Environmentally Benign Ritter Reaction Using Bismuth Salts as a Catalyst

Article abstract of DOI:10.1002/ejoc.201801882

We developed an environmentally benign Ritter reaction of alcohols with nitriles using a commercially available bismuth salt as a less harmful catalyst. The detailed reaction profiles revealed that consumption of the ether by-product as the reaction proceeded was the key for optimizing this reaction, and the yield of the target amide was improved by adding a small amount of water. This finding clearly reveals the significance of using a bismuth salt as the catalyst, as it is not deactivated in the presence of water. This catalyst system has a broad substrate scope, and even with 1 mol-% of the catalyst, the reaction progresses smoothly. It is also possible to react stoichiometric amounts of nitriles and alcohols, thus reducing the amount of organic solvent required for the reaction. Furthermore, as the inexpensive bismuth catalyst can be easily removed using aqueous hydrochloric acid, a purification process that only required washing and drying without any organic solvents was successfully established.

Full text of DOI:10.1002/ejoc.201801882

A Journal of
Accepted Article
Title: Environmentally Benign Ritter Reaction Using Bismuth Salts as a
Catalyst
Authors: Masaharu Ueno, Ryo Kusaka, Satoshi D. Ohmura, and
Norikazu Miyoshi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801882
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10.1002/ejoc.201801882
European Journal of Organic Chemistry
COMMUNICATION
Environmentally Benign Ritter Reaction Using Bismuth Salts as a
Catalyst
Masaharu Ueno,* Ryo Kusaka, Satoshi D. Ohmura and Norikazu Miyoshi
Abstract: We developed an environmentally benign Ritter reaction
of alcohols with nitriles using a commercially available bismuth salt
as a less harmful catalyst. The detailed reaction profiles revealed
that consumption of the ether by-product as the reaction proceeded
was the key for optimizing this reaction, and the yield of the target
amide was improved by adding a small amount of water. This finding
clearly reveals the significance of using a bismuth salt as the catalyst,
as it is not deactivated in the presence of water. This catalyst system
has a broad substrate scope, and even with 1 mol% of the catalyst,
the reaction progresses smoothly. It is also possible to react
stoichiometric amounts of nitriles and alcohols, thus reducing the
amount of organic solvent required for the reaction. Furthermore, as
the inexpensive bismuth catalyst can be easily removed using
aqueous hydrochloric acid, a purification process that only required
washing and drying without any organic solvents was successfully
established.
processes.
Lewis acid (LA) or
Brønsted acid (H+)
R2 R3
R2 R3
R1
O
C R4
nitrile (2)
+
N
R1 OH
alcohol (1)
N
R4
H
N-acyl protected
amine (amide) (3)
Scheme 1. The Ritter reaction.
Results and Discussion
When using an alcohol as a starting material for the Ritter
reaction, it is necessary to solve two main problems (Scheme 2).
The first is the possibility of deactivating the Lewis acid via the
formation of an alcoholate. At the same time, as a by-product of
alcoholate formation, equimolar amounts of water are generated
that can deactivate the Lewis acid by acting as a Lewis base.[9]
The second is that dehydration of the substrate can proceed,
especially in highly concentrated solutions, to give ethers via a
self-coupling reaction. We hypothesised that these problems
would be solved by using bismuth salts as environmentally
benign and less harmful catalysts for the Ritter reaction, as
these salts are known to behave as water-compatible Lewis
acids.[10,11] Focusing on these points, our laboratory has already
reported the reductive etherification of carbonyl compounds with
alcohols,[12] asymmetric Strecker reactions,[13] allylation
reactions,[13b] aldol reactions,[14] and Michael reactions[14] using
bismuth salts as a catalyst. Barrett et al. screened several metal
triflates for the catalytic Ritter reaction in water.[8] Although
Bi(OTf)3 was found to exhibit the best performance, 20 mol% of
the catalyst was still required. In this paper, we report the Ritter
reaction of alcohols with nitriles using bismuth salts as a catalyst.
With this reaction system, we improved the catalyst turnover
number to 84. Moreover, we succeeded in obtaining pure N-
acyl-protected amines in high yields without using any organic
solvents, not only in the reaction system but also during the
work-up procedure.
