A tandem aza-claisen rearrangement and ring closing metathesis reaction for the synthesis of cyclic allylic trichloroacetamides

Article abstract of DOI:10.1021/ol702299c

(Chemical Equation Presented) A one-pot tandem palladium(II)-catalyzed aza-Claisen rearrangement and ring closing metathesis process has been developed for the efficient synthesis of cyclic allylic trichloroacetamides. The use of chiral Pd(II) catalysts such as (S)-COP-Cl during the rearrangement stage results in the preparation of these compounds in excellent yields and in high enantiomeric excess.

Full text of DOI:10.1021/ol702299c

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5239-5242
A Tandem Aza-Claisen Rearrangement
and Ring Closing Metathesis Reaction
for the Synthesis of Cyclic Allylic
Trichloroacetamides
Michael D. Swift and Andrew Sutherland*
WestCHEM, Department of Chemistry, The Joseph Black Building, UniVersity of
Glasgow, Glasgow, UK G12 8QQ
andrews@chem.gla.ac.uk
Received September 25, 2007
ABSTRACT
A one-pot tandem palladium(II)-catalyzed aza-Claisen rearrangement and ring closing metathesis process has been developed for the efficient
synthesis of cyclic allylic trichloroacetamides. The use of chiral Pd(II) catalysts such as (S)-COP−Cl during the rearrangement stage results
in the preparation of these compounds in excellent yields and in high enantiomeric excess.
Interest in the development and application of tandem,
domino, and cascade processes continues to grow for obvious
reasons. These processes allow several transformations in
one synthetic operation, negating the need of handling and
isolating intermediates.1 Furthermore, the substantial reduc-
tion in waste generation using these processes has significant
benefits for the environment. One class of reaction that has
come to prominence in these processes is the ring closing
metathesis (RCM) reaction. For example, RCM has been
used in combination with dehydrogenation-hydrogenation
reactions,2 isomerizations,3 aza-Michael reactions,4 Claisen
rearrangements,5 Diels-Alder reactions,6 Kharasch addi-
tions,7 dihydroxylations,8 as well as ring opening metathesis
(ROM).9 The successful application of RCM to so many
tandem processes is mainly due to the continued development
of stable ruthenium alkylidene complexes used to catalyze
the transformation.
We recently reported the development of a diastereose-
lective Pd(II)-catalyzed ether-directed aza-Claisen (Overman)
rearrangement of allylic trichloroacetimidates,10 which has
been used for the synthesis of â- and γ-hydroxy-R-amino
acids.11 The products of these reactions were also easily
converted to dienes and used in RCM reactions for the
preparation of piperidines and pyrrolidines.12 During the
(1) For general reviews, see: (a) Tietze, L. F. Chem. ReV. 1996, 96,
115-136. (b) Pellissier, H. Tetrahedron 2006, 62, 1619-1665. (c) Pellissier,
H. Tetrahedron 2006, 62, 2143-2173. (d) Nicolaou, K. C.; Edmonds, D.
J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134-7186.
(2) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312-11313.
(3) (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J.
Am. Chem. Soc. 2002, 124, 13390-13391. (b) Schmidt, B. Eur. J. Org.
Chem. 2003, 816-819. (c) Schmidt, B. J. Org. Chem. 2004, 69, 7672-
7687. (d) Fustero, S.; Sa´nchez-Rosello´, M.; Jime´nez, D.; Sanz-Cervera, J.
F.; del Pozo, C.; Acen˜a, J. L. J. Org. Chem. 2006, 71, 2706-2714. (e)
Bo¨hrsch, V.; Blechert, S. Chem. Commun. 2006, 1968-1970.
(4) Fustero, S.; Jime´nez, D.; Sa´nchez-Rosello´, M.; del Pozo, C. J. Am.
Chem. Soc. 2007, 129, 6700-6701.
(5) Clark, D. A.; Kulkami, A. A.; Kalbarczyk, K.; Schertzer, B.; Diver,
S. T. J. Am. Chem. Soc. 2006, 128, 15632-15636.
(6) Lee, H.-Y.; Kim, H. Y.; Tae, H.; Kim, B. G.; Lee, J. Org. Lett. 2003,
5, 3439-3442.
(7) Seigal, B. A.; Fajardo, C.; Snapper, M. L. J. Am. Chem. Soc. 2005,
127, 16329-16332.
(8) Beligny, S.; Eibauer, S.; Maechling, S.; Blechert, S. Angew. Chem.,
Int. Ed. 2006, 45, 1900-1903.
(9) Liu, Z.; Rainier, J. D. Org. Lett. 2006, 8, 459-462.
(10) Overman, L. E.; Carpenter, N. E. In Organic Reactions; Overman,
L. E., Ed.; Wiley: Hoboken, NJ, 2005; Vol. 66, pp 1-107 and references
therein.
10.1021/ol702299c CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/09/2007

