Microwave assisted base dependent regioselective synthesis of partially reduced chromenes, isochromenes and phenanthrenes

Article abstract of DOI:10.1039/c3ob41962b

We have reported a microwave assisted base directed regioselective synthesis of partially reduced chromenes, isochromenes and phenanthrenes. Functionalized 4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]-chromen-2-one-3- carbonitriles have been used as precurs

Full text of DOI:10.1039/c3ob41962b

Organic &
Biomolecular Chemistry
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Microwave assisted base dependent regioselective
synthesis of partially reduced chromenes,
isochromenes and phenanthrenes†‡
Cite this: Org. Biomol. Chem., 2014,
12, 2228
Pratik Yadav, Surjeet Singh, Satya Narayan Sahu, Firasat Hussain and
Ramendra Pratap*
We have reported a microwave assisted base directed regioselective synthesis of partially reduced chrom-
enes, isochromenes and phenanthrenes. Functionalized 4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]-
chromen-2-one-3-carbonitriles have been used as precursors, which on reaction with functionalized
acetophenones in the presence of KOH in DMF under microwave irradiation yield (Z)-2-(2-aryl-5,6-
dihydro-4H-benzo[f]isochromen-4-ylidene)acetonitriles. The use of NaH in DMF provides 3-aryl-
1-(piperidin-1-yl)-9,10-dihydro phenanthrene-2-carbonitriles in excellent yield regioselectively. The use
of cyclohexanone as a nucleophile source yields (Z)-2-(3,4,7,8-tetrahydro-1H-naphtho[2,1-c]chromen-
6(2H)-ylidene)acetonitriles. The structure and geometry of isochromene have been proved without any
ambiguity by single crystal X-ray diffraction.
Received 27th September 2013,
Accepted 4th February 2014
DOI: 10.1039/c3ob41962b
www.rsc.org/obc
Introduction
The development of a new approach for the preparation of bio-
logically active molecules constitutes a great challenge in
modern organic chemistry. This challenge has led to growing
interest in the field of microwave-enhanced procedures due to
great reaction control and high reaction rates. Therefore,
microwave-assisted organic synthesis (MAOS) is an invaluable
technique for medicinal chemistry and drug discovery
applications.1,2
Chromenes and isochromene are well known structural
motifs that are frequently encountered in bioactive natural pro-
ducts.3 They are also considered to be a venerable pharmaco-
phore and exhibit a wide range of biological activities such as
anti-HIV,4 anticancer,5 antihypertensive,6 insecticidal,7 and
antifungal.8 Seselin i and lonchocarpene ii are used as anti-
cancer agents,9,10 whereas acolbifene iii, LG120746 iv and v are
a class of selective estrogen receptor modulators and progester-
one receptor modulators, respectively (Fig. 1).11,12 In addition,
cannabinol vi has affinity towards CB1 and CB2 receptors,
while moracin D vii is currently known as an antifungal agent
(Fig. 1).8,13 Apart from this, phenanthrenes have also drawn
Fig. 1 Some natural products and biologically potent molecules con-
taining chromene and isochromene skeletons.
great attention because of their wide presence in natural pro-
ducts as well as their applications in medicinal chemistry and
materials science.14
Among the various functionalized chromenes, 2-ylidene-
chromene is a very good progesterone receptor modulator.12
Recently, Yanai et al. have reported a triple carbon acid (KSAs)
catalysed synthesis of ylidene-isochromenes via reaction of lac-
tones with ketene silyl acetals,15 whereas Pal et al. used AlCl3/
Pd/C–Cu as a catalyst16 (Scheme 1). Organolithium reagents17
and Grignard reagents18 were also used to construct this chro-
mene skeleton. However, some protocols suffer from certain
drawbacks, such as the use of moisture and air sensitive
reagents, low yields and prolonged reaction time.16–18
Department of Chemistry, University of Delhi, North Campus, Delhi, 110007, India.
E-mail: ramendrapratap@gmail.com; Tel: +91 1127666646
†This manuscript is dedicated to Dr Vishnu Ji Ram on his 72nd birthday.
‡Electronic supplementary information (ESI) available: All the proton and 13C
NMR spectra are given in ESI. CCDC 959771. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c3ob41962b
2228 | Org. Biomol. Chem., 2014, 12, 2228–2234
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Scheme 2 Synthesis of 4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]-
chromen-2-ones 4.
In search of better reaction conditions to achieve our goal,
4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]chromen-2-one-3-
carbonitrile 4a and 4-bromoacetophenone 5e were taken as
model substrates. We have screened various base–solvent com-
binations at various temperatures using conventional heating
as well as microwave mediated heating. The use of NaH–DMF
at room temperature and 100 °C yields dihydrophenanthrene
regioselectively, without the formation of 7e (Table 1, entries 1
and 2). Previously, Ram et al. have already reported the regio-
selective synthesis of dihydrophenanthrenes using KOH–DMF
at room temperature.20 We checked the effect of temperature
on the earlier reported reaction and surprisingly got the
mixture of dihydrophenanthrene 6a and isochromenes 7e
(Table 1, entry 3). We envisioned that 7e might be synthesized
regioselectively under appropriate reaction conditions. With
the earlier results, we were encouraged to perform further
Scheme 1 Synthesis of 2-ylidene-chromenes and isochromenes using
various catalysts.
