Synthesis of substituted 2-cyanoarylboronic esters

Article abstract of DOI:10.1021/jo052400g

The synthesis of substituted 2-cyanoarylboronic esters is described via lithiation/in situ trapping of the corresponding methoxy-, trifluoromethyl-, fluoro-, chloro-, and bromobenzonitriles. The crude arylboronic esters were obtained in high yields and pu

Full text of DOI:10.1021/jo052400g

and heteroaromatic systems via Ir-catalyzed C-H activation has
also been developed.8
Synthesis of Substituted 2-Cyanoarylboronic
Esters
When synthesizing ortho-substituted arylboronic derivatives,
the directed ortho metalation (DOM) is an obvious choice for
generating the required organometallic intermediate, since it has
become one of the most reliable reactions available to the
synthetic chemist for the preparation of 1,2-disubstituted
aromatic systems.9 Innumerable examples of its use in synthesis
have appeared since its discovery in the 1930s by Wittig and
Gilman.10 The ability of different substituents to direct meta-
lation has been studied extensively, and a hierarchy between
different directed metalation groups (DMGs) has been estab-
lished experimentally.9b The DOM, and other metalation reac-
tions, are usually viewed as stepwise processes. Step one is the
generation of a metalated species via the action of a suitable
base. Step two is the reaction of that intermediate with the
chosen electrophile. This is also reflected in the way it is done
experimentally: First, the base is added to a solution containing
the substrate, and then, after a specified period of time has
passed, the electrophile is added. Alternatively, the substrate is
added to a solution containing the base so-called “inverse
addition.” Intuitively, certain requirements must be fulfilled for
this approach to be successful: (1) Metalation must prevail over
nucleophilic attack of the base on the DMG or other function-
alities in the substrate. (2) The stabillity of the metalated species
is important. Even if the metalation step is fast, some decom-
position, rearrangement, or self-condensation, etc., might be
faster. Thus, the metalated species will be consumed before the
electrophile is introduced. (3) If the metalation is reversible,
the base must be sufficiently strong to fully deprotonate the
substrate, i.e., there should be a difference of at least 4 pKa
units between the base and the substrate. Otherwise, one would
expect that the reaction would give a mixture of unchanged
substrate, desired product, and possibly the product arising from
the reaction between the base and the electrophile.
Morten Lyse´n, Henriette M. Hansen, Mikael Begtrup, and
Jesper L. Kristensen*
Department of Medicinal Chemistry, The Danish UniVersity of
Pharmaceutical Sciences, UniVersitetsparken 2,
DK-2100 Copenhagen, Denmark
jekr@dfuni.dk
ReceiVed NoVember 21, 2005
The synthesis of substituted 2-cyanoarylboronic esters is
described via lithiation/in situ trapping of the corresponding
methoxy-, trifluoromethyl-, fluoro-, chloro-, and bromoben-
zonitriles. The crude arylboronic esters were obtained in high
yields and purities and with good regioselectivities.
Arylboronic acid derivatives have become very valuable tools
in organic synthesis. They have gained immense popularity in
the synthesis of biaryls via cross-coupling reactions, and much
effort is still devoted to the development of these reactions with
respect to catalyst design, coupling partners, and application of
different arylboronic derivatives.1 The popularity of arylboronic
acid derivatives can be attributed to them being nontoxic, “shelf-
stable carbanions”. This has spawned the development of many
new applications for these derivatives, and the list of applications
continues to grow: synthesis of arylglycines,2 asymmetric Rh-
catalyzed 1,4-additiones to conjugated systems,3 coupling with
amines, alcohols, and thiols,4 synthesis of arylhalides.5 With
this increasing use of arylboronic acid derivatives, the demand
for efficient protocols for the preparation of diversely substituted
arylboronic acid derivatives is an ever more pressing issue.
Traditionally, arylboronic acid derivatives have been prepared
by reacting an aryllithium intermediate, generated by deproto-
nation or halogen/metal exchange, with a trialkylborate.6
Alternatively, arylboronic acid derivatives can be synthesized
from aryl halides via Pd(0)-catalyzed coupling with tetraalkoxy-
diboron or dialkoxyborane.7 Recently, the borylation of aromatic
In 1983, Krizan and Martin introduced the concept of in situ
trapping, i.e., using a sterically hindered base to generate an
unstable lithio intermediate in the presence of an electrophile.11
It is based on the following principle: Although the base may
not be strong enough to fully deprotonate the substrate, and the
lithiated species is unstable, the introduction of an electrophile
that is compatible with the base, but reacts with the lithiated
species, will push the reaction to completion, via an in situ
trapping of the lithiated species. In 1998, Caron and Hawkins
reported a variant of this reaction, using LDA/B(O-i-Pr)3 to
synthesize ortho-substituted arylboronic acids.12 Later, we
broadened the scope of this approach using LTMP/B(O-i-Pr)3
for the synthesis of ortho-substituted aryl- and heteroarylboronic
(7) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508. (b) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62,
6458.
