O-Benzenedisulfonimide and its chiral derivative as Bronsted acids catalysts for one-pot three-component Strecker reaction. Synthetic and mechanistic aspects

Article abstract of DOI:10.1039/c2ob25584g

o-Benzenedisulfonimide (OBS) has efficiently catalysed the one-pot three-component reaction of ketones and aromatic amines with trimethylsilyl cyanide (TMSCN) giving the corresponding α-amino nitriles in excellent yields (23 examples; average yield 85%). Reaction conditions were very simple, green and efficient. Theoretical calculations have allowed us to explain the mechanism of this reaction which has been found to take place in two phases; the first consists of the nucleophilic addition of the aniline to the ketone and the subsequent dehydration to an imine; the second one consists of the formal addition of cyanide anion to the protonated imine. OBS acts in all steps of this mechanism. Without an acid catalyst, the reaction mechanism is more simple but barriers are sensibly higher. A chiral derivative of OBS was also used and gave fairly good results.

Full text of DOI:10.1039/c2ob25584g

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PAPER
o-Benzenedisulfonimide and its chiral derivative as Brønsted acids catalysts
for one-pot three-component Strecker reaction. Synthetic and mechanistic
aspects†‡
Margherita Barbero, Silvano Cadamuro, Stefano Dughera* and Giovanni Ghigo*
Received 19th March 2012, Accepted 27th March 2012
DOI: 10.1039/c2ob25584g
o-Benzenedisulfonimide (OBS) has efficiently catalysed the one-pot three-component reaction of ketones
and aromatic amines with trimethylsilyl cyanide (TMSCN) giving the corresponding α-amino nitriles in
excellent yields (23 examples; average yield 85%). Reaction conditions were very simple, green and
efficient. Theoretical calculations have allowed us to explain the mechanism of this reaction which has
been found to take place in two phases; the first consists of the nucleophilic addition of the aniline to the
ketone and the subsequent dehydration to an imine; the second one consists of the formal addition of
cyanide anion to the protonated imine. OBS acts in all steps of this mechanism. Without an acid catalyst,
the reaction mechanism is more simple but barriers are sensibly higher. A chiral derivative of OBS was
also used and gave fairly good results.
toluene, CH2Cl2, or MeCN. Trimethylsilyl cyanide (TMSCN)
Introduction
has been the most commonly used cyanide source.3
The one-pot synthesis of α-amino nitriles via the reaction of a car-
bonyl compound, ammonia, and HCN (or other alkaline cyanide)
in aqueous solution is a three-component reaction commonly
known as the Strecker reaction.1 The importance of this reaction
lies in the fact that α-aminonitriles are versatile intermediates for
the synthesis of natural and non-natural amino acids,2a amides,
diamides and nitrogen-containing heterocycles.2b
Over the years, several changes to the original protocol have
been reported. Such modifications mainly consisted of varying
the cyanide sources, using aliphatic or aromatic amines instead
of ammonia, using either acids or bases as catalysts or organic
solvents instead of H2O.3 In particular, the toxic HCN has been
replaced by a number of safer cyanating agents.3 They have gen-
erally been employed in the presence of Brønsted or Lewis
acids,4 Lewis bases,5 metal complexes6 or mesoporous
materials7 in the role of catalysts and in organic solvents such as
It is interesting to note that the use of a catalyst is generally
required when employing ketones,8 whereas it has been reported
that no catalyst is necessary for aldehydes, especially in neat
conditions.9 Nevertheless, it must be stressed that the direct
three-component Strecker reaction with ketones as carbonyl part-
ners has proven to be quite difficult.8 In fact it is usually per-
formed by preparing ketimines as intermediates first and then
adding the cyano group in the presence of a catalyst.8,10
A number of different catalysts have been recently used in
Brønsted acid catalysed direct Strecker reactions between
ketones, amines and TMSCN in both heterogeneous and homo-
geneous conditions, these include: oxalic acid,11a xanthan sulfu-
ric acid,11b BINOL-derived phosphoric acids,8 Nafion solid
resins,11c alumina supported tungstosilicic acid,11d SBA 15 sup-
ported sulfonic acid,11e Sn montomorillonite,2b sulfamic acid-
functionalized magnetic Fe3O4 nanoparticles.11f
Catalyst and/or solvent free-conditions were recently reported by
Galletti et al.3 (using acetone cyanohydrin as cyanide source in
water), Matsumoto et al. (under high pressure)12 and Onaka et al.2b
In the light of growing interest in the one-pot three-component
Strecker reaction, we wish to report that o-benzenedisulfonimide
(OBS) 1 (Fig. 1) can catalyse the Strecker reaction between
ketones, aromatic amines and TMSCN under very mild and
green conditions (Scheme 1).
We have recently reported the use of OBS (1) in catalytic
amounts as a safe, non-volatile and non-corrosive Brønsted
acid in several acid-catalyzed organic reactions.13b The catalyst,
that possesses high acidity (pKa −4.1 at 20 °C), was easily
Dipartimento di Chimica Generale e Chimica Organica, Università di
Torino, C.so Massimo d’Azeglio 48, 10125 Torino, Italy.
E-mail: stefano.dughera@unito.it, giovanni.ghigo@unito.it
†Electronic supplementary information (ESI) available: 1. General pro-
cedure for the preparation of Strecker adducts 5; 2. 1H, 13C NMR, IR
and MS data of known products 5a, 5b, 5d, 5g, 5h, 5i, 5l, 5m, 5o, 5p,
5q, 5r, 5t, 5u, 5w; 3. 1H NMR and 13C spectra of unknown product 5c,
1
5e, 5f, 5j, 5k, 5n, 5v, 5x; 4. H NMR spectrum of the crude residue of
the reaction described in the second collateral proof (see Experimental);
5. GC spectra of the reaction performed with chiral catalyst 19; 6. Tabu-
lated energies (in a.u. and kcal mol−1). 7. Cartesian coordinates. See
DOI: 10.1039/c2ob25584g
‡Dedicated to the memory of Prof. Iacopo Degani
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slowed the reaction down (48 hours) and decreased the yield
(81%).
