Multicomponent Strecker reaction under high pressure

Article abstract of DOI:10.1002/hlca.200590136

For the first time, uncatalyzed, high-pressure (0.6 GPa) reactions with ketones have proven to be a powerful way to perform the three-component Strecker synthesis of α-amino nitriles in high yields. Two types of double Strecker reactions were achieved, but attempts to perform triple Strecker reactions were unsuccessful.

Full text of DOI:10.1002/hlca.200590136

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Multicomponent Strecker Reaction under High Pressure
by Kiyoshi Matsumoto*a), Jong Chul Kimb), Hirokazu Iidaa), Hiroshi Hamanaa), Koji Kumamotoc),
Hiyoshizo Kotsuki*c), and Ge¬rard Jenner*d)
a) Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba, 288-0025, Japan
(e-mail: kmatsumoto@cis.ac.jp)
b) Marine Biotechnology Laboratory, School of Earth and Environmental Sciences (BK21),
Seoul National University, Seoul 151-742, Korea
c) Faculty of Science, Kochi University, Kochi 780-8520, Japan
d
¬
¬
¬
) Laboratoire de Piezochimie Organique, Faculte de Chimie, Universite Louis Pasteur, 67008 Strasbourg,
France
Dedicated to Professor Rolf Huisgen, −Master of Cycloaddition×, on the occasion of his 85th birthday
For the first time, uncatalyzed, high-pressure (0.6 GPa) reactions with ketones have proven to be a
powerful way to perform the three-component Strecker synthesis of a-amino nitriles in high yields. Two types of
double Strecker reactions were achieved, but attempts to perform triple Strecker reactions were unsuccessful.
1. Introduction. The synthesis of organic chemicals has reached a high degree of
skillfulness. Improved analytical and separation methods contribute to more-efficient
synthetic steps. Recently, Wender et al. gave a definition of −ideal synthesis× [1]. Such a
synthesis should lead to the desired product in as few steps as possible, in good overall
yield, and by means of environmentally compatible reagents. The synthetic variables
that have to be optimized are time, costs, overall yield, simplicity of performance,
safety, and environmental acceptability. Reactions in which more than two starting
compounds react to form a product in such a way that the majority of the atoms of the
material can be found in the product are called multicomponent reactions (MCRs) [2
4] (for most-recent examples on MCRs, see [5]). This rough definition is suitable to
distinguish MCRs from traditional two-component reactions and domino reactions, in
which usually only one or two starting compounds are converted. A more-sophisticated
view is introduced in Table 1. In multistep syntheses, the temporal and preparative
complexity increases in proportion to the number of steps in a first approximation.
These aspects are reflected in many isolation and purification operations, such as
crystallization, extraction, distillation, or chromatography. Besides the multistep
sequential synthesis of a target molecule, the desired product can often also be obtained
Table 1. Basic Types of Multicomponent Reactions
Type
General reaction scheme
I
II
III
A ‡ B > C > ... O > P
A ‡ B > C > D... O ! P
A ! B ‡ C ! D ! ... O ! P
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 88 (2005)
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in one-pot reactions of three or more starting compounds. Therefore, MCRs are very
efficient in organic synthesis, and have represented a rapid upsurge in the literature.
The increasing interest in MCRs is best illustrated by the number of articles per year
on the topic (Fig. 1). MCRs in which starting compounds, intermediates, and products
are in a mobile equilibrium are classified as type-I reactions (Table 1). As different
states of balance can prevail, yields between 0 and 100% are possible. In most cases, the
products occur as mixtures with intermediates and starting materials, and are difficult
to isolate. As the reaction often is incomplete, side reactions may lead to further
impurities.
Fig. 1. Number of publications on multicomponent reactions between 1967 and 2004
MCRs whose elementary reactions are reversible or partially irreversible, and
whose last reaction step is irreversible, are type-II processes. Reactions of this type are
preparatively advantageous, as the total equilibrium is shifted to the side of the
products by the last irreversible step. Such irreversible steps are, e.g., the result of
strongly exothermic reactions such as the conversion of isocyanides, ring-closure
reactions, or aromatizations.
MCRs of type III are sequences of irreversible elementary reactions. They seldom
occur in preparative chemistry. Biochemical reactions in the living world typically fall
into this category. Many of these reactions are de facto irreversible partial reactions,
due either to the thermodynamic circumstances or to the combination of endothermal
with exothermal processes. These reactions correspond to enzymatically accelerated
and mostly highly selective reactions, so that significant amounts of side products are
rarely formed. Should this, nevertheless, be the case, the side products are eliminated
enzymatically and returned to the circuit. It must be considered in the above
classification that these are idealizations. Many reactions cannot be assigned to one of
the classes, rather the transitions are fluid.
In the following, the history and historical development of MCRs over the last
150 years are outlined. The Strecker synthesis of a-amino acids via a-amino nitriles was
first published in 1850; it is generally considered to be the first MCR. However, in the

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reaction of bitter almond oil and ammonia, twelve years earlier, Laurent and Gerhardt
isolated a poorly soluble product that had evolved in an MCR. In this reaction
(Scheme 1), benzaldehyde, HCN, and NH3 first react to the amino nitrile 1, which then
reacts with a second equivalent of benzaldehyde to give the Schiff base 2.
Scheme 1. Classical Strecker Reaction
Important heterocyclic compounds were first synthesized by Radziszewski and
Hantzsch more than 100 years ago in a MCR. Particularly, Hantzsch synthesized 1,4-
dihydropyridines such as 3 from NH3, aldehydes, and 3-oxobutanoates (Scheme 2). A
very powerful dihydropyridine derivative (nifedipine) for the therapy of cardiovascular
disease was developed at Bayer, based on the Hantzsch synthesis. Also, Mannich and
Ugi type reactions proved to be extremely valuable for the total synthesis of natural
products. Some more-important MCRs are listed in Table 2.
Scheme 2. Hantzsch Synthesis of 1,4-Dihydropyridine
Sequential double reactions are characterized by their great elegance, frequently
high stereoselectivity, and the simple manner in which they may be carried out. They
permit complex molecules to be constructed in one-pot or only a few steps [6 8]. For
example, Scheiber and Nemes [9] synthesized the tricyclic diamino ketone from
octahydro-2H-quinolizin-2-one by a double Mannich condensation (Scheme 3). Ihara
and Fukumoto [10] examined the intramolecular double Michael reaction by using
several bases (Scheme 4).
Scheme 3. Double Mannich Reaction

