Step-Growth Cyclo-Oligomerization for the Preparation of Di- and Tetrafunctionalized Pillar[5]arenes

Article abstract of DOI:10.1021/acs.joc.8b00073

The preparation of complex functionalized pillar[n]arenes (PA[n]s) is challenging by one-pot cocyclization or selective deprotection method. We developed a step-growth cyclo-oligomerization method to synthesize functionalized PA[5]s. Dimers, trimers, and tetramers were synthesized and characterized. With this new method, we were able to prepare three di- and tetrafunctionalized PA[5]s. By using a multistep synthetic strategy, the chance to form constitutional isomers and other by-products was reduced. Therefore, complex tetrafunctionalized PA[5]s were prepared with improved yield.

Full text of DOI:10.1021/acs.joc.8b00073

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Step-Growth Cyclo-Oligomerization for the Preparation
of Di- and Tetrafunctionalized Pillar[5]arenes
Weipeng Mao, Shuaijun Zhan, Bowei Zhu, and Da Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00073 • Publication Date (Web): 14 Mar 2018
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Step-Growth Cyclo-Oligomerization for the Preparation of
Di- and Tetrafunctionalized Pillar[5]arenes
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Weipeng Mao, Shuaijun Zhan, Bowei Zhu, and Da Ma,*
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Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China.
Abstract: The preparation of complex functionalized pillar[n]arenes (PA[n]s) is
challenging by one-pot co-cyclization or selective deprotection method. We
developed
a
step-growth cyclo-oligomerization method to synthesize
functionalized PA[5]s. Dimer, trimer and tetramer were synthesized and
characterized. With this new method, we were able to prepare three di- and
tetrafunctionalized PA[5]s. By using multi-step synthetic strategy, the chance to
form constitutional isomers and other by products was reduced. Therefore,
complex tetrafunctionalized PA[5]s were prepared with improved yield.
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Pillar[n]arenes (PA[n]s) are a new type of pillar-shaped synthetic receptors.
Discovered in 2008 by Ogoshi and co-workers,1,2 PA[n]s have attracted great
interest for their excellent host-guest recognition property,3,4 facile synthesis,5,6
and simple functionalization.7œ9 Various applications have been developed for
PA[n]s.10œ20
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PA[n]s are composed of n repeating units. For instance, PA[5] has five repeating
units, which are assigned as Ring A to Ring E (Figure 1). There are 10 substituent
groups on Ring A-E, which could be identical or different. The precise control of
substituent groups is crucial to achieve the desired function and application. Two
methods have been used to synthesize functionalized PA[n]s: (1) one-pot co-cyclization
reactions starting from two substituted hydroquinones; (2) selective deprotection of
PA[n] alkoxy moieties followed by substitution.2,21 Di-functionalized PA[5]s have been
prepared with relatively high yield.22œ25 Nevertheless, the more complex
tetrafunctionalized PA[5]s were synthesized with a low yield (≤8%) by either
method.9,26 The reason is that one-pot co-cyclization or deprotection method forms a
mixture of constitutional isomers, which leads to low yield and laborious purification.
A new synthetic method is needed to minimize the formation of constitutional isomers
and other by products to improve the yield of functionalized PA[n]s.
Figure 1. Assignments of repeating units and substituent groups of PA[5].
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Step-growth cyclo-oligomerization has been applied to prepare macrocyclic
hosts.27,28 The stepwise formation of oligomers often generate only one major product
in each step. The cyclo-oligomerization reaction reduce the chance of forming
constitutional isomers. We envision that this method is highly valuable for the
preparation of functionalized PA[n]s. Therefore, here, we report step-growth cyclo-
oligomerization as a new method to synthesize functionalized PA[n]s.
