Ligand-free palladium-catalyzed intramolecular arylation of chromones: An expedient synthesis of 1-benzopyrano[3,2-c]quinolines

Article abstract of DOI:10.1016/j.tetlet.2013.02.057

Synthesis of hitherto unreported 1-benzopyrano[3,2-c]quinolin-12-ones has been accomplished by a ligand-free Pd-catalyzed intramolecular C-H arylation protocol at the C-2 position of a chromone moiety in an Ugi product.

Full text of DOI:10.1016/j.tetlet.2013.02.057

Tetrahedron Letters 54 (2013) 2221–2225
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ligand-free palladium-catalyzed intramolecular arylation of chromones:
an expedient synthesis of 1-benzopyrano[3,2-c]quinolines
Jaydip Ghosh a, Pritam Biswas a, Sourav Maiti a, Tapas Sarkar b, Michael G. B. Drew c,
Chandrakanta Bandyopadhyay a,
⇑
a Department of Chemistry, R.K. Mission Vivekananda Centenary College, Rahara, Kolkata 700 118, West Bengal, India
b Chemistry Division, CSIR-Indian Institute of Chemical Biology, Jadavpur 700 032, West Bengal, India
c Department of Chemistry, The University of Reading, PO Box 224, Whiteknights, Reading RG6 6AD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of hitherto unreported 1-benzopyrano[3,2-c]quinolin-12-ones has been accomplished by a
ligand-free Pd-catalyzed intramolecular C–H arylation protocol at the C-2 position of a chromone moiety
in an Ugi product.
Received 2 January 2013
Revised 16 February 2013
Accepted 19 February 2013
Available online 26 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Arylation
Palladium-catalyst
Chromone
Ugi reaction
Chroman-3-carbaldehyde
1-Benzopyran
Chromones, flavones, isoflavones, and the heterocycles derived
from them are widely distributed in nature1 and possess a broad
range of activities of pharmaceutical importance.2 Arylation of
chromone at the C-2 or C-3 position generates flavones or
isoflavones, respectively. Arylation at the C-3 position has been
accomplished using 3-halochromone and arylboronic acid or tri-
arylbismuth in the presence of a palladium catalyst.3 Alkenylation
or alkynylation has also been accomplished using 3-halochro-
mone.4 Recently 3-alkynylation has been achieved by C–H activa-
tion at the 3-position of the chromone ring.5 Although C-3
arylation or olefination has been well-studied, direct C-2 arylation
on the chromone ring is scarce in the literature.6 Pd-catalyzed 1,4-
addition of arylboronic acid has been achieved using Fe(OTf)3 as
Lewis acid. The addition product on subsequent oxidation by
DDQ and KNO2 led to the formation of 2-arylchromone.7
1-Benzopyranoquinolines possess versatile biological activities
depending on the nature of fusion between the chromone and
quinoline rings. 1-Benzopyrano[4,3-b]quinolines are antispas-
modic and antihistaminic,8 whereas 1-benzopyrano[3,4-f]quino-
line acts as a nonsteriodal human progesterone receptor (HPR)
agonist.9 Recently, a naphthopyrano[4,3-b]quinoline-based fluo-
rescent off–on probe has been established for bioimaging.10 Earlier
we have reported the synthesis of 1-benzopyrano[4,3-b]quino-
lines11 and 1-benzopyrano[2,3-b]quinolines12 and herein we re-
port a ligand-free Pd-catalyzed intramolecular C–H arylation at
the C-2 position of the chromone moiety for the synthesis of hith-
erto unreported 1-benzopyrano[3,2-c]quinolines of biological
interest.
