CBr4 as a Halogen Bond Donor Catalyst for the Selective Activation of Benzaldehydes to Synthesize α,β-Unsaturated Ketones

Article abstract of DOI:10.1021/acs.orglett.7b00348

CBr₄ has been employed as a halogen bond donor catalyst for the selective activation of aldehyde, to achieve an efficient solvent- and metal-free CC bond forming reaction in the presence of strong acid sensitive groups such as methoxy, cyanide, ester, and ketal for the synthesis of α,β-unsaturated ketones. This unique capability of CBr₄ to act as a halogen bond donor has been explored and established using UV-vis as well as IR spectroscopy. Moreover, this unprecedented methodology enables the synthesis of the pharmaceutically important molecule licochalcone A.

Full text of DOI:10.1021/acs.orglett.7b00348

Letter
pubs.acs.org/OrgLett
CBr4 as a Halogen Bond Donor Catalyst for the Selective Activation
of Benzaldehydes to Synthesize α,β-Unsaturated Ketones
Imran Kazi, Somraj Guha, and Govindasamy Sekar*
Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600036, India
S
* Supporting Information
ABSTRACT: CBr4 has been employed as a halogen bond
donor catalyst for the selective activation of aldehyde, to
achieve an efficient solvent- and metal-free CC bond
forming reaction in the presence of strong acid sensitive
groups such as methoxy, cyanide, ester, and ketal for the
synthesis of α,β-unsaturated ketones. This unique capability of
CBr4 to act as a halogen bond donor has been explored and established using UV−vis as well as IR spectroscopy. Moreover, this
unprecedented methodology enables the synthesis of the pharmaceutically important molecule licochalcone A.
ketone9e and the synthesis of α-amino phosphonate via a
nonbonding interaction can be defined as a weak
Aelectromagnetic interaction between two molecules three-component reaction.9d
which does not involve the sharing of electrons.1a Studies on
We envisioned that CBr4, having vacant d and f orbitals in its
bromine atoms, can be used as an easily available halogen bond
donor catalyst to accomplish the synthesis of α,β-unsaturated
ketones via selective activation of benzaldehyde in the presence
of acid- and base-sensitive groups such as esters, cyanides,
ketals, etc. (Figure 1).
these weak interactions, which play crucial roles in biological
processes,1b have so far been limited in the field of
supramolecular chemistry spanning the areas of molecular
self-assembly, host−guest chemistry, molecular recognition,
etc.1c With only a few reports on hydrogen bond donor and
halogen bond donor catalysts, these interactions still remain
largely unexplored in the field of catalysis.2 These catalysts offer
mild but selective activation of a particular functional group as a
consequence of its weak interaction with the substrates.
It is a well-known fact that Lewis bases form adducts with
compounds having electrophilic halogens.3 The investigation of
such noncovalent interactions, which have recently been named
as halogen bonding, and their subsequent application in the
field of chemistry have come to the forefront in the past
decade.4 Just as thiourea derivatives take part in the activation
of electrophilic substances such as carbonyls via hydrogen
bonding, halogen bond donor catalysts, a new member in the
field of organocatalysis, may take part in carbonyl activation as
well.5 In fact, halogen bonds are stronger than hydrogen bonds
with high directionality.6
These halogen bond donor catalysts can be used as an
alternative for strong and harsh Lewis acid catalysts.7 Jungbauer
et al. reported the activation of carbonyl groups with halogen
bonding catalysis in Diels−Alder type reactions. They used a
dicationic imidazolium-based catalyst as an alternative to the
traditionally used strong Lewis acid catalysts.8 However, use of
a commercially available halogen-based reagent as a halogen
bond donor catalyst in the field of organic synthesis is still
unknown.7b
Figure 1. Activation of carbonyl group by nonbonding interaction.
