1694 J . Org. Chem., Vol. 67, No. 5, 2002
Notes
2,5-Dim eth yl-1,6-bis(p h th a lim id o)-2,5-h exa n ed iol (5b).
Using 4b9b (2.56 g, 18 mmol) and the general procedure, 5b
(white solid) was obtained as a mixture of diastereomers (2.5:1,
13C NMR analysis): yield 1.96 g (25%); mp 222-226 °C; Rf 0.36
(2:1 EtOAc/hexanes); IR (KBr) 3468, 2933, 1767 (sh), 1710, 1421,
1388, 1318, 1042, 719 cm-1; 1H NMR (DMSO-d6) δ 1.04 (s, 6 H),
1.53 (s, 4 H), 3.48-3.58 (m, 4 H), 4.37, 4.38 (2 s, 2 H), 7.80-
7.96 (m, 8 H); 13C NMR (DMSO-d6) δ 25.0, 33.5, 33.6, 47.8, 71.6,
122.9, 131.7, 134.2, 168.2; the other signals were not detected
and are believed to overlap with the observed peaks; the 13C
NMR data are in agreement with the DEPT spectrum; MS (+CI)
m/z 437 [M + 1]+; Mr (+CI) 437.17172 [M + 1]+ (calcd for
6.7) for 2a indicated that the two isomers had comparable
energy, in agreement with the corresponding energy
(computational, thermodynamic) values reported for 1,3-
dimethylcyclopentanes23,24 and the thermodynamic mea-
surements for 2,5-dialkyltetrahydrofurans.16c Similarly,
we learned that the cis-to-trans ratio for crude tetrahy-
dropyran salt 2c was 5.5:1, a finding predicted by the
energy minimization calculations (Tripos, Sybyl 6.7) for
2c and the reported thermodynamic measurements for
1,3-dimethylcyclohexanes.24,25 The observed diastereo-
meric ratios for 2a and 2c likely reflect the thermody-
namic consequences of the bis(aminomethyl) substituents
in five-memberd puckered16c and six-membered chair25
conformations, respectively.
In summary, we report a novel, concise method (Scheme
1) for the construction of cyclic diamines bridged by an
ether unit. This is a general preparative route for
medium-sized ether ring diamines, employs commercially
available dienes as starting materials, provides moderate
overall yields of cyclic ether diamine salts in three steps,
and is compatible with a wide range of ring substitution
patterns.
C
24H25N2O6 437.17126).
1,7-Bis(ph th alim ido)-2,6-h eptan ediol (5c). Using 4c9b (2.31
g, 18 mmol) and the general procedure, 5c (white solid) was
obtained as a mixture of diastereomers (2:1, 13C NMR analy-
sis): yield 3.57 g (47%); mp 165-170 °C; Rf 0.28 (2:1 EtOAc/
hexanes); IR (KBr) 3533, 2933, 1771 (sh), 1718, 1430, 1395, 1048,
721 cm-1; 1H NMR (DMSO-d6) δ 1.25-1.70 (m, 6 H), 3.41-3.58
(m, 4 H), 3.74 (br s, 2 H), 4.84-4.87 (m, 2 H), 7.81-7.88 (m, 8
H); 13C NMR (DMSO-d6) δ 21.2, 21.3, 34.3, 44.1, 67.1, 122.8,
131.7, 134.1, 167.9; the other signals were not detected and are
believed to overlap with the observed peaks; MS (+CI) m/z 423
[M + 1]+; Mr (+CI) 423.15639 [M + 1]+ (calcd for C23H23N2O6
423.15561).
Gen er a l P r oced u r e for th e P r ep a r a tion of Cyclic Eth er
Dia m in e Hyd r obr om id e Sa lts 2. Bis(phthalimido)alkanediol
5 (2.7 mmol) and aqueous 48% HBr (38 mL) were heated (70-
125 °C) for 2-27 d. After completion of reaction, the reaction
mixture was cooled to 4 °C (1 h) and then the precipitate
removed by filtration. The aqueous filtrate was washed with
Et2O (2 × 20 mL) and concentrated in vacuo to give 2.
