Nitrile reduction in the presence of Boc-protected amino groups by catalytic hydrogenation over palladium-activated Raney-nickel

Full text of DOI:10.1021/jo005637f

2480
J . Org. Chem. 2001, 66, 2480-2483
Notes
hydrides,9 especially NaBH4 + CoCl2‚6H2O,10 NaBH4 +
Nitr ile Red u ction in th e P r esen ce of
NiCl2‚6H2O,11 and LiAlH4 variations,12 have been used
successfully to achieve the nitrile-amine transformation.
Here we report the use of palladium activated Raney-
nickel for the reduction of nitriles to primary amines for
cases in which other methods were unsuccessful.
Boc-P r otected Am in o Gr ou p s by Ca ta lytic
Hyd r ogen a tion over P a lla d iu m -Activa ted
Ra n ey-Nick el
Burkhard Klenke and Ian H. Gilbert*
Welsh School of Pharmacy, Cardiff University,
Redwood Building, King Edward VII Avenue,
Cardiff CF10 3XF, U.K.
Resu lts a n d Discu ssion
Starting materials (Scheme 1) were prepared by adopt-
ing literature-reported Michael-addition procedures of the
corresponding diamines and acrylonitrile. For the ali-
phatic nitriles 1a -g, reactions were carried out in EtOH
at room temperature13 followed by Boc-protection using
Boc-anhydride/Et3N in MeOH at room temperature.14 For
the aromatic nitriles 1h -j, double-Michael-addition reac-
tions were performed in refluxing 1,4-dioxane with cop-
per(II) acetate as Lewis acid catalyst.15
Under standard hydrogenation conditions over Raney-
Nickel (EtOH/water, NaOH, rt, 45 psi, 8-15 h), nitriles
1a -c were smoothly converted into the amines 2a -c in
80-90% yield, although for R ) n-nonyl (1cf2c) a pro-
longed reaction time was necessary. Under the same
conditions, the conversion of 1d (R ) n-dodecyl) was
impractically slow. Furthermore, mono- and bisethylated
byproducts were detected by electrospray-MS. Presum-
ably, these byproducts were formed via reductive ethy-
lation of an imine intermediate. In all other cases
(1e-j), hydrogenation over Raney-nickel did not effect
any reaction or led to mixtures containing starting
material and ethylated amines.
To find suitable reduction conditions the nitrile 1f was
chosen as a model case. Reaction with different complex
metal hydrides (NaBH4 + CoCl2‚6H2O, LiAlH4 + AlCl3,
BH3‚THF) consumed the starting material within hours.
However, no pure product could be isolated, probably due
to formation of metal chelates and decomposition of the
products under rigorous workup conditions. To avoid
problems arising from the chelation of reduction inter-
mediates and products further investigation focused on
catalytic hydrogenation.
gilbertih@cardiff.ac.uk
Received September 6, 2000
In tr od u ction
Polyamines have attracted considerable interest, es-
pecially after the discovery of their ubiquitous presence
in living cells and their involvement in many metabolic
processes.1 As part of a program to synthesize homo-
logues and derivatives of naturally occurring poly-
amines, we utilized the reduction of nitriles in the
presence of Boc-protected amino groups. Nitriles are a
versatile synthon for amines in organic chemistry and
can be prepared by a variety of methods.2 Furthermore,
there are a number of methods available for the sub-
sequent reduction to amines.2 Catalytic hydrogenation3
has been carried out using Raney-nickel,4,5 Pd(OH)2/C,6
Pd/C,7 or PtO28 as catalyst. Alternatively, complex metal
* To whom correspondence should be addressed. Tel:
+44 (0)29 2087 5800. Fax: +44 (0)29 2087 4149.
(1) For the most recent reviews, see: (a) Kuksa, V.; Buchan, R.; Lin,
P. K. T. Synthesis 2000, 1189-1207. (b) Karigiannis, G.; Papaioannou,
D. Eur. J . Org. Chem. 2000, 1841-1863.
(2) Excellent reviews are available: (a) The chemistry of the cyano
group; Rappoport, Z., Ed.; Interscience: London, 1970. (b) Houben-
Weyl, 4th ed.; Grundmann, C., Ed.; Thieme: Stuttgart, 1985; Vol. E5,
p 1313-1441.