These interesting versatile pharmaceutical activities of
2-ylidene chromene have prompted us towards the improved
synthesis of this skeleton. As a part of our continual work
towards exploring the synthetic utility of functionalized 2-oxa-
benzochromene for the synthesis of various biologically impor-
tant aromatic nucleuses, we wish to report herein a simple and
efficient base catalysed microwave assisted regioselective syn-
thesis of isochromene, chromenes and dihydrophenanthrene.
The synthesized compounds contain both an exocyclic double
bond and an aryl ring attached to the chromene ring, which
were important for pharmaceutical activity.12
Table 1 Effect of base and solvent on the synthesis of 6a and 7ea
Results and discussion
For the synthesis of chromene, isochromenes and dihydro-
phenanthrenes,
4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]-
chromen-2-one-3-carbonitrile 4a has been taken as a precur-
sor. This precursor was synthesized in three steps. The first
step was synthesis of ethyl 2-cyano-3,3-dimethylthioacrylate 219
by reaction of ethyl cyanoacetate, carbon disulphide and
methyl iodide under basic conditions, which on reaction with
various 1-tetralones gives 4-(methylthio)-2-oxo-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitriles 3.20 We have tested com-
pound 3 as a precursor for the synthesis of chromenes and
dihydrophenanthrenes under various reaction conditions at
different temperatures, but fail to achieve the desired product
and end up with formation of a complex mixture. We assume
that the presence of the SMe group at position 4 is the most
probable reason for the formation of a complex mixture, as the
SMe group acts as a good leaving group and is responsible for
side reactions, and decomposed at high temperature.20 There-
fore in order to reduce the probability of side reactions, SMe
has been replaced by piperidine, a secondary amine to reduce
Yield of
Yield of
Entry
Baseb
Solvent
Condition
6ac (%)
7ec (%)
1
2
3
4
5
6
7
8
NaH
NaH
KOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
rtd
75
78
35
32
73
—
76
90
—
—
43
40
Trace
82
—
100 °Ce
100 °Ce
100 °Ce
100 °Ce
M.W. f
M.W. f
M.W. f
M.W. f
M.W. f
M.W. f
NaNH2
KOBut
KOH
KOBut
NaH
—
9
10
11
NaNH2
NaH
KOH
Mixture
—
Trace
—
48
DMSO
a The reaction was conducted with 2-oxo-4-(piperidin-1-yl)-5,6-dihydro-
the electrophilicity of C-4. 4-(Piperidin-1-yl)-5,6-dihydro- 2-benzo[h]chromene-3-carbonitrile 4a (0.5 mmol) and 4-bromo-
acetophenone 5e (0.5 mmol). b 0.75 mmol (1.5 eq.). c Yield of isolated
2H-benzo[h]chromen-2-one-3-carbonitrile 4 was synthesised
product. d Reaction time 4 hours. e Reaction time 1 hour. f Under a
by amination of
(Scheme 2).20
3 with piperidine in boiling ethanol
microwave reactor at 100 °C at a maximum applied power of 200 W,
15 minutes.
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optimization through various bases (KOH, NaNH2, and KOBut) contribution of heteroaryl methyl ketone and aliphatic ketone
in different solvents (DMF, DMSO and THF). It was found that as cyclohexanone to further expand the scope of the present
the use of KOH and NaNH2 resulted in the desired product 7e methodology, isochromenes 9a–b and chromenes 11a–b were
in 43% and 40% yield, whereas KOBut did not give satisfactory also synthesized and the results of this study are summarized
results and only 6a was obtained as a major product. In view in Tables 3 and 4.
of the previously reported organic synthesis to achieve high
All the ketone (aromatic and heteroaromatic) derivatives
regioselectivity,21 we turned our attention to a microwave showed equal ease towards the product formation with 2-oxo-
assisted procedure. In order to elaborate our study, the pre- 4-(piperidin-1-yl)-5,6-dihydro-2-benzo[h]chromene-3-carbo-
viously used bases were further screened to synthesize 7e nitriles 4. It is noteworthy that the yield of chromenes 11a–b
under microwave irradiation.
was slightly lower.
Surprisingly, when we carried out the reaction under micro-
Dihydrophenanthrenes 6a–c were also synthesised using
wave conditions (100 °C, at a maximum applied power of 200 NaH and DMF under microwave conditions in good to excel-
watts), interesting results were obtained. The use of KOH with lent yields (Table 5). It has been observed that the yield of 6 is
DMF yielded 7e as an exclusive product (Table 1, entry 6). very high and the reaction requires much less time as compared
Whereas KOBut and NaH were found to be inefficient at produ- to the conventional approach.
cing the desired product, 6a was obtained in 76% and 90%
The molecular make up of precursor 4 reveals that it pos-
yield respectively. A complex mixture of 6a and 7e was found sesses three electrophilic centers C-2, C-4, and C-10b. Among
when we used NaNH2 as a base. Furthermore, we performed them C-10b is highly susceptible to nucleophilic attack
the reaction in THF and DMSO with NaH and KOH to investi- because of extended conjugation due to the presence of an
gate the solvent effect under microwave conditions. The electron withdrawing CN substituent at C-3 in the chromene
desired product 7e was obtained in moderate yield in DMSO.