2,5-Bis(a m in om eth yl)tetr a h yd r ofu r a n Dih yd r obr om id e
(2a ).3,7 Meth od A. Using 5a (1.10 g, 2.7 mmol) and the general
procedure (90 °C, 10 d), crude 2a (yellow solid) was obtained as
a mixture of diastereomers (1.2:1, 1H NMR analysis): yield 0.79
g (∼100%); mp > 230 °C dec; IR (KBr) 3029, 1696, 1575, 1503,
1401, 1053, 1015, 967, 918, 788 cm-1; 1H NMR (CD3OD) δ 1.73-
1.83 (m, 2 H), 2.17-2.26 (m, 2 H), 2.95-3.21 (m, 4 H), 4.20-
4.37 (m, 2 H); 13C NMR (CD3OD) δ 29.6, 29.8, 44.2, 44.9, 76.8,
77.5; the 1H and 13C NMR data are in agreement with the COSY,
HMQC, and DEPT spectra; MS (+CI) m/z 131 [M + 1]+; Mr (+CI)
131.11850 [M + 1]+ (calcd for C6H15N2O 131.11844). A sample
(104 mg) was further purified by recrystallization (EtOH-Et2O)
to give 2a (21 mg) as a mixture of diastereomers (1.2:1, 13C NMR
analysis). Anal. Calcd for C6H16Br2N2O: C, 24.68; H, 5.52; N,
9.59. Found: C, 24.66; H, 5.36; N, 9.48.
Exp er im en ta l Section
1H and 13C NMR spectra were recorded on a General Electric
QE-300 spectrometer. Mass spectrometry (MS) data were ob-
tained by Dr. Mehdi Moini at the University of Texas at Austin.
The low-resolution MS studies were run on a Finnegan TSQ-70
triple quadrupole mass spectrometer, and the high-resolution
MS studies were conducted on
a Micromass ZAB-E mass
spectrometer. FT-IR spectra were run on a Mattson Galaxy
Series FT-IR 5000 spectrometer. Melting points were determined
in open capillary tubes using a Thomas-Hoover melting point
apparatus and are uncorrected. Microanalyses were provided by
Atlantic Microlab, Inc. (Norcross, GA).
Gen er a l P r oced u r e for th e P r ep a r a tion of Diep oxid es
4.9a,b To a stirred solution of diene 3 (8.4 mmol) in dry CH2Cl2
(17 mL) was added m-chloroperbenzoic acid (m-CPBA; 5.30 g,
68% by wt, 21.0 mmol) at 4 °C in four portions. The reaction
was maintained at either 4 °C or rt (3-24 h), then H2O (15 mL)
was added, and the mixture was extracted with CH2Cl2 (2 × 15
mL). The combined organic layers were washed with aqueous
1.0 N KOH (3 × 25 mL), dried (MgSO4), and concentrated to
give the diepoxide 4, which was used without further purifica-
tion.
Gen er a l P r oced u r e for th e P r ep a r a tion of Bis(p h th a l-
im id o)a lk a n ed iols 5. To a DMF (11 mL) solution of phthal-
imide (6.44 g, 44 mmol) maintained at 135 °C was added
dropwise 4 (18 mmol) with vigorous stirring. The reaction
mixture was heated (1 h, 135 °C) and then cooled. The precipi-
tate was filtered and successively washed with aqueous 1.0 N
NaOH, H2O, EtOH, and Et2O to give 5.
