Naryl-substituted anthranilamides with intramolecular hydrogen bonds

Article abstract of DOI:10.1016/j.tet.2014.09.057

Hydrogen bonding interaction as one type of non-covalent force has proven itself to be highly efficient for constructing structurally unique artificial secondary structures. Here, the structure of N_aryl-substituted anthranilamide in solution is demonstrated by various NMR technique, the intramolecular hydrogen bonds between amide attached to arylamine of the same ring is proposed, which is supported by its crystal structure in the solid phase. The substituent on the nitrogen atom of arylamine plays an important role in forming the presence of intramolecular hydrogen bonds. The chemical shift of the N_aryl-H downfield changes obviously, due to the formation of intramolecular hydrogen bonds and the deshielding effect of oxygen, and the neighboring C-H is activated and shows downfield protonic signal too. The presence of intramolecular hydrogen bonds probably provides the explanation for the transformation from N_aryl-substituted anthranilamide to imine, which could be converted into 2-aryl quinazolinone finally.

Full text of DOI:10.1016/j.tet.2014.09.057

Tetrahedron 70 (2014) 8588e8591
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Naryl-substituted anthranilamides with intramolecular hydrogen
bonds
,
,
b
b
Li-Xia Wang a, Ben-Quan Hu a c, Jun-Feng Xiang b , Jie Cui , Xiang Hao ,
*
Tong-Ling Liang b, Ya-Lin Tang a
,b,
*
a State Key laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, Chinese Academy of Sciences (ICCAS),
Beijing 100190, China
b Center for Physcochemical Analysis and Measurement, Institute of Chemistry, Chinese Academy of Sciences (ICCAS), Beijing 100190, China
c Key Laboratory for Environmentally Friendly Chemistry and Application, Department of Chemistry, Xiangtan University, Hunan 411105,
People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2014
Received in revised form 5 September 2014
Accepted 19 September 2014
Available online 28 September 2014
Hydrogen bonding interaction as one type of non-covalent force has proven itself to be highly
efficient for constructing structurally unique artificial secondary structures. Here, the structure of
Naryl-substituted anthranilamide in solution is demonstrated by various NMR technique, the intra-
molecular hydrogen bonds between amide attached to arylamine of the same ring is proposed, which is
supported by its crystal structure in the solid phase. The substituent on the nitrogen atom of arylamine
plays an important role in forming the presence of intramolecular hydrogen bonds. The chemical shift of
the Naryl-H downfield changes obviously, due to the formation of intramolecular hydrogen bonds and the
deshielding effect of oxygen, and the neighboring CeH is activated and shows downfield protonic signal
too. The presence of intramolecular hydrogen bonds probably provides the explanation for the trans-
formation from Naryl-substituted anthranilamide to imine, which could be converted into 2-aryl quina-
zolinone finally.
Keywords:
NMR spectroscopy
Naryl-substituted anthranilamides
Intramolecular hydrogen bonds
Chemical shifts
Crystal structure
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
N-groups as hydrogen-bond acceptors8 and they also work as
hydrogen-bond donors and acceptors simultaneously to form
Due to its directionality and strength, hydrogen bonding in-
teraction as one type of non-covalent force has proven itself to be
highly efficient for constructing structurally unique artificial
secondary structures.1 Particularly, a number of hydrogen-bonding-
mediated aromatic amide foldamers of well-defined conformations
have been assembled,2 some of which represent a new generation
of non-ring receptors for saccharides,3 alkylammoniums,4 or en-
capsulation of water.5 To achieve high binding stability and selec-
tivity, the design of hydrogen-bonding-mediated molecular
building blocks requires preorganization and rigidity of the back-
bones and binding sites of monomers, which is usually realized by
making use of intramolecular hydrogen bonds.6 Foldamers based
on oligoanthranilamides that are induced by intramolecular hy-
drogen bonds to adopt well-established secondary structures ex-
hibit special features.7
intramolecular hydrogen bonds between adjacent amideeamide
groups, to construct linear sheets and helical conformations.9 In our
research, the amide serves as hydrogen bond acceptor, the oxygen
of which is attached to arylamine NeH of the same aromatic ring, in
order to form intramolecular hydrogen bonds. The Naryl-substituted
oligoanthranilamides investigated here are very simple. However,
the presence of intramolecular hydrogen bonds of these structures
can be helpful to demonstrate the detailed structures and provide
a probable explanation for the mechanism starting from Naryl
-
substituted oligoanthranilamides, which can be converted into 2-
aryl quinazolinones finally.