(3) (a) Augustine, R. L. Catalytic Hydrogenation, Techniques and
Applications in Organic Synthesis; Marcel Denker, Inc.: New York,
1965. (b) Rylander, P. N. In Hydrogenation Methods, Best Synthetic
Methods; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Academic
Press: London, 1985.
(4) For the preparation of Raney-nickel of different activity see: (a)
Mozingo, R. Org. Synth. 1941, 21, 15-17. (b) Billica, H. R.; Adkins, H.
Org. Synth. 1949, 29, 24-29.
(9) Hajos, A. Complex Hydrides and related reducing agents in
organic synthesis; Elsevier: Amsterdam, 1979.
(5) For some recent examples in the presence of Boc-groups, see:
(a) Geneste, H.; Hesse, M. Tetrahedron 1998, 54, 15199-15214. (b)
Kruijtzer, J . A. W.; Lefeber, D. J .; Liskamp, R. M. J . Tetrahedron Lett.
1997, 38, 5335-5338. (c) Lim, D.; Burgess, K. J . Org. Chem. 1997, 62,
9382-9384. (d) Eisenbrand, G.; Lauck-Birkel, S.; Tang, W. C. Synthesis
1996, 10, 1246-1258. (e) Blessing, T.; Remy, J .-S.; Behr, J .-P. J . Am.
Chem. Soc. 1998, 120, 8519-8520. (f) Bergeron, R. J .; McMannis, J .
S. J . Org. Chem. 1988, 53, 3108-3111. (g) Ravikumar, V. T. Synth.
Commun. 1994, 24, 1767-1772.
(10) For some recent examples, see: (a) Ushio-Sata, N.; Matsunaga,
S.; Fusetani, N.; Honda, K.; Yasumuro, K. Tetrahedron Lett. 1996, 37,
225-228. (b) Osby, J . O.; Heinzman, S. W.; Ganem, B. J . Am. Chem.
Soc. 1986, 108, 67-72. (c) Dallaire, C.; Arya, P. Tetrahedron Lett. 1998,
39, 5129-5132. (d) Ushio-Sata, N.; Sugano, M.; Matsunaga, S.;
Fusetani, N. Tetrahedron Lett. 1999, 40, 719-722.
(11) For recent examples, see: (a) Kokotos, G.; Theodorou, V.;
Constantinou-Kokotou, V.; Gibbons, W. A.; Roussakis, C. Bioorg. Med.
Chem. Lett. 1998, 8, 1525-1530. (b) Constantinou-Kokotou, V.; Koko-
tos, G. Org. Prep. Proc. Int. 1994, 26, 599-602.
(12) For some recent examples, see: (a) Bergeron, R. J .; Burton, P.
S.; McGovern, K. A.; Kline, S. J . Synthesis 1981, 732-733. (b)
Kalivretenos, A. G.; Nakanishi, K. J . Org. Chem. 1993, 58, 6596-6608.
(13) Edwards, M. L.; Stemerick, D. M.; Bitonti, A. J .; Dumont, J .
A.; McCann, P. P.; Bey, P.; Sjoerdsma, A. J . Med. Chem. 1991, 34,
569-574.
(14) Krakowiak, K. E.; Bradshaw, J . S. J . Heterocycl. Chem. 1995,
32, 1639-1640.
(15) Heininger, S. A. J . Org. Chem. 1957, 22, 1213-1216.
(6) For some recent examples, see: (a) Huang, D.; Matile, S.; Berova,
N.; Nakanishi, K. Heterocycles 1996, 42, 723-736. (b) J asys, V. J .;
Kelbaugh, P. R.; Nason, D. M.; Phillips, D.; Rosnack, K. J . J . Am. Chem.
Soc. 1990, 112, 6696-6704.
(7) For some recent examples, see: (a) Sua´rez-Gea, M. L.; Garc´ıa-
Lo´pez, M. T.; Gonza´lez-Mun˜iz, R.; Herrero, S.; Herranz, R. Tetrahedron
Lett. 1996, 37, 2083-2084. (b) Bergeron, R. J .; Ludin, C.; Mueller, R.;
Smith, R. E.; Phanstiel, O. J . Org. Chem. 1997, 62, 3285-3290.
