Pd(0)-Catalyzed Asymmetric Carbohalogenation: H-Bonding-Driven C(sp3)-Halogen Reductive Elimination under Mild Conditions

Article abstract of DOI:10.1021/jacs.0c10797

Carbon-halogen reductive elimination is a conceptually novel elementary reaction. Its emergence broadens the horizons of transition-metal catalysis and provides new access to organohalides of versatile synthetic value. However, as the reverse process of f

Full text of DOI:10.1021/jacs.0c10797

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Pd(0)-Catalyzed Asymmetric Carbohalogenation: H‑Bonding-Driven
C(sp3)−Halogen Reductive Elimination under Mild Conditions
Xin Chen, Jixiao Zhao, Ming Dong, Ninglei Yang, Jiaoyang Wang, Yueqi Zhang, Kun Liu,*
and Xiaofeng Tong*
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ABSTRACT: Carbon−halogen reductive elimination is a con-
ceptually novel elementary reaction. Its emergence broadens the
horizons of transition-metal catalysis and provides new access to
organohalides of versatile synthetic value. However, as the reverse
process of facile oxidative addition of Pd(0) to organohalide,
carbon−halogen reductive elimination remains elusive and practi-
cally difficult. Overcoming the thermodynamic disfavor inherent to
such an elementary reaction is frustrated by the high reaction temperature and requirement of distinctive ligands. Here, we report a
general strategy that employs [Et3NH]+[BF4]− as an H-bond donor under a toluene/water/(CH2OH)2 biphasic system to efficiently
promote C(sp3)−halogen reductive elimination at low temperature. This enables a series of Pd(0)-catalyzed carbohalogenation
reactions, including more challenging and unprecedented asymmetric carbobromination with a high level of efficiency and
enantioselectivity by using readily available ligands. Mechanistic studies suggest that [Et3NH]+[BF4]− can facilitate the heterolytic
dissociation of halogen−PdIIC(sp3) bonds via a potential H-bonding interaction to reduce the energy barrier of C(sp3)−halogen
reductive elimination, thereby rendering it feasible in an SN2 manner.
advancements, there are only a limited number of capable
ligands, and a few of them turned out to be general for
different types of substrates.10 The high reaction temperature
together with the time- and effort-consuming ligand identi-
fication have severely hampered the development of such
Pd(0) catalysis involving the step of formidable C−X RE,
especially in an asymmetric fashion (Scheme 1b).
As applications of this elementary reaction for conceptually
novel access to organohalides continue to expand,4 the
demand for increasingly active and mild catalytic systems has
intensified, requiring a deeper understanding of the factors
underlying the C−X RE mechanism. As a notable example, the
Arndtsen group reported a light-promoted Pd(0)-catalyzed
acyl chloride synthesis featuring a novel single-electron
C(acyl)−Cl RE under ambient condition;11 however, no
applications for the formation of alkyl halide have been
demonstrated. In addition, such a radical pathway is believed
to be difficult in controlling stereochemistry and thus may not
be suitable for asymmetric catalysis. We sought to develop a
fundamentally different approach to rendering the classic two-
electron C−X RE more feasible and thus paving the way for
INTRODUCTION
■
Reductive elimination (RE) is a typical terminating elementary
step for product formation and catalyst regeneration in
numerous metal-catalyzed reactions.1 Expanding the scope of
such a fundamental reaction will no doubt broaden the
horizons of transition-metal catalysis. As is the case, the newly
emerging C−X (X = halogen) RE is particularly attractive since
the resulting organohalide product is a class of versatile
compounds in organic synthesis.2 However, because of the
reverse process of the facile and exergonic oxidative addition of
an organohalide to the Pd(0) complex,3 the C-X RE is
thermodynamically disfavored, rendering such an elementary
reaction strikingly less prevalent and practically difficult
(Scheme 1a,b).4 Nowadays, stoichiometric and catalytic
reactions involving the challenging C−X RE strongly rely on
