A sequential synthesis of substituted furans from aryl alkynes and ketones involving a cerium(IV) ammonium nitrate (CAN)-mediated oxidative cyclization

Article abstract of DOI:10.1016/j.tetlet.2014.08.039

A convenient, two-step synthesis of substituted furans from readily available aryl alkynes and ketones is reported. The furan-forming oxidative cyclization is mediated by the combination of cerium(IV) ammonium nitrate and potassium bromide and can be carried out in an open flask.

Full text of DOI:10.1016/j.tetlet.2014.08.039

Tetrahedron Letters 55 (2014) 5667–5670
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A sequential synthesis of substituted furans from aryl alkynes and
ketones involving a cerium(IV) ammonium nitrate (CAN)-mediated
oxidative cyclization
⇑
Sridhar Undeela, Joshi P. Ramchandra, Rajeev S. Menon
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient, two-step synthesis of substituted furans from readily available aryl alkynes and ketones is
reported. The furan-forming oxidative cyclization is mediated by the combination of cerium(IV) ammo-
nium nitrate and potassium bromide and can be carried out in an open flask.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 7 July 2014
Revised 6 August 2014
Accepted 9 August 2014
Available online 14 August 2014
Keywords:
Furans
Cerium(IV) ammonium nitrate
Oxidative cyclization
Alkynes
Ketones
Furans constitute a ubiquitous class of heterocycles widely
found in a variety of biologically active natural products and
man-made molecules alike.1 The furan unit is also a versatile build-
ing block for the synthesis of various cyclic and acyclic com-
pounds.2 They also form key structural units which impart the
desired properties in functional materials.3 As a consequence, the
synthesis of substituted furans has attracted a lot of attention.4
The cyclocondensation of 1,4-dicarbonyl compounds, known as
the Paal–Knorr furan synthesis is one of the oldest and most widely
used methods for the construction of 2,5-disubstituted furans.
Paal–Knorr synthesis often involves the use of strong acids and
harsh conditions such as microwave heating.5 Transition-metal
mediated cycloisomerization of alkynyl and allenyl substrates
bearing a suitably placed oxa-substituent is an important modern
method for furan synthesis.6 The synthesis of unsymmetrically
substituted furans, however, requires non-trivial, multi-step
assembly of the appropriate 1,4-dicarbonyl compound1c (Paal–
Knorr) or the oxa-alkyne/allene(cycloisomerization).6c In this con-
text, a two-step synthesis of 2,5-diarylfurans from aryl alkynes and
alcohols developed by Beller, Dixneuf, and co-workers is notewor-
thy (Scheme 1, Eq. 1).7 This method employs sequential ruthenium
and copper catalysis and 2,5-diarylfurans are generated from read-
ily available aryl alkynes. However, only symmetrically substituted
2,5-diarylfurans can be accessed by this method which requires
the use of a rather expensive ruthenium catalyst.
Recently, Trofimov and co-workers reported
promoted
-vinylation of ketones using aryl alkynes.8 The reaction
affords b, -unsaturated ketones 3 (Scheme 1, Eq. 2) which remark-
ably, do not isomerize to the ,b-unsaturated analogs and thereby
a superbase-
a
c
a
offer avenues for annulations9 involving the ketone oxygen func-
tionality and the olefin unit. We surmised that such an annulation
reaction may be triggered by electrophilic activation of the olefin
moiety in 3. Our studies along this direction using halogen electro-
philes culminated in the development of an operationally simple
and sequential synthesis of substituted furans 4 (Scheme 1, Eq.
2). The results of our investigations are presented in the following
sections.
