Efficient synthesis of fluorinated α- And β-amino nitriles from fluoroalkylated α,β-unsaturated imines

Article abstract of DOI:10.1016/j.tet.2010.12.046

A simple and efficient synthesis of fluoroalkylated α-amino nitrile (4) derivatives by regioselective 1,2-addition of trimethylsilyl cyanide to fluoroalkylated α,β-unsaturated imines (1) is described. Fluoroalkylated β-amino nitriles (7) are also prepared

Full text of DOI:10.1016/j.tet.2010.12.046

Tetrahedron 67 (2011) 1575e1579
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of fluorinated a- and b-amino nitriles from fluoroalkylated
a,
b-unsaturated imines
*
ꢀ
ꢀ
Francisco Palacios , Ana M. Ochoa de Retana, Sergio Pascual, Guillermo Fernandez de Troconiz
ꢀ
ꢀ
Departamento de Química Organica I, Facultad de Farmacia and Centro de Investigacion y Estudios Avanzados ‘Lucio Lascaray’, Universidad del País Vasco,
Apartado 450, 01080eVitoria, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthesis of fluoroalkylated
a
-amino nitrile (4) derivatives by regioselective
-unsaturated imines (1) is described. Fluo-
-amino nitriles (7) are also prepared by regioselective 1,2-addition of -carbanions derived
from acetonitrile to fluoroalkylated -unsaturated imines (1). Fluoroalkylated -(4) and -amino ni-
triles (7) are also prepared through an ‘one pot’ procedure by reaction of enaminophosphonate 2 with
BuLi, addition of aldehydes and subsequent addition of either trimethylsilyl cyanide or -carbanion
derived from acetonitrile. Basic hydrolysis of -(4) and -amino nitriles (7) gives fluoroalkylated -(5)
and -amino acids (8).
Received 20 September 2010
Received in revised form 10 December 2010
Accepted 15 December 2010
Available online 21 December 2010
1,2-addition of trimethylsilyl cyanide to fluoroalkylated
roalkylated
a,b
b
a
a
,b
a
b
a
ꢀ
In memoriam of Professor Dr. Jose Manuel
ꢀ
Concellon
a
b
a
b
Ó 2010 Published by Elsevier Ltd.
Keywords:
Phosphorylated enamines
Fluoroalkylated enamines
Fluorinated
Fluorinated
a
a
,
b
-unsaturated imines
and -amino nitriles
b
b
-Amino acid derivatives
1. Introduction
Strecker reaction of N-sulfinyl ketimines11a has been described and
four examples for the addition of trimethylsilyl cyanide to fluori-
nated N-substituted ketimines in the presence of palladium aceta-
te,11b gallium triflate,11c Lewis acids,11d or an acid polymer11e have
been reported.
Fluoroorganic compounds have received a great deal of attention
since the incorporation of a fluorine containing group into an or-
ganic molecule dramatically alters its physical, chemical and bi-
ological properties.1 Special interest has been focused on developing
synthetic methods for the preparation of fluorinated building blocks
as they can be used for the efficient and/or selective preparation of
fluorine-containing molecules with commercial applications2 and
interest in medicinal chemistry.3 The preparation of fluorinated
analogues of amino acids has recently been used tostabilize proteins
for their application in protein-based biotechnologies,4 and to the
preparation of fluorinated peptidomimetics.5
In this context, a,b-unsaturated imines (I, Scheme 1) also called
1-azadienes are a versatile family of compounds with a wide range
of applications in preparative organic chemistry.12 Besides the
well known aza-DielseAlder reaction13 for the preparation of
six membered heterocycles and [4þ1] cycloadditions for the
R'
H
R'
N
N
CN
RF
Furthermore, there is a growing need in organic synthesis for
efficient methodologies for the construction of quaternary carbon
R
R
RF
1,2 Ad.
I
II
centers6 and
a- and b-amino nitriles possess a wide variety of bi-
ological activities in search of new therapeutic agents,7 and are
versatile compounds for generating molecular diversity and amino
acid derivatives.8 The Strecker reaction,9 has been widely applied to
aldimines, however few examples were reported with ketimines.10
Specifically in the case of fluorinated imines, only the asymmetric
R
O
1,2 Ad.
NH2
Ref 26
O
NH2
RF
CN
(EtO)2P
R
RF
III
IV
Scheme 1. Fluorinated
a,b-unsaturated imines (I). Templates for the preparation of
* Corresponding author. Tel.: þ34 945 013103; fax: þ34 945 013049; e-mail
a
- and -amino nitriles.