the discovery and development of ligands with highly tailored
electronic and/or steric properties. Seminal studies by
Hartwig5 and Buchwald6 have established benchmarks for
C(aryl)−X RE through the use of sterically hindered
phosphorus ligands, which could be attributed to key species
aryl−PdII−X with an extremely congested environment at the
palladium center. This fundamental principle is further
exemplified in the Lautens’ Pd(0)-catalyzed carboiodination
reactions, wherein bulky ligand QPhos has been proven to be
essential.7 More recently, the Molandi group8 and our own
group9 have disclosed that some specific electron-poor ligands
are also able to promote C−X RE via reducing the electronic
density of the corresponding PdII center. Despite these
Received: October 12, 2020
Published: January 20, 2021
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Scheme 1. Challenges and Opportunities in Carbon Halogen Reduction Elimination
a
asymmetric catalysis. Computational studies have revealed that
the X−M (M = PdII, RhIII) bond dissociation of X−M−C(sp3)
species is a crucial step in dominating the C(sp3)−X RE event
no matter whether a concerted or stepwise mechanism is
operative (Scheme 1c).12 We accordingly realized that the
reliability and reversibility of an ionic hydrogen bond (YH =
H-bond donor)13 would render the H-bonding strategy ideally
suited to tackle C(sp3)−X RE (Scheme 1c). The former
feature would facilitate the heterolytic dissociation of the X−
PdII bond via H-bonding interaction YH···X−PdII. In addition,
unlike metal-type scavengers such as Ag+, the dynamic
reversibility of YH···X− would allow X− to re-enter the
catalytic cycle in due course to forge the C−X bond, furnishing
an H-bonding-driven C−X RE (Scheme 1c). Such a simple H-
bonding strategy could potentially reduce the energy barrier of
C−X RE and open the door to the development of a milder
catalytic system, which is vividly demonstrated in the efficient
Pd(0)-catalyzed asymmetric carbohalogenations (Scheme 1d).
Table 1. Establishment of an H-Bonding System
RESULTS AND DISCUSSION
■
Establishment of a Biphasic H-Bonding System. To
test our H-bonding strategy, we chose the Pd(0)-catalyzed
carboiodination of (Z)-1-iod-1,6-diene (1a) as the model case
(Table 1). Under our previous conditions (10 mol %
Pd(OAc)2, 30 mol % DPPF, 110 °C, toluene), the reaction
a
Conditions: 1a (0.2 mmol), Pd(OAc)2 (10%), DPPF (30%), toluene
(4 mL), and the indicated urea derivative (2.0 equiv) or
b
[Et3NH]+[BF4]− (2.0 equiv). 20% DPPF was used.
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ment after extensive screening. (See the Supporting
Information for details.) Given the fact that urea derivatives
can serve as competing ligands to disrupt the coordination
environment of the metal catalyst,16 we turned our attention to
ammonium-based H-bond donors.17 The initial attempt of
using [Et3NH]+[BF4]− afforded product 2a in only 11% yield
(Table 1, entry 5), which was likely due to the poor solubility
of this ammonium salt in nonpolar toluene. The addition of
water as a cosolvent boosted the yield to 53% (Table 1, entry
6). Product 2a was finally obtained in 83% yield when
additional ethylene glycol (EG) was introduced to form a
biphasic system (Table 1, entry 7). EG was believed to serve as
a second H-bond donor.18 Indeed, a 33% yield of product 2a
could be obtained in the absence of water and ammonium salt
(Table 1, entry 8). In contrast, only the use of water as an
additive led to a trace amount of product 2a (Table 1, entry 9).
Moreover, this biphasic H-bonding system could allow the
reduction of DPPF loading from 30 to 20 mol % while
maintaining the same level of isolated yield (Table 1, entry 10).
This result further demonstrated the power of the H-bonding
strategy since using 20 mol % DPPF has been shown to have
no effect on the reaction of 1a in toluene at 110 °C.14
Scheme 2. Verification of the Reliability of a Biphasic H-
Bonding System
a
To further verify the reliability of the newly developed
biphasic H-bonding system for C(sp3)−X RE, we examined
some other Pd(0)-catalyzed carbohalogenations (Scheme 2).
