Enantioselective palladium(II)-catalyzed formal [3,3]-sigmatropic rearrangement of 2-allyloxypyridines and related heterocycles

Article abstract of DOI:10.1021/ol9025759

(Figure Presented) Enantioselective palladium(II)-catalyzed formal [3,3]-sigmatropic rearrangement of (E)- and (Z)-allyloxy substituted N-heterocycles generates W-allyl N-heterocyclic amides In good yields and high enantioselectivities (up to 96% ee). The chiral palladacycle COP-Cl (5 mol %) Is used as a catalyst with silver(l) trifluoroacetate (10 mol %) at 35-45 °C. Examples of heterocycles synthesized include 2-pyridones, quinolin-2(1H)ones, and isoquinolin-1(2H)-ones.

Full text of DOI:10.1021/ol9025759

ORGANIC
LETTERS
2010
Vol. 12, No. 2
260-263
Enantioselective Palladium(II)-Catalyzed
Formal [3,3]-Sigmatropic Rearrangement
of 2-Allyloxypyridines and Related
Heterocycles†
Alessandro Rodrigues, Ernest E. Lee, and Robert A. Batey*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, M5S 3H6, Canada
rbatey@chem.utoronto.ca
Received November 5, 2009
ABSTRACT
Enantioselective palladium(II)-catalyzed formal [3,3]-sigmatropic rearrangement of (E)- and (Z)-allyloxy substituted N-heterocycles generates
N-allyl N-heterocyclic amides in good yields and high enantioselectivities (up to 96% ee). The chiral palladacycle COP-Cl (5 mol %) is used
as a catalyst with silver(I) trifluoroacetate (10 mol %) at 35-45 °C. Examples of heterocycles synthesized include 2-pyridones, quinolin-2(1H)-
ones, and isoquinolin-1(2H)-ones.
Methods for the asymmetric synthesis of chiral amines,
particularly those bearing a stereocenter R to the nitrogen
atom, are of considerable importance due to their presence
in natural products and pharmacologically active compounds.
Most approaches have focused upon the asymmetric syn-
thesis of chiral primary or secondary amines, as well as
R-amino acids.1 In contrast, direct approaches toward the
enantioselective synthesis of N-substituted heterocycles,
possessing a stereocenter R to the heterocyclic nitrogen atom,
are much less well explored. Conventional approaches to
chiral amine synthesis cannot often be directly applied to
these N-heterocycles, whereas indirect approaches, involving
conversion of chiral amines into the N-heterocycles, often
lack generality or occur in poor yields. One representative
class of such compounds are N-substituted 2-pyridones,
members of which possess interesting biological and phar-
macological properties, as exemplified by human rhinovirus
(HRV) protease inhibitor 1,2 glucokinase activator 2,3 and
the naturally occurring angiotension-converting enzyme
inhibitors A58365A and A58365B4 (Figure 1). Synthetic
approaches to these compounds have relied upon the indirect
synthesis of the pyridone ring from chiral amines.2,3,5
(2) Martinez, C. A.; Yazbeck, D. R.; Tao, J. Tetrahedron 2004, 60, 759–
764.
(3) Pfefferkorn, J. A.; Lou, J.; Minich, M. L.; Filipski, K. J.; He, M.;
Zhou, R.; Ahmed, S.; Benbow, J.; Perez, A.-G.; Tu, M.; Litchfield, J.;
Sharma, R.; Metzler, K.; Bourbonais, F.; Huang, C.; Beebe, D. A.; Oates,
P. J. Bioorg. Med. Chem. Lett. 2009, 19, 3247–3252.
(4) (a) Hunt, A. H.; Mynderse, J. S.; Samlaska, S. K.; Fukuda, D. S.;
Maciak, G. M.; Kirst, H. A.; Occolowitz, J. L.; Swartzendruber, J. K.; Jones,
N. D. J. Antibiot. 1988, 41, 771–779. (b) Mynderse, J. S.; Samlaska, S. K.;
Fukuda, D. S.; Du Bus, R. H.; Baker, P. J. J. Antibiot. 1985, 38, 1003–
1007. (c) O’Connor, S.; Somers, P. J. Antibiot. 1985, 38, 993–996.
