Synthesis of 4,5-dihydro-1H-imidazole-4-carboxylates from α-amino acid amidines

Article abstract of DOI:10.1055/s-2006-942476

Various β-hydroxy-substituted amidines were obtained starting from methyl serinates, aldehydes or ketones, and tosyl azide. These were converted via Mitsunobu intramolecular cyclization into enantiomerically pure methyl 2-alkyl-1-tosyl-4,5-dihydro-1H-imid

Full text of DOI:10.1055/s-2006-942476

PAPER
2693
Synthesis of 4,5-Dihydro-1H-imidazole-4-carboxylates from a-Amino Acid
Amidines
4
, 5-Dihydro-1
H
m
-imidazole-4-carbox
a
ylates from
n
a
-
Amino
A
u
cid
A
midine
e
s
la Erba,* Donato Pocar, Pasqualina Trimarco
Istituto di Chimica Organica ‘Alessandro Marchesini’ e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi
Etero-e Carbociclici, Università degli Studi di Milano, Via G. Venezian 21, 20133 Milano, Italy
Fax +39(0250)314476; E-mail: emanuela.erba@unimi.it
Received 22 March 2006; revised 10 April 2006
R1
R1
R1
Abstract: Various b-hydroxy-substituted amidines were obtained
starting from methyl serinates, aldehydes or ketones, and tosyl
azide. These were converted via Mitsunobu intramolecular cycliza-
tion into enantiomerically pure methyl 2-alkyl-1-tosyl-4,5-dihydro-
1H-imidazole-4-carboxylates.
N
Y
+
Y
NH2
O
NH
Y
R2
R2
R2
ArN3
R1
R2
R1 R2
Key words: N,N¢-disubstituted amidines, intramolecular cycliza-
tion, Mitsunobu reaction, 4,5-dihydro-1H-imidazole-4-carboxy-
lates, amino acid
N
N
N
HN
Y
N Ar
HN
Y
Ar
Scheme 2
4,5-Dihydro-1H-imidazole derivatives and particularly
4,5-dihydro-1H-imidazole-4-carboxylic acids have at-
tracted substantial interest due to their interesting biolog-
ical activity.1 In addition, these heterocycles have useful
functions, e.g. as chiral auxiliaries,2 chiral catalysts,3 and
ligands for asymmetric catalysis.4 Furthermore there are
very few reports of the synthesis of imidazole-based ami-
no acids.5 The aim of this work was the synthesis of 4,5-
dihydro-1H-imidazole-4-carboxylic acid derivatives from
a-amino acid ester amidines following the retrosynthetic
route shown in Scheme 1.
group was protected as the trimethylsilyl ether. The pro-
tected L-serine methyl ester (S)-1 was reacted with cyclo-
hexanone (2a) and tosyl azide yielding amidine (S)-3a.
Finally the silyl group was removed by acid hydrolysis
with citric acid7 and the amidine (S)-4a with a free hy-
droxy group was easily obtained. The structure of (S)-3a
and (S)-4a was established by analytical and spectroscop-
ic data. Due to the good results, the reaction was extended
to butanal (2b) and phenylacetaldehyde (2c) (Scheme 3,
Table 1). Cyclohexanone (2a) was also reacted with D-
serine (R)-1.
Z
Z
CO2R
CO2R
CO2R
NH
H
N
N
N
N
N
Table 1 b-Hydroxy-Substituted Amidines 4
X
X
X
Y
Y
Y
Substrates
(S)-1 + 2a
(R)-1 + 2a
(S)-1 + 2b
(S)-1 + 2c
Product(s) R1
R2
Yield (%)
56
Scheme 1
(S)-4a
(R)-4a
4b
(CH2)4
(CH2)4
Et
62
Our group recently reported a simple and useful synthetic
entry to optically pure a-amino acid amidines through het-
erocyclic transformations.6 The cycloaddition of tosyl
azide with enamines gives 4,5-dihydrotriazole intermedi-
ates, which, by loss of nitrogen and transposition of the R2
substituent from position 5 to 4, are transformed into the
expected amidines (Scheme 2). Starting from amino acid
esters, carbonyl compounds, and tosyl azide, we obtained
directly the amidines containing the entire amino acid
function.
