C2-symmetric recyclable organocatalyst for enantioselective Strecker reaction for the synthesis of α-amino acid and chiral diamine-an intermediate for APN inhibitor

Article abstract of DOI:10.1021/jo300349f

Recyclable chiral amide-based organocatalyst 5 efficiently catalyzed asymmetric Strecker reaction of various aromatic and aliphatic N-benzhydrylimines with ethyl cyanoformate as cyanide source at -10 °C to give a high yield (95%) of α-aminonitriles with excellent chiral induction (ee, up to 99%) with the added advantage of recyclability. Based on experimental observations a probable mechanism was proposed for this reaction. This protocol with catalyst 5 was extended for the synthesis of (R)-phenylalanine and pharmaceutically important drug intermediate (R)-3-phenylpropane-1,2-diamine in high yield with high enantioselectivity.

Full text of DOI:10.1021/jo300349f

Article
pubs.acs.org/joc
C2-Symmetric Recyclable Organocatalyst for Enantioselective
Strecker Reaction for the Synthesis of α-Amino Acid and Chiral
Diamine- an Intermediate for APN Inhibitor
S. Saravanan,† Arghya Sadhukhan,† Noor-ul H. Khan,*,† Rukhsana I. Kureshy,† Sayed H. R. Abdi,†
and Hari C. Bajaj†
†Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute (CSMCRI), Council of
Scientific & Industrial Research (CSIR), G. B. Marg, Bhavnagar 364 021, Gujarat, India
S
* Supporting Information
ABSTRACT: Recyclable chiral amide-based organocatalyst 5
efficiently catalyzed asymmetric Strecker reaction of various
aromatic and aliphatic N-benzhydrylimines with ethyl cyano-
formate as cyanide source at −10 °C to give a high yield (95%)
of α-aminonitriles with excellent chiral induction (ee, up to 99%)
with the added advantage of recyclability. Based on experimental
observations a probable mechanism was proposed for this
reaction. This protocol with catalyst 5 was extended for the
synthesis of (R)-phenylalanine and pharmaceutically important
drug intermediate (R)-3-phenylpropane-1,2-diamine in high
yield with high enantioselectivity.
asymmetric Strecker reaction with NCCOOEt is concerned,
aluminum-6v and titanium-based17a complexes have shown high
activity and enantioselectivity albeit with different classes of
aldimines and ketimines as substrates. While acknowledging the
pioneering advances in the use of organocatalyst for the
Strecker reaction, the need for very low temperatures (−70 to
−20 °C) and the use of stable and safer sources of cyanide are
major concerns. Besides these issues, catalyst recyclability is
also a concern, considering the high catalyst loading (typically
above 10%) and the cost involved in the synthesis (often
multistep) of these catalysts. Mechanistically, catalyst activity
heavily relies on the weak acid sites capable of forming
hydrogen bonds22 with the substrate, whereas the enantiose-
lectivity is greatly influenced by the electronic and steric
features of the substituents surrounding these sites. As a result,
sulfonamide- and amide-derived ligands have been extensively
studied in asymmetric catalysis. Based on these considerations,
we have synthesized a series of C1- and C2-symmetric
organocatalysts having sulfonamide and amide groups of
varying steric features with one to four chiral centers. All of
the catalysts were synthesized in two easy synthetic steps. The
effect of matched and mismatched chiral centers on the
enantioselectivity of those catalysts that have more than two
chiral centers was also assessed. To our advantage, some of the
C2-symmetric catalysts gave α-amino nitriles in high yield (up
to 95%) with excellent enantioselectivity (up to ee, 99%), in
INTRODUCTION
■
The most elemental quest in the organic synthesis is to explore
new synthetic strategies for preparing biologically active
molecules in an efficient and elegant manner. Chiral α-amino
acid derivatives and diamines are the classes of compounds
required in their high enantiomeric purity for their high-end
applications in the area of genetic engineering,1 bioactives,2
pharmaceuticals,3 and asymmetric catalysis.4 Asymmetric
Strecker reaction5 represents one of the simplest and atom-
economic multicomponent reactions via hydrocyanation of
imines to afford α-amino nitrile, which on subsequent
hydrolysis gives natural and unnatural α-amino acids.5 Both
metal6 and metal-free7 asymmetric Strecker reaction protocols
have been documented; however, metal-free protocols were
preferred in order to avoid metal contamination in the final
product. Since the application of chiral cyclic dipeptides by
Lipton et al.8 in the Strecker reaction, various other
organocatalysts, viz., bicyclic guanidines,9 ureas and thioureas,10
carbohydrates,11 N-oxides,12 bisformamides,13 ammonium
salts,14 Brønsted acids,15 amino acids,16 alkaloids,17 and
phase-transfer catalysts,18 have been used for this purpose.
TMSCN is the most frequently used cyanide source,3,5,19 but
few reports suggested the use of acetone cyanohydrin,18b
HCN,15 KCN,18 Bu3SnCN,6k and Et2AlCN.20 Ironically,
NCCOOEt,6v,21 which is among the safest to handle sources
of cyanide, did not find a place with organocatalysts for the
asymmetric Strecker reaction. Recently, dimethyl sulfoxide21 as
an organocatalyst was reported to promote nonenantioselective
Strecker reaction with NCCOOEt. As far as metal-catalyzed
Received: February 29, 2012
Published: April 12, 2012
© 2012 American Chemical Society
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a
Table 1. Screening of Chiral Organocatalysts 1−11 for Asymmetric Strecker Reaction
a
Enantioselective Strecker reaction of N-benzhydrylimine (0.12 mmol) was carried out with catalysts 1−11 using NCCOOEt (0.18 mmol) as a
b
c
*
source of cyanide. Isolated yield. ee were determined by chiral HPLC using an AD-H column. Catalyst.
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some cases, by using ethyl cyanoformate as a cyanide source at
moderate temperatures (−10 °C to rt).
If we look at catalyst 5 fabrication, it has three basic
components: (1) phenylalanine, (2) diphenyldiamine, and (3)
sulfonamide. When we changed any one component of catalyst
5, as in the case of subsequent catalysts 9−11, significant drops
in the product ee to 54, 40, and 61%, respectively, were
observed.
The catalyst 5 was found to be very active under the above
used reaction conditions for the hydrocyanation of N-
benzhydrylimine using TMSCN as a cyanide source giving
the product in 99% yield in 3 h but with lower ee (18%). The
ee of the product was improved to 30% on lowering the
temperature to −20 °C; however, it took 10 h for the reaction
to complete. Possibly the acidity of the catalyst is high enough
to release the HCN rapidly, thereby increasing the rate of the
nonenantioselective background reaction.
