Thieme Chemistry Journal awardees - Where are they now? Synthesis of p-phenylene ethynylene based macrocycles and bimacrocycle through formation of the imine bond

Article abstract of DOI:10.1055/s-0028-1087554

This paper describes the synthesis of three monomacrocycles and one bimacrocycle from two p-phenylene ethynylene frameworks. For two of the monomacrocycles, the two frameworks were linked by an amide unit and the macrocyclization involved the intramolecular formation of one imine bond. For another monomacrocycle and the bimacrocycle, the frameworks contained two and three amino or aldehyde units, respectively, and the macrocyclization involved the intermolecular formation of two and three imine bonds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087554

384
LETTER
Thieme Chemistry Journal Awardees – Where are They Now?
Synthesis of p-Phenylene Ethynylene Based Macrocycles and Bimacrocycle
through Formation of the Imine Bond
Synthesis of
p
-P
i
henyle
u
ne Ethynyle
n
-
e
Based
G
Macrocycles ang Wang, Zhan-Ting Li*
State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: ztli@mail.sioc.ac.cn
Received 20 October 2008
Abstract: This paper describes the synthesis of three monomacro-
cycles and one bimacrocycle from two p-phenylene ethynylene
frameworks. For two of the monomacrocycles, the two frameworks
were linked by an amide unit and the macrocyclization involved the
intramolecular formation of one imine bond. For another monomac-
rocycle and the bimacrocycle, the frameworks contained two and
three amino or aldehyde units, respectively, and the macrocycliza-
tion involved the intermolecular formation of two and three imine
bonds.
Key words: macrocycle, p-phenylene ethynylene, imine, reduction
Zhan-Ting Li was born in 1966 and received his B.Sc. degree in
1985 from Zhengzhou University. He earned his Ph.D. degree in
1992 with Professor Qing-Yun Chen at Shanghai Institute of Organic
Chemistry (SIOC). He did postdoctoral researches with Professor Jan
Becher at the University of South Denmark and with Professor
Steven C. Zimmerman at the University of Illinois at Urbana-
Champaign. Since 2003, he has been a professor at SIOC. His re-
search is concerned with unnatural secondary structures, molecular
recognition and dynamic covalent self-assembly and fluorine chemi-
stry.
In recent years, the self-assembly of shape-persistent
nanostructures with a high degree of structural control has
received great attention. In this context, phenylene ethy-
nylene derivatives have been developed as a class of ver-
satile rigid frameworks for constructing various
macrocyclic architectures.1–4 Most of the reported exam-
ples involved the use of m-phenylene ethynylene seg-
ments.2,3 Several o-phenylene ethynylene based macro-
cycles have also been reported.4 In contrast, p-phenylene
ethynylene oligomers, which possess straight conforma-
tions, have only been used to insert between other seg-
ments to help to construct extended cyclic systems,5 even
though they can be readily modified with discrete reactive
sites.1,6 With the increasing application of the dynamic co-
valent chemistry in constructing macrocyclic architec-
tures,7 we became interested in utilizing them as
backbones to construct macrocyclic structures, with a fur-
ther aim of creating new molecular ladders.8 Therefore,
we have designed several p-phenylene ethynylene deriva-
tives as model precursors which bear two or three amino
or aldehyde groups that can form reversible imine bond.9
In this letter, we describe that new monomacrocycles 1–3
and bimacrocycle 4 (Figure 1) can be prepared from them
in high yields.
Liu-Gang Wang was born in 1982 and received his B.Sc. degree
from Zhengzhou University in 2006. He is currengly a third-year gra-
duate student with Professor Zhan-Ting Li.
reduction of 510 to 6 by iron and ammonium chloride in
refluxed aqueous ethanol. Hydrogenation of 5 in the pres-
ence of Pd/C or Raney nickel was also attempted; this,
however, resulted in removal of the iodine atom. Com-
pound 6 was then coupled with 712 to produce 8 in 78%
yield.
Treatment of 8 with 9 in THF afforded 10 in 80% yield.
Compound 10 was further coupled with 1113 in triethyl-
amine to produce 12 in 80% yield. Removal of its Boc
group was performed in dichloromethane in the presence
1
of an excess of trifluoroacetic acid. The H NMR spec-
trum of the crude product, obtained after reaction
achieved equilibrium in approximately five hours and the
acid neutralized, in chloroform-d showed the existence of
the signal of the CHO proton, indicating that the CHO and
NH2 units were not completely converted into imine. To
realize complete conversion, the crude product was re-
fluxed in toluene azeotropically to remove the formed
water. The conversion was complete after ca. 60 hours
and macrocycle 114 obtained nearly quantitatively.
