An Indirect Synthetic Approach toward Conformationally Constrained 20-Membered Unclosed Cryptands via Late-Stage Installation of Intraannular Substituents

Article abstract of DOI:10.1021/acs.joc.8b02160

A new protocol for PTC-mediated O-alkylation of the intraannular position of 20-membered unclosed cryptands (UCs) is reported. In contrast to the classical, "direct" strategy, which requires functionalization of the lariat arm at the beginning of synthesis, this "indirect" approach enables the late-stage introduction of various benzylic substituents after an unfavorable macrocyclization step (11 examples, yields up to 98%). Notably, this method permits preparation of, previously inaccessible, crowded UCs bearing 1-acetylpyrene substituent and dimer joined by p-xylene linker.

Full text of DOI:10.1021/acs.joc.8b02160

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
An Indirect Synthetic Approach toward Conformationally
Constrained 20-Membered Unclosed Cryptands via Late-Stage
Installation of Intraannular Substituents
Janusz Jurczak,* Adam Sobczuk, Kajetan Dab̧ rowa, Marcin Lindner, and Patryk Niedbała
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
S
* Supporting Information
ABSTRACT: A new protocol for PTC-mediated O-alkylation of the intraannular position of 20-membered unclosed cryptands
(UCs) is reported. In contrast to the classical, “direct” strategy, which requires functionalization of the lariat arm at the
beginning of synthesis, this “indirect” approach enables the late-stage introduction of various benzylic substituents after an
unfavorable macrocyclization step (11 examples, yields up to 98%). Notably, this method permits preparation of, previously
inaccessible, crowded UCs bearing 1-acetylpyrene substituent and dimer joined by p-xylene linker.
ince the pioneering work of Pedersen1 and Cram,2
challenge, and to date, only a few methods addressing this
Sexpanded further by Lehn, macrocyclic compounds and problem have been reported.10
3
During our work on functional supramolecular architectures
we have developed a new class of geometrically constrained and
well-preorganized macrocyclic assemblies called unclosed
cryptands (UCs).11,12 As we designed and investigated the
smallest and formally achiral 16-, 19-, and 20-membered UCs,
we noticed that they might exhibit a controlled phenomenon of
planar chirality in the solid state.11 Atropisomerism, as a driving
force, proved to be strictly dependent on the type and bulkiness
of the intra-annularly mounted substituent (lariat arm) as well as
on the macrocyclic cavity size.11 For example, atropisomerism
was not observed for more extended 24-, 25-, and 26-membered
analogues which, however, due to their increased flexibility,
exhibit high selectivity (comparable to that of common
cryptands) toward biologically relevant anions.12b−e In addition,
extended UCs readily form crystals with unusually high packing
efficiency,13 thus providing a well-suited 3D-framework for
studying various supramolecular interactions and assemblies,
such as discrete water clusters12a,d and chalcogen−chalcogen
interactions.12b
cryptands have been extensively exploited in the construction of
various well-defined host−guest molecules. Among others, these
include the calix[n]arenes,4a resorcin[n]arenes,4b pilar[n]-
arenes,4c cucurbit[n]urils,4d cyclodextrins,4e and cyclophanes.4f
Nevertheless, preparation of such structures is often inefficient,
requiring a multistep procedure and tedious purification
protocols.5 Moreover, the entropically unfavorable closure of
the linear intermediate during macrocyclization is often a rate-
limiting step within the entire synthetic protocol. In addition,
the steric bulkiness of the macrocyclization partners further
lowers the cyclization yield due to competing oligomerization.5
The latter effect is of particular concern when a formed
macrocyclic skeleton contains a sterically demanding group
attached at crowded intraannular position. For such com-
pounds, even the application of well-established cyclization-
promoting strategies, such as conducting the reaction under
high-dilution conditions, the addition of a suitable template
agent,6 or the utilization of rigid building blocks,7 may prove
unsuccessful. This is a serious issue when robust access to an
array of derivatives of such structures is required, a situation
often encountered in the structure−activity optimization of
novel catalysts and drugs.8
For the above reasons, we became even more interested in
pursuing the structure−properties relationship of UCs. There-
fore, we designed and synthesized a new set of 20-membered
UCs with chemically diverse annular substituents, thus taking
advantage of an approach typically exploited by our group that is
based on the synthesis of an acyclic precursor with a
In this context, the ability of rapid and cost-effective
functionalization of the macrocyclic skeleton after the yield-
limiting macrocyclization step is a highly desirable strategy, but
it has so far been exploited mainly at the remote sites of
macrocyclic entities.9 In contrast, postsynthetic modification of
intraannular substituents has remained a great synthetic
Received: August 21, 2018
Published: October 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b02160
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
prefunctionalized lariat arm and subsequent macrocyclization
(i.e., the “direct” approach). Nevertheless, the strategy
employed may result in a certain handicap, manifested by a
modest and even low macrocyclization efficiency, in particular,
for UCs bearing large lariat-arm substituents (Scheme 1a).
Table 1. Synthesis of Target UCs 15−23 via Classical
Macrocyclization between α,ω-Diamines and α,ω-Diesters
Scheme 1. Direct and Indirect Strategies Devised for the
Assembly of Lariat Arm to the 20-Membered UCs
entry
diester
diamine
UC
yield (%)
1
2
3
4
5
6
7
8
9
4
5
6
4
5
6
4
5
6
12
12
12
13
13
13
14
14
14
15
16
17
18
19
20
21
22
23
37
18
26
23
11
27
15
34
21
For example, the highest overall yield is recorded for UCs 15−
17 originating from the least crowded diester 4, but replacing the
resorcinol ring with an electron donating group (EDG)
considerably lowered the yield (23 and 15% for UCs 18 and
21 bearing the OMe and NMe2 substituents, respectively).
Interestingly, the unexpectedly high yield for macrocyclization
of UC 22 suggests a favorable π−π stacking interaction between
positively and negatively charged surfaces of p-nitrophenyl and
5-NMe2-resorcinol rings, respectively.
It is notable that, contrary to previous reports on the synthesis
of UCs bearing larger 26-membered macrorings, the employ-
ment of hydrochloride salts of α,ω-diamines instead of free
amines had no effect improving the macrocyclization yield. The
20-membered macroring may plausibly be too small to
accommodate the templating chloride anion that is released
under the reaction conditions. This assumption is supported by
DFT calculations (B3LYP-D3/146-31G(d)/C-PCM-MeOH)
which suggest that chloride is bound outside the macrocyclic
cavity for both pseudocyclic intermediate and final cyclized
product (see the SI for details). Nevertheless, for this class of
macrocyclic host systems, the low yield of the macrocyclization
step is mainly related to the compact conformation of the
macrocyclic structures, and this is clearly exemplified by the
crystal structures of UCs 18, 20, and 23 (Figure 1).
