Synthesis of three-dimensional fused and spirocyclic oxygen-containing cyclobutanone derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.11.050

An approach to fused and spirocyclic oxygen-containing cyclobutanone derivatives based on ketene [2+2] cycloaddition with vinyl ethers is described. Using alicyclic chloroanhydrides as ketene sources as well as cyclic vinyl ethers in the reaction resulted in the formation of three-dimensional conformationally restricted building blocks of interest to medicinal chemistry and organic synthesis. In particular, 2-oxaspiro(bicyclo[3.2.0]heptane-7,1′-cycloalkane)-6-ones and 2-oxaspiro(bicyclo[4.2.0]octane-8,1′-cycloalkane)-6-ones were obtained. The procedure involves readily available and inexpensive starting materials and allows construction of complex molecular architectures on a large scale in a single run.

Full text of DOI:10.1016/j.tetlet.2014.11.050

Accepted Manuscript
Synthesis of three-dimensional fused and spirocyclic oxygen-containing cyclo-
butanone derivatives
Sergey V. Ryabukhin, Kateryna I. Fominova, Dmitriy A. Sibgatulin, Oleksandr
O. Grygorenko
PII:
S0040-4039(14)01943-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.050
TETL 45434
Reference:
Tetrahedron Letters
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4 November 2014
13 November 2014
Please cite this article as: Ryabukhin, S.V., Fominova, K.I., Sibgatulin, D.A., Grygorenko, O.O., Synthesis of three-
dimensional fused and spirocyclic oxygen-containing cyclobutanone derivatives, Tetrahedron Letters (2014), doi:
http://dx.doi.org/10.1016/j.tetlet.2014.11.050
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Synthesis of three-dimensional fused and
spirocyclic oxygen-containing cyclobutanone
derivatives
Sergey V. Ryabukhin, Kateryna I. Fominova, Dmitriy A. Sibgatulin, Oleksandr O. Grygorenko

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of three-dimensional fused and spirocyclic oxygen-containing
cyclobutanone derivatives
Sergey V. Ryabukhin,a Kateryna I. Fominova,a Dmitriy A. Sibgatulin,b Oleksandr O. Grygorenkoa
aNational Taras Shevchenko University of Kyiv, Volodymyrska Street, 64, Kyiv 01601, Ukraine
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An approach to fused and spirocyclic oxygen-containing cyclobutanone derivatives based on
ketene [2+2] cycloaddition with vinyl ethers is described. Using alicyclic chloroanhydrides as
ketene sources as well as cyclic vinyl ethers in the reaction resulted in the formation of three-
dimensional conformationally restricted building blocks of interest to medicinal chemistry and
organic synthesis. In particular, 2-oxaspiro(bicyclo[3.2.0]heptane-7,1'-cycloalkane)-6-ones and
2-oxaspiro(bicyclo[4.2.0]octane-8,1'-cycloalkane)-6-ones were obtained. The procedure
involves readily available and inexpensive starting materials and allows construction of complex
molecular architectures on large scale in a single run.
Available online
Keywords:
Three-dimensional frameworks
Cyclobutanes
[2+2] Cycloaddition
Oxygen heterocycles
Spiro compounds
2014 Elsevier Ltd. All rights reserved.
Fused and spirocyclic ring systems are the key structural
elements of numerous important organic molecules, including
many natural products and marketed drugs. Many synthetic
efforts in heterocyclic chemistry have been directed towards the
synthesis of heteroaromatic ring systems; apart from certain cases
such as steroid-like molecules and some other natural products,
fused and spirocyclic heteroaliphatic frameworks have received
less attention. The situation has since changed and recent trends
in medicinal chemistry have shifted towards three-dimensional
scaffolds as the central cores of potential drugs.1
Conformationally restricted templates, including spirocyclic
ones, have advantages for drug discovery, since, due to their pre-
organizaion, they have increased chance of potent and selective
binding with their biological targets. It is not surprising therefore,
that spirocyclic heteroaliphatic molecules have attracted
signifiacnt attention from synthetic and medicinal chemists.2
Furthermore, special attention has been paid to oxygen-enriched
molecules since it was shown that many compound collections
have less oxygen content compared to natural products and
marketed drugs.3 Therefore, fused and spirocyclic ring systems
based on saturated oxygen heterocycles are of particular interest.
ring systems 1 and 2, respectively (Scheme 1). Surprisingly,
vinyl ethers 3 and 4 are virtually unstudied in reactions with
ketenes. Most of the literature involved reactions of 3,6-dihydro-
2H-pyran (4) with more reactive aryl-substituted ketenes.5 Only a
single example described the [2+2]cycloaddition of 4 with
gaseous dimethylketene (5) (generated by pyrolysis of either
1,1,3,3-trimethylcyclobutanedione6 or isobutyryl anhydride5a),
leading to 2-oxabicyclo[4.2.0]octane derivative 6 (Scheme 2).
