Phototriggering of geometric dendrimer disassembly: An improved synthesis of 2,4-bis(hydroxymethyl)phenol based dendrimers

Article abstract of DOI:10.1016/j.tet.2004.06.078

Dendrimers capable of phototriggered disassembly were prepared up to the second-generation using an improved synthesis of 2,4-bis(hydroxymethyl)phenol based dendrimers. It was found that disassembly proceeds to 75-80% completion after 2 h of irradiation at 310 nm for all molecules studied. The lack of complete reaction is attributed to an inefficient photochemical deprotection process rather than the disassembly itself.

Full text of DOI:10.1016/j.tet.2004.06.078

Tetrahedron 60 (2004) 7261–7266
Phototriggering of geometric dendrimer disassembly:
an improved synthesis of 2,4-bis(hydroxymethyl)phenol
based dendrimers
*
Michael L. Szalai and Dominic V. McGrath
Department of Chemistry, University of Arizona, Rm 221, PO Box 210041, Tucson, AZ 85721-0041, USA
Received 27 May 2004; accepted 14 June 2004
Abstract—Dendrimers capable of phototriggered disassembly were prepared up to the second-generation using an improved synthesis of
2,4-bis(hydroxymethyl)phenol based dendrimers. It was found that disassembly proceeds to 75–80% completion after 2 h of irradiation at
310 nm for all molecules studied. The lack of complete reaction is attributed to an inefficient photochemical deprotection process rather than
the disassembly itself.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Dendrimers are a class of polymeric materials characterized
by their highly globular nature.1,2 Though normally
prepared as stable covalent structures, dendritic materials
with stimuli responsive linkages present attractive possi-
bilities for controlled alteration of the properties of a
system, including solubility, energy harvesting, or insu-
lating capabilities. Accordingly, development of methods
for the controlled degradation of dendrimers and dendritic
Figure 1. Geometric dendrimer disassembly process illustrating two
subsequent cleavages proceeding via intermediate quinone methides.
macromolecules into discrete subunits is a primary goal of
our research program. Recently, we3,4 and others5,6 have
reported the fragmentation of dendrimers whereby each
cleavable unit requires 1 equiv. of a triggering stimulus
in order to proceed (i.e., stoichiometric degradation).
quinone methide C. In the presence of a nucleophile (Nuc),
the quinone methide is rapidly trapped to generate a new
vinylogous hemiacetal anion D. Again, rapid cleavage
Envisioning a more efficient approach where multiple
occurs, releasing a second equivalent of alkoxide (2OR) and
cleavage events are triggered by a single stimulus, we
demonstrated the first dendritic system capable of dis-
a new quinone methide E. Nucleophilic trapping results in
phenoxide F. Within a disassembling dendrimer, released
assembly into its constituent parts along a linear cleavage
vector.7 To expand upon this concept, we8 and others9–11
disassemble similarly. For a single triggering event at the
alkoxides (2OR) are analogous in structure to B and
reported the preparation of dendrimers containing multiple
focal point of a dendron, the total number of periphery and
disassembly pathways within the dendritic subunit itself,
branching subunits released in a geometric disassembly is:
namely geometric disassembly.
Our dendrimer subunit, 2,4-bis(hydroxymethyl)phenol,
contains both ortho and para disassembly pathways
(Fig. 1).8 Removal of the trigger group (TG) in A generates
phenoxide B. This vinylogous hemiacetal anion rapidly
undergoes cleavage to yield an alkoxide (2OR) as well as
where Nb is the branching multiplicity and G is the
generation.
Keywords: Dendrimers; Disassembly; Tetrahydrofuran.
*
In a previous report,8 we demonstrated that the allyl group
was an effective trigger albeit under relatively harsh
Corresponding author. Tel.: þ1-520-626-4690; fax: þ1-520-621-8407;
e-mail address: mcgrath@u.arizona.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.078

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M. L. Szalai, D. V. McGrath / Tetrahedron 60 (2004) 7261–7266
conditions (Pd(PPh3)4/NaBH4). Herein we report the
preparation and disassembly of dendrons that require only
light and mild base to trigger disassembly. This current
preparation also improves significantly on our previous
synthesis of geometric disassembling dendrimers.8
In order to bypass this ester reduction step, we attempted to
use 2,4-bis(hydroxymethyl)phenol16 as our generational
building block. Reaction of this compound with 5 in DMF/
K2CO3 at 60 8C resulted in decomposition to lower
molecular weight compounds (GPC). Lowering the
temperature to 40 8C did not improve these results.
