Synthesis of a soluble ureido-naphthyridine oligomer that self-associates via eight contiguous hydrogen bonds

Article abstract of DOI:10.1021/ol050987f

(Chemical Equation Presented) An iterative synthetic route to organic-soluble ureido-naphthyridine oligomers has been developed. Use of this protocol allowed synthesis of a short ureido-naphthyridine oligomer, which presents a self-complementary DDAADDAA hydrogen bonding array (D = hydrogen bond donor, A = hydrogen bond acceptor). Strong self-association via eight hydrogen bonds was observed in organic solution.

Full text of DOI:10.1021/ol050987f

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3005-3008
Synthesis of a Soluble
Ureido-Naphthyridine Oligomer that
Self-Associates via Eight Contiguous
Hydrogen Bonds
Michael F. Mayer, Shoji Nakashima, and Steven C. Zimmerman*
Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue, MC712,
Urbana, Illinois 61801
sczimmer@uiuc.edu
Received May 1, 2005
ABSTRACT
An iterative synthetic route to organic-soluble ureido-naphthyridine oligomers has been developed. Use of this protocol allowed synthesis of
a short ureido-naphthyridine oligomer, which presents a self-complementary DDAADDAA hydrogen bonding array (D hydrogen bond donor,
hydrogen bond acceptor). Strong self-association via eight hydrogen bonds was observed in organic solution.
)
A
)
We recently suggested1 that oligo- or polymeric ureas of 2,7-
diamino-1,8-naphthyridine (1) might form either helical
folded structures or hydrogen bonded sheets.2 Model studies
on simple substructures showed that intramolecular hydrogen
bonds would break to form sheets with between three and
six intermolecular hydrogen bonds.1 Attempts to synthesize
longer oligomers or polymers, however, were thwarted by
the low solubility of 1 and longer oligoureas derived from
it. Given our interest in these compounds as well as the recent
use of amides of 1 for supramolecular chemistry,3-5 there
was a clear need for soluble analogues of 1. Herein we report
both the synthesis of 2, a mono-protected and soluble
analogue of 1, and its conversion to 3, which can form a
linear duplex containing eight hydrogen bonds.
The synthesis of 2 (Scheme 1) began with the amidation
of 2,6-diaminopyridine with ethyl 3-(4-methoxyphenyl)-3-
oxopropanoate and acid-mediated cyclization to 4. A service-
(1) (a) Corbin, P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 2000, 122,
3779. (b) Corbin, P. S.; Zimmerman, S. C.; Thiessen, P. A.; Hawryluk, N.
A.; Murray, T. J. J. Am. Chem. Soc. 2001, 123, 10475.
(2) For selected, sheetlike oligomers not based on amino acids see: (a)
Yang, X.; Martinovic, S.; Smith, R. D.; Gong, B. J. Am. Chem. Soc. 2003,
125, 9932. (b) Gong, H.; Krische, M. J. J. Am. Chem. Soc. 2005, 127, 1719.
(c) Bisson, A. P.; Carver, F. J.; Eggleston, D. S.; Haltiwanger, R. C.; Hunter,
C. A.; Livingstone, D. L.; McCabe, J. F.; Rotger, C.; Rowan, A. E. J. Am.
Chem. Soc. 2000, 122, 8856. (d) Leung, M.; Mandal, A. B.; Wang, C.-C.;
Lee, G.-H.; Peng, S.-M.; Cheng, H.-L.; Her, G.-R.; Chao, I. Lu, H.-F.; Sun,
Y.-C.; Shiao, M.-Y.; Chou, P.-T. J. Am. Chem. Soc. 2002, 124, 4287.
(3) (a) Park, T.; Zimmerman, S. C.; Nakashima, S. J. Am. Chem. Soc.
2005, 127, 6520. (b) Corbin, P. S.; Lawless, L. J.; Li, Z.; Ma, Y.; Witmer,
M. J.; Zimmerman, S. C. Proc. Nat. Acad. Sci. U.S.A. 2002, 99, 5099. (c)
Corbin, P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1998, 120, 9710. (d)
Park, T.; Mayer, M. F.; Nakashima, S.; Zimmerman, S. C. Synlett 2005,
1435.
10.1021/ol050987f CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/08/2005

