Preparation of mono Boc-protected unsymmetrical diamines

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Preparation of Mono Boc-Protected
Unsymmetrical Diamines
Hongbo Li a , Meng-an Hao a , Liping Wang a , Wu Liang a & Kai Chen
a
a College of Material Science and Engineering, Southwest University
of Science and Technology, Mianyang, Sichuan, P. R. China
Version of record first published: 10 Jul 2009.
To cite this article: Hongbo Li, Meng-an Hao, Liping Wang, Wu Liang & Kai Chen (2009): Preparation
of Mono Boc-Protected Unsymmetrical Diamines, Organic Preparations and Procedures International:
The New Journal for Organic Synthesis, 41:4, 301-307
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Organic Preparations and Procedures International, 41:301–307, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903077998
Preparation of Mono Boc-Protected
Unsymmetrical Diamines
Hongbo Li, Meng-an Hao, Liping Wang, Wu Liang, and Kai Chen
College of Material Science and Engineering, Southwest University of Science
and Technology Mianyang, Sichuan, P. R. China
Monofunctionalized unsymmetrical diamines have been frequently used as starting mate-
rials in the synthesis of biological active agents and pharmacophores.1–6 There have been
some reports that chemical and biological chip production requires monofunctionalized
diamines to hold functional molecules at the one end while the other end is free to be
attached on the solid surface,1,7–9 thus requiring a simple and efficient procedure for the
preparation of mono-protected unsymmetrical diamines. Among the large number of pro-
tective groups for amino functions, the tert-butoxycarbonyl (Boc) group is among the most
important,10 because it can readily be removed with anhydrous hydrogen chloride gas or
trifluoroacetic acid. Herein we report a facile synthetic route for preparation of mono-Boc-
protected mixed primary-secondary amines by a procedure, which is cost-effective and
applicable on a multigram scale (Schemes 1 and 2).
H
RNH2, KI
EtOH
Boc2O, Et3N
MeOH
NHBoc
N
Boc
NH2 HBr
Br
R
N
Br
n
n
n
H
1
2
3
n = 1 a) R = CH3; b) R = CH2CH3; c) R = CH(CH3)2; d) R = CH2C6H5
n = 2 e) R = CH3
Scheme 1
The synthesis of N1-alkyl-N2-(Boc)-protected diamines 3a–3e is outlined in Scheme 1.
Treatment of 2-bromoethylamine hydrobromide (1a) or 3-bromopropylamine hydrobro-
mide (1e) with Boc2O and Et3N in MeOH led to satisfactory yields of the N-(Boc)-2-
bromo-ethylamine 2a and N-(Boc)-3-bromopropylamine 2e (85–95%), which were thus
treated with excess aliphatic amines to afford 3a–3e (75–82%) in high purity as shown by
1H NMR analysis.
Received November 8, 2008; in final form March 27, 2009.
Address correspondence to Hongbo Li, College of Material Science and Engineering, Southwest
University of Science and Technology, Mianyang 621010, Sichuan, P. R. China. E-mail: li-honggg@
163.com
301

302
Li et al.
O
H
N
H
N
(Boc)2O
MeOH
Phthalic anhydride
H2O
R
R
NH2
N
n
n
4
O
5
O
Boc
N
Boc
N
H2O
NH2NH2
R
N
R
NH2
n
n
MeOH
6
O
7
n = 1 a) R = CH3 ; b) R = CH2CH3 ; c) R = CH(CH3)2 ; d) R = CH2C6H5
n = 2 e) R = CH3
Scheme 2
The synthesis of N1-alkyl-N1-(Boc)-protected diamines 7a–7e is outlined in Scheme 2.
Treatment of N-alkyl-1,2-ethanediamines 4a–4d or N-methyl-1,3-propanediamine 4e with
phthalic anhydride in H2O led to good yields of phthalimido derivatives 5a–5d or 5e
(70–80%). Reaction of these compounds with (Boc)2O in MeOH afforded the N-(Boc)-
phthalimido derivatives 6a-6e (58–68%). The conversion of 6 to the desired N-(Boc)-
diamines 7a–7e (81–87%) was accomplished by treatment with hydrazine hydrate in MeOH
at room temperature. The products obtained were quite pure as shown by 1H NMR analysis.
