Facile access to 2,5-disubstituted-4-chloromethyl-3-iodofuran derivatives via ICl-mediated cyclization of 1-alkyl-2-alkynylallylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2012.09.124

Substituted furans are conveniently synthesized from acyclic secondary 1-alkyl-2-alkynylallylic alcohol precursors via an ICl-promoted cyclization reaction. The furans generated by this method incorporate both iodine and chlorine atoms which may be useful for further elaborations via many known methods. The methodology is suitable for generating a wide array of furan products which can serve as useful building blocks for the synthesis of various biologically active molecules.

Full text of DOI:10.1016/j.tetlet.2012.09.124

Tetrahedron Letters 53 (2012) 6615–6619
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Tetrahedron Letters
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Facile access to 2,5-disubstituted-4-chloromethyl-3-iodofuran derivatives via
ICl-mediated cyclization of 1-alkyl-2-alkynylallylic alcohols
Charnsak Thongsornkleeb a,b, , Wangchuk Rabten a, Anon Bunrit b, Jumreang Tummatorn b,
⇑
Somsak Ruchirawat a,b
a Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, 54 Kamphaeng Phet 6,
Laksi, Bangkok 10210, Thailand
b Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted furans are conveniently synthesized from acyclic secondary 1-alkyl-2-alkynylallylic alcohol
precursors via an ICl-promoted cyclization reaction. The furans generated by this method incorporate
both iodine and chlorine atoms which may be useful for further elaborations via many known methods.
The methodology is suitable for generating a wide array of furan products which can serve as useful
building blocks for the synthesis of various biologically active molecules.
Received 2 September 2012
Revised 16 September 2012
Accepted 26 September 2012
Available online 2 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Furan
Conjugated enyne
Electrophilic cyclization
Iodine monochloride
Sonogashira cross-coupling
Furan is a widespread heterocyclic motif found in nature.1 It is
present in compounds used as major constituents in fragrance and
flavor components, agrochemical substances, as well as in pharma-
ceutical ingredients.2 In addition to serving as active entities in
many commercial products, furans also serve as versatile and valu-
able building blocks which can be elaborated to more complex cyc-
lic and acyclic structures of theoretical and biological interest.3
Numerous methods have been devised to construct furan
derivatives. These include intramolecular cyclization of an
oxygen-functional group onto a tethered unsaturated bond of an
appropriate length using bases,4 transition metal compounds,5
and electrophilic halogens; particularly molecular iodine (I2),
N-iodosuccinimide (NIS), and N-bromosuccinimide (NBS).6 The
products obtained using the latter methods usually contain a halo-
gen atom directly attached to the five-membered nucleus,7 which
may be further utilized. Our research emphasizes particularly the
utilization of an enyne tethered to an oxygen-functional group in
such cyclizations, which would provide a simple template for the
synthesis of functionalized furan derivatives. A number of publica-
tions have utilized acyclic oxygenated enyne precursors in such
reactions to produce efficiently polysubstituted furan derivatives.
The methodology devised for such cyclizations include the
base-promoted cyclization of enynyl alcohols of types 1 and 2,8
gold-catalyzed cyclization of enynyl alcohols9 of types 110a and
2,10b,c and gold-catalyzed and I2-promoted cascade cyclization–
nucleophilic substitution of enynyl ketones of types 3 and 4.11
Herein, we wish to report our protocol for the facile synthesis of
2,5-disubstituted-4-chloromethyl-3-iodofuran derivatives from
substituted enynyl alcohols of type 1.
We began our investigation by preparing enynyl alcohol 6a for
the optimization study. Thus hexanal was treated with lithium
TMS-acetylide in THF, followed by a standard desilylation protocol
to provide propargylic alcohol 5 in 53% yield. Sequential hydrobro-
mination12 of alcohol 5 and Sonogashira cross-coupling13 of the
resulting vinylic bromide with phenyl acetylene then furnished
the desired alcohol 6a in 41% yield over two steps (Scheme 1).
O
OH
1)
Li
TMS
H
2) K2CO3, MeOH
53%
5
Ph
OH
LiBr, TMSCl
TEAB, MeCN,
MW, 60 °C
PdCl2(PPh3)2, CuI,
Et3N, THF, reflux
6a
41% over 2 steps
⇑
Corresponding author. Tel.: +66 2 574 0622x1409; fax: +66 2 574 0622x1513.
E-mail address: charnsak@cri.or.th (C. Thongsornkleeb).
Scheme 1. Preparation of enyne 6a for the optimization study.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.124