When 1 was added as a catalyst (5 mol%) in neat conditions,
a dramatic decrease in the reaction time was observed (5 min;
Table 1, entry 4). The yield of 5a was always excellent (95%).
Polar, slightly polar solvents or H2O were also tested (Table 1,
entries 5–9). It was evident, however, that the best results were
obtained in solvent-free reaction conditions. We performed the
reaction in the presence of 5 mol% of five different Brønsted
acids under neat conditions (Table 1, entries 10–14) to compare
and contrast them with the catalytic activity of 1. The results
showed that only with 2,4-dinitrobenzenesulfonic acid were both
the reaction time and the yield similar to that obtained with 1.
In the light of these results, eight different ketones 2 and
eleven different amines 3 were reacted with 4, usually in the
presence of 5 mol% of 1 as a catalyst, at r.t. and under solvent-
free conditions and provided excellent yields of α-aminonitriles
5 (average yields 85%). Table 2 shows the results.
Fig. 1 o-Benzenedisulfonimide (OBS) 1.
Scheme 1 Three-component Strecker reaction catalyzed by 1.
prepared,13a recovered and purified, ready to be used in further
reactions.
In most cases, the presence of electron-donating or electron-
withdrawing groups on the aromatic ring of 2 or 3 did not affect
the times and the yields of the reactions. In fact, the majority of
them reached completion after 5–10 min with excellent target
products 5 yields (Table 2, entries 1, 2, 5–10, 12). In the absence
of electronic effects, longer times were probably due to the low
solubility of the solid amines 3c and 3d in 4 (Table 2, entries 3,
4, 11). The reactions was very fast and provides excellent yields
even with aliphatic 2e and 2f (Table 2, entries 15, 16). On the
other hand, in the presence of the strong electron-withdrawing
group CF3, the reaction was difficult. It was necessary to heat the
reaction mixture to 40 °C and to use 15 mol% of catalyst.
However, the yield of 5c was quite good (Table 2, entry 17).
The reactions between aliphatic amines 3i or 3j, 2a and 4 did
not occur because of the protonation of 3 by 1 (Table 2; entries
Results and discussion
Synthesis
Initially and in order to optimise the reaction conditions, the
model reaction between acetophenone (2a), aniline (3a) and
TMSCN (4) was studied under different reaction conditions
(Table 1).
First of all, the reaction was performed without 1 in neat con-
ditions and in an almost equimolar ratio (Table 1, entry 1) at r.t.
The target product, 2-phenyl-2-phenylaminopropanenitrile (5a)
was obtained in a very good yield (93%), exactly as reported by
Onaka et al.2b The reaction time, however, was long (24 hours).
The presence of a solvent (CH2Cl2; Table 1, entry 2) further
Table 1 Trial reactions
Entry
Solvent
Catalyst; mol%
Time
Yield (%) of 5a a,b
1
2
3
4
5
6
7
8
Neat
CH2Cl2
Neat
—
—
1; 2
1; 5
1; 5
1; 5
1; 5
1; 5
1; 5
24 h
48 h
6 h
5 min
1h
2 h
1 h
24 h
24 h
12 h
24 h
1 h
3 h
10 min
93
82
93
95
92
90
92
62c
41c
80
43c
93
91
95
Neat
MeCN
CH2Cl2
THF
Toluene
H2O
Neat
Neat
Neat
Neat
Neat
9
10
11
12
13
14
HBF4·Et2O 54%; 5
HCOOH; 5
MeSO3H; 5
NH2SO3H; 5
2,4-(NO2)2C6H3SO3H; 5
a Yields refer to the pure products. b Reactants 2a and 3a were in equimolar amounts (5 mmol). TMSCN (4) was in slight excess (6 mmol). c GC-MS
analyses showed the presence of starting products 2a and 3a. In order to remove them, the crude residues were filtered on a buchner funnel and
washed with a small amount of H2O and PE.
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Table 2 Three-component Strecker reaction catalyzed by 1
Entry
R in 2,5
R′ in 2,5
R′′ in 3,5
Products 5
Yield (%)a,b
Time
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2a
2a
2a
2a
2a
2a
2a
2b
2c
2b
2b
2c
2d
Ph
3a
3b
3c
3d
3e
3f
3g
3a
3a
3b
3c
3b
3a
5a
5b
5c
5d
5e
5f
5g
5h
5i
95
92
81
73
92
84
84
88
81
85
82
84
75
5 min
5 min
1 h
4-MeOC6H4
4-NO2C6H4
4-BrC6H4
4-FC6H4
2-MeOC6H4
3-MeOC6H4
Ph
2 h
10 min
5 min
5 min
5 min
10 min
5 min
1 h
4-MeC6H4
4-NO2C6H4
4-MeC6H4
4-MeC6H4
4-NO2C6H4
Ph
9
Ph
10
11
12
13
4-MeOC6H4
4-NO2C6H4
4-MeOC6H4
Ph
5j
5k
5l
10 min
6 h
5mc
14
Ph
Me
2a
3h
73
2 h
5nd,e
5o
15
16
Me
f
Me
2e
2f
Ph
Ph
3a
3a
85
85
5 min
10 min
5pe
17
18
19
20
21
CF3
Ph
Ph
Ph
Ph
Me
Me
Me
H
2g
2a
2a
2h
2a
Ph
3a
3i
3j
3a
3k
5qc,e
5re,g
5sg,h
5tj
72
5 h
24 h
24 h
1 min
PhCH2
n-Bu
Ph
75
i
95
Me
87k
30 min
5u
5v
22
23
Me
Me
2e
2i
3k
3a
92k
5 min
5 min
l
Ph
95m
5w
5x
l
24
2i
4-MeOC6H4
3b
92m
5 min
a All the reactions (unless otherwise stated) were performed at r.t. with 5 mol% of 1. The reactants 2 and 3 were used in equimolar amounts (5 mmol).
