Regioselective oxidative Pd-catalysed coupling of alkylboronic acids with pyridin-2-yl-substituted heterocycles

Article abstract of DOI:10.1039/c4cc10144h

A total of 19 alkylated heterocycles (thiophenes, benzothiophenes, pyrroles, furans) were prepared (36-99% yield) from the respective pyridin-2-yl-substituted precursors employing alkylboronic acids as the C-H alkylating reagents in an oxidative (Ag₂

Full text of DOI:10.1039/c4cc10144h

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Regioselective oxidative Pd-catalysed coupling of alkylboronic acids
with pyridin-2-yl-substituted heterocycles
Julian Wippich,a Ingo Schnapperelle,a and Thorsten Bach*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A total of 19 alkylated heterocycles (thiophenes, benzo-
thiophenes, pyrroles, furans) were prepared (36-99% yield)
from the respective pyridin-2-yl-substituted precursors
employing alkylboronic acids as the C-H alkylating reagents
Table 1 Regioselective oxidative Pdꢀcatalysed coupling of alkylboronic
acids with 2ꢀpyridinꢀ2ꢀylthiophene (1)a
10 in an oxidative (Ag2CO3 and 2,6-dimethyl-1,4-benzoquinone
as oxidants) Pd-catalysed coupling reaction.
Despite considerable progress in recent years, the direct CꢀH
alkylation of aromatic heterocycles by transitionꢀmetal
catalysis remains a considerable challenge.1 An appropriate
15 option to achieve the desired regioselectivity in this process is
based on the use of directing groups.2 In the thiophene series
the pyridinꢀ2ꢀyl group has frequently served to mediate a
reaction at position C3 if it was attached as directing group to
carbon atom C2.3,4 Upon Pd(II) catalysis, oxidative
20 dimerization of 2ꢀpyridinꢀ2ꢀylthiophene (1) proceeded
selectively at C35 as did the oxidative arylation with
arylboronic acids.6,7 The Pd(II) catalyzed arylation of 1 with
aryl bromides proceeded preferentially at C5 although the
regioselectivity was variable.8,9 In this communication we
25 disclose our results on the regioselective oxidative Pdꢀ
catalysed coupling of alkylboronic acids with 2ꢀ(pyridinꢀ2ꢀ
aThe substrate (c = 0.2 M) and all reagents were dissolved in dry tertꢀ
amyl alcohol. Upon stirring for five minutes at ambient temperature, the
sealed reaction tube was placed in a preꢀheated oil bath (100 °C). Workꢀ
up was performed with CH2Cl2 and aqueous Na2S solution. Yields are
given for isolated products after chromatographic purification. bGLC
analysis of the crude product revealed formation of a single regioisomer.
yl)ꢀsubstituted
thiophenes
and
related
heterocycles
(benzothiophene, furan, pyrrole).
The starting point of our study was a report by the Yu group,
30 who found that 2ꢀphenylpyridine could be alkylated with
alkylboronic acids (3.0 eq.) employing a reagent combination
of Pd(OAc)2 (10 mol%), Ag2O (1 eq.) and 1,4ꢀbenzoquinone
(0.5 eq.) at 100 °C in tertꢀamyl alcohol (tAmOH).10,11 Yields
varied between 51 and 75% (six examples) depending on the
35 alkyl group. When applying the same conditions to 2ꢀpyridinꢀ
confirmed the importance of 1,4ꢀbenzoquinone to complete
50 the catalytic cycle.13 In order to find a 1,4ꢀbenzoquinone,
which would be less susceptible towards alkylation, various
substituted derivatives were screened (see the ESI for further
information). The study revealed that 2,6ꢀdimethylꢀ1,4ꢀ
benzoquinone (2) was a superior coꢀcatalyst for the desired
55 reaction as compared to unsubstituted 1,4ꢀbenzoquinone.
Applying it to the otherwise unchanged reactions conditions,
the yield for the desired butylated product increased according
to GLC to 70% (92% conversion). On preparative scale, the
reaction delivered an almost identical result and 3ꢀ
60 butylthiophene 3a was isolated in 71% yield (Table 1).
Oxidative dimerisation (dehydrogenative coupling)14 to the
respective 5,5’ꢀdithiophene was a notable side reaction, which
may at least partially account for the moderate yields, which
were recorded for products 3bꢀ3e.15 Indeed, it was shown that
65 5,5’ꢀdithiophene 4 was formed in 60% yield from product 3a
if the latter was subjected to oxidative coupling conditions
2ꢀylthiophene (1) and butylboronic acid we recorded
a
conversion of 34% after 14 hours and a product yield of 30%
(determined by GLC with dodecane as internal standard).
