H2SO4-promoted synthesis of (E)-stilbenes from substituted phenylacetones and substituted benzaldehydes through tandem aldol-Grob reaction

Article abstract of DOI:10.1080/00397911.2010.488309

Stilbene derivates (stilbenoids) are present in plants and show a wide range of biological activities and potential therapeutic value. In continuation of our natural product synthesis program, an efficient, simple, and practical method has been developed to regioselectively synthesize (E)-stilbenes using H₂SO₄ as a catalyst in a short time (30-60 s) at room temperature in good to excellent yields.

Full text of DOI:10.1080/00397911.2010.488309

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H2SO4-Promoted Synthesis of
(E)-Stilbenes from Substituted
Phenylacetones and Substituted
Benzaldehydes Through Tandem
Aldol–Grob Reaction
T. Narender a , K. Papi Reddy a & Sriniwas Tiwari a
a Medicinal and Process Chemistry Division, Central Drug Research
Institute, Lucknow, India
Version of record first published: 20 Apr 2011
To cite this article: T. Narender, K. Papi Reddy & Sriniwas Tiwari (2011): H2SO4-Promoted Synthesis
of (E)-Stilbenes from Substituted Phenylacetones and Substituted Benzaldehydes Through Tandem
Aldol–Grob Reaction, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:11, 1572-1583
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Synthetic Communications1, 41: 1572–1583, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.488309
H2SO4-PROMOTED SYNTHESIS OF (E)-STILBENES
FROM SUBSTITUTED PHENYLACETONES AND
SUBSTITUTED BENZALDEHYDES THROUGH TANDEM
ALDOL–GROB REACTION
T. Narender, K. Papi Reddy, and Sriniwas Tiwari
Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, India
GRAPHICAL ABSTRACT
Abstract Stilbene derivates (stilbenoids) are present in plants and show a wide range of
biological activities and potential therapeutic value. In continuation of our natural product
synthesis program, an efficient, simple, and practical method has been developed to regio-
selectively synthesize (E)-stilbenes using H2SO4 as a catalyst in a short time (30–60 s) at
room temperature in good to excellent yields.
Keywords (E)-Stilbenes; H2SO4; phenylacetones; 1-phenylpropan-2-one
INTRODUCTION
Stilbene derivates (stilbenoids) are present in plants and show a wide range of
biological activities and potential therapeutic value (Fig. 1).[1] For example, resver-
atrol exhibits a variety of useful bioactivities including cancer chemopreventive,
antiplatelet aggregation, antioxidative, antibacterial, anti-inflammatory, and anti-
dyslipidemic activities.[2] Pterostilbene acts as an effective PPAR-a agonist[2b] and
hypolipidemic agent, and in vivo studies demonstrated that it also possesses lipid-
and glucose-lowering effects. Pinosylvin is a constituent of heartwood of pine and
exhibits antifungal and antibacterial activity.[3] Piceatannol is found in red wine
and shows anti-inflammatory, immunomodulatory, and antiproliferative activities.[4]
The cis and trans isomers of combretastain A4 are reported to have antitumor
Received January 21, 2010.
CDRI communication No. 7709.
Address correspondence to T. Narender, Medicinal and Process Chemistry Division, Central Drug
Research Institute, Lucknow 226 001, India. E-mail: t_narendra@cdri.res.in
1572

