A highly stereoselective ether directed palladium catalysed aza-Claisen rearrangement

Article abstract of DOI:10.1039/b501346c

A highly stereoselective rearrangement of allylic trichloroacetimidates to allylic trichloroamides has been achieved using adjacent ether groups to direct facial coordination of the palladium(II) catalyst. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b501346c

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C O M M U N I C A T I O N
A highly stereoselective ether directed palladium catalysed
aza-Claisen rearrangement†
Andrew G. Jamieson and Andrew Sutherland*
Department of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow,
UK G12 8QQ. E-mail: andrews@chem.gla.ac.uk; Fax: 0141 330 4888; Tel: 0141 330 5936
Received 6th October 2004, Accepted 26th January 2005
First published as an Advance Article on the web 7th February 2005
A highly stereoselective rearrangement of allylic trichloro-
acetimidates to allylic trichloroamides has been achieved
using adjacent ether groups to direct facial coordination of
the palladium(II) catalyst.
The thermal and metal-catalysed [3,3]-sigmatropic rear-
rangement of allylic trichloroacetimidates to give allylic
Scheme 2 Directed aza-Claisen rearrangement.
trichloroamides has found widespread use in synthetic organic
chemistry.1 Like other [3,3]-sigmatropic rearrangements, the
reaction pathway progresses via a highly ordered chair-like
transition state which allows the shift of stereochemical infor-
1b
mation from reactant to product. Moreover, the palladium(II)
catalysed version of this reaction is carried out under extremely
mild conditions allowing the isolation of products in high
1a,2
yields and excellent regio- and stereoselectivities. The metal
catalysed reaction has been studied by the groups of Overman
and Bosnich and shown to follow a stepwise pathway involving
intramolecular amino palladation of the alkene followed by re-
ductive elimination to generate the amide products (Scheme 1).3
Scheme 1 Palladium catalysed aza-Claisen rearrangement.
Scheme 3 Reagents and conditions: i. see reference 6; ii. DIBAL-H (1.05
eq.), Et2O, −78 ◦C; iii. triethyl phosphonoacetate, LiCl, DBU, MeCN;
iv. DIBAL-H (2.2 eq.), Et2O, −78 ◦C; v. DMSO, (COCl)2, NEt3, CH2Cl2,
−78 ◦C to RT, then triethyl phosphonoacetate, LiCl, DBU, yields of 6
from 1, Bn (46%), Tr (62%), TBDMS (26%), Me (16%), MOM (34%),
MEM (25%); vi. NaH, Cl3CCN, 0 ◦C.
More recently, efforts have focused on developing an asym-
metric palladium(II) catalysed aza-Claisen reaction of trichloro-
acetimidates. The best results to date have been achieved by
the Overman group using chiral palladium diamine complexes.4
Following on from our previous work on chiral rearrangements5
we envisaged a different approach involving the use of an
adjacent chiral functional group to initially coordinate to the
palladium catalyst and direct the metal intramolecularly to one
face of the alkene resulting in a diastereoselective rearrangement
(Scheme 2). We now report our preliminary investigations on the
use of ether groups to direct, diastereoselective, palladium(II)
catalysed rearrangements of allylic trichloroacetimidates.
In an effort to quantify the directing effect of different ether
groups in such a rearrangement process, a series of allylic tri-
chloroacetimidate substrates were synthesised (Scheme 3). Ether
derivatives of (S)-ethyl lactate 1 were prepared using standard
procedures,6 and these were then converted into the correspond-
ing aldehydes 3 using DIBAL-H. Subsequent reaction with tri-
ethyl phosphonoacetate under Horner–Wadsworth–Emmons
(HWE) conditions yielded the E-allylic esters 5, which were
then reduced to the allylic alcohols 6 again using DIBAL-H
as the reducing agent. Finally reaction with sodium hydride
and trichloroacetonitrile using the Overman protocol7 gave
substrates 7 for the rearrangement reaction. Decomposition
and volatility problems associated with the Me and MOM
substituted aldehydes were overcome by reducing these com-
pounds to the corresponding alcohols 4. A one-pot, Swern
oxidation–HWE reaction8 gave the E-allylic esters and these
were then converted into the desired Me and MOM ether allylic
trichloroacetimidates in a similar manner.
† Electronic supplementary information (ESI) available: Experimental
data and characterisation of compounds. See http://www.rsc.org/
suppdata/ob/b5/b501346c/
Allylic trichloroacetimidates 7 were subjected to rearrange-
ment conditions using bis(acetonitrile)palladium(II) chloride as
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 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 5 – 7 3 6
