Studies on a novel safety-catch linker cleaved by Pummerer rearrangement

Article abstract of DOI:10.1021/ol049120s

(Equation Presented) We describe the use of a sulfide linkage as a safety-catch linker. This linker is significantly stable to acidic as well as basic conditions and allows transformations to be carried out on solid supports. Moreover, its cleavage is facile by applying Pummerer rearrangement after transforming it to sulfoxide.

Full text of DOI:10.1021/ol049120s

ORGANIC
LETTERS
2004
Vol. 6, No. 17
2905-2908
Studies on a Novel Safety-Catch Linker
Cleaved by Pummerer Rearrangement1
Chih-Ho Tai, Hsiao-Ching Wu, and Wen-Ren Li*
Department of Chemistry, National Central UniVersity, Chung-Li, Taiwan, 32054
ch01@ncu.edu.tw
Received May 14, 2004
ABSTRACT
We describe the use of a sulfide linkage as a safety-catch linker. This linker is significantly stable to acidic as well as basic conditions and
allows transformations to be carried out on solid supports. Moreover, its cleavage is facile by applying Pummerer rearrangement after transforming
it to sulfoxide.
Combinatorial synthesis offers a way to prepare libraries of
compounds that can be screened to provide lead structures.
The successful applications of combinatorial chemistry to
the preparation of different libraries of compounds having a
wide range of activities have stimulated the interest of
academic and industrial researchers in this technique.2-6 The
efficiency of this technique for synthesizing molecules with
different functionalities depends on suitable supports, linkers,
and protecting groups.7,8 Despite the recent upsurge in the
use of this technique, only a few linkers are available that
can withstand a variety of chemical conditions in the series
of reaction steps.
The availability of the appropriate linker is the most
decisive factor for the success of a combinatorial synthetic
strategy. The best linker not only withstands all the reagents
used in the synthesis but also can be cleaved under mild
conditions at the end without affecting final products. A
popular way to achieve such unique linkers is to use a
“safety-catch” linking strategy. This strategy uses a linker
that is stable under various reaction conditions until it is
activated for cleavage. Thus, safety-catch linkers facilitate
the use of a wider range of reaction conditions in a synthetic
sequence at the cost of only one activation step. Many kinds
of safety-catch linkers based on different functionalities and
strategies have been reported.7,9-20
Oxides of sulfur, i.e., sulfoxides or sulfones, have been
significantly explored as linkers cleavable under various
conditions.11-14 However, the potential of sulfides as safety-
catch precursors has not yet been fully explored.21 As a part
of our continued search for novel linkers,22 we developed
(9) Zheng, A.; Shan, D.; Shi, X.; Wang, B. J. Org. Chem. 1999, 64,
7459.
(10) Backes, B. J.; Virgilio, A., A.; Ellman, J. A. J. Am. Chem. Soc.
1996, 118, 3055.
(11) Wade, W. S.; Yang, F.; Sowin, T. J. J. Comb. Chem. 2000, 2, 266.
(12) Maclean, D.; Hale, R.; Chen, M. Org. Lett. 2001, 3, 2977.
(13) Backes, B. J.; Ellman, J. A. J. Org. Chem. 1999, 64, 2322.
(14) Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1994, 116, 11171.
(15) Cano, M.; Ladlow, M.; Balasubramanian, S. J. Comb. Chem. 2002,
4, 44.
(16) Brik, A.; Keinan, E.; Dawson, P. E. J. Org. Chem. 2000, 65, 3829.
(17) Sola, R.; Saguer, P.; David, M.-L.; Pascal, R. J. Chem. Soc., Chem.
Commun. 1993, 1786.
(18) Beech, C. L.; Coope, J. F.; Fairley, G.; Gilbert, P. S.; Main, B. G.;
Ple, K. J. Org. Chem. 2001, 66, 2240.
(1) Preliminary account was presented at the 224th American Chemical
Society National Meeting, Boston, MA, Aug 18-22, 2002; Abstract ORGN
152.
(2) Dolle, R. E. J. Comb. Chem. 2001, 3, 477.
(3) Dolle, R. E. J. Comb. Chem. 2002, 4, 369.
(4) Dolle, R. E. J. Comb. Chem. 2003, 5, 693.
(19) Ingenito, R.; Drezˇnjak, D.; Guffler, S.; Wenschuh, H. Org. Lett.
2002, 4, 1187.
(5) Hall, D. G.; Manku, S.; Wang, F. J. Comb. Chem. 2001, 3, 125.
(6) Lorsbach, B. A.; Kurth, M. J. Chem. ReV. 1999, 99, 1549.
(7) James, I. W. Tetrahedron 1999, 55, 4855.
(20) (a) Lee, H. B.; Balasubramanian, S. J. Org. Chem. 1999, 64, 3454.
(b) Todd, M. H.; Oliver, S. F.; Abell, C. Org. Lett. 1999, 1, 1149.
(21) Marshall, D. L.; Liener, I. E. J. Org. Chem. 1970, 35, 867.
(22) Li, W.-R.; Lin, Y.-S.; Hsu, N.-M. J. Comb. Chem. 2001, 3, 634.
(8) Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091.
10.1021/ol049120s CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004

