Mechanochemical ritter reaction: A rapid approach to functionalized amides at room temperature

Article abstract of DOI:10.1002/ejoc.201500051

A fast and efficient mechanochemical Ritter reaction between alcohols and nitriles under mild conditions is demonstrated. The reaction proceeds rapidly at room temperature in a solvent-free or low-solvent environment by using a Br?nsted acid catalyst. Its general application has been verified through a substrate screening comprising a wide range of functionalized nitriles as well as secondary and tertiary alcohols. Gentle Ritter: A fast and efficient mechanochemical Ritter reaction under mild conditions is described. The reaction proceeds rapidly at room temperature in a solvent-free or low-solvent environment by using sulfuric acid as catalyst.

Full text of DOI:10.1002/ejoc.201500051

Job/Unit: O50051
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Date: 11-03-15 18:22:34
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201500051
Mechanochemical Ritter Reaction: A Rapid Approach to Functionalized
Amides at Room Temperature
[a]
[a]
ˇ
Irena Dokli and Matija Gredicak*
Keywords: Mechanochemistry / Organocatalysis / Ritter reaction / Amides
A fast and efficient mechanochemical Ritter reaction be- Brønsted acid catalyst. Its general application has been veri-
tween alcohols and nitriles under mild conditions is demon- fied through a substrate screening comprising a wide range
strated. The reaction proceeds rapidly at room temperature
in a solvent-free or low-solvent environment by using a
of functionalized nitriles as well as secondary and tertiary
alcohols.
at room temperature was published, however, the reaction
time was substantially longer.[11] A neutral and mild Ritter
reaction was achieved by using a gold(I) catalyst, yet the
protocol was not suitable for solid nitriles as nitrile was
used as the solvent.[12]
In addition, the above-mentioned protocols mostly de-
scribe the employment of non-functionalized nitriles as sub-
strates and provide a narrow substrate scope; functionalized
amides are still mostly prepared by standard acid chloride/
amine couplings or by recently developed ortho-directed
functionalizations,[13] metal-catalysed amidations[14] and
metal-free carboxyamidations.[15]
In this paper we report a general procedure for a
Brønsted acid catalysed mechanochemical Ritter reaction
under mild conditions: room temperature, short reaction
time, and a solvent-free or low-solvent environment. The
versatility of the protocol was verified through a wide sub-
strate screening that included functionalized nitriles as well
as secondary and tertiary alcohols.
Mechanochemistry has been recognized as one of the
most successful modes of solvent-free synthesis.[16] Mecha-
nochemical reactions, usually performed in ball mills, are
now used in all fields of chemistry, and their application in
organic synthesis is increasing.[17] Recently it was shown
that the conditions produced by a ball mill could be com-
pared with those produced when performing the same reac-
tion at elevated temperature in solution even though the
temperature in the vial remains virtually ambient.[18] Hence,
we reasoned that the activation energy of the Ritter reaction
could be overcome during ball milling.
Introduction
The Ritter reaction is an organic reaction that leads to
the formation of amides from a carbocation precursor (ter-
tiary alcohol or substituted olefin) and a nitrile by using a
strong acid catalyst.[1] Although the Ritter reaction has
found applications in drug[2] and natural product and natu-
ral-product-like syntheses,[3] the traditional use of stoichio-
metric amounts of strong corrosive acids at elevated tem-
peratures limits its wider application for reasons of func-
tional group stability.
Various
procedures
involving
sub-stoichiometric
amounts of mineral acids (usually sulfuric acid) have been
reported.[4] However, over the past decade, non-nucleophilic
organic Brønsted acids have emerged as viable catalysts,
mostly sulfonic acids.[5] The Ritter and Ritter-type reactions
have also been successfully catalysed by organic[6] and
metal[7] Lewis acids.
On the other hand, attempts to perform the reaction un-
der mild conditions, thus making it more environmentally
friendly, were met with limited success. Shorter reaction
[7c]
[7e]
times were achieved by utilizing FeCl3 and Ca(OTf)2
catalysts, although high temperatures were still required. A
fast protocol at room temperature with an excess of sulfuric
acid was established,[8] however, the reaction was substrate-
specific for tert-butyl acetate as carbocation precursor.
In the pursuit of a more convenient and efficient Ritter
reaction, solvent-free procedures employing solid-sup-
ported catalysts[9] and ionic liquids[10] have been reported,
but the main issue remains the high reaction temperature.
Recently, an environmentally benign solvent-free protocol
[a] Division of Organic Chemistry and Biochemistry, Rueer
Bosˇkovic´ Institute,
Results and Discussion
Bijenicˇka cesta 54, 10000 Zagreb, Croatia
E-mail: matija.gredicak@irb.hr
To test our hypothesis we performed a model reaction
between benzonitrile and tert-butyl alcohol[19] with a
Brønsted acid catalyst (Table 1).
http://www.irb.hr/eng/People/Matija-Gredicak
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500051.
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I. Dokli, M. Gredicˇak
FULL PAPER
Table 1. Optimization of the Ritter reaction performed in a ball model reaction was performed at 25 Hz to test the influence
mill.
of milling frequency. After 60 min, 86% conversion was ob-
served (Table 2, entry 2).
Table 2. Optimization of the ball mill conditions.