7 3 5
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Table 1 Palladium(II) catalysed rearrangement of trichloroacetimi-
dates 7
highly diastereoselective rearrangement. However, we sought
further evidence and this was achieved by investigating the
palladium catalysed rearrangement of a carbon analogue of the
MOM ether substrate. Substrate 11 was synthesized from (2R)-
2-methylhexanol11 10 in an analogous manner to that already
described for the corresponding MOM compound (Scheme 5).
Rearrangement of 11 using bis(acetonitrile)palladium(II) chlo-
ride gave the allylic trichloroamide product 12 in only a 2 : 1 ratio
of diastereomers thereby confirming that the highly selective
rearrangement observed for the Me, MOM and MEM ether
substrates takes place via an ether directed process.
Entry
R
Yielda (%)
Ratiob (8a : 8b)
1
2
3
4
5
6
TBDMS
Tr
Bn
Me
MOM
MEM
68%
70%
62%
49%
64%
60%
2 : 1
3 : 1
3 : 1
7 : 1
10 : 1
8 : 1
a Isolated combined yields of 8a and 8b from allylic alcohol 6. b Ratio in
crude reaction mixture.
the catalyst. As expected, the bulky, sterically hindered ether
groups (entries 1, 2, and 3) prevent efficient coordination to the
palladium resulting in allylic trichloroamides 8a and 8b in low
diastereoselectivity (Table 1).9,10 However, switching to the much
smaller methyl ether (entry 4) now allows effective coordination
to the catalyst leading to a substantial increase in diastereoselec-
tivity. This success prompted us to investigate whether additional
oxygen atoms within the ether moiety could enhance this effect
and indeed the use of the MOM group (entry 5) gave 8a and 8b
in an excellent 10 : 1 ratio. Further enhancement with the MEM
group (entry 6) was attempted and while the use of this group
does lead to a highly selective rearrangement, no improvement
on the MOM group was observed.
Scheme 5 Reagents and conditions: i. a) DMSO, (COCl)2, NEt3,
CH2Cl2, −78 ◦C to RT, then triethyl phosphonoacetate, LiCl, DBU,
34% over two steps, b) DIBAL-H (2.2 eq.), Et2O, −78 ◦C, 45%, c) NaH,
Cl3CCN, 0 ◦C, 60%; ii, PdCl2(MeCN)2, THF, 59%.
The stereochemistry of the major diastereomer can be ex-
plained if the reacting conformer is 9a, which is formed initially
by coordination of the palladium(II) metal centre to the ether
oxygen (Scheme 4). This then directs the catalyst to the back
face of the alkene, resulting in the allylic trichloroacetimidate
adopting a chair-like conformation in which allylic 1,3 strain
is minimized and where intramolecular attack can only take
place from the front face of the alkene leading to the major
diastereomer 8a. The minor diastereomer 8b is likely formed
from reacting conformer 9b where the catalyst coordinates
directly to the least hindered, front face of the alkene forcing
the rearrangement to proceed from the back face. Thus, for
substrates containing bulky ether groups that cannot efficiently
coordinate to the catalyst, this second pathway now becomes
more competitive than for the smaller substrates leading to the
observed, low diastereoselectivities.
In conclusion, we have demonstrated the use of ether groups
to effectively direct facial coordination of palladium during
the aza-Claisen rearrangement of allylic trichloroacetimidates
resulting in a highly diastereoselective process. Further investiga-
tion of the use of other directing groups during rearrangements
and the application of this process to natural product synthesis
is currently underway.
The authors wish to thank EPSRC (studentship to AGJ) and
the University of Glasgow for funding.
References
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6 T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic
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9 Determination of the diastereomeric ratio of the rearrangement
reactions was carried out by analysis of the 1H NMR spectra of
the crude reaction mixtures.
10 The relative stereochemistry of the rearrangement products was
determined by conversion of the allylic trichloroamides 8 into the
corresponding oxazolidin-2-ones (see supplementary information†).
Using NOE experiments then allowed assignment of the major
diastereomer.
11 A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky and
J. L. Gleason, J. Am. Chem. Soc., 1997, 119, 6496.
Scheme 4 Reacting conformations that lead to the major and minor
diastereomers.
These results strongly implicate the involvement of the
ether oxygen atoms in directing facial coordination of the
palladium catalyst to one face of the alkene resulting in a
7 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 5 – 7 3 6