Synthesis, characterisation and crystal structure of a novel pyridyl urea Macrocycle

Article abstract of DOI:10.3184/174751916X14792878808106

A novel pyridyl urea based macrocycle has been synthesised and fully characterised including a single crystal X-ray structure determination. The synthetic approach first involves the reaction of benzyloxycarbonylaminopropyl-3-isocyanate with t-butyl 2-[(2-Aminopyridin-3- yl)oxy]acetate resulting in a coupling product. After deprotection of the amine and acid moieties and coupling subsequent coupling in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a macrocycle is formed. The structures of the compounds were confirmed by mass spectrometry and NMR spectroscopy. The X-ray crystal structure of the macrocycle reveals as expected a non-binding conformation with an intramolecular hydrogen bond between the urea NH and the pyridyl nitrogen.

Full text of DOI:10.3184/174751916X14792878808106

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 DECEMBER, 753–757
RESEARCH PAPER 753
Synthesis, characterisation and crystal structure of a novel pyridyl urea
macrocycle
Shagufta Perveena*, Jeremy D. Kilburnb, Areej M. Al-Taweela and Mark E. Lightc
aDepartment of Pharmacognosy, College of Pharmacy, King Saud University. PO Box 22452, Riyadh 11495, Kingdom of Saudi Arabia
bUniversity of Aberdeen, University Office, King‘s College, Aberdeen AB24 3FX, UK
cSchool of Chemistry, University of Southampton, Highfield Campus, SO17 1BJ, Southampton, UK
AnovelpyridylureabasedmacrocyclehasbeensynthesisedandfullycharacterisedincludingasinglecrystalX-raystructuredetermination.
The synthetic approach first involves the reaction of benzyloxycarbonylaminopropyl-3-isocyanate with t-butyl 2-[(2-aminopyridin-3-
yl)oxy]acetate resulting in a coupling product. After deprotection of the amine and acid moieties and coupling subsequent coupling in
the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a macrocycle is formed. The structures of the compounds were
confirmed by mass spectrometry and NMR spectroscopy. The X-ray crystal structure of the macrocycle reveals as expected a non-binding
conformation with an intramolecular hydrogen bond between the urea NH and the pyridyl nitrogen.
Keywords: macrocycle, X-ray crystal structure, intramolecular hydrogen bonding
Association between host and guest molecules is usually based
on simultaneous non-covalent intermolecular interactions
between the acceptor and donor, such as a cation and anion,
conformation.2 The aim of this work was to prepare a cyclic
N-pyridyl urea receptor which was expected to have a similar
non-binding conformation to the acyclic analogues. Thus, we
anticipated that protonation of these receptors could switch
their structural conformation and binding properties in a
similar manner to those of their acyclic counterparts (Fig. 1).
It was also expected that the anion complexation of these cyclic
systems would be stronger than that of their acyclic analogues
due to the macrocyclic effect.
or
a hydrogen bond acceptor-donor. The non-covalent
interactions are generally weak; therefore multiple interactions
are important to achieve strong and selective complexation of a
guest molecule. Many macrocyclic systems for binding anions
have been reported. These systems can incorporate one or more
anionic binding group such as thiourea, urea, guanidinium and
ammonium. Kilburn and coworkers have synthesised chiral
pyridyl-bisthiourea macrocycles and studied their binding
properties with various dicarboxylate salts.1
Results and discussion
The cyclic N-pyridyl urea was synthesised via a multistep
synthesis and the intermediate structures were confirmed using
standard instrumental techniques. The retrosynthetic approach
to the synthesis of macrocycle 1 is shown in Scheme 1.
Previously, we have reported the acyclic pyridylthiourea
as a switchable receptor which showed binding selectivity
with halides and carboxylates anions through change of
Acid substituent
R
HN NH N
O
OH
O
N
H
O
O
O
H
N
Amine substiuent
O
H
N
O
O
O
HN NH2
R
N
HN HN
R
N
Amide linkage
Macrocycle
Pyridyl moiety
Fig. 1 The general binding and non-binding conformations in a N-pyridyl urea macrocycle.
