Regio- and Diastereoselective Rhodium-Catalyzed Allylic Substitution with Unstabilized Benzyl Nucleophiles

Article abstract of DOI:10.1002/anie.202008071

We have developed a highly regio- and diastereoselective rhodium-catalyzed allylic substitution of challenging alkyl-substituted secondary allylic carbonates with benzylzinc reagents, which are prepared from widely available benzyl halides. This process utilizes rhodium(III) chloride as a commercially available, high-oxidation state and bench-stable pre-catalyst to provide a rare example of a regio- and diastereoselective allylic substitution in the absence of an exogenous ligand. This reaction tolerates electronically diverse benzylzinc nucleophiles and an array of functionalized and/or challenging aliphatic allylic electrophiles. Finally, the configurational fluxionality of the rhodium-allyl intermediate is exploited to develop a novel diastereoselective process for the construction of vicinal acyclic ternary/ternary stereogenic centers, in addition to a cyclic ternary/quaternary derivative.

Full text of DOI:10.1002/anie.202008071

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Regio- and Diastereoselective Rhodium-Catalyzed Allylic
Substitution with Unstabilized Benzyl Nucleophiles
Authors: Debasis Pal, Timothy B. Wright, Ryan O’Connor, and P.
Andrew Evans
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202008071
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10.1002/anie.202008071
Angewandte Chemie International Edition
RESEARCH ARTICLE
Regio- and Diastereoselective Rhodium-Catalyzed Allylic Substitution with
Unstabilized Benzyl Nucleophiles
Debasis Pal, Timothy B. Wright, Ryan O’Connor, and P. Andrew Evans*
Abstract: We have developed a highly regio- and diastereoselective
rhodium-catalyzed allylic substitution of challenging alkyl-substituted
A. Prevalance of Nucleophiles in Transition Metal-Catalyzed Allylic Substitutions
Nu
Nu
MLn
Soft–Nu
pKa <25
Hard–Nu
pKa >25
branched allylic carbonates with benzylzinc reagents, which are
prepared from widely available benzyl halides. This process utilizes
rhodium(III) chloride as a commercially available, high-oxidation state
and bench-stable pre-catalyst to provide a rare example of regio- and
diastereoselective allylic substitution in the absence of an exogenous
ligand. This reaction tolerates both electronically diverse benzylzinc
nucleophiles and an array of functionalized and/or challenging
aliphatic secondary allylic electrophiles. Finally, the configurational
fluxionality of the rhodium-allyl intermediate is exploited to develop a
novel diastereoselective process for the construction of vicinal acyclic
R1
R2
R1
*
R2
>
M = Pd, Ir, Rh,
Co, Ni
(Well-developed)
(Less-developed)
Aryl-M
>>
Alkyl-M
Alkenyl-M
~
Benzyl-M
M = Li, Mg, Zn, Zr
# Reports of the Type of Hard Nucleophile
B. Enantioselective Metal-Catalyzed Allylic Alkylation – Benzyl Nucleophiles – Recent Work
Pd
Pd
Ir
Pd/hn
Ir
Me
Me
CO2H
DHP
ternary/ternary stereogenic centers, in addition to
ternary/quaternary derivative.