REGIOSELECTIVE SYNTHESIS OF (E)-STILBENES
1573
Figure 1. Biologically active stilbene derivatives.
activity[5] (Fig. 1). Some of the synthetic stilbenes are used as optical brighteners,[6]
phosphors,[7] and scintillators.[8]
Several methods are available for the synthesis of stilbenes.[9–27] The currently
available methods for the synthesis of stilbenes have some limitations, such as (i) the
need for multistep synthesis,[27] (ii) the use of toxic metal complexes such as Pd-NHC
complexes,[15] [Pd(O2CCF3], [PdCl2(PPh3)]2, and [NiCl2 (PPh3)],[20] (iii) the require-
ment to prepare special synthons such as organozinc arylhalides,[20] aromatic boro-
nic acids, aryl or vinyl tellurides, aryl or vinyl trifluoroborate salts,[16] (iv) the lack of
stereoselectivity (cis and trans isomers),[27] (v) long reaction times,[15,20,21] and (vi)
harsh reaction conditions.[10,16] The development of new and simple methods to form
such bonds by procedures devoid of these disadvantages is still a challenge for
organic chemists.[28] Herein we show that (E)-stilbenes can be easily synthesized by
the reaction of 1-phenylpropan-2-one (1a), its derivative 1-p-chlorophenylpropan-2-
one (1b), and 1-p-methoxyphenylpropan-2-one (1c) with aryl aldehydes 2a–2h in the
presence of H2SO4 (Scheme 1, Table 1).
In 1890, Miller and Rohde described a reaction between 1-phenylpropan-2-one
(1a) and benzaldehyde (2a) using sulfuric acid and water (H2SO4-H2O, 3:1).[29]
However, so far the synthetic potential and the generalizability with respect to
the aldehyde and ketone in the synthesis of stilbenes has never been explored.
To investigate the scope and limitations of H2SO4 as a catalyst for the synthesis of
(E)-stilbenes, various aromatic aldehydes 2a–2h, on the one hand, and 1-phenyl-
propan-2-one (1a), 1-p-chlorophenyl propan-2-one (1b), and 1-p-methoxyphenyl-
propan-2-one (1c), on the other hand, were utilized as substrates (Scheme 1). The
results are summarized in Table 1.
Scheme 1. Synthesis of (E)-stilbene derivatives 3a, 3b, and 3e using H2SO4..

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1575

1576

1577

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T. NARENDER, K. PAPI REDDY, AND S. TIWARI
RESULTS AND DISCUSSION
The regioselective reaction between 1-phenylpropan-2-one (1a) and benzal-
dehyde (2a) in the presence of H2SO4 resulted in the formation of (E)-stilbene (3a)
stereoselectively in a short time (30–60 s). Further exploration with various substi-
tuted aromatic aldehydes 2b–2f also provided the (E)-stilbenes 3b–3f. To study the
reaction conditions, we carried out the reaction between 1-p-chlorophenylpropan-2-
one (1b) and substituted benzaldehydes 2a–2c and 2 g–2h, which provided the
(E)-stilbenes 3b and 3g–3j in excellent yields. To demonstrate the wider applicability
of this reaction, we carried out reactions between 1-p-methoxyphenylpropan-2-one
(1c) and substituted benzaldehydes 2a–2c, 2e, and 2h, which also afforded the
(E)-stilbenes 3e and 3k–3n exclusively in poor yields (Table 1). It is important to note
that in the presence of an activating group (OMe) on ketone, yields were poor,
whereas in the presence of a deactivating group (Cl) on ketone, yields were excellent.
The trans nature of the double bond of synthesized stilbenes was confirmed by their
1
coupling constants (J ¼ ꢀ16 Hz) in the H NMR spectra,[30] and we did not observe
their respective cis isomers (cis-stilbenes) during our isolation process.
It is noteworthy to mention here that under basic conditions (KOH) the
reaction between 1-phenylpropan-2-one (1a) and benzaldehyde (2a) resulted in the
synthesis of a mixture of 1,4-diphenyl-but-3-en-2-one and 3,4-diphenyl-but-3-en-2-
one in our own studies as described by Southwick and coworkers[30] (Scheme 1).
The reaction mechanism appears to be tandem aldol–Grob reaction sequence
(Fig. 2).[31] The rapid reaction at room temperature with a catalytic amount of
H2SO4 in our studies might be due to presence of benzylic hydrogens adjacent to
ketones 1a–1c.
In summary, we described an efficient, simple, and practical method for the
synthesis of (E)-stilbenes from 1-phenylpropan-2-one (1a), its derivatives 1-p-
chlorophenylpropan-2-one (1b), and 1-p-methoxyphenylpropan-2-one (1c) with
aromatic aldehydes 2a–2h in the presence of H2SO4 in good to excellent yields.
The advantages of this method are the following: the reaction proceeds regioselec-
tively to provide stereoselective (E)-stilbenes, it uses a simple experimental procedure
Figure 2. Tandem aldol–Grob reaction sequence in the formation of stilbenes.