More successful were our attempts to use the corresponding
phthalaldehyde derivative as a building block. Specifically,
reaction of 4-hydroxy isophthalaldehyde (1b)17 with 2
gave dialdehyde 3b in good yields, and subsequent
reduction of 3b with sodium borohydride proceeded
smoothly to give bis(benzyl alcohol) 4 in 93% yield, a
significant improvement over the diester reduction (Scheme
1). Chlorination of 4 using thionyl chloride yielded 5
and subsequent coupling with 2 equiv. of 1b gave
first-generation tetraaldehyde 6b. To our delight, selec-
tive reduction of 6b using relatively mild conditions
(NaBH4/THF at RT) gave tetraalcohol 7 in good yields.
Chlorination with thionyl chloride proceeded smoothly
resulting in tetrachloride 8.
2. Synthesis
To prepare the target dendrons it was first necessary to
attach a photolabile group to the dendrimer subunit and
proceed by a divergent synthetic strategy. We chose to use
an o-nitrobenzyl derivative owing to its well-understood
and relatively clean photodegradation.12 Our initial plan
was to proceed through the synthesis utilizing dimethyl
4-hydroxyisophthalate (1a) as the generational building
block as we previously reported.8 Indeed, alkylation of 1a
with photolabile benzyl bromide trigger 2 (Scheme 1)
proceeded smoothly to give diester 3a. However, selective
reduction of the ester moieties of 3a gave diol 4 in only
poor to moderate yields (maximum 45%), presumably
complicated by the presence of the nitro group.
Scheme 2.
The p-nitrophenoxide ion exhibits a strong absorption band
1
(430 nm) and a distinctive H NMR signal. Thus, in order
to easily monitor the disassembly of these dendrons,
p-nitrophenoxy moieties were installed at the periphery of
both dendrons to indicate the extent of disassembly.
Accordingly, reaction of 5 and 8 with a slight excess of
p-nitrophenol (Scheme 2) gave the first generation (9) and
second generation (10) reporter labeled dendrons, respect-
ively, in good yields. Coupling of p-nitrophenol with the
o-nitrobenzyl bromide trigger 2 furnished control com-
pound 11 consisting of the reporter moiety directly attached
to the photolabile trigger group.
Scheme 1.
Despite these troubling results in the early stages of the
synthesis, we chose to proceed using 1a as the building
block. Chlorination of 4 using thionyl chloride provided
dichloride 5 in excellent yields and its coupling with
2 equiv. of 1a gave tetraester 6a in 73% yield. However,
selective reduction of 6a to tetraalcohol 7 proved problem-
atic. We attempted this reduction using: KBH4/LiCl in THF
or THF–MeOH both at room temperature and at reflux;13
NaBH4/THF/MeOH at reflux;14 LiBH4/THF/MeOH both at
room temperature and at 60 8C; LAH/THF at room
temperature; and LAH/SiO2 in Et2O15 at room temperature.
Only LiBH4/THF/MeOH at 60 8C provided the desired
product albeit with a small amount of incomplete reduction
products that were not easily removed.

M. L. Szalai, D. V. McGrath / Tetrahedron 60 (2004) 7261–7266
7263
3. Disassembly studies
3.1. UV–Vis spectroscopy
disappearance of the starting material in the 1H NMR
spectrum with concomitant increase of a new upfield
AA0BB0 pattern (8.11 and 6.92 ppm) and singlet at
11.0 ppm, indicative of the release of p-nitrophenol.
However, the aromatic protons of the photocleavable trigger
completely disappear and no new corresponding peaks
arise. In addition, the methoxy singlet (3.88 ppm) and the
methylene triplet (4.06 ppm) decrease in intensity but over
10 h of irradiation this region of the spectra becomes
crowded with a multitude of unidentified peaks. It appears
that the photocleavage product decomposes over time under
the conditions of these experiments. Indeed, we saw similar
results in this regard when studying compounds 9 and 10.
This information further confirms that the inefficiency seen
in the UV–Vis experiments (80% completion) arises
primarily in the photodeprotection process and not in the
disassembly itself. Photodecomposition of veratryl based
nitrobenzyl ethers are known to be accompanied by
complicating side reactions.18
Compounds 9–11 were thermally stable yet upon release of
the photolabile group with irradiation (310 nm) under basic
conditions, dendrimer disassembly occurs. Because of the
liberation of the strongly absorbing (430 nm) p-nitrophen-
oxide ion, we were able to monitor this process by UV–Vis
spectroscopy. Irradiation of DMF solutions (NaBH4, 1 mg/
mL) of 9–11 at 310 nm for increasing time intervals
resulted in a decrease of the absorbance band at 310 nm with
a concomitant increase of the band at 430 nm (Fig. 2).
Substrate concentrations were adjusted such that the final
p-nitrophenoxide ion absorbance would equal 1.0 upon
complete disassembly based on the absorptivity of the ion.
