Efficient synthesis of 3-substituted 2-arylindoles via Suzuki coupling reactions on the solid phase

Article abstract of DOI:10.1016/S0040-4039(01)00857-7

2-Aryl-3-alkylindoles were prepared on solid phase via palladium-mediated heteroannulation of 1-alkyl-2-(trimethylsilyl)acetylene with amide resin-bound o-iodoaniline 1, followed by transformation of trimethylsilyl to iodide and then Suzuki coupling react

Full text of DOI:10.1016/S0040-4039(01)00857-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4751–4754
Efficient synthesis of 3-substituted 2-arylindoles via Suzuki
coupling reactions on the solid phase
Han-Cheng Zhang,* Hong Ye, Kimberly B. White and Bruce E. Maryanoff
Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776, USA
Received 7 May 2001; accepted 15 May 2001
Abstract—2-Aryl-3-alkylindoles were prepared on solid phase via palladium-mediated heteroannulation of 1-alkyl-2-(trimethyl-
silyl)acetylene with amide resin-bound o-iodoaniline 1, followed by transformation of trimethylsilyl to iodide and then Suzuki
coupling reactions. Traceless synthesis of symmetrical and unsymmetrical 2,3-diarylindoles was achieved via palladium-mediated
one-pot coupling/intramolecular indole cyclization of aryl-substituted terminal alkynes with sulfonyl resin-bound o-iodoaniline 6,
followed by regioselective bromination and Suzuki coupling reactions. © 2001 Elsevier Science Ltd. All rights reserved.
The 2-arylindole unit is present in diverse biologically
active molecules, and various 2-aryl-3-alkylindoles and
2,3-diarylindoles exhibit interesting biological activi-
ties,1 such as antiestrogen,1b,d 5-HT2A antagonism,1f
anti-inflammatory,1a,c,g and cytotoxicity.1e Introduction
of an aryl group into the 2- or 3-position of an indole
ring is usually achieved either by de novo indole ring
construction,2 such as Fischer indole synthesis,1a or
cross-coupling reactions of 2- or 3-indolylmetal species
with an aryl halide.3 Palladium-mediated coupling reac-
tions of 2- or 3-haloindoles with an arylmetal species
has also been used for the synthesis of arylindoles,4 but
this application has been somewhat limited by the
inaccessibility of the haloindoles.5 Recently, Gribble
disclosed a solution-phase synthesis of symmetrical 2,3-
diarylindoles via a stepwise preparation of 2,3-dihalo-
indoles, followed by one-pot bis-Suzuki coupling reac-
tions.6 In this regard, we wish to report our studies on
the solid-phase synthesis of 2-aryl-3-alkylindoles, sym-
metrical and unsymmetrical 2,3-diarylindoles via
sequential palladium-mediated indole construction,
regioselective indole halogenation, and Suzuki coupling
reaction.7
Given the importance of the indole nucleus in medicinal
chemistry, we8 and others9 have developed efficient
solid-phase methods for the construction of the indole
nucleus. However, little work has been done to further
functionalize the indole nucleus on the solid support to
obtain more diverse indole derivatives. In the palla-
O
O
Me
I
Me3Si C C Me
N
H
N
H
SiMe3
Pd(OAc)2, PPh3, Bu4N+Cl-,
Na2CO3, DMF, 80 °C
N
NH2
O
H
1
2
O
Me
Me
1) ArB(OH)2, [Pd]
2) TFA, CH2Cl2
NIS
CH2Cl2
N
H
H2N
I
Ar
N
N
R
R
3
5
R = H
Cs2CO3,
RBr, DMF
4a R = Bn
4b R = 4-F-Bn
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00857-7

4752
H.-C. Zhang et al. / Tetrahedron Letters 42 (2001) 4751–4754
dium-mediated heteroannulation of unsymmetrical
internal alkynes with a resin-bound o-iodoaniline,8b,10
excellent regioselectivity was achieved by using a
trimethylsilylalkyne, where the bulky trimethylsilyl
group served as a regiochemistry directing group to
provide 2-(trimethylsilyl)-3-alkylindole predominantly.
