Catalytic asymmetric synthesis of allylic aryl ethers

Article abstract of DOI:10.1021/ol070110b

(Chemical Equation Presented) The reaction of trichloroacetimidate derivatives of (Z)-2-alken-1-ols with phenol nucleophiles in the presence of the palladium(II) catalyst [COP-OAc]₂ provides 3-aryloxy-1-alkenes in high yields and high enantiomeric purity (typically 63-90% yield and 90-97% ee). The reaction is exemplified by 20 examples. The method employs 1 mol % of the commercially available catalysts (S)- or (R)-[COPOAc]₂, produces the branched isomer with unprecedented regioselectivity, and is compatible with the presence of base-labile functionality in either reactant.

Full text of DOI:10.1021/ol070110b

ORGANIC
LETTERS
2007
Vol. 9, No. 5
911-913
Catalytic Asymmetric Synthesis of
Allylic Aryl Ethers
Stefan F. Kirsch,† Larry E. Overman,* and Nicole S. White
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
leoVerma@uci.edu
Received January 15, 2007
ABSTRACT
The reaction of trichloroacetimidate derivatives of (Z)-2-alken-1-ols with phenol nucleophiles in the presence of the palladium(II) catalyst
[COP-OAc]2 provides 3-aryloxy-1-alkenes in high yields and high enantiomeric purity (typically 63 90% yield and 90 97% ee). The reaction is
−
−
exemplified by 20 examples. The method employs 1 mol % of the commercially available catalysts (S)- or (R)-[COPOAc]2, produces the branched
isomer with unprecedented regioselectivity, and is compatible with the presence of base-labile functionality in either reactant.
Enantioenriched chiral allylic aryl ethers are valuable build-
ing blocks for asymmetric synthesis. In recent years, useful
catalytic asymmetric methods for their construction from
phenols (or phenoxides) and prochiral allylic precursors have
been described that employ Pd,1 Ru,2 or Ir3 complexes.4
Allylic substitutions of 2-alken-1-ol precursors brought about
by Pd(0) or Ru(II) complexes afford branched 3-aryloxy-1-
alkene products in generally high enantioselectivity, although
yields can be diminished by competitive formation of achiral
linear products.1,2 The best combination of high enantio-
selectivity, yield, and branched/linear ratios is achieved in
the Ir(I)-catalyzed reactions developed by Hartwig and co-
workers.3 The need to use phenoxides as nucleophiles,
however, provides some limitation to the iridium-catalyzed
method. In this communication, we report a broadly ap-
plicable enantioselective synthesis of chiral 3-aryloxy-1-
alkenes that employs Pd(II) catalysts, proceeds with here-
tofore unprecedented branched/linear ratios, and tolerates
base-labile functionality.
Recently, we disclosed that trichloroacetimidate derivatives
of prochiral (Z)-allylic alcohols are transformed in high
enantioselectivity to branched allylic esters when exposed
to carboxylic acids in the presence of the palladium(II)
catalyst [COP-OAc]2 (1, Figure 1).5,6 In this reaction, the
catalyst is believed to activate the carbon-carbon π-bond
† Current address: Department Chemie, Technische Universita¨t Mu¨nchen,
Lichtenbergstrasse 4, 85747 Garching, Germany.
(1) Reactions with phenols in the presence of Pd(0) complexes: (a)
Uozumi, Y.; Kimura, M. Tetrahedron: Asymmetry 2006, 17, 161-166.
(b) Trost, B. M.; Machacek, M. R.; Tsui, H. C. J. Am. Chem. Soc. 2005,
127, 7014-7024. (c) Trost, B. M.; Crawley, M. L. Chem.-Eur. J. 2004,
10, 2237-2252. (d) Trost, B. M.; Guzner, J. L.; Dirat, O.; Rhee, Y. H. J.
Am. Chem. Soc. 2002, 124, 10396-10415. (e) Trost, B. M.; Tsui, H. C.;
Toste, F. D. J. Am. Chem. Soc. 2000, 122, 3534-3535. (f) Trost, B. M.;
Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545-4554. (g) Trost, B. M.;
Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815-816. (h) Iourtchenko, A.;
Sinou, D. J. Mol. Catal. A: Chem. 1997, 122, 91-93.
(2) Reactions with phenols in the presence of Ru(II) complexes and K2-
CO3: Mbaye, M. D.; Renaud, J.; Demerseman, B.; Bruneau, C. Chem.
