Catalytic asymmetric synthesis of chiral allylic amines. Evaluation of ferrocenyloxazoline palladacycle catalysts and imidate motifs

Article abstract of DOI:10.1021/jo048490r

(Chemical Equation Presented) Palladium(II) catalysts based on a ferrocenyloxazoline palladacyclic (FOP) scaffold were synthesized and evaluated for the rearrangement of prochiral allylic N-(4-methoxyphenyl)benzimidates. When iodide-bridged dimer FOP precatalysts are activated by reaction with excess silver trifluoroacetate, the allylic rearrangement of both E and Z prochiral primary allylic N-(4-methoxyphenyl)-benzimidates takes place at room temperature to give the corresponding chiral allylic N-(4-methoxyphenyl)benzamides in high yield and good ee (typically 81-95%). Several allylic imidate motifs were evaluated also. Because the corresponding enantioenriched allylic amide products can be deprotected in good yield to give enantioenriched allylic amines, allylic N-aryltrifiuoroacetimidates were identified as promising substrates.

Full text of DOI:10.1021/jo048490r

Catalytic Asymmetric Synthesis of Chiral Allylic Amines.
Evaluation of Ferrocenyloxazoline Palladacycle Catalysts and
Imidate Motifs
Carolyn E. Anderson, Yariv Donde, Christopher J. Douglas, and Larry E. Overman*
Department of Chemistry, 516 Rowland Hall, University of California, Irvine, California 92697-2025
leoverma@uci.edu
Received August 27, 2004
Palladium(II) catalysts based on a ferrocenyloxazoline palladacyclic (FOP) scaffold were synthesized
and evaluated for the rearrangement of prochiral allylic N-(4-methoxyphenyl)benzimidates. When
iodide-bridged dimer FOP precatalysts are activated by reaction with excess silver trifluoroacetate,
the allylic rearrangement of both E and Z prochiral primary allylic N-(4-methoxyphenyl)-
benzimidates takes place at room temperature to give the corresponding chiral allylic N-(4-
methoxyphenyl)benzamides in high yield and good ee (typically 81-95%). Several allylic imidate
motifs were evaluated also. Because the corresponding enantioenriched allylic amide products can
be deprotected in good yield to give enantioenriched allylic amines, allylic N-aryltrifluoroacetimidates
were identified as promising substrates.
SCHEME 1. Pd(II)-Catalyzed Allylic Imidate
Rearrangement
Introduction
The [3,3]-rearrangement of allylic imidates is a widely
used reaction for the allylic interchange of alcohol and
amine functionality.1 Complexes of soft metal salts,
particularly those of mercury(II)2 and palladium(II),1a
catalyze the rearrangement of allylic trichloroacetimi-
dates and allow this transformation to be carried out at
temperatures much lower than those required to facili-
tate the rearrangement thermally.1 Substantial evidence
suggests that the catalyzed rearrangement proceeds by
a cyclization-induced rearrangement mechanism, which
is illustrated in Scheme 1 for a palladium(II) catalyst.1
Recent investigations in these laboratories have fo-
cused on the development of asymmetric palladium(II)
catalysts for the addition of external (nonmetal bound)
nucleophiles to prochiral alkenes.3-5 Such asymmetric
alkene activation is exemplified by the catalytic asym-
metric rearrangement of N-arylbenzimidates 5a to chiral
N-arylbenzamides 6a3a and the transformation of allylic
alcohol 7 to N-sulfonyl 2-oxazolidinone 8 (Scheme 2).5 In
both cases, the catalyst was generated in situ by reaction
of iodide-bridged ferrocene oxazoline palladacycle (FOP)
9a with an excess of silver trifluoroacetate.6
Since our initial report of the catalytic asymmetric
rearrangement of allylic N-arylbenzimidates using cat-
ionic Pd(diamine) complexes such as 10 and cationic Pd-
(bis-oxazoline) complexes,3b several additional chiral
(1) (a) Overman, L. E. Acc. Chem. Res. 1980, 13, 218-224. (b)
Overman, L. E. Angew. Chem., Int. Ed. Eng. 1984, 23, 579-586. (c)
Metz, P.; Mues, C.; Schoop, A. Tetrahedron 1992, 48, 1071-1080. (d)
Schenck, T. G.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2058-2066.
(2) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597-599. (b)
Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901-2910.
(3) (a) Donde, Y.; Overman, L. E. J. Am. Chem. Soc. 1999, 121,
2933-2934. (b) Calter, M.; Hollis, T. K.; Overman, L. E.; Ziller, J.;
Zipp, G. G. J. Org. Chem. 1997, 62, 1449-1456. (c) Hollis, T. K.;
Overman, T. K. Tetrahedron Lett. 1997, 38, 8837-8840. (d) Cohen,
F.; Overman, L. E. Tetrahedron: Asymmetry 1998, 9, 3213-3222.
(4) (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.; Overman, L.
E.; Watson, M. P. J. Org. Chem. 2004, 69, 8101-8104.
(5) Overman, L. E.; Remarchuk, T. P. J. Am. Chem. Soc. 2002, 124,
12-13.
(6) The ferrocene moiety in the catalyst generated under these
conditions has been shown recently to be a ferrecenium cation; see:
Remarchuk, T. P. Ph.D. Dissertation, University of California, Irvine,
2003.
10.1021/jo048490r CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/21/2004
648
J. Org. Chem. 2005, 70, 648-657

Asymmetric Synthesis of Chiral Allylic Amines
ligands.3,4 Palladacyclic catalysts containing a metal-
locene fragment, including the FOP precatalyst 9a3a and
the COP catalysts 15a and 15b,4 emerged from these
investigations as being particularly effective. By design,
these catalysts project substituents above and below the
palladium(II) square plane, a topography that should be
particularly effective for influencing enantioselective
steps that involve square-based pyramidal intermediates
or transition states.8
SCHEME 2. Reactions Catalyzed by FOP Complex
9a
In this paper, we describe in full detail the synthesis
and evaluation of FOP precatalysts 9a and 40 (Scheme
5), the first precatalysts reported that, when activated,
achieved >90% ees in the production of chiral allylic
amides from prochiral allylic imidates.3a We also describe
the synthesis and evaluation of a small library of other
FOP catalysts that vary in both the relative orientation
of the chiral oxazoline and CpFe fragments and in the 3
substituent of the palladated cyclopentadienyl ring.
