Nickel-catalyzed allylic alkylation with diarylmethane pronucleophiles: Reaction development and mechanistic insights

Article abstract of DOI:10.1002/anie.201507494

Palladium-catalyzed allylic substitution reactions are among the most efficient methods to construct C-C bonds between sp³-hybridized carbon atoms. In contrast, much less work has been done with nickel catalysts, perhaps because of the different mechanisms of the allylic substitution reactions. Palladium catalysts generally undergo substitution by a "soft"-nucleophile pathway, wherein the nucleophile attacks the allyl group externally. Nickel catalysts are usually paired with "hard" nucleophiles, which attack the metal before C-C bond formation. Introduced herein is a rare nickel-based catalyst which promotes substitution with diarylmethane pronucleophiles by the soft-nucleophile pathway. Preliminary studies on the asymmetric allylic alkylation are promising. Just a softy: Contrary to what would be predicted, organosodium nucleophiles derived from diarylmethane pronucleophiles are shown to behave as soft nucleophiles in nickel-catalyzed allylic substitution reactions. This general reaction is demonstrated to proceed through a double inversion pathway. A promising asymmetric version is presented.

Full text of DOI:10.1002/anie.201507494

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International Edition: DOI: 10.1002/anie.201507494
German Edition: DOI: 10.1002/ange.201507494
Asymmetric Catalysis
Nickel-Catalyzed Allylic Alkylation with Diarylmethane
Pronucleophiles: Reaction Development and Mechanistic Insights
Sheng-Chun Sha, Hui Jiang, Jianyou Mao, Ana Bellomo, Soo A. Jeong, and Patrick J. Walsh*
Abstract: Palladium-catalyzed allylic substitution reactions
À
are among the most efficient methods to construct C C bonds
between sp3-hybridized carbon atoms. In contrast, much less
work has been done with nickel catalysts, perhaps because of
the different mechanisms of the allylic substitution reactions.
Palladium catalysts generally undergo substitution by a “soft”-
nucleophile pathway, wherein the nucleophile attacks the allyl
group externally. Nickel catalysts are usually paired with
À
“hard” nucleophiles, which attack the metal before C C bond
formation. Introduced herein is a rare nickel-based catalyst
which promotes substitution with diarylmethane pronucleo-
philes by the soft-nucleophile pathway. Preliminary studies on
the asymmetric allylic alkylation are promising.
M
etal-catalyzed allylic substitution reactions remain one of
3
3
À
the most efficient approaches to construct C(sp ) C(sp )
bonds. Among transition-metal catalysts used in allylic
substitutions, palladium has met with the greatest success.
Many enantioselective palladium catalysts have been devel-
oped and elegantly applied to the synthesis of natural
products.[1–6]
Scheme 1. Mechanism of transition metal catalyzed allylic substitution.
catalyzed AAAs has attracted attention.[11–14] In contrast to
palladium-catalyzed allylic substitutions, which have been
extensively used with soft nucleophiles, nickel catalysts have
generally been paired with hard nucleophiles, such as
Grignard reagents and other main-group organometal-
lics.[6,15–29] An advantage of nickel catalysts over palladium is
their lower cost.
