Modified guanidines as potential chiral superbases. 2. Preparation of 1,3-unsubstituted and 1-substituted 2-iminoimidazolidine derivatives and a related guanidine by the 2-chloro-1,3-dimethylimidazolinium chloride-induced cyclization of thioureas

Article abstract of DOI:10.1021/jo000745n

Simple preparation methods for modified guanidines were explored for new chiral superbases. Thus, (4S,5S)-4,5-diphenyl- and diastereomeric cyclohexane-fused 2-iminoimidazolidines were prepared from (1S,2S) - 1,2 -diphenylethylenediamine and (1R,2R)- or (1S,2S)-1,2-diaminocyclohexanes through cyclization of protected thiourea intermediates with 2-chloro-1,3-dimethylimidazolinium chloride (DMC) as a key reaction. In the (4S,5S)-4,5-diphenyl series 1-methyl-2-iminoimidazolidines and 2-diethylaminoimidazoline were also prepared as related guanidines.

Full text of DOI:10.1021/jo000745n

7774
J . Org. Chem. 2000, 65, 7774-7778
Mod ified Gu a n id in es a s P oten tia l Ch ir a l Su p er ba ses. 2.
P r ep a r a tion of 1,3-Un su bstitu ted a n d 1-Su bstitu ted
2-Im in oim id a zolid in e Der iva tives a n d a Rela ted Gu a n id in e by th e
2-Ch lor o-1,3-d im eth ylim id a zolin iu m Ch lor id e-In d u ced Cycliza tion
of Th iou r ea s
Toshio Isobe,†,‡ Keiko Fukuda,‡ Tatsuhiro Tokunaga,§ Hiroko Seki,§ Kentaro Yamaguchi,§ and
Tsutomu Ishikawa*,†
Faculty of Pharmaceutical Sciences and Chemical Analysis Center, Chiba University,
1-33 Yayoi, Inage, Chiba 263-8522, J apan, and Central Research Laboratory, Shiratori Pharmaceutical
Co. Ltd., 6-11-24 Tsudanuma, Narashino, Chiba 275-0016, J apan
benti@p.chiba-u.ac.jp
Received May 15, 2000
Simple preparation methods for modified guanidines were explored for new chiral superbases. Thus,
(4S,5S)-4,5-diphenyl- and diastereomeric cyclohexane-fused 2-iminoimidazolidines were prepared
from (1S,2S)-1,2-diphenylethylenediamine and (1R,2R)- or (1S,2S)-1,2-diaminocyclohexanes through
cyclization of protected thiourea intermediates with 2-chloro-1,3-dimethylimidazolinium chloride
(DMC) as a key reaction. In the (4S,5S)-4,5-diphenyl series 1-methyl-2-iminoimidazolidines and
2-diethylaminoimidazoline were also prepared as related guanidines.
Sch em e 1
In tr od u ction
Due to their strongly basic character,1 guanidines can
be considered as superbases2 and, although chiral
guanidines are expected to have potential as asymmetric
reagents, their limited use3 in asymmetric synthesis as
chiral auxiliaries is due mainly to the absence of simple
preparation methods. In the preceding paper4 we re-
ported the preparation of 1,3-disubstituted 2-iminoimi-
dazolidine derivatives as potential chiral superbases. In
this paper we describe the straightforward preparation
of thirteen (4S,5S)-4,5-diphenyl- 67-79 and two diaster-
eomeric cyclohexane-fused 2-iminoimidazolidines 80 and
81 as 1,3-unsubstituted 2-iminoimidazolidines from
(1S,2S)-1,2-diphenylethylenediamine (7) and (1R,2R)- or
(1S,2S)-1,2-diaminocyclohexanes (8R and 8S) through
cyclization of thiourea derivatives using 2-chloro-1,3-
dimethylimidazolinium chloride (DMC).5 In the 4,5-
diphenyl series 2-imino-1-methylimidazolidines 85 and
86 and 2-diethylaminoimidazoline 90 were also prepared
as 1-substituted 2-iminoimidazolidines and a related
guanidine, respectively.
