Addition of organometallic reagents to nitriles promoted by titanium(IV) isopropoxide as a procedure of synthesis of primary tert-alkylamines

Article abstract of DOI:10.1134/S1070428007100016

Grignard reagents are able to add twice to nitriles in the presence of titanium(IV) isopropoxide providing primary tert-alkylamines in a fair yield. The conditions and structural features of reagents required for successful reaction were established. A po

Full text of DOI:10.1134/S1070428007100016

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 10, pp. 1421−1426. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © O.A. Tomashenko, V.V. Sokolov, A.A. Tomashevskii, A.A. Potekhin, A. de Meijere, 2007, published in Zhurnal Organicheskoi
Khimii, 2007, Vol. 43, No. 10, pp. 1431−1436.
Addition of Organometallic Reagents to Nitriles Promoted
by Titanium(IV) Isopropoxide as a Procedure of Synthesis
of Primary tert-Alkylamines
†
O. A. Tomashenkoa, V. V. Sokolova, A. A. Tomashevskiia, A. A. Potekhin a, and A. de Meijereb
aSt. Petersburg State University, St. Petersburg, 198504 Russia
e-mail: vsokolo@mail.ru
..
.. ..
bInstitut fu r Organische und Biomolekulare Chemie, Georg-August-Universitat Gottingen, Tammannsstrasse 2, D-37077,
..
Gottingen, Germany
Received February 28, 2007
Abstract—Grignard reagents are able to add twice to nitriles in the presence of titanium(IV) isopropoxide providing
primary tert-alkylamines in a fair yield. The conditions and structural features of reagents required for successful
reaction were established. A possibility to apply two different organometallic reagents was demonstarated, in
particular, the use of organolithium compounds in the second stage.
DOI: 10.1134/S1070428007100016
The preparation of primary tert-alkylamines is a dif-
ficalt problem. One of the most general and widely used
method of their synthesis is Ritter reaction providing the
amines in two stages proceeding from nitriles and tertiary
alcohols or alkenes capable of generating stable carbo-
cations in acid medium [1]. An essential disadvantage of
this procedure alongside the relatively low overall yield
is the stringent deacylation condition in the last stage.
A similar synthetic route to the primary tert-alkylamines,
the reduction of tert-alkylazides obtained as a rule from
the corresponding halides [2] or alcohols [3], is also
inconvenient.
twice add to various nitriles are compounds formally
described as RCeCl2 obtained in situ from the cor-
responding organolithium reagents and CeCl3 [8]. This
method is however very expensive.
Tertiary cyclopropylamines are obtained by Kulink-
ovich–de Meijere reaction from tertiary amides and
Grignard reagents in the presence of (i-PrO)4Ti [9]. The
attempts to prepare analogously primarily cyclopropyl-
amines from nitriles and Grignard reagents were unsuc-
cessful until it was found, that addition of BF3·Et2O to
the end of the process forced the formation of the desired
product [10]. However the practical application of this
procedure revealed that at least with ethylmagnesium
bromide disregarding the nitrile structure formed as side
products the corresponding α,α-diethyl-alkyl-amines (3–
5 mol%). It is presumable that their formation originates
from the ability of (i-PrO)4Ti not only to generate
titanacyclopropane intermediates but also to operate as
a Lewis acid increasing the electrophilicity of the carbon
atom of the imine group. It was therefore of interest to
differentiate both these types of reactivity directing it to
the route leading to primary tert-alkylamines.
Although the addition oof organometallic reagents to
ketimines is not regarded as a general procedure for the
synthesis of tert-alkylamines [4], infrequently from the
specifically substituted ketimines primary amines were
obtained after deblocking [5]. However as a rule the addi-
tion of organolithium and organomagnesium reagents to
N-metallated ketimines does not occur excluding the
direct preparation of primary tert-alkylamines from
nitriles and excess of the corresponding organometallic
reagent. As exception may be cited, on the one hand,
some nitriles with acceptor groups in the α-position [6],
and on the other hand, allylmagnesium bromide [7] where
the second stage apparently proceeded in a concerted
mode. The only known organometallic reagents capable
Inasmuch as cyclopropanation is possible only with
Grignard reagents with β-hydrogen in the molecule, the
most promising for preparation primary tert-alkylamines
seem the Grignard reagents lacking this structural
feature. We selected as test system propionitrile (Ia) –
† Deceased.
