Simple procedures for the preparation of 1,3,5-substituted 2,4,6-trimethoxybenzenes

Article abstract of DOI:10.1055/s-0033-1339639

We describe straightforward protocols for the preparation of a number of 1,3,5-substituted 2,4,6-trimethoxybenzenes. A two-step procedure for the preparation of a 1,3,5-tris-methylamino-2,4,6-trimethoxybenzene and further synthetic elaboration of this key substrate to yield a triamide, a tricarbamate and three different triureas is described. We also present a computational (DFT) study that investigates the different possible conformations of the overcrowded benzene substrate and a single-crystal X-ray structure of one of the key intermediates. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339639

LETTER
▌2437
lSetitemr ple Procedures for the Preparation of 1,3,5-Substituted 2,4,6-Trimethoxy-
benzenes
Preparation of 1,3,5-Substituted 2,4,6-Trimethoxybenzenes
Bjarne E. Nielsen, Henrik Gotfredsen, Brian Rasmussen, Christian G. Tortzen, Michael Pittelkow*
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark
Fax +4535320212; E-mail: pittel@kiku.dk
Received: 09.07.2013; Accepted after revision: 23.07.2013
Abstract: We describe straightforward protocols for the prepara-
tion of a number of 1,3,5-substituted 2,4,6-trimethoxybenzenes. A
two-step procedure for the preparation of a 1,3,5-tris-methylamino-
2,4,6-trimethoxybenzene and further synthetic elaboration of this
key substrate to yield a triamide, a tricarbamate and three different
triureas is described. We also present a computational (DFT) study
that investigates the different possible conformations of the over-
crowded benzene substrate and a single-crystal X-ray structure of
one of the key intermediates.
(From left to right) Michael Pittelkow was born in 1977 and raised
in Brøndby Strand, near Copenhagen. At the University of Copenha-
gen he received his PhD degree in 2006. During his studies he spent
extended periods in Australia (CSIRO in Melbourne), The Nether-
lands (The Technical University of Eindhoven) and England (the Uni-
versity of Cambridge). He undertook postdoctoral studies in the UK
with Prof. J. K. M. Sanders (the University of Cambridge) before
moving back to Denmark to start as an Assistant Professor at the De-
partment of Chemistry, University of Copenhagen in November
2008. In 2013 he became Associate Professor at the same department.
His research interests include organic synthesis, physical organic
chemistry, dendrimers and supramolecular chemistry.
Brian Rasmussen was born in 1980 in Denmark and initiated his
chemistry studies at the University of Copenhagen in 2001. Under the
guidance of Associate Professor Jørn B. Christensen, his Bachelor’s
and Master’s project work concerned supramolecular chemistry at
dendrimer surfaces, and his PhD work was concentrated on dendrimer
synthesis and the development of new organocatalytic dendrimers for
the Diels–Alder reaction. From 2010, he has been employed as a Post
Doc at the University of Copenhagen under the guidance of Associate
Professor Michael Pittelkow where he is mainly working with or-
ganoselenium chemistry, supramolecular chemistry, and dynamic
combinatorial chemistry.
Henrik Gotfredsen received his Bachelor’s degree at the University
of Copenhagen under the guidance of Associate Professor Michael
Pittelkow in 2013 where he worked with organoselenium chemistry
and dynamic combinatorial chemistry. Henrik is currently pursuing a
Master’s degree in the same group.
Bjarne E. Nielsen received his Master’s degree at the University of
Copenhagen under the guidance of Associate Professor Michael Pit-
telkow in 2013 where he worked with dynamic combinatorial chem-
istry for the recognition of carbohydrates. He is now pursuing a PhD
degree in the same group working with the development of new near-
infrared dyes.
