Intramolecular reaction of a phenonium ion. Novel lactonization of 4-aryl-5-tosyloxypentanoates and 4-aryl-5-tosyloxyhexanoates concomitant with a phenyl rearrangement

Article abstract of DOI:10.1021/jo010500q

The novel lactonizations of methyl 4-aryl-5-tosyloxypentanoate 1 and 4-aryl-5-tosyloxyhexanoate 3 concomitant with a phenyl rearrangement are reported. The lactonizations were promoted by silica gel or heating in various solvents. By examining the effects of substituents of the aromatic ring on the reactivity, it was found that the reaction proceeded via a phenonium ion. This finding was supported by the stereochemical results for the lactonization of optical active 1. Silica gel-promoted lactonization of 1 gave only γ-lactone 2, whereas that of 3 afforded γ-lactone 4 and δ-lactone 5. These lactonizations proved to be kinetically controlled. On the other hand, when 3c was heated in CH₃NO₂ at 70°C, the highly selective formation of 4c was observed. Further detailed experiments confirmed that the thermal lactonization in CH₃NO₂ was thermodynamically controlled.

Full text of DOI:10.1021/jo010500q

In tr a m olecu la r Rea ction of a P h en on iu m Ion . Novel La cton iza tion
of 4-Ar yl-5-tosyloxyp en ta n oa tes a n d 4-Ar yl-5-tosyloxyh exa n oa tes
Con com ita n t w ith a P h en yl Rea r r a n gem en t1
Shinji Nagumo,*,† Machiko Ono,‡ Yo-ichiro Kakimoto,† Tsuneo Furukawa,‡ Tomoaki Hisano,†
Megumi Mizukami,† Norio Kawahara,† and Hiroyuki Akita*,‡
Hokkaido College of Pharmacy, Katsuraoka 7-1, Otaru, Hokkaido 047-0264, J apan, and School of
Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, J apan
nagumo@hokuyakudai.ac.jp; akita@phar.toho-u.ac.jp
Received May 17, 2001
The novel lactonizations of methyl 4-aryl-5-tosyloxypentanoate 1 and 4-aryl-5-tosyloxyhexanoate
3 concomitant with a phenyl rearrangement are reported. The lactonizations were promoted by
silica gel or heating in various solvents. By examining the effects of substituents of the aromatic
ring on the reactivity, it was found that the reaction proceeded via a phenonium ion. This finding
was supported by the stereochemical results for the lactonization of optical active 1. Silica gel-
promoted lactonization of 1 gave only γ-lactone 2, whereas that of 3 afforded γ-lactone 4 and
δ-lactone 5. These lactonizations proved to be kinetically controlled. On the other hand, when 3c
was heated in CH3NO2 at 70 °C, the highly selective formation of 4c was observed. Further detailed
experiments confirmed that the thermal lactonization in CH3NO2 was thermodynamically controlled.
SCHEME 1
In tr od u ction
Symmetrical σ-bridged ethylenebenzenium (phenoni-
um) ions were proposed by Cram to explain the stereo-
chemical results in solvolyses of optically active threo-
and erythro-3-aryl-2-butyltosylates.2 Brown claimed that
these experimental findings could alternatively be ex-
plained by considering weakly π-bridged, rapidly equili-
brating open ions.3 This controversy became the most
important topic in modern physical organic chemistry,
and many reports on this subject have been published.4
On the basis of the results of these studies, Brown
concluded that a continuous spectrum of ions, from open
to completely bridged ions, exists depending upon the
solvent and substituent in the ions.5 Furthermore, NMR
spectral6 and theoretical7 studies have indicated that the
intermediate has a σ-bridged phenonium ion structure
rather than an equilibrating open ion structure. Despite
the impressive advances in phenonium ion chemistry due
to the contribution of results of many studies, the ion has
not been widely applied to synthetic chemistry. If a
phenonium ion has appropriately aligned intramolecular
nucleophilic functional groups, a novel type of ring
formation induced by the ion should proceed (Scheme 1).
