The first intramolecular silene Diels-Alder reactions

Article abstract of DOI:10.1039/c3cc49526d

The synthesis of silaheterocycles through the first examples of an intramolecular silene Diels-Alder reaction is described.

Full text of DOI:10.1039/c3cc49526d

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The first intramolecular silene Diels–Alder
reactions†
Cite this: Chem. Commun., 2014,
50, 2919
Michal Czyzewski,a Jonathan D. Sellars,a Tamaz Guliashvili,b Julius Tibbelin,b
Lisa Johnstone,a Justin Bower,‡c Matthew Box,c Robert D. M. Davies,c
Henrik Ottosson*b and Patrick G. Steel*a
Received 16th December 2013,
Accepted 28th January 2014
DOI: 10.1039/c3cc49526d
www.rsc.org/chemcomm
The synthesis of silaheterocycles through the first examples of an with a particular emphasis on preparation of examples that are
intramolecular silene Diels–Alder reaction is described.
kinetically stabilised with respect to dimerisation through the incor-
poration of bulky substituents.4a,9 In this respect it is surprising to
As evidenced by the vast range of transformations mediated by silyl note that intramolecular reactions of silenes beyond simple rearran-
hydrides, ethers and enol ethers and vinyl, aryl and allyl silanes, gements have not been described.10,11 To explore this option we
organosilicon compounds play an important role in organic syn- initiated a programme to study the structural requirements for such a
thesis. Moreover, although formally isostructural, the replacement of process and in this communication describe the first examples of
a carbon atom by a silicon atom can have profound effects on intramolecular silene cycloadditions that provide access to novel
molecular properties. For example, this ‘‘silicon-switch’’ has been heterocyclic silanes.
exploited in the design of new odorants,1 pharmaceutical com-
Building on our earlier experience for the generation of silenes
pounds2 and organic materials. The challenge for the continued through either a thermal 1,3-silyl shift of an acyl polysilane12 or a sila-
development of these reagents is that there are relatively limited Peterson reaction,13a initial attempts focused on simple acyclic
methods for the preparation of functionalised silanes, particularly substrates combining silene precursor and dienyl fragments
when the silicon centre is contained within a ring structure.3 One (Scheme 1). Hepta-4,6-dienol 3 could be readily generated through
option that remains largely unexplored is the application of low- a sequence involving the Claisen ortho ester rearrangement of divinyl
coordinate silicon compounds. Such compounds, silenes (and dis- carbinol 1 and reduction of the resultant ester 2. Following
ilenes), silynes and silylenes which represent the organosilicon
equivalents of alkenes, alkynes and carbenes respectively, display a
fascinating array of chemistry that has much to offer synthetic
chemistry.4 We and others have begun to explore this area and have
demonstrated that such reagents can provide ready access to a variety
of functionalised organosilanes that would be difficult to achieve
using classical synthetic methodology.5–7 The challenges in this reside
in the high electrophilicity of a low-coordinate silicon centre and the
relatively weak nature of the silicon–carbon multiple bond. For
example, silenes are highly reactive, most commonly transient,
species that in the absence of a suitable trapping molecule readily
dimerise or oligomerise.8 Consequently, they have largely been the
subject of fundamental studies into reactivity, structure and bonding
a Department of Chemistry, University of Durham, Durham, DH1 3LE, UK.
E-mail: p.g.steel@durham.ac.uk; Fax: +44 (0)1913844737
b Department of Chemistry - BMC, Uppsala University, Box 576, S-751 23 Uppsala,
Sweden. E-mail: henrik.ottosson@kemi.uu.se
c Astra Zeneca, Alderley Park, Alderley Edge, Cheshire, SK10 4TF, UK
† Electronic supplementary information (ESI) available: Experimental procedures
and spectra of cycloadducts 14, 20–25. See DOI: 10.1039/c3cc49526d
‡ Current address: The Beatson Institute for Cancer Research, Garscube Estate,
Scheme 1
Switchback Road, Bearsden, Glasgow, G61 1BD, UK.
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Table 1 Thermal cycloaddition reactions of transient silenes generated
from acylpolysilanes
phosphine mediated halogenation, reaction of the resulting dienyl
iodide with the silenolate generated from acyl silanes 4a and 4b
afforded acyl polysilane 5a and carbamoyl silane 5b, respectively.14
Initial attempts to generate the silene followed protocols established
in our groups based on the thermal 1,3-silicon shift to generate
Brook-type silenes. Disappointingly all such attempts led to extensive
decomposition of the starting diene with no evidence for the
formation of the desired cycloadduct. Disappointed by these results
we then turned to low temperature silene generation based on our
previously described methods using a sila-modified Peterson reac-
tion. The precursors for this could simply be accessed by oxidation of
the alcohol 3 to the aldehyde and reaction with the hypersilyl
