Asymmetric Aza-Wacker-Type Cyclization of N-Ts Hydrazine-Tethered Tetrasubstituted Olefins: Synthesis of Pyrazolines Bearing One Quaternary or Two Vicinal Stereocenters

Article abstract of DOI:10.1021/jacs.8b02865

We have developed an asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins, affording optically active pyrazolines bearing chiral tetrasubstituted carbon stereocenters. This reaction is tolerant to a broad range of substrates under mild reaction conditions, giving the desired chiral products with high enantioselectivities. Generation of two vicinal stereocenters on the C=C double bonds was also achieved with high selectivities, a process which has been rarely studied for Wacker-type reactions. A mechanistic study revealed that this aza-Wacker-type cyclization undergoes a syn-aminopalladation process. It was also found that for substrates bearing two linear alkyl substituents on the outer carbon atom of the olefin, both of which are larger than a methyl group, the alkyl substituent that is cis to the intranucleophilic group participates more readily in β-hydride elimination. When one of the two alkyl substituents on the outer carbon atom of the olefin is a methyl group, β-hydride elimination proceeds selectively at the methylene side, thus both diastereomers can be prepared via switching the configuration of the olefin. Furthermore, the product can be converted to a pharmaceutical compound in high yields over three steps.

Full text of DOI:10.1021/jacs.8b02865

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Article
Asymmetric Aza-Wacker-type Cyclization of N-Ts Hydrazine-
Tethered Tetrasubstituted Olefins: Synthesis of Pyrazolines
Bearing One Quaternary or Two Vicinal Stereocenters
Xuezhen Kou, Qihang Shao, Chenghao Ye, Guoqiang Yang, and Wanbin Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02865 • Publication Date (Web): 26 May 2018
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Journal of the American Chemical Society
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Asymmetric Aza-Wacker-type Cyclization of N-Ts Hydrazine-
Tethered Tetrasubstituted Olefins: Synthesis of Pyrazolines
Bearing One Quaternary or Two Vicinal Stereocenters
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Xuezhen Kou,† Qihang Shao,† Chenghao Ye,† Guoqiang Yang,*,† and Wanbin Zhang*,†
†Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai Jiao
Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
Supporting Information Placeholder
ABSTRACT: We have developed an asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins, affording optically
active pyrazolines bearing chiral tetrasubstituted carbon stereocenters. This reaction is tolerant to a broad range of substrates under mild reaction con-
ditions, giving the desired chiral products with high enantioselectivities. Generation of two vicinal stereocenters on the C=C double bonds was also
achieved with high selectivities, a process which has been rarely studied for Wacker-type reactions. A mechanistic study revealed that this aza-Wacker-
type cyclization undergoes a syn-aminopalladation process. It was also found that for substrates bearing two linear alkyl substituents on the outer carbon
atom of the olefin, both of which are larger than a methyl group, the alkyl substituent that is cis to the intra-nucleophilic group participates more readily
in β-hydride elimination. When one of the two alkyl substituents on the outer carbon atom of the olefin is a methyl group, β-hydride elimination pro-
ceeds selectively at the methylene side, thus both diastereomers can be prepared via switching the configuration of the olefin. Furthermore, the product
can be converted to a pharmaceutical compound in high yields over 3 steps.
Scheme 1. Asymmetric Aza-Wacker-type Reactions
INTRODUCTION
Chiral nitrogen-containing heterocycles are present in numerous natu-
ral products and drug molecules.1 The transition-metal-catalyzed intra-
molecular amination of alkenes is a powerful method for the synthesis of
nitrogen-containing heterocycles.2 Therefore, related enantioselective
versions have attracted significant attention. Among the various meth-
odologies, transition-metal-catalyzed asymmetric oxidative aza-cycliza-
tions represent one of the most efficient intramolecular amination meth-
ods, but they have not been widely reported. Two general metals have
been explored, copper and palladium, as suitable catalyst metal sources
for these types of reactions, most likely due to their inherent properties
that make them suitable for organometallic catalysis and the relative sta-
bility of these complexes to a wide range of oxidants. With respect to
copper catalysis, a series of asymmetric intramolecular alkene oxidative
difunctionalizations have been developed by the Chemler group, initi-
ated by the aminocupration of alkenes.2i,2l,3,4 For palladium catalysis, sev-
eral groups have contributed greatly to this area. Yang has developed a
novel class of palladium-catalyzed highly enantioselective aerobic tan-
dem aza-cyclization/Heck-type reactions.5,6 Sasai and coworkers real-
ized an asymmetric aza-cyclization/alkoxycarbonylation cascade cycli-
zations.7 Recently, Liu reported an interesting Pd-catalyzed asymmetric
intramolecular oxidative aminoarylation of alkenes, including a C-H
functionalization process, for the construction of chiral indoline/isoin-
dolinone skeletons.8 While the aforementioned approaches have been
utilized to accomplish asymmetric oxidative aza-cyclizations for build-
ing chiral heterocycles, aza-Wacker reactions are especially appealing
due to the generation of an additional alkene in the product which can
enable downstream diversification.