development of this directed rearrangement process and in
an effort to optimize the diastereoselectivity of the reaction,
a series of metal complexes were screened as catalysts.13
Interestingly, it was found that ruthenium complexes do not
catalyze the Overman rearrangement. This led to our proposal
of a one-pot tandem process for the synthesis of cyclic allylic
trichloroacetamides involving a palladium-catalyzed Over-
man rearrangement followed by a ruthenium-catalyzed RCM
reaction of the resulting diene (Scheme 1). One of the reasons
Scheme 2. Synthesis of E-Allylic Alcohol 3
Scheme 1. One-Pot Tandem Aza-Claisen Rearrangement and
RCM Reaction
Allylic alcohol 3 was then converted to allylic trichloro-
acetimidate 4 using trichloroacetonitrile and a catalytic
amount of DBU (Scheme 3).20 An initial attempt at preparing
Scheme 3. Development of the One-Pot Reaction
for our interest in developing such a process for the synthesis
of these compounds is that cyclic allylic trichloroacetamides
have been widely used as substrates for a range of reactions
including dihydroxylations,14 epoxidations,15 Kharasch,7,16
and other types of cyclization reactions.17
In this paper, we now report a one-pot tandem rearrange-
ment and RCM reaction for the highly efficient synthesis of
cyclic allylic trichloroacetamides as well as the use of chiral
Pd(II) catalysts for the development of an asymmetric version
of this process.
Initial investigations began with developing this one-pot
process for the synthesis of a six-membered cyclic allylic
trichloroacetamide. Accordingly, the corresponding allylic
alcohol 3 was prepared in two steps from 5-hexen-1-ol 1 as
outlined in Scheme 2. Thus, the use of a one-pot Swern
oxidation and Horner-Wadsworth-Emmons (HWE) reac-
tion18,19 gave (E)-R,â-unsaturated ester 2 in 69% yield.
Subsequent reduction of ester 2 using DIBAL-H gave allylic
alcohol 3 in 87% yield.
(11) (a) Jamieson, A. G.; Sutherland, A. Org. Biomol. Chem. 2005, 3,
735-736. (b) Jamieson, A. G.; Sutherland, A. Tetrahedron 2007, 63, 2123-
2131. (c) Fanning, K. N.; Jamieson, A. G.; Sutherland, A. Org. Biomol.
Chem. 2005, 3, 3749-3756. (d) Swift, M. D.; Sutherland, A. Org. Biomol.
Chem. 2006, 4, 3889-3891.
cyclic allylic trichloroacetamide 6 in a one-pot process by
adding both the rearrangement and RCM catalysts (10 mol
% of both) at the start of the reaction and heating the reaction
mixture under reflux returned only rearrangement product
5. As the Overman rearrangement takes place at room
temperature, a second attempt involved the addition of both
catalysts and allowed the rearrangement to take place at room
temperature (∼3 h), before heating the reaction under reflux
to effect the RCM reaction. However, this also gave only
rearrangement product 5. These results suggested that the
RCM catalysts used in these attempts, Grubbs first-genera-
tion, Grubbs second-generation,21 and Hoveyda-Grubbs
(12) Jamieson, A. G.; Sutherland, A. Org. Lett. 2007, 9, 1609-1611.
(13) Jamieson, A. G.; Sutherland, A. Org. Biomol. Chem. 2006, 4, 2932-
2937.
(14) (a) Donohoe, T. J.; Blades, K.; Helliwell, M.; Moore, P. R.; Winter,
J. J. G. J. Org. Chem. 1999, 64, 2980-2981. (b) Donohoe, T. J.; Blades,
K.; Moore, P. R.; Waring, M. J.; Winter, J. J. G.; Helliwell, M.; Newcombe,
N. J.; Stemp, G. J. Org. Chem. 2002, 67, 7946-7956.
(15) O’Brien, P.; Childs, A. C.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.;
Dearden, M. J.; Oxenford, S. J.; Rosser, C. M. Org. Lett. 2003, 5, 4955-
4957.
(16) Nagashima, H.; Wakamatsu, H.; Ozaki, N.; Ishii, T.; Watanabe, M.;
Tajima, T.; Itoh, K. J. Org. Chem. 1992, 57, 1682-1689.
(17) (a) Cardillo, G.; Orena, M.; Sandri, S. J. Chem. Soc., Chem.
Commun. 1983, 1489-1490. (b) Cassayre, J.; Dauge, D.; Zard, S. Z. Synlett
2000, 471-474.
(18) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198-
2200.
(19) For high yielding preparation of (E)-alkenes from the one-pot Swern
oxidation and HWE reaction, we use Masamune-Roush conditions for the
HWE step. For reference, see: Blanchette, M. A.; Choy, W.; Davis, J. T.;
Essenfeld, A. P.; Masumune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183-2186.
(20) Anderson, C. E.; Overman, L. E.; Watson, M. P. Org. Synth. 2005,
82, 134-139.
(21) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. Acc. Chem. Res. 1995, 28,
446-452. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-
29.
5240
Org. Lett., Vol. 9, No. 25, 2007

