Pd-Catalyzed Enantioselective Syntheses of Trisubstituted Allenes via Coupling of Propargylic Benzoates with Organoboronic Acids

Article abstract of DOI:10.1021/jacs.0c02876

Enabled by the newly developed ligand, Ming-Phos, the first example of palladium-catalyzed highly enantioselective coupling of racemic propargylic benzoates with organoboronic acids for chiral allenes synthesis has been developed. Excellent asymmetric induction has been achieved with a decent substrate scope. Synthetic potentials for the construction of polycyclic compounds with multiple chiral centers have been demonstrated.

Full text of DOI:10.1021/jacs.0c02876

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Article
Pd-Catalyzed Enantioselective Syntheses of Trisubstituted Allenes
via Coupling of Propargylic Benzoates with Organoboronic Acids
Huanan Wang, Hongwen Luo, ZhanMing Zhang, Wei-Feng
Zheng, Yu Yin, Hui Qian, Junliang Zhang, and Shengming Ma
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02876 • Publication Date (Web): 25 Apr 2020
Downloaded from pubs.acs.org on April 25, 2020
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Pd‐Catalyzed Enantioselective Syntheses of Trisubstituted Allenes
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via Coupling of Propargylic Benzoates with Organoboronic Acids
Huanan Wang,a,† Hongwen Luo,a,† Zhanming Zhang,a,† Wei‐Feng Zheng,a Yu Yin,a Hui Qian,*a
Junliang Zhang,*a,b and Shengming Ma*a,b
a Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Han‐
dan Lu, Shanghai 200433, P. R. China.
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, P. R. China.
ABSTRACT: Enabled by the newly developed ligand, Ming‐Phos, the first example of palladium‐catalyzed highly enanti‐
oselective coupling of racemic propargylic benzoates with organoboronic acids for chiral allenes synthesis has been de‐
veloped. Excellent asymmetric induction has been achieved with a decent substrate scope. Synthetic potentials for the
construction of polycyclic compounds with multiple chiral centers have been demonstrated.
Scheme 1. Transition Metal‐Catalyzed Coupling Reac‐
tion from Racemic Propargylic Alcohol Derivatives.
INTRODUCTION
As an important class of unsaturated hydrocarbons, al‐
lenes are different from alkenes, 1,3‐alkadienes, and al‐
kynes due to the intrinsic axial chirality of the 1,2‐diene
functionality1,2 and have been drawing more and more
attention from organic chemists,3 medicinal chemists,4
and materials scientists.5 On the other hand, transition
metal‐catalyzed cross coupling reaction of propargylic
alcohol derivatives and organometallic reagents has also
been applied to the syntheses of racemic allene.6 So far,
chiral allene syntheses via the chirality transfer strategy
utilizing optically pure propargylic alcohols derivatives
RESULTS AND DISCUSSION
We began our study on the coupling of 1‐phenylhept‐2‐
and organometallic reagents as the starting materials
have been relatively well developed.7‐12 On the other hand,
ynyl methyl carbonate (1a‐A) and phenylboronic acid (2a).
Various commercially available chiral ligands were tested
for this reaction in dioxane under the catalysis of
Pd2(dba)3•CHCl3 at the room temperature (Table 1). Un‐
fortunately, no allene product was detected with L1‐L19.
The reaction proceeded smoothly to afford (R)‐3aa in 76%
NMR yield with L20 as the ligand; however, the enantio‐
meric excess was only 2%. SKP ligand L21 could improve
the ee to 35%.
