A novel series of homoallylic amines as potential antimicrobials

Article abstract of DOI:10.1007/s00044-011-9607-3

An efficient catalytic three-component reaction of aldehydes, amines, and allyltributylstannate has been successfully developed to produce homoallylic amines at 25°C, in excellent yields, in the presence of 1 mol% of trifluoroacetic acid an inexpensive and environmentally friendly catalyst. Newly synthesized compounds were confirmed by spectral studies. Compound 3o was characterized by single crystal X-ray analysis. All the compounds were also screened for their antimicrobial activity. Halogen-substituted compounds namely 3d, 3g, 3n, and 3o have showed excellent antibacterial activity. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9607-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1090–1097
DOI 10.1007/s00044-011-9607-3
ORIGINAL RESEARCH
A novel series of homoallylic amines as potential antimicrobials
•
U. Sankappa Rai Arun M. Isloor
•
•
Prakash Shetty Nishitha Isloor
•
•
Mahesh Padaki Hoong-Kun Fun
Received: 7 August 2010 / Accepted: 18 February 2011 / Published online: 25 March 2011
Ó Springer Science+Business Media, LLC 2011
Abstract An efficient catalytic three-component reaction
of aldehydes, amines, and allyltributylstannate has been
successfully developed to produce homoallylic amines at
25°C, in excellent yields, in the presence of 1 mol% of
trifluoroacetic acid an inexpensive and environmentally
friendly catalyst. Newly synthesized compounds were
confirmed by spectral studies. Compound 3o was charac-
terized by single crystal X-ray analysis. All the compounds
were also screened for their antimicrobial activity. Halo-
gen-substituted compounds namely 3d, 3g, 3n, and 3o have
showed excellent antibacterial activity.
Introduction
Homoallylic amines are valuable intermediates in organic
synthesis (Yamaguchi et al., 1985) as starting materials in
the preparation of biologically active substances (Moser
et al. 1982), as resolving agents (James 1989) and as chiral
auxiliaries for asymmetric synthesis (Sabine and Horst,
1991). They are used for the synthesis of b-amino acids
(Xie et al., 1989), as well as b-lactams (Wright et al.,
2000a, b) and HIV-protease inhibitors (Bloch 1998). The
homoallylic amine moiety is not widely present in natural
products, however, compounds like eponemycin (Schmidt
and Schmidt 1994), which exhibits potent activity against
B16 melanoma cells, or a depsipeptide cryptophycin 337
(Russell et al., 2000), which is an analog of a potent anti-
tumor compound cryptophycin, contain this subunit.
Keywords Homoallylic amines ꢀ Allyltributyl stannate ꢀ
CF3COOH ꢀ Antibacterial activity
On the other hand, homoallylic amines are excellent
building blocks for the synthesis of numerous nitrogen-
containing natural products (Puentes and Kouznetsov 2002),
Chiral homoallylic amines were utilized as the key inter-
mediates in the preparation of many natural products, such as
an amino-sugar vancosamine isolated from vancomycin
(Wright et al., 2000a, b), a spirocycle alkaloid alichlorine
isolated from a Japanese sponge Halichondria okadai Ka-
dota (Ciufolini et al., 1989), an alkaloid from Prosopis
africana, desoxoprosopinine (Felpin and Lebreton 2003),
and many others. With the utilization of ring-closing
metathesis methodology, numerous piperidine alkaloids can
be easily prepared from the corresponding aminodienes
(Voigtmann and Blechert 2000). Preparation of b-amino
acids is of particular interest to medicinal and bioorganic
chemists as various b-amino acid moieties can be found in
taxoids, b-lactam antibiotics, and other compounds.
U. Sankappa Rai
Department of Chemistry, Manipal Institute of Technology,
Manipal University, Manipal, India
A. M. Isloor (&) ꢀ M. Padaki
Department of Chemistry, Organic Chemistry Division, National
Institute of Technology-Karnataka, Surathkal 575 025, India
e-mail: isloor@yahoo.com
P. Shetty
Department of Printing Technology, Manipal Institute
of Technology, Manipal University, Manipal, India
N. Isloor
Department of Biotechnology, Chemical Engineering, National
Institute of Technology-Karnataka, Surathkal 575 025, India
H.-K. Fun
X-ray Crystallography Unit, School of Physics, Universiti Sains
Malaysia, USM, 11800 Penang, Malaysia
In general, Homoallylic amines are prepared either by
the addition of organometallic reagents to imines or by
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Med Chem Res (2012) 21:1090–1097
1091
nucleophillic addition of allylsilanes, allyltin, allylboron,
or allyl germane reagents to imines (Keck and Enholm,
1985) in the presence of catalysts such as LiClO4,
[(Yadav et al., 2002), Sn(OTf)3 (Manoj Pandey et al.,
2005), Bi(OTf)3ꢀnH2O (Ollevier et al., 2003), PdCl2
(PPh3)2 (Nakamura et al., 1996). Recently, HClO4–SiO2
(Nagarapu et al., 2007) have been employed for this
transformation. However, most of the synthesis protocols
reported so far requires long reaction times, stringent
conditions, and highly toxic reagents/catalysts (Ponnabo-
ina and Kim, 2009) the catalysts are often expensive and
tedious to prepare. The reactions are often characterized
by low yields. Therefore, there is a need for the devel-
opment of simple, convenient, and environmentally
benign approaches for the synthesis of homoallylic
amines.