Early examples of nickel-catalyzed allylic substitution
reactions include the work from Hiyama and co-workers who
used (S,S)-chiraphos (Scheme 2a).[15] In a clever application
of achiral ligands to optimize enantioselectivity,[30] Hoveyda
and co-workers used the [(S,S)-chiraphos]/Ni catalyst in the
presence of PR3 and Grignard reagents to develop a synthesis
of enol ethers and ketones with high ee values (Sche-
me 2b).[16] Consiglio and co-workers determined that
EtMgBr attacked the nickel center (transmetallation) first
with subsequent reductive elimination to form the product
(Scheme 2c).[6,19] They found excellent enantioselectivity was
obtained with EtMgBr, but MeMgBr and (nPr)MgBr exhib-
ited significantly lower enantioselectivities (Scheme 2c).[18]
Unlike hard nucleophiles, soft nucleophiles in nickel-cata-
lyzed AAAs generally exhibit poor enantioselection
(Scheme 2d).[31]
The mechanisms of allylic substitution reactions pro-
moted by a variety of catalysts with different nucleophiles
have been investigated.[1,2] From these studies, trends in
reaction pathways have emerged and are now well accepted.[1]
The reaction pathway has been found to depend on the nature
of the nucleophile.[1] In general, anionic nucleophiles (NuÀ)
are divided into two classes based on the pKa value of the
À
pronucleophile (Nu H): carbon nucleophiles derived from
pronucleophiles with pKa values less than 25 are considered
stabilized or “soft” nucleophiles, while those from pronu-
cleophiles with pKa values greater than 25 are categorized as
unstabilized or “hard” nucleophiles. The difference between
these two classes is that soft nucleophiles attack the p-allyl
moiety externally while hard nucleophiles bind directly to the
À
metal center (by transmetallation) before C C bond forma-
tion with the allyl group (Scheme 1). Importantly, it has
proven easier to control enantioselectivity with soft nucleo-
philes in palladium-catalyzed asymmetric allylic alkylations
(AAAs) rather than with hard nucleophiles.[1,3,7–10] Thus
expanding the scope of soft nucleophiles in palladium-
Our interest in the Tsuji–Trost reaction has been to
expand the scope with respect to soft nucleophiles. We
recently demonstrated that diarylmethane pronucleophiles
behave as soft nucleophiles in palladium-catalyzed allylic
substitutions under basic conditions, thus raising the pKa limit
of soft nucleophiles from 25 to at least 32.[13] In the current
study, we asked 1) if diarylmethane pronucleophiles were
suitable substrates for nickel-catalyzed allylic substitutions?
2) if they would react through the hard or soft-nucleophile
[*] S.-C. Sha, H. Jiang, J. Mao, A. Bellomo, S. A. Jeong, P. J. Walsh
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for
High-Throughput Experimentation, Department of Chemistry
University of Pennsylvania
231 South 34th Street, Philadelphia, PA 19104-6323 (USA)
E-mail: pwalsh@sas.upenn.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507494.
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choice in our palladium-catalyzed version of this reac-
tion.[13,14] We then examined the nickel to ligand ratio,
however, attempts to reduce the ligand loading led to lower
yields (entries 2 and 3). DME proved to be a better solvent
than THF, CPME (cyclopentyl methyl ether), 1,4-dioxane,
and 2-MeTHF (entry 1 versus entries 4–7). Nickel sources
such as NiCl2 and NiBr2 resulted in decreased yields (entries 8
and 9 versus entry 1). Finally, 88% yield of the isolated
product was obtained with a 7.5 mol% nickel loading
(entry 10).
With the optimized reaction conditions (Table 1,
entry 10), we probed the scope with respect to the diphenyl-
methane derivatives 1 (Table 2). The reaction with 4-fluoro
diphenylmethane (1b) afforded the desired product 3ba in
Table 2: Scope with respect to the diarylmethanes in allylic alkylation
reactions.[a]
Scheme 2. Previous nickel-catalyzed asymmetric allylic alkylation reac-
tions. COD=1,5-cyclooctadiene, THF=tetrahydrofuran.
Entry Ar
Base
1/base/2a Product Yield [%][b]
1
2
3
4
5
6
Ph
KHMDS
KHMDS
NaHMDS 1:5:3
NaHMDS 1:5:3
KHMDS
KHMDS
1:5:3
1:4:3
3aa
3ba
3ca
3da
3ea
3 fa
88
67
98
89
61
65
4-C6H4F
4-C6H4Cl
4-C6H4Br
4-C6H4Me
2-C6H4Me
pathway? and 3) if highly enantioselective versions would be
possible? Herein, we communicate that these basic nucleo-
philes react through the soft-nucleophile pathway and we
disclose a promising preliminary nickel-catalyzed AAA.
We initiated our study of the nickel-catalyzed allylic
substitution by examining 24 of the most common mono- and
bidentate phosphine ligands with [Ni(COD)2], KN(SiMe3)2,
and the Boc-protected allyl 2a (see the Supporting Informa-
tion for details). DPPF was the most promising ligand [72%
1H NMR assay yield (AY); Table 1, entry 1], thus outper-
forming van Leeuwenꢀs Xantphos, which was the ligand of
1:5:3
1:5:3
7
LiOtBu
1:1.5:1.2
3ga
83
[a] Reactions conducted on a 0.1 mmol scale. [b] Yield of product
isolated after chromatographic purification. HMDS=hexamethyldisil-
azide.
