Tin mediated allylation reactions of enol ethers in water

Article abstract of DOI:10.1021/ol102825t

Under tin-mediated Barbier-type reaction conditions, hydration of enol ethers takes place to form aldehydes that undergo allylation reactions. By using this process, various homoallylic alcohols and 2-halohomoallylic alcohols are produced in good to excel

Full text of DOI:10.1021/ol102825t

ORGANIC
LETTERS
2011
Vol. 13, No. 2
332-335
Tin Mediated Allylation Reactions of
Enol Ethers in Water
Mei-Huey Lin,* Shiang-Fu Hung, Long-Zhi Lin, Wen-Shing Tsai, and
Tsung-Hsun Chuang
Department of Chemistry, National Changhua UniVersity of Education,
Changhua, Taiwan 50007
mhlin@cc.ncue.edu.tw
Received November 21, 2010
ABSTRACT
Under tin-mediated Barbier-type reaction conditions, hydration of enol ethers takes place to form aldehydes that undergo allylation reactions.
By using this process, various homoallylic alcohols and 2-halohomoallylic alcohols are produced in good to excellent yields.
Water is a readily available, environmentally benign solvent.
Recently, the use of water as a solvent in chemical reactions
has received considerable attention owing to cost, safety, and
environmental concerns.1 In this regard, metal-mediated C-C
bond forming reactions occurring in aqueous media have
been intensively investigated.2 Metal-mediated Barbier al-
lylation reactions in water have several advantages over those
carried out in organic solvents. Typically, allylation reactions
of hemiacetals, catalyzed by InCl3 and Me3SiBr, are per-
formed in organic solvents and lead to direct substitution of
the hydroxyl group.3 Whitesides4 reported that addition of
tin, indium, or zinc complexed allyl anions to the glycosidic
carbons of unprotected carbohydrates, which exist in water
predominantly as cyclic hemiacetals, takes place smoothly
in aqueous/organic solvent mixtures. Thus, the carbonyl
group of ring-opened hydroxyaldehydes is the actual reactant
in these allylation reactions. Likewise, mucohalic acids exist
predominantly as a mixture of lactol and aldehyde forms,
the latter of which is favored in aqueous media (eq 1). Zhang5
has demonstrated that γ-allylic R,ꢀ-unsaturated γ-butyro-
lactones can be produced via indium or tin mediated
allylation reactions of mucohalic acids (eq 1). Later, Loh6
described a one-pot indium trichloride-catalyzed allylation
process in aqueous solution that transforms dihydropyrans
and dihydrofurans to lactols. Apparently, water plays an
important role in the formation of aldehydes from the
corresponding hemiacetals, which then undergo allylation in
the presence of allyl anion equivalents.
(1) (a) Li, C. J. Chem. ReV. 2005, 105, 3095. (b) Lindstro¨m, U. M. Chem.
ReV. 2002, 102, 2751. (c) Chan, T. H.; Issac, B. M. Pure Appl. Chem. 1996,
68, 919. (d) Li, C. J. Tetrahedron 1996, 52, 5643. (e) Li, C. J.; Chan, T. H.
Organic Reactions in Aqueous Media; John Wiley & Sons, Inc.: New York,
1997. (f) Paquette, L. A. In Green Chemistry: Frontiers in Benign Chemical
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University Press: New York, 1998.
(2) Li, C. J. Metal-Mediated C-C Bond Formations in Aqueous Media.
In Organic Reactions in Water Principles, Strategies and Applications;
Lindstro¨m, U. M., Ed.; Blackwell: Ames, IA, 2007.
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71, 8516.
(4) Kim, E.; Gordon, D. M.; Schmid, W.; Whitesides, G. W. J. Org.
Chem. 1993, 58, 5500.
10.1021/ol102825t  2011 American Chemical Society
Published on Web 12/13/2010