(8) For two recent examples, see: (a) Sakai, N.; Matile, S. Tetrahe-
dron Lett. 1997, 38, 2613-2616. (b) Xue, C.-B.; DeGrado W. F.
Tetrahedron Lett. 1995, 36, 55-58.
10.1021/jo005637f CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/03/2001

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2481
Michael addition product N1-(3-aminopropyl)-1,4-ben-
zenediamine in a 60:40 ratio. Attempted separation
resulted in decomposition. Replacing LiOH with other
bases, such as aqueous NH3, or omitting the base totally
caused formation of several side products.
Sch em e 1
In conclusion, we reported a highly efficient hydroge-
nation procedure for the reduction of nitriles to primary
amines, which can be carried out under atmospheric
hydrogen pressure using commercially available cata-
lysts. Both Boc groups and aromatic moieties present in
the starting material are well tolerated under the mild
optimized conditions. Therefore, this procedure should
complement available hydrogenation methods especially
for some more tedious cases.
When the nitrile 1f was shaken in a hydrogen atmo-
sphere (45 psi) at rt using a mixture of Pd/C and Raney-
nickel as catalyst in 1,4-dioxane/water (4:1) and LiOH
as base, the desired amine (2f) was formed within 20 h
in almost quantitative yield. 1,4-Dioxane was chosen as
inert solvent to suppress the formation of N-alkylated
byproducts, which were found with ethanol as solvent.
The presence of water was necessary as in the absence
of water virtually no reaction took place. Similarly,
neither Raney-nickel nor Pd/C alone affected any reaction
under a diversity of conditions. Other catalyst mixtures
such as Raney-nickel + PtO2 or Pd/C + PtO2 failed to
give the desired product. As aging of the catalyst might
be a factor in some cases,3 the hydrogenation was
performed with freshly purchased catalysts as well as
with at least 1-year-old catalysts without any change in
results. The choice of base might be less crucial, although
the rather weak base LiOH seems to be very well suited.
Reactions in acidic media were not investigated as
problems with partial deprotection, acylation, and salt
formation were expected. Finally, the hydrogenation over
palladium activated Raney-nickel was also carried out
successfully under atmospheric hydrogen pressure at 50
°C avoiding the use of a Parr hydrogenator. No formation
of any byproducts, such as secondary amines, aldehydes,
and amino alcohols, was observed under these conditions.
The optimized hydrogenation conditions (Scheme 1)
were successfully applied to the other cases. The aliphatic
nitriles 1c-g were cleanly reduced to the corresponding
amines 2c-g within 15-20 h and isolated in 85-95%
yield. While nitrile 1c could be reduced in the presence
and absence of additional Pd-catalyst without significant
changes in reaction time and yield, hydrogenation of
compounds 1d -g was only successful in the presence of
Pd.
Exp er im en ta l Section
Solvents and reagents were used as purchased. All new
compounds were characterized by their 1H, 13C, and MS data.
1H and 13C NMR data were recorded in CDCl3 (2b-g) or CD3-
OD (2h -j) on a 300 MHz NMR spectrometer using CHCl3 or
CH3OH as internal standard. Mass spectra were recorded at a
Platform II mass spectrometer (Micromass). Ionization was
achieved in the positive electrospray mode using a 1:1 solvent
mixture of acetonitrile and water or methanol as mobile phase
(ES-MS). High-resolution mass spectra were recorded by the
National Mass Spectrometry Service Centre in Swansea using
the same ionization procedure. Accurate mass measurement was
performed by peak matching. Combustion analyses were per-
formed by MEDAC LTD, Surrey, U.K. The synthesis of 2a by
hydrogenation over Raney-nickel5e and by hydride reduction
using NaBH4 + CoCl2‚6H2O10d has been reported previously
without analytical data. The synthesis of 2b16 and 2j17 by
hydrogenation over Raney-nickel has been reported previously
without experimental details.