Results and discussion
Synthesis
The reaction of benzaldehyde, 1-naphthylamine, and al-
lyltributyl in the presence of 0.1 equivalents CF3COOH in
acetonitrile at 25°C resulted in the formation of the
homoallylic amines in 68–98% yield. The scope and gen-
erality of this process is illustrated with respect to different
substrates. Aromatic, aliphatic, cyclic and heterocyclic
aldehydes reacted smoothly with different amines to afford
the corresponding homoallylic amines in high to excellent
yields of the products within 25–60 min, whereas ketones
did not yield any product even after long reaction times
(15–29 h.) Synthetic route has been presented in Scheme 1.
Compounds containing an electron withdrawing group
on the aldehydes reacted more efficiently resulting with
higher yields, e.g. 3f. Amines bearing an electron donating
group also favored the reaction under the standard reaction
conditions to give products less than 1 h, e.g. 3c. Fur-
thermore, acid-sensitive aldehyde, furfuraldehyde worked
well without any decomposition under the reaction condi-
tions because of low concentration of acid and at ambient
temperature. Enolizable aldehydes, such as cyclohex-
anecarboxaldehyde also produced the corresponding ho-
moallylamines in good yields. In all cases, no homoallylic
alcohol (the adduct of aldehyde and allyltributyltin) was
obtained under these reaction conditions due to rapid for-
mation and activation of imines in the presence of catalytic
amount of CF3COOH. Results are summarized in Table 1.
CF COOH
3
Allyltributyltin
R
O
+
R1
NH2
RT/
65
R
NH
R1
(1)
(3)
(2)
Scheme 1 Synthetic route for the Homoallylic amines
Table 1 Newly synthesized homoallylic amines
S. no
R
R1
Reaction time (min)
Yield (%)
3a
3b
3c
3d
3e
3f
Benzaldehyde
Napthylamine
30
35
30
45
30
45
45
30
60
30
45
60
60
45
30
45
30
95
90
98
89
90
95
82
85
78
88
75
73
68
75
78
68
72
Benzofuran-2-aldhyde
3,4-Diflurobenzylamine
4-t-Butylaniline
Cyclopropanecarboxaldehyde
2,4-Difluorobenzaldehyde
Benzofuran-2-aldhyde
2,4,5-Trifluoroaniline
Napthylamine
2,4-Difluoro-benzaldehyde
2-Fluoro-5-methoxy benzaldehde
Cyclopropane carboxaldehyde
Cyclohexane carboxaldehyde
Cyclohexane carboxaldehyde
2-Allyloxy benzaldehyde
5-(2-Chlorophenyl)furan-2-carbaldehyde
1-Acetyl-1H-indole-3-carbaldehyde
2,4-Difluorobenzaldehyde
2,6-Difluorobezaldehyde
4-t-Butylaniine
3g
3h
3i
3-Fluoroaniline
4-Fluoro-3-trifluoromethylaniline
4-Morpholinobenzenamine
2,5-Dimemethylaniline
4-(4-Chlorophenoxy)benzenamine
4-(4-Chlorophenoxy)benzenamine
Benzo[d]thiazol-7-amine
2,4-Difluoroaniline
3j
3k
3l
3m
3n
3o
3p
3q
4-Chloro-3-fluoroaniline
4-Cyanoaniline
Thiophen-3-carboxaldehyde
3-Ethoxybenzaldehyde
4-Fluoroaniline
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Med Chem Res (2012) 21:1090–1097
Characterization
P. aeruginosa were picked off a fresh isolation plate and
inoculated in corresponding tubes containing 5 mL of
trypticase soya broth. The broth was incubated for 6 h at
37°C until there was visible growth. Mc Farland No.5
standard was prepared by adding 0.05 ml of 1% w/v
BaCl2ꢀ2 H2O in Phosphate Buffered saline (PBS) to
9.95 ml of 1% v/v H2SO4 in PBS. The growth of all the
four cultures was adjusted to Mc Farland No.5 turbidity
standard using sterile PBS. This gives a 108 cfu/ml sus-
pension. The working inoculums of aforementioned four
different microorganisms containing 105 cfu/ml suspen-
sion was prepared by diluting the 108 cfu/ml suspension,
103 times in trypticase soya broth.
