Synthesis of naphthyridin-2(1: H)-one derivatives via ring expansion of 3-substituted-1 H -pyrrolo[2,3- b] pyridin-2(3 H)-one derivatives

Article abstract of DOI:10.1039/c8cc01518j

The reaction of 3-substituted 1H-pyrrolo[2,3-b]pyridin-2(3H)-one derivatives with sodium azide or azidotrimethylsilane under microwave irradiation provided 3- and 4-amino-naphthyridin-2(1H)-one derivatives through cycloaddition-ring expansion. The inserti

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Synthesis of naphthyridin-2(1H)-one derivatives via a ring
expansion of 3-substituted-1H-pyrrolo[2,3-b]pyridin-2(3H)-one
derivatives.
Received 00th January 20xx,
Accepted 00th January 20xx
C. Croix,a* S. Massipb and M.-C. Viaud-Massuarda*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The reaction of 3-substituted 1H-pyrrolo[2,3-b]pyridin-2(3H)-one 7-azaoxindoles under the Tinarelli and Paolucci’s conditions.
derivatives with sodium azide or azidotrimethylsilane under We demonstrate an original rearrangement of our scaffold
microwaves irradiation provided 3- and 4-amino-naphtyridin- leading in one step a convenient synthesis of two new
2(1H)-one derivatives through cycloaddition-ring expansion. The aminonaphtyridin-2(1H)-one derivatives
insertion of the azide into the α,β unsaturated carbonyl of 3- separated by conventional chromatography. As NMR analysis
substituted pyrrolo[2,3-b]pyridine-2(3H)-one derivatives are not sufficient to identify the structure of the rearranged
2
and
3
easily
proceeded via an unusual rearrangement. This methodology
provided 39 ring expansion examples in moderate to good yields.
Nitrogen heterocycles display a wide range of applications in
[1]
biological, pharmaceutical and material sciences. Therefore
the study of the preparation and the reactivity of heterocyclic
compounds are important for organic chemists. 7-Azaindoles
(1H-pyrrolo[2,3-b]pyridine) are the most nitrogen analogue of
the indole ring system.[2] In the past few years, 3-benzylidene-
1H-pyrrolo[2,3-b]pyridine-2(3H)-one
derivatives
(7-
azaoxindoles) have become interesting scaffolds for their
reactivity[3] and biological[4] activity. Naphtyridine units are
[5]
present in numerous natural products
and have attracted
[6]
great interest due to their synthesis
variety of pharmacological and biological activities.[7]
but also due to their
Michael and hetero-Michael addition are powerful reactions
for the formation of carbon-carbon and carbon-heteroatom
bonds.[8] Due to their structure, 3-benzylidene-1H-pyrrolo[2,3-
compounds, this one was unambiguously confirmed by X-ray
diffraction analysis (Figure 1).[11]
b]pyridin-2(3H)-ones
1 seem to be an appropriate scaffold as
Michael acceptor derivatives. We have previously reported
that 7-azaoxindoles are good candidates for rhodium-catalyzed
1,4-addition with organoboronic acids (Scheme 1a).[9]
Following this first study, we tried the Tinarelli and Paolucci[10]
conditions in order to introduce an azide group by 1,4-addition
(Schemes 1b and 1c). Herein we report the reaction of various
Scheme 1. a) and b) 1,4-addition reactions. c) Unexpected rearrangement of 7-
azaoxindoles
Figure 1. Molecular structure of compounds 2a and 3a.
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Table 1. Optimization of the
reaction conditions. a
Entry
1c
2
[N3]
DBU (equiv)
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
H2O
temp (°C)
time
1 week
1 week
1 week
1 week
48 h
Yield (%)b
Me3SiN3
NaN3
0.3
0.3
1
RT
RT
21
51
84
90
54
55d
3
Me3SiN3
NaN3
RT
4
1
RT
5
Me3SiN3
Me3SiN3
NaN3
0.3
1
120
6
120
48 h
d
7
0.3
0.3
1
120
24 h
-
8
Me3SiN3
Me3SiN3
Me3SiN3
NaN3
130, MW
110, MW
110, MW
110, MW
110, MW
2 h
80d
94
66
91
83
9
1 h
10
11
12
1
1 h
1
1
H2O
toluene
1 h
1 h
NaN3
a
b
Conditions: 1a (0.25 mmol), N3 source (2.5 mmol), AcOH (2.5 mmol), DBU in solvent (2 mL) at the indicated temperature. Isolated yield. Initial
c
d
conditions described by Tinarelli and Paolucci.
