Electrophilic cyclization of 2-(2',3'-allenyl)acetylacetates with iodine using calcium hydride as the base

Article abstract of DOI:10.1002/ejoc.201200527

A facile and efficient protocol for the synthesis of 4,5-dihydrofuran derivatives via iodine-mediated cyclization of various 2-(2',3'-allenyl) acetylacetates with CaH₂ as the base has been developed. The yields range from moderate to good. The resulting products can be used for further elaboration by palladium-catalyzed coupling reactions. A facile and efficient protocol for the synthesis of 4,5-dihydrofuran derivatives via iodine-mediated cyclization of various 2-(2',3'-allenyl)acetylacetates with CaH₂ as the base has been developed. The yields range from moderate to good. The resulting products can be used for further elaboration by palladium-catalyzed coupling reactions. Copyright

Full text of DOI:10.1002/ejoc.201200527

Job/Unit: O20527
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Date: 28-06-12 10:15:38
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FULL PAPER
DOI: 10.1002/ejoc.201200527
Electrophilic Cyclization of 2-(2Ј,3Ј-Allenyl)acetylacetates with Iodine Using
Calcium Hydride as the Base
Baoqiang Wan,[a] Xuefeng Jiang,[a] Guochen Jia,*[b] and Shengming Ma*[a,c]
Keywords: Cyclization / Iodine / Allenes / Oxygen heterocycles
A facile and efficient protocol for the synthesis of 4,5-di-
hydrofuran derivatives via iodine-mediated cyclization of
various 2-(2Ј,3Ј-allenyl)acetylacetates with CaH2 as the base
has been developed. The yields range from moderate to
good. The resulting products can be used for further elabora-
tion by palladium-catalyzed coupling reactions.
Introduction
Results and Discussion
Heterocycles are extremely important in organic chemis-
try, medicinal chemistry, and natural products chemistry.[1,2]
In particular, furan and dihydrofuran derivatives are con-
stituents of a number of biologically active compounds and
are also important intermediates in organic synthesis.[3]
Thus, the development of efficient methods for the synthesis
of dihydrofuran derivatives is still of high interest.[4]
Recently, electrophilic cyclizations of functionalized
alkynes[5,6] and allenes[7] have been developed as efficient
methods for the synthesis of heterocycles under mild condi-
tions. Furthermore, the iodine-containing substrates leave
further opportunity for elaboration such as transition-
metal-catalyzed transformations. In 2007, Liang reported
an electrophilic cyclization of acetylenic malonates and
ketones for the synthesis of indene derivatives;[8] Barluenga
et al. reported iodocarbocyclization of 2-(3Ј-alkynyl)acetyl-
acetates to give iodocyclopentenes;[9] Recently, we reported
the Pd- and Au-catalyzed cyclization of 2-(2Ј,3Ј-allenyl)-
acetylacetates to construct cyclic compounds.[10] In our con-
tinuous interest in electrophilic iodocyclization of function-
alized allenes,[11] we envisioned iodocyclization of 2-(2Ј,3Ј-
allenyl)acetylacetates. Herein, we disclosed a facile and ef-
ficient protocol for the construction of 4,5-dihydrofuran de-
rivatives by iodocyclization of 2-(2Ј,3Ј-allenyl)acetylacet-
ates.
The initial electrophilic cyclization experiment was con-
ducted by using 2-(2Ј,3Ј-allenyl)acetylacetate (1a), I2
(6 equiv.), and tBuOK (1.2 equiv.) in THF at room tem-
perature. We detected the formation of 4,5-dihydrofuran 2a
in only 18% yield, as determined by NMR spectroscopy
(Table 1, Entry 1). To improve the yield, a series of bases
including K2CO3, K3PO4, and NaOH were investigated,
and they all showed better results than tBuOK for the for-
mation of 2a (Table 1, Entries 2–4). Using bases such as
Et3N and NaH, the reactions afforded 2a in good yields
(Table 1, Entries 5 and 6). Further study revealed that the
use of more convenient and user friendly CaH2 as base af-
forded the best result, as 2a was formed in 80% yield under
these conditions (Table 1, Entry 7). Subsequent study of the
Table 1. Base and solvent effects of the iodocyclization of 2-(2Ј,3Ј-
allenyl)acetylacetates.[a]
Entry
Solvent
Base (x equiv.)
Yield of 2a [%][b]
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
THF
CH3CN
CH3NO2
Et2O
toluene
CH2Cl2
tBuOK (1.2)
K2CO3 (1.2)
K3PO4 (1.2)
NaOH (1.2)
Et3N (1.2)
NaH (1.2)
CaH2 (0.6)
CaH2 (0.6)
CaH2 (0.6)
CaH2 (0.6)
CaH2 (0.6)
CaH2 (0.6)
18
28
54
57
70
75
80
67
56
28
22
37
[a] State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China
Fax: +86-21-6260-9305
E-mail: masm@sioc.ac.cn
[b] Department of Chemistry,
9
The Hong Kong University of Science and Technology,
Clear Water Bay,
10
11
12
Kowloon, Hong Kong
[c] Shanghai Key Laboratory of Green Chemistry and Chemical
Process, Department of Chemistry, East China Normal
University,
[a] The reaction was carried out with 1a (0.2 mmol), I2 (1.2 mmol),
and base in the indicated solvent (2 mL). [b] Determined by 1H
NMR spectroscopic analysis by using 1,3,5-trimethylbenzene as the
internal standard.
