Simple preparation of chiral 1,3-dimethyl-2-iminoimidazolidines (monocyclic guanidines) and applications to asymmetric alkylative esterification

Article abstract of DOI:10.1016/S0957-4166(98)00152-9

New chiral 1,3-dimethyl-2-iminoimidazolidines (monocyclic guanidines) were simply prepared by the action of primary amines on 2-chloro-1,3- dimethylimidazolinium chlorides, derived from the corresponding urea, in high yields. Modest asymmetric induction i

Full text of DOI:10.1016/S0957-4166(98)00152-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1729–1735
Simple preparation of chiral 1,3-dimethyl-2-iminoimidazolidines
(
monocyclic guanidines) and applications to asymmetric
alkylative esterification
a,b
a
b,∗
Toshio Isobe, Keiko Fukuda and Tsutomu Ishikawa
a
Central Research Laboratory, Shiratori Pharmaceutical Co. Ltd, 6-11-24 Tsudanuma, Narashino, Chiba 275-0016, Japan
b
Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
Received 13 March 1998; accepted 17 April 1998
Abstract
New chiral 1,3-dimethyl-2-iminoimidazolidines (monocyclic guanidines) were simply prepared by the action of
primary amines on 2-chloro-1,3-dimethylimidazolinium chlorides, derived from the corresponding urea, in high
yields. Modest asymmetric induction in alkylative esterification of benzoic acid with (1-bromoethyl)benzene was
observed when the 1,3-dimethyl-4,5-diphenyl-2-[(1-phenyl-or 1-naphthyl)ethylimino]imidazolidineswith all S (or
R) configurations were used as bases. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The use of chiral guanidine derivatives as synthetic tools has appeared limited because of diffi-
culties in their preparation, in spite of the potential usefulness of guanidine derivatives as stronger
1
bases than amines. Successful asymmetric inductions were observed in the aldol reaction of benz-
2
aldehyde with nitromethane and in the Strecker amino acid synthesis using guanidines with C -
2
symmetry and a simple guanidine with a cyclic peptide, respectively, as catalysts. Recently Mioskowski
3
4
et al. reported the simple preparation of chiral guanidinium salts. We have explored 2-chloro-1,3-
dimethylimidazolinium chloride (DMC) 1 as a new dehydrating reagent to replace dicyclohexylcarbo-
5
diimide (DCC) 2 and demonstrated its synthetic utilities. 1,3-Dimethyl-2-iminoimidazolidines as mono-
cyclic guanidines could be easily prepared from DMC 1 and related compounds by the action of
appropriate primary amines. Thus, we focused on the ability of chiral cyclic guanidines 3 based on
1,3-dimethylimidazolidines as functionalized catalysts for asymmetric induction.
∗
Corresponding author. E-mail: benti@p.chiba-u.ac.jp
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00152-9

1730
T. Isobe et al. / Tetrahedron: Asymmetry 9 (1998) 1729–1735
6
The formation of esters is a fundamental reaction in organic chemistry, in which the most general
method is acylation of an alcohol through O–acyl bond formation. Thus, there are known asymmetric
esterifications using either achiral acylating agents in the presence of chiral auxiliaries such as optically
7
8
9
active amines and phosphines or chiral acylating agents. On the other hand, alkylation of carboxylic
acids through O–alkyl bond formation is an alternative useful method because of the advantage of the
neutral conditions, in which metal salts of acids were usually used as nucleophiles. Barton et al.10
succeeded in the preparation of hindered esters from the corresponding guanidinium salts of carboxylic
11
acids. However, no reports on asymmetric esterification by this O-alkylation method have appeared
to date. In this paper we present the simple preparation of chiral 1,3-dimethyl-2-iminoimidazolidines
(monocyclic guanidines) 3 and their first application to the asymmetric alkylative esterification of benzoic
acid 8 with (1-bromoethyl)benzene 9.
2. Results and discussion
Preparation of guanidines 3 is shown in Scheme 1. A guanidine 3a with one stereogenic center was
easily obtained by action of a chiral primary amine to DMC 1. Monocyclic guanidines 3b–h with
additional stereogenic centers were similarly prepared from the cyclic urea 5,12 derived from (1S,2S)-
1,2-diphenyl-1,2-ethylenediamine 4, through the corresponding imininum chloride 7 after methylation.
Scheme 1.
Before attempts at the asymmetric alkylative esterification, enantiomerically pure (R)-(−)-1-phenethyl
2
8
13
benzoate 10, [α]D −28.3 (c=1.00, CHCl ) {lit. [α] −28.8 (c=0.89, CHCl )} was prepared in 92%
3
D
3
yield by the condensation of benzoic acid 8 with (R)-(+)-1-phenethyl alcohol in the presence of DMC 1.
A solution of 8 (1 equiv.) and (1-bromoethyl)benzene 9 (2 equiv.) in either dichloromethane or benzene
in the presence of a chiral guanidine 3 (1 equiv.) was stirred at room temperature. The reaction was
monitored by TLC. After work-up, the crude product was purified by column chromatography. The
optical purity of the benzoate 10 was determined from its specific rotation. The results are summarized
in Table 1.

