One-pot formation of aromatic tetraurea macrocycles

Article abstract of DOI:10.1021/ol300684j

Treating derivatives of m-phenylenediamine having different electron-richness and reactivities with triphosgene in the presence of triethylamine led to aromatic tetraurea macrocycles in high yields. Factors important for efficiently forming these macrocycles include the molar ratio (2:1) between the diamine and triphosgene, reaction temperature (-75 °C), and solvent (CH₂Cl₂). By controlling the order and rate for adding diamines, tetraurea macrocycles consisting of two different types of monomeric residues have also been obtained in high yields.

Full text of DOI:10.1021/ol300684j

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2504–2507
One-Pot Formation of Aromatic Tetraurea
Macrocycles
Zehui Wu,† Ting Hu,† Lan He,*,‡ and Bing Gong*,§
College of Chemistry, Beijing Normal University, Beijing 100875, China,
National Institutes for Food and Drug Control of China, Beijing 100050, China, and
Department of Chemistry, University at Buffalo, State University of New York, Buffalo,
New York 14260, United States
bgong@buffalo.edu; helan1961@hotmail.com
Received March 28, 2012
ABSTRACT
Treating derivatives of m-phenylenediamine having different electron-richness and reactivities with triphosgene in the presence of triethylamine
led to aromatic tetraurea macrocycles in high yields. Factors important for efficiently forming these macrocycles include the molar ratio (2:1)
between the diamine and triphosgene, reaction temperature (ꢀ75 °C), and solvent (CH2Cl2). By controlling the order and rate for adding diamines,
tetraurea macrocycles consisting of two different types of monomeric residues have also been obtained in high yields.
The creation of unnatural oligomers that fold into
well-defined conformations has attracted wide interest.1
Among known strategies, enforcing folded conformations
by introducing localized intramolecular hydrogen-bond-
ing has proven to be effective for creating foldamers with
persistent shapes.2 We developed aromatic oligoamides
that fold into well-defined conformations containing
cavities of different sizes.3 An attempted preparation of
helical aromatic polyamides based on the same folding
principle led to the discovery of a series of rigid aro-
matic oligoamide macrocycles.4 This discovery marked
the beginning of the synthesis of several classes of shape-
persistent macrocycles with different backbones by us.5
Along with other shape-persistent macrocycles,6 these newly
discovered macrocycles have started to exhibit interesting
properties.7
(2) (a) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc.
1996, 118, 7529. (b) Berl, V.; Huc, I.; Khoury, R. G.; Lehn, J. M.
Chem.;Eur. J. 2001, 7, 2798. (c) Huc, I.; Maurizot, V.; Gornitzka, H.;
Leger, J. M. Chem. Commun. 2001, 578. (d) van Gorp, J. J.; Vekemans, J.
A. J. M.; Meijer, E. W. Chem. Commun. 2004, 60. (e) Hou, J. L.; Shao,
X. B.; Chen, G. J.; Zhou, Y. X.; Jiang, X. K.; Li, Z. T. J. Am. Chem. Soc.
2004, 126, 12386. (f) Hu, Z. Q.; Hu, H. Y.; Chen, C. F. J. Org. Chem.
2004, 71, 1131. (g) Garric, J.; Leger, J. M.; Huc, I. Angew. Chem., Int. Ed.
2005, 44, 1954. (h) Yan, Y.; Qin, B.; Shu, Y. L.; Chen, X. Y.; Yip, Y. K.;
Zhang, D. W.; Su, H. B.; Zeng, H. Q. Org. Lett. 2009, 11, 1201.
(i) Mousseau, J. J.; Xing, L. Y.; Tang, N.; Cuccia, L. A. Chem.;Eur.
J. 2009, 15, 10030.
† Beijing Normal University.
‡ National Institutes for Food and Drug Control of China.
§ University at Buffalo.
(1) Reviews: (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(b) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. Rev. 2001, 101, 3893. (c) Gong, B. Chem.;Eur. J. 2001, 7, 4336.
