Highly regio- and stereoselective cyclic iodoetherification of 4,5-alkadienols. An efficient preparation of 2-(1′(Z)-iodoalkenyl) tetrahydrofurans

Article abstract of DOI:10.1021/jo802079b

(Chemical Equation Presented) In this paper, an efficient way to synthesize 2-(1′(Z)-iodoalkenyl)tetrahydrofurans from 4,5-alkadienols and I ₂ was developed. The reaction of the 4,5-allenols with a substituent in the 3-position afforded the trans-2,3-disubstituted tetrahydrofurans with very high diastereoselectivity. However, when the axially optically active 4,5-allenol was treated with I₂ in n-hexane, the efficiency for chirality transfer was low. This problem was circumvented by conducting the reaction in CH₂Cl₂ at room temperature and applying N-iodosuccinimide as the electrophilic reagent; however, the Z/E ratio for the products is much lower. Highly optically active Z-products may be prepared via the kinetic resolution via a Sonogashira coupling reaction with propargyl alcohol.

Full text of DOI:10.1021/jo802079b

synthesis of substituted tetrahydrofuran derivatives.5 Ba¨ckvall
et al. reported the Pd(OAc)2-catalyzed bromoetherification
of 4,5-allenols in which the Z/E selectivity ranged from 84/
16 to 94/6.6 Herein, we wish to report an efficient cyclic
iodoetherification of 4,5-allenols with I2 or N-iodosuccinimide
(NIS), which is cheap/readily available and forms the
tetrahydrofuran derivatives including the optically active ones
with very high regio- and stereoselectivity.
The starting 4,5-allenols were prepared according to the
published procedure from propargylic alcohols 1.6 Claisen
rearrangement and the subsequent reduction would form 3,4-
allenols 2a-n, which were tosylated and subsequently treated
with NaCN to afford 4,5-allenylic nitriles. Hydrolysis of the
nitriles with NaOH and reduction of the acids with LiAlH4
would finally afford 4,5-allenols 5a-n (Tables S1-4 in the
Supporting Information). Such methods were also used for the
preparation of optically active 4,5-allenols (R)-5b and (R)-5c
using readily available propargylic alcohols (R)-1b and (R)-1c
as the starting material (Scheme 1).
Highly Regio- and Stereoselective Cyclic
Iodoetherification of 4,5-Alkadienols. An Efficient
Preparation of
2-(1′(Z)-Iodoalkenyl)tetrahydrofurans
Bo Lu¨, Xinpeng Jiang, Chunling Fu,* and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis,
Department of Chemistry, Zhejiang UniVersity, Hangzhou
310027, Zhejiang, People’s Republic of China
masm@mail.sioc.ac.cn
ReceiVed September 20, 2008
Electrophilic Cyclization. The initial electrophilic cycliza-
tion experiment was conducted by stirring a mixture of 4,5-
decadienol 5a and I2 in CH2Cl2 at room temperature.
Fortunately, we observed the formation of tetrahydrofuran
product 6a in 81% yield with a Z/E ratio of 96/4. The
Z-configuration of the carbon-carbon double bond in 6a was
In this paper, an efficient way to synthesize 2-(1′(Z)-
iodoalkenyl)tetrahydrofurans from 4,5-alkadienols and I2 was
developed. The reaction of the 4,5-allenols with a substituent
in the 3-position afforded the trans-2,3-disubstituted tetrahy-
drofurans with very high diastereoselectivity. However, when
the axially optically active 4,5-allenol was treated with I2 in
n-hexane, the efficiency for chirality transfer was low. This
problem was circumvented by conducting the reaction in
CH2Cl2 at room temperature and applying N-iodosuccinimide
as the electrophilic reagent; however, the Z/E ratio for the
products is much lower. Highly optically active Z-products
may be prepared via the kinetic resolution via a Sonogashira
coupling reaction with propargyl alcohol.
1
determined by its H-1H NOESY analysis (Figure 1 and
Supporting Information). Seven-membered ring 2-butyl-3-
iodo-2,5,6,7-tetrahydrooxepin 7a was not formed (entry 1,
Table 1). Encouraged by these results, we screened a series
of solvents including CH3CN, THF, and DMF; however, they
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of allenes from this group, see: (a) Zhou, C.; Fu, C.; Ma, S. Angew. Chem., Int.
