Mechanistic Studies on a Cu-Catalyzed Asymmetric Allylic Alkylation with Cyclic Racemic Starting Materials

Article abstract of DOI:10.1021/jacs.7b02440

Mechanistic studies on Cu-catalyzed asymmetric additions of alkylzirconocene nucleophiles to racemic allylic halide electrophiles were conducted using a combination of isotopic labeling, NMR spectroscopy, kinetic modeling, structure-activity relationships, and new reaction development. Kinetic and dynamic NMR spectroscopic studies provided insight into the oligomeric Cu-ligand complexes, which evolve during the course of the reaction to become faster and more highly enantioselective. The Cu-counterions play a role in both selecting different pathways and in racemizing the starting material via formation of an allyl iodide intermediate. We quantify the rate of Cu-catalyzed allyl iodide isomerization and identify a series of conditions under which the formation and racemization of the allyl iodide occurs. We developed reaction conditions where racemic allylic phosphates are suitable substrates using new phosphoramidite ligand D. D also allows highly enantioselective addition to racemic seven-membered-ring allyl chlorides for the first time.¹H and²H NMR spectroscopy experiments on reactions using allylic phosphates showed the importance of allyl chloride intermediates, which form either by the action of TMSCl or from an adventitious chloride source. Overall these studies support a mechanism where complex oligomeric catalysts both racemize the starting material and select one enantiomer for a highly enantioselective reaction. It is anticipated that this work will enable extension of copper-catalyzed asymmetric reactions and provide understanding on how to develop dynamic kinetic asymmetric transformations more broadly.

Full text of DOI:10.1021/jacs.7b02440

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Article
Mechanistic studies on a Cu-catalyzed asymmetric
allylic alkylation with cyclic racemic starting materials
Emeline Rideau, hengzhi You, Mireia Sidera, Timothy D. W. Claridge, and Stephen P Fletcher
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 31 Mar 2017
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Mechanistic studies on a Cu-catalyzed asymmetric allylic al-
kylation with cyclic racemic starting materials
Emeline Rideaua, Hengzhi Youa, Mireia Sideraa, Timothy D. W. Claridgea*, Stephen P. Fletchera*
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aDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA
ABSTRACT: Mechanistic studies on Cuꢀcatalyzed asymmetric additions of alkylzirconocene nucleophiles to racemic allylic halide
electrophiles were conducted using a combination of isotopic labelling, NMR spectroscopy, kinetic modeling, structureꢀactivity
relationships and new reaction development. Kinetic and dynamic NMR spectroscopic studies provided insight into the oligomeric
Cuꢀligand complexes, which evolve during the course of the reaction to become faster and more highly enantioselective. The Cuꢀ
counterions play a role in both selecting different pathways and in racemizing the starting material via formation of an allyl iodide
intermediate. We quantify the rate of Cuꢀcatalyzed allyl iodide isomerization and identify a series of conditions under which the
formation and racemization of the allyl iodide occurs. We developed reaction conditions where racemic allylic phosphates are suitꢀ
able substrates using new phosphoramidite ligand D. D also allows highly enantioselective addition to racemic 7ꢀmemberedꢀring
1
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allyl chlorides for the first time. H and H NMR spectroscopy experiments on reactions using allylic phosphates showed the imꢀ
portance of allyl chloride intermediates, which form either by the action of TMSCl or from an adventitious chloride source. Overall
these studies support a mechanism where complex oligomeric catalysts both racemize the starting material and select one enantioꢀ
mer for a highly enantioselective reaction. It is anticipated that this work will enable extension of copperꢀcatalyzed asymmetric
reactions and provide understanding on how to develop dynamic kinetic asymmetric transformations more broadly.
selectivity of these reactions is a subtle combination of variaꢀ
bles and is not well understood.
Introduction
Copper is highly valued in synthetic organic chemistry and
a great number of asymmetric Cuꢀcatalyzed methods have
recently been developed.1ꢀ4 However, the mechanisms and
structures of organocopper species involved in asymmetric
addition reactions are poorly understood5,6 despite extensive
studies on nonꢀstereoselective processes.6
CuꢀAAAs using chiral racemic substrates are rare.25,29ꢀ35
Racemic electrophiles bring even more mechanistic complexiꢀ
ty as the relative rates of addition, isomerization and eliminaꢀ
tion of two different chiral starting material / catalyst combiꢀ
nations must be considered. The vast majority of asymmetric
reactions involving racemic substrates and a chiral catalyst are
kinetic resolutions.36ꢀ41 To overcome the limitation of incomꢀ
plete conversions (50% maximum theoretical yield), elegant
processes have been designed to transform both enantiomers
of racemic starting materials into a single enantiomer of prodꢀ
uct. Dynamic kinetic resolution38,42,43 (DKR) involves the
rapid racemization of the starting material while only one
enantiomer of the starting material reacts. As far as we are
aware no Cuꢀcatalyzed methods have been developed which
apply the DKR strategy. Dynamic kinetic asymmetric transꢀ
formations9,32,44ꢀ48 (DYKATs) are deracemisation / symmetriꢀ
sation methods where both enantiomers of starting material are
converted into a common intermediate, usually a pseudoꢀ
prochiral πꢀcomplex as seen in Pdꢀ or Irꢀchemistry.
Alexakis reported CuꢀAAAs of Grignard reagents with raꢀ
cemic cyclic allylic bromides which were initially suspected to
proceed through DYKAT mechanisms25,32,33 (Figure 1b) where
racemic allyl bromides would form diastereomeric σꢀCu comꢀ
plexes that rapidly desymmetrize via πꢀallyl complexes. Howꢀ
ever, detailed study by Alexakis and coꢀworkers using a comꢀ
bination of experimental and computational analyses upended
the initially proposed mechanism.25 A series of insightful
studies concluded that in these reactions the catalyst promotes
a distinct reaction pathway for each enantiomer to provide a
common product. Such reactions are direct enantioconvergent
transformations (DETs).25,34
In the last decades, asymmetric allylic alkylation (AAA)
reactions have emerged as powerful tools7ꢀ12 that may accomꢀ
modate both achiral and chiral substrates. Enantioselective Cuꢀ
catalyzed AAA to prochiral materials can now be readily
achieved by an array of nucleophiles, ligands, and leaving
groups.1,2,10,12ꢀ18 While numerous mechanistic overviews have
been outlined, detailed analyses of asymmetric Cuꢀcatalyzed
pathways are scarce and rely on analogy with work on stoichiꢀ
ometric nonꢀenantioselective methods. To date, the most inꢀ
sight into these mechanisms has been brought by the Bäckꢀ
vall,19ꢀ21 Nakamura,6,22ꢀ24 Alexakis25 and Feringa10 groups, all
of which clearly emphasize the complexity of these mechaꢀ
nisms and the challenges associated with their study.
