An unusual macrocyclization reagent for highly selective one-pot synthesis of strained macrocyclic aromatic hexamers

Article abstract of DOI:10.1039/c3cc48576e

One-pot, multi-molecular macrocyclization allows the highly selective preparation of strained macrocyclic aromatic hexamers structurally stabilized by an inward-pointing continuous hydrogen-bonding network. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc48576e

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An unusual macrocyclization reagent for highly
selective one-pot synthesis of strained
macrocyclic aromatic hexamers†
Cite this: Chem. Commun., 2014,
50, 3582
Received 10th November 2013,
Accepted 11th February 2014
Haoliang Fu,a Hu Chang,b Jie Shen,cd Lin Yu,a Bo Qin,*b Kun Zhang*a and
Huaqiang Zeng*cd
DOI: 10.1039/c3cc48576e
www.rsc.org/chemcomm
One-pot, multi-molecular macrocyclization allows the highly selective
preparation of strained macrocyclic aromatic hexamers structurally
stabilized by an inward-pointing continuous hydrogen-bonding network.
Macrocyclic foldamers with their shape-persistent macrocyclic frame-
works rigidified by strong intramolecular H-bonds have attracted
much interest over the past decade.1 A number of these H-bonded
folding macrocycles have been shown to be capable of (i) catalyzing
highly efficient transition metal-free arylations of unactivated
arenes,2a (ii) selectively recognizing alkali metal ions,2b,c organic
cationic species,2d,e or neutral guests,2f,g (iii) serving as an ion
transporter across cell membranes,2h and (iv) stabilizing DNA
G-quadruplex structures.2i A rapid and efficient synthetic access to
these H-bonded macrocycles should greatly facilitate their sub-
sequent applications in the construction of increasingly sophisti-
cated functional supramolecular architectures and materials.
Fig. 1 (a) and (b) describe one-pot synthesis of macrocyclic pentamers 2a
and 4a from 1a and 3a by using macrocyclization reagents POCl3 and BOP,
Accordingly, a one-pot H-bonding-assisted macrocyclization strategy respectively under mild conditions. (c) shows that no macrocyclization
reagent thus far has been identified for the synthesis of fluoropentamer 6
from its monomeric amino ester 5. Our computational results invariably
suggest the pentameric backbones seen in 2a, 4a and 6 are more stable
than their corresponding tetramers or hexamers.
has been recently developed that, as one of the newest additions to
the macrocyclization toolbox, has allowed the rapid construction of
H-bonded macrocyclic foldamers of various structures, enclosing a
cavity from as small as 1.4 Å to as large as 15 Å in radius.1,3
In line with these recent developments, we also reported ‘‘greener’’
one-pot syntheses of H-bonded pentameric macrocycles such as 2a4a–d of 1–5% after more than 15 steps and several months of effort. One
and 4a,4e respectively, formed from monomeric methoxybenzene and perplexing observation during our investigations is that POCl3 and
pyridone motifs 1a and 3a with yields of as high as 46% in about a day BOP allow only circular pentamers 2a and 4a to be formed from
(Fig. 1a and b). These newly discovered greener protocols compare building blocks 1a and 3a, respectively, and do not yield any circular
very favorably with our previously reported lengthy step-by-step fluoropentamer 6 or pyridine-based pentamer from their corre-
processes2b,c,4f,g that produced circular pentamers in marginal yields sponding monomeric fluorobenzene 55a,b or pyridine5c–e amino acids.
This suggests that every type of monomer building block destined to
form the most stable circular structure may possibly require its own
unique ‘‘cognate’’ macrocyclization reagents that appear to be ‘‘ortho-
a Faculty of Chemical Engineering and Light Industry,
Guang Dong University of Technology, Guang Dong, 510006, China
b College of Chemistry and Chemical Engineering, Chongqing University, Chongqing,
gonal’’ to each other and function well only against its own specific set
of ‘‘cognate’’ monomer units. It is therefore of outstanding interest to
us to continue searching for suitable one-pot macrocyclization
reagents capable of selectively producing other types of pentamers
such as 6 from its monomeric building block 5.