However neither 6a nor 7e was observed in THF. Thus KOH
Table 3 Synthesis of (Z)-2-(2-(thiophen-2-yl)-5,6-dihydro-4H-benzo-
[f]isochromen-4-ylidene)acetonitriles 9a
and NaH were found to be the best bases in DMF for the regio-
selective synthesis of isochromene 7e and dihydrophen-
anthrene 6a, respectively.
Under these optimized reaction conditions, the generality
of this procedure has been examined. Various functionalized
isochromenes 7a–g were synthesized in very good yields
(Table 2).
The structure and geometry of isochromene have been
confirmed unambiguously by spectroscopic techniques and
1
9
R1
Yield (%)
single crystal X-ray crystallography. The H NMR spectrum of
the desired product 7 exhibits a low δ value for proton
(∼4.40 ppm) at the carbon adjacent to the nitrile group due to
the high shielding effect of pyran oxygen.22 To assess the
a
b
H
OMe
78
76
a Reactions were performed under microwave irradiation at 100 °C and
at a maximum applied power of 200 W for 15 minutes by use of 4
(0.5 mmol), 8 (0.5 mmol), and KOH (0.75 mmol) in 2.0 mL DMF.
Table 2 Synthesis of (Z)-2-(2-aryl-5,6-dihydro-4H-benzo[f]isochromen-
4-ylidene)acetonitriles 7a
Table 4 Synthesis of (Z)-2-(3,4,7,8-tetrahydro-1H-naphtho [2,1-c]-
chromen-6(2H)-ylidene)acetonitriles 9a
7
R1
R2
Yield (%)
a
b
c
d
e
f
H
H
H
H
H
OMe
OMe
H
OMe
F
Cl
Br
Br
OMe
77
79
84
80
82
85
78
11
R1
Yield (%)
a
b
H
OMe
72
69
g
a Reactions were performed under microwave irradiation at 100 °C and a Reactions were performed under microwave irradiation at 100 °C and
at a maximum applied power of 200 W for 15 minutes by use of 4 at a maximum applied power of 200 W for 15 minutes by use of 4
(0.5 mmol), 5 (0.5 mmol) and KOH (0.75 mmol) in 2.0 mL DMF.
2230 | Org. Biomol. Chem., 2014, 12, 2228–2234
(0.5 mmol), 10 (0.5 mmol), and KOH (0.75 mmol) in 2.0 mL DMF.
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differences between the conventional approach and the micro-
wave assisted approach is regioselectivity for the product for-
mation (Table 1, entries 3 and 6). We proposed that fast and
uniform heating in microwave is responsible for regioselec-
tivity, which is difficult through conventional heating. On the
basis of the obtained regioselectivity, we propose that KOH
stabilized the enolate form at high temperature, while NaH
stabilized the keto form at both high and low temperatures.
Table 5 Synthesis of 3-phenyl-1-(piperidin-1-yl)-9,10-dihydro phen-
anthrene-2-carbonitriles 6a
6
R1
R2
Yield (%)
X-ray structural analysis
X-ray diffraction studies23 of (Z)-2-(2-(4-bromophenyl)-5,6-
dihydro-4H-benzo[f]isochromen-4-ylidene)acetonitrile (7e)
showed that the compound has a non-planarity induced chiral-
ity due to distortion in the aromatic rings. The conformation
is shown as an ORTEP diagram in Fig. 2.
The X-ray studies further showed that the terminal rings A
and C are nearly planar, while the central ring B adopts a half
chair conformation. The average mean plane angle (torsion
angle) for the twist between the terminal rings A and C is
17.8°.
The X-ray studies further confirmed that the Z geometry of
the molecule and the nitrile group is present at the syn posi-
tion to oxygen in the ring C (Fig. 2a). Crystal packing of (Z)-2-
(2-(4-bromophenyl)-5,6-dihydro-4H-benzo[f]isochromen-4-
ylidene)acetonitrile (7e) has shown some significant intermole-
cular interactions. It has been observed that moderate hydro-
gen bonding interaction (C–H⋯Br = 2.991 Å) occurs between
the bromo (Br1) group and ortho hydrogen (H3) of ring D with
the neighbouring molecules (Fig. 2b). This molecule also
a
b
c
H
H
OMe
Br
OMe
Br
90
86
87
a Reactions were performed under microwave irradiation at 100 °C and
at a maximum applied power of 200 W for 15 minutes by use of 4
(0.5 mmol), 5 (0.5 mmol), and NaH 0.75 mmol in 2.0 mL DMF.
ring. Keeping this fact in mind we hypothesized the mechan-
ism of our reaction as shown in Scheme 3. The reaction com-
mences with the formation of intermediate P by a nucleophilic
attack of carbanion generated in situ at the C-10b position of 4.
P undergoes decarboxylation to form Q. Thereafter the reac-
tion may follow either path A for the formation of chromene or
isochromene derivatives 7, 9, 11 via elimination of piperidine
through SNi reaction of enolate formed in the presence of a
base or path B to yield dihydrophenanthrene 10 via cyclization
involving C-3 of chromene and the carbonyl group of ketone
followed by aromatization via dehydration. One of the key
Fig. 2 (a) ORTEP diagram of (Z)-2-(2-(4-bromophenyl)-5,6-dihydro-
4H-benzo[f]isochromen-4-ylidene)acetonitrile (7e); (b) capped stick
model of 7e showing intermolecular interactions.