Overall, the organocatalyst 5 was distinctly better in terms of
activity and enantioselectivity under the reaction conditions
used above. In order to improve the results, particularly the
enantioselectivity, the catalyst 5 (Table 1, entry 5) was
subjected to reaction condition optimization experiments
using N-benzhydrylimine as a model substrate and ethyl
cyanoformate as a cyanide source at rt. The role of additives on
the reactivity and enantioselectivity of asymmetric Strecker
reaction is well documented;5a therefore, first we took different
protic additives (mainly alcoholic) viz., MeOH, EtOH, and i-
PrOH (2.0 equiv) (Table 2, entries 1−3), in place of water that
RESULTS AND DISCUSSION
■
The organocatalysts 1−10 (Table 1) were derived from L-
phenylalanine, whereas catalyst 11 was based on L-alanine. The
catalyst 1 was directly obtained by the reaction of L-
phenylalanine with p-toluenesulfonyl chloride in a 1:1.2 molar
ratio. The carboxylic acid group of catalyst 1 was converted to
acid chloride in high yield by its reaction with SOCl2 in slight
stoichiometric excess (1:1.5 equiv) in dry chloroform.
Incidentally, other chlorinating agents like PCl5, POCl3, ethyl
chloroformate, and neat SOCl2 do not give desirable products.
The acid chloride of the catalyst 1 was directly reacted with
various chiral amines, amino alcohols, and diamines to give
catalysts 2−9 in quantitative yields. Catalyst 10 was prepared
by the condensation of (1S,2S)-(−)-1,2-diphenyldiaminoethane
with Boc-protected L-phenylalanine acid chloride. (Character-
ization data are given in the Supporting Information).
Moreover, the DCC coupling of catalyst 1 with these chiral
amines gave the targeted catalysts in low yield and required
column chromatographic separation to get desirable purity.
It is understood from the body of the literature available that
the activation of substrate−imine with organocatalyst is solely
via noncovalent interactions (mostly H-bonding), while
enantioselectivity is greatly influenced by the orientation of
the substrate vis-a-
̀
vis chiral catalyst.21 Therefore, in an
Table 2. Effect of Additives and Temperature on Asymmetric
organocatalyst the steric factors and/or placement of bulkier
groups in space play a significant role in manifesting the
enantio-induction. Keeping these factors in mind, the catalyst
1−11 were designed and screened for their efficacy in the
asymmetric Strecker reaction of N-benzhydrylimine (as a test
substrate) using ethyl cyanoformate (safer source of cyanide) as
a cyanide source and water as an additive as well as a source of
proton in toluene at rt. First, we took the sulfonamide derivate
of (S)-phenylalanine 1 as a catalyst that gave the product in
high yield (80%) but with 7% ee (Table 1, entry 1). It is
possible that the free terminal −COOH group of catalyst 1
might strongly bind imine, thereby undermining the influence
of the groups surrounding the chiral center of the catalyst to
give the product with low ee. Hence, we converted the
−COOH group of catalyst 1 to amide group by using (S)-1-
phenylethylamine; consequently the −NH− group thus
generated in the catalyst 2 was placed between the two chiral
centers. This situation closely resembled the chiral urea used as
catalyst in Strecker reaction.10e The catalyst 2 with two chiral
centers indeed improved enantioselectivity significantly (ee,
42%, entry 2). Noticeably, when the (R)-form of the amine was
used, as in catalyst 3, there was a steep fall in the product ee
(16%, entry 3) indicating the strong influence of orientation of
the substituents around chiral centers. The catalyst 4, which
was prepared by condensation of catalyst 1 with (1R,2S)-2-
amino-1,2-diphenylethanol that bears a free alcohol group, gave
poor ee (10%, entry 4) in the product as was the case with
catalyst 1. Switching over to C2-symmetric catalysts 5−11 from
the C1-symmetric catalysts 1−4 was of a distinct advantage
particularly in terms of enantioselectivity (entries 5−9). Among
these, the catalyst 5 (all S chiral centers) and 8 (all R chiral
centers) derived by the condensation of catalyst 1 with 1,2-
diamino-1,2-diphenylethane were found to be most effective to
give product ee's of 73% (with R in excess) and 71% (with S in
excess), respectively. The mismatched chirality in the catalysts
6 and 7 gave product with lower ees 42 and 33%, respectively.
a
Strecker Reaction
b
c
entry additive (equiv) temp (°C) time (h) yield (%) ee (%)
1
2
3
4
5
6
7
8
MeOH (2.0)
EtOH (2.0)
i-PrOH(2.0)
i-PrOH (1.0)
i-PrOH (3.0)
i-PrOH (2.0)
i-PrOH (2.0)
i-PrOH (2.0)
rt
rt
10
10
12
15
10
15
20
36
83
82
85
76
85
85
85
74
58
47
82
73
80
84
90
89
rt
rt
rt
0
−10
−20
a
Enantioselective Strecker reaction of N-benzhydrylimine (0.12
mmol) was carried out with catalyst 5 in toluene using NCCOOEt
b
c
(0.18 mmol)as a source of cyanide. Isolated yield. ee were
determined by chiral HPLC using AD-H column.
was used as an additive and proton source while screening of
the catalysts 1−11. Evidently, the use of i-PrOH significantly
improved the enantioselectivity (ee, 82%) of the product α-
aminonitrile without affecting the product yield. We next
optimized the loading of i-PrOH by keeping the other
parameters constant (Table 2, entries 3−5), which showed
that at lower i-PrOH loading (1.0 equiv) there was a decrease
in the product ee and yield but when the amount of i-PrOH
was increased (3.0 equiv) the reactivity and enantioselectivity
remained similar; therefore, 2.0 equiv of additive loading was
taken as an optimum (Table 2, entry 3). Further, variation in
reaction temperature revealed that lowering the temperature to
−10 °C had some beneficial effect on the product ee (from rt
82% to 90%) though the reaction took a longer time (from rt
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a
10 to 20 h) to complete. A further lowering of the temperature
(−20 °C) did not have any positive impact on the product ee
because at the same time reaction became too sluggish (36 h).
Therefore, −10 °C was taken as optimum for further studies.
Further, the catalyst loading of 10 mol %, which was used in
the preceding experiments, was found to be optimum as it was
observed that by decreasing the catalyst loading (5 mol %) the
product yield (78%) and ee (73%) dropped significantly. On
the other hand, on increasing the catalyst loading (15 mol %),
the reaction was faster but with a marginal drop in ee (88%),
while the product yield remained the same (Table 3, entry 3).
Table 4. Scope of Substrates Catalyzed by Catalyst 5
b
c
entry
R
time (h)
yield (%)
ee (%)
d
1
2
Ph (1a)
20
24
24
24
24
20
20
20
20
20
20
20
20
20
24
85
92
95
91
90
86
85
78
75
79
88
90
77
70
74
91 (R)
2-Br-C6H4 (1b)
2-NO2-C6H4 (1c)
2-F-C6H4 (1d)
2-Cl-C6H4 (1e)
2-MeO-C6H4 (1f)
3-MeO-C6H4 (1g)
4-MeO-C6H4 (1h)
2-EtO-C6H4 (1i)
2-Me-C6H4 (1j)
tert-butyl (1k)
96
99
99
92
78
65
28
86
74
95
93
81
60
85
3
4
Table 3. Exploring the Appropriate Catalyst Loading (mol
%) and Effect of Solvent on Asymmetric Strecker Reaction
a
5
6
7
8
9
10
11
12
13
14
15
catalyst loading
(mol %)
time
(h)
yield
(%)
ee
Ph-CH2 (1l)
entry
solvent
toluene
(%)
isobutyl (1m)
1
2
3
4
5
6
7
10
5
20
20
16
12
12
16
20
85
78
85
90
88
70
88
90
73
88
72
65
52
82
3-pyridinyl (1n)
2-naphthyl (1o)
toluene
toluene
CH2Cl2
CHCl3
THF
15
10
10
10
10
a
Enantioselective Strecker reaction of imine (0.12 mmol) was carried
out with catalyst 5 using NCCOOEt (0.18 mmol) as a source of
b
c
cyanide in the presence of i-PrOH (2 equiv). Isolated yield. ee were
determined by chiral HPLC using AD-H and OD-H columns.