(d) Huc, I. Eur. J .Org. Chem. 2004, 17. (e) Li, Z. T.; Hou, J. L.; Li, C.; Yi,
H. P. Chem. Asian J. 2006, 1, 766. (f) Goodman, C. M.; Choi, S.;
Shandler, S.; DeGrado, W. F. Nature Chem. Biol. 2007, 3, 252.
r
10.1021/ol300684j
Published on Web 05/04/2012
2012 American Chemical Society

Among the shape-persistent macrocycles we reported
are macrocycles 1 that consist of four benzene residues
connected via urea linkages.5a The design of 1 was based
on the assumption that the presence of intramolecular
H-bonds would enforce crescent conformations on the
corresponding uncyclized precursors and thus faciliatate
similar macrocyclization observed for aromatic oligo-
amide macrocycles.4b Macrocycles 1 are featured by a rigid,
preparation of macrocycles 1 was hampered by the highly
deactivated nature of the corresponding monomeric di-
amines that bear two electron-withdrawing ester groups.
In fact, macrocycles 1 could only be obtained in multiple
steps under harsh conditions from the condensation of
the corrsponding dimeric precurosors, with low overall
yields.5a
˚
planar backbone and a small (∼5 A across) internal cavity
defined by four inward-pointing urea oxygen atoms.5a
With their planar shape and noncollapsible cavities, these
macrocyclic molecules are reminiscent of porphyrins8
or expanded porphyrins.9 Unfortunately, the efficient
(3) (a) Gong, B. Acc. Chem. Res. 2008, 41, 1376. (b) Gong, B.; Zeng,
H. Q.; Zhu, J.; Yuan, L. H.; Han, Y. H.; Cheng, S. Z.; Furukawa, M.;
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D. K.; Szyperski, T.; Gong, B. J. Am. Chem. Soc. 2004, 126, 16528.
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J. S.; Yamato, K.; Zhu, J.; Zeng., H. Q.; Gong, B. J. Org. Chem. 2005, 70,
10660.
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D. G.; Guo, H.; Gong, B. J. Am. Chem. Soc. 2004, 126, 11120. (b) Feng,
W.; Yamato, K.; Yang, L. Q.; Ferguson, J.; Zhong, L. J.; Zou, S. L.;
Yuan, L. H.; Zeng, X. C.; Gong, B. J. Am. Chem. Soc. 2009, 131, 2629.
(c) Yang, L. Q.; Zhong, L. J.; Yamato, K.; Zhang, X. H.; Feng, W.;
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729.
(5) (a) He, H.; An, Y.; Yuan, L. H.; Yamato, K.; Feng, W.; Gerlitz,
O.; Zheng, C.; Gong, B. Chem. Commun. 2005, 3788–3790. (b) Zhang,
A. M.; Han, Y. H.; Yamato, K.; Zeng, X. C.; Gong, B. Org. Lett. 2006, 8,
803. (c) He, L.; An, Y.; Yuan, L. H.; Feng, W.; Li, M. F.; Zhang, D. C.;
Yamato, K.; Zheng, C.; Zeng, X. C.; Gong, B. Proc. Natl. Acad. Sci.
U.S.A. 2006, 103, 10850. (d) Ferguson, J. S.; Yamato, K.; Liu, R.; He, L.;
Zeng, X. C.; Gong, B. Angew. Chem., Int. Ed. 2009, 48, 3150. (e) Geng,
M. W.; Zhang, D. C.; Wu, X. X.; He, L.; Gong, B. Org. Lett. 2009,
11, 923.
We report herein the highly efficient, one-pot formation
of aromatic tetraurea macrocycles that share the same
backbone with 1. In this work, we have elucidated the
optimal conditions for efficiently forming aromatic tetra-
urea macrocycles, with or without backbone-rigidifying
intramolecular H-bonds, from the one-pot condensation
of readily available monomeric diamines under mild con-
ditions. The one-pot synthetic method described in this
paper allows the introduction of a variety of side chains to
the aromatic tetraurea backbones, leading to macrocycles
of tunable properties.
Scheme 1. One-Pot Formation of Macrocycles 2
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H. Q. J. Am. Chem. Soc. 2010, 132, 9564. (n) Frischmann, P. D.; Facey,
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M. J. J. Am. Chem. Soc. 2010, 132, 3893.