TMSCN was in slight excess (6 mmol). b Yields refer to the pure and isolated products. c The reaction was performed with 15 mol% of 1 and heating
to 40 °C. d The reaction was performed with 15 mol% of 1 at r.t. The PE used for wash 5m, was removed under reduced pressure. Starting products
2d and 3a were detected on GC-MS analyses of the residue. e The reaction mixture was poured into Et2O–H2O (50 ml, 1 : 1). The aqueous layer was
separated and extracted with Et2O (2 × 50 ml). The combined organic extracts were washed with H2O (2 × 50 ml) and dried over Na2SO4. After
solvent removal under reduced pressure, the crude residue was the virtually pure (GC, GC-MS, 1H NMR, 13C NMR) compounds 5. The aqueous
layers were evaporated under reduced pressure, obtaining a tarry solid. No significant products were detected on GC-MS analyses. Passing the tarry
solid on a Dowex ion-exchange resin column, pure 1 was recovered. f The reactant was cyclopentanone (2f). g The reaction was performed without
i
catalyst 1. In the presence of 1, no traces of 5r were detected. h The reaction was performed without catalyst 1. After 24 hours, only few traces of 5s
j
were detected on GC-MS analyses. MS (EI): m/z (%) = 202 [M+](1), 175 (80). The reaction was performed without catalyst 1, the reaction time was
15 min and the yields of 5t 95%. k The reaction was performed with 10 mmol of 2a or 2e, 5 mmol of 3k, 12 mmol of 4 and with 10 mol% of 1. l The
reactant was 1,4-diacetylbenzene (2i). m The reaction was performed with 5 mmol of 2i, 10 mmol of 3a or 3b, 12 mmol of 4 and 10 mol% of 1.
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18, 19). However, it was possible to obtain 5r in the absence of
1 and the yield was quite good (Table 2, entry 18).
89%), by simply evaporating the aqueous washings under
reduced pressure. Recovered 1 was reused as a catalyst in
another five consecutive reactions between 2a and 3a. The
results are listed in Table 3. During the different runs, it can be
seen a slight deactivation of the catalyst; in fact the reaction
times increased after each run. However, the yields of 5a and the
recovery yield of 1 between each run were consistently good.
Steric effects were important for both 2 and 3. In fact the reac-
tion with 3a, 4 and bulky 2d needed 15 mol% of 1 and heating
at 40 °C for 6 hours (Table 2, entry 13). Moreover, although the
reaction the reaction with 3h, 2a and 4 also needed 15% mol of
1; however, it was not necessary to heat it (Table 2, entry 14). In
both cases the yields of 5m and 5n were good.
We also tested two different kinds of double Strecker reaction.
It must be stressed that, to the best of our knowledge, this reac-
tion using ketones as carbonyl partners, had only been per-
formed previously by Matsumoto et al.12 and in that experiment
it was done under high pressure. In the first case, we reacted 1,4-
diaminobenzene (3k) with 2a or 2e and 4 in the presence of
10 mol% of 1 (Table 2, entries 21, 22). In the second, we reacted
1,4-diacetylbenzene (2i) with 3a or 3b again in the presence of
10 mol% of 1 (Table 2, entries 23, 24). In both cases we
obtained excellent results.
As mentioned above, it has been reported that the aldehydes
reacts easily without any catalyst in neat conditions.9 In fact, the
reaction between 2h, 4 and 3a furnished 5t in almost quantitative
yields after 15 min. The reaction was virtually instantaneous
upon the addition of 1 (Table 2, entry 20).
Mechanism
Two different mechanisms have been proposed for this reaction
in the literature (Scheme 2).
In the first one, the nitrogen atom of 3 carries out a nucleophi-
lic attack on carbonyl group of 2 giving rise to an amino alcohol
7 which, by passing through an imine (or iminium ion) inter-
mediate 8, affords 5 by the subsequent addition of cyanide
anion.2b,4e,11b,12 An acid catalyst 6, interacting with the carbonyl
group, facilitates the nucleophile attack of the nitrogen.
In the second proposed mechanism, it was hypothesized that
nucleophilic attack of cyanide occurs directly on 7, without
passing through 8.7 Interestingly, Ma and coworkers conjectured
that the two mechanisms coexist.8
The copious and homogeneous results collected in this work
provide a good basis for some comments on the mechanism
involved.
With only four exceptions (Table 2, entries 14, 16–18), where
compounds 5 were not solid, the work-up was very easy and
convenient. It was sufficient to add H2O to the crude residue,
filter and wash the resulting solid with additional H2O and a
small amount of PE on a Buchner funnel. Furthermore, 1 was
recovered in excellent yields (for example Table 3, entry 1,
First of all, we decided to react 2a and 3a in the presence of
5 mol% of 1 and without 4 (see Collateral proof 1 in Experimen-
tal). After 1 hour, the reaction mixture was quenched with water.
GC and GC-MS analyses showed that only a small amount of
N-(1-phenylethylidene)benzeneamine 8a (about 4%) was
present. On the other hand, a large amount of starting products
2a and 3a was detected. 1H NMR analyses (in anhydrous
CDCl3) performed on the crude residue before its quenching
with water, showed the presence of a weak peak at δ = 2.18 ppm
(see 1H NMR spectrum on ESI†). This could be the signal of the
Table 3 Consecutive runs with recovered 1
Entry
Time (min)
Yield (%) of 5aa
Recovery (%) of 1b
1
2
3
4
5
6
5
95c
92
90
90
88
88
91 (50 mgd)
84 (42 mge)
81 (34 mgf)
79 (27 mgg)
78 (21 mgh)
76 (16 mg)
15
20
30
40
45
1
methyl group of 13a (see Scheme 3 below). In fact, H NMR
analyses of the crude residue after its quenching with water,
showed a small but significant shift (δ = 2.25 ppm) of this peak.