Enol ethers are electron-rich alkenes that participate in
certain organic processes, such as the Diels-Alder and the
Claisen rearrangement reactions.7 In general, they do not
serve as good substrates in allylation reactions with metal-
allyl reagents. However, the outcome could be different if
these processes were carried out in aqueous solution. In
water, hydration of enol ethers can occur via oxocarbonium
ion intermediates, which then react with water to form
hemiacetals and finally aldehydes and alcohols.8 Tin and tin-
containing Lewis acids have been extensively used in organic
chemistry owing to their low cost, commercial availability,
and modestly low toxicity.9 Several examples of methods
that use tin metal and stannic chloride to promote allylation
reactions of aldehydes in aqueous media have been de-
scribed.10 When taking into account both of these features,
we envisioned that enol ethers would serve as substrates in
organotin mediated allylation reactions in aqueous solutions.
Below, we describe the results of a study which demonstrate
that enol ethers serve as starting materials for tin mediated
reactions with various allylating reagents, including allyl
bromide and 2-bromo- and 2-iodo-3-bromopropene.
Table 1. Metal-Mediated Allylation of Dihydropyran in Watera
entry
metal/additive
solvent
H2O
THF or Et2O
H2O
THF or Et2O
H2O
yield (%)
1
2
Sn
Sn
Sn/HBr
Sn/HBr
Al
85
0
91
36
0
3b
4b
5
6
Zn
H2O
0
7
8
9
10
11
12c
SnCl2/Al
SnCl2/Zn
SnCl2/Cu
SnCl2/CuCl2
SnCl2/TiCl3
SnCl2/KI
H2O
H2O
H2O
H2O
H2O
H2O
76
85
0
0
0
90
a Conditions: Dihydropyran (DHP, 1.0 mmol), allyl bromide (1.5 mmol),
and indicated metal (1.0 mmol) in 2.0 mL of solvent at rt. b HBr (0.1 mL)
was used as an additive, and 1.9 mL of the solvent was added. c SnCl2 (1.5
mmol)/KI (1.5 mmol).
This effort began with an investigation of tin mediated
allylation reactions of 5,6-dihydropyran with allyl bromide, in
which various in situ generated allylstannane sources were
screened for their reactivity in aqueous solution. The conditions
employed and the results of the reactions are presented in Table
1. The allylation reaction promoted by tin metal proceeded
smoothly when water was used as the solvent (Table 1, entry
1). In contrast, no allylation product formed when the process
was carried out in organic solvents, such as ether or THF (Table
1, entry 2), and the reaction occurred only slowly and inef-
ficiently even when aqueous HBr was added to these solvents
(Table 1, entry 4). The results show that water is required in
order to facilitate the hydration step that initiates the process.
In addition, formation of the allylstannane intermediate by
reaction of allyl bromide with tin appears to create a sufficiently
acidic solution to enable hydration of the enol ether moiety so
that addition of hydrobromic acid does not play a dramatic role
in enhancing the overall rate of allylation (Table 1, entry 1
versus 3). Use of a combination of SnCl2 with Al or Zn led to
successful operation of the allylation process, but the reaction
does not take place when Al or Zn was used alone (Table 1,
entries 5-8). None of the desired product was produced when
tin chloride, accompanied by other metals such as copper,
copper(II) chloride, and titanium(III) chloride, was utilized
(entries 9-11). The allylation product was generated efficiently
when SnCl2 and KI were used as promoters (entry 12). It should
be noted that the SnCl2 and KI combination has not only been
used in allylation reactions of aldehydes10c but also in those of
acetals.11
Transition metal-catalyzed cross-coupling reactions of vinyl
halides have proven to be a powerful method for C-C bond
formation.12 We believe that 2-haloallylation reactions of enol
ethers could have similarly wide applications in organic
synthesis. Therefore, our attention turned to an exploration of
the 2-iodoallylation reaction of dihydropyran. As can be seen
by viewing the results summarized in Table 2, dihydropyran is
(5) Zhang, J.; Blazecka, P. G.; Berven, H.; Belmont, D. Tetrahedron
Lett. 2003, 44, 5579.
(6) Juan, S.; Hua, Z.-H.; Qi, S.; Ji, S.-J.; Loh, T.-P. Synlett 2004, 5,
829.
Table 2. Metal-Mediated 2-Iodoallylation of Dihydropyran
(7) (a) Pindur, U.; Gundula, L.; Otto, C. Chem. ReV. 1993, 93, 741. (b)
Oppolzer, W. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 5, Part 4.1, p 315. (c) Wipf, P. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, Part 7.2, p 827. (d) Ziegler, F. E. Chem.
ReV. 1988, 88, 1423.
(8) Kresge, A. J. Acc. Chem. Res. 1987, 20, 364.
entry
metal/additive
solvent
H2O
H2O
H2O
H2O
H2O/THF
H2O
yield (%)a
(9) (a) Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis;
Butterworth: London, 1987. (b) Smith, P. J. Toxicological Data on
Organotin Compounds; International Tin Research Inst.: London, 1978.
(10) (a) Nokami, J.; Otera, J.; Sudo, T.; Okawara, R. Organometallics
1983, 2, 191. (b) Einhorn, C.; Luche, J.-L. J. Organomet. Chem. 1987,
322, 177. (c) Houllemare, D.; Outurquin, F.; Paulmier, C. J. Chem. Soc.,
Perkin Trans. 1 1997, 1629. (d) Chan, T. H.; Yang, Y.; Li, C. J. J. Org.
Chem. 1999, 64, 4452. (e) Tan, X.-H.; Shen, B.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2002, 43, 9373. (f) Tan, X.-H.; Shen, B.; Deng, W.; Zhao,
H.; Liu, L.; Guo, Q.-X. Org. Lett. 2003, 5, 1833. (g) Zhou, C.; Zhou, Y.;
Jiang, J.; Xie, Z.; Wang, Z.; Zhang, J.; Wu, J.; Yin, H. Tetrahedron Lett.
2004, 45, 5537. (h) Tan, X.-H.; Hou, Y.-Q.; Huang, C.; Liu, L.; Guo, Q.-
X. Tetrahedron 2004, 60, 6129.
1
2
3
4
5
6
In/InCl3
Sn
Sn/HBr
SnCl2/Zn
Sn/HBr
SnCl2/KI
0
0
<5
0
70
87
a The product was isolated as the corresponding acetate derivative after
the diol was treated with Ac2O, DIEA, and DMAP in ether.
Org. Lett., Vol. 13, No. 2, 2011
333