Experimental Section
Mps were determined on a Yanaco MP-500 micro-melting point apparatus and are uncor-
rected. IR spectra were recorded neat or as KBr pellets on a Nicolet-1705X IR spectrometer.
1H NMR spectra were acquired on a Bruker AC-200MHz in CDCl3 using Me4Si as internal
standard. Mass spectra were obtained on a Finnigan MAT 4510 spectrometer. Elemen-
tal analyses were determined on a Carlo Erbo-1160 elemental analyzer. Silica gel (200–
300 mesh, Qingdao, China) was used for flash column chromatographies. All of the reagents
and solvents were obtained commercially and used without further purification.
N-tert-Butoxycarbonyl-2-bromoethylamine (2a). Representative Procedure.
A solution of (Boc)2O (20.5 g, 94 mmol) in MeOH (60 mL) was added over a period of 0.5 h
to a solution of 2-bromoethylamine hydrobromide (1a, 12.3 g, 60 mmol), Et3N (10.1 g,
100 mmol) in MeOH (60 mL). The mixture was stirred for 18 h at room temperature. Then
the reaction mixture was concentrated to dryness in vacuo to give a residue, which was
added water (100 mL), extracted with CH2Cl2 (3 × 30 mL). The combined extract was dried
(MgSO4) and concentrated to dryness. Column chromatography (silica gel, hexane/EtOAc,
1
8:1) to afford 2a (11.9 g, 89%) as a colorless oil. H NMR: δ 1.43 [s, 9H, C(CH3)3],
3.45–3.57 (m, 4H, CH2-CH2), 4.97(br. s, 1H, NH); IR (neat): 3312, 2973, 1675, 1250,
735 cm−1; MS (m/z): 224(M+).

Preparation of Mono Boc-Protected Unsymmetrical Diamines
303
Anal. Calcd for C7H14BrNO2: C, 37.52; H, 6.30; N, 6.25. Found: C, 37.49; H, 6.23;
N, 6.34.
N-tert-Butoxycarbonyl-3-bromopropylamine (2e), mp. 38–40◦C, lit.11 mp.
38–39◦C, was obtained as a colorless oil in 95% yield from 3-bromopropylamine hy-
drobromide (1e) using a method similar to that for 2a; 1H NMR: δ 1.44 [s, 9H, C(CH3)3],
2.09(m, 2H, CH2-CH2-CH2), 3.24(m, 2H, CH2-NH), 3.46 (t, 2H, BrCH2), 4.59 (br. s, 1H,
NH); IR (neat): 3350, 2982, 1670, 1255, 728 cm−1; MS (m/z): 238(M+).
Anal. Calcd for C8H16BrNO2: C, 40.33; H, 6.77; N, 5.88. Found: C, 40.53; H, 6.59;
N, 5.73.
N1-tert-Butoxycarbonyl-N2-methyl-1,2-ethanediamine (3a). Representative Procedure.
To a solution of 2a (18.6 g, 83 mmol) in EtOH (100 mL), methylamine (16 mL, 40% w/v,
187 mmol) and KI (0.3 g, 1.8 mmol) as catalyst were added. Then the mixture was heated
to 50◦C till 2a was completely consumed. The solution was concentrated in vacuo and then
extracted with CH2Cl2 (3 × 30 mL). The organic phase was dried (MgSO4) and removal
of the solvent gave 3a (11.7 g, 81%) as a colorless oil. 1H NMR: δ 1.46 [s, 9H, C(CH3)3],
2.40 (s, 3H,CH3-NH), 2.78 (t, 2H, NH-CH2), 3.23 (t, 2H, CH2-NHBoc), 4.97 (br. s, 1H,
NH); IR (neat): 3400, 2960, 1660, 1250, 739 cm−1; MS (m/z): 174(M+).
Anal. Calcd for C8H18N2O2: C, 55.15; H, 10.41; N, 16.08. Found: C, 55.25; H, 10.61;
N, 16.17.
