Synthesis of five- and six-membered dihalogenated heterocyclic compounds by electrophile-triggered cyclization

Article abstract of DOI:10.1021/jo101085f

Highly substituted dihalogenated dihydrofurans, dihydropyrroles, and dihydro-2H-pyrans bearing alkyl, vinyl, aryl, and heteroaryl moieties can be prepared in good to excellent yields (up to 99%) by allowing 1,4-butyne-diol, 4-aminobut-2-yn-1-ol, and pent-2-yne-1,5-diol derivatives to react with different electrophiles (I₂, IBr, and ICl) at room temperature. Both halogen atoms generated from electrophiles were used effectively. The resulting halides can be further exploited by using palladium-catalyzed coupling reactions. The presence of trace amount of water is essential for this electrophilic cyclization.

Full text of DOI:10.1021/jo101085f

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Synthesis of Five- and Six-Membered Dihalogenated Heterocyclic
Compounds by Electrophile-Triggered Cyclization
Ke-Gong Ji,† Hai-Tao Zhu,† Fang Yang,† Ali Shaukat,† Xiao-Feng Xia,†
Yan-Fang Yang,† Xue-Yuan Liu,† and Yong-Min Liang*,†,‡
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China, and
‡State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, China
liangym@lzu.edu.cn
Received June 4, 2010
Highly substituted dihalogenated dihydrofurans, dihydropyrroles, and dihydro-2H-pyrans bearing
alkyl, vinyl, aryl, and heteroaryl moieties can be prepared in good to excellent yields (up to 99%) by
allowing 1,4-butyne-diol, 4-aminobut-2-yn-1-ol, and pent-2-yne-1,5-diol derivatives to react with
different electrophiles (I2, IBr, and ICl) at room temperature. Both halogen atoms generated from
electrophiles were used effectively. The resulting halides can be further exploited by using palladium-
catalyzed coupling reactions. The presence of trace amount of water is essential for this electrophilic
cyclization.
Introduction
molecular frameworks are present in the structure of several
biologically interesting compounds. In particular, dihydro-
furans, dihydropyrroles, and dihydro-2H-pyrans are impor-
tant intermediates for the synthesis of pharmaceuticals
and biologically active molecules, such as lepadiformine,2
nicotine,3 phytane-type diterpenedilactones 3-7,4 citreo-
viral,5 (þ)-anamarine, and (þ)-ambruticin6 (Figure 1). Thus,
In past decades, the synthesis of heterocycles has contin-
ued to attract the interest of synthetic chemists due to the
number of these compounds that show antidepressant, anti-
hypertensive, and hypoglycemic activities as well as other
biological effects.1 Among these heterocycles, the five- and
six-membered oxygenated or nitrogenated heterocycles are
probably one of the most common structural subunits in
numerous natural products. From simple to complex, these
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Published on Web 07/23/2010
DOI: 10.1021/jo101085f
r
2010 American Chemical Society

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SCHEME 1
with alkynes has proven to be an effective method for the
synthesis of heterocyclic compounds.7-25 We7 and others
have reported that the electrophilic cyclization8 of alkynes
can be a very powerful tool for the preparation of a wide
variety of important heterocyclic compounds due to the
mild, efficient, and clean reactions. Many important hetero-
cycles, such as benzo[b]thiophenes,9 benzofurans,10 2,3-di-
hydropyrroles and pyrroles,11 furans,7b,12 dihydropyrans,7f,13
indoles,14 isochromenes,15 isocoumarins and R-pyrones,16 iso-
quinolines and quinolines,17 isoxazoles,18 and oxazoles,19 fura-
nones,20 furopyridines,21 spiro[4,5]trienones,22 coumestans and
coumestrols,23 naphthols,24 and naphthalenes,25 have been re-
ported based on this strategy. Thus, electrophilic cyclization
reactions continue to be an area of active research in the field of
synthetic chemistry. However, the electrophilic cyclization of
heteroatomic nucleophiles with allenes has often been consid-
ered to be synthetically less attractive due to the lack of efficient
control of the regio- and stereoselectivity. Not long ago, Ma
and co-workers reported an interesting cyclization of substi-
tuted allenoic acids in the presence of electrophiles to afford
halogenated butenolides (Scheme 1).26 So, the chemistry of
allenes as organic synthons still needs to be explored more.