† Faculty of Pharmaceutical Sciences, Chiba University.
‡ Shiratori Pharmaceutical Co. Ltd.
§ Chemical Analysis Center, Chiba University.
Resu lts a n d Discu ssion
(1) Yamamoto, Y.; Kojima, S. The Chemistry of Amidines and
Imidates; Patai, S.; Rappoport, Z., Eds.; J ohn Wiley & Sons Inc.: New
York, 1991; Vol. 2, pp 485-526.
(2) Costa, M.; Chiusoli, G. P.; Taffurelli, D.; Dalmonego, G. J . Chem.
Soc., Perkin Trans. 1 1998, 1541-1546.
(3) (a) For the nitroaldol (Henry) reaction, see Chinchilla, R.; Najera,
C.; Sanchez-Agullo, P. Tetrahedron: Asymmetry 1994, 5, 1393-1402.
(b) For the Strecker reaction, see Iyer, M. S.; Gigstad, K. M.; Namdev,
N. D.; Lipton, M. J . Am. Chem. Soc. 1996, 118, 4910-4911. Corey, E.
J .; Grogan, M. J . Org. Lett. 1999, 1, 157-160. (c) For the Michael
reaction, see Alcazar, V.; Moran, J . R.; deMendoza, J . Tetrahedron Lett.
1995, 36, 3941-3944. Ma, D.; Cheng, K. Tetrahedron: Asymmetry
1999, 10, 713-719. Howard-J ones, A.; Murphy, P. J .; Thomas, D. A.
Caulkett, P. W. R. J . Org. Chem. 1999, 64, 1039-1041.
(4) Isobe, T.; Fukuda, K.; Ishikawa, T. J . Org. Chem. 2000, 65, 7770-
7773.
We planned the preparation of chiral guanidines with
an imidazolidine ring system such as 4, 5, and 6 from
chiral ethylenediamines 1 according to the general
synthetic route as shown in Scheme 1, in which a key
reaction is the DMC-induced cyclization of a thiourea
deivative 2. In the case of disubstituted thiourea 2 (A2 )
H) cyclization followed by deprotection could afford 1,3-
unsubstituted 2-iminoimidazolidine 4, whereas inclusion
of a methylation step on the cyclized product 3 into the
above reaction sequence leads to 2-imino-1-methylimi-
dazolidine 5. On the other hand, the use of trisubstituted
thiourea 2 (A2 ) alkyl or aryl) in the DMC-induced
cyclization could yield 2-aminoimidazoline 6. In these
(5) (a)Isobe, T.; Ishikawa, T. J . Org. Chem. 1999, 64, 5832-5835.
(b) Isobe, T.; Ishikawa, T. J . Org. Chem. 1999, 64, 6984-6988. (c) Isobe,
T.; Ishikawa, T. J . Org. Chem. 1999, 64, 6989-6992.
10.1021/jo000745n CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Modified Guanidines as Potential Chiral Superbases. 2.
J . Org. Chem., Vol. 65, No. 23, 2000 7775
Ta ble 1. P r ep a r a tion of Isoth iocya n a tes 9-16 fr om
Ta ble 2. P r ep a r a tion of Th iou r ea s 17-27 fr om
Eth ylen ed ia m in es 7, 8R, a n d 8S
P r im a r y Am in es th r ou gh Th ioca r ba m a tes
synthetic trials (1S,2S)-1,2-diphenylethylenediamine (7)
was chosen as a convenient source of the ring nitrogens
in imidazolidine skeletons. Enantiomeric 1,2-diaminocy-
clohexanes [8R for (1R,2R)- and 8S for (1S,2S)-deriva-
tives] were also examined as additional examples.