The synthetic route for compound 1 is shown in
Scheme 1. The precursor 12 bears both CHO and NHBoc
units.11 The amino group was protected with Boc because
molecules that contain CHO and NH2 units are difficult to
manipulate. It was expected, the acid-catalyzed deprotec-
tion of 12 would initiate the formation of the imine bond
to yield the macrocycle. The synthesis started from the
Compound 12 has an intramolecular five-membered
1
N–H···O hydrogen bond,15 as evidenced by its H NMR
SYNLETT 2009, No. 3, pp 0384–0389
Advanced online publication: 21.01.2009
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x.
x
x.
2
0
0
9
DOI: 10.1055/s-0028-1087554; Art ID: S10908ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of p-Phenylene Ethynylene Based Macrocycles
385
Fe, NH4Cl, EtOH–H2O
OC8H17
H
I
OR
NO2
I
OR
NH2
reflux, 6 h, 100%
N
N
6
8
5
O
H
6, PdCl2(PPh3)2
CuI, Et3N, THF
C8H17O
OR
NH2
1
r.t., 25 h, 78%
NHBoc
NHBoc
7
N
NH
O
OR
I
8, THF, Et3N
NH
NHBoc
2
O
I
0 °C, 4 h, 80%
OC8H17
COCl
10
9
N
N
OHC
10, PdCl2(PPh3)2, CuI, Et3N
H
C8H17O
r.t., 24 h, 80%
3
11
OC8H17
OR
i) TFA, CH2Cl2, 0 °C, 9 h
1
N
N
N
NHBoc
N
H
ii) toluene, reflux, 60 h, >95%
OHC
O
R = n-C8H17
C8H17O
4
12
Figure 1
Scheme 1 Synthesis of macrocycle 1
spectrum in chloroform which showed the peak of the
amide hydrogen in the downfield area (d = 9.24 ppm).
Considering the high stability of this intramolecular hy-
drogen bonding pattern,16 it is reasonable to propose that
it also exists in 1. To detect whether this hydrogen bond-
ing promoted the formation of 1 through conformational
preorganization, its isomer 2 was also prepared. Scheme 2
provides the synthetic route. Thus, compound 1317 was
first octylated in refluxed acetonitrile to give 14 in 96%
yield. The latter was then quantitatively reduced to 15 also
by iron and ammonium in ethanol. Palladium(II)-
catalyzed coupling of 15 with 7 in triethylamine afforded
16 in 88% yield. With 16 available, compound 19 was
prepared from the Pd(II)-catalyzed coupling reaction of
17 and 1818 in triethylamine. Hydrolysis of 19 to 20 was
performed in aqueous THF and methanol with lithium
hydroxide as the base. The acid was unstable in the pres-
ence of strong protic acid.19 Therefore, the neutralization
of unconsumed lithium hydroxide needed to be performed
at 0 °C with diluted aqueous acetic acid. Without further
purification, 20 was converted into 21 by treating with
oxalyl chloride in THF and then the latter reacted with 16
to produce 22 in 40% yield. Treatment of 22 with TFA in
dichloromethane afforded a residue, which was further re-
fluxed azeotropically in benzene to give 214 in 94% yield.
The result suggests that, without the assistance of the in-
tramolecular hydrogen bonding, monomacrocycle can
also be generated in high yield, which implies that it is
more stable than other possible macrocyclic or linear
products.
The self-assembly of macrocycles from two precursors
was then tested. The strategy was straightforward – to it-
eratively introduce the identical reactive sites to one pre-
cursor. Thus, 24 was first produced quantitatively by
octylation of 2320 in acetonitrile and then coupled with
2521 under the catalysis of Pd(II) in triethylamine and THF
to afford precursor 26 in 62% yield. With 26 available, an-
other precursor 28 was prepared in 91% yield from the
reaction of 6 with 2722 in triethylamine. The reaction of 26
and 28 was first performed in chloroform. However, the
precursors could not be consumed completely after the
reaction reached equilibrium, which can be attributed to
its reversible feature. Under the condition of refluxing
azeotropically in toluene, macrocycle 3 could be generat-
ed nearly quantitatively (Scheme 3). In principle, the reac-
tion should give rise to other linear oligomers or even
larger macrocycles. Selective formation of 3 from the
reaction indicates that this macrocycle was also substan-
tially more stable than other possible products, which
might be generated at the early stage, but could be con-
verted into 3 due to the reversible feature of the imine
bond.9,23
Encouraged by the above result, longer precursors 38 and
43 were then designed and synthesized. The synthetic
route for 38 is provided in Scheme 4. Thus, 29 was first
treated with sodium nitrite and citric acid in hexane and
dichloromethane to give 30 in 53% yield.24 The latter was
