A novel multicomponent tandem phosphine-catalyzed Umpolung reaction: Facile access to highly functionalized α-aminonitriles

Article abstract of DOI:10.1055/s-0031-1290946

The first phosphine-catalyzed multicomponent tandem Strecker-γ- umpolung-addition reaction has been developed, which provides a facile access to functionalized allylic α-aminonitriles. The reaction is highly efficient, rapid, versatile and economical, and it is hoped that it will find great practical application in organic synthesis. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290946

SPECIAL TOPIC
▌1849
special topic
A Novel Multicomponent Tandem Phosphine-Catalyzed Umpolung Reaction:
Facile Access to Highly Functionalized α-Aminonitriles
Synthesis of Highly Functionalized α-Aminonitriles
Jian-Ming Chen, Yin-Zhi Fang, Zhong-lin Wei, Wei-Wei Liao*
Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, P. R. of China
Fax +86(431)85153812; E-mail: wliao@jlu.edu.cn
Received: 27.02.2012; Accepted after revision: 07.03.2012
could be established by utilizing three-component Strecker
Abstract: The first phosphine-catalyzed multicomponent tandem
reaction and phosphine catalyzed γ-umpolung addition of
Strecker–γ-umpolung-addition reaction has been developed, which
nucleophiles to activated allenes, which may not only de-
liver highly functional α-aminonitriles with quaternary
provides a facile access to functionalized allylic α-aminonitriles.
The reaction is highly efficient, rapid, versatile and economical, and
it is hoped that it will find great practical application in organic syn- carbon centers, but also afford a synthetic complement to
thesis.
SAA reaction. Herein, we demonstrate a novel tandem
Strecker–γ-umpolung-addition reaction for the construc-
tion of highly functionalized α-aminonitriles (Scheme 1).
Key words: Strecker reaction, umpolung addition, α-aminonitrile,
allene, phosphine catalysis
R1 CHO
R2
R2
HN
+
Nucleophilic phosphine catalysis has received consider-
able attention because it has displayed the diversity of
synthetic transformations involving activated allenes as
starting materials.1 Within this field, umpolung addition
of nucleophiles to activated allenes plays an important
role, which provides an efficient C–C formation reaction.
Since the first report by Trost,2 there has been increasing
interest in phosphine-catalyzed γ-umpolung additions of
pronucleophiles to electron-deficient alkynes and al-
lenes.3 However, the construction of synthetically useful
intermediates via a multicomponent tandem phosphine-
catalyzed umpolung additions has received less attention4
in contrast to direct umpolung addition pathways, since it
will provide a highly efficient and economic approach to
access valuable molecular constructs. α-Aminonitriles are
exceptionally versatile intermediates in synthetic chemis-
try and also proposed as being prebiotic precursors to por-
phyrins, corrins, and nicotinic acids.5 α-Aminonitriles
bearing an α-hydrogen have been widely used in the gen-
eration of multiple polyfunctional structures.6 To the best
of our knowledge, the construction of α-aminonitriles in-
cluding densely functional quaternary carbon centers via
a multicomponent tandem umpolung additions to activat-
ed allenes by phosphine catalyst is still unexploited.7
HN
R1
P catalyst
R2 NH2
CO2R6
R1
NC
CN
+
R5
R4
R4
R3 CN
1
3
R5
CO2R6
2
Scheme 1 Strategy of multicomponent tandem γ-umpolung reaction
Initially, the reaction of preformed α-aminonitrile 1a with
ethyl buta-2,3-dienoate (2a) in the presence of catalytic
triphenylphosphine was investigated. Gratifyingly, this
inverse conjugate addition proceeded well in acetonitrile,
and affording γ-umpolung adduct 3a (E/Z = 3.6:1) in 94%
yield along with a small amount of β-addition product 4a
(Table 1, entry 1). The solvent effects were first examined
by using triphenylphosphine as the catalyst. Although γ-
umpolung addition reactions took place in all screened
solvents, sluggish reactions were observed in solvents
such as toluen, tetrahydrofuran, and 1,4-dioxane (Table 1,
entries 2, 5, 6). When the reactions were carried out in di-
chloromethane and 1,2-dichloroethane, no β-addition
product was detected (Table 1, entries 3, 4). Several com-
monly used phosphine catalysts were assessed in the nu-
cleophilic addition reaction between 1a and 2a. More
nucleophilic phosphanes catalyzed this reaction to give
the product 3a in shorter time with slightly higher selec-
tivities. Of these catalysts, tributylphosphine gave 3a in a
slightly low yield with the highest E/Z selectivity and an
increased amount of β-addition product 4a (Table 1, entry
12). In the absence of catalyst, no conversion of the start-
ing material was observed (Table 1, entry 14). Decreasing
the reaction temperature facilitated Michael-type addition
(4a) instead of improving E/Z selectivity of the product of
γ-umpolung addition reaction (Table 1, entry 13). Further
study showed that Z-isomer 3 was easily isomerized into
E-isomer 3 in the presence of more nucleophilic phos-
phane catalyst, which may provide a potential to obtain E-
isomer with high selectivities (Equation 1).
