Synthesis of α-aminonitriles under mild catalytic, metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2013.11.035

α-Aminonitriles have been synthesized by a Strecker synthesis from aldehydes and ketones under mild catalytic, metal-free conditions. Aromatic aldehydes (1 equiv) were reacted with aromatic and 1 or 2 aliphatic amines (1 equiv) in EtOH containing 3 mol %

Full text of DOI:10.1016/j.tetlet.2013.11.035

Accepted Manuscript
Synthesis of α-aminonitriles under mild catalytic, metal-free conditions
Baskar Nammalwar, Chelsea Fortenberry, Richard A. Bunce
PII:
S0040-4039(13)01971-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.035
TETL 43830
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 October 2013
5 November 2013
10 November 2013
Please cite this article as: Nammalwar, B., Fortenberry, C., Bunce, R.A., Synthesis of α-aminonitriles under mild
catalytic, metal-free conditions, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.11.035
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Synthesis of α-aminonitriles under mild
catalytic, metal-free conditions
Baskar Nammalwar, Chelsea Fortenberry and Richard A. Bunce*
H
R
CN
O
Methods A, B or C
R'
TMSCN
R'-NHR"
N
R
R
H
R"
Method A: 3 mol% NH4Cl, EtOH, reflux, 80 oC, 74-92%
Method B: 1.2 equiv TMSCN, EtOH, reflux, 80 oC, 80-95%
Method C: 1.2 equiv TMSCN, neat, MW, 90 oC, 82-96%
31 examples
R' CN
R"
R
O
Methods D or E
TMSCN
R"-NH2
N
R'
H
Method D: 30 mol% NH4Cl, EtOH, reflux, 80 oC, 78-90%
Method E: 30 mol% NH4Cl, neat, MW, 90 oC, 80-92%
11 examples

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of α-aminonitriles under mild catalytic, metal-free conditions
∗
Baskar Nammalwar, Chelsea Fortenberry and Richard A. Bunce
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071 USA
ARTICLE INFO
ABSTRACT
Article history:
Received
α-Aminonitriles have been synthesized by a Strecker synthesis from aldehydes and ketones
under mild catalytic, metal-free conditions. Aromatic aldehydes (1 equiv) were reacted with
aromatic and 1˚ or 2˚ aliphatic amines (1 equiv) in EtOH containing of 3 mol% of NH4Cl to give
high yields of α-aminonitriles. An alternative to adding NH4Cl as a catalyst involved the use of
excess TMSCN (1.2 equiv) to promote the process. The reaction was also successful under
microwave conditions using excess TMSCN with no solvent. Ketones similarly reacted with
aromatic amines and excess TMSCN under conventional and microwave heating, but 30 mol%
of added NH4Cl was required for optimum conversion.
Received in revised form
Accepted
Available online
Keywords:
Strecker synthesis
NH4Cl catalyst
2009 Elsevier Ltd. All rights reserved.
Multicomponent reaction (MCR)
Bronsted acid
In recent years, α-aminonitriles, prepared by
a
poor solvent for most of the substrates, and required sealed tube
o
heating at 95 C for up to 13 h. The second, which employed
multicomponent reaction (MCR) of an aldehyde or ketone, an
amine and a cyanide source (commonly referred to as the
Strecker synthesis), have attracted considerable attention as
synthetic targets due to their diverse biological activities.1 α-
Aminonitriles have also proven to be versatile intermediates for
the synthesis of natural and unnatural amino acids, peptides and
amides in addition to an assortment of nitrogen heterocycles.2
Furthermore, Strecker products have served as precursors for the
o
CH3CN at 23 C, appeared more promising but required longer
reactions times (ca 16 h). Both of these studies, however,
recorded lower average yields than the current work.
Based on our previous success using NH4Cl as a catalyst for
the preparation of benzo-fused five-membered heterocycles,10 we
decided to explore these same conditions to promote the Strecker
synthesis. Several trial reactions, involving equimolar 2-chloro-
benzaldehyde, aniline and TMSCN along with varying amounts
of NH4Cl (1, 5, 10, 20 and 50 mol%) in EtOH were performed at
synthesis of important
pharmaceuticals, most notably
ecteinascidin-743, phthalascidin-650, and saframycin A.3
o
In the last decade, a myriad of catalysts including inorganic
Lewis acids,4 solid-supported Bronsted acids,5 organic proton
donors,7 biopolymer-anchored catalysts,6 and even a Mitsunobu
protocol8 have been developed to facilitate this reaction.
Although the majority of these promoters were found to be
effective for this transformation, most had drawbacks such as low
reactivity, high catalytic loading, prohibitive cost, moisture
sensitivity, harsh reaction conditions, tedious work-up, extended
reaction times, or post-reaction waste remediation. Recently, a
great deal of attention has been focused on minimizing the use of
environmentally toxic catalysts in the synthesis of α-
aminonitriles. Two reports have described the current reaction in
solvents without an added catalyst.9 The first utilized H2O, a
23 C for 24 h to yield 30-64% of the expected α-aminonitrile.
This same transformation, under optimized conditions with 3
mol% of NH4Cl at 80 oC, gave an 82% yield after 5-8 min. Thus,
while NH4Cl has often been employed as a source of ammonia
for this reaction in base,11 it can be an effective catalyst when
present in low concentration under weakly acidic conditions.
Indeed, when 10-50 mol% of NH4Cl was used in our test reaction
o
at 80 C, the proportion of byproducts increased dramatically.12
On the other hand, a similar experiment without catalyst afforded
only 60% of the α-aminonitrile, confirming that some acid is
necessary for maximum conversion. Finally, evaluation of
solvents indicated that 95-100% EtOH (for complete solvation of
the substrates) gave the best results (see Figure 1). Other media,
———
∗ Corresponding author. Tel.: +1-405-744-5950; fax: +1-405-744-6007; e-mail: rab@okstate.edu

