Facile synthesis of chromeno[4,3-b]quinolin-6-ones from unexpected reactions of aryl isocyanides with 4-chloro-2-oxo-2H-chromene-3-carbaldehyde

Article abstract of DOI:10.1039/b600540c

The facile synthesis of chromenol[4,3-b]quinolin-6-ones from unexpected reactions of aryl isocyanide with 4-chloro-2-oxo-2H-chromene-3-carbaldehyde was investigated. The reaction was studied with 4-chloro-2-oxo-2H-chromene-3- carbaldehyde, which was selected as suitable substrate for reaction development. This reaction represents a highly efficient and practical route to chromeno[4,3-b]quinolin-6-ones. The efficiency of the process will make it potentially attractive for library construction.

Full text of DOI:10.1039/b600540c

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Facile synthesis of chromeno[4,3-b]quinolin-6-ones from unexpected reactions
of aryl isocyanides with 4-chloro-2-oxo-2H-chromene-3-carbaldehyde†
a
b
Jie Wu* and Xiaocong Wang
Received 13th January 2006, Accepted 7th February 2006
First published as an Advance Article on the web 27th February 2006
DOI: 10.1039/b600540c
An unexpected reaction of aryl isocyanides with 4-chloro-2-oxo-2H-chromene-3-carbaldehyde leads to
chromeno[4,3-b]quinolin-6-ones in good yields.
A goal of chemical genetics is to find small molecules that
modulate the individual functions of gene products with high po-
tency and high specificity. Natural products and natural product-
perchloric acid (Scheme 2), a white crystalline solid precipitated
from the reaction mixture when left to stand overnight at room
temperature (46% yield). After purification, however, the product
of this reaction was not the expected one (A or B). From
spectral characterization, it was found to be generated from 1
1
derived compounds provide many of the most striking examples,
particularly in terms of their specificity. It seems unlikely that
natural products alone will provide the hypothetical “complete”
set of small molecules that would allow the functions of all
proteins, as well as their individual domains, to be determined.
For chemistry to have its maximal effect on biology, efficient
methods for discovering natural product-like compounds are in
1
equiv. of 1a and 1 equiv. of 2a. Structure elucidation by H,
1
3
C NMR and mass spectroscopy, as well as comparison of the
1
standard H NMR spectra of the compound we made from
4-(4-methoxyphenyl)amino coumarin and POCl
5
3
, revealed this
precipitate to be 9-methoxychromeno[4,3-b]quinolin-6-one 3a.
Following an extensive investigation, we found that, without
any promoters, the reaction of 4-chloro-2-oxo-2H-chromene-
3-carbaldehyde 1a with 4-methoxyphenyl isocyanide 2a in
MeOH also proceeded smoothly to give 9-methoxychromeno[4,3-
b]quinolin-6-one 3a at room temperature in high yield (87%). It
is noteworthy that this reaction could be run under air without
loss of efficiency. In contrast to the formation of A or B, which
1
great demand in the field of chemical genetics. On the other
hand, multicomponent reactions (MCR) have emerged as a
powerful tool for delivering the molecular diversity needed in
the combinatorial approaches for the preparation of bioactive
2
compounds. In 1998, Bienaym e´ reported a highly efficient and
practical approach to fused 3-amino-imidazoles of high structural
3
diversity (Scheme 1). Its reliability, the ready availability of the
3
starting materials, and the versatility of the resulting products
make it a very important process for library generation.
results from multicomponent reaction of the Bienaym e´ product,
the formation of 3a is less easy to understand.
Although the mechanism is not clear, a possible mechanistic
rationalization for the reaction is given in Scheme 3. The initial
event is the formation of amine a from the isocyanide and
methanol. The amine a can react with compound 1 via 1,4-addition
and elimination resulting in the formation of 5. After cyclization by
attacking the aldehyde, intermediate 6 could be formed, which then
delivers the primary adduct 7. The latter then losses a molecule of
Scheme 1 MCRs reported by Bienaym e´ .
As part of a program aimed at developing new approaches
to construct natural product-like compound libraries, we are
interested in isocyanide involved multicomponent reactions de-
H O to give the final product 3. Evidence in support of this is now
being investigated.
2
Further screening revealed that methanol is the solvent of
choice. Other solvents, such as benzene and DMF, gave unsat-
isfactory results. To explore the scope of the reaction, a set of
substrates were subjected to the reaction (Table 1). Complete
conversion and moderate to good isolated yields were observed for
all substituted coumarin substrates employed. Electronic effects
both in the 4-chloro-2-oxo-2H-chromene-3-carbaldehyde 1 and in
the aryl isocyanides 2 showed similar influences on the reaction.