Ed. 2007, 46, 4379. (b) Gu, Z.; Deng, Y.; Shu, W.; Ma, S. AdV. Synth. Catal.
2007, 349, 1653. (c) Fu, C.; Li, J.; Ma, S. Chem. Commun. 2005, 4119. (d)
Chen, G.; Fu, C.; Ma, S. J. Org. Chem. 2006, 71, 9877. (e) He, G.; Zhou, C.;
Fu, C.; Ma, S. Tetrahedron 2007, 63, 3800. (f) Zhou, C.; Fu, C.; Ma, S
Tetrahedron 2007, 63, 7612. For electrophilic cyclization reactions, see: (g) Fu,
C.; Ma, S. Eur. J. Org. Chem. 2005, 3942. (h) Chen, G.; Fu, C.; Ma, S.
Tetrahedron 2006, 62, 4444. (i) Jiang, X.; Fu, C.; Ma, S. Chem.sEur. J. 2008,
14, 9656. For a review on electrophilic addition of allenes, see: Ma, S. Chapter
10 in ref 1c.
(3) (a) Jiang, Z.; Chen, R.-Y.; Chen, Y.; Yu, D.-Q. J. Nat. Prod. 1998, 61,
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J. Nat. Prod. 2005, 68, 1656. (b) Hashimoto, T.; Harusawa, S.; Araki, L.;
Zuiderveld, O. P.; Smit, M. J.; Imazu, T.; Takashima, S.; Yamamoto, Y.;
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J.; Dulce`re, J.-P. Org. Lett. 2004, 6, 2027. (f) Yang, X.; Wang, Z.; Zhu, Y.;
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Org. Chem. 2003, 2388.
Although allenes were considered to be highly unstable
for a long period of time, during the last 10 years, much
attention has been paid to this area demonstrating the
potential of allenes in organic synthesis.1 Recently, we have
reported electrophilic cyclization of functionalized allenes
with high regioselectivity.2 On the other hand, tetrahydrofuran
is a very important unit in many potentially useful natural
products.3,4 Recently, many groups have focused on the
(1) For most recent reviews on the chemistry of allenes, see: (a) Ma, S. Chem.
ReV. 2005, 105, 2829. (b) Ma, S. Acc. Chem. Res. 2003, 36, 701. (c) Krause,
N.; Hashmi, A. S. K. Modern Allene Chemistry; Wiley-VCH: Weinheim, 2004.
(d) Sydnes, L. K. Chem. ReV. 2003, 103, 1133. (e) Zimmer, R.; Dinesh, C. U.;
Nandanan, E.; Khan, F. A. Chem. ReV. 2000, 100, 3067. (f) Marshall, J. A.
Chem. ReV. 2000, 100, 3163. (g) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000,
39, 3590. (h) Bates, R. W.; Satcharoen, V. Chem. Soc. ReV. 2002, 31, 12. (i)
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Res. 2003, 36, 284. (k) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34,
535. (l) Wang, K. K. Chem. ReV. 1996, 96, 207. (m) Ma, S. Aldrichchim. Acta
2007, 40, 91. (n) Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003,
36, 773.
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438 J. Org. Chem. 2009, 74, 438–441
10.1021/jo802079b CCC: $40.75 2009 American Chemical Society
Published on Web 12/03/2008

SCHEME 1
tereoselectively (entries 6-9, Table 2) and the relative con-
figurations of these products 6f-i were confirmed to be trans
according to 1H-1H NOESY analysis of 6i (Figure 1 and
Supporting Information).
The reactions of 6,6-disubstituted-4,5-allenols 5j,k were also
conducted under the optimized conditions to afford the elec-
trophilic cyclization products 6j,k. The reaction of 5l with a
methyl substituted at the 3-position also afforded the trans-
product 6l with a dr of >99/1 (Scheme 2).
SCHEME 2
all showed poor stereoselectivity for the formation of the
carbon-carbon double bond (entries 2-4, Table 1). Further
study revealed that the reaction in n-hexane could afford the
product 6a in a higher stereoselectivity, although the yield
was lower (entry 6, Table 1). With 1 equiv of I2, the yield is
88% with the same level of stereoselectivity (entry 7, Table
1). However, the reaction at -20 °C afforded 6a in relatively
lower yield and stereoselectivity (entry 8, Table 1).
