FeCl2·4H2O catalyzed ritter reaction with nitriles and halohydrocarbons

Article abstract of DOI:10.1007/s11696-018-0585-5

An efficient and inexpensive synthesis of N-substituted amides from the Ritter reaction of nitriles with various halohydrocarbons catalyzed by FeCl₂·4H₂O is described. FeCl₂·4H₂O economically efficiently catalyzed the Ritter reaction under solvent-free conditions. A range of halohydrocarbons (benzyl, tert-butyl and sec-alkyl halohydrocarbons) were coupled with nitriles to provide the corresponding amides in high to excellent yields.

Full text of DOI:10.1007/s11696-018-0585-5

Chemical Papers
https://doi.org/10.1007/s11696-018-0585-5
ORIGINAL PAPER
FeCl ·4H O catalyzed ritter reaction with nitriles
2
2
and halohydrocarbons
Cheng‑Liang Feng1 · Gui‑Bo Yin · Bin Yan · Jun‑Qing Chen · Min Ji
1
1
2
2
Received: 3 May 2018 / Accepted: 30 August 2018
©
Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
An efcient and inexpensive synthesis oꢀ N-substituted amides ꢀrom the Ritter reaction oꢀ nitriles with various halohydro-
carbons catalyzed by FeCl ·4H O is described. FeCl ·4H O economically efciently catalyzed the Ritter reaction under
2
2
2
2
solvent-ꢀree conditions. A range oꢀ halohydrocarbons (benzyl, tert-butyl and sec-alkyl halohydrocarbons) were coupled with
nitriles to provide the corresponding amides in high to excellent yields.
Keywords FeCl ·4H O · Amides · Nitriles · Halohydrocarbons · Ritter reaction
2
2
Introduction
(Barbero et al. 2009), Iodine (I ) (Theerthagiri et al. 2010),
2
ꢀerric trichloride (FeCl ) (Anxionnat et al. 2009), Cobalt(II)
3
3
+
The amide compounds are versatile building blocks in
organic synthesis. They not only constitute versatile inter-
mediates ꢀor the synthesis oꢀ various peptides and lactam
structures, but also serve as key precursors in the synthesis
oꢀ a variety oꢀ natural products and pharmaceuticals (Zia-
rani et al. 2013). The Ritter reaction is a simple and one-
pot procedure ꢀor amide ꢀormation involving condensation
oꢀ alcohols, suitably substituted alkenes, or tertiary halides
with nitriles in the presence oꢀ a stoichiometric amount oꢀ
a strong acid (Jiang et al. 2014). However, the large amount
oꢀ toxic and corrosive acids is the main disadvantage which
results in environmental pollution and application limited.
Thus, a number oꢀ new catalysts have been developed to
replace the amount oꢀ the acids in recent years. These cat-
alysts include boron triꢁuoride (Firouzabadi et al. 1994),
Naꢂon-H (Yamato et al. 2007), o-Benzenedisulꢀonimide
chloride (CoCl ) (Mukhopadhyay et al. 1995), Fe -Mont-
2
modlonite K10 (Lakouraj et al. 2000), 2, 4-dinitrobenze-
nesulꢀonic acid(DNBSA) (Sanz et al. 2007), CoFe O @
2
4
SiO –DASA (Zhao et al. 2014) and so on.
2
The classical Ritter reaction is the reaction oꢀ nitriles with
alcohols or alkenes to produce amides (Ziarani et al. 2013).
Nevertheless, halohydrocarbons were also applied in the Rit-
ter reaction, which was ꢂrst described by Olah et al. 1979
(Olah et al. 1979). To the best oꢀ our knowledge, the Ritter
reaction with halohydrocarbons has been rarely studied until
Bi et al. (Bi et al. 2010) reported a photo-Ritter-type reac-
tion. Aꢀterwards, Kalkhambkar et al. (Kalkhambkar et al.
