Probing electronic effects in the asymmetric Heck reaction with the BIPI ligands.

Article abstract of DOI:10.1021/ol0340179

[structure: see text] The new BIPI ligands are phosphinoimidazolines that can be electronically tuned in three different ligand regions to explore electronic effects in asymmetric catalysis. Their application to the asymmetric Heck reaction (AHR) in the c

Full text of DOI:10.1021/ol0340179

ORGANIC
LETTERS
2003
Vol. 5, No. 4
595-598
Probing Electronic Effects in the
Asymmetric Heck Reaction with the BIPI
Ligands
Carl A. Busacca,* Danja Grossbach,† Regina C. So, Erin M. O’Brien, and
Earl M. Spinelli
Department of Chemical DeVelopment, Boehringer-Ingelheim Pharmaceuticals, Inc.,
900 Ridgebury Rd., Ridgefield, Connecticut 06877
cbusacca@rdg.boehringer-ingelheim.com
Received January 6, 2003
ABSTRACT
The new BIPI ligands are phosphinoimidazolines that can be electronically tuned in three different ligand regions to explore electronic effects
in asymmetric catalysis. Their application to the asymmetric Heck reaction (AHR) in the creation of a chiral quaternary center is described.
Enantioselectivity is shown for the first time to depend linearly on phosphine electron density. Changing the ligand basicity by variation of
the R or R substituents reverses facial selectivity.
2
3
In 2001 we patented a novel series of ligands for asymmetric
catalysis, the BIPI ligands.1 Our intellectual starting point
was the phosphinooxazolines (PHOX) pioneered by Pfaltz,
Helmchen, and Williams.2 We felt that phosphinoimidazo-
lines would provide a more flexible ligand scaffold, since
the basicity of the ligating nitrogen could be easily tuned by
replacement of the R3 substituent. Importantly, the electronic
requirements of asymmetric reactions could be probed, and
a wide variety of metals and substrates could be accom-
modated by a single ligand class. The ligands are constructed
in modular fashion as shown in Scheme 1.3 Condensation
of an o-haloimidate 1 with a chiral diamine 2 furnishes the
haloimidazolines 3a,b. These compounds were all stable
crystalline solids, with pKa values of 8.5-9.5.3 SNAr reaction
of phosphide nucleophiles with 3a gave phosphinoimidazo-
lines 4. The SNAr reaction required only 1 equiv of nucleo-
phile, despite the presence of the imidazoline NH. This reac-
tion proved to be more sluggish with electron-rich arylfluo-
rides (e.g., R2 ) p-OMePh) though and failed completely
when addition of electron-deficient phosphines was attempted.
For access to these intermediates, we proceeded through
the iodoimidazolines 3b. These species were first substituted
on nitrogen to give 5 and then cross-coupled with a secondary
phosphine or phosphine borane4 complex under palladium
catalysis to afford the desired ligand. Introduction of R3
substituents that were electron-withdrawing facilitated the
cross-coupling, likely by increasing the rate of oxidative
addition. We found the cross-coupling method of Kraatz4 in
† Current address: Schering AG Process Research, D-13342 Berlin.
(1) Busacca, Carl A. U.S. Patent 6,316,620, 2001. Boehringer-Ingelheim
Phosphinoimidazolines. For a recent application of the BIPI ligands to
asymmetric hydrogenation, see: Menges, F.; Neuburger, M.; Pfaltz, A. Org.
Lett. 2002, 4, 4713.
(2) For a review, see: Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000,
33(6), 336-345.
(3) Full experimental details for all ligands are found in Supporting
Information.
(4) (a) Kraatz, H.-B.; Pletsch, A. Tetrahedron: Asymmetry 2000, 11,
1617. (b) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K. J.
Am. Chem. Soc. 1990, 112, 5244.
10.1021/ol0340179 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/30/2003