1421

TOMASHENKO et al.
1422
Table 1. Primary tert-alkylamines RR2'NH2 obtained from
nitriles RCN and Grignard reagents R'MgX
To outline the limits of the reaction applicability we
investigated nitriles and Grignard reagents of various
structure (Table 1).Aliphatic and aromatic nitriles lacking
labile hydrogen atoms gave with phenylmagnesium
bromide (IIa) and substituted analogs IIb and IIc the
corresponding primary tert-alkylamines IIIa–IIIg in 25–
77% yields. Unexpectedly and quite in contrast to the
data [7] with benzylmagnesium chloride (IId) the yields
of primary tert-alkylamines IIIh–IIIm are quite plausible
and reach in some events 60–70%. Methylmagnesium
chloride (IIe) provided in reaction with benzonitrile (Ie)
and isobutyronitrile (Id) the corresponding amines IIIn–
IIIo in moderate yields.
In all above reactions the Grignard reagents employed
were incapable of cyclopropanation.An obvious interest
consisted in revealing whether the primary tert-alkyl-
amines could be obtained from a Grignard reagent
containing a β-hydrogen under the conditions where the
cyclopropanation was suppressed simply by changing
the order of the reagents addition to the nitrile and by
increasing the overall amount of the Grignard reagent. It
proved that if in reaction of benzonitrile (Ie) with EtMgBr
(IIf), the classical Grignard reagent for cyclopropana-
tion, first would be added to the nitrile 3 equiv of reagent
(IIf), and then 1 equiv of (i-PrO)4Ti the main reaction
product instead of 1-phenylcyclopropylamine became
α,α-diethylbenzylamine (IIIp) (yield 60%).
In reaction of benzyl cyanide with phenylmagnesium
bromide (IIa) no amines were isolated from the reaction
mixture. It is apparently due to the high CH-acidity of
the benzyl cyanide resulting in side processes already at
the stage of reaction with Grignard reagent. Vinyl-
magnesium chloride and ethynylmagnesium chloride
although incapable to enter into the cyclopropanation
neither give primary tert-alkylamines.
phenylmagnesium bromide (IIa) – (i-PrO)4Ti. In proce-
dure [10] to the solution of nitrile in ether first (i-PrO)4Ti
was added, then two equiv of Grignard reagent. This
sequence of addition seemed questionable for the solution
of the target problem; the primary generation of imine
magnesium derivative looked more reasonable, and only
afterwards should be performed activation of the inter-
mediate obtained by (i-PrO)4Ti. One of the main
problems was the molar ratio of the nitrile, Grignard
reagent, and (i-PrO)4Ti . It turned out that at the use of
0.1 equiv of (i-PrO)4Ti and 2 equiv of the Grignard
reagent in ether the expected 1,1-diphenylpropylamine
(IIIa) did not form at all, and at equimolar amount of (i-
PrO)4Ti it was obtained in a low yield (11%). The yield
was successfully raised to 60% only by increasing the
quantity of the Grignard reagent to three equivalents.
Variation of reaction conditions showed that the best yield
was obtained at room temperature: at low temperature
(0°C) and at boiling the yield diminished (48 and 60%
respectively). The addition of the second equiv of
Grignard reagent to the magnesium imine derivative did
not reuire much time: In 10 min the yield was 57%, in 1 h,
77%, after 24 h, the same 77%. The attempt to use THF
as solvent resulted in decreased yield (25%) and more
difficult purification of the product. Thus we
demonstrated fundamental possibility to obtain in the
reaction under study the target tert-alkylamines and to
a certain degree optimized the preparation procedure.
Another interesting problem was an extension of the
application range of the reaction by successive addition
to the nitrile two different Grignard reagents in order to
obtain amines with three different substituents. This idea
was fulfilled proceeding from propionitrile (If), methyl-
magnesium chloride (IIe), and phenylmagnesium
bromide (IIa) (Table 2). One of the reasons of low yield
of 1-methyl-1-phenylpropylamine (IIIq) was the forma-
tion of a side product, 1,1-diphenylpropylamine (IIIa).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

ADDITION OF ORGANOMETALLIC REAGENTS
1423
Table 2. Cross-coupling of nitriles R1CN with various
organometallic reagents
Even wider prospects provides the use in the second
stage of this cross-coupling of organolithium reagents
characterized by a wide range of possible structures. In
this way we succeeded in preparation of the cor-
responding tert-alkylamines IIIr–IIIt (Table 2).
microanalysis, Institut für Organische und Biomolekulare
Chemie, Georg-August-Universität Göttingen.