Such a reaction should offer possibilities that are not
available in the case of an intermolecular reaction. For
* To whom correspondence should be addressed. For S.N.: phone
+81-(0)134-62-1842; fax +81-(0)134-62-5161. For H. A.: phone +81-
(0)474-72-1805; fax, +81-(0)474-72-1825.
† Hokkaido College of Pharmacy.
‡ Toho University.
(1) A part of this work was reported as a preliminary communica-
tion. (a) Nagumo, S.; Furukawa, T.; Ono, M.; Akita, H. Tetrahedron
Lett. 1997, 38, 2849. (b) Nagumo, S.; Hisano, T.; Kakimoto, Y.;
Kawahara, N.; Ono, M.; Furukawa, T.; Takeda, S.; Akita, H. Tetra-
hedron Lett. 1998, 39, 8109.
(2) (a) Cram, D. J . J . Am. Chem. Soc. 1949, 71, 3863. (b) Cram, D.
J .; Davis, R. J . Am. Chem. Soc. 1949, 71, 3871. (c) Cram, D. J . J . Am.
Chem. Soc. 1949, 71, 3875. (d) Cram, D. J . J . Am. Chem. Soc. 1964,
86, 3767.
(6) (a) Olah, G. A.; Head, N. J .; Rasul, G.; Prakash, G. K. S. J . Am.
Chem. Soc. 1995, 117, 875. (b) Manner, J . A. M.; Cook, J . A., J r.;
Ramsey, B. G. J . Org. Chem. 1974, 39, 1199. (c) Olah, G. A.; Porter,
R. D. J . Am. Chem. Soc. 1971, 93, 6877. (d) Olah, G. A.; Porter, R. D.
J . Am. Chem. Soc. 1970, 92, 7627. (e) Olah, G. A.; Comisarow, M. B.;
Namanworth, E.; Ramsey, B. J . Am. Chem. Soc. 1967, 89, 5259.
(7) (a) Sieber, S.; Schleyer, P. v. R. J . Am. Chem. Soc. 1993, 115,
6987. (b) Yamabe, S.; Tanaka, T. Nippon Kagaku Kaishi 1986, 1388.
(c) Loupy, A.; Ancian, B. Tetrahedron Lett. 1975, 951. (d) Hehre, W. J .
J . Am. Chem. Soc. 1972, 94, 5919.
(3) Brown, H. C.; Morgan, K. J .; Chloupek, F. J . J . Am. Chem. Soc.
1965, 87, 2137.
(4) For a review, see: (a) Lancelot, C. J .; Cram, D. J .; Schleyer, P.
v. R. In Carbonium Ions; Olah, G. A., Schleyer, P. v. R., Eds.; Wiley-
Interscience: New York, 1972; Vol. III, Chapter 27. (b) Vogel, P. In
Carbocation Chemistry; Elsevier: Amsterdam, 1985; Chapter 7.
(5) Brown, H. C.; Kim, C. J .; Lancelot, C. J .; Schleyer, P. v. R. J .
Am. Chem. Soc. 1970, 92, 5244.
10.1021/jo010500q CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/22/2002
6618
J . Org. Chem. 2002, 67, 6618-6622

Intramolecular Reaction of a Phenonium Ion
TABLE 1. La cton iza tion of Meth yl 4-Ar yl-5-tosyloxyp en ta n oa tes
entry
tosylate
R1
R2
R3
R4
R5
yield (%)
time (h)
1
2
3
4
1a
1b
1c
1d
1e
H
H
H
OMe
Me
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
H
no reaction
no reaction
83
86
85
74
81
96
OMe
Me
OMe
OMe
OMe
H
Me
Me
Me
144
48
48
48
3
5
2
120
270
4
5
6a
7
(S)-1e (79%ee)
Me
1f
1g
1h
1h
1h
1i
OMe
OMe
OMe
OMe
OMe
Me
8
9
91
95
10b
11c
12
13
14
99 (2h :1h ) 2:1)d
OMe
OMe
OMe
81
84
84
1j
1k
OMe
OMe
5
72
OMe
H
a
b
This lactonization produced (S)-2e (77%ee). This lactonization was carried out in Et2O and hexane (1:1). c This lactonization was
carried out in AcOEt and hexane (1:1). The yield of crude mixture of 2h and 1h is shown. The ratio was estimated by 1H NMR.