Thus, we observed approximately 80% p-nitrophenoxide
liberation for 9–11 and the disassembly process concluded
within 2 h of irradiation. Because the control compound 11
releases only 80% of the expected reporter ion, we conclude
that non-quantitative reporter ion liberation arises from the
photochemical deprotection process of the o-nitrobenzyl
trigger rather than from the subsequent disassembly that
occurs in compounds 9 and 10.
Addition of sodium borohydride to the sample of 11 after
10 h of irradiation results in the disappearance of the singlet
at 11.0 ppm and an upfield shift of the AA0BB0 pattern to
7.73 and 5.96 ppm, indicating formation of p-nitro-
phenoxide ion. Performing the irradiation of the sample in
the presence of sodium borohydride does not alter the
ultimate results but we clearly see generation of the
p-nitrophenoxide ion over time rather than p-nitrophenol.
The photochemical process appears to be complete after
6–10 h of irradiation time.
Irradiation of 9 in the absence of base similarly releases the
phenolic form of the dendron intact (Fig. 4, center). This is
indicated by a new singlet at 10.0 ppm (phenol OH) and an
upfield shift of the peaks assigned to the isophthalyl
branching subunit. In addition, the three benzyl singlets
(5.48, 5.28, and 5.21 ppm) decrease over irradiation time
and we observe two new singlets (5.17 and 5.12 ppm) in the
benzyl region. Addition of sodium borohydride results in the
complete disappearance of phenol (10.0 ppm) and the two
new benzyl singlets (5.17 and 5.12 ppm) with the con-
comitant generation of p-nitrophenoxide ion (7.72 and
5.96 ppm) and two new singlets at 2.12 and 2.04 ppm.
The upfield singlets are independently confirmed to be the
2,4-dimethylphenoxide ion. Irradiation of the sample in the
presence of borohydride ultimately gives the same results
but the process is less clean.
Figure 2. Left: absorbance of p-nitrophenoxide ion (430 nm) monitored as
a function of 310 nm irradiation time during disassembly of 9–11. Right:
UV–Vis absorption spectra of a solution of 9 containing 1 mg/mL NaBH4
in DMF after irradiation at 310 nm for various times (0, 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 15, 20, 25, 30, 45, 60, 90, and 120 min).
3.2. NMR spectroscopy
The photodisassembly of compounds 9–11 was also
monitored by 1H NMR spectroscopy in DMSO-d6
(18 mM) upon irradiation in a Rayonet photochemical
chamber (350 nm). The photolabile o-nitrobenzyl group is
known to cleave at the benzyl ether bond releasing liberated
alcohol and the appropriate o-nitroso benzaldehyde deriva-
tive. Initial NMR spectroscopic studies were carried out on
11 (Fig. 3). After various irradiation times there is clearly
Figure 4. Characteristic 1H NMR chemical shifts observed while
monitoring the disassembly of compound 9. Conditions: DMSO-d6,
18 mM, 350 nm irradiation.
After 10 h of irradiation of a sample of 10 and the addition
of sodium borohydride we see the same ultimate results as
with compound 9, i.e. generation of p-nitrophenoxide and
Figure 3. Characteristic 1H NMR chemical shifts observed while
monitoring the disassembly of compound 11. Conditions: DMSO-d6,
18 mM, 350 nm irradiation.

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M. L. Szalai, D. V. McGrath / Tetrahedron 60 (2004) 7261–7266
2,4-dimethyl phenoxide. It appears, though, that the
photocleavage process for this compound is not complete
even after 10 h because we can still see significant amounts
of the benzyl peaks of the starting material after the addition
of the borohydride. However, the sample irradiated in the
presence of borohydride shows complete disappearance of
all benzyl peaks after 10 h.
5.1.2. 4-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy)-
isophthalaldehyde (3b). mixture of (10.2 g,
A
2
23.6 mmol), 1b (3.54 g, 23.6 mmol), K2CO3 (6.53 g,
47.2 mmol) and DMF (200 mL) was stirred at 40 8C under
argon overnight. The reaction mixture was cooled to room
temperature and water (300 mL) was added. After stirring
for 10 min the precipitated solid was filtered and washed
thoroughly with water. The solid was dissolved in CH2Cl2
and the solution was dried (MgSO4), filtered, and concen-
trated. Recrystallization of the yellow solid from CH2Cl2/
hexanes gave the desired product (3b) as a light yellow solid
(9.87 g, 84%): 1H NMR (300 MHz, CDCl3) d 10.45 (s, 1H),
10.0 (s, 1H), 8.37 (d, J¼2.1 Hz, 1H), 8.16 (dd, J1¼2.1 Hz,
J2¼8.4 Hz, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.32 (d, J¼
8.4 Hz, 1H), 5.68 (s, 2H), 4.10 (t, J¼6.9 Hz, 2H), 4.07 (s,
3H), 1.90 (m, 2H), 1.22–1.58 (m, 18H), 0.87 (t, J¼6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 189.7, 188.4, 163.2,
154.6, 147.8, 138.7, 136.5, 134.3, 130.1, 126.8, 125.2,
113.6, 109.7, 109.0, 69.5, 68.2, 56.7, 31.9, 29.6, 29.59, 29.5,
29.49, 29.3, 28.8, 25.8, 22.6, 14.1; MS (FAB) m/z 499.7
(Mþ, C28H37NO7 requires 499.3).