H
H
51
4c + 4d
Ph
31 + 23
As expected, the behavior of phenylacetaldehyde (2c),
was different from that of the other carbonyl compounds.8
In the literature examples, phenylacetaldehyde can react
with ketones or aldehydes and tosyl azide to give form-
amidines with loss of diazophenylmethane. In this case a
substantial amount of phenylacetamidine 3c was obtained
beside the expected formamidine 3d. All protected
amidines were hydrolyzed and to give 4a–d with a free
hydroxy group. It is of interest to note that the amidines 3
and 4, arising from optically pure amino acids, retain their
optical activity. The intramolecular cyclization of the
amidines 4a–c, target of this study, was easily performed
under Mitsunobu conditions. The reaction was carried out
With the aim to realize the proposed retrosynthetic
scheme and to synthesize b-substituted amidines, methyl
serinates were selected as the amino acid substrate. To
avoid unwelcome secondary reactions, the serine hydroxy
SYNTHESIS 2006, No. 16, pp 2693–2696
Advanced online publication: 11.07.2006
DOI: 10.1055/s-2006-942476; Art ID: Z05306SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
6

2694
E. Erba et al.
PAPER
O
HO
Ts
CO2Me
NH
CO2Me
TMSO
+
R2
TsN
R1
N
H2N
CO2Me
R1
N
2
1
R2
R2
R1
a
(S)-4a,b,c
(S)-5a,b,c
R1
R2
N
HO
CO2Me
NH
CO2Me
N
N
NH
MeO2C
TsN
Ts
N
N
Ts
TMSO
R2
R1
R2
R1
(R)-4a
(R)-5a
Scheme 4 Reagents and conditions: amidine (1 mmol), Ph3P (1
mmol), DEAD (1 mmol), THF, r.t., 2 h.
CO2Me
NH
TMSO
Ts
CO2Me
NH
TMSO
Table 2 Methyl 2-Alkyl-1-tosyl-4,5-dihydro-1H-imidazole-4-car-
boxylates 5a–c
N
N
R1
Substrate
(S)-4a
(R)-4a
4b
Product
(S)-5a
(R)-5a
5b
R1
R2
Yield (%)
Ts
R2
3d
3a–c
(CH2)4
(CH2)4
Et
45
47
39
32
b
b
H
H
4c
5c
Ph
CO2Me
NH
HO
CO2Me
NH
HO
Ts
Products 5a–c, examined by HPLC using chiral column
(Chiralcell OD, hexane–i-PrOH, 7:3 as eluent), showed
the retention of the original enantiomeric purity.
N
N
R1
Ts
R2
4a–c
4d
Mps were determined by a Büchi 510 (capillary) apparatus. Optical
rotation was measured with Perkin Elmer 343 Plus polarimeter (c
10% in CHCl3; 20 °C). IR spectra were measured with a JASCO IR
Report 100 instrument. NMR spectra were obtained with Bruker
Advance 300 and Varian Gemini 200 instruments. J values are giv-
en in Hz for solutions in CDCl3. HPLC was performed with HP
1050 DAD, Merck–Hitachi L 7100 pump, Rheodyne loop 20 mL in-
jector, Chiralcel OD column, 1 mL/min flow. MS were recorded
with LCQ Advantage Thermofinnigan equipped with electrospray
ionization. (S)- or (R)-O-(Trimethylsilyl)serine was synthesized by
a literature method11 from (S)- or (R)-serine methyl ester hydrochlo-
ride.
Scheme 3 Reagents and conditions: (a) amino acid ester 1 (6
mmol), carbonyl compound 2 (6 mmol), TsN3 (6 mmol), MS 4 Å (7
g), CH2Cl2, r.t., 16–18 h; (b) citric acid (6 mmol), MeOH, r.t., 2 h.
under an inert atmosphere with anhydrous tetrahydrofu-
ran as solvent. A molar amount of diethyl azodicarboxy-
late and triphenylphosphine was added to the solution of
amidine 4a–c (Scheme 4, Table 2). The cyclization reac-
tion was accomplished in 1–2 hours affording methyl 2-
alkyl-1-tosyl-4,5-dihydro-1H-imidazole-4-carboxylates
5a–c. The 1H NMR, 13C NMR spectra, and mass data were
in agreement with the proposed structures. Cyclization of
4d gave several indistinct products.
