A flexible three-component synthesis of novel δ-amino acids incorporating an imidazo[1,2-a]pyridine backbone

Article abstract of DOI:10.1055/s-2006-942506

Methyl 2-trimethylsiloxycyclopropanecarboxylates 1,2-aminopyridine (2), and isonitriles 3 combine in a one-pot reaction to provide a series of novel δ-amino acids 4 incorporating an imidazo[1,2-a]pyridine backbone. Scope and limitations of this new three-

Full text of DOI:10.1055/s-2006-942506

PAPER
2677
A Flexible Three-Component Synthesis of Novel d-Amino Acids Incorporating
an Imidazo[1,2-a]pyridine Backbone
d
-Amino
v
Acids
w
ith
a
I
midazo
n
a
]pyridin
a
e
B
ackbone Veljkovic, Reinhold Zimmer, Hans-Ulrich Reissig,* Irene Brüdgam, Hans Hartl
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 3 March 2006; revised 18 April 2006
In Memory of Professor Ivar Ugi
Abstract: Methyl 2-trimethylsiloxycyclopropanecarboxylates 1, 2-
aminopyridine (2), and isonitriles 3 combine in a one-pot reaction
to provide a series of novel d-amino acids 4 incorporating an imida-
zo[1,2-a]pyridine backbone. Scope and limitations of this new
three-component synthesis were investigated. Several reactions of
compounds 4 affording suitably protected derivatives such as 5, 6
and 9 were performed to allow couplings with L-alanine derivatives.
The expected peptides 11 and 12 were obtained by standard cou-
pling reactions with excellent or moderate yield. Cyanide-catalyzed
reactions converted compounds 4e and 4h into tricyclic d-lactams
10e and 10h in very good yields.
N
N
R
O
R
R
R
NH
R
NH HN
R
CO2Me
CO2Me
R
A
B
Figure 1 Equivalence of methyl (3-aminoimidazo[1,2-a]pyridin-2-
yl)propanoates A to B
Key words: amino acids, cyclopropanes, pyridines, lactams, pep-
tides
broad range of physiological effects (e.g. antibacterial, an-
tiviral, anti-inflammatory, analgesic activities).7
In this paper we report on scope and limitations of the syn-
thesis of compounds A starting from siloxycyclopropanes
and we also reveal first model reactions to couple these
novel d-amino acids with L-alanine derivatives to produce
small peptides.
Synthesis as well as structural and biological evaluation of
amino acids and peptides derived thereof with modified –
in particular restricted – conformations are recent topics in
bioorganic and medicinal chemistry.1 Simple, efficient
and highly flexible methods to generate new ‘unnatural’
amino acids are of particular importance, and among other
strategies multicomponent reactions have found numer-
ous applications to approach this goal.2 In many of these
reactions aldehydes are crucial components in the pro-
ceeding reaction cascades. In several examples we could
demonstrate that methyl 2-siloxycyclopropanecarboxy-
lates are equivalents of functionalized and substituted car-
bonyl compounds.3 They are prepared from the
trimethylsiloxycyclopropane derivatives under very mild
conditions (either neutral, with fluoride or slightly acidic
or basic media) and thus these cyclopropane derivatives
can directly be introduced into multicomponent reac-
tions.4,5 Recent reports on the synthesis of imidazo[1,2-
a]pyridines by an Ugi-type reaction of 2-aminopyridine
with aldehydes and isonitriles attracted our attention,6
since a related process with methyl 2-siloxycyclopropane-
carboxylates as aldehyde equivalents should directly pro-
vide compounds A. The expected products are d-amino
acids incorporating an imidazo[1,2-a]pyridine backbone,
which can be regarded as a conformationally altered
dipeptide B (Figure 1). In addition, imidazo[1,2-a]pyri-
dine derivatives are of general interest because of their
Methyl 2-siloxycyclopropanecarboxylates 1 (1 to 1.1
equiv), 2-aminopyridine (2) (1 equiv), and isonitriles 3 (1
equiv) were stirred in a mixture of acetic acid (2 equiv)
and methanol for 19–48 hours at room temperature. After
acidic work up (which destroys remaining isonitrile) and
chromatographic purification we obtained methyl (3-ami-
noimidazo[1,2-a]pyridin-2-yl)propanoates 4 in moderate
to good yields (Scheme 1). With respect to the cyclopro-
panes 1, the parent compound (entries a, b), monomethyl
substituted (entry c), dimethyl substituted (entries d, e, f,
g), and trimethyl substituted (entry h) derivatives were
also suitable aldehyde equivalents. The isonitrile compo-
nent can bear a tertiary alkyl, a benzyl, or an aryl substitu-
ent. Although not examined, other 2-aminopyridine
derivatives may also be used. Hence, this one-pot three-
component reaction leading to d-amino acid derivatives 4
with an imidazo[1,2-a]pyridine backbone seems to allow
a fairly broad substitution pattern. For the synthesis of
compound 4g (entry g) the yield was 62% when the mix-
ture was exposed to microwave irradiation,8 whereas only
43% yield was obtained under the standard conditions ap-
plied for all other entries of Scheme 1.
For heterocycle 4g, we could also obtain suitable crystals
for an X-ray analysis, which not only proved the constitu-
tion of the product but also showed that the propanoate
side chain is spatially in close proximity to the arylamino
group (Figure 2).
SYNTHESIS 2006, No. 16, pp 2677–2684
x
x.
x
x
.
2
0
0
6
Advanced online publication: 19.07.2006
DOI: 10.1055/s-2006-942506; Art ID: T03306SS
© Georg Thieme Verlag Stuttgart · New York

2678
I. Veljkovic et al.
PAPER
R4 NC
3
AcOH,
MeOH
ammonium salt derived from 4f facilitates the cleavage of
the methyl ester. According to the X-ray crystal structure
of the related dimethyl substituted compound 4g, the
methoxycarbonyl is in close proximity of the amino sub-
stituents (Figure 2) which might exhibit a neighboring
group effect. No further attempts have been made to selec-
tively deprotect compound 4f. Employing sodium hy-
dride, DMAP and Boc-anhydride, compound 7 was
converted into the N-protected d-amino acid 8 with rea-
sonable efficacy (Scheme 2). We had to recognize already
here that the amino groups of imidazo[1,2-a]pyridine de-
rivatives are fairly unreactive under acylation conditions.
