Aminomethylation of functionalized organozinc reagents and grignard reagents using immonium trifluoroacetates

Article abstract of DOI:10.1055/s-2000-6307

New immonium trifluoroacetates 1 and 2 react readily with functionalized organozinc or magnesium reagents leading to the corresponding aminomethylated products of type 5 and 7. The resulting bis-allylamines were deallylated leading to primary amines.

Full text of DOI:10.1055/s-2000-6307

PAPER
941
Aminomethylation of Functionalized Organozinc Reagents and Grignard
Reagents Using Immonium Trifluoroacetates
Nicolas Millot, Claudia Piazza, Salvatore Avolio, Paul Knochel*
Institut für Organische Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, D-81377 München, Germany
Fax +49(89)21807680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 3 February 2000
(CF3CO)2O
Abstract: New immonium trifluoroacetates 1 and 2 react readily
CH2Cl2 , 25°C, 1 h
H
N
with functionalized organozinc or magnesium reagents leading to
the corresponding aminomethylated products of type 5 and 7. The
resulting bis-allylamines were deallylated leading to primary
amines.
-(allyl)2NCOCF3
H
OCOCF3
aq.CH2O
1
R2N
NR2
R2NH
Key words: organometallic reagents, zinc, magnesium, aminome-
3 : R = allyl : 71%
4 : R = Bn : 77%
thylation, primary amines, deprotection
R = allyl, Bn
Ph
(CF3CO)2O
H
N
Ph
Functionalized organozinc1 reagents are available either
by direct insertion of zinc powder,1,2 by the boron-zinc ex-
change reaction3 or by transmetallation of polyfunctional
organolithiums4 at low temperature. In the presence of
CuCN•2LiCl, they are converted in highly reactive zinc-
copper intermediates which react with organic electro-
philes leading to highly functionalized products. Ami-
nomethylation is an important transformation and has
been performed with various immonium salts5-7 or imini-
um salts precursors.8,9 Since organozinc reagents them-
selves display a relatively low reactivity, highly reactive
aminomethylation reagents are therefore necessary. In
this work, we wish to report the direct reaction of orga-
nozinc reagents with immonium trifluoroacetates. We
have prepared immonium trifluoroacetates7 1 and 2 be-
cause the allyl or benzyl moieties could be removed to af-
ford aminomethylated products. Their preparation is
based on the work of Tietze.7 Thus heating an aqueous so-
lution of formaldehyde with diallylamine and dibenzy-
lamine results in the formation of the aminals 3 and 4, in
71% and 77% yield respectively. The treatment of 3 in
CH2Cl2 (25 °C, 1 h) or 4 in diethyl ether (25 °C, 1 h) with
trifluoroacetic anhydride provides solution of the immo-
nium trifluorocetates 1 or 2 in essentially quantitative
yields (Scheme 1).
ether, 25°C, 1 h
Bn2NCOCF3
H
OCOCF3
2
Scheme 1
THF, CH2Cl2
R1ZnX or R12Zn
H
H
N
R1CH2N
30 min
H
H
OCOCF3
1
5a-i : 64-96 %
Ph
Ph
THF, Et2O
30 min
R1ZnX or R12Zn
N
Ph
R1CH2N
Ph
OCOCF3
5j-n : 73-92 %
2
Scheme 2
Interestingly functionalized organomagnesium com-
pounds prepared by iodine-magnesium exchange10 react
at low temperature with the immonium salt 1 (see Scheme
3 and Table 2). While arylmagnesium bromides 6a-b and
6e-f smoothly undergo addition at -60 °C or -40 °C (see
Entries 1, 2, 5 and 6 of Table 2), the functionalized mag-
nesium carbenoids 6c-d are best reacted at -78 °C (En-
tries 3 and 4). This is essential in the case of the sensitive
The immonium salts 1 and 2 are readily soluble in
CH2Cl2/THF and Et2O/THF mixtures and rapidly react
with various functionalized organozinc reagents (R1ZnX
or R1 Zn) providing the aminomethylated products 5a-n
2
(see Scheme 2 and Table 1).
Whereas arylzinc halides and benzylic zinc halides al-
ready undergo addition at -78 °C (see Entries 1, 2, 9 and
13 of Table 1), alkylzinc halides are best added at 25 °C.
The reactions are always complete within 30 min. Various
functional groups like an ester group (Entries 4, 7, 11 and
12), a cyano group (Entries 2, 3, 9, 10 and 13) or an imide
function (Entry 8) are perfectly tolerated.
THF, CH2Cl2
R1MgX
H
N
+
R1CH2N
30 min
H
OCOCF3
6a-f
1
7a-f : 70-81%
Scheme 3
Synthesis 2000, No. 7, 941–948 ISSN 0039-7881 © Thieme Stuttgart · New York

942
N. Millot et al.
PAPER
Table 1 Aminomethylated Products 5a−n Obtained by Reaction of Organozinc Halides or Diorganozincs with the Immonium Salts 1 or 2
Entry
Organozinc Reagent
PhZnCl
Immonium
Salts 1 or 2
Temp.
(°C)
Product
of Type 5
Yield
(%)a
1
2
1
−78
−78
5a
85
1
5b
96
3
4
5
NC(CH2)3ZnI
EtO2C(CH2)3ZnI
c-HexZnI
1
1
1
25
25
25
5c
5d
5e
68
73
83
6
7
1
1
25
25
5f
91
75
EtO2C(CH2)5ZnI
5g
8
9
1
1
25
5h
5i
64
72
–78
10
11
12
NC(CH2)3ZnI
2
2
2
25
25
25
5j
5k
5l
77
74
77
EtO2C(CH2)3ZnI
EtO2C(CH2)5ZnI
13
14
2
2
−78
5m
5n
92
73
25
a Isolated yields of analytically pure products.
carbenoids 6c-d which already decompose at -70 °C.11
The desired aminomethylated products 7a-f are obtained
in 70-81% yield.
um reagents using aminomethylation and selective
deallylation reactions.
