The nitrile functionality as a directing group in the Palladium-catalysed addition of aryl boronic acids to alkynes

Article abstract of DOI:10.2174/157017810790533931

The nitrile group is shown to direct the palladium-catalysed hydroarylation of internal alkynes bearing a pendant nitrile with boronic acids.

Full text of DOI:10.2174/157017810790533931

Letters in Organic Chemistry, 2010, 7, 7-10
7
The Nitrile Functionality as a Directing Group in the Palladium-Catalysed
Addition of Aryl Boronic Acids to Alkynes
Arantxa Rodriguez and Wesley J. Moran*
Department of Chemical & Biological Sciences, University of Huddersfield, Queensgate, Huddersfield, HD1 3DH, UK
Received April 15, 2009: Revised December 02, 2009: Accepted December 03, 2009
Abstract: The nitrile group is shown to direct the palladium-catalysed hydroarylation of internal alkynes bearing a
pendant nitrile with boronic acids.
Keywords: Palladium, catalysis, nitrile, directing-group, hydroarylation.
The nitrile group is a useful functional group because of
its ease of installation, its inertness to many nucleophiles at
low temperature, and its ready transformation into other
functionalities such as a primary amine and a carboxylic
acid. The nitrile group is very small and linear with a bond
length of 1.14 Å and it is well known for its ability to
coordinate to metals [1]. Surprisingly, there is only one
report in the chemistry literature of a metal-catalysed process
that is directed by this interaction – the ruthenium-catalysed
ortho-olefination of aromatic nitriles [2]. Examples of the
use of nitriles as directing groups in non-catalysed reactions
are also few but this phenomenon has been proposed in an
intramolecular thermal [6+4] cycloaddition [3], Lewis acid
mediated intramolecular Diels-Alder cycloadditions [4], a
thermal Diels-Alder cycloaddition [5], an 8ꢀ-electro-
cyclisation [6] and the oxymercuration of cyclohex-3-
enecarbonitrile [7].
extended this to the arylative cyclisation of alkyne tethered
alkenes and aldehydes [13]. In 2003, Oh and co-workers
published their work on the palladium-catalysed addition of
arylboronic acids and alkenylboronic acids to alkynes in the
presence of acetic acid [14]. Zeng and Hua reported the
hydrophenylation of alkynes under conditions similar to
those of Oh but with sodium tetraphenylborate instead of
boronic acids [15]. These reactions suffer from low
regioselectivity when unsymmetrical alkynes are used,
unless one of the substituents is an ester or phosphonate
group for the rhodium chemistry, or a hydrogen atom for the
palladium chemistry. A further report from Oh described
their efforts to improve the regioselectivity of their process
with alcohol directing groups; however they found that
regioselectivity was hugely dependent on the alkyne
substituents at both ends of the alkyne [16]. Cheng and co-
workers recently reported the cobalt(II)-catalysed
hydroarylation of alkynes with organoboronic acids [17].
As part of our research programme, we were interested in
developing transition-metal catalysed cycloaddition and
cycloisomerisation reactions of alkynyl nitrile substrates.
Unfortunately, the nitrile group proved to be remarkably
stable to most of the conditions investigated. However, we
came across an interesting effect whereby the pendant nitrile
group can be seen to direct the palladium-catalysed addition
of aryl boronic acids to alkynes.
We discovered that the hydroarylation of prop-1-
ynylbenzene (1a) with phenylboronic acid occurred with
palladium acetate, triphenylphosphine and two equivalents
of potassium carbonate in refluxing dioxane to afford a 1:1.5
mixture of regioisomeric alkene products (2a and 3a) (Table
1, entry 1). The major product was that with the two phenyl
groups trans to each other. Under the same conditions, 3-
phenylprop-2-yn-1-ol (1b) preferentially formed the other
regioisomer in a 4:1 ratio (entry 2). This result suggests a
directing effect akin to that reported by Oh et al.
Unsurprisingly, converting the alcohol into a benzyl ether
and repeating the reaction led to lower regioselectivity being
observed (entry 3). The presence of a pendant ester group
was expected to lead to higher regioselectivity, but this was
not the case and a 2:1 mixture was obtained (entry 4).
However, the presence of a pendant nitrile group led to an
increase in regioselectivity (3:1) and chemical yield (entry 5)
[18]. Clearly, the nitrile substituent has a positive effect on
the selectivity observed in this reaction.
The transition-metal catalysed cross-coupling reaction of
organoboron derivatives with organic halides has been the
subject of considerable research over many years [8]. The
transition-metal catalysed addition of heteroatom-hydrogen
bonds to alkynes, including hydroboration, has also been
widely studied [9] while the transition-metal catalysed
hydroarylation of alkynes though direct functionalisation of
carbon-hydrogen bonds has gained interest in recent years
[10]. In contrast, little attention has been devoted to the
transition-metal catalysed addition of boronic acids to
alkynes [11].
The rhodium-catalysed addition of arylboronic acids to
alkynes was reported in 2001 by Hayashi [12] and they
The differences in regioselectivity for the but-2-yne-1-ol
derivatives were investigated next (Scheme 1). With an ester
substituent
a moderate yield of a 3:1 mixture of
regioisomeric products (5a and 6a) was obtained, whereas
with the nitrile substrate (4b) the selectivity was increased to
4:1 and the yield was almost doubled to 77%.
*Address correspondence to this author at the Department of Chemical &
Biological Sciences, University of Huddersfield, Queensgate, Huddersfield,
HD1 3DH, UK; Fax: +44 (0)1484 472182; E-mail: w.j.moran@hud.ac.uk
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