diazabicyclo[5.4.0]undec-7-ene, MW – microwaves
Degradation. See supporting information for additional screening conditions. DBU - 1,8-
We began our study by using the 3-benzylidene-1-methyl-1H- have been synthesized by condensation between 1-methyl-1H-
pyrrolo[2,3-b]pyridin-2(3H)-one (1a) as a substrate to optimize pyrrolo[2,3-b]pyridin-2(3H)-one and various aromatic,
the reaction conditions (Table 1 and see also the Supporting heteroaromatic and aliphatic aldehydes.
Information, Table S1). Initially we observed the formation of The products have been obtained in a mixture of inseparable E
3-amino-1-methyl-4-phenyl-1,8-naphthyridin-2(1H)-one
(
2a)
and Z isomers with good to excellent yields. Indeed as we
and 4-amino-1-methyl-3-phenyl-1,8-naphthyridin-2(1H)-one previously described, 3-benzylidene-1H-pyrrolo[2,3-b]pyridine-
[9]
(
3a) with very low yield with Tinarelli and Paolucci’s conditions 2(3H)-one derivatives isomerise in solution. The ratio of E
after 1 week (entry1). Use of sodium azide instead of and Z isomers were determined by 1H NMR just after the
azidotrimethylsilane gave a higher yield but the reaction was preparation of the sample and were summarized in Scheme
extremely slow and the conversion was not complete after 1 2.To study the influence of the N-substitution on the pyrrole,
week (entry 2). To study the influence of each reactants we have also prepared the 3-benzylidene-1H-pyrrolo[2,3-
several attempts have been carried out with various quantities b]pyridin-2(3H)-one derivative 1t in modest yield. To extend
of DBU and acetic acid. The presence of DBU and acetic acid is our study to indole scaffold, we have also prepared the 3-
essential for the reaction to occur. Increasing the quantity of benzylidene-1-methylindolin-2-one 1u with
DBU permitted 100% of conversion of 1a in 2a and 3a with (Scheme 2).
a good yield
very good yields but only after 1 week of reaction (entries 3 We subsequently examined the substrate scope using the
and 4). To accelerate the reaction, some attempts were carried optimized reaction conditions (Me3SiN3, AcOH, DBU, toluene,
out in refluxing toluene but formation of degradation products MW, 110 °C, 1 h. or NaN3, AcOH, DBU, H2O, MW, 110 °C, 1 h)
occurred rapidly and reactions did not to completion (entries with the 7-azaoxindoles previously prepared. The results are
5-7). To avoid degradation and improve the conversion of 1a
various conditions have been tested under microwave groups such as methyl, bromine, acetoxy and nitro were found
irradiation (entries 8-12). Higher yields were obtained at 110 to be well tolerated in our reaction (2b 2h and 3b 3h).
°C for 1 h with azidotrimethylsilane in toluene or with sodium However with methoxy and hydroxy groups (2k and 3i 3k), the
,
summarized in scheme 3. Various substitutions on the aryl
-
-
-
azide in water (entries 9 and 11). Attempts were also made to yields are lower and only traces of compounds 2i and 2j were
promote the nucleophilic addition of the azide and observed. Replacement of the phenyl ring with the 2-naphtyl
consequently permit the synthesis of only one of the two ring or with an alkyl chain was equally successful (2l
rearranged products, however the formation of compounds 2a 3m).
