"One-pot" tandem C - H borylation/1,4-conjugate addition/reduction sequence

Article abstract of DOI:10.1021/ol102518v

A microwave-assisted, one-pot, iridium-catalyzed aromatic C - H borylation/rhodium-catalyzed 1,4-conjugate addition sequence provides a highly robust protocol suitable for high-throughput array synthesis. Selective formation of either β-aryl-substituted ketones or the corresponding alcohols can be achieved in good overall yields by simple variation of the reaction conditions.

Full text of DOI:10.1021/ol102518v

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5700-5703
“One-Pot” Tandem C-H Borylation/
1,4-Conjugate Addition/Reduction
Sequence
Hazmi Tajuddin,† Lena Shukla,‡ Aoife C. Maxwell,‡ Todd B. Marder,*,† and
Patrick G. Steel*,†
Department of Chemistry, Durham UniVersity, South Road, Durham, DH1 3LE, U.K.,
and GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road,
Hertfordshire, SteVenage, SG1 2NY, U.K.
todd.marder@durham.ac.uk; p.g.steel@durham.ac.uk
Received October 18, 2010
ABSTRACT
A microwave-assisted, one-pot, iridium-catalyzed aromatic C-H borylation/rhodium-catalyzed 1,4-conjugate addition sequence provides a
highly robust protocol suitable for high-throughput array synthesis. Selective formation of either ꢀ-aryl-substituted ketones or the corresponding
alcohols can be achieved in good overall yields by simple variation of the reaction conditions.
The use of combinatorial or array chemistry to build chemical
libraries for rapid exploration of structure-activity relationships
is an important strategy to enhance drug discovery.1 Effective
protocols typically need to be robust and efficient under
generalized reaction conditions across a wide range of substrate
structures. The direct borylation of aromatic C-H bonds
promoted by iridium trisboryl complexes2 has developed into
a popular and powerful method for the functionalization of
arenes.3 This transformation is ideally suited to array chemistry
as it avoids the need for specifically functionalized precursors
and exploits the diverse chemistry of the resulting boronate ester.
This is most effective when carried out in a single vessel, and
such in situ elaboration of the initially formed boronate ester
can provide rapid access to a variety of functionalized arenes.4
Recently, we have contributed to this methodological toolbox
by developing the use of MTBE (methyl-tert-butyl ether) as a
compatible solvent for both the borylation and Suzuki-Miyaura
cross-coupling reactions and showing that both processes can
be efficiently accelerated using microwave irradiation.5 In this
communication, we describe the efficient one-pot conversion
of arenes to either ꢀ-aryl-substituted ketones or the correspond-
ing alcohols through a tandem sequence involving Ir-catalyzed
† Durham University.
‡ GlaxoSmithKline.
(1) Easson, M. A. M.; Rees, D. C. Medicinal Chemistry: Principles and
Practice, 2nd ed.; King, F. D., Ed.; The Royal Society of Chemistry:
Cambridge, 2002; Chapter 16, pp 359-381.
(4) (a) Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Org. Lett. 2007,
9, 761. (b) Holmes, D.; Chotana, G. A.; Maleczka, R. E., Jr.; Smith, M. R.,
III Org. Lett. 2006, 8, 1407. (c) Shi, F.; Smith, M. R., III; Maleczka, R. E.,
Jr. Org. Lett. 2006, 8, 1411. (d) Murphy, J. M.; Liao, X.; Hartwig, J. F.
J. Am. Chem. Soc. 2007, 129, 15434. (e) Maleczka, R. E., Jr.; Shi, F.;
Holmes, D.; Smith, M. R., III J. Am. Chem. Soc. 2003, 125, 7792. (f)
Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. 2007, 9, 757.
(5) (a) Harrisson, P.; Morris, J.; Steel, P. G.; Marder, T. B. Synlett 2009,
147. (b) Harrisson, P.; Morris, J.; Marder, T. B.; Steel, P. G. Org. Lett.
2009, 11, 3586.
(2) (a) Nguyen, P.; Blom, H. P.; Westcott, S. A.; Taylor, N. J.; Marder,
T. B. J. Am. Chem. Soc. 1993, 115, 9329. (b) Ishiyama, T.; Takagi, J.;
Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc.
2002, 124, 390. (c) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.,
Jr.; Smith, M. R., III Science 2002, 295, 305.
(3) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
Hartwig, J. F. Chem. ReV. 2010, 110, 890.
10.1021/ol102518v  2010 American Chemical Society
Published on Web 11/15/2010

