Stereoselective synthesis of bio-hybrid amphiphiles of coumarin derivatives by Ugi-Mannich triazole randomization using copper catalyzed alkyne azide click chemistry

Article abstract of DOI:10.1016/j.bmcl.2012.01.111

An efficient synthesis of ester-triazole-amide amphiphiles of coumarin derivatives by triazole randomization based on click approach is described. Twenty-five small peptide azides were synthesized using Ugi or alternate Mannich-type multi-component reactions. The new azides were then used for the triazole randomization of alkyne functionalized coumarin ester under CuAAC conditions. Sixty-five new peptide bio-hybrids are obtained in near quantitative yield with high regio and stereoselectivity.

Full text of DOI:10.1016/j.bmcl.2012.01.111

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2598–2603
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Stereoselective synthesis of bio-hybrid amphiphiles of coumarin derivatives
by Ugi–Mannich triazole randomization using copper catalyzed
alkyne azide click chemistry
⇑
P. Pramitha, D. Bahulayan
Department of Chemistry, University of Calicut, Malappuram 673635, Kerala, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of ester-triazole-amide amphiphiles of coumarin derivatives by triazole randomi-
zation based on click approach is described. Twenty-five small peptide azides were synthesized using Ugi
or alternate Mannich-type multi-component reactions. The new azides were then used for the triazole
randomization of alkyne functionalized coumarin ester under CuAAC conditions. Sixty-five new peptide
bio-hybrids are obtained in near quantitative yield with high regio and stereoselectivity.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 26 November 2011
Revised 26 January 2012
Accepted 30 January 2012
Available online 9 February 2012
Keywords:
Bio-hybrids
Amphiphiles
Coumarin
Ugi reaction
Click chemistry
OH
O
H
O
O
OH
Click chemistry represents an ideal set of near perfect reac-
tions.1 In recent years, click chemistry has emerged as a fast and
powerful approach to the synthesis of novel compounds with
desired properties. Among the various click reactions capable of
producing wide range of functional organic molecules, the copper
catalyzed [3+2] azide and alkyne cycloaddition (CuAAC) resulting
in the formation of 1,2,3-triazoles has drawn considerable atten-
tion as an archetypical example of click chemistry.2 CuAAC is
particularly useful for the synthesis of a variety of molecules rang-
ing from enzyme inhibitors to molecular materials.3 1,2,3-Triazoles
are important class of target molecules due to their interesting
biological properties such as anti-allergic,4 anti-bacterial,5 and
anti-HIV activity.6 Some of these classes of drug molecules are
now available in the market or in the final stage of clinical trials
(Fig. 1).7 Additionally, due to the resemblance in physiochemical
S
N
O
S
O
O
N
N
H
N
N
N
N
N
O
N
O
AB2
COOH
Tazobactam
Anti-bacterial β-lactamases
HIV Protease Inhibitor
O
HO
O
N
N
H2N
H2N
N
NH
S
NH2
N
Cl
N
N
N
O
Cl
H
COOH
Cefatrizine
O
Cl
CAI
Anti-bacterial
Anti-cancer
Figure 1. Representative drug examples of 1,2,3-triazole derivatives.
properties such as planarity, dipole moment, C
a distance and
of ‘bio-hybrid’ amphiphiles consists of both amide and triazole
functionality, which are highly useful in materials development.10
Coumarin and its derivatives are one of the important classes of
compounds possessing diverse range of pharmacological and
therapeutic properties. Several therapeutically active compounds
containing coumarin derivatives have been reported, such as
anti-bacterials,11a anti-fungals,11b anti-coagulants11c and anti-HIV
agents.11d The pharmacological, biochemical and therapeutic
properties of coumarin derivatives are strongly depend on the
nature as well as position of the structural substituents.12 For
example, 3-phenyl coumarin based compounds containing
H-bond acceptor properties (of the lone pairs in nitrogen atoms),
1,2,3-triazoles are considered as peptide bond isosteres.8 In addi-
tion to this, 1,2,3-triazole ring is highly chemically stable under
hydrolytic as well as reductive and oxidative conditions.
Consequently, amide-to-triazole substitutions are now common
in drug-like molecules whose amide bonds are known to be crucial
for biological activity.9 A recent trend in this field is the synthesis
⇑
Corresponding author. Tel.: +91 9995538062; fax: +91 494 2400269.