The Wacker reaction was discovered at the dawn of organometallic
chemistry.9 The study of Wacker and Wacker-type reactions has re-
mained a long-standing research topic.2f,10 However, asymmetric cata-
class of axially chiral binaphthyl bisoxazoline ligand, improving the en-
lytic versions of these reactions have not been widely studied compared
antioselectivity of this reaction significantly.13 The Stoltz group has also
with other classic organometallic reactions.11 The seminal work of Ho-
contributed greatly to work in the area of asymmetric Wacker-type cy-
sokawa and Murahashi initiated the studies in this area.12 The Hayashi
clizations, achieve high levels of enantioselectivity under simple aerobic
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group found an efficient catalytic system employing a novel

Journal of the American Chemical Society
Page 2 of 11
conditions.14 The Sasai group and our group have developed several
were tested and only a substrate bearing a Ts group exhibited reactivity
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8
classes of chiral ligands for this type of reaction, showing high enantiose-
lectivity and good substrate tolerance.15,16 The Sigman group has re-
ported an elegant intermolecular asymmetric Wacker-type reaction of
phenols with allylic alcohols.17 This group has also divulged several ele-
gant enantioselective difunctionalizations of styrenes containing an or-
tho-phenol.18 Compared with oxy-Wacker-type reactions, the enanti-
oselective version of aza-Wacker-type reactions were not developed un-
til much later due to the dependence of the mechanism on the substrate
and catalytic conditions.19,20 Since the first report concerning aerobic
Pd-catalyzed aza-Wacker-type cyclizations from the Stahl group in
2002,21 the development of related enantioselective processes has been
a long-term challenge. Recently, the Stahl group and our group inde-
pendently reported two asymmetric aza-Wacker-type cyclizations of to-
sylamide with disubstituted olefins, giving chiral alkenyl pyrrolidines or
indolines in moderate to excellent ees, with up to 99% ee being obtained
with Stahl’s catalytic system (Scheme 1, A).22 Later, our group devel-
oped an asymmetric aza-Wacker-type cyclization of N-methoxyl amide
with trisubstituted olefins for the preparation of chiral isoindolinones
with up to 99% ee (Scheme 1, B).23 However, the types of nucleophilic
nitrogen sources remain very limited. In addition, following an increase
in the number of substituents on the olefin, the steric hindrance is in-
creased, resulting in lower reactivity. Thus, the use of tetrasubstituted
olefins in aza-Wacker-type reactions remains challenging (not only for
the asymmetric version). Furthermore, the generation of two vicinal ste-
reocenters on the C=C double bonds has not been studied for asymmet-
ric aza-Wacker-type reactions,24 maybe due to the difficulty in control-
ling the olefin migration and sterically discriminating between the two
alkyl substituents on the outer carbon of C=C bond,24a which links with
Pd(II) through a rotatable single bond after aminopalladation (Scheme
1, C-I).
for this reaction. Previous studies showed that the nature of the solvent
has a great influence on the asymmetric aza-Wacker-type reaction. For
the first type of aza-Wacker-type reaction, nonpolar solvent toluene was
found to be the best solvent (Scheme 1, A).22 For the second type of aza-
Wacker-type reaction, the strongly coordinating solvent, MeCN, was
found to be the best solvent (Scheme 1, B).23 Therefore, a wide range of
solvents were screened for this new asymmetric aza-Wacker-type reac-
o
tion at a temperature of 60 C under an oxygen atmosphere and using
Pd(OAc)2/tBu-Pyrox as the catalyst complex (Table 1 and Table S1 in
SI). Reaction in a less polar solvent, such as toluene, can give the desired
product but with only moderate yield and ee (Table 1, entry 1). Ether
solvents, such as THF, can significantly improve the reactivity but not
enantioselectivity compared with the results obtained in toluene (entry
2). To our delight, the strongly coordinating MeCN could significantly
enhance the ee (entry 3). Alcohol solvents bearing bulkier substituents
have a slight influence on the reactivity and enantioselectivity of this re-
action, differing to the strong effects observed in our previous study (en-
tries 4-6).23 The screening of different carbonyl-containing solvents
showed that ketone solvents are better than others for this reaction (en-
tries 7-9), and the best ee was observed in acetone solvent (entry 8).
