Efficient synthesis of bisallylic ethers from Baylis-Hillman adducts promoted by molecular iodine

Article abstract of DOI:10.1055/s-2008-1042937

A straightforward and efficient synthesis of functionalized ethers from Baylis-Hillman (MBH) adducts was disclosed. In the presence of I₂, MBH adducts underwent smooth dehydration to give a series of bisallylic symmetrical ethers in moderate to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042937

932
LETTER
Efficient Synthesis of Bisallylic Ethers from Baylis–Hillman Adducts
Promoted by Molecular Iodine
Synthesis of
B
e
isallylic
E
t
i
Department of Chemistry, Shanghai University, Shanghai 200444, P. R. of China
Fax +86(21)66132797; E-mail: xsjia@mail.shu.edu.cn
Received 2 November 2007
presence of iodine, the Baylis–Hillman adduct underwent
smooth dehydration to give the symmetrical bisallylic
ether 28 and its unsymmetrical isomer 3 in 60% yields.
Subsequently, a series of experimental parameters includ-
ing temperature and solvent were changed to optimize the
reaction conditions. It was interesting that the amount of
iodine added played an important role in this reaction. No-
tably, the ratio of the bisallylic ether 2 with 3 increased
significantly along with the elevated dosage of iodine (en-
tries 1–3). For instance, the ratio of 2:3 was up to 3:1 when
one equivalent of iodine was used (entry 3). During our
investigation, we also found that the dimerization product
2 and its isomer 3 were often obtained as an inseparable
mixture. To overcome this problem, we turned our atten-
tion to further experimental modifications. To our delight,
the symmetrical ether 2 was afforded exclusively when 3
equivalents of iodine were used. In such a case, no unsym-
metrical isomer 3 was produced and the expected product
2 could be isolated as pure compound. On the other hand,
product conversion was susceptible to temperature chang-
es. At room temperature, the reaction was quite sluggish
and the dimerization did not take place. In addition, sev-
eral other solvents were also screened and nitromethane
exhibited its superiority over other solvents. For example,
the employment of MeCN led to long reaction times and
Abstract: A straightforward and efficient synthesis of functional-
ized ethers from Baylis–Hillman (MBH) adducts was disclosed. In
the presence of I2, MBH adducts underwent smooth dehydration to
give a series of bisallylic symmetrical ethers in moderate to good
yields.
Key words: Baylis–Hillman adduct, iodine, bisallylation, symmet-
rical, ether
The Morita–Baylis–Hillman (MBH) reaction is one of the
powerful carbon–carbon bond-forming methods in organ-
ic synthesis.1 The MBH reaction provides molecules pos-
sessing hydroxy, alkenyl, and electron-withdrawing
groups in close proximity, which makes it valuable in a
number of stereoselective transformation processes.2 Fur-
thermore, many strategies/methodologies have been suc-
cessfully employed in the syntheses of biologically active
molecules and natural products.3
Due to the synthetic importance of these structurally
unique bisallylic ethers, much effort has been made to-
wards the syntheses of such compounds.4 Among such
transformations, the use of readily available MBH adducts
as substrates provides a new pathway. However, most
published methods suffered from the strict conditions
such as high pressure or poor yields partly due to the low
reactivity of Baylis–Hillman adducts.5 Therefore, the de-
velopment of more efficient and practical methods is
highly desirable. More recently, we have reported an effi-
cient preparation of asymmetric bisallylic ethers via the
dimerization of MBH adducts.6 We are also interested in
the preparation of symmetrical analogues although this
still remains to be a challenge. In the past several years,
we paid much attention to the application of Baylis–Hill-
man adducts, and many interesting results were also re-
ported.7 As a continuation of our interest in Baylis–
Hillman chemistry, herein we wish to report a novel strat-
egy for the symmetrical dimerization of Baylis–Hillman
adducts promoted by molecular iodine.
Table 1 Optimization on the Selective Dimerization of Baylis–Hill-
man Adducts Promoted by Molecular Iodinea
Entry
I2
Solvent
Time
(h)
Yield of 2 + 3
(mol%)
(%, 2/3 ratio) b,c
1
2
3
4
5
6
7
5
15
100
300
5
MeNO2
MeNO2
MeNO2
MeNO2
MeCN
THF
3
1
67 (1:3)
70 (1:1)
65 (3:1)
71 (100:0)
8 (1:2)d
0.5
0.5
24
24
24
Our initial experiments were carried out using Baylis–
Hillman adduct 1a as model substrate (Scheme 1). In a
typical procedure, a catalytic amount of iodine (5 mol%)
was added to a stirred suspension of 1 mmol substrate 1a
in nitromethane (10 mL) at 80 °C (Table 1, entry 1). In the
e
5
–
e
5
CH2Cl2
–
a Unless otherwise noted, all attempts were carried out with 1 mmol
of 1a at 80 °C.
b Isolated yields.
c The ratio was confirmed from 1H NMR spectroscopy.
d In such cases, the total conversion was very low even an equivalent
amount of iodine was used.
SYNLETT 2008, No. 6, pp 0932–0934
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042937; Art ID: W19807ST
© Georg Thieme Verlag Stuttgart · New York
e No reaction occurred.

