The ritter reaction under truly catalytic bronsted acid conditions

Article abstract of DOI:10.1002/ejoc.200700562

Simple organic acids like 2,4-dinitrobenzenesulfonic acid (DNBSA) catalyze the Ritter reaction of secondary benzylic alcohols giving rise to the corresponding N-benzylacetamides in usually high yields. Reactions can be conducted without exclusion of oxygen and without the need of dry solvents. With tertiary α,α-dimethylbenzylic alcohols a different pathway involving a formal dimerization reaction takes place under the acid-catalytic conditions used. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700562

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700562
The Ritter Reaction under Truly Catalytic Brønsted Acid Conditions
Roberto Sanz,*[a] Alberto Martínez,[a] Verónica Guilarte,[a] Julia M. Álvarez-Gutiérrez,[a]
and Félix Rodríguez[b]
Keywords: Alcohols / Amides / Ritter reaction / Homogeneous catalysis / Brønsted acids
Simple organic acids like 2,4-dinitrobenzenesulfonic acid vents. With tertiary α,α-dimethylbenzylic alcohols a different
(DNBSA) catalyze the Ritter reaction of secondary benzylic
alcohols giving rise to the corresponding N-benzylacet-
amides in usually high yields. Reactions can be conducted
without exclusion of oxygen and without the need of dry sol-
pathway involving a formal dimerization reaction takes place
under the acid-catalytic conditions used.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
action is supposed to proceed through a catalytic cycle such
as that shown in Scheme 1.
Introduction
The Ritter reaction is a general method for the amidation
of alcohols or alkenes with nitriles.[1] The reaction typically
requires a strongly ionizing solvent and a stoichiometric
amount of a strong acid (usually sulfuric acid), thus limit-
ing its applicability to compounds with groups that survive
such harsh conditions.[2] This reaction works well in the
case of tertiary alcohols but, the reaction proves more chal-
lenging with less substituted centres due to the instability
of the intermediate carbocation.[3] For instance, 2-methyl-
1-phenylpropan-1-ol affords only moderate yields (ca. 35%)
of N-(1,1-dimethyl-2-phenylethyl)acetamide or N-(2-
methyl-1-phenylpropyl)acetamide depending on the reac-
tion conditions,[3b] showing the tendency of molecular re-
arrangements in the course of Ritter reactions with second-
ary alcohols. Different procedures have been developed to
promote the reaction of less substituted centres, most of
them employing heteroatoms.[4] However, in the last years
Brønsted acid-mediated reactions of different alcohols with
nitriles have been shown to be useful for the preparation of
interesting amides.[5]
Scheme 1. Proposed catalytic cycle for the Ritter reaction of 1a.
The reaction of a benzylic alcohol such as 1a with an
acid forms the carbocation 2a. This is trapped with a mole-
cule of acetonitrile to generate the nitrilium cation 3a,
which is captured by the water produced in the first step of
the process to afford 4a regenerating a molecule of acid. So,
in principle, the acid could be used in a catalytic amount.
However, as mentioned before, the standard conditions
to perform the reaction involve the use of stoichiometric
amounts of concentrated sulfuric acid and, to the best of
our knowledge, there is no general method reported in the
literature for the Ritter reaction using only catalytic
amounts of a Brønsted acid. In this context, we have
recently found that simple Brønsted acids like p-toluene-
sulfonic acid (PTS) or triflic acid (TfOH) are able to cata-
lyze the direct nucleophilic substitution of propargylic
alcohols,[10] as well as benzylic and allylic ones.[11] In the
following we wish to report that simple organic Brønsted
acids when used in catalytic amounts efficiently promote
the Ritter reaction of secondary benzylic alcohols.