Entry
Acid (amount [equiv.]) Time
Conversion [%][a]
1
2
3
4
5
6
7
8
TfOH (1)
H3PO4 (1)
60 min
60 min
60 min
30 min
90 min
180 min
60 min
60 min
60 min
90 min
8 d
53
96
74
98
42
40
12
–
Entry Ball material Number Frequency
Time
[min]
Conversion
[%][a]
H3PO4 (0.5)
H2SO4 (0.5)
CF3COOH (2)
HCOOH (5)
BF3·OEt2 (1)
FeCl3·6H2O (1)
H2SO4 (0.25)
H2SO4 (0.1)
H2SO4 (0.5)[b]
of balls
[Hz]
1
2
3
4
5
WC
WC
1
1
1
1
2
30
25
30
30
30
30
60
60
60
30
98
86
73
88
94
Teflon®
Corundum
Corundum
9
10
11
23
–
43
1
[a] Determined by H NMR spectroscopy.
[a] Determined by 1H NMR spectroscopy. [b] The reaction was
performed in a flask with stirring at room temperature.
When a larger, but lighter Teflon® ball (d = 10 mm, m =
1.76 g) was used, the reaction yielded 73% conversion after
60 min, whereas in the reaction with a corundum ball (d =
Due to the corrosive nature of strong acids, a Teflon® 6 mm, m = 1 g), 88% conversion was observed in the same
vial and a tungsten carbide ball (WC; d = 7 mm, m = 4 g) period of time (Table 2, entries 3 and 4). Excellent conver-
were used. In the first reaction, trifluoromethanesulfonic sion after 30 min was obtained with two corundum balls
acid (1 equiv.) was used. After 1 h, the conversion to N- (Table 2, entry 5), however, due to an excessive deteriora-
tert-butylbenzamide (1) was observed in 53% yield (Table 1, tion of the balls during milling, this protocol was not found
entry 1). Encouraged by this result, we carried out screen- to be suitable for the indicated reaction. Thus, the best pa-
ings of both the catalyst and the reaction conditions. Em- rameter combination for the investigated process is ball
ploying phosphoric acid (1 equiv.) as a catalyst resulted in milling at 30 Hz with a single tungsten carbide ball.[21]
96% conversion after 60 min (Table 1, entry 2); lowering its
With the optimized reaction conditions in hand, we
loading diminished the conversion to 74% (Table 1, en- turned our attention to investigating the substrate scope
try 3). On the other hand, 98% conversion was observed and limitations of the reaction. First, we investigated the
after 30 min of ball milling when 0.5 equiv. of sulfuric acid Ritter reactions of various nitriles with tert-butyl alcohol as
was used as catalyst (Table 1, entry 4).
the model alcohol (Table 3).
Nucleophilic organic acids usually hinder the Ritter reac-
When 2-iodobenzonitrile was used in the reaction, only
tion because they react with carbocations to yield esters.[20] traces of amide 2 were observed. Because the reaction mix-
However, we decided to test nucleophilic organic acids in ture was a solid, we presumed that the carbocation could
this reaction and found that the reactions with trifluoro- not be stabilized long enough for the reaction to occur.
acetic and formic acid proceeded without the formation of Therefore liquid-assisted grinding (LAG)[22] was performed
traces of ester (Table 1, entries 5 and 6) although the trans- with a polar, non-nucleophilic additive with the ability to
formation only gave moderate conversions and required stabilize the carbocation. Indeed, upon the addition of ni-
longer reaction times with an excess of acid (2 equiv. of tri- tromethane (1 equiv., η = 0.26 μL/mg),[23] the isolated yield
fluoroacetic acid and 5 equiv. of formic acid, respectively). rapidly improved to 79% (Table 3, 2). The transformation
Lewis acids were also tested, but poor conversions were ob- remained effective upon introducing various halogen atoms
served (Table 1, entries 7 and 8). Lowering the sulfuric acid at different positions in the aromatic ring (Table 3, 3–6).
loading led to increased reaction times and significantly The reaction was tolerant of other aromatic ring deactivat-
lower conversion (Table 1, entries 9 and 10).
ing groups (nitro group 7, ester group 8, CF3 group 9), as
Hence the optimized reaction involved the solvent-free well as of aromatic ring activating groups (o-methyl group
ball milling of a nitrile (1 equiv.) and an alcohol (1.1 equiv.) 10, p-methyl group 11, methoxy group 12). Moderate iso-
with sulfuric acid as catalyst (0.5 equiv.) at 30 Hz for lated yields were observed with o-trifluoromethyl- and o-
30 min. To prove the efficiency of the mechanochemical methyl-substituted benzonitriles 9 and 10, presumably due
Ritter reaction, the optimized reaction conditions were used to steric hindrance. The use of alkyl and allyl nitriles was
for the reaction in a flask with stirring at room temperature; also successful, generating the corresponding amides 13–15
the conversion was 43% after 8 d (Table 1, entry 11).
in excellent yields.
In addition to chemical parameters, the technical and
Having surveyed the reactivity of various nitriles in the
process parameters also required attention, for example, the mechanochemical Ritter reaction, the scope of secondary
frequency of milling, the size and number of balls, and the and tertiary alcohols in the reaction was explored by using
material from which the balls were made.[17c] First, the aceto- and benzonitrile as the nucleophiles (Table 4).
2
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Mechanochemical Ritter Reaction
Table 3. Substrate scope of nitriles in the Ritter reaction.[a]
Table 4. Substrate scope of alcohols in the Ritter reaction.[a]
[a] The yields are for the isolated material. [b] MeCN (5 equiv.).
