Dirhodium(II)/Xantphos-Catalyzed Relay Carbene Insertion and Allylic Alkylation Process: Reaction Development and Mechanistic Insights

Article abstract of DOI:10.1021/jacs.1c05701

Although dirhodium-catalyzed multicomponent reactions of diazo compounds, nucleophiles and electrophiles have achieved great advance in organic synthesis, the introduction of allylic moiety as the third component via allylic metal intermediate remains a formidable challenge in this area. Herein, an attractive three-component reaction of readily accessible amines, diazo compounds, and allylic compounds enabled by a novel dirhodium(II)/Xantphos catalysis is disclosed, affording various architecturally complex and functionally diverse α-quaternary α-amino acid derivatives in good yields with high atom and step economy. Mechanistic studies indicate that the transformation is achieved through a relay dirhodium(II)-catalyzed carbene insertion and allylic alkylation process, in which the catalytic properties of dirhodium are effectively modified by the coordination with Xantphos, leading to good activity in the catalytic allylic alkylation process.

Full text of DOI:10.1021/jacs.1c05701

pubs.acs.org/JACS
Article
Dirhodium(II)/Xantphos-Catalyzed Relay Carbene Insertion and
Allylic Alkylation Process: Reaction Development and Mechanistic
Insights
Bin Lu, Xinyi Liang, Jinyu Zhang, Zijian Wang, Qian Peng,* and Xiaoming Wang*
Cite This: J. Am. Chem. Soc. 2021, 143, 11799−11810
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Although dirhodium-catalyzed multicomponent re-
actions of diazo compounds, nucleophiles and electrophiles have
achieved great advance in organic synthesis, the introduction of
allylic moiety as the third component via allylic metal intermediate
remains a formidable challenge in this area. Herein, an attractive
three-component reaction of readily accessible amines, diazo
compounds, and allylic compounds enabled by a novel dirhodium-
(II)/Xantphos catalysis is disclosed, affording various architectur-
ally complex and functionally diverse α-quaternary α-amino acid
derivatives in good yields with high atom and step economy.
Mechanistic studies indicate that the transformation is achieved
through a relay dirhodium(II)-catalyzed carbene insertion and
allylic alkylation process, in which the catalytic properties of
dirhodium are effectively modified by the coordination with Xantphos, leading to good activity in the catalytic allylic alkylation
process.
Scheme 1. Introduction to Dirhodium(II) Complexes-
Catalyzed Multicomponent Reactions by Trapping of
Onium Ylides (a) and Our Work (b)
1. INTRODUCTION
Dirhodium(II) complexes of the tetracarboxylate type have
been widely utilized in the discovery and development of
valuable synthetic methodologies.1−3 Especially, dirhodium(II)
complexes-catalyzed multicomponent reactions (MCRs) in-
volving electrophilic trapping of metal-associated onium ylide
intermediates generated in situ from metal carbenoids with
various nucleophiles have emerged as a powerful protocol for
construction of structurally complex and diverse molecules
(Scheme 1a).4 Trapping of onium ylides by nucleophilic
addition to aldimines, carbonyls, activated alkenes (Michael
acceptors) and so on, as well as a few examples via the formal
SN1 pathway, have been reported.5−9 Despite the recent
progress and the great significance of allylic group in organic
synthesis, the introduction of allylic moiety as the third
component through allylic metal intermediate remains a
formidable challenge in dirhodium(II)-catalyzed MCRs
(Scheme 1a). To achieve this challenging transformation, the
following issues must be addressed: (1) In principle,
dirhodium(II) complex is unfavorable for two-electron
oxidative addition to form allylic dirhodium species.10,11 (2)
The competitive direct allylic substitutions between the
nucleophilic substrates and allylic substrates should be
avoided.12 (3) Dirhodium(II)-catalyzed cyclopropanation
reaction between diazo compounds and CC bond of allylic
substrates may be a problematic side reaction.1e,q
Received: June 2, 2021
Published: July 23, 2021
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810
© 2021 American Chemical Society
11799

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
The development of efficient methods for the preparation of
unnatural α-tetrasubstituted α-amino acids continues to attract
considerable research interest and has become a significant
goal in the fields of medicinal chemistry and organic
synthesis.13,14 Here we disclose an unique reactivity of a
Rh(II)/Xantphos catalytic system, which can efficiently
catalyze a multicomponent reaction of readily available α-
diazo esters, amines and allylic substrates, providing various
architecturally complex and functionally diverse α-quaternary
α-amino acid derivatives in an one-pot fashion (Scheme 1b).
With an allyl group as a synthetic handle, the α-amino acid
derivatives can serve as convenient starting materials to prepare
some important intermediates for biologically active molecules.
A relay dirhodium(II)-catalyzed carbene insertion and ligand-
enabled [Rh2]-catalyzed allylic alkylation process was proposed
to explain the programmed assembly of these three
components.
Table 1. Optimization for Dirhodium(II)/Xantphos-
Catalyzed Multicomponent Reaction of 1a, 2a and 3a
a
b
yield (%)
entry
cat.
Rh2(Oct)4
ligand (mol%)
4a
5a
6a
1
2
3
4
5
6
7
Xantphos (2.0)
Xantphos (2.0)
Xantphos (2.0)
tBu-Xantphos (2.0)
BINAP (2.0)
PPh3 (4.0)
tBu3P·HBF4 (4.0)
iPr-NHC (4.0)
Xantphos (1.5)
Xantphos (1.0)
Xantphos (0.5)
−
0
0
4
83
69
30
95
89
0
0
>99
72
<1
<1
0
91
0
2
11
26
0
[Rh(COD)2](BF4)
RhCl3·3H2O
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
0
5
c
8
0
11
91
86
82
0
9
0
0
0
0
10
11
12
4
8
95
a
Unless otherwise noted, all reactions were carried out using 1a (0.25
2. RESULTS AND DISCUSSION
mmol), 2a (0.40 mmol), 3a (0.35 mmol), Rh catalyst (1.0 mol%),
ligand (2.0 mol%), and Cs2CO3 (150 mol%) in CH3CN (2.0 mL)
under Ar at r.t. for 9.0 h. Rh2(Oct)4 = rhodium(II) octanoate dimer.
2.1. Reaction Discovery. We initiated our study by
examining a Rh(II)/Pd(0) dual system in the reaction of N-
methylaniline 1a, α-diazo ester 2a, and allylic substrate 3a,
based on a hypothesized domino Rh(II)-carbene-induced N−
H insertion and Pd-catalyzed allylic alkylation process (Scheme
2; for details, see the Supporting Information (SI)).15 In the
b
c
GC yield. iPr-NHC = 1,3-bis(2,6-di-isopropylphenyl)-4,5-dihydroi-
midazol-2-ylidine.
91% yield (entry 9). Further decreasing the amount of
Xantphos to 1.0 or 0.5 mol% resulted in slightly lower yield of
6a (86% and 82% yield, respectively, entries 10, 11). The
results indicated that at most 1.0 equiv Xantphos per Rh
dimers is involved in the three-component reaction. It is worth
mentioned that although CH3CN can coordinate to dirhodium
complex, the dirhodium-catalyzed reaction of 1a with phenyl-
diazoacetate 2a could happen smoothly in CH3CN at room
temperature, which might be attributed to the fast dynamic
coordination−dissociation in solution between free and axial-
coordinated ligand (solvent and so on).1a,16
Scheme 2. Preliminary Attempt on the Reactions of 1a, 2a,
and 3a Using Different Catalysts: Rh2(Oct)4 (a), Pd2(dba)3/
Xantphos (b), Rh2(Oct)4/Pd2(dba)3/Xantphos (c), and
Rh2(Oct)4/Xantphos (d)
2.2. Scope and Synthetic Applications. With the
optimized reaction conditions in hand, the generality of this
reaction was explored (Scheme 3a). To our delight, N-
ethylaniline 1b and indoline 1c reacted smoothly with
substrates 2a and 3a under the standard conditions, giving
the corresponding products 6b and 6c in 84% and 72% yield,
respectively. Surprisingly, primary amines, such as BocNH2 and
aniline, were also well tolerated, affording the corresponding
products 6d and 6e in good yields (77% and 87%). Various
anilines with different groups on the benzene ring, including o-
Me, o-Br, m-F, m-Cl, m-Br, m-I, and p-Me, performed well in
the reactions with 2a and 3a, providing the corresponding
products (6f−6l) in 69%−90% yields. Compared with the
substrate 1m containing an electron-donating methoxy group
on the para position, substrates 1n and 1o with electron-
withdrawing groups (p-CN, p-CF3) gave much better yields in
the reactions (40% vs 85% and 92%). Additionally, for
ortho,para-dibromo-substituted aniline and α-naphthylamine,
the reactions also proceeded smoothly, giving the products 6p
and 6q in good yields, respectively. Moreover, the structures of
6d and 6n were unambiguously determined by X-ray
crystallographic analysis (see the SI).
absence of added ligand or additional Pd catalyst, the mixture
of 1a, 2a and 3a gave only the product (4a) of carbene
insertion reaction between 1a and 2a (Scheme 2a), while the
direct allylic amination product 5a was formed in 95% yield
using Pd2(dba)3/Xantphos as the sole catalyst (Scheme 2b).
Additionally, only a minor amount of 6a (16%) was observed
when combining Rh2(Oct)4, Pd2(dba)3, and Xantphos
together as the catalyst, along with 5a as the major product
(Scheme 2c). Surprisingly, the combination of a catalytic
amount of Rh2(Oct)4 and Xantphos afforded the target
product 6a in 91% yield (Scheme 2d). Neither the carbene
insertion product 4a nor allylic amination product 5a was
detected in this case. It is worth mentioning that no any
cyclopropanation product 7a was observed in all the cases
(Scheme 2a−d). Intriguingly, changing the rhodium source
from a Rh(II) carboxylate to a Rh(I) or a Rh(III) salt mainly
gave the product 5a, suggesting the corresponding Rh species
preferably catalyze allylic amination reaction, rather than the
carbene insertion reaction (Table 1, entries 2 and 3). Further
screening of the ligands including tBu-Xantphos, BINAP, PPh3,
On the basis of these results, the scope of the α-diazo esters
2 in the reactions with aniline (1e) and allyl ethyl carbonate
(3a) was further investigated. As shown in Scheme 3b,
changing methyl ester to ethyl ester had no obvious influence
on the reaction outcomes, providing the product 6r in 79%
i
PtBu3·HBF4, and Pr-NHC provided the carbene insertion
product 4a as the major product, which indicated that
Xantphos should play a unique role in the allylic alkylation
process (entry 1 vs 4−8). When the amount of Xantphos was
decreased to 1.5 mol%, the reaction still gave the product 6a in
t
yield. However, the diazo compound with Bu ester gave
11800
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Scheme 3. Substrate Scope of Amines (a), Diazo Compounds (b), and Allylic Compounds (c)
a
Reaction conditions: the mixture of 1 (0.25 mmol), 2 (0.40 mmol), 3 (0.35 mmol), Rh2(Oct)4 (1.0 mol%), Xantphos (1.5 mol%), and Cs2CO3
b
(150 mol%) in CH3CN (2.0 mL) was stirred at room temperature for 9.0 h. Isolated yields of the products are reported. The isolated yields of the
reactions in the absence of Xantphos are presented in parentheses in (c).
