Efficient halogen-lithium exchange reactions to functionalize poly(alkyl aryl ether) dendrimers

Article abstract of DOI:10.1016/j.tet.2006.04.052

Poly(alkyl aryl ether) dendrimers were functionalized with bromophenyl groups at their peripheries, so as to have 3, 6, 12, and 24 groups in the zero, first, second, and third generation dendrimers, respectively. The new bromophenyl functionalized dendrim

Full text of DOI:10.1016/j.tet.2006.04.052

Tetrahedron 62 (2006) 6228–6235
Efficient halogen–lithium exchange reactions to functionalize
poly(alkyl aryl ether) dendrimers
*
Jayaraj Nithyanandhan and Narayanaswamy Jayaraman
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
Received 9 February 2006; revised 5 April 2006; accepted 20 April 2006
Available online 12 May 2006
Abstract—Poly(alkyl aryl ether) dendrimers were functionalized with bromophenyl groups at their peripheries, so as to have 3, 6, 12, and
24 groups in the zero, first, second, and third generation dendrimers, respectively. The new bromophenyl functionalized dendrimers were
assessed for their reactivities in C–heteroatom and C–C bond forming reactions. For this purpose, the bromophenyl functionalized dendrimers
were converted quantitatively to their polylithiated derivatives, using n-BuLi in benzene. The polylithiated dendrimers were reacted either
with D2O or with CO2, so as to afford the corresponding deuterated and carboxylic acid functionalized dendrimers, respectively. The carbox-
ylic acid functionalized dendrimers were modified further to the methyl esters during their characterization.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
dendrimers up to the third generation, which exhibit 24
peripheral lithiated arenes, are presented herein.
Alkyl- and aryllithium derivatives are versatile intermediates
in organic and organometallic synthesis.1 Most often the
lithium derivatives are derived by exchange reactions involv-
ing alkyl- or arylhalide and a lithium source.2 Lithiation of
an alkyl- or an aryl substrate is one of the important reaction
in the course of many C–C bond forming, C–heteroatom
bond forming and C–varied metal bond forming reactions.3
Many theoretical and synthetic studies have been reported
due to wide utility of organolithium compounds.4 Poly-
lithiation of macromolecules represents a system wherein
multiple simultaneous lithiations are performed and such
polylithiated intermediates are then used to prepare a variety
of functionalized macromolecules.5 Uniformly branched
dendritic macromolecules6 are recent additions in polylithia-
tions. Carbosilane-based dendrimers were the only ones
explored thus far in terms of their polylithiation and further
functionalization.7 As a strategy to functionalize poly(alkyl
aryl ether) dendrimers,8 polylithiations of the dendrimers
were undertaken, in an effort to exploit the rich lithiation
chemistry as applicable to this class of dendrimers. The
polylithiated dendrimers, obtained by a halogen–metal
exchange reaction, were subjected to reactions with a few
electrophiles. The syntheses and reactions of polylithiated
2. Results and discussion
Poly(alkyl aryl ether) dendrimers are constituted with phloro-
glucinol as the core and branching component and a penta-
methylene as the linker connecting the branches. endo- and
exo-Receptor properties of these dendrimers have been
explored and beneficial effects of the dendritic architectures
have been previously identified.9 The poly(alkyl aryl ether)
dendrimers exhibit multiple phenolic hydroxyl groups at
their peripheries and the zero, first, second, and third gener-
ation dendrimers present 3, 6, 12, and 24 such groups, re-
spectively.8 These phenolic hydroxyl groups were utilized
to install functionalities necessary for polylithiations.
Bromophenyl functionality was chosen for its subsequent
bromide–lithium exchange reaction. Multiple phenolic O-al-
kylation of the dendrimer peripheries with a bromophenyl
group containing monomer was thus conducted across dif-
ferent generations of the poly(alkyl aryl ether) dendrimers.
2.1. Synthesis of bromophenyl group functionalized
monomer
The bromophenyl group containing derivative 2 was ob-
tained upon reaction of 1,5-dibromopentane with 4-bromo-
phenol (1) (Scheme 1). The mono-O-alkylated product 2
was utilized to alkylate the peripheral phenolic groups of
the dendrimers.
Keywords: Alkylation; C–C bond formation; Dendrimers; Lithiation.
* Corresponding author. Tel.: +91 80 2293 2406/2403; fax: +91 80 2360
0529; e-mail: jayaraman@orgchem.iisc.ernet.in
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.052

J. Nithyanandhan, N. Jayaraman / Tetrahedron 62 (2006) 6228–6235
6229
The first, second, and third generation bromophenyl group
containing dendrimers were obtained by multiple O-alkyl-
ation of the corresponding phenolic dendrimers with mono-
mer 2. The O-alkylations were performed in the presence of
K2CO3 and 18-C-6 (cat.) in 2-butanone (DMF) and the bro-
mophenyl terminated first (5), second (6), and third genera-
tion (7) dendrimers were obtained in moderate yields. The
zero, first, second, and third generation dendrimers were thus
functionalized with 3, 6, 12, and 24 bromophenyl groups at
their peripheries, respectively (Scheme 3 and Fig. 1).