[c] MeCN (5 equiv.), H2SO4 (2 equiv.), 60 min. [d] LAG: MeNO2
(1 equiv.), 60 min.
most likely due to steric hindrance between the two phenyl
groups.
It is worth noting that many of the amides prepared in
this work have been obtained here for the first time, and a
number of others have now been obtained by the Ritter
reaction rather than the more expensive methods men-
tioned earlier.
The scale-up of the developed protocol was also ex-
plored. The gram-scale reaction between benzonitrile and
tert-butyl alcohol afforded tert-butylbenzamide (1) in 84%
isolated yield (Scheme 1).
[a] The yields are for the isolated materials. [b] LAG: MeNO2
(1 equiv.). [c] 60 min.
The reaction proved to be effective with tertiary alcohols,
furnishing amides 16–18 in high yields. However, under the
optimized reaction conditions, only traces of amide 19 were
obtained; the major product was an olefin formed by intra-
molecular trapping of the carbocation.[24] Because the intra-
molecular trapping of the carbocation is in competition
with its trapping by the nitrile group, we reasoned that
using an excess of a nitrile would direct the reaction
Scheme 1. Scale-up of the Ritter reaction.
Conclusions
We have developed an efficient mechanochemical Ritter
towards the amide. After systematically increasing the reaction between nitriles and alcohols under mild condi-
nitrile component, the amide 19 was obtained as the sole tions by using a Brønsted acid catalyst. The transformation
product in 74% yield with 5 equiv. of acetonitrile.
is fast, proceeds at room temperature and is tolerant of vari-
The effectiveness of the reaction was also tested on sec- ous functionalities on the nitriles as well as secondary and
ondary alcohols. As with the previous example, under the tertiary alcohols. This process offers a rapid approach to
optimized reaction conditions 1-phenylethanol afforded the functionalized amides and may find application in the
elimination product styrene rather than the amide 20. In- synthesis of complex frameworks and natural product
creasing the amount of nitrile did not change the reaction analogues comprising sensitive functional groups.
outcome; in addition to 5 equiv. of acetonitrile, 2 equiv. of
sulfuric acid and a longer reaction time were required to
afford the desired amide in an isolated yield of 84%. The
Experimental Section
Ritter reaction between diphenylmethanol and acetonitrile
General: The experiments were carried out in a Retsch MM400 mill
to afford amide 21 also required a longer reaction time, at a frequency of 30 Hz using a 10 mL Teflon® grinding vial and
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I. Dokli, M. Gredicˇak
(5):[15]
3-Chlorobenzonitrile
(85 mg, 0.62 mmol) afforded amide 5 as a white solid. Purified by
recrystallization (ethyl acetate/hexane), yield 111 mg, 86%. η =
FULL PAPER
a single tungsten carbide ball (d = 7 mm, m = 4 g). NMR spectra
were recorded with Bruker Avance 600 MHz and 300 MHz spec-
trometers. Infrared spectra were recorded with a Bruker Tensor 27
FTIR spectrometer. Mass spectrometry measurements were per-
formed with an HPLC system coupled with a triple quadrupole
mass spectrometer, operating in a positive electrospray ionization
(ESI) mode. High resolution mass spectrometry (HRMS) was per-
formed with a 4800 Plus MALDI TOF/TOF Analyzer. Solvents
were used as supplied by Kemika (analytical or HPLC grade) with-
out further purification. Products were purified by recrystallization
or by flash column chromatography.
General Procedure for the Synthesis of Amides 1–15: A Teflon®
grinding vial (10 mL) with a single tungsten carbide ball (d = 7 mm,
m = 4 g) was charged with a nitrile (1 equiv.), tert-butyl alcohol
(1.1 equiv.) and sulfuric acid (0.5 equiv.), with or without nitro-
methane (1 equiv.), and mixed in a ball mill for 30 min at 30 Hz.
The reaction mixture was dissolved in ethyl acetate and washed
with satd. NaHCO3, water and brine. The amide was recrystallized
from ethyl acetate/hexane or purified by flash column chromatog-
raphy.
N-(tert-Butyl)-3-chlorobenzamide
1
0.36 μL/mg. H NMR (600 MHz, CDCl3): δ = 7.69 (t, J = 1.6 Hz,
1 H), 7.56 (t, J = 8.7 Hz, 1 H), 7.44–7.39 (m, 1 H), 7.32 (t, J =
7.8 Hz, 1 H), 5.99 (br. s, 1 H), 1.46 (s, 9 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 165.5, 137.8, 134.6, 131.0, 129.7, 127.1,
124.9, 51.9, 28.8 ppm. MS (ESI): m/z = 212 [M + H]+.
3-Bromo-N-(tert-butyl)-5-fluorobenzamide (6): 3-Bromo-5-fluoro-
benzonitrile (100 mg, 0.50 mmol) afforded amide 6 as a white solid.
Purified by flash column chromatography (petroleum ether/ethyl
acetate, 5:1), yield 100 mg, 73%. η = 0.28 μL/mg, m.p. 102.0–
102.5 °C. 1H NMR (300 MHz, CDCl3): δ = 7.59 (s, 1 H), 7.40–7.29
(m, 2 H), 5.99 (br. s, 1 H), 1.46 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 164.2 (d, J = 2.4 Hz), 162.5 (d, J = 252.5 Hz), 139.5
(d, J = 7.0 Hz), 125.7 (d, J = 3.2 Hz), 122.7 (d, J = 9.2 Hz), 121.5
(d, J = 24.5 Hz), 113.3 (d, J = 22.7 Hz), 52.1, 28.7 ppm. IR (KBr):
ν = 3348, 3085, 2970, 1645, 1579, 1537, 1313, 1220, 1090 cm–1.
