An unusual silicon mediated transannular cyclopropanation

Article abstract of DOI:10.1039/c2cc37739j

A silicon mediated intramolecular 1,4-conjugate addition of a homoallylic carbon nucleophile leading to cyclopropanation is reported. Specifically, treatment of 6-trimethylsilyl-5,6-dihydroazocinones with fluoride gives 4-azabicyclo(5.1.0)octenones, presenting an unusual extension to the repertoire of silyl group reactivity.

Full text of DOI:10.1039/c2cc37739j

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An unusual silicon mediated transannular
cyclopropanation†
Cite this: Chem. Commun., 2013,
49, 795
Bing You, Kate Hamer, William Lewis and James Dowden*
Received 24th October 2012,
Accepted 20th November 2012
DOI: 10.1039/c2cc37739j
www.rsc.org/chemcomm
A silicon mediated intramolecular 1,4-conjugate addition of a the infrared spectrum from B1735 cmÀ1 for the azetidinones 2 to
homoallylic carbon nucleophile leading to cyclopropanation is B1657 cmÀ1 for the azocinone 3. NMR spectroscopy of this
reported. Specifically, treatment of 6-trimethylsilyl-5,6-dihydro- compound shows significantly broadened peaks, presumably due
azocinones with fluoride gives 4-azabicyclo(5.1.0)octenones, to slow conformational exchange as observed for related
presenting an unusual extension to the repertoire of silyl group compounds.10
reactivity.
The identity of the 6-trimethylsilyl-5,6-dihydroazocinone 3
was confirmed by X-ray crystallography (Fig. 1).‡ Notably, the
Silyl groups impart versatile reactivity to their compounds.1 3,4-alkene is twisted out of conjugation by 621 from the amide
Adapting this useful reactivity to direct common precursors carbonyl; attempted conjugate addition with external nucleo-
toward varied molecular architectures is attractive,2,3 not least philes, such as thiophenol and caesium carbonate in THF,
to provide escape from the ‘sameness’ perceived to restrict returned starting material 3 (not shown).
discovery especially in chemical biology.4 Pursuit of this objective
revealed an apparently unique mode of silicon mediated
cyclopropanation.
Beta-lactams (azetidin-2-ones) are readily accessible and
stable, yet adequately strained to drive skeletal rearrangements.5
We were intrigued by reports of thermal Cope rearrangement of
cis-3,4-divinyl-azetin-2-ones (e.g. 2, Scheme 1), leading to
5,6-dihydroazocinones (e.g. 3) in good yield.6–8 Apart from their
unusual shape, the rich functionality displayed by these
products is attractive for further transformation. Speculatively,
Scheme 1 Reagents and conditions: (a) 4-methoxyaniline, MgSO4, CH2Cl2, rt,
we sought installation of a silyl group within such 5,6-dihydro-
azocinones with a view to exploring subsequent reactivity for
access to novel structures.
10 min; then E-crotonyl chloride, Et3N, MgSO4, CH2Cl2, rt, 16 h, 57%; (b) toluene,
120 1C, sealed tube, 88%.
(E)-3-(Trimethylsilyl)propenal 1,9 4-methoxyaniline and
crotonyl chloride were transformed by Staudinger reaction with
triethylamine in dichloromethane at room temperature, to
produce the corresponding 3,4-divinylazetidin-2-one 2 in acceptable
yield (Scheme 1). Subsequent heating of azetindinone 2 to 120 1C
in toluene in a sealed tube effected Cope rearrangement to give
5,6-dihydroazocinone 3 in excellent yield. The transformation is
accompanied by a characteristic change in the carbonyl stretch in
School of Chemistry, University of Nottingham, University Park, Nottingham,
NG7 2RD, UK. E-mail: james.dowden@nottingham.ac.uk; Fax: +44 (0)115 9513565;
Tel: +44 (0)115 9513566
† Electronic supplementary information (ESI) available: Full experimental and
spectroscopic information. CCDC 906817 and 906818. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2cc37739j
Fig. 1 Crystal structure of 5,6-dihydroazocinone 3. Ellipsoids are drawn at the
50% probability level.
c
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Chem. Commun., 2013, 49, 795--797 795