Fortunately, the unprecedented carbobromination of 1-bromo-
1,6-diene (3a), which involves a more challenging C(sp3)−Br
RE compared with the iodine version,12a,19 was also achieved
to give product 4a in 56% yield, although increased catalyst
loading (20 mol % Pd(OAc)2/40 mol % DPPF) and a higher
temperature (80 °C) were required (Scheme 2a). The absence
of [Et3NH]+[BF4]− and H2O/EG led to only a trace amount of
4a even at 110 °C. Moreover, the benefit of this system could
be successfully extended to aryl halide substrates. Lautens and
co-workers have found that high temperature (>90 °C) is a
prerequisite for the efficient Pd(0)/QPhos-catalyzed carboio-
donation of aryl iodide 5a.7a We also found that, under the
Lautens’ catalytic system, lower temperature (60 °C) indeed
sharply reduced the yield of product 6a (ca. 10%) along with
undesired product 6a′ (15% yield) (Scheme 2b). To our
delight, the use of our biphasic H-bonding system could
significantly improve the yield of 6a to 67%. The reaction of
highly active substrate 5b under this biphasic system gave
product 6b in 84% yield. The carbobromination of aryl
bromide substrate 5c could also be realized at higher
temperature (100 °C), delivering product 6c in 52% yield
(Scheme 2b).
a
The reactions were performed on the 0.2 mmol scale. Isolated yields
b
were reported. The reaction was conducted at 100 °C.
Scheme 3. Chiral Ligand Screening
Pd(0)-Catalyzed Asymmetric Carbohalogenation.
With the establishment of the reliable biphasic system, we
then turned our attention to its potential with respect to the
Pd(0)-catalyzed asymmetric carbohalogenation of (Z)-1-halo-
1,6-dienes. In 2019, the Zhang group came up with its own
chiral ligand, L1, to realize the version of Lautens’
carboiodination with high enantioselctivity for the first
time.20a Simultaneously, Xu et al. utilized chiral phosphor-
amidite ligand L2 to achieve an interesting asymmetric
isomerization of 3-(2-iodoaryl)cyclobutanone, which involves
the step of C(sp3)−I RE.20b To the best of our knowledge, no
precedent exists for the asymmetric carbobromination. In our
hands, chiral ligands L1 and L2 used in these two reactions
failed to promote the carboiodination of 1a, and ligands L3−
L12 with diverse chiral skeletons were also proven to be futile.
(For the structures of L1−L12, see Table S3.) With the
of 1a afforded product 2a in 87% yield.14 Lowering the
temperature to 60 °C led to no reaction (Table 1, entry 1),
which served as a starting point for our study. We first
employed urea-type H-bond donors since they are good
acceptors of the halogen anion.15 To our delight, up to a 39%
yield of 2a was isolated when 1,3-di(perfluorophenyl)urea was
used (Table 1, entries 2−4), albeit with no further improve-
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Scheme 4. Substrate Scope of Asymmetric Carboiodination
Scheme 5. Substrate Scope of Asymmetric Carboiodination
Scheme 6. Chemical Manipulations
success of DPPF in racemic reactions, well-known chiral
FerroPhos ligands21 L13−L19 were then tested (Scheme 3).
Even so, a dilemma still arose where high temperature was
necessary for a good yield and low temperature was essential
for high enantioselectivity (Scheme 3). It was not until the use
of a biphasic system that such a puzzle was completely solved.
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1,6-dienes. The results are summarized in Scheme 4. Substrate
1b with an NNs linkage shows activity similar to that of 1a,
affording product 2b in 77% yield and 94% ee. A wide range of
phenyl substituents on the vinyl iodide moiety (R1 group)
were well tolerated, giving products 2c−2i in moderate to
good yields and with high enantioselectivity (86%−94% ee).
Substrates 1h and 1i with an alkyl substituent also reacted
smoothly to give products 2h and 2i in ca. 50% yield with high
enantioselectivity. The relatively lower yields might stem from
the reluctant oxidative addition of their vinyl iodides to the
Pd(0) catalyst. Moreover, the reaction was found to tolerate a
wide range of alkyl substituents on the alkene part, affording
products 2j−2o with high ee. Substrates 1l and 1m show
relatively lower reactivity, likely due to the sterichindrance
imposed by cyclohexyl and benzyl groups. An alkyl chain with
both BzO and TBSO groups was also compatible, as
exemplified by the isolation of products 2p−2s. Substrates
1t−1w bearing other functional groups, such as ester, chloride,
and amino groups as well as glycol acetal, reacted well under
optimal conditions, providing products 2t−2w in moderate to
good yields and with high enantioselectivity. While the
reaction could be extended to substrates 1x and 1y with an
O linkage, the enantioselectivity sharply dropped to 55 and
35%, respectively. On the other hand, substrate 1z with a
C(CO2Me)2 linkage exhibited good reactivity to deliver
product 2z in 70% yield with 87% ee.
