Electrophile-induced cyclization/migration reaction for the synthesis of 2,3-dihydro-5-iodopyran-4-one

Article abstract of DOI:10.1021/jo800556e

(Chemical Equation Presented) A novel method for the construction of 2,3-dihydro-5-iodopyran-4-one through a domino cyclization/migration reaction of 1-alkynyl-2,3-epoxy alcohol was developed. Wet solvent is essential for this reaction. The resulting iodine-containing product can be readily elaborated to more complex products by using known organopalladium chemistry.

Full text of DOI:10.1021/jo800556e

the application in a tandem reaction.9 Despite this, most of these
reactions are catalyzed by Lewis acid and the reaction induced
by a π-activator is rare.
Electrophile-Induced Cyclization/Migration
Reaction for the Synthesis of
2,3-Dihydro-5-iodopyran-4-one
Shu-Guang Wen,†,‡ Wei-Min Liu,† and Yong-Min Liang*,†,§
State Key Laboratory of Solid Lubrication, Lanzhou Institute
of Chemical Physics, Chinese Academy of Science,
Lanzhou 730000, People’s Republic of China, Graduate
School of Chinese Academy of Science, Beijing 100039,
People’s Republic of China, and State Key Laboratory of
Applied Organic Chemistry, Lanzhou UniVersity, Lanzhou
730000, People’s Republic of China
Electrophilic cyclization has emerged as an important topic
in organic chemistry.10 Many kinds of heterocycles and car-
bocycles can be constructed by this method. The electrophile
has been proven to be very reactive to the unsaturated bond.
Recently Kirsch has reported an interesting tandem reaction for
the synthesis of 4-iodo-3-furanone from 2-alkynyl-2-silyloxy
carbonyl compounds.11 This reaction was believed to combine
the process of a heterocyclization with a 1,2-alkyl shift. As part
of our program of electrophile induced reaction,12 we envisioned
that 2,3-dihydro-5-iodopyran-4-one would be produced from the
iodo-induced semipinacol reaction of 1-alkynyl-2,3-epoxy al-
cohol (eq 1). In this paper, we will report our results.
liangym@lzu.edu.cn
ReceiVed March 12, 2008
The epoxide alcohol 1a was synthesized and the reaction was
examined under various conditions (Table 1). The reaction was
initially examined with 3 equiv of I2 as the electrophile in the
presence of 3 equiv of NaHCO3 in CH3CN at 0 °C for 12 h
(entry 1). The expected rearrangement product 2a was produced
in 60% yield and the enone 3a was isolated in 23% yield.13 No
reaction was detected with NIS as the reagent. Then ICl was
tested in dry CH3CN and no reaction occurred. However, the
A novel method for the construction of 2,3-dihydro-5-
iodopyran-4-one through a domino cyclization/migration
reaction of 1-alkynyl-2,3-epoxy alcohol was developed. Wet
solvent is essential for this reaction. The resulting iodine-
containing product can be readily elaborated to more complex
products by using known organopalladium chemistry.
(6) (a) Magnusson, G.; Thoren, S. J. Org. Chem. 1973, 38, 1380. (b) Wang,
F.-P.; Chen, Q.-H.; Li, B.-G. Tetrahedron 2001, 57, 4705. (c) Hauer, B.; Bickley,
J. F.; Massue, J.; Pena, P. C. A.; Roberts, S. M.; Skidmore, J. Can. J. Chem.
2002, 80, 546.
(7) (a) Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Shi, Y. Org. Lett.
2002, 4, 363. (b) Li, X.; Wu, B.; Zhao, X. Z.; Jia, Y. X.; Tu, Y. Q.; Li, D. R.
Synlett 2003, 623.
