Regioselective reactions of 1-alkylidene-2-oxyallyl cations with furan: Control of [4 + 3] cycloaddition, [3 + 2] cycloaddition, and electrophilic substitution

Article abstract of DOI:10.1021/ol061655t

The ring opening of alkylidenecyclopropanone acetal under acidic conditions produces the 1-alkylidene-2-oxyallyl cation as an intermediate, which reacts with furan to give the [3 + 2] and [4 + 3] cycloadducts as well as an electrophilic substitution produ

Full text of DOI:10.1021/ol061655t

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4113-4116
Regioselective Reactions of
1-Alkylidene-2-oxyallyl Cations with
Furan: Control of [4
+ 3] Cycloaddition,
[3 2] Cycloaddition, and Electrophilic
+
Substitution
Morifumi Fujita,* Makoto Oshima, Sakuro Okuno, Takashi Sugimura, and
Tadashi Okuyama
Graduate School of Material Science, Himeji Institute of Technology,
UniVersity of Hyogo, Kohto, Kamigori, Hyogo 678-1297, Japan
fuji@sci.u-hyogo.ac.jp
Received July 6, 2006
ABSTRACT
The ring opening of alkylidenecyclopropanone acetal under acidic conditions produces the 1-alkylidene-2-oxyallyl cation as an intermediate,
which reacts with furan to give the [3 2] and [4 3] cycloadducts as well as an electrophilic substitution product. The product distribution
is controlled by the oxy substituents of the cation and by the solvent employed.
+
+
Alkylideneallyl cations contain two electrophilic carbon
atoms of sp and sp2 hybridizations.1,2 Hybridization affects
the electronic and steric character of these reaction sites
toward nucleophilic reagents. The electronic property was
deduced from the 13C NMR chemical shifts of the alkylidene-
allyl cations measured under superacidic conditions.1,2 The
reactivities of these ambident electrophiles with various
nucleophiles are of interest from both mechanistic and
synthetic viewpoints. However, few examples have been
reported for the reaction of alkylideneallyl cations with
nucleophiles: the solvolysis of 2-bromo-1,3-dienes and 2,3-
dienyl alcohols took place via an alkylideneallyl cation
intermediate that gave a solvolysis product.2 The Lewis acid-
catalyzed reaction of cyclonona-1,2-dien-4-one acetal with
dienes gave [4 + 2] cycloadducts.3
(1) Apeloig, Y.; Mu¨ller, T. In Dicoordinated Carbocations; Rappoport,
Z., Stang, P. J., Eds.; John Wiley & Sons: Chichester, 1997; Chapter 2.
Siehl, H.-U. In Dicoordinated Carbocations; Rappoport, Z., Stang, P. J.,
Eds.; John Wiley & Sons: Chichester, 1997; Chapter 5 and references
therein.
(2) For recent examples, see: Siehl, H.-U.; Brixner, S. J. Phys. Org.
Chem. 2004, 17, 1039-1045. Siehl, H.-U.; Mu¨ller, T.; Gauss, J. J. Phys.
Org. Chem. 2003, 16, 577-581.
We have recently found that the ring opening of alkyli-
denecyclopropanone acetal 1 with a Lewis acid4a,b and a
Brønsted acid5a,c generated the 1-alkylidene-2-oxyallyl cation,
10.1021/ol061655t CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/11/2006