All aldehydes, amines, allyltributyltin, CF3CO2H, and
solvents are purchased from commercial sources and all the
aldehydes and solvents were distilled before use. Reactions
were monitored on TLC by comparison with the starting
materials. Yields refer to the isolated yields of the products
after purification by flash chromatography. H-NMR, 13C-
1
NMR were recorded on 400 MHz Brucker spectrometer,
Elemental analysis was performed on a Thermo Finnigan
FLASH EA 1112 CHN analyzer. Melting points were
recorded (uncorrected) on a Buchi Melting Point B-545
apparatus.
All the reactions are monitored by mass analysis of
crude reaction mixture and by TLC using ethylacetate:
hexane as eluent. An unambiguous structure proof of
compound 3 was achieved by an examination of the crystal
structure of compound 3o (Fun et al., 2009). Figure 1
shows a crystal structure of compound 3o. In the crystal
structure, weak intermolecuar N–HꢀꢀꢀF hydrogen bonds
link molecules into centrosymmetric dimers which are
arranged in molecular sheets parallel to the ac plane.
Preparation of anti-microbial suspension (50 lg/ml)
Dissolved 0.5 mg of each compound in 10 ml of trypticase
soya broth to get 50 lg/ml. This suspension was filter
sterilized in syringe filters.
Preparation of dilutions
In all, for each of the 11 anti-microbial compounds and
standard antimicrobial i.e. Ceftriaxone, 24 tubes of 5 ml
capacity were arranged in four rows with each row con-
taining six tubes. Then, 1.9 ml of trypticase soya broth was
added in the first tube in each row and 1 ml in the
remaining tubes. Now, 100 ll of filtered anti-microbial
suspension was added to the first tube in each row and after
mixing the content, 1 ml was serially transferred from
these tubes to the second tube in each of the rows. The
contents in the second tube of each of the rows were mixed
and transferred to the third tube in each of the rows. This
serial dilution was repeated till the sixth tube in each of the
rows. This provided anti-microbial concentrations of 50,
25, 12.5, 6.25, 3.125, 1.6125 lg/ml in the first to sixth tube,
respectively, in each row. Finally, 1 ml of 105 cfu/ml of
S. aureus, B. subtilis, E. coli, and P. aerogenosa suspension
were added to the first, second, third, and fourth rows of
tubes, respectively. Along with the test samples and Cef-
triaxone (standard), the inoculums control (without anti-
microbial compound) and broth control (without
antimicrobial compound and inoculum) were maintained.
All the test sample and control tubes were then incubated
for 16 h at 37°C. The results are summarized in Table 2.
Antimicrobial studies
All the newly synthesized compounds were screened for
their antibacterial activity. For this, Staphylococcus aureus,
Bacillus subtilis, Escherichia coli, and Pseudomonas
aeruginosa microorganisms were employed. Antimicrobial
study was assessed by Minimum Inhibitory Concentration
(MIC) by serial dilution method (Collee et al., 1989).
Several colonies of S. aureus, B. subtilis, E.coli, and
Interpretation
After incubation, the tubes showing no visible growth was
considered to be representing the MIC. The details of
results are furnished in Table 2. Inoculum control showed
visible growth, whereas the broth control showed no
growth.
Fig. 1 The structure of 3o, showing 50% probability displacement
ellipsoids and the atom-numbering scheme. (Figure reproduced from
Acta Cryst 2009, E65 o1027–o1028)
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Med Chem Res (2012) 21:1090–1097
1093
Table 2 Antibacterial activity data in MIC (lg/ml)
Compound no.
S. aureus
B.subtilis
E.coli
P.aeruginosa
3a
3b
3c
3d
3e
3f
25
25
25
25
1.6125
3.125
3.125
3.125
Growth in all concentrations Growth in all concentrations Growth in all concentrations Growth in all concentrations
1.6125
1.6125
3.125
1.6125
1.6125
6.250
6.250
3.125
3.125
12.5
1.6125
1.6125
3.125
1.6125
1.6125
6.250
12.5
1.6125
25.00
1.6125
Growth in all concentrations
3.125
3.125
3g
3h
3i
1.6125
1.6125
Growth in all concentrations Growth in all concentrations
6.250
12.5
25
3j
12.5
3k
3l
3.125
3.125
12.5
6.250
3.125
12.5
25.00
3.125
12.5
3m
3n
3o
3p
3q
1.6125
3.125
6.250
3.125
1.6125
1.6125
6.250
3.125
1.6125
1.6125
1.6125
3.125
3.125
1.6125
1.6125
1.6125
6.250
3.125
1.6125
Ceftriaxone (Standard) 3.125
Inoculum control
Broth control
Growth in all concentrations Growth in all concentrations Growth in all concentrations Growth in all concentrations
No growth No growth No growth No growth
Experimental
RT = 3.4 min, m/z = 274 [M?H]?). Anal. Calc. for
C20H19N: C 87.91, H 6.96, N 5.13. Found: C 87.9, H 6.95,
N 5.11%.