N1,N4-Di(ter t-bu tyloxycar bon yl)-N1,N4-di(3-am in opr opyl)-
1,4-bu ta n ed ia m in e (2a ). Nitrile 1a (1.70 g, 4.31 mmol) was
dissolved in a mixture of absolute ethanol (80 mL) and THF (20
mL). Raney-nickel (2.1 g, 17.8 mmol) as a 50% suspension in
water was added together with NaOH (10 mL, 2 N solution in
water), and the reaction mixture was shaken under 45 psi
hydrogen pressure at room temperature for 8 h. The catalyst
was filtered off, the solvents were removed in vacuo, and a
mixture of water (100 mL) and CH2Cl2 (30 mL) was added. After
phase separation, the aqueous phase was extracted three times
with CH2Cl2 (30 mL), the combined organic layers were dried
over sodium sulfate, and the solvent was removed in vacuo.
Amine 2a (1.45 g, 84%) was obtained as yellow, highly viscous
oil: Rf (SiO2, 35% aq NH3/MeOH 1:10) 0.36; 1H NMR δ 3.21 (m,
4H), 3.14 (m, 4H), 2.66 (t, 4H, 3J ) 6.68 Hz), 1.68 (m, 4H, NH2),
1.61 (t, 4H, J ) 6.86 Hz), 1.50-1.38 (m, 4H), 1.42 (s, 18H); 13
C
3
NMR δ 155.8 (s), 79.4 (s), 46.6 (t), 44.0 (t), 39.2 (t), 31.8 (t), 25.6
t
(t), 28.5 (q); MS m/z 403 (M + H+, 30), 303 (M + 2H+ - CO2 -
+
Bu+, 12), 202 ((M + 2H+)/2, 65); HRMS calcd for C20H43N4O4
403.3284, found 403.3286. Column chromatography on SiO2
using Et3N/MeOH 1:10 as eluent afforded an analytically pure
sample. Anal. Calcd for C20H42N4O4: C, 59.67; H, 10.52; N, 13.92.
Found: C, 59.74; H, 10.24; N, 13.90.
The aromatic nitriles 1h and 1i were cleanly converted
into the amines 2h and 2i as indicated by ES-MS. 2h
and 2i are highly polar, very sensitive compounds, which
are hardly extracted into CH2Cl2, EtOAc, or toluene.
However, the crude products isolated after filtration and
removal of the solvents in vacuo gave satisfactory MS
N1,N7-Di(ter t-bu tyloxycar bon yl)-N1,N7-di(3-am in opr opyl)-
1,7-h ep ta n ed ia m in e (2b). Nitrile 1b (1.49 g, 3.41 mmol) was
dissolved in a mixture of absolute ethanol (80 mL) and THF (20
mL). Raney-nickel (0.8 g, 6.8 mmol) as a 50% suspension in
water was added together with NaOH (10 mL, 2 N solution in
water), and the reaction mixture was shaken under 45 psi
hydrogen pressure at room temperature for 8 h. The catalyst
was filtered off, the solvents were removed in vacuo, and a
mixture of water (100 mL) and CH2Cl2 (30 mL) was added. After
phase separation, the aqueous phase was extracted three times
1
and H and 13C NMR analysis, although they contained
large amounts of LiOH. All purification attempts by
cation-exchange chromatography on Dowex50WX2-200
or column chromatography on SiO2 and deactivated Al2O3
(basic, Brockmann grade V) with different alkaline and
neutral solvent mixtures resulted in complete decomposi-
tion. In the hydrogenation of nitrile 1j under identical
conditions two products were formed. The mixture was
(16) Tye, C.-K.; Kasinathan, G.; Barrett, M. P.; Brun, R.; Doyle, V.
E.; Fairlamb, A. H.; Weaver, R.; Gilbert, I. H. Bioorg. Med. Chem. Lett.
1998, 8, 811-816.
(17) Weinstock, L. T.; Rost, W. J .; Cheng, C. C. J . Pharm. Sci. 1981,
70, 956-959.
1
identified by MS and H and 13C NMR spectroscopy to
contain amine 2j and the hydrogenated mono-retro-

2482 J . Org. Chem., Vol. 66, No. 7, 2001
Notes
with CH2Cl2 (30 mL), the combined organic layers were dried
over sodium sulfate, and the solvent was removed in vacuo.