Studies aimed at identifying imidates other than allylic
N-arylbenzimidates that rearrange in high yields and
high enantioselectivities, and whose allylic amide prod-
ucts are deprotected efficiently to form the corresponding
allylic amines, are reported also.
palladium(II) catalysts have been described by our
group3,4 (complexes 12, 14a, and 14b) and others7 (com-
plexes 11, 13, 16a, and 16b) for this transformation
(Figure 1). The major reaction pathway competing with
the allylic imidate rearrangement, observed with the
earliest catalysts,3b is ionization of the allylic imidate to
give an allylic cation that then loses a proton to form
diene products or is trapped indiscriminately by nucleo-
philes in the reaction mixture. This process undoubtedly
is promoted by coordination of the imidate nitrogen to
the palladium catalyst.3b,7a Our recent work has focused
on asymmetric Pd(II) catalysts that differ from the early
dicationic catalysts by containing two monoanionic
Results
A. Synthesis of Ferrocenyl Oxazoline Pallada-
cycles. Ferrocenyl oxazoline palladacycles 9a, 23, and
24 were prepared from the known enantioenriched fer-
rocenyl oxazoline 17 (Scheme 3).9 Ortholithiation of
ferrocene 17 with s-BuLi, followed by quenching of the
resulting lithium reagent with either chlorotrimethyl-
silane or chlorotriethylsilane, provided disubstituted
ferrocenes 18 and 19 in 70% and 77% yield, respectively.
In both cases, diastereoselection was observed to be
greater than 20:1.9 The minor diastereomer formed in
each case could be removed by recrystallization from
hexanes to provide chiral ferrocenes 18 and 19 as single
diastereomers. Ortholithiation of diastereomerically pure
ferrocenes 18 and 19 with t-BuLi, followed by reaction
of the resulting lithium intermediates with diiodoethane,
provided iodides 20 and 21 in 70% and 95% yield,
respectively.10,11 Removal of the TMS group of ferrocene
20 occurred in high yield upon reaction with TBAF in
refluxing THF. In this way, access to disubstituted
ferrocenyl iodide 22 was achieved. Subsequent reaction
of iodides 20, 21, and 22 with 1 equiv of Pd2(dba)3‚CHCl3
at room temperature provided iodide-bridged dimers 9a,
(7) (a) Uozumi, Y.; Kato, K.; Hayashi, T. Tetrahedron: Asymmetry
1998, 9, 1065-1072. (b) Jiang, Y.; Longmire, J. M.; Zhang, X.
Tetrahedron Lett. 1999, 40, 1449-1450. (c) Leung, P,-H.; Ng, K.-H.;
Li, Y.; White, A. J. P.; Williams, D. J. Chem. Commun. 1999, 2435-
2436. (d) Kang, J.; Yew, K. H.; Kim, T. H.; Choi, D. H. Tetrahedron
Lett. 2002, 43, 9509-9512. (e) Kang, J.; Kim, T. H.; Yew, K. H.; Lee,
W. K. Tetrahedron: Asymmetry 2003, 14, 415-418.
(8) For a brief discussion of catalyst design and a review of our early
work in this area, see: Hollis, T. K.; Overman, L. E. J. Organomet.
Chem. 1999, 576, 290-299.
(9) Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995,
60, 10-11.
(10) These conditions are adapted from the following: Rebiere, F.;
Samuel, O.; Kagan, H. B. Tetrahedron Lett. 1990, 31, 3121-3124.
(11) A slight deficiency of t-BuLi was employed in these reactions
to minimize the formation of side products resulting from lithiation of
both Cp ligands of the ferrocene.
FIGURE 1. Asymmetric catalysts for the rearrangement of
allylic N-arylbenzimidates.
J. Org. Chem, Vol. 70, No. 2, 2005 649

Anderson et al.
SCHEME 3. Synthesis of FOP Complexes
SCHEME 4. Synthesis of Aryl-Substituted FOP
Complexes
23, and 24 in 86%, 73%, and 75% yields, respectively;12
complexes 9a and 23 have the S,Sp configuration and 24
has the S,Rp configuration.13 These complexes are air-
stable and can be purified by column chromatography
on silica gel or florisil. The 1H NMR spectra of these
palladacyclic complexes show that they exist in solution
as a cis/trans mixture about the Pd square planes (Figure
2); a single C1 symmetric isomer is ruled out because the
TABLE 1. Synthesis of Arylpalladacycles 29-36
26a-h,
yield (%)
27a-h,
yield (%)
29-36,
entry
aryl (Ar)
yield (%)
1
2
3
4
5
6
7
8
Ph
a, 84
b, 88
c, 33a
d, 20
e, 92
f, 89
a, 78
b, 73
c, 57
d, 61
e, 66
f, 74
g, 80
h, 80
29, 81
30, 90
31, 89
32, 90
33, 98
34, 81
35, 90
36, 79b
4-MeOC6H4
4-CF3C6H4
2,6-(MeO)2C6H3
1-C10H7
2-MeC6H4
2-MeOC6H4
4-MeSC6H4
g, 83
h, 76
a Suzuki coupling required 4 equiv of 4-trifluoromethylphenyl-
boronic acid. b Ar ) 4-MeSO2C6H4 (see Scheme 4).
4).4a,15 Coupling eight commercially available arylboronic
acids with iodide 25 in the presence of PdCl2dppf‚CH2-
Cl2 (10 mol %) and aqueous NaOH in DME at 85 °C
provided the aryl ferrocenyl oxazoline complexes 26a-h
(Scheme 4, Table 1).16 The steric environment presented
by the boronic acids affected the efficiency of these cross
coupling reactions. For example, aryl boronic acids
containing one ortho substituent coupled with iodide 25
in good to excellent yields (entries 5-7, 83-92%). Con-
versely, coupling of 2,6-dimethoxyphenylboronic acid with
iodide 25 was inefficient, occurring in only 20% yield
(entry 4); in this case, longer reaction times did not
improve the yield of the cross-coupled product 26d, with
iodide 25 being recovered. Arylboronic acids containing
an electron-releasing substituent coupled in good yields
(entries 2, 6-8; 76-89%), whereas arylboronic acids
containing electron-withdrawing groups coupled poorly
or not at all. In the case of (4-trifluoromethyl)phenyl-
boronic acid, 4 equiv of the arylboronic acid was required
to realize even a low yield of the coupled product 26c
(entry 3, 33%).17 Other electron-deficient aryl boronic
FIGURE 2. Isomers about the palladium square plane of
iodide-bridged dimer 9a.
signals for the two isomers do not occur in a 1:1 ratio.
Alternate approaches to this family of catalysts involving
direct cyclopalladation or transmetalation were less
successful, presumably because the Pd(II) salts employed
in these procedures promoted oxidative decomposition of
the ferrocene unit.14
A collection of additional ferrocenyl oxazoline pallada-
cyclic complexes were synthesized from (Sp)-2-[(4S)-4,5-
dihydro-tert-butyl-2-oxazolyl]-1-iodoferrocene 25 (Scheme
(12) For other examples using oxidative addition for the synthesis
of palladacycles, see: (a) Denmark, S. E.; Stavenger, R. A.; Faucher,
A.-M.; Edwards, J. P. J. Org. Chem. 1997, 62, 3375-3389. (b) Mateo,
C.; Cardenas, D. J.; Fernandez-Rivas, C.; Echavarren, A. M. Chem.
