Bifunctional Aryloxylate Esters as potential oxidatively cleavable linkers

Article abstract of DOI:10.1016/j.tetlet.2011.04.083

Selectively cleavable linkers are essential parts in environmentally responsive materials. Here, we introduce aryl oxalate esters (AOE) as one of the first examples for oxidatively cleavable linkers. To this end a series of novel AOEs was synthesized and explored regarding the H₂O ₂-dependent degradation. All AOEs were cleaved selectively at the oxalate group. The degradation rate was clearly dependent on the substituents. Further, it was found that the H₂O₂ based degradation undergoes an autocatalysis mechanism.

Full text of DOI:10.1016/j.tetlet.2011.04.083

Tetrahedron Letters 52 (2011) 3551–3554
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bifunctional Aryloxylate Esters as potential oxidatively cleavable linkers
⇑
P. v. Czarnecki, A. Kampert, S. Barbe, J. C. Tiller
Department of Bio and Chemical Engineering, TU Dortmund, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Selectively cleavable linkers are essential parts in environmentally responsive materials. Here, we intro-
duce aryl oxalate esters (AOE) as one of the first examples for oxidatively cleavable linkers. To this end a
series of novel AOEs was synthesized and explored regarding the H2O2-dependent degradation. All AOEs
were cleaved selectively at the oxalate group. The degradation rate was clearly dependent on the substit-
uents. Further, it was found that the H2O2 based degradation undergoes an autocatalysis mechanism.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 7 March 2011
Revised 16 April 2011
Accepted 20 April 2011
Available online 1 May 2011
Keywords:
Aryloxalate ester
Oxidative cleavable linker
Autocatalysis
Reaction kinetics
Materials that interact with their environment, so-called respon-
sive or smart materials, are in the focus of current material science.
One way to create such materials is to form polymer networks that
contain selectively cleavable chemical bonds. Active agents en-
trapped into such networks can be released as a response to com-
pounds that cleave the bonds in an aqueous environment. In the
past decade many selectively cleavable linkers or degradable poly-
mers have been developed for this purpose and built into several net-
works. They represent modern key materials for controlled drug
delivery and tissue engineering. In general, the cleavable bonds are
built in the main chain of polymers, which are then fully hydrolyzed
or fermented.1,2 Alternatively, they can act as cleavable linkers, which
are selectively spliced and result in degradation of the polymer net-
work. The trigger for cleaving the linkers was tailored in many differ-
ent ways, including hydrolysis,3–7 temperature,8–10 light,11,12 enzyme
catalysis,13–16 reduction17–19, and rarely oxidation.20
Particularly oxidatively cleavable linkers are of current interest
in modern medicine, because the human body locally produces
hydrogen peroxide and other reactive oxygen species (ROS), for
example, in inflamed tissue.21–24 The selective reaction to an
inflammation is a very desirable application for drug delivery, for
instance to limit the unnecessary use of antibiotics or anesthetics.
So far, the only way to react on an increase in hydrogen peroxide
concentration is the selective drug delivery from polysulfide con-
taining vesicles.25 Solid matrices that allow the release of drugs
in the presence of hydrogen peroxide are not known. One reason
for this is the lack of chemical linkers that are cleaved by the ROS.
The goal of this work was to prepare bifunctional compounds
that can be degraded by hydrogen peroxide. Although many oxida-
tion reactions of H2O2 with, for example aldehydes26 or nitriles27 are
known, only a few lead to bond cleavage. The most prominent exam-
ples are aromatic hydrazides28 and aryl oxalate esters (AOE).29–33
Particularly aromatic oxalates are known to show chemilumines-
cence when reacting with hydrogen peroxide. Although a vast
amount of work has been done to optimize this reaction, particularly
in glow or light sticks,34 such oxalates have never been considered as
potentially oxidative cleavable crosslinkers.
We have synthesized a series of compounds with a symmetric
aromatic oxalate unit and two functional groups and investigated
them regarding their reaction with hydrogen peroxide.