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First, we prepared oligomers 2-4 and tetrafunctionalized dimers 2a-b. Oligomers
2-3 were synthesized based on improved literature procedures.29,30 As depicted in
Scheme 1A, dimer 2 was prepared by the condensation reaction of monomer 1a and
monomer 1b with a yield of 70%. To prepare trimer 3, we first tried the condensation
reaction of monomer 1a and monomer 1c. Nevertheless, this reaction yields dimer 2 as
the major product, which was formed by the condensation reaction with a 1:1
stoichiometry followed by the elimination of one bromomethyl substituent. Based on
this observation, we used the Lewis acid catalyzed condensation reaction of monomer
1c and dimer 2 to get trimer 3 with a yield of 70%. Tetramer 4 was synthesized by the
condensation reaction of dimer 2 and paraformaldehyde with a relatively low yield of
10% due to the formation of polymers. Functionalized dimers 2a-2b were prepared by
condensation reactions of functionalized monomer 1h and functionalized monomer
1g/1j (Scheme 2B).
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Scheme 1. Synthetic procedures to prepare (A) oligomers
2-4 and (B)
functionalized dimers 2a-b. Conditions: (a) TFA, CH2Cl2, r.t.; (b) AlCl3, CH2Cl2,
r.t.; (c) (HCHO)n, BF3·Et2O, CHCl3, r.t.; (d) BrCH2CH2Br, K2CO3, CH3CN,
reflux; (e) NaBH4, CH3OH, r.t.; (f) propargyl bromide, K2CO3, DMF, r.t..
Oligomers
(Supporting information). We obtained single crystal structure for oligomers
. As shown in Figure 2, the crystal structure of oligomer is twisted to have the
two aromatic planes almost perpendicular to each other. The crystal structure of
oligomer is in an S shape with the protons on the two methylene bridges
pointing to the opposite directions.
2-4 were characterized by NMR, Mass spectroscopy and XRD
2
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Figure 2. Single crystal structure of dimer
grey, H white, O red.
2 (a) and trimer 3 (b). Colour code: C
PA[n] formation reaction is a dynamic covalent bond forming process,31
during which oligomers are dynamically formed and cyclized to generate PA[n]s.
The formation and consumption of oligomers 2-4 were investigated in a typical
one-pot cyclization reaction to form PA[n]s (Figure 3).32 We used reverse phase
HPLC to monitor the reaction (Figure 3). The concentrations of oligomers 2-4
reached a maximum of 1.5 mM, 1.1 mM and 0.9 mM, respectively, which are
significantly lower than the initial concentration of 1a (125 mM). After the peak
concentration, the consumption rate surpassed the formation rate. Oligomers
could cyclize to form macrocyclic PA[n]s. As shown in Figure S25, trimer and
dimer cyclization (
3+2) in CH2Cl2 quickly forms PA[5] as the major product due
to the solvent template effect.33 By comparison, when using CHCl3 as solvent,
3
+2
cyclization reaction generated a mixture of PA[n] homologues (Figure S26).
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Therefore, oligomers could cyclize to form PA[n]s in a dynamic process. To
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minimize isomerization and other side reactions, a quick cyclization is essential.
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Figure 3. The time-dependent concentration change of oligomers
conventional PA[n] formation reaction. Square, dimer ; circle, trimer
tetramer . Reaction condition: [1a] = [(HCHO)n] = [BF3·OEt2] = 125 mM,
solvent CHCl3, 25 •
2
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4
in a
2
3; triangle,
4
Step-growth cyclo-oligomerization method was used to synthesize
functionalized PA[5]s. We used two oligomer combinations: (1) cyclization
reactions of tetramer and monomer (
4+1); (2) cyclization reactions of trimer and
dimer ( ). The reactions were carried out in CH2Cl2 to form predominately
3+2
functionalized PA[5]s. As depicted in Scheme 2, in either of these two
cyclization reactions, the formation of only two methylene bridges (highlighted
in red) are required in order to form the macrocyclic PA[5]s. By comparison, in
a one-pot co-cyclization reaction, the formation of five methylene bridges are
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required to form functionalized PA[5]s. Therefore, oligomer cyclization is
expected to quickly form the right product to minimize the generation of isomers
and other by products.
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Scheme 2. Cartoon depicting the oligomer cyclization reactions to form
functionalized PA[5]s. Top: tetramer + monomer; bottom: trimer + dimer.
