Synthesis of heterospiranes by cyclization of dinucleophiles with 1,1-bis(tosyloxymethyl)cyclopropane and -cyclobutane

Article abstract of DOI:10.1016/j.tetlet.2007.11.123

A variety of heterocyclic spiranes were prepared by cyclization of dinucleophiles with 1,1-bis(tosyloxymethyl)cyclopropane and -cyclobutane.

Full text of DOI:10.1016/j.tetlet.2007.11.123

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Tetrahedron Letters 49 (2008) 675–677
Synthesis of heterospiranes by cyclization of dinucleophiles with
1,1-bis(tosyloxymethyl)cyclopropane and -cyclobutane
Sven Rotzoll a,b, Helmut Reinke a, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 19 October 2007; revised 16 November 2007; accepted 21 November 2007
Abstract
A variety of heterocyclic spiranes were prepared by cyclization of dinucleophiles with 1,1-bis(tosyloxymethyl)cyclopropane and
-cyclobutane.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Cyclizations; Cyclopropanes; Cyclobutanes; Heterocycles; Spiranes
Spirocyclopropanes and -cyclobutanes are of consider-
able current interest, due to their pharmacological proper-
ties. For example, the illudins S and M represent cytotoxic
constituents of the fungus Omphalotus illudens.1 They
possess a 1-hydroxyspiro[5.2]cyclooct-4-en-2-one structure.
Synthetic analogues show a considerable anti-proliferative
activity against human leukaemia HL 60 cells.2 Spirocyclo-
propanes containing aromatic rings fused to the double
bonds are present, for example, in the cytotoxic natural
products CC-1065 and duocarmycin SA.3 Spirocyclopro-
panes and spirocyclobutanes are also of considerable struc-
tural and theoretical interest.4,5 However, these compounds
are not readily available. In fact, known syntheses of
heterocyclic spirocyclopropanes, which rely on cyclization
reactions of 1,1-bis(bromomethyl)cyclopropane, suffer
from very low yields and many side-reactions (vide infra).
The synthesis of heterocyclic spirocyclobutanes has only
scarcely been reported in the literature to date. Herein,
we report a practical and high-yielding synthesis of various
spirocyclopropanes and spirocyclobutanes based on cycli-
zation reactions of 1,1-bis(tosyloxymethyl)cyclopropane
and -cyclobutane. These reactions provide what is, to the
best of our knowledge, the most efficient synthetic
approach to heterocyclic spirocyclopropanes and -cyclo-
butanes at present.
Our strategy was benchmarked by the reaction of 1,1-
bis(tosyloxymethyl)cyclopropane (1a), readily available in
two steps from dimethyl cyclopropane-1,1-dicarboxylate,5
with phenol (2a). The sodium hydroxide mediated reaction
of 1a with 2a (DMF, 16 h, 160 °C) afforded 1,1-bis(phenyl-
oxymethyl)cyclopropane (3a) in 60% yield (Scheme 1, Table
1). Noteworthy, the reaction of phenol with 1,1-bis(bromo-
methyl)cyclopropane was previously reported to give 3a in
only 8% yield.6 The reaction of 4-bromophenol and 4-
bromothiophenol with 1a and its cyclobutane-analogue 1b
afforded the novel ethers and thioethers 3b–e in good yields.
R
X
R
R
OTs OTs
i
+
X
(CH2)n
XH
2a-c
1a,b
(CH2)n
3a-e
*
Scheme 1. Synthesis of 3a–e. Reagents and conditions: (i) NaOH, DMF,
16 h, 160 °C.
Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.123

