Tsuji–Trost Reaction of Non-Derivatized Allylic Alcohols

Article abstract of DOI:10.1002/chem.201705164

Palladium-catalyzed allylic substitution of non-derivatized enantioenriched allylic alcohols with a variety of uncharged N-, S-, C- and O-centered nucleophiles using a bidentate BiPhePhos ligand is described. A remarkable effect of the counter ion (X) of the XPd[κ²-BiPhePhos][η³-C₃H₅] was observed. When ClPd[κ²-BiPhePhos][η³-C₃H₅] (complex I) was used as catalyst, non-reproducible results were obtained. Study of the complex by X-ray crystallography, ³¹P NMR spectroscopy, and ESI-MS showed that a decomposition occurred where one of the phosphite ligands was oxidized to the corresponding phosphate, generating ClPd[κ¹-BiPhePhosphite-phosphate][η³-C₃H₅] species (complex II). When the chloride was exchanged to the weaker coordinating OTf^? counter ion the more stable Pd[κ²-BiPhePhos][η³-C₃H₅]⁺+[OTf] ^? (complex III) was formed. Complex III performed better and gave higher enantiospecificities in the substitution reactions. Complex III was evaluated in Tsuji–Trost reactions of stereogenic non-derivatized allylic alcohols. The desired products were obtained in good to excellent yields (71–98 %) and enantiospecificities (73–99 %) for both inter- and intramolecular substitution reactions with only water generated as a by-product. The methodology was applied to key steps in total synthesis of (S)-cuspareine and (+)-lentiginosine. A reaction mechanism involving a palladium hydride as a key intermediate in the activation of the hydroxyl group is proposed in the overall transformation.

Full text of DOI:10.1002/chem.201705164

DOI: 10.1002/chem.201705164
Full Paper
&
Synthetic Methods
Tsuji–Trost Reaction of Non-Derivatized Allylic Alcohols
Sunisa Akkarasamiyo,[a] Supaporn Sawadjoon,[a] Andreas Orthaber,*[b] and
Joseph S. M. Samec*[a]
In memory of Prof. Takao Ikariya
Abstract: Palladium-catalyzed allylic substitution of non-de-
rivatized enantioenriched allylic alcohols with a variety of
uncharged N-, S-, C- and O-centered nucleophiles using a bi-
dentate BiPhePhos ligand is described. A remarkable effect
of the counter ion (X) of the XPd[k2-BiPhePhos][h3-C3H5] was
observed. When ClPd[k2-BiPhePhos][h3-C3H5] (complex I) was
used as catalyst, non-reproducible results were obtained.
Study of the complex by X-ray crystallography, 31P NMR
spectroscopy, and ESI-MS showed that a decomposition oc-
curred where one of the phosphite ligands was oxidized to
the corresponding phosphate, generating ClPd[k1-BiPhe-
Phosphite-phosphate][h3-C3H5] species (complex II). When
the chloride was exchanged to the weaker coordinating
OTfÀ counter ion the more stable Pd[k2-BiPhePhos][h3-
À
C3H5]+ +[OTf] (complex III) was formed. Complex III per-
formed better and gave higher enantiospecificities in the
substitution reactions. Complex III was evaluated in Tsuji–
Trost reactions of stereogenic non-derivatized allylic alco-
hols. The desired products were obtained in good to excel-
lent yields (71–98%) and enantiospecificities (73–99%) for
both inter- and intramolecular substitution reactions with
only water generated as a by-product. The methodology
was applied to key steps in total synthesis of (S)-cuspareine
and (+)-lentiginosine. A reaction mechanism involving a pal-
ladium hydride as a key intermediate in the activation of the
hydroxyl group is proposed in the overall transformation.
Introduction
The Tsuji–Trost reaction is one of the most powerful synthetic
tools to form carbon–carbon (CÀC) or carbon–heteroatom (CÀ
X) bonds in organic synthesis.[1] Traditionally, the hydroxyl (OH)
group of easily accessible allylic alcohols is transformed into a
better leaving group such as an ester, carbonate, or halide in a
separate reaction step prior to the reaction to promote the CÀ
O bond cleavage (Scheme 1a). This derivatization step gener-
ates waste and lowers the atom economy and increases the
environmental factor (E-factor).[2] The substitution of the OH
group was recently voted the second most desired transforma-
tion that a round table of pharmaceutical companies wanted
greener alternatives for.[3]
Scheme 1. Derivatization of the OH-group leads to a high E-factor and lower
atom efficiency.
During the last two decades, development of direct substitu-
tion reactions of allylic alcohols without prior derivatization
has attracted considerable attention with respect to lowering
the number of reaction steps and increasing the atom econo-
my and thereby the environmental friendliness of the overall
transformation. In such reactions, the only by-product generat-
ed is water (Scheme 1b). One successful strategy has been to
employ an activator such as a Lewis or Brønsted acid to pro-
mote the CÀO bond cleavage of palladium-catalyzed Tsuji–
Trost reactions.[4,5] Another successful strategy is to use elec-
tron-deficient phosphorous-based ligands (phosphites, phos-
phoamidates, phospholes, phosphaalkene) in combination
with palladium to promote CÀO bond cleavage of allylic alco-
hols (Figure 1).[4,6]
[a] Dr. S. Akkarasamiyo, Dr. S. Sawadjoon, Prof. Dr. J. S. M. Samec
Department of Organic Chemistry, Stockholm University
106 91 Stockholm (Sweden)
E-mail: joseph.samec@su.se
[b] Dr. A. Orthaber
Department of Chemistry, Šngstrçm Laboratories
Uppsala University, Box 523, 75120 Uppsala (Sweden)
E-mail: andreas.orthaber@kemi.uu.se
Stereospecific substitution of the OH-group of easily accessi-
ble enantioenriched allylic alcohol with chirality transfer to the
product is an even more challenging reaction and also enan-
tioenriched allylic compounds are versatile chiral building
blocks. There is a correlation between the enantiospecificity of
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under https://doi.org/10.1002/
chem.201705164.