O
O
O
N
O
CbzHN
O
NCO
O
N
H
N
N
NH
H
N
H
N
H
H
NHCbz
O
+
O
O
N
HN
O
N
H
O
O
N
O
NH2
1
N
Scheme 1 Retrosynthesis of N-pyridyl urea receptor.
* Correspondent. E-mail: shagufta792000@yahoo.com

754 JOURNAL OF CHEMICAL RESEARCH 2016
The product N-pyridyl urea macrocycle 1 is composed of
two symmetric urea moieties linked together through amide
bonds. As shown in the retrosynthesis (Scheme 1), a key
intermediate is an isocyanate, which could be coupled with an
aminopyridine affording a urea with the potential to cyclise to
access macrocycle 1. Coupling of 2 and 3, shown in Scheme
2, afforded amine 4 which was used as the pyridyl moiety for
the synthesis of compound 1. Adogen 464 was used as a phase
transfer catalyst, which is soluble in the organic phase and
is an anionic reagent, which is soluble in the aqueous phase.
The catalyst brings the anionic reagent into the organic phase
where it reacts with the substrate. The yield of this reaction was
generally low (40–50%) due to the competitive formation of the
intramolecular cyclic amide 5 (Scheme 2). Reactions as shown in
Scheme 3 permitted the transformation of 1,3-diaminopropane
6 via the intermediates 7–9 to give the required isocyanate 10.
Monoprotection of commercially available 1,3-diaminopropane
6 gave amine 7 and diprotection of 7 with CbzCl gave the
protected compound 8, which was then converted into the
corresponding isocyanate 10 in the presence of trifluoroacetic
acid and phosgene solution (Scheme 3).
15 and was subsequently cyclised in modest yield to afford the
macrocycle 1 (Table 2).
X–ray structure and NMR analysis of macrocycle 1
The X-ray crystal structure of macrocycle 1 reveals the
expected non-binding conformation with an intramolecular
hydrogen bond between the urea NHs and the pyridyl nitrogens,
and between N and O, the distance between N3H…N1 is 2.01
Å, the distance from N4H…O1 is 1.97 Å, the distance between
N2H…O1 is 2.01 Å and the distance from N4H…O2 is 2.19 Å.
The distances between N…..O and N…N were also measured, the
distance N3…N1 is 2.72 Å, N4…O1 has a distance of 2.78 Å and
N2…O1 has a distance of 2.85 Å (Fig. 2). This conformation
1
was also confirmed by the H NMR spectrum, as it revealed a
downfield shift of 10.2 ppm (relative to TMS in CDCl3) for the
bonded N3–H and chemical shifts of 9.58 and 9.88 ppm for the
unbound N2–H and amide N4–H, respectively.
Macrocycle 1 was sparingly soluble in a range of solvents and
was found to be soluble in a 1:1 mixture of CHCl3:MeOH. Crystals
were grown from a mixture of Et2O and the 1:1 CHCl3:MeOH
mixture and the single crystal X-ray structure is shown in Fig. 2.
The reaction with triphosgene and diphosgene was straight
forward but the yields of isocyanate 10 were low. In contrast,
the reaction with phosgene was very sensitive and the reaction
was complete after a shorter reaction time in good yield (70%,
Table 1).
Coupling of amine 4 with aryl isocyanate 10 gave acyclic
urea 11, the key intermediate for the synthesis of macrocycle 1
(Scheme 4). Urea 11 was advanced through the intermediates
12–15, intermediate 16 was accessed by the deprotection of
Attempts to synthesise the protonated salt of macrocycle 1
Treatment of macrocycle 1 with 2 equiv. hydrochloric acid,
hydrobromic acid, tetrafluoroboric acid and sulfuric acid in
1:1 CHCl3:MeOH led to precipitates of the corresponding salts.
The salts were sparingly soluble in a range of solvents such as
CH3CN, CHCl3 and MeOH and only soluble in DMSO. The
attempts to dissolve the salt in DMSO led to deprotonation of
the salt giving back the neutral macrocycle as confirmed by
O
O
O
O
OH
O
NH2
Adogen 464
O
NH
NH2
Br
+
+
N
40% NaOH
DCM
O
N
N
2
3
4 50%
5
Scheme 2 Use of amine 4 as the pyridyl moiety.