p-tritylsulfanyl phenol as a safety-catch linker. The principle
of this linker is that the sulfide linkage attached to a
Merrifield resin will be relatively inert and can be activated
by oxidation to sulfoxide before Pummerer cleavage. Pum-
merer rearrangement is the popular method for converting
sulfoxides to aldehydes or alcohols.23-34
wide range of reaction conditions. This linkage can be easily
activated before cleavage to sulfoxide by oxidation. Pum-
merer rearrangement, followed by different cleavage condi-
tions, leads to either aldehydes or alcohols.
Schemes 3-5 illustrate the application of the general
strategy to synthesize various compounds. In the first step
(Scheme 3), the resin-bound linker 3 was alkylated. Alkyl
The safety-catch linker was assembled on Merrifield resin
using the sequence of reactions shown in Scheme 1.
Scheme 3. Use of Halides, Alcohols, Tosylates, and
Mesylates as Substrates
Scheme 1. Synthesis of Safety-Catch Linker-Functionalized
Resin
halides, alcohols, mesylates, and tosylates were used as
substrates. Alkylations with alkyl halides were effected using
different bases, viz. NaH, Cs2CO3, or Et3N. All of these bases
gave good yields in solution reactions. However, only NaH
was effective in the solid-phase transformations (route 1).
For alkyl chlorides, KI was required to be added to the
alkylation reactions. In route 2, resin-bound linker 3 was
alkylated using alcohols in the presence of PPh3 and DEAD.
Tosylates and mesylates in the presence of NaH were also
used for the alkylation of linker 3 (route 3). Scheme 4 shows
p-Hydroxylthiophenol (1) was reacted at room temperature
with chlorotriphenylmethane in the presence of pyridine to
give p-tritylsulfanylphenol as a white solid in 97% yield.
This trityl derivative was tethered to Merrifield resin using
NaH in DMF to afford resin 2, which was converted to thiol
3 by treatment with trifluoroacetic acid (TFA) and triethyl-
silane in CH2Cl2.35
Scheme 2 presents a general strategy for the synthesis of
aldehydes or alcohols using thiol 3 as the resin-bound safety-
Scheme 4. Use of Epoxides as Substrates
Scheme 2. Safety-Catch Linker Strategy
the use of epoxides as substrates. Epoxides were reacted with
linker 3 in the presence of Et3N to obtain the corresponding
alcohols. The alcohols obtained either were directly subjected
to oxidation (route 1) or were treated with various acyl
chlorides using pyridine as the base and solvent to obtain
acyl derivatives (route 2). The use of pyridine resulted in
poor yields.
After alkylation, the sulfide linkage was subjected to
oxidation to prepare it for rearrangement. Various oxidizing
agents such as m-CPBA, MMPP, NaIO4, H2O2, and tert-
butylhydroperoxide (t-BuOOH) were tried with different
solvent systems. These reactions were monitored by magic
angle spinning gel-phase NMR. We found that t-BuOOH/
10-camphorsulfonic acid (CSA) was superior to other oxidiz-
ing agents with a better reaction rate, high yield, and
catch linker. Linker 3 can be reacted with various kinds of
electrophiles to obtain a sulfide linkage that is stable to a
(23) Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org. Chem.
2003, 68, 7983.
(24) Roush, W. R.; Limberakis, C.; Kunz, R. K.; Barda, D. A. Org. Lett.
2002, 4, 1543.
(25) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000,
122, 10521.
(26) Soo, Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K.
B.; Walker, F. J. Science 1983, 220, 949.
(27) Waizumi, N.; Itoh, T.; Tohru, F. Tetrahedron Lett. 1998, 39, 6015.
(28) Rolland, C.; Hanquet, G.; Ducep, J.-B.; Solladie, G. Tetrahedron
Lett. 2001, 42, 7563.
(29) Solladie, G.; Wilb, N.; Bauder, C. Tetrahedron Lett. 2000, 41, 4189.
(30) Craig, D.; Daniels, K. Tetrahedron Lett. 1990, 31, 6441.
(31) Raghavan, S.; Reddy, S. R. J. Org. Chem. 2003, 68, 5754.
(32) Mori, I.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55,
5966.
(33) Carreno, M. C.; Mazery, R. D.; Urbano, A.; Colobert, F.; Solladie,
G. J. Org. Chem. 2003, 68, 7779.
(34) Mandai, T.; Mizobuchi, K.; Kawada, M.; Otera, J. 1984, 49, 3403.
(35) Horton, J. R.; Stamp, L. M.; Routledge, A. Tetrahedron Lett. 2000,
41, 9181.
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Org. Lett., Vol. 6, No. 17, 2004