4. Summary
We have prepared dendrimers capable of phototriggered
disassembly up to the second generation. During the course
of this work it was found that the preferred synthetic route
utilizes isophthalaldehyde building blocks rather than
isophthalate esters because of the incompatibility of the
trigger with the various reaction conditions of the synthesis.
The dendrimers are thermally stable but disassemble upon
irradiation under basic conditions.
5. Experimental
5.1.3. 1-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy)-
2,4-bis(hydroxymethyl)benzene (4). To a solution of 3b
(8.6 g, 17.3 mmol), THF (200 mL), and methanol (1.5 mL)
was added NaBH4 (1.95 g, 51.9 mmol) over 5 m. The
reaction mixture was stirred at room temperature under
argon for 1 h, after which time it was quenched with water
(30 mL) and 0.5 N HCl (2 mL) sequentially and stirred for
30 min after the addition of each. CH2Cl2 (50 mL) was
added to the mixture and the layers were separated. The
organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated. Recrystallization of the yellow
solid from CH–Cl3 gave the desired product (4) as a light
5.1. General methods
NMR spectroscopy and mass spectrometry (MS) were
obtained using commercially available instrumentation.
Tetrahydrofuran (THF) was distilled under N2 from
sodium-benzophenone ketyl. Dichloromethane (CH2Cl2)
was distilled under N2 from CaH2. Acetone was dried
˚
over crushed 3 A molecular sieves. All other needed
reagents were purchased from commercial suppliers and
used as received. Flash chromatography was performed by
the method of Still et al. [J. Org. Chem. 1978, 43, 2923–
2925] using silica gel (40–63m, Merck, Darmstadt,
Germany). Thin-layer chromatography (TLC) was per-
formed on precoated plates (Silica Gel 60 F254, 250 mm,
Merck, Darmstadt, Germany). Melting points are
uncorrected.
1
yellow solid (8.11 g, 93%): H NMR (300 MHz, CDCl3) d
7.76 (s, 1H), 7.37 (m, 2H), 7.27 (m, 1H), 6.93 (d, J¼8.1 Hz,
1H), 5.51 (s, 2H), 4.81 (s, 2H), 4.64 (s, 2H), 4.08 (t, J¼
6.6 Hz, 2H), 3.94 (s, 3H), 2.17 (br s, 1H), 1.88 (m, 2H), 1.79
(br s, 1H), 1.22–1.58 (m, 18H), 0.88 (t, J¼6.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 155.4, 154.4, 147.5, 139.0, 133.9,
129.4, 128.6, 128.1, 128.0, 111.8, 109.4, 109.1, 69.5, 67.1,
64.8, 61.7, 56.4, 31.89, 31.87, 30.9, 29.63, 29.61, 29.6, 29.5,
29.3, 28.9, 25.9, 22.7, 14.1; MS (FABþ) m/z 503.4 (Mþ,
C28H41NO7 requires 503.3).
5.1.1. 4-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy) iso-
phthalic acid dimethyl ester (3a). A mixture of 2 (4.30 g,
10 mmol), 1a (2.21 g, 10.5 mmol), K2CO3 (4.14 g,
30 mmol), 18-crown-6 (50 mg) and acetone (75 mL) was
stirred at room temperature under argon for 2 days. The
solvent was removed and the residue was partitioned
between CH2Cl2 (100 mL) and water (100 mL). The layers
were separated and the organic layer was washed with sat.
NaHCO3 (3£50 mL) and brine. The combined aqueous
layers were extracted with CH2Cl2, the organic layers were
combined, dried over MgSO4, filtered, and concentrated.