2
Tetrahedron
such as dioxane, tetrahydrofuran, acetonitrile and chloroform
the generality of the method, a selection of aldehydes with
provided somewhat lower yields.
varying substituent groups was reacted with a series of amines
and the isolated yields are summarized in Scheme 1. All three
methods furnished α-aminonitriles in high yields with minimal
purification requirements—direct crystallization from the
reaction mixture for solid derivatives and column
chromatography for oils. Aldehydes such as 5-iodovanillin
and 3-furaldehyde, which are prone to polymerization under
acidic conditions,5c gave excellent yields using the current
method. Substituted anilines, benzylamines and even
secondary amines such as morpholine underwent reaction
without complications.
Two other alternative procedures also gave superior results for
this transformation. In the first, it was found that the use of a
slight excess of TMSCN (1.2 equiv) in EtOH, which presumably
generated some HCN in situ,13 also produced high yields of the
α-aminonitrile. In the second, a greener version of the process
o
was achieved using microwave (MW) heating (400 W, 90 C)
without solvent. These conditions delivered the product in 30-
240 s with yields similar to those obtained under conventional
conditions. Thus, three successful methods have been developed
for the synthesis of α-aminonitriles from aldehydes: (Method A)
conventional heating with TMSCN (1 equiv) in EtOH containing
3 mol% of added NH4Cl, (Method B) conventional heating with a
slight excess of TMSCN (1.2 equiv) in EtOH, and (Method C)
MW heating with a similar excess of TMSCN and no solvent.
Once, the Strecker protocol was established for aldehydes the
same strategy was extended to ketones. Disappointingly, our
initial efforts, using excess TMSCN (1.2 equiv), failed to afford
significant conversion. Larger quantities of TMSCN (up to 8
equiv) promoted the condensation, but only in modest yield.
Further adjustment of the reaction conditions to include 30 mol%
of added NH4Cl and 1.2 equiv of TMSCN (Method D), however,
increased the rate of the reaction as well as the product yield.12
This same procedure, carried out under MW conditions (400 W,
o
90 C) without solvent (Method E), produced yields comparable
to the conventional method with much shorter reaction times
(240-420 s). A variety of substrates including dialkyl, cycloalkyl
and aromatic ketones were attempted along with various aromatic
amines, and the yields are presented in Scheme 2. Benzylamines
did not yield satisfactory results in reactions with ketones.
Figure 1: Solvent optimization for the reaction of 2-chlorobenzaldehyde
with aniline and TMSCN using 3 mol% of added NH4Cl
Scheme 2
To determine the functional group tolerance and to establish