Scheme 1. Ligand Synthesisa
Scheme 2. Asymmetric Heck Reactiona
a Reagents and conditions: (a) CO, 100 psi, Pd(OAc)2/dppp,
N-methylaminophenol, TEA, DMF, 55%; (b) Tf2O/DMAP, 89%
(c) BIPI ligands, Pd2dba3, PMP, Ph2O, 95 °C 18 h.
Overman using BINAP as ligand.7b We also utilized the
triflate rather than the iodide as our starting point, reasoning
that our ligands would likely be similar to the PHOX ligands
where triflates were found to be superior.6c The substrate
was prepared in two steps via carbonylation of vinyltriflate
6 with N-methylaminophenol and subsequent sulfonation
(Scheme 2).
Our first experiments involved BINAP and the tert-butyl-
phosphinooxazoline ligands. We found that BINAP furnished
the product 8 in 65% ee3 and 90% yield, whereas the t-Bu-
PHOX gave 46% ee in dioxane (20% yield) as determined
by chiral HPLC analysis. We envisioned that triflate 7 was
therefore an interesting and challenging asymmetric Heck
substrate for us to examine with the BIPI ligands.
A single experimental protocol was developed and strictly
adhered to for all ligands.3 The reaction was heated for 18
h at 95 °C and then worked up regardless of the level of
completion, and the product chromatographically isolated.
We felt this would give us some measure of the practicality
of the reaction as the long reaction times common to much
of the asymmetric Heck literature would not be used. We
used diphenyl ether as solvent after examining several
solvents of different dielectric constants and found the less
polar solvents gave the highest enantioselectivities. This
observation has previously been made with a variety of
triflate substrates in the AHR6c reaction. This solvent has
both a fairly low dielectric constant (e ) 3.65) and a high
boiling point, 242 °C, making its use convenient.
The initial screening results are collected in Table 1.
Several conclusions could readily be made. When basic
ligands (R3 ) Me, Bn) were used, we always obtained the
enantiomer opposite from that found with the nonbasic lig-
ands (N-acylated) with the same underlying diamine stereo-
chemistry. In addition, the imidazolines substituted on car-
bon by alkyl groups (fused cyclohexyl, t-butyl) always gave
the enantiomer opposite from that with imidazolines substi-
a Reagents and conditions: (a) EtOH/reflux or TEA/DCM, 44-
98%; (b) Ar2PM, M ) Li, Na, K, THF, 42-90%; (c) R3X, base,
41-88%; (d) R3X, base, 70-99%; (e) Ar2PH, Pd, base, 27-62%.
DMSO to be broadly applicable in this regard. In general,
cross-coupling via the iodide was found to be the more gen-
eral approach, since all ligands could be prepared by this
method, regardless of the phosphine nucleophilicity or aryl-
halide electrophilicity involved. The SNAr reactions are gen-
erally higher yielding, though, and thus were utilized where
possible. In all cases, the moderately air-sensitive ligands
were then purified by chromatography. We utilized C18 flash
chromatography extensively for this purpose. Since oxygen
is far less soluble in polar solvents than in nonpolar ones,
little or no oxidation occurred during purification with the
MeCN-H2O and alcohol-H2O eluents used for this tech-
nique.5
With the newly developed ligands in hand, we chose an
asymmetric Heck reaction (AHR) as our first area of study.
The majority of the work in this area has been carried out
on dihydrofuran and dihydropyrrole substrates.6 Part of the
enantiocontrol in these systems can occur by means of kinetic
resolution of the intermediates which follow â-hydride
elimination.6b We were instead interested in studying the
“moment of truth” in which the new stereocenter was created
and to explore the electronic requirements for this transfor-
mation. To accomplish this for the asymmetric Heck reaction,
it is therefore necessary to generate a quaternary center
without the possibility for olefin isomerization in the product.
This can only be achieved through an intramolecular
process.7
We chose triflate 7 (Scheme 2) as our initial substrate since
its oxindole product 8 had previously been prepared by
(5) (a) Ohsaka, T.; Che, Y.; Tokuda, K. Bull. Chem. Soc. Jpn. 1998, 71,
651. (b) James, H. J.; Broman, R. F. Anal. Chim. Acta 1969, 48, 411.
(6) (a) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis
1997, 1338. (b) Ozawa, F.; Hayashi, T. J. Organomet. Chem. 1992, 428,
267. (c) Ozawa, F.; Kobatake, Y.; Hayashi, T. Tetrahedron Lett. 1993, 34,
2505.
(7) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6477. (b) Ashimori, A.; Bachand, B.; Calter, M. A.;
Govek, S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120,
6488.
596
Org. Lett., Vol. 5, No. 4, 2003