However, 4-monosubstituted 4,5-allenol 5m showed poor
selectivity toward I2 under the optimized conditions affording
a mixture of the expected tetrahydrofuran derivative 6m and a
E/Z mixture of 5,6-diiodo-4-(n-butyl)-4-hexenol 8m. In addition,
the reaction of 4,6,6-trisubstituted allenol 5n under the standard
reaction failed to afford cyclization product. Luckily, by
introducing NIS the iodoetherification reaction in CH2Cl2
afforded the expected cyclization products 6m and 6n easily at
room temperature in 84% and 50% yields, respectively (Scheme
3).
SCHEME 3
FIGURE 1. 1H-1H NOESY analysis of 6a and 6i.
The scope of the cyclic iodoetherification of 4,5-allenols was
explored under the optimized conditions (entry 7, Table 1).
Some typical results are summarized in Table 2. It is noteworthy
that the reaction afforded 2-(1′(Z)-iodoalkenyl)tetrahydrofuran
derivatives in good yield and fairly high Z-stereoselectivity. R1
may be alkyl group and R2 as well as R3 can be H or alkyl
group. In addition, if a substituent R3 was introduced at the
3-position, only one diastereoisomer was formed highly dias-
TABLE 1. Cyclic Iodo-etherification of 5a under Different
Conditions
entry I2 (equiv)
solvent
time (h) yield of 6aa (%)
Z/Ea
1
2
3
4
5
6
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.0
CH2Cl2
CH3CN
THF
1.5
1.4
1.8
81
89
85
82
76
58
88
75
96/4
91/9
89/11
89/11
97/3
99/1
98/2
95/5
In addition, it is surprising for us to observe that when
optically active 4,5-allenol (R)-5b was used, its reaction with
I2 in n-hexane afforded the related products (S)-6b in 80% yield
with only 20% ee. Further screening led to the observations
that the reaction of (R)-5b and (R)-5c with NIS in CH2Cl2
afforded (S)-Z-6b, (R)-E-6b and (S)-Z-6c, (R)-E-6c in a Z/E ratio
of 90/10 without obvious loss of the chirality. Further kinetic
DMF
16
c-hexane
n-hexane
n-hexane
n-hexane
1.2
1.9
1.5
2
7
8 b
a
Determined by H NMR analysis (400 MHz). b This experiment was
1
carried out at -20 °C.
J. Org. Chem. Vol. 74, No. 1, 2009 439

TABLE 2. Iodocyclization Reaction of Differently Substituted 4,5-Allenols with I2
entry
R1
R2
R3
yield of 6 %a
time (min)
Z/Eb
dr (trans/cis)b
1
2
3
4
5
6
7
8
9
n-C4H9
n-C5H11
n-C6H13
CH3
n-C3H7
CH3
CH3
n-C6H13
n-C4H9
H
H
H
H
H
H
H
H
(5a)
(5b)
(5c)
(5d)
(5e)
(5f)
(5g)
(5h)
(5i)
81 (6a)
79 (6b)
76 (6c)
42 (6d)
78 (6e)
73 (6f)
59 (6g)
81 (6h)
81 (6i)
45
50
60
40
60
30
40
25
33
97/3
97/3
97/3
>99/1
>99/1
97/3
97/3
98/2
96/4
C2H5
n-C4H9
H
H
H
H
n-C3H7
C2H5
n-C3H7
CH3
>98/2
>97/3
>98/2
>96/4
b
a Isolated yield after flash chromatography on silica gel. Determined by H NMR analysis and H-1H NOESY analysis.
1
1
SCHEME 4
SCHEME 5
resolution via Sonogashira coupling7 afforded (S)-Z-6b and (S)-
Z-6c with >99/1 Z/E ratio and the same enantiopurity of the
starting 4,5-allenols (Scheme 4).
