Direct Transformation of Ethylarenes into Primary Aromatic Amides with N -Bromosuccinimide and I2-Aqueous NH3

Article abstract of DOI:10.1021/acs.orglett.6b00048

A variety of ethylarenes were converted into the corresponding primary aromatic amides in good yields via treatment with N-bromosuccinimide in the presence of a catalytic amount of 2,2′-azobis(isobutyronitrile) in a mixture of ethyl acetate and water, acetonitrile and water, or chloroform and water, followed by reaction with molecular iodine and aq NH₃ in one pot. It was found that aryl α-bromomethyl ketones and/or aryl methyl ketones were formed at the first reaction step and their iodoform-type reaction occurred at the second reaction step to provide primary aromatic amides. The present reaction is a useful and practical transition-metal-free method for the preparation of primary aromatic amides from ethylarenes. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.6b00048

Letter
pubs.acs.org/OrgLett
Direct Transformation of Ethylarenes into Primary Aromatic Amides
with N‑Bromosuccinimide and I2−Aqueous NH3
Shohei Shimokawa,† Yuhsuke Kawagoe,† Katsuhiko Moriyama,†,‡ and Hideo Togo*,†
†Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
‡Molecular Chirality Research Center, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: A variety of ethylarenes were converted into the corresponding primary
aromatic amides in good yields via treatment with N-bromosuccinimide in the presence of
a catalytic amount of 2,2′-azobis(isobutyronitrile) in a mixture of ethyl acetate and water,
acetonitrile and water, or chloroform and water, followed by reaction with molecular iodine and aq NH3 in one pot. It was found
that aryl α-bromomethyl ketones and/or aryl methyl ketones were formed at the first reaction step and their iodoform-type
reaction occurred at the second reaction step to provide primary aromatic amides. The present reaction is a useful and practical
transition-metal-free method for the preparation of primary aromatic amides from ethylarenes.
rimary aromatic amides are valuable compounds that are
by the reaction with molecular iodine and aq NH3. In the
course of our present study, a one-pot conversion of
ethylarenes into primary aromatic amides with molecular
iodine and TBHP in aq NH3 at 100 °C for 3 h was reported.10
As the reaction looked highly useful and attractive, we checked
its applicability to the one-pot preparation of primary aromatic
amides from ethylbenzene and p-bromoethylbenzene with
molecular iodine, TBHP, and aq NH3 under the same reaction
conditions.10 However, we question the veracity of the report;
although we performed the above reaction carefully on the basis
of the reported reaction conditions, we obtained only 6% of
benzamide and 7% of p-bromobenzamide, together with
starting ethylarenes and complicated reaction mixtures. Thus,
we found that the reaction is not reproducible. Here, we report
a practical one-pot transformation of ethylarenes into primary
aromatic amides by treatment with NBS, followed by the
reaction with molecular iodine and aq NH3.
Treatment of ethylbenzene 1a (0.5 mmol) with NBS (2.5
equiv) in the presence of AIBN (10 mol %) in a mixture of
chloroform and H2O (10 equiv) at 60 °C for 4 h followed by
reaction with molecular iodine (3.0 equiv) and aq NH3 (28−
30%) at room temperature for 12 h gave benzamide 2a in 5%
yield (Table 1, entry 1). To improve the yield of benzamide 2a,
optimization of the reaction conditions by changing the solvent,
namely mixtures of chloroform and water (9:1), carbon
tetrachloride and water (9:1), tert-butyl methyl ether
(TBME) and water (9:1), ethyl acetate and water (9:1), and
acetonitrile and water (9:1), was carried out, and it was found
that the mixture of ethyl acetate and water was the best choice,
giving benzamide 2a in 63% yield (Table 1, entries 2−6).