Recently, we reported the novel tandem cyanation–allyl-
ic-alkylation (CAA) reaction and Strecker–allylic-alkyla-
tion (SAA) reaction by using amine catalysts, which
provided facile accesses to densely functionalized prod-
ucts containing O-substituted or N-substituted quaternary
centers.8 The accomplishment of these transformations is
relied heavily on the combination of the in situ generation
of nucleophilic regents, electrophilic regents, and further
coupling. Inspired by these, we further envisaged that an
attractive multicomponent tandem γ-umpolung reaction
SYNTHESIS 2012, 44, 1849–1853
Advanced online publication: 20.04.2012
0
0
3
9
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7
8
8
1
1
4
3
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DOI: 10.1055/s-0031-1290946; Art ID: SS-2012-C0201-ST
© Georg Thieme Verlag Stuttgart · New York

1850
J.-M. Chen et al.
SPECIAL TOPIC
order to increase the production of 3. Indeed, charging
benzaldehyde, aniline, and TMSCN in one flask, subse-
quently adding triphenylphosphine (20 mol%) and 2a un-
der optimized solvent, readily furnished the desired
product 3a in high yield (Table 2, entry 1). The scope and
generality of this novel tandem reaction was evaluated.
First, the reactions of different primary amines with benz-
aldehyde, TMSCN, and 2a were examined. Of note, ani-
lines with electron-withdrawing or -donating substituents
at the para-position, can be smoothly employed in this re-
action to furnish 3 in good to high yield (Table 2, entries
3, 4). In particular, N-PMP substitution of 3 may provide
a potential handle for further elaboration, due to their fac-
ile deprotection.9 However, N-benzyl protected 3c was
not observed at all when benzylamine was used (Table 2,
entry 5). When secondary amine such as morpholine was
used, the tandem reactions did not provide the desired
Table 1 Optimization of Phosphine-Catalyzed γ-Umpolung Addi-
tions of α-Aminonitriles to Electron-Deficient Allenesa
Ph
HN
Ph
CN
Ph
Ph
1a
catalyst
solvent
HN
HN
NC
+
+
CO2Et
Ph
Ph
CO2Et
CO2Et
CN
(E)-3a
•
2a
4a
E/Zb
Entry Catalyst
Solvent
Time
(h)
Yield
(%)c
1
2
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
MeCN
PhMe
CH2Cl2
DCE
2.5
15
3
3.6:1 94 (3a); 2 (4a)
d
8 [(E)-3a]
–
3
3.1:1 64 (3a)
4
6
1.9:1 67 (3a)
Table 2 Substrate Scope of Multicomponent Tandem Phosphine-
Catalyzed γ-Umpolung Reactiona
d
5
THF
15
13 [(E)-3a]
<5 (3a)
–
R2
R3
d
catalyst
solvent
N
6
1,4-dioxane 15
–
O
+ R2R3NH2 + TMSCN
CO2Et
R1
R1
7
t-BuOH
2.5
3.1:1 31 (3a)
CO2Et
CN
(E)-3 (major)
•
5
6
2a
8
DMF
1
3.8:1 59 (3a);13 (4a)
R1
NR2R3
E/Z b
Entry
Time
(h)
Yield
(%)c
9
(4-FC6H4)3P MeCN
5
3:1
83 (3a); 5 (4a)
10
11
12
Et(Ph)2P
Et2(Ph)P
Bu3P
MeCN
MeCN
MeCN
MeCN
MeCN
0.7
0.7
0.7
1
3.5:1 91 (3a); 5 (4a)
5.2:1 88 (3a); 8 (4a)
1
Ph
NHPh
NHPh
3.5
1
4.3:1 81(3a)
5:1 76 (3a)
2d
3
Ph
7:1
5.1:1 52 (3a); 26 (4a)
– nr
82 (3a); 16 (4a)
Ph
NH(4-ClC6H4) 2.5
6.4:1 74 (3b)
4.7:1 85 (3d)
13e
14
Bu3P
4e
5
Ph
NHPMP
NHBn
3
none
1
Ph
–
–
–
nr
nr
a Reactions were performed with 1a (0.2 mmol), 2a (0.3 mmol), and
catalyst (20 mol%) in solvent (2.0 mL) at 30 °C.
b Determined by 1H NMR analysis.
