I-Pr2NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions

Article abstract of DOI:10.1021/acs.orglett.9b02899

The direct preparation of ketones from carboxylate anions is greatly limited by the required use of organolithium reagents or activated acyl sources that need to be independently prepared. Herein, a specific magnesium amide additive is used to activate and control the addition of more tolerant Grignard reagents to carboxylate anions. This strategy enables the modular synthesis of ketones from CO₂ and the preparation of isotopically labeled pharmaceutical building blocks in a single operation.

Full text of DOI:10.1021/acs.orglett.9b02899

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
i‑Pr2NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition
of Grignard Reagents to Carboxylate Anions
Kilian Colas, A. Catarina V. D. dos Santos, and Abraham Mendoza*
Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory, 106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: The direct preparation of ketones from carboxylate
anions is greatly limited by the required use of organolithium
reagents or activated acyl sources that need to be independently
prepared. Herein, a specific magnesium amide additive is used to
activate and control the addition of more tolerant Grignard
reagents to carboxylate anions. This strategy enables the modular
synthesis of ketones from CO2 and the preparation of isotopically
labeled pharmaceutical building blocks in a single operation.
etones (1) are some of the cornerstones of organic
Kchemistry, being a fundamental class of products and
essential synthetic intermediates. Aromatic ketones are
particularly relevant drugs and fragrances, and they are key
to the synthesis of heterocyclic cores in valuable products.1 As
a result, extensive research has been dedicated to obtaining
ketones from raw carboxylic acids (2) and CO2 (3). However,
the addition of localized carbon nucleophiles to carboxylic
acids is a key transformation that remains challenging after
decades of research (Scheme 1A). Most approaches elaborate
carboxylic acids 2 into more electrophilic derivatives 4, such as
acyl chlorides,2 anhydrides,3 thioesters,2f,4 cyanides,5 keti-
mines,6 imides,7 amides,8 and Weinreb amides.9 Special
carbon nucleophiles 5 with lower reactivity like cuprates,10
organozincs,4,11 and boronates2g,3b,7,12 are often used to avoid
the rapid overaddition to the resulting ketone products 1.
Alternatively, the direct coupling of carbon nucleophiles with
unactivated carboxylic acids requires unstable organolithium
reagents, often in excess.13,14 These addition reactions to
lithium carboxylate anions Li-6 benefit from the stability of
addition complex Li-7 but are limited by competing metalation
reactions, carbonyl reduction, and the narrow functional scope
of the lithium organometallics.14 Grignard reagents (8) are
preferred nucleophiles for their enhanced stability and
functional-group tolerance, particularly in large-scale pro-
cesses.15,16 Unlike organolithiums, Grignard reagents (8) are
poorly reactive toward carboxylate anions (6), and the
resulting addition intermediates are unstable, giving rise to
tertiary alcohol overaddition byproducts.13d,14
chelate-assisted heteroaryl substrates17 or lithium propylamide
as an additive (Scheme 1B).18 However, the application of
these processes in organic synthesis is severely limited by the
narrow scope, and the inhibition in the presence of
tetrahydrofuran,18 which is the most common solvent for
synthesizing, storing, and distributing Grignard reagents.16,19
Overcoming the challenges associated with the direct addition
of Grignard nucleophiles (8) to carboxylate anions (6) is key
to enabling an extended modular synthesis of ketones from
CO2 (3).13d Carboxylates 6 are readily obtained from aryl
Grignard reagents (8) and CO2 (3),20 and these anions could
ideally undergo coupling with a second organomagnesium
nucleophile. The enhanced scope bestowed by Grignard
reagents16 would enable access to diversely functionalized
ketones in a single operation.13d The use of CO2 also offers a
more sustainable alternative for scale-up than current methods
based on CO, CO sources, and/or expensive transition metal
catalysts,12,21 particularly for the synthesis of isotopically
carbon-labeled pharmaceuticals used in biodistribution studies
and trace analysis.22
We have recently discovered the differential behavior of
Grignard reagents in combination with the hindered turbo-
Hauser base i-Pr2NMgCl·LiCl (9a)23 in the context of
Pummerer reactions.24 We hypothesized that the enhanced
“ate” character19a,25 of the turbo-organomagnesium amides
thus formed could (1) enhance the nucleophilicity of the initial
Grignard reagent to overcome the low electrophilicity of the
carboxylate anion, (2) stabilize the addition complex through
strong coordination2e,9a and/or rapid intramolecular enoliza-
tion, and in a broader sense (3) address the efficiency and
The addition of aromatic Grignard reagents to benzoates
would give rise to important benzophenone compounds,1h but
it is particularly problematic due to the lower reactivity of
aromatic carboxylates and aryl Grignard reagents. To the best
of our knowledge, this reaction has only been studied using
Received: August 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. State of the Art in the Synthesis of Ketones and
Our Approach Using Grignard Reagents
Table 1. Activation and Control of Grignard Reagents by i-
Pr2NMgCl·LiCl (9a)
a
composition (%)
M
additive (9)
2a
1a
10a
11a
1
2
3
4
5
6
7
8
Na
Na
Na
−
94
97
9
0
0
0
0
14
0
0
3
0
4
15
4
3
0
0
0
5
5
25
0
4
0
8
PrNHLi
i-Pr2NMgCl·LiCl (9a)
i-Pr2NMgCl·LiCl (9a)
i-Pr2NMgCl·LiCl (9a)
i-Pr2NMgCl·LiCl (9a)
TMPMgCl·LiCl (9c)
i-Pr2NMgCl (9d)
−
i-Pr2NLi (9e)
TMPLi (9f)
PrNHLi (9b)
LiCl (9g)
77
92
28
49
26
36
18
22
25
21
15
MgCl
MgCl
MgCl
MgCl
MgCl
MgCl
MgCl
MgCl
MgCl
MgCl
0
b
c
67
26
72
55
64
70
61
65
57
9
10
11
12
13
8
0
0
14
28
a
Conditions: 2a (0.1 mmol), NaH or t-BuMgCl (0.1 mmol), toluene,
0 °C; PhMgBr (8a, 0.12 mmol) and 9 (0.12 mmol), 0 °C, ultrasound;
rt, 7 h. Determined by 1H NMR using 1,1,2,2-tetrachloroethane as an
b
c
internal standard. No premixing of 8a and 9a. No ultrasound. TMP,
2,2,6,6-tetramethylpiperid-1-yl.
