7772 J . Org. Chem., Vol. 65, No. 23, 2000
Isobe et al.
133 °C; IR (KBr) νmax 1610, 1570, 830 cm-1; UV λmax 209.6 (ꢀ
13900), 228.8 (12900) nm; [R]22D -3.6 (c 1.00, CHCl3); 1H NMR
δ 1.73 (d, J ) 7.0 Hz, 3H), 2.81 (s, 3H), 2.95 (s, 6H), 3.67-
3.81 (m, 2H), 3.86-3.97 (m, 2H), 7.29-7.44 (m, 5H); 13C NMR
δ 17.2, 32.1, 36.0, 49.5, 59.3, 126.8, 128.7, 129.2, 138.4, 164.1.
Anal. Calcd for C14H24N3PF6: C, 44.57; H, 5.88; N, 11.14.
Found: C, 44.91; H, 5.89; N, 10.93.
Con clu sion s
In summary, fully substituted chiral guanidines and
guanidinium salts with a imidazolidine ring system were
simply prepared by the reaction of chloroamidine deriva-
tives with primary and secondary amines, respectively.
Chiral guanidinium salts had been prepared by reaction
of symmetrical phosgeniminium salts and chiral second-
ary amines,8 in which the phosgeniminium salts leading
to 2-iminium groups in the guanidinium systems were
used as electrophiles. Thus, our preparation method for
chiral guanidinium salts through chloroamidines are
complementary to the reported method.8 Although only
limited examples are shown in this paper, these methods
are applicable to preparation of similar types of modified
guanidines.
A Typ ica l P r oced u r e for P r ep a r a tion of Gu a n id in iu m
Sa lts 6 a n d 7 by Meth yla tion of 2-Im in oim id a zolid in es:
N-[(S)-1-(1-Na p h th yl)eth yl]-N,N′,N′′-tr im eth yl-N′,N′′-eth -
ylen egu a n id in iu m Iod id e (7). A solution of 1,3-dimethyl-
2-[(S)-1-(1-naphthyl)ethyl]iminoimidazolidine4 (1.68 g, 6.30
mmol) and methyl iodide (1.07 g, 7.56 mmol) in benzene (50
mL) was stirred at room temperature for 5 days. The precipi-
tates were collected by filtration and recrystallized from
CHCl3-toluene to give 7 as colorless fine prisms (1.19 g, 46%),
mp 191-193 °C (decomp); IR (KBr) νmax 1595, 1560 cm-1; UV
λmax 222.4 (ꢀ 101800), 284.0 (9200) nm; [R]23 +179.6 (c 1.00,
D
CHCl3); 1H NMR δ 1.95 (d, J ) 7.0 Hz, 3H), 2.83 (s, 6H), 2.87
(s, 3H), 3.66-3.80 (m, 2H), 4.15-4.29 (m, 2H), 5.59 (q, J )
7.0 Hz, 1H), 7.50-7.94 (m, 7H); 13C NMR δ 17.0, 33.2, 36.9,
50.2, 54.9, 121.6, 124.4, 125.0, 126.3, 127.2, 129.6, 129.7, 130.3,
133.8, 134.4, 165.0. Anal. Calcd for C18H24N3I: C, 52.82; H,
5.91; N, 10.27. Found: C, 52.75; H, 5.90; N, 10.17.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. 1H (300 MHz) and
13C NMR (75 MHz) spectra were recorded in CDCl3 with TMS
as an internal reference unless otherwise stated. UV spectra
were measured in MeOH. Organic extract was dried over
MgSO4 or Na2SO4 and evaporated under reduced pressure.
Columns for chromatography contained silica gel 60 (SiO2)
(70-230 mesh ASTM; Merck).
1,3-Bis[(S)-1-p h en yleth yl]-2-th ioxoim id a zolid in e (25).