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tion catalyzed by Ir, Ru, and other metals has also been report-
ed, by mainly Carreira.[11,12] Another environmental friendly
route to synthesize enantioenriched allylic compounds is to
use Lewis or Brønsted acid catalysis without the intermediacy
of a p-allyl intermediate.[13–16] Enantioenriched allylic alcohols
are easily accessible organic compounds.[17] Given that a round
table of pharmaceutical companies voted the direct substitu-
tion of alcohols as the second most desired reaction that they
wanted greener alternatives to, with a special emphasis on ste-
reoselective/specific versions,[3] we thought it would be worth-
while to study and develop such chemistry. We here present a
robust catalytic system for the enantiospecific substitution of
the easily accessible non-derivatized enantioenriched allylic al-
cohols by O-, N-, S-, and C-centered nucleophiles with an ex-
emplification to natural product synthesis from biomass de-
rived allylic alcohol as well as the study on the Pd-BiPhePhos
complexes.
Figure 1. Successful ligands for direct substitution of the OH group of allylic
alcohols.
Pd-catalyzed allylic substitutions and leaving group ability, in
which poor leaving groups lead to worse results. The rational
is that a poor leaving group will lower the rate of ionization
and give a higher concentration of Pd0 that is responsible for
the racemization (vide infra).[7] In addition to the poor leaving
group ability of the OH group, racemization of the stereocen-
ter by h3-h1-h3 isomerization of the p-allyl palladium intermedi-
ate may be an additional challenge depending on the sub-
strate.[7] To our knowledge, only one single example is reported
for a Pd-catalyzed intermolecular stereospecific amination of a
non-derivatized allylic alcohol with water as the only by-prod- Results and Discussion
uct. Ozawa and Yoshifuji reported a stereospecific Pd-catalyzed
A. Catalyst studies
intermolecular amination of an enantioenriched allylic alcohol
without using acid activator at room temperature employing
an electron-deficient bidentate diphosphinidene–cyclobutene
(DPCB) ligand (Scheme 2).[6a] Elegant intermolecular cross-cou-
The catalyst screening was initially performed by mixing palla-
dium precursor and ligands in situ and monitoring yield and
stereospecificity. (S)-Cinnamyl alcohol 1a and benzyl alcohol
2a were used as substrates to screen the enantiospecificity in
the intermolecular Tsuji–Trost reaction to yield 3a. Oxygen nu-
cleophiles are very challenging where only one previous report
describes the intermolecular substitution using alcohols as nu-
cleophiles via an p-allyl intermediate in which 30 mol% of a
Pd-catalyst was used.[14a] [Pd(-allyl)Cl]2 was used as source of
palladium to circumvent high concentrations of Pd0 in the be-
ginning of the reaction. Using P(OPh)3 as ligand gave a very
poor reactivity (Table 1, entry 1).[18] We hypothesized that a bi-
dentate phosphite-based catalyst would be efficient with re-
spect to stability and reactivity. Therefore, the P(OPh)3 was ex-
changed for the BiPhePhos ligand.[19] The reaction gave high
reactivity, however the stereospecificity differed between ex-
periments (Table 1, entry 2). When the counter ion was
changed to the less coordinating triflate (OTf), an efficient
catalysis with high enantiospecificity was obtained
(Table 1, entry 3). Bidendate phosphine ligands worked poorly
(Table 1, entry 4). Using Pd(dba)2 as palladium precursor gave
Scheme 2. Tsuji–Trost reaction of non-derivatized stereogenic allylic alcohols.
pling reactions of optically active allylic alcohols with boronic
acid (carbon nucleophile) have been reported by Ikariya, Tian,
and Szabo.[8] A series of sophisticated enantioselective Tsuji– lower enantiospecificity (Table 1, entry 5). Toluene was the best
Trost reactions using a chiral catalyst to promote stereoinduc-
tion in which racemic mixtures of alcohols can be used to
yield enantioenriched product have been reported.[9] Also, allyl-
ic substitutions in which a prochiral nucleophile is asymmetri-
cally allylated have been reported.[10] In 2014, Beller and co-
workers reported an enantioselective allylation of aniline deriv-
atives to generate chiral allylic amines by employing a chiral
phosphoric acid and a chiral palladium complex.[9a] An asym-
metric allylic alkylation using an acetone nucleophile generat-
ed a chiral allylic compound was reported by Zhang et al.[9b]
Recently, Tian also reported a kinetic resolution of racemic al-
lylic alcohols through a palladium/sulfonyl-hydrazide-catalyzed
enantioselective allylation.[9c] Asymmetric Tsuji–Trost type reac-
solvent of those tested for this reaction (Table 1, entries 3,
6, 7).
In order to understand the reaction better, the nature of the
catalyst was studied. Crystals of ClPd[k2-BiPhePhos][h3-C3H5]
(complex I) were grown and the molecular structure in
Figure 2 shows a square planar geometry with a chloride
weakly coordinating in the apical position (PdÀCl, 2.67 Š). We
found that the catalyst was rather unstable and that one of
the phosphites readily was oxidized to generate ClPd[k1-BiPhe-
Phos-oxo][h3-C3H5] (complex II), in which the chloride had ex-
changed the phosphorous coordinating to the palladium
(Figure 2). This was observed in the 31P NMR spectrum, where
the intensity of complex I with a chemical shift at 148.5 ppm
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Table 1. Optimization of reaction conditions.[a]
Entry
Pd source
(mol%)
Ligand
(mol%)
Solvent
Conv.