General procedure
To a mixture of aldehyde (10 mmol), amine (10 mmol),
and allyltributyltin (10 mmol) in acetonitrile (5 ml),
CF3COOH (1 mmol) was added. The reaction mixture was
stirred at 25°C under nitrogen atmosphere for an appro-
priate time (Table 1). After completion of the reaction, as
indicated by TLC and mass analysis, the reaction mixture
was extracted with diethyl ether (3 9 20 mL). The com-
bined organic layers were concentrated in vacuum and
purified by flash chromatography to afford the pure
homoallylic amines.
(1-Benzofuran-2-yl-but-enyl)-(3,5-difluoro-benzyl)-amine
(3b)
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.4), Thick liquid. 1H-
NMR (400 MHz, CDCl3, 24°C): d = 2.59–2.75 (m, 2H,
CH2), 3.71–3.75 (m, 1H,), 3.83–3.3.92 (m, 2H, CH2),
5.08–5.17 (m, 2H, CH2), 5.71–5.81 (m, 1H, CH), 6.64 (s,
1H, NH), 6.77–6.84 (m, 2H, Ar-H), 7.24–7.37 (m, 3H, Ar-
H), 7.48–7.50 (m, 1H, Ar-H), 7.55–7.57 (m, 1H, Ar-H).
13C-NMR (400 MHz, CDCl3, 24°C): d = 39.12, 44.3,
55.4, 103.4, 104, 110.9, 111, 118, 120.7, 122, 123, 128,
131.13, 134.2, 154.8, 158, 159.8, 162. LCMS (96.3%,
Method; 0.1% HCOOH; ACN, Flow 1 ml/min, Column C
18 75 9 4.6 mm 5 lm, RT = 1.0 min, m/z = 314
[M?H] ?). Anal. Calc. for C19H17F2NO; C 72.84, H 5.43,
N 4.47. Found: C 72.82, H 5.44, N 4.45%.
Naphthalene-1-y-(1-phenyl–but-3-enyl)-amine (3a)
1
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C):d = 2.72–2.83 (m, 2H,
CH2), 4.55–4.61 (m, 1H,CH), 5.18–5.22 (d, 1H,
J = 16 Hz), 5.31–5.36 (m, 1H, CH2), 5.80–5.90 (m, 1H,
CH2), 6.36 (br. s, 1H, NH), 7.14–7.27 (m, 4H, Ar-H),
7.31–7.38 (m, 2H, Ar-H), 7.41–7.78 (m, 4H, Ar-H),
7.93–7.7.95 (m, 1H, Ar-H). 13C-NMR (400 MHz, CDCl3,
24°C): d = 43.4, 57.0, 106.3, 117, 118.6, 119.7, 123.4,
124.7, 125.6, 126.2, 127.0, 128.7, 128.9, 134.2, 134.7,
141.8, 143.0. LCMS (97.9%, Method; 0.1% HCOOH;
ACN, Flow 1 ml/min, Column C 18 75 9 4.6 mm 5 lm,
(4-tert-Butyl-phenyl)-(1-cyclopropyl-3-but-enyl)-amine
(3c)
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.6), Thick liquid. 1H-
NMR (400 MHz, CDCl3, 24°C): d = 0.330.35 (m, 2H,
CH2), 0.50 (m, 2H, CH2), 1.09 (m, 1H, CH), 1.29 (s, 9H,
t-butyl), 2.44–2.47 (m, 2H, CH2), 2.95–2.97 (m, 1H, CH),
123

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Med Chem Res (2012) 21:1090–1097
[1-(2-Fluoro-6-methoxy-phenyl)-but-3-enyl]-(3-
fluorophenyl)-amine (3g)
3.5 (bs, 1H, NH), 5.12 (m, 2H, CH2), 5.97–5.99 (m, 1H,
CH), 6.60–6.62 (d, 2H, J = 8 Hz, Ar-H),7.237.24 (d, 2H,
J = 8 Hz, Ar-H). 13C-NMR (400 MHz, CDCl3, 24°C):
d = 2.6, 3.40, 16, 31.6, 39.7, 56.8, 113, 117, 125.9, 135.2,
139.9, 145.4. LCMS (95%, Method; 0.1% HCOOH; ACN,
Flow 1 ml/min, Column C 18 75 9 4.6 mm 5 lm,
RT = 4.1 min, m/z = 244 [M?H]?). Anal. Calc. for
C17H25N;C 83.95, H 10.29, N 5.76. Found: C 83.97, H
10.26, N 5.75%.
