Synthesis of Macrocycles Derived from Substituted Triazines

Article abstract of DOI:10.1002/cbic.201800475

A triazine ring derivatized with morpholine, an N-alkyl-N′-BOC-hydrazine (alkyl=isopropyl or benzyl) and the diethylacetal of glycinylpropionaldehyde undergoes spontaneous dimerization in good yields upon acid-catalyzed deprotection. The resulting 24-member macrocycles can be characterized by NMR spectroscopy, mass spectrometry, and single crystal X-ray diffraction. In the solid state, both homodimers adopt a taco-like conformation. Although each shows π–π stacking between the triazine rings, different patterns of hydrogen bonds emerge. The crystal structure of the isopropyl dimer shows that it includes two molecules of trifluoracetic acid per macrocycle. The trifluoroacetate anion charge balances the protonated triazines, which engage in bifurcated hydrogen bonds with the carbonyl acceptor of the distant glycine. This carbonyl also forms a hydrogen bond with the NH of the proximate glycine. The crystal structure of the benzyl derivative does not include trifluoracetic acid. Instead, two hydrogen bonds form, each between a glycine NH and the lone pair of the C=N nitrogen of the hydrazine group. In the solid state, both molecules present the alkyl side chains and morpholine groups in close proximity. A heterodimer is accessible in approximately statistical yields—along with both homodimers—by mixing the two protected monomers prior to subjecting them to deprotection.

Full text of DOI:10.1002/cbic.201800475

Accepted Article
Title: Synthesis of macrocycles derived from substituted triazines
Authors: Akop Yepremyan, Arshad Mehmood, Parham Asgari,
Benjamin G Janesko, and Eric E Simanek
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10.1002/cbic.201800475
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Synthesis of macrocycles derived from substituted triazines
Akop Yepremyan,[a] Arshad Mehmood,[a] Parham Asgari,[b] Benjamin G. Janesko,[a] and Eric E.
Simanek*[a]
Dedicated to Professor Chi-Huey Wong on the occasion of his 70th birthday.
Scheme 1. Strategy for macrocyclization.
EtO
EtO
Abstract: A triazine ring derivatized with morpholine, an N-alkyl-N’-
BOC-hydrazine (alkyl=isopropyl or benzyl) and the diethylacetal of
glycinylpropionaldehyde undergoes spontaneous dimerization in
good yields upon acid-catalyzed deprotection. The resulting 24-
member macrocycles can be characterized by NMR spectroscopy,
mass spectrometry and single crystal x-ray diffraction. In the solid
state, both homodimers adopt a taco-like conformation. While each
shows pi-pi stacking occuring between the triazine rings, different
patterns of hydrogen-bonds emerge. Crystal structures of the
isopropyl dimer includes two molecules of trifluoracetic acid per
R1
O
N
NHBOC
NH
N
O
N
N
HN
N
N
N
NH
N
N
N
O
NH
OEt
OEt
BOCHN
O
R2
macrocycle.
The trifluoroacetate anion charge-balances the
protonated triazines which engage in bifurcated hydrogen bonds with
the carbonyl acceptor of the distant glycine. This carbonyl also forms
a hydrogen bond with the NH of the proximate glycine. The crystal
structure of the benzyl derivative does not include trifluoracetic acid.
Instead, two hydrogen bonds form, each between a glycine NH and
lone pair of the C=N nitrogen of the hydrazine group. In the solid state,
both molecules present the alkyl sidechains and morpholine groups
in close proximity. A heterodimer is accessible in approximately
statistical yields—along with both homodimers—by mixing the two
protected monomers prior to subjecting them to deprotection.
1 R1 = R2 = CH(CH3)2
2 R1 = R2 = CH2C6H5
TFA
R1
O
N
N
N
H
N
N
HN
N
O
N
N
N
N
N
O
NH
N
N
NH
R2
O
Introduction
3 R1 = R2 = CH(CH3)2
4 R1 = R2 = CH2C6H5
5 R1 = CH(CH3)2; R2 = CH2C6H5
Macrocycles—both naturally-occurring and synthetic—have
captured the attention of chemists for decades for reasons of
[1]
biological activity,
interesting topologies[2] that can be
incorporated into molecular machines,[3] devices[4] and sensors[5],
as well as testing grounds for the limits of synthetic
methodology.[6] While some classes of macrocycles are
amenable to facile synthesis including cyclodextrins,[7]
calixarenes[8] and related constuctions,[9] most present challenges
to methodology. To these ends, macrocyclization has been
probed using template-directed strategies[10] and a variety of
synthetic methods[11,12] including stapling[13] or the incorporation of
labile covalent bonds such as the formation of disulfides,[14]
Results and Discussion
Synthesis of precursors 1 and 2. Compositional differences
between 1 and 2 rest in choice of alkyl group on the hydrazine
residue. To this end, the N-isopropyl-N’-BOC-hydrazine[18] (for 1)
and N-benzyl-N’-BOC-hydrazine[19] (for 2) were prepared starting
with tert-butyl carbazate. Following a 12 hour incubation with an
excess of either acetone or benzaldehyde in ether at room
temperature, the solvent was removed. The residues were
redissolved in anhydrous tetrahydrofuran and sodium
cyanoborohydride was added. For the isopropyl derivative, acetic
acid was added at low temperature and following warming, the
reaction stirred for 30 hours. For the benzyl derivative, toluene
sulfonic acid and bromocresol green were employed at room
temperature over 2 hours.
