Practical carbonyl-ene reactions of α-methylstyrenes with paraformaldehyde promoted by a combined system of boron trifluoride and molecular sieves 4A

Article abstract of DOI:10.1021/ol025719l

Matrix presented A combined system of boron trifluoride and molecular sieves is an efficient promoter for the carbonyl-ene reaction of a-methylsyrenes with paraformaldehyde. The coexistence of BF₃-OEt₂ and molecular sieves 4A is esse

Full text of DOI:10.1021/ol025719l

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1667-1669
Practical Carbonyl-Ene Reactions of
r-Methylstyrenes with Paraformaldehyde
Promoted by a Combined System of
Boron Trifluoride and Molecular
Sieves 4A
,†
Takahiro Okachi,† Katsuhiko Fujimoto,‡ and Makoto Onaka*
Department of Chemistry, Graduate School of Arts and Sciences, The UniVersity of
Tokyo, Komaba, Meguro, Tokyo 153-8902, Japan, and Process DeVelopment
Laboratories, Sankyo Co., Ltd., Hiratsuka, Kanagawa 254-8560, Japan
conaka@mail.ecc.u-tokyo.ac.jp
Received February 14, 2002
ABSTRACT
A combined system of boron trifluoride and molecular sieves is an efficient promoter for the carbonyl-ene reaction of r-methylsyrenes with
paraformaldehyde. The coexistence of BF3‚OEt2 and molecular sieves 4A is essential for obtaining high yields of ene products.
The carbonyl-ene reaction promoted by Lewis acid is a
powerful tool for the preparation of various homoallylic
alcohols.1,2However, there have been few practical synthetic
methods to promote efficiently the carbonyl-ene reaction of
R-methylstyrene derivatives. This is partly because a homo-
allylic alcohol product (ene adduct) forms a complex (A)
with a Lewis acid promoter to generate a strongly acidic
proton. This acidic proton migrates intramolecularly to a
double bond of the ene adduct or intermolecularly to a
starting styrene derivative to produce a labile cationic
intermediate, which triggers various side reactions as shown
in Figure 1.1d Therefore, the key to success in the carbonyl-
ene reaction is to find how to activate a carbonyl group and
scavenge the acidic proton effectively.
In 1997, Uemura et al. reported carbonyl-ene reactions
catalyzed by metal-cation-exchanged montmorillonites.2d By
use of their method, R-methylstyrene and its methylated
derivative produced homoallylic alcohols in moderate yields,
but styrenes with electron-withdrawing groups gave poor
results.
† The University of Tokyo.
‡ Sankyo Co., Ltd.
(1) (a) Snider, B. B.; Price, R. T. Tetrahedron 1981, 37, 3927. (b) Snider,
B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J. Am. Chem. Soc. 1982,
104, 555. (c) Snider, B. B.; Cordova, R.; Price, R. T. J. Org. Chem. 1982,
47, 3643. (d) Snider, B. B.; Philips, G. B. J. Org. Chem. 1983, 48, 2789.
(e) Snider, B. B. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 527. (f) Mikami, K.;
Terada, M.; Shimizu, M.; Nakai, T. J. Synth. Org. Chem., Jpn. 1990, 48,
292. (g) Mikami, K.; Shimizu, M. Chem. ReV. 1992, 92, 1021.
(2) (a) Charles, C.; Schidle, C. J. J. Am. Chem. Soc. 1949, 71, 2860. (b)
Maruoka, K.; Concepcion, A. B.; Hirayama, N.; Yamamoto, H. J. Am.
Chem. Soc. 1990, 112, 7422. (c) Maruoka, K.; Concepcion, A. B.; Hirayama,
N.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 3943. (d) Tateiwa, J.;
Uemura, S. J. Chem. Soc., Perkin Trans. 1 1997, 2169.
Here we propose a new practical method for the carbonyl-
ene reaction of R-methylstyrenes 1 with paraformaldehyde
using a combination of BF3‚OEt2 and molecular sieves 4A
(MS 4A).
Initially we tested the reaction of 3,4-dichloro-R-methyl-
styrene 1a with paraformaldehyde using acids shown in Table
1. There is a single precedent2a in which the reaction was
catalyzed by H2SO4 to afford the corresponding ene adduct
2a in 46% yield (entry 1). Although alkylaluminum halides
10.1021/ol025719l CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/25/2002