d
example, a low-nucleophilic functional group such as an
ester group would be expected to couple with the phe-
nonium ion in an intramolecular reaction. We therefore
examined the solvolyses of various â-arylalkyltosylates
with an internal ester group.
tion proceeded with inversion of the stereo center by
performing it with optically active tosylate (s)-1e.9,10
Silica gel promoted lactonization of 38 produced δ-lac-
tone 5 along with γ-lactone 4 (Table 2). Interestingly, the
ratio of 4 and 5 depended on the presence of ortho
substituents. The solvolytic lactonization of 3a and 3c
having no ortho substituent afforded γ-lactone 4a ,c and
δ-lactone 5a ,c with a ratio of ca. 1:1 (entries 1 and 3).
On the other hand, the same reaction of 3b, 3d , and 3e
bearing a methoxy or methyl group at the ortho position
resulted in preferential formation of δ-lactone (entries
2, 8, and 9).
Since we were particularly interested in the effect of
o-methyl group on regioselectivity, we carried out ac-
etolyses of â-aryl tosylates 6a ,b11 and 7a ,b11 (Table 3) in
order to clarify the generality of the effect of an o-methyl
group. Solvolysis of 6a proceeded smoothly at 70 °C to
give an inseparable mixture of 8a and 9a in 73% yield
at a ratio of 1:1.3. The ratio of acetates 8a and 9a was
determined by comparing the respective proton peaks at
the benzyl position in 1H NMR. Solvolysis of 7a under
the same conditions afforded a mixture of 8a and 9a in
74% yield at a ratio of 1:1.5. The ratios of the products
in these acetolyses are not significantly different. Inter-
estingly, when solvolyses of 6b and 7b having an o-
methyl group were performed under the same conditions,
a remarkable difference in the ratio of products was
observed. The ratio of 8b and 9b was 3:1 in the solvolysis
of 6b, while it was 1:8 in the solvolysis of 7b.
Resu lts
Table 1 summarizes the results of the solvolytic lac-
tonization of 4-aryl-5-tosyloxypentanoates 1a -k .8 As we
expected, pentanoates 1c-k having o- and p-methoxy
groups underwent a solvolytic rearrangement concomi-
tant with lactone ring closure upon treatment with silica
gel in hexane to yield only γ-lactones 2c-k in good yields.
On the other hand, pentanoates 1a ,b having no o- and
p-methoxy groups did not react. Their reactivities were
remarkably affected by the substituent patterns in the
aromatic ring. The lactonization of 1c was completed in
6 days. Compounds 1d ,e were somewhat more reactive
than was 1c. The lactonization of tosylates 1f-j, which
have two methoxy groups in the ortho or para positions,
was completed in a few hours. On the other hand, the
reactivity of 1k was much less than that of 1f-j in spite
of their having o- and p-methoxy groups. Increasing the
polarity of the solvent makes the reaction rate slower
(Table 1, entries 9-11). It was found that the lactoniza-
(8) Compounds 1a -k , 3a -e, and 10 were synthesized from methyl
4-aryl-5-hydroxy-2-pentenoate or methyl 4-aryl-5-hydroxy-2-hexenoate.
For detailed procedure, see Supporting Information. See also: (a) Ono,
M.; Yamamoto, Y.; Todoriki, R.; Akita, H. Heterocycles 1994, 37, 181.
(b) Ono, M.; Todoriki, R.; Yamamoto, Y.; Akita, H. Chem. Pharm. Bull.
1994, 42, 1590. (c) Ono, M.; Yamamoto, Y.; Akita, H. Chem. Pharm.
Bull. 1995, 43, 553. (d) Ono, M.; Ogura, Y.; Hatogai, K.; Akita, H.
