Reversible nucleophilic addition can lower the observed enantioselectivity in palladium-catalyzed allylic amination reactions with a variety of chiral ligands

Article abstract of DOI:10.1016/j.tetlet.2015.08.010

Palladium-catalyzed allylic amination is an important synthetic reaction that is also frequently used as a benchmark for the design and evaluation of new chiral ligands. The effect of reversible nucleophilic addition on the reaction of benzylamine with (E)-1,3-diphenylallyl ethyl carbonate (1) in CH₂Cl₂ was examined with 12 different chiral ligands across a range of scaffolding types. In 8 out of 12 cases the observed ee was significantly higher when DBU or Cs₂CO₃ was added to suppress the proton-driven reversibility. For chiral ligand screening with this test reaction, adding DBU or Cs₂CO₃ provides a better measure of the ligand's inherent enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2015.08.010

Tetrahedron Letters 56 (2015) 5445–5448
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Reversible nucleophilic addition can lower the observed
enantioselectivity in palladium-catalyzed allylic amination reactions
with a variety of chiral ligands
Nicholas S. Caminiti, Madison B. Goodstein, Isabelle N.-M. Leibler, Bryan S. Holtzman, Zitong B. Jia,
⇑
Michael L. Martini, Nathaniel C. Nelson, Richard C. Bunt
Department of Chemistry & Biochemistry, Middlebury College, Middlebury, VT 05753, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalyzed allylic amination is an important synthetic reaction that is also frequently used as a
benchmark for the design and evaluation of new chiral ligands. The effect of reversible nucleophilic addi-
tion on the reaction of benzylamine with (E)-1,3-diphenylallyl ethyl carbonate (1) in CH2Cl2 was exam-
ined with 12 different chiral ligands across a range of scaffolding types. In 8 out of 12 cases the observed
ee was significantly higher when DBU or Cs2CO3 was added to suppress the proton-driven reversibility.
For chiral ligand screening with this test reaction, adding DBU or Cs2CO3 provides a better measure of the
ligand’s inherent enantioselectivity.
Received 20 July 2015
Revised 6 August 2015
Accepted 8 August 2015
Available online 12 August 2015
Keywords:
Enantioselective
Palladium catalysis
Allylic amination
Reversibility
Ó 2015 Elsevier Ltd. All rights reserved.
Chiral ligand
Enantioselective allylic substitutions have proven very effective
for synthesizing chiral molecules,1 and palladium-catalyzed allylic
aminations, in particular, have been widely studied due to their
utility.2 During our ongoing Hammett studies of electronically
modified phosphinooxazoline (PHOX) ligands,3,4 we noted
some unusual and inconsistent enantioselective results with
palladium-catalyzed benzyl amine additions to 1,3-diphenylallyl
substrates that led us to believe that reversible product formation
was lowering the observed enantioselectivities. Previous mecha-
nistic studies by Amatore and Jutland5 have established the
reversibility of product formation with secondary amine nucle-
ophiles and achiral bidentate ligands. Additionally, regiospecific
formation and isomerization during palladium-catalyzed synthesis
of unsymmetrical allylic amine products (branched vs linear) have
demonstrated that the reaction conditions have a large impact on
the reversibility of product formation.6–8 Yudin6a,g showed that
adding 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), but few other
bases they screened,9 significantly increased the reaction selectiv-
ity for the kinetically favored, branched allyl amine isomer by
preventing or greatly reducing its proton-driven isomerization
to the linear product that proceeds via reformation of the
Because of our own observations with modified PHOX ligands
and the widespread use of allylic amination as a benchmark test
reaction for asymmetric catalysis and chiral ligand design,10 we
undertook a wider study of enantioselective palladium-catalyzed
allylic aminations. Herein, we present the first examples of asym-
metric palladium catalysis in which the reversible nucleophilic
addition of benzylamine can lower the observed enantioselectivity.
We found that DBU and Cs2CO3, a base not previously examined,
can mitigate these effects with most of the chiral ligands tested.
