Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids

Article abstract of DOI:10.1002/anie.202002271

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low-abundance starting materials. In contrast, amide formation is the most-used bond-construction method in medicinal chemistry because the che

Full text of DOI:10.1002/anie.202002271

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Accepted Article
Title: Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling
of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids
Authors: Jiang Wang, Megan Hoerrner, Mary P. Watson, and Daniel
John Weix
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Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling
of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids
Jiang Wang,[a] Megan E. Hoerrner,[b] Mary P. Watson[b]* and Daniel J. Weix[a]*
Abstract: While ketones are among the most versatile functional
groups, their synthesis remains reliant upon reactive and low
abundance starting materials. In contrast, amide formation is the
most-used bond construction in medicinal chemistry because the
chemistry is reliable and draws upon large, diverse substrate pools. A
new method for the synthesis of ketones is presented here that
draws from the same substrates used for amide bond synthesis:
amines and carboxylic acids. A nickel terpyridine catalyst couples
N-alkyl pyridinium salts with in-situ formed carboxylic acid fluorides or
2-pyridyl esters under reducing conditions (Mn metal). The reaction
has broad scope, as demonstrated by the synthesis of 35 different
ketones bearing a wide variety of functional groups with an average
yield of 60 ± 16%. This approach is capable of coupling diverse
substrates, including pharmaceutical intermediates, to rapidly form
complex ketones.
substrate pool.
We show here how recent developments in our two research
groups can be combined to achieve a general synthesis of dialkyl
ketones from alkyl amines and alkyl carboxylic acids (Scheme 1).
On one hand, cross-electrophile[ 7 ] approaches to ketone
synthesis have been developed to eliminate the need for
organometallic reagents by coupling of activated esters (-Cl,
-SPy, -OCO2R) with alkyl halides[ 8 ] or, recently, a second
carboxylic acid activated as an N-hydroxyphthalimide ester.[9] On
10
]
the other hand, deaminative cross-couplings[
of alkyl
including
pyridinium salts have rapidly progressed,
cross-electrophile couplings with aryl halides.[11] We show here
how these advances can be combined to form ketones from
amines and carboxylic acid derivatives.[12,13]
The ketone functional group plays a central role in organic
synthesis: it is present in many target molecules (natural
products, drugs, materials), and is also a key intermediate in the
synthesis of C-C bonds and alcohols.[1] However, the synthesis
of ketones continues to rely upon methods that are limited in
functional group compatibility and use starting materials of low
abundance (Scheme 1). Ketones are most often synthesized by
the addition of an organometallic reagent to an aldehyde followed
by oxidation[1a] or, more recently, the coupling of an
organometallic reagent to an activated ester.[ 2 , 3 ] This latter
strategy is useful because there are many more alkanoic acids
than aliphatic aldehydes, yet the organometallic coupling partner
has limited availability and functional group compatibility.
In contrast, amide bond formation is among the most reliable
coupling reactions.[4] A recent analysis ranked it as the most
used reaction in medicinal chemistry, accounting for 25% of all
reactions used in drug discovery. This is driven, in part, by the
large numbers of amines and carboxylic acids that are
commercially available.[5] A ketone synthesis that could utilize
these substrate pools would dramatically increase easily
available chemical space. In this vein, Matsuo recently reported
an exciting advance: the cross-coupling of N-aroylsuccinimides
with alkylpyridinium salts.[6] This approach worked for benzoic
acid derivatives, but was not useful for the larger alkanoic acid
Scheme 1. How to make ketones from amine and carboxylic acid derivatives.
The main challenge to realizing this transformation was
achieving high cross-selectivity without resorting to a large
excess of one coupling partner. Previous cross-electrophile
couplings of alkyl pyridinium salts with aryl halides had shown
that this balance of reactivity and selectivity could be challenging
to achieve.[11] Based upon the hypothesis that the ketone product
forms from the coupling of an acylnickel(II) intermediate with an
pyridinium-salt-derived alkyl radical (Scheme 1),[8i,12e, 14 ] we
sought an acyl donor that would react quickly with the nickel
catalyst, would not be easily reduced to form a radical,[15] and
could be isolated or formed in situ.
