7-endo selective Friedel-Crafts type cyclization of vinyloxiranes linked to an ester group

Article abstract of DOI:10.1016/S0040-4039(02)00211-3

Treatment of arylpropyl vinyloxiranes linked to ester with BF₃ was found to produce seven-membered ring products in excellent yields. This reaction proceeded in an inversion fashion.

Full text of DOI:10.1016/S0040-4039(02)00211-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2223–2226
7-endo Selective Friedel–Crafts type cyclization of vinyloxiranes
linked to an ester group
Shinji Nagumo,a,* Irie Miyoshi,a Hiroyuki Akitab and Norio Kawaharaa,*
aHokkaido College of Pharmacy, Katuraoka 7-1, Otaru 047-0264, Japan
bSchool of Phamaceutical Science, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
Received 15 October 2001; revised 21 January 2002; accepted 25 January 2002
Abstract—Treatment of arylpropyl vinyloxiranes linked to ester with BF3 was found to produce seven-membered ring products
in excellent yields. This reaction proceeded in an inversion fashion. © 2002 Elsevier Science Ltd. All rights reserved.
Nature abounds with compounds containing seven-
membered carbocycles as prominent structural features.
Since many of these materials also show important
biological activities, there is much interest in the devel-
opment of new efficient methods for the construction of
polyfunctional seven-membered carbon rings. Taylor et
al. found that arylalkyl epoxides, as well as arylalkyl
halides, olefins, and alcohols, are good substrates for
intramolecular Friedel–Crafts (FC) reaction.1 An
intramolecular FC reaction of arylalkyl epoxide can be
applied to the construction of seven-membered carbo-
cycles. Distinct from other functional groups, epoxide
can react in either of two directions. Consequently,
regioselectivity is an important issue in this reaction. It
should be noted that 7-endo cyclization by intramolecu-
lar FC reaction is generally difficult. Treatment of 1
with BF3·Et2O underwent only 6-exo cyclization to give
2 and 3 (Scheme 1).2 It has been reported that the
cyclization mode of epoxides with an internal nucle-
ophilic moiety can be regulated by the p-orbital of a
vinyl group linked to it under both acidic and alkaline
conditions.3 Such an effect of the p-orbital on the
regioselectivity of intermolecular FC reaction has also
been found.4 It is thought that the effect of the p-
orbital plays an important role in regioselectivity of the
intramolecular FC reaction. We report here the devel-
opment of 7-endo selective cyclization of arylalkyl vinyl-
oxiranes, as shown in Scheme 1.
These vinyloxiranes were synthesized from aldehydes
4a–b (Scheme 2). Wittig reaction of 4a–b5,6 followed by
DIBAH reduction and epoxidation with mCPBA gave
epoxyalcohols 5a–d.6 These compounds were converted
into the vinyloxiranes 6a–d6 and 76 by the sequence of
Dess–Martin oxidation7 and Wittig reaction.
At first, intramolecular FC reaction of vinyloxirane 7
was carried out upon treatment with BF3·Et2O (0.5
equiv.) at −30°C to give an inseparable mixture (ca. 1:1)
of two seven-membered ring compounds 86 in high
yield (Scheme 3). Unfortunately, the cyclization pro-
ceeded non-stereoselectively. This stereochemical result
can be rationalized by considering that an overly strong
Scheme 1. Reagents and conditions: (a) BF3·Et2O, CH2Cl2,
−30°C.
* Corresponding authors. Tel.: 81-134-62-1842; fax: 81-134-62-5161;
e-mail: nagumo@hokuyakudai.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00211-3

