Efficient synthesis of symmetrical α,α-disubstituted β-amino acids and α,α-disubstituted aldehydes via dialkylation of nucleophilic β-alanine equivalent

Article abstract of DOI:10.1021/jo902699t

(Figure Presented) Homologation of the nucleophilic β-alanine equivalent β-Ala Ni(II)-PABP [Ni(II) complex of β-alanine Schiff base with 2-[N-(α-picolyl)amino]benzophenone (PABP), 1] via alkyl halide alkylation was systematically studied as a general method for preparing symmetrically α,α-disubstituted β-amino acids. The dialkylation reactions could be easily performed and did not require inert atmosphere, dried solvents, and low temperatures, thereby affording the benefits of operationally convenient experimental procedure and high atom economy. Further, the methodology developed by us can also be used to generate symmetrical α,α-disubstituted aldehydes through an alternative decomposition method.

Full text of DOI:10.1021/jo902699t

pubs.acs.org/joc
Efficient Synthesis of Symmetrical r,r-Disubstituted β-Amino
Acids and r,r-Disubstituted Aldehydes via Dialkylation of Nucleophilic
β-Alanine Equivalent
Daizong Lin, Guanghui Deng, Jiang Wang, Xiao Ding, Hualiang Jiang, and Hong Liu*
The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai 201203, People’s Republic of China
hliu@mail.shcnc.ac.cn
Received December 21, 2009
Homologation of the nucleophilic β-alanine equivalent β-Ala Ni(II)-PABP [Ni(II) complex of
β-alanine Schiff base with 2-[N-(R-picolyl)amino]benzophenone (PABP), 1] via alkyl halide alkyla-
tion was systematically studied as a general method for preparing symmetrically R,R-disubstituted
β-amino acids. The dialkylation reactions could be easily performed and did not require inert
atmosphere, dried solvents, and low temperatures, thereby affording the benefits of operationally
convenient experimental procedure and high atom economy. Further, the methodology developed by
us can also be used to generate symmetrical R,R-disubstituted aldehydes through an alternative
decomposition method.
Introduction
and proteins, still await systematic studies. Therefore, the
development of efficient synthetic methods of these com-
pounds has received much attention. To date, the Mannich
reaction5 and the alkylation of β-alanine derivatives6 have
commonly been utilized as synthetic routes to R,R-disubsti-
tuted β-amino acids; in addition, other routes such as the
hydrogenation of 2-cyanoacetic acid derivatives,7 Mitsunobu
reaction,8 and reductive amination4 have been reported.
These approaches employ relatively rare substances and
therefore require restrained reaction conditions that might
limit their broad synthetic applications. Although there exist
a number of methods for the preparation of R,R-dialkyl
β-alanines, these methods mainly focus on the synthesis of
R,R-dimethyl β-alanine; thus, very few substituted variants have
R,R-Dialkyl β-alanines are useful building blocks in potent
pharmaceutical drugs and functional materials.1 For in-
stance, R,R-dialkyl β-alanines are a constituent of crypto-
phycin fragment A,2 adenosine analogues,3 and inhibitors of
protein kinase and diacylglycerol acyltransferase 1 (DGAT1).4
Furthermore, the biological properties and applications of
these substituted compounds, for example, as sterically
constrained scaffolds for the rational design of peptides
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DOI: 10.1021/jo902699t
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Lin et al.
JOCArticle
been synthesized until date. In particular, cyclic R,R-disub-
stituted β-amino acids are considered as good candidates for
drug design.9 However, despite the substantial interest in
these amino acids and their applications in drug design, there
are few synthetic approaches for preparing these compounds,
with most of them being rather impractical.
SCHEME 1. Synthesis of r,r-Disubstituted β-Amino Acids and
r,r-Disubstituted Aldehydes via a Ni(II) Complex
During the preparation of R,R-disubstituted β-alanines in
this study, we unexpectedly obtained R,R-disubstituted alde-
hydes. The R,R-disubstituted aldehydes are commonly uti-
lized in organic synthesis and medical chemistry,10 but there
are few reports on the synthesis of these compounds.11 We
accidentally obtained R,R-disubstituted aldehydes while
synthesizing β-amino acids. To our knowledge, this is the
first example of the method to prepare aldehydes from β-Ala
Ni(II)-PABP.