Primary tert-alkylamines IIIa–IIId, IIIh, IIIj–IIIp.
General procedure. To a solution of 10 mmol of nitrile
in 30–50 ml of ether was added within 15 min at room
temperature while vigorously stirring 30 mmol of
Grignard reagent (1–2 M solution in ether), and the mix-
ture was stirred for 30 min more. Then 2.84 g (10 mmol)
of (i-PrO)4Ti was added (the solution usually became
dark-brown). The reaction mixture was left overnight and
then treated with 40 ml of 10% solution of NaOH. The
suspension was filtered off from the precipitate of
inorganic compounds, the precipitate was washed with
dichloromethane. The organic layer was separated, the
water layer was extracted with dichloromethane. The
combined organic solutions were evaporated to dryness
in a vacuum at 40°C, the residue was treated with a small
quantity of ether and extracted with 5% solution of HCl.
The combined acid solutions were washed with a small
quantity of ether, alkalinized, and thrice extracted with
ether. The combined organic solution was dried over
sodium sulfate and evaporated to dryness in a vacuum.
Amines obtained (save amines IIIa and IIId) were slowly
crystallizing oily substances. They were converted into
the corresponding hydrochlorides by acidifying their
solution in dichloromethane with saturated HCl solution
in ether or with several drops of concn. hydrochloric acid.
The solution was evaporated to dryness, the hydro-
chlorides were additionally purified if necessary by
passing through a bed of silica gel and/or by recrystal-
lization from a mixture ethanol–ether.
The problem of the reaction mechanism is yet
unsolved. If the action of (i-PrO)4Ti is limited just to the
increasing the electrophilicity of the carbon atom in the
imine group then (i-PrO)4Ti would be possible to be
replaced by another Lewis acid. Yet at the attempt to use
in this position (i-PrO)3Al, BF3·Et2O, and SnCl4 no
primary tert-alkylamines were formed showing that (i-
PrO)4Ti was a unique coreagent in this reaction.
EXPERIMENTAL
1H and 13C NMR spectra were registered on
spectrometers Bruker DPX-300 at operating frequencies
300.130 and 75.54 MHz, Varian Mercury-300 at
operating frequencies 300.141 and 75.478 MHz, and
Varian Unity-300 at operating frequencies 300.544 and
75.579 MHz. Chemical shifts were measured from the
residual solvent signal [7.26 (CHCl3), 77.0 (CDCl3), 2.49
(DMSO-d5), 39.7 ppm (DMSO-d6)]. The mixture
DMSO-d6–CCl4 was always 1:2 v/v. The coupling
constants in the proton spectra were measured in the first
order approximation. The multiplicity of signals in the
13C NMR spectra was estimated using standard pulse
sequences DEPT-135 and APT. To give the spectral
information in a uniform format the following
interpretation of DEPT-135 and APT spectra was done:
13
For every signal in the C NMR spectrum the type of
Primary tert-alkylamines IIIe–IIIg. General
procedure. The synthesis of these compounds is carried
out by procedure identical to above described, but these
amines are not extracted from the ether solution with
5% HCl solution. Their hydrochlorides crystallized
within a night from the preliminary acidified ether-
dichloromethane solution (amines IIIe and IIIg).Another
carbon atom was indicated (C, CH, CH2, CH3). Mass
spectra were measured on Finnigan MAT-95 instrument,
electrospray ionization with registering positively
charged species, and on Finnigan MAT Incos-50, electron
impact ionization, ionizing electrons energy 70eV.
Elemental analyses were carried out on an automatic
CHN-analyzer HP-185 and in the laboratory of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

TOMASHENKO et al.
1424
means of obtaining pure hydrochlorides consists in
filtering of acidified reaction mixure through a silica gel
bed, eluent CHCl3–MeOH (amine IIIf).
H 8.07; N 5.06. C17H21N·HCl. Calculated, %: C 74.03;
H 8.04; N 5.08.
