Iodine and Br?nsted acid catalyzed C–C bond cleavage of 1,3-diketones for the acylation of amines

Article abstract of DOI:10.1080/00397911.2019.1691736

A metal-free N-acylation method of anilines with 1,3-diketones has been developed, by using iodine and p-toluene sulfonic acid as the co-catalysts. The reaction can proceed in 1,4-dioxane at elevated temperature to produce the corresponding amides with 48–89% yields. Further, the gram-scale experiment was carried out under the standard conditions and the possible mechanism was proposed.

Full text of DOI:10.1080/00397911.2019.1691736

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Iodine and Brønsted acid catalyzed C–C bond
cleavage of 1,3-diketones for the acylation of
amines
Xiao-Yu Zhou, Xia Chen & Dan Yang
To cite this article: Xiao-Yu Zhou, Xia Chen & Dan Yang (2019): Iodine and Brønsted
acid catalyzed C–C bond cleavage of 1,3-diketones for the acylation of amines, Synthetic
Communications, DOI: 10.1080/00397911.2019.1691736
To link to this article: https://doi.org/10.1080/00397911.2019.1691736
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1691736
Iodine and Brønsted acid catalyzed C–C bond cleavage of
1,3-diketones for the acylation of amines
Xiao-Yu Zhou, Xia Chen, and Dan Yang
School of Chemistry and Materials Engineering, Liupanshui Normal University, Liupanshui, China
ABSTRACT
ARTICLE HISTORY
Received 5 August 2019
A metal-free N-acylation method of anilines with 1,3-diketones has
been developed, by using iodine and p-toluene sulfonic acid as the
co-catalysts. The reaction can proceed in 1,4-dioxane at elevated
temperature to produce the corresponding amides with 48–89%
yields. Further, the gram-scale experiment was carried out under the
standard conditions and the possible mechanism was proposed.
KEYWORDS
Acylation; amine;
1,3-diketones; iodine;
p-toluene sulfonic acid
GRAPHICAL ABSTRACT
I2 (10 mol%)
TsOH•H2O (20 mol%) R'
1,4-dioxane, 140 oC
R
O
O
O
R'
+
R
NH
R
NH
2
@ Metal-Free
@ BrØnsted Acid and Iodine Catalysis
@ C-C Bond Cleavage
N-acylation is one of the most widely practical transformations of organic molecules,
which further has a great value for the preparation of natural products, pharmaceuticals,
and other functional molecules. Equally important, it plays a key role in the protective
group chemistry.[1] Therefore, much efforts have been devoted to the preparation of
amides and protection of amines.
The normal and direct methods to get amides are the acylation of amines with acyl
halides,[2] anhydrides,[3] esters[4] and carboxylic acids.[5] But these methods have many
limitations, such as poor functional group compatibility, low regioselectivity, and harsh
reaction conditions. In order to extend the synthetic methods of amides, the develop-
ment of reaction conditions and acylation reagents with appropriate selectivity and
reactivity is an essential project in this field. Recently, many novel strategies for the
preparation of amides, such as N-heterocyclic carbenes (NHC) catalyzed amidation
between esters and amines or hydrazines,[6] N-acylation of amines via the transamida-
tion of amides,[7] Nb2O5 catalyzed amidations of carboxylic acids with amines,[8]
Wells–Dawson heteropolyacid catalyzed N-acylation of sulfonamides with anhydrides,[9]
CONTACT Xiao-Yu Zhou
Zhouxiaoyu20062006@126.com; Xia Chen
xia811@live.cn
School of Chemistry and
Materials Engineering, Liupanshui Normal University, Liupanshui, 553004, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website
ß 2019 Taylor & Francis Group, LLC