Key words: supramolecular chemistry, tripodal receptors, ureas,
amides, overcrowded aromatics
The subtle interplay between rigidity and flexibility
makes the design of receptors in supramolecular chemis-
try complex and sometimes unpredictable.1 Preorganiza-
tion has proven a reliable strategy in receptor design, but
this is only truly effective if there is a good fit with the
binding partner. A particularly popular and simple scaf-
fold that relies on preorganization is the 1,3,5-substituted
2,4,6-triethylbenzene scaffold.2 Receptors based on this
scaffold have the unique feature that the three ethyl sub-
stituents predominantly orient themselves towards one
side of the central benzene ring, while the three other sub-
stituents point towards the other side of the benzene ring.3
This feature has been used extensively in the preparation
of receptors for a wide range of guest molecules.2 The
central benzene ring can potentially engage in the molec-
ular recognition events. This has inspired a renewed inter-
est in the preparation of tripodal structures with
alternative substitution patterns on the central benzene
ring. This opens up new opportunities for fine-tuning the
binding properties of these privileged receptor structures.
A strategy to improve the binding properties of the tripo-
dal receptors is to modify the electronic properties of the
benzene ring by changing the three ethyl substituents to
three methoxy substituents.4 This subtle change in design
(three CH2 groups substituted for three oxygens) appears
to provide less preorganized structures, presumably be-
cause three almost aligned O–Me dipoles in a completely
alternating structure would not be favorable, and receptors
based on this design would need other favorable interac-
tions to outweigh this effect.5 Here we describe reliable
synthetic protocols for the preparation of a series of 1,3,5-
Christian G. Tortzen is a scientist at the Department of Chemistry at
the University of Copenhagen with specialty in NMR spectroscopy
and organic synthesis. Christian received his Master’s degree under
the guidance of Prof. Jesper Wengel and Associate Prof Otto Dahl at
the University of Copenhagen and has since worked in the laborato-
ries of Prof. John Nielsen at the University of Copenhagen and Prof.
Varinder Aggarwal at the University of Bristol, UK.
tris-substituted 2,4,6-trimethoxybenzenes. We also quan-
tify, by means of DFT calculations, the relative energetics
of the different conformations of the 1,3,5-substituted
2,4,6-trimethoxybenzenes.
SYNLETT 2013, 24, 2437–2442
Advanced online publication: 27.08.2013
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DOI: 10.1055/s-0033-1339639; Art ID: ST-2013-W0636-L
© Georg Thieme Verlag Stuttgart · New York

2438
B. E. Nielsen et al.
LETTER
Bromomethylation of 1,3,5-trimethoxybenzene (1) was and by carbamate formation. The formation of the
performed using a modified literature procedure.6,7 Treat- tris(tert-butyl)carbamate (Boc) compound 4 (Scheme 2)
ment of 1,3,5-trimethoxybenzene with paraformaldehyde was effective by treatment with di-tert-butyl dicarbonate
and HBr in AcOH for three hours at 85 °C in a sealed con- in dioxane and water, and was easily purified by column
tainer yielded the tris-bromomethylated product (2) in chromatography.9 The yield was moderate but acceptable
49% yield. This procedure reliably yields >10 g of 2 as a due to the three-fold reaction (above 60% yield per carba-
white solid material. The transformation into the tris- mate formation) and easy purification protocol. We also
methylamino compound (3) proceeded smoothly by dis- developed conditions for the preparation of an amide, 5,
solving 2 in liquid ammonia in a sealed bomb at room by coupling of the triamine and terephthalic acid mono-
temperature for 18 hours. When optimized, this transfor- methyl ester and a coupling reagent (either Me3P/I2 or
mation proceeded in quantitative yield. Simple evapora- PYBOP) in CH2Cl2.10 This material was also purified by
tion of the ammonia, addition of water and filtration chromatography on silica revealing 66% of the triamide.
yielded after concentration in vacuo the tris-hydro-
Formation of amides was also attempted by an alternative
bromide as a pale yellow solid (Scheme 1).8 This protocol
route. 1,3,5-Trimethoxybenzene gave, via reaction with
was concentration dependent and a concentration of the
tribromide of 0.1 gram per 40 mL ammonia proved to be
the optimal conditions to avoid side reactions.
N-(hydroxymethyl)phthalimide, the triphthalimide 611
and ways of opening the phthalimide functionalities by re-
action with amines as described by Gali et al. were at-
tempted (Scheme 3).12 However, the isolated product in
O
Br
O
BrH3N
O
these attempts was the N-alkyl-substituted phthalimide of
the amine.