the magnesium carboxylate. Furthermore, related lithium
amides 9e and 9f, or LiCl (9g) alone, were deemed to be
ineffective (entries 10−12, respectively), thus indicating the
singular activating effect of the magnesium amide LiCl
complex 9a in the addition to the carboxylate anion. To the
best of our knowledge, organomagnesium amides have been
used as bases only in challenging deprotonation reactions,28c
and the performance of their LiCl adducts as carbon
nucleophiles has not been explored before our work.24
selectivity problems that are associated with classic organo-
metallic “ate” reagents [R3M]− (M = Mg, Cu, or Zn).10,11,25
In agreement with the general notion in the literatu-
re,10,13a,d,17,18,26 our exploratory studies (Table 1) revealed that
no addition of phenylmagnesium bromide (8a) occurs to the
sodium carboxylate (Na-6a; entry 1), and a similar result is
obtained in the presence of PrNHLi (9b; entry 2), probably
due to the THF in the commercial Grignard solution.18 In
stark contrast, i-Pr2NMgCl·LiCl (9a) has a dramatic effect in
enhancing the conversion and selectivity of the reaction,
yielding ketone 1a as the major product (entry 3). After
extensive experimentation, we found that the more soluble
magnesium carboxylate MgCl-6a further suppresses the
formation of overaddition product 10a (entry 4). Interestingly,
only slight conversion is observed when the premixing of 8a
and 9a is omitted (entry 5). Ultrasonic homogenization of this
mixture decreases the level of formation of addition−reduction
byproduct 11a in small-scale experiments (entry 6; for details,
see Scheme 4) but is not required in large-scale reactions as
stirring proves to be sufficient (Scheme 2). Interestingly, subtle
changes in the steric hindrance of the turbo-Hauser base have a
noticeable effect on the efficiency of the reaction (entry 7).
LiCl is essential in the Hauser base to achieve high conversion
(entry 8), probably indicating its role in the aggregation27 of
the turbo-organomagnesium amide formed upon mixing of
Grignard 8a and 9a (for a discussion, see Scheme 4).28 Control
experiments in the absence of i-Pr2NMgCl·LiCl (9a; entry 9)
confirm its critical role in promoting the addition reaction to
With these optimized conditions in hand, we next studied
the substrate scope, which benefits from the enhanced
tolerance of Grignard nucleophiles (Scheme 2).16 Readily
available carboxylic acids are coupled with phenylmagnesium
bromide to produce ketones 1a−c in high yields. A range of
aromatic Grignard reagents bearing oxygen-based (1d), sulfur-
based (1e), or nitrogen-based (1f) substituents provide
ketones in good to excellent yields. Notably, the localized
Grignard reagents allow the regioselective preparation of meta-
substituted electron-rich products that would be problematic
through Friedel−Crafts acylation (1e and 1f). Electron-poor
nucleophiles bearing halogens (1g) and π-deficient hetero-
cycles (1h) are also tolerated. It is important to underscore the
integration with the in situ telescoped C−H metalation of
phenylpyridine (1h) and the compatibility with bromine-
containing carboxylic acids (1h and 1i) without engaging in
halogen−magnesium exchange by-processes. Furthermore,
heterocyclic moieties can be introduced from both coupling
partners (1h−l), enabling for instance the expedient
preparation of important thiazolyl-ketones.1g Unlike previous
reports,17 the presence of a nitrogen center ortho to the
reacting site is not required (1l). Interestingly, naphthol-
derived ketone 1m can be prepared without protection of its
phenol function (vide infra). To our delight, aliphatic Grignard
reagents also readily engage in this transformation, provided
that 2 equiv of the turbo-organomagnesium amide is used.