(8) (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M.
R. Science 2002, 295, 305. (b) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura,
N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 391. (c)
Ishiyama, T.; Takagi, J.; Nobuta, Y.; Miyaura, N. Org. Synth. 2005, 82,
126.
(9) (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1. (b)
Snieckus, V. Chem. ReV. 1990, 90, 879.
(10) (a) Wittig, G.; Pockels, U.; Dro¨ge, H. Chem. Ber. 1938, 9, 1903.
(b) Gilman, H.; Bebb, R. L. J. Am. Chem. Soc. 1939, 61, 109.
(11) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155.
(12) Caron, S.; Hawkins, J. M. J. Org. Chem. 1998, 63, 2054.
(1) For an extensive list of references, see: Miura, M. Angew. Chem.,
Int. Ed. 2004, 43, 2201.
(2) Petasis, N. A.; Goodman, A.; Zavualov, I. A. Tetrahedron 1997, 53,
16463.
(3) Hayashi, T. Pure Appl. Chem. 2004, 76, 465.
(4) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(5) (a) Thompson, A. L. S.; Kabalka, G. W.; Akula, M. R.; Huffman, J.
W. Synthesis 2004, 4, 547. (b) Szumigala, R. H.; Devine, P. N.; Gauthier,
D. R.; Volante, R. P. J. Org. Chem. 2004, 69, 566.
(6) Ko¨nig, W.; Scharrnbeck, W. J. Prakt. Chem. 1930, 128, 153.
10.1021/jo052400g CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/24/2006
2518
J. Org. Chem. 2006, 71, 2518-2520

TABLE 1. In Situ Trapping of Para-Substituted Benzonitriles
TABLE 2. In Situ Trapping of Meta-Substituted Benzonitriles
entry
X
6
7
yieldb (%)
purityc (%)
1
2
3
4
5
OMe (a)
CF3 (b)
F (c)
Cl (d)
Br (e)
>99
<1
>99
>99
>99
<1
>99
<1
96
98
96
e
>99
>99
95d
e
entry
base
X
2
3
4
yieldb (%) purityc (%)
1
2
3
4
5
6
7
8
9
LTMP OMe (a)
LTMP CF3 (b)
LTMP F (c)
LTMP Cl (d)
LTMP Br (e)
LDA
LDA
LDA
LDA
LDA
30
70
96
99
94
99
98
95
99
95
95
99
<1
>99 <1
<1
96
95f
40
93
90
25
40
35
60
70
60
7
10
25 60
60
45 20
a See the Experimental Section for details. b Isolated yield of crude
product on a 10 mmol scale. c Purity of crude product with respect to 6a-
e/7a-e, as determined from NMR and GC-MS. d Contains 5% diborylated
product. e See text for details. f Contains 3% of 5e and 2% of diborylated
product.
OMe (a)
CF3 (b)
F (c)
Cl (d)
Br (e)
35
25
5
5
10
a See the Experimental Section for details. b Isolated yield of crude
product on a 10 mmol scale. c Purity of crude pruduct with respect to 2a-
e/3a-e, as determined from NMR and GC-MS.
The lithiation of meta-substituted benzonitriles 5a-e gave
the arylboronic esters resulting from lithiation between the two
substituents on the ring; see Table 2. The exception was 5b,
where lithiation occurred exclusively para to the CF3 group,
giving 7b as the only detectable species in 98% isolated yield.
This result is in good agreement with observations made by
Schlosser, who showed that trifluoromethylbenzenes possessing
a DMG in the 3-position are lithiated in the 4-position when
bulky bases like LTMP are employed.18
Arylboronic ester 6d proved impossible to isolate as a single
entity: It readily hydrolyzed to give a mixture of the boronic
acid and boronic acid anhydrides. Furthermore, 6d deborylated
to give the 5d upon storage at rt. This was also the case for 6e,
which deborylated upon storage at rt. for several weeks.19
Szumigala et al. reported the borylation of 5c using LDA/
B(OiPr)3 giving the arylboronic acid analogous to 6c in 75%
yield, but were unable to fully characterize this species as it
was obtained as a complex mixture of the free acid and different
anhydrides.5b Cyanoarylboronic ester 6c was isolated and easily
characterized as a single, stable entity with well-defined 1H and
13C NMR spectra.