Finally, we found that treatment of ethylbenzene 1a with NBS
(3.5 equiv) in the presence of AIBN in a mixture of ethyl
acetate and water (5:1) at 60 °C for 4 h, followed by the
reaction with molecular iodine and aq NH3 (28% ∼ 30%) at
1
Pused as pharmaceuticals
and intermediates for the
synthesis of aromatic nitriles, carboxylic acids, and heterocyclic
compounds, such as oxazoles. As typical conventional methods
for the preparation of primary aromatic amides, the treatment
of aroyl chlorides with aqueous ammonia (Schotten−Baumann
reaction), the dehydration of arenecarboxylic acids and
ammonia, and the hydration of aromatic nitriles are known.2
The amidation of electron-rich aromatics with EtOCONH2 and
AlCl3 was also reported.3 On the other hand, the Lieben
iodoform reaction is useful for the preparation of primary
amides, particularly primary aromatic amides, from aryl methyl
ketones or α-arylethanols with molecular iodine and aq NH3
under transition-metal-free and low-toxicity conditions.4 The
reaction of aryl trichloromethyl ketones with primary amines
was reported to give secondary aromatic amides.5 Recently, the
tetrabutylammonium iodide mediated transformation of aryl
methyl ketones with tert-butyl hydrogen peroxide (TBHP) and
aq NH3 at 100 °C into primary aromatic amides6a and the I2-
mediated transformation of aryl methyl ketones with primary
amines and TBHP at 0 °C into secondary aromatic amides6b
were reported. Moreover, the reaction of aryl methyl ketones
and α-arylethanols with molecular iodine and aq NH3 at 60 °C
was reported to provide the corresponding primary aromatic
amides.7 Recently, we reported the one-pot transformation of
methylarenes into aromatic nitriles, which involved the
treatment with N-bromosuccinimide (NBS) or 1,3-dibromo-
5,5-dimethylhydantoin (DBDMH) and a catalytic amount of
2,2′-azobis(isobutyronitrile) (AIBN) or benzoyl peroxide
(BPO) under warming conditions or irradiation with a tungsten
lamp, followed by reaction with molecular iodine and aq NH3
at 60 °C,8a and treatment with aq H2O2 and aq HBr under
warming conditions or irradiation with a tungsten lamp,
followed by reaction with molecular iodine and aq NH3 at 60
°C.8b Here, as part of our study of molecular iodine for organic
synthesis,9 we report a one-pot transformation of ethylarenes
into primary aromatic amides by treatment with NBS followed
Received: January 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00048
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Organic Letters
Letter
Table 1. Optimization of Reaction Conditions with
Ethylbenzene
Table 2. Transformation of Ethylarenes into Primary
Aromatic Amides
first step
second step
temp
I2
yield
(%)
entry oxidant (equiv)
solvent
CHCl3
(°C)
(equiv)
a
1
2
3
4
5
6
NBS (2.5)
NBS (2.5)
NBS (2.5)
NBS (2.5)
NBS (2.5)
NBS (2.5)
60
60
60
60
60
60
3.0
3.0
3.0
3.0
3.0
3.0
5
7
CHCl3/H2O (9:1)
CCl4/H2O (9:1)
TBME/H2O (9:1)
AcOEt/H2O (9:1)
0
16
63
43
CH3CN/H2O
(9:1)
7
8
9
NBS (3.5)
NBS (3.5)
AcOEt/H2O (9:1)
AcOEt/H2O (5:1)
AcOEt/H2O (5:1)
60
60
60
2.5
2.5
2.5
80
85
82
DBDMH
(1.75)
10
11
12
13
NBA (3.5)
AcOEt/H2O (5:1)
60
60
40
60
2.5
2.5
2.5
2.5
20
81
0
BrNPhth (3.5) AcOEt/H2O (5:1)
NBS (3.5)
NIS (3.5)
AcOEt/H2O (5:1)
AcOEt/H2O (5:1)
0
a
H2O (10 equiv) was added at the first reaction step.