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Table 2. Historically Significant Multicomponent Reactions
Name
Discovery
1850
Example
Strecker synthesis
Radziszewski
imidazole synthesis
1882
1890
Hantzsch
pyrrole synthesis
Biginelli reaction
Mannich reaction
1891
1912
1941
Bucherer Bergs
hydantoin synthesisa)
Ugi reaction
1959
a) Tˆ Thymine
The development of this type of synthetic method can lead to a reduction in the
amount of undesired by-products, thereby contributing to the protection of the
environment. That is, the quantity of solvents and eluents required in comparison with
stepwise processes is considerably reduced. Sequential reactions should, therefore, be
more-frequently included in future synthetic planning. In some cases, biogenesis could
serve as a prototype, but fundamentally new reaction types must also be developed.

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Scheme 4. Intramolecular Double Michael Reaction
MCRs under high pressure have hardly been studied1) [12]. For example, Yamada
et al. [11e,f] reported the surprising result that a yield of 63 % of the sterically crowded
tripeptide 4 was achieved in a modified Ugi reaction at high pressure (0.9 GPa;
Scheme 5). The b-amino ester derivatives 5 were obtained by Reiser and co-workers
from aldehydes, phosphonates, and N-nucleophiles at 0.8 GPa (Scheme 6) [12].
Scheme 5. Four-Component Ugi Reaction at High Pressure
Scheme 6. Horner Wadsworth Emmons Michael Domino Reaction at High Pressure
However, high-pressure effects in Strecker syntheses have not been investigated,
although a-amino nitriles have been prepared for 150 years, since their discovery by
Strecker. Therefore, we now wish to report, in full detail, on high-pressure-mediated
multicomponent Strecker reaction of ketones with amines and trimethylsilyl cyanide
(Me3SiCN)2).
2. Results and Discussion.
Generally, the Strecker reaction without catalyst
involves aldehydes as carbonyl compounds [14 16]3). The analogous reactions with
ketones have been rarely studied due to slow or even very slow reaction rates (probably
due to steric hindrance). Thus, it was anticipated that ketones in comparison to
1
)
For examples of high-pressured-promoted MCRs, see [11a 11d] (Mannich reaction), [11e,f] (Ugi
reaction), and [11g,h] (Passerini reaction).
For preliminary communication, see [13].
2
3
)
)
For recent examples, see [16b e].

Helvetica Chimica Acta Vol. 88 (2005)
1739
aldehydes would react under high pressure. In the case of Michael and related reactions,
the strength of the base was considered, because a carbanion could be obtained from a
ketone by deprotonation with the amine. Although this formation of the carbanion was
very slow under thermal conditions, it was greatly accelerated at high pressure [17]. By
the attack of the carbanion on the carbonyl C-atom of another ketone, the aldol
reaction itself can be accelerated by high pressure [18]. Therefore, aromatic amines of
very weak basicity were examined to minimize formation of aldol by-products.
Me3SiCN was used as the CN group donor. It readily reacts with ketones in the
presence of a Lewis acid to form the corresponding organosilicon adducts. However, no
reaction between a ketone and Me3SiCN in the absence of a catalyst, neither at
atmospheric nor at high pressure, has been reported [19]. For example, in the absence
of catalyst, the cyanosilylation of aromatic ketones by Me3SiCN did not proceed at
0.1 MPa or 0.3 GPa, i.e., at 1 atm or 300 atm, respectively. However, when an Et2O
solution of LiClO4 was used, the reaction product was obtained at atmospheric pressure
in 98% yield (Scheme 7).
Scheme 7. Cyanosilylation of Aromatic Ketones with Me3SiCN
In the present MCRs, toluene was used as an apolar, aprotic, stable solvent so as not
to influence the reaction under high pressure.
First, the effect of pressure change on multicomponent Strecker reactions was
investigated with acetophenone, aniline, and Me3SiCN in toluene (Scheme 8). The
product 6 was obtained under pressures ranging from atmospheric pressure to 0.6 GPa.
The MCR did not take place at atmospheric pressure, whereas increased pressure
resulted in the accelerated formation of product. A very dramatic effect of increasing
pressure from 0.4 to 0.6 GPa was observed, as can be seen from Fig. 2. Similar results
have been reported by Jenner [20], and Dauben et al. [21].
Scheme 8. Strecker Reaction with Acetophenone, Aniline, and Me3SiCN

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Fig. 2. Effect of pressure on multicomponent Strecker reaction. Conditions as in Table 3.
Next, a Strecker MCR with several ketones was examined at 0.6 GPa and 308. The
results are summarized in Tables 3 and 4. The reactions under high pressure were
dependent on the substituent of the ketone. On the whole, when the chain length of
ketones increased (Table 3, Entries 1 3), the yield of compounds 7 was slightly
reduced because of the increase in volume. Changes from aliphatic to aromatic
Table 3. Synthesis of a-Amino Nitriles from Aliphatic Ketones, Aniline, and Me3SiCN at 0.6 GPa and 308 for 24 h
Entry
1
R1
R2
Product
No.
Yielda) [%]
99b)
Me
Me
7a
2
3
Me
Et
Et
Et
7b
7c
98
95
4
5
À(CH2)5À
7d
7e
97
À(CH2)12
À
94c)
a) Yields of isolated material based on ketones. b) Yield of 22% at atmospheric pressure and r.t. c) For 48 h.

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Table 4. Synthesis of a-Amino Nitriles from Aromatic Ketones, Aniline, and Me3SiCN at 0.6 GPa and 308 for
24 h
Entry
1
R1
R2
Ph
Product
No.
Yielda) [%]
88
Me
7f
2
Me
4-Me-C6H4
7g
82
3
4
Me
Me
1-Naphthyl
2-Naphthyl
7h
68
96
7i
5
6
Me
Ph
9-Anthracenyl
Ph
0
0
7
Bn
Bn
7j
60b)
8
Et
Ph
7k
81
a) Yields of isolated material. b) At 258.