Scheme 1.
Scheme 2.
In this work, we have turned our attention to fused and
spirocyclic oxygen-containing ring systems based on the
cyclobutanone motif, namely, 2-oxaspiro(bicyclo[3.2.0]heptane-
7,1'-cycloalkane)-6-ones (1) and 2-oxaspiro(bicyclo[4.2.0]-
octane-8,1'-cycloalkane)-6-ones (2). Since the classical method
for the construction of the polysubstituted cyclobutanones relies
on [2+2] cycloaddition with ketenes,4 cyclic vinyl ethers 3 and 4
First of all, we have checked if compound 6 could be obtained
using dimethylketene generated in situ from isobutyryl chloride
and triethylamine. It was found that a complex mixture was
obtained when a 1:1.5 ratio of 4 and 5 (as described by Martin
and co-workers5a) was used. We found that compound 6 did form
———
would be the starting materials of choice for the construction of
 Corresponding author. Tel.: +38-044-239-3315; fax: +38-044-573-2643; e-mail: gregor@univ.kiev.ua

2
Tetrahedron Letters
in a substantial amount in the presence of at least a three-fold
excess of 4; increasing the ratio of 4 and 5 further improved the
reaction outcome, such that when using a 10:1 ratio of the
starting materials, the isolated yield of 6 was 43% (after
fractional distillation)7 – a result very similar to that obtained by
Krapcho and Lesser.6 The method was also amenable to the
preparation of adduct 78 (64% yield) starting from 2,3-
dihydrofuran (3).
1. (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752–6756. (b) Kingwell, K. Nature Rev. Drug Discov. 2009, 8,
931. (c) Lovering, F. Med. Chem. Commun. 2013, 4, 515–519.
2. For selected examples, see: (a) Burkhard, J. A.; Gurot, C.; Knust,
H.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2010, 12, 1944–
1947. (b) Hawkinson, J. E.; Szoke, B. G.; Garofalo, A. W.; Hom,
D. S.; Zhang, H.; Dreyer, M.; Fukuda, J. Y.; Chen, L.; Samant, B.;
Simmonds, S.; Zeitz, K. P.; Wadsworth, A.; Liao, A.; Chavez, R.
A.; Zmolek, W.; Ruslim, L.; Bova, M. P.; Holcomb, R.; Butelman,
E. R.; Ko, M.-C.; Malmberg, A. B. J. Pharmacol. Exp. Ther. 2007,
322, 619–630. (c) Fröhlich, J.; Sauter, F.; Blasl, K. Heterocycles
1994, 37, 1879–1891. (d) Prusov, E.; Maier, M. E. Tetrahedron
2007, 63, 10486–10496. (e) Zhu, J.; Quirion, J.-C.; Husson, H.-P.
J. Org. Chem. 1993, 58, 6451–6456. (f) Ciblat, S.; Canet, J.-L.;
Troin, Y. Tetrahedron Lett. 2001, 42, 4815–4817.
It was found that the procedure was efficient with alicyclic
acyl chlorides 8b–d: the corresponding fused and spirocyclic
cyclobutanones 1 and 2 were obtained in 56–67% yields (Table
1). No product 2a was formed in the reaction of
cyclopropanecarbonyl chloride (8a) and 4; obviously, the
corresponding ketene was too strained to be formed efficiently
under the reaction conditions.
3. Feher, M.; Schmidt, J. M. J. Chem. Inf. Comput. Sci. 2003, 43,
218–227.
4. (a) Tidwell, T. T. Ketenes, 2nd Ed.; John Wiley and Sons: New
York, 2006, 656 pp. (b) Ghosez, L.; Marchand-Brynaert, J. In:
Comprehensive Organic Synthesis, Vol. 5, Trost, B.; Fleming, I.;
Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991, pp. 85–122.
(c) Patai, S. Chemistry of Ketenes, Allenes, and Related
Compounds; John Wiley and Sons: New York, 1980, pp. 1–982.
5. (a) Hasek, R. H.; Gott, P. G.; Martin, J. C. J. Org. Chem. 1964, 29,
1239–1241. (b) Huisgen, R.; Feiler, L. A.; Otto, P. Chem. Ber.
1969, 120, 3405–3427. (c) Hurd, C. D.; Kimbrough, R. D. J. Am.
