Cu(I)-catalyzed, α-selective, allylic alkylation reactions between phosphorothioate esters and organomagnesium reagents

Article abstract of DOI:10.1021/ja202954b

Regiocontrol of allylic alkylation reactions involving hard nucleophiles remains a significant challenge and continues to be an active area of research. The lack of general methods in which α-alkylation is favored underscores the need for the development of new processes for achieving this type of selectivity. We report that Cu(I) catalyzes the allylic substitution of phosphorothioate esters with excellent α-regioselectivity, regardless of the nature of the Grignard reagent that is used. To the best of our knowledge, the Cu-catalyzed allylic alkylation of phosphorothioate esters has never been described. We have also developed a simple protocol for inducing high α selectivity starting from secondary allylic halides. This is accomplished by using sodium phosphorothioates as an additive.

Full text of DOI:10.1021/ja202954b

ARTICLE
pubs.acs.org/JACS
Cu(I)-Catalyzed, r-Selective, Allylic Alkylation Reactions between
Phosphorothioate Esters and Organomagnesium Reagents
Andrew M. Lauer, Farzeen Mahmud, and Jimmy Wu*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States
S Supporting Information
b
ABSTRACT: Regiocontrol of allylic alkylation reactions
involving hard nucleophiles remains a significant challenge and
continues to be an active area of research. The lack of general
methods in which R-alkylation is favored underscores the need
for the development of new processes for achieving this type of selectivity. We report that Cu(I) catalyzes the allylic substitution of
phosphorothioate esters with excellent R-regioselectivity, regardless of the nature of the Grignard reagent that is used. To the best of
our knowledge, the Cu-catalyzed allylic alkylation of phosphorothioate esters has never been described. We have also developed a
simple protocol for inducing high R selectivity starting from secondary allylic halides. This is accomplished by using sodium
phosphorothioates as an additive.
’ INTRODUCTION
Primary allylic electrophiles are somewhat less problematic
but also typically exhibit γ selectivity. While there are a few
examples in which R-substituted products can be obtained using
Cu(I) complexes, there remains no general method for achieving
R regioselectivity. B€ackvall, Julia, and Calꢀo have reported some
R-selective, Cu(I)-promoted reactions with allylic acetates/
chlorides, sulfones, benzothiazoles, respectively.3aÀd As with
secondary substrates, the primary focus of these studies was
not the development of R-selective transformations.
Transition metal-mediated alkylations of allylic electrophiles
with hard nucleophiles such as Grignard reagents have received
considerably less attention than reactions with stabilized nucleo-
philes. Regiocontrol of reactions involving hard nucleophiles
remains a significant challenge since unsymmetrically substituted
allylic substrates can furnish regioisomeric products which arise
from either R- or γ-displacement of the leaving group (eq 1).
Uncatalyzed reactions between Grignard reagents and allylic
halides usually result in a mixture of both regioisomeric
products.1 Although the use of transition metals can promote
cross-couplings with good regiocontrol, it overwhelmingly favors
γ-alkylated products.2
With respect to other transition metals, F€urster and co-
workers demonstrated that Fe complexes with formal À2 oxida-
tion states are capable of catalyzing alkylation reactions between
allylic chlorides and PhMgBr with good R selectivity.5 However,
vinyl chlorides also participate in the cross-coupling reaction, in
principle, precluding their presence. Yamamoto has shown that
Ni(II) and Fe(III) complexes furnish products with R selec-
tivity.6 Notably, the same reactions catalyzed by Cu(I) complexes
completely reverse this selectivity to provide exclusively
γ-substituted products.7 Yamamoto and Butsugan both reported
that, in the absence of transition metals, primary allylic phos-
phates undergo coupling reactions to give good R selectivities.8
However, the former is limited to allylic Grignard reagents, while
the latter is restricted to geranyl- and neryl-derived phosphates.
The lack of general methods in which R-alkylation is favored
underscores the need for the development of new processes for
achieving this type of selectivity. Our group previously demon-
strated that phosphorothioate esters undergoes transition metal-
free, allylic substitutions that exhibit R-selectivity when aromatic
and vinyl Grignards are used while secondary aliphatic Grignards
reacted at the γ position.9 To the best of our knowledge,
transition metal-catalyzed cross-coupling reactions utilizing
allylic phosphorothioate esters have not been described before.
