One-pot synthesis of pyrano[4,3-b]quinolinones from 2-alkynyl-3- formylquinolines via oxidative 6-endo-dig ring closure

Article abstract of DOI:10.1016/j.tetlet.2011.11.016

A new regioselective one-pot procedure to synthesize pyranoquinolinones from readily available 2-alkynyl 3-formylquinolines under mild NaClO ₂/H₂O₂ conditions in good yields has been explored. This reaction sequence, invol

Full text of DOI:10.1016/j.tetlet.2011.11.016

Tetrahedron Letters 53 (2012) 235–238
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of pyrano[4,3-b]quinolinones from
2-alkynyl-3-formylquinolines via oxidative 6-endo-dig ring closure
⇑
Priyabrata Roy, Binay K. Ghorai
Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711 103, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new regioselective one-pot procedure to synthesize pyranoquinolinones from readily available 2-alkynyl
3-formylquinolines under mild NaClO2/H2O2 conditions in good yields has been explored. This reaction
sequence, involving oxidation followed by regioselective electrophilic 6-endo-dig cyclization is more
efficient over the traditional Pd(0)-mediated synthesis. When scavenger-free conditions were used, unu-
sual chlorinated furoquinolinone derivatives were obtained.
Received 2 September 2011
Revised 30 October 2011
Accepted 4 November 2011
Available online 10 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyranoquinolinone
6-Endo-dig regioselective
NaClO2-oxidation
Chlorinated furoquinolinone
Syntheses of various heterocycles have been a research objec-
tive for over a century, and a variety of well-established methods
are available in the literature. Development of new approaches
for their syntheses, employing efficient and economical routes, is
currently a popular research area.1 Substituted heterocycles are
structural components of a vast number of biologically active nat-
ural and non-natural compounds. Pyranoquinolinone derivatives
are of particular interest as they are known to be present in many
alkaloids and possess a wide range of pharmacological and biolog-
ical activities such as anticoagulant, coronary constricting, optical
brightening, antifungal, antihistamine, and antiallergic effects.2
Halogen-containing quinoline and their derivatives are of signifi-
cant interest as the halogen atom plays a pivotal role in the com-
that affords pyrano[4,3-b]quinolinones 3 through an intramolecu-
lar 6-endo-dig pathway (Scheme 1).8
A two-step approach to pyranoquinolinones has been examined
involving: (i) preparation of 2-alkynyl 3-formylquinolines 1 and 2-
alkynyl 3-formylquinoxaline 6 using the Sonogashira coupling
reaction (Scheme 2)5p and (ii) cyclization of 1/6 under mild NaClO2
oxidation conditions (Table 1).
Interesting observations emerge from the data in Table 1. It was
observed that the aldehyde derivative 1a was smoothly oxidized
using sodium chlorite to yield the 3-substituted pyranoquinoli-
none 3a in a 65% yield and no isomeric compound 3a0 was isolated
(Table 1, entry 1). The reaction was performed in MeOH/H2O and
since the chlorite ion is unstable at low pH, the solution was buf-
pound’s bioactivity, and such compounds provide
a
further
fered with NaH2PO4 at pH 4.3. Hypochlorite ion (ClOꢀ) is generated
2
avenue for structure elaboration.3 Reported methods for the syn-
thesis of pyranoquinolinones is limited, multistep, and suffer from
poor availability of starting materials.4
in this reaction and it must be removed in order to avoid side reac-
tions. Thirty five percent H2O2 was used in this regard. The effect of
various organic solvents was checked with 1a as substrate. The
yield was increased using less hydrophilic alcohols (entries 1–4).
No change in yield was observed when the reaction mixture was
allowed to stir for a longer time (entry 5). Increase of reaction tem-
perature (80 °C) did not improve the product yield (entry 6). Tolu-
ene greatly reduced the reaction rate, required 24 h for complete
conversion of the substrate (entry 7).