R3 R2
N
R1
N
Me3SiO
+
R1
r.t.,
19–48 h
N
NH2
R4 NH
CO2Me
R3
CO2Me
R2
1
2
4
Entry R1
R2
R3
R4
Yield
56%
a
b
c
d
e
f
H
H
H
H
H
H
t-Bu
CMe2CH2CMe3 79%
H
Me
Me
Me
Me
Me
Me
H
t-Bu
t-Bu
Bn
57%
46%
57%
H
Me
Me
Me
Me
Me
H
H
H
CMe2CH2CMe3 56%a
p-MeOC6H4
Bn
g
h
62%b
40%
N
CF3CO2H, CH2Cl2 (1:1)
Me
N
N
N
a In addition of 30% of compound 7.
b Under microwave conditions.
r.t., 2 h
94%
H2N
N
CO2Me
H
CO2Me
Scheme 1 Synthesis of methyl (3-aminoimidazo[1,2-a]pyridin-2-
yl)propanoates 4 by one-pot reaction of siloxycyclopropanes 1, 2-
aminopyridine 2 and isonitriles 3
5
4b
N
CF3CO2H, CH2Cl2 (1:1)
N
N
N
r.t., 5 min 25% 6, 50% 7
H2N
r.t., 2 h
80% 7
N
CO2Me
H
CO2Me
6
4f
N
N
H2N
Boc2O, NaH,
DMAP, THF
CO2H
7
78%
N
N
Figure 2 X-ray crystal structure of compound 4g
BocHN
CO2H
Since we wanted to prepare small model peptides includ-
ing d-amino acids derived from 4, we had to convert these
compounds into suitably protected intermediates. Treat-
ment of compound 4b with trifluoroacetic acid for two
hours at room temperature furnished the expected amino
ester 5 in excellent yield (Scheme 2).9 Surprisingly, when
identical conditions were applied to the higher substituted
analog 4f not only the tetramethylbutyl group was dis-
placed, but in addition the methyl ester was cleaved pro-
viding the amino acid 7 in 80% yield. Precursor 4f seems
to be particular sensitive to acid since amino acid 7 was
isolated as a by-product in 30% yield during synthesis of
4f. We therefore shortened the reaction time of 4f with tri-
fluoroacetic acid to five minutes at room temperature and
obtained a mixture of the required amino ester 6 (25%
yield) and of the amino acid 7 (50% yield). The deprotec-
tion reactions of 4f thus occur under milder acidic condi-
tions. We speculate that the particular conformation of the
8
Scheme 2 Trifluoroacetic acid promoted deprotections of 4b and 4f
leading to amino esters 5, 6 and amino acid 7 and Boc-protection of 7
to d-amino acid 8
Saponification of the amino ester 4e proceeded without
problem and afforded the expected N-benzyl-protected
amino acid 9 in 77% yield (Scheme 3). It should be men-
tioned here that attempts to debenzylate compounds such
as 4e and 4h were not successful and in general led to de-
composition of the heterocycles. However, we discovered
a smooth cyclization method to transform d-amino acid
derivatives into tricyclic d-lactam derivatives. By cyanide
catalysis in refluxing methanol10 (most likely via the cor-
responding acyl cyanides11) precursors 4e and 4h deliv-
ered the dipyrido[1,2-a;3¢,2¢-d]imidazol-2-ones 10e and
10h in excellent yields (Scheme 3).
Synthesis 2006, No. 16, 2677–2684 © Thieme Stuttgart · New York

PAPER
d-Amino Acids with an Imidazo[1,2-a]pyridine Backbone
2679
this problem and take profit of the apparently restricted
conformation of this particular skeleton.
LiOH,
H2O, MeOH, THF
N
N
N
N
In conclusion, we have demonstrated that the novel three-
component synthesis of siloxycyclopropanes 1 with 2-
aminopyridine (2) and isonitriles 3 efficiently provided
new d-amino acid derivatives 4 incorporating a 2-imida-
zo[1,2-a]pyridine backbone. This transformation again
proved the equivalence of siloxycyclopropanes 1 to sub-
stituted and functionalized aldehydes, which are difficult
to prepare by alternative methods. In various model reac-
tions the heterocyclic amino acid derivatives 4 were suit-
ably protected and coupled with L-alanine derivatives to
afford the expected peptides 11 or 12. Furthermore, a mild
method was found to convert compounds 4 into the tricy-
clic d-lactams 10. Future studies should be devoted to the
synthesis of longer peptide chains – optionally under mul-
tiple inclusion of derivative 4 – and to the elucidation of
the influence of the 2-imidazo[1,2-a]pyridine backbone
on the conformation of the resulting constructs.
Bn
Bn
N
r.t., 22 h
N
H
H
77%
CO2Me
CO2H
4e
9
N
N
cat. NaCN, MeOH
reflux, 43–48 h
N
N
R
Bn
Bn
N
N
H
CO2Me
O
R
4e (R = H)
4h (R = Me)
10e (92%)
10h (98%)
Scheme 3 Preparation of d-amino acid 9 and of dipyrido[1,2-
a;3¢,2¢-d]imidazol-2-ones 10e and 10h
With amino acid derivatives 8 and 5 we tried model reac-
tions to generate small peptides. The peptide coupling of
acid 8 with L-alanine methyl ester was conventionally
performed with benzotriazol-1-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate12 (BOP) as activating
agent and furnished almost quantitatively compound 11,
which may be regarded as a tripeptide equivalent
(Scheme 4). On the other hand, reaction at the amino
group of ester 5 with N-Boc-protected L-alanine required
the very powerful coupling reagent tetramethylfluoro-
formamidinium hexafluorophosphate13 (TFFH) and still
only 26% of the desired product 12 was obtained. It
should be mentioned that experiments employing the di-
methyl substituted compound 6 did not result in peptide
formation. This may again be the effect of the conforma-
tions of these compounds (see discussion above and
Figure 2). Further investigations are required to overcome
All reactions were performed under argon in flame-dried flasks, and
the components were added by means of syringes. All solvents were
dried by standard methods. TLC was carried out on commercial
Polygram Sil G/UV254 or Polygram Alox N/UV254 (Macherey &
Nagel). Column chromatography was performed using 70–230
mesh silica gel (Merck) or neutral aluminum oxide (activity grade-
III; Fluka or Merck). Nucleosil 50-5 (Macherey & Nagel) was used
for HPLC. Unless stated otherwise, 1H NMR and 13C NMR spectra
were determined on Bruker (AM-270, AC-500) or JEOL (Eclipse
500) instruments. The chemical shifts are related to TMS or to the
CDCl3 signal (dH = 7.26, dC = 77.0). Higher order NMR spectra
were approximately interpreted as first-order spectra, if possible.
Missing signals could not be unambiguously identified due to low
intensity. IR spectra were measured on Nicolet spectrometer FTIR
5 SXC. MS and HRMS analyses were performed on Finnigan MAT
711 (EI, 80 eV, 8 kV), MAT CH7A (EI, 80 eV, 3 kV) and CH5DF
(FAB, 80 eV, 3 kV) instruments. Elemental analyses were per-
formed on a Perkin Elmer CHN analyzer 2400. Melting points were
determined with a Büchi MP 510 apparatus and are uncorrected.
_
+
H3N
CO2Me
Cl
BOP, DIEA, CH2Cl2
97%
N
N
N
N
BocHN
BocHN
CO2H
NH
O
CO2Me
8
11
BocHN
CO2H
TFFH, DIEA, CH2Cl2
N
N
N
N
O
H2N
N
26%
BocHN
H
CO2Me
CO2Me
5
12
Scheme 4 Couplings of L-alanine derivatives with amino acid 8 to peptide 11 and with amino ester 5 to peptide 12
Synthesis 2006, No. 16, 2677–2684 © Thieme Stuttgart · New York

2680
I. Veljkovic et al.
PAPER
Boiling points of compounds obtained in small-scale experiments
refer to the temperature in a Büchi Kugelrohrofen. Starting materi-
als 114 and p-methoxyphenylisocyanide15 were prepared using
known procedures. All other chemicals were commercially avail-
able and were used as received.
