Acetyl nitrate mediated conversion of methyl ketones to diverse carboxylic acid derivatives

Article abstract of DOI:10.1039/d1ob00786f

The development of a novel acetyl nitrate mediated oxidative conversion of methyl ketones to carboxylic acid derivatives is described. By analogy to the haloform reaction and supported by experimental and computational investigation we propose a mechanism for this transformation.

Full text of DOI:10.1039/d1ob00786f

Organic &
Biomolecular Chemistry
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Acetyl nitrate mediated conversion of methyl
ketones to diverse carboxylic acid derivatives†
Cite this: Org. Biomol. Chem., 2021,
19, 5298
Joseph N. Capilato, Peter J. Pellegrinelli, Josephine Bernard, Logan Schnorbus,
Received 22nd April 2021,
Accepted 26th May 2021
Shane Philippi, Joseph Mattiucci, Erik P. Hoy
and Lark J. Perez
*
DOI: 10.1039/d1ob00786f
rsc.li/obc
The development of a novel acetyl nitrate mediated oxidative con- achieve this transformation, the well-known haloform reaction
version of methyl ketones to carboxylic acid derivatives is allows ready access to the corresponding carboxylic acids
described. By analogy to the haloform reaction and supported by however does not allow for the direct assembly of other car-
experimental and computational investigation we propose
a
boxylic acid derivatives.10,13 Hence, a reaction enabling direct
conversion of aromatic methyl ketones to a diverse array of car-
boxylic acid derivatives would be desirable.
mechanism for this transformation.
Synthetic methodologies enabling the oxidative cleavage of
carbon–carbon single bonds is an area of considerable recent
interest.1–7 The development of methodologies to achieve this
transformation would be anticipated to be of significant utility
by expanding substrate scope for oxidative C–C functionali-
zation reactions in academic and industrial applications. Due
to the high activation energy for this transformation and the
ubiquitous nature of C–C bonds, strategies that achieve selec-
tive cleavages remain challenging. To overcome these chal-
lenges several methodologies have been developed including
employing strained scaffolds,8 chelation assisted reactions3,4
and adjacent keto functionality.5,6,9 Here we report a general
strategy for the synthesis of carboxylic acid derivatives by oxi-
dative cleavage of methyl ketones.
Aromatic carboxylic acid derivatives are prevalent structural
motifs in drug molecules and materials. Synthetic access to
these compounds is most commonly achieved by initial car-
boxylation of the corresponding arene, requiring strong oxi-
dants (e.g. KMnO4, chromium-based oxidants) and harsh reac-
tion conditions.10 Preparation of carboxylic acid derivatives
requires a subsequent transformation of the carboxylic acid.
Aromatic methyl ketones serve as an attractive alternative to
aromatic carboxylic acids as they are readily available and can
be efficiently prepared by acylation.11,12 Conversion of this
alternative substrate requires the oxidative cleavage of a C–C
single bond. The most widely employed methodology to
Inspired by the reliability of the well-established haloform
reaction10,14 and based on early industrial studies on the reac-
tivity of acetyl nitrate, we envisioned a process enabling the net
oxidative C–C bond cleavage of aromatic methyl ketones.15,16
Analogous to the haloform reaction this process was anticipated
to proceed via a series of sequential α-nitration reactions and
subsequent nucleophilic displacement of an activated di- or
trinitromethane.17–25 Contrasting the haloform reaction, in
which the base (e.g. KOH) typically serves as nucleophile
forming carboxylic acids we envisioned the ability to easily
modulate the nature of the second nucleophile to allow direct
access to a diverse array of carboxylic acid derivatives.
Acetyl nitrate, formed in situ by the reaction of nitric acid
with acetic anhydride,26 has been reported to mediate the acy-
lation of acetoacetic esters in the presence of a protic or Lewis
acid catalyst.16 We initially evaluated the efficiency of
α-nitration of 4-bromoacetophenone using in situ generated
acetyl nitrate under acidic reaction conditions. Our initial
screen evaluated the consumption of 4-bromoacetophenone
and evaluated varying the stoichiometry of reagents and
solvent (Table 1). We found that a minimum of 3.0 equiv. of
acetyl nitrate was required to achieve <42% conversion of start-
ing material (entries 1–4). The addition of a Lewis Acid addi-
tive (entry 5) provided minimal benefit however excess nitric
acid (entries 6) provided a notable enhancement in the con-
sumption of 4-bromoacetophenone to predominantly a single
1
new chemical species by H-NMR. We subsequently evaluated
a series of potential solvents for the reaction (entries 6–10), of
which acetonitrile (entry 9) provided the highest level of con-
version in these evaluations.