OH
Br
O
(i)
Br
Br
2
1
Scheme 1. (i) 1,5-Dibromopentane, K2CO3, 18-C-6, Me2CO, 70 ꢀC, 7 h,
80%.
(i)
2.2. Synthesis of bromophenyl group functionalized
dendrimer
G -(Br)
1
6
G -(OH)
1
6
5
85 %
The zero-generation dendrimer 4, containing the bromo-
phenyl group, was obtained by a three-fold alkylation of a tri-
bromide 3 with 4-bromophenol, in good yields (Scheme 2).
(i)
G -(Br)
2
2
12
24
G -(OH)
2
12
6
70 %
Br
(i)
Br
O
G -(Br)
3
O
G -(OH)
3
24
34 %
Br
O
O
7
(i)
Br
Br
O
O
O
O
+
Scheme 3. (i) K2CO3, 18-C-6 (cat.), 2-butanone, DMF, reflux.
O
OH
Br
Dendrimers 4–7 were freely soluble in solvents such as, THF,
PhMe, and MeOH whereas, their solubilities in MeOH,
Et2O, and hexane were moderate to poor. In terms of loading,
the bromophenyl group constituted 3.53, 2.78, 2.52, and
G -(Br)
0
4
3
Br
3
1
Scheme 2. (i) K2CO3, 18-C-6, 2-butanone, 70 ꢀC, 12 h, 86%.
Br
Br
Br
Br
O
O
O
O
Br
Br
O
O
O
O
O
O
O
Br
O
O
O
O
O
O
O
O
O
O
O
O
Br
O
Br
Br
O
O
O
O
O
O
O
O
O
O
O
Br
O
O
O
O
O
O
O
Br
O
O
Br
Br
O
Br
O
O
Br
O
G -(Br)
1
5
O
O
O
6
Br
Br
O
O
O
O
Br
Br
O
O
O
O
O
Br
O
O
O
O
O
O
O
O
O
O
O
O
Br
O
O
O
O
O
O
Br
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Br
O
O
O
Br
O
O
O
O
Br
Br
O
O
O
Br
Br
O
O
O
O
O
O
O
O
O
Br
O
O
O
O
O
O
O
O
O
O
Br
Br
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Br
O
Br
O
Br
Br
Br
O
Br
O
O
O
O
O
O
Br
G -(Br)
3
7
24
Br
Br
Br
G -(Br)
12
6
2
Figure 1. Molecular structures of bromophenyl group functionalized G1-(Br)6 (5), G2-(Br)12 (6), and G3-(Br)24 (7) dendrimers.

6230
J. Nithyanandhan, N. Jayaraman / Tetrahedron 62 (2006) 6228–6235
2.40 mmol/g in zero (4), first (5), second (6), and third (7)
generation dendrimers, respectively.
dendrimers 4–7, in benzene atw50 ꢀC, afforded the lithiated
derivatives 8–11 (Scheme 4).
The lithiated derivatives precipitated as a white solid from
the reaction mixture. Without isolation, lithiated products
were reacted with electrophiles, so as to yield the C–hetero-
atom or C–C bond formed product. In one series, the lithi-
ated derivatives were treated with D2O (Scheme 4) and the
deuterated dendrimers were obtained in good to excellent
yields as the only isolable product of the reaction (Fig. 2).
2.3. Characterization
The constitutions and the structural homogeneities of the
dendrimers were ascertained by H and 13C NMR spectros-
1
copiesand elementalanalyses. Specifically, the phloroglucinol
protonsappearedasasingletat 6.05 ppmandthe bromophenyl
moiety atw6.70 andw7.30 ppm, as a pair of doublets in the
1H NMR spectra of the dendrimers. The CH (methine) and C
(q) carbons of the phloroglucinol moiety appeared atw93.5
and 160.5 ppm, respectively, in the 13C NMR spectra. The
resonances of CH (methine) and C (q) of the peripheral
bromophenyl moieties were observed atw116.0,w132.0 and
w112.5,w158.8 ppm, respectively. Mass spectral analysis by
MALDI-TOF and ES methods, could not be accomplished
even after several trials. Gel permeation chromatography
was conducted to assess the GPC profiles of the dendrimers
in THF as the eluant. The retention times of various genera-
tions were: 7: 6.81 min; 6: 7.37 min; 5: 8.09 min; 4:
9.13 min and monomer 2: 10.63 min, consistent with the
proposed Mr values.
Complete deuteration of the dendrimer peripheries was con-
firmed by the characteristic double doublet resonances, cen-
tered at 6.89 and 7.27 ppm, of the peripheral phenyl groups
of the dendrimers in the 1H NMR spectra. The corresponding
13C NMR resonances for the deuterated phenyl group were
observed atw114.4, 129.3, 129.4, and 159.0 ppm. Elemental
analyses of the deuterated products confirmed the structural
homogeneities of the dendrimers.
Upon accomplishing deuteration of the lithiated dendrimers,
efforts were focused to subject them to a C–C bond forming
reaction. Specifically, the reaction mixture containing the
lithiated product was treated with CO2 (g), at 0 ꢀC for
w45 min and left to stir further at room temperature for
15 h. Acidification of the reaction mixture with aq HCl
afforded a precipitate, which was then triturated with ice-
cold water. The precipitatewas dried further to afford the car-
boxylic acid functionalized dendrimers 16–19 (Scheme 5
and Fig. 3).