The first UC 18 bearing an electron-donating OMe group on
the resorcinol fragment crystallized as a methanol solvate in a
P21/n space group. The host molecule adopts an S-type
conformation with the benzyl arm directed out of the macroring.
One NH amide proton is directed toward the macrocyclic cavity,
while the carbonyl oxygen atom is engaged in a strong and
directional interaction with a methanol molecule (dO···HO = 2.77
Å, ∠NHO = 174°). The remaining NH amide proton is directed
outside and is engaged in a weak hydrogen bonding interaction
with a carbonyl oxygen atom from the adjacent host molecule
(dNH···O = 2.92 Å, ∠NHO = 168°). On the other hand, the host
molecules 20 and 23 terminating with −OMe and −NMe2
groups, respectively, form isostructural crystals (P-1 space
group) with the 1,3-dichlorobenzylic arm directed toward the
interior of the macrocyclic cavity. Both host molecules adopt a
C-shaped conformation with both amide NH protons directed
inside the macroring. Such an orientation of amide groups
facilitates the formation of intramolecular hydrogen bonds with
This obviously could be attributed to steric hindrance
generated by the bulky intraannular substituent (lariat arm),
which hampers the final cyclization of the linear intermediate
obtained after a first amide bond is formed.
To circumvent this problem, we selected UCs bearing a
relatively small benzyl group which could be readily function-
alized after near quantitative deprotection (the “indirect”
method). This not only helps to significantly improve the
efficiency of the UCs’ preparation but also paves the way to a
novel, comprehensive method for the late-stage functionaliza-
tion of the sterically demanding macrocycles at an intraannular
position.
Herein, we demonstrate and discuss two approaches (the
“direct” and “indirect” approach) to the synthesis of a broad
library of sterically demanding UCs. Note that the proposed
“indirect” method proceeds through a late-stage benzyl
deprotection and thus allows for the highly efficient introduction
of various benzylic substituents after an unfavorable macro-
cyclization step.
As is shown in Table 1, the preparation of 20-membered UCs,
irrespective of the synthetic route, is initiated from the
preparation of suitable α,ω-diesters 4−6 and α,ω-diamines
12−14 (see Schemes S1 and S2). Briefly, diesters 4−6 were
readily prepared from inexpensive 1,2,3-trihydroxybenzene
(pyrogallol) via consecutive O-alkylation at the 2- and 1,3-
positions by a suitable benzyl bromide and methyl bromoace-
tate, respectively (Scheme S1). Consecutively, double O-
alkylation of either resorcinol or phloroglucinols 7 and 8 at
1,3-positions by chloroacetonitrile afforded dinitriles 7, 10, and
11 in good yields. The nitrile function was subsequently reduced
by a Me2S−BH3 complex in refluxing THF to deliver the
diamines 4−6 in near-quantitative yields (Scheme S2).
Having all of the required partners for the macrocyclization in
hand, we attempted to synthesize the target 20-membered UCs
by employing the classical methodology, relying on MeONa-
mediated double amidation in methanol at rt (Table 1).
The data presented in Table 1 demonstrate that the target
macrocyclic products were obtained in relatively low yields
(11−37%), irrespective of the electronic properties of the
diamine substrate. In addition, the correlation between
bulkiness of the lariat arm and the cyclization yield is not trivial.
B
DOI: 10.1021/acs.joc.8b02160
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Note
Table 2. Synthesis of Macrocycles 15−23 via Post-
functionalization of the Lariat Arm under PTC Conditions
(Indirect Approach)
entry
phenol
aryl bromide
UC
yield (%)
1
2
3
4
5
6
7
8
9
24
25
26
24
25
26
24
25
26
Ph
Ph
Ph
15
16
17
18
19
20
21
22
23
98
99
98
95
72
86
89
99
72
p-C6H4NO2
p-C6H4NO2
p-C6H4NO2
2,6-C6H4Cl2
2,6-C6H4Cl2
2,6-C6H4Cl2
Figure 1. Front (left) and side (right) views of the crystal structures of
UCs 18 (a), 20 (b), and 23 (c). Nonacidic protons and solvent
molecules omitted for clarity.
Scheme 2. Synthesis of UC 27 Bearing a Crowded
Acetylopyrene Lariat Arm
neighboring oxygen ether atoms, forcing the flat conformation of
the macrocyclic entities (dNH···O = 2.59−2.64 Å). In addition,
efficiency of packing UCs 18, 20, and 23 in the crystal lattice is
much higher than the mean value for organic molecules (CPk =
0.80−0.81 vs 0.68−0.75),11 which exemplifies a pronounced
steric hindrance in these macrocyclic systems.
To evaluate the applicability of the indirect approach as a
synthetic protocol for the late-stage introduction of the lariat
arm, we first attempted to unlock the phenolic function by a
detachment of the lariat arm in UCs 15, 18, and 21. We selected
an O-benzyl protection group, among others, since it could be
easily removable under very mild conditions. The required
macrocyclic phenols 24−26 were readily obtained via Pd/C
catalyzed reductive cleavage of benzyl protection by H2 (1 atm)
in near-quantitative yields (98−99%). Subsequently, the
released phenol group was O-alkylated by the corresponding
benzyl bromides in a biphasic H2O/CH2Cl2 solvent mixture
using a tetrabutylammonium bromide (TBAB) as a phase-
transfer catalyst. The yield are generally very high, confirming
the potential of this approach (Table 2).
UC 28 in high yield (95%). Attempts to couple these molecules
using Grubbs (first and second generation), Hoveyda−Grubbs
(first and second generation), as well as Grela catalysts, however,
did not provide the anticipated pincer-type product UC 29
(Scheme 3a).
Scheme 3. Attempts To Synthesize Pincer-Type UC 29 via
Alkene Metathesis (a) and the Crystal Structure of UC 28 (b)
Only in two cases (Table 2, entries 5 and 9) was the yield
considerably lower, albeit still very good. The established path
proceeded irrespective of the size of the moiety that plays the
role of the lariat arm, as an electron-rich substituent.
To verify whether the indirect approach is a suitable method
for the preparation of UCs bearing a bulkier lariat arm, we
synthesized UC 27 bearing the 1-O-acetylpyrene moiety.