67% yield (entry 2). With 4-chloro- and 4-bromodiphenyl-
methane NaN(SiMe3)2 proved to be a better base, thus
providing products 3ca (98%) and 3da (89%), respectively
(entries 3 and 4). It is remarkable that generation of the Ni/p-
Table 1: Optimization of allylic alkylation with diphenylmethane (1a).[a]
À
allyl species is faster than the oxidative addition of C Cl and
À
C Br bonds under our reaction conditions. 4-Methyl diphe-
nylmethane gave 3ea in 61% yield (entry 5). Sterically
hindered 2-methyl diphenylmethane reacted to provide 3 fa
in 65% yield (entry 6). Fluorene derivatives are interesting
components in materials science and photochemistry.[32]
Because of the increased acidity of fluorene, 1.5 equivalents
of LiOtBu could be used with 1.2 equivalents of 2a to provide
3ga in 83% yield (entry 7). Unfortunately, because of the
higher pKa value of 4-methoxy diphenylmethane, poor yields
were obtained despite additional optimization.
We next turned our attention to biologically relevant
heterocyclic pronucleophiles (4a–f; Table 3). Pleasingly,
a lower catalyst loading could be applied to these more
acidic pronucleophiles. Pyridine-containing diarylmethanes
are useful in drug discovery.[33] 2-Benzylpyridine underwent
coupling under the standard reaction conditions to afford 5aa
in 91% yield (entry 1). Likewise, 3- and 4-benzylpyridine
provided desired products 5ba (91%) and 5ca (93%),
respectively (entries 2 and 3). 3,3’-Dipyridylmethane was
Entry
Ni Source
Ni/DPPF
[mol %]
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
[Ni(COD)2]
[Ni(COD)2]
[Ni(COD)2]
[Ni(COD)2]
[Ni(COD)2]
[Ni(COD)2]
[Ni(COD)2]
NiCl2
5:10
5:5
DME
DME
DME
THF
CPME
1,4-dioxane
2-Me-THF
DME
DME
DME
72
39
46
5:7.5
5:10
5:10
5:10
5:10
5:10
5:10
7.5:15
46
<5
<5
52
35
NiBr2
[Ni(COD)2]
51
90 (88)[c]
[a] Reactions conducted on a 0.1 mmol scale. [b] Yields determined by
1H NMR spectroscopy of the crude reaction mixtures. [c] Yield of the
product isolated after chromatographic purification. Boc=tert-butoxy-
carbonyl, DME=1,2-dimethoxyethane, DPPF=1,1’-bis(diphenylphos-
phino)ferrocene.
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Table 3: Scope of heterocyclic diarylmethanes in allylic alkylation
product 8aa was isolated in 90% yield [Eq. (1)]. Similarly, 2-
(1-phenylethyl)pyridine (7b) also underwent allylation to
form 8ba in 92% yield [Eq. (2)]. These initial results bode
well for further development of nickel-catalyzed allylic
substitutions.
reactions.[a]
Entry Ar
Ar’
Base
4/base/2a Product Yield [%][b]
1
2
3
4
5
2-Py
Ph
Ph
Ph
NaHMDS 1:2:1.2
NaHMDS 1:3:1.2
5aa
5ba
5ca
5da
5ea
91
91
93
90
82
3-Py
4-Py
3-Py
LiHMDS
1:2:1.2
1:3:1.2
3-Py LiHMDS
2-thienyl Ph
NaHMDS 1:2:1.2
6
LiHMDS
1:3:1.2
5 fa
81
[a] Reactions conducted on a 0.1 mmol scale. [b] Yield of product
isolated after chromatographic purification.
also a viable substrate, thus generating 5da in 90% yield
(entry 4). Thiophene-containing products are important in
agrochemicals and pharmaceuticals.[34] 2-Benzylthiophene
rendered the coupling product 5ea in 82% yield (entry 5).
Xanthene derivatives are building blocks for the synthesis of
dyes.[32] Application of our standard reaction conditions to
xanthene furnished 5 fa in 81% yield (entry 6).