Although strongly coordinating solvents, such as MeCN, MeOH, ac-
etone and DMF, showed excellent reactivity and enantioselectivity (en-
tries 3, 4, 8 and 9), it appears that these results were not (or not solely)
caused by the coordinating ability of the solvent as comparably good re-
sults were also obtained when the reaction was carried out in weakly co-
ordinating solvents such as DCE (entry 10). This solvent effect differs
significantly from previous reports and cannot be explained in detail at
present.22,23
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Table 1. Solvent Screeninga
Pyrazolines, as analogues of pyrrolines and pyrrolidines, are a class of
important heterocycles for pharmaceutical research,25 such as 1,25b
a
compound showing antiinflammatory and analgesic activity, 2,25g a cho-
lesterol 24 hydroxylase inhibitor, and 3,25c a modulator of a selective an-
drogen receptor. Therefore, the asymmetric synthesis of chiral 4,5-dihy-
dro-1H-pyrazole derivertives is highly desired.25a,26 However, there are
few reports concerning the synthesis of chiral 4,5-dihydro-1H-pyrazoles
via enantioselective catalysis.26
entry
solvent
yield (%)b
ee (%)c
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5
6
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8
Toluene
THF
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98
92
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91
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67
94
91
90
Figure 1. Pyrazolines with Bioactivity
MeCN
MeOH
EtOH
tBuOH
AcOEt
Acetone
DMF
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10
The using of N-Ts hydrazone as a nitrogen nucleophile in asymmetric
aza-Wacker-type reactions has never been reported, possibly because
they readily decompose via a carbene intermediate27 (Scheme 1, C-II)
or hydrolysis. Herein, we report an asymmetric aza-Wacker-type cycliza-
tion of N-Ts hydrazone, which is also the first aza-Wacker-type reaction
with tetrasubstituted olefins, providing pyrazolines bearing chiral
tetrasubstituted carbon stereocenters (Scheme 1, C). Importantly, gen-
eration of two vicinal stereocenters on the C=C double bonds was
achieved with high selectivities under our catalytic conditions.
DCE
aReactions were carried out on a 0.20 mmol scale using Pd(OAc)2 (10
mol %) and ligand (15 mol %) in solvent (2.0 mL) under O2 atmosphere
(1 atm, sealed tube) at 60 oC for 12 h. bYield of isolated product. cDeter-
mined by HPLC using a chiral column.
Table 2. Condition Optimizationa
RESULTS AND DISCUSSION
Enantioselective Construction of Chiral Pyrazolines via Asymmetric
Aza-Wacker-type Cyclization. To initiate our investigation, we elected
to use phenyl-substituted hydrazone as the intramolecular nucleophilic
group and a tetrasubstituted olefin bearing three methyl groups as the
intramolecular electrophile. Different protecting groups for the nitrogen
entry
1
ligand
L1
temp. (oC)
60
yield (%)b
95
ee (%)c
94
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conditions for this reaction: tBu-Pyrox (L1) as chiral ligand, Pd(OAc)2
as palladium source, acetone as solvent, a reaction temperature of 40 oC
and a reaction time of 36 h under O2 atmosphere.
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12d
13e
14f
15g
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L1
L1
L1
L1
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-2
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Scheme 2. Scope of Substrates Bearing Aryl Groups at the Hydra-
zone Positiona,b
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13
aReactions were carried out on a 0.20 mmol scale using Pd(OAc)2 (10
mol %) and ligand (15 mol %) in acetone (2.0 mL) under O2 atmos-
phere (1 atm, sealed tube) at 60 oC for 12 h. bYield of isolated product.
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cDetermined by HPLC using a chiral column. Pd(TFA)2 instead of
d
Pd(OAc)2, 24 h. 40 C for 36 h. f25 C, 72 h. Pd(OAc)2 (5 mol %),
e
o
o
g
L1(7.5 mol %), 40 oC for 72 h.