then reduced with iron and ammonium chloride to 31 in
Synlett 2009, No. 3, 384–389 © Thieme Stuttgart · New York

386
L.-G. Wang, Z.-T. Li
LETTER
OR
OH
OH
OR
CHO
CHO
I
I
RBr, K2CO3, KI
Fe, NH4Cl, EtOH
reflux, 1 h, 100%
RBr, K2CO3, KI
MeCN, reflux, 4 h, 98%
MeCN, reflux
5 h, 96%
24
23
I
I
NO2
OR
NO2
13
14
H
CHO
CHO
RO
24, PdCl2(PPh3)2
I
CuI, Et3N, THF
7, PdCl2(PPh3)2, CuI
OR
Et3N, r.t., 18 h
88%
r.t., 24 h, 62%
CHO
26
28
NHBoc
NH2
25
27
NH2
16
15
H
MeO2C
OHC
NH2
NH2
OR
6, PdCl2(PPh3)2
PdCl2(PPh3)2, CuI, Et3N
r.t., 2 h, 85%
CuI, Et3N
+
H
I
r.t., 11 h, 91%
NH2
17
CHO
18
CHO
26, toluene
reflux, 12 h, >95%
R = n-C8H17
3
LiOH, MeOH–THF–H2O
r.t., 10 h, 100%
Scheme 3 Synthesis of macrocycle 3
CO2Me
CO2H
20
OH
OH
CHO
19
citric acid
NaNO2, SiO2
Fe, NH4Cl
EtOH–H2O
NO2
hexane–CH2Cl2
r.t., 2.5 h, 53%
reflux, 12 h, 69%
(COCl)2, DMF
THF, 0 °C, 1 h
16, Et3N, THF
0 °C, 7 h, 40%
29
I
30
OH
I
OH
COCl
7
NH2
NHBoc
PdCl2(PPh3)2
(Boc)2O, EtOH
r.t., 36 h, 74%
RO
21
CuI, Et3N, THF
r.t., 11 h, 74%
31
32
I
I
i) TFA, CH2Cl2, r.t., 9 h
ii) benzene, reflux
Tf2O, CH2Cl2, Et3N
0 °C, 3 h, 92%
2
NHBoc
NH
OH
OHC
O
42 h, 94%
NHBoc
NHBoc
33
R = n-C8H17
TMS
H
PdCl2(PPh3)2, CuI, NEt3
22
OTf
THF, 80 °C, 19 h, 90%
Scheme 2 Synthesis of macrocycle 2
NHBoc
NHBoc
NHBoc
34
35
36
K2CO3,
69% yield. Treatment of 31 with di-tert-butyl dicarbonate
in ethanol produced 32 in 74% yield. Compound 33 was
then prepared in 74% yield from its coupling reaction with
7 in THF. The phenol was then converted into trifluoro-
methanesulfonate 34, which was further coupled with
ethynyltrimethylsilane to yield 35. This intermediate was
treated with potassium carbonate in methanol and dichlo-
romethane to yield 36 in 87% yield. Its coupling reaction
with 6 in triethylamine produced 37 in 75% yield. In the
presence of TFA, 37 was deprotected in dichloromethane
to give 38 in 88% yield. The compound was instable and
used immediately for the next reaction.
MeOH–CH2Cl2
SiMe3
r.t., 2.5 h, 87%
NHBoc
6, PdCl2(PPh3)2,
CuI, Et3N
H
THF, r.t., 10 h, 75%
NHBoc
NHBoc
NHBoc
NHBoc
TFA, CH2Cl2
OR
r.t., 6 h, 88%
NH2
37
38
With compound 38 available, trialdehyde 43 was also pre-
pared (Scheme 5). Thus, compound 39 was first prepared
in 72% yield from the coupling reaction of 23 and 25 in
THF and then converted to trifluoromethanesulfonate 40
in dichloromethane. The latter was then coupled with
ethynyltrimethylsilane in triethylamine to afford 41 in
58% yield. Its deprotection was performed with potassium
OR
NH2
NH2
NH2
R = n-C8H17
Scheme 4 Synthesis of precursor 38
Synlett 2009, No. 3, 384–389 © Thieme Stuttgart · New York

LETTER
Synthesis of p-Phenylene Ethynylene Based Macrocycles
387
CHO
CHO
OH
CHO
CHO
OTf
PdCl2(PPh3)2
CuI, Et3N, THF
Tf2O, CH2Cl2, Et3N
0 °C, 5 h, 89%
23 + 25
40
r.t., 9 h, 72%
39
CHO
CHO
CHO
CHO
TMS
H
K2CO3, MeOH–CH2Cl2
PdCl2(PPh3)2, CuI, Et3N
TMS
H
0 °C, 1 h, 92%
THF, 80 °C, 13 h, 58%
42
41
CHO
CHO
CHO
24, PdCl2(PPh3)2
CuI, Et3N, THF
38, CHCl3–MeOH
R = n-C8H17
4
OR
reflux, 5 d, 80%
r.t., 11 h, 61%
43
Scheme 5 Synthesis of macrocycle 4
carbonate in methanol and dichloromethane to give 42 in In conclusion, we have demonstrated that p-phenylene
92% yield. Compound 42 was then coupled with 24 in ethynylene derivatives are useful frameworks for building
THF to afford 43 in 61% yield. A solution of 38 and 43 in macrocyclic architectures, while the dynamic covalent ap-
chloroform and methanol was refluxed for five days af- proach enables their generation in high yields. The fact
forded bimacrocycle 4 as a precipitate. The solid was in- that bimacrocycle 4 could be produced from two straight
soluble in organic solvents, including chloroform, precursors through the formation of three imine bonds
dichloromethane, DMF, and DMSO, even at higher tem- bodes well for future assembly of multicyclic architec-
1
perature. Therefore, no H NMR and 13C NMR spectra tures by using the new approach, although the issue of sol-
could be recorded. However, the MALDI-TOF mass ubility has to be addressed carefully. The new
spectrometry of the product exhibited the strong molecu- macrocyclic backbones should also possess very rigid pla-
lar ion peak of 4, while its IR spectrum showed no band of nar shape, which may exhibit unique stacking behavior
the CHO unit. In addition, the elemental analysis result that merits further investigation.