1,6-Bis(p h th a lim id o)-2,5-h exa n ed iol (5a ). Using 4a 9a (2.00
g, 18 mmol) and the general procedure, 5a (white solid) was
obtained as a mixture of diastereomers (2.2:1, 13C NMR analy-
sis): yield 3.80 g (52%); mp 235-240 °C; Rf 0.30 (2:1 EtOAc/
hexanes); IR (KBr) 3502, 2931, 1770 (sh), 1705, 1427, 1392, 1076,
960, 728 cm-1; 1H NMR (DMSO-d6) δ 1.25-1.65 (m, 4 H), 3.42-
3.56 (m, 4 H), 3.74 (br s, 2 H), 4.87-4.90 (m, 2 H), 7.82-7.88
(m, 8 H); 13C NMR (DMSO-d6) δ 30.2, 30.7, 44.1, 66.8, 67.5,
122.8, 131.7, 134.1, 167.9; the other signals were not detected
and are believed to overlap with the observed peaks; the 1H and
13C NMR data are in agreement with the COSY and DEPT
spectra; MS (+CI) m/z 409 [M + 1]+; Mr (+CI) 409.13898 [M +
1]+ (calcd for C22H21N2O6 409.13996).
Meth od B. Using 5a (1.10 g, 2.7 mmol) and the general
procedure (120-125 °C, 1 d), crude 2a (yellow solid) was
obtained as a mixture of diastereomers (1.3:1, 1H NMR analy-
sis): yield 0.78 g (99%); 1H NMR (CD3OD) δ 1.75-1.85 (m, 2
H), 2.17-2.28 (m, 2 H), 2.97-3.23 (m, 4 H), 4.23-4.40 (m, 2 H);
13C NMR (CD3OD) δ 29.6, 29.8, 44.2, 44.9, 76.7, 77.4.
2,5-Bis(a m in om eth yl)-2,5-d im eth yltetr a h yd r ofu r a n Di-
h yd r obr om id e (2b). Using 5b (1.18 g, 2.7 mmol) and the
general procedure (70 °C, 9 d), crude 2b (brown solid) was
obtained as a mixture of diastereomers (1.3:1, 13C NMR analy-
1
sis): yield 0.85 g (98%); H NMR (D2O) δ 1.29, 1.33 (2 s, 6 H),
1.95-2.13 (m, 4 H), 2.69 (s, impurity, 1.5 H), 3.02-3.14 (m, 4
H); 13C NMR (D2O) δ 23.9, 24.0, 34.4, 34.7, 47.5, 47.8, 81.1, 81.3.
The product was purified for analysis by recrystallization
(EtOH-Et2O) to give a flocculent solid as an apparent single
diastereomer (>9:1, 13C NMR analysis): yield 0.10 g (11%); mp
> 270 °C dec; IR (KBr) 3427, 3029, 2971, 2922, 2655, 2559, 1581,
1495, 1467, 1396, 1145, 1056, 981, 764 cm-1; 1H NMR (CD3OD)
δ 1.38 (s, 6 H), 2.09 (s, 4 H), 3.00-3.13 (m, 4 H); 13C NMR (CD3-
OD) δ 25.2, 36.5, 49.4, 82.9; no signals were detected for the
1
other diastereomer; the H and 13C NMR data are in agreement
with the HMQC spectrum; MS (+CI) m/z 159 [M + 1]+; Mr (+CI)
159.14896 [M + 1]+ (calcd for C8H19N2O 159.14974). Anal. Calcd
for C8H20Br2N2O: C, 30.02; H, 6.30; N, 8.75. Found: C, 30.21;
H, 6.32; N, 8.75.
(23) Pitzer, K. S.; Donath, W. E. J . Am. Chem. Soc. 1959, 81, 3213-
3218.
(24) Robert, C. W. CRC Handbook of Chemistry and Physics, 59th
ed.; CRC Press: West Palm Beach, FL, 1978-1979; Section D, p D-38.
(25) Beckett, C. W.; Pitzer, K. S.; Spitzer, R. J . Am. Chem. Soc. 1947,
69, 2488-2495.
2,6-Bis(a m in om eth yl)tetr a h yd r op yr a n Dih yd r obr om id e
(2c). Using 5c (1.14 g, 2.70 mmol) and the general procedure
(90 °C, 25 d), crude 2c (brown solid) was obtained as a mixture
of diastereomers (5.5:1, 13C NMR analysis): yield 0.83 g (∼100%);
13C NMR (CD3OD) δ 18.3, 22.9, 27.9, 28.9, 42.7, 44.9, 69.3, 74.7.