CbzCl, NaHCO3
Boc2O
CHCl3
H2N
NH2
H2N
NHBoc
CbzHN
NHBoc
CHCl3
8
6
7
TFA
DCM
+
COCl2, NaHCO3
DCM
CbzHN
NH3 CF3COO-
OCN
NHCbz
9
10 79 %
Scheme 3 Synthesis of precursor 10.
Table 1 Conditions used for the synthesis of isocyanate 10
Table 2 Cyclisation step under various conditions
Entry Conditions
Yield of 10 /%
Entry Conditions
Yield of 1 /%
1
2
3
Triphosgene, DCM, 1M NaOH, r.t., 17 h
Diphosgene, DCM, 1M NaOH, r.t., 17 h
Phosgene, DCM, aq. NaHCO3, 0 °C to r.t., 10 h
30
27
79
1
2
3
Pybop, DIPEA, CHCl3, r.t., 48 h
DDC, DIPEA, CHCl3, r.t., 48 h
EDC, DIPEA, CHCl3, r.t., 48 h
19
20
30

JOURNAL OF CHEMICAL RESEARCH 2016 755
O
O
O
O
O
O
H
H
CbzHN
NCO
+
NH2
NHCbz
N
N
10
N
4
O
11
N
, 39%
H2, Pd, MeOH
TFA, 20% in DCM
HO
O
O
O
O
O
H
H
H
H
NHCbz
NH2
N
N
N
N
13, 91%
12, 98%
O
O
N
N
O
EDC, DIPEA
CHCl3
NHCbz
O
N
O
O
HN
HN
O
TFA (20% in DCM)
HO
N
H
O
N
H
HN
O
O
H
H
N
O
N
N
O
14, 40%
O
HN
O
H
N
N
O
HN
N
NHCbz
15, 87%
H2, Pd/C MeOH
95%
HO
N
O
O
O
H
H
H
O
N
N
O
N
N
N
O
NH
EDC, DIPEA, 30 %
H
O
HN
O
O
O
H
N
H
O
HN
N
N
H
Macrocycle 1
N HN
NH2
O
N
16, 95%
Scheme 4 Synthetic route of macrocycle 1.
NMR spectroscopy. As a result of its limited solubility, it would
be difficult to accurately NMR the salt in the same solvent as
the neutral macrocycle making direct comparison challenging.
hydrogen bonding between the urea N–H and pyridyl–N as
confirmed by both its X-ray crystal structure and its H NMR
1
spectrum. The tetrafluoroborate, chloride, bromide and sulfate
salts of macrocycle 1 were prepared following the same method
as used for their acyclic urea analogue, but these salts were
sparingly soluble in a range of solvents and were only soluble in
DMSO. Attempts to dissolve in DMSO led to deprotonation of
the salts giving back the neutral macrocycle 1.
Conclusion
An N-pyridyl-urea macrocycle 1 has been synthesised in a
facile procedure and was obtained by a final cyclisation in 30%
yield. It showed the expected conformation with intramolecular

756 JOURNAL OF CHEMICAL RESEARCH 2016
Fig. 2 X-ray crystal structure of macrocycle 1 showing labelling scheme
and hydrogen bond interactions. Distances are given in full in Table 3.
Thermal ellipsoids drawn at the 35% probability level.
Experimental
3.12–3.02 (4H, m, 2 × CH2), 1.47 (2H, quint, J = 6 Hz, CH2CH2CH2),
1.30 (9H, s, 3 × CH3); 13C NMR (75 MHz, CDCl3) δ 156.7 (s), 156.4 (s),
136.6 (s), 129.4 (s), 128.9 (s), 127.0 (s), 79.4 (s), 73.4 (s), 37.8 (s), 37.5
(s), 30.6 (s), 28.4 (s); LRMS (ES) m/z (%): 309 [M + H]+ (12), 331 [M +
Na]+ (100), 372 [M + Na + CH3CN]+ (13), 639 [2 M + Na]+ (15).7
Synthesis of t-butyl 2-[(2-aminopyridin-3-yl)oxy]acetate (4):
A mixture of 3-hydroxy-2-aminopyridine 2 (3 g, 27 mmol), tert-
butylbromoacetate 3 (4 mL, 27 mmol), Adogen-464 (168 mg) and
NaOH solution (40% in water, 15 mL) was dissolved in DCM (25 mL).