2.4. Lithiations of bromophenyl functionalized
dendrimers
Lithiation of the bromophenyl functionalized dendrimers
was followed using lithium metal. The lithiated dendrimers
would allow incorporation of various electrophiles in the
course of carbon–heteroatom and carbon–carbon bond for-
mation. Thus, lithiation reactions were conducted with the
most widely used reagent and solvent, namely, n-BuLi and
THF. Lithiation, followed by a subsequent reaction with an
electrophile, was conducted across a series of dendrimers.
In the event, it turned out that the electrophilic substituent
on the product could not be identified. Rather, only the
debromination of the bromophenyl functionality occurred.
On the other hand, use of Et2O as the solvent, in place of
THF, allowed the reaction to proceed in the anticipated
manner, leading to incorporation of the electrophile at the
carbon subjected to the halogen–lithium exchange reaction.
However, the successful reaction in Et2O for the zero-gener-
ation dendrimer with three bromophenyl functionalities
could not be extended to other dendrimers, due to the insolu-
bility of the dendrimers in Et2O. Benzene as the solvent of
the reaction atw50 ꢀC was then identified for the lithiation
reaction. Thus, the reaction of bromophenyl functionalized
Dendrimers 16–19 were viscous hygroscopic solids and thus
were derivatized as the methyl ester derivatives (Scheme 5).
Treatment of the carboxylic acid functionalized dendrimers
with MeOH, in the presence of H2SO4 (cat.), refluxing the
reaction mixture for w24 h, work-up, and purification af-
forded the carboxylic acid methyl ester derivatives of the
dendrimers 20–23 (Fig. 3). The constitutions of the methyl
ester functionalized dendrimer were ascertained by spectro-
scopic methods and elemental analysis. Syntheses of a series
of deuterated and carboxylic acid functionalized dendrimers
thus illustrated the efficient formation of lithiated den-
drimers from the corresponding bromide derivatives.
Only the polysilane dendrimers have thus far been explored
for their lithiation reactions, followed by reactions with elec-
trophiles.7 Within the polysilane dendrimers, the largest den-
drimer contained up to 12 lithiated centers at the peripheries
of the dendrimers. The studies reported herein add to the
(ii)
(i)
Br
Li
D
n
n
n
n =
n =
3
6
4
5
6
7
n =
n =
3
6
12
13
14
15
n =
n =
3
6
8
9
n = 12
n = 24
n = 12
n = 24
n = 12 10
n = 24 11
Scheme 4. (i) n-BuLi, PhH, 50 ꢀC, 45 min and (ii) D2O, rt, 15 h.

J. Nithyanandhan, N. Jayaraman / Tetrahedron 62 (2006) 6228–6235
6231
D
D
O
D
O
D
O
O
O
O
O
O
O
O
D
O
O
O
O
O
O
D
D
O
O
O
O
O
D
O
O
D
O
D
D
D
O
O
O
O
O
O
O
O
D
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
D
O
O
O
O
O
O
D
D
O
O
O
O
O
O
O
O
O
O
D
O
O
D
D
D
O
D
D
D
D
D
O
O
O
O
D
O
O
O
O
D
O
O
O
O
O
O
O
O
O
O
O
D
O
O
O
O
O
O
O
D
O
D
O
O
D
O
O
D
O
O
O
O
O
D
O
O
O
O
O
O
O
D
O
O
O
O
O
O
O
O
D
O
O
O
O
O
O
O
O
O
O
O
O
O
O
D
O
O
D
O
O
O
O
O
O
O
O
D
O
D
O
O
O
O
D
O
O
O
O
O
O
O
O
O
D
O
D
D
D
D
Figure 2. Molecular structures of deuterated G0-(D)3 (12) and G1-(D)6 (13) and G2-(D)12 (14) and G3-(D)24 (15) dendrimers.
(i)
(ii)
Li
CO H
CO Me
2
2
n
n
n
n =
n =
3
6
16
17
n =
n =
3
6
20
21
n =
n =
3
6
8
9
n = 12 18
n = 24 19
n = 12 22
n = 24 23
n = 12 10
n = 24 11
Scheme 5. (i) CO2 (gas), rt, 15 h and (ii) MeOH, H2SO4 (cat.), reflux, 24 h.

6232
J. Nithyanandhan, N. Jayaraman / Tetrahedron 62 (2006) 6228–6235
R
R
R
O
R
O
O
O
O
O
O
O
O
O
R = CO H 16
2
R
O
O
R = CO Me 20
O
2
O
O
O
R
O
O
O
R
O
O
R
O
O
R
R
R
O
R
O
O
O
O
O
O
O
O
R
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
R
R
O
O
O
O
O
O
O
O
O
R
R
R
R
O
O
R
R = CO H 18
2
R
R = CO H 17
R = CO Me 22
2
2
R = CO Me 21
2
R
R
R
R
O
O
O
O
R
O
O
O
O
R
O
O
O
O
O
O
O
O
O
O
O
R
O
O
O
O
O
O
O
R
O
R
O
O
O
R
O
O
O
R
O
O
O
O
O
R
O
O
O
O
O
O
O
R
O
O
O
O
O
O
O
R = CO H 19
2
R
O
O
O
O
O
O
O
O
R = CO Me 23
2
O
O
O
O
R
O
O
R
O
O
O
O
O
O
O
O
O
R
O
R
O
O
O
O
R
O
O
O
O
O
O
O
O
O
R
O
R
R
R
R
Figure 3. Molecular structures of carboxylic acid and methyl ester functionalized poly(alkyl aryl ether) dendrimers.
efforts targeting the widely practiced lithiations into the
general area of dendrimer chemistry.
and carboxylated dendrimers. Having established the forma-
tion of lithiated dendrimers, reaction of such dendrimers
with varied electrophiles will be conducted further.