A solution of thiophosgene (4.63 g, 40.3 mmol) in CH2Cl2 (20
mL) was slowly added to a mixture of N,N′-bis[(S)-1-phenyl-
ethyl]ethylenediamine6 (24) (10.8 g, 40.3 mmol) and Et3N (8.1
g, 80.5 mmol) in CH2Cl2 (110 mL) at 0 °C. The whole was
stirred at room temperature for 3 h, diluted with CH2Cl2, and
washed with water. The residue obtained from the organic
extract was purified by column chromatography (hexane-
EtOAc ) 1:1) to give 25 (10.5 g, 84%) as colorless prisms, mp
147 °C, which were recrystallized from MeOH; IR (KBr) νmax
A
Typ ica l P r oced u r e for P r ep a r a t ion of 1,3-Di-
m eth yl-2-im in oim id a zolid in es 2, 3, a n d 9-21: (4S,5S)-
1,3-Dim eth yl-4,5-d ip h en yl-2-[(R)-1-h yd r oxym eth yl-2-m e-
th ylp r op ylim in o]im id a zolid in e (16). According to the re-
ported method,4 to a solution of (R)-1-hydroxymethyl-2-
methylpropylamine (1.00 g, 9.69 mmol) and Et3N (1.89 g, 18.7
mmol) in MeCN (100 mL) was added 8 (3.00 g, 9.35 mmol) at
room temperature. The whole was stirred at room temperature
for 0.3 h, poured into 5% HCl solution, and extracted with CH2-
Cl2. The residue obtained from the organic extract was
dissolved in water and washed with toluene. The aqueous
solution was made alkaline with 5% NaOH aqueous solution
and extracted with toluene. The residue obtained from the
organic extract was given as a colorless viscous oil, which was
slowly solidified to colorless prisms, mp 66-69 °C; IR (neat)
1325, 1300, 1275 cm-1; UV λmax 205.6 (ꢀ 25200), 244.0 (23400)
1
nm; [R]23 -188.4 (c 1.00, CHCl3); H NMR δ 1.53 (d, J ) 7.0
D
Hz, 6H), 3.01-3.11 (m, 2H), 3.26-3.39 (m, 2H), 6.18 (q, J )
7.0 Hz, 2H), 7.23-7.40 (m, 10H); 13C NMR δ 15.2, 40.8, 53.3,
127.2, 127.4, 128.4, 140.0, 181.4; FABMS m/z 311 (M + H)+
1,3-Bis[(S)-1-ph en yleth yl]-2-ch lor oim idazolin iu m Ch lo-
r id e (26). A mixture of 25 (5.7 g, 18.4 mmol) and oxalyl
chloride (2.8 g, 22 mmol) in anhydrous toluene (114 mL) was
heated at 70 °C for 24 h. After cooling, precipitates were
collected by filtration under protection of moisture to afford
26 (5.1 g, 80%) as a colorless hygroscopic solid; IR (KBr) νmax
νmax 1655 cm-1; UV λmax 207.2 (ꢀ 32900) nm; [R]23 +83.2 (c
D
1.00, CHCl3); 1H NMR δ 0.99 (s, 6H), 1.78-1.89 (m. 1H), 2.64
(br s, 3H), 2.82 (br s, 3H), 3.59-3.65 (m, 1H), 3.69-3.79 (m,
2H), 3.85-3.90 (m, 2H), 6.91-7.35 (m, 10H); 13C NMR δ 19.1,
19.3, 31.8, 33.6, 37.7, 60.8, 64.4, 72.7, 75.1, 127.5, 128.1, 128.6,
138.7, 157.8. Anal. Calcd for C22H29N3O: C, 75.17; H, 8.32; N,
11.96. Found: C, 75.02; H, 8.38; N, 11.84.
1595 cm-1; [R]24 +6.8 (c 1.00, CHCl3); 1H NMR δ 1.77 (d, J )
D
7.0 Hz, 6H), 3.89-3.97 (m, 2H), 4.27-4.35 (m, 2H), 5.33 (q, J
) 7.0 Hz, 2H), 7.31-7.45 (m, 10H); 13C NMR δ 17.6, 44.8, 57.2,
127.0, 129.1, 129.3, 136.0, 153.5; HRFABMS m/z 313.1471 (M
+ H+, C19H22ClN2 requires m/z 313.1472), 315.1451 (M + 2 +
H+, C19H22ClN2 requires m/z 315.1448).
