Metal-free oxidative nitration of α-carbon of carbonyls leads to one-pot synthesis of thiohydroximic acids from acetophenones

Article abstract of DOI:10.1021/acs.orglett.6b01807

A metal-free nitration of the α-C-H to carbonyl in propiophenones was achieved with I₂/NaNO₂ in the presence of an oxidant in dimethyl sulfoxide (DMSO) as the medium. Conversely under similar conditions, reaction of acetophenones produced thiohydroximic acids via a radical-based cascade event which involves oxidative nitration of the α-carbon to a carbonyl followed by Michael addition of the thiomethyl group from DMSO and subsequent rearrangement. Besides DMSO, the scope of the reaction encompasses other symmetrical and unsymmetrical dialkylsulfoxides.

Full text of DOI:10.1021/acs.orglett.6b01807

Letter
pubs.acs.org/OrgLett
Metal-Free Oxidative Nitration of α‑Carbon of Carbonyls Leads to
One-Pot Synthesis of Thiohydroximic Acids from Acetophenones
Shashikant U. Dighe,†,∥ Sushobhan Mukhopadhyay,†,∥ Kumari Priyanka,†,§ and Sanjay Batra*,†,‡
†Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road,
Lucknow 226031, India
‡Academy of Scientific and Innovative Research, New Delhi 110025, India
S
* Supporting Information
ABSTRACT: A metal-free nitration of the α-C−H to carbonyl in propiophenones was achieved with I2/NaNO2 in the presence
of an oxidant in dimethyl sulfoxide (DMSO) as the medium. Conversely under similar conditions, reaction of acetophenones
produced thiohydroximic acids via a radical-based cascade event which involves oxidative nitration of the α-carbon to a carbonyl
followed by Michael addition of the thiomethyl group from DMSO and subsequent rearrangement. Besides DMSO, the scope of
the reaction encompasses other symmetrical and unsymmetrical dialkylsulfoxides.
Scheme 1. Reported α-C−H Functionalization of Ketones
he hypoiodite-mediated oxidative coupling reactions
Tinvolving a stoichiometric amount of iodine or iodide
together with a co-oxidant are considered to be valuable organic
transformations. In pioneering work, the Ishihara group utilized
in situ generated chiral quaternary ammonium hyopoiodite for
oxidative α-phenoxyetherification and α-oxyacylation of carbon-
yl compounds.1 Subsequently, diverse oxidative coupling
reactions have been investigated employing this approach.2
Notably, these reactions resulted in C−O, C−N, or C−C
coupling at the proximal carbon to the carbonyl group.3−5 In
addition, metal-based α-functionalization of carbonyls under
oxidative conditions is also known.6 However, the oxidative
nitration at the α-carbon to the carbonyl group under metal or
metal-free conditions remains elusive. We recently demonstrated
the I2/NaNO2-mediated oxidative nitration of nitroalkanes for
the formation of 3-nitroisoxazoles.7 Based on the analogy to our
work and literature reports about hypoiodite-mediated coupling
reactions we reasoned that I2/NaNO2 in the presence of
dimethyl sulfoxide (DMSO) as the co-oxidant may induce
oxidative nitration of the α-carbon to the carbonyl resulting into
α-nitroketones. Such metal-free simple synthesis of α-nitro-
ketones is especially attractive since they are versatile synthons in
organic synthesis for obtaining diverse heterocycles and acyclic
amides, ketones, aminoketones, and tosyl hydrazones.8 Here, we
disclose synthesis of α-nitro ketones from propiophenones via
oxidative nitration of the α-carbon to the carbonyl with I2/
NaNO2 in the presence of aq. hydrogen peroxide (H2O2).
Intriguingly under similar conditions, reactions of acetophe-
nones resulted into thiohydroximic acids (Scheme 1).