a cyclic
N
BF3
Cr(CO)3
Walsh
Stabilized Nucleophiles
EWG
X
R
Trost
Lundgren
Yu
You
Radical
Neutral
Introduction
C. Regio- and Diastereoselective Allylic Benzylation with a Rh(III) Pre-catalyst – This Work
R3
OLg
R3
The transition metal-catalyzed allylic substitution reaction is a
particularly versatile C-C and C-X cross-coupling reaction for
target-directed synthesis.[1] Nevertheless, despite the recent
advances in the repertoire of soft nucleophiles that can be
deployed in this process, the development of the analogous
process with hard “unstabilized” nucleophiles is significantly more
challenging (Scheme 1A).[2-6] This striking dichotomy can
presumably be attributed to the high reactivity of hard
nucleophiles; namely, main-group organometallic reagents (e.g.,
M = Li, Mg, etc.) towards the metal-allyl intermediate and/or
electrophilic functional groups within the substrate. Although
recent efforts have expanded the scope of hard nucleophiles, we
are only aware of a single allylic benzylation with a benzylic
organometallic reagent, which affords the linear achiral
derivative.[6] Hence, given that this motif is omnipresent in an
array of bioactive natural products and medicinally important
agents, the preparation of the branched ternary allylic benzyl motif
remains highly desirable.[7] Notwithstanding the aforementioned
limitations, several elegant and creative approaches that
circumvent using a reactive organometallic intermediate have
been devised (Scheme 1B). For instance, Trost and Walsh
R1
cat. RhCl3
Privileged Motif
>15 000
Scifinder Hits
ZnX
+
R1
R2
R1/R2 = H, Me,
iPr, OR, etc.
R2
Hard–Nu
R3 = H, EWG, EDG
• Hard Benzyl Nucleophiles • Aliphatic Electrophiles • Bench-Stable Pre-catalyst
Scheme 1. Background for the development of the regio- and
diastereoselective benzylation of acyclic secondary allylic carbonates with hard
benzyl nucleophiles.
independently described the utility of the Lewis acid complexes of
2-methylpyridine
and
chromium-bound
toluene
pronucleophiles.[8,9] More recently, Lundgren and coworkers
have developed a process that employs electron-deficient aryl
acetic acids for allylic benzylation with concomitant
decarboxylation.[10] Alternatively, free radical and neutral cross-
coupling partners have been employed in allylic benzylation
reactions by Yu and You, respectively.[11,12] Nevertheless, the
direct and branched selective allylic alkylation with an unstabilized
benzyl nucleophile for the installation of simple and electronically
unbiased toluene derivatives has not been reported. Herein,
we now describe the regio- and diastereoselective rhodium-
catalyzed allylic alkylation with hard benzylzinc species for
the direct construction of vicinal acyclic ternary/ternary
stereogenic centers. Notably, this process represents a rare
example of an allylic substitution that employs a high-valent
transition metal pre-catalyst without the necessity for an
[*]
D. Pal, T. B. Wright, and Professor P. A. Evans
Department of Chemistry, Queen’s University
90 Bader Lane, Kingston, ON K7L 3N6 (Canada)
E-mail: andrew.evans@chem.queensu.ca
Homepage: http://www.chem.queensu.ca/people/faculty/evans/
pae.htm
exogenous ligand [13]
.
Professor P. A. Evans
In a program directed towards the development of regio-
and stereoselective rhodium-catalyzed allylic alkylation
reactions,[14,15] we have previously described the arylation of
fluorinated allylic carbonates using arylzinc bromides and a
low-valent rhodium catalyst.[16] We hypothesized that the
rhodium-catalyzed allylic substitution with unstabilized
benzyl nucleophiles would significantly expand the scope of
this process to include sp3 organometallic reagents, albeit
Xiangya School of Pharmaceutical Sciences
Central South University, Changsha, 410013
Hunan, P. R. of China
R. O’Connor
Department of Chemistry, University of Liverpool
Crown Street, Liverpool L69 7ZD (UK)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202008071
Angewandte Chemie International Edition
RESEARCH ARTICLE
there are several inherent challenges associated with this
type of cross-coupling. For instance, the rhodium-catalyzed
allylic substitution with benzyl nucleophiles undergoes
slower reductive elimination (sp3 vs sp2),[17] which is further
complicated by the tendency of benzylic organometallic
species to undergo Wurtz homocoupling.[18] Indeed, the
challenges presented by the Wurtz homocoupling process
has been a significant obstacle in the deployment of benzyl
nucleophiles in metal-catalyzed cross-coupling reactions.[19]
Consequently, we envisioned that the development a
regioselective rhodium-catalyzed allylic alkylation of
equivalents of benzylmagnesium bromide in the presence of
catalytic rhodium(III) chloride trihydrate affords the allylic
benzylation product 2a with moderate yield and
regioselectivity (Table 1, entry 1).
transmetallation of the benzyl Grignard reagent with zinc
chloride resulted in significant improvement in
Importantly, the
a
regioselectivity, albeit with reduced efficiency (entry 2).