b
address: francisco.palacios@ehu.es (F. Palacios).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.12.046

1576
F. Palacios et al. / Tetrahedron 67 (2011) 1575e1579
synthesis of pyrroles,14 unsaturated imines have been extensively
used in the synthesis of several natural products.15 Moreover,
Table 1
Fluoroalkylated a-amino nitriles 4
Entry
Compound
R1
R2
RF
Yield(%)a
owing to their ambident electrophilic character, a,b-unsaturated
imines can either undergo (1,2)16 or conjugate (1,4)17 nucleophilic
addition processes. However, generally, the control on the regio-
selectivity, is difficult and very often the double nucleophilic ad-
dition products are obtained.18
1
2
4a
4b
H
H
p-MeeC6H4
CF3
CF3
81 (85)b
78 (83)b
O
3
4
4c
H
H
CF3
CF3
68
84
The simplest method for the synthesis of a,b-unsaturated im-
S
ines implies condensation of
a,b-unsaturated carbonyl com-
4d
pounds (1,2-addition) with primary amines.19 This method is often
complicated by Michael addition reaction (1,4-addition), espe-
C6H5
5
6
7
8
9
10
11
4e
4f
4g
4h
4i
Me
Me
H
H
Me
H
p-MeeC6H4
p-NO2eC6H4
p-MeeC6H4
p-FeC6H4
p-MeeC6H4
p-MeeC6H4
p-NO2eC6H4
CF3
CF3
69
65 (70)b
78 (83)b
82(86)b
58 (62)b
62 (66)b
58
cially in the case of
using the AzaeWittig reaction20,21 of phosphazenes and has been
recently applied for the construction of -unsaturated imines
derived from
-aminoesters22a and -aminophosphonates.22b
Likewise, an olefination reaction of -phosphonylated imines or
a,b-unsaturated ketones, but can be avoided by
CHF2
CHF2
CHF2
C2F5
C2F5
a,b
4j
4k
a
a
Me
a
a
enamines with aldehydes to generate the conjugated C]C bond of
Yield of isolated purified compounds obtained from 1 (procedure A).
Yield obtained from 2 (procedure B).
b
1-azadienes is usually a good alternative.23
In this context, we described the preparation of fluorine-
substituted aminophosphonates from fluorinated aziridines24 and
from enamines25 and we applied this strategy for the preparation of
These a-amino nitriles 4 can also be prepared through treatment
of enaminophosphonates28 2 with BuLi, addition of aldehydes 2 and
subsequent addition of the cyanide 3 (Scheme 2, Procedure B, Table 1,
entries 1, 2, 6e10). Nitrile hydrolysis was first tried with hydrochlo-
ride acid (4 M), and a very complex reaction mixture was obtained.
first stable N-unsubstituted
a
,
b
-unsaturated imines26 I (R¼H) from
primary enaminophosphonates27 IV. Here, we report our own re-
sults concerning the preparation of fluorinated
nitriles derivatives III (see Scheme 1).
a- II and b-amino-
However, basic hydrolysis of
RF¼CF3) with NaOH in refluxing methanol gave
a
-amino nitrile 4c (R1¼H; R2¼2-thienyl;
a-amino acid 5 in low
yield (32%). As far as we know, N-unsubstituted fluoroalkylated
amino nitriles 4 were described and obtained by the first time.
a-
2. Results and discussion
2.1. Synthesis of fluoroalkylated a-amino nitriles 4
2.2. Synthesis of fluoroalkylated b-amino nitriles 7
Unsaturated imines 1 were prepared by deprotonation of pri-
mary enamines 2 with butyllithium, followed by the addition of
aldehydes in a stereoselective fashion and in good yields.26 For
synthetic purposes imines 1 can be used without isolation. Tri-
methylsilyl cyanide 3 in methanol was added over the fluorinated
imines 1 (RF¼CF3, CHF2, C2F5), and the reaction mixture was heated
at methanol reflux (24e36 h, see Experimental section) to give only
The versatility of
for the preparation of acyclic compounds being known, the syn-
thetic applications of these substrates -unsaturated imines 1 as
intermediates in the preparation of -amino nitriles was also ex-
a,b-unsaturated imines as starting materials
a,b
b
plored. Addition of the C-a carbanion derived from acetonitrile 6
at ꢀ78 ꢁC over azadienes 1, and after the reaction mixture was
allowed to warm to room temperature, gave trifluoromethylated
fluoroalkylated a-amino nitriles 4 in good yields keeping the trans-
b
-amino nitrile 7 (Scheme 3, Procedure A, Table 2, entries 1e5) in
a regioselective fashion. The formation of this functionalized nitrile
7 involves a selective 1,2-addition of the C- carbanion derived
from acetonitrile 6 to the C]N imine moiety of -unsaturated
imine 1 with the formation of adducts 7. Fluorinated -amino
nitriles 7 may also be prepared from enaminophosphonate28
with BuLi, addition of aldehydes and subsequent addition of the
C- carbanion derived from acetonitrile 6 (Scheme 3, Procedure B,
configuration of the CeC double bond (Scheme 2, procedure A,
Table 1, entries 1e11). The scope of the process is very wide, be-
cause the variation of the aldehyde (R2) proved to be possible (ar-
omatic-, heteroaromatic- or cinnamaldehyde) and the fluoroalkyl
group (RF) was not restricted to trifluoromethyl (RF¼CF3, Table 1,
entries 1e6) or perfluoroethyl (RF¼C2F5, Table 1, entries 10, 11)
given that difluoromethyl-substituted derivatives (RF¼CHF2, Table
1, entries 7e9) can also be prepared. Formation of fluoroalkylated
a
a,b
b
2
a
Table 2, entries 1e4). The scope of this process for the preparation
of amino nitriles 7 is wide, because variation of aldehyde (R1)
proved to be aromatic or heteroaromatic, and trifluoromethyl-
a
-amino nitriles 4 involves a regioselective 1,2-addition of cyanide
3 to -unsaturated imines 1 (see Scheme 2). Conjugate addition
(1,4-addition) of trimethylsilyl cyanide 3 was not detected.