Introduction
The Ritter reaction is one of the useful synthetic methods for
preparing N-acyl-protected amines, which are ubiquitous
functional groups in various natural and synthetic materials, from
alcohols or alkenes and nitriles (Scheme 1).[1-3] As the reaction
mechanism is proposed to involve a carbocation intermediate,
this reaction is useful for synthesising bulky amines. However, a
general drawback of the classical Ritter reaction is that at least
stoichiometric amounts of a strong Brønsted acid (i.e. conc.
H2SO4) or Lewis acid under harsh conditions are required.[4] To
overcome this problem, several catalytic systems have been
developed recently.[5-8] Akhlaghinia et al. reported an Al(HSO4)3-
catalysed Ritter reaction;[6] however, this catalyst is not
commercially available (it must be prepared from aluminium
chloride and sulfuric acid) and the reaction generally requires 50
mol% of the catalyst. Sadeghi et al. reported an inexpensive and
less harmful salt, KAl(SO4)2·12H2O (alum), as a catalyst.[7]
Although this reaction was conducted under neat conditions
without a solvent, the amount of catalyst required was still high
(21 mol%). From a ‘green chemistry’ perspective, a more
environmentally friendly and inexpensive catalyst is required for
this reaction. Additionally, as the catalyst must be removed from
the reaction system, it is desirable that no organic solvents are
used during any operation, including the work-up and purification
Dr. M. Ueno, Mr. R. Kusaka, Dr. S. D. Ohmura, Prof. Dr. N. Miyoshi
Department of Natural Sciences, Graduate School of Advanced
Technology and Sciences, Tokushima University
Minami-Josanjima 2-1, Tokushima 770-8506 (Japan)
E-mail: ueno.masaharu@tokushima-u.ac.jp
URL: https://researchmap.jp/read0206871/
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.201801882.
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European Journal of Organic Chemistry
COMMUNICATION
R2 R3
At higher temperatures, we found that not only the yield of the
amide increased, but also, the yield of the ether product
decreased (entries 3–5). Furthermore, we suspected that the
ether compound was consumed via transformation into the
amide when the reaction time was prolonged at temperatures
above 90 °C (entry 5).
HO LA
R2 R3
O
R2 R3
R1
R1 OH
1
R1
N
H
R4
N
R4
(regeneration)
3
LA
Lewis acid
(LA) or H+
N C R4
nitrile (2)
desired pathway
R2 R3
R2 R3
R1
carbocation
intermediate
undesired pathway
(ether formation)
R1 OH
LA
R2 R3
Table 2. Effect of temperature and reaction time on a model Ritter reaction
R1 OH
HO LA
1
O
pathway for
catalyst
deactivation
R2 R3
OH
HN
Ph
R2 R3R2 R3
R1 OH
BiBr3 (10 mol%)
+
+
+
H
R2 R3
R1
O
4
R1
Ph
Ph
O
Ph
CH3CN (2a)
Temp, Time
1a
(1 mmol)
3a
4
LA +
H2O
R1
O
Yield / %[b]
Scheme 2. Proposed mechanism for the Ritter reaction.
Entry
Temp./˚C [a]
Time / h
3a
21
26
67
72
75
4
First, we tested the Ritter reaction of 1-phenyl-1-propanol 1a
with acetonitrile as a solvent in the presence of 10 mol%
bismuth salts at 50 °C (Table 1). Among the nine bismuth salts
tested, we found that BiBr3 exhibited catalytic activity for the
model reaction, providing desired product 3a in 21% yield (entry
8). However, as expected, dehydrated ether compound 4 was
also formed (22% yield).
1
2
3
4
5
50
50
12
24
24
24
48
22
23
16
14
11
90
120
120
[a] Bath temperature. [b] Yield was determined by 1H-NMR analysis using
Table 1. Screening of bismuth salts as catalysts for a model Ritter reaction
4,4’-di-tert-butyl-1,1’-biphenyl as a standard.
