Tandem synthesis of pyrrolo[2,3-b]quinolones via cadogen-type reaction

Article abstract of DOI:10.1021/acs.orglett.7b02558

A tandem [3 + 2] cycloaddition/reductive cyclization of nitrochalcones with activated methylene isocyanides for the efficient synthesis of pyrrolo[2,3-b]- quinolones is reported. In this reaction, the in situ generated dihydropyrroline acts as the interna

Full text of DOI:10.1021/acs.orglett.7b02558

Letter
pubs.acs.org/OrgLett
Tandem Synthesis of Pyrrolo[2,3‑b]quinolones via Cadogen-Type
Reaction
Zhichen Lin,†,§ Zhongyan Hu,†,‡,§ Xin Zhang,‡ Jinhuan Dong,‡ Jian-Biao Liu,*,‡ De-Zhan Chen,‡
and Xianxiu Xu*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for
Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong
Normal University, Jinan 250014, China
S
* Supporting Information
ABSTRACT: A tandem [3 + 2] cycloaddition/reductive
cyclization of nitrochalcones with activated methylene
isocyanides for the efficient synthesis of pyrrolo[2,3-b]-
quinolones is reported. In this reaction, the in situ generated
dihydropyrroline acts as the internal reductant to convert the
nitro into an electrophilic nitroso group, which undergoes
subsequent C−N bond formation. Transition-metal-free,
simple experimental procedure and ready accessibility of
starting materials characterize the present transformation.
Scheme 1. Reductive Cyclization of Nitroarenes
eductive cyclization of o-functionalized nitroarenes is one of
the most efficient tools for the synthesis of N-containing
R
heterocycles.1−9 Several named reactions starting from the
readily available and cheap nitroarenes, such as Reissert indole
synthesis,2a,b Leimgruber−Batcho reaction,2c Bartoli indole
synthesis,2d,e and Cadogan reaction,2f−h were developed for the
preparation of a wide range of aromatic heterocycles. Cadogan
reductive cyclization of nitroaromatics using boiling triethyl
phosphite is a classic synthetic method for the construction of
indoles and carbazoles (Scheme 1, eqs 1 and 2).2f−h,3 The
generally accepted mechanism of Cadogan reaction was
suggested by Houk et al., which involves deoxygenation of the
nitro group to generate a nitroso intermediate, followed by 6π
electrocyclization to form the pyrrole ring.4 Recent develop-
ments on Cadogan-type reaction mainly focus on improvement
of its efficiency and practicality, thus superstoichiometric
quantities of a reductant such as Grignard reagent,5 [Mo-
7
(CO)6],6 TiCl3 or high pressures of CO8 were investigated
under mild conditions. However, tandem Cadogan-type
bicyclization of nitroarenes for the construction of heterocycles
remains scarce.9
Pyrrolo[2,3-b]quinolines are commonly found in pharmaco-
logically active compounds, for example, blebbistatin as myosin II
inhibitor,10 PGP-4008 as P-gp-specific drug release MDR
modulator,11 and some N-acyl-2,3-dihydro-lH-pyrrolo[2,3-b]-
quinoline derivatives used as inhibitors of DU-145 cell
proliferation.12 Since first example of the synthesis of pyrrolo-
[2,3-b]quinoline derivatives,13 considerable effort has been
devoted to developing new methods for the preparation of
these frameworks.14−19 Generally, previous methods focused on
stepwise annulations of preformed substituted quinolones14 or 3-
alkylidene-2-(phenylimino)pyrrolidines.15 Recently, new strat-
egies based on tandem reactions of carbodiimides for one-pot
synthesis of these scaffolds were developed.14−18 In 2010, a facile
synthesis of pyrrolo[2,3-b]quinolines via a Rh(I)-catalyzed
Received: August 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02558
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
carbodiimide−Pauson−Khand-type reaction was reported.16 In
2016, an elegant Rh(II)-catalyzed cyclization of azidomethylene-
cyclopropanes (MCPs) and isonitriles to afford pyrrolo[2,3-
b]quinolones was reported.17 In the same year, I2/CHP-
mediated reaction of amino-MCPs with isonitriles for the
synthesis of pyrroloquinolines was developed.18 An alkoxide-
induced rearrangement of 10-membered N-acyl cyclic ureas was
developed for the synthesis of pyrrolo[2,3-b]quinolines.19 As a
result of our studies on the isocyanide-based annulations,20 we
report herein an unprecedented tandem [3 + 2] cycloaddition/
Cadogan-type reaction between ortho-nitrochalcones and
activated methylene isocyanides for the facile and convenient
one-pot synthesis of pyrrolo[2,3-b]quinolones (Scheme 1, eq 3).
