, J=7.5 Hz, 3-HAr), 7.22 (1H, dd,
J=7.6, 4.5 Hz, 5-HPy), 7.66 (1H, dt, J=7.6, 1.5 Hz, 4-
HPy), 8.49 (1H, dd, J=4.5, 1.5 Hz, 6-HPy), 8.66 (1H, d,
J=2.0 Hz, 2-HPy); 13C NMR (100 MHz) d 22.1, 22.4,
27.4, 43.4, 54.6, 111.7, 117.7, 119.2, 123.6, 124.9, 126.5,
132.3, 133.9, 134.0, 139.0, 143.2, 148.4, 148.5. MS m/z
(EI) 266 (M+, 5%), 225 (MꢀC3H5, 100%). Found: C,
81.34; H, 8.45; N, 10.17; calcd for C18H22N2: C, 81.20;
H, 8.27; N, 10.53.
4-N-(4-Chlorophenyl)amino-4-(3-pyridyl)-1-butene (70).
Yellow crystals. Mp 84–86 ꢁC. Yield 69%. IR (KBr) r
1
3305 cmꢀ1 (s, NH). H NMR (400 MHz) d 2.42 (1H,
quin., J=7.5 Hz, 3-HB), 2.53 (1H, quin., J=5.9 Hz, 3-
HA), 4.16 (1H, s, H–N), 4.31 (1H, quin., J=4.8 Hz, 4-
H), 5.08 (1H, s, 1-Htrans), 5.12 (1H, d, J=4.1 Hz, 1-
Hcis), 5.60–5.68 (1H, m, 2-H), 6.30 (2H, dt, J=8.9, 3.1
Hz, 2(6)-HAr), 6.93 (2H, dt, J=8.8, 3.0 Hz, 3(5)-HAr),
7.16 (1H, dd, J=7.5, 4.8 Hz, 5-HPy), 7.55 (1H, dt,
J=7.5, 1.5 Hz, 4-HPy), 8.42 (1H, dd, J=4.8, 1.5 Hz, 6-
HPy), 8.53 (1H, d, J=2.0 Hz, 2-HPy); 13C N MR
(100 MHz) d 42.8, 55.0, 114.5 (2C), 119.2, 122.4, 123.5,
128.9 (2C), 133.8, 133.8, 138.2, 145.2, 148.5, 148.6. MS
m/z (EI) 258 (M+ for 35Cl, 4%), 217 (MꢀC3H5, 100%).
Found: C, 69.55; H, 5.97; N, 10.95; calcd for
C15H15ClN2: C, 69.63; H, 5.80; N, 10.83.
4-N-(4-Methoxyphenyl)amino-4-(3-pyridyl)-1-butene (67).
Red crystals. Mp 57–58 ꢁC. Yield 60%. IR (KBr) n
1
3255 cmꢀ1 (s, NH). H NMR (300 MHz) d 2.47 (1H,
quin., J=6.0 Hz, 3-HB), 2.56 (1H, quin-d, J=4.1, 1.1
Hz, 3-HA), 3.65 (3H, s, CH3O), 3.95 (1H, br.s, H–N),
4.34 (1H, dd, J=6.0, 4.1 Hz, 4-H), 5.13 (1H, s, 1-Htrans),
5.18 (1H, dd, J=4.7, 1.1 Hz, 1-Hcis), 5.66–5.78 (1H, m,
2-H), 6.41 (2H, dd, J=6.6, 1.7 Hz, 2(6)-HAr), 6.66 (2H,
dd, J=6.6, 1.7 Hz, 3(5)-HAr), 7.02 (1H, dd, J=5.8, 3.6
Hz, 5-HPy), 7.65 (1H, dt, J=5.8, 1.1 Hz, 4-HPy), 8.46
(1H, dd, J=3.6, 1.1 Hz, 6-HPy), 8.60 (1H, d, J=1.7 Hz,
2-HPy); 13C NMR (75 MHz) d 43.2, 55.8, 55.8, 114.9
(4C), 119.1, 123.7, 134.0, 134.2, 139.2, 144.2, 148.5,
148.7, 152.3. MS m/z (EI) 254 (M+, 7%), 213
(MꢀC3H5, 100%). Found: C, 75.28; H, 7.24; N, 11.31;
calcd for C16H18N2O: C, 75.59; H, 7.09; N, 11.02.
4-N-(4-Fluorophenyl)amino-4-(3-pyridyl)-1-butene (71).
Orange crystals. Mp 67–68 ꢁC. Yield 73%. IR (KBr) n
1
3264 cmꢀ1 (s, NH). H NMR (300 MHz) d 2.48 (1H,
quin., J=6.1 Hz, 3-HB), 2.60 (1H, quin-d, J=4.7, 0.8
Hz, 3-HA), 4.08 (br.s, 1H, H–N), 4.36 (1H, t, J=4.7 Hz,
4-H), 5.16 (1H, s 1-Htrans), 5.19 (2H, dd, J=12.7, 1.1
Hz, 1-Hcis), 5.67–5.79 (1H, m, 2-H), 6.39 (2H, dd,
J=6.8, 3.3 Hz, 2(6)-HAr,), 6.77 (2H, t, J=6.8 Hz, 3(5)-
HAr), 7.23 (1H, dd, J=5.8, 3.6 Hz, 5-HPy), 7.64 (1H, dt,
J=5.8, 1.1 Hz, 4-HPy), 8.49 (1H, dd, J=3.6, 1.1 Hz, 6-
HPy), 8.61 (1H, d, J=1.7 Hz, 2-HPy,); 13C N MR
(75 MHz) d 43.2, 55.6, 114.4 (2C, d, J=5.15 Hz), 115.7
(2C, d, J=16.6 Hz), 119.3, 123.7, 133.7, 134.0, 138.7,
4-N-(3,4-Methylenedioxyphenyl)amino-4-(3-pyridyl)-1-
butene (68). Red crystals. Mp 55–56 ꢁC. bp 165–170 ꢁC/

L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1543
143.1, 148.7, 148.8, 155.0 (d, J=ꢀ225.0 Hz). MS m/z
(EI) 242 (M+, 3%), 201 (MꢀC3H5, 100%). Found: C,
74.11; H, 6.46; N, 11.34; calcd for C15H15FN2: C, 74.38;
H, 6.20; N, 11.57.
113.7, 117.2, 127.4, 127.9 (2C), 128.6 (2C), 131.1 (2C),
131.2, 134.9 (2C), 139.5, 158.9, 170.8. MS m/z (EI) 295
(M+, 4%). Found: C, 77.08; H, 7.35; N, 4.55; calcd for
C19H21NO2: C, 77.29; H, 7.12; N, 4.74.
4-N-(2,4-Difluorophenyl)amino-4-(3-pyridyl)-1-butene (72).
1
N-(1-Phenyl-3-buten-1-yl)-N-(4-methoxyphenyl)allylamine
(82). A suspension of 56 (0.70 g, 2.8 mmol) in 10 mL
acetone with allyl bromide (0.67 g, 5.5 mmol) and
potassium carbonate (1.53 g, 11.0 mmol) was allowed to
reflux for 24 h. The mixture was treated with water. The
products were extracted with ether (3ꢄ10 mL), the
organic layer was dried (Na2SO4) and the residue pur-
ified by a short chromatographic column (silica gel) to
give 82 as brown oil. Yield 15% (0.12 g). IR (film) n 916
Red oil. Yield 58%. IR (film) n 3425 cmꢀ1 (s, NH). H
NMR (400 MHz) d 2.48 (1H, quin., J=6.0 Hz, 3-HB),
2.56 (1H, quin., J=8.1 Hz, 3-HA), 4.28 (1H, s, H–N),
4.31 (1H, s, 4-H), 5.10 (1H, s, 1-Htrans), 5.13 (1H, d,
J=8.1 Hz, 1-Hcis), 5.68 (1H, m, 2-H), 6.19 (1H, sext,
JHF=9.1 Hz, 3-HAr), 6.48 (1H, t, JHH=8.1 Hz, 6-HAr),
6.66 (1H, ddd, JHF=11.1, JHH=8.1, 3.0 Hz, 5-HAr), 7.20
(1H, dd, J=8.1, 4.0 Hz, 5-HPy), 7.59 (1H, d, J=8.1 Hz,
4-HPy), 8.43 (1H, d, J=4.0 Hz, 6-HPy), 8.56 (1H, s,
2-HPy); 13C NMR (100 MHz) d 42.7, 55.1, 103.3 (dd,
J=23.0, 22.3 Hz), 110.2 (dd, J=21.6, 3.4 Hz), 112.9
(dd, J=8.8, 8.8 Hz), 119.1, 123.5, 131.6 (dd, J=11.5,
3.4 Hz), 133.1, 133.7, 138.1, 148.2, 148.5, 150.7 (dd,
J=ꢀ242.0, 11.5 Hz), 154.2 (dd, J=ꢀ238.0, 11.5 Hz).
MS m/z (EI) 260 (M+, 2%), 219 (MꢀC3H5, 100%).
Found: C, 69.02; H, 5.68; N, 10.43; calcd for
C15H14F2N2: C, 69.23; H, 5.38; N, 10.77.
