The α-chlorination of aryl methyl ketones under aerobic oxidative conditions

Article abstract of DOI:10.1002/adsc.201301012

The novel reaction system air/ammonium nitrate/iodine/hydrochloric acid [air/NH₄NO_3(cat.)/I_2(cat.)/HCl] is introduced as a simple, safe, cheap, efficient and regioselective mediator for the α-chlorination of aryl, heteroaryl and alkyl methyl ketones under aerobic oxidative conditions. The inventive use of a catalytic amount of iodine enabled the moderate to quantitative, regioselective chlorination of a comprehensive scope of different methyl ketone derivatives including those bearing oxidizable heteroatom (S, N) substituents, some of which possess declared potential biological and pharmaceutical activity. Air oxygen under a slight overpressure plays the role of the terminal oxidant catalytically activated by redox cycles of nitrogen oxides released from the catalytic amount of ammonium nitrate (NH₄NO₃) under acidic conditions of hydrochloric acid (HCl) and co-catalyzed by elemental iodine (I₂), which was found to be essential for the high efficiency of the reaction system.

Full text of DOI:10.1002/adsc.201301012

FULL PAPERS
DOI: 10.1002/adsc.201301012
The a-Chlorination of Aryl Methyl Ketones under Aerobic
Oxidative Conditions
Rok Prebila and Stojan Stavbera,b,*
a
ˇ
Laboratory for Organic and Bioorganic Chemistry at “Jozef Stefan” Institut, Jamova 39, 1000 Ljubljana, Slovenia
Fax : (+386)-477-3822; phone: (+386)-477-3660; e-mail: stojan.stavber@ijs.si
Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova 39, 1000 Ljubljana,
Slovenia
b
Received: November 14, 2013; Revised: January 9, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301012.
Abstract: The novel reaction system air/ammonium activity. Air oxygen under a slight overpressure plays
nitrate/iodine/hydrochloric acid [air/NH4NO3(cat.)
/
the role of the terminal oxidant catalytically activat-
I
2(cat.)/HCl] is introduced as a simple, safe, cheap, effi- ed by redox cycles of nitrogen oxides released from
cient and regioselective mediator for the a-chlorina- the catalytic amount of ammonium nitrate
tion of aryl, heteroaryl and alkyl methyl ketones (NH4NO3) under acidic conditions of hydrochloric
under aerobic oxidative conditions. The inventive acid (HCl) and co-catalyzed by elemental iodine (I2),
use of a catalytic amount of iodine enabled the mod- which was found to be essential for the high efficien-
erate to quantitative, regioselective chlorination of cy of the reaction system.
a comprehensive scope of different methyl ketone
derivatives including those bearing oxidizable
hetero
ACHTUNGTRENNUNGatom (S, N) substituents, some of which pos- Keywords: air; ammonium nitrate; aryl methyl ke-
sess declared potential biological and pharmaceutical tones; chlorination; iodine; nitrogen oxides
Introduction
novel, highly effective pharmaceuticals with a broad
spectrum of bioresponses.[1,3] These complex bioactive
Organic molecules containing a halogen atom are molecules – pharmaceuticals – could significantly
highly versatile synthetic intermediates and building alter metabolic activities, have significant blood pres-
blocks that are extensively employed in cross-cou- sure effects or the ability to increase the bioavailabil-
pling reactions, in nucleophilic substitutions, or uti- ity absorption factor of medications into the blood cir-
lized as precursors to organometallic reagents. Due to culation system.[1b,4] Moreover, thienyl and phenyl a-
their useful properties, bromo-, chloro- and fluoroar- halomethyl ketones, particularly chloro analogues,
enes are widely used as building blocks of fine chemi- were found to be new, efficient non-ATP competitive
cals, pharmaceuticals and agrochemicals, and are rou- inhibitors of glycogen synthase kinase 3b (GSK-3b),
tinely elaborated in the synthesis of natural products which is causing neurodegeneration in general and
and materials.[1] Moreover, iodinated compounds are Alzheimerꢀs disease in particular.[4a,b]
widely used in medicinal diagnostics or as radioactive-
Over the last years and especially in the past two
ly labelled markers.[2] Given the worldwide demand decades numerous methods and procedures were in-
for these compounds there is an ever increasing need vented for the preparation of this highly important
to synthesize them under environmentally more ac- class of organic compounds. Traditionally, a-chloro-
ceptable “green” conditions while at the same time methyl ketones have been prepared by chlorination
achieving atom economy, selectivity and high yields.