Scheme 4. Late-Stage Functionalization of Complex Architectures (a) and Synthetic Applications (b)
relative lower yield (6s, 55%), probably due to the large steric
hindrance of the ester moiety. Diazo compounds with either
electron-withdrawing (F-, Cl-, Br-) or electron-donating
(MeO-, BnO-) groups on the aryl group performed well
affording the corresponding products smoothly in moderate to
excellent yields (6t−6y, 47%−90%). The thienyl motif in diazo
ester was also tolerated very well, giving the corresponding
product 6z in 89% yield. Next, allylic substrates 3 bearing
various leaving groups were investigated in the reactions with
aniline (1e) and α-diazo ester 2a (Scheme 3c). All the tested
allylic alcohol esters 3b−3f and allylic chloride 3g performed
well in this reaction, providing the product 6e in moderate to
good yields (53%−85%). It is noteworthy that, in the absence
of Xantphos, the reactions gave only a trace amount of product
6e in these cases, with isolation of the N−H insertion product
as the major product instead, thus highlighting the unique
effect of the ligand in the allylic alkylation again. When allyl
halides 3h and 3i were used in the reaction, the product 6e was
obtained in moderate yields with or without Xantphos, along
with some allylic amination product, which might be due to
11801
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Scheme 5. Reaction Profiles of the Three-Component Reaction (Left) and Controlled Experiments (Right, a−f)
their relatively higher electrophilicities. For 2-methyl-substi-
tuted substrate 3j, the reaction gave the desired product 6aa in
only 25% yield, probably caused by the large steric hindrance
effect.
overall yield for two steps). In addition, treatment of 6d with
allylic bromide smoothly furnished the compound 10 in 74%
yield, which then underwent a ring-closing metathesis reaction
and a Pd/C-catalyzed hydrogenation to afford the piperidine
derivative 12 (75% yield for two steps). Finally, the
deprotection of N-Boc of 12 delivered the key intermediate
13 in 81% yield, which could be transformed to NK1 receptor
antagonist (Scheme 4b-iv).18a
To show the applicability of the methodology developed
herein, the transformations using natural products, pharma-
ceuticals, or their derivatives as the reaction partners for the
three-component process were carried out. Notably, two
interesting drugs with free NH groups (procaine and
tetracaine) could be directly applied as the amine sources in
this three-component reaction with 2a and 3a, generating
quaternary α-amino acid derivatives 6ab and 6ac smoothly in
good yields (Scheme 4a, 70% and 50%, respectively).
Moreover, α-diazo esters derived from isoxepac, worked
smoothly in this MCR with 1e and 3a, successfully introducing
synthetically important allylic and amine groups into the α
position of the acid derivative (6ad, 75% yield). Additionally, a
series of alcohols, such as geraniol, (S)-(−)-β-citronellol,
dehydroepiandrosterone, and L-menthol, can be readily
transformed into the corresponding α-diazo esters, which
were subjected to the reactions with 1e and 3a. To our delight,
all the catalytic reactions proceed smoothly to afford 6ae−6ah
in moderate to good yields (74%−90%), showing good
functional group compatibility with ketone and olefins. All
these results indicated that this approach opens new
opportunities for direct late-stage functionalization of some
drugs and natural products, which may assist new drug
discovery in future.
The synthetic utility of this approach was further
demonstrated in the reactions shown in Scheme 4b. Gram-
scale reaction of 1a, 2a, and 3a proceeded smoothly with little
decrease in efficiency (Scheme 4b-i). The reaction of 1d and
3a with 2i gave the desired product 6ai in 55% yield, which has
been utilized as the key intermediate for the synthesis of BMS-
561392, a tumor necrosis factor-α converting enzyme inhibitor
(Scheme 4b-ii).17 2,2-Disubstituted pyrrolidines and piper-
idines having at least one aryl substituent represent an
important series of pharmaceutically relevant molecules.18
Starting from the product 6d, α-phenylproline derivative 9 was
conveniently synthesized through hydroboration−oxidation of
the double bond and Mitsunobu reaction (Scheme 4b-iii, 40%
2.3. Mechanistic Studies. As shown in Scheme 5, the
kinetic profiles of this reaction under the standard conditions
clearly indicated that carbene insertion product 4a was
generated in the first 5 min and further converted to the
final product 6a. Additionally, the reaction of 1a with 2a and
1
3a in CD3CN was monitored by H NMR spectroscopy, and
the results further identified the real intermediate to be 4a
rather than metal-dissociated free ylide (for details, see the SI).
Moreover, treatment of 4a with the allylic substrate 3a under
the standard conditions indeed gave the final product 6a in a
remarkably high yield. However, no 6a was observed in the
absence of any single component of Rh2(Oct)4, Xantphos or
Cs2CO3 (94% vs 0%, Scheme 5a). These results above
suggested a relay carbene-induced N−H insertion and [Rh2]/
Xantphos-catalyzed allylic alkylation process, which is different
from the well-known binuclear Rh(II)-catalyzed MCRs,
wherein a mechanism involving an oxonium ylide generated
in situ and trapped by the third component directly.4 Notably,
neither the allylic amination nor cyclopropanation reaction was
favorable when 3a was treated with 1a or 2a under the
standard conditions (Scheme 5b,c, respectively), which could
be the key factors for the success of the titled three-component
reaction. Additionally, Xantphos remained unchanged in the
presence of diazo compound 2a in CH3CN, suggesting the
phosphine-azine compound is not likely involved in this
multicomponent reaction (for details, see the SI).19
Furthermore, the reaction between allylic amination product
5a and α-diazo ester 2a only gave trace amount of product 6a,
indicating the [2,3]-sigmatropic rearrangement is unlikely to
be responsible for the formation of the target product (Scheme
5d).3d,20 To further understand the allylic substitution process,
deuterated allylic substrate 3a-D was treated in the reaction
and two products 6a-D and 6a-D′ were observed in 87:13 ratio
11802
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(Scheme 5e).10a Furthermore, the reaction of substrate 3k only
gave the branched product 6aj, suggesting the mechanism that
insertion of CC bond followed by the β-oxygen elimination
of 3k is unlikely to be involved in the reaction (Scheme 5f).
Both the results in Scheme 5e,f provided evidence in
supporting the intermediacy of a σ-bound allylic rhodium
complex, which is consistent with the general rhodium-
catalyzed allylic substitution.10
[Rh2] complexes (A and B) were formed. (Note: Complexes A
and B can be formed within 5.0 min; for details, see the SI.) By
simple filtration, a purple filtrate containing complex A and an
orange filter residue (Complex B, 79% yield) were obtained.
Concentration of the filtrate mainly afforded mono-Xantphos-
coordinated complex A, Rh2(Oct)4(Xantphos), which was
characterized by NMR and MS techniques, and its 31P NMR
spectrum is consistent with the new signals that appeared in
Figure S9a (for details, see the SI). Complex B was
characterized as Rh2(Oct)4(Xantphos)2 by single-crystal X-
ray analysis. The structure of B shows that it is an axially
ligated dirhodium(II) complex coordinated by two phosphorus
atoms from two Xantphos ligands, each capping a Rh center
with one of its PPh2 moieties, while the other P is left free. The
Rh−Rh bond length (2.453 Å) is longer than
Rh2(OAc)4(H2O)2(2.385 Å), probably due to the strongly σ-
donating nature of the axially ligating P atoms.21 The Rh−Rh−
P angle is 176.5°, which is 3.5° deviated from linearity.
Additionally, the Rh−P distance (2.498 Å) is longer than that
in the complex of Rh2(OAc)4(PPh3)2 (2.477 Å),21a,d which
might be caused by the larger steric hindrance of Xantphos.
Interestingly, slow evaporation of the purple solution of A in
CH3CN at room temperature for 2 weeks gave dark green
crystals (complex C·CH3CN, Rh2(Oct)3(PPC)·CH3CN). X-
ray diffraction showed that the two Rh atoms are bridged by
three carboxylate groups and by one molecule of Xantphos,
where metalation has occurred at one of the phenyl rings of
PPh2 moiety. In this complex, Xantphos ligand acts as a P,P,C
tridentate ligand, which means that one P atom bonds to the
axial position of the Rh−Rh, while the other P atom and
orthometalated phenyl group bond to the two Rh atoms
respectively, replacing one of the original bridging (Oct)
anions. The Rh−Rh bond length of complex C·CH3CN (2.480
Å) is slightly longer than that of complex B (2.453 Å). The
Rh−Rh−P angle is 167.7°, which is 12.3° deviated from
linearity, completing the slightly distorted octahedral coordi-
nation around the metal atom. The P−Rh distance (2.548 Å)
at axial position is longer than that in complex B, which might
be caused by the rigid structure. It should be noted that
structural chemistry of Rh2(O2CR)4‑x(PC)x (x = 1 or 2,
wherein PC = (C6H5)2P(C6H4)), have been well studied since
their first synthesis reported by Cotton et al. in 1985.22,23
Complex C can also be obtained in 75% yield from the
reaction of Rh2(Oct)4 with Xantphos in toluene at 80 °C for
24 h, and its 31P NMR spectrum is consistent with the new
signals that appear in Figure S9b. The formation of complex C
from complex A is probably caused by the release of an
octanoate anion and the coordination of the second P atom to
Rh to form intermediate III, followed by the subsequent
metalation of the phenyl group.23c,d In this vein, a similar
dirhodium(II) complex with a chelating N,N-ligand (2,2′-
bipyridine) binding to one of the Rh(II) atoms and three
bridging OAc− groups has been reported in 1991,24 further
supporting that it is reasonable to propose the intermediate III
wherein one metal center of the dirhodium core is chelated by
the Xantphos ligand.
It is well known that mono-rhodium complexes can catalyze
allylic substitution reactions.10,11b−k In contrast, only one
example regarding dirhodium(II) was reported by Tsuji’s
n
group in 1984, in which Rh2(OAc)4 together with Bu3P was
used as catalyst for allylic alkylation (at 65 °C).11a To
investigate the possibility for the generation of monomeric
Rh(I) and/or Rh(III) species in the catalytic reaction
conditions,2a,d,16 a mixture of Rh2(Oct)4, Xantphos, and
Cs2CO3 was stirred at room temperature in CH3CN for 9.0
h. However, the 31P NMR signal corresponding to Rh(I) or
Rh(III)/Xantphos was not observed in the reaction mixtures.
Notably, a single peak at −22.7 ppm and a doublet of doublets
which might be due to coupling to 103Rh1−103Rh2 at −36.0
ppm (J = 93.7, 30.8 Hz) were observed at 9.0 h, and the other
two doublet of doublets at 2.5 ppm (J = 140.9, 5.7 Hz) and
−57.0 ppm (J = 79.4, 67.4 Hz) appeared after prolonging the
time to 4 days, indicating that some novel rhodium complexes
formed between [Rh2] and Xantphos along with the time
(Figure S9 in the SI). Additionally, mono Rh/Xantphos and
[Rh2]/Xantphos show significantly different activity in allylic
amination of 1a and 3a, suggesting it is unlikely to form mono
Rh species from [Rh2]/Xantphos under the standard
conditions. Taking these factors into consideration, the
binuclear Rh−Rh core structure is mostly likely retained in
the reaction process, though the formation of a trace amount
of mono-Rh species below the detection limit cannot be totally
ruled out.
Although the isolation of the key Rh2-allylic complex
intermediate from the reaction of Rh2(Oct)4, Xantphos and
various allylic substrates failed, some evidence of the
interaction between [Rh2] and Xantphos ligand was observed.