In the literature, the reported δ of the methyl group of 8a is
2.2514a or 2.2714b ppm. Interestingly, when the reaction was per-
formed in the presence of 10 mol% of 1 (see Collateral proof 4)
a sharp increase in 13a (see Scheme 3) and, consequently, in 8a
could be seen in both GC and 1H-NMR analyses. However,
upon adding 4 to the reaction mixture after 1 hour, aminonitrile
5a was formed almost immediately (see Collateral proof 2).
a Yields refer to the pure products. b The amount (in mg) of recovered
OBS is reported in brackets. c The reaction was performed with 5 mmol
of 2a and 3a, 6 mmol of 4 and 5 mol% of 1 (55 mg, 0.25 mmol).
d Recovered 1 was used as catalyst in entry 2. e Recovered 1 was used as
catalyst in entry 3. f Recovered 1 was used as catalyst in entry 4.
g Recovered 1 was used as catalyst in entry 5. h Recovered 1 was used as
catalyst in entry 6.
Scheme 2 Mechanisms proposed in the literature for three-component Strecker reaction.
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Scheme 3 Mechanism of three-component acid-catalyzed Strecker reaction. First phase.
Scheme 4 Mechanism of three-component acid-catalysed Strecker reaction. Second phase.
It must be stressed that we also obtained almost the same results
when using MeCN as a solvent (see Collateral proof 3).
A theoretical study of the acid-catalysed Strecker reaction
(in MeCN) shows that this one takes place in two phases. These
are illustrated in Schemes 3 and 4 while Fig. 2 and 3 show the
related enthalpy (dashed lines) and free energy (solid lines)
profiles. To reduce the calculation times, OBS 1 was modelled
by the acid HZ where the aromatic ring is substituted by a
vinylidene.
mol−1 in terms of Gibbs energy. Finally, the loss of H2O gives
the free iminium (with its counterion Z−) 13a, which is the reac-
tant for the second phase of the reaction. As an alternative, 11a
can also lose the acid (grey lines and labels in Fig. 2) leaving the
free amino alcohol 7a. However, this process is less competitive
because it is reversible and less exoergic (in term of absolute
free energy) than the irreversible dehydration and water loss
(yielding 13a and H2O).
The energy profiles shown in Fig. 2 take the isolated reactants
as reference points for all energies. However, in neat conditions,
the ketone and the aniline are already in tight contact, therefore
the complex between these two reactants (2a*3a, ΔG* = 4.6 kcal
mol−1) is a better choice as a starting point (and therefore as a
reference for the energies). This leads to a general lowering of
the free energy profiles because the reference is now the free
energy of the complex. So, the free energy (ΔG*rds in Fig. 2) of
the rate determining transition structure (TSH/CO) is now
18.2 kcal mol−1 (ΔH*rds = 4.9 kcal mol−1). In this condition
In the first phase (Scheme 3 and Fig. 2), reactants 2a and 3a
form a complex (2a*3a) which is followed by a reversible
proton transfer from the acid ZH to the ketone yielding a new
complex (9a*3a) between the protonated ketone (with Z− as
counterion) 9a and the aniline 3a. This equilibrium is followed
by a transition structure (TSAdd) consisting of the very fast acid-
catalysed nucleophilic addition of the aniline 3a to the proto-
nated ketone 9a which yields the protonated adduct 10a. The
catalytic role of acids in this reaction is well known and it has
also been theoretically studied.15a The second step (TSHZ-disp
)
phase 1 is exoergic both in term of enthalpy (−5.8 kcal mol−1
)
consists of the deprotonation of the nitrogen atom and the for-
mation of the complex (11a) between the amino alcohol and
ZH. This step is followed by the concerted asynchronous proton
transfer and dehydration (through TSH/CO, Fig. 4) in 11a yield-
ing a complex (12a) between the protonated imine and water.
This process is the rate determining step of the first phase of the
Strecker reaction and the energy (with respect to all reactants) of
TSH/CO is 0.5 kcal mol−1 in terms of enthalpy and 22.8 kcal
and Gibbs free energy (−5.1 kcal mol−1).
TMSCN 4 appears in the second phase of the reaction
(Scheme 4) and can react with the iminium 13a (black energy
profiles and labels in Fig. 3) or with the deprotonated imine 8a
(grey energy profiles and labels in Fig. 3). The first pathway is
the preferred as can be seen from the enthalpy and free energy
profiles shown in Fig. 3. This pathway is also the simplest
because the formation of the complex (13a*4) between the
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Fig. 2 Enthalpy (dashed lines) and 1 M standard free energy (solid lines) profiles (in kcal mol−1) for the first phase of the acid-catalysed Strecker
reaction. See text and Scheme 3 for the labels.
Fig. 3 Enthalpy (dashed lines) and 1 M standard free energy (solid lines) profiles (in kcal mol−1) for the second phase of the acid-catalyzed Strecker
reaction. See text and Scheme 4 for the labels.
reactants is immediately followed (TS′Add, Fig. 5) by the
addition of 4 to the iminium yielding the final product 5a and 14
(trimethylsilyl bound to Z−). 14, after reaction with H2O, yields
the silanol 15. Indeed, instead of the latter, we detected on
GC-MS analyses bis(trimethylsilyl) ether, possibly due of acid-
catalyzed dehydration of 15.
enthalpy (with respect to the reactants 2a, 3a, 4 and HZ) is quite
low (4.9 kcal mol−1) but its Gibbs energy is 25.0 kcal mol−1
.
The alternative pathway requires, as its first step, the endother-
mic loss of the acid HZ from the iminium 13a. This process pre-
sents an unfavourable reaction enthalpy which is not fully
compensated for by the entropy gain which in turn leads to posi-
tive reaction free energy (ΔG* = 8.3 kcal mol−1, to compare with
the exoergic loss of HZ from 11a, ΔG* = −6.3 kcal mol−1).
The rate determining step of this phase (TS′Add) is also the
slowest step of the whole Strecker reaction in MeCN. Its
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yielding adduct 18. This intermediate, after reaction with H2O
(not shown) will lead to the final products 5a and 15.