Scheme 3 A plausible mechanism for the synthesis of isochromenes 7
and 9, chromenes 11 and dihydrophenanthrenes 6.
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exhibits weak pi interaction (C9⋯C14 = 3.275 Å) between rings
C and A of neighbouring molecules.
(Z)-2-(2-Phenyl-5,6-dihydro-4H-benzo[f]isochromen-4-ylidene)-
acetonitrile (7a). Red solid; yield: 84%; melting point:
155–157 °C; IR (film): 2926 (CH), 2195 (CN) cm−1 1H NMR
;
(400 MHz, CDCl3): δ 2.41 (t, J = 8.0 Hz, 2H), 2.90 (t, J = 8.0 Hz,
2H), 4.40 (s, 1H), 6.84 (s, 1H), 7.31–7.34 (m, 2H), 7.39–7.49 (m,
4H), 7.57–7.59 (m, 1H), 7.83–7.90 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 21.8, 27.2, 63.9, 97.6, 118.7, 121.2, 123.9, 124.9,
125.1, 127.2, 128.3, 128.9, 129.8, 130.3, 131.4, 134.9, 137.0,
155.2, 166.0; m/z (CI) 320 (M + 23, 100%); HRMS (m/z):
[M + H]+ calcd for C21H16NO: 298.1232; found: 298.1226.
(Z)-2-(2-(4-Methoxyphenyl)-5,6-dihydro-4H-benzo[f]isochro-
men-4-ylidene)acetonitrile (7b). Red solid; yield: 79%;
melting point: 190–192 °C; IR (film): 2933 (CH), 2192 (CN)
Conclusion
In summary, we have developed a simple, efficient, non-cata-
lytic regioselective synthesis of biologically important chro-
mene, isochromene and dihydrophenanthrene derivatives
from 2-oxabenzo[h]chromene under microwave irradiation.
Our protocol avoids the use of expensive, moisture and air sen-
sitive metal catalysts, organometallic reagents and ligands.
Microwave irradiation played a major role in achieving regios-
electivity and high yields. Thus, formation of two products
from a single reaction can be performed in a regioselective
manner via a cascade route using different bases. The struc-
ture of isochromene has also been confirmed unambiguously
by spectroscopic analysis and X-ray diffraction study.
cm−1 1H NMR (400 MHz, CDCl3): δ 2.39 (t, J = 8.0 Hz, 2H),
;
2.88 (t, J = 8.0 Hz, 2H), 3.84 (s, 1H), 4.35 (s, 1H), 6.71 (s, 1H),
6.95 (d, J = 6.4 Hz, 2H), 7.22–7.32 (m, 4H), 7.83 (d, J = 6.4 Hz,
2H); 13C NMR (100 MHz, CDCl3): δ 21.7, 27.2, 55.4, 63.2, 96.0,
114.3, 119.0, 120.0, 123.8, 123.9, 126.6, 127.1, 128.2, 129.7,
130.5, 135.2, 137.0, 155.2, 161.3, 166.2; HRMS (m/z): [M + H]+
calcd for C22H18NO2: 328.1338; found: 328.1330.
(Z)-2-(2-(4-Fluorophenyl)-5,6-dihydro-4H-benzo[f]isochromen-
4-ylidene)acetonitrile (7c). Red solid; yield: 84%; melting
Experimental section
General remarks
point: 188–190 °C; IR (film): 2927 (CH), 2193 (CN) cm−1 1H
;
Commercially available reagents were used without purifi-
cation. 1H and 13C NMR spectra were taken on a 400 MHz
NMR spectrometer and CDCl3 was used as a solvent. Chemical
shifts are reported in parts per million shift (δ-value) from
(CDCl3) (δ 7.24 ppm for 1H) or based on the middle peak of
the solvent (CDCl3) (δ 77.00 ppm for 13C NMR) as an internal
standard. Signal patterns are indicated as s, singlet; d,
doublet; dd, double doublet; t, triplet; m, multiplet; bs, broad
singlet; bm, broad multiplet. Coupling constants (J) are given
in hertz (Hz). Infrared (IR) spectra were recorded on a Perkin-
Elmer AX-1 spectrophotometer and reported in wave number
(cm−1). All the reactions were performed on a CEM microwave
synthesizer. The reaction was performed at a constant temp-
erature of 100 °C for 15 min with a maximum applied power of
200 W in a microwave synthesizer.
NMR (400 MHz, CDCl3): δ 2.42 (t, J = 7.7 Hz, 2H), 2.90 (t, J =
7.7 Hz, 2H), 4.41 (s, 1H), 6.78 (s, 1H), 7.12–7.17 (m, 2H),
7.26–7.34 (m, 3H), 7.56–59 (m, 1H), 7.86–7.90 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 21.8, 27.2, 64.1, 97.3, 116.1 (d, J =
20 Hz, 2C), 118.7, 121.0, 123.9, 127.0, 127.1 (d, J = 10 Hz, 2C),
127.6, 128.3, 129.9, 130.3, 134.9, 137.0, 154.2, 164.0 (d, J =
250 Hz, 1C), 166.0; m/z (CI) 316 (M + 1, 100%); HRMS (m/z):
[M + H]+ calcd for C21H15FNO: 316.1138; found: 316.1132.