The reaction mixture was stirred at room temperature for 24 h. The
mixture was then washed with water (3 × 50 mL) and the organic layers
combined. The organic portion was dried, (MgSO4) and concentrated
in vacuo. The resulting crude yellow oil was purified by column
chromatography (silica gel, 3% MeOH in DCM) to afford amine 4:
Synthesis
of
3-benzyloxycarbonylaminopropylammonium
trifluoroacetate (9): A solution of 8 (11.00 g, 35.60 mmol) in
TFA, (20% in DCM, 50 mL) was stirred at room temperature for
2 h. Toluene (50 mL) was added and the solvent was removed under
reduced pressure to give salt 9: White solid, yield 9.70 g, 84%; IR (νmax
,
cm–1) film: 2435 (w), 2962 (w), 2689 (s), 1668 (m), 1524 (s), 1131 (s);
1H NMR (300 MHz, CDCl3) δ 8.00 (3H, br. s, N+H3), 7.18 (5H, m, 5 ×
ArH), 5.45 (1H, br. s, NHCbz), 4.96 (2H, br. s, CH2Ph), 3.03 (2H, br.
s, CH2N+H3), 2.79 (2H, br. s, CH2NHCbz), 1.62 (2H, quint, J = 6 Hz,
CH2CH2CH2); 13C NMR (75 MHz, CDCl3) δ 161.3 (s), 136.6 (s), 129.4
(d), 128.7 (d), 127.5 (d), 67.4 (t), 36.6 (t), 36.5 (t), 27.3 (t); LRMS (ES)
m/z (%): 209 [M + H]+ (100), 231 [M + Na]+ (5).8
Yellow oil; yield 2.3 g, 38%; Rf (5% MeOH in DCM) 0.50; IR (νmax
,
cm–1) film: 3483 (w), 1748 (s), 1616 (s), 1476 (s), 1154 (s); H NMR
(300 MHz, CDCl3) δ 7.67 (1H, d, J = 5 Hz, H py), 6.80 (1H, d, J = 8 Hz,
H py), 6.55 (1H, dd, J = 8, 5 Hz, H py), 4.85 (2H, br. s, NH2), 4.49 (2H,
s, CH2), 1.45 (9H, s, 3 × CH3); 13C NMR (75 MHz, CDCl3) δ 167.7 (s),
150.7 (s), 140.9 (s), 140.1 (d), 117.7 (d), 113.3 (d), 82.9 (s), 66.3 (t), 28.2
(q); LRMS (ES) m/z (%): 266 [M + H + CH3CN]+ (30).3–5
1
Synthesis of benzyloxycarbonylaminopropyl-3-isocyanate (10): Salt
9 (1.75 g, 5.43 mmol) was dissolved in DCM (100 mL) and saturated
NaHCO3 solution (100 mL). The mixture was stirred at 0 °C in an ice
bath for 30 min. The stirring was then stopped and the two phases were
allowed to separate prior to the addition of phosgene solution (5.00 mL,
1.06 g, 10.80 mmol) to the organic layer and the stirring was resumed
in an ice bath for 10 min then at room temperature for 17 h. The organic
layer was separated and the product further extracted with DCM
(2 × 150 mL). The combined organic layers were concentrated in vacuo
to give isocyanate 10: White solid; yield 1.01 g, 79%; Rf (5% MeOH
in DCM) 0.80; IR (νmax, cm–1) neat: 3400 (m), 1700 (s), 1513 (m), 1370
(m), 1250 (s), 1153 (s); 1H NMR (300 MHz, CD3CN) δ 7.36 (5H, br. s,
5 × ArH), 5.62 (1H, br. s, NHCbz), 5.05 (2H, br. s, CH2NHCbz), 3.12
(4H, m, 2 × CH2), 1.55 (2H, quint, J = 6 Hz, CH2CH2CH2); 13C NMR