The resulting bis-allylated amines can be deprotected ac-
cording to the method of Guibé.12 Thus, the reaction of di-
allylamines of type 7 with N,N’-dimethylbarbituric acid
in presence of Pd(PPh3)4 (2 mol%) in CH2Cl2 at 35 °C
produces within 1 to 3 h the primary amines 8a-j in satis-
factory yields (Scheme 4 and Table 3). Debenzylation of
the amines 5j-n was unsucessful under various hydroge-
nation conditions with Pearlman’s catalyst and no other
efficient deprotection has been found.13
Pd(PPh3)4 (2 mol%)
O
O
R1CH2NH2
+
R1CH2N
N
N
CH2Cl2, 35 °C, 1 to 3 h
Me
Me
O
5a-i or 7a-f
8 : 50-87%
Scheme 4
All reactions were carried out under argon. THF and ether were
freshly distilled from sodium/benzophenone and CH2Cl2 from
CaH2. Reactions were monitored by GC analysis of worked up re-
action aliquots. Zinc foil was activated with 1,2-dibromoethane and
In summary, functionalized primary amines were prepa-
red in a two step sequence from organozinc and magnesi-
Synthesis 2000, No. 7, 941–948 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Aminomethylation of Functionalized Organozinc Reagents and Grignard Reagents
943
Table 2 Aminomethylated Products 7a−f Obtained by the Reaction of Functionalized Organomagnesium Reagents with the Immonium Salt 1
Entry
1
Organomagnesium Reagent
Temp.
(°C)
Product of Type 7
Yield
(%)a
-60
70
6a
7a
2
3
-60
-78
76
73
6b
6c
7b
7c
4
5
-78
-40
81
76
6d
7d
7e
6e
6f
6
-40
77
7f
a Isolated yields of analytically pure products.
TMSCl. Analytical TLC was performed using Merck silica gel (60
F-254) plates (0.25 mm) precoated with a fluorescent indicator.
Column chromatography was carried out on silica gel 60 (70-230
mesh). NMR spectra were recorded on a 200 or 300 MHz NMR
spectrometer. The ionization method used for mass spectrometry
was electron impact (EI, 70 eV). In the case of 8e Fast Atom Bom-
bardment was used. Elemental analyses were performed by the Mi-
croanalytical Service Laboratory of Universität München.
mixture was refluxed for 3.5 h. After cooling to r.t. the solid was
crystallized from hexane (50 mL) to afford the product (31.3 g, 77%
yield) as white crystals (Table 4).
Immonium Trifluoroacetates 1 and 2
Trifluoroacetic anhydride (0.85 mL, 6.0 mmol) was added slowly at
0 °C to a solution of the aminal 3 (2.4 g, 6.0 mmol) in CH2Cl2
(12 mL). After stirring at r.t. for 1 h, the resulting orange solution
was ready for use. The preparation of the aminal 2 was performed
in ether following the same procedure to give a clear yellow solu-
tion.
N,N,N’,N’-Tetraallylmethanediamine (3)
A 37% aq solution of formaldehyde (8.9 g, 0.11 mol) was added
slowly at 0 °C to diallylamine (24.7 mL, 0.20 mol) placed in a two-
necked flask equipped with a refluxing condenser and the mixture
was refluxed for 2 h. After cooling to r.t. the upper layer was sepa-
rated and dried (KOH pellets). The residue was distilled under re-
duced pressure (bp 95 °C/15 Torr) to afford the product (14.6 g,
71% yield) as a colorless liquid (Table 4).
Aminomethylation of Functionalized Organozinc Reagents Af-
fording the Amines 5; General Procedure A
A solution of the functionalized organometallic reagent (1.3 to
1.5 equiv) in THF was added at the temperature indicated in Table
1 to a solution of immonium trifluoroacetate (1 equiv) in CH2Cl2
(salt 1) or Et2O (salt 2). After stirring for 30 min, the reaction was
quenched with sat. aq Na2CO3 (or NH4Cl) and extracted with
CH2Cl2 or Et2O. The combined organic layers were washed with
H2O, brine and dried (MgSO4). The products were isolated after
evaporation of the solvents and purification by flash-chromatogra-
N,N,N’,N’-Tetrabenzylmethanediamine (4)
A 37% aq solution of formaldehyde (8.9 g, 0.11 mol) was added
slowly at 0 °C to a two-necked flask equipped with a refluxing con-
denser and containing dibenzylamine (38 mL, 0.20 mol) and the
Synthesis 2000, No. 7, 941–948 ISSN 0039-7881 © Thieme Stuttgart · New York

944
N. Millot et al.
PAPER
Table 3 Deallylation of Bis-allylamines 5 or 7 Using N,N’-Dimeth-
ylbarbituric Acid Leading to Primary Amines 8a−j
the crude residue was purified by flash chromatography on silica gel
(CH2Cl2/MeOH, 99:1) affording the product 5a (400 mg, 85%).
3-[2-(N,N-diallylamino)ethyl]benzonitrile (5b)
Amine
Product of Type 8
Yield
(%)a
The reaction was carried out according to General Procedure A us-
ing 3-cyanobenzylzinc bromide (11.3 mmol), freshly prepared from
3-bromomethylbenzonitrile (8.7 g, 44.0 mmol) and activated zinc
foil (8.63 g, 0.13 mol) in THF (40 mL), and a solution of 1
(7.6 mmol) in CH2Cl2 (15 mL) at -78 °C. After workup the crude
residue was purified by flash chromatography on silica gel (CH2Cl2/
MeOH 99:1) affording the product 5b (1.6 g, 96%).