2011) used the [BMIM][PF ]/NOPF system ꢀor the syn-
6
6
thesis oꢀ amides via the reaction oꢀ nitriles with bromides
in 2011. The last report is that Qu et al. (Qu et al. 2012) ꢂrst
described metal catalyst system ꢀor the synthesis oꢀ amides
via the reaction oꢀ nitriles with halohydrocarbons. These
catalytic protocols are efcient, but the expensive catalysts,
high reaction temperature and longer reaction time have
imposed limitations on large-scale applications. In this
respect, the development oꢀ inexpensive, easily available and
non-toxic catalysts is highly attractive ꢀor the Ritter reaction
oꢀ nitriles with halohydrocarbons.
Electronic supplementary material The online version oꢀ this
article (https://doi.org/10.1007/s11696-018-0585-5) contains
supplementary material, which is available to authorized users.
*
Min Ji
cl085620@163.com
ꢀ
1
Institute oꢀ Pharmaceutical Engineering, Jiangsu College
oꢀ Engineering and Technology, Nantong 226000, Jiangsu,
People’s Republic oꢀ China
Iron catalysts have attracted much attention as a promis-
ing alternative catalyst ꢀor diꢃerent organic reactions due to
its abundance, low price, non-toxicity and environmentally
well-suited character. A variety oꢀ iron-catalyzed oxidations
2
School oꢀ Biological Sciences & Medical Engineering,
Southeast University, Nanjing 211189, Jiangsu,
People’s Republic oꢀ China
(Nakanishi and Bolm 2007), hydrogenations (Bullock 2007),
Vol.:(0
1
123456789)
3

Chemical Papers
rearrangements (Zhang et al. 2008) and epoxidations (Anilku-
mar et al. 2007) have been successꢀully explored. It has been
proven that iron is highly capable oꢀ catalyzing the reaction oꢀ
nitriles with benzylic alcohols, tert-butyl acetate (Anxionnat
et al. 2009), amines (Allen et al. 2009), binor-S (Khusnutdinov
et al. 2018), benzylic C–H bonds (Liu et al. 2016), alcohol
and alkynes (Jeꢃeries and Cook 2014) and benzyl chlorides
100 MHz): δ 167.4, 138.2, 134.4, 131.6, 128.8, 128.6, 127.9,
127.6, 127.0, 44.1. (Qu et al. 2012).
N-(2-chlorobenzyl)benzamide (1b) White pow-
1
der. M.p.113–114 °C. H NMR (CDCl , 400 MHz): δ
3
1
3
7.80–7.24(m, 9H), 6.68(s, 1H), 4.74(d, J =6 Hz, 2H).
C
NMR (CDCl , 100 MHz): δ 167.3, 135.6, 134.3, 133.7,
3
131.6, 130.4, 129.6, 129.1, 128.6, 127.2, 126.9, 42.1. (Qu
(Karabulut and Kacan 2002) to aꢃord amides.
et al. 2012).
Recently, we tried to ꢂnd a new catalyst which could cata-
N-cyclopentylbenzamide (1c) White powder.
1
lyze the Ritter reaction with nitriles and halohydrocarbons to
produce amides. It is lucky to ꢂnd that the reaction oꢀ nitriles
and halohydrocarbons can be transꢀormed into amides by treat-
ment with FeCl ·4H O. The reaction proceeded well and gave
M.p.142–143 °C. H NMR (CDCl , 400 MHz): δ 7.76(m,
3
2H), 7.50–7.39(m, 3H), 6.16(s, 1H), 4.43–4.38(m, 1H),
2.13–2.05(m, 2H), 1.75–1.63(m, 4H), 1.54–1.46(m, 2H).
1
3
C NMR (CDCl , 100 MHz): δ167.2, 134.9, 131.2, 128.5,
2
2
3
the corresponding amides in high to excellent yields. Herein,
we report this result.
126.8, 51.7, 33.2, 23.8. (Qu et al. 2012).
N-isopropylbenzamide (1d) White powder. M.p.
1
8
9–90 °C. H NMR (CDCl , 400 MHz): δ 7.77(m,
3
Experimental
2H), 7.49–7.40(m, 3H), 6.01(s, 1H), 4.31–4.29(m, 1H),
1
3
1
.28–1.26(m, 6H). C NMR (CDCl , 100 MHz): δ 166.7,
3
Materials and instruments
134.9, 131.3, 128.5, 126.8, 41.9, 22.9. (Qu et al. 2012).