aromatic C-H borylation followed by the Rh-catalyzed conjugate
addition of the arylboronate to enones. While there are many reports
describing the conjugate addition of boronic acids to enones,6 the
application of the corresponding pinacol boronate esters is limited
to a small number of acrylate and enamide acceptors.7
precautions were required to exclude oxygen from the
reactions, leading us to explore alternative catalyst systems.
[Rh(COD)Cl]2 has been reported to be an effective catalyst
for the conjugate addition of boronic acids to R,ꢀ-unsaturated
carbonyl compounds.10 Moreover, functioning in the absence
of added ligand, it is ideal for array chemistry. Pleasingly,
application of this catalyst to the microwave-accelerated one-
pot sequence, using m-xylene 1 as the arene and 2 as the
acceptor, afforded the desired ketone 4a in moderate yield
(35%) (entry 3). However, a substantial amount of the
corresponding alcohol product 5a (24%) was also isolated,
clearly as a result of an unprecedented reduction of the
Table 1. One-Pot C-H Borylation/1,4-Conjugate Addition Sequence
Scheme 1. Percent Deuterium Incorporation during the Tandem
C-H Borylation/1,4-Conjugate Addition Sequence
entry
Rh precatalyst
enone yield 4 (%)a yield 5 (%)a
1
2
3
4
5
6
Rh(acac)(CO)2/dppbb
Rh(acac)(CO)2/dppbb
[Rh(COD)Cl]2
2
3
2
2
2
2
4a (68)
4b (8)
4a (35)
4a (40)
4a (37)
4a (14)
5a (0)
5b (0)
5a (24)
5a (24)
5a (30)
5a (51)
Table 2. [Rh(COD)Cl]2 Catalyzed 1,4-Conjugate Addition of
m-XylylBpin to MVK 2 in the Presence of Various Ir Complexes
c
c
c
(i)
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
(ii)
(iii)
isolated yield (%)
entry
solvent
[Ir]a
4a
5a
a Purified isolated yield. b No K3PO4. c Reaction conditions were modified
to: (i) expel H2 from reaction; (ii) extend quenching time; or (iii) combine
both H2 expulsion and extend quenching time prior to heating in the second
step. See Supporting Information for details.
1
2
3
4
MeOH
MeOH
MeOH
MeOH
noneb
A
B
C
56
63
66
45
0
0
0
10
a A ) [Ir(COD)OMe]2; B ) [Ir(COD)OMe]2 + dtbpy; C ) [Ir(COD)-
OMe]2 + dtbpy + B2pin2. b 1,4-Conjugate addition was carried out following
rapid filtration of the borylation reaction mixture through a short plug of
silica to remove any Ir complexes.
Initial attempts to explore this sequence involved the use
of Rh(acac)(CO)2 and dppb for the 1,4-conjugate addition
step as originally reported by Miyaura for ArB(OH)2.8
Following complete consumption of the arene, the borylation
reaction was quenched with aq K3PO4. Subsequent addition
of the Rh catalyst and enone in MeOH initiated the 1,4-
conjugate addition step. Although the in situ generated Bpin
ester proved to be a viable substrate, the transformation was
slow. However, microwave heating greatly accelerated the
reaction giving complete conversion of ArBpin in minutes
rather than hours. To our knowledge, previous microwave
acceleration of 1,4-conjugate addition has only been observed
using boronic acids with acrylate and enamide acceptors.9
While this method proved effective with unsubstituted enone
MVK (methylvinylketone) 2 as the acceptor (Table 1, entry
1), the yield was substantially lower for substituted enones
such as cyclohex-2-enone 3 (entry 2). Additionally, strict
Table 3. Solvent Effects in the Second Step of One-Pot Tandem
C-H Borylation of 1/1,4-Conjugate Addition to 2 Sequencea
isolated yield (%)
entry
solvent
additivec time (min)
4a
5a
1
2
3
4
5
6
7
8
acetone
MTBE
THFb
MeOH
IPA
-
-
-
-
-
-
A
B
C
-
20
20
20
150
20
80
20
20
20
20
80
73
71
67
10
26
0
47
7
0
0
0
0
42
49
62
17
11
10
0
IPA
MeOH
MeOH
MeOH
MTBE
IPA
9
(6) For reviews see. (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103,
169. (b) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
(7) (a) Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944. (b)
Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65,
5951. (c) Horn, J.; Li, H. Y.; Marsden, S. P.; Nelson, A.; Shearer, R. J.;
Campbell, A. J.; House, D.; Weingarten, G. G. Tetrahedron 2009, 65, 9002.
(8) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229.
(9) (a) Mondiere, A.; Pousse, G.; Bouyssi, D.; Balme, G. Eur. J. Org.
Chem. 2009, 4225. (b) Frost, C. G.; Penrose, S. D.; Lambshead, K.; Raithby,
P. R.; Warren, J. E.; Gleave, R. Org. Lett. 2007, 9, 2119. (c) Iyer, P. S.;
O’Malley, M. M.; Lucas, M. C. Tetrahedron Lett. 2007, 48, 4413.
10d
11d
68
0
-
61
a Conditions: (i) 1 (1 equiv), [Ir(OMe)COD]2/dtbpy (3 mol %), B2pin2
(1 equiv), µW, 80 °C, 60 min; (ii) aq K3PO4 (5 M, 6 equiv), [Rh(COD)Cl]2
in solvent, 2 (2 equiv), µW, 100 °C, stated time. b C-H borylation step
was also carried out in THF. c A ) 9,10-dihydroanthracene; B )
1,4-cyclohexadiene; C ) ammonium formate. d aq KOH (3.8 M, 2 equiv)
in place of aq K3PO4 (5 M, 6 equiv).
Org. Lett., Vol. 12, No. 24, 2010
5701