5b
63
8a
5c
NC(CH2)4NH2
8b
59
57
5-(N,N-Diallylamino)pentanenitrile (5c)
The reaction was carried out according to General Procedure A us-
ing a solution of 3-cyanopropylzinc iodide (3.75 mmol), freshly
prepared from 3-iodopropionitrile (0.73 g, 3.75 mmol) and activat-
ed zinc foil (0.74 g, 11.25 mmol) in THF (2 mL), and a solution of
1 (2.75 mmol) in CH2Cl2 (4 mL) at 25 °C. After workup the crude
residue was purified by flash chromatography on silica gel (CH2Cl2/
MeOH, 97:3) affording the product 5c (330 mg, 68%).
5d
8c
Ethyl 5-(N,N-Diallylamino)pentanoate (5d)
5f
74
The reaction was carried out according to General Procedure A us-
ing a solution of 4-carboethoxypropylzinc iodide (3.0 mmol), fresh-
ly prepared from ethyl 4-iodobutanoate (0.72 g, 3.0 mmol) and
activated zinc foil (0.59 g, 9.0 mmol) in THF (2.3 mL), and a solu-
tion of 1 (2.0 mmol) in CH2Cl2 (4 mL) at 25 °C. After workup the
crude residue was purified by flash chromatography on silica gel
(CH2Cl2/MeOH, 98:2) affording the product 5d (330 mg, 73%).
8d
5g
5i
EtO2C(CH2)6NH2
8e
71b
80
N-Cyclohexylmethyl-N,N-diallylamine (5e)
The reaction was carried out according to General Procedure A us-
ing cyclohexylzinc iodide (30.7 mmol), freshly prepared from io-
docyclohexane (6.5 mL, 50.0 mmol) and activated zinc foil (10.1 g,
0.155 mol) in THF (48 mL), and a solution of 1 (20.0 mmol) in
CH2Cl2 (42 mL) at 25 °C. After workup the crude residue was puri-
fied by flash chromatography on silica gel (CH2Cl2/MeOH, 98:2)
affording the product 5e (3.2 g, 83%).
8f
7b
87
N-Myrtanylmethyl-N,N-diallylamine (5f)
8g
8h
The reaction was carried out according to General Procedure A us-
ing dimyrtanylzinc (3.40 mmol), freshly prepared from (-)-b-
Pinene (16 mL, 0.10 mol), BH3•SMe2 (3 mL, 0.03 mol) and Et2Zn
(12 mL, 0.12 mol) in THF (40 mL), and a solution of 1 (2.0 mmol)
in CH2Cl2 (4 mL) at 25 °C. After workup the crude residue was pu-
rified by flash chromatography on silica gel (CH2Cl2/MeOH, 98:2)
affording the product 5f (450 mg, 91%).
7d
7e
62
50
Ethyl 7-(N,N-Diallylamino)heptanoate (5g)
The reaction was carried out according to General Procedure A us-
ing a solution of 6-ethoxycarbonylhexylzinc iodide (10 mmol),
freshly prepared from ethyl 6-iodoheptanoate (2.7 g, 10 mmol) and
activated zinc foil (2.0 g, 30 mmol) in THF (5 mL), and a solution
of 1 (7 mmol) in CH2Cl2 (14 mL) at 25 °C. After workup the crude
residue was purified by flash chromatography on silica gel (CH2Cl2/
MeOH, 100:0 to 97:3) affording the product 5g (1.33 g, 75%).
8i
8j
7f
60
2-[4-(N,N-Diallylamino)butyl]isoindole-1,3-dione (5h)
The reaction was carried out according to General Procedure A us-
ing a solution of 3-phthalimidopropylzinc iodide (10 mmol), freshly
prepared from N-(3-iodopropyl)phthalimide (3.1. g, 10 mmol) and
activated zinc foil (1.96 g, 30 mmol) in THF (5 mL), and a solution
of 1 (7 mmol) in CH2Cl2 (14 mL) at 25 °C. After workup the crude
residue was purified by flash chromatography on silica gel (CH2Cl2/
MeOH, 98:2 to 97:3) affording the product 5h (1.33 g, 64%).
a Isolated yields of analytically pure products.
b Product isolated as its hydrochloride salts.
phy on silica gel. The NMR and mass spectral data of compounds
5a-n are shown in Table 4.