room temperature for 12 h gave benzamide 2a in 85% yield
(Table 1, entry 8). Here, α-bromoacetophenone was the major
product in the reaction with NBS in a mixture of ethyl acetate
and water at 60 °C for 4 h (the first reaction step), and the
yield was in 81% yield. N-Iodosuccinimide (NIS) was not
effective at all (Table 1, entry 13). Treatment of ethylbenzene
1a with DBDMH or N-bromophthalimide (BrNPhth) instead
of NBS under the same procedure and conditions gave
benzamide 2a in 82% and 81% yields, respectively, whereas the
yield of benzamide 2a was low when N-bromobenzamide
(NBA) was used under the same conditions (Table 1, entries
9−11). Lowering the temperature of the first reaction step was
also detrimental to the present reaction, even if NBS was used
in a mixture of ethyl acetate and water (5:1) (Table 1, entry
12). On the basis of these results, various ethylarenes 1 were
treated with NBS (3.5 equiv) in the presence of AIBN (10 mol
%) in a mixture of ethyl acetate and water (5:1) at 60 °C for the
indicated time, followed by the reaction with molecular iodine
(2.5 equiv) and aq NH3 (28−30%) at room temperature for 12
h to give primary aromatic amides, as shown in Table 2
(conditions A). At first, the semilarge-scale treatment of
ethylbenzene 1a (10 mmol) under the same procedure and
conditions gave benzamide 2a in 79% yield. Treatment of
ethylarenes 1, such as 4-methyl-1-ethylbenzene 1b, 4-tert-butyl-
1-ethylbenzene 1c, 4-phenyl-1-ethylbenzene 1d, 4-bromo-1-
ethylbenzene 1e, and 4-iodo-1-ethylbenzene 1f under the same
procedure and conditions provided the corresponding primary
aromatic amides 2b, 2c, 2d, 2e, and 2f in good yields. When
ethylarenes 1, such as 3-ethylthiophene 1g and 2-ethyl-
benzothiophene 1h, were treated under the same procedure
and conditions with 6.0 and 5.0 equiv of NBS, respectively, at
the first reaction step, brominated amides 2,5-dibromothio-
phene-3-carboxamide 2g and 3-bromobenzothiophene-2-car-
boxamide 2h were obtained in good yields. When 4-
ethylphenylboronic acid 1i was reacted with 5.0 equiv of
a
b
First step was carried out at 80 °C. Solvent was removed under
c
reduced pressure before the second step. Reaction was carried out on
d
e
a 10 mmol scale. Second step was carried out at 1rt or 260 °C. NBS
f
(13.5, 5.0, or 6.0 equiv) was used. I2 (12.5, 3.0, or 5.0 equiv) was
2
3
2
3
g
1
2
3
used. Reaction was carried out under conditions A, B, or C (time
1:10 h). First step was carried out without H2O, and second step was
carried out at 80 °C for 24 h. Volume of CHCl3/H2O in the first step
was 6.0 mL instead of the usual 3.0 mL.
h
i
NBS under the same procedure and conditions, p-bromoben-
zamide 2e was obtained in 76% yield.
B
DOI: 10.1021/acs.orglett.6b00048
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Organic Letters
Letter
When conditions A were adopted for 4-cyano-1-ethyl-
benzene 1j, 4-cyanobenzamide was obtained in only 21%
yield. However, when ethylarenes 1 bearing an electron-
withdrawing group, such as 4-cyano-1-ethylbenzene 1j, 4-
methoxycarbonyl-1-ethylbenzene 1k, 4-nitro-1-ethylbenzene 1l,
4-methanesulfonyl-1-ethylbenzene 1m, 2-methanesulfonyloxy-
1-ethylbenzene 1n, 2-bromo-1-ethylbenzene 1o, 2-iodo-1-
ethylbenzene 1p, 3,5-dibromo-1-ethylbenzene 1q, and 2-ethyl-
9,10-anthraquinone 1r, were treated with NBS (3.5 equiv) in
the presence of AIBN (10 mol %) in a mixture of acetonitrile
and water (5:1) at 60 °C for the indicated time, followed by the
reaction with molecular iodine (3.0 equiv or 2.5 equiv) and aq
NH3 (28−30%) at 60 °C for 12 h, primary aromatic amides 2j,
2k, 2l, 2m, 2n, 2o, 2p, 2q, and 2r were produced in good yields,
as shown in Table 2 (conditions B). Here, aryl α-bromomethyl
ketone and aryl methyl ketone were the main products of the
first reaction step. When 4-ethylpyridine 1s was used, the first
reaction step was carried out in acetonitrile alone with NBS
(5.0 equiv) and AIBN at 60 °C for 12 h, and the second
reaction step was carried out with molecular iodine (5.0 equiv)
and aq NH3 at 80 °C for 24 h due to low reactivity, giving
isonicotinamide 2s in good yield. Here, the product of the first
reaction step was 4-(α,α-dibromoethyl)pyridine. On the other
hand, when 4-methoxy-1-ethylbenzene 1t was treated with
conditions A and B, 3-bromo-4-methoxybenzamide 2t was
obtained in 29% and 0% yield, respectively. Thus, to improve
the yield of aromatic amides 2, ethylarenes 1 bearing an
electron-donating group, such as 4-methoxy-1-ethylbenzene 1t,
4-isopropoxy-1-ethylbenzene 1u, 2-methoxy-1-ethylbenzene 1v,
2-ethoxy-1-ethybenzene 1w, and 2-ethylthiophene 1x, were
treated with NBS (5.0 equiv) in the presence of AIBN (10 mol
%) in a mixture of chloroform and water (5:1) at 60 °C for the
indicated time, followed by the reaction with molecular iodine
(3.5 equiv) and aq NH3 (28% ∼ 30%) at 60 °C for 12 h to give
brominated primary aromatic amides 2t, 2u, 2v, 2w, and 2x in
good yields, as shown in Table 2 (conditions C), although a
slightly diluted condition was used at the first reaction step for
compound 1x. Here, aryl methyl ketones were the main
products of the first reaction step. The same treatment of 1-
ethylnaphthalene 1y and 2-ethylnaphthalene 1z using con-
ditions C with NBS (3.5 equiv) gave 1-naphthamide 2y and 2-
naphthamide 2z in good yields, although a slightly diluted
condition was used at the first reaction step for compound 1y.