13C NMR (CDCl3, 125.8 MHz): d = 22.8 (t, CH2), 29.1 (q, CH3),
31.7 (s, CMe3), 31.9 (q, CH3), 33.3 (t, CH2), 51.4 (q, OCH3), 56.8
(t, CH2), 59.5 (s, NCMe2), 110.6 (d, C-6), 116.6 (d, C-8), 123.2 (d,
C-7), 123.5 (d, C-5), 123.8 (s, C-3), 139.2 (s, C-2), 142.0 (s, C-9),
173.9 (s, C=O).
MS (EI): m/z (%) = 331 (27, [M]+), 220 (14), 219 (100), 218 (79),
186 (22), 161 (12), 160 (71), 159 (16), 158 (12), 146 (21), 131 (16),
119 (11), 85 (53), 84 (71), 79 (11), 78 (40), 57 (42), 55 (18), 49 (14),
47 (18), 43 (20), 41 (23), 29 (15), 28 (34).
Ugi-Type Reaction of Methyl Siloxycyclopropanecarboxylates
1 and Isonitriles 3 with 2-Aminopyridine (2), General Proce-
dure
Methyl siloxycyclopropanecarboxylate 1 (1–1.1 equiv), 2-amino-
pyridine (2; 1 equiv) and the corresponding isonitrile 3 (1 equiv)
were dissolved in anhyd MeOH (2.5–3 mL/mmol of 2) under argon.
After addition of AcOH (2 equiv), the mixture was stirred at r.t. for
the time indicated in the individual experiment. Then 1 M HCl so-
lution was added to adjust pH 1, the mixture was stirred for 30 min
to destroy unreacted isocyanide 3 and then evaporated to dryness.
The residue was taken up in sat. aq NaHCO3 solution (2 mL/mmol
of 2) and extracted with EtOAc (3 × 10 mL/mmol of 2). The com-
bined organic phases were dried (Na2SO4) and the solvent was re-
moved under reduced pressure. The resulting crude product was
purified by column chromatography on silica gel (EtOAc–
hexane, 2:1) and in some cases followed by HPLC (20% i-PrOH–
hexane).
HRMS: m/z calcd for C19H29N3O2: 331.2260; found: 331.2264.
Methyl 3-(3-tert-Butylaminoimidazo[1,2-a]pyridin-2-yl)bu-
tanoate (4c)
According to general procedure, a mixture of methyl 3-methyl-2-
trimethylsiloxycyclopropanecarboxylate (0.202 g, 1.00 mmol), 2-
aminopyridine (0.094 g, 1.00 mmol), tert-butyl isocyanide (0.084 g,
1.00 mmol) and AcOH (0.120 g, 2.00 mmol) in MeOH (3 mL) gave
after 12 h at r.t., 0.166 g (57%) of 4c as amber crystals; mp 63–
65 °C.
IR (KBr): 3320–3220 (N–H), 3060–2850 (=C–H, C–H), 1730
(C=O), 1635 (C=N) cm–1.
1H NMR (CDCl3, 270 MHz): d = 1.20 (s, 9 H, t-C4H9), 1.45 (d, J = 7
Hz, 3 H, CH3), 1.65 (s, 1 H, NH), 2.60 (d, J = 7 Hz, 2 H, CH2), 2.80
(d, J = 7 Hz, 2 H, CH2), 3.45 (br s, 1 H, NH), 3.48–3.53 (m, 1 H,
CH), 3.55 (s, 3 H, CO2CH3), 6.65 (dd, J = 7, 7.5 Hz, 1 H, 6-H), 7.05
(dd, J = 7.5, 9 Hz, 1 H, 7-H), 7.45 (d, J = 9 Hz, 1 H, 8-H), 8.15 (d,
J = 7 Hz, 1 H, 5-H).
13C NMR (CDCl3, 125.8 MHz): d = 20.1 (q, CH3), 27.5 (d, CH),
30.1, 54.9 (q, s, t-C4H9), 41.2 (t, CH2), 51.3 (q, OCH3), 110.5 (d, C-
6), 116.6 (d, C-8), 123.2 (d, C-5), 123.3 (s, C-3), 123.5 (d, C-7),
142.1, 142.9 (2 s, C-2, C-9), 173.6 (s, C=O).
MS (EI): m/z (%) = 289 (37, [M]+), 274 (10, [M – CH3]+), 258 (7,
[M – OMe]+), 233 (37, [M – C4H8]+), 232 (100, [M – C4H9] +), 160
(28), 79 (16, [C5H5N]+), 78 (46, [C5H4N]+), 57 (13, [t-Bu]+), 41 (12,
[C3H5]+), 29 (8, [C2H5]+).
Methyl 3-(3-tert-Butylaminoimidazo[1,2-a]pyridin-2-yl)pro-
panoate (4a)
According to general procedure, a mixture of methyl 2-trimethylsi-
loxycyclopropanecarboxylate (0.510 g, 2.71 mmol), 2-aminopyri-
dine (0.258 g, 2.74 mmol), tert-butyl isocyanide (0.225 g, 2.67
mmol) and AcOH (0.325 g, 5.41 mmol) in MeOH (8 mL) gave after
12 h at r.t., 0.420 g (56%) of 4a as a foamy resin.
IR (neat): 3330–3220 (N–H), 3060–2800 (=C–H, C–H), 1730
(C=O), 1630 (C=N) cm–1.
1H NMR (CDCl3, 270 MHz): d = 1.20 (s, 9 H, t-C4H9), 2.75 (t, J = 7
Hz, 2 H, CH2), 3.00 (t, J = 7 Hz, 2 H, CH2), 3.40 (s, 1 H, NH), 3.55
(s, 3 H, OCH3), 6.60 (dd, J = 7, 7.5 Hz, 1 H, 6-H), 7.05 (dd, J = 7.5,
9 Hz, 1 H, 7-H), 7.45 (d, J = 9 Hz, 1 H, 8-H), 8.10 (d, J = 7 Hz, 1 H,
5-H).
HRMS: m/z calcd for C16H23N3O2: 289.1790; found: 289.1772.
13C NMR (CDCl3, 67.9 MHz): d = 22.6 (t, CH2), 30.2, 55.4 (q, s, t-
C4H9), 33.3 (t, CH2), 51.5 (q, OCH3), 110.7 (d, C-6), 116.5 (d, C-8),
123.4 (d, 2 C, C-5, C-7), 124.1 (s, C-3), 138.8 (s, C-2), 141.9 (s, C-
9), 174.1 (s, C=O).
MS (EI): m/z (%) = 275 (41, [M]+), 260 (2, [M – CH3]+), 244 (9, [M
– OMe]+), 218 (100, [M – C4H9]+), 191 (12), 186 (10), 160 (28), 159
(13), 78 (45, [C5H4N]+), 57 (7, [t-Bu]+), 41 (5, [C3H5]+), 29 (5,
[C2H5]+).
Methyl 3-(3-tert-Butylaminoimidazo[1,2-a]pyridin-2-yl)-3-
methylbutanoate (4d)
According to general procedure, a mixture of methyl 3,3-dimethyl-
2-trimethylsiloxycyclopropanecarboxylate (0.648 g, 3.00 mmol), 2-
aminopyridine (0.283 g, 3.00 mmol), tert-butyl isocyanide (0.253 g,
3.00 mmol) and AcOH (0.361 g, 6.00 mmol) in MeOH (9 mL) gave
after 12 h at r.t., 0.419 g (46%) of 4d as colorless crystals; mp 183–
185 °C.
