Catalytic asymmetric rearrangement of allylic trichloroacetimidates. A practical method for preparing allylic amines and congeners of high enantiomeric purity

Article abstract of DOI:10.1021/ja037086r

COP-Cl catalyzes the rearrangement of (E)-allylic trichloroacetimidates to provide transposed allylic trichloroacetamides of high enantiopurity, a transformation that underlies the first truly practical method for transforming prochiral allylic alcohols t

Full text of DOI:10.1021/ja037086r

Published on Web 09/19/2003
Catalytic Asymmetric Rearrangement of Allylic Trichloroacetimidates. A
Practical Method for Preparing Allylic Amines and Congeners of High
Enantiomeric Purity
Carolyn E. Anderson and Larry E. Overman*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine, California 92697-2025
Received July 5, 2003; E-mail: leoverma@uci.edu
Table 1. Enantioselective Formation of Allylic Trichloroacetamides
2 from (E)- and (Z)-Allylic Trichloroacetimidates 1a
The rearrangement of allylic trichloroacetimidates to allylic
trichloroacetamides (1 f 2), first reported in 1974,1 is the preferred
method for converting allylic alcohols to transposed allylic amines
and their derivatives.2 This transformation can be accomplished at
elevated temperatures or at room temperature in the presence of
imidate
amide
c
entry
cpds
R
E/Z
temp (°C)
yield (%)b
%ee /conf
1
2
3
4
5
6
7
8
9
a
a
b
c
c
d
e
f
g
g
h
i
n-Pr
n-Pr
n-Pr
i-Bu
i-Bu
i-Bu
Me
E
E
Z
E
E
Z
E
E
E
E
E
E
rt
80
99
17
95
92
8
85
82
83
93
13
7
94/S
95/S
71/R
96/S
98/S
73/R
92/S
96/S
96/S
93/S
ndf
1
catalysts such as Hg(OCOCF3)2 or PdCl2 complexes.3 Attempts
38 °C
38 °C
38 °C
38 °Cd
38 °C
rt
to date to develop asymmetric Pd(II) catalysts for the rearrangement
of prochiral allylic trichloroacetimidates have been unsuccessful,
being plagued by competing elimination reactions, slow reaction
rates, and low enantioselectivities.4 The first two of these difficulties
likely arise from competitive complexation of the small, basic
trichloroacetimidate nitrogen to palladium.5 Consequently, success
in developing asymmetric Pd(II) catalysts for allylic imidate
rearrangements has been realized only with N-arylimidates (3 f
4).4,6 As coordination of an imidate nitrogen to a neutral palladium
Cy
38 °Ce
rt
38 °C
rt
CH2CH2Ph
CH2CH2Ph
Ph
10
11
12
t-Bu
38 °C
ndf
a Conditions: 5 mol % catalyst 5, CH2Cl2 (0.6 M), 18 h. b Duplicate
experiments ((3%). c Determined by HPLC analysis of duplicate experi-
ments ((2%). d 1 mol % 5, CH2Cl2 (1.2 M). e CH2Cl2 (1.0 M). f nd ) not
determined.
92-96% ee and 80-85% yield (entries 1, 7, and 9); at 38 °C, yields
of these rearrangements were improved (93-99%) with little or
no erosion of enantioselection (entries 2 and 10). (E)-Allylic
trichloroacetimidates containing i-Bu or cyclohexyl C3 substituents
(1c and 1f) rearranged slowly at room temperature; however, at 38
°C these precursors provided the corresponding (S)-allylic trichlo-
roacetamides 2c and 2f in 96% ee and high yield (entries 4 and 8).
When the substrate concentration was increased to 1.2 M, a catalyst
loading of only 1 mol % could be employed, as demonstrated by
the formation of 2c in 92% yield and 98% ee (entry 5). The
rearrangement was slowed drastically when R was t-Bu (entry 12).
Also unreactive were (Z)-allylic trichloroacetimidates which gave
the corresponding (R)-allylic trichloroacetamides 2 in poor yield
and moderate enantioselectivity (entries 3 and 6). One additional
limitation was identified: (E)-cinnamyl trichloroacetimidate 1h
provided amide 2h in low yield with the major product resulting
from formal [1,3]-rearrangement (entry 11).9
center should be less favorable than to a cationic Pd(II) complex,
typically employed in asymmetric allylic imidate rearrangements,4,6
the recent discovery that chloride-bridged dimer 57 is an excellent
catalyst for asymmetric rearrangement of N-(p-methoxyphenyl)-
trifluoroacetimidates6f suggested that COP-Cl (5) might also
catalyze allylic rearrangement of synthetically more important allylic
trichloroacetimidates. In this Communication, we report that 5 is
indeed an outstanding catalyst for transforming prochiral (E)-allylic
trichloroacetimidates into allylic trichloroacetamides of high enan-
tiopurity.
The rearrangement of a series of (E)-allylic trichloroacetimidates
containing various Lewis basic substituents was examined to explore
the functional group compatibility of the COP-Cl-catalyzed
reaction (Table 2). Oxygen functionality (including ester, acetal,
ketone, and silyl ether) was well tolerated, with allylic trichloro-
acetamide products being formed in 92-96% ee and excellent yield
(entries 1-7). Trichloroacetimidate 1o containing a free hydroxyl
group rearranged in high yield in the presence of COP-Cl (entry
8); however, enantioselection in this case was lower (80% ee).
Nitrogen functionality proved more problematic. Substrate 1p