Scheme 7. General Reaction Mechanism
Scheme 8. Effect of Additional NaI on the Reaction
Performance
Subsequently, we evaluated the potential of the biphasic
system toward the asymmetric carbobromination of (Z)-1-
bromo-1,6-diene 3 (Scheme 5). Although this system was also
applicable to substrate 3b, the reaction became very sluggish
and the desired carbobromination product, 4b, was isolated in
15% yield even though a greater catalyst loading (20 mol %)
and higher temperature (80 °C) were employed. We believed
that, in addition to more challenging C(sp3)−Br RE, a
relatively inferior oxidative addition of Pd(0) to vinyl bromine
appears to be a second adverse factor in the carbobromination
reaction. We therefore exploited an electron-richer ligand, L18,
to overcome the reluctant oxidative addition, which indeed
afforded product 4b in 43% yield with 94% ee. Although a
relatively higher catalyst loading was employed, this reaction,
to our knowledge, represents the first example of catalytic
asymmetric carbobromination. We then briefly examined the
scope of asymmetric carbobromination by using ligand L18.
Gratefully, corresponding products 4c−4f were isolated in
moderate yields and with excellent enantioselectivity (Scheme
5).
Scheme 9. Effect of [Et3NH]+[BF4]− on the Reactions under
the Heterogenous and Homogenous Systems
To demonstrate the robustness of this process, the reaction
of 1aa was conducted on a 1 mmol scale under standard
conditions, and product 2aa was still obtained in 58% yield and
86% ee (Scheme 6). In an attempt to explore the elaboration
of product 2aa, the intramolecular Friedel−Crafts reaction was
examined. With the use of trifluoromethanesulfonic acid as a
solvent, bridged bicycle 5 was easily isolated in 72% yield with
87% ee. Moreover, product 2a underwent an SN2 reaction with
2-iodo-N-methylbenzamide to give compound 6, which was
useful for the construction of fused bicycle 7. Chiral spirocycle
9 (96% ee) could also be obtained from product 2v via Boc-
group deprotection and subsequent SN2 reaction. These
chemical manipulations clearly demonstrated that both alkene
and alkyl iodide groups of the carboiodination products are
convenient handles for constructing structurally complex
compounds (Scheme 6).
Among them, ligand L16 was optimal, which afforded product
(S)-2a in 79% yield and 93% ee.
Next, we investigated the substrate scope of Pd(0)/L16-
catalyzed asymmetric carboiodination under the biphasic H-
bonding system. This asymmetric catalytic system was found
to be robust and could be applicable to a range of (Z)-1-iodo-
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Scheme 10. DFT Calculations and Establishment of the SN2-Type Mechanism on the Step of C(sp3)−I RE
Mechanistic Considerations. On the basis of our
previous studies,14 a general reaction mechanism is proposed
(Scheme 7). First, the oxidative addition of 1a to the Pd(0)
catalyst generates alkenyl−PdII−I intermediate A. Next,
migratory insertion of the tethered alkene gives rise to
alkyl−PdII−I intermediate B, which is the enantio-determining
step (EDS). Finally, intermediate B undergoes C(sp3)−I RE to
give product (S)-2a and regenerate the Pd(0) catalyst. Under
the biphasic system, [Et3NH]+[BF4]− would develop a
potential H-bond with the iodide in intermediate B to
accelerate C(sp3)−I RE, therefore rendering the reaction
more facile. To interrogate how and when these additives
influenced the carbohalogenation reaction, we carried out
several mechanistic studies.
employed, the reaction produced a 27% yield of (Ph3P)2Pd-
(Ph)I along with a 63% yield of recovered (Ph3P)2Pd(Me)I
(eq 2). These results clearly demonstrate a critical role of the
biphasic system on the key step of C(sp3)−I RE.Then, two
more control experiments on NaI testing were conducted
(Scheme 8). It is known that additional NaI has no negative
impact on carboiodonation under the previously established
H-bond-donor-free conditions.19a,23 However, the introduction
of NaI (2.0 equiv) into the current biphasic system completely
shut down the reaction of 1a (Scheme 8, entry 1). Notably,
this reaction was retriggered when the iodide in the aqueous
phase was removed by the addition of Ag2O (1.02 equiv),
resulting in the isolation of product 2a in 64% yield (Scheme 8,
entry 2). These findings could be interpreted as the additional
iodine anion being capable of outcompeting the interaction of
[Et3NH]+[BF4]− with intermediate B. We believe that this
interaction is most likely to be an H-bonding interaction,
although we cannot provide more direct evidence at this stage.
