Synthesis of spiro ethers by ring closing metathesis

Article abstract of DOI:10.1055/s-1998-1943

Starting from the cyclic ketones 1a-d, the dienes 3a-e were prepared. The ring closing metathesis reaction of these dienes using the Grubbs catalyst 5 provided the corresponding spiro ethers 4a-e in good yield. Force field calculations indicate that the conformer with the oxygen in axial position is favored.

Full text of DOI:10.1055/s-1998-1943

1390
LETTERS
SYNLETT
Synthesis of Spiro Ethers by Ring Closing Metathesis
*
Martin E. Maier , Michael Bugl
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany, FAX: (+49) 7071 29 5137, e-mail:
martin.e.maier@uni-tuebingen.de
Received 21 August 1998
Abstract: Starting from the cyclic ketones 1a-d, the dienes 3a-e were
prepared. The ring closing metathesis reaction of these dienes using the
Grubbs catalyst 5 provided the corresponding spiro ethers 4a-e in good
yield. Force field calculations indicate that the conformer with the
oxygen in axial position is favored.
Although spiro compounds are encountered less frequently in natural
products as compared to anealated or bridged ring systems they are of
1
some importance in spiroacetals. These are usually generated by
internal acetalization of a dihydroxyketone. Spiro centers that are
connected to fewer oxygen atoms present a more formidable challenge
from a synthetic point of view. A common strategy involves the
formation of a bond to the spiro center in a substrate that carries one
ring. Some methods that are useful in this context are the double
α-alkylation of a cyclic ketone with a bis-electrophile, intramolecular
2
ene reactions, Heck cyclizations, oxidative cyclizations on aryl
3
4
derivatives, and certain rearrangement reactions. Alternatively, one
5,6
spiro compound may be rearranged to another one. Finally, there is
yet another approach that uses the cyclization on a ring system that
already contains a ring carrying two geminal functional groups. Again,
this can be realized in many ways. With the advent of the ring-closing
7,8
metathesis (rcm) as a practical tool in organic synthesis, the latter
approach can be implemented very easily. In this paper we illustrate the
9
use of the rcm reaction for the synthesis of some spiro ethers.
It was of interest to see whether the construction of 5- and 6-membered
oxacycles would be feasible. The synthesis started with the cyclic
ketones 1a-d which were converted to the tertiary homoallylic alcohols
10,11
2a-d by reaction with allylmagnesium chloride in THF.
12
Subsequently, etherification of the corresponding potassium alkoxides
with allyl bromide in refluxing THF furnished the dienes 3a-d (Scheme
1). In the case of 1b, a similar sequence starting with vinylmagnesium
13
chloride gave the 1-(allyloxy)-1-vinylcyclohexane (3e).
The structures of the spiro compounds are supported by spectroscopic
14
+
data. Thus, the MS spectra of 4a-e are characterized by a strong M
peak. In addition, the NMR spectra are in accordance with the assigned
structures. Finally, it should be noted that the spiro compounds 4a-e
have a characteristic fruity smell. Of some interest is certainly the
Scheme 1
1
conformation of the spiro compounds. We therefore performed force-
15
field calculations (Hyperchem 3.0) on the ether 4b. It turned out that
The crucial ring closing reactions were performed by refluxing a
dichloromethane (0.03-0.2 M) solution of the dienes 3a-e in the
presence of 5 mol% of the Grubbs ruthenium carbene catalyst 5 for
several hours. Gratifyingly, the spiro compounds 4a-e were formed in
the energy difference between the conformer with the axial and
-1
equatorial C-O-bond amounts to 4.7 kJ mol . The more stable
conformer is the one with an axial C-O-bond (Scheme 2).
14
yields ranging from 53-91%. (Table 1).