N-(tert-butyl)benzamide (1e) White powder.
1
All reagents were purchased ꢀrom commercial sources and
used without ꢀurther puriꢂcation. Melting points were deter-
mined on a RY-1 hot stage microscope and are uncorrected.
M.p.118–120 °C. H NMR (CDCl , 400 MHz): δ 7.73(m,
3
1
3
2H), 7.47–7.39(m, 3H), 5.98(s, 1H), 1.48(s, 9H). C NMR
(CDCl , 100 MHz): δ 166.9, 135.9, 131.1, 128.5, 126.7,
3
1
13
H NMR and C NMR spectra were recorded on a Bruker
51.6, 28.9. (Qu et al. 2012).
Avance DPX-400 MHz instrument in CDCl , chemical shiꢀts
N-cyclohexylbenzamide (1f) White powder.
3
1
(
δ) were given in part per million(ppm) relative to TMS as an
M.p.140–141 °C. H NMR (CDCl , 400 MHz): δ 7.77(m,
3
internal standard. All reactions were monitored by TLC on
silica gel GF-254 glass plates (E.Merck) and viewed under
UV light at 254 nm.
2H), 7.51–7.40(m, 3H), 6.05(s, 1H), 4.0–3.97(m, 1H),
1
3
2.05–2.02(m, 2H), 1.74–1.23(m, 8H). C NMR (CDCl ,
3
100 MHz): δ 166.6, 135.1, 131.2, 128.5, 126.8, 48.7, 33.2,
2
5.6, 24.9. (Qu et al. 2012).
Typical experimental procedure for the reaction of nitriles
and halohydrocarbons
N-(4-nitrobenzyl)benzamide (1g) White powder. M.p.
1
156–157 °C. H NMR (CDCl , 400 MHz): δ 8.21(m, 2H),
3
7
.83(d, J = 7.16 Hz, 2H), 7.55–7.45(m, 5H), 6.70(s, 1H),
13
A mixture oꢀ nitrile (10 mmol), halohydrocarbons (11 mmol)
and FeCl ·4H O (2 mol %) was placed in a round bottom
4.77(d, J=6 Hz, 2H). C NMR (CDCl , 100 MHz): δ 167.6,
3
147.3, 145.9, 133.7, 132.0, 128.8, 128.3, 127.8, 127.0, 43.3.
2
2
ꢁ
ask. Then the reaction mixture was heated at 80 °C ꢀor the
(Qu et al. 2012).
given time. Aꢀter completion oꢀ the reaction monitored by thin
layer chromatography (TLC), 5 ml water was added into reac-
tion system and extracted with ethyl acetate (3×5 ml). The
organic layers were collected, combined, washed with water
N-(4-methylbenzyl)benzamide (1h) White powder.
1
M.p.129–131 °C. H NMR (CDCl , 400 MHz): δ 7.79(m,
3
2H), 7.49–7.39(m, 3H), 7.23–7.15(m, 4H), 6.45(s, 1H),
1
3
4.61(d, J = 5.48 Hz, 2H), 2.45(s, 3H). C NMR (CDCl ,
3
(
3×10 ml), dried over anhydrous Na SO , and concentrated
100 MHz): δ 167.3, 137.4, 135.1, 134.4, 131.5, 129.4, 128.5,
2
4
under vacuum. The pure product was obtained by directly
passing through a silica gel (200–300 mesh) column using
127.9, 126.9, 43.9, 21.1. (Qu et al. 2012).
N-(2-methylbenzyl)benzamide (1i) White powder.
1
1
petroleum ether/ethyl acetate and identiꢂed by HNMR and
M.p.112–113 °C. H NMR (CDCl , 400 MHz): δ 7.78(m,
3
1
3
C NMR.