With the best solvent in hand, different classes of ligands were
screened (Table 2 and Table S2 in SI), including pyridine-oxazoline lig-
ands, pyridine-imine ligands, bisoxazoline ligands, ligands forming five-
membered ring complexes, ligands forming six-membered ring com-
plexes and ligands bearing a biphenyl backbone. All of these ligands
could promote the reaction to give the desired product in moderate to
excellent yields.28 Pyridine-oxazoline skeletons that allow for the for-
mation of five-membered ring complexes with palladium (with no sub-
stituent at the ortho position of the pyridine) were the best choice for
this asymmetric aza-Wacker-type reaction (entries 1-7), with the tBu-
substituted oxazoline moiety proving to be the best enantio-inducing
group (entry 1 vs 2-4, 6 vs 7). Similar chiral ligands exhibiting ortho-ste-
ric hindrance were effective with regards to catalytic activity but lacked
enantio-inducing ability (entries 8 and 9). Interestingly, the BOX-type
ligand L10 could also promote this asymmetric aza-Wacker-type reac-
tion and showed promising results (entry 10). This indicates that bisox-
azoline ligands should also be useful for the development of other aza-
Wacker-type reactions. A bisoxazoline ligand bearing a biphenyl back-
bone, which is an effective chiral ligand for oxy-Wacker-type reaction,16
showed only moderate catalytic activity and almost no enantio-induct-
ing ability (entry 11).
aReactions were carried out on a 0.20 mmol scale using Pd(OAc)2 (10
mol %) and tBu-Pyrox (15 mol %) in acetone (2.0 mL) under O2
atmosphere at 40 oC for 36 h. Yields correspond to isolated product. Ees
are determined by HPLC using a chiral column. bIn most cases, substrate
was fully converted but hydrolysis occurred to give ketone as a major
byproduct.
With the optimized reaction conditions in hand, substrate scope
was explored (Scheme 2-5). Firstly, the influence of different aryl groups
as R substituents on the hydrazone substrate was studied (Scheme 2).
Based on the results of substrates bearing mono-substituted phenyl
groups, it can be concluded that electron-donating or electron-
withdrawing substituents at the para or meta-positions of the benzene
ring have little effect on the enantioselectivity, while electron-donating
substituents slightly decreased the reactivity of the substrate comparing
with the results of the corresponding substrates bearing electron-
withdrawing substituents at the same position (5b-5l). The cyclization
of substrates bearing meta-substituted phenyl groups afforded the
corresponding products with better yields than those bearing para-
substituted phenyl groups (5b-5g vs 5h-5l). Importantly, bromide and
chloride groups were tolerated, presenting the opportunity for
subsequent diversification via cross-coupling. The asymmetric
cyclization of substrates bearing ortho-substituted phenyl groups
To improve the ee, further screening of the palladium source and re-
action temperature was also carried out. The palladium source,
Pd(TFA)2, has shown better catalytic activity and enantio-inducting
ability than Pd(OAc)2 in the other two types of asymmetric aza-Wacker-
type reaction.22,23 However, the opposite effect is observed for our new
asymmetric aza-Wacker-type reaction (entry 12 vs 1). When the reac-
o
tion was carried out at 40 C, acceptable reactivity and higher ee were
obtained (entry 13 vs 1 and 14). Good results could also be furnished
when a lower catalyst loading was employed (entry 15), but a very long
reaction time was required. Although carrying out the reaction at 60 oC
for 12 h can give the desired product with good results, in consideration
of enantioselectivity, we chose the following conditions as the optimal
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proved to be difficult, therefore the catalytic reactions were conducted
alkyl groups as R1 on the inner carbon of the olefin were also highly re-
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3
4
5
6
7
8
with longer reaction times, affording the corresponding products in high
yields with only slightly lower ees compared with those bearing
substituents at other positions (5m and 5n). Product 5m bears the back-
bone of the cholesterol 24 hydroxylase inhibitor 2. Substrates bearing
disubstituted-phenyl groups gave their corresponding product with
good results (5n and 5o). A substrate bearing a β-naphthyl group
afforded the desired product in good yield and excellent ee (5p).
Products 5q and 5r bearing thienyl or furyl substituents were obtained
in lower yields but still with excellent ees, as compared with other
substrates listed in Scheme 2.
active, allowing for asymmetric aza-Wacker-type reaction under the
standard reaction conditions (5y-5ad). A benzyl substituted olefin sub-
strate provided cyclization product 5ab in high yield and excellent ee.
Product 5ad, which was also obtained with excellent results, may be fur-
ther derivatized via reaction of its benzyl protected oxygen group.
Scheme 5. Asymmetric Aza-Wacker-type Cyclization for Construc-
tion of Two Vicinal Stereocentersa,b
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Scheme 3. Scope of Substrates Bearing Alkenyl and Alkyl Groups at
the Hydrazone Position
Substrates bearing other substituents, except aryl groups at the
hydrazone side, have also been tested in this asymmetric cyclization
(Scheme 3). A β-styrenyl-substituted hydrozone substrate could give
the desired product with good results(5s). Interestingly, no endo-
cyclization at the styrene double bond was detected. The reason for this
may be explained by the Pd(II)/Pyrox being an electrophilic complex
that favors coordination with the more electron-rich double bond.