Amine 2b (1.21 g, 80%) was obtained as yellow, highly viscous
oil: Rf (SiO2, 35% aq NH3/MeOH 1:10) 0.38; 1H NMR δ 3.24 (m,
4H), 3.12 (m, 4H), 2.74 (t, 4H, 3J ) 6.60 Hz), 1.62 (m, 4H), 1.70-
N1,N2-Di(ter t-bu tyloxycar bon yl)-N1,N2-di(3-am in opr opyl)-
1,2-cycloh exa n ed ia m in e (2f). Nitrile 1f (500 mg, 1.19 mmol)
was dissolved in a mixture of dioxane (20 mL) and water (5 mL).
Raney-nickel (200 mg, 1.70 mmol) as a 50% suspension in water
and 10% palladium on charcoal (120 mg, 0.113 mmol) were
added together with lithium hydroxide monohydrate (150 mg,
3.57 mmol), and the reaction mixture was stirred under hydro-
gen atmosphere at 50 °C for 20 h. The catalysts were filtered
off, the solvents were removed in vacuo, and a mixture of water
(50 mL) and CH2Cl2 (25 mL) was added. After phase separation,
the aqueous phase was extracted twice with CH2Cl2 (15 mL),
the combined organic layers were dried over sodium sulfate, and
the solvent was removed in vacuo. Amine 2f (480 mg, 94%) was
obtained as colorless, highly viscous oil: Rf (SiO2, 35% aq NH3/
MeOH 1:10) 0.47; 1H NMR δ 4.11-3.97/3.85-3.56 (2m, 2H),
3.29-3.01/2.94-2.76 (2m, 4H), 2.61 (t, 4H, 3J ) 6.86 Hz), 1.93-
1.76 (m, 2H), 1.76-1.59 (m, 4H), 1.50-1.30 (m, 6H, NH among
here), 1.42 (s, 18H), 1.30-1.15 (m, 4H); 13C NMR δ 155.8 (s),
79.3 (s), 55.1 (d), 41.2 (t), 40.3 (t), 34.9 (t), 31.3 (t), 28.6 (q), 25.5
(t); MS m/z 429 (M + H+, 100), 329 (M - Boc + 2H+, 10); HRMS
calcd for C22H45N4O4+ 429.3441, found 429.3435. Column chro-
matography on SiO2 using Et3N/MeOH 1:10 as eluent afforded
an analytically pure sample. Anal. Calcd for C22H45N4O4: C,
61.65; H, 10.35; N, 13.07. Found: C, 61.27; H, 10.29; N, 12.88.
1.57 (m, 4H, NH2), 1.50-1.42 (m, 22H), 1.35-1.30 (m, 6H); 13
C
NMR δ 156.0 (s), 79.5 (s), 47.1 (t), 44.2 (t), 39.6 (t), 32.8 (t), 32.2
(t), 29.6 (t), 27.3 (t), 28.7 (q); MS m/z 467 (M + Na+, 23), 445 (M
+
+ H+, 100), 223 ((M + 2H+)/2, 30); HRMS calcd for C23H49N4O4
445.3754, found 445.3753.
N1,N9-Di(ter t-bu tyloxycar bon yl)-N1,N9-di(3-am in opr opyl)-
1,9-n on a n ed ia m in e (2c). Nitrile 1c (1.15 g, 2.48 mmol) was
dissolved in a mixture of dioxane (80 mL) and water (20 mL).
