Investigation of the electronic origin of asymmetric induction in palladium-catalyzed allylic substitutions with phosphinooxazoline (PHOX) ligands by Hammett and Swain-Lupton analysis of the 13C NMR chemical shifts of the (π-allyl)palladium intermediates

Article abstract of DOI:10.1021/om3007163

Isomeric 4′- and 5′-substituted phosphinooxazoline (PHOX) ligands are used to probe the electronic origins of enantioselective nucleophilic additions to (1,3-diphenylallyl)palladium PHOX ligand complexes. Hammett analysis of the ¹³C NMR chemical shifts of the allyl C-1 and C-3 carbons shows that the major exo diastereomer is less susceptible to differential changes at C-1 and C-3 and that the location of the substituent has a smaller impact on these changes. In contrast, the minor endo diastereomer is more susceptible to differential ¹³C NMR changes at C-1 and C-3 and the location of the substituent has a greater impact on these changes. The endo diastereomer exhibits a pronounced cis effect by the ligating nitrogen and phosphorus atoms across the palladium center that explains its lower reactivity and, therefore, how the enantioselectivity typically obtained with PHOX ligands exceeds the approximately 8/1 ratio of exo to endo intermediates. Swain-Lupton analysis reveals the importance of both resonance and field effects by the substituents regardless of their location and supports the overall electronic control model for enantioselection by PHOX ligands. For rational chiral ligand design and electronic tuning of ligand properties, these results suggest that the overall electronic impact of a remote substituent generally depends more on its identity than on its location within the ligand.

Full text of DOI:10.1021/om3007163

Article
pubs.acs.org/Organometallics
Investigation of the Electronic Origin of Asymmetric Induction in
Palladium-Catalyzed Allylic Substitutions with Phosphinooxazoline
13
(PHOX) Ligands by Hammett and Swain−Lupton Analysis of the C
NMR Chemical Shifts of the (π-Allyl)palladium Intermediates
Paul B. Armstrong, Elizabeth A. Dembicer, Andrew J. DesBois, Jay T. Fitzgerald, Janet K. Gehrmann,
Nathaniel C. Nelson, Amelia L. Noble, and Richard C. Bunt*
Department of Chemistry & Biochemistry, Middlebury College, Middlebury, Vermont 05753, United States
S
* Supporting Information
ABSTRACT: Isomeric 4′- and 5′-substituted phosphinooxazoline
(PHOX) ligands are used to probe the electronic origins of
enantioselective nucleophilic additions to (1,3-diphenylallyl)palladi-
um PHOX ligand complexes. Hammett analysis of the 13C NMR
chemical shifts of the allyl C-1 and C-3 carbons shows that the major
exo diastereomer is less susceptible to differential changes at C-1 and
C-3 and that the location of the substituent has a smaller impact on
these changes. In contrast, the minor endo diastereomer is more
susceptible to differential 13C NMR changes at C-1 and C-3 and the
location of the substituent has a greater impact on these changes. The endo diastereomer exhibits a pronounced “cis effect” by
the ligating nitrogen and phosphorus atoms across the palladium center that explains its lower reactivity and, therefore, how the
enantioselectivity typically obtained with PHOX ligands exceeds the approximately 8/1 ratio of exo to endo intermediates.
Swain−Lupton analysis reveals the importance of both resonance and field effects by the substituents regardless of their location
and supports the overall electronic control model for enantioselection by PHOX ligands. For rational chiral ligand design and
electronic tuning of ligand properties, these results suggest that the overall electronic impact of a remote substituent generally
depends more on its identity than on its location within the ligand.
because electronic tuning is a widely used strategy in chiral
ligand design,11 it is important to understand how the
electronic effects are transmitted from the ligand to the reactive
center(s) and how they impact both the major and the minor
nucleophilic addition pathways. To address these issues, we
expanded our set of 4′-substituted PHOX ligands (2a−f, 4′-
PHOX), synthesized isomeric 5′-substituted PHOX ligands
(3a−f, 5′-PHOX), prepared the corresponding (π-allyl)-
palladium complexes (5a−f and 6a−f), and studied the 13C
NMR chemical shifts of the allyl C-1 and C-3 carbons by two
different linear free energy relationship (LFER)12 methods
single-parameter Hammett analysis and dual-parameter Swain−
Lupton analysis.
Analysis of LFERs has proven useful for understanding a
number of transition-metal-catalyzed reactions,13 and 13C NMR
chemical shifts, though not a direct measure of electron density,
have been correlated both to positive charge density and to the
regioselectivity of nucleophilic attack on (π-allyl)palladium
complexes.14 With achiral ligands, Hammett analysis has been
used to successfully correlate the 13C NMR chemical shifts of
substituted (π-allyl)palladium complexes to the regiochemistry
of nucleophilic attack.15 More broadly, 13C NMR chemical
INTRODUCTION
■
The phosphinooxazoline (PHOX) ligands 1 introduced by
Helmchen, Pflatz, and Williams in 19931 have proven to be one
of the most effective non-C2-symmetric ligand classes for
palladium-catalyzed allylic substitutions.2−4 These ligands are
understood to function both sterically, by controlling the ratio
of the exo to endo (π-allyl)palladium intermediates 4, as well as
electronically, by directing nucleophilic addition trans to
phosphorus (the better acceptor ligand)5 in the favored exo
diastereomer.6 In particular, the low-temperature NMR
structure of the initially formed (alkene)palladium(0) product
complex established the major nucleophilic addition pathway as
trans to phosphorus in the exo diastereomer,7 but it did not
provide any information about the pathway(s) leading to the
minor enantiomer or the role of the minor endo diastereomer
in determining the level of enantioselectivity. Furthermore,
despite the success and intuitive appeal of electronically based
stereocontrol in these systems, steric effects still predominate in
many mixed donor ligands in which a strong electronic trans
effect would have been expected.8 Our previous Hammett
studies of the reaction enantioselectivity with 4′-substituted
PHOX ligands 29 and the 13C NMR chemical shifts and X-ray
structures of (π-allyl)palladium intermediates 510 provided
direct support for the electronic, rather than steric, basis for this
regiocontrol in the nucleophilic addition step. Nevertheless,
Received: July 27, 2012
Published: September 14, 2012
© 2012 American Chemical Society
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Scheme 1. Ligand Synthesis Routes
shifts have been correlated by LFERs in a variety of
systems.16,17 In many instances, 13C NMR chemical shifts
have been found to correlate better with dual-parameter
Swain−Lupton analysis than with single-parameter Hammett
analysis or other dual-parameter methods.18 Although the
Swain−Lupton field (F) and resonance (R) parameters may
not perfectly separate out field and resonance components,12c,19
the F and R parameters are nearly orthogonal to one another as
regression constants.20
revealed that the field contribution is much larger than the
resonance contribution and that the location of the substituent
is less important than its identity.
RESULTS AND DISCUSSION
■
Ligand Synthesis. Most of the 4′-PHOX ligands were
prepared in a manner similar to the original synthesis of the
parent PHOX ligand 122 (Scheme 1, route A). Coupling of
commercially available 4-substituted benzoic acids 7a−e and
(S)-2-amino-3-methyl-1-butanol with Mukiayama’s reagent23
and ring closure with tosyl chloride24 provided oxazolines 9a−
e. Directed ortho lithiation25 and reaction with chlorodiphe-
nylphosphine2a provided ligands 2a−e. The 5′-methyl-sub-
stituted ligand 3c was also prepared by this route. The
regioselectivity of the lithiation and phosphine addition was
confirmed by analysis of the 1H NMR aromatic coupling
patterns, which showed the 2′-hydrogen in 10c had been
replaced by the diphenylphosphino group in 3c and that the
isolated 6′-hydrogen remained.
In studying the isomeric 4′- and 5′-PHOX ligand complexes,
our primary hypothesis was that the change in location of the
substituent relative to both nitrogen (via the oxazoline ring)
and phosphorus would allow us to determine if the substituent
effects are transmitted more via one ligating atom than the
other. In the 4′-PHOX ligands (2a−f) the substituents are meta
to phosphorus and para to nitrogen, but in the 5′-PHOX
ligands (3a−f) they are meta to nitrogen and para to
phosphorus. Comparative Hammett fits employing either σm
for the 4′-PHOX ligands and σp for the 5′-PHOX ligands or σp
for the 4′-PHOX ligands and σm for the 5′-PHOX ligands
should indicate whether nitrogen or phosphorus more
effectively transmits the substituent effects through palladium.
These effects would then have an impact on the allyl C-1 and
C-3 carbons where the nucleophilic addition takes place,
presumably via the trans effect.21 In this manner, the differential
roles of nitrogen and phosphorus in controlling the
enantioselectivity obtained with PHOX ligands can be
distinguished. This goal was only partially realized, as the exo
diastereomers did not show dramatically different 13C NMR
data or Hammett plots. Analysis of the endo diastereomers,
however, was much more differential in terms of both 13C
NMR data and Hammett plots. The Hammett analysis also
revealed a pronounced “cis effect” for the endo diastereomer.
Finally, Swain−Lupton analysis of the substituent effects
Synthesis of the 5′-PHOX ligands was initially envisioned
starting from the commercially available 5-substituted salicylic
acids employing a palladium-catalyzed cross-coupling of the aryl
triflate with (trimethylsilyl)diphenylphosphine26 (Scheme 1,
route B). We developed a convenient protocol that coupled the
salicylic acid to (S)-2-amino-3-methyl-1-butanol, closed the
oxazoline ring, and made the aryl triflate in a single pot.
Although we prepared several other aryl-substituted triflates by
this route (R2 = OMe, Me, F), only the chloro derivative 12e
successfully cross-coupled to give ligand 3e. A number of other
palladium and nickel catalyst/diphenylphosphine combina-
tions27 were tried without success in our hands. These attempts
all resulted in either recovered starting material or decom-
position. Ultimately, we employed the more recent Stoltz t-
BuPHOX synthesis protocol11e using Buchwald’s copper-
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catalyzed cross-coupling28 to prepare most of the 5′-PHOX
ligands (Scheme 1, route C). Formation of oxazolines 15f and
16a,b,d,f proceeded as before from the 4- or 5-substituted 2-
bromobenzoic acids,29 and these underwent cross-coupling
with diphenylphosphine to give both ligand 2f, which could not
be prepared by route A due to rapid decomposition under the
isolation conditions following ortho lithiation/coupling, and
ligands 3a,b,d,f. Thus, by multiple routes we had access to a
variety of 4′- and 5′-substituted PHOX ligands (2a−f and 3a−
f).
a
Table 1. 13C NMR Chemical Shifts of (π-Allyl)palladium
Complexes 5a−f (4′-PHOX)
complex substituent C-1 (exo) C-3 (exo) C-1 (endo) C-3 (endo)
5a
NMe2
OMe
Me
70.10
70.80
70.81
70.98
71.48
71.54
71.85
1.75
100.30
101.06
101.06
101.11
101.56
101.64
101.78
1.48
74.31
74.96
74.85
75.02
75.62
75.62
75.82
1.51
94.42
95.27
95.40
95.56
96.01
96.12
96.62
2.20
5b
5c
4
H
5d
5e
5f
F
Cl
CF3
a → f
(π-Allyl)palladium Complex Formation and NMR
Assignments. Complexes 4, 5a−f, and 6a−f (Chart 1) were
range
a
All chemical shifts are reported in ppm relative to the center line of
the CD2Cl2 pentet at 55.00 ppm.