We found that 1,4-butyne-diol, 4-aminobut-2-yn-1-ol,
and pent-2-yne-1,5-diol derivatives could isomerize to give
the halogenated allene intermediates. These reactions are
generally believed to proceed by a stepwise mechanism
involving the allene cation intermediate formation in the
presence of electrophiles, which can be readily trapped by
nucleophiles (e.g., Cl, Br, I), then electrophilic activation of
FIGURE 1. Somepharmaceuticals and biologically activemolecules.
a mild, metal-free, environmently benign and atom econom-
ic protocol for the straightforward annulation of five- and
six-membered heterocyclic rings is still of high demand.
In recent years, the electrophilic cyclization of hetero-
atomic nucleophiles, such as oxygen, nitrogen, and sulfur,
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SCHEME 2. General Mechanism
TABLE 1. Optimization of Reaction Conditionsa
entry
solvent
IBr (equiv) additive (equiv) time (h) yield (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
dry CH2Cl2
dry CH2Cl2
dry CH2Cl2
dry CH2Cl2
dry CH2Cl2
1.2
1.5
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
6
4
2
55
85
90
88
trace
50
38
mixture
49
80
2
12
12
2
2
2
12
6
2
12
12
12
12
12
TsOH (1.0)
TFA (1.0)
TfOH (1.0)
HSbF6 (1.0)
TsOH (1.0)
10 CH2Cl2
11 DCE
12 CHCl3
13 MeOH
14 THF
15 1,4-dioxane
16 DMF
17 CH3CN
85
SCHEME 3. Preparation of the Requisite Starting Materials
80
nrb
40
53
nrb
66
aConditions: 0.3 mmol of 1 with IBr in CH2Cl2 (2.0 mL) at room
temperature. bNo reaction.
6-9). When TsOH was used as an additive in wet CH2Cl2, no
higher yield was obtained. With an attempt to optimize the
yield of the product, we further studied the influence of
different reaction media (entries 11-17). From the results
obtained, it can be seen that DCE and CHCl3 gave almost
identical results, albeit with a very slightly lower yield. DMF
and MeOH proved to be ineffective, whereas THF, 1,4-
dioxane, and CH3CN were less effective. With a series of
detailed investigations mentioned above, the reaction con-
ditions were eventually optimized as (entry 3): 1.0 equiv of 1
and 2.0 equiv of IBr in wet CH2Cl2 at room temperature.
To explore the scope of this electrophilic cyclization stra-
tegy, the reactions of 1 with different electrophiles (e.g., I2,
NIS, ICl, PhSeBr, and PhSeCl) have been studied under the
optimized conditions. When using I2 and ICl as the electro-
philic reagents, the corresponding products 47 and 48 have
been obtained in good to excellent yields (up to 99%). While
using NIS, PhSeBr, and PhSeCl as the electrophilic reagents,
no desired products were obtained. The other representative
1,4-butyne-diol derivatives were also subjected to the above
conditions, as depicted in Table 2, and the corresponding
products 49-77 were obtained in moderate to excellent
yields. The reaction can tolerate a variety of functional
groups at the ortho, meta, and para positions on the phenyl
moiety of 1,4-butyne-diols, indicating that the steric effect
had little impact on this transformation. The reaction works
well with aromatic R groups (entries 7-21). Interestingly, it
was found that substrate 5 with an o-MeOC6H4 group gave
different products by changing the amount of IBr. When
using 2 equiv of IBr as the electrophilic reagent, the corre-
sponding product 55 was obtained in 55% after 4 h at room
temperature (entry 13), whereas when the amount of IBr was
decreased to 1.5 equiv, an 86% yield of 56 was obtained after
1 h at -25 °C (entry 14), showing the fact that 56 is formed
first which then changes to 55 in the presence of IBr. A
substrate such as 8 with different electrophiles (e.g., I2, IBr)
was also tested in this reaction. It was found that the yield of
the carbon-carbon double bond of the halogenated allene
intermediate followed by intramolecular nucleophilic attack
on the cationic intermediate (Scheme 2).
