Convenient synthesis of 1H-indol-1-yl boronates via palladium(0)-catalyzed borylation of bromo-1H-indoles with 'pinacolborane'

Article abstract of DOI:10.1002/hlca.200690097

An atom-economic Pd⁰-catalyzed synthesis of a series of pinacol-type indolylboronates 3 from the corresponding bromoindole substrates 2 and pinacolborane (pinBH) as borylating agent was elaborated. The optimal catalyst system consisted of a 1:2 mixture of [Pd(OAc)₂] and the ortho-substituted biphenylphosphine ligand L-3 (Scheme 4, Table). Our synthetic protocol was applied to the fast, preparative-scale synthesis of 1-substituted indolylboronates 3a-h in the presence of different functional groups, and at a catalyst load of only 1 mol-% of Pd.

Full text of DOI:10.1002/hlca.200690097

936
Helvetica Chimica Acta – Vol. 89 (2006)
Convenient Synthesis of 1H-Indol-1-yl Boronates via Palladium(0)-Catalyzed
Borylation of Bromo-1H-indoles with ꢀPinacolboraneꢁ
by Josef F. Stadlwieser* and Markus E. Dambaur
Discovery Resarch, ALTANA Pharma AG, Byk-Gulden-Strasse 2, D-78467 Konstanz,
(e-mail: josef.stadlwieser@altanapharma.com)
An atom-economic Pd0-catalyzed synthesis of a series of pinacol-type indolylboronates 3 from the
corresponding bromoindole substrates 2 and pinacolborane (pinBH) as borylating agent was elaborated.
The optimal catalyst system consisted of a 1:2 mixture of [Pd(OAc)2] and the ortho-substituted biphenyl-
phosphine ligand L-3 (Scheme 4, Table). Our synthetic protocol was applied to the fast, preparative-scale
synthesis of 1-substituted indolylboronates 3a–h in the presence of different functional groups, and at a
catalyst load of only 1 mol-% of Pd.
1. Introduction. – Arylboronic acids and their esters [1][2] have emerged as widely
used nucleophiles in Pd0-catalyzed carbonꢀcarbon bond formation. They exhibit
improved chemical stabilities compared to the corresponding Mg and Zn compounds,
as well as lower toxicities relative to nucleophilic organostannanes commonly used in
cross-coupling reactions [3][4].
Dealing with the high-throughput synthesis of compounds containing pharmaceuti-
cally relevant structural moieties, we were particularly interested in the efficient syn-
thesis of diverse indolylboronates. Indolylboronic acids and their esters are often pre-
pared by transmetalation (see, e.g., [5]). However, the requirement of highly reactive
lithiated intermediates prevents the presence of a range of versatile functional groups
and, therefore, limits the applicability of this methodology to the synthesis of pharma-
cologically interesting building blocks.
Recently, the borylation of indole by Ir-catalyzed CꢀH activation was reported
[6–8]. This elegant and atom-economic method was demonstrated to allow the prepa-
ration of indol-2-yl- or indol-3-yl-boronates from indoles with the aid of the reagents
bis(pinacolato)diboron (pin2B2) or, alternatively, pinacolborane (pinBH)1) at ambient
temperature [9][10].
The Pd0-catalyzed borylation with pin2B2, first reported by Miyaura and co-workers
[11], is an additional interesting methodology due to the wide range of tolerated func-
tional groups [12–17]. However, the use of bromoindoles as substrates requires high
loads of catalyst, judicious choice of reaction conditions [13][14], or microwave heating
[15] to obtain good yields of 1H-indol-1-yl boronates. Borylation of 4-chloroindole was
1
)
Systematic name: 4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
ꢀ 2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
937
achieved with the aid of a combination of [Pd(dba)2]2) and tricyclohexylphosphane,
(C6H11)3P, as catalyst [16].
AHCTREUNG
In this communication, we describe the development of an upscalable and widely
applicable Pd-catalyzed borylation of bromoindoles with pinBH as borylating agent
under conditions allowing the presence of a range of functional groups.
2. Results and Discussion. – 2.1. Preparation of Substrates. The model substrates 5-
bromo-1-(triisopropylsilyl)-1H-indole (2a) and 1-(triisopropylsilyl)-1H-indole (4) were
prepared according to literature procedures [18][19]. The bromoindoles 2b [20][21],
2c–d, 2e [18], 2h–j, 2k [22], and 2l were prepared by alkylation of the commercially
available bromoindoles 1a–d using an appropriate alkylating agent and NaH as base.
The reactions were performed at ambient temperature in 1,2-dimethoxyethane
(DME) containing 10% of DMSO (Scheme 1).
Scheme 1
The alkylating agent 8 was prepared by selective N-formylation of commercially
available (piperidin-4-yl)methanol (7) with HCO2
A
crude intermediate with methanesulfonyl chloride (MsCl) in the presence of Et3N
U
(overall yield: 88%; Scheme 2,a). Finally, the bromoindoles 2f and 2g were prepared
in 92 and 93% yield, respectively, by mesylation of the alcohol 5 [23], followed by reac-
tion of 6 with 5 equiv. of Me2NH or 1-methylpiperazine (Scheme 2,b).
R
2.2. Catalyst Screening. In a first attempt based on Masudaꢁs protocol [24][25], we
used 2a as a substrate, and the Pd complexes [Pd(dppf)Cl2]3) and [Pd(PPh3)4] as cata-
2
)
)
The term ꢂdbaꢁ refers to ꢂdibenzylideneacetoneꢁ.
The term ꢂdppfꢁ refers to diphenylphosphinoferrocen.