Building on these observations we sought to isolate and
fully characterize the species produced through the action of
Rowan University, Department of Chemistry & Biochemistry, 201 Mullica Hill Rd.,
Glassboro, NJ, 08028, USA. E-mail: perezla@rowan.edu
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, spectroscopic analysis, computational details. See DOI: 10.1039/
d1ob00786f
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Table 1 Initial survey of the reaction of a methyl ketone with in situ
generated acetyl nitratea
HNO3
(equiv.)
Ac2O
(equiv.)
Solvent
(0.5 M)
Entry
% Conversionb
1
2
3
1
2
2
3
3
6
6
6
6
6
1
1
2
3
3
3
3
3
3
3
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
THF
DMSO
MeCN
DMF
2%
15%
15%
42%
43%
61%
46%
51%
83%
0%
4
5c
6
7
8
9
10
a Reactions were performed with 1 (1.0 equiv.), HNO3, Ac2O, additives
in the indicated solvent (0.5 M). b All percent conversions were deter-
mined by monitoring the disappearance of the 1H-NMR signal of
4-bromoacetophenone (δ 7.52, d). c With boron trifluoride diethyl ethe-
rate (0.1 equiv.).
Fig. 1 One-pot acetyl nitrate-mediated conversion of methyl ketones
to carboxylic acid derivatives. Examples varying the heteroatom nucleo-
phile. Yield based on heteroatom nucleophile.
alkylation.30,31 Notably, even highly unreactive heteroatom
nucleophiles including aniline and carbamates were competent
in this process (13 and 14), however, with diminished yield.
With a range of heteroatom nucleophiles having been
identified as competent in this transformation, we turned
attention to evaluate some examples changing the structure of
the methyl ketone (Fig. 2) . In addition to 4-bromo substituted
acetyl nitrate on 4-bromoacetophenone in the presence of
excess HNO3. In the reaction of 4-bromoacetophenone in
MeCN with 6.0 equiv. HNO3 and 3.0 equiv. Ac2O, we were
delighted to successfully isolate the product 2, the enol tauto-
mer of the desired dinitro methyl ketone.27 While sufficient
quantities of 2 could be purified by flash silica gel chromato-
graphy, this species proved to be reactive and readily converts
to 4-bromobenzoic acid upon storage or exposure to water.
Having confirmed the production of a nitrated intermediate
(i.e. 2) through the action of acetyl nitrate on a methyl ketone,
we sought to examine if this intermediate species could be
trapped by the addition of a suitable nucleophile for the one
pot conversion of a methyl ketone to carboxylic acid derivatives.
Therefore, following reaction of the methyl ketone with HNO3
and Ac2O the reaction mixture was neutralized with i-Pr2NEt
and treated with an alcohol or amine nucleophile for the syn-
thesis of esters and amides, respectively (Fig. 1). To our delight
we found that oxygen-based nucleophiles effectively engaged
the intermediate nitrated species in productive reaction.
Beyond simply trapping the intermediate through the addition
of water to provide a carboxylic acid, reactivity directly parallel-
ing the haloform reaction, we found that aliphatic alcohols and
phenol could be efficiently used directly providing esters 6–8.
Notably, these reactions proceed directly from the free alcohol,
without the need for preformation of an alkoxide, demonstrat-
ing the electrophilicity of the dinitroketone intermediate.
Additionally, we find that both primary and secondary aliphatic
amines can be engaged in reaction to directly provide amides
9–11 in moderate to good yields. The Weinreb-Nahm
amide28,29 can be prepared in high yield providing an alterna-
tive strategy for the conversion of a methyl ketone into a differ-
Fig. 2 One-pot acetyl nitrate-mediated conversion of methyl ketones
to carboxylic acid derivatives. Examples varying the methyl ketone sub-
strate. a Yield based on methyl ketone. b Yield based on heteroatom
entially
substituted
ketone,
complementing
enolate nucleophile.