Commun. 2004, 1870-1871.
(3) Reactions with phenoxides in the presence of Ir(I) complexes: (a)
Shekhar, S.; Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 11770-11771. (b) Leitner, A.; Shu, C.; Hartwig, J. F. Org. Lett.
2005, 7, 1093-1096. (c) Kiener, C. A.; Incarvito, C.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 14272-14273. (d) Lopez, F.; Ohmura, T.; Hartwig,
J. F. J. Am. Chem. Soc. 2003, 125, 3426-3427.
(4) A number of useful catalytic asymmetric methods for the synthesis
of allylic alkyl ethers have been developed also; representative examples
include: (a) Lyothier, I.; Defieber, C.; Carreira, E. M. Angew. Chem., Int.
Ed. 2006, 45, 6204-6207. (b) Shu, C.; Hartwig, J. F. Angew. Chem., Int.
Ed. 2004, 43, 4794-4797. (c) Trost, B. M.; McEachern, E. J.; Toste, F. D.
J. Am. Chem. Soc. 1998, 120, 12702-12703.
(5) Kirsch, S.; Overman, L. E. J. Am. Chem. Soc. 2005, 127, 2866-
2867.
10.1021/ol070110b CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/03/2007

We next examined other reaction variables and the scope
of the reaction of (Z)-allylic trichloroacetimidate 4a with a
range of phenols. The nature of the solvent had a considerable
effect on the catalytic rate, with the yield of (R)-5a produced
under otherwise identical conditions decreasing in the
following order: CH2Cl2 (85%) > PhMe (38%) > THF
(26%) > MeCN (5%) > DMSO (0%).12 Selecting CH2Cl2
as the optimal solvent, we explored the scope of the reaction
of various phenols with allylic imidate 4a at 38 °C in the
presence of 1 mol % of [(S)-COP-OAc]2 (Table 1). Reactions
Figure 1. Palladium(II) catalysts examined in the allylic etheri-
fication.
Table 1. [(S)-COP-OAc]2-Catalyzed Asymmetric Synthesis of
Allylic Aryl Ethers 5 from Allylic Trichloroacetimidate 4aa,b
time
[h]
yield
[%]c
ee [%]d
(abs configuration)
for attack by the external oxygen nucleophile, with the
trichloroacetimidate functional group both templating the
catalyst to the double bond and serving as a leaving group.
We report herein the [COP-OAc]2-catalyzed reaction of
phenols with (Z)-allylic trichloroacetimidates to provide
branched allylic aryl ethers in high enantiopurity and yield
under mild reaction conditions.
The reaction of (Z)-allylic trichloroacetimidate 4a7,8 with
phenol to give enantioenriched allylic phenyl ether 5a (R2
) H, eq 1) was initially examined using several palladium-
(II) complexes (Scheme 1). Of the catalysts screened, [(S)-
entry
R2
5
1
2
3
4
5
6
7
8
9e
10e
H
36
96
96
36
24
36
36
36
72
72
5a
5b
5c
5d
5e
5f
5g
5h
5i
86
79
63
96
87
93
90
91
90
90
92 (R)
90 (R)
90 (R)
91 (R)
90 (R)
94 (R)
90 (R)
92 (R)
94
4-Me
4-OMe
4-Cl
2-Br
4-OAc
2-OAc
3-OAc
3-CHO
3-NO2
5j
65
a
Conditions: 0.41 mmol of 4a, 1.0 mol % of [(S)-COP-OAc]2, 1.23
mmol (3 equiv) of ArOH, CH2Cl2 (1.0 M), 38 °C. % yields and % ee’s
b
c
are an average of reactions run in triplicate. Yield of pure product after
d
column chromatography. Determined by SFC or HPLC analysis using a
Scheme 1
e
chiral stationary phase. 2 equiv of ArOH.