In this transformation, the dihydropyrroline moiety of the in situ
generated intermediate A acts as the reductant to convert the
nitro group into reactive nitroso functionality, which facilitates
the subsequent C−N bond formation to form the tricyclic
framework. Note that, in this reaction, a six-membered pyridone
ring is built by forming the C−N bond, whereas in the traditional
Cadogen reaction, a five-membered pyrrole ring is generally
built.
BuOK (Table 1, entry 3), t-PeONa (Table 1, entry 4), Cs2CO3
(Table 1, entry 5), and DBU (Table 1, entry 6). The reaction
gave slightly lower yield of 3a either decreasing the amount of t-
PeONa to 0.5 equiv (Table 1, entry 7) or increasing the amount
to 2.0 equiv (Table 1, entry 8). Selected solvents, such as MeOH,
i-PrOH, t-BuOH, CH3CN, toluene, DCE, and 1,4-dioxane, were
examined but gave 3a in lower yields (Table 1, entries 9−15).
When the reaction temperature was increased to 150 °C, 3a was
obtained in 50% yield (Table 1, entry 16), whereas upon
decreasing the temperature to 120 °C, the yield of 3a was much
lower (Table 1, entry 17). When the reaction was performed
under more diluted conditions (Table 1, entries 18−20), the
yield of 3a was increased to 73% (concentration = 0.03 M, Table
1, entry 19).
With the optimal conditions in hand (Table 1, entry 19), the
scope of viable 1 was examined; the results are summarized in
Scheme 2. A wide range of substrates 1 were tolerated in this
a,b
Scheme 2. Scope of Nitrochalcones 1
Initially, the reaction of the nitrochalcone 1a with ethyl
isocyanoacetate 2a was used as a model reaction to optimize the
reaction conditions (Table 1). In the presence of NaOH (1.0
equiv) in ethanol at 140 °C for 2 h, the reaction of 1a (0.3 mmol)
and 2a (0.6 mmol) gave pyrrolo[2,3-b]quinolone 3a21 in 52%
along with pyrrole 4a in 21% yield (Table 1, entry 1). It was
found that t-PeONa (Table 1, entry 4) was the optimal choice
after screening different bases such as KOH (Table 1, entry 2), t-
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
base (1.0 equiv)
solvent
temp (°C)
3a
52
4a
21
a
Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol) and t-PeONa (1.0
1
2
3
4
5
6
NaOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
i-PrOH
t-BuOH
CH3CN
toluene
DCE
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
150
120
140
140
140
b
c
equiv) in EtOH (10 mL) at 140 °C. Isolated yields. 1 mmol scale.
KOH
40
41
56
17
40
40
51
55
47
33
31
37
29
45
11
33
21
27
26
11
trace
t-BuOK
t-PeONa
Cs2CO3
DBU
reaction, and a series of pyrrolo[2,3-b]quinolones (3a−v) were
produced in good to high yields by the reactions of 2a with a wide
range of 1 bearing various R1 groups, e.g., para- (1b−e), meta-
(1f,g), and ortho-substituted aryl groups (1h−j), disubstituted
phenyl groups (1k), trisubstituted phenyl groups (1l), 1- and 2-
naphthyl (1m,n), heteroaryl groups (1o,p), vinyl group (1q),
and alkyl groups (1r−t). This reaction also tolerated 1 bearing
both electron-withdrawing (1u) and -donating R2 groups (1v).
Subsequently, the scope of the reaction was evaluated with
respect to activated methylene isocyanides 2 (Scheme 3). Under
the optimal conditions (Table 1, entry 19), methyl isocyanoa-
cetate 2b, tert-butyl isocyanoacetate 2c, and isocyanoacetamide
2d gave the corresponding pyrrolo[2,3-b]quinolones 3w−y in
moderate yields. Furthermore, the reaction also tolerated
substituted benzyl isocyanides 2f and 2g and gave the 2-aryl-
substituted pyrrolo[2,3-b]quinolones 3z−3aa in moderate
yields. Reaction of 1a with tosylmethyl isocyanide 2e gave
pyrrole product 5a with the nitro groups intact, and the
corresponding pyrrolo[2,3-b]quinolone 3ab was not detected.