Table 4. Optimized One-Pot C-H Borylation/1,4-Conjugate Addition for Selective Access to ꢀ-Arylketone or the Corresponding
Alcohol Product and the Corresponding Results under Array Conditions
a Conditions: (i) arene (1 equiv), B2pin2 (1 equiv), 1/2[Ir(COD)OMe]2/dtbpy (3 mol % Ir), MTBE, 80 °C, µW, (ii) aq KOH (2 equiv), [Rh(COD)Cl]2 (2
mol % Rh) in MTBE, enone (1 equiv). b Conditions: (i) arene (1 equiv), B2pin2 (1 equiv), 1/2[Ir(COD)OMe]2/dtbpy (3 mol % Ir), MTBE, 80 °C, µW, (ii)
aq KOH (2 equiv), [Rh(COD)Cl]2 (2 mol % Rh) in IPA, enone (1 equiv). c Individually performed reactions with optimized reaction times under a strictly
inert atmosphere using Schlenk techniques. d Reactions were carried out in parallel in air with common reaction times for each array. e (Syn:anti) as determined
by H NMR spectroscopic analysis of crude reaction mixture. f Diastereoisomers were inseparable and could not be unambigously defined. See Supporting
1
Information for details.
initially formed ketone. Attempts to improve the ketone yield
by suppressing the reductive pathway via expulsion from
the reaction vessel of H2, generated in the arene borylation
process (entry 4), or prolonged quenching times to ensure
complete decomposition of residual HBpin prior to addition
of the enone, were unsuccessful (entry 5). Interestingly, the
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Org. Lett., Vol. 12, No. 24, 2010