Most nonꢀstabilized nucleophiles (R2Zn, RMgX and AlR3)
used in asymmetric Cuꢀcatalyzed reactions are assumed to
undergo transmetallation to Cuꢀspecies as a key step. Howevꢀ
er, as far as we are aware, spectroscopic demonstration of
transmetallation has only been observed in the addition of
Grignard reagents to preꢀcatalytic Cuꢀferrocenyl dimers,26
addition of diorganozinc nucleophiles to Cuꢀphosphoramidite
ligand complexes27 and for organolithium reagents used in Cuꢀ
catalyzed AAAs.28 Upon addition of the allylic substrate,
oxidative addition is believed to occur, providing many plauꢀ
sible σꢀ or πꢀCuꢀsubstrate complexes, which may rapidly
interconvert and involve various SN2 or SN2’ and syn or anti
mechanisms, and is followed by reductive elimination (Figure
1a). What controls the overall chemoꢀ, regioꢀ and enantioꢀ
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(Scheme 1).61 A variety of highly enantioenriched products
could be obtained at room temperature in high yield, and the
method was also used to synthesize bioactive natural products
used as traditional treatments for tuberculosis and leprosy.
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Scheme 1. Cu-AAA using racemic cyclic allyl chloride 1 and alkylzir-
conocenes.61
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aPrepared using (R,R,R)ꢀA.
During this work we observed a clear dependence between
ee and Cuꢀhalides (Figure 2a, entry 1ꢀ3). CuI gave the best
results which we attribute to the iodide promoting racemizaꢀ
tion of the starting material. However, CuOTf also provided
products with reasonably high levels of ee (71% ee, entry 5).
1H NMR spectroscopic studies aimed at identifying the
pathways involved were carried out by in situ NMR and
showed clean and slow conversion of allyl chloride 1 to prodꢀ
uct, as well as the constant presence of allyl iodide 2 in low
(~3 mol%) concentrations. The CuI-A catalyst is believed to
form 2 from 1 via SN2’ chemical exchanges, as observed by
EXSY (Figure 2b) and we speculated that this reaction would
racemize 2. Further studies using allyl bromide showed that
CuI-A both formed allyl iodide 2 and mediated isomerization
of the allyl bromide. Further, interconversion between allyl
bromide and 2 occur solely by SN2’ mechanisms on the NMR
timescale. We also observed deshielding of catalyst benzylic
signals over the course of the reaction by 1H NMR spectroscoꢀ
py (Figure 2c).62 Interestingly, this correlates well to an inꢀ
crease in the ee of the product over time; from 85% ee at
10 min, 90% ee at 2 h and 95% ee overnight. It would seem
that the catalytic species are evolving toward a more highly
enantioselective catalyst, and we speculated that the catalyst
species evolved to contain chloride anions during the reaction.
Based on these experiments we proposed the mechanism
shown in Figure 2d. This does not provide any insight into the
CꢀC bondꢀforming step, but is suggestive of a generally useful
pathway for racemic starting materials where a catalyst selects
one enantiomer of an allylic substrate for the reaction, while
racemization of the starting material replenishes the more
reactive enantiomer. Overall such a process may be highly
stereoselective – depending on the kinetics (as well as selecꢀ
tivity and robustness) of all of these different processes. A Cuꢀ
catalyzed heterocyclic AAA of alkylzirconocenes to racemic
3,6ꢀdihydroꢀ2Hꢀpyrans was also developed.63 Unfortunately
these systems do not work well, but showed remarkable mechꢀ
anistic diversity for a priori similar conditions.
Figure 1. Mechanisms of copper-catalyzed asymmetric allylic alkyla-
tions. a) Generally understood mechanism using prochiral starting materiꢀ
als, this process is highly complex and still not well understood. b) Initialꢀ
ly proposed mechanism for a Cuꢀcatalyzed AAA with racemic allyl broꢀ
mides and Grignard reagents.25,32,33 c) Example of a Cuꢀcatalyzed direct
enantioconvergent transformation.34
There are other examples of DETs providing very high
yields and enantioselectivity, even though the design of DETs
is presumably extremely challenging, as substrateꢀ and cataꢀ
lystꢀcontrolled selectivities need to be somehow balanced. For
example, Sawamura34 described a Cuꢀcatalyzed DET of boꢀ
ronic ester nucleophiles to racemic cyclic esters (Figure 1c).
This group has recently reported a different Cuꢀcatalyzed
AAA with linear racemicꢀspecies that may involve multiple
allylcopper(III) species in rapid equilibrium.35
In some cases considerable mechanistic insight into comꢀ
plex organometallic reactions can be elucidated by in situ
NMR spectroscopic studies.6,49ꢀ53 Mechanistic NMR studies of
asymmetric Cuꢀcatalyzed methods are rare, presumably beꢀ
cause of the high reactivity of the reagents (requiring cryogenꢀ
ic temperatures and rigorously dry conditions), the complexity
of the reactions, the sensitivity of these processes to reaction
parameters (requiring expensive NMR solvents) and the large
quadrupole moment of Cu precluding its ready observation by
NMR. Primary organocopper(I) species are dynamic and reacꢀ
tive entities with a tendency to aggregate, resulting in complex
mixtures of species.50 Here aggregation and reactivity are
strongly linked to reaction outcome (yield, chemoꢀ and enanꢀ
tioꢀselectivity) and are highly dependent on solvent interacꢀ
tions, counterion and ligand effects as well as more tractable
variables such as concentration and temperature.3,26,50,54ꢀ56
Gschwind’s elegant work shed light on the nature of preꢀ
catalytic
Cuꢀcomplexes
in
solution
using
NMR
spectroscopy.27,57ꢀ60
We recently reported a Cuꢀcatalyzed AAA with racemic
cyclic allyl chlorides 1 and alkylzirconocenes using CuIꢀA
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Entry LG CuX Solvent ee§
Time
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Cl
CuI
CHCl3 93
Cl CuBr CH2Cl2 73
Cl CuCl CH2Cl2 49
Cl
CuOTf CH2Cl2 71
CuI CHCl3 77
Br
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Figure 2. Previously described experiments and initial mechanistic observations. a) Selected screening experiments. b) 2D NMR EXSY (800 ms mixꢀ
ing time) during CuꢀAAA reaction. c) The chemical shift of a ligand benzylic H signal over the course of the reaction. Spectra taken at different times
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following the visible light spectrum of color for clarity. d) Proposed mechanism of Cuꢀcatalyzed AAA of allyl chloride 1 using alkylzirconocenes.
Several aspects of these AAA mechanisms remain to be
elucidated; in particular, details of the Cuꢀcatalyzed AAA step,
the structure and dynamics of the catalyst, and also the rate,
robustness and generality of the racemization process. Here
we describe detailed studies using a combination of structureꢀ
activity relationships, new reaction development, isotopic
labeling, NMR spectroscopy, and kinetic modeling.
the reaction dies in the NMR tube after 5 h and has a halfꢀlife
of 1 h. In reaction flasks, the ee of the product obtained using
CuCl catalyst decreases over time: 82% ee at 10 min, 68% ee
at 2 h and 54% ee at completion. EXSY experiments suggest
that CuClꢀA does not isomerize 1 on the NMR relaxation
timescale (See SI pS73). This is consistent with studies on
recovered 1 during the CuCl catalyzed reactions, which show
the formation on nonꢀracemic 1 (~7% ee after 1 h, >11 % ee
after 2 h) as judged by GC analysis (see SI p S51).
