Synthesis of N,N-dialkylaminobenzonitriles and halo-(N,N-dialkyl) benzamidines by reaction of halobenzonitriles with lithium amides

Article abstract of DOI:10.1016/j.tet.2011.06.066

3- and 4-N,N-Dialkylaminobenzonitriles and 4-chloro-(N,N-dialkyl) benzamidines were isolated by reacting 4-chlorobenzonitrile with hindered lithium amides under thermodynamic (0 °C) and kinetic control conditions (-78 °C), respectively. As previously repo

Full text of DOI:10.1016/j.tet.2011.06.066

Tetrahedron 67 (2011) 6944e6952
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Synthesis of N,N-dialkylaminobenzonitriles and halo-(N,N-dialkyl)benzamidines
by reaction of halobenzonitriles with lithium amides
*
Paola Vitale , Leonardo Di Nunno, Antonio Scilimati
ꢀ
Dipartimento Farmaco-Chimico, Universita degli Studi di Bari “A. Moro”, Via Orabona 4, 70125 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2011
Received in revised form 7 June 2011
Accepted 20 June 2011
Available online 25 June 2011
3- and 4-N,N-Dialkylaminobenzonitriles and 4-chloro-(N,N-dialkyl)benzamidines were isolated by re-
acting 4-chlorobenzonitrile with hindered lithium amides under thermodynamic (0 ꢀC) and kinetic
control conditions (ꢁ78 ꢀC), respectively. As previously reported, a benzyne mechanism seems to be
confirmed since N,N-dialkylaminobenzonitriles are formed. Only benzamidines were isolated in fair to
high yields at both 0 ꢀC and ꢁ78 ꢀC with non-hindered lithium amides. Exploitation and mechanistic
rationale of the reaction of different halobenzonitriles are also reported.
Keywords:
N,N-Dialkylaminobenzonitriles
Lithium amides
Ó 2011 Elsevier Ltd. All rights reserved.
Benzyne mechanism
Thermodynamic and kinetic control
N,N-Dialkylbenzamidines
1. Introduction
dialkylaminobenzonitriles by reacting halobenzonitriles with hin-
dered lithium amides. This reaction was first observed by us8 dur-
Aminobenzonitriles are important targets in organic synthesis,
due to their potential applications as electron donoreacceptor
(EDA) molecules, as probes to study materials properties,1 for the
development of optical switches, and for the potential conversion
of photon energy into electricity. The photodynamics of some
4-(dialkylamino)benzonitriles have been studied by time-resolved
X-ray diffraction,2e4 femtosecond UV/Vis, and mid-IR absorption
spectroscopy, both on single crystal or solubilized in polar/non
polar solvents,5,6 because these compounds (Fig. 1) often undergo
dual fluorescence and fast intramolecular charge transfer (ICT)
reactions.
ing a study of the reactivity of 3-(4-chlorophenyl)isoxazole and 3-
(2-chlorophenyl)isoxazole in the presence of LDA, in which some
chlorobenzonitriles were formed by partial fragmentation of iso-
xazoles,9 as depicted in Scheme 1 for 3-(4-chlorophenyl)isoxazole.
Cl
Cl
N
H
1h, THF
Cl
CN
O
+
+
N
Li
0°C
O
N
O
N
Cl
H
LDA
N
N
N
+
N
CN
N
CN
Scheme 1. Isolation of 3- and 4-diisopropylaminobenzonitrile from the reaction of
3-(4-chlorophenyl)isoxazole with LDA.
CN
CN
CN
Accordingly, similar results were also obtained directly starting
from the commercially available 4- and 2-chlorobenzonitrile under
the same experimental conditions. On the other hand, concerning
the mechanism of substitution of chlorine by LDA, a benzyne
mechanism was postulated, as both normal- (NS) and cine-
substitution (CS) products were observed.
Fig. 1. 4-(Dialkylamino)benzonitriles
Various starting materials and synthetic strategies, mainly
based on transition-metal catalytic processes,7 are used to prepare
these compounds. Herein, we report a simple approach to N,N-
This mechanistic hypothesis is also in accord with the reported
conversion of chlorobenzonitriles into arylboronic derivatives by
* Corresponding author. Tel.: þ39 080 2773; fax: þ39 080 2231; e-mail address:
paola.vitale@farmchim.uniba.it (P. Vitale).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.066

P. Vitale et al. / Tetrahedron 67 (2011) 6944e6952
6945
reaction with LDA and B(OiPr)3 at ꢁ78 ꢀC.10 The first step of this
reaction, in fact, consists only of the removal of the protons ortho to
chlorine and cyano-group (Scheme 2), the former reaction being
also the first step in the benzyne formation.
On the other hand, the benzyne mechanism is generally
expected when good electron withdrawing groups are absent and
the nucleophile is a very strong base. However, this is not the case
of 4-chlorobenzonitrile and 4-bromobenzonitrile, provided with
C^N group with electronic effects not very different from those of
classical EWGs (e.g., spNO2¼0.81yspCN¼0.70).13 So, in principle,
a SNAr mechanism14 could be expected, at least as a competitive
mechanism of reaction (Scheme 4).
O
B
O
N
CN
Cl
Cl
O
1) LDA, B(OiPr)3
2) neopentylglycol
O
O
B
Cl
CN
+
+
THF, -78 °C
r.t.
CN
Cl
X-
X
N
N
35%
65%
5%
LDA
X
CN
(NS) PRODUCT
Scheme 2. Synthesis of arylboronic derivatives from the reaction of 4-
C
N
chlorobenzonitrile with LDA.
CN
benzyne pathway
LDA
However, no nucleophilic substitution of chlorine is observed at
ꢁ78 ꢀC,10 possibly because the elimination of Clꢁ (rate determining
step in the benzyne formation from chlorobenzenes)11 is too slow
at this temperature.
SNAr pathway
CN
LDA
Clearly, the temperature plays a very important role in de-
termining the course of this reaction. Besides, an important role is
expected to be played also by the nature of the halogen, as well as
by the structure of the lithium amide.
Thus, with the aim of a deeper elucidation of such a complex
behaviour, particularly important in order to optimize the condi-
tions for the formation of the aminobenzonitriles, we decided to
deepen and extend the study of such a reaction using various hal-
obenzonitriles and lithium amides, as well as different reaction
conditions.
N
N
N
CN
CN
CN
N
CN
2. Results and discussion
CS-PRODUCT
NS-PRODUCT
Scheme 4. Reaction of 4-halobenzonitriles and LDA: hypothesis of both SNAr and
benzyne mechanisms.
As reported above,8 the formationof 3- and 4-(diisopropylamino)
benzonitrile (DIABN) was the only reaction observed by reacting
4-chlorobenzonitrile with an excess of LDA at 0 ꢀC, in accordance
with a benzyne mechanism of substitution. In order to confirm such
a mechanism, we investigated the same reaction starting from other
different 4-halobenzonitriles (Scheme 3 and Table 1). As expected,
a similar behaviour was observed in the case of 4-chloro and
4-bromobenzonitrile, both able to react via a benzyne intermediate,
In contrast, the formation of both NS and CS products in similar
relative amounts starting from chloro- and bromo-derivatives
suggests the occurrence of only the benzyne mechanism. This is
also in agreement with the absence of nucleophilic substitution of
the halogen in the case of the 4-fluorobenzonitrile, unfavoured
towards a benzyne mechanism but hypothetically favoured to-
wards the SNAr mechanism. Hence, this may constitute an example
of benzyne mechanism induced only (or mainly) by the large steric
hindrance of the nucleophile, and not by the absence of one acti-
vating group on the aromatic ring.
while
a completely different behaviour was observed for
4-fluorobenzonitrile, conceivably not able to undergo dehydro-
fluorination under these experimental conditions,12 and so to react
by the same mechanism.
However, as said above, no halogen substitution is observed
when the reaction is carried out at ꢁ78 ꢀC instead of 0 ꢀC. In this case
the addition of LDA onto the cyano-group is found for all hal-
obenzonitriles, affording benzamidines 5ae7a (Scheme 5, Table 2).15
Furthermore, when the reaction mixture of 4-chlorobenzonitrile
and LDA at ꢁ78 ꢀC is allowed to reach 0 ꢀC, NS and CS substitution
products were obtained in the same relative amounts observed by
performing the reaction directly at 0 ꢀC (Scheme 5, Table 2, entry 4:
comparison with Table 1, entry 1).
X
N
N
1h, 0 °C
+
N
Li
+
THF
CN
CN
CN
1
2a
3a
(26% X=Cl)
(29% X=Br)
(73% X=Cl)
(71% X=Br)
Finally, when 4-chloro-N,N-diisopropylbenzimidamide 5a was
lithiated at 0 ꢀC, formation of N,N-diisopropylaminobenzonitriles
2a and 3a in the same relative amounts was observed after 1 h
(Scheme 6).
All of the above data clearly indicates that the reaction is sub-
jected to both kinetic and thermodynamic control, giving different
products depending on the temperature used.
At this point, to better define the scope of this synthetic
methodology for the synthesis of N,N-dialkylaminobenzonitriles
2 and 3, the behaviour of 4-chlorobenzonitrile with a wide
number of different lithium amides at both 0 and ꢁ78 ꢀC was
investigated.
Scheme 3. Synthesis of 3-DIABN and 4-DIABN from the reaction of 4-
halobenzonitriles with 1.5 equiv of LDA at 0 ꢀC.
Table 1
Percentages (%) of products isolated by reacting 4-halobenzonitriles with 1.5 equiv
of LDA at 0 ꢀCa
Entry
X
2a (%)
3a (%)
1
2
3
Cl
Br
F
26b
29
73b
71
dc
dc
a
Percentages determined by GC on reaction crude.
