Migratory Reductive Acylation between Alkyl Halides or Alkenes and Alkyl Carboxylic Acids by Nickel Catalysis

Article abstract of DOI:10.1021/acscatal.9b00521

A mild migratory reductive acyl cross-coupling has been achieved through NiH-catalyzed chainwalking and subsequent cross-coupling from two abundant starting materials, alkyl bromides, and carboxylic acids. This strategy allows the direct acylation of the

Full text of DOI:10.1021/acscatal.9b00521

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Letter
Migratory Reductive Acylation between Alkyl Halides or
Alkenes and Alkyl Carboxylic Acids by Nickel Catalysis
Jun He, Peihong Song, Xianfeng Xu, Shaolin Zhu, and You Wang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00521 • Publication Date (Web): 11 Mar 2019
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Migratory Reductive Acylation between Alkyl Halides or Alkenes and Alkyl Carboxylic Acids by
Nickel Catalysis
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Jun He, Peihong Song, Xianfeng Xu, Shaolin Zhu*, and You Wang*
State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China.
ABSTRACT: A mild migratory reductive acyl cross-coupling has been achieved through NiH-catalyzed chainwalking and
subsequent cross-coupling from two abundant starting materials, alkyl bromides and carboxylic acids. This strategy
3
allows the direct acylation of the benzylic sp C–H bond with high yield as a single regioisomer. As an alternative, the
alkyl bromide could be replaced by the proposed olefin intermediate and commercially available n-PrBr to achieve a
remote hydroacylation process.
KEYWORDS: acylation, C–H activation, isomerization, migration, nickel, reductive cross-coupling
Reductive
cross-electrophile
coupling,1-3
direct
halides or olefins are generally more widely available
13
coupling of two shelf-stable electrophiles, typically
involving the abundant alkyl halides , has received
than the region-specific ones (some activated halides,
such as benzylic halides, are not stable enough and have
the issue of chemoselective control in reductive cross-
coupling (homo- vs cross-coupling)), strategy to produce
the same site-specific ketone from any isomer of alkyl
halides or olefins (or isomeric mixtures) turns out to be
attractive in organic synthesis (Figure 1a, bottom). If
chainwalking, enabled by NiH generated in situ through
β-hydride elimination of an alkylnickel species derived
from the alkyl halide starting material, could take place
before the selective acyl cross-coupling, migratory
4
considerable attention in recent years owing to the
benefit of circumventing the synthesis of organometallic
reagents which have limited stability and commercial
availability. This attractive strategy allows direct
formation of C–C bonds at the halogen-bearing carbon
of alkyl halides – the ipso carbon; thus, new bonds that
can be introduced are limited to the position of the
halogen. Hence, site-selective cross-coupling at different
positions other than this carbon along the hydrocarbon
chain of alkyl halides would have considerable synthetic
potential and would be complementary to the current
3
acylation could happen potentially at a distal, inert sp
C–H position and the sensitive ketone group could be
preserved under these mild reaction conditions (Figure
1b). Here we describe our development of such an
acylation reaction based on a migratory reductive cross-
electrophile coupling strategy.
3
coupling strategy. The recently emerging sp C–H
functionalization,5 would undoubtedly be an ideal
alternative solution. However, to ensure good reactivity
and regioselectivity, most of these processes need a
polar directing group in the proximity and this limits
their application in organic synthesis. A synergistic
6
combination of metal-hydride catalyzed chainwalking
and transition-metal-catalyzed cross-coupling provides
7-11
an attractive approach to this goal.
Catalytic reductive acyl cross-coupling from carboxylic
acid derivatives is an efficient approach for ketone
3a
3b,3h
3c-3f
synthesis. Previously, Mukaiyama, Weix,
Gong,
3g
and Reisman reported elegant work concerning nickel-
12
catalyzed
reductive acylation reactions from two
abundant feedstock chemicals, alkyl halides and
carboxylic acid derivatives (Figure 1a, top). This
conventional strategy requires the regio-specific starting
material of alkyl halide. In contrast, unrefined alkyl
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a) Reductive strategies for retrosynthesis of ketone
X
Table 1. Variation of Reaction Parameters.