The lithiation of ortho-substituted benzonitriles was generally
more regioselective than the lithiation of para-substituted
benzonitriles; see Table 3. Most noteworthy is the completely
selective borylation of 2-methoxybenzonitrile (8a) in which 9a
is produced exclusively in excellent yield and purity. Compared
with the borylation of 1a, which gave a 30:70 mixture (Table
1, entry 1), this result is quite astounding. We speculate that
the highly selective lithiation of 8a is due to hindered rotation
of the methoxygroup because of the adjacent cyanogroup,
impeding coordination of the oxygen lone pair to LTMP.
2-Fluorobenzonitrile (8c) furnished a similar unselective
mixture of regioisomers as was the case with 1c. In the lithiation
of 2-chlorobenzonitrile (8d) and 2-bromobenzonitrile (8e), the
regioselectivity was improved to give only 5% and 2% of the
other regioisomer.15
esters.13 The nonnucleophillic nature of LTMP makes it possible
to ortho-lithiate benzonitrile and ethyl benzoate, substrates not
suited for classical DOM reactions. This procedure is easily
scalable to produce multigrams of material.14 Herein, we wish
to report the extension of this methodology to the ortho-
lithiation/in-situ borylation of ortho-, meta-, and para-substituted
benzonitriles. We intentionally chose to include substrates that
were expected to yield mixtures of regioisomers to test the scope
of the reaction.
Submitting para-substituted benzonitriles 1a-e to our stan-
dard condition for in situ trapping on a 10 mmol scale gave
full conversion of the starting benzonitriles to yield mixtures
of the two possible regioisomeric neopentylglycol arylboronic
esters; see Table 1, entries 1-5. The borylation of 4-methoxy-
benzonitrile (1a) and 4-fluorobenzonitrile (1c) was unselective,
giving 30:70 and 40:60 mixtures of the two possible isomers.
In contrast, 4-trifluoromethylbenzonitrile (1b) yielded a single
arylboronic ester (2b) in 99% isolated yield. Chloro- and bromo-
substituted benzonitriles 1d and 1e yielded preparatively useful
93:7 and 90:10 mixtures of the corresponding arylboronic
esters.15
Attempts to improve the selectivity in the in situ trapping
with LTMP/B(O-i-Pr)3 via the addition of TMEDA were
unsuccessful.16 LDA/B(O-i-Pr)3 was tested, but as seen from
Table 1, the selectivity remained largely unchanged (entries 7
and 8) or dropped (entries 6, 9, and 10). Furthermore, the N,N-
diisopropylbenzamides 4a-e, resulting from nucleophilic attack
of LDA on the cyanogroups in 1a-e, were produced as
byproducts in 5-60% yield.17
(13) (a) Kristensen, J. L.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Lett.
2001, 3, 1435. (b) Hansen, H. M.; Lyse´n, M.; Begtrup, M.; Kristensen, J.
L. Tetrahedron 2005, 61, 9955.
(14) Kristensen, J. L.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Synth.
2005, 81, 134.
(15) Isomerically pure 2d, 2e, 9d, and 9e can be obtained through
recrystallization, but the purity of the crude products is sufficient to be
used directly in most subsequent transformations. Isomerically pure samples
of 2a/3a, 2c/3c, and 9c/10c were not obtained.
(16) (a) Fraser, R. R.; Mansour, T. S. Tetrahedron Lett. 1986, 27, 331.
(b) For an exellent discussion on the use of TMEDA, see: Collum, D. B.
Acc. Chem. Res. 1992, 25, 488.
(17) Recently, Chotana et al. obtained very similar product ratios in the
synthesis of cyanoarylboronic esters via Ir-catalyzed coupling of 1a-c with
pinacolborane. The regioisomeric mixtures of pinacolarylboronic esters were
isolated in 65-76% yield based on the borylating agent; see: Chotana, G.
A.; Rak, M. A.; Smith, M. R. J. Am. Chem. Soc. 2005, 127, 10539.
(18) Schlosser, M. Angew. Chem., Int. Ed. 1998, 110, 1496.