3. Conclusion
4. Experimental
Poly(alkyl aryl ether) dendrimers, having up to 24 bromo-
phenyl functionalities at their peripheries, were explored
for their efficacies in lithiation reactions. The halide–lithium
exchange reaction was found to be facile and the resulting
lithiated dendrimers underwent reactions with deuterium
and carbon electrophiles, leading, respectively, to deuterated
4.1. General methods
Chemicals were purchased from commercial sources and
were used without further purification. Powdered K2CO3
(Ar grade) was dried at 120 ꢀC for 24 h before being used.

J. Nithyanandhan, N. Jayaraman / Tetrahedron 62 (2006) 6228–6235
6233
Solvents were dried and distilled according literature pro-
cedures.10 Analytical TLC was performed on commercial
Merck plates coated with silica gel GF254 (0.25 mm). Silica
gel (230–400 mesh) was used for column chromatography.
Melting points determined are uncorrected. Microanalyses
were performed on an automated C, H, N analyzer. Benzene
is a carcinogenic substance. Experiments involving this sol-
vent were performed using safety gloves and in a well-venti-
concentrated. Excess of 2 was removed by triturating the
crude residue with Et2O and the resulting residue was
purified further (SiO2, PhMe/EtOAc¼95:5) to afford 5,
as a colorless oil (0.77 g, 85%). TLC Rf 0.71 (PhMe/
1
EtOAc¼96:4). H NMR (300 MHz, CDCl3) d: 1.64 (m,
18H), 1.83 (m, 36H), 3.93 (t, J¼6.3 Hz, 36H), 6.06 (s,
12H), 6.76 (d, J¼9.3 Hz, 12H), 7.34 (d, J¼9.3 Hz, 12H);
13C NMR (75.5 MHz, CDCl3) d: 22.7, 28.9, 67.7, 68.0,
93.9 (Ar. (t)), 112.7 (periphery Ar. (q)), 116.3 (periphery
Ar. (t)), 132.2 (periphery Ar. (t)), 158.2 (periphery Ar. (q)),
160.7 (Ar. (q)); Anal. Calcd for C105H126Br6O18: C, 58.51;
H, 5.89. Found: C, 58.77; H, 6.19.
1
lated fume hood. H and 13C NMR spectral analyses were
performed on a 300 MHz or 400 MHz and 75 MHz spec-
trometer, respectively, with residual solvent signal acting as
the internal standard. The following abbreviations are used
to explain the multiplicities: s, singlet; d, doublet; t, triplet; m,
multiplet; band, several overlapping signals, and br, broad. In
addition, the following abbreviations are used to denote
various carbon nuclei: Ar. (q) and Ar. (t) for phloroglucinol
(quaternary) and phloroglucinol (tertiary), respectively;
periphery Ar. (q) and periphery Ar. (t) for peripheral aromatic
(quaternary) and aromatic (tertiary), respectively.
4.1.4. G2-Br12 (6). A mixture of G2-(OH)12 (0.2 g,
0.423 mmol), 2 (0.527 g, 1.536 mmol), K2CO3 (0.21 g,
1.536 mmol), and 18-C-6 (cat.) in 2-butanone (15 mL) and
DMF (5 mL) was heated at 70 ꢀC for 36 h. Solvents were
then removed in vacuo and the resulting residue was dis-
solved in CH2Cl2, washed with water, dried (Na2SO4), and
concentrated. Excess of 2 was removed by triturating the
crude residue with Et2O and the resulting residue was puri-
fied further (SiO2, PhMe/EtOAc¼95:5) to afford 6, as a
colorless oil (0.374 g, 70%). TLC Rf 0.54 (PhMe/EtOAc¼
4.1.1. Synthesis of monomer 2. 4-Bromophenol (3.0 g,
17.3 mmol), 1,5-dibromopentane (8.44 g, 36.77 mmol),
K2CO3 (2.4 g, 17.3 mmol), and 18-crown-6 (cat.) were dis-
solved in acetone (50 mL) and refluxed for 7 h. The reaction
mixture was cooled, filtered, the solvents were removed un-
der reduced pressure, and the residue was dissolved in
CHCl3 (100 mL) and washed with H2O (2ꢁ100 mL). The
organic layer was concentrated, dried (Na2SO4), and purified
by column chromatography (100–200 mesh, SiO2, petro-
leum ether/EtOAc¼95:5) to afford the required mono-alky-
lated monomer 2 as a waxy solid (4.5 g, 80%, relative to
4-bromophenol). Rf 0.60 (petroleum ether/EtOAc¼95:5).