Chart 1. Exo and Endo (π-Allyl)palladium Complexes
a
Table 2. 13C NMR Chemical Shifts of (π-Allyl)palladium
Complexes 6a−f (5′-PHOX)
complex substituent C-1 (exo) C-3 (exo) C-1 (endo) C-3 (endo)
6a
NMe2
OMe
Me
69.98
70.70
70.82
70.98
71.41
71.51
71.92
1.94
100.39
100.92
101.03
101.11
101.53
101.64
101.89
1.50
73.78
74.61
74.80
75.02
75.41
75.58
76.11
2.33
94.85
95.43
95.48
95.56
96.09
96.06
96.39
1.54
6b
6c
4
H
6d
6e
6f
F
Cl
CF3
a → f
range
prepared from the corresponding ligand and (1,3-
diphenylallyl)palladium chloride dimer by reaction with silver
tetrafluoroborate in acetone.15c Filtration and removal of the
solvent gave the complexes in essentially quantitative yield and
with sufficient purity for NMR spectroscopy. Complexes 46b,30
and 5a−e10 have been previously reported and characterized,
but they were reprepared for direct comparison with complexes
5f and 6a−f in this investigation.31 Although stable for days to
weeks in solution, all the complexes were prepared immediately
prior to acquiring the NMR data. All NMR spectra were taken
in CD2Cl2 and referenced relative to the center line of the
CD2Cl21pentet at 55.00 ppm.
a
All chemical shifts are reported in ppm relative to the center line of
the CD2Cl2 pentet at 55.00 ppm.
(2.20 ppm vs 1.51 ppm) and for 6a−f it is larger at C-1 than at
C-3 (2.33 ppm vs 1.54 ppm). This reversal of which carbon
exhibits the larger range of chemical shifts for the endo
diastereomer indicates that the substituent at the 4′-position
(5a−f) has a greater effect on C-3 (trans to phosphorus) and
the substituent at the 5′-position (6a−f) has a greater effect on
C-1 (trans to nitrogen). Second, the differences in chemical
shift between the 4′-PHOX and 5′-PHOX isomers for any
given substituent vary but are generally much larger for the
endo diastereomers than for the exo diastereomers. The
absolute differences in chemical shifts due to the location of the
substituent vary from 0.00 ppm (5e vs 6e, C-3 exo) to 0.53
ppm (5a vs 6a, C-1 endo). However, for the exo diastereomers
the average absolute difference in chemical shifts at both C-1
and C-3 is 0.07 ppm (5a−f vs 6a−f), but for the endo
diastereomer the average absolute difference in chemical shift at
C-1 is 0.25 ppm and at C-3 is 0.17 ppm (5a−f vs 6a−f). These
two different trends in the 13C NMR chemical shift data both
show that the endo diastereomer is more affected by the
identity and location of the substituent than the exo
diastereomer. Hammett analysis (see below) provides further
insight into this differential behavior of the endo diastereomer.
The difference in 13C chemical shift (Δδ) between C-3 and
C-1 in (π-allyl)palladium complexes has been related to the
overall enantioselectivity of the ligand.32 These differences for
5a−f and 6a−f are reported in Table 3. Overall, the exo
diastereomers show a larger Δδ (∼30.1 ppm) than the endo
diastereomers (∼20.5 ppm). Neither Δδ changes that much
with the identity of the substituent (a → f), though for most of
the complexes the Δδ value gets slightly smaller for more
electron withdrawing substituents. The larger Δδ for the exo
diastereomer has been reported in (1,3-dialkylallyl)palladium
complexes of 1 and related ligands.6c The smaller Δδ value for
The H and 13C NMR assignments for the exo and endo
diastereomers were tentatively made on the basis of analogy
with the literature data for complex 4, which has been
established to exist predominantly in the exo conformation in
solution.31 To confirm the NMR assignments for each of the
complexes in this study, a COSY spectrum was taken to identify
the H-1 and H-3 allyl hydrogens for both the exo and endo
1
diastereomers by their coupling to H-2. This H chemical shift
information was then used to identify the corresponding 13C
signals in the HMQC spectrum (see the Supporting
Information for sample 2D NMR spectra of 5d). Finally, a
13C NMR spectrum was used to obtain the chemical shift values
reported and was used in the following LFER analyses.
13C NMR Chemical Shift Data and Exo/Endo Ratios.
The 13C NMR chemical shifts of allyl carbons C-1 and C-3 in
both the exo and endo diastereomers move downfield as the
substituents become more electron withdrawing (a → f) for
both 5a−f (Table 1) and 6a−f (Table 2). Two trends are of
note: (1) the range of chemical shifts as the substituents change
(a → f) and (2) the difference in chemical shifts due to the
location of the substituent (4′-PHOX vs 5′-PHOX). For the
exo diastereomers the ranges of chemical shift changes for 5a−f
and 6a−f at C-1 and C-3 are quite similar (1.75 and 1.94 ppm
at C-1; 1.48 and 1.50 ppm at C-3). In contrast, for the endo
diastereomer the range for 5a−f is larger at C-3 than that at C-1
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a
b
a
Table 3. Changes in Chemical Shifts (Δδ and Δ(Δδ) ) for
(π-Allyl)palladium Complexes
Table 4. Exo/Endo Ratios for (π-Allyl)palladium
Complexes
4, 5a−f (4′-
4, 6a−f (5′-
exo/endo
PHOX)
PHOX)
substituent
4, 5a−f (4′-PHOX)
4, 6a−f (5′-PHOX)
Δδ
substituent (exo)
Δδ
Δδ
Δδ
Δ(Δδ)
Δ(Δδ)
NMe2
OMe
Me
H
89/11
90/10
88/12
90/10
90/10
89/11
89/11
90/10
91/9
(endo)
(exo)
(endo)
(exo)
(endo)
NMe2
OMe
Me
H
30.20
30.26
30.25
30.13
30.08
30.10
29.93
20.11
20.31
20.55
20.54
20.39
20.50
30.41
30.22
30.21
30.13
30.12
30.13
29.97
21.07
20.82
20.68
20.54
20.68
20.48
20.28
+0.21
−0.04
−0.04
+0.96
+0.51
+0.13
90/10
90/10
87/13
90/10
90/10
F
Cl
F
+0.04
+0.03
+0.04
+0.29
−0.02
−0.52
CF3
Cl
a
Determined by integration of the allyl H-3 signals at δ 5.8−6.0 ppm
CF3
20.80
(exo) and δ 5.5−5.7 ppm (endo) in the corresponding 1H NMR
a
b
Δδ = δ(C-3) − δ(C-1). Δ(Δδ) = Δδ(6a−f) − Δδ(5a−f).
spectra.
similar PHOX ligand (1,3-diphenylallyl)palladium complexes as
8/1 in THF-d8, 11/1 in DMSO-d6, and 6/1 in CDCl3.2,33
Hammett Analysis of 13C NMR Data. On the basis of our
hypothesis that the differing backbone locations of the
substituents on the PHOX ligand (i.e., 5a−f vs 6a−f) would
provide insight into the manner that the electronic influences of
nitrogen and phosphorus are transmitted from the ligand
through palladium to the π-allyl fragment, we carried out
Hammett analysis of the 13C NMR data from Tables 1 and 2
with least-squares linear regression. To compare the effect via
nitrogen or phosphorus, we employed either σm for 5a−f and
σp for 6a−f (Figure 1) or σp for 5a−f and σm for 6a−f (Figure
2). The rationale for these two methods is that in 5a−f the
substituents are meta to phosphorus and para to nitrogen (via
the oxazoline ring) and in 6a−f the substituents are para to
phosphorus and meta to nitrogen. Thus, either σm or σp could
be the “correct” parameter to employ for either ligand isomer if
either nitrogen (trans to C-1) or phosphorus (trans to C-3) has
a dominant effect. These two limiting scenarios would be
distinguished by better correlating Hammett plots in Figure 1 if
the effects via phosphorus (meta to the substituent in 5a−f and
para in 6a−f) dominate or Figure 2 if the effects via nitrogen
(para to the substituent in 5a−f and meta in 6a−f) dominate.
For all of the Hammett plots the slopes are positive,
reflecting the downfield chemical shifts as the substituents
become more electron withdrawing, and vary from +1.20 to
+1.73 in magnitude. For the exo diastereomers (solid symbols
and lines), the goodness of the linear data fits does not differ
that much with either version of the Hammett plot (Figure 1 vs
Figure 2). The R2 values range from 0.72 to 0.81 for all four of
the exo Hammett plots. This outcome suggests that the
electronic influences via nitrogen and phosphorus are both
important and cannot be so easily separated. However, for the
endo diastereomers (open symbols and dashed lines) the C-1
Hammett plot in Figure 1b with σm for 5a−f and σp for 6a−f
(substituent positions relative to phosphorus) is much better
(R2 = 0.91 vs R2 = 0.56) than the corresponding C-1 Hammett
plot in Figure 2b (substituent positions relative to nitrogen). In
contrast, the C-3 endo Hammett plot in Figure 2a with σp for
5a−f and σm for 6a−f (substituent positions relative to
nitrogen) is much better (R2 = 0.87 vs R2 = 0.62) than the
corresponding C-3 endo Hammett plot in Figure 1a
(substituent positions relative to phosphorus). Furthermore,
the slopes for these two better-fitting endo Hammett plots are
the largest of all the Hammett plots at +1.73 and +1.59,
respectively. The better correlations for these two Hammett
plots imply that for the endo diastereomer the dominant effect
the endo complexes in comparison to that for the exo
complexes is likely one of the major reasons that the
enantioselectivity obtained with PHOX ligands, often 95−99+
% ee, can greatly exceed the typical 8/1 ratio of exo to endo
intermediates.2,10 The endo diastereomer must be either less
reactive or less selective than the exo diastereomerlower
reactivity or selectivity for nucleophilic addition trans to
phosphorus by the endo diastereomer would lead to less
formation of the minor enantiomer. Experiments with unsym-
metrical π-allyl substrates and PHOX ligands have shown that
the preference for nucleophilic addition trans to phosphorus is
very high (>104).6b This strong preference suggests that the
difference that allows high enantioselectivity with PHOX
ligands is primarily the lower reactivity of the endo
diastereomer.
As with the chemical shift data itself, the effect of the position
of the substituent (4′ vs 5′) can also be seen in the Δδ data.
The Δδ differences between 5a−f and 6a−f are much smaller
for the exo diastereomers than for the endo diastereomers.
Subtracting the Δδ for 6a−f from Δδ for 5a−f, this Δ(Δδ)
ranges from +0.21 ppm to −0.04 ppm for the exo complex but
ranges from +0.96 ppm to −0.52 ppm for the endo complex
(Table 3). For the endo diastereomer electron-donating groups
at the 5′-position increase the chemical shift difference between
C-3 and C-1 (Δδ) and electron-withdrawing groups at the 5′-
position, −CF3 in particular, reduce it. These Δ(Δδ) trends
provide a different way of viewing the differing overall ranges
and the individual changes in chemical shifts due to the
position of the substituent discussed previously. The Δ(Δδ)
trends also make it easier to see that the endo diastereomers
vary more consistently with the nature of the substituent (a →
f) than the exo diastereomers in a way that relates directly to
the reactivity of the complex.
