Synthesis of m-carboranyl amides via palladium-catalyzed carbonylation

Article abstract of DOI:10.1016/j.tetlet.2012.12.019

m-Carboranyl amides have been synthesized via the one-pot one-step carbonylation reaction of 1-I-m-carborane with primary and secondary amines in the presence of a palladium catalyst and under carbon monoxide atmosphere (Heck reaction). Different catalysts, ligands, bases, and experimental conditions have been evaluated and the results in terms of yield and formation of by-products are discussed.

Full text of DOI:10.1016/j.tetlet.2012.12.019

Tetrahedron Letters 54 (2013) 941–944
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Tetrahedron Letters
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Synthesis of m-carboranyl amides via palladium-catalyzed carbonylation
⇑
Kiran Babu Gona, Vanessa Gómez-Vallejo, Jordi Llop
Radiochemistry Department, CIC biomaGUNE, Paseo Miramón 182, San Sebastián 20009, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
m-Carboranyl amides have been synthesized via the one-pot one-step carbonylation reaction of 1-I-m-
carborane with primary and secondary amines in the presence of a palladium catalyst and under carbon
monoxide atmosphere (Heck reaction). Different catalysts, ligands, bases, and experimental conditions
have been evaluated and the results in terms of yield and formation of by-products are discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 4 October 2012
Revised 5 December 2012
Accepted 7 December 2012
Available online 19 December 2012
Keywords:
Carbonylation
Carborane
Carbon monoxide
Carboranyl amide
Palladium
Dicarba-closo-dodecaboranes, generally referred as carboranes,
are polyhedral clusters of boron, carbon, and hydrogen atoms with
unique physico-chemical properties. Their rich derivative chemis-
try makes carborane clusters, and particularly dicarba-closo-dodec-
aboranes, suitable building blocks with application for the
preparation of macro-molecular and supramolecular entities,1
nonlinear optics,2 catalysis,3 and medicinal chemistry, particularly
in the context of BNCT,4 as hydrophobic pharmacophores of bioac-
tive molecules5 or as additives in bone cements.6
Carboranes exist as ortho, meta, and para isomers (o-, m-, and p-
carborane, respectively). Independently of their isomeric form, car-
boranes can be attached to other molecules either via their carbon
or boron atoms. Up to date, functionalization of carboranes at the
carbon position has been extensively studied7 and because of its
difficulty, the production of monosubstituted carboranes is espe-
cially interesting.8 One of the commonly used alternatives for the
functionalization of carboranes consists in the formation of car-
boxyl-substituted carboranes via reactions of C-lithio or C-MgBr
derivatives with CO2 followed by acidification.9 The carboxylic
acids can be further converted into the corresponding acid chlo-
rides10 which in turn can combine with alcohols or amines to form
esters11 or amides,12 respectively.
as a catalyst, have not been assayed to date for the preparation of
carborane derivatives substituted either at the carbon or boron
positions. Such strategy might be anticipated to be suitable for
the preparation of carborane derivatives due to the three-dimen-
sional delocalization of skeletal electrons which derive in a
three-dimensional aromaticity, as supported by different theoreti-
cal investigations.14
Recently, we have synthesized and characterized different
raclopride (a D2 receptor antagonist) analogues incorporating o-
and m-carborane in their structures.5c Although these carboranyl
amides could be successfully synthesized and isolated, the 3 step
synthetic strategy (Scheme 1) offered moderate yields while labo-
rious work up was required at each step.
In the current Letter, a method for the palladium catalyzed
carbonylation of 1-iodo-1,7-dicarba-closo-dodecaborane (5) for
the one-pot one-step formation of amides is presented for the first
time. The reported reaction, employed herein for the preparation of
amides, might be used as well for the preparation of other car-
boxyl-substituted carboranes and could be potentially extended
also to the preparation of o- and p-carboranyl derivatives. Interest-
ingly, the reaction conditions might be also easily translated into
the radiochemistry field, where radiosynthetic routes for the prep-
aration of 11C-labeled radiotracers starting from the radioactive
precursor [11C]CO have been developed so far.15 Thus, the biologi-
cal activity of the resulting radiotracers could be assessed in vivo
by using positron emission tomography (PET) a non-invasive, ul-
tra-sensitive molecular imaging technique.
Surprisingly, other strategies for the preparation of amides like
the Heck carbonylation reaction,13 which is a powerful method for
the synthesis of secondary and tertiary amides by reaction of aryl
bromides and vinyl iodides with primary or secondary amines un-
der CO atmosphere in the presence of a palladium complex acting
The scheme of the reaction used for the synthesis of carboranyl
amides via the Heck carbonylation reaction is shown in Scheme 2.
In first instance, we investigated the carbonylation reaction of 5
⇑
Corresponding author. Tel.: +34 943 005 300; fax: +34 943 005 301.
E-mail address: jllop@cicbiomagune.es (J. Llop).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.019