Contrary to the direct approach, which gives only traces of
product, we were able to isolate the anticipated macrocyclic
product in a good 63% yield (Scheme 2).
To further evaluate the indirect protocol, we attempted to
synthesize the even more structurally demanding pincer-type
UCs 29 and 30 in which two macrocyclic skeletons are joined by
1,4-but-2-ene and p-xylene linkers, respectively. Such C2-
symmetric structures are most likely inaccessible by a classical
direct approach due to the overformation of polymeric side
products. First, the macrocyclic phenol 25 was reacted with allyl
bromide under PTC conditions to give the O-allyl-terminated
Extensive self-aggregation of UCs 28 probably prevents the
access of the metal complex to an alkene tether, as deduced from
the corresponding X-ray structure (Scheme 3b).
Nevertheless, employing a larger p-xylene linker and
conducting the coupling under PTC conditions provided a
pincer-type product 30 in a moderate (53%) to a very high
(93%) yield, depending on the base and the solvent used
C
DOI: 10.1021/acs.joc.8b02160
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Note
coupling constants values are reported in Hz. Melting points are
uncorrected. High-resolution mass spectra (HRMS) were recorded
using ESI-TOF technique on a Mariner mass spectrometer from
PerSeptive Biosystem. Elemental analyses were obtained on the
PerkinElmer 240 elemental analyzer. The structures of chloride
complexes were calculated at DFT/B3LYP-D3/6-31G(d)/C-PCM-
MeOH level of theory using program Spartan’16 Parallel Suite.15 The
crystals suitable for the X-ray measurements were obtained by the slow
diffusion of pentane into corresponding methanolic solution of UCs 18,
20, 23, 28, and 30. The crystal packing coefficients (CPk) were
calculated using formula 112b,d
(Scheme 4a). The structure of UC 30 was unambiguously
confirmed by the X-ray structure analysis (Scheme 4b).
Scheme 4. Synthesis of Pincer-Type C2h-Symmetric Dimer
UC 30 (a) and Its X-ray Structure (b, c)
−1
CP = Z·Vmol·V
(1)
k
cell
where Z is the number of molecules in the unit cell, Vcell is the volume of
the cell taken from the X-ray structure, and Vmol is the volume of the
molecule calculated at the DFT/B3LYP-D3/6-31G(d) level of theory
using constrained positions of heavy atoms.
5-Methoxyresorcinol 8 is commercially available, compounds 1 and
4 were prepared as previously described,16 and N,N-dimethylresorcinol
9 was prepared by the reaction of phloroglucinol with an aqueous
solution of dimethylamine in DMF in 69% yield. The α,ω-diesters 5 and
6 and α,ω-diamines 12−14 were prepared as described in Schemes S1
and S2, respectively.
General Procedure A for Obtaining 2-O-Benzylated Pyro-
gallols 1−3. To a suspension of NaH (26.4 g, 1.1 mol) in anhydrous
DMF (400 mL) was slowly added dropwise a solution of pyrogallol
(141.5 g, 1.1 mol) in anhydrous DMF (500 mL), keeping the
temperature between −10 and −5 °C. The mixture was stirred
continuously for 0.5 h, and the corresponding benzyl halide (1.1 mol)
was carefully added at t = 0−5 °C. The reaction mixture was stirred for
48 h at rt, and the solvent was evaporated under vacuum to yeild a
residue which was diluted with 0.2 M aqueous of HCl (1.2 L) and
extracted successively with EA (3 × 0.5 L). The combined organic
phases were dried over anhydrous MgSO4, and the solvent was removed
under reduced pressure to yield a dark brown oily residue which was
purified by silica gel chromatography using gradient of EA in hexanes
(5:95 → 1:9, v/v) as eluent.
The solid-state structure reveals that the p-xylene linker is
arranged in a Z-shaped conformation forming a C2h-symmetric
structure. The pincer-type UCs 30 are involved in multiple π−π
interactions between resorcinol···pyrogallol (d = 4.02 Å) and
resorcinol···xylene (d = 3.75 Å) rings, respectively, thus forming
an infinite 1D tape (Scheme 4c).
General Procedure B for Obtaining α,ω-Diesters 5 and 6. To
the solution of the corresponding 2-O-benzyl-functionalized pyrogallol
2 or 3 (0.4 mol) in anhydrous DMF (1.2 L) was added finely powdered
anhydrous K2CO3 (226.0 g, 1.6 mol). After 15 min of stirring, methyl
bromoacetate (92.0 mL, 1.0 mol) was slowly added dropwise, and the
suspension was heated at 80 °C for 24 h. The inorganic salts were
filtered through a plug of Celite, and the solvent was removed under
reduced pressure to yield a solid residue which was purified by silica gel
chromatography using a gradient of EA in hexanes (5:95 → 1:9, v/v) as
eluent.
General Procedure C for Obtaining Macrocyclic Compounds
15−23 by Employing a Classical Approach. To a solution of
corresponding α,ω-diester 4−6 (10 mmol) and α,ω-diamine 12−14
(10 mmol) in methanol (0.3 L) was added a solution of MeONa (30
mmol) in methanol (0.1 L). The starting material (α,ω-diester) was
consumed within 2−7 days as indicated by TLC analysis (MeOH in
DCM, 5:95 v/v). Afterward, the solvent was removed under reduced
pressure to yield a solid residue which was purified by silica gel
chromatography with 100% EA as eluent.
CONCLUSION
■
In conclusion, we discussed two synthetic approaches toward
sterically hindered 20-membered Unclosed Cryptands with
varying bulkiness of the lariat arm. We demonstrated that a novel
“indirect” approach, relying on the consecutive reductive
cleavage and PTC-mediated O-alkylation of the intraannular
position of benzyl-protected UCs 15, 18, and 21, enables late-
stage introduction of various benzylic substituents after an
unfavorable macrocyclization step (11 examples, yields up to
98%). In contrast, despite the shorter synthetic protocol, the
employment of the classical, “direct” approach, which requires
prefunctionalization of the lariat arm at the beginning of
synthesis, was shown to be less effective or even impractical for
UCs bearing particularly bulky lariat arms. The superiority of the
indirect approach is exemplified by the straightforward
preparation of crowded UC 27 derivatized with a 1-acetylpyrene
substituent and UC 30, a dimer joined by the p-xylene linker.