1
cmꢀ1 (s, ¼C–H). H NMR (200 MHz) d 2.40–2.67 (2H,
m, 3-H), 3.73 (3H, s, OCH3), 4.28–4.37 (3H, m, 4-H and
N–CH2), 4.94–5.06 (2H, m, 1-H), 5.13–5.22 (2H, m,
¼CH2), 5.57–5.90 (1H, m, 2-H), 5.95–6.05 (1H, m,
CH¼), 6.16 (2H, d, J=2.6 Hz, 2(6)-HAr), 6.62 (2H, dd,
J=8.8, 2.6 Hz, 3(5)-HAr), 7.21–7.36 (5H, m, HPh). MS
m/z (EI) 293 (M+, 9%), 252 (M-C3H5, 100%). Found:
C, 81.73; H, 7.87; N, 4.89; calcd for C20H23NO: C,
81.91; H, 7.85; N, 4.78.
4-N-(2-Iodophenyl)amino-4-(3-pyridyl)-1-butene
(73).
Compound 83 has been reported previously in ref 10
and compound 84 in ref 11.
Red crystals. Mp 46–47 ꢁC. Yield 25%. IR (KBr) n
1
3406 cmꢀ1 (s, NH). H NMR (400 MHz) d 2.50 (1H,
quin., J=8.1 Hz, 3-HB), 2.60 (1H, quin., J=6.0 Hz, 3-
HA), 4.17 (1H, s, H–N), 4.42 (1H, s, 4-H), 5.15 (1H, s, 1-
Htrans), 5.19 (1H, d, J=9.1 Hz, 1-Hcis), 5.68–5.78 (1H,
m, 2-H), 6.46 (2H, d, J=8.1 Hz, 4(6)-HAr), 6.66 (1H, t,
J=8.1 Hz, 5-HAr), 7.07 (1H, t, J=8.1 Hz, 3-HAr), 7.22
(1H, t, J=5.0 Hz, 5-HPy), 7.65 (1H, d, J=8.1 Hz, 4-
HPy), 8.48 (1H, d, J=5.0 Hz, 6-HPy), 8.55 (1H, s, 2-
HPy); 13C NMR (100 MHz) d 43.0, 54.9, 113.4, 117.8,
119.0, 123.5, 129.1, 133.6, 133.9, 138.8, 146.7, 148.4,
148.5. MS m/z (EI) 350 (M+, 3%), 309 (MꢀC3H5,
100%). Found: C, 51.73; H, 4.11; N, 8.20; calcd for
C15H15IN2: C, 51.43; H, 4.29; N, 8.00.
General procedure for the synthesis of aminoalcohols
(85–89) and tetrahydroquinolines (90–94)
Sulfuric acid 75% w/v (2.0 mL) was added to 1.0 g of
the aminobutenes (41, 42, 45, 46, 53–55, and 57) and the
mixture was heated to 60 ꢁC for 8 h while stirring vig-
orously. The reaction progress was monitored via TLC
(heptane, chromatoplates of Silufol UV254). After the
reaction was completed, the mixture was cooled down
to room temperature and a concentrated ammonium
hydroxide solution was added (pH 8–9). Two 30-mL
extractions with Et2O were performed. The organic
layers were combined and dried with anhydrous
Na2SO4. The residue after ether evaporation was pur-
ified by column chromatography over silica to give
4-aminobutanols (85–89) and tetrahydroquinolines
(90–94).
4-N-Arylamino-4-(8-quinolinyl)-1-butenes (74–78)
Have been reported previously in refs 11 and 12.
4-N-Benzylamino-4-pyridyl-1-butenes (79 and 80). Have
been reported in refs 19 and 20.
4-N-(4-Bromophenyl)amino-2-heptanol (85). Reddish oil.
1
Yield 63%. IR (film) n 3371 cmꢀ1 (s, NH, OH). H
N-(1-Phenyl-3-buten-1-yl)-N-(4-methoxyphenyl)acetamide
(81). Compound 56 (0.70 g, 2.8 mmol) was heated under
reflux for 9 h in acetic anhydride (1.0 mL, 10.5 mmol).
The reaction was monitored via TLC. At the end of the
reaction the pH was brought to 7–8 with sodium bicar-
bonate. The organic products were extracted with ethyl
acetate (3ꢄ10 mL). The combined extracts were dried
(Na2SO4) and concentrated. The oily residue was pur-
ified by column chromatography (silica gel) with ethyl
acetate and heptene (1:10) to give 81 as brownish oil.
NMR (400 MHz) d 0.85–0.90 (3H, m, 7-CH3), 1.17 (3H,
d, J=4.0 Hz, 1-CH3), 1.22–1.35 (2H, m, 3-H), 1.40–1.55
(4H, m, 5- and 6-H), 1.60–1.70 (1H, m, 4-H), 3.45 (1H,
quin., J=4.0 Hz, 2-HIsomer A), 3.55 (1H, quin., J=8.0
I
Hz, 2-HIsomer B), 3.97 (1H, br. s., H–N), 6.48–6.58 (2H,
m, 2(6)-HAr), 7.19–7.24 (2H, m, 3(5)-HAr); 13C N MR
(100 MHz) d 14.0, 18.7/19.1, 23.9/24.1, 37.5, 43.1/43.5,
50.3/53.5, 64.8/67.7, 110.0, 114.7 (2C), 131.8 (2C),
147.1; GC: two isomers (tR A=23.96, tR B=24.08 min).
MS m/z (EI) for isomer A: 285 (M+ for 79Br, 30%); for
isomer B: 287 (M+ for 81Br, 31%). Found: C, 54.78; H,
6.44; N, 5.06; calcd for C13H20BrNO: C, 54.55; H, 6.99;
N, 4.90.
1
Yield 96% (0.78 g). IR (film) n 1652 cmꢀ1 (s, CO). H
NMR (400 MHz) d 1.74 (3H, s, CH3), 2.58 (2H, dd,
J=16.0, 8.0 Hz, 3-H), 3.77 (3H, s, OCH3), 5.11 (1H, t,
J=12.0 Hz, 1-HB), 5.18 (1H, s, 1-HA), 5.81–5.85 (1H,
m, 2-H), 6.27 (1H, t, J=8.0 Hz, 4-H), 7.14–7.23 (7H, m,
HAr); 13C NMR (100 MHz) d 23.1, 34.9, 55.1, 55.8,
4-Phenyl-4-N-phenylamino-2-butanol (86). Brownish
solid. Yield 7%. Mp 130 ꢁC. IR (KBr) n 3272 cmꢀ1 (s,

1544
L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1
NH), d cmꢀ1 (s). H NMR (300 MHz) d 1.22 (3H, d,
J=6.2 Hz, 1-CH3), 1.81–1.95 (2H, m, 3-H), 4.00 (1H,
sext., J=6.2 Hz, 2-H), 4.55 (1H, dd, J=8.8, 5.1 Hz, 4-
H), 6.59 (2H, dd, J=7.7, 0.8 Hz, 2(6)-HAr), 6.89 (1H, t,
J=7.7 Hz, 4-HAr), 7.10 (2H, t, J=7.7 Hz, 3(5)-HAr),
7.21–7.35 (5H, m, HPh); 13C NMR (75 MHz) d 24.5,
47.3, 58.4, 67.8, 114.6 (2C), 118.2, 126.4, 127.2 (2C),
128.8 (2C), 129.2 (2C), 143.9, 147.2. MS m/z (EI) 241
(M+, 8%). Found: C, 79.55; H, 8.00; N, 5.97; calcd for
C16H19NO: C, 79.67; H, 7.88; N, 5.81.
143.6/143.8, 144.1; GC: two isomers (tR A=26.71, tR
B=26.95 min). MS m/z (EI) for isomer A: 283 (M+,
26%); for isomer B: 283 (M+, 24%). Found: C,80.89;
H, 8.54; N, 4.88; calcd for C19H25NO: C, 80.57; H, 8.83;
N, 4.95.
Tetrahydroquinolines 90 and 91 have been reported
previously in ref 7.
4-Methyl-2-(n-propyl)-1,2,3,4-tetrahydroquinoline (92).
Yellowish oil. Yield 73%. IR (film) n 3392 cmꢀ1 (s,
1
4-N-(4-Methylphenyl)amino-4-phenyl-2-butanol
(87).
NH). H NMR (400 MHz) d 0.86 (3H, t, J=8.0 Hz,
Brownish solid. Yield 21%. Mp 140 ꢁC. IR (KBr) n
H3C-Pr), 1.15 (1H, d, J=7.1 Hz, 3-Ha), 1.21 (3H, d,
J=6.7 Hz, 4-CH3), 1.30–1.34 (4H, m, (CH2)2–Pr), 1.82
(2H, ddd, J=11.4, 5.3, 2.6 Hz, 3-He), 2.80–2.84 (1H, m,
4-H), 3.17–3.20 (1H, m, 2-H), 3.47 (1H, br. s., H-N),
6.31 (1H, dd, J=7.8, 1.2 Hz, 8-H), 6.55 (1H, td, J=8.0,
1.2 Hz, 6-H), 6.82 (1H, td J=7.8, 1.2 Hz, 7-H), 7.01
(1H, d, J=7.6 Hz, 5-H); 13C NMR (100 MHz) d 14.2,
18.8, 20.2, 30.7, 38.5, 39.1, 51.4, 113.9, 116.9, 126.3,
126.8, 128.8, 144.6; GC: two isomers (tR A=17.47, tR
B=18.05 min). MS m/z (EI) for isomer A: 189 (M+,
100%); for isomer B: 189 (M+, 100%). Found: C,
82.33; H, 10.34; N, 7.37; calcd for C13H19N: C, 82.54;
H, 10.05; N, 7.41.
