Iodine-catalyzed oxidative C-C bond cleavage for benzoic acids and benzamides from alkyl aryl ketones

Article abstract of DOI:10.1039/c6ra02962k

Iodine-catalyzed oxidative C-C bond cleavage has been performed for the facile synthesis of both benzoic acids and benzamides from readily available alkyl aryl ketones. Additionally benzylidene acetones and phenylacetylenes were also converted to the corresponding aromatic acids under the same conditions. This approach features the use of inexpensive iodine as a catalyst, broad substrate scope and open air conditions.

Full text of DOI:10.1039/c6ra02962k

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Iodine-catalyzed oxidative C–C bond cleavage for
benzoic acids and benzamides from alkyl aryl
ketones†
Cite this: RSC Adv., 2016, 6, 22749
Received 1st February 2016
Accepted 18th February 2016
Pochampalli Sathyanarayana, Atul Upare, Owk Ravi, Prathap Reddy Muktapuram
*
and Surendar Reddy Bathula
DOI: 10.1039/c6ra02962k
www.rsc.org/advances
Iodine-catalyzed oxidative C–C bond cleavage has been performed iodine mediated C–C bond cleavage processes are indispens-
for the facile synthesis of both benzoic acids and benzamides from able as well as demanding for environmental friendly processes.
readily available alkyl aryl ketones. Additionally benzylidene acetones Herein, we demonstrate iodine catalyzed aerobic oxidative C–C
and phenylacetylenes were also converted to the corresponding bond cleavage for benzoic acids and benzamides (Scheme 1E
aromatic acids under the same conditions. This approach features the and F). This is complementary to our earlier report of copper
use of inexpensive iodine as a catalyst, broad substrate scope and catalyzed C–C bond cleavage for benzoic acid.
open air conditions.
In continuation of our efforts on the oxidative C(NOH)–
C(alkyl) bond cleavage of aryl alkyl ketones9 and inspired by
a report from Sandip et al.15 on molecular iodine catalyzed
oxidative C–C bond cleavage of aryl methyl ketones, we aimed
for the iodine catalyzed C–C bond cleavage adjacent to oxime.
Our research commenced with the reactions of acetophe-
none (1a) and 2 equiv. of hydroxylamine hydrochloride in the
presence of 10 mol% iodine at 50 ꢀC in DMSO under air (Table
1, entry 1), where we obtained only oxime 2a in 85% yield.
Increase of hydroxyl amine to 4 equiv. triggered C(NOH)–CH3
bond cleavage reaction and led to the formation of 3a in a 12%
yield along with 50% of 2a (Table 1, entry 2). Increase of
Carbon–carbon bond cleavage reactions are gaining promi-
nence in organic chemistry due to their potential applications
in developing novel functionalization processes and biodegra-
dation methods.1 However, achieving such transformations is
difficult because of the high C–C bond strength and uncon-
trollable selectivity.1 Representative methods of C–C bond
cleavage are mostly based on strain2 and chelation3 assisted
strategies. Furthermore, Cu catalyzed oxidative C(CO)–C(alkyl)
bond cleavage methods are also emerging as effective substi-
tutes for such strenuous processes.4–8 Recently, we too have
demonstrated a copper catalyzed aerobic oxidative C(CO)–C
bond cleavage reaction for the synthesis of benzoic acids.9
However, most of these processes are transition metal medi-
ated. Despite great advantages, transition-metal-catalyzed
reactions are oen impracticable due to their cost, toxicity
and sensitivity to air and moisture.10 Hence, the development of
metal free processes for C–C bond cleavage is highly desirable.
Amongst the non-metallic C–C bond cleavage methods, iodine
mediated haloform reaction11 is well known for the synthesis of
carboxylic acids from methyl ketones (Scheme 1A). In addition,
recently, Erick,12 Wu13 and Narendar14 research groups have
independently developed iodine mediated C–C bond cleavage
reactions for the synthesis of amides from methyl ketones
(Scheme 1B–D). All these processes require stoichiometric (3–6
equiv.) amount of iodine. Therefore, the discovery of catalytic
ꢀ
temperature to 80 C dramatically improved the yield of 3a to
60% together with the formation of 20% oxime 2a (Table 1,
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad-500007, India. E-mail: bsreddy@iict.res.in
† Electronic supplementary information (ESI) available: Experimental procedures
and compound characterization data. See DOI: 10.1039/c6ra02962k
Scheme 1 Iodine mediated C–C bond cleavage for the synthesis of
benzoic acids and benzamides.