The success of this dihalogenation prompted us to estab-
lish the relative reactivity of various functional groups
through cyclization.
Results and Discussion
This electrophilic cyclization has been applied to a variety
of substrates, and the resulting products were characterized
in order to determine the relative reactivities of various
functional groups. The required starting materials are read-
ily prepared from propargyl alcohol derivatives and alde-
hyde/ketone through the Grignard reaction (Scheme 3).
Initially, we started by using 0.3 mmol of 1-phenylbut-2-
yne-1,4-diol 1 and 1.2 equiv of IBr in wet CH2Cl2 at room
temperature; to our delight, the desired product 4-bromo-3-
iodo-2-phenyl-2,5-dihydrofuran 46 was isolated in 55%
yield after 6 h (Table 1, entry 1). When the amount of IBr
was increased to 1.5 equiv, an 85% yield of 46 was obtained
after 4 h (entry 2), and when the amount of IBr was added to
2 equiv, a 90% yield of 46 was obtained (entry 3). Surpris-
ingly, increasing the amounts of IBr to 3 equiv gave a slightly
decreased yield of 88% (entry 4). The reaction was also tested
in dry CH2Cl2, but only a trace amount of 46 was observed,
revealing the fact that protons are needed in this reaction
system (entry 5). Hence, the effect of acids was then inves-
tigated in dried CH2Cl2. It was found that protic acids such
as TsOH, TFA, TfOH, and HSbF6 played an important role
in this reaction, but no superior results were obtained (entries
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TABLE 2. Synthesis of 3,4-Dihalogenated Dihydrofurans 46-77 from 1,4-Butyne-diol Derivatives 1-23a
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TABLE 2. Continued
aAll reactions were run under the following conditions, unless otherwise indicated: 0.30 mmol of 1,4-butyne-diols and 2.0 equiv of electrophiles
in 3 mL of solvent were stirred at room temperature. bWith 0.3 mmol of 5 with 1.5 equiv of IBr in CH2Cl2 (3.0 mL) at -25 °C for 1 h. cThe reaction was
carried out at 40 °C.
SCHEME 4
corresponding product 60 was better than 59, which might be
due to the fact that the reactivity of IBr is higher than I2
(entries 17 and 18). 1,4-Butyne-diol possessing a heterocyclic
ring, such as a furan nucleus, can also afford the desired pro-
duct 63 in 80% yield (entry 22). Substrates such as 14-18 with
aliphatic groups can also give corresponding dihalogenated
heterocyclic compounds 66-72 in good to excellent yields
(entries 25-31). Other substrates such as 19-23 can also afford
corresponding products 73-77 in good yield (entries 32-36).
Much more important from the viewpoint of industrial
preparation was our investigation about the reaction of 10
mmol (2.38 g) of 1,4-diphenylbut-2-yne-1,4-diol 19 in the
presence of 2 equiv of I2; fortunately, 3,4-diiodo-2,5-diphen-
yl-2,5-dihydrofuran 78 was obtained in 70% yield after 2 h,
FIGURE 2. Structure of 79.
along with 2,3-diiodo-1-phenylnaphthalene 79 (3% yield),
confirming the existence of the intermediates C1 and C2
(Scheme 4). The molecular structure of the representative
product 79 was determined by X-ray crystallography (Figure 2).