1
(TLC, Petether/EtOAc, 1:1, Rf = 0.7), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C): d = 2.4 (m, 1H, CH2), 2.5
(m, 1H, CH2), 3.6 (s, 3H, –OCH3), 4.59 (t, 1H, J = 4 Hz,
CH), 5.1 (m, 2H, CH2), 5.6 (m, 1H, CH), 6.1 (dd, 1H,
J = 4 Hz, Ar-H), 6.39 (m, 2H, Ar-H), 6.6 (m, 1H, Ar-H),
6.7 (m, 1H, Ar-H), 6.9 (m, 2H, Ar-H). 13C-NMR
(400 MHz, CDCl3, 24°C): d = 40.9, 51.2, 55.8, 100.2,
104.4, 112.8, 113, 115, 116, 127, 128, 130, 133, 148, 152.
LCMS (90%, Method; 0.1% HCOOH; ACN, Flow 0.8 ml/
min, Column C 18 75 9 4.6 mm 5 lm, RT = 3.5 min, m/
z = 290 [M?H]?). Anal. Calc. for C17H17F2NO; C 70.59,
H 5.88, N 4.84. Found: C 70.60, H 5.85, N 4.83%.
[1-(2,4-Diflurophenyl)-but-3-enyl]-(2,4,5-trifluoro-
phenyl)-amine (3d)
1
(TLC, Petether/EtOAc, 1:1, Rf = 0.4), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C): d = 2.47–2.2.63 (m,2H,
CH2), 4.13–4.26 (m, 2H, 2CH), 5.20–5.24 (m, 2H, CH2),
5.70–5.77 (m, 1H, CH), 6.11–6.5 (m, 1H, Ar-H), 6.84–6.88
(m, 1H, Ar-H), 7.09-7.73 (m, 3H, Ar-H). 13C-NMR
(400 MHz, CDCl3, 24°C): d = 42.9, 56.5, 101, 104, 115,
117, 119, 122, 132, 139, 139.7, 144, 147, 150. LCMS
(94.6%, Method; 0.1% HCOOH; ACN, Flow 0.8 ml/min,
Column C 18 75 9 4.6 mm 5 lm, RT = 3.8 min, m/
z = 312 [M-H]). Anal. Calc. for C16H12F5 N;C 61.34, H
3.83, N4.47. Found: C 61.33, H 3.84, N 4.45%.
(1-Cyclopropyl-but-3-enyl)-(4-fluoro-3-trifluoromethyl-
phenyl)-amine (3h)
1
(TLC, Petether/EtOAc, 1:1, Rf = 0.8), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C): d = 0.33–0.35 (m, 2H,
CH2), 0.50 (m, 2H, CH2), 2.4 (q, 2H, J = 8 Hz, CH), 2.9
(q, 1H, J = 8 Hz, CH), 5.2 (m, 2H, CH2), 5.9 (m, 1H, CH),
6.68 (t, 1H, J = 4 Hz, Ar-H), 6.76 (t, 1H, J = 4 Hz, Ar-
H), 7.0 (m, 1H, Ar-H). 13C-NMR (400 MHz, CDCl3,
24°C): d = 2.8, 3.1, 15.8, 39.3, 57, 110, 117.2, 118, 118.5,
121.5, 134, 144, 153. LCMS (93.5%, Method; 0.1%
(1-Benzofuran-2-yl-but-3-eny)-napthalen-1-yl-amine (3e)
1
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5), Thick liquid. H-
HCOOH; ACN, Flow 1.0 ml/min, Column
C
18
75 9 4.6 mm 5 lm, RT = 1.9 min, m/z = 272 [M–H]).
Anal. Calc. for C14H15F4N; C 61.54, H 5.49,N 5.13. Found:
C 61.57, H 5.47, N 5.11%.
NMR (400 MHz, CDCl3, 24°C): d = 2.93 (t, 2H,
J = 8 Hz, CH2), 4.90 (t, 1H, J = 4 Hz, CH), 5.35 (m, 2H,
CH2), 5.94 (m, 1H, CH), 6.64 (m, 1H, Ar-H), 7.23–7.29
(m, 2H, Ar-H), 7.44–7.50 (m, 5H, Ar-H), 7.8(m, 1H, Ar-
H), 7.90 (m, 1H, Ar-H). 13C-NMR (400 MHz, CDCl3,
24°C): d = 39.2, 51.69, 102, 106, 111, 118, 119, 120, 123,
124, 125.2, 126, 128, 133, 134, 154.3, 158. Anal. Calc. for
C22H19NO; C 84.35, H 6.07, N 4.47. Found: C 84.32, H
6.06, N 4.46%.
