Sodium Methyl Carbonate as an Effective C1 Synthon. Synthesis of Carboxylic Acids, Benzophenones, and Unsymmetrical Ketones

Article abstract of DOI:10.1021/acs.orglett.9b00773

Reported is the synthesis of carboxylic acids, symmetrical ketones, and unsymmetrical ketones with selectivity achieved by exploiting the differential reactivity of sodium methyl carbonate with Grignard and organolithium reagents.

Full text of DOI:10.1021/acs.orglett.9b00773

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sodium Methyl Carbonate as an Effective C1 Synthon. Synthesis of
Carboxylic Acids, Benzophenones, and Unsymmetrical Ketones
Timothy E. Hurst, Julie A. Deichert, Lucas Kapeniak, Roland Lee,† Jesse Harris, Philip G. Jessop,*
and Victor Snieckus*
Department of Chemistry, Queen’s University, Chernoff Hall, Kingston, ON, Canada K7L 3N6
S
* Supporting Information
ABSTRACT: Reported is the synthesis of carboxylic acids,
symmetrical ketones, and unsymmetrical ketones with
selectivity achieved by exploiting the differential reactivity of
sodium methyl carbonate with Grignard and organolithium
reagents.
he use of carbon dioxide as a C1 synthon in organic
synthesis has a rich history stemming from its low cost,
T
high abundance, and low toxicity.1 The Kolbe−Schmitt
synthesis of salicylic acid derivatives from phenols and the
Bosch−Mesier process for the production of urea from
ammonia and carbon dioxide constitute key examples of
industrial processes using CO2 as a reagent.2,3 The importance
of CO2 as a building block is also evident in the traditional
synthesis of carboxylic acids from CO2 and nucleophilic
organometallic reagents, in particular highly reactive organo-
lithium and Grignard reagents.4,5 In recent years, the directed
ortho metalation (DoM) reaction, a powerful strategy for the
construction of highly substituted aromatic and heteroaromatic
compounds, has been used to apply carboxylation with CO2 as a
wide-ranging method for the regioselective synthesis of 2-
substituted benzoic acids.6
Likewise, synthetic equivalents of the carbonyl dication CO+
+ C1 synthon [e.g., (tri)phosgene, CDI, and dialkyl
formamides] have proven to be invaluable in the synthesis of
symmetrical ketones from organometallic species. Conversely, a
general one-pot synthesis of unsymmetrical ketones under this
reaction manifold has proven to be challenging. This problem
has been addressed by Sarpong, whose carbonyl linchpin N,O-
dimethylhydroxylamine pyrrole (CLAmP) reagent allows the
one-pot synthesis of unsymmetrical ketones from organolithium
and Grignard reagents with a broad substrate scope.7 However,
the synthesis of CLAmP involves a two-step procedure from
costly reagents and requires purification via silica-gel chroma-
tography.
Figure 1. Synthesis and reactivity of alkyl metal carbonates.
alkoxide to CO2 (pellets or gas) and simple filtration of the
resulting solid product.8 In this manner, control over the desired
electronic and steric properties of the alkyl metal carbonate is
We considered metal alkyl carbonates 1 (Figure 1), which are
stable solids at room temperature, to represent an attractive and
inexpensive source of the C1 synthon. They are easily prepared
by exposure of an alcoholic solution of the corresponding metal
Received: March 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00773
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of Carboxylic Acids from Sodium Methyl Carbonate (SMC) and Grignard Reagents
a
b
Commercially available Grignard reagent. Grignard reagent prepared from the corresponding aryl bromide via magnesium−halogen exchange.
c
Grignard reagent prepared from the corresponding alkyne via direct magnesiation.
readily achieved through simple selection of the appropriate
metal counterion (Li, Na, K, or Mg) and alcohol solvent
(primary, secondary, or tertiary).
SMC to 1.2 equiv proved to be detrimental to the reaction,
giving benzoic acid in a reduced yield of 63%.
In pursuit of generalization of the reaction, the addition of
variously substituted aryl Grignard reagents to SMC was
undertaken (Scheme 1). The sterically encumbered mesityl
Grignard (6c) was well tolerated, as were aromatics bearing
electron-donating (6e−g) and electron-withdrawing substitu-
ents (6h−k). Addition of commercially available [3-bis-
(trimethylsilyl)amino]phenylmagnesium chloride to the SMC
electrophile afforded 3-aminobenzoic acid (6e) due to cleavage
of the TMS groups upon acidic workup. Furthermore, the
alkenyl Grignard reagent 1-methyl-1-propenylmagnesium bro-
mide proved to be an equally viable substrate, producing an
inseparable 2:1 mixture of tiglic (6m) and angelic (6m′) acids in
a combined 82% yield.