Recently, the Ni(II) complex of glycine Schiff base has
been widely used to synthesize amino acids.12 The PABP
ligand was introduced by Soloshonok’s group13 and was
utilized in the preparation of R-amino acids successfully.14 In
particular, PABP and the new generation of the ligand were
shown to be very efficient for preparation of sym-R,R-
disubstituted R-amino acids and therefore can be further
applied for the synthesis of the corresponding β-deriva-
tives.15 Subsequently, a convenient one-pot, two-step proto-
col to generate novel nucleophilic β-alanine equivalent,
namely β-Ala Ni(II)-PABP 1, has been reported and em-
ployed in the synthesis of β-amino acids derivatives.16 Here-
in, we report that the alkylation of β-Ala Ni(II)-PABP
directly afforded a dialkylated product of the Ni(II) complex
3, which can be hydrolyzed through two methods to yield
R,R-disubstituted aldehydes 4 and amino acids 5, respectively
(Scheme 1).
Results and Discussion
Dialkylation of Ni(II) Complex 1 and 1-(Bromomethyl)-4-
nitrobenzene 2a Using Various Bases and Solvents at Different
Temperatures. We investigated the reaction of 1 with
1-(bromomethyl)-4-nitrobenzene 2a, which was used as the
model substrate, using 2-[N-(R-picolyl)amino]benzophen-
one as the achiral nucleophilic equivalent and optimized
the reaction conditions, including bases, solvents, and tem-
peratures, as summarized in Table 1. In the preparation of
alkyl-substituted R-amino acid,15 we selected potassium
hydroxide as the base for alkylation of the Ni(II) complex
1 and performed the reaction in dimethyl formamide
(DMF). However, we failed to obtain the Ni(II) complex
of R,R-disubstituted β-amino acid 3a (Table 1, entry 1). This
result is likely due to the poor solubility of potassium
hydroxide in DMF. Subsequently, we investigated a variety
of alternative bases. DBU produced the same result as that of
potassium hydroxide (Table 1, entry 2); therefore, we em-
ployed strong bases such as KH, t-BuONa, and t-BuOK
(Table 1, entries 3-5). As we expected, 3 equiv of t-BuOK
afforded the Ni(II) complex 3a in 60% yield (Table 1, entry
5). With the view of industrial application, we determined if a
smaller amount of equiv of the base provided similar yields.
The reaction of benzylic bromide 2a with 1 in the presence of
2 equiv of t-BuOK afforded the diallylated complex 3a in
45% yield (Table 1, entry 4); similar results were obtained
using 3 and 4 equiv of t-BuOK. Optimization of the solvents
revealed that DMF was more superior than others solvents
(Table 1, entries 5, 7, and 8). Further optimization studies
established that the reaction with the base t-BuOK and DMF
afforded good yields at various temperatures from þ60 to
-20 °C (Table 1, entries 5, 10-13). Lowering the tempera-
ture decreased the reaction rate and the conversion. Further,
an increase in the reaction time lowered the yields of the
target products. From the viewpoint of practical applica-
tions, we selected t-BuOK as a base and DMF as a solvent at
ambient temperature and investigated the general utility of
the dialkylation reaction (Table 1, entry 5).
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Takeda, T. J. Org. Chem. 2007, 72, 3816–3822. (d) Shono, T.; Nagasawa, T.;
Tsubouchi, A.; Takeda, T. Tetrahedron Lett. 2007, 48, 3521–3524.
(e) Rinaldi, T. A.; Tersariol, I. L. S.; Dyszy, F. H.; Prado, F. M.; Nascimento,
O. R.; Di Mascio, P.; Nantes, I. L. Free Radical Biol. Med. 2004, 36, 802–810.
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A. D. Org. Biomol. Chem. 2003, 1, 2886–2899.
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V. I.; Vitt, S. V.; Batsanov, A. S.; Struchkov, Y. T.; Belikov, V. M. J. Chem.
Soc., Perkin Trans. 1 1990, 2301–2310. (b) Soloshonok, V. A.; Cai, C.;
Hruby, V. J. Angew. Chem., Int. Ed. 2000, 39, 2172–2175. (c) Soloshonok, V.
A.; Cai, C.; Yamada, T.; Ueki, H.; Ohfune, Y.; Hruby, V. J. J. Am. Chem.
Soc. 2005, 127, 15296–15303. (d) Soloshonok, V. A.; Tang, X.; Hruby, V. J.;
Van Meervelt, L. Org. Lett. 2001, 3, 341–343. (e) Wang, J.; Shi, T.; Deng, G.;
Jiang, H.; Liu, H. J. Org. Chem. 2008, 73, 8563–8570. (f) Wang, J.; Shi, J. M.;
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Yamazaki, T. J. Org. Chem. 2000, 65, 6688–6696. (c) Ueki, H.; Ellis, T. K.;
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Martin, C. H.; Ueki, H.; Soloshonok, V. A. Tetrahedron Lett. 2003, 44, 1063–
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Dialkylation between Ni(II) Complex 1 and 2. After the
reaction conditions were optimized, the generality of the
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JOCArticle
TABLE 1. Optimization of the Reaction Conditionsa
entry
base
KOH
DBU
solution
equiv of base
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH2Cl2
t-BuOH
DMF
DMF
DMF
DMF
10
3
3
3
3
2
4
3
3
3
3
3
3
20
20
20
20
20
20
20
20
20
-20
0
0
0
KH
10
30
60
45
60
0
t-BuONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
0
47
54
60
62
40
60
aReactions were run with 0.47 mmol of 1 and 1.34 mmol of 2a in 2 mL of solvent for 4 h.