To determine if these substituent effects have an impact on
the relative stability of the exo and endo diastereomers, the
exo/endo ratio for all of the complexes was determined by
1
integration of the allyl H-3 signals in the H NMR spectrum
(Table 4). This signal was used because it is uniformly distinct
and free from any other overlapping signals for all of the
complexes. The exo/endo ratio is fairly constant around 8/1 to
9/1 for all of the complexes in CD2Cl2 and shows no clear
trends with the changing substituents (a → f). Thus, the
favorability of the exo (π-allyl)palladium intermediate does
seem predominantly steric in nature or is at least unaffected by
these electronic perturbations to the ligand. The exo/endo ratio
has shown some solvent dependence and has been reported for
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13
◆
Figure 1. Hammett plots of δ( C) vs σm for 5a−f and σp for 6a−f, with substituent positions relative to phosphorus: (a) C-3 exo ( ) and C-3 endo
◇
(
□ ■
); (b) C-1 endo ( ) and C-1 exo ( ).
on C-1 occurs via phosphorus and the dominant effect on C-3
occurs via nitrogen, both cis to one another relative to the
palladium center. This combination of phosphorus affecting C-
1 to produce a downfield change in chemical shift and nitrogen
affecting C-3 to produce an upfield change in chemical shift
partially offsets the normal trans effect of phosphorus in the
endo diastereomer that causes the chemical shift of C-3 to be
downfield of C-1 in both diastereomers in the first place.
A “cis effect”, or diminished trans effect, in the endo
diastereomer is not that surprising, considering the steric
factors that influence the exo/endo ratio in the first place.
Unfavorable interactions between the allyl phenyl group and
the equatorial-like phenyl ring on phosphorus disfavor the endo
diastereomer relative to the exo diastereomer, where these
interactions are minimized.2 In palladium complexes of PHOX
ligands with an unsubstituted allyl ligand (π-C3H5) lacking
these steric interactions, the endo diastereomer is actually
favored (55−60%) in solution and the solid state. The endo
diastereomer also shows a greater Δδ value in the 13C NMR
shifts than the minor exo diastereomer (24 ppm vs 18 ppm).34
On the basis of these observations, it is the steric interactions
between the ligand and the allyl group that dictate how well
and in what manner the electronic influences of the ligand are
transmitted across the palladium center to the allyl C-1 and C-3
carbons in each diastereomer. In the 1,3-diphenylallyl
complexes 4−6, both the minor endo diastereomer is more
sensitive to electronic perturbations overall and the allyl C-1
and C-3 carbons are influenced by the cis ligating atom more
than they are in the exo diastereomer. Consequently, the “cis
effect” in the endo diastereomer explains its smaller Δδ and
therefore its lower reactivity than the exo complex.
One of the most notable outliers on all the Hammett plots is
the m-NMe2 group (labeled in Figures 1 and 2). In fact, if this
single data point is removed from the analysis, the R2 values get
dramatically better for all the Hammett plots (Figures S1 and
S2, Supporting Information). The overall similarities for the exo
complexes and differences for the endo complexes, however,
remain as previously described. Removing this data point is not
claimed to be supported on statistical grounds but merely
shows that it contributes a great deal to the scatter in the data.
The −0.16 value of σm for −NMe2 seems to poorly represent
the impact of the substituent on the chemical shift. In fact,
complexes 5a and 6a exhibit the most upfield chemical shifts at
C-1 and C-3 in both the exo and endo diastereomers. For
−NMe2, the σm value reflects more of the inductive electron-
withdrawing nature of the group, and clearly the resonance
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Figure 2. Hammett plots of δ(13C) vs σp for 5a−f and σm for 6a−f, with substituent positions relative to nitrogen: (a) C-3 exo ( ) and C-3 endo
◆
◇
(
□ ■
); (b) C-1 endo ( ) and C-1 exo ( ).
a
Table 5. Swain−Lupton Dual-Parameter Fits of 13C NMR
donation of the −NMe2 group is important regardless of its
position relative to nitrogen and phosphorus. In fact, this type
of impact is more general than just the −NMe2 group. In
separate Hammett plots of the data for complexes 5a−f and
6a−f, each versus σm or σp, both ligand series fit σp better than
σm. (Figures S3−S6, Supporting Information). This outcome
not only supports the importance of resonance effects, as σp is
known to have a strong resonance component,12 but also
suggests that Swain−Lupton field and resonance dual-
parameter analysis might be effective.
Data vs Field (F) and Resonance (R) Parameters
f
% f
r
% r
R2
4, 5a-f
4, 6a-f
average
exo
C-1
C-3
C-1
C-3
C-1
C-3
C-1
C-3
1.99
1.66
2.05
2.12
1.95
1.66
2.16
1.79
1.92
63
63
68
59
60
62
57
64
62
1.15
0.98
0.94
1.49
1.32
1.01
1.62
0.99
1.19
37
37
32
41
40
38
43
36
38
0.99
0.97
0.99
0.99
0.99
0.98
0.99
0.98
endo
exo
endo
Swain−Lupton Analysis of 13C NMR Data. Dual
-parameter regression analysis (δ = f·F + r·R) of the 13C
NMR chemical shift data from Tables 1 and 2 was carried out
with the modified Swain−Lupton parameters that Hansch
recalculated12a,20 to scale directly with Hammett’s original σ
constants. The values for the f and r parameters for all eight
equations are shown in Table 5. Unlike Hammett’s σ constants,
the F and R parameters do not depend on position;
consequently, the data for 5a−f and 6a−f were analyzed
separately. In all cases the correlations are very good (R2 ≥
0.97). Although the separate Hammett plots for 5a−f and 6a−f
(Figures S3−S6, Supporting Information) showed much better
a
δ = f·F + r·R. Values for F and R are taken from ref 12a.
correlations with σp, which suggested the importance of
resonance contributions, the field parameter coefficient (f) is
significantly larger (average of 62% relative contribution) than
the resonance parameter coefficient (r) for all eight equations.
However, this result is not contradictory, as it shows that the
resonance component of each substituent has about the same
impact (average of 38% relative contribution) regardless of its
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location. In addition, this result agrees with the broad
observation that the location of the substituent (5a−f vs 6a−
f) does not have a large impact on the 13C NMR chemical shifts
of the complexes, particularly for the exo diastereomers. The
larger field component also makes sense, considering the
similar chemical shift data trends for 5a−f and 6a−f as well as
the “cis effect” for the endo diastereomer. Thus, the Swain−
Lupton treatment explains the data for the exo diastereomers,
which did not correlate as well with σm and σp by either of our
previous methods, as well as the data for the endo
diastereomers in a consistent fashion.
To provide a more visual assessment of the Swain−Lupton
analysis and to compare the exo and endo diastereomers more
directly, the average values of f (62%) and r (38%) were used to
calculate composite σS‑L constants for each substituent from the
F and R parameters (σS‑L = 0.62F + 0.38R) (Table 6).34 With
both the exo and endo diastereomers. Furthermore, it shows
that the transmission of electronic effects via both nitrogen and
phosphorus is important and does not depend very much on
the position of the substituent relative to nitrogen and
phosphorus.
CONCLUSIONS
■
The results of Hammett and Swain−Lupton analysis work
together to provide complementary information about how
electronic effects influence enantioselectivity in palladium-
catalyzed π-allyl additions with PHOX ligands. Although much
is made of the favorability of nucleophilic addition trans to
phosphorus in the exo diastereomer for electronic reasons,
which these data and analysis supports, it is equally important
to the success of the PHOX ligands that nucleophilic addition
trans to phosphorus in the endo diastereomer is suppressed.
The endo diastereomer is actually more sensitive to electronic
effects than the exo diastereomer and exhibits a stronger “cis
effect”. The transmission of these influences occurs through
both nitrogen and phosphorus via resonance and, more
significantly, field effects. The position of the substituent on
the ligand (4′ or 5′), though useful in these analyses, does not
have a large effect on the overall nature of electronic impact of
the substituent. For rational chiral ligand design that involves
electronic tuning,11 these results suggest that the identity of the
substituent is much more important than its position. This
knowledge should be of great utility to others seeking to
synthesize electronically modified ligands to optimize reactivity
or selectivity, as it is often much easier to introduce electronic
tuning groups at certain ligand locations rather than other
locations due to the starting materials available, the nature of
the substituents, and the types of reactions employed in the
synthesis.
Table 6. Calculated σS‑L Values from Swain−Lupton Analysis
a
substituent
σS‑L
NMe2
OMe
Me
H
−0.279
−0.0330
−0.0622
0.0186
0.130
F
Cl
0.188
CF3
0.296
a
Calculated by the equation σS‑L = 0.62F + 0.38R (the average values
of f and r from Table 5) and the values of F and R taken from ref 12b.
these σS‑L values, the 13C NMR chemical shift data can now be
plotted like a single-parameter LFER. Because the σS‑L values,
like F and R, are independent of position (meta vs para), the
two sets of data (5a−f and 6a−f) were graphed separately
(Figures 3 and 4). In all cases the correlations are very good (R2
≥ 0.97). The success of this σS‑L single-parameter approach is
due to the very similar field and resonance contributions to all
of the 13C NMR chemical shift changes. Moreover, the σS‑L
plots provide a very good graphical impression of how well all
the 13C NMR data are treated with the Swain−Lupton
approach in comparison to the treatment with single-parameter
Hammett analysis (Figures 1 and 2). In addition, the slopes of
the best-fit lines provide a simple measure of the relative
sensitivity of the 13C NMR data to the electronic
perturbationssomething much harder to gauge from the
dual-parameter regression in Table 5. With one exception (C-1
for 5a−f), the slopes of the endo plots are larger than the slopes
for the exo plots for the same carbon. This outcome more
graphically shows that the endo complexes are more sensitive
to electronic perturbations than the exo complexes, as seen
before in the Δ(Δδ) data and the Hammett plots (Figures 1
and 2, with the same exception for C-1 in Figure 2). In
addition, the slopes of all the Hammett plots versus σS‑L are
much larger in magnitude than the slopes for the original
Hammett plots (Figures 1 and 2). Primarily, this increased
slope is a consequence of the compressed range of σS‑L values
(−0.279 to +0.296, a → f). Nonetheless, by taking into account
the dual field and resonance properties of the substituents in a
single parameter with the same fixed proportions of F and R for
all of the substituents, the magnitude of the electronic effects
(i.e., the slope) and the goodness of the fits both increase
dramatically. Overall, the Swain−Lupton analysis provides a
more comprehensive treatment of the electronic effects for
EXPERIMENTAL SECTION
■
General Procedures. All reactions were carried out under
nitrogen or argon, as indicated, in glassware that was oven- or
flame-dried unless otherwise noted. THF, dichloromethane, and
diethyl ether were dried by passage through activated alumina on a
commercial solvent purification system. Hexane and toluene were
purchased in anhydrous grade over 4 Å molecular sieves. Copper(I)
iodide was purified by continuous extraction (Soxhlet) with THF.