T. Isobe et al. / Tetrahedron: Asymmetry 9 (1998) 1729–1735
1731
Table 1
Attempted asymmetric esterification of benzoic acid 8 with (1-bromoethyl)benzene 9 in the presence
of a chiral cyclic guanidine 3
The simple guanidine 3a without diphenyl substituents led to precipitation of the guanidium salt of 8
during the reaction when benzene was used as the solvent (run 1). Although the complete reaction was
achieved by the replacement of benzene by dichloromethane, essentially no asymmetric induction was
observed (run 2).
In the case of (4S,5S)-diphenyl substituted guanidines 3b–h: (i) benzene was found to be a more
suitable solvent than dichloromethane (runs 3 and 4); (ii) guanidines 3b and 3d, derived from (S)-1-
naphthylethyl- or (S)-1-phenethylamines (runs 4 and 6), are more matched than 3c and 3e from the
enantiomeric (R)-amines (runs 5 and 7); (iii) the absolute configuration of the product was dependent
upon that of an amine outside of the imidazolidine ring in these cases; (iv) no improvement was observed
when guanidines 3f, 3g, and 3h derived from amino alcohols and an achiral amine, respectively, were
used.
A comparable reaction using quinine as a base also resulted in an incomplete reaction with less
effective asymmetric induction (run 11).
In conclusion, we could show the potential possibility of chiral monocyclic guanidines for basic
auxiliaries in organic reactions. At present we are examining their further utility in asymmetric reactions
such as the Michael reaction.
3. Experimental section
IR spectra were recorded with a JASCO IR-700 spectrophotometer. H and 13C NMR spectra were
1
recorded in CDCl solution with JEOL JNM GSX-300 spectrometers with tetramethylsilane as an
3