6
Ph
N-morpholinyl
NHPh
–
c Isolated yield. nr = no reaction.
7
4-ClC6H4
4-MeC6H4
3-MeOC6H4
2-BrC6H4
2-naphthyl
2-furyl
2.5
2.5
2.5
2.5
4
4.6:1 80 (3ab)
4.6:1 75 (3ac)
5.9:1 88 (3ad)
3.7:1 59 (3ae)
4.7:1 59 (3af)
3.5:1 81 (3ag)
7.4:1 61 (3ah)
d No detection.
8
NHPh
e Reaction was carried out at 0 °C.
9
NHPh
Ph
Ph
Ph3P or Bu3P
(20 mol%)
10
11
12
13d,f
14
NHPh
HN
HN
CO2Et
Ph
NHPh
MeCN
60 °C
9 h
Ph
CN
(Z)-3a
CN
CO2Et
NHPh
2.5
2
(E)-3a
with Ph3P: < 1%
with Bu3P: 75%
(E)-PhCH=CH NHPh
i-Pr NHPh
–
–
nr
Equation 1
a Aldehyde (0.2 mmol), amine (1.05 equiv), and TMSCN (1.05 equiv)
were stirred at 30 °C for 50 min. Catalyst (20 mol%), 2a (0.3 mmol),
and solvent were added. The mixture was stirred for mentioned reac-
tion time at 60 °C.
With these preliminary results in hand, next the multicom-
ponent tandem γ-umpolung addition reaction was studied.
The results are summarized in Table 2. Straightforwardly
mixing benzaldehyde, aniline, TMSCN, triphenylphos-
phine (20 mol%), and ethyl buta-2,3-dienoate (2a) in one
flask in acetonitrile resulted in the desired product 3a in
low yield (46%) and side product formation. We hypo-
thesized that the order of reagent mixing may be crucial in
b Determined by 1H NMR analysis.
c Isolated yield. nr = no reaction.
d Reaction was carried out at 30 °C in the presence of Bu3P (20
mol%).
e Compound 2a (0.4 mmol) was added.
f Compound 2a was added via syringe pump over 50 min.
Synthesis 2012, 44, 1849–1853
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Highly Functionalized α-Aminonitriles
1851
were recorded on 100 MHz spectrometer in CDCl3, with chemical
shift values (δ) reported in ppm relative to the internal standard
TMS. IR spectra were obtained with a Nicolet Avatar 360 FT-IR.
HRMS was measured with Bruker MicrOTOF Q II.
product (Table 2, entry 6). A variety of aromatic and het-
eroaromatic aldehydes were evaluated next with aniline as
the amine component. To our delight, the reactions took
place efficiently in good yields for all studied aldehydes
(Table 2, entries 7–12). The electronic properties of the Multicomponent Tandem Phosphine-Catalyzed Umpolung
Reaction; Compounds 3; General Procedure
aromatic system of the aldehyde component do not seem
to influence the yield. Aromatic aldehydes with electron-
To a dried reaction tube were added the required aldehyde (0.2
mmol) and amine (0.21 mmol). After stirring the mixture at 30 °C
withdrawing or electron-donating substituent at the para-
position furnished the desired products in good yields
(Table 2, entries 7, 8). Aromatic aldehyde with ortho-sub-
stituent at aryl group, which potentially causes steric hin-
drance effect, also gave moderate yield (Table 2, entry
10). The tandem reaction with aliphatic aldehyde did not
give rise to the desired product, which reveals a dramatic
dependence on the pKa value of pronucleophile (Table 2,
entry 14). In addition, α,β-unsaturated aldehydes were
also applied in this reaction, which would provide more
synthetically useful allylic and vinyl substituted α-amino-
nitrile derivatives, and afforded desired products 3ah in
high yield (Table 2, entry 13).
for 20 min, TMSCN (0.21 mmol) was added, and the mixture was
vigorously stirred. After 50 min, MeCN (2 mL), catalyst (20 mol%),
and compound 2 (0.3 mmol) were added under N2 atmosphere, and
the mixture was heated to 60 °C. The reaction was monitored by
TLC (eluent: EtOAc–petroleum ether). Upon completion, the stir-
ring bar was removed and the mixture was evaporated under re-
duced pressure to give the crude products. The crude mixture was
purified by column chromatography [silica gel, EtOAc–petroleum
ether (bp 60–90 °C)] to provide 3.