Bis(μ-chloro)bis(1,3-diphenyl-η3-allyl)dipalladium,15c and
(trimethylsilyl)diphenylphosphine27b were prepared by literature
methods. 4-(Trifluoromethyl)-2-bromobenzoic acid (13f) was pur-
chased from Ivy Chemicals, and 5-(trifluoromethyl)-2-bromobenzoic
acid (14f) was purchased from Matrix Scientific. All other chemicals
were purchased from standard suppliers and used as received unless
1
otherwise noted. IR spectra were obtained by diffuse reflectance. H
NMR chemical shifts are reported relative to Me4Si and referenced to
the residual CHCl3 solvent signal at 7.27 ppm or the CHDCl2 solvent
signal at 5.32 ppm. 13C NMR chemical shifts are reported relative to
Me4Si and referenced to the center line of the CD2Cl2 pentet at 54.00
ppm. 13C NMR spectra of complexes 5a−f and 6a−f were taken at 25
°C at a concentration of approximately 0.1 M. Multiple quantum
filtered COSY experiments with gradient filtering were obtained in
magnitude mode. HMQC experiments with gradient filtering were
obtained in magnitude mode. Oxazolines 9a−e,9 ligand 1,2 and ligands
2a−e9 have previously been reported and characterized. Complexes
431 and 5a−e10 have previously been reported and characterized but
were reprepared for direct comparison in this study (see the
1
Supporting Information for H, 13C, and 31P NMR data).
5-(Dimethylamino)-2-bromobenzoic Acid (14a).30 To a 100
mL round-bottom flask was added 1.08 g of 5-amino-2-bromobenzoic
acid (5.0 mmol, 1.0 equiv), 2.5 mL of acetic acid, 25.0 mL of
methanol, and 405 mg of formaldehyde as a 37 wt % solution in water
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Figure 3. Hammett plots of δ(13C) vs σS‑L values (from Table 6) for 5a−f: (a) C-3 exo ( ) and C-3 endo ( ); (b) C-1 endo ( ) and C-1 exo ( ).
◆
◇
□
■
(13.5 mmol, 2.7 equiv). The solution was stirred vigorously and cooled
to 0 °C. To the solution was added 943 mg of sodium
cyanoborohydride (15.0 mmol, 3 equiv) in three small portions.
The reaction mixture was warmed to room temperature and then
stirred for an additional 2 h. The solution was concentrated in vacuo,
and the product was then diluted with 100 mL of saturated aqueous
sodium chloride. The resulting solution was adjusted to pH 6 with
saturated aqueous sodium bicarbonate and extracted with ethyl acetate
(3 × 50 mL). The combined organic layers were dried over anhydrous
sodium sulfate and concentrated in vacuo, to give 1.13 g (92%) of a
acid). The reaction mixture was stirred under nitrogen at room
temperature for 2 h. The reaction mixture was concentrated in vacuo,
and the amide was isolated by flash column chromatography (70%
ethyl acetate in hexanes) as a white solid that was used without further
purification in the subsequent step.
To a round-bottom flask containing the amide intermediate (1.0
equiv) was added p-toluenesulfonic acid (1.1 equiv), triethylamine (5
equiv; distilled), and dichloromethane (0.3 M based on amide). The
reaction mixture was heated at reflux under nitrogen for 23 h. Then 0.3
mL of water was added and heating was continued for 1 h. The
reaction mixture was cooled to room temperature, diluted with
dichloromethane, and washed with water (three portions). The
organic layer was dried over anhydrous sodium sulfate and then
concentrated in vacuo. The product was isolated by flash column
chromatography (10−15% ethyl acetate in hexanes) to give the
substituted aryl oxazoline.
(−)-(4S)-4,5-Dihydro-2-(5′-methoxy-2′-bromophenyl)-4-isopro-
pyloxazole (16b). In a 100 mL round-bottom flask was added 248 mg
of (S)-(+)-2-amino-3-methyl-1-butanol (2.4 mmol, 1.2 equiv), 462 mg
of 5-methoxy-2-bromobenzoic acid (14b; 2.0 mmol, 1.0 equiv), 613
mg of 2-chloro-1-methylpyridinium iodide (2.4 mmol, 1.2 equiv), 486
mg of triethylamine (4.8 mmol, 2.4 equiv; distilled), and 20.0 mL of
dichloromethane. The reaction mixture was stirred under nitrogen at
room temperature for 2 h. The reaction mixture was concentrated in
vacuo, and the amide was isolated by flash column chromatography (3
1
yellow solid, confirmed by H NMR to be sufficiently pure for use in
the next step. For analysis, the product was recrystallized from
dichloromethane to yield a pale yellow solid, which was then further
purified by flash column chromatography (3 cm ×13 cm, 80% ethyl
acetate in hexanes). Mp: 149 °C. 1H NMR (400 MHz, CDCl3): δ 9.2
(s, 1 H), 7.5 (d, J = 8.9 Hz, 1 H), 7.3 (d, J = 3.2 Hz, 1 H), 6.7 (dd, J =
8.9, 3.2 Hz, 1 H), 3.0 (s, 6 H). 13C{1H} NMR (100 MHz, CDCl3): δ
171.6, 149.3, 134.8, 130.6, 117.2, 115.6, 107.6, 40.4. IR (solid): 2882,
2813, 2385, 1681, 1120, 813 cm−1. Anal. Calcd for C9H10BrNO2: C,
44.29; H, 4.13; N, 5.74. Found: C, 44.64; H, 4.11; N, 5.80.
General Procedure for Oxazolines 10c, 15f, and 16a,b,d,f. To
a round-bottom flask was added (S)-(+)-2-amino-3-methyl-1-butanol
(1.2 equiv), the substituted benzoic acid (1.0 equiv), 2-chloro-1-
methylpyridinium iodide (1.2 equiv), triethylamine (2.4 equiv;
distilled), and dichloromethane (0.1 M based on substituted benzoic
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Figure 4. Hammett plots of δ(13C) vs σS‑L (from Table 6) for 6a−f: (a) C-3 exo ( ) and C-3 endo ( ); (b) C-1 endo ( ) and C-1 exo ( ).
◆
◇
□
■
cm × 11 cm, 70% ethyl acetate in hexanes) to give 625 mg of a white
solid that was used without further purification in the following step.
1H NMR (400 MHz, CDCl3): δ 7.4 (d, J = 8.8 Hz, 1 H), 7.0 (d, J = 3.1
Hz, 1 H), 6.8 (dd, J = 9.2, 3.1 Hz, 1 H), 6.5 (d, J = 8.5 Hz, 1 H), 3.8
(m, 1 H), 3.8 (s, 3 H), 3.7 (m, 2 H), 3.1 (bs, 1 H), 2.0 (m, 1 H), 1.03
(d, J = 2.1 Hz, 3 H), 1.0 (d, J = 2.0 Hz, 3 H).
(−)-(4S)-4,5-Dihydro-2-(5′-methylphenyl)-4-isopropyloxazole
(10c). Following the general procedure, 544 mg of 5-methylbenzoic
acid (8c; 4.0 mmol) gave 722 mg (89%) of oxazoline 10c as a clear oil.
Data for the amide are as follows. 1H NMR (400 MHz, CDCl3): δ 7.55
(s, 1 H), 7.52 (d, J = 7.1 Hz, 1 H), 7.2 (m, 2 H), 6.8 (d, J = 8.7 Hz, 1
H), 3.9 (m, 1 H), 3.8 (bs, 1 H), 3.7 (m, 2 H), 2.3 (s, 3 H), 2.0 (m, 1
H), 0.95 (m, 6 H). Data for the oxazoline are as follows. [α]D
=
In a 50 mL round-bottom flask containing 625 mg (2.0 mmol, 1.0
equiv) of the amide was added 419 mg of p-toluenesulfonic acid (2.2
mmol, 1.1 equiv), 1.01 g of triethylamine (10.0 mmol, 5 equiv;
distilled), and 6.0 mL of dichloromethane. The reaction mixture was
heated at reflux under nitrogen for 23 h. Then 0.3 mL of water was
added and heating was continued for 1 h. The reaction mixture was
cooled to room temperature, diluted with 25 mL of dichloromethane,
and washed with water (3 × 10 mL). The organic layer was dried over
anhydrous sodium sulfate and then concentrated in vacuo. Flash
column chromatography (3 cm × 12 cm, 15% ethyl acetate in
hexanes) gave 406 mg (68% overall) of oxazoline 16b as a clear oil.
−77.1° (c 2.47, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.9 (m, 1 H),
7.8 (m, 1 H), 7.35 (m, 2 H), 4.5 (m, 1 H), 4.2 (m, 2 H), 2.4 (s, 3 H),
1.95 (m, 1 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ 163.4, 137.8, 131.8, 128.7,
128.0, 127.6, 125.2, 72.3, 69.9, 32.6, 21.1, 18.8, 17.9. IR (neat): 2958,
2900, 1650, 1353, 969, 709 cm−1. Anal. Calcd for C13H17NO: C,
76.81; H, 8.43; N, 6.89. Found: C, 76.60 ; H, 8.52; N, 7.01.
(−)-(4S)-4,5-Dihydro-2-(4′-(trifluoromethyl)-2′-bromophenyl)-4-
isopropyloxazole (15f). Following the general procedure, 538 mg of
4-trifluoromethyl-2-bromobenzoic acid (13f; 2.0 mmol) gave 336 mg
(1.0 mmol) of oxazoline 15f as a clear oil (50%). Data for the amide
are as follows. 1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1 H), 7.61 (s, 2
H), 6.34 (d, J = 8.4 Hz, 1 H), 3.95 (m, 1 H), 3.80 (m, 2 H), 2.50 (bs, 1
H), 2.0 (m, 1 H), 1.05 (d, J = 6.8 Hz, 3 H), 1.04 (d, J = 6.8 Hz, 3 H).
Data for the oxazoline are as follows: [α]D = −41.0° (c 2.05, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.9 (s, 1 H), 7.8 (d, J = 8.1 Hz, 1 H),
1
[α]D = −48.6° (c 1.20, CHCl3). H NMR (400 MHz, CDCl3): δ 7.5
(d, J = 8.8 Hz, 1 H), 7.2 (d, J = 3.0 Hz, 1 H), 6.8 (dd, J = 8.8, 3.0 Hz, 1
H), 4.4 (m, 1 H), 4.15 (m, 2 H), 3.78 (s, 3 H), 1.9 (m, 1 H), 1.0 (d, J
= 6.8 Hz, 3 H), 0.97 (d, J = 6.7 Hz, 3 H). 13C{1H} NMR (100 MHz,
CDCl3): δ 162.5, 158.4, 134.3, 130.6, 117.8, 116.1, 111.9, 72.8, 70.2,
55.4, 32.5, 18.6, 18.1. IR (neat): 3051, 2959, 2903, 2873, 1656, 1467,
1223, 1043, 1016, 839, 732 cm−1. Anal. Calcd for C13H16BrNO2: C,
52.36; H, 5.41; N, 4.70. Found: C, 52.51; H, 5.52; N, 4.75.
7.6 (dd, J = 8.1, 0.6 Hz, 1 H), 4.4 (m, 1 H), 4.2 (m, 2 H), 1.9 (m, 1 H),
1.05 (d, J = 6.8 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H). 13C{1H} NMR
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(100 MHz, CDCl3): δ 161.7, 133.6, 133.2 (q, J = 33 Hz), 131.7, 130.7
(q, J = 4 Hz), 123.9 (q, J = 4 Hz), 122.8 (q, J = 273 Hz), 122.2, 73.1,
70.6, 32.6, 18.6, 18.2. IR (neat): 2961, 1656, 1318, 1130 cm−1. Anal.
