Facile solid-phase construction of indole derivatives based on a traceless, activating sulfonyl linker

Article abstract of DOI:10.1021/ol991255o

(formula presented) Palladium-mediated coupling/intramolecular indole cyclization of terminal alkynes with resin 8, followed by cleavage of the sulfonamide linkage, were executed under mild conditions to provide diverse indoles 10 in excellent yield and purity. This chemistry benefits from a dual-activation process that derives from use of a traceless N-sulfonyl linker. Also, direct mercuration of 9 (X = H, R = 4-Me-C₆H₄), followed by palladium-mediated coupling with methyl acrylate, efficiently provided 3-functionalized product 12.

Full text of DOI:10.1021/ol991255o

ORGANIC
LETTERS
2000
Vol. 2, No. 1
89-92
Facile Solid-Phase Construction of
Indole Derivatives Based on a
Traceless, Activating Sulfonyl Linker
Han-Cheng Zhang,* Hong Ye,1 Alessandro F. Moretto, Kimberly K. Brumfield, and
Bruce E. Maryanoff
Drug DiscoVery, The R. W. Johnson Pharmaceutical Research Institute,
Spring House, PennsylVania 19477
hzhang@prius.jnj.com
Received November 17, 1999
ABSTRACT
Palladium-mediated coupling/intramolecular indole cyclization of terminal alkynes with resin 8, followed by cleavage of the sulfonamide linkage,
were executed under mild conditions to provide diverse indoles 10 in excellent yield and purity. This chemistry benefits from a dual-activation
process that derives from use of a traceless N-sulfonyl linker. Also, direct mercuration of 9 (X ) H, R ) 4-Me-C6H ), followed by palladium-
4
mediated coupling with methyl acrylate, efficiently provided 3-functionalized product 12.
Substituted heterocyclic compounds offer a high degree of
structural diversity and have proven to be broadly useful as
therapeutic agents. Thus, there has been a great deal of
interest in the development of strategies for generating
heterocyclic libraries on solid supports.2 Given that the indole
nucleus is present in a wide variety of biologically active
compounds, we3 and others4 have devised efficient solid-
phase syntheses of indole derivatives for the generation of
indole-based combinatorial libraries. However, all of these
solid-phase methods are based on amide, ester, or ether
linkers, which remain in the final products after cleavage.
Since extraneous substituents such as CONH2, CO2H, or OH
could well be undesirable in certain libraries, there is a need
to develop solid-phase synthetic routes to indoles that rely
on traceless linkers. Already, there have been several
traceless-linker strategies described for the solid-phase
synthesis of small organic molecules, such as those involving
silicon,5 oxidation-labile,6 and safety-catch7 linkers, as well
(1) Affiliated with the Janssen Research Foundation, Spring House, PA
19477.
(2) Reviews: (a) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. ReV.
1997, 97, 449. (b) Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96,
555. (c) Balkenhohl, F.; von dem Bussche-Hunnerfeld, C.; Lansky, A.;
Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288. (d) Fru¨chtel, J.
S.; Jung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17. (e) Booth, S.;
Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1998,
54, 15385.
(3) (a) Zhang, H.-C.; Maryanoff, B. E. J. Org. Chem. 1997, 62, 1804.
(b) Zhang, H.-C.; Brumfield, K. K.; Maryanoff, B. E. Tetrahedron Lett.
1997, 38, 2439. (c) Zhang, H.-C.; Brumfield, K. K.; L. Jaroskova;
Maryanoff, B. E. Tetrahedron Lett. 1998, 39, 4449.
(4) (a) Collini, M. D.; Ellingboe, J. W. Tetrahedron Lett. 1997, 38, 7963.
(b) Fagnola, M. C.; Candiani, I.; Visentin, G.; Cabri, W.; Zarini, F.;
Mongelli, N.; Bedeschi, A. Tetrahedron Lett. 1997, 38, 2307. (c) Arumugam,
V.; Routledge, A.; Abell, C.; Balasubramanian, S. Tetrahedron Lett. 1997,
38, 6473. (d) Yun, W.; Mohan, R. Tetrahedron Lett. 1996, 37, 7189. (e)
Stephensen, H.; Zaragoza, F. Tetrahedron Lett. 1999, 40, 5799.
(5) Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1995, 60, 6006.
(6) (a) Stieber, F.; Grether, U.; Waldmann, H. Angew. Chem., Int. Ed.
1999, 38, 1073. (b) Gayo, L. M.; Suto, M. J. Tetrahedron Lett. 1997, 38,
211.
10.1021/ol991255o CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/17/1999