Ethyl (E)-5-Cyano-5-phenyl-5-(phenylamino)pent-2-enoate
[(E)-3a]
Yield: 42 mg (66%); colorless oil.
IR (KBr): 3372, 3043, 2924, 2854, 2233, 1716, 1654, 1605, 1499,
1186, 753, 694 cm–1.
Finally, tandem γ-umpolung addition reactions of substi- 1H NMR (300 MHz, CDCl3): δ = 7.65–7.56 (m, 1 H), 7.47–7.32 (m,
2 H), 7.09 (t, J = 7.9 Hz, 1 H), 6.89 (ddd, J = 15.2, 8.5, 6.5 Hz, 1 H),
6.79 (t, J = 7.4 Hz, 1 H), 6.53 (d, J = 7.9 Hz, 1 H), 6.01 (d, J = 15.6
Hz, 1 H), 4.37 (br s, 1 H), 4.20 (q, J = 7.1 Hz, 1 H), 3.01–2.85 (m,
2 H), 1.29 (t, J = 7.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 165.16, 143.16, 139.05, 137.54,
129.06, 128.75, 127.24, 125.33, 119.83, 119.33, 115.82, 60.50,
60.22, 46.82, 13.98.
HRMS (ESI): m/z calcd for C20H21N2O2 ([M + H]+): 321.1598;
tuted allenoates were investigated (Scheme 2). For exam-
ple, when allenoate with a substituent at the α-position,
such as α-methyl-substituted allenoate 2c was employed,
the inverse conjugate addition gave the expected product
in moderate yield, albeit as a 1.5:1 mixture of E- and Z-
olefins. However, γ-methyl-substituted allenoate 2b
failed to give rise to the desired product, presumably due
to the increasing repulsive force between in situ generated
found: 321.1593.
nucleophilic reagent and γ-substituent of allenoate 2b.
Ethyl (Z)-5-Cyano-5-phenyl-5-(phenylamino)pent-2-enoate
[(Z)-3a]
Ph
Bu3P (20 mol%)
MeCN, 30 °C
Yield: 9.6 mg (15%); colorless oil.
HN
O
TMSCN
CO2Et
PhNH
+
+
IR (KBr): 3372, 3027, 2957, 2925, 2237, 1715, 1653, 1603, 1499,
1204, 753, 698 cm–1.
2
CO2Et Ph
NC
Ph
R5
3
R4
1H NMR (300 MHz, CDCl3): δ = 7.63–7.60 (m, 2 H), 7.40–7.35 (m,
3 H), 7.12–7.06 (m, 2 H), 6.77–6.72 (m, 1 H), 6.51–6.49 (m, 2 H),
6.23–6.09 (m, 2 H), 5.42 (br s, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.48
(ddd, J = 9.0, 8.1, 0.5 Hz, 1 H), 3.29 (ddd, J = 8.7, 7.1, 0.9 Hz, 1 H),
1.34 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.52, 143.53, 139.92, 138.04,
129.06, 128.85, 128.69, 125.60, 125.30, 119.55, 119.34, 115.38,
60.76, 60.53, 43.13, 14.11.
R5
R4
5
6
2
2b R4 = H; R5 = Me; no product detected
2c R4 = Me; R5 = H; 63% (3j); E/Z = 1.5:1
Scheme 2 Multicomponent tandem γ-umpolung reaction of substi-
tuted allenoates
In conclusion, we have developed a multicomponent tan-
dem γ-umpolung reaction with aldehydes, amines and
electron-deficient allenes, which provided an efficient
HRMS (ESI): m/z calcd for C20H21N2O2 ([M + H]+): 321.1598;
found: 321.1596.
synthetic route for the preparation of densely functional- Ethyl3-[Cyano(phenyl)(phenylamino)methyl]but-3-enoate(4a)
(Table 1, entry 13)
ized α-aminonitriles bearing an N-substituted quaternary
carbon centers. A number of aldehydes could be success-
fully applied to give multifunctional desired products with
moderate selectivities. Further studies on synthetic appli-
cations and asymmetric catalysis are ongoing in our labo-
ratories and will be reported in due course.