2
X.-Y. ZHOU ET AL.
Scheme 1. Synthesis of amides.
acyltransferase catalyzed N-acylation of amines with esters,[10] potassium promoted syn-
thesis of aryl thioamides from a-oxocarboxylic acids and tetraalkylthiuram disulfides,[11]
copper-catalyzed acetylation of anilines with potassium thioacetate as acetylating
reagent,[12] organocatalytic N-acylation of amides with aldehydes[13]
,
have
been developed.
On the other hand, the application of novel acylating reagents is a meaningful way for
the amidation of amines. In the previous researches, vinyl and iso-propenyl acetates[14]
,
potassium acyltrifluoroborates[15] had been used as acylating reagents for the acylation of
amines or amides. Notably, 1,3-diketones also can be employed as acylating reagent for
the acylation of amines via a C-C bond cleavage process, in which FeCl3 catalyzed[16] or
silica sulfuric acid (SSA)/oxygen promoted[17] methods have been carried out to realize
this transformation (Scheme 1, Eq. 1) and the mechanisms were proposed by the authors.
Besides, metal-free N-acylation systems were the attractive fields for chemists (Eq. 2).
Most recently, TBSOTf-promoted N-formylation with DMF,[18] NH4I-promoted N-acyl-
ation of amines with DMF and DMA,[19] catalyst-free transamidation of aromatic amines
with formamide derivatives and tertiary amides[20] had been achieved.
In 2014, Bao’s group reported the synthesis of benzothiazoles, benzoxazoles, and ben-
zimidazoles via the Brønsted acid- or Brønsted acid/CuI-catalyzed reactions of 2-amino
phenols, 2-amino thiophenols and anilines with 1,3-diketones.[21] In which, p-TsOH
could serve as an efficient acidic catalyst to promote the initial condensation step. In
light of these results, we have developed a new acylation method of anilines with 1,3-
diketones by using p-TsOH/I2 as the co-catalysts as described herein.
Our study began by evaluating the acylation of p-toluidine (1a) with pentane-2,4-
dione (2a, Table 1). After some experiments, we found that a protocol consisting of I2
(10 mol%) and p-toluene sulfonic acid monohydrate (p-TsOHꢀH2O, 20 mol%) in 1,4-
dioxane at 140 ꢁC could afford N-(p-tolyl)acetamide (3a) in 71% isolated yield
(Entry 1). Subsequently, the effects of catalyst, solvent, and temperature were screened.
In agreement with our previous studies, pentane-2,4-dione (1.2 equiv) was proved to be
the better choice (Entry 2), presumably because the catalytic activity of iodine and
TsOHꢀH2O were weakened by excessive substrate. Notably, iodine and TsOHꢀH2O were