Control experiments were performed to clarify the reaction
mechanism. In the presence of Ag2CO3 (0.3 equiv), the reaction
c
7
d
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
t-PeONa
8
9
10
11
12
13
14
15
16
17
trace
trace
trace
50
dioxane
EtOH
EtOH
EtOH
EtOH
EtOH
29
23
26
22
21
44
e
18
63
f
19
g
73
20
72
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), base (0.3
b
mmol), solvent (2 mL), air atmosphere, 2 h. Yield of isolated
products. t-PeONa (0.5 equiv) was added. t-PeONa (2.0 equiv) was
added. EtOH (5 mL). EtOH (10 mL). EtOH (15 mL).
c
d
e
f
g
B
DOI: 10.1021/acs.orglett.7b02558
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
gain further insight into this interesting redox-neutral trans-
formation, DFT calculations were carried out at the B3LYP level
(see Supporting Information). As shown in Scheme 5, the
Scheme 3. Scope of Activated Methylene Isocyanides 2
Scheme 5. Plausible Reaction Pathways
a
Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol) and t-PeONa (1.0
b
c
equiv) in EtOH (10 mL) at 140 °C. Isolated yields. MeOH as
solvent. t-BuOH as solvent. ND = not detected.
d
e
of 1a with 2a took place easily at room temperature within 0.5 h
to give dihydropyrroline 6a in 97% yield (Scheme 4, eq 1). 6a was
Scheme 4. Control Experiments
enthalpy profile indicates that the reaction initiating from 1a and
2a proceeds through [3 + 2] cycloaddition to form 6a.20c,d,22
Deprotonation of 6a takes place to form anion I, then
intramolecular cyclization of intermediate I produces the spiro
intermediate II9,23 via TS1 (TS = transition state) with an
activation barrier of 14.6 kcal/mol. Cope-type elimination24 of II
by way of TS2 forms anion III, which undergoes successive
dehydroxylation and proton shift to form the reactive 8a via
transition states TS3 and TS4, with activation barriers of 4.3 and
30.3 kcal/mol, respectively. Nucleoaddition of nitroso to
pyrrole5 furnishes intermediate V with an activation barrier of
21 kcal/mol. It is most likely that two possible paths exist on the
way from V to 3a. In path a, a hydride shift from N to O atom
occurs to give intermediate VI with an activation barrier of 13.8
kcal/mol, following by proton shift to generate N-hydroxy
pyrroloquinolone VII via TS7 with an activation barrier of 20.6
kcal/mol. The cleavage of the N−O bond of VII may provide the
final product 3a.4,7 In path b, nucleoaddition of an ethoxy anion
to V results in intermediate VIII, which is followed by the
elimination of EtOO− to furnish IX via TS8 with an activation
barrier of 29.1 kcal/mol.9 Finally, proton shift of intermediate IX
leads to 3a via TS9 with an activation barrier of 7.6 kcal/mol. At
this stage, the evidence for the reductive cleavage of the N−O
bond of VII seems absent, thus path b may be the preferred way.
To demonstrate the synthetic potential of this bicyclization
reaction, transformations of the generated pyrroloquinolone 3
were conducted (Scheme 6). 3a was readily converted to 4-
chloropyrrolo[2,3-b]quinoline 9 by chlorination with POCl3 in
high yield. Substitution of the chloro group with primary amines
converted to 3a in 71% yield under the standard conditions
(Scheme 4, eq 2). These results show that 6a is probably the
intermediate in this tandem [3 + 2] cycloaddition/C−N bond
formation reaction. When ortho-nitrobenzoylpyrrole 4a was
treated with the standard conditions, 3a was not detected
(Scheme 4, eq 3). However, 3a was obtained in 10% yield when
4a was reduced with Fe/HCl (Scheme 4, eq 4). Furthermore,
when ortho-aminobenzoylpyrrole 7a was treated with the
standard conditions, 3a was not detected either, in contrast, 3a
was obtained in 74% yield from the reaction of ortho-
nitrosobenzoylpyrrole 8a under the standard conditions
(Scheme 4, eq 5). These results suggested that 8a was most
likely an intermediate on the way to 3a.