Although in the past some alternative methodologies
have been developed for the Ritter reaction where sulfuric
acid is replaced by metal complexes,[6] triflic anhydride,[7]
BF3·Et2O,[8] or inmobilized reagents on solid supports,[9]
most of these methods suffer from drawbacks such as the
use of compounds that are corrosive, toxic, or expensive,
whereas others involve anhydrous conditions. The Ritter re-
[a] Área de Química Orgánica, Departamento de Química, Facul-
tad de Ciencias, Universidad de Burgos,
Pza. Misael Bañuelos s/n, 09001 Burgos, Spain
Fax: +34-947258831
E-mail: rsd@ubu.es
[b] Instituto Universitario de Química Organometálica “Enrique
Moles”, Unidad Asociada al C.S.I.C., Universidad de Oviedo,
c/ Julián Clavería 8, 33006 Oviedo, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4642–4645

Ritter Reaction under Truly Catalytic Brønsted Acid Conditions
2-methyl-1-phenylpropan-1-ol (1m) afforded N-(2-methyl-1-
phenylpropyl)acetamide (5m) in high yield (Table 2, entry
13). By contrast, under the standard stoichiometric condi-
tions reported for the Ritter reaction, the use of this sub-
strate was shown to be problematic.[3b]
Results and Discussion
In the course of our studies about the nucleophilic substi-
tution of 1-phenylethanol 1a with different nucleophiles un-
der Brønsted acid catalysis, we had observed that the use of
acetonitrile as solvent gave mainly rise to N-(1-phenylethyl)-
acetamide (5a), precluding the substitution by the external Table 2. Preparation of N-benzylacetamides
5 from benzylic
nucleophile.[11a] So, we decided to investigate in depth the
alcohols 1.
model reaction of 1a with acetonitrile to give acetamide
5a by using several different Brønsted acids as catalysts
(Table 1).
Table 1. Catalyst screening for the Ritter reaction of 1-phenyle-
thanol (1a).
Entry
Alcohol Ar
R
Amide
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
Me
Me
Me
Me
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
15
24
48
30
24
50
72
9
24
15
48
24
15
30
82
83
4-FC6H4
4-ClC6H4
4-BrC6H4
70[b]
74[b]
66
3-MeOC6H4 Me
Entry Acid catalyst Amount [mol-%] T [°C]
t [h]
Yield [%][a]
2-BrC6H4
2-IC6H4
2-naphthyl
4-BrC6H4
Ph
Ph
4-ClC6H4
Ph
Me
Me
Me
Et
nPr
nBu
nBu
iPr
62
82[b]
80[b]
63[b]
75[c]
62[c,d]
55[c]
89
1
2
3
4
5
PTS
DNBSA
TfOH
H2SO4
DNBSA
10
10
10
10
5
reflux
reflux
reflux
reflux
reflux
48
12
12
15
24
84
85
85
82
75[b]
9
10
11
12
13
14
[a] Isolated yields based on starting alcohol 1a; Ͼ95% conversion
was observed for all the cases. [b] A 7:1 mixture of 5a/6a was deter-
Ph
tBu
66
1
mined by H NMR analysis of the crude reaction mixture.
[a] Isolated yields after chromatography based on starting alcohol
1. [b] Trace amounts (Ͻ5%) of the corresponding styrene deriva-
tives were also observed. [c] A ca. 10% of the corresponding styrene
derivatives were also isolated. [d] Under PTS catalysis ca. 20% of
the elimination product was obtained.
Gratifyingly, the amidation reaction of 1a took place by
using different Brønsted acids as catalysts (10 mol-%). The
only difference observed between these acids was the reac-
tion time required for complete conversion of the starting
material (Table 1, entries 1–4). As shown, the temperature
On the other hand, benzhydrylamine derivatives are im-
of the reaction was raised to reflux in order to obtain the portant structural features of various physiologically active
final amide in reasonable time. It is also interesting to note compounds and are also used as protecting groups.[14] The
that in all cases we observed the initial formation of bis(1- classical syntheses of diarylmethylamines form benzhydrol
phenyethyl) ether 6a and its progressive transformation into precursors involve their previous transformation into chlo-
the final amide 5a (see Scheme 1). After this study, we de- rides or mesylates, followed by substitution with ammo-
cided to use 2,4-dinitrobenzenesulfonic acid (DNBSA)[12] nia.[15] Interestingly, a synthesis of para di- and mono-
(10 mol-%) as catalyst in the successive experiments due to substituted benzhydrylamines has been developed from
its high activity and easiness of handling. Lowering the cat- beznhydrol precursors and phenyl carbamate under acidic
alyst loading from 10 mol-% to 5 mol-% (Table 1, entries 2 conditions.[16] In order to get this kind of compounds in a
and 5) resulted in a significant increase in the reaction time simple way, we thought of applying the Ritter reaction un-
required for the formation of 5a (the transformation of the der the catalytic conditions previously described, i.e. a cata-
initially formed ether 6a into amide 5a is slower under these lytic amount of DNBSA in MeCN at reflux temperature.
conditions).