(5) For syntheses, see: (a) Reichelt, A.; Bur, S. K.; Martin, S. F.
Tetrahedron 2002, 58, 6323–6328. (b) Straub, C. S.; Padwa, A. Org. Lett.
1999, 1, 83–85. (c) Clive, D. L. J.; Coltart, D. M.; Zhou, Y. J. Org. Chem.
1999, 64, 1447–1454. (d) Clive, D. L. J.; Coltart, D. M. Tetrahedron Lett.
1998, 39, 2519–2522. (e) Clive, D. L. J.; Zhou, Y.; de Lima, D. P. Chem.
Commun. 1996, 1463–1464. (f) Moeller, K. D.; Wong, P. L. J. Am. Chem.
Soc. 1993, 115, 11434–11445. (g) Moeller, K. D.; Wong, P. L. Bioorg.
Med. Chem. Lett. 1992, 2, 739–742. (h) Fang, F. G.; Danishefsky, S. J.
Tetrahedron Lett. 1989, 30, 3621–3624.
† Dedicated to Prof. George Fleet on the occasion of his 65th birthday.
(1) (a) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290–4299. (b)
Na´jera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584–4671.
10.1021/ol9025759  2010 American Chemical Society
Published on Web 12/17/2009

The goal of our study was to establish whether enantiose-
lective formal [3,3]-sigmatropic rearrangement of allyloxy
substituted N-heterocycles 5 could be achieved using metal
catalysis (Scheme 1). Venkataratnam demonstrated that Pd(II)-
catalyzed rearrangement of 2- allyloxypyridines at room tem-
perature proceeds cleanly to provide only the desired [3,3]-aza-
oxa-Cope products.9-11 Furthermore, chiral Pd(II) catalysts
have been demonstrated in other enantioselective 3-aza-1-
oxa-Cope rearrangements. Overman first demonstrated this
strategy in rearrangements of allylic imidates to allylic
amides.12,13 The strategy was also extended to related
reactions, such as the enantioselective rearrangements of
O-allyl carbamothioates to S-allyl carbamothioates14 and of
allyloxy iminophospholidines to allyl phosphoramides.15,16
These enantioselective variants have mainly used the com-
mercially available palladacyclic Pd(II) catalyst COP-Cl17
and related chiral palladacycle catalysts (Figure 2).
Figure 1. Examples of chiral 2-pyridones.
Direct approaches for the asymmetric synthesis of 2-py-
ridones and related heterocyclic compounds, therefore,
constitute an important challenge. We now report an enan-
tioselective formal [3,3]-sigmatropic rearrangement strategy
for the formation of pyridones and other heterocycles using
Pd(II) catalysis (Scheme 1). The approach uses readily available
Scheme 1. [3,3]-Sigmatropic Approach to Enantioselective
Formation of Chiral 2-Pyridones and Related Heterocycles
Figure 2. Planar chiral Pd(II) complex (S)-COP-Cl 7.
Allyloxypyridine (E)-8a was chosen as a test substrate for
the rearrangements and was accessed through a nucleophilic
(9) Reddy, A. C. S.; Narsaiah, B.; Venkataratnam, R. V. Tetrahedron
Lett. 1996, 37, 2829–2832
.
(10) Pd(0)-catalyzed rearrangement of E-crotyloxypyridine leads to a
mixture of both formal [1,3]- and [3,3]-sigmatropic rearranged products,
whereas Pd(II) leads to clean [3,3]-rearrangement: Itami, K.; Yamazaki,
D.; Yoshida, J. Org. Lett. 2003, 5, 2161–2164
.
(11) Limited success was found using Lewis acid and transition metal
catalyzed reactions, such as with SnCl4, BF3·OEt2, H2PtCl6, and Pt(PPh3)4.
See: (a) Stewart, H. F.; Seibert, R. P. J. Org. Chem. 1968, 33, 4560–4561.
(b) Balavoine, G.; Guibe, F. Tetrahedron Lett. 1979, 41, 3949–3952
.
allylic alcohols 3 as precursors. Nucleophilic aromatic substitu-
tion of heterocycles 4 by 3 was expected to generate allyloxy
substituted N-heterocycles 5, which could then undergo rear-
rangement to the product heterocycles 6.