Reactions of substrates with linear alkyl
R groups gave the
corresponding cyclized products in lower yields than that of substrate
bearing a branched alkyl group(iPr) (5t, 5u vs 5x). The introduction of
a phenyl group at the end of alkyl chain led to a reduction in product
yield (5v and 5w).
A benzyl-substituted substrate afforded the
corresponding product with significantly lower ee than other substrates
(5w), while others could give the desired products with good ees (5s-5v,
5x).
Scheme 4. Scope of Substrates Bearing Different R1 on the Olefin
aReactions were carried out on a 0.20 mmol scale using Pd(OAc)2 (10
mol %) and tBu-Pyrox (15 mol %) in acetone (2.0 mL) under O2
atmosphere at 40 oC for 36 h. Yields correspond to isolated product. Ees
were determined by HPLC using a chiral column. The dr values were
1
b
determined by H NMR. In most cases, substrate was fully converted
After testing the effect of different R groups at the hydrazone side of
the molecule, we next turned our attention to altering the olefin group
of the substrates (Scheme 4). Gratifyingly, substrates bearing different
but hydrolysis occurred to give ketone as a major byproduct. cEe was
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Journal of the American Chemical Society
determined after hydrogenation of C=C double bonds in the six-
membered ring.
In order to gain insight into the universality of this asymmetric aza-
Wacker-type reactions is the Pd(II) mediated insertion step to form a
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2
3
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new bond between the heteroatom and one carbon of the C=C
bond.10o,13d,14b,18,19b,20,31 Two possible mechanistic pathways for this step
of the aza-Wacker-type reaction are syn-aminopalladation and anti-ami-
nopalladation, and the pathway usually depends on the type of nucleo-
phile, electrophile, catalyst, and reaction conditions, as discovered by
the Stahl group.19,20 The Stahl group reported that the Pd(TFA)2/Ph-
6MePyrox-catalyzed aza-Wacker-type cyclization of the substrate shown
in eq. 1 proceeds through an anti-aminopalladation process to give the
cyclized product in excellent yield and ee, whereas switching the Pd(II)
source to Pd(OAc)2 resulted in the reaction proceeding through a syn-
aminopalladation mechanism giving very low ee and moderate yield (eq.
2).19b
Wacker-type reaction, substrates bearing different substituents on the
outer carbon atom of the olefin were also examined (Scheme 5). Inter-
estingly, products bearing two vicinal stereogenic centers were obtained
with high diastereoselectivity following olefin migration, which has not
been previously reported for aza-Wacker-type reactions. This phenom-
enon was first observed by testing substrate 4ae bearing two ethyl groups,
in order to obtain an internal olefin product, however, product 5ae bear-
ing a terminal olefin and two vicinal stereocenters was obtained in good
yield with excellent ee and diastereoselectivity (99% ee, > 20/1 dr). Sev-
eral substrates bearing different aryl groups were tested and gave the cor-
responding products in 58~71% yields with excellent ees (5af-5ak).
Again, electron-donating substituents decreased the reactivity of the
substrate compared with the results of the corresponding substrates
bearing electron-withdrawing substituents. The relatively lower yields of
these substrates compared with the substrates shown in Scheme 2-4 is
caused by the larger steric hindrance of the R2 and R3 groups. The abso-
lute configurations of these two vicinal stereocenters were identified by
X-ray crystallographic analysis of product 5af (Figure 2). If the catalyst
remains both ligated to the substrate and on the same face of the alkene
throughout the iterative β-hydride elimination/migratory-insertion
events, the dehydrogenated ethyl group on the outer carbon of the olefin
should be R3 (see Mechanistic Considerations section).
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Figure 3. ORTEP Representation of 7a
To study the olefin “chain-walking” ability of the [Pd-H] under our
reaction conditions,29,30 substrate 4al bearing two propyl groups was pre-
pared and used for this asymmetric reaction. Unfortunately, a mixture of
olefin isomers was obtained with a 1/1.9 ratio of internal olefin to termi-
nal olefin. To further probe which of the two alkyl groups on the outer
carbon of the olefin is the one that does not react and which one is de-
hydrogenated, substrates 4am and 4an were employed in this asymmet-
ric cyclization. Products 5am and 5an were obtained with excellent ees
and diastereoslectivities. The dehydrogenated alkyl group should thus
be R3. However, when substrates 4ao and 4ap bearing a methyl group as
R2 or R3, respectively, were tested under the standard reaction condi-
tions, these two substrates gave the corresponding products as a couple
of diastereomers (5ao and 5ap) bearing a dehydrogenated ethyl group.