3

938
Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 2
lysts (Scheme 3). We observed the formation of the desired compound 3a, along with a
minor amount of the debrominated compound 4 at a poor conversion, even after pro-
longed heating (Table, Entries 1 and 2). Interestingly, when [Pd(OAc)2] was used as the
catalyst in the absence of ligand, but under otherwise identical conditions, slow forma-
tion of 4 was the only observed reaction (Entry 3).
Assuming that Pd catalysts with electron-rich ligands facilitate oxidative addition to
bromoindoles [16], we next studied the borylation of 2a in the presence of commer-
cially available [Pd{P(C6H11)3}2Cl2]. Unfortunately, 3a was only formed in trace
amounts after prolonged heating. On the other hand, unwanted 4 was not detected
(HPLC) in the reaction mixture (Entry 4). The catalyst prepared from [Pd(OAc)2]
and the imidazolium salt L-1 in the presence of Et3N – a system reported for micro-
G
wave-assisted borylation of electron-poor aryl chlorides [26] – also proved inefficient
to catalyze the transformation of 2a into 3a. Compound 4 was formed as the major
product in a sluggish reaction (Entry 5).
Next, we investigated the combination of [Pd(OAc)2] with electron-rich and bulky
ortho-(dialkylphosphino)biphenyl ligands. Such ligands have been extensively applied
by Buchwald and co-workers in Pd-catalyzed coupling reactions (see, e.g., [27]). A cat-
alyst generated from [Pd(dba)2] and L-2 was also disclosed to facilitate the borylation
of 4-chlorobenzaldehyde with pin2B2 [16]. Noteworthy, the combination of [Pd(dba)2]
with L-2 or L-3 was reported to lead to debromination when applied to the borylation
of 3-bromo-2-nitrothiophene with pinBH [28]. For other substrates like ortho-substi-
tuted bromobenzenes, an efficient borylation with pinBH in the presence of
[Pd(OAc)2] and L-3 requires an exceptionally high catalyst load [29].
In our hands, the catalyst prepared from [Pd(OAc)2] and L-2 (Entry 6) did not effi-
ciently catalyze the transformation of 2a. Besides minor amounts of desired 3a, com-
pound 4 was formed as the main product (48%). Fortunately, when the less-bulky

Helvetica Chimica Acta – Vol. 89 (2006)
939
Scheme 3
Table. Reaction of 2a with Pinacolborane (pinBH) and Different Catalysts (see Scheme 3). Conditions: 2a
(2.0 mmol); pinBH (2.4 mmol), Pd (2.0 mol-%), Pd/ligand 1:2, Et3N (6.0 mmol), 1,4-dioxane, T=808.
AHCTREUNG
Entry
Catalyst
Time [h]
Product distribution [%]a)
2a
3a
4
1
2
3
4
5
6
7
8
9
[Pd(dppf)Cl2]3)
[Pd(PPh3)4]
[Pd(OAc)2]
[Pd{P(C6H11)3}2Cl2]
[Pd(OAc)2]/L-1
[Pd(OAc)2]/L-2
[Pd(OAc)2]/L-3
[Pd(OAc)2]/L-4
[Pd(OAc)2]/L-5
[Pd(OAc)2]/L-6
[Pd(OAc)2]/L-7
22
22
22
22
22
22
2
2
2
22
22
75
68
55
98
66
35
0
0
0
25
3
21
28
0
2
8
17
92
89
83
34
55
4
4
45
0
26
48
8
11
17
41
42
10
11
a) Based on a calibrated UV experiment (trace at 230 nm).
ligand L-3 was used, fast transformation of 2a into 3a was observed, with only a small
amount of 4 being formed after complete consumption of 2a (Entry 7). Catalysts pre-
pared from [Pd(OAc)2] and the 2-substituted ligands L-4 and L-5 also induced a fast
transformation of 2a, but compared to the catalyst ligated by L-3, the amount of 4

940
Helvetica Chimica Acta – Vol. 89 (2006)
increased (Entries 8 and 9). The 2,6-disubstituted ligands L-6 and L-7 proved to be less
efficient and led to substantial debromination, as reflected by the dominant formation
of 4 (Entries 10 and 11).
2.3. Preparative-Scale Synthesis. Based on the screening results outlined above, we
decided to use the inexpensive catalyst prepared from [Pd(OAc)2] and L-3 for the prep-
arative-scale (25 mmol) synthesis of various substituted indole-based ꢂpinacolboro-
natesꢁ. A catalyst load of 1.0 mol-% of [Pd(OAc)2] and 2.2 mol-% of L-3 was sufficient
to provide 3a in 82% isolated yield from the reaction of 2a with 1.2 equiv. of pinBH and
3.0 equiv. of Et3N in 1,4-dioxane at 808; the side product 4 was isolated in 6% yield after
G
chromatographic separation.
Under these conditions, the 4-bromoindoles 2b–d, the 5-bromoindoles 2e–g, the 6-
bromoindoles 2i–k, and 7-bromo-1-methylindole (2l) were all transformed into the cor-
responding pinacolboronates in isolated yields of 69–84% (Scheme 4). The compounds
resulting from debromination of the starting materials, although detected by LC/MS in
the crude reaction mixtures, could be readily removed by chromatography.
Noteworthy, the transformation of the amide-bearing substrate 2h into 3h required
1.5 equiv of pinBH and a prolonged reaction time to achieve complete transformation
(77% yield). Two minor side products were detected by LC/MS, but not isolated.
Scheme 4

Helvetica Chimica Acta – Vol. 89 (2006)
941
Conclusion. – We have established a procedure to synthesize pinacol-type indolyl-
boronates from substituted 4-, 5-, 6-, or 7-bromoindoles. The inexpensive pinBH was
demonstrated to be an efficient borylating agent. The reaction is readily catalyzed by
the complex formed from [Pd(OAc)2] (1 mol-%) and the biphenylphospine ligand L-
3 (2.2 mol-%).