MS 4A, an undesired dimeric product 3 was the sole product
in 70% yield (entry 7). Therefore, a combination of BF3‚
OEt2 and MS 4A turned out to be essential for obtaining the
ene product in good yield.3
At first we speculated that MS 4A would scavenge water
from incompletely dried reagents, solvents, or equipment that
coordinated to the Lewis acid to produce strong Brønsted
acids and that these strong acids would cause the polymer-
ization or isomerization of alkenes as side reactions. How-
ever, the use of a dehydrating agent, MgSO4, instead of MS
4A resulted in a low yield (22%) of 2a.
Another potential role of molecular sieves (zeolites) is to
trap acidic protons of the coordinated allylic alcohol (A) and
to retard the side reactions in Figure 1.4 We applied several
sodium ion exchanged zeolites with different Si/Al ratios
such as X- and Y-type zeolites and mordenite as well as
MS 4A (A-type zeolite) to the ene reaction (Table 2). Zeolites
Table 2. Carbonyl-Ene Reactions in the Presence of Zeolites
Having Various Amounts of Base Sitesa
Figure 1. Conceivable paths to side products via an ene-adduct.
have been known as good promoters for the carbonyl-ene
reaction,1 Me2AlCl gave very low yield in this case (entry
2). The reaction using BF3‚OEt2 also afforded complex
mixtures (entry 3). Interestingly, when MS 4A was added
to the reaction system with BF3‚OEt2, the ene adduct 2a was
obtained in good yield (entry 4). MS 4A and commercially
available solid acid K-10 independently did not promote the
reaction (entries 5 and 6). By the combined use of K-10 and
entry
zeolites
pore size6 (nm)
Si/Alc
yield (%)d
1b
2
3
MS 4A (NaA)
NaX
NaY
0.41
0.74
0.74
0.65 × 0.70
1.0
1.5
2.7
9.2
72
69
46
35
4
Na-mordenite
a
Zeolite (0.5 wt equiv to 1a), BF3‚OEt2 (2.0 equiv), (HCHO)n (2.0
equiv). b MS 4A (1.0 wt equiv), BF3‚OEt2 (1.2 equiv), (HCHO)n (1.0 equiv).
c The Si/Al ratios of zeolite. d Determined by 1H NMR using chloroacetone
as internal standard.
Table 1. Acid-Promoted Carbonyl-Ene Reactionsa
are crystalline aluminosilicates with intrinsic pore structures
and generally function as acid and base.5 Roughly speaking,
the total number of base sites on a zeolite is proportional to
the Al content in the zeolite framework. In other words, the
smaller the Si/Al ratio is, the more base sites exist in the
zeolite. Therefore, the order of base site amounts on the
zeolites is estimated as follows: MS 4A (NaA, Si/Al ) 1.0)
> NaX (1.5) > NaY (2.7) > Na-mordenite (9.2).
entry
acid (equiv)
H2SO4 (0.2)b
conditions
35 °C, 1.0 h
-10 to -5 °C, 3.0 h
-30 to -10 °C, 0.5 h
yield (%)d
1
2
3
4
5
6
7
46
28
tre
72
0f
0f
0g
Me2AlCl (1.0)
BF3‚OEt2 (1.2)
BF3‚OEt2 (1.2)/MS 4Ac -20 to -5 °C, 5.0 h
Table 2 clearly shows that the yield of 2a was increased
with an increase in the number of base sites on the zeolite.
MS 4Ac
K-10c
K-10/MS 4Ac
-20 °C to reflux, 5.0 h
0 °C to rt, 24.0 h
0 to 5 °C, 3.0 h
(3) Trioxane, which is more easily soluble in CH2Cl2 than paraformal-
dehyde, was unusable as formaldehyde precursor in this carbonyl-ene
reaction.
(4) (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111,
1940. (b) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112,
3949. (c) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1994, 116,
2812. (d) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, J. J. Mol.
Catal. A 1998, 132, 165.
a (HCHO)n, 1.0 equiv. b Solvent ) Ac2O. c One weight equivalent of
MS 4A (K-10) to 1a was used. d Determined by 1H NMR using chloro-
acetone as internal standard. e Complex mixtures were formed. f Styrene
1a was recovered. g Dimeric product 3 was formed.
(5) (a) Breck, D. W. In Zeolite Molecular SieVes; John Wiley & Sons:
New York, 1974. (b) Izumi, Y., Urabe, K., Onaka, M. In Zeolite, Clay,
and Heteropoly Acid in Organic Reactions; Kodansha: Tokyo, 1992. (c)
Onaka, M., Kawai, M., Izumi, Y. Bull. Chem. Soc. Jpn. 1986, 59, 1761.
(6) Baerlocher, Ch.; Meier, W. M.; Olson, D. H. Atlas of Zeolite
Framework Types, 5th ed.; Elsevier: New York, 2001.
1668
Org. Lett., Vol. 4, No. 10, 2002

