Michael addition of α-azido ketones on iminocoumarin derivatives: An efficient access to new functionalized azido chromenes

Article abstract of DOI:10.1016/j.tetlet.2011.05.101

A facile one-pot synthesis of functionalized azido chromenes was achieved by Michael addition of α-azido ketones on iminocoumarin derivatives obtained from salicylaldehydes and malononitrile. Synthesized azido chromenes were successfully transformed into

Full text of DOI:10.1016/j.tetlet.2011.05.101

Tetrahedron Letters 52 (2011) 4093–4096
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Michael addition of
a-azido ketones on iminocoumarin derivatives:
an efficient access to new functionalized azido chromenes
⇑
Thelagathoti Hari Babu, Jayabal Kamalraja, Doraiswamy Muralidharan, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile one-pot synthesis of functionalized azido chromenes was achieved by Michael addition of
-azido ketones on iminocoumarin derivatives obtained from salicylaldehydes and malononitrile. Syn-
thesized azido chromenes were successfully transformed into triazolyl chromenes by the [3+2] cycload-
Received 28 April 2011
Revised 18 May 2011
Accepted 22 May 2011
Available online 6 June 2011
a
dition reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Michael addition
a-Azido ketones
Azido chromenes
Triazolyl chromenes
a
-Azido ketones 1 are a synthetically valuable group of azides
developing new methods for the preparation of heterocyclic com-
pounds in one-pot, multicomponent reactions,7 we report an effi-
cient and simple synthesis of highly functionalized azido
chromene derivatives.
that exhibit double reactivity in C–C bond formation. The electro-
philic carbonyl function provides a target for the attack of carba-
nions leading to adducts such as compounds 2 and the chemistry
has been utilized by Langer et al.1 (Scheme 1). On the other hand,
2-Aminochromenes are employed as pigments,8 cosmetics,
agrochemicals,9 and are major constituents of many natural prod-
ucts. In continuation of our work involving three component reac-
tion of salicylaldehydes, malononitrile and various other
nucleophiles,10 we herein introduce phenacyl azides as new nucle-
ophiles in these three-component reactions.
a
-azido ketones possessing an a-hydrogen show enhanced C–H
acidity due to the anion stabilizing effect of the azido group. The
controlled generation of carbanions 3 followed by trapping with
various carbon electrophiles results in the formation of aldol-type
products 4 (Scheme 1).
a
-Azido ketones represent useful precursors of the synthetically
important 1,2-amino alcohols,2 2-azido alcohols,3
a-amino ke-
tones4 by the reduction process. The reaction of phenacyl azides
with trivalent phosphorous compounds (phosphines, phosphites,
etc.) leads to iminophosphoranes which upon hydrolysis provides
nucleophilic center
electrophilic center
O
N3
R 1
amines.5 Addition of carbanion of
a-azidoacetophenone to highly
R2
O
O
B :
stabilized Michael acceptors, such as methyl 2-arylidenecyanoace-
tate, 2-arylidene-2-cyanoacetophenone, or 2-arylidenemalononit-
rile was reported to give polysubstituted pyrroles via the attack
of the carbanion to electron-deficient C-b carbon of the Michael
acceptor followed by deprotonation-induced formation of an imino
anion by loss of nitrogen. Finally, an intramolecular nucleophilic
addition to the ester, ketone, or cyano function leads to pyrroles.6
1
R3
R5
O
-
N3
R 1
R4
R2
3
RCH=X
XH
R4
R3
Although a-azidoketones are widely employed in reduction, oxida-
R5
HO
O
tion reactions, but their applicability as nucleophilic species in
multicomponent reactions to synthesize heterocycles has not been
explored to any great extent. As part of our program aimed at
R2
R 1
O
O
R
R 1
N3
N3
R2
2
4
⇑
Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Scheme 1. Reactivity of a-azido ketones in C–C bond formation reactions.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.101

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T. H. Babu et al. / Tetrahedron Letters 52 (2011) 4093–4096
1
O
2
N3
CHO
OH
Br
40 mol% piperidine
O
3
+
+
Br
CN
CN
NC
N3
Ethanol, rt, 55 min
O
NH2
1a
2
3a
4a
Scheme 2.