General Procedure D for Obtaining Macrocyclic Compounds
15−23, 27, 28, and 30 by Employing the Indirect Approach. The
macrocyclic phenol (1.2 mmol) and the corresponding halide (1.4
mmol) in DCM (7 mL) were added to the 2 M aqueous solution of
NaOH (3 mL). Subsequently, the PTC catalyst (0.12 mmol, TBAHS or
TBAB) was added, and the heterogeneous mixture was vigorously
stirred at rt for 1−24 h. After consumption of the starting material
(macrocyclic phenol), the organic layer was separated and aqueous
layer was extracted successively with DCM (3 × 20 mL). The combined
organic phases were dried over anhydrous Na2SO4, and the solvent was
removed under reduced pressure to yield a solid residue which was
purified by silica gel chromatography using 100% EA as eluent.
General Procedure E for Obtaining Macrocyclic Receptors
24−26. To the solution of 2-O-benzylated macrocycle (10 mmol) in
EXPERIMENTAL SECTION
■
Materials and Methods. All of the reagents were used as received.
The solvents were dried by distillation over the appropriate drying
agents. All reactions were performed avoiding moisture by standard
procedures and under a nitrogen atmosphere. Flash column
chromatography was performed on silica gel (230−400 mesh), thin-
layer chromatography (TLC) was carried out on aluminum sheets
1
precoated with silica gel. H NMR and 13C{1H} NMR spectra were
recorded on Bruker Mercury 500 and 400 MHz spectrometers. Proton
and carbon chemical shifts are reported in ppm (δ) (CDCl3: 1H NMR δ
= 7.26 and 13C NMR δ = 77.26; DMSO-d6: 1H NMR δ = 2.50 and 13
C
NMR δ = 39.52). NMR spectra were processed using MestreNova. J
D
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Note
methanol (100 mL) was added 10% Pd/C. The suspension was stirred
under hydrogen atmosphere, and the reaction progress was monitored
using TLC. After 24 h, a 1 M methanolic solution of NaOH (20 mL)
was added, and stirring was carried out for 3 h. Subsequently, the
catalyst was filtered off, and the solvent was evaporated under vacuum.
The solid was dissolved in water (50 mL), and 10 mL of hydrochloric
acid was added until pH 5−6. After 30 min of stirring, the resulting
precipitate was filtered, washed with cold water, and recrystallized from
methanol.
General Procedure F for Obtaining α,ω-Dinitriles 7, 10, and
11. To a solution of resorcinol (0.4 mol) in 1000 mL of acetone was
added finely powdered anhydrous K2CO3 (165.8 g, 1.2 mol). Then
potassium iodide (6.6 g, 40 mmol) and chloroacetonitrile (151.0 g, 2.0
mol) were added. The suspension was refluxed for 24 h. After the
inorganic salts were cooled and filteed, the solvent was evaporated in
vacuo. The residue was recrystallized from ethanol.
General Procedure G for Obtaining α,ω-Diaminoethers 12−
14. To the solution of α,ω-dinitrile 7, 10, or 11 (110 mmol) in 250 mL
of anhydrous THF was carefully added dropwise the BH3−Me2S
(BMS) complex (41.7 mL, 440 mmol). The mixture was then refluxed
for 3 h under argon. Subsequently, after cooling, 20 mL of methanol was
added with caution. Then 120 mL of 2 M hydrochloric acid in methanol
was added. The mixture was then refluxed for 3 h. Subsequently, the
solvents were evaporated under vacuum, and the residue was
neutralized with a saturated aqueous solution of K2CO3 (500 mL)
and extracted three times with DCM (3 × 200 mL). The combined
organic phases were dried over anhydrous MgSO4. The solvent was
evaporated under vacuum, and the target diamine was used in the
subsequent macrocyclization step without further purification. For later
use, the product was stored at 0 °C under argon atmosphere.
2-(4-Nitrobenzyloxy)benzene-1,3-diol (2). Following general pro-
cedure A and using 4-nitrobenzyl chloride, the product (188.1 g, 65%)
was obtained as a yellowish waxy solid. 1H NMR (400 MHz, DMSO-
d6): δ 9.05 (s, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H),
6.67 (t, J = 8.1 Hz, 1H), 6.31 (d, J = 8.1 Hz, 2H), 4.91 (s, 2H). 13C{1H}
NMR (100 MHz, DMSO-d6): δ 151.0, 137.7, 134.2, 130.8, 130.2,
123.5, 120.6, 107.4, 72.3. HRMS (ESI, MeOH): m/z calcd for
C13H11NO5Na [M + Na]+ 284.0535, found: 284.0524.
(mp 103−104 °C). 1H NMR (400 MHz, DMSO-d6): δ 7.36 (t, J = 8.4
Hz, 1H), 6.82−6.75 (m, 3H), 5.18 (s, 4H). 13C{1H} NMR (100 MHz,
DMSO-d6): δ 157.5, 130.6, 116.4, 108.6, 102.5, 53.5. HRMS (ESI,
MeOH): m/z calcd for C10H8N2O2Na [M + Na]+ 211.0483, found
211.0474. Anal. Calcd for C10H8N2O2: C, 63.83; H, 4.28; N, 14.89.
Found: C, 63.92; H, 4.50; N, 14.83.
3,5-Dihydroxy-N,N-(dimethylamino)benzene (9). To the solution
of phloroglucinol (99.3 g, 0.77 mol) in a mixture of DMF (1.0 L) and
water (0.45 L) was added a 3 M aqueous solution (0.20 L) of
dimethylamine (0.6 mol). The mixture was stirred for 24 h.
Subsequently, a 3 M aqueous solution (50 mL, 0.15 mol) of
dimethylamine was added. The mixture was stirred for 24 h. The
crude product was recrystallized from chloroform to yield product
(85.0 g, 71%) as light pink crystals (mp 117−119 °C). 1H NMR (400
MHz, DMSO-d6): δ 8.78 (s, 2H), 5.60 (s, 3H), 2.78 (s, 6H). 13C{1H}
NMR (100 MHz, DMSO-d6): δ 158.7, 152.30, 94.1, 92.0, 91.5. HRMS
(ESI, MeOH): m/z calcd for C8H12NO2 [M + H]+ 154.0863, found:
154.0864.
3,5-Bis(cyanomethylenoxy)methoxybenzene (10). Following gen-
eral procedure F, the product (60.2 g, 69%) was obtained as yellowish
crystals (mp 98−99 °C). 1H NMR (400 MHz, DMSO-d6): δ 6.43−6.34
(m, 3H), 5.16 (s, 4H), 3.76 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-
d6): δ 161.4, 158.2, 116.4, 95.3, 94.8, 55.6, 53.6. HRMS (ESI, MeOH):
m/z calcd for C11H10N2O3Na [M + Na]+ 241.0584, found 241.0596.