and 3a is concomitant. We prepared a series of other 3-
-2m and 3l-
subsituted-1H-pyrrolo[2,3-b]pyridine-2(3H)-one derivatives to
evaluate their reactivity with the azide source under our
optimized conditions. These 7-azaoxindoles (from 1b to 1s
)
2 | J. Name., 2012, 00, 1-3
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R
O
a or b
+
RCHO
X = N, CH R1 = H, Me
N
R1
O
X
N
X
R1
R2
1a R2 = H, 85%,a E/Z = 94/6
1f R2 = 2-NO2, 98%,b
1g R2 = 3-NO2, 85%,b
1h R2 = 4-NO2, 98%,b
1i R2 = 4-OMe, 70%,a
1j R2 = 4-OH, 85%,b
/
= 100/0
= 78/22
E Z
1b R2 = 4-Me, 93%,b E/Z = 96/4
/
E Z
E Z
E Z
1c R2 = 4-Br, 90%,b
1d R2 = 2-Br, 95%,a
/
= 90/10
= 100/0
/
= 100/0
= 80/20
E Z
E Z
/
/
O
1e R2 = 4-C(O)Me, 76%,a E/Z = 82/18
E Z
/ = 80/20
N
N
O
N
O
O
N
O
O
O
O
= 83/17
N
N
N
N
N
N
N
1l 85%,b
/
E Z
1m
65%,a E/Z = 83/17
1n 86%,b E/Z = 100/0
1k 98%,b
/
= 81/19
E Z
N
N
S
S
O
O
O
O
N
N
N
N
N
N
N
N
1q 73%,a
1p 81%,b E/Z = 91/9
1r 76%,a E/Z = 53/47
1o 70%,a E/Z = 64/36
E Z
/ = 100/0
O
O
O
O
N
N
N
H
N
N
1u 87%,b %E = 90/10
1s 86%,b
E Z
/ = 50/50
1t 52%,a E/Z= 90/10
Scheme 2. Synthesis of 3-benzylidene-1H-pyrrolo[2,3-b]pyridine-2-(3H)ones.
a
1H-pyrrolo[2,3-b]pyridine-2-(3H)ones (1 mmol), appropriatbe aldehyde (1.5
mmol), piperidine (0.4 mmol), toluene (2.5 mL), RT, 16 h. 1H-pyrrolo[2,3-
b]pyridine-2-(3H)ones (1 mmol), appropriate aldehyde (1.2 mmol), piperidine
(0.1 mmol), ethanol (5 mL), reflux, 1 h.
Instead of an aryl moiety, heteroaryl groups were tested.
With a pyridinyl ring, rearrangement reactions afforded 2n
-2p
and 3n-3p in excellent yields. In contrast, with a 2-thiophenyl
moiety, the compound 3q was isolated in a low yield (36%) and
only traces of rearranged products were observed with a 2-
furyl group.
On the other hand when the heteroatom is in position 3, the
2r-2s and 3r-3s compounds were isolated in moderate yields.
Despite a total conversion of the starting material, the
unprotected 3-benzylidene-1H-pyrrolo[2,3-b]pyridin-2(3H)-one
derivative 1t afforded the two rearranged products 2t and 3t
with only moderate yields (46%) due to the adducts low
solubility. Finally, to study the influence of the pyridine ring on
our scaffold, the reaction was attempted on the 3-
benzylidene-1-methylindolin-2-one 1u. Due to the solubility of
the starting material, the reaction was conducted in methanol
and afforded the two final product 2u and 3u with a very good
yield.
[12]
the triazoline intermediate
A
.
Then, the thermal- or acid-
(pH 4-5) promoted decomposition of triazoline through loss of
nitrogen allows the formation of strained aziridine
intermediates. The isomerisation in solution of the double
bond[9] don’t allowed the synthesis of only one chiral
spiroaziridine.
A plausible reaction pathway for the formation of
is proposed in the scheme 4. The tandem [3+2] cycloaddition
of the azide as a 1,3-dipoles with the unsaturated carbonyl
2 and 3 from
1
Scheme 3. Scope of the ring expansion reaction.
a
α,β
1 (0.25 mmol), Me3SiN3 (2.5 mmol), AcOH (2.5 mmol), DBU (0.25 mmol),
b
toluene (2 mL), MW, 110 °C, 1 h. 1 (0.25 mmol), NaN3 (2.5 mmol), AcOH (2.5
of the 3-substituted-1H-pyrrolo[2,3-b]pyridine-2(3H)-one
mmol), DBU (0.25 mmol), H2O (2 mL), MW, 110 °C, 1 h. c 1 (0.25 mmol), Me3SiN3
(2.5 mmol), AcOH (2.5 mmol), DBU (0.25 mmol), methanol (2 mL), MW, 110 °C, 1
through azide derivatives such as NaN3 or Me3SiN3, generates
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h
Cheng, C.-H. Han, C.-C. Tzeng, Bioorg. Med. Chem., 2012, 20
4397. (d) N. F. Abdel-Ghaffar, Nat. Sci., 2011,
Schreiber, Science, 2000, 287, 1964.