[a]
[b]
Dr. Jiang Wang and Prof. Daniel J. Weix*
Department of Chemistry
University of Wisconsin-Madison
Madison, WI 53706 (USA)
E-mail: dweix@wisc.edu
Megan E. Hoerrner and Prof. Mary P. Watson
Department of Chemistry and Biochemistry
University of Delaware
Examination of activating strategies for carboxylic acids led
us to acyl fluorides.[16] Acyl fluorides have several advantages:
they can be made in situ (an advantage over N-acylimides or
imides[ 17 ]), the liberated fluoride does not interfere with
productive catalysis (a problem for thioesters[8d,8g]), and they can
be purified if needed (unlike anhydrides or acid chlorides).
Newark, DE 19716 (USA)
E-mail: mpwatson@udel.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202002271
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formation (entry 10).[19] Finally, purified acid fluoride could be
Table 1. Optimal conditions for primary pyridinium salts.
replaced by in-situ-generated acid fluoride (entry 2). Among
several
fluoro-N,N,N′,N′-bis(tetramethylene)formamidinium
hexafluorophosphate (TFFH)
methods
tested,
with
1,8-bis(dimethylamino)naphthylene (proton-sponge) was the
most useful.[16e] While in-situ activation of the carboxylic acid was
successful, we obtained low yields with an unpurified pyridinium
salt (22% NMR yield of 1 as in Table 1, entry 2).
We found that secondary alkyl pyridinium salts required
modified conditions (Table 2 and Tables S2.5-S2.7 in Supporting
Information). These secondary alkyl reagents typically undergo
more facile C–N bond cleavage, making formation of
dihydropyridine byproduct even more competitive.[11a] To avoid
this byproduct, these changes were made: 1) using 2-pyridyl
esters instead of acyl fluorides; 2) changing the solvent to THF
and lowering the temperature; 3) switching the ligand to L4 (entry
2). The use of NiBr2(dme) and a slight increase in the amount of
pyridinium salt, from 1.0 to 1.5 equiv, further increased the yield
to 72% (entry 4).
Entry[a]
Change in condition from scheme
None
G
F
1 (%)[b]
1
82 (79)
2[c]
3
In situ formation of acyl fluoride
L1 instead of L5
L2 instead of L5
L3 instead of L5
L4 instead of L5
Different G
F
75
62
65
53
41
4
Table 2. Optimal conditions for secondary pyridinium salts.
F
4
F
5
F
6
F
Entry[a]
1
Change in condition from scheme
None
G
8 (%)[b]
14
7
SPy
OPy
F
F
8
Different G
11
5
2[c]
L4 instead of L5 in THF
OPy
OPy
61
9[e]
10[d]
11[d]
12[e]
Zn instead of Mn
No nickel
3[c]
As entry 2, NiBr2(dme) instead of
NiCl2(dme)
66
F
0
No ligand
F
0
4[c]
As entry 3, 1.5 equiv of pyridinum
OPy
72
No Mn reductant
F
0
[a] Pyridinium salt (0.125 mmol, 1 equiv), acyl fluoride or 2-pyridyl ester (0.125
mmol, 1 equiv), NiCl2(dme) (0.0125 mmol, 10 mol%), ligand (0.0125 mmol, 10
mol%), Mn (0.1875 mmol, 1.5 equiv) was stirred in corresponding solvent (0.8
mL) at 60 °C for 24 h. [b] GC yield vs 1,3.5-trimethoxybenzene standard. [c]
Reaction conducted at r.t. G = Activating group.
[a] Pyridinium salt (0.125 mmol, 1 equiv), acyl fluoride (0.125 mmol, 1 equiv),
NiCl2(dme) (0.0125 mmol, 10 mol %), ligand (0.0125 mmol, 10 mol %), Mn
(0.1875 mmol, 1.5 equiv) was stirred in NMP (0.8 mL) at 60 °C for 24 h. [b] GC
yield vs 1,3.5-trimethoxybenzene standard. Isolated yield in parentheses. [c]
Carboxylic acid (0.125 mmol,
1 equiv), TFFH (0.125 mmol, 1 equiv),
1,8-bis(dimethylamino)naphthylene (0.125 mmol, 1 equiv), NMP (0.8 mL). [d]
Significant amount of acyl fluoride recovered. [e] Both starting materials
recovered. G = Activating Group.
The scope of these conditions is broad, as demonstrated by
the 35 examples in Table 3. The majority of these examples used
in-situ activation of the carboxylic acid, but in some cases
purification of the product from proton-sponge-derived side
products was difficult and pre-formed acyl fluorides were used.