˜
HRMS (ESI): calcd. for C11H13BrFNO [M + H]+ 274.0237; found
274.0247.
Procedure for the Scale-up Synthesis of 1: A Teflon® grinding vial
(10 mL) with a single tungsten carbide ball (d = 7 mm, m = 4 g)
was charged with benzonitrile (1 mL, 9.71 mmol), tert-butyl
alcohol (1 mL, 10.68 mmol) and sulfuric acid (249 μL, 4.68 mmol)
and mixed in a ball mill for 30 min at 30 Hz. The reaction mixture
was dissolved in ethyl acetate and washed with satd. NaHCO3,
water and brine. The amide 1 was recrystallized from ethyl acetate/
hexane to give a white solid (1.44 g, 84%).
N-(tert-Butyl)-2-chloro-5-nitrobenzamide (7): 2-Chloro-5-nitroben-
zonitrile (57 mg, 0.31 mmol) afforded amide 7 as a white solid.
Purified by recrystallization (ethyl acetate/hexane), yield 67 mg,
82%. η = 0.30 μL/mg, m.p. 113.0–113.9 °C. 1H NMR (600 MHz,
CDCl3): δ = 8.37 (d, J = 2.7 Hz, 1 H), 8.20–8.11 (m, 1 H), 7.55 (d,
J = 8.8 Hz, 1 H), 5.98 (br. s, 1 H), 1.48 (s, 9 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 163.6, 146.5, 137.8, 137.4, 131.2, 125.1,
124.6, 52.8, 28.7 ppm. IR (KBr): ν = 3308, 3109, 2964, 1672, 1648,
˜
N-(tert-Butyl)benzamide (1):[25] Benzonitrile (64 μL, 0.62 mmol) af-
forded amide 1 as a white solid. Purified by recrystallization (ethyl
1527, 1347, 1307, 1050 cm–1. HRMS (ESI): calcd. for
C11H13ClN2O3 [M + H]+ 257.0688; found 257.0684.
1
acetate/hexane), yield 103 mg, 94%. H NMR (300 MHz, CDCl3):
Methyl 4-(tert-Butylcarbamoyl)benzoate (8):[8] Methyl 4-cyano-
benzoate (81 mg, 0.50 mmol) afforded amide 8 as a white solid.
Purified by flash column chromatography (petroleum ether/ethyl
acetate, 5:1), yield 72 mg, 61%. η = 0.33 μL/mg. 1H NMR
(300 MHz, CDCl3): δ = 8.08–7.99 (m, 2 H), 7.81–7.71 (m, 2 H),
6.12 (br. s, 1 H), 3.92 (s, 3 H), 1.48 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.3, 166.1, 139.9, 132.2, 129.7, 126.8, 52.3,
51.9, 28.8 ppm. MS (ESI): m/z = 236 [M + H]+, 258 [M + Na]+.
δ = 7.80–7.67 (m, 2 H), 7.53–7.34 (m, 3 H), 6.01 (br. s, 1 H), 1.49
(s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.9, 135.9, 131.1,
128.5, 126.7, 51.6, 28.9 ppm. MS (ESI): m/z = 178 [M + H]+.
N-(tert-Butyl)-2-iodobenzamide (2):[26] 2-Iodobenzonitrile (70 mg,
0.31 mmol) afforded amide 2 as a white solid. Purified by flash
column chromatography (petroleum ether/ethyl acetate, 5:1), yield
74 mg, 79%. η = 0.26 μL/mg. 1H NMR (600 MHz, CDCl3): δ =
7.84–7.80 (m, 1 H), 7.40–7.31 (m, 2 H), 7.06 (td, J = 7.9, 2.0 Hz,
1 H), 5.55 (br. s, 1 H), 1.48 (s, 9 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 168.7, 143.3, 139.7, 130.7, 128.1, 92.4, 52.2, 28.7 ppm.
MS (ESI): m/z = 304 [M + H]+.
N-(tert-Butyl)-2-(trifluoromethyl)benzamide (9): 2-(Trifluorometh-
yl)benzonitrile (66 μL, 0.50 mmol) afforded amide 9 as a white so-
lid. Purified by flash column chromatography (petroleum ether/
ethyl acetate, 5:1), yield 57 mg, 47%, m.p. 107.9–108.4 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.66 (d, J = 7.7 Hz, 2 H), 7.61–7.44
(m, 3 H), 5.55 (br. s, 1 H), 1.45 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.0, 137.2, 132.0, 129.4, 128.6, 126.9 (d, J =
31.7 Hz), 126.2 (q, J = 5.1 Hz), 123.8 (d, J = 273.8 Hz), 52.2,
N-(tert-Butyl)-2-fluorobenzamide
(3):[26]
2-Fluorobenzonitrile
(68 μL, 0.62 mmol) afforded amide 3 as a yellow oil. Purified by
flash column chromatography (petroleum ether/ethyl acetate, 5:1),
yield 106 mg, 88%. 1H NMR (600 MHz, CDCl3): δ = 8.05 (td, J
= 8.0, 1.8 Hz, 1 H), 7.47–7.39 (m, 1 H), 7.29–7.20 (m, 1 H), 7.12–
7.05 (m, 1 H), 6.58 (br. s, 1 H), 1.47 (s, 9 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 162.3, 160.4 (d, J = 245.9 Hz), 132.8 (d, J
= 9.2 Hz), 131.8 (d, J = 2.1 Hz), 124.7 (d, J = 3.3 Hz), 122.4 (d, J
= 11.8 Hz), 115.9 (d, J = 25.3 Hz), 51.8, 28.9 ppm. MS (ESI): m/z
= 196 [M + H]+.