In contrast, R-selective alkylations between Grignard reagents
and allylic electrophiles are rarer and often limited in scope.3
Most of these examples are interspersed among others in which
the predominant mode of reactivity is at the γ-position. Sub-
strates in which the leaving group is positioned on a secondary
carbon center represent an especially difficult problem for two
reasons. First, there is less of a steric difference between the R-
and γ-positions, thereby making the two reactive ends more
difficult to distinguish. Second, highly substituted secondary
allylic halides and phosphates, especially those that are disubsti-
tuted in the γ-position, can be thermally unstable and are often
incompatible with silica gel chromatography.4 These compounds
are usually prepared and used without purification. This practice
is far from ideal since trace impurities can lead to catalyst
deactivation and diminished selectivity. Because of these com-
plicating issues, R selectivity in alkylation reactions between
Grignard reagents and secondary allylic electrophiles is not
common in the literature.3f,g
Received: March 31, 2011
Published: May 18, 2011
r
2011 American Chemical Society
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Herein, we report that Cu(I) catalyzes the allylic substitution of
phosphorothioate esters10 with excellent R-regioselectivity, re-
gardless of the nature of the Grignard reagent. As we have
previously disclosed, phosphorothioate esters can be conveni-
ently prepared from electrophiles possessing oxygen-based leav-
ing groups (i.e., alcohols, alkyl/benzyl/silyl ethers, benzoates)
under photochemical or Ga(OTf)3-catalyzed conditions.9,11 In
contrast to secondary allylic halides or phosphates, even highly
substituted allylic phosphorothioate esters are air, moisture, and
chromatographically stable.
’ RESULTS AND DISCUSSION
Table 1 summarizes some of the key experiments in our
optimization study. A control reaction without the addition of
Cu(I) proceeded with acceptable rates only at rt and favored
formation of theγ-alkylated product with poor selectivity (entry 1).
With the exception of CuCN, regioselectivity was generally
insensitive to the copper source or solvent. When CuCN was
employed, a complete reversal in selectivity was observed (entry 5).
Others have also reported that CuCN appears to be unique in its
ability to promote γ-selectivity in these types of alkylation
reactions.3h,i,12 The use of i-PrMgCl LiCl complex provided
3
only the R-alkylated product (entry 10). However, the addition
of exogenous LiCl did not seem to affect the selectivities of
reactions involving Grignard reagents other than in the case of i-
PrMgCl. In all examples in which we observed R selectivity, E
alkenes were formed exclusively.
Table 1. Reaction Optimization Studies
Next, we conducted a survey of the reaction scope. As
illustrated in Table 2, consistent excellent R-regioselectivities
were observed in nearly every reaction. The electrophiles were
selected on the bais of maximizing substrate diversity. The range
of amenable nucleophiles includes primary and secondary ali-
phatic, benzylic, aromatic, and vinylic Grignards. Notably, the
results for cyclohexenyl phosphorothioate ester 12 are comple-
mentary to those of our prior study in which transition metal-free
alkylations with secondary aliphatic Grignard reagents pro-
ceeded with excellent γ-regioselectivities.9 The products ob-
tained when vinyl Grignard is employed are 1,4-dienes (i.e.,
“skipped dienes”). These are important structural motifs in
numerous bioactive compounds.13 Despite its large steric bulk,
t-BuMgBr also participated, albeit with diminished regioselec-
tivity (entry 7). Selectivity below 90:10 (R/γ) was observed in
entry
catalyst
modifications
R:γa
E/Za
yield (%)b
d
1
none, rt
CuCl
À
19:81
87:13
87:13
87:13
<5:95
87:13
87:13
87:13
>95:5
>95:5
>95:5
>95:5
>95:5
86:14
>95:5
>95:5
>95:5
>95:5
À
d
2
À
À
d
3
CuBr
À
À
d
4
Cul
À
À
d
5
CuCN
CuTCc
CuTCc
CuSCN
CuSCN
À
À
6
À
75
d
7
Et2O solvent
À
d
9
À
À
10
i-PrMgCl LiCl
91
3
a As determined by1H NMR spectroscopy. b Isolated yields. c TC =
thiophene-2-carboxylate. d Not determined.
Table 2. Scope of r-Selective Allylic Alkylation
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only two instances, each of which occurred with the electron-rich
phosphorothioate ester 6 (entries 13, 15).
observed no reaction between diisopropyl thioate 16b and allylic
chloride 14. It is likely that the greater van der Waals radius of
isopropyl versus ethyl is responsible for retarding the rate of
chloride displacement. Consequently, unselective cross-coupling
between allylic chloride 14 and the Grignard occurs preferen-
tially to formation of phosphorothioate ester 1.
For purposes of comparison, we carried out an analogous
cross-coupling with the corresponding secondary allylic chloride
14 (Table 3). Under the same conditions, this reaction resulted
in very poor regioselectivity (entry 1). When the allylic pivaloate
15 was utilized, good R regioselectivity was observed; however,
the product was isolated in low yield (57%, entry 2). Substantially
superior results were achieved with the use of phosphorothioate
1 in which both excellent R regioselectivity and yields were
obtained (entry 3).