Eur. J. 1996, 2, 1596-1606.
(13) We use the descriptors for planer chirality in π-complexes
codified by Schlo¨gl: (a) Schlo¨gl, T. Top. Stereochem. 1967, 1, 39-91.
These differ from the descriptors based on CIP rules: (b) Chan, R. S.;
Ingold, C. K.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1966, 5, 385-
414, which are occasionally used in the current literature.
(14) For a review of palladacycle synthesis, see: Canty, A. J. In
Comprehensive Organometallic Chemistry II; Pergamon: Oxford, New
York, 1995; Vol. 9, pp 242-248.
(15) Bolm, C.; Mun˜iz-Ferna´ndez, K.; Seger, A.; Raabe, G.; Gu¨nther,
K. J. Org. Chem. 1998, 63, 7860-7867.
(16) These conditions are adapted from Knapp, R.; Rehahn, M. J.
Organomet. Chem. 1993, 452, 235-240.
(17) The monosubtituted ferrocenyl complex resulting from reduc-
tion of the iodide and the biaryl resulting from homo-coupling of the
boronic acid comprised the remainder of the mass.
650 J. Org. Chem., Vol. 70, No. 2, 2005

Asymmetric Synthesis of Chiral Allylic Amines
SCHEME 5. Synthesis of Additional FOP
Complexes
acids, such as pentafluorophenylboronic acid, did not
couple with iodide 25 to any detectable extent.
To complete the syntheses of the palladacyclic cata-
lysts, ferrocenyl oxazolines 26a-h were ortholithiated
with t-BuLi, followed by quenching of the lithium inter-
mediates with diiodoethane to provide ferrocenyl iodides
27a-h in moderate to good yields (57-80%, Table 1). At
this point, it was possible to access an additional FOP
catalyst having an electron-deficient aryl substituent by
oxidation of methyl sulfide 27h with m-CPBA to provide
sulfone 28 in 46% yield. Reaction of ferrocenyl iodides
27a-g and 28 with 1 equiv of Pd2(dba)3‚CHCl3 in benzene
at room temperature then provided the palladacyclic
dimers 29-36 having the S,Rp configuration, in high
yields (79-98%, Table 1).
FIGURE 3. X-ray models of complexes 9a (A) and 40 (B).
instances, the trans isomer preferentially crystallized. A
search of the Cambridge Structure Database (CSD v5.25)
shows these to be the first single-crystal X-ray structures
of ferrocenyl palladacycle dimers in which the bridging
atom is iodide; the majority of related structures are
chloride-bridged dimers.19 The trans isomers of complexes
9a and 40 are C2 symmetric in the solid state. The four-
membered ring, containing the Pd and I atoms, is
puckered, placing both FeCp fragments on the concave
face, typical of halide-bridged ferrocenyl palladacycles.
The degree of puckering about the central four-membered
ring in these iodide-bridged dimers, measured as the
dihedral angle between the two Pd(II) square planes
(64.5° for 9a and 66.7° for 40), is greater than that
previously observed (4.3-52.1°) in five-membered ring
chloride- or bromide-bridged ferrocenyl palladacyclic
dimers.19 This conformation places the FeCp fragment
and the 4 substituent of the oxazoline ring on opposite
sides, nearly perpendicular, to the palladium square
plane.
Two additional FOP precatalysts were synthesized
using an analogous sequence of transformations (Scheme
5). Synthesis of the palladacycle of (S,Sp)-37, in which
the tert-butyl and ferrocene moieties occupy space on the
same face of the Pd(II) square plane, was realized in 34%
yield by direct reaction of iodide 25 with Pd2(dba)3‚CHCl3.
In addition, substitution of a 1-methoxy-1-ethylpropyl
group for the t-Bu group of ferrocene 18 allowed for the
preparation of “pseudo”-enantiomeric FOP complex (S,Rp)-
40. Complex 40 was prepared by reaction of known
ferrocenyl complex 389 (a 13:1 mixture of diastereomers
about the ferrocene stereocenter) with t-BuLi followed
by quenching of the resulting anion with diiodoethane.
Subsequent reaction of iodide 39 with Pd2(dba)3‚CHCl3
yielded FOP precatalyst 40 as a mixture of iodide-bridged
The sequences illustrated in Schemes 3-5 are suf-
ficiently efficient to conveniently provide palladacyclic
complexes 9a, 29-36, and 40 in multigram quantities.
1
dimers (as observed by H NMR analysis) in 68% yield
over the two steps. Each of these palladacycles, including
those containing aryl substituents on the functionalized
cyclopentadienyl ring, exhibited 1H NMR spectra consis-
tent with them existing in solution as mixtures of cis/
trans isomers about the Pd(II) square planes.
The structures of complexes 9a and 40 were estab-
lished by X-ray crystallography;18 representations of
these X-ray models are shown in Figure 3. In both
(19) For X-ray crystallography of chloride-bridged ferrocenyl palla-
dacycles, see: (a) Dunina, V. V.; Gorunova, O. N.; Livantsov, M. V.;
Grishin, Y., K.; Kuz’mina, L. G.; Kataeva, N. A.; Churakov, A. V.
Tetrahedron: Asymmetry 2000, 11, 3967-3984. (b) Zhao, G.; Yang,
Q. C-.; Mak, T. C. W. Organometallics 1999, 18, 3623-3636. (c) Zhao,
G.; Wang, Q. G-.; Mak, T. C. W. Tetrahedron: Asymmetry 1998, 9,
1557-1561. (d) Wu, Y. J.; Cui, X. L.; Du, C. X.; Wang, W. L.; Guo, R.
Y.; Chen, R. F. J. Chem. Soc., Dalton Trans. 1998, 3727-3730. (e) Zhao,
G.; Wang, Q. G-.; Mak, T. C. W. Polyhedron 1998, 18, 577-584. (f)
Lo´pez, C.; Bosque, R.; Solans, X.; Font-Bardia, M. Tetrahedron:
Asymmetry 1996, 7, 2527-2530. (g) Reference 3d. For bromide-bridged
ferrocenyl palladacycles, see: (h) Zhao, G.; Wang, Q. C-.; Mak, T. C.
W. J. Chem. Soc., Dalton Trans. 1998, 3785-3789. (i) Reference 19b.
(18) The authors have deposited coordinates for these compounds
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.
J. Org. Chem, Vol. 70, No. 2, 2005 651

Anderson et al.