2H), 7.49–7.39(m, 3H), 7.29–7.19(m, 4H), 6.33(s, 1H),
1
3
4
1
.63(d, J = 5.2 Hz, 2H), 2.36(s, 3H). C NMR (CDCl ,
3
00 MHz): δ 167.2, 136.6, 135.7, 134.3, 131.5, 130.6, 128.7,
Characterization of compound
128.6, 127.9, 126.9, 126.3, 42.3, 19.1. (Li et al. 2015).
N-(4-chlorobenzyl)benzamide (1j) White powder.
1
N-benzylbenzamide (1a) White powder. M.p. 97–98 °C.
M.p.138–139 °C. H NMR (CDCl , 400 MHz): δ 7.80(m,
3
1
H NMR (CDCl , 400 MHz): δ 7.80(m, 2H), 7.78–7.25(m,
2H), 7.51–7.41(m, 3H), 7.32–7.28(m, 4H), 6.60(s, 1H),
3
13
13
8
H), 6.51(s, 1H), 4.64(d, J=5.8 Hz, 2H). C NMR (CDCl ,
4.61(d, J = 5.76 Hz, 2H). C NMR (CDCl , 100 MHz):
3
3
1
3

Chemical Papers
δ 167.4, 136.8, 134.1, 133.4, 131.7, 129.2, 128.8, 128.6,
N-cyclopentyl-4-methoxybenzamide (1s) White pow-
1
1
26.9, 43.4. (Li et al. 2015).
der. M.p.150–151 °C. H NMR (CDCl , 400 MHz): δ
3
N-benzyl-3-methylbenzamide (1k) White powder. M.p.
7.74(d, J = 8.8 Hz, 2H), 6.92(d, J = 8.76 Hz, 2H), 6.05(s,
1
9
7
2
1
1
8–99 °C. H NMR (CDCl , 400 MHz): δ 7.61–7.55(m, 2H),
1H), 4.42–4.37(m, 1H), 3.85(s, 3H), 2.11–2.06(m, 2H),
3
1
3
.34–7.28(m, 7H), 6.55(s, 1H), 4.62(d, J = 5.64 Hz, 2H),
1.73–1.63(m, 4H), 1.53–1.45(m, 2H). C NMR (CDCl ,
3
1
3
.37(s, 3H). C NMR (CDCl , 100 MHz): δ 167.6, 138.4,
100 MHz): δ 166.7, 162.0, 128.6, 127.2, 113.7, 55.4, 51.6,
3
38.3, 134.3, 132.3, 128.8, 128.4, 127.9, 127.7, 127.6,
33.3, 23.8. (Tu et al. 2017).
23.9, 44.1, 21.3. (Qu et al. 2012).
N-cyclohexyl-4-(triꢁuoromethyl)benzamide (1t) White
1
N-benzyl-2-methylbenzamide (1l) White powder.
powder. M.p.168–169 °C. H NMR (CDCl , 400 MHz):
3
1
M.p.96–98 °C. H NMR (CDCl , 400 MHz): δ 7.36–7.15(m,
δ 7.87(d, J = 8.12 Hz, 2H), 7.69(d, J = 8.16 Hz, 2H),
6.08(d, J=6.24 Hz, 1H), 3.99(m, 1H), 2.06–2.03(m, 2H),
1.80–1.75(m, 2H), 1.79–1.70(m, 1H), 1.45–1.42(m, 2H),
3
1
3
9
H), 6.16(s, 1H), 4.61(d, J=5.76 Hz, 2H), 2.44(s, 3H).
C
NMR (CDCl , 100 MHz): δ 170.0, 138.1, 136.2, 133.3,
3
1
3
1
31.0, 129.9, 128.8, 127.8, 127.6, 126.7, 125.7, 43.9, 19.8.
1.28–1.22(m, 3H). C NMR (CDCl , 100 MHz): δ 165.4,
3
(
Qu et al.2012).
138.4, 133.5 (q, J =33 Hz), 127.4, 125.6 (q, J =4 Hz),
C–F
C–F
N-benzyl-4-methylbenzamide (1m) White powder.
125.1 (q, J = 271 Hz), 49.0, 33.2, 25.5, 24.9. (Prosser
C–F
et al. 2010).