was also consistent with the structure of 4. These results
support that 4 was generated. However, for future prepa-
ration of multicyclic structures, suitable side chains have
Acknowledgment
We thank the National Science Foundation of China (Nos.
20732007, 20621062, 20425208, 20572126, 20672137), the Na-
tional Basic Research Program (2007CB808000) and Chinese Aca-
demy of Sciences for financial support.
to be developed to provide enough high solubility.
OC8H17
NH
NH
References and Notes
O
(1) (a) Pinto, M. R.; Schanze, K. S. Synthesis 2002, 1293.
(b) James, D. K.; Tour, J. M. Top. Curr. Chem. 2005, 257,
33. (c) Breitenkamp, R. B.; Arnt, L.; Tew, G. N. Polym. Adv.
Technol. 2005, 16, 189. (d) Weder, C. Angew. Chem. Int.
Ed. 2008, 47, 448.
44
OC8H17
(2) Höger, S. In Acetylene Chemistry; Diederich, F.; Stang,
P. J.; Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, 2005,
427–452.
NH
NH
(3) (a) Stone, M. T.; Heemstra, J. M.; Moore, J. S. Acc. Chem.
Res. 2006, 39, 11. (b) Höger, S. Angew. Chem. Int. Ed.
2005, 44, 3806.
(4) (a) Seo, S. H.; Jones, T. V.; Seyler, H.; Peters, J. O.; Kim,
T. H.; Chang, J. Y.; Tew, G. N. J. Am. Chem. Soc. 2006, 128,
9264. (b) Tahara, K.; Furukawa, S.; Ujii, H.; Uchino, T.;
Ichikawa, T.; Zhang, J.; Mamdouh, W.; Sonoda, M.;
De Schryver, F. C.; De Feyter, S.; Tobe, Y. J. Am. Chem.
Soc. 2006, 128, 16613. (c) Johnson, C. A. II; Lu, Y.; Haley,
M. M. Org. Lett. 2007, 9, 3725.
(5) Höger, S. In Functional Organic Materials; Müller, T. J. J.;
Bunz, U. H. F., Eds.; Wiley-VCH: Weinheim, 2007, 225–
260.
(6) (a) Englert, B. C.; Scholz, S.; Leech, P. J.; Srinivasarao, M.;
Bunz, U. H. F. Chem. Eur. J. 2005, 11, 995. (b) Zhao, Y.;
Shirai, Y.; Slepkov, A. D.; Cheng, L.; Alemany, L. B.;
C8H7O
45
Figure 2
The reduction of the macrocycles was also investigated.
Treatment of 1 with sodium triacetoxyborohydride in
chloroform afforded 44 in 82% isolated yield. Under sim-
ilar reaction conditions, 3 could be reduced to 45 in 60%
isolated yield (Figure 2). Attempt to reduce 4 failed possi-
bly due to its poor solubility.
Synlett 2009, No. 3, 384–389 © Thieme Stuttgart · New York

388
L.-G. Wang, Z.-T. Li
LETTER
Sasaki, T.; Hegmann, F. A.; Tour, J. M. Chem. Eur. J. 2005,
11, 3643. (c) Yang, J.-S.; Yan, J.-L.; Hwang, C.-Y.; Chiou,
S.-Y.; Liau, K.-L.; Tsai, H.-H. G.; Lee, G.-H.; Peng, S.-M.
J. Am. Chem. Soc. 2006, 128, 14109. (d) Satrijo, A.;
Swager, T. M. J. Am. Chem. Soc. 2007, 129, 16020.
