One-pot synthesis of α-aminonitriles from alkyl and aryl cyanides: a Strecker reaction via aldimine alanes

Article abstract of DOI:10.1016/j.tetlet.2009.02.004

A one-pot Strecker reaction using various alkyl, arylalkyl and arylnitriles is developed. Aldimine alanes were generated in situ from nitriles by the addition of diisobutylaluminium hydride, and were converted into the corresponding imines on reaction wit

Full text of DOI:10.1016/j.tetlet.2009.02.004

Tetrahedron Letters 50 (2009) 1844–1846
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of a-aminonitriles from alkyl and aryl cyanides:
a Strecker reaction via aldimine alanes
*
Szabolcs Sipos, István Jablonkai
Department of Applied Organic Chemistry, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences,
Pusztaszeri ut 59/67, H-1025 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot Strecker reaction using various alkyl, arylalkyl and arylnitriles is developed. Aldimine alanes
were generated in situ from nitriles by the addition of diisobutylaluminium hydride, and were converted
into the corresponding imines on reaction with (S)-(À)-1-phenylethylamine. Nucleophilic addition to the
imines in the presence of catalytic triethylamine, using acetone cyanohydrin as a cyanide source, pro-
Received 8 October 2008
Revised 16 January 2009
Accepted 4 February 2009
Available online 8 February 2009
vided a-aminonitriles.
Ó 2009 Elsevier Ltd. All rights reserved.
a-Aminonitriles are important intermediates of the Strecker
with ammonia or primary amines yielding Schiff bases.12,13 Based
reaction for preparing
a-amino acids. The classic Strecker reaction
on these findings, it was conceivable to prepare a-aminonitriles
is a three-component reaction involving condensation of an alde-
hyde, an ammonia and a cyanide followed by subsequent hydroly-
by reacting nitriles with DIBAL-H and then convert the resulting
alane complexes to imines by adding an amine followed by nucle-
ophilic addition of a cyanide to the intermediate imine.
sis of the resulting
a-aminonitrile. In addition, a-aminonitriles
have been applied in many organic transformations. Reduction of
Our objective was to develop a simple and efficient one-pot
the nitrile group provides a convenient method for the preparation
method for the synthesis of
a-aminonitriles starting from various
of 1,2-diamines.1
a
-Aminonitriles can undergo loss of cyanide to
form stable iminium ions from which variously substituted amines
have been synthesized.2
-Aminonitriles possessing an -hydro-
alkyl, aryl and arylalkyl cyanides, chiral amines and acetone cyano-
hydrin as the cyanide source. (S)-(À)-1-Phenylethylamine, which is
reported to induce asymmetry in Strecker reactions, was used as a
chiral inducing agent.14 Catalytic triethylamine was added since it
has been reported4 to catalyze the Strecker reaction in the pres-
ence of acetone cyanohydrin.
a
a
gen can be deprotonated and the carbanions formed are able to re-
act with various electrophiles.3
Typically, a-aminonitriles are prepared by the reaction of alde-
hydes with amines using various cyanides such as HCN, KCN,
TMSCN, (EtO)2P(O)CN, Et2AlCN, Bu3SnCN, acetone cyanohydrin or
acyl cyanides.4,5 Preformed imines which are intermediates of
A series of nitriles were reacted with an excess of DIBAL-H in
dichloromethane at À78 °C to afford aldimine alane complexes 1
on 0.5–2.0 mmol scale (Scheme 1).15 The alanes were formed in
30 min and were not isolated. After quenching the excess of hy-
dride with ethyl acetate, (S)-(À)-1-phenylethylamine and catalytic
triethylamine were added to generate the respective imines 2. Fi-
a
-aminonitrile formation during the Strecker synthesis are widely
used starting materials in catalytic asymmetric Strecker synthe-
ses.6 Treatment of
-hydroxynitriles with amines also yields
-aminonitriles.7 RuCl3-catalyzed oxidative cyanation of tertiary
amines with sodium cyanide results in the corresponding
-aminonitriles.8 However, no examples of Strecker reactions
a
a
nally, addition of excess acetone cyanohydrin gave
3 in an overnight reaction at room temperature. The diastereo-
meric mixture of -aminonitrile was isolated by standard silica
a-aminonitriles
a
a
using nitriles as starting materials have been published despite
the fact that the nitriles can serve as aldehyde equivalents follow-
ing their reductive hydrolysis using DIBAL-H. Organoaluminium
imine complexes formed by the reduction of nitriles with dialkylal-
uminium hydrides are common intermediates in organic synthe-
sis.9 The preparation and characterization of stable
dialkylaluminium aldimine complexes have been reported.10,11
Various dialkylaluminium aldimine complexes were found to react
gel chromatography. The by-product, 2-methyl-2-(1-phenylethyl-
amino)propane-nitrile, formed in the reaction of acetone cyanohy-
drin and (S)-(À)-1-phenylethylamine,16 was also isolated.