(75 MHz, CDCl3) δ 159.9 (s), 157.3 (s), 138.4 (s), 129.3 (d), 128.6 (d),
127.5 (d), 66.6 (t), 37.8 (t), 36.9 (t), 30.6 (t).9
Synthesis of t-butyl 2-(3-aminopropylamino)acetate (7):
A
solution of tert-butyl dicarbonate (9.8 g, 45 mmol) in CHCl3 (300 mL)
was added dropwise to a solution of 1,3-propanediamine 6 (10 g,
135 mmol) in chloroform (30 mL) over 8 h, and the reaction mixture
was then stirred at room temperature for 15 h. The reaction mixture
was washed with saturated sodium bicarbonate solution (4 × 100 mL)
and water (3 × 100 mL) and the organic phase was dried (MgSO4)
and concentrated in vacuo to afforded amine 7: Colourless oil; yield
5.41 g, 69%; IR (νmax, cm–1) film: 3357 (w), 2975 (w), 1689 (s), 1517
1
(s), 1250 (s); H NMR (300 MHz, CDCl3) δ 5.15 (1H, br. s, NHBoc),
3.04 (2H, m, CH2NHBoc), 2.62 (2H, t, J = 7 Hz, CH2NH2), 1.47 (2H,
quint, J = 7 Hz, CH2CH2CH2), 1.31 (9H, s, 3 × CH3) 1.28 (2H, br. s,
NH2); 13C NMR (75 MHz, CDCl3) δ 155.4 (s), 77.8 (s), 38.6 (t), 37.3
(t), 32.5 (t), 26.9 (q); LRMS (ES) m/z (%) 175 [M + H]+ (100), 215 [M
+ CH3CN]+ (25). The data coincided with those reported in literature.6
Synthesis of t-butyl 2-(3-benzyloxycarbonylaminopropylamino)
acetate (8): Benzyl chloroformate (CbzCl) (7.3 mL, 51.1 mmol) was
added to a solution of amine 7 (8.9 g, 51 mmol) in CHCl3 (150 mL) and
saturated NaHCO3 solution (30 mL). The mixture was stirred at room
temperature for 12 h and then washed with saturated NaHCO3 solution
(2 × 100 mL). The product was extracted with CHCl3 (3 × 50 mL). The
combined organic phases were dried (MgSO4) and concentrated in
Synthesis
of
{2-[3-(3-benzyloxycarbonylaminopropyl)ureido]
pyridin-3-yloxy} t-butyl acetate (11): A solution of isocyanate 10
(0.12 g, 0.51 mmol) in DCM (2 mL) was added to a stirred solution of
amine 4 (0.1 g, 0.45 mmol) in DCM (2 mL) and the mixture refluxed at
50 °C for 24 h. The solvent was removed under reduced pressure and
the crude yellow oil was purified by column chromatography (silica
gel, 0.5% MeOH in DCM) to afford urea 11: Yellow oil; 0.08 g, 39%;
Rf (5% MeOH in DCM) 0.60; IR (νmax, cm–1) neat: 3254 (w), 2978 (w),
vacuo to give carbamate 8: White solid; yield 12.70 g, 81%; IR (νmax
,
cm–1) film: 3334 (m), 2977 (w), 1683 (s), 1528 (s), 1365 (w), 1249 (s),
1
1
1166 (s); H NMR (300 MHz, CDCl3) δ 7.18 (5H, m, 5 × ArH), 5.41
1673 (s), 1541 (s), 1410 (w), 1227 (s), 1151 (s); H NMR (300 MHz,
(1H, br. s, NHCbz), 5.16 (2H, s, CH2Ph), 4.75 (1H, br. s, NHBoc),
CDCl3) δ 9.49 (1H, br. s, NH), 7.79 (1H, d, J = 5 Hz, H py), 7.52 (1H, br.