substituted phosphines fall on the line generated. Here the
enantioselectivities cover a broader range (40-78%), and
the best result, R1 ) 3,5-difluoro, is significantly better than
either BINAP or the PHOX ligand for this substrate. This
dependence of stereoselectiVity on phosphine electron density
has neVer been reported in the asymmetric Heck literature.
The diarylimidazoline electronics were then evaluated,
using both para and meta substituents. The results are
collected in Table 2. For the eight ligands examined, the
Table 1. Enantioselectivities from the Initial Ligand Set
R1
R2
R3
solvent yielda (%)
eeb (%)
H
H
H
H
H
H
H
H
(S,S)-C6H5
(R,R)-C6H5
(S,S)-C6H5
(S,S)-C6H5
(S,S)-C6H5
(S,S)-C6H5
benzoyl
p-CF3Bz
2-naphc
1-naphc
methyl
benzyl
Ph2O
Ph2O
Ph2O
Ph2O
DMA
DMA
anisd
Ph2O
76
90
68
85
17
16
21
88
42.2 (+)
41.9 (-)
44.6 (+)
40.6 (+)
20.5 (-)
11.9 (-)
29.2 (+)
29.1 (-)
(R,R)-(CH2)4- acetyl
(S,S)-t-Bu acetyl
a Chromatographically isolated yield after 18 h. b Determined by chiral
HPLC, sign of rotation of major enantiomer. c Naphthoyl. d Anisole.
Table 2. Effect of Diamine Electronics on Enantioselectivity
tuted by aryl groups, irrespective of the N-substituent. The
cyclohexyl system is the least sterically demanding species
we have prepared, and the bis-tert-butyl system is the most
sterically demanding, and yet they give the same major enan-
tiomer in identical ee. Furthermore, higher enantioselectivities
are found with the less bulky aryl substituents. The alkyl-
substituted imidazolines must therefore impart their reversal
of facial selectivity by a purely electronic mechanism. This
was the premise for the development of the BIPI ligands.
The gross electronic tuning (basic vs nonbasic) therefore
allows access to either enantiomeric product. It was also
observed, however, that lower catalytic turnover was found
with the N-alkyl species, so we focused on the N-aroyl
substituents for all of the subsequent Hammett studies. We
first examined the N-benzoyl para substituent. The Hammett
plot of log er (enantiomer ratio) vs σp showed a random
distribution, and the ee’s spanned a fairly small range,
33-48%. We concluded that this substituent is simply too
remote from the metal center to affect the enantioselectivity.
We then turned to the phosphine para and meta substituents.
We maintained the 2-naphthoyl R3 substituent for all
Hammett studies because it gave the highest ee of the
electron-withdrawing groups screened. We also hoped to
minimize any conformational changes in the ligands by
holding this substituent constant. An eight-point Hammett
plot is shown in Figure 1. We were excited to find a clear
linear relationship with F ) +0.53 between the electronic
constant and enanatioselectivity. Both para- and meta-
R1
R2
R3
yielda (%)
eeb (%)
H
H
H
H
H
H
H
H
(S,S)-p-OMeC6H4
(R,R)-p-MeC6H4
(S,S)-C6H5
2-naphc
2-naphc
2-naphc
2-naphc
2-naphc
2-naphc
2-naphc
2-naphc
13
25
68
61
17
12
85
93
51.6 (+)
45.2 (-)
44.6 (+)
48.3 (+)
61.5 (+)
64.6 (-)
46.7 (+)
62.7 (+)
(S,S)-p-FC6H4
(S,S)-p-ClC6H4
(R,R)-p-CF3C6H4
(S,S)-3,5-Me2C6H3
(S,S)-3,5-F2C6H3
a Chromatographically isolated yield after 18 h. All reactions in Ph2O
solvent with PMP as base. b Determined by chiral HPLC, sign of rotation
of major enantiomer. c 2-Naphthoyl.
observed ee range for the transformation was 45-65%, with
both electron-donating and electron-withdrawing groups
Table 3. Optimized BIPI Ligands
R1
R2
R3
yielda (%)
eeb (%)
4-Cl
4-Cl
4-Cl
4-Cl
3,5-F2
3,5-F2
(R,R)-3,5-F2C6H3
(R,R)-3,5-F2C6H3
(R,R)-3,5-F2C6H3
(R,R)-3,5-F2C6H3
(R,R)-3,5-F2C6H3
(R,R)-3,5-F2C6H3
2-naphc
2-naphc
p-OMeBz
p-CF3Bz
2-naphc
2-naphc
25
80.6 (-)
79.3 (-)
78.2 (-)
74.9 (-)
86.8 (-)
87.6 (-)
51d
28
26
50d
38
a Chromatographically isolated yield after 18 h; remainder unreacted s.m.
Reactions in Ph2O with PMP as base unless otherwise noted. b Determined
by chiral HPLC, sign of rotation of major enantiomer. c 2-Naphthoyl.
d 1-(1′-Cyclohexylethyl)-pyrrolidine as base.
Figure 1. Phosphine Hammett plot.
Org. Lett., Vol. 5, No. 4, 2003
597