E-mail address: bahulayan@yahoo.com (D. Bahulayan).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.111

P. Pramitha, D. Bahulayan / Bioorg. Med. Chem. Lett. 22 (2012) 2598–2603
2599
carbamate groups are relatively efficient for inhibiting the cell
cycle arrest activity of the HIV-1Vpr.11d (HIV-1Vpr is an accessory
protein that has been shown to have multiple roles in the human
immunodeficiency virus-1 (HIV-1) pathogenesis). Here also, the
presence of the amide functionality in the 3-substituted coumarin
scaffold was reported to be critical for the activity against the viral
protein.
In our previous papers, we reported the synthesis of small
peptide like b-acetamido carbonyl compounds which are amenable
to further end group transformation to produce highly functional-
ized scaffolds.13 We envisaged that, the combination of our
b-N-substituted carbonyl compounds chemistry with click chemis-
try could be interesting for the access of new scaffolds useful for
medicinal chemistry research. Herein we report a concise proce-
dure for the synthesis of a series of bio-hybrid amphiphiles of
coumarin by randomization of terminal alkyne functionalized
coumarin esters with a series of small peptide like functional
azides using CuAAC reaction (Scheme 1).
Synthesis of alkyne 1 was carried out by esterification of
commercially available coumarin-3-carboxylic acid with propar-
gyl alcohol under alkaline condition (Scheme 2). The carboxylic
acid was efficiently esterified by stirring with propargyl alcohol
in the presence of N,N-dicyclohexyl cabodiimide (1.1 equiv), and
4-dimethylaminopyridine (0.1 equiv) in dichloromethane.14
We then synthesized two series of terminal azides. The type 1
azides, based on Mannich-type b-amido ketone derivatives were
R1
N
R1
N3
CuSO4.5H2O,
Sod.ascorbate
N
O
O
O
N
O
O
O
O
DMSO/t-BuOH/H2O
O
Br
O
NH
R1
=
H
N
N
O
O
or
Cl
O
Br
Scheme 1. Triazole randomization of coumarin ester with small peptide azides.
O
O
O
O
O
O
OH
DCC, DMAP
DCM, R.T
O
1
OH
Scheme 2. Esterification of coumarin-3-carboxylic acid with propargyl alcohol
Table 1
List of type
derivatives
1
azides prepared from Mannich-type b-amido ketone
Cl
Cl
Br
O
O
O
Br
Cl
NC
H
BF3.Et2O
R.T, 2 days
NH
O
+
2
O
Br
NaN3
Br
O
Cl
Br
R.T, 4 hrs
K2CO3
NH
O
O
3e
N3
O
HN
N3
Cl
O
O
HN
Cl
N3
3a
79%
Cl
Br
O
O
Br
N3
O
HN
3d
93%
O
N3
Cl
HN
O
3b Br
96%
Br
N3
3e
O
HN
92%
Cl
Cl
3c
91%

2600
P. Pramitha, D. Bahulayan / Bioorg. Med. Chem. Lett. 22 (2012) 2598–2603
Table 2
List of type 2 azides prepared from Ugi-type
a
-amino acyl amide derivatives
Cl
Cl
+
H
O
N
O
DCM
HO
O
NaN3
N
O
Cl
N
H
N3
N
H
+
R.T, 3 days
K2CO3
R.T, 4 hrs
H2N
O
O
CN
Cl
Cl
4
5e
NH
NH
NH
NH
O
O
N
O
N
O
Br
Br
Br
N
N
O
O
Br
O
O
5b
5c
5a
94%
5d
N3
N3
N3
N3
96%
95%
96%
NH
F
NH
NH
NH
O
Br
Cl
Cl
O
O
N
O
N
Br
N
N
O
O
O
O
5h
88%
N3
5f
5e
N3
N3
N3 5g
96%
93%
94%
NH
O
NH
O
NH
NH
F
O
O
O
O
Br
Cl
F
F
Br
N
N
N
N
O
O
5l
95%
5j
89%
5k
5i
N3
N3
N3
N3
90%
86%
NH
NH
Br
NH
NH
O
O
O
O
Cl
Br
Cl
Br
N
N
N
N
O
O
O
O
5m
97%
5n
65%
5o
5p
66%
N3
N3
N3
N3
68%
NH
NH
NH
NH
Cl
F
O
O
O
O
F
N
N
N
N
O
O
O
O
5s
N3
5t
77%
5q
64%
5r
N3
N3
N3
65%
64%