B
DOI: 10.1021/acs.orglett.9b02899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
d
Scheme 2. Synthesis of Ketones through turbo-Hauser Base-Enabled Grignard Addition to Carboxylic Acids
a
b
c
d
Reaction temperature of 65 °C. t-BuMgCl (2.0 equiv) was used. MeMgCl (2.0 equiv) was used instead of t-BuMgCl. See the Supporting
Information for experimental conditions; ultrasound only required on a small scale. Isolated yields.
Thus, electron-rich and electron-poor acids are coupled to
provide valerophenones 1n−q in excellent yields. Using benzyl
and homobenzyl nucleophiles, the corresponding α- and β-
arylated ketones are obtained (1r and 1s). The latter (1s) is a
key intermediate in the synthesis of the antihypertensive
propafenone (Arythmol).1d,e Moreover, Grignard reagents
containing an alkene (1t and 1v) or a free alcohol functionality
(1u) can be introduced in high yields. Remarkably, the
electron-rich, unprotected m- and o-salicylic acids, including
hydroxy-naphthoic acid, are excellent substrates for this
reaction, thus enabling the preparation of medicinally relevant
phenolic and/or morpholine derivatives 1s and 1v−x.
Likewise, alcohol-containing ketone 1y, an intermediate to
the essential antipsychotic haloperidol (Haldol),1c is prepared
in excellent yield. Secondary alkyl nucleophiles can also be
used to prepare electron-deficient ketones 1x and 1z−ac in
high yields, in combination with trifluoromethyl and
halogenated benzoic acids. Unprotected anthranilic acids are
also compatible (1ad), thus providing valuable intermediates
for the preparation of benzodiazepine pharmaceuticals.1m−o
Upon scale-up, sonication is unnecessary, as illustrated by the
gram-scale synthesis of fluorinated ketones 1c and 1z. The
generality demonstrated by this method and the edge of i-
Pr2NMgCl·LiCl (9a) over the previously developed lithium
propylamide additive (9b)18 are remarkable (see 1a, 1g, 1j, 1l,
1m, 1o, 1r, 1w, 1y, and 1ad). Still, tertiary alkyl Grignard
reagents do not engage in this reaction, which is of benefit in
the selective deprotonation of the carboxylic acid substrates
(2) with t-BuMgCl. Interestingly, aliphatic acids are recovered
unreacted under these conditions due to their fast
enolization,13e a limitation that we are currently investigating.
Carboxylate anions (6) can also be readily obtained from the
reaction of Grignard reagents (8) with carbon dioxide (3).20a
The combination of this process with the transformation
uncovered herein enables a modular synthesis of ketones from
two carbon nucleophiles, using CO2 as a safe and available
source of the central carbonyl group (Scheme 3).13d In this
way, functionalized Grignard reagents, prepared in situ by
halogen−magnesium exchange19a or direct metalation,23
enable the direct use of aryl halides or arenes in the one-pot
synthesis of complex ketones.16 As such, dichloropyridine is
directly combined with CO2 and different Grignard reagents to
provide 1ae and 1af in excellent yields. Likewise, ketone 1ag is
obtained directly from an ester-containing thiophene substrate
and furane. This method also allows for the preparation of
isotopically labeled ketones simply by using carbon dioxide, the
most available source of labeled carbon. [13C]1y and [13C]1ah
are obtained in excellent yields, which are precursors of the
isotopically labeled pharmaceuticals haloperidol ([13C]12) and
ketoprofen ([13C]13), respectively.1c,22,29
The excellent selectivity observed toward the ketone
products indicates that the postaddition intermediate must
be stable until the reaction is quenched. In the presence of 9a
under the standard reaction conditions (Scheme 4A), the
model benzophenone 1ai undergoes rapid addition of an aryl
Grignard (10ai; entry 1). However, extensive reduction (11ai)
takes place when using an aliphatic Grignard reagent (entry 2).
Control experiments revealed that the reduction side product
C
DOI: 10.1021/acs.orglett.9b02899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
b
Scheme 3. Modular Synthesis of Radiolabeled Ketones from
Functionalized Grignards and CO2
Scheme 4. Mechanistic Studies and Proposal
b
a
Commercial Grignard solution in THF (Et2O can also be used).
b
See the Supporting Information for experimental conditions. Isolated
yields.