3274 cmꢀ1 (s, NH). H NMR (300 MHz) d 1.22 (3H, d,
1
J=4.7 Hz, 1-CH3), 1.84–1.96 (2H, m, 3-H), 2.18 (3H, s,
CH3Ar), 4.03 (1H, sept., J=2.5 Hz, 2-H), 4.52 (1H, dd,
J=6.8, 3.8 Hz, 4-H), 6.53 (2H, d, J=6.3 Hz, 2(6)-HAr),
6.92 (2H, d, J=6.3 Hz, 3(5)-HAr), 7.22–7.38 (5H, m,
HPh); 13C NMR (75 MHz) d 20.5, 24.4, 47.2, 58.9, 68.0,
114.9 (2C), 126.2, 127.2, 128.7 (2C), 128.8 (2C), 129.7
(2C), 143.9, 144.7. MS m/z (EI) 255 (M+, 15%). Found:
C, 80.24; H, 8.11; N, 5.76; calcd for C17H21NO: C,
80.00; H, 8.24; N, 5.49.
4-N-(4-Bromophenyl)amino-4-phenyl-2-butanol
(88).
Brownish solid. Yield 17%. IR (film) n 3266 cmꢀ1 (s,
NH). 1H NMR (400 MHz) isomer A: d 1.14 (3H, d,
J=4.7 Hz, 1-CH3), 1.70–1.90 (2H, m, 3-H), 3.83–3.90
(1H, m, 2-H), 4.36 (1H, dd, J=8.7, 5.6 Hz, 4-H), 6.31
(2H, d, J=8.8 Hz, 2(6)-HAr), 7.04 (2H, d, J=8.8 Hz,
3(5)-HAr), 7.14–7.23 (5H, m, HPh). 1H NMR (400 MHz)
isomer B: d 1.15 (3H, d, J=6.1 Hz, 1-CH3), 1.70–1.90
(2H, m, 3-H), 4.36 (1H, dd, J=8.7, 5.6 Hz, 4-H), 4.50
(1H, dd, J=8.0, 4.1 Hz, 2-H), 6.29 (2H, d, J=8.8 Hz,
2(6)-HAr), 7.00 (2H, d, J=8.8 Hz, 3(5)-HAr), 7.14–7.23
(5H, m, HPh); 13C NMR (100 MHz) d 24.0/24.5, 46.4/
47.1, 55.4/58.1, 67.2/67.4, 108.6/109.4, 115.0, 116.0,
126.1, 127.2 (2C), 129.0 (2C), 131.7 (2C), 143.0/143.4,
146.3; GC: tR=31.67 min. MS m/z (EI) 319 (M+ for
79Br, 15%). Found: C, 59.87; H, 5.78; N, 4.66; calcd for
C16H18BrNO: C, 60.00; H, 5.63; N, 4.37.
4,8-Dimethyl-2-(n-propyl)-1,2,3,4-tetrahydroquinoline (93).
Yellowish oil. Yield 58%. IR (film) n 3430 cmꢀ1 (s,
NH). H NMR (200 MHz) d 0.85 (3H, t, J=8.1 Hz,
1
CH3-Pr), 1.20 (3H, d, J=6.2 Hz, 4-CH3Isomer A), 1.22
(3H, d, J=6.2 Hz, 4-CH3Isomer B), 1.26–1.85 (6H, m, 3-
H and (CH2)2), 2.15 (3H, s, 8-CH3), 3.56–3.79 (1H, m,
4-H), 3.96–4.13 (1H, m, 2-H), 6.58–7.16 (3H, m, HAr);
GC: two isomers (tR A=18.64, tR B=19.17 min). MS
m/z (EI) for isomer A: 203 (M+, 15%); for isomer B:
203 (M+, 15%). Found: C, 82.89; H, 10.21; N, 6.99;
calcd for C14H21N: C, 82.76; H, 10.34; N, 6.90.
6-Fluoro-4-methyl-2-(n-propyl)-1,2,3,4-tetrahydroquinoline
(94). Yellowish oil. Yield 21%. IR (film) n 3410 cmꢀ1 (s,
1
NH). H NMR (400 MHz) d 0.86 (3H, t, J=8.3 Hz,
H3C-Pr), 1.12 (1H, d, J=12.0 Hz, 3-Ha), 1.16 (3H, d,
J=6.0 Hz, 4-CH3), 1.31 (4H, br.s, (CH2)2–Pr), 1.81 (1H,
ddd, J=12.0, 5.3, 2.5 Hz, 3-He), 2.77 (1H, sext., J=8.1
Hz, 4-H), 3.11 (1H, dt, J=12.0, 2.5 Hz, 2-H), 3.60 (1H,
br. s., H–N), 6.25 (1H, dd, J=8.0, 4.0 Hz, 8-H), 6.54
(1H, t, J=4.0 Hz, 7-H), 6.72 (1H, d, J=4.0 Hz, 5-H); 13C
NMR (100 MHz) d 14.1, 18.7, 20.1, 30.9, 38.1, 38.9, 51.6,
112.8, 113.2, 114.9, 127.9, 140.7, 155.6 (J=233.0 Hz, 6-
C); GC: two isomers (tR A=17.75, tR B=18.20 min).
MS m/z (EI) for isomer A: 207 (M+, 13%); for isomer B:
207 (M+, 11%). Found: C, 75.12; H, 8.99; N, 6.85; calcd
for C13H18FN: C, 75.36; H, 8.70; N, 6.76.
4-Phenyl-4-N-(2-isopropylphenyl)amino-2-butanol (89).
Yellowish oil. Yield 41%. IR (film) n 3398 cmꢀ1 (s,
NH, OH), n 1131 cmꢀ1 (s, C–O–C). 1H N MR
(400 MHz) isomer A: d 1.20 (3H, d, J=8.0 Hz, 1-CH3),
1.28 (3H, d, J=6.6 Hz, CH3-i-Pr), 1.30 (3H, d, J=6.6
Hz, CH03-i-Pr), 1.87–2.02 (2H, m, 3-H), 2.99 (1H, quin.,
J=6.6 Hz, H-C-i-Pr), 4.01–4.03 (1H, m, 2-H), 4.54 (1H,
dd, J=8.0, 4.8 Hz, 4-H), 6.45 (1H, d, J=8.0 Hz, 6-HAr),
6.69 (1H, t, J=7.5 Hz, 4-HAr), 6.91 (1H, dd, J=8.0, 7.5
Hz, 5-HAr), 7.13 (1H, d, J=7.5 Hz, 3-HAr), 7.26–7.33
1
(5H, m, HPh). H NMR (400 MHz) isomer B: d 1.20
(3H, d, J=8.0 Hz, 1-CH3), 1.28 (3H, d, J=6.6 Hz,
CH3-i-Pr), 1.30 (3H, d, J=6.6 Hz, CH03-i-Pr), 1.87–2.02
(2H, m, 3-H), 2.99 (1H, quin., J=6.6 Hz, H-C-i-Pr),
3.96–4.01 (1H, m, 2-H), 4.68 (1H, dd, J=8.7, 4.8 Hz, 4-
H), 6.33 (1H, d, J=8.1 Hz, 6-HAr), 6.64 (1H, t, J=7.6
Hz, 4-HAr), 6.91 (1H, dd, J=8.0, 7.5 Hz, 5-HAr), 7.13
(1H, d, J=7.5 Hz, 3-HAr), 7.26–7.33 (5H, m, HPh); 13C
NMR (100 MHz) d 22.4, 22.5, 24.1/24.5, 27.2/27.4, 46.4/
47.4, 55.4/58.4, 65.3/67.8, 111.3/112.8, 116.8/117.9,
124.8, 126.4, 126.7, 127.0 (2C), 128.7 (2C), 133.1/133.9,
4-[N-Acetyl-N-(4-methylphenyl)]amino-4-phenyl-2-butyl
acetate (95). To a solution of 87 (2.7 mmol) in dry ben-
zene (100 mL), an excess of acetic anhydride was added;
after the addition was complete, the solution was heated
under reflux 24 h. The reaction mixture was extracted
with ethyl acetate (2ꢄ30 mL). The ethyl acetate layer
was separated, dried (Na2SO4) and the solvent was eva-
porated. The residue was purified by column chroma-
tography over silica (with heptane/ether) to give 95 as

L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1545
reddish oil. Yield 86%. IR (film) n 1738 and 1657 cmꢀ1
(s, CO). H NMR (200 MHz) d 1.35 (3H, d, J=6.0 Hz,
1-CH3), 1.74 (3H, s, CH3CO), 2.04 (3H, s, CH3COO),
2.32 (3H, s, CH3), 1.83–1.97 (2H, m, 3-H), 4.95 (1H, q,
J=6.6, 6.2 Hz, 2-H), 6.23 (1H, dd, J=8.8, 6.9 Hz, 4-H),
7.02–7.27 (9H, m, HAr and HPh). MS m/z (EI) 339 (M+,
10%). Found: C, 74.21; H, 7.49; N, 4.33; calcd for
C21H25NO3: C, 74.34; H, 7.37; N, 4.13.
min). MS m/z (EI) for isomer A: 224 (M+, 100%); for
isomer B: 224 (M+, 100%). Found: C, 80.20; H, 7.38;
N, 12.62; calcd for C15H16N2: C, 80.36; H, 7.14; N,
12.50. Compound 98 have been previously reported in
ref 16.