of methyl ketones with molecular chlorine (Cl2),[1a] or
a-Halocarbonyl derivatives are an important class by using various inorganic or organic chlorinating
of organic compounds and have always been receiving agents such as metal halides,[5] N-chlorosuccinimide
much attention due to their versatile building utilities (NCS)[6] and related or similar reagents.[7] The above-
in combinatorial synthesis. Their high reactivity mentioned methods exhibit quite a few drawbacks
makes them prone to react with a large number of nu- such as indirect chlorination over several steps, with
cleophiles producing numerous functionalized carbo- low halogen atom economy, problems of over-chlori-
and heterocyclic compounds used in the design of nation,[7d] nuclear chlorination of activated aromatic
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Rok Prebil and Stojan Stavber
rings,[7e,8] non-reactivity with deactivated aromatic ported on efficient and selective iodination[10,23] and
rings[8] and incompatibility with acid-sensitive or bromination[10,17e,24] of aryl methyl ketones at the
easily oxidizable groups.[7e] Microwaves, as ever popu- alpha position and just recently the iodination of
lar in academic research, offer another interesting arenes[25] under aerobic oxidative conditions exploit-
mode of activation for the synthesis of a-chlorometh- ing the NO/NO2 oxidative catalytic redox cycle, while
yl ketones. Carbonyl compounds are treated with chlorination under the same conditions seems to be
[hydroxy
um halides under solvent-free microwave irradiation sufficient oxidative properties of molecular oxygen in
conditions.[9]
combination with nitrogen oxides catalysts (NO/NO2)
ACHTUNGTRENNUNG(tosyloxy)iodo]benzene followed by magnesi- much less or not efficient. We can assume that the in-
On the other hand in nature enzymatically support- and high redox potentials of chloride ions can be the
ed oxidative halogenation processes, are co-catalyzed reason for the insufficient generation of a critical
by high valence metal species and use oxygen or hy- amount of electrophilic chloro species for positive
drogen peroxide as terminal oxidants. In these pro- overall conversion.[26] Despite this reason a few arti-
cesses natural halo organic compounds, including a- cles do successfully report about efficient oxidative a-
halo carbonyl substituted molecules, are formed. In chlorination in different ionic liquids containing ni-
parallel, in classical organic synthesis, halo organic trate anion,[27] but to the best of our knowledge no
compounds should be produced by oxidative halogen- data are available for a-chlorination under clear non-
ation methodology using environmentally friendly ox- enzymatic aerobic oxidative conditions of organic
idants leading to a minimum amount of waste after compounds.
catalytic rather than non-catalytic processes. From the
As a part of our continued interest in developing
viewpoint of cost efficiency, atom economy and over- “greener” methods for halogenation[23,24,27a] we now
all green and sustainable development, aqueous hy- report the discovery and the development of a system
drogen peroxide and especially atmospheric molecu- for side chain chlorination of methyl ketones under
lar oxygen represent the most acceptable and superior aerobic oxidative conditions using catalytic amounts
choices in these tasks.[10] Hydrogen peroxide has some of iodine (I2) and ammonium nitrate (NH4NO3) as
drawbacks such as a demand for certain safety pre- a cheap and readily accessible source of nitrogen
cautions, when used in higher amounts or higher than oxides (NO/NO2) under acidic conditions.