3,5-Bis(cyanomethylenoxy)-N,N-(dimethylamino)benzene (11).
Following general procedure F, the product (55.5 g, 60%) was obtained
as yellowish crystals (mp 82−83 °C). 1H NMR (400 MHz, DMSO-d6):
δ 6.10 (t, J = 1.9 Hz, 1H), 6.06 (d, J = 2.0 Hz, 2H), 5.13 (s, 4H), 2.91 (s,
6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 158.2, 152.3, 116.6,
93.3, 90.1, 53.4, 39.9. HRMS (ESI, MeOH): m/z calcd for
C12H13N3O2Na [M + Na]+ 254.0905, found: 254.0918.
Macrocyclic Compound 15. Following general procedure C, the
product (1.8 g, 37%) was obtained after recrystallization from a
methanol/pentane mixture as colorless crystals (mp 117−118 °C).
Following general procedure D, the product (0.58 g, 98%) was obtained
after recrystallization from a methanol/pentane mixture as colorless
crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.63 (dd, J = 6.4, 4.9 Hz,
2H), 7.45 (dd, J = 7.7, 1.6 Hz, 2H), 7.37−7.31 (m, 3H), 7.13 (t, J = 8.2
Hz, 1H), 6.59−6.50 (m, 3H), 6.47 (dd, J = 8, 2 Hz, 2H), 6.04 (t, J = 2.3
Hz, 1H), 5.03 (s, 2H), 4.59 (dAB, J = 15.0 Hz, 2H), 4.39 (dAB, J = 15.0
Hz, 2H), 4.01−3.94 (m, 2H), 3.88−3.80 (m, 2H), 3.67−3.57 (m, 2H),
3.32−3.25 (m, 2H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 167.9,
159.5, 151.7, 137.4, 137.1, 129.7, 128.7, 128.1, 127.9, 123.7, 108.1,
106.7, 104.4, 74.8, 68.6, 66.6, 38.0. HRMS (ESI, MeOH): m/z calcd for
C27H28N2O7Na [M + Na]+ 515.1794, found 515.1770. Anal. Calcd for
C27H28N2O7: C, 65.84; H, 5.73; N, 5.69. Found: C, 65.84; H, 5.84; N,
5.61.
2-(2,6-Dichlorobenzyloxy)benzene-1,3-diol (3). Following general
procedure A and using 2,6-dichlorobenzyl chloride, the product (146.8
1
g, 47%) was obtained as colorless waxy solid. H NMR (400 MHz,
DMSO-d6): δ 8.81 (s, 2H), 7.48−7.43 (m, 2H), 7.36 (dd, J = 8.8, 7.1
Hz, 1H), 6.65 (t, J = 8.1 Hz, 1H), 6.28 (d, J = 8.1 Hz, 2H), 5.26 (s, 2H).
13C{1H} NMR (100 MHz, DMSO-d6): δ 151.0, 136.5, 134.3, 133.1,
130.8, 128.4, 123.4, 107.3, 68.1. HRMS (ESI, MeOH): m/z calcd for
C13H10Cl2O3Na [M + Na]+: 306.9905 (monoisotopic mass), found:
306.9891. Anal. Calcd for C13H10Cl2O3: C 54.76, H 3.54, Cl 24.87,
found: C 54.98, H 3.79, Cl 24.57.
Dimethyl 2,2′-((2-(4-nitrobenzyloxy)-1,3-phenylene)-bisoxy-diac-
etate (5). Following general procedure B, the product (139.4 g, 86%)
was obtained as yellowish waxy solid. 1H NMR (400 MHz, DMSO-d6):
δ 7.55 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.94 (t, J = 8.4 Hz,
1H), 6.63 (d, J = 8.4 Hz, 2H), 4.99 (s, 2H), 4.80 (s, 4H), 3.71 (s, 6H).
13C{1H} NMR (100 MHz, DMSO-d6): δ 169.1, 151.7, 137.2, 136.7,
Macrocyclic Compound 16. Following general procedure C, the
product (1.2 g, 23%) was obtained after recrystallization from a
methanol/pentane mixture as colorless crystals (mp 127−128 °C).
Following general procedure D, the product (0.45 g, 69%) was obtained
after recrystallization from a methanol/pentane mixture as colorless
crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.46 (bm, 2H), 7.38 (m,
2H), 7.32 (m, 3H), 6.95 (t, J = 8.4 Hz, 1H), 6.55 (d, J = 8.4 Hz, 2H),
5.86 (t, J = 2.1 Hz, 1H), 5.81 (d, J = 2.1 Hz, 2H), 4.99 (s, 2H), 4.51 (dAB
,
130.9, 130.3, 123.6, 120.8, 107.1, 73.2, 65.3, 51.8. HRMS (ESI,
MeOH): m/z calcd for C19H19NO9Na [M + Na]+ 428.0952, found
428.0947.
J = 15.0 Hz, 2H), 4.40 (dAB, J = 15.0 Hz, 2H), 4.05−4.00 (m, 2H),
3.98−3.94 (m, 2H), 3.93−3.87 (m, 2H), 3.40−3.33 (m, 2H), 2.89 (s,
6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.1, 160.4, 152.5,
152.3, 138.1, 136.6, 129.4, 128.6, 128.4, 124.8, 108.9, 94.5, 92.6, 76.6,
69.2, 67.0, 40.6, 38.38, 38.36. HRMS (ESI, MeOH): m/z calcd for
C27H27N3O9Na [M + Na]+ 560.1645, found 560.1632. Anal. Calcd for
C27H27N3O9: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.17; H, 5.13; N,
7.68.
Macrocyclic Compound 17. Following general procedure C, the
product (0.8 g, 15%) was obtained after recrystallization from a
methanol/pentane mixture as colorless crystals (mp 174−176 °C).
Following general procedure D, the product (0.64 g, 95%) was obtained
after recrystallization from a methanol/pentane mixture as colorless
crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.57 (bd, J = 6.1 Hz, 2H),
7.31 (d, J = 8 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 8.2 Hz, 1H),
Dimethyl 2,2′-((2-(2,6-Dichlorobenzyloxy)-1,3-phenylene)bis-
(oxy))diacetate (6). Following general procedure B, the product
1
(90.7 g, 53%) was obtained as colorless waxy solid. H NMR (400
MHz, DMSO-d6): δ 7.48−7.43 (m, 2H), 7.37 (dd, J = 9.0, 6.9 Hz, 1H),
6.94 (t, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 2H), 5.30 (s, 2H), 4.69 (s,
4H), 3.68 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 169.0,
151.9, 136.8, 136.5, 132.6, 130.9, 128.3, 123.8, 107.4, 68.5, 65.5, 51.7.