O
Bismuth salt
(10 mol%)
OH
HN
Ph
+
Ph
Ph
O
4
Ph
To clarify the temperature-dependence of the consumption of
the ether and its concomitant conversion to the amide product,
reaction profiles were obtained at 50 and 90 °C (Figure 1). At
50 °C, both the amide and ether were obtained as the starting
material was consumed; however, after 6 h, the formation of the
amide by the Ritter reaction continued to proceed gradually with
almost no change in the ether compound yield. In contrast, at
90 °C, although the rate of amide formation was higher, the
ether compound was preferentially afforded until 6 h. Further,
the amide formation rate corresponded to the consumption rate
of the ether. In general, the ether cleavage reaction is very
difficult to proceed as compared with the ether formation
reaction because the by-product of the ether formation reaction
is water, which deactivates the Lewis acid. Therefore, the
formation of ether causes the dead-end path of the catalyst, and
the method in which ether is not produced is important for
development of conventional Ritter reaction. On the other hand,
bismuth salts can afford the amide product even with
simultaneous ether formation. When the reaction profile was
confirmed under the condition of adding 50 µL/mmol of water,
there was almost no difference in the production rates of the
amide product 3a. However, it was found to be effectively
suppress the formation of the ether compound in the initial stage
(Figure 1c). We also performed the Ritter reaction of the ether
product both with and without water at 90 ˚C (Scheme 3). The
ether product 4 was converted to the amide product 3a and the
starting alcohol 1a at almost the same conversion rate with and
CH3CN (2a)
50 oC, 12 h
1a
(1 mmol)
3a
Yield / %[a]
Entry
Bismuth salt
3a
16
18
NR
NR
NR
NR
19
21
4
4
7
Bi(NO3)3•5H2O
Bi2(SO3)3
Bi(OH)3
Bi2O3
1
2
3
4
5
6
7
8
9
8
NR
NR
NR
NR
19
22
4
BiOCl
BiF3
BiCl3
BiBr3
BiI3
[a] Yield was determined by 1H-NMR analysis using 4,4’-di-tert-butyl-1,1’-
biphenyl as a standard. NR: no reaction.
As the ether cleavage reaction might proceed under high
temperature conditions in the presence of a Lewis acid, we
continued to search for optimal conditions (Table 2). No
improvement was achieved when the reaction time was simply
prolonged (entry 2); thus, we elevated the reaction temperature.
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10.1002/ejoc.201801882
European Journal of Organic Chemistry
COMMUNICATION
without water, respectively. However, the conversion rate of 1a
to 3a is faster than that of 4 to 3a. Therefore, suppression of the
formation of the ether product by adding water promotes the
completion of the Ritter reaction. We think that this is one of the
attractive features of bismuth salts as catalysts.
1
2
3
4
5
0
0.5
0.5
0.5
0.5
0.2
75
88
82
70
90
11
8
30 (16.7 eq.) [b]
50 (27.8 eq.) [b]
100 (55.6 eq.) [b]
30 (16.7 eq.) [b]
8
11
5
a)
100
b)
c)
[a] Yield was determined by 1H-NMR analysis using 4,4’-di-tert-butyl-1,1’-
biphenyl as a standard. [b] Equivalents of water relative to BiBr3 in the
parenthesis.
80
60
40
Under the optimized conditions, we screened the substrate
scope of the Ritter reaction of several secondary alcohols with
nitriles to prepare the corresponding N-acyl protected amines
(Table 4). The reaction preceded smoothly even in the presence
of 10 mol% BiBr3 as a catalyst. To improve the catalyst activity,
we reduced the amount of the catalyst for the model reaction
(entry 13, 14). Even if the catalyst amount was reduced to 1
mol%, the reaction progressed without deactivating the catalyst,
and it was possible to achieve a very high catalyst turnover
20
0
0
6
12
18
24 0
6
12
18
24
0
6
12
18
24
Time [h]
Time [h]
Time [h]
Figure 1. Reaction profiles at a) 50 °C (without water), b) 90 °C (without
water), and c) 90 °C (with 50 µL/mmol water); (triangles: starting alcohol 1a,
squares: ether product 4, diamonds: amide 3a). The yields were determined
by 1H-NMR analysis using 4,4′-di-tert-butyl-1,1′-biphenyl as a standard.