Intramolecular cyclization through alkyne activation has
emerged as an effective protocol in the preparation of a variety
of heterocycles.5 Recently, a one-pot synthesis involving oxidation
followed by 5-exo-dig electrophilic cyclization of 2-alkynylbenzal-
dehydes for the synthesis of phthalides has been reported.6 How-
ever, oxidative cyclization of 2-alkynyl-3-formylquinolines has
not been explored so far. In this Letter, we report a one-pot highly
regioselective cyclization of 2-alkynyl-3-formylquinolines 1 under
environmentally friendly sodium chlorite oxidative conditions7
Having prepared pyranoquinolinone 3a9 successfully, we
decided to explore the scope and generality of this reaction in
the synthesis of other analogues varying the substituent at C-3.
Accordingly, a variety of 2-alkynyl 3-formylquinolines 1 were
reacted with sodium chlorite (Table 2) under the optimized condi-
tions (Table 1, entry 4). Various functional groups including alkyl,
hydroxyl, and phenyl present in alkynes 1 were well tolerated
⇑
Corresponding author. Tel.: +91 33 26684561; fax: +91 33 26682916.
E-mail address: bkghorai@yahoo.co.in (B.K. Ghorai).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.016

236
P. Roy, B. K. Ghorai / Tetrahedron Letters 53 (2012) 235–238
O
O
NaClO2-H2O2,
NaH2PO4
CHO
O
ONa
R
t-BuOH, rt
N
R
N
N
R
1
2
3
Scheme 1. Synthesis of pyrano[4,3-b]quinolinones.
Y
N
CHO
Y
N
CHO
I
(Ph3P)2PdCl2, CuI,
R
+
THF, Et3N, r.t.,
5
R
12-16 h
4
1a-e/ 6
Scheme 2. Sonogashira reaction of heteroaryl iodide with different alkynes. 1a–e: Y@CH; quinoline series, 6: Y@N; quinoxaline series.
Table 1
a
Effect of reaction conditions on oxidative cyclization of 1a with NaClO2–H2O2
NaClO2-H2O2,
NaH2PO4
O
O
CHO
Bu
O
O
solvent
N
1a
N
3a
Bu
N
3a'
Bu
Not observed
Entry
Solvent
T (°C)
t (h)
Yieldb (%)
1
2
3
4
5
6
7
MeOH–H2O
EtOH–H2O
25
25
25
25
25
80
25
4
4
4
4
12
4
24
65
69
71
79c
79
77
61
i-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
Toluene
a
Reaction conditions: 1a (1.0 equiv), NaClO2 (3.7 equiv), H2O2 (1.2 equiv), NaH2PO4 (5 equiv) in a solvent at the indicated temper-
ature and reaction time.
b
Isolated yields.
For a representative procedure see, ref. 9.
c
Table 2
Synthesis of pyrano[4,3-b]quinolinones via oxidation followed by electrophilic cyclizationa
NaClO2-H2O2,
O
O
O
Y
N
CHO
NaH2PO4
Y
O
O
O
t-BuOH, rt,
N
N
N
R
4 h
R
Ph
1/ 6
3/ 7
9
8
OH
Entry
Substrate
Y
R
Product
Yieldb (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
6
CH
CH
CH
CH
CH
N
n-Butyl
SiMe3
C(CH3)2OH
Ph
CH2OH
Ph
3a
3b
3c
3d
3e
7
79
64
68c
67d
73
70
a
b
c
Reaction conditions: 1/6 (1.0 equiv), NaClO2 (3.7 equiv), H2O2 (5.2 equiv), NaH2PO4 (5 equiv) in t-BuOH–H2O (2:1/ v:v) at rt for 4 h.
Isolated yield.
Corresponding isomeric 5-exo-dig cyclized product
8
isolated in 5% yield was tentatively identified by 1H NMR, IR, mass
spectroscopy.
d
Corresponding isomeric 5-exo-dig cyclized product 9 was isolated in 17% yield.
during the course of the reaction. Similar results were obtained
starting from quinoxaline derivative 6 (entry 6, Table 2).