Tetrahedron: Asymmetry 1995, 6, 1829. (e) Nagumo, S.; Irie, S.; Akita,
H. J . Chem. Soc., Chem. Commun. 1995, 2001. (f) Nagumo, S.; Irie,
S.; Akita, H. Chem. Pharm. Bull. 1996, 44, 675. (g) Nagumo, S.; Irie,
S.; Hayashi, K.; Akita, H. Heterocycles 1996, 43, 1175. (h) Akita, H.;
Umezawa, I.; Takano, M.; Matsukura, H.; Oishi, T. Chem. Pharm. Bull.
1991, 39, 3094.
Solvolytic lactonization of 3c also occurred in various
heating solvents at 70 °C without silica gel (Table 2,
entries 4, 6, and 7). The ratio of 4c and 5c depended
(9) For the synthesis of (S)-1d , see Supporting Information.
(10) Absolute configuration of (S)-2d was detected by chemical
conversion. For detail, see Supporting Information.
(11) Compounds 6a ,b and 7a ,b were synthesized from 4c,d and
5c,d , respectively. For detailed procedure, see Supporting Information.
J . Org. Chem, Vol. 67, No. 19, 2002 6619

Nagumo et al.
TABLE 2. Silica Gel P r om oted La cton iza tion of 4-Ar yl-5-tosyloxyh exa n on a tes
entry
tosylate
R1
R2
R3
solvent
hexane
hexane
hexane
CH3NO2
CH3NO2
tBuOH
CH3COOH
hexane
additive
temp
4 (yield, %)
5 (yield, %)
ratio (4:5)
time (h)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3c
3c
3c
3c
3d
3e
H
OMe
H
H
H
H
H
Me
OMe
H
H
OMe
H
silica gel
silica gel
silica gel
rt
rt
rt
70 °C
70 °C
70 °C
70 °C
rt
30
11
34
61
20
31
29
7
42
67
36
3
57
39
41
73
68
1:1.4
1:6
1:1.05
20
10
46
5
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
Me
20:1
MS4Å
1:2.85
1:1.3
1:1.4
1:10
1:5
5
14
0.5
15
6
silica gel
silica gel
H
hexane
rt
14
TABLE 3. Acetolysis of â-Ar ylh ep tyltosyla tes
SCHEME 2
5c was treated with TsOH‚H2O (1 equiv) and silica gel
in hexane at room temperature, the rate of ring trans-
formation was remarkabaly slow and 4c was obtained
in only 5% yield after 46 h. On the other hand, the
conversion of 4c into 5c was not observed under any of
the conditions described above. Finally, conversion of 108
into 2h did not occur upon treatment with silica gel/TsOH
(1 equiv) or silica gel/TsOMe in hexane (Scheme 2).
entry tosylate R1
R2
R3
8 + 9 (yield, %) ratio (8:9)
1
2
3
4
6a
7a
6b
7b
H
H
Me
Me
OMe OMe
OMe OMe
H
H
73
74
78
72
1:1.3
1:15
3:1
OMe
OMe
Discu ssion
1:8
The silica gel promoted lactonization of 1 and 3 is
thought to proceed via a phenonium ion on the basis of
the following facts: (1) a complete or partial phenyl
rearrangement occurs to produce 2 and 4, (2) the reactiv-
ity of 1 depends on the substituent patterns in the
aromatic ring, (3) the lactonization proceeds with com-
plete inversion at the C4 position, and (4) the relative
configuration of 5 is trans. The reaction seems to take
place on the surface of silica gel,12 because the reaction
rate of 1h is very slow in ether/hexane (1:1) or AcOEt/
hexane (1:1). It is noteworthy that isolated 4c and 5c
were almost not interconverted upon treatment with
t
strongly on the solvent. The lactonization in BuOH or
CH3COOH afforded a slight excess of δ-lactone 5c, while
the reaction in CH3NO2 gave γ-lactone 4c preferentially.
Interestingly, when the change in the composition of the
reaction mixture with the passage of time was confirmed
by monitoring of TLC, 5c proved to be preferentially
formed at an early stage also in CH3NO2. The addition
of 4 Å molecular sieves (MS4Å) to the heating solution
of 3c in CH3NO2 caused a reversal of the selectivity to
give 5c as a major product (entry 5).