30% aqueous solutions since higher temperatures
and/or impurities and traces of metallic catalysts can
induce some undesirable decomposition to H2O and Results and Discussion
O2 during reactions.[11] In this manner efficient oxida-
tive halogenating methods for a-chlorination were in- Primarily, the novel multi-component and cost-benefi-
vented, exploiting hydrogen peroxide or its varieties cial reaction system air/NH4NO3(cat.)/HCl(cat.)/I2 was
such as urea-hydrogen peroxide[12] or commercially tested on 1-(4-methoxyphenyl)ethanone 1b used as
available Oxoneꢂ[13] (KHSO5 – potassium hydrogen a model compound. The reaction result of these tests
persulfate) as activator in combination with different are summarized in Table 1. In our initial mmol-scale
halogen atom sources. Usually ammonium chloride, experiment, the efficiency of the reaction system for
hydrochloric acid or aluminium chloride hexahydrate iodination of 1b was tested. To a solution of 1b in ace-
were used as a cheap source of halogen atom for a- tonitrile, 20 mol% of NH4NO3, 50 mol% of I2, and
chlorination of methyl ketones.[12–14] On the other 20 mol% of HCl (aqueous 37% solution) were con-
hand molecular oxygen, especially when used in its secutively added in five minute intervals (Table 1,
natural diluted source as air, is the most abundant ter- entry 1). The reaction vessel was closed with an air
minal oxidant and atom economical oxidant known balloon (1 L) and the reaction mixture was stirred for
1
today, giving great benefits from the viewpoints of 24 h at 608C. The H NMR analysis of the isolated
cost efficiency and green chemistry. Transformations crude reaction mixture revealed regioselective side
of organic substrates using molecular oxygen usually chain halogenation, 2-iodo-1-(4-methoxyphenyl)-
need transition metal catalysis to promote the reac-
ACHUTGTNRENNUGethanACHTUNGTRENoNUNG ne 2b’ (21%) being the main product and, to
tion rate and selectivity to partial oxidation products. our surprise, also 2-chloro-1-(4-methoxyphenyl)etha-
For this purpose organometallic complexes[15] or solid none 2b (13%) was formed as the side product, while
supported species[16] are often used, while nitrites no ring halogenated products were detected, but
(NaNO2),[17] nitrates (MgNO3,[18] NH4NO3[19]) or ni- a low conversion of starting material observed. After
tric(V) acid (HNO3)[20] as transition metal-free cata- that the a-chlorination reaction was investigated, in
lysts for aerobic transformations of organic com- order to increase the efficiency and selectivity of this
pounds were recently used.[17a,21] Nitric oxide donors reaction.
play also an important role as reactive compounds
First we performed a control experiment if a catalyt-
useful in several chemical and biological application- ic amount of I2 (5 mol%) and stoichiometric amount
s.[21a,22] Over the last decade many articles have re- of HCl (aqueous 37% solution, 1.1 mmol) with the
2
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The a-Chlorination of Aryl Methyl Ketones under Aerobic Oxidative Conditions
Table 1. Aerobic oxidative a-halogenation of 1-(4-methoxyphenyl)ethanone 1b using the air/NH4NO3(cat.)/I2/HCl reaction sys-
tem.[a]
Entry
I2 (mol%)
HCl (mmol)
MeCN (mL)
Relative distribution [%][b]
1b
2b
2b’
1
2
3
4
50
5
5
0.2
1.1
1.5
1.5
5
5
5
2
66
32
18
5
13
68
82
95
21
–
–
5
–
[a]
Reaction conditions: 1-(4-methoxyphenyl)ethanone 1b (1 mmol), NH4NO3 (20 mol%), I2 (5 or 50 mol%), HCl (aqueous
37% solution), MeCN, 608C, 24 h, air balloon.
Conversion of 1b to 2b and 2b’ determined from H NMR spectra of the crude reaction mixtures.
[b]
1
Table 2. The role of each component in the air/NH4NO3(cat.)/I2(cat.)/HCl reaction system.[a]
Entry
Reaction system variants: air or argon/NH4NO3(cat.)/I2(cat.)/HCl
Conversion 1b!2b [%][b]
1
2
3
4
argon/NH4NO3(cat.)/I2(cat.)/HCl
air/I2(cat.)/HCl
air/NH4NO3(cat.)/HCl
18
3
4
air/NH4NO3(cat.)/I2(cat.)/H2SO4
0
[a]
Reaction conditions: 1b (1 mmol), NH4NO3 (20 mol%), I2 (5 mol%), HCl (aqueous 37% solution, 1.5 mmol), 2 mL
MeCN, 608C, 24 h, air or argon balloon.
Conversion of 1b to 2b determined from the H NMR spectra of crude reaction mixtures.
[b]
1
same substrate 1b would give the desired 2-chloro-1- nitrile were thus checked in order to improve a green
(4-methoxyphenyl)ethanone 2b in a reaction with profile of the investigated reaction and results are
20 mol% NH4NO3 in 5 mL of acetonitrile (Table 1, given in the Supporting Information (Table S1). Un-
entry 2). Air was again used as terminal oxidant and fortunately chlorination under aerobic conditions with
only 2b was isolated with 100% selectivity in high our reaction system under solvent-free reaction condi-
yield. After this success we aimed to increase the effi- tions as well as in H2O failed, while the reaction
ciency of reaction to a quantitative level. By increas- barely took place and low conversion of substrate was
ing the amounts of added acid HCl to 1.5 mmol observed in MeOH, 2-methyltetrahydrofuran, cyclo-
(Table 1, entry 3) the conversion of starting material pentyl methyl ether, Solkaneꢂ (1,1,1,3,3 pentafluoro-
to 2b was selectively increased, while almost quantita- butane, HFC 365), and an acetonitrile/water (4:1)
tive formation of 2b was achieved by decreasing the mixture. Acetonitrile thus seems to be the best choice
solvent volume to 2 mL (Table 1, entry 4).
so far.