4-(N,N-Diallylaminomethyl)benzonitrile (5i)
N-Benzyl-N,N-diallylamine (5a)
The reaction was carried out according to General procedure A us-
ing 4-cyano-phenylzinc bromide (13.4 mmol), freshly prepared
from 4-bromo-benzonitrile (2.4 g, 13.1 mmol), n-BuLi 15% hexane
solution (9.0 mL, 14 mmol) and ZnBr2 (3.15 g, 14 mmol) in THF
(14 mL), and a solution of 1 (5.2 mmol) in CH2Cl2 (10 mL) at
The reaction was carried out according to General Procedure A us-
ing a solution of phenylzinc chloride (3.75 mmol), freshly prepared
from a 1.7 M cyclohexane/Et2O solution of PhLi (2.2 mL,
3.75 mmol) and ZnCl2 (0.51 g, 3.75 mmol) in THF (5.5 mL), and a
solution of 1 (2.5 mmol) in CH2Cl2 (5 mL) at -78 °C. After workup
Synthesis 2000, No. 7, 941–948 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Aminomethylation of Functionalized Organozinc Reagents and Grignard Reagents
945
Table 4 NMR and Mass Spectral Data of Compounds 3, 4 and 5a−n
Product
1H NMR (CDCl3, 300 MHz)
13C NMR (CDCl3, 75 MHz)
MS a
d, J (Hz)
d
m/z (%)
3
5.81-5.62 (2 H, m), 5.00 (2 H, d, J = 12.2), 4.93 (2 H,
d, J = 6.0), 3.02 (4 H, d, J = 6.4), 2.98 (1 H, s)
150.5, 128.7, 124.9, 59.6
205, 110
4
7.29-7.19 (10 H, m), 3.61 (4 H, s), 3.10 (1 H, s)
140.2, 129.4, 128.6, 127.2, 72.8, 56.6
406, 314, 210,
106, 91
5a
7.27-7.15 (5 H, m), 5.84 (2 H, ddt, J = 16.6, 10.2,
6.4), 5.12 (2 H, d, J = 16.6, 5.07 (2 H, d, J = 10.2),
3.51 (2 H, s), 3.01 (4 H, d, J = 6.4)
139.5, 135.7, 129.0, 128.2, 126.9, 117.5,
57.6, 56.4
187, 160, 110,
96, 91
5b
5c
5d
7.41-7.28 (4 H, m), 5.78-5.67 (2 H, m), 5.13-5.05
(4 H, m), 3.07 (4 H, d, J = 6.4), 2.70 (2 H, t, J = 6.5),
2.61 (2 H, t, J = 6.5)
142.5, 135.8, 133.8, 132.7, 130.1, 129.4,
119.4, 118.0, 112.6, 57.3, 54.7, 33.4
226, 199, 110,
41
5.76-5.65 (2 H, m), 5.07 (2 H, d, J = 15.0 ), 5.02
(2 H, d, J = 9.0), 2.95 (4 H, d, J = 6.0), 2.34 (2 H, t,
J = 6.0), 2.26 (2 H, t, J = 6.0), 1.58-1.49 (4 H, m)
136.0, 120.2, 118.0, 57.3, 52.3, 26.4, 23.8,
17.5
178, 151, 110
225, 184, 110
5.70 (2 H, m), 5.06 (2 H, d, J = 15.0), 5.01 (2 H, d,
J = 6.0), 4.03 (2 H, q, J = 6.0), 2.97 (4 H, d, J = 9.0),
2.32 (2 H, t, J = 6.0), 2.20 (2 H, t, J = 6.0), 1.56-1.35
(4 H, m), 1.14 (3 H, t, J = 6.0)
174.1, 136.2, 117.8, 60.7, 57.3, 53.2, 34.7,
26.9, 23.4, 14.7
5e
5f
5.84-5.71 (2 H, m), 5.12-5.02 (4 H, m), 2.98 (4 H,
d, J = 6.3), 2.12 (2 H, d, J = 7.0), 1.72-0.74 (11 H, m)
135.2, 115.9, 59.5, 56.4, 34.9, 30.8, 25.2
193, 110, 73
2.63 (4 H, m), 2.37-0.80 (19 H, m)
131.5, 117.6, 67.1, 45.5, 40.5, 40.0, 39.6,
37.8, 37.7, 32.7, 29.4, 27.2, 23.4, 22.9
246, 135, 107,
82
5g
5.95-5.75 (2 H, m), 5.16 (2 H, d, J = 17.1), 5.11 (2 H,
d, J = 7.2), 4.12 (2 H, q, J = 7.2), 3.9 (4 H, d, J = 6.3),
2.41 (2 H, t, J = 7.2), 2.28 (2 H, t, J = 7.5), 1.70-1.58
(2 H, m), 1.54-1.42 (2 H, m), 1.33-1.29 (4 H, m),
1.25 (3 H, t, J = 7.2)
174.1, 135.9, 117.8, 60.5, 57.2, 53.6, 34.7,
28.7, 27.5, 27.2, 25.3, 14.6
253, 212, 208,
110
5h
7.83 (2 H, m), 7.75 (2 H, m), 5.83 (2 H, m), 5.15 (2
H, d, J = 18.0), 5.10 (2 H, q, J = 9.0), 3.69 (2 H, t, J =
9.0), 3.06 (4 H, d, J = 6.0), 2.45 (2 H, t, J = 6.0), 1.71-
1.64 (2 H, m), 1.52-1.47 (2 H, m)
168.8, 136.1, 134.2, 132.5, 123.5, 117.7,
57.2, 53.0, 38.3, 26.9, 24.8
298, 257, 160,
110
5i
5.79-5.68 (2 H, m), 5.12-5.03 (4 H, m), 3.51 (2 H,
s), 2.97 (4 H, d, J = 6.3)
146.1, 135.7, 132.4, 129.2, 119.4, 118.1,
111.0, 57.5, 57.0
212, 185, 116,
89
5j
5k
7.34-7.22 (10 H, m), 3.52 (4 H, s), 2.41 (2 H, t, J =
6.3), 2.10 (2 H, t, J = 6.9), 1.64-1.60 (4 H, m)
140.0, 129.5, 128.8, 127.4, 120.2, 58.9, 52.1,
26.3, 23.3, 16.9
278, 210, 91
7.37-7.20 (10 H, m), 4.10 (2 H, q, J = 7.2), 3.53 (4 H,
s), 2.39 (2 H, t, J = 7.5), 2.39 (2 H, t, J = 7.5), 1.56-
1.45 (4 H, m), 1.24 (7 H, t, J = 6.0)
174.3, 140.5, 129.2, 128.6, 127.2, 60.6, 58.8,
53.7, 34.8, 29.4, 27.3, 25.4, 14.7
353, 308, 262,
210, 91
5l
7.37-7.20 (10 H, m), 4.09 (2 H, q, J = 6.9), 3.53 (4 H,
s), 2.41 (2 H, t, J = 6.9), 2.18 (2 H, t, J = 6.9), 1.62-
1.54 (4 H, m), 1.22 (3 H, t, J = 6.9)
174.1, 140.3, 129.3, 128.6, 127.2, 60.5, 58.7,
53.2, 34.5, 26.9, 23.0, 14.7
325, 210, 91
5m
5n
7.38-7.13 (14 H, m), 3.52 (4 H, s), 2.69 (2 H, t, J =
6.9), 2.61 (2 H, t, J = 6.9)
141, 138.2, 126-132, 118.0, 111.1, 57.4,
324, 233, 210,
91
53.1, 32.1
7.24-7.08 (10 H, m), 3.44 (4 H, s), 2.31 (4 H, t, J =
7.5), 2.15-0.69 (15 H, m)
140.5, 129.3, 128.6, 127.2, 58.8, 52.4, 46.8,
42.0, 41.5, 39.5, 35.3, 34.1, 28.7, 27.1, 23.8,
23.0
324, 233, 210,
91, 65
a
Mass spectra were measured using electron impact ionization (EI).