enantioselective coupling of propargylic alcohol deriva‐
tives with hard nucleophiles to afford chiral alkynes has
been reported (Scheme 1, path a).13 Such a catalytic enan‐
tioselective coupling for chiral allenes syntheses has never
been realized (Scheme 1, path b).14,15 Recently, one of the
corresponding authors, Junlinag Zhang, developed a new
type of chiral sulfinamide‐phosphine ligands, which have
demonstrated very unique potentials in enantioselective
catalysis.16 With the joint efforts of these two groups,17n
herein, we are able to conquer this challenge and report
here the first palladium‐catalyzed enantioselective cou‐
pling reaction of readily available racemic propargylic
alcohol derivatives with organoboronic acids by using
Ming‐Phos affording allenes with an excellent enantiose‐
lectivity.17
Table 1. Primary Ligand Screening with 1a‐A as Sub‐
strate.a
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2 mol% Pd2(dba)3•CHCl3
8 mol% ligand
OCO2Me
Ph
n-Bu
H
of Ming‐Phos with different substituents and examined
•
PhB(OH)2
+
dioxane, rt, 9 h
Ph
Ph
their performances in this asymmetric coupling reaction
(Table 2). The efficiency of para‐ or meta‐methyl substi‐
tuted Ming‐Phos (L22 and L23) was similar. The ortho‐
methyl substituted L24 could afford 93% of allene product
(R)‐3aa, however, the ee was only 1%. para‐Methoxy‐
substituted Ming‐Phos L26 could improve the ee to 31%.
The performance of ortho‐methoxy‐substituted L28 was
similar to L24. It’s obvious that para‐substituent is more
efficient for this asymmetric transformation. Other para‐
substituents, such as OEt, t‐Bu, Ph, and F were then stud‐
ied, Ming‐Phos L32 could afford 34% of (R)‐3aa with 42%
ee.
n-Bu
1a-A
2a
(R)-3aa
5
6
7
8
O
O
O
PPh2
PPh2
P(3,5-Xyl)2
P(3,5-Xyl)2
PPh2
PPh2
MeO
MeO
PAr2
PAr2
PPh2
PPh2
O
L1
L2
L3
L4 Ar = 4-MeOC6H4
no desired pdt
L5
no desired pdt
no desired pdt
no desired pdt
no desired pdt
9
Me Me
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PPh2
P
t-Bu
t-Bu
O
O
O
O
H
H
NH HN
PPh2
P
PPh2 Ph2
P
PPh2
PPh2
L6
L7
L8
L9
no desired pdt
no desired pdt
no desired pdt
no desired pdt
Me
PPh
2O
O
Me
Me
P
t-Bu
PPh2
P
P
O
Me
Me
Various palladium catalysts were then screened with
L32 as the ligand: No expected allene product was formed
with PdCl2, [Pd(π‐allyl)Cl]2, and [Pd(π‐cinnamyl)Cl]2 (Ta‐
ble 3, entries 1‐3); Lower yields were obtained with
Pd(OAc)2, Pd(acac)2, or Pd(OTf)2 (Table 3, entries 4‐6);
among Pd(0) catalysts, such as Pd(dba)2, Pd(dmdba)2, and
Pd2(dba)3•CHCl3, Pd(dmdba)2 was the best affording 26%
of (R)‐3aa with 46% ee (Table 3, entry 8). With the opti‐
mal palladium catalyst in hand, we studied the solvent
effect (Table 4). Most of the examined ether solvents
could afford (R)‐3aa in 22‐68% yields with 28‐54% ee (en‐
tries 1‐7). No improvement was obtained when ethyl ace‐
tate or chlorine‐containing solvents, such as DCM and
DCE, was applied (entries 8‐10). Moderate yield and enan‐
tioselectivity were obtained when toluene was used (entry
11); c‐hexane was the best in terms of the enantioselectivi‐
ty (entry 12). With this information, we went back to tune
the structure of Ming‐Phos again (Table 5) with the para‐
position being substituted with Me (L22), OMe (L26), t‐
Bu (L30), Ph (L31), and F (L32). L26 was identified to be
the best. Ligands L33 and L34 with 1‐ or 2‐naphthyl as the
Ar group failed to give better results.
Me
P
N
N
Me
PPh2
HN
N
Ph2
NH
t-Bu
P
O
Me
L10
no desired pdt
L11
no desired pdt
L12
no desired pdt
L13
no desired pdt
Me
P
O
P
O
NMe2
Ph2
P
Fe
O
Me
P N
Bn
Ph
Fe
Me
Fe
Me
Ph
O
O
P
PPh2
P
NMe2
L14
O
Me
L15
no desired pdt
L16
no desired pdt
L17
no desired pdt
no desired pdt
Me
HN
Ph
O
N
i-Pr
N
N
PPh2
O
O
PPh2
PPh2
PPh2 Ph2
P
L18
no desired pdt
L19
no desired pdt
L20
76%, 2% ee
L21
23%, 35% ee
a The reaction was conducted with 1a-A (0.5 mmol), 2a (0.75 mmol), Pd2(dba)3•CHCl3 (2.0 mol%), and ligand (8 mol%)
in dioxane (2 mL) at r.t. under Ar atmosphere. Tthe yield was determined by 1H NMR analysis and ee value was
determined by HPLC analysis.