1
M.p. 133–134 °C. H NMR (CDCl , 400 MHz): δ 7.71(d,
3
J = 8.12 Hz, 2H), 7.36–7.21(m, 7H), 6.47(s, 1H), 4.65(d,
13
J=5.52 Hz, 2H), 2.36(s, 3H). C NMR (CDCl , 100 MHz):
3
δ 167.4, 142.0, 138.3, 131.5, 129.3, 128.7, 127.9, 127.6,
Results and discussion
1
27.0, 44.1, 21.5. (Li et al. 2015).
N-benzyl-4-(triꢁuoromethyl)benzamide (1n) White pow-
At the initial stage oꢀ this study, the reaction oꢀ benzyl
chloride (11 mmol) and benzonitrile (10 mmol) was ꢂrst
examined using Fe(III)-catalysts (5 mol %). Initially, we
1
der. M.p.168–170 °C. H NMR (CDCl , 400 MHz): δ 7.91(d,
3
J=8.12 Hz, 2H), 7.71(d, J=8.2 Hz, 2H), 7.38–7.32(m, 5H),
1
3
6
1
1
4
.49(s, 1H), 4.67(d, J = 5.64 Hz, 2H). C NMR (CDCl ,
hoped that Fe(OTꢀ) could catalyze this reaction because
3
3
00 MHz): δ166.1, 137.7, 137.6, 133.5 (q, J = 33 Hz),
it is a highly stable catalyst in water, does not decompose
under aqueous conditions and could reuse in a lot oꢀ reac-
tions (Feng et al. 2014). So, the reaction was ꢂrst examined
C–F
28.8, 128.0, 127.9, 127.5, 125.6, 125.0 (q, J =271 Hz),
C–F
4.3. (Li et al. 2015).
N-benzyl-3-ꢁuorobenzamide(1o) White powder. M.p.
using Fe(OTꢀ) at 100 °C under solvent-ꢀree conditions.
3
1
9
2
2
1
1
J
1–92 °C. H NMR (CDCl , 400 MHz): δ 7.54–7.49(m,
Unꢀortunately, although the reaction produced a pale yellow
mixture aꢀter 5 h, the expected product N-benzylbenzamide
(1a) was separated in only 37% yield (Table 1, entry 1).
To improve the efciency oꢀ the reaction, several Iron(III)-
Lewis acids were tried which were believed to be able to
3
H), 7.46–7.16(m, 7H), 6.74(s, 1H), 4.60(d, J = 5.68 Hz,
1
3
H). C NMR (CDCl , 100 MHz): δ166.3(q, J =2 Hz),
3
C–F
63.9 (q, J = 246 Hz), 137.9, 136.6 (q, J = 7 Hz),
C–F
C–F
30.3 (q, J =17 Hz), 128.8, 128.4 127.9, 127.7, 122.5 (q,
C–F
=3 Hz), 118.7 (q, J =21 Hz), 114.6 (q, J =22 Hz),
catalyze this reaction and the substrate FeCl , a normally
C–F
C–F
C–F
3
4
4.2. (Cheng et al. 2018).
used Lewis acid, was ꢂrst tried, and the reaction produced
(1a) in a slightly improved yield in 43% (Table 1, entry 2).
Then Fe(NO ) ·9H O was employed to catalyze this reac-
N-benzyl-4-nitrobenzamide (1p) White powder.
1
M.p.145–146 °C. H NMR (CDCl , 400 MHz): δ 8.28(d,
3
3 3
2
J=8.84 Hz, 2H), 7.96(d, J=8.8 Hz, 2H), 7.38–7.33(m, 5H),
tion because it was used to synthesize amides ꢀrom nitriles
and amines beꢀore (Allen et al. 2009). However, the aimed
product (1a) was obtained in only 17% yield (Table 1,
entry 3). Later, FeBr , Fe(acac) and Fe(ClO ) ·xH O were
1
3
6
1
1
.57(s, 1H), 4.67(d, J = 5.64 Hz, 2H). C NMR (CDCl ,
3
00 MHz): δ 165.3, 149.6, 139.9, 137.4, 128.9, 128.2, 128.0,
23.9, 44.5. (Qu et al.2012).