As shown in Scheme 6, the combination of Rh2(Oct)4 (1.0
equiv) and Xantphos (1.5 equiv) in CH3CN under room
temperature for 9.0 h led to an orange slurry, in which two new
Scheme 6. Synthesis of the [Rh2]/Xantphos Complexes
To this end, a parallel comparison of their catalytic
performance of complexes A, B and C in the allylic alkylation
of 3a with 4a was carried out by following the kinetic profiles
of the reaction process (Figure 1). It was found that all three
catalytic systems (complexes A and B and the in situ generated
catalyst from Rh2(Oct)4 with Xantphos) resulted in the same
reaction profiles, suggesting that a common active species
11803
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
remain a challenge.25,26 It is known that binuclear species can
undergo bimetallic oxidative addition to activate small
molecules, as a result of the beneficial electronic communica-
tion between the two metals.27 For the dirhodium complexes,
the [Rh2]4+ core can also undergo an oxidation process to
generate [Rh2]6+ species under some oxidative condi-
tions,26f,27b,28 suggesting that the oxidative addition of
[Rh2]4+/Xantphos with allylic substrate to form [Rh2]6+/
Xantphos/allylic complex is possible. In this work, it can be
expected that the electron density at [Rh2]4+ core is increased
by the chelating σ-donation of Xantphos to one of the Rh
atoms through the electronic communication between the two
Rh atoms.29,30 As a result, the [Rh(II)2] moiety of intermediate
III is more susceptible to oxidation addition of allylic substrate
3 (in other words, nucleophilic attack of [Rh(II)2] core to
electrophilic allylic substrate) as compared with the phosphine-
free or mono-phosphine-coordinated Rh2(Oct)4.10 Xantphos
turns out to be the best ligand to bidentate coordinate with the
[Rh(II)2] core and promote the oxidative addition to form the
[Rh2]-allylic intermediate, while labilizing one of the bridging
carboxylate ligands to facilitate substrate coordination. Taking
all the factors above together, it was tempting to tentatively
propose that Xantphos-[Rh]2 III undergo oxidative addition
with allylic substrate to form a possible [Rh2]6+ allylic
intermediate V via substrate-ligated IV. Subsequent nucleo-
philic attack by 4 takes place with the assistance of a base to
give the final product 6 and regenerates the intermediate III
(Scheme 7, Cycle II). It is also possible that CH3CN
coordinates to some dirhodium intermediates in the catalytic
cycle. Due to the electronic communication between the two
Rh atoms, the whole [Rh2] core can be considered as one
catalytically active site in the [Rh2]/Xantphos-catalyzed allylic
alkylation process. For ease of understanding, it can also be
considered that the allylic alkylation happens at one of the Rh
atoms while the other Rh atom with the bound Xantphos plays
a role in catalysis through electronic communication, which is
similar to some mechanistic proposals for bimetallic-catalyzed
reactions in the literature.30a−h,31
Figure 1. Reaction profiles of the two-component reactions. Reaction
conditions: 3a (0.70 mmol), 4a (0.50 mmol), Cs2CO3 (150 mol%),
r.t., CH3CN (4.0 mL) as the solvent, Rh catalyst: (a) Rh2(Oct)4 (1.0
mol%), Xantphos (1.5 mol%), (b) complex A (1.0 mol%), (c)
complex B (1.0 mol%), and (d) complex C (1.0 mol%).
might operate the catalytic system. However, the reaction
using complex C as the catalyst precursor showed slower
reaction rate, suggesting the partial transformation of complex
C to active species might occur, which may also be in
equilibrium with complex A or B. It is also possible that
complex C acts as a less efficient active species, although the
exact role of C is still unclear.
Although the exact mechanism of the reaction is still not
clear, a tentative mechanism for this relay catalysis is proposed
in Scheme 7 based on the results herein and previous studies.4
Scheme 7. Proposed Mechanism
3. SUMMARY AND CONCLUSIONS
In summary, we have developed a Xantphos-enabled, Rh(II)-
catalyzed, efficient and versatile three-component reaction of
amines, diazo compounds, and allylic compounds, affording
various architecturally complex and functionally diverse α-
quaternary α-amino acid derivatives in good to excellent yields
with high atom and step economy. Mechanistic studies
indicate that the catalytic properties of the dirhodium
carboxylate are tuned by the coordination with Xantphos,
resulting in novel reactivity of dirhodium in catalytic allylic
alkylation. As the dirhodium complex can be modified with
additional ligands, further development of this catalytic system
into asymmetric reactions and efforts to elucidate the reaction
mechanism in more details are under way in our laboratory.
Both the phosphine-free and Xantphos-coordinated [Rh(II)2]
can catalyze carbene insertion reaction, affording the
intermediate 4 (Cycle I). Considering the fact that bidentate
phosphine-Xantphos is essential for the allylic alkylation step
(Scheme 5a), whereas almost no 6a but only 4a was observed
in this dirhodium-catalyzed MCRs using monophosphine
t
ligand (such as PPh3 and Bu3P; Table 1, entries 6 and 7),
[Rh2] complex with a monodentate-coordinated Xantphos is
unlikely to be responsible for the allylic alkylation. Addition-
ally, a tridentate (P,P,C)-coordinated complex C has also been
demonstrated less effective for the allylic alkylation. Thus,
complex III bearing a chelate-coordinated Xantphos is
proposed as the active species that can initiate the following
allylic alkylation of intermediate 4 (Cycle II). It is notable that
though the combination of a dirhodium(II) complex with a
sophisticated ligand has led to some novel and attractive
catalytic transformations, to thoroughly investigate and fully
understand the origins of the novel catalytic activities still
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05701.
Experimental procedures, complete characterization
data, and NMR spectra (PDF)
11804
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Accession Codes
REFERENCES
■
CCDC 2050251−2050253 and 2050272 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(1) For selected reviews, see: (a) Boyar, E. B.; Robinson, S. D.
Rhodium(II) Carboxylates. Coord. Chem. Rev. 1983, 50, 109−208.
(b) Doyle, M. P. Catalytic Methods for Metal Carbene Trans-
formations. Chem. Rev. 1986, 86, 919−939. (c) Ye, T.; McKervey, M.
A. Organic Synthesis with α-Diazo Carbonyl Compounds. Chem. Rev.
1994, 94, 1091−1160. (d) Doyle, M. P.; Forbes, D. C. Recent
Advances in Asymmetric Catalytic Metal Carbene Transformations.
Chem. Rev. 1998, 98, 911−936. (e) Lebel, H.; Marcoux, J.-F.;
Molinaro, C.; Charette, A. B. Stereoselective Cyclopropanation
Reactions. Chem. Rev. 2003, 103, 977−1050. (f) Davies, H. M. L.;
Manning, J. R. Catalytic C−H Functionalization by Metal Carbenoid
and Nitrenoid Insertion. Nature 2008, 451, 417−424. (g) Padwa, A.
Domino Reactions of Rhodium(II) Carbenoids for Alkaloid Syn-
thesis. Chem. Soc. Rev. 2009, 38, 3072−3081. (h) Doyle, M. P.; Duffy,
R.; Ratnikov, M.; Zhou, L. Catalytic Carbene Insertion into C-H
Bonds. Chem. Rev. 2010, 110, 704−724. (i) Davies, H. M. L.; Morton,
D. Guiding Principles for Site Selective and Stereoselective
Intermolecular C−H Functionalization by Donor/Acceptor Rhodium
Carbenes. Chem. Soc. Rev. 2011, 40, 1857−1869. (j) Davies, H. M. L.;
Lian, Y. The Combined C−H Functionalization/Cope Rearrange-
ment: Discovery and Applications in Organic Synthesis. Acc. Chem.
Res. 2012, 45, 923−935. (k) Zhu, S.-F.; Zhou, Q.-L. Transition-Metal-
Catalyzed Enantioselective Heteroatom−Hydrogen Bond Insertion
Reactions. Acc. Chem. Res. 2012, 45, 1365−1377. (l) Gillingham, D.;
Fei, N. Catalytic X−H Insertion Reactions Based on Carbenoids.
Chem. Soc. Rev. 2013, 42, 4918−4931. (m) Murphy, G. K.; Stewart,
C.; West, F. G. Intramolecular Generation and Rearrangement of
Oxonium Ylides: Methodology Studies and Their Application in
Synthesis. Tetrahedron 2013, 69, 2667−2686. (n) Ford, A.; Miel, H.;
Ring, A.; Slattery, C. N.; Maguire, A. R.; McKervey, M. A. Modern
Organic Synthesis with α-Diazocarbonyl Compounds. Chem. Rev.
2015, 115, 9981−10080. (o) Candeias, N. R.; Paterna, R.; Gois, P. M.
Homologation Reaction of Ketones with Diazo Compounds. Chem.
Rev. 2016, 116, 2937−2981. (p) Xia, Y.; Qiu, D.; Wang, J. Transition-
Metal-Catalyzed Cross-Couplings through Carbene Migratory In-
sertion. Chem. Rev. 2017, 117, 13810−13889. (q) Davies, H. M. L.
Finding Opportunities from Surprises and Failures. Development of
Rhodium-Stabilized Donor/Acceptor Carbenes and Their Application
to Catalyst-Controlled C−H Functionalization. J. Org. Chem. 2019,
84, 12722−12745.
(2) For selected books, see: (a) Catalysis by Di- and Polynuclear
Metal Cluster Complexes; Adams, R. D., Cotton, F. A., Eds.; Wiley-
VCH: New York, 1998; pp 443−508. (b) Doyle, M. P.; McKervey, M.
A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley: New York, 1998; pp 112−162, 355−432.
(c) Doyle, M. P.; Ren, T. The Influence of Ligands on Dirhodium(I1)
on Reactivity and Selectivity in Metal Carbene Reactions; John Wiley &
Sons, Inc., 2001; pp 113−168. (d) Timmons, D. J.; Doyle, M. P. In
Multiple Bonds between Metal Atoms, 3rd ed.; Cotton, F. A., Murillo, C.
A., Walton, R. A., Eds.; Springer Science and Business Media Inc.:
New York, 2005; pp 591−626. (e) Chifotides, H. T.; Saha, B.;
Patmore, N. J.; Dunbar, K. R.; Bera, J. K. In Molecular Metal-Metal
Bonds: Compounds, Synthesis, Properties; Liddle, S. T., Ed.; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, Germany, 2015; pp 279−
317.
(3) For selected elegant studies on Rh(II)-catalyzed carbene transfer
reaction, see: (a) Xu, X.; Qian, Y.; Zavalij, P. Y.; Doyle, M. P. Highly
Selective Catalyst-Dependent Competitive 1,2-C-C, -O-C, and -N-C
Migrations from β-Methylene-β-silyloxy-β-amido-α-diazoacetates. J.