(8) (a) Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Chen, W. M. Synlett
2003, 1497. (b) Wang, M.; Wang, B. M.; Shi, L.; Tu, Y. Q.; Fan, C. A.; Wang,
S. H.; Hu, X. D.; Zhang, S. Y. Chem. Commun. 2005, 5580.
Semipinacol rearrangement is a powerful means of creating
a new carbon-carbon bond, frequently with high stereocontrol.1
It has found wide application in the construct of various
structures, such as stereodefined mono- and disubstituted aldol
adducts,2 diols,3 ketones,4 ring-expanded5 and ring-contracted6
products, ꢀ-amino ketones,7 and ꢀ-halo ketones.8 Furthermore,
some more complex structures could be synthesized through
(9) (a) Jung, M. E.; Heuvel, A. v. d. Org. Lett. 2003, 5, 4705. (b) Marson,
C. M. Tetrahedron 2000, 56, 8779. (c) Fan, C.-A.; Wang, B.-M.; Tu, Y.-Q.;
Song, Z.-L. Angew. Chem., Int. Ed. 2001, 40, 3877.
(10) For selected recent papers on the electrophilic iodocyclizations of
arylalkynes, see: (a) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org.
Lett. 2005, 7, 763. (b) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432. (c)
Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511. (d) Yue,
D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292. (e) Yue, D.; Yao, T.;
Larock, R. C. J. Org. Chem. 2006, 71, 62. (f) Hu, T.; Liu, K.; Shen, M.; Yuan,
X.; Tang, Y.; Li, C. J. Org. Chem. 2007, 72, 8555. (g) Pattarozzi, M.; Zonta,
C.; Broxterman, Q. B.; Kaptein, B.; De Zorzi, R.; Randaccio, L.; Scrimin, P.;
Licini, G. Org. Lett. 2007, 9, 2365. (h) Worlikar, S. A.; Kesharwani, T.; Yao,
T.; Larock, R. C. J. Org. Chem. 2007, 72, 1347. (i) Ciochina, R.; Grossman,
R. B. Chem. ReV. 2006, 106, 3963. (j) Fischer, D.; Tomeba, H.; Pahadi, N. K.;
Patil, N. T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 4764. (k) Barluenga,
J.; Palomas, D.; Rubio, E.; Gonzalez, J. M. Org. Lett. 2007, 9, 2823.
(11) Crone, B.; Kirsch, S. F. J. Org. Chem. 2007, 72, 5435.
† Lanzhou Institute of Chemical Physics.
‡ Graduate School of Chinese Academy of Science.
§ Lanzhou University.
(1) For a recent review on semipinacol rearrangement, see : Snape, T. J.
Chem. Soc. ReV. 2007, 36, 1823.
(2) (a) Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimazaki,
M.; Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 3827. (b) Shimazaki, M.;
Hara, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 5891. (c)
Marson, C. M.; Khan, A.; Porter, R. A.; Cobb, A. J. A. Tetrahedron Lett. 2002,
43, 6637. (d) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208.
(e) Jung, M. E.; Heuvel, A. v. d.; Leach, A. G.; Houk, K. N. Org. Lett. 2003, 5,
3375. (f) Jung, M. E.; Hoffmann, B.; Rausch, B.; Contreras, J.-M. Org. Lett.
2003, 5, 3159.
(12) (a) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou, F.-R.; Huang, S.-H.; Liu,
X.-Y.; Liang, Y.-M. Org. Lett. 2007, 9, 397. (b) Wen, S.-G.; Liu, W.-M.; Liang,
Y.-M. Synthesis 2007, 3295. (c) Xie, Y.-X.; Liu, X.-Y.; Wu, L.-Y.; Han, Y.;
Zhao, L.-B.; Fan, M.-J.; Liang, Y.-M. Eur. J. Org. Chem. 2008, 1013.
(13) The enone 3a was the product of Meyer-Schuster rearrangement and
the structure was conformed by NMR and DEPT spectra. A similar result was
observed in ref 11. For a related reaction, see: (a) Swaminathan, S.; Narayanan,
K. V. Chem. ReV. 1971, 71, 429. (b) Douglas, A. E.; Gregory, B. D. Org. Lett.
2006, 8, 4027.
(3) Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.; Tu, Y. Q. Angew. Chem., Int. Ed.
2004, 43, 1702.
(4) Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337.