3
3
4 3
2
N-benzyl-3-bromobenzamide (1q) White powder. M.p.
checked, and the reaction also aꢃorded 1a in a very low
yield (Table 1, entry 4–6). So, the results displayed that the
Fe(III)-catalysts were not suitable to this reaction.
1
8
7
7–88 °C. H NMR (CDCl , 400 MHz): δ 7.92(s, 1H),
3
.70–7.60(m, 2H), 7.34–7.26(m, 6H), 6.57(s, 1H), 4.61(d,
1
3
J = 5.64 Hz, 2H). C NMR (CDCl , 100 MHz): δ 166.0,
Next, the Fe(II)-catalysts were investigated to ꢂnd a suit-
3
1
1
37.8, 136.3, 134.5, 130.2, 130.1, 128.8, 127.9, 127.7,
able catalyst ꢀor this reaction. Fe(OTꢀ) was ꢂrst used to
2
25.6, 122.8, 44.3. (Li et al. 2015).
catalyze this reaction. It was worth noting that the prod-
N-benzyl-4-methoxybenzamide (1r) White powder.
uct (1a) was obtained in moderate yield in 69% aꢀter 5 h
1
M.p.110–111 °C. H NMR (CDCl , 400 MHz): δ 7.77(d,
(Table 1, entry 7). Then, the use oꢀ FeBr greatly ꢀacilitated
3
2
J=8.76 Hz, 2H), 7.35–7.28(m, 5H), 6.91(d, J=8.8 Hz, 2H),
the reaction, which gave 1a in 75% yield aꢀter 5 h (Table 1,
13
6
.45(s, 1H), 4.63(d, J=5.24 Hz, 2H), 3.83(s, 3H). C NMR
entry 8). The employment oꢀ FeCl ·4H O led to a more
2
2
(
CDCl , 100 MHz): δ 166.9, 162.2, 138.4, 128.8, 128.7,
clean reaction, which produced 1a the highest yield oꢀ 96%
3
1
27.9, 127.6, 126.6, 113.8, 55.4, 44.1. (Qu et al. 2012).
aꢀter 2 h(Table 1, entry 9). Other Fe(II)-catalysts including
1
3

Chemical Papers
Table 1 Optimization oꢀ reaction conditions
o
(%)a
Entry
Catalyst
T ( C)
Amount (mol %)
Time (h)
Yield
1
2
3
4
5
6
7
8
9
Fe(OTꢀ)3
FeCl3
100
100
100
100
100
100
100
100
100
100
100
100
100
5
5
5
5
5
5
5
5
2
5
5
5
5
5
5
5
5
5
5
5
5
2
5
5
5
5
37
43
17
22
26
41
69
75
96
NR
52
Trace
Trace
Fe(NO ) ·9H O
3
3
2
FeBr3
Fe(acac)3
Fe(ClO ) ·xH O
4
3
2
Fe(OTꢀ)2
FeBr2
FeCl ·4H O
2
2
10
11
12
13
FeSO ·7H O
4
2
Fe(acac)2
Fe(Ac)2
Fe(C O )·2H O
2
4
2
Benzyl chloride (11 mmol) and benzonitrile (10 mmol) were used
a
Isolated yields
FeSO ·7H O, Fe(acac) , Fe(Ac) and Fe(C O )·2H O were
Table 2 Optimizing amount oꢀ catalyst Benzyl chloride (11 mmol),
benzonitrile (10 mmol) and 100 °C were used in preparation oꢀ 1a
4
2
2
2
2
4
2
also checked, but none oꢀ them showed superior results com-
pared with FeCl ·4H O (Table 1, entries 10–13 vs entry 9).
Yield (%)a
2
2
Entry
Catalyst/mol %
Time/h
This result prompted an investigation oꢀ the amount oꢀ the
catalyst and the reaction temperature. Similarly, benzyl chlo-
ride (11 mmol) and benzonitrile (10 mmol) were selected as
the model substrates to optimize the amount oꢀ FeCl ·4H O.