(7) (a) Sanford, A. R.; Yuan, L. H.; Feng, W.; Yamato, K.; Flowers,
R. A.; Gong, B. Chem. Commun. 2005, 4720. (b) Helsel, A. J.; Brown,
A. L.; Yamato, K.; Feng, W.; Yuan, L. H.; Clements, A.; Harding, S. V.;
Szabo, G.; Shao, Z. F.; Gong, B. J. Am. Chem. Soc. 2008, 130, 15784.
(c) Yamato, K.; Yuan, L. H.; Feng, W.; Helsel, A. J.; Sanford, A. R.;
Zhu, J.; Deng, J. G.; Zeng, X. C.; Gong, B. Org. Biomol. Chem. 2009, 7,
3643–3647. (d) Yang, Y. A.; Feng, W.; Hu, J. C.; Zou, S. L.; Gao, R. Z.;
Yamato, K.; Kline, M.; Cai, Z. H.; Gao, Y.; Wang, Y. B.; Li, Y. B.;
Yang, Y. L.; Yuan, L. H.; Zeng, X. C.; Gong, B. J. Am. Chem. Soc. 2011,
133, 18590.
The preparation of macrocycles 2 was first attempted
by treating the corresponding diamine with triphosgene
(Scheme 1). With their electron-donating alkoxy groups,
the diamines were expected to have enhanced reactivity
and may lead to improved yields of 2. However, initial
atttempts to convert the diamines into their correspond-
ing isocyanates by heating with excess triphosgene led to
complex mixtures of products.
The conditions for forming macrocycle 2a were then
systematically probed by adding diamine 2A (0.96 mmol)
and triethylamine in CH2Cl2 to triphosgene in CH2Cl2
under N2 by varying temperature, concentration, and
solvents (Scheme 1). As shown in Table 1, in CH2Cl2, no
2a was formed when 2A was treated with triphosgene by
refluxing the reaction mixture, which may be due to the
instability of either diamine 2A or the intermediate formed
in the reaction at elevated temperature.
(8) Dolphin, D. The Porphyrins; Academic Press: New York, 1978; Vol. 1.
(9) Sessler, J. L.; Tvermoes, N. A.; Davis, J.; Anzenbacher, P.;
Jursikova, K.; Sato, W.; Seidel, D.; Lynch, V.; Black, C. B.; Try, A.;
Andrioletti, B.; Hemmi, G.; Mody, T. D.; Magda, D. J.; Kral, V. Pure
Appl. Chem. 1999, 71, 2009.
Org. Lett., Vol. 14, No. 10, 2012
2505

The above experiments revealed the major factors re-
sponsible for the highly efficient, one-pot formation of
macrocycle 2a. These include the molar ratio (2:1) between
2A and triphosgene, the reaction temperature (around
ꢀ75 °C), and solvent (CH2Cl2). It was found that applying
the same procedure to the reaction of diamines 2B and 2C
withtriphosgene led to macrocycles 2band 2c in high (81%
for both) yields,11 which demonstrates the reliability of this
one-pot procedure.