REGIOSELECTIVE SYNTHESIS OF (E)-STILBENES
1579
within a short reaction time (30–60 s) using mild reaction conditions (room tem-
perature), it is a solvent-free reaction in the case of at least one liquid reactant,
and catalyst is inexpensive. This method might also be useful for the synthesis of
diphenyl-substituted polyenes. Our reaction avoids the use of toxic metal complexes,
multistep synthesis, preparation of special synthons, long reaction times and harsh
reaction conditions.
EXPERIMENTAL
Infrared (IR) spectra were recorded on a Perkin-Elmer AC-1 spectrometer.
1H NMR spectra were run on Bruker Advance DPX 200 and 300 MHz in CDCl3;
13C NMR spectra were recorded at 75 MHz and 50 MHz in CDCl3. Chemical shifts
are reported as values in parts per million (ppm) relative to CHCl3 (7.26) in CDCl3,
and tetramethylsilane (TMS) was used as internal standard. Electrospray ionization
(ESI) mass spectra were recorded on a Jeol SX 102=DA-6000 instrument. Chroma-
tography was executed with silica gel (60–120 mesh) using mixtures of ethyl acetate
and hexane as eluants. Ethyl acetate and hexane were dried and purified by distil-
lation prior to use.
Representative Procedure for the Preparation of (E)-1-Chloro-4-
(4-isopropylstyryl)benzene (3j)
Concentrated H2SO4 (three drops by syringe) was added gradually to a stirred
solution of 1-p-chlorophenylpropan-2-one (1b) (200 mg, 1.5 mmol) and isopropyl-
benzaldehyde (2h) (210 mg, 1.4 mmol) at room temperature. The resultant solution
was stirred for 30–60 s. After dilution with ethyl acetate (100 mL), the solution
was washed with water (3 ꢁ 30 mL) to decompose the H2SO4 complex. The organic
solution obtained after extraction was dried over anhydrous Na2SO4 and filtered,
and the solvent was evaporated under reduced pressure. The crude mixture was pur-
ified by silica-gel column chromatography using hexane–ethyl acetate to afford the
desired (E)-1-chloro-4-(4-isopropylstyryl)benzene (3j) (264 mg, 87%).
Data
(E)-1-Chloro-4-(4-isopropylstyryl)benzene (3j). IR (KBr) 2925, 2857, 1460,
1216, 965, 763 cmꢂ1; 1H NMR (300 MHz, CDCl3) d 7.49 (d, J ¼ 8.3 Hz 2H), 7.46 (d,
J ¼ 8.5 Hz 2H), 7.35 (d, J ¼ 8.5 Hz, 2H), 7.28 (d, J ¼ 8.3 Hz, 2H), 7.12 (d, J ¼ 16.4 Hz,
1H), 7.04 (d, J ¼ 16.4 Hz, 1H), 2.97 (m, 1H), 1.32 (d, J ¼ 6.9 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 148.8, 136.0, 134.6, 132.9, 129.4, 128.9 (2C), 127.7 (2C), 126.9
(2C), 126.7 (2C), 126.6, 34.1, 23.9.
(E)-1,2-Diphenylethene (3a). 1H NMR (200 MHz, CDCl3) d 7.62–7.58 (m,
4H), 7.48–7.3 (m, 6H), 7.20 (brs, 2H); 13C NMR (75 MHz, CDCl3) d 137.4, 128.8,
128.7 (2C), 127.6, 126.5.
(E)-1-Chloro-4-styrylbenzene (3b). 1H NMR (200 MHz, CDCl3) d 7.55–7.45
(m, 5H), 7.43–7.25 (m, 4H), 7.08 (brs, 2H); 13C NMR (75 MHz, CDCl3) d 138.2,
136.3, 133.6, 129.7, 129.3 (2C), 129.2 (2C), 128.3, 128.1 (2C), 127.8, 126.9 (2C).