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Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Rodriguez and Moran
Table 1. Differences in Regioselectivity Caused by Alkyne Substituents
Ph
Ph
Ph
5 mol% Pd(OAc)2
10 mol% PPh3
Me
Me
2 equiv K2CO3
1.5 equiv PhB(OH)2
dioxane, 101 oC
R
R
R
3a-e
2a-e
1a-e
Entry
Substrate
R
Product
Yield/%a
Selectivity 2 : 3b
1
2
3
4
5
1a
1b
1c
1d
1e
H
OH
2a + 3a
2b + 3b
2c + 3c
2d + 3d
2e + 3e
54
50
59
45
72
1:1.5
4:1
OBn
2:1
OCH2CO2Et
OCH2CN
2:1
3:1
aYield of isolated product. bDetermined by 1H NMR analysis.
Me
Ph
Ph
5 mol% Pd(OAc)2
10 mol% PPh3
Me
Me
R
R
2 equiv K2CO3
O
O
1.5 equiv PhB(OH)2
dioxane, 101 oC
R
5a,b
O
6a,b
4a,b
a R = CO2Et
b R = CN
40% Yield
77% Yield
Selectivity 3:1
Selectivity 4:1
Scheme 1. Directing effects of ester and nitrile groups.
OMe
OMe
MeO
5 mol% Pd(OAc)2
10 mol% PPh3
Ar
2 equiv K2CO3
N
1.5 equiv ArB(OH)2
dioxane, 101 oC
O
Ar
NC
9a,b
O
NC
O
8a,b
7
a Ar = Ph
b Ar = p-ClC6H4
Selectivity 2.5:1
Selectivity 3.5:1
68% Yield
64% Yield
Scheme 2. Electronic effects on selectivity.
The electronic effects of the aryl substituents on the
reaction outcome, if any, were investigated in turn (Scheme
2). Accordingly, the p-methoxyphenyl alkynyl nitrile (7) was
synthesised and under the reaction conditions a diminished
regioselectivity of 2.5:1 (8a and 9a) was observed with
phenyl boronic acid, compared with 3:1 for the parent phenyl
alkynyl nitrile (1e). However, with p-chlorophenylboronic
acid a superior 3.5:1 ratio of (8b and 9b) was obtained.
These results indicate that the electronics of the substrate and
the boronic acid both play roles in determining the
regioselectivity of the reaction.
case (Table 1, entry 5 versus Table 2, entries 1 and 2), but
again p-chlorophenyl boronic acid resulted in higher
selectivity being observed (Table 2, entry 3).
The mechanism of this transformation is not fully
understood, however, the nitrile is envisaged to coordinate to
the palladium centre during the addition of the aryl group to
the alkyne Fig. (1). Oh et al. reported acidic conditions for
their hydroarylation reaction [14] whereas here we describe a
basic reaction medium. It is reasonable to assume that these
processes proceed by different mechanisms.
In conclusion, the presence of a pendant nitrile group has
been shown to improve the regioselectivity of the palladium-
catalysed addition of arylboronic acids to alkynes. This is a
Increasing the tether length by a methylene unit between
the alkyne and the ether or between the nitrile and the ether
led to a drop in regioselectivity from 3:1 to 2.5:1 in each