Yield: 17 mg (26%); colorless oil.
IR (KBr): 3348, 3057, 2925, 2853, 2239, 1728, 1647, 1603, 1499,
1198, 754, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.61–7.59 (m, 2 H), 7.41–7.39 (m,
3 H), 7.18–7.13 (m, 2 H), 6.85–6.80 (m, 1 H), 6.67–6.64 (m, 2 H),
5.85 (s, 1 H), 5.38 (s, 1 H), 5.21 (br s, 1 H), 4.14 (q, J = 7.1 Hz, 2
H), 3.13 (s, 2 H), 1.29–1.24 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 171.89, 143.46, 139.49, 136.45,
129.16, 129.08, 128.92, 126.66, 120.09, 119.93, 118.77, 116.13,
66.18, 61.56, 37.14, 14.13.
All reactions were carried out under inert atmospheric condition un-
less otherwise noted, and solvents were dried according to estab-
lished procedures. Reactions were monitored by TLC visualizing
with ultraviolet light (UV), KMnO4; column chromatography puri-
fications were carried out using silica gel. 1H NMR spectra were re-
corded on 300 MHz spectrometer in CDCl3, and 13C NMR spectra
+
HRMS (ESI): m/z calcd for C20H21N2O2 ([M + H]+): 321.1598;
found: 321.1601.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1849–1853

1852
J.-M. Chen et al.
SPECIAL TOPIC
Ethyl (E)-5-(4-Chlorophenylamino)-5-cyano-5-phenylpent-2-
enoate [(E)-3b]
Yield: 45 mg (64%); yellow oil.
HRMS (ESI): m/z calcd for C21H23N2O2 ([M + H]+): 335.1754;
found: 335.1755.
Ethyl (E)-5-Cyano-5-(3-methoxyphenyl)-5-(phenylamino)pent-
2-enoate [(E)-3ad]
IR (KBr): 3365, 3030, 2983, 2936, 2231, 1718, 1657, 1600, 1494,
1198, 819, 732, 700 cm–1.
Yield: 52 mg (75%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.59–7.56 (m, 2 H), 7.46–7.36 (m,
3 H), 7.09–7.04 (m, 2 H), 6.89 (ddd, J = 15.4, 8.8, 6.3 Hz, 1 H),
6.49–6.44 (m, 2 H), 6.04 (dt, J = 15.6, 1.2 Hz, 1 H), 4.29 (br s, 1 H),
4.22 (q, J = 7.1 Hz, 2 H), 3.00 (ddd, J = 14.2, 6.3, 1.6 Hz, 1 H), 2.89
(ddd, J = 14.3, 8.8, 1.1 Hz, 1 H), 1.31 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.17, 141.54, 138.74, 137.22,
129.48, 129.26, 129.00, 128.02, 125.38, 119.02, 117.24, 60.91,
60.12, 47.46, 14.21.
IR (KBr): 3364, 3063, 2927, 2854, 2235, 1718, 1658, 1603, 1499,
1194, 1041, 787, 753, 697 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.33 (t, J = 8.0 Hz, 1 H), 7.23–7.17
(m, 1 H), 7.16–7.06 (m, 3 H), 6.97–6.85 (m, 2 H), 6.81 (t, J = 7.4
Hz, 1 H), 6.55 (d, J = 7.7 Hz, 2 H), 6.03 (d, J = 15.6 Hz, 1 H), 4.27
(br s, 1 H), 4.22 (q, J = 7.2 Hz, 2 H), 2.99 (ddd, J = 14.1, 6.3, 1.5
Hz, 1 H), 2.95–2.83 (m, 1 H), 1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.22, 160.36, 143.04, 139.46,
139.06, 130.45, 129.04, 127.77, 120.35, 119.24, 117.68, 116.04,
114.37, 111.22, 60.82, 60.12, 55.38, 47.41, 14.21.
HRMS (ESI): m/z calcd for C20H20ClN2O2 ([M + H]+): 355.1208;
found: 355.1209.
Ethyl (E)-5-Cyano-5-(4-methoxyphenylamino)-5-phenylpent-2-
enoate [(E)-3d]
Yield: 49 mg (70%); yellow oil.