1H NMR (300 MHz, CDCl3) d: 1.58 (m, 2H), 1.78 (m, 2H),
1.91 (m, 2H), 4.32 (t, J¼6.6 Hz, 2H), 3.91 (t, J¼6.3 Hz,
2H), 6.75 (d, J¼9.3 Hz, 2H), 7.34 (d, J¼9.3 Hz, 2H); 13C
NMR (75.5 MHz, CDCl3) d: 24.8, 28.3, 32.4, 33.5, 67.8,
112.7 (periphery Ar. (q)), 116.3 (periphery Ar. (t)), 132.2 (pe-
riphery Ar. (t)), 158.1 (periphery Ar. (q)); Anal. Calcd for
C11H14OBr2: C, 41.03; H, 4.38. Found: C, 41.07; H, 4.57.
1
98:2). H NMR (300 MHz, CDCl3) d: 1.60 (m, 42H), 1.80
(m, 84H), 3.92 (m, 84H), 6.06 (s, 30H), 6.75 (d, J¼9.0 Hz,
24H), 7.34 (d, J¼9.0 Hz, 24H); 13C NMR (75.5 MHz,
CDCl3) d: 15.2, 22.7, 65.8, 67.6, 67.9, 93.8 (Ar. (t)), 112.6
(periphery Ar. (q)), 116.2 (periphery Ar. (t)), 132.1 (peri-
phery Ar. (t)), 158.1 (periphery Ar. (q)), 160.8 (Ar. (q));
Anal. Calcd for C237H288Br12O42: C, 59.71; H, 6.09.
Found: C, 59.27; H, 5.92.
4.1.5. G3-Br24 (7). A mixture of G3-(OH)24 (0.15 g,
0.036 mmol), 2 (0.353 g, 1.03 mmol), K2CO3 (0.143 g,
1.03 mmol), and 18-C-6 (cat.) in 2-butanone (15 mL) and
DMF (2 mL) was heated at 100 ꢀC for 96 h. Solvents were
then removed in vacuo and the resulting residue was dis-
solved in CH2Cl2, washed with water, dried (Na2SO4), and
concentrated. Excess of 2 was removed by triturating the
crude residue with MeOH and the resulting residue was
purified further (SiO2, PhMe/EtOAc¼95:5) to afford 7, as
a brown oil (0.12 g, 34%). TLC Rf 0.40 (PhMe/EtOAc¼
4.1.2. G0-Br3 (4). A mixture of 3 (0.618 g, 1.079 mmol), 1
(0.671 g, 3.88 mmol), K2CO3 (0.536 g, 3.88 mmol), and
18-C-6 (cat.) in 2-butanone (20 mL) was stirred at 70 ꢀC
for 12 h. The reaction mixture was filtered and solvents
were then removed in vacuo, the resulting residue was dis-
solved in CH2Cl2, washed with water, dried, concentrated,
and purified (SiO2, PhMe/EtOAc¼98:2) to afford 4, as
a white solid (0.84 g, 92%). Mp: 67–69 ꢀC. TLC Rf 0.62
1
98:2). H NMR (300 MHz, CDCl3) d: 1.61 (m, 90H), 1.81
(m, 180H), 3.92 (m, 180H), 6.05 (s, 66H), 6.74 (d, J¼
8.4 Hz, 48H), 7.33 (d, J¼8.4 Hz, 48H); 13C NMR
(75.5 MHz, CDCl3) d: 22.7, 28.9, 29.0, 67.6, 67.9, 93.8
(Ar. (t)), 112.6 (periphery Ar. (q)), 116.2 (periphery Ar.
(t)), 132.1 (periphery Ar. (t)), 158.1 (periphery Ar. (q)),
160.8 (Ar. (q)); Anal. Calcd for C501H612Br24O90: C,
60.22; H, 6.17. Found: C, 59.90; H, 6.29.
1
(PhMe/EtOAc¼98:2). H NMR (300 MHz, CDCl3) d: 1.63
(m, 6H), 1.82 (m, 12H), 3.92 (t, J¼6.6 Hz, 12H), 6.05 (s,
3H), 6.75 (d, J¼9.3 Hz, 6H), 7.34 (d, J¼9.3 Hz, 6H); 13C
NMR (75.5 MHz, CDCl3) d: 22.7, 28.8, 28.9, 67.7, 67.9,
93.8 (Ar. (t)), 112.6 (periphery Ar. (q)), 116.2 (periphery
Ar. (t)), 132.1 (periphery Ar. (t)), 158.1 (periphery Ar. (q)),
160.8 (Ar. (q)); GC–MS m/z: 850 [M]+; Anal. Calcd for
C39H45Br3O6: C, 55.14; H, 5.34. Found: C, 55.27; H, 5.34.