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substituents (Table 4) generally resulted in reduced yields. These results are probably
attributed to the increasing steric hindrance around the carbonyl C-atom, and
stabilization through delocalization.
Interestingly for acetonaphthones (Table 4, Entries 3 and 4), good yields were
obtained in contrast to methyl anthracen-9-yl ketone and benzophenone (Entries 5 and
6). The reaction leading to 7h was faster than that affording 7i, and in the latter, a more-
stable intermediate was formed. The lower yield of 7h, in turn, is due to steric
hindrance (peri-H effect). These results are in good agreement with those for other
ketones. It is apparent that this reaction was retarded by steric hindrance as well as by
stabilization through the delocalization of the aromatic substituent of the ketone. At
first, it was expected that the addition of aniline to methyl 1-naphthyl ketone could
produce a more-compact Schiff base as an intermediate than that from other ketones
because of the volume reduction under high pressure. In the classical Strecker reaction,
cyanohydrins [22][23] or imines [24][25] (via iminium ions) were formed as
intermediates (Scheme 9) [26]. However, the low yield of 7h (Table 4) suggests that
a Schiff base was not formed in the present case. Investigations by Merino and co-
workers [27] on a-amino nitrile synthesis, by addition of Me3SiCN to charge-developed
nitrone systems, showed that addition of CNÀ took place without Lewis acids in good
yields (Scheme 10).
It is interesting that the yield of 7i (Table 4) was better than that of 7f (Table 4).
This is perhaps evidence that an iminium ion, which is more stable because of the
resonance effect, is formed as an intermediate. Hence, it is likely that the aniline N-
atom attacks the CˆO group of the ketone to produce an amino alcohol, which, via an
iminium ion (not an imine), affords the a-amino nitrile by subsequent addition of CNÀ
(Scheme 11).
Next, Strecker reaction with N-methylaniline was examined under high pressure,
the base strength of N-methylaniline being similar to that of aniline. When acetone and
acetophenone were used as ketones, the reactions, unfortunately, did not take place. We
think that the inactivity of N-methylaniline is due to the steric hindrance of the N-
methyl group. Therefore, Strecker reactions of sterically hindered amines with
aldehydes and Me3SiCN will be the subject of future communications.
In the early days of organic synthesis, only simple molecules could be prepared by
rational design. However, over the years, the need for more-complex molecules has
arisen in many areas of sciences and technologies. Complex molecules could be
synthesized elegantly via sequential double reactions like double Mannich (for recent
examples, see [28]), double Michael (for a review, see [29a]; for recent examples, see
[29b d]), and double Diels Alder reactions (for recent examples, see [30a c]; for
examples of double (or consecutive) 1,3-dipolar cycloadditions from our studies, see
[30d g]). However, double Strecker reactions have been studied less often. For
instance, Takahashi et al. [31] reported that double Strecker reaction of glutaraldehyde
with hydrazine or ethane-1,2-diamine gave heterocyclic 1-amino- or 1-(2-aminoethyl)-
2,6-dicyanopiperidine. Gibson and co-workers [32] prepared acyclic bis(a-amino
nitriles) from aldehyde, sodium bisulfite, amine, and NaCN in high yields by double
Strecker reaction. These reactions involved aldehydes as the carbonyl compound (for
recent examples of double Strecker reactions, see [33]). To our knowledge, no double
Strecker reaction based on ketones has been investigated.

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Scheme 9. Comparative Mechanism of Strecker Synthesis and Related Reactions
Scheme 10. Addition of Me3SiCN to a Charge-Developed System
First, a double Strecker reaction with 1,4-diacetylbenzene, aniline, and Me3SiCN
was attempted under various conditions. The results are summarized in Table 5. 1,4-
Diacetylbenzene was almost inert at room temperature and atmospheric pressure, even
in dipolar solvents. However, at 308 and 0.6 GPa, solvent polarity was found to be

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Scheme 11. Plausible Mechanism of Three-Component Strecker Reaction
crucial. Investigations of the contributions of solvent polarity were performed by
employing the empirical solvent-polarity parameter ET of Reichardt, which is based on
solvatochromism of a pyridinium-N-phenoxide betain [34 36]. The ENT values for
toluene, CH2Cl2, and MeCN are 0.099, 0.309, and 0.460, respectively. At high pressure,
increasing solvent polarity led to an increase in the yield of 8, with an excellent
correlation between ENT and yield (Fig. 3).
A similar reaction, but with an aliphatic 1,2-diketone, aniline, and Me3SiCN
succeeded at 308 and 0.6 GPa in toluene. However, only 25% of product 9 was obtained
(Scheme 12).
1,4-Diaminobenzene also underwent another type of double Strecker reaction, with
different ketones and Me3SiCN in MeCN at 308 and 0.6 GPa (Table 6). When the bulk
of substituents around the CˆO group increased, the yield was reduced because of
increased steric hindrance. The yield of product 10b was lower than that of 10a,
although the single multicomponent Strecker reaction of cyclohexanone proceeded in
excellent yield. In organic solvents, 10b is very unstable, and it is considered that the
low yield of this product is due to its instability.

Helvetica Chimica Acta Vol. 88 (2005)
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Table 5. High-Pressure and Solvent Effects on Double Strecker Reaction with 1,4-Diacetylbenzene, Aniline, and
Me3SiCN
Entry
Pressure [GPa]
Solvent
Temp. [8]
Time [h]
Yielda) [%]
1
2
3
4
5
6
a.p.b)
a.p.
0.6
0.6
0.6
THF
r.t.
r.t.
30
30
30
30
72
24
24
48
24
24
0
5
0
0
48
93
MeCN
Toluene
Toluene
CH2Cl2
MeCN
0.6
a) Yields of isolated material based on diketone. b) Ambient pressure.
Fig. 3. Correlation between solvent polarity (in terms of ENT ) and product yield in the high-pressure reaction of
1,4-diacetylbenzene with aniline and Me3SiCN
In contrast, methyl 1-naphthyl ketone was inert under these conditions. Similar
reactions of ketones with other benzenediamines were also feasible (Table 7). For
instance, acetone underwent a four-component double Strecker reaction in excellent
yield, also providing the single Strecker product 11e, which, however, was not stable
enough for elemental analysis.