28.5 ppm. IR (KBr): ν = 3300, 2973, 1646, 1543, 1316, 1125 cm–1.
˜
HRMS (ESI): calcd. for C12H14F3NO [M + H]+ requires 246.1100;
found 246.1110.
N-(tert-Butyl)-2-methylbenzamide (10): o-Toluonitrile (73 μL,
0.62 mmol) afforded amide 10 as a colourless oil. Purified by flash
column chromatography (petroleum ether/ethyl acetate, 5:1), yield
52 mg, 44%. 1H NMR (300 MHz, CDCl3): δ = 7.35–7.23 (m, 2 H),
7.22–7.11 (m, 2 H), 5.59 (br. s, 1 H), 2.42 (s, 3 H), 1.46 (s, 9 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 169.7, 137.9, 135.4, 130.8, 129.4,
3-Bromo-N-(tert-butyl)benzamide (4): 3-Bromobenzonitrile (90 mg,
0.49 mmol) afforded amide 4 as a white solid. Purified by
recrystallization (ethyl acetate/hexane), yield 95 mg, 76%. η =
1
0.30 μL/mg, m.p. 106.3–107.1 °C. H NMR (600 MHz, CDCl3): δ
126.4, 125.6, 51.7, 28.9, 19.5 ppm. IR (KBr): ν = 3307, 2923, 1647,
˜
= 7.85 (t, J = 1.7 Hz, 1 H), 7.66–7.61 (m, 1 H), 7.61–7.57 (m, 1
H), 7.31–7.25 (m, 1 H), 5.91 (br. s, 1 H), 1.47 (s, 9 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 165.4, 138.0, 134.0, 130.0, 129.9,
1541, 1316 cm–1. HRMS (ESI): calcd. for C12H17NO [M + H]+
192.1383; found 192.1390.
125.4, 122.6, 51.9, 28.8 ppm. IR (KBr): ν = 3273, 3069, 2984, 1637, N-(tert-Butyl)-4-methylbenzamide (11):[8] p-Toluonitrile (58 mg,
˜
1542, 1317, 1069 cm–1. HRMS (ESI): calcd. for C11H14BrNO [M 0.50 mmol) afforded amide 11 as a white solid. Purified by flash
+ H]+ 256.0331; found 256.0337.
column chromatography (petroleum ether/ethyl acetate, 5:1), yield
4
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Mechanochemical Ritter Reaction
74 mg, 78%. η = 0.40 μL/mg. 1H NMR (300 MHz, CDCl3): δ = NMR (75 MHz, CDCl3): δ = 166.6, 136.1, 131.0, 128.4, 126.7, 52.3,
7.61 (d, J = 8.1 Hz, 2 H), 7.20 (d, J = 7.9 Hz, 2 H), 5.92 (br. s, 1 41.7, 36.4, 29.5 ppm. MS (ESI): m/z = 256 [M + H]+.
H), 2.38 (s, 3 H), 1.46 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3):
N-(1-Benzylcyclohexyl)benzamide
(104 mg, 0.50 mmol) afforded amide 18 as a white solid. Purified
by flash column chromatography (petroleum ether/ethyl acetate,
5:1), yield 114 mg, 81%, m.p. 99.4–100.3 °C. H NMR (600 MHz,
(18):
1-Benzylcyclohexanol
δ = 166.8, 141.4, 133.1, 129.1, 126.7, 51.5, 28.9, 21.4 ppm. MS
(ESI): m/z = 192 [M + H]+.
1
N-(tert-Butyl)-4-methoxybenzamide (12):[8] 4-Methoxybenzonitrile
(67 mg, 0.50 mmol) afforded amide 12 as a white solid. Purified by
flash column chromatography (petroleum ether/ethyl acetate, 5:1),
CDCl3): δ = 7.65 (d, J = 7.4 Hz, 2 H), 7.45 (t, J = 7.4 Hz, 1 H),
7.38 (t, J = 7.6 Hz, 2 H, 9-H, 10-H), 7.22–7.11 (m, 5 H), 5.44 (br.
s, 1 H), 3.19 (s, 2 H), 2.22 (d, J = 12.3 Hz, 2 H), 1.63 (d, J =
10.2 Hz, 3 H), 1.52–1.39 (m, 4 H), 1.34–1.25 (m, 1 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 167.5, 137.6, 136.4, 131.1, 130.7,
128.6, 127.8, 126.7, 126.2, 56.7, 43.7, 35.0, 25.7, 21.9 ppm. IR
1
yield 65 mg, 63%. η = 0.37 μL/mg. H NMR (300 MHz, CDCl3):
δ = 7.74–7.66 (m, 2 H), 6.96–6.86 (m, 2 H), 5.88 (br. s, 1 H), 3.85
(s, 3 H), 1.48 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.4,
161.9, 128.4, 128.2, 113.6, 55.4, 51.5, 29.0 ppm. MS (ESI): m/z =
208 [M + H]+.