as cyclization/cleavage.8 A traceless solid-phase synthesis
of indoles based on a THP resin was also recently disclosed.9
Herein, we report our synthetic studies on the construction
of indoles on the solid phase with a traceless sulfonyl linker,
which further capitalizes on a “dual-activation process”. That
is, the traceless sulfonyl linker serves as an activating group
to facilitate indole cyclization and, after indole formation,
is activated and poised for cleavage under mild conditions.
Scheme 1
A particularly useful approach to 2-substituted indoles
involves palladium-mediated heteroannulation of 2-iodoa-
nilines with terminal alkynes.3c,4a,b,10 Thus, an aryl iodide is
coupled with a terminal alkyne to form the sp2-sp coupling
product, which then undergoes intramolecular cyclization to
form an indole ring. In this process, unlike the palladium-
mediated heteroannulation of a 2-haloaniline with an internal
alkyne,3b,11 activation of the amine is required to effect the
cyclization. The efficiency of the cyclization depends on the
nitrogen substituent and on forcing conditions, such as a
strong base and high temperature, which are normally applied
with substituents such as acyl or alkoxycarbonyl.10a,12 By
contrast, when the amine is activated by a strong electron-
withdrawing group such as sulfonyl, the sp2-sp coupling
and the indole cyclization can occur in one pot under
relatiVely mild conditions.3c,13 Therefore, we considered
employing a sulfonyl resin attached to nitrogen as a traceless
and activating linker for the solid-phase synthesis of indoles.
Sulfonyl linkers have been developed14 and used for various
chemical transformations on the solid phase.14a,15 Cleavage
of a sulfonyl linker from nitrogen in solid-phase synthesis
can require inconvenient conditions, such as anhydrous HF;
however, this linkage in our chemistry can be easily removed
from the indole nitrogen under mild conditions.
washing, the resulting resin was subjected to cleavage. An
initial attempt to cleave the sulfonyl linker with KOH, the
most common base used in solution-phase deprotection of
the tosyl group from indole nitrogen, proved to be problem-
atic. For example, cleavage of 5 (R ) Ph) with 5% KOH in
MeOH/1,4-dioxane/water (1:1:0.1) occurred very slowly at
23 °C. Increasing the reaction temperature to 70 °C for 5 h
afforded desired indole 6a with only 41% yield and 67%
purity as determined by HPLC (Table 1, entry 1). Prolonging
Table 1. Cleavage of Resin [5 (R ) Ph) f 6a]
To test this process, we first used 2-iodoaniline 2 and the
commercially available PS-TsCl resin 1a (polystyrene sul-
fonyl chloride; Argonaut Technologies). We loaded resin 1a
with 2 in the presence of pyridine/CH2Cl2 to give resin-bound
precursor 3 (Scheme 1). Treatment of resin 3 with pheny-
lacetylene (4, R ) Ph, 6 molar equiv), a catalytic amount of
Pd(PPh3)2Cl2 (10 mol %), CuI (20 mol %), and Et3N in DMF
at 70 °C for 6 h resulted in a black reaction mixture. After
(7) (a) Backes, B. J.; Virgilio, A. A.; Ellman, J. A. J. Am. Chem. Soc.
1996, 118, 3055. (b) Backes, B. J.; Ellman, J. A. J. Org. Chem. 1999, 64,
2322. (c). Todd, M. H.; Oliver, S. F.; Abell, C. Org. Lett. 1999, 1, 1149.
(8) Smith, A. L.; Thomson, C. G.; Leeson, P. D. Bioorg. Med. Chem.
Lett. 1996, 6, 1483.
(9) Smith, A. L.; Stevenson, G. I.; Swain, C. J.; Castro, J. L. Tetrahedron
Lett. 1998, 38, 8317.
(10) (a) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988,
27, 2225. (b) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992,
33, 3915.
(11) Larock, R. C.; Yum E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(12) Tetramethylguanidine has been reported to promote the coupling/
cyclization in one pot. See ref 4b.
a Crude yields (based on loading level of resin 3). b Determined by
reversed-phase HPLC. c MeOH/1,4-dioxane/water (1:1:0.1). d THF/MeOH
(1:1).
(13) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H.
Chem. Pharm. Bull. 1988, 36, 1305.
(14) (a) Zhong, H. M.; Greco, M. N.; Maryanoff, B. E. J. Org. Chem.
1997, 62, 9326. (b) Roush, W. R.; Feitler, D.; Rebek, J. Tetrahedron Lett.
1974, 15, 1391.
(15) (a) Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1994, 116, 11171.
(b) Hunt, J. A.; Roush, W. R. J. Am. Chem. Soc. 1996, 118, 9998. (c) Rueter,
J. K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz, A. B. Tetrahedron
Lett. 1998, 39, 975. (d) Baxter, E. W.; Rueter, J. K.; Nortey, S. O.; Reitz,
A. B. Tetrahedron Lett. 1998, 39, 979. (e) Jin, S. J.; Holub, D. P.; Wustrow,
D. J. Tetrahedron Lett. 1997, 38, 3651.
the reaction time at 70 °C increased the cleavage, but more
impurities were also generated. Therefore, efforts were made
to identify a relatively mild method to effectively cleave this
sulfonyl linker. Other bases, a variety of fluoride reagents,
and a reductive cleavage method using magnesium were
surveyed. As shown in Table 1, potassium tert-butoxide was
much better than KOH for the cleavage of 5 (R ) Ph),
providing desired product 6a in quantitative yield with 94%
90
Org. Lett., Vol. 2, No. 1, 2000