imines,[15]
and hydrazones[16] to take advantage of self-
assembly[17]
.
Here, we report the fortuitous and selective macrocyclization of
substituted triazines comprising both a protected hydrazine group
and masked aldehyde. Upon acid-catalyzed deprotection of 1 or
2, dimerization yields 24-membered rings 3 or 4, respectively
(Scheme 1). Characterization of these macrocycles is afforded
by 1H and 13C NMR spectroscopies, mass spectrometry, LC-MS,
HPLC, and single crystal x-ray diffraction. A mixture containing
heterodimer 5 can also be accessed as well (vide infra).
The syntheses of precursors 1 and 2 takes advantage of the
stepwise substitution of cyanuric chloride (Scheme 2). First, the
appropriate alkylated tert-butyl carbazate is added to cyanuric
chloride. Morpholine is then added at room temperature to yield
6 or 7. Microwave irradiation is employed to facilitate the
substitution with ethyl glycinate to yield intermediates 8 or 9.[20]
Following saponification[21] of each to 10 or 11, EDC-mediated
couplings[22] with 3,3-diethyoxypropane-1-amine completes the
syntheses. Overall, 3 and 4 are obtained in 5 steps with overall
[a]
Akop Yepremyan, Arshad Mehmood, Benjamin G. Janesko and Eric
E. Simanek
Department of Chemistry & Biochemistry, Texas Christian University
Fort Worth, TX USA
E-mail: e.simanek@tcu.edu
Dr. Parham Asgari
[b]
Shimadzu Center of the University of Texas-Arlington
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yields of 38% and 35%, respectfully. Both materials are white
solids. The detailed characterization of these intermediates is
provided later and spectra of the intermediates appear in the
Supporting Information.
proximity (which is indicated with a purple arc in Figure 1). Figure
3 shows the thermal ellipsoids for 3.
Figure 1. The pattern of hydrogen bonds formed in the solid state structures of
3 b(a) and 4 (b). The purple arc identifies groups at the top edge of the ‘taco’.
Hydrogen bonds are indicated with dotted red lines.
Scheme 2. Facile synthesis of the protected precursors. a) N-alkyl-t-
butylcarbazate, (0.95 eq), DIPEA (3.5 eq), anhydrous THF, 0 °C, 2 h; b)
morpholine (1.05 eq), rt, 12 h; c) glycine ethyl ester hydrochloride (3 eq), DIPEA
(3.5 eq), 1,4-dioxane, MW, 90 °C, 3 h; d) NaOH (3 eq), MeOH/H2O/THF (1:1:1
v/v), rt, 12 h; e) 1-amino-3,3-diethoxypropane (1.2 eq), EDC.HCl (1.5 eq), HOBt
(1.5 eq), DIPEA (3 eq), rt, 12 h.
N
N
H
H
O
N
N
N
N
H
N
N
O
N
+
N
N
NH
H
O
N
N
O
N
O
H
H
N
H
N
N
N
N
R
R
N
N
N
O
N
N
NHBOC
N
Cl
N
N
N
NHBOC
c
+
H
N
N
HN
N
O
N
N
N
N
N
N
N
O
a,b
N
N
O
N
Cl
O
N
N
HN
Cl
Cl
OEt
6 R = CH(CH3)2
7 R = CH2C6H5
8 R = CH(CH3)2
9 R = CH2C6H5
O
3
4
Figure 2. Solid-state structures of 3 (a,b) and 4 (c,d) shown from the edge and
R
side with hydrogen bonds shown as dashed red lines.
N
N
NHBOC
d
e
O
N
N
1 or 2
N
HN
OH
O
10 R = CH(CH3)2
11 R = CH2C6H5
Synthesis and characterization of macrocycles 3 and 4.
