Synergistic Visible-Light Photoredox/Nickel-Catalyzed Synthesis of Aliphatic Ketones via N-C Cleavage of Imides

Article abstract of DOI:10.1021/acs.orglett.7b00989

An electrophilic, imide-based, visible-light-promoted photoredox/Ni-catalyzed cross-coupling reaction for the synthesis of aliphatic ketones has been developed. This protocol proceeds through N-C(O) bond activation, made possible through the lower activation energy for metal insertion into this bond due to delocalization of the lone pair of electrons on the nitrogen by electron-withdrawing groups. The operationally simple and mild cross-coupling reaction is performed at ambient temperature and exhibits tolerance for a variety of functional groups.

Full text of DOI:10.1021/acs.orglett.7b00989

Letter
pubs.acs.org/OrgLett
Synergistic Visible-Light Photoredox/Nickel-Catalyzed Synthesis of
Aliphatic Ketones via N−C Cleavage of Imides
Javad Amani, Rauful Alam, Shorouk Badir, and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: An electrophilic, imide-based, visible-light-
promoted photoredox/Ni-catalyzed cross-coupling reaction
for the synthesis of aliphatic ketones has been developed.
This protocol proceeds through N−C(O) bond activation,
made possible through the lower activation energy for metal
insertion into this bond due to delocalization of the lone pair
of electrons on the nitrogen by electron-withdrawing groups.
The operationally simple and mild cross-coupling reaction is
performed at ambient temperature and exhibits tolerance for a
variety of functional groups.
group diversity could be introduced into the synthesis of alkyl
cylation is one of the most powerful protocols for the
Achemoselective formation of ketones, which are among ketones.
Recently, our laboratory developed a novel visible-light-
the most fundamental and widespread functional groups in
nature.1 Among transition-metal-catalyzed acylation strategies,
Suzuki coupling has become an increasingly essential protocol
to forge acyl−carbon bonds.2 Although the scope of the
electrophilic partner in the acylative Suzuki coupling has been
extended to different types of carboxylic acid derivatives, the
use of acyl donors such as anhydrides,3 active esters,4 thiol
esters,5 and amides6 is particularly attractive compared with acyl
halides because these functional groups are generally more
stable, nontoxic, and more widely available.
In contrast to the relative ease of carrying out transition-
metal-catalyzed acylation using more highly electrophilic
carboxylic acid derivatives such as carboxylic acid halides,
anhydrides, and thioesters, cross-coupling via N−C bond
oxidative addition of amides to generate acylmetal intermedi-
ates is inherently more challenging because of the strong
conjugation interaction between the nN and πC*O orbitals in
amides, which engenders a higher barrier for metal insertion
into the C(O)−N bond.7 The disruption of this conjugation by
steric effects that increase the nonplanarity about the C−N
amide bond or the delocalization of the lone pair of electrons
on the nitrogen by electron-withdrawing groups results in a
lower barrier for the formation of the acylmetal intermediate.6
Although significant advances have taken place in transition-
metal-catalyzed cross-couplings of amides with arylboronic
acids, alkylation reactions have been restricted to the use of
Weinreb amides with highly reactive organometallic nucleo-
philes8 and minimally functionalized alkylzinc reagents9 in
transition-metal-catalyzed transformations. Extension of an
acylative cross-coupling between amides and more functional-
group-tolerant alkylboron reagents was viewed as a useful,
complementary means by which more structural and functional
promoted photoredox/Ni dual-catalytic cross-coupling method
based on single electron transfer (SET) oxidation of
alkyltrifluoroborates.10 In this method, under the collaborative
roles of two distinct catalysts, an effective transmetalation
occurs via the formation of radicals generated upon oxidation of
the potassium alkyltrifluoroborates. In fact, this synergistic dual-
catalytic approach is a versatile method that allows synthetically
3
2
challenging Csp −Csp bond formation processes to occur under
mild conditions. We recently extended the scope of electro-
philes to which this dual-catalytic cross-coupling could be
applied from aryl halides to acyl chlorides.11 In a similar vein,
the Doyle group previously utilized photoredox/Ni dual
catalysis to acylate α to amines using anhydrides and
thioesters,12 and in a collaborative effort the Rovis and Doyle
groups developed an elegant enantioselective desymmetrization
of meso-anhydrides using benzyltrifluoroborates as radical
precursors by photoredox/Ni dual catalysis.13 In the course
of our investigation to broaden the applications of this protocol,
and also considering the abundance of amides and their stability
in organic transformations,14 we investigated the efficiency of a
similar protocol in acylation of potassium alkyltrifluoroborates
via N−C bond activation of amides to generate aliphatic
ketones (Scheme 1).