HRMS: m/z calcd for C15H21N3O2: 275.1638; found: 275.1656.
IR (KBr): 3300–3230 (N–H), 3080–2860 (=C–H, C–H), 1730
(C=O), 1630 (C=N) cm–1.
1H NMR (CDCl3, 270 MHz): d = 1.25 (s, 9 H, t-C4H9), 1.55 (br s, 1
H, NH), 1.65 (s, 6 H, CH3), 3.05 (s, 2 H, CH2), 3.55 (s, 3 H, OCH3),
7.15 (dd, J = 7.5, 8.0 Hz, 1 H, 6-H), 7.60 (dd, J = 7.5, 9.0 Hz, 1 H,
7-H), 8.35 (d, J = 9.0 Hz, 1 H, 8-H), 8.50 (d, J = 8.0 Hz, 1 H, 5-H).
13C NMR (CDCl3, 67.9 MHz): d = 28.7 (q, CH3), 31.2, 54.8 (q, s, t-
Bu), 34.8 (s, CMe2), 45.5 (t, CH2), 51.6 (q, OCH3), 113.4 (d, C-6),
115.5 (d, C-8), 124.3 (s, C-3), 124.7 (d, C-5), 131.2 (d, C-7), 133.8,
137.2 (2 s, C-2, C-9), 171.9 (s, C=O).
MS (EI): m/z (%) = 303 (35, [M]+), 287 (3, [M – CH4]+), 272 (6, [M
– OMe]+), 247 (27, [M – C4H8]+), 246 (100, [M – t-Bu]+), 214 (29),
198 (10), 78 (29, [C5H4N]+), 73 (18, [C4H11N]+), 57 (85, [t-Bu]+), 43
(65, [C3H7]+), 29 (19, [C2H5]+).
Methyl 3-{3-(1,1,3,3-Tetramethylbutyl)aminoimidazo[1,2-a]py-
ridin-2-yl}propanoate (4b)
According to general procedure, a mixture of methyl 2-trimethylsi-
loxycyclopropanecarboxylate (0.827 g, 4.40 mmol), 2-aminopyri-
dine (0.376 g, 4.00 mmol), 1,1,3,3-tetramethylbutyl isocyanide
(0.558 g, 4.00 mmol) and AcOH (0.500 g, 8.00 mmol) in MeOH (12
mL) gave after 48 h at r.t., 1.07 g (79%) of 4b as a yellowish oil.
IR (neat): 3335 (N–H), 3090–2870 (C–H), 1735 (C=O), 1630
(C=N) cm–1.
1H NMR (CDCl3, 270 MHz): d = 1.05, 1.12 (2 s, 9 H, 6 H, CH3),
1.64 (s, 2 H, CH2), 2.76 (t, J = 6.8 Hz, 2 H, CH2), 3.01 (t, J = 6.8 Hz,
2 H, CH2), 3.21 (br s, 1 H, NH), 3.56 (s, 3 H, OCH3), 6.63 (td,
J = 6.8, 1.2 Hz, 1 H, 6-H), 6.86 (ddd, J = 9.0, 6.8, 1.2 Hz, 1 H, 7-H),
7.34 (dt, J = 9.0, 1.2 Hz, 1 H, 8-H), 8.11 (dt, J = 6.8, 1.2 Hz, 1 H, 5-
H).
HRMS: m/z calcd for C17H25N3O2: 303.1947; found: 303.1911.
Synthesis 2006, No. 16, 2677–2684 © Thieme Stuttgart · New York

PAPER
d-Amino Acids with an Imidazo[1,2-a]pyridine Backbone
2681
Methyl 3-(Benzylaminoimidazo[1,2-a]pyridin-2-yl)-3-methyl-
butanoate (4e)
According to general procedure, a mixture of methyl 3,3-dimethyl-
2-siloxycyclopropanecarboxylate (0.216 g, 1.00 mmol), 2-amino-
pyridine (0.094 g, 1.00 mmol), benzyl isocyanide (0.118 g, 1.00
mmol) and AcOH (0.120 g, 2.00 mmol) in MeOH (3 mL) gave after
19 h at r.t., 0.201 g (57%) of 4e as a pale yellow oil.
1H NMR (CDCl3, 250 MHz): d = 1.50 (s, 6 H, CH3), 2.82 (s, 2 H,
CH2), 3.55, 3.72 (2 s, 3 H, 3 H, OCH3), 5.79 (s, 1 H, NH), 6.20–6.26
(m, 2 H, Ar), 6.50 (td, J = 6.8, 1.2 Hz, 1 H, 6-H), 6.54–6.60 (m, 2
H, Ar), 6.94 (ddd, J = 9.1, 6.8, 1.2 Hz, 1 H, 7-H), 7.34 (dt, J = 9.1,
1.2 Hz, 1 H, 8-H), 7.58 (dt, J = 6.8, 1.2 Hz, 1 H, 5-H).
13C NMR (CDCl3, 67.9 MHz): d = 28.3 (q, CH3), 35.3 (s, CMe2),
46.0 (t, CH2), 51.1 (q, OCH3), 55.6 (q, ArOCH3), 111.4 (d, C-6),
114.0 (d, C-8), 115.1 (d, C-5), 117.2 (d, C-7), 118.6 (s, C-3), 122.6,
124.0 (2 d, Ar), 139.2 (s, Ar), 141.4 (s, C-2), 146.3 (s, C-9), 153.1
(s, Ar), 172.9 (s, C=O).
MS (EI): m/z (%) = 354 (100, [M]+), 294 (30), 281 (38), 151 (11),
147 (25), 112 (15), 95 (12), 94 (42), 86 (21), 85 (16), 84 (42), 83
(17), 78 (28), 73 (21), 71 (23), 70 (20), 69 (32), 67 (15), 60 (22), 57
(46), 56 (19), 55 (35), 45 (37), 44 (37), 43 (71), 42 (14), 39 (19).
IR (KBr): 3375 (N–H), 3085–2950 (=C–H, C–H), 1735 (C=O),
1630 (C=N) cm–1.
1H NMR (CDCl3, 250 MHz): d = 1.58 (s, 6 H, CH3), 2.82 (s, 2 H,
CH2), 3.50 (s, 3 H, OCH3), 3.62 (br s, 1 H, NH), 4.13 (s, 2 H,
CH2Ph), 6.69 (td, J = 6.8, 1.2 Hz, 1 H, 6-H), 7.06 (ddd, J = 9.0, 6.8,
1.2 Hz, 1 H, 7-H), 7.25–7.49 (m, 6 H, 8-H, C6H5), 7.94 (dt, J = 6.8,
1.2 Hz, 1 H, 5-H).
13C NMR (CDCl3, 67.9 MHz): d = 28.4 (q, CH3), 35.3 (s, CMe2),
46.5 (t, CH2), 51.1 (q, OCH3), 52.9 (t, CH2Ph), 111.1 (d, C-6), 117.1
(d, C-8), 122.2 (d, C-5), 123.2 (d, C-7), 124.8 (s, C-3), 127.5, 128.0,
128.6 (3 d, C6H5), 139.2 (s, C6H5), 140.4 (s, C-2), 143.1 (s, C-9),
172.6 (s, C=O).