SCHEME 6. Rearrangement of
N-(4-Trifluoromethylphenyl)benzimidates
SCHEME 7. Synthesis of a FOP Chloride Complex
TABLE 2. Rearrangement of Imidate 5b to Amide 6b
(R ) n-Pr)a
imidate
entry precatalyst stereoisomer time yield (%) ee (%)/confb
1
2
3
4
5
6
7
8
9
10
9a
9a
23
23
24
24
37
37
40
40
Z
E
Z
E
Z
E
Z
E
Z
E
3 d
2 d
6 d
63 h
2 d
2 d
3 d
2 d
6 d
3 d
67
57
89
76
15
77
28
86
81
95
91/R
79/S
90/R
76/S
49/R
69/S
53/R
8/S
TABLE 3. Effect of the Silver Salt in Activation of FOP
Precatalyst 9a for the Rearrangement of Allylic Imidate
5aa
imidate
yield ee (%)/
entry silver salt stereoisomer
R
time (%) confb
1
2
3
4
5
6
7
8
AgOCOCF3
AgOTs
Z
Z
Z
E
Z
Z
Z
E
n-Pr
n-Pr
n-Pr
i-Bu
i-Bu
18 h 83
2 d 83
2 d 67
25 h 97
25 h 89
91/R
88/R
89/R
84/S
96/R
90/R
88/R
63/R
92/S
72/R
AgONs
AgOCOCF3
AgOCOCF3
AgOCOCF3
AgOCOCF3
AgOCOCF3
a Conditions: 5 mol % of the precatalyst was preactivated by
reaction with 4 equiv of Ag (OCOCF3) in CH2Cl2 (0.1 M in
substrate). b For determination of absolute configuration, see ref
4.
c
CH2C6H11 26 h 87
Bn
Ph
23 h 85
26 h 59
a Conditions: 5 mol % of 9a was preactivated by reaction with
4 equiv of the silver salt in CH2Cl2 (0.1 M in substrate) at room
temperature. b For determination of absolute configuration, see ref
4. c C6H11 ) cyclohexyl.
Moreover, the presence of crystalline intermediates al-
lows for diastereomerically pure intermediates to be
isolated by simple recrystallization, thus negating the
need for chromatographic purification of such species. For
example, palladacycle 40 was recrystallized from benzene/
hexanes after its preparation, removing the minor dia-
stereomer generated during the installation of the TMS
group. All of the arylferrocenyl palladacycles, as well as
37, were obtained as single stereoisomers by recrystal-
lization of iodide 25 from hexanes after its preparation
from ferrocene 17.
from 24 also rearranged allylic imidate (Z)-5b (R ) n-Pr)
in low 15% yield, providing 6b in 49% ee (entry 5).
As changing the ferrocenyl silyl substituent from SiMe3
to SiEt3 did not significantly affect enantioselectivity,
FOP precatalyst iodide-bridged dimer 9a and its chloride
congener 9b were chosen for further studies. The latter
complex was prepared from the corresponding (chlo-
romercuric)ferrocenyl complex 41 by transmetalation
with sodium tetrachloropalladate (Scheme 7). The iodide-
bridged dimer 9a itself was a poor catalyst for the
rearrangement of 5a, providing allylic amide 6a in only
20% yield and 41% ee after 5 days. The chloride congener
9b rearranged imidate 5b at a slow rate, providing 6b
in <10% yield after 3 days; however, the product was 79%
ee. We initially investigated activation of 9a with other
silver salts (Table 3), surveying catalytic efficacy in the
asymmetric rearrangement of (Z)-2-hexenyl N-(4-meth-
oxyphenyl)benzimidate (5a, R ) n-Pr). Catalysts gener-
ated using silver tosylate or silver p-nitrophenylsulfonate
behaved similarly to the catalyst generated with silver
trifluoroacetate. The reaction of 9a with silver triflate
resulted in decomposition of the complex.
As there appeared to be no advantage to using silver
salts other than AgOCOCF3, the rearrangements of five
additional allylic N-(4-methoxyphenyl)benzimidates 5a
were examined using the catalyst generated from the
reaction of 9a with this silver salt (Table 3). The
rearrangement was found to be tolerant to incorporation
of branched alkyl groups or a Bn group at C4 of the allylic
imidate, providing rearranged allylic amides 6a in good
yields (85-97%) and high enantiomeric excesses (84-
96% ee, entries 4-7). As had been observed previously,3a
a Z allylic imidate rearranged with a higher level of
enantioinduction (entry 5) than the corresponding E
B. Evaluation of FOP Catalysts for the Asym-
metric Rearrangement of Various Allylic N-Aryl-
benzimidates. An initial evaluation of FOP catalysts
examined the rearrangement of both (E) and (Z)-2-
hexenyl N-(4-trifluoromethylphenyl)benzimidates 5b (R
) n-Pr) with catalysts derived from complexes 9a, 23,
24, 37, and 40 (Scheme 6). In this initial survey, the
iodide-bridged dimer precatalysts (5 mol % relative to
substrates) were activated by reaction with 4 equiv of
silver trifluoroacetate in CH2Cl2 at room temperature for
3 h. The results of these experiments are summarized
in Table 2. Similar levels of enantioselectivity in forming
allylic amide 6b were observed with cationic catalysts
generated from 9a, 23, and 40; as expected, the last of
these delivered the opposite enantiomer compared to
catalysts formed from 9a and 23 (entries 1-4, 9, and 10).
The catalyst formed from 37, in which the t-Bu group
and CpFe fragment are oriented on the same face of the
palladium square plane (SP configuration of the ferrocene
moiety), rearranged allylic imidate (E)-5b (R ) n-Pr) in
acceptable 86% yield but with low enantioselection,
providing 6b in only 8% ee (entry 8). This same catalyst
provided amide 6b (R ) n-Pr) in 28% yield and 53% ee
from the corresponding Z-configured allylic imidate
(entry 7). The catalyst derived from 24, a diastereomer
of 37 having the opposite Rp configuration, rearranged
allylic imidate (E)-5b (R ) n-Pr) in acceptable 77% yield,
providing 6b in 69% ee (entry 6). The catalyst derived
652 J. Org. Chem., Vol. 70, No. 2, 2005

Asymmetric Synthesis of Chiral Allylic Amines
TABLE 4. Rearrangement of Allylic N-(4-Methoxyphenyl)benzimidates 5a to Allylic N-(4-Methoxyphenyl)benzamides
6a with Catalysts Generated from Various FOP Precatalystsa
R ) (E)-n-Pr
R ) (Z)-n-Pr
R ) (E)-i-Bu
R ) (Z)-i-Bu
yield of 6a,
yield of 6a,
yield of 6a,
yield of 6a,
precatalyst
ferrocenyl C3
%
ee %/ confb
%
ee %/ confb
%
ee %/ confb
%
ee %/ confb
9a
24
29
30
31
32
33
34
35
36
TMS
93
70
77
95
85
95
77
71
91
83
83/S
81/S
83/S
88/S
82/S
88/S
85/S
87/S
84/S
81/S
83
20
71
70
84
70
77
70
82
77
91/R
56/R
90/R
88/R
91/R
94/R
93/R
91/R
93/R
91/R
97
84/S
89
96/R
H
Ph
80
80
85
80
71
78
83
70
81/S
82/S
83/S
86/S
84/S
85/S
87/S
80/S
71
71
70
85
72
75
83
78
91/R
88/R
94/R
91/R
90/R
85/R
92/R
95/R
4-MeOC6H4
4-CF3C6H4
2,6-(MeO)2C6H3
1-C10H7
2-MeC6H4
2-MeOC6H4
4-MeSO2C6H4
a Conditions: 5 mol % of 9 was preactivated by reaction with 4 equiv of Ag(OCOCF3) in CH2Cl2 (0.1 M in substrate) at room temperature
for 3 h. b For determination of absolute configuration, see ref 4.