Absolute configurations were assigned in comparison to the literature
d
toluene/DCM
(1:0.5)
reports12c and optical rotation.
8
10
toluene/DCM
(1:1)
20
90
80
a
Enantioselective Strecker reaction of N-benzhydrylimine (0.12
mmol) was carried out with catalyst 5 using NCCOOEt as a source
Mechanism. To understand the mechanism of the Strecker
reaction with the present catalyst, a series of experiments were
carried out. It is well-known in the literature that HCN can add
to imine in the absence of a catalyst at rt.6h Therefore, at first
we wanted to understand whether NCCOOEt or HCN (in situ
generated) is the real source of cyanide. To verify this, we
conducted the reaction of N-benzhydrylimine with NCCOOEt
under dry conditions at rt, which showed only trace amounts of
cyanated product. However, in the presence of i-PrOH, the
same reaction gave racemic product in ∼10% yield in 12 h,
while in the presence of catalyst 5 under similar conditions the
reaction proceeded well to give the product in 85% yield and
82% ee in 12 h. Therefore, it can be safely presumed that
NCCOOEt is the cyanating agent while the additive (i-PrOH)
is primarily the source of proton to get the final product. The
next issue was the mode of binding of the catalyst with aldimine
substrates. It is obvious that the imine nitrogen would prefer a
binding with the more acidic proton of the catalyst, which is the
b
c
of cyanide in presence of i-PrOH (2 equivalents). Isolated yield. ee
were determined by chiral HPLC using AD-H column.
For the solvent variation, CH2Cl2, CHCl3, and THF and a
mixture of toluene and CH2Cl2 were used for easy handling for
carrying out the Strecker reaction under the above-optimized
conditions (entries 4−8). However, toluene remained the
solvent of choice (Table 3, entry 1).
Having established the reaction parameters for the use of the
catalyst 5 in the asymmetric Strecker reaction with the reactants
N-benzhydrylimine and ethyl cyanoformate at −10 °C, we next
looked for its utility in different substrates having various
substituents on the imine functionality (Table 4). In these
cases, product yield was found to be very good to excellent
(75−95%). Both electronic features and placement of
substituent in the phenyl group significantly influence the ee
of the product. Thus, R with electron-withdrawing groups like
NO2, Br, F, and Cl gave excellent ees of 99%, 96%, 99%, and
92% respectively (entries 2−5) in the product. As far as
placement of substituent on Ph of the aldehyde arm (o-/m-/p-
OMe Ph), the trend for ee in the product was found to be o >
m > p (entries 6−8). On the other hand, in the cases where R is
alkyl the steric feature seems to be play a larger role in
introducing higher ee's in the products (entries 9−11), while
heteroarene-based aldimines like the pyridyl derivative and
naphthalene-derived aldimine gave ee's of 60% and 85%,
respectively (Table 4, entries 12 and 13). Conclusively, the
catalyst 5 was able to catalyze asymmetric Strecker reaction of
fairly broad range of aldimines with good to excellent ee in the
product.
1
proton of sulfonamide origin. The H NMR spectra of the
mixture of catalyst 5 and N-benzhydrylimine show that a
doublet for sulfonamide proton at 4.94 ppm shifted significantly
downfield to appear at 5.02 ppm as a broad peak (Figure 1),
whereas the proton of amide origin was not much affected. A
similar observation was obtained in 13C NMR as well (Figure
2). Therefore, it can be concluded that the contact between the
sulfonamide proton of the catalyst and the imine nitrogen of
the substrate is established to form intermediate I-1 in the
catalytic cycle (Scheme 1). Although there was no direct
observation for the activation of NCCOOEt, the 13C NMR of
the mixture of catalyst 5 and NCCOOEt showed an additional
set of two peaks for −CH peaks belonging to phenylalanine and
diphenylamine moieties at 63.2 and 64.1 ppm, respectively
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1
Figure 1. H NMR spectra were taken in CDCl3: (a) catalyst 5; (b) catalyst 5 after interaction with imine.
Figure 2. 13C NMR spectra recorded in CDCl3: (a) catalyst 5; (b) catalyst 5 after interaction with imine.
(Supporting Information). Originally, in the absence of
NCCOOEt, there was only one set of peaks at 58.6 and 59.6
ppm for these carbons. These observations clearly indicate that
NCCOOEt is placed somewhere in between these two carbons
via an intermediate I-2 during the cyanide transfer in the
catalytic cycle. Accordingly, a probable mechanism is proposed
as shown in the Scheme 1, which also follows the sequence of
the addition of each reactant used in our all experiments.
Recyclability of Catalyst. Often, catalysts used under
homogeneous condition are not recycled due to their inherent
problem of separation in the postcatalysis workup. However, it
is prudent to attempt catalyst recyclability to know its stability
under the reaction conditions. Additionally the increased
turnover number of the catalyst as a result of its successful
reuse would offset the overall catalyst cost and make the
protocol suitable for practical application. Therefore, reuse
experiments were conducted using 2-NO2-Ph substituent on N-
benzhydrylimine as a representative substrate with catalyst 5
(10 mol %) and ethyl cyanoformate as a source of cyanide at
−10 °C in toluene in the presence of i-PrOH. After the catalytic
run, the amount of the solvent was reduced, and the
organocatalyst 5 was precipitated by addition of an excess
amount of n-hexane. The precipitated organocatalyst was
washed thoroughly with hexane, dried in vacuum, stored
under dry and inert atmosphere, and used for the subsequent
catalytic run without further purification. The recovered catalyst
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Scheme 1. Probable Mechanism for Enantioselective Strecker Reaction Catalyzed by 5
worked well for the asymmetric Strecker reaction of 2-NO2-Ph
substituents on N-benzhydrylimine without any loss of its
reactivity and enantioselectivity up to three cycles (Figure 3).
Application of Catalyst 5 in the Synthesis of (R)-
Phenylalanine and (R)-3-Phenylpropane-1,2-diamine.
The present catalytic asymmetric Strecker protocol with
catalyst 5 was successfully extended to the synthesis of valuable
unnatural (R)-phenylalanine 12 and (R)-3-phenylpropane-1,2-
diamine derivatives 13 and 14, an pharmaceutically important
drug intermediate for aminopeptidase N (APN) inhibitor23
(Scheme 2). The compounds 12 and 14 were obtained in fewer
steps with high yield and marginal effect on the enantiose-
lectivity (experimental procedures and characterization data are
provided in the Supporting Information).