α,α-Bis[3-(trifluoromethyl)phenyl]benzylamine
1
hydrochloride (IIIg). Yield 25%, mp 165–168°C. H
1,1-Diphenylpropylamine (IIIa). Yield 77%, mp 70–
72°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.85 t (3H,
J 7.8 Hz), 1.79 br.s (2H), 2.29 q (2H, J 7.8 Hz), 7.24–
7.29 m (2H), 7.33–7.39 m (4H), 7.43–7.46 m (4H).
13C NMR spectrum (CDCl3), δ, ppm: 9.0 (CH3), 35.5
(CH2), 61.7 (C), 126.7 (CH), 127.1 (CH), 128.5 (CH),
149.1 (C). Mass spectrum (electron impact), m/z (Irel,
%): 182 [M – C2H5]+ (100), 152 (2), 134 [M – C6H5]+
(19), 115 (9), 104 [M – C6H5 – C2H6]+ (43), 91 (22), 77
(34), 65 (3), 51 (18), 39 (5). Found, %: C 85.34; H 7.88;
N 6.79. C15H17N. Calculated, %: C 85.26; H 8.11; N 6.63.
NMR spectrum (DMSO-d6–CCl4), δ, ppm: 7.24–7.45 m
(13H), 10.48 br.s (3H). 13C (DMSO-d6–CCl4), δ, ppm:
68.5 (C), 124.5 q (C, J 273 Hz), 125.8 (CH), 126 (CH),
129.1 (CH), 129.3 (CH), 129.5 (CH), 130.7 q (C,
J 31.9 Hz), 130.1 (CH), 133.2 (CH), 143.1 (C), 141.2
(C). Mass spectrum (electron impact), m/z (Irel, %): 395
[M – HCl – H]+ (1), 318 [M – HCl – C6H5]+ (20), 250
[M – HCl – C7H4F3]+ (55), 182 (100), 172 (20), 145 (12),
104 (30), 77 (22), 51 (5). Found, %: C 58.59; H 3.69;
N 3.47. C21H15NF6·HCl. Calculated, %: C 58.41; H 3.73;
N 3.24.
1,1-Diphenylethylamine hydrochloride (IIIb).
Yield 57%, mp 228–229°C (229–231°C [11]).
1,1-Dibenzylethylamine hydrochloride (IIIh). Yield
40%, mp 215–216°C. H NMR spectrum (DMSO-d6),
1
3-Methoxy-1,1-diphenylpropylamine hydro-
chloride (IIIc).Yield 40%, mp 100–101°C. 1HNMR spec-
trum (DMSO-d6), δ, ppm: 2.74 t (2H, J 9.0 Hz), 3.15 s
(3H), 3.30 t (2H, J 9.0 Hz), 7.33–7.42 m (10H), 8.30 br.s
(3H). 13C NMR spectrum (DMSO-d6), δ, ppm: 37.7 (C),
58.2 (CH3), 63.2 (CH2), 67.8 (CH2), 126.8 (CH), 128.1
(CH), 128.5 (CH), 141.0 (C). Mass spectrum (electro-
spray), m/z (Irel, %): 242 [M – Cl]+ (100).
δ, ppm: 1.44 s (3H), 2.90 d (2H, J 13.4 Hz), 3.10 d (2H,
J 13.4 Hz), 7.25–7.36 m (10H), 8.26 br.s (3H). 13C NMR
spectrum (DMSO-d6), δ, ppm: 22.1 (CH3), 43.6 (CH2),
56.1 (C), 126.8 (CH), 128.2 (CH), 130.8 (CH), 134.9
(C). Mass spectrum (electrospray), m/z (Irel, %): 487
[2M – Cl]+ (28), 226 [M – Cl]+ (100). Found, %: C 73.17;
H 7.54; N 5.22. C16H19N·HCl. Calculated, %: C 73.41;
H 7.70; N 5.35.
