Regio- and stereoselective Ferrier reaction of O-1,3-dienyl acetals promoted by organoaluminum complexes

Article abstract of DOI:10.1021/ol062042j

The Ferrier reaction of O-1,3-dienyl acetals promoted by organoaluminum complexes such as methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD) is shown to proceed with a high degree of regio- and stereoselectivity to afford the corresponding α-al

Full text of DOI:10.1021/ol062042j

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5437-5439
Regio- and Stereoselective Ferrier
Reaction of O-1,3-Dienyl Acetals
Promoted by Organoaluminum
Complexes
Eiji Tayama* and Wataru Isaka
Graduate School of Science and Technology, Niigata UniVersity,
Niigata 950-2181, Japan
tayama@gs.niigata-u.ac.jp
Received August 18, 2006
ABSTRACT
The Ferrier reaction of O-1,3-dienyl acetals promoted by organoaluminum complexes such as methylaluminum bis(2,6-di-tert-butyl-4-
methylphenoxide) (MAD) is shown to proceed with a high degree of regio- and stereoselectivity to afford the corresponding -alkenyl-substituted
-alkoxy aldehydes in good yields. The mechanistic origin of the high regiocontrolling ability of MAD is elucidated. This method, coupled with
the easy availability of the requisite substrates, expands the synthetic scope of the Ferrier reaction.
r
â
The Ferrier reaction1 of O-vinylic acetals (1-alkenyl 1-alkoxy-
alkyl ethers) is a useful synthetic transformation because it
can easily convert the O-C bond into a new C-C bond to
provide the corresponding â-alkoxyaldehydes (Scheme 1, eq
1) and hence has found wide application (as a kind of formal
aldol-type reaction) for the synthesis of oxygen-containing
heterocycles such as tetrahydropyranyl derivatives and C-
glycosides.2 However, little attention has been paid to the
O-1,3-dienyl version of the Ferrier reaction which might pose
the regiochemical problem (Scheme 1, eq 2).3 Very recently,
we have developed an efficient synthetic method for O-1,3-
dienyl acetals (1-alkoxyalkyl 1,3-dienyl ethers) based on the
1,4-elimination of the O-4-methoxy-(2Z)-alkenyl acetals with
Scheme 1. Ferrier Reaction of O-Vinylic Acetals (1) and
O-1,3-Dienyl Acetals (2)
(1) (a) Ferrier, R. J. Chem. ReV. 1993, 93, 2779. (b) Ferrier, R. J. J.
Chem. Soc., Perkin Trans. 1 1979, 1455.
(2) (a) Shenoy, S. R.; Woerpel, K. A. Org. Lett. 2005, 7, 1157. (b) Suzuki,
T.; Inui, M.; Hosokawa, S.; Kobayashi, S. Tetrahedron Lett. 2003, 44, 3713.
(c) Zhang, Y.; Reynolds, N. T.; Manju, K.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 9720. (d) Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc.,
Perkin Trans. 1 2000, 2385. (e) Petasis, N. A.; Lu, S.-P. Tetrahedron Lett.
1996, 37, 141. (f) Takahashi, M.; Suzuki, H.; Moro-oka, Y.; Ikawa, T.
Tetrahedron Lett. 1982, 23, 4031. (g) Takahashi, M.; Suzuki, H.; Moro-
oka, Y.; Ikawa, T. Tetrahedron Lett. 1982, 23, 1079.
(3) A example of Ferrier reaction of 1,3-dienyl acetals: Inui, M.; Hoso-
kawa, S.; Nakazaki, A.; Kobayashi, S. Tetrahedron Lett. 2005, 46, 3245.
10.1021/ol062042j CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/24/2006

