Base-catalyzed cross coupling of secondary alcohols and aryl-aldehydes with concomitant oxidation of alcohols to ketones: An alternative route for synthesis of the Claisen-Schmidt condensation products

Article abstract of DOI:10.1016/j.tetlet.2017.05.093

Base-catalyzed C–C cross coupling of secondary alcohols and aryl-aldehydes was achieved, when an alcoholic solution of an aryl-aldehyde was stirred under reflux for 45?h in the presence of a catalytic (20?mol%) amount of K₂CO₃. The consistent formation of α,α′-bis-(benzylidene) alkanones was obtained in moderate to good yields using various secondary alcohols and substituted aryl-aldehydes. Herein, α,α′-bis-(benzylidene)alkanones, which are the classical products of Claisen-Schmidt (cross aldol) condensation, have been synthesized via an alternative strategy using secondary alcohols. Bis-(benzylidene) alkanones are an integral part of various drug regimes and the production of bis-(benzylidene) alkanones without using any precious metal is a major outcome of the present reaction.

Full text of DOI:10.1016/j.tetlet.2017.05.093

Accepted Manuscript
Base-catalyzed cross coupling of secondary alcohols and aryl-aldehydes with
concomitant oxidation of alcohols to ketones: An alternative route for synthesis
of the Claisen-Schmidt condensation products
Naveen Satrawala, Kamal N. Sharma, Leah C. Matsinha, Latisa Maqeda,
Shepherd Siangwata, Gregory S. Smith, Raj K. Joshi
PII:
S0040-4039(17)30695-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.093
TETL 48986
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 May 2017
30 May 2017
31 May 2017
Please cite this article as: Satrawala, N., Sharma, K.N., Matsinha, L.C., Maqeda, L., Siangwata, S., Smith, G.S.,
Joshi, R.K., Base-catalyzed cross coupling of secondary alcohols and aryl-aldehydes with concomitant oxidation
of alcohols to ketones: An alternative route for synthesis of the Claisen-Schmidt condensation products, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.093
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Base-catalyzed cross coupling of secondary
alcohols and aryl-aldehydes with
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concomitant oxidation of alcohols to ketones:
An alternative route for synthesis of the
Claisen-Schmidt condensation products
Naveen Satrawala,a, ‡ Kamal N. Sharma,a, ‡ Leah C. Matsinha,b Latisa Maqeda,b Shepherd Siangwata,b Gregory
S. Smithb, * and Raj K. Joshia, c,
*