We used the oligomer cyclization method to prepare three di- and
tetrafunctionalized PA[5]s (Scheme 3). Tetramer
4 and 2-bromoethoxy
substituted monomer 1h were used in the cyclization reaction. The Lewis
4+1
acid catalyzed condensation reaction quickly yielded the desired product PA[5]
5a with an isolated yield of 24%. By comparison, the co-cyclization method was
reported to synthesize compound 5a with a yield of 19%.23 We also tried using
ethyl ester substituted monomer (R1 = CH2COOEt) in the
4+1 cyclization
reaction. Nevertheless, the target product was not obtained due to the electron
withdrawing and deactivating effect of ester substituents. Subsequently, we
tested
3
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cyclization reactions of trimer and functionalized dimer 2a
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2b. The
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cyclization reaction of trimer
3
and dimer 2a yielded tetrafunctionalized PA[5]
and dimer
5b with an isolated yield of 17%. Similarly, the reaction of trimer
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2b yields tetrafunctionalized PA[5] 5c with an isolated yield of 15%. Side
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products were formed in the above cyclization reactions. For instance, for the
above 4+1 cyclization reaction, in addition to target product 5a, compound 5b
was also formed with an isolated yield of 7%. The formation of side products is
due to dynamic nature of oligomers and macrocyclic PA[n]s, which could
convert to each other throughout the reaction. For all the above three cyclo-
oligomerization reactions, the target products were formed quickly. For example,
PA[5] 5b was formed with a simple product distribution after 7 min (Figure S27).
After this time point, more side products were formed, which were most likely
constitutional isomers and polymers. Nevertheless, when the reaction was
stopped at the right time, the products could be easily isolated.
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Scheme 3. Synthetic procedures for di- and tetrafunctionalized PA[5]s 5a
Condition a: (HCHO)n, BF3·Et2O, CH2Cl2, 25 •.
-c.
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As shown above, the step-growth cyclo-oligomerization method could be
used to synthesize functionalized PA[5]s. By introducing bromoethyl and alkyne
groups, further modifications were possible by nucleophilic substitution and Cu(I)
catalyzed alkyne-azide cycloaddition (—Click“ reaction). By co-cyclization
protocol, the yield of a tetrafunctionalized PA[5] similar to compound 5b was
low (8%).9 Similarly, the deprotection method only gave trace amount of
oxidation product to the neighbouring rings of A and B (0.3%).26 By comparison,
by oligomer cyclization, we were able to obtain tetrafunctionalized PA[5] 5b
with an improved yield of 17%. As for the more complex tetrafunctionalized
PA[5] 5c with two different types of functionalization (R1 ≠ R2), it would require
the co-cyclization of three types of monomers by co-cyclization method.
Therefore, by the conventional methods, it is very difficult to synthesize PA[5]
5c, if not impossible. By step-growth cyclo-oligomerization, we were able to
prepare the target product with a decent yield of 15%.
In conclusion, complex functionalized PA[5]s can be prepared by step-growth
cyclo-oligomerization. The use of step-growth method to construct oligomers and
functionalized PA[5]s significantly reduces the formation of undesired isomers and
improves the yield. We believe it is a powerful tool to achieve precise control of PA[n]
substituent groups.
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EXPERIMENTAL SECTION
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General experimental.
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All reagents and solvents were purchased from commercial suppliers and were used
without further purification. Compounds 1c and 1h were prepared according to
literature procedures.34,35 NMR spectra were recorded on an AVANCE III 400
spectrometer. Mass spectrometry was performed using a Bruker MicrOTOF11
instrument (Electro-Spray Ionization). Melting point was measured on a microscopic
melting point apparatus (Shanghai Jingke). Reverse phase high-performance liquid
chromatography (RP-HPLC) was performed using an Agilent 1200 infinity Series
system with a diode array detector equipped with a C18 column (Eclipse XDB-C18,
Agilent Scientific, 4.6 x 250 mm, 5 ꢀm particle size).
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Synthetic procedures.