6616
C. Thongsornkleeb et al. / Tetrahedron Letters 53 (2012) 6615–6619
furan products.11 When 2.2 equiv of ICl was employed to initiate
Table 1
Screening for the optimal cyclization conditions of 6a
the cyclization in acetone, the reaction proceeded to completion
very rapidly and we were able to isolate a product. Initially, furans
7a–I was anticipated from the reaction. However, the product iso-
lated was found to be furan 7a14 which was obtained in 29% yield
(entry 5). Observing this positive outcome with ICl, we proceeded
to investigate the effect of different solvents on this cyclization
reaction (entries 6–14).
O
OH
electrophilic halogen
solvent, temperature
X
I
7a
6a
;
X = Cl
7a-I; X = I
Entry
Solvent
Reagent (equiv)
Yielda (%)
In acetonitrile, enyne 6a was converted cleanly to give furan 7a,
albeit in only 33% yield (entry 6). In nitromethane, furan 7a was
obtained in high yield (67%)15 while the yield was lower (59%)
when the reaction was conducted at 0 °C (entries 7 and 8).16 We
suspected that at lower temperature, the cyclization proceeded
less readily which allowed other side-reactions to occur. We also
attempted the reaction in tetrahydrofuran, hexane, toluene, dichlo-
romethane, and chloroform (entries 9–13) and found that the yield
could not be improved greater than 47%. It should be noted that all
of these reactions proceeded to completion very rapidly, except in
toluene when the reaction required overnight stirring at room
temperature to achieve full conversion. Thus using the optimal
conditions, enynyl alcohol 6a was cleanly and rapidly (within
5 min) converted into iodofuran 7a in 67% yield when treated with
2.2 equiv of ICl in nitromethane at room temperature.17
After finding the optimal conditions for the cyclization of 6a, we
next studied the scope of the reaction by applying these conditions
to other alkynylallylic alcohols (6b–6k)18 and the results are sum-
marized in Table 2.19 For the secondary enynyl alcohols substituted
with an n-pentyl group (entries 1–4), the cyclization of the hydro-
xyl group onto the triple bond substituted with aryl substituents
occurred readily to give the corresponding furan products in 45–
67% yields. Aryl rings containing either electron-donating (6b–
6c; entries 2 and 3) or electron-withdrawing (6d; entry 4) groups
gave lower yields of the corresponding furans compared to com-
pound 6a. However, among the substituted aromatic systems, sub-
strates containing electron-donating groups gave better yields of
products than those containing an electron-withdrawing group
(compare entries 2 and 3 and entry 4). It is noteworthy to mention
that we did not observe over-halogenation in any of the products
containing the electron-rich phenyl ring, for example, 7c (entry 3).
For the phenethyl substituted secondary enynyl alcohols (en-
tries 5–9), the reactions also proceeded readily to give the corre-
sponding furan products in 32–81% yields. Among these
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Acetone
Acetone
Acetone
THF
Acetone
MeCN
MeNO2
MeNO2
THF
Hexane
Toluene
CH2Cl2
CHCl3
I2 (2.2)
I2 (4.0)
I2 (2.2)
I2 (2.2)
NR
NR
NRb
NRb
29
ICl (2.2)
ICl (2.2)
ICl (2.2)
ICl (2.2)
ICl (2.2)
ICl (2.2)
ICl (2.2)
ICl (2.2)
ICl (2.2)
ICl (2.2)
33
67
59c
47
36
18d
26
46
Dec
MeOH
a
b
c
Isolated yield.
NaHCO3 was employed as an additive.
Reaction was conducted at 0 °C.
Reaction was stirred overnight at rt to reach completion.
d
O
n
OH
R1
R2
R3
OH
O
R
1
R1
R1
R2
R2
Y
R3
R4
R3
R2
1
2
4
3;
n = 1-3, Y = C or O
Figure 1. Oxygenated conjugated enynes used in furan synthesis.
We next attempted the cyclization of alcohol 6a, the results of
which are summarized in Table 1. Initially, we found that excess
I2 was inactive toward the cyclization of this alcohol even in the
presence of NaHCO3 (entries 1–4); no furan 7a–I was obtained.
This was in a stark contrast to Larock’s ketone substrates (3 and
4; Fig. 1) which readily underwent cyclization to give the desired
Table 2
Scope of the ICl-promoted cyclization of alkynylallylic alcohols 6a
Entry
1
Substrate
Product
Yieldb (%)
O
OH
Cl
67
I
7a
6a
OMe
OBn
O
OMe
OBn
OH
Cl
Cl
2
3
57
62
I
7b
6b
6c
O
OH
OBn
I
7c
OBn