HRMS (ESI, MeOH): m/z [M + Na]+ calcd for C19H18Cl2O7Na [M +
Na]+ 451.0327 (monoisotopic mass), found 451.0314. Anal. Calcd for
C19H18Cl2O7·(H2O)0.5: C, 52.07; H, 4.37; Cl, 16.18. Found: C, 52.32;
H, 4.33; Cl, 16.23.
1,3-Bis(cyanomethylenoxy)benzene (7). Following general proce-
dure F, the product (64.6 g, 86%) was obtained as yellowish crystals
E
DOI: 10.1021/acs.joc.8b02160
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
6.91 (t, J = 8.2 Hz, 1H), 6.49 (d, J = 8.4 Hz, 2H), 6.41 (dd, J = 8.2 Hz,
2.4 Hz, 2H), 6.35 (t, J = 2.3 Hz, 1H), 5.41 (s, 2H), 4.53 (dAB, J = 15.1
Hz, 2H), 4.40 (dAB, J = 15.1 Hz, 2H), 4.18−4.15 (m, 2H), 4.06−3.98
(m, 2H), 3.88−3.81 (m, 2H), 3.44−3.35 (m, 2H). 13C{1H} NMR (100
MHz, DMSO-d6): δ 167.6, 159.5, 152.2, 137.1, 136.8, 132.1, 130.3,
129.6, 128.1, 124.7, 107.6, 106.5, 106.4, 69.3, 68.4, 67.3, 37.8. HRMS
(ESI, MeOH): m/z calcd for C27H26N2O7Cl2Na [M + Na]+ 583.1015,
found 583.0998. Anal. Calcd for C27H26N2O7Cl2: C, 57.76; H, 4.67; N,
4.99. Found: C, 58.01; H, 4.70; N, 4.92.
Macrocyclic Compound 18. Following general procedure C, the
product (0.9 g, 18%) was obtained after recrystallization from a
methanol/pentane mixture as colorless crystals (mp 117−118 °C).
Following general procedure D, the product (0.62 g, 99%) was obtained
after recrystallization from a methanol/pentane mixture as colorless
crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.45−7.33 (m, 7H), 6.93
(t, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 6.0 (m, 3H), 5.0 (s, 2H),
4.53 (dAB, J = 15.1 Hz, 2H), 4.40 (dAB, J = 15.1 Hz, 2H), 4.03−3.97 (m,
2H), 3.95−3.86 (m, 4H), 3.73 (s, 3H), 3.40−3.30 (m, 2H). 13C{1H}
NMR (100 MHz, DMSO-d6): δ 168.1, 161.6, 160.3, 152.2, 138.1,
136.6, 129.3, 128.6, 128.5, 124.8, 108.8, 98.4, 93.9, 76.7, 69.1, 67.1,
55.4, 38.1. HRMS (ESI, MeOH): m/z calcd for C28H30N2O8Na [M +
Na]+ 545.1900, found 545.1912. Anal. Calcd for C28H30N2O8: C,
64.36; H, 5.79; N, 5.79. Found: C, 64.43; H, 5.98; N, 5.42.
Macrocyclic Compound 22. Following general procedure C, the
product (1.6 g, 27%) was obtained after recrystallization from a
methanol/pentane mixture as yellowish crystals (mp 136−139 °C).
Following general procedure D, the product (0.50 g, 72%) was obtained
after recrystallization from a methanol/pentane mixture as yellowish
crystals. 1H NMR (400 MHz, DMSO-d6): δ 8.14 (d, J = 8.7 Hz, 2H),
7.54 (d, J = 8.7 Hz, 2H), 7.35 (bm, 2H), 7.0 (t, J = 8.4 Hz, 1H), 6.58 (d,
J = 8.4 Hz, 2H), 5.87 (t, J = 2.1 Hz, 1H), 5.8 (d, J = 2.1 Hz, 2H), 5.06 (s,
2H), 4.59 (dAB, J = 15.1 Hz, 2H), 4.49 (dAB, J = 15.1 Hz, 2H), 4.09−4.04
(m, 2H), 4.02−3.96 (m, 2H), 3.91−3.83 (m, 2H), 3.46−3.39 (m, 2H),
2.91 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 167.6, 160.1,
152.3, 151.6, 147.5, 143.5, 137.5, 128.9, 124.9, 123.2, 108.3, 94.9, 92.3,
74.7, 68.7, 67.1, 40.2, 38.2. HRMS (ESI, MeOH): m/z calcd for
C29H32N4O9Na [M + Na]+ 603.2067, found 603.2055. Anal. Calcd for
C29H32N4O9: C, 59.99; H, 5.56; N, 9.65. Found: C, 59.70; H, 5.63; N,
9.58.
Macrocyclic Compound 23. Following general procedure C the
product (1.3 g, 21%) was obtained after recrystallization from a
methanol/pentane mixture as colorless crystals (mp 193−194 °C).
Following general procedure D, the product (0.62 g, 86%) was obtained
after recrystallization from a methanol/pentane mixture as colorless
crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.57 (dd, J = 7.4, 3.6 Hz,
2H), 7.46 (d, J = 7.8 Hz, 2H), 7.37 (dd, J = 8.7, 7.4 Hz, 1H), 6.83 (t, J =
8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 2H), 5.78 (d, J = 2.0 Hz, 2H), 5.64 (t, J
= 1.9 Hz, 1H), 5.32 (s, 2H), 4.43 (dAB, J = 15.2 Hz, 4H), 4.05−3.99 (m,
2H), 3.87−3.80 (m, 2H), 3.72−3.64 (m, 2H), 3.28−3.21 (m, 2H), 2.82
(s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 167.7, 160.3, 152.2,
152.1, 137.0, 132.1, 130.3, 128.1, 124.8, 107.9, 94.5, 92.1, 69.3, 68.6,
66.9, 40.3, 38.0. HRMS (ESI, MeOH): m/z calcd for
C29H31N3O7Cl2Na [M + Na]+ 626.1437 (monoisotopic mass), found
626.1452. Anal. Calcd for C30H33N3O7Cl4 (C29H31N3O7Cl2·CH2Cl2):
C, 57.62; H, 5.17; N, 6.95; Cl, 11.73. Found: C, 57.49; H, 5.07; N, 6.85;
Cl, 11.63.