Chem. Soc. 1960, 82, 1373–1376. (d) Kimbrough, R. D. J. Org.
Chem. 1963, 28, 3577–3578. (e) Brady, W. T.; Parry III, F. H.;
Stockton, J. D. J. Org. Chem. 1971, 36, 1486–1489. (f) Swieton,
G.; Jouanne, J. von; Kelm, H.; Huisgen, R. J. Chem. Soc., Perkin
Trans. 2, 1983, 37–43.
6. Krapcho, A. P.; Lesser, J. H. J. Org. Chem. 1966, 31, 2030–2032.
7. General procedure for the [2+2] cycloadditions: To a solution of
the vinyl ether 3, 4, or 9 (20 mol) in dry methyl tert-butyl ether
(1.8 L), Et3N (2.6 mol) was added. The reaction mixture was
cooled to 0 C and the acyl chloride (2 mol) was added dropwise
at this temperature with stirring. The resulting mixture was stirred
at rt for 0.5 h and at reflux for 1–2 d. The precipitate was filtered
off, and the filtrate was washed with H2O (0.5 L), sat. aq NaHCO3
(0.5 L), and brine (0.5 L), dried over MgSO4, and evaporated
under reduced pressure. The residue was subjected to fractional
distillation in vacuo to give the corresponding cyclobutanones 1,
2, 6, 7, or 10.
Table 1. Synthesis of fused, spirocyclic cyclobutanones 1 and 2
Entry
Starting materialsa
8c + 3
m
2
0
1
2
3
n
1
2
2
2
2
Product
1c
Yield (%)
Ref.
9
1
2
3
4
56
0
8a + 4
2a
–
8b + 4
2b
57
62
67
10
11
12
8c + 4
2c
5
8d + 4
2d
a
Ratio of 8, 3(4) and Et3N = 1:10:1.3
Since alicyclic ketenes have rarely been used in reactions with
vinyl ethers previously,13 we also checked if the method worked
with acyclic substrates, namely, ethyl vinyl ether (9) (Scheme 3).
Reaction of 9 with the ketene generated from 8c gave the
corresponding adduct 10 in 50% yield.14
8. 7,7-Dimethyl-2-oxa-bicyclo[3.2.0]heptan-6-one (7). Yield 13.5 g
(64%). Colorless liquid. Bp 42–43 C / 1 mmHg. Anal. Calcd for
C8H12O2 C 68.55, H 8.63. Found C 68.38, H 8.84. MS (EI, m/z):
140 (M+), 112, 97, 70, 41. 1Н NMR (500 MHz, DMSO-d6), δ 4.32
(d, J = 5.8 Hz, 1H), 4.09 (ddd, 9.1 Hz, 6.0 Hz and 1.3 Hz, 1H),
4.01 (td, J = 8.4 Hz and 2.9 Hz, 1H), 3.70–3.63 (m, 1H), 2.04–
1.98 (m, 1H), 1.89–1.78 (m, 1H), 1.14 (s, 3H), 0.93 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 217.6, 79.6, 69.6, 60.9, 60.7, 27.8,
21.6, 14.2.
9. 2-Oxaspiro[bicyclo[3.2.0]heptane-7,1'-cyclopentan]-6-one (1c):
Yield 11.3 g (56%). Colorless liquid. Bp 50–52 C / 0.07 mmHg.
Anal. Calcd for C10H14O2 C 72.26, H 8.49. Found C 72.53, H 8.28.
Scheme 3.
In conclusion, a convenient method for the preparation of
oxygen-containing fused and spirocyclic cyclobutanone
derivatives, in particular, 2-oxaspiro(bicyclo[3.2.0]heptane-7,1'-
cycloalkane)-6-ones and 2-oxaspiro(bicyclo[4.2.0]octane-8,1'-
cycloalkane)-6-ones, is described. The procedure involves readily
available and inexpensive starting materials and could be scaled
up to prepare 100 g of the product in a single run. The building
blocks obtained are of particular interest in medicinal chemistry
as three-dimensional scaffolds for the generation of lead-like
libraries, as well as in other areas of chemistry as versatile
synthetic intermediates.
1
MS (EI, m/z): 166 (M+), 138, 98. H NMR (500 MHz, CDCl3) δ
4.38 (d, J = 5.7 Hz, 1H), 4.04 (t, J = 8.4 Hz, 1H), 3.82 – 3.75 (m,
1H), 3.67 – 3.58 (m, 1H), 2.16 – 2.08 (m, 1H), 1.90 – 1.79 (m,
2H), 1.79 – 1.70 (m, 2H), 1.70 – 1.55 (m, 5H). 13C NMR (126
MHz, CDCl3) δ 218.8, 79.6, 71.1, 68.6, 61.5, 35.9, 28.4, 26.3,
25.8, 25.5.