1
4,6-Dimethyl-2-(20-pyridyl)-1,2,3,4-tetrahydroquinoline
(99). Yellow viscous oil. n2D0 1.6052. Yield 79%. IR
1
(film) n 3356 cmꢀ1 (s, NH). H NMR (400 MHz) cis
4-Methyl-2-(n-propyl)quinoline (96). To a solution of 1.0
mmol of tetrahydroquinoline 92 dissolved in 30 mL of
benzene, 2.1 mmol of DDQ dissolved in benzene were
added slowly. The reaction mixture was stirred at room
temperature for 4 h, monitoring progress via TLC
(heptane/ethylacetate (50:1), chromatoplates of Silufol
UV254). At the end of the reaction the mixture was fil-
tered (solid product is DDHQ). The benzene was dis-
tilled; the residue was purified by column
chromatography over silica (with heptane/ethylacetate,
isomer: d 1.30 (3H, d, J=6.8 Hz, 4-CH3), 1.60 (1H, q,
J=12.4, 11.5 Hz, 3-Ha), 2.03 (1H, ddd, J=12.4, 5.8, 2.6
Hz, 3-He), 2.25 (3H, s, 6-CH3), 2.83–3.29 (1H, m, 4-H),
4.30 (1H, br. s, H–N), 4.58 (1H, dd, J=11.5, 2.6 Hz, 2-
H), 6.53 (1H, d, J=8.1 Hz, 8-H), 6.94 (1H, d, J=7.3
Hz, 7-H), 7.14 (1H, dd, J=7.7 Hz, 30-HPy), 7.24 (1H, s,
5-H), 7.44 (1H, dd, J=7.7, 3.3 Hz, 50-HPy), 7.63–7.67
(1H, m, 40-HPy), 8.55–8.57 (1H, m, 60-HPy); GC: two
isomers (1:2.5) (tR A=30.48, tR B=31.32 min). MS m/z
(EI) for isomer A: 238 (M+, 76%), 160 (MꢀC6H6,
100%); for isomer B: 238 (M+, 63%), 160 (MꢀC6H6,
100%). Found: C, 80.80; H, 7.45; N, 11.76; calcd for
C16H18N2: C, 80.67; H, 7.56; N, 11.77.
1
50:1) to give 96 as reddish oil. Yield 58%. H N MR
(400 MHz) d 0.85 (3H, t, J=8.3 Hz, H3C–Pr), 1.22–1.30
(4H, br. s., (CH2)2–Pr), 1.25 (3H, s, 4-CH3), 7.12 (1H, s,
3-H), 7.48 (1H, t, J=7.0 Hz, 6-H), 7.65 (1H, t, J=8.3
Hz, 7-H), 7.92 (1H, d, J=8.3 Hz, 8-H), 8.03 (1H, d,
J=8.6 Hz, 5-H); 13C NMR (100 MHz) d 14.1, 18.7,
22.7, 41.2, 122.1, 123.5, 125.4, 127.0, 128.9, 129.3, 144.3,
147.5, 162.5. MS m/z (EI) 185 (M+, 8%). Found: C,
84.55; H, 8.03; N, 7.46; calcd for C13H15N: C, 84.32; H,
8.11; N, 7.57.
4,6-Dimethyl-2-(40-pyridyl)-1,2,3,4-tetrahydroquinoline
(100). Yellow crystals. Mp 138–139 ꢁC. Yield 72%. IR
1
(KBr) n 3300 cmꢀ1 (s, NH). H NMR (200 MHz) cis
isomer: d 1.34 (3H, d, J=6.6 Hz, 4-CH3), 1.70 (1H, q,
J=12.8, 11.3 Hz, 3-Ha), 2.11 (1H, ddd, J=12.8, 5.5, 2.6
Hz, 3-He), 2.26 (3H, s, 6-CH3), 3.12 (1H, sept., J=6.6
Hz, 4-H), 3.86 (1H, br.s, H–N), 4.44 (1H, dd, J=11.3,
2.6 Hz, 2-H), 6.50 (1H, d, J=8.0 Hz, 8-H), 6.86 (1H,
dd, J=8.0, 0.7 Hz, 7-H), 7.00 (1H, br.s, 5-H), 7.36 (2H,
dd, J=4.4, 1.5 Hz, 30(50)-HPy), 8.58 (2H, dd, J=4.4, 1.5
Hz, 20(60)-HPy); GC: two isomers (1:2) (tR A=27.50, tR
B=27.98 min). MS m/z (EI) for isomer A: 238 (M+,
100%); for isomer B: 238 (M+, 100%). Found: C,
80.46; H, 7.78; N, 11.86; calcd for C16H18N2: C, 80.67;
H, 7.56; N, 11.77.
General procedure for the synthesis of 2-pyridyl-
tetrahydroquinolines (97–101, 103–107)
85% (v/v) Sulfuric acid (4 mL) was added dropwise at
0 ꢁC to the homoallylamine (1.0 g) in chloroform; the
resulting mixture was heated at 95–100 ꢁC for 12–15 h
while stirring vigorously. The reaction progress was
monitored via TLC. At the end of the reaction the mix-
ture was cooled down to 0 ꢁC and concentrated sodium
hydroxide solution was added to pH 12. Three 20-mL
extractions with chloroform were performed. The
organic layers were combined, dried (Na2SO4) and con-
centrated. The residue was purified by column chroma-
tography over alumina with heptane and ethyl acetate.
Tetrahydroquinoline 102 was obtained using polypho-
sphoric acid [relation 1:10 (p/p) of homoallylamine/
acid].
4-Methyl-8-isopropyl-2-(30-pyridyl)-1,2,3,4-tetrahydroqui-
noline (101). Yellow crystals. Mp 61–62 ꢁC. Yield 79%.
IR (KBr) n 3385 cmꢀ1 (s, NH). 1H NMR (400 MHz) cis
isomer: d 1.25 (3H, d, J=6.8 Hz, CH3i-Pr), 1.29 (3H, d,
J=6.8 Hz, CH03i-Pr), 1.40 (3H, d, J=6.6 Hz, 4-CH3),
1.69 (1H, q, J=12.1, 12.1 Hz, 3-Ha), 2.01 (1H, ddd,
J=12.1, 6.0, 2.5 Hz, 3-He), 2.70 (1H, sept., J=6.8 Hz;
H-Ci-Pr), 3.01 (1H, sept., J=6.0 Hz, 4-H), 3.88 (1H, s,
H-N), 4.45 (1H, d, J=11.3 Hz, 2-H), 6.68 (1H, t, J=7.6
Hz, 6-H), 6.96 (1H, d, J=7.3 Hz, 7-H), 7.02 (1H, d,
J=7.6 Hz, 5-H), 7.22 (1H, dd, J=7.8, 5.0 Hz, 50-HPy),
7.70 (1H, d, J=7.8 Hz, 40-HPy), 8.47 (1H, d, J=5.0 Hz,
60-HPy), 8.59 (1H, s, 20-HPy), trans isomer: d 1.25 (3H, d,
J=6.8 Hz, CH3i-Pr), 1.29 (3H, d, J=6.8 Hz, CH03i-Pr),
1.56 (3H, d, J=6.6 Hz, 4-CH3), 1.77 (1H, dt, J=12.1,
10.1 Hz, 3-Ha), 1.95 (1H, ddd, J=12.1, 5.5, 2.5 Hz, 3-
He), 2.85 (1H, sept., J=6.8 Hz, H-Ci-Pr), 3.64 (1H,
sept., J=5.0 Hz, 4-H), 4.01 (1H, s, H–N), 4.41 (1H, d,
J=2.5 Hz, 2-H), 6.75 (1H, t, J=7.6 Hz, 6-H), 6.91 (2H,
d, J=7.6 Hz, 5(7)-H), 7.12 (1H, dd, J=7.6, 5.0 Hz, 50-
HPy), 7.58 (1H, d, J=7.6 Hz, 40-HPy), 8.34 (1H, d,
J=5.0 Hz, 60-HPy), 8.56 (1H, s, 20-HPy); 13C N MR
(100 MHz) d 20.3/20.0, 22.1/22.2, 22.5/22.6, 27.2/27.8,
31.5/31.8, 41.1/41.2, 54.6/54.8, 117.2/117.5, 122.9/123.0,
4-Methyl-2-(30-pyridyl)-1,2,3,4-tetrahydroquinoline (97).