The Ugi product (5)13 derived from a 3-formylchromone (1), a
2-haloaniline (2), an isocyanide (3), and a carboxylic acid (4) pro-
vides a privileged structure for the synthesis of polycyclic hetero-
cycles (Scheme 1). A close look at the
a-arylaminoamides (5)
bearing a chromone and -halophenyl moiety reveals that there
a
are two possible modes for Pd-catalyzed cyclization: (i) C–N cou-
pling between the o-halophenyl and the amide NH group14 to form
the ketopiperazine 7 or (ii) C–C coupling between the C-2 or C-3
position of the chromone ring and the o-halophenyl group. Consid-
ering all these possibilities a mixture of 5b (0.2 mmol), Pd(OAc)2
(10 mol %), K2CO3 (0.4 mmol), and Ph3P (20 mol %) was heated in
DMF (10 mL) at 100–110 °C under argon atmosphere for 2 h
(Scheme 1). After the usual work-up the reaction mixture pro-
duced 6b in 24% yield (Scheme 1) (Table 1, entry 1).
Enlightened by this selective cyclization, attempts were made
to improve the yield of 6. The intramolecular Heck reaction was
standardized using 5b as the substrate and varying the source of
palladium, base, and solvent. The effect of the ligand was also
tested (Table 1). PdCl2 was found to be a more effective catalyst
⇑
Corresponding author.
E-mail address: kantachandra@rediffmail.com (C. Bandyopadhyay).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.057

2222
J. Ghosh et al. / Tetrahedron Letters 54 (2013) 2221–2225
Z
NH2
O
O
X
+
O
O
R3COOH (4)
X
2
+
R NC
R3
RT, 30 min
N
R1
R1
CHO
3
Z
2
1
O
O
5
NH
R2
2a: X = Br, Z = H
2b: X = I, Z = H
3a: R2 = Cyclohexyl
3b: R2 = t-Butyl
2c: X = Cl, Z = H
2d: X = Br, Z = CH3
Pd-Catalyst, Base, Solvent,
Argon Atmosphere, Noligand
R3
O
O
X
Z
N
R1
O
7
O
Z
N
R2
O
R3
N
O
R1
O
O
HN
R2
6
Scheme 1. Synthesis of 6.
Table 1
Pd(II)
Optimization of reaction conditions for the synthesis of 6b from 5b
5
Entry
Catalyst
Base
Solvent
Ligand
Additives
6b (%)
AcOH + KX
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
10% Pd(OAc)2
10% PdCl2
10% Pd(OAc)2
10% PdCl2
10% PdCl2
10% PdCl2
10% PdCl2
10% PdCl2
10% PdCl2
10% PdCl2
10% PdCl2
10% PdCl2
10% PdCl2
15% PdCl2
5% PdCl2
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
Dioxan
PhCH3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
dba
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
24
30
10
15
5
14
40
20
15
15
—
Pd(0)
Oxidative addition of Pd(0)
Z
KOAc
NaOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
O
H-Pd-X
PdX
R3
N
R1
O
O
8
HN
O
Phen
7
6
Z
54
52
25
35
30
26
R2
Insertion reaction
H
O
10% PdCl2
10% PdCl2
10% Pd(OAc)2
TBAB
PA
—
R3
N
R1
PdX
HN
O
‘Phen’ stands for 9,10-phenanthroline; ‘dba’ for dibenzylideneacetone; ‘TBAB’ for
(nBu4N)Br; ‘PA’ for Pivalic acid.
O
O
9
R2
Scheme 2. Mechanism for the formation of 6 from 5.
than Pd(OAc)2 (entries 1–4). Different bases such as K2CO3, Cs2CO3,
Et3N, NaOAc, and KOAc were tested and KOAc was found to be the
base of choice (entries 1–7). Among the solvents DMF, CH3CN,
dioxane, and toluene, DMF was the best solvent (entries 7–10).
Use of ligands showed a detrimental effect. A much better yield
was obtained without adding any ligand (entries 7 and 11–13).