3663 North Zhongshan Lu, Shanghai 200062, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200527.
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B. Wan, X. Jiang, G. Jia, S. Ma
FULL PAPER
solvent effects indicated that the solvent was also critical yield (Table 3, Entry 2). The reaction of substrates 1b–f
for this reaction (Table 1, Entries 7–12): in comparison with bearing different R1 groups, such as alkyl, benzyl, and
CH3CN, CH3NO2, Et2O, toluene, and CH2Cl2, THF gave phenyl, afforded the corresponding 4,5-dihydrofurans 2b–f
the best yield.
in moderate to good yields (Table 3, Entries 3–7). An R3
Using CaH2 (0.6 equiv.) as the base and THF as the sol- substituent may also be introduced onto the allene moiety
vent, the effect of the loading of I2 was also investigated. to afford the same type of products with a quaternary car-
A decrease in the loading of I2 to 5 or 4 equiv. showed a bon atom in good yields (Table 3, Entries 8 and 9). In ad-
limited effect on the yield (Table 2, Entries 2 and 3). How- dition, the reaction of 2-(2Ј,3Ј-allenyl)acetylacetates 1i and
ever, a further decrease in the loading of I2 influenced the 1j bearing two substituents at the terminal position of the
reaction yield dramatically (Table 2, Entries 4–6). By bal- allenyl moiety also afforded the corresponding 4,5-dihy-
anced consideration of yield and the amount of I2, the fol- drofurans 2i and 2j smoothly (Table 3, Entries 10 and 11).
lowing optimized reaction conditions were defined for fur-
ther study: CaH2 (0.6 equiv.), I2 (4 equiv.), and THF at
room temperature (Table 2, Entry 3).
Table 3. Iodine-mediated cyclization of 2-(2Ј,3Ј-allenyl)acetylacet-
ates.[a]
Table 2. Effect of the amount of I2 on the iodine-mediated cycliza-
tion of 2-(2Ј,3Ј-allenyl)acetylacetates.[a]
Entry
R1/R2/R3/R4 (1)
Yield of 2 [%][b]
Entry
I2 [equiv.]
Yield of 2a [%][b]
1
2
3
4
5
6
7
8
CH3/Et/H/H (1a)
CH3/Et/H/H (1a)
CH3/CH3/H/H (1b)
Et/CH3/H/H (1c)
iPr/CH3/H/H (1d)
Bn/CH3/H/H (1e)
Ph/Et/H/H (1f)
CH3/Et/Et/H (1g)
iPr/CH3/Bn/H (1h)
iPr/CH3/H/CH3 (1i)
iPr/CH3/H/(CH2)5 (1j)
74 (2a)
78 (2a)[c]
66 (2b)
72 (2c)
80 (2d)
61 (2e)[d]
83 (2f)
82 (2g)
70 (2h)
83 (2i)
1
2
3
4
5
6
6
5
4
3
2
1
80
79
76 (74)[c]
62
34[d]
7[e]
[a] The reaction was carried out with 1a (0.2 mmol) and CaH2
(0.12 mmol) in THF (2 mL). [b] Determined by H NMR spectro-
scopic analysis by using 1,3,5-trimethylbenzene as the internal stan-
dard. [c] Number shown in parentheses is the isolated yield.
[d] 17% of starting material 1a remained. [e] 42% of starting mate-
rial 1a remained.
9
10
11
1
52 (2j)
[a] The reaction was carried out with 1 (0.2 mmol) and CaH2
(0.12 mmol) in THF (2 mL). [b] Isolated yield. [c] The reaction was
carried out on a 1-g scale. [d] Reaction time: 50 min.
To test the versatility of this iodocyclization strategy, the
reaction of various 2-(2Ј,3Ј-allenyl)acetylacetates 1 with I2
However, when there is only one substituent at the ter-
were studied (Table 3). To our delight, the reaction of 1a minal position of the allenyl moiety, the reaction of 1k and
conducted on one-gram scale afforded product 2a in a high 1l afforded the corresponding products 2k and 2l as a mix-
Scheme 1.
2
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Electrophilic Cyclization of 2-(2Ј,3Ј-Allenyl)acetylacetates
Scheme 2.
Scheme 3.
ture of stereoisomers in Z/E ratios of 87:13 and 85:15,
respectively, in good yields. Further kinetic resolution via
Sonogashira coupling[12] afforded Z-2l as the only isomer,
and the relative C=C bond configuration was confirmed by
Conclusions
In conclusion, we have developed a facile and efficient
protocol for the synthesis of 4,5-dihydrofuran derivatives
via electrophilic cyclization of various 2-(2Ј,3Ј-allenyl)acet-
ylacetates with I2. The reaction proceeds smoothly at room
temperature within a short period of time. Subsequent elab-
oration of the resulting products by palladium-catalyzed
coupling reactions leads to some other dihydrofuran skel-
etons. Further studies in this area are being carried out in
our laboratory.
1
its H–1H NOESY study (Scheme 1 and Supporting Infor-
mation).
A rationale for the stereoselectivity is shown in Scheme 2:
the regioselective facile interaction of I2 with the C=C bond
close to the nucleophilic group leads to the formation of
three-membered iodonium intermediates int1 and int2. Due
to the steric interaction between the R group and the nucle-
ophilic group, int2 is less favored than int1.[13] Subsequent
deprotonation and anti-attack of the enolic oxygen would
afford the 4,5-dihydrofuran with the Z isomer as the major
product.
Experimental Section
General Information: All reactions were carried out in oven-dried
Schlenk tubes. THF and toluene were distilled from sodium wire
with diphenyl ketone as the indicator. CH3CN was dried with cal-
cium hydride before distillation. NMR spectra were recorded with
a Bruker AM-300 instrument. Chemical shifts are reported in ppm
relative to TMS or solvent residual peaks [1H: δ = 0.00 ppm (TMS),
δ = 7.26 ppm (CDCl3); 13C: δ = 77.0 ppm (CDCl3)]. IR spectra
were measured with a Nexus FT-IR spectrometer or a Bruker Ten-
The formation of the C–I bond via this iodocyclization
protocol leaves further opportunity for elaboration.[14] For
example, the Suzuki–Miyaura coupling of 2a with phen-
ylboronic acid or (1E)-hexenylboronic acid afforded C-sub-
stituted derivative 3 or 4 in good yield, respectively;[15] Son-
ogashira coupling of 2a with 1-hexyne proceeded smoothly
to afford product 5 in 84% yield (Scheme 3).[16]
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B. Wan, X. Jiang, G. Jia, S. Ma
FULL PAPER
sor27 instrument. MS analyses were performed with an Agilent
Technologies 5975C instrument. HRMS analyses were performed
with a Waters GCT Premier instrument. Elemental analyses were
carried out with a Vario EL III instrument.