Diallylation to construct quaternary carbon centers was
achieved using an excess amount of the allyl electrophile with
5 mol % nickel and 10 mol % DPPF (4a–c, 4e,f, and 1g;
Table 4). Presumably, the products could be cyclized using
ring-closing metathesis.[35] 2-Benzyl, 3-benzyl, and 4-benzyl
As outlined in the introduction, nickel-catalyzed allylic
substitutions with hard nucleophiles, such as Grignard
reagents, undergo reactions predominantly by transmetalla-
tion and subsequent reductive elimination (Scheme 1).[6,19]
The nucleophiles employed in Tables 2–4 are organopotas-
sium, organosodium, and organolithium derivatives, which
would be predicted to undergo reaction through the hard-
nucleophile pathway. To probe this key step, we initially
explored cyclic 2b to determine if it was viable in nickel-
catalyzed allylic substitution reactions. By employing the
electrophile 2b with NaN(SiMe3)2 the substitution product
9db was afforded in 91% yield [Eq. (3)].
Table 4: Scope of diallylation of diarylmethanes.
Entry Ar
Ar’ Base
4/base/2a Product Yield [%][b]
1
2
3
4
2-Py
3-Py
4-Py
Ph KHMDS
Ph KHMDS
Ph KHMDS
1:5:3
1:5:3
1:5:3
1:5:3
6aa
6ba
6ca
6da
84
78
75
83
To determine if the nucleophile derived from 3,3’-
dipyridylmethane (4d) and NaN(SiMe3)2 behaves as a hard
or soft nucleophile, we employed the stereoprobe rac-2c
[Eq. (4)]. If the reaction proceeds with a single inversion, the
trans diastereomer will predominate, thus leading to the
conclusion that reaction took place through the hard-nucle-
ophile pathway (Scheme 1). In contrast, formation of the
cis product would indicate a double inversion, where the
nucleophile attacks the allyl moiety opposite the nickel (soft-
nucleophile pathway, Scheme 1). Conducting the allylic sub-
stitution under the standard reaction conditions led to
formation of the product 10dc in 89% yield [Eq. (4)].
Analysis of the 1H NMR coupling constants of the product[14]
led to its assignment as the cis diastereomer, thus arising from
a double inversion pathway. The stereochemistry of the
product, therefore, indicates that the reaction proceeded by
nucleophilic attack directly on the Ni/allyl species (soft-
nucleophile pathway). It is surprising that this basic nucleo-
2-thienyl Ph KHMDS
5
6
KOtBu
1:5:3
6ea
6 fa
90
89
NaHMDS 1:5:3
[a] Reactions conducted on a 0.1 mmol scale. [b] Yield of product
isolated after chromatographic purification.
pyridine all gave good yields (75–84%, entries 1–3). 2-
Benzylthiophene provided the diallylation product 6da in
83% yield under the standard reaction conditions. Fluorene
and xanthene were also good substrates, thus leading to
products in 89–90% yield (entries 5 and 6).
After exploring the diallylation, we wanted to determine
À
if other tertiary C H moieties could be allylated using our
method. Thus, with triphenylmethane (7a), the allylated
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phile behaves as a soft nucleophile with catalysts derived from
Acknowledgments
either nickel or palladium.[13]
We thank the National Institutes of Health (NIGMS 104349)
and National Science Foundation (CHE-1464744) for finan-
cial support. H.J. thanks China Scholarship Council
[201406350156] for financial support.
Keywords: allylic compounds · asymmetric catalysis ·
cross-coupling · nickel · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 1070–1074
Angew. Chem. 2016, 128, 1082–1086
The AAA with diarylmethane pronucleophiles is chal-
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with 3 equivalents of base, 3,3’-dipyridylmethane, and
2 equivalents of 2b in the nickel-catalyzed AAA. We
identified a Josiphos derivative (L1; Scheme 3) as the best
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hit with 75% assay yield and 70% ee. After optimization (see
the Supporting Information), we were able to obtain 9db in
91% yield with 92% ee (Scheme 3a). Likewise, with the
seven-membered ring (n = 2), we obtained the product 9dd in
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which indicates the nucleophile reacts by the soft-nucleophile
pathway (Scheme 3b).
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