11ai can be obtained using only i-Pr2NMgCl·LiCl (9a; entry
3). Interestingly, LiCl is essential to observe this reduction
(entry 4), which we observe in trace amounts in our ketone
synthesis. We reason that the reduction products stem from a
Meerwein−Ponndorf−Verley-type (MVP) hydride transfer
from the magnesium amide (see 14). These results support
the stability of the addition intermediates, as early release of
the ketone product 1 would lead to significant overaddition
and reduction byproducts. Furthermore, deuteration experi-
ments reveal that the enolate of product 15a is formed when
using aliphatic nucleophiles (Scheme 4B), which opens the
door for further functionalizations in situ. The deprotonation of
the product also explains the need for 2 equiv of the reagents
to synthesize enolizable ketone products from alkyl Grignard
reagents (Scheme 2). On the basis of these results, we propose
the mechanism shown in Scheme 4C. We reason that the
crucial premixing of 8 and 9a before addition to carboxylate
anion 6 and the noticeable effect of the structure of the amide
ligand (see Table 1) are consistent with the aggregation of 8
and 9a. Given the data available on the structure of turbo-
Hauser bases27 and organomagnesium amides,28b,c we presume
that a turbo-organomagnesium amide (16) is formed. Unlike
conventional Grignard reagents or their LiCl complexes (Table
1, entry 13), 16 is sufficiently nucleophilic to add to
magnesium carboxylates (6) without the limitations of
organometallic “ate” reagents.10,11,25 The combination of
lithium, magnesium, and a singular bulky amide base has
proven to be essential for this activation (Table 1). When using
aromatic nucleophiles, we propose that the resulting
intermediate 17 is stabilized through coordination with the
amide ligand, while in the case of aliphatic Grignard reagents,
we have demonstrated that addition intermediate 18 evolves
into enolate 15. The stability of putative intermediates 15 and
17 until the reaction is quenched explains the high selectivity
obtained toward ketone products 1. Otherwise, byproducts
a
Determined by 1H NMR using 1,1,2,2-tetrachloroethane as an
b
internal standard. M = LixMgyLn. See the Supporting Information for
details.
stemming from overaddition (10) and reduction (11) would
dominate, which has been demonstrated above (Scheme 4A).
In summary, turbo-Hauser base i-Pr2NMgCl·LiCl (9a)
activates and controls the addition of Grignard reagents to
carboxylate anions. This reaction likely proceeds through
organomagnesium amide intermediates featuring enhanced
nucleophilicity and the capacity to stabilize the resulting
addition products. The wide scope of this transformation in
both coupling partners allows swift synthesis of relevant
aromatic ketones on a preparative scale. Integration with
Grignard carbonation enables the sequential assembly of
ketones using CO2 as a carbonyl equivalent, thus facilitating
the synthesis of isotopically labeled pharmaceuticals.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02899.
D
DOI: 10.1021/acs.orglett.9b02899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, optimization details, and
Letter
Marchese, G.; Naso, F. One-step Synthesis of 1,n-Dicarbonyl
Compounds from Carboxylic Acid Derivatives and di-Grignard
Reagents in the Presence of Transition Metal Catalysts. J. Organomet.
Chem. 1991, 405, 53. (d) Malanga, C.; Aronica, L. A.; Lardicci, L.
Direct Ni-mediated Synthesis of Ketones from Acyl Bromides and
Grignard Reagents. Tetrahedron Lett. 1995, 36, 9185. (e) Wang, X.-j.;
Zhang, L.; Sun, X.; Xu, Y.; Krishnamurthy, D.; Senanayake, C. H.
Addition of Grignard Reagents to Aryl Acid Chlorides: An Efficient
Synthesis of Aryl Ketones. Org. Lett. 2005, 7, 5593. (f) Kumar, V. P.;
Babu, V. S.; Yahata, K.; Kishi, Y. Fe/Cu-Mediated One-Pot Ketone
Synthesis. Org. Lett. 2017, 19, 2766. (g) Amani, J.; Molander, G. A.
Synergistic Photoredox/Nickel Coupling of Acyl Chlorides with
Secondary Alkyltrifluoroborates: Dialkyl Ketone Synthesis. J. Org.
Chem. 2017, 82, 1856.
(3) (a) Gooßen, L. J.; Ghosh, K. Palladium-Catalyzed Synthesis of
Aryl Ketones from Boronic Acids and Carboxylic Acids Activated in
situ by Pivalic Anhydride. Eur. J. Org. Chem. 2002, 2002, 3254.
(b) Amani, J.; Molander, G. A. Direct Conversion of Carboxylic Acids
to Alkyl Ketones. Org. Lett. 2017, 19, 3612.
(4) (a) Lee, J. H.; Kishi, Y. One-Pot Ketone Synthesis with Alkylzinc
Halides Prepared from Alkyl Halides via a Single Electron Transfer
(SET) Process: New Extension of Fukuyama Ketone Synthesis. J. Am.
Chem. Soc. 2016, 138, 7178. (b) Tokuyama, H.; Yokoshima, S.;
Yamashita, T.; Fukuyama, T. A Novel Ketone Synthesis by a
Palladium-Catalyzed Reaction of Thiol Esters and Organozinc
Reagents. Tetrahedron Lett. 1998, 39, 3189.
characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: abraham.mendoza@su.se.
ORCID
Abraham Mendoza: 0000-0001-9199-6736
Notes
The authors declare no competing financial interest.
