Silicon and tin-directed Tiffeneau–Demjanov reaction†
Leonie Chow, Melanie McClure and Jonathan White*
School of Chemistry, The University of Melbourne, Parkville 3010, Melbourne, Australia.
E-mail: whitejm@unimelb.edu.au
Received 20th November 2003, Accepted 12th January 2004
First published as an Advance Article on the web 27th January 2004
Silicon and tin substituents surprisingly have only a
moderate directing effect on the Tiffeneau–Demjanov reac-
tion. The low selectivity is rationalised as being due to the
reactive nature of the diazonium ion leaving group, the
weaker oxydiazene leaving group was found to give better
yields of the silicon-directed ring expanded product.
The strength of the directing effect is exemplified by the
observation that a 1Њ carbon, which is β to silicon has a
migratory aptitude between that of a 2Њ and 3Њ carbon in the
Baeyer–Villiger reaction, while β-Tin raises the migratory
aptitude of a 1Њ carbon to be above that of a 3Њ carbon.
The Tiffeneau–Demjanov ring enlargement of cyclic ketones
is shown in Scheme 3 and involves the intermediate diazonium
species 6.17 Breakdown of the diazonium intermediate 6 has
similarities with the breakdown of the tetrahedral intermediate
5 in the Baeyer–Villiger reaction (Scheme 2). Given the strong
directing influence that silicon and tin have on the Baeyer–
Villiger reaction, we were interested to establish whether these
substituents would exert a similar degree of control over the
Tiffeneau–Demjanov ring enlargement of cyclic ketones and on
the related chain extension reaction of acyclic ketones.
The stabilisation of positive charge at the β position by group 4
metal substituents (the so called ‘β effect’) has been well estab-
lished.1–7 The magnitude of this stabilisation increases down the
group Si < Ge << Sn and is related to the ability of the C–metal
bond to donate electrons to the carbenium ion p orbital by
hyperconjugation (Fig. 1).6,7
To test this proposal we prepared the series of the silicon and
tin substituted cyclic ketones 7–11 by conjugate addition of
trimethylsilyllithium or trimethylstannyllithium to precursor
enones. These were converted to the primary amines 12–16
(which are the precursors to the Tiffeneau–Demjanov reaction)
by two different methods; Method A (Scheme 4) involved
treatment of ketones 7–11 with trimethylsilylcyanide followed
by reduction with lithium aluminium hydride.18 By this method
the amines 12, 13, 14 and 16 were obtained as inseparable mix-
tures of diastereoisomers which were used without further
purification. The trans-isomer of 15 was the major product
from application of Method A to the cyclohexanones 9 and 10.
The cis-isomers of amines 14 and 15 were prepared by epox-
idation of the ketones 9 and 10 with Corey’s ylide (Method B,
Scheme 5),19 ring opened with azide ion20 and the intermediate
azides 17 and 18 reduced with sodium borohydride.21
Fig. 1
The β effect (particularly that of silicon) has been widely
exploited in synthetic organic chemistry.8–16 Silicon directs the
outcome of reactions, or rearrangements, which involve carb-
enium ion intermediates or polarised transition states. These
reactions are biased towards pathways which result in the
development of positive charge on the carbon β to the metal
substituent. For example, both silicon and tin substituents have
been demonstrated to exert a high degree of regiochemical con-
trol on the Baeyer–Villiger reaction of the cyclic ketones 1 and 2
resulting in the exclusive formation of the lactones 3 and 4 by
preferential insertion of the oxygen adjacent to the carbon
which is β to the silicon or tin substituent (Scheme 1).14–16
The acyclic ketones 19 and 20 were prepared by literature
methods22,23 and converted to the amino alcohols 21 and 22
using Method A.
Scheme 1
Tiffeneau–Demjanov reactions of 12–16, 21 and 22 were
effected by treating the amines with sodium nitrite in acetic acid
1
overnight.24,25 The product mixtures were analysed by H and
The directing effect of the silicon or tin substituent is believed
to manifest in the breakdown of the tetrahedral intermediate 5
(Scheme 2), the migrating carbon develops a partial positive
charge at the transition state, thus the carbon which is β to the
silicon or tin substituent migrates preferentially.
13C NMR, identification was made by comparison with known
compounds. The results of these are summarised in Table 1.
It is clear from the results summarised in Table 1 that both
silicon and tin direct the course of the Tiffeneau–Demjanov
ring expansion and chain extension reactions, however the
degree of regioselectivity is surprisingly low, although com-
parison of the regioselectivities for the ring expansions of both
isomers of 14 and 15 suggests that the regioselectivity is slightly
higher for the cis-isomers. This contrasts with the powerful
directing influence that these substituents have on the Baeyer–
Villiger reaction.
appointing result can be made by comparing the transition
states for these two reactions (Fig. 2).
A possible rationalisation of this dis-
Scheme 2
There are two fundamental differences between these
two transition states; the nature of the leaving group being
† Electronic supplementary information (ESI) available: experimental
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 4 8 – 6 5 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
648
Chow, Leonie