LETTER
Synthesis of Bisallylic Ethers
933
COOMe
O
OH
conditions
COOMe
O
+
COOMe
COOMe
MeOOC
1
2
3
Scheme 1
COOMe
O
nating groups seemed to facilitate this dehydration pro-
cess and shortened the reaction time (Table 2, entries 2
and 3). However, 2-chloro-substituted substrate resulted
in a lower yield (45%), which could be contributed to the
steric hindrance (entry 6). We also noticed that no dimer-
ization product was formed when a 3-nitro group was
present (entry 8). In such case, only a small amount of the
corresponding allylic iodide was isolated. Furthermore,
methoxy-group-substituted substrate also failed to give
the desired bisallylic ether 2 under optimized conditions.
Notably, the present methodology showed excellent E-
stereoselectivity and no Z-isomer was detected. To further
establish the generality of the present strategy, an ana-
logue of 1 (R = 4-t-BuC6H4), in which the COOMe group
was replaced by a CN group, was prepared and subjected
to the same reaction conditions. To our delight, the corre-
sponding dimerization ether was isolated in 78% yield,
and the symmetrical ether was also produced as major
product in a 5:1 ratio with the unsymmetrical one as the
minor product.
OH
I2
MeNO2, 80 °C
COOMe
R
R
R
MeOOC
1
2
Scheme 2
Table 2 Efficient Synthesis of Bisallylic Ether 2 from Baylis–Hill-
man Adducts Promoted by Iodinea
Entry
R
Time (min)
Yield (%)b,c
1
2
3
4
5
6
7
8
9
Ph
30
71
66
81
75
52
45
66
4-MeC6H4
4-t-BuC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-O2NC6H4
4-MeOC6H4
15
10
30
100
50
In summary, we reported here a facile and novel method-
ology for the synthesis of symmetric bisallylic ether 2
from Baylis–Hillman adducts.10 Indeed, the usefulness of
this reaction lays in the high degree of functionality
present in the products for further transformations. We be-
lieved that our current procedure would be an excellent al-
ternative to existing methods. Further applications of the
bisallylic ether 2 in organic synthesis are underway in our
laboratory.
40
d
100
100
–
e
–
a Unless otherwise noted, all reactions proceeded with Baylis–Hill-
man adduct 1 (1 mmol), I2 (3 mmol) at 80 °C in MeNO2 (10 mL).
b All new compounds were characterized by 1H NMR, 13C NMR, el-
emental analysis, and IR spectroscopy.
c Isolated yields.
d In such case, only a little amount of allylic iodine derivative was af-
forded.
Acknowledgment
e Substrate was transformed to unrecognized mixture.
We thank the National Natural Science Foundation of China (No:
20472048 and 20572068) for financial support.
References and Notes
low yields, whereas no reaction occurred when CH2Cl2 or
THF was used as solvent (entries 5–7).
(1) For reviews, see: (a) Ciganek, E. Org. React. 1997, 51, 201.
(b) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001. (c) Basavaiah, D.; Rao, A. J.;
In addition, the present transformation also manifested ex-
cellent E-stereoselectivity and no Z-isomer was ob-
served.9
Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(2) For selected examples, see: (a) Ramachandran, P. V.;
Madhi, S.; Bland-Berry, L.; Reddy, M. V. R.; O’Donnel, M.
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Venkataiah, B.; Dong, G. Organometallics 2005, 24, 762.
(c) Chung, Y. M.; Gong, J. H.; Kim, T. H.; Kim, J. N.
Tetrahedron Lett. 2001, 42, 9023. (d) Singh, V.; Saxena, R.;
Batra, S. J. Org. Chem. 2005, 70, 353. (e) Patra, A.; Roy, A.
K.; Batra, S.; Bhaduri, A. P. Synlett 2003, 1819.
We then focused our attention to substrate generality us-
ing the optimized reaction conditions (Scheme 2). Several
Baylis–Hillman adducts were examined under the optimal
conditions and the results were summarized in Table 2. In
most cases, the reaction proceeded smoothly to give the
corresponding bisallylic ethers 2 in moderate to good
yields. It was noteworthy that the presence of electron-do-
Synlett 2008, No. 6, 932–934 © Thieme Stuttgart · New York