Raney-nickel (550 mg, 4.69 mmol) as a 50% suspension in water
and 10% palladium on charcoal (165 mg, 0.155 mmol) were
added together with lithium hydroxide monohydrate (225 mg,
5.36 mmol), and the reaction mixture was stirred under hydro-
gen atmosphere at 50 °C for 18 h. The catalyst was filtered off,
the solvents were removed in vacuo, and a mixture of water (100
mL) and CH2Cl2 (30 mL) was added. After phase separation,
the aqueous phase was extracted three times with CH2Cl2 (30
mL), the combined organic layers were dried over sodium sulfate,
and the solvent was removed in vacuo. Amine 2c (1.01 g, 86%)
was obtained as a yellow, highly viscous oil: Rf (SiO2, 35% aq
NH3/MeOH 1:10) 0.38; 1H NMR δ 3.22 (m, 4H), 3.10 (m, 4H),
2.64 (t, 4H, 3J ) 6.59 Hz), 1.61 (m, 4H), 1.68-1.55 (m, 4H, NH2),
1.42 (m, 22H), 1.24 (m, 10H); 13C NMR δ 155.9 (s), 79.3 (s), 47.0
(t), 44.5 (t), 43.9 (t), 39.5 (t), 39.3 (t), 32.7 (t), 31.9 (t), 29.7 (t),
29.4 (t), 28.6 (q), 27.0 (t); MS m/z 473 (M + H+, 20), 237 ((M +
2H+)/2, 30), 181 ((M + 3Na+)/3, 30), 159 ((M + 3H+)/3, 30), 137
N1,N4-Di(ter t-bu tyloxycar bon yl)-N1,N4-di(3-am in opr opyl)-
1,4-cycloh exa n ed ia m in e (2g). Nitrile 1g (1.67 g, 3.97 mmol)
was dissolved in a mixture of dioxane (40 mL) and water (10
mL). Raney-nickel (500 mg, 4.26 mmol) as a 50% suspension in
water and 10% palladium on charcoal (400 mg, 0.376 mmol) were
added together with lithium hydroxide monohydrate (450 mg,
10.7 mmol), and the reaction mixture was stirred under hydro-
gen atmosphere at 50 °C for 20 h. The catalysts were filtered
off, the solvents were removed in vacuo, and a mixture of water
(100 mL) and CH2Cl2 (30 mL) was added. After phase separation,
the aqueous phase was extracted four times with CH2Cl2 (30
mL), the combined organic layers were dried over sodium sulfate,
and the solvent was removed in vacuo. Amine 2g (1.53 g, 90%)
was obtained as yellow, highly viscous oil: Rf (SiO2, 35% aq NH3/
MeOH 1:10) 0.29; 1H NMR δ 3.54-3.24 (m, 2H), 3.20-2.97 (m,
4H), 2.68-2.48 (m, 4H), 1.72 (m, 4H, NH2), 1.59 (m, 8H), 1.47-
1.32 (m, 4H); 13C NMR δ 155.6 (s), 79.5 (s), 56.0 (d), 54.2 (d),
41.5 (t), 39.7 (t), 34.8 (t), 30.1 (t), 28.6 (q); MS m/z 429 (M + H+,
+
(100); HRMS calcd for C25H53N4O4 473.4067, found 473.4063.
N1,N12-Di(ter t-bu tyloxyca r bon yl)-N1,N12-d i(3-a m in op r o-
p yl)-1,12-d od eca n ed ia m in e (2d ). Nitrile 1d (800 mg, 1.58
mmol) was dissolved in a mixture of dioxane (20 mL) and water
(5 mL). Raney-nickel (200 mg, 1.70 mmol) as a 50% suspension
in water and 10% palladium on charcoal (165 mg, 0.155 mmol)
were added together with lithium hydroxide monohydrate (135
mg, 3.22 mmol), and the reaction mixture was stirred under
hydrogen atmosphere at 50 °C for 20 h. The catalysts were
filtered off, the solvents were removed in vacuo, and a mixture
of water (50 mL) and CH2Cl2 (25 mL) was added. After phase
separation, which was accelerated by addition of sodium chlo-
ride, the aqueous phase was extracted three times with CH2Cl2
(15 mL), the combined organic layers were dried over sodium
sulfate, and the solvent was removed in vacuo. Amine 2d (750
mg, 92%) was obtained as light yellow oil: Rf (SiO2, 35% aq NH3/
100), 329 (M - Boc + 2H+, 50); HRMS calcd for C22H45N4O4
429.3441, found 429.3445.