1
2
3
4
5
6
1
2
4
5
10
1
2
2
2
2
2
90
96
95
96
95
94
2
2
Table 2 showed that the mixture was stirred in the presence
oꢀ 1, 2, 4, 5 and 10 mol % FeCl ·4H O and the product
2
2
10
(
1a) was separated with yields oꢀ 90, 96, 95, 96 and 95%,
aIsolated yields
respectively. Accordingly, 2 mol % oꢀ catalyst was seen to be
sufcient to obtain the best yield without adversely aꢃecting
the product yields (Table 2, Entry 2). Although employment
oꢀ 1 mol % oꢀ the catalyst also proceeded well, long reaction
times were typically required to achieve yields compara-
ble with those obtained with 2 mol % oꢀ catalyst (Table 2,
Entry 6). Further investigation oꢀ the reaction temperature
Table 3 Optimizing the reaction temperature Benzyl chloride
(
11 mmol), benzonitrile (10 mmol) and FeCl ·4H O (2 mol %) were
2
2
used in preparation oꢀ 1a
o
Yield (%)a
(
Table 3) indicated that 80 °C was suitable to the reaction.
Prompted by the efciency oꢀ the above methodology, the
Entry
Temperature ( C)
Time/h
1
2
3
4
5
20
40
60
80
100
10
10
5
2
2
NR
NR
67
96
96
scope and generality oꢀ the Ritter reaction were examined
with FeCl ·4H O (2 mol %) under solvent-ꢀree conditions
2
2
at 80 °C. First, a wide range oꢀ halohydrocarbons (benzyl,
tert-butyl and sec-alkyl halohydrocarbons) were investigated
ꢀor the reaction with benzonitrile. Table 4 showed that the
aIsolated yields
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Chemical Papers
Table 4 Reaction oꢀ benzonitrile and halohydrocarbons
Entry
1
R-X
Time (h)
2
Product
Yield (%)a
96
1a
2
3
4
5
6
7
8
2
2
4
5
5
5
5
96
93
90
88
89
88
92
1
a
1b
1
c
1d
1
e
1d
1f
1
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Chemical Papers
Table 4 (continued)
Entry
R-
X
Time (h)
Product
Yield (%)a
9
4
88
1g
1
0
1
2
2
2
94
93
92
1
h
1
1
i
j
j
12
1
1
13
2
92
Halohydrocarbons (11 mmol), benzonitrile (10 mmol) and FeCl ·4H O (2 mol %) were used
2
2
a
Isolated yields
reactions proceeded well and high yields were obtained.
It was noted that benzyl halides bearing either electron-
donating or -withdrawing substituents (Table 4, entries
para, Ortho and meta site oꢀ the benzonitrile could proceed
well and produce the similar yields. For example, 4-methylb-
enzonitrile, 2-methylbenzonitrile and 3-methylbenzonitrile
aꢃorded the corresponding amides (1k–1m) in same yields
with 95% (Table 5, entries 1–3). Similarly, we also ꢀound
that the electron-donating or electron-withdrawing substit-
uents on the para, ortho and meta site oꢀ the benzonitrile
also gave the products in high yields (Table 5, entries 3–7).
For example, 4-methylbenzonitrile (Table 5, entry 3) and
4-(triꢁuoromethyl)benzonitrile (Table 5, entry 4) gave the
corresponding products 1m and 1n in 95% and 99% yield,
respectively. Otherwise, it was noted that acetonitrile did not
react with benzyl chloride (Table 5, entry 11).
3
, 9–13) gave the products in similar yields; this result
led us to conclude that no remarkable electronic eꢃects
were displayed in this reaction. For example, 1-chloro-2-
(
chloromethyl)benzene, 1-(bromomethyl)-4-nitrobenzene
and 1-(bromomethyl)-4-methylbenzene aꢃorded the corre-
sponding amides (1b, 1g and 1h) in 93, 88 and 94% yields,
respectively. This result was also observed in the literature
reported (Qu et al. 2012). Additionally, the reaction with
benzyl halohydrocarbons proceeded readily requiring a
shorter time than that required ꢀor the reaction with tert-
butyl and sec-alkyl halohydrocarbons.