Further studies probed the impact of the zinc(II) halide salt
used in the transmetallation, which demonstrated they are
identical in the context of regiocontrol. Nevertheless, zinc(II)
iodide provides optimal efficiency for the formation of 2a and
minimizes the formation of the Wurtz homocoupling product
4a (entries 2-3 vs 4). In contrast, the identity of the halide
within the Grignard reagent is less significant, as
benzylmagnesium chloride furnishes 2a with similar
efficiency and selectivity (entry 4 vs 5). At this point, while
the allylic benzylation of 1a afforded good efficiency and
excellent regioselectivity, the isolation of the target product
was complicated by the formation of the Wurtz homocoupling
derivative 4a, which often coelutes with the non-polar allylic
unstabilized benzyl nucleophiles would represent
significant advance in this area.
a
Results and Discussion
Preliminary studies demonstrated that benzylzinc
nucleophiles deliver the benzylation product 2a in moderate
to good yields with several rhodium(I) catalysts.[20] However,
we envisioned that using a high-oxidation state rhodium(III)
pre-catalyst, which could undergo in situ reduction[21] to
provide an active rhodium(I) catalyst (vide infra), may provide
a more robust pre-catalyst. The use of a high-valent
transition metal complexes (e.g., Rh(III), Ir(III), etc.) as pre-
catalysts is rare in allylic substitution reactions, albeit they
are generally deployed in processes that generate a metal-
allyl intermediate via allylic C-H activation.[22] Remarkably,
we found that the commercially available and bench-stable
pre-catalyst rhodium(III) chloride trihydrate is capable of
delivering the allylic benzylation product with similar
efficiency and selectivity.
alkylation adduct 2a
.
Further studies indicate that either
increasing or decreasing the amount of Grignard reagent
leads to lower efficiency and selectivity (entry 6 and 7), albeit
a benzyl Grignard to zinc(II) salt ratio of 1:1 significantly
reduces the formation of the Wurtz coupling by-product.
Hence, we rationalized that increasing the amount of
nucleophile while maintaining the same stoichiometry would
provide the optimal efficiency for this process. Gratifyingly,
increasing the amount of benzylmagnesium bromide and
zinc(II) iodide (1.5 equiv.) furnished the branched allylic
benzylation product 2a with optimal efficiency and selectivity
(entry 8).
Table 2 delineates the scope of the benzyl nucleophile,[23]
which is tolerant of several 4-substituted benzyl derivatives
with both electron-withdrawing and electron-donating
substituents (entries 1-6). The ability to employ highly
electron-rich benzyl nucleophiles (e.g., 4-OMe) is particularly
significant given their propensity to undergo Wurtz
homocoupling reactions. For instance, in these cases, the
nucleophile was prepared using the method reported by
Knochel,[24] which involves the direct insertion of zinc into the
benzyl chloride to afford the more challenging allylic
benzylation adducts 2ae and 2af in moderate yield. The
current process is also amenable to a variety of 3-
substituents as well as a 2-fluoro derivative, albeit with
reduced regioselectivity for the latter case (entries 7-12).