Macrocyclic Compound 24. Following general procedure E, the
product (3.9 g, 9.8 mmol, 98%) was obtained as a colorless amorphous
powder. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.32 (t, J =
5.7 Hz, 2H), 7.06 (t, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.71−6.64 (m, 3H),
6.41 (dd, J = 8.2, 2.2 Hz, 2H), 4.41 (s, 4H), 4.04 (t, J = 4.8 Hz, 4H), 3.56
(dd, J = 10.0, 5.0 Hz, 4H). 13C{1H} NMR (100 MHz, DMSO-d6): δ
168.0, 160.0, 146.7, 136.9, 129.6, 118.8, 109.9, 107.4, 103.8, 69.5, 67.0,
38.1. HRMS (ESI, MeOH): m/z calcd for C20H22N2O7Na [M + Na]+
425.1325, found 425.1312. Anal. Calcd for C20H22N2O7: C, 59.70; H,
5.51; N, 6.96. Found: C, 58.14; H, 5.52; N, 6.79.
Macrocyclic Compound 25. Following general procedure E, the
product (4.3 g, 99%) was obtained as a colorless amorphous powder.
1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.32 (t, J = 5.7 Hz,
2H), 7.06 (t, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.71−6.64 (m, 3H), 6.41
(dd, J = 8.2, 2.2 Hz, 2H), 4.41 (s, 4H), 4.04 (t, J = 4.8 Hz, 4H), 3.56 (dd,
J = 10.0, 5.0 Hz, 4H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.0,
160.0, 146.7, 136.9, 129.6, 118.8, 109.9, 107.4, 103.8, 69.5, 67.0, 38.1.
HRMS (ESI, MeOH): m/z calcd for C21H24N2O8Na [M + Na]+
455.1430, found 455.1445. Anal. Calcd for C21H24N2O8·(CH3OH)0.5:
C, 57.58; H, 5.84; N, 6.25. Found: C, 57.55; H, 5.82; N, 6.31.
Macrocyclic Compound 26. Following general procedure E, the
product (4.4 g, 98%) was obtained as a colorless amorphous powder.
1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.47 (bs, 2H), 6.73 (s,
3H), 6.19 (s, 1H), 5.77 (s, 2H), 4.46 (s, 4H), 4.06 (t, J = 4.4 Hz, 4H),
3.58 (m, 4H), 2.86 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ
168.9, 161.2, 147.5, 137.8, 119.6, 110.9, 107.8, 103.4, 93.5, 70.4, 67.4,
41.7, 39.1. HRMS (ESI, MeOH): m/z calcd for C22H28N3O7 [M + H]+
446.1922, found 446.1938.
Macrocyclic Compound 19. Following general procedure C, the
product (0.6 g, 11%) was obtained after recrystallization from a
methanol/pentane mixture as yellowish crystals (mp 131−133 °C).
Following general procedure D, the product (0.49 g, 72%) was obtained
after recrystallization from a methanol/pentane mixture as yellowish
crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.46 (bm, 2H), 7.38 (m,
2H), 7.32 (m, 3H), 6.95 (t, J = 8.4 Hz, 1H), 6.55 (d, J = 8.4 Hz, 2H),
5.86 (t, J = 2.1 Hz, 1H), 5.81 (d, J = 2.1 Hz, 2H), 4.99 (s, 2H), 4.51 (dAB
,
J = 15.0 Hz, 2H), 4.40 (dAB, J = 15.0 Hz, 2H), 4.05−4.00 (m, 2H),
3.98−3.94 (m, 2H), 3.93−3.87 (m, 2H), 3.40−3.33 (m, 2H), 2.89 (s,
6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.1, 160.4, 152.5,
152.3, 138.1, 136.6, 129.4, 128.6, 128.4, 124.8, 108.9, 94.5, 92.6, 76.6,
69.2, 67.0, 40.6, 38.4. HRMS (ESI, MeOH): m/z calcd for
C28H29N3O10Na [M + Na]+ 590.1751, found 590.1745. Anal. Calcd
for C28H29N3O10: C, 59.26; H, 5.15; N, 7.40. Found: C, 58.88; H, 5.30;
N, 7.37.
Macrocyclic Compound 20. Following general procedure C, the
product (2.0 g, 34%) was obtained after recrystallization from a
methanol/pentane mixture as colorless crystals (mp 205−207 °C).
Following general procedure D, the product (0.59 g, 85%) was obtained
after recrystallization from a methanol/pentane mixture as colorless
crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.54 (bm, 2H), 7.31 (d, J =
8 Hz, 2H), 7.19 (t, J = 8.5 Hz, 2H), 6.94 (t, J = 8.4 Hz, 1H), 6.51 (d, J =
8.4 Hz, 1H), 5.97 (m, 3H), 5.41 (s, 2H), 4.52 (dAB, J = 15.1 Hz, 2H),
4.40 (dAB, J = 15.1 Hz, 2H), 4.13−4.05 (m, 2H), 4.03−3.97 (m, 2H),
3.89−3.82 (m, 2H), 3.72 (s, 3H), 3.44−3.35 (m, 2H). 13C NMR (100
MHz, DMSO-d6): δ 167.6, 161.2, 160.1, 152.2, 137.0, 136.9, 132.1,
130.4, 128.1, 124.8, 98.6, 93.4, 69.3, 68.5, 67.2, 55.1, 37.8. HRMS (ESI,
MeOH): m/z calcd for C28H28N2O8Cl2Na [M + Na]+ 613.1120, found
613.1130. Anal. Calcd for C28H28N2O8Cl2: C, 56.86; H, 4.77; N, 4.74.
Found: C, 56.90; H, 4.79; N, 4.63.
Macrocyclic Compound 21. Following general procedure C, the
product (1.4 g, 26%) was obtained after recrystallization from a
methanol/pentane mixture as colorless crystals (mp 104−107 °C).