These results suggest that: (i) for substrates bearing two linear alkyl sub-
stituents on the outer carbon atom of the olefin, both of which are larger
than a methyl group, the substituent that is cis to the intra-nucleophilic
group participates more readily in β-hydride elimination; (ii) when one
of the two alkyl substituents on the outer carbon atom of the olefin is a
methyl group, β-hydride elimination proceeds selectively at the meth-
ylene side, rather than the methyl side, thus both diastereomers can be
prepared via switching the configuration of the olefin. Two other sub-
strates (4aq and 4ar) bearing a methyl group as R3 could also afford the
corresponding products bearing two stereocenters with excellent ees
and diastereoselectivities, and so also support the conclusion that β-hy-
dride elimination proceeds selectively at the methylene side.
In order to gain insight into the aminopalladation step of our asym-
metric aza-Wacker-type cyclization, we decided to use compound 6 as a
substrate for catalysis, a choice inspired by Stoltz’s studies on the car-
bopalladation of olefins.32 The standard reactions were employed except
2,2´-bispyridine (Bpy) was used as a ligand in place of Pyrox (Scheme 6,
A). Product 7a was obtained in 76% yield, while the formation of 7b was
not observed. The structure of compound 7a was determined by X-ray
analysis with the NTs group being cis to the BnO group (Figure 3). Re-
action conditions employing 5 equiv of HOAc as an additive or
Pd(TFA)2 instead of Pd(OAc)2 as metal source provided similar results,
thus suggesting that these variations in the reaction conditions did not
obviously affect the aminopalladation step of this reaction, not as in pre-
vious reports concerning other types of aza-Wacker-type reactions.19,20
Product 7a is proposed to be generated via the mechanism shown in
Scheme 6-B. Firstly, substrate 6 coordinates to Pd(II)L as a bidentate
ligand to form 8. Then, syn-aminopalladation of 8 leads to the formation
of 9. In previous reports concerning the chain-walking of the [Pd-H],
dissociation from the olefin during the chain-walking process is disfa-
vored for catalyst systems bearing electron-deficient ligands (Py-
rox),29b,29c,33 while for Pd catalytic systems bearing an electron-rich lig-
and (Cy2PCH2CH2PCy2 or tBu2PCH2CH2PtBu2),29d,29k dissocia-
tion/re-coordination occurs. This may be due to the more electrophilic
nature of the palladium cation of the Pd/Pyrox catalytic system. In our
case, we propose that the catalyst remains both ligated to the substrate
and on the same face of the alkene throughout the successive β-hydride
elimination/migratory-insertion events. Intermediate 9 can undergo β-
hydride elimination of its hydrogen on C3 because it is syn to the palla-
dium. This step will generate 10 as an intermediate. Subsequently, olefin
“chain-walking” of 10 can only proceed to the methyl group to yield 7a;
Figure 2. ORTEP Representation of 5af
Mechanistic Considerations for the Asymmetric Aza-Wacker-type Cy-
clization. The major concern relating to the mechanistic study of
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chain-walking to C4 or a more distant carbon cannot occur since the hy-
aza-Wacker-type reaction can occur. The anti-aminopalladation mecha-
1
2
3
4
drogen on C4 is trans to the palladium in intermediate 11. If Pd(II)L
coordinates with 6 syn to the Me group on C3, there is no hydrogen
atom available for β-hydride elimination after aminopalladation, thus no
nism should generate intermediate 13, which will result in the formation
of 7b (Scheme 6, C). Therefore, we believe that our newly developed
asymmetric aza-Wacker-type cyclization proceeds via a syn-amino-
palladation mechanism.
5
6
Scheme 6. Mechanistic Study
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8
9
10
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A catalytic cycle was proposed using substrate 4a as the model
substrate, as shown in Scheme 7-A. The Pd(Pyrox)(OAc)2 complex
binds to the nitrogen of the NTs group of substrate 4a with generation
of HOAc. The olefin group of 4a coordinates with Pd(II) to form a
cationic complex 15. Coordination of the olefin group prior to
coordination of the NTs group is largely unfavored, since it is a
tetrasubstituted olefin which is sterically very congested (This may be
one of the reasons as to why the reaction proceeds through a syn-amino-
palladation mechanism under various conditions which usually can lead
to a change in the aminopalladation mechanism).34 This complex
undergoes syn-aminopalldation to form intermediate 16, which should
be the rate-limiting and enantio-determining step of the cyclization
reaction.20 β-Hydride elimination of 16 gives 5a ligated Pd(II) complex
17. Dissociation of 17 then yields the desired cyclized product 5a and a
PdH(Pyrox)OAc complex. This complex undergoes reductive
elimination and reacts with O2 and HOAc to regenerate the initial
catalyst complex Pd(Pyrox)(OAc)2 and one H2O molecule. For
intermediate 15, an OAc anion should surround the cationic Pd(II)
center. Since switching from OAc to TFA anions does not switching the
mechanism from syn-aminopalladation to anti-aminopalladation, we
propose that the anion effect on the ee is a result of different distances
between the cationic Pd(II) center and its counter ion in these two cases.