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5
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5
5
5
5
5
5
5
6
(conventional)
ling
2
p
R1
R
acylation at original site
u
()n+1
o
c
so-
ip
O
R
regio-specific alkylhalide
O
carboxylic acid
or derivative
Ni
Mn/Zn
+
2
R
R1
R
Y
()n+1
m
ig
r-
X
()n
co
up
R1
R2
ketone
selective acylation
at remote site
ling
(
this work)
unrefined alkylhalide
mixtures
b) Design: migratory reductive acylation between carboxylic acid and alkyl bromide
O
alkyl
O
Br
cat. Ni/L
Zn
Ar
R
+
()n
R
alkyl
OH
Ar
()n+1
0
1
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alkyl bromide
cat. Ni/L Zn
carboxylic acid
migratory acylation
Boc2O activation
O
O
BocO
Ar ()n Ni H
R
chainwalking
Ni
Ni
alkyl
R
alkyl
OBoc
R
Ar
()n+1
Ar
()n+1
NiH generated in situ
alkylnickel species
selective-coupling
aYields determined by GC using n-dodecane as the
internal standard, the yield in parentheses is the isolated
yield and is an average of two runs (0.20 mmol scale).
Figure 1. Design plan: Migratory reductive acyl cross-
coupling for the synthesis of ketone.
Based on Gong’s reductive ipso-acylation conditions,3f
we began our investigation by studying the coupling of
1-bromo-4-phenylbutane (1a) with 3-phenylpropanoic
acid (2a) (Table 1). After extensive examination of a
range of nickel sources, ligands, reductants, additives,
solvents, and a range of other parameters (for detailed
optimization studies, see the Supporting Information, SI),
b
Regioselectivities (rr) were determined by GC and GCMS
c
d
e
analysis. The major product was 3A. Without NaI. With or
without NaI.
With the optimal conditions in hand, we proceeded to
evaluate the substrate scope of both carboxylic acids and
alkyl bromides. As shown in Table 2, the regioselectivity
in general, is excellent and only one regioisomer (the
benzylic isomer) is observed in all cases. For the
carboxylic acid substrate (Table 2a), a myriad of primary
we found that a combination of NiBr
substituted bipyridine as the metal/ligand choice, Zn
dust as the reductant, MgCl /NaI as the additive, and
Boc O as the acid activation reagent (an acid anhydride
2
·3H O/C6-methyl
2
2
(
2a–2j) and secondary (2k–2p) aliphatic carboxylic acids
2
all deliver the corresponding benzylic acylation products
in good to excellent yields. Under these mild conditions,
a wide range of functional groups, including an aryl
fluoride (2b), ethers (2c, 2o), an alkyl chloride (2g), and
esters (2h, 2i) are well tolerated. Gratifyingly, carboxylic
acids bearing heterocyclic motifs, such as a furan (2d), a
thiophene (2e), and an indole (2f) are also competent
coupling partners. Moreover, a carboxylic acid with an α-
stereocenter could participate in this reaction with full
preservation of this adjacent stereocenter (2l). For the
alkyl bromide substrate, both primary (Table 2a) and
secondary (Table 2b) alkyl bromides underwent this
transformation smoothly. Notably, when an isomeric
mixture of alkyl bromides (e.g. equimolar amounts of 1a
and 1y) was used, only one single regioconvergent
benzylic acylation product (3a) was observed. Moreover,
the efficacy of chainwalking was not hindered by the
beginning position of the C−Br bond (1a versus 1q).
Substrates containing both electron-withdrawing (1r–1u)
and electron-donating (1v) substituents on the remote
aryl ring are suitable for this transformation. Additionally,
heterocycle substrates, such as those containing a furan
(1w) or a thiophene (1x) in place of the aryl group, are
likewise suitable for this reaction.
is formed in situ) in DMA at 30 °C provides the desired
migratory acylation product (3a) in 70% isolated yield as
essentially a single regioisomer (entry 1). Use of other
Ni(II) precatalysts, such as NiBr
diminished yields (entries 2, 3). It is particularly
2
or NiI
2
leads to
interesting that no migratory but only the ipso-coupling
product (3A) is observed when Ni(cod) is used (entry 4).
2
14
Replacement of L1 by the parent bipyridine ligand also
results in only the ipso-acylation product (entry 5),3
demonstrating the critical role of C6-alkyl substituents in
the ligand backbone. Changing the reductant to a
manganese compound results in a lower yield (entry 6);
and THF is not a suitable solvent (entry 7). The addition
of sodium iodide dramatically improves the reactivity
(
entry 1 versus entry 8). In the absence of NaI, the alkyl
bromide (1a) provides the desired product (3a) in lower
yield while the corresponding alkyl iodide improves the
reaction efficiency, indicating that the role of NaI is to
generate the more reactive alkyl iodide in situ from the
alkyl bromide (entries 8, 9). Notably, the alkyl chloride
was unreactive under current reaction conditions
regardless of the presence of NaI (entry 10). Control
experiments show that the additive MgCl
2
and the
activation reagent Boc O are essential for the reaction to
2
15
occur (entries 11, 12).