(44.7 mg, 72%) after chromatography (petroleum ether/dichloro-
methane, 2:1) as a liquid. H NMR (300 MHz, CDCl3): δ = 6.38
1
(s, 1 H, one proton of H2C=C), 5.86 (s, 1 H, one proton of
H2C=C), 4.82 (dd, J = 10.7, 7.4 Hz, 1 H, OCH), 3.70 (s, 3 H,
OCH3), 3.07 (dd, J = 14.9, 11.0 Hz, 1 H, one proton of C=CCH2),
2.85–2.53 (m, 3 H, one proton of C=CCH2 and CH2), 1.16 (t, J =
7.5 Hz, 3 H, CH3) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 171.9,
165.8, 125.9, 111.3, 100.3, 85.4, 50.9, 36.7, 21.1, 11.2 ppm. IR
Typical Procedure for the Iodine-Mediated Cyclization of 2-(2Ј,3Ј-
Allenyl)acetylacetates
3-(Ethoxycarbonyl)5-(1Ј-iodovinyl)-2-methyl-4,5-dihydrofuran (2a):
To
a flame-dried Schlenk tube was added CaH2 (5.2 mg,
(neat): ν = 2976, 2945, 2875, 1707, 1647, 1437, 1360, 1331, 1250,
˜
1209, 1190, 1135, 1097, 1017 cm–1. MS (70 eV, EI): m/z (%) = 308
(21.73) [M]+, 57 (100). HRMS: calcd. for C10H13O3I [M]+
307.9909; found 307.9908.
0.12 mmol) and THF (1 mL). The resulting mixture was stirred at
room temperature for 5 min, and then I2 (205.0 mg, 0.8 mmol), 1a
(36.2 mg, 0.2 mmol), and THF (1 mL) were added to the above
solution. The mixture was stirred at room temperature and moni-
tored by TLC. After 0.5 h, the reaction mixture was quenched by
a saturated aqueous solution of Na2S2O3 (10 mL), extracted with
Et2O (3ϫ 15 mL), and dried with anhydrous Na2SO4. After fil-
tration and evaporation of the solvent, chromatography on silica
gel (petroleum ether/dichloromethane, 1:1) afforded 2a (45.2 mg,
5-(1Ј-Iodovinyl)-2-isopropyl-3-(methoxycarbonyl)-4,5-dihydrofuran
(2d): The reaction of CaH2 (5.2 mg, 0.12 mmol), I2 (206.0 mg,
0.8 mmol), and 1d (38.9 mg, 0.2 mmol) in THF (2 mL) afforded 2d
(51.3 mg, 80%) after chromatography (petroleum ether/dichloro-
1
methane, 3:2) as a liquid. H NMR (300 MHz, CDCl3): δ = 6.38
(s, 1 H, one proton of H2C=C), 5.85 (s, 1 H, one proton of
H2C=C), 4.81 (dd, J = 10.8, 7.5 Hz, 1 H, OCH), 3.74–3.55 (m, 4
H, OCH3 and C=CCH), 3.05 (dd, J = 14.9, 11.0 Hz, 1 H, one
proton of C=CCH2), 2.74 (dd, J = 14.9, 7.7 Hz, 1 H, one proton
of C=CCH2), 1.18 (d, J = 7.2 Hz, 3 H, CH3), 1.12 (d, J = 6.9 Hz,
3 H, CH3) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 174.9, 165.8,
125.7, 111.5, 99.0, 85.2, 50.8, 36.7, 26.7, 19.7, 19.5 ppm. IR (neat):
1
74%) as a liquid. H NMR (300 MHz, CDCl3): δ = 6.38 (s, 1 H,
one proton of H2C=C), 5.87 (s, 1 H, one proton of H2C=C), 4.83
(dd, J = 10.5, 7.8 Hz, 1 H, OCH), 4.17 (q, J = 7.2 Hz, 2 H,
CO2CH2), 3.07 (dd, J = 13.7, 11.9 Hz, 1 H, one proton of
C=CCH2), 2.76 (dd, J = 14.9, 7.7 Hz, 1 H, one proton of
C=CCH2), 2.22 (s, 3 H, C=CCH3), 1.28 (t, J = 7.1 Hz, 3 H,
CH3) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 166.9, 165.6, 125.9,
ν = 2971, 2940, 2873, 1706, 1643, 1465, 1438, 1355, 1298, 1258,
˜
111.1, 101.7, 85.6, 59.6, 36.7, 14.4, 13.9 ppm. IR (neat): ν = 2979,
˜
1232, 1185, 1119, 1046 cm–1. MS (70 eV, EI): m/z (%) = 322 (29.98)
[M]+, 251 (100). HRMS: calcd. for C11H15O3I [M]+ 322.0066;
found 322.0064.
1696, 1654, 1618, 1445, 1381, 1314, 1255, 1220, 1171, 1142, 1126,
1080, 1017 cm–1. MS (70 eV, EI): m/z (%) = 308 (26.06) [M]+, 43
(100). HRMS: calcd for C10H13O3I [M]+ 307.9909; found 307.9911.