10. 2-Oxaspiro[bicyclo[4.2.0]octane-8,1'-cyclobutan]-7-one
(2b):
Yield 12.5 g (57%). Colorless liquid. Bp 54–55 C / 0.08 mmHg.
Anal. Calcd for C10H14O2 C 72.26, H 8.49. Found C 72.40, H 8.71.
MS (EI, m/z): 166 (M+), 138, 110, 84. 1H NMR (500 MHz,
CDCl3) δ 4.09 (d, J = 5.5 Hz, 1H), 3.73 (d, J = 10.9 Hz, 1H), 3.23
(td, J = 11.2, 3.2 Hz, 1H), 3.06 (t, J = 5.6 Hz, 1H), 2.28 – 2.18 (m,
1H), 2.16 – 2.03 (m, 3H), 2.00 – 1.93 (m, 1H), 1.93 – 1.78 (m,
2H), 1.56 – 1.45 (m, 1H), 1.44 – 1.32 (m, 2H). 13C NMR (126
MHz, CDCl3) δ 211.4, 70.9, 65.0, 64.4, 52.3, 29.2, 21.8, 20.9,
18.0, 15.8.
Acknowledgments
11. 2-Oxaspiro[bicyclo[4.2.0]octane-8,1'-cyclopentan]-7-one
(2c):
The authors thank Mr. Dmytro Granat for his help with
synthetic experiments.
Yield 10.8 g (62%). Colorless liquid. Bp 63–64 C / 0.1 mmHg.
Anal. Calcd for C11H16O2 C 73.30, H 8.95. Found C 73.09, H 9.24.
1
MS (EI, m/z): 180 (M+), 152, 96. H NMR (500 MHz, CDCl3) δ
References and notes
3.96 (d, J = 5.7 Hz, 1H), 3.76 (d, J = 11.0 Hz, 1H), 3.29 – 3.19 (m,
2H), 2.09 – 1.99 (m, 1H), 1.91 – 1.83 (m, 1H), 1.83 – 1.64 (m,

3
4H), 1.64 – 1.48 (m, 4H), 1.48 – 1.34 (m, 2H). 13C NMR (126
MHz, CDCl3) δ 213.8, 72.4, 71.9, 64.4, 53.6, 35.6, 25.9, 25.4,
25.2, 21.8, 18.2.
12. 2-Oxaspiro[bicyclo[4.2.0]octane-8,1'-cyclohexan]-7-one
(2d):
Yield 14.6 g (67%). Colorless liquid. Bp 70–71 C / 0.09 mmHg.
Anal. Calcd for C12H18O2 C 74.19, H 9.34. Found C 73.88, H 9.62.
1
MS (EI, m/z): 194 (M+), 166, 110. H NMR (500 MHz, CDCl3) δ
4.10 (d, J = 6.1 Hz, 1H), 3.79 (d, J = 11.0 Hz, 1H), 3.29 (t, J = 6.3
Hz, 1H), 3.24 (td, J = 11.1, 2.4 Hz, 1H), 2.07 – 1.98 (m, 1H), 1.76
– 1.28 (m, 13H). 13C NMR (126 MHz, CDCl3) δ 214.9, 70.2, 67.7,
64.4, 51.4, 32.4, 25.3, 24.8, 22.6, 22.6, 21.9, 18.1.
13. (a) Matsuo, J.-I.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Chem.
Commun. 2010, 46, 934–936. (b) Morita, N.; Asao, T.; Kitahara,
Y. Tetrahedron Lett. 1975, 33, 2821–2824.
14. 3-Ethoxyspiro[3.4]octan-1-one (10): Yield 12.3
g
(50%).
Colorless liquid. Bp 36–38 C / 0.1 mmHg. Anal. Calcd for
C10H16O2 C 71.39, H 9.59. Found C 71.06, H 9.63. MS (CI, m/z):
1
169 (MH+). H NMR (400 MHz, CDCl3) δ 3.91 (dd, J = 6.9, 5.6
Hz, 1H), 3.54 – 3.38 (m, 2H), 3.11 (dd, J = 17.6, 6.9 Hz, 1H), 2.91
(dd, J = 17.6, 5.5 Hz, 1H), 2.11 – 2.02 (m, 1H), 1.95 – 1.85 (m,
1H), 1.74 – 1.55 (m, 6H), 1.21 (t, J = 7.0 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 213.2, 73.2, 72.5, 64.9, 50.5, 34.5, 28.1, 25.8
(2C), 14.9.