(e) Burnworth, M.; Mendez, J. D.; Schröter, M.; Rowan,
S. J.; Weder, C. Macromolecules 2008, 41, 2157.
Compound 28: Pale brown solid; mp 96–97 °C. 1H NMR
(300 MHz, CDCl3): d = 0.89 (t, J = 6.6 Hz, 3 H), 1.29–1.49
(m, 10 H), 1.82 (q, J = 6.9 Hz, 2 H), 3.83 (br, 2 H), 4.00 (t,
J = 6.6 Hz, 2 H), 4.25 (br, 2 H), 6.70–6.74 (m, 3 H), 6.88–
6.93 (m, 2 H), 7.11 (td, J1 = 7.8 Hz, J2 = 1.5 Hz, 1 H), 7.33
(d, J = 7.8 Hz, 1 H). 13C NMR (100.4 MHz, CD3OD): d =
14.5, 23.8, 27.3, 30.5, 30.6, 33.1, 69.5, 84.7, 96.2, 109.8,
112.3, 115.6, 116.9, 118.6, 118.9, 123.4, 130.2, 132.7,
138.0, 148.8, 149.8. ESI-MS: m/z = 337.1 [M + H]+. ESI-
HRMS: m/z calcd for C22H29N2O [M]+: 337.22744; found:
337.2283.
(7) (a) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders,
J. K. M.; Stoddart, J. F. Angew. Chem. Int. Ed. 2002, 41,
899. (b) Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.;
Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Chem. Rev. 2006,
106, 3652. (c) Meyer, C. D.; Joiner, C. S.; Stoddart, J. F.
Chem. Soc. Rev. 2007, 36, 1705. (d) Lehn, J.-M. Chem. Soc.
Rev. 2007, 36, 151. (e) Ludlow, R. F.; Otto, S. Chem. Soc.
Rev. 2008, 37, 101.
Compound 43: Yellow solid; mp 153–154 °C. 1H NMR (300
MHz, CDCl3): d = 0.89 (t, J = 6.6 Hz, 3 H), 1.25–1.39 (m,
8 H), 1.45–1.54 (m, 2 H), 1.88 (q, J = 6.6 Hz, 2 H), 4.13 (t,
J = 6.6 Hz, 2 H), 7.02 (d, J = 8.7 Hz, 1 H), 7.50 (t, J = 7.8
Hz, 1 H), 7.59–7.68 (m, 3 H), 7.70–7.75 (m, 2 H), 7.97 (d,
J = 7.8 Hz, 1 H), 8.03 (d, J = 2.1 Hz, 1 H), 8.10 (d, J = 1.5
(8) (a) Hopf, H. Angew. Chem. Int. Ed. 2003, 42, 2822.
(b) Hartley, C. S.; Elliott, E. L.; Moore, J. S. J. Am. Chem.
Soc. 2007, 129, 4512.
Hz, 1 H), 10.48 (s, 1 H), 10.59 (s, 1 H), 10.61 (s, 1 H). 13
C
(9) Zhao, D.; Moore, J. S. J. Org. Chem. 2002, 67, 3548.
(10) Wu, Z.-Q.; Li, C.-Z.; Feng, D.-J.; Jiang, X.-K.; Li, Z.-T.
Tetrahedron 2006, 62, 11054.
NMR (100.4 MHz, CDCl3): d = 14.5, 22.6, 26.0, 28.9, 29.2,
29.2, 31.7, 69.0, 84.4, 87.8, 94.5, 97.3, 112.9, 114.3, 122.8,
124.9, 125.8, 126.7, 127.6, 129.2, 130.6, 131.9, 133.3,
133.4, 133.8, 135.7, 135.9, 136.2, 138.8, 161.8, 188.7,
190.5, 191.2. Anal. Calcd for C33H30O4: C, 80.79; H, 6.16.
Found: C, 80.63; H, 6.22. MS (MALDI-TOF): m/z = 491.0
[M + H]+. HRMS (MALDI-TOF): m/z calcd for C33H31O4:
491.2217; found: 491.2218.
(11) Analytical Data
Compound 12: Pale yellow oil. 1H NMR (300 MHz, CDCl3):
d = 0.82 (t, J = 6.9 Hz, 3 H), 1.09–1.24 (m, 10 H), 1.46 (t,
J = 6.6 Hz, 2 H), 1.55 (s, 9 H), 3.78 (t, J = 6.6 Hz, 2 H), 6.86
(d, J = 8.4 Hz, 1 H), 6.97 (t, J = 7.5 Hz, 1 H), 7.28 (d, J = 8.1
Hz, 2 H), 7.39–7.52 (m, 5 H), 7.58 (d, J = 7.5 Hz, 1 H), 7.65
(q, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.96–7.99 (m, 1 H), 8.18
(d, J = 8.4 Hz, 1 H), 8.93 (d, J = 1.5 Hz, 1 H), 9.24 (s, 1 H),
9.86 (s, 1 H). 13C NMR (100.4 MHz, CDCl3): d = 13.9, 22.4,
25.6, 28.1, 28.517, 28.9, 29.0, 31.4, 68.7, 80.6, 83.0, 88.3,
94.0, 96.1, 110.7, 111.3, 115.0, 117.3, 119.1, 121.9, 122.4,
123.5, 127.6, 127.7, 128.9, 129.1, 129.3, 129.7, 130.7,
131.6, 132.7, 133.1, 136.2, 136.9, 137.4, 139.2, 147.7,
152.3, 164.7, 190.9. ESI-MS: m/z 691.2 [M + Na]+. ESI-
HRMS: m/z calcd for C43H44N2O5Na [M + Na]+: 691.31424;
found: 691.3137.