Dissolution of 1 or 2 in a 1:1 mixture of dichloromethane and
trifluoroacetic acid[23] followed by stirring for 12 hours yields
macrocycles 3 or 4, respectively. To purify these materials, the
reaction solvent is removed and the residues are resuspended in
hexanes. The suspension is pelleted using centrifugation to 3 in
88% yield. Pelleting by centrifugation followed aluminum oxide
gel chromatography yields 4 in 93% yield. These macrocycles
were characterized by mass spectrometry, 1H and 13C NMR
spectroscopies, liquid chromatography-mass spectrometry, high
performance liquid chromatography, and single-crystal x-ray
diffraction. The appearance of signals in the 1H NMR
corresponding to the methyne -N=CH- between 7.5 – 8.0 ppm is
indicative of hydrazone formation.
Figure 3. Thermal ellipsoids from the solid-state structure of 3 (a) and 4 (b).
Solid state structures of 3 and 4. Details of the crystal
structures of 3 and 4 are shown in Figures 1-3. Crystallographic
data tables appears in Supporting Information. Briefly, the
structure of 3 was solved and refined in the triclinic space group
P-1, with Z = 2. Each macrocycle co-crystallizes with two
molecules of TFA. The basicity of the triazine (pKa ~5) leads to
disproportionation of trifluoroacetic acid. Protonation of the
triazine occurs on the nitrogen opposite the morpholine
substituent. For 3, This proton and the NH of adjacent glycine
residue form a bifurcated hydrogen bond with the carbonyl group
of the distant glycine as shown schematically in Figure 1.
Unlike 3, macrocycle 4 does not co-crystallize with TFA. Still, this
neutral molecule adopts a similar taco-like shape as shown in
Figure 2. Briefly, macrocycle 4 crystallizes in the monoclinic
space group P21/c with Z = 2. Two symmetric hydrogen bonds
were identified with the –C=N- nitrogen acting as the acceptor and
the proximate NH of the glycinamide donating the hydrogen.
These interactions are illustrated in panel (b) of Figure 1. Relative
to 3, the crystal structure of 4 shows less pi-pi stacking of the
triazines that create the sidewalls of the taco. As before, the
substituents—both benzyl groups and both morpholines—are
This network of hydrogen bonds forms the bottom of the ‘taco.’
The sidewalls are created by pi-pi stacking of the triazine rings.
Edge and side views are provided in panels (a) and (b) of Figure
2 (with the trifluoroacetate anions omitted for clarity) which reveal
the taco-like shape of the macrocycle in the solid state. The figure
also reveals that the substituents—the isopropyl groups and
morpholine rings—occupy the top edge of the structure in close
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clustered along the upper rim of the architecture. Figures 2 and
3 (panels b) provide edge and side views as well as thermal
ellipsoids derived from the solid state structure.
products were identified; 3, 4, and 5 in ratios that approximate the
statistical expectation. That is, the mixture appeared to be 50%
3+4 and 50% 5. Slight deviation from the expected 1:2:1 ratio is
attributed to the different solubility of these materials in hexanes.
The trace from liquid chromatography-mass spectrometry and the
corresponding mass spectra are shown in Figure 4 along with the
corresponding mass spectrums.
Heterodimer 5. To complete this preliminary study, a 1:1 mixture
of
1
and
2
were dissolved in
a
1:1 mixture of
dichloromethane:trifluoroacetic acid. After stirring for 12 hours,
Conclusions
Figure 4. The chromatography trace (a) of the reaction yielding 5 by mixing
equimolar amounts of 1 and 2 and the mass spectra of macrocycles 3 (b), 4 (c)
and 5 (d) obtained by LC-MS.
The fortuitous dimerization of monomers 1 and 2 to form
macrocyclic dimers offers a route to compositional diversity. In
addition to being readily accessible by synthesis, the protected
monomers offer three sites for manipulation including the
substituent on the triazine ring (here, morpholine), the N-alkyl
substituent on the hydrazine group (here, isopropyl or benzyl) and
the choice of amino acid (here, glycine). The scope and limitations
of substitution at these positions remains to be determined in
terms of both ready access to macrocycle and conservation of
shape.
Experimental Procedure
General procedure. All reagents and solvents were obtained
from commercial sources and used as received, unless noted
otherwise. NMR spectra were recorded on a Bruker Avance III HD
400 MHz spectrometer. 1H NMR chemical shifts were referenced
to CDCl3 (7.26 ppm), D2O (4.80 ppm), CD3OD (3.31 ppm) and
DMSO-d6 (2.55 ppm). 13C NMR chemical shifts were referenced
to CDCl3 (77.23 ppm), CD3OD (49.86 ppm) and DMSO-d6 (39.52
ppm). The following abbreviations were used to describe
multiplets: s (singlet), d (doublet), t (triplet), q (quartet), and m
(multiplet). The following format was used to report peaks:
chemical shifts in ppm [multiplicity, coupling constant(s) in Hz,
integral, and assignment]. High-resolution mass spectra (HR-MS)
were recorded on an Agilent Technologies 6224 TOF LC/MS
system.