These results suggest that MS 4A and NaX function as solid
base, i.e., a competent proton scavenger in the reaction as
proposed in Figure 2. A slight difference in promotion of
but in very low yield. On the basis of the result in Table 3,
it was found that MS 4A and NaX zeolites are very unique
as bases in the ene reaction.
We applied the BF3‚OEt2/MS 4A system to various
R-methylstyrenes as shown in Table 4. The reactions of
Table 4. BF3-Promoted Carbonyl-Ene Reactions in the
Presence of Molecular Sieves 4A
conditionsa
yield (%)b
Figure 2. A proposed role of molecular sieves (zeolite).
entry
1
R1
R2
1
2
3
4
5
1a
1b
1c
1d
1e
Cl
F
H
H
H
Cl
F
F
H
Me
A
A
A
B
B
2a (72)
2b (72)
2c (59)
2d (41)
2e (tr)c
the reaction between MS 4A and NaX is that greater amounts
of BF3‚OEt2 are needed to get the reaction completed (entries
1 and 2). This arises from the difference in pore size between
the two zeolites. Since the pore size of NaX is 0.74 nm,
some BF3 (molecular size 0.44 nm) is readily adsorbed on
base sites inside the pores of NaX and hence deactivated.
On the other hand, MS 4A has smaller pores of 0.41 nm in
diameter, and BF3 is less able to go into the pores of MS
4A and works as an effective acid promoter for paraform-
aldehyde. Therefore, MS 4A would exclusively capture the
acidic proton generated and stabilize the ene product (Figure
2).
a A: MS 4A (1.0 wt equiv to 1), BF3•‚Et2 (1.2 equiv), (HCHO)n (1.0
equiv). B: MS 4A (3.0 wt equiv), BF3‚OEt2 (1.2 equiv), (HCHO)n (1.0
equiv). b Determined by 1H NMR using chloroacetone as internal standard.
c Polymeric products were formed as byproducts.
styrene derivatives 1a-d afforded 2a-d in moderate to good
yields (entries 1-4), whereas unfortunately this system was
not applicable to the styrene 1e with an electron-donating
group (entry 5). Our system is complementary to the clay-
catalyzed system2d in the carbonyl-ene reaction of R-meth-
ylstyrenes with paraformaldehyde.
In summary, we have developed a practical method to
promote efficiently the carbonyl-ene reaction of electron-
deficient R-methylstyrene derivatives with paraformaldehyde.
The key to our success was the combined use of homoge-
neous Lewis acid BF3‚OEt2 and solid base MS 4A, which
activate paraformaldehyde and trap acidic protons from labile
intermediates, respectively. Further studies on more detailed
mechanistic aspects of this system are under way.
Other typical solid and organic bases were also applied
to the reaction in the presence of BF3‚OEt2. Among the bases
tested, only 2,6-di-tert-butylpyridine could give the product
Table 3. Carbonyl-Ene Reactions of 1a Using Various Basesa
entry
base
yield of 2a (%)c
1
2
3
4
5
MS 4Ab
NaHCO3
Et(i-Pr)2N
2,6-di-tert-butylpyridine
proton sponge
72
trd
trd
16
trd
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Base (1.0 equiv), BF3‚OEt2 (1.0 equiv), (HCHO)n (1.0 equiv). b MS
1
4A (1 wt equiv to 1a). c Determined by H NMR using chloroacetone as
internal standard. d Styrene 1a was recovered.
OL025719L
Org. Lett., Vol. 4, No. 10, 2002
1669