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Scheme 12. Double Strecker Reaction with Butane-2,3-dione
Table 6. Synthesis of Bis(a-Amino Nitriles) with Benzene-1,4-diamine, Ketones, and Me3SiCN at 0.6 GPa and 308
for 48 h
Entry
1
Ketone
Product
Yielda) [%]
77
10a
2
3
4
10b
10c
53
27
0
a) Yields of isolated material based upon benzene-1,4-diamine.
Unfortunately, triple Strecker reactions were unsuccessful in our hands
(Scheme 13). Further work on application of the present approach to synthesize a
variety of heterocyclic compounds in one pot is now in progress.
3. Conclusions. Strecker multicomponent reactions (MCRs) under high pressure
between ketones, aromatic amines, and Me3SiCN in the absence of catalyst were
investigated. First of all, the effect of pressure change on Strecker MCRs was disclosed
with acetophenone, aniline and Me3SiCN in toluene. Increased pressure led to
accelerated formation of product, especially at 0.4 GPa to 0.6 GPa. Next, Strecker
MCRs with different ketones were examined at 0.6 GPa and 308. In general, the yield

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Table 7. Synthesis of Bis(a-Amino Nitriles) from Benzenediamines, Ketones, and Me3SiCN at 0.6 GPa and 308
for 48 h
Entry
1
Ketone
1,3-and 1,2-Diaminobenzene
Product
Yielda) [%]
90
11a
2
11b
11c
11d
11e
40
7
3
4b)
91
9
a) Yields of isolated material based on diaminobenzene. b) 24 h.
was slightly reduced, when the chain length of the ketones increased. Intriguingly, the
yield of the product in the case of methyl 2-naphthyl ketone was better than that of
methyl phenyl ketone (acetophenone). Thus, presumably, the intermediary iminiun
ion, which is more stable because of resonance effects, is formed. A plausible reaction
mechanism involves attack of the aniline N-atom at the carbonyl C-atom of the ketone
to produce an amino alcohol, which gives an iminium ion (not a Schiff base), to which
finally CNÀ adds to afford the a-amino nitrile.
Double Strecker reactions were also shown to be useful under high pressure. The
solvent effect of this reaction with 1,4-diacetylbenzene, aniline, and Me3SiCN was
examined. Toluene, THF, CH2Cl2, and MeCN were used as solvents. An excellent

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Scheme 13. Attempted Triple Strecker Reaction under High Pressure
linear correlation between solvent polarity (ENT ) and yield was found, which indicates
that the high-pressure double Strecker reaction is sensitive to solvent polarity.
This work was supported, in part, by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan (to H. K. and K. M.). The authors are also grateful to the
Ministry of Education, Culture, Sports, Science, and Technology, Japan, for purchasing high-field NMR
instruments (JEOL JNM-A500 and JNM-EX270) by the special fund to K. M. (Graduate School of Human and
Environmental Studies, Kyoto University) in 1992. This work was also supported, in part, by a Grant-in-Aid for
Encouragement of Young Scientists (B, No. 16710157) from the Japan Society for the Promotion of Science (to
H. I.). Finally, H. I. extends his gratitude to Sasakawa Scientific Research Grants (Nos. 6-182 and 7-199K) and
Sasakawa Grants for Science Fellows (No. F 02-109) from the Japan Science Society for supporting this research.
Experimental Part
General. High-pressure reactions: KP10 or KP15 instruments (Hikari High Press, Inc., Hiroshima). M.p.:
Yanaco MP-J3 micro-melting-point apparatus; uncorrected. IR Spectra: Shimadzu FTIR-8600 PC or JASCO
1
FT-IR 5300 spectrophotometers; in cmÀ1. H- and 13C-NMR Spectra: JEOL JNM-Ex 270 (270 and 67.8 MHz,
resp.) or JEOL JNM-A 500 (500 and 125.65 MHz, resp.), or JEOL LA400 (400 and 100 MHz, resp.); in CDCl3
with Me4Si as internal standard; d in ppm, J in Hz. Mass spectroscopic data are given in m/z.
Synthesis of 2-Methyl-2-(phenylamino)propanenitrile (7a) at High Pressure. A soln. of acetone (349 mg,
6.0 mmol), aniline (466 mg, 5.0 mmol), and Me3SiCN (595 mg, 6.0 mmol) in toluene (6 ml) was placed in a
Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric pressure, the
capsule was opened. A mixture of a yellow solid and a small amount of soln. was obtained. The solvent was
removed by evaporation under reduced pressure. Cyclohexane (6 ml) was added, the solid was filtered off, and
dried in vacuum to afford 793 mg of 7a (99%, based on aniline). Recrystallization from EtOH/H2O 85 :15 gave
colorless crystals. M.p. 94 958. IR (KBr): 3373, 3030, 2235 (CN). 1H-NMR (270 MHz): 1.71 (s, 6 H); 3.68 (br. s,
1 H); 6.91 7.29 (m, 5 H). 13C-NMR (125.65 MHz): 28.2; 49.1; 117.6; 120.9; 121.8; 129.2; 143.3. MS: 160, 145,
133. Anal. calc. for C10H12N2: C 74.97, H 7.55, N 17.48; found: C 75.13, H 7.59, N 17.58.
Synthesis of 7a at Atmospheric Pressure. A soln. of acetone (349 mg, 6.0 mmol), aniline (466 mg,
5.0 mmol), and Me3SiCN (595 mg, 6.0 mmol) in toluene (6 ml) was placed in one-neck flask, which was
perfectly sealed. The mixture was stirred at r.t. for 24 h. The solvent was removed by evaporation under reduced
pressure. Cyclohexane (6 ml) was added, the solid was filtered off, and dried to afford 7a (173 mg, 22%).
2-Methyl-2-(phenylamino)butanenitrile (7b). A soln. of butan-2-one (433 mg, 6.0 mmol), aniline (466 mg,
5.0 mmol), and Me3SiCN (595 mg, 6.0 mmol) in toluene (6 ml) was placed in a Teflon capsule. Pressure was
applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric pressure, the capsule was cooled to 08. A
yellow solid and a small amount of soln. were obtained. The solvent was removed by evaporation under reduced
pressure at 15 208. Cyclohexane (6 ml) was added, the solid was filtered off, dried in vacuum, and
chromatographed (SiO2; hexane/AcOEt 80 :20) to afford 7b (851 mg, 98%, based on aniline). Recrystallization