[%][b]
ee
[%]
e.s.
[%][c]
1
2
3
4
5
6
7
[Pd(allyl)Cl]2 (0.5)
[Pd(allyl)Cl]2 (0.5)
[Pd(allyl)Cl]2 (0.5)
[Pd(allyl)Cl]2 (0.5)
[Pd(dba)2] (5)
P(OPh)3 (8)
BiPhePhos (1.1)
BiPhePhos (1.1) AgOTf (1)
dppf (1.1)
BiPhePhos (5.5)
PhMe
PhMe
PhMe
PhMe
PhMe
MTHF
MTBE
<10
>95
>95
0
>95
0
–
11–94
94
–
47
–
12–95
95
–
48
[Pd(allyl)Cl]2 (0.5)
[Pd(allyl)Cl]2 (0.5)
BiPhePhos (1.1) AgOTf (1)
BiPhePhos (1.1) AgOTf (1)
–
–
–
–
<10
[a] Reaction conditions: 1a (99%ee) (0.5 mmol), 2 (0,75 mmol), [Pd(allyl)Cl]2 (0.5 mol%), BiPhePhos (1.1 mol%), AgOTf (5 mol%), toluene (0.5 mL). [b] Conver-
sion determined by 1H NMR using xylene as an internal standard. [c] % enantiospecificity (%ee of product/%ee of substrate).
Figure 2. X-ray structure of Palladium complexes I (left), II (middle), and III (right) (top) and ChemDraw representations (below). For details see the supporting
information.
decreased in favor of two new peaks in a 1:1 ratio at 136 and
À2.8 ppm. Also other peaks were observed in the 31P NMR
spectrum. We were able to isolate complex II and grow crystals
for X-ray crystallography (Figure 2). The decomposition of com-
plex I to II was also observed during catalytic reactions.[20]
Complex II was unreactive in the reaction with 1a and 2a to
give 3a, however became reactive after addition of AgOTf. Im-
portant to note, in this case no enantiospecificity was ob-
tained. The complex obtained after addition of AgOTf to com-
plex I, Pd[k2-BiPhePhos][h3-C3H5]+ +[OTf]À, (complex III) was
also crystallized. X-ray diffraction of complex III revealed the
square planar geometry similar to that of I (Figure 3). The dis-
tance between the Pd-X differed between the two complexes
where the PdÀCl distance (2.67 Š) of complex I is significantly
shorter than that of Pd-F where no interaction was observed
(3.75 Š). The 31P NMR spectrum of complex III showed two
doublets with a coupling constant of J=91.8 Hz at 145.7 and
147.0 ppm (vide infra). This pure complex gave high reactivity
and enantiospecificity in the conversion of 1a and 2a to give
3a. The Pd[k2-BiPhePhos][h3-C3H5]+ +[BF4]À and Pd[k2-BiPhe-
Phos][h3-C3H5]+ +[PF6]À complexes also showed similar results
as the triflate complex III (See Supporting Information).
Complexes I and III were more closely studied at variable
temperatures using 31P NMR spectroscopy. Complex I appeared
as a singlet at 148.5 ppm at room temperature (Figure 3).
When cooling down the NMR probe, the signal widened and
at 08C appeared as a broad singlet. At À108C the signal split
to two broad signals at 147.4 and 149.4 ppm. When cooling
the probe to À208C the signals split to two distinguishable
doublets. At À388C, the doublets are sharp with coupling con-
stants of J=91 Hz. The results from the variable temperature
experiment with catalyst I is in accordance with that the chlo-
ride, that is loosely bound to the palladium (2.67 Š), is coordi-
nating and decoordinating from the metal center forming a
dynamic spectrum above À108C (vide infra).
Complex III shows two sharp doublets already at room tem-
perature. When heating up the probe 1008C, the two doublets
remain. However at this temperature, complex III starts to de-
compose. This shows clearly that complexes I and III have dif-
ferent characteristics in which the chloride in complex I inter-
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Important to note, no complexes with oxidized phosphates
were observed when starting from complex III. A possible ex-
planation for the higher stability of the triflate complex is that
the non-coordinating triflate enhances the coordination be-
tween the phosphites and the palladium. The stronger coordi-
nating chloride facilitate the decoordination of one of the
phosphites and this would promote oxidation of the phosphite
followed by decomposition of the complex to several species
including complex II (vide infra).
B. Intermolecular Tsuji–Trost reaction of non-derivatized
allylic alcohols
Complex III was readily generated in situ by mixing [Pd(p-al-
lyl)Cl]2, BiPhePhos, and AgOTf in DCM for 30 minutes followed
by evaporation. The substrate scope of allylic substitution of
the OH group by different nucleophiles and stereogenic allyl
alcohols was examined. First oxygen-centered nucleophiles
were used as nucleophiles. Benzylic, furfuryl, and aliphatic alco-
hols were tested as nucleophiles in the intermolecular substitu-
tion of (E,S)-4-phenylbut-3-en-2-ol ((E,S)-1a) and the non-aro-
matic (E,S)-4-cyclohexylbut-3-en-2-ol ((E,S)-1b). The reactions
proceeded smoothly and products (E,S)-3a-e were obtained in
good to excellent yields and with enantiospecificities above
85% (Table 2). Next, carbon-centered nucleophiles were trialed.