(a)
(b)
Br
NH3Br
Another functionality derived from amines is the urea
group which has been widely used in the design of hosts
towards hydrogen bond accepting guests.1 We studied
convenient ways of converting the triamine 3 into triurea
O
O
O
O
O
O
Br
BrH3N
1
2
3
Scheme 1 Synthesis of 1,3,5-tris-methylamino-2,4,6-trimethoxy- derivatives, and it was found that reaction between 3 and
benzene (3). Reagents and conditions: (a) paraformaldehyde, 33%
HBr in AcOH, sealed vessel, 49%; (b) NH3, sealed vessel, >98%.
tert-butylisocyanate under mild conditions gave the de-
sired triurea derivative 7.13 The binding properties of this
compound were studied by NMR in chloroform, and the
With the triamine in hand, we explored the possibilities host showed a modest affinity towards chloride ions (see
for functionalization via simple amide coupling reaction Supporting Information).
O
O
O
O
O
O
NH
NH
O
O
O
O
O
O
O
(b)
(a)
H
N
H
H
H
O
N
N
N
O
O
O
O
O
O
O
4
5
BrH3N
O
NH3Br
OH
STr
O
O
O
O
NH
O
NH
O
BrH3N
3
NH
NH
O
O
O
H
N
H
H
N
H
N
(c)
(d)
H
N
H
N
H
H
N
N
N
TrS
STr
O
O
O
O
O
O
HO
O
O
OH
7
8
Scheme 2 Functionalization of the triamine 3 to carbamates, amides, and ureas. Reagents and conditions: (a) Boc2O; (b) Me3P, I2, terephthalic
acid monomethyl ester; (c) tert-butylisocyanate; (d) (i) 1,1′-carbonyldiimidazole; (ii) S-tritylcysteine (protected cysteine).
Synlett 2013, 24, 2437–2442
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of 1,3,5-Substituted 2,4,6-Trimethoxybenzenes
2439
O
O
O
N
O
O
O
(a)
N
O
O
O
O
O
1
N
6
O
(b)
H
N
Figure 1 Part of the 13C NMR spectra of the reaction mixture for the
activation of triamine 3 with 1,1′-carbonyldiimidazole after different
reaction times. From below, the spectra were recorded after 0, 10, 20,
and 60 minutes.
R
R
O
O
O
NH
NH
O
O
O
N
H
N R
O
O
The final step was most efficient when aliphatic amines
were used. When 3-aminobenzoic acid was reacted with
the triactivated triamine the desired triurea, 9, was isolated
in 21% yield even after optimization with respect to reac-
tion temperature and choice of added base.16
O
HN
HN
O
O
The activation towards urea formation can also be carried
out by activating the amine that is coupled to the central
benzene core. This was illustrated by activation of the
methyl ester of PMB-protected cysteine followed by reac-
tion with the triamine 3 to give the desired triurea com-
pound 10 (Scheme 4).17
R
Scheme 3 Alternative attempts to functionalize triamine 3 with
amides. Reagents and conditions: (a) N-hydroxymethylphthalimide,
boron triflouride etherate; (b) RNH2.
We studied ways to urea functionalize the triamine 3 with-
out the need of isocyanate reagents. The compound 1,1′-
carbonyldiimidazole has previously been used as an urea
activating reagent by formation of an activated imidazole
urea intermediate which can be reacted with a second
amine giving the unsymmetrical urea.14 This activation
method is particularly challenging with a substrate con-
taining multiple amine functionalities because reactions
between activated and non-activated amines at the early
stages of the activation process can give rise to unwanted
urea side products. We studied this triple activation step
carefully, and under optimized conditions it was found
that complete triple activation could be achieved. The op-
timized conditions were found by following the progress
of reaction for every ten minutes using 13C NMR spectros-
copy directly on the reaction mixture. Even in the non-
deuterated reaction mixture the carbon signal originating
from the methoxy CH3 group was easily identified and
could be monitored during the activation (Figure 1). As
the triamine began to react with the activation reagent the
overall symmetry of 3 was broken and therefore the signal
split up. After 60 minutes of reaction a single signal was
again obtained indicating that the overall symmetry had
been reestablished due to complete activation. After com-
plete activation, trityl-protected cysteine was added to the
mixture to give the desired unsymmetrical triurea com-
pound 8.15
O
O
PMB
S
O
O
(a)
(b)
PMB
S
O
HN
NH2
N
N
PMB
O
S
O
O
NH
NH
O
O
H
N
H
H
H
N
PMB
N
N
PMB
S
S
O
O
O
O
O
O
O
10
Scheme 4 Alternative activation order in the urea formation of tri-
amine 3. Reagents and conditions: (a) 1,1′-carbonyldiimidazole; (b) 3
and imidazole.