400030, China. E-mail: qinbo@cqu.edu.cn
c Department of Chemistry, National University of Singapore, 3 Science Drive 3,
117543, Singapore. E-mail: chmzh@nus.edu.sg; Tel: +65-6516-2683
d Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
138669, Singapore. E-mail: hqzeng@ibn.a-star.edu.sg
Encouraged by the earlier and recent reports on the use of strong
† Electronic supplementary information (ESI) available: A full set of characteriza-
tion data including 1H NMR, 13C NMR, and (HR)MS. See DOI: 10.1039/c3cc48576e alkali or other metal salts (NaH, BuLi, and AlMe3, etc.) to directly
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Table 1 Searching for suitable reagentsa for one-pot preparation of
hexamer 8a from monomer 7a
Selective synthesis of hexamer 8a vs. pentamer 2a is surprising in
view of the computational results at the B3LYP/6-31G* level (Fig. 2b
and c), pointing to a highly distorted structure for 8a that is energe-
tically less stable than nearly planar 2a by 0.69 and 7.96 kcal molÀ1
per repeating unit in THF and the gas phase, respectively. This high
level ab initio calculation has consistently allowed us to predict
diverse structures of a series of H-bond-rigidified foldamer mole-
cules including 2a that were subsequently verified by their crystal
structures.2c,4f,5a,f,7 The inherent instability and high structural
distortion in 8a may suggest more stable and more planar 2a to
be produced predominantly in the macrocyclization reactions.
In fact, our earlier investigations do show that macrocyclization
reagent POCl3 invariably produces 2a as the major product in a
yield of up to 46% and 8a as the minor product in a yield of up to
33% from monomer 1a in acetonitrile.4a–d By using 7a as the
starting material and AlMe3 as the macrocyclization reagent, an
opposite trend is found, i.e., less stable and more distorted 8a was
unexpectedly produced as the major product (entry 6, Table 1). This
trend persists in solvents (e.g., toluene, dioxane and dichloro-
methane) where macrocyclization can take place, albeit with lower
yields of 8a and higher yields of 2a (entries 7–9). This AlMe3-
mediated cyclohexamerization reaction likely proceeds via for-
mation of an intermediate aluminium amide by the reaction of
AlMe3 with RNH2 with the loss of methane, followed by coordina-
tion of the Al center to the carbonyl group to activate the ester and
deliver the amide nucleophile to form amide bonds. In light of this
mechanism, such reactions are expected to be prone to inhibition
by Lewis basic solvents and additives. The use of Lewis basic
solvents such as DMF, DMSO, CH3CN, acetone and ethyl acetate
indeed completely halts the macrocyclization reaction, not resulting
in generation of 2a and 8a. Similarly, in the presence of Lewis basic
additives such as HMPA, TMEDA and PMDTA, circular products 2a
and 8a remain undetectable as well.
Yieldb (%)
Entry
Coupling reagent
Anhydrous solvent
2a
8a
c
1
2
3
4
5
6
7
8
9
10
MH (M = Li, Na, or K)
CaH2
ZnEt2
LiHMDS
AlEt3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
THF
THF
THF
THF
THF
THF
Toluene
Dioxane
CH2Cl2
CHCl3
—
—
—
—
1
3
6
c
c
c
11
24
17
15
15
6
4
c
—
a
Reaction conditions: 7a (0.5 mmol, 100 mM), coupling reagents
b
(1.5 mmol), solvent (5.0 mL), 70 1C, 12 h. Isolated yield by flash
column chromatography. No circular products 2a or 8a were detected.
c
convert unactivated esters into amides via ester aminolysis,6 we
decided to explore the possibility of using these metal salts to
effect one-pot macrocyclization reactions for a possible produc-
tion of circularly folded aromatic pentamers 2a, 4a and 6 (Fig. 1).
In a typical reaction setup, an amino ester such as 7a (0.5 mmol)
was dissolved in anhydrous THF (5.0 mL), to which the metal salt
(1.5 mmol) was added in one pot under nitrogen. The reaction
vessel was then tightly sealed and heated at 70 1C under constant
stirring for 12 h. Under these reaction conditions and with the use
of various metal salts (entries 1–6 of Table 1), hexamer 8a (Fig. 2a)
was produced from 7a in 24% yield along with trace amounts of
pentamer 2a by using aluminum salts (entries 5 and 6 of Table 1).
Under the same conditions, no pyridone- or fluorobenzene-based
circular pentamers 4a and 6 or the hexameric versions were
generated from the corresponding monomeric amino esters.
With respect to entry 1 in Table 2, either a deviation from the
optimum reagent concentration of 100 mM, as seen in entries 2–4,
or addition of the same amount of AlMe3 in three portions, as seen
in entry 5, decreases the yield of 8a from 24% to 14–22%.