Amidines 4a–d: General Procedure
(S)- or (R)-O-(Trimethylsilyl)serine 1 (6 mmol) was suspended in
CH2Cl2 (20 mL) and carbonyl compound 2a–c (6 mmol), molecular
sieves 4 Å (7 g), and tosyl azide (6 mmol) were added. The mixture
was stirred at r.t. until disappearance of starting material (TLC,
EtOAc–cyclohexane, 1:1; 16–18 h). The suspension was filtered
and evaporated. The crude product 3 was suspended in MeOH (10
mL) and citric acid (6 mmol) was added. The mixture was stirred at
r.t. for 2 h and then evaporated. The resulting raw amidine 4 was
washed with NaHCO3 soln, dried (Na2SO4), and purified by chro-
matography (silica gel, EtOAc–cyclohexane, 1:1).
The separation of the reaction byproducts from products 5
was difficult and time consuming. In fact the crude reac-
tion mixtures were evaporated and diethyl hydrazine-1,2-
dicarboxylate was partially removed by crystallizing
twice from toluene (other dialkyl azodicarboxylates
showed a similar solubility). After evaporation the crude
residue was chromatographed on a silica gel column.
Some fractions had to be discarded as they were contami-
nated by diethyl hydrazine-1,2-dicarboxylate. Diethyl
azodicarboxylate polymer-supported9 and polyfluorinated
reagents10 were tested without encouraging results.
Methyl (S)-2-{[Cyclopentyl(tosylimino)methyl]amino}-3-hy-
droxypropanoate [(S)-4a]
White crystals (EtO2–pentane); yield: 56%; mp 84 °C.
[a]D20 +21.34 (c 10% in CHCl3).
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4,5-Dihydro-1H-imidazole-4-carboxylates from a-Amino Acid Amidines
2695
IR (Nujol): 1740 cm–1 (C=O).
13C NMR (75 MHz): d = 21.50 (CH3), 53.3 (CH3), 56.3 (CH), 61.8
(CH2), 126.6 (CH), 129.4 (CH), 138.4 (C), 143.1 (C), 157.4 (C),
169.8 (C).
1H NMR (200 MHz): d = 1.64–2.37 (m, 9 H, cyclopentyl, OH), 2.40
(s, 3 H, CH3), 3.75 (s, 3 H, OCH3), 3.80–3.91 (m, 1 H, CHC=N),
3.90–4.00 (m, 2 H, CH2O), 4.58–4.65 (m, 1 H, CH=N), 6.45 (d,
J = 6.6 Hz, 1 H, NH), 7.23–7.42 (m, 2 H, ArH), 7.75–7.86 (m, 2 H,
ArH).
13C NMR (75 MHz): d = 21.7 (CH3), 25.8 (CH2), 25.8 (CH2), 32.1
(CH2), 32.2 (CH2), 43.0 (CH), 56.4 (CH3), 56.4 (CH), 62.1 (CH2),
126.4 (CH), 129.4 (CH), 140.9 (C), 142.5 (C), 170.6 (C), 172.4 (C).
MS (ESI): m/z = 301.2 [M + H+].
Anal. Calcd for C12H16N2O5S: C, 58.04; H, 7.14; N, 9.02. Found: C,
57.89; H, 7.30; N, 8.98.
Methyl 2-Alkyl-1-tosyl-4,5-dihydro-1H-imidazole-4-carboxy-
lates 5a–c: General Procedure
The amidine 4a–c (1 mmol) was dissolved in anhyd THF (10 mL)
under N2 at r.t. Ph3P (1 mmol) and DEAD (1 mmol) were added and
the mixture was stirred for 2 h until disappearance of starting mate-
rials (TLC, EtOAc–cyclohexane, 3:2). The soln was evaporated at
reduced pressure and diethyl hydrazine-1,2-dicarboxylate was re-
moved by repeated crystallization (toluene). The toluene soln was
evaporated and the residue chromatographed (EtOAc–cyclohexane,
1:1).
MS (ESI): m/z = 369.2 [M + H+]
Anal. Calcd for C17H24N2O5S: C, 55.42; H, 6.57; N, 7.60. Found: C,
55.30; H, 6.77; N, 7.48.
Methyl (R)-2-{[Cyclopentyl(tosylimino)methyl]amino}-3-
hydroxypropanoate [(R)-4a]
White crystals (EtO2–pentane); yield: 62%; mp 84 °C.
[a]D20 –21.34 (c 10% in CHCl3).
Methyl (S)-2-Cyclopentyl-1-tosyl-4,5-dihydro-1H-imidazole-4-
carboxylate [(S)-5a]
Light yellow oil; yield: 45%.
[a]D20 +80.60 (c 10% in CHCl3).
IR (Nujol): 1744 cm–1 (C=O).