synthesized by a two stage process. The first stage involved the
synthesis of the bromo derivative 2 based on a solvent less three
component coupling reaction between an aldehyde, ketone and
3-bromopropionitrile in the presence of acetyl chloride and cata-
lytic amount of boron trifluoride etherate at room temperature.13
The aqueous workup of the reaction mixture followed by solvent
wash afforded the bromo derivative 2 in pure form for the use in
the second step. The same protocol was adopted for the synthesis
of five such bromo-b-amido ketones with different substitution
patterns. The bromo derivatives were then quantitatively
converted to corresponding keto-amide azides by treating with
sodium azide in presence of potassium carbonate in DMF at room
temperature (Table 1).15
the Ugi reaction product 4 by azide functionalization. The Ugi-4
component reaction16 between chloroacetic acid, an aromatic
aldehyde, an amine source and tert-butyl isocyanide in dichloro-
methane afforded the Ugi type small peptide chloride 4.17 Follow-
ing the same procedure, we have synthesized twenty Ugi derived
chlorides (see Supplementary data) with different substitution pat-
terns. The Ugi type chlorides were then quantitatively converted to
the corresponding Ugi derived azides by treating with sodium
azide in presence of potassium carbonate in DMF at room temper-
ature (Table 2).18
With alkyne and azides in hand, we tested the feasibility of
randomizing coumarin using CuAAC reaction. As shown in
Scheme 1, in a typical CuAAC reaction of alkyne 1 and a type
1 azide(keto-amide azide) 3d in a solvent mixture of t-BuOH,
H2O and DMSO (4:2:1) in the presence of copper sulphate
The type 2 azides based on Ugi-type
a-amino acyl amides listed
in Table 2 were synthesized by the post reaction modification of

P. Pramitha, D. Bahulayan / Bioorg. Med. Chem. Lett. 22 (2012) 2598–2603
2601
Table 3
List of products obtained from the click reactions of coumarin 1 with Mannich type b-amido ketone
azides
Br
N
O
N
O
N
Br
HN
Br
NH
O
+
O
O
O
O
CuSO4.5H2O,
N3
O
Sod.ascorbate
O
O
O
DMSO/ t-BuOH/H2O
6e
O
Br
Cl
O
O
O
O
O
O
Cl
O
O
NH
O
NH
O
N
O
N
Br
N
O
N
6b (1+3d)
99%
N
Cl
N
6a (1+3a)
98%
O
Cl
O
O
NH
O
6c (1+3e)
99%
O
Cl
O
O
O
N
N
O
N
Br
N
NH
O
O
Br
O
O
O
N
N
Cl
N
O
6d (1+3c)
99%
NH
O
O
O
Br
N
N
6e (1+3b)
100%
and sodium ascorbate at room temperature afforded the ester-
triazole-ketoamide amphiphile 6b in 99% yield.19 Good conver-
sions and yields were observed in all the five reactions (Table
3). The 1,4-disubstituted 1,2,3-triazoles 6a–e were easily iso-
lated by aqueous workup and identified by spectral methods.
In a similar manner, we have conducted the CuAAC reactions
ties are known to influence the polarization of the azide group and
allows the orientation of the cycloaddition to proceed in the
anti-selective manner.22b In the present study, the observed anti-
diastereoselectivity may be due to the polarizing effect exerted
by electron withdrawing keto-amide functionality present in the
azide side chain (For a proposed mechanism, see Scheme 4 given
in Supplementary data).
of akyne 1 and Ugi-type
a-amino acyl amide azides (type 2).