December 1998
SYNLETT
1391
(14) 1-Allyl-1-allyloxycyclohexane (3b): To a suspension of potassium
hydride (4.29 g, 107.0 mmol) in dry THF (150 ml) was added
10
1-allylcyclohexanol (2b) (4.77 g, 34.0 mmol) dropwise over a
period of 20 min. Subsequently, the mixture was stirred for 1 h at
70 °C. The mixture was cooled to room temp. before allyl
bromide (4.83 g, 39.9 mmol) was added dropwise. The mixture
was refluxed for 11 h, cooled, then treated with satd. aqueous
Scheme 2
In summary, we have described
a straightforward synthesis of
NH Cl (20 ml) and extracted with diethyl ether (2 × 100 ml). The
4
1-oxaspiro compounds by rcm reaction of 1-allyl- and 1-vinyl-1-
(allyloxy)cycles. The oxaspiro compounds contain a double bond which
should allow for further functionalization reactions.
combined organic layers were washed with brine, dried (MgSO ),
4
filtered and evaporated in vacuo. Distillation of the residue
o
provided 3b as a colorless oil (4.23 g, 69%), b.p. 40 C/0.5 mbar.
1
H NMR (250 MHz, CDCl ): δ = 1.08-169 (m, 10 H, CH ), 2.16
3
2
(dt, J = 7.2, 1.5 Hz, 2 H, CH CH=CH ), 3.79 (dt, J = 5.3, 1.5 Hz,
2
2
Acknowledgment.
Forschungsgemeinschaft and the Fonds der Chemischen Industrie is
gratefully acknowledged.
Financial
support
by
the
Deutsche
OCH ), 4.92-5.07 (m, 4 H, CH=CH ), 5.70-5.92 (m, 2 H,
2
2
13
CH=CH ). – C NMR (62.9 MHz, CDCl ): δ = 22.7, 25.9, 34.4
2
3
(cyclohexyl CH ), 41.8 (allyl C), 61.5 (CH O), 75.2, 115.5, 117.1,
2
2
134.2, 136.0. – MS (EI), m/z (%): 139 (100), 123 (9), 81 (22), 69
(11), 55 (10), 41 (47). – C O (180.29): calcd. C 79.53, H
References and Notes
H
12 20
(1) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617-1661.
12.32; found C 79.75, H 11.12.
General procedure for the preparation of the spiroethers (4a-e)
using rcm: To a solution of the diene (3a-e) (0.03-0.2 M) in dry
and degassed dichloromethane was added ruthenium carbene 5 (5
mol%). After refluxing the reaction mixture for 8 h, the solvent
was removed in vacuo and the residue purified by flash
chromatography on silica gel.
6-Oxaspiro[4.5]dec-8-ene (4a): cyclization of 3a (500 mg, 3.01
mmol) in dichloromethane (15 ml) in the presence of 5 (123 mg,
0.15 mmol) gave after flash chromatography (n-hexane/ethyl
(2) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6477-6487.
(3) Braun, N. A.; Ciufolini, M. A.; Peters, K.; Peters, E.-M.
Tetrahedron Lett. 1998, 39, 4667-4670.
(4) (a) Nakamura, E.; Kuwajima, I. Org. Synth. 1987, 65, 17-25.
(b) Dinesh, C. U.; Kumar, P.; Reddy, R. S.; Pandey, B.; Puranik, V.
G. Tetrahedron: Asymmetry 1995, 6, 2961-2970. (c) Fitjer, L.;
Steeneck, C.; Gaini-Rahimi, S.; Schröder, U.; Justus, K.; Puder, P.;
Dittmer, M.; Hassler, C.; Weiser, J.; Noltemeyer, M.; Teichert, M.
J. Am. Chem. Soc. 1998, 120, 317-328.
acetate, 97:3) 4a as a colorless oil (220 mg, 53%).
1
TLC (n-hexane/ethyl acetate, 97:3): R = 0.82. – H NMR (250
f
(5) Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95,
MHz, CDCl ): δ = 1.35-1.92 (m, 8 H, cyclopentyl CH ), 2.05-
3
2
5321-5334.