number as
material.15
a Ritter reaction using alcohol as a starting
O
Table 4. Substrate scope of the Ritter reaction under optimised conditions
BiBr3 (20 mol%)
Additive
OH
HN
Ph
+
O
Ph
O
Ph
Ph
CH3CN (2a)
90 oC, 1 h
BiBr3 (10 mol%)
H2O (30 µL/mmol)
4
(0.5 mmol)
R3
1a
3a
OH
HN
No additive; 1a:3a:4 =12:9:78
With H2O (100 µL); 1a:3a:4 =16:7:74
R1 R2
R1 R2
R3CN (2a-e), 120 oC, 48 h
1a-f
(1 mmol)
3a-l
Scheme 3. Initial ratio of the Ritter reaction of the ether product 4 with and
without water. The yields were determined by 1H-NMR analysis using 4,4′-di-
tert-butyl-1,1′-biphenyl as a standard.
Entry
Alcohol (R1, R2)
Nitrile (R3)
Yield [%]a
90 (3a)
92 (3b)
92 (3c)
72 (3d)
82 (3e)
54 (3f)
86 (3g)
95 (3h)
96 (3i)
1
2
R1= Ph, R2 =Et (1a)
Me (2a)
As bismuth salts act as a catalyst without decomposition in
water, the further effect of accelerating the decomposition of the
ether compound was investigated by adding water (Table 3). As
expected, an improvement in the yield was observed with the
addition of water (entries 1–3), but the presence of excess water
tended to inhibit the reactivity (entry 4). Finally, by reducing the
reaction concentration, we succeeded in obtaining the desired
amide in 90% yield (entry 5).
1a
Et (2b)
3
1a
iPr (2c)
4
1a
CH2CH2OCH3 (2d)
5
R1= (4-Cl)-C6H4, R2 =Et (1b)
2a
2a
6
R1= (4-CH3)-C6H4, R2 =Et (1c)
7
R1= Ph, R2 =Me (1d)
2a
8
R1= Ph, R2 =Ph (1e)
2a
Table 3. Effect of water and concentration on a model Ritter reaction
O
9
1e
1e
2b
BiBr3 (10 mol%)
OH
HN
Ph
H2O (µL)
10
Ph (2e)
93 (3j)
+
Ph
Ph
O
Ph
CH3CN (2a)
OH
120 oC, 48 h
1a
(1 mmol)
3a
4
11
2a
99 (3k)
(1f)
Yield / %[a]
Entry
H2O / µL
Concentration / M
12
1f
2b
2a
92 (3l)
97 (3a)
3a
4
13 [b]
1a
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10.1002/ejoc.201801882
European Journal of Organic Chemistry
COMMUNICATION
14 [c]
1a
2a
84 (3a)
desired product, the reaction vessel contains a small amount of
unreacted nitrile, the catalyst residue, and the ether by-product.
Thus, we considered whether these materials could be removed
by washing. It was found that the nitrile and bismuth salt could
be removed by washing with 3 M hydrochloric acid aqueous
solution, whereas the ether compound could be removed by
washing with hot water (90 °C). After washing, the residual
material was dried in an oven under reduced pressure to obtain
the target amide in the same yield as by purification via the
conventional procedure (Scheme 5, bottom route). This
procedure is important from the viewpoint of green chemistry, as
it allows the product produced on gram scale to be purified in a
small number of steps by simple washing and drying without
organic solvents or silica gel.
[a] Yield was determined by 1H-NMR analysis using 4,4’-di-tert-butyl-1,1’-
biphenyl as a standard. [b] 5 mol% BiBr3 was used for 72 h. [c] 1 mol% BiBr3
was used for 1 week.
Ritter reaction with tertiary alcohols and styrene as starting
materials did not proceed due to the unique features of BiBr3;
therefore, the desired amides were obtained only with secondary
alcohols (Scheme 4). This is considered one of the characteristic
points of BiBr3, which has not too strong Lewis acidity and large
molecular radius. Interestingly, this functional group selectivity,
i.e. only the secondary alcohol undergoes the Ritter reaction, is
not found when other catalysts, including Bi(OTf)3, are used.