As for the first phase of the reaction, we expect to find all
species in tight contact in neat conditions, therefore, the starting
point (and reference for the energies) for second phase should
be the complex (13a*4) between the iminium and TMSCN.
This leads again to a general lowering of the free energy profiles.
The free energy (ΔG* in Fig. 3) of the rate determining
rds
transition structure (TS′Add) is now 20.7 kcal mol−1 (ΔH*rds
=
20.3 kcal mol−1).
To combine the two phases in neat conditions, we should bear
in mind that the starting point should be a complex of all the
reactants but the acid (2a, 3a and 4). However, because 4 is not
involved in the first phase, the smaller complex 2a*3a is already
a reliable starting point (and energy reference point). Once the
iminium 13a (located 5.1 kcal mol−1 below the Gibbs energy of
complex 2a*3a) is formed this reacts in the second phase with 4.
Since we assume that 4 had already been present as “inactive
spectator” from the very beginning, we also assume that its
complex with the iminium (13a*4) presents the same energy as
the iminium alone. Therefore, the free energy of TS′Add with
respect to the complex 2a*3a*4 would be 15.6 kcal mol−1
(15.2 kcal mol−1 in terms of enthalpy). Because the free energy
of TSH/CO is, as had been estimated previously for these con-
ditions, 18.2 kcal mol−1, this is the rate determining step of the
Strecker reaction in neat conditions. This value is 7 kcal mol−1
lower than the value for the rate determining state in MeCN and
explains why the reaction is much faster in neat conditions than
in solvent (compare entries 4 and 5 in Table 1). Of course, in
solvent the concentration factor will play its role as well.
Fig. 4 Transition structure (TSH/CO) for the rate determining step of
the first phase of the Strecker reaction.
An important point of note in the second phase is that HZ
(and therefore, 1) is made available for a new conversion of the
reactants only after the reaction of 13a (the complex between the
iminium and Z−) with 4. In fact, after the dehydration of 11a,
HZ is not available for further reaction because it is bound to the
imine. This feature is confirmed by the experimental findings
(see before) which show that, without 4, the reaction stops after
the formation of an amount of iminium proportional to the
amount of the acid 1. On the basis of the theoretical study, the
intermediate specie between phases 1 and 2 of the Strecker reac-
tion should be 13a (and not 8a) seeing as dissociation here is
thermodynamically unfavourable (although 8a is possibly the
specie really detected in the analytical procedure). After reaction
with 4, the acid is recycled into a new phase 1. From the mech-
anism described above (and from the pKa), it is clear that OBS
behaves as a strong Brønsted acid. Therefore, the mechanism we
propose should be adaptable for any other strong acid.
This work would not be complete without the study of the
three-component Strecker reaction without the acid catalyst. The
mechanism is simple and Scheme 2 already contains all the
necessary elements while Fig. 6 shows the relative enthalpy and
free energy profiles. As we were interested to simulate the neat
conditions the complexes between reactants were assumed as
starting points.
Fig. 5 Transition structure (TS′Add) for the rate determining step of the
second phase of the Strecker reaction.
Therefore, the whole free energy reaction profile of this pathway,
now starting from the free imine 8a, is raised with respect to the
previous one. We will briefly describe it for the sake of compari-
son. The first step is the addition (through TSSi-Add) of 4 to yield
the Si adduct 16. Then, the Si–CN bond breaks in the rate deter-
mining step TSCN-Det (ΔH = 22.1 kcal mol−1, ΔG* = 34.8 kcal
mol−1 with respect to reactants 2a, 3a and 4) leading to complex
The first step is the nucleophilic addition of the aniline 3a to
the ketone 2a. Without any other molecule, this step shows a
very high free energy barrier (more than 40 kcal mol−1
,
see ESI†). This is not a surprise, similar values have already
been encountered in other studies.15 However, in neat conditions
17 which is followed by the addition of the cyanide (TSCN-Add
)
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Fig. 6 Enthalpy (dashed line) and 1 M standard free energy (solid line) profiles (in kcal mol−1) for the uncatalyzed Strecker reaction. See text and
Scheme 2 for the labels.
Fig. 8 Chiral derivative of 1.
between 5a and 15) is, in any case, exoergic by 24 kcal mol−1 in
term of enthalpy and 28 kcal mol−1 in term of free energy.
Use of a chiral catalyst
Fig. 7 Transition structure (TSExch) for the rate determining step of the
uncatalyzed Strecker reaction.
We have very recently reported16 the preparation of a chiral
derivative of 1, namely (R)-(−)-4-methyl-3-(2-tolyl)-1,2-benzene-
disulfonimide (19, Fig. 8).
a second aniline 3a molecule can assists the reaction leading to a
distinct reduction in the barrier.15a,c Starting from a complex
between the three reactants 3a*2a*3a, the free energy barrier
(TS′′Add) is now 30 kcal mol−1, still nearly 20 kcal mol−1
higher than the same step with acid catalyst. Moreover, the reac-
tion is endoergic; the free energy of the amino alcohol 7a is
7 kcal mol−1 above that of the reactant complex. The second
irreversible phase of the reaction is the exchange of the hydroxyl
with the cyanide from the TMSCN 4. Its free energy barrier is
30.2 kcal mol−1. Taking into account the fact that we start from
the adduct from the first phase, the free energy of this rate deter-
mining step (TSExch, Fig. 7) is 37.4 kcal mol−1. This value is
19.2 kcal mol−1 higher that the one found for the catalysed reac-
tion (18.2 kcal mol−1) and confirms the fundamental role of the
acid catalyst. The whole reaction (product is the complex
We decided to test it as a chiral catalyst in this reaction. First
of all we analysed 5a on a GC with a chiral column and its two
enantiomers were clearly detected (see chromatogram 1 in
ESI†). In an initial proof, reacting 2a, 3a and 4 in the presence
of 5 mol% of 19 at r.t. we found a poor enantioselectivity (ee
32%, chromatogram 2 in ESI†). There was, however, a slight
increase in enantioselectivity (ee 56%, chromatogram 3 in ESI†)
upon cooling the reaction to 0 °C. No significant results were
obtained upon further cooling. It must be stressed that the cataly-
tic asymmetric Strecker reaction has been usually performed
starting from imines17 and has been described as a one-pot three-
component Strecker reaction catalysed by a chiral catalyst in a
few papers.8,17a Although the results obtained with 19 as chiral
catalyst are fairly good, further investigations into its role are
currently underway.