This silyl group could then be easily removed during
resin cleavage with trifluoroacetic acid (TFA)8b or serve
as a useful precursor to other 2-substituted indole
derivatives via silyl group transformation. We identified
an efficient method to convert this 2-(trimethylsilyl)-3-
alkylindole to diverse 2-aryl-3-alkylindoles on the solid
phase via iodination and a Suzuki coupling reaction.
Thus, palladium-mediated heteroannulation of 1-
methyl-2-(trimethylsilyl)acetylene with resin-bound o-
ity of heteroannulation of an 1-aryl-2-(trimethylsilyl)-
acetylene with 1 decreased significantly. For example,
the heteroannulation of 1-phenyl-2-(trimethylsi-
lyl)acetylene with resin 1 under the same conditions as
described in Scheme 1 afforded only 56% of desired
2-trimethylsilyl-3-phenylindole, along with 27% of the
regioisomer, 3-trimethylsilyl-2-phenylindole deriva-
tive.8b We recently reported a facile solid-phase con-
struction of 2-substituted indole derivatives via
palladium-mediated coupling/intramolecular indole
cyclization of terminal alkynes based on a traceless,
activating sulfonyl linker.8d When an aryl-substituted
terminal alkyne was used, the process could be applied
to the regiospecific synthesis of a 2-arylindole. We have
now extended this method for the synthesis of symmet-
rical and unsymmetrical 2,3-diarylindoles. Thus, palla-
iodoaniline 18b at 80°C for
5
h
afforded
2-(trimethylsilyl)-3-methylindole 2 (Scheme 1). Treat-
ment of resin 2 with N-iodosuccinimide (NIS) in methy-
lene chloride at 23°C for 2 h cleanly provided resin-
bound 2-iodoindole 3. In solution phase, a 2-haloindole
has been obtained via directed 2-lithiation of an N-pro-
tected indole, followed by quenching lithiated species
with a halogen.6,11 Indole 3 was alkylated with benzyl
bromide or 4-fluorobenzyl bromide in DMF to give 4a
or 4b, respectively. Suzuki coupling of resin-bound
2-iodoindoles 3 or 4 with various arylboronic acids
occurred smoothly to provide, after resin cleavage with
TFA, 2-aryl-3-methylindoles 5 with good to excellent
yields and high purity (Table 1). For the Suzuki coup-
ling reaction, procedure B was generally more effective
than procedure A.
dium-mediated
coupling/intramolecular
indole
cyclization of aryl-substituted terminal alkynes 7 with
resin 68d afforded resin-bound 2-arylindoles 8 (Scheme
2). The regioselective halogenation at the 3-position of
8 was achieved with N-bromosuccinimide (NBS, 3–4
equiv.) in 1,4-dioxane or THF at 60°C to afford 2-aryl-
3-bromoindoles 9. Less clean results were observed
when DMF was used as solvent or NIS as halogenating
agent. Suzuki coupling reactions of resins 9 with vari-
ous aryl(heteroaryl)boronic acids 10 was followed by
resin cleavage with tetrabutylammonium fluoride
(TBAF, 5 mol equiv.)8d in THF to provide unsymmetri-
cal 2,3-diarylindoles 11 with good to excellent yields
and high purity (Table 2).12 Starting with appropriate
aryl-substituted terminal alkynes and arylboronic acids,
our process could provide symmetrical 2,3-diaryl
indoles, as prepared by one-pot bis-Suzuki coupling reac-
tions in solution phase.6 However, the latter approach
has not been successful so far for unsymmetrical 2,3-
diarylindoles via tandem bis-Suzuki coupling of 2,3-
dihaloindoles.6 Our method can also be used for the
Our process could also be applied to the synthesis of
other 2-aryl-3-(substituted-alkyl)indole derivatives by
using an appropriate 1-(substituted-alkyl)-2-(trimethyl-
silyl)acetylene.8b However, an attempt to prepare 2,3-
diarylindoles was less successful since the regioselectiv-
Table 1. Solid-phase synthesis of 2-arylindoles 5a
Entry
R
Ar
Procedure
Time (h)
Yield (%)b
Purity (%)c
1
2
3
4
5
6
7
H
H
H
H
H
4-F-Bn
4-F-Bn
Ph
A
A
B
B
A
A
B
20
26
6
68d
65d
93
4-Me-C6H4
4-MeO-C6H4
1-Naphthyl
Ph
4-Me-C6H4
4-MeO-C6H4
89
98
90
6
96
20
18
6
85
75d
74d
a Conditions for the Pd-mediated Suzuki coupling of resins 3 or 4: ArB(OH)2 (5 equiv.), K2CO3 (5 equiv.), Pd2(dba)3 (0.1 equiv., procedure A)
or Pd(PPh3)4 (0.1 equiv., procedure B), DMF (procedure A) or 9:1 DMF–H2O (procedure B), 80°C.