CONCLUSION
■
The chiral organocatalyst 5 is highly efficient for the catalysis of
the asymmetric Strecker reaction of aromatic and aliphatic
aldimines with ethyl cyanoformate as a source of cyanide for
the first time. High yields and ee’s were achieved with a wide
range of substrates, in particular, with 2-NO2 and 2-F
substituents on N-benzhydrylimine where yield and enantiose-
lectivity for the product α-aminonitrile was excellent. The
Figure 3. Recyclability of catalyst 5 using 2-NO2-Ph-substituted N-
benzhydrylimine.
Scheme 2. Transformation of the Chiral α-Aminonitrile to Value-Added Products
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diluted with excess dichloromethane. After filtration and removal of
solvent under vacuum, the white residue was recrystallized using ethyl
acetate to give pure catalyst 10 as a white solid in 90% yield (1.19 g).
catalyst 5 was recycled three times and was employed
successfully in the synthesis of (R)-phenylalanine and
pharmaceutically important drug intermediate (R)-3-phenyl-
propane-1,2-diamine in high yield and enantioselectivity within
three convenient steps.
Catalyst 1: yield 1.8 g, 95%; white crystals; mp 163 °C; [α]27
=
D
−15 (c = 2, CH3COCH3); FTIR 3286, 3035, 1730, 1675, 1597, 1424,
1
1336, 1212, 1159, 1075, 907, 812, 746, 676 cm−1; H NMR (500
MHz, CDCl3) δ = 2.39 (s, 3H), 2.96−3.00 (dd, J = 6.5, 14 Hz, 1H),
3.06−3.10 (dd, J = 5.5, 14 Hz, 1H), 4.18−4.22 (q, J = 6 Hz, 1H), 5.16
(d, J = 9 Hz, 1H), 7.05−7.07 (m, 2H), 7.19−7.25 (m, 5H), 7.57−7.58
(d, J = 8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ = 21.6, 39.0, 56.5,
127.2, 127.5, 128.8, 129.6,129.8, 134.8, 136.6, 143.9, 178.5; TOF-MS
(ESI+) calcd for (C16H17NO4S + Na+) 342.36, found 342.4.
EXPERIMENTAL SECTION
■
Preparation of Catalyst 5. Step 1: Typical Procedure for the
Synthesis of Catalyst 1.24 To a solution of
L
-phenylalanine (1 g,
6.05 mmol) dissolved in 15 mL of 1.5 N NaOH was added p-
toluenesulfonyl chloride (1.38 g, 7.26 mmol) in diethyl ether
(10 mL) at room temperature. After 8 h of stirring, concd HCl
was added to the viscous white solution until it became
homogeneous. The ether layer was separated, and the aqueous
layer was extracted twice with ether. The crude product was
recrystallized from ether and ethanol mixture to give pure
compound as white crystals (Scheme 3).
Catalyst 2: yield 0.71 g, 88%; white powder; mp 215 °C; [α]27
=
D
−156 (c = 1, CHCl3); FTIR 3305, 3249, 3060, 2978, 2915, 2367,
1
1950, 1636, 1534, 1434, 1327, 1157, 187, 930, 709, 691 cm−1; H
NMR (200 MHz, CDCl3) δ = 1.34 (d, J = 7 Hz, 3H), 2.421 (s, 3H),
2.85 (dd, J = 6.6, 13.8 Hz, 1H), 3.04 (dd, J = 6.4, 13.8 Hz, 1H), 3.88
(q, J = 6.6 Hz, 1H), 4.95 (m, 2H), 6.38 (d,J = 8.2 Hz, 1H), 6.93 (m,
2H), 7.1 − 7.3 (m, 10 H), 7.59 (d,, J = 8.4 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ = 22.0, 38.7, 49.4, 58.0, 116.4, 126.3, 127.4,127.5,
128.9, 129.2, 129.5, 130.1, 135.4, 142.6, 144.2, 148.3, 169.2. Anal.
Calcd for C24H26N2O3S: C, 68.22; H, 6.20; N, 6.63; S, 7.59; O, 11.36.
Found: C, 68.25; H, 6.18; N, 6.69; S, 7.45; O, 11.26. TOF−MS (ESI
+) Calcd for (C24H26N2O3S+H+) 423.54, Found: 423.22.
Scheme 3. Preparation of Catalyst 1
Catalyst 3: yield 0.70 g, 87%; white powder; mp 192 °C; [α]27
=
D
−102 (c = 0.5, CHCl3); FTIR 3309, 3251, 3058, 2981, 2921, 2367,
1
1950, 1636, 1543, 1439, 1328, 1159, 185, 932, 710, 692 cm−1; H
NMR (200 MHz, CDCl3) δ = 1.34 (d, J = 7 Hz, 3H), 2.42 (s, 3H),
2.85 (dd, J = 6.6, 13.8 Hz, 1H), 3.04 (dd, J = 6.4, 13.8 Hz, 1H), 3.88
(q, J = 6.6 Hz, 1H), 4.95 (m, 2H), 6.38 (d, J = 8.2 Hz, 1H), 6.93 (m,
2H), 7.1 − 7.3 (m, 10 H), 7.59 (d,, J = 8.4 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ = 22.0, 38.7, 49.4, 58.0, 116.4, 126.3, 127.4, 127.5,
128.9, 129.2, 129.5, 130.1, 135.4, 142.6, 144.2, 148.4, 169.3; TOF-MS
(ESI+) calcd for (C24H26N2O3S + H+) 423.54, found 423.19. Anal.
Calcd for C24H26N2O3S: C, 68.22; H, 6.20; N, 6.63; S, 7.59; O, 11.36.
Found: C, 68.28; H, 6.10; N, 6.58; S, 7.53; O, 11.16.
Step 2: Typical Procedure for the Synthesis of Catalyst 5. To the
tosyl-protected L-phenylalanine 1 (1 g, 3.13 mmol) in dry chloroform
was added dropwise freshly distilled thionyl chloride (341 μL, 4.70
mmol), and the resulting mixture was stirred at room temperature for
1 h. Subsequently, the solution was refluxed for a further 2 h. The clear
yellow solution thus obtained was distilled completely to give a
quantitative yield of acid chloride as yellow solid. The formed acid
chloride was then immediately dissolved in dry CH2Cl2 under nitrogen
atmosphere and cooled to 0 °C. To the cooled solution was added
(1S,2S)-1,2-diphenylethane-1,2-diamine (316 mg, 1.5 mmol) in
CH2Cl2 dropwise under nitrogen atmosphere. After the solution was
stirred for 2 h, the reaction temperature was gradually increased to
room temperature and the mixture was allowed to stir at room
temperature for 8 h. Then, the solution was extracted with water (50
mL × 5) and dried over anhydrous Na2SO4. Consequently, the solvent
was removed under reduced pressure, the resulting pale yellow solid
was dissolved in a minimum amount of dichloromethane and an excess
amount of hexane was added to precipitate out the desired product.
The precipitate was washed twice with hexane, filtered, and dried
completely to give catalyst 5 as white solid in 92% yield (Scheme 4).