The b,c-unsaturated ketone 3a prepared from phenyl acetylene
and acetophenone was subjected to treatment with various halo-
gen electrophiles. Initially, a one-pot approach was explored
wherein the halogen-containing reagents were added to the reac-
tion mixture containing 3a directly. Addition of N-bromosuccini-
mide gave no reaction whereas addition of iodine resulted in the
formation of a number of unidentified products (Table 1, entries
1–2). Nair has reported that the combination of potassium bromide
and cerium(IV)ammonium nitrate (CAN) is a convenient and effi-
cient means to brominate alkenes.10 This method, when employed
as a one-pot procedure, afforded 2,5-diphenylfuran 4a as the only
isolable product in low yields (entry 3). Pleasingly, an isolated sam-
ple of 3a reacted with CAN-KBr combination to afford the furan 4a
⇑
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189.
E-mail address: srajeevmenon@gmail.com (R.S. Menon).
http://dx.doi.org/10.1016/j.tetlet.2014.08.039
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5668
S. Undeela et al. / Tetrahedron Letters 55 (2014) 5667–5670
R3
R2
Prior work (Beller & Dixneuf)
R2
R3
O
CAN, KBr
R1
CH2Cl2-water
Ru(II) cat.
+
R1
MeOH
2
O
rt, open flask
2h
R1
THF, rt
Ref. 7
R1 OMe
R1
4a-i
3a-m
42-92%
p-TSA,
CuCl2
3a, R1, R2 = Ph; R3 = H
, R = Ph, R = 2-naphthyl; R = H
, R = Ph, R = 4-tolyl; R = H
(1)
R1
R1
O
1
2
3
3b
3c
3d
air, 70 °C
1
2
3
a) Only symmetrical diaryl
furans can be made
1
2
3
, R = Ph, R = 4-fluorophenyl; R = H
b) Expensive Ru catalyst
3e, R1= Ph, R2 = 4-biphenyl; R3 = H
3f, R1= Ph, R2 = 4-methoxyphenyl; R3 = H
This work
1
2
3
3g
R2
, R , R = Ph; R = Me
O
3h, R1= 4-ethylphenyl, R2 = 2-naphthyl; R3 = H
3i, R1= 4-fluorophenyl, R2 = 4-tolyl; R3 = H
O
t-BuOK
DMSO
R3
R2
+
R1
1
R
100 °C
30 min.
R3
3
R1
2
1 = aryl
Ref. 8
Ph
Ph
Ph
Ph
O
O
R3
R2
CAN, KBr
4a, 75%
CH2Cl2-water
R1
(2)
4b, 60%
O
4
rt, open flask
a) Different substituents
b) Operationally simple
c) Readily available starting
materials
Ph
O
O
F
Me
a
4d
, 60%
4c, 86%
Scheme 1. Synthesis of 2,5-disubstituted furans from alkynes.
Ph
Table 1
Reaction of b,
Ph
O
O
c
-unsaturated ketone 3a with electrophilic halogen sources
Ph
F
4d, 55%b
4e, 42%
Ph
O
O
t-BuOK
DMSO
Me
+
Conditions
Ph
Ph
Ph
Ph
O
100 °C
O
Ph
O
OMe
F
1a
2a
Ph
4a
3a
4g, 51%
4f, 45%
Et
No. Conditions
Yield/result
1a
2a
1.5 equiv NBS, rt, 12 h
1.5 equiv I2, rt, 12 h
No reaction
Unidentified
products
10% (4a)
49% (4a)
69% (4a)
75% (4a)
Mostly 3a
21% (4a)
35% (4a)
O
O
3a
4b
5b
6b
7b
8b
9b
3.0 equiv CAN, 3.0 equiv KBr, rt, 2 h
1.5 equiv CAN, 1.5 equiv KBr, rt, 2 h
2.0 equiv CAN, 2.0 equiv KBr, rt, 2 h
3.0 equiv CAN, 3.0 equiv KBr, rt, 2 h
2.3 equiv CAN, rt, 12 h
1.5 equiv Br2, CH2Cl2, rt, 6 h
0.1 equiv p-TSA, 0.1 equiv CuCl2, Toluene, O2,
70 °C
4h
, 48
Me
%
4i, 92%
aformed from 4'-fluoroacetophenone and phenyl acetylene;
b formed from acetophenone and 4-fluorophenyl acetylene;
a
One-pot operation starting from 1a and 2a in DMSO.