R'
R
CN
O
TMSCN
Scheme 1
R"-NH2
R"
N
H
R
R'
H
R
CN
O
TMSCN
R'
R'NHR"
N
+
R
H
Yields (%)
Da
R"
R"
Eb
R
R'
Yields (%)
Bb
CH3CH2
CH3
C6H5
80
88
85
90
R
R'
R"
Aa
Cc
4-ClC6H4
C6H5
H
H
H
H
78
82
92
80
84
90
94
82
87
92
96
88
−(CH2)4−
C6H5
82
87
90
86
90
92
4-ClC4H4
4-ClC6H4
4-CF3C6H4
4-CF3C6H4
4-CH3OC6C4CH2
−(CH2)5−
C6H5
78
80
84
80
83
84
4-ClC6H4
4-CF3C6H4
C6H5
H
H
H
H
82
80
90
76
84
84
90
93
80
84
87
92
95
85
92
4-ClC4H4
4-CF3C6H4
4-CF3C6C4CH2
C6H5
CH3
Cl
C6H5
83
85
83
85
88
82
4-ClC6H4
4-CF3C6H4
−(CH2)2O(CH2)2−
C6H5
4-ClC4H4
H
H
H
H
H
80
84
91
74
78
84
85
86
95
80
81
86
85
88
96
82
83
86
aMethod D: 1.2 equiv TMSCN, 30 mol% NH4Cl, EtOH, 80 oC,
0.75-8 h; bMethod E: 1.2 equiv TMSCN, 30 mol% NH4Cl, no
solvent, MW, 400 W, 90 oC, 240-420 s.
4-CF3C6H4
4-CH3OC6C4CH2
4-CF3C6C4CH2
OCH3
−(CH2)2O(CH2)2−
I
In conclusion, we have developed several strategies for
transforming aldehydes and ketones to α-aminonitrile derivatives
using an MCR approach. None of our procedures required the
use of strong Lewis or Bronsted acids for successful conversion.
Interestingly, this appears to be the first report that employs low
concentrations of NH4Cl or excess TMSCN to promote the
reaction. The current method is efficient, mild, functional group
tolerant, inexpensive, and can be performed in the presence of
solvent with conventional heating or in the absence of solvent
under microwave conditions.
C6H5
4-ClC4H4
4-CF3C6H4
H
H
H
75
82
90
80
90
92
82
92
90
HO
OCH3
C6H5
4-ClC4H4
4-CF3C6H4
H
H
H
86
90
92
80
92
92
94
82
92
94
96
88
CH3O
OCH3
OCH3
−(CH2)2O(CH2)2−
C6H5
4-ClC4H4
4-CF3C6H4
H
H
H
83
85
89
84
86
90
84
86
92
SPh
C6H5
4-ClC4H4
4-CF3C6H4
H
H
H
81
82
86
84
82
88
86
84
87
Acknowledgments
C6H5
4-ClC4H4
4-CF3C6H4
H
H
H
76
84
88
80
88
90
84
90
92
O
aMethod A: 1.0 equiv TMSCN, 3 mol% NH 4Cl, EtOH, 80 oC, 0.25-1 h;
Method B: 1.2 equiv TMSCN, EtOH, 80 oC, 0.25-1 h; Method C: 1.2 equiv
TMSCN, no solvent, MW, 400 W, 90 oC, 30-240 s.

3
C. F. wishes to thank Oklahoma State University for a Niblack
Scholarship to support her undergraduate research. The authors
are also pleased to acknowledge funding for the Statewide NMR
facility by the NSF (BIR-9512269), the Oklahoma State Regents
for Higher Education, the W. M. Keck Foundation, and Conoco,
Inc. We are further indebted to the OSU College of Arts and
Sciences for funds to upgrade our departmental FT-IR and GC-
MS instruments.
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Supplementary data (experimental details, 1H- and 13C-NMR
spectra, and analytical data for all of the cyclized products) can
be found, in the online version, at http://dx.doi.org
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4
Tetrahedron
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