Compound 2. To a solution of compound 1a (6.90 g, 50 mmol) and compound 1b (840
mg, 5.0 mmol) in CH2Cl2 (100 mL), trifluoroacetic acid (10 mL) was added. The
solution was stirred at room temperature for 6 h. The reaction was quenched by adding
sat. aqueous Na2CO3 solution. The product was extracted with CH2Cl2 and the solvent
was removed by rotary evaporation. The residue was purified by column
chromatography (CH2Cl2/hexane, v:v, 1:2) to yield compound 2 as a white solid (1.00
g, 3.5 mmol, 70%). M. p. 84.5-86.2 •. 1H NMR (400 MHz, CDCl3): / = 3.705 (s, 6H),
3.782 (s, 6H), 3.910 (s, 2H), 6.640 (s, 1H), 6.647 (s, 1H), 6.691 (d, 1H, J = 8.8 Hz),
6.698 (d, 1H, J = 8.8 Hz), 6.788 (d, 2H, J = 8.8 Hz). 13C NMR (100 MHz, CDCl3): / =
29.9, 55.6, 56.0, 111.0, 111.2, 116.8, 130.2, 151.9, 153.4 (9 out of 9 resonances
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observed). HR-MS (m/z): [M+H]+ calcd for C17H21O4 289.1434; found 289.1436. Rf =
0.37 (CH2Cl2/hexane, v/v, 1:2).
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Compound 3. To a solution of compound 1c (324 mg, 1.0 mmol) and compound 2
(2.88 g, 10 mmol) in CH2Cl2 (60 mL), AlCl3 (399 mg, 3 mmol) was added at 0 oC. The
suspension was stirred at room temperature for 6 h. The reaction was quenched by
adding 1 M HCl. The product was extracted with CH2Cl2, and the solvent was removed
by rotary evaporation. The residue was purified by column chromatography
(CH2Cl2/hexane, v:v, 1:2) to yield compound 3 as a white solid (306 mg, 0.70 mmol,
70%). M. p. 149.1-150.2 •. 1H NMR (400 MHz, CDCl3): / = 3.685 (s, 6H), 3.703 (s,
6H) 3.802 (s, 6 H), 3.900 (s, 4H), 6.630 (s, 1H), 6.638 (s, 1H), 6.649 (s, 2H), 6.684 (d,
1H, J = 8.8 Hz), 6.692 (d, 1H, J = 8.8 Hz), 6.788 (d, 2H, J = 8.8 Hz). 13C NMR (100
MHz, CDCl3): / = 29.8, 55.6, 56.0, 56.1, 110.8, 111.1, 113.7, 116.7, 127.1, 130.8, 151.5,
151.8, 153.4 (13 out of 13 resonances observed). HR-MS (m/z): [M+Na]+ calcd for
C26H30O6Na 461.1935; found 461.1927. Rf = 0.20 (CH2Cl2/hexane, v:v, 1:2).
Compound 4. To a solution of compound 2 (1.44 g, 5 mmol) and paraformaldehyde
(75 mg, 2.5 mmol) in CHCl3 (60 mL), BF·Et2O (310 ꢀL, 2.5 mmol) was added. The
solution was stirred at room temperature for 6 h. The reaction was quenched by adding
water. The resulting mixture was extracted with CH2Cl2, and the solvent was removed
by rotary evaporation. The residue was purified by column chromatography
(CH2Cl2/hexane, v:v, 1.5:1) to yield compound 4 as a white solid (150 mg, 0.26 mmol,
10%). M. p. 158.9-160.8 •. 1H NMR (400 MHz, CDCl3): / = 3.675 (s, 6H), 3. 696 (s,
6H), 3.704 (s, 6 H), 3.798 (s, 6H), 3.891 (s, 2H), 3.899 (s, 4H), 6.618 (s, 1H), 6.626 (s,
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1H), 6.644 (s, 2H), 6.650 (s, 2H), 6.678 (d, 1H, J = 8.8 Hz), 6.685 (d, 1H, J = 8.8 Hz),
6.784 (d, 2H, J = 8.8 Hz). 13C NMR (100 MHz, CDCl3): / = 29.7, 29.8, 55.5, 56.0, 56.1,
56.1, 110.7, 111.0, 113.6, 116.7, 126.9, 127.7, 130.8, 151.4, 151.5, 151.8, 153.5 (16 out
of 16 resonances observed). HR-MS (m/z): [M+Na]+ calcd for C35H40O8Na 611.2615;
found 611.2620. Rf = 0.26 (CH2Cl2/hexane, v:v, 1:1).