2-Benzyl-5-(1Ј-iodovinyl)-3-(methoxycarbonyl)-4,5-dihydrofuran
(2e): The reaction of CaH2 (5.4 mg, 0.12 mmol), I2 (204.0 mg,
0.8 mmol), and 1e (49.9 mg, 0.2 mmol) in THF (2 mL) afforded 2e
(46.1 mg, 61 %) after chromatography (petroleum ether/diethyl
ether, 10:1) as a liquid. 1H NMR (300 MHz, CDCl3): δ = 7.39–
7.17 (m, 5 H, Ar-H), 6.12 (s, 1 H, one proton of H2C=C), 5.74 (s,
1 H, one proton of H2C=C), 4.86 (dd, J = 10.5, 7.5 Hz, 1 H, OCH),
4.06 (d, J = 13.8 Hz, 1 H, one proton of CH2 of Bn), 3.96 (d, J =
14.1 Hz, 1 H, one proton of CH2 of Bn), 3.75 (s, 3 H, OCH3), 3.09
(dd, J = 15.0, 10.8 Hz, 1 H, one proton of C=CCH2), 2.79 (dd,
J = 15.0, 7.2 Hz, 1 H, one proton of C=CCH2) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 168.3, 165.7, 136.3, 129.1, 128.4, 126.8,
Synthesis of 3-(Ethoxycarbonyl)-5-(1Ј-iodovinyl)-2-methyl-4,5-di-
hydrofuran 2a On One-Gram Scale: To a flame-dried Schlenk flask
was added CaH2 (139.1 mg, 3.3 mmol) and THF (30 mL). The re-
sulting mixture was stirred at room temperature for 10 min, and
then I2 (5.5840 g, 22.0 mmol) and 1a (1.0014 g, 5.5 mmol) were
added to the above solution. After 0.5 h, the reaction mixture was
quenched by saturated aqueous Na2S2O3 (40 mL), extracted with
Et2O (3ϫ 40 mL), and dried with anhydrous Na2SO4. After fil-
tration and evaporation of the solvent, chromatography on silica
gel (petroleum ether/dichloromethane, 1:1) afforded 2a (1.3207 g,
1
78%) as a liquid. H NMR (300 MHz, CDCl3): δ = 6.39 (s, 1 H,
one proton of H2C=C), 5.86 (s, 1 H, one proton of H2C=C), 4.83
(dd, J = 10.2, 7.8 Hz, 1 H, OCH), 4.17 (q, J = 7.2 Hz, 2 H,
CO2CH2), 3.07 (dd, J = 14.4, 11.1 Hz, 1 H, one proton of
C=CCH2), 2.76 (dd, J = 15.0, 7.5 Hz, 1 H, one proton of
C=CCH2), 2.22 (s, 3 H, C=CCH3), 1.28 (t, J = 7.2 Hz, 3 H,
CH3) ppm.
125.7, 110.5, 101.4, 85.6, 51.1, 36.5, 33.6 ppm. IR (neat): ν = 3026,
˜
2948, 1708, 1645, 1617, 1495, 1435, 1366, 1257, 1234, 1191, 1124,
1078, 1055 cm–1. MS (70 eV, EI): m/z (%) = 370 (61.30) [M]+, 91
(100). HRMS: calcd. for C15H15O3I [M]+ 370.0066; found
370.0067.
3-(Ethoxycarbonyl)-5-(1Ј-iodovinyl)-2-phenyl-4,5-dihydrofuran (2f):
The reaction of CaH2 (5.4 mg, 0.12 mmol), I2 (202.4 mg,
0.8 mmol), and 1f (47.7 mg, 0.2 mmol) in THF (2 mL) afforded 2f
(59.7 mg, 83%) after chromatography (petroleum ether/ethyl acet-
ate, 3:2) as a liquid. 1H NMR (300 MHz, CDCl3): δ = 7.88–7.77
(m, 2 H, Ar-H), 7.52–7.34 (m, 3 H, Ar-H), 6.47 (s, 1 H, one proton
of H2C=C), 5.92 (s, 1 H, one proton of H2C=C), 4.98 (dd, J =
10.7, 8.0 Hz, 1 H, OCH), 4.15 (q, J = 7.2 Hz, 2 H, CO2CH2), 3.33
(dd, J = 15.5, 11.0 Hz, 1 H, one proton of C=CCH2), 3.02 (dd, J
= 15.5, 7.7 Hz, 1 H, one proton of C=CCH2), 1.22 (t, J = 7.1 Hz,
3 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 164.7, 164.0, 130.4,
129.5, 129.3, 127.6, 126.1, 111.0, 102.1, 85.0, 59.9, 38.4, 14.2 ppm.
5-(1Ј-Iodovinyl)-3-(methoxycarbonyl)-2-methyl-4,5-dihydrofuran
(2b): The reaction of CaH2 (5.0 mg, 0.12 mmol), I2 (203.6 mg,
0.8 mmol), and 1b (34.6 mg, 0.2 mmol) in THF (2 mL) afforded 2b
(39.7 mg, 66%) after chromatography (petroleum ether/dichloro-
1
methane, 2:1) as a liquid. H NMR (300 MHz, CDCl3): δ = 6.38
(s, 1 H, one proton of H2C=C), 5.86 (s, 1 H, one proton of
H2C=C), 4.83 (dd, J = 10.5, 7.5 Hz, 1 H, OCH), 3.70 (s, 3 H,
OCH3), 3.06 (dd, J = 13.5, 10.5 Hz, 1 H, one proton of C=CCH2),
2.76 (dd, J = 14.9, 7.4 Hz, 1 H, one proton of C=CCH2), 2.22 (s,
3 H, C=CCH3) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 167.3,
166.0, 126.0, 111.0, 101.4, 85.7, 50.9, 36.7, 13.9 ppm. IR (neat): ν
˜
= 2949, 2867, 1706, 1654, 1619, 1438, 1383, 1256, 1223, 1190, 1136,
1088 cm–1. MS (70 eV, EI): m/z (%) = 294 (22.56) [M]+, 43 (100).