tert-butyl 2-benzylhydrazonecarboxylate: The procedure
follows a known synthesis[18]. To a stirred solution of tert-butyl
carbazate (6.00 g, 45.5 mmol) in Et2O (30 mL), freshly distilled
benzaldehyde (6.30 g, 59.4 mmol) was added at rt. After 12 h the
precipitate was filtered, washed with cold Et2O and dried under
vacuum to yield as white solid (8.23 g, 77%). 1H NMR (CDCl3, 400
MHz): d 8.13 (s, 1H), 7.73-7.65(m, 2H), 7.39-7.34 (m, 3H), 1.56
(s, 9H). 13C NMR (CDCl3, 125 MHz): d 152.5, 143.7, 133.9, 129.8,
128.6, 127.2, 81.5, 28.3.
tert–butyl-2-benzylidenehydrazine-1-carboxylate:
The
procedure follows a known synthesis[19]. To a stirred solution of
tert–butyl-2-benzylidenehydrazone-1-carboxylate (4.00g, 18.0
mmol) in dry THF (40 mL), NaBH3CN (2.82 g, 44.9 mmol) was
slowly added at 0 °C. Acetic acid (27.0 mL, 471.1 mmol) was then
added, and the reaction was stirred for 18 h at room temperature.
An additional amount of NaBH3CN (2.82 g, 44.9 mmol) was added,
and the reaction was stirred for 12 h. The solvent was removed
by rotary evaporation under reduced pressure and extracted with
sat. NaHCO3 (100 mL) and ethyl acetate (100 mL x 2). The
organic layer was collected and concentrated in vacuo. The crude
the solvent was removed and the residue was resuspended in
hexanes. A pellet obtained by centrifugation was analyzed by
NMR spectroscopy and mass spectrometry. All three expected
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product was dissolved in a mixture of methanol (35 mL) and 1M
aqueous NaOH (35 mL) and stirred at room temperature for 12 h.
Following concentration, the product was extracted with H2O (100
mL) and ethyl acetate (100 mL x 2). The organic layer was
Argon. 1-Amino-3,3-diethoxypropane (0.21 mL, 1.5 mmol) was
then added and the reaction was stirred at rt for 12 h. The solvent
was removed by rotary evaporation under reduced pressure and
extracted with H2O (100 mL) and DCM (100 mL x 2). The organic
collected, dried over Na2SO4 and filtered. Following concentration, layer was collected, dried over Na2SO4 and filtered. Following
the crude product was purified by flash column chromatography
(SiO2, hexanes: EtOAc 2:1 to 1:1) to afford compound 1b (3.13 g,
78%) as clear oil. 1H NMR (CDCl3, 400 MHz): d 7.54-7.22(m, 5H),
4.01(s, 2H), 1.49 (s, 9H). 13C NMR (CDCl3, 125 MHz): d 156.7,
137.6, 129.0, 128.5, 127.5, 80.6, 55.8, 28.4.
concentration, the crude product was purified by flash column
chromatography (SiO2, DCM: MeOH 20:1 to 9:1) to afford
monomer 2 (0.59 g, 77%) as clear solid.1H NMR (CDCl3, 400
MHz): d 7.42-7.24 (m, 5H), 5.07-4.85 (m, 2H), 4.56-4.44 (m, 1H),
4.13-3.87 (m, 2H), 3.83-3.57 (m, 10H), 3.55-3.25 (m, 4H), 1.89-
1.74 (m, 2H), 1.46 (s, 9H), 1.19 (t, J = 6.7 Hz, 6H). 13C NMR
(CDCl3, 125 MHz): d 170.0, 167.0, 166.6, 165.1, 155.8, 137.8,
128.6, 128.4, 127.3, 102.2, 81.0, 66.8, 61.9, 52.4, 45.1, 43.6, 35.3,
29.7, 28.2, 15.3. HR-MS (ESI) m/z calcd for C28H45N8O6 [M + H]+
589.3462; found 589.3616.
tert-butyl 2-isopropylhydrazonecarboxylate: The procedure
follows a known synthesis[18].To a stirred solution of tert-butyl
carbazate (6.00 g, 45.5 mmol) in Et2O (24 mL), acetone (12.8 mL,
172.1 mmol) was added and stirred at room temperature for 12 h.
The solvent was removed by rotary evaporation under reduced
pressure and the crude product was purified by flash column
chromatography (SiO2, DCM: MeOH 10:1) to afford a white solid
(7.22 g, 92%). 1H NMR (CDCl3, 400 MHz): d 2.04 (s, 3H), 1.82 (s,
3H), 1.51 (s, 9H). 13C NMR (CDCl3, 125 MHz): d152.9, 149.9, 80.9,
28.3, 25.4, 16.0.