We commenced our study by the addition of phenacyl azide 3a
to iminocoumarin derivative obtained from the reaction of salicyl-
aldehyde 1a and malononitrile 2, in ethanol in the presence of an
equivalent amount of piperidine at room temperature. The reac-
tion went to completion within 30 min and resulted in the forma-
tion of azido chromene 4a in 67% yield as a mixture of syn and anti
isomers in the ratio of 77:23, as determined by crude 1H NMR
analysis. When we carried out the reaction by employing a
catalytic amount of piperidine, the reaction was clean affording
product 4a in 85% yield as a mixture of syn and anti isomers in
the ratio of 88:12 with the preference of syn diastereoselectivity
and took 55 min for the completion of the reaction. Column
chromatography afforded a diastereomerically pure syn-4a isomer
(Scheme 2). Assignment of syn and anti isomers was done by
comparison with the previous literature data.11 In 1H NMR, the
syn isomer showed signal for H-2 hydrogen at higher field
d = 5.07 ppm with J = 3.8 Hz, whereas for the anti isomer H-2
resonated at lower field d = 4.87 ppm with J = 5.35 Hz. Further
the syn stereochemistry of the compound 4c has been confirmed
using 1-D NOE experiment (see the Supplementary data). Selective
irradiation of the C3–H hydrogen effected the enhancement of
the signals of C2–H. Based on these diagnostic tools, we assigned
the stereochemistry in the entire series of the compounds. The
compound 4k (Table 1, entry 11) was isolated as its diastereopure
syn form. This may be attributed to the steric factors. Table 1 sum-
marizes our results on the one-pot reaction of various salicylalde-
hydes and malononitrile with a-azido ketones.
Different salicylaldehydes either bearing electron-withdrawing
groups (such as halide) or electron-donating groups (such as alk-
oxy group) gave expected products in good to high yields under
the same reaction conditions.18 As indicated in Table 1, 6-substi-
tuted azido chromenes exhibit syn selectivity as a preference,
whereas in the case of 8-substituted azido chromenes, the anti dia-
stereoselectivity was observed.
Nitrogen-containing heterocycles (azaheterocycles) occur in a
wide variety of natural and biologically active compounds.12
Although efficient methods for the synthesis of nitrogen-contain-
ing molecules merit further investigations, very little attention
has been focused on the copper promoted C–N bond formation-
based protocols.13 Among them, undoubtedly, ‘click reaction’14
and in particular Huisgen [3+2] cycloaddition15 has emerged as a
‘near perfect’ (very fast, selective, high-yield, and wide scope)
carbon–nitrogen bond forming reaction toward the synthesis of
N-substituted 1,2,3-triazoles. This process that occurs between
organic azides and alkynes is significantly accelerated by Cu(I)
catalysis,16 and it offers easy access to the 1,4-disubstituted
Table 1
Three component synthesis of azido chromenes
O
N3
R1
R2
CHO
OH
N3
N3
3a
40 mol% piperidine
O
O
+
CN
+
NC
R1
R2
CN
(or)
R1
R2
CN
Ethanol, rt, 55-80 min
O
R3
(or)
O
NH2
O
NH2
2
1a-g
R3
R3
N3
4i-k
3b
4a-h
Entry
R1
R2
R3
Azido ketone
Product
Time (m)
Yielda,b (%)
syn/antic
1
2
3
4
3
6
7
8
9
Br
Cl
H
H
H
Br
I
H
H
H
Br
H
H
H
H
H
H
H
OCH3
H
H
H
H
OCH3
OCH2CH3
H
Br
I
H
H
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
4a
4b
4c
4d
4e
4f
4g
4h
4i
55
60
75
70
63
80
85
80
75
72
63
85
81
79
75
83
73
69
80
84
77
82
88:12
68:32
40:60
41:59
48:52
47:53
49:51
26:74
50:50
48:52
100:0
10
11
OCH3
H
4j
4k
H
a
b
c
Yield of the isolated purified compounds 4a–k.