In a few experiments the formation of 4-chloro-3-[(4-chlorophenyl)(imino)
b
methyl]benzonitrile (4) was observed (see Experimental section).
c
An unidentified complex fluorinated products mixture was obtained.
The obtained results are summarized in Scheme 7 and Table 3.

6946
P. Vitale et al. / Tetrahedron 67 (2011) 6944e6952
X=Cl
X
X
HN
N
Li
from
-78 to 0 °C
-78 °C
NH4Cl
+
-78 °C
N
N
NC
X
CN
N
Li
+
N
N
NH4Cl
NC
5a (X=Cl)
6a (X=F)
7a (X=Br)
5a-Li (X=Cl)
6a-Li (X=F)
7a-Li (X=Br)
2a
3a
Scheme 5. Reaction of 4-halobenzonitriles with LDA under thermodynamic and kinetic control conditions.
Table 2
Percentages (%) of products isolated by reacting 4-halobenzonitriles with LDA at ꢁ78 ꢀCa
Entry
BASE/S
X
T (ꢀC)
4-Halobenzonitrile (%)
2a (%)
3a (%)
Benzamidine (%)
1
2
3
4
5
6
1.5:1
3:1
1.5:1
1.5:1
1.5:1
1.5:1
Cl
Cl
Cl
Cl
F
ꢁ78
77
40
d
d
d
70
d
d
d
d
d
29
d
d
22 (5a)
60 (5a)
40 (5a)
d
76 (6a)c
23 (7a)
ꢁ78
ꢁ78
60 (79% D)b
d
From ꢁ78 to 0
ꢁ78
8
Br
ꢁ78
74 (62% D)d
a
Percentages (%) determined by GC on reaction crude.
b
Quenched with CD3OD; percentages determined by GCeMS and 1H NMR on reaction crude [2-deutero-/3-deutero-4-chlorobenzonitrile (1-2D/1-3D) ratio¼40:60]: see
Experimental section.
c
4-Fluoro-2-[(4-fluorophenyl)iminomethyl]benzonitrile (8) (16%) was also detected.
d
Quenched with CD3OD; percentages determined by GCeMS and 1H NMR on reaction crude.
N
NC
N
CN
LDA
N
NC
N
Li
N
H N
N
Li
+
0 °C
Cl
NH4Cl
Cl
Cl
5a-Li
5a
1
2a
3a
Scheme 6. 3-DIABN and 4-DIABN formation in the reaction of 4-chloro-N,N-diisopropylbenzimidamide (5a) with LDA at 0 ꢀC.
As it can be observed, in the presence of hindered lithium am-
ides with one or both bulky substituent on the amide nitrogen
atom, the formation of both aminobenzonitriles 2aeo and 3aeo
was observed at 0 ꢀC. On the other hand, the nucleophilic addition
to C^N giving benzamidines 5aeo was obtained at ꢁ78 ꢀC, with
the exception of the reaction of 4-chlorobenzonitrile and LTMP,
where just lithiation was observed, as previously reported for the
synthesis of arylboronic derivatives,10 and confirmed by us through
a deuteration experiment (Table 3, entry 18).
allowed to warm up to 0 ꢀC, we observed the formation of NS and
CS products, the same as performing the reaction directly at 0 ꢀC
(Table 4, entries 1 and 2).
Again a different behaviour was observed by reacting 2-
chlorobenzonitrile (10) with (n-Pr)2NLi. In the presence of this
less hindered base, in fact, benzamidine formation was again ob-
served both at ꢁ78 and 0 ꢀC (Table 4, entry 4), just as previously
observed in the case of 4-chlorobenzonitrile.
Further studies are in progress to exploit the use of these re-
actions to synthesize benzamidines endowed with unexplored
properties. Some fluorescence emission spectra of some amino-
benzonitriles in different solvents were also recorded,17 to explore
potential interesting properties as EDA molecules or new dual-
fluorescence probes.18 Although, deeper investigations are also in
progress regarding the photophysical properties of selected novel
dual fluorescent compounds, prepared by our above described
methodology, since ratiometric fluorescent probes and sensors are
powerful analytical tools, especially in studies using biological
samples, such as living cells and tissues.
In contrast, only benzamidines were obtained at both ꢁ78 and
0
ꢀC in the case of non-hindered lithium amides. This different
behaviour is plausibly due to the higher stability of 5-Li adducts
formed from non-hindered lithium amides, so that the latter are at
the same time the kinetic and thermodynamic products.
Afterwards, if required, benzamidines could be easily further
functionalized as indicated by the ‘one pot’ N-methylation of 5d-
Li, accomplished simply by adding iodomethane at ꢁ78 ꢀC
(Scheme 8).
On the other hand, with reference to the reaction with LDA, we
extended our investigation also to 2-chlorobenzonitrile both at 0 ꢀC
and ꢁ78 ꢀC, observing
a
behaviour quite similar to 4-
3. Conclusions
chlorobenzonitrile (Scheme 9, Table 4). In fact, at ꢁ78 ꢀC the for-
mation of benzamidine 12a (entry 3, Table 4) was observed to-
gether with unreacted 2-chlorobenzonitrile (recovered largely
deuterated at both 3 and 6 positions when the reaction was
quenched with CD3OD: see Experimental section). In contrast,
when the reaction was performed at ꢁ78 ꢀC for 1 h, and then
In conclusion, a number of N,N-dialkylaminobenzonitriles
were prepared by reacting o- and p-chlorobenzonitrile with
bulky lithium amides at 0 ꢀC, whereas halo-(N,N-disubstituted)
benzamidines were isolated in fair to high yields at low tem-
peratures (ꢁ78 ꢀC) starting from the same reagents. Based on the

P. Vitale et al. / Tetrahedron 67 (2011) 6944e6952
6947
R1
R1
R2
NH
N
R2
R1
R2
1h, T °C,
NH4Cl
THF
Cl
+
NC
N
N
+
Cl
NC
N
R1
R2
Li
NC
5a-o
1
2a-o
3a-o
Scheme 7. Reaction of 4-chlorobenzonitrile and lithium amides.
Table 3
Yields of products isolated from reaction of 4-chlorobenzonitrile and lithium amides (substrate/base ratio¼1:1.5), under thermodynamic (0 ꢀC) or kinetic control conditions
(ꢁ78 ꢀC)a
Entry
T (ꢀC)
R1
R2
1 (%)
2aeo (%)
3aeo (%)
5aeo (%)
1
2
3
4
5
6
7
8
0
0
0
0
0
0
0
0
0
0
0
0
0
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
i-Pr
Cy
n-Bu
Bn
i-Pr
Cy
n-Bu
d
2a (26)
2b (32)
d
3a (73)
3b (51)
d
d
16
d
d
5c (>98)
5d (97)
d
a
-CH3Bn
d
d
2e (33)b,c
d
d
3e (49)b
d
TMP
d
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
n-Pr
Et
18
d
5f (79)
d
Cy
Bn
Bn
Et
2g (16)
d
3g (83)
d
35d
5h (49)
d
9
8e
d
2i (11)
2l (32)f
d
3i (11)
3l (46)f
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
d
n-Pr
20
13
d
5m (80)
5n (87)
5o (1)
5a (40)
5b (17)
5c (>98)
5d (56)
d
eCH2CH2eOeCH2CH2e
cis-2,6-DMP
i-Pr
Cy
n-Bu
Bn
d
d
2o (24)
d
3o (57)
d
i-Pr
Cy
n-Bu
60
83
d
d
d
d
d
(S)
a
-CH3Bn
43
100g
17
89
19
d
d
d
TMP
d
d
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
n-Pr
Et
d
d
5f (83)
5g (11)
5h (81)
5i (>95)
5l (20)
5m (94)
5n (>95)
5o (>95)
Cy
Bn
Bn
Et
d
d
d
d
d
d
80
6
d
d
n-Pr
d
d
eCH2CH2eOeCH2CH2e
cis-2,6-DMP
d
d
d
d
d
d
a
Percentages determined by 1H NMR spectra recorded on reaction crudes.
Percentages determined by GC on reaction crude.
An unidentified compound (18%) was detected by GC in reaction crude.
An unidentified compound (16%) was detected by GC in reaction crude.
b
c
d
e
Low yields of products 2i and 3i were obtained when benzyl was one of the nitrogen substituents, probably due to a complex mixture of lithiated intermediates formed in
this reaction. N-benzylidene-2-methylpropan-2-amine formation (18%) was detected in the complex reaction mixture crude by GC, probably due to the base-decomposition,
and through the LiH elimination.16
f
4-Chloro-3-[(4-chlorophenyl)(imino)methyl]benzonitrile (4) (11%) was also observed in the reaction crude.
g
Deuterated 4-chlorobenzonitrile (93%) was isolated by quenching the reaction mixture with CD3OD; the product percentages were determined by GCeMS and 1H NMR in
reaction crude and revealed a 2-deutero-/3-deutero-4-chlorobenzonitrile (1-2D/1-3D) ratio¼83:17; see Experimental section.
Ph
Ph
(S)
( S)
N
N
Ph
N
N
Ph
CN
Li
H3C
Ph
I
CH3
1h, -78 °C
THF
(S)
Ph
N
+
Li
Cl
Cl
Cl
9 (90%)
5d-Li
1
Scheme 8. Synthesis of (S)-N-benzyl-4-chloro-N0-methyl-N-(1-phenylethyl)benzimidamide (9).
isolation of both the normal- and cine-substitution products
from o- and p-chlorobenzonitriles, and on other experimental
evidences, a benzyne mechanism seems to be confirmed for the
dialkylaminobenzonitriles, and a deeper insight of the reaction
mechanism was gained.