Transformation of 6a to 8a is a redox-neutral process, in which
the dihydropyrroline moiety of 6a acts as the internal reductant
to convert the nitro group into reactive nitroso functionality. To
C
DOI: 10.1021/acs.orglett.7b02558
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Conrad, J.; Klaiber, I.; Mika, S.; Beifuss, U. Angew. Chem., Int. Ed. 2007,
46, 3353. (h) Song, J. J.; Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Yee, N.
K.; Senanayake, C. H. Arkivoc 2010, i, 390.
Scheme 6. Potential Synthetic Applications of 3
(3) For a review, see: Cadogan, J. I. G. Synthesis 1969, 1969, 11.
(4) Davies, I. W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6, 743.
(5) Gao, H.; Xu, Q.-L.; Yousufuddin, M.; Ess, D. H.; Kurti, L. Angew.
̈
Chem., Int. Ed. 2014, 53, 2701.
(6) Jana, N.; Zhou, F.; Driver, T. G. J. Am. Chem. Soc. 2015, 137, 6738.
(7) Tong, S.; Xu, Z.; Mamboury, M.; Wang, Q.; Zhu, J. Angew. Chem.,
Int. Ed. 2015, 54, 11809.
furnished the 4-aminopyrrolo[2,3-b]quinoline 10a,b in good to
excellent yields.
(8) (a) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59,
3375. (b) Soderberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62, 5838.
̈
In summary, a tandem [3 + 2] cycloaddition/reductive
cyclization of nitrochalcones with activated methylene iso-
cyanides was developed for the efficient and practical synthesis of
pyrrolo[2,3-b]quinolones. Control experiments showed that the
in situ formed dihydropyrroline acting as the internal reductant
converts the nitro into a reactive nitroso group, which rendered
the subsequent C−N bond formation. Transition-metal-free,
simple experimental procedure, ready accessibility of the starting
materials, and good to high yields characterize the present
transformation. The investigation of tandem Cadogen-type
cyclization of nitroarenes is ongoing.
(c) Smitrovich, J. H.; Davies, I. W. Org. Lett. 2004, 6, 533. (d) Davies, I.
W.; Smitrovich, J. H.; Sidler, R.; Qu, C.; Gresham, V.; Bazaral, C.
Tetrahedron 2005, 61, 6425. (e) Hsieh, T. H. H.; Dong, V. M.
Tetrahedron 2009, 65, 3062.
(9) Lee and co-workers recently described an elegant external
reductant-free tandem annulation of 2-nitrocinnamaldehyde or 2-
nitrochalcone with ketones for the synthesis of carbazoles: Poudel, T.
N.; Lee, Y. R. Chem. Sci. 2015, 6, 7028.
(10) (a) Straight, A. F.; Cheung, A.; Limouze, J.; Chen, I.; Westwood,
N. J.; Sellers, J. R.; Mitchison, T. J. Science 2003, 299, 1743.
(b) Allingham, J. S.; Smith, R.; Rayment, I. Nat. Struct. Mol. Biol.
2005, 12, 378.
(11) (a) Lee, B. D.; French, K. J.; Zhuang, Y.; Smith, C. D. Oncol. Res.
2003, 14, 49. (b) Lee, B. D.; Li, Z.; French, K. J.; Zhuang, Y.; Xia, Z.;
Smith, C. D. J. Med. Chem. 2004, 47, 1413.
(12) Gakh, A. A.; Krasavin, M.; Karapetian, R.; Rufanov, K. A.;
Konstantinov, I.; Godovykh, E.; Soldatkina, O.; Sosnov, A. V. Anti-
cancer agents based on N-acyl-2,3-dihydro-lH-pyrrolo[2,3-b] quinoline
derivatives and a method of making. U.S. Patent Appl. 8,420,815 Bl,
2013.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02558.
■
S
Experimental procedures and characterization data for all
compounds (PDF)
X-ray data of 3a′ (CIF)
(13) Perkin, W. H., Jr; Robinson, R. J. Chem. Soc., Trans. 1913, 103,
1973.
(14) (a) Khan, M. A.; da Rocha, J. F. Heterocycles 1977, 6, 1229.
(b) Murugesan, M.; Soundararajan, N.; Ramasamy, K.; Shanmugam, P.
Synthesis 1979, 1979, 352. (c) Prakash, K. S.; Nagarajan, R. Tetrahedron
Lett. 2015, 56, 69. (d) Asthana, M.; Kumar, R.; Gupta, T.; Singh, R. M.