White crystals. Mp 125–127 ꢁC. Yield 77%. IR (KBr) n
1
3265 cmꢀ1 (s, NH). H NMR (400 MHz) cis isomer: d
1.34 (3H, d, J=6.8 Hz, 4-CH3), 1.75 (1H, q, J=12.9,
11.4 Hz, 3-Ha), 2.08 (1H, ddd, J=12.9, 5.2, 2.7 Hz, 3-
He), 3.12 (1H, sept., J=6.8 Hz, 4-H), 4.03 (1H, br.s, H-
N), 4.47 (1H, dd, J=11.4, 2.6 Hz, 2-H), 6.53 (1H, dd,
J=7.8, 0.9 Hz, 8-H), 6.72 (1H, td, J=7.6 Hz, 6-H), 7.00
(1H, t, J=7.6 Hz, 7-H), 7.18 (1H, d, J=7.6 Hz, 5-H),
7.26 (1H, dd, J=8.0, 4.9 Hz, 50-HPy), 7.74 (1H, dt,
J=8.0, 1.6 Hz, 40-HPy), 8.51 (1H, dt, J=4.9, 1.9 Hz, 60-
HPy), 8.60 (1H, d, J=2.0 Hz, 20-HPy); 13C N MR
(100 MHz) d 20.0, 31.0, 41.3, 54.5, 114.3, 117.9, 123.5,
125.8, 126.8, 126.9, 134.1, 139.6, 144.3, 148.5, 150.0;
GC: two isomers (1 : 2.5) (tR A=29.98, tR B=30.62

1546
L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
123.6/123.7, 124.3/124.4, 125.7/125.8, 131.4, 134.2/
134.3, 140.2/140.4, 140.2/141.0, 148.1/148.2, 148.6/
149.1; GC: two isomers (1.6:6.4) (tR A=32.75, tR
B=33.52 min). MS m/z (EI) for isomer A: 266 (M+,
100%); for isomer B: 266 (M+, 100%); Found: C,
81.33; H, 8.45; N, 10.29; calcd for C18H22N2: C, 81.20;
H, 8.27; N, 10.53.
8.52 (1H, s, 60-HPy), 8.59 (1H, d, J=1.5 Hz, 20-HPy);
trans isomer: d 1.39 (3H, d, J=7.0 Hz, 4-CH3), 1.75
(1H, dt, J=12.9, 5.5 Hz, 3-Ha), 1.91 (1H, sept., J=3.3
Hz, 3-He), 3.38 (1H, br.s, H-N), 3.54 (1H, sext., J=3.3
Hz; 4-H), 4.38 (1H, t, J=3.3 Hz, 2-H), 6.54 (1H, d,
J=8.6 Hz, 8-H), 6.95 (1H, dd, J=8.6, 2.5 Hz, 7-H), 7.04
(1H, s, 5-H), 7.13 (1H, dd, J=8.1, 5.0 Hz, 50-HPy), 7.57
(1H, dt, J=8.1, 2.0 Hz, 40-HPy), 8.34 (1H, d, J=2.0 Hz,
60-HPy), 8.52 (1H, s, 20-HPy); 13C NMR (100 MHz) d
19.0/19.8, 31.1/31.8, 40.7, 54.5, 117.3, 123.3/123.6,
126.9/127.1, 130.0, 132.5/132.6, 134.2, 135.4, 139.3,
142.7/142.8, 148.0/148.3, 148.4/149.1; GC: two isomers
(1:1.7) (tR A=35.84, tR B=36.72). MS m/z (EI) for
isomer A: 258 (M+ for 35Cl, 100%); for isomer B: 258
(M+ for 35Cl, 100%). Found: C, 69.53; H, 5.89; N,
10.76; calcd for C15H15ClN2: C, 69.63; H, 5.80; N,
10.83.
6-Methoxy-4-methyl-2-(30-pyridyl)-1,2,3,4-tetrahydroqui-
noline (102). White crystals. Mp 135–137 ꢁC. Yield 48%.
IR (KBr) n 3351 cmꢀ1 (s, NH). 1H NMR (400 MHz) cis
isomer: d 1.26 (3H, d, J=6.6 Hz, 4-CH3), 1.67 (1H, q,
J=13.1, 11.6 Hz, 3-Ha), 2.02 (1H, ddd, J=13.1, 5.5, 2.5
Hz, 3-He), 3.06 (1H, sept., J=6.6 Hz, 4-H), 3.68 (3H, s,
CH3O), 4.34 (1H, dd, J=11.6, 2.5 Hz, 2-H), 6.43 (1H,
d, J=8.6 Hz, 8-H), 6.56 (1H, dd, J=8.6, 2.5 Hz, 7-H),
6.71 (1H, d, J=2.5 Hz, 5-H), 7.20 (1H, dd, J=7.6, 4.5
Hz, 50-HPy), 7.69 (1H, dt, J=7.6, 1.5 Hz, 40-HPy), 8.46
(1H, dd, J=4.5, 1.5 Hz, 60-HPy), 8.55 (1H, d, J=2.0 Hz,
20-HPy); 13C NMR (100 MHz) d 20.3; 31.4, 41.4, 54.8,
55.8, 112.5, 113.1, 115.3, 123.6, 127.8, 134.2, 138.5,
139.8, 148.6, 149.0, 152.4; GC: two isomers (1:20) (tR
A=31.00, tR B=31.91 min). MS m/z (EI) for isomer A:
254 (M+, 100%); for isomer B: 254 (M+, 100%).
Found: C, 75.45; H, 7.32; N, 11.30; calcd for
C16H18N2O: C, 75.59; H, 7.09; N, 11.02.
6-Fluoro-4-methyl-2-(30-pyridyl)-1,2,3,4-tetrahydroquino-
line (105). Yellow crystals. Mp 114–115 ꢁC. Yield 52%.
IR (KBr) n 3269 cmꢀ1 (s, NH). 1H NMR (400 MHz) cis
isomer: d 1.26 (3H, d, J=6.6 Hz, 4-CH3), 1.67 (1H, q,
J=13.1, 11.6 Hz, 3-Ha), 2.03 (1H, ddd, J=13.1, 6.0, 2.5
Hz, 3-He), 3.06 (1H, sept., J=6.0 Hz, 4-H), 3.81 (1H,
br.s, H–N), 4.38 (1H, dd, J=11.6, 2.5 Hz, 2-H), 6.41
(1H, dd, J=8.6, 5.6 Hz, 8-H), 6.67 (1H, td, J=8.1 Hz,
7-H), 6.83 (1H, dd, J=10.1, 2.0 Hz, 5-H), 7.23 (1H, dd,
J=7.6, 5.0 Hz, 50-HPy), 7.64 (1H, dt, J=7.6, 1.5 Hz, 40-
HPy), 8.48 (1H, dd, J=5.0, 1.5 Hz, 60-HPy), 8.55 (1H, s,
20-HPy); trans isomer: d 1.42 (3H, d, J=6.6 Hz, 4-CH3),
1.77 (1H, dt, J=13.1, 10.1 Hz, 3-Ha), 1.96 (1H, sept.,
J=6.6 Hz, 3-He), 2.82 (1H, sext., J=7.1 Hz, 4-H), 3.84
(1H, br.s, H–N), 4.42 (1H, d, J=3.5 Hz, 2-H), 6.41 (1H,
dd, J=8.6, 5.6 Hz, 8-H), 6.67 (1H, td, J=8.1 Hz, 7-H),
6.83 (1H, dd, J=10.1, 2.0 Hz, 5-H), 7.23 (1H, dd,
J=7.6, 5.0 Hz, 50-HPy), 7.64 (1H, dt, J=7.6, 1.5 Hz, 40-
HPy), 8.48 (1H, dd, J=5.0, 1.5 Hz, 60-HPy), 8.55 (1H, s,
20-HPy); 13C NMR (100 MHz) d 20.1/23.9, 31.3/36.5,
37.8/41.0, 50.1/54.7, 113.4 (d, J=22.3 Hz), 113.5 (d,
J=23.0 Hz), 115.1 (d, J=7.4 Hz), 123.6, 127.5 (d,
J=6.1 Hz), 134.2, 139.5, 140.5 (d, J=2.0 Hz), 148.6,
149.2, 156.2 (d, J=ꢀ235.0 Hz); GC: two isomers (1:6.8)
(tR A=26.30, tRB=26.78 min). MS m/z (EI) for isomer
A: 242 (M+, 100%); for isomer B: 242 (M+, 100%).
Found: C, 74.03; H, 6.52; N, 11.33; calcd for
C15H15FN2: C, 74.38; H, 6.20; N, 11.57.
6-Bromo-4-methyl-2-(30-pyridyl)-1,2,3,4-tetrahydroquino-
line (103). Yellow crystals. Mp 135–137 ꢁC. Yield 34%.
IR (KBr) n 3261 cmꢀ1 (s, NH). 1H NMR (400 MHz) cis
isomer: d 1.31 (3H, d, J=6.6 Hz, 4-CH3), 2.06 (1H, br.d,
J=12.1 Hz, 3-He), 1.69 (1H, q, J=12.1, 11.6 Hz, 3-Ha),
3.07 (1H, quin., J=5.5 Hz, 4-H), 4.06 (1H, br.s, H–N),
4.44 (1H, d, J=10.6 Hz, 2-H), 6.33 (1H, d, J=8.1 Hz,
8-H), 7.07 (1H, d, J=8.1 Hz, 7-H), 7.16–7.27 (2H, m, 5-
H and 50-HPy), 7.72 (1H, d, J=7.6 Hz, 40-HPy), 8.51
(1H, s, 60-HPy), 8.58 (1H, d, J=2.0 Hz, 20-HPy); trans
isomer d: 1.41 (3H, d, J=6.5 Hz, 4-CH3), 1.76 (1H, d,
J=12.6 Hz, 3-Ha), 1.89–1.93 (1H, m, 3-He), 2.79 (1H,
br.s, 4-H), 4.15 (1H, br.s, H–N), 4.23 (1H, s, 2-H), 6.54
(1H, d, J=8.6 Hz, 8-H), 6.95 (1H, dd, J=8.6, 2.5 Hz, 7-
H), 7.04 (1H, s, 5-H), 7.13 (1H, dd, J=8.1, 5.0 Hz, 50-
HPy), 6.46 (1H, d, J=8.1 Hz, 40-HPy), 8.38 (1H, s, 60-
HPy), 8.61 (1H, s, 2-HPy); 13C NMR (100 MHz) d 19.8/
23.5, 29.4/31.1, 37.5/40.7, 49.8/54.4, 115.7/115.8, 116.6,
123.5/123.6, 129.5/129.6, 131.8/131.9, 134.1/134.2,
139.6, 139.2, 142.5/143.3, 148.4/148.5, 148.9/149.2; GC:
two isomers (1:4.1) (tR A=34.84, tR B=35.90 min). MS
m/z (EI) for isomer A: 302 (M+ for 79Br, 100%); for
isomer B: 304 (M+ for 81Br, 100%). Found: C, 59.54;
H, 5.11; N, 9.12; calcd for C15H15BrN2: C, 59.41; H,
4.95; N, 9.24.