The stereoselectivity may be explained via the protocol shown
in Scheme 5: the three-membered iodonium intermediate formed
was intramolecularly attacked by the oxygen atom to form the five-
membered ring. The steric interaction between the R group and
the hydroxy group determines the Z-selectivity.2b Deprotonation
would lead to the formation of the substituted tetrahydrofuran
products. With NIS as the electrophile, the steric repulsion between
the R group and NIS becomes another major issue, which reduced
the Z/E selectivity. However, the diastereoselectivity observed in
the formation of 6f-i,l must be formed via a 2-iodo-π-allylic
cationic intermediate (Scheme 5).
In conclusion, we have developed a convenient method for the
efficient and stereoselective synthesis of 2-(1′(Z)-iodoalkenyl)tet-
rahydrofurans by the cyclic iodoetherification reaction of 4,5-
allenols with high regio- and high stereoselectivity. For the
substrates with a substituent at the 3-position, the reaction with I2
in n-hexane afforded the trans-2,3-disubstituted tetrahydrofurans
highly diastereoselectively. For the transfer of axial chirality, the
reaction should be carried out with NIS in CH2Cl2. Further studies
in this area are being conducted in our laboratory.
(7) For kinetic resolution using Sonogashira coupling, see: Ma, S.; Ma, Z.
Synlett 2006, 6, 1263. For recent reviews of Sonogashira reaction, see: (a)
Chinchilla, R.; Na´jera, C. Chem. ReV. 2007, 107, 874. (b) Doucet, H.; Hierso,
J.-C. Angew. Chem., Int. Ed. 2007, 46, 834.
440 J. Org. Chem. Vol. 74, No. 1, 2009

NIS. The mixture was extracted with 25 mL of ether, washed with
10 mL of water and 10 mL of brine, and dried over anhydrous
Na2SO4. Filtration, evaporation, and flash column chromatography
on silica gel (eluent: petroleum ether/ethyl acetate ) 40/1) afforded
(S)-Z-6b and (R)-E-6b (54.3 mg, 93%, Z/E ) 90/10) as a liquid:
1H NMR (300 MHz, CDCl3) δ [6.31, (t, J ) 7.8 Hz, E-isomer,
0.1H), 5.90 (t, J ) 6.8 Hz, Z-isomer, 0.9H)], 4.18 (t, J ) 6.5 Hz,
1H), 4.08-3.95 (m, 1H), 3.92-3.80 (m, 1H), 2.21-2.10 (m, 2H),
2.10-1.80 (m, 4H), 1.46-1.22 (m, 6H), 0.88 (t, J ) 6.8 Hz, 3H).
Kinetic Resolution of Z,E-Isomers of Optically Active (S)-
(Z)-6b, (R)-(E)-6b. Typical Procedure. A mixture of Pd(PPh3)2Cl2
(4.9 mg, 0.007 mmol), CuI (1.6 mg, 0.008 mmol), Et2NH (4.4 mg,
0.06 mmol), prop-2-yn-1-ol (3.2 mg, 0.057 mmol), and a mixture
of (S)-(Z)-6b, (R)-(E)-6b (54.3 mg, 0.18 mmol, Z/E ) 90/10) in 2
mL of CH3CN was stirred at room temperature (20 °C) for 20 min
under nitrogen. Filtration, washed by Et2O, evaporation, and flash
column chromatography on silica gel (petroleum ether/ethyl acetate
) 40:1) afforded (S)-Z-6b (44.1 mg, 81% recovered, Z/E > 99/1,
95%ee). HPLC conditions: Chiralpak AD-H, rate: 0.5 mL/min, λ
) 254 nm, n-hexane/i-PrOH ) 99/1: 1H NMR (300 MHz, CDCl3)
δ 5.90 (t, J ) 6.6 Hz, 1H), 4.18 (t, J ) 6.3 Hz, 1H), 4.05-3.95
(m, 1H), 3.92-3.81 (m, 1H), 2.21-2.10 (m, 2H), 2.10-1.80 (m,
4H), 1.46-1.22 (m, 6H), 0.88 (t, J ) 6.2 Hz, 3H); [R]20D ) +14.0
(c ) 0.89, CHCl3).