Regarding catalyst loading, 10% PdCl2 was found to be the optimal
(entries 13–15). Additives like TBAB or pivalic acid lowered the
yield (entries 16 and 17). Use of Pd(OAc)2 in place of PdCl2 in the
absence of ligand lowered the yield of 6 markedly (entries 13
and 18). The detrimental effects of ligands, additive (pivalic acid),
or of using Pd(OAc)2 instead of PdCl2 may be due to steric crowding
across the palladium center in the intermediate 8 (Scheme 2).
Bulky groups attached to palladium hinder the achievement of
the required conformation for cyclization as shown in 8.
served that the yield of 5 was much better (94–99%) (entries 1, 2, 6,
and 9) using 2a as the amine component compared to that when
2b or 2c was used (entries 3–5), whereas changing the acid compo-
nent from acetic acid to propanoic acid, was found to decrease the
Table 2
Synthesis of Ugi product 5
Entry
R1 in 1
2
3
R3 in 4
Product
mp (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
H
2a
2a
2b
2c
2b
2a
2d
2d
2a
2a
3a
3a
3a
3a
3b
3b
3a
3b
3b
3a
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
CH3
C2H5
5a
5b
5c
5d
5e
5f
5g
5h
5i
188–190
232–234
212–214
224–226
212–214
206–208
176–178
218–220
162–164
224–226
98
94
80
79
75
94
90
82
99
71
CH3
CH3
CH3
H
After finding the optimized reaction conditions15 (entry 13), the
scope of the reaction was explored using various substrates. The
versatility of substrate 5 arises from the four components utilized
in the Ugi reaction. Different o-haloanilines (2, Z = H, X = Cl, Br and
I) were used for the formation of 5, which was then employed for
the synthesis of 6. During the synthesis of 5a–j (Table 2), it was ob-
H
CH3
CH3
CH3
CH3
10
5j

J. Ghosh et al. / Tetrahedron Letters 54 (2013) 2221–2225
2223
Table 3
Synthesis of 1-benzopyrano[3,2-c]quinolines 6 from 5
Entry
Substrate
Product
mp (°C)
Yield (%)
O
O
Br
CH3
N
N
CH3
1
242–243
50
O
O
O
HN
O
O
O
HN
6a
Cyclohexyl
Cyclohexyl
5a
O
O
Br
CH3
N
N
CH3
2
3
4
182–184
182–184
182–184
54
59
25
H3C
H3C
H3C
H3C
O
O
O
O
HN
Cyclohexyl
O
HN
O
5b
6b
Cyclohexyl
O
I
N
CH3
6b
O
O
O
HN
Cyclohexyl
5c
O
O
Cl
CH3
N
6b
O
O
HN
5d
Cyclohexyl
O
O
I
CH3
N
N
CH3
5
248–250
70
O
O
O
O
O
HN
O
HN
O
6e
5e
O
Br
N
CH3
6
6e
248–250
58
O
O
HN
5f
CH3
N
CH3
N
O
O
Br
7
216–218
59
CH3
CH3
H3C
H3C
O
O
Cyclohexyl
O
O
Cyclohexyl
CH3
O
O
HN
HN
6g
5g
CH3
O
O
O
Br
C2H5
8
220–222
66
N
N
C2H5
H3C
H3C
O
O
O
O
O
HN
HN
5h
6h
(continued on next page)

2224
J. Ghosh et al. / Tetrahedron Letters 54 (2013) 2221–2225
Table 3 (continued)
Entry
Substrate
Product
mp (°C)
Yield (%)
O
O
O
Br
N
N
CH3
CH3
9
246–248
56
H3C
H3C
O
O
O
O
O
O
HN
HN
HN
HN
5i
5j
6i
O
O
O
O
Br
C2H5
N
N
C2H5
10
168–170
48
H3C
H3C
O
O
O
Cyclohexyl
6j
Cyclohexyl
in 6]. This may be explained by considering the extended conjuga-
tion of the ring nitrogen with the carbonyl functionality of the
chromone ring in 6. Finally the structure of 6i was confirmed by
single crystal X-ray diffraction analysis (Fig 1).18
Formation of 6 from 5 may be rationalized by considering the
oxidative addition of Pd(0) to the aryl halide moiety of 5 to form
8, which undergoes intramolecular palladation at the C2–C3 dou-
ble bond of the chromone moiety (?9). Compound 6 is produced
from 9 by the elimination of HPdX, which regenerates Pd(0) by
the action of base (Scheme 2).