We have shown that DMC is a useful reagent for the
construction of heterocycles through intramolecular
dehydration.5c Thus, we examined the DMC-induced
cyclization of thiourea derivatives, leading to protected
2-iminoimdazolidines such as 3 in Scheme 1. Treatment
of protected thioureas prepared above with DMC in
boiling acetonitrile in the presence of triethylamine
(Et3N) expectedly afforded cyclized products (Table 5).
Seventeen 4,5-diphenyl-2-iminoimdazolidine derivatives
48-64 and isomeric cyclohexane-fused ones 65 and 66
were thus obtained in moderate to excellent yields,
irrespective of the protecting groups used.
Deprotection of the cyclized products under appropriate
conditions, dependent upon the protecting group, smoothly
afforded 1,3-unsubstituted 2-iminoimidazolidines (Table
6). Thirteen (4S,5S)-4,5-diphenyl-2-iminoimdazolidines
67-79 and diastereomeric cyclohexane-fused ones 80 and
81 were prepared in high yields. Interestingly in the
deprotection of carbobenzyloxy (Cbz) group of compound
60 easier removal under basic conditions (10% MeONa
in MeOH, Reagent C in Table 6: 100% after 68 h) was
observed compared to standard acidic conditions (30%
HBr in AcOH, Reagent D in Table 6: 44% after 216 h).
In the above imidazolidine systems positional isomers11
[an imino-type isomer 82 with an exo double bond and
P r ep a r a tion of (4S,5S)-4,5-Dip h en yl-2-Im in oim i-
d a zolid in es 67-79 a n d Dia ster eom er ic Cycloh ex-
a n e-F u sed Der iva tives 80 a n d 81 a s 1,3-Un su bsti-
tu ted 2-Im in oim id a zolid in es. At first the preparation
of 1,3-unsubstituted 2-iminoimidazolidines such as com-
pound 4 in Scheme 1 was examined. The intermediate
protected thiourea 2 (A2 ) H) in Scheme 1 could be
prepared by either formation of the thiourea followed by
protection or the reverse sequence. Isothiocyanates serve
as a source of thiourea functionality in each case. Thus,
six isothiocyanates 9-14 were prepared from the corre-
sponding chiral or achiral primary amines in high yields
by the DMC-induced elimination5b of hydrogen sulfide in
triethylammonium dithiocarbamates (Table 1). However,
ineffective elimination was observed when aniline de-
rivatives 15 and 16 incorporating sterically bulky tert-
butyl group at the ortho position were used as starting
amines. Following the former reaction sequence treat-
ment of ethylenediamines 7, 8R, or 8S with isothiocy-
anates gave thioureas 17-27 (Table 2), conventional
protection of which smoothly yielded the corresponding
protected thioureas 28-41 (Table 3). Amide- or urethane-
type protecting groups both proved of utility in the
protection reactions.
In the latter sequence, in which protection precedes
thiourea formation, diphenylethylenediamine 7 was used
as the starting ethylenediamine. Ethoxycarbonylated
ethylenediamine 42, readily derived from 7, was con-
verted into the corresponding protected thioureas 43-
47 by treatment with isothiocyanates. Heating was found
to be necessary for completion of reaction in the cases of
44-47 (Table 4).
(6) Terentev, A. P.; Rukhadze, E. G.; Dunina, V. V. Dokl. Akad.
Nauk. SSSR 1969, 187, 1328-1331 (Chem. Abstr. 1969, 71, 123767).
(7) Bonfichi, R.; Dallanoce, C.; Lociuro, S.; Spada, A. J . Chromatogr.
A 1995, 707, 355-365.
(8) Bach, E.; Kjaer, A. Acta Chem. Scand. 1971, 25, 2629-2634.
(9) J ochims, J . C.; Seeliger, A. Angew. Chem., Int. Ed. 1967, 6, 174-
175.
(10) J ohnson, A. L. U.S. Patent 3637731, 1972 (Chem. Abstr. 1972,
76, 113215).