Type 2 azides also afforded the 1,4-disusbstituted triazoles
7a–t in near quantitative yield (Table 4). Among the twenty
click products obtained from the reactions of type 2 azides,
the formation of the fluorinated analogues 7h–m proceed with
100% yield in many cases. On the other hand, the CuAAC reac-
tions of Ugi-type azides bearing substituents other than fluo-
rine did not show any significant change in yield with respect
to the nature of the substituents present in them. Fluorinated
analogues of small peptide like molecules are important class
of drug-like molecules due to the ability of fluorine to increase
the intrinsic activity, the chemical and metabolic stability, and
the bioavailability required for drug action.20 A wide range of
pharmaceuticals across therapeutic categories contain fluoro
groups, including anti-depressants, anti-inflammatory agents,
anti-malarial drugs, anti-psychotics, anti-viral agents, steroids,
and anaesthetics.21
It is reported that, the regio and stereo control in CuAAC reac-
tion is strongly depends on the nature of the catalysts and reagents
employed.22a Copper (I) salts are known to afford exclusively 1,4-
adducts, while catalysts like cyclopentadienyl ruthenium (II)
promotes 1,5-adduct formation. In order to suggest the regio and
stereo selectivity in triazole formation, we have compared the
spectral data of our compounds with literature values. The 1H
NMR spectra shows a similar signal corresponds to the triazole
proton of the anti 1,4-regio isomer. More over the presence of
electron withdrawing groups present in the alkyne or azide moie-
For generalizing the protocol, we have prepared three more
coumarin derived alkynes 8, 9 and 10 shown in Scheme 3 and
conducted the click reactions with type 1 and type 2 azides. All
the reactions afforded the corresponding click products in near
quantitative yield (For details, see Tables 5–10 given in Supple-
mentary data).
Drug-likeness of molecules are mainly depends on their molec-
ular size, liphophilicity (logP), polarity (accessed by the polar sur-
face area, tPSA), and the presence of optimal number of rotatable
bonds.23a Drug like molecules usually have logP values in between
À0.4 and 5.6.23b Compounds with molecular weight between 160
and 480 with tPSA between 75 and 150 Å2 are considered as orally
bioavailable.23c Some of the molecules with higher molecular
weight (>500) and logP (>7) are identified as prodrugs.24 In order
to give an indication about the drug-likeness of our compounds,
we have calculated the values of logP and tPSA using Molinspira-
tion Property Calculation Service (www.molinspiration.com). Most
of the compounds have logP value in between 4.2 and 5.63 with
tPSA between 126.73 and 129.97 Å2 (see Table 11 given in Supple-
mentary data).
In summary, we have developed a convenient and near perfect
CuAAC process for the regio and stereo controlled synthesis of es-
ter-triazole-amide amphiphiles of coumarin. Primary success of
the process reveals the possibility of developing large number li-
brary of structurally complex and diversely substituted extended
peptide like scaffolds of coumarin for screening purpose.

2602
P. Pramitha, D. Bahulayan / Bioorg. Med. Chem. Lett. 22 (2012) 2598–2603
Table 4
List of products obtained from click reaction of alkyne 1 with Ugi-type
a
-amino acyl amide azides
NH
O
Br
N
Br
Br
O
N
N
N
5d
N3
O
O
O
CuSO4.5H2O,
Sod.ascorbate
+
O
N
O
O
O
O
Br
DMSO/ t-BuOH/H2O
O
O
HN
1
7d
Br
N
N
N
N
N
N
N
N
N
O
N
O
O
O
O
O
O
N
N
O
O
O
O
O
O
O
HN
O
O
O
7b (1+5b)
99%
O
HN
HN
7a (1+5a)
99%
7c (1+5c)
99%
Br
Br
N
N
N
N
N
N
N
N
N
O
N
O
O
N
O
O
O
O
N
O
O
O
O
O
Br
O
O
O
O
O
HN
HN
O
7d (1+5d)
100%
HN
7e (1+5e)
99%
7f (1+5f)
Cl
100%
Br
Br
Br
N
N
N
N
N
N
N
N
N
O
N
O
N
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
HN
HN
HN
7i (1+5i)
100%
7g (1+5g)
100%
7h (1+5h)
99%
Cl
F
F
Br
F
N
N
N
N
N
O
O
N
HN
O
N
O
O
N
O
O
O
O
O
O
N
O
O
O
O
O
O
HN
HN
7l (1+5s)
7k (1+5k)
100%
N
7j (1+5j)
99%
98%
N
N
F
F
Cl
HN
F
HN
HN
O
O
O
O
O
O
O
O
O
N
O
O
O
N
N
O
O
O
O
N
N
N
N
N
O
N
N
O
7o (1+5q)
99%
7n (1+5t)
99%
N
7m (1+5r)
N
98%
Br
Br
HN
O
HN
O
O
O
O
O
N
H
N
O
O
O
O
O
N
N
O
O
7r (1+5n)
N
N
O
O
O
O
N
O
O
N
N
N
N
7p (1+5p)
7q (1+5o)
99%
Cl
N
N
99%
99%
Cl
Cl
HN
HN
O
O
O
O
O
N
O
O
N
N
O
N
O
O
O
Br
7t (1+5l)
99%
7s (1+5m)
100%
N
N
N
N

P. Pramitha, D. Bahulayan / Bioorg. Med. Chem. Lett. 22 (2012) 2598–2603
2603
(700 mg) are taken in dimethyl acetamide (4 mL). To this, K2CO3 (1 g) was
added and stirred at room temperature for 4 h. The reaction mixture was then
diluted with water. The white precipitate obtained was filtered and washed
repeatedly with water to afford the pure azide 3e (1.06 g, 97%).