Recrystallization of the residue from CH2Cl2 gave the
desired product (3a) as a light yellow solid (4.05 g, 72%):
1H NMR (300 MHz, CDCl3) d 8.58 (d, J¼2.1 Hz, 1H), 8.20
(dd, J1¼2.1 Hz, J2¼8.4 Hz, 1H), 8.06 (s, 1H), 7.76 (s, 1H),
7.27 (m, 1H), 7.19 (d, J¼9.0 Hz, 1H), 5.58 (s, 2H), 4.11 (s,
3H), 4.07 (t, J¼6.9 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 1.88
(m, 2H), 1.22–1.58 (m, 18H), 0.87 (t, J¼6.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 165.9, 164.8, 161.1, 154.9, 147.3,
138.2, 135.5, 133.8, 128.3, 122.6, 119.4, 112.7, 110.3,
108.7, 69.5, 67.7, 56.9, 52.2, 51.9, 31.9, 29.63, 29.61, 29.57,
29.5, 29.3, 28.9, 25.9, 22.7, 14.1; MS (FABþ) m/z 560.4
(MþH2, C30H42NO9 requires 560.3).
5.1.4. 1-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy)-
2,4-bis(chloromethyl)benzene (5). To a rapidly stirred
mixture of 4 (6.23 g, 12.4 mmol) and CH2Cl2 (300 mL)
under argon at room temperature was added SOCl2 via
syringe over 5 m. After 20 min the reaction was quenched
with sat. NaHCO3 (30 mL) and stirred for an additional
30 m. The layers were separated and the organic layer was
washed thoroughly with sat. NaHCO3, dried over MgSO4,
filtered, and concentrated. Recrystallization of the yellow
solid from chloroform/hexanes gave the desired product (5)
1
as a light yellow solid (6.38 g, 95%): H NMR (300 MHz,
CDCl3) d 7.78 (s, 1H), 7.53 (s, 1H), 7.41 (d, J¼2.4 Hz, 1H),
7.35 (dd, J1¼2.4 Hz, J2¼8.1 Hz, 1H), 6.96 (d, J¼8.7 Hz,
1H), 5.57 (s, 2H), 4.75 (s, 2H), 4.57 (s, 2H), 4.09 (t, J¼
6.9 Hz, 2H), 3.98 (s, 3H), 1.89 (m, 2H), 1.22–1.54 (m,
18H), 0.88 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 156.0, 154.6, 147.4, 138.7, 131.3, 130.9, 130.4, 128.5,
126.1, 112.1, 109.4, 109.0, 69.5, 66.9, 56.7, 45.6, 42.1, 31.9,

M. L. Szalai, D. V. McGrath / Tetrahedron 60 (2004) 7261–7266
7265
29.63, 29.62, 29.6, 29.5, 29.3, 28.9, 25.9, 22.7, 14.1; MS
(FAB) m/z 540.39 (MþHþ, C28H40NO5Cl2 requires
540.23).
2,4-bis(3,5-bis(hydroxymethyl)phenoxy)benzene (7). To
a stirred solution of 6b (1.07 g, 1.39 mmol), THF (50 mL),
and methanol (1 mL) was added NaBH4 (0.42 g,
11.2 mmol) and the reaction mixture was stirred at room
temperature under argon for 4 h. The reaction was slowly
quenched with water (10 mL) with stirring. A precipitate
formed as water was added. The precipitate was filtered and
washed thoroughly with water, CH2Cl2, and acetone
sequentially. No further purification was required and the
product 7 was isolated as a light yellow solid (0.83 g, 77%):
1H NMR (300 MHz, DMSO-d6) d 7.70 (s, 1H), 7.54 (d,
J¼1.8 Hz, 1H), (dd, J1¼1.8 Hz, J2¼8.4 Hz, 1H), 7.34 (m,
3H), 7.15 (d, J¼8.4 Hz, 1H), 7.10 (m, 2H), 6.95 (d, J¼
8.4 Hz, 1H), 6.94 (d, J¼8.4 Hz, 1H), 5.46 (s, 2H), 5.13 (s,
2H), 4.95 (br s, 4H), 4.51 (s, 4H), 4.41 (s, 4H), 4.04 (t,
J¼6.3 Hz, 2H), 3.64 (s, 3H), 1.71 (m, 2H), 1.18–1.46 (m,
18H), 0.84 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, DMSO-
d6) d 155.1, 153.9, 153.8, 153.4, 147.0, 139.1, 134.4, 134.2,
130.3, 130.3, 129.9, 128.6, 128.3, 127.4, 125.7, 125.66,
125.6, 125.4, 112.1, 111.2, 110.8, 110.3, 108.9, 68.9, 68.7,
66.8, 65.0, 62.9, 58.0, 57.9, 55.7, 31.3, 29.1, 29.05, 29.01,
29.0, 28.74, 28.72, 28.4, 25.4, 22.1, 14.0; MS (MALDI in
dithranol) m/z 798.3 (MþNa, C44H57NO11Na requires
798.4).