(19) All other cyanoarylboronic esters reported herein are stable for
several months at rt when stored without special precautions.
J. Org. Chem, Vol. 71, No. 6, 2006 2519

TABLE 3. In Situ Trapping of Ortho-Substituted Benzonitriles
SCHEME 1. Application of 2-Cyanoarylboronic Esters in
the Two-Step Synthesis of Phenanthridinesa
entry
X
9
10
yieldb (%)
purityc (%)
1
2
3
4
5
OMe (a)
CF3 (b)
F (c)
Cl (d)
Br (e)
>99
>99
40
95
98
<1
<1
60
5
96
99
99
96
97
>99
>99
>99
>99
>99
In conclusion, we have demonstrated that the lithiation/in situ
trapping protocol with LTMP/B(O-i-Pr)3 is a very efficient
procedure for the preparation of substituted 2-cyanoarylboronic
esters.
2
a See the Experimental Section for details. b Isolated yield of crude
product on a 10 mmol scale. c Purity of crude pruduct respect to 9a-e/
10a-e, as determined from NMR and GC-MS.
Experimental Section
2-Cyanoarylboronic esters are very efficiently employed in
Suzuki couplings with aryl halides13a and carbamoyl chlorides.20
They are also readily acylated,21 aminated,22 or converted to
indenones and indanones.23 Furthermore, cyanoarylboronic
esters can be converted to the corresponding aryltetrazole
boronic esters via treatment with TMSN3.24 To briefly demon-
strate the synthetic utility of the arylboronic esters reported in
this study, a two-step synthesis of a substituted phenanthridine
was performed (see Scheme 1).
Coupling of crude 7b with 1-bromo-4-chloro-2-fluorobenzene
under standard Suzuki coupling conditions produced the cor-
responding biphenyl 11 in 67% unoptimized yield on a 5 mmol
scale. This biphenyl was converted to the corresponding
6-substituted phenanthridine 12 in 74% isolated yield via
addition of lithium morpholide to the cyano group followed by
intramolecular displacement of the fluorine.25
General Procedure for the Lithiation/In Situ Trapping on
Substituted Benzonitriles: Synthesis of Cyanoarylboronic Es-
ters. In a 100 mL dry Schlenk flask under N2 was dissolved 2,2,6,6-
tetramethylpiperidine (12 mmol) in dry THF (25 mL) and the
mixture was cooled to -10 °C before n-buLi (12 mmol) was added
over 2 min. The mixture was stirred for 10 min before cooling to
-78 °C. At -78 °C, B(O-i-Pr)3 (14 mmol) was added over 2 min
and stirred for 5 min at -78 °C before the benzonitrile (10 mmol)
dissolved in dry THF (10 mL) was added dropwise over 5 min.
The reaction was left in the dry ice bath overnight, slowly reaching
room temperature. The reaction was quenched with glacial acetic
acid (14 mmol) followed by addition of 2,2-dimethyl-1,3-pro-
panediol (15 mmol). The mixture was stirred for 1 h at room
temperature and then transferred to a separating funnel with CH2-
Cl2 (75 mL) and washed with aqueous KH2PO4 (10 w/v %) (4 ×
60 mL). The combined water phase was back-extracted once with
CH2Cl2 (15 mL), the combined organic phase was dried over
MgSO4, and the solvents were evaporated to give the crude
cyanoarylboronic ester.
(20) Lyse´n, M.; Kelleher, S.; Begtrup, M.; Kristensen, J. L. J. Org. Chem.
2005, 70, 5342.
(21) (a) Urawa, Y.; Ogura, K. Tetrahedron Lett. 2003, 44, 271. (b) Urawa,
Y.; Nishiura, K.; Souda, S.; Ogura, K. Synthesis 2003, 2882.
(22) Nishiura, K.; Urawa, Y.; Souda, S. AdV. Synth. Catal. 2004, 346,
1679.
(23) Miura, T.; Murakami, M. Org Lett. 2005, 7, 3339.
(24) Schlutz, M. J.; Coats, S. J.; Hlasta, D. J. Org. Lett. 2004, 6, 3265.
(25) Lyse´n, M.; Kristensen, J. L.; Vedsø P.; Begtrup, M. Org. Lett. 2002,
4, 257.
Supporting Information Available: Full experimental details
and charaterization of new compounds, including copies of 1H NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052400G
2520 J. Org. Chem., Vol. 71, No. 6, 2006