N-Heterocyclic carbene catalyzed intramolecular crossed aldehyde-ketone benzoin condensation in the chalcone of o-phthalaldehyde: A facile synthesis of naphthalenones

Article abstract of DOI:10.1016/j.tetlet.2011.05.070

The intramolecular crossed aldehyde-ketone benzoin condensation in the chalcone of o-phthalaldehyde (OPA) catalyzed by N-heterocyclic carbene (NHCs) generated in situ from readily available imidazolium and thiazolium salts is described. In this reaction,

Full text of DOI:10.1016/j.tetlet.2011.05.070

Tetrahedron Letters 52 (2011) 3828–3831
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N-Heterocyclic carbene catalyzed intramolecular crossed aldehyde–ketone
benzoin condensation in the chalcone of o-phthalaldehyde: a facile synthesis
of naphthalenones
Shravankumar Kankala a, Ravikrishna Edulla a, Sarangapani Modem a, Ravinder Vadde a,
,
⇑
Chandra Sekhar Vasam b,
⇑
a Department of Chemistry, Kakatiya University, Warangal 506 009, India
b Department of Chemistry, Satavahana University, Karimnagar 505 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The intramolecular crossed aldehyde–ketone benzoin condensation in the chalcone of o-phthalaldehyde
(OPA) catalyzed by N-heterocyclic carbene (NHCs) generated in situ from readily available imidazolium
and thiazolium salts is described. In this reaction, bicyclic a-hydroxyl ketones (naphthalenone type ter-
tiary alcohol) were selectively produced in good yields (75–94%) in shorter reaction times (20 min)
through nucleophilic addition of acyl anion generated by umpolung in OPA–chalcone (regio controlled).
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 March 2011
Revised 14 May 2011
Accepted 16 May 2011
Available online 20 May 2011
Keywords:
N-Heterocyclic carbene
Intramolecular benzoin condensation
Umpolung
o-Phthalaldehyde
Naphthalenone
Umpolung (polarity inversion) in carbonyl compounds
catalyzed by organo N-heterocyclic carbene catalysts (NHCs) is a
versatile transformation to process traditional C–C bond formation
via unconventional reaction path both in nature and laboratory
in 1958 first recognized that the NHCs could also serve all these
roles similar to that of cyanide ion in benzoin condensation,5 and
NHCs are better nucleophiles and leaving groups than cyanide.
Nevertheless, the discovery of stable carbenes6 by Arduengo in
1991 provided the access to develop a variety of NHC catalysts7
for benzoin condensation.
chemistry.1 The transformation of
a-keto acids to the correspond-
ing carbonyl anions by an NHC derived from thiamine (vitamin B1)
is one of the best example for this concept, which inspired the
related chemical processes.2 Depending on the nature of aldehyde,
either acyl anion or homoenolate anion synthones were found to
form via the addition of NHC during these catalytic cycles.
Benzoin condensation is a kind of umpolung process, which can
be achieved by generating an acyl anion equivalent from an
aldehyde moiety of a molecule which adds to a second aldehyde
moiety of another molecule (intermolecular) or keto/aldehyde
moiety in the same molecule (intramolecular).1a,3 Liebig in 1832
first discovered the intermolecular benzoin condensation cata-
lyzed by cyanide salts.4 Cyanide ion can serve four distinct roles,
namely, (i) high nucleophilic activity, (ii) facilitating the proton
transfer, (iii) ability to stabilize the negative charge in active alde-
hyde intermediate, and (iv) ability to depart finally. Later, Breslow
As compared to the investigations on intermolecular benzoin
condensation,1a,2b,8 intramolecular benzoin condensation reac-
tions, while known, only represent a small portion of the litera-
ture.9 Nevertheless the contributions by Enders and Suzuki are
much interesting.10 This is due to the rarity of suitable dicarbonyls
for the intramolecular reaction to take place. Among these reac-
tions, aldehyde–ketone cross benzoin condensation appears to be
worth studying. We planned to investigate the intramolecular
crossed benzoin condensation in some pre-synthesized chalcones
(aldehyde–ketone) (1a–j) of o-phthaladehyde (OPA) using an
organo-NHC catalyst. The formation of C–C bond in this reaction
will lead to carbocylization via umpolung mechanism to produce
naphthalenone type metabolites. Previously, hydroxylative dearo-
matization and oxygenation of phenols and naphthaols were used
to obtain these targets.11 Earlier, we have reported the application
of OPA as a good starting material in the synthesis of quinazolines
and Schiff base ligands and their biological and catalytic studies.12
Regarding other reports on OPA–chalcone, selective reduction of
enone and imine of OPA–chalcone to carbocycles and heterocycles
using organoiodotin hydride has been reported.13
⇑
Corresponding authors. Tel.: +91 878 2255911; fax: +91 878 2255933 (C.S.V.);
tel.: +91 870 2461419; fax: +91 870 2438800 (R.V.).
E-mail addresses: ravichemku@rediffmail.com (R. Vadde), vasamcs@yahoo.co.in
(C.S. Vasam).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.070