reaction was investigated. The results are summarized in
Table 2. The applications of halides show that the reaction
has broad applicability. In general, functionalized benzyl
bromide derivatives are excellent substrates for the reaction,
regardless of their electronic effect. The aromatic system
bearing electron-donating and electron-withdrawing groups
is well tolerated (Table 2, entries 1-5). Further, we investi-
gated the steric effect of benzyl bromide. Three regioisomeric
benzyl bromine derivatives were applied in the dialkylation
reaction, and equal yields were achieved (Table 2, entries
6-8). The reactivity of benzyl bromide for different allylic
halides was as follows: allylic iodide > allylic bromide >
allylic chloride, comparison of reactivities is shown in Table 2
(Table 2 entries 9-11), which was a typical characteristic of
alkyl reactions. This method could be applied to other allylic
halides to afford the corresponding products in moderate
yields (Table 2, entries 12 and 13). The use of the activated
alkyl halide, namely, iodomethane decreased the chemical
yield (Table 2, entry 14) due to the low stability in the
reaction conditions, and no product was obtained when
the iodobutane was used (Table 2, entry 15). We found that
the benzyl products were obtained in lower yields than the
allylic ones. This result may be consistent with the view that
activated stable alkyl halides with low steric hindrance afford
dialkylated products in good yields. Under similar condi-
tions, the cyclic compound (Table 2, entry 16) was obtained
in lower yield (35%).
analysis of the major product 3a formed by the reaction of
Ni(II) complex 1 with 2a. The results indicated a C-N
double bond shift, which was due to a base-catalyzed 1,3-
proton shift across the azaallylic system. The transposition
of the imine-functionality increased the acidity of R-position
to the carboxylic group resulting the bis-alkylation of the
same methelyene, which explained the formation of R,R-
disubstituted aldehydes. Under these conditions, the hydro-
lysis of compound 3 might generate β-aldehyde acids inter-
mediates and undergo subsequent decarboxylation to
produce R,R-disubstituted aldehydes (Scheme 2).
SCHEME 2. Decomposition of Ni(II) Complex 3 to Release
Aldehyde 4
Decomposition of Products 3a and 3b. The analysis of 1H
and 13C nuclear magnetic resonance (NMR) spectra of the
product 3a revealed a C-N double bond shift in the struc-
ture. In addition, the hydrolysis of compound 3a under
standard conditions by stirring the suspension of 3a in
methanol/1 N HCl afforded the product 2,2-di(4-nitro-
benzyl)acetaldehyde 4a in high yield (90%) rather than,
the target amino acid (R,R-disubstituted β-amino acids).
To confirm this result, we performed single-crystal X-ray
However, since various symmetrical R,R-disubstituted
β-amino acids have several important applications, it
was more important to develop a simple and practical
method for preparing these compounds. Hydrogena-
tion of the C-N double bond in 3b was attempted
under several conditions (Pd/C, NaBH4, and Raney Ni).
NaBH4 catalyzed the hydrogenation of 3b. Subsequently,
methanol/1 N HCl was added to this reaction mixture at
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JOCArticle
TABLE 2. Dialkylation of Ni(II) Complex 1 with Alkylating Agent 2a
aReactions were run with 0.466 mmol of 1, 1.34 mmol of 2a-2m in 2 mL of DMF under 1.34 mmol of t-BuOK for 4 h. bReaction was run with
0.466 mmol of 1, 0.67 mmol of 2n in 2 mL of DMF under the 1.34 mmol of t-BuOK for 4 h.
synthesize sterically constrained symmetrically R,R-disub-
stituted β-amino acids and R,R-disubstituted aldehydes.
The dialkylation reactions were conducted under normal
conditions without recourse to inert atmosphere, dried sol-
vents, and low temperatures, thereby providing the key
advantages of simple experimental procedure and attractive
cost structure. The method has been shown to be particularly
successful for the preparation of symmetrical R,R-disubsti-
tuted β-amino acids and R,R-disubstituted aldehydes.