MS (EI): m/z (%) = 337 (32, [M]+), 247 (16), 246 (100), 219 (22),
214 (21), 105 (32), 78 (29), 73 (13).
Anal. Calcd for C20H23N3O3 (353.4): C, 67.97; H, 6.56; N, 11.89.
Found: C, 67.83; H, 6.47; N, 11.44.
Crystal Data
C20H23N3O3, Mr = 353.4; T = 173(2) K; crystal size: 0.5 × 0.2 × 0.1
mm; monoclinic, space group P2(1)/c, a = 9.870(4), b = 10.817(4),
c = 17.218(7) A; Z = 4; Dc = 1.290 Mg/m3; F(000) = 752; m(Mo-
K) = 0.088 mm–1. Q Range for data collection: 2.08–30.55°, index
ranges: –12£h£14, –15£k£14, –22£l£24; reflections collected/
unique: 13376/5119 (Rint = 0.0296); final R [I>2s(I)]: R1 = 0.0526,
wR2 = 0.1400. For structure solution and refinement, the programs
SHELXS97 and SHELXL97 were used.16,17
HRMS: m/z calcd for C20H23N3O2: 337.1790; found: 337.1784.
Methyl 3-{3-(1,1,3,3-Tetramethylbutyl)imidazo[1,2-a]pyridin-
2-yl}-3-methylbutanoate (4f)
According to general procedure, a mixture of methyl 3,3-dimethyl-
2-trimethylsiloxycyclopropanecarboxylate (0.951 g, 4.40 mmol), 2-
aminopyridine (0.376 g, 4.00 mmol), 1,1,3,3-tetramethylbutyl iso-
cyanide (0.558 g, 4.00 mmol) and AcOH (0.480 g, 8.00 mmol) in
MeOH (12 mL) gave after 48 h at r.t., 0.797 g (56%) of 4f as a pale
yellow oil and 0.280 g (30%) of 7 as colorless crystals (for analyti-
cal and spectral data of 7, see below).
Methyl 3-(Benzylaminoimidazo[1,2-a]pyridin-2-yl)-2,3-dimeth-
ylbutanoate (4h)
According to general procedure, a mixture of methyl 1,3,3-trimeth-
yl-2-trimethylsiloxycyclopropanecarboxylate (0.277 g, 1.20
mmol), 2-aminopyridine (0.094 g, 1.00 mmol), benzyl isocyanide
(0.118 g, 1.00 mmol) and AcOH (0.120 g, 2.00 mmol) in MeOH (3
mL) gave after 17 h at r.t., 0.140 g (40%) of 4h as a pale yellow oil.
IR (neat): 3370 (N–H), 3075–2870 (=C–H, C–H), 1735 (C=O),
1630 (C=N) cm–1.
IR (KBr): 3375 (N–H), 3085–2950 (=C–H, C–H), 1735 (C=O),
1630 (C=N) cm–1.
1H NMR (CDCl3, 270 MHz): d = 1.08, 1.22, 1.58 (3 s, 9 H, 3 H, 3
H, CH3), 1.69, 2.91 (2 s, 2 H, 2 H, CH2), 3.11 (s, 1 H, NH), 3.52 (s,
3 H, OCH3), 6.63 (td, J = 6.8, 1.2 Hz, 1 H, 6-H), 6.99 (ddd, J = 9.0,
6.8, 1.2 Hz, 1 H, 7-H), 7.38 (dt, J = 9.0, 1.2 Hz, 1 H, 8-H), 8.16 (dt,
J = 6.8, 1.2 Hz, 1 H, 5-H).
13C NMR (CDCl3, 67.9 MHz): d = 29.0, 30.3, 31.9 (3 q, CH3), 32.0,
35.9 (2 s, CMe3, CMe2), 46.6 (t, CH2), 51.1 (q, OCH3), 57.8 (t,
CH2), 58.8 (s, NCMe2), 110.3 (d, C-6), 116.8 (d, C-8), 122.5 (d, C-
5), 123.1 (d, C-7), 123.8 (s, C-3), 140.8 (s, C-2), 144.9 (s, C-9),
172.6 (s, C=O).
1H NMR (CDCl3, 250 MHz): d = 1.06 (d, J = 7.2 Hz, 3 H, CH3),
1.54 (s, 6 H, CH3), 3.17 (q, J = 7.2 Hz, 1 H, CH), 3.44 (t, J = 6.4 Hz,
1 H, NH), 3.50 (s, 3 H, OCH3), 4.07 (d, J = 6.4 Hz, 2 H, CH2Ph),
6.66 (td, J = 6.8, 1.1 Hz, 1 H, 6-H), 7.04 (ddd, J = 9.0, 6.8, 1.1 Hz,
1 H, 7-H), 7.24–7.55 (m, 6 H, 8-H, C6H5), 7.91 (dt, J = 6.8, 1.1 Hz,
1 H, 5-H).
13C NMR (CDCl3, 62.9 MHz): d = 13.1, 24.0, 26.0 (3 q, CH3), 38.5
(s, CMe2), 48.5 (d, CH), 51.0 (q, OCH3), 52.8 (t, CH2Ph), 111.2 (d,
C-6), 117.0 (d, C-8), 122.1 (d, C-5), 123.3 (d, C-7), 125.3 (s, C-3),
127.5, 127.9, 128.6 (3 d, C6H5), 139.0 (s, C6H5), 140.2 (s, C-2),
142.3 (s, C-9), 176.2 (s, C=O).
MS (EI): m/z (%) = 359 (66, [M]+), 328 (11), 248 (18), 247 (86),
246 (100), 219 (29), 215 (13), 214 (51), 188 (17), 174 (44), 105
(17).
MS (EI): m/z (%) = 351 (34, [M]+), 264 (14), 261 (20), 260 (100),
233 (16), 229 (12), 228 (66), 201 (10), 174 (16), 176 (15), 158 (14),
121 (21) 105 (19), 91 (10, [Bn]+), 78 (13).
HRMS: m/z calcd for C21H33N3O2: 359.2573; found: 359.2554.
Anal. Calcd for C21H33N3O2 (359.5): C, 70.16; H, 9.25; N, 11.69.
Found: C, 69.90; H, 9.14; N, 11.70.
HRMS: m/z calcd for C21H25N3O2: 351.1947; found: 351.1963.
Methyl 3-(3-Aminoimidazo[1,2-a]pyridin-2-yl)propanoate (5)
Compound 4b (0.643 g, 1.94 mmol) was dissolved in trifluoroacetic
acid–CH2Cl2 solution (1:1; 5 mL) and stirred for 2 h at r.t. The mix-
ture was loaded on a Dowex cation exchange resin, washed with
MeOH until it was acid-free and then eluted with MeOH saturated
with ammonia. The solvent was removed under reduced pressure
and the residue was purified by column chromatography (silica gel,
CH2Cl2–MeOH, 19:1); yield: 0.399 g (94%) of 5 as yellowish oil.