Results and Discussion
Kinetics via in situ 1H NMR spectroscopy
With CuOTf, AAA is much faster than with Cu halides
Based on our previous insights using 1H NMR spectroscoꢀ
py, we decided to obtain kinetic data in situ. We were able to
follow the reaction in time, showing consumption of starting
material 1, formation of product 3, and the presence of allyl
iodide intermediate 2 on a CuIꢀcatalyzed reaction as shown in
Figure 3a. Using nonꢀlinear leastꢀsquares regression on
DynaFit4,64 we attempted to build a simple model of the reacꢀ
tion while taking into account the reversible formation of 2.
Attempts to fit the data always led to significant divergence of
the model from experiment (see SI pS46). In order to obtain a
reasonable fit we had to take into account the modification of
the catalyst observed by NMR (Figure 2c)61 and speculate that
the leaving group generates chloride anions during AAA (Figꢀ
ure 3a, Equation 1) which become incorporated into the cataꢀ
lyst and generates a more enantioselective catalyst as the reacꢀ
tion proceeds – perhaps the simplest form of the 2nd generation
catalyst would be Cu2IClA2, a dimer of CuIA where one haloꢀ
gen has been replace by Cl. A model using Cu2IClA2 as a
second ‘reactionꢀenhanced’ catalyst (Equation 2) suggested
that this AAA is 3 times faster than AAA with the starting
catalyst (Equation 1). Chemical exchange between 2 and 1 is
relatively fast: kallyliodide= 0.0080 mol%.minꢀ1 for formation of 2
(Equation 3) with regeneration of 1 being more than 3 times
faster (kallylchloride=0.029 mol%.minꢀ1, Equation 4). This model
supports the idea that AAA is slow compared to isomerization
of 1 and 2 (>102 times slower), allowing replenishment of the
reactive enantiomer of 1.
and stops within ~80 min as determined by in situ H NMR
1
spectroscopy (Figure 3c). Another feature of the OTf– reaction
is that the ee of the product stays constant over time (71% ee).
In the modelling, a good fit was obtained by taking into acꢀ
count that the reaction does not go to completion because of
catalyst decomposition. Decomposition was calculated to
occur at kdec2 = 0.026 mol%.minꢀ1, ~3x faster than the CuOTfꢀ
A catalyzed CꢀC bond formation (kOTf = 7.7x10ꢀ3 mol%.minꢀ1).
This catalyst instability is consistent with our qualitative obꢀ
servations on the reactivity of CuOTf complexes.
As the CuI AAA is ~10 times slower than with CuCl
(kCl=5.9x10ꢀ4 mol%.minꢀ1) and 102 times slower than with
CuOTf (kOTf=7.7 x10ꢀ3 mol%.minꢀ1) the Cu counterion impacts
the catalytic species present throughout the reaction.
Upon addition of Cp2ZrClEt to CuIꢀA, we do not observe
1
any color changes nor significant changes in H and 31P NMR
spectra. We speculate that CuIꢀA and Cp2ZrClEt do not react
before addition of 1 even though most mechanistic proposals
with nonꢀstabilized nucleophiles involve transmetallation
processes.1,2,26,27,65 In contrast, upon addition of Cp2ZrClEt to
CuClꢀA, a yellow to dark brown color change occurs within a
few minutes and changes are observed by 1H NMR and
31P NMR spectroscopy (see SI pS50). In the 31P NMR spectra,
the peak associated with CuClꢀA drastically broadens without
a significant change of chemical shift. At completion, the
strong 31P NMR signals earlier seen at 140ꢀ120 ppm, disapꢀ
pear, suggesting catalyst decomposition, consistent with our
kinetics and modelling (see Figure 3b). It appears that preꢀ
catalytic CuOTfꢀA exists as at least 2 entities in a 1:0.3 ratio in
CDCl3 at 298 K as there are two sets of distinct benzylic and
methyl signals in the 1H NMR and two signals in the 31P NMR
spectrum (See SI pS23). With CuOTfꢀA, upon addition of
1
In situ H NMR spectroscopic kinetic studies were also
carried out for the CuCl and CuOTf catalyzed AAA (Figure 3b
and 3c respectively). The obtained experimental data was
fitted by nonꢀlinear leastꢀsquares regression.64 In the case of
CuCl (Figure 3b) we observe clean conversion of 1 to 3 but
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Cp2ZrClEt the reaction mixture turns brown instantaneously
suggesting the formation of a single species. From the inforꢀ
mation gathered, the mechanism of CuOTf–A catalyzed AAA
appears to be different than that of CuꢀhalideꢀA complexes.
1
and changes are observed in the H and 31P NMR spectra
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Hb
Hb
Hb
I
Cl
Hc
Ha
Ha
Ha
ZrCp2Cl
Hc
A
CuX- , CDCl3
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F
igure 3. Experimental and modeled kinetic data of Cu-AAA with 1 as monitored by in situ
1H NMR spectroscopy using a) CuI, b) CuCl and c) CuOTf. Conditions: ethylene (1 atm), Cp2ZrClH (2.0 eq), CD2Cl2, CuX (10 mol%), (S,S,S)ꢀA
1
(10 mol%), allyl chloride 1 (1.0 eq), in CDCl3, 298 K. The experimental data recorded by H NMR are shown as diamonds. Based on those data points,
modelling was performed using Dynafit4. The fitted curves are shown as solid lines and the input equations with their rates are below the corresponding
graphs.
Supramolecular structures of the pre-catalytic complexes
In an attempt to gain insight into the structure of the active
catalysts we carried out diffusion NMR spectroscopy experiꢀ
ments. Gschwind extensively used these to study preꢀcatalytic
Cuꢀphosphoramidite complexes at 220 K58,59,66 and found that
the diffusion coefficients obtained are accurate enough to
determine the number of ligands in a complex, but not the
number of salt units.57,58 Morris et al67 have described a pragꢀ
matic correlation function, using the concept of an effective
mean density for solute and solvent molecules, to estimate the
molecular weight of a smallꢀmolecule species based on its
diffusion coefficient. We note that although the correlation
was developed and demonstrated only for molecules comprisꢀ
ing light atoms (< Cl), the estimated molecular weights would
nevertheless help us establish the presence of supramolecular
assemblies of CuXꢀA complexes since the ligand unit makes
up the bulk of the molecular weight (540 g.molꢀ1) as opposed
to the heavy atom Cu (64 g.molꢀ1) and halides (35 g.molꢀ1 for
Cl, 127 g.molꢀ1 for I).