(Z)-2-(2-(4-Chlorophenyl)-5,6-dihydro-4H-benzo[f]isochromen-
4-ylidene)acetonitrile (7d). Red solid; yield: 80%; melting
point: 192–194 °C; IR (film): 2924 (CH), 2194 (CN) cm−1 1H
;
NMR (400 MHz, CDCl3): δ 2.37 (t, J = 7.6 Hz, 2H), 2.85 (t, J =
7.6 Hz, 2H), 4.37 (s, 1H), 6.77 (s, 1H), 7.18–7.29 (m, 3H), 7.36
(d, J = 8.0 Hz, 2H), 7.51–7.53 (m, 1H), 7.76–7.78 (d, J = 8 Hz,
2H); 13C NMR (100 MHz, CDCl3): δ 21.8, 27.1, 29.7, 64.4, 97.9,
118.6, 121.5, 123.9, 126.2, 127.2, 128.3, 129.2, 129.8, 130.0,
130.2, 136.3, 136.9, 154.0, 165.8; m/z (CI) 332 (M + 1, 100%);
HRMS (m/z): [M + H]+ calcd for C21H15ClNO: 332.0842; found:
332.0835.
General procedure for the synthesis of (Z)-2-(2-aryl-5,6-dihydro-
4H-benzo[f]isochromen-4-ylidene)acetonitriles (7a–k), (Z)-2-(2-
(thiophen-2-yl)-5,6-dihydro-4H-benzo[f]isochromen-4-ylidene)-
acetonitriles (9a–b), (Z)-2-(3,4,7,8-tetrahydro-1H-naphtho[2,1-c]-
chromen-6(2H)-ylidene)acetonitrile (11a–b)
(Z)-2-(2-(4-Bromophenyl)-5,6-dihydro-4H-benzo[f]isochromen-
4-ylidene)acetonitrile (7e). Red solid; yield: 82%; melting
A dried microwave vial containing an equimolar mixture of point: 190–192 °C; IR (film): 2929 (CH), 2195 (CN) cm−1 1H
;
4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]chromen-2-one-3- NMR (400 MHz, CDCl3): δ 2.39 (t, J = 7.6 Hz, 2H), 2.90 (t, J =
carbonitriles 4 (0.5 mmol) and functionalized acetophenones 7.6 Hz, 2H), 4.41 (s, 1H), 6.81 (s, 1H); 13C NMR (100 MHz,
5 or 2-acetylthiophene 8 or cyclohexanone 10 (0.5 mmol), pot- CDCl3): δ 21.8, 27.1, 64.4, 97.9, 118.6, 121.5, 123.8, 124.6,
assium hydroxide (0.75 mmol) and DMF (2.0 mL) was placed 126.3, 126.5, 127.2, 128.3, 130.0, 130.2, 132.1, 134.7, 136.9,
in a microwave reactor for 15 minutes at 100 °C with a 154.0, 165.8; m/z (CI) 376 (M + 1, 100%); HRMS (m/z): [M + H]+
maximum applied power of 200 W. Completion of the reaction calcd for C21H15BrNO: 376.0337; found: 376.0323.
was monitored by TLC. After the completion, the reaction
(Z)-2-(2-(4-Bromophenyl)-8-methoxy-5,6-dihydro-4H-benzo[f]-
mixture was poured onto crushed ice with vigorous stirring fol- isochromen-4-ylidene)acetonitrile (7f). Red solid; yield: 80%;
lowed by neutralization with 10% HCl. The precipitate melting point: 228–230 °C; IR (film): 2923 (CH), 2188 (CN)
obtained was filtered, dried and purified using 20% ethyl cm−1 1H NMR (400 MHz, CDCl3): δ 2.39 (t, J = 7.8 Hz, 2H),
;
acetate in hexane as an eluent.
2.87 (t, J = 7.8 Hz, 2H), 3.84 (s, 3H), 4.35 (s, 1H), 6.77–6.78 (m,
2232 | Org. Biomol. Chem., 2014, 12, 2228–2234
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1H); 13C NMR (100 MHz, CDCl3): δ 21.8, 27.6, 55.4, 63.2, 97.9, 121.3, 123.9, 130.0, 138.1, 141.1, 155.0, 159.8, 165.9; m/z (CI)
112.3, 114.0, 118.9, 119.4, 123.1, 124.6, 125.5, 126.4, 130.4, 306 (M + 1, 100%); HRMS (m/z): [M + H]+ calcd for C20H20NO2:
132.1, 134.7, 139.1, 153.9, 161.0, 165.9; m/z (CI) 428 (M + 23, 306.1489; found: 306.1496.
100%); HRMS (m/z): [M
+
H]+ calcd for C22H17BrNO2:
General procedure for the synthesis of 3-aryl-1-(piperidin-1-yl)-
406.0437; found: 406.0443.