Methyl 3-{(4-Methoxyphenyl)aminoimidazo[1,2-a]pyridin-2-
yl}-3-methylbutanoate (4g)
According to general procedure, a mixture of methyl 3,3-dimethyl-
2-trimethylsiloxycyclopropanecarboxylate (0.238 g, 1.10 mmol), 2-
aminopyridine (0.094 g, 1.00 mmol), 4-methoxyphenyl isocyanide
(0.133 g, 1.00 mmol) and AcOH (0.120 g, 2.00 mmol) in MeOH (3
mL) gave after 60 min under microwave conditions (200 W,
Tmax = 30 °C), 0.218 g (62%) of 4g as pale brownish crystals;
mp 140–143 °C.
IR (KBr): 3320–3180 (N–H), 2950–2850 (=C–H, C–H), 1730
(C=O), 1670 (C=N) cm–1.
IR (KBr): 3270 (N–H), 3105–2825 (=C–H, C–H), 1730 (C=O),
1675 (C=N) cm–1.
Synthesis 2006, No. 16, 2677–2684 © Thieme Stuttgart · New York

2682
I. Veljkovic et al.
PAPER
1H NMR (CDCl3, 500 MHz): d = 2.78 (t, J = 6.7 Hz, 2 H, CH2),
3.02 (t, J = 6.7 Hz, 2 H, CH2), 3.52 (s, 3 H, OCH3), 6.05 (br s, 2 H,
NH2), 6.76 (t, J = 6.8 Hz, 1 H, 6-H), 7.03–7.19 (m, 1 H, 7-H), 7.42
(d, J = 9.1 Hz, 1 H, 8-H), 8.00 (d, J = 6.8 Hz, 1 H, 5-H).
13C NMR (CDCl3, 125.8 MHz): d = 21.6, 33.2 (2 t, CH2), 51.6 (q,
OCH3), 111.6 (d, C-6), 116.7 (d, C-8), 122.1 (d, C-5), 123.3 (d, C-
7), 123.4 (s, C-3), 132.7 (s, C-2), 140.2 (s, C-9), 174.1 (s, C=O).
MS (EI): m/z (%) = 219 (58, [M]+), 188 (16), 161 (14), 160 (100),
159 (19), 146 (52), 133 (14), 121 (16), 119 (25), 115 (14), 80 (24),
79 (82), 55 (15), 51 (17).
3-{3-[(tert-Butoxycarbonyl)amino]imidazo[1,2-a]pyridin-2-yl}-
3-methylbutanoic Acid (8)
A stirred solution of amino acid 5 (0.090 g, 0.386 mmol) in THF (6
mL) was treated with NaH (0.016 g, 0.038 mmol; 60% suspension
in oil), and further stirred for 1 h at r.t. Boc2O (0.168 g, 0.772 mmol)
was then added to the mixture, stirred for 1 h, and then treated with
a catalytic amount of DMAP followed by stirring for 1 h. The mix-
ture was partitioned between EtOAc and sat. aq NH4Cl solution and
the organic phase was separated and dried (Na2SO4). The solvent
was removed under reduced pressure and the resulting crude prod-
uct was purified by column chromatography (silica gel; 10%
i-PrOH–hexane) to give 0.100 g (78%) of 8 as brownish oil.
HRMS: m/z calcd for C11H13N3O2: 219.1008; found: 219.1016.
IR (KBr): 3445 (N–H), 3050–2875 (=C–H, C–H), 1785, 1740
(C=O), 1635 (C=N), 1290 (C–O) cm–1.
1H NMR (CDCl3, 250 MHz): d = 1.36 (s, 6 H, CH3), 1.49 (s, 9 H, t-
C4H9), 2.57 (s, 2 H, CH2), 6.75 (t, J = 6.9 Hz, 1 H, 6-H), 7.07 (t,
J = 6.9 Hz, 1 H, 7-H), 7.43–7.53 (m, 2 H, 8-H, 5-H).
13C NMR (CDCl3, 62.9 MHz): d = 26.0 (q, CH3), 27.7, 85.2 [q, s,
C(CH3)3], 31.6 (s, CMe2), 50.4 (t, CH2), 111.8 (d, C-6), 117.5 (d, C-
8), 118.0 (s, C-3), 122.7 (d, C-5), 123.0 (d, C-7), 140.4 (s, C-2),
142.3 (s, C-9), 148.5, 172.4 (2 s, C=O).
Methyl 3-(3-Aminoimidazo[1,2-a]pyridin-2-yl)-3-methylbu-
tanoate (6) and 3-(3-Aminoimidazo[1,2-a]pyridin-2-yl)-3-meth-
ylbutanoic Acid (7)
Compound 4f (0.116 g, 0.32 mmol) was dissolved in trifluoroacetic
acid–CH2Cl2 solution (1:1; 2 mL) and stirred for 5 min at r.t. The
mixture was loaded on a Dowex cation exchange resin, washed with
MeOH until it was acid-free and then eluted with MeOH saturated
with ammonia. The solvent was removed under reduced pressure
and the residue was purified by column chromatography (silica gel,
CH2Cl2–MeOH, 19:1); yield: 0.020 g (25%) of 6 as a yellow oil and
0.037 g (50%) of 7 as colorless crystals; mp 250–251 °C.
MS (EI): m/z (%) = 315 (2, [M – H2O]+), 215 (62), 200 (100), 78
(15), 57 (27).
According to the preparation described above, compound 4f (0.861
g, 2.40 mmol) was dissolved in trifluoroacetic acid–CH2Cl2 solu-
tion (1:1; 5 mL) and stirred for 2 h at r.t. Purification by column
chromatography (silica gel, CH2Cl2–MeOH, 19:1) gave 0.450 g
(80%) of 7 as colorless crystals.
HRMS: m/z calcd for C17H21N3O3 [M – H2O]+: 315.1583; found:
315.1573.
3-[3-(Benzylamino)imidazo[1,2-a]pyridin-2-yl]-3-methylbu-
tanoic Acid (9)
To a solution of compound 4e (0.109 g, 0.320 mmol) in MeOH–
THF (1 mL/3 mL), was added a solution of LiOH·H2O (0.041 g,
0.096 mmol) in H2O (1 mL), and the resulting mixture was stirred
for 22 h at r.t. Then aq 2 M HCl was added to adjust the pH to 7,
followed by Et2O and the layers were separated. The aqueous layer
was extracted with Et2O, the combined organic phases were dried
(MgSO4) and the solvent was evaporated. Purification of the crude
product by column chromatography (silica gel, hexane–EtOAc, 1:2)
gave 0.080 g (77%) of 9 as a pale yellow solid; mp 111–115 °C.
Compound 6
IR (KBr): 3380–3085 (N–H, O–H), 2950–2875 (=C–H, C–H), 1720
(C=O), 1610 (C=N) cm–1.
1H NMR (CDCl3, 500 MHz): d = 1.35 (s, 6 H, CH3), 2.54 (s, 2 H,
CH2), 3.91 (s, 3 H, OCH3), 6.75 (td, J = 6.7, 1.2 Hz, 1 H, 6-H), 7.02
(ddd, J = 9.0, 6.7, 1.2 Hz, 1 H, 7-H), 7.49 (dt, J = 9.0, 1.2 Hz, 1 H,
8-H), 8.09 (dt, J = 6.7, 1.2 Hz, 1 H, 5-H); the NH2 signal could not
be detected.