Unfortunately, the reaction was unsuccessful, and therefore, it
was repeated under heating at 100 °C. Gratifyingly, the reaction
at elevated temperature was completed in 12 h furnishing a
mixture of products from which the major compound that was
isolated in 39% yield was identified as the expected 2-nitro-1-
phenylpropan-1-one (2a). This result prompted us to optimize
the reaction for improving the yield of 2a (refer to Table 1 in
Supporting Information (SI)). Performing the reaction in
DMSO as solvent and co-oxidant furnished 2a in 58% yields.
Notably, however, using DMSO as solvent and adding external
oxidant not only improved the yield of 2a but also decreased the
reaction time to 8 h. Perhaps the external oxidant facilitated the
oxidation of iodide to iodine. The best yield of 2a (72%) was
obtained when H2O2 (35 wt % in H2O) was employed as the
external oxidant whereas with K2S2O8, Oxone, TBHP (70 wt % in
H2O), and O2 the yield of 2a ranged between 62% and 70%. We
also investigated the reaction in the presence of 30 mol % of
TBAI and H2O2 (2.0 equiv) in DMSO resulting in the formation
of 2a in 43% yield. Conversely, replacing DMSO with DMF as
the medium and using H2O2 as the sole oxidant afforded 2a in
We commenced the study by treating propiophenone (1a)
with iodine (30 mol %), NaNO2 (1.2 equiv), and DMSO (5.0
equiv) using DMF as the medium at room temperature.
Received: June 21, 2016
© XXXX American Chemical Society
A
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Letter
48% yield. Thus, the optimized conditions that produced the best
yield of 2a was propiophenone (1a, 1.5 mmol), NaNO2 (1.2
equiv), I2 (30 mol %), and H2O2 (2.0 equiv) in DMSO (5.0 mL)
at 100 °C for 8 h (see SI).
Subsequently, we tested the generality of the protocol by
subjecting other substrates (1b−e) in the reaction and found that
in each case the transformation was successful, affording the
corresponding products 2b−e (Scheme 2). Next, we investigated
this context, the reaction of 7b was screened under different
conditions (for summary of results refer to Table 2 in the SI).
Replacing the external oxidant H2O2 with TBHP improved the
overall yield, but the two products 8b and 3b were formed in 38%
and 41% yields. The yield of the products, however, decreased in
the presence of oxone. Enhancing the amount of iodine to 50 mol
% and using TBHP as the oxidant boosted the overall yield of the
mixture. Subsequently performing the reaction at 120 °C
completed it in 6 h but produced more benzoic acid whereas
at 90 °C it gave a 2:1 mixture of 8b and 3b. Next the reaction was
conducted in the absence of an external oxidant maintaining the
temperature at 90 °C. Although the reaction was now completed
in 12 h, gratifyingly 3b was formed in a minor quantity only.
Increasing the amount of iodine further to 1.0 equiv was found to
have a detrimental impact on the formation of 8b. Alternating
iodine with NIS gave the product in 63% yield with no detection
of acid. We also screened the reaction in the presence of copper
salts but without any success. Screening the reaction in different
mediums revealed that in water 3b (64%) was the sole product
whereas in MeCN the reaction failed. Replacing DMSO with
DMF produced 2-hydroxy-1-(4-bromophenyl)ethan-1-one (9)
(52%) with recovery of the starting substrate (26%) (see SI
Table 2). Thus, for conversion of acetophenones to thiohy-
droximic acids, the optimized conditions were 7b (0.2 g, 1.01
mmol), NaNO2 (1.2 equiv), and iodine (50 mol %) in DMSO (5
mL) under heating at 90 °C for 12 h.