To elucidate the reaction mechanisms of silica gel
promoted lactonization and thermal lactonization, we
performed the following experiment using isolated 4c and
5c. When 5c was treated with TsOH‚H2O (1 equiv) in
CH3NO2 at 70 °C, 4c was obtained in 99% yield after 2
h. The ring transformation of 5c in CH3COOH proceeded
slowly to give 4c in 94% yield after 48 h. The ring
transformation in BuOH did not proceed. It is notewor-
thy that the ring transformation did not proceed when
TsOMe was used instead of TsOH‚H2O (1 equiv). When
(12) For example, see: (a) Nagumo, S.; Suemune, H.; Sakai, K.
Tetrahedron Lett. 1991, 32, 5585. (b) Nagumo, S.; Suemune, H.; Sakai,
K. Tetrahedron 1992, 48, 8667. (c) Motorina, I. A.; Sviridova, L. A.;
Golubeva, G. A.; Bundel, Y. G. Tetrahedron Lett. 1989, 30, 117. (d)
Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J . Org. Chem. 1986,
51, 404. (e) Mandai, T.; Moriyama, T.; Nakayama, Y.; Sugino, K.;
Kawada, M.; Otera, J . Tetrahedron Lett. 1984, 5913. (f) Tamagaki, S.;
Suzuki, K.; Takagi, W. Chem. Lett. 1982, 1237. (g) Tsuboi, S.; Fujita,
H.; Muranaka, K.; Seko, K.; Takeda, A. Chem. Lett. 1982, 1909. (h)
Bartlett, P. D.; Blakeney, A. J .; Kimura, M.; Watson, W. H. J . Am.
Chem. Soc. 1980, 102, 1383.
t
6620 J . Org. Chem., Vol. 67, No. 19, 2002

Intramolecular Reaction of a Phenonium Ion
SCHEME 3
SCHEME 5
SCHEME 4
1H NMR measurement of the resulting reaction mix-
ture.6b
It was surprising that lactonization of 3d produced
δ-lactones preferentially, because the methyl group has
no nonbonding electrons. The results of the acetolyses
using â-aryl tosylates 6a ,b and 7a ,b suggest the neigh-
boring effect of ortho methyl group similar to that of
methoxy group plays an important role in the solvolytic
lactonization of 3d . The fact that ratios of 8a and 9a are
not significantly different means that only a common
intermediate, which should be a phenonium ion, is
present in both acetolyses of 6a and 7a . On the other
hand, the results of the acetolyses of â-aryl tosylates 6b
and 7b confirm the presence of an alternative pathway
due to the neighboring effect of the methyl group because
the ratios of 8b and 9b are remarkably different in the
reactions. Although such an alternative pathway should
also be present in lactonization of 3d , the detailed
structure of the intermediate has not yet been deter-
mined.
silica gel/TsOH or TsOMe in hexane at room tempera-
ture. These results confirm that the regioselectivity of
the lactonization of 3 is mostly kinetically controlled.
Likewise, exclusive formation of 2 in the lactonization
of 1 can be considered to also be kinetically controlled
because treatment of 10 with silica gel and TsOH showed
no conversion into 3 (Scheme 2).
The regioselectivity of 1 and that of 3 are attributed
to an electronic factor under kinetic conditions. A phe-
nonium ion derived from 1 includes methylene (C5) and
methine carbon (C4) on the cyclopropane ring and reacts
with the internal ester group at the C4 position, whose
positive character is greater than that at the C5 position.