SCHEME 8. Synthesis of N-Arylbenzimidates
configured imidate (entry 4). The rearrangement of the
allylic imidate derived from cinnamyl alcohol 5a (R )
Ph) was less efficient, providing the allylically transposed
amide in lower overall yield and enantioselectivity (entry
8). The lowered yield and enantioselectivity observed in
this case likely results from the competitive ionization-
recombination pathway, which would proceed via a
stabilized aryl-substituted allyl cation intermediate.
With the goal of improving the yield and enantio-
selectivity of the rearrangement of N-arylbenzimidates,
the panel of arylferrocenyl palladacyclic FOP catalysts
was evaluated. The catalytic asymmetric rearrangement
of four allylic N-(4-methoxyphenyl)benzimidates 5a [R )
(E)-n-Pr, (Z)-n-Pr, (E)-i-Bu, and (Z)-i-Bu] was studied
with catalysts generated by pretreatment of complexes
9a, 29-36, and 24 with 4 equiv of silver trifluoroacetate
in CH2Cl2 at room temperature for 3 h; in each case, 5
mol % of the iodide-bridged dimer was employed. Filtra-
tion through Celite under an inert atmosphere removed
any precipitated silver salt and provided the active
catalysts. The appropriate imidate was then added to the
activated catalyst solution, and the reaction was carried
out at room temperature for a set time of 24 h.
The results from rearrangement of these four N-(4-
methoxyphenyl)benzimidates 5a with this series of cata-
lysts are summarized in Table 4. With the exception of
the rearrangement of (Z)-2-hexenyl N-(4-methoxyphenyl)-
benzimidate 5a (R1 ) (Z)-n-Pr) with the catalyst formed
from 24 (R2 ) H), the enantiomeric excess of the resulting
N-(4-methoxyphenyl)benzamides 6a was only slightly
impacted by the substituent present on the ferrocenyl
ring. The isolated yields of the allylic benzamide products
changed somewhat more than the enantiomeric excess
as this substituent was varied. Overall, the TMS-
substituted precatalyst 9a provided enantioselectivities
comparable to or better than those achieved with the
arylferrocenyl catalysts. As such, precatalyst 9a was
again chosen for further studies, this time with the goal
of identifying new allylic imidate motifs that would
provide allylic amide products upon rearrangement that
would be more amenable to cleavage, thus providing an
improved route to chiral allylic amines of high enan-
tiopurity.
C. Development of More Useful Imidates for the
Synthesis of Chiral Nonracemic Allylic Amines
from Allylic Alcohols.
C.1. Synthesis of Protected Allylic Imidates. The
search for new imidate motifs with more suitable nitro-
gen protecting groups began by expanding our suite of
N-arylbenzimidates to include N-(2-methoxyphenyl)-
benzimidates 5c and N-(2,4-dimethoxyphenyl)benzimi-
dates 5d, with the anticipation that these aryl groups
would be more easily removed from the resulting amide
under oxidative conditions. The synthesis of (2-meth-
oxyphenyl)benzimidates 5c was achieved in a manner
analogous to the preparation of N-(4-methoxyphenyl)-
benzimidates 5a and N-(4-trifluoromethylphenyl)benz-
imidates 5b (Scheme 8).3a Reaction of benzamides 42a-c
with PCl5 gave the imidoyl chlorides 43a-c in good yields
(81-95%). This procedure, however, failed to provide
useful quantities of N-(2,4-dimethoxyphenyl)benzimidoyl
chloride 43d. Imidoyl chloride 43d was accessed, albeit
in low yield (38%), by reaction of benzoic acid and 2,4-
dimethoxyaniline in the presence of triphenylphosphine
and triethylamine in refluxing carbon tetrachloride.20
(20) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J. Org. Chem. 1993, 58, 32-35.
J. Org. Chem, Vol. 70, No. 2, 2005 653

Anderson et al.
SCHEME 9. Synthesis of
N-Benzyloxycarbonylbenzimidate 46
SCHEME 11. Synthesis of
N-(4-Methoxyphenyl)trifluoroacetimidates 52a
SCHEME 10. Synthesis of
N-tert-Butylsulfonylbenzimidate 50
TABLE 5. Rearrangement of Allylic (E)-Hexenyl
Imidates 5a-d, 46, 50, and 52a with the FOP Catalyst
Generated from 9aa
entry
imidate
yield of allylamide (%) % ee/confc
1
2
3
4
5
6
7
5a
5b
5c
5d
46
50
67
79/S
83/S
80/S
83/S
5/S
83
75
76
68
no reaction
n/a
52a (R ) n-Pr, E)
88b
76/S
a Conditions: 5 mol % of 9a was preactivated by reaction with
4 equiv of Ag (OCOCF3) in CH2Cl2 (0.1 M in substrate) at room
temperature for 24 h. b 7.5 mol % of 9a and 20 mol % 1,8-
bis(dimethylamino)naphthalene. c Determined by chiral HPLC
after cleavage of the trifluoroacetate group; absolute configuration
established by correlation with products reported in ref 4.33
Treatment of imidoyl chlorides 43a-d with the sodium
or lithium salt of (E)-2-hexen-1-ol in THF provided the
allylic N-arylbenzimidates 5a-d in variable yields (27-
81%).
Examination of other classes of nitrogen protecting
groups began with the synthesis of an allylic imidate
having nitrogen protected with a benzyloxycarbonyl
group. Methyl benzimidate hydrochloride21 44 was first
treated with cold aqueous NaHCO3 and pentane to
provide the free base, which was allowed to directly react
with benzyl chloroformate and K2CO3 to provide the Cbz-
protected methyl benzimidate 45 in 46% yield (Scheme
9). Alkoxide exchange with (E)-2-hexen-1-ol in the pres-
ence of catalytic potassium tert-butoxide in benzene at
85 °C then gave allylic imidate 46 in 53% yield. At the
elevated temperatures required for this transformation,
alkoxide exchange was complicated by competitive sub-
stitution at the carbamate center to provide byproduct
47.