Disubstituted aryl substituents also furnish the allylic
benzylation adducts with good efficiency and regioselectivity
(entries 13-15), which includes a dihalogenated derivative
2am that can be further functionalized via conventional
cross-coupling. Table 2 also demonstrates the application of
the optimized reaction conditions (Table 1, entry 8) to several
acyclic secondary allylic carbonates 1a-o, which illustrates
the process is tolerant of a number of functionalized allylic
scaffolds. For example, whereas the copper- and iridium-
catalyzed allylic alkylation of hard nucleophiles is generally
optimal with cinnamyl derivatives, which presumably
circumvent -hydride elimination to form dienes, the rhodium-
catalyzed process is remarkably efficient and regioselective
Table 1. Optimization of the regioselective rhodium-catalyzed allylic substitution
with benzyl nucleophiles[a]
BnMgBr
(x equiv)
ZnX2
(y equiv)
Yield
(%)[b]
2a+3a:
Entry
2a:3a[c]
4a[c]
1
2
2.0
2.0

-
-
60
47
81:19
98:2
98:2
98:2
98:2
88:12
99:1
99:1
83:17
77:23
75:25
88:12
87:13
72:28
92:8
ZnCl2
ZnBr2
ZnI2

1.0

3
39
4
5[d]
78


74


6
3.0
1.0
1.5
1.0
1.0
1.5
41

7
45
82(80)[e]

8
ZnI2
93:7
[a] All reactions were performed on a 0.2 mmol scale using 10 mol%
RhCl3•3H2O, in Et2O (0.025 M) for ca. 16 h. [b] GC yield of 2a. [c] Determined
by GC analysis of the crude reaction mixture. [d] BnMgCl was used. [e] Isolated
yield in parenthesis.
Table 1 outlines the development of a highly regioselective
allylic benzylation using rhodium(III) chloride as the pre-
with aliphatic electrophiles.
For instance, protected
catalyst.
Treatment of the acyclic fluorinated allylic
hydroxymethyl carbonates (entries 16-17), benzyl and n-
carbonate 1a (see SI for leaving group study) with 2
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10.1002/anie.202008071
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butyl derivatives (entries 18-19) undergo the allylic
benzylation in good yield and with excellent branched
selectivity. Furthermore, the reaction tolerates a variety of
Table 2. Benzyl Nucleophile and allylic carbonate scope of the regioselective
rhodium-catalyzed allylic substitution with benzyl nucleophiles [a-e]
-, - and -branched substrates (entries 20-23), including a
cyclic acetal (entry 23), which all afford excellent efficiency
and selectivity. A key feature with this transformation is the
regioselective allylic substitution of this substrate class,
which is particularly challenging. Additionally, the rhodium-
catalyzed benzylation is also tolerant of various
functionalized aliphatic allylic carbonates, including terminal
alkene, alkyne and para-methoxybenzyl ether containing
motifs (entries 24-26). Finally, the utility of employing
benzylzinc nucleophiles is highlighted by the chemoselective
allylic benzylation of substrates bearing potentially reactive
functional groups, such as a primary chloride, pivalate ester,
secondary amide and aryl nitrile (entries 27-30). Overall, the
ability to facilitate the regioselective benzylation of acyclic
allylic carbonates using a bench-stable and commercially
available rhodium(III) pre-catalyst in the absence of
exogenous ligand with a variety of electronically diverse
benzylzinc nucleophiles makes this a versatile protocol for
the synthesis of this privileged motif.
Table 3. Substrate scope of the regio- and diastereoselective rhodium-
catalyzed allylic substitution with benzyl nucleophiles [a-d]
[a] All reactions were performed on a 0.25 mmol scale using 10 mol %
RhCl3•3H2O, 1.5 equiv of ArCH2MgBr and 1.5 equiv of ZnI2 in Et2O (0.025 M)
for ca. 16 h. [b] Isolated yields. [c] Regioselectivity was determined by 500 MHz
1H NMR analysis of the isolated products. [d] Benzylzinc nucleophiles
generated by direct zinc insertion of benzylchlorides, see SI for details. [e]
Reactions were performed 2 mol % RhCl3•3H2O.
[a] All reactions were performed on a 0.25 mmol scale using 10 mol %
RhCl3•3H2O, 2 equiv of ArCH2MgBr and 2 equiv of ZnI2 in Et2O (0.025 M) for ca.
16 h. [b] Isolated yields. [c] Regio- and diastereoselectivity was determined by
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10.1002/anie.202008071
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RESEARCH ARTICLE
500 MHz 1H NMR analysis of the isolated products. [d] Reactions were
stereospecific (vide supra). The fact that the diastereochemical
outcome is similar regardless of the starting material makes this
an attractive process for synthetic applications, given that the
reaction can be conducted with diastereomeric mixtures of the
starting material.
performed using 2 mol % RhCl3•3H2O.