N-(tert-Butyl)acetamide (13):[6b] Acetonitrile (32 μL, 0.62 mmol) af-
forded amide 13 as a white solid. Purified by recrystallization (ethyl
acetate/hexane), yield 67 mg, 93%. 1H NMR (600 MHz, CDCl3):
δ = 5.22 (br. s, 1 H), 1.91 (s, 3 H), 1.36 (s, 9 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 169.4, 51.2, 28.8, 24.5 ppm. MS (ESI): m/z
= 116 [M + H]+.
(KBr): ν = 3371, 3055, 2923, 1635, 1533, 1449 cm–1. HRMS (ESI):
˜
calcd. for C20H23NO [M + H]+ 294.1852; found 294.1866.
N-(2-methyl-1-phenylpropan-2-yl)acetamide (19): 2-Methyl-1-phen-
ylpropan-2-ol (colourless oil; 75 mg, 0.50 mmol) afforded amide 19
as a white solid. Purified by flash column chromatography (petro-
leum ether/ethyl acetate, 3:1), yield 70 mg, 74%, m.p. 92.9–93.7 °C.
1H NMR (300 MHz, CDCl3): δ = 7.32–7.17 (m, 3 H), 7.16–7.09
(m, 2 H), 5.18 (br. s, 1 H), 3.04 (s, 2 H), 1.88 (s, 3 H), 1.31 (s, 6
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.8, 138.1, 130.5,
N-(tert-Butyl)-3-chloropropanamide (14): 3-Chloropropionitrile
(48 μL, 0.62 mmol) afforded amide 14 as a white solid. Purified by
recrystallization (ethyl acetate/hexane), yield 92 mg, 91%, m.p.
127.9, 126.3, 54.0, 44.6, 27.4, 24.5 ppm. IR (KBr): ν = 3283, 3088,
˜
2958, 1644, 1564, 1362 cm–1. HRMS (ESI): calcd. for C12H17NO
[M + H]+ 192.1383; found 192.1384.
1
90.6–91.4 °C. H NMR (600 MHz, CDCl3): δ = 5.67 (br. s, 1 H),
3.78 (t, J = 6.5 Hz, 2 H), 2.55 (t, J = 6.5 Hz, 2 H), 1.36 (s, 9
N-(1-Phenylethyl)acetamide (20):[6c] 1-Phenylethanol (colourless oil;
61 mg, 0.50 mmol) afforded amide 20 as a white solid. Purified by
flash column chromatography (petroleum ether/ethyl acetate, 3:1),
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.8, 51.6, 40.4, 40.3,
28.7 ppm. IR (KBr): ν = 3284, 3091, 2970, 1647, 1566, 1362 cm–1.
˜
HRMS (ESI): calcd. for C7H14ClNO [M + H]+ 164.0837; found
164.0829.
1
yield 68 mg, 84%. H NMR (300 MHz, CDCl3): δ = 7.43–7.20 (m,
5 H), 5.81 (br. s, 1 H), 5.13 (quint, J = 7.0 Hz, 1 H), 1.98 (s, 3 H),
1.49 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
169.1, 143.2, 128.7, 127.4, 126.2, 48.8, 23.5, 21.7 ppm. MS (ESI):
m/z = 164 [M + H]+.
N-(tert-Butyl)acrylamide (15):[6b] Acrylonitrile (41 μL, 0.62 mmol)
afforded amide 15 as a white solid. Purified by recrystallization
(ethyl acetate/hexane), yield 70 mg, 90%. 1H NMR (600 MHz,
CDCl3): δ = 6.22 (dd, J = 16.9, 1.4 Hz, 1 H), 6.04 (dd, J = 16.9,
10.2 Hz, 1 H), 5.56 (dt, J = 8.8, 4.4 Hz, 1 H), 5.52 (s, 1 H), 1.40 (s,
9 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 164.8, 132.1, 125.5,
51.3, 28.8 ppm. MS (ESI): m/z = 128 [M + H]+.
General Procedure for the Synthesis of Amides 16–21: A Teflon®
grinding vial (10 mL) with a single tungsten carbide ball (d = 7 mm,
m = 4 g) was charged with an alcohol (1 equiv.), acetonitrile or
benzonitrile (1.1 equiv.) and sulfuric acid (0.5 equiv.), with or with-
out nitromethane (1 equiv.), and mixed in a ball mill for 30 min at
30 Hz. The reaction mixture was dissolved in ethyl acetate and
washed with satd. NaHCO3, water and brine. The amides were
recrystallized from ethyl acetate/hexane or purified by flash column
chromatography.
N-Benzhydrylacetamide (21):[27] Diphenylmethanol (colourless oil;
92 mg, 0.50 mmol) afforded amide 21 as a white solid. Purified by
flash column chromatography (petroleum ether/ethyl acetate, 3:1),
1
yield 83 mg, 74%. η = 0.35 μL/mg. H NMR (300 MHz, CDCl3):
δ = 7.34–7.18 (m, 10 H), 6.36 (br. s, 1 H), 6.22 (d, J = 8.1 Hz, 1
H), 1.99 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.3,
141.6, 128.6, 127.4, 57.0, 23.2 ppm. MS (ESI): m/z = 226 [M +
H]+, 248 [M + Na]+.
Supporting Information (see footnote on the first page of this arti-
cle): Substrate syntheses, detailed procedures and NMR spectra.