Our studies began by focusing on finding the best activated
amide for this coupling reaction. Therefore, the cross-coupling
of a variety of sterically and electronically activated amides
derived from hydrocinnamic acid, as well as benzotriazole
derivative 2c, was investigated by means of microscale high-
Received: April 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00989
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Organic Letters
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Scheme 1. Photoredox/Ni Dual-Catalytic Cross-Coupling of
Amides with 2° Alkyl R−BF3K
Scheme 3. Proposed Mechanism for the Photoredox Cross-
Coupling of N-Acylpyrrolidine-2,5-diones with Alkyl−BF3K
throughput experimentation (HTE) using potassium cyclo-
hexyltrifluoroborate as the coupling partner in the presence of
Ir[dF(CF3)ppy]2(bpy)PF6 (1) [dF(CF3)ppy = 2-(2,4-difluor-
ophenyl)-5-(trifluoromethyl)pyridine, bpy = 2,2′-bipyridine] as
a photocatalyst, nickel(II) chloride ethylene glycol dimethyl
ether complex as a cross-coupling catalyst, and 4,4′-di-tert-
butyl-2,2′-bipyridine (L1, dtbbpy) as a ligand at room
temperature (Scheme 2).15 Both 1-(3-phenylpropanoyl)-
photocatalyst, Ni catalyst, ligand, and additive) was carried
out using HTE to find the best overall conditions for the
photoredox/Ni dual catalytic cross-coupling of N-acylpyrroli-
dine-2,5-diones with potassium alkyltrifluoroborates. In these
screens, 2e and potassium cyclohexyltrifluoroborate were
chosen as model coupling partners. As a result of the screens,
although bpy and NiBr2·dme exceeded other ligands and nickel
sources, respectively, in performance, preformed [Ni(dtbbpy)-
(H2O)4]Cl2 illustrated the best performance under the
experimental conditions and afforded the highest yield (Figures
S2 and S3).15 Interestingly, unlike our previous protocol using
acyl chlorides as the electrophile,11 after screening of a variety
of additives the best result was obtained without any additive
(Figure S4). An investigation of the impact of the solvent on
this cross-coupling revealed that 2-MeTHF was the best solvent
(Figure S5). Further screens showed that using cyclopentyl
methyl ether (CPME) as a cosolvent (2-MeTHF/CPME 5:1)
increased the yield of the desired product. Finally, control
experiments showed that all of the parameters were essential for
the reaction to proceed (Table S1).15 Accordingly, treatment of
2e with potassium cyclohexyltrifluoroborate in the presence of
3 mol % photocatalyst 1 and 6 mol % [Ni(dtbbpy)(H2O)4]Cl2
in 2-MeTHF/CPME (5:1) as the solvent mixture at room
temperature produced the desired ketone 3a in the highest
yield (78%; Scheme 4).
Scheme 2. Graphical Chart of P/IS of the Cross-Coupling of
a Variety of Activated Amides with
Cyclohexyltrifluoroborate
With suitable conditions in hand, a variety of imides were
reacted with different potassium alkyltrifluoroborates to
2
3
demonstrate the versatility of this novel Csp −Csp protocol
and to explore the substrate scope of the cross-coupling
reaction with regard to both the imide and the alkyltrifluor-
oborate partner under the developed conditions (Scheme 4).