SCHEME 3. Hydrogenation and Decomposition of Ni(II)
Complex 3 to Release Amino Acids 5
Experimental Section
General Procedures for the Synthesis of 3a. The Ni(II) com-
plex of β-alanine 1 (200 mg, 0.47 mmol) was dissolved in DMF
(2 mL). t-BuOK (157 mg, 1.34 mmol) was added under ambient
conditions. The mixture was then stirred at room temperature
for 0.5 h, the 1-(bromomethyl)-4-nitrobenzene 2a (288 mg, 1.34
mmol) was added in three batches within 1 h, and the reaction
mixture was continually stirred for 4 h. The reaction was quenched
by pouring the crude reaction mixture over 30 mL of aq satd NH4Cl.
The suspension was extracted with dichloromethane (3 times). The
combined organic layers were dried with MgSO4, concentrated, and
purified by column chromatography on silica gel (dichloromethane/
methanol = 100/1) to give 3a as a dark red solid.
room temperature, and the product 6b was obtained in 70%
yield; Pd/C then catalyzed the hydrogenolysis of 6b to the
target amino acid 5b, which was obtained in 62% yield
(Scheme 3).
Conclusion
In conclusion, we have successfully synthesized dialkyl-
ated products of Ni(II) complexes of β-alanine Schiff base
and developed a practical and highly efficient route to
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
(4-nitrobenzyl)-3-oxopropanoic Acid Schiff Base Complex 3a: dark
red solid; 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J = 8.4 Hz, 2H),
1720 J. Org. Chem. Vol. 75, No. 5, 2010

Lin et al.
JOCArticle
8.02 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 5.4 Hz, 1H), 7.84 (d, J = 7.5
Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.60 (d, J = 8.1 Hz,
1H), 7.50 (d, J = 8.7 Hz, 2H), 7.39-7.45 (m, 1H), 7.31-7.37 (m,
1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.15 (m,
2H), 7.09 (m, 1H), 7.03 (dd, J1= 0.9 Hz, J2 = 7.2 Hz, 1H), 6.54 (d,
J= 7.2 Hz, 2H), 5.00 (s, 1H), 4.14 (d, J= 13.8 Hz, 1H), 3.88 (d, J=
12.9 Hz, 1H), 3.21 (d, J = 12.9 Hz, 1H), 3.05 (d, J = 13.8 Hz, 1H);
13C NMR (CDCl3, 100 MHz): δ 44.1, 44.6, 59.3, 77.8, 123.2, 123.6,
124.1, 125.9, 126.0, 126.6, 127.8, 128.2, 128.5, 128.9, 129.7, 130.6,
131.7, 137.1, 140.5, 140.6, 142.5, 144.4, 147.3, 147.4, 152.4, 167.4,
171.9, 173.7; MS (EI, m/z) 699 [M]þ; HRMS (EI) calcd for
C36H27N5NiO7 [M]þ 699.1264, found 699.1256.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
benzyl-3-oxopropanoic Acid Schiff Base Complex 3b: dark red
solid; 1H NMR (CDCl3, 400 MHz) δ 8.12 (d, J = 8.0 Hz, 1H),
7.87 (d, J = 6.4 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.60 (d, J =
7.6 Hz, 1H), 7.56 (s, 1H), 7.29-7.37 (m, 6H), 7.10-7.27 (m, 6H),
7.00-7.08 (m, 2H), 6.87-6.95 (m, 3H), 6.47 (d, J = 7.6 Hz, 2H),
4.91 (s, 1H), 4.08 (d, J = 14.0 Hz, 1H), 3.72 (d, J = 13.2 Hz, 1H),
3.08 (d, J = 13.2 Hz, 1H), 2.88 (d, J = 14.0 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 44.2, 45.2, 59.4, 77.4, 122.8, 123.0, 125.4,
126.2, 127.0, 127.2, 128.1, 128.7, 128.9, 129.5, 130.9, 135.4,
137.4, 137.9, 139.9, 140.7, 144.8, 152.7, 167.7, 172.9, 174.7;
MS (EI, m/z) 609 [M]þ; HRMS (EI) calcd for C36H29N3NiO3
[M]þ 609.1562, found 609.1546.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