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SYNTHETIC COMMUNICATIONSV
3
Table 1. Conditions optimizationa.
Entry
1
Cat.
x
Solvent (T)
Yield (%)b
I2 (10 mol%)
1.2
1,4-dioxane (140)
71
p-TsOHꢀH2O (20 mol%)
2
I2 (10 mol%)
2.0
1,4-dioxane (140)
60
p-TsOHꢀH2O (20 mol%)
p-TsOHꢀH2O (20 mol%)
I2 (10 mol%)
3
4
5
1.2
1.2
1.2
1,4-dioxane (140)
1,4-dioxane (140)
1,4-dioxane (140)
40
22
16
NIS (10 mol%)
p-TsOHꢀH2O (20 mol%)
PhI(OAc)2 (10 mol%)
p-TsOHꢀH2O (20 mol%)
I2 (10 mol%)
CF3COOH (20 mol%)
I2 (10 mol%)
CF3SO3H (20 mol%)
I2 (10 mol%)
L-CSA (20 mol%)
I2 (10 mol%)
CH3COOH (200 mol%)
6
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1,4-dioxane (140)
1,4-dioxane (140)
1,4-dioxane (140)
1,4-dioxane (140)
1,4-dioxane (140)
1,4-dioxane (140)
EtOH (140)
48
20
31
31
23
70
17
47
57
63
53
7
8
9
10
11
12
13
14
15
16
I2 (10 mol%)
TsOHꢀH2O (40 mol%)
I2 (10 mol%)
p-TsOHꢀH2O (20 mol%)
I2 (10 mol%)
CH3CN (140)
p-TsOHꢀH2O (20 mol%)
I2 (10 mol%)
Toluene (140)
p-TsOHꢀH2O (20 mol%)
I2 (10 mol%)
1,4-dioxane (120)
1,4-dioxane (150)
p-TsOHꢀH2O (20 mol%)
I2 (10 mol%)
p-TsOHꢀH2O (20 mol%)
aReaction conditions: 1a (54 mg, 0.50 mmol), 2a (x equiv), catalysts and solvent (3.0 mL) at TꢁC, 24 h.
bIsolated yield.
all necessary because the decreased yields were obtained by omitting either iodine
(Entry 3) or TsOHꢀH2O (Entry 4). It also indicated that the iodine cannot be replaced
by N-iodosuccinimide (NIS), iodobenzene diacetate (PhI(OAc)2) (Entries 5 and 6).
Moreover, the stronger or weaker acids (Entries 7-10), such as trifluoroacetic acid
(CF3COOH), trifluoromethanesulfonic acid (CF3SO3H), camphor sulfonic acid (L-CSA),
and acetic acid all showed negative results. And the increased dosage of TsOHꢀH2O
(Entry 11) also had no more positive effect on this reaction. Besides, ethanol, aceto-
nitrile, and toluene led to lower yields (Entries 12–14). Lastly, the temperature had been
tested and the results showed that 140 ꢁC was a better choice (Entries 15 and 16).
With these conditions in hand, we next turned our attention to evaluating the sub-
strate scope of the reaction. As shown by the results compiled in Table 2, Entries 1–11,
the iodine and TsOHꢀH2O catalyzed acylation conditions can be applied to a wide num-
ber of aromatic amines (1a–k) possessing methyl, methoxy, chloro, bromo, nitro or
cyano substituents at either C3 or C4. Unfortunately, the standard conditions were not
appropriate for the N-acylation of amines with substituents at C2 (Entries 12-13) and

4
X.-Y. ZHOU ET AL.
Table 2. The screening on scope of substratea.
Yield
(%)b
Entry
1
2
3
1
71
86
63
2a
2a
1a
1b
1c
3aa
3ba
3ca
2
3
2a
2a
4
70
1d
1e
3da
3ea
5
6
7
2a
2a
2a
63
82
73
1f
3fa
1g
3ga
8
2a
69
1h
1i
3ha
9
2a
2a
2a
89
64
48
3ia
3ja
10
11
1j
1k
3ka
12
2a
No Reaction
---
1l
13
14
2a
2a
No Reaction
No Reaction
---
---
1m

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5
Table 2. Continued.
1n
15
1a
58
2b
3ab
16
17
1a
1a
No Reaction
---
---
2c
No Reaction
No Reaction
No Reaction
2d
18
19
1a
1a
---
2e
2f
---
aReaction conditions: 1 (0.50 mmol), 2 (0.6 mmol, 1.2 equiv), I2 (12.7 mg, 0.05 mmol, 10 mol%), TsOHꢀH2O
(19.0 mg, 0.10 mmol, 20 mol%), 1,4-dioxane (3.0 mL), 140 ꢁC, 24 h. bIsolated yield.
Scheme 2. Gram-scale experiment.
aliphatic amines (Entry 14), presumably due to the higher steric hindrance of C2 sub-
stituents and stronger alkalinity of aliphatic amines.
Subsequently, the scope of 1,3-diketones and its derivatives had been screened and
the strong steric effect was noticed. The results showed that only heptane-3,5-dione (2b,
entry 15) could be used as propionylation reagent. The standard reaction conditions
were not appropriate for the acylation of amines with 1,3-diketones 2c–e and ethyl ace-
toacetate 2f, which had sterically hindered substituents.
In order to test the practice of this reaction under scale-up conditions, p-toluidine 1a
(3.0 g) was input into the reaction with pentane-2,4-dione 2a. The target product 3a
was attained with 81.4% yield (Scheme 2). It indicated that the reaction system may be
appropriate for the scale-up production of amides.
Based on the known mechanism of catalyzed C–C bond cleavage of 1,3-diketones[21]
and iodine-catalyzed iso-Nazarov cyclization of conjugated dienals,[22] the possible
mechanism of iodine/Brønsted acid co-catalyzed acylation of aromatic amines with 1,3-
diketones was proposed along with the above results, as shown in Figure 1.
The intermediate A may be produced via the nucleophilic addition of amine and
ketone in the presence of Brønsted acid. And the intermediate A could be stabilized by
iodine to form the intermediate B and undergone a C–C bond cleavage process to pro-
duce the product 3a. In the other hand, the imine C could be formed from A easily,
which further might be activated by iodine to form an active intermediate D. The
nucleophilic addition of D and water was favorable to form B. In general, iodine could
be an activator of the intermediate A and C to promote the formation of intermediate
B stabilized by iodine.[22,23]