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T. Isobe et al. / Tetrahedron: Asymmetry 9 (1998) 1729–1735
internal reference. High resolution fast-atom bombardment MS (HRFABMS) was recorded on a JEOL
JMS-HX 110A and JMS-700-T spectrometers with a direct inlet system. For column chromatography,
silica gel 60 (70–230 mesh ASTM; Merck) was used, while for TLC and preparative TLC (PLC), silica
gel GF254 (Merck) was used.
3.1. (4S,5S)-1,3-Dimethyl-4,5-diphenylimidazolidin-2-one 6
To a suspension of NaH (55% in mineral oil, 2.0 g, 46 mmol) in DMF (50 ml) under a nitrogen
12
atmosphere, was added portionwise (4S,5S)-4,5-diphenylimidazolidin-2-one 5 (5.0 g, 21 mmol) and the
mixture was stirred at room temperature (rt) for 40 min. After addition of iodomethane (6.6 g, 46 mmol)
the mixture was stirred at rt overnight, poured into 5% HCl, and then extracted with dichloromethane
(
2×100 ml). The organic solution was washed with water, dried (MgSO ), and evaporated to dryness
4
under reduced pressure. Purification of the residue by column chromatography (CHCl ) followed by
recrystallization from MeOH gave 6 as colorless prisms (5.5 g, 99%), mp 153–155°C. IR (KBr) ν cm :
1
3
−
1
1
13
700. H-NMR δ: 2.70 (6H, s), 4.08 (2H, s), 7.12–7.15 (4H, m), 7.32–7.37 (6H, m). C-NMR δ:
2
9.98, 70.31, 127.26, 128.42, 128.84, 138.04, 161.84. [α]D24 +41.8 (c=1.00, CHCl ). Anal. calcd for
3
C H N O: C, 76.66; H, 6.81; N, 10.52. Found: C, 76.64; H, 6.78; N, 10.47.
17
18
2
3.2. (4S,5S)-2-Chloro-1,3-dimethyl-4,5-diphenylimidazolinium chloride 7
A solution of 6 (4.3 g, 16 mmol) and oxalyl chloride (2.5 g, 19 mmol) in anhydrous benzene (100 ml)
was refluxed for 12.5 h. After cooling, the precipitate was filtered, repeatedly washed with anhydrous
benzene, and dried under reduced pressure to give 7 as hygroscopic colorless prisms (2.1 g, 41%), mp
1
13
2
3
2
20–221°C. H-NMR δ: 3.21 (6H, s), 5.30 (2H, s), 7.43–7.45 (6H, m), 7.57–7.60 (4H, m). C-NMR δ:
4.08, 75.10, 128.86, 129.68, 130.32, 132.59, 157.96. [α]D27 −128.9 (c=1.00, CHCl ). HRFABMS m/z:
3
85.1158 (calcd for C H N Cl: 285.1160).
17
18
2
3.3. General procedure for preparation of (4S,5S)-2-imino-1,3-dimethyl-4,5-diphenylimidazolidines
To a solution of a primary amine (8.94 mmol) and triethylamine (1.81 g, 17.9 mmol) in
dichloromethane (50 ml) was added dropwise a solution of either 1 or 7 (8.94 mmol) in dichloromethane
40 ml) at rt. The mixture was stirred at rt for 20 min, poured into dil. HCl, and extracted with
(
dichloromethane (2×100 ml). The organic solution was evaporated to dryness. The residue was
dissolved in water and washed with toluene (2×100 ml). The aqueous solution was made alkaline with
dil. aq. NaOH and extracted with toluene. The toluene solution was dried (Na SO ) and evaporated to
2
4
dryness to yield pure guanidines. In some cases further purification was needed.
.4. 1,3-Dimethyl-2-[(1S)-1-(1-naphthyl)ethylimino]imidazolidine 3a
Colorless fine prisms (recryst. from MeOH), mp 77–78°C, in 94% yield. IR (KBr) ν cm : 1625.
3
−
1
1
UV (MeOH) λmax (ε): 224 (92900), 282 (7500). H-NMR δ: 1.54 (3H, d, J=6.4 Hz), 2.77 (6H, br s),
.09–3.19 (4H, m), 5.62 (1H, q, J=6.4 Hz), 7.26–7.52 (3H, m), 7.69 (1H, d, J=8.1 Hz), 7.85 (2H, d, J=7.7
3
13
Hz), 8.19 (1H, d, J=8.4 Hz). C-NMR δ: 27.48, 50.98, 123.31, 123.35, 124.92, 125.41, 125.92, 126.33,
1
7
28.86, 130.24, 133.83, 145.24, 155.72. [α]D23 +123.0 (c=1.00, CHCl ). Anal. calcd for C H N : C,
3
17 21
3
6.38; H, 7.92; N, 15.72. Found: C, 76.42; H, 7.90; N, 15.83.

