Palladium-catalyzed benzylation of N-Boc indole boronic acids

Article abstract of DOI:10.1016/j.tetlet.2010.02.124

The direct benzylation of indole 2-boronic acid can be efficiently achieved using trans-PdBr(N-Succ)(PPh₃)₂, alleviating the need for strong bases or toxic organotin reagents. Under these reaction conditions substituted indole-2-boro

Full text of DOI:10.1016/j.tetlet.2010.02.124

Tetrahedron Letters 51 (2010) 2281–2283
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Tetrahedron Letters
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Palladium-catalyzed benzylation of N-Boc indole boronic acids
*
Aaron M. Kearney , Adrienne Landry-Bayle , Laurent Gomez
Johnson & Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, California 92121, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct benzylation of indole 2-boronic acid can be efficiently achieved using trans-PdBr-
(N-Succ)(PPh3)2, alleviating the need for strong bases or toxic organotin reagents. Under these reaction
conditions substituted indole-2-boronic acids and substituted benzyl bromides are cross-coupled to
afford aryl(indolo)methanes in good yield.
Received 22 January 2010
Revised 17 February 2010
Accepted 19 February 2010
Available online 24 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Carbon–carbon bond-forming processes catalyzed by palladium
species are widely known and applied in organic chemistry.1 One
of the particular utilities is the broadly used and very efficient Su-
zuki cross-coupling of aryl and heteroaryl boronic acids with aryl
bromides or chlorides.2 A number of catalyst systems have been
developed in the laboratories of Buchwald,3 Fu,4 Kuwano,5 and
Taylor.6 However, the cross-coupling of N-heterocyclic 2-boronic
acids still remains a problem. The main issue with this type of
cross-coupling is the reduction of the boronic acid moiety in a pro-
cess known as protodeboronation.7
More specifically, the use of indole-2-boronic acids in Suzuki
cross-coupling reactions in combination with activated benzyl
groups has not been described in the literature. To accomplish
the desired transformation, two alternative methods have been
developed. The first involves the deprotonation of the 2-position
using lithium diisopropylamide and subsequent quenching with
the desired benzyl bromide.8 The downside of this route is the nec-
essary use of a strong base, which significantly decreases func-
tional group compatibility. The second approach requires the
synthesis of the aryl tin species through the same deprotonation
sequence as described above, followed by palladium-catalyzed
Stille cross-coupling reaction with benzyl bromides.9 The toxicity
associated with organotin species motivated us to investigate an
alternative method.
lyst system and potassium carbonate as a base (entry 5). While
this catalyst system generated the desired product 1a, an equal
amount of protodeboronated product 2 was also observed. Similar
results were observed when Pd(PPh3)4 was employed (entry 6). In
continuing to profile other palladium(II) catalysts, we investigated
trans-PdBr(N-Succ)(PPh3)2 in combination with aqueous Na2CO3
and, to our delight, a 4:1 ratio of cross-coupling product 1a to
the byproduct 2 was obtained (Table 1, entry 7). In an attempt to
better understand the rate of the reaction as well as other factors
associated with the protodeboronation event, a kinetic study was
conducted.
This investigation was conducted on 6-cyanoindole-2-boronic
acid in THF at 60 °C. In order to determine the potential role of
trans-PdBr(N-Succ)(PPh3)2 in the protodeboronation, the reactions
were run with or without the catalyst. In addition, the concentra-
tion of aqueous sodium carbonate was varied. The results of this
investigation are summarized in Table 2.
Initial experiments revealed that the rate of protodeboronation
was not significantly affected by the presence of the catalyst, as
both reactions led to similar ratios after 15 min (Table 2, entries
1 and 2). Furthermore, varying the concentration of base had no
influence on the formation of 2 (Table 2, entries 1 and 4). The re-
sults from the kinetic study indicated that the protodeboronation
event is fast with about 30% of 2 after only 5 min (Table 2, entries
3 and 5) and almost complete degradation of the starting material
1a after 30 min (Table 2, entry 6).
From the brief study of several readily available palladium cat-
alysts and with the knowledge on the stability of the starting mate-
rial under the reaction conditions, we established that trans-
PdBr(N-Succ)(PPh3)2 was the most effective catalyst. This palla-
dium source is able to efficiently catalyze the carbon–carbon bond
formation at a rate that competes with the protodeboronation
pathway.
In our initial experiments, different palladium catalysts and
pre-catalysts were screened for the formation of the desired cou-
pling product between 6-cyano-indole 2-boronic acid 1 and 3-flu-
orobenzyl bromide 2. The results of these reactions are
summarized in Table 1.
After screening both palladium(0) and palladium(II) species
with different phosphine (mono- and bidentate) and arsine li-
gands, the first successful reaction was accomplished using an
allylpalladium chloride dimer diphenylphosphino-pentane cata-
The scope of the palladium-catalyzed benzylation reaction was
explored by using 5% of palladium, 2 M Na2CO3 in THF at 60 °C for
1 h. A series of commercially available indole-2-boronic acids were
reacted with a variety of substituted benzyl bromides.10 The
* Corresponding author.
E-mail address: lgomez4@prdus.jnj.com (L. Gomez).
Formerly at J&J PRD.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.124