Conditions: salicylaldehyde (1 mmol), malononitrile (1 mmol), azido ketone (1.5 mmol), piperidine (40 mol %).
Determined by 1H NMR analysis.

T. H. Babu et al. / Tetrahedron Letters 52 (2011) 4093–4096
4095
N3
N
O
N
N
O
Br
CN
(20 mol%)
CuI
Br
CN
+
t-BuOH:H2O (1:1)
O
NH2
O
NH2
5
6a
4a
Scheme 3.
isomer. To contribute in this area of research, here we report an
interesting application of the ‘click reaction’ to -azido chromenes
a
with the aim to obtain new heterocyclic scaffolds. In this regard we
attempted the [3+2] cycloaddition reaction between phenyl
acetylene and the synthesized azido chromenes. As we are able
to separate only syn isomers of the azido chromenes in diastereo-
merically pure form by repeated column chromatography, we em-
ployed only the syn isomers for the [3+2] cyclo addition reactions.
In a typical experiment the syn-4a diastereomer is treated with
phenyl acetylene in 1:1 mixture of t-BuOH and water with CuI as
catalyst to afford expected 1,4-disubstituted 1,2,3-triazole deriva-
tive 6a in 71% yield (Scheme 3) (Table 2, entry 1).19 In an attempt
to optimize the efficiency of this reaction, we have changed the ra-
tio of the alkyne employed. It was observed that upon increasing
the amount of phenyl acetylene no significant improvement of
the yield was observed.
Figure 1. ORTEP diagram of compound 6c.
column chromatography. Moreover, as expected, disubstituted
acetylene, such as diphenylacetylene and dimethyl acetylene
dicarboxylate, did not react under these conditions.
In summary, to the best of our knowledge, this Letter represents
the first report on the three component synthesis of azido chrom-
enes by employing
a-azido ketones as nucleophiles on imino-
coumarin derivatives. The synthesized azido chromenes were
successfully transformed into N-substituted 1,2,3-triazole deriva-
tives by [3+2] cycloaddition with phenyl acetylene.
The product was confirmed by IR, 1H NMR and 13C NMR spec-
troscopy. In 1H NMR, triazolyl proton was resonated at
d
8.45 ppm and the peaks at d 146.9 and 130.5 ppm correspond to
the triazolic carbon atoms. The syn stereochemistry of compound
6c has been assigned using 1-D NOE experiment. Further the reg-
iochemistry and the absolute configuration of the triazolyl
chromene 6c are additionally confirmed by the impure (imino-
coumarin part can be seen in the structure) single crystal X-ray
structure as depicted in the ORTEP diagram (Fig. 1).17
Acknowledgment
The authors are thankful to the Council of Scientific and Indus-
trial Research, New Delhi, India for the financial assistance.
To explore the generality of the reaction, we have also tried the
reaction with aliphatic alkyne such as propargyl alcohol, but the
product was not able to be isolated due to decomposition during
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.101.
Table 2
References and notes
Synthesis of triazolyl chromenes
1. Langer, P.; Freifeld, I.; Shojaei, H. Chem. Commun. 2003, 3044; (a) Freifeld, I.;
Shojaei, H.; Langer, P. J. Org. Chem. 2006, 71, 4965; (b) Freifeld, I.; Shojaei, H.;
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(b) Wallner, S. R.; Lavandera, I.; Mayer, S. F.; Öhrlein, R.; Hafner, A.; Edegger, K.;
Faber, K.; Kroutil, W. J. Mol. Catal. B: Enzym. 2008, 55, 126.
