Hydrogenation of imino-bisnitriles - Synthesis of novel triamines

Article abstract of DOI:10.1080/00397910601038970

The hydrogenation of iminonitriles and iminobisnitriles of type 1a-f is a particularly difficult process as the intermediate dieneamines are highly susceptible to addition reactions. A short general method of preparation and purification of 2-aminomethylene-1,3-diamine of type 2a-e by catalytic hydrogenation of iminobisnitriles is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601038970

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Hydrogenation of Imino‐bisnitriles—Synthesis
of Novel Triamines
a
a
Raji Sundaramoorthi & Terence P. Keenan
a
ARIAD Pharmaceuticals Inc. , Cambridge, Massachusetts, USA
Published online: 06 Feb 2007.
To cite this article: Raji Sundaramoorthi & Terence P. Keenan (2007) Hydrogenation of
Imino‐bisnitriles—Synthesis of Novel Triamines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:3, 417-423, DOI: 10.1080/00397910601038970
To link to this article: http://dx.doi.org/10.1080/00397910601038970
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Synthetic Communications , 37: 417–423, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601038970
Hydrogenation of Imino-bisnitriles—
Synthesis of Novel Triamines
Raji Sundaramoorthi and Terence P. Keenan
ARIAD Pharmaceuticals Inc., Cambridge, Massachusetts, USA
Abstract: The hydrogenation of iminonitriles and iminobisnitriles of type 1a–f is a
particularly difficult process as the intermediate dieneamines are highly susceptible
to addition reactions. A short general method of preparation and purification of
2-aminomethylene-1,3-diamine of type 2a–e by catalytic hydrogenation of iminobis-
nitriles is described.
Keywords: hydrogenation, imino-bisnitrile, triamine
INTRODUCTION
One of the simplest methods for the preparation of polyamines involves
[1]
reduction of azide, nitro, imino, cyano, or amide functionalities. Such poly-
amines can serve important roles as biological and conjugate agents, as well as
[
2]
scaffolds for bivalent ligand approaches such as opiod receptor study,
[3]
structure–activity relationships (SAR) by NMR, or linker agents in combi-
natorial chemical approaches for the discovery of novel inhibitors such as the
[
4]
SH2 domain of c-src. The use of diamines as linker or spacer units for
pharmacologically relevant motifs that induce dimerization of chimeric
fusion proteins containing the mutant protein F36V-FKBP12 has been
[
5]
reported.
(
Efforts in this area resulted in the “dimerizer” AP1903
6]
Fig. 1), which has been evaluated in a phase I clinical trial and has
[
[7]
potential utility in the treatment of graft-versus-host disease (GvHD) in
adoptive T-lymphocyte therapy. An alternative dimerizer, AP20187, was
Received in the USA June 30, 2006
Address correspondence to Raji Sundaramoorthi, ARIAD Pharmaceuticals Inc.,
26, Landsdowne St., Cambridge, MA 02139, USA. E-mail: raji18@comcast.net;
tkeenan@helicontherapeutics.com
4
17

4
18
R. Sundaramoorthi and T. P. Keenan
Figure 1. FK36V-FKBP12-dimerizers.
developed as a more water-soluble agent. It has found wide utility in cellular
and large animal in vivo applications that allow a wide variety of cellular
processes to be chemically controlled, including proliferation, differentiation,
[8]
adhesion, transformation, and apoptosis. In efforts to develop an amine-con-
taining 1,3-diamino linker for the preparation of AP20187, a convenient
process for the synthesis of the novel 2-aminomethylene- 1,3-diamine
scaffold was developed.
RESULTS AND DISCUSSION
Ethoxymethylenemalononitrile is an inexpensive and suitably functionalized
[9]
[8]
malononitrile widely used in the synthesis of pyrimidines, pyridines,
[
10]
[11]
pyrazoles,
and a variety of other fused heterocyclic systems.
formic acid equivalent in the synthesis of fused imidazoles,
[12]
Treatment of ethoxy-
methylenemalononitrile with symmetrical secondary amines (Scheme 1)
Scheme 1.