+
N1,N2-Di(3-a m in op r op yl)-1,2-ben zen ed ia m in e (2h ). Ni-
trile 1h (500 mg, 2.33 mmol) was dissolved in a mixture of
dioxane (20 mL) and water (5 mL). Raney-nickel (270 mg, 2.30
mmol) as a 50% suspension in water and 10% palladium on
charcoal (200 mg, 0.188 mmol) were added together with lithium
hydroxide monohydrate (200 mg, 4.77 mmol), and the reaction
mixture was stirred under hydrogen atmosphere at 50 °C for
20 h. The catalysts were filtered off and rinsed with a mixture
of dioxane (20 mL) and water (10 mL), and the solvents were
removed from the filtrate in vacuo. A mixture (530 mg) of LiOH
and amine 2h was obtained as a brownish highly viscous oil:
Rf (SiO2, 35% aq NH3/MeOH 1:10) baseline; 1H NMR δ 6.70-
6.59 (m, 4H), 3.13 (t, 4H, 3J ) 6.95 Hz), 2.76 (t, 4H, 3J ) 7.04
Hz), 1.80 (tt, 4H, 3J ) 6.95, 3J ) 7.04 Hz), NH exchanged; 13C
NMR δ 138.3 (s), 119.7 (d), 112.5 (d), 43.2 (t), 40.7 (t), 33.5 (t);
MS m/z 229 (M + Li+, 50), 223 (M + H+, 100); HRMS calcd for
1
MeOH 1:10) 0.40; H NMR δ 3.24 (m, 4H), 3.12 (m, 4H), 2.67-
2.59 (m, 4H), 1.85 (m, 4H, NH2), 1.63 (m, 4H), 1.55-1.38 (m,
4H), 1.44 (s, 18H), 1.25 (m, 16H); 13C NMR δ 156.0 (s) 155.7 (s),
79.2 (s), 47.0 (t), 44.1 (t), 39.2 (t), 32.0 (t), 29.7 (t), 29.6 (t) 29.5
(t), 28.5 (q), 27.0 (t); MS m/z 515 (M + H+, 100); HRMS calcd
for C28H59N4O4+ 515.4536, found 515.4540. Column chromatog-
raphy on SiO2 using Et3N/MeOH 1:10 as eluent afforded an
analytically pure sample. Anal. Calcd for C28H58N4O4: C, 65.33;
H, 11.36; N, 10.88. Found: C, 64.98; H, 11.19; N, 10.49.
N1,N2-Di(ter t-bu tyloxycar bon yl)-N1,N2-di(3-am in opr opyl)-
1,2-p r op a n ed ia m in e (2e). Nitrile 1e (500 mg, 1.31 mmol) was
dissolved in a mixture of dioxane (20 mL) and water (5 mL).
Raney-nickel (200 mg, 1.70 mmol) as a 50% suspension in water
and 10% palladium on charcoal (120 mg, 0.113 mmol) were
added together with lithium hydroxide monohydrate (170 mg,
4.05 mmol), and the reaction mixture was stirred under hydro-
gen atmosphere at 50 °C for 20 h. The catalysts were filtered
off, the solvents were removed in vacuo, and a mixture of water
(50 mL) and CH2Cl2 (25 mL) was added. After phase separation,
the aqueous phase was extracted twice with CH2Cl2 (15 mL),
the combined organic layers were dried over sodium sulfate, and
the solvent was removed in vacuo. Amine 2e (430 mg, 84%) was
obtained as a colorless, highly viscous oil: Rf (SiO2, 35% aq NH3/
MeOH 1:10) 0.36; 1H NMR δ 4.18-3.71 (m, 1H), 3.53-2.94 (m,
6H), 2.72-2.56 (m, 4H), 1.60 (m, 4H), 1.42 (s, 18H), 1.33 (s, 4H,
+
C12H23N4 223.1922, found 223.1926.