942
K. B. Gona et al. / Tetrahedron Letters 54 (2013) 941–944
Scheme 1. Synthesis of 1,7-dicarba-closo-dodecaboran-1-yl-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}amide (1). Reagents and conditions: (a) n-BuLi, ether, CO2, then H2O; (b)
PCl5, distillation; (c) (S)-(ꢁ)-2-aminomethyl-1-ethylpyrrolidine.
Scheme 2. Aminocarbonylation reaction of 1-iodo-1,7-dicarba-closo-dodecaborane with primary and secondary amines to yield the corresponding amides.
(synthesized following a previously reported method16 with minor
modifications, see Supplementary data for details) with [(2R)-1-
ethyl-2-pyrrolidinyl]methanamine to yield 1. In order to assess
the effects of the catalyst, the ligand, and the base in the carbonyl-
ation reaction, a set of runs was carried out using different cata-
lysts (Pd2(dba)3, Pd(OAc)2, PdCl2, PdCl2(PPh3)2, and Pd(PPh3)4),
ligands (BINAP, DPPE, DPPF, TPP, Xantphos, and 2,20-bipyridine)
and bases (K2CO3, triethylamine, KtOBu, and K3PO4) in a carbon
monoxide atmosphere at 2 bar.17
First screening experiments were performed to choose the most
appropriate catalyst. BINAP, a bidentate ligand with a bite angle of
90–91°, was used as a ligand and K3PO4 was used as a base. The
formation of 1 could not be detected after 2 h of reaction when
Pd2(dba)3, Pd(OAc)2, and PdCl2 were used. Interestingly, formation
of the desired product could be observed when PdCl2(PPh3)2 and
Pd(PPh3)4 were used, with chemical conversions of 10.5% and
15.3%, respectively (Table 1, entries 1 and 2). Thus, all subsequent
reactions were performed with Pd(PPh3)4. To assess the effect of
the base, different experiments were performed using Pd(PPh3)4/
BINAP as catalyst/ligand. The addition of K2CO3 and triethylamine
led to moderately lower chemical conversions when compared to
K3PO4 (Table 1, entries 3 and 4), while the use of KtOBu decreased
the reaction rate with respect to K3PO4 by a factor of ꢀ30 (entry 5).
To assess the effect of the ligand, the reaction was repeated
using DPPF, DPPE, Xantphos, and bipyridine. All combinations led
to lower conversion values than those obtained with BINAP (Ta-
ble 1, entries 2 and 6–9).
The effect of the catalyst and ligand concentrations was also
investigated by using Pd(PPh3)4/BINAP at different molar ratios
with respect to compound 5. As can be seen in Table 1 (entries 2,
10 and 11) higher amounts of catalyst and ligand offered signifi-
cantly lower chemical conversion values.
The substitution of the iodine atom by bromine in the starting
m-carborane (6) in Table 1 did not lead to improved results (0.7%
conversion after 2 h reaction, entry 12) while no desired compound
could be detected when 1-trifluoromethanesulfonyl-1,7-dicarba-
closo-dodecaborane (7) in Table 1 was used as the starting material
(entry 13).
The kinetic profile of the reaction was monitored by GC–MS
under optimized conditions, that is, using Pd(PPh3)4/BINAP/
K3PO4. The reaction proceeded fast during the first 2 h (chemical
conversions of 8.5% and 15.3% after 1 and 2 h, entries 16 and 2,
respectively). However, at longer times the reaction rate signifi-
cantly decreased until a plateau was reached at conversions
ꢀ25% (entries 18 and 19). Significant amounts of m-carborane
could be detected in the chromatograms of the corresponding
reaction crudes, suggesting the de-iodination of 5. In parallel,
increasing amounts of the undesired symmetrical urea were ob-
served while increasing the reaction time. The relative formation
rate of the urea with respect to the desired amide decreased
when the CO pressure was decreased to 1 bar, and increased
when the pressure was increased to 10 bar, although chemical
conversion for the amide was lower than the one obtained at
P = 2 bar (Table 1, entries 2, 14 and 15).