(1-Cyclohexyl-but-3-enyl)-(4-morpholin-4-yl-phenyl)-
amine (3i)
1
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.3), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C): d = 1.0–1.32 (m, 4H,
2CH2), 1.5 (m, 2H, CH2), 1.6–1.8 (m, 5H, CH2), 2.2 (m,
2H, CH2), 2.95–3.3 (bs, 4H, –NCH2), 3.75 (m, 4H,
–OCH2), 5.2 (m, 2H, CH2), 5.75 (m, 1H, CH), 6.5–7.0 (bs,
4H, Ar-H). 13C-NMR (400 MHz, CDCl3, 24°C): d = 26.8,
29.5, 35.6, 41.2, 51.0, 58.2, 68.9, 114.1, 116, 118, 128, 129,
142. LCMS (96%, Method; 0.1% HCOOH; ACN, Flow
0.8 ml/min, Column C 18 75 9 4.6 mm 5 lm, RT =
3.9 min, m/z = 315 [M?H]?). Anal. Calc. for C20H30
N2O; C 76.43, H 9.55, N 8.92. Found: C76.41, H 9.54, N
8.91%.
(4-tert-Butyl-phenyl)-[1-(2, 4-difluoro-phenyl)-but-3-eny]-
amine (3f)
1
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.54), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C): d = 1.36 (s, 9H, t-butyl),
2.52 (m, 2H, CH2), 4.35 (q, 1H, J = 8 Hz, CH), 5.29 (m,
2H, CH2), 6.02 (m, 1H, Ar-H), 6.52 (d, 2H, J = 8 Hz, Ar-
H), 7.18–7.23 (m, 4H, Ar-H), 7.32 (m, 1H, Ar-H). 13C-
NMR (400 MHz, CDCl3, 24°C): d = 31.6, 33.7, 43.3,
56.77, 113, 115, 117, 118, 122, 125, 134, 140, 141, 144,
150. LCMS (90%, Method; 0.1% HCOOH; ACN, Flow
0.8 ml/min, Column C 18 75 9 4.6 mm 5 lm, RT =
4.3 min, m/z = 316 [M?H]?). Anal. Calc. for C20H23F2N;
C 76.19, H 7.30, N 4.44. Found: C 76.16, H 7.28,
N 4.42%.
(1-Cyclohexyl-but-3-enyl)-(2,5-dimethyl-phenyl)-amine
(3j)
1
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C): d = 1.1–1.3 (m, 5H,
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Med Chem Res (2012) 21:1090–1097
1095
CH2), 1.7 (m, 1H, CH2), 1.75 (m, 1H, CH2), 1.82 (m, 3H,
CH2), 1.92 (d, 1H, J = 12 Hz, CH2), 2.15 (s, 3H, Ar-CH3),
2.3 (m, 1H, CH2), 2.35 (s, 3H, Ar-CH3), 2.42 (m, 1H, CH2),
3.9 (q, 1H, J = 4 Hz, CH), 5.12(m, 2H, CH2), 5.8 (m, 1H,
CH), 6.48 (d, 2H, J = 8 Hz, Ar-H), 6.97 (d, 1H, J = 8 Hz,
Ar-H). 13C-NMR (400 MHz, CDCl3, 24°C): d = 17.2,
21.7, 26.5, 26.7, 29.5, 35.8, 41.2, 57.0, 110.8, 116.4, 117.1,
117.5, 130.2, 135.2, 135.7, 136.6. LCMS (96%, Method;
0.1% HCOOH; ACN, Flow 0.8 ml/min, Column C 18
75 9 4.6 mm 5 lm, RT = 3.9 min, m/z = 258 [M?H]?).
Anal. Calc. for C18H27N; C 84.05, H 10.51, N 5.45. Found:
C 84.02, H 10.50, N 5.43%.