HRMS (ESI): m/z calcd for C21H23N2O3 ([M + H]+): 351.1703;
found: 351.1701.
Ethyl (E)-5-(2-Bromophenyl)-5-cyano-5-(phenylamino)pent-2-
enoate [(E)-3ae]
Yield: 37 mg (46%); yellow oil.
IR (KBr): 3410, 2997, 2924, 2854, 2231, 1718, 1654, 1513, 1240,
1200, 825, 762, 700 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.63–7.59 (m, 2 H), 7.45–7.37 (m,
3 H), 6.89 (ddd, J = 15.3, 8.8, 6.3 Hz, 1 H), 6.71–6.65 (m, 2 H),
6.55–6.50 (m, 2 H), 6.01 (dt, J = 15.8, 1.2 Hz, 1 H), 4.21 (q, J = 7.1
Hz, 2 H), 4.00 (br s, 1 H), 3.69 (s, 3 H), 2.98 (ddd, J = 14.2, 6.3, 1.6
Hz, 1 H), 2.88 (ddd, J = 14.2, 8.7, 1.1 Hz, 1 H), 1.30 (t, J = 7.1 Hz,
3 H).
13C NMR (125 MHz, CDCl3): δ = 165.23, 154.29, 139.16, 137.90,
136.63, 129.27, 129.05, 127.70, 125.68, 119.49, 118.58, 114.47,
61.21, 60.77, 55.48, 47.28, 14.20.
IR (KBr): 3377, 3058, 2958, 2926, 2237, 1718, 1655, 1603, 1499,
1193, 752, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.77 (dd, J = 8.0, 1.5 Hz, 1 H),
7.62 (dd, J = 7.9, 1.3 Hz, 1 H), 7.38–7.33 (m, 1 H), 7.26–7.20 (m, 1
H), 7.16–7.11 (m, 2 H), 6.92 (ddd, J = 15.4, 8.5, 6.4 Hz, 1 H), 6.82
(t, J = 7.4 Hz, 1 H), 6.60–6.57 (m, 2 H), 6.08 (dt, J = 15.6, 1.2 Hz,
1 H), 4.40 (br s, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 3.44 (ddd, J = 14.6,
6.4, 1.5 Hz, 1 H), 3.21 (ddd, J = 14.8, 8.6, 0.7 Hz, 1 H), 1.30 (t, J =
7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.17, 142.53, 138.98, 136.05,
133.86, 130.65, 130.21, 128.98, 128.13, 127.69, 120.25, 119.84,
118.10, 115.81, 60.82, 60.68, 42.40, 14.20.
HRMS (ESI): m/z calcd for C21H23N2O3 ([M + H]+): 351.1703;
found: 351.1703.
Ethyl (E)-5-(4-Chlorophenyl)-5-cyano-5-(phenylamino)pent-2-
enoate [(E)-3ab]
Yield: 46 mg (66%); yellow oil.
HRMS (ESI): m/z calcd for C20H20BrN2O2 ([M + H]+): 399.0703;
found: 399.0704.
IR (KBr): 3361, 3057, 3032, 2981, 2926, 2231, 1703, 1654, 1603,
1498, 1199, 830, 750, 693 cm–1.
Ethyl (E)-5-Cyano-5-(naphthalen-2-yl)-5-(phenylamino)pent-
2-enoate [(E)-3af]
1H NMR (300 MHz, CDCl3): δ = 7.57–7.53 (m, 2 H), 7.42–7.38 (m,
2 H), 7.16–7.10 (m, 2 H), 6.94–6.81 (m, 2 H), 6.52 (d, J = 7.7 Hz, 1
H), 6.04 (d, J = 15.6 Hz, 1 H), 4.23 (q, J = 7.2 Hz, 1 H), 4.25 (br s,
1 H), 2.98 (ddd, J = 14.2, 6.3, 1.6 Hz, 1 H), 2.88 (ddd, J = 14.4, 8.7,
0.8 Hz, 1 H), 1.31 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 160.35, 137.91, 133.72, 131.60,
130.32, 124.85, 124.39, 123.38, 122.22, 115.88, 114.16, 111.35,
56.16, 54.92, 42.65, 9.46.
Yield: 36 mg (49%); white oil.