6,8-Difluoro-4-methyl-2-(30-pyridyl)-1,2,3,4-tetrahydroqui-
noline (106). Red oil. Yield 26%. IR (film) n 3356 cmꢀ1
1
(s, NH). H NMR (400 MHz) cis isomer: d 1.40 (3H, d,
J=7.1 Hz, 4-CH3), 1.75 (1H, q, J=14.6, 14.1 Hz, 3-
Ha), 1.89 (1H, ddd, J=14.6, 5.5, 2.5 Hz, 3-He), 3.53
(1H, br.s, H–N), 3.64 (1H, quint., J=7.1 Hz, 4-H), 4.46
(1H, t, J=14.1 Hz, 2-H), 6.29 (1H, d, JHH=3.0 Hz, 7-
H), 6.65 (1H, d, JHH=3.0 Hz, 5-H), 7.16 (1H, dd,
J=7.6, 4.5 Hz, 50-HPy), 7.59 (1H, d, J=7.6 Hz, 40-HPy),
6-Chloro-4-methyl-2-(30-pyridyl)-1,2,3,4-tetrahydroquino-
line (104). Yellow crystals. Mp 140–142 ꢁC. Yield 56%.
IR (KBr) n 3268 cmꢀ1 (s, NH). 1H NMR (400 MHz) cis
isomer: d 1.24 (3H, d, J=7.1 Hz, 4-CH3), 1.63 (1H, q,
J=12.9, 11.1 Hz, 3-Ha), 2.00 (1H, ddd, J=12.9, 5.0, 2.5
Hz, 3-He), 3.01 (1H, sept., J=5.0 Hz, 4-H), 4.00 (1H,
br.s, H–N), 4.38 (1H, dd, J=11.1, 2.5 Hz, 2-H), 6.38
(1H, d, J=8.6 Hz, 8-H), 6.87 (1H, dd, J=8.6, 2.0 Hz, 7-
H), 7.03 (1H, d, J=2.0 Hz, 5-H), 7.21 (1H, dd, J=7.6,
5.0 Hz, 50-HPy), 7.66 (1H, dt, J=7.6, 2.0 Hz, 40-HPy),
8.37 (1H, d, J=4.5 Hz, 60-HPy), 8.47 (s, 1H, 20-HPy); 13
C
NMR (100 MHz) d 19.1, 37.2, 46.9, 56.0, 101.7 (dd,
J=24.3, 23.6 Hz); 108.9 (dd, J=22.3, 3.4 Hz), 123.4,
128.6 (dd, J=12.8, 3.4 Hz), 131.9 (dd, J=7.4, 7.4 Hz),
134.9, 139.0, 148.0, 148.4, 151.5 (dd, J=ꢀ241.0, 12.8
Hz), 155.2 (dd, J=ꢀ239.0, 12.8 Hz); GC: one isomer
(tR=29.45 min). MS m/z (EI) 260 (M+, 100%). Found:

L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1547
C, 69.02; H, 5.55; N, 10.42; calcd for C15H14F2N2: C,
69.23; H, 5.38; N, 10.77.
J=5.8 Hz, 20(60)-HPy). MS m/z (EI) 234 (M+, 100%).
Found: C, 82.12; H, 5.87, N, 12.05; calcd for C16H14N2:
C, 82.05; H, 5.98; N, 11.97.
8-Iodo-4-methyl-2-(30-pyridyl)-1,2,3,4-tetrahydroquinoline
(107). Red crystals. Mp 98–100 ꢁC. Yield 12%. IR
4-Methyl-8-isopropyl-2-(30-pyridyl)quinoline
(112).
(KBr) n 3365 cmꢀ1 (s, NH). H NMR (400 MHz) cis
White solid. Mp 105–106 ꢁC. Yield 59%. 1H N MR
(200 MHz) d 1.44 (6H, d, J=6.9 Hz, CH3 and CH03-i-
Pr), 2.78 (3H, d, J=0.7 Hz, 4-CH3), 4.50 (1H, quin.,
J=6.9, H-C-i-Pr), 7.45 (1H, ddd, J=8.0, 4.8, 0.7 Hz, 50-
HPy), 7.55 (1H, d, J=8.0 Hz, 6-H), 7.64 (1H, dd, J=7.3,
1.8 Hz, 7-H), 7.75 (1H, d, J=0.7 Hz, 3-H), 7.87 (1H,
dd, J=8.0, 1.8 Hz, 5-H), 8.56 (1H, dt, J=8.0, 2.2 Hz,
40HPy), 8.68 (1H, dd, J=4.8, 1.5 Hz, 60-HPy), 9.45 (1H,
dd, J=2.2, 0.7 Hz, 20-HPy). MS m/z (EI) 262 (M+,
50%). Found: C, 82.22; H, 6.95; N, 10.57; calcd for
C18H18N2: C, 82.44; H, 6.87; N, 10.69.
1
isomer: d 1.18 (3H, d, J=6.6 Hz, 4-CH3), 1.70 (1H, q,
J=12.1, 12.0 Hz, 3-Ha), 2.02 (1H, dt, J=12.1, 2.5 Hz,
3-He), 3.11 (1H, sept., J=6.6 Hz, 4-H), 3.88 (1H, s, H-
N), 4.45 (1H, dd, J=11.1, 2.5 Hz, 2-H), 6.69 (1H, t,
J=7.6 Hz, 6-H), 6.97 (1H, d, J=7.6 Hz, 5-H), 7.02 (1H,
d, J=7.6 Hz, 7-H), 7.23 (1H, dd, J=7.6, 5.0 Hz, 50-
HPy), 7.71 (1H, d, J=8.1 Hz, 40-HPy), 8.48 (1H, d,
J=5.0 Hz, 60-HPy), 8.60 (1H, s, 20-HPy); 13C N MR
(100 MHz) d20.3, 30.3, 37.9, 50.1, 90.1, 123.0, 123.4,
123.7, 134.2, 136.7, 140.2, 141.0, 148.6, 149.1, 156.0;
GC: one isomer (tR=33.71 min). MS m/z (EI) 350 (M+,
100%). Found: C, 51.33; H, 4.45; N, 7.80; calcd for
C15H15IN2: C, 51.43; H, 4.29; N, 8.00.
6-Bromo-4-methyl-(30-pyridyl)quinoline (113). Yellow
crystals. Mp 120–121 ꢁC. Yield 25%. 1H
N MR
(300 MHz) d 2.74 (3H, d, J=1.0 Hz, 4-CH3), 7.45
(1H, ddd, J=7.7, 4.9, 0.7 Hz, 50-HPy), 7.73 (1H, s, 3-
H), 7.81 (1H, dd, J=9.0, 2.3 Hz, 7-H), 8.05 (1H, d,
J=9.0 Hz, 8-H), 8.17 (1H, d, J=2.3 Hz, 5-H), 8.50
(1H, dt, J=7.7, 1.6 Hz, 40-HPy), 8.72 (1H, dd, J=4.9,
1.6 Hz, 60-HPy), 9.35 (1H, d, J=1.3 Hz, 20-HPy) ). MS
m/z (EI) 300 (M+ for 81Br, 100%). Found: C, 59.92; H,
4.07; N, 9.51; calcd for C15H11BrN2: C, 60.20; H, 3.68;
N, 9.36.
General procedure for the synthesis of quinolines (108–
116)
In a 50 mL flask a mixture of powdered sulphur (0.03
mol) and tetrahydroquinoline (97–101 and 103–106)
(0.01 mol) is placed and the flask is then placed in a
sand bath which is heated to 260–280 ꢁC for 10–30 min,
until evolution of hydrogen sulphide has ceased. The
residue was purified by column chromatography over
alumina with heptane/ethyl acetate, to yield quinolines
(108–116).
