Efficient three-component strecker reaction of aldehydes/ketones via NHC-amidate palladium(II) complex catalysis

Full text of DOI:10.1021/jo900163w

synthesis applied to ketones and aliphatic amines remains a more
difficult reaction. Often with these substrates, the reaction is
carried out stepwise using premade imines or under high
pressure conditions.11 Although recently one-pot procedures
have been developed for the synthesis of R-aminonitriles using
a variety of Lewis acids such as lithium perchlorate,12 scandium
triflate,13 vanadyl triflate,14 zinc halides,15 ytterbium triflate,16
and montmorillonite;17 most of these methods involve the use
of strong acidic conditions, expensive reagents, extended
reaction times, harsh conditions, fast hydrolysis, and tedious
workup leading to the generation of a large amount of waste.
Therefore, more general and milder reaction conditions for
one-pot multicomponent Strecker reactions, particularly those
involving ketones, would be advantageous.
Efficient Three-Component Strecker Reaction of
Aldehydes/Ketones via NHC-Amidate
Palladium(II) Complex Catalysis
Jamie Jarusiewicz, Yvonne Choe, Kyung Soo Yoo,
Chan Pil Park, and Kyung Woon Jung*
Loker Hydrocarbon Research Institute and Department of
Chemistry, UniVersity of Southern California,
Los Angeles, California 90089-0166
kwjung@usc.edu
ReceiVed January 28, 2009
Recently, we found that N-heterocyclic carbene (NHC)-
amidate palladium(II) complex 1a acts as an effective catalyst
for asymmetric boron-Heck type carbon-carbon bond-
forming reactions under mild conditions.18 In addition, this
palladium(II) complex 1a was converted to the palladium
complex 1b by treating with aqueous AgBF4, and it was found
that the subsequent monomer/dimer equilibrium process
(1b T 1c) readily occurred in the aqueous solution (Scheme
1). Consequently, the catalytic reaction was not inhibited by
coordination of water to palladium metal since the presence
of strongly electron-donating groups such as the NHC,
amidate N, and O would increase the electron density of
palladium and allow for a weak interaction between elec-
trophilic Pd and water. Therefore, due to the stability toward
aqueous conditions and easy formation of a palladium open
site, we prepared new NHC-amidate palladium(II) analogue
2 having an ester moiety as a portable chelating group. We
herein report the results of its application in the synthesis of
R-amino nitriles from the corresponding aldehydes or ketones
and amines with trimethylsilyl cyanide (TMSCN) in dichlo-
romethane solvent. These reactions required no further
purification in most cases.
A simple and efficient one-pot, three-component method has
been developed for the synthesis of R-aminonitriles. This
Strecker reaction is applicable for aldehydes and ketones with
aliphatic or aromatic amines and trimethylsilyl cyanide in
the presence of a palladium Lewis acid catalyst in dichlo-
romethane solvent at room temperature.
The Strecker reaction, which employs aldehydes or ketones,
amines, and a cyanide source, is a well-established route for
the preparation of R-aminonitriles, which are versatile interme-
diate compounds and are particularly useful in the preparation
of R-amino acids and other biologically relevant molecules, such
as nitrogen-containing heterocycles.1 Successful examples of
this reaction have been demonstrated using titanium,2 iron,3 and
zirconium4 catalysts, Schiff bases,5 Lewis bases,6 gallium
triflate,7 ionic liquids,8 ꢀ-cyclodextrin,9 and other nonmetal
catalysts.10 However, most one-pot multicomponent variations
of the Strecker reaction involve aldehydes, and the Strecker
The preparation of ligand precursor 6 was carried out as
illustrated in Scheme 2. Treatment of 4, derived from the
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10.1021/jo900163w CCC: $40.75
Published on Web 03/05/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2873–2876 2873