The AOEs were prepared by conversion of oxalyl chloride with a
selection of bifunctional phenols in the presence of NaH in THF to a
yield of 45–86%. (for structures see Table 1) The identity of those
novel compounds was confirmed with 1H NMR and 13C NMR spec-
troscopy. The purity of all products was more than 99% as con-
firmed with HPLC.
Although, the most likely environment for the synthesized com-
pounds as hydrogel linkers would be water, we decided to explore
their susceptibility against H2O2 in acetonitrile, because the AOEs
are not soluble in water. First, all oxalates were dissolved in aceto-
nitrile and stirred at room temperature for one day. HPLC chro-
matograms of the reaction mixtures before and after this time
revealed that all compounds are stable under these conditions.
Next, the dissolved AOEs were reacted with hydrogen peroxide at
room temperature. The reaction was monitored by using HPLC.
As seen in Figure 1, which shows the conversion of the AOEs in
the presence of 50 mmol/L H2O2, all investigated esters are cleav-
able by the ROS hydrogen peroxide. In order to quantify the degra-
dation the half-lives of the oxalates are used as rate indicator.
⇑
Corresponding author. Tel.: +49 231 755 2479; fax: +49 231 755 2480.
E-mail address: joerg.tiller@tu-dortmund.de (J.C. Tiller).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.083

3552
P. v. Czarnecki et al. / Tetrahedron Letters 52 (2011) 3551–3554
Table 1
The AOEs with a substituent in ortho position (AOE1, AOE6) are
Synthesized AOEs36
oxidatively cleaved with a 10 times lower rate than the others. This
could be a result of two influences, adding up. First the higher ste-
ric hindrance of the ortho-substituent to the reactive oxalate ester
and second a higher +I effect from the ortho-substituent than the
meta-substituent, stabilize the ester binding. Moreover, the para-
alkyl-substituent (AOE4) stabilizes the ester binding better than
the meta-alkyl- or para-halogenide-substituents (AOE2, AOE3).
Hence the Tyramin-oxalate-ester (AOE5) should degrade with a
rate similar to the 4-(2-bromoethyl)-phenol-linker (AOE4), but it
seems that the BOC protected amine interacts in the degradation
process.
R1
R4
R2
R3
R4
O
R3
O
OH
THF, NaH,
-15°C, 4h
R3
R2
O
Cl
+
O
Cl
R2
O
R4
O
R1
R1
Yield (%) s1/2
#
R1
R2
R3
R4
s1/2
a
b
AOE1
AOE2
AOE3
H
H
Me
Cl
Cl
Br
H
Me
Me
Me
H
86
46
53
20
3
2
/
49
33
H
Br
In order to see the influence of the H2O2 concentration, we
decided to measure the reaction rate of the degradation at a 10-
fold lower H2O2 concentration.
AOE4
AOE5
AOE6
H
H
H
H
H
60
69
70
6
56
48
/
H
N
H
H
1
BOC
As seen in Table 1 the degradation slows down in all cases. As
expected from the mechanism the reaction rate is directly propor-
tional to the hydrogen peroxide concentration, except for AOE1
and AOE6 which are somehow more sensitive to the H2O2 content.
Preliminary work indicates that the degradation reaction might
be pH depended.33 In order to test that hypothesis, we decided to
investigate the degradation of AOE6 (Eugenol) with H2O2 in aceto-
nitrile in the presence of HCl and NaHCO3, respectively. The stabil-
ity of AOE6 in NaHCO3 without hydrogen peroxide was measured
as well.
As seen in Figure 2 and Table 2 the degradation of AOE6 is
clearly dependent on the pH. While HCl completely suppresses
the reaction, the carbonate accelerates it by a factor of 5. This
strongly supports our hypothesis that the reaction is catalyzed by
R–Oꢀ, which can either be the deprotonated phenol derivative or
an OHꢀ derived from the added base.
H
–OMe
22
a
50 mmol/L H2O2.
5 mmol/L H2O2.
b
The kinetics curves reveal two important facts:
1) Expectedly, the degradation rates significantly depend on
the position and nature of the substituents and can be tai-
lored in a range of half-life times of 1 h to 22 h (see Table 1,
7th column).
2) Surprisingly, the reaction rates do not cease with higher con-
version but are constant or even accelerate during the course
of the reaction.
Further, the control experiment shows that the basic conditions
alone do not afford a degradation of the AOE6.
100
Table 2
Half-lives of AOE6 at different conditions
75
#
Conditions
t1/2 [h]
AOE6
1
2
3
4
50 mmol/L H2O2
22
/
4
/
50 mmol/L water, NaHCO3 (solid)
50 mmol/L H2O2, NaHCO3 (solid)
50 mmol/L H2O2, 0.4 mmol/L HCl
50
AOE1
AOE2
AOE4
25
0
AOE3
AOE5
0
4
8
12
16
20
24
O
time [h]
ArO
H2O2
2 CO2
+
+
2 HOAr
OAr
O
Figure 1. Degradation of AOE1
(0.5 mg/mL oxalates, 50 mmol/L H2O2)
D, AOE2 s, AOE3 j, AOE4 –, AOE5x, AOE6 ꢀ.
Scheme 1. Sum reaction of the oxidative AOEs decomposition with H2O2.
NaHCO3, H2O
HCl, H2O2
100
50
0
100
50
0
H2O2
Eugenol
AOE6
NaHCO3, H2O2
16
0
4
8
12
20
24
0
4
8
12
16
20
24
time [h]
time [h]
Figure 2. The degradation of AOE6 under different conditions. 0.5 mmol/L oxalates
in MeCN a) ꢀ with 50 mmol/L H2O2; b) j with NaHCO3 (solid) and 50 mmol/L
water; c) N with NaHCO3 (solid) and 50 mmol/L H2O2; d) s with 0.4 mmol/L HCl
and 50 mmol/L H2O2.
Figure 3. Decreasing of AOE6 ꢀ and increasing of the corresponding phenol
derivate Eugenol e concentrations. + the summation of both curves. 0.5 mmol/L
linker in MeCN with NaHCO3 (solid) and 50 mmol/L H2O2. Before injected on the
HPLC diluted with MeCN 1:1.

P. v. Czarnecki et al. / Tetrahedron Letters 52 (2011) 3551–3554
3553
As for the mechanism of the reaction, it was observed in all
cases that the degradation rate increases over time at the begin-
ning and slows down only at very high conversions. This is a typ-
ical behavior of an autocatalytic reaction.
degradation of AOE2 as representative example. As seen in Fig-
ure 4a, the degradation process cannot be fitted satisfactorily using
Eq. 1. Obviously, the degradation rate is controlled by the forma-
tion of intermediates and/or catalysts.
Motoyoshiya and co-workers have suggested that the degrada-
tion of aromatic oxalates by H2O2 is resulting in CO2 and phenols
(Scheme 1).33 Since the authors were focusing on the high energy
intermediates, the full reaction was not investigated and thus the
autocatalytic behavior was not found. In order to obtain better in-
sights into the reaction mechanism the concentration of the peaks
in the HPLC were analyzed for the conversion of AOE6 with H2O2 as
shown in Figure 3 with respect to the simultaneously occurring
formation of the product Eugenol. It was found that the corre-
sponding phenol derivate was formed with the same rate as the
oxalate disappeared. Obviously the obtained products were indeed
the phenol and gaseous compounds. From these findings we sug-
gest the sum reaction depicted in Scheme 1:
d½Liꢁ
m
¼ ꢀ
¼ k ꢂ ½Liꢁ ꢂ ½H2O2ꢁ
ð1Þ
dt
As mentioned above the measured kinetics seems to show an
autocatalytic characteristic. Therefore, we suggest that the formed
phenol derivative might act as a catalyst. Considering this, the
reaction should be described by Eqs. 2 and 3, allowing the phenol
to form a 1:1 or a 2:1 intermediate complex with the AOEs.
d½Liꢁ
m
m
¼ ꢀ
¼ ꢀ
¼ k ꢂ ½Liꢁ ꢂ ½H2O2ꢁ ꢂ ½Pheꢁ
¼ k ꢂ ½Liꢁ ꢂ ½H2O2ꢁ ꢂ ½Pheꢁ
ð2Þ
ð3Þ
dt
d½Liꢁ
2
dt
However, none of the two Equations describes the reaction kinetics
in a proper way, as also shown in Figure 4a.
According to this, the reaction rate should be describable with
Eq. 1. In order to explore this, the function was fitted to the
Apparently, the experimental data in Figure 3a seem to follow a
mechanism according to Eq. 1 at the beginning and come closer to
the curve shape of Eqs. 2 and 3 at the end. Thus, we presumed that
the reaction has a finite rate without catalysis, which is increased
auto catalytically by formation of the product. Such a kinetics
can be described by Eqs. 4, 5.
2
Equ3
1.5
d½Liꢁ
m
m
¼ ꢀ
¼ ꢀ
¼ k1 ꢂ ½Liꢁ ꢂ ½H2O2ꢁ þ k2 ꢂ ½Liꢁ ꢂ ½H2O2ꢁ ꢂ ½Pheꢁ
¼ k1 ꢂ ½Liꢁ ꢂ ½H2O2ꢁ þ k2 ꢂ ½Liꢁ ꢂ ½H2O2ꢁ ꢂ ½Pheꢁ
ð4Þ
ð5Þ
dt
1
AOE2
d½Liꢁ
2
dt
0.5
Equ1
Both Equations allow an acceptable numeric fit to the decompo-
Equ2
sition of AOE2 as seen in Figure 4b. The best fit was achieved with
Eq. 5, indicating a 3-membered intermediate complex. The reac-
tion rate constants were calculated to as k1 = 3.56 L/(s mol) and
k2 = 1.6 ꢃ 106 L3/(s mol3).
0
0
1
2
3
4
5
6
7
8
9
time [h]
Altogether, the degradation of the AOEs seems to be a combina-
tion of two parallel reactions. One of them is catalyzed by the pro-
duced phenol. The reaction seems to follow an autocatalytic
mechanism as already presumed above. Therefore, we suggest
the following mechanisms of the oxidative cleavage in Scheme 1,
with k1 (3.56 L/(s mol) << k2 (117 [L3/(s mol3]1/3):
2
1.5
1
AOE2
The upper part in Scheme 2 shows the non catalyzed reaction
route which dominates the beginning of the reaction. A similar
mechanism has been proposed by Motoyoshiya et al.33 In contrast
to their mechanistic considerations, it seems that after the accor-
dant phenol occurs the alternative autocatalyzed route becomes
the major reaction route.
In closing, we have presented the synthesis of six novel aryl
oxalate esters, which might be used as oxidation sensitive linkers.
All oxalates were found to be specifically cleavable by hydrogen
0.5
0
Equ4
Equ5
0
1
2
3
4
5
6
7
8
9
time [h]
Figure 4. The numeric fitting of the Equations to the oxidative decomposition of
AOE2 s (0.5 mg/mL, 50 mmol/L H2O2). (a) Eqs. 1–3. (b) Eqs. 4 and 5.
OH
O
HO
k1
R
O
O
O
R
R
O
OH
H2O2
O
2
O
2 CO2
+
OH
O
O
HO
R
R
R
k2
O
O
O
R
R
R
OH
HO
Scheme 2. Proposed reaction routes of AOEs degradation by hydrogen peroxide.

3554
P. v. Czarnecki et al. / Tetrahedron Letters 52 (2011) 3551–3554
water (150 mL) was added to a mixture of tyramine (15.11 g, 110 mmol,
1.0 equiv) and BOC2O (24.5 mL, 112 mmol, 1.0 equiv) suspended in THF
(460 mL) and vigorously stirred. After 24 h the mixture was diluted with
excess ether and the aqueous was extracted with ether (2 ꢃ 150 mL). The
combined organic layers were sequentially washed with 0.5 M HCl, water and
brine then dried over Na2SO4. Concentration gave a crude yellow oil which was
purified by flash Silica chromatography (cyclohexane /ethyl acetate (3:1),
Rf = 0.3) to give N-t-BOC-tyramine as a white solid (24.07 g, 92%). Anal. Calcd
for C13H19NO3: C 65.8; H 8.1; N 5.9. Found: C 65.6; H 8.0; N 5.7.
peroxide. The reaction rate could be controlled by the nature and
the position of the substituents over more than one order of mag-
nitude. Also pH influenced the cleavage reaction greatly. Further, it
was found that the degradation follows a simple second order
kinetics at the beginning and becomes an autocatalytic reaction
at higher conversion. This has a very intriguing consequence for
the potential use of the AOEs as linkers – the reaction rate is nearly
constant until up to 90% conversion. Thus, a polymer network with
such a linker would be sensitive to H2O2 until it is nearly fully
degraded.
1H NMR (400 MHz, acetone): d = 1.40 (s, t-Butyl), 2.68 (t, 3J5,6 = 7.6, 5-H2), 3.16
3
3
3
3
(td, J6,5 = 7.6, J6,N = 6.5, 6-H2), 5.89 (m, JN,6 = 5.5, N-H1), 6.76 (d, J2,3 = 8.4, 2-
3
H2), 7.04 (d, J3,2 = 8.4, 3-H2, 3’-H2), 8.08 (s, O–H1) ppm.
Generally all AOEs were prepared by
a
modified synthesis of Lathi.30
Exemplarily shown by the synthesis of bis(4-chloro-2-methylphenol) oxalate
(AOE1).
References and notes
4-chloro-2-methylphenol (1.57 g; 11 mmol, 1.0 equiv) was solved in 10 mL of
dry THF at -15 °C under argon was added carefully in portions NaH (0.48 g, 60%
in oil, 12 mmol, 1.1 equiv). After the resultant white suspension was stirred for
30 min, oxalyl chloride (0.82 g, 6.5 mmol, 0.5 equiv) in 10 mL of THF was added
slowly dropwise with the reaction still cooled in an ice acetone bath. The
reaction was then stirred at -15 °C for 2 h. The final mix was poured onto ice,
washed with saturated NH4Cl, brine and water, and then dried over Na2SO4.
Evaporation under reduced pressure gave the crude product, which was
recrystallized from acetone/ethyl acetate twice to give a white powder of AOE1
(1.60 g, 86%). Anal. Calcd for C16H12Cl2O4: C 56.7; H 3.6. Found: C 56.6; H 3.7.
1H NMR (400 MHz, DMSO): d = 2.24 (s, 7-H3, 70-H3), 7.36 (d, 3J6,5 = 8.8, 6-H1, 60-
1. Jeong, B.; Gutowska, A. Trends Biotechnol. 2002, 20, 305–311.
2. Vert, M. J. Mat. Sci. – Mater. Med. 2009, 20, 437–446.
3. Bencherif, S. A.; Sheehan, J. A.; Hollinger, J. O.; Walker, L. M.; Matyjaszewski, K.;
Washburn, N. R. J. Biomed. Mater. Res., Part A 2009, 90A, 142–153.
4. Kramer, R. A.; Brohmer, M. C.; Forkel, N. V.; Bannwarth, W. Eur. J. Org. Chem.
2009, 4273–4283.
5. Rikkou, M. D.; Loizou, E.; Porcar, L.; Butler, P.; Patrickios, C. S. Macromolecules
2009, 42, 9412–9421.
6. Ruckenstein, E.; Zhang, H. M. Macromolecules 1999, 32, 3979–3983.
7. Stubbe, B. G.; Horkay, F.; Amsden, B.; Hennink, W. E.; De Smedt, S. C.;
Demeester, J. Biomacromolecules 2003, 4, 691–695.
8. Heath, W. H.; Palmieri, F.; Adams, J. R.; Long, B. K.; Chute, J.; Holcombe, T. W.;
Zieren, S.; Truitt, M. J.; White, J. L.; Willson, C. G. Macromolecules 2008, 41, 719–
726.
9. Otsuka, H.; Endo, T. Macromolecules 1999, 32, 9059–9061.
10. Themistou, E.; Kanari, A.; Patrickios, C. S. J. Polym. Sci., Part A: Polym. Chem.
2007, 45, 5811–5823.
11. Amir, R. J.; Pessah, N.; Shamis, M.; Shabat, D. Angew. Chem., Int. Ed. 2003, 42,
4494–4499.
12. McGrath, D. V. Mol. Pharm. 2005, 2, 253–263.
13. Grether, U.; Waldmann, H. Chem. Eur. J. 2001, 7, 959–971.
14. Meyer, Y.; Richard, J. A.; Delest, B.; Noack, P.; Renard, P. Y.; Romieu, A. Org.
Biomol. Chem. 2010, 8, 1777–1780.
15. Perry-Feigenbaum, R.; Baran, P. S.; Shabat, D. Org. Biomol. Chem. 2009, 7, 4825–
4828.
16. Seebach, D.; Herrmann, G. F.; Lengweiler, U. D.; Bachmann, B. M.; Amrein, W.
Angew. Chem., Int. Ed. 1996, 35, 2795–2797.
17. de Groot, F. M. H.; Albrecht, C.; Koekkoek, R.; Beusker, P. H.; Scheeren, H. W.
Angew. Chem., Int. Ed. 2003, 42, 4490–4494.
18. Gao, H. F.; Tsarevsky, N. V.; Matyjaszewski, K. Macromolecules 2005, 38, 5995–
6004.
19. Warnecke, A.; Kratz, F. J. Org. Chem. 2008, 73, 1546–1552.
20. Johnson, J. A.; Lewis, D. R.; Az, D. D. D. U.; Finn, M. G.; Koberstein, J. T.; Turro, N.
J. J. Am. Chem. Soc. 2006, 128, 6564–6565.
3
4
4
H1), 7.4 (dd, J5,6 = 8.8, J5,3 = 2.2, 5-H1, 50-H1), 7.50 (d, J3,5 = 1.8, 3-H1, 30-H1)
ppm.
13C NMR (400 MHz, DMSO): d = 15.40, 123.37, 126.94, 130.59, 130.78, 132.07,
147.29, 154.22 ppm.
Preparation of bis(4-chloro-3-methylphenol) oxalate (AOE2). Following the
general procedure it was prepared from 4-chloro-3-methylphenol (5.04 g;
35 mmol, 1.0 equiv), oxalyl chloride (2.24 g, 17 mmol, 0.5 equiv) and NaH
(1.57 g, 60% in oil, 39 mmol, 1.1 equiv), in a similar manner to that described
above. AOE2 (2.65 g) was obtained as white crystals in 46% yield. Anal. Calcd
for C16H12Cl2O4: C 56.7; H 3.6. Found: C 56.6; H 3.7.
3
1H NMR (400 MHz, DMSO): d = 2.37 (s, 7-H3, 70-H3), 7.19 (dd, J6,5 = 8.8,
4
3
4J6,2 = 2.8, 6-H1, 60-H1), 7.32 (d, J2,6 = 2.8, 2-H1, 20-H1), 7.55 (d, J5,6 = 8.8, 5-H1,
50-H1) ppm.
13C NMR (400 MHz, DMSO): d = 19.57, 120.10, 123.44, 129.65, 131.05, 137.06,
148.34, 154.44 ppm.
Preparation of bis(4-bromo-3,5-dimethylphenol) oxalate (AOE3). Following
the general procedure it was prepared from 4-bromo-3,5-dimethylphenol
(5.17 g; 26 mmol, 1.0 equiv), oxalyl chloride (1.63 g, 13 mmol, 0.5 equiv) and
NaH (1.05 g, 60% in oil, 26 mmol), in a similar manner to that described above.