Following general procedure D, the product (0.63 g, 98%) was obtained
after recrystallization from a methanol/pentane mixture as colorless
crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.46 (bm, 2H), 7.38 (m,
2H), 7.32 (m, 3H), 6.95 (t, J = 8.4 Hz, 1H), 6.55 (d, J = 8.4 Hz, 2H),
5.86 (t, J = 2.1 Hz, 1H), 5.81 (d, J = 2.1 Hz, 2H), 4.99 (s, 2H), 4.51 (dAB
,
Macrocyclic Compound 27. Following general procedure D, the
product (0.15 g, 63%) was obtained as a yellowish crystalline powder
(mp 105−106 °C). 1H NMR (400 MHz, CDCl3): δ 9.02 (d, J = 9.4 Hz,
1H), 8.28 (dd, J = 11.1, 4.6 Hz, 3H), 8.25−8.15 (m, 3H), 8.14−8.07
(m, 2H), 7.82 (d, J = 4.0 Hz, 2H), 7.05 (t, J = 8.2 Hz, 1H), 6.91 (t, J =
8.4 Hz, 1H), 6.69 (t, J = 2.3 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 6.41 (dd,
J = 15.0 Hz, 2H), 4.40 (dAB, J = 15.0 Hz, 2H), 4.05−4.00 (m, 2H),
3.98−3.94 (m, 2H), 3.93−3.87 (m, 2H), 3.40−3.33 (m, 2H), 2.89 (s,
6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.1, 160.4, 152.5,
152.3, 138.1, 136.6, 129.4, 128.6, 128.4, 124.8, 108.9, 94.5, 92.6, 76.6,
69.2, 67.0, 40.6, 38.4. HRMS (ESI, MeOH): m/z calcd for
C29H33N3O7Na [M + Na]+ 558.2216, found 558.2200. Anal. Calcd
for C29H33N3O7: C, 65.03; H, 6.21; N, 7.81. Found: C, 65.03; H, 6.40;
N, 7.63.
J = 8.2, 2.3 Hz, 2H), 5.47 (s, 2H), 4.63 (dAB, J = 15.2 Hz, 2H), 4.44 (dAB
,
J = 15.2 Hz, 2H), 4.22 (m, 2H), 4.09−3.94 (m, 4H), 3.40 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 198.4, 168.2, 160.0, 151.7, 138.4,
F
DOI: 10.1021/acs.joc.8b02160
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
134.5, 131.0, 130.5, 130.3, 130.2, 130.2, 129.9, 128.7, 128.6, 127.3,
127.0, 126.8, 126.7, 126.5, 126.1, 125.1, 125.0, 124.4, 124.1, 124.0,
108.4, 107.1, 106.0, 77.5, 77.4, 77.0, 76.7, 69.1, 67.3, 38.6. HRMS (ESI,
MeOH): m/z calcd for C38H32N2O8Na [M + Na]+ 667.2056, found
667.2051. Anal. Calcd for C38H32N2O8·(H2O)1.5: C, 67.95; H, 5.25; N,
4.18. Found: C, 68.39; H, 5.20; N, 4.23. Results of the elemental as well
as HPLC analysis (Figure S27, column: Bionacom Velocity C18-2, i.d.
4.6 × 250 mm, 5 μm, elution: MeOH−H2O (1:1 v/v), time: 30 min,
flow: 1 mL/min) indicate high purity (≥95%) of the compound.
Therefore, some small peaks that are visible in the aromatic region of
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1
the H NMR spectrum are attributed to the slow interconversion
between atropisomers of the macrocycle in the solvent studied
(CDCl3).
Macrocyclic Compound 28. Following general procedure D, the
product (0.63 g, 98%) was obtained as orange crystals (mp 151−152
°C). 1H NMR (500 MHz, DMSO-d6): δ 7.72 (t, J = 5.5 Hz, 2H), 6.75−
6.70 (m, 1H), 6.63 (d, J = 8.3 Hz, 2H), 6.07−5.97 (m, 1H), 5.83 (d, J =
1.9 Hz, 2H), 5.67 (s, 1H), 5.28 (dd, J = 17.2, 1.4 Hz, 1H), 5.15 (d, J =
10.4 Hz, 1H), 4.60 (dAB, J = 15.0 Hz, 2H), 4.45 (s, 2H), 4.44 (dAB, J =
15.0 Hz, 2H), 4.03−3.97 (m, 2H), 3.93−3.85 (m, 2H), 3.62−3.54 (m,
2H), 3.37−3.32 (m, 2H), 2.84 (s, 6H). 13C {1H} NMR (125 MHz,
DMSO-d6): δ 167.9, 160.2, 152.2, 151.7, 137.2, 134.6, 123.9, 117.9,
108.6, 92.9, 92.4, 74.0, 68.7, 66.5, 40.2, 38.1. HRMS (ESI, MeOH): m/
z calcd for C25H32N3O7 [M + H]+ 486.2240, found 486.2241.
Macrocyclic Compound 30. Following general procedure D, the
product (0.55 g, 51%) was obtained after recrystallization from a
methanol/pentane mixture as colorless crystals (mp 203−204 °C). 1H
NMR (400 MHz, DMSO-d6): δ 7.67 (t, J = 5.2 Hz, 4H), 7.42 (s, 4H),
7.13 (t, J = 8.2 Hz, 2H), 6.57−6.49 (m, 6H), 6.46 (dd, J = 8.2, 2.3 Hz,
4H), 6.06 (t, J = 2.2 Hz, 2H), 5.02 (s, 4H), 4.59 (dAB, J = 15.0 Hz, 4H),
4.40 (dAB, J = 15.1 Hz, 4H), 4.00−3.93 (m, 4H), 3.88−3.80 (m, 4H),
3.64−3.56 (m, 4H), 3.33−3.27 (m, 4H). 13C{1H} NMR (100 MHz,
DMSO-d6): δ 168.0, 159.5, 151.7, 137.1, 137.0, 129.7, 128.3, 123.7,
108.0, 106.8, 104.4, 74.4, 68.6, 66.6, 38.0. HRMS (ESI, MeOH): m/z
calcd for C48H50N4O14Na [M + Na]+: 929.3221, found 929.3188. Anal.
Calcd for C48H50N4O14·(H2O)0.5: C, 62.94; H, 5.61; N, 6.12. Found: C,
63.13; H, 5.76; N, 6.12.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02160.
■
S
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23, 28, and 30 (PDF)
X-ray data for compound 18 (CIF)
X-ray data for compound 20 (CIF)
X-ray data for compound 23 (CIF)
X-ray data for compound 28 (CIF)
X-ray data for compound 30 (CIF)
̈
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AUTHOR INFORMATION
Corresponding Author
*E-mail: jurczak_group@icho.edu.pl.
ORCID
Janusz Jurczak: 0000-0002-0351-6614
Kajetan Dab̧ rowa: 0000-0001-7767-5303
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to acknowledge Poland’s National Science
Centre (project 2014/15/B/ST5/05038) for financial support.
K.D. thanks the National Science Centre (UMO-2016/23/D/
ST5/03301) for financial support.
G
DOI: 10.1021/acs.joc.8b02160
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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