C. Thongsornkleeb et al. / Tetrahedron Letters 53 (2012) 6615–6619
6617
Table 2 (continued)
Entry
Substrate
Product
Yieldb (%)
Br
O
Br
OH
OH
Cl
4
5
45
81
I
7d
6d
O
Cl
I
6e
7e
OMe
OH
O
OMe
6
7
8
53
46
45
Cl
I
6f
7f
Br
OH
O
Br
Cl
I
6g
6h
7g
NO2
OH
OH
O
NO2
Cl
I
7h
O
9
32
68
71
Cl
6i
I
7i
OH
O
10
Cl
I
7j
6j
O
OH
11
Cl
I
6k
7k
a
Alcohol 6 (1.0 equiv) in MeNO2 (0.05 M) was treated with ICl (2.2 equiv) as a solution in MeNO2.
Isolated yield.
b
substrates, the trend in yields was consistent with the n-pentyl
butyl-substituted alkyne (6i) was subjected to the optimal cycliza-
tion conditions, furan 7i was obtained in only 32% yield. In other
secondary enynyl alcohols substituted with cyclohexyl and i-
propyl groups, the cyclization readily occurred to give the desired
furans 7j and 7k in 68% and 71% yields, respectively (entries 10 and
11).
In addition to the substrates in Table 2, these cyclization condi-
tions were applied to enynyl alcohols 6l and 6m. With alcohol 6l,
which contained a terminal alkyne, the reaction proceeded to give
series (vide supra). For the non-substituted phenyl substituent on
the triple bond, the cyclized product was obtained in high yield
(entry 5). However, when this phenyl ring was substituted with
either electron-donating (6f) or electron-withdrawing groups
(6g–6h), the yields were lower (45–53%; entries 6–8). Among these
entries, the substrate containing an electron-donating group pro-
vided a slightly better yield of the corresponding product (compare
entry 6 and entries 7 and 8). When the substrate containing an n-

6618
C. Thongsornkleeb et al. / Tetrahedron Letters 53 (2012) 6615–6619
R2
R1
OH
O
O
O
R1
R1
ICl, MeNO2
rt
I2, NuH
complex mixture
R2
Nu
R2
CH2Cl2, rt,1 h
R3
X
R3
6l
4; R3 = H
4
10
X = H (with AuCl3)
Substrate not examined
Y
O
I (with I2)
in Larock's protocol
ICl, MeNO2
rt
OH
Cl
R2
O
OH
R1
I
: major product
ICl, MeNO2
rt, 2-5 min
6m
R1
R2
7ma
; Y = Cl
7mb; Y = H : minor product
7mc
Cl
; Y = I : trace amount
I
7
6
Scheme 2. ICl-promoted cyclization of alcohols 6l and 6m.
Scheme 4. Comparison between Larock’s and our protocols.
H
R2
5
O
R1
pathway a
(within 5 min) and the enynyl alcohol substrates were completely
converted into the dihalofuran products in moderate to excellent
yields. The method reported herein should provide a simple and
efficient access to multi-substituted furan derivatives, which might
be useful as building blocks for the synthesis of complex organic
compounds.
I
I
9
R2
a
OH
R1
H
O
b
5
R1
R2
I
-HCl
Cl
I
Cl
I
6
8
R2
R2
Cl
O
O
ICl and/or Cl-
footnote 21
R1
R1
Acknowledgments
pathway b
I
I
I
This work was supported by Thailand Research Fund Grant
MRG5380094, and in part by Chulabhorn Research Institute, Chu-
labhorn Graduate Institute, Center of Excellence on Environmental
Health and Toxicology, CHE, Ministry of Education, and Thailand
International Development Cooperation Agency (TICA), for which
we are grateful.
7-I
Scheme 3. Proposed reaction mechanisms.
7
a complex mixture as observed by both TLC and 1H NMR spectros-
copy. For primary enynyl alcohol 6m, however, the reaction pro-
ceeded to give three different products in low combined yields as
shown in Scheme 2. The initial furan product 7mb underwent fur-
ther chlorination to give dichlorinated furan 7ma as the major
component in this mixture. A trace amount of diiodinated furan
7mc from iodination of 7mb was also detected by HRMS. The di-
rect chlorination of furan 7mb by ICl may be possible as this re-
agent has been reported to be able to act as a chlorinating agent.20
The proposed mechanism for the cyclization is shown in
Scheme 3. The reaction is believed to begin with coordination of
ICl to the triple bond of the alkyne, followed by intramolecular
nucleophilic addition of the hydroxyl group to give intermediate
8. The reaction could then take place via one of two possible path-
ways (Scheme 3). In pathway a, a lone pair of electrons on the oxy-
gen atom could assist in the electrophilic iodination with another
molecule of ICl at the methylene carbon to give the oxonium inter-
mediate 9 which quickly re-aromatized to the initial furan product
7-I. In pathway b, the re-aromatization of intermediate 8, which
occurred via loss of a proton at C-5, concurrently with the electro-
philic iodination with another molecule of ICl at the methylene
carbon, directly furnished the furan product (7-I). In the presence
of chloride (generated during the reaction) and/or excess ICl, furan
7-I was rapidly converted into the desired iodofuran 7.21
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.09.124.
References and notes
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The current method draws similarity with the previous study by
Larock and co-workers,11 whose protocol typically employed sub-
strates of types 3 and 4 (Fig. 1). However, no example of enynone
substrates containing a 1,1-disubstituted double bond (4; R3 = H)
were reported. Our work complements the work of Larock’s in that
it has demonstrated the viability in which enynyl alcohols, instead
of ketones, containing a 1,1-disubstituted double bond could par-
ticipate in ICl-initiated cyclization to furnish the corresponding
iodofuran products (Scheme 4).
4. (a) Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703–1708; (b) Marshall,
J. A.; Bennett, C. E. J. Org. Chem. 1994, 59, 6110–6113.
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K.; Ruppert, T. L.; Knöfel, T.; Bats, J. W. J. Org. Chem. 1997, 62, 7295–7304; (d)
In conclusion, we have demonstrated that ICl is an efficient
electrophilic halogenating agent which induces cyclization of sec-
ondary enynyl alcohols 6. The cyclization occurred very rapidly