To gain insights into the level of preorganization of the
1,3,5-tris-substituted 2,4,6-trimethoxybenzenes, we car-
ried out a study combining single-crystal X-ray structure
determination and DFT calculations. In Figure 2 the sin-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2437–2442

2440
B. E. Nielsen et al.
LETTER
(2) (a) Metzger, A.; Lynch, V. M.; Anslyn, E. V. Angew. Chem.
Int. Ed. 1997, 36, 862. (b) Abouderbala, L. O.; Belcher, W.
J.; Boutelle, M. G.; Cragg, P. J.; Dhaliwal, J.; Fabre, M.;
Steed, J. W.; Turner, D. R.; Wallace, K. J. Chem. Commun.
2002, 358. (c) Mazik, M.; Hartmann, A.; Jones, P. Chem.
Eur. J. 2009, 15, 9147. (d) Rakrai, W.; Morakot, N.;
Keawwangchai, S.; Kaewtong, C.; Wanno, B.;
gle-crystal X-ray structure of the tribromide 2 is illustrat-
ed, showing the co-crystallization of two different
conformers of 2. When the isolated crystals were dis-
solved in CDCl3 and analyzed by 1H NMR spectroscopy
the spectrum did not show separated signals for both con-
formers. This indicates that the energy barrier for con-
former conversion is sufficiently low to make the
conformer-exchange process fast on the chemical shift
time scale.
Ruangpornvisuti, V. Struct. Chem. 2011, 22, 839.
(e) Quioñero, D.; López, K. A.; Deyà, P. M.; Piña, M. N.;
Morey, J. Eur. J. Org. Chem. 2011, 6187.
(3) (a) Iverson, D. J.; Hunter, G.; Blount, J. F.; Damewood, J. R.
Jr.; Mislow, K. J. Am. Chem. Soc. 1981, 103, 6073. (b) Mori,
T.; Grimme, S.; Inoue, Y. J. Org. Chem. 2007, 72, 6998.
(4) (a) Perez-Balderas, F.; Morales-Sanfrutos, J.; Hernandez-
Mateo, F.; Isac-García, J.; Santoyo-Gonzalez, F. Eur. J. Org.
Chem. 2009, 2441. (b) Whiting, A. L.; Hof, F. Org. Biomol.
Chem. 2012, 10, 6885.
(5) Simaan, S.; Siegel, J. S.; Biali, S. E. J. Org. Chem. 2003, 68,
3699.
(6) (a) Li, H.; Homna, E. A.; Lampkins, A. J.; Ghiviriga, I. Org.
Lett. 2005, 7, 443. (b) Roy, R. K.; Ramakrishnan, S.
Macromolecules 2011, 44, 8398.
Figure 2 (a) Crystal structure of the tribromide 2 showing the co-
crystallization of two conformers.18 (b) B3LYP/6-31G(d) geometry
optimized structures of the same conformers.
(7) 1,3,5-Tris(bromomethyl)-2,4,6-trimethoxybenzene (2):
1,3,5-Trimethoxybenzene (10.0 g, 59.5 mmol) and
paraformaldehyde (11.0 g, 366 mmol) were suspended in
33% HBr in AcOH (85 mL) in a sealed stainless steel
reaction vessel. The mixture was stirred for 3 h at 85 °C.
After cooling to 25 °C CH2Cl2 (200 mL) was added, the
phases were separated, and the organic phase was washed
with H2O (3 × 75 mL). The CH2Cl2 phase was filtered
through silica (Ø = 50 mm, h = 60 mm) and the column was
flushed with further CH2Cl2 (2 × 150 mL). The solvent was
removed in vacuo, and the resulting yellow oil was dissolved
in a mixture of 2-propanol (100 mL) and CH2Cl2 (100 mL).