HRMS: calcd. for C9H11O3I [M]+ 293.9753; found 293.9752.
IR (neat): ν = 3056, 2979, 2931, 2866, 1709, 1616, 1599, 1576, 1493,
˜
1446, 1395, 1375, 1347, 1305, 1243, 1172, 1148, 1089, 1001 cm–1.
MS (70 eV, EI): m/z (%) = 370 (7.61) [M]+, 105 (100). HRMS:
calcd. for C15H15O3I [M]+ 370.0066; found 370.0067.
2-Ethyl-5-(1Ј-iodovinyl)-3-(methoxycarbonyl)-4,5-dihydrofuran (2c):
The reaction of CaH2 (5.3 mg, 0.12 mmol), I2 (204.0 mg, 3-(Ethoxycarbonyl)-5-ethyl-5-(1Ј-iodovinyl)-2-methyl-4,5-dihydro-
0.8 mmol), and 1c (36.7 mg, 0.2 mmol) in THF (2 mL) afforded 2c furan (2g): The reaction of CaH2 (5.2 mg, 0.12 mmol), I2 (203.6 mg,
4
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Electrophilic Cyclization of 2-(2Ј,3Ј-Allenyl)acetylacetates
0.8 mmol), and 1g (41.5 mg, 0.2 mmol) in THF (2 mL) afforded 2g
5-(1Ј-Iodo-1Ј-undecenyl)-2-isopropyl-3-(methoxycarbonyl)-4,5-di-
(54.5 mg, 82 %) after chromatography (petroleum ether/diethyl hydrofuran (2k): The reaction of CaH2 (5.3 mg, 0.12 mmol), I2
1
ether, 20:1) as a liquid. H NMR (300 MHz, CDCl3): δ = 6.36 (s,
1 H, one proton of H2C=C), 5.85 (s, 1 H, one proton of H2C=C),
4.15 (q, J = 7.1 Hz, 2 H, CO2CH2), 3.00 (d, J = 15.0 Hz, 1 H, one
proton of C=CCH2), 2.70 (d, J = 15.0 Hz, 1 H, one proton of
C=CCH2), 2.21 (s, 3 H, C=CCH3), 2.06–1.91 (m, 1 H, one proton
of CH2), 1.91–1.77 (m, 1 H, one proton of CH2), 1.26 (t, J =
(205.0 mg, 0.8 mmol), and 1k (63.3 mg, 0.2 mmol) in THF (2 mL)
afforded 2k (75.6 mg, 86%, Z/E = 87:13) after chromatography (pe-
troleum ether/diethyl ether, 20:1) as a liquid. H NMR (300 MHz,
CDCl3): δ = [6.34 (t, J = 7.8 Hz, 0.13 H, C=CH, E-isomer), 5.94
(t, J = 6.8 Hz, 0.87 H, C=CH, Z-isomer)], [4.92 (t, J = 9.5 Hz, 0.13
H, OCH, E-isomer), 4.81 (dd, J = 10.4 Hz, 8.0 Hz, 0.86 H, OCH,
1
7.1 Hz, 3 H, CH3), 0.88 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR Z-isomer)], 3.74–3.55 (m, 4 H, OCH3 and C=CCH), 3.07–2.92 (m,
(75.4 MHz, CDCl3): δ = 166.3, 165.8, 125.2, 114.3, 101.2, 92.1,
1 H, one proton of CH2), 2.82–2.62 (m, 1 H, one proton of CH2),
59.5, 41.1, 32.2, 14.4, 14.1, 7.6 ppm. IR (neat): ν = 2975, 2932, 2.16 (q, J = 7.0 Hz, 2 H, CH2), 1.47–1.05 (m, 20 H), 0.87 (t, J =
˜
2872, 1704, 1655, 1613, 1460, 1379, 1332, 1297, 1267, 1240, 1121,
6.2 Hz, 3 H, CH ) ppm. IR (neat): ν = 2926, 2855, 1705, 1643,
˜
3
1073 cm–1. MS (70 eV, EI): m/z (%) = 336 (10.04) [M]+, 293 (100). 1467, 1435, 1349, 1254, 1230, 1187, 1120, 1065, 1046 cm–1. MS
HRMS: calcd. for C12H17O3I [M]+ 336.0222; found 336.0221.
(70 eV, EI): m/z (%) = 448 (16.32) [M]+, 321 (100). HRMS: calcd.
for C20H33O3I [M]+ 448.1474; found 448.1473. C20H33IO3 (448.38):
calcd. C 53.57, H 7.42; found C 54.01, H 7.51.