Raw data for this article can be downloaded from Zenodo at
https://doi.org/10.5281/zenodo.3404804.
ACKNOWLEDGMENTS
■
Financial support from the Knut and Alice Wallenberg
Foundation (KAW2016.0153) and the European Research
Council (714737) is gratefully acknowledged. The authors are
indebted to the personnel of AstraZeneca Gothenburg and the
Department of Organic Chemistry at Stockholm University for
unrestricted support.
REFERENCES
■
(1) (a) Vooturi, S. K.; Cheung, C. M.; Rybak, M. J.; Firestine, S. M.
Design, Synthesis, and Structure−Activity Relationships of Benzo-
phenone-Based Tetraamides as Novel Antibacterial Agents. J. Med.
Chem. 2009, 52, 5020. (b) Kelly, C. B.; Mercadante, M. A.;
Leadbeater, N. E. Trifluoromethyl Ketones: Properties, Preparation,
and Application. Chem. Commun. 2013, 49, 11133. (c) Tyler, M. W.;
Zaldivar-Diez, J.; Haggarty, S. J. Classics in Chemical Neuroscience:
Haloperidol. ACS Chem. Neurosci. 2017, 8, 444. (d) Lowes, D.; et al.
Lead Optimization of Antimalarial Propafenone Analogues. J. Med.
Chem. 2012, 55, 6087. (e) Ngo, S. T.; et al. Anti-arrhythmic
Medication Propafenone a Potential Drug for Alzheimer’s Disease
Inhibiting Aggregation of Aβ: In Silico and in Vitro Studies. J. Chem.
Inf. Model. 2016, 56, 1344. (f) Zhang, G.; Li, Y.; Fang, L.; Pfeifer, B.
A. Tailoring Pathway Modularity in the Biosynthesis of Erythromycin
Analogs Heterologously Engineered in E. coli. Sci. Adv. 2015, 1,
No. e1500077. (g) Kokotos, G.; et al. Inhibition of Group IVA
Cytosolic Phospholipase A2 by Thiazolyl Ketones in Vitro, ex Vivo,
and in Vivo. J. Med. Chem. 2014, 57, 7523. (h) Wu, S.-B.; Long, C.;
Kennelly, E. J. Structural Diversity and Bioactivities of Natural
Benzophenones. Nat. Prod. Rep. 2014, 31, 1158. (i) Rulev, A. Y.;
Romanov, A. R. Unsaturated Polyfluoroalkyl Ketones in the Synthesis
of Nitrogen-bearing Heterocycles. RSC Adv. 2016, 6, 1984. (j) Nakato,
T.; Yamauchi, S. Enantioselective Synthesis of the Tetrahydrofuran
Lignans (−)- and (+)-Magnolone. J. Nat. Prod. 2007, 70, 1588.
(k) Maioli, A. T.; Civiello, R. L.; Foxman, B. M.; Gordon, D. M.
Asymmetric Synthesis of Sesaminone: Confirmation of Its Structure
and Determination of Its Absolute Configuration. J. Org. Chem. 1997,
62, 7413. (l) Surburg, H.; Panten, J. Common Fragrance and Flavor
Materials, 5th ed.; Wiley-VCH, 2016. (m) Carter, M. C.; et al. 1,4-
Benzodiazepines as Inhibitors of Respiratory Syncytial Virus. J. Med.
Chem. 2006, 49, 2311. (n) McDonald, I. M.; et al. Optimization of
1,3,4-Benzotriazepine-Based CCK2 Antagonists to Obtain Potent,
Orally Active Inhibitors of Gastrin-Mediated Gastric Acid Secretion. J.
Med. Chem. 2007, 50, 3101. (o) Siegrist, R.; et al. Structure−Activity
Relationship, Drug Metabolism and Pharmacokinetics Properties
Optimization, and in Vivo Studies of New Brain Penetrant Triple T-
Type Calcium Channel Blockers. J. Med. Chem. 2016, 59, 10661.
(2) (a) Dieter, R. K. Reaction of Acyl Chlorides with Organometallic
Reagents: A Banquet Table of Metals for Ketone Synthesis.
Tetrahedron 1999, 55, 4177. (b) Cardellicchio, C.; Fiandanese, V.;
Marchese, G.; Ronzini, L. Functionalized Ketones by Iron Mediated
Reaction of Grignard Reagents with Acyl Chlorides. Tetrahedron Lett.
1987, 28, 2053. (c) Babudri, F.; D’Ettole, A.; Fiandanese, V.;
(5) Duplais, C.; Bures, F.; Sapountzis, I.; Korn, T. J.; Cahiez, G.;
Knochel, P. An Efficient Synthesis of Diaryl Ketones by Iron-
Catalyzed Arylation of Aroyl Cyanides. Angew. Chem., Int. Ed. 2004,
43, 2968.
(6) Rong, J.; Collados, J. F.; Ortiz, P.; Jumde, R. P.; Otten, E.;
Harutyunyan, S. R. Catalytic Enantioselective Addition of Grignard
Reagents to Aromatic Silyl Ketimines. Nat. Commun. 2016, 7, 13780.