1H NMR (300 MHz): d = 1.60–1.99 (m, 8 H, 4 CH2), 2.40 (s, 3 H,
CH3), 3.29–3.40 (m, 1 H, CHC=N), 3.67 (s, 3 H, CH3O), 3.91–4.09
(m, 2 H, CH2), 4.51–4.60 (m, 1 H, CH), 7.31 (d, J = 7.14 Hz, 2 H,
ArH), 7.76 (d, J = 7.14 Hz, 2 H, ArH).
13C NMR (75 MHz): d = 21.8 (CH3), 25.8 (CH2), 25.9 (CH2), 32.1
(CH2), 32.4 (CH2), 38.9 (CH), 50.8 (CH2), 52.8 (CH3), 65.5 (CH),
127.4 (CH), 130.3 (CH), 135.6 (C), 144.9 (C), 166.2 (C), 171.3 (C).
Methyl (S)-3-Hydroxy-2-{[1-(tosylimino)butyl]amino}pro-
panoate (4b)
Light yellow oil; yield: 51%.
[a]D20 +21.82 (c 10% in CHCl3).
IR (Nujol): 1744 cm–1 (C=O).
1H NMR (200 MHz): d = 0.99 (t, J = 8.10 Hz, 3 H, CH3), 1.69–1.84
(m, 2 H, CH2), 2.40 (s, 3 H, CH3), 2.60 (br s, 1 H, OH), 2.70–2.93
(m, 2 H, CH2), 3.64 (s, 3 H, CH3), 3.91–3.94 (m, 2 H, CH2O), 4.61–
4.68 (m, 1 H, CH), 6.58 (d, J = 7.0 Hz, 1 H, NH), 7.26 (d, J = 7.1
Hz, 2 H, ArH), 7.76 (d, J = 7.1 Hz, 2 H, ArH).
13C NMR (75 MHz): d = 13.9 (CH3), 20.9 (CH2), 21.7 (CH3), 35.8
(CH2), 53.1 (CH3), 56.6 (CH), 62.2 (CH2), 126.6 (CH), 129.6 (CH),
140.6 (C), 142.6 (C), 169.0 (C), 170.5 (C).
MS (ESI): m/z = 351.3 [M + H+].
Anal. Calcd for C17H22N2O4S: C, 58.27; H, 6.33; N, 7.99. Found:
C, 58.02; H, 6.50; N, 7.78.
MS (ESI): m/z = 343.3 [M + H+].
Anal. Calcd for C15H22N2O5S: C, 52.62; H, 6.48; N, 8.18. Found: C,
52.48; H, 6.66; N, 8.01.
Methyl (R)-2-Cyclopentyl-1-tosyl-4,5-dihydro-1H-imidazole-4-
carboxylate [(R)-5a]
Light yellow oil; yield: 47%.
[a]D20 –80.60 (c 10% in CHCl3).
Methyl (S)-3-Hydroxy-2-{[2-phenyl-1-(tosylimino)ethyl]ami-
no}propanoate (4c)
Light yellow oil; yield: 31%.
[a]D20 +22.98 (c 10% in CHCl3).
IR (Nujol): 1750 cm–1 (C=O).
Methyl (S)-2-Propyl-1-tosyl-4,5-dihydro-1H-imidazole-4-car-
boxylate (5b)
Light yellow oil; yield: 39%.
[a]D20 +79.4 (c 10% in CHCl3).
IR (Nujol): 1740 cm–1 (C=O).
1H NMR (200 MHz): d = 0.99 (t, J = 7.95 Hz, 3 H, CH3), 1.73–1.85
(m, 2 H, CH2), 2.40 (s, 3 H, C6H4CH3), 2.80–2.95 (m, 2 H, CH2),
3.69 (s, 3 H, OCH3), 4.05–4.25 (m, 2 H, CH2), 4.74–4.83 (m, 1 H,
CH), 7.39 (d, J = 7.14 Hz, 2 H, ArH), 7.77 (d, J = 7.14 Hz, 2 H,
ArH).
13C NMR (75 MHz): d = 13.9 (CH3), 19.1 (CH2), 21.7 (CH3), 38.3
(CH2), 44.7 (CH2), 52.4 (CH), 53.0 (CH3), 127.2 (CH), 130.0 (CH),
136.9 (C), 143.9 (C), 170.9 (C), 173.9 (C).