To our delight, Ming‐Phos L22 could serve as the ligand
to yield 44% of (R)‐3aa with 23% ee (Table 2). Benefitted
from the easy synthesis of Ming‐Phos, we designed a se‐
ries
Table 3. The Effect of Palladium Catalysts.a
Table 2. The First Round Screening of Ming‐Phos Lig‐
ands with 1a‐A as Substrate.a
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Table 4. The Effect of Solvent.a
of methyl carbonate, the yield of (R)‐3aa was similar but
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the ee dropped to 63% (Entry 2). We were pleased to
found that the enantiomeric excess was further improved
to 80% with benzoate as the leaving group (Entry 3). 1‐
Naphthoate could further increase the ee to 82%, unfor‐
tunately the yield dropped to 18% (Entry 4). Other pro‐
pargylic carboxylates failed to improve the enantioselec‐
tivity (Entries 5 and 6). The yield was improved to 96%
when 5 mol% of Pd2(dba)3•CHCl3 and 10 mol% of L26 were
applied (entry 7).
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Table 6. The Effect of Leaving Group.a
Reducing the loading of 2a to 1.2 equiv led to the drop
of yield and a higher ee of 87% at a concentration of 0.067
M (Table 5, footnote b). Interestingly, after trial and error,
we found that with a mixed solvent of c‐hexane and
MTBE (4:1) the reaction afforded (R)‐3aa in 24% yield
with 76% ee in the presence of 0.5 equiv of water (see
Table S1 in supporting information for more details). The
yield could further improve to 44% when 2.5 mol% of
Pd2(dba)3 was used instead of Pd(dmdba)2.
Based on these data, the structure of Ming‐Phos was
tuned for the third time (Table 7). p‐Oi‐Pr (L35), SMe
(L36), and NMe2 (L37) did not improve the enantioselec‐
tivity. Poly‐substituted ligands L38‐L40 also failed. We
also tried the ligand with electron‐withdrawing CF3 sub‐
stituent (L41), but no desired allene product was obtained.
The ligand with an ethyl group L42 was also examined,
however, only 7% ee of (R)‐3aa was obtained. With 1‐
naphthyl substituent the substituent effect of the aryl ring
linked to phosphorous atom was studied (L43 to L45) and
4,5‐dimethoxyl substituted Ming‐Phos L45 was found to
be the best with an ee of 93%. Further changing the 1‐
naphthyl to 4‐methoxy phenyl (L46) led the reaction to
afford (R)‐3aa with 90% NMR yield and 90% ee. When
Pd2(dba)3•CHCl3 was replaced with Pd(dmdba)2, (R)‐3aa
was formed in 61% yield with 95% ee (entry 1). The yield
was improved to 73% by increasing the water to 2 equiva‐
lents (entry 2). As a control experiment (R)‐3aa was only
obtained in 58% yield with 84% ee in the absence of water
(entry 3), which demonstrated the importance of water.
Further increasing 1a to 2.5 equivalents led to the optimal
reaction conditions: 10 mol% of Pd(dmdba)2, 12 mol% of
L46, 2.5 equiv of 1a, and 2.0 equivalent of water in c‐
Hex/MTBE at room temperature affording the desired
allene (R)‐3aa in 84% NMR yield with 93% ee.
Table 5. The Second Round Screening of Ming‐Phos
Ligands with Pd(dmdba)2.a
Then we turned our attention to the effect of leaving
group (Table 6). When benzyl carbonate was used instead
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form the corresponding trisubstituted chiral allenes.
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There is no obvious influence on the steric effect since
aryl boronic acids bearing the methyl group at the ortho‐,
meta‐, and para‐position of the aryl group all afforded the
desired products with high ee ((R)‐3ab to (R)‐3ad). Aryl
boronic acids substituted with different halides are suita‐
ble substrates for this transformation ((R)‐3af to (R)‐3ah).