Macrocycle 3: To a stirred solution of 1 (0.20 g, 0.37 mmol) in
DCM (2.2 mL) was added TFA (2.2 mL). The reaction was stirred
for 12 h at room temperature. The solvent was removed by rotary
evaporation under reduced pressure and subjected to
centrifugation after suspension first with hexanes (10 mL x 2) then
using Et2O (10 mL x 2). The precipitate was filtered and dried to
afford macrocycle 3 (0.11 g, 88%) as white powder. 1H NMR
(CD3OD, 400 MHz): d 7.86 (t, J = 2.7 Hz, 2H), 5.20-4.80 (m, 2H)
4.36-4.29 (m, 2H), 4.23-4.18 (m, 2H), 4.01-3.81 (m, 10H), 3.80-
3.64 (m, 10H), 3.11-2.95 (m, 2H), 2.81-2.69 (m, 2H), 1.56-1.36 (m,
12H). 13C NMR (CDCl3, 125 MHz): d 171.3, 161.2, 155.1, 153.5,
148.2, 66.1, 54.4, 45.0, 43.4, 32.4, 19.5, 17.9. HR-MS (ESI) m/z
calcd for C30H49N16O4 [M + H]+ 697.4123; found 697.4300.
tert-butyl 2-isopropylhydrazinecarboxylate: The procedure
follows a known synthesis[19]. To a stirred solution of tert-butyl 2-
isopropylhydrazonecarboxylate (4.00g, 23.2 mmol) in dry THF
(150 mL), NaBH3CN (1.47 g, 23.2 mmol) and catalytic
bromocresol green were added, followed by a solution of p-
toluenesulfonic acid (4.41 g, 23.2 mmol) in dry THF (12 mL),
which was added dropwise over 1 h. The reaction was maintained
between pH 3.5-5.0. After stirring for an additional 1 h, the solvent
was then removed by rotary evaporation under reduced pressure
and extracted with sat. NaHCO3 (100 mL) and ethyl acetate (100
mL x 2). The organic layer was collected and concentrated in
vacuo. The crude product was dissolved in a mixture of methanol
(70 mL) and 1M aqueous NaOH (28 mL) and stirred at room
temperature for 2 h. Following concentration, the product was
extracted with H2O (100 mL) and ethyl acetate (100 mL x 2). The
organic layer was collected, dried over Na2SO4 and filtered.
Following concentration, the crude product was purified by flash
column chromatography (SiO2, DCM: MeOH 20:1) to afford a
white solid (2.87 g, 71%). 1H NMR (CDCl3, 400 MHz): d 3.14
Macrocycle 4: To a stirred solution of 2 (0.15 g, 0.25 mmol) in
DCM (1.5 mL) was added TFA (1.5 mL). The reaction was stirred
for 12 h at room temperature. The solvent was removed by rotary
evaporation under reduced pressure and subjected to
centrifugation after suspension in hexanes (10 mL x 2) then Et2O
(10 mL x 2). The precipitate was filtered, dried and purified by
flash alumina flash column chromatography (Al2O3, DCM: MeOH
1
9:1) to afford macrocycle 4 (92 mg, 93%) as white powder. H
NMR (CD3OD, 400 MHz): d 7.5 (s, 2H), 7.40-7.22 (m, 10H), 5.40-
5.25 (m, 4H), 4.33-4.20 (m, 4H), 4.00-3.63 (m, 20H), 2.68-2.58 (m,
4H). 13C NMR (CDCl3, 125 MHz): d 171.1, 161.6, 146.1, 133.7,
128.8, 127.7, 126.3, 66.1, 45.1, 44.9, 43.2 33.3, 32.0. HR-MS
(ESI) m/z calcd for C38H49N16O4 [M + H]+ 793.4123; found
793.4374.
(septet, J = 6.3 Hz, 1H), 1.47 (s, 9H), 1.04 (d, J = 6.3 Hz, 6H). 13
NMR (CDCl3, 125 MHz): d 156.9, 80.4, 50.7, 28.4, 20.6.