An allylic benzimidate having a tert-butylsulfonamide
(BUS) nitrogen protecting group was synthesized by the
sequence summarized in Scheme 10. Initially the BUS-
protected methyl benzimidate 49 was formed by reaction
of tert-butylsulfonamide 48 and trimethyl orthobenzoate
in the presence of catalytic p-toluenesulfonic acid at 160
°C.22 Using this procedure, BUS-protected methyl benz-
imidate 49 was prepared in 48% yield. Alkoxide exchange
upon reaction of methyl benzimidate 49 in the presence
of (E)-2-hexen-1-ol and potassium tert-butoxide delivered
the BUS-protected allylic imidate 50 in 68% yield.
Finally, N-aryltrifluoroacetimidate 52a was synthe-
sized with the expectation that the acyl group of the
allylic trifluoroacetamide product would be readily re-
moved by hydrolysis. Using the procedure of Tamura,
p-anisidine and trifluoroacetic acid were condensed with
triphenylphosphine, triethylamine, and carbon tetrachlo-
ride at reflux to provide imidoyl chloride 51 in 90%
yield.20 As in the synthesis of allylic benzimidates,
treatment of imidoyl chloride 51 with the sodium salt of
(E)-2-hexen-1-ol in THF provided allylic N-(4-meth-
oxyphenyl)trifluoroacetimidate 52a in 88% yield (Scheme
11).
C.2. Evaluation of Substituted Allylic Imidates in
the Asymmetric Allylic Imidate Rearrangement
with FOP Precatalyst 9a. Catalytic asymmetric rear-
rangements of allylic imidates 5a-d, 46, 50, and 52a
with the FOP catalyst generated from 9a by reaction with
4 equiv of silver trifluoroacetate were examined (Table
5). Each imidate was then exposed to 5 mol % of the
catalyst, and the reaction was maintained for 24 h at
room temperature prior to analysis. In the case of
trifluoroacetimidate 52a, the catalyst loading was 7.5 mol
%, and 20 mol % of 1,8-bis(dimethylamino)naphthalene
was added to prevent competitive decomposition of this
acid-sensitive trifluoroacetimidate.
Allylic N-arylbenzimidates 5a-d (entries 1-4) rear-
ranged to the corresponding allylic amides in similar
yields (67-83%), with enantioselectivities ranging from
79% to 83% ee. The absolute configuration of benzamides
6c and 6d were assigned by analogy to those previously
determined by chemical correlation of N-(4-methoxy-
phenyl)benzamide 6a (R ) Me) with (R)-N-benzoyl-
alanine methyl ester.3a The Cbz-protected allylic imidate
46 rearranged to give the desired allylic amide 53 in 68%
yield; however, the product was nearly racemic (Scheme
12; Table 5, entry 5). The BUS-protected allylic imidate
50 failed to rearrange under these conditions and was
(21) Casy, G.; Patterson, J. W.; Taylor, R. J. K. Org. Synth. 1988,
67, 193-197.
(22) (a) For use of the BUS group to protect amines, see: Sun, P.;
Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62, 8604-8608. (b)
For synthesis of tert-butylsulfonamide, see: Cogan, D. A.; Liu, G.; Kim,
K.; Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 8011-
8019.
654 J. Org. Chem., Vol. 70, No. 2, 2005

Asymmetric Synthesis of Chiral Allylic Amines
SCHEME 12. Rearrangement of Cbz-Protected
Benzimidates and N-Aryl Trifluoroacetimidates
SCHEME 13. Deprotection of
N-(4-Methoxyphenyl)trifluoroacetamides
TABLE 6. Rearrangement of Allylic
recovered unchanged from the reaction mixture (entry
6). The allylic N-(4-methoxyphenyl)trifluoroacetimidate
52a (R ) n-Pr) was more promising, providing the
corresponding allylic N-(4-methoxyphenyl)trifluoroaceta-
mide 54a (R ) n-Pr) in 88% yield and 76% ee (entry 7).
C.3. Deprotection of Enantioenriched Allylic
Amides and Exploration of Scope. Cleavage of the
nitrogen substituents of the enantioenriched allylic amides
synthesized by the reactions reported in Table 5 was
examined next. The N-(2,4-dimethoxyphenyl)benzamide
derived from imidate 5d (Scheme 8, Table 5, entry 4) was
subjected to oxidation under a variety of conditions (ceric
ammonium nitrate (CAN),23 AgNO3/(NH4)S2O8,20 and
Na2HPO4/K2S2O824), but the dearylated amide was not
obtained in greater than 30% yield. Likewise, removal
of the benzoyl group by reaction of 6a with HCl,25 HBr/
AcOH,26 NaOEt, KOt-Bu/H2O,27 KOH/MeOH, or DIBAL-
H28 prior to dearylation was also inefficient. The crowded
steric environment of benzamides 6 is likely responsible
for these difficulties.29 Similar results were obtained with
N-(2-methoxyphenyl)benzamide 6c. As the Cbz-protected
allylic imidate 46 and BUS-protected allylic imidate 50
performed poorly in the asymmetric allylic imidate
rearrangement, no attempts to deprotect the correspond-
ing allylic amides were made. Finally, deprotection of
allylic trifluoroacetamide 54a proved facile, providing the
allylic aniline 55a in 98% yield after treatment with
NaOEt in EtOH at 54 °C for 18 h (Scheme 13, R ) n-Pr).
Dearylation of 55a with CAN in MeCN/H2O at 0 °C gave
the corresponding primary allylic amine 56a, isolated as
the maleic acid salt, in 74% yield.4a
N-(4-Methoxyphenyl)trifluoroacetimidates 52 with the
Catalyst Generated from FOP Precatalyst 9aa
entry
imidate
E/Z
R
yield (%)
% ee/conf
1
2
3
4
5
6
52a
52b
52c
52d
52e
52f
E
Z
E
Z
E
E
n-Pr
n-Pr
i-Bu
i-Bu
Ph
88
21
73
21
46
81
76/S
87/R
84/S
90/R
45/R
73/S
CH2CH2Ph
a Conditions: 7.5 mol % of 9a was preactivated by reaction with
4 equiv of Ag(OCOCF3) and 20 mol % 1,8-bis(dimethylamino)-
naphthalene in CH2Cl2 (0.2 M in substrate) at room temperature
for 24 h.