All of the imides studied reacted well, generating the
corresponding ketones in good yields. A single aromatic
imide, generating ketone 3j, demonstrated the viability for this
substructural class of electrophiles. Additionally, imides
containing electrophilic functional groups, including esters
(3u) and nitriles (3k), which would be prone to side reactions
in the presence of more strongly nucleophilic organometallic
reagents, participated in the cross-coupling reaction with great
efficiency. The imide bearing a bulky group, 1-(adamantane-1-
carbonyl)pyrrolidine-2,5-dione, generated the desired product
in high yield (3s, 75%). Interestingly, imides possessing tert-
butoxycarbonyl- and carboxybenzyl-protected primary (3r) and
secondary amines (3m−q) were well-tolerated. Of note, our
previous efforts to generate these nitrogen-containing aliphatic
ketones via the cross-coupling of acyl chlorides with
piperidine-2,6-dione (2d) and 1-(3-phenylpropanoyl)-
pyrrolidine-2,5-dione (2e) generated the desired cross-coupled
product in good yields, but the highest product to internal
standard ratio (P/IS) was obtained for the cross-coupling
reaction of imide 2e. Incomplete consumption of starting
material was the reason for the lower P/IS for the reaction
using derivative 2d. Consequently, N-acylpyrrolidine-2,5-diones
would be the best candidates as the electrophilic partner in an
SET photoredox/Ni cross-coupling protocol. These imides are
highly stable and easily accessed from the corresponding
carboxylic acids.16 The proposed mechanism for this trans-
formation, which is adapted from our studies on the cross-
coupling of aryl halides with alkyltrifluoroborates, is shown in
Scheme 3.17
With the best amide derivative in hand, a more extensive
screening of various reaction parameters (e.g., solvent,
B
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Scheme 4. Scope of the Cross-Coupling Reaction of N-Acyl Succinimides with Potassium Alkyltrifluoroborates
a
Reaction performed on a 4.5 mmol scale with 1.5 mol % Ir photocatalyst 1 and 3 mol % [Ni(dtbbpy)(H2O)4]Cl2.
alkyltrifluoroborates were unsuccessful.11 Finally, 1-(5-
hexenoyl)pyrrolidine-2,5-dione was also found to be a suitable
reaction partner, with the terminal double bond remaining
intact (3l, 82%).
3p). Under the conditions established, β-trifluoroborato
ketones and esters could be coupled to generate 1,4-diketones
in moderate to good yields (3f and 3i). Finally, the scalable
nature of this coupling protocol was established by performing
the reaction on a 4.5 mmol scale (3a). In this reaction, using
half of the normal catalyst loadings (1.5 mol % 1 and 3 mol %
[Ni(dtbbpy)(H2O)4]Cl2) afforded the desired product in 72%
yield.
In conclusion, a visible-light photoredox/Ni electrophilic
imide-based acyl transfer cross-coupling reaction has been
developed to access a variety of aliphatic ketones in high yields.
In this protocol, N-acylpyrrolidine-2,5-diones have been used as
electrophilic reagents in transition-metal-catalyzed selective N−
C bond cleavage. These imides are readily accessed from the
corresponding carboxylic acids and are more stable and more
easily handled than the corresponding acyl chlorides or
anhydrides. The transformation developed proceeds under
extremely mild conditions using visible light without any
additive and exhibits tolerance of a variety of functional groups
in both coupling partners. This cross-coupling protocol thus
represents an expansion of the synergistic photoredox/Ni
catalytic paradigm into new electrophile space.
A variety of potassium alkyltrifluoroborates functioned
efficiently in this transition-metal-catalyzed acylation protocol
as well. In the acylation of sec-butyltrifluoroborate, no
regioisomerization was observed, and the desired product was
obtained in 70% isolated yield (3c). The products derived from
sterically hindered substrates such as 2-methylcyclopentyltri-
fluoroborate performed well with no isomerization and
generated the trans diastereomer as the only product (3b,
66%). Notably, the developed protocol readily tolerated amines
and nitrogen heterocycles (3k and 3m), which could be
problematic in transformations of this type using more
electrophilic acylating agents.18 Other aliphatic heterocyclic
trifluoroborates containing oxygen (3h) or protected nitrogen
atoms (3o−r) reacted efficiently under the reaction conditions.
Moreover, this protocol is amenable to the coupling of α-
aminoalkyltrifluoroborates (3e and 3o) to generate ketones
bearing α-amino substitution that are broadly represented
among pharmaceutically active compounds and complex
natural products.19 α-Alkoxy ketones, which are versatile and
valuable building blocks in the construction of various natural
products,20 were also obtained in excellent yields by the cross-
coupling reaction of α-alkoxymethyltrifluoroborates (3g and
C
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Organic Letters
Letter
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(16) Goodman, C. A.; Eagles, J. B.; Rudahindwa, L.; Hamaker, C. G.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00989.
■
S
Experimental procedures, HTE data, compound charac-
terization data, and NMR spectra for all compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*gmolandr@sas.upenn.edu
ORCID
Gary A. Molander: 0000-0002-9114-5584
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the NIGMS (R01 GM-113878)
and the Bengt Lundqvist Foundation (through the Swedish
Chemical Society) by a generous grant to R.A. Frontier
Scientific is thanked for the donation of boron compounds used
in this investigation. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data.
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