9,10-dihydrophenanthrene-2-carbonitriles (6a–c)
(Z)-2-(8-Methoxy-2-(4-methoxyphenyl)-5,6-dihydro-4H-benzo[f]-
isochromen-4-ylidene)acetonitrile (7g). Red solid; yield: 78%;
melting point: 156–158 °C; IR (film): 2935 (CH), 2192 (CN)
A dried microwave vial containing an equimolar mixture of
4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]chromen-2-ones
4
cm−1 1H NMR (400 MHz, CDCl3): δ 2.32 (t, J = 8.0 Hz, 2H),
;
(0.5 mmol) and different acetophenones 5 (0.5 mmol) with
NaH (0.75 mmol) and DMF (2 mL) was placed in a microwave
reactor for 15 minutes at 100 °C. The reaction was monitored
by TLC and after completion the reaction mixture was poured
onto crushed ice and neutralized by 10% HCl with vigorous
stirring. The precipitate was filtered, dried and purified using
20% ethyl acetate in hexane as an eluent. Compounds 6a and
6b have been reported in earlier literature.20
2.81 (t, J = 8.0 Hz, 2H), 3.78–3.79 (m, 6H), 4.24 (s, 1H), 6.62 (s,
1H), 6.71 (d, J = 2.8 Hz, 1H), 6.77 (dd, J = 8.8 Hz, J = 2.8 Hz,
1H), 6.90 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 8.8 Hz, 1H), 7.77 (d, J =
7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 21.7, 27.7, 55.4,
62.1, 94.0, 112.2, 113.9, 114.3, 117.9, 119.4, 123.4, 124.0, 125.6,
126.6, 135.3, 139.2, 155.1, 160.8, 161.3, 166.3; HRMS (m/z):
[M + H]+ calcd for C23H20NO3: 358.1443; found: 358.1438.
(Z)-2-(2-(Thiophen-2-yl)-5,6-dihydro-4H-benzo[f]isochromen-
4-ylidene)acetonitrile (9a). Red solid; yield: 78%; melting
3-(4-Bromophenyl)-7-methoxy-1-(piperidin-1-yl)phenanthrene-
2-carbonitrile (6c). Off white solid; yield: 87%; melting point:
point: 162–164 °C; IR (film): 2925 (CH), 2197 (CN) cm−1 1H
;
168–170 °C; IR (film): 2924 (CH), 2213 (CN) cm−1 1H NMR
;
NMR (400 MHz, CDCl3): δ 2.35 (t, J = 8.0 Hz, 2H), 2.84 (t, J =
8.0 Hz, 2H), 4.34 (s, 1H), 6.58 (s, 1H), 7.04 (t, J = 4.8 Hz, 1H),
7.16–7.18 (m, 1H), 7.25–7.29 (m, 2H), 7.34 (d, J = 4.8 Hz, 1H),
7.48–7.50 (m, 1H), 7.59 (d, J = 4.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 21.9, 27.2, 64.3, 96.9, 118.5, 120.7, 123.9, 126.8,
127.2, 127.7, 128.3, 129.9, 130.2, 134.9, 135.1, 136.9, 151.1,
165.6; m/z (CI) 326 (M + 23, 100%); HRMS (m/z): [M + H]+ calcd
for C19H13NOS: 304.0796; found: 304.0786.
(400 MHz, CDCl3): δ 1.73 (br, 6H), 2.81 (t, J = 8.0 Hz, 2H), 2.91
(t, J = 8.0 Hz, 2H), 3.26 (br, 4H), 3.84 (s, 3H), 6.79–6.84 (m,
2H), 7.41 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.62 (d, J =
8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 23.4, 24.1, 26.8,
28.9, 52.0, 55.4, 105.8, 112.7, 113.3, 118.7, 120.5, 122.7, 126.1,
126.5, 130.6, 131.7, 133.9, 138.0, 139.8, 140.1, 144.2, 154.8,
160.2; HRMS (m/z): [M + H]+ calcd for C27H25BrN2O: 473.1229;
found: 473.1223.
(Z)-2-(8-Methoxy-2-(thiophen-2-yl)-5,6-dihydro-4H-benzo[f]-
isochromen-4-ylidene)acetonitrile (9b). Red solid; yield: 76%;
melting point: 180–182 °C; IR (film): 2924 (CH), 2192 (CN)
Acknowledgements
cm−1 1H NMR (400 MHz, CDCl3): δ 2.37 (t, J = 7.8 Hz, 2H),
;
2.86 (t, J = 7.8 Hz, 2H), 3.83 (s, 3H), 4.32 (s, 1H), 6.59 (s, 1H),
6.76 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H),
7.08–7.10 (m, 1H), 7.37–7.38 (m, 1H), 7.47 (d, J = 8.8 Hz, 1H),
7.62–7.63 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 21.8, 27.6,
55.4, 63.0, 96.9, 112.3, 114.0, 118.5, 118.7, 123.1, 125.6, 126.7,
127.6, 128.2, 134.9, 135.2, 139.1, 151.0, 160.9, 165.7; HRMS
(m/z): [M]+ calcd for C20H15NO2S: 333.0823; found: 333.0879.
(Z)-2-(3,4,7,8-Tetrahydro-1H-naphtho[2,1-c]chromen-6(2H)-
ylidene)acetonitrile (11a). Viscous red liquid; yield: 72%; IR
(film): 2928 (CH), 2194 (CN) cm−1; 1H NMR (400 MHz, CDCl3):
δ 1.60–1.66 (m, 2H), 1.83–1.87 (m, 2H), 2.25 (t, J = 7.4 Hz, 2H),
2.57 (t, J = 6.4 Hz, 4H), 2.73 (t, J = 7.4 Hz, 2H), 4.28 (s, 1H),
7.21–7.28 (m, 3H), 7.49–7.51 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 21.8, 22.8, 23.2, 27.5, 27.8, 28.1, 61.8, 110.4, 119.3,
123.2, 126.2, 127.4, 127.8, 128.8, 131.1, 138.1, 138.9, 155.0,
165.8; HRMS (m/z): [M + H]+ calcd for C19H18NO: 276.1388;
found: 276.1383.