Alternatively, calibration curves have also been used to deꢀ
termine the oligomerisation of supramolecular complexes’
molecular weight.68ꢀ70 We thus ran diffusion experiments on
known Rh and Pd complexes in CDCl3 to generate a calibraꢀ
tion curve (See SI pS54). These experiments show, similar to
Gschwind’s results, that D has limited ability to predict the
stoichiometry of small bridging salts such as halides, but as
stated above, these methods may still be used to estimate the
molecular weight of the supramolecular complexes here, as
ligands make up the bulk of the molecular weight.
in the reaction. First as a control, we measured the diffusion
coefficient of free ligand A to be 8.74±0.16 10ꢀ10 m2.sꢀ1 (Table
1 – entry 1). The diffusion coefficient of A correlates to an
estimated molecular weight of 542±21 g.molꢀ1 using Morris’
correlation, close to the actual value of 540 g.molꢀ1.
The diffusion coefficient of CuIꢀA in CDCl3 at 298 K was
measured to be 6.13±0.05 10ꢀ10 m2.sꢀ1 (entry 2) which correꢀ
lates to an estimated molecular weight of 1163±20 g.molꢀ1. As
the measured diffusion coefficient is consistent with a comꢀ
plex containing two ligands A (>1080 g.molꢀ1), we propose the
species is a dimer of the formula Cu2I2A2 (1460 g.molꢀ1) rather
than a monomer (CuIA, 730 g.molꢀ1). We however note that
we cannot rule out other species as there are uncertainties in
these measurements.
CuClꢀA in CDCl3 had a diffusion coefficient of 5.87±0.09
10ꢀ10 m2.sꢀ1 (entry 3), which suggests a molecular weight of
1279±46 g.molꢀ1. Unlike the above result with Iꢀatoms, this
prediction actually correlates very well to a Cu2Cl2A2 dimer
(MW = 1277 g.molꢀ1). We also measured the diffusion coeffiꢀ
cient of mixed CuIꢀA/CuClꢀA complexes in a 1:1 ratio (entry
4) in an attempt to mimic the possible structure of the enꢀ
hanced enantioselective catalyst generated during AAA. The
diffusion coefficient was 5.89±0.11 10ꢀ10 m2.sꢀ1, a value very
close to that observed with the CuClꢀA complex.
When adding Cp2ZrClEt to CuIꢀA, the diffusion coeffiꢀ
cient was 5.95±0.18 10ꢀ10 m2.sꢀ1 (entry 5), within experimental
error of the diffusion coefficient for both CuIꢀA and CuClꢀA,
which taken together with the lack of change observed in the
1H and 31P NMR spectra when Cp2ZrClEt and CuIꢀA are
mixed, suggests that the dimeric aggregates do not change
significantly in the presence of the nucleophile.
We therefore carried out diffusion experiments with conꢀ
vection compensation71,72 of different CuXꢀA complexes at
298 K in CDCl3. These experiments were measured in tripliꢀ
cate at 0.05 M, the same concentration as the catalytic species
1
The diffusion coefficient of CuOTfꢀA, which the H and
31P NMR spectra suggest is two complexes in solution at
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298 K, was 6.70±0.11 10ꢀ10 m2.sꢀ1 (entry 6a), associated with a
ization (Table 2, entries 7 vs 8) is crucial to obtaining high
enantioselectivity in these reactions.
molecular weight of 956±36 g.molꢀ1. Even assuming that ionic
triflate pseudohalides are absent from the complex this value
is too low for a dimer (Cu2A22+, 1206 g.molꢀ1) but too high for
a monomer (CuA+, 603 g.molꢀ1) and the observed diffusion
coefficient may be an average of the two CuOTfꢀA complexes
found in solution. Measuring the diffusion coefficient for a
broader component at 7.072ꢀ6.671 ppm resulted in a diffusion
coefficient of 5.83±0.17 10ꢀ10 m2.sꢀ1, corresponding to molecuꢀ
lar weight of 1298±86 g.molꢀ1 (entry 6b) and possibly dimeric
Cu2A2OTf2 (1504 g.molꢀ1). Due to extensive NMR signal
overlap we were unable to obtain diffusion ordered (DOSY)
data, in which each complex could be separated.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Diffusion coefficients D, and estimated molecular weight, as
measured by NMR spectroscopy.a
CuXA
X
A
Cu
or
A Cu X
Monomer
X
X
I
Cu2X2A2
A
Cu
Cu
A
Figure 4. Negative non-linear effect observed in the CuI-A catalyzed
AAA of 1. Conditions: 4ꢀphenylꢀ1ꢀbutene (2.5 eq), Cp2ZrHCl (2.0 eq) in
CH2Cl2, CuX (10 mol%), (S,S,S)ꢀA (10 mol%), allyl chloride 1 (1.0 eq), in
CHCl3, room temperature.
Dimer
Cu2IClA2
A
Cu
Cu A
Mixed halide dimer
Predicted MWa
Cl
D
67
Species
(10-10 m2.s-1)
8.74±0.16
6.13±0.05
5.87±0.09
5.89±0.11
Table 2. Testing the generality of allyl iodide
mation/isomerization.
2
for-
1
2
3
4
A (control)
CuIꢀA
542±21
1163±20
1279±46
1269±55
CuClꢀA
Cl
I− source
I
CuI/CuClꢀAb
CuIꢀ
Solvent
1
5
5.95±0.18
1243±83
A+Cp2ZrClEtc
CuOTfꢀA
2
Entry I- source Ligand
Solvent
CDCl3
CDCl3
CDCl3
CDCl3
allyl iodide Exchanges
6a
6.70±0.11
5.83±0.17
956±36
1298±86
6bd
1
2
CuI
CuI
A
Binap
Yes
Yes
Yes
No
Yes
Yes
Yes
ꢀ
3
4
CuI
CuI
PPh3
Conditions: CuX (10 mol%), (S,S,S)ꢀA (10 mol%) in CDCl3 at 298 K.
NHCa
aNote that this technique is not accurate enough to determine halide numꢀ
b
bers.57,58, see accompanying text. CuI (5 mol%), CuCl (5 mol%), (S,S,S)ꢀ
5
6
7
8
9
10
11
CuI
CuI
TBAI
TMSI
CuI
Me2S
ꢀ
ꢀ
CDCl3
CDCl3
CDCl3
CDCl3
Benzeneꢀd6
THFꢀd8
CD3CN
traces
No
No
ꢀ
c
A (10 mol%) in CDCl3, 298 K. Ethylene (1 atm), Cp2ZrClH (2.0 eq) in
CD2Cl2, CuX (10 mol%), (S,S,S)ꢀA (10 mol%) in CDCl3 at 298 K. dCalcuꢀ
lated for a broader component at 7.072ꢀ6.761 ppm. The error values were
calculated from the standard deviation of diffusion coefficient found for
the CHꢀN signals at 4.65ꢀ4.31 ppm and the aromatic signals of the catalyst
in each diffusion experiment, which were run in triplicate.