Table 2. Migratory Acyl Coupling: Scope of the Alkyl Bromide and Carboxylic Acid.a
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aUnder each product is the percentage of isolated yield and regioselectivity (rr) (0.20 mmol scale, average of two runs);
regioselectivities were determined by GC and GCMS analysis.
The current migratory acyl coupling strategy could also
be extended to readily accessible alkene substrates
through the addition of a stoichiometric quantity of n-
PrBr (n-PrBr is more cheap and stable compared with
tolerated. Notably, heteroaromatic substrates, such as
those containing a furan (4d), a thiophene (4e), a pyrole
(4f), or a pyridine-linked aryl ring (4g) in place of the aryl
group, are compatible with the reaction. As expected,
E/Z mixtures of unactivated internal olefins (4h−4m) are
also suitable partners, regardless of the starting position
of the C=C bond. Moreover, olefins with a branched alkyl
chain, including an internally branched alkene (4n), a 1,1-
disubstituted alkene (4o), or a trisubstituted internal
alkene (4p), could also afford the desired migratory
products in moderate yields revealing that steric
constraints can be overcome. Finally, an estrone-derived
styrene (4r) is also a suitable partner to undergo
11h
hydrosilane), which is used as an extra hydride source
to generate, via β-H elimination, the NiH species
required for the chainwalking process. Notably,
migratory acylation of n-PrBr is not observed in this case.
As depicted in Table 3, a wide range of alkenes are
suitable substrates, providing the corresponding remote
hydroacylation products in good to excellent yield as
single regioisomers. Both terminal olefins (4a−4g) and
unactivated internal olefins (4h−4m) are generally
suitable, and a diverse range of electron deficient (4c,
16
hydroacylation under these conditions.
4
i−4j) and electron-rich (4h) remote arenes are
a
Table 3. Remote Hydroacylation: Scope of the Alkene and Carboxylic Acid.
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Yield and rr are as defined in Table 2, regioselectivities (rr) reported as >95:5 were determined by HNMR analysis of the
crude reaction mixture.
This transformation is highly regioconvergent, and
could be used for the conversion of isomeric mixtures of
olefins, generally more widely available than the pure
isomers, into value-added specialty chemicals. As shown
in Scheme 1a, starting from equimolar amounts of three
olefins - an isomeric mixture - on a 10 mmol scale, the
benzylic acylation product 5b can be obtained as a
single regioisomer.
arylation,11h a competition experiment was carried out in
the presence of both a carboxylic acid and an aryl
bromide (Scheme 1d), and migratory acylation product
(3a, 24% yield) was favorable relative to arylation
product (7, 5% yield). This indicates that the cross-
coupling rate of carboxylic acid (acylation) is faster than
that of aryl bromide (arylation).
To shed light on the migratory acylation process, some
preliminary experiments were carried out. Consistent
with our previous reports,
olefin isomers could be observed in the usual reaction
conditions both in the presence and absence of the
carboxylic acid, indicating chainwalking process is
unrelated to acyl coupling (see SI for details).
Furthermore, when deuterated PrBr-d
b), as its proposed role, transformation of deuterium
from alkyl bromide ( PrBr-d
incorporation of deuterium at all positions along the
hydrocarbon chain of the remote hydroacylation
products (5a-D) were observed. Moreover, when a
mixture of equimolar amounts of alkyl bromide 1a and
alkene 4k were subjected to the coupling conditions,
formation of both coupling products 3a and 5k was
observed (Scheme 1c), providing additional evidence of
fast dissociation and reassociation of the NiH/NiD
11h
a significant amount of
n
7
is used (Scheme
1
n
7
)
to olefin 4a and
Scheme 1. Regioconvergent, Isotopic, Crossover, and
Competition Experiments.
17
species
from olefins during chainwalking process.