Further studies are in progress with regard to N,N-disubstituted
benzamidines, that could be useful synthons in different syn-
thetic19ꢁ21 and pharmaceutical22,23 applications.
Moreover, deeper investigations are ongoing about N,N-
dialkylaminobenzonitriles and their photophysical properties,
since ratiometric fluorescent probes and sensors are powerful
reaction outcome at
0
ꢀC. Conversely, 4-chloro-(N,N-di-
substituted)benzamidines were always isolated in the presence
of less hindered lithium amides, regardless of the temperature of
the reaction. So, by this investigation we uncovered a new syn-
thetic approach for the synthesis of
a number of N,N-

6948
P. Vitale et al. / Tetrahedron 67 (2011) 6944e6952
R
N
R
R
HN
CN
N
R
R
R
R
Cl
NC
Cl
THF
T °C,
E+
N
N
Li
+
+
+
R
CN
10
2a
11
12 (a: R=iPr)
(b: R=nPr)
Scheme 9. Reaction of 2-chlorobenzonitrile with lithium amides.
Table 4
Percentages (%) of products isolated by reacting 2-chlorobenzonitrile with lithium amidesa
Entry
T (ꢀC)
Eþ
R
10 (%)
2a (%)
11 (%)
Benzamidine (%)
1
2
3
4
0
NH4Cl
NH4Cl
CD3OD
NH4Cl
i-Pr
i-Pr
i-Pr
n-Pr
d
57b
61b
d
16b
13b
d
d
ꢁ78/0
6
d
ꢁ78
65 (87% D)c
6
35 (12a)
92 (12b)
ꢁ78/0
d
d
a
Percentages determined by GC on reaction crude.
b
c
2-Chloro-6-[(2-chlorophenyl)(imino)methyl]benzonitrile or 2-chloro-3-[(2-chlorophenyl)(imino)methyl] benzonitrile (20%) was detected in reaction crudes by GC.
Quenched with CD3OD; percentages determined by GCeMS and 1H NMR on reaction crude [3-deutero-/6-deutero-2-chlorobenzonitrile (10-3D/10-6D) ratio¼46:54].
analytical tools, especially in bio-pharmacological studies
in vitro and in ex-vivo.
stirrer and a nitrogen inlet. After 15 min, to such a solution kept at
the temperature indicated in Tables 2e4, a solution of hal-
obenzonitrile (500 mg, 3.650 mmol) in anhydrous THF (10 mL) was
dropwise added and the obtained brown reaction mixture was
stirred for 1 h and then quenched by adding aq NH4Cl (or CD3OD
and then aq NH4Cl). The two phases were separated and the
aqueous layer was extracted three times with ethyl acetate. The
combined organic extracts were dried over anhydrous Na2SO4 and
then the solvent evaporated under reduced pressure. GC analysis or
1H NMR spectra were recorded on reaction crudes for the de-
termination of the percentages of substrate/products conversions.
After crude characterization, acid/base extraction was per-
formed for the separation of neutral and basic compounds. From
the work-up procedure of reactions performed at ꢁ78 ꢀC the neu-
tral extract afforded halobenzonitriles, while basic extract afforded
the benzamidines 5aeo in the yields indicated in Tables 2e4. At
variance, for the reactions performed at 0 ꢀC, column chromatog-
raphy (alumina or silica gel, petroleum ether/ethyl acetate¼19:1) of
the basic fraction residue afforded the N,N-dialkylaminobenzoni-
triles indicated in Schemes 3, 5, 7, 9 and Tables 1e4.
4. Experimental section
4.1. General methods
Melting points were taken on an electrothermal apparatus. 1H
NMR and 13C NMR spectra were recorded on a Varian-Mercury
300 MHz, on a Varian Inova 400 MHz spectrometer, or on
a Bruker-Aspect 3000 console-500 MHz spectrometer and chemical
shifts are reported in parts per million (d
). 19F NMR spectra were
recorded by using CFCl3 as an internal standard. Absolute values of
the coupling constants are reported. FT-IR spectra were recorded on
a PerkineElmer 681 spectrometer. GC analyses were performed on
an HP 6890 model, Series II by using an HP1 column (methyl si-
loxane; 30 mꢂ0.32 mmꢂ0.25
mm film thickness). Thin-layer
chromatography (TLC) was performed on silica gel sheets with
fluorescent indicator; TLC spots were observed under ultraviolet
light or were visualized by I2 vapour exposure. Chromatography
was conducted by using silica gel 60 with a particle size distribution
40e63
mm and 230e400 ASTM. GCeMS analyses were performed
4.2.1. 3-(Diisopropylamino)benzonitrile (2a). Yield8 20% (29.0 mg).
Yellow semi-solid. [Found: C, 76.56; H, 8.71; N, 13.74. C13H18N2 re-
quires C, 77.18; H, 8.97; N, 13.85%]; Rf (5% EtOAc/petroleum ether)
0.75; nmax (liquid film) 2971, 2932, 2875, 2228,1591,1569,1496,1370,
on HP 5995C model and elemental analyses on an Elemental An-
alyzer 1106-Carlo Erba-instrument. ESIeMS analyses were per-
formed on Agilent 1100 LC/MSD trap system VL.
Tetrahydrofuran (THF) from a commercial source was purified
by distillation (twice) from sodium wire under nitrogen. n-Butyl-
lithium (2.5 M) in hexanes was purchased from Aldrich Chemical
Co. Titration of n-butyllithium was performed by using N-pivaloyl-
o-toluidine.24 Dialkylamines were purified by distillation from
CaH2. All other chemicals and solvents were commercial grade
further purified by distillation or crystallization prior to use.
1334,1301,1196,1181,1149,1126,1000, 776, 689 cmꢁ1
; dH (400 MHz,
CDCl3) 7.23e7.19 (1H, m, ArH); 7.03e7.00 (2H, m, ArH); 6.95e6.91
(1H, m,ArH);3.82(2H, heptet, J6.8Hz,2CHMe2);1.25(12H,d, J6.8Hz,
CHMe2); dC (100 MHz, CDCl3) 148.3, 129.2, 120.8, 119.8, 119.23, 112.3,
47.4, 21.0; m/z (70 eV, rel Int.) 202 (13, Mþ),187 (49),159 (4),146 (11),
145 (100), 129 (6), 117 (3), 102 (12), 43 (6), 41 (6).
4.2.2. 4-(Diisopropylamino)benzonitrile(3a)8,25. Yield 70% (103.0 mg).
White crystals. Mp 85e86 ꢀC (lit. 81e84 ꢀC).25 Rf (5% EtOAc/petroleum
ether) 0.73; nmax (KBr) 2969, 2925, 2851, 2206, 1598, 1515, 1428, 1334,
4.2. Reaction of halobenzonitriles with lithium amides:
general procedure (Tables 1e4)
1303, 1180, 1156, 1119, 821 cmꢁ1
; dH (400 MHz, CDCl3) 7.41e7.39 (2H,
The amount of base indicated below refer to the reaction of 4-
chlorobenzonitrile with LDA. See Table 1 for other substrate/base
ratios and conditions.
A 2.5 M solution of n-BuLi in hexanes (1.61 mL, 4.01 mmol) was
added to a solution of the dialkylamine (0.670 mL, 4.82 mmol) in
anhydrous THF (10 mL) at 0 ꢀC under nitrogen atmosphere, using
a nitrogen-flushed three necked flask equipped with a magnetic
m, ArH);6.78e6.75 (m, 2H, ArH);3.92 (2H, septuplet, J 6.8 Hz, CHMe2);
1.30 (12H, d, J 6.8 Hz, CHMe2); dC (100 MHz, CDCl3) 150.9,132.9,120.8,
114.5,96.7, 47.4,20.7;m/z(70 eV,rel Int.) 202(15, Mþ),187(55),159(5),
146 (10), 145 (100), 129 (7), 102 (14), 43 (7), 41 (6).
4.2.3. 4-Chloro-3-[(4-chlorophenyl)(imino)methyl] benzonitrile (4)26
Yield 45% (45.0 mg). Pale semi-solid. Rf (5% EtOAc/petroleum ether)
.

P. Vitale et al. / Tetrahedron 67 (2011) 6944e6952
6949
0.6; dH (400 MHz, CDCl3) 9.8 (1H, br s, NH: exchanges with D2O),
7.86e7.24 (7H, m, ArH); dC (100 MHz, CDCl3) 172.2,140.5,138.0,136.4,
134.7, 133.6, 132.3, 131.3, 129.4, 128.9, 127.7, 117.1, 111.6; m/z (70 eV, rel
Int.) 276 (16, Mþþ2), 275 (18), 274 (25, Mþ), 273 (23), 241 (34), 240
(16),139 (100),165 (5),163 (14),140 (11),138 (33),111 (10),100 (7), 75
(10); this product was fully characterized after conversion in the
corresponding 4-chloro-3-(4-chlorobenzoyl) benzonitrile (13). This
isomer was identified by one proton coupled 13C NMR experiment,
where the C^N carbon was a triplet (J 4.6 Hz) and the Cipso(CN)
a doublet (3J 9.0 Hz); [Found: C, 60.49; H, 2.53; N, 5.03. C14H7Cl2NO
requiresC,60.90;H,2.56;N,5.07%];nmax(liquidfilm)3065,2961, 2918,
2850, 2233, 1729, 1672, 1586, 1463, 1401, 1259, 1088, 1049, 1014, 798,
m, ArH), 7.32 (1H, d, J 8.4 Hz, ArH), 7.21e7.16 (2H, m, ArH); dF
(376 MHz, CDCl3) ꢁ105.6 (m); ꢁ105.8 (m); m/z (70 eV, rel Int.) 243
(43, Mþ), 148 (19), 123 (100), 120 (11), 95 (33), 75 (13).