(5) Dake, G. R.; Fenster, M. D. B.; Fleury, M.; Patrick, B. O. J. Org. Chem.
2004, 69, 5676.
4342 J. Org. Chem. 2008, 73, 4342–4344
10.1021/jo800556e CCC: $40.75 2008 American Chemical Society
Published on Web 05/13/2008

TABLE 1. Optimization of Electrophile Induced Tandem Reaction
Conditionsa
TABLE 2. Synthesis of 2,3-Dihydro-5-iodopyran-4-one from
1-Alkynyl-2,3-epoxy Alcohola
yield (%)
entry
[I] (equiv)
additives
solvent
2a
3a
1b
2
I2 (3.0)
ICl (3.0)
NaHCO3
NaHCO3
CH3CN
CH3CN
60
23
64 (1:0.24)c
3
4
ICl (3.0)
ICl (3.0)
Na2CO3
HOAc
CH3CN
CH3CN
67 (1:0.29)c
60 (1:0.35)c
5
7
8
9
ICl (3.0)
ICl (3.0)
ICl (3.0)
ICl (3.0)
H2O
H2O
H2O
H2O
CH3CN
CH3OH
THF
71
0
0
0
66
30d
CH3NO2
decomposed
10
11
ICl (3.0)
ICl (1.5)
H2O
H2O
dioxane
CH3CN
decomposed
40
0
a All the reactions were run with 0.1 mmol 1a,
3
equiv of
electrophile, 3 equiv of additive in 1 mL of solvent at 15 °C for 5 min
unless otherwise specified; water was used in the ratio of 1/40 of the
solvent. b The reaction was run for 12 h. c The ratio (2a:3a) was
determined by H NMR. d About 14% of 1a was recovered.
1
reaction could be completed in 5 min after the addition of
NaHCO3 (entry 2). Total yield of 64% (2a:3a ) 1:0.24) was
achieved with 0.10 mmol of 1a, 3 equiv of NaHCO3, and 3
equiv of ICl in 1 mL of CH3CN at 15 °C. Similar results were
obtained with other additives such as Na2CO3 and HOAc (entries
3 and 4). To our surprise, the addition of water could give the
product 2a exclusively in 71% yield. This result makes the
workup process easier. Other solvents, such as MeOH and THF,
resulted in lower yields. The substrate decomposed in the solvent
dioxane or CH3NO2.
With the optimized conditions in hand, various substrates
were investigated and the results are summerized in Table 2.
The aryl alkynes bearing different functional groups, such as
acetyl, methyl, methoxy, chloro, and bromo groups, are readily
accommodated under the standard conditions (entries 2-6).
Although the reactive acetyl group is contained, 2b was still
obtained in 44% yield. The reaction also tolerated substitution
on the alkyne with the alkyl group and a yield of 55% was
achieved (entry 7). The substrates with different groups on the
oxirane were also investigated: 2h and 2i were obtained in 42%
and 70% yield. When R2 ) i-Pr, 2j was isolated in 53% yield.
Substitution on the cycle also facilitated this process and
moderate yields were achieved (entries 11 and 12). By protecting
the hydroxy group with TMS, 2a was isolated in 49% yield.
Theacycliccompound2-(phenylethynyl)-7-oxabicyclo[4.1.0]heptan-
2-ol was also investigated but it decomposed quickly under the
standard conditions.
a All the reactions were run with 0.2 mmol 1a, 3 equiv of ICl in 2
mL of wet CH3CN at 15 °C for 5 min; water was used in the ratio of 1/
40 of CH3CN. b Isolated yield. c The mixture of diastereoisomers was
used.
yields, thus accomplishing the synthesis of fully substituted 2,3-
dihydropyran-4-one.
The utility of 2,3-dihydro-5-iodopyran-4-ones produced by
this chemistry as useful synthetic intermediates for further
elaboration was briefly investigated by the palladium-catalyzed
reaction. The Sonogashira reaction14 (eq 2) and Suzuki cou-
pling15 (eq 3) of 2a afforded the anticipated products in good
Although the NMR spectroscopic data support the formation
of 2,3-dihydro-5-iodopyran-4-one (2), the structure was unam-
biguously secured by an X-ray crystal structure analysis of
compound 2a (Figure 1).