C. Thongsornkleeb et al. / Tetrahedron Letters 53 (2012) 6615–6619
6619
Larock, R. C.; Doty, M. J.; Han, X. Tetrahedron Lett. 1998, 39, 5143–5146; (e)
Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000,
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without it. In light of this observation, we decided to exclude the use of a base
additive in our optimal conditions.
17. Typical experimental procedure for ICl-promoted cyclization: Alcohol 6a (57.0 mg,
0.25 mmol) was dissolved in MeNO2 (5 mL) and added
a solution of ICl
(90.0 mg, 0.55 mmol) into MeNO2 (1 mL). After stirring at room temperature
for 5 min, the solvent was removed on a rotary evaporator and the crude
product was purified by column chromatography on silica gel (10% EtOAc/
hexane); the product was obtained as a colorless oil (65.0 mg, 67%). Rf (10%
6. (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999, 1432–
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3127.
EtOAc/hexane) 0.48; IR (neat):
mmax 2956, 2929, 2859, 1610, 1485, 1261, 1089,
956, 763, 691 cmÀ1 1H NMR (300 MHz, CDCl3) d 7.95 (d, J = 7.8 Hz, 2H), 7.43 (t,
.
J = 7.2 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 4.48 (s, 2H), 2.76 (t, J = 7.5 Hz, 2H), 1.76–
1.67 (m, 2H), 1.37–1.36 (m, 4H), 0.91 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 154.9, 150.2, 130.1, 128.3, 128.1, 126.1, 120.9, 66.4, 38.5, 31.3, 27.9,
26.6, 22.3, 13.9, LRMS (EI) m/z (rel intensity) 388 (M+, 71), 339 (10), 331 (100),
127 (15), 77 (5). TOF-HRMS (35Cl) Calculated for C16H18ClIO (M+Å) 388.0085.
Found 388.0085.
18. Substrates 6b–6k were prepared using the same synthetic sequence as
compound 6a; see Supplementary data for detailed preparations and
characterizations.
19. All the products in Table 2 were sufficiently stable at room temperature and
could be handled conveniently during purification on a silica gel column, and
in subsequent utilizations. However, on prolonged storage (from several hours
to several weeks) we did observe decomposition, including discoloration of the
compounds and conversion of these compounds into other unidentified by-
products. We found that these compounds could be kept significantly longer
without much change when stored frozen in benzene.
13. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–4470.
14. Compound 7a showed chemical shifts in the 13C NMR spectrum at 38.5 ppm
which belonged to the chloromethylene carbon at the C-4 position of the furan
ring, and at 66.4 ppm due to the carbon bearing iodine at C-3 position of the
furan ring. The identity of furan 7a was further confirmed by HRMS which
20. Boden, N.; Bushby, R. J.; Cammidge, A. N.; Headdock, G. Tetrahedron Lett. 1995,
36, 8685–8686.
21. For the conversion of 7-I into 7, chloride, generated during the reaction, could
potentially displace the iodide on the methylene carbon of 7-I in an SN2
substitution. In addition, it has been shown that rapid dissociation of an iodine
atom from an organic iodide could be induced via complexation of the iodine
atom with ICl. This generates a partially positive carbon which undergoes
substitution by chloride. For a detailed kinetic study of this latter process, see:
Schmid, G. H.; Gordon, J. W. J. Org. Chem. 1983, 48, 4010–4013.
revealed the molecular formula
Supplementary data for more details.
C16H18ClIO. See Ref. 17 below and
15. As a general practice, the reaction was worked up immediately after full
conversion of the starting material was observed by TLC.
16. In addition, we attempted the reaction in the presence of NaHCO3 as an
additive (2.2 equiv) and observed the reaction to proceed more slowly than