4.2.8. 3-(Dicyclohexylamino)benzonitrile (2b). Yield 32% (66 mg).
Pale yellow powder. Mp 78e80 ꢀC. Rf (1% EtOAc/petroleum ether)
0.78; [Found: C, 80.71; H, 9.35; N, 9.66. C19H26N2 requires C, 80.80;
H, 9.28; N, 9.92%]; nmax (neat) 2930, 2854, 2227, 1590, 1568, 1493,
1451, 1345, 1296, 1262, 1242, 1166, 1121, 1050, 894, 776, 690 cmꢁ1
;
dH (500 MHz, CDCl3) 7.16e7.10 (1H, m, ArH), 7.08e7.06 (2H, m, ArH),
6.96e6.92 (1H, m, ArH), 3.31e3.22 (2H, m, 2CHN), 1.84e1.47 (10H,
m), 1.39e1.10 (10H, m); dC (CDCl3, 125 MHz) 149.1, 129.0, 122.2,
120.5, 120.4, 119.9, 112.2, 57.9, 31.6, 26.3, 25.7; m/z (70 eV, rel Int.)
282 (28, Mþ), 239 (100), 157 (74), 144 (40), 129 (17), 102 (13), 55
(27), 41 (14).
755 cmꢁ1
; dH (400 MHz, CDCl3) 7.76e7.65 (4H, m, ArH), 7.62 (1H, d, J
8.4Hz, ArH),7.49(2H, d,J8.4Hz, ArH);dC (100MHz,CDCl3)191.8,141.4,
139.7, 136.6, 134.6, 134.0, 132.7, 131.55, 131.51, 129.6, 117.3, 111.7; m/z
(70 eV, rel Int.) 277 (15, Mþþ2), 275 (24, Mþ), 240 (2),177 (3),166 (6),
164 (18), 141 (33), 139 (100), 136 (10), 113 (9), 111 (27), 100 (9), 85 (3),
75 (17), 51 (2), 50 (5).
4.2.9. 4-(Dicyclohexylamino)benzonitrile (3b). Yield 51% (105 mg).
Brown powder. Mp 69e71 ꢀC. Rf (5% EtOAc/petroleum ether) 0.75;
[Found: C, 81.06; H, 9.40; N, 10.02. C19H26N2 requires C, 80.80; H,
9.28; N, 9.92%]; nmax (KBr) 2930, 2854, 2212, 1606, 1515, 1449, 1346,
4.2.4. 4-Chloro-N,N-diisopropylbenzimidamide
(5a). Yield 22%
(38.0 mg). Pale yellow semi-solid. Mp 82e85 ꢀC; [Found: C, 65.81; H,
8.06; N, 11.77. C13H19ClN2 requires C, 65.40; H, 8.02; N, 11.73%]; nmax
(liquid film)3310,3036, 3017, 2973,2932,1578,1446,1382,1366,1219,
1296, 1176, 1108, 894, 823, 732 cmꢁ1
; dH (500 MHz, CDCl3) 7.37 (2H,
m, J 9.0 Hz, ArH); 6.80 (2H, m, J 9.0 Hz, ArH); 3.41e3.33 (2H, m,
2CHN); 1.87e1.60 (16H, m); 1.42e1.10 (4H, m); dC (CDCl3, 125 MHz)
151.7, 132.8, 120.8, 115.2, 125.6, 97.0, 58.0, 31.2, 26.4, 25.6; m/z
(70 eV, rel Int.) 282 (30, Mþ), 240 (15), 239 (100), 157 (62), 144 (39),
129 (14), 102 (20), 55 (31), 41(19).
1171, 1077, 1027, 1010, 856, 824, 770, 729 cmꢁ1
; dH (400 MHz, CDCl3)
7.32e7.28 (2H, m, ArH), 7.18e7.14 (2H, m, ArH), 5.40e5.0 (1H, br s, NH:
exchanges with D2O), 3.56 (2H, septuplet, J 6.8 Hz, CHMe2), 1.27 (12H,
d,J6.8Hz, CHMe2); dC (CDCl3,125MHz)166.7,139.6,133.9,128.6,127.3,
48.3, 20.7; m/z (70 eV, rel Int.) 240 (3, Mþþ2), 239 (5), 238 (8, Mþ), 237
(11), 197 (33), 195 (100), 183 (20), 181 (58), 140 (21), 139 (8), 138 (61),
137 (8), 111 (14), 102 (10), 86 (9), 75 (7), 58 (19), 44 (14), 43 (12).
4.2.10. 4-Chloro-N,N-dicyclohexylbenzimidamide (5b). Yield 17%
(39 mg). Pale yellow semi-solid. [Found: C, 71.43; H, 8.20; N, 8.49.
C19H27ClN2 requires C, 71.56; H, 8.53; N, 8.78%]; nmax (neat) 3348,
2918, 2850, 1567, 1447, 1417, 1261, 1153, 1081, 1022, 873, 801 cmꢁ1
;
4.2.5. 4-Fluoro-N,N-diisopropylbenzimidamide
(6a). Yield
76%
dH (500 MHz, CDCl3) 7.32e7.28 (2H, m, ArH), 7.17e7.14 (2H, m, ArH),
3.14e3.05 (2H, m, 2CHN), 2.62e2.49 (4H, m); 2.1e1.9 (2H, m);
1.84e1.80 (2H, m), 1.75e1.52 (4H, m); 1.29e0.95 (8H, m); dC (CDCl3,
125 MHz) 167.5, 139.7, 133.8, 128.6, 127.2, 58.2, 31.0, 26.1, 25.3; m/z
(70 eV, rel Int.) 318 (8, Mþ), 238 (11), 237 (37), 236 (34), 235 (100),
207 (9), 195 (11), 194 (19), 193 (23), 181 (21), 179 (17), 155 (16), 140
(16), 139 (21), 138 (79), 137 (20), 98 (12), 56 (18), 55 (19), 41 (13).
(139 mg). Pale yellow oil. [Found: C, 70.22; H, 8.71; N, 12.40.
C13H19FN2 requires C, 70.24; H, 8.61; N, 12.60%]; nmax (liquid film)
3313, 2967, 2928, 1669, 1598, 1575, 1511, 1446, 1367, 1222, 1180,
1155, 1082, 1029, 841, 792 cmꢁ1
; dH (400 MHz, CDCl3) 7.29e7.19
(2H, m, ArH), 7.08e6.98 (2H, m, ArH), 5.2e4.6 (1H, br s, NH: ex-
changes with D2O), 3.6 (2H, septuplet, J 6.8 Hz, CHMe2),1.3 (12H, d, J
6.8 Hz, CHMe2); dC (CDCl3, 100 MHz) 166.9, 162.4 (d, 1JCeF 246 Hz),
4
3
2
137.1 (d, JCeF 3.2 Hz), 127.8 (d, JCeF 8 Hz), 115.4 (d, JCeF 21.5 Hz),
48.3, 20.8; dF (376 MHz, CDCl3) ꢁ117.3; m/z (70 eV, rel Int.) 222 (Mþ,
9), 221 (11), 180 (12), 179 (100), 165 (57), 122 (78), 121 (30), 95 (22),
94 (10), 86 (17), 75 (8), 58 (25), 44 (34).
4.2.11. N,N-Dibutyl-4-chlorobenzimidamide
(5c). Yield
98%
(190 mg). Colourless semi-solid. [Found: C, 67.43; H, 8.55; N, 8.42.
C15H23ClN2 requires C, 67.52; H, 8.69; N, 10.50%]; nmax(neat) 3312,
2959, 2925, 2853, 1580, 1455, 1380, 1367, 1221, 1178, 1092, 1029,
1015, 824, 736 cmꢁ1
; dH (400 MHz, CDCl3) 7.29e7.25 (2H, m, ArH),
4.2.6. 4-Bromo-N,N-diisopropylbenzimidamide (7a). Yield 23%
(36 mg). Pale yellow semi-solid. Mp 84e86 ꢀC. [Found: C, 55.10; H,
6.48; N, 9.67. C13H19BrN2 requires C, 55.13; H, 6.76; N, 9.89%];
nmax(KBr) 3306, 2970, 2929, 2867, 1579, 1559, 1557, 1449, 1385,
1366, 1221, 1174, 1128, 1082, 1063, 1029, 1009, 824, 785, 723,
7.19e7.15 (2H, m, ArH), 5.45e4.85 (1H, br s, NH, exchanges with
D2O), 3.16 (4H, triplet, J 7.3 Hz, 2CH2N), 1.47 (4H, quintet, J 7.3 Hz,
2CH2CH2CH2), 1.17 (4H, sextet, J 7.3 Hz, 2CH2CH2CH3), 0.80 (6H,
triplet, J 7.3 Hz, 2CH2CH3); dC (CDCl3, 125 MHz) 167.8, 137.7, 134.3,
128.5, 127.9, 47.6, 29.9, 20.0, 13.8; m/z (70 eV, rel Int.) 268 (10,
Mþþ2), 267 (27), 266 (30, Mþ), 265 (74), 237 (11), 225 (15), 224
(12), 223 (46), 211 (10), 209 (29), 183 (77), 182 (16), 181 (88), 169
(31), 168 (20), 167 (88), 140 (32), 139 (26), 138 (100), 111 (22), 102
(24), 86 (36), 75 (13), 72 (12), 57 (10), 44 (30), 41 (12).