2-Methyl-1,1-diphenylpropylamine (IIId). Yield
55%, mp 63–65°C. 1H NMR spectrum (CDCl3), δ, ppm:
0.92 d (6H, J 6.3 Hz), 1.76 br.s (2H), 2.98 septet (1H,
J 6.6 Hz), 7.18–7.23 m (2H), 7.30–7.35 m (4H), 7.54–
7.57 m (4H). 13C NMR spectrum (CDCl3), δ, ppm: 18.1
(CH3), 35.1 (CH), 64.1 (C), 126.4 (CH), 127.0 (CH),
128.5 (CH), 148.4 (C). Mass spectrum (electron impact),
m/z (Irel, %): 224 [M – H]+ (1), 182 [M – C3H7]+ (100),
148 [M – C6H5]+ (5), 115 (9), 104 [M – C6H5 – C3H8]+
(43), 90 (8), 77 (35), 43 (12). Found, %: C 85.10; H 8.52;
N 6.39. C16H19N. Calculated, %: C 85.29; H 8.50; N 6.22.
1,1-Dibenzylpropylamine hydrochloride (IIIi). On
acidifying the combined organic fractions hydrochloride
precipitated, insoluble both in water and organic solvents.
The precipitate was filtered off and was not further
1
purified. Yield 72%, mp >250°C. H NMR spectrum
(DMSO-d6–CCl4), δ, ppm: 1.06 t (3H, J 7.3 Hz), 1.49 q
(2H, J 7.3 Hz), 2.84 d (2H, J 13.8 Hz), 3.18 d (2H,
J 13.8 Hz), 7.24–7.34 m (10H), 8.32 br.s (3H). 13C NMR
spectrum (DMSO-d6), δ, ppm: 7.6 (CH3), 26.8 (CH2),
41.2 (CH2), 58.7 (C), 126.9 (CH), 128.4 (CH),
130.9 (CH), 134.9 (C). Mass spectrum (electrospray),
m/z (Irel, %): 1067 [4M – Cl]+ (46), 515 [2M – Cl]+ (18),
479 [2M – HCl – Cl]+ (10), 240 [M – Cl]+ (100). Found,
%: C 74.23; H 8.14; N 5.19. C17H21N·HCl. Calculated,
%: C 74.03; H 8.04; N 5.08.
1,1,1-Triphenylmethylamine (IIIe). Yield 55%, mp
101–102°C (100–102 °C [12]).
1,1-Bis(4-methylphenyl)propylamine hydro-
chloride (IIIf). To isolate the target compound the
acidified reaction mixture was passed through a silica
gel bed (eluent CHCl3–MeOH, 16:1). Yield 65%, mp
1,1-Dibenzylbutylamine hydrochloride (IIIj). Yield
1
67%, mp 196–198°C. H NMR spectrum (DMSO-d6),
1
195–196°C. H NMR spectrum (CDCl3), δ, ppm: 0.83 t
δ, ppm: 0.85 t (3H, J 6.9 Hz), 1.36–1.41 m (2H), 1.46–
1.55 m (2H), 2.90 d (2H, J 13.7 Hz), 3.07 d (2H,
J 13.7 Hz), 7.25–7.36 m (10H), 8.26 br.s (3H). 13C NMR
spectrum (DMSO-d6), δ, ppm: 13.9 (CH3), 15.8 (CH2),
36.4 (CH2), 41.6 (CH2), 58.5 (C), 126.8 (CH), 128.2
(CH), 130.8 (CH), 134.9 (C). Mass spectrum (electro-
spray), m/z (Irel, %): 1121 [4M – Cl]+ (64), 543 [2M –
(3H, J 7.3 Hz), 2.36 s (6H), 2.49 q (2H, J 7.3 Hz), 7.10 d
(4H, J 8.0 Hz), 7.26 d (4H, J 8.0 Hz), 9.52 br.s (3H).
13C NMR spectrum (CDCl3), δ, ppm: 8.9 (CH3), 21.5
(CH3), 32.5 (CH2), 66.1 (C), 127.6 (CH), 129.5 (CH),
137.7 (C), 138.3 (C). Mass spectrum (electrospray), m/z
(Irel, %): 223 [M – Cl – NH3]+ (100). Found, %: C 74.17;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

ADDITION OF ORGANOMETALLIC REAGENTS
1425
Cl]+ (20), 254 [M – Cl]+ (100). Found, %: C 74.25;
H 8.02; N 4.59. C18H23N·HCl. Calculated, %: C 74.59;
H 8.35; N 4.83.
spectrum (DMSO-d6), δ, ppm: 0.75 t (6H, J 9 Hz), 1.92–
2.88 m (4H), 7.29–7.52 m (5H), 8.75 br.s (3H). 13C NMR
spectrum (DMSO-d6), δ, ppm: 7.8 (CH3), 31.4 (CH2),
62.5 (C), 125.9 (CH), 127.4 (CH), 128.44 (CH), 139.4
(C).
