Method for activation and recycling of trityl resins

Article abstract of DOI:10.1021/jo300598d

This note describes a rapid and mild strategy for the loading of alcohols and anilines onto a polystyrene triphenylmethyl (trityl) resin. High loadings were obtained in a matter of minutes by treating resin-bound trityl chloride with triethyloxonium tetrafluoroborate followed by alcohols or anilines. Yields were comparable or better than known literature methods. Recycling of the recovered resin was also possible using the developed method.

Full text of DOI:10.1021/jo300598d

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Note
A method for activation and recycling of trityl resins
Itedale Namro Redwan, and Morten Grotli
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo300598d • Publication Date (Web): 18 Jul 2012
Downloaded from http://pubs.acs.org on August 6, 2012
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The Journal of Organic Chemistry is published by the American Chemical Society.
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A method for activation and recycling of trityl resins
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†
†,
Itedale Namro Redwan and Morten Grøtli *
Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg,
SE-41296 Göteborg, Sweden
grotli@chem.gu.se
TABLES OF CONTENTS GRAPHIC
*
Address correspondence to Department of Chemistry and Molecular Biology, Medicinal
Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden. Telephone: +46-31-7869017.
Fax: +46-31-772 1394.
E-mail: grotli@chem.gu.se
†
University of Gothenburg
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Abstract
This note describes a rapid and mild strategy for the loading of alcohols and anilines onto a
polystyrene triphenylmethyl (trityl) resin. High loadings were obtained in a matter of minutes by
treating resin bound trityl chloride with triethyloxonium tetrafluoroborate followed by alcohols or
anilines. Yields were comparable or better than known literature methods. Recycling of the
recovered resin was also possible using the developed method.
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Keywords: Solid-Phase, Trityl resin, Activation, Recycling
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The development of combinatorial chemistry has been accompanied by a huge interest in solid-
phase organic synthesis. A crucial feature of solid-phase synthesis is the attachment of the substrate
1
to the polymeric support. The first building block has to be attached efficiently, the linkage has to
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be stable to the subsequent chemical transformations, and conditions for release from the support
should be compatible with the final products. Commonly these linker groups are based on standard
1
,2
protecting groups used in traditional solution-phase synthesis. Trityl groups are often used in this
context and can serve as protecting groups for alcohols, acids, amides, amines, amino acids,
1
-3
hydroxamic acids, imidazoles, nucleotides, thiols, and thioureas. Using a trityl linker in solid-
phase synthesis allows the “protected” compound to be subjected to various chemical manipulations
4
-7
followed by release to afford pure compounds without the need for numerous purification steps.
The trityl linker is readily cleaved under mildly acidic conditions (1% TFA in dichloromethane)
8
owing to the high stability of trityl cations. The trityl linker is also orthogonal with protecting
8
groups that can be removed under stronger acidic conditions or basic conditions. However, the
formation of trityl ethers has limitations, e.g. some procedures require extensive preparation of
9
,10
reagents,
while other protocols require prolonged reaction times and harsh conditions and
1
1,12
reagents, such as high temperatures or strong bases.
Recently, Lundquist et al. published a method employing a silver triflate-assisted attachment of
6
alcohols to a trityl chloride resin. The described procedure enhances the limited reactivity of the
standard trityl chloride linker, but suffers from formation of insoluble silver chloride precipitate on
the resin and partial degradation of acid-sensitive alcohols. The use of a trityl bromide resin for
7
loading primary alcohols has been reported. This procedure requires ten equivalents of acetyl
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bromide (AcBr) for the preparation of polystyrene trityl bromide (PS-TrBr) from a trityl alcohol
1
3
14
resin (PS-TrOH). Loading of carboxylic acids and phenols to PS-TrBr has also been reported.
Herein we report an alternative method using three equivalents of triethyloxonium tetrafluoroborate
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(TEOTFB) for the activation of a trityl resin. We set out to investigate the loading of alcohols onto
a pre-activated polystyrene trityl chloride resin (PS-TrCl, 1). In addition, experiments with loading
anilines to the trityl resin were performed, since only a few examples can be found in the
4
literatures. Furthermore, we also became interested in investigating the recycling of the trityl resin.