Raising the silver concentration and replacing Ag2O by
40 Ag2CO3 as the silver source increased the conversion to 90%
and the yield to 58%. Despite this significant improvement, it
was notable that the butylboronic acid was largely consumed
by an undesired alkylation reaction, which occurred at 1,4ꢀ
benzoquinone. Indeed, it has been reported that 1,4ꢀ
45 benzoquinone can be alkylated by alkylboronic acids under
oxidative conditions in the presence of a Pd(II) catalyst.12 If
1,4ꢀbenzoquinone was omitted in the present reaction, the
turnover was retarded (37% conversion after 14 h), which
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DOI: 10.1039/C4CC10144H
(Scheme 1). Even in the presence of butylboronic acid, the
dimer was the only product isolated. Applying exactly the
reaction conditions used for the alkylation (Table 1), product
4 was obtained from 3a in 59% yield. A further alkylation was
not observed.
more electron rich thiophenes also withstood the oxidative
conditions of the coupling reaction. Product 5g was isolated in
almost quantitative yield and even the 5ꢀmethoxythiophene 5h
could be obtained with good chemoselectivity. Moreover, it
20 was possible to extend the reaction to 2ꢀpyridinꢀ2ꢀ
ylbenzothiophene resulting in the alkylation products 5i and
5j. Commericially available boronic acids were used in all
experiments and it was secured by NMR that no condensation
to the corresponding boroxines had occurred upon storage. In
25 the course of the reaction the initially green suspension turned
black possibly due to metal precipitation.
5
Scheme 1 Oxidative dimerisation of 3ꢀbutylated product 3a to the 3,3’ꢀ
dibutylꢀ5,5’ꢀdithiophene 4
Mechanistically, it is assumed that the reaction follows the
pathway previously preposed for the alkylation of benzenes.9
A
mechanistic scheme is given in Scheme 2 for the
When the 5ꢀposition in the thiophene was blocked the reaction
30 transformation 1 → 3a. In the event, Pd(OAc)2 attacks – upon
preꢀcoordination to the pyridinꢀ2ꢀyl directing group – the
thiophene core at position C3 leading to cyclopalladated
intermediate 6. Transmetallation generates the precursor 7 for
the reductive elimination step, in which a reduced palladium
35 species (Pd0) is formed. Reoxidation to the reactive PdX2
catalyst occurs stoichiometrically by the silver salt with
possible assistance by benzoquinone 2. As pointed out earlier,
benzoquinone may also be involved as ligand in the
transmetallation and reductive elimination step.12,16 In
40 addition, it appears as if the 2ꢀpyridinꢀ2ꢀyl group facilitates
transmetalation. After primary alkylation at C3, palladation
occurs at position C5 and oxidative dimerisation prevails over
oxidative coupling (vide supra).
10 outcome significantly improved (Table 2). For ethyl 2ꢀ
(pyridinꢀ2ꢀyl)ꢀ5ꢀthiophene carboxylate, alkylation reactions
proceeded cleanly and delivered products 5aꢀ5d in yields of
71ꢀ97%. The reactions conditions were compatible with
ketone (product 5e) and aldehyde (product 5f) functional
15 groups at position C5 of the thiophene core. Remarkably,
Table 2 Regioselective oxidative Pdꢀcatalysed coupling of alkylboronic
acids with 2ꢀpyridinꢀ2ꢀylꢀsubstituted thiophene and with 2ꢀpyridinꢀ2ꢀ
ylbenzothiophene,a
45 Scheme 2 Mechanistic proposal for the oxidative crossꢀcoupling with 2ꢀ
pyridinꢀ2ꢀylthiophenes such as 1 (X = anionic ligand, L = neutral ligand)
Given the strong directing power of the 2ꢀpyridinꢀ2ꢀyl group
it was probed whether a selective alkylation was also possible
at other positions of the thiophene ring and with other 2ꢀ
50 (pyridinꢀ2ꢀyl)ꢀsubstituted
heterocycles
as
substrates.
Butylboronic acid was used in these reactions as the
nucleophile (Scheme 3). Gratifyingly, it was found that
alkylation at position C417 of 3ꢀpyridinꢀ2ꢀylthiophene 8 was
indeed possible employing the conditions previously
55 established. Product 9 was obtained in moderate yield. In the
pyrrole series, it was observed that – in analogy to product
formation 3a vs. 5d – the alkylation reaction of the 5ꢀ
ethoxycarbonylꢀsubstituted pyrrole 11 (Y = COOEt) gave a
better yield that the reaction of the unsubstituted compound
60 10 (Y = H). Products yields for 12 and 13 were recorded as
58% and 90%. In the former case, competitive oxidative
dimerisation at position C5 is likely the reason for the lower
yields. Regarding the nitrogen protecting group, the benzyl
aThe substrate and all reagents were dissolved in dry tertꢀamyl alcohol.
Upon stirring for five minutes at ambient temperature, the sealed reaction
tube was placed in a preꢀheated oil bath (100 °C). Workꢀup was
performed with CH2Cl2 and aqueous Na2S solution. Yields are given for
isolated products after chromatographic purification.