1,1-Dibenzyl-2-methylpropylamine hydrochloride
1
(IIIk). Yield 28%, mp 193–194°C. H NMR spectrum
1-Methyl-1-phenylpropylamine hydrochloride
(IIIq). To a solution of 2.2 g (40 mmol) of propionitrile
(Ia) in diethyl ether was added at room temperature while
vigorous stirring 40 mmol of 3 M solution of MeMgCl
(IIe) in THF, after 30 min was added in succession
11.64 g (41 mmol) of (i-PrO)4Ti, and 80 mmol of
1.46 M solution of PhMgBr (IIa) in Et2O. The reaction
mixture was stirred for 24 h and worked up by the general
procedure. The obtained hydrochloride was purified by
column chromatography on silica gel (eluent CHCl3–
MeOH, 4:1). Yield 30%, mp 239–240°C (242–243°C
[15]).
(DMSO-d6), δ, ppm: 1.05 d (6H, J 6.7 Hz), 1.78 septet
(1H, J 6.7 Hz), 2.76 d (2H, J 14.2 Hz), 3.09 d (2H,
J 14.3 Hz), 7.24–7.34 m (6H), 7.45–7.47 m (4H),
8.16 br.s (3H). 13C NMR spectrum (DMSO-d6), δ, ppm:
17.1 (CH3), 31.5 (CH), 38.4 (CH2), 61.4 (C), 126.7 (CH),
128.1 (CH), 131.0 (CH), 134.7 (C). Mass spectrum
(electrospray), m/z (Irel, %): 1121 [4M – Cl]+ (100), 254
[M – Cl]+ (60). Found, %: C 74.23; H 8.27; N 5.10.
C18H23N·HCl. Calculated, %: C 74.59; H 8.35; N 4.83.
1,1-Dibenzyl-3-methoxypropylamine hydro-
1
chloride (IIIl). Yield 35%, mp 192–195°C. H NMR
spectrum (DMSO-d6), δ, ppm: 1.71 t (2H, J 6.9 Hz),
2.92 d (2H, J 13.8 Hz), 3.06 d (2H, J 13.8 Hz), 3.21 s
(3H), 3.59 t (2H, J 6.9 Hz), 7.25–7.38 m (10H), 8.26 br.s
(3H). 13C NMR spectrum (DMSO-d6), δ, ppm: 33.6
(CH2), 41.6 (CH2), 57.4 (C), 57.8 (CH3), 66.7 (CH2),
126.6 (CH), 128.0 (CH), 130.7 (CH), 134.4 (C). Mass
spectrum (electrospray), m/z (Irel, %): 1189 [4M – Cl +
4H]+ (51), 1188 [4M – Cl + 3H]+ (53), 1187 [4M – Cl +
2H]+ (100), 1185 [4M – Cl]+ (93), 270 [M – Cl]+ (57).
Found, %: C 70.43; H 7.68; N 4.31. C18H23NO·HCl.
Calculated, %: C 70.69; H 7.91; N 4.58.
1-Phenyl-1-(2-furyl)butylamine hydrochloride
(IIIr). To a solution of 1.7 g (25 mmol) of furan in 10 ml
of THF was added at –10°C while stirring 25 mmol of
2.9 M solution of BuLi in hexane, and the stirring was
continued at room temperature for 4 h. To a solution of
0.69 g (10 mmol) of butyronitrile (If) in 100 ml of diethyl
ether was added at stirring 10 mmol of 1.1 M solution of
PhMgBr (IIa) in Et2O.After 30 min 2.84 g (10 mmol) of
(i-PrO)4Ti was added and afterwards a solution of
2-furyllithium (IIg). The reaction mixture was stirred at
room temperature for 24 h more and then subjected to
common workup. The obtained hydrochloride was
purified by column chromatography on silica gel (eluent
1-Benzyl-1,2-diphenylethylamine hydrochloride
(IIIm). Yield 64%, mp 105–107°C. 1H NMR spectrum
(DMSO-d6), δ, ppm: 3.39 d (2H, J 13.6 Hz), 3.51 d (2H,
J 13.9 Hz), 7.05–7.08 m (4H), 7.15–7.18 m (6H), 7.30–
7.40 m (5H), 8.81 br.s (3H). 13C NMR spectrum (DMSO-
d6), δ, ppm: 44.6 (CH2), 62.9 (C), 126.4 (CH), 126.9
(CH), 127.6 (CH), 127.8 (CH), 127.9 (CH), 131.0 (CH),
134.3 (C), 138.4 (C). Mass spectrum (electrospray), m/z
(Irel, %): 288 [M – Cl]+ (100). Found, %: C 78.15; H 6.63;
N 4.51. C21H21N·HCl. Calculated, %: C 77.88; H 6.85;
N 4.32.