Table 1. Representative Examples of Compounds Generated on Solid Supports
a Cleavage conditions: TFAA,THF; Et3N, EtOH. b Reported yields are isolated yields after flash chromatography. The overall yields are based on the
initial loading of the Merrifield resin. c Cleavage conditions: TFAA,THF; Et3N, NaBH4, EtOH.
selectivity of formation of sulfoxide over sulfone. The use
of m-CPBA, MMPP, and NaIO4 resulted in over-oxidation,
yielding sulfone. In the case of H2O2, a large amount (∼20
equiv) and a long reaction time (∼2 days) were required.
Upon obtaining the corresponding sulfoxides, Pummerer
rearrangement23-34 was employed and the products were
cleaved from the solid supports. To accomplish Pummerer
rearrangement using sodium acetate and acetic anhydride, a
high temperature that cannot be tolerated by polystyrene
resins was required. Hence, we switched to trifluoroacetic
anhydride (TFAA)23,27-31 (Scheme 5). This reagent was found
to possess better activity and also was effective under mild
reaction conditions. Pummerer rearrangement led to rear-
ranged intermediates, viz. trifluoroacetoxythioacetals, which
Org. Lett., Vol. 6, No. 17, 2004
2907

Scheme 5. Pummerer Cleavage to Obtain Aldehydes or
Scheme 7. Solid-Phase Synthesis of Protected Amino Acid 5
Alcohols
were cleaved by treatment with Et3N in ethanol to give
aldehydes (Table 1). Usually, the obtained aldehydes are
reduced in a separate reaction step to afford alcohols.
However, we have successfully avoided an extra step of
reduction by developing a one-pot reaction. In the cleavage,
NaBH4 was added along with Et3N in one-pot to reduce
aldehydes to the corresponding alcohols (Table 1). In the
place of NaBH4, LiAlH4 was also tried, but it was too strong
to yield desired products.
amine was coupled with Boc-L-Phe-OH using HBTU and
DIPEA to afford amide 10. Then, the Boc protecting group
was removed and the resultant amine was reacted with
benzoyl chloride in the presence of Et3N to give compound
11. To obtain amide 5, oxidation, Pummerer rearrangement,
and cleavage were carried out as described previously for
Scheme 6. However, here in the cleavage step, NaBH4 was
added, as stated above, to obtain the desired alcohol. This
strategy furnished amide 5 in 73% overall yield for 10 steps.
As the applications of solid-phase synthesis expand to
various areas of chemical research, so will the demand for
new and novel linkers. The approach of using the safety-
catch linker will enable chemists to carry out a variety of
reactions on solid supports. The present strategy employing
a sulfide linkage as a novel safety-catch yielded aldehydes
and alcohols in excellent yields, and also the purity of crude
products ranged between 70 and 85%. An extra step of
reducing derived aldehydes to the desired alcohols has been
effectively avoided by developing the one-pot reaction. We
have proved the utility of this approach for different kinds
of substrates such as alkyl halides, alcohols, tosylates,
mesylates, and epoxides. Additionally, it is proposed that
this strategy can be successfully used for alkene substrates
because it has been reported that R,â-unsaturated ketones
can be coupled with thiophenols quantitatively through
Michael addition.37 Also the stability of the sulfide linkage
under acidic as well as basic reaction conditions has been
demonstrated. Given the diversity of substrates, the stability
under various reaction conditions, and the feasibility of
obtaining alcohols or aldehydes as final products, this linker
may find wide utility in combinatorial chemistry.
To further demonstrate the synthetic utility of this linker
system, two amides 4 and 5 were prepared as shown,
respectively, in Schemes 6 and 7. In the synthesis of amide
Scheme 6. Solid-Phase Synthesis of Amide 4
4 (Scheme 6), alcohol 6 was coupled to resin 3 by employing
the Mitsunobu protocol and then the trityl protecting group
was removed by using TFA to obtain phenol 7. Phenol 7
was alkylated using bromide 8 in the presence of K2CO3 to
give the resin-bound amide 9. The sulfide in compound 9
was oxidized by using t-BuOOH as described in Scheme 3.
To cleave the amide from the resin, we used TFAA which
did not work in the above-mentioned conditions. This
reaction yielded unexpected oxazoles because the R-acyl
amino amide moiety is susceptible to cyclization in the
presence of a strong acid.36 We tried various temperatures
(0-10 °C) and reaction times but could not obtain the desired
product. Hence, trichloroacetic anhydride (TCAA) and Et3N
were chosen and added dropwise after dilutions, respectively,
with THF and EtOH. This strategy yielded the desired
product 4 in 65% overall yield from compound 1. Synthesis
of protected amino acid 5 (Scheme 7) was initiated by
reacting resin 3 with 2-bromoethylamine, and the resultant
Acknowledgment. The authors are grateful to the Na-
tional Science Council, Taiwan, for the financial support (91-
2113-M-008-012) of this work.
Supporting Information Available: Representative ex-
1
perimental procedures and H and 13C NMR spectra of
compounds in Table 1 (entries 3-5, 7, and 14) and
compounds 8, and 11. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL049120S
(36) Lipshutz, B. H.; Hungate, R. W.; McCarthy, K. E. J. Org. Chem.
1983, 105, 7703.
(37) Liu, H.; Cohen, T. J. Org. Chem. 1995, 60, 2022.
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