In the case of 3b–3d, methylamine was replaced by ethylamine, iso-propylamine and
benzylamine respectively. Compound 3e was prepared from the reaction of methylamine
with 2e.
N1-tert-Butoxycarbonyl-N2-ethyl-1,2-ethanediamine (3b), mp. 54–56◦C, lit. 12 mp.
54–55◦C, recrystallized from pentane with cooling in a freezer to give a colorless solid
1
(80%). H NMR: δ 1.07 (t, 3H, CH3-CH2), 1.39 [s, 9H, C(CH3)3], 2.50–2.76 (m, 4H,
CH2-NH-CH2), 3.17 (m, 2H, CH2-NHBoc), 5.02 (br. s, 1H, NH); IR (neat): 3380, 2950,
1660, 1250, 735 cm−1; MS (m/z): 188(M+).
Anal. Calcd for C9H20N2O2: C, 57.42; H, 10.71; N, 14.88. Found; C, 57.32; H, 10.77;
N, 14.91.
N1-tert-Butoxycarbonyl-N2-iso-propyl-1,2-ethanediamine (3c), 78% yield as a col-
1
orless oil; H NMR: δ 1.04 [d, 6H, (CH3)2CH], 1.39 [s, 9H, C(CH3)3], 2.65 (t, 2H,
NH-CH2), 2.82 [spet, 1H, (CH3)2CH], 3.12 (t, 2H, CH2-NHBoc), 5.67 (br. s, 1H, NH); IR
(neat): 3370, 2960, 1670, 1245, 743 cm−1; MS (m/z): 206(M+).
Anal. Calcd for C10H22N2O2: C, 58.22; H, 10.75; N, 13.58. Found: C, 58.29; H, 10.87;
N, 13.45.
N1-tert-Butoxycarbonyl-N2-benzyl-1,2-ethanediamine (3d), 75% yield as a color-
1
less oil; H NMR: δ1.40 [s, 9H, C(CH3)3], 2.81–3.08 (m, 4H, CH2-CH2), 3.93 (s, 2H,
Ph-CH2), 7.24–7.26 (m, 5H, Ph-H), 6.02 (br s, 1H, NH); IR (neat): 3370, 3010, 2930, 1656,
1613, 1576, 1508, 1255, 745 cm−1; MS (m/z): 250(M+).
Anal. Calcd for C14H22N2O2: C, 67.17; H, 8.86; N, 11.19. Found; C, 67.37; H, 8.96;
N, 11.09.
N1-tert-Butoxycarbonyl-N2-methyl-1,3-propanediamine (3e), 82% yield as a col-
orless oil; 1H NMR: δ 1.40 [s, 9H, C(CH3)3], 1.67 (m, 2H, CH2-CH2-CH2), 2.47 (s, 3H,

304
Li et al.
CH3-NH), 2.81 (t, 2H, NH-CH2), 3.29 (t, 2H, CH2-NHBoc), 4.95 (br. s, 1H, NH); IR (neat):
3400, 2963, 1661, 1250, 728 cm−1; MS (m/z): 188(M+).
Anal. Calcd for C9H20N2O2: C, 57.42; H, 10.71; N, 14.88. Found: C, 57.52; H, 10.53;
N, 14.94.
N1-Methyl-N2-phthalyl-1,2-ethanediamine (5a). Representative Procedure.
Phthalic anhydride (12.0 g, 81 mmol) was added to a solution of N-methyl-1,2-
ethanediamine 4a (5.8 g, 78 mmol) in water (80 mL). The mixture was stirred at 100◦C for
3 h. The solvent was distilled off in vacuo and acetone (60 mL) was added to the resulting
residue. The insoluble solid was removed by filtration and the filtrate was concentrated to
dryness. The residue was recrystallized from isopropanol and dried to yield 5a (12.8 g,
80%) as a white solid. mp. 187–189◦C, lit. 13 mp. 187.5–189◦C; 1H NMR: δ 1.92 (br. s, 1H,
NH), 2.66 (s, 3H, CH3), 3.33 (m, 2H, NH-CH2), 3.86 (m, 2H, NH-CH2-CH2), 7.70–7.85
(m, 4H, Ar-H); IR (KBr): 3400, 3017, 2950, 1662, 1600, 1580, 1520, 743 cm−1; MS (m/z):
204(M+).