Experimental Section
Preparation of 4,5-Decadienol (5a). Typical Procedure. The
reaction of LiAlH4 (0.84 g, 22.1 mmol) and 4a (2.45 g, 14.6 mmol)
in anhydrous ether (37 mL) was monitored by TLC. After complete
consumption of the starting material, the mixture was quenched
with water, extracted with ether for three times, washed with brine,
and dried over anhydrous Na2SO4. Filtration, evaporation, and flash
column chromatographic separation on silica gel (petroleum ether/
ethyl acetate ) 5:1) afforded 5a (1.41 g, 63%) as a liquid:8 1H
NMR (400 MHz, CDCl3) δ 5.12-5.05 (m, 2H), 3.68 (t, J ) 6.4
Hz, 2H), 2.10-2.02 (m, 2H), 2.01-1.93 (m, 2H), 1.72-1.60 (m,
3H), 1.42-1.28 (m, 4H), 0.89 (t, J ) 7.0 Hz, 3H).
Preparation of 2-(1′-Iodo-1′(Z)-hexenyl)tetrahydrofuran (6a).
Typical Procedure. To a solution of 5a (61.9 mg, 0.40 mmol) in
1 mL of n-hexane were added sequentially iodine (103.1 mg, 0.41
mmol) and 1 mL of n-hexane at room temperature. After complete
conversion of the starting material as monitored by TLC, the
reaction mixture was quenched with 10 mL of H2O and saturated
aqueous Na2S2O3 to remove the excess I2. The mixture was
extracted with 15 mL of ether, washed with 10 mL of water and
10 mL of brine, and dried over anhydrous Na2SO4. After filtration
1
and evaporation, the Z/E ratio of 6a was determined by H NMR
analysis using 1,3,5-trimethylbenzene as the internal standard (18.5
µL, 0.13 mmol). Chromatography on silica gel (eluent: petroleum
ether/ethyl acetate ) 40/1) of the crude product afforded 6a (91.2
mg, 81%, Z/E ) 97/3) as a liquid: 1H NMR (400 MHz, CDCl3) δ
[6.30 (t, J ) 7.6 Hz, E-isomer, 0.03H); 5.89 (t, J ) 6.8 Hz,
Z-isomer, 1H)], 4.17 (t, J ) 6.2 Hz, 1H), 4.03-3.96 (m, 1H),
3.88-3.81 (m, 1H), 2.20-2.10 (m, 2H), 2.09-1.80 (m, 4H),
1.43-1.25 (m, 4H), 0.89 (t, J ) 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 135.5, 112.4, 84.7, 69.2, 35.2, 32.8, 30.3, 25.7, 22.2,
13.9; IR (neat) ν (cm-1): 2956, 2926, 2870, 1642, 1457, 1349, 1266,
1234, 1180, 1061; MS (70 eV, EI) m/z 280 (M+, 8.36), 153 (M+
- I, 68.17), 97 (100); HRMS calcd for C10H18OI (M+ + H)
281.0397, found 281.0391.
Preparation of Optically Active 2-(1′-Iodo-1′-heptenyl)tet-
rahydrofuran ((S)-(Z)-6b, (R)-(E)-6b). Typical Procedure. To a
solution of (R)-(-)-5b (33.4 mg, 0.20 mmol, 95%ee) in 1 mL of
CH2Cl2 were added sequentially NIS powder (54.4 mg, 0.24 mmol)
and an additional 1 mL of CH2Cl2. The resulting mixture was stirred
at room temperature. Upon completion of the reaction as monitored
by TLC, the reaction mixture was quenched with 10 mL of H2O
and washed with saturated aqueous Na2S2O3 to remove the excess
Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 20572093) and
the State Major Basic Research & Development Program
(2006CB806105) is greatly appreciated. We thank Mr. Guangke
He for reproducing the results presented in entries 3 and 9 of
Table 2 and the formation of (S)-Z-6b from the optically active
5b in Scheme 4.
Supporting Information Available: Experimental proce-
1
dures, analytical data, and copies of H and 13C NMR spectra
of 3,4-allenols, 4,5-allenylic nitriles, 4,5-allenoic acids, 4,5-
allenols and all 2-(1′(Z)-iodoalkenyl)tetrahydrofurans. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO802079B
(8) Enomoto, M.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1986, 27,
4599.
J. Org. Chem. Vol. 74, No. 1, 2009 441