Initially, we examined the enantioselectivity obtained with the
(S)-PHOX ligand (4) as a function of reaction time using racemic
carbonate 1 and benzylamine as the nucleophile (Scheme 1). We
employed CH2Cl2 as the solvent because it showed a greater
propensity than THF for product isomerization6a and we wanted
to test the enantioselectivity under potential ‘worst case’
conditions. We found that in the absence of added base the
observed ee of (R)-3 dropped significantly over time (Fig. 1). In
contrast, when 3.2 equiv of DBU or Cs2CO3 were employed as a
base additive for the reaction, the observed ee remained both
high and constant over time. Based on TLC and GC/MS analysis,
the reaction with ligand 4 went to completion in 2–3 h without
added base and 15–30 min with added base.11 Consequently, the
0.25 h and 1 h time points without DBU or Cs2CO3 are particularly
notable because they show significant erosion of the product ee
before the reaction is even complete.
p-allylpalladium intermediate.
⇑
Corresponding author. Tel.: +1 802 443 2559; fax: +1 802 443 2072.
E-mail address: rbunt@middlebury.edu (R.C. Bunt).
http://dx.doi.org/10.1016/j.tetlet.2015.08.010
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

5446
N. S. Caminiti et al. / Tetrahedron Letters 56 (2015) 5445–5448
PdIIL*
Ph
2 (L* = 4-15)
BnNH2 (3 equiv.)
OCO2Et
Ph
NHBn
Pd° / Chiral Ligand
CH2Cl2 40 °C
Ph
Ph
Ph
Ph
1
3
(R)-
(
added base)
BnNH2
Pd0L*
BnNH2
Pd0L*
BnNH2
Pd0L*
BnNH2
Pd0L*
Scheme 1. Standard test reaction for enantioselective amination.
The observed ee with no base at 24 h has a larger standard devi-
ation because the catalyst does not always remain active well
beyond the time necessary for the reaction to go to completion.
Once the active catalyst ‘dies’ (formation of palladium black or
other catalytically inactive species), the ee stays fixed at that value
regardless of the length of time the reaction is allowed to proceed.
Control reactions in which isolated samples of (R)-3 were resub-
jected to the reaction conditions without additional starting mate-
rial (1) did not show any change in the ee. However, when a small
amount of 1 was included, the ee of 3 decreased by much more
than could be accounted for by the additional amount of 3 pro-
duced in the reaction (data not shown). Thus, an actively function-
ing catalyst is necessary to observe the back reaction of 3, which
lowers the ee. We found that the rigorous exclusion of oxygen
using strict purge/backfill protocols with argon helped maintain
NH2Bn
NH2Bn
Ph
Ph
Ph
Ph
)-3-H+
(R)-3-H+
(
S
A
A
A
A
H-A
H-A
H-A
H-A
NHBn
Ph
NHBn
Ph
Ph
Ph
(R)-3
(S)-3
Scheme 2. Mechanism for equilibration of (R)-3 and (S)-3.
the active catalyst lifetime. The general robustness of p-allylpalla-
dium chemistry to air and water can obscure this point, as indeed,
O
such measures are not typically necessary.12
i-Pr
N
The racemization mechanism that equilibrates (R)-3 and (S)-3 is
O
shown in Scheme 2. With ligand 4, for example, the
p-allylpalla-
PPh2
Ph2P
N
Fe
dium complex (2) initially forms (R)-3-H+ with high enantioselec-
tivity. The discrete Pd(0)–alkene complex has been omitted from
Scheme 2 for simplicity as the timing of its formation or break-
down with respect to the proton transfer step does not impact this
analysis. (R)-3-H+ is then reversibly deprotonated by either the
excess benzylamine, another product molecule, or the ethyl car-
bonate leaving group acting as a base (AÀ) to give (R)-3. As the
reaction proceeds, more protons are generated and eventually
the palladium-catalyzed back reactions (dashed arrows) to reform
2 become favorable. Because (R)-3 is present in higher concentra-
tions due to the catalyst’s high enantioselectivity, its back reaction
is favored over the back reaction of (S)-3. Effectively (R)-3 and (S)-3
are in equilibrium because (S)-3 can also reform 2, albeit at a
slower rate initially. If the reaction is allowed to proceed long
enough and the palladium-catalyst remains active, an equal mix-
ture of (R)-3 and (S)-3 will result regardless of the initial ligand
enantioselectivity as an ultimate consequence of thermodynamics.