Scheme 2. Oxidative Nitration of the α-C−H to Carbonyl
substrates 1f and 1g bearing an electron-withdrawing group and
discovered both substrates (1f and 1g) gave benzoic acid 3a
exclusively which was in agreement with the literature.9 We
examined the scope of the reaction with a representative cyclic
substrate 7-methoxy-2-phenylchroman-4-one 4 as well and
found that, under the optimized conditions, 4 was dehydro-
genated only to afford the 7-methoxy-2-phenyl-4H-chromen-4-
one 5 in 86% yield (Scheme 3). On the other hand, performing
With the optimized conditions in hand, we turned our
attention toward testing the scope of the protocol with a variety
of acetophenones (7) including heteroaromatic variants. There-
fore, in the first set of reactions several substituted
acetophenones (1a−r) were evaluated, and it was found that
all substrates irrespective of the electronic nature of the
substituents present on the phenyl ring afforded thiohydroximic
acids (8a−8r) in 67−87% yields (Scheme 4). The structure of
these products was secured unambiguously by carrying out X-ray
analysis of the crystal of one of the analogues 8q. The
phenanthridine-based acetophenones also furnished the prod-
ucts 8s and 8t in good yields. Different heteroaromatic
acetophenones (7v−z, 7aa−ac) also underwent the reaction to
Scheme 3. Results of Reaction with 7-Methoxy-2-
phenylchroman-4-one (4)
the reaction of 4 in the absence of NaNO2 resulted in a mixture of
two products from which the major product (52%) was identified
as 3-iodo-7-methoxy-2-phenyl-4H-chromen-4-one (6) whereas
the minor product (24%) was identified to be compound 5.
Increasing the loading of iodine to 60 mol % however furnished 6
in 84% yield exclusively.
a
Scheme 4. Scope of the Protocol with Acetophenones
To overcome the limited commercial availability of
propiophenones and in our efforts to expand the scope of the
protocol, we considered probing the methodology with
acetophenones which are cheap and readily available and were
expected to afford α-nitroacetophenones. Accordingly, (4-
bromophenyl)acetophenone (7b) was treated with I2/NaNO2
under the standardized conditions leading to the formation of a
mixture of two products in 42% and 21% yields. The major
product was identified to be the corresponding benzoic acid 3b
whereas the minor product after detailed spectroscopic analysis
was delineated to be methyl 2-(4-bromophenyl)-N-hydroxy-2-
oxoethanimidothioate 8b. The formation of benzoic acid may be
attributed to transformation of acetophenone to phenylglyoxal
or glyoxalic acid followed by degradation10 while the isolation of
8b may be explained via simultaneous generation of α-
nitroacetophenone followed by addition of the methyl sulfide
group from DMSO (vide infra). It may be noted that the
nitronate ion produced by 2-nitroacetophenone is susceptible to
nucleophilic attack due to the presence of an α-hydrogen but
such an opportunity is unavailable in 2-nitropropiophenone.
Given the importance of thiohydroximic acids,11 we were
invoked to optimize the reaction to improve the yields of 8b. In
a
All reactions were performed at 0.2 g of acetophenones.
B
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give respective products (8v−z, 8aa−ac) in 72−91% yields. For
7x, the pyrrole ring was iodinated at the 5-position leading to 8x.
The reaction with ferrocene-2-acetophenone 7ad was successful
as well affording the product (8ad) in 48% yields. Scaling up the
reaction to the gram scale using 7b as the reactant produced 8b
without any attenuation in yield. However, when acetophenone
was replaced by 2-heptanone (7ae) the reaction failed to afford
the corresponding product (8ae).
regenerate molecular iodine and dimethyl sulfide. The
intermediate A is transformed to the carbocation intermediate
B via single electron oxidation.4d Subsequent nucleophilic
addition of the nitrate anion onto B results in α-nitro ketone
C. When R = H, the nitro group tautomerizes to the nitronate D
succeeded by attack of the in situ formed dimethyl sulfide on the
imine carbon leading to E. Subsequent rearrangement with loss
of methanol in F afforded the thiohydroximic acid.
Mechanistic considerations generated interest to investigate
the fate of the protocol with respect to other sulfoxides.
