Intramolecular ring-opening reactions of 1-(2-methoxyphenyl)-6- oxabicyclo[3.2.0]heptanes: spirocyclic dihydrobenzofurans from fused bicyclic oxetanes

Article abstract of DOI:10.1055/s-2007-990921

Treatment of fused oxetanes with Et₂AlCl, TMSCl, acetyl chloride, or ethereal hydrochloric acid leads to the formation of spirocyclic dihydrobenzofurans through intramolecular attack of an oxygen atom of a proximal phenolic methyl ether. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990921

LETTER
25
Intramolecular Ring-Opening Reactions of 1-(2-Methoxyphenyl)-6-oxabi-
cyclo[3.2.0]heptanes: Spirocyclic Dihydrobenzofurans from Fused Bicyclic
Oxetanes
S
pirocyclic
Dihyd
i
robenz
c
ofurans fro
h
m
Fused
B
ic
a
yclic
O
xet
r
a
nes d J. Boxall,a Richard S. Grainger,*b Caterina S. Aricò,b Leigh Ferrisc
a
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Fax +44(121)4144403; E-mail: r.s.grainger@bham.ac.uk
b
c
AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK
Received 5 July 2007
Further screening of reagents showed that even simpler
activators could be used in place of the metal Lewis acid:
treatment of oxetane 1a with trimethylsilyl chloride,
acetyl chloride or ethereal hydrochloric acid all resulted in
the formation of a spirobenzofuran in good yield (Table 1,
entries 2–4). In the case of trimethylsilyl chloride, the ini-
tial product was the trimethylsilyl ether (observable by
TLC), which subsequently hydrolyzed to alcohol 8a14
upon aqueous workup. Use of acetyl chloride directly led
Abstract: Treatment of fused oxetanes with Et2AlCl, TMSCl,
acetyl chloride, or ethereal hydrochloric acid leads to the formation
of spirocyclic dihydrobenzofurans through intramolecular attack of
an oxygen atom of a proximal phenolic methyl ether.
Key words: cyclizations, heterocycles, Lewis acids, neighboring-
group effects, spiro compounds
The regio- and stereoselective ring opening of oxetanes
has been extensively utilized in organic synthesis as a
route to functionalized alcohols.1 Intramolecular attack on
oxetanes has been less frequently studied than the inter-
molecular case, although examples of opening with car-
bon,2 nitrogen,3,4 sulfur,3 and oxygen3,5–11 nucleophiles
have been reported. Attack by oxygen nucleophiles is
known under both acidic and basic conditions. Masaki re-
ported the Lewis acid catalyzed rearrangement of mono-
substituted oxetanes to give ring-expanded cyclic ethers
accompanied by transfer of ethereal benzylic and allylic
groups.8 Intramolecular attack of phenoxide, generated in
situ by methyllithium-mediated deprotection of a pivaloyl
ester, on a disubstituted oxetane, led to the formation of a
substituted dihydrobenzofuran.3
N
OMe
OMe
O
OMe
O
R
i
ii
R
R
R
4a,b
a R = Me
b R = –(CH2)5–
5a,b
OMe
OMe
OMe
3
O
N
OMe
OMe
OMe
v
iii
iv
R
R
R R
6a,b
7a,b
OMe
O
As part of our studies on the application of an intramolec-
ular Paternò–Büchi photocyclization–oxetane fragmenta-
tion sequence to the synthesis of herbertane and cuparene
sesquiterpenes,11 we required a means of converting oxe-
tane 1a into the homoallylic alcohol 2. Oxetane 1a was
readily prepared in five steps from commercially avail-
able 2,5-dimethoxytoluene 3 (Scheme 1) according to a
general route we have previously developed.11,12 Attempt-
ed ring opening of 1a using the Yamamoto protocol (di-
ethylaluminium chloride and N-methylanilide in refluxing
benzene)13 failed to provide any of the expected homoal-
lylic alcohol 2, but instead led to recovery of starting ma-
terial. However, we fortuitously discovered that omission
of N-methylanilide led to the formation of a new com-
pound, the spirobenzofuran 8a, in reasonable yield at
room temperature (Table 1, entry 1).