2‐Naphthyl and heteroaryl boronic acids were also appli‐
cable, affording products (R)‐3ai to (R)‐3ak with high
enantioselectivies. Moreover, alkenyl boronic acids also
worked well in this reaction, affording the desired en‐
allene products (R,E)‐3al in 67% yield with 92% ee and
(R,E)‐3am in 71% yield with 93% ee. The reaction is ame‐
nable to the cyclic alkenyl boronic acids by furnishing the
corresponding products with excellent enantioselectivies
((R,E)‐3an and (R,E)‐3ao). However, no desired allene
product was observed when alkyl (R = Me or cyclopropyl)
boronic acid was applied.
Table 7. The Third Round Screening of Ming‐Phos
Ligands with 1a as Substrate.
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Scheme 3. Scope of Boronic Acids.a
Ming‐Phos (S,RS)‐L46 was easily synthesized on a gram
scale
from
commercial
available
2‐bromo‐4,5‐
dimethoxybenzaldehyde in three steps (Scheme 2). Pd‐
catalyzed coupling with diphenylphosphine followed by
condensation with (R)‐tert‐butansulfinamide would form
the (R)‐sulfinyl imine. Subsequent addition reaction of (4‐
methoxyphenyl)magnesium bromide to 10 mmol of the
(R)‐sulfinyl imine afforded 4.80 g of (S,RS)‐L46 in 85%
yield.
Scheme 2. Synthesis of (S,Rs)‐L46.
Next, we studied the substrate scope of propargylic al‐
cohol derivatives (Scheme 4). Ortho‐methyl substituted
(R)‐3ba was obtained with 69% ee while meta‐ or para‐
methyl substituted (R)‐3ca and (R)‐3da in 90~91% ee,
indicating that the steric hindrance has a great effect on
the enantioselectivity. Various functional groups, includ‐
ing halogens ((R)‐3ea to (R)‐3ga) and ester ((R)‐3ha) are
compatible. R1 group could be carbon chain substituted
with functional groups, such as halogen ((R)‐3ja) and C=C
bond ((R)‐3ka and (R)‐3kn). The absolute configuration
of the products was established via the specific optical
With the optimal conditions in hand, we next investi‐
gated the generality of the reaction substrates. First, the
reactivity of the different boronic acids was tested for the
reaction with 1a (Scheme 3). A variety of organoboronic
acids with electron‐neutral, electron‐rich, and electron‐
deficient aryl moieties all reacted smoothly with 1a to
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rotation of (R)‐3kn.7e For the substrates with R2 being an
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8
9
alkyl group were also studied, however, no corresponding
allene products were obtained ((R)‐3lg and (R)‐3ma). We
tried to synthesize tetra‐substituted allenes via the devel‐
oped protocol by subjecting the racemic tertiary propar‐
gylic benzoate (1l) and phenylboronic acid (2a) to the
optimal conditions, however, no desired product was ob‐
served. It is noteworthy that excellent regioselectivity was
achieved in all these succeeded cases without observing
the formation of any alkyne product.18
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Scheme 4. Scope of Propargylic Derivatives.a
OMe
10 mol% Pd(dmdba)2
12 mol% L46
2.0 equiv H2O
L46 =
R1
R3
R2
OBz
O
S
•
RB(OH)2
+
R2
MeO
MeO
N
H
PPh2
t-Bu
R3
c-Hex/MTBE = 4/1
23 oC, N2, 24 h
R
The synthetic potentials of the alkenyl allenes (R,E)‐3al
and 3ao have been demonstrated via their Diels‐Alder
reaction with N‐methylmaleimide and maleic anhydride
to afford bicyclic products 4, 5, and 6 with three continu‐
ous chiral centers with excellent enantioselectivities and
diastereoselectivities (Scheme 6).7e The absolute configu‐
rations in these bicyclic products were established by X‐
ray single crystal diffraction study. Moreover, the one‐pot
strategy could also be applied for the synthesis of tricyclic
compounds 7 and 8 from the cyclic alkenyl boronic acid
with an excellent diastereoselectivity.