purity (entry 4). However, the application of this base to
combinatorial synthesis could be limited since strongly basic
conditions may not accommodate a wide variety of functional
groups. Fortunately, tetrabutylammonium fluoride16 (TBAF,
5 molar equiv) in THF at 70 °C for 5 h proved to be
excellent, providing cleaved product 6a in quantitative yield
(after removal of the TBAF) with 95% purity (entry 11).
TBAF was easily eliminated from the crude product by
aqueous washing. This mild cleavage method should allow
the synthesis of diverse indole derivatives bearing either base-
or acid-sensitive functional groups.
Table 2. Traceless Solid-Phase Synthesis of Indoles 6 and 10a
The results in Table 1 clearly demonstrate that the
palladium-mediated sp2-sp coupling of 3 with phenylacety-
lene (4, R ) Ph) and sulfonyl linker-activated indole
cyclization occur efficiently in one pot under relatively mild
conditions. The cleavage of the sulfonamide linkage could
also be executed under mild conditions due to its activation
via indole formation. When a Merrifield resin-based sulfonyl
chloride 1b14a was used instead of 1a, the chemistry was
equally effective. For example, by using the same procedure
as described above, 2-iodoaniline was loaded onto resin 1b,
reacted with 4-ethynyltoluene in the presence of the pal-
ladium catalyst, and cleaved with TBAF to afford 6b in
quantitative yield with 92% purity.
a Np ) naphthyl. Conditions: (1) Pd-mediated coupling/indole cycliza-
tion (8 f 9): alkyne (6-8 molar equiv; for volatile alkynes, such as in
entries 5 and 6, 10-15 molar equiv was used), CuI (0.2 molar equiv),
Pd(PPh3)2Cl2 (0.1 molar equiv), Et3N-DMF (1:6-8); (2) resin cleavage
(9 f 10): TBAF (5 molar equiv), THF, 70 °C, 5 h. b Crude yields (based
on the loading level of resin 8). All products gave satisfactory analytical
data. c Determined by reversed-phase HPLC. d 50% of 2-vinylindole was
observed in crude product by 1H NMR. e The compound was unstable under
With these results in hand, we examined the scope of this
solid-phase method for the synthesis of diverse indoles by
using commercially available PS-TsCl resin 1a and TBAF
as a cleavage reagent. This dual-activation process turned
out to be very robust. As shown in Scheme 2 and Table 2,
1
reversed-phase HPLC condition. H NMR showed a single product.
Scheme 2
groups, and heterocycles. The substituent on 2-iodoaniline
7 can be either electron-donating or electron-withdrawing.
When 7 bore an electron-withdrawing substituent, such as
for 7b and 7d, it was loaded onto PS-TsCl resin 1a in ClCH2-
(17) Typical procedure: To a solution of 5-fluoro-2-iodoaniline (7b;
400 mg, 1.69 mmol) and pyridine (222 mg, 2.8 mmol) in 1,2-dichloroethane
(5 mL) was added PS-TsCl resin (Argonaut Technologies, Inc.; 352 mg,
0.56 mmol) in one portion. The suspension was stirred at 50 °C for 18 h,
filtered, washed sequentially with CH2Cl2, MeOH, and Et2O, and dried in
vacuo to give resin 8 (X ) 5-F; 470 mg). A suspension of resin 8 (X )
5-F; 89 mg, 0.11 mmol) in DMF (4 mL) was treated with 6-methoxy-2-
naphthylacetylene (120 mg, 0.66 mmol), CuI (4.2 mg, 0.022 mmol), Et3N
(0.5 mL), and Pd(PPh3)2Cl2 (7.7 mg, 0.011 mmol). After being stirred at
70 °C for 6 h, the black mixture was filtered, washed sequentially with
DMF, water, MeOH, CH2Cl2, MeOH, and Et2O, and dried in vacuo. The
resulting resin was suspended in THF (6 mL) and treated with Bu4NF (1.0
M in THF, 0.55 mL, 0.55 mmol). The mixture was stirred at 70 °C for 5
h and then filtered and washed with THF. The combined filtrates were
evaporated, and the residue was dissolved in EtOAc (60 mL). The solution
was washed with water (3 × 30 mL) and brine (20 mL) and dried (Na2-
SO4). Concentration in vacuo furnished 31 mg (97% yield) of the indole
10 (X ) 6-F, R ) 6-MeO-2-Np; Table 2, entry 10) with 95% purity
determined by reversed-phase HPLC. MS m/z 292 (MH+); FAB-HRMS
calcd for C19H14FNO + H+ 292.1138, found 292.1127. The structure was
excellent yields (>85%) and purities (>90%) were achieved
for most cases.17 The terminal alkyne, 4, is able to carry
diverse functionality such as alkyl, ether, thioether, alcohol,
acetal, aryl with electron-donating and electron-withdrawing
1
(16) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 3651.
Org. Lett., Vol. 2, No. 1, 2000
confirmed by H NMR.
91