The reaction was performed using N-methyl indole (2 f) and
the reaction proceeded to yield 3 f in 85% yield and an enan-
tiospecificity >99%. Indole (2g) was used as substrate, and
this substrate could potentially attack a p-allyl-palladium inter-
mediate in the 1- or 3-position. Noteworthy, the indole at-
tacked selectively in the 3-position to generate (E,S)-3g in high
yield and excellent enantiospecificity. 2-Methylpyrrole as nucle-
ophile gave corresponding product 3h, with selective C-cen-
tered reactivity, in high yield and enantiospecificity. Reaction
with less reactive 1b, gave smooth reactions to yield 3i and 3j
in moderate yields and high enantiospecificities. To our knowl-
edge, these are the first reported examples of a stereospecific
substitution of a non-derivatized allylic alcohol with a C-cen-
tered nucleophile in which water is generated as the only by-
product. S-Centered nucleophiles are challenging substrates
due to their susceptibility to coordinate and thus deactivate
transition metal catalysts and have to our knowledge never
been reported as a nucleophile in these reactions. Gratifyingly,
the reaction of 2k and (E,S)-1a generated substitution product
(E,S)-3k in near quantitative yields and enantiospecificity. X-ray
crystallography of the corresponding sulfone showed retention
of configuration at the stereocenter of this novel compound
(Figure 5).
Figure 3. 31P NMR spectra of complex I at À388C to 258 showing a dynamic
behavior above À108C.
acts with the metal center at temperatures of which the cata-
lytic experiments are performed.
The catalysts were also studied by ESI-MS in the reaction of
1a and 2a to generate 3a. Reactions using complex I gave
rise to several species, of which II and II’ were observed as
major complexes in the ESI-MS spectrum (Figure 4). When reac-
tions were performed using complex III, the reaction was
cleaner where only starting complex III and the complex from
the first turn over (III’) where observed in the ESI-MS spectrum.
Encouraged by this result, the reaction was performed with
stronger nucleophiles. Both benzyl- and also alkyl thiols gave
the corresponding products 3l and 3m in good to excellent
yields and enantiospecificities. The reaction also worked well
with less reactive 1b to give products 3n and 3o in good to
excellent yields and enantiospecificities. Inspired by this, pro-
tected (R)-cysteine was used as S-nucleophile. The reaction
proceeded to give diastereomer (R,S)-3p in reasonable yields
and high diastereoselectivity. Palladium-catalyzed allylic amina-
Figure 4. ESI-MS data for reactions using III that gives high chirality transfer,
95%e.s. (top) and for complex I that gave lower chirality transfer, 14%e.s.
(bottom).
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Table 2. Intermolecular allylic substitution.[a]
[a] Reaction condition: allylic alcohol 1a (99%ee) or 1b (96%ee) (0.5 mmol), nucleophile 2 (1 mmol), [Pd(allyl)Cl]2 (0.5 mol%), BiPhePhos (1.1 mol%), AgOTf
(5 mol%), toluene (0.5 mL), isolated yield was reported and %ee was measured by chiral HPLC, %e.s. is (%ee of product)/(%ee of substrate). [b] [Pd(allyl)Cl]2
(2.5 mol%), BiPhePhos (5.5 mol%), AgOTf (2.5 mol%) were used. [c] [Pd(allyl)Cl]2 (1 mol%), BiPhePhos (2.2 mol%), AgOTf (10 mol%) were used. [d] [Pd(al-
lyl)Cl]2 (2.5 mol%), BiPhePhos (5.5 mol%), AgOTf (25 mol%) were used and the reaction was run in MTBE (0.5 mL).
tions proceed with retention of configuration at the stereocen-
ter (determined by X-ray crystallography, see Figure 5). The re-
action of (E,S)-1a with sterically hindered secondary N-methyl-
aniline and (E,S)-1a gave (E,S)-3r in 83% yield and 98% enan-
tiospecificity. Even weakly nucleophilic N-Boc and N(Me)-Boc
worked as nucleophiles in the substitution reaction to yield
products 3s and 3t in moderate to high yields and enantio-
specificities. The scope of starting material was extended to
the less reactive aliphatic allylic alcohol (E,S)-1b. Gratifyingly,
product (E,S)-3u was obtained in a 71% yield and excellent
enantiospecificity. It should be noted that all reactions in
Table 2 proceeded to full conversion where no starting materi-
al and only desired product were observed in the 1H NMR
Figure 5. X-ray structures of novel compounds show that the reactions pro-
ceed with retention of configuration. ORTEP drawings, ellipsoids, are at 50%
probability levels. For further crystallographic details see supporting infor-
mation. Top left: (S)-3q.HCl. Top right: (S)-3k-sulfone. Bottom left: (Z,R)-
5a.HCl Bottom right: (E,R)-5d.HCl.
spectrum of the crude reaction mixtures.
As showed above, amination of (E,R)-1a proceeds with re-
tention of configuration to yield (E,R)-3q in high yield and
enantiospecificity. Using the corresponding Z-olefin (Z,S)-1a
gave the inverted product (E,R)-3q in excellent yield and
slightly lower enantiospecificity (Scheme 3).[5,6] This is consis-
tent with an h3-h1-h3 isomerization mechanism, where the pal-
ladium p-allyl isomerizes from the less stable Z-olefin to the
more stable E-olefin.[7] When substrate (E,R)-1a’ was used, in
which the olefinic position has been transposed, the nucleo-
philic attack was selective to the olefinic position to give (E,R)-
3q in excellent yield and chirality transfer via a formal SN2’ re-
tions by direct substitution of the OH group are challenging
reactions for which only one single example has been report-
ed.[5a] Taking into account the importance of stereogenic
amines in the pharmaceutical and agricultural industries, we
thought it would be worthwhile to explore these reactions. Al-
lylic amination of (E,S)-1a by aniline (2q) gave product (E,S)-3q
in 82% isolated yield and >99% enantiospecificity. The reac-
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mer in 85% yield and full enantiospecificity from substrate
(E,S)-4d disclosing the strength of this catalytic system. The ab-
solute configuration of the corresponding HCl salt was deter-
mined by X-ray crystallography (Figure 5).