To probe the feasibility of stereoselective carbon-carbon bond
formation using this protocol, we investigated the stereospecific
benzylation of enantiomerically enriched carbonate (R)-1a. In
sharp contrast to our previous report with arylzinc nucleophiles,[16]
the rhodium-catalyzed benzylation affords 2a with poor
conservation of enantiomeric excess (cee). Hence, this result is
consistent with a fluxional rhodium-allyl intermediate, which
undergoes stereochemical leakage via a conventional π-σ-π
isomerization at a comparable rate to product formation.
Consequently, given the excellent regiocontrol with α-branched
substrates and considering the fluxional nature of the rhodium-
allyl, we hypothesized that this may permit the development of a
diastereoselective allylic substitution with allylic carbonates
bearing α-stereogenic centers (Table 3).
Gratifyingly, the
rhodium-catalyzed allylic alkylation of anti-5a/syn-5a (1:4), affords
6a in good yield and with excellent regio- and diastereoselectivity.
The process is also applicable to electron-deficient and electron-
rich 4-substituted benzyl groups to afford 6b and 6c with similar
efficiency and selectivity (entries 1-3).
Notably, the
stereochemistry of the substrate does not significantly impact the
level of stereocontrol (entries 4-6), which provide the benzylation
adducts 6a-c with analogous efficiency and diastereoselectivity,
indicating that the reaction is feasible from diastereomeric
mixtures of 5. Additional studies examined the allylic carbonate
substitution and the nature of the -alkoxy group. To this end, the
methyl, benzyloxymethyl and cyclopentyl substituted allylic
carbonates undergo the benzylation in good yield and with
moderate to excellent diastereoselectivity (entries 7-9).
Furthermore, variations in the -alkoxy group, such as methyl,
benzyl and MOM ethers, also furnish the benzylation products in
high yields with good to excellent diastereoselectivity (entries 10-
12). The diastereoselective construction of contiguous acyclic
stereocenters with a hard benzyl nucleophile represents a novel
development, given that 1,2-stereoinduction via a fluxional metal-
allyl species in an allylic alkylation process has not been reported.
Scheme 2. Proposed catalytic cycle for the diastereoselective rhodium-
catalyzed allylic benzylation.
Additional studies explored the scalability and diastereocontrol
with a more challenging ternary allylic electrophile. Gratifyingly,
the allylic benzylation can be performed on gram-scale with
significantly reduced catalyst loading (2 mol%), which affords
similar efficiency and selectivity (Scheme 3A), in addition to a
reduction in the amount of Wurtz coupling adduct 4a (see SI).
Notably, we were able to demonstrate this reduction in catalyst
loading with several other substrates (cf. Table 2; Footnote [e] and
Table 3; Footnote [d]) on the standard reaction scale. We also
envisioned using this type of diastereoselective process to install
a challenging vicinal ternary/quaternary stereogenic centers. For
Scheme 2 outlines the proposed mechanism for the origin of
diastereoselectivity in this process. The formation of the active
rhodium(I) catalyst presumably occurs via reductive elimination
from the rhodium(III) pre-catalyst as part of a homocoupling
process in which the benzylzinc reagent functions as a sacrificial
reductant and is converted to the Wurtz-type side product 4
(Scheme 2A). The diastereoselective cross-coupling is thought
to involve a stereoconvergent process, which proceeds through
both a stereospecific and/or a stereoselective catalytic cycle
(Scheme 2B). For instance, in the stereospecific process, the
rhodium-catalyst complexes with allylic carbonate syn-5 to afford
syn-I, which permits oxidative addition with inversion of
configuration[14,15] to afford anti-ii that coordinate the benzyl
nucleophile to facilitate reductive elimination to furnish 6 with
excellent stereospecificity.
In contrast, the stereoselective
process generates the diastereomeric rhodium-allyl syn-ii, which
undergoes a rapid facial exchange of the metal via a conventional
 rearrangement to afford anti-ii and presumably alleviate
unfavorable steric interactions with the neighboring substituent.