JOURNAL OF CHEMICAL RESEARCH 2016 757
s, NH), 7.34 (5H, m, 5 × ArH), 6.96 (1H, d, J = 8 Hz, H py), 6.81 (1H,
dd, J = 8, 5 Hz, H py), 5.63 (1H, br. s, NHCbz), 5.09 (2H, s, CH2Ph),
4.54 (2H, s, CH2CO2t-Bu), 3.45 (2H, dt, J = 6, 6 Hz, CH2NHCONH),
3.28 (2H, dt, J = 6, 6 Hz, CH2NHCbz), 1.77 (2H, quint, J = 6 Hz,
CH2CH2CH2), 1.48 (9H, s, 3 × CH3); 13C NMR (75 MHz, CDCl3) δ
166.8 (s), 156.7 (s), 155.5 (s), 144.5 (s), 140.9 (s), 138.2 (d), 136.9 (s),
128.4 (d), 128.0 (d), 127.9 (d), 118.3 (d), 116.3 (d), 83.2 (s), 66.5 (t),
66.4 (t), 38.1 (t), 36.8 (t), 30.5 (t), 28.1 (q); LRMS (ES) m/z (%): 459 [M
+ H]+ (100), 481 [M + Na]+ (52), 917 [2 M + H]+ (12), 939 [2 M + Na]+
(30).
DCM, 15 mL) was stirred at room temperature for 2 h. Toluene (10 mL)
was added and the solvent removed under reduced pressure to give acid
15: White solid; yield 0.08 g, 87%; Rf (12% MeOH in DCM) 0.50; IR
(νmax, cm–1) film: 3307 (br), 3067 (br), 1671 (s), 1573 (s), 1182 (s), 1134
(s); 1H NMR (300 MHz, CD3CN) δ 10.30 (2H, br. s, 2 × NH), 8.64 (1H,
br. s, NH), 8.41 (1H, br. s, NH), 8.10 (1H, br. s, NH), 7.85 (2H, m, H py),
6.62 (2H, m, 2 × H py), 7.58 (5H, br. s, 5 × ArH), 7.18 (2H, m, 2 × H py),
5.85 (1H, br. s, NH), 5.04 (2H, br. s, CH2Ph), 4.83 (2H, br. s, CH2COOH),
4.66 (2H, s, CH2CONH), 3.33 (6H, br. s, 3 × CH2), 3.18 (2H, dt, J = 6, 6
Hz, CH2NHCbz), 1.71 (4H, quint, J = 6 Hz, 2 × CH2CH2CH2); LRMS
(ES) m/z (%): 653 [M + H]+ (100).
Synthesis
of
{2-[3-(3-benzyloxycarbonylaminopropyl)ureido]
Synthesis of (2-{3-[3-(2-{2-[3-(3-Aminopropyl)ureido]pyridin-3-
yloxy} acetylamino)propyl]ureido}pyridin-3-yloxy) acetic acid (16): A
solution of 15 (0.1 g, 0.15 mmol) in MeOH (5 mL) was hydrogenated over
palladium on charcoal (0.008 g, 0.075 mmol) and the reaction stirred at
room temperature overnight. The catalyst was filtered through a celite
pad, washed with MeOH and the filtrate concentrated in vacuo to give
amine 16: colourless oil; 0.075 g, 95%; LRMS (ES) m/z (%): 519 [M +
H]+ (100), 541 [M + Na]+ (20).