(14) (a) Miyaura, N.; Yanagi, T.; Suzuki, K. Synth. Commun. 1981, 11, 513.
(b) Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang,
P. J. Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2.
J. Org. Chem. Vol. 73, No. 11, 2008 4343

(MgSO4), and concentrated. The residue was purified by flash
column chromatography on silica (P/EtOAc ) 95/05) to give 2,3-
dihydro-5-iodopyran-4-one (2a) as a light yellow solid (61 mg,
71%): mp 128-130 °C; 1H NMR (300 MHz, CDCl3) δ 7.66-7.64
(m, 2H), 7.48-7.36 (m, 8H), 5.49 (s, 1H), 2.31-2.17 (m, 1H),
1.94-1.84 (m, 2H), 1.78-1.53 (m, 3H), 1.40-1.30 (m, 1H),
1.27-1.15 (m, 1H); 13C NMR (75 MHz) δ 193.2, 170.3, 135.5
135.3, 131.1, 129.7, 128.9, 128.4, 128.3, 127.9, 87.3, 55.7, 32.9,
30.5, 25.7; IR (neat, cm-1) 2952, 2868, 1668, 1552, 1447, 1280,
1049, 698. Anal. Calcd for C21H19IO2: C, 58.62; H, 4.45. Found:
C, 58.67; H, 4.72.
General Procedure for the Sonogashira Coupling of 2,3-Di-
hydro-5-iodopyran-4-one (2a). 2,3-Dihydro-5-iodopyran-4-one
(2a; 86 mg, 0.200 mmol), PdCl2(PPh3)2 (7 mg, 0.05 equiv),
phenylacetylene (22 mg, 1.0 equiv), and CuI (4 mg, 0.1 equiv)
were taken up in THF (2 mL) at 0 °C. Diisopropylamine (60 mg,
3.0 equiv) was added, and the resulting mixture was stirred at 23
°C for 6 h. The reaction mixture was diluted with Et2O (20 mL)
and washed with aqueous HCl (1 M, 20 mL). The layers were
separated and the aqueous layer was extracted with Et2O (2 × 10
mL). The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated under reduced pressure. Purification
of the residue by flash chromatography on silica (P/EtOAc ) 98/
02) gave 2,3-dihydropyran-4-one (4a) as a yellow solid (68 mg,
0.168 mmol, 84%): mp 178-180 °C; 1H NMR (300 MHz, CDCl3)
δ 8.12-8.09 (m, 2H), 7.52-7.39 (m, 10H), 7.32-7.25 (m, 3H),
5.49 (s, 1H), 2.36-2.26 (m, 1H), 1.93-1.88 (m, 2H), 1.76-1.59
(m, 3H), 1.40-1.29 (m, 1H), 1.23-1.17 (m, 1H); 13C NMR (75
MHz): δ 196.1, 171.2, 135.4, 133.0, 131.7, 131.2, 129.4, 128.8,
128.4, 128.3, 128.1, 128.0, 127.8, 123.7, 99.7, 94.8, 86.9, 83.4,
55.0, 32.0, 30.0, 25.9, 25.8; IR (neat, cm-1) 2954, 2867, 1660, 1552,
1384, 1269, 1140, 751, 693. Anal. Calcd for C29H24O2: C, 86.11;
H, 5.98. Found: C, 86.32; H, 5.77.
FIGURE 1. X-ray data for 2a.
SCHEME 1. Plausible Mechanism
An electrophile-induced cyclization/migration mechanism was
proposed for this reaction (Scheme 1). Coordination of the iodine
electrophile to the triple bond produces iodonium intermediate
A, which after nucleophilic attack of the oxygen generates
oxonium ion B. Subsequent 1,2-shift gives 2,3-dihydro-5-
iodopyran-4-one through a formal semipinacol rearrangement.6,16
In conclusion, an efficient synthesis of highly substituted 2,3-
dihydro-5-iodopyran-4-one starting from 1-alkynyl-2,3-epoxy
alcohol has been developed that contains a tandem heterocy-
clization and a 1,2-alkyl shift process. An iodide is readily
introduced into the 5-position by using ICl as the electrophile.