We thank the Council of Scientific and Industrial Research
(CSIR, New Delhi), University Grants Commission (UGC, New
Delhi), Department of Science and Technology (DST, New
Delhi) and University of Delhi, Delhi for financial support. PY
and SNS thank the University Grants Commission (UGC, New
Delhi) and SS thanks the Council of Scientific and Industrial
Research (CSIR, New Delhi) for research fellowship. The
authors thank University of Delhi for providing research
funding and instrumentation facility.
Notes and references
1 Microwaves in Organic Synthesis, ed. A. De La Hoz and
A. Loupy, Wiley-VCH, Weinheim, 3rd edn, 2013.
2 (a) N. E. Leadbeater and M. Marco, Org. Lett., 2002, 4, 2973;
(b) W. Li, Z. Xu, P. Sun, X. Jiang and M. Fang, Org. Lett.,
2011, 13, 1286.
3 (a) L. F. Tietze, G. Brasche and K. Gericke, Domino Reactions
in Organic Synthesis, Wiley-VCH, Weinheim, 2006, p. 672;
(b) K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew.
Chem., Int. Ed., 2006, 45, 7134.
4 (a) Y. L. Lin, C. C. Shen, Y. J. Huang and Y. Y. Chang, J. Nat.
Prod., 2005, 68, 381; (b) H. S. Kang, E. M. Jun, S. H. Park,
S. J. Heo, T. S. Lee, I. D. Yoo and J. P. Kim, J. Nat. Prod.,
(Z)-2-(10-Methoxy-3,4,7,8-tetrahydro-1H-naphtho[2,1-c]-
chromen-6(2H)-ylidene)acetonitrile (11b). Viscous red liquid;
yield: 69%; IR (film): 2927 (CH), 2192 (CN) cm−1 1H NMR
;
(400 MHz, CDCl3): δ 1.61–1.63 (m, 2H), 1.81 (t, J = 6.0 Hz, 2H),
2.21 (t, J = 7.4 Hz, 2H), 2.54 (t, J = 6.0 Hz, 4H), 2.69 (t, J =
7.4 Hz, 2H), 3.81 (s, 3H), 4.19 (s, 1H), 6.73–6.76 (m, 2H), 7.43
(d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 21.8, 22.6,
23.2, 27.5, 27.9, 28.6, 55.3, 60.7, 110.4, 111.2, 113.6, 119.6,
This journal is © The Royal Society of Chemistry 2014
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Paper
Organic & Biomolecular Chemistry
2007, 70, 1043; (c) E. J. Salaski, G. Krishnamurthy, 16 K. S. Kumar, D. Rambabu, B. Prasad, M. Mujahid,
W. D. Ding, K. Yu, S. S. Insaf, C. Eid, J. Shim, J. I. Levin,
K. Tabei, L. T. Barza, W. G. Zhang, L. A. McDonald,
G. R. Krishna, M. V. B. Rao, C. M. Reddy, G. R. Vanaja,
A. M. Kalle and M. Pal, Org. Biomol. Chem., 2012, 10, 4774.
E. Honores, C. Hanna, A. Yamashita, B. Johnson, Z. Li, 17 A. R. Hudson, S. L. Roach, R. I. Higuchi, D. P. Phillips,
L. Laakso, D. Powell and T. S. Mansour, J. Med. Chem.,
2009, 52, 2181.
5 (a) G. K. Hughes, F. N. Lakey, J. R. Price and L. J. Webb,
Nature, 1948, 162, 223; (b) R. T. Dorr, J. D. Liddil, D. D. Von
Hoff, M. Soble and C. K. Osborne, Cancer Res., 1989, 49,
340.
R. P. Bissonnette, W. W. Lamph, J. Yen, Y. Li, M. E. Adams,
L. J. Valdez, A. Vassar, C. Cuervo, E. A. Kallel,
C. J. Gharbaoui, D. E. Mais, J. N. Miner, K. B. Marschke,
D. Rungta, A. Negro-Vilar and L. Zhi, J. Med. Chem., 2007,
50, 4699.
18 C. M. Tegley, L. Zhi, K. B. Marschke, M. M. Gottardis,
Q. Yang and T. K. Jones, J. Med. Chem., 1998, 41, 4354.
6 (a) X. Hu, J. W. Wu, X. D. Zhang, Q. S. Zhao, J. M. Huang,
H. Y. Wang and A. J. Hou, J. Nat. Prod., 2011, 74, 816; 19 R. Gompper and W. Topfl, Chem. Ber., 1962, 95, 2861.
(b) R. N. Patel, Adv. Synth. Catal., 2001, 343, 527. 20 R. Pratap and V. J. Ram, J. Org. Chem., 2007, 72, 7402.
7 A. C. Whyte, J. B. Gloer, D. T. Wicklow and P. F. Dowd, 21 (a) J. J. V. Eynde, N. Hecq, O. Kataeva and C. O. Kappe,
J. Nat. Prod., 1996, 59, 1093.
Tetrahedron, 2001, 57, 1785; (b) D. D. Young and A. Deiters,
Angew. Chem., Int. Ed., 2007, 46, 5187; (c) R. A. Stockland
Jr., R. I. Taylor, L. E. Thompson and P. B. Patel, Org. Lett.,
2005, 7, 851; (d) F. Langa, P. D. L. Cruz, A. D. L. Hoz,
E. Espıldora, F. P. Cossıo and B. Lecea, J. Org. Chem., 2000,
65, 2499.