IR (KBr): 3370, 3061, 2955, 2852, 2245, 1715, 1659, 1605, 1499,
1188, 754, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.14 (s, 1 H), 7.91–7.85 (m, 3 H),
7.67 (dd, J = 8.7, 1.9 Hz, 1 H), 7.57–7.51 (m, 2 H), 7.08 (t, J = 7.9
Hz, 1 H), 7.00–6.90 (m, 1 H), 6.80 (t, J = 7.4 Hz, 1 H), 6.58 (d, J =
8.2 Hz, 2 H), 6.06 (d, J = 15.6 Hz, 1 H), 4.33 (s, 1 H), 4.21 (q, J =
7.1 Hz, 2 H), 3.12–2.94 (m, 2 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.16, 143.06, 138.93, 135.29,
133.43, 133.23, 129.58, 129.10, 128.39, 127.95, 127.75, 126.97,
126.87, 125.23, 122.36, 120.48, 119.30, 116.17, 60.83, 60.38,
47.50, 14.20.
HRMS (ESI): m/z calcd for C20H20ClN2O2 ([M + H]+): 355.1208;
found: 355.1204.
Ethyl (E)-5-Cyano-5-(phenylamino)-5-p-tolylpent-2-enoate
[(E)-3ac]
Yield: 41 mg (62%); yellow oil.
HRMS (ESI): m/z calcd for C24H23N2O2 ([M + H]+): 371.1754;
found: 371.1747.
IR (KBr): 3359, 3032, 2983, 2925, 2229, 1716, 1646, 1604, 1498,
1273, 820, 753, 691 cm–1.
Ethyl (E)-5-Cyano-5-(furan-2-yl)-5-(phenylamino)pent-2-eno-
ate [(E)-3ag]
Yield: 39 mg (63%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.47 (d, J = 8.3 Hz, 2 H), 7.21 (d,
J = 8.0 Hz, 2 H), 7.14–7.08 (m, 2 H), 6.96–6.84 (m, 1 H), 6.81 (t,
J = 7.4 Hz, 1 H), 6.56–6.53 (m, 2 H), 6.03 (dt, J = 15.6, 1.2 Hz, 1
H), 4.25–4.18 (m, 3 H), 2.98 (ddd, J = 14.2, 6.3, 1.6 Hz, 1 H), 2.88
(ddd, J = 14.3, 8.8, 1.1 Hz, 1 H), 2.36 (s, 3 H), 1.30 (t, J = 7.1 Hz, 3
H).
13C NMR (125 MHz, CDCl3): δ = 165.26, 143.13, 139.21, 138.96,
134.74, 130.02, 129.02, 127.69, 125.36, 120.25, 119.42, 116.08,
60.80, 59.94, 47.57, 21.10, 14.22.
IR (KBr): 3376, 3029, 2926, 2854, 2242, 1716, 1658, 1603, 1500,
1185, 752, 695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.45 (dd, J = 1.8, 0.9 Hz, 1 H),
7.22–7.15 (m, 2 H), 6.93–6.82 (m, 2 H), 6.75–6.70 (m, 2 H), 6.51
(dd, J = 3.4, 0.9 Hz, 1 H), 6.38 (dd, J = 3.4, 1.9 Hz, 1 H), 6.04 (dt,
J = 15.6, 1.4 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 4.05 (br, 1 H), 3.16
(ddd, J = 5.0, 4.5, 1.4 Hz, 1 H), 3.10 (ddd, J = 9.3, 6.1, 1.4 Hz, 1 H),
1.30 (t, J = 7.1 Hz, 3 H).
Synthesis 2012, 44, 1849–1853
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Highly Functionalized α-Aminonitriles
1853
13C NMR (125 MHz, CDCl3): δ = 165.26, 148.59, 143.60, 142.93,
138.54, 129.15, 127.59, 121.46, 117.70, 117.30, 110.88, 109.98,
60.78, 56.10, 43.35, 14.20.
(2) (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167.
(b) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116,
10819. (c) Trost, B. M.; Drake, G. R. J. Org. Chem. 1997,
62, 5670.
HRMS (ESI): m/z calcd for C18H19N2O3 ([M + H]+): 311.1390;
(3) For selected examples, see: (a) Zhang, C.; Lu, X. Synlett
1995, 645. (b) Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao,
P.; Zhang, X. J. Org. Chem. 1998, 63, 5631. (c) Alvarez-
Ibarra, C.; Csaky, A. G.; Oliva, C. G. Tetrahedron Lett.