Pyridinium salts of unbranched and -branched amines coupled
well, but salts of tertiary carbinamines are not suitable
substrates.[20] Primary, secondary, and tertiary carboxylic acids
coupled in high yield, but a particularly hindered tertiary
carboxylic acid, abietic acid, and α-amino acids coupled in low
yield (see Supporting Information Table S5 for additional
low-yielding substrates). Although not a focus of this study, in a
preliminary result, a prototypical aryl carboxylic acid, naphthoic
acid, could be coupled via its acid fluoride to give 35 in 41% yield,
but a general solution to aroyl acids will require further
optimization.[21] Finally, -alkoxy carboxylic acids, a common
motif found in cetirizine and other bioactive compounds,[22] could
be coupled with slightly modified conditions (29, 30).
After systematic screening of different ligands, solvents,
additives and reaction temperatures, we found optimal conditions
for coupling an acyl fluoride with a primary alkyl pyridinium salt
(Table 1): NiCl2(dme), L5, and Mn in NMP at 60 °C. These
conditions provided ketone product 1 in 79% isolated yield (entry
1, Table 1). While 62-65% yields were obtained with electron-rich
bipyridine ligands (L1 and L2, entries 3-4), terpyridine and
electron-poor bipyridine ligands were not effective for this
transformation (See Tables S2.1-S2.4 in Supporting Information).
[8d,
In contrast to our previous reports
9b], the analogous
S-2-pyridyl thioester (entry 7) or 2-pyridyl ester (entry 8) provided
a low yield of product 1 and primarily formed the deaminative
alkyl dimer 1,4-diphenylbutane. A lower yield was observed
when switching the reductant from Mn to Zn (entry 9). This could
be attributed to slower reduction of the catalyst[18] or direct
reduction of pyridinium salts by Mn being important for product
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Table 3. Substrate scope for the deaminative coupling of pyridinium salts with carboxylic acid derivatives.
[a] After initial acid fluoride formation using carboxylic acid (0.5 mmol, 1 equiv), TFFH (0.5 mmol, 1 equiv) and proton sponge (0.5 mmol, 1 equiv), the coupling
was run on 0.5 mmol scale with a 1:1 ratio of starting materials, ligand L5 (0.05 mmol, 10 mol%), Mn (0.75 mmol, 1.5 equiv) in NMP (3 mL) at 60 °C for 24 h. [b]
Reaction run at 0.5 mmol scale using pyridinium salt (0.75 mmol, 1.5 equiv) and pre-formed 2-pyridyl ester (0.5 mmol, 1 equiv) with NiBr2(dme) (0.05 mmol, 10
mol%), ligand L4 (0.05 mmol, 10 mol%), Mn (0.75 mmol, 1.5 equiv) in THF at r.t. for 24 h. [c] Reaction run on 5 mmol scale on benchtop, see Supporting
Information. [d] Pre-formed acyl fluoride was used. [e] L2 used instead of L5. [f] L1 was used instead of L5. [g] Reaction run on 0.178 mmol scale at standard
concentration. [h] NMR yield shown. Product was not separated from impurities, see Supporting Information for details. Boc = tert-butoxycarbonyl, TBS =
tert-butyldimethylsilyl.
Highlights of the functional group tolerance include basic
amines (4, 19, 20, 21, 27, 28, 29, 30, 32), pyridine (2), cis-alkene
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(34), and even a dihydropyridine (6) that could deactivate a metal
catalyst by coordination or be prone to oxidation under
photoredox catalysis[23] or electrochemical conditions.[24] Acidic
N-H bonds of Boc-β-alanine (14), a urea (31) or an N-aryl amide
(33) as well as esters (5-9, 12, 25-27) and ketones (10, 11, 13)
were tolerated, but would pose a problem for methods based
Keywords: Ketone Synthesis, Cross-Electrophile Coupling,
Pyridinium Salts, Acyl Fluorides, Nickel Catalysis.
upon
organomagnesium
or
organolithium
reagents.[2]
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Conveniently, the chemistry can be run preparatively on the
benchtop (740 mg of 19) and generally uses a 1:1 or 1:1.5 ratio
of starting materials.