giving higher enantioselectivity than the neutral (R2 ) H)
species. Deviation from this neutral species led to lower
isolated yields after the proscribed 18 h reaction time for
the para-substituted ligands. For the two meta-disubstituted
ligands, however, the product was afforded in excellent yield.
There appears to be an important steric acceleration of
turnover associated with meta disubstitution. The 3,5-difluoro
ligand clearly possessed the best combination of enantiose-
lectivity (63% ee) and yield (93%), so we focused on this
diamine substitution for our final optimization studies.
To conclude optimization of the BIPI ligands for this
substrate, we therefore combined the best substituents from
the three regions to prepare a small set of hybrid ligands.
These are shown in Table 3. We held the optimized 3,5-
difluoro substitution for the diamine constant and used either
the 4-chloro or 3,5-difluoro substitution on the phosphine.
Three electron-withdrawing R3 substituents were also ex-
amined. Turnover was somewhat diminished with these
highly electron-deficient ligands. We found, however, that
substituting cyclohexylethyl pyrrolidine for PMP as base led
to higher isolated yields after 18 h than was observed with
PMP with no loss in stereoselectivity.8 The 2-naphthoyl R3
substitution furnished the highest ee, as was observed in the
initial ligand set. By combining the best substituents from
the three tunable regions, we were able to arrive at an
optimized ligand that generated oxindole 8 in 88% ee. This
is significantly better than the best enantioselectivity one can
obtain with BINAP or PHOX for this difficult substrate.
Using the BIPI ligands as tools to probe the electronic
requirements of stereoinduction is under very active research.
A study of substrate and reaction scope, crystal structures
of metal complexes, and detailed NMR studies will be
reported shortly in a full paper.
Supporting Information Available: Tables of ee and log
er values and full experimental details and characterization
for all compounds cited. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0340179
(8) Full details of the effect of bases on turnover will be reported shortly
in a full paper.
598
Org. Lett., Vol. 5, No. 4, 2003