(3-cyanobenzyl)-3-oxopropanoic Acid Schiff Base Complex 3c:
dark red solid; 1H NMR (CDCl3, 300 MHz) δ 8.11 (d,
J = 8.1 Hz, 1H), 7.98 (d, J = 5.1 Hz, 1H), 7.88 (m, 1H), 7.79
(s, 1H), 7.22-7.68 (m, 12H), 7.00-7.11 (m, 3H), 6.93 (t, J = 7.5
Hz, 1H), 6.57 (d, J = 6.0 Hz, 2H), 4.96 (s, 1H), 4.09 (d,
J = 14.1 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 3.13 (d, J =
13.5 Hz, 1H), 2.94 (d, J = 14.1 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 43.8, 44.6, 59.1, 77.7, 113.0, 113.3, 117.7, 118.4, 123.3,
123.6, 126.3, 126.7, 127.8, 128.1, 128.4, 129.0, 129.4, 130.0,
131.1, 132.8, 134.2, 135.2, 136.8, 137.2, 138.5, 140.3, 140.5,
144.7, 152.4, 167.8, 172.0, 173.5; MS (EI, m/z) 659 [M]þ; HRMS
(EI) calcd for C38H27N5NiO3 [M]þ 659.1467, found 659.1461.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
(4-methylbenzyl)-3-oxopropanoic Acid Schiff Base Complex 3d:
dark red solid; 1H NMR (CDCl3, 300 MHz) δ 8.21 (d,
J = 8.4 Hz, 1H), 7.90 (d, J = 5.7 Hz, 1H), 7.88 (t, J = 7.5
Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.54 (s, 1H), 7.39 (t, J = 7.5
Hz, 1H), 7.14-7.32 (m, 8H), 7.00-7.07 (m, 4H), 6.68 (d, J = 7.5
Hz, 2H), 6.48 (d, J = 7.2 Hz, 2H), 4.90 (s, 1H), 4.03 (d,
J = 13.8 Hz, 1H), 3.66 (d, J = 13.2 Hz, 1H), 3.03 (d, J =
13.2 Hz, 1H), 2.84 (d, J = 13.8 Hz, 1H), 2.37 (s, 3H), 1.94 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 20.8, 21.0, 43.9, 44.8, 59.7, 77.5,
122.8, 123.0, 125.4, 125.9, 127.2, 127.9, 128.0, 128.2, 128.6,
129.0, 129.5, 129.6, 130.8, 132.5, 134.3, 136.8, 137.1, 137.6,
139.8, 140.8, 144.9, 152.9, 167.8, 173.1, 174.9; MS (EI, m/z)
637 [M]þ; HRMS (EI) calcd for C38H33N3NiO3 [M]þ 637.1857,
found 637.1889.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
(2-chlorobenzyl)-3-oxopropanoic Acid Schiff Base Complex 3f:
dark red solid; H NMR (CDCl3, 300 MHz) δ 8.02 (d, J =
1
4.2 Hz, 1H), 7.99 (s, 1H), 7.82 (m, 1H), 7.80 (s, 1H), 7.69 (d,
J = 7.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.41-7.50 (m, 2H),
7.27-7.38 (m, 4H), 7.13-7.23 (m, 3H), 6.94-7.05 (m, 3H), 6.87
(m, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.49 (d, J = 7.2 Hz, 2H), 4.89
(s, 1H), 3.92 (d, J = 14.4 Hz, 1H), 3.63 (s, 2H), 3.57 (d, J = 14.4
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 40.1, 42.1, 53.4, 60.5,
77.9, 122.9, 123.2, 125.6, 126.1, 127.1, 127.2, 127.8, 128.0, 128.6,
128.8, 129.2, 129.9, 130.5, 131.7, 132.5, 133.8, 135.2, 137.7,
140.0, 140.2, 144.7, 152.8, 167.6, 173.1, 174.1; MS (EI, m/z)
677 [M]þ; HRMS (EI) calcd for C36H27Cl2N3NiO3 [M]þ
677.0783, found 677.0781.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
(3-chlorobenzyl)-3-oxopropanoic Acid Schiff Base Complex 3g:
dark red solid; 1H NMR (CDCl3, 300 MHz) δ 8.12 (d,
J = 7.8 Hz, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.83 (m, 1H), 7.65
(d, J = 7.2 Hz, 1H), 7.56 (s, 2H), 7.28-7.38 (m, 5H), 7.19-7.26
(m, 4H), 6.97-7.06 (m, 3H), 6.71 (t, J = 7.8 Hz, 1H), 6.65 (d,
J = 7.5 Hz, 1H), 6.58-6.61 (m, 2H), 4.94 (s, 1H), 4.06 (d, J =
13.8 Hz, 1H), 3.71 (d, J = 13.2 Hz, 1H), 3.04 (d, J = 13.2 Hz,
1H), 2.86 (d, J = 13.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