n-butyllithium.4 With various O-dienyl acetals in hand, our
interest was now directed toward the regio- and stereochem-
istry in the Lewis acid promoted Ferrier reaction thereof.
We now wish to report that the Ferrier reaction of O-1,3-
dienyl acetal (1), when promoted by bulky organoaluminum
complexes such as methylaluminum bis(2,6-di-tert-butyl-4-
methylphenoxide) (MAD), proceeds with a remarkably high
regioselectivity to afford the corresponding R-alkenyl-
substituted â-alkoxy aldehydes (2).
tion that the aluminum dienolate involved would undergo
the alkylation predominantly at the γ-position because the
R-alkylation was effectively suppressed by the bulky ligands
(Scheme 2).7 Rather surprisingly, however, the stoichiometric
Scheme 2. Hypothesis for the Ferrier Reaction of 1a
Promoted by Organoaluminum Complexes
Because the Lewis acid promoted Ferrier reaction in
general is believed to proceed via the ionic cleavage forming
the enolate and carbocationic species followed by their
recombination, the Ferrier version now concerned might
involve the dienolate species and hence might provide the
R- and γ-alkylation products as mentioned above. Thus, the
choice of the Lewis acid used is crucial for efficient
regiocontrol. First, we examined the regiochemistry of the
reaction of O-1,3-dienyl acetal 1a in dichloromethane at -78
°C using typical Lewis acids (Table 1). The use of boron
Table 1. Ferrier Reaction of the O-1,3-Dienyl Acetal (1a)
Promoted by Several Representative Lewis Acids (LA)
use of MAD was found to result in the exclusive formation
of the R-product 2a in 89% yield, together with a high
diastereoselectivity (Table 1, entry 4). Only a trace amount
of γ-product 3a was detected in the product mixture. Similar
uses of MABR and ATPH provided equally high R-regi-
oselectivities (entries 5 and 6), although the latter showed a
slightly lowered diastereoselectivity.8
Significantly, the MAD-promoted Ferrier reaction of
γ-unsubstituted dienyl substrate 1b also showed an equally
high R-regioselectivity, whereas BF3- and TiCl4-promoted
reactions of 1b provided higher γ-selectivities than those of
the γ-substituted counterpart 1a (Scheme 3).
LA
(equiv)
temp, time
(°C, h)
yield (%)a of
3a
entry
2a (syn/anti)b
(dr)b
1
2
3
4
5
6
BF3‚OEt2 (0.1) -78, 1
75 (1:9)
80 (1:9)
51 (2:8)
89 (8:2)
88 (8:2)
91 (5:5)
9 (5:5)
18 (7:3)
33 (7:3)
trace
trace
trace
SnCl4 (0.2)
TiCl4 (1.1)
MAD (1.1)
MABR (1.1)
ATPH (1.1)
-78, 1
-78, 1
-78, 1
-78, 1
Scheme 3. MAD-Promoted Ferrier Reaction of 1ba-c
-78, 2 to -10, 1
a Isolated yield. b The diastereomeric ratios of 2a (syn/anti) and 3a (dr)
1
were determined by H NMR assay.
trifluoride diethyl etherate (BF3·OEt2), tin tetrachloride
(SnCl4), and titanium tetrachloride (TiCl4) was found to
provide a mixture of the R-product 2a and γ-regioisomer
3a, with the former predominating (Table 1, entries 1-3).
1
The R- and γ-regioisomers were assigned by H NMR
1
aThe yields were determined by H NMR analysis using 1,4-
analysis (olefinic protons: 5.3-5.6 ppm for 2a and 6.1-
6.8 ppm for 3a). The syn/anti stereochemistry of 2a was
determined by 1H NMR comparison with an authentic
sample.5 Next, we were intrigued by the use of bulky
aluminum complexes6 such as MAD, methylaluminum bis-
(2,6-di-tert-butyl-4-bromophenoxide) (MABR), and alumi-
num tris(2,6-diphenylphenoxide) (ATPH) with the expecta-
b
bis(trifluoromethyl)benzene as an internal standard. The syn/anti
1
c
stereoselectivities were determined by H NMR assay. The syn/
anti stereochemistry was determined by analogy to the chemical
shifts and coupling constants of syn-2a or anti-2a. For details, see
Supporting Information.
The question of the mechanistic origin of the high R-regio-
(4) Tayama, E.; Sugai, S. Synlett 2006, 849.
selectivity observed with the bulky aluminum complexes
5438
Org. Lett., Vol. 8, No. 24, 2006