The Nitrile Functionality as a Directing Group
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
9
Table 2. Effects of Tether Length on Regioselectivity
Ph
Ph
Ph
Ph
5 mol% Pd(OAc)2
N
10 mol% PPh3
Ph
n
n
2 equiv K2CO3
1.5 equiv ArB(OH)2
dioxane, 101 oC
m O
m O
NC
m
n
O
NC
10a m=1, n=2
10b m=2, n=1
11a-c
12a-c
Entry
Substrate
Ar
Product
Yield/%a
Selectivity 11: 12b
1
2
3
10a
10b
10b
Ph
Ph
11a + 12a
11b + 12b
11c + 12c
73
72
75
2.5:1
2.5:1
3:1
p-ClC6H4
aYield of isolated product. bDetermined by 1H NMR analysis.
[8]
(a) Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-coupling
reactions of organoboron compounds. Chem. Rev., 1995, 95, 2457.
(b) Suzuki, A. Recent advances in the cross-coupling reactions of
organoboron derivatives with organic electrophiles, 1995-1998. J.
Organomet. Chem., 1999, 576, 147. (c) For a recent review, see:
Alonso, F.; Beletskaya, I. P.; Yus, M. Non-conventional
methodologies for transition-metal catalysed carbon-carbon
R
Ar
Pd
O
N
coupling:
a critical overview. Part 2: the Suzuki reaction.
Fig. (1). Proposed coordination of the nitrile to the palladium
Tetrahedron, 2008, 64, 3047.
centre.
[9]
For reviews, see: (a) Beletskaya, I. P.; Pelter, A. Hydroborations
catalysed by transition metal complexes. Tetrahedron, 1997, 53,
4957. (b) Alonso, F.; Beletskaya, I.; Yus, M. Transition-metal-
catalyzed addition of heteroatom-hydrogen bonds to alkynes.
Chem. Rev., 2004, 104, 3079. (c) Trost, B. M.; Ball, Z. T. Addition
of metalloid hydrides to alkynes: hydrometallation with boron,
silicon, and tin. Synthesis, 2005, 853.
little investigated phenomenon in organic synthesis and
hopefully this report will inspire further studies.
[10]
For reviews, see: (a) Nevado, C.; Echavarren, A. M. Transition
metal-catalyzed hydroarylation of alkynes. Synthesis, 2005, 167.
(b) Kitamura, T. Transition-metal-catalyzed hydroarylation
reactions of alkynes through direct functionalization of C-H bonds:
a convenient tool for organic synthesis. Eur. J. Org. Chem., 2009,
1111.
ACKNOWLEDGEMENTS
The authors thank the University of Huddersfield for
funding.
[11]
[12]
For a recent example, see: Bush, A. G.; Jiang, J. L.; Payne, P. R.;
Ogilvie, W. W. Development of a palladium catalyzed addition of
boronic acids to alkynyl esters: synthesis of trisubstituted olefins as
single isomers. Tetrahedron, 2009, 65, 8502.
Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. Rhodium-
catalyzed hydroarylation of alkynes with arylboronic acids: 1,4-
shift of rhodium from 2-aryl-1-alkenylrhodium to 2-
alkenylarylrhodium intermediate. J. Am. Chem. Soc., 2001, 123,
9918.
(a) Shintani, R.; Tsurusaki, A.; Okamoto, K.; Hayashi, T. Highly
chemo- and enantioselective arylative cyclization of alkyne-
tethered electron-deficient olefins catalyzed by rhodium complexes
with chiral dienes. Angew. Chem. Int. Ed. Engl., 2005, 44, 3909;
(b) Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi,
T. Catalytic asymmetric arylative cyclization of alkynals:
phosphine-free rhodium/diene complexes as efficient catalysts. J.
Am. Chem. Soc., 2005, 127, 54.
Oh, C. H.; Jung, H. H.; Kim, K. S. The palladium-catalyzed
addition of organoboronic acids to alkynes. Angew. Chem. Int. Ed.
Engl., 2003, 42, 805.
Zeng H.; Hua, R. Palladium-catalyzed hydrophenylation of alkynes
with sodium tetraphenylborate under mild conditions. J. Org.
Chem., 2008, 73, 558.
Kim, N.; Kim, K. S.; Gupta, A. K.; Oh, C. H. On the
regioselectivity of Pd-catalyzed additions of organoboronic acids to
unsymmetrical alkynes. Chem. Commun., 2004, 618.
Lin, P.-S.; Jeganmohan, M.; Cheng, C.-H. Cobalt(II)-catalyzed
regio- and stereoselective hydroarylation of alkynes with
organoboronic acids. Chem. Eur. J., 2008, 14, 11296.
REFERENCES AND NOTES
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For reviews on nitrile chemistry see: (a) Fleming, F. F.; Zhang, Z.
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ꢀ-amino nitrile chemistry. Chem. Soc. Rev., 2000, 29, 359.
Kakiuchi, F.; Sonoda, M.; Tsujimoto, T.; Chatani, N.; Murai, S.
The ruthenium-catalyzed addition of C-H bonds in aromatic nitriles
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Gupta, Y. N.; Doa, M. J.; Houk, K. N. Intramolecular [6 + 4]
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[2]
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[4]
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(a) Toró
, A.; Lemelin, C.-A.; Préville, P.; Bélanger, G.;
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asymmetric synthesis of (+)-maritimol. Tetrahedron, 1999, 55,
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[14]
[15]
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Magnus, P.; Gazzard, L.; Hobson, L.; Payne, A. H.; Rainey, T. J.;
Westlund, N.; Lynch, V. Synthesis of the Kopsia alkaloids (±)-
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Representative procedure for the addition of phenylboronic acid to
2-(3-phenylprop-2-ynyloxy)acetonitrile 1e: A flask was charged
with 2-(3-phenylprop-2-ynyloxy)acetonitrile 1e (50 mg, 0.29