BiBr3 (10 mol%)
i) quench (3M HCl)
ii) extract (EtOAc)
iii) wash (H2O then brine)
vi) dry (Na2SO4)
v) filtration
No
Reaction
CH3CN (2a), 120 oC, 48 h
Ph
OH
Ph
OH
1g
78% Recoverd
BiBr3 (10 mol%)
No
Reaction
O
vi) evaporation
vii) column chromatography
CH3CN (2a), 120 oC, 48 h
Ph
1h
HN
Ph
Ph
viii) evaporation of eluent
ix) drying (in vacuo)
Ph
PhCN 2e (1.0 eq.)
BiBr3 (10 mol%)
H2O (100 µL)
Ph Ph
Ph OH
Ph Ph
Ph OH
97% Recoverd
BiBr3 (10 mol%)
No
Reaction
88% yield
3j (2.5 g)
Usual work up
CH3CN (2a), 120 oC, 48 h
OH
1i
120 oC, 72 h
O
Ph
Ph
Organic solvent free
work up (see text)
BiBr3 (10 mol%)
1e (10 mmol)
HN
Ph
Ph
No
Reaction
PhCN (2e), 120 oC, 48 h
OH
1j
i) wash (3M HCl)
ii) wash (Hot water)
iii) drying
Ph
88% yield
3j (2.5 g)
(60 oC, in vacuo)
Scheme 4. Attempted BiBr3-catalysed Ritter reactions of tertiary alcohols and
α-methyl styrene.
Scheme 5. Gram-scale synthesis via an organic-solvent-free process
Finally, as BiBr3 showed high reactivity as the catalyst, we tried
reducing the nitrile used as the solvent to the stoichiometric Conclusions
amount (Scheme 5). From the viewpoint of mass production, it is
desirable that excess amounts of a reagent are not used as a
solvent. However, because the amide product can also behave
as a Lewis base, it can suppress the reaction, especially at high
concentration. Therefore, we conducted experiments to
demonstrate the capability of the Lewis-acidic bismuth catalyst
in the gram-scale synthesis of amides at high concentration.
When only 1 equivalent of nitrile, without any excess as a
solvent, and a small amount (10 µL/mmol) of water were used, it
was necessary to prolong the reaction time. After completion of
the reaction, the usual work-up was performed, and the desired
amide was successfully obtained in 88% yield.
In summary, we developed an environmentally benign Ritter
reaction of alcohols with nitriles using a commercially available
bismuth salt as a less harmful catalyst. The detailed reaction
profiles revealed that consumption of the ether by-product as the
reaction proceeded was the key for optimizing this reaction, and
the yield of the target amide was improved by adding a small
amount of water. This finding clearly reveals the significance of
using a bismuth salt as the catalyst, as it is not deactivated in
the presence of water. This catalyst system has a broad
substrate scope, and even with 1 mol% of the catalyst, the
reaction progresses smoothly. It is also possible to react
stoichiometric amounts of nitriles and alcohols, thus reducing the
amount of organic solvent required for the reaction. Furthermore,
as the inexpensive bismuth catalyst can be easily removed
using aqueous hydrochloric acid, a purification process that only
required washing and drying without any organic solvents was
successfully established. Currently, the substrate generality of
this reaction and improvements of the purification method to
increase its suitability for industrial processes are under
investigation.
Although this procedure successfully reduced the amount of
organic solvent used in the reaction stage, we obtained the
desired amide in 88% yield after a conventional work-up on
laboratory scale that involved many steps (namely, quenching
the reaction, extraction, drying with a desiccant, removal of the
desiccant by filtration, concentration, column purification,
concentration of the eluent, and drying in vacuo) and generated
large amounts of organic solvent waste (Scheme 5, upper route).
As
a truly effective green chemistry approach, a simple
purification method that did not use organic solvents was
examined. After completion of the reaction, in addition to the
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10.1002/ejoc.201801882
European Journal of Organic Chemistry
COMMUNICATION
Gupta, Q. N. Ahmed, ChemistrySelect 2017, 2, 11136-11340; c) X. Ma,
B. Li, Y. Xiao, X. Yu, C. Su, Q. Xu, Chin. J. Org. Chem. 2017, 37, 2034-
2043; d) K. S. Indalkar, C. K. Khatri, G. U. Chaturbhuj, J. Chem. Sci.