There are a few examples in the literature where PS-TrCl has been recycled (regenerated or
1
5
16
17
reformed) from PS-TrOH using trimethylsilyl chloride , acetyl chloride or thionyl chloride . We
wanted to be able to recycle the activated resin without formation of PS-TrCl. TEOTFB is
commercial available, but is much more expensive than e.g. thionyl chloride. However, TEOTFB
can be prepared in a single-step reaction from inexpensive, commercially available, and
1
8
nonhazardous reagents.
A common method for attaching alcohols to PS-TrCl is to use pyridine both as solvent and base at
1
9
room temperature (Scheme 1, Path A). Formation of the reactive intermediate 2a or the
pyridinium intermediate (2b) is believed to be the rate determining step in the formation of trityl
9
,11,20
ethers with this method.
A
+
+
-
TrCl
Tr Cl
Tr
N
Pyridine
rt
Cl-
1
2a
2b
TEOTFB
DCM
ROH
B
ROH
ROH
DIPEA
+
Tr Cl-
+
-
Tr BF4
Tr OR
2a
3
4
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Scheme1. Path A: PS-trityl ether (4) formation using pyridine; Path B: PS-trityl ether formation using triethyloxonium
tetrafluoroborate.
We envisioned that treatment of PS-TrCl with TEOTFB could easily generate the more stable
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trityl cation and would facilitate the S 1 reaction to form the desired trityl ethers under milder
N
21,22
conditions.
When PS-TrCl (1) was treated with TEOTFB (Scheme 1, Path B) a deep red color
was initially observed, which indicated formation of the trityl cation. The color disappeared
immediately upon addition of alcohol indicating that the cation had been quenched and formation of
the trityl ether was complete. The replacement of the chloride counter-anion in 2a with the more
separated ion-pairs formed between the trityl cation and the tetrafluoroborate counter-anion in 3 is
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believed to enhance the reactivity of the trityl cation. We further hypothesized that a nucleophilic
attack of the chloride anion on an ethyl group from the triethyloxonium species takes place, which
in turn results in the irreversible release of chloroethane gas and thereby facilitating the formation
of 3. In order to establish general conditions that enable an efficient loading of alcohols, the initial
focus was set on optimizing the loading of 2,2-diphenylethanol (6) onto a commercially available
PS-TrCl resin (loading 1.7 mmol/g) using the TEOTFB method. Alcohol 6 was selected as a model
substrate based on its UV activity in the range from 200−400 nm. Several reaction parameters were
varied, including the amount of TEOTFB, activation time, amount of substrate (6), amount of N,N’-
diisopropylethyl amine (DIPEA) and reaction time (Table 1).
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Table 1. Loading of alcohol 6 onto resin 1 .
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Entry
TEOTFB Activation
Alcohol 6
DIPEA
(equiv)
Loading
Loading
b
(equiv)
(min)
(equiv)
time (min)
(%)
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180
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88
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69
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84
91
49
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1
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0
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960
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1
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a
b
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00 mg of PS-TrCl (loading 1.7 mmol/g). The loading (%) was quantified by weight of recovered alcohol 6 after
cleavage using the resin loading specified by the supplier.
Initially, the amount of TEOTFB needed to activate the trityl resin was investigated (Table 1,
entries 1−4). With one or two equivalents of TEOTFB only moderate loading of 6 was obtained.
Three equivalents (entry 3) resulted in an loading of 88%. A further increase to five equivalents
TEOTFB (entry 4) did not result in a significant enhancement in the loading of 6.
Variation of the activation time (entries 4−7) revealed that 15 min is required to get a high
loading, while shorter time (entries 5−6) reduced the loading of 6. An extension of the activation
time from 15 to 30 min (entry 7) did not result in a substantial increase in loading.
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Furthermore, variation of the loading times (entries 8−11) demonstrated that a one hour reaction
time (entry 10) is required in order to obtain a high loading of 6. The loading could be increased to
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The amount of alcohol (6) and DIPEA (entries 12−14) also have a significant influence on the
loading. One or two equivalents of 6 and DIPEA (entries 12 and 13) resulted in moderate loading.
Three equivalents of 6 and DIPEA (entry 10) resulted in a loading of 86 %. Additional amounts of 6
and DIPEA (entry 14) did not lead to any further improvement in loading.