In the alane-Strecker reaction, the majority of the nitriles were
converted into the required a-aminonitriles 3 in good yields (Table
1). The lowest yield (20%) was obtained for ethoxypropionitrile
(entry 6). Starting from 1,5-dicyanopentane (entry 5), in addition
to the diaminonitrile (43%), monoaminonitrile (30%) was also iso-
lated. Interestingly, no aminonitrile formation was detected with
2-tolunitrile, while a moderate yield (53%) was obtained from the
para-substituted analogue (entry 10). Starting from phthalonitrile,
* Corresponding author. Tel.: +36 1 438 1100x133; fax: +36 1 438 1145.
E-mail address: jabi@chemres.hu (I. Jablonkai).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.004

S. Sipos, I. Jablonkai / Tetrahedron Letters 50 (2009) 1844–1846
1845
CH3
N
R
DIBAL-H
(S)-(-)-1-phenylethylamine
Al
RCN
R
N
CH2Cl2
-78 oC, 0.5 h
Et3N, -78 oC, 2 h
2
1
R
CH3
-78oC - 20 oC
18 h
HO
CN
NC
N
H
3
Scheme 1. One-pot preparation of a-aminonitriles 3 via intermediate diisobutylaluminium aldimines 1.
Table 1
proton of the major isomers always appeared at a higher field than
that of the minor isomers. The structures of the aminonitriles pre-
pared in a previous study from (R)-(+)-1-phenylethylamine and
acetaldehyde as well as pivalaldehyde were confirmed, and a pre-
dominance of (R,R) diastereomers over (R,S) was found.17 Since the
Structures of the nitriles, isolated yields of
ratios
a-aminonitriles 3 and the diastereomeric
Entry
R–CN
Yield of 3 (%)
dr
1
2
3
4
5
6
CH3–
CH3CH2CH2–
(CH3)3C–
CH3(CH2)16
NC–(CH2)5–
92
82
91
67
43
20
1.80
2.05
1.85
1.95
2.32
2.99
chemical shifts of the diastereomers of the a-aminonitriles derived
from entries 1 and 3 with (S)-(À)-1-phenylethylamine (Table 1)
were exactly the same as reported for the aforementioned ana-
logues we can presume that the (S,S)-conformer is the predomi-
nant product in the alane-Strecker synthesis. The diastereomeric
ratios ranged from 1.41 to 3.41.
–
CH3CH2–O–CH2CH2–
The effect of reaction conditions on the yields and diastereomer
ratios was further studied using pivalonitrile (Table 2, entry 3).