13C NMR (CDCl3, 125.8 MHz): d = 27.0 (q, CH3), 32.2 (s, CMe2),
42.8 (t, CH2), 53.7 (q, OCH3), 111.8 (d, C-6), 117.1 (d, C-8), 121.5
(d, C-5), 122.4 (d, C-7), 127.5 (s, C-3), 135.8 (s, C-2), 141.9 (s, C-
9), 165.9 (s, C=O).
MS (EI): m/z (%) = 229 (100, [M – NH4]+), 215 (14), 214 (95), 200
(15), 199 (14), 91 (12, [Bn]+), 85 (21), 83 (21), 78 (21), 55 (40), 45
(25), 43 (74), 41 (46).
IR (KBr): 3230–3030 (O–H, N–H), 2960–2870 (=C–H, C–H), 1680
(C=O), 1235 (C–O) cm–1.
1H NMR (CDCl3, 250 MHz): d = 1.38 (s, 6 H, CH3), 2.74 (s, 2 H,
CH2), 5.23 (s, 2 H, CH2Ph), 6.65 (td, J = 6.9, 1.2 Hz, 1 H, 6-H), 7.01
(ddd, J = 9.1, 6.9, 1.2 Hz, 1 H, 7-H), 7.24–7.40 (m, 5 H, C6H5), 7.56
(dt, J = 9.1, 1.2 Hz, 1 H, 8-H), 7.76 (dt, J = 6.9, 1.2 Hz, 1 H, 5-H);
the NH signal could not be detected.
HRMS: m/z calcd for C13H13N2O2 [M – NH4]+: 229.0978; found:
229.0982.
13C NMR (CDCl3, 62.9 MHz): d = 26.4 (q, CH3), 31.6 (s, CMe2),
46.6 (t, CH2), 48.5 (t, CH2Ph), 112.8 (d, C-6), 118.2 (d, C-8), 121.8
(d, C-5), 121.9 (d, C-7), 122.1 (s, C-3), 126.8, 127.8, 129.0, 136.7
(3 d, s, C6H5), 138.6 (s, C-2), 141.5 (s, C-9), 171.0 (s, C=O).
Compound 7
IR (KBr): 3335–2865 (O–H, N–H, =C–H, C–H), 1680 (C=O), 1570
MS (EI): m/z (%) = 323 (31, [M]+), 305 (32), 233 (16), 232 (100,
[M – Bn]+), 215 (14), 214 (94), 205 (42), 121 (31), 105 (17), 91 (39,
[Bn]+), 83 (11), 79 (14), 78 (59), 41 (11).
(C=N) cm–1.
1H NMR (CD3OD, 500 MHz): d = 1.47 (s, 6 H, CH3), 2.78 (s, 2 H,
CH2), 6.88 (td, J = 6.8, 1.2 Hz, 1 H, 6-H), 7.13 (ddd, J = 9.2, 6.8, 1.2
Hz, 1 H, 7-H), 7.44 (dt, J = 9.2, 1.2 Hz, 1 H, 8-H), 8.06 (dt, J = 6.8,
1.2 Hz, 1 H, 5-H).
13C NMR (CD3OD, 125.8 MHz): d = 27.2 (q, CH3), 33.1 (s, CMe2),
48.0 (t, CH2), 113.8 (d, C-6), 117.5 (d, C-8), 121.3 (d, C-5), 122.5
(d, C-7), 123.9 (d, C-3), 139.3 (s, C-2), 142.1 (s, C-9), 172.4 (s,
C=O).
MS (EI): m/z (%) = 215 (87, [M – H2O]+), 201 (29), 200 (100), 173
(13), 172 (11), 158 (12), 145 (20), 79 (19), 78 (57), 52 (10), 51 (17),
41 (12), 39 (12), 28 (16), 27 (10).
HRMS: m/z calcd for C12H13N3O [M – H2O]+: 215.1059; found:
215.1063.
HRMS: m/z calcd for C19H21N3O2: 323.1634; found: 323.1663.
1-Benzyl-4,4-dimethyl-3,4-dihydro-1H-dipyrido[1,2-a;3¢,2¢-d]-
imidazol-2-one (10e)
Compound 4e (0.060 g, 0.178 mmol) was dissolved in anhyd
MeOH (2 mL) under argon, followed by addition of NaCN (1 mg,
0.02 mmol). The mixture was heated at 85 °C for 43 h, and then the
solvent was evaporated to dryness. EtOAc and H2O were added and
the layers were separated. The aqueous layer was extracted with
EtOAc, the combined organic layers were dried (Na2SO4) and the
solvent was removed under reduced pressure. The resulting crude
product was purified by column chromatography (alumina, activity
Synthesis 2006, No. 16, 2677–2684 © Thieme Stuttgart · New York

PAPER
d-Amino Acids with an Imidazo[1,2-a]pyridine Backbone
2683
III; hexane–EtOAc, 1:1) leading to 0.050 g (92%) of 10e as color-
less crystals; mp 138–140 °C.
13C NMR (CDCl3, 125.8 MHz): d = 17.7, 28.2 [2 q, CH3, C(CH3)3],
36.0 (s, CMe2), 47.7 (d, CH), 50.6 (t, CH2), 52.1 (q, OCH3), 81.3 (s,
CMe3), 112.0 (d, C-6), 117.0 (d, C-8), 122.9 (d, C-5), 124.7 (d, C-
7), 128.0 (s, C-3), 142.5 (s, C-2), 148.7 (s, C-9), 154.1, 171.4, 171.5
(3 s, C=O).
MS (EI): m/z (%) = 418 (6, [M]+), 345 (15), 344 (48), 318 (39), 242
(20), 223 (14), 216 (15), 215 (71), 214 (45), 200 (85), 188 (57), 175
(13), 174 (100), 173 (14), 158 (13), 147 (11), 121 (12), 79 (12), 78
(30), 57 (32).
IR (KBr): 3065–2865 (=C–H, C–H), 1680 (C=O), 1630 (C=N)
cm–1.
1H NMR (CDCl3, 250 MHz): d = 1.38 (s, 6 H, CH3), 2.74 (s, 2 H,
CH2), 5.23 (s, 2 H, CH2Ph), 6.64 (td, J = 6.9, 1.2 Hz, 1 H, 6-H), 7.01
(ddd, J = 9.1, 6.9, 1.2 Hz, 1 H, 7-H), 7.23–7.37 (m, 5 H, C6H5), 7.55
(dt, J = 9.1, 1.2 Hz, 1 H, 8-H), 7.77 (dt, J = 6.9, 1.2 Hz, 1 H, 5-H).
13C NMR (CDCl3, 62.9 MHz): d = 26.3 (q, CH3), 31.5 (s, CMe2),
46.5, 48.4 (2 t, CH2), 112.6 (d, C-6), 118.2 (d, C-8), 121.6 (d, C-5),
121.8 (d, C-7), 122.0 (s, C-3), 126.7, 127.7, 128.9, 136.6 (3 d, s,
C6H5), 138.6 (s, C-2), 141.4 (s, C-9), 170.9 (s, C=O).
HRMS: m/z calcd for C21H30N4O5: 418.2216; found: 418.2235.