-78 °C. After workup the crude residue was purified by flash chro-
matography on silica gel (CH2Cl2/MeOH, 99:1) affording the prod-
uct 5i (800 mg, 72%).
5-(N,N-Dibenzylamino)pentanenitrile (5j)
The reaction was carried out according to General Procedure A us-
ing a solution of 3-cyanopropylzinc iodide (9 mmol), freshly pre-
Synthesis 2000, No. 7, 941–948 ISSN 0039-7881 © Thieme Stuttgart · New York

946
N. Millot et al.
PAPER
Table 5 NMR and Mass Spectral Data of Compounds 7a−f and 8a−j
Product
1H NMR (CDCl3, 300 MHz)
13C NMR (CDCl3, 75 MHz)
MS a
d, J (Hz)
d
m/z (%)
7a
7.91 (2 H, d, J = 8.2), 7.33 (2 H, d, J = 8.2), 5.91-5.67
(2 H, m), 5.20-4.99 (4 H, m), 4.29 (2 H, q, J = 7.0),
3.53 (2 H, s), 2.99 (4 H, d, J = 6.5), 1.31 (3 H, t, J =
7.0)
167.0, 145.5, 136.0, 129.9, 129.5, 129.0,
118.0, 61.2, 57.7, 57.0, 14.7
259, 232, 163,
110, 96
7b
7c
7d
7e
7.43-7.21 (4 H, m), 5.86-5.73 (2 H, m), 5.15-5.02 (4
H, m), 3.62-3.56 (2 H, m), 3.50 (2 H, s), 3.27-3.12 (2
H, m), 3.00 (2 H, d, J = 6.3), 1.60-1.29 (6 H, m)
170.4, 141.1, 135.7, 135.1, 128.8, 126.9,
117.5, 57.2, 56.5, 48.8, 43.2, 26.5, 24.7
298, 271, 202,
174, 110, 96,
69
5.83-5.70 (2 H, m), 5.15-5.04 (4 H, m), 4.06 (2 H, t,
J = 6.0), 3.07 (4 H, d, J = 6.3), 2.64 (2 H, t, J = 6.0),
1.13 (9 H, s)
178.6, 135.8, 117.5, 62.8, 57.4, 51.5, 38.8,
27.3
184, 129, 110,
57
5.83-5.69 (2 H, m), 5.14-5.04 (4 H, m), 4.06 (2 H, t,
J = 6.2), 3.07 (4 H, d, J = 6.3), 2.63 (2 H, t, J = 6.2),
2.22 (1 H, m), 1.84-1.16 (10 H, m)
176.3, 136.0, 117.8, 62.6, 57.7, 51.8, 43.5,
29.4, 26.1, 25.8
210, 122, 110,
83, 81
7.72 (2 H, dd, J = 10.8, 1.5), 7.60 (1 H, dd, J = 10.8,
1.5), 7.41 (1 H, t, J = 10.8), 7.26 (1 H, t, J = 10.8),
5.89-5.80 (2 H, m), 5.18 (2 H, d, J = 17.1), 5.10 (2 H,
d, J = 10.2), 4.33 (2 H, q, J = 7.2), 3.88 (2 H, s), 3.07
(4 H, dt, J = 6.3, 1.2), 1.38 (3 H, t, J = 7.2)
168.7, 141.4, 136.1, 131.8, 131.5, 130.0,
126.9, 117.5, 61.2, 56.8, 56.0, 14.7
258, 218, 173,
172, 110
8a
8b
8c
8d
8e
7.54-7.39 (4 H, m), 3.01 (2 H, t, J = 6.5), 2.80 (2 H, t,
J = 6.5), 1.47 (2 H, br s)
140.4, 132.4, 131.3, 129.0, 128.2, 117.9 ,
111.4, 41.7, 38.5
145, 128, 117,
89, 75, 63
2.27 (2 H, t, J = 6.6), 2.39 (2 H, t, J = 6.6), 1.79-1.57
(4 H, m)
127.3, 48.8, 40.1, 30.5, 24.7
98
6.79 (1 H, br s), 3.25 (2 H, m), 2.29 (2 H, t, J = 6.0),
1.78-1.69 (4 H, m)
171.6, 41.2, 30.5, 21.3, 19.9
99
2.63 (m, 4 H), 2.37-0.80 (13 H, m)
131.5, 117.6, 67.1, 45.5, 40.5, 40.0, 39.6,
37.8, 37.7, 32.7, 29.4, 27.2, 23.4, 22.9
246, 135, 107,
82
4.15 (2 H, q, J = 7.1), 2.98 (6 H, t, J = 7.5), 2.37 (3 H,
t, J = 7.1), 2.35 (3 H, t, J = 7.2), 1.28 (3 H, t, J = 7.1)b
176.1, 60.0, 39.3, 33.3, 26.9, 25.7, 24.3, 22.1,
13.2 b
174, 146 c
8f
7.55-7.36 (4 H, m), 3.88 (2 H, s), 2.21 (2 H, br s),
147.3, 130.9, 126.7, 117.9, 109.6, 44.9
132, 104, 77
8g
7.25 (4 H, s), 3.77 (2 H, s), 3.65-3.40 (2 H, m), 3.40-
3.10 (2 H, m), 2.13 (2 H, s), 1.70-1.30 (6 H, m)
170.5, 144.5, 135.2, 127.3, 49.0, 46.2, 43.4,
26.7, 26.0, 24.8
217, 134, 105,
89
8h
8i
3.75-3.50 (2 H, m), 3.50-3.25 (2 H, m), 2.20-2.00 (1
H, m), 1.95-1.00 (10 H, m)
178.0, 62.2, 45.8. 42.6, 45.8, 30.0, 26.1
171, 153, 141,
128, 111, 83
8.25 (1 H, br s), 7.80 (1 H, m), 7.51-7.37 (3 H, m),
4.40 (2 H, s)
171.4, 142.7, 131.3, 130.7, 126.9, 122.6,
122.2, 44.8
133, 132, 105,