Furthermore, to expand the scope of this reaction, we also
investigated a range of 5-en-2-yne-1,4-diol derivatives 24-
26, and it was found that substrates 24-26 were converted
into 3,4-dihalogenated-2-vinyl-2,5-dihydrofurans 80-84 in
moderate to good yield, as depicted in Table 3. Noteworthy,
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TABLE 3. Synthesis of 3,4-Dihalogenated 2-Vinyl-2,5-dihydrofuran from 5-En-2-yne-1,4-diol Derivatives 24-26a
aAll reactions were run under the following conditions, unless otherwise indicated: 0.30 mmol of 5-en-2-yne-1,4-diols and 2.0 equiv of electrophiles in
3 mL of solvent were stirred at 0 °C. bThe reaction was carried out at -10 °C.
TABLE 4. Synthesis of 3,4-Dihalogenated Dihydropyrrolesa
aAll reactions were run under the following conditions, unless otherwise indicated: 0.30 mmol of 4-aminobut-2-yn-1-ols and 2.0 equiv of electrophiles
in 3 mL of solvent were stirred at room temperature. bThe reaction was carried out at 40 °C.
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the double bond was retained in this reaction, which provides
ways for further transformations.
Additionally, various representative 4-aminobut-2-yn-1-
ol derivatives were also investigated in this reaction. It was
found that, under the optimized conditions, substrates
27-35 were converted into 3,4-dihalogenated dihydropyr-
roles 85-95 in moderate to excellent yield, as depicted in
Table 4. The behavior of substrate N-(4-hydroxy-4-phenyl-
but-2-ynyl)-4-methylbenzenesulfonamide 27 with different
electrophiles (e.g., IBr, ICl, and I2) was investigated in this
reaction; to our delight, the corresponding 3,4-dihaloge-
nated dihydropyrroles 85-87 were obtained in 75-86%
yield (Table 4, entries 42-44). To further confirm the struc-
tural assignment of products, the relative configuration of
the product 89 was unambiguously assigned by X-ray crys-
tallography (Figure 3). Interestingly, substrates such as 30-
34 with aliphatic groups also gave corresponding dihaloge-
nated heterocyclic compounds 90-94 in moderate to good
yield (entries 47-52). Other substrate such as 35 can also be
converted into corresponding product 95 in 70% yield, with
double bonds retained.
FIGURE 3. Structure of 89.
Sonagashira coupling,29 Suzuki coupling,30 and Heck coupl-
ing31 of 3,4-diiodo-dihydrofuran 78 afforded the corre-
sponding disubstituted products 111-113 in moderate to
good yield. The dihydrofuran 78 can be oxidized to 3,4-
diiodo-2,5-diphenylfuran 114 by 2,3-dichloro-5,6-dicyano-
benzoquinone (DDQ) (Scheme 6).
Since the first preparation of indole by Baeyer in 1866,27 its
chemistry has been extensively investigated as a consequence
of its prevalence in the structures of many biologically active
natural products, including some useful drugs.27,28 Due to its
special characteristic, we also prepared the indole deriva-
tives 36 and 37, and it was found that, under the optimized
conditions, the corresponding dihalogenated indole hetero-
cyclic compounds 96 and 97 were obtained in 72-76% yield
(Scheme 5).
In a similar manner, the Sonogashira coupling of 3-bro-
mo-4-iodo-2,5-diphenyl-2,5-dihydrofuran 73 with phenyla-
cetylene gave disubstituted alkyne 111 in 92% yield, whereas
the reaction of 4-chloro-3-iodo-2-phenyl-1-tosyl-2,5-dihy-
dro-1H-pyrrole 86 with phenylacetylene afforded monosub-
stituted alkyne 115, and only the iodine atom was involved
in the palladium-catalyzed Sonogashira coupling reaction
(Scheme 7).
Due to the wide occurrence of six-membered pyran rings
as key structural subunits in numerous natural products,
such as (þ)-ambruticin and others,6 the straightforward
annulation of pyran rings is still needed. Under the opti-
mized conditions, we also investigated pent-2-yne-1,5-diol
derivatives 54-67; fortunately, the corresponding dihaloge-
nated pyran rings 98-111 were also obtained in moderate
yield, as depicted in Table 5. From these results, it can be seen
that this reaction works well with aromatic groups (Table 5,
entries 54-59). Electron-rich aryl groups showed better
results than those with an electron-withdrawing group in
this tandem reaction (39 vs 40). With different electrophiles
(e.g., I2, IBr, and ICl), substrate 41 with a styrene group can
also afford the desired products 104-106 in 72, 83, and 20%
yield, respectively (entries 60-62). Substrate such as 45 with
aliphatic groups also gave corresponding spiro skeletons
107-111 in moderate yield (entries 63-67).