Scheme 1. Synthesis of a Trifunctionalized 1,8-Naphthyridine
Scheme 3. Synthesis of the Ureido Terminus
The preparation of monoprotected diaminonaphthyridine 2
was accomplished in a one-pot, two-step process by reaction
of the halogenated mixture 9a/9b with p-methoxybenzyl-
amine. Thus, nucleophilic deacetylation was followed by
nucleophilic aromatic substitution with a second equivalent
of p-methoxybenzylamine. The bromide reacted more
smoothly than the chloride, and as a result, from most
preparations of 2 some N-deacetylated 9a was also isolated.
To prepare 11, the ureido terminus of target oligomer 3,
2 was treated with n-butylisocyanate, affording the desired
urea 10 in 83% yield. The remainder of the product consisted
of the regioisomeric urea (8%) and the bis-urea (9%). The
p-methoxybenzyl group in 10 was readily removed upon
treatment with TFA, 11 being isolated in 95% yield.
able 38% yield of 4 could be obtained on a 68 g scale, but
the reaction was somewhat unreliable, with one run giving
only a 5% yield. Elaboration of naphthyridone 4 in a manner
similar to that reported by Brown6 provided 6 with three
distinct sites for further functionalization. Demethylation of
6 provided phenol 7 in good yield. The product, however,
was found to consist of a ca. 1:1 mixture of 7a and 7b. Rather
than separating the mixture, we carried 7a and 7b forward
together.
Although in principle any number of solubilizing groups
could be readily attached to phenol 7, including simple linear
alkyl halides, we chose to use tosylate 8. It combined a
convenient and distinctive 1H NMR signature with a balance
of flexibility and a bulky aromatic substituent that was
expected to resist packing. The synthesis of 8, outlined in
Scheme 2, involved a five-step homologation that began with
The synthesis of naphthyridyl terminus 12, outlined in
Scheme 4, began with deacylated 6, which was obtained as
the main byproduct in the synthesis of 6 (vide supra). By
Scheme 2. Synthesis of a Solubilizing Group
Scheme 4. Synthesis of the Naphthyridyl Terminus
NBS bromination and cyanide displacement. Hydrolysis,
reduction, and tosylation afforded 8 in a 33% overall yield.
Tosylate 8 and the mixture of 7a and 7b were reacted
under basic conditions to provide 9a and 9b (Scheme 3).
(4) (a) Li, X.-Q.; Feng, D.-J.; Jiang, X.-K.; Li, Z.-T. Tetrahedron 2004,
60, 8275. (b) Zhao, X.; Wang, X.-Z.; Jiang, X.-K.; Chen, Y.-Q.; Li, Z.-T.;
Chen, G.-J. J. Am. Chem. Soc. 2003, 125, 15128. (c) Wang, X.-Z.; Li, X.-
Q.; Shao, X.-B.; Zhao, X.; Deng, P.; Jiang, X.-K.; Li, Z.-T.; Chen, Y.-Q.
Chem. Eur. J. 2003, 9, 2904.
(5) Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W.
J. Am. Chem. Soc. 2005, 127, 810.
(6) Brown, E. V. J. Org. Chem. 1965, 30, 1607.
3006
Org. Lett., Vol. 7, No. 14, 2005

carefully monitoring the reaction, hydrogenolysis of de-
acylated 6 was accomplished in high yield without reduction
of the naphthyridine nucleus. Demethylation of 13 with BBr3
produced 14, which was reacted with 8 to provide 2-ami-
nonaphthyridine 12.
room temperature from 50 µM to 50 mM, 13 exhibited NMR
spectral shifts that were independent of concentration.
Further evidence for a strong dimer with eight hydrogen
bonds came from a difference NOE study, the results of
which are summarized in Figure 2. Most notably, a key NOE
With the ureido (11) and the naphthyridyl (12) termini in
hand, coupling of the two in a urea-forming reaction was
investigated. Typically, the formation of an unsymmetrical
bis-heteroaryl urea is not trivial.7 It was found that treatment
of 12 with p-nitrophenylchloroformate8 (p-NPCF) followed
by reaction with 11 did produce a sufficient quantity of
compound 3 for study (Scheme 5).
Scheme 5. Coupling of the Ureido and Naphthyridyl Termini
Figure 2. Observed contacts from NOE difference spectra.
was observed between Ha and He. None of the singly or
doubly folded conformations for 3 place Ha proximal to He
(Scheme 6). Taken together, the 1H NMR data are consistent
with the unfolded, antiparallel dimer (3)2.
1H NMR was shown to be an excellent method for
establishing pairing. Intramolecularly hydrogen bonded py-
ridyl and naphthyridinyl ureas often exhibit broad NH
resonances due to slow conformational dynamics with the
non-hydrogen bonded NH groups appearing upfield (typical
aryl urea NH resonances δ ∼6.4-7.2 ppm).1 For example,
the spectrum of 11 in chloroform-d exhibits broad NH
resonances whereas the spectrum in DMSO-d6 is sharp (see
Supporting Information). In chloroform-d, the spectrum of
3 is very sharp with the aryl urea NH groups resonating
downfield at δ 13.22, 13.02, and 11.72 ppm (Figure 1). The
Scheme 6. Possible Folded Forms of 3
To assess the stability of dimer (3)2 NMR dilution
experiments were performed in chloroform-DMSO mix-
tures. From 423 µM to 13.5 mM in 10% (v/v) DMSO-d6-
CDCl3, the 1H NMR spectra of (3)2 were unchanged,
allowing a lower limit to be placed on the dimerization
constant, Kassoc g 4.5 × 105 M-1. Considering that DMSO
is a strongly competitive solvent for hydrogen bonded
complexes, this represents quite a stable dimer. However,
in 20% (v/v) DMSO-d6-CDCl3, the self-association was
dramatically reduced (Kdimer ) 40 M-1).
Attempts to crystallize 3 were unsuccessful, so its structure
and that of dimer (3)2 were examined computationally. As
seen in Figure 3a, the monomer is planar but has a very
distinctive crescent shape as a result of steric interactions
between the urea carbonyl group and the ortho protons on
the naphthyridine ring (CdO‚‚‚H-C). There are three
limiting ways in which 3 may dimerize. First, if the planarity
Figure 1. 1H NMR of 3 in CDCl3 showing aromatic region and
urea NH protons. See Figure 2 for labeling.
(7) L’abbe´, G. Synthesis 1987, 525.
(8) Choy, N.; Moon, K. Y.; Park, C.; Son, Y. C.; Jung, W. H.; Choi, H.;
Lee, C. S.; Kim, C. R.; Kim, S. C.; Yoon, H. Org. Prep. Proced. Int. 1996,
28, 173.
aliphatic urea NH group appears at δ 9.35 ppm, suggesting
that the terminal NH group is also paired. Importantly, at
Org. Lett., Vol. 7, No. 14, 2005
3007