Grignard reagent 6 derived from tetrakis(trimethylsilyl)silane to afford
silyl alcohol 7. Despite our earlier success exploring intermolecular
reactions with closely related silenes,13 none of these approaches
afforded evidence of the desired cycloadducts. Similarly, attempts to
generate the corresponding silenolate, by treatment of acylpolysilane
8 with KOtBu,14 only led to extensive oligomerisation and a complex
mixture of other products arising from the formation of a transient
silene e.g. dimers or ene type products. Speculating that difficulties in
attaining the necessary reactive conformations within the short life-
time of the silene were inhibiting the intramolecular cycloaddition we
modified the substrate to enhance this pathway. This could most
simply be achieved by incorporating an aromatic ring into the tether
for cyclisation. Initial attempts to couple a diene unit to salicyl-
aldehyde using simple Mitsunobu chemistry proved to be surpris-
ingly challenging giving only low yields of the desired ether.
Consequently, we turned to a more linear approach from methyl
salicylate 9 (Scheme 2). Coupling with hexadienol 10, prepared by
deconjugation of ethyl sorbate and reduction, followed by hydrolysis,
conversion to the acid chloride and reaction with KSi(SiMe3)3
afforded the acyl silane 12. Pleasingly, heating a toluene solution of
Timea
Yieldb
Entry Acylpolysilane
(min) Silacycloadduct (%; ds)
1
15
75
90
—c (2.0 : 1)
2
3
4
60 (2.7 : 1)
87 (3.7 : 1)
75 (2.2 : 1)
75
60
5
—e (—)
a
b
Time required for complete conversion of acylpolysilane. Yield of
purified cycloadduct, diastereoselectivity determined from 1H NMR
spectra (see ref. 15). Decomposed on attempted purification. EZ
and EE isomers. No cycloadduct obtained.
c
d
e
this afforded the desired cycloadduct 14 in 56% isolated yield. After required leading to extensive decomposition. A range of other
some experimentation optimum conversion was realised by heating substrates 15–19 varying the nature of the arene tether and diene
at 180 1C for 1 h affording a 2.7 : 1 mixture of diastereoisomers.15 substitution pattern were then investigated to explore the scope and
Attempts to enhance selectivity by conducting reactions at lower limitation of this cycloaddition (Table 1). The desired precursors
temperatures were not successful with the longer reaction times could be prepared in an identical fashion to that described above.
Intriguingly for the preparation of 19 deconjugation of methyl hepta-
2,4-dienoate in an analogous fashion to that employed for ethyl
sorbate followed by reduction afforded the desired hepta-3,5-dienol
favouring the EZ isomer (EZ : EE 84 : 16). Presumably, this reflects the
kinetic protonation of an ‘‘endo W’’16 shaped tri-enolate anion as
treatment of the EZ dienylester with a catalytic amount of iodine
resulted in isomerisation to the corresponding E,E diene.
Mirroring earlier work exploring intermolecular silene cyclo-
addition in which steric hindrance proved to be a critical parameter
1,4-disubstitued dienes proved not to be viable substrates (entry 5).
However, substitution on the aromatic tether was tolerated with a
3-methyl substituent leading to isolation of the silacycle 22 in 87%
yield, possibly reflecting a degree of conformational constraint in the
precursor. Introduction of a para-methoxy group was predicted to
enhance the stability of the silene facilitating its generation. Consis-
tent with this complete consumption of starting material was
observed within 15 minutes to afford a mixture of diastereomeric
cycloadducts (entry 1). However, these proved to be highly unstable
Scheme 2
and attempts to isolate them were unsuccessful. We then turned to
2920 | Chem. Commun., 2014, 50, 2919--2921
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(CASE award to MC); the EPSRC Mass Spectrometry Service for
accurate mass determinations, Dr A. M. Kenwright (University of
Durham) for assistance with NMR experiments and Dr J. A. Mosely
(University of Durham) for mass spectra.
Notes and references
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acyl polysilane is treated with an alkyl lithium reagent to initiate the
sila-Peterson olefination and afford the silene at much lower reaction
temperatures (Scheme 3).16 In earlier studies of the sila-Peterson
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significantly enhanced stereoselectivity and we speculate that when
the reactivity of the silene is taken into account the difference
between endo and exo transition state barriers is relatively small.
In conclusion, we have described the first examples of intra-
molecular silene Diels–Alder reactions. These provide access to a
range of polycyclic and heterocyclic organosilanes. Such complex
cyclic organosilanes have potential both as novel building blocks and
as structural entities in their own right. Work to explore these and
develop more efficient cycloaddition strategies are in progress.
We thank the EPSRC (DTA studentship to MC), AstraZeneca and
the Swedish Research Council (VR) for financial support of this work
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