N1,N3-Di(3-a m in op r op yl)-1,3-ben zen ed ia m in e (2i). Nitrile
1i (500 mg, 2.33 mmol) was dissolved in a mixture of dioxane
(20 mL) and water (5 mL). Raney-nickel (270 mg, 2.30 mmol)
as a 50% suspension in water and 10% palladium on charcoal
(270 mg, 0.254 mmol) were added together with lithium hydrox-
ide monohydrate (200 mg, 4.77 mmol), and the reaction mixture
was stirred under hydrogen atmosphere at 50 °C for 20 h. The
catalysts were filtered off and rinsed with a mixture of dioxane
(20 mL) and water (10 mL), and the solvents were removed from
the filtrate in vacuo. A mixture (560 mg) of LiOH and amine 2i
was obtained as a brownish solid: Rf (SiO2, 35% aq NH3/MeOH
1:10) baseline; 1H NMR δ 6.88 (m, 1H), 6.14-5.99 (m, 1H), 6.02
(m, 2H), 3.09 (t, 4H, 3J ) 6.95 Hz), 2.72 (t, 4H, 3J ) 7.04 Hz),
1.74 (tt, 4H, 3J ) 6.95 Hz, 3J ) 7.04 Hz), NH exchanged; 13C
NMR δ 151.2 (s), 130.6 (d), 104.4 (d), 99.3 (d), 42.8 (t), 40.5 (t),
3
NH2), 1.13 (d, 3H, J ) 6.40 Hz); 13C NMR δ 155.6 (s), 79.7 (s),
52.6 (d), 51.7 (d), 50.8 (d), 49.9 (t), 49.1 (t), 45.5 (t), 44.9 (t), 44.2
(t), 43.8 (t), 43.5 (t), 40.0 (t), 39.7 (t), 39.4 (t), 34.3 (t), 33.5 (t),
32.7 (t), 31.9 (t), 28.6 (q), 17.2 (q), 16.2 (q); MS m/z 411 (M +
Na+, 36), 389 (M + H+, 60), 195 ((M + 2H+)/2, 12); HRMS calcd
+
for C19H41N4O4 389.3128, found 389.3131.

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2483
33.5 (t); MS m/z 229 (M + Li+, 30), 223 (M + H+, 100), 112 ((M
NH3/MeOH 1:10); 1H NMR δ 2j (60%) 6.63 (m, 4H), 3.06 (t, 4H,
3J ) 7.01 Hz), 2.71 (t, 4H, 3J ) 7.04 Hz), 1.73 (tt, 4H, 3J ) 7.04,
+
+ 2H+)/2, 15); HRMS calcd for C12H23N4 223.1922, found
3
223.1924.
6.95 Hz); byp r od u ct (40%) 6.63 (m, 4H), 3.06 (t, 2H, J ) 7.01
N1,N4-Di(3-a m in op r op yl)-1,4-ben zen ed ia m in e (2j) a n d
N1-(3-Am in op r op yl)-1,4-ben zen ed ia m in e (Byp r od u ct). Ni-
trile 1j (500 mg, 2.33 mmol) was dissolved in a mixture of
dioxane (20 mL) and water (5 mL). Raney-nickel (270 mg, 2.30
mmol) as a 50% suspension in water and 10% palladium on
charcoal (200 mg, 0.188 mmol) were added together with lithium
hydroxide monohydrate (100 mg, 2.38 mmol), and the reaction
mixture was stirred under hydrogen atmosphere at 50 °C for
20 h. The catalysts were filtered off and rinsed with a mixture
of dioxane (20 mL) and water (10 mL), and the solvents were
removed from the filtrate in vacuo. A mixture (560 mg) of LiOH,
amine 2j, and a byproduct (N1-(3-a m in op r op yl)-1,4-ben zen e-
d ia m in e) was obtained as a brownish solid: Rf (SiO2, 35% aq
Hz), 2.71 (t, 2H, 3J ) 7.04 Hz), 1.73 (tt, 2H, 3J ) 7.04, 6.95 Hz),
NH exchanged; 13C NMR 2j δ 142.5 (s), 116.8 (d), 44.5 (t), 40.5
(t), 33.5 (t), byp r od u ct δ 143.2 (s), 139.5 (s), 118.6 (d), 116.6
(d), 44.9 (t), 40.9 (t), 33.9 (t); MS m/z 229 (M2j + Li+, 25), 223
(M2j + H+, 100), 166 (Mbyp r od u ct + H+, 45).
Ack n ow led gm en t. We would like to thank the
Wellcome Trust for funding and the EPSRC National
Mass Spectrometry Service Centre, which carried out
accurate mass determinations.
J O005637F