b Crude yields unless noted otherwise (for four or five steps; based on the loading level of resin 1). All products gave satisfactory analytical data.
c Determined by reverse-phase HPLC.
d Isolated yields.
Ar2
Br
1) Ar2B(OH)2 (10)
X
X
X
X
I
Ar1
[Pd]
C CH (7)
NBS
THF
Ar1
Ar1
Ar1
N
N
Pd(PPh3)2Cl2, CuI,
2) TBAF
N
H
NH
Et3N, DMF, 70 °C
Ar-SO2
Ar-SO2
Ar-SO2
11
6
8
9
Scheme 2.

H.-C. Zhang et al. / Tetrahedron Letters 42 (2001) 4751–4754
Table 2. Traceless solid-phase synthesis of 2,3-diarylindoles 11a
4753
Entry
X
Ar1
Ar2
Yield (%)b
Purity (%)c
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
Ph
4-MeO-C6H4
4-CO2Me-C6H4
4-Pyridyl
4-MeO-C6H4
4-Cl-C6H4
85
94
92
86
86
87
87
91
93
99
85
86
93
87
84
85
92
91
96
99
96
96
82
98
Ph
4-MeO-C6H4
1-Naphthyl
3-Thieyl
4-MeS-C6H4
2-Naphthyl
3,4-OCH2O-C6H3
9
H
H
10
11
12
5-CO2Me
5-CO2Me
Ph
a Conditions for Suzuki coupling of resins 9: Ar2B(OH)2 (4 equiv.), K2CO3 (3 equiv.), Pd(PPh3)4 (0.1 equiv.), DMF, 90°C, 5–10 h.
b Crude yields for four steps; based on the loading level of resin 6. All products gave satisfactory analytical data.
c Determined by reverse-phase HPLC.
Ar
Br
1) ArB(OH)2
[Pd]
NBS
Me3Si C CH
6
SiMe3
Ar
Br
THF or
1,4-dioxane
Pd(PPh3)2Cl2, CuI,
Et3N, DMF, 70 °C
2) TBAF
N
N
H
N
Ar-SO2
Ar-SO2
14
12
13
Ar
Yield(%) Purity(%)
4-MeO-C6H4
4-Me-C6H4
a:
b:
84
81
86
90
Scheme 3.
Acknowledgements
synthesis of other 3-substituted 2-arylindoles via Heck-
or Stille-type coupling of 9.
We thank Drs. Dennis Hlasta and Alessandro Moretto
for helpful discussions and support.
When aryl-substituted terminal alkyne 7 was replaced
with (trimethylsilyl)acetylene, the palladium-mediated
coupling/intramolecular indole cyclization of resin 6
provided resin-bound 2-trimethylsilylindole 12 (Scheme
3). One-pot treatment of 12 with excess NBS in THF or
1,4-dioxane afforded 2,3-dibromoindole 13 (use of NIS
was less successful). It is noteworthy that conversion of
the trimethylsilyl group in resin 12 to a halide was more
difficult than that in resin 2 probably partially due to
the electronic effect. One-pot bis-Suzuki coupling of 13
with 4-methoxybenzeneboronic acid followed by resin
cleavage afforded 84% yield (86% purity by HPLC) of
symmetrical 2,3-diarylindole 14a.13 Similarly, bis-
Suzuki coupling of resin 13 with 4-methylbenzene-
boronic acid gave 81% yield (with 90% purity) of
14b.