Indeed, N-benzhydrylacetamides 8 were obtained in high
The generality of the reaction was explored with func- yields from several benzhydrol derivatives 7 (Table 3). Re-
tionalized 1-arylethanols 1b–h. These experiments usually markably, even when strong electron-withdrawing groups
gave high yields of the desired N-(1-arylethyl)acetamides are present in the starting alcohol 7 (Table 3, Entries 2–4),
5b–h (Table 2, Entries 2–8).[13] In order to check if this ap- high yields of the corresponding acetamides 8 were ob-
proach could be applied to multigram synthesis, 3.77 g of tained.
5a (77% isolated yield) were easily prepared in one batch
Finally, we decided to study the catalyzed Ritter reaction
from 3.66 g of 1-phenylethanol (1a) by using 10 mol-% of of a tertiary benzylic alcohol like 2-phenylpropan-2-ol 9a
DNBSA as catalyst. Moreover, benzylic alcohols 1i–n, sub- (Ar = Ph; R = H) (Scheme 2). However, under DNBSA
stituted with primary- (Entries 9–12), secondary- (Entry catalysis in MeCN at reflux, the reaction with 9a did not
13), or tertiary-alkyl groups (Entry 14) were shown to be afford the expected N-benzylic acetamide 10a. Instead of it,
appropriate starting materials for the catalyzed Ritter reac- a 1.3:1 mixture of dimeric compounds 11a and 12a (Ar =
tion and only small amounts of the corresponding elimi- Ph) was obtained in combined 66% yield (Scheme 2 and
nation products were obtained in some cases. Interestingly, Table 4, entry 1). This kind of dimerization has previously
Eur. J. Org. Chem. 2007, 4642–4645
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www.eurjoc.org
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R. Sanz et al.
SHORT COMMUNICATION
Table 3. Preparation of N-benzhydrylacetamides 8 from benzhydrol
derivatives 7.
Entry Alcohol Ar1
Ar2
Amide
t [h] Yield [%][a]
1
2
3
4
5
6
7
7a
7b
7c
7d
7e
Ph
4-FC6H4
4-ClC6H4 4-ClC6H4
Ph
Ph
Ph
Ph
4-FC6H4
8a
8b
8c
8d
8e
8f
15
30
15
15
24
15
15
86
88
80
82
91
87
82
4-NO2C6H4
4-BrC6H4
4-ClC6H4
Scheme 2. Formation of 2,4-diarylpentene derivatives 11 and 12
from 2-aryl-2-propanol derivatives 9 (R = H) under Brønsted acid-
catalyzed conditions.
7f
7g[b]
2,2Ј-(C6H4-C6H4)
8g
[a] Isolated yields after chromatography based on starting benzhyd-
rol 7. [b] 9-Fluorenol.
tetramethyl-3-p-tolylindan, the corresponding cyclodimer
of intermediate carbocation 15e (Table 4, entry 5). Finally,
we treated alcohol 9f (Ar = Ph, R = Pr) under DNBSA
catalysis, but only the elimination product, i.e. styrene 13f,
was obtained showing that β-substitution in the intermedi-
ates 13 and 14 (R ϶ H) inhibits the dimerization process
(Table 4, entry 6).
been carried out under metal catalysis,[17] with aminium
salts acting as one electron oxidants,[18] and with excess of
concd. aqueous H2SO4 or HCl.[19] In this context, we have
recently reported a similar process for the formal dimeriza-
tion of styrenes under TfOH catalysis of the corresponding
secondary benzylic alcohols in MeNO2.[11b] The formation
of isomeric compounds 11a and 12a[20] could be understood
through protonation of 9a and formation of α-methylphen-
ylethyl cation 14a (Ar = Ph; R = H), which could undergo
an elimination reaction producing α-methylstyrene 13a (Ar
= Ph; R = H). Its addition to the benzylic carbocation 14a
would afford the dimer carbocation 15a (Ar = Ph). Subse-
quent elimination of a proton which could take place in
two different ways, accounts for the generation of the final
compounds (Scheme 2).
This catalytic and metal-free alternative for the formal
dimerization of α-methylstyrenes could be of interest and
so, we prepared several 2-arylpropan-2-ol derivatives 9b–e
and treated them under Brønsted acid-catalyzed conditions.