1H NMR (200 MHz): d = 2.04 (br s, 1 H, OH), 2.40 (s, 3 H, CH3),
3.67 (s, 3 H, OCH3), 3.85–3.89 (m, 2 H, CH2O), 4.31 (s, 2 H,
CH2Ph), 4.49–4.62 (m, 1 H, CH), 6.29 (d, J = 8.3 Hz, 1 H, NH),
7.21–7.38 (m, 7 H, ArH), 7.77 (d, J = 7.14 Hz, 2 H, ArH).
13C NMR (75 MHz): d = 21.7 (CH3), 39.7 (CH2), 53.1 (CH3), 56.7
(CH), 62.0 (CH2), 126.6 (CH), 128.4 (CH), 129.5 (CH), 129.6 (CH),
130.2 (CH), 132.9 (C), 140.3 (C), 142.8 (C), 166.9 (C), 170.1 (C).
MS (ESI): m/z = 391.3 [M + H+].
Anal. Calcd for C19H22N2O5S: C, 58.45; H, 5.68; N, 7.17. Found: C,
58.36; H, 5.79; N, 6.96.
MS (ESI): m/z = 325.2 [M + H+].
Methyl (S)-3-Hydroxy-2-{[(tosylimino)methyl]amino}pro-
panoate (4d)
Light yellow oil; yield: 23%.
[a]D20 +21.60 (c 10% in CHCl3).
IR (Nujol): 1742 cm–1 (C=O).
1H NMR (200 MHz): d = 1.79 (br, 1 H, OH), 2.39 (s, 3 H, CH3),
3.76 (s, 3 H, OCH3), 3.80–4.10 (m, 2 H, CH2), 4.68–4.75 (m, 1 H,
CH), 6.93 (br s, 1 H, NH), 7.26 (d, J = 7.14 Hz, 2 H, ArH), 7.73 (d,
J = 7.14 Hz, 2 H, ArH), 8.34 (d, J = 5.01 Hz, 1 H, CH=N).
Anal. Calcd C15H20N2O4S: C, 55.54; H, 6.21; N, 8.64. Found: C,
55.36; H, 6.35; N, 8.57.
Methyl (S)-2-Benzyl-1-tosyl-4,5-dihydro-1H-imidazole-4-car-
boxylate (5c)
Light yellow oil; yield: 32%.
[a]D20 +78.6 (c 10% in CHCl3).
IR (Nujol): 1743 cm–1 (C=O).
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E. Erba et al.
PAPER
(2) (a) Jones, R. C. F.; Turner, I.; Howard, K. J. Tetrahedron
1H NMR (200 MHz): d = 2.40 (s, 3 H, C6H4CH3), 3.74 (s, 3 H,
OCH3), 4.00–4.13 (m, 2 H, CH2), 4.21 (s, 2 H, CH2Ph), 4.67–4.71
(m, 1 H, CH), 7.05–7.75 (m, 9 H, ArH).
13C NMR (75 MHz): d = 21.5 (CH3), 35.4 (CH2), 50.2 (CH2), 52.7
(CH3), 65.4 (CH), 127.0 (CH), 127.2 (CH), 128.5 (CH), 129.2 (CH),
128.9 (CH), 134.8 (C), 134.9 (C), 144.6 (C), 160.2 (C), 170.8 (C).
Lett. 1993, 34, 6329. (b) Jones, R. C. F.; Howard, K. J.;
Snaith, J. S. Tetrahedron Lett. 1996, 37, 1707. (c)Langlois,
Y.; Dalko, P. I. J. Org. Chem. 1998, 63, 8107.
(3) (a) Doyle, M. P.; Morgan, J. P.; Colyer, J. T. J. Organomet.
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Lett. 2005, 7, 5035. (b) Menges, F.; Neuburger, M.; Pfaltz,
A. Org. Lett. 2002, 4, 4713.
MS (ESI): m/z = 373.3 [M + H+].
Anal. Calcd C19H20N2O4S: C, 61.27; H, 5.41; N, 7.52; Found: C,
61.05; H, 5.63; N, 7.43.
(5) (a) Haberhauer, G.; Rominger, F. Tetrahedron Lett. 2002,
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6, 1681.
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Acknowledgment
We thank Ministero dell’Istruzione, dell’Università e della Ricerca
(MIUR) for financial support.
(7) Bundy, G. L.; Peterson, D. C. Tetrahedron Lett. 1978, 19,
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Synthesis 2006, No. 16, 2693–2696 © Thieme Stuttgart · New York