We gratefully acknowledge the help of our colleagues, Dr. H.-C. Holst and Mrs. A. Rçsler (NMR);
Dr. J. Volz and Mrs. C. Schaub (HR-MS); Mrs. M. Beschle and Mrs. K.-M. Nagy (LC/MS), and Mrs. J.
Bald (excellent technical assistance). We also thank Dr. B. Bartels for helpful discussions during manu-
script preparation.
Experimental Part
General. All Pd-catalyzed reactions were performed under Ar atmosphere using Schlenk techniques.
1,4-Dioxane and Et3N for Pd-catalyzed reactions were distilled from CaH2 under Ar. [Pd(OAc)2]
N
(99.98%) was from Aldrich, [Pd(dppf)Cl2]·CH2Cl2 was from Alfa Aesar, [Pd{P(C6H11)3}2Cl2] was from
ABCR, [Pd(PPh3)4] was from Lancaster, L-1 was from Fluka, and L-2 to L-7 were purchased from
Strem. Neutral alumina (MP Alumina N – Super I) contained 5% H2O. Microwave-assisted reactions:
Biotage Initiator Sixty. Column chromatography (CC): silica gel 60 (230–400 mesh ASTM, Merck).
Bulb-to-bulb distillation: Büchi 585 apparatus. M.p.: Büchi 540 melting-point apparatus; uncorrected.
Anal. HPLC and LC/MS: Agilent 1100 system equipped with a binary pump, a well-plate autosampler,
a column thermostat, a diode-array detector, and an API-ESI-MS detector; gradient elution with solvent
A (H2O/MeCN/1M aq. HCO2H/1M aq. NH4HCO2 975 :15 :5 :5) and solvent B (H2O/MeCN/1M aq.
HCO2H/1M aq. NH4HCO2 15 :975 :5 :5). Condition 1: Agilent Zorbax SB-Aq column (3.5 mm, 2.1”50
mm; 1.0 ml/min), with the following gradient: 10% B for 0.5 min, 10–90% B in 2.5 min, 90% B for
2 min. Condition 2: Waters XTerra MS C18 column (3.5 mm, 4.6”30 mm, 1.5 ml/min), with the following
1
gradient: 50% B for 0.5 min, 50–80% B in 2.5 min, 80% B for 3 min. H-NMR: Bruker-DPX-200 (200
MHz) and Bruker AV-400 (400 MHz); d in ppm rel. to Me
J in Hz. HR-ESI-MS: Bruker Daltronic Microtof; in m/z.
A
(1-Formylpiperidin-4-yl)methyl Methanesulfonate (8). Methyl formate (18.02 g, 0.30 mol) was added
dropwise to a stirred soln. of 7 (23.04 g, 0.20 mol) in anh. CH2Cl2 (100 ml). After complete addition, stir-
ring was continued at r.t. for 16 h. The solvent was removed in vacuo, and the residue was dried azeotropi-
cally with toluene (3”100 ml). The resulting pale-yellow oil was dissolved in anh. CH2Cl2 (250 ml), and
Et3N (30.36 g, 0.30 mol) was added. To this stirred mixture cooled to 08 (ice/NaCl), a soln. of methane-
U
sulfonyl chloride (MsCl; 27.44 g, 0.24 mol) in anh. CH2Cl2 (100 ml) was added dropwise, keeping the
temp. below 158. After complete addition, stirring was continued for 2 h at r.t. The mixture was washed
with 1N aq. HCl (200 ml) and H2O (100 ml), dried (MgSO4), and filtered through a short pad of neutral
alumina (rinsing with several portions of CH2Cl2). The crude product was crystallized from AcOEt/hex-
1
ane to yield 38.82 g (88%) of pure 8. Colorless solid. M.p. 988 (AcOEt/hexane). H-NMR (200 MHz,
CDCl3): 8.03 (s, 1 H); 4.47 (m, 1 H); 4.09 (m, 2 H); 3.68 (m, 1 H); 3.10 (m, 1 H); 3.02 (s, 3 H); 2.64 (m,
1 H); 2.05 (m, 1 H); 1.86 (m, 2 H); 1.22 (m, 2 H). HR-ESI-MS: 222.0794 ([M+H]+, C8
A
G
N
222.0795).
General Procedure (GP 1) for the N-Alkylation of Bromoindoles. NaH (60% dispersion in mineral
oil; 5.00 g, ca. 125.0 mmol) was washed oil-free with hexane (25 ml), and then suspended in anh. DME
(225 ml) and DMSO (25 ml). The bromoindole 1 (100.0 mmol) was cautiously added to the well-stirred
suspension in small portions. The mixture was stirred at r.t. for 30 min, before the appropriate electro-
phile (120.0 mmol) was added slowly. Stirring was continued at r.t. until the starting material was con-
sumed (LC/MS, Condition 1). Ice-cold H2O (50 ml) was added dropwise, followed by brine (50 ml).
The mixture was stirred for another 15 min, the org. layer was separated, and concentrated in vacuo.
The aq. layer was extracted with AcOEt (3”100 ml), the org. phases were combined, washed with

942
Helvetica Chimica Acta – Vol. 89 (2006)
brine (50 ml), dried (MgSO4), filtered through a short pad of neutral alumina, and concentrated in vacuo.
The crude products were further purified by CC, followed by bulb-to-bulb distillation or crystallization.