which was trapped by chloride ion,5a,c methanol,5a and
siloxyalkenes5b (Scheme 1). The present communication
Table 2. Acid-Mediated Reactions of 2 with Furan
Scheme 1. Alkylideneallyl Cation Generated from 1
yield (%)b
[furan]
conditiona
(mM)
4
5(5S/5K)
6
7
8K
A
A
Ac
B
B
Bd
13
100
100
15
100
100
44
52
70
76
67
79
7(0/100)
7(0/100)
4(24/76)
<1
<1
3(0/100)
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
3
<1
<1
<1
<1
5
shows that the [4 + 3] and [3 + 2] cycloadditions of furan
with this cation are controlled by the oxy group of the
oxyallyl cation as well as by the reaction conditions including
the solvent.6,7
a See footnote a for Table 1. b Yields were determined by GC. c SnCl4
Cyclohexylidenecyclopropanone bis(trimethylsilyl)acetal
2 and the dimethylacetal 3 as well as the mixed acetal 1
were treated with TiCl4 at -78 °C in dichloromethane in
the presence of furan to give adducts of furan, 4 and 5, in
addition to a small amount of chloride 8, which was the
major product in the absence of furan5a,c (condition A of
Tables1-3). All the products are the result of the C2-C3
bond cleavage of 1-3 and are rationalized by a reaction
was employed instead of TiCl4. d In the presence of H2O (2% v/v).
mechanism that proceeds via the alkylideneallyl cation
intermediate. The reactions of 1 and 3 preferentially gave a
furanyl product 5 in contrast to the preferential formation
of the [4 + 3] cycloadduct 4 in the reaction of the disilyl
acetal substrate 2. The reaction also took place using SnCl4.
The reaction of 1 with furan also proceeds in 1,1,1,3,3,3-
hexafluoropropan-2-ol (HFIP) containing hydrogen chloride
at 0 °C to yield a cyclopentenone product 7 as well as the
products obtained in the reaction with Lewis acids, 4, 5, and
8 (condition B). The formation of the cyclopentenone product
7 was not apparent with a deficient amount (less than 1
equiv) of furan, but a simple cyclopentenone product 6 was
obtained. The addition of THF also retarded the formation
of 7 for the reaction in HFIP with the increasing yield of 5.
The preferential formation of the [4 + 3] cycloadduct 4 was
observed without the formation of 7 for the reaction of 2 in
HFIP as was observed with the Lewis acid in dichloro-
methane (Table 2). The reaction of 3 in HFIP gave 7 (Table
3) with a product distribution similar to that of 1 in HFIP.
The product distribution for the reaction of 1-3 with furan
depends on the reaction conditions as well as on the oxy
Table 1. Acid-Mediated Reactions of 1 with Furan
yield (%)b
[furan]
Table 3. Acid-Mediated Reactions of 3 with Furan
conditiona (mM)
4
5(5M/5S/5K)
6
7
8(8M/8S/8K)
A
A
B
B
30
200
6
5
11
4
44(93/7/0)
<1 <1
5(100/0/0)
10(100/0/0)
42(0/0/100)
4(0/0/100)
49(90/10/0) <1 <1
6(0/0/100) 26 <1
13(0/0/100) <1 43
15
5
B
Bc
Bd
100
100
100
<1 <1
<1 44 <1
<1
<1
10(0/0/100) <1 55
66(0/0/100) <1 <1
4(0/0/100)
7(0/0/100)
yield (%)b
[furan]
a Under the condition A, reaction of 1 (7 mM) was carried out at -78
°C for 30 min in dichloromethane containing furan and TiCl4 (14 mM).
Under the condition B, reaction of 1 (7 mM) was carried out at 0 °C for 5
min in HFIP containing furan and HCl (20 mM). b Yields were determined
by GC. c In the presence of H2O (1% v/v). d In the presence of THF (10%
v/v).
conditiona
(mM)
4
5(5M/5K)
6
7
8(8M/8K)
A
B
14
100
<1
<1
56(81/19)
<1
<1 <1
<1 75
20(89/11)
<1
a See footnote a for Table 1. b Yields were determined by GC.
4114
Org. Lett., Vol. 8, No. 18, 2006