a,b
NH2
NH
TMS CN (3)
NH
RF
NH2
H C CN
R2
CN
(6)
3
R2
RF
R2
CN
R2
RF
MeOH/ 65ºC
Procedure A
R1
R1
1
LDA, -78ºC
Procedure A
RF
R1
R1
1
4
7
R1= H; RF=CF3
BuLi, 0ºC
1. BuLi, 0ºC/
NaOH/MeOH/65ºC
Ref. 26
R2
O
2
1. BuLi, 0ºC/
O
R
BuLi, 0ºC
R2
O
32 %
2. LDA, -78ºC/ H C CN
2.
3
TMS CN/MeOH/ 65ºC
2
O
R
O
NH2
RF
NH2
COOH
O
NH2
RF
(EtO)2P
(EtO)2P
Ref. 26
Procedure B
R2
R1
F3C
R2 = 2-thienyl
-amino nitriles 4 and a-amino acid 5.
R1
2
2
5
Scheme 3. Synthesis of fluoroalkylated b-amino nitriles 7.
Scheme 2. Synthesis of fluoroalkylated
a

F. Palacios et al. / Tetrahedron 67 (2011) 1575e1579
1577
Table 2
blocks in organic synthesis and in the preparation of biologically
active compounds of interest in medicinal chemistry.
Fluoroalkylated b-amino nitriles 7
Entry
Compound
R1
R2
RF
Yield(%)a
1
2
3
4
5
7a
7b
7c
7d
7e
H
H
CH3
H
H
p-MeeC6H4
p-NO2eC6H4
p-MeeC6H4
p-FeC6H4
CF3
CF3
CF3
CHF2
C2F5
56 (60)b
52 (55)b
53 (57)b
50 (53)b
25
4. Experimental section
4.1. General methods
Solvents for extraction and chromatography were of technical
grade. All solvents used in reactions were freshly distilled. All other
reagents were recrystallized or distilled as necessary. All reactions
were performed under an atmosphere of dry nitrogen. Melting
points are uncorrected. FT-IR spectra were obtained as solids in KBr
or as neat oils in NaCl. Mass spectra (MS) were made by electron
impact (EI) at an ionizing voltage of 70 eV or by chemical ionization
(CI).1H (300, 400 MHz), 13C (75, 100 MHz) and 31P NMR
(120,160 MHz) spectra were recorded on a 300 MHz or 400 MHz
spectrometers, respectively, in CDCl3, as specified below. Chemical
shifts (dH) are reported in parts per million (ppm), relative toTMS as
internal standard. All coupling constants (J) values are given in
hertz. Chemical shifts (dC) are reported in parts per million (ppm),
relative to CDCl3, as internal standard in a broad band decoupled
mode. The abbreviations used are as follows: s, singlet; d, doublet;
dd, doubleedoublet; t, triplet; q, quartet; m, multiplet. Coupling
constants (J) are reported in Hertz. All the NH and NH2 exchanged
with D2O. Flash-column chromatography was carried out using
commercial grades of silica-gel finer than 230 mesh. Analytical thin
layer chromatography (TLC) was performed on precoated silica-gel
60 F254 plates, and spot visualization was accomplished by UV light
(254 nm) or KMnO4 solution. Unsaturated imines 1 were prepared
according to literature procedure.26
O
a
Yield of isolated purified compounds obtained from 1 (procedure A).
Yield obtained from 2 (procedure B).
b
(RF¼CF3) difluoromethyl- (RF¼CHF2) and pentafluoroethyl-
substituted compounds (RF¼C2F5) can also be prepared.
Amino nitriles are excellent intermediates in preparative organic
synthesis for generating molecular diversity and amino-acid de-
rivatives, and we used fluorinated b-amino nitrile 7a for the synthesis
of fluorinated b-amino acid and fluorinated diamine. Basic hydrolysis
of
b
-amino nitrile 7a (R1¼H, R2¼p-MeeC6H4; RF¼CF3) with NaOH
(25%) in refluxing methanol gave b-amino acid 8 in moderate yield
(54%), while the selective nitrile reduction of b-amino nitrile 7a with
LiAlH4 in etherledtothe formationof functionalized fluoromethylated
diamine 9 in excellent yield (93%). In both compounds 8 and 9 the
trans-configuration of the CeC double bond is retained (Scheme 4).