S. Kankala et al. / Tetrahedron Letters 52 (2011) 3828–3831
3829
Table 1
Cl
N
Cl
Optimization of reaction conditions for intramolecular benzoin condensation of OPA–
chalcone (1a)
N
N
N
N
But
tBu
OH
Cy
Cy
O
i
ii
NHC Precursor
DBU, DCM, rt
H3C
Cl
CHO
Cl
OH
O
N
S
N
Propi
iProp
Bn
1a
2a
iii
iv
Entry
NHC precursor
Reaction time (min)
GC yield (%)
Figure 1. NHC precursors investigated in the present work.
1
2
3
4
i
20
20
25
30
90
92
85
83
ii
iii
iv
In the present work we describe the application of OPA–
chalcone as a substrate to study the intramolecular crossed alde-
hyde–ketone benzoin condensation. In general, the condensation
reaction between simple mono aryl-aldehydes and acetopheneone
gives a common chalcone, that is, a,b,-unsaturated ketones. How-
ever, the present task needs an additional aldehyde functionality
condensation reaction of OPA and various acetophenones in alka-
line medium has provided the desired chalcones (1a–j).
on chalcone to initiate the cyclization process. In this respect, the
Table 2
Organo-NHC catalyzed intramolecular benzoin condensation of OPA–chalcones (1a–j)a
Entry
1
OPA–Chalcone (1a–j)
Naphthalenone (2a–j)
Reaction time (min) (yield, %)b
20 (92)
O
OH
O
CHO
O
HO
OH
CH3
2
3
20 (94)
22 (84)
OH
CHO
O
CH3
CH3
O
H3C
OH
CHO
CHO
O
O
O
CH3
CH3
4
180 (34)c
OH
OH
OH
OH
OH
O
CH3
5
6
18 (90)
20 (85)
CHO
CHO
CH3
OCH3
O
O
H3CO
O
O
O
O
O
O
O
OCH3
7
8
20 (85)
22 (76)
22 (75)
20 (80)
CHO
CHO
CHO
CHO
OCH3
Cl
Cl
Br
Br
9
OH
OH
O
O
O
O
O
O
10
a
b
c
All products were characterized by IR, 1H/13C NMR and mass spectral analysis.
Determined by GC.
Et3N as a base.