NMR spectroscopy is a research technique that exploits the
magnetic properties of certain nuclei, and has been a powerful and
inevitable tool for structure determination.10 The intramolecular
magnetic field around an atom in a molecule changes the resonance
frequency, thus giving access to details of the electronic structure of
a molecule. Herein, we demonstrated the structures of Naryl-sub-
stituted anthranilamides by various NMR techniques, and verified
the presence of intramolecular hydrogen bonds in solution, which
was supported by crystal structures in the solid phase. Comparing
The amide units are commonly used as hydrogen-bond donors
to form intramolecular hydrogen bonds with other O-groups or
* Corresponding authors. Tel.: þ86 10 62622090; fax: þ86 10 82617304; e-mail
addresses: jfxiang@iccas.ac.cn (J.-F. Xiang), tangyl@iccas.ac.cn (Y.-L. Tang).
http://dx.doi.org/10.1016/j.tet.2014.09.057
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

L.-X. Wang et al. / Tetrahedron 70 (2014) 8588e8591
8589
to the anthranilamides with the absence of intramolecular hydro-
gen bonds, the proton signals of amides, and arylamines showed
different assignments.
experiments of 3. The chemical shifts of all protons are consistent
for 3, varying from 20 mM to 0.5 mM (Fig. 2).
2. Results and discussion
The chemical shift of NeH in amide is always assigned at lower
magnetic fields, due to the deshielding effect of carbonyl group,
comparing to the alkylamine or arylamine. However, anthranila-
mides 1e9 (Scheme 1) in DMSO-d6 solution show the
H-10s (eArNHe) 8.00e10.05 ppm, which are assigned at the
minimum magnetic fields; and while the values of H-1s and H-2s
d values of
d
of the amide groups are found at 7.79e8.05 ppm and
7.12e7.46 ppm, respectively, due to the hindered rotation of CeN
bond. The partial picture of 1H NMR spectra of the anthranilamides
1e9 is shown in Fig. 1b. We propose that there is the presence of
intramolecular hydrogen bonds in anthranilamides 1e9, shown as
in Fig. 1a. Therefore, the chemical shifts of the H-10s downfield
changes obviously because of the deshielding effect of oxygen.
Coupling with the adjacent proton, the H-10 shows a multiplet
signal in the structures of 3e9.
Fig. 2. 1H NMR spectra of the dilution study of 3 in DMSO-d6 from 20 mM to 0.5 mM at
293 K.
N-(
a model to demonstrate the detailed structure in DMSO-d6 solution.
As listed in Table 1, a broad singlet signal at
¼7.85 ppm corre-
sponds to H-1 of the amide group, and the value of H-2 is covered
in the signal of H-16. A doublet signal at
¼8.67 ppm is identified
a-methyl)-benzyl-anthranilamide 4 was picked out as
d
d
d
O
O
O
for H-10 and has an obvious correlation with H-11 by the J¼6.5 Hz.
The signal assignments of active hydrogen atoms H-1, H-2, and H-
10 are further confirmed by 1He15N HSQC spectrum (Fig. 3), where
NH2
NH
R'
NH2
NH
Ph
NH2
R''
NH
R
the
The position of H-12 of methyl-is easy to be identified, showing
a doublet signal at
¼1.43 ppm and J¼7.0 Hz coupling with H-11. A
multiplet signal at
¼4.62e4.56 ppm is designated to be H-11,
linking to C-12, and coupled with the H-10 and H-12 in the
neighborhood. A double doublets signal at
d of N-amide is 105.1 ppm and the d of N-arylamine is 85.2 ppm.
3 R' = H
4 R' = Me
5 R' = Ph
6 R' = p-MeO-Ph
7 R' = p-Cl-Ph
d
8 R'' = 5-MeO
9 R'' = 4-NO2
1 R = Me
2 R = Ph
d
d
¼7.58 ppm and J¼8.0,
Scheme 1. Structures of Naryl-substituted anthranilamides 1e9 investigated.
1.5 Hz is identified as H-5, based on the results of COSY spectrum
(see Supplementary data) where the H-5 has a correlation with H-6
and H-7, and HMBC spectrum (see Supplementary data) where it
has a correlation with C-3 (eCOe group). By analogy to H-5, other
remaining protons are assigned.