White crystals were obtained by reducing the volume of the
solution to 50 mL and the precipitates were filtered off and
washed with 2-propanol. Yield: 13.0 g (49%); mp 125–126
°C. 1H NMR (500 MHz, CDCl3): δ = 4.60 (s, 6 H), 4.14 (s, 9
H). 13C NMR (125 MHz, CDCl3): δ = 160.3, 123.5, 62.9,
Gas-phase structure optimization and energy calculations
of ten possible conformers of 2 (see Supporting Informa-
tion) using DFT calculations indicate that these two co-
crystallizing conformers are among the three lowest ener-
gy structures. The most stable conformer was found to
have all substituents located on the same plane of the ben-
zene ring, and the highest energy structure was found to
have the substituents placed alternating.
We did not succeed in obtaining crystals of sufficient
quality for single-crystal X-ray determination of any of
the nitrogen-containing tripodal structures. NMR data,
however, was obtained and showed a number of signals
only possible if either the alternating conformer or the
conformer with all substituents on the same side of the
benzene ring were formed exclusively or if the conformer-
exchange process is fast on the chemical shift time scale.
+
22.7. HRMS: m/z [M + NH4]+ calcd for C12H19O3NBr3 :
461.8910; found: 461.8924.
(8) (2,4,6-Trimethoxybenzene-1,3,5-triyl)trimethanamine
Hydrobromide (3): 1,3,5-Tris(bromomethyl)-2,4,6-
trimethoxybenzene (401 mg, 0.898 mmol) and liquid NH3
(160 mL) were stirred at 25 °C for 18 h in a sealed reaction
vessel. The ammonia was removed by evaporation, and the
residue was dissolved in H2O (30 mL) and filtered.
Concentration in vacuo gave a colorless solid. Yield: 437 mg
(98%); mp 176 °C (dec.). 1H NMR (500 MHz, D2O): δ =
4.33 (s, 6 H), 3.92 (s, 9 H). 13C NMR (125 MHz, CDCl3): δ
= 160.3, 118.1, 63.0, 33.2. HRMS: m/z [2 M + H] calcd for
In summary, we have presented a straightforward two-
step protocol for the preparation of 1,3,5-tris-methylami-
no-2,4,6-trimethoxybenzene. We have shown how this
key substrate can be transformed into tricarbamates, tri-
amides, and triureas. Despite the preorganization of these
1,3,5-tris-substituted 2,4,6-trimethoxybenzenes towards
an alternating conformation appears to be less than that in
the triethyl substrates, we are optimistic regarding the fu-
ture use of these structures in the design of supramolecu-
lar receptors.4b
+
C24H43N6O6 : 511.3239; found: 511.3239.
(9) Tri-tert-butyl [(2,4,6-Trimethoxybenzene-1,3,5-
triyl)tris(methylene)]tricarbamate (4): The tribromide 2
(1.80 g, 4.02 mmol) was dissolved in THF–EtOH (100 mL;
1:1) and concentrated aq NH3 (80 mL) was added. The
reaction mixture was stirred for 14 h whereafter the solvent
was removed in vacuo. The residue was dissolved in
dioxane–H2O (70 mL, 1:1) and NaOH (0.80 g, 20 mmol)
was added. Boc2O (5.76 g, 26 mmol) in dioxane (20 mL) was
slowly added at 0 °C and the reaction was stirred for an hour
at 0 °C and 5 h at 25 °C. H2O was added and the solution was
extracted with CH2Cl2 (3 × 60 mL). The organic phase was
dried over Na2SO4, filtered and concentrated in vacuo. The
product was further purified by dry column chromatography
(Ø = 60 mm, h = 50 mm, heptane with 0.1% Et3N to EtOAc
with 0.1% Et3N with 5% gradient), followed by
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
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References and Notes
(1) (a) Steed, J. W.; Atwood, J. L. In Supramolecular
Chemistry, 2nd Ed.; John Wiley & Sons: Chichester, 2009.
(b) Sanders, J. K. M. Chem. Eur. J. 1998, 4, 1378.