2017, 129, 415-420; e) K. A. Gosai, A. S. Bhatt, M. R. Belani, R. S.
Somani, H. C. Bajaj, Indian J. Chem. 2017, 56A, 220-225; f) T. Tang,
Lei. Zhang, H. Dong, Z. Fang, W. Fu, Q. Yu, T. Tang, RSC Adv. 2017,
7, 7711-7717; g) D. Posevins, K. Suta, M. Turks, Eur. J. Org. Chem.
2016, 2016, 1414-1419; h) M. B. Gawande, A. K. Rathi, I. D. Nogueira,
R. S. Varma, P. S. Branco, Green Chem. 2013, 15, 1895-1899; i) H-M.
Shakeri, H. Tajik, K. Niknam, J. Chem. Sci. 2012, 124, 1025-1032, j) K.
V. Katkar, P. S. Chaudhari, K. G. Akamanchi Green Chem. 2011, 13,
835-838, and see also referenced therein.
Experimental Section
General procedure for substrate scope of the Ritter reaction (Table 4)
To the 10 mL reaction tube with stirring bar, bismuth bromide (44.9 mg,
0.1 mmol), alcohols (1) (1.0 mmol) in nitriles (2) (5.0 mL), and deionized
water (30 µL) were added then heated at 120 °C for 48 h. The reaction
mixture was quenched by 3M HCl aqueous solution (3.0 mL) after
cooling, then organic materials were extracted with ethyl acetate (10 mL)
three times, and the combined organic layers were washed successively
with water, brine, respectively and dried over anhydrous Na2SO4. After
evaporation of the solvent, the residue was purified by column
chromatography on silica gel (hexane / ethyl acetate then warmed
methanol) to give the corresponding amide (3).
[6]
[7]
[8]
[9]
E. Karimian, B. Akhlaghinia, S. S. E. Ghodsinia, J. Chem. Sci. 2016,
128, 429-439.
B. Sadeghi, E. Farahzadi, A. Hassanabadi, J. Chem. Res. 2012, 36,
539-540.
E. Callens, A. J. Burton, A. G. M. Barrett, Tetrahedron Lett. 2006, 47,
8699-8701.
Acknowledgements
In recent years, it has been reported that by controlling the direction of
nucleophilic attack by using a chiral neighboring effect or a chiral
alcohol as a leaving group, stereoretention or stereoinversion of Ritter-
type amidation reaction can be carried out even if via a carbocation
intermediate, see: a) M. H. Al-huniti, S. D. Lepore, Adv. Synth. Catal.
2013, 355, 3071-3076; b) S. V. Pronin, C. A. Reiher, R. A. Shenvi,
Nature 2013, 501, 195-199.
This work was supported by Grants-in-Aid for Scientific
Research from MEXT, Japan., and Kurita Water and
Environment Foundation Grant.
Keywords: Ritter reaction • Bismuth • Lewis acids • Organic
solvent free process • Catalyst
[10] In several commercial medicines, bismuth salts are used as ingredients.
Bismuth subsalicylate, commonly known as pink bismuth, is marketed
as an over-the-counter drug in some countries. It is an antacid used to
treat temporary discomfort of the stomach and digestive tract, such as
diarrhea, indigestion, heartburn, and nausea. Several bismuth salts are
used in pharmaceuticals, pigments, and cosmetics, see: C. R.
Hammond in CRC Handbook of Chemistry and Physics (81st ed.),
section 4, (Ed. D. R. Lide), CRC Press, Boca Raton, FL, 2004, pp5-6.
[11] Long-term use of bismuth is medically known to cause a rare skin
condition called "bismuthia", which results in a generalized persistent
skin discoloration resembling argyria. However, it occurs much more
rarely than with silver, see: H. Jeghers, N. Engl. J. Med. 1944, 231,
181-189.
[1]
Reviews, see: a) R. Bishop in Comprehensive Organic Synthesis II (2nd
ed)., Vol. (Eds.: P. Knochel and G. A. Molander), Elsevier,
6
Amsterdam, 2014, pp. 239-295; b) D. Jiang, T. He, L. Ma, Z. Wang,
RSC Adv. 2014, 4, 64936-64946; c) A. Guérinot, S. Reymond, J. Cossy,
Eur. J. Org. Chem. 2012, 19-28; d) L. I. Krimen, D. J. Cota, Organic
Reactions 1969, 17, 215-256.