1
Tetrahedron Letters
Base-catalyzed cross coupling of secondary alcohols and aryl-aldehydes with
concomitant oxidation of alcohols to ketones: An alternative route for synthesis of the
Claisen-Schmidt condensation products
Naveen Satrawala,a, ‡ Kamal N. Sharma,a, ‡ Leah C. Matsinha,b Latisa Maqeda,b Shepherd Siangwata,b
Gregory S. Smithb, * and Raj K. Joshia, *
aDepartment of Chemistry, Malaviya National Institute of Technology, Jaipur 302017, Rajasthan, India
bDepartment of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa
Email: rkjoshi.chy@mnit.ac.in, Phone: +91 141 2713279
‡
N.S. and K.N.S. have contributed equally
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Base-catalysed C−C cross coupling of secondary alcohols and aryl-aldehydes was achieved,
when an alcoholic solution of an aryl-aldehyde was stirred under reflux for 45 h in the presence
of a catalytic (20 mol%) amount of K2CO3. The consistent formation of α,α´-bis-(benzylidene)
alkanones was obtained in moderate to good yields using various secondary alcohols and
substituted aryl-aldehydes. Herein, α,α´-bis-(benzylidene)alkanones, which are the classical
products of Claisen-Schmidt (cross aldol) condensation, have been synthesized via an alternative
strategy using secondary alcohols. Bis-(benzylidene) alkanones are an integral part of various
drug regimes and the production of bis-(benzylidene) alkanones without using any precious
metal is a major outcome of the present reaction.
Available online
Keywords:
Cross Coupling
Base catalyzed
One-pot synthesis
Bis-(benzylidene) alkanones
Claisen-Schmidt condensation
2009 Elsevier Ltd. All rights reserved.
1. Introduction
Diarylidene ketones are of special interest due to their
intriguing biological activities such as HIV-1integrase inhibitors,1
antiangiogenics,2 methyltransferase inhibitors,3 quinine reductase
inducers,4 cholesterol-lowering activity,5 arginine cytotoxicity,6
and their use in various agrochemical, pharmaceutical and
perfume industries.7 Moreover, these are important precursors in
the synthesis of 2,7-disubstituted tropones,8 and natural products
such as cystodytins.9 The Claisen-Schmidt condensation reaction
is the classical method used for the synthesis of α,α´-bis-
(benzylidene)alkanones. Through this method, alkanones are
transformed to α-α´-bis-(benzylidene)alkanones in the presence
of strong acids10 and bases with or without solvent and
conventional heating.11 Several protocols for Claisen-Schmidt
condensation reaction have been reported using different
catalysts such as basic or acidic alumina,12 Na2CO3-TBAB,13
bis(p-methoxyphenyl)telluroxide,14 expensive Lewis acids (e.g.
amberlyst-15 and B2O3/ZrO2),15 and hazardous or toxic solvents.
The synthesis of α,α´-bis-(benzylidene)alkanones by direct C‒C
cross-coupling of alcohols at the β-position with aldehydes has
also been reported by Zhang and co-workers (Scheme 1).16
Scheme 1. Cross coupling reaction of primary and secondary
alcohols with aldehydes.
This is the only reported method which avoids the use of
alkanones. However, a rhodium catalyst was used to promote this
coupling. To the best of our knowledge, there is no method
reported where a metal-free coupling of secondary alcohols and
aryl-aldehydes through the β-position, with concomitant
oxidation of the alcohol to the ketone, has been reported. Hence,
to our mind, it seemed worthwhile to explore a metal-free C–C
cross-coupling strategy between secondary alcohols and aryl
aldehydes for the preparation of biologically important bis-
(benzylidene)alkanones. Moreover, the vast expense of rhodium
complexes and dwindling Rh resources, provides further
motivation for pursuing this metal-free route for the synthesis of
α,α´-bis-(benzylidene)alkanones.