690 cmꢁ1
; dH (400 MHz, CDCl3) 7.50 (2H, d, J 8.4 Hz, ArH), 7.14 (2H,
d, J 8.4 Hz, ArH), 3.60 (2H, septuplet, J 6.8 Hz, CHMe2), 1.31 (12H,d, J
6.8 Hz, CHMe2); dC (CDCl3, 125 MHz) 166.4, 139.0, 131.8, 127.7, 122.6,
48.7, 20.8; m/z (70 eV, rel Int.) 284 (Mþþ2, 6), 283 (10), 282 (6, Mþ),
281 (10), 241 (99), 239 (100), 227 (51), 225 (52), 184 (58), 182 (59),
157 (11), 155 (12), 103 (25), 102 (34), 86 (27), 76 (20), 75 (18), 58
(43), 50 (11), 44 (55), 43 (16), 41 (16).
4.2.12. (S)-N-Benzyl-4-chloro-N-(1-phenylethyl)benzimidamide
(5d). Yield 56e97% (142 mg). Pale yellow semi-solid. [Found: C,
75.33; H, 5.95; N, 7.74. C22H21ClN2 requires C, 75.74; H, 6.07; N,
4.2.7. 4-Fluoro-3-[(4-fluorophenyl)(imino)methy] benzonitrile (8).
Compound (8): m/z (70 eV, rel Int.) 242 (31, Mþ), 240 (100), 223 (3),
147 (8), 122 (32), 95 (5), 75 (6), 40 (7).
8.03%]; ½a 2D0
ꢁ123.2 (c 1.0, CHCl3); nmax (neat) 3317, 3086, 3062,
ꢃ
3029, 2977, 2934, 1582, 1494, 1447, 1416, 1349, 1179, 1090, 1028,
1015, 836, 729, 697, cmꢁ1
; dH (500 MHz, CDCl3) 7.4e7.1 (m, 14H,
The product, obtained in 16% yield, was fully characterized after
conversion in the corresponding 4-fluoro-3-(4-fluorobenzoyl)ben-
zonitrile (14). Yield 16 mg [Found: C, 69.10; H, 2.85; N, 5.70.
C14H7F2NO requires C, 69.14; H, 2.90; N, 5.76%]; nmax (neat): 2925,
2854, 2233, 1738, 1710, 1673, 1600, 1464, 1410, 1380, 1261, 1237,
ArH), 5.16e5.15 (1H, br q, CHMe), 4.67 (1H, d, J 16.2 Hz, PhCHaN),
4.5e3.5 (1H, br s, NH, exchanges with D2O); 4.09 (1H, d, J 16.2 Hz,
PhCHbN), 1.52 (d, 3H, J 7.1 Hz, CHCH3); dC (125 MHz, CDCl3) 168.4,
141.3, 139.3, 137.1, 135.0, 128.9, 128.5, 128.2, 127.9, 127.3, 126.9,
126.6, 126.5, 56.7, 46.8, 17.9; m/z (70 eV, rel Int.) 350 (7, Mþþ2), 349
(10), 348 (19, Mþ), 347 (16), 259 (32), 257 (96), 245 (19), 243 (54),
1157, 1108, 853, 802, 723 cmꢁ1
; dH (400 MHz, CDCl3) 7.88e7.82 (4H,

6950
P. Vitale et al. / Tetrahedron 67 (2011) 6944e6952
216 (22), 214 (68),140 (18),138 (56), 120 (60),106 (91),105 (43),103
(27), 91 (100), 79 (58), 77 (67), 65 (30), 51 (31).
An inseparable mixture of 3-(2,2,6,6-tetramethylpiperidin-1-yl)
benzonitrile (2e) and 4-(2,2,6,6-tetramethylpiperidin-1-yl)benzoni-
trile (3e)¼40:60 was obtained as a pale yellow solid. Rf (1% EtOAc/
petroleum ether) 0.81 (145 mg).
C16H23ClN2 requires C, 68.92; H, 8.31; N, 10.05%]; nmax (neat) 2928,
2854, 1580, 1444, 1385, 1368, 1264, 1208, 1174, 1119, 1090, 1015, 825,
799 cmꢁ1
; dH (400 MHz, CDCl3) 7.32 (2H, d, J 8.2 Hz, ArH), 7.18 (2H,
d, J 8.2 Hz, ArH), 5.25e5.00 (1H, br s, NH, exchanges with D2O), 3.64
(1H, heptet, J 6.8 Hz, CH(CH3)2), 3.15e3.00 (m, 1H), 2.10e1.9 (2H,
m), 1.80e1.70 (2H, m), 1.70e1.60 (2H, m), 1.60e1.50 (1H, m), 1.20
(1H, m), 1.31 (6H, d, J 6.8 Hz, CH(CH3)2), 1.17e1.00 (m, 3H); dC
(CDCl3, 100 MHz) 166.9, 139.1, 134.1, 128.7, 127.3, 58.2, 48.8, 31.0,
26.2, 25.3, 20.8; m/z (70 eV, rel Int.) 280 (2, Mþþ2), 279 (2), 278 (5,
Mþ), 235 (20), 197 (8), 196 (9), 195 (23), 183 (18), 181 (55), 140 (13),
138 (38), 98 (20), 58 (27), 56 (28), 55 (23), 43 (50).
4.2.13. 3-(2,2,6,6-Tetramethylpiperidin-1-yl)benzonitrile (2e). Yield
33%. dH (500 MHz, CDCl3) 7.52e7.44 (3H, m, ArH); 7.36 (t, 1H, J
7.9 Hz, ArH); 1.76e1.66 (2H, m); 1.56 (4H, t, J 5.9 Hz); 0.98 (s, 12H);
m/z (70 eV, rel Int.) 242 (2, Mþ), 228 (11), 227 (68),171 (13),159 (13),
143 (16), 102 (19), 69 (48), 56 (15), 55 (14), 43 (10), 42 (15).
4.2.19. 4-Chloro-N-benzyl-N-isopropylbenzamidine
(5h). Yield
4.2.14. 4-(2,2,6,6-Tetramethylpiperidin-1-yl)benzonitrile
(3e). Analytical data for (3e) are identical to those previously
reported.27 Yield 49%. dH (500 MHz, CDCl3) 7.56 (2H, d, J 7.9 Hz, ArH),
7.30 (2H, d, J 7.9 Hz, ArH),1.76e1.66 (2H, m),1.56 (4H, t, J 5.9 Hz),1.00
(s, 12H); m/z (70 eV, rel Int.) 242 (Mþ, 3), 228 (16), 227 (91), 171(15),
159 (23),143 (19),109 (10),102 (21), 69 (55), 56 (13), 55 (14), 42 (17).
dC (CDCl3, 125 MHz) (2e)þ(3e): 152.2, 139.3, 137.7, 135.0 (major
isomer), 131.8 (major isomer), 129.4, 128.8, 119.3 (major isomer),
110.5, 109.3 (major isomer), 108.7, 54.5 (major isomer), 54.4 (minor
isomer), 42.1 (major isomer), 42.08 (minor isomer), 29.8 (minor
isomer), 18.2.
49e81% (102 mg). Yellow oil. [Found: C, 71.15; H, 6.61; N, 9.69.
C17H19ClN2 requires C, 71.19; H, 6.68; N, 9.77%]; nmax (neat) 3086,
3060, 3029, 2969, 2928, 2872, 2854, 1579, 1560, 1493, 1451, 1413,
1368, 1352, 1182, 1089, 1054, 1015, 963, 837, 799, 728, 695 cmꢁ1
; dH
(400 MHz, CDCl3) 7.37e7.34 (2H, m, ArH), 7.32e7.28 (5H, m, ArH),
7.26e7.21 (2H, m, ArH), 5.1e4.70 (1H, br s, NH, exchanges with D2O),
4.55 (2H, s, PhCH2), 4.12e3.92 (1H, m, CH(CH3)2),1.13 (6H, d, J 6.6 Hz,
CH(CH3)2); dC (CDCl3, 100 MHz) 167.8, 139.3, 136.8, 135.0, 128.9,
128.3,127.8,126.6,126.5, 50.4, 45.1, 20.9; m/z (70 eV, rel Int.) 288 (19,
Mþþ2), 287 (14), 286 (19, Mþ), 285 (31), 245 (18), 243 (54), 214 (12),
197 (10), 195 (31), 140 (19), 139 (11), 138 (56), 111 (16), 106 (95), 102
(15), 91 (100), 79 (28), 77 (18), 65 (28), 58 (97), 51 (18), 43 (19).
4.2.15. 4-Chloro-(N-ethyl-N-isopropyl)benzimidamide
(5f). Yield
79e83% (129 mg). Yellow oil. [Found: C, 64.27; H, 7.55; N, 12.15.
C12H17ClN2 requires C, 64.13; H, 7.62; N, 12.47%]; nmax (neat) 3317,
2972, 2932, 2873,1576,1455,1426,1369,1350,1223,1090,1015, 834,
4.2.20. 3-(N-tert-Butyl-N-benzylamino)benzonitrile (2i). Yield 11%
(21 mg). Yellow semi-solid. Rf (1% EtOAc/petroleum ether) 0.76;
[Found: C, 81.73; H, 7.32; N, 10.52. C18H20N2 requires C, 81.78; H,
7.63; N, 10.60%]; nmax (neat) 3063, 3028, 2960, 2924, 2853, 2228,
736 cmꢁ1
; dH (400 MHz, CDCl3) 7.33e7.29 (2H, m, ArH), 7.22e7.18 (m,
2H, ArH), 5.50e5.20 (1H, br s, NH, exchanges with D2O), 3.90e3.70
(1H, m, CHCH3), 3.30 (2H, q, J 6.7 Hz, CH2CH3), 1.16 (3H, t, J 6.7 Hz,
CH2CH3), 1.07 (3H, d, J 6.7 Hz, CHCH3); dC (CDCl3, 100 MHz) 167.4,
138.3,134.5,128.9,127.8, 49.7, 36.2, 21.1,15.0; m/z (70 eV, rel Int.) 226
(10, Mþþ2), 225 (33), 224 (28, Mþ), 223 (89), 197 (31), 196 (11), 195
(91),183 (18),181 (55),169 (15),167(45),140 (33),138 (100),137 (14),
111 (26), 102 (16), 75 (14), 72 (21), 58 (20), 44 (19).