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Compounds 1e-f. A suspension of compound 1d (2.07 g, 15 mmol), BrCH2CH2Br (30
mL) and K2CO3 (2.84 g, 20 mmol) in MeCN (10 mL) was heated at reflux for 24 h.
After filtration, the filtrate was concentrated and purified by column chromatography
(ethyl acetate/hexane, v:v, 1:15) to yield compound 1f as a yellow solid (735 mg, 3.0
mmol, 20%), and compound 1e as a white solid (1.00 g, 2.8 mmol, 19%). Compound
1
1e: M. p. 80.4-82.8 •. H NMR (400 MHz, CDCl3): / = 3.632 (t, 2H, J = 6.0 Hz),
3.689 (t, 2H, J = 6.0 Hz), 4.298 (t, 2H, J = 6.0 Hz), 4.392 (t, 2H, J = 6.0 Hz), 6.945 (d,
1H, J = 9.2 Hz), 7.176 (d, 1H, J = 9.2 Hz), 7.346 (s, 1H), 10.505 (s, 1H). 13C NMR (100
MHz, CDCl3): / = 28.8, 29.0, 68.5, 69.0, 111.6, 114.9, 124.2, 125.6, 152.7, 155.5, 189.1
(11 out of 11 resonances observed). HR-MS (m/z): [M+H]+ calcd for C11H13Br2O3
350.9226; found 350.9211. Rf = 0.17 (CH2Cl2/hexane, v:v, 1:3). Compound 1f: M. p.
68.5-71.9 •. 1H NMR (400 MHz, CDCl3): / = 3.642 (t, 2H, J = 6.4 Hz), 4.292 (t, 2H,
J = 6.4 Hz), 6.954 (d, 1H, J = 9.2 Hz), 7.050 (s, 1 H), 7.185 (d, 1H, J = 9.2 Hz), 9.857
(s, 1 H), 10.687 (s, 1 H). 13C NMR (100 MHz, CDCl3): / = 29.0, 69.0, 117.1, 118.9,
120.1, 126.0, 151.1, 156.6, 196.0 (9 out of 9 resonances observed). HR-MS (m/z):
[M+H]+ calcd for C9H10BrO3 244.9808; found 244.9798. Rf = 0.35 (CH2Cl2/hexane, v:v,
1:3).
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Compound 1g. To a solution of compound 1e (352 mg, 1.0 mmol) in methanol (10
mL), NaBH4 (38 mg, 1.0 mmol) was added. The suspension was stirred at room
temperature for 6 h. The reaction was quenched by adding water. The product was
extracted with CH2Cl2, and the solvent was removed by rotary evaporation. The residue
was purified by column chromatography (CH2Cl2/hexane, v:v, 2:1) to yield compound
1g as a white solid (340 mg, 0.96 mmol, 96%). M. p. 89.7-90.8 •. 1H NMR (400 MHz,
CDCl3): / = 2.443 (s, 1H), 3.615 (t, 2H, J = 6.4 Hz), 3.680 (t, 2H, J = 6.4 Hz), 4.256 (t,
2H, J = 6.4 Hz), 4.311 (t, 2H, J = 6.4 Hz), 4.692 (s, 2 H), 6.764-6.800 (m, 2 H), 6.933
(s, 1H). 13C NMR (100 MHz, CDCl3): / = 29.2, 29.9, 61.8, 68.3, 68.6, 112.6, 114.5,
116.2, 131.0, 150.5, 152.6 (11 out of 11 resonances observed). HR-MS (m/z): [M+Na]+
calcd for C11H14Br2O3Na 374.9202; found 374.9184. Rf = 0.14 (CH2Cl2/hexane, v:v,
1:1).