(12) Ishizaki, M.; Zyo, M.; Kasama, Y.; Niimi, Y.; Hoshino, O.;
Nishitani, K.; Hara, H. Heterocycles 2003, 60, 2259.
(13) Frixa, C.; Mahon, M. F.; Thompson, A. S.; Threadgill, M. D.
Org. Biomol. Chem. 2003, 1, 306.
(14) Analytical Data
Compound 1: Pale yellow solid; mp 261–262 °C. 1H NMR
(300 MHz, CDCl3): d = 0.90 (t, J = 6.3 Hz, 3 H), 1.25–1.48
(m, 10 H), 1.83–1.78 (m, 2 H), 4.04 (t, J = 6.6 Hz, 2 H), 6.86
(d, J = 8.4 Hz, 1 H), 7.19–7.29 (m, 2 H), 7.35 (t, J = 7.5 Hz,
1 H), 7.40–7.50 (m, 3 H), 7.55 (d, J = 1.2 Hz, 1 H), 7.58 (s,
1 H), 7.60–7.66 (t, 3 H), 7.74 (s, 1 H), 8.61 (s, 1 H), 8.65 (s,
1 H), 8.68 (d, J = 1.8 Hz, 1 H). 13C NMR (100.4 MHz,
CDCl3): d = 14.1, 22.7, 26.1, 29.1, 29.3, 29.3, 31.7, 68.7,
87.8, 93.7, 111.4, 116.0, 118.3, 118.7, 121.6, 123.9, 125.9,
126.0, 126.4, 127.5, 127.9, 128.4, 128.6, 128.9, 129.8,
130.6, 131.2, 131.9, 132.2, 133.6, 136.8, 149.7, 152.8,
159.5, 166.4. MS (MALDI-TOF): m/z = 551.2 [M + H]+.
HRMS (MALDI-TOF): m/z calcd for C38H35N2O2 [M + H]+:
551.2693; found: 551.2704.
Compound 22: Pale yellow sticky solid. 1H NMR (300 MHz,
CDCl3): d = 0.83 (t, J = 6.0 Hz, 3 H), 1.22–1.33 (m, 8 H),
1.41–1.48 (m, 2 H), 1.54 (s, 9 H), 1.87 (q, J = .2 Hz, 2 H),
4.10 (t, J = 6.6 Hz, 2 H), 6.90 (d, J = 9.0 Hz, 1 H), 6.98 (t,
J = 7.5 Hz, 1 H), 7.31 (td, J1 = 7.9 Hz, J2 = 1.2 Hz, 1 H), 7.37
(dd, J1 = 7.2 Hz, J2 = 0.9 Hz, 1 H), 7.49–7.55 (m, 3 H), 7.60
(s, 1 H), 7.65–7.68 (m, 2 H), 7.71–7.74 (t, 2 H), 7.86 (d,
J = 7.5 Hz, 1 H), 8.00 (s, 1 H), 8.06 (dd, J1 = 6.0 Hz, J2 = 3.0
Hz, 1 H), 8.21 (d, J = 11.4 Hz, 1 H), 8.82 (s, 1 H), 9.96 (s,
1 H). 13C NMR (100.4 MHz, CDCl3): d = 14.0, 22.6, 25.9,
28.4, 29.0, 29.2, 29.3, 31.8, 69.2, 80.8, 88.7, 89.3, 92.0, 94,5,
111.4, 112.5, 113.0, 117.7, 119.1, 122.0, 122.0, 123.2,
124.4, 129.5, 129.5, 129.7, 130.0, 130.7, 130.9, 131.4,
133.0, 133.5, 136.6, 136.7, 137.0, 139.8, 152.7, 156.6,
164.5, 191.0. ESI-MS: m/z = 691.2 [M + Na]+, 707.1 [M +
K]+. ESI-HRMS: m/z calcd for C43H44N2O5Na [M + Na]+:
691.31424; found: 691.3140.
Compound 2: Pale yellow solid; mp 270–272 °C. 1H NMR
(300 MHz, CDCl3): d = 0.87 (t, J = 7.2 Hz, 3 H), 1.25–1.41
(m, 10 H), 1.88 (p, J = 7.5 Hz, 2 H), 4.08 (t, J = 6.9 Hz, 2 H),
6.94 (d, J = 9.0 Hz, 1 H), 7.19–7.25 (m, 2 H), 7.38 (dt,
J1 = 7.8 Hz, J2 = 1.5 Hz, 1 H), 7.52–7.56 (m, 3 H), 7.58–7.60
(m, 2 H), 7.68–7.74 (m, 3 H), 8.27–8.33 (m, 2 H), 8.58 (s,
1 H), 8.73 (s, 1 H), 9.45 (s, 1 H). 13C NMR (100.4 MHz,
CDCl3): d = 14.1, 22.7, 26.0, 29.2, 29.3, 29.4, 31.8, 69.4,
88.2, 91.5, 91.8, 96.3, 100.4, 113.3, 113.6, 117.3, 119.0,
119.3, 122.5, 122.7, 126.2, 126.3, 129.0, 129.1, 129.2,
129.4, 130.9, 131.0, 131.1, 131.4, 131.7, 134.5, 134.8,
137.0, 152.5, 155.9, 158.3, 163.4. MS (MALDI-TOF): m/z =
551.0 [M + H]+. HRMS (MALDI-TOF): m/z calcd for
C38H35N2O2 [M + H]+: 551.2693; found: 551.2698.