Early studies by Moffett demonstrated thermal [3,3]-sigma-
tropic rearrangement of 2-allyloxypyridine into N-allyl 2-pyri-
done at 245 °C.6 Unfortunately, the high temperature required
for this reaction led to competing Cope rearrangement to
3-allylpyridone. Moreover, in the case of thermal rearrangement
of E-crotyloxypyridine (R ) Me), a mixture of products arising
from [3,3]-sigmatropic rearrangement, Cope rearrangement, and
formal [1,3]-sigmatropic rearrangement was observed.7,8
(12) For a general overview of the Overman rearrangement, see:
Overman, L. E.; Carpenter, N. E. The Allylic Trichloroacetimidate
Rearrangement. In Organic Reactions; Overman, L. E., Ed.; Wiley:
Hoboken, NJ, 2005; Vol. 66, pp 1-107. See also: Majumdar, K. C.; Alam,
S.; Chattopadhyay, B. Tetrahedron 2008, 64, 597–643
.
(13) For selected references, see: (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)
Kirsch, S. F.; Overman, L. E.; Watson, M. P. J. Org. Chem. 2004, 69,
8101–8104. (d) Anderson, C. E.; Overman, L. E.; Watson, M. P. Org. Synth.
2005, 82, 134–139. (e) Weiss, M. E.; Fischer, D. F.; Xin, Z.-q.; Jautze, S.;
Schweizer, W. B.; Peters, R. Angew. Chem., Int. Ed. 2006, 45, 5694–5698.
(f) Watson, M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc.
2007, 129, 5031–5044. (g) Fischer, D. F.; Xin, Z.-q.; Peters, R. Angew.
Chem., Int. Ed. 2007, 46, 7704–7707. (h) Jautze, S.; Seiler, P.; Peters, R.
Chem.sEur. J. 2008, 14, 1430–1444. (i) Swift, M. D.; Sutherland, A.
Tetrahedron 2008, 64, 9521–9527
.
(14) Overman, L. E.; Roberts, S. E.; Sneddon, H. F. Org. Lett. 2008,
10, 1485–1488.
(6) Moffett, R. B. J. Org. Chem. 1963, 28, 2885–2886.
(7) Dinan, F. J.; Tieckelmann, H. J. Org. Chem. 1964, 29, 892–895.
(8) Similar problems and low yields have been reported in the rear-
rangements of other 2-allyloxy N-heterocycles, such as tetrachloropyridines,
quinolines, isoquinolines, benzoxazoles, benzthiazoles, and tetrazoles. See:
(a) Iddon, B.; Hans, S.; Taylor, J. A. J. Chem. Soc., Perkin Trans. 1 1979,
2756–2761. (b) Makisumi, Y. Tetrahedron Lett. 1964, 5, 3822–3838. (c)
Win, H.; Tieckelmann, H. J. Org. Chem. 1967, 32, 59–61. (d) Elwood,
J. K.; Gates, J. W., Jr. J. Org. Chem. 1967, 32, 2956–2959.
(15) Lee, E. E.; Batey, R. A. J. Am. Chem. Soc. 2005, 127, 14887–
14893
.
(16) See also: (a) Lee, E. E.; Batey, R. A. Angew. Chem., Int. Ed. 2004,
43, 1865–1868. (b) Chen, B.; Mapp, A. K. J. Am. Chem. Soc. 2005, 127,
6712–6718
.
(17) For synthesis of COP-based Pd(II) catalysts, see: Anderson, C. E.;
Kirsch, S. F.; Overman, L. E.; Richards, C. J.; Watson, M. P. Org. Synth.
2007, 84, 148–155.