1727, 1592, 1453, 1363, 1261, 1193, 1096, 1027, 801, 699 cmꢁ1
; dH
(400 MHz, CDCl3) 7.45e7.38 (1H, m, ArH), 7.37.7.30 (1H, m, ArH),
7.29e7.15 (6H, m, ArH), 7.12e7.08 (1H, m, ArH), 4.34 (2H, s, PhCH2),
1.22 (9H, s, (CH3)3); dC (100 MHz, CDCl3) 149.9, 140.2, 135.2, 133.5,
132.1, 128.8, 128.0, 127.9, 127.5, 126.5, 125.0, 119.1, 111.9, 55.9, 52.8,
28.4; m/z (70 eV, rel Int.) 264 (Mþ, 4), 250 (10), 249 (56), 208 (9),
207 (6), 205 (4), 179 (1), 143 (5), 131 (3), 129 (4), 102 (15), 92 (8), 91
(100), 77 (4), 76 (2), 75 (3), 65 (10), 57 (9), 41 (8).
4.2.16. 3-(N-Cyclohexyl-N-isopropylamino)benzonitrile (2g). Yield
16% (28 mg). Colourless oil; Rf (1% EtOAc/petroleum ether) 0.80;
[Found: C, 79.21; H, 9.10; N,11.59. C16H22N2 requiresC, 79.29; H, 9.15;
N,11.56%]; nmax (neat) 2964, 2930, 2854, 2227,1733,1591,1568,1494,
4.2.21. 4-(N-tert-Butyl-N-benzylamino)benzonitrile (3i). Yield 11%
(21 mg). Yellow oil. Rf (1% EtOAc/petroleum ether) 0.73; [Found: C,
81.41; H, 7.39; N, 10.45. C18H20N2 requires C, 81.78; H, 7.63; N,
10.60%]; nmax (neat) 3061, 3027, 2964, 2923, 2851, 2215, 1641, 1602,
1509, 1347, 1194, 1174, 1092, 1071, 1027, 828, 801, 744, 730,
1451, 1260, 1179, 1094, 1057, 1019, 798, 686 cmꢁ1
; dH (400 MHz,
CDCl3) 7.23e7.16 (1H, m, ArH), 7.07e7.00 (2H, m, ArH), 6.96e6.90
(1H, m, ArH), 3.80 (1H, heptet, J 7.0 Hz, CH(CH3)2), 3.34e3.24 (1H,
m, CH(CH2)2), 1.90e1.78 (2H, m), 1.78e1.53 (6H, m), 1.44e1.06 (8H,
m, CH(CH3)2þ2CH2); dC (100 MHz, CDCl3) 148.6, 132.9, 129.1, 121.4,
120.0,119.8,114.8, 57.7, 47.6, 31.4, 26.3, 25.7, 21.2; m/z (70 eV, rel Int.)
242 (20, Mþ), 227 (24), 199 (73), 185 (2), 171 (2), 157 (43), 145 (45),
129 (18), 116 (4), 102 (21), 83 (5), 75 (5), 55 (44), 43 (55).
698 cmꢁ1
; dH (400 MHz, CDCl3) 7.40 (2H, d, J 8.8 Hz, ArH), 7.30e7.16
(5H, m, ArH), 7.04 (2H, d, J 8.8 Hz, ArH), 4.50 (2H, s, PhCH2), 1.38 (9H,
s, (CH3)3); dC (100 MHz, CDCl3) 153.5, 140.4, 132.2, 128.4, 126.7,
126.6, 122.9, 119.8,102.5, 56.4, 53.3, 28.8; m/z (70 eV, rel Int.) 264 (6,
Mþ), 250 (9), 249 (47), 208 (16), 207 (6), 143 (4), 129 (4), 102 (13), 91
(100), 77 (4), 65 (9), 57 (8), 41 (8).
4.2.17. 4-(N-Cyclohexyl-N-isopropylamino)benzonitrile (3g). Yield
83% (147 mg). Yellow oil. Rf (1% EtOAc/petroleum ether) 0.78;
[Found: C, 79.15; H, 9.09; N, 11.51. C16H22N2 requires C, 79.29; H,
9.15; N, 11.56%]; nmax (neat) 2920, 2850, 2212, 1602, 1515, 1446,
4.2.22. N-tert-Butyl-N-benzyl-4-chlorobenzamidine (5i). Yield 95%
(208 mg). Yellow oil. [Found: C, 71.51; H, 7.08; N, 9.39. C18H21ClN2
requires C, 71.87; H, 7.04; N, 9.31%]; nmax (neat) 3088, 3063, 3028,
2964, 2925, 2871, 2856, 1580, 1565, 1484, 1454, 1406, 1359, 1205,
1419,1298,1176,1150, 1124,1091,1026, 873, 821 cmꢁ1
.
dH (400 MHz,
1179, 1089, 1014, 958, 836, 733, 700 cmꢁ1
; dH (400 MHz, CDCl3)
CDCl3) 7.39 (2H, d, J 9.0 Hz, ArH), 6.78 (2H, d, J 9.0 Hz, ArH), 3.91 (1H,
heptet, J 7.0 Hz, CH(CH3)2), 3.47e3.35 (m, 1H, CH(CH2)2), 1.92e1.82
(m, 2H), 1.78e1.63 (m, 6H), 1.45e1.08 (m, 2H), 1.31 (d, 6H, J 7.0 Hz,
CH(CH3)2); dC (100 MHz, CDCl3) 151.2, 132.8, 120.8, 114.8, 96.9, 57.8,
47.6, 31.0, 26.3, 25.6, 21.0; m/z (70 eV, rel Int.) 242 (25, Mþ), 227
(26), 200 (12), 199 (78), 171 (3), 157 (40), 145 (41), 144 (10), 143 (11),
129 (17), 102 (24), 83 (5), 75 (5), 55 (47), 43(55).
7.32e7.16 (9H, m, ArH), 5.00e4.60 (1H, br s, NH, exchanges with
D2O), 4.38 (s, 2H, PhCH2), 1.47 (9H, s, (CH3)3); dC (100 MHz, CDCl3)
140.9, 139.7, 134.7, 128.6, 128.3, 128.0, 126.9, 126.7, 57.5, 51.6, 28.9;
m/z (70 eV, rel Int.) 302 (2, Mþþ2), 301 (2), 300 (5, Mþ), 245 (25),
244 (12), 243 (69), 214 (10), 148 (10), 140 (11), 139 (17), 132 (30), 111
(11), 106 (57), 91 (100), 79 (11), 57 (22), 55 (20).
4.2.23. 3-(tert-Butyl(ethyl)amino)benzonitrile(2l). Yield 32% (47 mg).
Yellow oil. Rf (1% EtOAc/petroleum ether, alumina) 0.40; [Found: C,
77.22; H, 8.51; N, 13.73. C13H18N2 requires C, 77.18; H, 8.97; N,
4.2.18. 4-Chloro-N-cyclohexyl-N-isopropylbenzamidine (5g). Yield
11% (22 mg). Yellow oil. [Found: C, 68.10; H, 7.99; N, 10.14.

P. Vitale et al. / Tetrahedron 67 (2011) 6944e6952
6951
13.85%]; nmax (neat) 2923, 2851, 2230, 1736, 1593, 1464, 1380, 1360,
1262, 1101, 800, 703 cmꢁ1
dH (400 MHz, CDCl3) 7.44e7.33 (4H, m,
214 (6, Mþ), 200 (15), 199 (100), 145 (11), 144 (5), 143 (9), 129 (14),
102 (20), 90 (1), 77 (2) 75 (43), 55 (6) 41 (4).
;
ArH), 3.11 (2H, q, J 7.0 Hz), 1.10 (9H, s), 0.82 (3H, t, J 7.0 Hz); dC
(125 MHz, CDCl3) 149.7, 134.7, 133.1, 128.1, 119.1, 112.1, 55.6, 41.6, 28.1,
15.1; m/z (70 eV, rel Int.) 202 (Mþ, 6),188 (13),187 (100),159 (14),143
(8), 131 (38), 102 (11), 57 (10), 41 (6).
4.2.29. 4-[(2R,6S)-2,6-Dimethylpiperidin-1-yl]benzonitrile
(3o). Yield 57% (89 mg). Yellow oil. Rf (1% EtOAc/petroleum ether,
alumina) 0.71; [Found: C, 78.51; H, 8.33; N, 13.01. C14H18N2 re-
quires C, C, 78.46; H, 8.47; N, 13.07%]; nmax (neat): 2949, 2925,
2858, 2211, 1604, 1513, 1458, 1365, 1316, 1234, 1160, 1123, 1090,
4.2.24. 4-(tert-Butyl(ethyl)amino)benzonitrile (3l). Yield 46% (68 mg).