T. Isobe et al. / Tetrahedron: Asymmetry 9 (1998) 1729–1735
1733
3.5. (4S,5S)-1,3-Dimethyl-4,5-diphenyl-2-[(1S)-1-(1-naphthyl)ethylimino]imidazolidine 3b
Colorless prisms [purified by column chromatography (ethyl acetate:hexane=1:5)], mp 133–134°C, in
−
1
1
9
(
(
1
5% yield. IR (KBr) ν cm : 1670. UV (MeOH) λ
(ε): 224 (72200), 283 (6100). H-NMR δ: 1.72
max
3H, d, J=6.6 Hz), 2.74 (6H, s), 3.86 (2H, br s), 5.85 (1H, q, J=6.6 Hz), 6.88–7.27 (10H, m), 7.45–7.56
3H, m), 7.77 (1H, d, J=7.7 Hz), 7.88–7.92 (2H, m), 8.31 (1H, d, J=8.3 Hz). 13C-NMR δ: 27.36, 50.62,
23.32, 123.58, 124.99, 125.36, 125.77, 126.50, 127.46, 127.97, 128.46, 128.95, 130.56, 134.02, 138.65,
44.18, 155.80. [α]D +105.4 (c=1.00, CHCl ). Anal. calcd for C H N : C, 83.02; H, 6.97; N, 10.02.
Found: C, 82.83; H, 6.98; N, 10.04.
21
1
3
29 29
3
3.6. (4S,5S)-1,3-Dimethyl-4,5-diphenyl-2-[(1R)-1-(1-naphthyl)ethylimino]imidazolidine 3c
−
1
Amorphous mass, 80% yield. IR (KBr) ν cm : 1650. UV (MeOH) λ
(ε): 224 (97800), 282 (8600).
max
1
H-NMR δ: 1.62 (3H, d, J=6.4 Hz), 2.64 (6H, br s), 3.86 (2H, s), 5.75 (1H, q, J=6.4 Hz), 7.15–7.35 (10H,
m), 7.42–7.54 (3H, m), 7.72 (1H, d, J=8.1 Hz), 7.86 (1H, d, J=7.7 Hz), 8.03 (1H, d, J=7.1 Hz), 8.24 (1H,
13
d, J=8.3 Hz). C-NMR δ: 27.14, 51.27, 123.36, 123.65, 124.95, 125.42, 126.00, 126.43, 127.60, 128.03,
1
28.49, 128.85, 130.29, 133.84, 138.71, 145.45, 155.74. [α]D21 +3.3 (c=1.00, CHCl ). Anal. calcd for
3
C H N : C, 83.02; H, 6.97; N, 10.02. Found: C, 83.19; H, 7.01; N, 9.97.
29
29
3
3.7. (4S,5S)-1,3-Dimethyl-4,5-diphenyl-2-[(1S)-1-phenylethylimino]imidazolidine 3d
−
1
Colorless fine prisms, mp 69–71°C, in 75% yield. IR (KBr) ν cm : 1660. UV (MeOH) λ
(ε):
max
1
2
07 (39300). H-NMR δ: 1.57 (3H, d, J=6.4 Hz), 2.75 (6H, br s), 3.83 (2H, br s), 5.08 (1H, q, J=6.4
13
Hz), 7.04–7.37 (13H, m), 7.51 (2H, d, J=7.1 Hz). C-NMR δ: 28.59, 54.25, 125.91, 126.21, 127.46,
1
27.98, 128.08, 128.32, 128.46, 138.68, 149.14, 156.33. [α]D22 +40.2 (c=1.00, CHCl ). Anal. calcd for
3
C H N : C, 81.26; H, 7.36; N, 11.37. Found: C, 81.28; H, 7.35; N, 11.37.
25
27
3
3.8. (4S,5S)-1,3-Dimethyl-4,5-diphenyl-2-[(1R)-1-phenylethylimino]imidazolidine 3e
−
1
Colorless fine prisms, mp 108–109°C, in 70% yield. IR (KBr) ν cm : 1655. UV (MeOH) λ
max
1
(
ε): 208 (40600). H-NMR δ: 1.48 (3H, d, J=6.4 Hz), 2.68 (6H, s), 3.86 (2H, s), 5.07 (1H, q, J=6.4
13
Hz), 7.03–7.05 (4H, m), 7.13–7.35 (9H, m), 7.53 (2H, d, J=7.1 Hz). C-NMR δ: 27.59, 54.36, 125.87,
26.22, 127.53, 128.01, 128.06, 128.29, 128.47, 138.66, 149.26, 156.77. [α]D22 +68.1 (c=1.00, CHCl3).
Anal. calcd for C H N : C, 81.26; H, 7.36; N, 11.37. Found: C, 81.31; H, 7.38; N, 11.41.
1
25
27
3
3.9. (4S,5S)-2-[(1R)-1-Benzyl-2-hydroxyethylimino]-1,3-dimethyl-4,5-diphenylimidazolidine 3f
−
1
Colorless fine prisms, mp 112–114°C, in 85% yield. IR (KBr) ν cm : 1625. UV (MeOH) λ
(ε):
max
1
2
(
4
+
07 (38600). H-NMR δ: 2.70 (6H, br s), 2.82 (2H, d, J=6.8 Hz), 3.60 (1H, dd, J=10.1, 6.0 Hz), 3.71
1H, dd, J=10.1, 4.2 Hz), 3.57–3.73 (2H, m), 4.25–4.29 (1H, m), 7.04–7.36 (15H, m). 13C-NMR δ:
0.20, 57.00, 66.22, 125.88, 127.48, 128.09, 128.12, 128.51, 129.73, 138.38, 140.09, 157.97. [α]D23
76.5 (c=1.00, CHCl ). Anal. calcd for C H N O: C, 78.16; H, 7.32; N, 10.52. Found: C, 78.30; H,
3
26 29
3
7.43; N, 10.56.