5-Benzyl-5-(1Ј-iodovinyl)-2-isopropyl-3-(methoxycarbonyl)-4,5-di-
hydrofuran (2h): The reaction of CaH2 (5.4 mg, 0.12 mmol), I2
(204.0 mg, 0.8 mmol), and 1h (57.4 mg, 0.2 mmol) in THF (2 mL)
afforded 2h (57.9 mg, 70%) after chromatography (petroleum ether/
5-(2Ј-Cyclohexyl-1Ј-iodovinyl)-2-isopropyl-3-(methoxycarbonyl)-4,5-
dihydrofuran (2l): The reaction of CaH2 (5.2 mg, 0.12 mmol), I2
(203.1 mg, 0.8 mmol), and 1l (56.0 mg, 0.2 mmol) in THF (2 mL)
afforded 2l (70.3 mg, 86%, Z/E = 85:15) after chromatography (pe-
1
dichloromethane, 3:1) as a liquid. H NMR (300 MHz, CDCl3): δ
= 7.39–7.19 (m, 5 H, Ar-H), 6.21 (d, J = 1.5 Hz, 1 H, one proton
of H2C=C), 5.75 (d, J = 1.2 Hz, 1 H, one proton of H2C=C), 3.73–
3.51 (m, 4 H, OCH3 and C=CCH), 3.25 (d, J = 14.1 Hz, 1 H, one
proton of CH2), 3.13 (d, J = 14.7 Hz, 1 H, one proton of CH2),
3.08 (d, J = 15.3 Hz, 1 H, one proton of CH2), 2.84 (d, J = 15.3 Hz,
1 H, one proton of CH2), 1.16 (d, J = 6.6 Hz, 3 H, CH3), 1.13 (d,
J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (75.4 MHz, CDCl3): δ =
173.8, 165.8, 135.2, 130.6, 127.8, 126.8, 125.7, 114.4, 98.7, 90.9,
1
troleum ether/diethyl ether, 20:1) as a liquid. H NMR (300 MHz,
CDCl3): δ = [6.21 (d, J = 9.9 Hz, 0.15 H, C=CH, E-isomer), 5.74
(d, J = 8.7 Hz, 0.83 H, C=CH, Z-isomer)], [4.93 (t, J = 9.5 Hz,
0.15 H, OCH, E-isomer), 4.77 (dd, J = 10.4, 8.1 Hz, 0.83 H, OCH,
Z-isomer)], 3.75–3.55 (m, 4 H, OCH3 and C=CCH), 3.10–2.93 (m,
1 H, one proton of CH2), 2.81–2.62 (m, 1 H, one proton of CH2),
2.45–2.22 (m, 1 H, CH), 1.81–1.54 (m, 5 H), 1.42–1.02 (m, 11
50.8, 44.6, 41.1, 26.9, 19.9, 19.8 ppm. IR (neat): ν = 3030, 2970,
˜
H) ppm. IR (neat): ν = 2970, 2927, 2851, 1697, 1639, 1468, 1436,
˜
1348, 1300, 1258, 1230, 1189, 1120, 1065, 1044, 1009 cm–1. MS
(70 eV, EI): m/z (%) = 404 (15.48) [M]+, 43 (100). HRMS: calcd.
for C17H25O3I [M]+ 404.0848; found 404.0851. C17H25IO3 (404.29):
calcd. C 50.50, H 6.23; found C 50.87, H 6.44.
2947, 2872, 1705, 1646, 1614, 1497, 1468, 1455, 1435, 1360, 1351,
1285, 1245, 1190, 1126, 1099, 1065, 1038 cm–1. MS (70 eV, EI): m/z
(%) = 412 (5.67) [M]+, 321 (100). HRMS: calcd. for C18H21O3I
412.0535; found 412.0536.
5-(1Ј-Iodo-2Ј-methyl-1Ј-propenyl)-2-isopropyl-3-(methoxycarbonyl)-
4,5-dihydrofuran (2i): The reaction of CaH2 (5.2 mg, 0.12 mmol), I2
(203.5 mg, 0.8 mmol), and 1i (43.9 mg, 0.2 mmol) in THF (2 mL)
afforded 2i (56.9 mg, 83%) after chromatography (petroleum ether/
Procedure for Kinetic Resolution of the Z/E Isomer of 2l
Synthesis of 5-[2Ј(Z)-Cyclohexyl-1Ј-iodovinyl]-2-isopropyl-3-(meth-
oxycarbonyl)-4,5-dihydrofuran (Z-2l):[12] To a flame-dried Schlenk
tube were added Pd(PPh3)Cl2 (3.7 mg, 5.25 μmol), CuI (1.0 mg,
5.25 μmol), Et2NH (4.0 mg, 0.053 mmol), CH3CN (0.5 mL), prop-
2-yn-1-ol (3.0 mg, 0.053 mmol), CH3CN (0.5 mL), 2l (58.4 mg,
0.15 mmol, Z/E = 85:15), and CH3CN (0.5 mL) sequentially at
3 °C. After being stirred at 3 °C for 1.5 h under an atmosphere
of argon, the reaction mixture was concentrated and purified by
chromatography on silica gel (petroleum ether/diethyl ether, 15:1)
to afford Z-2l (45.6 mg, 78%) as a liquid. 1H NMR (300 MHz,
CDCl3): δ = 5.75 (d, J = 8.4 Hz, 1 H, C=CH), 4.78 (dd, J = 9.9,
8.4 Hz, 1 H, OCH), 3.73–3.55 (m, 4 H, OCH3 and C=CCH), 3.01
(dd, J = 14.9, 11.0 Hz, 1 H, one proton of CH2), 2.75 (dd, J =
14.9, 7.7 Hz, 1 H, one proton of CH2), 2.37–2.22 (m, 1 H, CH),
1.82–1.59 (m, 5 H), 1.42–1.02 (m, 11 H) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 175.1, 166.0, 142.1, 106.9, 99.3, 85.8, 50.8,
1
ethyl acetate, 30:1) as a liquid. H NMR (300 MHz, CDCl3): δ =
5.08 (t, J = 9.5 Hz, 1 H, OCH), 3.73–3.55 (m, 4 H, OCH3 and
C=CCH), 2.95 (dd, J = 14.7, 10.8 Hz, 1 H, one proton of CH2),
2.67 (dd, J = 14.7, 8.4 Hz, 1 H, one proton of CH2), 2.00 (s, 3 H,
CH3), 1.96 (s, 3 H, CH3), 1.18 (d, J = 6.9 Hz, 3 H, CH3), 1.10 (d,
J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (75.4 MHz, CDCl3): δ =
175.0, 166.0, 140.4, 105.2, 99.5, 80.4, 50.7, 37.2, 31.6, 26.7, 20.8,
19.61, 19.55 ppm. IR (neat): ν = 2970, 2932, 2869, 1699, 1637,
˜
1463, 1435, 1361, 1352, 1261, 1229, 1189, 1118, 1062, 1045 cm–1.
MS (70 eV, EI): m/z (%) = 350 (30.77) [M]+, 223 (100). HRMS:
calcd. for C13H19O3I [M]+ 350.0379; found 350.0380.