quences, 72 unique complexes can be formed, assuming full
pairing without mismatches. Of the 72 complexes, eight are
homodimers and 64 are heterodimers.
Which arrangements of donor and acceptor groups are
best? The (3)2 dimer is considerably stronger than the dimer
reported by Leung (Kdimer ) 3.4 × 102 in CDCl3).2d It is
tempting to attribute some of this difference to the two net
attractive secondary interactions present in the (DDAAD-
DAA)2 array as opposed to the (ADADADAD)2 dimer
possessing a total of 16 repulsive secondary electrostatic
interactions.10 However, the availability of stable folded
structures and geometrical issues such as the curvature in
the donor-acceptor array seen in Figure 3a complicate the
picture. Indeed, we recently reported that extending a
heterocomplex from three to four hydrogen bonds decreased
its stability due to a similar curvature of the donor-acceptor
array.11
In summary, the synthesis of a 2,7-diamino-1,8-naph-
thyridine subunit containing an organic solubilizing sub-
stituent has been developed. This enhanced solubility should
increase further the utility of this important module in
supramolecular science. As shown herein, it has allowed
extension of our previously described ureidonaphthyridine
oligomers to a very stable duplex containing eight hydrogen
bonds. With 2, 11, and 12 in hand, a number of iterative
syntheses can be envisioned providing access to custom
lengths of DDAA hydrogen bonding arrays.
Figure 3. Structure of (a) 3 and (b) (3)2. Minimization using the
MMFF force field and equilibrium geometry determined using the
HF-STO-3G method. Substituents left off for simiplicity.
is maintained with a shortening of the already close
CdO‚‚‚H-C contact, then the curvature seen in Figure 3a
can be reduced or eliminated. Alternatively, four to six central
hydrogen bonds may form, leaving the terminal urea and
naphthyridine units to stack with little or no hydrogen
bonding. Finally, as seen in Figure 3b, the docking of
compound 3 with itself leads to an energy-minimized
structure containing a substantial end-to-end twist, allowing
eight good hydrogen bonds.
Of the numerous abiotic, oligomeric duplexes that form
by interstrand hydrogen bonding,1,2,9 3 is the second wherein
a linear array of donor and acceptor groups pairs with
formation of eight hydrogen bonds. It is the first containing
the DDAADDAA hydrogen bonding motif, the other,
reported by Leung, having the DADADADAD motif (one
overhanging donors).2d These strands are just two of the 136
possible unique sequences with eight contiguous hydrogen
bond donor-acceptor sites. From these 136 possible se-
Acknowledgment. Funding of this work by the National
Science Foundation (CHE-0212772) and the ICI National
Starch and Chemical Co. is gratefully acknowledged. M.F.M.
thanks the NIH for a Ruth L. Kirschstein National Research
Service Award (GM-065707). Perry S. Corbin and Elizabeth
A. Unanue are gratefully acknowledged for synthetic con-
tributions.
Supporting Information Available: Detailed descrip-
tions of all experimental procedures along with characteriza-
1
tion data and H NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL050987F
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3008
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