α,β-Unsaturated ketones are important molecules in the field
of synthetic chemistry.10 They have antimalarial, antileishma-
nial, anticancer, anti-inflammatory, antimitotic, antitubercular,
and cardiovascular activity11 and are hence considered
medicinally important. The classic ways of preparing chalcones
include the Claisen−Schimdt reaction in the presence of a
quantitative amount of strong bases or a catalytic amount of
strong acids.12,13 However, most of the reported reagents
including the metal salts are hazardous, require harsh reaction
conditions, have less tolerance to sensitive functional groups,
and cannot be recovered.14
In addition, as organic solvents are known to have many
adverse effects on the environment, more focus and attention
are being given to solvent-free reactions. As part of our ongoing
research endeavors toward developing metal-free organic
reactions,15 herein, for the first time we report the efficiency
Recently, CBr4 has drawn the attention of chemists as a
metal-free organocatalyst.9a A stoichiometric amount of CBr4
has been used for the formation of C−S9b and S−S9c bonds. A
catalytic amount of CBr4 has been used in the cross-
dehydrogenative coupling of isocromans with aromatic
Received: February 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00348
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of CBr4 as a halogen bond donor, a recoverable catalyst for the
synthesis of chalcones from ketones and aldehydes under
solvent-free conditions (Scheme 1).
under the optimized conditions (Table 1, entry 4), and the
results are summarized in Scheme 2. A slight increase in the
a
Scheme 2. Scope of CBr4 Catalyzed Chalcone Synthesis
Scheme 1. Metal- and Solvent-Free Synthesis of Chalcones
Using CBr4 as Catalyst
Initially, 1 equiv of acetophenone 1a and 1.5 equiv of
benzaldehyde 2a in the presence of 20 mol % of CBr4 as a
catalyst under neat reaction conditions yielded 84% of the
chalcone 3aa at 60 °C in 24 h (Table 1, entry 1). Use of 1.0
equiv of 2a reduced the yield of the product 3aa to 71% (entry
2). Finally, it was inferred that 1.2 equiv of 2a was sufficient for
this reaction (entry 3).
Table 1. Optimization of CBr4 Catalyzed Chalcone
a
Synthesis
a
Isolated yield.
yield was observed in the presence of electron-donating groups
(Scheme 2, 3ba−3ea) while a significant decrease in yield was
observed when electron-withdrawing groups were present para
to the keto group of the acetophenone moiety (3fa). The
decrease in yield in the case of ortho-substituted moieties can be
attributed to steric crowding (3ea) while the decrease in the
case of 3ab with an electron-donating group can be explained
due to the reduced electrophilicity of the carbonyl group.
In contrast, good to excellent yields were obtained with
benzaldehydes having electron-withdrawing groups (entries
3ac−3ae). Moderate to good yields were obtained when
electron-rich acetophenone was reacted with electron-deficient
or -rich benzaldehydes (3bf−3cd). The yield was less when
both the acetophenones and benzaldehydes are electron-
deficient (3id−3ji). It is worth mentioning that substrates
with sensitive functional groups such as ester (3ad and 3bd−
3id), cyano (3ji and 3ae), and ketal (3hf) produced various
chalcone derivatives in good yield while keeping the functional
groups intact.16 Ketones, having bulky aromatic rings such as
naphthalene, gave good yields of product (3ka), while the yield
drastically decreased in the case of propiophenone (3la). In all
the cases, only the E-isomers formed which was confirmed by
2a
catalyst
solvent
(mL)
temp
time
(h)
yield
b
entry (equiv)
(mol %)
(°C)
(%)
1
1.5
1.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
CBr4 (20)
CBr4 (20)
CBr4 (20)
CBr4 (20)
CBr4 (20)
CBr4(10)
CBr4 (5)
neat
60
60
60
80
rt
24
24
24
36
36
36
36
22
24
24
24
24
24
24
24
24
24
84
71
2
neat
c
3
neat
86
4
neat
84
5
neat
trace
78
6
neat
60
60
60
60
60
60
60
60
60
60
60
60
7
neat
72
8
CCI4 (20)
NIS (20)
NBS (20)
CHCl3 (20)
DCE (20)
CBr4 (20)
CBr4 (20)
CBr4 (20)
HBr(10)
neat
53
9
neat
63
10
11
12
13
14
15
16
17
neat
56
d
neat
0
d
neat
0
e
EtOH
CH3CN
toluene
neat
77
53e
e
48
57
HBr(20)
neat
60
c
a
b
All the eactions are conducted in 1 mmol scale. Isolated yield. 90%
CBr4 was isolated after completion of the reaction. Reaction
conducted in pressure tube. 2 mL of solvent were used.
d
e
17
1
the H NMR spectroscopy.