Table 3. Comparison with Other Electrophiles
As proposed by several groups, we believe that initial forma-
tion of a π-Cu(I) complex is followed by oxidative addition to
generateatransientσ-allyl Cu(III) intermediate 21 (Scheme2).2,14
This occurs with inversion of stereochemistry. Fast reductive
elimination of 21 would lead to the kinetic product 22 (i.e., γ-
selective).15 This scenario is known to arise when strong-field
ligands such as cyanide are present and/or with the use of
monoalkyl copper reagents.3a,12a,16 Indeed, during the course
of our optimization studies, we observed that the use of CuCN
yielded cross-coupling products which favored high γ selectivity
(Table 1, entry 5). Alternatively, the presence of electron-rich
ligands (i.e., ÀSCN) and/or the use of dialkyl copper reagents, as
in the present methodology, is thought to promote rapid
equilibration between regioisomeric σ-allyl complexes 21 and
24. Reductive elimination from 24 wouldleadtoRselectivity.3a,12a,16
Along this line of reasoning, it is possible that the displaced
thioate leaving group 20 can act as an electron-rich ligand that
facilitates σ-allyl equilibration, and therefore R selectivity.
Formation of the regioisomer with the lower ground-state
energy (i.e., conjugated) may also contribute to the observed
selectivity.
We then developed a protocol to induce good R-selectivity
starting with allylic chloride 14. In principle, this could be accom-
plished by performing an in situ alkylation with sodium thioates
16aÀb to generate phosphorothioate ester 17 (Scheme 1). If the
chloride displacement were carried out in the presence of
CuSCN and a Grignard reagent, subsequent cross-coupling of
the resultant phosphorothioate esters should proceed with high
regioselectivity. This scenario is possible only if the rate of the
Cu-catalyzed cross-coupling of allylic chloride 14 (which pro-
ceeds with poor regioselectivity, entry 1) is slower than the
overall the rate of chloride displacement (14 f 17) followed by
alkylation with the Grignard (17 f 2a). Indeed, when we
performed the reaction between allylic chloride 14 and i-
We carried out several experiments to help support the
proposed mechanism. First, we examined alkylations with steri-
cally and electronically unbiased, deuterium-labeled phosphor-
othioate ester 26 (eq 3).17 Although cross-couplings with this
substrate resulted in the expected CÀC bond formation, almost
no regioselectivity was observed. When a 1:2 mixture of regioi-
someric starting materials 31/1 was used, alkylation occurred to
furnish only regioisomeric product 2a (eq 4). This convergent
regioselectivity stands in contrast to regiospecific transforma-
tions described by Yamamoto.18 Few regioconvergent cross-
coupling reactions of this sort are known, and they usually utilize
stoichiometric amounts of dialkylcuprates.3g,19 The results from
eqs 3 and 4 support the scenario outlined in Scheme 2 in which
reductive elimination from 21 (kRE1) is slower than both
PrMgCl LiCl in the presence of sodium thioate 16a (1 equiv)
3
and CuSCN (1 mol %), we isolated the desired product with high
R-regioselectivity (94:6, entry 2). As expected, the addition of
substoichiometric amounts of sodium thioate 16a furnished
substantially lower regioselectivity (entry 3). Curiously, the use
of diisopropyl thioate 16b (1 equiv) resulted in poor selectivity
(entry 4).
Equation 2 provides some insight regarding the disparate
results obtained with 16a and 16b. Subjecting allylic chloride
14 and diethyl sodium thioate 16a to typical cross-coupling
reactions, without the addition of Grignard, yielded the expected
phosphorothioate ester 18 (eq 2). This result supports the
scenario outlined in Scheme 1 in which in situ alkylation precedes
Cu-catalyzed allylic alkylation. Under these same conditions, we
Scheme 1. r-Selective Alkylations of Allylic Chlorides
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Scheme 2. Proposed Mechanism
σ-complex equilibration and reductive elimination from 24
(kRE2). We also examined the use of enantioenriched phosphor-
othioate 32. As expected, cross-coupling of this substrate with i-
’ ACKNOWLEDGMENT
Financial support for this research was provided by an NSF
CAREER Award (CHE-1052824), Dartmouth College, and the
Walter and Constance Burke Foundation.
PrMgCl LiCl was stereospecific and yielded 33 with predomi-
3
nant inversion of stereochemistry (eq 5).20
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copper-catalyzed allylic alkylation of organomagnesium reagents
utilizing phosphorothioate ester leaving groups. A wide range of
Grignard reagents and electrophiles are amenable. We have also
developed a method for achieving high R-regioselectivity starting
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Corresponding Author
Jimmy.wu@dartmouth.edu
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