934
P. Zhao et al.
LETTER
(3) For recent examples, see: (a) Radha Krishna, P.; Nasingam,
M.; Kannan, V. Tetrahedron Lett. 2004, 45, 4773.
(b) Rodgen, S. A.; Schaus, S. E. Angew. Chem. Int. Ed. 2006,
45, 3913. (c) Drewes, S. E.; Roos, G. H. P. Tetrahedron
1988, 44, 4653. (d) Brzezinski, L. J.; Rafel, S.; Leahy, J. M.
J. Am. Chem. Soc. 1997, 119, 4317. (e) Wori, M.; Kuroda,
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B. M.; Thiel, O. R.; Tsui, H. C. J. Am. Chem. Soc. 2003, 125,
13155.
(10) General Procedure for the Synthesis of the Symmetrical
Bisallylic Ether
To a stirred solution of Baylis–Hillman adduct 1 (1 mmol) in
MeNO2 (10 mL), I2 (3 mmol) was added. The resulting
mixture was then allowed to react at 80 °C in air. After
completion of the reaction, H2O was added to quench the
reaction, and the mixture was successively exacted with
Et2O (3 × 20 mL). The organic phase was washed with sat.
Na2S2O3 (15 mL), sat. brine (10 mL), dried over anhyd
Na2SO4, and filtered. The solvent was removed under
reduced pressure to give the crude products, which were
purified by column chromatography using EtOAc and
petroleum ether as eluent.
(4) For the application of bisallylic ethers in organic synthesis,
see: (a) Le Nôtre, J.; Brissieux, L.; Sémeril, D.; Bruneau, C.;
Dixneuf, P. H. Chem. Commun. 2002, 1772.
(b) Ben Ammar, H.; Le Nôtre, J.; Salem, M.; Kaddachi, M.
T.; Dixneuf, P. H. J. Organomet. Chem. 2002, 662, 63.
(c) Shanmugam, P.; Rajasingh, P. Chem. Lett. 2005, 34,
1494.
Selected Spectroscopy Data of Product 2
Compound 2a (R = Ph): white solid, mp 96.3–97.4 °C. IR
(KBr): 3404, 2948, 1714, 1629, 1244, 1006, 768, 694 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.99 (s, 2 H), 7.63–7.40 (m,
10 H), 4.41 (s, 4 H), 3.87 (s, 6 H) ppm. 13C NMR (125 MHZ,
CDCl3): d = 168.18, 145.47, 134.83, 130.27, 129.68, 128.78,
128.39, 64.93, 52.40 ppm. MS: m/z (%) = 389 [M + Na]+.
Anal. Calcd for C22H22O5: C, 72.13; H, 6.01. Found: C,
72.29; H, 5.97.
Compound 2d (R = 4-ClC6H4): white solid, mp 123.1–123.8
°C. IR (KBr): 3408, 1711, 1631, 1237, 816 cm–1. 1H NMR
(500 MHz, CDCl3): d = 7.93 (s, 2 H), 7.57 (d, 4 H, J = 8.5
Hz), 7.41 (t, 4 H, J = 8.5 Hz), 4.36 (s, 4 H), 3.87 (s, 6 H).
13C NMR (125 MHZ, CDCl3): d = 167.86, 144.21, 133.95,
133.20, 131.61, 129.12, 128.70, 64.85, 52.53. MS: m/z (%) =
457 [M + Na]+. Anal. Calcd for C22H20Cl2O5: C, 60.69; H,
4.59. Found: C, 60.63; H, 4.76.
(5) (a) Rose, P. M.; Clifford, A. A.; Rayner, C. M. Chem.
Commun. 2002, 968. (b) Basavaiah, D.; Bakthadoss, M.;
Jayapal Reddy, G. Synth. Commun. 2002, 32, 689.
(6) Liu, Y. K.; Li, J.; Zheng, H.; Xu, D. Q.; Xu, Z. Y.; Zhang, Y.
M. Synlett 2005, 2999.
(7) (a) Li, S. Y.; Li, J.; Jia, X. S. Synlett 2007, 1115. (b) Li, J.;
Wang, X. X.; Zhang, Y. M. Tetrahedron Lett. 2005, 46,
5233. (c) Li, J.; Wang, X. X.; Zhang, Y. M. Synlett 2005,
1039. (d) Li, J.; Qian, W. X.; Zhang, Y. M. Tetrahedron
2004, 60, 5793.
(8) All new compounds were characterized by 1H NMR, 13
NMR, elemental analysis, and IR spectroscopy.
C
(9) The stereochemistry of product 2 was assigned according to
published report.7d
Synlett 2008, No. 6, 932–934 © Thieme Stuttgart · New York