group of the acetal substrates 1-3. The diverse products of
the reaction of 1-3 with furan are rationalized by the reaction
pathways illustrated in Scheme 2. All the products are
ascribed to the difference in the oxy group of the alkylidene-
allyl cation intermediate: methyl acetals 1 and 3 give the
methoxy cation 9, and the disilyl acetal 2 produces the siloxy
cation 10. The preferential formation of the methoxy-
substituted allylic cation 9 from the unsymmetrical acetal 1
is rationalized by the higher basicity and leaving ability of
the trimethylsiloxy vs the methoxy group, and the same
tendency has been observed in the reactions with the Lewis
and Brønsted acids.5 It is possible for the [4 + 3] intermediate
11 to form concertedly but also in a stepwise manner via
12.8,9 The preferential formation of the [4 + 3] cycloadduct
4 from 2 was independent of the solvent employed for the
reaction in comparison with the solvent-dependent product
distribution of the reactions of 1 and 3, which may mainly
proceed via 12. The lack of a solvent effect is reasonable
for the concerted pathway of the [4 + 3] cycloaddition of
10 with furan derived from 2.10 That is, the competition
between the concerted reaction of the siloxy cation 10 and
the stepwise one of the methoxy cation 9 may result in the
product distribution depending on the oxy groups of the
substrates 1-3 and on the reaction conditions including the
solvent. Theoretical and stereochemical studies for the
cycloadditions of 2-oxyallyl cations with dienes indicate that
an electron-donating 2-oxy group decreases the electro-
philicity of the cation resulting in a favorable concerted
mechanism.8a,11 The effect of the oxy group of the 2-oxyallyl
cations agrees well with the difference between the methoxy-
and siloxy-substituted alkylideneallyl cations (9 and 10).
The solvent-dependent product distribution for the reac-
tions of 1 and 3 is rationalized by the reaction pathways
bifurcated from the cation 12. The acidic HFIP solvent
retards the deprotonation from 12 to result in the promotion
of an internal cyclization to give 13. Tetrahydrofuran acts
as a base to promote the deprotonation from 12 to yield 5 in
HFIP. An excess amount of furan acts as a nucleophile
toward 13 and/or 14 to yield the double addition product 7
as illustrated in Scheme 3 but does not work as a base due
to the lower basicity. The use of a smaller amount of furan
provides a single addition product 6 instead of the double
addition product 7. The formation of these two products may
Scheme 2. Possible Pathways for the Reaction of 9 (10) with
Furan
provided by the nucleophilic addition of furan to the
alkylideneallyl cation intermediate 9 (10), which is generated
by the acid-mediated ring opening of cyclopropanone acetals
1-3. The [4 + 3] cycloadduct 4 is simply formed via 11,
and the furanyl product 5 is formed by the deprotonation of
12. The cyclopentenone structure of 6 and 7 may be formed
via 13 that is a result of the [3 + 2] cycloaddition of 9 (10)
with furan. The [4 + 3] cycloaddition must be concerted,
whereas the [3 + 2] reaction should occur in a stepwise
manner. Transformation from the dihydrofuran of 13 to the
carbaldehyde of 6 and 7 is rationalized by the acid-mediated
ring opening of the dihydrofuran via the carbon protonation
(see below).
The reaction of 2 preferentially gave the [4 + 3] cyclo-
adduct 4 in both HFIP and dichloromethane solvents,
whereas only a small amount of 4 was obtained in the
reactions of 1 and 3, in which the product distribution
depended upon the reaction conditions including the solvent.
The contrasting tendency of the product distribution may be
Scheme 3. Possible Pathways Leading to 6 and 7
(3) (a) Grob, C. A.; Spaar, R. HelV. Chim. Acta 1970, 53, 2119-2129.
(b) Olsson, L.-I.; Claesson, A.; Bogentoft, C. Acta Chem. Scand. 1973, 27,
1629-1636. (c) Gelin, R.; Gelin, S.; Albrand, M. Bull. Soc. Chim. Fr. 1972,
720-723.
(4) Gassman, P. G.; Lottes, A. C. Tetrahedron Lett. 1991, 32, 6473-
6476.
(5) (a) Fujita, M.; Fujiwara, K.; Mouri, H.; Kazekami, Y.; Okuyama, T.
Tetrahedron Lett. 2004, 45, 8023-8026. (b) Fujita, M.; Fujiwara, K.;
Okuyama, T. Chem. Lett. 2006, 35, 382-383. (c) Fujita, M.; Hanagiri, S.;
Okuyama, T. Tetrahedron Lett. 2006, 47, 4145-4148.
(6) (a) The [3 + 2] cycloaddition reactions of the alkylidenecyclopropanes
have been reported, but the reaction proceeds via a metal complex6b and
trimethylenemethane6c to result in a different regioselectivity. (b) For
example: Binger, P.; Scha¨fer, B. Tetrahedron Lett. 1988, 29, 4539-4542.
Kawasaki, T.; Saito, S.; Yamamoto, Y. J. Org. Chem. 2002, 67, 4911-
4915. (c) Nakamura, E.; Yamago, S. Acc. Chem. Res. 2002, 35, 867-877.
(7) (a) Palladium-catalyzed reactions of alkylidenecyclopropane with
furans gave an electrophilic substitution product at the 2-position of furan.7b
(b) Nakamura, I.; Saito, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122,
2661-2662. Nakamura, I.; Siriwardana, A. I.; Saito, S.; Yamamoto, Y. J.
Org. Chem. 2002, 67, 3445-3449.
Org. Lett., Vol. 8, No. 18, 2006
4115