CH2Cl and the reaction temperature was increased to 50 °C.
It is noteworthy with 3-butyn-1-ol as the alkyne component
that about 50% (based on H NMR) of 2-vinylindole was
Scheme 3
1
obtained in the final product 10 (Table 2, entry 7). This
dehydration might be attributed to the electron-withdrawing
nature of the sulfonyl linker attached to the indole nitrogen.
Thus, a sulfonyl resin-bound 2-vinylindole, a potentially
useful resin-bound intermediate for the solid-phase synthesis
of biological active compounds, such as tetrahydrocarbazoles
via Diels-Alder reaction, can be accessed by treating resin
9 (R ) HOCH2CH2) with an appropriate acid.
The usefulness of a sulfonyl linker is illustrated further in
the functionalization of the 3-position of resin-bound indoles
9. We sought a resin-bound organometallic from 9, which
should be a useful precursor for the introduction of diverse
substituents into the 3-position. Our preliminary results with
direct mercuration18 of 9 (X ) H, R ) 4-Me-C6H4) were
very promising. Treatment of 9 (X ) H, R ) 4-Me-C6H4)
with mercury(II) acetate and a catalytic amount of HClO4
afforded synthetically versatile resin-bound organomercurial
11 (Scheme 3). The 3-indolylmercury species could be
converted to other organometallics or coupled with a suitable
substrate by either a catalytic or a stoichiometric process.
For example, coupling of 11 with methyl acrylate in the
presence of stoichiometric Pd(OAc)2 gave, after resin cleav-
age with TBAF, 2,3-disubstituted indole 12 in 60% isolated
yield. A resin-bound organomercurial might also be useful
for the study of relatively unexplored solid-phase radical
reactions.19 The sulfonyl linker could also be used as an
activating group to direct the solid-phase deprotonation at
the 2-position of indole followed by reaction with a variety
of electrophiles. The investigation of this sulfonyl linker-
directed metalation of indole, and its applications in chemical
library synthesis, are in progress and will be reported in due
course.
In conclusion, we have described a facile traceless solid-
phase construction of diverse indoles based on a sulfonyl
linker via a dual-activation process. We have also shown
that a sulfonyl linker is effective during mercuration at the
3-position of indole on a solid support. Given the ready
availability of a variety of terminal alkynes, the high loading
and low price of the PS-TsCl resin, the mild reaction
conditions, and high yields, our traceless-linker method
should be valuable for the generation of indole-based
combinatorial libraries.
Acknowledgment. We thank Drs. Michael Greco, Chih-
Yung Ho, and Michael Kukla for helpful discussions and
support. We thank William Jones for HRMS data.
Supporting Information Available: Characterization
data (1H NMR and MS) for the compounds in Table 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2658.
(19) Miyabe, H.; Tanaka, H.; Naito, T. Tetrahedron Lett. 1999, 40, 8387.
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