Helvetica Chimica Acta Vol. 88 (2005)
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1
from EtOH/H2O 80 :20 gave white crystals. M.p. 45 468. IR (KBr): 3364, 2982, 2237 (CN). H-NMR (270 MHz,
CDCl3): 1.14 (t, J ˆ 7.6, 3 H); 1.63 (s, 3 H); 1.84 2.06 (m, 2 H); 3.61 (br. s, 1 H); 6.87 7.29 (m, 5 H). 13C-NMR
(125.65 MHz): 8.54; 25.2; 33.6; 53.5; 117.3; 120.5; 121.3; 129.1; 143.6. Anal. calc. for C11H14N2: C 75.82, H 8.10, N
16.08; found: C 75.92, H 8.06, N 16.34.
2-Ethyl-2-(phenylamino)butanenitrile (7c). A soln. of pentan-3-one (258 mg, 3.0 mmol), aniline (279 mg,
3.0 mmol), and Me3SiCN (357 mg, 3.6 mmol) in toluene (3.5 ml) was placed in a Teflon capsule. Pressure was
applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric pressure, the capsule was cooled to 08. A
yellow solid and a small amount of soln. were obtained. The solvent was removed by evaporation under reduced
pressure at 15 208. Cyclohexane (3 ml) was added, the solid was filtered off, dried in vacuum, and
chromatographed (SiO2; hexane/AcOEt 80 :20) to afford 7c (536 mg, 95%, based on ketone). Recrystallization
from EtOH/H2O 80 :20 gave white crystals. M.p. 518. IR (KBr): 3358, 2968, 2241 (CN). 1H-NMR (270 MHz):
1.07 (t, J ˆ 7.6, 6 H); 1.84 2.07 (m, 4 H); 3.55 (br. s, 1 H); 6.85 7.26 (m, 5 H). 13C-NMR (125.65 MHz): 8.04;
29.6; 57.6; 116.9; 120.2; 120.9; 129.1; 143.8. Anal. calc. for C11H14N2: C 76.55, H 8.57, N 14.88; found: C 76.66, H
8.49, N 14.84.
1-(Phenylamino)cyclohexane-1-carbonitrile (7d). A soln. of cyclohexanone (982 mg, 10.0 mmol), aniline
(931 mg, 10.0 mmol), and Me3SiCN (1.191 g, 12.0 mmol) in toluene (8 ml) was placed in a Teflon capsule.
Pressure was applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric pressure, the capsule was
opened. A yellow solid and a small amount of soln. were obtained. The solvent was removed by evaporation
under reduced pressure at 15 208. Cyclohexane (8 ml) was added, the solid was filtered off, dried in vacuum,
and chromatographed (SiO2 ; hexane/AcOEt 80 :20) to afford 7d (1.94 g, 97%, based on ketone).
Recrystallization from EtOH/H2O 85 :15 gave white crystals. M.p. 75 768. IR (KBr): 3354, 2934, 2226 (CN).
1H-NMR (270 MHz): 1.55 1.80 (m, 8 H); 2.33 (m, 2 H); 3.61 (br. s, 1 H); 6.90 7.24 (m, 5 H). 13C-NMR
(125.65 MHz): 22.2; 24.9; 36.7; 54.4; 117.7; 120.7; 121.1; 129.2; 143.5. Anal. calc. for C13H16N2: C 77.96, H 8.05, N
13.99; found: C 78.10, H 8.11, N 14.17.
1-(Phenylamino)cyclotridecane-1-carbonitrile (7e). A soln. of cyclotridecanone (506 mg, 97%, 2.5 mmol),
aniline (233 mg, 2.5 mmol), and Me3SiCN (298 mg, 3.0 mmol) in toluene (2.5 ml) was placed in a Teflon capsule.
Pressure was applied at 0.6 GPa and 308 for 48 h. After returning to atmospheric pressure, the capsule was
opened. A yellow solid and a small amount of soln. were obtained. The solvent was removed by evaporation
under reduced pressure at 15 208. Cyclohexane (3 ml) was added, the solid was filtered off, and dried in
vacuum to afford 7e (0.70 g, 94%, based on ketone). Recrystallization from toluene gave white crystals. M.p.
1
135 1368. IR (KBr): 3381, 2928, 2241 (CN). H-NMR (270 MHz): 1.36 (s, 20 H); 1.97 (m, 4 H); 3.63 (br. s, 1 H);
6.87 7.24 (m, 5 H). 13C-NMR (125.65 MHz): 20.5; 25.15; 25.22; 26.3; 26.9; 35.3; 55.7; 116.4; 119.9; 121.2; 129.1;
143.5. Anal. calc. for C13H16N2: C 80.48, H 10.13, N 9.39; found: C 80.29, H 9.95, N 9.28.
2-Phenyl-2-(phenylamino)propanenitrile (7f). A soln. of acetophenone (481 mg, 4.0 mmol), aniline
(373 mg, 4.0 mmol), and Me3SiCN (476 mg, 4.8 mmol) in toluene (4 ml) was placed in a Teflon capsule. Pressure
was applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric pressure, the capsule was opened. A
yellow solid and a small amount of soln. were obtained. The solvent was removed by evaporation under reduced
pressure at 20 258. Cyclohexane (5 ml) was added, the solid was filtered off, and dried in vacuum to afford 7f
(780 mg, 88%, based on ketone). Recrystallization from EtOH/H2O 80 :20 gave white crystals. M.p. 139 1408.
IR (KBr): 3387, 2990, 2228 (CN). 1H-NMR (270 MHz): 1.95 (s, 3 H); 4.27 (br. s, 1 H); 6.52 7.64 (m, 10 H).
13C-NMR (125.65 MHz): 33.4; 57.1; 115.8; 120.0; 120.7; 124.9; 128.6; 129.0; 129.2; 139.9; 143.5. Anal. calc. for
C15H14N2: C 81.05, H 6.35, N 12.60; found: C 81.06, H 6.39, N 12.59.
2-(4-Methylphenyl)-2-(phenylamino)propanenitrile (7g). A soln. of methyl 4-methylphenyl ketone
(1.342 g, 10.0 mmol), aniline (931 mg, 10.0 mmol), and Me3SiCN (1.489 g, 15.0 mmol) in toluene (8 ml) was
placed in a Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric
pressure, the capsule was opened. A yellow solid and a small amount of soln. were obtained. The solvent was
removed by evaporation under reduced pressure at 20 258. Cyclohexane (8 ml) was added, the solid was
filtered off, and dried in vacuum to afford 7g (1.94 g, 82%, based on ketone). Recrystallization from EtOH/H2O
80 :20) gave white crystals. M.p. 128 1298. IR (KBr): 3387, 2986, 2228 (CN). 1H-NMR (270 MHz): 1.93 (s, 3 H);
2.36 (s, 3 H); 4.25 (br. s, 1 H); 6.53 7.51 (m, 9 H). 13C-NMR (125.65 MHz): 21.0; 33.3; 56.8; 115.5; 119.7; 120.6;
124.6; 128.7; 129.6; 136.7; 138.2; 143.3. Anal. calc. for C15H14N2: C 81.32, H 6.82, N 11.85; found: C 81.42, H 6.90,
N 11.75.
2-(Naphthalen-1-yl)-2-(phenylamino)propanenitrile (7h). A soln. of methyl naphthalen-1-yl ketone
(851 mg, 5.0 mmol), aniline (466 mg, 5.0 mmol), and Me3SiCN (595 mg, 6.0 mmol) in toluene (6 ml) was
placed in a Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric
pressure, the capsule was opened. A yellow solid and a small amount of soln. were obtained. The solvent was