7776 J . Org. Chem., Vol. 65, No. 23, 2000
Isobe et al.
Ta ble 3. P r ep a r a tion of P r otected Th iou r ea s 28-41 by
P r otection of Th iou r ea s 17-27
Ta ble 5. P r ep a r a tion of P r otected
2-Im in oim id a zolid in es 48-66 by th e DMC-In d u ced
Cycliza tion of Th iou r ea Der iva tives 28-41 a n d 43-47
Ta ble 4. P r ep a r a tion of P r otected Th iou r ea s 43-47 fr om
Dip h en yleth ylen ed ia m in e 7 th r ou gh th e
Eth oxyca r bon yla ted Eth ylen ed ia m in e 42
lidines may exist as an imino-type isomers such as 82
(X ) Y ) H) in the solid state.
P r ep a r a t ion of (4S,5S)-4,5-Dip h en yl-2-im in o-1-
m et h ylim id a zolid in es 85 a n d 86 a s 1-Su b st it u t ed
2-Im in oim id a zolid in es a n d 2-Dieth yla m in oim id a -
zolin e 90 a s a Rela ted Gu a n id in e. Second, the prepa-
ration of 2-imino-1-methylimidazolidines such as 5 in
Scheme 1 as the 1-substituted imidazolidines was exam-
ined. Thus, (4S,5S)-4,5-diphenyl-2-[(R)-1-phenylethylimi-
no]imidazolidine (48) protected with tert-butoxycarbonyl
(Boc) group was converted into the corresponding 3-
methyl derivatives 84 in 93% yield by treatment with
n-BuLi followed by methylation with methyl iodide.
Removal of the Boc group with 30% trifluoroacetic acid
(TFA) in dichloromethane (CH2Cl2) afforded (4S,5S)-4,5-
diphenyl-1-methyl-2-[(R)-1-phenylethylimino]imidazoli-
dine (85) in 97% yield as a desired 1-substituted 2-imi-
noimidazolidine (Scheme 2). The corresponding diastereo-
meric guanidine 86 was also given in 88% yield from
(4S,5S)-1-Boc-4,5-diphenyl-2-[(S)-1-phenylethylimino]im-
idazolidine (49) through two steps by the same treatment
mentioned above.
an amino-type one 83 with an endo double bond] could
be theoretically formed due to the position of a C-N
double bond as shown in Figure 1. Although no experi-
mental evidence was available on the protected imida-
zolidines 82 or 83 (X ) COR′, Y ) H), X-ray analysis of
2,5-di(tert-butyl)phenyl derivative 79 (see Supporting
Information) suggested that 1,3-unsubstituted imidazo-
In the methylated imidazolidines, positional isomers
[See Figure 1; 82 or 83 (X ) COR′, Y ) Me)] are also
possible. Examination of the NMR spectra of the methyl-
(11) Tanatani, A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo,
K.; Kagechika, H. J . Am. Chem. Soc. 1998, 120, 6433-6442.
1
ated product 84 including H-15N HMBC experiments12

Modified Guanidines as Potential Chiral Superbases. 2.
J . Org. Chem., Vol. 65, No. 23, 2000 7777
Ta ble 6. Dep r otection of P r otected Im id a zolid in es
48-58 a n d 60-66 to Ch ir a l 1,3-Un su bstitu ted
2-Im in oim id a zolid in es 67-81
Sch em e 2
Sch em e 3
Con clu sion s
It has been shown that 1,3-unsubstituted and 1-sub-
stituted 2-iminoimidazolidines could be simply prepared
from optically active ethylenediamines. The related 2-di-
ethylaminoimidazoline was also prepared as an alterna-
tive 1,3-unsubstituted guanidine. Thus, 15 novel 1,3-
unsubstituted and two 1-substituted 2-iminoimidazolidines
and one 2-aminoimidazoline have been described in this
present paper. This method should be widely applicable
to preparation of the same class of guanidines by use of
appropriate chiral ethylenediamines.