676
S. Rotzoll et al. / Tetrahedron Letters 49 (2008) 675–677
Table 1
Table 2
Products and yields
Products and yields
a
3
n
X
R
%
4
5
n
X
R1
R2
R3
% (5)a
a
b
c
d
e
1
1
1
2
2
O
O
S
O
S
H
60b
56
72
65
72
a
b
a
c
d
e
f
a
b
c
d
e
f
1
1
2
2
2
2
1
2
O
S
H
H
H
Me
tBu
tBu
H
H
H
H
H
H
H
H
H
H
H
tBu
H
65 (7)
77 (28)
80
60
63
Br
Br
Br
Br
O
O
O
O
O
O
0
a
Isolated yields.
g
h
–C4H4–
–C4H4–
77 (6)
81
Compound 3a was previously prepared in 8% yield.6
b
f
H
a
Isolated yields; previously reported7 yields of compounds 5 are given in
parentheses.
The reaction of 1,2-dihydroxybenzene (4a) with 1,1-
bis(bromomethyl)cyclopropane was previously reported
to give spirocyclopropane 5a, albeit, in only 7% yield.7
The reaction of 4a with bis(tosylate) 1a afforded 5a in
65% yield (Scheme 2, Table 2).8 Spirocyclopropane 5b
was previously prepared from dithiol 4b and 1,1-bis-
(bromomethyl)cyclopropane in 28% yield.6 The yield
of 5b could be again significantly improved (77%) by
employment of 1a. The cyclization of 4a with 1,1-bis-
(tosyloxymethyl)cyclobutane (1b) afforded the novel
spirocyclobutane 5c in a very good yield. The structure of
5c was independently confirmed by X-ray crystal structure
analysis (Fig. 1).9 The cyclization of 1b with 1,2-dihydroxy-
benzenes 4c and 4d afforded spirocyclobutanes 5d and 5e,
respectively. The reaction of 1b with 1,2-dihydroxy-3,5-
di(tert-butyl)benzene (4e) was unsuccessful, due to the steric
influence of the tert-butyl located next to the hydroxyl
group. The cyclization of 2,3-dihydroxynaphthalene (4f)
with 1a and 1b afforded spiranes 5g and 5h in very good
yields, respectively. The cyclization of 4f with 1,1-bis(bro-
momethyl)cyclopropane was previously reported to give
5g, however, in only 6% yield.7
O
O
O
O
(CH2)n
(CH2)n
6a (n = 1): 30% (10%)7 6c (n = 1): 32% (9%)7
6b (n = 2): 49% 6d (n = 2): 50%
Scheme 3. Synthesis of spiranes 6a,b. Reagents and conditions: (i) NaOH,
DMF, 16 h, 160 °C.
OTs OTs
Se Se
i
7: 40%
1a
Scheme 4. Synthesis of diselenaspirane 7. Reagents and conditions: (i)
NaBH4, Se, EtOH, 72 h, reflux.
The cyclization of 1a and 1b with (racemic) 2,20-dihy-
droxybiphenyl afforded spiranes 6a and 6b, respectively
(Scheme 3). Spiranes 6c and 6d were prepared by cycliza-
tion of 1a,b with (racemic) 2,20-dihydroxybinaphthyl. The
synthesis of spirocyclopropanes 6a and 6c was previously
reported, albeit, in only 10% and 9% yield, respectively.7
The cyclization of 1a with disodium diselenide,10a gener-
ated in situ by the reaction of sodium boronhydride with
selenium in ethanol,10b afforded the novel 2,3-diselenaspi-
ro[2.4]cycloheptane (7) (Scheme 4). The synthesis of the
sulfur analogue of 7 was previously reported.11
Fig. 1. ORTEP plot of 5c.
In conclusion, an efficient method for the synthesis of
heterocyclic spiranes based on cyclization reactions of
dinucleophiles with 1,1-bis(tosyloxymethyl)cyclopropane
and -cyclobutane was reported. These reactions provide a
convenient access to spirocyclopropanes and -butanes,
which are not readily available by other methods.
R1
X
R2
X
R1
R2
OTs OTs
R3
i
R3
XH
+
(CH2)n
HX
(CH2)n
5a-h
4a-f
Acknowledgement
1a,b
Financial support by the Degussa-Stiftung (scholarship
for S.R.) is gratefully acknowledged.
Scheme 2. Synthesis of spiranes 5a–h. Reagents and conditions: (i) NaOH,
DMF, 16 h, 160 °C.

S. Rotzoll et al. / Tetrahedron Letters 49 (2008) 675–677
677
6. Jamrozik, J. J. Prakt. Chem. 1980, 322, 909.
7. Smolinski, S.; Jamrozik, J. Tetrahedron 1975, 31, 1237.
References and notes
8. Typical procedure: A solution of 1,1-bis(tosyloxy)cyclopropane 1a
(205 mg, 0.50 mmol), NaOH (46 mg, 1.15 mmol), catechol (4a)
(58 mg, 0.53 mmol) and DMF (10 mL) was heated in a sealed tube
for 16 h at 160 °C. After cooling to room temperature, water
(50 mL) was added and the solution was extracted with CH2Cl2
(3 ꢀ 30 mL). The combined organic layers were dried (Na2SO4),
filtered and the solvent of the filtrate was removed in vacuo.
The residue was purified by column chromatography (silica gel,
heptane/ethyl acetate = 5:1) to give spirane 5a (57 mg, 65%) as
a colourless solid; mp 68 °C. 1H NMR (300 MHz, CDCl3): d 0.67
(s, 4H, CH2), 3.90 (s, 4H, OCH2), 6.94–6.97 (m, 2H, Ar), 6.99
(m, 2H, Ar). 13C NMR (75 MHz, CDCl3): d 9.2 (2 CH2), 23.0 (C),
78.3 (2 OCH2), 122.1 (2 CHAr), 123.8 (2 CHAr), 151.4 (2CAr). IR
(KBr, cmꢁ1): ~m ¼ 3377 (br, m), 2924 (s), 2855 (s), 1596 (m), 1492 (s),
1456 (s), 1260 (br, m), 752 (br, m). MS (EI, 70 eV): m/z (%) = 176
([M]+, 49), 148 (100), 121 (22), 110 (37), 80 (13), 67 (25), 52 (20).
HRMS (EI): ([M]+) calcd for C11H12O2, 176.08318; found,
176.08285.
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