Finally, we analyzed the sample consisting of toluene-d8,
H2O, EG, and [Et3NH]+[BF4]− by means of 1H NMR. To our
surprise, there is no presence of EG and [Et3NH]+[BF4]− in
toluene-d8, strongly implying that the proposed H-bonding
interaction would take place on the liquid−liquid interphase.
Nevertheless, the biphasic system was found to be essential to
the reaction outcome, especially to maintain a consistent
enantioselectivity. As shown in Scheme 9a, increased loading of
[Et3NH]+[BF4]− improved the yield of 2a significantly but had
little effect on the enantioselectivity when the reaction of 1a
was performed in the toluene/H2O/EG biphasic system.
Surprisingly, opposite enantioselectivity was observed, albeit
with a low value when a homogeneous system, dioxane/H2O/
EG, was instead employed under otherwise identical
conditions (Scheme 9a). In principle, the ammonium salt
First, we prepared a known X-PdII−C(sp3) complex,
(Ph3P)2Pd(Me)I.22 This complex was found to be very stable,
and no decomposition was observed even after it was
incubated in toluene at 60 °C for 36 h. Thus, PhI was
introduced with the hope of capturing any Pd(0) species
generated from the reductive elimination of (Ph3P)2Pd(Me)I.
When the mixture of PhI (10.0 equiv) and (Ph3P)2Pd(Me)I
was subjected to toluene at 60 °C, no reaction was observed
and (Ph3P)2Pd(Me)I was recovered in nearly quantitative yield
(eq 1). In sharp contrast, once the biphasic system was
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was able to develop H-bonds with intermediates A and B
(Scheme 9b). The former would become apparent and lead to
the formation of H-bonding adduct A′ due to a much higher
concentration of [Et3NH]+ in the case of a homogeneous
system. As a result, the kinetically facial migratory insertion in
the EDS would be interrupted, so intermediate C′ was
generated as the major diastereoisomer, which was responsible
for the observed opposite enantioselectivity. On the other
hand, the toluene/H2O/EG biphasic system was believed to
place a threshold on the concentration of [Et3NH]+ so that it
imposed minor ramification on the EDS while promoting the
C(sp3)−I RE via H-bonding adduct C (Scheme 9b).
AUTHOR INFORMATION
Corresponding Authors
■
Kun Liu − College of Chemistry, Tianjin Normal University,
Tianjin 300387, China; Email: hxxyliuk@tjnu.edu.cn
Xiaofeng Tong − Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China; orcid.org/0000-0002-6789-1691; Email: txf@
cczu.edu.cn
Authors
Xin Chen − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China
Jixiao Zhao − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China
Ming Dong − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China
Ninglei Yang − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China
Jiaoyang Wang − Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China
Yueqi Zhang − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China
To better understand the role of H-bonding in the C(sp3)−I
RE, a preliminary computational study was carried out, which
disclosed that the stepwise-type RE is favored over the
concerted one. (For details, see Figure S7.) Moreover, the free
energy of I−PdII bond heterolytic dissociation is 41.3 kcal/mol,
and the energy barrier of C(sp3)−I RE is as high as 41.7 kcal/
mol via transition state TS1 in the absence of [Et3NH]+[BF4]−
(Scheme 10a). In the presence of [Et3NH]+[BF4]−, the H-
bonding interaction is exergonic by 2.0 kcal/mol and the
elongation of the I−PdII bond is indicative (2.835 Å vs 2.774
Å), which facilitates I−PdII bond dissociation at as low as 5.3
kcal/mol free energy. This may also contribute to the
stabilization of the resulting [alkyl-Pd]+ by [BF4]− (Pd−F:
2.267 Å). The reductive elimination via transition state TS2
requires an overall activation energy of 34.9 kcal/mol, which is
the turnover-determining step in the whole catalytic cycle
(Figure S7). Taken together, the computational study clearly
pointed out that the H-bonding interaction is able to greatly
reduce the reaction barrier of C(sp3)−I RE (ΔΔG = −6.8
kcal/mol). Moreover, transition state TS2 implies SN2-type
mechanism C(sp3)−I RE, which was confirmed by the
stereochemical outcome of the reaction of (Z)-1a-D under
optimal conditions (Scheme 10b). However, more studies are
still needed to establish the working mode of H-bonding and
to elucidate the mechanism of the challenging C(sp3)−I RE.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10797
CONCLUSIONS
Notes
■
The authors declare no competing financial interest.