From mechanistic point oꢀ view, the catalytic efciency oꢀ
2
+
To ꢀurther determine the scope oꢀ the procedure, the next
various nitriles were investigated under the same reaction
conditions. Table 5 shows that most nitriles could react with
halohydrocarbons to aꢃord the corresponding the amides
with high yields. It was ꢀound that the substituents on the
Fe in this reaction might be attributed to its Lewis acidity
which promoted the Ritter reaction via ꢀacilitation oꢀ C–Cl
cleavage by attack oꢀ nitrile group. Thus, according to the
electronic eꢃects, we proposed the ꢀollowing mechanism
(Scheme 1).
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Chemical Papers
Table 5 Reaction oꢀ various
nitriles and halohydrocarbons
Entry
1
R
1
-CN
R
2
-Cl
Time (h)
1.5
Product
Yield (%)a
95
1
k
2
1.5
95
1
l
3
4
5
6
7
8
9
1.5
1
95
1
m
99
1
n
1.5
5
94
86
94
92
90
1
o
p
q
1
1.5
1.5
4
1
1
r
1
s
10
4
94
1
t
11
CH
3
CN
24
NR
1
u
1
3

Chemical Papers
Table 5 (continued)
Nitriles (10 mmol), halohydrocarbons (11 mmol) and FeCl ·4H O (2 mol %) were used
2 2
Isolated yields
a
Scheme 1 Proposed mecha-
nism ꢀor FeCl ·4H O-catalyzed
2
2
Ritter reaction with nitriles and
halohydrocarbons
Bullock RM (2007) An iron catalyst ꢀor ketone hydrogenations under
mild conditions. Angew Chem Int Ed 46:7360–7363. https://doi.
org/10.1002/anie.200703053
Conclusions
A simple and efcient method ꢀor synthesizing amides via
FeCl ·4H O catalyzed Ritter reaction with nitriles and halo-
Cheng H, Xiong MQ, Cheng CX, Wang HJ, Lu Q, Liu HF, Yao FB,
Chen C, Verpoort F (2018) In situ generated ruthenium catalyst
systems bearing diverse N—heterocyclic carbene precursors ꢀor
atom—economic amide synthesis ꢀrom alcohols and amines.
Chem An Asian J 13:440–448
2
2
hydrocarbons was described under solvent-ꢀree conditions.
The procedure aꢃorded the products with good to excellent
yields at reduced reaction time and with a reduced amount oꢀ
catalyst. In contrast to the catalysts reported in the literature,
the present method oꢃers the reaction with short reaction
time, low temperature, no side reaction and byproducts and
low cost.
Feng CL, Chu NN, Zhang SG, Cai J, Hu HY, Ji M (2014) Solvent-
ꢀree synthesis oꢀ beta-enamino ketones and esters catalysed by
recyclable iron(III) triꢁate. Chem Pap 68:1097–1103. https://doi.
org/10.2478/s11696-014-0544-8
Firouzabadi H, Sardarian AR, Badparva H (1994) Highly selective ami-
dation oꢀ benzylic alcohols with nitriles—a modiꢂed Ritter reac-
tion. Synth Commun 24:601–607. https://doi.org/10.1080/00397
919408012637
Acknowledgements We are grateꢀul to Nantong City Science Founda-
tion (No. 2015) and Science program oꢀ Jiangsu College oꢀ Engineering
and Technology ꢀor ꢂnancial support.
Jeꢃeries LR, Cook SP (2014) Alcohols as electrophiles: iron-catalyzed
Ritter reaction and alcohol addition to alkynes. Tetrahedron
7
0:4204–4207. https://doi.org/10.1016/j.tet.2014.03.072
Jiang DH, He T, Ma L, Wang ZY (2014) Recent developments in Rit-
ter reaction. RSC Adv 4:64936–64946. https://doi.org/10.1039/
C4RA10784E
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