Am. Chem. Soc. 2013, 135, 1244−1247. (b) Liao, K.; Negretti, S.;
Musaev, D. G.; Bacsa, J.; Davies, H. M. L. Site-selective and
Stereoselective Functionalization of Unactivated C−H Bonds. Nature
2016, 533, 230−234. (c) Liao, K.; Pickel, T. C.; Boyarskikh, V.;
Bacsa, J.; Musaev, D. G.; Davies, H. M. L. Site-selective and
Stereoselective Functionalization of Non-Activated Tertiary C−H
Bonds. Nature 2017, 551, 609−613. (d) Zhang, Z.; Sheng, Z.; Yu, W.;
Wu, G.; Zhang, R.; Chu, W.-D.; Zhang, Y.; Wang, J. Catalytic
Asymmetric Trifluoromethylthiolation via Enantioselective [2,3]-
AUTHOR INFORMATION
■
Corresponding Authors
Qian Peng − State Key Laboratory of Elemento-Organic
Chemistry and Frontiers Science Center for New Organic
Matter, College of Chemistry, Nankai University, Tianjin
300071, China; orcid.org/0000-0002-1218-5976;
Email: qpeng@nankai.edu.cn
Xiaoming Wang − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China; School of Chemistry and Materials
Science, Hangzhou Institute for Advanced Study, University
of Chinese Academy of Sciences, Hangzhou 310024, China;
orcid.org/0000-0001-7981-3757; Email: xiaoming@
sioc.ac.cn
Authors
Bin Lu − State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Xinyi Liang − State Key Laboratory of Elemento-Organic
Chemistry and Frontiers Science Center for New Organic
Matter, College of Chemistry, Nankai University, Tianjin
300071, China
Jinyu Zhang − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China
Zijian Wang − State Key Laboratory of Elemento-Organic
Chemistry and Frontiers Science Center for New Organic
Matter, College of Chemistry, Nankai University, Tianjin
300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05701
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21821002, 21890722, 21950410519),
Shanghai Pujiang Program (19PJ1411500), the Natural
Science Foundation of Tianjin City (19JCJQJC62300,
18JCYBJC21400), Frontiers Science Center for New Organic
Matter of Nankai University (Grant Number 63181206), and
Tianjin Research Innovation Project for Postgraduate Students
(2019YJSB081) is gratefully acknowledged. The authors
appreciate valuable discussion with Prof. Wenhao Hu at Sun
Yat-sen University. This Article is dedicated to the 100th
anniversary of Chemistry at Nankai University.
11805
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Sigmatropic Rearrangement of Sulfonium Ylides. Nat. Chem. 2017, 9,
(7) Zhou, C. Y.; Wang, J. C.; Wei, J.; Xu, Z. J.; Guo, Z.; Low, K. H.;
Che, C. M. Dirhodium Carboxylates Catalyzed Enantioselective
Coupling Reactions of α-diazophosphonates, Anilines, and Electron-
Deficient Aldehydes. Angew. Chem., Int. Ed. 2012, 51, 11376−11380.
(8) (a) Mai, B. K.; Szabó, K. J.; Himo, F. Mechanisms of Rh-
Catalyzed Oxyfluorination and Oxytrifluoromethylation of Diazo-
carbonyl Compounds with Hypervalent Fluoroiodine. ACS Catal.
2018, 8, 4483−4492. (b) Mai, B. K.; Szabó, K. J.; Himo, F.
Mechanisms of Rh-Catalyzed Oxyaminofluorination and Oxyamino-
trifluoromethylthiolation of Diazocarbonyl Compounds with Electro-
philic Reagents. Org. Lett. 2018, 20, 6646−6649. (c) Yuan, W.; Szabó,
K. J. Rhodium-Catalyzed Oxy-Aminofluorination of Diazoketones
with Tetrahydrofurans and N-Fluorobenzenesulfonimide. ACS Catal.
2016, 6, 6687−6691. (d) Yuan, W.; Eriksson, L.; Szabó, K. J.
Rhodium-Catalyzed Geminal Oxyfluorination and Oxytrifluoro-
Methylation of Diazocarbonyl Compounds. Angew. Chem., Int. Ed.
2016, 55, 8410−8415.
́
̃
970−976. (e) Deng, Y.; Massey, L. A.; Rodriguez Nunez, Y. A.;
Arman, H.; Doyle, M. P. Catalytic Divergent [3 + 3]- and [3 + 2]-
Cycloaddition by Discrimination Between Diazo Compounds. Angew.
Chem., Int. Ed. 2017, 56, 12292−12296. (f) Fu, J.; Ren, Z.; Bacsa, J.;
Musaev, D. G.; Davies, H. M. L. Desymmetrization of Cyclohexanes
by Site- and Stereoselective C−H Functionalization. Nature 2018,
564, 395−399. (g) Liao, K.; Yang, Y. F.; Li, Y.; Sanders, J. N.; Houk,
K. N.; Musaev, D. G.; Davies, H. M. L. Design of Catalysts for Site-
Selective and Enantioselective Functionalization of Non-Activated
Primary C-H Bonds. Nat. Chem. 2018, 10, 1048−1055. (h) Garlets,
Z. J.; Sanders, J. N.; Malik, H.; Gampe, C.; Houk, K. N.; Davies, H.
M. L. Enantioselective C−H Functionalization of Bicyclo[1.1.1]-
pentanes. Nat. Catal. 2020, 3, 351−357. (i) Hatridge, T. A.; Liu, W.;
Yoo, C.-J.; Davies, H. M. L.; Jones, C. W. Optimized Immobilization
Strategy for Dirhodium(II) Carboxylate Catalysts for C-H Function-
alization and Their Implementation in a Packed Bed Flow Reactor.
Angew. Chem., Int. Ed. 2020, 59, 19525−19531. (j) Yang, L.-L.;
Ouyang, J.; Zou, H.-N.; Zhu, S.-F.; Zhou, Q.-L. Enantioselective
Insertion of Alkynyl Carbenes into Si−H Bonds: An Efficient Access
to Chiral Propargylsilanes and Allenylsilanes. J. Am. Chem. Soc. 2021,
143, 6401−6406.
(9) (a) Niu, L.; Pi, R.; Dong, S.; Liu, S. Aromatic C−H Bond
Functionalized via Zwitterion Intermediates to Construct Bioxindole
Containing Continuous Quaternary Carbons. J. Org. Chem. 2019, 84,
15192−15200. (b) Toda, Y.; Kaku, W.; Tsuruoka, M.; Shinogaki, S.;
Abe, T.; Kamiya, H.; Kikuchi, A.; Itoh, K.; Suga, H. Three-
Component Reactions of Diazoesters, Aldehydes, and Imines Using
a Dual Catalytic System Consisting of a Rhodium(II) Complex and a
Lewis Acid. Org. Lett. 2018, 20, 2659−2662. (c) Murarka, S.; Golz,
C.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Biology-
Oriented Synthesis of 3,3-Spiro(2-tetrahydrofuranyl)oxindoles. Syn-
thesis 2017, 49, 87−95. (d) Rajasekaran, T.; Sridhar, B.; Reddy, B. V.
S. Rh2(OAc)4 Catalyzed Highly Diastereoselective Synthesis of 2,4,5-
Triaryl-1,3-oxazolidines and Spirooxindolyl Oxazolidines. Tetrahedron
2016, 72, 2102−2108. (e) Qiu, L.; Wang, D.; Lv, F.; Guo, X.; Hu, W.;
Yang, L.; Liu, S. Three-Component Reactions Based on Trapping
Ammonium Ylides with N-sulfonyl Aldimines via Cooperative
Catalysis of Squaramides and Rh2(OAc)4. Tetrahedron 2014, 70,
1471−1477. (f) Dawande, S. G.; Kanchupalli, V.; Lad, B. S.; Rai, J.;
Katukojvala, S. Synergistic Rhodium(II) Carboxylate and Brønsted
Acid Catalyzed Multicomponent Reactions of Enalcarbenoids: Direct
Synthesis of α-Pyrrolylbenzylamines. Org. Lett. 2014, 16, 3700−3703.
(g) Rajasekaran, T.; Karthik, G.; Sridhar, B.; Reddy, B. V. S. Dual
Behavior of Isatin-Based Cyclic Ketimines with Dicarbomethoxy
Carbene: Expedient Synthesis of Highly Functionalized Spiroox-
indolyl Oxazolidines and Pyrrolines. Org. Lett. 2013, 15, 1512−1515.
(h) Hashimoto, Y.; Itoh, K.; Kakehi, A.; Shiro, M.; Suga, H.
Diastereoselective Synthesis of Tetrahydrofurans by Lewis Acid
Catalyzed Intermolecular Carbenoid−Carbonyl Reaction−Cyclo-
addition Sequences: Unusual Diastereoselectivity of Lewis Acid
Catalyzed Cycloadditions. J. Org. Chem. 2013, 78, 6182−6195.
(i) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Callejo, R.; Ruiz, M.
P.; Torres, M. R. Diastereoselective Synthesis of β-Lactam−Oxindole
Hybrids Through a Three-Component Reaction of Azetidine-2,3-
diones, α-Diazo-oxindoles, and Alcohols Catalyzed by [Rh2(OAc)4].
Eur. J. Org. Chem. 2012, 2012, 2359−2366. (j) Galliford, C. V.;
Scheidt, K. A. Catalytic Multicomponent Reactions for the Synthesis
of N-Aryl Trisubstituted Pyrroles. J. Org. Chem. 2007, 72, 1811−1813.
(k) Torssell, S.; Kienle, M.; Somfai, P. 1,3-Dipolar Cycloadditions of
Carbonyl Ylides to Aldimines: A Three-Component Approach to syn-
α-Hydroxy-β-amino Esters. Angew. Chem., Int. Ed. 2005, 44, 3096−
3099. (l) Muthusamy, S.; Gunanathan, C.; Nethaji, M. Multi-
component Reactions of Diazoamides: Diastereoselective Synthesis of
Mono- and Bis-spirofurooxindoles. J. Org. Chem. 2004, 69, 5631−
5637. (m) Skaggs, A. J.; Lin, E. Y.; Jamison, T. F. Cobalt Cluster-
Containing Carbonyl Ylides for Catalytic, Three-Component
Assembly of Oxygen Heterocycles. Org. Lett. 2002, 4, 2277−2280.
(10) For selected reviews, see: (a) Turnbull, B. W. H.; Evans, P. A.
Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions:
Discovery, Development and Applications to Target-Directed Syn-
thesis. J. Org. Chem. 2018, 83, 11463−11479. (b) Thoke, M. B.; Kang,
Q. Rhodium-Catalyzed Allylation Reactions. Synthesis 2019, 51,
2585−2631.
(4) (a) Guo, X.; Hu, W. Novel Multicomponent Reactions via
Trapping of Protic Onium Ylides with Electrophiles. Acc. Chem. Res.
2013, 46, 2427−2440. (b) Medvedev, J. J.; Nikolaev, V. A. Recent
Advances in the Chemistry of Rh Carbenoids: Multicomponent
Reactions of Diazocarbonyl Compounds. Russ. Chem. Rev. 2015, 84,
737−757. (c) Thumar, N. J.; Wei, Q. H.; Hu, W. H. Recent Advances
in Asymmetric Metal-Catalyzed Carbene Transfer from Diazo
Compounds toward Molecular Complexity. Adv. Organomet. Chem.
2016, 66, 33−91. (d) Zhang, D.; Hu, W. Asymmetric Multi-
component Reactions Based on Trapping of Active Intermediates.
Chem. Rec. 2017, 17, 739−753. (e) Shilpa, T.; Dhanya, R.; Saranya,
S.; Anilkumar, G. An Overview of Rhodium-Catalysed Multi-
Component Reactions. ChemistrySelect 2020, 5, 898−915.
(5) For selected examples, see: (a) Kang, Z.; Shou, J.; Xing, D.; Hu,
W. Rh(II)/Ag(I)-Cocatalyzed Three-Component Reaction via SN1/
SN1′-Type Trapping of Oxonium Ylide with the Nicholas
Intermediate. J. Org. Chem. 2020, 85, 9850−9862. (b) Che, J.; Niu,
L.; Jia, S.; Xing, D.; Hu, W. Enantioselective Three-Component
Aminomethylation of α-Diazo Ketones with Alcohols and 1,3,5-
Triazines. Nat. Commun. 2020, 11, 1511. (c) Kang, Z.; Wang, Y.;
Zhang, D.; Wu, R.; Xu, X.; Hu, W. Asymmetric Counter-Anion-
Directed Aminomethylation: Synthesis of Chiral α-Amino Acids via
Trapping of an Enol Intermediate. J. Am. Chem. Soc. 2019, 141,
1473−1478. (d) Kang, Z.; Zhang, D.; Shou, J.; Hu, W.