5.1.5. 1-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy)-
2,4-bis(3,5-carbomethoxyphenoxy)benzene (6a). Com-
pound 5 (2.38 g, 4.40 mmol) was dissolved in 50 mL of
DMF with heating (50 8C). 1a (1.94 g, 9.24 mmol), K2CO3
(2.43 g, 17.6 mmol) and 18-crown-6 (20 mg) were added to
the solution and the reaction mixture was stirred at 50 8C
under argon for 1 day. The reaction mixture was cooled to
room temperature and poured into ice water (350 mL). The
cloudy mixture was extracted with CH2Cl2 (5£100 mL) and
the combined organic layers were dried over MgSO4,
filtered, and concentrated. Recrystallization of the resulting
yellow solid from CH2Cl2/hexanes gave the desired product
(6a) as an off-white solid (2.86 g, 73%): 1H NMR
(300 MHz, CDCl3) d 8.49 (m, 2H), 8.10 (m, 2H), 7.76 (s,
1H), 7.69 (m, 1H), 7.43 (dd, J1¼1.7 Hz, J2¼8.6 Hz, 1H),
7.23 (s, 1H), 7.08 (d, J¼8.7 Hz, 1H), 7.04 (d, J¼9.0 Hz,
1H), 7.01 (d, J¼7.8 Hz, 1H), 5.55 (s, 2H), 5.37 (s, 2H), 5.22
(s, 2H), 4.08 (t, J¼6.9 Hz, 2H), 3.91 (s, 2H), 3.90 (s, 2H),
3.89 (s, 2H), 3.87 (s, 2H), 3.79 (s, 3H), 1.88 (m, 2H), 1.22–
1.54 (m, 18H), 0.88 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 166.0, 165.9, 165.6, 165.5, 161.5, 161.4, 155.1,
154.2, 147.6, 139.1, 134.89, 134.86, 133.7, 133.6, 129.1,
128.3, 128.2, 127.7, 124.7, 122.5, 122.4, 120.4, 113.2,
113.0, 112.3, 109.5, 109.2, 70.3, 69.5, 67.7, 66.3, 56.2, 52.1,
52.09, 31.9, 29.63, 29.61, 29.6, 29.5, 29.3, 28.9, 25.9, 22.7,
14.1; MS (FABþ) m/z 886.6 (Mþ, C48H57NO15 requires
887.4).
5.1.8. 1-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy)-
2,4-bis(3,5-bis(chloromethyl)phenoxy)benzene (8). To a
stirred solution of 7 (2.64 g, 3.4 mmol) and DMF (100 mL)
was added SOCl2 via syringe. After 30 min, CH2Cl2
(50 mL) was added, the reaction was quenched slowly
with sat. NaHCO3 and stirred for an additional 30 min. The
layers were separated and the organic layer was washed
thoroughly with sat. NaHCO3, dried over MgSO4, filtered,
and concentrated. Flash chromatography (SiO2, 2:1
CH2Cl2–hexanes) of the residue gave the desired product
5.1.6. 1-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy)-
2,4-bis(3,5-diformylphenoxy)benzene (6b). Compounds
5 (5.23 g, 9.68 mmol) and 1b (3.05 g, 20.3 mmol) were
dissolved in 200 mL of DMF with heating at 50 8C. K2CO3
(5.35 g, 9.68 mmol) was added to the solution and the
reaction mixture was stirred at 50 8C under argon for 2 days.
The reaction mixture was cooled to room temperature and
poured into water (300 mL). The precipitate was filtered and
washed thoroughly with water. The solid was dissolved in
CH2Cl2 and washed with sat. NaHCO3 and brine. The
organic layer was dried over MgSO4, filtered, and
concentrated to a yellow solid. Flash chromatography
(SiO2, gradient CH2Cl2 to 5% ethyl acetate in CH2Cl2)
gave the desired product (6b) as a light yellow solid (3.9 g,
1
(8) as a colorless solid (1.73 g, 60%): H NMR (300 MHz,
CDCl3) d 7.76 (s, 1H), 7.59 (d, J¼2.1 Hz, 1H), 7.43 (m,
2H), 7.40 (s, 1H), 7.29 (m, 3H), 7.06 (d, J¼8.4 Hz, 1H),
6.96 (d, J¼8.4 Hz, 1H), 6.90 (d, J¼8.4 Hz, 1H), 5.54 (s,
2H), 5.28 (s, 2H), 5.11 (s, 2H), 4.65 (overlapping s, 4H),
4.56 (s, 2H), 4.55 (s, 2H), 4.09 (t, J¼6.6 Hz, 2H), 3.67 (s,
3H), 1.89 (m, 2H), 1.22–1.54 (m, 18H), 0.88 (t, J¼6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 156.5, 156.3, 155.6,
154.2, 147.5, 138.9, 131.1, 131.0, 130.4, 130.3, 130.1,
129.9, 129.5, 128.8, 128.6, 128.3, 126.6, 126.5, 125.0,
112.3, 112.2, 112.0, 109.2, 109.0, 69.8, 69.5, 67.5, 66.0,
56.0, 45.9, 45.8, 41.4, 41.3, 31.9, 29.63, 29.61, 29.6, 29.5,
29.3, 28.8, 25.9, 22.7, 14.1; MS (FABþ) m/z 846.9 (Mþ,
C44H53NO7Cl4 requires 847.3), 848.9 [Mþ2].