Methyl 3-(3-{[N-(tert-Butoxycarbonyl)-l-alanyl]amino}imida-
zo[1,2-a]pyridin-2-yl)propanoate (12)
MS (EI): m/z (%) = 305 (32, [M]+), 215 (14), 214 (100, [M – Bn]+),
Amino ester 5 (0.026 g, 0.12 mmol), Boc-Ala-OH (0.022 g, 0.12
mmol) and DIEA (0.06 mL, 0.36 mmol) were dissolved in anhyd
CH2Cl2 (3 mL), cooled in an ice bath, and then TFFH (0.042 g, 0.15
mmol) was added. The temperature was allowed to rise to r.t. After
4 d, the mixture was successively washed with aq 1 M HCl, sat. aq
NaHCO3 solution and brine, dried (Na2SO4) and the solvent was re-
moved under reduced pressure. Purification by column chromato-
graphy [silica gel; hexane–EtOAc (4:1), then MeOH–CH2Cl2 (4:1),
and finally HPLC 50% i-PrOH–hexane, 64 mL/min, 124 bar] gave
0.012 g (26%) of 12 as pale yellow oil; [a]D –25.6 (c = 0.09,
MeOH).
91 (13, [Bn]+), 78 (18).
HRMS: m/z calcd for C19H19N3O: 305.1528; found: 305.1536.
1-Benzyl-3,4,4-trimethyl-3,4-dihydro-1H-dipyrido[1,2-a;3¢,2¢-
d]imidazol-2-one (10h)
According to the preparation of 10e, compound 4h (0.414 g, 1.12
mmol), NaCN (6 mg, 0.12 mmol) and MeOH (14 mL) gave after 48
h at 85 °C and purification by column chromatography (alumina,
activity III; hexane–EtOAc, 1:1), 0.350 g (98%) of 10h as colorless
crystals; mp 114–115 °C.
IR (KBr): 3295 (N–H), 3055–2855 (=C–H, C–H), 1715 (C=O),
1635 (C=N) cm–1.
IR (KBr): 3085–2870 (=C–H, C–H), 1680 (C=O), 1635 (C=N)
cm–1.
1H NMR (CDCl3, 500 MHz): d = 1.46 (s, 9 H, t-C4H9), 1.55 (d,
J = 7.2 Hz, 3 H, CH3), 2.75–2.82 (m, 2 H, CH2), 2.91–2.97 (m, 2 H,
CH2), 3.60 (s, 3 H, OCH3), 4.43 (q, J = 7.2 Hz, 1 H, CH), 5.15 (br
s, 1 H, NH), 6.75 (td, J = 6.8, 1.1 Hz, 1 H, 6-H), 7.13 (ddd, J = 9,
6.8, 1.1 Hz, 1 H, 7-H), 7.46 (dt, J = 9, 1.1 Hz, 1 H, 8-H), 7.73 (d,
J = 6.8 Hz, 1 H, 5-H), 8.75 (br s, 1 H, NH).
1H NMR (CDCl3, 500 MHz): d = 1.11 (s, 3 H, CH3), 1.19 (d, J = 7.1
Hz, 3 H, CH3), 1.42 (s, 3 H, CH3), 2.66 (q, J = 7.1 Hz, 1 H, 10-H),
5.16, 5.23 (2 dd, J = 16.3 Hz, 2 H, CH2), 6.62 (td, J = 6.9, 1.2 Hz, 1
H, 6-H), 6.98 (ddd, J = 9.1, 6.9, 1.2 Hz, 1 H, 7-H), 7.19–7.33 (m, 5
H, C6H5), 7.54 (dt, J = 9.1, 1.2 Hz, 1 H, 8-H), 7.72 (dt, J = 6.9, 1.2
Hz, 1 H, 5-H).
13C NMR (CDCl3, 125.8 MHz): d = 18.2 (q, CH3), 21.9 (t, CH2),
28.3 [q, C(CH3)3], 33.0 (t, CH2), 38.6 (s, CMe2), 50.6 (d, CH), 51.7
(q, OCH3), 80.3 (s, CMe3), 111.8 (d, C-6), 115.5 (s, C-3), 117.1 (d,
C-8), 123.6 (d, C-5), 124.2 (d, C-7), 138.6 (s, C-2), 142.8 (s, C-9),
155.8, 172.7, 174.6 (3 s, C=O).
13C NMR (CDCl3, 125.8 MHz): d = 10.0, 21.3, 25.3 (3 q, CH3), 34.3
(s, CMe2), 46.6 (t, CH2), 48.8 (d, CH), 112.5 (d, C-6), 118.1 (d, C-
8), 121.3 (d, C-5), 121.5 (d, C-7), 121.7 (s, C-3), 126.6, 127.6,
128.8, 136.7 (3 d, s, C6H5), 139.0 (s, C-2), 141.2 (s, C-9), 173.9 (s,
C=O).
MS (EI): m/z (%) = 390 (15, [M]+), 334 (12), 247 (13), 246 (86),
219 (56), 218 (18), 214 (16), 186 (20), 160 (38), 159 (14), 146 (15),
131 (15), 79 (42), 73 (19), 59 (29), 57 (100), 55 (16), 44 (59), 43
(42).
MS (EI): m/z (%) = 319 (53, [M]+), 258 (17), 229 (17), 228 (100,
[M – Bn]+), 121 (30), 108 (22), 106 (17), 94 (25), 91 (38, [Bn]+), 86
(37), 84 (64), 78 (33), 70 (37), 69 (15), 67 (17), 55 (23), 47 (16), 43
(21), 41 (24).
HRMS: m/z calcd for C19H26N4O5: 390.1903; found: 390.1914.
HRMS: m/z calcd for C20H21N3O: 319.1685; found: 319.1666.
Methyl N-(3-{3-[(tert-Butoxycarbonyl)amino]imidazo[1,2-a]py-
ridin-2-yl}-3-methylbutanoyl)-l-alaninate (11)
Acknowledgment
Acid 8 (0.074 g, 0.222 mmol), H-Ala-OMe·HCl (0.036 g, 0.26
mmol) and BOP (0.115 g, 0.26 mmol) were dissolved in anhyd
CH2Cl2 (2 mL), and then DIEA (0.1 mL, 0.66 mmol) was added.
The reaction was stirred for 10 d at r.t. EtOAc and H2O were added
and the layers were separated. The organic layer was successively
washed with sat. aq NaHCO3 solution, brine and H2O, dried
(Na2SO4) and the solvent was removed under reduced pressure. Pu-
rification by column chromatography [silica gel; hexane–EtOAc
(1:2), then MeOH–CH2Cl2 (1:1), and finally HPLC 50% i-PrOH–
hexane, 64 mL/min, 124 bar] yielded 0.089 g (97%) of 11 as a col-
orless solid; mp 70–72 °C; [a]D –27.4 (c = 0.95, MeOH).
Support by the Deutsche Forschungsgemeinschaft (Graduiertenkol-
leg ‘Hydrogen Bridges and Hydrogen Transfer’), the Fonds der
Chemischen Industrie and the Schering AG is most gratefully ack-
nowledged. We also thank Simon Braun for his experimental help.
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Synthesis 2006, No. 16, 2677–2684 © Thieme Stuttgart · New York