with phenols containing electron-donating or mild electron-
withdrawing groups provided the corresponding allylic aryl
ethers 5a-e in 90-92% ee and 63-96% yield (entries
1-5).13 Successful reaction of trichloroacetimidate 4a with
2-acetoxy-, 3-acetoxy-, and 4-acetoxyphenol to provide
allylic ethers 5f-h in 90-94% ee and 93-95% yield
demonstrates the compatibility of this synthetic method with
base-labile functionality (entries 6-8). The reaction of
imidate 4a with 3-hydroxybenzaldehyde to give allylic ether
5i in 94% ee and 90% yield also highlights the mildness of
this method (entry 9). Whereas 3-nitrophenol was a com-
petent nucleophile, providing allylic ether 5j in 90% yield,
albeit with reduced enantioselectivity (65% ee, entry 10),14
2-nitrophenol, 4-nitrophenol, 2-cyanophenol, and 2-allylphe-
nol failed to furnish the corresponding allylic ethers.15 The
R absolute configuration of allylic ethers 5a-h was estab-
lished by direct comparison with authentic samples.16,17
COP-OAc]2 (1) and (S)-COP-acac (2) proved to be the most
effective, giving (R)-5a in 92% ee and 86-90% yield; the
chloride-bridged dimer [(S)-COP-Cl]2 (3) showed comparable
enantiomeric selectivity but an inferior catalytic rate.6,9
Because both enantiomers of [COP-OAc]2 are available
commercially, this catalyst was chosen for additional stud-
ies.10,11
(6) (a) Anderson, C. E.; Kirsch, S. F.; Overman, L. E.; Richards, C. J.;
Watson, M. P. Org. Synth. 2007, 84, 148-155. (b) Anderson, C. E.;
Overman, L. E.; Richards, C. J.; Watson, M. P.; White, N. Org. Synth.
2007, 84, 139-147. (c) Stevens, A. M.; Richards, C. J. Organometallics
1999, 18, 1346-1348.
(7) Allylic trichloroacetimidates used in this study were prepared by the
reaction of allylic alcohols with 1 equiv of trichloroacetonitrile (0.2 M in
dichloromethane) in the presence of 0.06 equiv of DBU at room temper-
ature.8
(8) (a) Numata, M.; Sugimoto, M.; Koike, K.; Ogawa, T. Carbohydr.
Res. 1987, 163, 209-225. (b) Nishikawa, T.; Asai, M.; Ohyabu, N.;
Yamamoto, N.; Fukuda, Y.; Isobe, M. Tetrahedron 2001, 57, 3875-3883.
For a discussion of various ways to prepare allylic trichloroacetimidates,
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.
(9) Using 1 mol % of the dimeric catalysts 1 or 3 (or 2 mol % of
monomeric catalyst 2) and identical reaction conditions (3 equiv of phenol,
38 °C, [4a] ) 1 M in CH2Cl2, 36 h). Enantiomeric excess was determined
by HPLC analysis; see Supporting Information for details.
(10) Both enantiomers of [COP-OAc]2 are available from Aldrich
Chemical Co. The planar chiral fragment of enantiomer 1 [(S)-COP-OAc]2
has Rp absolute configuration;10 thus, more precisely, 1 would be called
[(Rp,S)-COP-OAc]2. ent-1, which we have termed [(R)-COP-OAc]2, has
the Sp,R absolute configuration.
(11) The convention of Schlo¨gl is used: Schlo¨gl, K. Top. Stereochem.
1967, 1, 39-91.
(12) Reaction conditions: 3 equiv of phenol, 38 °C, [4a] ) 1 M, 36 h;
all reactions provided (R)-5a in high enantiopurity (92-94% ee).
(13) Identical reaction of imidate 4a with phenol in the presence of [(R)-
COP-OAc]2 provided ent-5a in 86% yield and 92% enantiopurity.
(14) The enantiopurity of 5j decreased to 38% ee when 3 equiv of
3-nitrophenol was employed.
912
Org. Lett., Vol. 9, No. 5, 2007

A salient feature of this catalytic asymmetric synthesis of
3-aryloxy-1-alkenes from 2-alken-1-ol precursors is the
exceptionally high preference for forming the branched allylic
ether product. For example, the corresponding (Z)- or (E)-
1-phenoxy-2-alkenes were not seen by 1H NMR analysis of
crude reaction products. Moreover, capillary GC analysis
showed the branched/linear ratio in the formation of 3-phe-
noxy-1-hexene (5a) to be at least 800:1.18,19
Table 2. Scope of the [(S)-COP-OAc]2-Catalyzed Asymmetric
Synthesis of Allylic Aryl Ethers with Precursors Containing
Additional Functionalitya,b
The scope of the [COP-OAc]2-catalyzed synthesis of
allylic phenyl ethers was explored further by reactions of
four diversely functionalized allylic trichloroacetimidates
4b-e with various phenols (Table 2). These reactions gave
the corresponding allylic ethers 5k-q and 5s-v in 90-97%
ee and 70-97% yield (entries 1-7 and 9-12). 1-Naphthol
was also a competent nucleophile, providing allylic ether 5r
in 98% ee and 61% yield (entry 8). Reactions of imidate 4f
(R1 ) CH2CH2OAc) with phenol and 4-acetoxyphenol gave
the corresponding allylic ethers 5w and 5x in 92-96% ee
and 91-93% yield, again highlighting the compatibility of
this method with base-labile functionality (entries 13 and
14). This catalytic substitution reaction takes place at a
practical rate only when the γ-substituent of the allylic
imidate is unbranched; for example, allylic ether 5y was
obtained in 30% yield after 96 h (entry 15). Reactions of
the E stereoisomer of trichloroacetimidate 4a with phenol
in the presence of 1 mol % of [(S)-COP-OAc]2 under
standard reaction conditions provided (S)-5a in 90% ee and
32% yield, the major side product being the branched allylic
trichloroacetamide product.