Alcohols as nucleophiles also worked in the intramolecular
stereoselective substitution reaction. When (E,S)-4e was run,
the corresponding (E,S)-5e was obtained with excellent enan-
tiospecificity through a formal SN2’ reaction.
C. Natural product synthesis
To test the efficiency and the robustness of the Pd[BiPhePhos]-
catalyzed stereospecific substitution we sought to apply the
methodology in the total synthesis of natural products. (S)-cus-
pareine, tetrahydroquinoline alkaloid isolated from Galipea offi-
cinalis, which shows antiplasmodial activity,[21] was synthesized
in 7 steps from commercially available 7 without needing any
protecting groups. The synthesis starts out with a Grignard re-
action, followed by reduction and a lipase-catalyzed kinetic res-
olution to generate stereogenic precursor 8 (Scheme 4). The
stereospecific substitution reaction by complex III ring-closes
the (R)-allylic alcohol intermediate 9 to generate tetrahydroqui-
noline 10 in 71 yield and 96% enantiomeric excess. (S)-cuspar-
eine was finally obtained by hydrogenation of 10. This demon-
strates that a natural product can by prepared from an accessi-
ble chiral allylic alcohol.[22] Azasugar, (+)-lentiginosine isolated
from Astralagus lentiginosus, which shows amyloglycosidase
and Hsp90 inhibitory activities,[23] was synthesized from cheap
and abundant d-galactose. The synthesis was carried out by
applying the Bernet–Vasella reaction of the iodo-galacto pyro-
noside 12[24] to yield oxime 13 in a one-pot transformation.
The oxime 13 was reduced and transformed to Boc-protected
amino allylic alcohol 14. This key intermediate was then used
in the complex III-catalyzed stereospecific substitution and
ring-closure to give 15 in a high yield with excellent diastereo-
specificity (96%ee). The Boc group was exchanged for a buten-
yl group to generate intermediate 16. The diene 16, was ring-
closed using Grubbs (2nd generation) catalyst and this inter-
mediate was then reduced and deprotected in one step by Pd-
catalysis to give (+)-lentiginosine.[25] This synthetic route shows
that the catalyst is quite robust even to demanding substrates
having several functional groups and demonstrates the poten-
tial to use bio-based starting material as feedstock to produce
a natural product.
Scheme 3. Absolut configuration of the product is dependent on both the
absolute configuration of the substrate as well as the geometry of the
olefin.
action. Thereby, the configuration of the stereocenter of the
new CÀN bond is, as expected, dependent on both the abso-
lute configuration of chiral substrate and the geometry of the
olefin.
B. Intramolecular Tsuji–Trost reaction of non-derivatized
allylic alcohols
Even though a series of methodologies of PdII- and AuI-cata-
lyzed intramolecular substitution reactions of stereogenic alco-
hols by both N-, and O-centered nucleophiles with chirality
transfer to generate 6-membered rings have been developed
and studied by the Uenishi, Widenhoefer, Aponick groups, the
corresponding intramolecular reactions proceeding through a
p-allyl-palladium intermediate has been less studied.[14] In the
case of PdII- and AuI-catalyzed intramolecular reactions, a fa-
vored bicyclic transitions state is required for the reactivity.[14j]
Because the present methodology proceeds through a p-allyl-
palladium intermediate, we assumed that other ring-sizes
would be possible, hence greatly expand the current substrate
scope. Gratifyingly, substrate (Z,S)-4a was reacted to form the
desired heterocycle (E,S)-5a as the major product in a good
yield and excellent enantiospecificity (Table 3, entry 1). The cor-
responding Z-isomer was isolated as a minor side-product. The
corresponding E-isomer, substrate (E,R)-4a, was reacted under
the same reaction conditions to give a 3:1 ratio of products
(E,S)-5a and (Z,R)-5a. The absolute configuration of (Z,R)-5a
was determined by X-ray crystallography (Figure 5). Substrate
4b has never been used in a substitution reaction with enan-
tiospecificity, because the substrate is typically not susceptible
towards formal SN2 reactivity.[13–16] Using the current approach,
the reaction proceeded smoothly to give (E,S)-5b with no loss
in enantiospecificity. To expand this methodology to smaller
ring sizes, substrate (Z,S)-4c was studied. The diastereomer of
the corresponding 5-membered heterocycle (5c) was generat-
ed in a 14(E,S):1(Z,R) ratio. The generation of both 5-, and 6-
membered cycles are favored kinetically and/or thermodynami-
cally; in contrast, seven membered rings are not. To our knowl-
edge the generation of a 7-membered ring from the corre-
sponding stereogenic alcohol with has not yet been reported.
Gratifyingly, we could generate (E,R)-5d as the single diastereo-
Mechanistic discussion
The Pd[BiPhePhos] catalyst is an efficient catalyst for the CÀO
bond cleavage in the nucleophilic substitution of the OH
group in allylic alcohols. We were intrigued by the counter ion
effect, where complex III, with an OTf anion gave a more
stable and efficient catalyst than the corresponding Cl com-
plex I. From the X-ray crystal structure of complex I (Figure 2),
a weak coordination of the chloride to palladium (2.67 Š) is ob-
served. Thereby, an equilibrium (K1) between k2-I and k1-I will
be present in solution (Scheme 5). This equilibrium is apparent
when complex I was studied by 31P NMR at variable tempera-
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the irreversible oxidation of one of the phosphites
and thereby explains the stability of complex III.