2282
A. M. Kearney et al. / Tetrahedron Letters 51 (2010) 2281–2283
Table 1
Examples of catalysts screened for the palladium-catalyzed cross-coupling of indole 2-boronic acids and benzyl bromides
F
F
OH
OH
Br
B
+
[Pd ](1 - 5%)
N
N
N
NC
NC
NC
Boc
ligand, additive
solvent
Boc
Boc
1
1a
2
Entry
Catalyst
Ligand
Additive
Solvent
T (°C)
t (h)
1a:2a
1
2
3
4
5
6
7
Pd(OAc)2
PPh3
PCy3
AsPh3
DPPPent
DPPPent
K3PO4
K3PO4
Ag2O
Na2CO3
K2CO3
Dioxane
Dioxane
Dioxane
THF
DMF
Dioxane/H2O
THF
80
100
80
60
60
12
18
12
0.5
3
NDb
Pd2(dba)3
PdCI2(MeCN)2
Pd(dba)2
0:100
NDb
0:100
50:50
60:40
80:20
[Pd(
g
3-C3H5)Cl]2
Pd(PPh3)4
trans-PdBr(Succ)(PPh3)2
—
—
K3PO4
2 M Na2CO3
90
60
3
2
a
% Conversion by HPLC.
Uncharacterized byproducts.
b
coupling partners, further expanding the toleration of base-sensi-
tive functionality. An aryl bromide moiety was introduced in an at-
tempt to invoke cross reactivity within the palladium catalytic
cycle. Interestingly, the reaction appears to be highly selective for
reaction with a benzyl bromide rather than an aryl bromide (Table
3, entries 1c and 1d). The position of the benzyl group was verified
via 2-D NMR NOESY experiments. It should be noted that the reac-
Table 2
Kinetic study on the effects of catalyst and base present on protodeboronation side
reaction
OH
OH
OH
OH
[Pd] (5 mol%)
B
B
+
N
N
N
additive
NC
NC
NC
Boc
Boc
Boc
THF, 60 °C
1
1
2
Entry
Catalyst
NONE
trans-PdBr(N-Succ)(PPh3)2
NONE
Additive
t (min)
Ratio (1:2)a
tion of an indole-2-boronic acid with
typical reaction conditions afforded only the protodeboronation
product, suggesting that substitution at the -position impedes
a-bromoethylbenzene under
1
2
3
4
5
6
2 M Na2CO3
2 M Na2CO3
4 M Na2CO3
4 M Na2CO3
4 M Na2CO3
4 M Na2CO3
10
10
5
20
5
23:77
36:64
67:33
11:89
72:28
10:90
a
the catalytic cycle, permitting uncontrollable side reaction.
In summary, the Suzuki cross-coupling reaction of substituted
indole-2-boronic acids with substituted benzyl bromides has been
reported. This reaction eliminates the need for strong bases or
toxic reagents. Conditions that tolerate a variety of sensitive func-
tional groups and minimize protodeboronation were identified.
The benzylated indole products are formed in moderate to high
yields while retaining the N-Boc functionality, thus allowing for
further manipulation.
NONE
trans-PdBr(N-Succ)(PPh3)2
trans-PdBr(N-Succ)(PPh3)2
30
a
Ratio determined by HPLC (k = 254 nm).
results of these experiments are shown in Table 3. The transforma-
tion appears to be compatible with many functional groups; elec-
tron-donating as well as electron-withdrawing groups were
equally tolerated on both the indole and benzyl bromide reaction
partner. It should be noted that esters were also allowed, resulting
in clean conversion to the desired products (Table 3, entries 1g and
1j) without any hydrolysis. Ketones (Table 3, entry 1d) and silyl-
protected phenols (Table 3, entry 1i) were also used as successful
Acknowledgments
We thank Drs. Jake Wiener and Alice Lee-Dutra for their contri-
butions to the editing of this manuscript.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.124.
Table 3
The palladium-catalyzed cross-coupling of indole-2-boronic acids and benzyl
bromides
References and notes
Br
R2
R2
O
H
1. Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., de
Meijere, A., Eds.; Wiley-VCH: New York, 2004.
2. Tyrell, E.; Brookes, P. Synthesis 2004, 4, 469–483.
3. Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 4695–4698. and
references cited therein.
4. Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282–1284.
5. Kuwano, R.; Yokogi, M. Org. Lett. 2005, 7, 945–947.
6. (a) Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.; Kapdi, A. R.; Taylor, R. J. K.;
Whitwood, A. C. Tetrahedron 2005, 61, 9736–9751; (b) Fairlamb, I. J. S.; Kapdi,
A. R.; Lynam, J. M.; Taylor, R. J. K.; Whitwood, A. C. Tetrahedron 2004, 60, 5711–
5718.
7. Brown, R. D.; Buchanan, A. S.; Humffray, A. A. Aust. J. Chem. 1965, 18, 1521–
1525.
8. (a) Iwanowicz, E. J.; Lau, W. F.; Lin, J.; Roberts, D. G. M.; Seiler, S. M. Bioorg. Med.
Chem. Lett. 1996, 6, 1339–1344; (b) Beckers, T.; Baasner, S.; Klenner, T.;
Mahboobi, S.; Pongratz, H.; Frieser, M.; Hufsky, H.; Hockemeyer, J.; Fiebig, H.-
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B
R1
R1
trans-PdBr(N-Succ)(PPh3)2
N
N
1a-j
OH
Boc
Boc
2 M Na2CO3, THF
60 °C, 1 h
Entry
R1
H
R2
Yielda (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
6-CN
3-F
3-F
3-F
60
55
60
60
77
79
82
62
85
58
4-Br
4-Br
4-COMe
2-Me
4-OMe
H
7-OMe
7-OMe
6-CO2Me
6-CI
4-CF3
3-Cl
5-OTBS
6-OBn
1J
4-CO2Me
a
Isolated yield.