1999, 40, 8465. (d) Alvarez-Ibarra, C.; Csaky, A. G.; Oliva,
C. G. J. Org. Chem. 2000, 65, 3544. (e) Lu, C.; Lu, X. Org.
Lett. 2002, 4, 4677. (f) Pakulski, Z.; Demchuk, O. M.;
Frelek, J.; Luboradzki, R.; Pietrusiewicz, K. M. Eur. J. Org.
Chem. 2004, 3913. (g) Virieux, D.; Guillouzic, A.-F.;
Cristau, H.-J. Tetrahedron 2006, 62, 3710. (h) Chung, Y. K.;
Fu, G. C. Angew. Chem. Int. Ed. 2009, 48, 2225. (i) Smith,
S. W.; Fu, G. C. J. Am. Chem. Soc. 2009, 131, 14231.
(j) Cardoso, A. L.; Matos Beja, A.; Ramos Silva, M.; de los
Santos, J. M.; Palacios, F.; Abreu, P. E.; Pais, A. A. C. C.;
Pinho e Melo, T. M. V. D. Tetrahedron 2010, 66, 7720.
(k) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc. 2010,
132, 2550.
found: 311.1385.
Ethyl (2E,6E)-5-Cyano-7-phenyl-5-(phenylamino)hepta-2,6-di-
enoate [(E)-3ah]
Yield: 38 mg (54%); red oil.
IR (KBr): 3364, 3029, 2925, 2854, 2231, 1717, 1653, 1603, 1498,
1187, 751, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.31 (m, 5 H), 7.24–7.18 (m,
2 H), 7.06–6.96 (m, 2 H), 6.92–6.87 (m, 3 H), 6.13 (d, J = 15.9 Hz,
1 H), 6.10 (dt, J = 15.6, 1.5 Hz, 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 3.96
(br s, 1 H), 3.01–2.86 (m, 2 H), 1.31 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.29, 143.36, 138.87, 134.90,
133.89, 129.25, 128.85, 127.83, 127.57, 126.99, 120.97, 118.64,
116.83, 60.86, 57.97, 44.48, 14.23.
HRMS (ESI): m/z calcd for C22H23N2O2 ([M + H]+): 347.1754;
found: 347.1751.
(4) For examples of phosphine-catalyzed tandem reactions, see:
(a) Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677. (b) Gabillet, S.;
Lecerclé, D.; Loreau, O.; Dézard, S.; Gomis, J.-M.; Taran, F.
Synthesis 2007, 515. (c) Guan, X.-Y.; Wei, Y.; Shi, M. Org.
Lett. 2010, 12, 5024.
Acknowledgment
Support of this work by NSFC (No. 21102054) and Open Project of
State Key Laboratory for Supramolecular Structure and Materials
(sklssm201220) is greatly appreciated.
(5) For selected reviews, see: (a) Albright, J. D. Tetrahedron
1983, 39, 3207. (b) Enders, D.; Shilvock, J. P. Chem. Soc.
Rev. 2000, 29, 359. (c) Opatz, T. Synthesis 2009, 1941.
(6) For selected examples, see: (a) Freifelder, M.; Hasbrouck,
R. B. J. Am. Chem. Soc. 1960, 82, 696. (b) Gaiffe, A.;
Padovani, A. C. R. Acad. Sci., Ser. C 1969, 269, 144.
(c) Enders, D.; Lotter, H. Tetrahedron Lett. 1982, 23, 639.
(d) Taillades, J.; Commeyras, A. Tetrahedron 1974, 30, 127.
(7) Recent examples on quaternary α-aminonitrile synthesis via
Strecker reaction: (a) Rueping, M.; Sugiono, E.; Moreth, S.
A. Adv. Synth. Catal. 2007, 349, 759. (b) Baeza, A.; Nájera,
C.; Sansano, J. M. Synthesis 2007, 1230. (c) Abell, J. P.;
Yamamoto, H. J. Am. Chem. Soc. 2009, 131, 15118. (d) Liu,
Y-L.; Zhou, F.; Cao, J-J.; Ji, C-B.; Ding, M.; Zhou, J. Org.
Biomol. Chem. 2010, 8, 3847. (e) Zhang, G-W.; Zheng, D.-
H.; Nie, J.; Wang, T.; Ma, J.-A. Org. Biomol. Chem. 2010,
8, 1399.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.onmorinIfatgnonmSorti
nipfurotIangSiuptor
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1849–1853