The synthesis of C-3β functionalized indoles via a hydroboration/Suzuki-Miyaura coupling sequence

Article abstract of DOI:10.1016/j.tetlet.2006.09.112

A method for the functionalization of C-3β of vinyl indoles is described. The procedure involves a hydroboration, followed by a Suzuki-Miyaura cross-coupling with the intermediate alkyl borane. Triflates, bromides, and iodides are suitable coupling partne

Full text of DOI:10.1016/j.tetlet.2006.09.112

Tetrahedron Letters 47 (2006) 8579–8582
The synthesis of C-3b functionalized indoles via a
hydroboration/Suzuki–Miyaura coupling sequence
Eric M. Ferreira and Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratory for Chemical Synthesis, Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, CA 91125, USA
Received 1 September 2006; accepted 21 September 2006
Abstract—A method for the functionalization of C-3b of vinyl indoles is described. The procedure involves a hydroboration, fol-
lowed by a Suzuki–Miyaura cross-coupling with the intermediate alkyl borane. Triflates, bromides, and iodides are suitable coupling
partners, allowing access to a variety of elaborated indole compounds.
ꢀ 2006 Elsevier Ltd. All rights reserved.
R1
R2
Indoles are important structural moieties in a number of
biologically relevant compounds.1 The development of
synthetic methods involving indole-containing com-
pounds remains an active area of research.1a,2 During
the course of our studies on the palladium-catalyzed oxi-
dative annulation of indoles,3 it became necessary to
synthesize substrates with olefin tethers at the C-3 posi-
tion. Specifically, we desired compounds where the
indole tethers had olefins attached to the b carbon. We
envisioned that indoles of this type could arise via sp2–
sp3 palladium-catalyzed cross coupling chemistry. The
Suzuki–Miyaura reaction has proven widely effective
in the construction of carbon–carbon bonds.4 We antici-
pated that a sequence consisting of a hydroboration of a
3-vinyl indole followed by a palladium-catalyzed cross
coupling with a halide or triflate would afford the
desired indole products (Scheme 1).
MeN
1
R1
R2
[B]
halide or
triflate
X =
X
MeN
2
3
Scheme 1.
would result in boron substitution at four different
sites, C-2, C-3, C-3a, and C-3b, the desired location
(Scheme 2).
The regioselectivity of a hydroboration on a vinyl indole
compound was uncertain at the beginning of this study.
Styrenyl compounds generally react with hydroborating
agents to afford compounds with boron substitution at
the terminal (b) position, although functionalization of
the internal carbon is often observed in catalytic reac-
tions. The hydroboration of more electron-rich hetero-
arenes, however, could potentially be complicated by
the numerous nucleophilic sites. It could be envisioned
that the hydroboration of N-methyl-3-vinyl indole
In the event, the hydroboration/Suzuki–Miyaura
coupling sequence proved to be remarkably effective
(Scheme 3). Starting with N-methyl-3-vinyl indole (4),
hydroboration with 9-BBN afforded B-alkyl intermedi-
ate 9, which was treated with triflate 10 under standard
Suzuki–Miyaura coupling conditions.5 After the reac-
tion was completed, analysis of the crude material
revealed that there was only one compound present
arising from boron substitution at C-3b (11). No prod-
ucts arising from hydroboration at any other sites on
4 were observed. This outcome is strongly suggestive
that the regioselectivity of the hydroboration event
*
Corresponding author. Tel.: +1 626 395 6064; fax: +1 626 564
9297; e-mail: stoltz@caltech.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.112