Org. Lett., Vol. 12, No. 2, 2010
261

aromatic substitution reaction of the corresponding allylic
alcohol on 2-bromopyridine. Deprotonation of (E)-2-penten-
1-ol using NaH and subsequent microwave heating of the
alkoxide at 160 °C with 2-bromopyridine led to the desired
product in good yield. Initial attempts for the rearrangement
of (E)-8a in CH2Cl2 (0.2 M solution) with 5 mol % (S)-
COP-Cl at room temperature provided the desired product
9a in low conversion (23%) but good enantioselectivity (90%
ee) (Table 1). The rearrangement proved to be clean, with
Table 2. Variation in the Rearrangement of Substituted
2-Allyloxypyridines 8 into Chiral 2-Pyridones 9
yielda ee (%)
entry substrate
R
product
(%)
(config)
1
2
3
4
5
6
7
8
(E)-8a
(Z)-8a
(E)-8b
(Z)-8b
(Z)-8c
(Z)-8d
(E)-8e
(Z)-8f
(Z)-8g
(Z)-8h
(Z)-8i
(Z)-8j
Et
Et
9a
9a
9b
9b
9c
9d
9e
9f
83
87
91
88
92
0
33
90
88
61
87
93
86 (S)
96 (R)
85 (S)
88 (R)
90 (R)
-
47 (R)
88 (S)
85 (S)
83 (R)
87 (R)
83 (R)
Table 1. Enantioselective Palladium(II)-Catalyzed
Rearrangement of 2-Allyloxypyridine 8a into 9a
nPr
nPr
nHex
Chx
Ph
CH2OTBDMS
CH2OTBDPS
(CH2)2OTBDMS
(CH2)3OBn
9
9g
9h
9i
[8a] tempb convn
ee
(%)
10
11
12
entry
solvent
AgOCOCF3
(M)
(°C)
(%)a
(CH2)2Ph
9j
1
2
3
4
5
6
7
a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
-
0.2
0.2
1.0
1.0
1.0
1.0
1.0
rt
rt
23
31
92
g98
67
90
90
86
87
87
88
82
a Isolated yields. b Reactions carried out in sealed vessels.
10 mol %
-
10 mol %
10 mol %
10 mol %
10 mol %
1
45
45
45
45
45
the enantiomer was obtained in 87% yield and with 96% ee
from substrate (Z)-8a. Similar results were obtained for the
other straight chain aliphatic derived substrates 8b-8c (Table
2, entries 3-5). The rearrangement reaction is however
sensitive to steric effects, and for the more sterically hindered
substrate 8d, bearing a cyclohexyl group, rearrangement did
not occur and only starting material was recovered (Table
2, entry 6). The cinnamyl alcohol derived substrate 8e reacted
sluggishly, providing the product 9e in low yield (33%) and
enantioselectivity (47%). The reaction occurred in good yields
and enantioselectivities for the TBDMS, TBDPS, and benzyl
ether substitued precursors 8f-i and for the phenylethyl-
substituted precursor 8j (Table 2, entries 8-12). Removal of
the TBDMS group from 9f provided the corresponding alcohol
10, the absolute configuration of which was determined as (S)
by X-ray crystallographic analysis (Figure 3). The absolute
benzene
toluene
g98
88
Conversion measured by H NMR. b Reactions carried out in sealed
vessels.
only unreacted starting material observed by 1H NMR
spectroscopy of the reaction mixture. Dechlorination of the
(S)-COP-Cl catalyst with 10 mol % AgOCOCF3 under the
same conditions afforded a small improvement in conversion
(31%) with no change in enantioselectivity (90% ee).
Increasing the reaction temperature to 45 °C and substrate
concentration to 1.0 M greatly improved the conversions for
both rearrangements with (S)-COP-Cl and the (S)-COP-Cl/
AgOCOCF3 combination (92% and g98%, respectively).
The increase in temperature also resulted in a slight decrease
in enantioselectivity (86% and 87% ee). Rearrangement of
(E)-8a with 5 mol % (S)-COP-Cl and 10 mol % AgOCOCF3
at 45 °C in MeCN resulted in lower conversion (67%), while
reaction in toluene provided 9a in slightly lower enantiose-
lectivity (82% ee). Reaction in benzene provided nearly
identical results to that obtained in CH2Cl2, and as a result
CH2Cl2 was selected as the optimal solvent.