The coordination of the nucleophile then promotes reductive
elimination in an analogous manner to afford the same
diastereoisomer, namely 6. Consequently, the rate of the facial
exchange from syn-ii to anti-ii is faster than reductive elimination,
which is supported by the fact that the reaction is not
Scheme 3.
Gram-scale reaction and cyclic diastereocontrol in the rhodium-catalyzed allylic
benzylation.
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10.1002/anie.202008071
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RESEARCH ARTICLE
[3] For metal-catalyzed allylic substitution of hard aryl nucleophiles,
see: Pd: a) J.-C. Fiaud, L. Aribi-Zouioueche, J. Organomet. Chem.
1985, 295, 383; b) T. Hayashi, A. Yamamoto, T. Hagihara, J. Org.
Chem. 1986, 51, 723; Pd and Ni: c) T. Hayashi, M. Konishi, K.-I.
Yokota, M. Kumada, J. Chem. Soc. Chem. Comm. 1981, 313; d) Y.
Takuma, N. Imaki, J. Mol. Catal. 1993, 79, 1; Ni: e) T. Hiyama, N.
Wakasa, Tetrahedron Lett. 1985, 26, 3259; f) K.-G. Chung, Y.
Miyake, S. Uemura, J. Chem. Soc., Perkin Trans. 1 2000, 2725; Co:
g) K. Mizutani, H. Yorimitsu, K. Oshima, Chem. Lett. 2004, 33, 7;
Co and Rh h) H. Yasui, K. Mizutani, H. Yorimitsu, K. Oshima,
Tetrahedron 2006, 62, 1410; Rh: i) B. L. Ashfeld, K. A. Miller, A.
J. Smith, K. Tran, S. F. Martin, J. Org. Chem. 2007, 72, 9018; Ir:
(j) A. Alexakis, S. E. Hajjaji, D. Polet, X. Rathgev, Org. Lett. 2007,
9, 3393.
[4] For metal-catalyzed allylic substitution of hard alkyl nucleophiles,
see: Ni: a) N. Nomura, T. V. RajanBabu, Tetrahedron Letters 1997,
38, 1713; Ir: b) J. Y. Hamilton, D. Sarlah, E. M. Carreira, Angew.
Chem. Int. Ed. 2015, 54, 7644.1(g),1(h)
[5] For metal-catalyzed allylic substitution of hard alkenyl
nucleophiles, see: Pd: Y. Hayasi, M. Riediker, J. S. Temple, J.
Schwartz, Tetrahedron Lett. 1981, 22, 2629.
instance, the rhodium-catalyzed benzylation of the allylic
benzoate 8, which is prepared from (–)-menthone, affords the
alkylation adducts 9/10 in 70% yield and with excellent
diastereocontrol for 9, albeit with modest regioselectivity (Scheme
3B). The direct and stereoselective construction of challenging
vicinal quaternary/ternary stereogenic centers in this manner
highlights the potential synthetic utility of this process.
Conclusion
In conclusion, we have developed a highly regio- and
diastereoselective benzylation of acyclic fluorinated allylic
carbonates under mild conditions using rhodium(III) chloride as
the pre-catalyst. This protocol offers a direct approach to the
installation of a privileged ternary benzyl scaffold, which is
ubiquitous in medicinal chemistry. The current method is a rare
example of the direct catalytic cross-coupling of a simple and
electronically unbiased toluene nucleophiles without the necessity
of modifying or pre-activating the aryl scaffold. The ability to
employ various sterically diverse and functionalized allylic
carbonates, along with a variety of benzyl nucleophiles, makes
this an attractive method. Notably, the configurational fluxionality
of the rhodium-allyl intermediate facilitated the development of a
diastereoselective variant for the construction of vicinal acyclic
stereocenters, and contiguous ternary/quaternary stereogenic
centers in a cyclic system. Overall, the associated challenges
with catalytic cross-couplings of benzyl nucleophiles, coupled with
the practicality of the pre-catalyst, make this an important addition
in this area.