44.0, 45.0, 59.1, 77.6, 123.0, 123.3, 125.8, 126.5, 127.0, 127.5,
127.7, 127.8, 128.0, 128.2, 129.0, 129.1, 129.4, 130.3, 130.5,
134.8, 135.2, 137.4, 139.3, 140.0, 140.6, 145.1, 152.7, 168.0,
172.5, 174.0; MS (EI, m/z) 677 [M]þ; HRMS (EI) calcd for
C36H27Cl2N3NiO3 [M]þ 677.0783, found 677.0773.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
(4-chlorobenzyl)-3-oxopropanoic Acid Schiff Base Complex 3h:
dark red solid; 1H NMR (CDCl3, 300 MHz) δ 8.21 (d,
J = 7.8 Hz, 1H), 7.81-7.89 (m, 2H), 7.66 (d, J = 7.2 Hz,
1H), 7.54 (s, 1H), 7.22-7.43 (m, 9H), 6.99-7.09 (m, 4H), 6.84 (d,
J = 8.1 Hz, 2H), 6.47 (d, J = 6.9 Hz, 2H), 4.94 (s, 1H), 4.02 (d,
J = 13.8 Hz, 1H), 3.67 (d, J = 13.2 Hz, 1H), 3.02 (d, J = 13.2
Hz, 1H), 2.84 (d, J = 13.8 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 43.6, 44.3, 59.6, 77.8, 123.0, 123.4, 125.6, 127.0, 127.7,
128.1, 128.3, 128.9, 129.2, 131.0, 132.1, 133.4, 133.7, 133.8,
135.7, 137.2, 140.2, 140.7, 144.5, 152.8, 167.7, 172.6, 174.2;
MS (EI, m/z) 677 [M]þ; HRMS (EI) calcd for C36H27Cl2N3NiO3
[M]þ 677.0783, found 677.0793.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
allyl-3-oxopropanoic Acid Schiff Base Complex 3i: dark red
1
solid; H NMR (CDCl3, 300 MHz) δ 8.12-8.16 (m, 2H), 7.88
(m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.29-7.47 (m,
7H), 7.02-7.12 (m, 2H), 6.43 (m, 1H), 5.90 (m, 1H), 5.33 (d, J =
9.9 Hz, 1H), 5.17-5.22 (m, 3H), 5.04 (d, J = 17.1 Hz, 1H), 3.45
(dd, J1 = 13.8 Hz, J2 = 7.8 Hz, 1H), 3.24 (dd, J1 = 13.2 Hz,
J2 = 7.2 Hz, 1H), 3.05 (dd, J1 = 14.1 Hz, J2 = 4.8 Hz, 1H), 2.34
(dd, J1 = 14.1 Hz, J2 = 9.0 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 40.7, 44.6, 55.8, 77.2, 119.0, 122.0, 123.1, 123.5, 126.0,
126.1, 127.1, 128.2, 128.3, 129.1, 129.3, 131.6, 134.5, 138.2, 140.3,
140.6, 145.3, 153.2, 167.9, 172.2, 177.1; MS (EI, m/z) 509 [M]þ;
HRMS (EI) calcd for C28H25N3NiO3 [M]þ 509.1249, found
509.1251.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
(4-methoxybenzyl)-3-oxopropanoic Acid Schiff Base Complex
3e: dark red solid; 1H NMR (CDCl3, 300 MHz) δ 8.19 (d, J =
8.4 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H),
7.61 (d, J = 7.5 Hz, 1H), 7.54 (s, 1H), 7.36 (m, 1H), 7.13-7.28
(m, 6H), 7.00-7.05 (m, 4H), 6.87 (d, J = 8.4 Hz, 2H), 6.49 (d,
J = 7.5 Hz, 2H), 6.42 (d, J = 8.4 Hz, 2H), 4.92 (s, 1H), 3.95 (d,
J = 13.8 Hz, 1H), 3.79 (s, 3H), 3.60 (d, J = 13.2 Hz, 1H), 3.43 (s,
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
cinnamyl-3-oxopropanoic Acid Schiff Base Complex 3j: dark
red solid; 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J = 8.1 Hz,
1H), 8.01 (d, J = 5.4 Hz, 1H), 7.67-7.73 (m, 2H), 7.17-7.42 (m,
12H), 6.96-7.13 (m, 9H), 6.62 (m, 2H), 6.30 (m, 1H), 5.12 (s,
1H), 3.20-3.34 (m, 2H), 2.89 (dd, J1 = 13.2 Hz, J2 = 6.9 Hz,
1H), 2.55 (dd, J1 = 13.8 Hz, J2 = 9.6 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): δ 41.7, 41.8, 57.6, 77.3, 122.9, 123.2, 125.5,
125.8, 126.0, 126.2, 126.3, 127.3, 127.6, 128.0, 128.6, 129.1,
133.8, 136.1, 136.5, 137.4, 137.7, 139.7, 140.4, 144.6, 152.7,
167.9, 172.4, 175.4; MS (EI, m/z) 661 [M]þ; HRMS (EI) calcd
for C40H33N3NiO3 [M]þ 661.1875, found 661.1899.