Reactions carried out with isolated 3a in CH2Cl2-water.
Scheme 2. Sequential synthesis of substituted furans; yields of isolated products
listed.
b
in 75% yield under optimized conditions (entry 6).11 Since the
furan 4a was the outcome of an oxidative cyclization of 3a and
contained no bromine, the reaction was attempted in the absence
of KBr, however, without success (entry 7). Furan 4a was obtained
in low yield along with unidentified side products when 3a was
treated with bromine (entry 8) as well as when 3a was subjected
to the conditions of oxidative cyclization as reported by Beller7
(entry 9).
The oxidative cyclization reaction seems to be quite general as
it proceeded readily to afford a variety of 2,5-disubstituted furans
4a–i. The combination of phenylacetylene/40-fluoroacetophenone
and 4-fluorophenylacetylene/acetophenone afforded the same
4-fluorophenyl bearing furan 4d. The trisubstituted furan 4g is
accessible in two steps from propiophenone and phenylacetylene.
Aryl-substituted phenylacetylenes could also be successfully
employed in the sequential synthesis to furnish the 2,5-diarylfuran
derivatives 4d, h, i.
The generality and scope of the furan synthesis was then
explored under the optimized reaction conditions. An assortment
Interestingly, the oxidative cyclization was followed by site-
selective ring bromination in a few cases (Scheme 3). b,c-Unsatu-
of b,c
-unsaturated ketones 3a–m was prepared8a,b,12 and subjected
to the oxidative cyclization. The results are summarized in
rated ketones (3k–m) underwent oxidative cyclization and ring
Scheme 2.
bromination under the reaction conditions to afford the products

S. Undeela et al. / Tetrahedron Letters 55 (2014) 5667–5670
5669
O
via loss of HBr to afford the furan 4a (Scheme 4). It is important to
note that atmospheric oxygen does not interfere in the reaction
even though it is carried out in an open flask. Additionally, when
the reaction was run separately in the presence of radical scaveng-
ers (TEMPO and p-benzoquinone) no significant decrease in the
yield of the product 4a was observed (69% and 74%, respectively
compared to 75% in the absence of radical scavenger). These obser-
vations suggest that the involvement of any carbon-centered radi-
cal (formed by the addition of bromine radical to the olefin in 3a)
may be ruled out. The site-selectivity of bromination in 5b–c
indicates that the aromatic bromination most likely proceeds after
the furan ring is formed (the keto group present in 3l–m should
disfavor the bromination at the observed positions).
In conclusion, a facile and operationally simple synthetic route
to furans has been developed. A variety of substituted furans can
be accessed in two steps from commercially available aryl alkynes
and ketones thus alleviating the need for a lengthy substrate syn-
thesis. Moreover, the oxidative cyclization can be run in aqueous
dichloromethane in an open flask. The 2,5-diarylfuran unit present
in 4a–i is an important structural fragment found in a number of
anticancer14 and anti-inflammatory1d compounds. Additionally,
the products 5a–c of the site-selective bromination offer synthetic
opportunities for further functionalization of the aryl rings via the
Br
Ph
MeO
MeO
CAN, KBr
O
MeO
MeO
CH2Cl2-water
rt, 2h
30%
OMe Ph
OMe
3k
5a
O
CAN, KBr
CH2Cl2-water
rt, 2h
53%
Ph
O
Me
O
S
O
Me
Br
Ph
O
3l
5b
CAN, KBr
CH2Cl2-water
rt, 2h
Ph
O
S
Br
56%
Ph
3m
5c
Scheme 3. Tandem oxidative cyclization-ring bromination of electron rich
substrates.