8 (a) M. Takasugi, S. Nagao, S. Ueno, T. Masamune,
A. Shirata and K. Takahashi, Chem. Lett., 1978, 1239;
(b) A. Shirata, K. Takahashi, M. Takasugi, S. Nagao,
S. Ishikawa, S. Ueno, L. Munoz and T. Masamune, Sanshi
Shikenjo Hokoku, 1983, 28, 793.
9 A. A. L. Gunatilaka, D. G. I. Kingston, E. M. K. Wijeratne, 22 A. Goel, G. Taneja, A. Raghuvanshi, R. Kant and
B. M. R. Bandara, G. A. Hofmann and R. K. Johnson, J. Nat.
Prod., 1994, 57, 518.
10 (a) N. Fang and J. E. Casida, Proc. Natl. Acad. Sci. U. S. A.,
1998, 95, 3380; (b) N. Fang and J. E. Casida, J. Nat. Prod.,
1999, 62, 205; (c) M. Kaouadji, A. Agban, A. M. Mariotte
and M. Tissut, J. Nat. Prod., 1986, 49, 281.
11 N. Jain, R. M. Kanojia, J. Xu, G. J. Zhong, E. Pacia,
M. T. Lai, F. Du, A. Musto, G. Allan, D. W. Hahn,
S. Lundeen and Z. Sui, J. Med. Chem., 2006, 49, 3056.
12 (a) J. P. Edwards, L. Zhi, C. L. F. Pooley, C. M. Tegley,
S. J. West, M. W. Wang, M. M. Gottardis, C. Pathirana,
W. T. Schrader and T. K. Jones, J. Med. Chem., 1998, 41,
2779; (b) L. Zhi, C. M. Tegley, B. Pio, J. P. Edwards,
M. Motamedi, T. K. Jones, K. B. Marschke, D. E. Mais,
B. Risek and W. T. Schrader, J. Med. Chem., 2003, 46, 4104.
13 A. Mahadevan, C. Siegel, B. R. Martin, M. E. Abood,
I. Beletskaya and R. K. Razdan, J. Med. Chem., 2000, 43,
3778.
P. R. Maulik, Org. Biomol. Chem., 2013, 11, 5239.
23 Crystal data for C21H14BrNO: a red crystal (0.11 × 0.10 ×
0.03 mm) was mounted on a capillary tube for indexing
and intensity data collection at 293(2) K on an Oxford Xcali-
bur Sapphire3 CCD single-crystal diffractometer (Mo Kα
radiation, λ = 0.71073 Å). Routine Lorentz and polarization
corrections were applied, and an absorption correction was
performed using the ABSCALE 3 program [CrysAlis Pro soft-
ware system, Version 171.34; Oxford Diffraction Ltd,
Oxford, UK, 2011]. Patterson methods were used to locate
the heavy metal atoms (SHELXS-86), and the remaining
atoms were located from successive Fourier maps
(SHELXL-97). All the non-hydrogen atoms were refined
anisotropically; hydrogen atoms were located at calculated
positions using a riding model. All hydrogen atoms were
calculated after each cycle of refinement using a riding
model, with C–H = 0.93 Å + Uiso(H) = 1.2 Ueq(C) for
aromatic H atoms, and with C–H = 0.97 Å + Uiso(H) =
14 (a) J. P. Edwards, L. Zhi, C. L. F. Pooley, C. M. Tegley,
S. J. West, M. W. Wang, M. M. Gottardis, C. Pathirana,
W. T. Schrader and T. K. Jones, J. Med. Chem., 1998, 41,
2779; (b) L. Zhi, C. M. Tegley, B. Pio, J. P. Edwards,
M. Motamedi, T. K. Jones, K. B. Marschke, D. E. Mais,
B. Risek and W. T. Schrader, J. Med. Chem., 2003, 46, 4104;
(c) M. Rueping, U. Uria, M. Y. Lin and I. Atodiresei, J. Am.
Chem. Soc., 2011, 133, 3732.
1.2 Ueq(C) for methylene
C21H14BrNO; Mr = 376.25, crystal system: triclinic; space
H
atoms. Crystal data:
ˉ
group P1, a = 7.3715(4) Å, b = 9.3781(7) Å, c = 12.8371(12) Å,
α = 96.360(7)°, β = 99.202(7)°, γ = 111.905(6)°, V =
798.57(10) Å3, Z = 2, ρcalcd = 1.565 g cm−3, μ = 2.580 mm−1
,
F(000) = 380, R1 = 0.0759 and wR2 = 0.2085 for I > 2σ(I) and
226 parameters, R1 = 0.0892 and wR2 = 0.2198, gof = 1.097
for all data. CCDC (Deposit no. 959771) contains the sup-
plementary crystallographic data.
15 H. Yanai and T. Taguchi, Chem. Commun., 2012, 48, 8967.
2234 | Org. Biomol. Chem., 2014, 12, 2228–2234
This journal is © The Royal Society of Chemistry 2014