Yellow oil. Rf (1% EtOAc/petroleum ether, alumina) 0.38; [Found: C,
77.22; H, 8.51; N, 13.73. C13H18N2 requires C, 77.18; H, 8.97; N,
13.85%]; nmax (neat) 2967, 2927, 2854, 2225, 1734, 1602, 1501, 1466,
982, 909, 817, 734 cmꢁ1
; dH (400 MHz, CDCl3) 7.46 (2H, d, J 9.0 Hz,
ArH), 6.80 (2H, d, J 9.0 Hz, ArH), 4.10e3.97 (2H, m, 2CH(CH3)),
1.92e1.64 (4H, m), 1.60e1.44 (2H, m), 1.14 (6H, d, J 7.0 Hz,
2CH(CH3)); dC (100 MHz, CDCl3) 151.2, 133.5, 129.7, 125.0, 120.5,
113.4, 47.5, 33.4, 31.0, 20.3, 18.5, 14.7; m/z (70 eV, rel Int.) 214 (10,
Mþ), 200 (15), 199 (100), 157 (6), 145 (11), 144 (6), 143 (8), 129 (17),
102 (20), 81 (1), 75 (3), 55 (6).
1452, 1363, 1264, 1200, 1177, 1096, 1022, 846, 800, 739 cmꢁ1
; dH
(400 MHz, CDCl3) 7.51 (2H, d, J 8.4 Hz, ArH), 7.13 (d, 2H, J 8.4 Hz,
ArH), 3.25 (2H, q, J 7.0 Hz), 1.22 (9H, s), 0.85 (3H, t, J 7.0 Hz); dC
(100 MHz, CDCl3) 153.2, 132.1, 126.4, 119.7, 104.7, 56.0, 41.7, 28.6,
15.4; m/z (70 eV, rel Int.) 202 (Mþ, 8), 188 (14), 187 (100), 159 (16),
143 (10), 131 (46), 102 (14), 57 (12), 41 (6).
4.2.30. (4-Chlorophenyl)[(2R,6S)-2,6-dimethylpiperidin-1-yl]meth-
animine (5o). Yield 95% (173 mg). Yellow semi-solid. [Found: C,
67.36; H, 7.77; N, 11.19. C14H19ClN2 requires C, 67.05; H, 7.64; N,
11.17%]; nmax (neat) 3313, 2966, 2934, 2869, 2854, 1574, 1558, 1425,
4.2.25. N-tert-Butyl-N-ethyl-4-chlorobenzamidine (5l). Yield 20%
(20 mg). Yellow oil; [Found: C, 65.21; H, 7.77; N, 11.51. C13H19ClN
requires C, 65.40; H, 8.02; N, 11.73%]; nmax (neat) 3303, 2964, 2926,
2872, 2855, 1584, 1407, 1360, 1209, 1186, 1089, 1042, 1014, 837, 796,
1248, 1184, 1117, 1090, 1052, 1015, 902, 836, 790, 734, 683cmꢁ1
; dH
(400 MHz, CDCl3) 7.32 (d, 2H, J 7.7 Hz, ArH), 7.21 (d, 2H, J 7.7 Hz,
ArH), 5.60e5.30 (1H, br s, NH, exchanges with D2O), 4.23e4.07 (2H,
m, 2CH(CH3)), 1.90e1.75 (1H, m), 1.73e1.58 (2H, m), 1.58e1.45 (3H,
m),1.20 (6H, d, J 7.0 Hz, 2CH(CH3)); dC (100 MHz, CDCl3) 168.0,137.9,
134.3, 128.7, 127.7, 47.4, 30.3, 20.3, 14.0; m/z (70 eV, rel Int.) 252 (12,
Mþþ2), 251 (29), 250 (37, Mþ), 249 (71), 237 (2), 235 (6), 223 (6),
221 (16), 210 (9), 209 (37), 208 (28), 207 (100), 196 (5), 195 (19), 194
(14), 193 (40), 181 (10), 168 (9), 167 (5), 166 (28), 141 (11), 140 (30),
139 (51), 138 (82), 137 (49), 132 (8), 113 (11), 112 (14), 111 (26), 103
(6), 102 (29), 98 (52), 76 (10), 75 (25), 70 (28), 56 (12), 55(13), 50
(11), 44 (12), 42 (21), 41 (17).
687 cmꢁ1
; dH (400 MHz, CDCl3) 7.34e7.26 (4H, m, ArH), 4.60e3.90
(1H, br s, NH, exchanges with D2O), 3.17 (2H, q, J 7.1 Hz), 1.5 (9H, s),
0.98 (3H, t, J 7.1 Hz); dC (100 MHz, CDCl3) 168.8, 139.8, 134.6, 128.5,
128.0, 56.7, 42.0, 29.0, 16.5; m/z (70 eV, rel Int.) 240 (1, Mþþ2), 239
(2), 238 (2, Mþ), 237 (6), 223 (1), 195 (2), 184 (4), 183 (20), 182 (24),
181 (48), 169 (32), 168 (11), 167 (89), 140 (22), 139 (37), 138 (68), 137
(96), 111 (18), 102 (30), 86 (100), 75 (22), 58 (31), 57 (13), 50 (14), 44
(12), 41 (18).
4.2.26. 4-Chloro-N,N-dipropylbenzamidine (5m). Yield 80e94%
(139 mg). Yellow oil. [Found: C, 65.28; H, 7.68; N, 11.52. C13H19ClN
requires C, 65.40; H, 8.02; N, 11.73%]; nmax (neat) 3318, 3045, 2964,
2932, 2873, 1679, 1582, 1459, 1425, 1380, 1211, 1173, 1090, 1015, 928,
4.2.31. (S)-N-Benzyl-4-chloro-N0-methyl-N-(1-phenylethyl)benzimi-
damide (9). Yield 90% (237 mg). Yellow oil. [Found: C, 76.20; H,
893, 836, 785, 743, 682 cmꢁ1
.
dH (400 MHz, CDCl3) 7.35e7.32 (2H,
6.29; N, 7.66. C23H23ClN2 requires C, 76.12; H, 6.39; N, 7.72%]; ½a D20
ꢃ
m, ArH), 7.24e7.22 (2H, m, ArH), 4.8 (s,1H), 3.20 (2H, t, J 7.5 Hz),1.58
(s, 2H, J 7.5 Hz), 0.84 (3H, t, J 7.5 Hz); dC (100 MHz, CDCl3) 168.0,
137.8, 134.4, 128.6, 128.0, 49.6, 21.0, 11.2; m/z (70 eV, rel Int.) 240
(10, Mþþ2), 239 (32), 238 (28, Mþ), 237 (83), 223 (2), 211 (4), 209
(13), 197 (8), 195 (25), 181 (3), 169 (34), 168 (21), 167 (100), 153 (4),
140 (26), 139 (12), 138 (79), 137 (14), 125 (4), 113 (7), 111 (19), 102
(14), 86 (3), 75 (10), 72 (18), 58 (13), 41 (9).
ꢁ87.8 (c 0.5, CHCl3); nmax 3087, 3060, 3028, 2972, 2928, 2863, 1617,
1609, 1490, 1449, 1394, 1307, 1089, 831, 727, 697 cmꢁ1
; dH
(400 MHz, CDCl3) 7.40e7.20 (9H, m, ArH), 7.19e7.10 (4H, m, ArH),
5.16e4.95 (1H, br q, CHMe), 4.62 (br d, 1H, J 16.0 Hz, PhCHaN), 4.02
(d, 1H, J 16.0 Hz, PhCHaN), 2.77 (s, 3H), 1.43 (d, 3H, J 6.9 Hz); dC
(100 MHz, CDCl3) 161.7, 142.3, 140.7, 134.3, 133.0, 129.0, 128.9, 128.4,
127.9, 127.1, 127.0, 126.8, 126.1, 55.3, 46.3, 38.1, 18.1; m/z (70 eV, rel
Int.) 364 (0.4, Mþþ2), 362 (2, Mþ), 273 (16), 271 (43), 259 (13), 257
(41), 214 (3), 166 (2), 154 (33), 152 (100), 138 (7), 113 (3), 111 (10),
105 (13), 91 (22), 77 (10), 65 (5), 51 (2).
4.2.27. (4-Chlorophenyl)-1-morpholinomethanimine
(5n). Yield
87e95% (142 mg). Yellow oil. [Found: C, 58.56; H, 5.40; N, 12.11.
C11H13ClN2O requires C, 58.80; H, 5.83; N, 12.4%]; nmax (neat) 3305,
2963, 2917, 2896, 2852,1590,1563,1455,1428,1367,1176,1142,1115,
4.2.32. 2-(Diisopropylamino)benzonitrile(11). Yield 13e16% (19 mg).
Yellow semi-solid. [Found: C, 77.41; H, 9.22; N, 13.74. C13H18N2 re-
quires C, 77.18; H, 8.97; N, 13.98%]; Rf (5% EtOAc/petroleum ether)
0.78; nmax (neat): 2963, 2920, 2850, 2228, 1592, 1486, 1463, 1382,
1089, 1008, 877, 831, 747 cmꢁ1
; dH (400 MHz, CDCl3) 7.27 (2H, d, J
8.4 Hz, ArH), 7.19 (2H, d, J 8.4 Hz, ArH), 6.12e5.64 (1H, br s, NH, ex-
changes with D2O), 3.62e3.58 (4H, m, 2CH2O), 3.24e3.21 (4H, m,
2CH2N); dC (100 MHz, CDCl3) 168.6, 135.8, 135.3, 128.9, 128.3, 66.5,
46.5; m/z (70 eV, rel Int.) 226 (7, Mþþ2), 225 (34), 224 (17, Mþ) (17),
223 (100),195 (17),193 (44),181 (4),179 (4),169 (3),168 (3),167 (10),
166 (6),140 (21),139 (19),138 (63),137 (24),113 (7),111 (21),102 (17),
86 (11), 76 (10), 75 (20), 57 (21), 56 (13), 51 (5), 50 (8), 42 (5).