It is worth mentioning in order to illustrate the es-
The use of organic solvents in chemical processes is
one of the most concerning issues from the green sential role of each component in the air/NH4NO3(cat.)
/
chemistry point of view.[28] Solvent losses are a major
I
2(cat.)/HCl reaction system, i.e., air oxygen and HCl as
contributor to the high E (environmental) factor. The reagent, and NH4NO3 and I2 as catalysts, blank ex-
most desirable are solvent-free transformations or periments were performed and are gathered in
those performed in environmentally friendly alterna- Table 2. Conversion up to 18% in an anaerobic ex-
tives such as water, lower alcohols, esters, some ethers periment (Table 2, entry 1) is probably due to the
or use of green renewable media such as ionic liquids. presence of catalytic amounts of NO2 and the absence
Several “greener” solvents and alternatives to aceto- of a redox cycle (re-oxidation of NO to NO2). All
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Table 3. Chlorination of aryl methyl ketones under aerobic oxidative conditions using the air/NH4NO3(cat.)/I2(cat.)/HCl reaction
system.[a]
[a]
Reaction conditions: aryl methyl ketone (1 mmol), NH4NO3 (20–25 mol%), HCl (aqueous 37% solution, 1.5 mmol), 2 mL
MeCN, 608C, 24 h, air balloon.
Conversion determined from the H NMR spectra of crude reaction mixtures.
Yield determined after purification by column chromatography (SiO2; dichloromethane/petroleum ether) or by crystalli-
zation in hexane.
[b]
[c]
1
other experiments (entries 2, 3, 4, Table 2) gave nega- ology used enabled high chemoselectivity since no a-
tive results and 1-(4-methoxyphenyl)ethanone 1b iodo aryl methyl ketone derivatives were detected.
could not be successfully converted to 2-chloro-1-(4-
methoxyphenyl)ethanone 2b if any one of the compo- ble or acid-sensitive heteroatoms such as sulfur or ni-
nents is absent. trogen in the target molecules could represent addi-
The presence of functional groups bearing oxidiza-
Encouraged by these preliminary results, we ap- tional reaction centres for side reactions. We thus ex-
plied the air/NH4NO3(cat.)/I2(cat.)/HCl reaction system amined the efficiency and selectivity of the chlorina-
under the described reaction conditions for the a- tion of some interesting heteroaryl methyl ketones in
chlorination of a series of aryl methyl ketones. As it order to make the methodology more general. The re-
can be seen from Table 3, a variety of structure types sults are collected in Table 4. Oxygen-containing het-
of aryl methyl ketones could be efficiently and selec- erocyclic methyl ketone derivatives such as 1-(benzo-
tively converted into their corresponding a-chloroaryl furan-2-yl)ethanone 3a (entry 1) and 1-(2,3-dihydro-
methyl ketones in relatively high isolated yields after
ACHUTGTNRNEUGbN enzo[b]ACHUTNGTRENN[UNG 1,4]dioxin-6-yl)ethanone 3b (entry 2) were
20–25 h. In general we found that electron-withdraw- efficiently converted to their chloromethyl derivatives
ing as well as electron-donating substituents on the 4a and 4b, respectively. Acetyl-substituted coumarins
phenyl ring supported the transformation of tested as target molecules often exhibit potential bioactivity
compounds 1a–f to their chloromethyl derivatives 2a– of pharmaceutical interest,[29] 3-acetyl-2H-chromen-2-
f. The compound bearing a nitro substituent (1d, one 3c was successfully and selectively chlorinated
entry 4) was found to be slightly more reactive. Sub- and 3-(2-chloroacetyl)-2H-chromen-2-one 4c was iso-
strates bearing a phenol functionality (1e and 1f, en- lated (entry 3) in high yield. Moreover, we managed
tries 5 and 6) as well as 1-(3,5-dihydroxyphenyl)ethan- to chlorinate 1-(thiophen-2-yl)ethanone 3d to the
ACHTUNGTRENNUNGone were also efficiently a-chlorinated without any in- chloromethyl derivative 4d which was declared to
conveniences, but the purification of the final product possess non-ATP competitive inhibitory activity on
in the latter case caused some troubles. A phenan- enzyme GSK-3b,[4a,b] and 1-(1-methyl-1H-pyrrol-2-
threne derivative, 1-(phenanthren-3-yl)ethanone 1g yl)ethanone 3e (entry 5) was chlorinated to 2-chloro-
(entry 7) was readily converted to 2-chloro-1-(phen- 1-(1-methyl-1H-pyrrol-2-yl)ethanone 4e although in
ACHTUNGTRENNUNGanthren-3-yl)ethanone 2g. What is more, the method- moderate yield.