2
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DOI: 10.1039/C4CC10144H
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For recent work on directed CꢀH activation reactions at 2ꢀpyridinꢀ2ꢀ
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group was shown to be superior as compared to
45
50
55
60
65
70
75
80
85
methanesulfonyl (Ms), toluenesulfonyl (Ts) and paraꢀ
methoxybenzyl (PMB). The respective 2ꢀpyridinꢀ2ꢀylpyrroles
gave lower yields in the oxidative coupling reactions. The
oxidation sensitive 2ꢀpyridinꢀ2ꢀylfuran gave only traces of
coupling product under the standard reaction condition. The
less electonrich ethyl 5ꢀfuran carboxylate 14, however, could
be converted into the respective alkylation product 15 albeit in
relatively low yield.
3
4
5
B(OH)2 (3 eq.)
N
N
2 (0.5 eq.), 10 mol% Pd(OAc)2
Ag2CO3 (2 eq.)
100 °C, 14 h (tAmOH)
COOEt
COOEt
S
S
8
9 (52%)
see above
N
N
Y
Y
N
N
Bn
Bn
5
10
11
Y = H
12 (58%)
13 (90%)
6
7
Y = COOEt
see above
N
N
EtOOC
EtOOC
O
O
8
9
14
15 (36%)
10
Scheme 3 Regioselective oxidative Pdꢀcatalysed coupling of butylboronic
acids with pyridinꢀ2ꢀylꢀsubstituted heterocycles
In summary, it was shown that the pyridinꢀ2ꢀyl group exerts a
powerful directing influence on the Pdꢀcatalysed CꢀH
15 alkylation of fiveꢀmembered heterocycles with alkylboronic
acids. The alkylation reactions occur exclusively in orthoꢀ
position to the directing group resulting in the formation of
the respective 3ꢀsubstituted (pyridinꢀ2ꢀyl at C2) or 4ꢀ
substituted (pyridinꢀ2ꢀyl at C3) products. 2,6ꢀDimethylꢀ1,4ꢀ
20 benzoquinone (2) was found to be a superior coꢀreagent to
promote in combination with Ag2CO3 the oxidative coupling.
If the orthoꢀposition relative to the directing group are
substitued, oxidative dimerisation occurs under the oxidative
reaction conditions at position C5 of 3ꢀalkylꢀ2ꢀ(pyridinꢀ2ꢀ
25 yl)thiophenes.
10 X. Chen, C.E. Goodhue and J.ꢀQ. Yu, J. Am. Chem. Soc., 2006, 128,
12634ꢀ12635.
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agents, see: S. R. Neufeldt, C. K. Seigermann and M. S. Sanford,
Org. Lett., 2013, 15, 2302ꢀ2305.
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P. S. Baran, J. Am. Chem. Soc., 2011, 133, 3292ꢀ3295.
13 X. Chen, J.ꢀJ. Li, X.ꢀS. Hao, C. E. Goodhue and J.ꢀQ. Yu, J. Am.
Chem. Soc., 2006, 128, 78ꢀ79.
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39, 540ꢀ548.
15 The use of cyclopropyl boronic acid led to an inseparable mixture of
This project was supported by the Deutsche Forschungs-
gemeinschaft (Ba 1372ꢀ19/1), by the Elitenetzwerk Bayern
(scholarship to J.W.), by the graduate college NanoCat
(scholarship to I.S.) and by the TUM Graduate School.
30 Helmut Krause and Burghard Cordes are acknowledged for
help with the HRMS analyses.
95
product and substrate (35% conversion after 14 h).
16 (a) K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2009, 131,
9651ꢀ9653; (b) C. Sköld, J. Kleimark, A. Trejos, L. R. Odell, S. O. N.
Lill, P.ꢀO. Norrby and M. Larhed, Chem. Eur. J., 2012, 18, 4714ꢀ
4722.
100 17 For the C4ꢀselective oxidative coupling of thiophenes with aryl
boronic acids, see: (a) S. Kirchberg, S. Tani, K. Ueda, J. Yamaguchi,
A. Studer and K. Itami, Angew. Chem. Int. Ed., 2011, 50, 2387ꢀ2391;
(b) I. Schnapperelle, S. Breitenlechner and T. Bach, Org. Lett., 2011,
13, 3640ꢀ3643. (c) K. Yamaguchi, J. Yamaguchi, A. Studer and K.
Notes and references
a Address: Department Chemie and Catalysis Research Center (CRC),
Technische Universität München, 85747 Garching, Germany. Fax: +49
35 89 28913315; Tel: +49 89 28913330; E-mail: thorsten.bach@ch.tum.de
† Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
105
Itami, Chem. Sci., 2012, 2, 2165ꢀ2169; (d) I. Schnapperelle and T.
Bach, ChemCatChem, 2013, 5, 3232ꢀ3236; (e) I. Schnapperelle and
T. Bach, Chem. Eur. J., 2014, 20, 9725ꢀ9732.
1
For a recent review, see: L. JeanꢀGérard, R. Jazzar and O. Baudoin in
Metal-Catalyzed Cross-Coupling Reactions and More (Eds.: A. de
Meijere, S. Bräse, M. Oestreich), WileyꢀVCH, Weinheim, 2014, pp.
1427ꢀ1493.
40
2
Reviews: (a) M. Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li and W. Su,
Org. Chem. Front., 2014, 1, 843ꢀ895; (b) R. Giri, S. Thapa and A.
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