3830
S. Kankala et al. / Tetrahedron Letters 52 (2011) 3828–3831
At first, we investigated the intramolecular crossed benzoin
O
condensation in the chalcone 1a using four different readily
available azolium salts (imidazolium/thiazolium) as NHC catalyst
precursors (i–iv, Fig. 1) to optimize the reaction conditions and
to investigate the role of NHC ligand on the rate of the reaction.
The details of the reactant and product yields are shown in Table
1. A base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used to
generate NHC catalysts in situ in DCM at room temperature via
the deprotonation of C2-proton of azolium salts. The three imi-
dazolium salts (i–iii) were synthesized according to the procedure
described by Arduengo,14 whereas the thiazolium salt (iv) is com-
mercially available.
In order to suppress the side reactions such as possible base-
catalyzed aldol reaction of 1a by DBU, NHC catalyst was generated
in situ before the addition of 1a in DCM. The in situ generated NHC
was then allowed to react with 1a. Upon careful observation, we
have noticed that the benzoin condensation reaction was accom-
plished smoothly within 20 min turning the reaction solution to
a wine red color under simple stirring at room temperature as
determined by TLC. It is noticeable that there was no reaction with-
out organo-NHC catalyst. All the four NHCs generated in situ from
azolium salts efficiently catalyzed the benzoin condensation and
provided opportunity to afford selectively the naphthalenone
(bicyclic tertiary alcohol) product (2a) in reasonably good yields
(83–92% GC, Table 1).15 Further, no intermolecular benzoin con-
densed product was observed in the above work. Besides, when
Et3N was used as a base, very less yield of 2a (Table 2, entry 4)
was noted, indicating the influence of the base.
Ar
But
But
O
N
DBU
N
N
N
tBu
tBu
H
But
Ar
Ar
OH
N
N
O
O
O
But
H
But
Ar
N
N
O
HO
But
Scheme 2. A plausible mechanism for the formation of naphthalenones.
mation of a six-membered cyclic transition state,1a,9b–d which leads
to form the final products, that is, 2-hydroxy-2-aryl-2H-naphtha-
len-1-ones.
In summary, we have developed a facile one-pot synthetic route
to obtain naphthalenone based bicyclic tertiary alcohols in good
yields from OPA–chalcone via intramolecular aldehyde–ketone
crossed benzoin condensation reaction catalyzed by NHC-pro-
moted umpolung mechanism. The use of Ag(I)–NHCs as precursors
to provide free NHC catalyst to study the benzoin condensation is
under progress.
The formation of product 2a was determined by IR, mass, 1H
and 13C NMR spectroscopic data. For instance, the disappearance
of aldehydic proton of chalcone and the appearance of new hydro-
xyl proton in 1H NMR spectral analysis supports the formation of
condensed product (2a). Despite the fact that the aldehyde–ketone
crossed benzoin condensation is unfavorable compared with con-
ventional aldehyde–aldehyde benzoin condensation the target
compound 2a is a bicyclic tertiary alcohol having a quaternary ste-
reo centre.
Acknowledgments
The authors thank the University Grant Commission (UGC,
F. No. 34-363/2008(SR)), New Delhi, India for the financial support.
The authors also thank Professor A.J. Arduengo and Professor I.J.B.
Lin for their suggestions on NHC chemistry.
After the above effort, the intramolecular crossed benzoin
protocol was extended to study other OPA–chalcones (1b–j)
(Scheme 1). The investigations were carried out by using only
the imidazolium salt (ii) as NHC precursor. Similar to the reaction
of 1a, the proposed reactions of 1b–j were also accomplished
smoothly and produced selectively the desired bicyclic tertiary
alcohols (naphthalenones 2b–j) in good yields (GC, 75–94%, Table
2), which are further analyzed and confirmed by IR, mass, and
NMR spectroscopies.
Based on the above results obtained, a possible umpolung
mechanism involved in the intramolecular benzoin condensation
of abovementioned chalcone is proposed and is depicted in Scheme
2. The NHC generated in situ will attack the aldehyde functionality
of chalcone via nucleophilic addition and form initially a homoen-
olate. The hydrogen bond formed now between enol hydrogen and
carbonyl oxygen of keto-group of homoenolate intermediate
before the nucleophilic attack of the ketone will facilitate the for-
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic characterization) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.05.070.
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Scheme 1. Organo-NHC catalyzed intramolecular crossed aldehyde–ketone ben-
zoin condensation reaction.

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the reaction solution to
a wine red color under simple stirring at room
temperature. The reaction was quenched with saturated aqueous NH4Cl. The
product was extracted with DCM (2 Â 20 ml). The combined organic layers
were dried (anhydrous Na2SO4) and evaporated under reduced pressure to
afford a crude product which was subjected to chromatography (silica gel,
60–120 mesh, eluent; n-hexane/EtOAc gradient) to afford pure 2-hydroxy-
2-phenyl-2H-naphthalen-1-one (2a) as
a light brown solid mp 91–92 °C
(0.217 g, 92%). IR (KBr, cmÀ1): 3426, 3020, 1690, 1600, 1025, 756 and 695. 1H
NMR (200 MHz, CDCl3): d 4.52 (s, 1H), 6.12 (d, 1H), 6.82 (d, 1H), 7.12–7.18 (m,
5H, Ar–H), 7.45–7.56 (m, 4H, Ar–H); 13C NMR (50 MHz, CDCl3): d 88.21, 126.52,
126.80, 127.22, 127.54, 127.94, 128.30, 129.25, 130.44, 132.63, 134.32, 135.60,
135.81, 176.42; MS (EI, 70 eV): m/z (%) 259 [M+Na]+. EA calcd for C16H12O2:
(236.08): calcd C 81.34, H 5.12; found C 81.33, H 5.10.