It is interesting that hydroxyl products 4a and 4b were obtained
when 4-diethylaminophenyl isocyanide 2c reacted with 1b and 1d
(entries 5 and 9). This is maybe due to the isomerization via [1,3]-H
shift from intermediate 7. The operation process is very simple:
after completion of reaction, the reaction mixture was filtered
and precipitate was collected. The solid obtained could be used
for spectra analysis directly without further purification in some
cases.
3
veloped by Bienaym e´ , based on 4-chloro-2-oxo-2H-chromene-
3
-carbaldehyde 1, due to our ongoing research in coumarin
4
chemistry.
The reaction was initially studied with 4-chloro-2-oxo-2H-
chromene-3-carbaldehyde 1a, which was selected as suitable
substrate for reaction development. During an attempt to prepare
compound A or B from 1a, 4-methoxyphenyl isocyanide 2a,
and 2-aminopyrimidine in MeOH, treated with 10 mol% of
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai,
2
00433, China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6510 2412;
Tel: +86 21 5566 4619
b
Department of Chemistry, College of Science, Tianjin University of Science
and Technology, Tianjin, 300222, China
1
13
†
Electronic Supplementary Information (ESI) available: H and C NMR
spectra of compound 3f. See DOI: 10.1039/b600540c
1
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Scheme 2 Initial studies.
Scheme 3 Proposed possible mechanism.
5
Conclusions
9-Methoxy-6H-chromeno[4,3-b]quinolin-6-one 3a . White
◦
1
solid. Mp: 237–238 C. H NMR (500 MHz, CDCl
3
) d (ppm):
.00 (s, 3H), 7.27 (s, 1H), 7.39–7.46 (m, 2H), 7.56–7.60 (m, 2H),
.14 (d, J = 9.5 Hz, 1H), 8.75 (d, J = 8.0 Hz, 1H), 9.10 (s, 1H).
C NMR (125 MHz, CDCl ) d (ppm): 56.0, 105.8, 116.2, 117.5,
20.1, 125.0, 125.1, 127.3, 128.8, 131.2, 132.0, 139.2, 147.7, 147.9,
In summary, the reaction described here represents a highly
efficient and practical route to chromeno[4,3-b]quinolin-6-ones.
It is likely that the efficiency and novelty of this method combined
with the operational simplicity of the present process will make it
potentially attractive for library construction. Mechanism studies
and investigations aimed at exploring the scope of the reaction are
currently under way.
4
8
13
3
1
1
+
52.6, 158.6, 161.8. MS [C17
H
11NO ], m/z (M + 1): calcd 278.08,
3
found 278.25. HRMS: Anal. Calcd. for C17
Found, 277.0742.
H
11NO , 277.0739.
3
5
9
-Chloro-6H-chromeno[4,3-b]quinolin-6-one 3b . White solid.
◦
1
Mp: 246–247 C. H NMR (500 MHz, CDCl
m, 2H), 7.58–7.63 (m, 1H), 7.84 (dd, J = 9.5, 2.5 Hz, 1H), 7.99
(d, J = 2.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.75 (dd, J = 8.0,
1.5 Hz, 1H), 9.13 (s, 1H). C NMR (125 MHz, CDCl ) d (ppm):
3
) d (ppm): 7.38–7.46
Experimental
(
General procedure for the reaction of 4-chloro-2-oxo-2H-
chromene-3-carbaldehyde 1 with aryl isocyanide 2
1
3
3
1
16.7, 117.7, 119.6, 125.3, 125.5, 127.9, 128.0, 131.4, 132.9, 133.6,
Aryl isocyanide (0.25 mmol) was added to a solution of 4-chloro-
134.5, 140.2, 149.7, 150.1, 152.9, 161.2. MS [C16
H
8
ClNO ], m/z
2
2
-oxo-2H-chromene-3-carbaldehyde 1 (0.25 mmol) in MeOH
+
(
M + 1): calcd 282.03, found 282.22. HRMS: Anal. Calcd. for
(
4 mL). The reaction mixture was stirred at room temperature
C
16
H
8
ClNO
2
, 281.0244. Found, 281.0237.
overnight. After the reaction was complete (monitored by TLC),
the mixture was filtered. The precipitate was collected and
purified by flash chromatography column (silica gel) to afford the
corresponding product 3 or 4. (The solid obtained could be used
for spectral analysis directly without further purification in some
cases.)