Catalyst 4: yield 0.73 g, 92%; white powder; mp 178 °C; [α]27
=
D
−57 (c = 1, CHCl3); FTIR 3306, 3035, 2924, 2364, 1654, 1540, 1450,
1331, 1234, 1157, 1089, 1045, 942, 812, 750, 699, 543 cm−1; 1H NMR
(500 MHz, CDCl3) δ = 2.39 (s, 3H), 2.72 (d, J = 5 Hz, 1H), 2.86 (m,
2H), 3.87 (q, J = 5 Hz, 1H), 4.83 (d, J = 5.5 Hz, 1H), 5.03 (t, J = 5 Hz,
1H), 5.18 (q, J = 4.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 2H), 6.94 (s, J = 7.5
Hz, 2H), 7.01 (t, J = 7.5 Hz, 2H), 7.13−7.32 (m, 12H), 7.49 (d, J = 8
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ = 21.8, 38.4, 58.0, 59.6,
76.9, 126.7, 127.5, 128.1, 128.2, 128.4, 129.2, 129.4, 130.1, 135.4,
135.9, 136.7, 139.7, 144.2, 170.1; TOF-MS (ESI+) calcd for
(C30H30N2O4S + H+) 515.19, found 516.23. Anal. Calcd for
C30H30N2O4S: C, 70.01; H, 5.88; N, 5.44; S, 6.23; O, 12.44. Found:
C, 69.94; H, 5.81; N, 5.50; S, 6.14; O, 12.56.
Catalyst 5: yield 0.43 g, 92%; white powder; mp 214 °C; [α]27
=
D
−127 (c = 1, CHCl3); FTIR 3274, 3064, 2926, 2374, 1950, 1659,
Scheme 4. Preparation of Catalyst 5
1544, 1435, 1375, 1332, 1158, 1089, 1030, 958, 917, 812, 745, 699,
1
666, 553 cm−1; H NMR (500 MHz, CDCl3) δ = 2.41 (s, 6H), 2.82
(dd, J = 6, 14.5 Hz, 2H), 2.94 (dd, J = 7, 14.5 Hz, 2H), 4.09 (q, J = 7
Hz, 2H), 4.95 (d, J = 7 Hz, 2H), 5.12 (m, 2H), 6.80 (d, J = 7 Hz, 4H),
6.92−6.94 (m, 4H), 7.07 (t, J = 7.5 Hz, 4H), 7.15−7.18 (m, 12H),
7.57 (d, J = 8 Hz, 4H), 7.68 (bs, 2H); 13C NMR (125 MHz, CDCl3) δ
= 21.73, 38.17, 58.56, 59.55, 126.69, 127.13, 127.69, 127.89, 128.58,
128.66, 129.32, 129.82, 136.35, 136.59, 138.40, 143.56, 171.39; TOF-
MS (ESI+) calcd for (C46H46N4O6S2) 815.01, found 815.81. Anal.
Calcd for C46H46N4O6S2: C, 67.79; H, 5.69; N, 6.87; S, 7.87; O, 11.78.
Found: C, 67.81; H, 5.65; N, 6.81; S, 7.91; O, 11.84.
Catalyst 6: yield 0.42 g, 90%; white powder; mp 179 °C; [α]27
=
D
Preparation of Catalyst 10.25 To a solution of Boc-L-phenyl-
alanine (1 g, 3.77 mmol) in 15 mL of dry dichloromethane was slowly
added triethylamine (0.525 mL, 3.77 mmol) at 0 °C. To this cooled
solution was added dropwise ethyl chloroformate (0.409 mL, 3.77
mmol) and the resulting solution stirred at the same temperature for
15 min. Then optically pure diamine (0.4 g, 1.89 mmol) was added,
and the resulting solution was stirred for 8 h. The whole solution was
−67 (c =1, CHCl3); FTIR 3291, 3082, 2931, 2367, 1955, 1654, 1554,
1438, 1385, 1334, 1160, 1084, 1032, 954, 921, 819, 745, 698, 668, 555
cm−1; 1H NMR (500 MHz, CDCl3) δ = 2.42 (s, 6H), 2.81 (dd, J = 6,
14.5 Hz, 2H), 2.91 (dd, J = 7.5, 7 Hz, 2H), 4.09 (q, J = 7 Hz, 2H), 4.94
(d, J = 7 Hz, 2H), 5.12 (m, 2H), 6.81 (d, J = 7 Hz, 4H), 6.92−6.95 (m,
4H), 7.08 (t,J = 7.5 Hz, 4H), 7.14−7.18 (m, 12H), 7.57 (d, J = 8 Hz,
4H), 7.67 (bs, 2H); 13C NMR (125 MHz, CDCl3) δ = 21.73, 38.17,
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Article
58.56, 59.55, 126.69, 127.13, 127.69, 127.89, 128.58, 128.66, 129.32,
129.82, 136.35, 136.59, 138.40, 143.56, 171.39; TOF-MS (ESI+) calcd
for (C46H46N4O6S2) 815.01, found 815.27. Anal. Calcd for
C46H46N4O6S2: C, 67.79; H, 5.69; N, 6.87; S, 7.87; O, 11.78.
Found: C, 67.82; H, 5.64; N, 6.89; S, 7.91; O, 11.36.
solution was stirred for 2 h at rt. Then the solution was cooled to −10
°C, and NCCOOEt (0.375 mmol) was added slowly over a period of
30 min followed by the very slow addition of i-PrOH (20 μL).
(Caution: the order for the addition of reagents should be maintained as
mentioned; otherwise, the ee of the product will drop.) The reaction was
monitored by TLC using hexane/ethyl acetate (90/10) as eluent. After
the reaction was complete, the solvent was removed on a rotavapor
and the product was purified by flash column chromatography on silica
gel (eluted with hexane/ethyl acetate = 90:10). The purified products
Catalyst 7: yield 0.42 g, 91%; white powder; mp 186 °C; [α]27
=
D
−39 (c = 1, CHCl3); FTIR 3287, 3092, 2945, 2376, 1957, 1661, 1523,
1443, 1378, 1352, 1164, 1087, 1035, 951, 923, 821, 741, 698, 667, 551
cm−1; 1H NMR (500 MHz, CDCl3) δ = 2.41 (s, 6H), 2.82 (dd, J = 6,
14.5 Hz, 2H), 2.91 (dd, J = 7, 14.5 Hz, 2H), 4.09 (q, J = 7 Hz, 2H),
4.94 (d, J = 7 Hz, 2H), 5.12 (m, 2H), 6.81 (d, J = 7 Hz, 4H), 6.92−
6.96 (m, 4H), 7.08 (t, J = 7.5 Hz,4H), 7.14−7.18 (m, 12H), 7.57 (d, J
= 8 Hz, 4H), 7.67 (bs, 2H); 13C NMR (125 MHz, CDCl3) δ = 21.73,
38.17, 58.56, 59.55, 126.69, 127.13, 127.69, 127.89, 128.58, 128.66,
129.32, 129.82, 136.35, 136.59, 138.40, 143.56, 171.39; TOF-MS (ESI
+) calcd for (C46H46N4O6S2) 815.01, found 815.81. Anal. Calcd for
C46H46N4O6S2: C, 67.79; H, 5.69; N, 6.87; S, 7.87; O, 11.78. Found:
C, 67.74; H, 5.71; N, 6.84; S, 7.79; O, 11.67.