containing carbamate functionality rearranged cleanly to give 2p
in 95% ee (96% yield at 38 °C), as did trichloroacetimidate 1q
containing a distal tertiary amine to provide 2q in 97% ee (82%
yield at 23 °C). However, the allylic rearrangement was prevented,
The trichloroacetimidates employed in this study were prepared
in 68-99% yield by DBU-catalyzed addition of allylic alcohols to
trichloroacetonitrile.8 Table 1 summarizes results obtained from
catalytic rearrangements of nine representative primary allylic
trichloroacetimidates with 5 mol % COP-Cl (5) in CH2Cl2 (0.6
M) for 18 h. (E)-Allylic trichloroacetimidates containing unbranched
R substituents at C3 rearranged within 18 h at room temperature
to provide the corresponding (S)-allylic trichloroacetamides 2 in
9
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J. AM. CHEM. SOC. 2003, 125, 12412-12413
10.1021/ja037086r CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Synthesis of Allylic Trichloroacetamides
2 from (E)-Allylic Trichloroacetimidates 1 Containing Lewis Basic
Functionalitya
alcohols are readily available, their trichloroacetimidate derivatives
are prepared in high yield from commercially available trichloro-
acetonitrile, oxidative removal of an N-aryl protecting group from
the allylic amide product is not required, and the trichloroacetamide
group can be easily cleaved or transformed to other functional
arrays,17 this catalytic asymmetric method for preparing chiral allylic
amines and congeners should find considerable use in enantio-
selective synthesis.
c
entry
cpds
R
temp (°C)
yield (%)b
%ee /conf
1
2
3
4
5
6
7
8
9
j
j
k
l
m
m
n
o
p
p
q
(CH2)3OAc
(CH2)3OAc
rt
38 °C
rt
rt
rt
38 °C
38 °C
rt
rt
38 °C
rt
74
97
73
85
80
98
98
84
87
96
82
92/S
92/S
95/S
95/S
94d/S
95d/S
96/R
80/R
95/S
95/S
97/S
(CH2)2CO2Me
(CH2)3(OCH2CH2O)
(CH2)2COMe
(CH2)2COMe
CH2OTBDMS
CH2OH
(CH2)3NBn(Boc)
(CH2)3NBn(Boc)
(CH2)9NBn2
Acknowledgment. We thank the NSF (CHE-9726471) for
financial support, Drs. C. J. Richards and T. Remarchuk for useful
discussions, and Dr. J. Ziller for X-ray analysis of 2e. C.E.A. thanks
Amgen for a predoctoral fellowship. NMR and mass spectra were
determined at UCI with instruments purchased with the assistance
of NSF and NIH shared instrumentation grants.
Note Added after ASAP. In the version published on the Web
9/19/2003, the structure for 2n, 2k, 2f, and 8 in eqs 2-4 were
incorrect. The version published 9/22/2003 and the print version
are correct.
10
11
a Conditions: 5 mol % 5, CH2Cl2 (0.6 M), 18 h. b Duplicate experiments
((3%). c Determined by HPLC analysis of duplicate experiments ((2%).
d Determined by chiral GC analysis of duplicate experiments ((2%).
at least at 38 °C, by tertiary amine functionality at C6, secondary
amine functionality at either C6 or C12, or a thioether substituent
at C6 of the (E)-2-alkenyl trichloroacetimidate starting material.
As only (E)-allylic trichloroacetimidates are viable substrates in
the COP-Cl-catalyzed allylic rearrangement, ent-COP-Cl (ent-
5) was prepared to access the opposite enantiomer of allylic
trichloroacetamide products.10 Thus, rearrangement of crotyl tri-
chloroacetimidate 1e and 4-(tert-butyldimethylsiloxy)-2-butenyl-
trichloroacetimidate (1n) with ent-5 using conditions reported for
these substrates in Tables 1 and 2, respectively, provided (R)-2e
and (R)-2n in 92% ee (83% yield) and 96% ee (98% yield).
To illustrate the potential utility of enantioenriched allylic
trichloroacetamide products, and establish the absolute configura-
tions of 2n and 2k, the following transformations were carried out.
Cleavage of the silyl protecting group of 2n followed by tosylation
provided (R)-N-tosyl-4-vinyloxazolidinone 6 of high enantiopurity
(eq 2).11 The GABA aminotransaminase inhibitor (S)-vigabatrin
(7)12 was readily prepared from 2k by acidic cleavage of the
trichloroacetyl and ester groups.13 To illustrate the use of allylic
trichloroacetamide products for enantioselective synthesis of un-
natural R-amino acids, the double bond of 2f was cleaved with
ozone in basic methanol14 to deliver the differentially protected (S)-
R-amino ester 8 with no detectable loss of enantiomeric purity.15,16
Supporting Information Available: Representative experimental
procedures for trichloroacetimidate preparation and catalytic rearrange-
ment, copies of HPLC and GC traces used to determine enantiopurity,
and copies of 1H and 13C NMR spectra for all new compounds (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
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allylic trichloroacetimidates to provide transposed allylic trichloro-
acetamides in high yield and 92-98% ee, thus providing the first
truly practical method for transforming prochiral allylic alcohols
to enantioenriched allylic amines and their analogues. As (E)-allylic
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