In conclusion, we have achieved the synthesis of hitherto unre-
ported 1-benzopyrano[3,2-c]quinolin-12-ones by an intramolecu-
lar C–H arylation at the C-2 position of the chromone moiety in
the Ugi product derived from 3-formylchromone (1), o-haloani-
lines (2), isocyanides (3), and carboxylic acids (4).
Acknowledgments
We gratefully acknowledge CSIR, New Delhi [Project no.
02(0029)/11/EMR-II] for financial assistance; IICB, Jadavpur for
spectral analysis and finally the college authority for providing re-
search facilities. J.G. thanks CSIR for Junior Research Fellowship.
Figure 1. ORTEP diagram of 6i.
yield of 5 (entries 7–10) and when pivalic acid (4, R3 = CMe3) was
used as the acid component, 5 (R3 = CMe3) could not be isolated.
Transformation of 5a–j to the corresponding compounds 6a–j
was successfully accomplished. It was observed that the arylation
reactions using iodo-compounds gave better yields than those
using the corresponding bromo or chloro compounds (Table 3, en-
tries 2–4). Ugi products (5) having the N-tert-butylamide group
produced 6 in slightly better yields than those with the N-cyclo-
hexylamide group (entries 1, 6, 2, and 9). It has been reported ear-
lier that in a Pd-catalyzed isocyanide-insertion reaction tert-butyl
isocyanide acted more efficiently than cyclohexyl isocyanide.16
Use of 5e having both N-tert-butylamide and iodoaryl moieties
yielded 6e in 70% yield (entry 5). The small effect of an extra
methyl group was reflected in the yields of 6g (entries 2 and 7)
and 6j (entries 2 and 10).
References and notes
1. (a) Harborane, J. B.; Mabry, T. J.; Mabry, H. The Flavonoids; Academic Press: New
York, 1975; (b) Pietta, P. G. J. Nat. Prod. 2000, 63, 1035–1042.
2. (a) Valenti, P.; Bisi, A.; Rampa, A.; Belluti, F.; Gobbi, S.; Zampiron, A.; Carrara, M.
Bioorg. Med. Chem. 2000, 8, 239–246; (b) Larget, R.; Lockhart, B.; Renard, P.;
Largeron, M. Bioorg. Med. Chem. Lett. 2000, 10, 835–838; (c) Boumendjel, A.;
Bois, F.; Beney, C.; Mariotte, A.-M.; Conseil, G.; Pietro, A. D. Bioorg. Med. Chem.
Lett. 2001, 11, 75–77; (d) Yasuzawa, T.; Saitoh, Y.; Sano, H. J. Antibiot. 1990, 43,
485–491.
3. (a) Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc. Jpn. 1988, 61, 3008–
3010; (b) Yokoe, I.; Sugita, Y.; Shirataki, Y. Chem. Pharm. Bull. 1989, 37, 529–
530; (c) Dawood, K. M. Tetrahedron 2007, 63, 9642–9651; (d) Rao, M. L. N.;
Venkatesh, V.; Jadhav, D. N. Synlett 2009, 2597–2600.
4. (a) Davies, S. G.; Mobbs, B. E.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1987,
2597–2604; (b) Larock, R. C.; Tian, Q. J. Org. Chem. 1998, 63, 2002–2009; (c)
Patonay, T.; Vasas, A.; Kiss-Szikszai, A.; Silva, A. M. S.; Cavaleiro, J. A. S. Aust. J.
Chem. 2010, 63, 1582–1593.