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aromatic methyl ketones other aromatic halogens are well tol-
erated (15–18). Further, the electron poor 2-nitro, 3-nitro and
4-nitro substituted methyl ketones engaged effectively in this
reaction (19). Substrate scope for the methyl ketone was found
to be limited for aromatic substrates in which ring nitration
serves as a competing reaction process. For example; acetophe-
none, para-methoxy acetophenone and heterocyclic methyl
ketones did not produce any desired product. Contrasting this
limitation, aliphatic ketones were found to be capable of
serving as substrates in this reaction with moderate to high
efficiency. Alkyl ketones in which only one enol can form were
converted into amides and carboxylic acids effectively (20 and
21). Alkyl ketones for which isomeric enols are possible pro-
ceeded with varying efficiency. In certain examples (i.e. 22),
providing only low yield of the desired product. However, in
the case of cyclohexyl methyl ketone, this transformation
proved reliable, providing 23 in high yield.
Having defined an acetyl-nitrate mediated process for the
direct conversion of aromatic methyl ketones to a diverse
array of carboxylic acid derivatives, we sought to further
expand on the utility of this methodology in the synthesis of
heterocycles from methyl ketones. We rationalized that the
Fig. 4 Proposed mechanism for acetyl nitrate-mediated synthesis of
carboxylic acid derivatives from methyl ketones.
introduction of a bis-functionalized nucleophile may enable mononitrated intermediate 31.32 The requirement for an
the one-pot oxidative conversion of methyl ketones to hetero- additional acid additive is likely important in allowing for
cycles and therefore evaluated the reaction with a di-amine efficient enol formation for reaction with acetyl nitrate as the
and amino-alcohols (24, Fig. 3). Pleasantly, we found that keto form of the starting material (4) will be favoured over the
this methodology proved useful in the synthesis of benzimi- required enol form (29).33 Subsequent enol formation from
dazole 26 and benzoxazoles 27–28 in moderate to excellent this mono-nitrated intermediate provides 32 which again
yields.
reacts with acetyl nitrate to produce the penultimate dini-
Based on our observations from the development of this trated intermediate 33. Our isolation and characterization of
reaction process and by analogy to the mechanism of the the enol tautomer of this ketone (34) and the absence of the
haloform reaction, we developed a proposed sequence of keto tautomer of this species (33) by NMR analysis suggests
events for the current reaction (Fig. 4). Firstly, in reactions that the enol tautomer of the dinitro ketone is thermo-
with in situ generated acetyl nitrate we observe the production dynamically favoured. We note that this contrasts the halo-
of a dinitro enol, 34. This intermediate, while sensitive form reaction performed under acidic enol formation con-
to reaction with water and other heteroatom nucleophiles, ditions in which each successive addition of halide further
is isolable, enabling characterization by 1H-NMR and disfavours the formation of a nucleophilic enol. For this
13C-NMR.27 Therefore, we propose that keto to enol tautomeri- reason, the haloform reaction under acidic enol forming con-
zation of the starting material (4) precedes the reaction of ditions is most widely employed for selective mono-halogena-
enol 29 with in situ generated acetyl nitrate 30 to produce tion of a ketone.34 Contrasting the haloform, this reaction
process may, in fact, favour additional nitration events and
thereby enable haloform-like reactivity under acidic conditions
where the traditional haloform reaction would not be success-
ful.14 We note that the dinitromethyl ketone 33/34 can
undergo further nitration to produce a trinitromethyl ketone
intermediate.17 While we have not observed evidence to
support the existence of this intermediate, we cannot fully
exclude its formation. By contrast, we can isolate the dinitro
intermediate 33/34 (i.e. 2) and confirm that this intermediate
proceeds to 6 upon exposure to water. Further, we have con-
firmed that dinitration is sufficient for carbon–carbon bond
cleavage as propiophenone undergoes efficient oxidative C–C
bond cleavage to produce the carboxylic acid (see ESI†).
Therefore, we hypothesize that the dinitro intermediate
(33/34) may be operative in the addition of heteroatom nucleo-
Fig. 3 One-pot conversion of an aromatic methyl ketone to hetero-
cycles. Yield based on heteroatom nucleophile.
philes, ultimately producing a diverse array of carboxylic acid
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derivatives (5) with the expulsion of dinitromethane. This molecules.37 We note that the energy difference between 33
process could reasonably proceed from either/both of the tau- and 34 is smaller than the transition state energy, accordingly
tomers, 33 and 34.15 To help distinguish between the two path- both tautomers are predicted to be energetically accessible for
ways (Fig. 4), we examined simplified versions of each pathway this reaction.