Table 3. Intramolecular allylic substitution.[a]
It is known that the stereospecificity in allylic sub-
stitution is dependent on a low concentration of free
Pd0 species present in solution. This is even more im-
portant in the case of allyl substrates with poor leav-
ing groups, as in the present case with non-derivat-
ized allylic alcohols. In this case, there will be a com-
petition of the Pd0 species to promote oxidative ad-
dition with either the allyl alcohol or a formed Pd p-
allyl complex present in solution. The mechanism for
the latter case is depicted in Scheme 6, where Pd0
promotes an oxidative addition of the chiral palladi-
um allyl species and thereby racemize the complex.
The Pd[BiPhePhos] complex that is very reactive in
the CÀO bond cleavage of non-derivatized allylic al-
cohols will not promote the racemization in
Scheme 6. This is supported by the fact that complex
III gives high conversion and enantiospecificties and
a low degree of catalyst degradation. However, in the
case of complex I, degradation to monodentate spe-
cies were observed at the same time as the reactions
gave poorer and less reliable enantiospecificities. This
can be explained by that a less reactive complex will
lead to a higher concentration of Pd0 species. These
generated Pd0 species are not reactive in the CÀO
bond cleavage in allylic alcohols. However, these less
reactive species are reactive in the racemization reac-
tion depicted in Scheme 5. This was supported by an
experiment in which Pd0 (1 equiv to III) was added to
the reaction mixture of the reaction of 1a and 2a to
generate 3a. The addition of Pd0 led to a decrease in
the enantiospecificity from 98% to below 44%. This
was further supported by the fact that starting the
reaction using Pd0 with the BiPhePhos ligand gave
poorer enantiospecificity (Table 1, entry 5). An alter-
native explanation for the racemization is that the
degradation species promote a hydrogen borrowing
pathway in which the allylic alcohol would be dehy-
drogenated to the corresponding achiral ketone.[26]
An experiment was performed in which 1a and 2a
were reacted in the presence of complex I and ben-
zoquinone. The formation of hydroquinone was ob-
Entry Substrate
Product
Yield (%)[b]
es
(%)[c]
>99
(E)
97 (Z)
74 (E/
Z=10:1)
1
(Z,S)-4a (96%ee)
(E,S)-5a (96%ee)
>99
(E)
96 (Z)
86 (E/
Z=3:1)
2
(E,R)-4a (95%ee)
(E,S)-5a (95%ee) (Z,R)-5a
(91%ee)
6
84
>99
(E,S)-4b (77%ee)
(Z,S)-4c (91%ee)
(E,S)-5b (79%ee)
(E,S)-5c (90%ee)
87 (E/
Z>14:1)
3
4
99
75 (E/
Z>20:1)
>99
(E,S)-4d (74%ee)
(E,R)-4e (78%ee)
(E,R)-5d (74%ee)
(E,S)-5e (74%ee)
5
61
95
[a] Reaction condition: allylic alcohol (0.5 mmol), [Pd(-allyl)Cl]2 (0.5 mol%), BiPhePhos
(1.1 mol%),AgOTf (5 mol%) toluene (2 mL) [b] Isolated yield [c] % e.s. is (%ee of prod-
uct)/(%ee of substrate), %ee was determined by chiral HPLC.
tures (Figure 3). At catalysis temperatures the broad signal in
the 31P NMR spectrum alludes to an equilibrium between k2-I
and k1-I. Even though this equilibrium is strongly shifted to k2-
I (K1 = <1), a low concentration of k1-I will be present in solu-
tion. The highly reactive k1-I undergoes a rapid and irreversible
oxidation to the corresponding phosphate to generate com-
plex II. In the case of the triflate complex III, there is no interac-
tion between the triflate and the palladium. The crystal struc-
ture of complex III shows a distance of 3.75 Š between palladi-
um and the triflate. By studying fluxional behavior of complex
III by 31P NMR, no interaction between triflate and metal were
observed (Figure 3). Thereby, in the case of complex III, the X-
ligand cannot promote the equilibrium to the corresponding
k1-complex in analogy to complex I (K1 = !1). This prevents
served however, no increase in enantiospecificity was ob-
served. Thereby, the hydrogen borrowing pathway is not oper-
ating in the current reaction. We have recently studied the re-
action mechanism of the related Pd[P(OPh)3]3-catalyzed reac-
tion and based on rate order determination, kinetic isotope
effect, and ESI-MS a reaction mechanism that proceeded
through a palladium hydride intermediate was proposed.[18b]
Ozawa and Yoshifuji proposed a similar reaction mechanism
for their Pd[DPCB] catalyst, based on thorough studies on both
Pd and Pt catalysts.[27] The palladium hydride intermediate is
responsible for the CÀO bond cleavage to generate the p-allyl
palladium intermediate. With the Pd[BiPhePhos] we propose a
similar reaction mechanism (Scheme 7). In this reaction mecha-
nism, the Pd[BiPhePhos] promotes the generation of the reac-
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Scheme 4. Total synthesis of (S)-cuspareine and (+)-lentiginosine using Pd[BiPhePhos]-catalyzed stereospecific allylic substitution in the key step.
(Scheme 7, red pathway). Finally, the nucleophile attacks from
the outer sphere to generate a product with retention of con-
figuration.
Conclusion
In conclusion, novel palladium BiPhePhos catalyst (III) has
been synthesized and fully characterized. The stability and
Scheme 5. The chloride promotes oxidation to generate complex II.
thereby also the efficiency of this catalyst in the CÀO bond
cleavage reaction of allylic alcohols are highly dependent on
the counter anion. With less coordinating anions, such as the
triflate, the coordination of the phosphites of the BiPhePhos
ligand to palladium becomes stronger and this promotes the
stability of the catalyst. With a more coordinating anion such
as the chloride, an equilibrium between k2-I and k1-I occurs.