C
Heterodimer 5: To a stirred solution of 2 (30 mg, 0.05 mmol) and
1 (27 mg, 0.05) in DCM (0.5 mL), TFA (0.5 mL) was added. The
reaction was stirred for 12 h at room temperature. The solvent
was removed by rotary evaporation under reduced pressure. The
residue was suspended in hexanes and subjected to
centrifugation to produce a pellet (10 mL x 2). The procedure was
repeated using Et2O (10 mL x 2). The precipitate was filtered and
dried to afford a total yield of 77% of which macrocycle 3 (1.7 mg,
12%), macrocycle 4 (5.4 mg, 38%) and macrocycle 5 (7.2 mg,
50%) were formed as white powder. 1H NMR (CD3OD, 400 MHz):
d 7.90-7.84 (m, 1H), 7.57-7.52 (m, 1H), 7.42-7.22 (m, 5H), 5.40-
5.24 (m, 2H), 5.10-4.95 (m, 1H), 4.35-4.24 (m, 2H), 4.23-4.15 (m,
2H), 4.00-3.60 (m, 20H), 2.81-2.74 (m, 2H), 2.67-2.60 (m, 2H),
1.51-1.41 (m, 6H). HR-MS (ESI) m/z calcd for C34H49N16O4 [M +
H]+ 745.4123; found 745.4440.
Monomer 1: To a stirred solution of 10 (0.70 g, 1.7 mmol) in
anhydrous THF (6.8 mL), EDC.HCl (0.49 g, 2.5 mmol), HOBt
(0.39 g, 2.5 mmol) and N,N-diisopropylethylamine (0.54 mL, 5.1
mmol) were added. The reaction was stirred for 10 minutes under
argon. 1-Amino-3,3-Diethoxypropane (0.28 mL, 2.0 mmol) was
then added and the reaction was stirred at rt for 12 h. The solvent
was removed by rotary evaporation under reduced pressure and
extracted with H2O (100 mL) and DCM (100 mL x 2). The organic
layer was collected, dried over Na2SO4 and filtered. Following
concentration, the crude product was purified by flash column
chromatography (SiO2, DCM: MeOH 20:1 to 9:1) to afford
compound 1 (0.72 g, 78%) as clear solid.1H NMR (CDCl3, 400
MHz): d 5.00-4.80 (m, 1H), 4.57-4.45 (m, 1H), 4.10-3.92 (m, 1H),
3.86-3.56 (m, 11H), 3.55-3.25 (m, 4H), 1.88-1.72 (m, 2H), 1.56-
1.36 (m, 9H), 1.27-1.09 (m, 12H). 13C NMR (CDCl3, 125 MHz): d
170.2, 166.2, 165.1, 156.7, 102.6, 81.4, 66.8, 62.0, 48.0, 45.1,
43.6, 35.3, 33.0, 28.2, 19.5, 15.3. HR-MS (ESI) m/z calcd for
C24H45N8O6 [M + H]+ 541.3462; found 541.3573.
Compound 6: To a stirred solution of cyanuric chloride (1.11 g,
6.0
mmol)
in
THF
(38
mL),
tert-butyl
2-
isopropylhydrazinecarboxylate (1.00 g, 5.7 mmol) and N,N-
diisopropylethylamine (2.97 mL, 17.1 mmol) were added at 0 °C.
After 2 h, morpholine (0.54 mL, 6.3 mmol) was added and the
reaction was stirred for 12 h at room temperature. The solvent
was removed by rotary evaporation under reduced pressure and
Monomer 2: To a stirred solution of 11 (0.60 g, 1.3 mmol) in
anhydrous THF (5.2 mL), EDC.HCl (0.38 g, 1.9 mmol), HOBt
(0.30 g, 1.9 mmol) and N,N-diisopropylethylamine (0.57 mL, 3.3
mmol) were added. The reaction was stirred for 10 minutes under
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extracted with H2O (100 mL) and DCM (100 mL x 2). The organic
layer was collected, dried over Na2SO4 and filtered. Following
concentration, the crude product was purified by flash column
chromatography (SiO2, Hexanes: EtOAc 4:1) to afford compound
was then acidified to pH 3 with acetic acid at 0 °C. After extraction
the aqueous layer was washed with DCM (100 mL) and the
combined organic layers were collected, dried over Na2SO4 and
filtered. Following concentration under reduced pressure
compound 10 was obtained in quantitative yields as a white solid.
Compound 10 was carried on to the next step without further
purification. 1H NMR (CDCl3, 400 MHz): d 4.79 (quint, J = 6.4 Hz,
1H), 4.15-3.65 (m, 10H), 1.46 (s, 9H), 1.22 (d, J = 5.8, 6H). 13C
NMR (CDCl3, 125 MHz): d 175.5, 162.3, 157.7, 155.8, 155.6, 81.4,
66.6, 50.2, 44.8, 44.4, 28.1, 19.4. HR-MS (ESI) m/z calcd for
C17H30N7O5 [M + H]+ 412.2308; found 412.2354.
1
6 (1.63 g, 77%) as clear oil. H NMR (CDCl3, 400 MHz): d 5.02-
4.75 (m, 1H), 3.95-3.55 (m, 8H), 1.56-1.34 (m, 9H), 1.19 (d, J =
6.4, 6H). 13C NMR (CDCl3, 125 MHz): d 169.7, 165.9, 164.5, 156.4,
81.5, 66.7, 48.8, 43.7, 28.1, 19.5. HR-MS (ESI) m/z calcd for
C15H26ClN6O3 [M + H]+ 373.1755; found 373.1775.