Calcd for C13H13BrF3NO: C, 46.45; H, 3.90; N, 4.17. Found: C, 46.46;
H, 3.83; N, 4.25.
red reaction mixture was washed with 25 mL of water and 3 × 25 mL
of saturated aqueous sodium bicarbonate. The organic layer was dried
over anhydrous sodium sulfate and then concentrated in vacuo. Flash
column chromatography (13 × 4.5 cm, 8% ethyl acetate in hexanes)
gave 1.07 g (36%) of 12e as a pale yellow oil. [α]D = −35.4° (c 1.70,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.0 (d, J = 2.5 Hz, 1 H), 7.5
(dd, J = 8.8, 2.8 Hz, 1 H), 7.24 (d, J = 8.8 Hz, 1 H), 4.45 (m, 1 H),
4.15 (m, 2 H), 1.9 (m, 1 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.97 (d, J = 6.8
Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.2, 158.7, 146.1,
134.1, 132.2, 131.6, 123.8, 119.1 (q, J = 239 Hz), 73.1, 70.6, 32.7, 18.8,
18.3. IR (neat): 2963, 1653, 1428, 1204, 1138, 875, 692 cm−1. Anal.
Calcd for C13H13ClF3NO4S: C, 42.00; H, 3.52; N, 3.77. Found: C,
42.29; H, 3.54; N, 3.63.
(−)-(4S)-4,5-Dihydro-2-(5′-(dimethylamino)-2′-bromophenyl)-4-
isopropyloxazole (16a). Following the general procedure, 473 mg of
5-dimethylamino-2-bromobenzoic acid (14a; 1.95 mmol) gave 299 mg
(41%) of oxazoline 16a as a clear/yellow oil. Data for the amide are as
follows. 1H NMR (400 MHz, CDCl3): δ 7.3 (d, J = 8.9 Hz, 1 H), 6.8
(d, J = 3.1 Hz, 1 H), 6.5 (dd, J = 8.9, 3.1 Hz, 1 H), 6.4 (d, J = 8.6 Hz, 1
H), 3.9 (m, 1 H), 3.7 (m, 1 H), 3.1 (bs, 1 H), 2.9 (s, 6 H), 2.0 (m, 1
H), 1.0 (d, J = 6.8 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H). Data for the
1
oxazoline are as follows. [α]D = −34.5° (c 2.13, CHCl3). H NMR
(−)-(4S)-4,5-Dihydro-2-(5′-methyl-2′-(diphenylphosphino)-
phenyl)-4-isopropyloxazole (3c). In a 100 mL round-bottom flask
was added 7.7 mL of anhydrous hexanes and 2.5 mL of 1.04 M sec-
butyllithium in cyclohexane (2.4 mmol, 1.2 equiv). The solution was
cooled to −78 °C, and 234 mg of N,N,N′,N′-tetramethylethylenedi-
amine (2.2 mmol, 1.1 equiv) was added dropwise over 1−2 min. After
the mixture was stirred for 10 min, a solution of 406 mg of 10c (2.0
mmol, 1 equiv) in 1.0 mL of anhydrous hexanes was added dropwise
via cannula over 5 min. The flask was rinsed with an additional 1.0 mL
of anhydrous hexane, which was also added via cannula. The resulting
dark red solution was stirred at −78 °C for 2 h. A solution of 883 mg
of chlorodiphenylphosphine (4.0 mmol, 2 equiv) in 2.0 mL of
anhydrous hexanes was then added dropwise via cannula over 5 min.
The reaction mixture was stirred at −78 °C for 3 h before it was
warmed to room temperature overnight. The reaction was quenched
with 3.0 mL of dry silica gel added via syringe. The mixture was
concentrated in vacuo to absorb the crude product onto the silica gel.
Flash column chromatography (3 cm × 13 cm, 10% ethyl acetate in
(400 MHz, CDCl3): δ 7.3 (d, J = 9.0 Hz, 1 H), 6.9 (d, J = 3.1 Hz, 1
H), 6.5 (dd, J = 8.9, 3.1 Hz, 1 H), 4.3 (m, 1 H), 4.1 (m, 2 H), 2.9 (s, 6
H), 1.85 (m, 1 H), 1.0 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ 163.2, 145.0, 133.5, 129.8,
115.2, 114.4, 106.9, 72.6, 69.9, 40.1, 32.4, 18.6, 18.0. IR (neat): 2958,
1594, 1491, 1362, 1226, 1172, 1109, 1012, 973, 729 cm−1. Anal. Calcd
for C14H19BrN2O: C, 54.03; H, 6.15; N, 9.00. Found: C, 53.99; H,
6.27; N, 8.92.
(−)-(4S)-4,5-Dihydro-2-(5′-fluoro-2′-bromophenyl)-4-isopropy-
loxazole (16d). Following the general procedure, 657 mg of 5-fluoro-
2-bromobenzoic acid (14d; 3.0 mmol) gave 638 mg (74%) of
1
oxazoline 16d as a clear oil. Data for the amide are as follows. H
NMR (400 MHz, CDCl3): δ 7.6 (dd, J = 8.8, 5.0 Hz, 1 H), 7.5 (dd, J =
8.4, 3.0 Hz, 1 H), 7.0 (ddd, J = 8.8, 3.0, 8.4 Hz, 1 H), 6.23 (m, 1 H),
4.0 (m, 1 H), 3.8 (m, 2 H), 2.1 (m, 1 H), 1.86 (bs, 1 H), 1.0 (d, J = 6.8
Hz, 6 H). Data for the oxazoline are as follows. [α]D = −67.4° (c 1.45,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.5−7.6 (dd, J = 8.8, 5.1 Hz,
1 H), 7.4 (dd, J = 8.8, 3.1 Hz, 1 H), 6.9−7.0 (ddd, J = 8.8, 8.8, 3.1 Hz,
1 H), 4.4 (m, 1 H), 4.1−4.2 (m, 2 H), 1.85 (m, 1 H), 1.0 (d, J = 6.8
Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H). 13C{1H} NMR (100 MHz,
CDCl3): δ 161.6 (d, J = 2 Hz), 161.2 (d, J = 248 Hz), 135.1 (d, J = 8
Hz), 131.5 (d, J = 8 Hz), 118.7 (d, J = 22 Hz), 118.4 (d, J = 25 Hz),
116.0 (d, J = 3 Hz), 73.0, 70.4, 32.6, 18.6, 18.1. IR (neat): 2960, 2874,
2360, 1653 cm−1. Anal. Calcd for C12H13BrFNO: C, 50.37; H, 4.58; N,
4.90. Found: C, 50.57; H, 4.43; N, 4.99.
hexanes) gave 428 mg (55%) of the ligand as a oil/foam. [α]D
=
−32.4° (c 2.61, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.8 (m, 1H),
7.3 (m, 10 H), 7.1 (dq, J = 7.9, 0.7 Hz, 1 H), 6.8 (dd, J = 7.9, 4.1 Hz, 1
H), 4.2 (m, 1 H), 3.9 (m, 2 H), 2.4 (s, 3 H), 1.55 (m, 1 H), 0.86 (d, J
= 6.7 Hz, 3 H), 0.75 (d, J = 6.7 Hz, 3 H). 13C{1H} NMR (100 MHz,
CDCl3): δ 163.2, 138.4 (d, J = 12 Hz), 138.2 (d, J = 10 Hz), 135.1 (d,
J = 23 Hz), 134.2, 134.0, 133.9, 133.6 (d, J = 21 Hz), 131.2, 130.5 (d, J
= 4 Hz), 128.4 (d, J = 8 Hz), 128.2, 128.1 (d, J = 11 Hz), 72.8, 70.0,
32.6, 20.8, 18.8, 18.3. 31P{1H} NMR (162 MHz, CDCl3): δ −6.3. IR
(neat): 2960, 1652 cm−1. Anal. Calcd for C25H26NOP: C, 77.50; H,
6.76; N, 3.62. Found: C, 77.27; H, 6.93; N, 3.58.
(−)-(4S)-4,5-Dihydro-2-(5′-(trifluoromethyl)-2′-bromophenyl)-4-
isopropyloxazole (16f). Following the general procedure, 1.08 g of 5-
trifluoromethyl-2-bromobenzoic acid (14f) (4.0 mmol), gave 656 mg
(49%) of oxazoline 16f as a clear oil. Data for the amide are as follows.
1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 2.0 Hz, 1 H), 7.75 (d, J =
(−)-(4S)-2-(5-Chloro-2-(diphenylphosphino)phenyl)-4-iso-
propyl-4,5-dihydrooxazole (3e). In a 25 mL round-bottom flask
was added 750 mg of 12e (2.02 mmol, 1.0 equiv) and 77.5 mg of
dichlorobis(benzonitrile)palladium (0.20 mmol, 0.1 equiv), and the
flask was purged/back-filled with argon three times before the addition
of 5.0 mL of toluene (anhydrous). The solution was then heated to
110 °C, and 785 mg of (trimethylsilyl)diphenylphosphine (3.04 mmol,
1.5 equiv) was added, at which point the solution turned dark red. The
reaction mixture was cooled to room temperature after 19 h and was
then diluted with 10 mL of dichloromethane. The organic mixture was
then washed with 10 mL of saturated aqueous sodium bicarbonate, 10
mL of water, and 10 mL of saturated aqueous sodium chloride before
drying over anhydrous sodium sulfate. The solution was then filtered
and concentrated in vacuo. Flash column chromatography (12 × 4.5
cm, 10% diethyl ether in hexanes) gave 339 mg (41%) of the ligand as
8.4 Hz, 1 H), 7.55 (dd, J = 8.4, 2.0 Hz, 1 H), 6.35 (bs, 1 H), 4.0 (m, 1
H), 3.85 (m, 2 H), 2.5 (bs, 1 H), 2.05 (m, 1 H), 1.08 (d, J = 6.8 Hz, 6
H). Data for the oxazoline are as follows. [α]D = −50.4° (c 2.20,
1
CHCl3). H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 1.8 Hz, 1 H),
7.76 (d, J = 8.4 Hz, 1 H), 7.5 (dd, J = 8.3, 2.0 Hz, 1 H), 4.45 (m, 1 H),
4.2 (m, 2 H), 1.9 (m, 1 H), 1.05 (d, J = 7.2 Hz, 3 H), 0.99 (d, J = 6.8
Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.5, 134.5, 130.9,
129.4 (q, J = 34 Hz), 128.2 (q, J = 4 Hz), 127.9 (q, J = 4 Hz), 125.9
(m), 123.4 (q, J = 272 Hz), 73.1, 70.6, 32.6, 18.7, 18.2. IR (neat):
2961, 2906, 1657, 1698 cm−1. Anal. Calcd for C13H13BrF3NO: C,
46.45; H, 3.90; N, 4.17. Found: C, 46.34; H, 3.87; N, 4.34.