Enantioselective Trapping of Oxonium Ylides by 3-Hydroxyisoindo-
linones via a Formal SN1 Pathway for Construction of Contiguous
Quaternary Stereocenters. Org. Lett. 2018, 20, 983−986. (e) Qiu, H.;
Li, M.; Jiang, L.-Q.; Lv, F.-P.; Zan, L.; Zhai, C.-W.; Doyle, M. P.; Hu,
W.-H. Highly Enantioselective Trapping of Zwitterionic Intermedi-
ates by Imines. Nat. Chem. 2012, 4, 733. (f) Jiang, J.; Xu, H.-D.; Xi, J.-
B.; Ren, B.-Y.; Lv, F.-P.; Guo, X.; Jiang, L.-Q.; Zhang, Z.-Y.; Hu, W.-
H. Diastereoselectively Switchable Enantioselective Trapping of
Carbamate Ammonium Ylides with Imines. J. Am. Chem. Soc. 2011,
133, 8428−8431. (g) Hu, W.; Xu, X.; Zhou, J.; Liu, W.-J.; Huang, H.;
Hu, J.; Yang, L.; Gong, L.-Z. Cooperative Catalysis with Chiral
Brønsted Acid-Rh2(OAc)4: Highly Enantioselective Three-Compo-
nent Reactions of Diazo Compounds with Alcohols and Imines. J. Am.
Chem. Soc. 2008, 130, 7782−7783. (h) Wang, Y.; Zhu, Y.; Chen, Z.;
Mi, A.; Hu, W.; Doyle, M. P. A Novel Three-Component Reaction
Catalyzed by Dirhodium(II) Acetate: Decomposition of Phenyl-
diazoacetate with Arylamine and Imine for Highly Diastereoselective
Synthesis of 1,2-Diamines. Org. Lett. 2003, 5, 3923−3926.
(6) Ren, L.; Lian, X.-L.; Gong, L.-Z. Brønsted Acid/Rhodium(II)
Cooperative Catalytic Asymmetric Three-Component Aldol-Type
Reaction for the Synthesis of 3-Amino Oxindoles. Chem. - Eur. J.
2013, 19, 3315−3318.
11806
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(11) For selected examples, see: (a) Tsuji, J.; Minami, I.; Shimizu, I.
Allylation of Carbonucleophiles with Allylic Carbonates under
Neutral Conditions Catalyzed by Rhodium Complexes. Tetrahedron
Lett. 1984, 25, 5157−5160. (b) Tsuji, J.; Minami, I.; Shimizu, I.
Synthesis of γ,δ-Unaturated Ketons by the Intramolecular Decarbox-
ylative Allylation of Allyl β-Keto Carboxylates and Alkenyl Allyl
Carbonates Catalyzed By Molybdenum, Nickel, and Rhodium
Complexes. Chem. Lett. 1984, 13, 1721−1724. (c) Hayashi, Y.;
Komiya, S.; Yamamoto, T.; Yamamoto, A. Regioselective C-O Bond
Cleavage Of Allylic Phenyl Carbonates Promoted by Group 8
Transtion Metal Hydrido Complexes. Chem. Lett. 1984, 13, 977−980.
(d) Minami, I.; Shimizu, I.; Tsuji, J. Reactions of Allylic Carbonates
Catalyzed by Palladium, Rhodium, Ruthenium, Molybdenum, and
Nckel complexes; Allylation of Carbonucleophiles and Decarbox-
ylation-Dehydrogenation. J. Organomet. Chem. 1985, 296, 269−280.
(e) Tom, M. J.; Evans, P. A. Regioselective and Stereospecific
Rhodium-Catalyzed Allylic Cyanomethylation with an Acetonitrile
Equivalent: Construction of Acyclic β-Quaternary Stereogenic
Nitriles. J. Am. Chem. Soc. 2020, 142, 11957−11961. (f) Huang,
W.-Y.; Lu, C.-H.; Ghorai, S.; Li, B.; Li, C. Regio- and Enantioselective
Allylic Alkylation of Terminal Alkynes by Synergistic Rh/Cu
Catalysis. J. Am. Chem. Soc. 2020, 142, 15276−15281. (g) Wright,
T. B.; Turnbull, B. W. H.; Evans, P. A. Enantioselective Rhodium-
Catalyzed Allylic Alkylation of β,γ-Unsaturated α-Amino Nitriles:
Synthetic Homoenolate Equivalents. Angew. Chem., Int. Ed. 2019, 58,
9886−9890. (h) Tang, S. B.; Zhang, X.; Tu, H. F.; You, S. L. Regio-
and Enantioselective Rhodium-Catalyzed Allylic Alkylation of
Racemic Allylic Alcohols with 1,3-Diketones. J. Am. Chem. Soc.
2018, 140, 7737−7742. (i) Turnbull, B. W. H.; Chae, J.; Oliver, S.;
Evans, P. A. Regio- and Stereospecific Rhodium-Catalyzed Allylic
Alkylation with an Acyl Anion Equivalent: an Approach to Acyclic α
-Ternary β,γ-Unsaturated Aryl Ketones. Chem. Sci. 2017, 8, 4001−
4005. (j) Hayashi, T.; Okada, A.; Suzuka, T.; Kawatsura, M. High
Enantioselectivity in Rhodium-Catalyzed Allylic Alkylation of 1-
Substituted 2-Propenyl Acetates. Org. Lett. 2003, 5, 1713−1715.
(k) Arnold, J. S.; Nguyen, H. M. Rhodium-Catalyzed Dynamic
Kinetic Asymmetric Transformations of Racemic Tertiary Allylic
Trichloroacetimidates with Anilines. J. Am. Chem. Soc. 2012, 134,
8380−8383.
90, 8−27. (b) Cardillo, G.; Gentilucci, L.; Tolomelli, A. Unusual
Amino Acids: Synthesis and Introduction into Naturally Occurring
Peptides and Biologically Active Analogues. Mini-Rev. Med. Chem.
2006, 6, 293−304. (c) Venkatraman, J.; Shankaramma, S. C.;
Balaram, P. Design of Folded Peptides. Chem. Rev. 2001, 101,
3131−3152. (d) Evans, M. C.; Pradhan, A.; Venkatraman, S.; Ojala,
W. H.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. Synthesis and
Dopamine Receptor Modulating Activity of Novel Peptidomimetics
of L-Prolyl-L-Leucyl-Glycinamide Featuring α,α-Disubstituted Amino
Acids. J. Med. Chem. 1999, 42, 1441−1447.
(14) For selected reviews, see: (a) Vogt, H.; Bräse, S. Recent
Approaches towards the Asymmetric Synthesis of α,α-Disubstituted
α-Amino Acids. Org. Biomol. Chem. 2007, 5, 406−430. (b) Mizota, I.;
Shimizu, M. Umpolung Reactions of α-Imino Esters: Useful Methods
for the Preparation of α-Amino Acid Frameworks. Chem. Rec. 2016,
16, 688−702. (c) Jiang, H.; Jin, Y.; Lin, J. New Progress in
Asymmetric Synthesis of Quaternary α-Amino Acids. Mini-Rev. Org.
Chem. 2017, 14, 434−447. (d) Dickstein, J. S.; Kozlowski, M. C.
Organometal Additions to α-Iminoesters: N-Alkylation via Umpo-
lung. Chem. Soc. Rev. 2008, 37, 1166−1173. (e) Carloni, A.; Porzi, G.;
Sandri, S. Stereoselective Synthesis of Uncommon α,α′-Dialkyl-α-
Aminoacids. Part 1. Tetrahedron: Asymmetry 1998, 9, 2987−2998.
(f) Bera, K.; Namboothiri, I. N. N. Asymmetric Synthesis of
Quaternary α-Amino Acids and Their Phosphonate Analogues.
Asian J. Org. Chem. 2014, 3, 1234−1260. (g) Ager, D. J. Amino
Acids, Peptides and Proteins in Organic Chemistry; Hughes, A. B., Ed.;
Wiley-VCH: Weinheim, 2009; Vol. 1, pp 495−526. (h) Non-natural
Amino Acids: Methods and Protocols; Pollegioni, L., Servi, S., Eds.;
Springer: New York, 2012; pp 1−249. (i) Ohfune, Y.; Shinada, T.
Enantio- and Diastereoselective Construction of α,α-Disubstituted α-
Amino Acids for the Synthesis of Biologically Active Compounds. Eur.
J. Org. Chem. 2005, 2005, 5127−5143.
(15) (a) Wang, X. X.; Huang, X. Y.; Lei, S. H.; Yang, F.; Gao, J. M.;
Ji, K.; Chen, Z. S. Relay Rh(II)/Pd(0) Dual Catalysis: Synthesis of α-
Quaternary β-Keto-esters via a [1,2]-Sigmatropic Rearrangement/
Allylic Alkylation Cascade of α-Diazo Tertiary Alcohols. Chem.
Commun. 2020, 56, 782−785. (b) Chen, L.-H.; Ma, Y.-T.; Yang, F.;
Huang, X.-Y.; Chen, S.-W.; Ji, K.; Chen, Z.-S. Chemo-selective
Rh(II)/Pd(0) Dual Catalysis: Synthesis of All-Carbon C3-Quaternary
Allylic Oxindoles from N-Aryl α-Diazo-β-Keto-Amides with Function-
alized Allyl Carbonates. Adv. Synth. Catal. 2019, 361, 1307−1312.
(c) Huang, L.-Z.; Xuan, Z.; Jeon, H. J.; Du, Z.-T.; Kim, J. H.; Lee, S.-
g. Asymmetric Rh(II)/Pd(0) Relay Catalysis: Synthesis of α-
Quaternary Chiral β-Lactams through Enantioselective C−H
Insertion/Diastereoselective Allylation of Diazoamides. ACS Catal.
2018, 8, 7340−7345. (d) Chen, Z.-S.; Huang, X.-Y.; Chen, L.-H.;
Gao, J.-M.; Ji, K. Rh(II)/Pd(0) Dual Catalysis: Regiodivergent
Transformations of Alkylic Oxonium Ylides. ACS Catal. 2017, 7,
7902−7907. (e) Chen, Z.-S.; Huang, X.-Y.; Gao, J.-M.; Ji, K. Relay
Rh(II)/Pd(0) Dual Catalysis: Selective Construction of Cyclic All-
Quaternary Carbon Centers. Org. Lett. 2016, 18, 5876−5879.
(16) (a) Telser, J.; Drago, R. S. Solution Chemistry of Rhodium
Trifluoroacetate in the Presence of Phosphorus Donors. Inorg. Chem.
1986, 25, 2989−2992. (b) Telser, J.; Drago, R. S. Reactions of
Rhodium Trifluoroacetate with Various Lewis Bases. Formation of 4:1
Complexes with Pyridine and tert-Butyl Isocyanide and Bond
Cleavage with Phosphorus Donors. Inorg. Chem. 1984, 23, 2599−
2606.
(17) (a) Savage, S. A.; Waltermire, R. E.; Campagna, S.; Bordawekar,
S.; Toma, J. D. R. Development and Large-Scale Preparation of an
Oral TACE Inhibitor. Org. Process Res. Dev. 2009, 13, 510−518.
(b) Maduskuie, T. P., Jr.; Duan, J.; Mercer, S. E. (Dupont
Pharmaceuticals Company, U.S.A.). Novel Lactam Metalloprotease
Inhibitors. PCT Int. Appl. WO 2002/004416 A2, 2002-01-17.
(18) (a) Harrison, T.; Williams, B. J.; Swain, C. J. Gem-
Disubstituted Amino-Ether Based Substance P Antagonists. Bioorg.