Compound 3: Pale brown solid; mp 226–227 °C. 1H NMR
(300 MHz, CDCl3): d = 0.89 (t, J = 2.2 Hz, 6 H), 1.26–1.56
(m, 20 H), 1.83 (p, J = 6.6 Hz, 2 H), 1.91 (p, J = 6.6 Hz, 2
H), 4.03 (t, J = 6.6 Hz, 2 H), 4.11 (t, J = 6.6 Hz, 2 H), 6.89
(d, J = 8.7 Hz, 1 H), 6.94 (d, J = 8.4 Hz, 1 H), 7.16–7.24 (m,
2 H), 7.34 (t, J = 8.1 Hz, 1 H), 7.38–7.43 (m, 3 H), 7.51–7.54
(m, 2 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.65 (s, 1 H), 8.27 (t, 1
Compound 26: Orange solid; mp 71–72 °C. 1H NMR (300
MHz, CDCl3): d = 0.89 (t, J = 6.9 Hz, 3 H), 1.29–1.54 (m, 10
H), 1.87 (q, J = 6.6 Hz, 2 H), 4.12 (t, J = 6.6 Hz, 2 H), 7.00
(d, J = 9.0 Hz, 1 H), 7.44 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1 H),
7.53–7.63 (m, 2 H), 7.70 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 1 H),
7.94 (d, J = 7.5 Hz, 1 H), 8.02 (d, J = 2.1 Hz, 1 H), 10.48 (s,
1 H), 10.61 (s, 1 H). 13C NMR (100.4 MHz, CDCl3): d =
14.0, 22.6, 25.9, 28.9, 29.1, 29.2, 31.7, 68.9, 84.5, 95.0,
112.8, 114.6, 124.8, 126.6, 127.3, 128.5, 131.7, 133.1,
133.7, 135.7, 138.7, 161.6, 188.8, 191.5. MS (EI): m/z = 362
[M]+. Anal. Calcd for C24H26O3: C, 79.53; H, 7.23. Found: C,
79.49; H, 7.07.
Synlett 2009, No. 3, 384–389 © Thieme Stuttgart · New York

LETTER
H), 8.59 (d, J = 1.8 Hz, 1 H), 8.92 (s, 1 H), 9.34 (s, 1 H). 13
Synthesis of p-Phenylene Ethynylene Based Macrocycles
389
C
J1 = 8.1 Hz, J2 = 1.8 Hz, 1 H), 7.17 (d, J = 1.5 Hz, 1 H),
NMR (100.4 MHz, CDCl3): d = 14.1, 22.6, 22.7, 25.9, 26.0,
26.0, 29.0, 29.2, 29.2, 29.3, 29.3, 29.4, 31.7, 31.8, 68.6, 69.3,
85.4, 86.5, 94.1, 95.9, 112.1, 113.3, 115.0, 116.3, 117.4,
119.8, 123.0, 125.1, 125.2, 126.0, 126.7, 128.2, 129.0,
130.4, 130.7, 131.4, 131.7, 132.3, 135.2, 137.0, 141.3,
152.8, 153.7, 154.9, 159.1, 159.1. MS (MADI-TOF): m/z =
663.8 [M + H]+. HRMS (MALDI-TOF): m/z calcd for
C46H51N2O2 [M + H]+: 663.3945; found: 663.3945.
Compound 4: Pale yellow solid; mp >320 °C. IR (KBr):
2921, 2852, 2204, 1621, 1600, 1589, 1560, 1510, 1472,
1270, 1249, 826, 815, 758, 742 cm–1. MS (MALDI): m/z =
889.1 [M + H]+. HRMS (MALDI-TOF): m/z calcd for
C63H58N3O2: 888.4524; found: 888.4528. Anal. Calcd for
C63H59N3O3·H2O: C, 83.50; H, 6.56; N, 4.64. Found: C,
83.28; H, 6.56; N, 4.42.