4-Bromo-1-methyl-1H-indole (2b). Prepared according to GP 1 from 4-bromoindole (1a) and MeI,
and purified by CC (SiO2; cyclohexane/AcOEt 9 :1). Yield: 20.00 g (95%). Pale-yellow oil after bulb-to-
bulb distillation (958/3”10ꢀ3 mbar). 1H-NMR (200 MHz, CDCl3): 7.27 (d, J=7.6, 1 H); 7.26 (d, J=7.8, 1
H); 7.09 (d, J=3.2, 1 H); 7.07 (d, J=7.8, 1 H); 6.53 (d, J=3.2, 1 H); 3.79 (s, 3 H). HR-ESI-MS: 209.9916
([M+H]+, C9
N
N
4-Bromo-1-(2-methoxyethyl)-1H-indole (2c). Prepared according to GP 1 from 1a and 1-bromo-2-
methoxyethane, and purified by CC (SiO2; cyclohexane/AcOEt 4 :1). Yield: 24.13 g (95%). Pale-yellow
oil after bulb-to-bulb distillation (1808/8”10ꢀ3 mbar), solidifying upon standing at r.t. M.p. 388. 1H-NMR
(400 MHz, CDCl3): 7.30 (d, J=7.9, 1 H); 7.27 (d, J=7.9, 1 H); 7.21 (d, J=3.2, 1 H); 7.06 (dd, J=7.9, 1 H);
6.55 (dd, J=3.2, 0.6, 1 H); 4.27 (t, J=5.5, 2 H); 3.69 (t, J=5.5, 2 H); 3.30 (s, 3 H). HR-ESI-MS: 254.0170
([M+H]+, C21
A
G
N
Methyl (4-Bromo-1H-indol-1-yl)acetate (2d). Prepared according to GP 1 from 1a and methyl bro-
moacetate, and purified by CC (SiO2; cyclohexane/AcOEt 4 :1). Yield: 18.72 g (70%). Pale-yellow oil
1
after bulb-to-bulb distillation (1808/8”10ꢀ3 mbar). H-NMR (200 MHz, CDCl3): 7.30 (d, J=7.3, 1 H);
7.19 (d, J=7.8, 1 H); 7.13 (d, J=3.2, 1 H); 7.07 (dd, J=7.8, 7.3, 1 H); 6.62 (d, J=3.2, 1 H); 4.84 (s, 2
H); 3.74 (s, 3 H). HR-ESI-MS: 267.9974 ([M+H]+, C11
N
N
5-Bromo-1-methyl-1H-indole (2e). Prepared according to GP 1 from 1b and MeI, and purified by CC
(SiO2; cyclohexane/AcOEt 9 :1). Yield: 15.81 g (75%). Colorless solid. M.p. 418 (hexane) (lit. m.p.
42–438 [17]). 1H-NMR (200 MHz, CDCl3): 7.73 (d, J=1.8, 1 H); 7.29 (dd, J=8.7, 1.8, 1 H); 7.17 (d,
J=8.7, 1 H); 7.03 (d, J=3.1, 1 H); 6.41 (d, J=3.1, 1 H); 3.76 (s, 3 H). HR-ESI-MS: 209.9918
([M+H]+, C9
N
N
4-[(5-Bromo-1H-indol-1-yl)methyl]piperidine-1-carbaldehyde (2h). Prepared according to GP 1
from 1b and 8, and purified by CC (SiO2; AcOEt). Yield: 26.58 g (83%). Colorless solid. M.p. 88–898
(AcOEt/hexane). 1H-NMR (200 MHz, CDCl3): 7.99 (s, 1 H); 7.75 (d, J=2.0, 1 H); 7.29 (dd, J=8.8,
2.0, 1 H); 7.16 (d, J=8.8, 1 H); 7.03 (d, J=3.2, 1 H); 6.44 (d, J=3.2, 1 H); 4.44 (m, 1 H); 3.99 (m, 2
H); 3.60 (m, 1 H); 2.98 (m, 1 H); 2.54 (m, 1 H); 2.11 (m, 1 H); 1.60 (m, 2 H); 1.20 (m, 2 H). HR-ESI-
MS: 343.0417 ([M+Na]+, C15
A
G
N
6-Bromo-1-methyl-1H-indole (2i). Prepared according to GP 1 from 1c and MeI, and purified by CC
(SiO2; cyclohexane/AcOEt 9 :1). Yield: 19.88 g (95%). Pale-yellow oil after bulb-to-bulb distillation (908/
3”10–ꢀ3 mbar). 1H-NMR (200 MHz, CDCl3): 7.47 (d, J=8.3, 1 H); 7.46 (br. s, 1 H); 7.19 (dd, J=8.3, 1.6, 1
H); 7.01 (d, J=3.1, 1 H); 6.44 (d, J=3.1, 1 H); 3.75 (s, 3 H). HR-ESI-MS: 209.9920 ([M+H]+, C9
N
N
calc. 209.9913).
6-Bromo-1-(2-methoxyethyl)-1H-indole (2j). Prepared according to GP 1 from 1c and 1-bromo-2-
methoxyethane, and purified by CC (SiO2; cyclohexane/AcOEt 4 :1). Yield: 25.10 g (99%). Pale-yellow
oil after bulb-to-bulb distillation (1808/7”10ꢀ3 mbar), solidifying upon standing at r.t. M.p. 468. 1H-NMR
(400 MHz, CDCl3): 7.50 (s, 1 H); 7.47 (d, J=8.4, 1 H); 7.19 (d, J=8.4, 1 H); 7.13 (d, J=3.2, 1 H); 6.46 (d,
J=3.2, 1 H); 4.23 (t, J=5.5, 2 H); 3.68 (t, J=5.5, 2 H); 3.31 (s, 3 H). HR-ESI-MS: 254.0180 ([M+H]+,
C
N
G
moacetate, and purified by CC (SiO2; cyclohexane/AcOEt 4 :1). Yield: 19.05 g (71%). Pale-yellow oil
1
after bulb-to-bulb distillation (1808/4”10ꢀ2 mbar), solidifying upon standing at r.t. M.p. 758. H-NMR
(200 MHz, CDCl3): 7.48 (d, J=8.3, 1 H); 7.40 (s, 1 H); 7.24 (dd, J=8.3, 1.7, 1 H); 7.05 (d, J=3.2, 1
H); 6.53 (d, J=3.2, 1 H); 4.81 (s, 2 H); 3.76 (s, 3 H). HR-ESI-MS: 267.9958 ([M+H]+, C11
N
N
calc. 267.9968).