TABLE 7. Deprotection of Allylic Trifluoroacetamides
54 to Form Enantioenriched Allylic Amines 56
entry
amide
R
yield 55 (%)
yield 56 (%)
1
2
3
4
54a
54c
54e
54f
n-Pr
i-Bu
Ph
98
99
89
93
74
70
70
80
CH2CH2Ph
oxyphenyl)trifluoroacetimidates 52 was explored. The
starting allylic imidates 52 were prepared in good yields
(62-96%) by the procedure described in Scheme 11. The
results of the rearrangement of these allylic imidates
with 7.5 mol % of the FOP catalyst generated in the
standard fashion from precatalyst 9a are summarized in
Table 6. Rearrangement of E allylic imidates containing
an alkyl (entry 3) or phenethyl substituent (entry 6) at
C4 took place in good yields (73% and 81%, respectively)
with enantiomeric excesses of 84% ee and 73% ee,
respectively. Allylic trifluoroacetimidates derived from Z
allylic alcohols, however, gave low yields of the corre-
sponding allylic amides, even after prolonged reaction
times (entries 2 and 4). Allylic imidate 52e, derived from
cinnamyl alcohol, also rearranged in low yield and with
low enantioselectivity (entry 5).
Deprotection of the allylic N-(4-methoxyphenyl)trifluo-
roacetamides 54 to form the parent allylic amines is
readily accomplished (Table 7). Cleavage of the trifluo-
roacetate group by reaction with 3 M NaOEt in EtOH at
55 °C provided amines 54 in excellent yields (89-99%).
Subsequent cleavage of the aryl group from amines 55
by reaction with CAN proceeded efficiently to provide
primary amine maleic acid salts 56 in 70-80% yield.
Encouraged by these results, the scope of the enantio-
selective allylic rearrangement of allylic N-(4-meth-
(23) Saito, S.; Hatanaka, K.; Yamamoto, H. Org. Lett. 2000, 2, 1891-
1894.
(24) Fetter, J.; Lempert, K.; Gizur, T.; Nyitrai, J.; Kajta´r-Peredy,
M.; Simig, G.; Hornya´k. G.; Doleschall, G. J. Chem. Soc., Perkin Trans.
1 1986, 221-227.
(25) Hughes, P.; Clardy, J. J. Org. Chem. 1988, 53, 4793-4796.
(26) Ben-Ishai, D.; Altman, J.; Peled, N. Tetrahedron 1977, 33,
2715-2717.
(27) (a) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J. J. Am.
Chem. Soc. 1976, 98, 1275-1276. (b) Gassman, P. G.; Schenk, W. N.
J. Org. Chem. 1977, 42, 918-919.
(28) Treatment of amide 6a with DIBAL-H resulted in inseparable
mixtures (1:1 to 4:1) of the desired product and the reduced product,
N-benzyl-N-(4-methoxyphenyl)-(1-propyl-allyl) amine. For procedure
see: (a) Gutzwiller, J.; Uskokovic, M. J. Am. Chem. Soc. 1970, 92, 204-
205. (b) Gutzwiller, J.; Uskokovic, M. Helv. Chem. Acta 1973, 56, 1494-
1503. (c) Gutzwiller, J.; Pizzolato, G.; Uskokovic, M. R. Helv. Chem.
Acta 1981, 64, 1663-1671.
Discussion
(29) For a brief discussion of side reactions in the oxidative removal
of N-aryl groups from amides, see: Corley, E. G.; Karady, S.; Abram-
son, N. L. Tetrahedron Lett. 1988, 29, 1497-1500.
Catalyst Synthesis and Evaluation. Several prop-
erties of the FOP series of catalysts are apparent from
J. Org. Chem, Vol. 70, No. 2, 2005 655

Anderson et al.
this study. Whereas the synthesis of ferrocenyl oxazoline
palladacycle 9a (Scheme 2, R ) SiMe3) could be per-
formed on multigram scale to provide an air-stable solid,
the corresponding desilyl congener 24a (Scheme 3, R )
H) is markedly less stable, requiring storage in an
oxygen-free atmosphere to prevent decomposition. Simi-
larly, FOP complex 37 (Scheme 5) that also lacks a
substituent at C3 of the palladated cyclopentadienyl ring
displays similar instability. A substituent at C3 of this
ring obviously increases the stability of FOP catalysts.
Suzuki cross-coupling of ferrocenyl iodide 25 (Scheme
4) and aryl boronic acids proved to be a general method
to incorporate aryl substituents at C3 of the palladated
cyclopentadienyl ring. Electron-rich aryl boronic acids,
even those having an ortho substituent, coupled with
iodide 25 in high yields. More sterically hindered 2,6-
disubstituted aryl boronic acids coupled in lower yield.
Electron-deficient aryl boronic acids were also poor
coupling partners for the cross-coupling reaction as
reduction of the ferrocenyl iodide 25 and homo-coupling
of the aryl boronic acid were competitive with cross-
coupling.30
Several trends are apparent from this study of the
rearrangement of allylic N-arylbenzimidates 5 with FOP
series catalysts. First, activation of the halide-bridged
dimer FOP complexes by reaction with a silver salt is
required to generate kinetically competent catalysts for
the rearrangement of allylic N-arylbenzimidates.31 With
all the catalysts examined, somewhat higher enantio-
selectivity was observed in the rearrangement of the Z
stereoisomers of 5 than that realized in rearrangements
of the corresponding E alkene isomers. In general, Z
allylic N-arylbenzimidates rearranged to allylic amides
more slowly than the corresponding E stereoisomers. The
catalysts generated from silyl-containing complexes 9a
(Scheme 3, SiMe3) and 23 (Scheme 3, SiEt3) performed
similarly, producing benzamide 6b in >90% ee. The FOP
catalysts containing electron-rich or electron-poor aryl
groups, rather than silyl, at the C3 position of the
cyclopalladated cyclopentadienyl ring provided quite
similar results. In general, no trend in catalyst efficacy,
either in terms of rate or enantioselectivity, is apparent
as the substituents on the aryl ring are varied. The lower
enantioselectivity observed with the catalyst formed from
the unsubstituted complex 24 (Scheme 3) likely results
from decomposition of this catalyst to generate a less
selective catalyst as evidenced by the formation of a black
precipitate and mirror on the reaction vessel during the
course of the rearrangement. Rearrangements facilitated
by the catalyst generated from 40 (Scheme 5) having the
Rp configuration and the opposite relative configuration
of the oxazoline fragment yielded the opposite enantiomer
of benzamide 6b (with similar ee) to that formed with
catalysts generated from the S,Sp and S,Rp pseudo-
enantiomeric complexes 9a and 24 (Scheme 2), respec-
tively. The catalyst generated from 37 (Scheme 5) having
the S,Sp configuration gave exceptionally poor enanti-
oselectivity in the rearrangement of (E)-5b and dimin-
ished enantioselectivity in rearranging the Z stereoiso-
mer isomer compared to pseudo-diastereomeric catalysts
(9a-(S,Sp), 23-(S,Sp), and 40-(S,Rp). Despite the problems
of stability of the catalyst generated from 24 (the S,Rp
diastereomer of 37), this complex also gave much higher
enantioselectivity in the rearrangement of (E)-5b than
the catalyst generated from 37. This decrease in enan-
tioselectivity with the catalyst generated from 37 is
consistent with our hypothesis that substituents must
reside both above and below the square plane of the
palladium(II) catalyst to induce high levels of enantio-
selectivity.8
Development of More Useful Imidates for the
Synthesis of Chiral Nonracemic Allylic Amines
from Allylic Alcohols. Replacing the aryl substituent
of N-arylbenzimidates 5a (Scheme 8) with common,
electron-withdrawing nitrogen protecting groups pro-
duced imidates that either did not participate in the FOP-
catalyzed asymmetric allylic imidate rearrangement,
such as the BUS-protected benzimidate 50 (Scheme 10),
or did so with low enantioselectivity, such as the Cbz-
protected imidate 46 (Scheme 9). N-Arylbenzimidates
5b-d (Scheme 8) underwent facile rearrangement to
provide the corresponding N-arylbenzamides 6b-d in
good ee (Table 5); however, removal of the N-aryl sub-
stituent from the product allylic amides was largely
unsuccessful.29,32
N-(4-Methoxyphenyl)trifluoroacetimidates, however,
were found to be promising substrates for the catalytic
asymmetric allylic imidate rearrangement with cationic
FOP catalysts. These trifluoroacetimidates underwent
asymmetric rearrangement with enantioselectivities some-
what less than those realized in rearrangements of
comparable N-arylbenzimidates. However, the allylic
amide products formed from the former allylic imidates
have readily removed N-trifluoroacetyl substituents.