Scheme 6. Pd0 promotes racemization of chiral palladium p-allyl complexes.
The resulting decoordination of one of the phosphites of the
BiPhePhos leads to an irreversible oxidation to the correspond-
tive palladium hydride intermediate A that is responsible for
the CÀO bond cleavage reaction to generate the p-allyl palladi-
um intermediate B (Scheme 7, black path). The Pd[BiPhePhos]
is very reactive in the initial steps in the reaction mechanism
and this leads to that this species will always be present at low
concentration. However, the degradation products, such as
complex II and Pd[P(OPh)3]2, are not reactive enough in these
reaction steps and therefore the concentration of Pd0 species
may build up during the reaction. These less reactive Pd0 spe-
cies can promote the oxidative addition of a p-allyl palladium
intermediate and this leads to the observed racemization
ing non-coordinating phosphate. This decomposition leads to
palladium species in solution that are not reactive in the reac-
tion steps leading to the palladium-p-allyl complex. However,
these Pd0 species are reactive in the oxidative addition of a
palladium-p-allyl complex which leads to a racemization. Grati-
fyingly, suppressing this unwanted pathway is easily conducted
using a non-coordinating anion. Highly reactive complex III is
readily prepared in situ by mixing Pd precursor, BiPhePhos
ligand and silver triflate. The resulting catalyst (III) is very reac-
tive in a broad scope of both inter- and intramolecular stereo-
specific substitution of the OH group in enantioenriched allylic
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ration was performed with HPLC (YL-Clarity HPLC instrument)
using Daicel Chiralcel column AD, OD-H and OJ-H.
Procedure for preparation of the Pd[k2-BiPhePhos][h3-C3H5]+
+
[OTf]À: A flame-dried Schlenk tube was charged with [Pd(allyl)Cl]2
(0.028 mmol), BiPhePhos (0.051 mmol), AgOTf (0.11 mmol) and
CH2Cl2 (0.5 mL). The mixture was degassed by three freeze–pump–
thaw cycles and stirred at room temperature for 30 min then AgCl
was filtered off through syringe filter and the solvent was removed
under vacuum.
General procedure for catalytic enantiospecific nucleophilic sub-
stitution of allylic alcohol: A solution of enantiopure allylic alcohol
(0.50 mmol), NuH (0.75 mmol) in toluene or MTBE (0.5 mL, 1.0m)
was added to the Pd[k2-BiPhePhos][h3-C3H5]+ +[OTf]À (complex III)
(1–5 mol%). The slurry was degassed by three freeze–pump–thaw
cycles and stirred at 08C or room temperature. The reaction was
1
monitor by H NMR, when the reaction had reached full conversion
it was purified by column chromatography on silica gel.
Experimental procedure for catalytic asymmetric synthesis of
(E,S)-(3-(benzyloxy)but-1-en-1-yl)benzene, (S)-3a: A flame-dried
Schlenk tube containing a stir bar was charged with [Pd(allyl)Cl]2
(0.9 mg, 0.5 mol%) and BiPhePhos (4.3 mg, 1.1 mol%) and AgOTf
(6.3 mg, 5 mol%) and CH2Cl2 (0.5 mL). The mixture was degassed
by three freeze–pump–thaw cycles and stirred at room tempera-
ture for 30 min, after which the AgCl was filtered off and solvent
was removed under vacuum. A solution of allylic alcohol (S)-1a
(74 mg, 0.50 mmol), benzyl alcohol 2a (50 mL, 0.75 mmol) in tolu-
ene (0.5 mL, 1m) was added to the [Pd-BiPhePhos]OTf complex.
The slurry was degassed by three freeze-pump-thaw cycles and
Scheme 7. Proposed reaction mechanism for the Tsuji–Trost reaction of allyl-
ic alcohols.
alcohols by a variety of N-, S-, C-, and O-centered nucleophiles.
The corresponding products were obtained in good to excel-
lent yields and enantiospecificities with water as the only by
product. The efficiency of this catalyst was further demonstrat-
ed in the total synthesis of (S)-cuspareine and (+)-lentiginosine
where the methodology was used in key steps. We hope that
this easily accessible catalyst will be used in the allylic substitu-
tion of non-derivatized alcohols in both academia and in in-
dustry.
1
stirred at room temperature. The reaction was monitor by H NMR,
when the reaction had reached full conversion it was purified by
column chromatography on silica gel eluting with pentane:EtOAc
(50:1) to give the desired product (S)-3a as colorless oil (108 mg,
1
0.45 mmol, 91% yield). H NMR (400 MHz, CDCl3): d 7.43–7.21 (m,
10H), 6.54 (d, J=16.0 Hz, 1H), 6.17 (ddd, J=1.3, 7.8, 16.0 Hz, 1H),
4.62 (dd, J=1.3, 12.0 Hz, 1H), 4.44 (dd, J=1.3, 12.0 Hz, 1H), 4.15–
4.05 (m, 1H), 1.37 (dd, J=1.3, 6.4 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d 138.8, 136.6, 131.7, 131.4, 128.6 (2), 128.3 (2), 127.7 (3),
127.4, 126.5 (2), 75.8, 70.0, 21.7; IR (neat, cmÀ1): 3027, 2970, 2861,
1493, 1450, 1229, 1217, 1068; HRMS (ESI) Calcd. for C17H18NaO,
[M+Na]+: 261.1250 Found 261.1244; HPLC condition for 3a:
Experimental Section
General information
Daicel Chiralpak OJ-H, n-hexane/iPrOH (97:3), flow rate 1 mLminÀ1
tR =9 min for S-isomer, tR =11 min for R-isomer.