In general, from the experiments summarized in Table 1 it was concluded that the optimized
reaction conditions are; the use of three equivalents of TEOTFB for activation, the activation is
rapid and requires 15 minutes, three equivalents of substrate to be loaded and DIPEA are sufficient
for obtaining excellent loadings and the reaction time (loading time) should at least be one hour
with the best results obtained when the reaction was performed overnight. The use of large excess
of reagents (5−10 equivalents) as in other literature methods, is not required using this protocol.
The TEOTFB activation of resin 1 according to reaction conditions in Entry 11 were then used
with
a
variety
of
alcohols
and
aniline
derivatives
(Table
2).
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Table 2. TEOTFB assisted loading of alcohols and aniline derivatives to trityl resin.
Trityl
ether
Alcohol / amine
Yields
(%)
/
amine
6
7
90
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Br
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OH
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a
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00 mg of PS-TrCl (loading 1.7 mmol/g). The loading (%) was quantified by weight of recovered substrate (6−13)
after cleavage using the resin loading specified by the supplier.
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The trityl ethers from alcohols 6−10 using resin 1 activated by TEOTFB, were obtained in yields
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63−90% which are comparable to other published procedures. The benefits of performing the trityl
ether formation using this protocol include short activation time, use of small amounts of reagents
and short reaction times. In addition, no precipitates are formed unlike in previously reported
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methods.
The favorable results obtained with alcohols prompted adaptation of our new TEOTFB activation
method to the solid phase attachment of anilines 11−13. The amines were loaded in moderate to
good (44−76%) yields using this protocol. The purity of the obtained compounds 6−13 was
ascertained by elemental analysis.
The use of trityl resin would become more environmentally friendly and cost effective, especially
for large scale applications, if the resin could be recycled. Recycling of hydroxytrityl resins has
1
5-17
been reported.
We anticipated that it should be possible to recycle the trityl resin using
TEOTFB activation of PS-TrOMe (15) (Scheme 3).
Scheme 2. Efficient recycling of the trityl resin.
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Resin 1 was activated with TEOTFB and subsequently reacted with alcohol 6 in the presence of
DIPEA for 16h. Excess reagents were washed away and the product was cleaved off with 5% TFA
in DCM. After careful washing of the resin with DCM, MeOH was added in order to generate PS-
TrOMe (15). This material was activated with TEOTFB followed by thorough washing with DCM
for the next synthesis cycle. Cleavage of alcohol 6 from the trityl linker using 5% TFA in DCM
resulted in a deep red color typical for the formation of a trityl cation (resin 3). We therefore
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became interested in exploring the possibility of recycling resin 14 after cleavage of alcohol 6
followed by thorough washing with DCM for the next synthesis cycle. Three cycles were carried
out using the same equivalents of reagents in each cycle and the results are summarized in Table 3.
+
-
Table 3. Recycling of trityl resin starting from PS-TrOMe or PS-Tr TFA .
a
b
b
b
Resin Loading Loading Loading
cycle 1
%)
cycle 2
(%)
cycle 3
(%)
(
15
88
79
61
14
86
76
58
a
b
300 mg of PS-TrCl (loading 1.7 mmol/g), alcohol 6 (3 equiv) and DIPEA (3 equiv) was used. The loading (%) was
quantified by weight of recovered alcohol 6 after cleavage using the resin loading specified by the supplier.
In order to minimize the moisture that reaches the reaction vessels only freshly distilled solvents
were used and all reactions and manipulations performed under nitrogen atmosphere. The first cycle
resulted in a loading of alcohol 6 in 88%. The loading dropped slightly in the second and third
cycles. Similar yields were obtained when starting from 14.
In order to confirm the correct identity of the intermediates the same reactions were repeated in
solution and the isolated products were characterized by NMR spectroscopy and purity confirmed
by elemental analysis.
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Scheme 3. Reaction pathways for the formation of trityl ethers in solution. a) MeOH, reflux, 3h; b) TEOTFB (0.9
equiv), DCM, 15 min, room temp; c) alcohol 6 (1 equiv); d) TFA (5% in DCM), 15 min, room temp
Trityl chloride (16) was refluxed in anhydrous MeOH using a slightly modified literature procedure
25
and methyl trityl ether (17) was obtained in 96% yield. When TEOTFB was added to 17 a bright
yellow/orange color was observed and the reaction mixture was left for 15 min. The bright yellow
color disappeared instantly after addition of alcohol 6 and trityl ether 20 was isolated in 30% yield
after purification using column chromatography. Attempts to increase the yield of 20 by increasing
the amount of TEOTFB (3 equiv) were unsuccessful due to the formation of an undesired byproduct
(O-ethylated 2,2-diphenylethanol). This result highlights the advantage of performing this reaction
on solid phase, as excess reagents are washed off, the byproduct formation can be avoided. Heating
the reaction mixture after the addition TEOTFB to 19, lead to the formation of triphenylmethane as
a byproduct. The formation of trityl ether 20 (50−55% yield) was also demonstrated using TFA (5%
in DCM) as a reagent starting from 16 or 17.
Conclusion
In conclusion, a novel, mild and rapid procedure for the loading of resin-bound alcohols and
anilines in good yields has been developed. We envision that the described procedure should be
useful e.g. for the solid-phase preparation of peptides containing natural and non-natural amino
acids with alcohol functionalities in the side chain as well as for the preparation of modified
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heterocycles with aniline functionalities. The protocol offers the advantage of avoiding otherwise
long loading times by using a commercial starting resin, which only requires a simple activation
prior to the loading step. The resin recycling capability has been demonstrated using this protocol
and proposed reaction intermediates have been identified by performing the corresponding reactions
in solution.
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section
General
All commercial chemicals were used as received. DCM was freshly distilled from CaH prior to use.
Column chromatography was performed by manual flash chromatography (wet packed aluminum
1
3
oxide activated, neutral, ~150 mesh). 1H NMR spectra were recorded at 400 MHz and C spectra
were recorded at 100 MHz.. Melting points are not corrected.
General procedure for triethyloxonium tetrafluoroborate assisted trityl resin loading Method
A
Trityl resin (300 mg, loading ~1.7 mmol/g) was added to polypropylene fritted tubes, pre-swelled
and washed with DCM (3 x 2mL). The resin was put under N atm in sealed tubes. A solution of
2
triethyloxonium tetrafluoroborate (4.4 mL, 0. 35M) was added and the resin was agitated at room
temperature for 15 min. The resin was drained and washed thoroughly with DCM (10 x 3 mL) and
put under N . The substrates 6−13 (1.53 mmol, 3 eq) and DIPEA (0.27 mL, 1.53 mmol, 3 eq) were
2
dissolved in DCM (2 mL) and added to the resin. The resin was agitated 16 h at room temperature
under N atm, washed with DMF (3 x 3 mL), MeOH (3 x 3 mL), DCM (3 x 3 mL), MeOH (3 x 3
2
mL) and DCM (3 x 3 mL). The resin was pre-swelled in DCM and TFA (2 mL, 5% in TFA) was
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added, the resin was left for 20 min then drained and washed with DCM (2 mL). A second portion
of TFA (2 ml, 5% in DCM) was added and the resin was left 5 min then drained and washed
thoroughly with DCM (5 x 3 mL) and MeOH (2 x3 mL). If the resin was to be reused it was also
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
washed with DCM (3 x 3 mL) as the final washing step then put under N atm. All washings were
2
combined and the collected residue obtained after cleavage of substrate from the resin was flushed
with a stream of N and the solvents were removed under reduced pressure.
2
2,2-Diphenylethanol (6)
Following method A, 6 (303 mg, 1.53 mmol) was added to the activated resin. Compound 6 was
isolated after cleavage from the resin as a white crystalline material in 90% yield (90 mg, 0.45
26
1
13
mmol), m.p. 54−56 °C (lit. 54−55 °C) . H and C NMR data were in agreement with published
6
data. Anal. Calcd for C H O: 84.81 (C); 7.12 (H); Found: 84.83(C); 7.13 (H).
1
4
14
4
-Phenyl-2-butanol (7)
Following method A, 7 (0.24 mL, 230 mg, 1.53 mmol) was added to the activated resin. Compound
1
13
7
was obtained as a colorless liquid in 63% yield (48 mg, 0.32 mmol). H and C NMR data were
6
in agreement with published data. Anal. Calcd for C H O: 79.95 (C); 9.39 (H); Found: 79.99 (C);
1
0
14
9
.40 (H).
4-(Chloromethyl)benzyl alcohol (8)
Following method A, 8 (240 mg, 1.53 mmol) was added to the activated resin. Compound 8 was
obtained as a white crystalline material in 65% yield (52 mg, 0.33 mmol), m.p. 59 61 °C (lit. 58 60
°C ). H and C NMR data were in agreement with published data. Anal. Calcd for C H ClO:
−
−
27
1
13
6
8
9
6
1.35 (C); 5.79 (H); Found: 61.37(C); 5.81(H).
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
-Chloro-1-hexanol (9)
Following method A, 9 (0.20 mL, 209 mg, 1.53 mmol) was added to the activated resin. Compound
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
9
was obtained as a colorless liquid in 68% yield (47 mg, 0.34 mmol). H and C NMR data were
6
in agreement with published data. Anal. Calcd for C H ClO: 52.75 (C); 9.59 (H); Found: 52.79
6
13
(C); 9.61 (H).
2-Bromoethanol (10)
Following method A, 10 (0.10 mL, 198 mg, 1.53 mmol) was added to the activated resin. 10 was
1
13
obtained as a colorless liquid in 74% yield (47 mg, 0.38 mmol). H and C NMR data were in
6
agreement with published data. Anal. Calcd for C H BrO: 19.22 (C); 4.03 (H); Found: 19.24 (C);
2
5
4
.05 (H).
2
-Aminopyridine (11)
Following method A, 11 (144 mg, 1.53 mmol) was added to the activated resin. 11 was obtained as
28
1
a beige crystalline material in 44% yield (21 mg, 0.22 mmol), m.p. 55
−
59 °C (lit. 54
−58 °C ). H
1
3
6
and C NMR data were in agreement with published data. Anal. Calcd for C H N : 63.81 (C);
5
6
2
6
.43 (H); 29.77 (N); Found: 63.84 (C); 6.45 (H); 29.79 (N).
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Aniline (12)
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Following method A, 12 (0.14 mL, 143 mg, 1.53 mmol) was added to the activated resin. The TFA
salt of 12 was obtained as a beige crystalline material in 76% yield (80 mg, 0.39 mmol), m.p.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
29
1
13
6
1
19
−121 °C (lit. 120 °C) . H and C NMR data were in agreement with published data. Anal.
Calcd for C H F NO : 46.16 (C); 4.36 (H); 6.73 (N); Found: 46.18 (C); 4.35 (H); 6.75 (N).
8
9
3
2
9
-Ethyladenine (13)
Following method A, 13 (250 mg, 1.53 mmol) was added to the activated resin. Compound 13 was
obtained as a white crystalline material in 46% yield (38 mg, 0.23 mmol), m.p. 194 197 °C (lit.
95-197 °C). H and C NMR data were in agreement with published data. Anal. Calcd for
C H N : 51.52 (C); 5.56 (H); 49.92 (N); Found: 51.53 (C); 5.57 (H); 49.95 (N).
−
3
0 1
13
6
1
7
9
5
Methyl triphenylmethyl ether (17)
2
5
Using a modified literature procedure trityl chloride (558 mg, 2.0 mmol) and methanol (15 mL)
were refluxed at 105 °C for 3 h under N atm. The solvent was removed under reduced pressure and
2
1
7 was obtained as white crystalline material in 99% yield (546 mg, 2.0 mmol), m.p. 82−84 °C (lit.
1
13
31,32
8
2 °C). H and C NMR data were in agreement with published data.
(2,2-Diphenylethoxy)triphenylmethyl ether (20)
Method B
Triethyloxonium tetrafluoroborate (62.3 mg, 0.33 mmol) was suspended in DCM (1 mL) and added
to a solution of 17 (100 mg, 0.37 mmol) in DCM (1 mL). The bright yellow reaction mixture was
stirred 15 min at room temperature under N atm, thereafter a solution of 2,2-diphenylethanol (6)
2
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
72.3 mg, 0.37 mmol) in DCM (1mL) was added and the reaction mixture turned colorless. After
stirring for 1 h under N atm the reaction was quenched by the addition of water (3 mL), the
2
aqueous layer extracted with DCM (3 x 5 mL), the combined organic layers were dried over MgSO4
and solvent removed under reduced pressure. The residue was purified using flash chromatography
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(2% DCM in heptane) and 20 was obtained as white crystalline material in 33% yield (48.0 mg,
0
.11 mmol).