Exp er im en ta l Section
Gen er a l. Starting chiral ethylenediamines were purchased
from Wako Co. Ltd. (J apan). 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 extracts
were dried over MgSO4 or Na2SO4 and evaporated under
reduced pressure. Columns for chromatography contained
silica gel 60 (SiO2) (70-230 mesh ASTM; Merck) or NH-type
silica gel (NH-SiO2) (Chromatorex NH-DM1020; Fuji Silysia
Chemical Ltd.).
F igu r e 1. Possible positional isomers of the imidazolidine
systems.
Gen er a l P r oced u r e for P r ep a r a tion of Isoth iocya n -
a tes (Ta ble 1). A solution of an amine (31 mmol), CS2 (31
mmol), and Et3N (7.48 g, 74 mmol) in CH2Cl2 (80 mL) was
stirred at room temperature for 1 h. To the mixture was
dropped a solution of DMC (37 mmol) in CH2Cl2 (30 mL), and
then the whole was stirred at room temperature for 1 h. After
evaporation, the residue was purified by column chromatog-
raphy (SiO2, hexane or hexane-CHCl3) to afford an isothio-
cyanate.
Gen er a l P r oced u r e for P r ep a r a tion of Th iou r ea s
(Ta ble 2). An isothiocyanate (26 mmol) was dropped to a
solution of an ethylenediamine (26 mmol) in CH2Cl2 (50 mL),
and then the whole was stirred at room temperature for ca. 1
day. After evaporation, the residue was purified by column
chromatography (SiO2: CHCl3 or CHCl3-MeOH) to afford a
thiourea.
allowed us to deduce that methylation occurred at the
internal nitrogen to give 84 with an exo double bond.13
Finally the preparation of 2-aminoimidazoline deriva-
tive was examined. The use of diethylthiocarbamoyl
chloride (87) instead of an isothiocyanate in the reaction
with an ethoxycarbonylated diamine 42 gave a trisub-
stituted thiourea 88. The DMC-induced cyclization of 88
without purification afforded a cyclized product 89 in 63%
yield through two steps. Treatment of 89 with 14%
MeONa in MeOH yielded (4S,5S)-2-diethylamino-4,5-
diphenylimidazoline (90) quantitatively as an alternative
1,3-unsubstituted guanidine (Scheme 3).
(12) For example, a strong cross-peak between an imino nitrogen
(δN -176.8) and benzyl methyl protons (δH 1.37) was observed.
(13) No examination was carried out on identifying possible geo-
metrical isomers around the exo CdN double bond.
Gen er a l P r oced u r e for P r otection of Th iou r ea s (Ta ble
3). A mixture of a thiourea (16.6 mmol), a protecting agent
(16.6 mmol), and Et3N (1.68 g, 16.6 mmol) in CH2Cl2 (100 mL)

7778 J . Org. Chem., Vol. 65, No. 23, 2000
Isobe et al.
was stirred at room temperature. After completion of reaction,
the mixture was successively washed with water and saturated
NaHCO3 aqueous solution. The residue obtained from organic
extract was purified by column chromatography (SiO2, CHCl3
or CHCl3-MeOH), in some cases followed by recrystallization,
to afford a protected thiourea.
stirred at room temperature for 5 h, poured into water, and
extracted with CH2Cl2. The residue obtained from the organic
extract was purified by column chromatography (SiO2, hex-
anes-EtOAc ) 1:1) to afford 84 as a colorless viscous oil (3.86
g, 93%); IR (neat) νmax 1725, 1660 cm-1; [R]24 -19.6 (c 1.00,
D
1
CHCl3); UV λmax 207.2 (ꢀ 46300) nm; H NMR δ 1.19 (s, 9H),
Gen er a l P r oced u r e for P r ep a r a tion of P r otected Th io-
u r ea s fr om 42 (Ta ble 4). 42 (4.04 g, 14.2 mmol) was treated
with an isothiocyanate (14.2 mmol) in an appropriate solvent
(100 mL) under the conditions noted in Table 4 and cooled.