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S. Nagumo et al. / Tetrahedron Letters 43 (2002) 2223–2226
cyclization proceeded stereoselectively to afford only
OMe
OMe
OH
O
R1
R1
CHO
9a–b in almost quantitative yield (Scheme 3). The
structure of 9a–b has been identified by 1H and 13C
NMR and HRMS.8 As a further confirmation, 9a
was converted to a six-membered lactone 10,8 whose
IR spectrum showed a peak at 1725 cm−1. The stereo-
chemistry of 9a was determined to be trans by a cou-
pling constant (10.3 Hz) between two ring juncture
protons in 10.
a,b,c
R2
4a (R1 = H)
4b (R1 = OMe)
5a (R1 = H, R2 = H)
5b (R1 = OMe, R2 = H)
5c (R1 = H, R2 = Me)
5d (R1 = OMe, R2 = Me)
OMe
O
R1
COOMe
d,e
This reaction would be more useful if seven-mem-
bered ring compounds possessing quarternal carbon
are prepared from trisubstituted epoxide. However, it
has been reported by Jung et al. that treatment of
2-methyl-2-vinyl-3-alkyloxiranes with Lewis acid
undergoes facile 1,2-alkyl or 1,2-hydride migration.9,10
We thus thought that such migrations would be a
problem in the intramolecular FC reaction of three
substituted epoxides. When vinyloxirane 6c was sub-
jected to the FC reaction, the desired 7-endo cycliza-
tion took place to provide 116 (44%) and 126 (4%)
(Scheme 4). Unfortunately, the success of this cycliza-
tion was diminished to some extent by the formation
of fluorohydrin 136 (36%), ketone 146 (7%) and alde-
hyde 156 (4%). It should be noted that a fluorohydrin
product was not obtained in Jung’s rearrangement of
vinyloxiranes.9,11 Formation of 13 is thought to be due
to the presence of a conjugated ester group.
R2
6a (R1 = H, R2 = H, 40%)
6b (R1 = OMe, R2 = H, 38%)
6c (R1 = H, R2 = Me, 69%)
6d (R1 = OMe, R2 = Me, 66%)
OMe
O
d,f
12%
5a
7
Scheme 2. Reagents and conditions: (a) Ph3PꢀCHCOOMe or
Ph3PꢀCMeCOOEt, 60–79%; (b) DIBAH, −30°C, 86–100%;
(c) mCPBA, 75–90%; (d) Dess–Martin oxd.; (e)
Ph3PꢀCHCOOMe; (f) Ph3PꢀCH2.
OH
On the other hand, the intramolecular FC reaction of
vinyloxirane 6d proceeded smoothly to provide 166 in
high yield along with a small amount of ketone 176
(Scheme 4). Fluorohydrine and aldehyde compounds
were not obtained in the reaction of 6d. The stereo-
chemistry of 16 was determined by NOE correlation
of the corresponding acetate 186 as shown. The
remarkable improvement of 7-endo cyclization by the
methoxy group at the C4% position surprised us
because the methoxy group has no resonance effect
on alkylation at C2% or C6% positions. As an alterna-
tive possibility, the mechanistic route including the
ipso-cyclization of vinyloxirane and the subsequent
skeletal rearrangement can also be considered
(Scheme 5). If so, the methoxy group at the C4% posi-
tion might strongly accelerate the ipso-cyclization, and
the methoxy group at the C3% position might be
essential for the skeletal rearrangement of spirobenze-
nium ion A into B in the sequential process.
a
7
MeO
8 (85%)
MeOOC
OH
R
a
6a
6b
MeO
9a (R = H, 97%)
9b (R = OMe, 95%)
O
O
H
b, c, d
H
9a
MeO
10 (56% from 9a)
In conclusion, we have developed an intramolecular
FC reaction of arylalkyl vinyloxiranes showing a
selective 7-endo cyclization mode. An a,b-unsaturated
ester group was found to be the best activator of the
CꢁO bond of epoxide adjacent to it. Di- and tri-sub-
stituted epoxides were acceptable for this new reac-
tion. In both cases, excellent yields and high regio-
and stereoselectivities were achieved. Obtained seven-
membered ring products having polyfunctional groups
should be useful for synthetic applications. Mechanis-
tic studies and possible synthetic applications of this
reaction are in progress.
Scheme 3. Reagents and conditions: (a) BF3·Et2O, CH2Cl2,
−30°C; (b) 20% Pd(OH)2-C, H2, MeOH; (c) K2CO3, MeOH,
H2O; (d) DCC, DMAP, toluene.
resonance effect induces the formation of a fully open
cation intermediate. Since an ester group was
expected to lower the resonance effect of the vinyl
group toward epoxide, we next carried out the
intramolecular FC reaction of vinyloxiranes 6a–b
linked to the ester group. As our expectation, 7-endo-