be a result of the [3 + 2] cycloaddition of 9 with furan,
followed by the acid-mediated opening of the furan ring to
give the formylmethylcyclopentenone (6 and 7).12
To obtain further information on the [3 + 2] cycloaddition
of the alkylideneallyl cation 9, the reaction with 2,3-
benzofuran was carried out as shown in Scheme 4. The
nucleophilic addition of furan selectively proceeds at the sp
carbon of the alkylideneallyl cation 9 to yield 5-7 via 12.13
The selective addition of furan at the sp carbon of 9 is in
contrast to the sp2 addition observed for the reaction with
siloxyalkenes and methanol. Although reasons for the
regioselective addition at the sp carbon are not clear, the
frontier orbital interactions between furan and the allyl cation
may control the regioselectivity14 because the sp selectivity
is not compatible with the electronic and steric advantages
of the sp2 addition of nucleophiles to 9.1,2,5b
Scheme 4. Reaction of 1 with Benzofuran
In summary, the 1-alkylidene-2-oxyallyl cations (9 and
10) generated from the alkylidenecyclopropanone acetals
1-3 were employed for the reaction with furan. The [4 +
3] cycloaddition effectively takes place for the reaction via
the siloxyallyl cation (10). The [3 + 2] cycloaddition
preferentially proceeds for the reaction of the methoxyallyl
cation (9) in a nonbasic HFIP solution. Control of the modes
of these cycloadditions is rationalized by the concerted and
stepwise mechanisms for the reaction of the 1-alkylidene-
2-oxyallyl cations with furan.
reaction of 1 gave a simple [3 + 2] cycloadduct 15 as a
single regioisomer in 76% isolated yield. No regioisomer
1
16 was detected by H NMR measurements. The regio-
isomeric structure of 15 confirmed by NOE measurements
is quite compatible with the cyclic structure of 13. These
results are consistent with the mechanism, in which the
Supporting Information Available: General procedures
and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(8) For recent reviews of [4 + 3] cycloaddition, see: (a) Rigby, J. H.;
Pigge, F. C. Org. React. 1997, 51, 351-478. (b) Harmata, M.; Rashatasa-
khon, P. Tetrahedron 2003, 59, 2371-2395. (c) Harmata, M. Acc. Chem.
Res. 2001, 34, 595-605. (d) Hoffmann, H. M. R. Angew. Chem., Int. Ed.
Engl. 1984, 23, 1-19. (e) Hartung, I. V.; Hoffmann, H. M. R. Angew.
Chem., Int. Ed. 2004, 43, 1934-1949.
OL061655T
(13) (a) If the [3 + 2] cycloaddition was initiated by nucleophilic addition
at the sp2 carbon of 9, the nucleophilic site of furan should be the 3-position
that has a poorer reactivity toward an electrophile than the 2-position. The
electrophilic substitution of furan with carbocations proceeds at the
2-position.13b (b) For example, see: Mu¨hlthau, F.; Schuster, O.; Bach, T.
J. Am. Chem. Soc. 2005, 127, 9348-9349.
(14) (a) An alternative mechanism for the preferential sp addition may
be the formation of 12 by the ring opening of the concertedly formed 11.
A similar ring opening reaction has been reported for the [4 + 3]
cycloaddition products of a 2-oxyallyl cation with furan.14b However, the
same regiochemistry as 13 was observed for the [3 + 2] cycloaddition of
2,3-benzofuran with 9 despite the improbable [4 + 3] cycloaddition with
benzofuran. Treatment of 4 with TiCl4 in dichloromethane at -78 °C gave
no 5. Therefore, 12 may be directly formed from 9 but not via 11. (b)
Mann, J.; Wilde, P. D.; Finch, M. W. Tetrahedron 1987, 43, 5431-5441.
(9) The [4 + 3] cycloaddition via nucleophilic addition at the sp2 carbon
of 9 (10) cannot be excluded, but there is no evidence of sp2 addition
products.
(10) (a) Solvent effects on the reaction of the 2-oxyallyl cation with furans
have been reported.10b (b) Shimizu, N.; Tanaka, M.; Tsuno, Y. J. Am. Chem.
Soc. 1982, 104, 1330-1340.
(11) (a) Cramer, C. J.; Barrows, S. E. J. Phys. Org. Chem. 2000, 13,
176-186. (b) Cramer, C. J.; Barrows, S. E. J. Org. Chem. 1998, 63, 5523-
5532.
(12) If the carbaldehyde was formed before the internal cyclization of
12, the cyclopentenones 6 and 7 could not have been obtained.
4116
Org. Lett., Vol. 8, No. 18, 2006