A. M. Kearney et al. / Tetrahedron Letters 51 (2010) 2281–2283
2283
9. (a) Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59, 4250–4252; (b) Farina, V.;
Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50.
10. General procedure for the benzylation of N-Boc-protected indoles. 6-Cyano-2-(3-
60 °C and allowed to stir for 1 h. Analytical methods (TLC, HPLC) showed
complete consumption of the starting boronic acid, the reaction was then
cooled to room temperature and diluted with water (10 mL). The resulting
solution was extracted with EtOAc (3 Â 20 mL), and the combined organic
layers were dried over anhydrous Na2SO4 and concentrated to afford the crude
product as an orange oil. The residue was purified by flash chromatography on
silica gel (EtOAc/hexanes) to afford the pure indole product as an oil (148 mg,
60%): 1H NMR (400 MHz, CDCl3) d 8.44 (s, 1H), 7.46 (dt, J = 8.1, 4.7, 2H), 7.33–
7.27 (m, 1H), 7.01–6.93 (m, 2H), 6.93–6.87 (m, 1H), 6.22 (s, 1H), 4.39 (s, 2H),
1.61 (s, 9H). HPLC Rf = 3.4 min, 92% purity. MS (ESI) mass calcd for
C21H19N2O2F, 350.39; m/z found, 351.0 [M+H]+.
fluoro-benzyl)-indole-1-carboxylic acid tert-butyl ester (1a): To
a 20 mL
scintillation vial containing stir bar was added 1-Boc-6-cyanoindole-2-
a
boronic acid (286 mg, 1 mmol) and trans-bromo(N-succinimidyl)-
bis(triphenylphosphine)palladium(II) (purchased from Aldrich Chemical Co.)
(40 mg, 0.05 mmol) followed by the addition of anhydrous THF (2.5 mL). Upon
dissolution, 3-fluorobenzyl bromide (122 lL, 1 mmol) was added as a single
portion via syringe. The pale orange reaction mixture was diluted with 2.0 M
Na2CO3 (1.25 mL) to form a biphasic reaction mixture that was warmed to