The residue was purified by column chromatography (SiO2,
CHCl3 or CHCl3-MeOH), in some cases followed by recrys-
tallization, to afford a protected thiourea.
Gen er a l P r oced u r e for P r ep a r a tion of P r otected 2-Im -
in oim id a zolid in es (Ta ble 5). To a solution of a protected
thiourea (15.1 mmol) and DMC (3.07 g, 18.2 mmol) in MeCN
(100 mL) was added Et3N (4.58 g, 45.4 mmol), and the whole
was refluxed. After cooling, the whole was poured into water
and extracted with CH2Cl2. The residue was purified by
column chromatography (SiO2, CHCl3 or CHCl3-MeOH), in
some cases followed by recrystallization, to afford a protected
2-iminoimidazolidine.
1.37 (d, J ) 6.4 Hz, 3H), 2.85 (s, 3H), 4.12 (d, J ) 2.9 Hz, 1H),
4.85 (d, J ) 2.9 Hz, 1H), 4.99 (q, J ) 6.4 Hz, 1H), 7.16-7.42
(m, 13H), 7.56 (d, J ) 7.3 Hz, 2H); 13C NMR δ 27.6, 27.7, 32.1,
57.0, 68.0, 69.7, 82.1, 125.8, 125.9, 126.2, 126.6, 127.87, 127.91,
128.1, 128.8, 129.0, 140.7, 142.1, 145.4, 148.1, 153.1; HR-
FABMS m/z 456.2645 (M + H+, C29H34N3O2 requires m/z
456.2651).
(4S,5S)-4,5-Dip h en yl-1-m eth yl-2-[(R)-1-p h en yleth ylim -
in o]im id a zolid in e (85). A solution of 84 (3.39 g, 7.45 mmol)
and TFA (12.0 g, 105.2 mmol) in CH2Cl2 (28 mL) was stirred
at room temperature for 19 h, poured into 5% NaOH aqueous
solution, and extracted with CH2Cl2. The residue obtained from
the organic extract was purified by column chromatography
(NH-SiO2, hexane-CHCl3 ) 1:1) to afford 85 as colorless
prisms (2.56 g, 97%), mp 43-45 °C; IR (neat) νmax 1645, 1595,
1575 cm-1; [R]27D +84.2 (c 1.00, CHCl3); UV λmax 207.2 (ꢀ 36900)
nm; 1H NMR (on the HCl salt) δ 1.93 (d, J ) 6.8 Hz, 3H), 3.21
(s, 3H), 4.39 (d, J ) 8.6 Hz, 1H), 4.60 (d, J ) 8.6 Hz, 1H), 4.83
(m, 1H), 7.10-7.13 (m, 4H), 7.34-7.45 (m, 9H), 7.59-7.62 (m,
2H); 13C NMR (on the HCl salt in CD3OD) δ 23.8, 31.7, 55.4,
68.5, 76.3, 127.7, 128.5, 129.1, 129.7, 130.6, 130.8, 131.2, 131.3,
137.9, 139.9, 143.4, 159.2; HRFABMS m/z 356.2135 (M + H+,
C24H26N3 requires m/z 356.2127).
P r ep a r a t ion of 1,3-Un su b st it u t ed 2-Im in oim id a zo-
lid in es (Ta ble 6). (i) A Typ ica l P r oced u r e for Dep r otec-
tion w ith 30% TF A in AcOH (Meth od A): (4S,5S)-4,5-
Dip h en yl-2-[(S)-1-p h en yleth ylim in o]im id a zolid in e (68)
fr om 49. TFA (2.58 g, 22.7 mmol) was added to a solution of
49 (1.00 g, 2.27 mmol) in CH2Cl2 (6.5 mL) at room temperature.