6-Chloro-4-methyl-(30-pyridyl)quinoline (114). Yellow
crystals. Mp 127–128 ꢁC. Yield 75%. 1H
N MR
(400 MHz) d 2.75 (3H, s, 4-CH3), 7.45 (1H, dd, J=8.0,
4.8 Hz, 50-HPy), 7.67 (1H, dd, J=8.9, 2.3 Hz, 8-H), 7.97
(1H, d, J=2.2 Hz, 5-H), 7.73 (1H, s, 3-H), 8.09 (1H, d,
J=8.9 Hz, 7-H), 8.47 (1H, dt, J=8.0, 1.8 Hz, 40-HPy),
8.70 (1H, dd, J=4.8, 1.8 Hz, 60-HPy), 9.33 (1H, d,
J=2.2 Hz, 20-HPy). MS m/z (EI) 254 (M+ for 35Cl,
100%). Found: C, 70.47; H, 4.49, N, 11.33; calcd for
C15H11ClN2: C, 70.73; H, 4.32; N, 11.00.
4-Methyl-2-(30-pyridyl)quinoline (108). White crystals.
Mp 67–68 ꢁC. Yield 76%. H NMR (200 MHz) d 2.79
1
(3H, d, J=0.7 Hz, 4-CH3), 7.45 (1H, ddd, J=8.0, 4.8,
0.7 Hz, 50-HPy), 7.58 (1H, ddd, J=8.4, 7.7, 1.5 Hz; 6-H),
7.79–7.81 (2H, m, 3(7)-H ), 8.02 (1H, dd, J=8.4, 1.5 Hz,
8-H), 8.18 (1H, ddd, J=8.4, 1.5, 0.7 Hz, 5-H), 8.50 (1H,
dt, J=8.0, 2.2 Hz, 40-HPy), 8.70 (1H, dd, J=4.8, 1.5 Hz,
60-HPy), 9.34 (1H, dd, J=2.2, 0.7 Hz, 20-HPy). MS m/z
(EI) 220 (M+, 100%). Found: C, 81.87; H, 5.66; N,
12.50; calcd for C15H12N2: C, 81.82; H, 5.45; N, 12.73.
6-Fluoro-4-methyl-2-(30-pyridyl)quinoline (115). Yellow
crystals. Mp 103–104 ꢁC. Yield 83%. 1H
N MR
(200 MHz) d 2.70 (3H, s, 4-CH3), 7.59–7.42 (3H, m,
Quinoline 109 has been reported previously in ref 16
5(8)-H and 50-HPy), 7.70 (1H, s, 3-H), 8.13 (1H, dd,
J=9.1, JH,F=5.6 Hz, 8-H), 8.52 (1H, d, J=7.5 Hz, 40-
4
HPy), 8.67 (1H, d, J=4.6 Hz, 60-HPy), 9.32 (1H, s, 20-
HPy). MS m/z (EI) 238 (M+, 100%). Found: C, 75.45;
H, 4.72; N, 11.66; calcd for C15H11FN2: C, 75.63; H,
4.62; N, 11.77.
4,6-Dimethyl-2-(20-pyridyl)quinoline (110)
Yellow crystals. Mp 134–135 ꢁC. Yield 84%. H N MR
1
(200 MHz) d 2.58 (3H, s, 6-CH3), 2.77 (3H, d, J=0.7
Hz, 4-CH3), 7.38 (1H, ddd, J=7.7, 4.8, 1.5 Hz, 50-HPy),
7.56 (1H, dd, J=8.4, 1.8 Hz, 7-H), 7.78 (1H, s, 5-H),
7.86 (1H, td, J=8.0 Hz, 30-HPy), 8.07 (1H, d, J=8.4 Hz,
8-H), 8.36 (1H, d, J=0.7 Hz, 3-H), 8.62 (1H, dt, J=8.0,
1.8 Hz, 40-HPy), 8.73 (1H, ddd, J=4.8, 1.8, 1.1 Hz, 60-
HPy). MS m/z (EI) 234 (M+, 100%). Found: C, 81.98;
H, 5.87; N, 12.14; calcd for C16H14N2: C, 82.05; H, 5.98;
N, 11.97.
6,8-Difluoro-4-methyl-2-(30-pyridyl)quinoline
(116).
ꢁ
1
Brown crystals. Mp 150–151 C. Yield 41%. H N MR
(200 MHz) d 2.72 (3H, s, 4-CH3), 7.34–7.48 (3H, m,
5(7)-H and 50-HPy), 7.78 (1H, s, 3-H), 8.51 (1H, dt,
J=8.0, 1.6 Hz, 40-HPy), 8.68 (1H, dd, J=4.6, 1.6 Hz, 6-
HPy), 9.30 (1H, d, J=1.3 Hz, 20-HPy); 13C N MR
(50 MHz) d 19.4, 103.3 (dd, J=21.4, 4.6 Hz), 105.4 (dd,
J=29.0, 22.9 Hz), 111.4 (dd, J=21.4, 3.1 Hz), 120.8,
123.8, 128.9 (dd, J=10.7, 3.1 Hz), 133.0, 135.0, 147.0,
148.6, 150.4, 153.8, 159.2 (dd, J=ꢀ260.9, 13.7 Hz),
159.6 (dd, J=ꢀ247.2, 12.2 Hz). MS m/z (EI) 256 (M+,
100%). Found: C, 70.56; H, 3.58; N, 10.86; calcd for
C15H10F2N2: C, 70.31; H, 3.91; N, 10.94.
4,6-Dimethyl-2-(40-pyridyl)quinoline (111). Yellow crys-
tals. Mp 168–169 ꢁC. Yield 75%. 1H NMR (200 MHz) d
2.59 (3H, s, 6-CH3), 2.77 (3H, s, 4-CH3), 7.59 (1H, dd,
J=8.8, 1.8 Hz, 7-H), 7.71 (1H, s, 3-H), 7.78 (1H, s, 5-
H), 8.01–8.12 (3H, m, 8-H and 30(50)-HPy), 8.76 (2H, d,

1548
L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
General procedure for the synthesis of nitroquinolines
(117 and 118)
Found: C, 77.22; H, 6.15; N, 16.54; calcd for C16H15N3:
C, 77.11; H, 6.02; N, 16.87.
Quinolines (109 and 110) (8.55 mmol) were dissolved, at
ꢀ8 ꢁC, in concentrated sulfuric acid (40 mL). A mixture
of concentrated sulfuric acid (10 mL) and nitric acid
(8.65 mmol) was added, slowly, at ꢀ8 ꢁC. The reaction
mixture was stirred and held at 0 ꢁC for 0.5 h after all of
the nitric acid has been added. The reaction mixture was
poured on ice and the solution made alkaline with con-
centrated NH4OH to precipitate the product. The pro-
duct was extracted with CHCl3 (4ꢄ50 mL). The
combined organic layers were dried over sodium sulfate
and evaporated under reduced pressure. The solid was
purified by a short chromatography column over alu-
mina (with heptane/ethyl acetate).
2-Pyridyl-tetrahydro-[2]benzazepines (120 and 121).
Compounds 120 and 121 been obtained from 4-N-ben-
zylamino-4-pyridyl-1-butenes and reported in ref 20.
N-(1-Allylcycloalkyl) arylamino derivatives (122–141).
Compounds 122–141 have been obtained from corre-
sponding ketimines and allylmagnesium bromide fol-
lowing the general procedure.21ꢀ23
Biological Evaluation
Microorganisms and media
4,6-Dimethyl-5-nitro-2-(30-pyridyl)quinoline (117). Green
crystals. Mp 160–161 ꢁC. Yield 98%. IR (KBr) n 1528,
1374 cmꢀ1 (s, NO2). 1H NMR (300 MHz) d 2.68 (3H, s,
6-CH3), 2.49 (3H, s, 4-CH3), 7.47 (1H, dd, J=8.0, 4.8
Hz, 50-HPy), 7.61 (1H, d, J=8.7 Hz, 8-H), 7.77 (1H, s, 3-
H), 8.21 (1H, d, J=8.7 Hz, 7-H), 8.48 (1H, dt, J=8.0,
1.1 Hz, 40-HPy), 8.73 (1H, dd, J=4.8, 1.1 Hz, 60-HPy),
9.35 (1H, d, J=1.9 Hz, 20-HPy); 13C NMR (75 MHz) d
18.0, 19.6, 119.2, 123.3, 124.1, 129.2, 131.9, 133.1, 134.4,
135.2, 142.8, 146.9, 147.8, 149.2, 151.1, 155.0. MS m/z
(EI) 279 (M+, 100%). Found: C, 68.43; H, 4.57; N,
14.92; calcd for C16H13N3O2: C, 68.82; H, 4.66; N,
15.05.
Dermatophytes. M. canis C 112, Trichophyton rubrum C
113, E. floccosum C 114, and M. gypseum C 115 as well
as Candida tropicalis C 131 are clinical isolates and were
kindly provided by CEREMIC (Centro de Referencia
Micologica, Facultad ded Ciencias Bioquımicas y
Farmaceuticas, Suipacha 531 (2000) Rosario, Argen-
tina.
The strains were maintained on slopes of Sabouraud-
dextrose agar7 (SDA, Oxoid) and subcultured every 15
days to prevent pleomorphic transformations. Spore
suspensions were obtained according to reported proce-
dures27 and adjusted to 106 spores with colony forming
ability/mL.