S. Nagumo et al. / Tetrahedron Letters 43 (2002) 2223–2226
2225
COOMe
OH
COOMe
OH
MeO
a
6c
+
MeO
11 (44%)
12 (4%)
F
COOMe
O
CHO
COOMe
COOMe
OH
+
+
+
OMe
15 (4%)
OMe
OMe
14 (7%)
13 (36%)
O
NOE
(9%)
COOMe
COOMe
H
H
MeO
MeO
a
OR
+
6d
OMe
OMe
17 (9%)
16 (R = H, 87%)
18 (R = Ac)
b
68%
Scheme 4. Reagents and conditions: (a) BF3·Et2O, CH2Cl2, −30°C; (b) Ac2O, Py.
Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335, 5330;
(b) Stork, G.; Kobayashi, Y.; Suzuki, T.; Zhao, K. J.
Am. Chem. Soc. 1990, 112, 1661.
R
R
OH
O
MeO
MeO
4'
MeO
MeO
4. (a) Akita, H.; Umezawa, I.; Takano, M.; Matsukura, H.;
Oishi, T. Chem. Pharm. Bull. 1991, 39, 3094; (b) Ono, M.;
Todoriki, R.; Yamamoto, Y.; Akita, H. Chem. Pharm.
Bull. 1994, 42, 1590; (c) Ono, M.; Yamamoto, Y.;
Todoriki, R.; Akita, H. Heterocycles 1994, 37, 181; (d)
Ono, M.; Yamamoto, Y.; Akita, H. Chem. Pharm. Bull.
1995, 43, 553.
5. Compound 4a was obtained by DIBAH reduction of
3-methoxybenezene butanenitrile, whose preparation was
previously reported: Nystrom, R. F.; Brown, W. G. J.
Am. Chem. Soc. 1948, 70, 3738. Compound 4b was
synthesized from commercially available 3,4-dimethoxy-
benzenebutanoic acid by LAH reduction and Swern
oxidation.
3'
6d
A
R
H
OH
MeO
MeO
16
B
R = CH=CHCOOMe
Scheme 5.
References
6. All new compounds gave spectroscopic data in agreement
with the assigned structures.
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8. 9a (colorless oil): IR (neat) 3462, 1721, 1649 cm−1 1H
.
NMR (270 MHz, CDCl3) l 7.20 (dd, J=15.6, 5.6 Hz,
1H), 7.05 (d, J=9.0 Hz, 1H), 7.04–6.67 (m, 2H), 5.60 (dd,
J=15.6, 2.1 Hz, 1H), 4.20 (br, 1H), 3.88 (td, J=5.6, 2.1
Hz, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 2.85–2.74 (m, 1H),
2.69–2.60 (m, 1H), 2.05–1.86 (m, 2H), 1.75–1.65 (m, 2H),
1.58 (br, 1H). 13C NMR (68 MHz, CDCl3) l 166.9, 159.1,
147.8, 144.1, 133.3, 127.6, 122.0, 116.6, 111.1, 70.5, 55.4,
55.2, 51.5, 35.8, 34.7, 21.6. HR-MS (EI) calcd for
C16H20O4 (M+) 276.1360. Found 276.1383. 9b (white
needles): mp 144°C (toluene). IR (neat) 3498, 1717, 1653
2. Scheme 1 is our unpublished data. For other 6-exo
selective FC type cyclizations, see: Ref. 1.
1
cm−1. H NMR (270 MHz, CDCl3) l 7.18 (dd, J=15.5,
3. (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.;
5.3 Hz, 1H), 6.66 (s, 1H), 6.64 (s, 1H), 5.60 (dd, J=15.5,

2226
S. Nagumo et al. / Tetrahedron Letters 43 (2002) 2223–2226
2.0 Hz, 1H), 4.23 (br, 1H), 3.87 (s, 3H), 3.86 (br, 1H),
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1956, 78, 4394; (c) House, H. O.; Ryerson, G. D. J. Am.
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3.85 (s, 3H), 3.72 (s, 3H), 2.78 (m, 1H), 2.61 (m, 1H),
2.04–1.86 (m, 2H), 1.74–1.63 (m, 2H), 1.57 (s, 1H). 1H
NMR (270 MHz, C6D6) l 7.30 (dd, J=15.7, 5.6 Hz, 1H),
6.47 (s, 1H), 6.40 (s, 1H), 5.77 (dd, J=15.7, 2.0 Hz, 1H),
3.91–3.84 (m, 1H), 3.55–3.50 (m, 1H), 3.43 (s, 3H), 3.41
(s, 3H), 3.40 (s, 3H), 2.58 (dd, J=14.3, 11.0 Hz, 1H), 2.27
(dd, J=14.3, 6.3 Hz, 1H), 1.78–1.51 (m, 3H), 1.46–1.33
(m, 1H), 1.26–1.18 (m, 1H). 13C NMR (68 MHz, CDCl3)
l 166.8, 147.8, 147.4, 147.0, 134.9, 127.3, 121.9, 115.8,
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Anal. calcd for C17H22O5 C, 66.65; H, 7.24. Found C,
66.71; H, 7.37%. 10 (white needles): mp 104°C (n-hex-
ane:toluene=2:1). 1H NMR (270 MHz, CDCl3) l 7.15
(d, J=8.3 Hz, 1H), 6.76 (dd, J=8.3, 2.7 Hz, 1H), 6.71 (d,
J=2.7 Hz, 1H), 4.04 (td, J=10.3, 3.7 Hz, 1H), 3.80 (s,
3H), 3.11 (td, J=10.3, 4.7 Hz, 1H), 2.91–2.67 (m, 3H),
2.53 (ddd, J=5.0, 11.2, 17.2 Hz, 1H), 2.40–2.24 (m, 2H),
2.20–2.04 (m, 2H), 1.95–1.80 (m, 1H), 1.51–1.37 (m, 1H).
13C NMR (67.8 MHz, CDCl3) l 171.2, 158.6, 144.7,
130.1, 125.9, 115.4, 111.2, 83.4, 55.2, 41.6, 39.0, 34.8,
30.5, 25.5, 24.1. IR (CHCl3) 1725 cm−1. Anal. calcd for
C15H18O3 C, 73.15; H, 7.37. Found: C, 73.30; H, 7.49%.
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