R1
2
(R)-3
rac-1
n-Bu
H
n-Bu
H
n-Bu
H
n-Bu
Ph
H
•
•
•
•
Ph
Ph
Ph
Me
Me
(R)-3ba
(R)-3ca
(R)-3da
Me
(R)-3ea
F
69%, 69% ee
n-Bu
Ph
63%, 91% ee
71%, 90% ee
81%, 92% ee
n-Bu
H
i-Pr
H
n-Bu
Ph
H
•
•
•
Ph
H
Ph
•
Ph
(R)-3fa
91%, 92% ee
(R)-3ga
82%, 92% ee
(R)-3ha
52%, 90% ee
(R)-3ia
65%, 92% ee
CO2Me
Cl
Br
Scheme 6. Diels‐Alder Reaction of En‐Allene (R,E)‐3al
to (R, E)‐3ao with Dienophiles.
Cl
Ph
H
H
H
H
•
•
3
•
•
n-Pr
Ph
Ph
Cl
MeO
(R)-3ja
(R)-3ka
(R)-3kn
82%, 90% ee
77%, 94% ee
65%, 95% ee
not observed
Me
n-Bu
H
n-Bu
•
•
Ph
Bn
Ph
Ph
not observed
not observed
a
The reaction was conducted with 1.25 mmol of 1a, 0.5 mmol of 2, 10 mol% of Pd(dmdba)2, 12
mol% of L46, and 1.0 mmol of H2O in 12 mL of cyclohexane and 3 mL of methyl tertiary-butyl ether
at 23 oC for 24 h under N2 atmosphere.
In order to unveil of the role of each chiral center in
Ming‐Phos for enantiocontrol, the remaining three iso‐
mers of (S,RS)‐L46 were synthesized. As expected, when
the enantiomeric ligands (S, RS)‐L46 and (R, SS)‐L46 were
applied, both enantiomers (R)‐3aa and (S)‐3aa could ob‐
tained with 93% and 94% ee, respectively (Scheme 5a & b).
(R)‐3aa and (S)‐3aa were afforded with a lower ee of 89%
ee when the diastereomeric ligands (S, SS)‐L46 and (R,
RS)‐L46 were used (Scheme 5c & d). These data led to the
conclusion that the configurations of these two chiral
centers also helped to ensure the observed excellent en‐
antioselectivity.
Scheme 5. Ligand Effect on Enantioselectivity of the
Product.
MECHANISTIC STUDIES AND DISCUSSION
In addition, we found the ee of recovered benzoate 1a
after the complete reaction was 35%, indicating that the
reaction was mostly a dynamic kinetic resolution (Scheme
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7a). To gain insight into the mechanism, the relationship
of allenylic intermediate III affords the allene product 3
4
5
6
7
8
9
between the ee value of L46 and that of 3aa was investi‐
gated (Scheme 7b). A positive non‐linear effect was ob‐
served at both lower19 and higher conversions, which in‐
dicates that more than one Ming‐Phos L46 may coordi‐
nate to the palladium atom.20‐22 However, further studies
are needed to clarify the nature of the key intermediates.
and regenerates the catalytically active Pd(0) complex.
The flexible coordination nature of the ligand L46 invited
more than just one ligand in the catalytic cycle, which led
to the observation of positive non‐linear effect shown in
Scheme 7b.
Scheme 8. The Proposed Mechanism
Scheme 7. Mechanistic Studies.