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
ꢀ
A
A
A
CuI
CuI
Conditions: Iodide source (10 mol% for CuI, 1.0 eq for TMSI and TBAI),
ligand (10 mol%), allyl chloride 1 (1.0 eq), in solvent, 298 K. aNHC
ligand used: 1ꢀ(S)ꢀLeucinolꢀ3ꢀ(2,4,6ꢀtrimethylphenyl)ꢀ3Hꢀimidazolium
hexafluorophosphate.
Examining the correlation between the ee of the ligand and
the ee of the product in the CuI catalyzed reaction shows a
negative nonꢀlinear effect (Figure 4),73ꢀ75 consistent with the
active catalyst being an oligomer in ligand.
Under the reaction conditions used for the highly enantiꢀ
oselective AAA we set out to quantify the exchange observed
in 2 using NMR spectroscopy (Table 3). We first used selecꢀ
tive 1DꢀEXSY76,77 at various temperatures and derived the
Ha/Hc exchange rate constants from the initial slopes of norꢀ
malized intensity buildꢀup profiles (Entries 1ꢀ3, see SI pS75).
These results show the rate of Ha/Hc exchange in 2 exponenꢀ
tially increases with respect to temperature. To corroborate
these data, we also ran selective inversion transfer53,78ꢀ80 (Entry
4) and spin saturation transfer difference (SSTD)81 experiꢀ
ments (Entry 5) at 298 K (see SI, pS75). All three methods
gave similar results emphasizing the validity and accuracy of
the results. The data analyses also yielded longitudinal relaxaꢀ
tion time constants (T1s) for the protons of 2 which were obꢀ
served to be unusually large, with values ranging from 15ꢀ25 s
for Ha, Hb and Hc (see SI, pS75). These values were compaꢀ
rable to those determined from (nonꢀselective) inversion reꢀ
covery experiments for 1 and 2, and we attribute these large
Isomerization of allyl iodide 2
We first decided to examine various conditions which may
mediate the formation of 2 from 1 and its isomerization. Using
CuI and CDCl3, 2 was only observed when used in combinaꢀ
tion with a phosphine ligand (A, BINAP, or PPh3, Table 2,
entries 1ꢀ3). The absence of ligand (entry 6) or use of NHC
(entry 4) or sulfur (entry 5) based ligands either gave no 2 or
only traces of 2. Alternative I– sources such as TBAI (entry 7)
and TMSI (entry 8) formed 2 in 4% and 70% yield respectiveꢀ
ly. Although 2 was formed in the presence of TBAI, no exꢀ
changes by EXSY were observed (entry 7), whereas in other
cases when 2 was formed it was rapidly isomerizing. Using
CuIꢀA, formation and isomerization of 2 occurred in all solꢀ
vents examined (CDCl3, benzene, THF, MeCN).
CuClꢀA catalyzed reactions (which normally give 49% ee,
Figure 2a, entry 3) carried out in the presence of 10 mol%
TMSI gave 4 in 76% ee, while a reaction with 10 mol% TBAI
gave 4 in 52% ee. Supporting the idea that allyl halide isomerꢀ
5
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values to the use of the argon degassing and lack of paramagꢀ Allyl acetate did not react under these conditions (Figure 5a,
1
2
3
4
5
6
7
8
netic O2 in the sample.
entry 1), both the trifluoroacetate and pivalate derivatives
behaved poorly (entries 2 and 3), but a phosphate gave promꢀ
ising results (>95% conversion, 40% ee, entry 4).
Table 3. Allyl iodide isomerization rate measurements by multiple
NMR experiments.
With allyl phosphate 5, different copper sources (Figure
5b, entries 1ꢀ3) and ligands (entries 4ꢀ8) were tested. A phosꢀ
phoramidite D bearing a chiral amine (see SI pS26 for prepaꢀ
ration) gave the highest ee (81% ee, entry 6). We examined
the effect of solvents and found that nonꢀchlorinated solvents
were poorly selective. We thus tried different chlorinated
solvents such as CHCl3 which gave high (85%) ee (entry 9),
CCl4 which inhibited the reaction (entry 10), and dichloroꢀ
ethane which gave 57% ee (entry 11). Although we were able
to obtain 85% ee, the procedure was not very reproducible.
We suspected that an impurity was causing variations in our
results from run to run and tested several additives (for examꢀ
ple entries 12ꢀ16). The AAA was surprisingly tolerant to many
additives and improved to 89% ee when using diethylchloroꢀ
phosphate (entry 12). After substantial experimentation, 1.0 eq
of TMSCl, reproducibly gave 80% yield and 89% ee (entry
15), although additional TMSCl decreased the ee (for example
5.0 eq, 80% ee, entry 16). When using 1.0 eq of TMSCl, using
CHCl3 and CH2Cl2 gave the same results.
We then tested the scope of alkenes (Figure 5c). Products
bearing simple alkyl chains (compound 6 and 7) were obtained
in high yields (>77%) and ee’s (>85% ee). The presence of
more elaborate functional groups such as 4ꢀCF3–Ph (8, 86%,
65% ee), TMS (9, 28%, 93% ee) and Cl (10, 44%, 75% ee)
were tolerated but caused a drop in the ee or the yield. We
note that this AAA of allyl phosphates is more sensitive to the
presence of functionalized alkene starting materials than the
corresponding reactions with allyl chlorides.
Entry
Experiment
1DꢀEXSY
1DꢀEXSY
1DꢀEXSY
T (K) Rate of isomerization (s-1)
9
1
2
3
4
5
273
298
313
0.02
0.11
0.60
0.10
0.08
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Inversion Recovery 298
SSTD 298
Conditions: CuI (10 mol%), (S,S,S)ꢀA (10 mol%), allyl chloride 1 (1.0 eq),
in CDCl3, room temperature. NMR spectra recorded at indicated temperaꢀ
ture.
Development of a new AAA system
It would also be desirable to use less reactive electrophiles
than allyl chlorides. These may be more chemically stable and
less prone to isomerization during formation or routine manipꢀ
ulations. Furthermore, we anticipated that less reactive starting
materials would aid mechanistic studies described in the next
section. From this perspective, we attempted to develop a new
AAA with alternative allyl species. Different cyclic allylic
alcohol derivatives were tested using our previous conditions.