5. Kim, D.; Hong, S. Org. Lett. 2011, 13, 4466–4469.
The structure of 6 was determined on the basis of 1H, 13C NMR,
IR, and mass spectral analyses.17 In the 1H NMR spectrum of 6, the
disappearance of the singlet peak for H-2 of the chromone moiety
in 5 and the presence of a broad doublet signal for the cyclohexyl
NH or the broad singlet of the tbutyl NH rule out the possibility of
the formation of 7. One observation in support of structure 6
(R3 = CH3) is that after cyclization the CH3 protons of the NCOCH3
group are highly deshielded [ꢀd 1.86 in 5 (R3 = CH3) to ꢀd 2.36
6. (a) Kim, K. H.; Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2012, 53, 2761–
2764; (b) Min, M.; Choe, H.; Hong, S. Asian J. Org. Chem. 2012, 1, 47–50.
7. Kim, D.; Ham, K.; Hong, S. Org. Biomol. Chem. 2012, 10, 7305–7312.
8. Mohanty, N.; Rath, P. C.; Rout, M. K. J. Indian Chem. Soc. 1967, 44, 1001–1004.
9. Zhi, L.; Tegley, C. M.; Kallel, E. A.; Marschke, K. B.; Mais, D. E.; Gottardis, M. M.;
Jones, T. K. J. Med. Chem. 1998, 41, 291–302.
10. Kand, D.; Kalle, A. M.; Varma, S. J.; Talukdar, P. Chem. Commun. 2012, 48, 2722–
2724.
11. Bandyopadhyay, C.; Sur, K. R.; Patra, R.; Sen, A. Tetrahedron 2000, 56, 3583–
3587.

J. Ghosh et al. / Tetrahedron Letters 54 (2013) 2221–2225
2225
12. Bandyopadhyay, C.; Sur, K. R.; Patra, R.; Banerjee, S. J. Chem. Res. (S) 2003, 459–
460. J. Chem. Res. (M) 2003, 847–856.
14. Kalinski, C.; Umkehrer, M.; Ross, G.; Kolb, J.; Burdack, C.; Hiller, W. Tetrahedron
Lett. 2006, 47, 3423–3426.
13. General synthesis of 5:
A
mixture of chromone-3-carboxaldehyde (1,
15. General Procedure for the synthesis of 2-acyl-1-N-substitutedcarbamoyl-1,2-
0.5 mmol), o-haloaniline (2, 0.5 mmol) and isocyanide (3, 0.6 mmol) in
acetic acid (5 mL) was stirred at room temperature for 30 min. The reaction
mixture was poured into ice-water (50 g) to get a faint yellow solid, which
was filtered, washed with water, dried in air and crystallized from toluene–
light petroleum to produce a white crystalline solid 5. Although compound
5 developed a single spot in TLC, its NMR spectrum showed a mixture of
diastereomers. Earlier reports19 also mentioned the presence of a mixture
of diastereomers in the Ugi product when o-substituted anilines were used
as the amine component.
dihydro-12H-1-benzopyrano[3,2-c]quinolin-12-one (6):
A
mixture of
5
(0.2 mmol), PdCl2 (10 mol %) and KOAc (0.4 mmol) was heated in DMF
(10 mL) at 100–110 °C for 2 h. The resultant reaction mixture was cooled and
poured into ice-water (300 g) with stirring. Saturated brine solution (20 mL)
was added and stirred vigourously for 1 h when a grey solid separated out. The
separated solid was filtered and dissolved in CHCl3. The CHCl3 solution was
washed with water, dried over Na2SO4 and chromatographed over silica gel to
yield 6 when eluted with 40% ethyl acetate in light petroleum.