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Table 1 Optimization of hydroxyl amine mediated carbon–carbon
methoxy, ethoxy and cyclohexyl groups gave their correspond-
ing products (3b–c, 3f, 3j–l and 3p) in excellent yields with high
efficiency. Similarly, the reaction proceeded well with good
yields when electron-withdrawing groups (EWG) (e.g., –F, –Cl,
–Br, –NO2, and –CN) were substituted at the ortho-, meta-, or
para-positions on the benzene ring (3d–e, 3g–i, 3m–o and 3q).
2-Acetylfuran and 2-acetylthiophene also underwent this reac-
tion smoothly to deliver the corresponding heteroaryl products
3r and 3s in 80% and 89% yields, respectively.
The scope of this reaction was subsequently extended to
several aryl ketones with varying alkyl chain lengths. To our
delight, reactions with aryl ketones 4a–h proceeded smoothly to
give the acids 3a–b, 3j, 3t and 3u in good yields. However, in
contrast to the reaction of acetophenones 1, much longer
reaction times (9–11 h) were required for efficient trans-
formation. Interestingly, in case of substrates 4g and 4h, both
the aryl terminals were converted to the corresponding acids
(Table 3).
Encouraged by the results achieved above, we hoped that the
substrates of this efficient reaction system could be further
extended. Next, benzylideneacetone (5a) was examined under
the standard reaction conditions to nd whether an alkenyl
group can act as a terminator to the above oxidation process.
Interestingly, no expected product (cinnamic acid) was obtained
but we isolated benzoic acid as a product aer cleavage of the
C–C double bond of benzylideneacetone. To probe the substrate
scope for this reaction, a series of substituted benzylideneace-
tones 5 were subjected to the optimized reaction conditions
(Table 4). The electronic properties of the 5 exerted some
inuence on this transformation; benzylideneacetones bearing
electron-donating groups provided the corresponding acids in
better yields (3c, 3j and 3t) than those with electron-
withdrawing substituents (3d, 3u–w). This protocol was
further extended to fused benzylideneacetones and hetero-
aromatic vinyl ketones, and the desired products were obtained
in moderate to good yields (3r–s, and 3x).
bond cleavage reaction conditionsa
Yieldsb (%)
Temp
Entry
[I2]
NH2OH$HCl
Solvent
(ꢀC)
2a
3a
1
2
3
4
5
6
7
8
9
10
0.1 eq.
0.1 eq.
0.1 eq.
0.1 eq.
0.1 eq.
0.1 eq.
0.1 eq.
0.1 eq.
—
2 eq.
4 eq.
4 eq.
4 eq.
4 eq.
4 eq.
4 eq.
4 eq.
4 eq.
—
DMSO
DMSO
DMSO
DMSO
DMF
EtOH
DCE
H2O
50
50
80
100
100
80
100
100
100
100
85
50
20
—
20
—
—
—
20
—
—
12
60
78
c
—
—
—
—
—
—
c
c
c
c
c
DMSO
DMSO
0.1 eq.
a
Reaction conditions: 1a (1.0 mmol), NH2OH$HCl (4.0 mmol), I2 (0.1
b
mmol) in DMSO at 100 ꢀC for 4 h under air. Isolated yields.
c
Starting material recovered.
entry 3). Further increase of temperature to 100 ꢀC produced 3a
as only product in 78% yield (Table 1, entry 4). We next screened
reaction in different solvents such as DMF, DCE, EtOH and
water (Table 1, entries 5–8). However, no product formation was
observed. No product was detected in the absence of iodine and/
or hydroxylamine (Table 1, entries 9 and 10), suggesting that
both the catalyst and reagent were essential for this reaction.
Upon the establishment of viable reaction conditions, a wide
range of (het) aryl methyl ketones were employed as substrates
in this transformation (Table 2). Substrates bearing electron-
donating substituents on benzene ring such as methyl,
Table 2 Synthesis of aromatic acids from aryl methyl ketonesa
R ¼ H (3a, 5 h, 78%)
R ¼ 4-OMe (3j, 4 h, 93%)
R ¼ 4-OEt (3k, 4 h, 88%)
R ¼ 4-cyclohexyl (3l, 4 h, 65%)
R ¼ 4-F (3m, 5 h, 62%)
R ¼ 2-Me (3b, 4 h, 80%)
R ¼ 2-OMe (3c, 4 h, 86%)
R ¼ 2-Br (3d, 5 h, 58%)
R ¼ 2-NO2 (3e, 6 h, 61%)
R ¼ 3-OMe (3f, 5 h, 90%)
R ¼ 3-F (3g, 5 h, 64%)
R ¼ 3-Br (3h, 6 h, 70%)
R ¼ 3-NO2 (3i, 6 h, 62%)
R ¼ NO2 (3n, 6 h, 72%)
R ¼ 4-CN (30, 6 h, 61%)
R ¼ 2,4-di Me (3p, 4 h, 87%)
R ¼ 2,4-di Cl (3q, 5 h, 52%)
a
Reaction conditions: 1 (1.0 mmol), NH2OH$HCl (4.0 mmol), I2 (0.1 mmol) in DMSO at 100 ꢀC, under air. Yields are based on isolated products.