O
O
O
O
O
O
O
O
O
16. (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8; (b) Ugi, I.; Domling, A.; Horl, W.
Endeavour 1994, 18, 115; (c) Ugi, I.; Domling, A.; Gruber, B.; Almstetter, M.
Croat. Chem. Acta 1997, 70, 631; (d) Domling, A. Chem. Rev. 2006, 106, 17.
17. Typical experimental procedure for the synthesis of Ugi chloride 4i: An equi-
molar amount of 2-fluoro benzaldehyde (1.24 g, 0.01 mol) and 4-bromo aniline
are taken in dichloromethane (8 mL) and stirred in room temperature for
20 min. to form the schiff-base. To this, one equivalent of tert-butyl isocyanide
(0.83 g, 0.01 mol) and chloroacetic acid (0.95 g, 0. 01 mol) were added and
stirred at room temperature. The reaction was monitored by TLC and found to
complete after 48 h. The solvent was then evaporated off under vacuum. The
crude product obtained was washed with petroleum ether (5 Â 15 mL) to
10
9
8
Scheme 3. Structure of alkynes 8, 9 and 10 used for the click reactions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2012.01.111.
afford the pure Ugi chloride 4i (4.01 g, 88%). FT-IR, KBr, cmax: 3334.3, 2963.1,
1690.3, 1658.5, 1540.9, 1485.9, 1455.0, 1382.7, 1363.4, 1256.4, 1232.3, 1014.4,
759.8, 629.6; 1H NMR (400 MHz, DMSO-d6): d 7.982 (s, 1H), 7.551–6.869 (m,
8H), 6.236 (s, 1H), 4.106–3.899 (m, 2H), 1.255 (s, 9H); MS: m/z Calcd for
References and notes
C
20H21BrClFN2O2, 455.7; Found, 457.1.
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C. L.; Wang, C.; Wang, Q. Chem. Soc. Rev. 2010, 39, 1233; (c) El-Sagheer, A. H.;
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18. Typical experimental procedure for the synthesis of Ugi azide 5d: An equi-
molar amount of the corresponding Ugi chloride (1.29 g, 0.0025 mol) and
sodium azide (700 mg) are taken in dimethyl acetamide (4 mL). To this
K2CO3 (1 g) was added and stirred at room temperature for 4 h. The
reaction mixture was then diluted with water. The white precipitate
obtained was filtered and washed repeatedly with water to afford the
pure azide 5d (1.24 g, 95%). FT-IR, KBr,
9, 1684. 5, 1658. 4, 1536. 0, 1486. 8, 1391. 3, 1267. 2, 1015. 3, 740. 5; 1H
NMR (400 MHz, DMSO-d6): 8.089 (s, 1H), 7. 547–7.528 (d, J = 7.6 Hz,
2H), 7. 129–7.092 (m, 4H), 6. 938–6. 920 (d, J = 7.2 Hz, 2H), 6.22 (s, 1H),
3. 889–3.542 (m, 2H), 1. 265 (s, 9H); MS: m/z Calcd for 20H21Br2N5O2,
523.22; Found, 524.0. Compound 5e: FT-IR, KBr, cmax 3304. 4, 3072.0,
2972.7, 2101.0, 1643.8, 1552.4, 1220.7, 1040.4, 948.8, 749.209; 1H NMR
(400 MHz, DMSO-d6): 8.096–8.073 (d, J = 9.2 Hz, 1H), 7.373–6.843 (m,
9H), 6.341 (s, 1H), 4.902–4.577 (m, 2H), 4.206-3.914 (m, 2H) 1. 162 (s,
cmax: 3349.7, 3059.5, 2965.0, 2104.