Synlett 2013, 24, 2437–2442
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of 1,3,5-Substituted 2,4,6-Trimethoxybenzenes
2441
recrystallization from heptane. Yield: 0.517 g (23%); mp
(15) 2,2′,2′′-{[{[(2,4,6-Trimethoxybenzene-1,3,5-
93.5–95 °C. 1H NMR (500 MHz, CDCl3): δ = 5.12 (s, 3 H),
4.39 (d, 6 H), 3.81 (s, 9 H), 1.44 (s, 27 H). 13C NMR (125
MHz, CDCl3): δ = 158.5, 155.1, 122.6, 79.1, 62.4, 34.8,
28.6. HRMS: m/z [M + Na]+ calcd for C27H45N3O9Na+:
578.3048; found: 578.3069.
triyl)tris(methylene)]tris(azanediyl)}tris(carbonyl)]tris-
(azanediyl)}tris[3-(tritylthio)propanoic Acid] (8): The
triamine 3 (100 mg, 0.200 mmol) was dissolved in DMF (10
mL) and a solution of 1,1′-carbonyldiimidazole (100.9 mg,
0.622 mmol) in MeCN (10 mL) was added. The reaction
mixture was stirred for an hour and S-tritylcysteine (233.5
mg, 0.643 mmol) and Et3N (0.142 mL, 1 mmol) were added.
The reaction mixture was stirred overnight whereafter the
volatiles were removed. The residue was redissolved in
CHCl3 and washed with 0.5 M HCl (3 × 50 mL). The organic
phase was dried over Na2SO4, filtered and concentrated in
vacuo. The product was further purified by preparative
HPLC to give a white solid material. Yield: 121 mg (45%);
mp 177–179 °C. 1H NMR (500 MHz, DMSO-d6): δ = 12.70
(s, 3 H), 7.17–7.40 (m, 45 H), 6.42 (d, J = 8.3 Hz, 3 H), 6.30
(t, J = 5.4 Hz, 3 H), 4.25 (d, J = 5.4 Hz, 6 H), 4.20 (ddd, J =
8.3, 6.8, 5.1 Hz, 3 H), 3.72 (s, 9 H), 2.41 (dd, J = 11.7, 6.8
Hz, 3 H), 2.33 (dd, J = 11.7, 5.1 Hz, 3 H). 13C NMR (125
MHz, DMSO-d6): δ = 172.60, 158.04, 156.69, 144.16,
129.00, 128.03, 126.78, 122.54, 65.80, 62.13, 51.60, 34.31,
(10) Trimethyl 4,4′,4′′-[{[(2,4,6-Trimethoxybenzene-1,3,5-
triyl)tris(methylene)]tris(azanediyl)}tris(carbonyl)]tri-
benzoate (5): Iodine (458 mg, 1.81 mmol) was added to an
ice-cooled solution of trimethyl phosphite (0.213 mL, 1.81
mmol) in CH2Cl2 (40 mL). When all the iodine had
dissolved, terephthalic acid monomethyl ester (325 mg, 1.81
mmol) and Et3N (1.12 mL, 8.03 mmol) were added and the
solution was stirred for 20 min under continued cooling. The
triamide 3 (200 mg, 0.401 mmol) was added and the mixture
was stirred for 10 min at 0 °C and for 3 h at 25 °C. Sat.
NaHCO3 was added and the aqueous phase was extracted
with CH2Cl2 (50 mL). The organic phase was washed with 2
M HCl (2 × 50 mL) and brine (50 mL), dried over Na2SO4,
and filtered. The product was further purified by dry column
chromatography (Ø = 40 mm, h = 40 mm, CH2Cl2 to 12%
MeOH in CH2Cl2 with 1.5% gradient). Yield: 0.31 g (66%);
mp 212–213 °C. 1H NMR (500 MHz, DMSO-d6): δ = 8.60
(t, J = 4.8 Hz, 3 H), 7.94–8.02 (m, 12 H), 4.58 (d, J = 4.8 Hz,
6 H), 3.88 (s, 9 H), 3.83 (s, 9 H). 13C NMR (125 MHz,
DMSO-d6): δ = 165.69, 165.21, 158.98, 138.58, 131.60,
128.98, 127.75, 121.01, 62.17, 52.33, 33.92. HRMS: m/z [M
+ H]+ calcd for C39H40N3O12+: 742.2607; found: 742.2613.