Ph
radicals
combine
O
2 Ce(IV)
2 Ce(III)
2 Br
well-established
metal-mediated
coupling
reactions
of
2 Br
'Br2'
Ph
bromoarenes.15
3a
Efforts to apply this method in the synthesis of a library of
furans for medicinal chemistry applications and extension of this
methodology to pyrrole synthesis are currently underway.
Br
Br
Ph
Ph
Ph
O
O
-HBr
Ph
O
Ph
Ph
Acknowledgments
6
7
4a
Financial support from the Department of Science and Technol-
ogy (DST), India in the form of a Ramanujan fellowship and a fast-
track project to RSM is acknowledged. Financial support in part
from the XII five year plan project ‘‘Affordable Cancer Therapeutics
(ACT)’’ (CSC 0301) and Research Fellowships for JPR and SU from
the Council of Scientific and Industrial Research (CSIR), India are
also acknowledged.
Scheme 4. A mechanistic hypothesis for oxidative cyclization.
5a–c. For example, the highly electron rich trimethoxyphenyl unit
of 3l was brominated selectively to afford the product 5a. The 1H
NMR spectrum of 5a exhibited resonances corresponding to the
furan hydrogens as mutually coupled (J = 3.4 Hz) doublets at
d 7.22 and 6.79. The singlet resonance at d 7.25 is attributed to
the lone hydrogen on the bromo-trimethoxyphenyl ring. In the
13C NMR, the bromine-carrying carbon resonated at d 107.2.
Similarly, in the 1H NMR spectrum of 5b, two mutually coupled
doublets of the central furan ring were observed at d 6.81 and
6.72. The lone hydrogen on the methylfuran ring resonated as a
multiplet at d 6.14–6.13 due to coupling with the methyl group
on the adjacent carbon. Additionally, the bromine-bearing carbon
resonated at d 95.9 in the 13C NMR spectrum.
Supplementary data
Supplementary data (experimental procedure, product charac-
terization and 1H and 13C NMR spectra for all the new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.08.039.
It is notable that the cyclization-bromination sequence
observed in 3k–m is selective in two ways. Bromine is incorpo-
rated on only one out of the two aryl rings of 3k–m (trimethoxy-
phenyl, methylfuranyl, and thienyl). It is clear that these rings
are significantly electron rich (compared to the other phenyl ring)
and this observation conforms to the known propensity of CAN to
promote ring iodination of electron rich aromatic compounds.13
Additionally, the site selectivity of bromination in 3l–m is also
noteworthy.
The exact mechanistic details of the oxidative cyclization are
not clear at this stage, however, a rationalization can be made as
follows. A comparison of the redox potentials of the Brꢀ/BrÅ
(1.03 V vs NHE) and Ce(IV)/Ce(III) (1.61 V vs NHE) systems indicate
that the cerium(IV)-mediated oxidation of bromide anion to
bromine radical is presumably the initial event.10 The bromine rad-
icals combine to produce ‘nascent’ molecular bromine which reacts
with the olefin in 3a. The benzylic carbon of the resultant bromo-
nium ion 6 is suitably placed to interact with the oxygen end of the
ketone functionality. This cyclization is followed by aromatization
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(355 mg, 3 mmol) in dichloromethane (10 mL) in an open flask at room
temperature. When the reaction was complete (TLC analysis), it was diluted
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(165 mg, 75%). mp 83–84 °C (CH2Cl2-hexane); IR (KBr)
m
max: 3037, 1610, 1488,
;
1479, 1469, 1447, 1156, 1079, 1024, 927, 911, 795 cmꢀ1
1H NMR (500 MHz,
CDCl3) d 7.76–7.74 (4H, m), 7.43–7.39 (4H, m), 7.29–7.26 (2H, m), 6.75 (2H, s);
13C NMR (125 MHz, CDCl3) d 153.3, 130.7, 128.7, 127.3, 123.7, 107.2; HRMS
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