4.2. General procedure for the synthesis of deuterated
dendrimers
Dendrimer (1.0 equiv) was dissolved in benzene (2 mL) and
the system was charged with an inert atmosphere (N2 atm).
n-BuLi (2.0 equiv per bromophenyl group) was added and
warmed to 50 ꢀC for 45 min. The white precipitate was
cooled to 0 ꢀC and D2O (99.9 atom %, Aldrich, 2.0 equiv
per bromophenyl group) was added slowly over a period
of 5 min and the reaction mixture was allowed to stir at
room temperature for another 15 h. Solvents were removed
under reduced pressure, washed with CHCl3 (10 mL), and
4.1.3. G1-Br6 (5).
A mixture of G1-(OH)6 (0.3 g,
0.423 mmol), 2 (1.05 g, 3.04 mmol), K2CO3 (0.42 g,
3.04 mmol), and 18-C-6 (cat.) in 2-butanone (20 mL) and
DMF (2 mL) was heated at 70 ꢀC for 36 h. Solvents were
then removed in vacuo and the resulting residue was dis-
solved in CH2Cl2, washed with water, dried (Na2SO4), and

6234
J. Nithyanandhan, N. Jayaraman / Tetrahedron 62 (2006) 6228–6235
H2O (2ꢁ5 mL). The organic layer was dried (Na2SO4) and
concentrated to afford the required deuterated dendrimers
in good yield.
3430.7, 1685.5, 1606.5; 1H NMR (400 MHz, DMSO-d6) d:
1.55 (m, 6H), 1.76 (m, 12H), 3.97-4.03 (m, 12H), 6.21 (s,
3H), 6.99 (d, J¼8.0 Hz, 6H), 7.87 (d, J¼8.0 Hz, 6H); 13C
NMR (75.5 MHz, DMSO-d6) d: 22.0, 22.1, 22.2, 28.1,
28.3, 67.7, 68.0, 92.1 (Ar. (t)), 114.1 (periphery Ar. (t)),
123.1 (periphery Ar. (q)), 131.3 (periphery Ar. (t)), 156.6
(Ar. (q)), 162.2 (periphery Ar. (q)), 167.1 (carbonyl).
4.2.1. G0-(D)3 (12). G0-(Br)3 (62 mg, 0.073 mmol). G0-(D)3
(40 mg, 90%). TLC Rf 0.50 (PhMe/EtOAc¼98:2). 1H NMR
(300 MHz, CDCl3) d: 1.64 (m, 6H), 1.88 (m, 12H), 3.94 (m,
12H), 6.07 (s, 3H), 6.89 (d, J¼8.7 Hz, 6H), 7.27 (d,
J¼8.7 Hz, 6H); 13C NMR (75.5 MHz, CDCl3) d: 22.7,
29.0, 29.1, 67.6, 67.7, 93.8 (Ar. (t)), 114.4 (periphery Ar.
(t)), 129.3 (periphery Ar. (t)), 129.4 (periphery Ar. (t)),
159.0 (periphery Ar. (q)), 160.8 (Ar. (q)); HRMS m/z: 850
[M]+; Anal. Calcd for C39H45D3O6: C, 76.06; H, 8.35.
Found: C, 76.00; H, 8.37.
4.3.2. G1-(CO2H)6 (17). G1-(Br)6 (56 mg, 0.026 mmol). G0-
(CO2H)3 (45 mg, 90%). IR (KBr, cmꢂ1): 3436.5, 1685.5,
1604.5; H NMR (300 MHz, DMSO-d6) d: 1.64 (m, 18H),
1
1.82 (m, 36H), 4.03–4.06 (m, 36H), 6.26 (s, 12H), 7.01
(d, J¼8.4 Hz, 12H), 7.94 (d, J¼8.4 Hz, 12H); 13C NMR
(75.5 MHz, DMSO-d6) d: 21.7, 22.0, 22.2, 28.1, 28.2,
28.3, 67.7, 67.9, 92.1 (Ar. (t)), 114.2 (periphery Ar. (t)),
114.4 (periphery Ar. (t)), 122.9 (periphery Ar. (q)), 131.3
(periphery Ar. (t)), 156.6 (Ar. (q)), 162.2 (periphery Ar.
(q)), 167.1 (carbonyl).
4.2.2. G1-(D)6 (13). G1-(Br)6 (40 mg, 0.019 mmol). G1-(D)6
(27 mg, 86%). TLC Rf 0.55 (PhMe/EtOAc¼96:4). 1H NMR
(300 MHz, CDCl3) d: 1.64 (m, 18H), 1.82 (m, 36H), 3.97
(m, 36H), 6.06 (s, 12H), 6.89 (d, J¼8.4 Hz, 12H), 7.26
(d, J¼8.4 Hz, 12H); 13C NMR (75.5 MHz, CDCl3) d:
22.7, 29.0, 67.6, 67.7, 68.0, 93.8 (Ar. (t)), 114.5 (periphery
Ar. (t)), 129.4 (periphery Ar. (t)), 129.5 (br Ar. (t)), 159.0
(periphery Ar. (q)), 160.8 (Ar. (q)); Anal. Calcd for
C105H126D6O18: C, 74.70; H, 8.24. Found: C, 74.39; H, 7.93.
4.3.3. G2-(CO2H)12 (18). G2-(Br)12 (50 mg, 0.011 mmol).
G2-(CO2H)12 (38 mg, 84%). IR (KBr, cmꢂ1): 3436.5,
1637.5, 1604.5; H NMR (400 MHz, DMSO-d6) d: 1.49
1
(m, 42H), 1.71 (m, 84H), 3.94 (m, 84H), 6.17 (s, 30H),
6.92 (br s, 24H), 7.85 (br s, 24H); 13C NMR (75.5 MHz,
DMSO-d6) d: 22.0, 22.1, 22.2, 28.2, 28.3, 67.7, 68.0, 92.1
(Ar. (t)), 114.2 (periphery Ar. (t)), 114.4 (periphery Ar.
(t)), 123.2 (Ar. (q)), 131.4 (periphery Ar. (t)), 156.7 (Ar.
(q)), 162.2 (periphery Ar. (q)), 167.2 (carbonyl).
4.2.3. G2-(D)12 (14). G2-(Br)12 (35 mg, 7.34 mmol). G2-
(D)12 (20 mg, 71%). TLC Rf 0.51 (PhMe/EtOAc¼98:2).
1H NMR (300 MHz, CDCl3) d: 1.64 (m, 42H), 1.84 (m,
84H), 3.94 (m, 84H), 6.06 (s, 30H), 6.88 (d, J¼8.4 Hz, 24H),
7.26 (d, J¼8.4 Hz, 24H); 13C NMR (75.5 MHz, CDCl3) d:
22.7, 28.9, 29.0, 67.6, 67.7, 93.8 (Ar. (t)), 114.4 (periphery
Ar. (t)), 129.3 (periphery Ar. (t)), 129.4 (br Ar. (t)), 159.0
(periphery Ar. (q)), 160.8 (Ar. (q)); Anal. Calcd for
C237H288D12O42: C, 74.26; H, 8.20. Found: C, 74.10; H, 7.98.
4.3.4. G3-(CO2H)24 (19). G2-(Br)12 (36 mg, 3.6 mmol). G2-
(CO2H)12 (20 mg, 60%). IR (KBr, cmꢂ1): 3424.8, 1683.6,
1606.4; H NMR (400 MHz, DMSO-d6) d: 1.62 (m, 90H),
1
1.81 (m, 180H), 3.91 (m, 180H), 6.05 (s, 66H), 6.78 (br d,
48H), 7.25 (br d, 48H); 13C NMR (75.5 MHz, DMSO-d6)
d: 21.9, 22.0, 28.2, 28.3, 67.7, 68.0, 92.2 (Ar. (t)), 114.2
(periphery Ar. (t)), 114.4 (periphery Ar. (t)), 123.1 (peri-
phery Ar. (q)), 131.3 (periphery Ar. (t)), 156.6 (Ar. (q)),
162.2 (periphery Ar. (q)), 167.1 (carbonyl).
4.2.4. G3-(D)24 (15). G3-(Br)24 (30 mg, 3.0 mmol). G3-(D)24
(18 mg, 75%). TLC Rf 0.35 (PhMe/EtOAc¼98:2). 1H NMR
(300 MHz, CDCl3) d: 1.62 (m, 90H), 1.81 (m, 180H), 3.91
(m, 180H), 6.05 (s, 66H), 6.78 (br d, 48H), 7.25 (br d,
48H); 13C NMR (75.5 MHz, CDCl3) d: 22.7, 29.0, 67.6,
67.8, 93.8 (Ar. (t)), 114.6 (periphery Ar. (t)), 129.3 (periphery
Ar. (t)), 129.4 (periphery Ar. (t)), 159.0 (periphery Ar. (q)),
160.8 (Ar. (q)); Anal. Calcd for C501H612D24O90: C, 74.08;
H, 8.19. Found: C, 72.87; H, 7.96.
4.4. Esterification of carboxylic acid functionalized
dendrimers
To a solution of acid functionalized dendrimer in methanol a
catalytic amount of concd H2SO4 was added and refluxed for
24 h. Solvents were removed in vacuo, the crude reaction
mixture was washed with CHCl3 and H2O. The organic layer
was dried (Na2SO4), concentrated, and purified by column
chromatography (SiO2, 100–200 mesh) to afford the corre-
spondingesterfunctionalizeddendrimersasaglassymaterial.
4.3. General procedure for the synthesis of carboxylic
acid functionalized dendrimers
Dendrimer (1.0 molar equiv) was dissolved in benzene
(2 mL) and the system was charged with inert atmosphere
(N2 atm). n-BuLi (2.0 molar equiv) was added and warmed
to 50 ꢀC for 45 min. The white precipitate was cooled to 0 ꢀC
and CO2 (g) was passed over a period of 45 min and allowed
to stir at room temperature for 15 h. The reaction mixture
was cooled to 0 ꢀC, ice was added, allowed to stir for
30 min, followed by the addition of concd HCl (0.5 mL).
The pink color precipitate was separated by filtration,
washed with ice-cold water (50 mL), co-evaporated with
benzene (5ꢁ2 mL), and dried to afford the acid functional-
ized dendrimers, as a light pink color solid.