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Table 3 Synthesis of benzoic acids from aryl alkyl ketonesa
Table 5 Synthesis of benzoic acids from phenylacetylensa
4a, R ¼ H, n ¼ 1, 3a,
10 h, 41%
4d, R ¼ 4-Me, n ¼ 1,
3t, 10 h, 55%
R ¼ H (3a, 8 h, 49%)
R ¼ 3-F (3g, 8 h, 60%)
R ¼ 4-Me (3t, 7 h, 65%)
R ¼ 4-t-Bu (3y, 8 h, 61%)
4b, R ¼ 2-OMe, n ¼ 1,
4e, R ¼ 4-Br, n ¼ 1,
R ¼ 4-OMe (3j, 6 h, 71%) R ¼ 4F (3m, 8 h, 62%)
3b, 9 h, 52%
3u, 10 h, 51%
4c, R ¼ 4-OMe, n ¼ 1,
3j, 9 h, 56%
4f, R ¼ 4-Me, n ¼ 5,
3t, 11 h, 41%
a
Reaction conditions: 6 (1.0 mmol), NH2OH$HCl (4.0 mmol), I2
(0.1 mmol) in DMSO at 100 ꢀC, under air. Yields are based on isolated
products.
benzamide, we further optimized the reaction conditions as
shown in Table 6. Increase of sodium azide to 6.0 equiv. did not
change the outcome (16% of 7a, entry 2). Interestingly, addition
of water as co-solvent helped to improve the yield of product 7a
to 30% (entry 3). Increase of amount of I2 to 30 mol% could
further improve the yield to 46% (entry 4). To our delight, use of
AcOH as an additive provided the desired product cleanly in
70% yield (Table 6, entry 5). However, additional increase of the
amount of I2 to 0.5 equivalents did not offer any improvement
in the yield (entry 6). The controlled experiments revealed the
essentiality of both I2 and DMSO (entries 7 & 8).
Under the optimized reaction conditions, a study on the
substrate scope was carried out. As shown in Table 7, several
substituents, namely –OMe, t-Bt, Cl, Br and NO2, on the
aromatic ring at the acetophenone were well tolerated (7b–h).
For example, 4-t-Bt and 2,4-di OMe substituted acetophenones
successfully furnished 7b and 7c in 87% and 72% respectively.
Halogen groups, Cl and Br, were also compatible with the
optimal conditions (7d–f), which will enable subsequent
modications at the halogenated positions. Modest yields (53%
and 56%) of 7g and 7h were observed when nitro functionality
was present at acetophenone. 2-Acetylthiophene also smoothly
furnished corresponding product (7i, 75%) in good yield.
Next, some control experiments were performed to elucidate
the mechanism for the iodine catalyzed C–C bond cleavage.
When 4-methoxyacetophenone oxime 2j was subjected to the
standard conditions, product 3j was obtained in 90% yield
(Scheme 2A). However, 2j was not converted to 3j in 12 h in the
absence of hydroxylamine (Scheme 2B). Also, glyoxal 8 was
smoothly transformed to the corresponding acid 3j in 80% yield
(Scheme 2C). Moreover, dioxime 9 furnished 3j in 93% yield
under standard conditions (Scheme 2D). Under optimized
condition, anisaldehyde 10 was converted to nitrile 11 in 93%
yield (Scheme 2E). Furthermore, it was found that 11 could not
produce 3j under the standard conditions (Scheme 2F). Taken
together, these control experiments clearly demonstrated that
a
Reaction conditions: 4 (1.0 mmol), NH2OH$HCl (4.0 mmol), I2
(0.1 mmol) in DMSO at 100 ꢀC, under air. Yields are based on isolated
products.