104, 77
8j
7.46 (1 H, d, J = 3.7), 6.83 (1 H, d, J = 3.7), 4.26 (2 H,
q, J = 7.2), 4.00 (2 H, s), 1.31 (3 H, t, J = 10.9)
161.3, 154.0, 133.9, 131.3, 129.2, 60.0, 14.7
184, 155, 140,
112, 78
a
Mass spectra were measured using electron impact ionization (EI).
b 1H and 13C NMR spectra were recorded in CD3OD.
c Mass spectrum was measured using Fast Atom Bombardment desorption (FAB).
pared from 3-iodopropionitrile (1.75 g, 9 mmol) and activated zinc
foil (1.76 g, 27 mmol) in THF (4 mL), and a solution of 2 (6 mmol)
in Et2O (12 mL) at 25 °C. After workup the crude residue was puri-
fied by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0)
affording the product 5j (1.28 g, 77%).
zinc foil (1.76 g, 27 mmol) in THF (4 mL), and a solution of 2
(6 mmol) in Et2O (4 mL) at 25 °C. After workup the crude residue
was purified by flash chromatography on silica gel (CH2Cl2/MeOH,
100:0 to 95:5) affording the product 5k (1.46 g, 74%).
Ethyl 7-(N,N-Dibenzylamino)heptanoate (5l)
Ethyl 5-(N,N-Dibenzylamino)pentanoate (5k)
The reaction was carried out according to General Procedure A us-
ing a solution of 6-carboethoxyhexylzinc iodide (10 mmol), freshly
prepared from ethyl 6-iodoheptanoate (2.70 g, 10 mmol) and acti-
vated zinc foil (2.0 g, 30 mmol) in THF (5 mL), and a solution of 2
The reaction was carried out according to General Procedure A us-
ing a solution of 4-carboethoxypropylzinc iodide (9 mmol), freshly
prepared from ethyl 4-iodobutanoate (2.18 g, 9 mmol) and activated
Synthesis 2000, No. 7, 941–948 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Aminomethylation of Functionalized Organozinc Reagents and Grignard Reagents
947
(7 mmol) in Et2O (14 mL) at 25 °C. After workup the crude residue
was purified by flash chromatography on silica gel (CH2Cl2/MeOH,
100:0 to 96:4) affording the product 5l (1.90 g, 77%).
Ethyl 2-(N,N-Diallylaminomethyl)benzoate (7e)
The reaction was carried out according to General Procedure B us-
ing a solution of 6e (10.0 mmol), freshly prepared from ethyl 2-io-
dobenzoate (2.76 g, 10.0 mmol) and i-PrMgCl 0.8 M THF solution
(13 mL, 10.5 mmol) in THF (20 mL), and a solution of 1 (7.0 mmol)
in CH2Cl2 (14 mL) at -40 °C. After workup the crude residue was
purified by flash chromatography on silica gel (CH2Cl2/MeOH,
99:1) affording the product 7e (1.37 g, 76%).
3-[2-(N,N-Dibenzylamino)ethyl]benzonitrile (5m)
The reaction was carried out according to General Procedure A us-
ing 3-cyanobenzylzinc bromide (11.7 mmol), freshly prepared from
3-bromomethylbenzonitrile (8.7 g, 40 mmol) and activated zinc foil
(8.6 g, 130 mmol) in THF (40 mL), and a solution of 2 (10.0 mmol)
in Et2O (20 mL) at -78 °C. After workup the crude residue was pu-
rified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0)
affording the product 5m (3.0 g, 92%).
Ethyl 5-(N,N-Diallylaminomethyl)-2-thiophencarboxylate (7f)
The reaction was carried out according to General Procedure B us-
ing 6f (7.7 mmol), freshly prepared from (1.8 g, 7.7 mmol) and
i-PrMgBr (0.8 M THF solution, 11 mL, 8.8 mmol) in THF (12 mL),
and a solution of 1 (4.9 mmol) in CH2Cl2 (10 mL) at -40 °C. After
workup the crude residue was purified by flash chromatography on
silica gel (CH2Cl2/MeOH, 100:0) affording the product 7f (1.0 g,
77%).