1
CHCl3–MeOH 30:1). Yield 25%, mp 158–160°C. H
NMR spectrum (DMSO-d6–CCl4), δ, ppm: 0.93 t (3H,
J 7.2 Hz), 1.15–1.45 m (2H), 2.25–2.42 m (2H), 6.46 m
(1H), 6.57–6.58 m (1H), 7.29–7.37 m (5H), 7.55 m (1H),
9.47 br.s (3H). 13C NMR spectrum (DMSO-d6–CCl4), δ,
ppm: 14.7 (CH3), 17.7 (CH2), 41.1 (CH2), 61.6 (C), 109.9
(CH), 111.2 (CH), 127.2 (CH), 128.6 (CH), 128.9 (CH),
130.5 (C), 143.4 (CH), 153.7 (C). Mass spectrum
(electrospray), m/z (Irel, %): 970 [4M – Cl]+ (16), 199
[M – Cl – NH3]+ (100). Found, %: C 66.69; H 7.31; N 5.26.
C14H17NO·HCl. Calculated, %: C 66.79; H 7.21; N 5.56.
α,α-Dimethylbenzylamine hydrochloride (IIIn).
Yield 44%, mp 238–239°C (240–241°C [13]).
1,1,2-Trimethylpropylamine hydrochloride (IIIo).
Yield 27%, mp >250°C (292°C [14]) 1H NMR spectrum
(DMSO-d6), δ, ppm: 0.88 d (6H, J 6 Hz), 1.17 s (6H),
1.86 septet (1H, J 6 Hz), 8.14 br.s (3H). 13C NMR
spectrum (DMSO-d6), δ, ppm: 16.9 (CH3), 22.2 (CH3),
35.0 (CH), 56.2 (C).
1-(2-Picolyl)-1-phenylbutylamine hydrochloride
(IIIs). To a solution of 2.33 g (25 mmol) 2-picoline in
10 ml of THF was added at –20°C 25 mmol of 2.9 M
solution of BuLi in hexane, and the stirring was continued
at room temperature for 1 h. To a solution of 0.69 g
(10 mmol) of butyronitrile (If) in 100 ml of diethyl ether
was added at stirring 10 mmol of 1.1 M solution of
PhMgBr (IIa) in Et2O.After 30 min 2.84 g (10 mmol) of
α,α-Diethylbenzylamine hydrochloride (IIIp).
1
Yield 60%, mp 225–230°C (253°C [15]). H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

TOMASHENKO et al.
1426
(i-PrO)4Ti was added and afterwards a solution of
2-picolyllithium (IIh). The reaction mixture was stirred
at room temperature for 24 h more and then subjected to
common workup. The obtained hydrochloride was
purified by column chromatography on silica gel (eluent
(C), 143.6 (C). Mass spectrum (electrospray), m/z (Irel,
%): 215 [M – Cl – NH3]+ (100).
REFERENCES
1
1.Ritter, J.J. and Kalish, J., J. Am. Chem. Soc., 1948, vol. 70,
p. 4045; Ritter, J.J. and Kalish, J., J. Am, .Chem. Soc.,
1948, vol. 70, p. 4048.
2.Koziara, A., Osowska-Parewicka, K., Zawadzki, C., and
Zwierzak, A. Synthesis, 1987, p. 487.
3.Koziara, A. and Zwierzak, A. Tetrahedron Lett., 1987,
vol. 28, p. 6513.
4.Wakefield, B.J., Organolithium methods, London:
Academic Press, 1988.