4.4.1. G0-(CO2Me)3 (20). Yield: 81%. TLC Rf 0.48 (PhMe/
EtOAc¼9:1). IR (KBr, cmꢂ1): 1724.1; 1H NMR (300 MHz,
CDCl3) d: 1.67 (m, 6H), 1.87 (m, 12H), 3.88 (s, 9H), 3.94
(t, J¼6.3 Hz, 6H), 4.03 (t, J¼6.3 Hz), 6.06 (s, 3H), 6.90
(d, J¼9.0 Hz, 6H), 7.98 (d, J¼9.0 Hz, 6H); 13C NMR
(75.5 MHz, CDCl3) d: 22.7, 28.9, 51.80, 67.7, 67.9, 93.8
(Ar. (t)), 114.03 (periphery Ar. (t)), 122.4 (periphery Ar.
(q)), 131.6 (periphery Ar. (t)), 160.9 (Ar. (q)), 162.8 (Ar.
(q)), 166.9 (carbonyl); HRMS m/z: 809.1497 [M+Na]+;
Anal. Calcd for C45H54O12: C, 68.68; H, 6.92. Found: C,
68.87; H, 7.04.
4.3.1. G0-(CO2H)3 (16). G0-(Br)3 (60 mg, 0.071 mmol). G0-
(CO2H)3 (40 mg, 63%). Mp: 81.4–83.4 ꢀC. IR (KBr, cmꢂ1):
4.4.2. G1-(CO2Me)6 (21). Yield: 90%. TLC Rf 0.37 (PhMe/
EtOAc¼8:2). IR (KBr, cmꢂ1): 1724.1, 1712.5; H NMR
1

J. Nithyanandhan, N. Jayaraman / Tetrahedron 62 (2006) 6228–6235
6235
(300 MHz, CDCl3) d: 1.67 (m, 18H), 1.84 (m, 36H), 3.88 (s,
References and notes
18H), 3.94 (m, 12H), 4.02 (m, 24H), 6.06 (s, 12H), 6.89 (d,
J¼9.3 Hz, 12H), 7.97 (d, J¼9.3 Hz, 12H); 13C NMR
(75.5 MHz, CDCl3) d: 22.7, 28.8, 28.9, 51.80, 67.7, 67.9,
93.8 (Ar. (t)), 114.0 (periphery Ar. (t)), 122.4 (periphery
Ar. (q)), 131.5 (periphery Ar. (t)), 160.8 (Ar. (q)), 162.8 (pe-
riphery Ar. (q)), 166.9 (carbonyl); Anal. Calcd for
C117H144O30: C, 69.21; H, 7.15. Found: C, 69.37; H, 7.08.
1. (a) Mallan, J. M.; Bebb, R. L. Chem. Rev. 1969, 69, 693; (b)
Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300;
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Strohmann, C.; Schildbach, D. Chemistry of Organolithium
Compounds; Rappoport, Z., Marek, I., Eds.; Wiley:
Chichester, UK, 2004; p 941.
4.4.3. G2-(CO2Me)12 (22). Yield: 84%. TLC Rf 0.45 (PhMe/
3. Najera, C.; Sansano, J. M.; Yus, M. Tetrahedron 2003, 59, 9255.
4. (a) Maercker, A.; Theis, M. Top. Curr. Chem. 1987, 138, 1; (b)
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1
EtOAc¼7:3). IR (KBr, cmꢂ1): 1724.1, 1716.6; H NMR
(300 MHz, CDCl3) d: 1.67 (m, 42H), 1.84 (m, 84H), 3.88
(s, 36H), 3.94 (m, 60H), 4.02 (m, 24H), 6.06 (s, 30H),
6.89 (d, J¼9.3 Hz, 24H), 7.97 (d, J¼9.3 Hz, 24H); 13C
NMR (75.5 MHz, CDCl3) d: 22.7, 28.9, 29.0, 51.9, 67.7,
67.9, 93.9 (Ar. (t)), 114.0 (periphery Ar. (t)), 122.4 (periph-
ery Ar. (q)), 131.6 (periphery Ar. (t)), 160.9 (Ar. (q)), 162.8
(periphery Ar. (q)), 166.9 (carbonyl); Anal. Calcd for
C261H324O66: C, 69.39; H, 7.23. Found: C, 69.53; H, 7.07.
4.4.4. G3-(CO2Me)24 (23). Yield: 76%. TLC Rf 0.41 (PhMe/
1
EtOAc¼7:3). IR (KBr, cmꢂ1): 1724.1, 1716.6; H NMR
(300 MHz, CDCl3) d: 1.63 (m, 90H), 1.85 (m, 180H), 3.88
(s, 72H), 3.94 (m, 132H), 4.03 (t, J¼6.3 Hz, 48H), 6.06 (s,
66H), 6.89 (d, J¼10.8 Hz, 48H), 7.97 (d, J¼10.8 Hz, 48H);
13C NMR (75.5 MHz, CDCl3) d: 22.7, 28.9, 29.2, 29.5, 51.8,
67.9, 93.8 (Ar. (t)), 114.0 (periphery Ar. (t)), 120.1 (periph-
ery Ar. (q)), 131.6 (periphery Ar. (t)), 160.9 (Ar. (q)), 162.8
(periphery Ar. (q)), 165.6 (carbonyl); Anal. Calcd for
C549H684O138: C, 69.47; H, 7.26. Found: C, 69.63; H, 7.06.
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Acknowledgements
We are grateful to Council of Scientific and Industrial
Research (CSIR), New Delhi, for their financial support.
J.N. thanks CSIR for a research fellowship.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.04.052.
10. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.