7.21–7.31 (dd, 2 H), 7.34–7.41 (m, 2 H), 7.42–7.28 (t, 2 H),
7.54 (d, J = 6.9 Hz, 1 H), 7.82 (s, 1 H). 13C NMR (100.4
MHz, CDCl3): d = 14.1, 22.7, 26.1, 29.2, 29.2, 29.2, 29.3,
29.3, 29.4, 29.7, 31.8, 31.8, 41.1, 46.2, 68.3, 68.5, 83.8, 85.9,
94.7, 96.6, 109.3, 110.3, 110.6, 111.0, 114.3, 115.1, 115.5,
117.1, 120.5, 122.9, 126.4, 127.0, 127.9, 128.4, 129.3,
129.5, 131.3, 131.5, 131.7, 138.2, 140.6, 147.0, 149.1,
156.4. MS (MALDI-TOF): m/z = 667.8 [M + H]+. HRMS
(MALDI-TOF): m/z calcd for C46H55N2O2 [M + H]+:
667.4258; found: 667.4273.
(15) (a) Gong, B. Chem. Eur. J. 2001, 7, 4336. (b) Huc, I. Eur. J.
Org. Chem. 2004, 17. (c) Li, Z.-T.; Hou, J.-L.; Li, C.; Yi,
H.-P. Chem. Asian J. 2006, 1, 766.
(16) (a) Jiang, H.; Léger, J.-M.; Guionneau, P.; Huc, I. Org. Lett.
2004, 6, 2985. (b) Yuan, L.; Feng, W.; Yamato, K.; Sanford,
A. R.; Xu, D.; Guo, H.; Gong, B. J. Am. Chem. Soc. 2004,
126, 11120. (c) Zhu, Y.-Y.; Li, C.; Li, G.-Y.; Jiang, X.-K.;
Li, Z.-T. J. Org. Chem. 2008, 73, 1745.
(17) Yusubov, M. S.; Tveryakova, E. N.; Krasnokutskaya, E. A.;
Perederyna, I. A.; Zhdankin, V. V. Synth. Commun. 2007,
37, 1259.
(18) Spivey, A. C.; McKendrick, J.; Srikaran, R.; Helm, B. A.
J. Org. Chem. 2003, 68, 1843.
Compound 44: Pale yellow solid; mp 237–239 °C. 1H NMR
(300 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3 H), 1.25–1.46
(m, 10 H), 1.79 (t, J = 6.9 Hz, 2 H), 4.02 (t, J = 6.6 Hz, 2 H),
4.36 (d, J = 2.4 Hz, 2 H), 4.87 (br, 1 H), 6.70–6.78 (q, 2 H),
6.86 (d, J = 8.7 Hz, 1 H), 7.22–7.28 (m, 2 H), 7.31–7.34 (m,
2 H), 7.36–7.38 (d, J = 7.2 Hz, 1 H), 7.42–7.50 (q, 3 H), 7.56
(d, J = 6.6 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.71 (s, 1 H),
7.94 (s, 1 H), 8.41 (s, 1 H). 13C NMR (75.3 MHz, CDCl3):
d = 14.1, 22. 7, 26.1, 29.1, 29.3, 29.3, 31.8, 48.2, 68.797,
85.2, 87.0, 93. 7, 95.8, 108.5, 109.9, 111.7, 115.5, 117.0,
121.4, 123.9, 125.2, 126.5, 127.4, 127.6, 128.51, 128.7,
129.3, 129.5, 129.7, 131.0, 132.2, 139.0, 140.2, 149.0,
149.9, 166.7. ESI-MS: m/z 553.2 [M + H]+, 575.1 [M + Na]+.
MS (MALDI-TOF): m/z 553.0 [M + H]+. HRMS (MALDI-
TOF): m/z calcd for C38H37N2O2 [M + H]+: 553.2850; found:
553.2863.
(19) Bellina, F.; Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron
2000, 56, 2533.
(20) Toumi, M.; Couty, F.; Evano, G. Angew. Chem. Int. Ed.
2007, 46, 572.
(21) Austin, W. B.; Bilow, N.; Kelleghan, W. J.; Lau, K. S. Y.
J. Org. Chem. 1981, 46, 2280.
(22) Nguyen, N.-H.; Apriletti, J. W.; Baxter, J. D.; Scanlan, T. S.
J. Am. Chem. Soc. 2005, 127, 4599.
(23) Lin, J.-B.; Xu, X.-N.; Jiang, X.-K.; Li, Z.-T. J. Org. Chem.
2008, 9403.
(24) Zolfigol, M. A.; Ghaemi, E.; Madrakian, E. Synlett 2003,
Compound 45: White solid; mp 226–227 °C. 1H NMR (300
MHz, CDCl3): d = 0.89 (t, J = 6.9 Hz, 6 H), 1.26–1.53 (m, 20
H), 1.78–1.89 (m, 4 H), 4.03 (tt, 4 H), 4.44 (d, J = 5.4 Hz, 2
H), 4.61 (t, J = 4.5 Hz, 1 H), 4.64 (d, 2 H), 4.98 (t, J = 4.8 Hz,
1 H), 6.72 (t, 2 H), 6.84 (s, 1 H), 6.87 (s, 1 H), 6.91 (dd,
191.
Synlett 2009, No. 3, 384–389 © Thieme Stuttgart · New York

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