d
C
:
d
9H). Compound 5g: FT-IR, KBr, cmax
: 3392.2, 3343.9, 2965.0, 2928.4,
2103.9, 1686.4, 1655.0, 1538.9, 1485.9, 1391.4, 1257.4, 1014.4, 743.4; 1H
NMR (400 MHz, DMSO-d6): d 8.081 (s, 1H), 7.377–7.358 (d, J = 7.6 Hz, 2H),
6.950–6.931 (d, J = 7.6 Hz, 2H), 7.206–7.170 (m, 2H), 7.107–7.070 (m, 2H),
6.628 (s, 1H), 3.913–3.522 (m, 2H), 1.266 (s, 9H).
6. Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.; De Clercq, E.; Perno, C.-F.;
Karlsson, A.; Balzarini, J.; Camarasa, M. J. J. Med. Chem. 1994, 37, 4185.
7. Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem. Asian J. 2011, 6, 2696.
8. Kolb, H. C.; Sharpless, B. K. Drug Discovery Today 2003, 8, 1128.
9. (a) Brik, A.; Alexandratos, J.; Lin, Y.-C.; Elder, J. H.; Olson, A. J.; Wlodawer, A.;
Goodsell, D. S.; Wong, C.-H. ChemBioChem 2005, 6, 1167; (b) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
19. General procedure for the Cu (I) 1, 3-dipolar cycloaddition reactions: An equi-
molar amount of prop-2-yn-1-yl 2-oxo-2H-chromene-3-carboxylate
1
(57.05 mg, 0.25 mmol) and the Ugi azide 5d (130.8 mg, 0.25 mol) are
dissolved in minimum amount of DMSO. To this, 2 ml of t-BuOH, 1 ml of
water, CuSO4Á5H2O (200 mg) and sodium ascorbate (150 mg) are added and
stirred in room temperature for 12 h. and then poured in to cold water. The
precipitated click product was filtered, washed with water and dried under
10. Justin, M. H.; Kent, K. Chem. Soc. Rev. 2010, 39, 1325.
vacuum to afford 7d in pure form (180 mg, 97%). FT-IR, KBr,
cmax: 3312.1,
11. (a) Kayser, O.; Kolodziej, H. Z. Naturforsch 1999, 54c, 169–174; (b) Sharma, R.
C.; Parashar, R. K. J. Inorg. Biochem. 1988, 32, 163; (c) Garazd, Y. L.; Kornienko, E.
M.; Maloshtan, L. N.; Garazd, M. M.; Khilya, V. P. Chem. Nat. Prod. 2005, 41, 508;
(d) Ong, E. B.; Watanabe, N.; Saito, A.; Futamura, Y.; Abd El Galil, K. H.; Koito,
A.; Najimudin, N.; Osada, H. J. Biol. Chem. 2011, 286, 14049.
2970.8, 2933.2, 2107.8, 1773.3, 1706.7, 1671.9, 1610.3, 1565.9, 1484.9, 1391.4,
1206.3, 764.6; 1H NMR (400 MHz, DMSO-d6): d 8.756 (s, 1H), 8.127 (S, 1H),
8.028 (s, 1H), 7.924–7.904 (d, J = 8.0 Hz 2H),7.742–7.700 (m, 1H), 7.546–7.527
(d, J = 7.6 Hz, 1H), 7.424–7.362 (m, 3H), 7.114–7.085 (m, 3H), 6.923–6.905 (d,
J = 7.2 Hz, 2H), 6.260 (s, 1H), 5.332 (s, 2H), 5.169–4.312 (m, 2H), 1.252 (s, 9H);
MS: m/z Calcd for C33H29Br2N5O6, 751.4; Found, 752.0.