[2]
[3]
Original report of Ritter reaction, see: a) J. J. Ritter, J. Kalish, J. Am.
Chem. Soc. 1948, 70, 4048-4050; b) J. J. Ritter, P. P. Minieri, J. Am.
Chem. Soc. 1948, 70, 4045-4048.
In recent, the decarboxylative Ritter-type amination of carboxylic acids
bearing an α-quaternary carbon center, or Ritter-type C–H amination of
sp3 carbon were reported, see: a) K. Kiyokawa, T. Watanabe, L. Fra, T.
Kojima, S. Minakata, J. Org. Chem. 2017, 82, 11711-11720; b) K.
Kiyokawa, K. Takemoto, S. Minakata, Chem. Commun. 2016, 52,
13082−13085; c) Q. Michaudel, D. Thevenet, P. S. Baran, J. Am. Chem.
Soc. 2012, 134, 2547-2550, and see also referenced therein.
Recent studies for the stoichiometric amount of Lewis acid mediated
Ritter reactions, see: a) M. Hatakeyama, T. Aoyama, T. Kobayashi, T.
Takido, M Kodomari, Synlett 2014, 25, 2365-2369; b) K. Niknam, M. A.
Zolfigol, T. Dadabadi, J. Iran. Chem. Soc. 2007, 4, 199-204; c) P.
Salehi, M. M. Khodaei, M. A. Zolfigol, K Keyvan, Synth. Commun. 2001,
31, 1947-1951, and see also referenced therein.
[12] M. Wada, S. Nagayama, K. Mizutani, R. Hiroi, N. Miyoshi, Chem. Lett.
2002, 248-249.
[13] a) M. Wada, T. Takahashi, T. Domae, T. Fukuma, N. Miyoshi, K. Smith,
Tetrahedron: Asymm. 1997, 8, 3939-3946; b) N. Komatsu, M. Uda, H.
Suzuki, T. Takahashi, T. Domae, M. Wada, Tetrahedron Lett. 1997, 38,
7215-7218.
[4]
[5]
[14] M. Wada, E. Takeichi, T. Matsumoto, Bull. Chem. Soc. Jpn. 1991, 64,
990-994.
[15] To the best of our knowledge, there is only one report of the Ritter
reaction of alcohols using less than 1.0 mol% catalyst, see: J. S. Yadav,
B. V. Subba Reddy, T. Pandurangam, Y. Jayasudan Reddy, M. K.
Gupta, Catal. Commun. 2008, 9, 1297-1301.
Recent studies for the catalytic amount of Lewis acid mediated Ritter
reactions, see: a) N. Li, L. Wang, L. Zhang, W. Zhao, J. Qiao, X. Xu, Z.
Liang, ChemCatChem 2018, 10, 3532-3538; b) S. Khan, A. Kumar, R.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801882
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
O
We developed the environmentally
Masaharu Ueno,* Ryo Kusaka,
cat. Biꢀ
benign Ritter reaction using
commercially available, less
Satoshi D. Ohmura and Norikazu
Miyoshi
PhCNꢀ
(10 mmol)
HN
Ph
i) wash (3M HCl),
ii) wash (Hot water)
Ph
Ph
harmful bismuth salt as a catalyst.
The reaction proceeded smoothly
even using stoichiometric amount
of nitrile to alcohol without any
solvents. We also succeeded in
establishing a purification process
without using any organic solvents.
+
iii) drying (60 oC, in vacuo)
Page No. – Page No.
OH
88% (2.5 g)
Environmentally Benign Ritter
Reaction Using Bismuth Salts as a
Catalyst
Ph
Ph
(10 mmol)
i) quench, ii) extract, .... ix) drying
(total 9 processes !!)
88% (2.5 g)
• Cheap and less harmful bismuth salts as a catalyst
• Water acceleration • 1 mol% of catalyst available
• Organic solvent free work up available
Key Topic: Ritter Reactions
This article is protected by copyright. All rights reserved.