Method C
TFA (1 mL, 5% in DCM) was added to 17 (100 mg, 0.37 mmol). The bright yellow reaction
mixture was stirred 15 min at room temperature under N atm, thereafter a solution of 6 (86.7 mg,
2
0.44 mmol) in DCM (1mL) was added and the reaction mixture turned colorless. After stirring for 1
h under N atm the reaction was quenched by the addition of water (3 mL), the aqueous layer
2
extracted with DCM (3 x 5 mL), the combined organic layers were dried over MgSO and solvent
4
removed under reduced pressure. The residue was purified using flash chromatography (2% DCM
in heptane) and 20 was obtained as white crystalline material in 50% yield (80.0 mg, 0.18 mmol).
Method D
TFA (2 mL, 5% in DCM) was added to triphenylchloromethane (16) (300 mg, 1.08 mmol). The
bright yellow reaction mixture was stirred 15 min at room temperature under N atm, thereafter a
2
solution of 6 (214 mg, 1.08 mmol) in DCM (1mL) was added and the reaction mixture turned
colorless. After stirring for 1 h under N atm the reaction was quenched by the addition of water (3
2
mL), the aqueous layer extracted with DCM (3 x 5 mL), the combined organic layers were dried
over MgSO and solvent removed under reduced pressure. The residue was purified using flash
4
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chromatography (2% DCM in heptane) and 20 was obtained as white crystalline material in 55%
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13
yield (262 mg, 0.60 mmol), m.p. 38−40 °C. H and C NMR data were in agreement with
6
published data.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Recycling of resin using TEOTFB method
Following method A, 6 (303 mg, 1.53 mmol) was added to the activated resin. The resin was
regenerated two times and the procedure was performed for the total of three times with the same
batch of resin. The first cycle the resin was agitated 3 h, second cycle 3 h and third cycle 3 h. 6 was
obtained as white crystalline material in 88% yield (89 mg, 0.45 mmol), the second cycle in 79%
(
80 mg, 0.40 mmol) and the third cycle in 61% (62 mg, 0.31 mmol), m.p. 54
−
56. °C (lit. 54
−55
2
6 1
13
6
°C). H and C NMR data were in agreement with published data. Anal. Calcd for C H O:
14
14
8
4.81 (C); 7.12 (H); Found: 84.83(C); 7.13 (H).
Recycling of resin using TFA method
Trityl resin (300 mg, loading ~1.7 mmol/g) was added to polypropylene fritted tubes, pre-swelled
and washed with DCM (3 x 2mL). The resin was put under N atm in sealed tubes. TFA (2 mL 5%
2
in DCM) was added and the resin was agitated at rt for 15 min. The resin was drained and washed
with DCM (3 x 3 mL) and put under N . A mixture of 6 (303 mg, 1.53 mmol) and DIPEA (0.27
2
mL, 1.53 mmol) in DCM (2 mL) was added to the resin. The resin was agitated 3 h at rt under N2
atm, washed with DMF (3 x 3 mL), MeOH (3 x 3 mL), DCM (3 x 3 mL), MeOH (3 x 3 mL) and
DCM (3 x 3mL). The resin was pre-swelled in DCM and TFA (2 mL, 5% in DCM) was added, the
resin was left for 20 min then drained and washed with DCM (2 mL). A second portion of TFA (2
ml, 5% in DCM) was added and the resin left 5 min then drained and washed thoroughly with DCM
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
5 x 3 mL) then put under N atm. The procedure was performed for the total of three times with the
2
same batch of resin. The second time the resin was agitated 3 h and the third cycle 3 h. The
collected residue obtained after cleavage of substrate from the resin was flushed with a stream of N2
and the solvents were removed under reduced pressure. 6 was obtained as white crystalline material
in 86% yield (87 mg, 0.44 mmol), the second cycle in 76% (77 mg, 0.39 mmol) and the third cycle
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
6 1
13
in 58% (59 mg, 0.30 mmol), m.p. 54−56. °C (lit. 54−55 °C). H- and C- NMR data were in
6
agreement with published data. Anal. Calcd for C H O: 84.81 (C); 7.12 (H); Found: 84.83(C);
14
14
7.13 (H).