When the reaction was carried out at room temperature, the yield
was decreased significantly without significantly affecting the ratio
of the diastereomers. The reduced yield (37%) in the absence of tri-
ethylamine is probably due to the decreased degree of dissociation
of the cyanohydrin into acetone and HCN which therefore slows
the hydrocyanation of the imine. The dissociation of acetone cya-
nohydrin was previously shown to be catalyzed by triethylamine.18
Since the dissociation was extremely slow in dioxane,18 we can as-
sume that the dramatically lowered yield in tetrahydrofuran can
also be explained by the repressed dissociation of the cyanohydrin
in this solvent. The alane-Strecker reaction also proceeded excel-
lently in toluene. The effect of commercially available Jacobsen’s
thiourea catalyst 4 (Fig. 1), which was applied successfully in the
asymmetric Strecker reaction of preformed imines and HCN,19 on
the diastereoselectivity of the reaction was studied briefly. In the
presence of 2 mol % of organocatalyst 4 added after imine forma-
tion, a poor yield (18%) and only a slightly higher diastereomer ra-
tio was detected. When triethylamine and the catalyst 4 (4 mol %)
7
52
92
75
53
80
87
45
60
94
3.41
1.90
3.06
2.32
1.44
1.41
2.19
2.39
1.52
BnO
8
9
10
11
12
13
14
15
H3C
MeO
O2N
O
Table 2
Effect of the reaction conditions on the yields and diastereomeric ratios in the alane-
Strecker reaction carried out with pivalonitrile
Solvent
Aminea
Et3N
Catalystb
Temperature (°C)
Yield (%)
dr
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
S
S
S
S
+
–
–
+
+
+
+
+
+
–
–
+
20
À78
À78
À78
À78
À78
À78
À78
À78
59
37
18
33
22
90
43
2
1.99
2.08
2.17
1.80
2.20
1.79
2.04
1.33
1.96
c
a tar-like crude product was obtained which did not contain the
expected di- or monoaminonitrile according to mass spectrometry.
These findings indicate the importance of steric factors in aminoni-
trile formation. Reactions carried out with allyl cyanide, acryloni-
trile and cinnamonitrile resulted in no aminonitrile formation.
Since the diastereomers were not separable, the diastereomeric ra-
tios (dr) of the alane-Strecker reactions were determined from the
integral values of the RCH–CN protons of the new stereogenic cen-
tre in the product 1H NMR spectra. The signals due to the methine
+
Sd
R
R
S
–
–
+
–
–
Toluene
S
92
a
S: (S)-(À)-1-phenylethylamine, R: (R)-(+)-1-phenylethylamine.
2 mol % of catalyst 4, see Ref. 19.
4 mol % of catalyst 4, see Ref. 19.
2 equiv of (S)-(À)-1-phenylethylamine and 5 equiv of acetone cyanohydrin
b
c
d
were applied.

1846
S. Sipos, I. Jablonkai / Tetrahedron Letters 50 (2009) 1844–1846
CH3 tBu
N
S
Acknowledgements
The authors thank Dr. Pal Szabo for the mass spectrometry anal-
yses. Excellent technical assistance from Janosne Keri and Eva Peter
is gratefully acknowledged.
N
N
H3C
H
H
N
H
O
HO
tBu
O
References and notes
4
O
tBu
1. Hassan, N. A.; Bayer, E.; Jochims, J. C. J. Chem. Soc., Perkin Trans. 1 1998, 3747–
3757.
2. Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359–373.
3. Enders, D.; Kirchhoff, J.; Gerdes, P.; Mannes, D.; Raabe, G.; Runsink, J.; Boche, G.;
Marsch, M.; Ahlbrecht, H.; Sommer, H. Eur. J. Org. Chem. 1998, 63–72.
4. Paraskar, A. S.; Sudalai, A. Tetrahedron Lett. 2006, 47, 5759–5762.
5. Pan, S. C.; List, B. Synlett 2007, 318–320.
Figure 1. Jacobsen’s thiourea catalyst.
were added together the yield was somewhat improved but the
diastereoselectivity was reduced slightly. When (R)-(+)-1-phenyl-
ethylamine was employed as the chiral inducer the presence of
the thiourea catalyst 4 decreased the yield without any significant
effect on the diastereoselectivity.