(11) 2,2′,2′′-[(2,4,6-Trimethoxybenzene-1,3,5-
+
33.03. HRMS: m/z [M + H]+ calcd for C81H79N6O12S3 :
1423.4913; found: 1423.4884.
(16) 3,3′,3′′-{[{[(2,4,6-Trimethoxybenzene-1,3,5-
triyl)tris(methylene)]tris(azanediyl)}tris(carbonyl)]tris-
(azanediyl)}tribenzoic Acid (9): The triamine 3 (202 mg,
0.406 mmol) was dissolved in DMF (20 mL) and a solution
of 1,1′-carbonyldiimidazole (3.1 equiv, 204 mg, 1.26 mmol)
in MeCN (20 mL) was added. The reaction mixture was
stirred for an hour at r.t. 3-Aminobenzoic acid (3.2 equiv,
178 mg, 1.30 mmol), Et3N (21.2 equiv, 1.2 mL, 8.6 mmol)
and DMAP (0.1 equiv, 5.1 mg, 0.042 mmol) were added and
the reaction mixture was stirred for 3 d. Thereafter, the
reaction mixture was poured into an ice-cold solution of 2 M
HCl, the precipitate was filtered off and dried in vacuo.
Finally, the crude product was washed once with 2 M NaOH
(20 mL), reacidified with 2 M HCl, filtered and dried in
vacuo. Yield: 62.9 mg (21%). 1H NMR (500 MHz, DMSO-
d6): δ = 9.24 (s, 3 H), 8.06 (s, 3 H), 7.58 (d, J = 7.7 Hz, 3 H),
7.44 (d, J = 7.7 Hz, 3 H), 7.31 (t, J = 7.7 Hz, 3 H), 6.57 (s, 3
H), 4.38 (s, 6 H), 3.84 (s, 9 H). 13C NMR (125 MHz,
DMSO): δ = 167.36, 158.22, 154.79, 140.90, 131.19,
128.78, 122.34, 121.73, 121.48, 118.00, 62.37, 32.98.
HRMS: m/z [M + H]+ calcd for C36H37N6O12+: 745.2464;
found: 745.2489.
(17) Trimethyl 2,2′,2′′-{[{[(2,4,6-Trimethoxybenzene-1,3,5-
triyl)tris(methylene)]tris(azanediyl)}tris(carbonyl)]tris-
(azanediyl)}tris{3-[(4-methoxybenzyl)thio]propanoate}
(10): The PMB-protected cysteine (234 mg, 0.830 mmol)
was dissolved in DMF (20 mL) and a solution of 1,1′-
carbonyldiimidazole (143.1 mg, 0.883 mmol) in MeCN (20
mL) was added. The mixture was stirred for 30 min and the
triamine 3 (100 mg, 0.201 mmol) and imidazole (136 mg,
2.00 mmol) were added. The reaction mixture was stirred
overnight whereafter the volatiles were removed. The
residues were redissolved in CH2Cl2 (80 mL) and washed
with 0.5 M HCl (3 × 50 mL) and brine. The organic phase
was dried over Na2SO4, filtered, and concentrated in vacuo.
The product was further purified by dry column
triyl)tris(methylene)]tris(isoindoline-1,3-dione) (6):
1,3,5-Trimethoxybenzene (500 mg, 2.97 mmol) and N-
hydroxymethylphthalimide (1.65 g, 9.31 mmol) were
dissolved in boron triflouride etherate (25 mL) by gentle
heating. Afterwards the solution was stirred at 25 °C for 3 h.
The reaction mixture was poured into an ice–sodium acetate
mixture (100 g/15 g) and stirred for an hour. The aqueous
phase was extracted with CH2Cl2 (3 × 50 mL) and the
combined organic phase was washed with H2O (50 mL),
dried over Na2SO4, filtered and concentrated in vacuo. The
product was further purified by dry column chromatography
(Ø = 40 mm, h = 40 mm, toluene to 15% MeCN in toluene
with 3% gradient). Yield: 0.31 g (16%); mp 223–224 °C. 1H
NMR (500 MHz, DMSO-d6): δ = 7.65–7.78 (m, 12 H), 4.77
(s, 6 H), 3.73 (s, 9 H). 13C NMR (125 MHz, DMSO-d6): δ =
167.24, 158.18, 134.22, 131.30, 122.73, 119.02, 61.82,
+
32.27. HRMS: m/z [M + H]+ calcd for C36H28N3O9 :
646.1820; found: 646.1794.