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The a-Chlorination of Aryl Methyl Ketones under Aerobic Oxidative Conditions
Table 4. Chlorination of heteroaryl methyl ketones under aerobic oxidative conditions using the air/NH4NO3(cat.)
/
I2(cat.)/HCl reaction system.[a]
[a]
Reaction conditions: aryl methyl ketone (1 mmol), NH4NO3 (20–25 mol%), HCl (aqueous 37% solution,
1.5 mmol), 2 mL MeCN, 608C, 24 h, air balloon.
Conversion determined from the H NMR spectra of crude reaction mixtures.
Yield determined after purification by column chromatography (SiO2; dichloromethane/petroleum ether) or
by crystallization.
[b]
[c]
1
Furthermore, limitations of the air/NH4NO3(cat.)
/
of starting material not higher than 42% was ach-
I
2(cat.)/HCl reaction system such as versatility, efficien- ieved, while chlorination of its cyclic analogue 3,4-di-
cy and selectivity for chlorination on branched dialkyl hydronaphthalen-1(2H)-one (5c, entry 3) gave no pos-
ketones at the alpha position were tested. The results itive result.
are presented in Table 5. 4-Methylpentan-2-one 5a
We could only speculate that a larger steric hin-
(entry 1) was consumed in 80% and selectively chlori- drance at the alpha position to the carbonyl could be
nated only on the alpha methyl position as deter- the cause of the lower or even no conversion rates of
mined from the crude reaction mixture. No other substrates 5b and 5c (Table 5, entry 2 and 3).
halogenated product was detected. Propiophenone 5b
Furthermore, a representative of non-aryl sub-
(entry 2), as representative of more branched alkyl strates, 1-acetyladamantane 5d, was chlorinated with
substrates, was chlorinated with decreased efficiency the reaction system under aerobic conditions yielding
exclusively on the alpha position but a consumption selectively 1-chloroacetyladamantane 6d in reasona-
ble yield. It is a well-known that SN2 substitution reac-
tion rates are greatly increased and favored on pri-
mary methyl substrates at a position alpha to the car-
Table 5. Regioselectivity and limitations of the use of the
air/NH4NO3(cat.)/I2(cat.)/HCl reaction system for the chlorina- bonyl moiety when halide nucleophiles are involved.
tion of different dialkyl or aryl alkyl ketones.
Further branching at the alpha position decreases the
rate. Tertiary systems seldom react by the SN2 type of
reaction.[30]
We also checked the practical applicability of our
new procedure for possible use on a large scale. To
demonstrate the practicality of scaling up the proce-
dure, we treated 3 g (20 mmol) of 1-(4-methoxyphen-
AHCTUNGTRENNGyUN l)ethanone 1b in MeCN (50 mL) solution with
25 mol% NH4NO3, 5 mol% I2 and HCl (aqueous 37%
solution, 30 mmol, 2.5 mL) in a flask (100 mL)
equipped with condenser with attached balloon filled
with air at 608C. After completion of the reaction,
a white solid was filtered off and identified as ammo-
nium chloride (NH4Cl), solvent was distilled off under
reduced pressure, the crude reaction mixture was ex-
tracted with ethyl acetate (3ꢃ10 mL) and analyzed by
1H NMR spectroscopy. To examine the efficiency of
reaction system under ambient pressure, exactly the
[a]
Reaction conditions: substrate (1 mmol), NH4NO3 (20–
25 mol%), HCl (aqueous 37% solution, 1.5 mmol), 2 mL
MeCN, 608C, 24 h, air balloon.
[b]
Conversion determined from the 1H NMR spectra of
crude reaction mixtures. Value in bracket refers to pure
product obtained after column chromatography.