References
1. (a) Szmuszkovicz, J.; Glenn, E. M.; Heinzelman, R. V.;
Hester, Jr., J. B.; Youngdale, G. A. J. Med. Chem. 1966,
9, 527; (b) von Angerer, E.; Knebel, N.; Kager, M.;
Ganss, B. J. Med. Chem. 1990, 33, 2635; (c) Ismail, M.
M. F.; Shmeiss, N. A. M. M.; El-Diwani, H. I.; Arbid,
M. S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 1997, 36B, 288; (d) Biberger, C.; von Angerer, E.
J. Steroid Biochem. Mol. Biol. 1998, 64, 277; (e) Medarde,
M.; Ramos, A. C.; Caballero, E.; De Clairac, R. P.-L.;
Lopez, J. L.; Gravalos, D. G.; Feliciano, A. S. Bioorg.
Med. Chem. Lett. 1999, 9, 2303; (f) Stevenson, G. I.;
Smith, A. L.; Lewis, S.; Michie, S. G.; Neduvelil, J. G.;
Patel, S.; Marwood, R.; Patel, S.; Castro, J. L. Bioorg.
Med. Chem. Lett. 2000, 10, 2697; (g) Nakkady, S. S.;
Fathy, M. M.; Hishmat, O. H.; Mahmond, S. S.; Ebeid,
M. Y. Boll. Chim. Farm. 2000, 139, 59; (h) Colletti, S. L.;
Li, C.; Fisher, M. H.; Wyvratt, M. J.; Meinke, P. T.
Tetrahedron Lett. 2000, 41, 7825.
In conclusion, we have developed facile solid-phase
approaches to 2-aryl-3-alkylindoles and 2,3-diaryl-
indoles via palladium-mediated indole formation, fol-
lowed by regioselective halogenation of indole ring and
Suzuki coupling reactions. The sulfonyl linker approach
proved to be particularly efficient for the traceless
synthesis of symmetrical or unsymmetrical 2,3-diaryl-
indoles, as well as other 2-arylindole derivatives. These
methods should prove valuable for the generation of
biologically interesting arylindole-based chemical
libraries.
2. For a recent review on indole ring synthesis, see: Gribble,
G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
3. (a) Rewcastle, G. W.; Katritzky, A. R. Adv. Heterocycl.
Chem. 1993, 56, 155; (b) Hudkins, R. L.; Diebold, J. L.;

4754
H.-C. Zhang et al. / Tetrahedron Letters 42 (2001) 4751–4754
Marsh, F. D. J. Org. Chem. 1995, 60, 6218; (c) Amat, M.;
10. Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113,
6689.
Hadida, S.; Pshenichnyi, G.; Bosch, J. J. Org. Chem.
1997, 62, 3158; (d) Kawasaki, I.; Yamashita, M.; Ohta, S.
Chem. Pharm. Bull. 1996, 44, 1831; (e) Johnson, C. N.;
Stemp, G.; Anand, N.; Stephen, S. C.; Gallagher, T.
Synlett 1998, 1025.