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a) Proposed catalytic cycle
OBz
R2
R1
R2
H
L*nPd(0)
R1
R
3
1
reductive
elimination
oxidative
addition
R1
[Ln*Pd]
R2
R1
R2
H
H
III
[Ln*Pd]
OBz
(Ra)-I
R
transmetalation
R1
H2O
R2
H
BzOH
[Ln*Pd]
II
RB(OH)2
OH
b) Dynamic interconversion between (Ra)-I and (Sa)-I for chiral induction
R2
H
R1
OBz
(Ra)
R1
R2
H
L*nPd(0)
•
H
R2
BzO
Pd
L*n
(Ra)-I
anti-
step1a
R
R1
3
(S)-1
50
:
BzO
PdL*n
via
50
R2
R1
3-I
OBz
R2
H
R1
Pd
R1
H
(Sa)
•
L*nPd(0)
H
R2
BzO
R1
R2
anti-
step 1b
R
ent-3
(R)-1
L*n
(Sa)-I
L* = L46
CONCLUSION
In summary, we have developed the first asymmetric
coupling between propargylic derivatives and organobo‐
ronic acids for the synthesis of chiral allenes. It is a new
addition to the family of catalytic asymmetric syntheses of
allenes without using stoichiometric amounts of chiral
starting materials: Enabled by the newly developed Ming‐
Phos, this Pd‐catalyzed reaction proceeds efficiently un‐
der mild conditions with a decent compatibility of syn‐
thetically usefully functional groups. Preliminary mecha‐
nistic studies demonstrated that the reaction was mostly
dynamic kinetic resolution. Further studies in this area
including the exact role of water on the reaction are being
actively pursued in this laboratory.
Based on these data and literature, a mechanism is pro‐
posed as shown in Scheme 8a. L*nPd(0) (L* = L46) would
undergo SN2’‐type anti‐oxidative addition7 with (S)‐ or
(R)‐enantiomer in the racemic propargylic benzoate 1 to
give the same allenylic palladium intermediate (Ra)‐I
through ‐‐rearrangement23 of (Sa)‐I via the intermedia‐
cy of 3‐I as shown in Scheme 8b. Due to the ee value of
the recovered 1a, there should be a rate difference for step
1a and step 1b. The benzoate anion may be protonated
with water to generate Pd hydroxide intermediate II,7e,7f
which may undergo easier transmetalation with boronic
acid to form the intermediate III. Reductive elimination
ASSOCIATED CONTENT
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Hammond, G. B. Functionalized Fluorinated Allenes. ACS Symp.
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental procedures, characterization and NMR
spectra for obtained compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
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*E‐mail: qian_hui@fudan.edu.cn
*E‐mail: junliangzhang@fudan.edu.cn.
*E‐mail: masm@sioc.ac.cn
ORCID
Huanan Wang: 0000‐0001‐9699‐3358
Hui Qian: 0000‐0002‐5606‐9213
Shengming Ma: 0000‐0002‐2866‐2431
Author Contributions
† H.W., H.L., and Z.Z. contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support from the National Natural Science Founda‐
tion of China (Grant No. 21690063 and 21988101 for S. Ma and
Grant No. 21801041 for H. Qian) and Shanghai Sailing Pro‐
gram (18YF1402000 for H. Qian) are greatly appreciated. We
thank Mr. Xiaoyan Wu and Mr. Can Li in this group for re‐
producing the results of (R)‐3ac, (R)‐3ha, and (3aS, 7R, 7aS)‐5
presented in Scheme 3, 4 & 6.
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Hydrogen‐Bond‐Stabilized Enynamides. Org. Lett. 2019, 21, 2468.
(r) Tsukamoto, H.; Konno, T.; Ito, K.; Doi, T. Palladi‐
um(0)−Lithium Iodide Cocatalyzed Asymmetric Hydroalkylation
of Conjugated Enynes with Pronucleophiles Leading to 1,3‐
Disubstituted Allenes. Org. Lett. 2019, 21, 6811.
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(18) For reports on selective generation of alkynes, see: (a)
Matsuda, I.; Komori, K. Itoh, K. Ir‐Catalyzed Substitution of
Propargylic‐type Esters with Enoxysilanes. J. Am. Chem. Soc.
2002, 124, 9072. (b) Ardolino, M. J.; Morken, J. P. Construction of
1,5‐Enynes by Stereospecific Pd‐Catalyzed Allyl–Propargyl Cross‐
Couplings. J. Am. Chem. Soc. 2012, 134, 8770. (c) Ambrogio, I.;
Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Iazzetti, A. Palladium‐
Catalyzed Nucleophilic Substitution of Propargylic Carbonates
and Meldrum's Acid Derivatives. Eur. J. Org. Chem. 2015, 3147. (d)
Huang, X.; Wu, S.; Wu, W.; Li, P.; Fu, C. Ma, S. Palladium‐
Catalysed Formation of Vicinal All‐Carbon Quaternary Centres
via Propargylation. Nat. Commun. 2016, 7, 12382. (e) Ma, S.;
Zhang, A. Tuning of Regioselectivity in the Coupling Reaction
Involving Allenic/Propargylic Palladium Species. J. Org. Chem.