Hydrogenation of Imino-bisnitriles
419
provided the corresponding N,N-dialkylaminomethylenemalononitriles 1a–f
as crystalline solids in good yield. Reduction of the enemalononitriles 1a–e
in ethanol by hydrogenation in the presence of PtO2 and concentrated
hydrochloric acid (6 eq.) at 70 psi afforded diamines 2a–e, which could be
crystallized from the crude reaction mixture as hydrochloride salts in a
modest 30–40% yield and of analytical purity with negligible trace NH Cl
4
content. A notable exception was piperazine derivative 1f containing a
distal secondary amine, which afforded piperazine dihydrochloride in quanti-
tative yield. Likewise, the use of 4-toluenesulfonic acid (PTSA) in lieu of con-
centrated hydrochloric acid afforded the piperazine PTSA salt in essentially
quantitative yield.
CONCLUSION
A convenient and rapid method of access into the 2-aminomethylene-1,3-
diamine scaffold system has been developed. The modest yield of reduction
is offset by the ease of isolation of the trihydrochloride salt with good analyti-
cal purity.
EXPERIMENTAL
General
All reagents and solvents were obtained from commercial sources and used
without further purification. Melting points were measured on a Laboratory
1
Devices MEL-TEMP II apparatus and are uncorrected. H (300 MHz) and
1
3
C (75 MHz) spectra were obtained at 300 K on a Bruker ARX-300 instru-
3
1
ment using D O as solvent as well as reference (4.78 ppm). DEPT
2
C
NMR spectral information are identified by the (þ) and (2) signs present
in the chemical shift data. Positive resonances indicate a singlet or triplet
multiplicity, and negative resonances indicate a doublet or quartet multi-
plicity. Elemental analyses were obtained from Robertson Microlit Labs
(
(
Madison, NJ, USA). Flash chromatography was performed on silica gel
Merck, 230–400 mesh) and analytical thin-layer chromatography (TLC)
was performed on silica-gel 60 F254 plates (Merck) with EtOAc/hexane
3 : 1) as eluant unless noted otherwise.
(
General Procedure for 1a–e
A solution of ethoxymethylenemalononitrile (12.2 g, 100 mmol) in CH Cl
2
2
(100 mL) was cooled to 08C and treated, dropwise, with a 2.0 M THF
solution of amine (105 mmol) over a 15-min period. The resulting mixture

4
20
R. Sundaramoorthi and T. P. Keenan
was then allowed to warm to room temperature and stir for 1 h. The reaction
was then evaporated, and the crude product purified as detailed.
Data
2-Dimethylaminomethylene-malononitrile 1a
Crystallized from EtOAc /pentane/charcoal to afford a beige solid (81%): mp
[
13]
84–858C, lit. mp 818C.
2-Diethylaminomethylene-malononitrile 1b
Chromatographed on silica gel with EtOAc/hexane (3:1) as eluant followed
by crystallization from EtOAc/hexane to afford a beige solid (76%): mp
7
2.5–738C; R ¼ 0.29; anal. calcd. for C H N : C, 64.40; H, 7.43; N,
f
8 11 3
2
8.15. Found: C, 64.36; H, 7.41; N, 28.40.
2-Pyrrolidin-1-ylmethylene-malononitrile 1c
Crystallized from EtOAc/pentane/charcoal to afford a beige solid (81%), mp
8.5–89.58C; R ¼ 0.27; anal. calcd. for C H N : C, 65.29; H, 6.16; N, 28.55.
8
Found: C, 65.07; H, 6.11; N, 28.70.
f
8 9 3
2-Piperidin-1-ylmethylene-malononitrile 1d
Crystallized from EtOAc/pentane/charcoal to afford a beige solid (90%), mp
0–918C; R ¼ 0.29; anal. calcd. for C H N : C, 67.06; H, 6.88; N, 26.07.
9
Found: C, 66.88; H, 6.76; N, 26.13.
f
9 11 3
2-Morpholin-1-ylmethylene-malononitrile 1e
Crystallized from EtOAc/charcoal to afford a beige solid (93%), mp 148–
498C. R ¼ 0.17; anal. calcd. for C H N O: C, 58.89; H, 5.56; N, 25.75.
1
Found: C, 58.77; H, 5.41; N, 25.68.
f
8 9 3
2-Piperazin-1-ylmethylene-malononitrile 1f
A solution of piperazine (105 mmol, 2.0 M THF) was treated dropwise with a
solution of ethoxymethylenemalononitrile (12.2 g, 100 mmol) in CH Cl
2
2
(
100 mL) over a 15-min period. The resulting mixture was then allowed to
warm to room temperature and stir for 1 h. The reaction was then evaporated,
dissolved in CH Cl (100 mL), filtered, and again evaporated. The crude
product was then crystallized from EtOAc/charcoal to afford a beige solid
2
2