1750
Helvetica Chimica Acta Vol. 88 (2005)
removed by evaporation under reduced pressure at 20 258. Cyclohexane (6 ml) was added, the solid was
filtered off, and dried in vacuum to afford 7h (931 mg, 68%, based on ketone). Recrystallization from EtOH
gave white crystals. M.p. 124 1268. IR (KBr): 3373, 3003, 2230 (CN). 1H-NMR (270 MHz): 2.25 (s, 3 H);
4.35(br. s, 1 H); 6.64 8.83 (m, 12 H). 13C-NMR (125.65 MHz): 30.3; 57.8; 116.3; 120.3; 121.2; 124.3; 125.09;
125.14; 125.9; 126.5; 129.0; 129.3; 129.4; 130.2; 133.3; 134.8; 143.6. Anal. calc. for C15H14N2: C 83.79, H 5.92, N
10.29; found: C 83.71, H 5.98, N 10.24.
2-(Naphthalen-2-yl)-2-(phenylamino)propanenitrile (7i). A soln. of methyl naphthalen-2-yl ketone
(511 mg, 3.0 mmol), aniline (279 mg, 3.0 mmol), and Me3SiCN (357 mg, 3.6 mmol) in toluene (3 ml) was
placed in a Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric
pressure, the capsule was opened. A yellow solid and a small amount of soln. were obtained. The solvent was
removed by evaporation under reduced pressure at 20 258. Cyclohexane (3 ml) was added, the solid was
filtered off, and dried in vacuum to afford 7i (801 mg, 98%, based on ketone). Recrystallization from EtOH
gave white crystals. M.p. 176 177. IR (KBr): 3381, 2988, 2228 (CN). 1H-NMR (270 MHz): 2.02 (s, 3 H); 4.34
(br. s, 1 H); 6.57 8.14 (m, 12 H). 13C-NMR (500 MHz): 33.3; 57.4; 115.9; 120.1; 120.7; 122.1; 124.4; 126.7; 127.7;
128.3; 129.1; 129.4; 133.2; 133.3; 137.4; 143.5. MS: 272, 245, 230, 118, 77. Anal. calc. for C15H14N2: C 83.79, H 5.92,
N 10.29; found: C 83.51, H 6.08, N 10.17.
3-Phenyl-2-(phenylamino)-2-(phenylmethyl)propanenitrile (7j). A soln. of 1,3-diphenylpropan-2-one
(1.893 g, 9.0 mmol), aniline (838 mg, 9.0 mmol), and Me3SiCN (1.071 g, 10.8 mmol) in toluene (8 ml) was
placed in a Teflon capsule. Pressure was applied at 0.6 GPa and 258 for 24 h. After returning to atmospheric
pressure, the capsule was cooled to 08. Ayellow solid and a small amount of soln. were obtained. The solvent was
removed by evaporation under reduced pressure at 15 208. Cyclohexane (8 ml) was added, the solid was
filtered off, and dried in vacuum to afford 7j (1.68 g, 60%, based on ketone). Recrystallization from EtOH gave
white crystals. M.p. 130 1318. IR (KBr): 3337, 3032, 2245 (CN). 1H-NMR (270 MHz): 3.16 (dd, J ˆ 13.8, 30.5,
4 H); 3.76 (br. s, 1 H); 6.90 7.38 (m, 15 H). 13C-NMR (125.65 MHz): 43.5; 47.5; 117.8; 120.7; 127.0; 127.4; 127.8;
128.3; 128.9; 130.2; 130.5. Anal. calc. for C15H14N2: C 84.58, H 6.45, N 8.97; found: C 84.69, H 6.66, N 8.83.
2-Phenyl-2-(phenylamino)butanenitrile (7k). A soln. of ethyl phenyl ketone (671 mg, 5.0 mmol), aniline
(466 mg, 5.0 mmol), and Me3SiCN (695 mg, 7.0 mmol) in toluene (5 ml) was placed in a Teflon capsule. Pressure
was applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric pressure, the capsule was opened. A
yellow solid and a small amount of soln. were obtained. The solvent was removed by evaporation under reduced
pressure at 20 258. Cyclohexane (5 ml) was added, the solid was filtered off, and dried in vacuum to afford 7k
(780 mg, 88%, based on ketone). Recrystallization from EtOH/H2O 80 :20 gave white crystals. M.p. 142 1438.
IR (KBr): 3381, 2970, 2237 (CN). 1H-NMR (270 MHz): 1.06 (t, J ˆ 7.6, 3 H); 2.15 (m, 2 H); 4.27 (br. s, 1 H);
6.52 7.60 (m, 10 H). 13C-NMR (125.65 MHz): 8.8; 38.4; 62.1; 115.7; 119.9; 125.7; 128.6; 128.99; 129.03; 138.3;
143.6. Anal. calc. for C16H16N2: C 81.32, H 6.82, N 11.85; found: C 81.39, H 6.81, N 11.93.
2,2'-(1,4-Phenylene)bis[2-(phenylamino)propanenitrile] (8). A soln. of 1,4-diacetylbenzene (243 mg,
1.5 mmol), aniline (279 mg, 3.0 mmol), and Me3SiCN (357 mg, 3.6 mmol) in MeCN (3 ml) was placed in a
Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 24 h. After returning to atmospheric pressure, the
capsule was opened. A yellow solid and a small amount of soln. were obtained. The solvent was removed by
evaporation under reduced pressure at 20 258. Cyclohexane (3 ml) was added, and the solid was filtered off,
washed with anh. Et2O, and dried in vacuum to afford 8 (93%, based on diketone) as a white solid. M.p. 208
210. IR (KBr): 3381, 3055, 2228 (CN). 1H-NMR (270 MHz): 1.95 (s, 6 H); 4.29 (br. s, 2 H); 6.50 (d, J ˆ 7.8, 4 H);
6.81 (t, J ˆ 7.6, 2 H); 7.11 (t, J ˆ 7.3, 4 H); 7.66 (s, 4 H). 13C-NMR (125.65 MHz): 32.2; 56.2; 115.0; 118.2; 120.8;
125.5; 128.4; 140.8; 144.5. Anal. calc. for C24H22N4: C 78.66, H 6.05, N 15.29; found: C 78.45, H 6.04, N 15.32.
2,3-Dimethyl-2,3-bis(phenylamino)butane-1,4-dinitrile (9).
A soln. of butane-2,3-dione (215 mg,
2.5 mmol), aniline (466 mg, 5.0 mmol), and Me3SiCN (595 mg, 6.0 mmol) in toluene (8 ml) was placed in a
Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 48 h. After returning to atmospheric pressure, the
capsule was opened. A yellow solid and a small amount of soln. were obtained. The solvent was removed by
evaporation under reduced pressure at 20 258. Cyclohexane (5 ml) was added, the solid was filtered off, washed
with toluene, and dried in vacuum to afford 9 (25%, based on diketone) as a white solid. M.p. 125 1268. IR
(KBr): 3360, 3053, 2249 (CN). 1H-NMR (270 MHz): 1.72 (s, 6 H); 4.24 (br. s, 2 H); 7.16 7.40 (m, 10 H).
13C-NMR (125.65 MHz): 20.0; 62.5; 119.1; 124.7; 125.3; 129.5; 141.5. Anal. calc. for C24H22N4: C 74.46, H 6.25, N
19.30; found: C 74.22, H 6.38, N 19.01.
2,2'-(1,4-Phenylenediimino)bis(2-ethylbutanenitrile) (10a). A soln. of pentan-3-one (517 mg, 6.0 mmol),
1,4-phenylenediamine (315 mg, 2.9 mmol), and Me3SiCN (714 mg, 7.2 mmol) in MeCN (8 ml) was placed in a
Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 48 h. After returning to atmospheric pressure, the
capsule was opened. A solid and a small amount of soln. were obtained. The solvent was removed by