A prolonged reaction time of up to 48 hours marginally helps in
increasing the yield of 8a by up to 2% (entry 3 vs. entries 6 and 8).
Table
2
Effects of the solvent volume, reaction time and addition
sequence involving AlMe3 in one-pot preparation of hexamer 8a from
monomer 7a in THF at 70 1C
Yielda,b (%)
Entry
Solvent volume (mL)
Reaction time (h)
2a
8a
1
2
3
4
5
6
7
8
5.0
2.5
12
12
12
12
12
24
36
48
3
2
2
2
2
2
2
2
24
22
18
15
14
19
19
20
10.0
15.0
10.0c
10.0
10.0c
10.0
Fig. 2 (a) General structures of strained macrocyclic hexamers 8. Top and side
views of ab initio-optimized structures of methoxy-containing circularly folded
pentamer 2a (b) and hexamer 8a (c) in tetrahydrofuran (THF) at the B3LYP/6-31G*
level. Computationally, 8a takes a highly distorted conformation that is less stable
than nearly planar 2a by 0.69 and 7.96 kcal molÀ1 per repeating unit in THF and
the gas phase, respectively. The computationally derived planar backbone and
geometry of 2a are nearly identical to those found in its crystal structure.5f For
a
Reaction conditions: 7a (0.5 mmol), AlMe3 (1.5 mmol), THF, 70 1C,
b
c
12 h. Isolated yield by flash column chromatography. AlMe3 was
added in three portions at intervals of 4 and 12 h for entries 4 and 7,
clarity of the view, all the interior methyl groups in (b) and (c) have been removed. respectively.
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Table 3 Temperature-dependent distributions of intermediate and circular
oligomers from one-pot cyclohexamerization of 7a in THF
Financial support for this work to B.Q. by the National
Science Foundation of China (No. 21272293) and to H.Z. by
SPORE (COY-15-EWI-RCFSA/N197-1) and the NRF CRP Grant
(R-154-000-529-281) is gratefully acknowledged.
Notes and references
1 For recent reviews on H-bonding-assisted one-pot macrocyclization
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Chem. Commun., 2012, 48, 12142.
Yielda,b (%)
Intermediate oligomers Circular oligomers
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Temp. (1C)
P2
P3
P4
P5 2a
8a
25
40
60
70
20
14
6
15
7
4
12
11
7
7
6
4
3
1
1
2
3
4
11
19
24
3
2
3
a
Reaction conditions: 7a (0.5 mmol), AlMe3 (1.5 mmol), THF (5 mL),
b
12 h. Isolated yield by flash column chromatography.
The substrate scope was then examined by applying the
optimized macrocyclization conditions to monomeric 7b–d
(Fig. 2). Except for 7b for which no macrocyclization product
8b was observed, 8c and 8d both were produced satisfactorily
from 7c and 7d with respective yields of 17% and 12%.
Previously, we showed that strained hexamer 8a is generated
predominantly from bimolecular reactions between dimer
and tetramer molecules or between two trimer molecules for
POCl3-mediated one-pot cyclooligomerization of 1a.4d This
bimolecular reaction mechanism, rather than a chain-growth
mechanism,4c seems to be in operation as well for AlMe3-
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related structures,4f,g hexamer P6 is computationally deter-
mined to adopt a helically folded structure that is rigidified
by strong H-bonds (see the structure in Table 3). As a result, the
two reacting end groups in P6 are rigidly placed far away from
each other and the intramolecular ring-closing reaction thus
does not occur readily to produce 8a. Consistent with this
structural constraint and going from 25 to 70 1C, 8a is produced
increasingly more with increasing consumptions of P2–4 via
bimolecular reactions. In regard with the yields of pentamer 2a,
the presence of equal or more amounts of P5 at various
temperatures suggests an energetically less favoured process
for conversion of P5 into 2a during the AlMe3-mediated cyclo-
oligomerization reaction. Similar unfavorability is expected for
conversions of P5 into P6 and of P6 into 8a.
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find any ‘‘cognate’’ macrocyclization reagent for monomeric
fluorobenzene 55a,b and pyridine5c–e motifs, our continued
investigations do help to identify trimethyl aluminum as a very
surprising macrocyclization reagent, selectively producing
energetically less favored strained macrocyclic hexamers such
as 8a via one-pot cyclohexamerization of 7a. We are currently
investigating the possible structural origins accounting for this
unusual selectivity.
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3584 | Chem. Commun., 2014, 50, 3582--3584
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