Although we have not yet studied the reaction mechanism,
the
similarities
to
other
cross-electrophile
coupling
initial
reactions[8i,12e,14] suggest an analogous mechanism:
oxidative addition of the acyl fluoride to nickel(0)[16e] followed by
radical addition to the resulting acylnickel(II) intermediate
(Scheme 1). The resulting acyl-alkyl nickel(III) species could
reductively eliminate ketone product. Formation of alkyl radicals
from N-alkylpyridinium salts can be mediated by nickel or arise
from direct reduction with manganese.[6, 10a, 10i, 11a, 11b, 11e] Another
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The ability to use carboxylic acids and amines as a substrate
pool is valuable because these are two of the largest pools of
commercially available alkyl fragments.[5] This flows from the
reliance of medicinal chemistry on amide bond formation.[4]
Indeed, alkyl amines are unique in that there are more listed for
sale than reported in the literature![ 26 ] In some cases this
translates to lower prices (see analysis in the Supporting
Information), but it also means that complex amines and acids
can be repurposed as starting materials, such as a mosapride
intermediate (19-21, 27-29, 32), amlodipine (6), cetirizine (30),
an atorvastatin intermediate (33 and a side-chain fragment in 7),
biotin (31), and lithocholic acid (32). The ability to leverage these
pools to make ketones instead of amides opens up new areas of
chemical space with minimal effort, adding another dimension to
the medicinal chemist’s toolbox.
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Acknowledgments
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under award numbers R01GM097243 (DJW)
and R35GM131816 (MPW) and the University of Wisconsin
(DJW). The authors thank Kai Kang, Daniel Enny and Benjamin
Chi (Univ. of Wisconsin) for assistance with characterization of
compounds. Data were acquired at UD on instruments obtained
with assistance of NSF and NIH funding (NSF CHE0421224,
CHE1229234, CHE0840401, and CHE1048367; NIH P20
GM104316, P20 GM103541, and S10 OD016267). The following
instrumentation in the PBCIC was supported by: Thermo Q
Exactive™ Plus by NIH 1S10 OD020022-1; Bruker Avance III
400 by NSF CHE-1048642; Bruker Avance III 500 by a generous
gift from Paul J. and Margaret M. Bender. We thank Joe Barendt
and Chiral Technologies for the kind donation of achiral SFC
columns used in this work.
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Conflict of interest: The authors declare no conflict of interest.
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COMMUNICATION
[18] L. Huang, L. K. G. Ackerman, K. Kang, A. M. Parsons, D. J. Weix, J. Am.
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[19] We have observed significant amount of dihydropyridine byproduct from
crude NMR. The structure is consistent with our previous observed
byproduct (see ref. 11a), and the structure was assigned to be:
[11] For reductive cross-electrophile couplings of alkyl pyridinium salts with aryl
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[20] Tertiary carbinamines cannot be converted into 2,4,6-triphenylpyridinium
salts, except for cyclopropyl examples, presumably due to steric
hindrance between the tertiary alkyl group and 2,6-phenyl groups.
[21] At this time, reference [6] contains a more general, higher yielding route to
aryl alkyl ketones from aryl carboxylic acids and amines.
[22] A search of the REAXYS database for HO2CCH2OR found 22844
substances with pharmacological data. This includes pesticides such as
2,4-dichlorophenoxyacetic acid (2,4-D) and fluroxypyr as well as drugs
such as treprostinil, aceclofenac, cefixime, cetirizine, and rifamycin B.
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[ 12 ] Carbonylative methods are also known, although most require
a
pre-functionalized organometallic reagent. Carbonylative
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see: a) M. Oçafrain, M. Devaud, M. Troupel, J. Périchon, J. Chem. Soc.,
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C. Hansen, Org. Process Res. Dev. 2019, 23, 1746−1751. c) K.-J. Jiao,
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[25] J. Liu, C. Lei, H. Gong, Sci. China. Chem, 2019, 62, 1492–1496.
[26] Alkyl-NH2: 1.26 million in Beilstein Database, 1.40 million listed in
eMolecules commercial availability database. Alkyl-Br: 308 thousand
in Beilstein, 201 thousand in eMolecules. See also an analysis of
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This article is protected by copyright. All rights reserved.

10.1002/anie.202002271
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Jiang Wang, Megan E. Hoerrner, Mary P. Watson* Daniel
J. Weix*
Nickel-Catalyzed Synthesis of Dialkyl
Ketones from the Coupling of N-Alkyl
Pyridinium Salts with Activated
Carboxylic Acids
Can ketones be made from amines and carboxylic
acids? The answer is Yes! We show here how
complex ketones can be synthesized from amines
and carboxylic acids. The keys to this discovery are:
1) the use of alkyl pyridinium salts, which are formed
in one step from amines, as alkyl radical donors; 2)
the use of in situ generated acyl fluorides or 2-pyridyl
esters as acyl donors and 3) a nickel catalyst with a
terpyridine ligand to unite the two intermediates.
This article is protected by copyright. All rights reserved.