2.72 (m, 1H, CH2), 2.88 (m, 1H, CH2), 4.78 (q, 1H,
J = 4 Hz, CH), 5.26 (m, 2H, CH2), 5.85 (m, 1H, CH), 6.87
(d, 1H, J = 8 Hz, Ar-H), 7.0 (s, 1H, Ar-H), 7.27–7.41 (m,
3H, Ar-H), 7.7 (m, 1H, Ar-H), 7.89 (d, 2H, J = 8 Hz, Ar-
H), 8.46 (bs, 1H, NH), 8.67 (s, 1H, Ar-H). 13C-NMR
(400 MHz, CDCl3, 24°C): d = 26.9, 40.4, 50.4, 103.8,
105, 105.7, 115.1, 117.0, 118.9, 122.5, 123.6, 123.7, 123.8,
125.5, 128, 134, 135.7, 136.6, 145.6, 146.1, 168.6.LCMS
(76%, Method; 0.1% HCOOH; ACN, Flow 1.0 ml/min,
Column C 18 75 9 4.6 mm 5 lm, RT = 3.7 min, m/z =
362 [M?H]?). Anal. Calc. for C21H19N3OS: C 69.81, H
5.26, N 11.63. Found: C 69.79, H 5.25, N 11.60%.
[1-(2-Allyloxy-phenyl)-but-3-enyl]-[4-(4-chloro-phenoxy)-
phenyl]-amine (3k)
(2, 4-Difluoro-phenyl)-[1-(2,4-difluoro-phenyl)-but-3-
enyl]-amine (3n)
1
(TLC, Petether/EtOAc, 1:1, Rf = 0.5), Thick liquid. H-
1
(TLC, Petether/EtOAc, 1:1, Rf = 0.6), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C): d = 2.55 (m, 1H, CH2),
2.75 (m, 1H, CH2), 4.3 (bs, 1H, NH), 4.68 (t, 2H,
J = 4 Hz, –OCH2), 5.3 (m, 1H, CH), 5.36–5.39 (m, 2H,
CH2), 5.51 (d, 1H, J = 16 Hz, CH), 5.84 (d, 1H,
J = 13.6 Hz, CH2), 5.9 (m, 1H, CH), 6.13–6.20 (m, 1H,
Ar-H), 6.54 (d, 2H, J = 12 Hz, CH), 6.82–6.9 (m, 4H, Ar-
H), 6.9 (m, 2H, Ar-H), 7.2 (m, 3H, Ar-H), 7.39 (d, 1H,
J = 8 Hz, Ar-H). 13C-NMR (400 M Hz, CDCl3, 24°C):
d = 40.6, 52.0, 68.5, 11.6, 114.2, 117.0, 117.6, 118.2,
120.8, 123, 126.5, 127.1, 127.7, 130.2, 130, 133.2, 135.2,
144.2, 147.0, 155.6, 157.7. LCMS (98%, Method; 0.1%
HCOOH; ACN, Flow 1.0 ml/min, Column C 18 75 9
4.6 mm 5 lm, RT = 2.6 min, m/z = 406 [M?H]?).
Anal. Calc. for C25H24ClNO2; C 73.98, H 5.92, N 3.45.
Found: C 73.97, H 5.90, N3.44%.
NMR (400 MHz, CDCl3, 24°C), d = 2.5–2.6 (m, 2H,
CH2), 4.3 (bs, 1H, NH), 4.69 (m, 1H, CH), 5.24 (m, 2H,
CH2), 5.74 (m, 1H, CH), 6.34 (m, 1H, Ar-H), 6.59 (m, 1H,
Ar-H), 6.64–6.87 (m, 3H, Ar-H), 7.3 (m, 1H, Ar-H). 13C-
NMR (400 MHz, CDCl3, 24°C): d = 41.2, 50.7, 103, 110,
11.4, 112.9, 119.0, 125.2, 128.5, 131.6, 133.4, 149.6,
152.1, 153.3, 155.6, 160.7 LCMS (94.7%, Method; 0.1%
HCOOH; ACN, Flow 0.8 ml/min, Column C 18 75 9
4.6 mm 5 lm, RT = 3.9 min, m/z = 295.9 [M?H]?).
Anal. Calc. for C16H13F4N; C 65.08, H 4.41, N4.75. Found:
C 65.10, H 4.39, N 4.73%.
(4-Chloro-2-fluoro-phenyl)-[1-(2,6-difluoro-phenyl)-but-3-
enyl]-amine (3o)
(TLC, Petether/EtOAc, 1:1, Rf = 0.65), White Solid; m.p.
1
[4-(4-Chloro-phenoxy)-phenyl]-{1-[5-(2-chloro-phenyl)-
furan-2-yl]-but-3-enyl}-amine (3l)
126-127°C. H-NMR (400 MHz, CDCl3, 24°C): d = 2.72
(m, 1H, CH2), 2.87 (m, 1H, CH), 4.95 (m, 1H, CH), 5.28
(m, 1H, CH2), 5.71 (m, 2H, CH2, NH), 5.81(m, 1H, CH),
6.68 (m, 1H, Ar-H), 6.8–6.9 (m, 4H, Ar-H), 7.2 (m, 1H, Ar-
H). 13C-NMR (400 MHz, CDCl3): d = 39.5, 48.3, 111.6,
113.0, 115.3, 117.5, 118.3, 121.2, 124.4, 128.9, 129.0,
133.7, 152, 160, 162.5. LCMS (99.5%, Method; 0.1%
HCOOH; ACN, Flow 0.8 ml/min, Column C 18 75 9
4.6 mm 5 lm, RT = 4.2 min, m/z = 311.9 [M?H]?).