The whole was stirred at room temperature for 5 h, poured
into 5% NaOH aqueous solution, and extracted with CH2Cl2.
The residue obtained from the organic extract was purified
by column chromatography (NH-SiO2, CHCl3) to afford an
(4S,5S)-2-Dieth yla m in o-4,5-d ip h en yl-1-eth oxyca r bon -
ylim id a zolin e (89). A mixture of 42 (4.19 g, 14.8 mmol), Et3N
(1.53 g, 15.2 mmol), and diethylthiocarbamoyl chloride (87)
(2.30 g, 15.2 mmol) in CH2Cl2 (50 mL) was refluxed for 16 h
with stirring, acidified with 10% HCl, and extracted with CH2-
Cl2. The CH2Cl2 solution was successively washed with water
and saturated NaHCO3 aqueous solution. The residue (6.03
g) obtained from the organic extract was dissolved in MeCN
(10 mL) containing DMC (3.91 g, 23.1 mmol). To the solution
was dropped Et3N (4.67 g, 46.3 mmol), and the whole was
refluxed for 1 h. After addition of water, the mixture was
extracted with CH2Cl2. The residue obtained from the organic
extract was purified by column chromatography (SiO2, hex-
anes-EtOAc ) 3:1) to afford 89 as a colorless viscous oil (3.41
amorphous mass (0.56 g, 85%); IR (KBr) νmax 1600, 1575 cm-1
;
1
[R]23 -33.3 (c 1.00, CHCl3); UV λmax 207.2 (ꢀ 34600) nm; H
D
NMR δ 1.46 (d, J ) 6.8 Hz, 3H), 4.12 (br s, 2H), 4.52 (s, 2H),
4.73 (q, J ) 6.8 Hz, 1H),7.05-7.39 (m, 15H); 13C NMR δ 23.9,
53.0, 72.8, 126.0, 126.2, 127.1, 127.2, 128.5, 128.7, 143.9, 145.2,
159.8; HRFABMS m/z 342.1945 (M + H+, C23H24N3 requires
m/z 342.1970).
(ii) A Typ ica l P r oced u r e for Dep r otection w ith 10%
MeONa in MeOH (Meth od C): (4S,5S)-2-ter t-Bu tylim in o-
4,5-d ip h en ylim id a zolid in e (75) fr om 58. A solution of 58
(5.00 g, 12.6 mmol) in 10% MeONa in MeOH (78 g) was stirred
at room temperature for 1.5 h, poured into water, and
extracted with CH2Cl2. The residue obtained from the organic
extract was purified by column chromatography (SiO2, CHCl3)
followed by recrystallization from CH2Cl2-hexane to afford
colorless fine prisms (3.50 g, 98%), mp 177-178 °C; IR (KBr)
g, 63%); IR (neat) νmax 1725, 1620 cm-1; [R]23 +6.4 (c 1.00,
D
1
CHCl3); UV λmax 205.6 (ꢀ 32800) nm; H NMR δ 1.14 (t, J )
7.0 Hz, 3H), 1.26 (t, J ) 7.1 Hz, 6H), 3.26-3.38 (m, 2H), 3.53-
3.64 (m, 2H), 4.03-4.15 (m, 2H), 4.84 (d, J ) 2.0 Hz, 1H), 5.09
(d, J ) 2.0 Hz, 1H), 7.21-7.39 (m, 10H); 13C NMR δ 12.8, 14.2,
43.7, 62.2, 70.9, 73.6, 125.8, 125.9, 127.3, 127.7, 128.7, 128.8,
142.3, 143.7, 152.9, 157.0; HRFABMS m/z 366.2179 (M + H+,
C22H28N3O2 requires m/z 366.2182).