OMe
O
OR'
vi
R
MeO
R
MeO
R
R
1a,b
8a,b R' = H
9a,b R' = Ac
OMe
OH
MeO
2
Scheme 1 Reagents and conditions: i) for 4a: Me2CHCOCl, AlCl3,
CH2Cl2, 0 °C to r.t., 2 h, 98%; for 4b: C6H11COCl, AlCl3,
ClCH2CH2Cl, r.t., 3 h, 70%; ii) acrylonitrile, tetrabutylammonium hy-
droxide (1 M, MeOH), 1,4-dioxane, 35 °C; for 5a: 72 h, 82%; for 5b:
48 h, 20% (+70% RSM); iii) Ph3PMeBr, KOt-Bu, toluene, 60 °C; for
6a: 17 h, 94%; for 6b: 48 h, 67%; iv) DIBAL-H, CH2Cl2, –78 °C to
0 °C, 3 h; for 7a: 85%; for 7b: 91%; v) hexane, medium-pressure (125
W) mercury arc lamp, Pyrex immersion well photoreactor, r.t.; for 1a:
0.01 M, 18 h, 61%; for 1b: 0.005 M, 4 h, 53%; vi) Table 1.
SYNLETT 2008, No. 1, pp 0025–0028
x
x.
x
x.
2
0
0
7
Advanced online publication: 03.12.2007
DOI: 10.1055/s-2007-990921; Art ID: D20307ST
© Georg Thieme Verlag Stuttgart · New York

26
R. J. Boxall et al.
LETTER
to the corresponding ester 9a15 (entry 4). Formation of hours at room temperature (Table 1, entry 7). A reason-
1,3-chlorohydrins, typical products in the intermolecular able yield of acetate 12 was obtained using acetyl chloride
opening of oxetanes with acid derivatives, was not ob- activation after 48 hours (entry 8).
served under any of these conditions.
A plausible mechanism for these transformations is
We have used this methodology to rapidly assemble an shown in Scheme 2, exemplified for the reaction of oxet-
unusual bis-spirocyclic ring system. Oxetane 1b, contain- ane 1a with acetyl chloride. Activation of the Lewis basic
ing a cyclohexane ring in place of the geminal dimethyl oxetane oxygen is followed by intramolecular attack by
group in 1a, was prepared in a manner analogous to that the neighboring phenolic ether on 13 to cleave the strained
of 1a (Scheme 1). Treatment of 1b with ethereal hydro- heterocycle. Loss of chloromethane from 14 through a
chloric acid gave alcohol 8b (Table 1, entry 5), whereas second nucleophilic displacement leads to the spirobenzo-
acetyl chloride gave rise to the acetate 9b (entry 6).
furan 9a.
Ring opening of oxetane 10,11 containing just one meth- We have also evaluated neighboring-group participation
oxy group on the aromatic ring, was also investigated. Re- in the ring opening of the isomeric [2.2.1]oxabicyclic
actions were slower than with the dimethoxy ethers 1a ether 15, prepared from oxetane 1a in two steps
and 1b. Under acidic conditions, 34% of alcohol 11 was (Scheme 3). Although oxetane 1a proved inert to the
obtained, along with 52% recovered oxetane 10 after 24 Yamamoto conditions13 and to NaH in DMA at 100–
Table 1 Formation of Spirobenzofurans from Oxetanes
Entry
1
Oxetane
Conditions
Spirobenzofuran
Yield (%)
59
Et2AlCl (10 equiv), toluene, 0 °C to r.t., 1 h
OMe
O
OH
O
MeO
MeO
8a
8a
1a
1a
2
3
4
TMSCl (10 equiv), DCE, r.t., 18 h
HCl (10 equiv), Et2O, 0–5 °C, 18 h
AcCl (10 equiv), DCE, r.t., 18 h
76
78
81
1a
1a
8a
O
OAc
OH
MeO
9a
5
6
HCl (10 equiv), Et2O, 0 °C to r.t., 18 h
71
61
OMe
O
O
MeO
MeO
8b
1b
1b
AcCl (10 equiv), DCE, r.t., 5 h
O
OAc
MeO
9b
7
8
HCl (10 equiv), Et2O, 0 °C to r.t., 24 h
34a
O
OMe
OH
O
11
12
10
10
AcCl (10 equiv), DCE, r.t., 48 h
65
O
OAc
a Starting material (52%) was recovered.