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Compound 2a. To a solution of compound 1g (177 mg, 0.5 mmol) and compound 1h
(1.6 g, 5 mmol) in CH2Cl2 (9 mL), trifluoroacetic acid (1 mL) was added. The solution
was stirred at room temperature for 12 h. The reaction was quenched by adding sat.
aqueous Na2CO3 solution. The product was extracted twice with CH2Cl2, and the
solvent was removed by rotary evaporation. The residue was purified by column
chromatography (CH2Cl2/hexane, v:v, 1:2) afforded compound 2a as a white solid (224
mg, 0.34 mmol, 68%). M. p. 92.8-94.6 •. 1H NMR (400 MHz, CDCl3): / = 3.579 (t,
4H, J = 6.4 Hz), 3.606 (t, 4H, J = 6.0 Hz), 3.979 (s, 2H), 4.198 (t, 4H, J = 6.4 Hz), 4.241
(t, 4H, J = 6.0 Hz), 6.687-6.771 (m, 6H). 13C NMR (100 MHz, CDCl3): / = 29.3, 29.6,
30.2, 68.5, 68.9, 112.8, 113.1, 118.2, 131.1, 150.8, 152.5 (11 out of 11 resonances
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observed). HR-MS (m/z): [M+NH4]+ calcd for C21H28NBr4O4 673.8746; found
673.8739. Rf = 0.30 (CH2Cl2/hexane, v:v, 1:2).
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Compound 1i. To a suspension of compound 1f (490 mg, 2 mmol) and K2CO3 (414
mg, 6 mmol) in DMF (2 mL), propargyl bromide (0.5 mL, 4 mmol, 80% solution in
toluene) was added. The suspension was stirred at room temperature for 12 h. The
reaction was quenched with water (50 mL) and extracted with CH2Cl2. The solvent was
removed with rotary evaporation. The residue was purified by column chromatography
(ethyl acetate/hexane, v:v, 1:10) to yield compound 1i as a white solid (500 mg, 1.8
mmol, 90%). M. p. 75.5-76.7 •. 1H NMR (400 MHz, CDCl3): / = 2.561 (t, 1H, J =
2.4 Hz), 3.631 (t, 2H, J = 6.0 Hz), 4.297 (t, 2H, J = 6.0 Hz), 4.795 (d, 2H, J = 2.4 Hz),
7.090 (d, 1H, J = 9.2 Hz), 7.190 (d, 1H, J = 9.2 Hz), 7.345 (s, 1H), 10.436 (s, 1H). 13C
NMR (100 MHz, CDCl3): / = 29.0, 57.2, 68.5, 76.5, 77.8, 111.6, 115.6, 124.0, 126.1,
152.9, 154.9, 189.1 (12 out of 12 resonances observed). HR-MS (m/z): [M+H]+ calcd
for C12H12BrO3 282.9964; found 282.9969. Rf = 0.34 (CH2Cl2/hexane, v:v, 1:2).
Compound 1j. To a solution of compound 1i (500 mg, 1.76 mmol) in MeOH (10 mL),
NaBH4 (80 mg, 2.11 mmol) was added. The suspension was stirred at room temperature
for 6 h. The reaction was quenched by adding water. The product was extracted with
CH2Cl2, and the solvent was removed by rotary evaporation. The residue was purified
by column chromatography (CH2Cl2/hexane, v:v, 2:1) to yield compound 1j as a white
solid (485 mg, 1.70 mmol, 96%). M. p. 51.7-53.1 •. 1H NMR (400 MHz, CDCl3): /
= 2.205 (s, 1H), 2.514 (t, 1H, J = 2.4 Hz), 3.611 (t, 2H, J = 6.4 Hz), 4.251 (t, 2H, J =
6.4 Hz), 4.672 (s, 2H), 4.698 (d, 2H, J = 2.4 Hz), 6.796-6.825 (m, 1H), 6.914-6.952 (m,
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2H). 13C NMR (100 MHz, CDCl3): / = 29.3, 56.7, 61.4, 68.6, 75.7, 78.6, 113.4, 114.3,
115.8, 131.4, 149.8, 152.8 (12 out of 12 resonances observed). HR-MS (m/z): [M+Na]+
calcd for C12H13BrO3Na 306.9940; found 306.9953. Rf = 0.17 (CH2Cl2/hexane, v:v, 1:1).