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Conclusions
Experimental
In summary, a new application of the organocatalyst OBS (1)
has been reported. This strong bench-stable Brønsted acid has
been shown to efficiently catalyse the three-component Strecker
reaction between ketones, amines and TMSCN in very easy and
green conditions.
General
Analytical grade reagents and solvents were used and reactions
were monitored by GC, GC-MS and TLC. Petroleum ether (PE)
refers to the fraction boiling in the range 40–70 °C. Room temp-
erature (r.t.) is 20–25 °C. Mass spectra were recorded on an HP
5989B mass selective detector connected to an HP 5890 GC,
cross-linked methyl silicone capillary column. Chiral analyses
were performed on a Perkin Elmer Autosystem GC connected to
a J&W Scientific Cyclosil-B column; stationary phase: 30% hep-
takis (2,3-di-O-methyl-6-O-t-butyldimethylsilyl)-β-cyclodextrin
in DB-1701. 1H NMR and 13C NMR spectra were recorded on a
Brucker Avance 200 spectrometer at 200 and 50 MHz respect-
ively. IR spectra were recorded on a Perkin Elmer Spectrum BX
FT-IR spectrometer as solutions in CHCl3. o-Benzenedisulfo-
nimide (1)13a and (R)-(−)-4-methyl-3-(2-tolyl)-1,2-benzene-
disulfonimide (19)16 were prepared as reported in the literature.
All the reagents were purchased from Sigma-Aldrich. All the
reactions were performed in open air flasks. The structures and
purity of the products 5a,12 5b,8 5d,8 5g,8 5h,11b 5i,4e 5l,8 5m,2
5o,8 5p,11a 5q,4c 5r,11b 5t,28 5u,12 5w12 were confirmed by com-
parison of their physical and spectral data with those reported in
the literature. Products 5n29and 5v30 are known in the literature,
but no physical and spectral data are reported. Satisfactory
microanalyses were obtained for the new compounds 5c, 5e, 5f,
5j, 5k, 5x. Spectral and physical data of the known products 5
are reported on ESI.†
From a mechanistic point of view, the acid-catalysed three-
component Strecker reaction has been found to take place in two
phases: the first one consists of the nucleophilic addition of the
aniline to the ketone and the subsequent dehydration to an
imine; the second one consists of the formal addition of cyanide
anion to the protonated imine. The Brønsted acid acts in all steps
of this mechanism. In solvent (MeCN) the rate determining step
(rds) appears in the second phase (TS′Add) which presents an
enthalpy of 4.9 kcal mol−1 and a Gibbs energy of 25.0 kcal
mol−1 with respect to the reactants. In neat conditions, where all
reactants but the acid are already in tight contact, the starting
points are the complexes of all the reactants except the acid and
the rds is now the dehydration (TSH/CO, first phase) whose ener-
gies are: ΔH = 17.3 and ΔG = 18.2 kcal mol−1
.
The reaction mechanism is simpler without the acid catalyst
but barriers are higher and the rds is found in the exchange of
the hydroxyl group with the cyano group (TSExch) whose ener-
gies (in neat conditions) are ΔH = 32.1 and ΔG = 37.4 kcal
mol−1. The fundamental role of the Brønsted acid is evident
from the presence of lower energy barrier for the catalysed reac-
tion. This had already been stressed in literature but the mechan-
ism has never really been explored,2b,7,8,11b with one
exception17c where the catalytic role of the BINOL–phosphoric
acid in the addition of HCN to the imine was fully explored.
The use of chiral catalyst (R)-(−)-4-methyl-3-(2-tolyl)-1,2-
benzenedisulfonimide (19) allowed us to obtain fair
enantioselectivity.
2-Phenyl-2-phenylaminopropanenitrile (5a): representative
procedure for the preparation of Strecker adducts 5
TMSCN (4; 0.60 g, 6 mmol) was added to a mixture of OBS (1;
5 mol%; 55 mg, 0.25 mmol), acetophenone (2a; 0.60 g,
5 mmol) and aniline (3a; 0.46 g, 5 mmol) The mixture was
stirred at r.t. for 5 min until the GC and GC-MS analyses
showed the complete disappearance of 2a and 3a and the com-
plete formation of product 5a. The by-product bis(trimethylsilyl)
ether, MS (EI) m/z: (%) 162 [M+](10), 147 (100) was also
detected. However, it was impossible to isolate it.
Cold H2O (20 ml) was added to the reaction mixture, under
vigorous stirring. The resulting solid was filtered on a buchner
funnel and washed with additional cold H2O (2 × 5 ml) and
small amount of PE (5 ml). It was virtually pure (GC, GC-MS,
1H NMR, 13C NMR) title compound 5a, a white solid; yield:
95% (1.05 g). The aqueous washings were collected and evapor-
ated under reduced pressure. After the removal of H2O, virtually
pure (1H NMR) o-benzenedisulfonimide (1) was recovered
(50 mg, 91% yield). The recovered 1 was employed in another
five catalytic cycles under the conditions described above, react-
ing with 2a and 3; Table 3 reported the yields of 5a and the
yields of recovered 1.
Theoretical method
The reaction mechanism was investigated using the density
functional method (DFT),18 with the recently developed func-
tional M06-2X.19 All stationary points were optimised and
characterised with the 6-31+G(d)20a,b basis set and the nature of
the critical points was checked by vibrational analysis.21 For the
transition structures (TS), when the inspection of the normal
mode related to the imaginary frequency was not sufficient to
confidently establish its connection with the initial and final
stable species, IRC22 calculations were performed. The energy
values are then refined through single-point calculations with
the basis set 6-311+G(2df,p)20c,d and combined with the
thermal corrections obtained with the smaller basis set to get
enthalpy (H) and free energy values (G) at room temperature.