β-Keto esters with the acid labile ester functionality located α
to the ketones were examined to determine the feasibility of the
reaction (Scheme 3). The ester group remained unaffected, and
We observed that there was negligible change in the yield of
the desired product 3aa when the temperature was increased
(entry 4), whereas a decrease in the temperature and catalyst
loading lowered the yield substantially (entries 5−7). To
increase the efficiency of this synthetic transformation, a range
of catalysts were further screened (entries 8−12). When CCl4
was used, the yield of 3aa reduced to 53% (entry 8). NIS and
NBS also provided less product (entries 9 and 10). The
reaction failed when CHCl3 and DCE were used as catalysts
(entries 11 and 12). Different solvents were screened in a bid to
improve the yield of 3aa (entries 13−15). It was observed that
the methodology works best in neat conditions, and polar
protic solvents such as ethanol provided better yields of 3aa as
compared to other aprotic solvents.
a
Scheme 3. Scope of of the Methodology for β-Keto Esters
To investigate the scope of the CBr4-catalyzed reaction, a
library of acetophenones and benzaldehydes were examined
a
Isolated yield.
B
DOI: 10.1021/acs.orglett.7b00348
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Organic Letters
Letter
a moderate to good yield was obtained (Scheme 3). Electron-
rich benzaldehydes gave good yields (5ak) except for the ortho-
substituted one (5ah). The presence of strong electron-
withdrawing substituents such as fluoro and nitro in
benzaldehyde decreases the yield of the product (5al−5an).
Good yields were obtained when weaker electron-withdrawing
groups such as bromo and chloro were present (5ao−5ai). In
all the cases reported thus far, a highly selective (>95%) E-
product was obtained which was proven by X-ray crystallog-
raphy of 5aa.18
with the help of IR spectroscopic experiments which showed
the emergence of a new carbonyl band at lower frequency
(1603.52 cm−1). This may be attributed to the halogen bonding
interaction of the aldehyde group with the bromine atom of
CBr4.20 Subsequently, to establish this hypothesis, a UV−vis
experiment21 was carried out with a 1:1 mixture of CBr4 and 3-
nitrobenzaldehyde22 after stirring it at 60 °C for 2 h. A broad
band around 450 to 520 nm (Figure 2, spectrum R) clearly
showed the pronounced halogen bonding interaction between
CBr4 and aldehyde group at 60 °C.20
The scalability of the reaction was also examined, and for a
10 g scale reaction (Scheme 4), the optimized reaction
Scheme 4. Gram Scale Reaction
conditions gave an 80% yield of 3aa and a 73% yield of 5aa.
Medicinally important compounds licochalcone A or oxy-
genated chalcones 8 and 11, having antileishmanial and
antimalarial activity, were prepared using this methodology
resulting in a moderate yield in the presence of acid-sensitive
groups such as methoxy and ether (Scheme 5).11
Figure 2. UV−vis experiment to support the halogen bonding
interaction between CBr4 and 3-nitrobenzaldehyde. P and Q are the
spectra for 3-nitrobenzaldehyde and CBr4. R and S are the spectra for
their 1:1 mixture at 60 °C and rt.
Scheme 5. One-Step Synthesis of Medicinally Important
Licochalcones A
On the basis of literature reports and our experimental
evidence, it has been postulated that ketone 12 undergoes
enolization to generate the enol 13 which further reacts with
the activated aldehyde 14 to form the aldol 15. Further, the
interaction of CBr4 with the hydroxyl group of aldol 15 helps in
elimination of water to yield the final chalcone and the CBr4 is
regenerated in the reaction mixture (Scheme 7).