1580
T. NARENDER, K. PAPI REDDY, AND S. TIWARI
(E)-1-Methyl-4-styrylbenzene (3c). 1H NMR (200 MHz, CDCl3)
d
7.56–7.53 (m, 2H), 7.48–7.39 (m, 5H), 7.21 (d, J ¼ 8.0 Hz, 2H), 7.12 (brs, 2H), 2.40
(s, 3H); 13C NMR (50 MHz, CDCl3) d 137.8, 137.7, 134.8, 129.6 (2C), 128.9 (3C),
127.9, 127.6, 126.7 (2C), 126.6 (2C), 22.4 (3H).
(E)-1-Fluoro-4-styrylbenzene (3d). 1H NMR (200 MHz, CDCl3) d 7.58–7.50
(m, 4H), 7.50–7.41 (m, 2H), 7.38–7.32 (m, 1H), 7.18–7.00 (m, 4H); 13C NMR
(50 MHz, CDCl3), 165.3 (C-1),ꢃ 160.4 (C-1),ꢃ 137.6, 134.0 (C-4),ꢃ 133.9 (C-4),ꢃ
129.2 (2C), 129.0 (C-7),ꢃ 128.9 (C-7),ꢃ 128.5 (C-3=5),ꢃ 128.4 (C-3=5),ꢃ 128.1
(C-2=6),ꢃ 127.9 (C-2=6),ꢃ 126.9 (2C), 116.3, 115.9. Asterisks (ꢃ) denote splitting due
to long-range coupling with fluorine substitution on the phenyl ring (F).
(E)-1-Methyl-4-styrylbenzene (3e). 1H NMR (200 MHz, CDCl3)
d
7.53–7.47 (m, 4H), 7.40–7.35 (m, Hz, 2H), 7.26 (m, 1H), 7.10 (d, J ¼ 16.3 Hz, 1H),
7.00 (d, J ¼ 16.3 Hz, 1H) 6.93 (d, J ¼ 7.8 Hz, 2H), 3.85 (s, 3H); 13C (75 MHz, CDCl3)
d 159.3, 137.6, 130.1, 128.6 (2C), 128.2, 127.7 (2C), 126.2, 126.6, 126.2 (2C), 114.1
(2C), 55.3.
(E)-1,2-Difluoro-4-styrylbenzene (3f). IR (KBr) 2924, 1596, 1510, 1431,
1
1271, 1112, 959 cmꢂ1; H NMR (300 MHZ, CDCl3) d 7.55–7.49 (m, 2H), 7.44–7.27
(m, 4H), 7.23–7.10 (m, 2H), 7.02 (brs, 2H); 13C NMR (50 MHz, CDCl3) d 153.6
(C-2),ꢃ 153.4 (C-2),ꢃ 152.8 (C-1),ꢃ 152.6 (C-1),ꢃ 148.7 (C-2),ꢃ 148.4 (C-2),ꢃ 147.9
(C-1),ꢃ 147.6 (C-1),ꢃ 137.1, 135.2–135.0 (q, C-4), 130.3–130.2 (d, C-7),ꢃ 129.2 (2C),
128.5, 127.0 (2C), 126.9 (d, C-8),ꢃ 123.3–123.1 (q, C-5),ꢃ 118.0–117.6 (C-6),ꢃ
115.2–114.9 (C-3).ꢃ Asterisks denote splitting due to long-range coupling of fluorine
(F) substitution on the phenyl ring.
(E)-1,2-Bis(4-chlorophenyl)ethene (3g). IR (KBr) 2923, 1588, 1487, 1406,
1
1090, 828 cmꢂ1; H NMR (300 MHz, CDCl3) d 7.45 (d, J ¼ 8.5 Hz, 4H), 7.33 (d,
J ¼ 8.5 Hz, 4H), 7.03 (s, 2H); 13C (75 MHz, CDCl3) d 135.5 (2c), 133.4 (2C), 128.9
(4C), 127.9 (2C), 127.7 (4C).
(E)-1-Chloro-4-(4-methylstyryl)benzene (3h). 1H NMR (300 MHz, CDCl3)
d 7.45 (d, J ¼ 8.4 Hz, 2H), 7.42 (d, J ¼ 7.8 Hz, 2H), 7.33 (d, J ¼ 8.4 Hz, 2H), 7.20 (d,
J ¼ 7.8 Hz, 2H), 7.09 (d, J ¼ 16.3 Hz, 1H), 7.01 (d, J ¼ 16.3 Hz, 1H), 2.38 (s, 3H);
13C NMR (75 MHz, CDCl3) d 137.8, 136.0, 134.2, 132.9, 129.4 (2C), 129.2, 128.8
(2C), 127.5 (2C), 126.5 (2C), 126.3, 21.3 (3H).
(E)-2,4-Dichloro-1-(4-chlorostyryl)benzene (3i). IR (KBr) 3021, 2925,
1588, 1491, 1216, 1095, 761 cmꢂ1; 1H NMR (300 MHz, CDCl3) d 7.59 (d, J ¼ 8.6 Hz,
Hz, 1H), 7.48–7.34 (m, 6H), 7.25 (dd, J ¼ 8.6, 1.9 Hz, 1H), 7.0 (d, J ¼ 16.3 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 135.2, 134.0, 133.9, 133.7, 130.4, 129.6, 128.9 (2C),
128.0 (2C), 127.3, 127.1, 124.2.
(E)-4-(4-Chlorostyryl)phenol (3k). 1H NMR (200 MHz, CDCl3) d 7.48–7.38
(m, 4H), 7.32–7.26 (m, 2H), 7.04 (d, J ¼ 16.4 Hz, 2H), 6.94–6.86 (m, 3H), 3.83 (s,
3H); 13C NMR (50 MHz, CDCl3) d 159.9, 136.6, 133.1, 130.2, 129.3, 129.2 (2C),
128.2 (2C), 127.8 (2C), 125.7, 114.6 (2C), 55.7.
(E)-1-Methoxy-4-(4-methylstyryl)benzene (3l). 1H NMR (200 MHz,
CDCl3) d 7.43–7.34 (m, 4H), 7.12 (d, J ¼ 8.2 Hz, 2H), 7.05–6.94 (m, 2H), 6.86 (d,