time
[h]
yield
ee
entry
R1
R2
5
[%]c [%]d,e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CH2OTBDPS (4c) 4-OMe
CH2OTBS (4c)
72 5k
72 5l
96 5m 70 97
36 5n
36 5o
36 5p
96 5q
82 97 (S)f
81 96
H
4c
4c
4c
4c
4c
4c
4-Me
4-Cl
4-OAc
2,6-F
3-OMe
90 96
97 96
97 90
80 97
61 98
87 90
97 92
91 95
97 92
91 92
93 96
30 90
1-naphtyl 72 5r
CH2CH2OTBS (4d)
H
24 5s
24 5t
36 5u
36 5v
72 5w
48 5x
96 5y
4d
4-OAc
H
4-OAc
H
4-OAc
4-OAc
CH2CH2Ph (4e)
4e
CH2CH2OAc (4f)
4f
C6H11 (4g)
a
Conditions: 0.41 mmol of 4, 1 mol % of [(S)-COP-OAc]2, 1.23 mmol
b
(3 equiv) of ArOH, CH2Cl2 (1.0 M), 38 °C. % yields and % ee’s are an
average of reactions run in triplicate. c Yield of pure product after column
d
chromatography. Determined by SFC or HPLC analysis using a chiral
stationary phase. For entries 1-10, % ee was determined after cleavage
of the silyl protecting group. Absolute configuration was determined by
optical rotation of the product formed after ceric ammonium nitrate
deprotection.
e
f
In summary, a mild catalytic asymmetric etherification is
described that uses a palladium(II) catalyst and phenol
nucleophiles to construct 3-aryloxy-1-alkenes in high enan-
tiopurity and high yield. Attractive features of the method
include the following: only 1 mol % of the commercially
available catalysts (S)- or (R)-[COP-OAc]2 is used; products
are produced in high yields and high % ees; the branched
product is produced with unprecedented regioselectivity; and
the method is compatible with the presence of base-labile
functionality in either reactant.
Acknowledgment. We thank the NSF (CHE-0200786)
for financial support and the Alexander von Humboldt
Foundation for a Feodor Lynen Postdoctoral Fellowship
S.F.K.
(15) When trichloroacetimidate 4a (1 M) was allowed to react with 3
equiv of phenol and 1 equiv of 2-nitrophenol (or 4-nitrophenol, 2-cyanophe-
nol, or 2-allylphenol) in the presence of 1 mol % of [(S)-COP-OAc]2 in
CH2Cl2 at 38 °C for 72 h, the corresponding allylic ether 5a was obtained
in low yields. These experiments and NMR studies of catalyst compositions
show that these 2-substituted phenols deactivate the catalyst.
(16) Prepared from (S)-1-hexyn-3-ol by Mitsunobu reaction with the
phenol followed by Lindlar hydrogenation.17
(17) (a) Landor, S. R.; Miller, B. J.; Tatchell, A. R. J. Chem. Soc. (C)
1971, 2339-2341. (b) Anand, R. V.; Baktharaman, S.; Singh, V. K. J. Org.
Chem. 2003, 68, 3356-3359.
(18) The limits of detection of the branched products by this method
were 0.01%.
Supporting Information Available: Representative ex-
perimental procedures, copies of SFC and HPLC traces used
to determine enantiopurity, 1H and 13C NMR spectra of new
compounds, and details of experiments to establish absolute
configuration of products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) Studies to optimize this transformation are underway.
OL070110B
Org. Lett., Vol. 9, No. 5, 2007
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