The reason for the formation of the six-membered ring over
their five-member counterpart was not clear. However, a tentative
mechanism, on the basis of the obtained results is proposed
(Scheme 3). The cyclization process selectively proceeds via the
formation of more stable anionic intermediate 11, in which the
negative charge is adjacent to electron-deficient ortho position of

P. Roy, B. K. Ghorai / Tetrahedron Letters 53 (2012) 235–238
237
O
O
N
H
R
O
O
11
O-
O
N
H
10
N
R
R
3
O
O
N
H
R
12
Scheme 3. Proposed mechanism for regioselectivity.
Table 3
Synthesis of pyrano[4,3-b]quinolinones under scavenger free NaClO2 oxidation conditionsa
NaClO2
O
O
O
CHO
NaH2PO4
O
+
N
N
R
t-BuOH, rt
N
R
R
Cl
1a-c
3a-c
13a-c
Entry
Identifier 3, 13
R
Yieldb 3 (%)
Yieldb 13 (%)
1
2
3
a
b
c
n-Butyl
SiMe3
C(CH3)2OH
67
35
45
20
55
35
a
Reaction conditions: 1 (1.0 equiv), NaClO2 (3.7 equiv), NaH2PO4 (5 equiv) in t-BuOH–H2O (2:1/ v:v) at rt for 4 h.
Isolated yields.
b
O
10%Pd/C, PPh3
Y
N
Y
N
CO2H
Ph
Y
N
CO2H
I
O
+
Ph
Ph
CuI, Et3N, EtOH
80 °C, 16h
5b
14, Y=CH
15, Y=N
16
3d, Y=CH, 35%
7, Y=N, 21%
Scheme 4. Pd/C-mediated synthesis of pyranoquinolinone/quinoxalinone.
the quinoline ring. The presence of electron-donating aryl or alkyl
group makes the anionic intermediate 12 unstable. Subsequently,
6-endo-dig cyclization is favored over 5-exo-dig cyclization.
During our work on converting 2-alkynyl-3-formylquinolines 1
into their corresponding pyrano[4,3-b]quinolinones 3 under scav-
enger free very mild NaClO2 oxidation conditions, we observed
the formation of various amounts of chlorinated 3-substituted
furo[3,4-b]quinolinone derivatives 13 (Table 3).7,10
Finally, to further study the efficiency of this oxidative cycli-
zation under mild NaClO2/H2O2 oxidation conditions compared
to the traditional Pd(0)-mediated synthesis,11 Sonogashira-type
coupling of o-haloheteroarylcarboxylic acid followed by electro-
philic cyclization of the resulting alkyne (possessing a carboxyl-
ate in proximity to the triple bond) was briefly investigated
(Scheme 4). Mechanistically, the reaction proceeds via a C–C
bond forming reaction between the halide 14/15 and phenyl
acetylene in the presence of Pd(0) generated in situ. The result-
ing alkyne 16 thus formed undergoes 6-endo-dig ring closure in
an intramolecular fashion to give the desired six-membered
lactone rings 3d/7 in poor yield compared to the conversion of
1/6 to 3/7. The requisite halide 14/15 was prepared from 4 using
NaClO2 oxidation.
In conclusion, we have highlighted the potential of NaClO2/H2O2
as a cheap, non-toxic system for the facile oxidative cyclization of
2-alkynyl 3-formylquinolines under mild conditions to synthesize
pyranoquinolinones in good yields. Chlorinated 3-substituted
furo[3,4-b]quinolinone derivatives were also obtained under scav-
enger-free conditions. Moreover, cyclization under mild NaClO2/
H2O2 oxidation conditions is a convenient, alternative method to
traditional Pd(0)-mediated synthesis of pyranoquinolinone
derivatives.