2
Tetrahedron
2. Results and discussion
60% (Entry 8, Table 1). Other alkali bases viz. Cs2CO3, NaOH,
KOH, and KOt-Bu are also effective for the reaction but require
longer times for the reaction to be completed in comparison with
K2CO3. Moreover, the yield of the products are significantly
reduced (Entry 11-14, Table 1). It was also observed that the
yield of the desired product decreases when strong alkali bases
such as NaOH and KOH are used. Moreover, benzyl alcohol and
benzoic acid (Cannizzaro reaction products) formed as the major
products. The formation of the products was not observed with
alkaline earth bases, i.e. Ca(OH)2, CaCO3 Mg(OH)2, MgCO3
(Entries 15-18, Table 1). Careful selection of the alkali base is
therefore essential for the selective preparation of the desired
products. In addition, the mol% of alkali base also influences the
course of reaction and yields of product as well. After performing
a series of reactions, it was established that 20 mol% is an ideal
quantity of the base (K2CO3) required for the reaction (Entries 2-
4, Table 1), while further increasing the mol% of the base drove
the reaction towards the Cannizzaro reaction and results in the
fomration of the benzyl alcohol and benzoic acid, as the major
products of the reaction (Entry 5, Table 1). Lowering the mol%
of the base significantly reduced the yield of the products
(Entries 2-4, Table 1).
When a secondary alcohol (2-propanol) and benzaldehyde
were heated at 90 °C for 45 h in the presence of catalytic K2CO3,
the formation of a new light yellow product, α,α´-bis-
(benzylidene)alkanone was observed in a significant amount.
Scheme 2. Base catalyzed cross coupling of secondary alcohols
with aldehydes.
It was quite surprising to obtain the Claisen-Schmidt product
without using any alkanone. It is probable that the alcohol
transforms in situ to the alkanone and then initiates the Claisen-
Schmidt reaction. However, there is no report available which
indicates dehydrogenation of a secondary alcohol without using
aluminium alkoxides.17 Since, the alcohol is working as a reagent
as well as solvent for this reaction, the purity of alcohols has also
been confirmed through gas chromatography (GC) analysis and
refractive indexes. The optimization of the solvents was further
investigated in different primary, secondary (Scheme 2), and
tertiary alcohols. However, the exclusive formations of α,α´-bis-
(benzylidene)alkanone was observed only with secondary
alcohols (Table 1).
The duration of reaction also influences the course of reaction.
The initial formation of desired products was detected after 10-15
h of the reaction. However, a further 20-40 h of stirring is
required to obtain the best yields. The reaction time profile of
representative reactions of benzaldehyde with various secondary
alcohols i.e. cyclopentanol, 2-propanol, and cyclohexanol under
ambient reaction conditions was studied and is shown in Figure
1.
Table 1. Optimization of base and alcohols for the C−C
cross coupling of secondary alcohols with benzaldehyde
Entry
Base
Alcohol
Base
(mol%)
–
Time
(h)
65
45
45
45
45
48
48
60
65
48
48
45
45
48
60
60
60
60
Yielda
(%)
–
1
–
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
Methanol
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
NaOH
KOH
tBuOK
Ca(OH)2
CaCO3
Mg(OH)2
MgCO3
5
10
25
55
35b
–
3
10
20
30
20
20
20
20
20
20
20
20
20
20
20
20
20
4
5
6
7
Ethanol
–
8
Cyclopentanol
Cyclohexanol
tert-butanol
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
60
32
–
9
10
11
12
13
14
15
16
17
18
45
23b
31b
40
–
–
–
–
aReaction conditions: benzaldehyde (0.212 g, 2.0 mmol), alcohol (excess, 15
mL), base.
Figure 1. Time profile of base promoted C−C coupling of
benzaldehyde with cyclopentanol/2-propanol/cyclohexanol.
bStarting material consumed; desired product as minor and Cannizzaro
reaction product as major product is observed.
This study reveals that maximum conversion can be achieved
in 45-50 h, increasing the time of the reaction with keeping the
amount of base constant does not bring significant changes to the
product yield, even after 60 h. This reaction has also been
investigated at high pressure using either Argon or N2 at 20 bar
and at 100 °C in an autoclave. A slight improvement in the yield
of the desired product was observed whilst maintaining similar
reaction parameters.
It was also observed, that cyclopentanol is a slightly better
reactant and solvent compared to other secondary alcohols i.e., 2-
propanol and cyclohexanol (Entry 8, Table 1). It was noted that
the reaction does not proceed using 1° and 3°-alcohols (Entries
6-7, Table 1). This indicates that secondary alcohols containing a
β-hydrogen is an elementary prerequisite for this transformation.
The presence of an alkali base is an essential necessity for this
transformation and it was observed that the reaction does not
initiate in the absence of an alkali base (Entry 1, Table 1). The
reaction was further explored using various alkali and alkaline
earth metal bases, and it was found that K2CO3 is the most
suitable base for this catalytic reaction, resulting in good yield of
To examine the scope of the present coupling reaction,
different combinations of secondary alcohols with benzaldehyde
and various substituted benzaldehydes were explored. This is
summarized in Table 2.

3
Table 2. Base promoted C−C cross coupling of secondary alcohols with aryl-aldehydes for synthesis of diarylidene ketones
The transformations proceeded efficiently and give the desired
bis-benzylidene ketones with various alcohols and aldehydes.
However, the group bonded to the benzene ring influences the
yield of the desired products. An electron-donating group bonded
to the benzene ring favours high conversions (in the range 68–
82%) for 3b, 3f, 3g, 3k, 3i, 3j, 3m, and 3n. In contrast, the yield
of products remarkebly reduced (up to 35% for 3s) when an
electron-withdrawing group is attached to benzene ring. For the
ferrocene-based substrates, the yield of products range between
moderate to average, i.e. for 3u and 3t 58% and 35%,
respectively. The reaction of ferrocene-aldehyde and
cyclohexanol yielded only a trace amount (1-2%) of the desired
product. This may be due to the bulkier nature of ferrocene,
which can sterically hinder the formation of the desired product.
spectrometry. FT-IR spectra of the product show the stretching
frequencies between 3100-3000 cm–1, 1711-1640 cm–1 and 1640-
1606 cm-1 for the C-H (alkene), C=O (carbonyl) and C=C
(alkene) functional entities, respectively. This confirmed the
1
basic skeleton of bis-benzylidene alkanones. In the H NMR
spectra, doublets for the α and β C-H protons of α,β-unsaturated
ketones appear in the range δ 6.58-7.33 ppm and δ 7.37–8.04
ppm, respectively. The vicinal coupling constants (3JH–H) in the
range 12-18 Hz, confirm the trans configuration of the alkene
hydrogens in the product.18 Mass spectral analysis of the
compounds further support the formation of the desired products
and also confirm the exact composition of the compounds.
Details of the spectral analysis have been provided separately in
the Supplementary Material.
All coupling products were structurally characterized using
FT-IR, 1H NMR and 13C NMR spectroscopy and mass
For the afore-mentioned C−C coupling reactions, we have
proposed a mechanistic pathway, depicted in Scheme 3.