(7) Amani, J.; Alam, R.; Badir, S.; Molander, G. A. Synergistic
Visible-Light Photoredox/Nickel-Catalyzed Synthesis of Aliphatic
Ketones via N−C Cleavage of Imides. Org. Lett. 2017, 19, 2426.
(8) (a) Chen, C.; Liu, P.; Luo, M.; Zeng, X. Kumada Arylation of
Secondary Amides Enabled by Chromium Catalysis for Unsymmetric
Ketone Synthesis under Mild Conditions. ACS Catal. 2018, 8, 5864.
(b) Bechara, W. S.; Pelletier, G.; Charette, A. B. Chemoselective
Synthesis of Ketones and Ketimines by Addition of Organometallic
Reagents to Secondary Amides. Nat. Chem. 2012, 4, 228. (c) Shi, S.;
Szostak, M. Nickel-Catalyzed Diaryl Ketone Synthesis by N−C
Cleavage: Direct Negishi Cross-Coupling of Primary Amides by Site-
Selective N,N-Di-Boc Activation. Org. Lett. 2016, 18, 5872. (d) Liu,
C.; Achtenhagen, M.; Szostak, M. Chemoselective Ketone Synthesis
by the Addition of Organometallics to N-Acylazetidines. Org. Lett.
2016, 18, 2375. (e) Lei, P.; Meng, G.; Ling, Y.; An, J.; Nolan, S. P.;
Szostak, M. General Method for the Suzuki−Miyaura Cross-Coupling
of Primary Amide-Derived Electrophiles Enabled by [Pd(NHC)-
(cin)Cl] at Room Temperature. Org. Lett. 2017, 19, 6510.
(9) (a) Nahm, S.; Weinreb, S. M. N-methoxy-N-methylamides as
Effective Acylating Agents. Tetrahedron Lett. 1981, 22, 3815.
(b) Davies, S. G.; Fletcher, A. M.; Thomson, J. E. Direct Asymmetric
Syntheses of Chiral Aldehydes and Ketones via N-Acyl Chiral
Auxiliary Derivatives including Chiral Weinreb Amide Equivalents.
Chem. Commun. 2013, 49, 8586. (c) Singh, J.; Satyamurthi, N.;
Aidhen, I. S. The Growing Synthetic Utility of Weinreb′s Amide. J.
Prakt. Chem. 2000, 342, 340. (d) Senatore, R.; Castoldi, L.; Ielo, L.;
Holzer, W.; Pace, V. Expeditious and Chemoselective Synthesis of α-
Aryl and α-Alkyl Selenomethylketones via Homologation Chemistry.
Org. Lett. 2018, 20, 2685.
(10) Genna, D. T.; Posner, G. H. Cyanocuprates Convert Carboxylic
Acids Directly into Ketones. Org. Lett. 2011, 13, 5358.
(11) Murata, R.; Hirano, K.; Uchiyama, M. Highly Chemoselective
and Versatile Method for Direct Conversion of Carboxylic Acids to
Ketones utilizing Zinc Ate Complexes. Chem. - Asian J. 2015, 10,
1286.
E
DOI: 10.1021/acs.orglett.9b02899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(12) Bjerglund, K. M.; Skrydstrup, T.; Molander, G. A. Carbon-
ylative Suzuki Couplings of Aryl Bromides with Boronic Acid
Derivatives under Base-Free Conditions. Org. Lett. 2014, 16, 1888.
(13) (a) Levine, R.; Karten, M. J.; Kadunce, W. M. Reactions of
Organolithium Compounds and Grignard Reagents with Lithium
Carboxylates. J. Org. Chem. 1975, 40, 1770. (b) Levine, R.; Karten, M.
J. Reactions of Carboxylic Acids with Organolithium Compounds. J.
Org. Chem. 1976, 41, 1176. (c) Alonso, F.; Lorenzo, E.; Yus, M.
Direct Easy Synthesis of Ketones from Carboxylic Acids and
Chlorinated Compounds. J. Org. Chem. 1996, 61, 6058. (d) Wu, J.;
Yang, X.; He, Z.; Mao, X.; Hatton, T. A.; Jamison, T. F. Continuous
Flow Synthesis of Ketones from Carbon Dioxide and Organolithium
or Grignard Reagents. Angew. Chem., Int. Ed. 2014, 53, 8416. (e) For
reactions mediated by Ce(III) salts, see: Ahn, Y.; Cohen, T.
Cerium(III) Chloride Remarkably Increases the Rates of Formation
and Yields of Ketones in the Reaction of Lithium Carboxylates with
Organolithiums. Tetrahedron Lett. 1994, 35, 203. During the
preparation of this work, an elegant synthesis of ketones has been
reported, although it still requires the addition of organolithiums to
carboxylate anions: (f) Hurst, T. E.; Deichert, J. A.; Kapeniak, L.; Lee,
R.; Harris, J.; Jessop, P. G.; Snieckus, V. Sodium Methyl Carbonate as
an Effective C1 Synthon. Synthesis of Carboxylic Acids, Benzophe-
nones, and Unsymmetrical Ketones. Org. Lett. 2019, 21, 3882.