Table 1
The numbering scheme of molecular structure of compound 4 and the full assign-
ment of the proton and carbon peaks
Atom
1H
13C
HMBC
1
2
3
4
5
6
7
8
7.85
7.20
d
d
d
d
d
172.2
149.3
129.5
132.7
112.9
114.61
145.9
d
d
H2
4
H1
d
d
N
7.58
7.09
6.47
6.42
d
C3, C4, C6
C4, C7
C8
C7
d
3
5
6
7
O
9
10
NH
8
14'
15
11
9
12
15'
16
10
11
12
13
14, 15
16
8.66
4.62e4.56
1.43
d
C8, C11
C13, C14
C11, C13
C12, C15
C13, C16
C14, C15
13
51.9
25.4
114.56
129.0, 127.1
126.2
14
2
Fig. 1. (a) Structures with intramolecular hydrogen bonds. (b) Partial picture of 1H
NMR spectra of compounds 1e9 in DMSO-d6 solution at 298 K, H-10: solid circle, H-1
and H-2: hollow circle.
7.34e7.28
7.19
Anthranilamides 1e9 dissolved in non-polar deuterated CHCl3
Carbon C-3 presents chemical shift at
d
¼172.2 ppm, which is
solution also give the similar results: the
d
values of H-10s
assigned as eCOe of amide group. C-11 and C-12 are identified at
51.9 and 25.4 ppm, respectively, based on the correlations observed
with atoms H-11 and H-12 in the HSQC spectrum (see
Supplementary data). In the same way, carbons C-5 to C-8 and C-14
to C-18 are assigned. The quaternary carbon C-4 shows the chem-
(eArNHe) are assigned at the minimum magnetic fields shown as
in Fig. S1, showing the chemical shifts 8.33e8.65 ppm; and the
protons of the amide groups give a broad and single peak near to
5.72 ppm. The 1H NMR spectra in DMSO-d6 and CHCl3-d solution
both indicate that the presence of intramolecular hydrogen bonds
in anthranilamides 1e9, which is verified further by dilution
ical shift at
d
¼149.3 ppm, based on the correlations observed with
C-5 and C-3 in the HMBC spectrum (see Supplementary data).

8590
L.-X. Wang et al. / Tetrahedron 70 (2014) 8588e8591
Fig. 3. 1He15N correlation spectrum of compound 2 (HSQC) in DMSO-d6 solution at
298 K. The horizontal axis shows 1D 1H spectrum; the vertical axis shows 15N
projection.
Other remaining quaternary carbons C-9 and C-13 are assigned,
according to the same procedure.
2-Methyl-2-phenyl-1,2,3,4-(H)-quinazolinone 10, with amide
Fig. 5. Crystal structures: (a) Packing diagram of compound 5, intramolecular hydro-
gen bonds: red rectangle, and intermolecular hydrogen bonds: blue rectangle. (b)
Dimer structure of compound 10 by intermolecular hydrogen bonds.
and arylamine groups existed in the same ring, gives the
d
values of
H-1 and H-9 as two singlet signals at
d
¼8.77 and 7.51 ppm, re-
spectively (Fig. 4b). With the absence of intramolecular hydrogen
bonds, the proton signal of amide is assigned at higher magnetic
fields than arylamine. The positions of H-1 and H-9 in DMSO-d6
solution are verified further by the 1He15N HSQC spectrum (Fig. 4c),
ꢀ
arylamine group, with the distance of OeN was 2.687 A. The in-
termolecular hydrogen bonds were also observed between oxygen
ꢀ
and NeH of amide groups, with the distance of OeN was 2.859 A
where the
d value of N-amide is 128.3 ppm and the d value of
ꢀ
and 2.900 A separately. For compound 10, the formation of quina-
N-arylamine is 86.6 ppm.
zolinone-4(H) prevented the free rotation of amide group, there
was no intramolecular hydrogen bonds observed. However, the
amide units of compound 5 functioned as hydrogen bond donors
and acceptors simultaneously to form a dimer complex by in-
termolecular hydrogen bonds (Fig. 5b).
A few of N-substituted anthranilamides with intramolecular
hydrogen bonds have been reported previously, however, nobody
has provided the detailed signal assignments and demonstrated
the presence of intramolecular hydrogen bonds. For example,
Buchwald et al. synthesized Naryl-substituted anthranilamides, and
the 1H NMR signals of ArNH- were assigned 9.44e9.78 ppm
(300 MHz, CDCl3) at the minimum magnetic fields,11 due to the
intramolecular six-membered rings between amides and aryl-
amines formed by hydrogen bonds. For the simplest substrate
Anthranilamide (see Supplementary data), or other 2-amino ben-
zamides,13 there was the absence of intramolecular hydrogen
bonds found, showing chemical shifts of Naryl-Hs in the higher
magnetic fields comparing to the amides of the same aromatic
rings, probably because of the rapid exchange of the two protons of
Naryl-Hs. These results suggest that the substituent on the nitrogen
atom of arylamine plays an important role in forming the presence
of intramolecular hydrogen bonds, which can tolerant the Naryl
-
substituted anthranilamides with varied electronic properties.