1
were characterized by H NMR which was in agreement with the
reported values.12c
(R)-2-(Benzhydrylamino)-2-phenylacetonitrile (Table 4,
Entry 1). The title compound was isolated by column chromatog-
raphy (hexane/ethyl acetate 95/5) as a white solid: [α]27D = 104 (c =
1
0.4, CHCl3); H NMR (500 MHz, CDCl3) δ 2.15 (d, J = 12.5 Hz,
1H), 4.60 (d, J = 12.5 Hz, 1H), 5.24 (s, 1H), 7.22−7.57 (m, 15H);
CHIRALCEL AD-H column, hexane/2-propanol = 80:20, flow rate 1
mL/min, tR1 (major) = 6.8 min, tR2 (minor) = 13.06 min.
Catalyst 8: yield 0.48 g, 94%; white powder; mp 182 °C; [α]27
=
(R)-2-(Benzhydrylamino)-2-(2-bromophenyl)acetonitrile
D
(Table 4, Entry 2). The title compound was isolated by column
+81 (c = 1, CHCl3); FTIR 3294, 3075, 2926, 2381, 1953, 1662, 1538,
1439, 1368, 1334, 1161, 1091, 1034, 956, 927, 815, 747, 694, 661, 554
cm−1; 1H NMR (500 MHz, CDCl3) δ = 2.41 (s, 6H), 2.82 (dd, J = 6,
14.5 Hz, 2H), 2.94 (dd, J = 7, 14.5, Hz, 2H), 4.09 (q, J = 7 Hz, 2H),
4.95 (d, J = 7 Hz, 2H), 5.12 (m, 2H), 6.80 (d, J = 7 Hz, 4H), 6.91−
6.94 (m, 4H), 7.07 (t, J = 7.5 Hz, 4H), 7.15−7.18 (m, 12H), 7.57 (d, J
= 8 Hz, 4H), 7.68 (bs, 2H); 13C NMR (125 MHz, CDCl3) δ = 21.73,
38.17, 58.56, 59.55, 126.69, 127.13, 127.69, 127.89, 128.58, 128.66,
129.32, 129.82, 136.35, 136.59, 138.40, 143.56, 171.39; TOF-MS (ESI
+) calcd for (C46H46N4O6S2) 815.01, found 815.27. Anal. Calcd for
C46H46N4O6S2: C, 67.79; H, 5.69; N, 6.87; S, 7.87; O, 11.78. Found:
C, 67.73; H, 5.66; N, 6.80; S, 7.81; O, 11.86.
chromatography (hexane/ethyl acetate 95/5) as a white solid: [α]27
=
D
62 (c = 0.1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.18 (d, J = 12.5
Hz, 1H), 4.61 (d, J = 12.5 Hz, 1H), 5.22 (s, 1H), 7.21−7.36 (m, 8H),
7.40−7.45 (m, 3H), 7.52−7.56 (m, 3H); CHIRALCEL AD-H column,
hexane/2-propanol = 80:20, flow rate 1 mL/min, tR1 (major) = 4.63
min, tR2 (minor) = 5.17 min.
(R)-2-(Benzhydrylamino)-2-(2-nitrophenyl)acetonitrile
(Table 4, Entry 3). The title compound was isolated by column
chromatography (hexane/ethylacetate 95/5) as a white solid: [α]27
=
D
78 (c = 0.1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.16 (d, J = 12.5
Hz, 1H), 4.62 (d, J = 12.5 Hz, 1H), 5.21 (s, 1H), 7.56 (m, 14H);
CHIRALCEL ADH column, hexane/2-propanol = 80:20, flow rate 1
mL/min, tR1 (major) = 6.86 min, tR2 (minor) = 7.54 min.
Catalyst 9: yield 0.47 g, 85%; white powder; mp 238 °C; [α]27
=
D
−114 (c = 1, CHCl3); FTIR 3302, 3096, 3034, 2931, 2861, 2362,
1924, 1644, 1540, 1451, 1331, 1158, 1091, 953, 815, 740, 696, 669,
553 cm−1; 1H NMR (500 MHz, CDCl3) δ = 1.04 (q, J = 10 Hz, 2H),
1.25 (t,J = 10 Hz, 2H), 1.69 (d, J = 8 Hz, 2H), 1.93 (d, J = 12 Hz, 2H),
2.49 (s, 6H), 2.85 (dd, J = 5.5, 14 Hz, 2H), 2.92 (dd, 7.5, 14 Hz, 2H),
3.51 (m, 2H), 3.92 −3.96 (m, 2H), 4.85 (d, J = 7 Hz, 2H), 6.86 (d, J =
5, Hz, 2H), 6.91 (d, J = 6.5, Hz, 4H), 7.13 (m, 10H), 7.52 (d, J = 8.5
Hz, 4H); 13C NMR (125 MHz, CDCl3) δ = 21.8, 24.7, 32.0, 38.0,
54.3, 57.8, 127.5, 129.1, 129.6, 130.1, 135.7, 136.3, 143.9, 171.3; TOF-
MS (ESI+) calcd for (C38H44N4O6S2 + H+) 717.27, found 718.20.
Anal. Calcd for C38H44N4O6S2: C, 63.66; H, 6.199; N, 7.82; S, 8.95; O,
13.39. Found: C, 63.64; H, 6.10; N, 7.85; S, 8.99; O, 13.29.
(R)-2-(Benzhydrylamino)-2-(2-fluorophenyl)acetonitrile
(Table 4, Entry 4). The title compound was isolated by column
chromatography (hexane/ethylacetate 95/5) as a white solid: [α]27
=
D
85 (c = 0.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.15 (d, J = 12.5
Hz, 1H), 4.62 (d, J = 12.5 Hz, 1H), 5.24 (s, 1H), 7.22−7.37 (m, 8H),
7.41−7.46 (m, 3H), 7.51−7.54 (m, 3H); CHIRALCEL ADH column,
hexane/2-propanol = 80:20, flow rate 1 mL/min, tR1 (major) = 4.8
min.
(R)-2-(Benzhydrylamino)-2-(2-chlorophenyl)acetonitrile
(Table 4, Rntry 5). The title compound was isolated by column
chromatography (hexane/ethyl acetate 95/5) as a white solid: [α]27
=
D
121 (c = 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.09 (d, J = 12.5
Hz, 1H), 4.74 (d, J = 12.5 Hz, 1H), 5.04 (s, 1H), 7.22−7.37 (m, 8H),
7.41−7.46 (m, 3H), 7.51−7.54 (m, 3H); CHIRALCEL ADH column,
hexane/2-propanol = 80:20, flow rate 1 mL/min, tR1 (minor) = 4.5
min, tR2 (major) = 5.2 min.
Catalyst 10: yield 1.19 g, 90%; white powder; mp 173 °C; [α]27
=
D
−94 (c = 1, CHCl3); FTIR 3300, 3060, 3030, 2925, 2861, 2370, 1953,
1653, 1502, 1453, 1340, 1290, 1111, 1028, 914, 845, 746, 699, 618,
536 cm−1; 1H NMR (500 MHz, CDCl3) δ = 1.41 (s, 18H), 3.08 (dd, J
= 4, 13.5 Hz, 2H), 1.69 (d, J = 4, 13.5 Hz, 2H), 3.56 (m, 2H), 5.16 (m,
2H), 5.25 (m, 2H), 7.05−7.07 (m, 4H), 7.22 −7.25 (m, 12H) 7.36−
7.38 (m, 4H); 13C NMR (125 MHz, CDCl3) δ = 28.8, 41.4, 56.8, 58.7,
80.3, 126.6, 127.4, 127.6, 128.4, 129.2, 138.6, 142.0, 158.1, 174.6;
TOF-MS (ESI+) calcd for (C42H50N4O6 + H+) 706.87, found 707.91.