Therefore, 7b was treated with different sulfoxides 13a−d, and it
was found that while 13a−c smoothly furnished the correspond-
ing hydroximic acids 14a−c, 13d failed to give 14d inferring that
dialkylsulfoxides are essentially required for the success of the
protocol (Scheme 7). Since oxidative conditions were used for
In a classical event,4a,6a the reaction of 7a with iodine is
expected to produce 2-iodo-1-phenylethanone 10 that may
undergo nucleophilic substitution with NaNO2 to afford 2-nitro-
1-phenylethanone 11 which on addition of dimethyl sulfide
produces 8a. In support of the suggested mechanism control
experiments were carried out. Treating 10 with I2/NaNO2 under
the standardized conditions gave 8a in a trace amount only with
the major product being the acid 3a. A similar reaction of 10 in
the absence of I2 also resulted in trace formation of 8a while most
of the starting 7a was recovered unreacted. These results
suggested that perhaps 10 is not the possible intermediate and
the proposed nucleophilic substitution pathway may not be
operating. Consequently, as reported by Guo et al.,4d the
possibility of a radical mechanism was probed. Accordingly,
acetophenone 7a was treated with I2/NaNO2 in DMSO in the
presence of TEMPO or 2,6-di-tert-butyl-4-methylphenol
(BHT). Whereas the reaction of TEMPO afforded 8a in 24%
yield, the reaction with BHT gave 8a in a trace amount only
(Scheme 5). Simultaneously treating 2-nitro-1-phenylethanone
a
Scheme 7. Scope of Protocol with Sulfoxides
a
All reactions were performed at 0.1 g of 7b and 3.0 mL of sulfoxide.
the reaction, for extending the scope, in a model reaction we
treated secondary benzyl alcohol 15 under the standardized
conditions to expectedly isolate 8a in 62% yield (Scheme 8).
Scheme 5. Control Experiments
Scheme 8. Scope of Protocol with Secondary Alcohol
Finally, a few synthetic transformations of the α-nitration
products and thiohydroximic acids using 2a and 8b as the model
substrates were performed. Treating 2a with (S)-1-phenylethan-
1-amine under neat conditions15 produced the corresponding
amide 16 while Nef-reaction of 2a in the presence of DBU
furnished 1-phenylpropane-1,2-dione (17) (Scheme 9). For 8b,
11 with iodine in the presence of DMSO furnished 8a in 82%
yield indicating 11 as the possible intermediate in this
transformation. Although in the recent past there have been
several reports related to the introduction of the SMe group from
DMSO,13,14 to independently gain supporting evidence we
performed the reaction of 7b in the presence of deuterated
DMSO to obtain 12 containing a deuterated thiomethyl moiety.
On the basis of the above experiments a tentative reaction
mechanism is delineated in Scheme 6. Initially the molecular
iodine decomposes into an iodine radical that abstracts the α-
hydrogen of the ketone to form the radical intermediate A
together with liberation of HI which is trapped by DMSO to
Scheme 9. Synthetic Transformations of α-Nitration Product
2a
a
a
Reactions were carried out with 0.1 g of 2a.
representative transformations on all three functional groups
were attempted. Reducing the ketone in the presence of NaBH4
afforded the alcohol 18 while acetylation and tosylation of the
oxime moiety resulted in N-acetoxy (19) and N-tosyloxy (20)
derivatives, respectively (Scheme 10). Oxidizing the thiomethyl
group of 8b in the presence of H2O2 gave the methylsulfinyl
derivative 21 in 82% yield.16
Scheme 6. Plausible Mechanism of Reaction
In summary, we have demonstrated I2/NaNO2/DMSO to be
an effective reagent for α-nitration of carbonyls. In contrast to
propiophenones or higher homologues wherein α-nitroketones
were isolated, acetophenones afforded thiohydroximic acids.
C
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Scheme 10. Synthetic Transformations of Thiohydroximic
Acid 8b
a
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a
Reactions were carried out with 0.1 g of 8b.