We next investigated the scope of reversible product formation
and the generality of DBU and Cs2CO3 in preventing it. We selected
a variety of commercially available chiral ligands (5–15) having
both C1 and C2 symmetry across a range of scaffolding types
including many of the so called ‘privileged’ chiral ligands13
(Fig. 2). We carried out the same test reaction for each one, but
i-Pr
5 ( , )-FerrocenylPHOX
S SP
4 (S)-PHOX
PPh2
Ar2P
Ar2P
H3C
PPh2
Fe
Fe
H3C
Ar = 3,5-dimethylphenyl
Ar = 3,5-di(trifluoromethyl)phenyl
6 (S,RP)-Josiphos
7 (R,RP)-Walphos
O
O
PPh2
PPh2 MeO
PPh2
PPh2
PAr2
PAr2
MeO
O
O
Ar = 3,5-dimethylphenyl
10
(R)-MeOBIPHEP
8
9
(R)-BINAP
(R)-SEGPHOS
PPh2 Ph2P
NH HN
PPh2 Ph2P
NH HN
O
O
O
O
11 (R,R)-Trost Ligand
12 (R,R)-Naphthyl Trost Ligand
Ph
Ph2P
CH3
PPh2
P
OMe
PPh2
MeO
P
O
O
Ph2P
Ph
CH3
H3C CH3
13 (S,S)-DPPB
14 (S,S)-DIOP
15 (S,S)-DIPAMP
Figure 2. Structures of chiral ligands 4–15.
did not attempt to optimize the reaction conditions (time, temper-
ature, or solvent) to obtain the best enantioselectivity for each chi-
ral ligand. Rather, we kept the reaction conditions standard
(Scheme 1) and looked for differences in the ee when DBU or
Cs2CO3 were added (Table 1). We used 4 h as the initial reaction
time for each ligand. If the reaction was not complete in 4 h, we
used 24 h for that ligand.
Figure 1. Effect of reaction time and added base on the observed ee of (R)-3 with
ligand 4 (PHOX). Each time point is the average of 4–7 individual reaction trials
with error bars showing 1 standard deviation.

N. S. Caminiti et al. / Tetrahedron Letters 56 (2015) 5445–5448
5447
Table 1
problem for DIOP. Regardless, the low enantioselectivity observed
for 14 agrees with literature findings for related alkylation
reactions.20
Observed eea of (R or S)-3 with chiral ligands 4–15
Chiral ligand
Time (h)
% ee no base
% ee DBU
% ee Cs2CO3
DIPAMP (15), likewise, showed low enantioselectivity with or
without base, similar to literature findings for related alkylation
reactions.21 Surprisingly though, with Cs2CO3 the opposite product
enantiomer was obtained. As with ligand 12 and DBU, Cs2CO3 in
this case must have altered the catalyst in some way. Perhaps a
P,O-chelation mode is also possible with 15, but it is without liter-
ature precedent that we are aware of. With ee’s only in the 20–30%
4
5
6
7
8
9
10
11
12
13
14
14
15
4
4
24
24
4
48 5 (R)
27 5 (R)
11 4 (S)
62 2 (S)
96 1 (R)
76 1 (R)
64 ( 2) (S)
41 3 (S)
95 2 (R)
98 1 (R)
91 1 (R)
68 3 (S)
93 4 (R)
77 7 (R)
62 3 (S)
35 8 (S)
97 2 (R)
97 1 (R)
93 3 (R)
66 2 (S)
28 7 (R)
70 2 (S)
14 2 (R)
14 1 (R)
19 4 (S)
5
9
4 (R)
2 (R)
4
4
13 2 (R)
30 2 (S)
78 2 (R)
24
24
24
4
24
24
8
2 (S)
range, the differences in
DG between the (R) and (S) pathways are
4
6
6
1 (S)
3 (R)
2 (R)
60 2 (S)
only 1–1.5 kJ/mol. Consequently, any mechanistic rationale is
rather speculative.