second-generation catalysts,22 were all decomposing, prob-
ably due to a side reaction with the Pd(II) catalyst, before
completion of the rearrangement step. To overcome this, a
one-pot reaction was attempted involving stepwise addition
of the catalysts. Thus, addition of bis(acetonitrile)palladium-
(II) chloride to allylic trichloroacetimidate 4 and stirring the
reaction mixture at room temperature for 3 h followed by
the addition of Grubbs first-generation catalyst and heating
under reflux allowed the one-pot tandem synthesis of 6 in
an excellent 89% yield over the three steps from allylic
alcohol 3 (Scheme 3 and Table 1).23 Similar results were
we sought to expand the scope of this process for the
preparation of other ring sizes. A series of allylic trichloro-
acetimidates, 7, 9, and 11 (Table 1) were prepared as
described for compound 4. Reaction of allylic trichloroace-
timidate 7 using the one-pot tandem procedure under the
same conditions as for 4 (substrate concentration of 0.08 M
and 10 mol % of both catalysts) produced cyclopentene
analogue 8 in 84% yield from the corresponding allylic
alcohol. Attempted synthesis of the cycloheptene
analogue 10 using these standard conditions gave a mixture
of the desired and dimeric products. However, repeating the
reaction under more dilute conditions (0.005 M)25 allowed
the isolation of 10 in an excellent 93% yield over the three
steps.
Table 1. Synthesis of Different Ring Sizes
Surprisingly, use of these optimized conditions for the
synthesis of the cyclooctene analogue 12 gave only the
rearrangement product, suggesting that Grubbs first-
generation catalyst was unable to form the eight-
membered ring.26 Careful experimentation with other cata-
lysts using higher catalyst loadings and more dilute
reaction mixtures did yield 12. For example, the use of 20
mol % of Grubbs second-generation catalyst and a
substrate concentration of 0.0013 M gave cyclooctene 12 in
62% yield.
Our aim in developing a simple, one-pot tandem process
for the highly efficient synthesis of cyclic allylic trichloro-
acetamides was for application in natural product synthesis.
To realize this goal, the development of an asymmetric
process for the enantioselective synthesis of these com-
pounds was necessary. In 2003, Overman and co-workers
reported a new chiral palladium catalyst, (S)-COP-Cl (13)
(Scheme 4), which could catalyze the asymmetric rearrange-
ment of allylic trichloroacetimidates in high yields and
with excellent enantioselectivity.20,27 Using this catalyst
or the R-enantiomer (both of which are commercially
available) during the first stage of our one-pot tandem
rearrangement and RCM process allowed the asymmetric
synthesis of cyclohexenes 14 and 15 (Scheme 4). For
example, treatment of allylic trichloroacetimidate 4 with
(S)-COP-Cl (13) at room temperature followed by the
addition of Grubbs first-generation catalyst and heating the
reaction mixture under reflux gave the S-enantiomer 14 in
an excellent 90% yield from allylic alcohol 3 and in 88%
ee.28 Similar results were obtained for the synthesis of the
R-enantiomer 15 using (R)-COP-Cl. In this study, these
a RCM step was done using Grubbs second-generation catalyst.
(24) As highlighted in Scheme 3, use of Grubbs second-generation and
Hoveyda-Grubbs second-generation catalysts gave cyclic allylic trichlo-
roacetamide 6 in slightly higher yield than with the Grubbs first-generation
catalyst. Nevertheless, in developing the subsequent reactions, we have used
mainly Grubbs first-generation catalyst due to its relatively low cost and
availability compared to the other catalysts.
(25) Hodgson, D. M.; Robinson, L. A.; Jones, M. L. Tetrahedron Lett.
1999, 40, 8637-8640.
(26) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem.
Soc. 1995, 117, 2108-2109.
obtained using Grubbs second-generation and Hoveyda-
Grubbs second-generation catalysts.24
Having successfully determined the reaction conditions for
a one-pot synthesis of cyclic allylic trichloroacetamide 6,
(27) (a) Overman, L. E.; Owen, C. E.; Pavan, M. M.; Richards,
C. J. Org. Lett. 2003, 5, 1809-1812. (b) Anderson, C. E.; Overman,
L. E. J. Am. Chem. Soc. 2003, 125, 12412-12413. (c) Watson,
M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007, 129, 5031-
5044.
(28) The enantiomeric excess of compounds 14 and 15 was determined
by chiral HPLC. See Supporting Information for full details.
(22) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179.
(23) Allylic trichloroacetimidates are relatively unstable and, therefore,
are not subjected to extensive purification. Hence, yields quoted for the
preparation of the cyclic allylic trichloroacetamides are from the corre-
sponding allylic alcohols.
Org. Lett., Vol. 9, No. 25, 2007
5241