We have developed a unique strategy to enable Pd(0)-
catalyzed carbohalogenation reactions at much lower temper-
ature. This strategy features simple operation with the addition
of [Et3NH]+ salt as the H-bond donor under the toluene/
H2O/EG biphasic system. These advantages allow us to easily
achieve asymmetric carboiodination and carbobromination
with high levels of reaction efficiency and enantioselectivity by
using the readily available chiral FerroPhos ligand. The
putative H-bonding interaction between the [Et3NH]+ and
X-PdII−C(sp3) species significantly enhances X−PdII bond
heterolytic dissociation, which plays an essential role in the
reduction of the C(sp3)−I RE reaction barrier. We hope that
the newly developed biphasic system would open up a new
avenue to stimulate the potential of palladium catalysis in the
asymmetric synthesis of organohalides via C(sp3)−X RE.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21772016) and the Jiangsu Province
Advanced Catalysis and Green Manufacturing Collaborative
Innovation Center is gratefully acknowledged. This work is
dedicated to the 70th anniversary of the Shanghai Institute of
Organic Chemistry (SIOC).
REFERENCES
■
(1) Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to
Catalysis; University Science Books: Sausalito, CA, 2010.
(2) Sasson, Y. Formation of Carbon-Halogen Bonds (Cl, Br, I) in
Halides, Pseudo-Halides and Azides; Patai, P., Rappoport, Z., Eds.; John
Wiley and Sons: New York, 1995.
(3) Xue, L.; Lin, Z. Theoretical aspects of palladium-catalysed
carbon−carbon cross-coupling reactions. Chem. Soc. Rev. 2010, 39,
1692−1705.
(4) For reviews, see Jones, D. J.; Lautens, M.; McGlacken, G. P. The
emergence of Pd-mediated reversible oxidative addition in cross
coupling, carbohalogenation and carbonylation reactions. Nat. Catal.
2019, 2, 843−851. (b) Petrone, D. A.; Ye, J.; Lautens, M. Modern
transition-metal-catalyzed carbon-halogen bond formation. Chem. Rev.
2016, 116, 8003−8104. (c) Chen, C.; Tong, X. Synthesis of organic
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10797.
Experimental procedures, characterization data of
products, and calculation details (PDF)
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halides via palladium(0) catalysis. Org. Chem. Front. 2014, 1, 439−
446.
phosphine ligands in asymmetric catalysis. Acc. Chem. Res. 2020, 53,
1905−1921. (e) Fanourakis, A.; Docherty, P. J.; Chuentragool, P.;
Phipps, R. J. Recent developments in enatioselective transition metal
catalysis featuring attractive noncovalent interactions between ligand
and substrate. ACS Catal. 2020, 10, 10672−10714.
(16) Li, M.-L.; Yu, J.-H.; Li, Y.-H.; Zhu, S.-F.; Zhou, Q.-L. Highly
enantioselective carbene insertion into N−H bonds of aliphatic
amines. Science 2019, 366, 990−994.
(5) (a) Roy, A. H.; Hartwig, J. F. Reductive elimination of aryl
halides from palladium(II). J. Am. Chem. Soc. 2001, 123, 1232−1233.
(b) Roy, A. H.; Hartwig, J. F. Directly observed reductive elimination
of aryl halides from monomeric arylpalladium(II) halide complexes. J.
Am. Chem. Soc. 2003, 125, 13944−13945.
(6) (a) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Formation of ArF from
LPdAr(F): catalytic conversion of aryl triflates to aryl fluorides. Science
2009, 325, 1661−1664. (b) Maimone, T. J.; Milner, P. J.; Kinzel, T.;
Zhang, Y.; Takase, M. K.; Buchwald, S. L. Evidence for in situ catalyst
modification during the Pd-catalyzed conversion of aryl triflates to
aryl fluorides. J. Am. Chem. Soc. 2011, 133, 18106−18109.