Conclusions
Highly substituted dihalogenated dihydrofurans, dihy-
dropyrroles, and dihydro-2H-pyrans have been obtained in
moderate to excellent yields from simple starting materials
by the electrophilic cyclization of 1,4-butyne-diols, 4-amino-
but-2-yn-1-ols, and pent-2-yne-1,5-diols by electrophiles (I2,
IBr, and ICl), during which several C-X (O, N, Cl, Br, I)
bonds were formed. This method tolerates many alkyl, vinyl,
aryl, and heteroaryl functional groups. Both halogen atoms
generated from electrophiles were used effectively. The
dihalogenated moiety can be readily introduced into the
heterocycle in a position not easily obtained previously.
Subsequent functionalization of the resulting heterocycles
by palladium-catalyzed coupling reactions leads to a number
of interesting five- and six-membered substituted skeletons.
In addition, the presence of a trace amount of water is needed
for this electrophilic cyclization.
A standard feature of this process is the fact that the
dihalogenated heterocyclic compounds produced by electro-
philes (e.g., I2, IBr, and ICl) can be further exploited by using
various palladium-catalyzed processes. For example, the
Experimental Section
General Procedure A: Synthesis of 1,4-Butyne-diol Deriva-
tives. To a stirred solution of the propargyl alcohol (10 mmol)
in THF was added ethylmagnesium bromide (20 mmol) at room
temperature. The resulting solution was refluxed for 1 h at 80 °C.
Then aldehyde (1.0 equiv) in THF (0.35 M) was added slowly by
(27) (a) Baeyer, A. Justus Liebigs Ann. Chem. 1866, 140, 295. For
historical overviews of indole chemistry, see: (b) Julian, P. L.; Meyer,
E. W.; Printy, H. C. In Heterocyclic Compounds; Elderfield, R. C, Eds.;
Wiley: New York, 1952; Vol. 3, pp 1-274. (c) Sundberg, R. J. The Chemistry
of Indoles; Academic Press: New York, 1970. (d) Sundberg, R. J. Indoles
Academic Press: London, 1996.
(30) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Suzuki, A. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998; Chapter 2.
(31) For leading reviews of the Heck reaction, see: (a) De Meijere, A.;
Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (b) Shibasaki, M.;
Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371. (c) Cabri, W.;
Candiani, I. Acc. Chem. Res. 1995, 28, 2. (d) Overman, L. E. Pure Appl.
Chem. 1994, 66, 1423.
(28) Brancale, A.; Silvestri, R. Med. Res. Rev. 2007, 27, 209.
(29) For reviews, see: (a) Campbell, I. B. The Sonogashira Cu-Pd-
Catalyzed Alkyne Coupling Reaction. In Organocopper Reagents; Taylor,
R. T. K., Ed.; IRL Press: Oxford, UK, 1994; pp 217-235. (b) Sonogashira,
K.; Takahashi, S. Yuki Gosei Kagaku Kyokaishi 1993, 51, 1053. (c)
Sonogashira, K. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 521-549.
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Ji et al.
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SCHEME 5. Synthesis of Dihalogenated Indole Derivatives 96 and 97
TABLE 5. Synthesis of 4,5-Dihalogenated 3,6-Dihydro-2H-pyrana
aAll reactions were run under the following conditions, unless otherwise indicated: 0.30 mmol of pent-2-yne-1,5-diols and 2.0 equiv of electrophiles in
3 mL of solvent were stirred at room temperature. bThe reaction was carried out at -10 °C.
syringe to the resulting solution at room temperature and stirred
for 3 h. The reaction mixture was quenched by addition of
saturated aqueous ammonium chloride (40 mL) and extracted
with ethyl ether (2 ꢀ 40 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude material was purified by flash
column chromatography to obtain the pure 1,4-butyne-diol
derivatives.