Hydrogenation of Imino-bisnitriles
421
(
52%), mp 106–1078C; R ¼ 0.23; MeOH/CHCl (1:4); anal. calcd. for
f
3
C H N : C, 59.24; H, 6.21; N, 34.54. Found: C, 59.31; H, 6.21; N, 34.80.
8 10 4
General Procedure for 2a–e
A solution of 1a–e (1.0 g) in ethanol (45 mL) was treated with PtO (500 mg)
2
followed by concentrated hydochloric acid (6 equiv.), and the mixture was
shaken in a Parr hydrogenator in an atmosphere of hydrogen at 60–70 psi
for 9 h at rt. The reaction was then filtered, and the catalyst was washed
two times with EtOH (2 ꢀ 10 mL) in the case of compounds 2a and 2b. In
the case of the less soluble compounds, 2c–e, the filter cake was washed
with water (20 mL) followed by EtOH (10 mL). The combined filtrates
were evaporated, crystallized as described, and dried for 48 (2a) or 24 h
(2b–e) in vacuo in an Abderhalden with P O as the drying agent and
dichloromethane (2a) or toluene (2b–e) as heat source.
2 5
Data
1
-Aminomethyl-N ,N -dimethylpropane-1,3-diamine,
1
2
Trihydrochloride 2a
Dissolved in hot MeOH (75 mL), filtered, and concentrated to afford product
1
as a colorless solid (34%). H NMR 3.59 (d, J ¼ 6.8, 2H), 3.46 (d, J ¼ 6.1,
1
3
4
H), 3.17 (s, 6H), 2.98–2.89 (m, 1H); C NMR 56.8 (þ), 44.1 (2), 38.9
6 20 3 3
(
þ), 32.1 (2). Anal. calcd. for C H Cl N : C, 29.62; H, 8.69; N, 17.29;
þ
4
Cl, 43.55. Found: C, 29.95; H, 8.38; N, 17.46; Cl, 44.20; NH , ,0.05.
1
1
-Aminomethyl-N ,N -diethylpropane-1,3-diamine, Trihydrochloride 2b
2
1
Recrystallized from EtOH to afford product as a colorless solid (27%). H
1
3
NMR 3.55–3.48 (m, 6H), 3.46 (d, J ¼ 6.1, 4H), 2.90 (t, J ¼ 6.4, 6H);
C
NMR 52.2 (þ), 48.4 (þ), 39.0 (þ), 32.1 (2), 8.2 (2). Anal. calcd. for
C H Cl N : C, 35.77; H, 9.00; Cl, 39.59; N, 15.64. Found: C, 34.34; H,
8
24
3 3
þ
8
.80; Cl, 39.39; N, 15.10; NH , ,0.01.
4
2
-Pyrrolidin-1-ylmethyl-propane-1,3,-diamine, Trihydrochloride 2c
1
Recrystallized from EtOH to afford product as a colorless solid (30%). H
NMR 4.0–3.4 (br s, 4H), 3.64 (d, J ¼ 6.8, 2H), 3.47 (d, J ¼ 6.2, 4H),
1
3
2
3
3
.95–2.84 (m, 1H), 2.28 (br s, 4H); C NMR 55.7 (þ), 54.1 (þ), 38.9 (þ),
3.3 (2), 23.0 (þ). Anal. calcd. for C H Cl N : C, 36.04; H, 8.32; Cl,
8
22
3 3
þ
9.89; N, 15.76. Found: C, 36.04; H, 8.48; Cl, 40.88; N, 15.52; NH , ,0.005.
4

4
22
-Piperidin-1-ylmethyl-propane-1,3,-diamine, Trihydrochloride 2d
Recrystallized from water/EtOH (3:97) to afford product as a colorless solid
R. Sundaramoorthi and T. P. Keenan
2
1
(
35%). H NMR 3.9–3.6 (br s, 2H), 3.51 (d, J ¼ 6.5, 2H), 3.46 (d, J ¼ 6.2,
1
H), 3.3–3.0 (br s, 2H), 2.99–2.91 (m, 1H), 2.1–1.7 (br s, 6H); C NMR
3
4
5
6.2 (þ), 54.7 (þ), 39.2 (þ), 31.5 (2), 23.0 (þ), 21.3 (þ). Anal. calcd. for
C H Cl N : C, 38.51; H, 8.62; Cl, 37.89; N, 14.97. Found: C, 38.23; H,
24
9
3 3
þ
8.79; Cl, 36.60; N, 14.65; NH , ,0.01.
4
2-Morpholin-4-ylmethylene-propane-1,3,-diamine, Trihydrochloride 2e
Recrystallized from water/EtOH (3:97) to afford product as a colorless solid
1
(
32%). H NMR 4.18 (br s, 4H), 3.7 (obs br s, 4H), 3.61 (d, J ¼ 6.5, 2H), 3.48
1
3
(
d, J ¼ 6.3, 4H), 3.03–2.95 (m, 1H); C NMR 64.0 (þ), 56.7 (þ), 53.1 (þ),
3
9.1 (þ), 31.0 (2). Anal. calcd. for C H Cl N O: C, 34.00; H, 7.85; Cl,
þ
4
8
22
3 3
3
7.63; N, 14.87. Found: C, 33.93; H, 7.81; Cl, 37.60; N, 14.92; NH , 0.06.
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