2-Isopropyl-3-(methoxycarbonyl)-5-(2Ј,2Ј-pentamethylene-1Ј-iodo-
vinyl)-4,5-dihydrofuran (2j): The reaction of CaH2 (5.2 mg, 0.12
mmol), I2 (206.0 mg, 0.8 mmol), and 1j (52.6 mg, 0.2 mmol) in
THF (2 mL) afforded 2j (40.6 mg, 52%) after chromatography (pe-
troleum ether/dichloromethane, 2:1) as a liquid. 1H NMR
(300 MHz, CDCl3): δ = 5.16 (t, J = 9.6 Hz, 1 H, OCH), 3.73–3.55
(m, 4 H, OCH3 and C=CCH), 2.94 (dd, J = 14.6, 10.8 Hz, 1 H,
one proton of CH2), 2.69 (dd, J = 14.6, 8.9 Hz, 1 H, one proton
of CH2), 2.57–2.36 (m, 4 H, 2 CH2), 1.72–1.37 (m, 6 H, 3 CH2),
1.19 (d, J = 6.9 Hz, 3 H, CH3), 1.11 (d, J = 6.9 Hz, 3 H, CH3) ppm.
13C NMR (75.4 MHz, CDCl3): δ = 175.1, 166.0, 147.7, 103.2, 99.6,
79.7, 50.7, 42.2, 37.5, 32.5, 28.1, 27.3, 26.7, 26.4, 19.62, 19.60 ppm.
44.2, 37.0, 31.4, 26.7, 25.8, 25.5, 25.4, 19.7, 19.5 ppm. IR (neat): ν
˜
= 2927, 2851, 1697, 1639, 1468, 1436, 1348, 1300, 1258, 1230, 1189,
1120, 1065, 1044, 1009 cm–1. MS (70 eV, EI): m/z (%) = 404 (17.70)
[M]+, 43 (100). HRMS: calcd. for C17H25O3I [M]+ 404.0848; found
404.0850.
Typical Procedure for Suzuki–Miyaura Coupling of 2a
3-(Ethoxycarbonyl)-2-methyl-5-(1Ј-phenylvinyl)-4,5-dihydrofuran
(3): To a flame-dried Schlenk tube were added Pd(PPh3)4 (8.5 mg,
7.5 μmol), K3PO4·3H2O (80.9 mg, 0.3 mmol), phenylboronic acid
(27.1 mg, 0.225 mmol), toluene (1 mL), 2a (45.3 mg, 0.15 mmol),
and toluene (0.5 mL) sequentially under an atmosphere of argon.
The mixture was stirred at 110 °C in a preheated oil bath. Upon
completion of the reaction as monitored by TLC, the resulting mix-
IR (neat): ν = 2970, 2931, 2854, 1700, 1638, 1468, 1435, 1350, 1261,
˜
1228, 1119, 1065, 1046 cm–1. MS (70 eV, EI): m/z (%) = 390 (14.95)
[M]+, 181 (100). HRMS: calcd. for C16H23O3I [M]+ 390.0692;
found 390.0693.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20527
/KAP1
Date: 28-06-12 10:15:38
Pages: 8
B. Wan, X. Jiang, G. Jia, S. Ma
FULL PAPER
ture was concentrated and purified by chromatography on silica gel
tion of China (NO. 21072167) is greatly appreciated. We thank Mr.
Dengke Ma in our group for reproducing the results of 2e, 2k, and
(petroleum ether/ethyl acetate, 20:1) to afford 3[11a] (31.1 mg, 82%)
1
as a liquid. H NMR (300 MHz, CDCl3): δ = 7.41–7.27 (m, 5 H, 2l.
Ar-H), 5.53 (t, J = 9.6 Hz, 1 H, OCH), 5.43 (s, 1 H, one proton of
H2C=C), 5.35 (s, 1 H, one proton of H2C=C), 4.14 (q, J = 7.1 Hz,
2 H, CO2CH2), 3.12 (dd, J = 13.2, 11.7 Hz, 1 H, one proton of
C=CCH2), 2.67 (dd, J = 14.3, 8.3 Hz, 1 H, one proton of
C=CCH2), 2.28 (s, 3 H, C=CCH3), 1.24 (t, J = 7.2 Hz, 3 H,
CH3) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 167.5, 166.1, 147.3,
138.2, 128.5, 128.0, 126.6, 112.4, 101.8, 82.3, 59.5, 36.1, 14.4,
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14.1 ppm. IR (neat): ν = 2980, 1697, 1651, 1496, 1444, 1384, 1324,
˜
1259, 1224, 1143, 1081 cm–1. MS (70 eV, EI): m/z (%) = 258 (2.16)
[M]+, 141 (100).
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S. Yu, M. Zhang, K. Liao, L. Wang, P. Zhang, J. Org. Chem.
2010, 75, 5743–5745.
3-(Ethoxycarbonyl)-2-methyl-5-[octa-1Ј,3Ј(E)-dien-2Ј-yl]-4,5-di-
hydrofuran (4): The reaction of Pd(PPh3)4 (9.0 mg, 7.5 μmol),
K3PO4·3H2O (79.1 mg, 0.3 mmol), (1E)-hexenylboronic acid
(29.2 mg, 0.225 mmol), and 2a (46.2 mg, 0.15 mmol) in toluene
(1.5 mL) afforded 4 (32.1 mg, 81%) after chromatography (petro-
leum ether/diethyl ether, 25:1) as a liquid. 1H NMR (300 MHz,
CDCl3): δ = 6.03 [d, J = 16.2 Hz, 1 H, (C=C)CH=C], 5.62 [dt, J
= 15.9, 6.9 Hz, 1 H, (C=C)C=CH], 5.23 (dd, J = 10.5, 8.7 Hz, 1
H, OCH), 5.07 (s, 1 H, one proton of H2C=C), 5.01 (s, 1 H, one
proton of H2C=C), 4.16 (q, J = 7.1 Hz, 2 H, CO2CH2), 3.15 (t, J
= 12.3 Hz, 1 H, one proton of C=CCH2), 2.68 (dd, J1 = 13.8, J2
= 7.8 Hz, 1 H, one proton of C=CCH2), 2.24 (s, 3 H, C=CCH3),
2.10 (q, J = 6.7 Hz, 2 H, CH2), 1.46–1.20 (m, 7 H, 2 CH2 and
CH3), 0.90 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 167.6, 166.1, 145.3, 131.9, 128.3, 111.5, 101.8, 81.0,
59.4, 36.4, 32.8, 31.3, 22.2, 14.4, 14.0, 13.9 ppm. IR (neat): ν =
˜
2957, 2929, 1703, 1655, 1647, 1461, 1383, 1331, 1257, 1227, 1142,
1084 cm–1. MS (70 eV, EI): m/z (%) = 264 (8.50) [M]+, 43 (100).