(a) U. P. Bandarage, M. P. Clark, E. Perola, H. Gao, M. D.
Jacobs, A. Tsai, J. Gillepsie, J. M. Kennedy, F. Maltais, M. W.
Ledeboer, I. Da-vies, W. Gu, R. A. Byrn, K. N. Addae, H.
Bennett, J. R. Leeman, S. M. Jones, C. O’Brien, C. Memmott,
,
9, 190. (e) S. L.
In none of the described cases it has been possible to isolate
intermediates in order to confirm this mechanism. The mixture
of diastereoisomeric compounds could have two possibilities
of ring-expanded rearrangement through carbon- carbon bond
cleavage. The presence of DBU and AcOH are essential for this
reaction, which affords a mixture of naphthyridin-2(1H)-ones
substituted either in the 3 or 4 position by an amino group and
vice versa with an alkyl, aryl or heteroaryl derivatives. Due to
this mechanism it seems difficult to impact on the selectivity of
the reaction. Nevertheless the strength of our study is the
synthesis in one step of two new compounds.
2
Y. Bennani, P. S. Charifson, ACS Med. Chem. Lett., 2017, 8,
261. (b) Y. Kim, S. Hong, Chem. Commun., 2015, 51, 11202.
(c) S. R. Walker, E. J. Carter, B. C. Huff, J. C. Morris, Chem.
Rev., 2009, 109, 3080.
(a) V. P. Shym, S. S. Pal, R. S. Pathare, L. K. K. Reddy, A.
Pathak, Tetrahedron Lett., 2015, 56, 6370. (b) E. Bacqué, M.
El Qacemi, S. Z. Zard, Org. Lett., 2004, 6, 3671.
(a) M. Wang, C. Ye, M. Liu, Z. Wu, L. Li, C. Wang, X. Liu, H.
Guo, Bioorg. Med. Chem. Lett., 2015, 25, 2782. (b) G. Chen,
Q. Weng, L. Fu, Z. Wang, P. Yu, Z. Liu, X. Li, H. Zhang, G. Liang,
Bioorg. Med. Chem., 2014, 22, 6953. (c) W. Chu, D. Zhou, V.
Gaba, J. Liu, S. Li, X. Peng, J. Xu, D. Dhavale, D. P. Bagchi, A.
Avignon, N. B. Shakerdge, B. J. Bacskai, Z. Tu, P. T. Kotzbauer,
R. H. Mach, J. Med. Chem., 2015, 58, 6002. (d) S. Shah, C.
Lee, H. Choi, J. Gautam, H. Jang, G. J. Kim, Y.-J. Lee, C. L.
Chaudhary, S. W. Park, T.-G. Nam, J.-A. Kim, B.-S. Jeong, Org.
Biomol. Chem., 2016, 14, 4829. (e) J. Zhang, W. Shen, X. Li, Y.
Chai, S. Li, K. Lv, H. Guo, M. Liu, Molecules, 2016, 21, 1674.
3
4
5
6
(a) M. Sekar, K. J. Rajendra Prasad, J. Nat. Prod., 1998, 61,
294. (b) L. Puricelli, G. Innocenti, G. Delle Monache, R.
Caniato, R. Filippini, E. M. Cappelletti, Nat. Prod. Lett., 2002,
16, 95. (c) M. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, A.
T. Mcphail, G. A. Sim, J. Am. Chem. Soc., 1966, 88, 3888. (d)
M. E. Wall, M. C. Wani, J. Ethnopharmacol., 1996, 51, 239.
(a) C. Alonso, M. Gonzalez, F. Palacios, G. Rubiales, J. Org.