AOE3 (3.14 g) was obtained as white crystals in 53% yield. Anal. Calcd for
C
18H16Br2O4: C 47.4; H 3.5. Found: C 47.6; H 3.7.
1H NMR (400 MHz, DMSO): d = 2.40 (s, 5-H3, 50-H3, 500-H3, 5000-H3), 7.17 (s, 2-H1,
2-H1, 200-H1, 2000-H1) ppm.
13C NMR (400 MHz, DMSO): d = 23.33, 120.62, 124.09, 139.16, 148.30,
154.48 ppm.
21. Delmaestro, R. F. Acta Physiol. Scand. 1980, 153–168.
22. Klinger, M. M.; Rahemtulla, F.; Prince, C. W.; Lucas, L. C.; Lemons, J. E. Crit. Rev.
Oral Bio. Med. 1998, 9, 449–463.
23. Halliwell, B.; Clement, M. V.; Long, L. H. FEBS Lett. 2000, 486, 10–13.
24. Napoli, A.; Boerakker, M. J.; Tirelli, N.; Nolte, R. J. M.; Sommerdijk, N. A. J. M.;
Hubbell, J. A. Langmuir 2004, 20, 3487–3491.
25. Rehor, A.; Hubbell, J. A.; Tirelli, N. Langmuir 2005, 21, 411–417.
26. Rieche, A. Angew. Chem., Int. Ed. 1958, 70, 251–266.
27. Wiberg, K. B. J. Am. Chem. Soc. 1955, 77, 2519–2521.
28. McCapra, F. Methods Enzymol. 2000, 305, 3–47.
29. Rauhut, M. M. Acc. Chem. Res. 1969, 2, 80–87.
30. Lahti, P. M.; Modarelli, D. A.; Rossitto, F. C.; Inceli, A. L.; Ichimura, A. S.; Ivatury,
S. J. Org. Chem. 1996, 61, 1730–1738.
31. Bollyky, L. J.; Whitman, R. H.; Roberts, B. G.; Rauhut, M. M. J. Am. Chem. Soc.
1967, 89, 6523–6526.
Preparation of bis(4-(2-bromoethyl)phenol) oxalate (AOE4). Following the
general procedure it was prepared from 4-(2-bromoethyl)phenol (1.00 g;
5 mmol, 1.0 equiv), oxalyl chloride (0.32 g, 2.5 mmol, 0.5 equiv) and NaH
(0.20 g, 60% in oil, 5 mmol), in a similar manner to that described above. AOE4
(0.68 g) was obtained as white crystals in 60% yield. Anal. Calcd for
C
18H16Br2O4: C 47.4; H 3.5. Found: C 47.7; H 3.9.
1H NMR (400 MHz, DMSO): d = 3.17 (t, 3J5,6 = 7.2, 5-H2, 50-H2), 3.77 (t, 3J6,5 = 7.2,
6-H2, 60-H2), 7.26 (d, 3J2,3 = 8.3, 2-H2, 2’-H2), 7.41 (d, 3J3,2 = 8.3, 3-H2, 3’-H2) ppm.
13C NMR (400 MHz, DMSO): d = 34.35, 37.67, 121.09, 130.08, 137.41, 148.80,
155.02 ppm.
Preparation of bis(N-t-BOC-tyramine) oxalate (AOE5). Following the general
procedure it was prepared from N-t-BOC-tyramine (10.48 g, 44 mmol,
1.0 equiv), oxalyl chloride (2.81 g; 22 mmol, 0.5 equiv) and NaH (1.76 g, 60%
in oil, 44 mmol, 1.0 equiv), in a similar manner to that described above. AOE5
(8.08 g) was obtained as white crystals in 69% yield. Anal. Calcd for
32. Rauhut, M. M.; Bollyky, L. J.; Roberts, B. G.; Loy, M.; Whitman, R. H.; Iannotta, A.
V.; Semsel, A. M.; Clarke, R. A. J. Am. Chem. Soc. 1967, 89, 6515–6522.