NRb
NRb
In summary, for the majority of ligands tested, the reversibility
of the nucleophilic addition step can lower the observed reaction
enantioselectivity. The magnitude of the effect is time, ligand,
and based on Yudin’s work,6a solvent dependent. Adding either
DBU or Cs2CO3 preserves, or at least more closely approximates,
the inherent enantioselectivity of the chiral ligand by preventing
or substantially minimizing reprotonation of the initial amine
product. DBU and Cs2CO3 have largely similar effects, but they
show some differential impacts on the catalyst reactivity and
absolute configuration of the product in some cases. We are
continuing to investigate the reaction and ligand parameters that
influence reversibility and therefore loss of enantioselectivity in
palladium-catalyzed allylic aminations.
20 5 (R)
29 6 (R)
a
Average of 3–7 individual reaction trials with error range of 1 standard devi-
ation. The ee was determined by chiral HPLC (Chiralcel OJ, 15% i-PrOH/Hexanes).
b
No reaction, only starting material observed by TLC.
Overall, eight out of the twelve ligands tested (4–6, 8–11, and
13) followed a pattern similar to that depicted in Figure 1. The
observed ee was significantly higher when DBU or Cs2CO3 was
added to the reaction. These results suggest that the proton-driven
reversibility shown in Scheme 2 is a pervasive, potential problem
for ligand evaluation and screening. For example, amination with
ligand 5 to form (R)-3 without added base under otherwise fairly
similar conditions (CH2Cl2, 25 °C, 24 h) has been reported in 41%
ee10a (vs 76% or 77% ee with DBU or Cs2CO3 in this study). It
seems likely that in many other cases as well, the addition of
DBU or Cs2CO3 would give a better measure of a chiral ligand’s
inherent enantioselectivity for asymmetric amination.
Four of the ligands tested (7, 12, 14, and 15), however, showed
somewhat disparate results. Both 7 and 12 gave higher ee’s with-
out added base. It is possible for these ligands that reversible
nucleophilic addition is already slow or simply not the reason for
the lower enantioselectivity, or both. Furthermore, it is not surpris-
ing that DIOP (14) and DIPAMP (15) gave low ee’s under all condi-
tions tested as they are more well known for success in
asymmetric hydrogenation reactions.14
The ferrocene based ligands (5–7) all have the possibility for
matched versus mismatched diastereomers (carbon-centered chi-
rality vs planar chirality of ferrocene).15 Although we did not
specifically test for this, mismatched chirality could explain the
somewhat lower ee’s obtained even with added base for all three
ligands. Alternatively, they may simply be inherently less selective
catalysts for this reaction. Regardless, with Walphos (7), DBU and
Cs2CO3 affected the catalyst system in some way that resulted in
lower enantioselectivity than with no base.
With the naphthyl Trost ligand (12), the addition of DBU and
Cs2CO3 resulted in both a much lower ee (vs no base). In fact,
DBU formed a slight excess of the opposite enantiomer of the prod-
uct. The coordination behavior of the Trost ligands (11 and 12) can
be complicated due to the 13-membered ring formed when acting
as a P,P-chelate for palladium in their most enantioselective
mode.16 However, oligomerization and P,O-chelation are also pos-
sible,17 particularly for naphthyl ligand 12.18 Monophosphine ana-
logs of 11 that can only exhibit P,O-chelation also showed reduced
enantioselectivity and gave the opposite enantiomer of the product
in other test reactions.19 Thus, it seems possible that for 12 the
lower ee and reversal of chirality observed with DBU is due to
increased oligomerization or a P,O-chelation mode induced in
some manner by the added base.
Acknowledgments
We thank the Donors of The Petroleum Research Fund, admin-
istered by the American Chemical Society, and the National Science
Foundation (CHE-071451) for support of this research. N.S.C., M.B.
G., and I.N.-M.L. thank Middlebury College for summer financial
support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08.
010.
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