11. Bergman, J.; Venelman, L. J. Org. Chem. 1992, 57, 2495.
12. Typical procedure for 2,3-diarylindole 11 (Ar1=4-NO2-
C6H4, Ar2=3-thienyl, X=H, Table 2, entry 9): To a
suspension of resin 88d (616 mg, 0.67 mmol; Ar1=4-NO2-
C6H4, X=H) in 20 mL of 1,4-dioxane was added NBS
(475 mg, 2.67 mol). The mixture was stirred at 70°C for
24 h, and then filtered, washed with DMF, MeOH,
CH2Cl2, and Et2O, dried in vacuo to give resin 9 (634
mg). A suspension of resin 9 (150 mg, 0.16 mmol) in
DMF (5 mL) was treated with thiophene-3-boronic acid
(80.6 mg, 0.63 mmol), K2CO3 (65.3 mg, 0.47 mmol), and
Pd(PPh3)4 (18.2 mg, 0.016 mmol). After stirring at 90°C
for 8.5 h, the mixture was filtered, washed sequentially
with DMF, MeOH, CH2Cl2, and Et2O, and dried in
vacuo (145 mg). The resin (140 mg, 0.15 mmol) was
suspended in THF (6 mL) and treated with Bu4NF (1.0
M in THF, 0.76 mL, 0.76 mmol). The mixture was stirred
at 70°C for 5 h and then filtered, washed with THF. The
combined filtrates were evaporated and the residue was
dissolved in EtOAc (100 mL). The solution was washed
with water (5×30 mL), brine (30 mL), and dried
(Na2SO4). Concentration in vacuo furnished 45 mg (93%
yield) of the indole 11 (Ar1=4-NO2-C6H4, Ar2=3-
thienyl, X=H) with 96% purity determined by reverse-
phase HPLC. CI-MS m/z 321 (MH+). The structure was
4. (a) Merlic, C. A.; McInnes, D. M. Tetrahedron Lett.
1997, 38, 7661; (b) Chu, L.; Fisher, M. H.; Goulet, M. T.;
Wyvratt, M. J. Tetrahedron Lett. 1997, 38, 3871; (c)
Smith, A. L.; Stevenson, G. I.; Lewis, S.; Patel, S.;
Castro, J. L. Bioorg. Med. Chem. Lett. 2000, 10, 2693.
5. (a) Joseph, B.; Malapel, B.; Merour, J.-Y. Synth. Com-
mun. 1996, 26, 3289; (b) Malapel-Andrieu, B.; Merour,
J.-Y. Tetrahedron 1998, 54, 11079.
6. Liu, Y.; Gribble, G. W. Tetrahedron Lett. 2000, 41, 8717.
7. For Suzuki coupling reactions on the solid phase, see: (a)
Franzen, R. Can. J. Chem. 2000, 78, 957; (b) Lorsbach,
B. A.; Kurth, M. J. Chem. Rev. 1999, 99, 1549; (c) Guiles,
J. W.; Johnson, S. G.; Murray, W. V. J. Org. Chem.
1996, 61, 5169; (d) Brown, S. D.; Armstrong, R. W. J.
Am. Chem. Soc. 1996, 118, 6331.
8. (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.; Jaroskova, L.; Maryanoff, B. E. Tetra-
hedron Lett. 1998, 39, 4449; (d) Zhang, H.-C.; Ye, H.;
Moretto, A. F.; Brumfield, K. K.; Maryanoff, B. E. Org.
Lett. 2000, 2, 89.
9. (a) Yun, W.; Mohan, R. Tetrahedron Lett. 1996, 37,
7189; (b) Collini, M. D.; Ellingboe, J. W. Tetrahedron
Lett. 1997, 38, 7963; (c) Fagnola, M. C.; Candiani, I.;
Visentin, G.; Cabri, W.; Zarini, F.; Mongelli, N.;
Bedeschi, A. Tetrahedron Lett. 1997, 38, 2307; (d) Aru-
mugam, V.; Routledge, A.; Abell, C.; Balasubramanian,
S. Tetrahedron Lett. 1997, 38, 6473; (e) Smith, A. L.;
Stevenson, G. I.; Swain, C. J.; Castro, J. L. Tetrahedron
Lett. 1998, 39, 8317; (f) Stephensen, H.; Zaragoza, F.
Tetrahedron Lett. 1999, 40, 5799.
1
confirmed by H NMR.
13. Compound 14a (indoxole) is an antiinflammatory agent
with comparable activity to indomethacin in certain anti-
inflammatory and antiarthritic assays: (a) Glenn, E. M.;
Bowman, B. J.; Kooyers, W.; Koslowske, T.; Myers, M.
L. J. Pharmacol. Exp. Ther. 1967, 155, 157; (b) Brune,
K.; Graf, P.; Glatt, M. Agents Actions 1976, 6, 159; (c)
Klug, R. D.; Krohn, D. L.; Breitfeller, J. M.; Dieterich,
D. Ophthalmic Res. 1981, 13, 122.
.