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.81; H, 6.12;
N, 13.54.
Compounds 5b–5e were prepared and purified as in the procedure for 5a.
N1-Ethyl-N2-phthalyl-1,2-ethanediamine (5b), 74% yield as a white solid, mp.
1
232–235◦C, lit.14 mp. 232–234◦C; H NMR: δ 1.67 (s, 3H, CH3), 1.95 (br. s, 1H, NH),
2.53–2.74 (m, 4H, CH2-NH-CH2), 3.47 (t, 2H, NH-CH2-CH2), 7.65–7.80 (m, 4H, Ar-H);
IR (KBr): 3420, 3020, 2970, 1665, 1603, 1585, 1510, 752 cm−1; MS (m/z): 218(M+).
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C, 66.14; H, 6.57;
N, 12.66.
N1-iso-Propyl-N2-phthalyl-1,2-ethanediamine (5c), 79% yield as a white solid, mp.
14
1
192–193◦C, lit. mp. 192–193◦C; H NMR: δ 1.12 [d, 6H, (CH3)2CH], 1.89 (br. s, 1H,
NH), 2.64 (m, 2H, NH-CH2), 2.78 [spet, 1H, (CH3)2CH], 3.83 (m, 2H, NH-CH2-CH2),,
7.70–7.82 (m, 4H, Ar-H); IR (KBr): 3425, 3033, 2950, 1666, 1606, 1576, 1500, 745 cm−1
MS (m/z): 232(M+).
;
Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.34; H, 6.88;
N, 12.22.
N1-Benzyl-N2-phthalyl-1,2-ethanediamine (5d), 70% yield as a white solid, mp.
245–247◦C; 1H NMR: δ 1.99 (br. s, 1H, NH), 2.75 (m, 2H, NH-CH2), 3.86 (m, 2H, NH-
CH2-CH2), 4.01 (s, 2H, Ph-CH2), 7.16–7.30 (m, 5H, Ph-H), 7.69–7.85 (m, 4H, Ar-H); IR
(KBr): 3440, 3035, 2941, 1665,,1603, 1585, 1507, 761 cm−1; MS (m/z): 280(M+).
Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.71; H, 5.79; N,
9.89.
N1-Methyl-N2-phthalyl-1,3-propanediamine (5e), 72% yield as a white solid, mp.
15
1
204–206◦C, lit. mp. 204–207◦C; H NMR: δ 1.25 (br. s, 1H, NH), 1.69 (m, 2H, CH2-
CH2-CH2), 2.60 (s, 3H, CH3-NH), 2.75 (m, 2H, NH-CH2), 3.91 (m, 2H, CH2-CH2-N),
7.68–7.85 (m, 4H, Ar-H); IR (KBr): 3430, 3028, 2930, 1658, 1600, 1570, 1520, 730 cm−1
MS (m/z): 218(M+).
;
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C, 66.14; H, 6.41;
N, 12.75.

Preparation of Mono Boc-Protected Unsymmetrical Diamines
305
N1-tert-Butoxycarbonyl-N1-methyl-N2-phthalyl-1,2-ethanediamine (6a).
Representative Procedure.
A solution of (Boc)2O (11.8 g, 54 mmol) in MeOH (30 mL) was added dropwise over 1 h
to a solution of 5a (5.5 g, 27 mmol) in MeOH (20 mL). The mixture was stirred at 45◦C for
36 h, then concentrated to dryness. The solid obtained was washed with MeOH (20 mL)
and warm (50◦C) water (2 × 15 mL), dissolved in acetone, dried (MgSO4) and evaporated
in vacuo. The residue was recrystallized from acetone/water to give 6a (5.6 g, 68%) as a
white solid. mp. 94–96◦C, lit. 12 mp. 94–95◦; 1H NMR: δ 1.23 [s, 9H, C(CH3)3], 2.84 (s,
3H, CH3-NBoc), 3.47 (m, 2H, NBoc-CH2), 3.80 (m, 2H, CH2-CH2-N), 7.70–7.88 (m, 4H,
Ar-H); IR (KBr): 3080, 2970, 1654, 1600, 1578, 1500, 741cm−1; MS (m/z): 304(M+).