Finally, to compare the reactivity of acylation with
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In summary, using a ubiquitous alkyl carboxylic acid
directly as the acylation reagent, we have developed a
mild nickel-catalyzed migratory acylation reaction from
alkyl bromide or olefin substrates. This strategy provides
2007, 63, 1146–1153. (b) Czaplik, W. M.; Mayer, M.; Jacobi von
1
2
3
4
5
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Wangelin, A. Direct Cobalt-Catalyzed Cross-Coupling Between
Aryl and Alkyl Halides. Synlett 2009, 2009, 2931–2934. (c)
Amatore, M.; Gosmini, C. Direct Method for Carbon–Carbon
Bond
Cobalt-Catalyzed Alkylation of Aryl Halides. Chem. – Eur. J.
010, 16, 5848–5852. (d) Everson, D. A.; Shrestha, R.; Weix, D. J.
Formation:
The
Functional
Group
Tolerant
3
an attractive approach to remote sp C–H acylation
under mild conditions with broad substrate scope and
excellent regioselectivity. The asymmetric version of the
current transformation is currently in progress and will
be reported in due course.
2
Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with
Alkyl Halides. J. Am. Chem. Soc. 2010, 132, 920–921. (e) Yu, X.;
Yang, T.; Wang, S.; Xu, H.; Gong, H. Nickel-Catalyzed Reductive
Cross-Coupling of Unactivated Alkyl Halides. Org. Lett. 2011, 13,
1
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138–2141. (f) Everson, D. A.; Jones, B. A.; Weix, D. J. Replacing
ASSOCIATED CONTENT
Supporting Information
Conventional Carbon Nucleophiles with Electrophiles: Nickel-
Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides.
J. Am. Chem. Soc. 2012, 134, 6146–6159. (g) Wang, S.; Qian, Q.;
Gong, H. Nickel-Catalyzed Reductive Coupling of Aryl Halides
with Secondary Alkyl Bromides and Allylic Acetate. Org. Lett.
The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acscatal.xxx.
2
012, 14, 3352–3355. (h) Leon, T.; Correa, A.; Martin, R. Ni-
Full experimental data, details on methods and starting
materials, and copies of spectral data (PDF)
Catalyzed Direct Carboxylation of Benzyl Halides with CO . J.
Am. Chem. Soc. 2013, 135, 1221–1224. (i) Cherney, A. H.;
Kadunce, N. T.; Reisman, S. E. Catalytic Asymmetric Reductive
Acyl Cross-Coupling: Synthesis of Enantioenriched Acyclic α,α-
Disubstituted Ketones. J. Am. Chem. Soc. 2013, 135, 7442–7445.
2
AUTHOR INFORMATION
Corresponding Author
(
j) Molander, G. A.; Traister, K. M.; O’Neill, B. T. Reductive Cross-
Coupling of Nonaromatic, Heterocyclic Bromides with Aryl and
Heteroaryl Bromides. J. Org. Chem. 2014, 79, 5771–5780. (k)
Cherney, A. H.; Reisman, S. E. Nickel-Catalyzed Asymmetric
Reductive Cross-Coupling Between Vinyl and Benzyl
Electrophiles. J. Am. Chem. Soc. 2014, 136, 14365–14368. (l)
Ackerman, L. K.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J.
*
E-mail: wangyou@nju.edu.cn, shaolinzhu@nju.edu.cn.
Author Contributions
J.H, S.Z, and Y.W. designed the project. J.H. performed the
experiments. P.S. and X.X. synthesized some of the
substrates. All authors co-wrote the manuscript, analyzed
the data, discussed the results and commented on the
manuscript.
Cobalt
Co-Catalysis
for
Cross-Electrophile
Coupling:
Diarylmethanes from Benzyl Mesylates and Aryl Halides. Chem.
Sci. 2015, 6, 1115–1119. (m) Kadunce, N. T.; Reisman, S. E.
Nickel-Catalyzed
Asymmetric
Reductive
Cross-Coupling
Notes
between Heteroaryl Iodides and α-Chloronitriles. J. Am. Chem.
Soc. 2015, 137, 10480–10483. (n) Zhang, P.; Le, C. C.; MacMillan,
D. W. C. Silyl Radical Activation of Alkyl Halides in
Metallaphotoredox Catalysis: A Unique Pathway for Cross-
Electrophile Coupling. J. Am. Chem. Soc. 2016, 138, 8084–8087.
(o) Poremba, K. E.; Kadunce N. T.; Suzuki, N.; Cherney, A. H.;
Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-
Coupling to Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017,
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Support was provided by “1000-Youth Talents Plan”, NSFC
(
21702102, 21772087, 21822105).
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(
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