7-Bromo-1-methyl-1H-indole (2l). Prepared according to GP 1 from 1d and MeI, and purified by CC
(SiO2; cyclohexane/AcOEt 9 :1). Yield: 16.65 g (79%). Colorless solid. M.p. 528 (hexane). 1H-NMR (200
MHz, CDCl3): 7.52 (dd, J=7.7, 0.9, 1 H); 7.33 (dd, J=7.7, 0.9, 1 H); 6.97 (d, J=3.1, 1 H); 6.89 (dd, J=7.7,
1 H); 6.44 (d, J=3.1, 1 H); 4.14 (s, 3 H). HR-ESI-MS: 209.9915 ([M+H]+, C9
N
G
2-(5-Bromo-1H-indol-1-yl)ethyl Methanesulfonate (6). Et(i-Pr)2
ACHTREUNG
(dimethylamino)pyridine (DMAP; 0.90 g, 7.38 mmol) was added to a soln. of 5 [23] (17.72 g, 73.81
mmol) in anh. CH2Cl2 (270 ml). The stirred mixture was cooled to 08, and a soln. of MsCl (10.14 g,

Helvetica Chimica Acta – Vol. 89 (2006)
943
88.56 mmol) in anh. CH2Cl2 (100 ml) was added dropwise at a rate to keep the temp. below 158. After
complete addition, stirring was continued for 1 h at r.t. The mixture was washed with H2O (100 ml),
dried (MgSO4), and filtered through a short pad of neutral alumina (rinsing with several portions of
CH2C2). The crude product was purified by CC (SiO2; cyclohexane/AcOEt 1:1), and crystallized from
AcOEt/hexane to yield 22.48 g (96%) of 6. Colorless solid. M.p. 648. 1H-NMR (200 MHz, CDCl3):
7.76 (d, J=1.7, 1 H); 7.33 (dd, J=8.8, 1.7, 1 H); 7.22 (d, J=8.8, 1 H); 7.14 (d, J=3.2, 1 H); 6.48 (d,
J=3.2, 1 H); 4.47 (m, 4 H); 2.66 (s, 3 H). HR-ESI-MS: 317.9795 ([M+H]+, C11
317.9794).
A
G
N
General Procedure (GP 2) for the Reaction of 6 with Secondary Amines. Six pressure vials, each
equipped with a stirring bar, were charged with equal parts of a soln. of 6 (15.91 g; 50.0 mmol) and
the appropriate amine (250.0 mmol) in THF (50 ml). The vials were capped, and heated in a single-
mode microwave oven at 1408 for 30 min. The mixtures were pooled, and concentrated in vacuo. The res-
idue was partitioned between AcOEt (250 ml) and H2O (100 ml). The org. layer was washed with brine
(100 ml), dried (MgSO4), and filtered through a short pad of neutral alumina (rinsing with several por-
tions of AcOEt). The crude products were further purified by bulb-to-bulb distillation.
2-(5-Bromo-1H-indol-1-yl)-N,N-dimethylethanamine (2f). Prepared according to GP 2 from 6 and
an 11M aq. Me2NH soln. Yield: 12.25 g (92%). Colorless oil after bulb-to-bulb distillation (1608/
A
1
3”10ꢀ2 mbar). H-NMR (200 MHz, CDCl3): 7.74 (d, J=1.7, 1 H); 7.28 (dd, J=8.8, 1.7, 1 H); 7.20 (d,
J=8.8, 1 H); 7.14 (d, J=3.2, 1 H); 6.42 (d, J=3.2, 1 H); 4.20 (t, J=7.1, 2 H); 2.68 (t, J=7.1, 2 H); 2.28
(s, 6 H). HR-ESI-MS: 267.0496 ([M+H]+, C12
N
N
5-Bromo-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indole (2g). Prepared according to GP 2 from 6
and 1-methylpiperazine. Yield: 15.05 g (93%). Pale-yellow oil after bulb-to-bulb distillation (1958/
1
3”10ꢀ2 mbar), solidifying upon standing at r.t. M.p. 628. H-NMR (200 MHz, CDCl3): 7.73 (d, J=2.0,
1 H); 7.28 (dd, J=8.8, 2.0, 1 H); 7.21 (d, J=8.8, 1 H); 7.14 (d, J=3.2, 1 H); 6.41 (d, J=3.2, 1 H); 4.20
(t, J=6.9, 2 H); 2.73 (t, J=6.9, 2 H); 2.48 (m, 8 H); 2.28 (s, 3 H). HR-ESI-MS: 322.0911 ([M+H]+,
C
N
G
[Pd(OAc)2] (9 mg, 0.040 mmol) and an the appropriate ligand (0.088 mmol) under Ar atmosphere.