Synlett 2008, No. 1, 25–28 © Thieme Stuttgart · New York

LETTER
Spirocyclic Dihydrobenzofurans from Fused Bicyclic Oxetanes
27
OMe
steps respectively. Interestingly, 17 contains the core
structure of spirobenzofuran 18, a bioactive fungal metab-
olite isolated from Acremonium sp. HKI 0230,21 which
has recently been synthesized for the first time.22
O
O
OAc
AcCl
MeO
MeO
1a
9a
Acknowledgment
– MeCl
AcCl
We thank the EPSRC and King’s College London for funding (stu-
dentship to R.J.B.), and AstraZeneca for a CASE award to R.J.B.
R.S.G. is the recipient of an EPSRC Advanced Research Fellowship
(2005-2010).
Cl –
Cl–
Me
Me
O
O
O
+
+
O
OAc
References and Notes
MeO
MeO
(1) Linderman, R. J. In Comprehensive Heterocyclic Chemistry
II, Vol. 1B; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.;
Padwa, A., Eds.; Elsevier: Oxford, 1996.
(2) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1984, 25, 4549.
(3) (a) Bach, T.; Kather, K. J. Org. Chem. 1996, 61, 7642.
(b) Bach, T.; Kather, K.; Krämer, O. J. Org. Chem. 1998, 63,
1910.
(4) (a) Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J.
Tetrahedron Lett. 2002, 43, 545. (b) Ng, F. W.; Lin, H.;
Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812.
(5) Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571.
(6) Capek, K.; Vydra, T.; Sedmera, P. Carbohydr. Res. 1987,
168, c1.
13
14
Scheme 2
140 °C,16 ring opening to homoallylic alcohol 2 was ac-
complished by treatment of 1a with an excess of butyllith-
ium, diisopropylamine, and potassium tert-butoxide in
refluxing THF.17 Treatment of alkene 2 with mercuric ac-
etate followed by reduction of the intermediate organo-
mercurial resulted in formation of the [2.2.1]oxabicyclic
ether 15 through a formal 5-endo-trig ring closure.18 Sub-
jecting 15 to acetyl chloride did not result in spirobenzo-
furan formation, but instead to the formation of
chloroacetate 16 in low yield.19 However, when 15 was
treated with ZnI2 and acetic anhydride, known conditions
for the cleavage of tetrahydrofurans,20 the spirocyclic
ether 17 was produced in good yield.
(7) Khan, N.; Morris, T. H.; Smith, E. H.; Walsh, R. J. Chem.
Soc., Perkin Trans. 1 1991, 865.
(8) Itoh, A.; Hirose, Y.; Kashiwagi, H.; Masaki, Y. Heterocycles
1994, 38, 2165.
(9) In taxoids, the close proximity of the C-2 hydroxy group
with the oxetane ring allows for a particularly facile
intramolecular SN2 displacement at C-20 leading to the
formation of tetrahydrofurans: (a) Farina, V.; Huang, S.
Tetrahedron Lett. 1992, 33, 3979. (b) Wahl, A.; Guéritte-
Voegelein, F.; Guénard, D.; Le Goff, M.-T.; Potier, P.
Tetrahedron 1992, 48, 6965. (c) Klein, L. L. Tetrahedron
Lett. 1993, 34, 2047. (d) Nicolaou, K. C.; Renaud, J.;
Nantermet, P. G.; Couladouros, E. A.; Guy, R. K.; Wrasidlo,
W. J. Am. Chem. Soc. 1995, 117, 2409. (e) Danishefsky, S.
J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.;
Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W.
G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, M. J. J. Am.
Chem. Soc. 1996, 118, 2843. (f) Ojima, I.; Lin, S.; Inoue, T.;
Miller, M. L.; Borella, C. P.; Geng, X.; Walsh, J. T. J. Am.
Chem. Soc. 2000, 122, 5343.