1-Phenylbut-2-yne-1,4-diol (1): solid, mp 83-85 °C; 1H NMR
(300 MHz, CDCl3) δ ppm 7.54 (dd, J = 7.8, 1.2 Hz, 2H),
J. Org. Chem. Vol. 75, No. 16, 2010 5677

Ji et al.
JOCArticle
SCHEME 6
General Procedure C: Synthesis of 3,4-Dihalogenated 2-Vinyl-
2,5-dihydrofurans 80-84. To a solution of 24 (0.30 mmol) in wet
CH2Cl2 (3.0 mL) was added 0.6 mmol, 2 equiv of electrophiles
IBr at -10 °C; 0.5 h later, the reaction was considered complete
as determined by TLC analysis, and the reaction mixture was
extracted with ethyl ether (40 mL), washed with water and satu-
rated brine, dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by chromatography on Al2O3 to
afford corresponding dihalogenated heterocyclic compound 81.
(E)-4-Bromo-3-iodo-2-styryl-2,5-dihydrofuran 81. Compound
81 was isolated in 76% yield as an oil following the general
procedure C: reaction time = 0.5 h; 1H NMR (400 MHz, CDCl3)
δ ppm 7.41 (d, J = 7.2 Hz, 2H), 7.34-7.28 (m, 3H), 6.69 (d, J =
15.6 Hz, 2H), 6.09 (dd, J = 16.0, 8.0 Hz, 1H), 5.25-5.20 (m, 1H),
4.73-4.66 (m, 2H); 13C NMR (100 MHz, CDCl3) δ ppm 135.9,
134.5, 128.6, 128.2, 126.9, 126.2, 125.3, 96.1, 92.2, 78.2; IR (neat,
cm-1) 1075, 1449, 1360, 1220, 1061, 696; HRMS (ESI) calcd for
C12H10BrIO M þ NH4 = 393.9298, found 393.9302.
General Procedure D: Synthesis of 3,4-Dihalogenated Dihy-
dropyrroles. To a solution of 4-aminobut-2-yn-1-ol derivatives
27-35 (0.30 mmol) in wet CH2Cl2 (3.0 mL) was added 0.6
mmol, 2 equiv of electrophiles at room temperature. When the
reaction was considered complete as determined by TLC anal-
ysis, the reaction mixture was extracted with ethyl ether (40 mL),
washed with water and saturated brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was purified by
chromatography on silica gel to afford corresponding 3,4-
dihalogenated dihydropyrroles 85-95.
SCHEME 7. Palladium-Catalyzed Sonogashira Coupling
Reaction
4-Bromo-3-iodo-2-phenyl-1-tosyl-2,5-dihydro-1H-pyrrole 85.
Compound 85 was isolated in 82% yield as a solid following
the general procedure D: reaction time = 3 h; mp 124-126 °C;
1H NMR (400 MHz, CDCl3) δ ppm 7.43 (d, J = 8.0 Hz, 2H),
7.32-7.29 (m, 3H), 7.20-7.17 (m, 4H), 5.42 (dd, J = 5.6, 2.4 Hz,
1H), 4.50 (dd, J = 14.0, 2.4 Hz, 1H), 4.34 (dd, J = 13.6, 2.4 Hz,
1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 143.7,
137.8, 134.8, 129.6, 128.6, 128.5, 128.0, 127.1, 123.1, 98.1, 76.1.
59.4, 21.5; IR (neat, cm-1) 1347, 1160, 1093, 1042, 818, 672, 579;
HRMS (ESI) calcd for C17H15BrINO2S M þ H = 503.9124,
found 503.9128.
General Procedure E: Synthesis of 4,5-Dihalogenated 3,6-
Dihydro-2H-pyrans 98-110. To a solution of pent-2-yne-1,5-
diol derivatives 54-67 (0.30 mmol) in wet CH2Cl2 (3.0 mL) was
added 0.6 mmol, 2 equiv of electrophiles at room temperature.