Compound 2b. To a solution of compound 1j (216 mg, 1 mmol) and compound 1h
(3.24 g, 10 mmol) in CH2Cl2 (45 mL), trifluoroacetic acid (5 mL) was added. The
solution was stirred at room temperature for 6 h. The reaction was quenched by adding
sat. aqueous Na2CO3 solution. The product was extracted with CH2Cl2 and the solvent
was removed by rotary evaporation. The residue was purified by column
chromatography (CH2Cl2/hexane, v:v, 1:1) to yield compound 2b as a white solid (233
mg, 0.40 mmol, 40%). M. p. 79.7-81.3 •. 1H NMR (400 MHz, CDCl3): / = 2.513 (t,
1H, J = 1.6 Hz), 3.562-3.620 (m, 6H), 3.959 (s, 2H), 4.184-4.253 (m, 6H), 4.654 (d,
2H, J = 2.0 Hz), 6.704-6.774 (m, 5H), 6.903 (d, 1H, J = 8.8 Hz). 13C NMR (100 MHz,
CDCl3): / = 29.3, 29.6, 30.2, 56.7, 68.5, 68.9, 75.2, 79.1, 112.6, 113.1, 113.2, 113.4,
117.9, 118.1, 131.0, 131.2, 150.3, 150.8, 152.5, 152.6 (20 out of 20 resonances
observed). HR-MS (m/z): [M+NH4]+ calcd for C22H27NBr3O4 605.9485; found
605.9490. Rf = 0.33 (CH2Cl2/hexane, v:v, 1:2).
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Compound 5a. To a suspension of compound 4 (200 mg, 0.34 mmol),
paraformaldehyde (20 mg, 0.68 mmol) and compound 1h (110 mg, 0.34 mmol) in
CH2Cl2 (5 mL), BF·Et2O (96 mg, 0.6 mmol) was added. After stirring at 25 • for 10
min, the reaction was quenched by adding water. The product was extracted with
CH2Cl2 and the solvent was removed by rotary evaporation. The residue was purified
by column chromatography (CH2Cl2 /hexane, v:v, 1:2) to yield compound 5a as a white
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solid (64 mg, 0.082 mmol, 24%). Characterization data match literature report.23 1
H
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NMR spectrum was reported as Figure S21.
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Compound 5b. To a suspension of compound 2a (132 mg, 0.20 mmol),
paraformaldehyde (18 mg, 0.60 mmol) and compound 3 (88 mg, 0.20 mmol) in CH2Cl2
(3 mL), BF·Et2O (85 mg, 0.6 mmol) was added. The suspension was stirred at 25 •
for 7 min. The reaction was quenched by adding water. The product was extracted with
CH2Cl2 and the solvent was removed by rotary evaporation. The residue was purified
by column chromatography (CH2Cl2 /hexane, v:v, 1:1) to yield compound 5b as a white
solid (38 mg, 0.034 mmol, 17%). M. p. 104.5-105.8 •. 1H NMR (400MHz, CDCl3):
/ = 3.479 (t, 4H, J = 6.0 Hz), 3.534 (t, 4H, J = 6.0 Hz), 3.697 (s, 6H), 3.721 (s, 6H),
3.731 (s, 6H), 3.786 (s, 4H), 3.801 (s, 4H), 3.811 (s, 2H), 4.071 (t, 4H, J = 6.0 Hz),
4.158 (t, 4H, J = 6.0 Hz), 6.752 (s, 2H), 6.816-6.822 (m, 8H). 13C NMR (100 MHz,
CDCl3): / = 29.4, 29.5, 29.6, 30.0, 30.1, 55.8, 56.0, 68.6, 69.0, 113.8, 113.9, 114.1,
115.6, 116.4, 127.7, 128.1, 128.5, 128.7, 129.4, 149.6, 149.8, 150.6 (22 out of 22
resonances observed). HR-MS: (m/z): [M+Na]+ calcd for C49H54Br4O10Na: 1141.0343;
found 1141.0380. Rf = 0.23 (CH2Cl2 /hexane, v:v, 1:2).