2-Fluoro-9-methoxy-6H-chromeno[4,3-b]quinolin-6-one 3c.
◦
1
White solid. Mp: 226–227 C. H NMR (500 MHz, CDCl ) d
(ppm): 4.00 (s, 3H), 7.22–7.28 (m, 2H), 7.34–7.38 (m, 1H), 7.58
3
(dd, J = 9.5, 2.5 Hz, 1H), 8.13 (d, J = 9.0 Hz, 1H), 8.40 (dd,
1
3
J = 8.0, 1.5 Hz, 1H), 9.08 (s, 1H). C NMR (125 MHz, CDCl
3
)
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a
Table 1 Reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehydes with aryl isocyanides
b
Entry
1
Aldehyde
Isocyanide
Product
Yield (%)
77
2
3
79
82
4
5
6
7
80
63
78
75
8
9
76
61
a
Reaction conditions: aryl isocyanide (0.25 mmol), 4-chloro-2-oxo-2H-chromene-3-carbaldehyde (0.25 mmol) in MeOH (4 mL) at room temperature,
b
overnight. Isolated yield.
d (ppm): 56.0, 105.8, 110.8, 111.0, 115.9, 119.2, 121.4, 127.6,
7.27–7.33 (m, 1H), 7.36–7.40 (m, 1H), 7.86 (dd, J = 9.0, 2.5 Hz,
1
29.1, 131.3, 139.2, 146.9, 147.8, 148.6, 158.9, 160.8, 161.5. MS
1H), 8.01 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 8.40 (dd,
+
13
[C
17
H
10FNO
3
], m/z (M + 1): calcd 296.07, found 296.24. HRMS:
J = 8.0, 1.5 Hz, 1H), 9.13 (s, 1H). C NMR (125 MHz, CDCl
3
) d
Anal. Calcd. for C17
H
10FNO
3
, 295.0645. Found, 295.0651.
(ppm): 111.1, 111.3, 116.5, 119.3, 120.0, 120.9, 128.0, 128.2, 131.4,
1
34.0, 134.8, 140.4, 149.2, 149.6, 158.9, 160.8. MS [C16
H
7
ClFNO ],
2
+
9
-Chloro-2-fluoro-6H-chromeno[4,3-b]quinolin-6-one 3d. White
m/z (M + 1): calcd 300.02, found 300.18. HRMS: Anal. Calcd.
◦
1
solid. Mp: 239–240 C. H NMR (500 MHz, CDCl
3
) d (ppm):
for C16
H
7
ClFNO
2
, 299.0149. Found, 299.0143.
1
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+
9
-Chloro-2-methyl-6H-chromeno[4,3-b]quinolin-6-one 3e. White
[C20
H
19FN
2
O
3
], m/z (M + 1): calcd 355.15, found 355.35. HRMS:
◦
1
solid. Mp: 252–253 C. H NMR (500 MHz, CDCl
3
) d (ppm): 2.51
Anal. Calcd. for C20 , 354.1380. Found, 354.1386.
H
19FN
2
O
3
(
s, 3H), 7.24–7.27 (m, 1H), 7.37–7.40 (m, 1H), 7.82 (dd, J = 9.0,
2
-Chloro-9-(diethylamino)-7-hydroxy-7H -chromeno[4,3-b]-
2
8
2
1
.5 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H),
.48 (s, 1H), 9.08 (s, 1H). C NMR (125 MHz, CDCl ) d (ppm):
1.2, 115.6, 116.7, 117.4, 119.0, 125.1, 127.9, 131.2, 133.5, 133.8,
◦
1
1
3
quinolin-6(12H)-one 4b. White solid. Mp: 231–232 C. H NMR
500 MHz, CDCl
) d (ppm): 1.32 (t, J = 7.0 Hz, 6H), 3.20–3.80 (m,
H), 6.94 (s, 1H), 7.26–7.30 (m, 2H), 7.40–7.49 (m, 3H), 7.60–7.90
3
(
5
3
34.4, 135.1, 140.2, 149.6, 150.1, 151.0, 161.3. MS [C17
H
10ClNO ],
2
−
1
+
(br, 1H), 10.24 (s, 1H). IR: 3400 cm . MS [C20
H
19ClN
2
3
O ], m/z
m/z (M + 1): calcd 296.05, found 296.26. HRMS: Anal. Calcd.
for C17
+
(
C
M + 1): calcd 371.12, found 371.31. HRMS: Anal. Calcd. for
H
10ClNO
2
, 295.0400. Found, 295.0396.