Scheme 7. Plausible Reaction Mechanism for the α,β-
Unsaturated Ketones Synthesis
The synthetic application of chalcones has been demon-
strated by its selective reduction to saturated benzylic ketones
12 which act as important precursors for different organic
reactions. Treatment of chalcone with DBU and NBS resulted
in affording β-amino ketone 13, a Mannich base having
anticancer, antifilarial, antibacterial, and antifungal activities
(Scheme 6).19
In conclusion, a recoverable CBr4-catalyzed metal- and
solvent-free methodology has been developed to synthesize
chalcones. The methodology allows us to avoid the use of
stoichiometric amounts of bases and strong acids which may
lead to the hydrolysis of acid- and base-sensitive groups or may
lead to a competitive Cannizaro reaction. Application of this
methodology to synthesize the medicinally important molecule
licochalcone A has been successfully demonstrated. Further
studies to gain major insight into the role of CBr4 as a halogen
bond donor catalyst and the mechanism of interaction are
presently underway.
Scheme 6. Synthetic Transformation of Chalcone 3aa
The mechanism of the reaction was interpreted noting the
halogen bond donor property of CBr4. An array of experiments
were performed to rule out the possibility of the decomposition
of CBr4 to HBr, which may take part in catalyzing a background
reaction during the course of the reaction.20 Further, the
coordination of CBr4 with the aldehyde group was established
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00348.
■
S
C
DOI: 10.1021/acs.orglett.7b00348
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
Experimental methods; H and 13C NMR spectra of all
compounds (PDF)
J. V.; Garcia-Raso, A.; Cabello, J. A.; Marinas, J. M. Synthesis 1984,
1984, 502. (c) Varma, S. K.; Kabalka, G. K.; Evans, L. T.; Pagni, P. M.
Synth. Commun. 1985, 15, 279.
(13) (a) Szell, T.; Sohar, I. Can. J. Chem. 1969, 47, 1254. (b) Irie, K.;
Watanabe, K. Bull. Chem. Soc. Jpn. 1980, 53, 1366. (c) Mazza, L.;
Guarna, A. Synthesis 1980, 1980, 41. (d) Ogiwara, Y.; Takahashi, K.;
Kitazawa, F.; Sakai, N. J. Org. Chem. 2015, 80, 3101.
(14) Only a few catalysts are reported as recoverable for chalcone
synthesis, and most of them are difficult to prepare. (a) Zhang, L.;
Wang, A.; Wang, W.; Huang, Y.; Liu, X.; Miao, S.; Liu, J.; Zhang, T.
ACS Catal. 2015, 5, 6563. (b) Yi, W.-B.; Cai, C. J. Fluorine Chem.
2008, 129, 524.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gsekar@iitm.ac.in.
ORCID
Govindasamy Sekar: 0000-0003-2294-0485
Notes
(15) Guha, S.; Rajeshkumar, V.; Kotha, S. S.; Sekar, G. Org. Lett.
2015, 17, 406.
The authors declare no competing financial interest.
(16) This reaction offers tolerance to the carbomethoxy group
(COOMe) containing benzaldehydes which is only reported with
basic alumina by Pagni et al. (see ref 12c). Methoxy, cyano, and nitro
groups can deactivate the Lewis acid by coordinating with it, and
hence those groups containing benzaldehydes are unsuitable as
substrates in Lewis acid catalyzed reactions [see ref 13d].
(17) All the E- products were confirmed using the coupling constant
J value of the olefinic protons. For details, see the Supporting
Information.
(18) Hema, R.; Parthasarathi, V.; Ravikumar, K.; Sridhar, B.;
Pandiarajan, K. Acta Crystallogr., Sect. E: Struct. Rep. Online 2006, 62,
708.
(19) (a) Kalluraya, B.; Chimbalkar, R. M.; Hegde, J. C. Indian J.
Heterocycl. Chem. 2005, 15, 15. (b) Ivanova, Y.; Momekov, G.; Petrov,
O.; Karaivanova, M.; Kalcheva, V. Eur. J. Med. Chem. 2007, 42, 1382.
(20) For details see Supporting Information
ACKNOWLEDGMENTS
■
We thank DST, New Delhi (SB/S1/OC-72/2013) for financial
support. I.K. thanks IIT Madras for a fellowship. S.G. thanks
CSIR, New Delhi for the SRF. We thank Ayan Bhattacharya
and Dr. E. Prasad from IIT Madras for the UV−vis experiment.
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