16. Wang, Y.; Wang, H.; Peng, J.; Zhu, Q. Org. Lett. 2011, 13, 4604–4607.
17. Characterisation data of 6i. White crystalline compound, mp 246–248 °C; yield
Characterisation data of 5i (mixture of diastereomers D1:D2::4:1). White
crystalline compound, mp 162–164 °C; yield 99%; IR (KBr): 3310, 2932,
56%; IR (KBr): 3305, 2914, 1687, 1673, 1635, 1603 cmÀ1 1H NMR (CDCl3) d
;
2852, 1655, 1642, 1542 cmÀ1
;
1H NMR (CDCl3) d 8.53 (1H, s, H-2, D2), 7.98
8.07 (1H, br s, H-11), 7.95 (1H, br d, J = 7.8 Hz, ArH), 7.58–7.49 (4H, m, ArH),
7.33–7.28 (1H, m, ArH), 7.03 (1H, br s, NH), 6.59 (1H, br s, H-1), 2.50
(3H, s, ArCH3), 2.36 (3H, s, COCH3), 1.24 (9H, s, CMe3); 13C NMR (CDCl3) d 175.9,
169.8, 167.3, 153.8, 139.6, 135.7(2C), 135.4 (2C), 132.2, 125.2 (2C), 125.1,
124.5, 124.3, 122.9, 117.8, 77.2, 51.2, 28.7 (3C), 22.8, 20.9; MS: m/z 427
(M+Na+), 405 (M+H+); Anal. Calcd for C24H24N2O4: C, 71.27; H, 5.98; N, 6.93.
Found: C, 71.15; H, 6.04; N, 6.87.
(1H, br s, H-5, D1+D2), 7.66 (1H, br d, J = 7.8 Hz, ArH, D1+D2), 7.62 (1H, s,
H-2, D1), 7.51 (1H, br d, J = 7.8 Hz, ArH, D1+D2), 7.45–7.40 (2H, m, ArH,
D1+D2), 7.29–7.17 (2H, m, ArH, D1+D2), 6.66 (1H, br s, exchangeable, NH,
D1), 6.64 (1 H, s, methine H, D1), 6.36 (1H, br s, exchangeable, NH, D2),
5.93 (1H, s, methine H, D2), 2.45 (3H, s, ArCH3, D2), 2.44 (3H, s, ArCH3, D1),
1.88 (3H, s, COCH3, D2), 1.86 (3H, s, COCH3, D1), 1.34 (9H, s, CMe3,
D1), 1.27 (9H, s, CMe3, D2); 13C NMR (CDCl3).
d
176.4 (D2), 176.0 (D1),
18. CCDC 917221 contains the supplementary crystallographic data for this Letter.
This data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).
19. (a) Bararjanian, M.; Hosseinzadeh, S.; Balalaie, S.; Bijanzadeh, H. R. Tetrahedron
2011, 67, 2644–2650; (b) Zhang, Y.; Wang, L.; Ding, M.-W. Tetrahedron 2011,
67, 3714–3723.
171.6 (D2), 171.3 (D1), 168.7 (D1), 165.8 (D2), 158.5 (D2), 157.9 (D1), 154.0
(D2), 153.8 (D1), 141.3 (D2), 138.7 (D2), 135.5 (D2), 135.3 (D1), 135.2 (D2),
134.9 (D1), 133.5 (D2), 133.4 (D1), 132.2 (D1), 131.5 (D2), 130.4 (D1), 129.9
(D2), 128.8 (D1), 128.7 (D2), 128.3 (D1), 126.7 (D1), 125.5 (D1), 125.3 (D2),
123.2 (D1), 119.2 (D2), 117.9 (D2), 117.7 (D1), 116.5 (D1), 57.9 (D2), 53.1
(D1), 51.4 (D1), 31.6 (D2), 28.6 (3C, D1+D2), 23.2 (D1), 23.1 (D2), 22.6 (D2),
20.9 (D1), 14.1 (D2); MS: m/z 509 (M+2+Na+), 507 (M+Na+), 487 (M+2+H+),
485 (M+H+); Anal. Calcd for C24H25BrN2O4: C, 59.39; H, 5.19; N, 5.77.
Found: C, 59.48; H, 5.09; N, 5.66.