Compound 7: To a stirred solution of cyanuric chloride (0.87 g,
4.7 mmol) in THF (50 mL), tert–butyl-2-benzylidenehydrazine-1-
carboxylate (1.00 g, 4.5 mmol) and N,N-diisopropylethylamine
(2.35 mL, 13.5 mmol) were added at 0 °C. After 2 h morpholine
(0.43 mL, 5.0 mmol) was added and the reaction was stirred for
12 h at room temperature. The solvent was removed by rotary
evaporation under reduced pressure and extracted with H2O (100
mL) and DCM (100 mL x 2). The organic layer was collected, dried
over Na2SO4 and filtered. Following concentration, the crude
product was purified by flash column chromatography (SiO2,
Hexanes: EtOAc 4:1 to 2:1) to afford compound 7 (1.47 g, 78%)
as white solid.1H NMR (CDCl3, 400 MHz): d 7.40-7.25 (m, 5H),
5.10-4.85 (m, 2H), 3.90-3.57 (m, 8H), 1.55-1.30 (m, 9H). 13C NMR
(CDCl3, 125 MHz): d 170.3, 167.1, 164.5, 155.5, 136.7, 128.6,
128.1, 127.7, 81.9, 66.7, 53.4, 43.9, 28.2. HR-MS (ESI) m/z calcd
for C19H26ClN6O3 [M + H]+ 421.1755; found 421.1800.
Compound 11: To a stirred solution of 9 (0.70 g, 1.4 mmol) in
1:1:1 MeOH:H2O:THF (6 mL), NaOH (0.18 g, 4.3 mmol) was
added. The reaction was stirred at rt for 12 h. The solvent was
removed by rotary evaporation under reduced pressure and
extracted with H2O (100 mL) and DCM (100 mL x 2). The aqueous
layer was collected and DCM (50 mL) was added. The solution
was then acidified to pH 3 with acetic acid at 0 °C. After extraction
the aqueous layer was washed with DCM (100 mL) and the
combined organic layers were collected, dried over Na2SO4 and
filtered. Following concentration under reduced pressure
compound 11 was obtained in quantitative yields as a white solid.
Compound 11 was carried on to the next step without further
purification. 1H NMR (CDCl3, 400 MHz): d 7.39-7.25 (m, 5H), 5.20-
4.70 (m, 2H), 4.11-3.60 (m, 10H), 1.45 (s, 9H). 13C NMR (CDCl3,
125 MHz): d 172.8, 162.3, 159.0, 156.1, 155.1, 135.5, 128.7,
128.2, 127.9, 81.6, 66.6, 53.3, 44.8, 44.5, 28.2. HR-MS (ESI) m/z
calcd for C21H30N7O5 [M + H]+ 460.2308; found 460.2381.
Compound 8: To a stirred solution of 6 (1.00 g, 2.7 mmol) in 1,4-
dioxane (17 mL), glycine ethyl ester hydrochloride (1.13 g, 8.1
mmol) and N,N-diisopropylethylamine (2.12 mL, 12.2 mmol) was
added. The reaction was stirred in a CEM 300 W microwave
under dynamic mode at 90 °C for 4 h. The solvent was removed
by rotary evaporation under reduced pressure and extracted with
H2O (100 mL) and DCM (100 mL x 2). The organic layer was
collected, dried over Na2SO4 and filtered. Following concentration,
the crude product was purified by flash column chromatography
(SiO2, Hexanes: EtOAc 2:1) to afford compound 8 (0.86 g, 73%)
as clear oil. 1H NMR (CDCl3, 400 MHz): d 4.98-4.80 (m, 1H), 4.23
(q, J = 7.1 Hz, 2H), 4.17-4.05 (m, 2H), 3.83-3.61 (m, 8H), 1.60-
1.33 (m, 9H), 1.29 (t, J = 7.1 Hz, 3H), 1.16 (d, J = 5.4, 6H). 13C
NMR (CDCl3, 125 MHz): d 170.8, 166.2, 166.1, 165.2, 156.9, 80.6,
66.8, 61.2 47.8, 43.5, 43.1, 28.3, 19.5, 14.2. HR-MS (ESI) m/z
calcd for C19H34N7O5 [M + H]+ 440.2621; found 440.2686.