Med. Chem. Lett. 1994, 4, 2733−2734. (b) Van Betsbrugge, J.;
Tourwé, D.; Kaptein, B.; Kierkels, H.; Broxterman, R. A Convenient
Synthesis of Protected (R)-α-Phenylproline Derivatives using the
(12) (a) Huang, H.-M.; Bellotti, P.; Glorius, F. Transition Metal-
Catalysed Allylic Functionalization Reactions Involving Radicals.
Chem. Soc. Rev. 2020, 49, 6186−6197. (b) Han, J.-F.; Guo, P.; Zhang,
X.-G.; Liao, J.-B.; Ye, K.-Y. Recent Advances in Cobalt-Catalyzed
Allylic Functionalization. Org. Biomol. Chem. 2020, 18, 7740−7750.
(c) Zhang, H.; Gu, Q.; You, S.-L. Recent Advances in Ni-Catalyzed
Allylic Substitution Reactions. Chin. J. Org. Chem. 2019, 39, 15−27.
(d) Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.; You,
S.-L. Iridium-Catalyzed Asymmetric Allylic Substitution Reactions.
Chem. Rev. 2019, 119, 1855−1969. (e) Kumar, D.; Vemula, S. R.;
Balasubramanian, N.; Cook, G. R. Indium-Mediated Stereoselective
Allylation. Acc. Chem. Res. 2016, 49, 2169−2178. (f) Butt, N. A.;
Zhang, W. Transition Metal-Catalyzed Allylic Substitution Reactions
with Unactivated Allylic Substrates. Chem. Soc. Rev. 2015, 44, 7929−
7967. (g) Bruneau, C.; Achard, M. Allylic Ruthenium(IV) Complexes
in Catalysis. Coord. Chem. Rev. 2012, 256, 525−536. (h) Alexakis, A.;
̀
Bäckvall, J. E.; Krause, N.; Pamies, O.; Diéguez, M. Enantioselective
Copper-Catalyzed Conjugate Addition and Allylic Substitution
Reactions. Chem. Rev. 2008, 108, 2796−2823. (i) Lu, Z.; Ma, S.
Metal-Catalyzed Enantioselective Allylation in Asymmetric Synthesis.
Angew. Chem., Int. Ed. 2008, 47, 258−297. (j) Belda, O.; Moberg, C.
Molybdenum-Catalyzed Asymmetric Allylic Alkylations. Acc. Chem.
Res. 2004, 37, 159−167. (k) Enders, D.; Jandeleit, B.; von Berg, S.
Synthesis of Highly Enantioenriched Compounds via Iron Mediated
Allylic Substitutions. Synlett 1997, 1997, 421−431. (l) Trost, B. M.;
Van Vranken, D. L. Asymmetric Transition Metal-Catalyzed Allylic
Alkylations. Chem. Rev. 1996, 96, 395−422.
(13) (a) Maity, P.; König, B. Enantio- and Diastereoselective
α
Syntheses of Cyclic C -tetrasubstituted α-Amino Acids and Their Use
to Induce Stable Conformations in Short Peptides. Biopolymers 2008,
11807
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Mitsunobu Reaction. Tetrahedron 1997, 53, 9233−9240. (c) Xiao, D.;
Wang, C.; Palani, A.; Reichard, G.; Aslanian, R.; Shih, N.-Y.; Buevich,
A. Two Complementary, Diversity-Driven Asymmetric Syntheses of a
2,2-Disubstituted Piperidine NK1 Antagonist. Tetrahedron: Asymmetry
2006, 17, 2596−2598. (d) Sheikh, N. S.; Leonori, D.; Barker, G.;
Firth, J. D.; Campos, K. R.; Meijer, A. J. H. M.; O’Brien, P.; Coldham,
I. An Experimental and in Situ IR Spectroscopic Study of the
Lithiation−Substitution of N-Boc-2-phenylpyrrolidine and -piper-
idine: Controlling the Formation of Quaternary Stereocenters. J. Am.
Chem. Soc. 2012, 134, 5300−5308. (e) Nicolle, S. M.; Lewis, W.;
Hayes, C. J.; Moody, C. J. Stereoselective Synthesis of Functionalized
Pyrrolidines by the Diverted N-H Insertion Reaction of Metal-
locarbenes with β-Aminoketone Derivatives. Angew. Chem., Int. Ed.
2016, 55, 3749−3753.
Reactions in Binuclear Dirhodium Compounds. Synthesis and
Molecular Structure of an Unsymmetrical Rh24+Compound with
Two Different Ortho-Metalated Phosphines. Inorg. Chem. 1988, 27,
1010−1013. (c) Lahuerta, P.; Payá, J.; Solans, X.; Ubeda, M. A.
Ortho-Metalation Reactions in Binuclear Dirhodium Compounds.
Molecular Structure and Reactivity of a Monometalated Compound
with the Phosphine P(o-ClC6H4)(C6H5)2. Inorg. Chem. 1992, 31,
385−391. (d) Lahuerta, P.; Payá, J.; Pellinghelli, M. A.; Tiripicchio, A.
Fast Ortho-Metalation Reactions in Binuclear Dirhodium Com-
pounds. Syntheses and Molecular Structures of a Monometalated
Compound and Two Doubly Metalated Compounds with Head-to-
Head Configurations. Inorg. Chem. 1992, 31, 1224−1232. (e) Estevan,
́
F.; Lahuerta, P.; Pérez-Prieto, J.; Sanau, M.; Stiriba, S.-E.; Ubeda, M.
A. Ligand Effects on the Chemoselectivity of Ortho-Metalated
Rhodium(II) Catalyzed α-Diazo Ketone Transformations. Organo-
metallics 1997, 16, 880−886. (f) Taber, D. F.; Malcolm, S. C.; Bieger,
K.; Lahuerta, P.; Sanau, M.; Stiriba, S.-E.; Perez-Prieto, J.; Monge, M.
A. Synthesis, Structure, and Reactivity of the First Enantiomerically
Pure Ortho-Metalated Rhodium(II)Dimer. J. Am. Chem. Soc. 1999,
121, 860−861. (g) Barberis, M.; Estevan, F.; Lahuerta, P.; Pérez-
̈
(19) (a) Staudinger, H.; Meyer, J. Uber neue organische
Phosphorverbindungen. Helv. Chim. Acta 1919, 2, 612−618.
(b) Staudinger, H.; Meyer, J. Ueber neue organische Phosphorver-
bindungen II. Phosphazine. Helv. Chim. Acta 1919, 2, 619−635.
(c) Ramirez, F.; Levy, S. Reaction of Diazocyclopentadiene with
Triphenylphosphine. J. Org. Chem. 1958, 23, 2036−2037. (d) Weil,
T.; Cais, M. A Simplified Procedure for The Preparation of
Diazocyclopentadiene and Some Related Compounds. J. Org. Chem.
1963, 28, 2472−2472.
́
Prieto, J.; Sanau, M. New Dinuclear Catalysts Rh2(N-O)2[(C6H4)-
P(C6H5)2]2 with Imidate Ligands: Synthesis and Isomerization from
Head-to-Tail to Head-to-Head Configuration of the Imidate Ligands.
Inorg. Chem. 2001, 40, 4226−4229. (h) Estevan, F.; Herbst, K.;
Lahuerta, P.; Barberis, M.; Pérez-Prieto, J. Chiral Dirhodium(II)
Catalysts with Orthometalated Aryl Phosphine Ligands: Synthesis and
Application for Enantioselective C-H Insertion of α-Diazo Ketones.
Organometallics 2001, 20, 950−957. (i) Nowotny, M.; Maschmeyer,
T.; Johnson, B. F. G.; Lahuerta, P.; Thomas, J. M.; Davies, J. E.
Heterogeneous Dinuclear Rhodium(II) Hydroformylation Catalysts-
Performance Evaluation and Silsesquioxane-Based Chemical Model-
ing. Angew. Chem., Int. Ed. 2001, 40, 955−958. (j) Cotton, F. A.;
Murillo, C. A.; Wang, X.; Yu, R. Chiral Organometallic Triangles with
Rh-Rh Bonds. 1. Compounds Prepared from Racemic cis-
Rh2(C6H4PPh2)2(OAc)2. Inorg. Chem. 2004, 43, 8394−8403.
(20) (a) West, T. H.; Daniels, D. S. B.; Slawin, A. M. Z.; Smith, A. D.
An Isothiourea-Catalyzed Asymmetric [2,3]-Rearrangement of Allylic
Ammonium Ylides. J. Am. Chem. Soc. 2014, 136, 4476−4479.
(b) Sweeney, J. B. Sigmatropic Rearrangements of ‘Onium’ Ylids.
Chem. Soc. Rev. 2009, 38, 1027−1038. (c) Workman, J. A.; Garrido,
N. P.; Sancon, J.; Roberts, E.; Wessel, H. P.; Sweeney, J. B.
Asymmetric [2,3]-Rearrangement of Glycine-Derived Allyl Ammo-
nium Ylids. J. Am. Chem. Soc. 2005, 127, 1066−1067. (d) Li, A.-H.;
Dai, L.-X.; Aggarwal, V. K. Asymmetric Ylide Reactions: Epoxidation,
Cyclopropanation, Aziridination, Olefination, and Rearrangement.
Chem. Rev. 1997, 97, 2341−2372. (e) Doyle, M. P.; Tamblyn, W. H.;
Bagheri, V. Highly Effective Catalytic Methods for Ylide Generation
from Diazo Compounds. Mechanism of the Rhodium- and Copper-
Catalyzed Reactions with Allylic Compounds. J. Org. Chem. 1981, 46,
5094−5102. (f) Lin, X.; Yang, W.; Yang, W.; Liu, X.; Feng, X.
Asymmetric Catalytic [2,3] Stevens and Sommelet−Hauser Rear-
rangements of α-Diazo Pyrazoleamides with Sulfides. Angew. Chem.,
Int. Ed. 2019, 58, 13492−13498. (g) Laconsay, C. J.; Tantillo, D. J.
Metal Bound or Free Ylides as Reaction Intermediates in Metal-
Catalyzed [2,3]-Sigmatropic Rearrangements? It Depends. ACS Catal.
2021, 11, 829−839. (h) Zhang, Y.; Wang, J. Catalytic [2,3]-
sigmatropic rearrangement of sulfur ylide derived from metal carbene.
Coord. Chem. Rev. 2010, 254, 941−953.
(21) (a) Tan, J.; Kuang, Y.; Wang, Y.; Huang, Q.; Zhu, J.; Wang, Y.
Axial Tri-tert-butylphosphane Coordination to Rh2(OAc)4: Synthesis,
Structure, and Catalytic Studies. Organometallics 2016, 35, 3139−
3147. (b) Norman, J. G.; Kolari, H. J. Strength and Trans Influence of
the Rhodium-Rhodium Bond in Rhodium(II) Carboxylate Dimers. J.
Am. Chem. Soc. 1978, 100, 791−799. (c) Christoph, G. G.; Halpern,
J.; Khare, G. P.; Koh, Y. B.; Romanowski, C. Interpretation of σ and π
components in M-P bonds. Comparison of the Bis-
(triphenylphosphine) and Bis(triphenyl phosphite) Adducts of
Dirhodium Tetraacetate. Inorg. Chem. 1981, 20, 3029−3037.
(d) Moszner, M.; Głowiak, T.; Ziółowski, J. J. The Crystal and
Molecular Structure of Rh2(CH3CO2)4[HCON(CH3)]2Effect of
Ligands on Metal-Metal Bonding. Polyhedron 1985, 4, 1413−1417.