N-Myrtanylmethyl-N,N-dibenzylamine (5n)
The reaction was carried out according to General Procedure A us-
ing dimyrtanylzinc (4.0 mmol), freshly prepared from (-)-b-pinene
(16 mL, 0.10 mol), BH3•SMe2 (3 mL, 0.03 mol) and Et2Zn (12 mL,
0.12 mol) in THF (40 mL), and a solution of 2 (3.6 mmol) in Et2O
(10 mL) at 25 °C. After workup the crude residue was purified by
flash chromatography on silica gel (pentane/Et2O, 98:2) affording
the product 5n (910 mg, 73%).
Deprotection of Functionalized Diallylamines 8; General Proce-
dure C
A solution of diallylamine 5 or 7 (1 equiv) in CH2Cl2 (2.5 mL/
equiv) was added to N,N’-dimethylbarbituric acid (6 equiv) and
Pd(PPh3)4 (0.02 equiv). The mixture was stirred at 35 °C for 1 to 3
h. After cooling to r.t., the solvents were evaporated and the residue
dissolved with a 1:1 mixture of Et2O and 1 N HCl. The aqueous lay-
er was extracted three times with Et2O and basified with a sat. aq so-
lution of Na2CO3. The amine was extracted 6 to 9 times with
CH2Cl2. The product was isolated after drying (MgSO4), filtration
and evaporation of the solvents. In the case of 8e, Guibé’s workup12
was used to isolate the product. The NMR and mass spectral data of
compounds 8a-j are given in Table 5.
Aminomethylation of Functionalized Magnesium Reagents Af-
fording the Amines (7); General Procedure B
A solution of immonium trifluoroacetate (1equiv) in CH2Cl2 was
added at the temperature indicated in the Table 2 to a solution of the
functionalized organomagnesium reagent (1.25 equiv) in THF. Af-
ter stirring for 30 min, the reaction was quenched with sat. aq
Na2CO3 (or NH4Cl) and extracted with CH2Cl2 or Et2O. The com-
bined organic layers were washed with H2O, brine and dried
(MgSO4). The products were isolated after evaporation of the sol-
vents and purification by flash-chromatography on silica gel. The
NMR and mass spectral data of compounds 7a-f are shown in Ta-
ble 5.
3-(2-Aminoethyl)benzonitrile (8a)
The reaction was carried out according to General Procedure C us-
ing 5b (0.45 g, 2.0 mmol) in CH2Cl2 (5 mL) containing N,N’-dime-
thylbarbituric acid (1.86 g, 11.9 mmol) and Pd(PPh3)4 (69 mg,
0.06 mmol). The product was isolated as an oil (182 mg, 63%).
Ethyl 4-(N,N-Diallylaminomethyl)benzoate (7a)
The reaction was carried out according to General Procedure B us-
ing a solution of 6a (3.0 mmol), freshly prepared from ethyl 4-iodo-
benzoate (0.83 g, 3.0 mmol) and i-PrMgBr (3.3 mmol) in THF/NBP
(N-butylpyrrolidinone) (5:1 mixture, 6 mL), and a solution of 1 (2.4
mmol) in CH2Cl2 (5 mL) at -60 °C. After workup the crude residue
was purified by flash chromatography on silica gel (pentane/Et2O,
9:1) affording the product 7a (470 mg, 70%).
5-Aminopentanenitrile (8b)
The reaction was carried out according to General Procedure C us-
ing 5c (0.18 g, 1.0 mmol) in CH2Cl2 (2.5 mL) containing N,N’-di-
methylbarbituric acid (0.94 g, 6.0 mmol) and Pd(PPh3)4 (23 mg,
0.02 mmol). The product was isolated as an oil (58 mg, 59%).
Piperidino 4-(N,N-Diallylaminomethyl)benzoate (7b)
2-Piperidinone (8c)
The reaction was carried out according to General Procedure B us-
ing a solution of 6b (3.0 mmol), freshly prepared from piperidino-
4-iodobenzoate (0.95 g, 3.0 mmol) and i-PrMgBr (3.3 mmol) in
THF/NBP (5:1 mixture, 6 mL), and a solution of 1 (2.4 mmol) in
CH2Cl2 (5 mL) at -60 °C. After workup the crude residue was pu-
rified by flash chromatography on silica gel (pentane/Et2O, 8:2) af-
fording the product 7b (580 mg, 81%).
The reaction was carried out according to General Procedure C us-
ing 5d (0.31 g, 1.4 mmol) in CH2Cl2 (3.5 mL) containing N,N’-di-
methylbarbituric acid (1.32 g, 8.4 mmol) and Pd(PPh3)4 (32 mg,
0.03 mmol). The product was isolated as an oil (79 mg, 57%).
Myrtanylmethylamine (8d)
The reaction was carried out according to General Procedure C us-
ing 5f (0.40 g, 1.6 mmol) in CH2Cl2 (3 mL), N,N’-dimethylbarbitu-
ric acid (1.58 g, 10.0 mmol) and Pd(PPh3)4 (50 mg, 0.04 mmol).
The product was isolated as an oil (200 mg, 74%).
2-(N,N-Diallylamino)ethyl Pivalate (7c)
The reaction was carried out according to General Procedure B us-
ing a solution of 6c (3.0 mmol), freshly prepared from 2-iodometh-
ylpivalate (0.72 g, 3.0 mmol) and i-PrMgBr (3.3 mmol) in THF/
NBP (5:1 mixture, 6 mL), and a solution of 1 (2.4 mmol) in CH2Cl2
(5 mL) at -78 °C. After workup the crude residue was purified by
flash chromatography on silica gel (pentane/Et2O, 9:1) affording the
product 7c (380 mg, 74%).