Then, to clarify the reaction mechanism underlying the
present one-pot reaction, blank experiments were carried out,
as shown in Scheme 1. When ethylbenzene 1a was treated with
NBS (3.5 equiv) in the presence of AIBN (10 mmol %) in a
mixture of ethyl acetate and water (5:1) at 60 °C for 4 h, α-
bromoacetophenone was obtained in 81% yield, together with
α,α-dibromoacetophenone and acetophenone in 11% and 4%
yields, respectively (eq 1). Therefore, α-bromo ketone was the
major product of the first reaction step under conditions A. α-
Bromoethylbenzene, which is the first reaction product of the
Wohl−Ziegler reaction, and α-hydroxyethylbenzene, which
may be formed by hydrolysis of α-bromoethylbenzene, were
treated with NBS (2.5 equiv) in the presence of AIBN (10 mol
%) in a mixture of ethyl acetate and water (5:1) at 60 °C for 4
h, followed by the reaction with molecular iodine (2.5 equiv)
and aq NH3 (28−30%) at room temperature for 12 h to give
benzamide 2a in 80% and 72% yields, respectively (eqs 2 and
3). In addition, when α,α-dibromoethylbenzene, which may be
formed by the second Wohl−Ziegler reaction of α-
bromoethylbenzene, was treated with NBS (1.5 equiv) in the
Scheme 1. Control Experiments
presence of AIBN (10 mol %) in a mixture of ethyl acetate and
water (5:1) at 60 °C for 4 h, followed by the reaction with
molecular iodine (2.5 equiv) and aq NH3 (28−30%) at room
temperature for 12 h, benzamide 2a was obtained in 72% yield
(eq 4). Thus, α-bromoethylbenzene, α-hydroxyethylbenzene,
and α,α-dibromoethylbenzene could be also converted into
benzamide 2a using the present reaction procedure and
conditions. When α,α-dibromoethylbenzene was directly
treated with molecular iodine (5.0 equiv) and aq NH3 (28%
∼ 30%) at 80 °C for 24 h, benzamide 2a was obtained in 77%
yield (eq 5). This reaction proceeded for the case of 4-
ethylpyridine 1s, and 4-(α,α-dibromoethyl)pyridine was the
product of the first reaction step. Finally, when acetophenone
and α-bromoacetophenone were treated with aq NH3 and 3.5
equiv and 2.5 equiv of molecular iodine at room temperature
for 12 h, benzamide 2a was obtained in 90% and 98% yields,
respectively (eqs 6 and 7). Based on those blank experiments,
we propose the following reaction mechanism, as shown in
Scheme 2. α-Bromoethylarene is formed in the reaction of
ethylarene 1 with bromine atom formed from NBS (Wohl−
Ziegler reaction). The second Wohl−Ziegler reaction of α-
bromoethylarene occurs to give α,α-dibromoethylarene mainly.
The hydrolysis of α,α-dibromoethylarene in a mixture of ethyl
acetate (or acetonitrile or chloroform) and water under
warming conditions proceeds to give aryl methyl ketone.
Simultaneously, the hydrolysis of α-bromoethylarene may
occur to form α-hydroxyethylarene as a minor product. α-
Hydroxyethylarene can be easily oxidized by NBS or Br2 to aryl
methyl ketone. Once aryl methyl ketone is formed, it smoothly
reacts with NBS or Br2 to form aryl α-bromomethyl ketone.