,
All catalysts, reagents and solvent were purchase from Sigma–Al-
drich Company. Solvents were dried by distillation from the appro-
priate drying reagents prior to use. Toluene and dichloromethane
were distilled from calcium hydride under argon. Aniline was dis-
tilled under reduced pressure and stored under argon. Moisture-
and air-sensitive reactions were carried out under an atmosphere
of argon using standard Schlenk techniques. Analytical thin-layer
chromatography (TLC) was conducted using Merck analyticl TLC
plates (silica gel 60 F-254). Compounds were visualized by ultravio-
let light and/or by heating the plate after dipping in a 1% solution
of vanillin in 0.1m sulfuric acid in ethanol. Flash column chroma-
tography was performed on silica gel (35–70 micron). Infrared (IR)
spectra were recorded on a PerkinElmer FT-IR spectrometer. Proton
and carbon nuclear magnetic resonance (NMR) spectra were ob-
tained using a Varian 400 MHz spectrometer, Bruker 400 MHz spec-
trometer and Bruker 500 MHz spectrometer. Chemical shifts were
recorded as d values in ppm. Coupling constants (J) are given in
Hz, and multiplicity is defined as follows: br=broad, s=singlet,
d=doublet, dd=doublet of doublet, ddd=doublet of doublet of
doublet, dt=doublet of triplet, dq=doublet of quintet, t=triplet,
td=triplet of doublet, tt=triplet of triplet, q=quartet, quint=
quintet, hep=heptet, m=multiplet. High resolution mass spec-
trometry was recorded on Bruker Daltonics MicrOTOF. Chiral sepa-
Experimental procedure for the catalytic transformation of (Z,S)-
4a to (E,S)-5a: A flame-dried Schlenk tube containing a stir bar
was charged with [Pd(allyl)Cl]2 (0.86 mg, 0.5 mol%) and BiPhePhos
(4.1 mg, 1.1 mol%) AgOTf (6 mg, 5 mol%) and CH2Cl2 (0.5 mL). The
mixture was degassed by three freeze–pump–thaw cycles and
stirred at room temperature for 30 min, after which the AgCl was
filtered off and solvent was removed under vacuum. A solution of
allylic alcohol (Z,S)-4a (103 mg, 0.47 mmol), in toluene (5 mL,
0.25m) was added to the [Pd-BiPhePhos]OTf complex. The slurry
was degassed by three freeze–pump–thaw cycles and stirred at
1
room temperature. The reaction was monitor by H NMR, when the
reaction had reached full conversion it was purified by column
chromatography on silica gel eluting with pentane:EtOAc (50:1) to
give the piperidine (E)-5a as a colorless oil (70 mg, 0.35 mmol,
75% yield with 10:1 E/Z mixture). (E,S)-5a: 1H NMR (400 MHz,
CDCl3): d 7.20 (dd, J=7.4, 8.2 Hz, 2H), 6.88 (d, J=8.2 Hz, 2H), 6.76
(t, J=7.4 Hz, 1H), 5.47–5.42 (m, 2H), 4.22 (br, 1H), 3.30 (dt, J=3.2,
9.0 Hz, 1H), 3.12–3.03 (m, 1H), 1.91–1.49 (m, 6H), 1.59 (d, J=
3.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): d 151.3, 129.9, 128.8 (2),
126.8, 118.6, 117.1 (2), 57.5, 45.6, 31.2, 25.9, 20.2, 17.9; IR (neat,
cmÀ1): 3023, 2932, 2854, 1596, 1479, 1447, 1377, 1246, 1166, 1023;
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HRMS (ESI) Calcd. for C14H20N, [M+H]+: 202.1590 Found 202.1589;
HPLC condition for (E)-5a: Daicel Chiralpak OJ-H, n-hexane/iPrOH
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(98:2), flow rate 0.5 mLminÀ1
, tR =10.7 min for S-isomer, tR =
12.1 min for R-isomer; (Z,R)-5a: 1H NMR (400 MHz, CDCl3): d 7.19
(td, J=7.4, 1.7 Hz, 2H), 6.90 (d, J=7.8 Hz, 2H), 6.81 (tt, J=0.8,
7.2 Hz, 1H), 5.54–5.33 (m, 2H), 4.35–4.30 (m, 1H), 3.15 (t, J=4.9 Hz,
2H), 1.80–1.56 (m, 6H), 1.60 (d, J=6.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d 151.8, 130.5, 128.7 (2), 124.6, 120.0, 118.7 (2), 54.1, 48.5,
31.8, 26.2, 21.2, 13.2; IR (neat, cmÀ1): 3016, 2928, 2856, 1598, 1500,
1369, 1216; HRMS (ESI) Calcd. for C14H20N, [M+H]+: 202.1590
Found 202.1599; HPLC condition for (Z)-5a: Daicel Chiralpak OJ-H,
n-hexane/iPrOH (98:2), flow rate 0.5 mLminÀ1, tR =9.2 min for R-
isomer, tR =12.6 min for S-isomer.
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Acknowledgements
Financial support from Swedish Research Council (Formas) and
Stiftelsen Olle Engkvist Byggmästare) is gratefully acknowl-
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · cuspareine · OH activation ·
palladium · Tsuji–Trost reaction
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Manuscript received: October 31, 2017
Accepted manuscript online: November 27, 2017
Version of record online: January 12, 2018
Chem. Eur. J. 2018, 24, 3488 –3498
www.chemeurj.org
3498
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim