Halide binding and self-assembling behavior of Triazole-based acyclic and cyclic molecules

Article abstract of DOI:10.1016/j.tet.2010.11.078

The present study demonstrates the use of triazole moiety in designing molecules endowed with the ability for self-assembly and molecular recognition. The receptors 7a and 9a having open structures bind to fluoride ion with good affinity. Various cyclopha

Full text of DOI:10.1016/j.tet.2010.11.078

Tetrahedron 67 (2011) 727e733
Contents lists available at ScienceDirect
Tetrahedron
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Halide binding and self-assembling behavior of Triazole-based acyclic
and cyclic molecules
,
a
b
V. Haridas a , Srikanta Sahu , P. Venugopalan
*
a Department of Chemistry, Indian Institute of Technology, Hauz Khas, New Delhi-110016, India
b Department of Chemistry, Panjab University, Chandigarh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The present study demonstrates the use of triazole moiety in designing molecules endowed with the
ability for self-assembly and molecular recognition. The receptors 7a and 9a having open structures bind
to fluoride ion with good affinity. Various cyclophanes with 19-, 20-, 21-, 38-, and 40-membered rings
containing triazole units were designed and synthesized. X-ray crystal structure of macrocycle 16
showed a tubular like architecture. Triazolophane 22 possesses bifurcated CH/N intramolecular hy-
drogen bonds and it further organizes in the solid state using CH/N interactions. Triazole based com-
pounds are potential store house for exploiting CH/O and CH/N hydrogen bonding interactions for
molecular self-assembly.
Received 28 September 2010
Received in revised form 29 October 2010
Accepted 19 November 2010
Available online 27 November 2010
Keywords:
Anion receptor
Molecular recognition
Self-assembly
Triazole
Ó 2010 Elsevier Ltd. All rights reserved.
Click reaction
1. Introduction
of bonds to organize around a guest molecule. Most often it is dif-
ficult to design highly preorganized and rigid receptors with ac-
The ever-increasing number of receptor designs for ions and
neutral molecules has been highlighted in the literature, especially
exotic structures with unusual binding abilities.1e4 However, de-
spite a large number of efforts directed towards receptor design;
general design strategies for receptors with high affinity and
specificity for a given analyte are rare. This lacuna is partly due to
the intricacies of the weak forces involved in binding inter alia and
the precise requirement of spatial and temporal factors.5e7 These
limitations stem from our inability to predict the conformation of
receptor in solution a priori and the innumerable non-covalent
interactions that play an integral role in deciding whether or not
a molecule can act as a receptor for specific guest. The design of
receptors incorporating non-conventional hydrogen bonding in-
teractions continues to be challenging even though enormous ad-
vancements have been made during the last two decades in the
understanding of non-conventional hydrogen bonding.8e10
curate atomic level complementarity with the guest molecule.
Therefore, a semi-rigid system that can adopt a favorable confor-
mation with less bond rotation to fit the guest molecule is especially
useful. The advantage of such design is the possibility to generate
receptors for any given guest molecule through simple modulation
of the receptor. We report a simple, uncharged triazole-based semi-
rigid receptor molecule capable of anion recognition utilizing non-
conventional hydrogen bonding and also report triazolophanes
with tubular and string-like architecture in the solid state.
2. Results and discussion
The Huisgen reaction (or 1,3-dipolar cycloaddition) involving an
alkyne and azide unit is the simplest method to introduce a triazole
entity. This reaction has been central to many investigations in
recent years for applications in bioconjugation and in supramo-
lecular chemistry.14e16 Triazole derivatives17 and triazolophanes18
have been demonstrated as excellent entities for molecular recog-
nition utilizing the CH/O and CH/N interactions. A triazole ring
with three nitrogens and a CeH donor site can be engineered to
make a specific receptor exploiting the donor/acceptor interactions.
Making use of these hydrogen bond donor/acceptor sites for mo-
lecular recognition requires a precise arrangement of the triazole
moiety in appropriate spatial disposition to maximize the in-
teraction with the guest molecule. This requires use of an
Molecular engineering of receptors requires a precise control of
binding interactions, correct cavity size and solvation among other
parameters.11,12 One path for successful molecular engineering is
design and synthesis of preorganized receptors that will have an
energetic advantage over other flexible structures.13,17c However,
a conformationally rigid system may hamper the torsional motion
* Corresponding author. Tel.: þ91 11 26591380; e-mail address: h_haridas@
hotmail.com (V. Haridas).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.078

728
V. Haridas et al. / Tetrahedron 67 (2011) 727e733
appropriate scaffold that can display the triazole units in the right
orientation for binding to anions.
amide close to the aryl ring may provide a suitable environment
for the relatively acidic C2H of the aromatic ring to participate in
binding. Upon addition of tetrabutylammonium halide (TBAX) to
9a in CDCl3 resulted in shifting of amide NHs, aromatic ring hy-
drogen (C2H) and both triazole ring CHs to downfield (Fig. 1). The
detailed NMR titration experiments performed on 9a showed that
In search of a molecular scaffold for the ideal disposition of
triazole units, we embarked on a systematic analysis of rigid aro-
matic scaffolds. Anchoring triazole moieties on a benzenoid scaf-
fold may provide rigidity, and thus may act as receptors for anions.
We synthesized molecules 3 and 5 embodying two triazole moie-
ties in their structures and evaluated their binding affinities toward
anions. The Boc protected propargylamine was reacted with m-
xylylene diazide in the presence of catalytic amounts of CuI to yield
3. Similarly, 5 was synthesized from p-xylylene diazide and Boc-
propargylamine (Scheme 1).
9.3
9.1
TBAF
8.9
TBACl
8.7
N3
TBABr
TBAI
8.5
8.3
N
N
N3
N
N
N
2
8.1
-2
N
8
Equivalents of anion
18
28
CuI
NH HN
O
O
Fig. 1. Variation of aromatic CH (isopthaloyl) proton chemical shift upon addition of
TBAX to a solution of 9a in CDCl3 at room temperature.
O
O
O
3
N
H
O
it indeed binds to Fꢀ, Clꢀ, Brꢀ, and Iꢀ (Fig. 1 and Table 1). The
binding constants were determined using WinEQ NMR analysis of
the NMR data (Supplementary data).19 Receptor 9a binds to fluo-
ride strongly (Ka 1973ꢁ150 Mꢀ1), followed by weak binding to Clꢀ,
Brꢀ, and Iꢀ (Table 1). Job plots indicated the formation of 1:1
complex (Supplementary data). Receptor 13a with triazole entities
1
N
N
N
N
N
N
CuI
N3
N3
NH
HN
O
O
4
O
O
Table 1
5
Binding constants of triazole derivatives 9a and 7a along with dialkyne 8a as the
control
Scheme 1. Synthesis of 3 and 5.
Anion salts
Ka (Mꢀ1
(9a)
)
Ka (Mꢀ1
(7a)
)
Ka (Mꢀ1
(8a)
)
The anion binding properties of all the synthesized compounds
were investigated using a 1H NMR titration technique. The addi-
tion of tetrabutylammonium halide (TBAX) to a solution of 3 and 5
in CDCl3 showed no noticeable changes in the NMR spectra, in-
dicating no binding of anions. Therefore, we designed compounds
9a and 13a (Scheme 2), anticipating that the incorporation of the
Fꢀ
1973ꢁ150
914ꢁ15
436ꢁ7
1383ꢁ90
1606ꢁ41
553ꢁ8
1028ꢁ97
548ꢁ34
222ꢁ5
Clꢀ
Brꢀ
Iꢀ
115ꢁ3
248ꢁ15
104ꢁ7
on the 1,4-positions of an aromatic ring was insoluble in CDCl3 and
the binding studies were carried out in DMSO-d6. The NMR ti-
tration experiments show that molecule 13a binds only to the
fluoride ion with weak binding (Kaw82 Mꢀ1) affinity. The change
from amide linkages to ester linkages (9a and 9b or 13a and 13b)
resulted in complete lack of anion binding. The two amide NHs
and two acidic triazole CHs, in concert with an aromatic proton in
close proximity are essential for binding. The influence of phenyl
rings at the terminal positions were investigated by using azido-
methyl acetate instead of benzylazide in the reaction (Scheme 3).
The receptors 7a and 7b showed improved solubility behavior;
additionally the selectivity towards anions was also changed as
a result of change in the terminal groups. Receptor 7a binds to
chloride stronger than fluoride (Table 1, Fig. 2), unlike receptor 9a
that binds fluoride more strongly than chloride. The different af-
finities of 7a and 9a towards anions might be due to flexibility of
the structure as a result of the change in terminal groups. As
control experiments, dialkyne 8a was analyzed for binding to-
wards various anions and found that the Ka values (Table 1) are
lesser than that of the receptors 7a and 9a. Receptors with triazole
units on the 1,3 positions of the benzene ring are better binders of
anions than the receptors wherein the triazole units were attached
to 1,4-positions of the phenyl ring implying the right cavity size is
essential for binding. Mere introduction of triazole units on the
aromatic scaffold is also not sufficient as receptor 3 bound anions
O
O
O
O
X
X
X
X
N
N
N
N
8a, 8b
N
N
CuI
N3
9a, X = -NH
9b, X = -O
10
O
X
O
X
CuI
O
O
N
N
N
X
X
N
N
N
12a X = -NH
12b X = -O
13a X = -NH
13b
X = -O
Scheme 2. Synthesis of 9a, 9b, 13a and 13b.

V. Haridas et al. / Tetrahedron 67 (2011) 727e733
729
with lesser affinity than 7a and 9a. The amide bonds are essential
for halide binding as none of the ester-linked molecules (9b, 13b)
showed affinity for halide ions. These results clearly demonstrate
that triazole units provide additional hydrogen bond donor sites,
which in concert with the precise arrangement of additional hy-
drogen bond donor moieties such as amide bonds can enhance
binding affinities.
cyclic structure and amide linkages. Similarly, ester-linked biphenyl
macrocycle 22 with a 21-membered ring showed no affinity for the
halide ions. Our observation is that all the amide-based triazole
compounds synthesized had poorer solubility than their ester
counterparts. Therefore, we believe that the rigid triazolophanes
with amide linkages might arrange in the solid state using very
strong intermolecular hydrogen bonding interactions.
O
O
N3
N3
O
O
HN
NH
O
HN
O
NH
N
N
4
8a
N
N
O
O
N
N
N
N
CuI
N
N
N
N
N
N
CuI
N
N
N
N
N
N
O
14
O
N3
O
H3CO
OCH3
O
O
7a
H3CO
N
N
O
O
N3
N
N
N3
+
N
N
6
O
O
O
O
O
N
15
N
N
N
O
O
NH
HN
CuI
CuI
O
O
16
17
N
N
N
X
X
12a
N
N
N
O
8a, 8b
O
O
O
O
X = -NH
X = -O
N
N
N
N
H3CO
OCH3
N
N
7b
O
O
Scheme 3. Synthesis of 7a and 7b.
+
O
O
N3
N3
N
N
18
N
N
N
N
N
N
CuI
N
N
N
19
N
O
O
9.17
8.97
8.77
8.57
8.37
8.17
TBACl
N3
N3
O
O
O
N
O
20
TBAF
TBABr
TBAI
21
O
O
N
N
N
N
N
22
Scheme 4. Synthesis of 14, 16 17, 19, 20, and 22.
0
5
10
15
Equivalents of anion
20
Fig. 2. Variation of aromatic CH (isopthaloyl) proton chemical shift upon addition of
TBAX to a solution of 7a in CDCl3 at room temperature.
This prompted us to use a more flexible linker to tether the two
triazole units. Semi-rigid amide/ester-linked triazolophanes with
four and six-methylenes in the ring were synthesized from the
corresponding diazides and dialkynes. For example, reaction of 1,4-
diazidobutane with dialkyne 8b resulted in 19- and 38-membered
macrocycles 16 and 17 in 67% and 12% yield, respectively. Similarly,
reaction of 1,6-diazidohexane with 8b provided 20 and 40-mem-
bered triazolophanes 19 and 20 in 56% and 15% yield, respectively. It
is noteworthy to mention that macrocycles 17 and 20 embody four
triazole units in their structures. Macrocycles 16e20 are highly
symmetric as evident form their 1H NMR spectra. Macrocycles 16
and 17 display two sets of peaks for the methylene protons of the
butyl chains, one singlet for the triazole CHs and one singlet repre-
senting the methylenes attached to the ester oxygens. 38-mem-
bered macrocycle 20 with four triazole units showed only one
We then turned our attention to restricting the conformation of
the receptors by synthesizing various triazole-based macrocycles
with the intention that the triazolophanes will act as constrained
analogs of the open chain structures. We envisaged that tri-
azolophanes with highly preorganized structure may bind anions
very strongly and with better selectivity. We anticipated that these
triazolophanes may also serve as a good model system for studying
their supramolecular interaction using non-conventional hydrogen
bonding. Therefore, various triazolophanes were designed and
synthesized (Scheme 4) to find application as receptors and also to
study their organization in the solid state. The p-xylylene diazide 4
was reacted with dialkyne 8a to provide the macrocycle 14 in 70%
yield. The 1H NMR spectrum of 14 indicated that it has a symmetric
structure as evident from the appearance of a singlet for benzylic
singlet for the triazole CHs at d 7.68 ppm (CDCl3) and very symmetric
distributions of methylene protons in the 1H NMR spectrum. The 1H
NMR spectrum of 19 showed one singlet for the two triazole CHs and
highly symmetric distributions of methylene protons. These tetra-
triazole compounds 17 and 20 open up new opportunities for
developing molecules with metal uptake ability. The attempted
protons at
d 5.52 ppm. Reaction of diazide 4 with terephthaloyl-
anchored dialkyne 12a resulted in highly insoluble material and
was unable to be characterized. Macrocycle 14 with 21-membered
ring showed very weak binding to halide anions in spite of its rigid

730
V. Haridas et al. / Tetrahedron 67 (2011) 727e733
synthesis of various amide analogs of triazolophanes by reaction of
8a with diazides 15, 18, and 21 resulted in highly insoluble material.
This hampered their characterization and the binding studies.
Macrocycles 16, 17, 19, 20, and 22 with ester linkages showed no
noticeable changes in their 1H NMR spectra afteraddition of variable
amounts of TBAX in CDCl3. The results underscore the stringent
requirements of the precise conformation; an adequate number of
binding moieties and flexibility of the structure are of paramount
importance in the design of receptors.
The ester-linked cyclophanes are interesting candidates for
studying their self-assembling properties since they do not have
any conventional hydrogen bond donor sites. These macrocyclic
structures without any conventional hydrogen bond donor sites
may organize in the solid state using CH/O and CH/N in-
teractions.20 Therefore, these compounds may serve as good
models for studying non-conventional and non-covalent hydrogen
bonding interactions.
used triazole nitrogen (N4) and oxygen of the ester carbonyl (O1) as
hydrogen bond acceptors, whereas the aromatic proton (H4) and
triazole hydrogen (H14) acted as the donors. The aliphatic butyl
moiety that links the two triazole units is disordered over two po-
sitions. Moreover, the benzene ring of the molecule takes an ap-
proximate perpendicular juxtaposition, in which it makes an angle
of 66.6ꢂ with N1 bearing triazole and 82.3ꢂ with N4 bearing triazole
ring. The lattice stabilization is achieved through weak CeH/X
(X¼O, N) hydrogen bonds and
p
/
p
stacking interactions. Two
stacked with
centrosymmetrically related benzene rings are
p
ꢀ
a shearing in such a way that the C2/C2 distance is 3.413 A and the
distance between the best least squares plane through these rings is
ꢀ
3.356 A (Supplementary data). Between these
p-stacked molecules
there is an additional CeH/N interaction between H6 and N4
ꢂ
ꢀ
(H6A/N4¼2.611 A, C6eH6A/N4¼152.1 ), thus generating a dimer
through a unison of CeH/N and interactions (Fig. 3a). Two
such dimers that are related by c glide are interconnected through
p/p
ꢂ
ꢀ
Triazolophane 16 was crystallized from a mixture of chloroform
and methanol. It crystallized in monoclinic crystal system (space
group, P21/c) with four molecules in the unit cell. Each macrocycle
another CeH.O (H14A/O1¼2.611 A, C14eH14A/O1¼133.3 )
hydrogen bond. This pattern is infinitely repeated to build up the
lattice as shown in Fig. 3b. When the packing is viewed down b axis,
because of the
p
-stacking, nanotube-like arrangements21 are
formed (Fig. 3b) and this arrangement is held in place through weak
CeH/O interactions.
The biphenyl linked cyclophane 22 was synthesized from 8b to
2,20-bis(azidomethyl)biphenyl 21 in 63% yield. Macrocycle 22 was
crystallized from a mixture of chloroform and methanol (2:1). The
X-ray crystal structure analysis (Fig. 4) revealed a string-like ar-
rangement of macrocycles connected by intermolecular CH/ꢂN
ꢀ
hydrogen bonding (H12A/N5¼2.732 A, C12eH12ꢂAeN5¼137.89 )
ꢀ
and (H12A/N4¼2.678 A, C12eH12AeN4¼134.80 ). One triazole
ring hydrogen (CH) is pointing inside the cavity, and the CH of
second triazole ring is projecting outwards, thus ideal for intra-
molecular and intermolecular interactions. The intramolecular
Fig. 4. (a) X-ray crystal structure of 22 (b) CPK model of the molecule showing the
internal cavity (c) The arrangement of 22 showing the intramolecular and in-
termolecular CH/N interactions.
Fig. 3. (a) The dimeric arrangement of 16 showing the
interactions (b) Packing diagram of 16.
pepand hydrogen bonding

V. Haridas et al. / Tetrahedron 67 (2011) 727e733
731
hydrogen bonding is between the triazole nitrogens (N1 and N2)
followed by dropwise addition of acid chloride (2.5 mmol) in dry
dichloromethane over 30 min. The reaction mixture was stirred for
12 h. The solvent was evaporated and the residue was washed se-
quentially with 2 N H2SO4, saturated solution of NaHCO3, water and
diethylether. The solid obtained was recrystallized from a mixture
of chloroform and methanol.
ꢀ
and the CH (H14A) of the other triazole unit (N1/H14A¼2.99 A,
ꢀ
N2/H14A¼2.99 A). The biphenyl system has an orthogonal
arrangement of phenyl rings, and the cavity size of the macrocycle
is different in the vertical and horizontal direction. The distance
ꢀ
between the atoms C12 and C14 is 5.53 A. The distance between
ꢀ
N2 and C14 is w3.64 A. The vertical distance between the atoms C2
and C22 is 8.52 A. X-ray crystal structures of two triazolophanes 16
4.2.1. Compound 8a. Yield 96%; mp 170e172 ꢂC; 1H NMR
ꢀ
and 22 thus demonstrated the intrinsic tendency to assemble in the
solid state using non-conventional hydrogen bonding interactions.
(300 MHz, DMSO-d6):
d
3.13 (s, 2H), 4.06 (d, J¼2.7 Hz, 4H), 7.56 (t,
J¼7.8 Hz, 1H), 7.97 (d, J¼7.5 Hz, 2H), 8.31 (s, 1H), 9.03 (br s, 2H); 13C
NMR (75 MHz, DMSO-d6):
d 28.6, 72.9, 81.1, 126.4, 128.5, 130.0,
3. Conclusions
134.1, 165.5; IR (KBr): 3315, 3256, 3079, 2928, 2113, 1649 (br), 1535,
1476, 1418, 1301, 1177, 1055, 1010 cmꢀ1; HRMS (ESI): m/z: calcd for
C14H13N2O2: 241.0977, found: 241.0980.
We demonstrated that placing triazole moieties on different
positions of an aromatic scaffold can change the binding affinity
towards anions. Various receptor designs described here empha-
size that simple triazole moiety is a potential CH hydrogen bond
donor for binding anions and for designing self-assembling sys-
tems. Macrocycles 14, 16, 17, 19, 20, and 22 containing triazole units
with small and large rings can be designed and synthesized using
click chemistry. The self-assembling properties of macrocycles 16
and 22 were investigated by X-ray crystallographic analysis. The
macrocycle 16 assembles as a nanotubular structure in the solid
state using entirely non-conventional non-covalent interactions.
The molecules synthesized here will be of potential use in bi-
ological ion-transport and thus may have nanobiotechnological
applications. The intrinsic tendency of the triazole moiety to or-
ganize in the solid state using non-conventional hydrogen bonding
will be a harbinger for further studies in the area of crystal
engineering.
4.2.2. Compound 12a. Yield 95%; mp 247e250 ꢂC; 1H NMR
(300 MHz, DMSO-d6):
d
3.15 (s, 2H), 4.08 (s, 4H), 7.95 (s, 4H), 9.08
29.0, 73.43, 81.6, 127.8,
(br s, 2H); 13C NMR (75 MHz, DMSO-d6):
d
136.7, 165.7; IR (KBr): 3285 (br), 3062, 2955, 2903, 2859, 2119,1638,
1543, 1494, 1443, 1356, 1285, 1231, 1161, 1113, 1064 cmꢀ1; HRMS
(ESI): m/z: calcd for C14H12N2O2Na: 263.0796, found: 263.0802.
4.3. General method of preparation of 7a, 7b, 9a, 9b, 13a,
and 13b
To an ice cold and homogeneous solution of dialkyne
(1.03 mmol) in dry acetonitrile was added DIEA (0.35 mL,
2.1 mmol), followed by benzylazide 10 or azidomethyl acetate 6
(2.07 mmol) under an N2 atmosphere. To the reaction mixture
under nitrogen, was added CuI (19.67 mg, 0.11 mmol) and stirred
for 24 h. The reaction mixture was evaporated and the solid
obtained was washed sequentially with aqueous solution of
NH4ClþNH4OH (9:1), 2 N H2SO4, saturated solution of NaHCO3,
water, and diethylether. The solid obtained was recrystallized from
a mixture of chloroform and methanol.
4. Experimental section
4.1. General method of preparation of 3 and 5
To an ice cold solution of Boc-propargylamine (1) (413 mg,
2.66 mmol) in dry acetonitrile was added diisopropylethylamine
(DIEA) (0.45 mL, 2.7 mmol), followed by diazide (200 mg,
1.06 mmol) under an N2 atmosphere. CuI (21 mg, 0.11 mmol) was
added and the reaction mixture was stirred for 24 h under an N2
atmosphere. The solvent was evaporated and the residue was dis-
solved in chloroform and washed with aqueous solution of
NH4ClþNH4OH (9:1), 2 N H2SO4, saturated solution of NaHCO3 and
water. The organic layer was dried over anhydrous Na2SO4 and
evaporated to obtain the product.
4.3.1. Compound 7a. Yield 89%; mp 159e160 ꢂC; 1H NMR
(300 MHz, DMSO-d6):
4H), 7.66 (t, J¼7.95 Hz, 1H), 8.02e8.15 (m, 4H), 8.46 (s, 1H), 9.27 (br
s, 2H); 13C NMR (75 MHz, DMSO-d6):
35.3, 50.6, 52.9, 124.9, 126.9,
128.9, 130.4, 134.8, 145.5, 166.2, 168.2; IR (KBr): 3413, 3278, 3138,
3067, 2993, 2954, 1754, 1643, 1534, 1443, 1377, 1291, 1226 cmꢀ1
d
3.78 (s, 6H), 4.63 (d, J¼4.2 Hz, 4H), 5.46 (s,
d
;
HRMS (ESI): m/z: calcd for C20H22N8O6Na: 493.1560, found:
493.1556.
4.3.2. Compound 7b. Yield: 92%; mp 222e224 ꢂC; 1H NMR
4.1.1. Compound 3. Yield 80%; mp 93e96 ꢂC; 1H NMR (300 MHz,
(300 MHz, DMSO-d6):
4H), 7.95 (s, 4H), 7.99 (s, 2H), 9.21 (br s, 2H); 13C NMR (75 MHz,
DMSO-d6): 35.3, 50.6, 52.9, 124.9, 127.9, 136.8, 145.4, 165.9, 168.2;
d
3.70 (s, 6H), 4.54 (d, J¼5.1 Hz, 4H), 5.37 (s,
CDCl3):
4H), 7.11 (s, 1H), 7.22 (d, J¼7.5 Hz, 2H), 7.37 (t, J¼7.5 Hz, 1H), 7.44 (s,
2H); 13C NMR (75 MHz, CDCl3):
28.3, 36.1, 53.6, 79.6, 121.9, 127.3,
d
1.42 (s, 18H), 4.38 (d, J¼5.7 Hz, 4H), 5.19 (br s, 2H), 5.48 (s,
d
d
IR (KBr): 3333, 3291, 3146, 3080, 3007, 2957, 1739, 1660, 1634, 1554,
1499, 1444, 1416, 1372, 1293, 1248, 1149, 1052 cmꢀ1; HRMS (ESI):
m/z: calcd for C20H23N8O6: 471.1741, found: 471.1737.
128.1, 129.8, 135.7, 146.1, 155.8; IR (KBr): 3348, 3140, 2979, 2938,
1694, 1526, 1443, 1365, 1281, 1248, 1171, 1046 cmꢀ1; HRMS (ESI):
m/z: calcd for C24H34N8O4Na: 521.2601, found: 521.2617.
4.3.3. Compound 9a. Yield: 90%; mp 196e197 ꢂC; 1H NMR
4.1.2. Compound 5. Yield 90%; mp 184e185 ꢂC; 1H NMR (300 MHz,
(300 MHz, CDCl3þDMSO-d6):
d
4.66 (d, J¼5.1 Hz, 4H), 5.49 (s, 4H),
CDCl3):
d
1.42 (s, 18H), 4.36 (d, J¼6.0 Hz, 4H), 5.08 (br s, 2H), 5.49 (s,
7.24e7.44 (m, 10H), 7.48 (t, J¼6.0 Hz, 1H), 7.62 (s, 2H), 8.04 (d,
4H), 7.25 (m, 4H), 7.44 (s, 2H); 13C NMR (75 MHz, CDCl3):
d
28.3,
J¼7.5 Hz, 2H), 8.31 (m, 3H); 13C NMR (75 MHz, DMSO-d6):
d 33.4,
36.1, 53.6, 79.7, 121.8, 128.7, 135.3, 146.0, 155.8; IR (KBr): 3399, 3115,
3066, 2977, 2938, 1691, 1511, 1434, 1365, 1332, 1266, 1167,
1050 cmꢀ1; HRMS (ESI): m/z: calcd for C24H35N8O4: 499.2781,
found: 499.2785.
51.2, 121.6, 124.9, 126.5, 126.6, 126.9, 127.2, 128.4, 132.7, 134.6, 143.6,
164.2; IR (KBr): 3289, 3122, 3070, 2939, 1642, 1537, 1427, 1353,
1303, 1231, 1131, 1050 cmꢀ1
; HRMS (ESI): m/z: calcd for
C28H27N8O2: 507.2257, found: 507.2269.
4.2. General method for the preparation of 8a and 12a
4.3.4. Compound 9b. Yield: 98.7%; mp 122e126 ꢂC; 1H NMR
(300 MHz, CDCl3):
7.49 (t, J¼7.8 Hz, 1H), 7.62 (s, 2H), 8.20 (d, J¼7.5 Hz, 2H), 8.64 (s, 1H);
13C NMR (75 MHz, CDCl3):
54.2, 58.3, 123.9, 128.1, 128.6, 128.8,
d 5.45 (s, 4H), 5.54 (s, 4H), 7.25e7.45 (m, 10H),
To an ice cold solution of propargylamine (0.34 mL, 4.9 mmol) in
dry dichloromethane was added triethylamine (1.4 mL, 9.8 mmol)
d

732
V. Haridas et al. / Tetrahedron 67 (2011) 727e733
129.1, 130.2, 131.0, 134.1, 134.3, 142.9, 165.5; IR (KBr): 3133, 3081,
3037, 2959, 1723, 1601, 1445, 1383, 1339, 1296, 1234, 1167, 1124,
1084 cmꢀ1; HRMS (ESI): m/z: calcd for C28H25N6O4: 509.1937,
found: 509.1927.
1387, 1301, 1231 cmꢀ1; HRMS (ESI): m/z: calcd for C36H37N12O8:
765.2857, found: 765.2862.
4.5.3. Compound 19. Yield: 56%; mp 206e207 ꢂC; 1H NMR
(300 MHz, CDCl3):
4H), 5.46 (br s, 4H), 7.59 (s, 2H), 7.62 (s, 1H), 8.32 (d, J¼7.8 Hz, 2H),
8.39 (s, 1H); 13C NMR (75 MHz, CDCl3):
25.4, 29.9, 50.0, 58.9, 123.1,
128.9, 129.7, 130.0, 134.7, 142.6, 165.5; IR (KBr): 3410, 3136, 3093,
2947, 2866, 1715, 1561, 1459, 1387, 1307, 1229, 1142, 1079 cmꢀ1
d
1.24 (br s, 4H), 1.87 (br s, 4H), 4.41 (t, J¼4.8 Hz,
4.3.5. Compound 13a. Yield: 93%; mp 246e248 ꢂC; 1H NMR
(300 MHz, DMSO-d6):
d
4.52 (d, J¼5.4 Hz, 4H), 5.56 (s, 4H), 7.35 (m,
d
10H), 7.93 (s, 4H), 8.04 (s, 2H), 9.13 (t, J¼5.5 Hz, 2H); 13C NMR
(75 MHz, DMSO-d6):
d
34.9, 52.7, 123.1, 127.3, 128.0, 128.1, 128.7,
;
136.1, 136.4, 145.2, 165.5; IR (KBr): 3366, 3122, 3067, 2946, 1638,
1541, 1496, 1450, 1366, 1301, 1232, 1164, 1125, 1055 cmꢀ1; HRMS
(ESI): m/z: calcd for C28H27N8O2: 507.2257, found: 507.2256.
HRMS (ESI): m/z: calcd for C20H23N6O4: 411.1781, found: 411.1793.
4.5.4. Compound 20. Yield: 15%; mp 228e230 ꢂC; 1H NMR
(300 MHz, CDCl3):
d
1.35 (br s, 8H), 1.90 (br s, 8H), 4.34 (t, J¼6.3 Hz,
4.3.6. Compound 13b. Yield: 93%; mp 206e208 ꢂC; 1H NMR
8H), 5.47 (s, 8H), 7.51 (t, J¼7.35 Hz, 2H), 7.68 (s, 4H), 8.23 (d,
(300 MHz, CDCl3):
d
5.45 (s, 4H), 5.53 (s, 4H), 7.28 (m, 4H), 7.37 (m,
54.3, 58.4,
J¼7.2 Hz, 4H), 8.63 (s, 2H); 13C NMR (75 MHz, CDCl3):
d 25.7, 29.9,
6H), 7.60 (s, 2H), 8.05 (s, 4H); 13C NMR (75 MHz, CDCl3):
d
50.1, 58.5, 124.0, 128.8, 130.2, 130.9, 134.3, 142.6, 165.5; IR (KBr):
3427, 3138, 2928, 2860, 1725, 1611, 1443 (br), 1381, 1305, 1232, 1129,
1084 cmꢀ1; HRMS (ESI): m/z: calcd for C40H45N12O8: 821.3483,
found: 821.3501.
123.9, 128.2, 128.9, 129.2, 129.7, 133.7, 134.3, 142.9, 165.5; IR (KBr):
3119, 3063, 2958, 1717, 1499, 1450, 1400, 1274, 1219, 1106, 1057,
1023 cmꢀ1; HRMS (ESI): m/z: calcd for C28H25N6O4: 509.1937,
found: 509.1923.
4.5.5. Compound 22. Yield: 63%; mp 322e324 ꢂC; 1H NMR
(300 MHz, CDCl3):
d
5.35e5.70 (m, 8H), 7.03 (d, J¼7.2 Hz, 2H),
4.4. Preparation of 14
7.20e7.50 (m, 6H), 7.58 (t, J¼7.65 Hz, 1H), 7.76 (s, 2H), 8.26 (d,
J¼7.5 Hz, 2H), 8.84 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 51.8, 59.5,
To an ice cold and well-stirred solution of 8a (149 mg,
0.62 mmol) in dry acetonitrile was added DIEA (0.23 mL, 1.4 mmol),
4 (130 mg, 0.68 mmol), and CuI (12 mg, 0.062 mmol). The reaction
mixture was left stirred under nitrogen for 24 h. Afterwards, the
solvent was evaporated and the residue was washed sequentially
with saturated solution of NH4ClþNH4OH (9:1), 2 N H2SO4, satu-
rated solution of NaHCO3, water, and ether. The solid obtained was
subjected to vacuum to obtain the product 14. Yield: 70%; mp above
122.1,128.2,128.8,129.0,130.1,130.2,131.4,133.3,134.1,138.8,143.4,
164.9; IR (KBr): 3431, 3136, 3097, 2945, 1724, 1452, 1362, 1313, 1231,
1155, 1103, 1048 cmꢀ1; HRMS (ESI): m/z: calcd for C28H23N6O4:
507.1781, found: 507.1790.
Acknowledgements
250 ꢂC; 1H NMR (300 MHz, DMSO-d6):
7.29 (s, 4H), 7.54 (t, J¼7.5 Hz, 1H), 7.96 (d, J¼7.5 Hz, 2H), 8.02 (s, 2H),
8.32 (s, 1H), 9.06 (br s, 2H); 13C NMR (75 MHz, DMSO-d6):
34.9,
d 4.50 (s, 4H), 5.52 (s, 4H),
V.H. thanks DST-New Delhi, CSIR-New Delhi and IIT-Delhi for
financial support.
d
52.4, 123.2, 126.4, 128.4, 129.9, 134.2, 135.9, 145.3, 165.7; IR (KBr):
3284, 1646, 1535, 1428, 1275, 1177, 1129, 1054 cmꢀ1; HRMS (ESI):
m/z: calcd for C22H20N8O2Na: 451.1607, found: 451.1614.
Supplementary data
Detailed experimental procedures and compound character-
ization. Supplementary data related to this article can be found
online version, at doi:10.1016/j.tet.2010.11.078.
4.5. General method of preparation of 16, 17, 19, 20 and 22
To an ice cold and well-stirred solution of 8b (150 mg,
0.62 mmol) in dry acetonitrile was added DIEA (0.21 mL,
1.25 mmol), followed by diazide (0.68 mmol) under N2 atmosphere.
CuI (21 mg, 0.11 mmol) was added to the reaction mixture and
stirred for 24 h. The solvent was evaporated and the residue was
dissolved in chloroform. The chloroform soluble part was washed
sequentially with an aqueous solution of NH4ClþNH4OH (9:1), 2 N
H2SO4, saturated solution of NaHCO3 and water. The chloroform
part was dried over anhydrous Na2SO4, evaporated, and purified by
silica gel column chromatography using chloroform/methanol as
the eluents.
References and notes
1. (a) Ghadiri, M. R.; Granja, J. R.; Buehler, L. K. Nature 1994, 369, 301e304; (b)
Dougherty, D. A.; Stauffer, D. A. Science 1990, 250, 1558e1560; (c) Zhong, Z.;
Anslyn, E. V. J. Am. Chem. Soc. 2002, 124, 9014e9015.
2. (a) Gale, P. A. Acc. Chem. Res. 2006, 39, 465e475; (b) Chang, K. J.; Moon, D.;
Lah, M. S.; Jeong, K. S. Angew. Chem., Int. Ed. 2005, 44, 7926e7929; (c) Farnham, W.
B.; Roe, D. C.; Dixon, D. A.; Calabrese, J. C.; Marlow, R. L. J. Am. Chem. Soc.1990, 112,
7707e7718; (d) Brown, A.; Mullen, K. M.; Ryu, J.; Chmielewski, M. J.; Santos, S. M.;
Felix, V.; Thompson, A. L.; Warren, J. E.; Pascu, S. I.; Beer, P. D. J. Am. Chem. Soc.
2009, 131, 4937e4952; (e) Namor, A. F. Dd.; Khalife, R. J. Phys. Chem. B 2008, 112,
15766e15774; (f) Bresner, C.; Aldridge, S.; Fallis, I. A.; Jones, C.; Ooi, L. L. Angew.
Chem., Int. Ed. 2005, 44, 3606e3609; (g) Hiroto, S.; Aratani, N.; Shibata, N.;
Higuchi, Y.; Sasamori, T.; Tokitoh, N.; Shinokubo, H.; Osuka, A. Angew. Chem., Int.
Ed. 2009, 48, 2388e2390; (h) Camiolo, S.; Gale, P. A. Chem. Commun. 2000,
1129e1130; (i) Cametti, M.; Cort, A. D.; Mandolini, L.; Nissinen, M.; Rissanen, K.
New J. Chem. 2008, 32, 1113e1116; (j) Lehaire, M. L.; Scopelliti, R.; Piotrowski, H.;
Severin, K. Angew. Chem., Int. Ed. 2002, 41, 1419e1422; (k) Fillaut, J. L.; Andries, J.;
Toupet, L.; Desvergne, J. P. Chem. Commun. 2005, 2924e2926; (l) Veale, E. B.;
Tocci, G. M.; Pfeffer, F. M.; Kruger, P. E.; Gunnlaugsson, T. Org. Biomol. Chem. 2009,
7, 3447e3454.
4.5.1. Compound 16. Yield: 67%; mp 212e214 ꢂC; 1H NMR
(300 MHz, CDCl3):
d
1.86 (br s, 4H), 4.53 (br s, 4H), 5.41 (s, 4H), 7.61
27.9, 49.7, 59.3,
(s, 3H), 8.34 (m, 3H); 13C NMR (75 MHz, CDCl3):
d
122.8, 129.1, 129.7, 130.3, 134.6, 143.2, 164.9; IR (KBr): 3573, 3379,
3142, 3094, 2956, 1719, 1563, 1459, 1389, 1309, 1226, 1145,
1068 cmꢀ1; HRMS (ESI): m/z: calcd for C18H19N6O4: 383.1468,
found: 383.1474.
3. (a) Beer, P. D.; Gale, P. A. Angew. Chem., Int. Ed. 2001, 40, 486e516; (b)
Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997, 97, 1609e1646; (c) Gibson, S. E.;
Lecci, C. Angew. Chem., Int. Ed. 2006, 45, 1364e1377.
4. (a) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2002, 41,
3423e3426; (b) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Nature 1998, 394,
764e766.
5. (a) Hunter, C. A. Angew. Chem., Int. Ed. 2004, 43, 5310e5324; (b) Desiraju, G. R.
Acc. Chem. Res. 2002, 35, 565e573.
4.5.2. Compound 17. Yield: 12%; mp above 300 ꢂC; 1H NMR
(300 MHz, DMSO-d6):
d 1.77 (br s, 8H), 4.38 (br s, 8H), 5.38 (s, 8H),
7.65 (t, J¼7.8 Hz, 2H), 8.05e8.25 (m, 8H), 8.35 (s, 2H); 13C NMR
(75 MHz, CDCl3):
d 27.2, 49.1, 58.7, 125.3, 129.9, 130.1, 130.3, 134.3,
6. (a) Cametti, M.; Rissanen, K. Chem. Commun. 2009, 2809e2829; (b) Coletti, C.;
Re, N. J. Phys. Chem. A 2009, 113, 1578e1585.
142.0, 165.0; IR (KBr): 3421, 3132, 2955, 2877, 1713, 1609, 1444,

V. Haridas et al. / Tetrahedron 67 (2011) 727e733
733
7. (a) Ilioudis, C. A.; Tocher, D. A.; Steed, J. W. J. Am. Chem. Soc. 2004, 126,
12395e12402; (b) Dietrich, B.; Guilhem, J.; Lehn, J. M.; Pascard, C.; Sonveaux, E.
Helv. Chim. Acta 1984, 67, 91e104.
8. (a) Berryman, O. B.; Sather, A. C.; Hay, B. P.; Meisner, J. S.; Johnson, D. W. J. Am.
Chem. Soc. 2008, 130, 10895e10897; (b) Yoon, D. W.; Gross, D. E.; Lynch, V. M.;
Sessler, J. L.; Hay, B. P.; Lee, C. H. Angew. Chem., Int. Ed. 2008, 47, 5038e5042.
9. (a) Bryantsev, V. S.; Hay, B. P. J. Am. Chem. Soc. 2005, 127, 8282e8283;
(b) Hay, B. P.; Bryantsev, V. S. Chem. Commun. 2008, 2417e2728.
10. (a) Zhu, S. S.; Staats, S.; Brandhorst, K.; Grunenberg, J.; Gruppi, F.; Dalcanale, E.;
Lutzen, A.; Rissanen, K.; Schalley, C. A. Angew. Chem., Int. Ed. 2008, 47, 788e792;
(b) Amendola, V.; Boiocchi, M.; Fabbrizzi, L.; Palchetti, A. Chem.dEur. J. 2005,
11, 5648e5660; (c) Boiocchi, M.; Boca, L. D.; Gomez, D. E.; Fabbrizzi, L.;
Licchelli, M.; Monzani, E. Chem.dEur. J. 2005, 11, 3097e3104.
11. (a) Kotch, F. W.; Sidorov, V.; Lam, Y. F.; Kayser, K. J.; Li, H.; Kaucher, M. S.;
Davis, J. T. J. Am. Chem. Soc. 2003, 125, 15140e15150; (b) Shi, X.; Mullaugh, K. M.;
Fettinger, J. C.; Jiang, Y.; Hofstadler, S. A.; Davis, J. T. J. Am. Chem. Soc. 2003, 125,
10830e10841; (c) Sessler, J. L.; Kim, S. K.; Gross, D. E.; Lee, C.-H.; Kim, J. S.;
Lynch, V. M. J. Am. Chem. Soc. 2008, 130, 13162e13166; (d) Hamon, M.;
Menand, M.; Gac, S. L.; Luhmer, M.; Dalla, V.; Jabin, I. J. Org. Chem. 2008, 73,
7067e7071; (e) Wintergerst, M. P.; Levitskaia, T. G.; Moyer, B. A.; Sessler, J. L.;
Delmau, L. H. J. Am. Chem. Soc. 2008, 130, 4129e4139; (f) Lankshear, M. D.;
Cowley, A. R.; Beer, P. D. Chem. Commun. 2006, 612e614; (g) Garozzo, D.;
Gattuso, G.; Notti, A.; Pappalardo, A.; Pappalardo, S.; Parisi, M. F.; Perez, M.;
Pisagatti, I. Angew. Chem., Int. Ed. 2005, 44, 4892e4896; (h) Custelcean, R.;
Delmau, L. H.; Moyer, B. A.; Sessler, J. L.; Cho, W. S.; Gross, D.; Bates, G. W.; Brooks,
S. J.; Light, M. E.; Gale, P. A. Angew. Chem., Int. Ed. 2005, 44, 2537e2542;
(i) Bazzicalupi, C.; Bencini, A.; Bianchi, A.; Borsari, L.; Giorgi, C.; Valtancoli, B.
J. Org. Chem. 2005, 70, 4257e4266; (j) Chellappan, K.; Singh, N. J.; Hwang, I. C.;
Lee, J. W.; Kim, K. S. Angew. Chem., Int. Ed. 2005, 44, 2899e2903.
C. A. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 10425e10429; (d) Hunter, C. A.;
Anderson, H. L. Angew. Chem., Int. Ed. 2009, 48, 2e14.
13. (a) Lee, C. H.; Na, H. K.; Yoon, D. W.; Won, D. H.; Cho, W. S.; Lynch, V. M.;
Shevchuk, S. V.; Sessler, J. L. J. Am. Chem. Soc. 2003, 125, 7301e7306; (b)
Bisson, A. P.; Lynch, V. M.; Anslyn, E. V. Angew. Chem., Int. Ed. 1997, 36,
2340e2342.
14. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596e2599; (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2001, 40, 2004e2021.
15. (a) Speers, A. E.; Cravatt, B. F. Chem. Biol. 2004, 11, 535e546; (b) DeForest, C. A.;
Polizzotti, B. D.; Anseth, K. S. Nat. Mater. 2009, 8, 659e664; (c) Best, M. D.
Biochemistry 2009, 48, 6571e6584; (d) Polito, L.; Monti, D.; Caneva, E.; Delnevo, E.;
Russo, G.; Prosperi, D. Chem. Commun. 2008, 621e623; (e) Sohma, Y.; Kiso, Y.
ChemBioChem 2006, 7, 1549e1557.
16. (a) Horne, W. S.; Stout, D. C.; Ghadiri, M. R. J. Am. Chem. Soc. 2003, 125,
9372e9376; (b) van Maarseveen, J. H.; Horne, W. S.; Ghadiri, M. R. Org. Lett.
2005, 7, 4503e4506; (c) Boisselier, E.; Diallo, A. K.; Salmon, L.; Ornelas, C.;
Ruiz, J.; Astruc, D. J. Am. Chem. Soc. 2010, 132, 2729e2742.
17. (a) Li, Y.; Flood, A. H. Angew. Chem., Int. Ed. 2008, 47, 2649e2652; (b) Hua, Y.;
Flood, A. H. Chem. Soc. Rev. 2010, 39, 1262e1271; (c) Lee, S.; Hua, Y.; Park, H.;
Flood, A. H. Org. Lett. 2010, 12, 2100e2102; (d) Juwarker, H.; Lenhardt, J. M.;
Pham, D. M.; Craig, S. L. Angew. Chem., Int. Ed. 2008, 47, 3740e3743; (e)
Meudtner, R. M.; Hecht, S. Angew. Chem., Int. Ed. 2008, 47, 4926e4930.
18. (a) Li, Y.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 12111e12122; (b) Haridas, V.;
Lal, K.; Sharma, Y. K.; Upreti, S. Org. Lett. 2008, 10, 1645e1647.
19. Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311e312.
20. (a) Sutor, D. J. Nature 1962, 195, 68e69; (b) Taylor, R.; Kennard, O. J. Am. Chem.
Soc. 1982, 104, 5063e5070; (c) Desiraju, G. R. Acc. Chem. Res. 1991, 24, 290e296;
(d) Thalladi, V. R.; Gehrke, A.; Boese, R. New J. Chem. 2000, 24, 463e470.
21. (a) Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.; Khazanovich, N.
Nature 1993, 366, 324e327; (b) Ranganathan, D.; Haridas, V.; Gilardi, R.;
Karle, I. L. J. Am. Chem. Soc. 1998, 120, 10793e10800.
12. (a) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F.
Angew. Chem., Int. Ed. 2002, 41, 898e952; (b) Oshovsky, G. V.; Reinhoudt, D. N.;
Verboom, W. Angew. Chem., Int. Ed. 2007, 46, 2366e2393; (c) Jiang, W.; Schalley,