The latter have been converted from the gas phase to the 1 M
standard state at 1 atm and 298.15 K.23 Solvent effects (MeCN)
were introduced both in geometry optimisation and single point
calculations by the Polarized Continuum Method (PCM)24
within the universal Solvation Model Density (SMD).25 Calcu-
lations were performed by the quantum package Gaussian
09-A.02.26 Fig. 4, 5 and 7 were obtained with the graphical
program Molden.27
2-(4-Nitrophenylamino)-2-phenylpropanenitrile (5c). Yellow
solid; 1.08 g (yield 81%); mp 134–135 °C (EtOH). Found: C,
67.35; H, 4.92; N, 15.80. C15H13N3O2 requires: C, 67.41; H,
4.90; N, 15.72%. 1H NMR (200 MHz, CDCl3): δ = 1.95 (s, 3H),
5.22 (br s, 1H), 6.50 (d, J = 9.2 Hz, 2H), 7.33–7.48 (m, 5H),
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7.95 (d, J = 9.2 Hz, 2H). 13C NMR (50 MHz, CDCl3): δ = 33.1,
56.8, 115.8, 120.0, 120.7, 124.8, 126.4, 129.3, 142.9, 147.3,
148.2. MS (EI) m/z: (%) 240 [M+ − HCN](72), 225 (100), 179
(60). IR (CHCl3) ν (cm−1): 3429 (NH), 2248 (CN).
MS (EI) m/z: (%)188 [M+ − 2 HCN](85), 173 (100), 117 (30),
79 (22). IR (CHCl3) ν (cm−1): 3418 (NH), 2257 (CN).
2,2′-(1,4-Phenylene)bis[2-(4-methoxyphenylamino)propaneni-
trile] (5x). White solid; 1.74 g (yield 92%); mp 122–123 °C
(EtOH). Found: C 73.38; H 6.19; N 13.09. C26H26N4O2
requires: C 73.33; H 6.14; N 13.14%. 1H NMR (200 MHz,
CDCl3): δ = 1.85 (s, 6H), 3.66 (s, 6H), 6.47 (d, J = 9.0 Hz, 2H),
6.64 (d, J = 9.0 Hz, 2H), 7.61 (s, 4H). 13C NMR (50 MHz,
DMSO-d6): δ = 32.5, 55.7, 57.6, 114.7, 117.2, 121.9, 126.3,
138.9, 141.5, 153.0. MS (EI) m/z: (%) 372 [M+ − 2 HCN](65),
357 (100). IR (CHCl3) ν (cm−1): 3429 (NH), 2255 (CN).
2-(4-Fluorophenylamino)-2-phenylpropanenitrile
(5e). Pale
grey solid; 1.10 g (yield 92%); mp 125–126 °C (EtOH). Found:
C 75.05; H 5.39; F 7.82; N 11.74. C15H13FN2 requires: C 74.98;
1
H 5.45; F 7.91; N 11.66%. H NMR (200 MHz, CDCl3): δ =
1.87 (s, 3H), 6.41–6.48 (m, 2H), 6.72–6.81 (m, 2H), 7.32–7.40
(m, 3H), 7.53–7.58 (m, 2H). 13C NMR (50 MHz, CDCl3): δ =
33.3, 57.9, 115.6, 116.0, 117.6 (d, J2 = 7.6 Hz), 120.9, 125.1,
128.9, 129.5, 139.7, 157.5 (d, J1 = 236.5 Hz). MS (EI) m/z: (%)
213 [M+ − HCN](65), 198 (100). IR (CHCl3) ν (cm−1): 3431
(NH), 2256 (CN).
Collateral proofs
1. A mixture of 1 (5 mol%; 55 mg, 0.25 mmol), 2a (0.60 g,
5 mmol) and 3a (0.46 g, 5 mmol) was stirred at r.t. for 1 hour.
1H NMR (anhydrous CDCl3) analysis of the reaction mixture
showed, among others, a weak peak at δ = 2.18 ppm (probably
the methyl group of 13a; see the spectrum on ESI†). Then, the
reaction mixture was poured into water and extracted with Et2O
(100 ml). On GC and GC-MS analysis of crude residue, a small
amount of N-(1-phenylethylidene)benzeneamine (8a), MS (EI)
m/z: (%) 195 [M+](60), 180 (100), 77 (35) was detected (about
4%) besides unreacted 2a and 3a. The 1H NMR analysis of
the crude residue showed the shift of the methyl group at
δ = 2.25 ppm.
2-(2-Methoxyphenylamino)-2-phenylpropanenitrile (5f). Pale
brown solid; 1.06 g (yield 84%); mp 80–81 °C (EtOH). Found:
C 76.08; H 6.44; N 11.15. C16H16N2O requires: C 76.16;
H 6.39; N 11.10%. 1H NMR (200 MHz, CDCl3): δ 1.93 (s, 3H),
3.86 (s, 3H), 4.90 (br s, 1H), 6.19–6.23 (m, 1H), 6.56–6.75 (m,
3H), 7.29–7.38 (m, 3H), 7.55–7.59 (m, 2H). 13C NMR
(50 MHz, CDCl3): δ = 33.4, 55.7, 57.1, 109.8, 114.3, 119.4,
120.9, 125.1, 128.5, 129.4, 133.5, 140.4, 147.6. MS (EI) m/z:
(%) 225 [M+ − HCN](45), 210 (100). IR (CHCl3) ν (cm−1):
3430 (NH), 2258 (CN).