LG
OAc
O2CCF3
OPiv
OP(O)(OEt)2
Conv.§ Ee*(%)
1
2
3
4
0%
35
ꢀ
45
<10
>95
−85
40
CuX
CuCl
CuOTf
CuBF4
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L*
A
A
A
B
C
D
E
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CCl4
(ClCH2)2
CHCl3
CHCl3
CHCl3
CHCl3
Additive
Ee*
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15a
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
33
21
47
41
81
−27
73
85
Np
57
89
75
71
89
F
D
D
D
D
D
D
D
ꢀ
ꢀ
PCl(O)(OEt)2
pyridine
B(OiPr)3
TMSCl
TMSCl
(5.0 eq)
16
CuI
D
CHCl3
80
Figure 5. Development of a new AAA system. a) Leaving group screening. Conditions: substrate (1.0 eq), 4ꢀphenylꢀ1ꢀbutene (2.5 eq), Cp2ZrHCl (2.0
§
*
eq), CH2Cl2, CuI (10 mol%), A (10 mol%), CHCl3, room temperature, overnight. Conversion was determined by crude NMR. Ee was determined by
HPLC. b) Optimizing conditions. Conditions: allyl phosphate (1.0 eq), 4ꢀphenylꢀ1ꢀbutene (2.5 eq), Cp2ZrHCl (2.0 eq), CH2Cl2, CuX (10 mol%), L* (10
mol%), solvent, additive (1.0 eq unless specified), room temperature, overnight. *Ee was determined by HPLC. c) Scope of AAA of allyl phosphate. Conꢀ
ditions: alkene (2.5 eq), Cp2ZrClH (2.0 eq), CH2Cl2, CuI (10 mol%), D (10 mol%), allyl phosphate (1.0 eq), TMSCl (1.0 eq) in CHCl3, room temperature. d)
AAA using ligand D with 6- and 7-membered ring allyl chlorides. Conditions: alkene (2.5 eq), Cp2ZrClH (2.0 eq), CH2Cl2, CuI (10 mol%), D
(10 mol%), allyl chloride (1.0 eq), in CHCl3, room temperature. aUsing CH2Cl2 gave the same results and was used in subsequent scope for convenience.
bPrepared using (R,R)ꢀD.
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When using a sevenꢀmembered allyl phosphate, we obꢀ
product 21a in 72% yield with 83% ee (Scheme 2c ꢀ bottom).
These empirical results show divergence in reactivity between
the allyl chloride and allyl phosphate substrates.
1
2
3
4
5
6
7
8
tained 11 in good yield (65%) with excellent 90% ee. The
ability to use sevenꢀmembered rings here is important because
these were not suitable substrates for the previous AAA with
allyl chlorides (use of 12 gave 23% ee). We tested ligand D in
an AAA using the sevenꢀmembered chloride 12 and excellent
(94ꢀ95% ee) enantioselectivity and good yield (>68%) was
observed for the three alkenes tested (Figure 5d).
Generally, ligand D appears to be an excellent alternative to
A in these AAA reactions as it allows reactions with 7ꢀ
membered substrates. Also, in the case of 6ꢀmembered allyl
chloride 1 we obtained 72% yield and 95% ee, a similar result
obtained with A (88% yield, 93% ee).
Scheme 2. Cu-Catalyzed AAA of substituted allyl chlorides and allyl
phosphates.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Substituted starting materials
We next studied substituted racemic cyclic starting materiꢀ
als, which can ‘desymmetrize’ the substrates and give rise to
diastereomeric intermediates and products. This work probes
the scope and limitations of these processes and suggests
realistic synthetic applications. We also hoped these studies
would shed light on the reaction mechanism, but interpretation
is complicated.
Synthesis of allyl chloride 15 always produced an insepaꢀ
rable mixture of 15a and 15b in a ~2:1 ratio, despite several
synthetic approaches. Some enantiomerically enriched methyl
substituted allyl chlorides are known, but these are reported to
rapidly racemize.82,83 During AAA of 15 with 4ꢀphenylꢀ1ꢀ
butene, regioisomeric products were obtained using stoichioꢀ
metric nonꢀchiral CuBr·DMS as catalyst (1:1 ratio) or catalytic
CuIꢀA (2:1 ratio) but the ee’s of the mixture could not be
determined due to their aliphatic nature. Using a single enantiꢀ
omer (>99% ee) chiral alkene nucleophile allowed us to deꢀ
termine the ‘ee’ of the products by measuring the diastereotopꢀ
ic ratios of 16a and 16b isomers by NMR spectroscopy.84 We
obtained 16a and 16b in a 5:1 ratio with 51% ‘ee’ and 18%
‘ee’ respectively (Scheme 2a ꢀ left).
In contrast to 15, allyl phosphate 17 could be prepared as a
single racemic regioisomer, and optimized conditions gave
SN2/SN2’ products 16a and 16b in 3:1 ratio in favor of SN2’
with poor enantioselectivity (61% and 33% ‘ee’ respectively)
(Scheme 2a ꢀ right). Overall, these results are difficult to interꢀ
pret, but these AAA reactions favor formation of the (more
hindered) SN2’ product, albeit not with synthetically useful
enantioselectivity, and we are uncertain of the structure of the
allylic species that actually undergo CꢀC bond formation.
5,5ꢀdisubstituted allyl chloride 18 was found to give 19
with high ee (86%) but only low (30%) conversion resulting in
a very poor yield (19%), so it appears that bulky diꢀ
substitution impairs reactivity (Scheme 2b).
5ꢀphenylꢀsubstituted allyl chlorides 20, prepared and used
as a racemic 4:1 trans:cis diastereomeric mixture, provided a
single product, cisꢀ21a in 66% yield with 93% ee (Scheme 2c
– left). This result is remarkable as it shows that in appropriꢀ
ately designed substrates, a mixture of 4 isomers (2 racemic
diastereomers) may be converted into a single diastereomeriꢀ
cally and enantiomerically pure product. We speculate that
rapid CuIꢀA mediated isomerization of substrates 20 allows
the catalyst to select one isomer of starting material for a highꢀ
ly enantioselective reaction.
Method A: alkene (2.5 eq), Cp2ZrClH (2.0 eq), CH2Cl2, CuI (10 mol%), A
(10 mol%), allylchloride (1.0 eq) in CHCl3, room temperature. Method B:
alkene (2.5 eq), Cp2ZrClH (2.0 eq), CH2Cl2, CuI (10 mol%), D (10 mol%),
allylphosphate (1.0 eq) TMSCl (1.0 eq) in CH2Cl2, room temperature.
Isolated yields. Ee was determined by NMR or HPLC. aPrepared using
(R,R,R)ꢀA. bThe ee of these products could not be determined due to
overlapping signals (see SI, pS113).
NMR studies on AAA reactions using allyl phosphate 5
In an AAA of allyl phosphate 5 followed by in situ
1H NMR spectroscopy, we observe clean conversion of 5 to
product 3 (Figure 6a). 5 was consumed much more rapidly
(<1 h) than product was formed (11 h to completion). We
identified allyl chloride 1 as an important intermediate. The
presence of allyl iodide 2 was also observed but 2 behaves
differently than described above (Figure 2). Here 2 rapidly
forms at the beginning of the reaction, reaches a maximum
concentration of ~10 mol% after ~2 min and is consumed
within 30 min. Signals characteristic of SN2’ isomerization
processes were never observed by in situ EXSYs during this
AAA (see SI pS43).
We modelled these kinetics,64 assuming AAA preferentialꢀ
ly uses allyl chloride 1 as substrate, but some allyl phosphate 5
undergoes AAA. The model fits formation of 3 from 1 being
20 times faster (k1 = 0.042 mol%.minꢀ1) (Equation 9) than
from 5 (k2 = 0.023 mol%.minꢀ1) (Equation 10). We assume
TMSCl forms 1 from 5 (kTMSCl = 0.212 mol%.minꢀ1) (Equation
11) and formation of 1 is measured to be ~5 times faster than
AAA. This model requires that AAA generates stoichiometric
Cl– which reacts with 5 to generate more 1 (Equation 12) at a
similar rate (kCl = 0.05 mol%.minꢀ1) to AAA with 1.