3. Benaissa, T.; Hamman, S.; Beguin, C. G. J. Fluorine Chem. 1988, 38, 163.
4. Nakajima, M.; Loeschorn, C. A.; Cimbrelo, W. E.; Anselme, J. P. Org. Prep. Proced.
Int. 1980, 12, 265.
5. (a) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437;
(b) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353; (c) Eguchi, S.;
Matsushita, Y.; Yamashita, K. Org. Prep. Proced. Int. 1992, 24, 209; (d) Molina, P.;
Vilaplana, M. J. Synthesis 1994, 1197; (e) Wamhoff, H.; Richardt, G.; Stolben, S.
In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: San
Diego, 1995; Vol. 64, pp 159–240; (f) Barluenga, J.; Palacios, F. Org. Prep. Proced.
Int. 1991, 23, 1; (g) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de los
Santos, J. M. Tetrahedron 2007, 63, 523.
N3
N
O
N
N
O
R1
R2
CN
(20 mol%)
CuI
R1
CN
+
t-BuOH:H2O (1:1)
O
NH2
R2
O
NH2
R3
4a-d
R3
5
6a-d
6. Marco, J. L.; Martinez-Grau, A.; Martin, N.; Seoane, C. Tetrahedron Lett. 1995, 36,
5393.
Entry
R1
R2
R3
Producta
Time (h)
Yielda,b (%)
1
2
3
4
Br
Cl
H
H
H
H
H
H
H
OCH3
6a
6b
6c
6d
1.5
1.7
2.0
2.1
71
68
61
63
7. (a) Savitha, G.; Niveditha, S. K.; Muralidharan, D.; Perumal, P. T. Tetrahedron
Lett. 2007, 48, 2943; (b) Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2007, 48,
6785; (c) Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. Tetrahedron 2007, 63,
2057; (d) Babu, T. H.; Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2009, 50,
2881; (e) Selvam, N. P.; Babu, T. H.; Perumal, P. T. Tetrahedron 2009, 65, 8524.
8. Ellis, G. P. In The Chemistry of Heterocyclic Compounds. Chromenes, Chromanes
and Chromones; Weissberger, A., Taylor, E. C., Eds.; John Wiley: New York, 1977;
pp 11–141. Chapter II.
H
OCH2CH3
a
Yield of the isolated purified compounds 6a–d.
Conditions: syn azido chromene (1 mmol), phenyl acetylene (1 mmol), CuI
(20 mol %), t-BuOH/H2O (1:1).
b

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T. H. Babu et al. / Tetrahedron Letters 52 (2011) 4093–4096
9. Hafez, E. A.; Elnagdi, M. H.; Elagamey, A. G. A.; El-Taweel, F. M. A. A.
Heterocycles 1987, 26, 903.
10. (a) Shanthi, G.; Perumal, P. T. Synlett 2008, 2791; (b) Jayashree, P.; Shanthi, G.;
Perumal, P. T. Synlett 2009, 917.
Spectral data of compound syn-4b: 2-amino-4-(1-azido-2-oxo-2-phenylethyl)-
6-chloro-4H-chromene-3-carbonitrile; white puffy solid, mp 128–130 °C; (30%
AcOEt/petroleum ether); IR (KBr): 3431, 3315, 3192, 2185, 2105, 1650, 1417,
1228, 691 cmÀ1 1H NMR (500 MHz, CDCl3): d 4.19 (d, J = 3.8 Hz, 1H), 4.92 (s,
;
11. See, for example: The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.;
Academic Press: San Diego, CA, 2000; Vol. 54,. and others in this series.
12. (a) Juhász-Tóth, É.; Patonay, T. Eur. J. Org. Chem. 2002, 3055; (b) Patonay, T.;
Juhász-Tóth, É.; Bényei, A. Eur. J. Org. Chem. 2002, 285.
13. For a review on copper-mediated coupling reactions and their applications in
natural products and designed biomolecules synthesis, see: Evano, G.;
Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
14. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
15. Huisgen, R. In Padwa, A., Ed.; 1,3-Dipolar Cycloaddition Chemistry; Wiley: New
York, 1984; Vol. 1, pp 1–177.