Anal. Calcd for C16H20N2O4: C, 63.21; H, 6.63; N, 9.21. Found: C, 63.14; H, 6.74; N,
9.11.
The analogues 6b–6e were prepared and purified as in the procedure given for 6a.
N1-tert-Butoxycarbonyl-N1-ethyl-N2-phthalyl-1,2-ethanediamine (6b), 65% yield
as a white solid, mp. 50–52◦C, lit. 12 mp. 50–52◦C; 1H NMR: δ 1.00 (m, 3H, CH3-CH2),
1.26 [s, 9H, C(CH3)3], 3.21 (m, 2H, CH3-CH2), 3.43 (m, 2H, NBoc-CH2), 3.72 (t, 2H,
CH2-CH2-N), 7.63–7.81 (m, 4H, Ar-H); IR (KBr): 3075, 2974, 1647, 1604, 1582, 1509,
752 cm−1; MS (m/z): 318(M+).
Anal. Calcd for C17H22N2O4: C, 64.13; H, 6.97; N, 8.80. Found: C, 64.27; H, 6.75; N,
8.91.
N1-tert-Butoxycarbonyl-N1-iso-propyl-N2-phthalyl-1,2-ethanediamine (6c), 61%
1
yield as a white solid, mp. 82–83◦C; H NMR: δ 1.01 [d, 6H, (CH3)2CH], 1.27[s, 9H,
C(CH3)3], 2.67 [spet, 1H, (CH3)2CH], 3.20 (m, 2H, NBoc-CH2), 3.82 (m, 2H, CH2-CH2-
N), 7.70–7.82 (m, 4H, Ar-H); IR (KBr): 3030, 2944, 1646, 1601, 1577, 1504, 745 cm−1
MS (m/z): 332(M+).
;
Anal. Calcd for C18H24N2O4: C, 65.04; H, 7.28; N, 8.43. Found: C, 65.24; H, 7.04; N,
8.56.
N1-tert-Butoxycarbonyl-N1-benzyl-N2-phthalyl-1,2-ethanediamine (6d), 58%
12
1
yield as a white solid, mp. 111–112◦C, lit. mp. 111–113◦C; H NMR: δ 1.34 [s, 9H,
C(CH3)3], 3.54 (m, 2H, NBoc-CH2), 3.75 (m, 2H, CH2-CH2-N), 4.39 (t, 2H, Ph-CH2),
7.16–7.26 (m, 5H, Ph-H), 7.69–7.82 (m, 4H, Ar-H); IR (KBr): 3025, 2932, 1636, 1611,
1580, 1500, 748 cm−1; MS (m/z): 380(M+).
Anal. Calcd for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36. Found: C, 69.57; H, 6.28; N,
7.25.
N1-tert-Butoxycarbonyl-N1-methyl-N2-phthalyl-1,3-propanediamine (6e), 64%
1
yield as a white solid, mp. 74–76◦C; H NMR: δ 1.24 [s, 9H, C(CH3)3], 1.86 (m, 2H,
CH2-CH2-CH2), 3.14 (s, 3H, CH3-NBoc), 3.36 (m, 2H, NHBoc-CH2), 3.74 (m, 2H, CH2-
CH2-N), 7.73–7.89 (m, 4H, Ar-H); IR (KBr): 3018, 2976, 1635, 1607, 1569, 1511, 727
cm−1; MS (m/z): 318(M+).
Anal. Calcd for C17H22N2O4: C, 64.13; H, 6.97; N, 8.80. Found: C, 64.23; H, 6.90; N,
8.70.
N1-tert-Butoxycarbonyl-N1-methyl-1,2-ethanediamine (7a).
Representative Procedure.