Helvetica Chimica Acta Vol. 88 (2005)
1751
evaporation under reduced pressure at 20 258. Cyclohexane (8 ml) was added, the solid was filtered off, washed
with anh. EtOH, and dried in vacuum to afford 10a (675 mg, 79%, based on diamine). M.p. 131 1328. IR (KBr):
3389, 2982, 2222 (CN). 1H-NMR (270 MHz): 1.07 (t, J ˆ 7.6, 12 H); 1.89 (m, 8 H); 3.31 (br. s, 2 H); 6.89 (s, 4 H).
13C-NMR (125.65 MHz): 8.0; 29.5; 58.8; 120.7; 121.4; 138.1. Anal. calc. for C18H26N4: C 72.44, H 8.78, N 18.77;
found: C 72.27, H 8.92, N 19.03.
1,1'-(1,4-Phenylenediimino)bis(cyclohexanecarbonitrile) (10b).
A soln. of cyclohexanone (295 mg,
3.0 mmol), 1,4-phenylenediamine (165 mg, 1.5 mmol), and Me3SiCN (357 mg, 3.6 mmol) in MeCN (3 ml)
was placed in a Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 48 h. After returning to atmospheric
pressure, the capsule was opened. A solid and a small amount of soln. were obtained. The solvent was removed
by evaporation under reduced pressure at 15 208. Cyclohexane (3 ml) was added, the solid was filtered off,
washed with anh. EtOH and cyclohexane, and dried in vacuum to afford 10b (253 mg, 53%, based on diamine).
M.p. 156 1588. IR (KBr): 3371, 2932, 2228 (CN). 1H-NMR (270 MHz): 1.57 2.24 (m, 20 H); 3.38 (br. s, 2 H);
6.91 (s, 4 H). 13C-NMR (125.65 MHz): 22.3; 25.0; 36.6; 55.5; 121.5; 138.2. Anal. calc. for C20H26N4: C 74.50, H
8.13, N 17.38; found: C 74.20, H 8.03, N 17.54.
2,2'-(1,4-Phenylenediimino)bis(2-phenylpropanenitrile) (10c).
A soln. of acetophenone (721 mg,
6.0 mmol), 1,4-phenylenediamine (315 mg, 2.9 mmol), and Me3SiCN (714 mg, 7.2 mmol) in MeCN (8 ml)
was placed in a Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 48 h. After returning to atmospheric
pressure, the capsule was opened. A solid and a small amount of soln. were obtained. The solvent was removed
by evaporation under reduced pressure at 20 258. Cyclohexane (8 ml) was added, and the solid was filtered off,
washed with anh. EtOH, and dried in vacuum to afford 10c (286 mg, 27%, based on diamine). M.p. 140 1428.
IR (KBr): 3389, 3001, 2232 (CN). 1H-NMR (270 MHz): 1.87 (s, 3 H); 6.39 7.58 (m, 7 H). 13C-NMR
(125.65 MHz): 32.4; 57.0; 115.5; 116.1; 124.6; 128.1; 128.9; 137.2; 141.0. MS: 366, 340, 326, 312, 297, 281, 195, 77.
2,2'-(1,3-Phenylenediimino)bis(2-ethylbutanenitrile) (11a). A soln. of pentan-3-one (517 mg, 6.0 mmol),
1,3-phenylenediamine (315 mg, 2.9 mmol), and Me3SiCN (714 mg, 7.2 mmol) in MeCN (8 ml) was placed in a
Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 48 h. After returning to atmospheric pressure, the
capsule was opened. A solid and a small amount of soln. were obtained. The solvent was removed by
evaporation under reduced pressure at 20 258. Cyclohexane (8 ml) was added, and the solid was filtered off,
washed with anh. EtOH, and dried in vacuum to afford 11a (806 mg, 90%, based on diamine). M.p. 107 1098.
IR (KBr): 3406, 2978, 2222 (CN). 1H-NMR (270 MHz): 1.07 (t, J ˆ 7.6, 12 H); 1.98 (m, 8 H); 3.55 (br. s, 2 H);
6.38 (dd, J ˆ 2.4, 7.8, 2 H); 6.48 (t, J ˆ 2.4, 1 H); 7.06 (t, J ˆ 8.1, 1 H). 13C-NMR (125.65 MHz): 8.0; 29.6; 57.4;