4,6-Dimethyl-5-nitro-2-(20-pyridyl)quinoline (118). Yel-
low crystals. Mp 134–136 ꢁC. Yield 67%. IR (KBr) n
Antifungal assays
1
1530, 1373 cmꢀ1 (s, NO2). H NMR (200 MHz) d 2.46
(3H, s, 6-CH3), 2.67 (3H, d, J=0.7 Hz, 4-CH3), 7.37
(1H, ddd, J=7.7, 4.8, 1.1 Hz, 50-HPy), 7.55 (1H, d,
J=8.8 Hz, 7-H), 7.9 (1H, td, J=8.0 Hz, 30-HPy), 8.18
(1H, d, J=8.8 Hz, 8-H), 8.44 (1H, d, J=1.1 Hz, 3-H),
8.60 (1H, dt, J=8.0, 1.8 Hz, 40-HPy), 8.73 (1H, ddd,
J=4.8, 1.8, 0.7 Hz, 60-HPy). MS m/z (EI) 279 (M+,
100%). Found: C, 68.43; H, 4.57; N, 14.92; calcd for
C16H13N3O2: C, 68.82; H, 4.66; N, 15.05.
The antifungal activity of homoallylamines, tetra-
hydroquinolines, quinolines and related compounds was
evaluated with the agar dilution method by using
Sabouraud-chloramphenicol agar for dermatophyte
species as previously described.24,28 Stock solutions of
compounds (10 mg/mL in DMSO) were diluted to give
serial 2-fold dilutions that were added to each medium
resulting in concentrations ranging from 0.10 to 250 mg/
mL. MIC for each compound was defined as the lowest
concentration that produces no visible fungal growth
after the incubation time.
5-Amino-4,6-dimethyl-2-(30-pyridyl)quinoline
(119).
Under N2 atmosphere, a solution of 5-nitroquinoline
117 (0.2 g, 0.72 mmol) in methanol (25 mL) was poured
into a mixture of 10% palladium on charcoal (0.006 g)
in methanol (5 mL). Sodium borohydride (0.068 g, 1.80
mmol) was added. The reaction mixture was stirred for
1.5 h. and then was acidified by 10% HCl (3 mL), neu-
tralized by 1 M sodium hydroxide (5 mL) and con-
centrated under reduced pressure. The resulting mixture
was extracted with CHCl3 (4ꢄ10 mL). The combined
organic layers were dried (Na2SO4) and evaporated
under reduced pressure. Recrystallyzation in ethyl ace-
tate gave 5-amino-4,6-dimethyl-2-(30-pyridyl)quinoline
119 as orange brilliant crystals. Mp 155–157 ꢁC. Yield
Enzymatic assays
Strains and culture conditions. The S. cerevisiae strain
used was MATa trpI ura3 leu2 his3 pep4::HIS3
nuc1::LEU2. Routine yeast growth (YEPD) was as
described.29
Enzyme preparation. Cell extracts were obtained essen-
tially as described previously.30 Early logarithmic phase
cells grown in 100 mL YEPD medium were collected,
washed once with 50 mM Tris–HCl pH 7.5, suspended
in 100 mL of the same buffer and broken with glass
beads in a FastPrep FP120 apparatus (Savant, BIO 101,
Inc.) (once a 15 s pulse at speed of 6.0). Broken material
was collected and cell debris was removed by low speed
centrifugation (5.000ꢄg, 5 min at 4 ꢁC). The super-
natant was centrifuged at 18.000ꢄg for 30 min at 4 ꢁC
1
95%. IR (KBr) n 3342, 3234 cmꢀ1 (s, NH2). H N MR
(400 MHz) d 2.31 (3H, s, 6-CH3), 3.06 (3H, s, 4-CH3),
4.36 (2H, br.s, H2N), 7.36–7.45 (3H, m, 3(7, 8)-H), 7.55
(1H, d, J=8.4 Hz, 50-HPy), 8.46 (1H, dt, J=8.4, 1.9 Hz,
40-HPy), 8.66 (1H, dd, J=4.8, 1.6 Hz, 60-HPy), 9.29 (1H,
d, J=1.6 Hz, 20-HPy). MS m/z (EI) 249 (M+, 100%).

L. Y. Vargas M. et al. / Bioorg. Med. Chem. 11 (2003) 1531–1550
1549
and the pellet was resuspended in 50 mM Tris–HCl pH
7.5 containing 33% glycerol (at a concentration of
approximately 3 mg protein per mL) and stored at
ꢀ80 ꢁC. Protein was quantified by the Bradford dye-
binding procedure31 using the Bio-Rad Protein Assay
Dye Reagent and bovine serum albumin as standard.
RIIDDMED (Iberoamerican Network on Investigation
and Development of Medicines) from CYTED is grate-
fully acknowledged. R.D.E. is a career researcher of
CONICET.
References and Notes
(1,3)-ꢀ-D-Glucan synthase assay. (1,3)-b-d-Glucan syn-
thase assay was essentially as described previously.30
The standard assay mixture contained 5 mL enzyme (15
mg protein), in a total volume of 40 mL. Two mL of
methanol or the corresponding compounds (kept in
stock solution, 10 mg/mL in methanol at ꢀ20 ꢁC) were
added to each reaction. The reaction was incubated for
30 min at 30 ꢁC and stopped by addition of 1 mL 10%
trichloroacetic acid. All reactions were carried out in
duplicate. The drug Papulacandin B was a generous
gifts from K. Scheibli and P. Traxler (Novartis, Basel,
Switzerland). The antibiotic was kept in stock solution
(10 mg/mL in methanol) at ꢀ20 ꢁC.
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Adis International: San Jose, 2001; Vol. 61, Supplement 1,
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3. Selitrennikoff, C. P. Antifungal Drugs: (13)–ꢀ-Glucan-syn-
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4. Barrett-Bee, K. J.; Ryder, N. S. In Emerging Targets in
Antibacterial and Antifungal Chemotherapy; Sutcliffe, J.,
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ough, L. Curr. Med. Chem. 1999, 6, 1151.
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performed as described previously.32 The standard
assay mixture contained 10 mL enzyme (30 mg protein)
in a total volume of 50 mL. Two mL of methanol or the
corresponding compounds (kept in stock solution, 10
mg/mL in methanol at ꢀ20 ꢁC) were added to each
reaction. Enzyme activation was performed by partial
proteolysis of the reaction mixture with 2 mL trypsin
(0.25 mg/mL) during 15 min at 30 ꢁC and stopped by the
addition of 2 mL trypsin inhibitor (0.375 mg/mL). The
reaction was incubated for 90 min at 30 ꢁC and stopped
by addition of 1 mL 10% trichloroacetic acid. All reac-
tions were carried out in duplicate.
7. Urbina, J. M.; G-Cortes, J. C.; Palma, A.; Lopez, S. N.;
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J. C.; Devia, C.; Rodrıguez, A. M.; Enriz, R. D. Bioorg. Med.
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9. Zacchino, S. A.; Rodrıguez, G. E.; Pezzenati, G.; Santec-
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¨
11. Ocal, N.; Yolac
¸ an, C.; Kaban, S.; Vargas, M.,L.Y.;
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Computational methods
13. Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153.
14. Detailed report on spatial structure of diastereoisomeric
tetrahydroquinolines will be published elsewhere.
15. Kuznetsov, V. V.; Aliev, A. E.; Prostakov, N. S. Khimiya
Geterotsiklicheskikh Soedinenii 1994, 1, 73; Chem. Abst. 1994
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The extensive search for low-energy conformations on
the potential energy surface for homoallylamines repor-
ted here was carried out by first using the systematic
routine GASCOS33ꢀ35 in connection with the MM2
force field. Subsequently, ab-initio HF/3-21G calcula-
tions were used in the geometry optimization jobs, using
the GAUSSIAN98 program. Molecular Electrostatic
Potentials (MEPs)37 were calculated using RHF/3-21G
38
wave functions from the SPARTANprogram.
36
18. Lutun, S.; Guichard, E.; Hasiak, B.; Couturier, D. Synth.
Commun. 1999, 29, 175.
´
19. Kouznetsov, V. V.; Palma, A.; Aliev, A. E. Anales Quı-
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A. E.; Shevtsov, V. K.; Varlamov, A. V.; Prostakov, N. S.
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Acknowledgements
This work was supported by grants to SAZ (Agencia de
Promociones Cientıficas y Tecnologicas de la Argentina
PICT # 06-06454); to SNL (Grantee IFS F/3114-2F), to
RDE (Proyecto 81-01, Univ. Nac. San Luis) and to
VVK (Colciencias, Colombia). The authors wish to
thank Prof. A. Duran (CSIC/Univ. de Salamanca) for
helping and supporting part of this work. This work is
part of the Iberoamerican Project X.7-PIBEAFUN
(Search and development of new antifungal agents)
from Red X.A-RIPRONAMED (Iberoamerican Net-
work on Medicinal Natural Products), of the Iber-
oamerican Program for the Development of Science and
Technology (CYTED). Collaboration of Red X.E-
24. Zacchino, S. A.; Rodrıguez, G. E.; Pezzenati, G.; Orellana,
G.; Enriz, R. D.; Gonzalez Sierra, M. J. Nat. Prod. 1997, 60, 659.
25. Tkacz, J. In Emerging Targets in Antibacterial and Anti-
fungal Chemotherapy; Sutcliffe J. M., Georgopapadakou, N.
H., Eds.; Chapman and Hall: New York, 1992; p 495.

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Diego, 1990; Vol. 138, p 643.
27. Wright, L.; Scott, E.; Gorman, S. J. Antimicrob. Che-
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28. Zacchino, S. A.; Lopez, S. N.; Pezzenati, G.; Furlan, R. L.;
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