Anal. Calcd for C42H50N4O6: C, 71.36; H, 7.13; N, 7.93; O, 13.58.
Found: C, 71.31; H, 7.17; N, 7.95; O, 13.64.
(R)-2-(Benzhydrylamino)-2-(2-methoxyphenyl)acetonitrile
(Table 4, Entry 6). The title compound was isolated by column
chromatography (hexane/ethyl acetate 95/5) as a white solid: [α]27
=
D
36 (c = 0.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.14 (d, J = 12.5
Hz, 1H), 3.87 (s, 3H), 4.60 (d, J = 12.5 Hz, 1H), 5.22 (s, 1H), 7.21−
7.36 (m, 8H), 7.40−7.45 (m, 3H), 7.52−7.56 (m, 3H); CHIRALCEL
OD-H column, hexane/2-propanol = 80:20, flow rate 1 mL/min, tR1
(minor) = 5.5 min, tR2 (major) = 6.5 min.
Catalyst 11: yield 0.47 g, 91%; pale yellow powder; mp 112 °C;
[α]27 = −56 (c = 0.8, CHCl3); FTIR 3321, 3071, 3042, 2943, 2876,
(R)-2-(Benzhydrylamino)-2-(3-methoxyphenyl)acetonitrile
D
2371, 1945, 1661, 1548, 1457, 1349, 1151, 1071, 958, 821, 747, 684,
(Table 4, Entry 7). The title compound was isolated by column
1
658, 545 cm−1; H NMR (500 MHz, CDCl3) δ = 1.13 (d, J = 7 Hz,
chromatography (hexane/ethyl acetate 95/5) as a white solid: [α]27
=
D
51 (c = 0.1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.12 (d, J = 12.5
Hz, 1H), 3.84 (s, 3H), 4.58 (d, J = 12.5 Hz, 1H), 5.20 (s, 1H), 6.88
(m, 1H), 7.05−7.16 (m, 2H), 7.22−7.40 (m, 7H), 7.44−7.47 (m, 2H),
7.53−7.56 (m, 2H); CHIRALCEL AD-H column, hexane/2-propanol
= 80:20, flow rate 1 mL/min, tR1 (major) = 4.9 min, tR2 (minor) = 5.6
min.
6H), 2.42 (s, 6H), 3.86 (q,J = 7 Hz, 2H), 5.17−5.19 (m, 2H), 7.00−
7.02 (m, 4H), 7.12−7.14 (m, 6H), 7.26−7.30 (m, 5H), 7.61 (bs, 2H),
7.80 (d, J = 6 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ = 18.0, 21.9,
52.7, 59.5, 127.8, 127.7, 128.0, 128.7, 130.2, 137.4, 138.6, 144.2,
172.32; TOF-MS (ESI+) calcd for (C42H50N4O6 + H+) 663.82, found
663.27. Anal. Calcd for C34H38N4O6S2: C, 61.61; H, 5.78; N, 8.45; S,
9.68; O, 14.48. Found: C, 61.69; H, 5.82; N, 8.49; O, 14.54.
Typical Experimental Procedure for the Enantioselective
Strecker Reaction of N-Benzhydrylimines Using Catalyst 5. In
an oven-dried reaction vial, catalyst 5 (10 mol %) and imine (0.25
mmol) were dissolved in dry toluene (2 mL), and the resulting
(R)-2-(Benzhydrylamino)-2-(4-methoxyphenyl)acetonitrile
(Table 4, Entry 8). The title compound was isolated by column
1
chromatography (hexane/ethyl acetate 90/10) as a liquid: H NMR
(500 MHz, CDCl3) δ 2.10 (d, J = 12.5 Hz, 1H), 3.81 (s, 3H), 4.54 (d,
J = 12.5 Hz, 1H), 5.21 (s, 1H), 6.91−6.95 (m, 2H), 7.20−7.54 (m,
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1H NMR (500 MHz, D2O) δ = 3.02 (dd, J = 8, 13 Hz, 1H), 3.20 (dd, J
12H); CHIRALCEL ADH column, hexane/2-propanol = 80:20, flow
rate 1 mL/min, tR1 (major) = 9.1 min, tR2 (minor) = 16.9 min.
(R)-2-(Benzhydrylamino)-2-(2-ethoxyphenyl)acetonitrile
(Table 4, Entry 9). The title compound was isolated by column
= 7, 12 Hz, 1H), 3.84−3.90 (m, 1H), 7.22 − 7.33 (m, 5H); 13C NMR
(125 MHz, D2O) δ = 36.5, 56.2, 127.8, 129.3, 129.5, 135.3, 174.0.
Procedure for the Conversion of α-Amino Nitrile to Diamine
Derivative.27 The aminonitrile 2j (250 mg, 0.80 mmol) was dissolved
in dry methanol (15 mL), cooled to 0 °C, and stired to obtain a clear
solution, and then Boc2O (350 mg, 1.60 mmol) and NiCl2·6H2O (20
mg, 0.08 mmol) were added. To this solution was added NaBH4 (296
mg, 8 mmol) in small portions over 2 h. The reaction was exothermic
and effervescent. The resulting reaction mixture containing a finely
divided black precipitate was allowed to warm to room temperature
and allowed to stir for a further 3 h, at which point triethylenetetra-
amine (115 μL mg, 0.8 mmol) was added. The mixture was allowed to
stir for 2 h before solvent evaporation. The purple residue was
dissolved in EtOAc (50 mL) and extracted with saturated NaHCO3 (3
× 50 mL). The organic layer was dried over NaSO4 and the solvent
removed under vacuum to give the product 13 as a white oil in 90%
yield (289 mg): [α]27D = 164 (c = 0.1, CHCl3); 1H NMR (500 MHz,
CDCl3) δ = 1.44 (s, 9H), 1.67 (bs, 1H), 2.69−2.76 (m, 2H), 2.80−
2.83 (m, 1H), 2.99−3.03 (m, 1H), 3.26−3.29 (m, 1H), 4.89 (s, 1H),
4.94 (bs, 1H), 7.08 (d, J = 7.5 Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H), 7.16−
7.21 (m, 5H), 7.26 (q, J = 7 Hz, 4H), 7.321 (d, J = 7.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ = 28.7, 39.5, 43.3, 56.2, 64.3, 79.3, 126.6,
127.3, 127.4, 127.7, 128.7, 129.6, 138.7, 143.8, 156.5; TOF-MS (ESI+)
calcd for (C27H32N2O2 + Na+) 439.54, found 439.27.
chromatography (hexane/ethylacetate 90/10) as a white solid: [α]27
D
= 82 (c = 0.1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.31 (t, J = 10
Hz, 3H) 2.14 (d, J = 12.5 Hz, 1H), 3.99 (q, J = 10 Hz, 2H), 4.61 (d, J
= 12.5 Hz, 1H), 5.22 (s, 1H), 7.21−7.36 (m, 8H), 7.40−7.45 (m, 3H),
7.52−7.56 (m, 3H); CHIRALCEL ADH column, hexane/2-propanol
= 80:20, flow rate 0.8 mL/min, tR1 (major) = 4.7 min, tR2 (minor) =
5.7 min.