4
Tetrahedron
isolated, and characterized through FT-IR, NMR and mass
spectral analyses.
Acknowledgments
R. K. J. and G. S. S. thank DST-NRF for providing Indo-
South African joint research grant no. DST/INT/South Africa/P-
09/2014. N.S. and K.N.S. thank CSIR (01(2760)/13/EMR-II) and
SERB (YSS/2015/000698), respectively for providing the
fellowships. Authors also thank to MRC, MNIT Jaipur for
providing characterization facilities.
References and notes
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Scheme 3. Plausible mechanism for base catalyzed C-C cross
coupling of secondary alcohol and aldehydes
3.
4.
5.
6.
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It has been assumed that a combinatory mechanism involving
the well-understood Meerwein-Ponndorf-Verley (MPV)19
reduction, reverse Oppenauer oxidation20 and Claisen-Schmidt
condensation21 is responsible for the final outcome of this
reaction. Most probably, the secondary alcohol is first converted
into an alkoxide in the presence of a base e.g., K2CO3 or
potassium iso-propoxide. It transfers a hydride to the carbonyl of
benzaldehyde through MPV reduction type six-membered
concerted mechanism resulting in acetone and this immediately
initiates the Claisen-Schmidt condensation reaction with
benzaldehyde and providing the diarylidene ketones. Moreover,
the MPV reduction is reversible and has the ability to undergo
the reverse Oppenauer oxidation. Thus, the reaction runs under a
thermodynamic equilibrium with the ratio of the products related
to their relative thermodynamic stabilities.
7.
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9.
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YJ, Shi L, Cao K. Adv. Synth. Catal. 2008; 350:2189–2193.
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E. J. Org. Chem. 2007; 72:9376–9378. (b) Lee J, Ryu T, Park S,
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18. Williams DH, Fleming, I. Table 3.27", Spectroscopic Methods in
Organic Chemistry (4th rev. ed. McGraw-Hill, 1989.
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Synthesis 1994:1007–1017. (b) Nishide K, Node M. Chirality
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3. Conclusion
A base-catalyzed, mild and very feasible methodology for the
catalytic
synthesis
of
biological
important
bis-
(benzylidene)alkanones from readily available secondary
alcohols and aryl/ferrocenyl-aldehydes, has been developed. The
presented method can be considered as one of the favored and
conventional methods, since the ultimate goal of the current
research was to develop economically viable and metal-free
reactions using simple and easily available reagents for bulk
synthesis of organic products. Moreover, the use of secondary
alcohols in place of alkanones can serve as alternatives for the
Claisen-Schmidt condensation reactions.
General procedure for the catalytic reaction. In an oven-
dried 100 mL two neck flask, mixture of aryl-aldehyde (2.0
mmol), K2CO3 (20.0 mol%) and secondary alcohol (15 mL) was
heated at 90 °C with continuously stirring for 45-60 h under
aerobic reaction conditions. Progress of the reaction was
continuously monitored on TLC until the maximum conversion
of aldehyde to the desired product observed. After completion,
the reaction mixture was cooled to room temperature and a
yellow/orange compound was extracted with ethyl acetate (2 ×
25 mL). This extract was further washed with water and dried
over anhydrous Na2SO4. Finally, the solvent was reduced through
rotary evaporator. Obtained crude product was further purified by
column chromatography on silica gel using ethyl acetate/hexane
as eluent. A dark orange band (for ferrocene derivatives) and a
light yellow oily band (for benzaldehyde derivatives) was

5
Supplementary Material
Supplementary material has been provided separately.
Highlights
 Base-catalyzed formation of α,α´-bis-
(benzylidene) alkanones using sec-alcohols.
 Alternative route for Claisen-Schmidt
condensation products without using
alkanones.
 C−C cross coupling of sec-alcohols and
aryl-aldehydes with no use of transition
metal catalyst or additives.