(7) For selective examples, see (a) Newman, S. G.; Lautens, M.
Palladium-catalyzed carboiodination of alkenes: carbon-carbon bond
formation with retention of reactive functionality. J. Am. Chem. Soc.
2011, 133, 1778−1780. (b) Le, C. M.; Menzies, P. J. C.; Petrone, D.
A.; Lautens, M. Synergistic steric effects in the development of a
palladium-catalyzed alkyne carbohalogenation: stereodivergent syn-
thesis of vinyl halides. Angew. Chem., Int. Ed. 2015, 54, 254−257.
(c) Petrone, D. A.; Lischka, M.; Lautens, M. Harnessing reversible
oxidative addition: application of diiodinated aromatic compounds in
the carboiodination process. Angew. Chem., Int. Ed. 2013, 52, 10635−
10638. (d) Petrone, D. A.; Malik, H. A.; Clemenceau, A.; Lautens, M.
Functionalized chromans and isochromans via a diastereoselective
Pd(0)-catalyzed carboiodination. Org. Lett. 2012, 14, 4806−4809.
(8) Lee, Y. H.; Morandi, B. Palladium-catalyzed intermolecular
aryliodination of internal alkynes. Angew. Chem., Int. Ed. 2019, 58,
6444−6448.
(9) Chen, C.; Hou, L.; Cheng, M.; Su, J.; Tong, X. Palladium(0)-
catalyzed iminohalogenation of alkenes: synthesis of 2-halomethyl
dihydropyrroles and mechanistic insights into the alkyl halide bond
formation. Angew. Chem., Int. Ed. 2015, 54, 3092−3096.
(10) Petrone, D. A.; Yoon, H.; Weinstabl, H.; Lautens, M. Additive
effects in the palladium-catalyzed carboiodination of chiral N-allyl
carboxamides. Angew. Chem., Int. Ed. 2014, 53, 7908−7912.
(11) (a) Quesnel, J. S.; Arndtsen, B. A. A palladium-catalyzed
carbonylation approach to acid chloride synthesis. J. Am. Chem. Soc.
2013, 135, 16841. (b) Torres, G. M.; Liu, Y.; Arndtsen, B. A. A dual
light-driven palladium catalyst: breaking the barriers in carbonylation
reactions. Science 2020, 368, 318−323.
(17) For reviews, see Ruan, J.; Xiao, J. From α-arylation of olefins to
acylation with aldehydes: a journey in regiocontrol of the Heck
reaction. Acc. Chem. Res. 2011, 44, 614−626. (b) Ballester, P. Anion
binding in covalent and self-assembled molecular capsules. Chem. Soc.
Rev. 2010, 39, 3810−3830. (c) Llinares, J. M.; Powell, D.; Bowman-
James, K. Ammonium based anion receptors. Coord. Chem. Rev. 2003,
240, 57−75.
(18) (a) Hyder, Z.; Ruan, J.; Xiao, J. Hydrogen-bond-directed
catalysis: faster, regioselective and cleaner Heck arylation of electron-
rich olefins in alcohols. Chem. - Eur. J. 2008, 14, 5555−5566.
(b) McConville, M.; Blacker, J.; Xiao, J. Heck reaction in diols and
cascade formation of cyclic ketals. Synthesis 2010, 49, 349−360.
(c) Vallin, K. S. A.; Larhed, M.; Hallberg, A. Aqueous DMF-
potassium carbonate as substitute for thallium and silver additives in
the palladium-catalyzed conversion of aryl bromides to acetyl arenes.
J. Org. Chem. 2001, 66, 4340−4343.
(19) (a) Newman, S. G.; Howell, J. K.; Nicolaus, N.; Lautens, M.
Palladium-catalyzed carbohalogenation: bromide to iodide exchange
and domino processes. J. Am. Chem. Soc. 2011, 133, 14916−14919.
(b) Petrone, D. A.; Franzoni, I.; Ye, J.; Rodríguez, J. F.; Poblador-
Bahamonde, A. I.; Lautens, M. Palladium-catalyzed hydrohalogena-
tion of 1,6-enynes: hydrogen halide salts and alkyl halides as
convenient HX surrogates. J. Am. Chem. Soc. 2017, 139, 3546−
3557. (c) Hao, W.; Wei, J.; Geng, W.; Zhang, W.-X.; Xi, Z. Transfer of
aryl halide to alkyl halide: reductive elimination of alkylhalide from
alkylpalladium halides containing syn-β-hydrogen atoms. Angew.