(−)-(4S)-4-Chloro-2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-
phenyl Trifluoromethanesulfonate (12e). In a 100 mL round-
bottom flask was added 1.38 g of 5-chlorosalicylic acid (11e; 8 mmol,
1.0 equiv), 244 mg of 4-dimethylaminopyridine (2 mmol, 0.25 equiv),
991 mg of (S)-(+)-2-amino-3-methyl-1-butanol (9.6 mmol, 1.2 equiv),
50.0 mL of dichloromethane, and 1.84 g of 1-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide (9.6 mmol, 1.2 equiv). The
reaction mixture was stirred at room temperature for 24 h. The
solution was then cooled to −78 °C, and 3.68 g of triethylamine (40
mmol, 5 equiv; distilled) was added. Then, 6.05 g of trifluorometha-
nesulfonic anhydride (24 mmol, 3 equiv) was added dropwise via
syringe over 15 min. After it was stirred for 2.5 h, the solution was
transferred to a 0 °C ice bath before being warmed slowly to room
temperature (the ice bath was allowed to melt) and subsequently
heated to reflux for 12 h. After it was cooled to room temperature, the
1
a yellow oil. [α]D = −34.2° (c 0.97, CHCl3). H NMR (400 MHz,
CDCl3): δ 7.95 (dd, J = 3.3, 2.5 Hz, 1 H), 7.32 (s, 10 H), 7.24 (dd, J =
8.3, 2.3 Hz, 1 H), 6.83 (dd, J = 8.3, 3.5 Hz, 1 H), 4.2 (m, 1 H), 3.9 (m,
2 H), 1.5 (m, 1 H), 0.83 (d, J = 6.8 Hz, 3 H), 0.73 (d, J = 6.8 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ 161.8, 148.8, 137.8 (d, J = 27
Hz), 137.7 (d, J = 24 Hz), 135.3, 134.4, 134.1, 133.8, 133.6, 130.3,
129.8, 128.63 (d, J = 28 Hz), 128.50 (d, J = 11 Hz), 128.47 (d, J = 19
Hz), 73.3, 70.3, 32.8, 18.8, 18.4. 31P{1H} NMR (162 MHz, CDCl3): δ
−6.2. IR (in CDCl3): 3069, 2958, 2928, 2903, 1762, 1654, 1547, 1464,
1434, 1349, 1239, 1206, 1144, 1080, 965 cm−1. Anal. Calcd for
C24H23ClNOP: C, 70.67; H, 5.68; N, 3.43. Found: C, 70.92; H, 5.86;
3.43.
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General Procedure for Ligands 2f and 3a,b,d,f.11c A round-
bottom Schlenk flask equipped with a glass stopcock valve, a glass
stopper, and a stir bar was dried with a heat gun under vacuum and
purged/back-filled with argon three times. After the flask was cooled to
room temperature, copper(I) iodide (0.125 equiv), diphenylphosphine
(1.88 equiv; distilled), N,N-dimethylethylenediamine (0.875 equiv),
and toluene (0.25 M based on aryl bromide, anhydrous) were added.
The solution was stirred at room temperature for 20 min. A solution of
the aryl bromide (1.0 equiv) in toluene (0.25 M, anhydrous) was
added to the mixture in the Schlenk flask, followed by the addition of
solid cesium carbonate (3.75 equiv). The flask was sealed and the
reaction mixture stirred at 110 °C for 6 h, initially forming a turbid
bright yellow solution which gradually darkened until the mixture was
dark red-brown. The reaction mixture was cooled to room
temperature, and the solution was filtered through Celite, which was
then rinsed with dichloromethane (3 × 10 mL). The combined
organic phases were concentrated in vacuo. Complete removal of the
toluene was necessary for clean chromatographic separation. Flash
column chromatography (10% ethyl acetate in hexanes) gave the
ligand.
(−)-(4S)-4,5-Dihydro-2-(5′-methoxy-2′-(diphenylphosphino)-
phenyl)-4-isopropyloxazole (3b). A 50 mL round-bottom Schlenk
flask equipped with a glass stopcock valve, a glass stopper, and a stir
bar was dried with a heat gun under vacuum and purged/back-filled
with argon three times. After the flask was cooled to room
temperature, 23.8 mg of copper(I) iodide (0.125 mmol, 0.125
equiv), 350 mg of diphenylphosphine (1.88 mmol, 1.88 equiv,
distilled), 77.1 mg of N,N-dimethylethylenediamine (0.875 mmol,
0.875 equiv), and 4.0 mL of toluene (anhydrous) were added. The
solution was stirred at room temperature for 20 min. A solution of 298
mg of 16b (1.0 mmol, 1.0 equiv) in 4.0 mL of toluene (anhydrous)
was added to the mixture in the Schlenk flask, followed by the addition
of 1.22 g of cesium carbonate (3.75 mmol, 3.75 equiv). The flask was
sealed and the reaction mixture stirred at 110 °C for 6 h, initially
forming a turbid bright yellow solution which gradually darkened until
the mixture was dark red-brown. The reaction mixture was cooled to
room temperature, and the solution was filtered through Celite, which
was then rinsed with dichloromethane (3 × 10 mL). The combined
organic phases were concentrated in vacuo. Flash column chromatog-
raphy (1.5 cm × 12.5 cm, 10% ethyl acetate in hexanes) gave 278 mg
(69%) of the ligand as a white solid. Mp: 78−79 °C. [α]D = −31.2° (c
1.88, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.5 (m, 1 H), 7.25−7.4
(m, 10 H), 6.88 (dd, J = 8.6, 2.6 Hz, 1 H), 6.81 (dd, J = 8.6, 3.5 Hz, 1
H), 4.2 (m, 1 H), 3.95 (m, 2 H), 3.85 (s, 3 H), 1.6 (m, 1 H), 0.85 (d, J
= 6.7 Hz, 3 H), 0.76 (d, J = 6.7 Hz, 3 H). 13C{1H} NMR (100 MHz,
CDCl3): δ 162.8 (d, J = 3 Hz), 159.1, 138.9 (d, J = 13 Hz), 138.7 (d, J
= 11 Hz), 135.6, 134.2 (d, J = 21 Hz), 133.6 (d, J = 20 Hz), 133.5 (d, J
= 22 Hz), 129.4 (d, J = 22 Hz), 128.3 (d, J = 20 Hz), 128.3 (d, J = 5
Hz), 116.6, 115.0 (d, J = 4 Hz), 73.2, 70.2, 55.4, 32.8, 18.9, 18.5.
31P{1H} NMR (162 MHz, CDCl3): δ −7.54. IR (solid): 3052, 2957,
general procedure, 190 mg of 16a (0.61 mmol) gave 128 mg (50%) of
3a as a white solid. Mp: 128 °C. [α]D = −33.8° (c 1.70, CHCl3). H
1
NMR (400 MHz, CDCl3): δ 7.2−7.3 (m, 10 H), 6.8 (dd, J = 8.6, 4.1
Hz, 1 H), 6.7 (dd, J = 8.6, 2.8 Hz, 1 H), 4.2 (m, 1 H), 3.9 (m, 2 H), 3.0
(s, 6 H), 1.6 (m, 1 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.77 (d, J = 6.7 Hz, 3
H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.7, 145.0, 139.4 (d, J =
18 Hz), 139.3 (d, J = 15 Hz), 135.3, 134.1, 133.9, 133.5, 133.4, 128.1
(d, J = 18 Hz), 128.05 (d, J = 11 Hz), 127.95 (d, J = 21 Hz), 122.8 (d,
J = 18 Hz), 114.0, 113.3 (d, J = 4 Hz), 73.0, 70.0, 40.1, 32.8, 18.8, 18.4.
31P{1H} NMR (162 MHz, CDCl3): δ −8.38. IR (solid): 2868, 1596,
1431, 1182, 1028, 857 cm−1. Anal. Calcd for C26H29PN2O: C, 74.98;
H, 7.02; N, 6.73. Found: C, 74.91; H, 7.05; N, 6.58.
(−)-(4S)-4,5-Dihydro-2-(5′-fluoro-2′-(diphenylphosphino)-
phenyl)-4-isopropyloxazole (3d). Following the general procedure,
377 mg of 16d (1.32 mmol) gave 302 mg (58%) of 3d as a clear oil.
[α]D = −40.3° (c 1.08, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.6−
7.7 (d, J = 9.5, 2.8 Hz, 1 H), 7.25−7.4 (m, 10 H), 7.0 (d, J = 8.4, 2.8
Hz, 1 H), 6.8−6.9 (ddd, J = 9.0, 5.9, 3.4 Hz, 1 H), 4.2 (m, 1 H), 3.85−
4.0 (m, 2 H), 1.55 (m, 1 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.75 (d, J = 6.7
Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.3 (d, J = 249 Hz),
161.7 (d J = 3 Hz), 138.2 (d, J = 13 Hz), 137.9 (d, J = 10 Hz), 136.0
(d, J = 8 Hz), 134.5 (d, J = 4 Hz), 134.3, 134.2, 134.1 (d, J = 21 Hz),
134.0, 133.9, 133.7 (d, J = 8 Hz), 133.5 (d, J = 20 Hz), 128.6, 128.5,
128.4, 128.33, 128.26, 117.3 (d, J = 20 Hz), 116.9 (d, J = 23 Hz), 73.2,
70.2, 32.7, 18.6, 18.4. 31P{1H} NMR (162 MHz, CDCl3): δ −6.8. IR
(neat): 3069, 2958, 2872, 2360, 1653 cm−1. Anal. Calcd for
C24H23PFNO: C, 73.64; H, 5.92; N, 3.58. Found: C, 73.57; H, 6.09;
N, 3.55.
( − ) - ( 4 S ) - 4 , 5 - D i h y d r o - 2 - ( 5 ′ - ( t r i fl u o r o m e t h y l ) - 2 ′ -
(diphenylphosphino)phenyl)-4-isopropyloxazole (3f). Following the
general procedure, 443 mg of 16f (1.31 mmol) gave 309 mg (54%) of
1
3f as a clear oil. [α]D = −27.9° (c 1.2, CHCl3). H NMR (400 MHz,
CDCl3): δ 8.23 (s, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.3−7.5 (m, 10 H),
7.0 (dd, J = 8.0, 3.5 Hz, 1 H), 4.25 (m, 1 H), 3.9 (m, 2 H), 1.55 (m, 1
H), 0.84 (d, J = 6.7 Hz, 3 H), 0.73 (d, J = 6.7 Hz, 3 H). 13C{1H} NMR
(100 MHz, CDCl3): δ 161.6 (d, J = 4 Hz), 144.2 (d, J = 30 Hz), 137.5
(d, J = 12 Hz), 137.1 (d, J = 9 Hz), 134.3 (d, J = 2 Hz), 134.2 (d, J =
21 Hz), 133.6 (d, J = 21 Hz), 132.6 (d, J = 21 Hz), 132.2 (d, J = 18
Hz), 130.1 (q, J = 33 Hz), 128.8 (d, J = 21 Hz), 128.5 (d, J = 7 Hz),
128.4 (d, J = 8 Hz), 126.4 (m), 123.7 (q, J = 272 Hz), 73.3, 70.2, 32.7,
18.8, 18.3. 31P{1H} NMR (162 MHz, CDCl3): δ −4.6. IR (neat):
3072, 2961, 1654, 1479, 1434, 1406, 1355 cm−1. Anal. Calcd for
C25H23F3NOP: C, 68.02; H, 5.25; N, 3.17. Found: C, 68.28; H, 5.18;
N, 3.24.
General Procedure for Complexes 5f and 6a−f.15b To a 10
mL round-bottom flask was added silver tetrafluoroborate (1.05
equiv), bis(μ-chloro)bis(1,3-diphenyl-η3-allyl)dipalladium (0.525
equiv), and acetone (0.33 M based on ligand; distilled and degassed).