1
52%): H NMR (300 MHz, CDCl3) d 10.48 (s, 1H), 10.45
(s, 1H), 9.95 (s, 1H), 9.94 (s, 1H), 8.322 (d, J¼2.1 Hz, 1H),
8.315 (d, J¼2.1 Hz, 1H), 8.09 (overlapping dd, J1¼2.1 Hz,
J2¼8.4 Hz, 2H), 7.73 (s, 1H), 7.58 (d, J¼2.1 Hz, 1H), 7.48
(dd, J1¼2.1 Hz, J2¼8.7 Hz, 1H), 7.24 (d, J¼9.3 Hz, 1H),
7.22 (d, J¼8.7 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J¼8.1 Hz,
1H), 5.55 (s, 2H), 5.43 (s, 2H), 5.27 (s, 2H), 4.07 (t,
J¼6.6 Hz, 2H), 3.78 (s, 3H), 1.88 (m, 2H), 1.22–1.54 (m,
18H), 0.88 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
190.1, 190.0, 188.3, 188.2, 164.8, 164.7, 157.1, 156.0,
154.0, 147.9, 139.4, 135.6, 132.0, 131.9, 129.9, 129.8,
129.7, 128.7, 128.1, 127.1, 125.1, 125.0, 124.2, 113.5,
113.47, 112.6, 109.8, 109.2, 70.5, 69.5, 67.9, 66.5, 56.1,
31.8, 29.6, 29.55, 29.5, 29.45, 29.3, 28.8, 25.8, 22.6, 14.1;
MS (FABþ) m/z 767.0 (Mþ, C44H49NO11 requires 767.3).
5.1.9. 1-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy)-
2,4-bis(4-nitrophenoxymethyl)benzene (9). A mixture of
5 (0.42 g, 0.78 mmol), p-nitrophenol (0.23 g, 1.64 mmol),
K2CO3 (0.32 g, 2.35 mmol), 18-crown-6 (10 mg), acetone
(10 mL), and DMF (10 mL) was stirred at reflux under
argon for 3 days. The acetone was partially concentrated in
vacuo and 1:1 water-brine (60 mL) was added to the
remaining DMF with stirring. The resulting precipitate was
filtered, washed thoroughly with sat. NaHCO3 and water,
redissolved in CH2Cl2, dried over MgSO4, filtered, and
concentrated. Flash chromatography (SiO2, 2:1 CH2Cl2–
hexane) of the residue gave the desired product (9) as a
colorless solid (0.49 g, 84%): 1H NMR (300 MHz, CDCl3) d
5.1.7. 1-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy)-

7266
M. L. Szalai, D. V. McGrath / Tetrahedron 60 (2004) 7261–7266
8.20 (d, J¼8.7 Hz, 4H), 7.75 (s, 1H), 7.53 (d, J¼1.8 Hz,
1H), 7.43 (dd, J1¼2.1 Hz, J2¼8.4 Hz, 1H), 7.06 (d, J¼
8.1 Hz, 1H), 7.04 (d, J¼9.3 Hz, 4H), 5.56 (s, 2H), 5.29 (s,
2H), 5.12 (s, 2H), 4.07 (t, J¼6.9 Hz, 2H), 3.74 (s, 3H), 1.89
(m, 2H), 1.22–1.54 (m, 18H), 0.88 (t, J¼6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 163.6, 163.5, 156.0, 154.1, 147.8,
141.74, 141.7, 139.3, 129.8, 129.3, 128.6, 127.7, 126.0,
125.9, 124.4, 114.8, 114.7, 112.5, 109.5, 109.2, 70.1, 69.6,
67.7, 66.2, 56.1, 31.9, 29.63, 29.61, 29.6, 29.5, 29.3, 28.8,
25.9, 22.7, 14.1; MS (FAB) m/z 745.5 (Mþ, C40H47N3O11
requires 745.3).