Acknowledgments
N-(3-Methyl-1-phenylpentan-3-yl)acetamide (16): 3-Methyl-1-phen-
ylpentan-3-ol (colourless oil; 80 mg, 0.45 mmol) afforded amide 16
as a colourless oil. Purified by flash column chromatography (pe-
troleum ether/ethyl acetate, 3:1), yield 75 mg, 77%. 1H NMR
(600 MHz, CDCl3): δ = 7.27–7.22 (m, 2 H), 7.19–7.12 (m, 3 H),
5.54 (br. s, 1 H), 2.55 (t, J = 8.5 Hz, 2 H), 2.16–2.07 (m, 1 H), 1.90
(s, 3 H), 1.95–1.82 (m, 2 H), 1.69–1.60 (m, 1 H), 1.28 (s, 3 H), 0.85
(t, J = 7.5 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 169.8,
142.4, 128.4, 128.4, 125.7, 56.7, 39.7, 31.0, 30.4, 24.2, 23.8,
We acknowledge the Croatian Ministry of Science, Education and
Sports and the Rueer Bosˇkovic´ Institute for financial support. We
are grateful to Dr. Josip Bronic´ for providing the ball mill, and to
Dr. Ivan Halasz and Dr. Krunoslav Uzarevic´ for useful discussions.
ˇ
[1] a) J. J. Ritter, P. P. Minieri, J. Am. Chem. Soc. 1948, 70, 4045–
4048; b) J. J. Ritter, J. Kalish, J. Am. Chem. Soc. 1948, 70,
4048–4050.
[2] a) J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic
Chemistry, 2001; b) R. Vardanyan, V. Hruby, Synthesis of Es-
sential Drugs, Elsevier, Amsterdam, 2006.
8.0 ppm. IR (KBr): ν = 3314, 3061, 2970, 1657, 1554, 1452, 1372,
˜
740, 696 cm–1. HRMS (ESI): calcd. for C14H21NO [M + H]+
220.1696; found 220.1707.
[3] a) L. Kurti, B. Czako, Strategic Applications of Named Reac-
tions in Organic Synthesis Elsevier Academic Press, Burlington,
2005; b) A. Chandra, J. N. Johnston, Angew. Chem. Int. Ed.
2011, 50, 7641–7644; c) D. Stoermer, C. H. Heathcock, J. Org.
Chem. 1993, 58, 564–568; d) O. L. Epstein, T. Rovis, J. Am.
Chem. Soc. 2006, 128, 16480–16481; e) B. Sarmah, G. Baishya,
N-[(3s,5s,7s)-Adamantan-1-yl]benzamide (17):[7a] Adamantan-1-ol
(35 mg, 0.23 mmol) afforded amide 17 as a white solid. Purified by
recrystallization (ethyl acetate/hexane), yield 45 mg, 85%. 1H
NMR (300 MHz, CDCl3): δ = 7.76–7.65 (m, 2 H), 7.50–7.34 (m, 3
H), 5.83 (br. s, 1 H), 2.13 (br. s, 9 H), 1.72 (br. s, 6 H) ppm. 13C
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O50051
/KAP1
Date: 11-03-15 18:22:34
Pages: 7
I. Dokli, M. Gredicˇak
FULL PAPER
R. K. Baruah, RSC Adv. 2014, 4, 22387–22397; f) J. S. Yadav, [14] H. Jiang, B. Liu, Y. Li, A. Wang, H. Huang, Org. Lett. 2011,
13, 1028–1031.
Y. J. Reddy, P. A. N. Reddy, B. V. S. Reddy, Org. Lett. 2013, 15,
546–549; g) B. V. S. Reddy, K. Ramesh, A. V. Ganesh, [15] Z. Xia, Q. Zhu, Org. Lett. 2013, 15, 4110–4113.
G. G. K. S. N. Kumar, J. S. Yadav, R. Grée, Tetrahedron Lett. [16] S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T.
2011, 52, 495–498.
Frisˇcˇic´, F. Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A.
Krebs, J. Mack, L. Maini, A. G. Orpen, I. P. Parkin, W. C.
Shearouse, J. W. Steed, D. C. Waddell, Chem. Soc. Rev. 2012,
41, 413–447.
[4] a) A. Guérinot, S. Reymond, J. Cossy, Eur. J. Org. Chem. 2012,
19–28; b) D. Jiang, T. He, L. Ma, Z. Wang, RSC Adv. 2014, 4,
64936–64946; c) F. Zhou, M. Ding, J. Zhou, Org. Biomol.
Chem. 2012, 10, 3178–3181.
[17] a) E. Boldyreva, Chem. Soc. Rev. 2013, 42, 7719–7738; b) I.
Huskic´, I. Halasz, T. Frisˇcˇic´, H. Vancˇik, Green Chem. 2012, 14,
1597–1600; c) G.-W. Wang, Chem. Soc. Rev. 2013, 42, 7668–
[5] a) B. Das, K. Laxminarayana, P. Thirupathi, B. Ramarao, Syn-
lett 2007, 3103–3106; b) M. Shi, G.-Q. Tian, Tetrahedron Lett.
2006, 47, 8059–8062; c) P. Rubenbauer, T. Bach, Chem. Com-
mun. 2009, 2130–2132; d) R. Sanz, A. Martínez, V. Guilarte,
J. M. Álvarez-Gutiérrez, F. Rodríguez, Eur. J. Org. Chem. 2007,
4642–4645; e) M. Barbero, S. Bazzi, S. Cadamuro, S. Dughera,
Eur. J. Org. Chem. 2009, 430–436; f) M.-S. Shakeri, H. Tajik,
K. Niknam, J. Chem. Sci. 2012, 124, 1025–1032.
7700; d) K. Uzarevic´, I. Halasz, I. ailovic´, N. Bregovic´, M.