REGIOSELECTIVE SYNTHESIS OF (E)-STILBENES
1581
J ¼ 8.6 Hz, 2H), 3.79 (s, 3H), 2.32 (s, 3H); 13C (75 MHz, CDCl3) d 159.4, 137.3,
135.1, 130.6, 129.6 (2C), 127.8 (2C), 127.5, 126.8, 126.4 (2C), 114.3 (2C), 55.5, 21.4.
(E)-1,2-Bis(4-methoxyphenyl)ethene (3m). 1H NMR (200 MHz, CDCl3) d
7.43 (d, J ¼ 8.8 Hz, 4H), 6.93 (s, 2H), 6.89 (d, J ¼ 8.8 Hz, 4H), 3.83 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 158.1, 139.4, 127.6 (4C), 126.3 (2C), 114.2 (4C), 55.5.
(E)-1-Isopropyl-4-(4-methoxystyryl)benzene (3n). 1H NMR (200 MHz,
CDCl3) d 7.48–7.42 (m, 4H), 7.24–7.20 (d, J ¼ 8.2 Hz, 2H), 7.09–6.99 (m, 2H),
6.90 (d, J ¼ 8.8 Hz, 2H), 3.83 (s, 3H), 2.92 (m, 1H), 1.27 (d, J ¼ 6.9 Hz, 6H);
13C NMR (50 MHz, CDCl3) d 159.4, 148.3, 135.5, 130.6, 127.8 (2C), 126.9 (2C),
126.8, 126.4 (2C), 114.3 (2C), 55.5, 34.1, 24.1 (2C).
ACKNOWLEDGMENTS
The authors are thankful to the director, Central Drug Research Institute
(CDRI), for support of the synthesis of natural product analogs, the SAIF Division
of CDRI for spectral data, and the Council of Scientific and Industrial Research,
New Delhi, and University Grants Commission (UGC), New Delhi, for financial
support.
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