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We found that treatment of the 6-trimethylsilyl-dihydro-
azocinone 3 with TBAF in THF resulted in clean conversion to
a single product in 90% yield (Scheme 2). Mass spectrometry
confirmed ablation of the trimethylsilyl group, yet the 1H NMR
spectrum showed well resolved peaks unrelated to the corres-
ponding azocinone 3. Upfield peaks at 0.86 and 0.47 ppm in
the 1H NMR spectrum and a corresponding methylene peak
at 8.1 ppm in the 13C NMR spectrum were suggestive of a
cyclopropane.
Scheme 3 Reagents and conditions: (a) Ph3PQCHCO2Et, NaH, THF, rt, 2 h, 77%;
(b) toluene, 120 1C, sealed tube, 3 h, 91%; (c) DBU, CH2Cl2, rt, 16 h, 92%.
Ultimately, we obtained a crystal structure that confirmed
the identity of the new fused cyclopropane 4 (Fig. 2).‡ The same
transformation could be achieved by treating the dihydro-
azocinone 3 with sodium hydroxide (20% aqueous) in ethanol
in 70% yield.
The idea that this was a silicon specific effect was promoted
by evaluating the analogous 5,6-dihydroazocinone bearing an
ester at the 6-position 6 (Scheme 3). Wittig olefination of
4-oxoazetidine-2-carbaldehyde 511 and Cope rearrangement
gave the corresponding 5,6-dihydroazocinone 6 in 70% overall
yield.7 Treatment of this compound with DBU gave tautomer 7,
but no cyclopropanation was observed under these conditions.
Alternative means of generating an anion at azocinone the
6-position have not yet been explored however.
An investigation into whether further substituents at the
5- and 6-positions of azocinone precursors were tolerated in
this cyclopropanation reaction was carried out (Scheme 4).
3-Methylcrotonoyl chloride and 3-phenylbut-2-enoyl chloride
were transformed to azetidin-2-ones 8 (49%)† and 9 (41%)†
respectively, then subject to rearrangement to give the corres-
ponding 5,6-dihydroazocinones with 4-methyl 10 (97%), or
4-phenyl 11 (87%). Treatment of either 5,6-dihydroazocinones
10, 11 with tetrabutylammonium fluoride resulted in transannular
cyclopropanation in high yield (12 R = Me, 93%, 13 R = Ph, 86%).
(E)-Pent-2-enoyl chloride, was transformed into the corres-
ponding azetidin-2-one 14, with the 3-propenyl group present
as a 1 : 1 mixture of E : Z isomers (63%). Rearrangement gave
5,6-dihydroazocinone 15 isolated as an approx. 1.5 : 1 mixture
of diastereoisomers, as determined by relative integration of
the 5-methyl group signals (54%). Reaction of this azocinone 14
with tetrabutylammonium fluoride gave cyclopropane 16 in
91% yield with an approx. 2 : 1 ratio of diastereoisomers as
determined by relative integration of the alkene peaks in the
1H NMR spectrum (Scheme 5).
Attempts to introduce additional functional groups adjacent
to silicon at the 6-position 20,† or two substituents at the
5-position 19,† of the azocinone were not successful since the
preceding azetidin-2-ones 17 and 18 respectively did not
undergo Cope rearrangement, presumably due to the steric
demands of this increased substitution (Scheme 6).
It is likely that the constraint provided by the boat-like
conformation of the 5,6-dihydroazocinone helps to guide the
observed cyclopropanation, although some conformational
rearrangement presumably facilitates the 1,4-conjugate
addition. Initial evaluation of an open-chain analogue of this
Scheme 2 Reagents and conditions: (a) 1 M TBAF in THF, CH2Cl2, rt, 24 h, 90%; or
Scheme 4 Reagents and conditions: (a) toluene, 120 1C, sealed tube (10 – 97%,
11 – 87%); (b) 1 M TBAF in THF, CH2Cl2, rt, 24 h, (12 – 93%, 13 – 86%).
(b) NaOH (20% aq.), EtOH, rt, 24 h, 70%.
Fig. 2 Crystal structure of 4-azabicyclo(5.1.0)octenone 4. Ellipsoids are drawn at
Scheme 5 Reagents and conditions: (a) toluene, 120 1C, sealed tube 54% (b) 1 M
the 50% probability level.
TBAF in THF, CH2Cl2, rt, 24 h, 90%.
c
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Notes and references
‡ Crystal data for 3. C17H23NO2Si, M = 301.45, monoclinic, a =
15.0245(13), b = 6.5615(6), c = 17.5471(16) Å, U = 1681.5(3) Å3. T =
150(2) K, space group P21/n, Z = 4, 14 250 reflections measured, 5415
unique with R = 0.0419 wR2 = 0.1060. CCDC 906817. Crystal data for 4.
C14H15NO2, M = 229.27, monoclinic, a = 6.0221(8), b = 19.648(4), c =
9.7886(12) Å, U = 1146.0(3) Å3. T = 90(2) K, space group P21/c, Z = 4, 3912
reflections measured, 1246 unique with R = 0.1299 wR2 = 0.3104. CCDC
906818.
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´
´
´
´
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We thank BBSRC and University of Nottingham for student-
ships (KH and BY respectively).
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 795--797 797