immediately arose. To answer the question, we performed
crossover experiments to reconfirm the intramolecularity of
the Lewis acid promoted reactions concerned (Scheme 4).
Table 2. Ferrier Reaction of Various Types of O-1,3-Dienyl
Acetals and Ketal 1
Scheme 4. Crossover Reaction of 1c and 1d
temp, time
(°C, h)
yield (%)a
R2 R3 (syn/anti)b,c
entry
LA
R1
1
2
3
4
MAD -78, 1
MAD -78, 1
ATPH -78, 1 to -20, 1
ATPH -78, 2 to -20, 3
d
f
g
h
nBu Me
Me Me Me
H
88 (7:3)
90
92 (7:3)
78 (5:5)
-(CH2)4-
-(CH2)3-
H
H
1
a Isolated yield. b The ratios were determined by H NMR assay. c The
syn/anti stereochemistries were determined by analogy to chemical shifts
and coupling constants of syn-2a or anti-2a. For details, see Supporting
Information.
than MAD for the tetrahydropyranyl (1g) and tetrahydro-
furanyl (1h) derivatives.
Thus, an equimolar mixture of substrates 1c and 1d was
subjected to the BF3- and MAD-promoted reaction. Interest-
ingly enough, product analyses revealed that the MAD-pro-
moted reaction did not produce any detectable amount of
the crossover products (2e and 2a),9 whereas the BF3-pro-
moted reaction provided the crossover products in ca. 50%
yield.10 These observations suggest that the MAD-promoted
reaction would proceed via the “contact ion pair”, thus lead-
ing to the high R-regioselectivity as actually observed, where-
as the BF3-promoted reaction would proceed via the “separate
ion pair”, thus producing both R- and γ-products (Scheme 5).
In summary, we have demonstrated that the Ferrier
reaction of O-1,3-dienyl acetals in the presence of aluminum
complexes such as MAD proceeds with high R-regioselec-
tivity to afford the corresponding R-alkenyl-substituted
â-alkoxy aldehydes in good yields and high diastereoselec-
tivities. The high regioselectivity is suggested to arise from
the contact ion pair type intermediate. This method, coupled
with the easy availability of the requisite substrates, expands
the synthetic scope of the Ferrier reaction. Further work to
make the reaction catalytic is in progress in our laboratory.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan.
Scheme 5. Proposed Mechanism of R-Regioselective Ferrier
Reaction
Supporting Information Available: Experimental pro-
cedures and characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062042J
(5) The product 2a (syn/anti ) 8:2) was converted to 2-ethoxy-3-ethoxy-
methylnonane [(i) NaBH4, MeOH, 0 °C to rt; (ii) H2 (1 atm), Pd-C, EtOAc,
rt; (iii) EtI, NaH, THF, 0 °C to reflux], and the anti authentic sample was
prepared from n-octanoic acid BHT ester via the known anti-selective aldol
reaction with acetaldehyde. For more details, see Supporting Information.
(6) For review: Miyaura, N.; Maruoka, K. In Synthesis of Organometallic
Compounds; Komiya, S., Ed.; John Wiley & Sons Ltd.: Chichester, 1997;
pp 364-390.
(7) ATPH-promoted conjugate addition to R,â-unsaturated aldehydes
gave 1,4-adducts with high γ-regioselectivities. See: Maruoka, K.; Imoto,
H.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 4131.
(8) Use of trimethylaluminum (Me3Al) did not induce the reaction at all
(recovery of 1a in 92% yield). Use of methylaluminum bis(phenoxide)
[MeAl(OPh)2] gave a complex mixture.
To further expand the scope of the present regioselective
Ferrier reaction, we prepared a series of O-1,3-dienyl acetals
and carried out their aluminum complex-promoted reactions
(Table 2). In all cases, only R-products were obtained in high
yields. It is interesting to note that ATPH is more efficient
(9) The product ratios were determined by 500 MHz 1H NMR analysis.
All possible stereoisomers were prepared independently as authentic samples.
(10) For a few examples of the Ferrier reaction forming the crossover
products, see refs 2a and 2c.
Org. Lett., Vol. 8, No. 24, 2006
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