NaOH
NH2
CF3
NH2
MeOH/ 65ºC
CN
COOH
R2
7a
R2
F3C
54%
R2 = p-Me-C6H4
8
4.2. General procedure for the synthesis of fluoroalkylated
a
amino nitriles 4
LiAlH4/
Et2O/ 0ºC
93%
General procedure A: TMSCN (0.27 mL, 2 mmol) was added to
a solution of fluoroalkyated
anhydrous methanol (15 mL). The mixture was heated at methanol
reflux until TLC showed the disappearance of the fluorinated a,b-
unsaturated imine 1 (24e30 h). Then, the solvent was evaporated
under vacuum and the crude product was purified by chromatog-
raphy using silica-gel (hexane/ethyl acetate).
a,b-unsubstituted imine 1 (1 mmol) in
NH2
F3C
R2
NH2
9
Scheme 4. Synthesis of trifluoromethylated b-amino acid 8 and diamine 9.
General procedure B: Butyllithium (1.6 M in hexanes) (0.65 mL,
1 mmol) was added to a solution of corresponding
b-enamine
phosphonate 2 (1 mmol) in anhydrous THF (6 mL) at 0 ꢁC under
nitrogen atmosphere. The mixture was stirred for 1 h at the same
temperature. Then, a solution of corresponding aldehyde (1 mmol)
in THF (6 mL) was added and the reaction was stirred at room
temperature until TLC showed the disappearance of 2 (7e8 h).
Then, the solvent was evaporated under vacuum and the crude
residue was solved with anhydrous methanol (15 mL). TMSCN
(0.27 mL, 2 mmol) was added and the mixture was heated at
methanol reflux until TLC showed the disappearance of fluorinated
3. Conclusion
In conclusion, this account describes a very simple, mild and
convenient strategy for the preparation of -trifluoromethyl-,
-difluoromethyl- and perfluoroethyl- substituted - and -amino
b
b
a
b
nitrile derivatives by simple regioselective 1,2-addition of trime-
thylsilyl cyanide or metallated acetonitrile to fluoroalkylated
a,b-unsaturated imines 1. These new fluorinated amino nitriles
could be very interesting starting materials for the preparation of
new fluorinated diamines, fluoroalkylated amino acids and fluorine
containing peptidomimetics, in which the fluoroalkyl substituents
could stabilize the corresponding biologically active peptides or
a,b-unsubstituted imine 1 (24e30 h). Then, the solvent was evap-
orated under vacuum and the crude product was purified by
chromatography using silica-gel (hexane/ethyl acetate).
proteins.3,5 Fluoroalkylated
a
- and
b
-amino nitrile can also be
4.2.1. 2-Amino-4-p-tolyl-2-(trifluoromethyl)but-3-enenitrile
(4a). Compound 4a was obtained as a white solid (195 mg, 81%)
from imine 1, from enaminophosphonate 2 (204 mg, 85%) as de-
scribed in the general procedure. Mp 51e52 ꢁC. Rf 0.47 (hexane/
prepared by olefination reaction of enaminophosphonate 2 with
base (BuLi), addition of aldehydes and subsequent addition of tri-
methylsilyl cyanide or metallated acetonitrile. High chemical di-
versity can be achieved because the variation of the aldehyde (R1),
fluoroalkyl group (RF) proved to be possible. Additional diversity
can be introduced with the nitrile reagent, given that by means of
ethyl acetate, 7/3). IR (KBr)nmax 3394, 3332, 2921, 2219, 1180 cmꢀ1
;
1H NMR (CDCl3)
d 2.17 (s, 2H, NH2), 2.36 (s, 3H, CH3), 6.06 (d,
3
3JHH¼15.9 Hz, 1H,]CH), 7.15 (d, JHH¼15.9 Hz, 1H,]CH), 7.17 (d,
trimethylsilyl cyanide
a
-amino nitriles can be prepared, whereas
3JHH¼7.9 Hz, 2H, Har), 7.33 (d, 3JHH¼7.9 Hz, 2H, Har) ppm; 13C NMR
2
with the use of metallated acetonitrile
b
-amino nitriles can be
are important building
(CDCl3)
d
21.3, 59.4 (q, JFC¼31.7 Hz), 116.4, 117.3, 122.6 (q,
7,8
obtained. Amino nitrile derivatives (
a
,
b)
1JFC¼284.5 Hz), 127.2, 129.6, 131.3, 137.7, 139.8 ppm; 19F NMR

1578
F. Palacios et al. / Tetrahedron 67 (2011) 1575e1579
(CDCl3)
d
ꢀ79.4 ppm; MS (EI): m/z 240 (Mþ, 19); Anal. Calcd for
Calcd for C13H13F3N2: C, 61.41; H, 5.15; N, 11.02. Found: C, 61.57; H,
5.19; N, 11.10.