Anal.Calc. for C16H13ClF3N: C 61.64, H 4.17, N 4.49.
Found: C 61.61, H 4.14, N 4.47%.
1
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C): d = 2.7 (bs, 2H, CH2),
4.50 (t, 1H, J = 4 Hz, CH), 5.0 (m, 2H, CH2), 5.6 (m, 1H,
CH), 6.25 (s, 1H, Ar-H), 6.76 (m, 2H, Ar-H), 7.16 (m, 4H,
Ar-H), 7.18 (d, 1H, J = 4 Hz, Ar-H), 7.23 (m, 3H, Ar-H),
7.3 (m, 1H, Ar-H), 7.35 (d, 1H, J = 4 Hz, Ar-H), 773 (d,
1H, J = 4 Hz, Ar-H). 13C-NMR (400 MHz, CDCl3, 24°C):
d = 40, 60, 100, 111.6, 118.5, 118.8, 120, 126, 127.6,
127.9, 129, 129.4, 130.7, 133.5, 144.5, 149, 150, 157. Anal.
Calc. for C26H21Cl2NO2; C 69.33, H 4.67, N 3.11. Found:
C 69.34, H 4.65, N 3.10%.
4-(1-Thiophen-2-yl-butylamino)-benzonitrile (3p)
1
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5), Thick liquid. H-
1-{3-[1-(Benzothiazol-7-ylamino)-but-3-enyl]-indol-1-yl}-
ethanone (3m)
NMR (400 MHz, CDCl3, 24°C): d = 2.7 (m, 2H, CH2),
4.77 (m, 1H, CH), 5.2 (m, 2H, CH2), 5.7 (m, 1H, CH), 6.56
(d, 2H, J = 8.Hz, Ar-H), 6.97 (d, 2H, J = 4 Hz, Ar-H),
7.20 (d, 1H, J = 4 Hz, Ar-H), 7.38 (d, 2H, J = 8 Hz, Ar-
H). 13C-NMR (400 MHz, CDCl3): d = 42.6, 52.7, 99.4,
1
(TLC, Petether/EtOAc, 1:1, Rf = 0.2), Thick liquid. H-
NMR (400 MHz, CDCl3, 24°C): d = 2.5 (s, 1H, CH3),
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1096
Med Chem Res (2012) 21:1090–1097
113.1, 119.3, 120.3, 124.0, 124.4, 127.0, 133.3, 133.,
146.6, 150.1. LCMS (96.0%, Method; 0.1% HCOOH;
ACN, Flow 0.8 ml/min, Column C 18 75 9 4.6 mm 5 lm,
RT = 2.6 min, m/z = 355 [M?H]?). Anal. Calc. for
C15H14N2S; C 70.87, H 5.51, N 11.02. Found: C 70.85, H
5.50, N 11.01%.
against other two bacterial strains. Remaining compounds
showed moderate antibacterial activity.
Acknowledgments AMI is thankful to HOD Chemistry and Prof.
Sandeep Sancheti, Director, National Institute of Technology-Kar-
nataka, India for providing research facilities and encouragement and
also thankful to Board for Research in Nuclear Sciences, Department
of Atomic Energy, Government of India for ‘Young Scientist’ award.
Authors also thank Acta Crystallographica Section-E for the figure-1,
which was reproduced from lh2083.
[1-(3-Chloro-phenyl)-but-enyl]-(3-ethoxy-phenyl)-amine
(3q)
1
(TLC, Pet-ether/EtOAc, 1:1, Rf = 0.56), Thick liquid H-
References
NMR (400 MHz, CDCl3, 24°C): d = 1.43 (t, 3H, J =
6.8 Hz, CH3), 2.5 (m, 2H, CH2), 4.04 (m, 2H, –OCH2), 4.3
(bs, 1H, NH), 4.35 (m, 1H, CH), 5.2 (m, 2H, CH2), 5.8
(m, 1H, CH), 6.37 (q, 1H, J = 5.6 Hz, Ar-H), 6.62 (d, 1H,
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111.6, 112.5, 112.7, 117.32, 118.5, 129.7, 134.3, 134.7,
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4.6 mm 5 lm, RT = 4.0 min, m/z = 302 [M?H]?). Anal.
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71.65, H 6.61, N 4.61%.
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