1261, 1097, 1018, 799 cmꢁ1
; dH (400 MHz, CDCl3) 7.61 (1H, dd, J 7.7,
1.8 Hz, ArH), 7.51e7.46 (1H, m, ArH), 7.32 (1H, dd, J 8.8, 0.7 Hz, ArH),
3.60 (2H, heptet, J 6.2 Hz, CH(CH3)2), 1.05 (d, 6H, J 6.2 Hz, CH(CH3)2);
dC (100 MHz, CDCl3) 151.8, 133.2, 132.2, 129.5, 125.0, 118.9, 116.5,
50.0, 21.3; m/z (70 eV, rel Int.) 202 (6, Mþ), 188 (5), 187 (36), 159 (3),
146 (11), 145 (100), 129 (6), 118 (4), 117 (3), 102 (8), 91 (2), 77 (4), 75
(2), 43 (3).
4.2.28. 3-[(2R,6S)-2,6-Dimethylpiperidin-1-yl]benzonitrile(2o). Yield
24% (37 mg). Purified just in little amount from 4-[(2R,6S)-2,6-
dimethylpiperidin-1-yl]benzonitrile (3o) as a yellow oil; Rf (1% EtOAc/
petroleum ether) 0.72; diagnostic analytical data for meta isomer:
nmax (neat) 2927, 2857, 2229,1602,1591,1512,1494,1454,1363,1314,
4.2.33. 2-Chloro-N,N-diisopropylbenzimidamide (12a). Yield 35%.
Pale yellow powder. Mp 81e83 ꢀC. [Found: C, 65.79; H, 8.19; N,
11.94. C13H19ClN2 requires C, 65.40; H, 8.02; N, 11.73%]; nmax (KBr)
3304, 3056, 2972, 2930, 1578, 1445, 1367, 1221, 1090, 1025, 870, 831,
1065, 1005, 699 cmꢁ1
; dH (400 MHz, CDCl3) 7.36e7.32 (1H, m, ArH),
7.28e7.22 (3H, m, ArH), 3.35e3.25 (2H, m, 2CH(CH3)),1.92e1.44 (6H,
m), 0.88 (6H, d, J 6.6 Hz, 2CH(CH3)); dC (100 MHz, CDCl3) 150.7,126.4,
119.3, 112.8, 97.9, 53.4, 31.9, 29.3, 22.6, 20.2, 14.1; m/z (70 eV, rel Int.)
777, 751, 741 cmꢁ1 dH (60 ꢀC, 400 MHz, CD3OD) 7.49e7.29 (4H, m,
;
ArH), 3.90e3.40 (2H, br m, 2CHMe2), 1.43e1.23 (12H, br m,
2CHMe2); dC (25 ꢀC,100 MHz, CDCl3) 163.4,138.7,130.5,129.7,129.3,

6952
P. Vitale et al. / Tetrahedron 67 (2011) 6944e6952
127.7, 127.0, 53.0e45.0 (br), 20.1 (br); m/z (70 eV, rel Int.) 240 (4,
Mþþ2), 239 (8), 238 (12, Mþ), 237 (15), 203 (36),197 (33),195 (100),
183 (34), 181 (100), 140 (25), 138 (78), 102 (42), 75 (10), 58 (25), 44
(19), 41 (9).
Davide Nardi, Dr. Emanuele Petruzzella and Dr. Domenico Rizzitelli
for their contribution to the Experimental section.
Supplementary data
4.2.34. 2-Chloro-N,N-dipropylbenzimidamide (12b). Yield 92%. Yel-
low oil; [Found: C, 65.21; H, 7.99; N, 11.70. C13H19ClN2 requires C,
65.40; H, 8.02; N, 11.73%]; nmax (KBr) 3323, 3058, 2964, 2874, 1582,
1487, 1460, 1435, 1381, 1335, 1214, 1178, 1092, 1052, 1032, 931, 894,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.06.066. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
771, 743, 688 cmꢁ1
; dH (400 MHz, CDCl3) 7.40e7.35 (1H, m, ArH),
7.32e7.26 (1H, m, ArH), 3.47e3.30 (1H, br s, NH, exchanges with
D2O), 3.30e3.10 (4H, br s, 2CH2N), 1.70e1.50 (4H, br s, 2CH2CH3),
0.90e0.80 (6H, br t, 2CH2CH3); dC (100 MHz, CDCl3) 164.9, 138.2,
130.7, 129.5, 129.3, 128.6, 126.7, 50e48.5 (br s), 21.3e20.3 (br s),
11.2; m/z (70 eV, rel Int.) 240 (3, Mþþ2), 239 (12), 238 (9, Mþ), 237
(32),211 (3), 209 (11), 204 (11), 203 (80),197 (3), 195 (8), 181 (3), 175
(6), 169 (34), 168 (16), 167 (100), 161 (12), 153 (4), 140 (24), 139 (17),
138 (71), 137 (29), 125 (3), 111 (3), 102 (49), 86 (5), 77 (4), 75 (13), 72
(31), 58 (20), 51 (4), 43 (11), 41 (11).
References and notes
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J. Am. Chem. Soc. 2010, 132, 1450e1451.
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4.3. Deuteration of halobenzonitriles with lithium amides:
general procedure (Tables 1e4)
ꢁ
6. Druzhinin, S. I.; Ernsting, N. P.; Kovalenko, S. A.; Perez Lustres, L.; Senyushkina,
T.; Zachariasse, K. A. J. Phys. Chem. A 2006, 110, 2955e2969.
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63, 12388e12395.
A 2.5 M solution of n-BuLi in hexanes (0.438 mL, 1.095 mmol)
was added to a solution of the diisopropylamine (0.184 mL,
1.314 mmol) in anhydrous THF (9 mL) at 0 ꢀC under nitrogen at-
mosphere, using a nitrogen-flushed three necked flask equipped
with a magnetic stirrer and a nitrogen inlet. After 15 min, to such
a solution kept at ꢁ78 ꢀC, a solution of chlorobenzonitrile (100 mg,
0.730 mmol) in anhydrous THF (9 mL) was dropwise added and the
obtained brown reaction mixture was stirred for 1 h and then
quenched by adding CD3OD all at once. Then aq NH4Cl was added
and the two phases were separated. The aqueous layer was
extracted three times with ethyl acetate, the combined organic
extracts were dried over anhydrous Na2SO4 and then the solvent
evaporated under reduced pressure. The deuterium incorporation
was detected by 1H NMR and GCeMS on reaction crudes. After
crude characterization, acid/base extraction was performed for the
separation of neutral and basic compounds. Just, for example, the
analytical data for the mixture of 7% of 4-chlorobenzonitrile (1) (D)
with 93% of 1-D are here reported.
ꢁ
10. Lysen, M.; Hansen, H. M.; Begtrup, M.; Kristensen, J. L. J. Org. Chem. 2006, 71,
2518e2520.
11. Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mecha-
nisms and Structure, 6th ed.; John: Hoboken, N.Y, 2007; Chapter 13, p 861.
12. Ramirez, A.; Candler, J.; Bashore, C. G.; Wirtz, M. C.; Coe, J. W.; Collum, D. B. J. Am.
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15. In these reactions the incorporation of deuterium on the halobenzonitriles is
observed by quenching the reaction with CD3OD (Table 2, entry 3). This con-
firms that the proton abstraction actually occurs at ꢁ78 ꢀC, but no benzyne is
formed (and so no substitution of the halogen takes place) plausibly because
the CeX cleavage is very slow at ꢁ78 ꢀC.
16. Wittig, G.; Heyn, J. Justus Liebigs Ann. Chem. 1972, 756, 1e13.
17. See Supplementary data section.
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[2-Deutero-/3-deutero-4-chlorobenzonitrile (1-2D/1-3D) in 83:17
ratio, Table 3, entry 18]: nmax (KBr) 2962, 2927, 2856, 2220, 1684,
1587, 1465, 1260, 1091, 1018, 799 cmꢁ1
; dH (400 MHz, CDCl3)
7.63e7.57 (m, 2H of 1-2Dþ1H of 1-3Dþ2H of 1); 7.03e7.00 (m, 1H
of 1-2Dþ2H of 1-3Dþ2H of 1); m/z (70 eV, rel Int.) 140 (27, Mþþ2),
139 (11), 138 (100, Mþ), 137 (7), 103 (26), 102 (4), 77 (4), 76 (10), 75
(8), 52 (5), 51 (7), 50 (5).
23. Zhang, P.; Bao, L.; Fan, J.; Jia, Z. J.; Sinha, U.; Wong, P. W.; Park, G.; Hutch-
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Acknowledgements
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This work was financially supported by National Project PRIN
‘Stereoselezione in Sintesi Organica, Metodologie ed Applicazioni’
MiUR (Rome), and by the University of Bari. Thanks are due to
Istituto di Chimica dei Composti OrganoMetallici (ICCOM-CNR,
Bari) for NMR facilities. The authors would like to acknowledge Dr.
26. The amount of such a product increases by using LDA in a substoichiometric
amount compared to substrate (LDA/substrate ratio¼0.75:1) and higher re-
agents concentration. An excess amount of solvent and base (1.5 equiv) were
required to obtain high yields of N,N-diisopropylaminobenzonitriles.
27. del Amo, V.; Dubbaka, S. R.; Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 7838e7842.