and slow addition of 50 mL hexanes to this solution afforded
the product (11) as an off-white precipitate (105 mg, 62%):
1H NMR (300 MHz, CDCl3) d 8.24 (d, J¼8.7 Hz, 2H), 7.78
(s, 1H), 7.23 (s, 2H), 7.09 (d, J¼9.3 Hz, 2H), 5.58 (s, 2H),
4.09 (t, J¼6.9 Hz, 2H), 3.96 (s, 3H), 1.89 (m, 2H), 1.25–
1.59 (m, 18H), 0.88 (t, J¼6.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 162.9, 154.3, 147.8, 142.1, 139.1, 127.0, 126.0,
114.9, 109.4, 109.2, 69.6, 67.7, 56.4, 31.9, 29.61, 29.6,
29.54, 29.49, 29.31, 29.30, 28.8, 25.8, 22.7, 14.1; MS
(FABþ) m/z 488.8 (Mþ, C26H36N2O7 requires 488.3).
5.1.10. 1-(4-Dodecyloxy-5-methoxy-2-nitrobenzyloxy)-
2,4-bis(3,5-bis(4-nitrophenoxymethyl)phenoxy)benzene
(10). A mixture of 8 (0.13 g, 0.15 mmol), p-nitrophenol
(0.1 g, 0.7 mmol), K2CO3 (5.35 g, 9.68 mmol), and DMF
(10 mL) was stirred at 50 8C under argon for 28 h. The
reaction mixture was cooled to room temperature and
poured into water (30 m). The mixture was extracted
thoroughly with CH2Cl2 and washed with sat. NaHCO3
and brine. The organic layer was dried over MgSO4, filtered,
and concentrated to a yellow solid. Flash chromatography
(SiO2, gradient CH2Cl2 to 5% ethyl acetate in CH2Cl2) of
the yellow solid gave the desired product (10) as a light
Acknowledgements
This work was supported by the National Science
Foundation (CHE-0213537).
References and notes
1. Newkome, G. R.; Moorefield, C. N.; Vogtle, F. Dendrimers
and Dendrons: Concepts, Syntheses, Applications; VCH: New
York, 2001.
1
yellow solid (0.14 g, 76%): H NMR (300 MHz, CDCl3)
d 8.21 (d, J¼9.3 Hz, 2H), 8.19 (d, J¼9.3 Hz, 2H), 8.06
(d, J¼9.3 Hz, 2H), 7.96 (d, J¼9.3 Hz, 2H), 7.74 (s, 1H),
7.30–7.50 (m, 6H), 7.23 (s, 1H), 7.01 (d, J¼9.3 Hz, 2H),
7.00 (d, J¼9.3 Hz, 2H), 6.90–7.05 (m, 3H), 6.95 (d, J¼
9.3 Hz, 2H), 6.88 (d, J¼9.3 Hz, 2H), 5.48 (s, 2H), 5.20 (s,
2H), 5.15 (s, 2H), 5.13 (s, 2H), 5.10 (s, 2H), 5.08 (s, 2H),
5.00 (s, 2H), 4.08 (t, J¼6.9 Hz, 2H), 3.68 (s, 3H), 1.88 (m,
2H), 1.22–1.54 (m, 18H), 0.88 (t, J¼6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 163.7, 163.54, 163.52, 163.5, 156.4,
156.2, 155.7, 154.0, 147.7, 141.7, 141.6, 141.5, 139.2,
129.6, 129.5, 129.3, 129.1, 128.8, 128.7, 128.2, 128.16,
127.7, 125.93, 125.9, 125.8, 125.7, 125.1, 124.6, 114.8,
114.73, 114.72, 114.5, 112.2, 111.9, 111.8, 109.4, 109.1,
70.2, 70.16, 69.9, 69.5, 67.6, 65.8, 56.0, 31.9, 29.65, 29.62,
29.57, 29.5, 29.3, 28.9, 25.9, 22.7, 14.1; MS (MALDI in
dithranol) m/z 1282.2 (MþNa, C68H69N5O19Na requires
1282.4).
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nitrobenzene (11). A mixture of p-nitrophenol (51 mg,
0.367 mmol), K2CO3 (0.145 g, 1.05 mmol), 18-crown-6
(10 mg), and acetone (10 mL) was stirred at room
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temperature under argon for 30 min. Compound
2
14. Soai, K. O. H.; Takase, M.; Ookawa, A. Bull. Chem. Soc. Jpn
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(0.150 g, 0.35 mmol) was then added and the reaction
mixture was stirred at room temperature for 2 days. The
solvent was removed and the residue was partitioned
between CH2Cl2 (30 mL) and water (30 mL). The layers
were separated and the organic layer was washed with sat.
NaHCO3 (3£30 mL) and brine. The combined aqueous
layers were extracted with CH2Cl2, the organic layers were
combined, dried over MgSO4, filtered, and concentrated to
give a deep red oil. This was dissolved in 5 mL of CH2Cl2
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