CHCl3–MeOH, 100:1). Yield 55%. H NMR spectrum
(DMSO-d6), δ, ppm: 0.79 t (3H, J 7.3 Hz), 0.91–1.12 m
(1H), 1.19–1.38 m (1H), 1.81–1.95 m (1H), 2.27–
2.40 m (1H), 3.81 d (1H, J 14.1 Hz), 3.83 d (1H,
J 14.2 Hz), 7.32–7.50 m (3H), 7.59 d (2H, J 9 Hz), 7.75–
7.91 m (2H), 8.36 m (1H), 8.80 d (1H, J 6 Hz), 9.34 br.s
(3H). 13C NMR spectrum (DMSO-d6), δ, ppm: 13.7
(CH3), 16.1 (CH2), 39.1 (CH2), 42.9 (CH2), 61.9 (C),
125.3 (CH), 125.6 (CH), 127.9 (CH), 128.6 (CH), 128.8
(CH), 138.9 (C), 142.7 (CH), 144.4 (CH), 150.5 (C).
Mass spectrum (electrospray), m/z (Irel, %): 241 [M –
Cl]+ (100).
5.Davis, F.A. and Mancinelli, P.A., J. Org. Chem., 1977,
vol. 42, p. 398; Hirao, A., Hattori, I., Yamaguchi, K., and
Nakahama, C., Synthesis, 1982, p. 461.
6.Chastrette, M. and Axiotis, G.P., Synthesis, 1980, p. 889;
Amouroux, R. and Axiotis, G.P., Synthesis, 1981, p. 270.
7.Henze, H.R., Allen, B.B., and Leslie, W.B., J. Am. Chem.
Soc., 1943, vol. 65, p. 87; Henze, H.R. and Allen, B.B.,
J. Am. Chem. Soc., 1939, vol. 61, p. 1790.
8.Ciganek, E., J. Org. Chem., 1992, vol. 57, p. 4521.
9.Chaplinski, V. and de Meijere, A., Angew Chem., 1996,
vol. 108, p. 491.
10. Bertus, Ph. and Szymoniak, J., J. Org. Chem., 2002, vol. 67,
p. 3965.
11. Ege, C.N. and Sherk, K.W., J. Am. Chem. Soc., 1953,
vol. 75, p. 354.
2-Methyl-1-(2-thienyl)-1-phenylpropylamine
(IIIt). To a solution of 4.08 g (25 mmol) of 2-bromo
thiophene was added at –50°C while stirring 25 mmol
of 2.5 M solution of BuLi in hexane, and the stirring at
–60°C continued for 10 min. To a solution of 0.69 g
(10 mmol) of isobutyronitrile (Id) in 100 ml diethyl ether
was added at stirring 10 mmol of 1.1 M solution of
PhMgBr (IIa) in Et2O.After 30 min 2.84 g (10 mmol) of
(i-PrO)4Ti was added and afterwards a solution of
2-thienyllithium (IIi). The reaction mixture was stirred
at room temperature for 24 h more and then subjected to
common workup. The obtained hydrochloride was
purified by column chromatography on silica gel (eluent
12. Hemelian, C. and Silberstein, K., Ber. 1884, vol. 17,
p. 741.
1
CHCl3–MeOH, 100:1). Yield 30%. H NMR spectrum
13. Cope, C., Foster, T.T., and Towle, Ph.H., J. Am. Chem.
Soc., 1949, vol. 71, p. 3929.
14. Vejdelek, Z.G., Trcka, V., Vanecek, M., Kakac, B., and
Holubek, J., Coll. Czech. Chem. Commun., 1970, p. 2814.
15. Thiel, M., Schäfer, W., and Asinger, F., Lieb. Ann., 1958,
vol. 613, p. 128.
(CDCl3), δ, ppm: 1.00 d (3H, J 5.9 Hz), 1.09 d (3H,
J 5.8 Hz), 3.97 m (1H), 7.89–7.97 m (1H), 7.21–7.35 m
(5H), 7.37–7.40 m (1H), 7.52–7.61 m (1H), 9.44 br.s
(3H). 13C NMR spectrum (CDCl3), δ, ppm: 18.2 (CH3),
18.4 (CH3), 36.7 (CH), 67.9 (C), 125.8 (CH), 126.7 (CH),
127.3 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 138.7
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007