[6] For metal-catalyzed allylic substitution of hard benzyl
nucleophiles, see: Pd: V. Rosales, J. L. Zambrano, M. Demuth, J.
Org. Chem. 2002, 67, 1167.
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Schlabach, P. I. Graham, J. H. Condra, L. Gotlib, M. K. Holloway,
J. Lin, I.-W. Chen, K. Vastag, D. Ostovic, P. S. Anderson, E. A.
Emini, J. R. Huff, Proc. Natl. Acad. Sci. USA 1994, 91, 4096; c)
R. M. Gulick, J. W. Mellors, D. Havlir, J. J. Eron, C. Gonzalez, D.
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E. A. Emini, J. A. Chodakewitz, N. Engl. J. Med. 1997, 337, 734;
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Acknowledgements
[8] For examples of allylic substitution of methylpyridines and
heterocycles, see: a) B. M. Trost, D. A. Thaisrivongs, J. Am. Chem.
Soc. 2008, 130, 14092; b) B. M. Trost, D. A. Thaisrivongs, J. Am.
Chem. Soc. 2009, 131, 12056; c) X.-J. Liu, S.-L. You, Angew.
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J. Hartwig, J. Am. Chem. Soc. 2011, 133, 12439; e) R. Murakami,
K. Sano, T. Iwai, T. Taniguchi, K. Monde, M. Sawamura, Angew.
Chem. Int. Ed. 2018, 57, 9465.
[9] For examples involving allylic substitution of chromium-arene
complexes, see: a) J. Zhang, C. Stanciu, B. Wang, M. M. Hussain,
C.-S. Da, P. J. Carroll, S. D. Dreher, P. J. Walsh, J. Am. Chem. Soc.
2011, 133, 20552; b) J. Mao, J. Zhang, H. Jiang, A. Bellomo, M.
Zhang, Z. Gao, S. D. Dreher, P. J. Walsh, Angew. Chem. Int. Ed.
2016, 55, 2526; For the diarylmethane nucleophiles, see: (c) S.-C.
Sha, J. Zhang, P. J. Carroll, P. J. Walsh, J. Am. Chem. Soc. 2013,
135, 17602.
We sincerely thank the National Sciences and Engineering
Research Council (NSERC) for a Discovery Grant and Queen’s
University for financial support. NSERC is also thanked for
supporting a Tier 1 Canada Research Chair (PAE) and for a
PGDS3 Scholarship (TBW).
We also acknowledge the
Government of Ontario for an Ontario Graduate Scholarship
(TBW). We sincerely thank GlaxoWellcome for a studentship
(RO) through the EPSRC-Pharma Managed Programme for
(Synthetic) Organic Chemistry.
Conflict of interest
[10] P. J. Moon, Z. Wei, R. J. Lundgren, J. Am. Chem. Soc. 2018, 140,
17418.
The authors declare no competing financial interest.
[11] H.-H. Zhang, J. J. Zhao, S. Yu, J. Am. Chem. Soc. 2018, 140,
16914.
[12] X.-J. Liu, C. Zheng, Y.-H. Yang, S. Jin, S.-L. You, Angew. Chem.
Int. Ed. 2019, 58, 10493.
Keywords: allylic substitution • benzylzinc nucleophile • hard
nucleophile • regio- and diastereoselective • rhodium(III) chloride
[13] a) M. R. Luzung, F. D. Toste, J. Am. Chem. Soc. 2003, 125, 15760;
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[14] For reviews on the rhodium-catalyzed allylic substitution reaction,
see: a) P. A. Evans, D. K. Leahy, in Modern Rhodium-Catalyzed
Organic Reactions, P. A. Evans, Ed., Wiley-VHC: Weinheim,
Germany, 2005; Ch. 10, p. 191-214; b) S. Oliver, P. A. Evans,
Synthesis 2013, 45, 3179; c) B. W. H. Turnbull, P. A. Evans, J.
Org. Chem. 2018, 83, 11463.