(Alternatively, the tube was charged with 0.04 mmol of a Pd0 catalyst.) The tube was evaporated,
back-filled with Ar, and treated with 1,4-dioxane (5.0 ml) via syringe. After stirring for 30 min at r.t.,
Et3N (6.0 mmol) was added via syringe, followed by a soln. of 2a (705 mg, 2.0 mmol) in anh. 1,4-dioxane
N
(5.0 ml). Then, neat pinBH (307 mg, 2.4 mmol) was added, and the mixture was stirred at 808 (HPLC,
Condition 2). The rel. amounts of 2a, 3a, and 4 were determined from UV traces at 230 nm (see
Table). The rel. response rates were calculated from repeated injections of samples containing equimolar
amounts of 2a, 3a, and 4.
General Procedure (GP 3) for the Borylation of Bromoindoles. An Ar-filled Schlenk flask equipped
with a magnetic stirring bar was charged with [Pd(OAc)2] (0.056 g, 0.25 mmol) and ligand L-3 (0.193 g,
0.55 mmol). The flask was evaporated, back-filled with Ar, and anh. 1,4-dioxane (50 ml) was added.
After stirring for 30 min at r.t., Et3N (7.59 g, 75.0 mmol) was added via syringe, followed by a soln. of
G
the appropriate bromoindole (25.0 mmol) in anh. 1,4-dioxane (50 ml). Neat pinBH (3.83 g, 30.0 mmol,
1.2 equiv)4) was added, and the mixture was stirred at 808 (LC/MS; Condition 1). After complete con-
sumption of the starting material (2–8 h), the mixture was allowed to cool to r.t. Celite (1 g) and activated
charcoal (1 g) were added, and stirring was continued for 15 min. After suction filtration, the solvent was
removed in vacuo. The residue was diluted with cyclohexane (or AcOEt in the case of 3f–h), and filtered
through a short pad of neutral alumina (rinsing with several portions of cyclohexane (or AcOEt)). The
crude product was purified by CC, followed by bulb-to-bulb distillation or crystallization.
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[tris(1-methylethyl)silyl]-1H-indole (3a) and 1-
[Tris(1-methylethyl)silyl]-1H-indole (4). Prepared according to GP 3 from 2a, and purified by CC
(SiO2; hexane).
4
)
For 2h, 4.80 g (37.5 mmol, 1.5 equiv.) of pinBH were used.

944
Helvetica Chimica Acta – Vol. 89 (2006)
Data of 3a (slower eluting). Yield: 8.20 g (82%). Colorless oil after bulb-to-bulb distillation (1958/
1
8”10ꢀ3 mbar), solidifying upon standing at r.t. M.p. 1078. H-NMR (200 MHz, CDCl3): 8.15 (s, 1 H);
7.59 (d, J=8.4, 1 H); 7.49 (d, J=8.4, 1 H); 7.23 (d, J=3.3, 1 H); 6.63 (d, J=3.3, 1 H); 1.70 (sept.,
J=7.5, 3 H); 1.35 (s, 12 H); 1.13 (d, J=7.5, 18 H). HR-ESI-MS: 400.2841 ([M+H]+, C23
A
G
N
calc. 400.2838).
Data of 4 (faster eluting). See [19]. Yield: 0.40 g (6%). Colorless oil.
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (3b). Prepared according to GP 3
from 2b, and purified by CC (SiO2; cyclohexane/AcOEt 9 :1). Yield: 5.10 g (79%). Colorless solid.
1
M.p. 938 (hexane). H-NMR (200 MHz, CDCl3): 7.62 (d, J=6.9, 1 H); 7.42 (d, J=8.2, 1 H); 7.22 (dd,
J=8.2, 6.9, 1 H); 7.09 (d, J=3.1, 1 H); 6.97 (d, J=3.1, 1 H); 3.79 (s, 3 H); 1.38 (s, 12 H). HR-ESI-MS:
280.1477 ([M+Na]+, C15
N
N
1-(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (3c). Prepared accord-
ing to GP 3 from 2c, and purified by CC (SiO2; cyclohexane/AcOEt 3 :1). Yield: 5.19 g (69%). Colorless
solid. M.p. 1008 (tBuOMe/hexane). 1H-NMR (200 MHz, CDCl3): 7.61 (d, J=7.1, 1 H); 7.45 (d, J=8.3, 1
H); 7.21 (m, 2 H); 6.99 (d, J=3.2, 1 H); 4.29 (t, J=5.6, 2 H); 3.68 (t, J=5.6, 2 H); 3.28 (s, 3 H); 1.38 (s, 12
H). HR-ESI-MS: 302.1920 ([M+H]+, C17
N
N
Methyl [4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl]acetate (3d). Prepared
according to GP 3 from 2d, and purified by CC (SiO2; cyclohexane/AcOEt 3 :1). Yield: 6.22 g (79%).
1
Colorless solid. M.p. 818 (hexane). H-NMR (200 MHz, CDCl3): 7.64 (d, J=6.9, 1 H); 7.35 (d, J=8.1,
1 H); 7.22 (dd, J=8.1, 6.9, 1 H); 7.13 (d, J=3.2, 1 H); 7.06 (d, J=3.2, 1 H); 4.86 (s, 2 H); 3.71 (s, 3 H),
1.38 (s, 12 H). HR-ESI-MS: 316.1709 ([M+H]+, C17
N
N
1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (3e). Prepared according to GP 3
from 2e, and purified by CC (SiO2; cyclohexane/AcOEt 9 :1). Yield: 5.05 g (78%). Colorless solid.
1
M.p. 1128 (hexane). H-NMR (200 MHz, CDCl3): 8.15 (s, 1 H); 7.66 (d, J=8.3, 1 H); 7.31 (d, J=8.3, 1
H); 7.03 (d, J=3.1, 1 H); 6.49 (d, J=3.1, 1 H); 3.78 (s, 3 H); 1.36 (s, 12 H). HR-ESI-MS: 258.1656
([M+H]+, C15
N
N
N,N-Dimethyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl]ethanamine
(3f).