When the reaction was considered complete as determined by
TLC analysis, the reaction mixture was extracted with ethyl ether
(40 mL), washed with water and saturated brine, dried over Na2-
SO4, and evaporated under reduced pressure. The residue was
purified by chromatography on silica gel to afford corresponding
4,5-dihalogenated 3,6-dihydro-2H-pyrans 98-110.
4-Bromo-5-iodo-2,6-diphenyl-3,6-dihydro-2H-pyran 98. Com-
pound 98 was isolated in 75% yield following the general
procedure E: reaction time = 4 h; 1H NMR (400 MHz, CDCl3)
δ ppm 7.44-7.20 (m, 10H), [5.54(s), 5.31 (dd, J = 3.2, 1.8 Hz),
1H], [4.92 (dd, J = 10.4, 2.8 Hz), 4.91 (dd, J = 8.8, 5.2 Hz), 1H],
3.15-2.89 (m, 2H); 13C NMR (100 MHz, CDCl3) δ ppm 140.3,
140.0, 139.9, 137.1, 129.5, 128.8, 128.8, 128.7, 128.7, 128.5,
128.4, 128.4, 128.3, 128.0, 127.9, 127.8, 125.8, 125.8, 106.1,
100.7, 86.3, 84.3, 77.1, 69.7, 45.6, 44.5; IR (neat, cm-1) 1614,
1438, 1361, 1218, 1065, 816, 743, 552; HRMS (ESI) calcd for
C17H14BrIO M þ NH4 = 457.9611, found 457.9618.
7.41-7.32 (m, 3H), 5.49 (d, J = 5.7 Hz, 1H), 4.32 (dd, J = 6.0,
1.2 Hz, 2H), 2.87 (d, J = 5.7 Hz, 1H), 2.34 (t, J = 5.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ ppm 140.3, 128.6, 128.5, 126.6,
85.5, 84.9, 64.5, 51.0; IR (neat, cm-1) 1643, 1450, 1291, 1118,
1020, 692; HRMS (ESI) calcd for C10H10O2M þ H = 163.0754,
found 163.0758.
General Procedure B: Synthesis of 3,4-Dihalogenated 2,5-
Dihydrofuran Derivatives. To a solution of 1 (0.30 mmol) in
wet CH2Cl2 (3.0 mL) was added 0.6 mmol, 2 equiv of electro-
philes (I2, IBr, and ICl) at room temperature. When the reaction
was considered complete as determined by TLC analysis, the
reaction mixture was extracted with ethyl ether (40 mL), washed
with water and saturated brine, dried over Na2SO4, and evapo-
rated under reduced pressure. The residue was purified by
chromatography on silica gel to afford corresponding dihalo-
genated heterocyclic compounds.
4-Bromo-3-iodo-2-phenyl-2,5-dihydrofuran (46). Compound
46 was isolated in 90% yield following the general procedure
Acknowledgment. We thank the NSF (NSF-20732002,
NSF-2087205, NSF-20090443) and the Fundamental Re-
search Funds for the Central Universities for financial support.
1
B: reaction time = 4 h; H NMR (300 MHz, CDCl3) δ ppm
7.42-7.32 (m, 5H), 5.61 (dd, J = 5.4, 3.9 Hz, 1H), 4.87 (dd, J =
12.3, 6.0 Hz, 1H), 4.76 (dd, J = 12.3, 3.6 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ ppm 138.7, 128.9, 128.5, 127.5, 125.2, 97.2, 93.2,
78.7; IR (neat, cm-1) 1776, 1616, 1453, 1042, 753, 696; HRMS
(ESI) calcd for C10H8BrIO M þ NH4 = 367.9141, found 367.9150.
Supporting Information Available: Detailed experimental
procedure and copies of 1HNMRand13C NMR spectra of all com-
pounds, and X-ray data of 79 and 89 in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
5678 J. Org. Chem. Vol. 75, No. 16, 2010