16. (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057; (b)
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596.
2H, D2O exchangeable), 5.01 (d, J = 3.8 Hz, 1H), 6.80 (s, 1H), 6.95 (d, J = 8.4 Hz,
1H), 7.22 (dd, J = 2.3, 6.1 Hz, 1H), 7.57 (t, J = 7.65 Hz, 2H), 7.67 (t, J = 6.85 Hz,
1H), 7.98 (d, J = 7.6 Hz, 2H).; 13C NMR (125 MHz, CDCl3): d 38.9, 55.0, 69.2,
117.8, 119.0, 119.5, 128.3, 128.6 (2), 129.3 (2), 129.4, 129.9, 134.3, 134.6, 148.9,
162.1, 194.2.
19. General procedure for the synthesis of triazolyl chromenes (6a–d): To a to stirred
suspension of phenyl acetylene (1 mmol) and CuI (20 mol %) in t-BuOH/H2O
(1:1) (10 ml), was added, azido chromene and continued stirring until the
specified time. After the reaction was complete as indicated by thin layer
chromatography the reaction content was filtered through the bed of Celite to
remove the CuI and the filtrate was diluted with water (30 ml) and extracted
with ethyl acetate (3 Â 15 mL). The organic layers were then combined, dried
(Na2SO4), filtered and concentrated under vacuum to provide crude product
which was purified by column chromatography on silica gel (neutralized with
five drops of NEt3) (petroleum ether–ethyl acetate, 85/15–50/50).
17. Crystallographic data for compound 6c in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplemental publication No.
821386 Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, deposit@ccdc.cam.ac.uk).
Spectral data of compound 6b: 2-amino-6-chloro-4-(2-oxo-2-phenyl-1-(4-
phenyl-1H-1,2,3-triazol-1-yl)ethyl)-4H-chromene-3-carbonitrile; off white
solid, mp 162–164 °C (35%) AcOEt/petroleum ether); IR (KBr): 3475, 3352,
18. General procedure for synthesis of azido chromenes (4a–k): To a stirred solution
of salicylaldehyde (1 mmol) and malononitrile (1 mmol) in ethanol (5 ml), was
added piperidine (40 mol %) and allowed stirring until the formation of
precipitate. To this formed precipitate, was added azido ketone (1.5 mmol)
and stirring was continued for the specified time. The progress of the reaction
was monitored by thin layer chromatography using ethyl acetate: pet ether (3:
7) as an eluent. After the specified reaction time the ethanol was removed
under vacuo and the crude product was purified by flash chromatography on
silica gel (neutralized with five drops triethyl amine) (petroleum ether–ethyl
acetate, 90/10–75/25).
3138, 2195, 1645, 1414, 1244, 691 cmÀ1 1H NMR (500 MHz, DMSO-d6): d 4.55
;
(d, J = 5.35 Hz, 1H), 6.04 (s, 2H, D2O exchangeable), 6.53 (d, J = 5.35 Hz, 1H),
6.83 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 9.15 Hz, 1H), 7.22 (s, 1H), 7.32 (t, J = 7.6 Hz,
1H), 7.41 (t, J = 7.65 Hz, 2H), 7.51 (t, J = 7.65 Hz, 2H), 7.63 (t, J = 6.9 Hz, 1H), 7.85
(d, J = 7.65 Hz, 2H), 8.00 (d, J = 7.65 Hz, 2H), 8.33 (s, 1H); 13C NMR (125 MHz,
DMSO-d6): d 50.8, 68.5, 117.9, 119.1, 120.6, 121.0, 125.7 (2), 128.1, 128.3, 128.7
(2), 128.8 (2), 129.1 (2), 129.2 (2), 130.0, 130.5, 134.5, 134.7, 147.7, 148.8,
163.1, 192.9.