A comparison of the structure of 17 with that of spiroben-
zofuran 9a shows that regioisomeric acetates can be pre-
pared from the same starting oxetane 1a in one or three
OMe
OMe
OH
O
ii
i
MeO
MeO
1a
2
OMe
OMe
OAc
(10) Bach, T.; Schröder, J. J. Org. Chem. 1999, 64, 1265.
(11) Boxall, R. J.; Ferris, L.; Grainger, R. S. Synlett 2004, 2379.
(12) Grainger, R. S.; Patel, A. Chem. Commun. 2003, 1072.
(13) Kitagawa, Y.; Itoh, A.; Hashimoto, S.; Yamamoto, H.;
Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3864.
O
iii
Cl
MeO
MeO
15
16
(14) Typical Experimental for Oxetane Ring-Opening
Reaction with HCl
iv
To a solution of oxetane 1a (50 mg, 0.18 mmol) in Et2O (5
mL) at 0 °C HCl (1 M in Et2O, 1.80 mL, 1.80 mmol) was
added over a period of 10 min. The resulting solution was
stirred for 18 h at r.t. The resulting mixture was poured into
H2O (10 mL) and the aqueous layer was extracted with Et2O
(2 × 10 mL). The combined organic phases were washed
with brine (10 mL), dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified via
column chromatography (hexane–EtOAc, 8:2) to furnish
spirocycle 8a as a colorless oil (37 mg, 78%). Rf = 0.2
(hexane–EtOAc, 8:2); mp 88–90 °C. IR (neat): nmax = 3445,
2945, 2865, 1651, 1497, 1466, 1199 cm–1. 1H NMR (360
O
O
OH
OAc
O
MeO
HO
18
17
Scheme 3 Reagents and conditions: i) KOt-Bu (4 equiv), BuLi (3.8
equiv), diisopropylamine (4 equiv), hexane, reflux, 24 h, 68%; (ii) a)
Hg(OAc)2 (1.25 equiv), THF–H2O (1:1), r.t., 16 h; (b) 3 M NaOH, 0.5
M NaBH4 in 3 M NaOH, 88%; iii) AcCl, Et2O, 0 °C, r.t., 18 h, 18%;
iv) ZnI2 (1.5 equiv), Ac2O, r.t., 20 h, 78%.
Synlett 2008, No. 1, 25–28 © Thieme Stuttgart · New York

28
R. J. Boxall et al.
LETTER
MHz, CDCl3): d = 6.65 (1 H, s, CCHCOCH3), 6.58 (1 H, s,
CH2OCCHCCH3), 5.07 (1 H, dd, J = 6.8, 1.8 Hz, CHOH),
3.93 (1 H, d, J = 11.0 Hz, COCH2C), 3.79 (3 H, s, ArOCH3),
3.65 (1 H, d, J = 11.0 Hz, COCH2C), 2.19 (3 H, s, ArCH3),
2.16–2.11 (1 H, m, HOCHCH2CH2), 1.97–1.94 (1 H, m,
HOCHCH2CH2), 1.61–1.50 (1 H, m, HOCHCH2CH2), 1.49–
1.44 (1 H, m, HOCHCH2CH2), 1.26 (1 H, br, OH), 1.07 [3
H, s, C(CH3)2], 1.03 [3 H, s, C(CH3)2]. 13C NMR (100 MHz,
CDCl3): d = 17.0 (q), 24.6 (q), 26.7 (q), 32.2 (t), 40.9 (t), 44.9
(s), 56.9 (q), 64.9 (s), 65.2 (t), 92.8 (d), 108.6 (d), 111.7 (d),
125.3 (s), 128.2 (s), 152.1 (s), 156.1 (s). ESI-HRMS: m/z
calcd for C16H22O3Na: 285.1461; found: 285.1457; LRMS
(EI): m/z (%) = 262 (100) [M+], 231 (5), 205 (33), 192 (6),
175 (33), 163 (9).
20.9 (q), 24.6 (q), 26.4 (q), 31.9 (t), 39.6 (t), 44.9 (s), 56.4
(q), 61.7 (s), 67.1 (t), 92.3 (d), 109.0 (d), 111.2 (d), 125.9 (s),
127.3 (s), 151.4 (s), 154.8 (s), 171.0 (s). ESI-HRMS: m/z
calcd for C18H24O4Na: 327.1567; found: 327.1562. LRMS
(EI): m/z (%) = 304 (100) [M+], 262 (21), 175 (66), 160 (8),
115 (8), 91 (7), 69 (5), 43 (16).