(14) Jorgenson, M. J. In Organic Reactions; John Wiley and Sons,
Inc., 2011; Vol. 18.
(15) Tilstam, U.; Weinmann, H. Activation of Mg Metal for Safe
Formation of Grignard Reagents on Plant Scale. Org. Process Res. Dev.
2002, 6, 906.
(16) (a) Knochel, P.; Kmsovskiy, A.; Sapountzis, L. In Handbook of
Functionalized Organometallics: Applications in Synthesis; 2008; Vol. 1,
p 109. (b) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Highly Functionalized
Organomagnesium Reagents Prepared through Halogen−Metal
Exchange. Angew. Chem., Int. Ed. 2003, 42, 4302.
(17) Demkiw, K.; Araki, H.; Elliott, E. L.; Franklin, C. L.; Fukuzumi,
Y.; Hicks, F.; Hosoi, K.; Hukui, T.; Ishimaru, Y.; O’Brien, E.; Omori,
Y.; Mineno, M.; Mizufune, H.; Sawada, N.; Sawai, Y.; Zhu, L. A
Nitrogen-Assisted One-Pot Heteroaryl Ketone Synthesis from
Carboxylic Acids and Heteroaryl Halides. J. Org. Chem. 2016, 81,
3447.
Carbon Monoxide Precursors for Safe Carbonylation Reactions. Acc.
Chem. Res. 2016, 49, 594. (d) Campo, M. A.; Larock, R. C. Synthesis
of Fluoren-9-ones by the Palladium-Catalyzed Cyclocarbonylation of
o-Halobiaryls. J. Org. Chem. 2002, 67, 5616. (e) Wu, X.-F.; Anbarasan,
P.; Neumann, H.; Beller, M. Palladium-Catalyzed Carbonylative C-H
Activation of Heteroarenes. Angew. Chem., Int. Ed. 2010, 49, 7316.
(f) Zhang, H.; Shi, R.; Gan, P.; Liu, C.; Ding, A.; Wang, Q.; Lei, A.
Palladium-Catalyzed Oxidative Double C-H Functionalization/
Carbonylation for the Synthesis of Xanthones. Angew. Chem., Int.
Ed. 2012, 51, 5204. (g) Cernak, T. A.; Lambert, T. H. Multicatalytic
Synthesis of α-Pyrrolidinyl Ketones via a Tandem Palladium(II)/
Indium(III)-Catalyzed Amino-chlorocarbonylation/Friedel−Crafts
Acylation Reaction. J. Am. Chem. Soc. 2009, 131, 3124. (h) Zeng,
F.; Alper, H. Pd-Catalyzed Direct Coupling of Indoles with Carbon
Monoxide and Alkynes: Selective Synthesis of Linear α,β-Unsaturated
Ketones. Org. Lett. 2013, 15, 2034.
(22) Unkefer, C. J.; Martinez, R. A. The Use of Stable Isotope
Labelling for the Analytical Chemistry of Drugs. Drug Test. Anal.
2012, 4, 303.
(23) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Mixed Mg/Li
Amides of the Type R2NMgCl·LiCl as Highly Efficient Bases for the
Regioselective Generation of Functionalized Aryl and Heteroaryl
Magnesium Compounds. Angew. Chem., Int. Ed. 2006, 45, 2958.
(24) Colas, K.; Martín-Montero, R.; Mendoza, A. Intermolecular
Pummerer Coupling with Carbon Nucleophiles in Non-Electrophilic
Media. Angew. Chem., Int. Ed. 2017, 56, 16042.
(25) (a) Schnegelsberg, C.; Bachmann, S.; Kolter, M.; Auth, T.;
John, M.; Stalke, D.; Koszinowski, K. Association and Dissociation of
Grignard Reagents RMgCl and Their Turbo Variant RMgCl·LiCl.
Chem. - Eur. J. 2016, 22, 7752. (b) Neufeld, R.; Stalke, D. Solution
Structure of Turbo-Hauser Base TMPMgCl·LiCl in [D8]THF. Chem.
- Eur. J. 2016, 22, 12624. (c) Zaragoza-Calero, S.; Francos, J.;
Kennedy, A. R.; O’Hara, C. T. Solid State and Solution Studies of
Lithium Tris(N-butyl)magnesiates Stabilised by Lewis Donors. Dalton
Trans 2015, 44, 7258. (d) Kikuchi, M.; Niikura, S.; Chiba, N.;
Terauchi, N.; Asaoka, M. Conjugate Addition of RMgX−3MeLi to
α,β-Unsaturated Amides and α,β-Unsaturated Carboxylic Acids.
Chem. Lett. 2007, 36, 736. (e) Harrison-Marchand, A.; Mongin, F.