We also followed AAA with phosphateꢀ5 by in situ
31P NMR spectroscopy. Upon addition of Cp2ZrClEt to CuIꢀD
in CD2Cl2 no change was observed. Upon addition of 5 and
TMSCl, 5 is observed at –1.5 ppm and a new peak is formed
at 9.2 ppm (the phosphate leaving group anion, see SI pS118).
At completion, (Et2O)2P(O)O– is still present while 5 is fully
consumed and a variety of new, small, unsymmetrical broad
peaks were observed.
5ꢀphenylꢀsubstituted phosphate 22 could be isolated as eiꢀ
ther the trans- or cisꢀisomer. Transꢀ22a gave a 2:1 ratio of
products (Scheme 2c ꢀ middle). Cisꢀ22b solely gave the cisꢀ
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Simply adding TMSCl to 5 in CD2Cl2 shows quantitative consumed within the first 10 min. Here, no isomerization of 2
1
2
3
4
5
6
7
8
formation of 1 in 1 h, but 1 was not observed to isomerize by
EXSY. Addition of CuIꢀD to 5 did not result in any observable
nor 1 was observed by EXSY. TMSCl is known to accelerate
Cuꢀcatalyzed conjugate addition reactions, but not without
some lingering mechanistic ambiguity.85ꢀ91 In contrast, here the
overall reaction is faster in the absence of TMSCl and reaches
completion in 3.5 h, as opposed to 11 h with TMSCl, but both
AAAs have similar halfꢀlives (~1.5 h). However, despite the
overall lower rate of reaction, TMSCl facilitates conversion of
allyl phosphate 5 to allyl chloride 1. In the absence of TMSCl
consumption of 5 is slower (2 h) than in the presence of
TMSCl (1 h) and 1 reaches a maximum of 20 mol% at 1 h
(compared to 75 mol% with TMSCl), as 1 presumably gets
transformed to 3, limiting its concentration. 31P NMR specꢀ
troscopy of the TMSꢀfree AAA also shows 5 (–1.5 ppm) is
consumed within ~2 h and many nonꢀsymmetrical broad sigꢀ
nals appear in that region within 12 h (See SI pS120).
1
changes to the H or 31P NMR spectra (see SI pS120). So it
appears that, contrary to experiments with chlorideꢀ1, phosꢀ
phateꢀ5 does not directly react with the catalyst to form iodideꢀ
2. However, upon addition of TMSCl to a mixture of 5 and
CuIꢀD, allyl phosphate 5 is rapidly transformed to allyl chloꢀ
ride 1. Allyl iodide 2 is also formed and reaches a maximum
concentration of 10 mol% and is then consumed within 10 min
to give 1. Contrary to experiments carried out on the actual
CuꢀAAA of 5, isomerization of 2 was observed by EXSY
when 5, TMSCl and CuIꢀD are mixed in CD2Cl2.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Upon mixing Cp2ZrClEt and 5 in CD2Cl2, the H and
31P NMR spectra of 5 remain unaffected, and addition of
TMSCl forms 1. Under these conditions formation of 1 reachꢀ
es completion in 150 min, ~2.5 times slower than without
Cp2ZrClEt. In the presence of Cp2ZrClEt and TMSCl, 1 is not
observed to undergo SN2’ isomerization by EXSY. Overall, 1
seems to originate from addition of TMSCl, but its rate of
formation is affected by other reaction components.
In the AAA of 5 without TMSCl, a model64 fits formation
of 3 being 10 times faster from 1 (k1=0.26 mol%.minꢀ1, Equaꢀ
tion 13) than from 5 (k2=0.019 mol%.minꢀ1, Equation 14) and
faster than in the presence of TMSCl (k1 = 0.042 mol%.minꢀ1).
As Cp2ZrClEt and CH2Cl2 are the only possible initial sources
of chloride, we modelled formation of 1 using Cp2ZrClEt as
the source (Equation 15). The formation of 1 is very slow (kCl1
= 0.0018 mol%.minꢀ1) (Equation 15), but generating 1 from
Cl– produced during AAA is fast (kCl2 = 0.18 mol%.minꢀ1;
Equation 16) and of the same order of magnitude as formation
of 3 from 1.
We became curious about the mechanism of AAA with 5
in the absence of TMSCl (Figure 5b, entry 6). Using in situ
1H NMR spectroscopy, and the same conditions as above but
without TMSCl, we surprisingly observed that this reaction
also proceeds through allyl chloride 1 (Figure 6b). Allyl iodide
2 was also briefly present at a concentration of <2 mol% and
Hb
Hb
Hc
Hb
O
ZrCp2Cl
Ha
O
Hc
Cl
Ha
P
Ha
D
CuI, (R,R)- , CD2Cl2
O
O
additive
3
(R)-
1
5
1
Figure 6. Reaction kinetics of Cu-AAA with allyl phosphate 5 monitored by H NMR spectroscopy a) with TMSCl and b) without TMSCl and
modelled. Conditions: ethylene (1 atm), Cp2ZrClH (2.0 eq) in CD2Cl2, CuI (10 allyl iodide), (R,R)ꢀD (10 mol%), allyl phosphate 5 (1.0 eq), TMSCl (0 or
1
1.0 eq) in CD2Cl2, 298 K. Experimental data recorded by H NMR spectroscopy are shown as diamonds. Based on those data points, modelling was perꢀ
formed using Dynafit4 and the resulting fitted curves are shown as solid lines and the input equations, with their rates, below the corresponding graphs.
TMSCl plays a role in the formation of 1, and also affects
the catalyst. Upon addition of TMSCl to a solution of CuIꢀD,
Curiously these catalytic modifications do not occur in the
presence of Cp2ZrClR.
1
instantaneous changes are observed in H and 31P NMR specꢀ
We also synthesized deuterated allyl phosphate 23. In
2
tra suggesting formation of two species (see SI pS130). The
minor component of the two newly formed species resembles
CuClꢀD complexes but the major component is unknown and
is not observed during AAA of 5 in the presence of TMSCl.
AAAs with TMSCl monitored by in situ H spectroscopy
(Figure 7a), dꢀ23 is rapidly consumed to form dꢀallyl chlorides
24a and 24b in approximately equal amounts and the dꢀallyl
chlorides in turn form dꢀproducts 25a and 25b in a 1:1 ratio.
2H NMR spectroscopy on dꢀ23 without TMSCl in situ (Figure
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Journal of the American Chemical Society
7b) similarly showed that dꢀ23 is consumed slowly to form ꢀstood) addition of Cp2ZrClEt appears to reverse the selectiviꢀ
1
2
3
4
5
6
7
8
equal amounts of dꢀallyl chlorides 24a and 24b, which in turn
form a ~1:1 mixture of 25a and 25b.
ty observed with TMSCl alone.