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Table 6. The influence of air and NH4NO3 on the efficiency
same reaction procedure was performed using a con-
denser open to the air. In the case of a closed system
(balloon technique) 68% conversion was achieved,
while in the case of the open air system quantitative
and selective conversion to 2-chloro-1-(4-methoxy-
phenyl)ethanone 2b, without the need for further pu-
rification of final product was achieved.
of SN2 nucleophilic substitutions.[a]
Entry Reaction system variants: air or
argon/NH4NO3(cat.)/HCl
Conversion
2b’!2b [%][b]
Mechanistic Discussion
1
2
3
air/NH4NO3(cat.)/HCl
air/HCl
argon/NH4NO3(cat.)/HCl
100
67
98
Oxidative iodination and bromination of organic com-
pounds under aerobic oxidative conditions catalyzed
by nitric oxides (NO/NO2) with accompanying mecha-
nistic elucidation, declared as an electrophilic process,
have already been elaborated several times.[17e,23] The
corresponding chlorination under the same conditions
was found to be unsuccessful and attributed to the
too high redox potential of chloride ions.[26] It has
been assumed that the oxidative properties of molec-
[a]
Reaction conditions: 2b’ (1 mmol), NH4NO3 (20 mol%),
HCl (aqueous 37% solution, 1.5 mmol), 2 mL MeCN,
608C, 24 h, air or argon balloon.
[b]
1
Conversion of 2b’ to 2b determined from the H NMR
spectra of crude reaction mixtures.
ular oxygen in combination with nitrogen oxides cata- with chlorine thus forming chloromethyl derivative
lysts (NO/NO2) are insufficient in the generation of very reasonable. In order to confirm the SN2 mecha-
a critical amount of electrophilic chloro species for nism,
the efficient chloro derivatization of organic target (Table 6). Firstly, pure 2-iodo-1-(4-methoxyphenyl)-
molecules through an electrophilic reaction process. ethanone 2b’ was reacted in MeCN with the air/
a
series of experiments was performed
AHCTUNGTRENNUNG
As evident from Table 2 (entry 3) also our oxidative NH4NO3(cat.)/HCl reaction system and 2-chloro-1-(4-
cocktail is not strong enough to produce electrophilic methoxyphenyl)ethanone 2b was readily obtained in
chlorine species from chloride anions, although we 100% conversion (entry 1). Furthermore, the efficien-
have demonstrated recently that, by enrichment with cy of the reaction system and role of each member in
TEMPO co-catalyst, it could be used for the efficient it was tested. Again, model compound 2b’ was used
aerobic oxidation of alcohols to aldehydes or ke- and reacted with the air/HCl reaction system, using
tones.[19] On the other hand the reaction system air/ no catalyst NH4NO3 this time. At the end 67% con-
NH4NO3(cat.)/HCl seemed to be strong enough to oxi- version of 2b was achieved (entry 2). When using the
dize iodide (see Table 1, entry 1) and thus enabling argon/NH4NO3(cat.)/HCl reaction system, quantitative
aerobic oxidative iodination of organic compounds, conversion (98%) was reached and pure 2-chloro-1-
which will be elaborated in a forthcoming paper. On (4-methoxyphenyl)ethanone
2b
was
obtained
this basis we assumed the most probable reaction (entry 3). From the experiments performed it is evi-
pathway resulting in the formation of chloromethyl dent that the presence of catalyst NH4NO3 and nitro-
aryl ketones using the reaction system air/ gen oxides is essential for quantitative nucleophilic
NH4NO3(cat.)/I2(cat.)/HCl as aerobic oxidative iodination SN2 substitution giving quantitative yields. We assume
in the first and the a halogen exchange process in the that role of nitrogen oxides (NO/NO2) in particular in
second step of the reaction (Scheme 1).
SN2 substitution is the re-oxidation of released iodide
From theory it is well known that the usual order (Iꢀ) to iodine (I2) thus consequently moving the halo-
of halide nucleophilicity in aprotic polar solvents de- gen-exchange equilibrium more in the direction of
creases in the line: Clꢀ >Brꢀ >Iꢀ,[30] which makes SN2 formation of chlorinated product.
displacement of iodine from the iodomethyl moiety
As the chlorofunctionalization of only methyl
groups occurred efficiently (see Table 5), the halogen
exchange process seems even more probable, since
SN2 displacements are favored on less hindered
carbon atoms.