TABLE 1. Screening of Palladium Source and Catalyst Loadinga
SCHEME 1
entry
R
catalyst (mol %)
time (h)
yieldb (%)
1
2
3
4
5
6
Me
Me
Me
Me
H
72
24
24
24
24
24
15
11
99
99
68
95
PdCl2 (5)
2 (5)
2 (3)
PdCl2 (5)
2 (3)
H
a To a mixture of palladium catalyst, sodium sulfate (100 mg, 0.7
mmol), 7 (0.2 mmol), and 8 (0.2 mmol) in 1 mL of CH2Cl2 in a
Schlenk tube was added dropwise 9 (0.4 mmol). The mixture was stirred
for 24 h at room temperature. b Conversion yield.
SCHEME 2. Preparation of the Palladium Complex 2
to PdCl2 for reactions employing ketones. Therefore, complex
2 was evaluated for potential application to a wider scope of
substrates for the Strecker reaction, shown in Table 2. Reactions
were carried out with aliphatic and aromatic aldehyde and amine
substrates, and in all cases, regardless of differences in electronic
character of the aldehyde substrates, reactions were able to
proceed with high yields. For example, an electron-withdrawing
substituent (entries 2 and 9) was compatible with these
conditions, as were heteroatom-containing aldehydes (entries
3-5 and 10-12) and aliphatic aldehydes (entries 7, 14, and
15). Similar to previous reports using other Lewis acid catalysts,
aromatic (entries 1-7) and aliphatic (entries 8-15) amines were
compatible with these reactions as well.7,12-17 Without the use
of a desiccating agent, the formation of the imine intermediate
was hindered, and low conversion to the R-aminonitrile produt
was observed (not shown).
Due to the encouraging reactivity of complex 2 as a Lewis acid
catalyst for the Strecker reaction employing aldehydes, its feasibility
to promote reactions involving ketones was then evaluated. In the
presence of 2, good reactivity was observed for reactions involving
an aromatic amine and ketones with electron-donating (entry 2)
substituents, as indicated in Table 3. A bromo substituent was
tolerated as well (entry 3), but the electron-withdrawing nitro group
(entry 4) was not a feasible substrate. Lower yield with this
substrate may be attributed to low conversion to the imine
intermediate. In general, reactions employing aniline as the amine
provided the R-aminonitrile products in better conversion than did
those using benzylamine. Again, electron-withdrawing substituents
on the ketone substrate were not well-tolerated, although electron-
donating (entry 8) and heteroatom (entry 10) substituents provided
modest reactivities.
amidation of valine methyl ester and bromoacetyl bromide, with
benzimidazole 3 in the presence of KOH in DMF provided
compound 5 efficiently. The amido ester-substituted benzimi-
dazolium iodine salt 6 was then obtained by allowing 5 to react
with CH3I in refluxing THF. Formation of 6 was confirmed (1H
NMR spectroscopy in CDCl3) by observation of the new peak
assigned to the N-CH3 at 4.18 ppm, as well as the expected
chemical shift change for the imidazole-H (7.95 to 10.16 ppm)
as an iodine salt.
For coordination of 6 as an NHC to palladium, compound 6
was reacted with Ag2O in dichloromethane at room temperature
for 3 h and then the solvent was filtered under reduced pressure to
give the silver NHC complex as a light gray color solid. This
reaction could be carried out without any purification of the
intermediate. Subsequent treatment of the silver compound with
PdCl2(CH3CN)2 in CH3CN at room temperature for 3 h afforded
palladium complex 2 in 83% yield. The structure was confirmed
1
by H NMR spectroscopic analysis and HRMS data (molecular
peak at m/z 445.0371 [M + H]).
In summary, NHC-amidate ester palladium(II) complex 2
has been demonstrated to be a useful Lewis acid catalyst to
promote one-pot multicomponent Strecker reactions for the
synthesis of R-aminonitriles. Additionally, the application of 2
in reactions involving ketone substrates allowed for the forma-
tion of R-aminonitrile products containing a quaternary carbon.
The benefit of this methodology is the simplicity of the
procedure involved, which often avoided the use of tedious
chromatographic purification of products. Future studies involv-
ing optically active forms of 2 may allow for the formation of
R-aminonitriles in an enantioselective manner.
As shown in Table 1, an initial screening of palladium
catalysts was conducted. Using TMSCN as a cyanide source
and sodium sulfate as a desiccant, reactions were conducted in
dichloromethane solvent at room temperature. In the absence
of a palladium catalyst, reactivity was poor and provided low
conversion for the reaction between acetophenone and benzyl-
amine at room temperature (entry 1). While the use of PdCl2
led to low conversion for reactions involving ketone and
aldehyde (entries 2 and 5), optimal conversion (>95%) was
obtained using a 3 mol % loading of NHC-palladium complex
2 in reactions employing both carbonyl sources (entries 4 and 6).
In the initial screening, both PdCl2 and 2 were demonstrated
to be suitable catalysts for reactions involving aldehydes.
However, due to its stability in water released during the course
of the reaction, 2 appeared to promote better reactivity compared
Experimental Section
Palladium(II) Complex (2). The suspension of benzimidazolium
iodine salt 6 (500 mg, 1.16 mmol) and silver(I) oxide (185 mg, 0.8
2874 J. Org. Chem. Vol. 74, No. 7, 2009