Ethyl 7-Aminoheptanoate (8e)
The reaction was carried out according to General Procedure C us-
ing 5g (0.17 g, 1.0 mmol) in CH2Cl2 (3 mL), N,N’-dimethylbarbitu-
ric acid (0.94 g, 6.0 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol).
Using Guibé’s workup,12 the product was isolated as a solid
(143 mg, 71%).
2-(N,N-Diallylamino)ethylcyclohexancarboxylate (7d)
4-Aminomethylbenzonitrile (8f)
The reaction was carried out according to General Procedure B us-
ing a solution of 6d (3.0 mmol), freshly prepared from 2-iodoethyl-
1-cyclohexane carboxylate (0.85 g, 3.0 mmol) and i-PrMgBr (3.3
mmol) in THF/NBP (5:1 mixture, 6 mL), and a solution of 1 (2.4
mmol) in CH2Cl2 (5 mL) at -78 °C. After workup the crude residue
was purified by flash chromatography on silica gel (pentane/Et2O,
7:3) affording the product 7d (500 mg, 82%).
The reaction was carried out according to General Procedure C us-
ing 5i (0.40 g, 1.9 mmol) in CH2Cl2 (5 mL), N,N’-dimethylbarbitu-
ric acid (1.86 g, 11.9 mmol) and Pd(PPh3)4 (46 mg, 0.04 mmol). The
product was isolated as an oil (200 mg, 80%).
Piperidino 4-Aminomethylbenzoate (8g)
The reaction was carried out according to General Procedure C us-
ing 7b (0.60 g, 2 mmol) in CH2Cl2 (5 mL), N,N’-dimethylbarbituric
Synthesis 2000, No. 7, 941–948 ISSN 0039-7881 © Thieme Stuttgart · New York

948
N. Millot et al.
PAPER
(5) For an excellent review see : Arend, M.; Westermann, B.;
Risch, N. Angew. Chem. Int. Ed. 1998, 110, 1044.
(6) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A.
Angew. Chem. Intl. Ed. Engl. 1971, 10, 330.
(7) Kinast, G. Tietze, L.-F. Angew. Chem. Int. Ed. Engl. 1976, 15,
239.
acid (1.88 g, 12.0 mmol) and Pd(PPh3)4 (46 mg, 0.04 mmol). The
product was isolated as an oil (380 mg, 87%).
2-Aminoethylcyclohexancarboxylate (8h)
The reaction was carried out according to General Procedure C us-
ing 7d (0.30 g, 1.2 mmol) in CH2Cl2 (3 mL), N,N’-dimethylbarbitu-
ric acid (1.12 g, 7.2 mmol) and Pd(PPh3)4 (28 mg, 0.02 mmol). The
product was isolated as an oil (119 mg, 62%).
(8) (a) Zwierzak, A.; Slusarska, E. Synthesis 1979, 691.
(b) Bestmann, H.J.; Wölfel, G. Angew. Chem. Int. Ed. Engl.
1984, 96, 53.
Isoindolin-1-one (8i)
The reaction was carried out according to General Procedure C us-
ing 7e (0.50 g, 1.9 mmol) in CH2Cl2 (5 mL), N,N’-dimethylbarbitu-
ric acid (1.80 g, 11.6 mmol) and Pd(PPh3)4 (45 mg, 0.04 mmol). The
product was isolated as an oil (125 mg, 50%).
(c) Morimoto, T.; Takahashi, T; Sekiya, M. J. Chem. Soc.
Chem. Commun. 1984, 794.
(d) Katritzky, A.R.; Jiang, J.; Urogdi, L. Tetrahedron Lett.
1989, 30, 3303.
(9) (a) Hosl, C. E.; Wanner, K. Th. Heterocycles 1998, 48, 2653.
(b) Grumbach, H.-J.; Merla, B.; Risch, N. Synthesis 1999,
1027.
(10) Boymond, L.; Rottländer, M.; Cahiez, G.; Knochel, P. Angew.
Chem. Int. Ed. 1998, 110, 1801.
Ethyl 5-Aminomethyl-2-thiophencarboxylate (8j)
The reaction was carried out according to General Procedure C us-
ing 7f (0.29 g, 1.1 mmol) in CH2Cl2 (3 mL), N,N’-dimethylbarbitu-
ric acid (1.06 g, 6.8 mmol) and Pd(PPh3)4 (30 mg, 0.03 mmol). The
product was isolated as a solid (122 mg, 60%).
(11) Avolio, S.; Malan, C.; Marek, I.; Knochel, P. Synlett 1999, 11,
1820.
References
(12) Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993,
58, 6109.
(13) Greene, T.W. Protective Groups in Organic Synthesis, Third
Edition, Wiley: New York. 1999.
(1) Organozinc Reagents :A Practical Approach, Knochel, P.;
Jones, P., Eds., Oxford Press: Oxford, 1999.,
(2) (a) Knochel, P.; Almena, J.J.P.; Jones, P. Tetrahedron 1998,
54, 8275.
(b) Knochel, P.; Singer, R. Chem. Rev. 1993, 93, 2117.
(3) Knochel, P. Synlett 1995, 393.
(4) Tucker, C.E.; Majid, T.N.; Knochel, P. J. Am. Chem. Soc
1992, 114, 3983.
Article Identifier:
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Synthesis 2000, No. 7, 941–948 ISSN 0039-7881 © Thieme Stuttgart · New York