12. Burlison, J. A.; Neckers, L.; Smith, A. B.; Maxwell, A.; Blagg, B. S. J. J. Am. Chem.
Soc. 2006, 128, 15529.
20. (a) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303; (b) Begue, J.-P.;
Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992; (c) Kirk, K. L. J. Fluorine
Chem. 2006, 127, 1013; (d) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.;
Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, U. ChemBioChem 2004, 5, 637.
21. For recent reviews see: (a) Brunet, V. A.; O’GHagan, D. Angew. Chem. 2008, 120,
1198. Angew. Chem., Int. Ed. 2008, 47, 1179; (b) Bobbio, C.; Gouverneur, V. Org.
Biomol. Chem. 2006, 4, 2065; (c) Pihko, P. M. Angew. Chem. 2006, 118, 558.
Angew. Chem., Int. Ed. 2006, 45, 544; (d) Prakash, G. K. S.; Beier, P. Angew. Chem.
2006, 118, 2228. Angew. Chem. Int. Ed. 2006, 45, 2172; (e) Ma, J.-A.; Cahard, D.
Chem. Rev. 2004, 104, 6119; Lam, Y.-h.; Bobbio, C.; Cooper, I. R.; Gouverneur, V.
Angew. Chem., Int. Ed. 2007, 46, 5106.
13. (a) Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003, 68, 5735; (b) Shinu, V.
S.; Sheeja, B.; Purushothaman, E.; Bahulayan, D. Tetrahedron Lett. 2009, 50,
4838; (c) Shinu, V. S.; Pramitha, P.; Bahulayan, D. Tetrahedron Lett. 2011, 52,
3110.
14. Typical experimental procedure for the synthesis of prop-2-yn-1-yl 2-oxo-2H-
chromene-3-carboxylate 1: A solution of Coumarin-3-carboxylic acid (1.9 g,
0.01 mol), Propargyl alcohol (0.56 ml, 0.01 mol), N,N-dicyclohexyl cabodiimide
(2.3 g, 011 mol), and 4-dimethylaminopyridine (0.122 g, 0.001 mol) in
dichloromethane was stirred at room temperature for 6 h. After 6 h, the
precipitated N,N-dicyclohexylurea was filtered off and the filtrate was washed
with water, 5% acetic acid, and again with water. It was then dried over
magnesium sulphate and the solvent was evaporated. The residue obtained
was washed with petroleum ether to afford the ester 1 (2.4 g, 96%). FT-IR, KBr,
22. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
´
Ed. 2002, 41, 2596; (b) Estelle, M.; Gerardin-Charbonnier, C.; Selve, C. J. Fluorine
Chem. 2005, 126, 715.
c
max: 3229.2, 3057.6, 2929.3, 2851.2, 2118.4, 1749.9, 1713.4, 1615.1, 1563.9,
23. (a) Giulio, V.; Alessandro, P. Drug Discovery Today 2008, 13, 285; (b) Arup, K. G.;
Vellarkad, N. V.; John, J. W. J. Comb. Chem. 1999, 1, 55; (c) Martin, Y. A. J. Med.
Chem. 2005, 48, 3164.
24. Macdonald, C. M.; Turcan, R. G. Sites of Drug Metabolism, Prodrugs and
Bioactivation In Comprehensive Medicinal Chemistry; Hansch, C., Sammes, P. G.,
Taylor, J. B., Ramsden, C. A., Eds.; Pergamon Press: London, 1990; Vol. 5,.
1370.2, 1240.0, 1213.0, 1035.6, 999.9, 770.4; 1H NMR (400 MHz, DMSO-d6): d
8.826 (s,1H), 7.971–7.963 (m, 1H), 7.778–7.733 (m,1H), 7.459–7.400 (m, 2H),
4.942–4.937 (d, J = 2.0 Hz, 2H), 3.327 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d
161.8, 155.8, 154.7, 134.8, 130.5, 124.9, 117.8, 116.7, 116.2, 78.2, 78.1, 52.806;
MS: m/z 229.1 Calcd for C13H8O4, 228.2; Found, 229.1.
15. Typical experimental procedure for the synthesis of b-keto-amide azide 3e: An
equi-molar amount of b-ketoamide (1.09 g, 0.0025 mol) and sodium azide