Substrates 9b–d containing electron-withdrawing substitu-
ents produced the unsaturated dimers 11b–d and 12b–d in
high overall yields (Table 4, entries 2–4). Reaction times
with these alcohols were longer than that for the parent
alcohol 9a and also, small amounts of the corresponding
α-methylstyrenes 13b–d were isolated, indicating a lower
stabilization for carbocations 14b–d compared with 14a. On
the other hand, alcohol 9e containing one electron-donat-
ing substituent gave the expected open chain unsaturated
Conclusions
In summary, we have found that simple organic acids like
DNBSA catalyze the amidation of secondary benzylic
alcohols.[21] The reaction is tolerant towards air and moist-
ure. This metal-free method represents a clean and environ-
mentally friendly alternative to the established use of met-
allic catalysts or stoichiometric amounts of Brønsted acids.
The method is also amenable to large scale synthesis. On
the other hand, 2-arylpropan-2-ols undergo formal dimer-
ization through the corresponding styrenes under Brønsted
acid catalysis.
Experimental Section
General Procedure for DNBSA-Catalyzed Amidation of Alcohols 1
and 7: To a solution of the corresponding alcohol 1 or 7 (2 mmol)
in analytical grade MeCN (5 mL), DNBSA[22] (59 mg, 0.2 mmol)
was added. The reaction mixture was stirred at reflux and the com-
pletion of the reaction was monitored by GC-MS (see reaction
times in Tables 2 and 3). The solvent was removed under reduced
dimers 11e and 12e along with a small amount of 1,1,3,5- pressure and the residue was purified by column chromatography
Table 4. Brønsted acid-catalyzed reaction of tertiary benzylic alcohols 9.
Entry
Alcohol
Ar
R
t [h]
Products
Ratio[a]
Yield [%][b]
1
2
3
4
5
6
9a
9b
9c
9d
9e
9f
Ph
H
H
H
H
H
Pr
12
24
24
24
12
12
11a+12a
1.3:1
8:10:1
1.8:1:1
1.5:1:1
1.6:1
–
66
77
72
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
Ph
11b+12b+13b
11c+12c+13c
11d+12d+13d
11e+12e
67
70[c]
74
13f
[a] Determined by 1H-NMR analysis of the crude reaction mixture. [b] Combined isolated yields for 11 + 12 after chromatography based
on starting alcohol 9. [c] About 15% of 1,1,3,5-tetramethyl-3-p-tolylindane was also produced.
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Eur. J. Org. Chem. 2007, 4642–4645

Ritter Reaction under Truly Catalytic Brønsted Acid Conditions
a borate complex as catalyst, see: T. Maki, K. Ishihara, H.
Yamamoto, Org. Lett. 2006, 8, 1431–1434.
[7] A. García Martínez, R. Martínez Álvarez, E. Teso Vilar, A.
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on silica gel (eluent: hexane/ethyl acetate), affording the corre-
sponding acetamides 5 and 8.
Supporting Information (see also the footnote on the first page of
this article): Spectroscopic and characterization data for all com-
pounds.
[9] See, for instance: a) M. M. Lakouraj, B. Movassagh, J. Fasihi,
Synth. Commun. 2000, 30, 821–827; b) F. Tamaddon, M.
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Acknowledgments
We gratefully thank Junta de Castilla y León (BU012A06) and
Ministerio de Educación
(CTQ2004-08077-C02-02/BQU) for financial support. A. M. and
V. G. thank the MEC for MEC-FPU predoctoral fellowships.
J. M. A.-G. and F. R. are grateful to MEC and the Fondo Social
Europeo (“Ramón y Cajal” contracts).
[10]
a) R. Sanz, A. Martínez, J. M. Álvarez-Gutiérrez, F. Rodríg-
uez, Eur. J. Org. Chem. 2006, 1383–1386; b) R. Sanz, D. Mig-
uel, A. Martínez, J. M. Álvarez-Gutiérrez, F. Rodríguez, Org.
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[11] a) R. Sanz, A. Martínez, D. Miguel, J. M. Álvarez-Gutiérrez,
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[12] DNBSA has been reported as an efficient Brønsted acid cata-
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11a/12a was formed, showing the poor reproducibility on the
ratio of 11/12.
[21] We have also checked the reaction by using other nitriles dif-
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Details on this work will be published at due time.
[22] We used 2,4-dinitrobenzenesulfonic acid hydrate (Aldrich,
556971). Its elemental analysis gave the molecular formula
(NO2)2C6H3SO3H·2.5H2O.
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Received: June 19, 2007
Published Online: August 21, 2007
Eur. J. Org. Chem. 2007, 4642–4645
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