K. B. Gona et al. / Tetrahedron Letters 54 (2013) 941–944
943
Table 1
Experimental conditions and reaction extent for the synthesis of m-carboranyl secondary and tertiary amides via the Heck carbonylation reaction
Entrya
Precursor
Catalyst
Amounts of catalystb
(equiv)
Ligand
Amount of ligandb
(equiv)
Basec
Reaction time
(h)
CO pressure
(bar)
%
Reactiond
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
5
5
6
7
5
5
5
5
5
5
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.10
0.20
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
BINAP
BINAP
BINAP
BINAP
BINAP
DPPF
0.04
0.04
0.04
0.04
0.04
0.04
0.04
0.04
0.04
0.20
0.40
0.04
0.04
0.04
0.04
0.04
0.04
0.04
0.04
K3PO4
K3PO4
K2CO3
Triethylamine
KtOBu
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
2
2
2
2
2
2
2
2
2
2
2
2
2
1
10
2
2
2
2
10.5
15.3
4.3
5.2
0.4
1.7
3.2
1.5
2.1
7.7
1.5
0.7
0.0
14.4
2.1
8.5
18.1
25.3
26.7
DPPE
Xantphos
Bipyridine
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
9
10
11
12
13
14
15
16
17
18
19
4
16
24
a
b
c
All reactions were carried out in THF (1 mL) using 25 mg (0.09 mmol) of carborane precursor and 0.15 mmol of amine.
With respect to carborane precursor.
Amount of base: 0.27 mmol.
d
Chemical conversion as determined by GC–MS.
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Optimized experimental conditions (entry 19 in Table 1) were
applied to the synthesis of compounds 1–4 (Scheme 2). After puri-
fication by chromatography (see Supplementary data for details),
yields of 21%, 15%, 16%, and 10%, respectively, were obtained. All
compounds were characterized by 1H NMR, {1H–11B} NMR, 13C
NMR, 11B NMR, {11B–1H} NMR, 1H–13C HSQC, high resolution mass
spectrometry and elemental analysis (see Supplementary data).
In conclusion, we present here an unprecedented strategy for
the synthesis of 1-m-carboranyl amides via the one-pot one-step
reaction of 1-iodo-m-carborane with primary or secondary amines
under CO atmosphere in the presence of a palladium complex act-
ing as a catalyst. The effects of the catalyst, the ligand, the base, CO
pressure, and reaction time have been investigated. Under opti-
mized conditions, slightly lower yields than those previously re-
ported using alternative strategies have been obtained, but both
the number of steps and the workup required have been substan-
tially decreased. To the best of our knowledge, the preparation of
carboranyl derivatives using the Heck carbonylation reaction has
not been reported to date and could be a powerful tool for the syn-
thesis of more complex molecules containing a carborane cage.
Moreover, this strategy should be suitable for the preparation of
11C-labeled carboranyl amides using [11C]CO as the labeling agent
for further in vivo evaluation using PET. This work will be ap-
proached in our lab in the next future.
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Acknowledgment
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The authors would like to thank the Ministerio de Ciencia e
Innovación for the financial support (Grant Number CTQ2009-
08810).
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.019.
References and notes
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17. Representative experimental procedure: Compound 5 (25 mg, 0.09 mmol) was
dissolved in THF (1 mL) and introduced in a glass Tiny-clave (nominal volume:
25 mL). The catalyst, the base, the ligand, and the nucleophile were added, the
system was closed, and carbon monoxide was introduced until the appropriate
pressure was reached. The reaction mixture was heated under stirring at 85 °C.
After 2 h, the reaction was cooled at room temperature, carbon monoxide was
flushed, and a sample was analyzed by GC–MS (see Supplementary data for
details) to assess the chemical conversion, using reference compound 5 as
internal standard.