using acetophenone as our methyl ketone and hydroxide as
Examining the first transition state for both pathways we
the heteroatom nucleophile (Fig. 5). The modified 5, 33, 34, find a free energy barrier of 18.1 kcal mol−1 from 34 to 35 and
and 35 ground states and were optimized using the wB97x-D 30.4 kcal mol−1 for 33 to the products. The free energy barrier
DFT functional in the 6-31++G** basis set with solvent effects from 34 to 35, mechanistically analogous to a Michael addition
included using a PBF model for acetonitrile. The 2 transition to an α,β-unsaturated nitroalkene, is 12.3 kcal mol−1 lower
states (33-TS, 34-TS) were then obtained using the same func- than the barrier for direct nucleophilic addition to the ketone
tional, implicit solvent, and basis set. Considering the tauto- 33. This could suggest that the Michael addition pathway
mers, we found that 33 is thermodynamically favoured over 34 (pathway 2, Fig. 4) is overall favoured due to its lower free
by a free energy difference of 7.87 kcal mol−1. This finding energy barrier for reaction, however, we were not successful in
contrasts with the experimental result where only 34 tautomer identifying a definitive transition state for 35-TS. The scenario
was isolated.35–38 To confirm this preference, we examined described here in which the dinitroenol 34 is rapidly equili-
each tautomer with multiple functionals and a second basis brating with ketone 33 however proceeds through a lower
set. Free energy differences and other electronic structure data energy pathway to product would represent an example of
for these calculations are available in the ESI.† We found that Curtin-Hammett kinetics.39 We note that while computation-
the preference for the 33 tautomer was robust over a variety of ally we find the energy barrier lower for reaction from enol 34
functionals and basis sets (see ESI†). Interestingly in one case, the pathway from ketone 33 is viable based on the successful
B3PW97-D3/6-31++G**, a much smaller free energy difference C–C bond cleavage in propiophenone which can not form the
of 0.43 kcal mol−1 still in favour of 33 was observed. It may dinitroenol tautomer (see ESI†).
also be the case that the exclusive observation of the enol tau-
In summary, we have developed a new reaction that
tomer (i.e. 34) is a result of substituent effects on relative enol/ expands on the venerable haloform reaction. This reaction,
keto stability or solvent effects.35–38 To investigate this, we also mediated by acetyl nitrate, enables the one-pot conversion of
examined the free energy difference for 33/34 in an implicit methyl ketones into carboxylic acid derivatives and hetero-
chloroform solvent and found a very similar free energy differ- cycles. In this initial disclosure we have defined the scope and
ence of 8.79 kcal mol−1 in favour of the keto form (33). This illuminated some mechanistic aspects of this new reaction
result along with previous computational studies of keto/enol process. Future studies will seek to address some of the limit-
tautomers indict that implicit solvent DFT calculations alone ations of the current reaction process, further expand the
are not enough to characterize the tautomer equilibrium.36,37 scope and applicability of this direct synthetic conversion of
We are currently seeking to better refine our understanding of methyl ketones to a diverse array of carboxylic acid derivatives
the influence of stability differences between the enol and keto and continue to refine our understanding of the role of the
tautomers for both the haloform reaction as well as this trans- relative stability of enol/keto tautomers in these processes.
formation, including the possible impact of trace water com-
plicating correlation of our experimental vs. computational
studies and exploring the effect of including explicit solvent Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to the New Jersey Health Foundation (PC104-
77) and Rowan University for financial support.
Notes and references
1 F. Song, T. Gou, B.-Q. Wang and Z.-J. Shi, Chem. Soc. Rev.,
2018, 47, 7078–7115.
2 P. Dai, X. Ning, H. Wang, X. Cui, J. Liu, J. Qu and Y. Kang,
Angew. Chem., Int. Ed., 2019, 58, 5392–5395.
3 B. Rybtchinski and D. Milstein, Angew. Chem., Int. Ed.,
1999, 38, 870–883.
4 Z. Rong, H. N. Lim and G. Dong, Angew. Chem., Int. Ed.,
2018, 57, 475–479.
Fig. 5 Differences in total free energy between various states as com-
pared to 33 + OH−. Includes solvent and ZPE corrections. The product
from both pathways is benzoic acid.
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5 R. Ma, L.-N. He, A.-H. Liu and Q.-W. Song, Chem. Commun., 23 A. Langlet, N. V. Latypov, U. Wellmar, U. Bemm, P. Goede,
2015, 52, 2145–2148.