10
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Rodriguez and Moran
mmol, 1 equiv), phenylboronic acid (53 mg, 0.44 mmol, 1.5 equiv),
potassium carbonate (80 mg, 0.58 mmol, 2 equiv), palladium
acetate (3.3 mg, 0.15 mmol, 0.05 equiv) and triphenylphosphine
(7.6 mg, 0.029 mmol, 0.1 equiv). A reflux condenser was fitted to
the flask and a nitrogen atmosphere was introduced. Dry 1,4-
dioxane ( 1 mL) was added and the reaction mixture was heated at
4.21 (2H, s), 6.18 (1H, t, J = 7.0 Hz), 7.12-7.44 (10H, m). 2e 13C
NMR (100 MHz, CDCl3): ꢀ 54.6, 68.5, 115.4, 121.8, 127.0, 127.3,
1
127.4, 127.6, 127.7, 129.0, 137.8, 140.6, 146.6. 3e H NMR (400
MHz, CDCl3): ꢀ 4.26 (2H, s), 4.65 (2H, s), 7.12-7.44 (10H, m),
7.57 (1H, d, J = 7.9 Hz). 3e 13C NMR (100 MHz, CDCl3): ꢀ 54.8,
68.3, 125.6, 127.2 (2C), 127.9, 128.0 (2C), 128.2, 129.0, 135.2,
135.8, 139.7. IR (neat): 1088 (m), 1456 (w), 2858 (w), 2921 (w)
cm-1. HRMS: m/z calc’d for C17H15NNaO 272.1046, found
272.1046.
o
100 C. After 15 hours the volatiles were removed under reduced
pressure and the residue was purified by flash chromatography (9:1
petroleum ether 40-60/ethyl acetate). An inseparable 3:1 mixture of
2-(3,3-diphenylallyloxy)acetonitrile 2e and (E)-2-(2,3-diphenyl-
allyloxy)acetonitrile 3e was isolated as a yellow solid (52 mg,
1
72%). 2e H NMR (400 MHz, CDCl3): ꢀ 4.19 (2H, d, J = 7.0 Hz),