(12) Gali, H.; Prabhu, K. R.; Karra, S. R.; Katti, K. V. J. Org.
Chem. 2000, 65, 676.
(13) 1,1′,1′′-[(2,4,6-Trimethoxybenzene-1,3,5-
triyl)tris(methylene)]tris[3-(tert-butyl)urea] (7): The
triamine 3 (200 mg, 0.402 mmol) was suspended in CH2Cl2–
Et3N (50 mL, 9:1) and tert-butylisocyanate (318 mg, 3.21
mmol) was added. The reaction mixture was stirred for 3 d
at 25 °C. The volatiles were removed in vacuo and the
residues were redissolved in CH2Cl2 (75 mL) and washed
with 1 M hydrochloric acid (2 × 30 mL) and brine. The
product was further purified by preparative HPLC, to yield
58% yield of a white solid; mp 275 °C (dec.). 1H NMR (500
MHz, DMSO-d6): δ = 5.83 (s, 3 H), 5.71 (t, J = 5.3 Hz, 3 H),
chromatography (Ø = 40 mm, h = 40 mm, CH2Cl2 to 5%
MeOH in CH2Cl2 with 0.5% gradient) to yield a white solid.
Yield: 65 mg (28%); mp 195 °C (dec.). 1H NMR (500 MHz,
DMSO-d6): δ = 7.19 (d, J = 8.7 Hz, 6 H), 6.86 (d, J = 8.7 Hz,
6 H), 6.52 (d, J = 8.2 Hz, 3 H), 6.32 (t, J = 5.3 Hz, 3 H), 4.38–
4.49 (m, 3 H), 4.27 (d, J = 5.3 Hz, 6 H), 3.74 (s, 9 H), 3.72
(s, 9 H), 3.67 (s, 6 H), 3.61 (s, 9 H), 2.71 (dd, J = 13.6, 5.3
Hz, 3 H), 2.65 (dd, J = 13.6, 6.8 Hz, 3 H). 13C NMR (125
4.20 (d, J = 5.3 Hz, 6 H), 3.73 (s, 9 H), 1.20 (s, 27 H). 13
C
NMR (125 MHz, DMSO-d6): δ = 157.80, 156.82, 122.90,
62.00, 48.93, 32.64, 29.31. HRMS: m/z [M + H]+ calcd for
+
C27H49N6O6 : 553.3708; found: 553.3717.
(14) Diness, F.; Beyer, J.; Meldal, M. QSAR Comb. Sci. 2004, 23,
117.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2437–2442

2442
B. E. Nielsen et al.
LETTER
MHz, DMSO-d6): δ = 172.14, 158.16, 158.05, 156.72,
129.95, 129.79, 122.47, 113.73, 62.10, 55.00, 52.41, 51.91,
34.79, 33.07, 33.00. HRMS: m/z [M + H]+ calcd for
μ(Mo–Kα) = 0.07 mm–1; 94511 reflections measured, 11105
independent reflections (Rint = 0.112). The final R1 values
were 0.039 [F2 >2σ (F2)]. The final R1 values were 0.0688
(all data). The final wR(F2) (all data) values were 0.110. The
goodness of fit on F2 was 1.163. The structure of the
tribromide 2 has been submitted to the Cambridge
+
C51H67N6O15S3 : 1099.3821; found: 1099.3853.
(18) C12H15Br3N3; M = 446.97; monoclinic; a = 9.9840(8) Å, b =
16.845(2) Å, c = 18.806(2) Å, α = 90°, β = 112.224(8)°, γ =
90°; V = 2927.8(5) Å3; T = 122 K; space group P21/c; Z = 8;
Crystallographic Data Centre (CCDC) as CCDC 947822.
Synlett 2013, 24, 2437–2442
© Georg Thieme Verlag Stuttgart · New York