With the absolute configurations of the chiral cyclization products
and the mechanism determined, the stereochemical outcome can be
explained using the models shown in Scheme 7-B. For the Pyrox-type
ligand, the oxazoline ring acts as a relatively electron-rich ligand
compared with the relatively electron-deficient pyridine ring.28b As a
result of this electronic disparity (trans effect),35 the nitrogen of the
hydrazone is prefered to bind with the Pd center and is cis to the pyridine
group of the Pyrox;35d,36 the olefin is bound at the position that is cis to
the oxazoline moiety. When the olefin group bears two identical groups
on the outer carbon atom, the steric interaction will mostly result from
the hydrazone moiety and the tBu group on the oxazoline. Therefore,
the hydrazone moiety is oriented upward and thus positioned away from
the chiral group of the oxazoline in the favored intermediate 18 or
transition state. This leads to (R)-5 as the major enantioisomer. If the
hydrazone moiety is oriented downward, greater steric hindrance will be
present in intermediate 19, which will lead to (S)-5 as the minor product.
Obviously, increasing the size of the R2 and R3 groups will increase the
steric interaction between the substrate and the oxazoline ring of ligand,
thus decreasing the reactivity of the substrate (as results observed in
experiments, Scheme 5).
Scheme 7. Proposed Catalytic Cycle and Stereochemical Outcome Model for the Generation of the First Stereocenter
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48
Scheme 8. Isotopic Labeling Experiment for the Study of the Generation of the Second Stereocenter
Although the results for the reactions of 4am and 4an indicate that the
After aminopalladation of 20, intermediate 21 is generated (R’ is a 5-
pyrazolinyl group, Scheme 8-B). If the catalyst preferentially undergoes
β-hydride elimination at the methylene of R3, intermediate 22will be
formed (path a). A further hydride migratory-insertion (generating 23)
and a second β-hydride elimination proceed on the same face of the al-
kene without dissociation of the Pd catalyst,29,33 generating 24. Product
5as-1 is formed after dissociation of the [Pd-H] from 24. Alternatively,
if the catalyst preferentially undergoes β-hydride elimination at the
methylene of R2, intermediate 25 will be formed. If the successive hy-
dride migratory-insertion/β-hydride elimination events still proceed on
the same face of the alkene, product 5as-2 will be obtained (path b). The
dehydrogenated alkyl group should be R3, it is prudent to consider that
different R2 groups in 4am and 4an may cause some differences in the β-
hydride elimination/migratory-insertion events. Thus, we designed the
substrate (E)-4as, which bears a -CH2CD3 group as R2 and an Et group
as R3. The reaction of this substrate gave 5as-1 in xx yield with ee, which
contains a non-deuterated vinyl group and a terminal-deuterated ethyl
group (can also be named as DEt-5ae) (Scheme 8-A). The vinyl termi-
nally-deuterated diastereomer of 5ae (corresponding to 5as-2) and vinyl
terminally-deuterated 5ae (Dolefin-5ae, corresponding to 5as-3) were not
observed.
49
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54
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other possible mechanism for the generation of 5ae from 4ae is a [Pd-
in 92% yield. It could also be epoxidized efficiently by 3-chloroper-
1
2
3
4
5
6
7
8
H]-dissociation/re-coordination process; the path c corresponds to
substrate (E)-4as. Intermediate 25 undergoes dissociation of [Pd-H]
and re-coordination at the opposite face of the olefin to generate 26. The
intermediate 26 can then undergo hydride migratory-insertion/β-hy-
dride elimination via 27 and 28 to give product 5as-3. However, 5as-2
and 5as-3 were not observed in the experiment using (E)-4as as a sub-
strate. This experiment further proves the hypothesis that when R3 and
R2 are linear alkyl substituents larger than a methyl group, the R3 group
that is cis to the intra-nucleophilic group more easily participates in the
β-hydride elimination.36
benzoic acid (m-CPBA) to give 32. These two conversions of 5ac did
not reduce the enantiomeric purity. 5p was also converted to its corre-
sponding epoxide 33, in order to obtain single crystals for determining
the absolute configuration of the epoxide group via X-ray crystallo-
graphic analysis. The m-CPBA can only attack one side of the olefin
since the other side is blocked by the Ts group, thus high diastereoselec-
tivity is observed. Finally, the cholesterol 24 hydroxylase inhibitor 2 was
synthesized from product 5m. First, the olefin moiety was hydrogenated
to the isopropyl group. After screening a series of deprotecting methods,
we found that TBAF could remove the Ts group efficiently, without ef-
fecting the chiral center. A sequential process of partial hydrogenation
of compound 34 by Pd/C, isomerization under acidic conditions and
acylation using isonicotinoyl chloride, gave the target molecule 2 in 87%
total yield and 94% ee.