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Compound 5c. To a suspension of compound 2b (118 mg, 0.20 mmol),
paraformaldehyde (18 mg, 0.60 mmol) and compound 3 (88 mg, 0.20 mmol) in CH2Cl2
(3 mL), BF·Et2O (85 mg, 0.6 mmol) was added. The suspension was stirred at 25 •
for 10 min. The reaction was quenched by adding water. The product was extracted
with CH2Cl2 and the solvent was removed by rotary evaporation. The residue was
purified by column chromatography (CH2Cl2 /hexane, v:v, 1:1) to yield compound 5c
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as a white solid (31 mg, 0.03 mmol, 15%). M. p. 101.3-102.9 •. 1H NMR (400 MHz,
CDCl3): / = 1.764 (t, 1H, J = 2.0 Hz), 3.408 (t, 2H, J = 6.0 Hz), 3.430 (t, 2H, J = 6.0
Hz), 3.587 (t, 2H, J = 6.0 Hz), 3.702 (s, 9H), 3.721 (s, 9H), 3.772 (s, 4H), 3.781 (s, 2H),
3.803 (s, 2H), 3.842 (s, 2H), 4.007 (t, 2H, J = 6.0 Hz), 4.055 (t, 2H, J = 6.0 Hz), 4.203
(t, 2H, J = 6.0 Hz), 4.402 (d, 2H, J = 2.0 Hz), 6.663 (s, 1H), 6.714 (s, 1H), 6.739 (s,
1H), 6.764 (s, 1H), 6.797 (s, 1H), 6.802 (s, 1H), 6.812 (s, 2H), 6.825 (s, 1H), 6.835 (s,
1H). 13C NMR (100 MHz, CDCl3): / = 28.8, 29.4, 29.5, 29.7, 30.0, 30.1, 30.7, 31.5,
55.7, 55.8, 55.9, 56.1, 68.8, 68.8, 69.2, 74.9, 78.4, 113.7, 113.8, 114.0, 115.4, 115.8,
116.1, 116.6, 118.8, 119.0, 123.4, 124.3, 128.1, 128.2, 128.2, 128.4, 128.5, 128.6, 129.5,
129.6, 149.4, 149.7, 149.8, 150.4, 150.6, 150.6 (42 out of 42 resonances observed). HR-
MS: (m/z): [M+Na]+ calcd for C50H53Br3O10Na: 1073.1081; found 1073.1087. Rf = 0.27
(CH2Cl2 /hexane, v:v, 1:1.5).
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Determination of time-dependent oligomer concentrations.
Asuspension of 1a (138 mg, 1 mmol), paraformaldehyde (30 mg, 1 mmol) and BF·Et2O
(142 mg, 1 mmol) was incubated in CHCl3 (8 mL) at 25 °C. Take aliquots (80 ꢀL) at
certain time points and quenched with a solution of MeOH/CHCl3 (1.2 mL, 1:1, v:v).
The solution was analyzed by HPLC with an injection volume of 5 ꢀL (CH3CN in 0.1%
TFA aqueous solution, from 50% to 99% within 35 min, flow rate 1.2 mL/min). The
concentration of oligomer was determined based on standard curves.
3+2 cyclization reactions.
A suspension of tetramer 3 (0.5 mmol), dimer 2 (0.5 mmol), paraformaldehyde (1.2 eq)
and BF·Et2O (1.2 eq) was incubated in solvent (CH2Cl2, CHCl3 or ClCH2CH2Cl, 20
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mL) at 25 °C. Aliquots (50 ꢀL) were taken at certain time points and quenched with a
solution of MeOH/CHCl3 (1.2 mL, 1:3, v:v). The solution was analyzed by HPLC with
an injection volume of 5 ꢀL. HPLC method: CH3CN in 0.1% TFA aqueous solution,
from 50% to 99% within 35 min, flow rate 1.2 mL/min). HPLC method for the 4+4
reaction: CH3CN in 0.1% TFA aqueous solution, from 80% to 99% within 35 min, flow
rate 1.0 mL/min.
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ACKNOWLEDGEMENT
The authors are grateful to Fudan University (start-up grant) and National Natural
Science Foundation of China (51503042 and 21672042) for financial support.
ASSOCIATED CONTENT
Supporting Information Available
NMR spectra, HPLC and TLC trace and X-ray single crystal data. This material is
available free of charge via the internet at http://pubs.acs.org. Crystallographic data
have been deposited to Cambridge Structural Database: CCDC 1529351 (compound 2)
and 1529350 (compound 3).
AUTHOR INFORMATION
Corresponding Author
*Email: dama@fudan.edu.cn; Tel: +86-21-65647915.
ORCID
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Da Ma:0000-0002-5300-7500
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Notes
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The authors declare no competing financial interest.
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