3H), 3.00 (d, J = 13.2 Hz, 1H), 2.80 (d, J = 13.8 Hz, 1H); 13
C
NMR (CDCl3, 100 MHz) δ 43.3, 44.2, 54.8, 55.2, 60.0, 77.4,
114.2, 122.9, 123.0, 125.5, 125.9, 127.1, 127.5, 127.9, 128.0,
128.2, 128.7, 129.0, 129.4, 130.6, 131.9, 137.5, 139.8, 140.8,
144.9, 152.8, 158.8, 159.0, 167.8, 173.2, 174.9; MS (EI, m/z)
669 [M]þ; HRMS (EI) calcd for C38H33N3NiO5 [M]þ 669.1774,
found 669.1779.
J. Org. Chem. Vol. 75, No. 5, 2010 1721

Lin et al.
JOCArticle
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
(3,3-dimethylallyl)-3-oxopropanoic Acid Schiff Base Complex
3k: dark red solid; 1H NMR (CDCl3, 300 MHz) δ 8.15 (m,
2H), 7.86 (t, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.30-7.44
(m, 6H), 7.23 (d, J = 7.2 Hz, 2H), 7.00-7.10 (m, 2H), 6.15 (m,
1H), 5.15 (br, 1H), 5.09 (s, 1H), 2.81-2.88 (m, 2H), 2.61 (dd,
J1 = 13.8 Hz, J2 = 9.0 Hz, 1H), 2.42 (dd, J1 = 14.4 Hz, J2 = 9.3
0.5 h, and then 1 N HCl (1 mL) was added. The reaction mixture
was stirred at room temperature until the red color of the
solution disappeared and then evaporated to dryness. Water
(20 mL) was added to the residue to form a clear solution, and
then this solution was separated by column chromatography on
C18-reversed phase (230-400 mesh) silica gel. Pure water as
eluent was employed to remove the green NiCl2 and excess HCl,
and then methanol/water (4/1) was used to obtain the product
6b as a white solid. The column chromatography was washed
with 100 mL of methanol for further use.
2,2-Dibenzyl-3-(2-(N-(r-picolyl)amino)diphenylmethanamino)-
propanoic Acid Complex 6b: white solid; 1H NMR (CDCl3, 400
MHz) δ 9.88 (s, 1H), 8.55 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 7.2 Hz,
1H), 7.97 (d, J = 8.0 Hz, 1H), 7.90 (m, 1H), 7.50 (m, 1H), 7.35 (t,
J = 7.6 Hz, 1H), 7.09-7.26 (m, 14H), 6.99-7.03 (m, 2H), 6.93 (d,
J = 7.6 Hz, 1H), 4.74 (s, 1H), 3.38 (d, J = 13.2 Hz, 1H), 3.32 (d,
J = 14.0 Hz, 1H), 2.72-2.78 (m, 3H), 2.55 (d, J = 14.0 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ 43.5, 44.4, 51.0, 51.1, 63.2, 122.6,
124.0, 125.4, 126.5, 126.8, 127.1, 127.3, 127.9, 128.4, 128.5, 128.6,
128.9, 129.9, 130.1, 132.1, 134.9, 136.8, 137.7, 138.7, 147.9, 149.6,
162.4, 177.4; MS (EI, m/z) 555 [M]þ; HRMS (EI) calcd for
C36H33N3O3 [M]þ 555.2522, found 555.2514.
Hz, 1H), 1.74 (s, 3H), 1.71 (s, 3H), 1.66 (s, 3H), 1.12 (s, 3H); 13
C
NMR (CDCl3, 100 MHz): δ 17.2, 18.4, 25.9, 26.0, 36.6, 37.0,
57.7, 77.5, 118.9, 120.2, 123.0, 123.4, 125.9, 126.2, 127.1, 128.2,
128.5, 128.7, 129.0, 129.2, 135.4, 138.4, 139.8, 140.1, 140.6, 145.2,
153.2, 167.9, 172.9, 175.6; MS (EI, m/z) 565 [M]þ; HRMS (EI)
calcd for C32H33N3NiO3 [M]þ 565.1875, found 565.1874.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2,2-di-
methyl-3-oxopropanoic Acid Schiff Base Complex 3l: dark red
solid; 1H NMR (CDCl3, 300 MHz) δ 8.19 (d, J = 8.1 Hz, 1H),
8.13 (d, J = 5.1 Hz, 1H), 7.89 (t, J = 7.5 Hz, 1H), 7.80 (s, 1H),
7.75 (d, J = 7.8 Hz, 1H), 7.42-7.47 (m, 2H), 7.31-7.39 (m, 5H),
7.13 (d, J = 7.5 Hz, 1H), 7.05 (m, 1H), 5.24 (s, 1H), 2.58 (s, 3H),
1.53 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 23.8, 30.1, 48.6,
77.0, 123.1, 123.6, 126.0, 126.3, 127.1, 128.3, 128.4, 128.5,128.7,
129.0, 129.2, 129.3, 138.1, 140.5, 140.6, 145.4, 153.2, 168.2,
174.8, 180.0; MS (EI, m/z) 457 [M]þ; HRMS (EI) calcd for
C24H21N3NiO3 [M]þ 457.0936, found 457.0941.