To further explore the scope of SMC as a CO2 surrogate
electrophile, both primary and secondary aliphatic Grignard
reagents were exposed to our standard conditions to furnish the
corresponding carboxylic acids (6n−p) in excellent yields.
Finally, alkynyl Grignards were also reactive substrates,
delivering propiolic acids bearing at the terminus aromatic
(6q), vinylic (6r), or aliphatic (6s and 6t) groups. Efforts to
expand the scope of this method to a number of heterocyclic
substrates, prepared by either direct magnesiation or magne-
sium−halogen exchange, proved to be unsuccessful.
Furthermore, the ambiphilic nature of alkyl metal carbonates
allows their use as a C1 synthon under a variety of different
reaction manifolds (Figure 1). For example, lithium ethyl
carbonate acts as a nucleophile upon treatment with alkyl
halides, giving rise to an efficient synthesis of unsymmetrical
carbonates (1 → 2).9 The electrophilic nature of sodium ethyl
carbonate has been demonstrated in the synthesis of salicylic
acid derivatives (1 → 3),10 which may be considered as
analogous to the Kolbe−Schmitt process. Similarly, magnesium
methyl carbonate (commercially available as a solution in DMF)
has frequently been used in the carboxylation of activated
methylene compounds, e.g., nitroalkanes, ketones, and enol
ethers (1 → 4).11 More recently, potassium methyl carbonate
has found application in the copper-catalyzed carboxylation of
aryl boronates (1 → 5),12 and sodium tert-butyl carbonate was
shown to be a unique base in the first catalytic Wittig reaction.13
Nevertheless, alkyl metal carbonates remain an underexplored
class of reagents whose utility is ripe for further exploitation.
Herein, we report the ability of sodium methyl carbonate
(SMC) to act selectively as either a HCO2+ or a CO++ synthon
in reactions with Grignard and organolithium species. Thus, we
show that the reaction of SMC with Grignard reagents gives rise
to the formation of carboxylic acids (including a 13C-labeled
benzoic acid), while reaction with aryllithium reagents affords
symmetrical ketones. Furthermore, we demonstrate the
orthogonal reactivity of SMC with different organometallic
nucleophiles and exploit it in a one-pot synthesis of unsym-
metrical ketones. In view of the ready availability of reactants
and procedural ease and convenience, the protocol is anticipated
to be of considerable utility and application.
From a comparative practical point of view, these reactions
(a) proceed at room temperature with only 2 equiv of SMC
whereas, in stark contrast, carboxylations with CO2 often require
low-temperature conditions (−78 or −45 °C), (b) require
minimal organic solvent, being routinely run at a concentration
of 0.5 M, and (c) afford pure carboxylic acids that require no
purification by column chromatography. Taken in sum, these
results demonstrate SMC as an effective CO2 surrogate
electrophile.
In the initial experiment, addition of commercially available
phenylmagnesium bromide to a suspension of sodium methyl
carbonate (2 equiv) in THF (0.5 M) at room temperature
afforded benzoic acid 6a in 88% yield. Decreasing the amount of
The use of SMC to facilitate the synthesis of a 13C-labeled
carboxylic acid was also achieved (Scheme 2). [13C]SMC was
prepared by exposing a methanolic solution of NaOMe to 13CO2
B
DOI: 10.1021/acs.orglett.9b00773
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Scheme 2. Synthesis of 13C-Labeled Mesitoic Acid (13C-6c)
from [13C]Sodium Methyl Carbonate (13C-SMC)
Scheme 4. Synthesis of Symmetrical Ketones from Sodium
Methyl Carbonate (SMC) and Aryllithium Reagents
gas and subsequent filtration of the product. During the process,
treatment of mesitylmagnesium bromide with [13C]SMC
delivered carboxylic acid [13C]6c in 52% yield, thus demonstrat-
ing the ability of SMC to act as an effective carrier for isotopic
labeling.
The carboxylation reaction of Grignard reagents was then
compared to the corresponding reaction of organolithiums,
commencing with commercially available phenyllithium (9; Ar
= Ph) as the standard substrate. In stark contrast to the reaction
of Grignard reagents, the addition of PhLi to SMC provided the
corresponding symmetrical ketone 7a in 76% yield (Scheme 3).