HRMS: calcd. for C16H24O3 [M]+ 264.1725; found 264.1727.
Procedure for Sonogashira Coupling of 2a.
3-(Ethoxycarbonyl)-2-methyl-5-(oct-1Ј-en-3Ј-yn-2Ј-yl)-4,5-dihydro-
furan (5): To a flame-dried Schlenk tube was added Pd(PPh3)2Cl2
(4.1 mg, 6.0 μmol), CuI (1.2 mg, 6.0 μmol), Et3N (24.8 mg,
0.24 mmol), CH3CN (1 mL), 1-hexyne (34.7 mg, 0.4 mmol),
CH3CN (0.5 mL), 2a (60.5 mg, 0.2 mmol), and CH3CN (0.5 mL)
sequentially under an atmosphere of argon. The mixture was
stirred at room temperature and monitored by TLC. Upon comple-
tion, the resulting mixture was concentrated and purified by
chromatography on silica gel (petroleum ether/diethyl ether, 40:1)
to afford 5 (43.7 mg, 84%) as a liquid. 1H NMR (300 MHz,
CDCl3): δ = 5.38 (s, 1 H, one proton of H2C=C), 5.35 (s, 1 H, one
proton of H2C=C), 4.98 (dd, J = 10.1, 8.0 Hz, 1 H, OCH), 4.15 (q,
J = 7.1 Hz, 2 H, CO2CH2), 3.05 (dd, J = 14.4, 10.8 Hz,1 H, one
proton of C=CCH2), 2.89 (dd, J = 14.7, 7.5 Hz, 1 H, one proton
of C=CCH2), 2.29 (t, J = 6.8 Hz, 2 H, CH2), 2.20 (s, 3 H,
C=CCH3), 1.53–1.31 (m, 4 H, 2 CH2), 1.26 (t, J = 7.2 Hz, 3 H,
CH3), 0.88 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 167.3, 165.9, 131.5, 119.9, 101.9, 92.6, 82.9, 76.9, 59.4,
[5] For reviews, see: a) R. C. Larock, Acetylene Chemistry: Chem-
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Stang, R. R. Tykwinski), Wiley-VCH, Weinheim, Germany,
2005, ch. 2, pp. 51–99; b) Y. Yamamoto, I. D. Gridnev, N. T.
Patil, T. Jin, Chem. Commun. 2009, 5075–5087.
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Gridnev, Y. Yamamoto, J. Org. Chem. 2010, 75, 1266–1270; f)
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Chem. Commun. 2011, 47, 4541–4543.
35.2, 30.5, 21.8, 18.9, 14.4, 13.9, 13.5 ppm. IR (neat): ν = 2959,
˜
2933, 2871, 2224, 1702, 1654, 1462, 1383, 1321, 1255, 1224, 1142,
1085 cm–1. MS (70 eV, EI): m/z (%) = 262 (1.77) [M]+, 43 (100).
HRMS: calcd. for C16H22O3 [M]+ 262.1569; found 262.1569.
Supporting Information (see footnote on the first page of this arti-
[7]
a) N. Krause, A. S. K. Hashmi (Eds.), Modern Allene Chemis-
try, Wiley-VCH, Weinheim, Germany, 2004; b) S. Ma, Acc.
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cle): Copies of the 1H NMR and 13C NMR spectra of the products.
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X.-Y. Liu, Y.-M. Liang, Org. Lett. 2007, 9, 397–400, for an
earlier report on the iodocyclization of 4-alkynyl and 4-alkenyl-
malonate derivatives, see: b) O. Kitagawa, T. Inoue, K. Hirano,
T. Taguchi, J. Org. Chem. 1993, 58, 3106–3112.
Acknowledgments
Financial support from the National Basic Research Program of
China (2011CB808700) and the National Natural Science Founda-
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20527
/KAP1
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Pages: 8
Electrophilic Cyclization of 2-(2Ј,3Ј-Allenyl)acetylacetates
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Received: April 22, 2012
1653–1656.
Published Online: ᭿
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Job/Unit: O20527
/KAP1
Date: 28-06-12 10:15:38
Pages: 8
B. Wan, X. Jiang, G. Jia, S. Ma
FULL PAPER
Cyclization
B. Wan, X. Jiang, G. Jia,*
S. Ma* .............................................. 1–8
Electrophilic Cyclization of 2-(2Ј,3Ј-All-
enyl)acetylacetates with Iodine Using Cal-
cium Hydride as the Base
A facile and efficient protocol for the syn-
thesis of 4,5-dihydrofuran derivatives via
iodine-mediated cyclization of various 2-
(2Ј,3Ј-allenyl)acetylacetates with CaH2 as
the base has been developed. The yields
range from moderate to good. The re-
sulting products can be used for further
elaboration by palladium-catalyzed cou-
pling reactions.
Keywords: Cyclization / Iodine / Allenes /
Oxygen heterocycles
8
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