Then, treatment of aryl α-bromomethyl ketone (conditions A
and B) or aryl methyl ketones (condition B and C) with
molecular iodine and aq NH3 induces iodination to form aryl
α,α,α-bromodiiodomethyl ketone and aryl α,α,α-triiodomethyl
C
DOI: 10.1021/acs.orglett.6b00048
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Ed. 2006, 45, 1248. (c) Bray, B. L. Nat. Rev. Drug Discovery 2003, 2,
587. (d) Beckwith, A. L. J. Synthesis of Amides. In The Chemistry of
Amides; Zabicky, J., Ed.; Wiley-Interscience: New York, 1970; p 73.
(2) Larock, R. C. Comprehensive Organic Transformation, 2nd ed.;
Wiley, 1999; p 1623.
Scheme 2. Plausible Reaction Mechanism
(3) (a) Chakraborty, D. P.; Mandal, A. K.; Roy, S. K. Synthesis 1981,
1981, 977.
(4) (a) Lieben, A. Ann. 1870, 7, 218. (b) Newman, M. S.; Holmes, H.
L. Organic Syntheses; John Wiley & Sons, 1966; Collect. Vol. 2, p 428.
(5) (a) Foley, L. H.; Buchi, G. J. Am. Chem. Soc. 1982, 104, 1776.
̈
(b) Druzian, J.; Zucco, C.; Rezende, M. C.; Nome, K. J. Org. Chem.
1989, 54, 4767.
(6) (a) Sharif, M.; Chen, J.; Langer, P.; Beller, M.; Wu, X. Org.
Biomol. Chem. 2014, 12, 6359. (b) Zhu, C.; Wei, W.; Du, P.; Wan, X.
Tetrahedron 2014, 70, 9615.
(7) Cao, L.; Ding, J.; Gao, M.; Wang, Z.; Li, J.; Wu, A. Org. Lett.
2009, 11, 3810.
(8) (a) Tsuchiya, D.; Kawagoe, Y.; Moriyama, K.; Togo, H. Org. Lett.
2013, 15, 4194. (b) Kawagoe, Y.; Moriyama, K.; Togo, H. Eur. J. Org.
Chem. 2014, 4115.
(9) Reviews: (a) Togo, H.; Iida, S. Synlett 2006, 2006, 2159.
(b) Togo, H. Yuki Gosei Kagaku Kyokaishi 2008, 66, 652. Recent
papers: (c) Ishii, G.; Harigae, R.; Moriyama, K.; Togo, H. Tetrahedron
2013, 69, 1462. (d) Miyagi, K.; Moriyama, K.; Togo, H. Eur. J. Org.
Chem. 2013, 5886. (e) Dohi, S.; Moriyama, K.; Togo, H. Eur. J. Org.
Chem. 2013, 7815. (f) Harigae, R.; Moriyama, K.; Togo, H. J. Org.
Chem. 2014, 79, 2049. (g) Nakai, Y.; Moriyama, K.; Togo, H. Eur. J.
Org. Chem. 2014, 6077. (h) Tamura, T.; Moriyama, K.; Togo, H. Eur.
J. Org. Chem. 2015, 2023.
ketones, respectively, at the second reaction step. Aryl α,α,α-
bromodiiodomethyl ketone and aryl α,α,α-triiodomethyl
ketones smoothly react with aq NH3 to form primary aromatic
amide 2 and CHBrI2 and CHI3, respectively. CHBrI2 and CHI3
were observed by mass spectral measurements of the reaction
mixtures.
In conclusion, various ethylarenes were successfully trans-
formed into the corresponding primary aromatic amides or
brominated primary aromatic amides in good yields in one pot
under mild and transition-metal-free conditions via treatment
with NBS and a catalytic amount of AIBN in a mixture of ethyl
acetate and water, acetonitrile and water, or chloroform and
water, followed by the reaction with molecular iodine and aq
NH3. We believe the present method would be useful for the
conversion of ethylarenes into primary aromatic amides due to
the simple synthetic procedure, use of low-toxicity reagents,
and the generality of the reaction.
(10) Vadagaonkar, K. S.; Kalmode, H. P.; Prakash, S.; Chaskar, A. C.
Synlett 2015, 26, 1677.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00048.
Experimental details; characterization data by mp, IR, 1H
NMR, and 13C NMR (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: togo@faculty.chiba-u.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support in the form of a Grant-in-Aid for Scientific
Research (No. 25105710) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan, is acknowl-
edged.
REFERENCES
■
(1) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem., Int.
D
DOI: 10.1021/acs.orglett.6b00048
Org. Lett. XXXX, XXX, XXX−XXX