Acknowledgments
Financial support from CSIR [No.01 (2215)/08-EMR-II], Govern-
ment of India is gratefully acknowledged. We thank IICB, Kolkata
for providing us NMR facility. The CSIR, New Delhi, is also thanked
for the award of Senior Research Fellowship to P.R.

238
P. Roy, B. K. Ghorai / Tetrahedron Letters 53 (2012) 235–238
T.; Larock, R. C. J. Org. Chem. 2006, 71, 62–69; (j) Yue, D.; Cá, N. D.; Larock, R. C.
Supplementary data
Org. Lett. 2004, 6, 1581–1584; (k) Huang, Q.; Larock, R. C. Tetrahedron Lett. 2002,
43, 3557–3560; (l) Chen, Y.; Cho, C.-H.; Larock, R. C. Org. Lett. 2009, 11, 173–
176; (m) Zhang, H.; Larock, R. C. Tetrahedron Lett. 2002, 43, 1359–1362; (n)
Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203–5205; (o) Zhang, X.; Campo, M.
A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763–766; (p) Verma, A. K.; Rustagia,
V.; Aggarwal, T.; Singh, A. P. J. Org. Chem. 2010, 75, 7691–7703.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.016.
References and notes
6. Li, J.; Chin, E.; Lui, A. S.; Chen, L. Tetrahedron Lett. 2010, 51, 5937–5939.
7. For a review see: Krapcho, A. P. Org. Prep. Proc. Int. 2006, 38, 177–216.
8. Intramolecular cyclizations of carboxylic acids to carbon-carbon triple bonds
promoted by acid goes through 6-endo-dig pathway, see: Uchiyama, M.;
Ozawa, H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T.
Org. Lett. 2006, 8, 5517–5520.
1. Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442.
2. (a) Anniyappan, M.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2003, 18,
3653–3657; (b) Ravindranath, N.; Ramesh, C.; Reddy, M. R.; Das, B. Chem. Lett.
2003, 3, 222–223; (c) Singer, L. H.; Kong, N. P. J. Am. Chem. Soc. 1960, 88, 5213–
5219.
3. (a) Newhouse, B. J.; Bordner, J.; Augeri, D. J.; Litts, C. S.; Kleinman, E. F. J. Org.
Chem. 1992, 57, 6991–6995; (b) Torii, E. F.; Xu, L. H.; Sadakane, M.; Okumoto, H.
Synlett 1992, 513–514; (c) Miyachi, N.; Yanagawa, Y.; Iwasaki, H.; Ohara, Y.;
Hiyama, T. Tetrahedron Lett. 1993, 34, 8267–8270; (d) Croisey-Delcey, M.;
Croisy, A.; Carrez, D.; Huel, C.; Chiaroni, A.; Ducrot, P.; Bisagni, E.; Jin, L.;
Leclercq, G. Bioorg. Med. Chem. 2000, 8, 2629–2641.