33. Koike, R.; Kato, Y.; Motoyoshiya, J.; Nishii, Y.; Aoyama, H. Luminescence 2006,
21, 164–173.
34. Rouhi, M. Chem. Eng. News 1999, 77, 65.
35. Hart, M. E.; Suchland, K. L.; Miyakawa, M.; Bunzow, J. R.; Grandy, D. K.; Scanlan,
T. S. J. Med. Chem. 2006, 49, 1101–1112.
36. Materials. Oxalyl chloride, the phenols (Sigma Aldrich), sodium hydride,
NaHCO3, triethylamine (VWR), BOC2O, and hydrogen peroxide solutions
(30 wt %) (Merck) were used as received. Tetrahydrofuran (THF) was freshly
distilled from sodium–potassium. Acetonitrile was obtained in HPLC-Grade.
Cyclohexane and ethyl acetate has been distilled.
C
28H36N2O8: C 63.6; H 6.9; N 5.3. Found: C 63.4; H 6.8; N 5.2.
3
1H NMR (400 MHz, DMSO): d = 1.36 (s, 2 x t-Butyl), 2.72 (t, J5,6 = 7.0, 5-H2, 5’-
3
3
3
H2), 3.16 (td, J6,5 = 6.5, J6,N = 6.5, 6-H2, 6’-H2), 6.92 (t, JN,6 = 5.5, N-H1, N’-H1),
3
3
7.21 (d, J2,3 = 8.6, 2-H2, 2’-H2), 7.30 (d, J3,2 = 8.5, 3-H2, 3’-H2) ppm.
13C NMR (400 MHz, DMSO): d = 28.28, 34.82, 41.34, 77.53, 121.00, 129.91,
137.95, 148.42, 155.13, 155.55 ppm.
Preparation of bis(eugenol)oxalate (AOE6). Following the general procedure it
was prepared from Eugenol (2.25 g; 14 mmol, 1.0 equiv), oxalyl chloride
(0.89 g, 7 mmol, 0.5 equiv) and NaH (0.56 g, 60% in oil, 14 mmol, 1.0 equiv), in a
similar manner to that described above. AOE6 (1.34 g) was obtained as white
crystals in 70% yield. Anal. Calcd for C22H22O6: C 69.1; H 5.8. Found: C 69.1; H
5.7.
General Methods. 1H NMR and 13C NMR spectra were taken on a Bruker Avance
DRX 400 (400 and 100 MHz respectively). Data reported were calibrated to
internal TMS (0.0 ppm) for all solvents unless otherwise noted and are reported
as follows: chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; and m, multiplet), coupling constant, and integration. Analysis by
reverse phase HPLC were done with a VWR-Hitachi LaChrom Elite 2000 and a
LiChroCart 150-4,6 column (Merck).
1H NMR (400 MHz, DMSO): d = 3.40 (d, 3J7,8 = 7.0, 7-H2, 70-H2), 3.80 (s, OMe-H3,
3
2
4
OMe0-H3), 5.08 (ddt, J9E,8 = 10.3, J9E,9Z = 2.0, J9E,7 = 1.0, 9-E-H1, 90-E-H1), 5.13
3
2
3
(dd, J9Z,8 = 17.0, J9Z,9E = 2.0, 9-Z-H1, 90-Z-H1), 6.00 (ddt, J8,9Z = 17.0,
3J8,9E = 10.3, J8,7 = 7.0, 8-H1, 80-H1), 6.84 (dd, J5,6 = 8.0, J5,3 = 1.5, 5-H1, 50-H1),
3
3
4
4
3
7.05 (d, J3,5 = 1.5, 3-H1, 30-H1), 7.21 (d, J6,5 = 8.0, 6-H1, 60-H1) ppm.
13C NMR (400 MHz, DMSO): d = 39.25, 55.85, 113.19, 116.13, 120.47, 121.96,
136.53, 137.17, 140.05, 149.95, 154.61 ppm.
N-t-BOC-tyramine.35 A solution of NaHCO3 (11.38 g, 135 mmol, 1.27 equiv) in