Acknowledgment
We are grateful to the Department of Chemistry at University of Gothenburg, the Swedish
Academy of Pharmaceutical Sciences and the Swedish Research Council (project # 62120083533)
for financial support.
Supporting Information
1
13
Copies of H NMR and C NMR spectra for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(
(
1)
2)
Scott, P. J. H. Linker Strategies in Solid-Phase Organic Synthesis; Wiley & Sons Ltd.: Chichester, 2009.
Shchepinov, M. S.; Korshun, V. A. Chem. Soc. Rev. 2003, 32, 170.
rd
(3)
Greene, T. X.; Wuts, P. G. M. Protective Groups in Organic Synthesis; 3 ed.; John Wiley & Sons, Inc.: New
York, 1999.
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Park, J. G.; Langenwalter, K. J.; Weinbaum, C. A.; Casey, P. J.; Pang, Y. P. J. Comb. Chem. 2004, 6, 407.
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Rothman, D. M.; Vazquez, M. E.; Vogel, E. M.; Imperiali, B. J. Org. Chem. 2003, 68, 6795.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
(
(
(
(
(
9)
Hanessian, S.; Staub, A. P. A. Tetrahedron Lett. 1973, 3555.
Murata, S.; Noyori, R. Tetrahedron Lett. 1981, 22, 2107.
Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 95.
Hernandez, O.; Chaudhary, S. K.; Cox, R. H.; Porter, J. Tetrahedron Lett. 1981, 22, 1491.
Zikos, C. C.; Ferderigos, N. G. Tetrahedron Lett. 1994, 35, 1767.
Olsen, C. A.; Jorgensen, M. R.; Hansen, S. H.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. Org. Lett. 2005, 7,
1703.
Barlos, K.; Gatos, D.; Kallitsis, I.; Papaioannou, D.; Sotiriou, P. Liebigs Ann. Chem. 1988, 1079.
Fyles, T. M.; Leznoff, C. C. Can. J. Chem. 1976, 54, 935.
Harre, M.; Nickisch, K.; Tilstam, U. React. Funct. Polym. 1999, 41, 111.
Curphey, T. J. Org. Synth. 1988, 6, 1019
Chen, C. X.; Randall, L. A. A.; Miller, R. B.; Jones, A. D.; Kurth, M. J. J. Am. Chem. Soc. 1994, 116, 2661.
Swain, C. G.; Okamoto, Y. J. Am. Chem. Soc. 1970, 92, 3409.
Keck, G. E.; McLaws, M. D.; Wager, T. T. Tetrahedron 2000, 56, 9875.
Urban, F. J.; Anderson, B. G.; Orrill, S. L.; Daniels, P. J. Org. Process Res. Dev. 2001, 5, 575.
Bernini, R.; Maltese, M. Tetrahedron Lett. 2010, 51, 4113.
Dickert, F. L.; Fackler, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 295.
Huszthy, P.; Lempert, K.; Simig, G.; Tamas, J. J. Chem. Soc., Perkin Trans. 2 1982, 1671.
Hamlin, K. E.; Weston, A. W.; Fischer, F. E.; Michaels, R. J. J. Am. Chem. Soc. 1949, 71, 2734.
10)
11)
12)
13)
14)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)
(27)
http://www.sigmaaldrich.com/catalog/ProductDetail.do?lang=en&N4=526126|ALDRICH&N5=SEA
RCH_CONCAT_PNO|BRAND_KEY&F=SPEC (2012-03-05)
(28)
http://www.sigmaaldrich.com/catalog/ProductDetail.do?lang=en&N4=A77989|ALDRICH&N5=SEA
RCH_CONCAT_PNO|BRAND_KEY&F=SPEC (2012-03-05)
Ginsburg, V. A.; Abramova, L. V.; Kovalche.Ad; Tumanov, A. A.; Lebedeva, M. F. Journal of General
Chemistry Ussr 1969, 39, 218.
Hino, K.; Irie, A.; Uno, H. Chem. Pharm. Bull. 1975, 23, 1696.
Chadwick, D. J.; Hodgson, S. T. J. Chem. Soc., Perkin Trans. 1 1983, 93.
Elguero, J.; Claramunt, R. M.; Garceran, R.; Julia, S.; Avila, L.; Delmazo, J. M. Magn. Reson. Chem. 1987, 25,
(
29)
(
(
(
30)
31)
32)
2
60.
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