Due to the presence of the intramolecular hydrogen bonds, the
proton signals of Naryl-Hs downfield shifted obviously mentioned
above and the neighboring CeHs were involved in too, and pre-
sented downfield shifts 4.62e4.56 ppm of compound 4, comparing
Fig. 4. Compound 10: (a) Partial numbering. (b) Partial picture of 1H NMR spectrum.
(c) The 1H-15N HSQC spectrum in DMSO-d6 solution at 298 K.
to the precursor a-methylbenzylamine (4.00e3.96 ppm). (Fig. 6)
Therefore, the Naryl-substituted anthranilamides were oxidized
easily to imines, which were converted to 2-aryl quinazolinones
finally, as shown in Scheme 2.12,13 In our pervious report, the
o-(N-diphenylmethyl-amino) benzamide 5 was transferred into the
imine, which was verified indirectly due to the isolation of diphe-
nylmethanone as one by-product, under the established
conditions.12
Fortunately, we obtained the crystal structures of compound 5
and 10, respectively, by slow diffusion of CH3OH and CH3COCH2CH3
solution at room temperature for some days. In the solid phase of
compound 5 (Fig. 5a), we observed the intramolecular hydrogen
bonds intuitively between the oxygen of amide group and NeH of

L.-X. Wang et al. / Tetrahedron 70 (2014) 8588e8591
8591
zgpg30; Cosy spectra, cosygpppqf45; 1He13C and 1He15N HSQC
spectra, hsqcetgp; 1He13C HMBC spectra, hmbcgplpndqf.
Chemical shifts were given on the
erenced to the residual solvent signals
dC¼38.5 ppm); Coupling constants J were reported in hertz (Hz).
The abbreviations s, d, and m were used for singlet, doublet, and
multiplet, respectively.
d
scale (ppm) and were ref-
dH¼2.50 ppm,
(
Fig. 6. Partial picture of 1H NMR spectra of compound 4 and
DMSO-d6 solution at 298 K.
a-methylbenzylamine in
4.2.2. X-ray crystallographic spectra. Single crystals of 5 and 10
were prepared by slow diffusion of CH3OH and CH3COOCH2CH3
solution at room temperature.
Datas for compounds 5 and 10 were collected at 173 K with Mo
ꢀ
Ka
radiation (
l
¼0.73073 A) on a Rigaku Saturn 724 þ CCD diffrac-
tometer with frames of oscillation range 0.5ꢀ. All structures were
solved by direct methods, and non-hydrogen atoms were located
from difference Fourier maps. All non-hydrogen atoms were sub-
jected to anisotropic refinement by full-matrix least-squares on F2
by using the SHELXTL program.
Scheme 2. The transformation from Naryl-substituted anthranilamides to 2-aryl
quinazolinones.
Acknowledgements
3. Conclusion
The authors wish to thank the National Natural Science Foun-
dation of China (Grant No. 21302188, 81072576, 91027033) and
Chinese Academy of Sciences (Grant No. KJCX2-EW-N06-01 and
XDA09030307) for financial support.
In conclusion, we demonstrated the detailed structures of Naryl
-
substituted anthranilamides in solution by various NMR technique
for the first time. The intramolecular hydrogen bonds between
eCONH2e and aryleNHe was observed, which was verified by
crystal structures in the solid phase. The neighboring CeHs were
involved in, and presented downfield chemical shifts. Therefore, it
Supplementary data
Supplementary data include copies of NMR spectra of all com-
pounds mentioned above, and crystal data for compound 5 and 10.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.09.057.
probably provided the explanation for the mechanism from Naryl
-
substituted anthranilamides to imines by oxidation, which were
further converted into medically important 2-aryl quinazolinones.
Besides, we believe that this research will be helpful for the accu-
rate designation of protonic signals of anthranilamide derivatives.