20
H
19ClN
2
3
O , 370.1084. Found, 370.1076.
2
-Chloro-9-methoxy-6H -chromeno[4,3-b]quinolin-6-one 3f.
◦
1
White solid. Mp: 247–248 C. H NMR (500 MHz, CDCl ) d
(
1
8
NMR (125 MHz, CDCl
1
1
3
Acknowledgements
ppm): 4.00 (s, 3H), 7.22 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 8.5 Hz,
H), 7.50 (dd, J = 9.0, 2.0 Hz, 1H), 7.60 (dd, J = 9.5, 3.0 Hz, 1H),
Financial support from the National Natural Science Foundation
of China (20502004), the Ministry of Education of China, the
Science and Technology Commission of Shanghai Municipality,
and Fudan University is gratefully acknowledged.
13
.13 (d, J = 9.0 Hz, 1H), 8.70 (d, J = 2.5 Hz, 1H), 9.08 (s, 1H). C
3
) d (ppm): 56.0, 105.8, 115.9, 119.0, 121.4,
24.7, 127.6, 129.0, 130.8, 131.3, 131.8, 139.2, 146.5, 147.8, 150.9,
+
58.9, 161.2. MS [C17
H
10ClNO
3
], m/z (M + 1): calcd 312.04,
found 312.20. HRMS: Anal. Calcd. for C17
Found, 311.0355.
H
10ClNO
3
, 311.0349.
References
6
1 (a) S. L. Schreiber, Science, 2000, 287, 1964; (b) T. J. Mitchison,
Chem. Biol., 1994, 1, 3; (c) S. L. Schreiber, Bioorg. Med. Chem., 1998,
2
,9-Dichloro-6H -chromeno[4,3-b]quinolin-6-one 3g . White
◦
1
solid. Mp: 272–273 C. H NMR (500 MHz, CDCl ) d (ppm):
3
6
, 1127; (d) http://www-schreiber.chem.harvard.edu; and http://iccb.
7
.48 (d, J = 9.0 Hz, 1H), 7.55 (dd, J = 9.0, 2.5 Hz, 1H), 7.88 (dd,
med.harvard.edu.
2
For recent reviews, see: (a) I. Ugi, A. Domling and B. Werner,
J. Heterocycl. Chem., 2000, 37, 647; (b) H. Bienaym e´ , C. Hulme, G.
Oddon and P. Schmitt, Chem.–Eur. J., 2000, 6, 3321; (c) I. Ugi and S.
Heck, Comb. Chem. High Throughput Screening, 2001, 4, 1; (d) J. Zhu,
Eur. J. Org. Chem., 2003, 1133.
J = 9.5, 3.0 Hz, 1H), 8.02 (s, 1H), 8.20 (d, J = 9.5 Hz, 1H), 8.72 (s,
+
1
H), 9.14 (s, 1H). MS [C16
found 316.17. HRMS: Anal. Calcd. for C16
Found, 314.9851.
H
7
Cl
2
NO
2
], m/z (M + 1): calcd 316.00,
H
7
Cl
2
NO
2
, 314.9854.
3
H. Bienaym e´ and K. Bouzid, Angew. Chem., Int. Ed., 1998, 37, 2234.
9
-(Diethylamino)-2-fluoro-7-hydroxy-7H -chromeno[4,3-b]-
4 (a) J. Wu, Y. Liao and Z. Yang, J. Org. Chem., 2001, 66, 3642; (b) J. Wu
and Z. Yang, J. Org. Chem., 2001, 66, 7875; (c) J. Wu, L. Wang, R. Fathi
and Z. Yang, Tetrahedron Lett., 2002, 43, 4395; (d) J. Wu, X. Sun and L.
Zhang, Chem. Lett., 2005, 34, 796.
◦
1
quinolin-6(12H)-one 4a. White solid. Mp: 212–213 C. H NMR
(
(
500 MHz, CDCl
3
) d (ppm): 1.32 (t, J = 7.0 Hz, 6H), 3.20–3.80
m, 5H), 6.55 (d, J = 9.0 Hz, 1H), 7.23–7.33 (m, 2H), 7.42 (d,
5
K. Tabakovic, I. Tabakovic, N. Ajdini and O. Leci, Synthesis, 1987, 308.
−
1
J = 9.0 Hz, 2H), 7.88 (s, 2H), 10.24 (s, 1H). IR: 3350 cm . MS
6 D. Heber, Arch. Pharm. (Weinheim, Ger.), 1987, 320, 595.
This journal is © The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1348–1351 | 1351