2002, 67, 2287.
(19) Kalek, M.; Fu, G. C. Caution in the Use of Nonlinear Ef‐
fects as a Mechanistic Tool for Catalytic Enantioconvergent Re‐
actions: Intrinsic Negative Nonlinear Effects in the Absence of
Higher‐Order Species. J. Am. Chem. Soc. 2017, 139, 4225.
(20) For selected reviews on non‐linear effects in asymmetric
catalysis, see: (a) Girard, C.; Kagan, H. B. Nonlinear Effects in
Asymmetric Synthesis and Stereoselective Reactions: Ten Years
of Investigation. Angew. Chem. Int. Ed. 1998, 37, 2922. (b) Black‐
mond, D. G. Kinetic Aspects of Nonlinear Effects in Asymmetric
Catalysis. Acc. Chem. Res. 2000, 33, 402. (c) Satyanarayana, T.;
Abraham, S.; Kagan, H. B. Nonlinear Effects in Asymmetric Ca‐
talysis. Angew. Chem. Int. Ed. 2009, 48, 456.
(21) For selected reports with positive non‐linear effects, see:
(a) Katsuki, T.; Sharpless, K. B. The First Practical Method for
Asymmetric Epoxidation. J. Am. Chem. Soc. 1980, 102, 5974. (b)
Puchot, C.; Samuel, O.; Duñach, E.; Zhao, S.; Agami, C.; Kagan,
H. B. Nonlinear Effects in Asymmetric Synthesis. Examples in
Asymmetric Oxidations and Aldolization Reactions. J. Am. Chem.
Soc. 1986, 108, 2353. (c) Kitamura, M.; Okada, S.; Suga, S.; Noyori,
R. Enantioselective Addition of Dialkylzincs to Aldehydes Pro‐
moted by Chiral Amino Alcohols. Mechanism and Nonlinear
Effect. J. Am. Chem. Soc. 1989, 111, 4028. (d) Mikami, K.; Moto‐
yama, Y.; Terada, M. Asymmetric Catalysis of Diels‐Alder Cy‐
cloadditions by an MS‐Free Binaphthol‐Titanium Complex:
Dramatic Effect of MS, Linear vs Positive Nonlinear Relationship,
and Synthetic Applications. J. Am. Chem. Soc. 1994, 116, 2812.
(22) For selected reports on non‐linear effects in kinetic reso‐
lution and dynamic kinetic resolution, see: (a) Ismagilov, R. F.
Mathematical Description of Kinetic Resolution with an Enanti‐
omerically Impure Catalyst and Nonracemic Substrate. J. Org.
Chem. 1998, 63, 3772. (b) Luukas, T. O.; Girard, C.; Fenwick, D.
R.; Kagan, H. B. Kinetic Resolution When the Chiral Auxiliary Is
Not Enantiomerically Pure: Normal and Abnormal Behavior. J.
Am. Chem. Soc. 1999, 121, 9299. (c) Johnson, Jr., D. W.; Singleton,
D. A. Nonlinear Effects in Kinetic Resolutions. J. Am. Chem. Soc.
1999, 121, 9307. (d) Blackmond, D. G. Kinetic Resolution Using
Enantioimpure Catalysts: Mechanistic Considerations of Com‐
plex Rate Laws. J. Am. Chem. Soc. 2001, 123, 545.
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(23) For the reports on interconversion of such propar‐
gyl/allenyl intermediate leading to chiral allenes from racemic
propargylic carbonates, see: references 14a and 14b; For reports
on interconversion of such intermediate leading to racemization,
see: references 7b, 7f, and 7h.
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OBz
R2
R1
R
H
cat. [Pd]/Ming-phos
•
+
RB(OH)2
R2
OMe
R1
( )
26 examples
up to 91% yield
up to 95% ee
O
MeO
MeO
S
N
H
PPh2
t-Bu
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Newly identified
Ming-phos
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