combination of these modifications led to an increased
methanol concentration, owing to evaporation of some of
the MTBE, resulting in a higher proportion of the alcohol
product (entry 6). This suggested that the reduction proceeds
via transfer hydrogenation with the MeOH serving as the
hydrogen source.
replacing the K3PO4 base used in the reaction with 2 equiv
of aq KOH (3.8 M) provided equivalent yields and reactivity
but with the practical advantage of a homogeneous reaction
mixture (entries 10 and 11).
With these optimized conditions identified, we then
explored the general applicability of the reaction sequence,
carried out under an inert atmosphere using Schlenk tech-
niques. A wide variety of electron-rich and electron-poor
arenes and heteroarenes with R,ꢀ-unsubstituted, R-substi-
tuted, ꢀ-substituted, and cyclic R,ꢀ-unsaturated ketones were
screened under both nonreducing and reducing conditions
(Table 4). Good overall isolated yields were achieved for
R,ꢀ-unsubstituted and cyclic R,ꢀ-unsaturated ketones (entries
1-6). Acyclic enones bearing substitution at either the R-
or ꢀ-position resulted in slightly lower yields but remain
within an acceptable range for a two-step synthesis (entries
7-12). In each case, the remaining mass balance can be
accounted for (LCMS analysis) by unreacted ArBpin and
arene arising from incomplete borylation or competing
protiodeborylation during the conjugate addition step (see
Supporting Information). All reactions were repeated under
array conditions, i.e., in parallel, with common reaction times
and with no precautions to exclude oxygen. Somewhat lower,
but still acceptable, isolated yields were observed.
In conclusion, we have developed a highly robust micro-
wave-assisted, one-pot tandem Ir-catalyzed aromatic C-H
borylation/Rh-catalyzed 1,4-conjugate addition sequence
which is suitable for application in high-throughput array
format. Both ꢀ-aryl-substituted ketones and the correspond-
ing alcohols can be selectively accessed in good overall
isolated yields by employing nonreducing or reducing
conditions, respectively. Although the reduction proceeds
with low stereoselectivity, this can potentially be addressed
by the addition of chiral ligands. Studies in this direction
are ongoing and will be reported in due course.
Confirmation of this was achieved using deuterated
methanol in the second step of the sequence (Scheme 1). A
high level of deuterium incorporation (83%) was observed
at the carbinol carbon of the alcohol product 5a-d1 when
CD3OH was used. Further studies showed that the transfer
hydrogenation process requires an iridium complex to be
present (Table 2). Reduction was suppressed by filtering the
reaction mixture through silica gel prior to the 1,4-conjugate
addition step (entry 1). While addition of [Ir(COD)OMe]2
(entry 2) or a combination of this with dtbpy (entry 3) in
the Rh-catalyzed 1,4-conjugate addition of m-xylylBpin to
MVK resulted in no alcohol product being detected, the
addition of a premixed solution of B2pin2, [Ir(COD)OMe]2,
and dtbpy led to the alcohol product being observed once
again (entry 4). This suggested that the active species
responsible for the transfer hydrogenation process is gener-
ated through the quenching of the iridium trisboryl complex
[Ir(Bpin)3dtbpy] formed in the borylation step. In support
of this, reaction of purified ketone 4a with methanol in the
presence of the iridium species generated by quenching a
mixture of [Ir(OMe)COD]2 (3 mol % Ir), dtbpy (3 mol %),
and B2pin2 (10 mol %) with aq K3PO4 afforded alcohol 5 in
78% yield.
Having identified methanol as the reductant, we then
sought to optimize the sequence to obtain either the ketone
or alcohol product through solvent selection (Table 3). By
replacing the methanol solvent in the second step with a
nonoxidizable solvent such as acetone, MTBE, or THF
(entries 1-3), selective formation of the ketone product was
achieved. Alternatively, extending the reaction time and using
isopropanol (IPA) as a more efficient hydrogen source
afforded the alcohol product in good yield (entries 4-6).
Other hydrogen sources were less effective, suffering from
poor conversion of ArBpin due to competitive reduction of
the enone and lower reaction rates (entries 7-9). Finally,
Acknowledgment. We thank the EPSRC (EP/F068158/
1) and GSK for financial support of this work and Dr. Jackie
Moseley (Durham University) for mass spectra.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) (a) Xing, C.-H.; Liu, T.-P.; Zheng, J. R.; Ng, J.; Esposito, M.; Hu,
Q.-S. Tetrahedron Lett. 2009, 50, 4953. (b) Martina, S. L. X.; Minnaard,
A. J.; Hessen, B.; Feringa, B. L. Tetrahedron Lett. 2005, 46, 7159. (c) Itooka,
R.; Iguchi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000.
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