2-(4-Methoxyphenylamino)-2-(4-tolyl)propanenitrile (5j). Pale
grey solid; 1.13 g (yield 85%); mp 88–89 °C (EtOH). Found: C
76.59; H 6.87; N 10.54. C17H18N2O requires: C 76.66; H 6.81;
2. The formation of a white precipitate and the disappearance
of 2a and 3a was observed almost immediately upon the addition
of TMSCN (4; 0.60 g, 6 mmol) to a reaction mixture prepared as
above. The precipitate was filtered on a Buchner funnel and
washed with additional cold H2O (2 × 5 ml) and small amount
1
N 10.52%. H NMR (200 MHz, CDCl3): δ = 1.83 (s, 3H), 2.31
(s, 3H), 3.64 (s, 3H), 6.50 (d, J = 9.0 Hz, 2H), 6.64 (d, J = 9.0
Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H). 13C
NMR (50 MHz, CDCl3): δ = 26.5, 33.0, 55.7, 57.5, 114.3,
114.8, 117.7, 125.0, 128.4, 129.3, 129.8, 138.2, 153.4. MS (EI)
m/z: (%) 239 [M+ − HCN](70), 225 (100). IR (CHCl3) ν (cm−1):
3438 (NH), 2241 (CN).
1
of PE (5 ml). It was virtually pure (GC, GC-MS, H NMR, 13C
NMR) 5a, 1.00 g (yield 90%).
3. The reaction described in entry 1 was performed with
MeCN as a solvent. We obtained almost the same results.
2-(4-Nitrophenylamino)-2-(4-tolyl)propanenitrile (5k). Yellow
solid; 1.15 g (yield 82%); mp 102–103 °C (EtOH). Found: C
68.40; H 5.37; N 14.85. C16H15N3O2 requires: C 68.31; H 5.37;
4. The reaction described in entry 1 was performed with
10 mol% (101 mg, 0.5 mmol) of 1. A significant increase in the
quantity of 8a was observed. In fact, the amount of 8a increased
1
N 14.94%. H NMR (200 MHz, CDCl3): δ = 1.94 (s, 3H), 2.31
1
(s, 3H), 4.88 (br s, 1H), 6.50 (d, J = 9.0 Hz, 2H), 7.16 (d, J =
8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H).
13C NMR (50 MHz, CDCl3): δ 21.2, 33.3, 56.7, 113.5, 114.5,
124.7, 125.8, 126.6, 130.4, 135.5, 139.3, 149.4. MS (EI) m/z:
(%) 254 [M+ − HCN](75), 239 (100), 193 (50). IR (CHCl3) ν
(cm−1): 3421 (NH), 2255 (CN).
up (about 9%) in GC analyses. Furthermore, the H NMR ana-
lyses of the reaction mixture (performed with anhydrous CDCl3
and before its quenching with H2O) showed an increase in the
peak height at δ = 2.18 ppm.
Chiral sulfonimide 19 as a catalyst
2-(N-Methyl-N-phenylamino)-2-phenylpropanenitrile
(5n).
1
4 (37 mg, 0.37 mmol) was added to a mixture of (R)-(−)-4-
Viscous oil; 0.86 g (yield 73%). H NMR (200 MHz, CDCl3):
δ = 1.48 (s, 3H), 2.62 (s, 3H), 6.54–6.68 (m, 1H), 7.09–7.51 (m,
9H). 13C NMR (50 MHz, CDCl3): δ = 31.3, 40.7, 66.2, 112.6,
117.4, 120.0, 128.5, 128.8, 129.1, 129.2, 129.4, 148.8. MS (EI)
m/z: (%) 236 [M+](20), 208 (70), 118 (100), 77 (35). IR (CHCl3)
ν (cm−1): 2249 (CN).
methyl-3-(2-tolyl)-1,2-benzenedisulfonimide (19;
5
mol%;
5 mg, 0.0154 mmol), 2a (37 mg, 0.308 mmol) and 3a (29 mg,
0.308 mmol) that had been cooled to 0 °C. The mixture was
stirred at 0 °C for 3 hours until the GC and GC-MS analyses
showed the complete disappearance of 2a and 3a and the com-
plete formation of product 5a. After the same work-up as above,
5a was recovered (60 mg, 88% yield). After analyzing 5a on a
GC with a chiral column the presence of two enantiomers was
found; ee was 56%. When the same reaction was performed at
r.t., the ee was only 32%. The GC spectra are reported in ESI.†
2,2′-(1,4-Phenylenediamino)bis(2-methylpropanenitrile) (5v).
White solid; 1.11 g (yield 92%); mp 143–144 °C (EtOH).
1H NMR (200 MHz, CDCl3): δ = 1.60 (s, 12 H), 6.89 (s, 4H).
13C NMR (50 MHz, CDCl3): δ = 28.0, 500, 115.8, 120.5, 138.4.
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15 (a) R. M. Minyaev, Russ. Chem. Bull., 1998, 47, 8; (b) I. H. Williams,
J. Am. Chem. Soc., 1987, 109, 6299; (c) L. Pardo, R. Osman,
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16 M. Barbero, S. Bazzi, S. Cadamuro, L. Di Bari, S. Dughera, G. Ghigo,
D. Padula and S. Tabasso, Tetrahedron, 2011, 67, 5789.
17 (a) L. Yet, Angew. Chem., Int. Ed., 2001, 40, 875; (b) M. Rueping,
E. Sugiono and C. Azap, Angew. Chem., Int. Ed., 2006, 45, 2617;
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18 R. G. Parr and W. Yang, in Density Functional Theory of Atoms and Mol-
ecules, Oxford University, New York, 1989, ch. 3.
The reaction did not complete and ee was about 50% when the
reaction was cooled to −10 °C, for 6 hours.
Acknowledgements
This work has been supported by the University of Torino.
19 (a) Y. Zhao and D. G. Truhlar, Theor. Chem. Acc., 2008, 120, 215;
(b) Y. Zhao and D. G. Truhlar, Acc. Chem. Res., 2008, 41, 157.
20 (a) W. J. Hehre, R. Ditchfield and J. A. Pople, J. Chem. Phys., 1972, 56,
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(a) J. B. Foresman and Æ. Frisch, in Exploring Chemistry with Electronic
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23 R. F. Ribeiro, A. V. Marenich, C. J. Cramer and D. G. Truhlar, J. Phys.
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