(16) Joshi, B. V.; Rao, T. S.; Reese, C. B. J. Chem. Soc., Perkin
Trans. 1 1992, 2537.
(17) Thurner, A.; Faigl, F.; Tőke, L.; Mordini, A.; Valacchi, M.;
Reginato, G.; Czira, T. Tetrahedron 2001, 57, 8173.
(18) (a) Kočovský, P.; Pour, M. J. Org. Chem. 1990, 55, 5580.
(b) Polt, R.; Wijayaratne, T. Tetrahedron Lett. 1991, 32,
4831.
(19) Ring opening by chloride on activated 15 can lead to two
possible regioisomeric chloroacetates. The stucture of 16
was confirmed by a long-range COSY experiment, and
configuration at the chloro-substituted stereocenter was
possible through NOESY correlation. The stereochemical
outcome of this reaction suggests it also likely proceeds via
an SN2-type ring opening of the activated ether with chloride
nucleophile, where the regiochemical outcome is
presumably a result of the preferred attack by chloride at a
secondary carbon over a primary neopentyl-like carbon. For
an analogous example in oxetane ring opening using HCl,
see: Ceccherelli, P.; Curini, M.; Marcotullio, M. C. J. Chem.
Soc., Perkin Trans. 1 1985, 2173.
(15) Typical Experimental Procedure for Oxetane Ring-
Opening Reaction with AcCl
To a solution of oxetane 1a (50 mg, 0.18 mmol) in DCE (10
mL) at r.t., AcCl (0.13 mL, 1.80 mmol) was added. The
resulting solution was stirred overnight at r.t. poured into
H2O (10 mL) and the aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). The combined organic phases were
dried over MgSO4, filtered, and reduced in vacuo. The crude
product was purified via column chromatography (hexane–
EtOAc, 9:1) to furnish spirocycle 9a as a colorless oil (45
mg, 81%). Rf = 0.2 (hexane–EtOAc, 9:1). IR (neat): nmax
2950, 2869, 2252, 2105, 1739, 1651, 1490, 1464, 1223,
=
1047 cm–1. 1H NMR (360 MHz, CDCl3): d = 6.66 (1 H, s,
CCHCOCH3), 6.54 (1 H, s, CH2OCCHCCH3), 4.96 (1 H, dd,
J = 6.8, 1.6 Hz, CHOCOCH3), 4.45 (1 H, d, J = 11.1 Hz,
COCH2C), 4.16 (1 H, d, J = 11.2 Hz, COCH2C), 3.77 (3 H,
s, ArOCH3), 2.18 (3 H, s, ArCH3), 2.15–2.12 (1 H, m,
COCHCH2CH2), 1.97 (3 H, s, OCOCH3), 1.99–1.91 (1 H, m,
COCHCH2CH2), 1.63–1.55 (1 H, m, COCHCH2CH2), 1.52–
1.48 (1 H, m, COCHCH2CH2), 1.10 [3 H, s, C(CH3)2], 1.06
[3 H, s, C(CH3)2]. 13C NMR (125 MHz, CDCl3): d = 16.5 (q),
(20) (a) Benedetti, M. O. V.; Monteagudo, E. S.; Burton, G.
J. Chem. Res., Synop. 1990, 248. (b) Hernández, R.;
Velázquez, S. M.; Suárez, E. J. Org. Chem. 1994, 59, 6395.
(c) Abad, A.; Agulló, C.; Cuñat, A. C.; García, A. B.;
Giménez-Saiz, C. Tetrahedron 2003, 59, 9523.
(21) Kleinwächter, P.; Schlegel, B.; Dörfelt, H.; Gräfe, U.
J. Antibiot. 2001, 54, 526.
(22) Srikrishna, A.; Lakshmi, B. V. Tetrahedron Lett. 2005, 46,
7029.
Synlett 2008, No. 1, 25–28 © Thieme Stuttgart · New York

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