Chem., 2017, 82, 6379. (b) D. Nandini, M. Asthana, T. Gupta,
R. P. Singh, R. M. Singh, Tetrahedron, 2014, 70, 8592. (c) S.
Fadel, Y. Habjbi, M. Khouili, S. Lazar, F. Suzenet, G.
Guillaumet, Belstein J. Org. Chem., 2014, 10, 282. (d) Z.
Wang, X. Xing, L. Xue, F. Gao, L. Fang, Org. Biomol. Chem.,
2013, 11, 7334. (d) J. Zhou, B. Li, F. Hu, B.-F. Shi, Org. Lett.,
2013, 15, 3460.
(a) X. Zhi Zhao, S. J. Smith, M. Métifiot, C. Marchand, P. L.
Boyer, Y. Pommier, S. H. Hughes, T. R. Burke Jr, J. Med.
Chem., 2014, 57, 5190. (b) H. Ban, M. Muraoka, N. Ohashi,
Tetrahedron, 2005, 61, 10081. (c) J. S. Debenham, C. B.
Madsen-Duggan, T. F. Walsh, J. Wang, X. Tong, G. A. Doss, J.
Lao, T. M. Fong, M.-T. Schaeffer, J. Chen Xiao, C. R.-R. C.
Huang, C. P. Shen, Y. Feng, D. J. Marsh, D. S. Stribling, L. P.
Shear-man, A. M. Strack, D. E. MacIntyre, L. H. T. Van der
Ploeg, M. T. Goulet, Bioorg. Med. Chem. Lett., 2006, 16, 681.
(d) H. Ban, M. Muraoka, K. Ioriya, N. Ohashi, Bioorg. Med.
Chem. Lett., 2006, 16, 44.
Scheme 4. Plausible mechanism.
In summary, we have developed a straightforward method to
provide in one step 3- and 4-aminonaphthyridin-2(1H)-one
derivatives with very good yields starting from 7-azaoxindole
compounds. The reaction proceeds under microwave
irradiation in only 1 h and affords two new compounds never
described. This approach is applicable for a wide range of 3-
substituted-1H-pyrrolo[2,3-b]pyridine-2(3H)-one derivatives
and also on indole scaffolds.
7
This work was supported by the Laboratory of Excellence
Labex SYNORG, ANR-11-LABX-0029. This work has also
benefited from the facilities and expertises of the Biophysical
and Structural Chemistry plateform (BPCS) at IECB, CNRS
UMS3033,
Inserm
US001,
Bordeaux
University
http://www.iecb.u-
8
9
(a) P. Perlmutter in Conjugate addition reactions in organic
synthesis (tetrahedron organic chemistry), Permagon press,
Oxford, 1992. (b) J. Come-lles, M. Moreno-Mañas, A.
bordeaux.fr/index.php/fr/plateformestechnologiques. Thanks
also to Dr Francesca Bryden for the translation assistance.
Vallribera, ARKIVOC, 2005, 9, 207. (c) H.-C. Guo, J. A. Ma,
Angew. Chem. Int. Ed., 2006, 45, 354.
C. Croix, G. Prié, C. Chaulet, M.-C. Viaud-Massuard, J. Org.
Chem., 2015, 80, 3264.
Conflicts of interest
There are no conflicts to declare.
10 A. Tinarelli, C. Paolucci, J. Org. Chem., 2006, 71, 6630.
11 CCDC 1528553 (2a), and 1528554 (3a) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from TheCambridge
Crystallographic Data Centre.
12 (a) K. Suman, L. Srinu, S. Thennarasu, Org. Lett., 2014, 16
3732. (b) D. J. Guerin, T. E. Horstmann, S. Miller, Org. Lett.,
1999, , 1107.
Notes and references
‡ Footnotes relating to the main text should appear here. These
might include comments relevant to but not central to the
matter under discussion, limited experimental and spectral data,
and crystallographic data.
,
7
1
(a) C. Cabrele, O. Reiser, J. Org. Chem., 2016, 81, 10109. (b)
H. T. Pham, I. Chataigner, J.-L. Renaud, Curr. Org. Chem.,
2012, 16, 1754. (c) C.-H. Tseng, Y.-L. Chen, C.-L. Yang, C.-M.
4 | J. Name., 2012, 00, 1-3
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