On the other hand, the C4 and C5 positions of a phe-
nonium ion derived from 3 can be considered to be
electronically unbiased. This electronic situation should
contribute to the ratio (ca. 1:1) in the solvolytic lacton-
ization of tosylates 3a and 3c having no ortho substitu-
ent. Yamabe et al. reported the ab initio MO calculation
of a phenonium ion derived from â-aryltosylate 11, which
is the same type of phenonium ion as that derived from
1 (Scheme 3).7b The optimized geometry of the phenonium
ion by this calculation showed that the methyl group,
attached to the cyclopropane site, caused elongation of
the C1-C3 bond. Indeed, the solvolysis of tosylates 11 in
80% EtOH proceeded regioselectively to give 12.13
Interestingly, the silica gel promoted lactonization of
3b, 3d , and 3e, bearing a methoxy or methyl group at
the ortho position, shows the preferential formation of
δ-lactones. The selectivity for the lactonization of 3b or
3e can be rationalized by considering that the reaction
occurs by way of a phenonium ion and an oxonium ion
as intermediates, as shown in Scheme 4. In this scenario,
cyclization of the phenonium ion should produce both
lactones at a ratio of ca. 1:1, whereas that of the oxonium
ion should give only δ-lactone. Ramsey et al. reported the
presence of such an oxonium ion based on the ionization
of o-anisylethyl chloride in SbF5‚SO2 at -70 °C and
The thermal lactonization of tosylate 3c in CH3NO2 is
considered to proceed as shown in Scheme 5. At an early
stage, the phenonium ion A, which was spontaneously
formed from 3c at 70 °C, undergoes 6-endo cyclization
selectively to give 5c as a major product with a ratio of
ca. 3:1 (5c:4c), which is estimated on the basis of the
results shown in Table 2, entry 5. Concomitantly, tosy-
loxy and methyl groups are generated and react with
H2O, which is present in the reaction mixture, to form
TsOH and MeOH. When a sufficient amount of TsOH
has been generated, 5c is converted into more thermo-
dynamically stable 4c via phenonium ion B or A.
Consequently, the preferential formation of 4c can be
observed when 3c is completely consumed. Addition of
MS4Å to the reaction mixture inhibits the generation of
TsOH by capturing H2O to show the preferential forma-
tion of 5c (Table 2, entry 5). The assumption of conversion
of 5c into 4c is also supported by the fact that isolated
5c is converted into 4c upon treatment with TsOH‚H2O
in CH3NO2 at 70 °C, whereas TsOH does not promote
the ring transformation of isolated 4c into 5c in CH3-
NO2 at 70 °C. The ring transformation promoted by TsOH
is remarkably slow in CH3COOH and is not observed in
tBuOH. Consequently, the ratio of 4c and 5c for the
thermal lactonization in CH3COOH or tBuOH can be
concluded to be kinetically controlled (Table 2, entries 6
and 7).
(13) Raber, D. J .; Harris, J . M.; Schleyer, P. v. R. J . Am. Chem. Soc.
1971, 93, 4829.
J . Org. Chem, Vol. 67, No. 19, 2002 6621

Nagumo et al.
Con clu sion
Ack n ow led gm en t. A Grant-in Aid for Encourage-
ment of Young Scientists (08772039 to S.N.) from the
Ministry of Education, Science and Culture of J apan is
gratefully acknowledged.
We have reported a novel lactonization concomitant
with a phenyl rearrangement. This lactonization was
induced by treatment with silica gel or heating in
solvents. On the basis of the substituent effect and
stereochemistry, this lactonization is thought to proceed
via a phenonium ion. Silica gel promoted lactonization
of pentanoates 1 produced only γ-lactones 2, whereas that
of hexanoates 3 gave γ-lactones 4 and δ-lactones 5. The
regioselectivities were dependent on an electronic factor.
Thermal lactonization of hexanoate 3c in CH3NO2 af-
forded thermodynamically stable 4c, whereas that in
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures with spectroscopic data for lactonization of 1 and 3
and acetolysis of 6 and 7, synthesis of 1 including (S)-1d , 3, 6
and 7, the chemical conversion to determine the absolute
configuration of (S)-2d and the alternative synthesis of 4d for
the purpose of determination of its relative configuration;
1
copies of H NMR spectra for 4b, 4e, 5b, 5e, 8a , 8b, 9a and
t
CH3COOH or BuOH provided both lactones, whose ratio
9b. This material is available free of charge via the Internet
at http://pubs.acs.org.
was close to that of silica gel promoted lactoniztion. The
regioselectivity of the thermal lactonization of 3c in CH3-
NO2 was dependent on the conversion of 5c into 4c, which
occurred concomitantly.
J O010500Q
6622 J . Org. Chem., Vol. 67, No. 19, 2002