Mechanistically the formation of thiohydroximic acid is
suggested to proceed via a radical mechanism, and the protocol
is amenable to other dialkyl sulfoxides beside DMSO. Attractive
attributes of this protocol include that it is metal-free, uses
commercially available starting substrates, and is of general
nature and scalable. Further utility of the I2/NaNO2 system for
diverse synthetic objectives is being explored and will be reported
in the future.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01807.
(7) Dighe, S. U.; Mukhopadhyay, S.; Kolle, S.; Kanojiya, S.; Batra, S.
Angew. Chem., Int. Ed. 2015, 54, 10926.
(8) Lian, Z.; Friis, S. D.; Skrydstrup, T. Chem. Commun. 2015, 51, 3600
and references cited therein.
Experimental details, spectroscopic data, X-ray data for 8q,
1
and copies of H and 13C NMR data for all compounds
(PDF)
(9) Tada, N.; Shomura, M.; Cui, L.; Nobuta, T.; Miura, T.; Itoh, A.
Synlett 2011, 2011, 2896.
AUTHOR INFORMATION
Corresponding Author
■
(10) (a) Zhu, Y.-P.; Liu, M.-C.; Cai, Q.; Jia, F.-C.; Wu, A.-X. Chem. -
Eur. J. 2013, 19, 10132 and references cited therein. (b) Zhang, S.; Guo,
L.-N.; Wang, H.; Duan, X.-H. Org. Biomol. Chem. 2013, 11, 4308.
(c) Battini, N.; Padala, A. K.; Mupparapu, N.; Vishwakarma, R. A.;
Ahmed, Q. N. RSC Adv. 2014, 4, 26258−26263. (d) Viswanadham, K.
K. D. R.; Reddy, M. P.; Sathyanarayana, P.; Ravi, O.; Kant, R.; Bathula, S.
R. Chem. Commun. 2014, 50, 13517. (e) Venkateswarlu, V.; Kumar, K.
A. A.; Gupta, S.; Singh, D.; Vishwakarma, R. A.; Sawant, S. D. Org.
Biomol. Chem. 2015, 13, 7973.
*E-mail: batra_san@yahoo.co.uk, s_batra@cdri.res.in.
Present Address
§Kumari Priyanka is a Research Intern from NIPER, Raebareli in
the laboratory for the year 2015−2016.
Author Contributions
∥S.U.D. and S.M. contributed equally.
Notes
(11) Lemercier, B. C.; Pierce, J. G. Synlett 2016, 27, 181 and references
cited therein.
(12) (a) Gao, M.; Yang, Y.; Wu, Y. D.; Deng, C.; Shu, W. M.; Zhang, D.
X.; Cao, L. P.; She, N. F.; Wu, A. X. Org. Lett. 2010, 12, 4026.
(b) Mohammed, S.; Vishwakarma, R. A.; Bharate, S. B. J. Org. Chem.
2015, 80, 6915. (c) Zhu, Y. P.; Lian, M.; Jia, F. C.; Liu, M. C.; Yuan, J. J.;
Gao, Q. H.; Wu, A. X. Chem. Commun. 2012, 48, 9086.
(13) Some recent citations for DMSO as a source for the SMe group:
(a) Yin, G.; Zhou, B.; Meng, X.; Wu, A.; Pan, Y. Org. Lett. 2006, 8, 2245.
(b) Luo, F.; Pan, C.; Li, L.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.U.D. and S.M. gratefully acknowledge the financial support
from CSIR, New Delhi in the form of a fellowship. Authors
acknowledge the SAIF Division of CDRI for providing the
spectroscopic data. Prof. Sandeep Verma, IIT Kanpur and his
student (B. Mahopatra) are acknowledged for carrying out the X-
ray diffraction analysis of 8q. The work was carried out by funds
received under the CSIR Network project HOPE. CDRI
Communication No. 9306.
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