Scheme 3. Reaction of Sodium Methyl Carbonate (SMC)
with Phenyllithium (PhLi)
a
b
Commercially available aryllithium reagent. Aryllithium reagent
prepared from the corresponding aryl bromide via lithium−halogen
exchange.
corresponding reaction of 1-lithionaphthalene gave 1-butyl-
naphthalene (55% yield) as the major product, along with 1-
naphthoic acid (24%). The formation of the alkylated product
was rationalized by preferential reaction of the aryllithium with
bromobutane formed as a byproduct during the lithium−
halogen exchange. However, preparation of 2,2′-disubstituted
benzophenones was not precluded entirely, with the addition of
2-lithioanisole to SMC giving 2,2′-dimethoxybenzophenone 7e
in 46% yield. The lower yield of isolated 7f, derived from a more
highly electron-rich aryllithium, is due to impedance of the
second addition to the carboxylate intermediate, as evidenced by
isolation of the corresponding carboxylic acid as the major
product. Interestingly, the reaction of 2,2′-dilithiobiphenyl with
SMC affords fluorenone 7g in modest yield through an
intramolecular cyclization reaction.15
Having established the utility of SMC as both a HCO2+ and a
CO++ synthon owing to its differential reactivity with Grignard
reagents and alkyllithiums, we found the possibility of making
unsymmetrical ketones in a one-pot procedure to be an
attractive prospect. During the process, addition of an initial
Grignard reagent (8) to SMC delivered the expected
intermediate carboxylate salt (10), which remains stable under
the reaction conditions. Subsequent addition of the organo-
lithium to the reaction medium initiates nucleophilic attack on
the carboxylate salt and generated an unsymmetrical ketone
(11) in a single pot (Scheme 5).
This result was unexpected, because the classical reaction of
PhLi with CO2 delivers benzoic acid as the sole product. The
exclusive ketone formation may be rationalized by reference to
the textbook reaction of lithio carboxylates with RLi reagents. In
our case, presumably due to the attenuated electrophilicity of
SMC compared to CO2, reaction of the intermediate lithio
carboxylates with the organolithium reagent is fast compared to
that with SMC itself. This is in contrast to the reaction of the less
nucleophilic Grignard reagents. Attempts to retard the second
addition of PhLi to the carboxylate intermediate by varying the
stoichiometry, temperature, and solvent were explored and
proved to be unsuccessful.14 When the reaction was performed
in less polar solvents such as hexane or diethyl ether,
benzophenone formation once again prevailed.
With this result in hand, we established the generality of the
reaction of aryllithiums with SMC to give symmetrical
benzophenones (Scheme 4). The reaction was found to be
applicable also to organolithium reagents prepared from the
corresponding bromides via lithium−halogen exchange, giving
symmetrical ketones 7b−d in moderate yield. In contrast to the
formation of carboxylic acids, the synthesis of ketones proved to
be more sensitive to steric effects. For example, while 2-
lithionaphthalene delivered ketone 7d in 43% yield, the
To generalize, the addition of variously substituted aromatic
Grignard reagents to SMC followed by addition of PhLi
delivered the unsymmetrical benzophenone derivatives 11a−c
in synthetically useful yields (Scheme 5). Incorporation of a
C
DOI: 10.1021/acs.orglett.9b00773
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Organic Letters
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Experimental procedures (PDF)
Scheme 5. One-Pot Synthesis of Unsymmetrical Ketones by
Sequential Addition of Grignard and Aryllithium Reagents to
Sodium Methyl Carbonate (SMC)
Copies of 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jessop@queensu.ca.
*E-mail: victor.snieckus@chem.queensu.ca.
ORCID
Philip G. Jessop: 0000-0002-5323-5095
Victor Snieckus: 0000-0002-6448-9832
Present Address
†R.L.: Department of Physical Sciences, MacEwan University, 5-
138S, City Centre Campus, 10700-104 Avenue, Edmonton, AB,
Canada T5J 4S2.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
V.S. thanks NSERC DG for continuing support of synthetic
programs. P.G.J. thanks the Canada Research Chairs Program.
■
REFERENCES
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simple and effective C1 synthon in the synthesis of carboxylic
acids and symmetrical ketones. The attenuated electrophilicity
of SMC compared to that of CO2 allows its selective application
as either a HCO2+ or a CO++ synthon simply by choice of the
appropriate organometallic coupling partner. In addition, we
established this differential reactivity in a one-pot synthesis of
unsymmetrical benzophenone and acetophenone derivatives.
SMC is easy to prepare, using inexpensive reagents and isolation
by simple filtration, in contrast to alternative reagents that
require multistep syntheses from toxic and expensive precursors
(phosgene and CDI) and chromatography. We anticipate that
this method will complement or surpass traditional methods
(e.g., Friedel−Crafts), enjoy broad application, and stimulate
further studies on the use of alkyl metal carbonates in organic
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(14) See the Supporting Information for details.
(15) The attempted synthesis of symmetrical aliphatic ketones (e.g.,
by reaction of s-BuLi or n-HexLi with SMC) failed, with only
decomposition products being observed.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00773.
D
DOI: 10.1021/acs.orglett.9b00773
Org. Lett. XXXX, XXX, XXX−XXX