The essential role of each component of the system
could be illustrated by Scheme 2 following the cata-
lytic cycles already proposed to explain reaction path-
ways during air oxygen oxidative iodination and bro-
mination of organic compounds catalyzed by nit-
AHCTUNGTRENNUNG
rites.[17a,e,23a] In cycle A iodination of the enol form of
Scheme 1. Chlorination of aryl and heteroaryl methyl ke-
tones under aerobic oxidative conditions.
ketone with I2 at the alpha position to the carbonyl
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The a-Chlorination of Aryl Methyl Ketones under Aerobic Oxidative Conditions
Experimental Section
General Chemical Reagents and Inventory
All chemicals used in this study were of analytical grade,
commercially available and used without further purification
unless otherwise noted. Reactions were carried out in 10-
mL glass flasks. Balloons (1-L) with 10 mil wall thickness
were purchased from Sigma Aldrich and used as the air re-
servoir. Reactions were monitored with thin layer chroma-
tography on TLC silica gel 60 F254 aluminium sheets (20ꢃ
20 cm). Column chromatography (CC) and flash chromatog-
raphy (FC) were performed using silica gel 60 (particle size:
0.063–0.200 mm) and preparative thin layer chromatography
(preparative TLC) was done using PLC silica gel 60 F254
2 mm plates.
,
Scheme 2. Plausible catalytic mechanism for the a-chlorina-
tion of aryl and alkyl methyl ketones.
General Measurements
Conversions and yields were determined by NMR spectros-
copy. NMR spectra were recorded on a Varian INOVA 300
NMR instrument (1H: 303.0 MHz, 13C: 76.2 MHz) using
CDCl3 as the solvent with SiMe4 (TMS) as an internal refer-
ence. Mass spectra were measured with a high resolution
mass spectrometer Q-TOF Premier using the ESI technique.
Elemental analyses were performed on a Perkin–Elmer
2400-Series II apparatus. Melting points were determined
with a Bꢄchi 535 instrument.
occurs and I2 is reduced to HI, while the halogen ex-
change process, thus forming chloromethyl derivative
and releasing Iꢀ, is a consecutive process. The re-oxi-
dation of iodide to I2 by NO2 is illustrated as cycle B,
which is the key for the catalytic amount of iodine in
the reaction system. NO2 is reduced to NO when it
completes the oxidation of iodide while the oxidation
of NO to NO2 is a process accomplished with air
oxygen. Acidic conditions are essential and have two
main roles: the first role is to hydrolyze ammonium
nitrate to HNO3 [Eq. (1)] which is in thermally accel-
erated decomposing equilibrium with NO2 [Eq. (2)]
and the second is tuning the reactivity by increasing
enolization of the ketone.
Chlorination of Aryl Methyl Ketones under Aerobic
Oxidative Conditions; General Procedure
A 10-mL glass flask equipped with magnetic stirring bar was
charged with methyl or ethyl ketone (1 mmol) and acetoni-
trile (2 mL). To the thermostatted solution NH4NO3 (20–
25 mol%) and I2 (5 mol%) were added, followed after
10 min by the addition of hydrochloric acid (aqueous 37%
solution, 1.5 mmol). The flask was further equipped with
balloon filled with air (1-L) and magnetically stirred at
608C. The reaction system cyclically changed the colour
from brown-red to yellow and back. The consumption of the
starting material was monitored by TLC. After completion
of the reaction, the reaction mixture was cooled down to
room temperature and diluted with dichloromethane
(10 mL). Insoluble material identified as ammonium chlo-
ride was filtered off, the filtrate washed with aqueous 10%
solutions of NaHCO3 (10 mL) and Na2S2O3 (10 mL) and the
organic phase dried over anhydrous Na2SO4. Organic sol-
vent was distilled off under reduced pressure and the crude
product obtained was analyzed by 1H NMR. Finally the
crude product was purified using column chromatography
(SiO2, hexane/dichloromethane elution), preparative thin
layer chromatography or crystallized out of pure hexane
and hexane/ethyl acetate mixture to afford pure material
which was compared to authentic samples. Detailed data,
concerning catalyst loading, reaction times, yields of pure
products and their spectroscopic and other identification
data are given in Supporting Information, chapter: Charac-
terization Data of Isolated Final Products.
Conclusions
We have discovered and successfully developed
a four-component reaction system of air/NH4NO3(cat.)
2(cat.)/HCl for the efficient and selective chlorination
/
I
of aryl and alkyl methyl ketones at the alpha position
to the carbonyl moiety under mild conditions. The in-
ventive use of a catalytic amount of iodine enabled
the moderate to quantitative and regioselective
chlorination of a comprehensive range of different
methyl ketone derivatives including those with func-
tional groups bearing oxidizable heteroatoms (S, N).