104.1; 108.7; 121.0; 130.0; 144.9. Anal. calc. for C18H26N4: C 72.44, H 8.78, N 18.77; found: C 72.49, H 8.59, N
18.67.
2,2'-(1,2-Phenylenediimino)bis(2-ethylbutanenitrile) (11b). A soln. of pentan-3-one (517 mg, 6.0 mmol),
1,2-phenylenediamine (324 mg, 3.0 mmol), and Me3SiCN (714 mg, 7.2 mmol) in MeCN (8 ml) was placed in a
Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 48 h. After returning to atmospheric pressure, 1n aq.
HCl soln. (50 ml) was added to the reaction mixture. The mixture was extracted with AcOEt, the org. layer was
dried (Na2SO4) and concentrated in vacuo at 20 258, and the residue was chromatographed (SiO2; hexane/
AcOEt 80 :20) to afford 11b as an oil (365 mg, 40%, based on diamine). IR (KBr): 3312, 2976, 2226 (CN).
1H-NMR (270 MHz): 1.06 (t, J ˆ 7.6, 12 H); 1.88 (m, 8 H); 3.90 (br. s, 2 H); 6.96 7.30 (m, 4 H). 13C-NMR
(125.65 MHz, CDCl3): 8.1; 29.4; 58.6; 120.0; 121.4; 122.8; 135.6. Anal. calc. for C18H26N4: C 72.44, H 8.78, N
18.77; found: C 72.16, H 8.67, N 18.72.
2,2'-(1,2-Phenylenediimino)bis(2-phenylpropanenitrile) (11c).
A soln. of acetophenone (721 mg,
6.0 mmol), 1,2-phenylenediamine (324 mg, 3.0 mmol), and Me3SiCN (714 mg, 7.2 mmol) in MeCN (8 ml)
was placed in a Teflon capsule. Pressure was applied at 0.6 GPa and 308 for 48 h. After returning to atmospheric
pressure, the capsule was opened. A solid and a small amount of soln. were obtained. The solvent was removed
by evaporation under reduced pressure at 20 258. Cyclohexane (8 ml) was added, the solid was filtered off,
washed with anh. EtOH, and dried in vacuum to afford 11c (72 mg, 7%, based on diamine). M.p. 143 1458. IR
(KBr): 3348, 2991, 2224 (CN). 1H-NMR (270 MHz): 1.98 (s, 6 H); 4.28 (br. s, 2 H); 6.72 7.65 (m, 14 H).
13C-NMR (125.65 MHz): 32.1; 57.9; 119.5; 121.2; 122.5; 125.0; 128.9; 129.3; 134.3; 139.5. MS: 366, 339, 324, 312,
297, 284, 195, 77. Anal. calc. for C24H22N4: C 78.66, H 6.05, N 15.29; found: C 78.44, H 6.18, N 15.35.
2,2'-(1,2-Phenylenediimino)bis(2-methylpropanenitrile) (11d). This compound was prepared in analogy to
11a in 91% yield. As a side product, 2-[(2-aminophenyl)amino]-2-methylpropanenitrile (11e) was obtained in
9% yield.
Data of 11d. Colorless solid. M.p. 80 828. IR (KBr): 3302, 2226 (CN), 1599, 1509. 1H-NMR (400 MHz):
1.64 (s, 12 H); 3.91 (br. s, 2 H); 7.02, 7.27 (2m, 2 Â 2 H). 13C-NMR (100 MHz) 27.95; 49.83; 120.14; 122.46;
123.12; 135.59. Anal. calc. for C14H18N4: C 69.39, H 7.49, N 23.12; found: C 69.15, H 7.68, N 23.05.

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Helvetica Chimica Acta Vol. 88 (2005)
Data of 11e. Colorless oil that decomposed at elevated temperatures. IR (neat): 3320, 2224, 1612, 1504,
1456. 1H-NMR (400 MHz): 1.62 (s, 6 H); 3.19 (br., 1 H); 3.70 (br., 2 H); 6.75 (dd, J ˆ 7.8, 1.5, 1 H); 6.79 (dt, J ˆ
7.8, 1.5, 1 H); 6.95 (dt, J ˆ 7.8, 1.2, 1 H); 7.28 (dd, J ˆ 7.8, 1.2, 1 H). 13C-NMR (100 MHz): 27.76; 50.62; 116.36;
119.36; 122.97; 123.11; 124.85; 130.14; 141.47.
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Received March 12, 2005