The optimized conditions of (S)-COP-Cl (5 mol %) and
AgOCOCF3 (10 mol %) at 45 °C in CH2Cl2 were applied
toward the rearrangement of a variety of allyloxypyridine
substrates 8 (Table 2). The requisite substrates 8 were
obtained using microwave-assisted nucleophilic aromatic
substitution reactions.18 The (E)- and (Z)-pyridine substrates
8a both rearranged with good yield and enantioselectivity
at 45 °C (Table 2, entries 1 and 2). The product 9a was
obtained in 83% yield and with 86% ee from (E)-8a, while
Figure 3. Formation and X-ray crystal structure determination of
pyridone 10 to establish (S)-absolute stereochemistry of 9f.
configuration of the other products was assigned by analogy.
The absolute sense of stereoinduction matches that observed
in previous COP-Cl-based rearrangements.
(18) See the Supporting Information for details.
262
Org. Lett., Vol. 12, No. 2, 2010

The success of the enantioselective rearrangement of 8
prompted us to investigate related formal [3,3]-sigmatropic
rearrangements of other nitrogen heterocycles (Table 3). In
observed for the rearrangement of the (Z)-isomer (95% yield,
92% ee) than for the (E)-isomer (89% yield, 89% ee). A
similar trend in selectivity was observed for the benzothiazole
substrates (E)- and (Z)-11d which rearranged in good yield
(80% and 85%) and good enantioselectivity (83% and 92%
ee, respectively). More electron-deficient heterocycles such
as pyrimidine substrates 11e did not react under the optimal
conditions, and only starting material was recovered in these
reactions.20
Table 3. Rearrangement of 2-Allyloxy N-Heterocycles 11 into
12
The observation that the rearrangements of 8 and 11
occurred with better selectivity and yield for (Z)-substrates
than for (E)-substrates contrasts those obtained for the Pd(II)-
catalyzed rearrangements of allylic trichloroacetimidates13f
but is similar to that found for rearrangements of allyloxy
iminodiazaphospholidines15 and allylic N-(p-methoxyphe-
nyl)benzimidates.21
In summary, enantioselective formal [3,3]-rearrangement
of 2-allyloxy N-heterocycles occurs in good yields and high
enantioselectivities (up to 96% ee) using the commercially
available chiral palladacycle COP-Cl. The (Z)-substrates
show greater reactivity than the (E)-substrates, and the control
of absolute stereochemistry in the products is analogous to
that obtained for other COP-Cl-based formal [3,3]-sigma-
tropic rearrangements. Further applications of these methods
and related chemistry will be reported in due course.
Acknowledgment. The Natural Science and Engineering
Research Council (NSERC) of Canada funded this research.
EEL thanks NSERC for funding in the form of a PGS
scholarship. A.R. thanks Coordenac¸a˜o de Aperfeic¸oamento
de Pessoal de N´ıvel Superior (CAPES)-Brazil for a post-
doctoral fellowship. We also thank Dr. Alex Young (Uni-
versity of Toronto) for mass spectral analysis, Dr. Tim
Burrow (University of Toronto) for NMR assistance, and
Dr. Alan J. Lough (University of Toronto) for X-ray
crystallographic analysis.
b
a Isolated yields No reaction, only starting material observed by H
NMR.
1
Supporting Information Available: Detailed descriptions
of experimental procedures. Spectroscopic data of all new
compounds, chiral HPLC data, and an X-ray crystallographic
information file for 10 (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
the presence of 5 mol % (S)-COP-Cl/10 mol % AgOCOCF3
at 35 °C, pyridine 11a rearranged to 12a in good yield and
enantioselectivity. Rearrangement of the (E)- and (Z)-
quinoline substrates19 both occurred in good yields (Table
3). The (E)-substrate 11b produced 12b in 86% ee, while
(Z)-11b rearranged to the enantiomer in 95% ee. In the case
of the isoquinoline substrates 11c, better reactivity was
OL9025759
(20) 2-Allyloxypyrimidines have been reported to not undergo thermal
rearrangement at 200 °C. See ref 8d.
(19) Substrates 11a-e were prepared in a similar fashion to substrate
8 with conventional heating at 50 °C over 40 h instead of microwave
heating.
(21) Kang, J.; Kim, T. H.; Yew, K. H.; Lee, W. K. Tetrahedron:
Asymmetry 2003, 14, 415–418.
Org. Lett., Vol. 12, No. 2, 2010
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