To the best of our knowledge, the developed reaction
system is a novel one used for the chlorination of or-
ganic compounds. Each member of the reaction
system has an essential role in it. A plausible mecha-
nistic interpretation of the reaction pathway as the se-
quence of aerobic oxidative iodination, followed by
halogen exchange process was proposed. We believe
that our invention could open new perspectives and
improvements towards more economical, mild, simple
and environmental friendly methodologies for selec-
tive halogenation of organic compounds.
Adv. Synth. Catal. 0000, 000, 0 – 0
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Rok Prebil and Stojan Stavber
3-(2-Chloroacetyl)-2H-chromen-2-one (4c): One mmol of
3-acetyl-2H-chromen-2-one, NH4NO3 (25 mol%, 20 mg), I2
(5 mol%, 12.7 mg), HCl (aqueous 37% solution, 1.5 mmol,
124.6 mL), 2 mL MeCN, 608C, 24 h were used; flash chroma-
tography (SiO2, CH2Cl2) afforded a white solid; yield:
189.2 mg (85%); mp 178–1808C. 1H NMR (303.0 MHz,
CDCl3 with 2 drops of DMSO, 258C, TMS): d=4.96 (s, 2H),
7.39–7.44 (m, 2H), 7.70–7.79 (m, 2H), 8.70 (s, 1H);
13C NMR (76.2 MHz, CDCl3 with two drops of DMSO): d=
49.9, 116.5, 117.8, 121.9, 125.2, 130.4, 135.1, 149.3, 155.0,
158.8, 188.6; MS (ESI): m/z=225 [(M+2+H)+, 33%], 223
[(M+H)+, 100%]; HR-MS: m/z=223.0164, calculated for
C11H8O3Cl: 223.0162.
Chlorination of 1-(4-Methoxyphenyl)ethanone with
the Air/NH4NO3(cat.)/I2(cat.)/HCl System. Scaled-Up
Procedure
A 100-mL glass reactor equipped with magnetic stirring bar
and condenser (open or closed with balloon filled with air)
was charged with 1-(4-methoxyphenyl)ethanone (0.02 mol;
3.0 g) and totally dissolved in acetonitrile (50 mL). The solu-
tion was thermostatted at 608C for 20 min and then co-cata-
lyst I2 (5 mol%; 253.8 mg), HCl (aqueous 37% solution;
30 mmol; 2.5 mL) and the first portion of catalyst NH4NO3
(12.5 mol%; 200 mg) were added in consecutive 4 min inter-
vals. The reaction mixture was stirred (500 rpm) at 608C for
4 h under open air conditions and the second portion of cat-
alyst NH4NO3 (12.5 mol%; 200 mg) was added. The reaction
mixture was stirred for additional 68 h and then cooled to
room temperature, insoluble material identified as ammoni-
um chloride (375.6 mg recovered) was filtered off and
washed with acetonitrile (5 mL). In order to obtain carry-
over of the solvent, the filtrate was distilled under reduced
pressure, the crude reaction mixture was washed with
NaHCO3 (aqueous 10% solution, 10 mL) and Na2S2O3
(aqueous 10% solution, 10 mL) and extracted with ethyl
acetate (3ꢃ10 mL). The organic phase was dried over anhy-
drous Na2SO4. The organic solvent was distilled off under
reduced pressure and the crude product obtained was ana-
Acknowledgements
We are grateful to the staff of the National NMR Centre at
the National Institute of Chemistry, Ljubljana, Slovenia. The
authors are also grateful to the Slovenian Research Agency
(contracts: Programme ARRS P1-0134) and Young Re-
searchers Fellowship (ARRS1000-08-310039), and CIPKeBiB
(European
Regional
Development
Fund)
(OP
13.1.1.02.0005).
1
lyzed by H NMR. Under the open air system 100% conver-
sion was achieved and pure 2-chloro-1-(4-methoxyphenyl)-
ACHTUNGTRENNUNGethanone 2b was obtained; yield: 3.61 g (98%). Using a con-
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPERS
10 The a-Chlorination of Aryl Methyl Ketones under Aerobic
Oxidative Conditions
Adv. Synth. Catal. 2014, 356, 1 – 10
Rok Prebil, Stojan Stavber*
10
asc.wiley-vch.de
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!