6. Groger, H. Chem. Rev. 2003, 103, 2795–2827.
7. Besidsky, Y.; Luthman, K.; Hacksell, U. J. Heterocycl. Chem. 1994, 31, 1497–1502.
8. Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003, 125,
15312–15313.
9. Cainelli, G.; Panunzio, M.; Andreoli, P.; Martelli, G.; Spunta, G.; Giacomini, D.;
Bandini, E. Pure Appl. Chem. 1990, 62, 605–612.
10. Jensen, J. A. J. Organomet. Chem. 1993, 456, 161–166.
11. Gilbertson, R. D.; Haley, M. M.; Weakley, T. J. R.; Weiss, H.-C.; Boese, R.
Organometallics 1998, 17, 3105–3107.
12. Bogdanovic, B.; Konstantinovic, S. Liebigs Ann. Chem. 1970, 738, 202–205.
13. Zandbergen, P.; Van den Nieuwendijk, A. M. C. H.; Brussee, J.; Van der Gen, A.;
Kruse, C. G. Tetrahedron 1992, 48, 3977–3982.
The results obtained when using catalyst 4 were consistent with
our anticipations. The Jacobsen catalyst was shown to catalyze the
highly enantioselective hydrocyanation of imines by activation of
the electrophile with H-bonding between the acidic NH protons
of 4 and the imine lone pair.20 In our system, the excess of the chi-
ral amine and the catalytic Et3N can neutralize the acidity of the
catalyst therefore preventing it binding to the substrate. Also, the
acidic catalyst can decrease the dissociation of the acetone cyano-
hydrin. In order to improve the diastereoselectivity of the alane-
Strecker reaction a change of the cyanide source is necessary when
a chiral H-bond donor catalyst is employed.
14. Stout, D. M.; Black, L. A.; Matier, W. L. J. Org. Chem. 1983, 48, 5369–5373.
15. General procedure for the preparation of 3: Diisobutylaluminium hydride
(1.4 equiv, 2.8 mmol, 1 M in dichloromethane) was added to the nitrile
(1 mmol) in dichloromethane (5 mL) under argon at À78 °C. The mixture was
stirred for 30 min and the excess DIBAL-H was quenched by the addition of
ethyl acetate (0.4 mmol) at À78 °C. After 5 min, catalytic triethylamine
(0.1 equiv, 0.1 mmol) and (S)-(À)-1-phenylethylamine (5 equiv, 5 mmol)
were added, and the mixture was stirred for 2 h at dry ice temperature.
Next, acetone cyanohydrin (10 equiv, 10 mmol) was added via syringe and the
temperature was allowed to warm to 20 °C and the mixture was stirred
overnight. After dilution with dichloromethane (10 mL), the solution was
washed with 1 N sodium hydroxide (10 mL). The organic layer was dried over
magnesium sulfate and the solvent was removed in vacuum. The residue was
purified by column chromatography on silica gel using hexane/ethyl acetate as
eluent (93/7–9/1).
In conclusion, we have reported a convenient one-pot transfor-
mation of a variety of alkyl and aryl cyanides to diastereomeric
a-aminonitriles. The transformation is achieved through in situ
generation of the corresponding aldimine alanes using DIBAL-H
followed by reaction with a chiral amine to generate an imine,
which subsequently undergoes cyanide addition with acetone
cyanhydrin. Although the yields of the reactions were satisfactory,
the general lack of significant diasteroselectivity requires further
16. Jacobson, R. A. J. Am. Chem. Soc. 1945, 67, 1996–1998.
17. Inaba, T.; Fujita, M.; Ogura, K. J. Org. Chem. 1991, 56, 1274–1279.
18. Stewart, T. D.; Fontana, J. J. Am. Chem. Soc. 1940, 62, 3281–3285.
19. Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012–10014.
20. Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–1543.
study to access more diastereo-enriched
a-aminonitriles as valu-
able intermediates of N-substituted -amino acid building blocks.
a