(22) Chakravarty, A. R.; Cotton, F. A.; Tocher, D. A.; Tocher, J. H.
Structural and Electrochemical Characterization of the Novel Ortho-
Metalated Dirhodium(II) Compounds Rh2(O2CMe)2[Ph2P(C6H4)]2·
2L. Organometallics 1985, 4, 8−13.
́
(k) Esteban, J.; Estevan, F.; Sanau, M. Analysis of the Main Structural
Trends for Biscyclometalated Dinuclear Rhodium Compounds with
Nitrogen Donor Axial Ligands. Inorg. Chim. Acta 2009, 362, 1179−
1184. (l) Lloret, J.; Estevan, F.; Lahuerta, P.; Hirva, P.; Pérez-Prieto,
́
J.; Sanau, M. Dirhodium(II) Compounds with Bridging Thienylphos-
phines: Studies on Reversible P,C/P,S Coordination. Chem. - Eur. J.
2009, 15, 7706−7716.
(24) (a) Perlepes, S. P.; Huffman, J. C.; Matonic, J. H.; Dunbar, K.
R.; Christou, G. Binding of 2,2′-Bipyridine to the Dirhodium(II)
Tetraacetate Core: Unusual Structural Features and Biological
Relevance of the Product Rh2(OAc)4(bpy). J. Am. Chem. Soc. 1991,
113, 2770−2771. (b) Crawford, C. A.; Matonic, J. H.; Streib, W. E.;
Huffman, J. C.; Dunbar, K. R.; Christou, G. Reaction of 2,2′-
Bipyridine (bpy) with Dirhodium Carboxylates: Mono-bpy Products
with Variable Chelate Binding Modes and Insights into the Reaction
Mechanism. Inorg. Chem. 1993, 32, 3125−3133.
(25) For selected examples of axially coordinated dirhodium(II)
complexes in classic carbene-transfer reactions, see: (a) Snyder, J. P.;
Padwa, A.; Stengel, T.; Arduengo, A. J.; Jockisch, A.; Kim, H.-J. A
Stable Dirhodium Tetracarboxylate Carbenoid: Crystal Structure,
Bonding Analysis, and Catalysis. J. Am. Chem. Soc. 2001, 123, 11318−
11319. (b) Gomes, L. F. R.; Trindade, A. F.; Candeias, N. R.; Gois, P.
M. P.; Afonso, C. A. M. Intramolecular C−H Insertion using NHC−
di-Rhodium(II) Complexes: the Influence of Axial Coordination.
Tetrahedron Lett. 2008, 49, 7372−7375. (c) Gomes, L. F. R.;
Trindade, A. F.; Candeias, N. R.; Veiros, L. F.; Gois, P. M. P.; Afonso,
C. A. M. Cyclization of Diazoacetamides Catalyzed by N-Heterocyclic
Carbene Dirhodium(II) Complexes. Synthesis 2009, 2009, 3519−
3526. (d) Sarkar, M.; Daw, P.; Ghatak, T.; Bera, J. K. Amide-
Functionalized Naphthyridines on a RhII−RhII Platform: Effect of
Steric Crowding, Hemilability, and Hydrogen-Bonding Interactions
on the Structural Diversity and Catalytic Activity of Dirhodium(II)
Complexes. Chem. - Eur. J. 2014, 20, 16537−16549. (e) Anderson, B.
G.; Cressy, D.; Patel, J. J.; Harris, C. F.; Yap, G. P. A.; Berry, J. F.;
(23) (a) Barcelo, F.; Cotton, F. A.; Lahuerta, P.; Llusar, R.; Sanau,
M.; Schwotzer, W.; Ubeda, M. A. Synthesis and Structure of the
O r t h o - M e t a l a t e d D i r h o d i u m ( I I ) C o m p o u n d
Rh2(O2CCH3)3[(C6H4)P(C6H5)(C6F4Br)]·P(C6H5)2(C6F4Br). Or-
ganometallics 1986, 5, 808−811. (b) Cotton, F. A.; Barceló, F.;
Lahuerta, P.; Llusar, R.; Payá, J.; Ubeda, M. A. Ortho-Metalation
11808
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Darko, A. Synthesis and Catalytic Properties of Dirhodium
Paddlewheel Complexes with Tethered, Axially Coordinating
Thioether Ligands. Inorg. Chem. 2019, 58, 1728−1732. (f) Cressy,
D.; Zavala, C.; Abshire, A.; Sheffield, W.; Darko, A. Tuning Rh(II)-
Catalysed Cyclopropanation with Tethered Thioether Ligands. Dalton
Trans. 2020, 49, 15779−15787.
and Computational Characterization of the Transition State for C-X
Bimetallic Oxidative Addition at a Cu-Fe Reaction Center. Organo-
metallics 2015, 34, 3857−3864. (j) Thomas, C. M.; Napoline, J. W.;
Rowe, G. T.; Foxman, B. M. Oxidative Addition Across Zr/Co
Multiple Bonds in Early/Late Heterobimetallic Complexes. Chem.
Commun. 2010, 46, 5790−5792. (k) Powers, D. C.; Ritter, T.
Bimetallic Redox Synergy in Oxidative Palladium Catalysis. Acc. Chem.
Res. 2012, 45, 840−850. (l) Bonney, K. J.; Schoenebeck, F.
Experiment and Computation: A Combined Approach to Study the
Reactivity of Palladium Complexes in Oxidation States 0 to IV. Chem.
Soc. Rev. 2014, 43, 6609−6638. (m) Wang, W.; Ji, C.-L.; Liu, K.;
Zhao, C.-G.; Li, W.; Xie, J. Dinuclear Gold Catalysis. Chem. Soc. Rev.
2021, 50, 1874−1912. (n) Vigato, P. A.; Tamburini, S.; Fenton, D. E.
The Activation of Small Molecules by Dinuclear Complexes of
Copper and Other Metals. Coord. Chem. Rev. 1990, 106, 25−170.
(28) Selected examples of two-electron oxidation of [Rh2]4+ of
dirhodium(II) complexes to generate [Rh2]6+ species: (a) Nichols, J.
M.; Wolf, J.; Zavalij, P.; Varughese, B.; Doyle, M. P. Bis(phenyl)-
dirhodium(III) Caprolactamate: A Dinuclear Paddlewheel Complex
with No Metal-Metal Bond. J. Am. Chem. Soc. 2007, 129, 3504−3505.
(b) Doyle, M. P.; Shabashov, D.; Zhou, L.; Zavalij, P. Y.; Welch, C.;
Pirzada, Z. Does an Axial Propeller Shape on a Dirhodium(III,III)
Core Affect Equatorial Ligand Chirality? Organometallics 2011, 30,
3619−3627. (c) Lin, Y.; Zhu, L.; Lan, Y.; Rao, Y. Development of a
Rhodium(II)-Catalyzed Chemoselective C(sp3)-H Oxygenation.
Chem. - Eur. J. 2015, 21, 14937−14942. (d) Tejel, C.; Ciriano, M.
A.; Edwards, A. J.; Lahoz, F. J.; Oro, L. A. Metal Basicity of
Dirhodium and Diiridium Complexes Induced by Isocyanide Ligands.
Model for the Oxidative-Addition Reaction of Methyl Iodide with
Dinuclear Complexes. Organometallics 1997, 16, 45−53. (e) Das, K.;
Kadish, K. M.; Bear, J. L. Substituent and Solvent Effects on the
Electrochemical Properties of Tetra-μ-Carboxylato-Dirhodium(II).
Inorg. Chem. 1978, 17, 930−934. (f) Chavan, M. Y.; Zhu, T. P.; Lin,
X. Q.; Ahsan, M. Q.; Bear, J. L.; Kadish, K. M. Axial-Ligand-
Dependent Electrochemical and Spectral Properties of a Series of
Acetate- and Acetamidate-Bridged Dirhodium Complexes. Inorg.
Chem. 1984, 23, 4538−4545. (g) Bear, J. L.; Zhu, T. P.; Malinski,
T.; Dennis, A. M.; Kadish, K. M. Electrochemical Characterization of
a Rhodium(II) Dimer with N-Phenylacetamido Bridging Ligands.
Inorg. Chem. 1984, 23, 674−678. (h) Bear, J. L.; Yao, C. L.; Liu, L.
M.; Capdevielle, F. J.; Korp, J. D.; Albright, T. A.; Kang, S. K.; Kadish,
K. M. Synthesis, Molecular Structure, and Electrochemical Properties
of Two Geometric Isomers of Tetrakis(μ-2-anilinopyridinato)-
dirhodium Complexes. Inorg. Chem. 1989, 28, 1254−1262.
(i) Amo-Ochoa, P.; Jiménez-Aparicio, R.; Torres, M. R.; Urbanos,
F. A.; Gallego, A.; Gómez-García, C. J. MMX Chains and Molecular
(26) For selected examples of axially coordinated dirhodium(II)
complexes in other types of reactions, see: (a) Wang, D.; Zhao, Y.;
Yuan, C.; Wen, J.; Zhao, Y.; Shi, Z. Rhodium(II)-Catalyzed
Dehydrogenative Silylation of Biaryl-Type Monophosphines with
Hydrosilanes. Angew. Chem., Int. Ed. 2019, 58, 12529−12533. (b) Fu,
L.; Li, S.; Cai, Z.; Ding, Y.; Guo, X.-Q.; Zhou, L.-P.; Yuan, D.; Sun,
Q.-F.; Li, G. Ligand-Enabled Site-Selectivity in a Versatile Rhodium-
(II)-Catalysed Aryl C−H Carboxylation with CO2. Nat. Catal. 2018,
1, 469−478. (c) Rej, S.; Chatani, N. Rh(II)-Catalyzed Branch-
Selective C−H Alkylation of Aryl Sulfonamides with Vinylsilanes.
Chem. Sci. 2020, 11, 389−395. (d) Vora, H. U.; Silvestri, A. P.;
Engelin, C. J.; Yu, J. Q. Rhodium(II)-Catalyzed Nondirected
Oxidative Alkenylation of Arenes: Arene Loading at One Equivalent.
Angew. Chem., Int. Ed. 2014, 53, 2683−2686. (e) Kwak, J.; Kim, M.;
Chang, S. Rh(NHC)-Catalyzed Direct and Selective Arylation of
Quinolines at the 8-Position. J. Am. Chem. Soc. 2011, 133, 3780−
3783. (f) Kim, M.; Kwak, J.; Chang, S. Rhodium/N-heterocyclic
Carbene Catalyzed Direct Intermolecular Arylation of sp2 and sp3 C-
H Bonds With Chelation Assistance. Angew. Chem., Int. Ed. 2009, 48,
8935−8939. (g) Hong, J.-T.; Jang, H.-Y. Correlation of Electro-
chemical Characteristics and Catalytic Activity of Rh2(OAc)4 in the
Presence of Various Phosphines. Bull. Korean Chem. Soc. 2008, 29,
1624−1626. (h) Na, S. J.; Lee, B. Y.; Bui, N.-N.; Mho, S.-i.; Jang, H.-
Y. A New Dirhodium Tetraacetate Carbenoid: Synthesis, Crystal
Structure and Catalytic Application. J. Organomet. Chem. 2007, 692,
5523−5527. (i) Trindade, A. F.; Gois, P. M. P.; Veiros, L. F.; André,
V.; Duarte, M. T.; Afonso, C. A. M.; Caddick, S.; Cloke, F. G. N. Axial
Coordination of NHC Ligands on Dirhodium(II) Complexes:
Generation of a New Family of Catalysts. J. Org. Chem. 2008, 73,
4076−4086. (j) Gois, P. M. P.; Trindade, A. F.; Veiros, L. F.; André,
V.; Duarte, M. T.; Afonso, C. A. M.; Caddick, S.; Cloke, F. G. N.