Hydrazine hydrate (9.2 g, 80% w/w, 150 mmol) was added dropwise to a solution of 6a
(23.6 g, 78 mmol) in MeOH (100 mL) at 60◦C for 0.5 h. Then the mixture was stirred at

306
Li et al.
reflux for 4 h. After cooling to 25◦C, the solution was filtered to remove insoluble materials
and the filtrate was concentrated to dryness in vacuo to give an oily residue, to which
was added water (30 mL), and then extracted with CH2Cl2 (3 × 30 mL). The combined
extract was dried (Na2SO4) and concentrated to dryness. Column chromatography (silica
gel, MeOH/CH2Cl2, 1:8) to afford 7a (11.5 g, 85%) as a colorless oil. 1H NMR: δ 1.26 (br.
s, 2H, NH2), 1.48 [s, 9H, C(CH3)3], 2.76 (t, 2H, CH2-NH2), 2.85 (s, 3H, CH3-NBoc), 3.29
(t, 2H, NBoc-CH2); IR (neat): 2970, 1655, 1260, 735 cm−1; MS (m/z): 174(M+).
Anal. Calcd for C8H18N2O2: C, 55.15; H, 10.41; N, 16.08. Found: C, 55.27; H, 10.48;
N, 16.01.
Compounds 7b–7e were prepared via similar procedure given for 7a.
N1-tert-Butoxycarbonyl-N1-ethyl-1,2-ethanediamine (7b), 85% yield as a colorless
oil; 1H NMR: δ 1.10 (t, 3H, CH3-CH2), 1.21 (br s, 2H, NH2), 1.42 [s, 9H, C(CH3)3], 2.83
(t, 2H, CH2-NH2), 3.27 (m, 4H, CH2-NBoc-CH2,); IR (neat): 2957, 1646, 1255, 734 cm−1
MS (m/z): 188(M+).
;
Anal. Calcd for C9H20N2O2: C, 57.42; H, 10.71; N, 14.88. Found; C, 57.30; H, 10.82;
N, 14.96.
N1-tert-Butoxycarbonyl-N1-isopropyl-1,2-ethanediamine (7c), 83% yield as a col-
orless oil; 1H NMR: δ 1.15 [d, 6H, (CH3)2CH], 1.30 (br. s, 2H, NH2), 1.44 [s, 9H, C(CH3)3],
2.70 (t, 2H, CH2-NH2), 2.80 [spet, 1H, (CH3)2CH], 3.25 (t, 2H, NBoc-CH2); IR (neat):
2950, 1645, 1257, 734 cm−1; MS (m/z): 206(M+).
Anal. Calcd for C10H22N2O2: C, 58.22; H, 10.75; N, 13.58. Found: C, 58.03; H, 10.62;
N, 13.69.
N1-tert-Butoxycarbonyl-N1-benzyl-1,2-ethanediamine (7d), 81% yield as a color-
less oil; 1H NMR: δ 1.36 (br. s, 2H, NH2), 1.44 [s, 9H, C(CH3)3], 2.71 (m, 2H, CH2-NH2),
3.29 (m, 2H, CH2-NH2), 4.52 (s, 2H, Ph-CH2), 7.24–7.29 (m, 5H, Ph-H); IR (neat): 3020,
2943, 1640, 1603, 1575, 1490, 1240, 738 cm−1; MS (m/z): 250(M+).
Anal. Calcd for C14H22N2O2: C, 67.17; H, 8.86; N, 11.19. Found; C, 67.10; H, 8.74;
N, 11.35.
N1-tert-Butoxycarbonyl-N1-methyl-1,3-propanediamine (7e), 87% yield as a col-
1
orless oil; H NMR: δ 1.25 (br. s, 2H, NH2), 1.45 [s, 9H, C(CH3)3], 1.51–1.65 (m, 2H,
CH2-CH2-CH2), 2.76 (t, 2H, CH2-NH2), 2.90 (s, 3H, CH3-NBoc), 3.15 (t, 2H, NBoc-CH2);
IR (neat): 2973, 1658, 1243, 726 cm−1; MS (m/z): 188(M+).
Anal. Calcd for C9H20N2O2: C, 57.42; H, 10.71; N, 14.88. Found: C, 57.53; H, 10.60;
N, 14.76.
Acknowledgements
Financial support by China Sichuan Provincial Department of Science & Technology (No.
2006J13-143) and Project of SWUST (No. 053115) are gratefully acknowledged.
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