Prepared according to GP 3 from 2f, and purified by bulb-to-bulb distillation (1858/8”10ꢀ3 mbar). Col-
orless oil. Yield: 6.62 g (84%). 1H-NMR (200 MHz, CDCl3): 8.15 (s, 1 H); 7.65 (d, J=8.3, 1 H); 7.34 (d,
J=8.3, 1 H); 7.12 (d, J=3.2, 1 H); 6.50 (d, J=3.2, 1 H); 4.23 (t, J=7.1, 2 H); 2.68 (t, J=7.1, 2 H); 2.28 (s, 6
H); 1.36 (s, 12 H). HR-ESI-MS: 315.2248 ([M+H]+, C18
H28
G
E
1-[2-(4-Methylpiperazin-1-yl)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (3g).
Prepared according to GP 3 from 2g. Yield: 6.97 g (75%). Colorless solid. M.p. 1158 (SiO2; tBuOMe/hex-
1
ane). H-NMR (200 MHz, CDCl3): 8.15 (s, 1 H); 7.65 (d, J=8.3, 1 H); 7.34 (d, J=8.3, 1 H); 7.13 (d,
J=3.2, 1 H); 6.50 (d, J=3.2, 1 H); 4.24 (t, J=7.1, 2 H); 2.75 (t, J=7.1, 2 H); 2.49 (m, 8 H); 2.29 (s, 3
H); 1.36 (s, 12 H). HR-ESI-MS: 370.2642 ([M+H]+, C21
A
G
N
4-{[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl]methyl}piperidine-1-carbaldehyde
(3h). Prepared according to GP 3 from 2h, and purified by CC (SiO2; AcOEt). Yield: 7.16 g (78%). Col-
1
orless solid. M.p. 151–1528 (AcOEt/hexane). H-NMR (200 MHz, CDCl3): 8.17 (s, 1 H); 7.99 (s, 1 H);
7.66 (dd, J=8.3, 1.0, 1 H); 7.30 (d, J=8.3, 1 H); 7.02 (d, J=3.2, 1 H); 6.52 (d, J=3.2, 1 H); 4.42 (m, 1
H); 4.02 (m, 2 H); 3.58 (m, 1 H); 2.96 (m, 1 H); 2.53 (m, 1 H); 2.13 (m, 1 H); 1.60 (m, 2 H); 1.36 (s, 12
H); 1.19 (m, 2 H). HR-ESI-MS: 369.2352 ([M+H]+, C21
A
G
N
1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (3i). Prepared according to GP 3
from 2i, and purified by CC (SiO2; cyclohexane/AcOEt 9 :1). Yield: 4.64 g (72%). Colorless solid. M.p.
988 (hexane). 1H-NMR (200 MHz, CDCl3): 7.83 (s, 1 H); 7.62 (d, J=8.0, 1 H); 7.54 (d, J=8.0, 1 H); 7.10
(d, J=3.1, 1 H); 6.47 (d, J=3.1, 1 H); 3.83 (s, 3 H); 1.38 (s, 12 H). HR-ESI-MS: 258.1664 ([M+H]+,
C
N
G
ing to GP 3 from 2j, and purified by CC (SiO2; cyclohexane/AcOEt 3 :1). Yield: 5.95 g (79%). Colorless
solid. M.p. 718 (tBuOMe/hexane). 1H-NMR (200 MHz, CDCl3): 7.83 (s, 1 H); 7.63 (d, J=7.9, 1 H); 7.54
(d, J=7.9, 1 H); 7.23 (d, J=3.1, 1 H); 6.48 (d, J=3.1, 1 H); 4.33 (t, J=5.6, 2 H); 3.70 (t, J=5.6, 2 H); 3.30
(s, 3 H); 1.37 (s, 12 H). HR-ESI-MS: 302.1894 ([M+H]+, C17
N
N

Helvetica Chimica Acta – Vol. 89 (2006)
945
Methyl [6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl]acetate (3k). Prepared
according to GP 3 from 2k, and purified by CC (SiO2; cyclohexane/AcOEt 3 :1). Yield: 6.13 g (77%).
1
Colorless solid. M.p. 988 (tBuOMe/hexane). H-NMR (200 MHz, CDCl3): 7.74 (s, 1 H); 7.64 (d, J=7.9,
1 H); 7.57 (d, J=7.9, 1 H); 7.14 (d, J=3.2, 1 H); 6.57 (dd, J=3.2, 0.8, 1 H); 4.92 (s, 2 H); 3.74 (s, 3 H);
1.37 (s, 12 H). HR-ESI-MS: 316.1703 ([M+H]+, C17
N
N
1-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (3l). Prepared according to GP 3
from 2l, and purified by CC (SiO2; cyclohexane/AcOEt 9 :1). Yield: 4.79 g (74 %). Colorless solid. M.p.
958 (hexane). 1H-NMR (200 MHz, CDCl3): 7.71 (dd, J=7.5, 1.1, 1 H); 7.66 (dd, J=7.5, 1.1, 1 H); 7.09 (dd,
J=7.5, 1 H); 7.01 (d, J=3.2, 1 H); 6.48 (d, J=3.2, 1 H); 3.97 (s, 3 H); 1.39 (s, 12 H). HR-ESI-MS:
258.1652 ([M+H]+, C15
N
N
REFERENCES
[1] ꢂBoronic Acids: Preparation and Applications in Organic Synthesis and Medicineꢁ, Ed. D. G. Hall,
Wiley-VCH, Weinheim, 2005.
[2] E. Tyrrell, P. Brookes, Synthesis 2004, 469.