C12H11F3N2: C, 60.00; H, 4.62; N, 11.66. Found: C, 60.23; H, 4.70; N,
11.79.
4.5. Synthesis of 3-amino-5-p-tolyl-3-(trifluoromethyl)pent-
4.3. Synthesis of 2-amino-4-(thiophen-2-yl)-2-
4-enoic acid (8)
(trifluoromethyl)but-3-enoic acid (5)
A solution of
(8 mL) and NaOH 25% (22 mL) was heated at reflux during 2 h until
TLC showed the disappearance of the -aminonitrile 7a. After the
reaction was completed, the solvent was evaporated under vac-
uum. The crude residue was treated with HCl 2 M (5 mL) during
30 min. The crude reaction was extracted with CH2Cl2 (3ꢂ100 mL),
dried over anhydrous MgSO4, filtered and the solvent was evapo-
rated under vacuum. The crude product was purified by chroma-
tography using silica-gel (ethyl acetate) and gave the corresponding
b-aminonitrile 7a (0.254 g, 1 mmol) in methanol
A solution of
(8 mL) and NaOH 25% (22 mL) was heated at reflux during 1.5 h
until TLC showed the disappearance of -amino nitrile 4c. After the
a-aminonitrile 4c (0.252 g, 1 mmol) in methanol
b
a
reaction was completed, the solvent was evaporated under vac-
uum. The crude residue was treated with HCl 2 M (5 mL) during
30 min. The crude reaction was extracted with CH2Cl2 (3ꢂ100 mL),
dried over anhydrous MgSO4, filtered and the solvent was evapo-
rated under vacuum. The product 5 was obtained as a white solid
(80 mg, 32%). Mp 178e180 ꢁC. Rf 0.25 (hexane/ethyl acetate, 7/3). IR
b
-amino acid 8: obtained as a white solid (147 mg, 54%).
(KBr)nmax 3392, 3025, 1642, 1451 cmꢀ1 1H NMR (CDCl3)
; d 4.02 (s,
Mp:106e107 ꢁC. Rf 0.37 (ethyl acetate). IR (KBr)nmax 3371, 3351,
2H, NH2), 6.02 (d, 3JHH¼15.6 Hz, 1H,]CH), 7.06 (m, 1H, Har), 7.28 (d,
3302, 1662 cmꢀ1 1H NMR (CDCl3)
; d 2.27 (s, 3H, CH3), 2.63 (s, 2H,
3JHH¼3.2 Hz, 1H, Har), 7.40 (d, JHH¼5.0 Hz, 1H, Har) ppm, 7.83 (d,
CH2), 6.20 (d, 3JHH¼16.0 Hz, 1H,]CH), 6.79 (d, 3JHH¼16.0 Hz, 1H,]
3
2
3
3
3JHH¼15.6 Hz, 1H,]CH); 13C NMR (CDCl3)
d
49.6 (q, JFC¼21.7 Hz),
CH), 7.09 (d, JHH¼7.8 Hz, 2H, Har), 7.27 (d, JHH¼7.8 Hz, 2H,
1
116.1, 125.2 (q, JFC¼260.2 Hz), 128.1, 129.5, 131.8, 139.6, 141.4,
Har) ppm; 13C NMR (CDCl3)
d
21.2, 40.2, 61.0 (q, 1JFC¼25.5 Hz), 125.3,
170.3 ppm; 19F NMR (CDCl3)
d
ꢀ78.1 ppm; HRMS (EIþ) calcd for
127.7 (q, 1JFC¼284.5 Hz), 127.8, 130.3, 134.3, 134.6, 139.3, 174.0 ppm;
C9H8F3NO2S [Mþ] 251.0228, found Mþ251.0223.
19F NMR (CDCl3)
d
ꢀ81.3 ppm; MS (EI): m/z 273 (Mþ, 29); Anal.
Calcd for C13H14F3NO2: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.29; H,
5.22; N, 5.25.
4.4. Synthesis of fluoroalkylated b-amino nitriles 7
General procedure A: LDA (1.2 mmol) was added to a solution of
acetonitrile 6 (1 mmol) in anhydrous THF (6 mL) at ꢀ78 ꢁC under
nitrogen atmosphere. Then, a solution of fluorinated azadiene 1
(0.214 g, 1 mmol) in dry THF was added to the solution of metal-
lated acetonitrile and the mixture was stirred at ꢀ78 ꢁC until TLC
showed the disappearance of 1 (48e72 h). Then, the reaction was
allowed to reach room temperature and a saturated solution of
NH4Cl (10 mL) was added and the organic layer was extracted with
CH2Cl2 (3ꢂ25 mL), dried over anhydrous MgSO4, filtered and the
solvent was evaporated under vacuum and the crude product was
purified by chromatography using silica-gel (hexane/ethyl acetate).