The efficient formation of 2aꢀc was originally attrib-
uted to the enhanced activity of the corresponding electron-
rich diamines and the folded conformations of the uncy-
clized oligomeric precursors enforced by intramolecular
H-bonds between the alkoxy oxygens and the urea hydro-
gens. The mild conditions revealed by the formation of
macrocycles 2 prompted us to probe the macrocyclization
of other diamines of reduced activity, which would show
the generality of this system. The preparation of macro-
cycles 3a, 3b, 4a, and 4b, which lack intramolecular
H-bonds, was attempted on the basis of the same proce-
dures described above. The corresponding diamines were
treated with triphosgene in the presence triethylamine in
CH2Cl2 at ꢀ75 °C. Similar to the efficient formation of
2aꢀc, macrocycles 3a, 3b, 4a, and 4b were obtained in high
(76%, 78%, 80%, and 79%) yields after being purified
with column chromatography.11
Table 1. Reaction Conditions for Forming Macrocycle 2a
triphos-
solvent
(mL)
gene
(mg)
temp
reaction
time (h)
2a
entry
(°C)
(%)
1
2
CH2Cl2(71)
CH2Cl2(71)
CH2Cl2(71)
CH2Cl2(71)
CH2Cl2(71)
CH2Cl2(71)
CH2Cl2(71)
CH2Cl2(71)
CH2Cl2(91)
CH2Cl2(71)
CH2Cl2(71)
CH2Cl2(71)
THF(71)
140
140
140
140
140
140
140
140
140
100
280
560
140
140
reflux
20a
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
2c þ 5d
0
0
3
ꢀ10b
ꢀ25b
ꢀ40b
ꢀ50b
ꢀ60b
ꢀ75b
ꢀ75b
ꢀ75b
ꢀ75b
ꢀ75b
ꢀ75b
ꢀ75b
0
4
0
5
53.8
61.4
76.3
80.3
80.5
70.6
21.5
6.2
59.7
0
6
7
8
9
10
11
12
13
14
DMF(71)
a Temperature was controlled with a water bath. b Temperature was
controlled by using a low-temperature reactor. c Time for the dropwise
addition of a solution of diamine 2A (0.96 mmol, as HCl salt) and Et3N
(1.3 mL, 9.4 mmol) in CH2Cl2 to triphosgene in CH2Cl2. Shortening
(<1 h) or lengthening (>2 h) the addition time led to reduced yields.
Adding the solution of triphosgene to that of diamine did not lead to the
formation of 2a. d Time for stirring the reaction mixture at room
temperature after the addition of diamine was finished. Stirring at room
temperature for longer than 5 h did not lead to further change in yields.
Previous studies showed that in the presence of a base
such as a tertiary amine or aqueous sodium bicarbonate,
primary amines could be converted into the corresponding
isocyanates in good yields by treatment with phosgene,
diphosgene, or triphosgene at low temperature.10 Efforts
were thus made to probe the reaction of 2A and triphos-
gene at reduced temperatures. It was found that reactions
performed at 20 °C down to ꢀ25 °C did not lead to the
formation of 2a (entries 1ꢀ4). However, macrocycle 2a
started to appear asthe temperature was further decreased.
For example, macrocycle 2a was obtained in 54% yield at
ꢀ40 °C (entry 5). The yields of 2a continued to improve as
the reaction temperature was lowered and reached over
80% at ꢀ75 °C (entries 6ꢀ8). No additional improvement
of yields was observed at temperatures below ꢀ75 °C.
Further decrease of reaction temperature led to the pre-
cipitation of diamine and triethylamine, presumably as
their hydochloride salts. At ꢀ75 °C, lowering the concen-
trations of 2A and triphosgene by increasing the volume of
CH2Cl2, which did not change the molar ratio of the two
reactants, resulted in a slight improvement of the yield of
2a (entry 9). In contrast, changing the ratio of triphosgene
and 2A decreased the yield of the macrocycle (entries
10ꢀ12). At ꢀ75 °C, macrocycle 2a formed in significantly
lower yield in THF (entry 13) and failed to form in DMF
(entry 14).
The successful one-potpreparation ofmacrocycles3 and
4 indicates that rigidifying the oligourea precursors by
introducing intramolecular H-bonds, which presumably
preorganize the uncyclized precursor toward cyclization, is
not necessary for the efficient formation of these aromatic
tetraurea macrocycles. The partial rigidification and cu-
vature introduced by meta-linked benzene resiudes, along
with the transꢀtrans conformational preference5a of the
urea linkage, seem to provide sufficient preorganization
that promotes the macrocyclization process. In addition,
backbone CꢀH O interaction, which should be en-
3 3 3
hanced by the electron-withdrawing amide or ester side
chains, is very likely an additional driving force that
promotes the folding of the uncyclized precursors of these
tetraurea macrocycles. It thus expected that the above one-
pot procedure is generally applicable to the preparation of
a variety of aromatic tetraurea macrocycles from various
derivatives of 1,3-phenylenediamine.