[1] For reviews on the transition metal-catalyzed allylic substitution
reaction, see: a) Z. Lu, S. Ma, Angew. Chem. Int. Ed. 2008, 47, 258;
b) M. L. Crawley, in Science of Synthesis: Stereoselective Synthesis
3, J. G. de Vries, P. A. Evans and G. A. Molander, Eds., Thieme:
Stuggart, Germany, 2011, p. 403; c) Q. Cheng, H.-F. Tu, C. Zheng,
J.-P. Qu, G. Helmchen, S.-L. You, Chem. Rev. 2019, 119, 1855.
[2] The nature of the nucleophiles in allylic substitution reactions is
defined by the pKa of the pronucleophile, in which a pKa <25
designates soft and a pKa >25 is a hard nucleophile.
[15] For mechanistic studies, see: P. A. Evans, J. D. Nelson, J. Am.
Chem. Soc. 1998, 120, 5581.
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10.1002/anie.202008071
Angewandte Chemie International Edition
RESEARCH ARTICLE
[16] P. A. Evans, D. Uraguchi, J. Am. Chem. Soc. 2003, 125, 7158.
[17] a) J. J. Low, W. A. Goddard III, J. Am. Chem. Soc. 1986, 108, 6115;
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der Boom, L. J. W. Shimon, H. Rozenberg, D. Milstein, J. Am.
Chem. Soc. 2000, 122, 7723, and pertinent references cited therein.
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Cox, J. Am. Chem. Soc. 1970, 92, 6389.
[19] For select examples of the transition metal-catalyzed cross-
coupling of benzylic organometallic reagents, see: a) M. Piber, A.
E. Jensen, M. Rottländer, P. Knochel, Org. Lett. 1999, 1, 1323; b)
G. Manolikakes, M. A. Schade, C. M. Hernandez, H. Mayr, P.
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I. Knowll, P. Knochel, Org. Lett. 2016, 18, 3626.
[20] For example, the use of [Rh(COD)Cl]2 or TpRh(C2H4)2 (see ref. 16)
under conditions similar to Table 1, entry 4 afford the benzylation
product 2a with similar efficiency and selectivity.
[21] For an example of the in situ reduction of high-valent rhodium(III)
to provide an active rhodium(I) catalyst, see: Z. She, Y. Wang, D.
Wang, Y. Zhao, T. Wang, X. Zheng, Z.-X. Yu, G. Gai, J. You, J.
Am. Chem. Soc. 2018, 140, 12566.
[22] a) T. Cochet, V. Bellosta, D. Roche, J.-Y. Ortholand, A. Greiner, J.
Cossy, Chem. Commun. 2012, 48, 10745; b) Y. Shibata, E. Kudo,
H. Sugiyama, H. Uekusa, K. Tanaka, Organometallics 2016, 35,
1547; c) J. S. Burman, S. B. Blakey, Angew. Chem. Int. Ed. 2017,
56, 13666.
[23] The use of heterocyclic benzylzinc nucleophiles via
transmetallation or direct zinc insertion did not afford any
appreciable amount of the desired allylic substitution products
except for the thiophene derivative; see SI for details.
[24] A. Metzger, M. A. Schade, P. Knochel, Org. Lett. 2008, 10, 1107.
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Entry for the Table of Contents
cat. RhCl3•3H2O
Ar
Debasis Pal, Timothy B. Wright, Ryan
O’Connor and P. Andrew Evans*
i
OCO2 PrF
ArCH2MgBr, ZnI2
R1
R1
Et2O, 0 °C to RT
R2
R2
Page No. – Page No.
16 h
R1/R2 = H, Me,
45-87%
b/l and dr
Regio-
Rhodium-Catalyzed
and
Diastereoselective
Allylic
iPr, OR, etc.
40 examples
up to ≥19:1
Substitution with Unstabilized Benzyl
Nucleophiles
• Bench Stable RhCl3•3H2O • Benzyl Nucleophiles
• Alkyl Electrophiles • Regioselective • Diastereoselective
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