General procedure B: Butyllithium (1.6 M in hexanes) (0.65 mL,
4.6. Synthesis of 5-p-tolyl-3-(trifluoromethyl)pent-4-ene-1,3-
diamine (9)
A solution of b-amino nitrile 7a (0.254 g, 1 mmol) in anhydrous
ethyl ether (3 mL) was added to LiAlH4 (2.5 mmol) in anhydrous
ethyl ether (6 mL) at 0 ꢁC under nitrogen atmosphere. The mixture
was stirred for 1 h at the same temperature until TLC showed the
disappearance of fluorinated
b-amino nitrile 7a. Then, H2O was
added dropwise to the suspension, next NaOH was added and again
H2O. The mixture was filtered through Celite and concentrated
under vacuum afforded 240 mg (93%) of diamine 9, obtained as
a colorless oil. Rf 0.41 (ethyl acetate). IR (KBr)nmax 3370, 3330, 3296,
1 mmol) was added to a solution of corresponding
b-enamine
2926, 1112 cmꢀ1; 1H NMR (CDCl3)
d 1.76 (m, 2H, NH2), 2.13 (s, 4H, 2
phosphonate 2 (1 mmol) in anhydrous THF (6 mL) at 0 ꢁC under
nitrogen atmosphere. The mixture was stirred for 1 h at the same
temperature. Then, a solution of corresponding aldehyde (1 mmol)
in THF (6 mL) was added and the reaction was stirred at room
temperature until TLC showed the disappearance of 2 (7e8 h).
Then, the mixture was added to a solution of metallated acetonitrile
6 with LDA at ꢀ78 ꢁC in THF during 1 h and the reaction was stirred
at ꢀ78 ꢁC until TLC showed the disappearance of 1 (48e72 h). Then,
the reaction was allowed to reach room temperature and a satu-
rated solution of NH4Cl (10 mL) was added and the organic layer
was extracted with CH2Cl2 (3ꢂ25 mL), dried over anhydrous
MgSO4, filtered and the solvent was evaporated under vacuum and
the crude product was purified by chromatography using silica-gel
(hexane/ethyl acetate).
CH2), 2.22 (s, 3H, CH3), 2.70e2.73 (m, 2H, NH2),6.01 (d,
3
3JHH¼16.0 Hz, 1H,]CH), 6.69 (d, JHH¼16.0 Hz, 1H,]CH), 7.02 (d,
3JHH¼7.6 Hz, 2H, Har), 7.19 (d, 3JHH¼7.6 Hz, 2H, Har) ppm; 13C NMR
(CDCl3)
d
20.9, 36.0, 36.4, 60.2 (q, 1JFC¼26.1 Hz), 124.5, 126.3, 127.7
(q, 1JFC¼284.5 Hz), 129.1, 132.0, 132.9, 137.8 ppm; 19F NMR (CDCl3)
d
ꢀ82.5 ppm; MS (EI): m/z 258 (Mþ, 36); Anal. Calcd for C13H17F3N2:
C, 60.45; H, 6.63; N, 10.85. Found: C, 60.24; H, 6.69; N, 10.99.
Acknowledgements
The authors thank The University of the Basque Country (UPV/
EHU, GIU 09/56), The Education and Research Department from
ꢀ
Gobierno Vasco (GV, Vitoria, IT-422-10) and the Direccion General
ꢀ
de Investigacion del Ministerio de Ciencia y Tecnología (MICIN,
Madrid DGI, CTQ2009-12156) for supporting this work. G.F.T.
thanks the University of the Basque Country for a formation con-
tract. UPV/EHU-SGIKer technical support (MICINN, GV/EJ, European
Social Fond) is gratefully acknowledged.
4.4.1. 3-Amino-5-p-tolyl-3-(trifluoromethyl)pent-4-enenitrile
(7a). Compound 7a was obtained as a pale brown oil from imine 1
(142 mg, 56%), from enaminophosphonate 2 (152 mg, 60%) as de-
scribed in the general procedure. Rf 0.36 (hexane/ethyl acetate, 7/3).
IR (KBr)nmax 3397, 3335, 2257, 1177 cmꢀ1; 1H NMR (CDCl3)
d 2.29 (s,
3H, CH3), 2.95 (d, 2JHH¼16.9 Hz, 1H, CH2), 3.03 (d, 2JHH¼16.9 Hz, 1H,
Supplementary data
CH2), 6.22 (d, 3JHH¼16.0 Hz, 1H,]CH), 6.97 (d, 3JHH¼16.0 Hz, 1H,]
3
3
CH), 7.13 (d, JHH¼7.8 Hz, 2H, Har), 7.33 (d, JHH¼7.8 Hz, 2H,
Experimental procedures and characterization data (1H NMR,
13C NMR, 31P NMR, 19F NMR, IR and elemental analysis) for com-
pounds 4be4k, 7be7e. Supplementary data related to this article
can be found online at doi:10.1016/j.tet.2010.12.046.
Har) ppm; 13C NMR (CDCl3)
d
21.2, 26.4, 60.0 (q, 2JFC¼27.7 Hz), 117.1,
123.5, 127.5 (q, 1JFC¼285.5 Hz), 127.9, 130.4, 134.2, 135.6, 139.8 ppm;
19F NMR (CDCl3)
d
ꢀ81.0 ppm; MS (EI): m/z 254 (Mþ, 37); Anal.