The significantly reduced yields of 2a with increasing
percentages of triphosgene (entries 11 and 12, Table 1)
imply that diamine 2A did not undergo simultaneous
cyclization. With excess triphosgene, diamine 2A should
(10) (a) Nowick, J. S.; Powell, N. A.; Nguyen, T. M.; Noronha, G.
J. Org. Chem. 1992, 57, 7364. (b) Sigurdsson, S. T.; Seeger, B.; Kutzke,
U.; Eckstein, F. J. Org. Chem. 1996, 61, 3883. (c) Nowick, J. S.; Holmes,
D. L.; Noronha, G.; Smith, E. M.; Nguyen, T. M.; Huang, S. L. J. Org.
Chem. 1996, 61, 3929.
(11) See the Supporting Information for details.
2506
Org. Lett., Vol. 14, No. 10, 2012

be converted into the corresponding dicarbamoyl chloride
that gives diisocyanate by eliminating HCl in the presence
of triethylamine.10 The formed dicarbamoyl chloride and
diisocyanate could notundergofurther reaction since, with
excess triphosgene, most of the diamine molecules should
have been consumed before further reaction, which re-
sulted in the observed low yields.
Macrocycles 5a and 5b were obtained in 77% and 79%
yields, respectively, after being purified with column
chromatography.11 It was observed that slowly injecting
diamine 4B followed by rapidly adding the second diamine
3A or 2A was critical for forming the desired macrocyclic
product. If the injection of the second diamine took too
long, the yield of 5a or 5b was found to be compromised,
which may be due to the instability of the formed dicarb-
amoyl chloride or diisocyanate.
In summary, aromatic tetraurea macrocycles are ob-
tained in high yields from aromatic diamines of different
reactivities. By including various diamines derived from
m-phenylenediamine and its analogues, many of which are
commercially available or can be prepared on the basis of
simple procedures, this efficient one-pot macrocyclization
allows the preparation of different shape-persistent aromatic
tetraurea macrocycles. Sharing the same flat backbone and
noncollapsible internal cavity but bearing different side
chains that lead to different backbone electronic properties,
these macrocycles are expected to have interesting recogni-
tion properties or self-assembling behavior. For example,
macrocycles 1had been shown to be selective toward Kþ over
Naþ.5a Macrocycles 2ꢀ5 all give broad 1H NMR signals in
both polar and nonpolar solvents, suggesting their particu-
larly strong tendency for self-association. In contrast to the
limited accessibility of macrocycles 1, the ready availability of
2ꢀ5 and analogous macrocycles should greatly facilitate the
systematic study and applications of these compounds.
Scheme 2. Preparation of Macrocycles 5a and 5b
The above reasoning suggests that the reaction of a
diamine with triphosgene may stop at the stage of forming
the corresponding dicarbamoyl chloride or diisocyanate,
both of which can react with the same or different aromatic
diamines to form tetraurea macrocycles. By adding a
different diamine to the formed dicarbamoyl chloride or
diisocyanate, tetraurea macrocycles consisting of two dif-
ferent monomeric residues were formed. Such a possibility
was investigated by treating diamine 4B with trisphosgene,
followed by the rapid addition of a second diamine 2A or
3A (Scheme 2). Thus, a solution of 4B (0.48 mmol) and
triethylamine (4.7 mmol) in CH2Cl2 (11 mL) was slowly
injected into a well-stirred solution of triphosgene (0.48
mmol) CH2Cl2 (60 mL) over a period of 1 h under N2 at
ꢀ75 °C, followed by rapid injection of diamine 2A or 3A
(0.48 mmol) and Et3N (4.7 mmol) in CH2Cl2 (10 mL).
Acknowledgment. This work was supported by the
Natural Science Foundation of China (NSFC Grant No.
21072021), the Special Fund for Agro-scientific Research
in the Public Interest (Grant No. 201103027), the National
S&T Major Special Project on Major New Drug Innova-
tion (Grant No. 2011ZX09307-002-01), the US National
Science Foundation (Grant Nos. CBET-1036171 and
CBET-1066947), and the Petroleum Research Fund, ad-
ministered by the ACS (No. 51048-ND7).
Supporting Information Available. Synthetic proce-
dures, NMR and mass spectra, and analytical data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2507