TABLE 2. Strecker Reactions of Various Aldehydes and Amines
in the Presence of Palladium Complex 2a
TABLE 3. Strecker Reactions of Various Ketones and Amines in
the Presence of Palladium Complex 2a
a To a mixture of palladium catalyst, sodium sulfate (100 mg, 0.7
mmol), 7 (0.2 mmol), and 8 (0.52 mmol) in 1 mL of CH2Cl2 in a
Schlenk tube was added dropwise 9 (0.4 mmol). The mixture was stirred
for 24 h at room temperature. If necessary, compounds were purified by
column chromatography on silica gel with a gradient elution of hexanes/
ethyl acetate. b Isolated yields.
was stirred for 2 h and filtered through a plug of glass fiber filter
paper. The filtrate was evaporated to dryness in vacuo to afford
product 2 (418 mg, 81% yield) as an orange solid: 1H NMR
(CD3OD, 250 MHz) δ 7.63-7.59 (m, 1H), 7.51-7.48 (m, 1H),
7.38-7.33 (m, 2H), 5.82 (d, J ) 16.5 Hz, 1H), 5.63 (d, J ) 16.5
Hz, 1H), 4.41 (brs, 1H), 4.35 (s, 3H), 3.66 (s, 3H), 2.23-2.09 (m,
1H), 0.95 (d, J ) 2.5 Hz, 3H), 0.92 (d, J ) 2.5 Hz, 3H); 13C NMR
(CD3OD, 63 MHz) δ 18.6, 19.4, 31.7, 35.3, 52.0, 52.4, 59.6; Anal.
Calcd for C16H21ClN3O3Pd: C, 43.16; H, 4.75; N, 9.44; Cl, 7.96.
Found: C, 42.98; H, 4.81; N, 7.59; Cl, 7.38; HRMS-ESI (m/z) [M
+ H+] calcd for C16H22ClN3O3Pd 445.0385, found 445.0371.
Representative Procedure for the Synthesis of 13a. To a
mixture of 2 (3 mol %), sodium sulfate (100 mg, 0.7 mmol),
benzaldehyde (0.020 mL, 0.2 mmol), and aniline (0.018 mL, 0.2 mmol)
in 1 mL of CH2Cl2 in a pressure tube was added dropwise TMSCN
(0.053 mL, 0.4 mmol). The pressure tube was closed and stirred for
24 h at 23 °C. The mixture was then filtered, and the residue was
washed with CH2Cl2 (10 mL). The filtrate was collected, and the
solvent was removed under reduced pressure to obtain 2-phenyl-2-
(phenylamino)acetonitrile 13a (33 mg, 79% yield) as a light yellow
solid: mp 76-79 °C; 1H NMR (250 MHz) δ 4.67 (br s, 1H), 5.36 (s,
a To a mixture of palladium catalyst, sodium sulfate (100 mg, 0.7
mmol), 7 (0.2 mmol), and 8 (0.2 mmol) in 1 mL of CH2Cl2 in a
Schlenk tube was added dropwise 9 (0.4 mmol). The mixture was stirred
for 24 h at room temperature. b Isolated yields.
mmol) in CH2Cl2 (20 mL) was stirred for 3 h in the dark at room
temperature. The reaction mixture was concentrated under reduced
pressure to give a gray solid. To a suspension of the silver complex
in CH3CN (20 mL) was added PdCl2(CH3CN) (301 mg, 1.16 mmol)
in the dark at room temperature. Then, the resulting suspension
J. Org. Chem. Vol. 74, No. 7, 2009 2875

1H), 6.72 (d, J ) 7.8 Hz, 2H), 6.84 (t, J ) 7.4 Hz, 1H), 7.22 (t, J )
8.0 Hz, 2 H), 7.37-7.44 (m, 3H), 7.52-7.55 (m, 2H); 13C NMR (63
MHz) δ 50.1, 114.1, 118.1, 120.2, 127.2, 128.4, 129.2, 129.4, 134.0,
144.7.
Supporting Information Available: Experimental proce-
dures, compound characterization data, and copies of 1H NMR
and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We acknowledge generous financial sup-
port from the National Institute of General Medical Sciences
of the National Institutes of Health (RO1 GM71496).
JO900163W
2876 J. Org. Chem. Vol. 74, No. 7, 2009