J. Bergman and I. Romero, J. Org. Chem., 2002, 67, 7833–
6 P. Sathyanarayana, O. Ravi, P. R. Muktapuram and
S. R. Bathula, Org. Biomol. Chem., 2015, 13, 9681–9685.
7 F. Chen, T. Wang and N. Jiao, Chem. Rev., 2014, 114, 8613–
8661.
7838.
24 N. V. Latypov, M. Johansson, E. Holmgren, E. V. Sizova,
V. V. Sizov and A. J. Bellamy, Org. Process Res. Dev., 2006,
11, 56–59.
8 L. Souillart and N. Cramer, Chem. Rev., 2015, 115, 9410–9464. 25 M. Fileti and G. Ponzio, J. Prakt. Chem., 1897, 55, 186–201.
9 C. Zhang, P. Feng and N. Jiao, J. Am. Chem. Soc., 2013, 135, 26 F. G. Bordwell and E. W. Garbisch, J. Am. Chem. Soc., 1960,
15257–15262.
10 M. A. Ogliaruso and J. F. Wolfe, in Comprehensive Organic 27 V. M. Berestovitskaya, E. A. Pabolkova, A. V. Belyakov and
Functional Group Transformations, ed. A. R. Katritzky, O. E. V. Trukhin, Russ. J. Gen. Chem., 2007, 77, 1912–1918.
Meth-Cohn and C. W. Rees, Elsevier Science, 1995, pp. 28 S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22,
23–120. 3815–3818.
11 G. A. Olah and S. Kobayashi, J. Am. Chem. Soc., 1971, 93, 29 S. Balasubramaniam and I. S. Aidhen, Synthesis, 2008,
6964–6967. 3707–3738.
12 M. M. Heravi, V. Zadsirjan, P. Saedi and T. Momeni, RSC 30 M. C. Kohler, S. E. Wengryniuk and D. M. Coltart, in
82, 3588–3598.
Adv., 2018, 8, 40061–40163.
13 G. I. Nikishin, M. N. Elinson and I. V. Makhova, Angew.
Chem., Int. Ed., 1988, 27, 1716–1717.
Stereoselective Synthesis of Drugs and Natural Products, ed. V.
Andrushko and N. Andrushko, John Wiley & Sons, 2013,
183–213.
14 R. C. Fuson and B. A. Bull, Chem. Rev., 1934, 15, 275–309.
15 A. Chentsova, D. B. Ushakov, P. H. Seeberger and
K. Gilmore, J. Org. Chem., 2016, 81, 9415–9421.
16 S. Sifniades, J. Org. Chem., 1975, 40, 3562–3566.
31 A. Streitwieser, Y.-J. Kim and D. Z.-R. Wang, Org. Lett.,
2001, 3, 2599–2601.
32 G. B. Bachman and T. Hokama, J. Org. Chem., 1960, 25,
178–180.
17 Dinitromethane and trinitromethane salts have been 33 G. E. Lienhard and T.-C. Wang, J. Am. Chem. Soc., 1969, 91,
reported to be unstable and undergo detonation by heat or 1146–1153.
impact. We have not encountered any issues during our 34 A. Erian, S. Sherif and H. Gaber, Molecules, 2003, 8, 793–
studies in this area however proper safety considerations
are advised, especially when scaling up the reaction.
18 R. Ballini and G. Bosica, Tetrahedron, 1997, 53, 16131–
16138.
19 R. Ding, P. R. Bakhshi and C. Wolf, J. Org. Chem., 2017, 82,
1273–1278.
865.
35 S. W. Paine, A. J. Kresge and A. Salam, J. Phys. Chem., 2005,
109, 4149–4153.
36 P. V. Bharatam and S. Khanna, J. Phys. Chem., 2004, 108,
3784–3788.
37 G. Alagona, C. Ghio and P. I. Nagy, Phys. Chem. Chem.
Phys., 2010, 12, 10173–10188.
20 R. Ding and C. Wolf, Chem. Commun., 2016, 52, 3576–3579.
21 Y. Tang, C. He, G. H. Imler, D. A. Parrish and J. M. Shreeve, 38 The Chemistry of Enols, ed. Z. Rappoport, John Wiley,
Dalton Trans., 2019, 48, 7677–7684.
Chichester, U.K., 1990.
22 J. C. Turner, Chem. Commun., 1967, 0, 396–397.
39 J. I. Seeman, Chem. Rev., 1983, 83, 83–134.
5302 | Org. Biomol. Chem., 2021, 19, 5298–5302
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