6
X.-Y. ZHOU ET AL.
Figure 1. Proposed mechanism.
In conclusion, we have developed N-acylation of amines with 1,3-diketones that
accesses the corresponding amides via iodine and Brønsted acid catalyzed C–C bond
cleavage strategy. This approach allows for wide range of amines with up to 89% yield
but limited to the substrates with small steric hindrance. Furtherly, the gram-scale
experiment was carried out under the standard conditions and the possible mechanism
was proposed. Additional application of iodine and Brønsted acid catalyzed transform-
ation of 1,3-diketones are under active investigation in our laboratory and will be dis-
closed in due course.
Experimental section
General Methods: All commercially available reagents were used without further purifi-
cation. Column chromatography was performed on silica gel (200–300 mesh). The
1
chemical shifts (d) of the H NMR (600 MHz) signals are reported in ppm relative to
tetramethylsilane (TMS) and by employing the residual solvent resonance as the internal
standard. Data are reported in the following order: chemical shift, multiplicity [s (sing-
let), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), and m (multiplet)],
coupling constants (Hz), and integration. The chemical shifts (d) of the 13C NMR
(151 MHz) signals are reported in ppm relative tetramethylsilane (TMS) and by employ-
ing the solvent resonance as the internal standard.
Procedure
A mixture of amine 1 (0.50 mmol), 1,3-diketone 2 (0.60 mmol, 1.2 equiv), iodine
(12.7 mg, 0.05 mmol, 10 mol%) and TsOHꢀH2O (19.0 mg, 0.10 mmol, 20 mol%) in 1,4-

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7
dioxane (3 mL) was added into a Schlenk flask (25 mL) and stirred at room temperature.
The mixture was stirred at 140 ꢁC until the reaction was finished. Then, the solvent was
evaporated under reduced pressure and the residue was purified by column chromatog-
raphy (petroleum ether/ethyl acetate 5:1 to 2:1) to afford the product 3.
N-(p-tolyl)acetamide (3aa)
1
Yield: 71%, 53.2 mg, white solid, mp 145–147 ꢁC. H NMR (600 MHz, d6-DMSO) d 9.85
(s, 1H), 7.48 (d, J ¼ 8.4 Hz, 2H), 7.08 (d, J ¼ 8.3 Hz, 2H), 2.23 (s, 3H), 2.03 (s, 3H); 13C
NMR (151 MHz, d6-DMSO) d 168.5, 137.3, 132.3, 129.5, 119.4, 24.4, 20.9; HRMS Calcd
for C9H11NONa: 172.0738 [M þ Na]þ; found: 172.0741.
1
Full experimental detail, H and 13C NMR spectra. This material can be found via
the “Supplementary Content” section of this article’s webpage.
Funding
The work was supported by the Science and Technology Foundation Project of Guizhou
Province [Grant No. qiankehejichu (2018) number 1141], the Science and Technology
Foundation Project of Liupanshui [Grant No. 52020-2018-04-10] and the Science and
Technology Foundation Project of Guizhou Province [Grant No. qiankehe LH zi (2014) num-
ber 7450].
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