A Typ ica l P r oced u r e for P r ep a r a tion of Gu a n id in iu m
Sa lts 4, 5, 22, a n d 23 by Rea ction of Ch lor oim id a zo-
lin iu m Ch lor id es w ith Secon d a r y Am in es: N-[(S)-1-
P h en yleth yl]-N,N′,N′′-tr im eth yl-N′,N′′-eth ylen egu a n id in -
iu m Ch lor id e (4). A solution of N-methyl-N-[(S)-1-phenyl-
ethyl]amine (2.88 g, 21.3 mmol) and Et3N (2.15 g, 21.3 mmol)
in MeCN (20 mL) was added to a solution of 1 (3.60 g, 21.3
mmol) in MeCN (20 mL). The whole was refluxed for 3 h,
cooled, and evaporated. The residue was purified by column
chromatography (CHCl3-MeOH ) 10:1) to give 4 (5.62 g, 99%)
as a colorless oil; IR (neat) νmax 1600, 1565 cm-1; UV λmax 209.2
A Typ ica l P r oced u r e for P r ep a r a tion of 1,3-Bis[(S)-1-
p h en yleth yl]-2-im in oim id a zolid in es 27-31: 1,3-Bis[(S)-
1-p h en ylet h yl]-2-[(R)-1-(1-n a p h t h yl)et h ylim in o]im id a -
zolid in e (28). According to the above preparation method of
1,3-dimethyl-2-iminoimidazolidines treatment of 26 (2.06 g,
5.90 mmol) with (R)-1-(1-naphthyl)ethylamine (1.01 g, 5.90
mmol) and Et3N (1.19 g, 11.8 mmol) in CH2Cl2 (30 mL) at room
temperature for 1 h afforded 28 (2.16 g, 82%) as colorless
prisms (recrystallized from hexane), mp 115 °C; IR (KBr) νmax
1650 cm-1; UV λmax 225.6 (ꢀ 94800), 283.2 (8000) nm; [R]26
D
(ꢀ 12900), 229.2 (12000) nm; [R]21 -5.5 (c 1.00, CHCl3); 1H
1
D
-312.2 (c 1.00, CHCl3); H NMR δ 1.43 (d, J ) 7.1 Hz, 6H),
NMR δ 1.76 (d, J ) 7.0 Hz, 3H), 2.90 (s, 3H), 3.06 (s, 6H),
3.90-4.01 (m, 2H), 4.06-4.16 (m, 2H), 4.85 (q, J ) 7.0 Hz,
1H); 13C NMR δ 17.2, 32.3, 36.2, 49.7, 59.1, 126.6, 128.4, 128.9,
138.1, 163.9; FABMS m/z 232 (M+). Th e Hexa flu or op h os-
p h a te. The guanidinium chloride 4 was treated with an
equimolar amount of an aqueous solution of ammonium
hexafluorophosphate at room temperature for 1 h and ex-
tracted with CH2Cl2. Recrystallization of the residue, quanti-
tatively obtained from the organic extract, from toluene gave
the hexafluorophosphate as colorless fine prisms, mp 132-
1.60 (d, J ) 6.2 Hz, 3H), 2.63-2.99 (m, 4H), 5.67 (q, J ) 6.2
Hz, 1H), 7.17-7.22 (m, 10H), 7.37-7.51 (m, 3H), 7.67 (d, J )
8.1 Hz, 1H), 7.81 (d, J ) 7.7 Hz, 1H), 8.04 (d, J ) 7.1 Hz, 1H),
8.22 (d, J ) 8.3 Hz, 1H); 13C NMR δ 16.1, 27.7, 40.3, 52.6,
123.2, 123.4, 124.9, 125.4, 125.9, 126.5, 126.8, 127.3, 128.0,
128.8, 130.4, 133.9, 144.8, 153.4. Anal. Calcd for C31H33N3:C,
83.18; H, 7.43; N, 9.39. Found: C, 82.85; H, 7.40; N, 9.37.
(5S)-3-[(S)-1-P h en ylet h yl]-2-t h ioxo-1,3-d ia za b icyclo-
[3.3.0]octa n e (34). A solution of N-[(S)-1-phenylethyl]-(S)-
prolinamide7 (32) (9.0 g, 41.4 mmol) in THF (30 mL) was slowly
added to a suspension of LiAlH4 (4.7 g, 124 mmol) in THF (200
mL) at room temperature, and the whole was heated at 60 °C
for 14 h. After addition of saturated Na2SO4 aqueous solution
(8) Schlama, T.; Gouverneur, V.; Valleix, A.; Greiner, A.; Toupet,
L.; Mioskowski, C. J . Org. Chem. 1997, 62, 4200-4202.