To further expand the substrate scope, terminal aryl alkynes
were investigated using the conditions optimized for aromatic
ketones. On the basis of previous report,16 we found that a wide
range of terminal aryl alkynes in the presence of I2 in DMSO
could be easily transformed to glyoxal, which further reacted
with hydroxylamine to afford the corresponding benzoic acids
in one-pot (Table 5). Substrates with electron-rich, and electron-
decient groups were all compatible and provided the corre-
sponding products in moderate to good yields (49–71%; 3a, 3g,
3j, 3m, 3t and 3y).
We next turned curious to test the fate of the reaction with
the substitution of hydroxylamine hydrochloride with sodium
azide. Under the standard conditions, interestingly, we
observed the formation of trace amount of benzamide (7a from
1a) as a product (entry 1, Table 6). To improve the yield of the
Table 4 Vinyl bond cleavage of vinyl methyl ketonesa
4-methoxyacetophenoneoxime 2j, dioxime
9 and benzoyl
cyanide oxime d may be key intermediates in this reaction.
According to the aforementioned information and based on
previous reports,9 we propose a plausible mechanism of this
iodine-catalyzed C–C bond cleavage of aryl alkyl ketones for the
a
Reaction conditions: 5 (1.0 mmol), NH2OH$HCl (4.0 mmol), I2
(0.1 mmol) in DMSO at 100 ꢀC, under air. Yields are based on isolated
product.
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Table 6 Optimization of the reaction conditions for the synthesis of benzamide from acetophenonea
Entry
[I2] (equiv.)
NaN3 (equiv.)
Solvent (1 : 1)
AcOH
Temp (ꢀC)
Yieldsb (%)
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0.3
0.3
0.5
—
4
6
6
6
6
6
6
6
DMSO
DMSO
—
—
—
—
4 eq.
4 eq.
4 eq.
4 eq.
100
100
100
100
100
100
100
100
10c
16c
30c
46
DMSO/H2O
DMS/H2O
DMS/H2O
DMS/H2O
DMS/H2O
H2O
70
64
c
—
c
0.3
—
a
Reaction conditions: 1a (1.0 mmol), NaN3 (6.0 mmol), I2 (0.3 mmol) in DMSO/H2O (1 : 1) and AcOH (4 eq.) at 100 ꢀC for 12 h under air. b Isolated
yields. c Starting material recovered.
Table 7 I2-catalyzed synthesis of benzamides from acetophenonesa
R ¼ H (7a, 65%)
R ¼ 4-NO2 (7g, 53%)
R ¼ 4-t-Bu (7b, 87%)
R ¼ 2,4-OMe (7c, 72%)
R ¼ 3-Br (7d, 58%)
R ¼ 4-Br (7e, 62%)
R ¼ 2,4-di Cl (7f, 60%)
R ¼ 4-OMe, 3-NO2 (7h, 56%)
Scheme 3 Proposed mechanism.
a
Reaction conditions: 1a (1.0 mmol), NaN3 (6.0 mmol), I2 (0.3 mmol) in
DMSO/H2O (1 : 1) and AcOH (4 eq.) at 100 ꢀC for 12 h under air. Yields
are based on isolated products.
three membered cyclic intermediate oxazirene e along with
release of hydrogen cyanide (HCN) via C–C bond cleavage.
Finally, oxazirene undergoes a known hydrolysis17 to deliver the
desired acid.
We also propose a mechanistic possibility for the formation
of amides from acetophenones as depicted in Scheme 3B. In
this reaction, acid mediated nucleophilic addition of azide on
carbonyl of acetophenone 1 leads to the formation of interme-
diate I, which on iodination produces intermediate II. This II on
coupling with DMSO forms III. Elimination of dimethyl sulde
and formaldehyde form acyl azide V (via IV) which through
known conversion affords benzamide 7.12
synthesis of acids (Scheme 3A). Initially, acetophenone reacts
with hydroxylamine to produce oxime a and upon Kornblum
oxidation a gives a-oxo oxime b by releasing HI. Further
condensation of b with second hydroxylamine gives the dioxime
c. Subsequent dehydration of dioxime intermediate produces
benzoyl cyanide oxime d which aer decomposition produces
In summary, we have developed a new type of iodine-
catalyzed C(CO)–C(alkyl)bond cleavage of aryl/vinyl ketones/
phenylacetylenes for the synthesis of benzoic acids and
benzamides via an aerobic oxidation and oxygenation
process under air. This reaction has many advantages like
iodine as the metal free catalyst, air as the sole terminal
oxidant, cheap and readily available starting materials and
a wide substrate scope. Further studies toward the synthetic
utility of this novel C–C bond cleavage reaction are currently
underway.
Scheme 2 Control experiments.
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