Tuning the Reactivity of Dirhodium(II) Complexes with Axial N-
heterocyclic Carbene Ligands: the Arylation of Aldehydes. Angew.
Chem., Int. Ed. 2007, 46, 5750−5753.
(27) (a) Feng, M.; Chan, K. S. Synthesis and Reactivity of
Nonbridged Metal-Metal Bonded Rhodium and Iridium Phenanthro-
line-Based N2O2 Dimers. Organometallics 2002, 21, 2743−2750.
(b) Tejel, C.; Bordonaba, M.; Ciriano, M. A.; Edwards, A. J.; Clegg,
W.; Lahoz, F. J.; Oro, L. A. Oxidative-Addition Reactions of Diiodine
to Dinuclear Rhodium Pyrazolate Complexes. Inorg. Chem. 1999, 38,
1108−1117. (c) Basil, J. D.; Murray, H. H.; Fackler, J. P.; Tocher, J.;
Mazany, A. M.; Trzcinska-Bancroft, B.; Knachel, H.; Dudis, D.;
Delord, T. J.; Marler, D. O. Experimental and Theoretical Studies of
Dinuclear Gold(I) and Gold(II) Phosphorus Ylide Complexes.
Oxidative Addition, Halide Exchange, and Structural Properties
Including the Crystal and Molecular Structures of [Au(CH2)2PPh2]2
and [Au(CH2)2PPh2]2(CH3)Br. J. Am. Chem. Soc. 1985, 107, 6908−
6915. (d) Fafard, C. M.; Adhikari, D.; Foxman, B. M.; Mindiola, D. J.;
Ozerov, O. V. Addition of Ammonia, Water, and Dihydrogen Across a
Single Pd-Pd Bond. J. Am. Chem. Soc. 2007, 129, 10318−10319.
(e) Karunananda, M. K.; Mankad, N. P. E-Selective Semi-Hydro-
genation of Alkynes by Heterobimetallic Catalysis. J. Am. Chem. Soc.
2015, 137, 14598−14601. (f) Gramigna, K. M.; Dickie, D. A.;
Foxman, B. M.; Thomas, C. M. Cooperative H2 Activation across a
Metal-Metal Multiple Bond and Hydrogenation Reactions Catalyzed
by a Zr/Co Heterobimetallic Complex. ACS Catal. 2019, 9, 3153−
3164. (g) Baranger, A. M.; Bergman, R. G. Cooperative Reactivity in
the Interactions of X-H Bonds with a Zirconium-Iridium Bridging
Imido Complex. J. Am. Chem. Soc. 1994, 116, 3822−3835.
(h) Mazzacano, T. J.; Mankad, N. P. Base Metal Catalysts for
Photochemical C-H Borylation That Utilize Metal-Metal Coopera-
tivity. J. Am. Chem. Soc. 2013, 135, 17258−17261. (i) Karunananda,
M. K.; Parmelee, S. R.; Waldhart, G. W.; Mankad, N. P. Experimental
n+
Species Containing Rh2 (n = 4, 5, and 6) Units: Electrical
Conductivity in Crystal Phase of MMX Polymers. Eur. J. Inorg. Chem.
2010, 2010, 4924−4932. (j) Angelone, D.; Draksharapu, A.; Browne,
W. R.; Choudhuri, M. M. R.; Crutchley, R. J.; Xu, X.; Xu, X.; Doyle,
M. P. Dinuclear Compounds Without a Metal−Metal Bond.
Dirhodium(III,III) Carboxamidates. Inorg. Chim. Acta 2015, 424,
235−240. (k) Warzecha, E.; Berto, T. C.; Berry, J. F. Axial Ligand
Coordination to the C−H Amination Catalyst Rh2(esp)2: A Structural
and Spectroscopic Study. Inorg. Chem. 2015, 54, 8817−8824.
(l) Wolf, J.; Poli, R.; Xie, J.-H.; Nichols, J.; Xi, B.; Zavalij, P.;
Doyle, M. P. Removal of Metal-Metal Bonding in a Dimetallic
Paddlewheel Complex: Molecular and Electronic Structure of
Bis(phenyl) Dirhodium(III) Carboxamidate Compounds. Organo-
metallics 2008, 27, 5836−5845. (m) Xie, J.-H.; Nichols, J. M.; Lubek,
C.; Doyle, M. P. Synthesis of Bis(σ-aryl)dirhodium(III) Caprolacta-
mates by Oxidative Arylation with Arylboronic Acids. Chem. Commun.
2008, 2671−2673. (n) Xie, J.-H.; Zhou, L.; Lubek, C.; Doyle, M. P.
Hetero-bis(σ-aryl)dirhodium(III) Caprolactamates. Electronic Com-
munication Between Aryl Groups through Dirhodium(III). Dalton
Trans. 2009, 2871−2877.
(29) (a) Christoph, G. G.; Koh, Y. B. Metal-Metal Bonding in
Dirhodium Tetracarboxylates. Trans Influence and Dependence of
the Rhodium-Rhodium Bond Distance upon the Nature of the Axial
11809
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Ligands. J. Am. Chem. Soc. 1979, 101, 1422−1434. (b) Drago, R. S.;
Long, J. R.; Cosmano, R. Metal Synergism in the Coordination
Chemistry of a Metal-Metal Bonded System: Rh2(C3H7COO)4. Inorg.
Chem. 1981, 20, 2920−2927. (c) Bilgrien, C.; Drago, R. S.; Vogel, G.
C.; Stahlbush, J. Trans Influence Across a Rhodium-Rhodium Bond.
Effect of a Series of Lewis Bases on the Stretching Frequency of
Coordinated Carbon Monoxide. Inorg. Chem. 1986, 25, 2864−2866.
(d) Dikarev, E. V.; Li, B.; Zhang, H. Tuning the Properties at
Heterobimetallic Core: Mixed-Ligand Bismuth-Rhodium Paddle-
wheel Carboxylates. J. Am. Chem. Soc. 2006, 128, 2814−2815.
Cycloadditions of Vinylidenes and Dienes. Science 2019, 363, 857−
862.
(e) Collins, L. R.; van Gastel, M.; Neese, F.; Furstner, A. Enhanced
̈
Electrophilicity of Heterobimetallic Bi−Rh Paddlewheel Carbene
Complexes: A Combined Experimental, Spectroscopic, and Computa-
tional Study. J. Am. Chem. Soc. 2018, 140, 13042−13055. (f) Trindade,
A. F.; Coelho, J. A. S.; Afonso, C. A. M.; Veiros, L. F.; Gois, P. M. P.
Fine Tuning of Dirhodium(II) Complexes: Exploring the Axial
Modification. ACS Catal. 2012, 2, 370−383.
(30) For selected reviews, see: (a) Gade, L. H. Highly Polar metal -
Metal Bonds in “Early-Late” Heterodimetallic Complexes. Angew.
Chem., Int. Ed. 2000, 39, 2658−2678. (b) Buchwalter, P.; Rosé, J.;
Braunstein, P. Multimetallic Catalysis Based on Heterometallic
Complexes and Clusters. Chem. Rev. 2015, 115, 28−126. (c) Powers,
I. G.; Uyeda, C. Metal−Metal Bonds in Catalysis. ACS Catal. 2017, 7,
936−958. (d) Berry, J. F.; Lu, C. C. Metal-Metal Bonds: From
Fundamentals to Applications. Inorg. Chem. 2017, 56, 7577−7581.
(e) Farley, C. M.; Uyeda, C. Organic Reactions Enabled by
Catalytically Active Metal−Metal Bonds. Trends in Chemistry 2019,
1, 497−509. (f) Campos, J. Bimetallic Cooperation Across the
Periodic Table. Nat. Rev. Chem. 2020, 4, 696−702. (g) Xu, W.; Li, M.;
Qiao, L.; Xie, J. Recent Advances of Dinuclear Nickel- and Palladium-
Complexes in Homogeneous Catalysis. Chem. Commun. 2020, 56,
8524−8536. (h) Xiong, N.; Zhang, G.; Sun, X.; Zeng, R. Metal-Metal
Cooperation in Dinucleating Complexes Involving Late Transition
Metals Directed towards Organic Catalysis. Chin. J. Chem. 2020, 38,
185−201. (i) Lyngdoh, R. H. D.; Schaefer, H. F.; King, R. B. Metal−
Metal (MM) Bond Distances and Bond Orders in Binuclear Metal
Complexes of the First Row Transition Metals Titanium Through
Zinc. Chem. Rev. 2018, 118, 11626−11706. (j) Nielsen, M. C.;
Lyngvi, E.; Schoenebeck, F. Chemoselectivity in the Reductive
Elimination from High Oxidation State Palladium Complexes−
Scrambling Mechanism Uncovered. J. Am. Chem. Soc. 2013, 135,
1978−1985. (k) Fricke, C.; Sperger, T.; Mendel, M.; Schoenebeck, F.
Catalysis with Palladium(I) Dimers. Angew. Chem., Int. Ed. 2021, 60,
3355−3366.
(31) (a) Hostetler, M. J.; Bergman, R. G. Synthesis and Reactivity of
Cp2Ta(CH2)2Ir(CO)2: an Early-Late Heterobimetallic Complex that
Catalytically Hydrogenates, Isomerizes and Hydrosilates Alkenes. J.
Am. Chem. Soc. 1990, 112, 8621−8623. (b) Nishibayashi, Y.; Wakiji,
I.; Hidai, M. Novel Propargylic Substitution Reactions Catalyzed by
Thiolate-Bridged Diruthenium Complexes via Allenylidene Inter-
mediates. J. Am. Chem. Soc. 2000, 122, 11019−11020. (c) Tsutsumi,
H.; Sunada, Y.; Shiota, Y.; Yoshizawa, K.; Nagashima, H. Nickel(II),
Palladium(II), and Platinum(II) η3-Allyl Complexes Bearing a
Bidentate Titanium(IV) Phosphinoamide Ligand: A Ti-M2 Dative
Bond Enhances the Electrophilicity of the π-Allyl Moiety. Organo-
metallics 2009, 28, 1988−1991. (d) Rudd, P. A.; Liu, S.; Gagliardi, L.;
Young, V. G.; Lu, C. C. Metal−Alane Adducts with Zero-Valent
Nickel, Cobalt, and Iron. J. Am. Chem. Soc. 2011, 133, 20724−20727.
(e) Zhou, W.; Marquard, S. L.; Bezpalko, M. W.; Foxman, B. M.;
Thomas, C. M. Catalytic Hydrosilylation of Ketones Using a Co/Zr
Heterobimetallic Complex: Evidence for an Unusual Mechanism
Involving Ketyl Radicals. Organometallics 2013, 32, 1766−1772.
(f) Takaya, J.; Iwasawa, N. Synthesis, Structure, and Catalysis of
Palladium Complexes Bearing a Group 13 Metalloligand: Remarkable
Effect of an Aluminum-Metalloligand in Hydrosilylation of CO2. J.
Am. Chem. Soc. 2017, 139, 6074−6077. (g) Hara, N.; Saito, T.;
Semba, K.; Kuriakose, N.; Zheng, H.; Sakaki, S.; Nakao, Y. Rhodium
Complexes Bearing PAlP Pincer Ligands. J. Am. Chem. Soc. 2018, 140,
7070−7073. (h) Zhou, Y.-Y.; Uyeda, C. Catalytic Reductive [4 + 1]-
11810
https://doi.org/10.1021/jacs.1c05701
J. Am. Chem. Soc. 2021, 143, 11799−11810