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E. M. Ferreira, B. M. Stoltz / Tetrahedron Letters 47 (2006) 8579–8582
BR2
MeN
MeN
BR2
5
6
R2BH
(reaction at C-2)
(reaction at C-3)
BR2
MeN
4
BR2
MeN
MeN
7
8
(reaction at C-3β)
(reaction at C-3α)
Scheme 2.
1). Triflates derived from cyclohexanone derivatives
are efficient coupling partners for this reaction (entries
1–6). Vinyl and aryl halides are also viable substrates
for the construction of C-3b substituted indoles (entries
7–9).
9-BBN
THF
0 to 23 °C
BR2
MeN
MeN
4
9
A representative procedure is as follows: 9-BBN dimer
(203 mg, 0.830 mmol) was dissolved in THF (1.66 mL)
at 23 ꢁC under an argon atmosphere. Following dissolu-
tion, the reaction mixture was cooled to 0 ꢁC, and to the
solution was added a solution of vinyl indole 4 (261 mg,
1.66 mmol) in THF (1.66 mL). The reaction mixture was
warmed to 23 ꢁC, stirred for 3 h, and then treated with a
solution of triflate 10 (552 mg, 1.51 mmol) in THF
(7.55 mL), (dppf)PdCl2 (30.8 mg, 0.0378 mmol), and
K3PO4 (482 mg, 2.27 mmol). The reaction mixture was
heated to 65 ꢁC, and after 5 h, the reaction was cooled
to 23 ꢁC and treated with 1 mL NaOH (3.0 M aq) and
1 mL 30% H2O2, and the resulting mixture was stirred
1 h. The mixture was then partitioned between Et2O
(50 mL) and water (40 mL), and the aqueous phase
was extracted with Et2O (1 · 50 mL). The combined
organic phases were washed with brine, dried over
MgSO4, and concentrated in vacuo. Purification of the
OBn
TfO
OBn
10
2.5 mol% (dppf)PdCl2
1.5 equiv K3PO4
THF, 65 °C
MeN
11
75% yield
Scheme 3.
was extremely high for the terminal position of the vinyl
group.
A variety of C-3b substituted indoles can be synthesized
via this hydroboration/Suzuki–Miyaura method (Table
Table 1. C-3b Substituted indoles via a hydroboration/Suzuki–Miyaura coupling sequence
1. 9-BBN, THF, 0 to 23 °C
2.
R
or R-X
R
TfO
R
12
or
2.5 mol% (dppf)PdCl2
1.5 equiv K3PO4
THF, 65 °C
MeN
MeN
MeN
4
13
14
Entry
1
Triflate or R–X
Product
Yielda (%)
OBn
OBn
75
TfO
TfO
MeN
MeN
2
46

E. M. Ferreira, B. M. Stoltz / Tetrahedron Letters 47 (2006) 8579–8582
8581
Table 1 (continued)
Entry
Triflate or R–X
Product
Yielda (%)
3
4
56
TfO
TfO
MeN
OMe
OMe
61
MeN
OTBS
OTBS
OTBS
OTBS
5
73
72
TfO
TfO
MeN
MeN
6b
7
57
63
56
Br
Br
I
MeN
MeN
MeN
8b
9b
a Isolated yield.
b A minor amount (ꢀ5%) of the coupling product arising from boron substitution at C-3a was observed.
residue by flash chromatography (2:1 ! 1:1 hexanes/
CH2Cl2 eluent) afforded Suzuki product 11 (467 mg,
75% yield, RF = 0.20 in 4:1 hexanes/CH2Cl2) as a color-
less oil.
to E.M.F.), the Dreyfus Foundation, Merck Research
Laboratories, Research Corporation, Abbott Laborato-
ries, Pfizer, Amgen, GlaxoSmithKline, Lilly, and John-
son and Johnson for their generous financial support.
In summary, a hydroboration/Suzuki–Miyaura method
was utilized to functionalize 3-vinyl indoles. An array of
indole-containing compounds arising from triflates or
halides can be synthesized via this protocol. It is antici-
pated that this method could be applied to the synthesis
of a number of biologically interesting compounds
featuring the indole nucleus.
References and notes
1. (a) Sundberg, R. J. The Chemistry of Indoles; Academic
Press: New York, 1970; (b) The Monoterpenoid Indole
Alkaloids; Saxton, J. E., Ed.; The Chemistry of Heterocyclic
Compounds; Wiley & Sons: New York, 1983; Vol. 25, Part
4; (c) Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.;
The Chemistry of Heterocyclic Compounds; Wiley & Sons:
Chichester, UK, 1994; Vol. 25, Supplement to Part 4.
2. Sundberg, R. J. Indoles; Best Synthetic Methods; Academic
Press: London, 1996.
Acknowledgments
The authors wish to thank the NIH-NIGMS (R01
GM65961-01), Bristol-Myers Squibb Company (gradu-
ate fellowship to E.M.F.), the NSF (graduate fellowship
3. Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125,
9578–9579.

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E. M. Ferreira, B. M. Stoltz / Tetrahedron Letters 47 (2006) 8579–8582
4. For reviews of the Suzuki–Miyaura reaction, see: (a)
Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419–
2440; (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457–2483.
5. The conditions for the palladium-catalyzed coupling were
derived from a procedure described by Suzuki et al. See,
Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58,
2201–2208.