The resulting solution was stirred in the dark under nitrogen for 1 h.
The solution was then filtered through Celite in a sintered-glass funnel
into a 10 mL round-bottom flask containing the ligand (1.0 equiv) and
stirred overnight under nitrogen. The solvent was then removed in
vacuo to give the product as a yellow to orange solid in quantitative
yield suitable for NMR studies as an 8/1 to 9/1 mixture of exo/endo
diastereomers, as measured by integration of the allyl H-3 signal at δ
1652, 1593, 1222, 1091, 731 cm−1. Anal. Calcd for C25H26PNO2: C,
74.42; H, 6.50; N, 3.47. Found: C, 74.32; H, 6.58; N, 3.55.
( − ) - ( 4 S ) - 4 , 5 - D i h y d r o - 2 - ( 4 ′ - t r i fl u o r o m e t h y l - 2 ′ -
(diphenylphosphino)phenyl)-4-isopropyloxazole (2f). Following the
general procedure, 253 mg of 15f (0.75 mmol) gave 207 mg (63%) of
2f as a faint yellow oil. [α]D = −22.0° (c 1.34, CHCl3). 1H NMR (400
MHz, CDCl3): δ 8.05 (dd, J = 8.0 Hz, 3.3 Hz, 1 H), 7.6 (d, J = 8.1 Hz,
1 H), 7.2−7.4 (m, 10 H), 7.15 (s, 1 H), 4.2 (m, 1 H), 3.9 (m, 2 H), 1.5
(m, 1 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.75 (d, J = 6.7 Hz, 3 H). 13C{1H}
NMR (100 MHz, CDCl3): δ 161.8 (d, J = 3 Hz), 140.9 (d, J = 30 Hz),
137.2 (d, J = 19 Hz), 137.1 (d, J = 17 Hz), 134.9 (d, J = 18 Hz), 134.1
(d, J = 21 Hz), 133.6 (d, J = 21 Hz), 131.9 (q, J = 32 Hz), 130.3 (dq, J
= 2, 2 Hz), 130.1 (d, J = 2 Hz), 128.8 (d, J = 23 Hz), 128.55 (d, J = 7
Hz), 128.5, 128.4, 124.6 (q, J = 3 Hz), 123.6 (q, J = 273 Hz), 73.3,
70.25, 32.7, 18.8, 18.3. 31P{1H} NMR (162 MHz, CDCl3): δ −4.6. IR
(neat): 3209, 2959, 1652, 1320, 1127, 734, 695 cm−1. Anal. Calcd for
C25H23F3NOP: C, 68.02; H, 5.25; N, 3.17. Found: C, 68.04; H, 5.19;
N, 3.30.
1
5.8−6.0 ppm (exo) and δ 5.5−5.7 ppm (endo) in the H NMR.
(1,3-Diphenyl-η3-allyl)((−)-(4S)-4,5-dihydro-2-(5′-methoxy-2′-
(diphenylphosphino)phenyl)-4-isopropyloxazole)palladium(II) Tet-
rafluoroborate (6b). In a 10 mL round-bottom flask was added
16.9 mg of silver tetrafluoroborate (0.087 mmol, 1.05 equiv), 29.1 mg
of bis(μ-chloro)bis(1,3-diphenyl-η3-allyl)dipalladium (0.043 mmol,
0.525 equiv), and 249 μL of acetone (distilled and degassed). The
resulting solution was stirred in the dark under nitrogen for 1 h. The
solution was then filtered through Celite in a sintered-glass funnel into
a 10 mL round-bottom flask containing 33.4 mg of 3b (0.083 mmol,
1.0 equiv) and stirred overnight under nitrogen. The solvent was then
removed in vacuo to give complex 6b as a yellow solid in quantitative
yield suitable for NMR studies as a 91/9 mixture of exo/endo
diastereomers, as measured by integration of the allyl H-3 signal at δ
5.87 ppm (exo) and δ 5.54 ppm (endo) in the 1H NMR. The product
( − ) - ( 4 S ) - 4 , 5 - D i h y d r o - 2 - ( 5 ′ - ( d i m e t h y l a m i n o ) - 2 ′ -
(diphenylphosphino)phenyl)-4-isopropyloxazole (3a). Following the
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1
was purified for analysis by repeated washes with diethyl ether. Data
for the exo diastereomer are as follows. 1H NMR (400 MHz, CD2Cl2):
δ 6.8−7.8 (m, 24 H), 5.87 (dd, J = 13.8, 9.2 Hz, 1 H), 4.31 (d, J = 10.9
Hz, 1 H), 4.1 (m, 2 H), 3.88 (s, 3 H), 3.15 (m, 1 H), 1.5 (m, 1 H),
0.30 (d, J = 6.9 Hz, 3 H), 0.01 (d, J = 6.8 Hz, 3 H). 13C{1H} NMR
(100 MHz, CD2Cl2): δ 164.7, 111.68 (allyl C-2), 100.92 (allyl C-3),
70.70 (allyl C-1), 69.8, 69.0, 56.4, 31.7, 18.2, 13.9. 31P{1H} NMR (162
MHz, CD2Cl2): δ 19.7. Data for the endo diastereomer are as follows.
1H NMR (400 MHz, CD2Cl2): δ 6.8−7.8 (m, 22 H), 6.60 (t, J = 12.4
Hz, 1 H), 6.44 (dd, J = 12.0, 7.7 Hz, 1 H), 5.54 (t, J = 11.4 Hz, 1 H),
5.00 (d, J = 12.2 Hz, 1 H), 3.9 (m, 1 H), 3.84 (s, 3 H), 3.7 (m, 1 H),
3.45 (m, 1 H), 1.9 (m, 1 H), 1.0 (d, J = 6.9 Hz, 3 H), 0.7 (d, J = 6.9
Hz, 3 H). 13C{1H} NMR (100 MHz, CD2Cl2): δ 164.5, 111.22 (allyl
C-2), 95.43 (allyl C-3), 74.61 (allyl C-1), 69.8, 68.5, 56.4, 31.9, 18.63,
13.2. 31P{1H} NMR (162 MHz, CD2Cl2): δ 24.20. HRMS: calcd for
C40H39BF4NO2PPd 702.1753, found 702.1756.
ether. Data for the exo diastereomer are as follows. H NMR (400
MHz, CD2Cl2): δ 6.7−8.2 (m, 24 H), 5.89 (dd, J = 13.8, 9.2 Hz, 1 H),
4.34 (d, J = 11.0 Hz, 1 H), 4.1 (m, 2 H), 3.15 (m, 1 H), 2.45 (s, 3 H),
1.5 (m, 1 H), 0.3 (d, J = 6.8 Hz, 3 H), 0.0 (d, J = 6.8 Hz, 3 H).
13C{1H} NMR (100 MHz, CD2Cl2): δ 165.0, 111.77 (allyl C-2),
101.03 (allyl C-3), 70.82 (allyl C-1), 69.7, 69.0, 31.7, 21.6 (ArCH3),
18.2, 13.9. 31P{1H} NMR (162 MHz, CD2Cl2): δ 20.4. Data for the
1
endo diastereomer are as follows. H NMR (400 MHz, CD2Cl2): δ
6.7−8.2 (m, 22 H), 6.61 (t, J = 12.2 Hz, 1 H), 6.44 (dd, J = 11.8, 8.0
Hz, 1 H), 5.56 (t, J = 11.4 Hz, 1 H), 5.01 (d, J = 12.0 Hz, 1H), 3.85
(m, 1 H), 3.65 (m, 1 H), 3.45 (m, 1 H), 2.43 (s, 3 H), 1.7 (m, 1 H),
0.85 (d, J = 6.8 Hz, 3 H), 0.75 (d, J = 6.7 Hz, 3 H). 13C{1H} NMR
(100 MHz, CD2Cl2): δ 164.9, 111.27 (allyl C-2), 95.48 (allyl C-3),
74.80 (allyl C-1), 69.7, 68.5, 31.9, 21.3 (ArCH3), 17.6, 13.4. 31P{1H}
NMR (162 MHz, CD2Cl2): δ 24.7. Anal. Calcd for C40H39BF4NOPPd:
C, 62.08; H, 5.08; N, 1.81. Found: C, 62.06; H, 5.09; N, 1.84.
(1,3-Diphenyl-η3-allyl){(−)-(4S)-4,5-dihydro-2-(5′-fluoro-2′-diphe-
nylphosphinophenyl)-4-isopropyloxazole}palladium(II) Tetrafluoro-
borate (6d). Following the general procedure, complex 6d was
obtained as a yellow-orange solid in quantitative yield suitable for
NMR studies as an 87/13 mixture of exo/endo diastereomers, as
measured by integration of the allyl H-3 signal at δ 5.95 ppm (exo)
(1,3-Diphenyl-η3-allyl){(−)-(4S)-4,5-dihydro-2-(4′-trifluoromethyl-
2′-diphenylphosphinophenyl)-4-isopropyloxazole}palladium(II) Tet-
rafluoroborate (5f). Following the general procedure, complex 5f was
obtained as a yellow solid in quantitative yield suitable for NMR
studies as an 89/11 mixture of exo/endo diastereomers, as measured
by integration of the allyl H-3 signal at δ 5.98 ppm (exo) and δ 5.68
ppm (endo) in the 1H NMR. The product was purified for analysis by
repeated washes with diethyl ether. Data for the exo diastereomer are
1
and δ 5.61 ppm (endo) in the H NMR. For analysis, a foamy yellow
solid formed upon washing with diethyl ether and evaporating solvent
under high vacuum. Data for the exo diastereomer are as follows. H
1
1
as follows. H NMR (400 MHz, CD2Cl2): δ 6.8−8.4 (m, 24 H), 5.98
NMR (400 MHz, CD2Cl2): δ 6.7−7.9 (m, 24 H), 5.95 (dd, J = 13.9,
9.4 Hz, 1 H), 4.38 (d, J = 10.9 Hz, 1 H), 4.1 (m, 2 H), 3.13 (m, 1 H),
1.5 (m, 1 H), 0.3 (d, J = 6.9 Hz, 3 H), 0.0 (d, J = 6.8 Hz, 3 H).
13C{1H} NMR (100 MHz, CD2Cl2): δ 163.8, 111.82 (allyl C-2),
101.53 (allyl C-3), 71.41 (allyl C-1),70.0, 69.1, 31.6, 18.1, 13.9.