pyridin-3-yloxy} acetic acid (12): A solution of urea 11 (0.5 g,
1.09 mmol) and TFA, (20% in DCM, 30 mL) was stirred at room
temperature for 2 h. Toluene (10 mL) was added and the solvent was
removed under reduced pressure to give acid 5: White solid; yield
0.43 g, 98%; Rf (15% MeOH in DCM) 0.40; m.p. 150–153 °C; IR
(νmax, cm–1) film: 3307 (m), 1686 (s), 1544 (s), 1211 (br); 1H (300 MHz,
CD3CN) δ 8.61 (1H, br. s, NH), 7.80 (1H, d, J = 6 Hz, H py), 7.62 (1H,
d, J = 8 Hz, H py), 7.61 (5H, br. s, 5 × ArH), 7.18 (1H, dd, J = 8, 6 Hz,
H py), 5.82 (1H, br. s, NHCbz), 5.07 (2H, s, CH2Ph), 4.84 (2H, br. s,
CH2COOH), 3.34 (2H, dt, J = 6, 6 Hz, CH2NHCONH), 3.21 (2H, dt,
J = 6, 6 Hz, CH2NHCbz), 1.72 (2H, quint, J = 6 Hz, CH2CH2CH2);
13C NMR (75 MHz, CDCl3) δ 178.5 (s), 166.8 (s), 156.9 (s), 143.3 (s),
141.8 (s), 138.2 (d), 128.0 (s), 128.0 (d), 128.0 (d), 127.0 (d), 117.3 (d),
116.9 (d), 67.0 (t), 66.5 (t), 37.9 (t), 36.7 (t), 28.5 (t); LRMS (ES) m/z
(%): 403 [M + H]+ (100), 805 [2 M + H]+ (8), 827 [2 M + Na]+ (20).8
Synthesis of {2-[3-(3-aminopropyl)ureido]pyridin-3-yloxy} t-butyl
acetate (13): A solution of urea 11 (0.17 g, 0.37 mmol) in methanol (5
mL) was hydrogenated over palladium on charcoal (0.02 g, 0.19 mmol)
and the mixture was stirred overnight at room temperature. The catalyst
was filtered over a celite pad, washed with methanol and the filtrate was
concentrated in vacuo to give amine 13: Colourless oil; 0.11 g, 91%; IR
(νmax, cm–1) film: 3431 (w), 2976 (w), 1747 (m), 1678 (s), 1545 (s), 1484
(s), 1227 (s), 1154 (s); 1H NMR (300 MHz, CDCl3) δ 9.49 (1H, t, J = 6
Hz, NH), 7.77 (1H, d, J = 5, Hz, H py), 6.93 (1H, d, J = 8, Hz, H py),
6.79 (1H, dd, J = 8, 5 Hz, H py), 4.59 (2H, s, CH2CO2t-Bu), 3.44 (2H,
dt, J = 7, 7 Hz, CH2NHCONH), 2.80 (2H, t, J = 7 Hz, CH2NH2), 1.79
(2H, quint, J = 7 Hz, CH2CH2CH2), 1.49 (2H, br. s, NH2), 1.48 (9H, s, 3 ×
CH3); 13C NMR (75 MHz, CDCl3) δ 166.7 (s), 155.2 (s), 144.5 (s), 140.8
(s), 138.1 (d), 118.1 (d), 116.4 (d), 83.1 (s), 66.3 (t), 37.3 (t), 36.4 (t), 28.8
(t), 27.9 (q); LRMS (ES) m/z (%): 325 [M + H]+ (100), 649 [2 M + H]+
(5), 974 [3 M + Na]+ (20).10
Synthesis of 9,10,11,12,23,24,25,26-octahydro-6H,20H-dipyrido[3,2-
b:3,2-n][1,13,4,6,10,16,18,22]dioxahexaazacyclotetracosine-
7,13,21,27(8H,14H,22H,28H)-tetrone (1): Urea 16 (0.075 g, 0.15 mmol)
was dissolved in a solution of DMF:DCM (1:1, 5 mL) and EDC (0.03 g,
0.16 mmol) was added and the mixture stirred at room temperature for
30 min. Diisopropyl ethylamine (27 μl, 0.14 mmol) was then added and
the mixture stirred at room temperature for 36 h under nitrogen. The
solvent was removed under reduced pressure and the crude solid purified
by column chromatography (silica gel, 2% MeOH in DCM) to afford the
macrocycle 1: White solid; yield 0.016 g, 30%; Rf (5% MeOH in DCM)
0.50; m.p. 300–301 °C; IR (νmax, cm–1) film: 3212 (s), 3084 (w), 1650 (s),
1547 (s), 1489 (s), 1414 (s); 1H NMR (300 MHz, CD3CN) δ 10.20 (1H, br.