9
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Theβ-hydride elimination proceeds selectively at the methylene side
rather than the methyl side when one of the R3 and R2 substituents is a
methyl group; the reason for this is not entirely clear. In part, this may
be because the first β-hydride elimination is important for determining
the elimination direction. Elimination at the methylene side that pro-
ceeds through transition state 30 can be partially stabilized by the addi-
tional methyl group (in blue) via a hyperconjugation effect compared
with elimination at the at the methyl side (in light brown) that proceeds
through the transition state 29 (Scheme 9).
CONCLUSIONS
In conclusion, a Pd(II)-catalyzed asymmetric aza-Wacker-type cy-
clization of N-Ts hydrazone-tethered tetrasubstituted olefins has been
developed, giving optically active 4,5-dihydro-1H-pyrazoles bearing chi-
ral tetrasubstituted carbon stereocenters. A broad range of substrates
were converted to the desired chiral products in high yields with good to
excellent ees. Notably, generation of two vicinal stereocenters on the
C=C double bonds was also feasible with high selectivity, which is the
first example of such a Wacker-type reaction. Mechanistic studies re-
vealed that this aza-Wacker-type cyclization underwent a syn-amino-
palladation process. The stereochemical outcome of this asymmetric
aza-Wacker-type cyclization could be explained by our proposed steric
models. Two other important discoveries resulting from our experi-
ments are: (i) when R3 and R2 are linear alkyl substituents larger than a
methyl group, the R3 substituent that is cis to the intra-nucleophilic
group more readily participates in β-hydride elimination; and (II) β-hy-
dride elimination proceeds selectively at the methylene side, rather than
the methyl side, when one of the R3 and R2 substituents is a methyl group.
Furthermore, several transformations of the cyclization products, in-
cluding the conversion of 5m to a pharmaceutical compound, showed
the synthetic utility of the present process.
Scheme 9. Comparing the Transition States of the First β-Hydride
Elimination for Reactions of 4ao and 4ap
Scheme 10. Synthetic Utility of the Cyclization Products
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all reactions and
products, including 1H and 13C NMR spectra, HPLC spectra, crystal
data, and crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
X-ray crystallographic data for 4p (CCDC 1822512)
X-ray crystallographic data for 5p (CCDC 1820332)
X-ray crystallographic data for 5af (CCDC 1820334)
X-ray crystallographic data for 7a (CCDC 1820333)
X-ray crystallographic data for 21 (CCDC 1820335)
AUTHOR INFORMATION
Corresponding Author
gqyang@sjtu.edu.cn;
wanbin@sjtu.edu.cn.
ORCID
Guoqiang Yang: 0000-0002-8356-6653
Wanbin Zhang: 0000-0002-4788-4195
Synthetic Utility of the Cyclization Products. To display the synthetic
utility of the present methodologies, several transformations of the cy-
clization products have been carried out (Scheme 10). The olefin group
of 5ac was cleaved via oxidation by RuCl3/NaIO4 to give compound 31
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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(p) Michel, B. M.; Steffens, L. D.; Sigman, M. S. The Wacker Oxidation. In Or-
ganic Reactions; Denmark, S. E., Ed.; John Wiley and Sons, Inc., 2014; Vol. 84,
pp 75-414.
(11) Butt, N. A.; Zhang, W. Synthesis of Heterocycles via Palladium-Cata-
lyzed Wacker-Type Oxidative Cyclization Reactions of Hydroxy- and Amino-Al-
kenes. In Topics in Heterocyclic Chemistry; Wolfe, J. P., Ed., Springer: Berlin,
Heidelberg, 2013; Vol. 32, pp 77–108.
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21620102003 and 21772119), Science and Technology Commission of
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(36) We cannot completely exclude the alternative possibility for the for-
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