31P{1H} NMR (162 MHz, CD2Cl2): δ 20.2. Data for the endo
(dd, J = 13.8, 9.4 Hz, 1 H), 4.39 (d, J = 10.9 Hz, 1 H), 4.1−4.2 (m, 2
H), 3.15 (m, 1 H), 1.5−1.6 (m, 1 H), 0.3 (d, J = 6.9 Hz, 3 H), 0.0 (d, J
= 6.9 Hz, 3 H). 13C{1H} NMR (100 MHz, CD2Cl2): δ 164.0, 111.93
(allyl C-2), 101.78 (allyl C-3), 71.85 (allyl C-1), 70.0, 69.3, 31.7, 18.3,
13.9. 31P{1H} NMR (162 MHz, CD2Cl2): δ 21.5. Data for the endo
diastereomer are as follows. 1H NMR (400 MHz, CD2Cl2): δ 6.8−8.4
(m, 22 H), 6.66 (t, J = 12.3 Hz, 1 H), 6.44 (dd, J = 11.9, 7.8 Hz, 1 H),
5.68 (t, J = 11.5 Hz, 1 H), 5.13 (d, J = 12.3 Hz, 1 H), 4.1−4.2 (m, 1
H), 3.95 (t, J = 9.7 Hz, 1 H), 3.55 (m, 1 H), 1.5−1.6 (m, 1 H), 0.87 (d,
J = 6.9 Hz, 3 H), 0.70 (d, J = 6.9 Hz, 3 H). 13C{1H} NMR (100 MHz,
CD2Cl2): δ 163.8, 111.44 (allyl C-2), 96.62 (allyl C-3), 75.82 (allyl C-
1), 71.4, 68.9, 31.6, 18.8, 13.3. 31P{1H} NMR (162 MHz, CD2Cl2): δ
25.8. HRMS: calcd for C40H36BF7NOPPd: 740.1521. Found:
740.1521.
diastereomer are as follows. 1H NMR (400 MHz, CD2Cl2): δ 6.7−7.9
(m, 22 H), 6.63 (t, J = 12.3 Hz, 1 H), 6.44 (dd, J = 12.0, 7.7 Hz, 1 H),
5.61 (t, J = 11.6 Hz, 1 H), 5.03 (d, J = 11.9 Hz, 1 H), 3.92 (t, J = 9.7
Hz, 1 H), 3.67 (m, 1 H), 3.45 (m, 1 H), 1.8 (m, 1 H), 0.87 (d, J = 7.2
Hz, 3 H), 0.70 (d, J = 6.9 Hz, 3 H). 13C{1H} NMR (100 MHz,
CD2Cl2): δ 163.5, 111.38 (allyl C-2), 96.09 (allyl C-3), 75.41 (allyl C-
1), 69.4, 68.7, 31.7, 18.6, 13.3. 31P{1H} NMR (162 MHz, CD2Cl2): δ
24.6. Anal. Calcd for C39H37BF5NOPPd: C, 60.22; H, 4.66; N, 1.80.
Found: C, 59.85; H, 4.82; N, 1.94.
(1,3-Diphenyl-η3-allyl){(−)-(4S)-4,5-dihydro-2-(5′-dimethylamino-
2′-diphenylphosphinophenyl)-4-isopropyloxazole}palladium(II) Tet-
rafluoroborate (6a). Following the general procedure, complex 6a
was obtained as an orange solid in quantitative yield suitable for NMR
studies as a 90/10 mixture of exo/endo diastereomers as measured by
integration of the allyl H-3 signal at δ 5.82 ppm (exo) and δ 5.47 ppm
(1,3-Diphenyl-η3-allyl){(−)-(4S)-4,5-dihydro-2-(5′-chloro-2′-diphe-
nylphosphinophenyl)-4-isopropyloxazole}palladium(II) Tetrafluoro-
borate (6e). Following the general procedure, complex 6e was
obtained as a yellow-brown solid in quantitative yield suitable for
NMR studies as a 90/10 mixture of exo/endo diastereomers, as
measured by integration of the allyl H-3 signal at δ 5.93 ppm (exo)
and δ 5.59 ppm (endo) in the 1H NMR. The product was purified for
analysis by repeated washes with diethyl ether. Data for the exo
1
(endo) in the H NMR. The product was purified for analysis by
repeated washes with diethyl ether. Data for the exo diastereomer are
1
as follows. H NMR (400 MHz, CD2Cl2): δ 6.7−7.8 (m, 24 H), 5.82
1
(dd, J = 13.6, 9.2 Hz, 1 H), 4.24 (d, J = 10.7 Hz, 1 H), 4.1 (m, 2 H),
3.1 (m, 1 H), 3.04 (s, 6 H), 1.5 (m, 1H), 0.3 (d, J = 6.7 Hz, 3 H), 0.0
(d, J = 6.6 Hz, 3 H). 13C{1H} NMR (100 MHz, CD2Cl2): δ 165.5,
111.57 (allyl C-2), 100.39 (allyl C-3), 69.98 (allyl C-1), 69.7, 68.9,
40.2, 31.9, 18.2, 13.9. 31P{1H} NMR (162 MHz, CD2Cl2): δ 19.2. Data
for the endo diastereomer are as follows. 1H NMR (400 MHz,
CD2Cl2): δ 6.7−7.8 (m, 22 H), 6.58 (t, J = 12.4 Hz, 1 H), 6.43 (dd, J =
11.6, 8.0 Hz, 1 H), 5.47 (t, J = 11.5 Hz, 1 H), 4.92 (d, J = 11.4 Hz, 1
H), 3.9 (t, J = 9.6 Hz, 1 H), 3.75 (m, 1 H), 3.45 (m, 1 H), 2.99 (s, 6
H), 1.7 (m, 1 H), 1.0 (d, J = 6.5 Hz, 3 H), 0.70 (d, J = 6.6 Hz, 3 H).
13C{1H} NMR (100 MHz, CD2Cl2): δ 165.4, 111.12 (allyl C-2), 94.85
(allyl C-3), 73.78 (allyl C-1), 69.7, 68.7, 40.3, 32.1, 18.6, 13.4. 31P{1H}
diastereomer are as follows. H NMR (400 MHz, CD2Cl2): 6.8−8.3
(m, 24 H), 5.93 (dd, J = 13.9, 9.3 Hz, 1 H), 4.38 (d, J = 10.9 Hz, 1 H),
4.1−4.2 (m, 2 H), 3.15 (m, 1 H), 1.5 (m, 1 H), 0.29 (d, J = 6.9 Hz, 3
H), 0.00 (d, J = 6.8 Hz, 3 H). 13C{1H} NMR (100 MHz, CD2Cl2): δ
164.0, 111.83 (allyl C-2), 101.64 (allyl C-3), 71.51 (allyl C-1),70.0,
69.9, 32.1, 18.2, 13.9. 31P{1H} NMR (162 MHz, CD2Cl2): δ 20.4. Data
for the endo diastereomer are as follows. 1H NMR (400 MHz,
CD2Cl2): δ 6.8−8.3 (m, 22 H), 6.64 (t, J = 12.3 Hz, 1 H), 6.42 (dd, J =
11.9, 7.5 Hz, 1 H), 5.59 (t, J = 11.6 Hz, 1 H), 5.03 (t, J = 9.8 Hz, 1 H),
3.92 (t, J = 9.7 Hz, 1 H), 3.6 (m, 1 H), 3.4 (m, 1 H), 1.85 (m, 1 H),
0.87 (d, J = 6.9 Hz, 3 H), 0.68 (d, J = 7.0 Hz, 3 H).13C{1H} NMR
(100 MHz, CD2Cl2): δ 163.5, 111.38 (allyl C-2), 96.09 (allyl C-3),
75.41 (allyl C-1), 69.2, 68.8, 31.9, 18.7, 13.3. 31P{1H} NMR (162
MHz, CD2Cl2): δ 27.9. HRMS: calcd for C39H36BClF4NOPPd
706.1258, found 706.1257.
NMR (162 MHz, CD2Cl2):
δ 23.8. HRMS: calcd for
C41H42BF4N2OPPd 715.2070, found 715.2074.
(1,3-Diphenyl-η3-allyl){(−)-(4S)-4,5-dihydro-2-(5′-methyl-2′-di-
phenylphosphinophenyl)-4-isopropyloxazole}palladium(II) Tetra-
fluoroborate (6c). Following the general procedure, complex 6c was
obtained as a yellow solid in quantitative yield suitable for NMR
studies as a 90/10 mixture of exo/endo diastereomers, as measured by
integration of the allyl H-3 signal at δ 5.89 ppm (exo) and δ 5.56 ppm
(1,3-Diphenyl-η3-allyl){(−)-(4S)-4,5-dihydro-2-(5′-trifluoromethyl-
2′-diphenylphosphinophenyl)-4-isopropyloxazole}palladium(II) Tet-
rafluoroborate (6f). Following the general procedure, complex 6f was
obtained as a yellow solid in quantitative yield suitable for NMR
studies as a 90/10 mixture of exo/endo diastereomers, as measured by
integration of the allyl H-3 signal at δ 5.97 ppm (exo) and δ 5.65 ppm
1
(endo) in the H NMR. The product was purified for analysis by
1
recrystallization from acetonitrile by the slow vapor diffusion of diethyl
(endo) in the H NMR. The product was purified for analysis by
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dx.doi.org/10.1021/om3007163 | Organometallics 2012, 31, 6933−6946

Organometallics
Article
repeated washes with diethyl ether. Data for the exo diastereomer are
as follows. H NMR (400 MHz, CD2Cl2): δ 6.8−8.4 (m, 24H), 5.97
(7) (a) Junker, J.; Reif, B.; Junker, B.; Felli, I. C.; Reggelin, M.;
Griesinger, C. Chem. Eur. J. 2000, 6, 3281−3286. (b) Steinhargen, H.;
Reggelin, M.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1997, 36,
2108−2110.
1
(dd, J = 13.9, 9.3 Hz, 1H), 4.44 (d, J = 10.9 Hz, 1H), 4.1−4.2 (m, 2H),
3.15 (m, 1H), 1.55 (m, 1H), 0.3 (d, J = 6.9 Hz, 3H), 0.0 (d, J = 6.7 Hz,
3H). 13C{1H} NMR (100 MHz, CD2Cl2): δ 163.8, 111.93 (allyl C-2),
101.89 (allyl C-3), 71.92 (allyl C-1),70.0, 69.2, 31.6, 18.2, 13.8.
31P{1H} NMR (162 MHz, CD2Cl2): δ 21.2. Data for the endo
diastereomer are as follows. 1H NMR (400 MHz, CD2Cl2): δ 6.8−8.4
(m, 22H), 6.65 (t, J = 12.4 Hz, 1H), 6.44 (dd, J = 12.0, 7.5 Hz, 1H),
5.65 (t, J = 11.5 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 3.94 (t, J = 9.7 Hz,
1H), 3.76 (d, J = 13.1 Hz, 1H), 3.47 (m, 1H), 1.5 (m, 1H), 0.86 (d, J =
7.2 Hz, 3H), 0.70 (d, J = 6.9 Hz, 3H). 13C{1H} NMR (100 MHz,
CD2Cl2): δ 163.6, 111.41 (allyl C-2), 96.39 (allyl C-3), 76.11 (allyl C-
1), 71.3, 68.8, 31.7, 18.6, 13.2. 31P{1H} NMR (162 MHz, CD2Cl2): δ
25.5. Anal. Calcd for C40H36BF7NOPPd: C, 58.03; H, 4.38; N, 1.69.
Found: C, 57.66; H, 4.47; N, 1.92.
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■
S
Hammett plots without m-NMe2 (Figures S1 and S2), separate
Hammett plots for 5a−f and 6a−f versus σm or σp (Figures S3−
S6), substituent constants used (Table S1), NMR data for 4
and 5a−e, sample 2D and 13C NMR spectra for 5d (Figures
1
S7−S9), and H and 13C NMR spectra of 4, 5a−f, and 6a−f.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rbunt@middlebury.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Research Corp., the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, and the National Science Foundation (CHE-071451)
for support of this research and we thank Prof. Sunhee Choi for
helpful discussions of the data.
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