References and notes
4. Experimental section
4.1. Compounds
1. For reviews, see: (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173; (b) Stigers, K.
D.; Soth, M. J.; Nowick, J. S. Curr. Opin. Chem. Biol. 1999, 3, 714; (c) Hill, D. J.; Mio,
M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893; (d)
Cubberley, M. S.; Iverson, B. L. Curr. Opin. Chem. Biol. 2001, 5, 650; (e) Schmuck,
C. Angew. Chem., Int. Ed. 2003, 42, 2448; (f) Huc, I. Eur. J. Org. Chem. 2004, 17; (g)
Cheng, R. P. Curr. Opin. Struct. Biol. 2004, 14, 512; (h) Sanford, A.; Yamato, K.;
Yang, X. W.; Yuan, L. H.; Han, Y. H.; Gong, B. Eur. J. Biochem. 2004, 271, 1416; (i)
Licini, G.; Prins, L. J.; Scrimin, P. Eur. J. Org. Chem. 2005, 969; (j) Stone, M. T.;
Heemstra, J. M.; Moore, J. S. Acc. Chem. Res. 2006, 39, 11.
2. Zhu, J.; Lin, J. B.; Xu, Y. X.; Shao, X. B.; Jiang, X. K.; Li, Z. T. J. Am. Chem. Soc. 2006,
128, 12307e12313 and references cited therein.
3. (a) 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; (b) Yi, H. P.; Shao, X. B.; Hou, J. L.; Li, C.; Jiang, X. K.; Li, Z.
T. New. J. Chem. 2005, 29, 1213.
N
aryl-substituted-anthranilamides 2e9 were prepared from the
Ullmann coupling reactions between 2-iodobenzamide and aniline
or -substituted benzylamines, under the reaction conditions with
the presence of the base K2CO3 (2 equiv), under argon atmosphere
(1 atm, with extrusion of air), at 110 ꢀC for 4 h in DMSO. Naryl
a
-
methyl-anthranilamide 1 was prepared according to the reported
method.14
4. Li, C.; Ren, S. F.; Hou, J. L.; Yi, H. P.; Zhu, S. Z.; Jiang, X. K.; Li, Z. T. Angew. Chem.,
2-Methyl-2-phenyl-1,2,3,4-(H)-quinazolinone 10 was prepared
according to the reported method,15 starting from 2-amino-
benzamide and phenylacetylene in the presence of Ph3PAuNTf2,
under argon atmosphere (1 atm, with extrusion of air), at 100 ꢀC for
24 h in toluene.
Int. Ed. 2005, 44, 5725.
ꢁ
5. Garric, J.; Leger, J. M.; Huc, I. Angew. Chem., Int. Ed. 2005, 44, 1954.
6. (a) 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; (b) Mayer, M. F.; Nakashima, S.; Zimmerman, S. C. Org. Lett. 2005, 7,
3005.
7. Xia, B.; Bao, D. D.; Upadhyayula, S.; Jone, G., II; Vullev, V. I. J. Org. Chem. 2013, 78,
1994.
8. Selected literatures, see: (a) Fu, H. L.; Liu, Y.; Zeng, H. Q. Chem. Commun. 2013,
49, 4127; (b) Yan, Y.; Zhao, W. W.; Bhagavathy, G. V.; Faurie, A.; Misey, N. J.;
Petitjean, A. Chem. Commun. 2012, 48, 7829.
Anthranilamide,
a-methylbenzylamine, and other organic re-
agents were purchased from Beijing J&K Chemical Scientific
Company.
9. (a) Hamuro, K.; Geib, S. J.; Hamilton, A. D. Angew. Chem., Int. Ed. 1994, 33, 446;
(b) Hamuro, K.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1996, 118, 7529; (c)
Hamuro, K.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1997, 119, 10587.
10. Baranac-Stojanovic, M. RSC Adv. 2014, 4, 308.
4.2. Spectra
4.2.1. NMR spectra. All spectra were recorded on a Bruker Advance
III 500 spectrometer equipped with a 5-mm BBFO probe, in DMSO-
d6 solution at 298 K. Data processing was carried out with TopSpin
3.2 version (Bruker, German). The 1H and 13C NMR spectra were
operated at 500 and 125 MHz, respectively. Pulse programs for all
spectra were as follows: 1H NMR spectra, zg30; 13C NMR spectra,
11. Huang, X. H.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J.
Am. Chem. Soc. 2003, 125, 6653.
12. Wang, L. X.; Xiang, J. F.; Tang, Y. L. Eur. J. Org. Chem. 2014, 2682e2685.
13. (a) Xu, W.; Jin, Y. B.; Liu, H. X.; Jiang, Y. Y.; Fu, H. Org. Lett. 2011, 13, 1274; (b)
Hikawa, H.; Ino, Y.; Suzuki, H.; Yokoyama, Y. J. Org. Chem. 2012, 77, 7046.
14. Zhao, D.; Wang, T.; Li, J. X. Chem. Commun. 2014, 50, 6471e6474.
15. Natin, T. P.; Pediredla, G.; Vipender. Eur. J. Org. Chem. 2010, 4719.