(R)-2-(Benzhydrylamino)-2-(2-methylphenyl)acetonitrile
(Table 4, Entry 10). The title compound was isolated by column
chromatography (hexane/ethylacetate 90/10) as a white solid: [α]27
= 54 (c = 0.2, CHCl3); H NMR (500 MHz, CDCl3) δ 2.02 (d, J =
D
1
12.5 Hz, 1H) 2.24 (s, 3H), 4.63 (d, J = 12.5 Hz, 1H), 5.19 (s, 1H),
7.21- 7.28 (m, 7H), 7.30−7.34 (m, 2H), 7.38−7.40 (m, 2H), 7.42−
7.57 (m, 3H); CHIRALCEL ADH column, hexane/2-propanol =
80:20, flow rate 0.8 mL/min, tR1 (minor) = 4.4 min, tR2 (major) = 6.2
min.
(R)-2-(Benzhydrylamino)-3,3-dimethylbutanenitrile (Table 4,
Entry 11). The title compound was isolated by column chromatog-
raphy (hexane/diethyl ether 10/90) as a white solid: [α]27D = 89 (c =
0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.06 (s, 9H), 1.75 (d, J =
12.5 Hz, 1H), 3.04 (d, J = 12.5 Hz, 1H), 5.14 (s, 1H), 7.21−7.51 (m,
10H); CHIRALCEL AD-H column, hexane/2-propanol = 80:20, flow
rate 1 mL/min, tR1 (minor) = 4.9 min, tR2 (major) = 5.9 min.
(R)-2-(Benzhydrylamino)-3-phenylpropanenitrile(Table 4,
Entry 12). The title compound was isolated by column chromatog-
Procedure for the Preparation of Chiral 3-Phenylpropane-
1,2-diamine. The pure product 13 obtained by the reduction of
amino nitrile 2j was then transformed to 3-phenylpropane-1,2-diamine
14, a valuable intermediate for the aminopeptidase N (APN)
inhibitor.28 The deprotection of the Boc and benzhydryl groups was
done by refluxing the solution of 13 (1 mmol) in 6 N HCl (10 mL)
for 2 h. The reaction mixture was then cooled to room temperature
and washed with diethyl ether (3 × 10 mL), and the aqueous layer was
concentrated under reduced pressure, thus resulting in the hydro-
chloride salt of the diamine as a white powder in 85% yield (177 mg):
[α]27D = 112 (c = 0.5, H2O); 1H NMR (500 MHz, D2O) δ = 3.04 (dd,
J = 7.5, 15, Hz, 1H); 3.17 − 3.25 (m, 2H), 3.36 (dd, J = 7, 14 Hz, 1H);
3.679 (m, 1H), 7.10 (m, 2H), 7.39 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ = 39.2, 46.1, 56.0, 127.7, 128.7, 139.2, 136.2.
raphy (hexane/ethylacetate 95/5) as a white viscous liquid: [α]27
=
D
1
92 (c = 0.1, CHCl3); H NMR (500 MHz, CDCl3) δ 1.85 (bs, 1H),
2.96−3.04 (m, 2H), 3.59 (t, J = 6 Hz, 1H), 5.06 (s, 1H), 7.15−7.20
(m, 2H), 7.23−7.26 (m, 7H), 7.28−7.36 (m, 6H); 13C NMR (125
MHz, CDCl3) δ 39.7, 49.6, 65.5, 119.8, 127. 1, 127.4, 127.7, 127.7,
127.8, 127.9, 129.6, 135.3, 141.4, 143.3; CHIRALCEL ADH column,
hexane/2-propanol = 80:20, flow rate 1 mL/min, tR1 (minor) = 4.4
min, tR2 (major) = 4.7 min.
(R)-2-(Benzhydrylamino)-4-methylpentanenitrile (Table 4,
Entry 13). The title compound was isolated by column chromatog-
raphy (hexane/diethyl ether 10/90) as a white solid: [α]27D = 84 (c =
1
0.2, CHCl3); H NMR (500 MHz, CDCl3) δ 1.02 (d, J = 12.5 Hz,
ASSOCIATED CONTENT
6H), 1.66−1.74 (m, 3H), 1.98 (d, J = 13 Hz, 1H) 4.04 (q, 1H), 5.12
(s, 1H), 7.19−7.46 (m, 10H); CHIRALCEL AD-H column, hexane/2-
propanol = 80:20, flow rate 0.8 mL/min, tR1 (minor) = 7.1 min, tR2
(major) = 7.6 min.
(R)-2-(Benzhydrylamino)-2-(pyridin-3-yl)acetonitrile (Table
4, Entry 14). The title compound was isolated by column
■
S
* Supporting Information
1H and 13C NMR spectra and HPLC chromatograms for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
chromatography (hexane/diethyl ether 10/90) as a yellow solid:
1
[α]27 = 134 (c = 0.2, CHCl3); H NMR (500 MHz, CDCl3) δ 2.26
AUTHOR INFORMATION
D
■
(d, J = 12.5 Hz, 1H), 4.69 (d, J = 12.5 Hz, 1H), 5.27 (s, 1H), 7.32−
7.35 (m, 3H),7.38−7.43 (m, 4H), 7.48 (d, J = 7 Hz, 2H), 7.60 (d, J =
7.5 Hz, 2H), 7.92−7.92 (dd, J = 8 Hz, 1H), 8.66 (d, J = 3.5 Hz, 1H),
8.83 (d, J = 2 Hz, 1H); CHIRALCEL AD-H column, hexane/2-
propanol = 80:20, flow rate 1 mL/min, tR1 (minor) = 7.1 min, tR2
(major) = 10.7 min.
Corresponding Author
*Fax: +91-0278-2566970. E-mail: khan251293@yahoo.in.
Notes
The authors declare no competing financial interest.
(R)-2-(Benzhydrylamino)-2-(naphthalen-2-yl)acetonitrile
ACKNOWLEDGMENTS
■
(Table 4, Entry 15). The title compound was isolated by column
S.S. and N.H.K. are thankful to DST and the CSIR Network
project on catalysis for financial assistance and the Analytical
Division of the Institute for providing instrumentation facilities.
chromatography (hexane/diethyl ether 10/90) as a yellow solid:
1
[α]27 = 134 (c = 0.2, CHCl3); H NMR (500 MHz, CDCl3) δ 2.19
D
(d, J = 12.5 Hz, 1H), 4.72 (d, J = 12.5 Hz, 1 H), 5.71 (s, 1 H), 7.83−
7.19 (m, 17 H). CHIRALCEL AD-H column, hexane/2-propanol =
80:20, flow rate 1 mL/min, tR1 (minor) = 7.4 min, tR2 (major) = 11.7
min.
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dx.doi.org/10.1021/jo300349f | J. Org. Chem. 2012, 77, 4375−4384

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