[3] ꢂHandbook of Organopalladium Chemistry for Organic Synthesisꢁ, Eds. E. Negishi, A. de Meijere,
Wiley-Interscience, New York, 2002.
[4] ꢂMetal-Catalyzed Cross-Coupling Reactionsꢁ, Eds. F. Diederich, P. J. Stang, Wiley-VCH, Weinheim,
1998.
[5] X. Cai, V. Snieckus, Org. Lett. 2004, 6, 2293; A. Nishida, N. Miyashita, M. Fuwa, M. Nakagawa, Het-
erocycles 2003, 59, 473; C. G. Yang, G. Lui, B. Jiang, J. Org. Chem. 2002, 53, 9392; E. Vazquez, I. W.
Davies, J. F. Payack, J. Org. Chem. 2002, 67, 7551; K.-H. Doll, J. Org. Chem. 1999, 64, 1372; C. N.
Johnson, G. Stemp, N. Anand, S. C. Stephen, T. Gallagher, Synlett 1998, 1025; R. S. Hoerner, D.
Askin, R. P. Volante, P. J. Reider, Tetrahedron Lett. 1998, 39, 3455; I. Kawasaki, M. Yamashita,
S. Ohta, Chem. Pharm. Bull. 1996, 44, 1831.
[6] J. Takagi, K. Sato, J. F. Hartwig, T. Ishiyama, N. Miyaura, Tetrahedron Lett. 2002, 43, 5649.
[7] T. Tagata, M. Nishida, Adv. Synth. Catal. 2004, 346, 1655.
[8] K. Mertins, A. Zapf, M. Beller, J. Mol. Catal., A 2004, 207, 21.
[9] T. Ishiyama, J. Takagi, J. F. Hartwig, N. Miyaura, Angew. Chem., Int. Ed. 2002, 41, 3056.
[10] T. Ishiyama, Y. Nobuta, J. F. Hartwig, N. Miyaura, Chem. Commun. 2003, 2924.
[11] T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995, 60, 7508.
[12] T. Fryatt, H. I. Pettersson, W. T. Gardipee, K. C. Bray, S. J. Green, A. M. Z. Slawin, H. D. Beall, C. J.
Moody, Bioorg. Med. Chem. 2004, 12, 1667.
[13] K. C. Nicolaou, J. Hao, M. V. Reddy, P. B. Rao, G. Rassias, S. A. Snyder, X. Huang, D. Y.-K. Chen,
W. E. Brenzovich, N. Guiseppone, P. Giannakakou, A. OꢁBrate, J. Am. Chem. Soc. 2004, 126, 12897.
[14] K. C. Nicolaou, P. B. Rao, J. Hao, M. V. Reddy, G. Rassias, X. Huang, D. Y.-K. Chen, S. A. Snyder,
Angew. Chem., Int. Ed. 2003, 42, 1753.
[15] P. Appukkuttan, E. Van der Eycken, W. Dehaen, Synlett 2003, 1204.
[16] T. Ishiyama, K. Ishida, N. Miyaura, Tetrahedron 2001, 57, 9813.
[17] M. Prieto, E. Zurita. E. Rosa, L. Munoz, P. Lloyd-Williams, E. Giralt, J. Org. Chem. 2004, 69, 6812.
[18] R. M. Soll, J. A. Parks, T. J. Rimele, R. J. Haeslip, A. Wojdan, G. Oshiro, D. Grimes, A. Asselin, Eur.
J. Med. Chem. 1990, 25, 191.
[19] P. J. Beswick, C. S. Greenwood, T. J. Mowlem, G. Nechwatal, D. A. Widdowson, Tetrahedron 1988,
44, 7325.
[20] H. Ohno, K. Miyamura, T. Mizutani, Y. Kadoh, Y. Takeoka, H. Hamaguchi, T. Tanaka, Chem.–Eur.
J. 2005, 11, 3728.
[21] J. Baudoux, A. J. Blake, N. S. Simkins, Org. Lett. 2005, 7, 4087.
[22] M. Isaac, M. Slassi, T. Xin, J. Arora, A. OꢁBrian, L. Edwards, N. MacLean, J. Wilson, L. Demschy-
shin, P. Labrie, A. Naismith, S. Maddaford, D. Papac, S. Harrison, H. Wang, S. Draper, A. Tehim,
Bioorg. Med. Chem. Lett. 2003, 13, 4409.
[23] K. M. Jos Brands, U.-H. Dolling, R. B. Jobson, G. Marchesini, R. A. Reamer, J. M. Williams, J. Org.
Chem. 1998, 63, 6721.

946
Helvetica Chimica Acta – Vol. 89 (2006)
[24] M. Murata, T. Oyama, S. Watanabe, Y. Masuda, J. Org. Chem. 2000, 65, 164.
[25] M. Murata, S. Watanabe, Y. Masuda, J. Org. Chem. 1997, 62, 6458.
[26] A. Fürstner, G. Seidel, Org. Lett. 2002, 4, 541.
[27] T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 4685; J. E.
Mine, S. L. Buchwald, J. Am. Chem. Soc. 2004, 126, 13028; H. N. Nguyen, X. Huang, S. L. Buch-
wald, J. Am. Chem. Soc. 2003, 125, 11818; J. P. Wolfe, R. A. Singer, B. H. Yang, S. L. Buchwald,
J. Am. Chem. Soc. 1999, 121, 9550; D. W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc.
1988, 120, 9722.
[28] C. Christophersen, M. Bergtrup, S. Ebdrup, H. Petersen, P. Vedsø, J. Org. Chem. 2003, 68, 9513.
[29] O. Baudoin, D. Guꢃnard, F. Guꢃritte, J. Org. Chem. 2000, 65, 9268.
Received January 20, 2006