2.15 (m, 2 H, allyl H), 4.10-4.16 (m , 2 H, CH O), 5.60-5.85 (m, 2
2
13
(6) Maezaki, N.; Fukuyama, H.; Yagi, S.; Tanaka, T.; Iwata, C. J.
Chem. Soc. Chem. Commun. 1994, 1835-1836.
H, olefinic). – C NMR (62.9 MHz, CDCl ): δ = 23.8, 34.7, 36.7,
3
61.6 (CH O), 81.3 (spiro C), 124.1, 125.6 (olefinic C). – MS (EI),
2
+
(7) Reviews: (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem.
Res. 1995, 28, 446-452. (b) Schmalz, H.-G. Angew. Chem. 1995,
107, 1981-1984; Angew. Chem. Int. Ed. Engl. 1995, 34, 1833-
1836. (c) Schuster, M.; Blechert, S. Angew. Chem. 1997, 109,
2124-2145; Angew. Chem. Int. Ed. Engl. 1997, 36, 2036-2055. (d)
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388.
(e) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (f)
Fürstner, A. Top. Catal. 1997, 4, 285-299.
m/z (%): 138 (64%) [M ], 120 (16%), 109 (21%), 55 (100%). –
HR-MS (EI) calcd. for C H O: 138.1026, found 138.1026.
9
14
1-Oxaspiro[5.5]undec-3-ene (4b): cyclization of 3b (500 mg, 2.77
mmol) in dichloromethane (15 ml) in the presence of 5 (114 mg,
0.14 mmol) gave after flash chromatography (n-hexane/ethyl
acetate, 97:3) 4b as a colorless oil (299 mg, 71%).
1
TLC (n-hexane/ethyl acetate, 97:3): R = 0.80. – H NMR (250
f
MHz, CDCl ): δ = 1.21-1.74 (m, 10 H, cyclohexyl CH ), 1.91-
3
2
1.95 (m, 2 H, allyl CH ), 4.05-4.09 (m, 2 H, OCH ), 5.60-5.74 (m,
(8) Recent applications: (a) Fürstner, A.; Langemann, K. Synthesis
1997, 792-803. (b) Rutjes, F. P. J. T.; Schoemaker, H. E.
Tetrahedron Lett. 1997, 38, 677-680. (c) Ghosh, A. K.; Cappiello,
J.; Shin, D. Tetrahedron Lett. 1998, 39, 4651-4654. (d) Delgado,
M.; Martin, J. D. Tetrahedron Lett. 1997, 38, 6299-6300.
2
2
13
2 H, olefinic H). – C NMR (62.9 MHz, CDCl ): δ = 21.9, 26.2,
3
34.9 (cyclohexyl CH ), 35.4 (allyl C), 60.3 (OCH ), 122.89, 125.3
2
2
+
(olefinic C). – MS (EI), m/z (%): 152 (43) [M ], 135 (13), 109
(35), 96 (24), 67 (58), 55 (100), 41 (37). – HR-MS (EI) calcd. for
C
H O: 152.1201, found 152.1202.
10 16
(9) Synthesis of spiro systems using rcm: (a) Hammer, K.; Undheim,
K. Tetrahedron 1997, 53, 2309-2322. (b) Hammer, K.; Undheim,
K. Tetrahedron 1997, 53, 10603-10614. (c) van Hooft, P. A. V.;
Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.;
van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron Lett. 1998,
39, 6061-6064.
1-Oxaspiro[5.6]tetradec-3-ene (4c): cyclization of 3c (100 mg,
0.52 mmol) in dichloromethane (15 ml) in the presence of 5 (22
mg, 0.026 mmol) gave after flash chromatography (n-hexane/
ethyl acetate, 97:3) 4c as a colorless oil (65 mg, 91%).