The resulting iodine-containing products can be readily elabo-
rated to more complex products by using known organopalla-
dium chemistry.
General Procedure for the Suzuki Coupling of 2,3-Di-
hydro-5-iodopyran-4-one (2a). A solution of Na2CO3 (38 mg,
0.364 mmol) in water (0.10 mL) was added to a solution of 2,3-
dihydro-5-iodopyran-4-one (2a; 51 mg, 0.117 mmol) and phenyl-
boronic acid (19 mg, 0.152 mmol) in DMF (0.40 mL). The reaction
mixture was degassed with argon for 10 min. After addition of
Pd(OAc)2 (0.3 mg, 1 mol %) the reaction mixture was stirred at 40
°C for 24 h. The reaction mixture was quenched by addition of
saturated aqueous NH4Cl (10 mL) and diluted with Et2O (10 mL).
The layers were separated and the aqueous layer was extracted with
Et2O (2 × 10 mL). The combined organic layers were washed with
brine, dried (Na2SO4), and concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica (P/
EtOAc ) 98/02) gave 2,3-dihydropyran-4-one (5a) as a colorless
solid (35 mg, 0.092 mmol, 79%): mp 126-128 °C; 1H NMR (300
MHz, CDCl3) δ 7.51-7.49 (m, 2H), 7.44-7.39 (m, 3H), 7.27-7.20
(m, 6H), 7.19-7.11 (m, 2H), 7.08-7.05 (m, 2H), 5.54 (s, 1H),
2.32-2.26 (m, 1H), 1.98-1.94 (m, 2H), 1.75-1.58 (m, 3H),
1.38-1.34 (m, 1H), 1.25-1.16 (m, 1H); 13C NMR (75 MHz) δ
197.1, 166.3, 136.2, 134.5, 133.9, 131.6, 130.1, 129.9, 128.6, 128.5,
128.2, 128.0, 127.7, 126.8, 115.7, 86.3, 54.6, 31.9, 30.0, 25.9; IR
(neat, cm-1) 2954, 2868, 1661, 1591, 1566, 1367, 1230, 734, 698.
Anal. Calcd for C27H24O2: C, 85.23; H, 6.36. Found: C, 85.48; H,
6.16.
Experiment Section
General Experimental Details. All commercially available
chemicals were used without further purification. The 1-alkynyl-
2,3-epoxy alcohol compounds (1a-l) were synthesized as previ-
ously reported.17
General Procedure for the 2,3-Dihydro-5-iodopyran-4-one
Formation. To a solution of 1a (61 mg, 0.20 mmol) in 2 mL of
CH3CN/H2O (40:1) was added ICl (97 mg, 0.60 mmol). The mixture
was stirred at 15 °C for 5 min. The solution was quenched with aq
Na2S2O3 (5 mL) and extracted with Et2O (2 × 10 mL). The
combined organic phases were washed with saturated NaCl, dried
Acknowledgment. The authors thank the NSF (NSF-
20672049 and NSF-20621091) for financial support.
Supporting Information Available: Experimental details and
characterization data for all new compounds and X-ray data of
2a (CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
(15) (a) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566–1568. (b)
Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(16) Bickley, J. F.; Hauer, B.; Pena, P. C. A.; Roberts, S. M.; Skidmore, J.
J. Chem. Soc., Perkin Trans. 2001, 1, 1253.
(17) Shu, X.-Z.; Liu, X.-Y.; Xiao, H.-Q.; Ji, K.-G.; Guo, L.-N.; Qi, C.-Z.;
Liang, Y.-M. AdV. Synth. Catal. 2007, 349, 2493.
JO800556E
4344 J. Org. Chem. Vol. 73, No. 11, 2008