X-ray diffraction analysis. The colorless single crystals of
compounds 3 and 4 were grown at room temperature by slow
evaporation of a water, methanol and trifluoroacetic acid (TFA)
mixture. The X-ray diffraction data sets of both compounds were
collected at room temperature on
a Bruker D8 Quest
diffractometer equipped with a Photon 100 CMOS detector with
Kα radiation (λ = 0.71073 Å). The suitable crystal of each
compound was mounted on the goniometer head using Paratone-
N oil on the tip of MiTeGen MicroLoops LD™, 50 mm away from
the detector. The exposure time of 15 second was selected in
shutter-less mode with a scan angle of 0.75° per frame while
generator operating at 50 kV and 30 mA. The Bragg intensities of
data sets consisting of ω and fscans were indexed using APEX3
package[24] whereas the data reduction and absorption
corrections were carried out with the SAINT[25] and SADABS[26]
packages respectively. The space group was determined using
XPREP[24] through analysis of the Laue symmetry and systematic
absences. Structures were solved by the intrinsic phasing method
using the SHELXT[27] software. The solution of each compound
with the best figure of merit revealed the coordinates of all non-
hydrogen atoms which were refined using SHELXL[28] program
embedded in the OLEX2 package[29]. The hydrogen atoms were
located by the difference Fourier analysis and during the structure
refinement, the atomic displacement parameters of hydrogen
atoms were treated isotropically and non-hydrogen atoms were
anisotropically refined using the full-matrix least squares
procedure on F2 (using all data). The hydrogen atoms attached to
the carbon atoms were allowed to ride on their carrying atoms,
whereas those attached to heteroatoms were refined freely.
Compound 9: To a stirred solution of 7 (1.00 g, 2.4 mmol) in 1,4-
dioxane (15 mL), glycine ethyl ester hydrochloride (1.00 g, 7.2
mmol) and N,N-diisopropylethylamine (1.88 mL, 10.8 mmol) was
added. The reaction was stirred in a CEM 300 W microwave
under dynamic mode at 90 °C for 4 h. The solvent was removed
by rotary evaporation under reduced pressure and extracted with
H2O (100 mL) and DCM (100 mL x 2). The organic layer was
collected, dried over Na2SO4 and filtered. Following concentration,
the crude product was purified by flash column chromatography
(SiO2, Hexanes: EtOAc 2:1) to afford compound 9 (0.74 g, 63%)
1
as white solid. H NMR (CDCl3, 400 MHz): d 7.38-7.20 (m, 5H),
5.10-4.75 (m, 2H), 4.30-3.95 (m, 4H), 3.81-3.55 (m, 8H), 1.57-
1.29 (m, 9H), 1.30-1.15 (m, 3H). 13C NMR (CDCl3, 125 MHz): d
170.7, 167.1, 166.2 165.2, 155.8, 138.0, 128.7, 128.3, 127.2, 80.9,
66.8, 61.1, 52.5, 43.5, 43.1, 44.5, 28.2, 14.2. HR-MS (ESI) m/z
calcd for C23H34N7O5 [M + H]+ 488.2621; found 488.2714.
The asymmetric unit of 3 contains two TFA anions with multiple
disorders. During the refinement of these disorders, the sum of
the occupancies of the two disordered parts were fixed to unity.
The disordered atoms of both TFA moieties overlap, which
resulted in pathological displacement ellipsoids. This correlation
of the thermal parameters was avoided by constraining the atomic
displacement parameters (ADPs) of both parts to be equal during
refinement. The occupancies of the two components were refined,
Compound 10: To a stirred solution of 8 (0.80 g, 1.8 mmol) in
1:1:1 MeOH:H2O:THF (8 mL), NaOH (0.23 g, 5.6 mmol) was
added. The reaction was stirred at rt for 12 h. The solvent was
removed by rotary evaporation under reduced pressure and
extracted with H2O (100 mL) and DCM (100 mL x 2). The aqueous
layer was collected and DCM (50 mL) was added. The solution
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yielding an approximately 0.388(6):0.612(6) ratio. The details of
data collection, and statistics of structure refinement of both
compounds are given in Table S1.
[25]
[26]
[27]
[28]
[29]
Siemens Analytical X-ray Instrument Inc., Madison, WI,
1996.
SADABS: Area-Detector Absorption Correction,
Siemens Industrial Automation, Inc., Madison, WI, 1996.
G. Sheldrick, Acta Crystallographica Section A 2015, 71,
3-8.
G. Sheldrick, Acta Crystallographica Section C 2015, 71,
3-8.
O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K.
Howard, H. Puschmann, J. Appl. Crystallogr. 2009, 42,
339-341.
Acknowledgments
We thank the Welch Foundation (P-0008) and Texas Christian
University for support, and the Shimadzu Center at the University
of Texas-Arlington for assistance with characterization.
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Akop Yepremyan, Arshad Mehmood,
Parham Asgari, Benjamin G. Janesko
and Eric E. Simanek*
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Synthesis of macrocycles derived
from substituted triazines
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