9. Representative procedure. 3-Butylpyrano[4,3-b]quinolin-1-one (3a): To a stirred
mixture of 2-hex-1-ynylquinoline-3-carbaldehyde (1a) (237 mg, 1.0 mmol) in
t-BuOH (10 mL) and 35% H2O2 (0.5 mL, 5.2 mmol) at 10 °C, a solution of NaClO2
(334 mg, 3.7 mmol) and NaH2PO4.2H2O (780 mg, 5 mmol) in water (5 mL) was
added dropwise over a period of 25 min. The resultant solution was allowed to
slowly warm to room temperature with stirring over 4 h. The solution was then
concentrated in vacuo to approximately half its volume. Water (20 mL) was
added to the mixture and extracted with EtOAc (3 ꢁ 10 mL). The combined
organic layers were washed with brine (10 mL) and dried over anhydrous
Na2SO4. The solvent was removed on rotary evaporator and the residue was
purified by column chromatography (silica gel, ethyl acetate/petroleum ether
1:4) to yield the pyranoquinolinone derivative 3a (200 mg, 79%) as a white
solid. Mp: 103–105 °C; IR (KBr, cmꢀ1): 1742 (C@O); 1H NMR (300 MHz, CDCl3):
d 9.11 (s, 1H), 8.09 (d, 1H, J = 8.7 Hz), 7.97 (d, 1H, J = 8.1 Hz), 7.88 (t, 1H,
J = 7.5 Hz), 7.59 (t, 1H, J = 7.5 Hz), 6.62 (s, 1H), 2.62 (t, 2H, J = 7.5 Hz), 1.75
(pentet, 2H, J = 7.5 Hz), 1.46 (sextet, 2H, J = 7.5 Hz), 0.97 (t, 3H, J = 7.5 Hz); 13C
NMR (75 MHz, CDCl3): d 162.1, 161.8, 152.1, 150.9, 139.9, 132.9, 129.1, 128.4,
126.3 (2C), 114.7, 104.7, 33.1, 28.2, 21.7, 13.4; MS: m/e (relative intensity): 255
(MH++1, 15), 254 (MH+, 100); Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N,
5.53%. Found: C, 75.81; H, 5.87; N, 5.59.
4. (a) Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon Press: New York, 1996; pp 167–243. Vol. 5; (b) Sekar, M.;
9
Prasad, K. J. R. J. Nat. Prod. 1998, 61, 294–296; (c) Marco-Contelles, J.; Leon, R.;
9
Lopez, M. G.; García, A. G.; Villarroya, M. Eur. J. Med. Chem. 2006, 41, 1464–
1469; (d) Butenschon, I.; Moller, K.; Hansel, W. J. J. Med. Chem. 2001, 44, 1249–
1256; (e) Kalita, K. P.; Baruah, B.; Bhuyan, P. J. Tetrahedron Lett. 2006, 47, 7779–
7782.
5. For recent examples of cycloisomerization of alkynyl substrates, see: (a) Hellal,
M.; Cuny, G. D. Tetrahedron Lett. 2011, 52, 5508–5511; (b) Praveen, C.;
Iyyappan, C.; Perumal, P. T. Tetrahedron Lett. 2010, 51, 4767–4771; (c) Jean, M.;
Renault, J.; Weghe, P. V. D.; Asao, N. Tetrahedron Lett. 2010, 51, 378–381; (d)
Hellal, M.; Bourguignon, J.-J.; Bihel, F. J.-J. Tetrahedron Lett. 2008, 49, 62–65; (e)
Layek, M.; Rao, A. V. D.; Gajare, V.; Kalita, D.; Barange, D. K.; Islam, A.;
Mukkanti, K.; Pal, M. Tetrahedron Lett. 2009, 50, 4878–4881; (f) Layek, M.;
Gajare, V.; Kalita, D.; Islam, A.; Mukkant, K.; Pal, M. Tetrahedron Lett. 2009, 50,
3867–3871; (g) Gorja, D. R.; Batchu, V. R.; Ettam, A.; Pal, M. Beilstein J. Org.
Chem. 2009, 5. No. 64. doi:10.3762/bjoc.5.64; (h) Verma, A. K.; Aggarwal, T.;
Rustagia, V.; Larock, R. C. Chem. Commun. 2010, 46, 4064–4066; (i) Yue, D.; Yao,
10. For chlorination of organic compounds using NaClO2, see: (a) Lista, L.; Manini,
P.; Napolitano, A.; Pezzella, A.; d’Ischia, M. Steroids 2006, 71, 670–673; (b)
Yakabea, S.; Hiranoa, M.; Morimotoa, T. Synth. Commun. 1998, 28, 1871–1878.
11. For Pd(0)-mediated regioselective 6-endo-dig cyclization, see: Subramanian, S.;
Batchu, V. R.; Barange, D.; Pal, M. J. Org. Chem. 2005, 70, 4778–4783.