νmax 1625, 1595, 1565 cm-1; [R]26 -20.7 (c 1.00, CHCl3); UV
D
λmax 206.4 (ꢀ 28600) nm; 1H NMR δ 1.41 (s, 9H), 4.23 (br s,
2H), 4.56 (br s, 2H), 7.22-7.32 (m, 10H); 13C NMR δ 29.5, 50.9,
126.4, 127.0, 128.4, 144.4, 159.2; Anal. Calcd for C19H23N3: C,
77.77; H, 7.90; N, 14.32. Found: C, 77.92; H, 8.01; N, 14.41.
(iii) A Typ ica l P r oced u r e for Dep r otection w ith 30%
HBr in AcOH (Meth od D): (4S,5S)-4,5-Dip h en yl-2-eth -
ylim in oim id a zolid in e (76) fr om 60. A solution of 60 (0.900
g, 2.23 mmol) in 30% HBr in AcOH (13.3 g) was stirred at
room temperature for 216 h, poured into water, and washed
with hexane. The aqueous solution was made alkaline with
5% NaOH and extracted with CH2Cl2. The residue obtained
from the organic extract was purified by column chromatog-
raphy (NH-SiO2, CHCl3-MeOH ) 25:1) followed by recrys-
tallization from MeCN to afford colorless fine prisms (0.262
(4S,5S)-2-Dieth yla m in o-4,5-d ip h en ylim id a zolin e (90).
A solution of 89 (1.82 g, 4.99 mmol) in 14% MeONa in MeOH
(15.6 g) was stirred at room temperature for 71 h, poured into
water, and extracted with CH2Cl2. The residue obtained from
the organic extract was purified by column chromatography
(NH-SiO2, CHCl3) to afford 90 (1.46 g, 100%) as colorless
prisms, mp 99-100 °C; IR (KBr) νmax 1600, 1580, 1495 cm-1
;
1
[R]22 -11.9 (c 1.00, CHCl3); UV λmax 206.4 (ꢀ 35400) nm; H
D
NMR δ 1.24 (t, J ) 7.1 Hz, 6H), 3.28-3.51 (m, 4H), 4.03 (br s,
1H), 4.64 (s, 2H), 7.22-7.34 (m, 10H); 13C NMR δ 13.9, 42.8,
74.0, 126.5, 127.1, 128.5, 144.6, 160.9. Anal. Calcd for
g, 44%), mp 171-172 °C; IR (KBr) νmax 1625, 1595, 1560 cm-1
;
22
1
[R]
-40.0 (c 1.00, CHCl3); UV λmax 206.4 (ꢀ 26300) nm; H
D
NMR δ 1.11 (t, J ) 7.1 Hz, 3H), 3.15-3.27 (m, 2H), 4.55 (s,
2H), 7.18-7.31 (m, 10H); 13C NMR δ 15.4, 37.7, 73.4, 126.6,
128.5, 143.9, 160.7. Anal. Calcd for C17H19N3: C, 76.94; H,7.22;
N, 15.84. Found: C,76.70; H, 7.17; N, 15.89.
C
19H23N3: C, 77.77; H, 7.90; N, 14.32. Found: C, 77.64; H,
7.92; N, 14.34.
(4S,5S)-1-ter t-Bu toxyca r bon yl-4,5-d ip h en yl-3-m eth yl-
2-[(R)-1-p h en yleth ylim in o]im id a zolid in e (84). A 1.54 M
solution of n-BuLi in hexane (5.9 mL, 9.07 mmol) was dropped
to an ice-cooled solution of 48 (4.00 g, 9.07 mmol) in THF (31
mL) with stirring. After stirred at room temperature for 5 min,
methyl iodide (1.80 g, 12.7 mmol) was added. The whole was
Su p p or tin g In for m a tion Ava ila ble: Characterization
1
data of 12 and 16-81, H and 13C NMR charts of 68, 84, 85,
and 89, 2D NMR charts of 84. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O000745N