F. Palacios et al. / Tetrahedron 67 (2011) 1575e1579
1579
Y.; Arndt, H. D. J. Org. Chem. 2007, 72, 4205e4212; (c) Esquivias, J.; Gomez
Arrayas, R.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 1480e1481.
14. For recent contributions see: (a) Mizuno, A.; Kusama, H.; Iwasawa, N. Angew.
Chem., Int. Ed. 2009, 48, 8318e8320; (b) Lu, Y.; Arndtsen, B. A. Org. Lett. 2009, 11,
1369e1372.
15. (a) Atobe, M.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2005, 46,
2669e2673; (b) Schnermann, M. J.; Boger, D. L. J. Am. Chem. Soc. 2005, 127,
15704e15705.
References and notes
1. Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishnan, S., Eds.; Wiley:
New York, NY, 1991.
2. (a) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.; J. Wiley:
Chischester, UK, 2009; (b) Chambers, R. D. Fluorine in Organic Chemistry, 2nd ed.;
Blackwell: London, 2004; (c) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, 2004; (d) Enantiocontrolled Synthesis of Fluoro-Organic Com-
pounds: Stereochemical Challenges and Biomedical Targets; Soloshonok, V. A., Ed.;
Wiley: New York, NY, 1999; (e) Fluorine Containing Amino Acids, Synthesis and
Properties; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: New York, NY, 1995.
3. For recent reviews see: (a) Federsel, H. J. Acc. Chem. Res. 2009, 42, 671e680; (b)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
16. Contributions to selective 1,2 addition to
a,b-unsaturated imines: (a) Groe-
nendaal, B.; Vugts, D. J.; Schmitz, R. F.; de Kanter, F. J. J.; Ruijer, E.; Groen, M. B.;
Orru, R. V. A. J. Org. Chem. 2008, 73, 719e722; (b) Prakash, G. K. S.; Mandal, M.;
Olah, G. A. Org. Lett. 2001, 3, 2847e2850; (c) Denmark, S. E.; Stiff, C. M. J. Org.
Chem. 2000, 65, 5875e5878.
17. Recent contributions to selective conjugate addition to a,b-unsaturated imines:
€
320e330; (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359e4369; (d) Muller,
K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881e1886; (e) Kirk, K. L. J. Fluorine
Chem. 2006, 127, 1013e1029.
(a) Vicario, J.; Aparicio, D.; Palacios, F. J. Org. Chem. 2009, 74, 452e455; (b)
Palacios, F.; Vicario, J. Org. Lett. 2006, 8, 5405e5408; (c) Shimizu, M.; Takahashi,
A.; Kawai, S. Org. Lett. 2006, 8, 3585e3587.
4. For recent contributions see: (a) Chiu, H. P.; Kokona, B.; Fairman, R.; Cheng, R. P.
J. Am. Chem. Soc. 2009, 131, 13192e13343; (b) Salwiczek, M.; Samsonov, S.; Vagt,
T.; Nyakutura, E.; Fleige, E.; Numata, J.; Coelten, H.; Pisabarro, M. T.; Koksch, B.
Chem.dEur. J. 2009, 15, 7628e7636; (c) Meng, H.; Kumar, K. J. Am. Chem. Soc.
2007, 129, 15615e15622.
5. (a) Buer, B. C.; de la Salud-Bea, R.; Al Hashimi, H. M.; Marsh, E.; Neil, G. Bio-
chemistry 2009, 48, 10810e10817; (b) Meng, H.; Krishnaji, S. T.; Beinborn, M.;
Kumar, K. J. Med. Chem. 2008, 151, 7303e7307; (c) Binkert, C.; Frigerio, M.;
Jones, A.; Meyer, S.; Pesenti, C.; Prade, L.; Viani, F.; Zanda, M. ChemBioChem
2006, 7, 181e186.
6. For recent eviews see: (a) Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nature
Chem. 2010, 2, 192e196; (b) Dumas, A. M.; Fillion, E. Acc. Chem. Res. 2010, 43,
440e454; (c) Koester, D. C.; Werz, D. B. Angew. Chem., Int. Ed. 2009, 48,
7971e7973.
7. Undavia, N. K.; Patwa, B. S.; Navadiya, H. D.; Jivani, A. R.; Dave, P. N. Int. J. Chem.
Sci. 2009, 7, 1019e1026.
18. Contributions to double addition to
a
,
b
-unsaturated imines: (a) Van Meenen,
ꢀ
E.; Moonen, K.; Verwee, A.; Stevens, C. V. J. Org. Chem. 2006, 71, 7903e7906; (b)
ꢀ
Moonen, K.; Van Meenen, E.; Verwee, A.; Stevens, C. V. Angew. Chem., Int. Ed.