We investigated the effect of CuIꢀD (10 mol%) on the
formation of 24a and 24b from dꢀ23. Upon addition of
TMSCl, 24a and 24b are formed instantaneously as well as
traces amount of dꢀallyl iodides (see SI pS137). Here, the dꢀ
isomers are formed in equal amount suggesting that CuIꢀD
facilitates isomerization of the allyl halide species in the AAA
reaction itself.
Finally, we investigated the use of enantiomerically pure
allylphosphates (+)ꢀ5 and (–)ꢀ5 using CuIꢀD and TMSCl in a
reaction to form 4. Although these experiments are difficult
because of the very small amount of product formed at early
stages of the reaction (~10 min) no significant difference in
the enantiomeric excess of 4 formed from (–)ꢀ, (+)ꢀ or (±)ꢀ5
was observed (ee values obtained varied from run to run and
range form 84 to 93% ee).
Adding TMSCl (1.0 eq) to dꢀ23 (1.0 eq) shows that it is
completely transformed to dꢀchlorides 24a and 24b within
20 min. Both SN2’ and SN2 products are formed, but reaction
of 23 with TMSCl appears to prefer SN2’ pathways (65 mol%
βꢀdꢀ24a vs 35 mol% 24b, see SI pS136). As the ratio of 24a
and 24b remains largely unchanged under these conditions dꢀ
allyl chlorides 24 appear not to isomerize through SN2’ mechꢀ
anisms spontaneously, suggesting that TMSCl alone is not
responsible for the 1:1 ratio of 24a and 24b observed during
AAA.
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We studied the effect of Cp2ZrClEt (2.0 eq) on the forꢀ
mation of dꢀ24a and dꢀ24b with TMSCl (1.0 eq). Within
200 min, 65 mol% of 24b was formed while 35 mol% of 24a
was obtained (see SI pS137) so (for reasons that are not under
2
Figure 7. Reaction kinetics of Cu-AAA with d-23 as monitored by H NMR spectroscopy a) with TMSCl and b) without TMSCl. Conditions: ethꢀ
ylene (1 atm), Cp2ZrClH (2.0 eq) in CH2Cl2, CuI (10 mol%), (R,R)ꢀD (10 mol%), dꢀallyl phosphate 23 (1.0 eq), TMSCl (0 or 1.0 eq) in CH2Cl2, 298 K.
In the AAA of 5, we did not observe the constant presence
of allyl iodide 2 or see evidence of the SN2’ isomerisation of 1
or 2 by EXSY. However, these pathways may still operate at
rates undetectable by NMR. It seems likely that, regardless of
the source of chlorideꢀ1, both CuIꢀL* catalyzed AAAs with 1
occur via similar mechanisms, and that both reactions involve
rapidly racemizing starting materials and a DKR type mechaꢀ
nism. But it is not inconceivable that the reaction of phosphate
5 to give 3 goes through other pathways.
CuIꢀA mediated isomerization of allyl iodide 2 is 0.10±0.01 sꢀ
1, and kinetic modeling suggests that 1 and 2 interchange much
faster than CꢀC bond formation.
The catalysts involved in CꢀC formation are aggregates of
Cu and phosphoramidite which involve at least two ligands. A
critical dependence of the copper counterion was demonstratꢀ
ed, which affects many mechanistic aspects of the reaction.
Kinetic modeling suggests that the catalyst is modified during
the reaction to contain both I and Cl ions and becomes more
enantioselective and 3 times faster than the starting catalyst.
A second AAA system was developed using racemic allyl
phosphates and new ligand D which is also an excellent alterꢀ
native to A in AAAs with 1 and is superior with 7ꢀmembered
ring substrates. Structure reactivity relationships demonstrated
that, in some cases, excellent stereochemical control can be
achieved where racemic mixtures of diastereomers are conꢀ
verted to a single diastereoisomer of product with high ee.
AAA reactions with these allyl phosphates, as judged by
NMR spectroscopy and isotopic labeling studies, proceed via
allyl chlorides formed in situ, either by the action of TMSCl or
from adventitious Cl– generated from reaction components.
The ability to generate rapidly isomerizing allyl halide species
in situ from these phosphates is likely to be useful in chemisꢀ
Conclusion
High yield and enantioselectivity can be achieved in the
Cuꢀcatalyzed addition of alkylzirconium reagents to racemic
allyl chloride and allyl phosphate electrophiles. Our work
suggests a simple but powerful mechanism where CuIꢀ
mediated racemization of the starting materials coupled with a
highly selective CꢀC bond forming catalyst allows highly
enantioselective addition.
A number of different isomerizing agents have been identiꢀ
fied potentially facilitating the extension of this strategy to a
broader range of reactions. We have also shown that it is posꢀ
sible to quantify the rate of allyl halide isomerization using 3
different NMR techniques. Here experiments show the rate of
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try far beyond the present studies. We anticipate that this work
will aid development of new asymmetric addition reactions
using racemic starting materials.
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ASSOCIATED CONTENT
Supporting Information.
Experimental procedures, characterization data and relevant NMR
spectra can be found in the Supporting Information available free
of charge on the ACS Publication website at http://pubs.acs.org
DOI:
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AUTHOR INFORMATION
Corresponding Author
* Tim.claridge@chem.ox.ac.uk
* Stephen.fletcher@chem.ox.ac.uk
(22) Mori, S.; Nakamura, E. Tetrahedron Lett. 1999, 40, 5319.
(23) Yamanaka, M.; Kato, S.; Nakamura, E. J. Am. Chem. Soc.
2004, 126, 6287.
(24) Yoshikai, N.; Zhang, S. L.; Nakamura, B. J. Am. Chem.
Soc. 2008, 130, 12862.
Funding Sources
We are grateful to the EPSRC for financial support in the form of
a Career Acceleration Fellowship to SPF (EP/H003711/1) and a
Standard Grant (EP/N022246/1).
(25) Langlois, J.; Emery, D.; Mareda, J.; Alexakis, A. Chem.
Sci. 2012, 3, 1062.
ACKNOWLEDGMENT
The authors acknowledge Dr Barbara Odell for initial assistance
in NMR.
(26) Harutyunyan, S. R.; Lopez, F.; Browne, W. R.; Correa,
A.; Pena, D.; Badorrey, R.; Meetsma, A.; Minnaard, A. J.;
Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 9103.
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Chem. Soc. 2014, 136, 11389.
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Harutyunyan, S.; Feringa, B. Nat. Chem. 2011, 3, 377.
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2010, 132, 13152.
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ABBREVIATIONS
AAA, Asymmetric Allylic Alkylation; NHC, Nꢀheterocyclic
Carbene; DMS, Dimethyl sulfoxide; TBAI, Tetrabutylammonium
iodide; TMSI, Iodotrimethylsilane; DYKAT, Dynamic Kinetic
Asymmetric Transformation; DET, direct enantioꢀconvergent
transformation.
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