transformed to the corresponding lactol when reacted with
2-iodo-3-bromopropene in water using the In/InCl3 conditions
described by Loh5 (entry 1), tin metal (entry 2), or SnCl2/Zn
(entry 4). However, in each case none of the iodoallylation
product was produced. The results show that 2-iodoallylation
is a much more sluggish process than the closely related
allylation reaction (Table 2, entries 2, 3, and 4 versus Table 1,
entries 1, 3, and 8).
Table 3. Tin-Mediated Allylation of Enol Ethers
Reactions of 2,3-dibromopropene with acetals to form
bromo-homoallylic alcohols that occur via allyltin intermedi-
ates have been reported to take place under acid catalyzed
conditions.13 Yet, reaction of dihydropyran with 2-iodo-3-
bromopropene in an aqueous solution containing Sn and HBr
failed to produce the corresponding allylation product (Table
2, entry 3). By way of contrast, iodoallylation of dihydro-
pyran occurs with relatively high efficiency when the reaction
is carried out in a mixed THF/H2O solvent system (Table 2,
entry 3 versus 5). Moreover, this process is highly efficient
when promoted by SnCl2/KI in water (Table 2, entry 6). It
is important to note that the iodoallylation product is not
stable when stored at room temperature. Therefore, reaction
yields were determined by transformation of the alcohol
group in the product to its acetate derivative.
The substrate scope of allylation reactions of enol ethers
with allylic bromides was probed (Table 3).14 The γ-addition
product was formed predominantly in the reaction of
dihydropyran with crotyl bromide, but a low level of
diastereoselectivity accompanies this process (Table 3, entry
2). In addition, high yields were obtained for allylation
reactions of dihydropyran and dihydrofuran using a variety
of substituted allylic bromides (Table 3, entries 1-8).
However, the efficiency of the process was slightly lower
for the reaction of the sterically hindered cyclic enol ether,
2,3-dihydro-5-methylfuran, with allyl bromide (Table 3, entry
6 versus 9), and only starting materials are recovered when
this enol ether is reacted with 2-iodo-3-bromopropene (Table
3, entry 10). Allylation of benzofuran does not take place
under these conditions, presumably a consequence of the fact
a Anti/syn ) 1:1.27. b The product was isolated as the corresponding
acetate derivative. c Conditions: enol ether (1.0 mmol), allyl bromide (3.0
mmol), and tin powder (2.0 mmol) in water (2.0 mL) at rt. d Conditions:
enol ether (1.0 mmol), allyl bromide (2.0 mmol), tin powder (1.0 mmol)
and HBr (0.2 mL) in THF (1.0 mL)/water (0.8 mL) at rt.
(11) (a) Gremyachinskiy, D. E.; Smith, L. L.; Gross, P. H.; Samoshin,
V. V. Green Chem. 2002, 4, 317. (b) Samoshin, V. V.; Gremyachinskiy,
D. E.; Smith, L. L.; Bliznets, I. V.; Gross, P. H. Tetrahedron Lett. 2002,
43, 6329.
that it would be attended by partial loss of aromatic
stabilization of the substrate (Table 3, entry 11). In addition,
a bis-homoallylic alcohol is formed in a high yielding
allylation reaction of 6-methoxy-5,6-dihydropyran with allyl
bromide (Table 3, entry 12). In allylation reactions of
ꢀ-methoxystyrene with allylic bromides, including 2-bromo-
and 2-iodo-3-bromopropene, addition of hydrobromic acid
to the aqueous solutions was required to promote high
yielding conversions to product (Table 3, entries 13-15).
The success of these bromo-homoallylic alcohol forming
processes should be contrasted with the results of earlier studies,
which show that the reaction of 2,3-dibromopropene with
phenylacetaldehyde takes place in a very low yield (33%)15
when the procedure developed by Otera is employed.13 The
(12) de Meijere, A., Diederich, F., Eds. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004.
(13) Mandai, T.; Nokami, J.; Yano, T.; Yoshinaga, Y.; Otera, J. J. Org.
Chem. 1984, 49, 172.
(14) General procedure for tin-mediated allylation of enol ethers
(Table 3, entries 1, 2, 3, 6, 9, 11, 12): A mixture of an enol ether (1.0
mmol), an allylating agent (1.5 mmol), and tin powder (1.0 mmol) in water
(2.0 mL) was stirred at rt. Reaction was monitored by TLC until no starting
material was observed, and normally the reaction was stirred at rt overnight.
Et2O (5 mL) was then added to the reaction, and the mixture was transferred
to a separatory funnel. The organic layer was back extracted with Et2O (5
mL). The combined organic layers were washed with brine (3 mL × 2),
dried over Na2SO4, and concentrated in a rotary evaporator. The residue
was purified by silica-gel chromatography to give the product. Table 3,
entries 4, 5, 7, 8, 10: A mixture of an enol ether (1.0 mmol), an allylating
agent (1.5 mmol), and SnCl2 (1.5 mmol)/KI (1.5 mmol) in water (2.0 mL)
was stirred at rt overnight. Work-up and purification procedures were similar
to those described above. Table 3, entries 13-15: A mixture of an enol
ether (1.0 mmol), an allylating agent (2.0 mmol), tin powder (1.0 mmol),
and HBr (47-49% aqueous, 0.2 mL) in THF (1.0 mL)/water (0.8 mL) was
stirred at rt overnight. Work-up and purification procedures were similar
to those described above. Structures of the products and yields are indicated
in Table 3. Conditions presented in Table 3are through optimization.
(15) (a) Lei, M.-Y.; Fukamizu, K.; Xiao, Y.-J.; Liu, W.-M.; Twiddy,
S.; Chiba, S.; Ando, K.; Narasaka, K. Tetrahedron Lett. 2008, 49, 4125.
(b) Lei, M.-Y.; Xiao, Y.-J.; Liu, W.-M.; Fukamizu, K.; Chiba, S.; Ando,
K.; Narasaka, K. Tetrahedron 2009, 65, 6888.
334
Org. Lett., Vol. 13, No. 2, 2011