Ni(II)-2-[N-(r-picolyl)amino]diphenylmethanamine/2-formyl-
indan-2-carboxylic Acid Schiff Base Complex 3n: dark red solid;
1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J = 8.1 Hz, 1H), 8.12 (d,
J = 4.8 Hz, 1H), 7.94 (s, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.78 (d,
J = 7.8 Hz, 1H), 7.15-7.48 (m, 11H), 6.98-7.06 (m, 2H), 5.24
(s, 1H), 4.80 (d, J = 15.6 Hz, 1H), 4.56 (d, J = 15.6 Hz, 1H), 4.16
(d, J = 16.8 Hz, 1H), 3.24 (d, J = 16.2 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 41.0, 49.2, 60.0, 76.4, 123.2, 123.7, 124.3,
124.6, 124.8, 126.1, 126.8, 127.2, 127.6, 128.5, 128.8, 129.2,
138.0, 138.6, 140.4, 140.6, 140.7, 141.1, 145.4, 153.2, 168.2,
173.0, 180.6; MS (EI, m/z) 531 [M]þ; HRMS (EI) calcd for
C30H23N3NiO3 [M]þ 531.1093, found 531.1131.
Procedure for the Synthesis of 4a. The complex 3a was
hydrolyzed by stirring a suspension in a mixture of aqueous
1 N HCl (1 mL) and methanol (15 mL) for 30 min at room
temperature until the red color of the solution disappeared. The
reaction was evaporated to dryness and purified by flash column
chromatography (petroleum ether/ethyl acetate) to give 4a as
a white solid.
2,2-Di(4-nitrobenzyl)acetaldehyde Complex 4a: white solid;
1H NMR (CDCl3, 300 MHz) δ 9.74 (s, 1H), 8.17 (d, J = 8.7 Hz,
4H), 7.32 (d, J = 8.7 Hz, 4H), 3.13-3.20 (m, 3H), 2.85 (d, J =
12.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 34.5, 54.0, 123.9,
129.8, 145.7, 147.0, 201.4; MS (EI, m/z) 314 [M]þ; HRMS (EI)
calcd for C16H14N2O5 [M]þ 314.0903, found 314.0919.
Procedure for the Synthesis of 5b. In a hydrogenation flask
were placed compound 6b and methanol (10 mL) before the
addition of Pd/C. The resulting mixture was pressurized to
hydrogen and mechanically stirred at room temperature for 4 h.
The reaction mixture was filtered, and the filtrate was concentrated
in a rotary evaporator to afford the crude product. The crude
residue was purified by column chromatography on C18-reversed
phase (230-400 mesh) silica gel (water/ methanol = 11/9) to give
5b as a white solid in 62% yield, and the column chromatography
was washed with 100 mL of methanol for further use.
r,r-Dibenzyl-β-alanine complex 5b: white solid; 1H NMR
(CDCl3, 400 MHz) δ 7.33-7.47 (m, 10H), 3.41 (s, 1H), 3.22 (d,
J = 13.5 Hz, 2H), 2.96 (s, 2H), 2.87 (d, J = 13.5 Hz, 2H); 13
C
NMR (CDCl3, 100 MHz) δ 43.0, 44.7, 52.2, 129.9, 131.1, 132.6,
137.7, 179.2; MS (ESI, m/z) 268 [M - H]þ; HRMS (ESI) calcd
for C17H18NO2 [M - H]þ 268.1338, found 268.1346.
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation of
China (Grant Nos. 20721003 and 20872153), International
Collaboration Projects (Grant No. 20720102040), the 863
Hi-Tech Program of China (Grant 2006AA020602), and
National S&T Major Projects (Grant Nos. 2009ZX09501-
001 and 2009ZX09501-010).
Supporting Information Available: Detailed experimental
procedures, characterization data, copies of 1HNMR and
13CNMR spectra for all products, and crystallographic infor-
mation files (CIF) of 3a. This material is available free of charge
via the Internet at http://pubs.acs.org.
Procedure for the Synthesis of 6b. The complex 3b (200 mg,
0.328 mmol) was dissolved in methanol (10 mL), and then
NaBH4 (13 mg, 0.34 mmol) was added under ambient condi-
tions. The reaction mixture was stirred at room temperature for
1722 J. Org. Chem. Vol. 75, No. 5, 2010