s, NH), 9.88 (1H, br. s, NHCOCH2O), 9.58 (1H, br. s, NHCONH), 7.76
(2H, d, J = 5 Hz, 2 × H py), 7.03 (2H, d, J = 8 Hz, 2 × H py), 6.83 (2H,
dd, J = 8, 5 Hz, 2 × H py), 4.40 (4H, br. s, 2 × CH2CONH), 3.54 (4H, m,
2 × CH2NHCOCH2), 3.40 (4H, m, 2 × CH2NHCONH), 1.73 (4H, quint,
J = 6 Hz, 2 × CH2CH2CH2); 13C NMR (75 MHz, CDCl3) δ; 166.9 (s),
158.2 (s), 143.6 (s), 141.2 (s), 137.6 (d), 118.2 (d), 117.1 (d), 67.5 (t), 35.9
(t), 34.3 (t), 29.2 (t); LRMS (ES) m/z (%): 501 [M + H]+ (80), 523 [M +
Na]+ (100), 1023 [2 M + Na]+ (8).10
Acknowledgements
This research project was supported by a grant from the “Research
Center of the Female Scientific and Medical Colleges”, Deanship
of Scientific Research, King Saud University.
Synthesis of (2-{3-[3-(2-{2-[3-(3-benzyloxycarbonylaminopropyl)-
3-ureido]pyridin-3-yloxy}
acetylamino)propyl]ureido}pyridin-3-
yloxy) t-butyl acetate (14): Amine 13 (0.70 g, 2.16 mmol) was added to a
solution of acid 12 (0.9 g, 2.23 mmol) in dry DCM (10 mL), EDC (0.4 g,
2.09 mmol) and diisopropyl ethylamine (DIPEA) (0.4 mL, 0.29 g, 2.29
mmol) and the mixture was stirred at room temperature for 48 h under
nitrogen. The solution was concentrated in vacuo and the crude oil was
purified by column chromatography (silica gel, 2% MeOH in DCM) to
afford the urea 14: Colourless oil; 0.3 g, 20%; Rf (5% MeOH in DCM)
0.50; IR (νmax, cm–1) film: 3306 (m), 3063 (w), 2951 (w), 1689 (s), 1529
(s), 1453 (s), 1241 (s); 1H NMR (300 MHz, CD3CN) δ 9.90 (3H, m, 3 ×
NH), 9.81 (1H, t, J = 4 Hz, NH), 9.51 (1H, t, J = 6 Hz, NH), 7.78 (2H, m,
2H py), 7.30 (5H, br. s, 5 × ArH), 7.04 (1H, d, J = 7 Hz, H py), 6.82 (1H,
dd, J = 7, 5 Hz, H py), 6.74 (2H, br. s, 2 × H py), 5.75 (1H, br. s, NHCbz),
4.95 (2H, s, CH2Ph), 4.45 (2H, s, CH2CO2t-Bu), 4.39 (2H, s, CH2CONH),
3.48 (2H, dt, J = 6, 6 Hz, CH2NHCOCH2), 3.40 (4H, dt, J = 6, 6 Hz, 2 ×
CH2NHCONH), 3.20 (2H, dt, J = 6, 6 Hz, CH2NHCbz), 1.70 (4H, br. s,
2 × CH2CH2CH2), 1.37 (9H, s, 3 × CH3); 13C NMR (75 MHz, CDCl3) δ;
167.6 (s), 166.5 (s), 160.1 (s), 158.1 (s), 157.1 (s), 145.3 (s), 144.6 (s), 142.0
(s), 141.3 (s), 137.9 (d), 137.6 (d), 136.9 (s), 128.6 (d), 128.4 (d), 128.1 (d),
119.4 (d), 117.8 (d), 116.6 (d), 116.4 (d), 82.8 (s), 67.8 (t), 66.9 (t), 66.7 (t),
38.2 (t), 36.5 (t), 36.0 (t), 34.4 (t), 30.9 (t), 29.6 (t), 28.1 (q); LRMS (ES)
m/z (%): 709 [M + H]+ (100), 731 [M + Na]+ (45).
Electronic Supplementary Information
The ESI (Crystal data) is available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
Received 25 August 2016; accepted 24 October 2016
Paper 1604278 doi: 10.3184/174751916X14792878808106
Published online: 5 December 2016
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