2005, 44, 7407e7411; (c) Shimizu, M.; Kamiya, M.; Hachiya, I. Chem. Lett. 2005,
34, 1456e1457.
19. (a) Pearson, W. H.; Jacobs, V. A. Tetrahedron Lett. 1994, 35, 7001e7004; (b) Teng,
M.; Fowler, F. W. J. Org. Chem. 1990, 55, 5646e5653; (c) Brady, W. T.; Shieh, C. H.
J. Org. Chem. 1983, 48, 2499e2502.
20. For reviews see: (a) Palacios, F.; Aparicio, D.; Rubiales, G.; Alonso, C.; de los
Santos, J. M. Curr. Org. Chem. 2009, 13, 810e828; (b) Palacios, F.; Aparicio, D.;
Rubiales, G.; Alonso, C.; de los Santos, J. M. Tetrahedron 2006, 63, 523e575.
21. For contributions of creation of the C]N bouble bond by means of this process
ꢀ
see: (a) Palacios, F.; Herran, E.; Rubiales, G.; Alonso, C. Tetrahedron 2007, 63,
ꢀ
5669e5676; (b) Palacios, F.; Herran, E.; Alonso, C.; Rubiales, G.; Lecea, B.;
Ayerbe, M.; Cossío, F. P. J. Org. Chem. 2006, 71, 6020e6030; (c) Cossío, F. P.;
Alonso, C.; Lecea, B.; Ayerbe, M.; Rubiales, G.; Palacios, F. J. Org. Chem. 2006, 71,
2839e2847; (d) Palacios, F.; Alonso, C.; Rubiales, G.; Villegas, M. Tetrahedron
2005, 61, 2779e2794.
8. For recent reviews see (a) Wang, M. X. Chimia 2009, 63, 331e333; (b) Gonzalez-
Vera, J. A.; Garcia-Lopez, M. T.; Herranz, R. Mini-Rev. Org. Chem. 2008, 5,
209e221.
9. Strecker, A. Ann. Chem. Pharm. 1850, 75, 27e45.
10. (a) Connon, S. J. Angew. Chem., Int. Ed. 2008, 47, 1176e1178; (b) Vilaivan, T.;
22. (a) Palacios, F.; Vicario, J.; Aparicio, D. J. Org. Chem. 2006, 71, 7690e7696; (b)
Palacios, F.; Vicario, J.; Maliszewska, A. J. Org. Chem. 2007, 72, 2682e2685.
23. (a) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J. Org. Lett. 2002,
4, 769e772; (b) Palacios, F.; Aparicio, D.; Vicario, J. Eur. J. Org. Chem. 2002,
Bhanthumunavin, W.; Sritana-Anant, Y. Curr. Org. Chem. 2005, 9, 1315e1392; (c)
€
Groger, H. Chem. Rev. 2003, 103, 2795e2827.
ꢀ
4131e4136; (c) Palacios, F.; Aparicio, D.; García, J.; Rodríguez, E.; Fernandez-
11. (a) Wang, H.; Zhao, X.; Li, Y.; Lu, L. Org. Lett. 2006, 8, 1379e1381; (b) Yamasaki, Y.;
Maekawa, T.; Ishihara, T.; Ando, T. Chem. Lett. 1985, 1387e1390; (c) Prakash, G. K.
S.; Mathew, T.; Panja, C.; Alconcel, S.; Vaghoo, H.; Do, C.; Olah, G. A. Proc. Natl. Acad.
Sci. U.S.A. 2007, 104, 3703e3706; (d) Huguenot, F.; Brigaud, T. J. Org. Chem. 2006,
71, 7075e7078; (e) Prakash, G. K. S.; Thomas, T. E.; Bychinskaya, I.; Prakash, A. G.;
Panja, C. H.; Vaghoo, H.; Olah, G. A. Green Chem. 2008, 10, 1105e1110.
12. For reviews of 1-azadienes see (a) Groenendal, B.; Ruijer, E.; Orru, R. V. A. Chem.
Commun. 2008, 5474e5489; (b) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379e471; (c) Buonora, P.; Olsen, J. C.; Oh, T. Tetrahedron
2001, 57, 6099e6138.
Acebes, A. Tetrahedron 2001, 57, 3131e3141.
24. Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org. Chem. 2006, 71,
6141e6148.
25. Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J.; Pascual, S.; Fernandez de
Troconiz, G. J. Org. Chem. 2008, 73, 4568e4574.
26. Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J. J. Org. Chem. 2004,
69, 8767e8774.
27. For a review of b-aminophosphonates see: Palacios, F.; Alonso, C.; de los Santos,
J. M. Chem. Rev. 2005, 105, 899e931.
28. These primary enamines are stable and can be easily prepared from com-
13. For recent contributions see: (a) Singh, L.; Ishar, M. P. S.; Elango, M.; Sub-
ramaniam, V.; Gupta, V.; Kanwal, P. J. Org. Chem. 2008, 73, 2224e2233; (b) Lu, J.
mercially available starting materials.26