ˇ
ˇ
Rubcˇic´, D. Matkovic´-Calogovic´, V. Tomisˇic´, Angew. Chem. Int.
Ed. 2013, 52, 5504–5508; e) A. Stolle, T. Szuppa, S. E. S. Leon-
hardt, B. Ondruschka, Chem. Soc. Rev. 2011, 40, 2317–2329; f)
ˇ
D. Gracin, V. Strukil, T. Frisˇcˇic´, I. Halasz, K. Uzarevic´, Angew.
ˇ
Chem. Int. Ed. 2014, 53, 6193–6197.
[6] a) H. Firouzabadi, A. Sardarian, H. Badparva, Synth. Com-
mun. 1994, 24, 601–607; b) S. Khaksar, E. Fattahi, E. Fattahi,
Tetrahedron Lett. 2011, 52, 5943–5946; c) P. Theerthagiri, A.
Lalitha, P. N. Arunachalam, Tetrahedron Lett. 2010, 51, 2813–
2819.
[18] a) K. S. McKissic, J. T. Caruso, R. G. Blair, J. Mack, Green
Chem. 2014, 16, 1628–1632; b) L. Takacs, J. S. McHenry, J.
Mater. Sci. 2006, 41, 5246–5249.
[19] In all the experiments, tert-butyl alcohol was a liquid at ambi-
ent temperature.
[7] a) E. Callens, A. J. Burton, A. G. M. Barrett, Tetrahedron Lett. [20] G. C. Gullickson, D. E. Lewis, Synthesis 2003, 681–684.
2006, 47, 8699–8701; b) H. Basavaprabhu, V. V. Sureshbabu,
Org. Biomol. Chem. 2012, 10, 2528–2533; c) B. Anxionnat, A.
Guérinot, S. Reymond, J. Cossy, Tetrahedron Lett. 2009, 50,
[21] The experiment with two tungsten carbide balls was not con-
ducted. When we performed such experiments previously, the
balls were destroyed during milling.
3470–3473; d) G.-R. Qu, Y.-W. Song, H.-Y. Niu, H.-M. Guo, [22] a) D. Braga, L. Maini, F. Grepioni, Chem. Soc. Rev. 2013, 42,
J. S. Fossey, RSC Adv. 2012, 2, 6161–6163; e) S. Yaragorla, G.
Singh, P. Lal Saini, M. K. Reddy, Tetrahedron Lett. 2014, 55,
4657–4660.
7638–7648; b) T. Frisˇcˇic´, W. Jones, Cryst. Growth Des. 2009, 9,
1621–1637.
[23] The η value is a parameter describing the amount of solvent
additive with respect to the reagents. It is calculated from
V(solvent, μL)/m(sample, mg), for details, see: T. Frisˇcˇic´, S. L.
Childs, S. A. A. Rizvi, W. Jones, CrystEngComm 2009, 11, 418–
426.
[24] The olefins are formed by the elimination of either a benzyl
or methyl hydrogen, and can also exist as a mixture of both
elimination products. The olefin(s) were detected by TLC and
were not isolated.
[8] J. C. Baum, J. E. Milne, J. A. Murry, O. R. Thiel, J. Org. Chem.
2009, 74, 2207–2209.
[9] a) M. B. Gawande, A. K. Rathi, I. D. Nogueira, R. S. Varma,
P. S. Branco, Green Chem. 2013, 15, 1895–1899; b) L. Ma’mani,
A. Heydari, M. Sheykhan, Appl. Catal. A 2010, 384, 122–127.
[10] R. G. Kalkhambkar, S. N. Waters, K. K. Laali, Tetrahedron
Lett. 2011, 52, 867–871.
[11] G. Mohammadi Ziarani, A. Badiei, Z. Dashtianeh, P. Ghol-
amzadeh, N. Mohtasham, Res. Chem. Intermed. 2013, 39, [25] The data correspond to the commercially available compound.
3157–3163.
[26] E. Bellamy, O. Bayh, C. Hoarau, F. Trécourt, G. Quéguiner, F.
Marsais, Chem. Commun. 2010, 46, 7043–7045.
[27] S. M. Walter, F. Kniep, E. Herdtweck, S. M. Huber, Angew.
Chem. Int. Ed. 2011, 50, 7187–7191.
[12] N. Ibrahim, A. S. K. Hashmi, F. Rominger, Adv. Synth. Catal.
2011, 353, 461–468.
[13] E. Bellamy, O. Bayh, C. Hoarau, F. Trécourt, G. Quéguiner, F.
Marsais, Chem. Commun. 2010, 46, 7043–7045.
Received: January 13, 2015
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50051
/KAP1
Date: 11-03-15 18:22:34
Pages: 7
Mechanochemical Ritter Reaction
Ritter Reaction
ˇ
I. Dokli, M. Gredicak* ..................... 1–7
Mechanochemical Ritter Reaction: A Ra-
pid Approach to Functionalized Amides at
Room Temperature
Keywords: Mechanochemistry / Organo-
catalysis / Ritter reaction / Amides
Gentle Ritter: A fast and efficient mech-
anochemical Ritter reaction under mild
conditions is described. The reaction
proceeds rapidly at room temperature in a
solvent-free or low-solvent environment by
using sulfuric acid as catalyst.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7