Chem., Int. Ed. 2014, 53, 14533−14537.
(20) (a) Zhang, Z.-M.; Xu, B.; Wu, L.; Zhou, L.; Ji, D.; Liu, Y.; Li,
Z.; Zhang, J. Palladium/XuPhos-catalyzed enantioselective carboiodi-
nation of olefin-tethered aryl iodides. J. Am. Chem. Soc. 2019, 141,
8110−8115. (b) Sun, Y.-L.; Wang, X.-B.; Sun, F.-N.; Chen, Q.-Q.;
Cao, J.; Xu, Z.; Xu, L.-W. Enantioselective cross-exchange between C-
I and C-C σ bonds. Angew. Chem., Int. Ed. 2019, 58, 6747−6751.
(21) Schwink, L.; Knochel, P. Enantioselective preparation of C2-
symmetrical ferrocenyl ligands for asymmetric catalysis. Chem. - Eur. J.
1998, 4, 950−968.
(12) (a) Lan, Y.; Liu, P.; Newman, S. G.; Lautens, M.; Houk, K. N.
Theoretical study of Pd(0)-catalyzed carbohalogenation of alkenes:
mechanism and origins of reactivities and selectivities in alkyl halide
reductive elimination from Pd(II) species. Chem. Sci. 2012, 3, 1987−
1995. (b) Yu, J.-L.; Zhang, S.-Q.; Hong, X. Stepwise versus concerted
reductive elimination mechanisms in the carbon-iodide bond
formation of (DPEphos)RhMeI2 complex. Organometallics 2018, 37,
4711−4719. (c) Stevens, T. E.; Smoll, K. A.; Goldberg, K. I. Direct
formation of carbon(sp3)-heteroatom bonds from RhIII to produce
methyl iodide, thioethers, and alkylamines. J. Am. Chem. Soc. 2017,
139, 7725−7728.
(22) (a) Fitton, P.; Johnson, M. P.; McKeon, J. E. Oxidative
additions to palladium(0). Chem. Commun. 1968, 6−7. (b) Noskow-
ska, M.; Duczmal, W. Preparation of organometallic and silyl
complexes of palladium(II) via [PdCl(SnCl3)L2], where L = PPh3,
P(p-Tol)3. Collect. Czech. Chem. Commun. 2004, 69, 1464−1471.
(23) When the reaction of 1a was performed in toluene at 110 °C in
the presence of 10 mol% Pd(OAc)2, 30 mol% DPPF, and 3.0 equiv of
NaI, product 2a was still isolated in 85% yield.
(13) Meot-Ner, M. Update 1 of: strong ionic hydrogen bonds. Chem.
Rev. 2012, 112, PR22−PR103.
(14) Liu, H.; Li, C.; Qiu, D.; Tong, X. Palladium-catalyzed
cycloisomerizations of (Z)-1-iodo-1,6-dienes: iodine atom transfer
and mechanistic insight to alkyl iodide reductive elimination. J. Am.
Chem. Soc. 2011, 133, 6187−6193.
(15) (a) Scheerder, J.; van Duynhoven, J. P. M.; Engbersen, J. F. J.;
Reinhoudt, D. N. Solubilization of NaX salts in chloroform by
bifunctional receptors. Angew. Chem., Int. Ed. Engl. 1996, 35, 1090−
1093. (b) Doyle, A. G.; Jacobsen, E. N. Small-molecule H-bond
donors in asymmetric catalysis. Chem. Rev. 2007, 107, 5713−5743.
(c) Zhao, Q.; Wen, J.; Tan, R.; Huang, K.; Metola, P.; Wang, R.;
Anslyn, E. V.; Zhang, X. Rhodium-catalyzed asymmetric hydro-
genation of unprotected NH imines assisted by a thiourea. Angew.
Chem., Int. Ed. 2014, 53, 8467−8470. (d) Zhao, Q.; Chen, C.; Wen,
J.; Dong, X.; Zhang, X. Noncovalent interaction-assisted ferrocenyl
1931
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J. Am. Chem. Soc. 2021, 143, 1924−1931