Mixed AggregAte (MAA): A Single Concept for All Dipolar
Organometallic Aggregates. 1. Structural Data. Chem. Rev. 2013,
113, 7470.
(26) (a) Fiandanese, V.; Marchese, G.; Ronzini, L. One-step
Synthesis of Ketones from Carboxylic Acids and Grignard Reagents in
the Presence of a Nickel(II)-phosphine Catalyst. Tetrahedron Lett.
1983, 24, 3677. (b) Fujisawa, T.; Mori, T.; Sato, T. One-pot Synthesis
of Ketones from Carboxylic Acids and Grignard Reagents using N,N-
Diphenyl-p-methoxyphenylchloromethyleniminium Chloride. Tetra-
hedron Lett. 1982, 23, 5059.
(18) Ohki, M.; Asaoka, M. Synthesis of Ketones from Carboxylic
Acids with R(PrNH)Mg. Chem. Lett. 2009, 38, 856.
(19) (a) Krasovskiy, A.; Knochel, P. A LiCl-Mediated Br/Mg
Exchange Reaction for the Preparation of Functionalized Aryl- and
Heteroarylmagnesium Compounds from Organic Bromides. Angew.
Chem., Int. Ed. 2004, 43, 3333. (b) Knochel, P.; Barl, N. M.; Werner,
̈
V.; Samann, C. The Halogen/Magnesium-Exchange Using i-PrMgCl·
LiCl and Related Exchange Reagents. Heterocycles 2014, 88, 827.
(20) (a) Hussey, A. S. The Carbonation of Grignard Reagent
Solutions. J. Am. Chem. Soc. 1951, 73, 1364. (b) Gilman, H.; Ess, P. R.
v. The Preparation of Ketones by the Carbonation of Organolithium
Compounds. J. Am. Chem. Soc. 1933, 55, 1258. (c) Monticelli, S.;
Urban, E.; Langer, T.; Holzer, W.; Pace, V. A Straightforward
Homologation of Carbon Dioxide with Magnesium Carbenoids en
Route to α-Halocarboxylic Acids. Adv. Synth. Catal. 2019, 361, 1001.
For our recent work in the synthesis of carboxylic acids, see: (d) Bratt,
(27) Neufeld, R.; Teuteberg, T. L.; Herbst-Irmer, R.; Mata, R. A.;
Stalke, D. Solution Structures of Hauser Base iPr2NMgCl and Turbo-
i
Hauser Base Pr2NMgCl·LiCl in THF and the Influence of LiCl on
the Schlenk-Equilibrium. J. Am. Chem. Soc. 2016, 138, 4796.
(28) Organomagnesium amides are structurally characterized bases
for challenging metalation reactions: (a) Zhang, M.-X.; Eaton, P. E.
BuMgNiPr2: A New Base for Stoichiometric, Position-Selective
Deprotonation of Cyclopropane Carboxamides and Other Weak
CH Acids. Angew. Chem., Int. Ed. 2002, 41, 2169. (b) Conway, B.;
Hevia, E.; Kennedy, A. R.; Mulvey, R. E.; Weatherstone, S. Synthesis
and Characterisation of a Series of Alkylmagnesium Amide and
Related Oxygen-Contaminated ″Alkoxy″ Compounds. Dalton Trans
2005, 1532. (c) Rappoport, Z.; Marek, I. The Chemistry of
Organomagnesium Compounds; John Wiley & Sons Ltd., 2008.
́
E.; Suarez-Pantiga, S.; Johansson, M. J.; Mendoza, A. Mechanism and
Regioselectivity of the Anionic Oxidative Rearrangement of 1,3-
Diketones towards All-Carbon Quaternary Carboxylates. Chem.
Commun. 2019, 55, 8844.
(21) (a) Garrison Kinney, R.; Tjutrins, J.; Torres, G. M.; Liu, N. J.;
Kulkarni, O.; Arndtsen, B. A. A General Approach to Intermolecular
Carbonylation of Arene C−H Bonds to Ketones through Catalytic
Aroyl Triflate Formation. Nat. Chem. 2018, 10, 193. (b) Jensen, M.
T.; Rønne, M. H.; Ravn, A. K.; Juhl, R. W.; Nielsen, D. U.; Hu, X.-M.;
Pedersen, S. U.; Daasbjerg, K.; Skrydstrup, T. Scalable Carbon
Dioxide Electroreduction Coupled to Carbonylation Chemistry. Nat.
Commun. 2017, 8, 489. (c) Friis, S. D.; Lindhardt, A. T.; Skrydstrup,
T. The Development and Application of Two-Chamber Reactors and
(29) Neumann, H.; Brennfuhrer, A.; Beller, M. An Efficient and
̈
Practical Sequential One-Pot Synthesis of Suprofen, Ketoprofen and
Other 2-Arylpropionic Acids. Adv. Synth. Catal. 2008, 350, 2437.
F
DOI: 10.1021/acs.orglett.9b02899
Org. Lett. XXXX, XXX, XXX−XXX