1734
T. Isobe et al. / Tetrahedron: Asymmetry 9 (1998) 1729–1735
3.10. (4S,5S)-1,3-Dimethyl-4,5-diphenyl-2-[(1S)-1-hydroxymethyl-2-methylpropylimino]imidazolidine
3g
−
1
1
Colorless oil, 74% yield. IR (KBr) ν cm : 1665. UV (MeOH) λ
(ε): 207 (35000). H-NMR δ:
max
1
3
3
.03 (3H, d, J=6.8 Hz), 1.04 (3H, d, J=7.0 Hz), 1.81–1.95 (1H, m), 2.70 (6H, br s), 3.56–3.67 (2H, m),
13
.75–3.80 (1H, m), 3.89 (2H, br s), 7.12–7.15 (4H, m), 7.23–7.39 (6H, m). C-NMR δ: 18.66, 20.29,
2.25, 60.63, 64.07, 127.51, 128.16, 128.32, 128.58, 138.46, 156.68. [α]D20 +36.3 (c=1.00, CHCl3).
HRFABMS m/z: 352.2372 (calcd for C H N O: 352.2389).
22
30
3
3.11. (4S,5S)-1,3-Dimethyl-4,5-diphenyl-2-propyliminoimidazolidine 3h
−
1
Colorless fine prisms (recryst. from hexane), mp 83–85°C, in 90% yield. IR (KBr) ν cm : 1645.
1
H-NMR δ: 1.01 (3H, t, J=7.3 Hz), 1.24–1.27 (2H, m), 2.62 (3H, br s), 2.79 (3H, br s), 3.33–3.42 (1H,
13
m), 3.50–3.59 (1H, m), 3.84 (2H, s), 7.12–7.18 (4H, m), 7.26–7.33 (6H, m). C-NMR δ: 13.36, 27.99,
5
0.92, 129.01, 129.46, 129.93, 140.07, 158.42. [α]D22 +69.7 (c=1.00, CHCl ). Anal. calcd for C H N :
3
20 25
3
C, 78.14; H, 8.20; N, 13.67. Found: C, 77.96; H, 8.31; N, 13.59.
3.12. Preparation of optically pure (R)-(−)-10
To a solution of 8 (1.00 g, 8.19 mmol), (R)-(+)-1-phenylethanol (1.00 g, 8.19 mmol) and 1 (1.66
g, 9.83 mmol) in acetonitrile (20 ml) was added dropwise pyridine (1.55 g, 19.7 mmol) at rt. The
mixture was stirred at rt for 23 h, poured into water and extracted with dichloromethane (2×30 ml). The
organic solution was successively washed with 5% HCl, sat. aq. NaHCO and water, dried (MgSO ), and
3
4
evaporated to dryness. The residue was purified by column chromatography (ethyl acetate:hexane=1:50)
28
13
to give (R)-(−)-10 (1.70 g, 92%) as a colorless oil, [α]
−28.3 (c=1.00, CHCl ) {lit. [α] −28.8
D
3
D
(
c=0.89, CHCl )}.
3
3.13. Asymmetric alkylation in the presence of 3b: typical procedure (run 4 in Table 1)
To a solution of 8 (0.140 g, 1.15 mmol) and 9 (0.426 g, 2.30 mmol) in benzene (10 ml) was
added (4S,5S)-4,5-diphenyl-1,3-dimethyl-2-[(1S)-1-(1-naphthyl)ethylimino]imidazolidine 3b (0.483 g,
.15 mmol). The mixture was stirred at rt for 2 days, diluted with benzene (30 ml), successively washed
with 5% HCl, water and sat. aq. NaHCO , dried (MgSO ), and evaporated to dryness. The residue was
1
3
4
purified by column chromatography (ethyl acetate:hexane=1:100) to give 10 (0.193 g, 74%) as a colorless
23
oil, [α]D −4.3 (c=1.00, CHCl3).
Acknowledgements
We thank Mr. Hisao Matsumoto of the Yamanouchi Pharmaceutical Co. Ltd and Ms. Ritsuko Hara
of the Chemical Analysis Center, Chiba University for the measurement of the HRFABMS spectra and
Ms. Etsuko Yamaoka of the Yamanouchi Pharmaceutical Co. Ltd and Dr. Hiroko Seki of the Chemical
Analysis Center, Chiba University for the elemental analyses.

T. Isobe et al. / Tetrahedron: Asymmetry 9 (1998) 1729–1735
1735
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3. Evans, D. A.; Anderson, J. C.; Taylor, M. K. Tetrahedron Lett. 1993, 34, 5563–5566. Although Kabuto et al. [Kabuto, K.;
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2
1
enantiomer as [α]D −20.7 (c=2.28, EtOH), the specific rotation of our pure sample was [α]
D
−32.4 (c=2.28, EtOH).