TLC (n-hexane/ethyl acetate, 97:3): R = 0.78. – H NMR (250
MHz, CDCl ): δ = 1.30-1.85 (m, 12 H, cycloheptyl CH ), 1.92-
1.97 (m, 2 H, allyl CH ), 4.05-4.11 (m, 2 H, CH O), 5.68-5.72 (m,
2 H, olefinic H). – C NMR (62.9 MHz, CDCl ): δ = 21.9, 29.9,
35.8 (allyl C), 38.3, 60.7 (OCH ), 122.8, 125.3 (olefinic C). – MS
1
f
3
2
(10) Katzenellenbogen, J. A.; Lenox, R. S. J. Org. Chem. 1973, 38,
2
2
326-327.
13
3
(11) Chander, R. M. S.; Kishna, G. S. Indian J. Chem. Sect. B 1988, 27,
2
660-661.
+
(EI), m/z (%): 166 (45%) [M ], 149 (30%), 67 (23%), 55 (69%),
(12) Pandey, G.; Soma Sekhar, B. B. V. Tetrahedron 1995, 51, 1483-
41 (100%). – HR-MS (EI) calcd. for C H O: 166.1357, found
11 18
1494.
166.1334.
(13) Reuter, J. M.; Salomon, R. G. J. Org. Chem. 1977, 42, 3360-3364.
1,9-Dioxaspiro[5.5]undec-3-ene (4d): cyclization of 3d (150 mg,
0.82 mmol) in dichloromethane (15 ml) in the presence of 5 (34

1392
LETTERS
SYNLETT
mg, 0.041 mmol) gave after flash chromatography (n-hexane/
0.090 mmol) gave after flash chromatography (n-hexane/ethyl
acetate, 9:1) 4e as a colorless oil (132 mg, 53%).
ethyl acetate, 97:3) 4d as a colorless oil (82 mg, 65%).
1
1
TLC (n-hexane/ethyl acetate, 9:1): R = 0.50. – H NMR (250
TLC (n-hexane/ethyl acetate, 97:3): R = 0.65. – H NMR (250
f
f
MHz, CDCl ): δ = 1.55-2.20 (m, 10 H, cyclohexyl CH ), 1.94-
MHz, CDCl ): δ = 1.50-1.80 (m, 4 H, CH ), 1.94-2.02 (m, 2 H,
3
2
3
2
2.02 (m, 2 H, allyl CH ), 4.56-4.60 (m, 2 H, OCH ), 6.11-6.24 (m,
allyl CH ), 3.60-3.80 (m, 4 H, OCH ), 4.04-4.12 (m, 2 H,
2
2
2
2
13
13
2 H, olefinic H). – C NMR (62.9 MHz, CDCl ): δ = 23.4, 25.4,
OCH CH=CH), 5.61-5.78 (m, 2 H, olefinic H). – C NMR (62.9
3
2
37.0 (CH ), 73.5 (OCH ), 89.4 (spiro C), 125.16, 133.8 (olefinic
C). – MS (EI), m/z (%): 138 (18) [M ], 109 (11), 95 (100), 81
MHz, CDCl ): δ = 34.9, 35.5, 60.2, 63.7, 67.9 (spiro C), 122.4,
125.1 (olefinic C). – MS (EI), m/z (%): 154 (16%) [M ], 99
2
2
3
+
+
(25), 67 (25). – HR-MS (EI) calcd. for C H O: 138.1072, found
10 16
(34%), 81 (12%), 54 (100%). – HR-MS (EI) calcd. for C
H O :
10 16 2
138.1044.
154.0993, found 154.1013.
13
1-Oxaspiro[4.5]dec-3-ene (4e): cyclization of 3e (300 mg, 1.80
mmol) in dichloromethane (20 ml) in the presence of 5 (74 mg,
(15) Cohen, T.; In-Howa, J.; Boguslaw, M.; Bhupathy, M. J. Org.
Chem. 1990, 55, 1528-1536.