Tetrahedron Lett. 2015, 56, 907.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jianbiaoliu.thu@gmail.com.
*E-mail: xuxx677@sdnu.edu.cn.
(15) (a) Richter, R.; Ulrich, H. J. Org. Chem. 1973, 38, 2614. (b) Smith,
L.; Kiselyov, A. S. Tetrahedron Lett. 1999, 40, 5643.
(16) Saito, T.; Furukawa, N.; Otani, T. Org. Biomol. Chem. 2010, 8,
ORCID
Jian-Biao Liu: 0000-0002-2550-3355
De-Zhan Chen: 0000-0002-2192-4582
Xianxiu Xu: 0000-0001-7435-7449
Author Contributions
§Z.L. and Z.H. contributed equally.
Notes
1126.
(17) (a) Chen, K.; Tang, X.-Y.; Shi, M. Chem. Commun. 2016, 52, 1967.
(b) Yuan, Y.-C.; Yang, H.-B.; Tang, X.-Y.; Wei, Y.; Shi, M. Chem. - Eur. J.
2016, 22, 5146. (c) Fan, X.; Yu, L.-Z.; Wei, Y.; Shi, M. Org. Lett. 2017,
19, 4476. (d) Yu, L.-Z.; Chen, K.; Zhu, Z.-Z.; Shi, M. Chem. Commun.
2017, 53, 5935.
(18) Liu, C.-G.; Gu, Z.-Y.; Bai, H.-W.; Wang, S.-Y.; Ji, S.-J. Org. Chem.
Front. 2016, 3, 1299.
The authors declare no competing financial interest.
(19) Jones, A. M.; Patterson, S.; Lorion, M. M.; Slawin, A. M. Z.;
Westwood, N. J. Org. Biomol. Chem. 2016, 14, 8998.
ACKNOWLEDGMENTS
■
Financial support provided by the NSFC (21672034), the
Natural Sciences Foundation of Jilin Province (20160101330JC)
and Shandong Normal University (108-100801) is gratefully
acknowledged.
(20) (a) Hu, Z.; Yuan, H.; Men, Y.; Liu, Q.; Zhang, J.; Xu, X. Angew.
Chem., Int. Ed. 2016, 55, 7077. (b) Xu, X.; Zhang, L.; Liu, X.; Pan, L.; Liu,
Q. Angew. Chem., Int. Ed. 2013, 52, 9271. (c) Li, Y.; Xu, X.; Tan, J.; Xia,
C.; Zhang, D.; Liu, Q. J. Am. Chem. Soc. 2011, 133, 1775. (d) Tan, J.; Xu,
X.; Zhang, L.; Li, Y.; Liu, Q. Angew. Chem., Int. Ed. 2009, 48, 2868.
(21) CCDC 1558765 (3a′) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(22) (a) Guo, C.; Xue, M. X.; Zhu, M. K.; Gong, L. Z. Angew. Chem., Int.
Ed. 2008, 47, 3414. (b) Grigg, R.; Lansdell, M. I.; Thornton-Pett, M.
Tetrahedron 1999, 55, 2025.
(23) Hattori, H.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed.
2017, 56, 6980.
REFERENCES
■
(1) (a) Ohno, N. The Nitro Group in Organic Synthesis; Wiley-
Interscience: Weinheim, 2003. (b) Gui, J.; Pan, C.-M.; Jin, Y.; Qin, T.;
Lo, J. C.; Lee, B. J.; Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; La Cruz,
T. E.; Schmidt, M. A.; Darvatkar, N.; Natarajan, S. R.; Baran, P. S. Science
2015, 348, 886.
(2) (a) Reissert, A. Ber. Dtsch. Chem. Ges. 1897, 30, 1030. (b) Clark, R.
D.; Repke, D. B. Heterocycles 1984, 22, 195. (c) Batcho, A. D.;
Leimgruber, W. Org. Synth. 1985, 63, 214. (d) Bartoli, G.; Palmieri, G.;
Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129. (e) Bartoli,
G.; Dalpozzo, R.; Nardi, M. Chem. Soc. Rev. 2014, 43, 4728. (f) Cadogan,
(24) (a) DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431.
(b) Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243.
J. I. G.; Cameron-Wood, M. Proc. Chem. Soc. 1962, 361. (g) Meriso̧ r, E.;
D
DOI: 10.1021/acs.orglett.7b02558
Org. Lett. XXXX, XXX, XXX−XXX