the corresponding arylmethyl-homoallylic alcohols were pro-
duced in excellent yield (Table 4). Some of the products of
these reactions have been synthesized earlier by using more
complicated routes.17 Consequently, the results of this effort
have led to the development of a simple method for the
preparation of homoallylic alcohols from ꢀ-methoxystyrenes
by using a method that is superior to the more difficult allylation
reactions of 2-arylacetaldehydes.
Table 4. Tin-Mediated Allylation of ꢀ-Methoxystyrenes
In summary, in the observations made in this effort
demonstrate that tin mediated allylation and 2-haloallylation
reactions of enol ethers take place efficiently in aqueous
media. In addition the results show that the process serves
as an alternative and perhaps superior method for the
synthesis of highly functionalized homoallylic alcohols from
readily available enol ethers under simple, inexpensive, and
environmentally friendly conditions.
Acknowledgment. Financial support from the National
Science Council of the Republic of China, Taiwan (NSC98-
2119-M-018-001 and NSC99-2119-M-018-001) and National
Changhua University of Education is gratefully acknowl-
edged. We also thank Professor T. V. RajanBabu at The Ohio
State University for his suggestions during manuscript
preparation.
a Conditions: enol ether (1.0 mmol), allyl bromide (2.0 mmol), tin
powder (1.0 mmol), and HBr (0.2 mL) in THF (1.0 mL)/water (0.8 mL) at
Supporting Information Available: Complete charac-
terization data (1H and 13C NMR and mass spectral data)
for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
rt.
exceptional lability of phenylacetaldehyde might be the reason
behind the poor yield of its 2-bromoallylation reaction. This
problem is further complicated by the fact that 2-arylacetalde-
hydes are relatively difficult to prepare. Consequently, the results
of our studies show that by replacing 2-arylacetaldehydes with
ꢀ-methoxystyrene derivatives it is possible to efficiently generate
the corresponding bromo-homoallylic alcohols starting with
substrates that are readily prepared by straightforward Wittig
olefination of the corresponding benzaldehydes.16 To explore
this process further, ꢀ-methoxystyrenes, prepared in this manner,
were subjected to allylation reaction conditions. In each case,
OL102825T
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