Rearrangement of E allylic N-(4-methoxyphenyl)trifluo-
roacetimidates 52 (Schemes 11 and 12) took place in good
yields and enantioselectivities, whereas the correspond-
ing Z allylic trifluoroacetimidates rearranged only slowly,
providing the rearranged allylic amides in low yield even
after prolonged reaction times. Critical to obtaining good
yields in the rearrangement of E allylic trifluoroacetimi-
dates is the inclusion of an acid scavenger (20 mol % of
1,8-bis(dimethylamino)naphthalene) in the reaction mix-
ture. Without such an additive, decomposition of the
trifluoroacetimidate was observed. Presumably, the amine
sequesters adventitious acid, thus suppressing the de-
composition pathway; trace amounts of protic acid may
be formed from the reaction of residual AgOCOCF3 with
a small amount of water under the reaction conditions.33
The rearrangement of the cinnamyl alcohol derived allylic
trifluoroacetimidate 52e (Table 6) was also problematic,
proceeding in only low yield and enantioselectivity. The
inefficient rearrangement of this imidate results from a
competitive ionization-recombination pathway, signaled
(30) This type of side reaction is common in cross-coupling reactions.
A variety of mechanisms have been forwarded to explain results of
this type; see: Nguyen, P.; Yuan, Z.; Agocs, L.; Lesley, G.; Marder, T.
B. Inorg. Chim. Acta 1994, 220, 289-296 and references therein.
(31) This activation likely involves both salt metathesis, exchanging
the iodide of the palladacycle for trifluoroacetate, in addition to
oxidation of the ferrocene to a ferrocenium ion by the Ag(I). For studies
with precatalyst 9a, see ref 6.
(32) Oligimerization of the radical cation intermediate during oxida-
tive dearylation has been observed in similar sterically crowded anilide
systems and may account of the poor mass recovery from these
experiments.29
(33) Anderson, C. E. Ph.D. Dissertation, University of California,
Irvine, 2003.
656 J. Org. Chem., Vol. 70, No. 2, 2005

Asymmetric Synthesis of Chiral Allylic Amines
by the presence of an amide byproduct resulting from
formal [1,3]-rearrangement. This competitive reaction
pathway likely results from coordination of the palladium
catalyst to the imidate nitrogen, leading to the formation
of a stabilized aryl-substituted allyl cation intermediate.
Even in light of these limitations, N-aryltrifluoroacetimi-
dates 52 remain promising motifs for the asymmetric
allylic imidate rearrangement as facile hydrolysis of the
trifluoroacetate moiety and subsequent dearylation of
amides 54 can be accomplished to provide enantio-
enriched primary allylic amines 56 (Scheme 13) in good
yield over the sequence.
methoxyphenyl)trifluoroacetimidates emerged as prom-
ising substrates as the product allylic amides can be
converted to the parent allylic amines in good yields.
Rearrangement of E allylic N-(4-methoxyphenyl)trifluo-
roacetimidates take place in good yields, although enan-
tioselectivities were slightly less than those realized with
allylic N-arylbenzimidates. Further studies of catalytic
asymmetric rearrangements of allylic N-aryltrifluoro-
acetimidates identified catalysts related to the FOP
catalysts, e.g., COP-Cl, that are highly effective, provid-
ing the first practical catalytic asymmetric method for
transforming prochiral allylic trihaloacetimidates to
chiral allylic amines.4b
Conclusion
Acknowledgment. We thank NSF (CHE-9726471)
for financial support, Drs. C. J. Richards and T. Re-
marchuk for useful discussions, and Dr. J. Ziller for
X-ray analyses. Fellowship support to C.E.A. from
Amgen and to C.J.D. from the Achievement Rewards
for College Scientists Foundation (ARCS) and Bristol-
Myers Squibb (BMS) is gratefully acknowledged. NMR
and mass spectra were determined at UCI with instru-
ments purchased with the assistance of NSF and NIH
shared instrumentation grants.
Reported herein is the preparation and evaluation of
a small library of ferrocene oxazoline palladacycle (FOP)
complexes as asymmetric catalysts for the rearrangement
of prochiral allylic imidates. The catalyst library included
various members in which the C3 substituent of the
palladated cyclopentadienyl ring was varied. Although
substitution at the C3 position is important for catalyst
stability, it has little to no effect on the efficiency or
selectivity of the catalytic rearrangement. The most
readily prepared of this group, the silyl FOP catalysts
derived from 9 and 40, proved to be the best catalysts
for the asymmetric rearrangement of allylic N-aryl-
benzimidates and the first to realize >90% ees in the
production of chiral allylic amides from prochiral allylic
imidates.3a
Supporting Information Available: Experimental pro-
cedures for the preparation of 5c,d, 6c,d, 26a-h, 27a-c, 27e,f,
27h, 29-36, 43c,d, 45-47, 49, 50, and 53; tabulated charac-
terization data, copies of 1H and 13C NMR spectra for all new
compounds, and representative HPLC traces used to deter-
mine enantiopurity; and CIF files for 9a and 40. This material
is available free of charge via the Internet at http://pubs.acs.org.
In an effort to identify better imidate motifs for
asymmetric allylic imidate rearrangements, several al-
lylic imidates were prepared and evaluated. Allylic N-(4-
JO048490R
J. Org. Chem, Vol. 70, No. 2, 2005 657