use of these catalysts during the one-pot rearrangement and
RCM reaction of allylic trichloroacetimidates 7, 9, and 11
should lead to the asymmetric synthesis of the five-, seven-
and eight-membered analogues with similar enantioselec-
tivity.
Scheme 4. Development of the Asymmetric Tandem Reaction
In summary, we have developed a facile one-pot tandem
process for the highly efficient synthesis of cyclic allylic
trichloroacetamides that utilizes a palladium-catalyzed Over-
man rearrangement at room temperature followed by a
ruthenium-catalyzed RCM reaction under reflux. This process
is flexible enough for the preparation of various ring sizes,
and using commercially available chiral palladium catalysts
during the first stage allows the asymmetric synthesis of these
compounds in high enantiomeric excess. Further work is
currently underway to expand this two-step tandem process
to include additional reactions and to examine the synthetic
application of cyclic allylic trichloroacetamides in natural
product synthesis.
Acknowledgment. Financial support from EPSRC (DTA
award) and the University of Glasgow is gratefully acknowl-
edged. We would also like to thank Mikhail A. Kabeshov
and Dr. Andrei V. Malkov (University of Glasgow) for kind
assistance with chiral HPLC.
Supporting Information Available: Full experimental
procedures, spectroscopic data, and NMR spectra for all
compounds synthesized. This material is available free of
charge via the Internet at http://pubs.acs.org.
chiral catalysts were only used for the asymmetric synthesis
of the cyclohexene analogues. However, we believe the
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